PMID- 28799934 TI - Partially aerated submerged fixed-film bioreactor for simultaneous removal of carbon and nutrients from high-strength nitrogen wastewaters: effect of aeration rate and C:N:P ratio. AB - Influence of aeration rate and COD:N:P (C:N:P) ratio on the performance of an upflow partially aerated submerged fixed film (UP/ASFF) bioreactor for simultaneous carbon and nutrient removal from high-strength nitrogen wastewater was investigated during 6 months. Airflow rates at three levels of 1.5, 3, and 4.5 L/min and C:N:P ratios at four levels of 450:300:10, 450:150:10, 450:100:10, and 450:75:10 were selected as the two main input factors. All experiments were performed at constant chemical oxygen demand (COD), phosphorus (P) and hydraulic residence time of 450 mg COD/L, 10 mg PO43- -P/L and 7.3 h, respectively. The results showed when the airflow rate increased from 1.5 to 4.5 L/min, complete COD removal was achieved. At an airflow rate of 4.5 L/min, total nitrogen removal reached a maximum value of 75% for the C:N:P ratio of 450:75:10. A maximum value of 54% for total phosphorus removal, however, was obtained at an airflow rate of 3 L/min for the C:N:P ratio of 450:75:10. Analysis of variance for the obtained data revealed that aeration rate and nitrogen concentration had more impact on phosphorus removal than COD and nitrogen removal. The study demonstrated that the UP/ASFF system has considerable potential for use in simultaneous removal of carbon and nutrients for high-strength nitrogen wastewater. PMID- 28799935 TI - Effects of toxic Microcystis genotypes on natural colony formation and mechanism involved. AB - The cyanobacterium Microcystis occurs as colonies of different sizes with varying abundance of toxic genotypes versus non-toxic genotypes under natural conditions. To investigate the effects of toxic Microcystis genotypes on natural colony formation, samples collected from the mainstream of Haihe River from July to October 2015 were sieved into four colony classes with sizes of <8 MUm, 8-20 MUm, 20-90 MUm and >90 MUm. Each colony size class was analyzed for the proportion of toxic Microcystis genotypes, and microcystins (MCs) cellular production of toxic genotypes. The results showed the smallest size class of Microcystis colonies (<8 MUm) showed the lowest proportion of toxic genotypes and the highest MC-RR and MC YR cellular production. With the increasing colony sizes, the proportion of toxic Microcystis genotypes increased but the MC-RR and MC-YR cellular production decreased. A negative correlation between the MCs cellular production and the proportion of toxic genotypes was observed in all four colony size classes, suggesting that the less there were toxic Microcystis cells able to produce MCs, the more each toxic cell needed to produce that molecule. Toxic Microcystis played an important role in the colony formation in natural waters via producing MCs. PMID- 28799936 TI - Oily wastewater treatment by adsorption-membrane filtration hybrid process using powdered activated carbon, natural zeolite powder and low cost ceramic membranes. AB - In this research, four types of low cost and high performance ceramic microfiltration (MF) membranes have been employed in an in-line adsorption-MF process for oily wastewater treatment. Mullite, mullite-alumina, mullite-alumina zeolite and mullite-zeolite membranes were fabricated as ceramic MF membranes by low cost kaolin clay, natural zeolite and alpha-alumina powder. Powdered activated carbon (PAC) and natural zeolite powder in concentrations of 100-800 mg L-1 were used as adsorbent agent in the in-line adsorption-MF process. Performance of the hybrid adsorption-MF process for each concentration of PAC and natural zeolite powder was investigated by comparing quantity of permeation flux (PF) and total organic carbon (TOC) rejection during oily wastewater treatment. Results showed that by application of 400 mg L-1 PAC in the adsorption-MF process with mullite and mullite-alumina membranes, TOC rejection was enhanced up to 99.5% in comparison to the MF only process. An increasing trend was observed in PF by application of 100-800 mg L-1 PAC. Also, results demonstrated that the adsorption-MF process with natural zeolite powder has higher performance in comparison to the MF process for all membranes except mullite-alumina membranes in terms of PF. In fact, significant enhancement of PF and TOC rejection up to 99.9% were achieved by employing natural zeolite powder in the in-line adsorption MF hybrid process. PMID- 28799937 TI - Multi-criteria analysis of site selection for groundwater recharge with treated municipal wastewater. AB - Geographic information systems (GIS) and remote sensing techniques are used as a decision support system to identify potential soil aquifer treatment (SAT) sites for groundwater recharge of Kerman aquifer, which is located in the southeast of Iran. These sites are identified using a single-objective multi-criteria analysis. To ensure technical feasibility, environmental sustainability, social acceptability and economical viability a number of criteria are considered for the site selection. The criteria selected for the different variables and acceptable ranges are based on standards published in national and international guidelines and technical documents. Multi-criteria evaluation was performed combining all produced thematic maps by means of the weighted index overlay method in order to select sites meeting all the criteria. The resulting map of this analysis shows potential sites are located in the north, southwest and southeast of the study area. Considering field observations, a potential site, which is located in the southwest of the study area, is proposed as the most suitable site for SAT. The result indicates that the study area has sufficient required suitable space for groundwater recharge with treated wastewater. PMID- 28799938 TI - Improvement of phosphorus removal by calcium addition in the iron electrocoagulation process. AB - Small-scale wastewater treatment plants (SWTPs) are widely used as decentralized wastewater treatment systems in sparsely populated areas of Japan. Iron electrolysis, an electrocoagulation technology, is installed in these SWTPs for phosphorus removal. Phosphorus can be removed via the formation of an insoluble compound containing phosphate and iron, such as FePO4; however, it was necessary to determine the conditions under which phosphorus can be effectively and stably removed in actual SWTPs. According to previous studies using iron compounds, improved phosphorus removal was obtained by Ca addition. It is therefore thought that calcium addition may also be effective in improving the phosphorus removal during iron electrolysis in SWTPs. It is also important to determine the chemical state of iron to understand the phosphorus removal mechanism during iron electrolysis. In this study, laboratory-scale batch experiments with the iron electrolysis method were conducted to investigate the effect of phosphorus removal using treated wastewater from actual SWTPs without or with Ca addition. The results indicated that the addition of Ca improved the phosphorus removal performance. Furthermore, phosphorus removal was inhibited in the presence of high dissolved organic carbon (DOC). The X-ray absorption fine structure measurements of the produced particulates in the experiments showed no substantial change in the chemical state of iron without or with Ca addition. The statistical analyses revealed the range of improving or inhibiting effects on phosphorus removal due to the Ca and DOC. Thus, the results of this study provided useful information pertaining to the influence of coexisting substances on phosphorus removal and the chemical state of iron in the produced particulates. PMID- 28799939 TI - One-step hydrothermal synthesis of CTAB-modified SiO2 for removal of bisphenol A. AB - A stable SiO2 material marked as CTAB-Ms(x) was synthesized by a novel sol-gel method. It was modified with hexadecyl trimethyl ammonium bromide (CTAB), which resulted in high adsorption capacity. Its microstructure and surface functional groups were characterized by scanning electron microscope, transmission electron microscope and Fourier transform infrared. The results showed that CTAB-Ms(x) had a core/shell structure in which the core was a CTAB micelle and the shell was SiO2. The prepared material was applied to adsorb bisphenol A (BPA). Pseudo-first order kinetics equation, pseudo-second-order kinetics equation, Langmuir adsorption isotherm model, Temkin adsorption isotherm model, and thermodynamic equations were used to fit and analyze the experiment results. The theoretical maximum adsorption capacities calculated according to linear and non-linear forms of the Langmuir isotherm were 370.37 mg.g-1 and 198.80 mg.g-1, and the adsorption equilibrium time was 120 min. A mechanism study showed that the high adsorption capacity was attributed to the solubilization effect of the CTAB micelle. PMID- 28799940 TI - Experimental study on treating agate dyeing wastewater with sulfate-reducing bacteria strengthening peanut shells and scrap iron. AB - To solve the problems of high concentrations of Cr6+, SO42- and H+ in agate dyeing industrial wastewater and heavy pollution and high treating cost, single factor and orthogonal experiments were conducted to determine the optimum particle size, the ratio of adsorbents dosing and hydraulic retention time based on peanut shells and scrap iron. Experiments, using five dynamic columns filled with the peanut shells, scrap iron and sulfate-reducing bacteria (SRB), were also conducted to determine the effect and mechanism of treating the wastewater. The results show that the best treatment effect was obtained when the diameter of peanut shells was 3 mesh, scrap iron being 60 mesh size, scrap iron and peanut shells with a ratio of 1:2, and hydraulic retention time being 24 h. By the comprehensive comparison of five groups of columns, the treating effect of column 4 was best, in which the removal rate of SO42- and Cr6+ was 30.17% and 88.36% respectively before adding the microorganisms, and 25.34% and 99.31% respectively after adding the microorganisms. The average of chemical oxygen demand (COD) release quantity was 62.11 and 513.75 mg.L-1, and the average effluent pH was 7.09 and 7.93 before and after addition of microorganisms respectively. In conclusion, peanut shells, scrap iron and SRB had a certain synergistic effect on treating agate dyeing wastewater. PMID- 28799941 TI - Fluidized glass beads reduce fouling in a novel anaerobic membrane bioreactor. AB - This study focuses on the use of fluidized glass beads as turbulence promoters in a laboratory-scale anaerobic membrane bioreactor treating municipal wastewater at 20 degrees C. The addition of fluidized glass beads into an external tubular ceramic membrane enabled the operation at low crossflow velocities of 0.053-0.073 m/s (mean fluxes between 5.5 and 9.7 L/(m2.h)) with runtimes >300 h. Glass beads with a diameter of 1.5 mm were more effective than smaller ones with a diameter of 0.8-1.2 mm. Increasing the bed voidage from 74 to 80% did not show any beneficial effect. As scanning electron microscope examination showed, the fluidized glass beads damaged the used membrane by abrasion. The overall total chemical oxygen demand (COD) removal was between 77 and 83%, although mean hydraulic retention times were only between 1.3 and 2.3 h. The production of total methane was increased about 30% in comparison to the bioreactor without membrane. The increased methane production is presumably attributed to biological conversion of rejected, dissolved and particulate organic matter. The total required electrical energy was predicted to be about 0.3 kWh/m3. PMID- 28799942 TI - Effect of cycle run time of backwash and relaxation on membrane fouling removal in submerged membrane bioreactor treating sewage at higher flux. AB - Intermittent backwashing and relaxation are mandatory in the membrane bioreactor (MBR) for its effective operation. The objective of the current study was to evaluate the effects of run-relaxation and run-backwash cycle time on fouling rates. Furthermore, comparison of the effects of backwashing and relaxation on the fouling behavior of membrane in high rate submerged MBR. The study was carried out on a laboratory scale MBR at high flux (30 L/m2.h), treating sewage. The MBR was operated at three relaxation operational scenarios by keeping the run time to relaxation time ratio constant. Similarly, the MBR was operated at three backwashing operational scenarios by keeping the run time to backwashing time ratio constant. The results revealed that the provision of relaxation or backwashing at small intervals prolonged the MBR operation by reducing fouling rates. The cake and pores fouling rates in backwashing scenarios were far less as compared to the relaxation scenarios, which proved backwashing a better option as compared to relaxation. The operation time of backwashing scenario (lowest cycle time) was 64.6% and 21.1% more as compared to continuous scenario and relaxation scenario (lowest cycle time), respectively. Increase in cycle time increased removal efficiencies insignificantly, in both scenarios of relaxation and backwashing. PMID- 28799943 TI - Laboratory investigation of hydraulic characteristics of fly ash as a fill material from the aspects of pollutant transport. AB - Depending on the usage of fly ash, it is necessary to determine its environmental parameters, such as the potential for pollutant transport/leaching after its built-in. This study presents a methodology for determination of transport parameters (filtration coefficient, effective porosity, longitudinal dispersivity, and the mean residence time) from experimental data collected from column experiments with a conservative tracer on different mixtures of fly ash with stabilizers (4.8% lime and 5% cement). The transport parameters are determined using (1) numerical model results and (2) an adapted analytical solution results against measured outflow tracer concentrations. The study shows that the addition of stabilizers decreases the filtration coefficient by an order of magnitude and the effective porosity by half. The longitudinal dispersivity is not influenced by the addition of lime to the mixture, and is increased by 40% by the addition of cement. The pollutant contact time with fly ash increases by six or nine times with the addition of lime and cement, respectively. The adaptation of the analytical solution agrees well with both the numerical solution and the experimental results, and it is anticipated to be of high value for determination of transport parameters for practitioners not familiar with numerical methods. PMID- 28799944 TI - Experimental power of laboratory-scale results and transferability to full-scale anaerobic digestion. AB - Anaerobic digestion is today internationally acknowledged as an environmentally sound process for energy and nutrient recovery from organic wastes, and it is the dominant sludge treatment technology in most countries' wastewater treatment plants. Laboratory- or pilot-scale experiments are commonly used as a first step to investigate the potential of new ideas or to confirm research hypothesis before confirmation in full-scale. The objectives of this study were to investigate transferability of methane yield assessments between laboratory- and full-scale, and to compare the influence of experimental uncertainties on experimental power in parallel continuous digester experiments for the two scales. Both batch experiment data (used in a simple equation), as well as continuous laboratory experiments, could be used to predict full-scale methane yield with a high accuracy (<5% difference). Full-scale digesters significantly outperformed hand-fed laboratory digesters in terms of experimental power regarding relative differences in methane yield between two digesters operated in parallel. However, to justify costly long-term continuous laboratory-scale experiments with sufficient experimental power and potentially high transferability, resources also have to be allocated to measures that ensure a high data quality from full-scale reference facilities. PMID- 28799945 TI - Sediment transport modeling in deposited bed sewers: unified form of May's equations using the particle swarm optimization algorithm. AB - May proposed two dimensionless parameters of transport (eta) and mobility (Fs) for self-cleansing design of sewers with deposited bed condition. The relationships between those two parameters were introduced in conditional form for specific ranges of Fs, which makes it difficult to use as a practical tool for sewer design. In this study, using the same experimental data used by May and employing the particle swarm optimization algorithm, a unified equation is recommended based on eta and Fs. The developed model is compared with original May relationships as well as corresponding models available in the literature. A large amount of data taken from the literature is used for the models' evaluation. The results demonstrate that the developed model in this study is superior to May and other existing models in the literature. Due to the fact that in May's dimensionless parameters more effective variables in the sediment transport process in sewers with deposited bed condition are considered, it is concluded that the revised May equation proposed in this study is a reliable model for sewer design. PMID- 28799946 TI - First female prenatal case of osteopathia striata with cranial sclerosis in a fetus carrying a de-novo 1.9 Mbp interstitial deletion at Xq11.1q11.2. PMID- 28799947 TI - Care of 500-1500 Gram Premature Infants in Hybrid Incubators. AB - BACKGROUND: Although technological advances have improved devices used to maintain the temperatures of 500- to 1500-g infants, managing the thermal environment remains challenging. PURPOSE: To evaluate the effects of 2 methods of thermal support provided by a hybrid incubator during routine care in the first week of life. METHODS: This descriptive, comparative study evaluates changes in temperature, humidity, heart rate, and oxygen saturation in the incubator versus radiant warmer (canopy) modes of hybrid warmers using data downloaded from the incubator and the monitor. The impact of the Boost Curtain on temperature when opening the portholes during the incubator mode was also examined. Mixed-effects linear models and the log-rank test were used to analyze patient data to determine the effect of thermal support on temperature and humidity changes during care, as well as during the postcare period. RESULTS: Entering the incubator through the portholes improved temperature control compared with using the canopy mode. The Boost Curtain resulted in an overall temperature stability and heat gain. IMPLICATIONS FOR PRACTICE: Nurses caring for premature infants in hybrid incubators should minimize incubator openings and utilize portholes rather than the canopy whenever practical. The Boost Curtain should be used when opening the portholes during the incubator mode. IMPLICATIONS FOR RESEARCH: Comparing time, accuracy, and tolerance of procedures in the canopy versus incubator modes would improve nurses' ability to determine the best approach for different clinical scenarios. PMID- 28799948 TI - Anticancer drugs and the regulation of Hedgehog genes GLI1 and PTCH1, a comparative study in nonmelanoma skin cancer cell lines. AB - Nonmelanoma skin cancer is the most common cancer in humans, comprising mainly basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). BCC proliferation is highly dependent on the Hedgehog signaling pathway. We aimed to investigate a panel of anticancer drugs with known activity against skin cancer for their therapeutic potential in localized, enhanced topical treatment of SCC and BCC. Cytotoxicity profiles for vismodegib, 5-fluorouracil (5-FU), methotrexate (MTX), cisplatin, bleomycin, and vorinostat were established in terms of half maximal inhibitory concentration values in a panel of immortalized keratinocytes (HaCaT), BCC (UWBCC1 and BCC77015), and SCC (A431 and SCC25) cell lines. The impact of treatment on the regulation of Hedgehog pathway target genes (GLI1 and PTCH1), measured by real-time PCR, was compared between UWBCC1 and HaCaT. Varying cell line sensitivity profiles to the examined anticancer drugs were observed. Generally, 24-h drug exposure was sufficient to reduce cell viability. We found that 5-FU, MTX, and cisplatin significantly downregulated the expression of two genes controlled by the Hedgehog pathway (<=25-, 2.9-, and 12.5-fold, respectively, for GLI1 in UWBCC1 cells at 48 h, P<0.0001). The gene regulation showed clear concentration dependence and correlated with cytotoxicity for both 5 FU and MTX. We find a potential for the use of anticancer drugs in localized and enhanced topical treatment of nonmelanoma skin cancer. Of importance in the clinical setting, 24-h drug exposure may be sufficient for significant cytotoxicity for vismodegib, 5-FU, cisplatin, and bleomycin. MTX, 5-FU, and cisplatin may offer particular promise through combined cytotoxicity and downregulation of Hedgehog pathway genes GLI1 and PTCH1. PMID- 28799950 TI - Orthostatic Hypotension in Patients With Left Ventricular Assist Devices: Acquired Autonomic Dysfunction. AB - Contemporary left ventricular assist device (LVAD) technology uses nonphysiologic continuous flow to deliver blood into the circulation. This results in a reduction of pulsatility, which is implicated in some of the commonly associated side effects with LVAD therapy, including hypertension and gastrointestinal arterial-venous malformation with related bleeding. A less frequently observed side effect is orthostatic hypotension (OH) in patients supported with LVAD therapy. We present three cases of OH in patients with LVAD, followed by a discussion on how LVAD therapy may induce autonomic dysfunction. PMID- 28799949 TI - Quantifying the Effects of Prior Acetyl-Salicylic Acid on Sepsis-Related Deaths: An Individual Patient Data Meta-Analysis Using Propensity Matching. AB - OBJECTIVE: The primary objective was to conduct a meta-analysis on published observational cohort data describing the association between acetyl-salicylic acid (aspirin) use prior to the onset of sepsis and mortality in hospitalized patients. STUDY SELECTION: Studies that reported mortality in patients on aspirin with sepsis with a comparison group of patients with sepsis not on prior aspirin therapy were included. DATA SOURCES: Fifteen studies described hospital-based cohorts (n = 17,065), whereas one was a large insurance-based database (n = 683,421). Individual-level patient data were incorporated from all selected studies. DATA EXTRACTION: Propensity analyses with 1:1 propensity score matching at the study level were performed, using the most consistently available covariates judged to be associated with aspirin. Meta-analyses were performed to estimate the pooled average treatment effect of aspirin on sepsis-related mortality. DATA SYNTHESIS: Use of aspirin was associated with a 7% (95% CI, 2 12%; p = 0.005) reduction in the risk of death as shown by meta-analysis with considerable statistical heterogeneity (I = 61.6%). CONCLUSIONS: These results are consistent with effects ranging from a 2% to 12% reduction in mortality risk in patients taking aspirin prior to sepsis onset. This association anticipates results of definitive studies of the use of low-dose aspirin as a strategy for reduction of deaths in patients with sepsis. PMID- 28799951 TI - Surface-Engineered Blood Adsorption Device for Hyperphosphatemia Treatment. AB - Correspondence: Melanie S. Joy, PharmD, PhD, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Mail Stop C238, Room V20-4108, 12850 East Montview Blvd, Aurora, CO 80045. Email: Melanie.Joy@ucdenver.edu The research employed surface engineering methods to develop, optimize, and characterize a novel textile-based hemoadsorption device for hyperphosphatemia in hemodialysis-dependent end-stage kidney disease. Phosphate adsorbent fabrics (PAFs) were prepared by thermopressing alumina powders to polyester filtration fabrics and treatment with trimesic acid (TMA). For static experiments, phosphate adsorption capacity in buffer solution, plasma, and blood were evaluated by submersing the PAFs in 100 ml. For dynamic experiments, PAFs were equipped in a device prototype and incorporated in a pump driven circuit. Phosphates were determined by a colorimetric assay and an Ortho Clinical Diagnostics Vitros 5600 Integrated analyzer. The maximum loading amount of TMA-alumina on PAFs was approximately 35 g/m under 260 degrees C processing temperature. Phosphate adsorption capacity increased with initial concentration. Adsorption isotherms from buffer demonstrated a maximum phosphate adsorption capacity of approximately 893 mg/m at 37.5 degrees C, pH 7.4, with similar results from plasma and whole blood. Measured phosphate concentrations during simulations demonstrated a 42% reduction, confirming the high capacity of the PAFs for removing phosphate from whole blood. Results from the current study indicated that an alumina-TMA treated PAF can dramatically reduce phosphate concentrations from biological samples. The technology could potentially be used as a tunable adsorbent for managing hyperphosphatemia in kidney disease. PMID- 28799952 TI - Moving From Pre-ECMO Ventilation to Post-ECMO Ventilation and Mortality. PMID- 28799953 TI - Not Too Little, Not Too Much: Finding the Goldilocks Zone for Spinal Anesthesia to Facilitate External Cephalic Version. PMID- 28799954 TI - Effects of systemic glutamatergic manipulations on conditioned eyeblink responses and hyperarousal in a rabbit model of post-traumatic stress disorder. AB - Glutamatergic dysfunction is implicated in many neuropsychiatric conditions, including post-traumatic stress disorder (PTSD). Glutamate antagonists have shown some utility in treating PTSD symptoms, whereas glutamate agonists may facilitate cognitive behavioral therapy outcomes. We have developed an animal model of PTSD, based on conditioning of the rabbit's eyeblink response, that addresses two key features: conditioned responses (CRs) to cues associated with an aversive event and a form of conditioned hyperarousal referred to as conditioning-specific reflex modification (CRM). The optimal treatment to reduce both CRs and CRM is unpaired extinction. The goals of the study were to examine whether treatment with the N-methyl-D-aspartate glutamate receptor antagonist ketamine could reduce CRs and CRM, and whether the N-methyl-D-aspartate agonist D-cycloserine combined with unpaired extinction treatment could enhance the extinction of both. Administration of a single dose of subanesthetic ketamine had no significant immediate or delayed effect on CRs or CRM. Combining D-cycloserine with a single day of unpaired extinction facilitated extinction of CRs in the short term while having no impact on CRM. These results caution that treatments may improve one aspect of the PTSD symptomology while having no significant effects on other symptoms, stressing the importance of a multiple-treatment approach to PTSD and of animal models that address multiple symptoms. PMID- 28799955 TI - A serotonergic deficit in the dorsal periaqueductal gray matter may underpin enhanced panic-like behavior in diabetic rats. AB - It is known that diabetic (DBT) animals present dysregulation on the serotonergic system in several brain areas associated with anxiety-like responses. The aim of this study was to investigate the involvement of 5-HT1A receptors on dorsal periaqueductal gray (dPAG) in the behavioral response related to panic disorder in type-1 DBT animals. For this, the escape response by electric stimulation (ES) of dPAG in DBT and normoglycemic (NGL) animals was assessed. Both NGL and DBT animals were exposed to an open-field test (OFT) 28 days after DBT confirmation. The current threshold to induce escape behavior in DBT animals was reduced compared with NGL animals. No impairment in locomotor activity was observed when DBT animals were compared with NGL animals. An intra-dPAG injection of the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) increased the [INCREMENT] threshold in both DBT and NGL, suggesting a panicolytic like effect. DBT animals presented a more pronounced panicolytic-like response compared with NGL as a higher [INCREMENT] threshold was observed after 8-OH-DPAT treatment, which could be a consequence of the increased expression of the 5-HT1A receptor in the dPAG from DBT animals. Our results are in line with the proposal that a deficiency in serotonergic modulation of the dPAG is involved in triggering the panic attack and the 5-HT1A receptors might be essential for the panicolytic-like response. PMID- 28799956 TI - Peripheral Blunt Dissection: Using a Microhoe-Facilitated Method for Descemet Membrane Endothelial Keratoplasty Donor Tissue Preparation. AB - PURPOSE: To describe a modified technique for Descemet membrane donor tissue preparation that facilitates the original Melles stripping technique. METHODS: Descemet membrane is prepared using a Rootman/Goldich modified Sloane microhoe, using a blunt instrument as opposed to a sharp blade or needle and begins dissection within the trabecular meshwork. The trabecular tissue is dissected for 360 degrees, and then Descemet membrane is stripped to approximately 50%. A skin biopsy punch is then used to create fenestration in the cornea, which is used to mark an "F." on the stromal side of Descemet membrane to aid in orientation of the graft. Trephination of the membrane is then performed and stripping is completed. The tissue is stained with 0.06% trypan blue and aspirated into an injector for insertion into the anterior chamber. RESULTS: Before converting to the technique described, 5 of 75 (6.7%) tissues were wasted and 7 of 75 (9.3%) tissues with radial tears were salvaged for use. Since converting to the new technique, only 1 of 171 (0.6%) (P = 0.01) tissues was wasted and 7 of 171 (4.1%) (P = 0.2) tissues with radial tears were salvaged. CONCLUSIONS: The peripheral blunt dissection technique offers an improvement over the technique originally described by Melles et al, as the incidence of tissue wastage and tears is lower, it is easy to learn, has low stress, and is reproducible. Combining this with a stromal surface letter mark ensures correct orientation of the tissue against the corneal stroma of the recipient. PMID- 28799957 TI - Potential Clue to the Pathogenesis of Varicella-Zoster Virus Stromal Keratitis. PMID- 28799958 TI - Learning Curve of Small Incision Lenticule Extraction: Challenges and Complications. AB - PURPOSE: To describe the intraoperative complications observed during the initial learning curve of small incision lenticule extraction (SMILE) and their management. METHODS: Prospective evaluation of 100 consecutive eyes (50 patients) undergoing SMILE was performed at an apex tertiary care ophthalmic center. Patients older than 18 years with a stable refractive error ranging from -1.0 to 10.0 D myopia and up to 3.0 D astigmatism were included. Any intraoperative complications and their management were noted. Postoperative examination including visual acuity was performed on day 1, 1 week, and 1 month. RESULTS: Intraoperative difficulties observed in the initial 100 eyes included suction loss (2%), black spots (11%), opaque bubble layer (19%), epithelial defect (2%), and difficult lenticule extraction (9%). Difficult lenticule dissection and extraction was the most surgically challenging step and resulted in posterior stromal damage, anterior cap tear (1%), side-cut tears (4%), partially retained lenticule (1%), and completely retained lenticule (2%). Its incidence decreased from 16% (8/50) in the initial 50 cases to 2% (1/50) in the next 50 cases. Two eyes with completely retained lenticule were re-treated with flap-based excimer laser ablation after 3 months. Optimal visual and anatomical outcomes could be achieved, and no sight-threatening complication was observed in any case. CONCLUSIONS: The learning curve of SMILE is surgically challenging. Lenticule dissection and extraction is the most difficult step and leads to a multitude of complications. Most complications that result in delayed visual recovery are observed in the initial 50 cases. PMID- 28799959 TI - Trends and Determinants of Familial Consent for Corneal Donation in Chinese. PMID- 28799961 TI - Nurses' Perceptions of Psychosocial Care and Barriers to Its Provision: A Qualitative Study. AB - BACKGROUND: Psychosocial care is the culturally sensitive provision of psychological, social, and spiritual care through therapeutic communication. Current evidence suggests that effective psychosocial care improves patients' health outcomes and quality of life. PURPOSE: The aim of this study was to explore nurses' perceptions and experiences in providing psychosocial care to patients and to identify the related barriers and challenges. METHODS: An exploratory qualitative design using semistructured, individual, face-to-face interviews was adopted. A purposive sample of 18 registered nurses was recruited from the geriatric, medical, and surgical wards in an acute general hospital in Singapore. Interviews were audio-recorded, transcribed, and analyzed thematically. RESULTS: Four major themes emerged: patient-centered care, communication, interprofessional care, and barriers to psychosocial care. Nurses perceived that psychosocial care consists of providing holistic care, spiritual care, support to the patient and family members, and showing empathy. Furthermore, psychosocial care is composed of communication between nurses and the patient and family members as well as communication among nurses. In addition, psychosocial care involves collaboration between healthcare professionals as well as multidisciplinary care. Barriers that are perceived by nurses include lack of time, language barriers, being task-oriented, excessive documentation, lack of family involvement, and fear of complaints. CONCLUSIONS: This study highlighted the perceptions of nurses regarding psychosocial care and the challenges in providing this care. Future studies are needed to explore ways to overcome these barriers and to enhance nurses' competencies in providing psychosocial care. The findings indicate a need to plan future interventions to provide nurses with both skill development and support to improve their ability to integrate psychosocial care, which will improve patient outcomes. PMID- 28799960 TI - Critical Contact Lens Oxygen Transmissibility and Tear Lens Oxygen Tension to Preclude Corneal Neovascularization. AB - OBJECTIVE: The purpose of this study is to determine the peripheral oxygen transmissibility (pDk/t) and respective central oxygen transmissibility (cDk/t) in soft contact lenses (SCLs) which might preclude SCL-driven corneal neovascularization (NV) in healthy myopic SCL users. METHODS: Twenty subjectively successful SCL-wearing patients who presented with asymptomatic but active peripheral corneal NV (not ghost vessels) were recruited as study patients. Twenty-one patients who did not have NV were similarly recruited as controls. Demographic data were collected. Corneal NV was documented and photographed. Current habitual SCLs were collected and thicknesses measured to allow for the calculation of both pDk/t and cDk/t and estimation of local tear oxygen tensions. RESULTS: No statistical differences between study and control groups in patient age, refraction, or the numbers of years, days per week, or hours per day patients reported SCL wear were identified. Statistically significant differences were found between the two groups for both pDk/t (P=0.006) and cDk/t (P=0.004): mean (+/-SD) pDk/t was 38.0+/-23.5 and 19.2+/-17.7 Fatt units for control and study corneas, respectively. Mean cDk/t were 80.0+/-54.4 and 36.8+/-33.1 Fatt units for control and study corneas, respectively. Peripheral tear oxygen tension that "protected" corneas from vascular filling was over 84 mm Hg. CONCLUSION: Maintaining a pDk/t above 30 to 40 Fatt units with daily wear SCLs should protect most normal corneas from NV as a complication of SCL wear. PMID- 28799962 TI - Intention to Receive Breast Cancer Screening and Related Factors of Influence Among Vietnamese Women in Transnational Marriages. AB - BACKGROUND: Breast cancer is a major global health issue. Receiving regular breast cancer screenings aids in the early detection and treatment of breast cancer. Numerous factors influence whether a Vietnamese woman receives breast cancer screening. PURPOSE: The aims of this study were to understand current rates of breast cancer screening and explore the factors that influence intention to undergo breast cancer screening among Vietnamese women in transnational marriages. METHODS: This was a cross-sectional, community-based study. Data were collected via snowball sampling. We enrolled 250 women aged 18 years and over from September to December 2015. RESULTS: The percentage of participants who had received a breast self-examination, breast palpation, or breast ultrasound within the past year were 25.6%, 9.6%, and 21.2%, respectively. Moreover, only 6.8% of participants had received a mammography within the past 2 years. Participants with strong perceptions of breast cancer being a serious illness, who had fewer barriers to obtaining a breast cancer screening, or who had been advised by healthcare personnel to undergo screenings were more likely to report an intention to receive periodic breast self-examinations during the subsequent 1 year period. Participants who had lived in Taiwan for a longer period, had higher levels of perceived susceptibility to breast cancer, had prior experience with breast diseases, or had fewer barriers to obtaining a breast cancer screening were more likely to report an intention to receive a breast ultrasound during the subsequent 1-year period. Finally, participants who were older, perceived greater benefits from receiving breast cancer screening, and had not entered menopause were more likely to report an intention to receive a mammography during the following 2 years. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Medical care personnel should promote breast cancer screening among Vietnamese women in transnational marriages. The results may be useful in promoting greater awareness among medical care personnel of breast cancer issues and efficacy in performing breast cancer screening for Vietnamese women in transnational marriages and provide references for the establishment of breast cancer prevention and control policies. PMID- 28799963 TI - Factors Associated With Health-Related Quality of Life in Patients With Open Fractures. AB - OBJECTIVES: To analyze FLOW data to identify baseline patient, injury, fracture, and treatment factors associated with lower health-related quality of life (HRQoL) at 12-month postfracture. DESIGN: Prognostic study using data from a prospective randomized controlled trial. SETTING: Thirty-one clinical centers in the United States, Canada, Australia, and India. PATIENTS/PARTICIPANTS: One thousand four hundred twenty-seven patients with open fracture from the FLOW trial with complete 12-month Short Form-12 (SF-12) follow-up assessment and no missing data for selected baseline factors. INTERVENTION: Not applicable. MAIN OUTCOME MEASUREMENT: Physical Component Score (PCS) and the Mental Component Score (MCS) of the SF-12 at 12-month postfracture. RESULTS: One thousand four hundred twenty-seven patients were included in the SF-12 PCS and MCS linear regression models. Smoking, lower preinjury SF-12 PCS and MCS, and work-related injuries were significantly associated with lower SF-12 PCS and MCS at 12-month postfracture. A lower extremity fracture and a wound that was not closed at initial irrigation and debridement were significantly associated with lower 12 month SF-12 PCS but not MCS. Only the adjusted mean difference for lower extremity fractures approached the minimally important difference for the SF-12 PCS. CONCLUSIONS: We identified a number of statistically significant baseline factors associated with lower HRQoL; however, only the presence of a lower extremity fracture approached clinical significance. More research is needed to quantify the impact of these factors on patients and to determine whether changes to modifiable factors at baseline will lead to clinically significant improvements in HRQoL after open fractures. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 28799964 TI - The Effect of Adductor Canal Block on Knee Extensor Muscle Strength 6 Weeks After Total Knee Arthroplasty: A Randomized, Controlled Trial. AB - BACKGROUND: Total knee arthroplasty (TKA) reduces knee extensor muscle strength (KES) in the operated limb for several months after the surgery. Immediately after TKA, compared to either inguinal femoral nerve block or placebo, adductor canal block (ACB) better preserves KES. Whether this short-term increase in KES is maintained several weeks after surgery remains unknown. We hypothesized that 48 hours of continuous ACB immediately after TKA would improve KES 6 weeks after TKA, compared to placebo. METHODS: Patients scheduled for primary unilateral TKA were randomized to receive either a continuous ACB (group ACB) or a sham block (group SHAM) for 48 hours after surgery. Primary outcome was the difference in maximal KES 6 weeks postoperatively, measured with a dynamometer during maximum voluntary isometric contraction. Secondary outcomes included postoperative day 1 (POD1) and day 2 (POD2) KES, pain scores at rest and peak effort, and opioid consumption; variation at 6 weeks of Knee Osteoarthritis Outcome Score, patient satisfaction, and length of hospital stay. RESULTS: Sixty-three subjects were randomized and 58 completed the study. Patients in group ACB had less pain at rest during POD1 and during peak effort on POD1 and POD2, consumed less opioids on POD1 and POD2, and had higher median KES on POD1. There was no significant difference between groups for median KES on POD2, variation of Knee Osteoarthritis Outcome Score, patient satisfaction, and length of stay. There was no difference between groups in median KES 6 weeks after surgery (52 Nm [31-89 Nm] for group ACB vs 47 Nm [30-78 Nm] for group SHAM, P= .147). CONCLUSIONS: Continuous ACB provides better analgesia and KES for 24-48 hours after surgery, but does not affect KES 6 weeks after TKA. Further research could evaluate whether standardized and optimized rehabilitation over the long term would allow early KES improvements with ACB to be maintained over a period of weeks or months. PMID- 28799965 TI - In Response. PMID- 28799966 TI - In Response: Concerns With Rate of Rise of Carbon Dioxide During Apnea With Buccal Oxygenation. PMID- 28799967 TI - The Subtleties of Language as a Reason for Failure to Follow Preoperative Fasting Guidelines: The Differences Between Restricting, Allowing, and Encouraging. PMID- 28799968 TI - Core Temperature Monitoring in Obstetric Spinal Anesthesia Using an Ingestible Telemetric Sensor. AB - BACKGROUND: Perioperative hypothermia may affect maternal and neonatal outcomes after obstetric spinal anesthesia. Core temperature is often poorly monitored during spinal anesthesia, due to the lack of an accurate noninvasive core temperature monitor. The aim of this study was to describe core temperature changes and temperature recovery during spinal anesthesia for elective cesarean delivery. We expected that obstetric spinal anesthesia would be associated with a clinically relevant thermoregulatory insult (core temperature decrease >1.0 degrees C). METHODS: A descriptive study was conducted in 28 women. An ingestible telemetric temperature sensor was used to record core temperature over time (measured every 10 seconds). The primary outcome was the maximum core temperature decrease after spinal anesthetic injection. The secondary outcomes were lowest absolute core temperature, time to lowest temperature, time to recovery of core temperature, hypothermic exposure (degree-hours below 37.0 degrees C), and the time-weighted hypothermic exposure (median number of degrees below 37.0 degrees C per hour). Basic descriptive statistics, median spline smooth, and integration of the area below the 37.0 degrees C line of the temperature-over-time curve were utilized to analyze the data. RESULTS: Intestinal temperature decreased by a mean (standard deviation) of 1.30 degrees C (0.31); 99% confidence interval (CI), 1.14 to 1.46 after spinal anesthetic injection. The median (interquartile range [IQR]) time to temperature nadir was 0.96 (0.73-1.32) hours (95% CI, 0.88-1.22). Fourteen of the 28 participants experienced intestinal temperatures below 36.0 degrees C after spinal injection. Temperature was monitored for a minimum of 8 hours after spinal injection. In 8 of 28 participants, intestinal temperature did not recover to baseline during the monitored period. A median (IQR) of 4.59 (3.38 5.92) hours (95% CI, 3.45-5.90) was required for recovery to baseline intestinal temperature in the remaining 20 patients. Participants experienced a median (IQR) of 1.97 (1.00-2.68) degree-hours of hypothermic exposure (95% CI, 1.23-2.45). The median (IQR) number of degrees below 37.0 degrees C per hour was 0.45 (0.35-0.60) (95% CI, 0.36-0.58). CONCLUSIONS: During cesarean delivery under spinal anesthesia, women experienced a rapid decrease in core temperature. Using an intestinal telemetric sensor, the perioperative thermal insult and recovery were documented with high resolution. Fifty percent of participants in this study became hypothermic. Although the surgical procedure is typically of short duration, women undergoing spinal anesthesia for cesarean delivery experience significant hypothermic exposure and compromised thermoregulation for several hours. PMID- 28799971 TI - MACROANEURYSMS ASSOCIATED WITH CONGENITAL RETINAL MACROVESSELS. AB - PURPOSE: Congenital retinal macrovessels are large aberrant retinal blood vessels that cross the horizontal raphe and can traverse the central macula. Using multimodal imaging and optical coherence tomography angiography, we describe 2 cases of congenital retinal macrovessel associated with macroaneurysms. METHODS: Two patients presented for evaluation and were found to have congenital retinal macrovessels associated with macroaneurysms. Color photography, optical coherence tomography, fundus autofluorescence fluorescein angiography, and optical coherence tomography angiography were performed and used to establish the diagnosis and monitor resolution at follow-up visits. RESULTS: The first patient presented with central vision loss in the right eye and was noted to have a ruptured macroaneurysm and scattered microaneurysms along the course of a venous macrovessel. After 3 months of observation, the patient's vision improved. The second patient presented for evaluation of a cataract in her left eye and was incidentally found to have an arterial macrovessel in her right eye with an associated macroaneurysm. Both cases demonstrated an intricate capillary network in the central macula best visualized on optical coherence tomography angiography. CONCLUSION: Macroaneurysms can occur on both arterial and venous macrovessels. After rupture of these lesions, hemorrhage and exudation can resolve with observation alone. Macrovessels can also present with microaneurysms. Optical coherence tomography angiography can effectively image the complex capillary network associated with these vascular anomalies. PMID- 28799972 TI - Increased Pain Sensitivity in Accident-related Chronic Pain Patients With Comorbid Posttraumatic Stress. AB - OBJECTIVES: Posttraumatic stress disorder (PTSD) is prevalent in chronic pain, and associated with increased pain, hyperalgesia, and psychological distress. This study aimed to investigate antinociceptive and pronociceptive pain mechanisms, pain intensity, and psychological distress (depression, anxiety, pain catastrophizing, and fear of movement) in patients with accident-related chronic spinal pain with (N=44) and without (N=64) comorbid PTSD characteristics. MATERIALS AND METHODS: Cuff algometry was performed on lower legs to assess pressure pain threshold (cPPT), tolerance (cPTT), temporal summation of pain (increase in pain scores to 10 repeated stimulations), and conditioning pain modulation (increase in cPPT during cuff pain conditioning on the contralateral leg). Warmth detection threshold and heat pain threshold at the hand were also assessed. Clinical pain intensity (numerical rating scale), psychological distress, and PTSD symptomatology (ICD-11) were assessed with questionnaires. Mediation analyses were performed to investigate possible psychological mediators in the associations between PTSD and pain (intensity and mechanisms). RESULTS: Patients with PTSD demonstrated increased pain intensity, and psychological distress as well as reduced warmth detection threshold and cPTT compared with patients without PTSD (P<0.05). No significant differences in cPPT, heat pain threshold, temporal summation of pain, and conditioning pain modulation were found. The association between PTSD and pain intensity was mediated by pain catastrophizing, and fear of movement mediated the association with cPTT. DISCUSSION: The association between PTSD and pain intensity is in accordance with the mutual-maintenance and fear-avoidance models. Future studies should investigate changes in pain intensity and mechanisms after treatment targeting comorbid PTSD in chronic pain patients. PMID- 28799974 TI - Will primary care be the PA profession's future? PMID- 28799973 TI - Cross-sectional and Prospective Correlates of Recovery Expectancies in the Rehabilitation of Whiplash Injury. AB - OBJECTIVES: Investigations have shown that expectancies are significant prognostic indicators of recovery outcomes following whiplash injury. However, little is currently known about the determinants of recovery expectancies following whiplash injury. The purpose of the present study was to examine the cross-sectional and prospective correlates of recovery expectancies in individuals admitted to a rehabilitation program for whiplash injury. MATERIALS AND METHODS: Participants (N=96) completed measures of recovery expectancies, psychosocial variables, symptom severity, symptom duration, and disability at time 0 (admission) and time 1 (discharge). RESULTS: Consistent with previous research, more positive recovery expectancies at time 0 were related to reductions in pain at time 1 (r=-0.33, P<0.01). Scores on measures of pain catastrophizing, fear of movement and reinjury, and depression were significantly correlated with recovery expectancies. Pain severity, duration of work disability, and neck range of motion were not significantly correlated with recovery expectancies. Over the course of treatment, 40% of the sample showed moderate to large changes (an increase of >=20%) in recovery expectancies, there were small changes (<20%) in 30% of the sample, and negative changes in 20% of the sample. A hierarchical regression showed that decreases in fear of movement and reinjury (beta=-0.25, P<0.05) and pain catastrophizing (beta=-0.23, P<0.05) were associated with increases in recovery expectancies through the course of treatment. CONCLUSIONS: The discussion addresses the processes linking pain related psychosocial factors to recovery expectancies and makes recommendations for interventions that might be effective in increasing recovery expectancies. PMID- 28799976 TI - Effect of gene-gene and gene-environment interactions associated with antituberculosis drug-induced hepatotoxicity. AB - OBJECTIVES: This study evaluated the association between environmental factors and genetic variations in enzymes that metabolize antituberculosis (anti-TB) drugs [arylamine N-acetyltransferase 2, cytochrome P450 2E1 (CYP2E1), glutathione S-transferase theta 1 (GSTT1), and glutathione S-transferase mu 1] with antituberculosis drug-induced hepatotoxicity (ATDH). We also investigated the potential gene-gene and gene-environment interactions as well as their association with ATDH development in a population of hospitalized TB patients from Buenos Aires. PATIENTS AND METHODS: We investigated 364 TB patients who received anti-TB drugs. Physicians collected demographic and clinical data to identify environmental risk factors for ATDH development. Polymorphisms were detected using gene sequencing, PCR, and PCR-restriction fragment length polymorphisms. A binary logistic regression analysis was carried out to compare the results of TB patients with and without the development of hepatotoxicity. The multifactor dimensionality reduction method was used to examine genetic and environmental interactions in association with ATDH. RESULTS: This study suggests that the slow acetylator profile [odds ratio (OR): 3.02; 95% confidence interval (CI): 1.82-5.00; P<0.001], genotypes carrying the c2 variant (OR: 2.16; 95% CI: 1.33-3.51; P=0.002) or the A4 variant of CYP2E1 (OR: 2.13; 95% CI: 1.06-4.29; P=0.050), and female sex (OR: 1.94; 95% CI: 1.20-3.14; P=0.006) were independent predictor variables for ATDH. Patients carrying the slow acetylator profile and the c2 variant showed an increased risk (OR: 7.068; 95% CI: 3.34-14.95; P<0.001). We also identified a synergic interaction (epistasis) between GSTT1 and CYP2E1 associated with an increased risk for ATDH. A meaningful gene-environment interaction was associated with an increased risk of ATDH [testing balance accuracy=0.675 (P=0.001) and cross-validation consistency=10/10]. CONCLUSION: ATDH is a severe and prevalent adverse drug reaction and leads to drug discontinuation in 11% of TB patients. Our study created a prediction model that properly classified the 67.5% of TB patients in their risk of developing ATDH. The considerable number of TB patients in our country supports the use of pharmacogenetic testing and a comprehensive clinical history to identify patients with a high risk of suffering hepatotoxicity. PMID- 28799977 TI - Evidence-based approaches to breaking down language barriers. PMID- 28799978 TI - Role of fractional flow reserve in the evaluation and management of patients with acute coronary syndrome. AB - PURPOSE OF REVIEW: The aim of this review is to appraise the clinical and prognostic value and pitfalls of FFR across different spectra of ACS presentations and lesion subsets. RECENT FINDINGS: Preponderance of evidence on this subject is from observational nonrandomized studies with conflicting results and short-term outcomes. Multiple recent studies evaluating the role of FFR-based deferral in non-STE ACS from a potentially culprit lesion have demonstrated poor long-term prognosis as related to future risk of target vessel failure (myocardial infarction/revascularization). The prognostic power of nonischemic FFR seems favorable in clear nonculprit ACS lesions. SUMMARY: Fractional flow reserve evaluation can be helpful in clinical decision-making for certain subsets of ACS patients and lesions. Definite ACS-producing lesions should not be evaluated using FFR due to altered pathophysiology and distinct mechanisms underlying the disease process. In uncertain culprit lesions, FFR may be useful with complementary intracoronary imaging. PMID- 28799979 TI - Management strategies in acute type B aortic intramural hematoma. AB - PURPOSE OF REVIEW: Intramural hematoma (IMH) is one of the acute aortic syndromes. IMH was originally noted as an 'aortic dissection without intimal tear.' It had been speculated that IMHs were caused by ruptured vasa vasorum in the aortic media and distinguished from classical aortic dissections. However, the majority of IMHs are now detected with an intimal defect using high resolution computed tomography, which implies that IMHs may be a subset of aortic dissections with very limited flow in the false lumen. Management of IMHs had been controversial, but guidelines published in the early 2010 s recommend treating IMHs as classical aortic dissections: surgical repairs were indicated for type A IMHs; complicated acute type B IMHs were treated with endovascular or open repairs and uncomplicated type B IMHs were to be managed with antiimpulse therapy and close surveillance. To date, based on the favorable long-term outcomes of preemptive thoracic endovascular aortic repair (TEVAR) for uncomplicated type B aortic dissections, early TEVAR for uncomplicated type B IMHs has been attempted. In this review, we describe the pathophysiology and management strategies for acute IMHs. RECENT FINDINGS: IMHs have intimal tears or disruptions in 70-80%. SUMMARY: Type B IMH should be managed with antiimpulse therapy, unless the patient has persistent pain or large ulcer-like projection. PMID- 28799980 TI - Retrieval of a fractured angioplasty guidewire after percutaneous retrograde revascularization of coronary chronic total occlusion. PMID- 28799981 TI - Guided growth for angular correction in children: a comparison of two tension band plate designs. AB - : This retrospective cohort study examined 20 patients (48 physes), 11 boys and nine girls, who were treated with hinge-plate or eight-plate. The mean age of the patients at surgery was 11.9+/-2.6 years. The mean follow-up duration was 13+/ 2.7 months. The radiographic measurement of both distal femoral and proximal tibial deformity showed significant correction, with no difference between the hinge-plate and the eight-plate. Both screw divergence angle and the hinge angle showed significant changes at the last follow-up. The deformity correction of the distal femoral physis was quicker than the proximal tibial physis. The rate of mechanical femoral-tibial angle correction was 0.97 degrees /month if both femoral and tibial physes were treated. LEVEL OF EVIDENCE: III. PMID- 28799982 TI - A National Analysis of Long-term Survival Following Thoracoscopic Versus Open Lobectomy for Stage I Non-small-cell Lung Cancer. AB - OBJECTIVE: The objective of this study was to compare the long-term survival of open versus thoracoscopic (VATS) lobectomy for early stage non-small-cell lung cancer (NSCLC). BACKGROUND: Data from national studies on long-term survival for VATS versus open lobectomy are limited. METHODS: Outcomes of patients who underwent open versus VATS lobectomy for clinical T1-2, N0, M0 NSCLC in the National Cancer Data Base were evaluated using propensity score matching. RESULTS: The median follow-up of 7114 lobectomies (5566 open and 1548 VATS) was 52.0 months. Propensity score matching resulted in 1464 open and 1464 VATS patients who were well-matched by 14 common prognostic covariates including tumor size and comorbidities. The VATS approach was associated with a shorter median length of stay (5 vs. 6 days, P < 0.001) and better 5-year survival (66.0% vs. 62.5%, P = 0.026), and was not significantly different compared with the open approach with regard to nodal upstaging (11.2% vs. 12.5%, P = 0.46), and 30-day mortality (1.7% vs. 2.5%, P = 0.14). In the propensity-matched analysis of 2928 patients, there were no significant differences in 5-year survival between the VATS and open groups (66.3% vs. 65.8%, P = 0.92). CONCLUSIONS: In this national analysis, VATS lobectomy was used in the minority of patients with stage I NSCLC. VATS lobectomy was associated with shorter length of stay and noninferior long term survival when compared with open lobectomy. These results support previous findings from smaller single- and multi-institutional studies that suggest that VATS does not compromise oncologic outcomes when used for early-stage lung cancer and suggest the need for broader implementation of VATS techniques. PMID- 28799984 TI - Lidocaine spray as a local analgesic for intravenous cannulation: a randomized clinical trial. AB - OBJECTIVES: Lidocaine spray is an effective analgesic of mucous membranes. Lidocaine spray is also used during intravenous (i.v.) cannulation, especially in children. However, the analgesic effect of lidocaine spray during i.v. cannulation has not been studied. We aimed to assess the analgesic effectiveness of lidocaine spray during i.v. cannulation. METHODS: We conducted a randomized, double-blinded, placebo-controlled trial in seventeen healthy adults who received an i.v. cannulation in the right and left elbow, respectively, where the order of application of 60 mg lidocaine spray (Xylocaine 10% pump spray) or placebo spray (chlorhexidine gluconate 0.5% in 70% alcohol base) before i.v. cannulation was randomized. Thus, each participant had an i.v. cannulation in both arms: one with lidocaine spray and the other with placebo spray. The primary outcome was pain intensity assessed by a 100 mm Visual Analogue Scale. The secondary outcomes were adverse events, success rate of i.v. cannulation and the degree of difficulty of i.v. cannulation as estimated by the nurse performing the i.v cannulation. RESULTS: The pain score (Visual Analogue Scale) during i.v. cannulation was 18.0 mm (interquartile range: 5.0-34.5 mm) after lidocaine application and 21.0 mm (interquartile range: 11.0-30.5) after placebo application. These scores were not significantly different (95% confidence interval: -9.0-11.0, P=0.698). No adverse events occurred and all i.v. cannulations were successful at first attempt. CONCLUSION: Local administration of lidocaine is not effective in reducing pain during i.v. cannulation. PMID- 28799983 TI - Discrimination of Voice Pitch and Vocal-Tract Length in Cochlear Implant Users. AB - OBJECTIVES: When listening to two competing speakers, normal-hearing (NH) listeners can take advantage of voice differences between the speakers. Users of cochlear implants (CIs) have difficulty in perceiving speech on speech. Previous literature has indicated sensitivity to voice pitch (related to fundamental frequency, F0) to be poor among implant users, while sensitivity to vocal-tract length (VTL; related to the height of the speaker and formant frequencies), the other principal voice characteristic, has not been directly investigated in CIs. A few recent studies evaluated F0 and VTL perception indirectly, through voice gender categorization, which relies on perception of both voice cues. These studies revealed that, contrary to prior literature, CI users seem to rely exclusively on F0 while not utilizing VTL to perform this task. The objective of the present study was to directly and systematically assess raw sensitivity to F0 and VTL differences in CI users to define the extent of the deficit in voice perception. DESIGN: The just-noticeable differences (JNDs) for F0 and VTL were measured in 11 CI listeners using triplets of consonant-vowel syllables in an adaptive three-alternative forced choice method. RESULTS: The results showed that while NH listeners had average JNDs of 1.95 and 1.73 semitones (st) for F0 and VTL, respectively, CI listeners showed JNDs of 9.19 and 7.19 st. These JNDs correspond to differences of 70% in F0 and 52% in VTL. For comparison to the natural range of voices in the population, the F0 JND in CIs remains smaller than the typical male-female F0 difference. However, the average VTL JND in CIs is about twice as large as the typical male-female VTL difference. CONCLUSIONS: These findings, thus, directly confirm that CI listeners do not seem to have sufficient access to VTL cues, likely as a result of limited spectral resolution, and, hence, that CI listeners' voice perception deficit goes beyond poor perception of F0. These results provide a potential common explanation not only for a number of deficits observed in CI listeners, such as voice identification and gender categorization, but also for competing speech perception. PMID- 28799985 TI - Rapid detection of bacterial meningitis using a point-of-care glucometer. AB - BACKGROUND: In case of acute bacterial meningitis, a decision on the need for intensive care admission should be made within the first hour. The aim of this study was to assess the ability of a point-of-care glucometer to determine abnormal cerebrospinal fluid (CSF) glucose concentration at the bedside that contributes toward bacterial meningitis diagnosis. METHODS: We carried out a prospective study and simultaneously measured the glucose concentrations in CSF and blood using a central laboratory and a point-of-care glucometer. We compared CSF/blood glucose ratios obtained at the bedside with a glucometer versus those obtained by the central laboratory. We determined the performance characteristics of the CSF/blood glucose ratio provided by a glucometer to detect bacterial infection in the CSF immediately after CSF sampling. RESULTS: We screened 201 CSF collection procedures during the study period and included 172 samples for analysis. Acute bacterial meningitis was diagnosed in 17/172 (9.9%) of CSF samples. The median turnaround time for a point-of-care glucometer analysis was 5 (interquartile range 2-10) min versus 112 (interquartile range 86-154) min for the central laboratory (P<0.0001). The optimal cut-off of the CSF/blood glucose ratio calculated from a bedside glucometer was 0.46, with a sensitivity of 94.1% (95% confidence interval: 71.3-99.9%), a specificity of 91% (95% confidence interval: 85.3-95%), and a positive likelihood ratio of 10. CONCLUSION: A glucometer accurately detects an abnormal CSF/blood glucose ratio immediately after the lumbar puncture. This cheap point-of-care method has the potential to speed up the diagnostic process of patients with bacterial meningitis. PMID- 28799986 TI - Preface and Introduction. PMID- 28799987 TI - A Brief History of Limb Lengthening. AB - In the last 35 years, orthopaedic surgeons have witnessed 3 major advances in the technique of limb lengthening: "distraction osteogenesis" facilitated by Gavriil Ilizarov method and infinitely-adaptable circular fixator with fine-wire bone fragment fixation; the introduction of the "6-strut" computer program-assisted circular fixators to effect complex deformity correction simultaneously; and the development of motorized intramedullary lengthening nails. However, the principles and associated complications of these techniques are on the basis of observations by Codivilla, Putti, and Abbott from as much as 110 years ago. This review notes the contribution of these pioneers in limb lengthening, and the contribution of Thor Heyerdahl principles of tolerance and diversity to the dissemination of Ilizarov principles to the Western world. PMID- 28799988 TI - Preoperative Assessment for Complex Lower Limb Deformity. AB - Successful limb reconstruction surgery not only relies on surgical skill but probably more on assessment and planning before intervention. A clear appreciation of the child as a whole, an understanding of natural history and the ability to carefully evaluate the patient clinically are key to successful treatment. The appropriate use of investigations and the ability to analyze, plan and execute a treatment plan is challenging and requires experience and training. This paper outlines some of the steps required to assess the patient with a complex limb deformity. PMID- 28799989 TI - New Trends in Ring Fixators. AB - Multiple versions of ring fixators are currently available to orthopaedic surgeons. Although the traditional Ilizarov-type ring fixator is still available, many surgeons are now using computer-assisted hexapod frames. There has been a recent surge in the number of different hexapod ring fixators on the market. This article will review some of the new trends in ring fixator hardware and software as well as discuss possible future directions of ring fixator development. PMID- 28799990 TI - State of the Art: Amputation and Prosthetics. AB - Amputation is not a defeat or failure of treatment, but an effective management strategy for certain conditions in the pediatric population. The principles of management, especially in the pediatric population, have not changed. Current surgical strategies focus on providing an optimal residual limb for prosthetic fitting. New technology provides improvement in the design and fabrication of prosthetic devices. PMID- 28799991 TI - Treatment of Infantile Blount Disease: An Update. AB - Although the core principles of managing infantile Blount disease generally remain unchanged, treatment modalities have evolved over the years. Consensus has yet to be reached regarding the efficacy of bracing. Children with Blount disease commonly have advanced bone age, which may impact the timing and magnitude of (over) correction of angular deformity. Techniques of growth modulation, based on the tension band principle, continue to gain popularity. Although there are limited reports in the last decade on proximal tibial osteotomy for this developmental disorder, both acute and gradual correction remain viable treatment options in the appropriate setting. In certain older children (>7 y old) with advanced stages of the disease, a medial hemiplateau elevation combined with lateral proximal tibial hemiepiphysiodesis may be needed to address the epiphyseal deformity. Given the possibility of unpredictable proximal tibial physeal activity, all children with Blount disease should be followed at regular intervals till skeletal maturity. To provide sufficient granularity for pooled analyses and help establish evidence-based clinical guidelines, standardization of reporting clinical outcomes among children with Blount disease is encouraged. PMID- 28799992 TI - Guided Growth: Novel Applications in the Hip, Knee, and Ankle. AB - Hemiepiphyseodesis for angular deformities in the growing child is effective and avoids the complications of osteotomies and gradual correction with external fixation. This article reviews applications of screw hemiepiphyseodesis for coronal and sagittal plane deformities in the lower extremity. Indications, technical pearls, and pitfalls are discussed. PMID- 28799993 TI - Cubitus Varus-It's More Than Just a Crooked Arm! AB - Although cubitus varus has been regarded as a purely cosmetic problem in the pediatric population, symptomatic elbow instability, and ulnar neuropathy from the mechanical axis malalignment have been reported in adults. This overview discusses the biomechanical axis disruption that leads to soft tissue and morphologic bony alterations in the elbow and offers a compelling argument for corrective osteotomy to treat pediatric cubitus varus. PMID- 28799994 TI - Lower Extremity Deformity Management in Amyoplasia: When and How. AB - This article presents an approach to the musculoskeletal problems of children with amyoplasia. Although a very high percentage of children with have ambulatory potential, activity and function decline over time. Strong consideration of external resources and support available to the child and family are important considerations in recommending surgery as is the timing of interventions to align with childhood development. PMID- 28799995 TI - Fassier-Duval Telescopic System: How I Do It? AB - The author describes step-by-step the technique for Fassier-Duval rodding of both femurs and tibiae in osteogenesis imperfecta. Preoperative evaluations and planning, postoperative care and place of bisphosphonates as explained. Emphasis is given on the different tricks to avoid intraoperative problems. PMID- 28799996 TI - Tobacco, illicit drugs use and risk of cardiovascular disease in patients living with HIV. AB - PURPOSE OF REVIEW: There is a strong link between HIV, smoking and illicit drugs. This association could be clinically relevant as it may potentiate the risk of cardiovascular diseases (CVD). The purpose of this review is to bring readers up to date on issues concerning the cardiovascular risk associated with tobacco and illicit drugs in patients living with HIV (PLHIV), examining the studies related to this topic published in the last year. RECENT FINDINGS: There is a strong association between smoking and atherosclerotic disease in PLHIV, reducing life expectancy secondary to CVD by up to 6 years. Illicit drugs were associated with increased risk of atherosclerotic problems but to a lesser extent than smoking. A significant association of drugs such as cocaine with subclinical coronary atherosclerosis been demonstrated. The relation of marijuana, heroin and amphetamines with atherosclerosis generates more controversy. However, those drugs are associated with cardiovascular morbidity, independently of smoking and other traditional risk factors. SUMMARY: Tobacco and illicit drugs are linked to CVD in HIV patients. This leads to the need to create special programs to address the addiction to smoking and illicit drugs, in order to mitigate their consequences and reduce cardiovascular risk. PMID- 28799998 TI - Use of direct oral anticoagulants for treatment of atrial fibrillation in patients with HIV: a review. AB - PURPOSE OF REVIEW: Atrial fibrillation is increasingly common in the ageing population. Patients with atrial fibrillation and HIV have a higher stroke risk, with guidelines recommending anticoagulation in the majority. Whilst anticoagulation options have diversified in the last decade for the general population, there is limited evidence for the safety and efficacy of these medications when used concurrently with antiretroviral therapy. We review the potential for patients with HIV on antiretroviral therapy to have direct-acting oral anticoagulations (DOACs). RECENT FINDINGS: Several case reports have been published in the past 5 years, as well as theoretical analyses of anticipated drug interactions, which provide a starting point to guide use of DOACs with antiretroviral medications. SUMMARY: Caution is needed when prescribing DOACs in patients with atrial fibrillation and HIV due to potential drug interactions. Studies are lacking and current advice is based on case reports, expert opinion and knowledge of theoretical interactions. PMID- 28799997 TI - Epidemiology of ischemic heart disease in HIV. AB - PURPOSE OF REVIEW: The purpose of this review is to summarize and synthesize recent data on the risk of ischemic heart disease (IHD) in HIV-infected individuals. RECENT FINDINGS: Recent studies in the field demonstrate an increasing impact of cardiovascular disease (CVD) on morbidity and mortality in HIV relative to AIDS-related diagnoses. Studies continue to support an approximately 1.5 to two-fold increased risk of IHD conferred by HIV, with specific risk varying by sex and virologic/immunologic status. Risk factors include both traditional CVD risk factors and novel, HIV-specific factors including inflammation and immune activation. Specific antiretroviral therapy (ART) drugs may increase CVD risk, yet the net effect of ART with viral suppression is beneficial with regard to CVD risk. Management of cardiovascular risk and prevention of CVD is complex, because current general population strategies target traditional CVD risk factors only. Extensive investigation is being directed at developing tailored CVD risk prediction algorithms and interventions to reduce CVD risk in HIV. SUMMARY: Increased IHD risk is a significant clinical and public health challenge in HIV. The development and application of HIV-specific interventions to manage CVD risk factors and reduce CVD risk will improve the long-term health of this ageing population. PMID- 28799999 TI - Features of cardiovascular disease in low-income and middle-income countries in adults and children living with HIV. AB - PURPOSE OF REVIEW: The current article addresses crucial issues in identifying risk of cardiovascular disease (CVD) in people living with HIV in low-income and middle-income countries (LMICs). These issues are in need of urgent attention to advance our knowledge and inform actions to mitigate CVD in this population. We address CVDs in adults living with HIV as well as the unique aspects pertaining to children living with HIV (CLHIV), a group sorely under-represented in this field. RECENT FINDINGS: CVDs affecting adults such as hypertension, dyslipidemia, coronary artery disease, and heart failure, in addition to myocardial dysfunction, vascular diseases, and autoimmune phenomena are also being reported in CLHIV. In addition to the background disparity in prevalence of traditional CVD risk factors, it is also likely that differential access to antiretroviral treatment, the younger age of the HIV-infected population, and types of antiretroviral treatment commonly used in LMICs contribute to the observed differences. SUMMARY: Overall, the state of evidence for CVD in LMICs is limited and at times contradictory. We summarize the evidence with suggestions for high priorities for further scientific investigation. Now is the crucial time to intervene in modifying CVD risk in LMICs. PMID- 28800000 TI - Rural-Urban Differences in Medicare Quality Outcomes and the Impact of Risk Adjustment. AB - BACKGROUND: There has been considerable debate in recent years about whether, and how, to risk-adjust quality measures for sociodemographic characteristics. However, geographic location, especially rurality, has been largely absent from the discussion. OBJECTIVE: To examine differences by rurality in quality outcomes, and the impact of adjustment for individual and community-level sociodemographic characteristics on quality outcomes. DATA SOURCES: The 2012 Medicare Current Beneficiary Survey, Access to Care module, combined with the 2012 County Health Rankings. All data used were publicly available, secondary data. We merged the 2012 Medicare Current Beneficiary Survey data with the 2012 County Health Rankings data using county of residence. RESEARCH DESIGN: We compared 6 unadjusted quality of care measures for Medicare beneficiaries (satisfaction with care, blood pressure checked, cholesterol checked, flu shot receipt, change in health status, and all-cause annual readmission) by rurality (rural noncore, micropolitan, and metropolitan). We then ran nested multivariable logistic regression models to assess the impact of adjusting for community and individual-level sociodemographic characteristics to determine whether these mediate the rurality difference in quality of care. RESULTS: The relationship between rurality and change in health status was mediated by the inclusion of community-level characteristics; however, adjusting for community and individual level characteristics caused differences by rurality to emerge in 2 of the measures: blood pressure checked and cholesterol checked. For all quality scores, model fit improved after adding community and individual characteristics. CONCLUSIONS: Quality is multifaceted and is impacted by individual and community level socio-demographic characteristics, as well as by geographic location. Current debates about risk-adjustment procedures should take rurality into account. PMID- 28800001 TI - Basic Hemodynamic Monitoring Using Ultrasound or Electrical Cardiometry During Transportation of Neonates and Infants. AB - OBJECTIVES: Electrical cardiometry and heart ultrasound might allow hemodynamic evaluation during transportation of critically ill patients. Our aims were 1) to test feasibility of stroke volume monitoring using electrical cardiometry or ultrasound during transportation and 2) to investigate if transportation impacts on electrical cardiometry and ultrasound reliability. DESIGN: Prospective, pragmatic, feasibility cohort study. SETTING: Mobile ICUs specialized for neonatal and pediatric transportation. PATIENTS: Thirty hemodynamically stable neonates and infants. INTERVENTIONS: Patients enrolled underwent paired stroke volume measurements (180 before/after and 180 during the transfer) by electrical cardiometry (SVEC) and ultrasound (SVUS). MEASUREMENTS AND MAIN RESULTS: No problems or malfunctioning occurred neither with electrical cardiometry nor with ultrasound. Ultrasound lasted on average 90 (10) seconds, while 45 (15) seconds were needed to instigate electrical cardiometry monitoring. Coefficient of variation was higher for SVUS (before/after: 0.57; during: 0.66) than for SVEC (before/after: 0.38; during: 0.36). Correlations between SVEC and SVUS before/after and during the transfer were r equal to 0.57 and r equal to 0.8, respectively (p always < 0.001). Bland-Altman analysis showed that stroke volume tends to be higher if measured by electrical cardiometry. SVEC measured before (5.5 [2.4] mL), during (5.4 [2.4] mL), and after the transfer (5.4 [2.3] mL) are similar (p = 0.955); same applies for SVUS before (2.6 [1.5] mL), during (2.4 [2] mL), and after (2.9 [2] mL) the transfer (p = 0.268). CONCLUSIONS: Basic hemodynamic monitoring is feasible during pediatric and neonatal transportation both with electrical cardiometry and ultrasound. These two techniques show comparable reliability, although stroke volume was higher if measured by electrical cardiometry. The transportation itself does not affect the reliability of stroke volume measurements. PMID- 28800002 TI - Finding the sweet spot for metformin in 18F-FDG-PET. AB - PURPOSE: The effect of oral hypoglycemic agents on fluorine-18-flurodeoxyglucose (F-FDG) uptake is less understood than the effect of exogenous insulin. In this study, the effect of withholding metformin on F-FDG distribution in subsequent PET imaging was evaluated. PATIENTS AND METHODS: A retrospective observational study was carried out. A total of 15 patients taking metformin were grouped according to the time interval from the last dose of metformin to F-FDG-PET. Those who received PET after stopping metformin for less than 24 h were compared with those stopping metformin 24-48 h before PET. The F-FDG uptake and PET image fidelity for these groups were compared qualitatively and the associated blood glucose was recorded. The average standardized uptake value of the liver, tongue, and subcutaneous tissues among the groups were also compared. RESULTS: The F-FDG PET distribution and image quality were found to be the best at time points greater than 24 h following metformin dose. There was significantly increased F FDG uptake in the liver and tongue and tongue-to-liver ratio in patients who had metformin within 24 h of F-FDG-PET compared with those who last had metformin greater than 24 h before F-FDG-PET; however, the F-FDG uptake in the subcutaneous tissues was unchanged. CONCLUSION: Less than 24 h between metformin dose and F FDG-PET resulted in increased muscle and fat uptake in addition to increased bowel uptake. Abnormal F-FDG uptake can limit the diagnostic quality of an exam and affect F-FDG uptake in cancer. The emerging role of biguanides in the treatment of cancer calls for more personalized standardization for F-FDG-PET in the presence of oral hypoglycemic agents. PMID- 28800003 TI - Evaluation of tomographic image quality of extended and conventional parallel hole collimators using maximum likelihood expectation maximization algorithm by Monte Carlo simulations. AB - OBJECTIVE: One of the major problems associated with parallel hole collimators (PCs) is the trade-off between their resolution and sensitivity. To solve this problem, a novel PC - namely, extended parallel hole collimator (EPC) - was proposed, in which particular trapezoidal denticles were increased upon septa on the side of the detector. MATERIALS AND METHODS: In this study, an EPC was designed and its performance was compared with that of two PCs, PC35 and PC41, with a hole size of 1.5 mm and hole lengths of 35 and 41 mm, respectively. The Monte Carlo method was used to calculate the important parameters such as resolution, sensitivity, scattering, and penetration ratio. A Jaszczak phantom was also simulated to evaluate the resolution and contrast of tomographic images, which were produced by the EPC6, PC35, and PC41 using the Monte Carlo N-particle version 5 code, and tomographic images were reconstructed by using maximum likelihood expectation maximization algorithm. RESULTS: Sensitivity of the EPC6 was increased by 20.3% in comparison with that of the PC41 at the identical spatial resolution and full-width at tenth of maximum here. Moreover, the penetration and scattering ratio of the EPC6 was 1.2% less than that of the PC41. The simulated phantom images show that the EPC6 increases contrast-resolution and contrast-to-noise ratio compared with those of PC41 and PC35. CONCLUSION: When compared with PC41 and PC35, EPC6 improved trade-off between resolution and sensitivity, reduced penetrating and scattering ratios, and produced images with higher quality. EPC6 can be used to increase detectability of more details in nuclear medicine images. PMID- 28800004 TI - Sport-Specific Repeated Sprint Training Improves Punching Ability and Upper-Body Aerobic Power in Experienced Amateur Boxers. AB - Kamandulis, S, Bruzas, V, Mockus, P, Stasiulis, A, Snieckus, A, and Venckunas, T. Sport-specific repeated sprint training improves punching ability and upper-body aerobic power in experienced amateur boxers. J Strength Cond Res 32(5): 1214 1221, 2018-High-intensity interval training improves endurance and performance, but it is unclear whether sprint-type upper-body interval training is similarly effective. This study explored the effects of 4-week sport-specific sprint interval training on punch characteristics and endurance capacity in boxers. Experienced male amateur boxers (n = 18) participated in this 4-week training study and were divided into an experimental group (EG) and a control group (CG) (n = 9 per group). Both groups completed standard low-intensity training. The EG also completed 3 rounds (14 sets of 3-second all-out punching with a 10-second rest) of a simulated fight using a punching bag with a 1-minute rest between rounds 3 times per week, whereas the CG performed the same 3 rounds of a simulated fight at low intensity. Three rounds of 14 sets of 3-second all-out punching of a bag ergometer with a 10-second rest were performed to measure punching abilities. Peak oxygen consumption and peak power were measured during progressive arm cranking before and after training. In response to training peak oxygen consumption and peak power in arm-cranking test increased in EG, also punching force increased and maintenance of punching frequency and punch force improved during the simulated fight, which resulted in greater cumulative force throughout the 3 rounds. There were no changes in the CG. The study shows that 1 month of all-out punching training (3 sessions per week with ~2 minutes of all out punching per session) improved both upper-body aerobic power and punching abilities in experienced amateur boxers. PMID- 28800005 TI - The Effects of British Army Footwear on Ground Reaction Force and Temporal Parameters of British Army Foot-Drill. AB - High rates of occupational training-related lower-limb musculoskeletal [MSK] overuse injuries are reported for British Army recruits during basic training. Foot-drill is a repetitive impact loading occupational activity and involves striking the ground violently with an extended-knee [straight-leg] landing. Foot drill produces vertical ground reaction forces [vGRF] equal to and/or greater than those reported for high-level plyometric exercises/activities. Shock absorbing footwear aid in the attenuation of the magnitude of vGRF, resulting in a reduced risk of lower-limb MSK overuse injury when running. The potential shock absorbing characteristics of standard issue British Army footwear on the magnitude of vGRF and temporal parameters of foot-drill are scant. Therefore, this study sought to determine the magnitude of, and examine changes in vGRF and temporal parameters of foot-drill across three types of British Army footwear. Sampled at 1000hz, the mean of eight-trials from fifteen recreationally active males were collected from four foot-drills; stand-at-ease [SaE], stand-at attention [SaA], quick-march [QM] and halt. Analysis of a normal walk was included to act as a comparison with quick-march. Significant main effects [P<0.05] were observed between footwear and foot-drill. The training shoe demonstrated significantly greater shock absorbing capabilities when compared with the combat boot and ammunition boot. Foot-drill produced peak vGRF and peak vertical rate of force development in excess of 5bw, and 350bw/sec, respectively. Time to peak vGRF ranged from 0.016- 0.036ms across foot-drills, indicating that passive vGRF may not be under neuromuscular control. The marginal reductions in the magnitude of vGRF and temporal parameters in foot-drill associated with the training shoe may act to reduce the accumulative impact loading forces experienced by recruits, subsequently minimising the severity and rates of lower limb MSK overuse injuries and recruit medical discharges during basic training. PMID- 28800006 TI - Match Demands of Senior and Junior Players During International Rugby League. AB - Dempsey, GM, Gibson, NV, Sykes, D, Pryjmachuk, BC, and Turner, AP. Match demands of senior and junior players during International Rugby League. J Strength Cond Res 32(6): 1678-1684, 2018-This study aims to quantify and compare the positional game demands of international junior and senior rugby league competition for the first time. Global positioning system (GPS) and video analysis were used to track 118 elite male rugby league players (57 seniors aged 28.7 +/- 4.4 years; 61 juniors aged 17.2 +/- 0.5 years) over 10 international matches (6 senior; 4 junior) characterized as either forwards (n = 67) or backs (n = 51). There were significant increases in the offensive carries (0.18 cf. 0.09 n.min; r = 0.56) and defensive tackles (0.36 cf. 0.23 n.min; r = 0.3) between senior and junior players, and forwards and backs (0.16 cf. 0.09; r = 0.34 and 0.41 cf. 0.14; r = 0.52), respectively. Running demands were significantly greater in backs than forwards (independent of playing level) for total distance (6,962 +/- 1,263 m cf. 4,879 +/- 1,824 m; r = 0.55), individualized high-speed distances (310 +/- 158 m cf. 250 +/- 171 m; r = 0.2), high-intensity accelerations (28.7 +/- 12.1 m.s cf. 21.9 +/- 11.7 m.s; r = 0.27), and decelerations (57.2 +/- 18.3 m.s cf. 43.0 +/- 17.8 m.s; r = 0.38). Positional differences were eliminated when reported relative to minutes played. From a practical perspective, although running demands relative to time on the pitch may prepare junior players for senior competition, it is not representative of the increased body mass and contact frequency within the senior game. Coaches should therefore reflect these differences within their physical preparation programs to prepare junior athletes accordingly for progression to the senior level. PMID- 28800007 TI - Comparison of Epidermal Growth Factor Receptor Gene Mutations Identified Using Pleural Effusion and Primary Tumor Tissue Samples in Non-Small Cell Lung Cancer. AB - BACKGROUND: Although the use of pleural effusion samples for epidermal growth factor receptor (EGFR) testing in lung cancer is increasing, the accuracy rate and effectiveness of identifying EGFR mutations using these samples, rather than primary tumor tissue samples, is not established. MATERIALS AND METHODS: One hundred ninety-two advanced, non-small cell lung cancer patients were enrolled into this study. All patients had primary tumor tissue and corresponding pleural effusion samples, and we employed the Amplification Refractory Mutation System to detect EGFR gene mutations in these samples. RESULT: The number of EGFR mutations detected in primary tumor tissue and pleural effusion samples was 119 (61.98%) and 113 (58.85%), respectively. The EGFR-mutation rate was significantly higher in female than in male patients, and in adenocarcinoma than in nonadenocarcinoma patients (P=0.000). Single mutations in exons 19 and 21 were the predominant observed mutation type, and the overall concordance rate of EGFR-mutation status between the 192 matched pleural effusion and primary tumor tissue samples was 86.98%. CONCLUSIONS: We observed a high concordance rate between EGFR mutations identified using primary tumor tissue and corresponding pleural effusion samples by Amplification Refractory Mutation System. Thus, it is likely that pleural effusion sampling from advanced non-small cell lung cancer patients, especially those with adenocarcinoma, may be effective in EGFR-mutation screening. PMID- 28800008 TI - Epstein Barr Virus Infection Can be a Secondary Event in B-Cell Lymphomas: A Review of 338 Cases and a Novel Finding of Zonal EBER+ Tumor Cells Showing Features of Progression From Underlying EBV-negative Lymphoma. AB - Cases of B-cell lymphoma over an 8-year interval with diagnosis of EBER positivity were retrieved from archives and reviewed for classification and pattern of Epstein Barr Virus (EBV) expression. Of 46 cases that were EBV early RNA (EBER)+ by in situ hybridization staining, 7 had nonuniform staining among the neoplastic cells. Four of those cases showed a uniform admixture of EBER+ and EBER- tumor cells, compatible with the prevailing theory of episomal EBV loss with cell replication. Three cases of lymphomas showed a partial and zonal pattern and other features suggest that EBV infection occurred after the lymphoma was already established. In case 1, an EBV-negative follicular lymphoma and an EBV+ diffuse large B-cell lymphoma (DLBCL) of activated B cell type were contiguous in a lymph node. Both components showed a BCL2 translocation by fluorescence in situ hybridization. In case 2, a DLBCL of germinal center type in an human immunodeficiency virus positive patient contained clusters of EBR+ lymphoma cells with Reed-Sternberg morphology and shift to an activated B-cell immunophenotype. In case 3, an ulcerated and perforated DLBCL in the stomach showed a superficial swath of EBER+ tumor cells accompanied by a relative absence of reactive T cells. In all 3 cases the tumor cells in EBER+ areas expressed latent membrane protein-1 and showed strong CD30 positivity. All 3 patients were treated with chemotherapy are currently in remission. Heterogenous EBER positivity has been reported previously in DLBCLs, attributed to loss of the episomal viral DNA from a subset of fully transformed tumor cells. Previously reported cases did not include description of zonation of EBV or phenotypic differences correlating with the presence of EBV. The cases reported here suggest that in a subset of EBV+ DLBCLs, EBV infection may not be the "first hit." PMID- 28800009 TI - Pathologic Prognostic Factors of Pineal Parenchymal Tumor of Intermediate Differentiation. AB - INTRODUCTION: Pineal parenchymal tumor of intermediate differentiation (PPTID) is an uncommon tumor of the pineal gland. Although this behaves as a grade II/III tumor, the exact clinical behavior is not well known. There is no well established pathologic factor that can predict the behavior of PPTID. AIM AND OBJECTIVE: The aim of this study was to determine the pathologic prognostic factors in PPTID. MATERIALS AND METHODS: All PPTID cases diagnosed between 2006 and 2016 were analyzed retrospectively. Immunohistochemistry for synaptophysin, neurofilament protein (NFP), glial fibrillar acid protein, NeuN, and Ki-67 were performed in all cases. Cases were classified arbitrarily into low grade (mitosis <4/10 hpf and Ki-67 <5%) and high grade (mitosis >=4/10 hpf and Ki-67 >=5%). Clinical details including follow-up information were retrieved from the patients' files. RESULTS: A total of 16 patients (6 low grade and 10 high grade) were included in this study. The age ranged from 2 to 55 years (average, 28.2) with a mild male preponderance (male:female, 1.67:1). All cases showed strong and diffuse positivity for synaptophysin. Focal NFP positivity was seen in 2 low grade and 3 high-grade tumors. Only 2 cases showed focal NeuN positivity. Average Ki-67 index was 1.7% and 12.6% in low-grade and high-grade tumors, respectively. All patients with low-grade tumor were alive without recurrence. Among the patients with high-grade tumors, 2 had local recurrence, 1 had spinal metastasis, and 3 patients died. CONCLUSION: Mitosis and Ki-67 proliferation index are the most important pathologic prognostic factors in PPTID. NFP expression does not carry any prognostic significance. PMID- 28800010 TI - Cell Polarity Reversal Distinguishes True Micropapillary Growth From Retraction Artifact in Invasive Urothelial Carcinoma. AB - Focal micropapillary features in invasive urothelial carcinoma is sometimes difficult to distinguish from retraction artifact morphologically. Cell polarity reversal has been demonstrated in micropapillary tumors by epithelial membrane antigen (EMA) immunostaining. We have previously described the use of E-cadherin as a cell polarity marker in ovarian micropapillary serous borderline tumors. The aim of this study was to evaluate the utility of immunohistochemistry for EMA and E-cadherin in differentiating micropapillary urothelial carcinoma from retraction artifact. We identified 29 invasive urothelial carcinomas with micropapillary features and 30 invasive urothelial carcinomas without reported micropapillary features but with areas of retraction artifact. Cell polarity reversal was considered present if E-cadherin showed membranous apical cup-like staining or if EMA demonstrated a well-defined basal staining towards the stroma. Twenty-seven of 29 cases (93%) of urothelial carcinoma with micropapillary features demonstrated EMA or E-cadherin staining patterns consistent with cell polarity reversal. Staining consistent with micropapillary architecture was identified with both markers in 20 of these 27 cases (74%). Six cases showed reversal of polarity by E-cadherin alone, whereas 1 case showed polarity reversal by EMA alone. Retraction artifacts showed circumferential staining by E-cadherin and lacked well-defined basal staining by EMA. Three cases originally classified as with retraction artifact showed reversal of cell polarity by both EMA and E cadherin and were reclassified as micropapillary. Our data show that pathologists can reliably make this distinction in most cases. However, in some cases with ambiguous features, EMA and E-cadherin immunostaining may aid in resolving this diagnostic dilemma. PMID- 28800011 TI - RNA In Situ Hybridization for Epstein-Barr Virus and Cytomegalovirus: Comparison With In Situ Hybridization and Immunohistochemistry. AB - The RNAscope utilizes in situ hybridization (RISH) technology to detect single RNA molecules in a variety of tissue samples, including formalin fixed paraffin embedded (FFPE) tissues. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are found in association with neoplastic tissues and inflammatory lesions, and immunohistochemistry (IHC) or other techniques (ISH) are utilized to identify them. We compared the RNAscope RISH to ISH and IHC in the detection of EBV and CMV respectively to determine RNAscope utility in a clinical setting. Thirty-one FFPE tissues were stained by RISH to detect EBV and 24 samples of tissue for CMV. The RISH used the RNAscope (Leica BioSystems, Buffalo Grove, IL), the Bond III autostainer (Leica), and probes V-EBV and V-CMV (Advanced Cell Diagnostics, Newark, CA) as well as negative (DapB) and positive probe (PPIB) for RNA. Results were compared with those by ISH (Leica, EBV RNA probe), and IHC (CMV Dako, 1/160), respectively. RISH and ISH were concordant in 100% of cases positive for EBV by ISH (19/19). Of the cases negative for EBV by ISH, RISH showed positivity in an additional 25% of the samples (3/12). Overall concordance was 90.3% (28/31). RISH and IHC were concordant in 100% of cases positive for CMV by IHC (8/8). Of the cases negative for CMV by IHC, RISH detected positivity in an additional 50% of the samples (8/16). Overall concordance was 66.7% (16/24). RISH demonstrates increased sensitivity in the clinical setting, especially for CMV, detecting positive cells not stained by EBV ISH and CMV IHC. PMID- 28800012 TI - Quality Assessment of Prognostic Studies Using Cancer Stem Cell Markers in Oral Squamous Cell Carcinoma. AB - Cancer stem cells (CSC) have been investigated as prognostic markers in oral squamous cell carcinoma (OSCC). However, an assessment of the reporting quality of these studies has not been performed yet. The aim of this study was to describe the reporting quality of prognostic studies involving CSCs and OSCC, focusing mainly on the immunohistochemical reproducibility. By means a systematic review, 34 articles were selected. Analyses of both general reporting quality and immunohistochemistry technique were performed by using checklists for multiple aspects related to study reproducibility. A total of 21 different CSC markers were cited in the selected studies, evaluated by means of a wide range of antibodies, most of them (40.3%) without clone description. Discrepancies in intracellular immunolabeling were noted for some markers. The mean global score for general quality assessment revealed limits in the quality of the articles. The main problems were related to lack of report on OSCC characteristics and treatment, sample size rationale, and sensitivity analysis or internal validation of the markers. Although there was a high frequency of studies having "good or very good" score for immunohistochemistry reproducibility, the frequency of articles with "poor or very poor" score for individual items was expressive, mainly for description of immunolabeling analysis (38.2% of the studies were poorly described). In conclusion, although there is a significant range of CSC markers with promising results for prognosis of OSCC, the inadequate reporting of important sections in the published studies, including immunohistochemistry technique, may limit the quality of the investigation. PMID- 28800013 TI - Metastatic Acinic Cell Carcinoma to the Vagina: A First Reported Case. AB - This is a case of a 62-year-old woman with a remote history of acinic cell carcinoma of the parotid gland, who presented with a palpable vaginal mass, anterior vaginal wall prolapse, and stress urinary incontinence. A 2 cm firm mobile mass on the anterior vaginal wall was found on clinical examination. A computed tomographic scan revealed a mass between the vaginal vault and bladder that was eventually surgically excised. The histology, supported by the immunohistochemistry, revealed metastatic acinic cell carcinoma to the vagina after 37 years of her initial diagnosis. This is the first reported case in the literature to occur in the vagina. PMID- 28800014 TI - Large Tumefactive IgG4-related Disease: Histologic, Cytologic, and Immunohistochemical Features of a Very Unusual Case. AB - Immunoglobulin G4-related disease (IgG4-RD) is a regional or systemic multiorgan lymphoplasmacytic inflammatory disease of unknown etiology. It has been described in numerous organs and anatomic locations. Review of the literature shows that when the disease involves the retroperitoneum it causes retroperitoneal fibrosis. Tumefactive IgG4-RD of the retroperitoneum has not been previously reported. In this report, we describe the first case of a large retroperitoneal tumefactive IgG4-RD along with its histologic, cytologic, and immunohistochemical characteristics. PMID- 28800015 TI - The Utility of NKX2.2 and TLE1 Immunohistochemistry in the Differentiation of Ewing Sarcoma and Synovial Sarcoma. AB - Although molecular testing can definitively distinguish Ewing sarcoma (EWS) from synovial sarcoma (SS) it is frequently desirable to provide a confident preliminary diagnosis before such analysis can be completed. Recently, the nuclear markers NKX2.2 and TLE1 have been shown to have good sensitivity but imperfect specificity, respectively, for EWS and SS. However, the performance of these markers has not been extensively evaluated within this specific differential diagnosis. This study performed NKX2.2, TLE1, and CD99 immunohistochemistry in a group of EWS and SSs confirmed by reverse transcription polymerase chain reaction to evaluate the utility of these novel markers in this context. NKX2.2 staining was overall 75% sensitive and 91.7% specific for EWS and was never seen in SS. Although the specificity of TLE1 staining was impacted by antibody used, it was at best only 75% specific for SS. However, a lack of reactivity had a 100% negative predictive value against a SS diagnosis. Overall, immunohistochemistry for NKX2.2 and TLE1 can provide a useful first step in helping to distinguish EWS and SS. PMID- 28800016 TI - FISH Analysis of TOP2A and HER-2 Aberrations in Female Breast Carcinoma on Archived Material: Egyptian NCI Experience. AB - BACKGROUND: HER-2 and TOP2A genes are considered of great importance in breast cancer. Their copy number variability has been proposed to be a marker for the degree of chromosomal instability. Owing to the close proximity of TOP2A gene to HER-2 gene chromosome 17, TOP2A status is believed to affect therapeutic plan. The percentage of TOP2A aberrations is greatly variable among different studies. AIM OF WORK: Is to investigate the relation between TOP2A and HER-2 gene amplification using fluorescence in situ hybridization technique. MATERIALS AND METHODS: Archival blocks of 112 breast cancer Egyptian female patients were retrieved from the pathology department at NCI, Cairo University were retrieved and investigated using fluorescence in situ hybridization technique for TOP2A and HER-2 gene assessment. In addition, correlation with some clinicopathologic parameters was done. RESULTS: HER-2 gene amplification was encountered in about 33% of cases. TOP2A gene amplification and deletion were detected in 23.9% and 2.8% of studied cases. Moderate agreement was obtained between results of HER-2 gene and TOP2A gene amplification. CONCLUSIONS: HER-2 and TOP2A genes amplification are 2 separate genetic yet closely related events in breast cancer. Polysomy of chromosome 17 is proposed to be an early event in occurrence of TOP2A gene amplification. Further studies regarding effect of TOP2A gene in response to anthracyclines in Egyptian population should be planned for to establish its role in therapeutic planning. PMID- 28800017 TI - ATYPICAL FORM OF RETINOPATHY OF PREMATURITY WITH SEVERE FIBROVASCULAR PROLIFERATION IN THE OPTIC DISK REGION. AB - PURPOSE: To describe severe fibrovascular proliferation that developed in the optic disk region in an atypical form of retinopathy of prematurity (ROP). METHODS: Retrospective observational case reports. RESULTS: Four patients (8 eyes) with ROP were included. Three patients were born very prematurely (24-25 weeks of gestational age; weight, 500-1,000 grams); 1 patient was born at 33 weeks of gestational age. Among all eight eyes of four patients who received prompt ROP screening and underwent laser photocoagulation, six eyes had atypical and severe fibrovascular proliferation mainly in the optic disk region; the other two eyes, including one eye with classic ROP and one eye with aggressive posterior ROP, did not have the atypical form. All eight eyes had a total to partial retinal detachment. Among the six eyes with the atypical form, early vitreous surgery with lensectomy was possible in three eyes; only late vitreous surgery with lensectomy was possible in two eyes; one eye was inoperable. Three eyes had a partial or complete reattachment, whereas three eyes had a total retinal detachment. Among the six eyes with atypical fibrovascular proliferation, only two eyes obtained light perception vision. CONCLUSION: An atypical and severe form of ROP, in which fibrovascular proliferation grew mainly from the optic disk region, needs further investigation for treatment in addition to laser photocoagulation and vitreous surgery. PMID- 28800018 TI - THE EXPANDING CLINICAL SPECTRUM OF CHOROIDAL EXCAVATION IN MACULAR DYSTROPHIES. AB - PURPOSE: To assess the prevalence and the clinical course of focal choroidal excavation (FCE) in patients affected by macular dystrophies. METHODS: Prospective case series. All the patients underwent a complete ophthalmologic examination, including best-corrected visual acuity and spectral domain optical coherence tomography. The presence of choroidal neovascularization (CNV) was assessed on the basis of the leakage detected on fluorescein angiography. RESULTS: A total of 162 eyes from 81 patients with macular dystrophy were included in the study. FCE was diagnosed in seven eyes (4.3% of the eyes), including four eyes with Best vitelliform dystrophy, two eyes with pattern dystrophy associated with pseudoxanthoma elasticum, and one case of Stargardt disease. In eyes with FCE and macular dystrophy, the mean best-corrected visual acuity was 0.4 +/- 0.1 logarithm of the minimum angle of resolution (approximately corresponding to 20/50 Snellen equivalent) at baseline and was stable to 0.41 +/- 0.1 logarithm of the minimum angle of resolution (approximately corresponding to 20/50 Snellen equivalent) at the final visit. In four of these seven eyes, FCE was associated with a subfoveal CNV. The CNV was managed with one intravitreal anti-vascular endothelial growth factor injection, achieving the complete anatomical stabilization of the CNV and recovery of the best-corrected visual acuity. CONCLUSION: Focal choroidal excavation can be infrequently encountered in patients with macular dystrophies. The presence of CNV may complicate FCE in these patients, and anti-vascular endothelial growth factor seems to be an effective treatment with no progression of FCE over time. PMID- 28800019 TI - THE NATURAL HISTORY OF FULL-FIELD STIMULUS THRESHOLD DECLINE IN CHOROIDEREMIA. AB - PURPOSE: To evaluate full-field sensitivity thresholds (FSTs) across a wide range of choroideremia (CHM) disease stages and to determine their applicability as functional endpoints for CHM clinical trials. METHODS: Thirty CHM subjects (60 eyes) and 50 healthy controls (50 eyes) underwent FST testing under dark-adapted conditions to determine rod- and cone-mediated FSTs. Central retinal structure and function were assessed using fundus autofluorescence and microperimetry. Correlation and regression analyses were performed to compare FST responses with the residual area of retinal pigment epithelium in the peri- and parafoveal regions, as well as the mean and highest macular microperimetry sensitivity. RESULTS: All patients with CHM had a baseline of 18 dB elevation in dark-adapted rod FSTs, including the least affected individuals. Further FST sensitivity loss was exponentially associated with decrease in the area of residual peri- and parafoveal retinal pigment epithelium, with precipitous loss of sensitivity noted for fundus autofluorescence areas less than 5 mm. Cone FSTs were comparable with controls, except for advanced stages of CHM. Full-field sensitivity threshold responses showed high correlation with both mean and highest macular microperimetry thresholds (P < 0.001). In some cases of absent macular fundus autofluorescence, the peripheral retina could contribute to detectable rod FST responses but with severely diminished cone-driven responses. CONCLUSION: Full field sensitivity threshold testing demonstrated a baseline level of rod dysfunction in CHM present in all rod photoreceptors. Further decline in FST responses correlated strongly with the extent of central retina structural and functional loss. Full-field sensitivity threshold allowed quantification of residual rod function in peripheral islands of vision, which cannot be reliably achieved with other conventional tests. As such, the FST can serve as a complimentary tool to guide patient selection and expand the eligibility criteria for current and future CHM clinical trials. PMID- 28800020 TI - Correspondence. PMID- 28800021 TI - Correspondence. PMID- 28800022 TI - Reply. PMID- 28800023 TI - Reply. PMID- 28800024 TI - The roles of dermal white adipose tissue loss in scleroderma skin fibrosis. AB - PURPOSE OF REVIEW: Dermal white adipose tissue (DWAT) is distinct from subcutaneous white adipose tissue and is lost in scleroderma skin fibrosis. The roles of DWAT loss in scleroderma skin fibrosis have not been well understood, and here we discuss recent findings that begin to provide insight into the multiple mechanisms involved. RECENT FINDINGS: The DWAT loss in part reflects the direct contribution of DWAT cells to the fibrotic tissue, with the reprogramming of adipocytes to myofibroblasts. The DWAT contains reparative adipose-derived stromal cells and expresses antifibrotic cytokines such as adiponectin, and the loss of these skin-protective mechanisms with DWAT loss further contributes to skin fibrosis and injury. SUMMARY: Potentially, halting or reversing the transdifferentiation of adipocytes to myofibroblasts along with improving survival of reparative adipose-derived stromal cells (ADSCs) and expression of antifibrotic cytokines may be effective therapeutic avenues. PMID- 28800025 TI - Bile Acid Replacement in Bile Acid Synthesis Defects. PMID- 28800026 TI - ESPGHAN Distinguished Service Award 2017 to Professor Olivier Goulet. PMID- 28800027 TI - Economic burden of advanced melanoma in France, Germany and the UK: a retrospective observational study (Melanoma Burden-of-Illness Study). AB - The aim of this study was to estimate the cost-of-illness associated with completely resected stage IIIB/IIIC melanoma with macroscopic lymph node involvement, overall and by disease phase, in France, Germany and the UK. This retrospective observational study included patients aged older than or equal to 18 years first diagnosed with stage IIIB/IIIC cutaneous melanoma between 1 January 2009 and 31 December 2011. Data were obtained from medical records and a patient survey. Direct costs, indirect costs and patient out-of-pocket expenses were estimated in euros (?) (and British pounds, L) by collecting resource use and multiplying by country-specific unit costs. National annual costs were estimated using national disease prevalence from the European cancer registry and other published data. Forty-nine centres provided data on 558 patients (58.2% aged <65 years, 53.6% stage IIIB disease at diagnosis). The mean follow-up duration was 27 months (France), 26 months (Germany) and 22 months (UK). The mean total direct cost per patient during follow-up was ?23 582 in France, ?32 058 in Germany and ?37 970 (L31 123) in the UK. The largest cost drivers were melanoma drugs [mean ?14 004, ?21 269, ?29 750 (L24 385), respectively] and hospitalization/emergency treatment [mean: ?6634, ?6950, ?3449 (L2827), respectively]. The total mean indirect costs per patient were ?129 (France), ?4,441 (Germany) and ?1712 (L1427) (UK). Estimates for annual national direct cost were ?13.1 million (France), ?30.2 million (Germany) and ?27.8 (L22.8) million (UK). The economic burden of stage IIIB/IIIC melanoma with macroscopic lymph node involvement was substantial in all three countries. Total direct costs were the highest during the period with distant metastasis/terminal illness. PMID- 28800028 TI - Current status and future direction in the management of malignant melanoma. AB - The incidence of malignant melanoma is increasing rapidly on a global scale. Although some types of melanoma, for example primary cutaneous melanoma, can be managed by surgery, metastatic melanoma cannot and it has a high mortality rate. Both oncogene and immune-targeted strategies have shown marked efficacy in some patients, but their effect on overall survival is still variable. Therefore, newer therapeutic approaches are needed. Fortunately, new advances in molecular medicine have led to an understanding of an individual patient's cancer at the genomic level. This information is now being used in all stages of cancer treatment including diagnosis, treatment selection, and treatment monitoring. This new strategy of personalized medicine may lead to marked shifts in immunotherapeutic treatment approaches such as individualized cancer vaccines and adoptive transfer of genetically modified T cells. This review provides an overview of recent approaches in cancer research and expected impact on the future of treatment for metastatic melanoma. PMID- 28800029 TI - The role of depression and personality traits in patients with melanoma: a South European study. AB - We explored the potential association of depression history and personality, evaluated through a robust questionnaire tool, namely the Eysenck Personality Scale, with disease risk and progression among Greek patients. A total of 106 melanoma patients and their 1 : 1 sex-matched controls were interviewed on the basis of a questionnaire comprising phenotypic, sociodemographic, lifestyle and medical history variables, as well as information on history of lifetime major depression. The Eysenck Personality Questionnaire, measuring the four personality dimensions (extraversion, neuroticism, psychoticism, lie), was thereafter completed. Adjusted odds ratios (ORs) for melanoma risk were derived through multiple logistic regression analyses, whereas potential predictors of survival were explored using Cox proportional hazards models. Sun sensitivity score [OR: 1.55, 95% confidence interval (CI): 1.16-2.06] and major depression history (OR: 5.72, 95% CI: 1.38-23.73) were significantly associated with melanoma, whereas inverse associations of extraversion (OR: 0.90, 95% CI: 0.83-0.97) and psychoticism score (OR: 0.88, 95% CI: 0.78-1.00) were noted. These associations were more pronounced and remained solely among female patients; notably, decreased extraversion (OR: 0.86, 95% CI: 0.76-0.98) and psychoticism score (OR: 0.63, 95% CI: 0.43-0.91), as well as increased depression history (OR: 10.69, 95% CI: 1.43-80.03) were evident. Cox-derived hazard ratios showed nonsignificant associations of depression history and personality with disease outcome. Our data support the hypotheses that depression history and personality are associated with melanoma risk. No effect on survival after cancer diagnosis was observed. If confirmed in future studies, these associations may contribute toward better understanding the etiology of melanoma, enhancing health-related quality of life. PMID- 28800030 TI - Response to targeted therapy in two patients with metastatic melanoma carrying rare BRAF exon 15 mutations: A598_T599insV and V600_K601delinsE. AB - Concurrent BRAF-MEK inhibition improves clinical outcomes in patients with advanced BRAF V600E/K-mutant melanoma. There is currently less evidence for the efficacy of this treatment in patients with rare BRAF non-V600E/K genotypes. We report on two patients with rare BRAF exon 15 mutations - BRAF A598_T599insV and V600_K601delinsE - obtaining clinical benefit and a radiological response to inhibitors directed against the mitogen-activated protein kinase pathway. This highlights the importance of using tests that detect both V600E/K and non-V600E/K BRAF mutations to keep open the possibility of treatment with targeted therapy in patients with uncommon, yet potentially actionable, BRAF exon 15 mutations. PMID- 28800031 TI - Risk factors for development of melanoma brain metastasis and disease progression: a single-center retrospective analysis. AB - Melanoma metastasis to the brain is associated with a poor prognosis. We sought to determine patient demographics and primary tumor factors associated with the development of brain metastasis (BM) and survival. We also investigated whether the BM detection setting (routine screening vs. symptomatic presentation) affected clinical outcomes. A database of melanoma patients seen from 1999 to 2015 at our institution was reviewed to identify patients who developed BM. Patients with BM were matched by initial stage with patients who did not develop BM as a control group. Patient demographics, primary tumor characteristics, and clinical outcomes were analyzed. A total of 123 patients with BM were matched by initial presenting stage to 237 patients without BM. The characteristics of the primary melanoma tumor associated with BM development included location on the scalp (P=0.030), nodular histologic type (P=0.020), and Breslow depth more than 4 mm (P=0.048), whereas location on the leg was associated with decreased BM risk (P=0.006). In patients with BM, time to first recurrence for melanomas of the scalp was significantly shorter (10.8 vs. 24.8 months, P=0.007) than nonscalp head and neck tumors. Patient stage, tumor depth, nodular type, and ulceration were also associated with worse clinical outcomes. There were no differences in the clinical outcomes between patients whose BM were detected upon routine screening versus those detected upon symptomatic presentation. In summary, factors predictive of development of BM included primary scalp location, nodular type, and depth. In BM patients, scalp location, stage, tumor depth, nodular type, and ulceration, but not detection setting, were associated with worse clinical outcomes. PMID- 28800032 TI - Malignant melanoma incidence trends in a Mediterranean population following socioeconomic transition and war: results of age-period-cohort analysis in Croatia, 1989-2013. AB - The aim of this study was to analyse trends of malignant melanoma incidence in Croatia for men and women of different age groups by birth cohorts and time periods, and to interpret them in the context of national socioeconomic changes over time and the possible implications for future prevention in South-Eastern European postcommunist countries with high mortality rates. We used the Croatian National Cancer Registry data to analyse incidence trends of malignant melanoma of the skin (ICD-9 code 172 and ICD-10 code C43) in men and women aged 25-79 years by age-period-cohort modelling. Over the 25-year period, the incidence was increasing by 5.0% annually in men and 4.6% in women. The age-period model provided the best fit for data in both sexes, with steeply increasing incidence rates, followed by a stabilization after the 2000s. On the cohort scale, incidence rates increased in successive generations of men, whereas in women, the risk of malignant melanoma attenuated in recent cohorts. Even if some progress has been achieved in recent years, the increasing melanoma incidence without concomitant declines in mortality would indicate a need to rekindle prevention efforts in the country taking the specific socioeconomic context into account. PMID- 28800034 TI - The association of proton pump inhibitor therapy and small bowel bacterial overgrowth in children. PMID- 28800033 TI - Predictors of early discontinuation of interferon-free direct antiviral agents in patients with hepatitis C virus and advanced liver fibrosis: results of a real life cohort. AB - AIM: The aim of this study was to determine risk factors for premature treatment discontinuation among patients with hepatitis C and advanced fibrosis with advanced fibrosis treated with interferon (IFN)-free direct antiviral agents (DAA)-based therapy. PATIENTS AND METHODS: We included all patients with chronic hepatitis C virus infection and advanced liver fibrosis in whom treatment was initiated with IFN-free DAA therapy at a university hospital from December 2015 through June 2016. We prospectively collected data from medical records using standardized questionnaires and evaluated them using Epi Info 7.1.2.0. The primary outcome was treatment interruption and associated factors. RESULTS: In total, 214 patients were included in this study; 180 patients were treated with sofosbuvir (SOF)+daclatasvir+/-ribavirin (RBV), 31 received SOF+simeprevir+/-RBV, and three were treated with SOF+RBV. Treatment discontinuation rate was 8.9% (19 patients) and cirrhotic decompensation was the main reason [8 (42.1%)]. Among patients with Child B or C cirrhosis (31), 10 (32.2%) prematurely interrupted treatment. The risk factors for treatment discontinuation in univariate analysis were older age (P=0.0252), higher comorbidity index (P=0.0078), higher model for end-stage liver disease (P<0.0001), higher fibrosis index based on the 4 factores (P=0.0122), and lower hemoglobin (P=0.0185) at baseline. Multivariate analysis showed that older age (odds ratio: 1.1, 95% confidence interval: 1.02-1.19) and higher model for end-stage liver disease (odds ratio: 1.27, 95% confidence interval: 1.03-1.56) were associated with premature treatment interruption. CONCLUSION: Older age and advanced liver disease were related to treatment interruption. Identification of risk factors associated with treatment discontinuation is important to recognize patients who should be followed up closely during treatment, ando those whom possibly may not benefit from immediate DAA treatment or should be followed up closely during treatment. PMID- 28800035 TI - The Anti-Malarial Drug Artesunate Attenuates Cardiac Injury in a Rodent Model of Myocardial Infarction. AB - Ischaemic heart disease remains the leading cause of morbidity and mortality in the Western world. Artesunate is the WHO-recommended drug of choice for complicated malaria (with organ failure). The administration of high doses of artesunate is safe in healthy volunteers (up to 8 mg/kg i.v) and patients with severe malaria (2.4 mg/kg i.v). We investigated the effects of artesunate (1 mg/kg) or its active metabolite dihydroartemisinin (DHA; 0.1 mg/kg) in a model of transient myocardial ischaemia/reperfusion (I/R) and evaluated the mechanism of action of the observed cardioprotective effects of artesunate and DHA. We report here for the first time that the administration of artesunate at the onset of reperfusion attenuates the myocardial injury associated with I/R. The observed beneficial effects of artesunate are associated with i) activation of the PI3K/Akt/ERK 1/2 (RISK) pathway, ii) activation of eNOS, iii) inhibition of GSK 3beta, iv) inhibition of NF-kappaB, and v) activation of the STAT3 (SAFE) pathway. In conclusion, as artesunate has an excellent safety profile, the above data should stimulate clinical trials in patients with acute coronary syndromes. PMID- 28800036 TI - Improved Outcomes of Cardiopulmonary Resuscitation in Rats Treated With Vagus Nerve Stimulation and Its Potential Mechanism. AB - Studies have demonstrated that vagus nerve stimulation (VNS) reduces ischemia/reperfusion injury. In this study, we investigated the protective effects of VNS in a rat model of cardiopulmonary resuscitation (CPR). We further investigated whether the beneficial effects of VNS were dependent on the alpha 7 nicotinic acetylcholine receptor (alpha7nAChR). Forty animals were randomized into four groups and all underwent CPR (n = 10 each): CPR alone (control); VNS during CPR; alpha7nAChR antagonist methyllycaconitine citrate (MLA) with VNS; alpha7nAChR agonist 3-(2, 4-dimethoxybenzylidene) anabaseine (GTS-21 dihydrochloride) without VNS. The right vagus nerve was exteriorized in all animals. Ventricular fibrillation was induced and untreated for 8 min. Defibrillation was attempted after 8 min of CPR. VNS was initiated at the beginning of precordial chest compressions and continued for 4 h after return of spontaneous circulation (ROSC) in both the VNS and MLA groups. Hemodynamic measurements and myocardial function, including ejection fraction and myocardial performance index, were assessed at baseline, 1 and 4 h after ROSC. The neurological deficit score was measured at 24-h intervals for a total of 72 h. The heart rate was reduced in the VNS and MLA groups, while no difference was found in mean arterial pressure between the four groups. Better post resuscitation myocardial and cerebral function and longer duration of survival were observed in the VNS-treated animals. The protective effects of VNS could be abolished by MLA and imitated by GTS-21. In addition, VNS decreased the number of electrical shocks and the duration of CPR required. VNS improves multiple outcomes after CPR. PMID- 28800038 TI - Subclinical Rhythmic EEG Discharge of Adult (SREDA) in a Child With Generalized Epilepsy and Literature Review of SREDA in Children. AB - Subclinical rhythmic discharges of adult (SREDA) is a rare benign EEG variant in adults and is of unknown clinical significance. Its occurrence in children is extremely rare. In review of the literature, it has been described in only four children. We present a case of a 10-year-old female with generalized idiopathic childhood absence epilepsy who is noted to have SREDA in three subsequent EEGs performed across a 25-month span. She had no clinical change with these discharges and it was believed to be a benign variant. Including our patient, three of four children with SREDA presented with generalized epilepsy leading to the conclusion that, although rare, SREDA is more common in children presenting with generalized epilepsy. PMID- 28800037 TI - Primary Cilia Deficiency Induces Intracranial Aneurysm. AB - BACKGROUND: Intracranial aneurysm (IA) rupture is life-threatening. However, the mechanisms underlying IA initiation, progression, and rupture remain poorly understood. In the present study, we examined the role of primary cilia in IA development. RESULTS: IA was experimentally induced in mice with elastase and angiotensin II treatment. The number of cells with primary cilia was determined in both IA and peri-IA regions. The role of primary cilia in IA development was assessed through knocking out or manipulating the expression of important components of primary cilia. Finally the role of primary cilia in human IA patients was studied. In the mice model of IA, the primary cilia number was significantly decreased in the IA region. Knocking out Polycystin 1, Polycystin 2, and Intraflagellar Transport 88 in mice would increase the susceptibility of mice to IA development. The IA development could be modulated through manipulating the pathways that regulate primary cilia dynamics. And chemical screening showed that the three factors (PHA 680623, Rapamycin, and Forskolin) could efficiently suppress the IA development. Finally, we demonstrated that the primary cilia deficiency in IA development is conserved in humans. And IA patients had a higher frequency of gene mutations which are related to primary cilia regulation. CONCLUSION: Our study provides an important support for the role of primary cilia in the development of IA. The primary cilia stabilizing chemicals might be useful for preventing IA development. PMID- 28800039 TI - The Effect of Intelligent Physical Exercise Training on Sickness Presenteeism and Absenteeism Among Office Workers. AB - OBJECTIVE: The aim of this study was to investigate the effect of individually tailored intelligent physical exercise training (IPET) on presenteeism and absenteeism among office workers. METHODS: In a 1-year randomized controlled trial (RCT), employees were allocated to a training group TG (N = 193) or control group CG (N = 194). TG received 1-hour high-intensity IPET once a week within working hours, and was recommended to perform 30 minutes of moderate-intensity physical activity (PA) 6 days a week during leisure-time. RESULTS: An intention to-treat analysis showed no effect on absenteeism, but a significant 4% increase in workability and 9% increase in general health in TG compared with CG. A per protocol analysis [adherence of >=70% (N = 89)] in addition showed a significant 6% increase in productivity and a 29% reduction in absenteeism compared with CG. CONCLUSION: IPET combined with recommendations of leisure-time PA significantly improved presenteeism and decreased absenteeism if following the protocol. PMID- 28800040 TI - Effect of continuous positive airway pressure in hypertensive patients with obstructive sleep apnea and high urinary metanephrines. AB - OBJECTIVE: Some cases of pseudopheochromocytoma have been described among hypertensive patients with obstructive sleep apnea (OSA). This study examined whether a pathological rise of urinary metanephrines is a common feature in hypertensive OSA patients and, in such a case, whether the ventilation treatment during sleep (continuous or biphasic positive airway pressure) may normalize high metanephrines levels. METHODS: Patients with endocrine diseases, drug abuse, therapy with TCA and cardiovascular events in the previous 6 months were excluded. Thirty-four hypertensive patients with OSA (BMI 40.6 +/- 8.7 kg/m(2)) performed three 24-h urine collections for metanephrine assessment, before and after 1 month of ventilation therapy. RESULTS: Urinary normetanephrine (uNMT) was above the normal limit in 21 of 34 of the patients. In the 16 to 21 patients with high uNMT who were compliant to ventilation treatment, uNMT decreased in 13 by 26% and normalized in six of 13. uNMT levels were associated with apnea hypopnea index (AHI) (r = 0.799, P < 0.0001) and minimal SaO2 (r = -0.700, P < 0.01). The ventilation therapy-induced changes in AHI were associated with those in uNMT (r = 0.689, P < 0.005). In the multivariate analysis with uNMT changes as dependent variable and changes in AHI, BMI, SBP as independent variables, only AHI changes were independently associated with uNMT changes (beta = 0.738, P < 0.01). CONCLUSION: Two-thirds of OSA hypertensive patients have uNMT values above the normal limit. The early identification of these patients is important as ventilation therapy can correct the pathological sympathoadrenal activation. Patients who do not normalize uNMT with ventilation therapy deserve a strict follow-up as this lack of normalization may indicate insufficient ventilation therapy or resistance of sympathetic hyperactivity to this treatment, not excluding an early stage of a chromaffin tumor. PMID- 28800041 TI - Influence of preeclampsia and late-life hypertension on MRI measures of cortical atrophy. AB - OBJECTIVE: Women with a history of preeclampsia are at an increased risk of hypertension and structural brain changes. However, the combined effect of both preeclampsia and late-life hypertension on brain structural changes is not known and was investigated in this study. METHODS: Participants were identified from the population-based Rochester Epidemiology Project cohort. Four groups of women were recruited and investigated in this study: first, women with a history of normotensive pregnancy who have late-life hypertension (n = 8, median age = 62), second, women with a history of normotensive pregnancy who do not have late-life hypertension (n = 32, median age = 59), third, women with a history of preeclampsia who have late-life hypertension (n = 24, median age = 60), and fourth, women with a history of preeclampsia who do not have late-life hypertension (n = 16, median age = 57). Cerebrovascular disease lesions on MRI, and total gray matter volumes were assessed. RESULTS: Total gray matter volumes were smaller in women with a history of preeclampsia and late-life hypertension compared with the other groups. Voxel-based morphometry demonstrated that the volume changes were localized to the posterior brain regions, particularly the occipital lobe gray matter in women with a history of preeclampsia and late-life hypertension. CONCLUSION: Having late-life hypertension superimposed on a history of preeclampsia affects the brain structure differently than having either a history of preeclampsia alone or a history of normotensive pregnancy either with or without late-life hypertension. PMID- 28800043 TI - Quality of systematic reviews is poor, our fault, our responsibility. PMID- 28800042 TI - Blood pressure indices and cardiovascular disease mortality in persons with or without diabetes mellitus. AB - BACKGROUND: We examined the associations between blood pressure indices (SBP, DBP, mean arterial pressure and pulse pressure) and cardiovascular disease (CVD) mortality among persons with or without diabetes mellitus (NON-DM) in a multiethnic cohort. METHODS: We included 17 650 participants from National Health and Nutrition Examination Survey III and 1439 participants from Diabetes Heart Study (total n = 19 089, 16.3% had diabetes mellitus, mean age 48.5 years, 44.4% white, 27.1% black, 28.5% other race, 54.4% women). Cox proportional hazard, cubic spline and area under the curve analyses were used to assess the associations. CVD death was ascertained via social security registry or the National Death Index. RESULTS: After a mean (SD) of 16.2 (6.1) years of follow up, 17.9% of diabetes mellitus and 8.8% of those NON-DM died of CVD. Diabetes mellitus was associated with an increased risk of CVD death [hazard ratio (95% confidence interval): 1.50 (1.25-1.82)]. One SD increase in SBP was significantly associated with CVD mortality in NON-DM [1.28 (1.18-1.39)] but not diabetes mellitus [1.04 (0.88-1.23)] in the full Cox models. Adjusted cubic spline analysis showed significant nonlinear but different association between SBP and CVD mortality among diabetes mellitus (U-shaped) and NON-DM (J-shaped). The C statistics of our full model in NON-DM and diabetes mellitus were (0.888 vs. 0.735, P < 0.001). SBP showed a trend toward improving C statistics in NON-DM but not diabetes mellitus. CONCLUSION: The association between SBP and CVD mortality risk is nonlinear but different in diabetes mellitus (U-shaped) and NON-DM (J shaped), explaining why aggressive blood pressure lowering may have different outcomes in these two groups. PMID- 28800044 TI - Instruments for measuring undergraduate nursing students' knowledge, attitudes and skills in evidence-based practice: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE:: The objective of this systematic review is to identify and assess the properties of instruments for measuring undergraduate nursing students' knowledge, attitudes and skills in evidence-based practice (EBP).More specifically, the review questions are as follows. PMID- 28800045 TI - Textual synthesis of policies and guidance statements for remote healthcare practitioners on managing medical emergencies in the oil and gas industry: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE:: The objective of this review is to collate, synthesize and present the available evidence on the policies and guidance statements for remote healthcare practitioners on managing medical emergencies in the offshore oil and gas industry.More specifically, the review seeks to answer the following questions. PMID- 28800046 TI - Quality indicators for screening colonoscopies and colonoscopist performance and the subsequent risk of interval bowel cancer: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE:: The objective of this systematic review is to assess the association between quality indicators related to the individual colonoscopist's performance and subsequent interval cancers in patients participating in bowel cancer screening programs, following the JBI approach.This systematic review of association will search all relevant literature on the subject to answer the following review questions. PMID- 28800047 TI - Risk factors and nursing strategies to manage choking in adults with mental illness: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE:: The review objectives are:Specifically, this review seeks to answer the following questions. PMID- 28800048 TI - Mental practice for chronic pain in people with spinal cord injury: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE:: The primary objective of this systematic review is to identify the effects of mental practice (MP) interventions on chronic neuropathic and nociceptive pain and motor function recovery in individuals after spinal cord injury (SCI). Where possible, this review will also describe the optimal type and dosage (i.e. frequency, intensity and duration) of MP interventions for patients with SCI. PMID- 28800049 TI - Survival outcomes following aggressive treatment of oligometastatic breast cancer: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE:: The objective of this systematic review is to assess the effectiveness of aggressive treatment of oligometastatic breast cancer (OMBC) on survival outcomes by conducting a meta-analysis of current available evidence.More specifically, the objectives are to identify the effectiveness of intensified multidisciplinary treatment with aggressive locoregional therapies on survival time, five-year survival rates and disease free survival. The population is adult women (18 years and over) with OMBC defined as single or few (five or less) metastases limited to a single organ and the comparative group is conventional palliative treatment aimed at disease control. Secondary objectives to be assessed will be adverse outcomes associated with intensified treatment regimes. PMID- 28800050 TI - Patient perspectives on interprofessional collaboration between healthcare professionals during hospitalization: a qualitative systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE:: The objective of this qualitative systematic review is to examine the available evidence on interprofessional collaboration from the patients' perspectives, specifically on: i) interprofessional collaboration in adult or pediatric wards during hospitalization; ii) the influence of interprofessional collaboration on the patient's care, safety and well-being in adult or pediatric wards during hospitalization; and (iii) the patient's role in the interprofessional collaboration process in adult or pediatric wards during hospitalization. PMID- 28800051 TI - Alternative tests versus measurement of fasting plasma glucose and oral glucose tolerance test for diagnosis of pediatric type 2 pre-diabetes: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE:: The gold standard for the diagnosis of pre-diabetes is the measurement of fasting plasma glucose and the oral glucose tolerance test. The objective of this systematic review is to identify all alternative tests currently in use for the diagnosis of type 2 pre-diabetes mellitus in children and establish their accuracy relative to this gold standard. PMID- 28800052 TI - Pediatric post-anesthesia care unit discharge criteria: a scoping review protocol. AB - REVIEW OBJECTIVE/QUESTION: The objectives of this review are to explore existing literature on discharge criteria, tools and strategies utilized in pediatric post anesthesia care units (PACUs) after outpatient surgery, examine and conceptually map the evidence, and identify gaps in the literature.Specifically, the review question is: what criteria, tools and strategies are being used in pediatric PACUs for discharge? PMID- 28800053 TI - Frailty in nursing home residents: a scoping review protocol. AB - OBJECTIVES AND REVIEW QUESTIONS: The overall research objective of this scoping review is to determine the current evidence on frailty in nursing homes.The objectives of the scoping review are to map the following, as reported in international literature:The questions for the scoping review are. PMID- 28800054 TI - End user and implementer experiences of mHealth technologies for noncommunicable chronic disease management in young adults: a qualitative systematic review protocol. AB - REVIEW OBJECTIVE: The objective of this review is to systematically identify, review and synthesize relevant qualitative research on end user and implementer experiences of mobile health (mHealth) technologies developed for noncommunicable chronic disease management in young adults. "End users" are defined as young people aged 15-24 years, and "implementers" are defined as health service providers, clinicians, policy makers and administrators.The two key questions we wish to systematically explore from identified relevant qualitative studies or studies with qualitative components are. PMID- 28800055 TI - Metformin and Alzheimer's disease, dementia and cognitive impairment: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of the review is to assess the effect of metformin on the risk, progression and severity of Alzheimer's disease and other forms of dementia, as well as any measures of cognitive performance or impairment. PMID- 28800056 TI - Effectiveness of structured planned post discharge support to patients with chronic obstructive pulmonary disease for reducing readmission rates: a systematic review. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease, characterized by airflow limitation. The disease has a significant impact on the lives of patients and is a challenge for the health care due to readmissions to hospitals. OBJECTIVES: This review aimed to identify, appraise and synthesize the best available evidence on the effectiveness of discharge interventions that can reduce readmission of patients with COPD. TYPES OF PARTICIPANTS: Hospitalized patients, aged 18 years or over, who had been diagnosed with COPD and were admitted to hospital due to acute exacerbation. TYPES OF INTERVENTIONS: Studies that evaluated discharge interventions that supported patients managing symptoms of COPD. TYPES OF STUDIES: Randomized controlled trials, non-randomized controlled trials, quasi-experimental or cohort studies. OUTCOMES: Readmission, defined as hospitalization to the same or different hospital for any reason within the following year after discharge. SEARCH STRATEGY: Multiple databases (PubMed, Embase, CINAHL, the Cochrane Library, Pedro, Web of Science, Turning Research Into Practice [Trip] and Scopus) were searched from 1990 to June 2015. Studies published in English or Scandinavian. METHODOLOGICAL QUALITY: Two independent reviewers used the standard critical appraisal tool from the Joanna Briggs Institute to assess the methodological quality of studies. All studies were of good methodological quality. DATA EXTRACTION: The process of data extraction was undertaken independently by two reviewers using tools from the Joanna Briggs Institute. DATA SYNTHESIS: A narrative description of each study was performed. Outcomes were reported as the event rate (ER) in the intervention and control groups. Based on the ER relative risk reduction (RRR), absolute risk reduction (ARR), the number needed to treat (NNT), and relative risk (RR) with 95% confidence intervals were calculated. Continuous data were reported in natural units. RESULTS: This review includes ten studies all testing a mix of interventions. A meta-analysis included six studies, four at 30 days follow-up with RR 0.67 (0.45 to 0.98) and 180 days follow-up with RR 0.74 (0.51 to 1.08). The analysis could not identify a single set of interventions that could be recommended. CONCLUSIONS: Post discharge support and interventions in patients with COPD significantly reduce the readmission rate within 30 days after discharge from hospital and the interventions may significantly reduce readmission up to 180 days after initial discharge. This is a significant finding from the clinical and practical perspective. PMID- 28800057 TI - Experiences of gynecological cancer patients receiving care from specialist nurses: a qualitative systematic review. AB - BACKGROUND: The care needs of women with gynecological cancer are complex and change over the course of their cancer journey. Specialist nurses are well positioned to play a role in meeting the needs of women with gynecological cancer although their role and scope of practice have not been well defined. As patients are a key stakeholder, understanding their experience of care is an important step in better defining the role and scope of practice of specialist nurses in gynecological oncology in Australia and New Zealand. OBJECTIVES: This review sought to consider gynecological cancer patients' experiences of specialist nursing care. Exploring the patient's experience of care by a specialist nurse is one step in the process of better defining the role and scope of practice of specialist gynecological-oncology nurses in Australia and New Zealand. INCLUSION CRITERIA TYPES OF PARTICIPANTS: This review included studies with a focus on women with gynecological cancer who had been cared for by a specialist nurse. Studies of women with gynecological cancer at any point on the continuum of care from pre-diagnosis to survivorship or end of life, including those with a recurrence of the disease, were included, with no limit to the duration of care received for inclusion in the review. PHENOMENA OF INTEREST: Studies that explored how women with gynecological cancer experience the care and interventions of specialist nurses were included. TYPES OF STUDIES: Qualitative studies including, but not limited to, designs such as phenomenology, grounded theory, ethnography, action research and feminist research were considered for review. This review also considered the qualitative components of mixed method studies. CONTEXT: Research conducted in any country was considered for inclusion in this review providing that the study was reported in English. Studies conducted in any setting including, but not limited to, acute hospitals, outpatient/ambulatory clinics, chemotherapy or radiotherapy units, support groups, palliative care units or the patient's home were included. SEARCH STRATEGY: A three-step search strategy was utilized in this review. An initial limited search of MEDLINE and CINAHL was undertaken followed by a comprehensive search using all identified keywords and index terms across all included databases. The reference lists of all identified reports and articles were hand searched for additional studies. METHODOLOGICAL QUALITY: Each paper was independently assessed by two independent reviewers for methodological validity prior to inclusion in the review using the standardized critical appraisal instrument from the Joanna Briggs Institute the Qualitative Assessment and Review Instrument. When disagreement arose between the reviewers, the given paper was independently appraised by a third reviewer. DATA EXTRACTION: Data were extracted from papers included in the review using the standardized data extraction tool from Joanna Briggs Institute the Qualitative Assessment and Review Instrument. Data extraction was completed independently by two reviewers. DATA SYNTHESIS: Extracted findings from seven included papers were grouped according to similarity in meaning from which 11 categories were developed. These categories were then subjected to a meta-synthesis that produced a set of three synthesized findings. RESULTS: Key findings were extracted from six included papers and classified as unequivocal (U) or credible (C). A total of 30 findings were extracted and aggregated into 11 categories based on similarity in meaning. From the 11 categories, three synthesized findings were developed: i) Tailored care: specialist nurses play a role in understanding and meeting the individual needs of women with gynecological cancer; ii) Accessible care: specialist nurses guide women with gynecological cancer along the continuum of care and are an easily accessed source of knowledge and support; iii) Dependable expertise: women with gynecological cancer express trust and reassurance in the experience and expertise of the specialist nurse. CONCLUSIONS: This systematic review synthesized the findings of seven studies that captured the experiences of women with gynecological cancer who received care from a specialist nurse. The specialist nurse offers tailored, accessible and expert care to women with gynecological cancer. From the synthesis it is recommended that women with gynecological cancer have access to the services of a specialist nurse at key points on the continuum of care, that specialist nurses provide information to patients on their disease and treatment in the form preferred by the patient and ensure that this information has been understood, and that specialist nurses are afforded time to spend with patients to enable greater exploration and identification of patient needs and the provision of personalized care. Further study that considers other key stakeholders in the specialist nurse role in gynecological oncology is recommended in order to gain a full understanding of specialist nurses' contribution to the care of women with gynecological cancer. Additionally, it is recommended that further studies be conducted to seek the perspectives of women with gynecological cancer from culturally and linguistically diverse backgrounds and Indigenous populations on specialist nursing care as they appear to be under-represented in current research. PMID- 28800058 TI - Effectiveness of mifamurtide in addition to standard chemotherapy for high-grade osteosarcoma: a systematic review. AB - BACKGROUND: Osteosarcoma mostly occurs during the period of rapid bone growth in children and adolescents as high-grade osteosarcomas. Current treatment recommended for high-grade non-metastatic and metastatic and/or relapsed osteosarcoma involves neoadjuvant multiagent conventional chemotherapy, followed by surgical resection of macroscopically detected tumor and postoperative adjuvant chemotherapy. However, residual micrometastatic deposits that develop following surgery have shown resistance to postoperative/adjuvant chemotherapy. Therefore, there is a critical need for more effective and innovative therapeutic approaches such as immune stimulatory agents. The most extensively studied immune stimulatory agent in the treatment of osteosarcoma is mifamurtide. The aim of this systematic review was to identify and synthesize the evidence on the effectiveness of mifamurtide in addition to standard chemotherapy on survival outcomes. OBJECTIVES: To present the best available evidence on the treatment of high-grade non-metastatic and metastatic osteosarcoma with mifamurtide in addition to standard chemotherapy. INCLUSION CRITERIA TYPES OF PARTICIPANTS: All populations of patients regardless of age, gender or ethnicity with high-grade, resectable, non-metastatic and metastatic osteosarcoma based on histological diagnosis. TYPES OF INTERVENTIONS AND COMPARATORS: This review focused on intravenous infusion of either of the pharmaceutical formulations of mifamurtide (MTP-PE or L-MTP-PE) in addition to standard chemotherapy, and the comparator was chemotherapy alone. TYPES OF STUDIES: This review considered any experimental study design including randomized controlled trials, non-randomized trials and quasi-experimental studies. OUTCOMES: The primary outcomes of interest were event free survival, overall survival and recurrence of osteosarcoma. Secondary outcomes that were considered included health-related quality of life and any mifamurtide-related adverse events. SEARCH STRATEGY: A search for published and unpublished literature in English was undertaken (seven published literature databases, four unpublished literature databases, and three government agency and organizational websites were searched). Studies published between 1990 to June 2016 were considered. A three-step strategy was developed using MeSH terminology and keywords to ensure that all relevant studies were included related to this review. METHODOLOGICAL QUALITY: The methodological quality of included studies was assessed by two reviewers, who appraised each study independently, using a standardized Joanna Briggs Institute (JBI) critical appraisal tool. DATA EXTRACTION: Data was extracted from the studies that were identified as meeting the criteria for methodological quality using the standard JBI data extraction tool. DATA SYNTHESIS: Due to the heterogeneity of populations and interventions in available studies, meta-analysis was not possible and results are presented in narrative form. RESULTS: Three papers outlining two studies involving 802 patients evaluated the effectiveness of mifamurtide in addition of chemotherapy. Results indicated no significant difference in event-free survival between the addition of mifamurtide to standard chemotherapy regimen and chemotherapy alone, both in non-metastatic and metastatic osteosarcoma patients. There was a significant difference in progression-free survival favoring the addition of mifamurtide in pulmonary metastatic and/or relapsed osteosarcoma. There was no significant difference in overall survival between the addition of mifamurtide and chemotherapy alone in metastatic osteosarcoma; however there was a significant difference favoring the addition of mifamurtide in non-metastatic osteosarcoma patients. The addition of mifamurtide resulted in a significant difference in survival after relapse in pulmonary metastatic and/or relapsed osteosarcoma patients. Both studies reported on mifamurtide-related adverse events - the first was reported as toxicity which included haematological, hepatic, renal, gastrointestinal disorders, cardiac, rhythm and nervous system disorders, ear disorders and others (infection, fever; and performance status) in metastatic osteosarcoma patients. Results were similar across all combined treatment regimens. Although no statistical analysis was undertaken, the figures suggest there were no significant differences between the treatment regimens. In the other study, mifamurtide-related adverse events were reported as clinical toxic effects of mifamurtide in relapsed osteosarcoma, which included chills, fever and headache for the initial dose of mifamurtide, while for the subsequent doses of mifamurtide all patients reported toxicity as delayed fatigue. CONCLUSIONS: The available evidence on the effectiveness of mifamurtide in addition to a standard chemotherapy regimen for the treatment of high-grade osteosarcoma is limited and therefore no definitive conclusions can be made. PMID- 28800059 TI - The impact of educational interventions on attitudes of emergency department staff towards patients with substance-related presentations: a quantitative systematic review. AB - BACKGROUND: Visits to emergency departments for substance use/abuse are common worldwide. However, emergency department health care providers perceive substance using patients as a challenging group to manage which can lead to negative attitudes. Providing education or experience-based exercises may impact positively on behaviors towards this patient population. Whether staff attitudes are similarly impacted by knowledge acquired through educational interventions remains unknown. OBJECTIVES: To synthesize available evidence on the relationship between new knowledge gained through substance use educational interventions and emergency department health care providers' attitudes towards patients with substance-related presentations. INCLUSION CRITERIA TYPES OF PARTICIPANTS: Health care providers working in urban and rural emergency departments of healthcare facilities worldwide providing care to adult patients with substance-related presentations. TYPE OF INTERVENTION: Quantitative papers examining the impact of substance use educational interventions on health care providers' attitudes towards substance using patients. TYPES OF STUDIES: Experimental and non experimental study designs. OUTCOMES: Emergency department staff attitudes towards patients presenting with substance use/abuse. SEARCH STRATEGY: A three step search strategy was conducted in August 2015 with a search update in March 2017. Studies published since 1995 in English, French or Spanish were considered for inclusion. METHODOLOGICAL QUALITY: Two reviewers assessed studies for methodological quality using critical appraisal checklists from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI MAStARI). Reviewers agreed on JBI-MAStARI methodological criteria a study must meet in order to be included in the review (e.g. appropriate use of statistical analysis). DATA EXTRACTION AND SYNTHESIS: The data extraction instrument from JBI MAStARI was used. As statistical pooling of the data was not possible, the findings are presented in narrative form. RESULTS: A total of 900 articles were identified as relevant for this review. Following abstract and full text screening, four articles were selected and assessed for methodological quality. One article met methodological criteria for inclusion in the review: use of random assignment and comparable study groups and measurement outcomes in a reliable and consistent manner. The included study was a cluster randomized controlled trial. Participants were emergency medicine residents with a mean age of 30 years. The study assessed the impact of a skills-based educational intervention on residents' attitudes, knowledge and practice towards patients with alcohol problems. While knowledge and practice behaviors improved one year following the intervention, there were no significant differences between groups on attitudinal measures. CONCLUSIONS: Employing educational interventions to improve the attitudes of emergency department staff towards individuals with drug and alcohol related presentations is not supported by evidence. PMID- 28800060 TI - Relationship between physical activity level and psychosocial and socioeconomic factors and issues in children and adolescents with asthma: a scoping review. AB - BACKGROUND: Asthma is a heterogeneous chronic airway disease which may reduce capability for physical activity. In healthy peers, physical activity is influenced by psychosocial and socioeconomic factors. Knowledge about the role of these factors has not been mapped in children and adolescents with asthma. OBJECTIVE: The main objective of this scoping review was to identify psychosocial and socioeconomic factors associated with physical activity level in children and adolescents with asthma in the literature. The specific objectives were to map the instruments used to measure these factors, report on the construction and validation of these instruments, map psychosocial and socioeconomic issues related to physical activity level reported in qualitative studies, and identify gaps in knowledge about the relationship between psychosocial and socioeconomic factors and physical activity level in children and adolescents with asthma. INCLUSION CRITERIA TYPES OF PARTICIPANTS: Children and adolescents with asthma aged six to 18 years. CONCEPT: Psychosocial and socioeconomic factors related to physical activity level and participation. CONTEXT: All physical activity contexts. TYPES OF SOURCES: Quantitative and qualitative primary studies in English, with no date limit. SEARCH STRATEGY: The databases searched included nine major databases for health and sports science, and five databases for unpublished studies. After screening and identification of studies, the reference lists of all identified reports were searched, and forward citation searches were conducted using four databases. EXTRACTION OF THE RESULTS: The following data were extracted: (a) relevant study characteristics and assessment of physical activity level, (b) instruments used to assess psychosocial and socioeconomic factors, (c) association between physical activity level and these factors, (d) construction and validation of instruments, and (e) psychosocial and socioeconomic issues related to physical activity participation. PRESENTATION OF THE RESULTS: Twenty-one quantitative and 13 qualitative studies were included. In cross-sectional studies, enjoyment, physical self-concept, self-efficacy, attitudes and beliefs about physical activity and health, psychological distress, health-related quality of life, and social support were more often reported as being correlated with physical activity level. In three studies, the construct validity was assessed by factor analysis and construct reliability tests for the study population. Qualitative studies reported 10 issues related to physical activity participation, and capability and being like peers were most commonly reported. There was no direct evidence that qualitative research informed the development or adjustment of instruments in quantitative studies. CONCLUSIONS: Seven psychosocial factors correlated with physical activity level; capability and being like peers were the most commonly reported issues. Reports of the construction and validation of instruments were sparse. PMID- 28800061 TI - Applying Sensor-Based Technology to Improve Construction Safety Management. AB - Construction sites are dynamic and complicated systems. The movement and interaction of people, goods and energy make construction safety management extremely difficult. Due to the ever-increasing amount of information, traditional construction safety management has operated under difficult circumstances. As an effective way to collect, identify and process information, sensor-based technology is deemed to provide new generation of methods for advancing construction safety management. It makes the real-time construction safety management with high efficiency and accuracy a reality and provides a solid foundation for facilitating its modernization, and informatization. Nowadays, various sensor-based technologies have been adopted for construction safety management, including locating sensor-based technology, vision-based sensing and wireless sensor networks. This paper provides a systematic and comprehensive review of previous studies in this field to acknowledge useful findings, identify the research gaps and point out future research directions. PMID- 28800062 TI - Cellular Entry of Clostridium perfringens Iota-Toxin and Clostridium botulinum C2 Toxin. AB - Clostridium perfringens iota-toxin and Clostridium botulinum C2 toxin are composed of two non-linked proteins, one being the enzymatic component and the other being the binding/translocation component. These latter components recognize specific receptors and oligomerize in plasma membrane lipid-rafts, mediating the uptake of the enzymatic component into the cytosol. Enzymatic components induce actin cytoskeleton disorganization through the ADP-ribosylation of actin and are responsible for cell rounding and death. This review focuses upon the recent advances in cellular internalization of clostridial binary toxins. PMID- 28800063 TI - Fabrication and Characterization of Flexible and Miniaturized Humidity Sensors Using Screen-Printed TiO2 Nanoparticles as Sensitive Layer. AB - This paper describes the fabrication and the characterization of an original example of a miniaturized resistive-type humidity sensor, printed on flexible substrate in a large-scale manner. The fabrication process involves laser ablation for the design of interdigitated electrodes on PET (Poly-Ethylene Terephthalate) substrate and a screen-printing process for the deposition of the sensitive material, which is based on TiO2 nanoparticles. The laser ablation process was carefully optimized to obtain micro-scale and well-resolved electrodes on PET substrate. A functional paste based on cellulose was prepared in order to allow the precise screen-printing of the TiO2 nanoparticles as sensing material on the top of the electrodes. The current against voltage (I-V) characteristic of the sensor showed good linearity and potential for low-power operation. The results of a humidity-sensing investigation and mechanical testing showed that the fabricated miniaturized sensors have excellent mechanical stability, sensing characteristics, good repeatability, and relatively fast response/recovery times operating at room temperature. PMID- 28800064 TI - Epidemiology of Musculoskeletal Injury during Racing on New Zealand Racetracks 2005-2011. AB - The objective of the study was to determine the incidence of veterinary events that resulted in a horse failing to finish a race and identify risk factors for musculoskeletal injury (MSI) during a race. Data were obtained on Thoroughbred flat race starts in New Zealand between 1 August 2005 and 31 July 2011 (six racing seasons). Stipendiary Steward's reports were key-word searched to identify veterinary events that prevented a horse from finishing a race. Race data were used calculate the incidence of veterinary events per 1000 horse starts and Poisson regression was used to investigate risk factors for MSI. There were 188,616 race starts and 177 reported veterinary events. The incidence of MSI on race day was 0.72 per 1000 starts, whilst the incidence of respiratory events was 0.21 per 1000 starts. The rate of MSI was significantly lower on 'dead' and 'slow' tracks compared with 'good' tracks and significantly greater in longer races (>=1671 m) compared with races of <=1200 m. The rate of MSI during flat races in New Zealand appears lower than that reported worldwide, which may be due to the management and training of horses in New Zealand or differences in case definitions used in comparable studies. PMID- 28800065 TI - Validating MODIS and Sentinel-2 NDVI Products at a Temperate Deciduous Forest Site Using Two Independent Ground-Based Sensors. AB - Quantifying the accuracy of remote sensing products is a timely endeavor given the rapid increase in Earth observation missions. A validation site for Sentinel 2 products was hence established in central Germany. Automatic multispectral and hyperspectral sensor systems were installed in parallel with an existing eddy covariance flux tower, providing spectral information of the vegetation present at high temporal resolution. Normalized Difference Vegetation Index (NDVI) values from ground-based hyperspectral and multispectral sensors were compared with NDVI products derived from Sentinel-2A and Moderate-resolution Imaging Spectroradiometer (MODIS). The influence of different spatial and temporal resolutions was assessed. High correlations and similar phenological patterns between in situ and satellite-based NDVI time series demonstrated the reliability of satellite-based phenological metrics. Sentinel-2-derived metrics showed better agreement with in situ measurements than MODIS-derived metrics. Dynamic filtering with the best index slope extraction algorithm was nevertheless beneficial for Sentinel-2 NDVI time series despite the availability of quality information from the atmospheric correction procedure. PMID- 28800066 TI - Treatment of the First Acute Relapse Following Therapeutic Plasma Exchange in Formerly Glucocorticosteroid-Unresponsive Multiple Sclerosis Patients-A Multicenter Study to Evaluate Glucocorticosteroid Responsiveness. AB - Therapeutic options to treat multiple sclerosis (MS) relapses comprise glucocorticosteroids (GCS) as first-line and therapeutic plasma exchange (TPE) as second-line treatments in GCS-unresponsive patients. No guidelines exist for the treatment of another relapse following TPE. We retrospectively analyzed the responsiveness to GCS in a subsequent relapse following TPE in previously GCS unresponsive MS patients. Thirty-seven patients with GCS-unresponsive MS relapses received TPE (relapse A). All patients developed another relapse after the completion of TPE and received GCS again (relapse B). The primary study endpoint was the clinical response to GCS and TPE. Marked improvement was defined as clinically significant improvement in function, moderate improvement as a definite change of symptoms without significant impact on function, no effect comprised unchanged symptoms, and deterioration a worsening of symptoms or new deficits. The secondary endpoint was an improvement in expanded disability status scale (EDSS) scoring. All patients were GCS-unresponsive during relapse A and received TPE. During GCS treatment of relapse B, marked improvement was observed in 10, moderate improvement in 24, and no effect in three patients. The EDSS decreased in 15 patients. GCS might remain the first-line relapse treatment following TPE in formerly GCS-unresponsive MS patients. PMID- 28800067 TI - A Randomized Crossover Trial on Acute Stress-Related Physiological Responses to Mountain Hiking. AB - Green exercise, defined as physical activity in natural environments, might have positive effects on stress-related physiological measures. Little is known about the acute effects of green exercise bouts lasting longer than 60 min. Therefore, the aim of the present study was to analyze the acute effects of a three-hour green exercise intervention (mountain hiking) on stress-related physiological responses. Using a randomized crossover design, 42 healthy participants were exposed to three different conditions in a field-based experiment: outdoor mountain hiking, indoor treadmill walking, and sedentary control condition (three hours each). At baseline and at follow-up (five minutes after the condition), stress-related physiological responses (salivary cortisol, blood pressure, and heart rate variability) were measured. Salivary cortisol decreased in all conditions, but showed a larger decrease after both mountain hiking and treadmill walking compared to the sedentary control situation (partial eta2 = 0.10). No differences were found between mountain hiking and treadmill walking in salivary cortisol. In heart rate variability and blood pressure, changes from baseline to follow-up did not significantly differ between the three conditions. The results indicate that three hours of hiking indoors or outdoors elicits positive effects on salivary cortisol concentration. Environmental effects seem to play a minor role in salivary cortisol, blood pressure, and heart rate variability. PMID- 28800068 TI - Galectin-3 Performance in Histologic a Cytologic Assessment of Thyroid Nodules: A Systematic Review and Meta-Analysis. AB - The literature on Galectin-3 (Gal-3) was systematically reviewed to achieve more robust information on its histologic reliability in identifying thyroid cancers and on the concordance between Gal-3 test in histologic and cytologic samples. A computer search of the PubMed and Scopus databases was conducted by combinations of the terms thyroid and Gal-3. Initially, 545 articles were found and, after their critical review, 52 original papers were finally included. They reported 8172 nodules with histologic evaluation of Gal-3, of which 358 with also preoperative FNAC Gal-3 assessment. At histology, Gal-3 sensitivity was 87% (95% confidence intervals [CI] from 86% to 88%), and specificity 87% (95% CI from 86% to 88%); in both cases, we found heterogeneity (I2 85% and 93%, respectively) and significant publication bias (p < 0.001). The pooled rate of positive Gal-3 at fine needle aspiration (FNAC) among cancers with histologically proven Gal-3 positivity was 94% (95% CI from 89% to 97%), with neither heterogeneity (I2 14.5%) nor bias (p = 0.086). These data show high reliability of Gal-3 for thyroid cancer at histology, while its sensitivity on FNAC samples is lower. The limits of cytologic preparations and interpretation of Gal-3 results have to be solved. PMID- 28800069 TI - Effects of Lifetime Unemployment Experience and Job Insecurity on Two-Year Risk of Physician-Diagnosed Incident Depression in the German Working Population. AB - Unemployment and job insecurity have been reported to be associated with a higher risk of depression. The purpose of this study was to evaluate the separate and combined effects of lifetime unemployment experience and job insecurity on the incidence of depression in an unselected working population in Germany. Data from the German Socio-Economic Panel (GSOEP) study were used, as was a final sample of those currently employed, with complete data at baseline (2009) and follow-up (2011) restricted to those free of depression in 2009 (n = 7073). Poisson regression analysis was applied to test the prospective associations between unemployment, job insecurity, and a two-year incident of depression. Results showed that the experience of unemployment and perceived job insecurity were significantly associated with a higher risk of depression during the two-year follow-up (risk ratios 1.64; 95% confidence intervals (1.16, 2.31) and risk ratios 1.48; 95% confidence intervals (1.13, 1.92), respectively). Notably, the strongest risk was observed among participants with insecure jobs and past long term unemployment (risk ratios 2.15; 95% confidence intervals (1.32; 3.52)). In conclusion, even during employment, the experience of lifetime unemployment led to a higher risk of depression. The combination of previous unemployment experience and anticipated job insecurity increased the risk of developing depression. Results support health promotion with special emphasis on unemployment and precarious working conditions. PMID- 28800071 TI - Fabrication and Characterization of Magnesium Ferrite-Based PCL/Aloe Vera Nanofibers. AB - Composite nanofibers of biopolymers and inorganic materials have been widely explored as tissue engineering scaffolds because of their superior structural, mechanical and biological properties. In this study, magnesium ferrite (Mg ferrite) based composite nanofibers were synthesized using an electrospinning technique. Mg-ferrite nanoparticles were first synthesized using the reverse micelle method, and then blended in a mixture of polycaprolactone (PCL), a synthetic polymer, and Aloe vera, a natural polymer, to create magnetic nanofibers by electrospinning. The morphology, structural and magnetic properties, and cellular compatibility of the magnetic nanofibers were analyzed. Mg-ferrite/PCL/Aloe vera nanofibers showed good uniformity in fiber morphology, retained their structural integrity, and displayed magnetic strength. Experimental results, using cell viability assay and scanning electron microscopy imaging showed that magnetic nanofibers supported 3T3 cell viability. We believe that the new composite nanofibrous membranes developed in this study have the ability to mimic the physical structure and function of tissue extracellular matrix, as well as provide the magnetic and soluble metal ion attributes in the scaffolds with enhanced cell attachment, and thus improve tissue regeneration. PMID- 28800070 TI - Pathogenesis of Lafora Disease: Transition of Soluble Glycogen to Insoluble Polyglucosan. AB - Lafora disease (LD, OMIM #254780) is a rare, recessively inherited neurodegenerative disease with adolescent onset, resulting in progressive myoclonus epilepsy which is fatal usually within ten years of symptom onset. The disease is caused by loss-of-function mutations in either of the two genes EPM2A (laforin) or EPM2B (malin). It characteristically involves the accumulation of insoluble glycogen-derived particles, named Lafora bodies (LBs), which are considered neurotoxic and causative of the disease. The pathogenesis of LD is therefore centred on the question of how insoluble LBs emerge from soluble glycogen. Recent data clearly show that an abnormal glycogen chain length distribution, but neither hyperphosphorylation nor impairment of general autophagy, strictly correlates with glycogen accumulation and the presence of LBs. This review summarizes results obtained with patients, mouse models, and cell lines and consolidates apparent paradoxes in the LD literature. Based on the growing body of evidence, it proposes that LD is predominantly caused by an impairment in chain-length regulation affecting only a small proportion of the cellular glycogen. A better grasp of LD pathogenesis will further develop our understanding of glycogen metabolism and structure. It will also facilitate the development of clinical interventions that appropriately target the underlying cause of LD. PMID- 28800072 TI - Phosphate-Linked Silibinin Dimers (PLSd): New Promising Modified Metabolites. AB - By exploiting the regioselective protection of the hydroxyl groups of silibinin along with the well-known phosphoramidite chemistry, we have developed an efficient strategy for the synthesis of new silibinin-modified species, which we have named Phosphate-Linked Silibinin Dimers (PLSd), in which the monomer units are linked by phosphodiester bonds. The antioxidant abilities of the new PLSd were estimated on HepG2 cells using DPPH free radical scavenging and xanthine/xanthine oxidase assays. The new phosphate-metabolites showed a higher anti-oxidant activity than the silibinin, as well as very low toxicity. The ability to scavenge reactive oxygen species (ROS) such as singlet oxygen () and hydroxyl radical () reveals that the two dimers are able to scavenge about two times more effectively than silibinin. Finally, solubility studies have shown that the PLSd present good water solubility (more than 20 mg.L-1) under circumneutral pH values, whereas the silibinin was found to be very poorly soluble (less than 0.4 mg.L-1) and not stable under alkaline conditions. Together, the above promising results warrant further investigation of the future potential of the PLSd as anti-oxidant metabolites within the large synthetic polyphenols field. PMID- 28800073 TI - Electronegative Low-Density Lipoprotein L5 Impairs Viability and NGF-Induced Neuronal Differentiation of PC12 Cells via LOX-1. AB - There have been striking associations of cardiovascular diseases (e.g., atherosclerosis) and hypercholesterolemia with increased risk of neurodegeneration including Alzheimer's disease (AD). Low-density lipoprotein (LDL), a cardiovascular risk factor, plays a crucial role in AD pathogenesis; further, L5, a human plasma LDL fraction with high electronegativity, may be a factor contributing to AD-type dementia. Although L5 contributing to atherosclerosis progression has been studied, its role in inducing neurodegeneration remains unclear. Here, PC12 cell culture was used for treatments with human LDLs (L1, L5, or oxLDL), and subsequently cell viability and nerve growth factor (NGF)-induced neuronal differentiation were assessed. We identified L5 as a neurotoxic LDL, as demonstrated by decreased cell viability in a time- and concentration-dependent manner. Contrarily, L1 had no such effect. L5 caused cell damage by inducing ATM/H2AX-associated DNA breakage as well as by activating apoptosis via lectin-like oxidized LDL receptor-1 (LOX-1) signaling to p53 and ensuring cleavage of caspase-3. Additionally, sublethal L5 long-termly inhibited neurite outgrowth in NGF-treated PC12 cells, as evidenced by downregulation of early growth response factor-1 and neurofilament-M. This inhibitory effect was mediated via an interaction between L5 and LOX-1 to suppress NGF-induced activation of PI3k/Akt cascade, but not NGF receptor TrkA and downstream MAPK pathways. Together, our data suggest that L5 creates a neurotoxic stress via LOX-1 in PC12 cells, thereby leading to impairment of viability and NGF-induced differentiation. Atherogenic L5 likely contributes to neurodegenerative disorders. PMID- 28800074 TI - Phellinus linteus Grown on Germinated Brown Rice Increases Cetuximab Sensitivity of KRAS-Mutated Colon Cancer. AB - Colon cancer is one of the most common types of cancer, and it has recently become a leading cause of death worldwide. Among colon cancers, the v-ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated form is notorious for its non-druggable features. Cetuximab, a monoclonal antibody that binds to the epidermal growth factor receptor, has been introduced as an antitumor therapy; however, secondary resistance and side effects significantly limit its effective use in these cancers. In this study, we prepared Phellinuslinteus on germinated brown rice (PBR) extracts to increase the sensitivity of KRAS-mutated colon cancers to cetuximab. The combined treatment of PBR extract and cetuximab suppressed SW480 cell viability/proliferation, with the cells exhibiting altered cellular morphology and clonogenic potential. AnnexinV-fluorescein isothiocyanate/propidium iodide-stained flow cytometry and Western blotting were performed, and PBR extract combined with cetuximab treatment increased apoptosis of the SW480 cells and suppressed their KRAS protein expression. The potential of PBR as a synergistic anticancer agent was further investigated in a tumor xenografted mouse model. Tumor growth was significantly suppressed with PBR extract and cetuximab co-treatment. In conclusion, PBR increased the sensitivity of KRAS-mutated colon cancer cells to cetuximab, which indicates the potential use of PBR as a medical food against colon cancer. PMID- 28800077 TI - Comparison of Medium Manganese Steel and Q345 Steel on Corrosion Behavior in a 3.5 wt % NaCl Solution. AB - A cyclic wet/dry accelerated corrosion test was used to compare the corrosion behavior of medium-Mn steel and Q345 steel. In terms of scanning electron microscope (SEM), using X-ray diffraction (XRD), electron probe microanalysis (EPMA), X-ray photoelectron spectroscopy (XPS), and analysis of the corrosion process, the results showed that the medium-Mn steel did not exhibit higher corrosion resistance than Q345 steel due to the greater content of Mn-rich compounds in the rust layer. Moreover, the effect of a small amount of anti corrosion elements in medium-manganese steel can regulate the corrosion rate. The conceptual model of the corrosion process of the medium-Mn steel in a 3.5 wt % NaCl solution is proposed. PMID- 28800076 TI - Human Dental Pulp Cells Differentiate toward Neuronal Cells and Promote Neuroregeneration in Adult Organotypic Hippocampal Slices In Vitro. AB - The adult mammalian central nerve system has fundamental difficulties regarding effective neuroregeneration. The aim of this study is to investigate whether human dental pulp cells (DPCs) can promote neuroregeneration by (i) being differentiated toward neuronal cells and/or (ii) stimulating local neurogenesis in the adult hippocampus. Using immunostaining, we demonstrated that adult human dental pulp contains multipotent DPCs, including STRO-1, CD146 and P75-positive stem cells. DPC-formed spheroids were able to differentiate into neuronal, vascular, osteogenic and cartilaginous lineages under osteogenic induction. However, under neuronal inductive conditions, cells in the DPC-formed spheroids differentiated toward neuronal rather than other lineages. Electrophysiological study showed that these cells consistently exhibit the capacity to produce action potentials, suggesting that they have a functional feature in neuronal cells. We further co-cultivated DPCs with adult mouse hippocampal slices on matrigel in vitro. Immunostaining and presto blue assay showed that DPCs were able to stimulate the growth of neuronal cells (especially neurons) in both the CA1 zone and the edges of the hippocampal slices. Brain-derived neurotrophic factor (BDNF), was expressed in co-cultivated DPCs. In conclusion, our data demonstrated that DPCs are well-suited to differentiate into the neuronal lineage. They are able to stimulate neurogenesis in the adult mouse hippocampus through neurotrophic support in vitro. PMID- 28800075 TI - Biofilms in Endodontics-Current Status and Future Directions. AB - Microbiota are found in highly organized and complex entities, known as biofilms, the characteristics of which are fundamentally different from microbes in planktonic suspensions. Root canal infections are biofilm mediated. The complexity and variability of the root canal system, together with the multi species nature of biofilms, make disinfection of this system extremely challenging. Microbial persistence appears to be the most important factor for failure of root canal treatment and this could further have an impact on pain and quality of life. Biofilm removal is accomplished by a chemo-mechanical process, using specific instruments and disinfecting chemicals in the form of irrigants and/or intracanal medicaments. Endodontic research has focused on the characterization of root canal biofilms and the clinical methods to disrupt the biofilms in addition to achieving microbial killing. In this narrative review, we discuss the role of microbial biofilms in endodontics and review the literature on the role of root canal disinfectants and disinfectant-activating methods on biofilm removal. PMID- 28800078 TI - Response to Comments on Montagna et al. "Evaluation of Legionella Air Contamination in Healthcare Facilities by Different Sampling Methods: An Italian Multicenter Study" Int. J. Environ. Res. Public Health 2017, 14, 670. AB - We would like to thank Collins andWalker for their comments and for acknowledging that this is an area requiring more research to improve our basic understanding of Legionella [1]. [...]. PMID- 28800079 TI - Challenging the Metallothionein (MT) Gene of Biomphalaria glabrata: Unexpected Response Patterns Due to Cadmium Exposure and Temperature Stress. AB - Metallothioneins (MTs) are low-molecular-mass, cysteine-rich, metal binding proteins. In most animal species, they are involved in metal homeostasis and detoxification, and provide protection from oxidative stress. Gastropod MTs are highly diversified, exhibiting unique features and adaptations like metal specificity and multiplications of their metal binding domains. Here, we show that the MT gene of Biomphalaria glabrata, one of the largest MT genes identified so far, is composed in a unique way. The encoding for an MT protein has a three domain structure and a C-terminal, Cys-rich extension. Using a bioinformatic approach involving structural and in silico analysis of putative transcription factor binding sites (TFBs), we found that this MT gene consists of five exons and four introns. It exhibits a regulatory promoter region containing three metal responsive elements (MREs) and several TFBs with putative involvement in environmental stress response, and regulation of gene expression. Quantitative real-time polymerase chain reaction (qRT-PCR) data indicate that the MT gene is not inducible by cadmium (Cd) nor by temperature challenges (heat and cold), despite significant Cd uptake within the midgut gland and the high Cd tolerance of metal-exposed snails. PMID- 28800080 TI - H2S-Mediated Protein S-Sulfhydration: A Prediction for Its Formation and Regulation. AB - Protein S-sulfhydration is a newly discovered post-translational modification of specific cysteine residue(s) in target proteins, which is involved in a broad range of cellular functions and metabolic pathways. By changing local conformation and the final activity of target proteins, S-sulfhydration is believed to mediate most cellular responses initiated by H2S, a novel gasotransmitter. In comparison to protein S-sulfhydration, nitric oxide-mediated protein S-nitrosylation has been extensively investigated, including its formation, regulation, transfer and metabolism. Although the investigation on the regulatory mechanisms associated with protein S-sulfhydration is still in its infancy, accumulated evidence suggested that protein S-sulfhydration may share similar chemical features with protein S-nitrosylation. Glutathione persulfide acts as a major donor for protein S-sulfhydration. Here, we review the present knowledge on protein S-sulfhydration, and also predict its formation and regulation mechanisms based on the knowledge from protein S-nitrosylation. PMID- 28800081 TI - Autonomic Dysfunction after Mild Traumatic Brain Injury. AB - A mild traumatic brain injury (mTBI) is a complex pathophysiologic process that has a systemic effect on the body aside from solely an impairment in cognitive function. Dysfunction of the autonomic nervous system (ANS) has been found to induce abnormalities in organ systems throughout the body, and may contribute to cardiovascular dysregulation and increased mortality. Autonomic dysfunction, also known as dysautonomia, has been studied in moderate and severe TBI, and has emerged as a major contributing factor in the symptomatology in mTBI as well. Analysis of the ANS has been studied through changes in heart rate variability (HRV), pupillary dynamics, eye pressure, and arterial pulse wave in those with mild TBI. Graded exercise testing has been studied as both a method of diagnosis and as a means of recovery in those with mild TBI, especially in those with persistent symptoms. Given the studies showing persistence of autonomic dysfunction after symptomatic resolution of concussions, further research is needed to establish return to play protocols. PMID- 28800082 TI - Complete Chloroplast Genome Sequence and Phylogenetic Analysis of the Medicinal Plant Artemisia annua. AB - The complete chloroplast genome of Artemisia annua (Asteraceae), the primary source of artemisinin, was sequenced and analyzed. The A. annua cp genome is 150,995 bp, and harbors a pair of inverted repeat regions (IRa and IRb), of 24,850 bp each that separate large (LSC, 82,988 bp) and small (SSC, 18,267 bp) single-copy regions. Our annotation revealed that the A. annua cp genome contains 113 genes and 18 duplicated genes. The gene order in the SSC region of A. annua is inverted; this fact is consistent with the sequences of chloroplast genomes from three other Artemisia species. Fifteen (15) forward and seventeen (17) inverted repeats were detected in the genome. The existence of rich SSR loci in the genome suggests opportunities for future population genetics work on this anti-malarial medicinal plant. In A. annua cpDNA, the rps19 gene was found in the LSC region rather than the IR region, and the rps19 pseudogene was absent in the IR region. Sequence divergence analysis of five Asteraceae species indicated that the most highly divergent regions were found in the intergenic spacers, and that the differences between A. annua and A. fukudo were very slight. A phylogenetic analysis revealed a sister relationship between A. annua and A. fukudo. This study identified the unique characteristics of the A. annua cp genome. These results offer valuable information for future research on Artemisia species identification and for the selective breeding of A. annua with high pharmaceutical efficacy. PMID- 28800083 TI - Effect of Angelica sinensis Root Extract on Cancer Prevention in Different Stages of an AOM/DSS Mouse Model. AB - Angelica sinensis root (ASR) extract was obtained to investigate its effects on colorectal carcinogenesis in different stages of an Azoxymethane/Dextran sodium sulphate (AOM/DSS) model. In this study, we showed that ASR extract administration in the initial stage of the AOM/DSS model had cancer preventive effects with decreasing tumor incidence and a high-grade of intraepithelial neoplasia incidence. With respect to DNA damage, the amounts of 8-oxoguanine and gamma-H2AX were suppressed in colon tissue. The balance of apoptosis and proliferation was approaching the normal state. In contrast, ASR extract administration in the promotion stage of the AOM/DSS model accelerated the progression of carcinogenesis. The maximum tumor size reached 49.85 +/- 25.04 mm3. High-grade pathological changes were significantly increased. Decreased DNA damage and P53 level reflected the disrupted reactive oxygen species (ROS) concentration in colorectal tissue, which led to an imbalance of proliferative and apoptotic relationships. These findings suggested that the cancer-preventive effect of ASR extract may be stage-dependent in the process of carcinogenesis. PMID- 28800084 TI - The Dry Sliding Wear Properties of Nano-Sized TiCp/Al-Cu Composites at Elevated Temperatures. AB - Nano-sized ceramic particle reinforced aluminum composites exhibit excellent room temperature mechanical properties. However, there is limited research on the dry sliding wear behavior of those composites at elevated temperatures, which should be one of the major concerns on elevated temperature applications. Here the Al-Cu composites reinforced with nano-sized TiCp were fabricated. The dry sliding wear behaviors of the nano-sized TiCp/Al-Cu composites at various temperatures (140 220 degrees C) and loads (10-40 N) with different TiCp contents were studied, and the results showed that the nanocomposites exhibited superior wear resistance. For instance, the relative wear resistance of the 0.5 wt.% nano-sized TiCp/Al-Cu composite was 83.5% higher than that of the Al-Cu matrix alloy at 180 degrees C under 20 N, and was also 16.5% higher than that of the 5 wt.% micro sized TiCp/Al-Cu composite, attributed to the pronounced Orowan strengthening effect of nanoparticles. The wear rates of the nanocomposites were always lower than those of the Al-Cu matrix alloy under the same test condition, which increased with the increase in temperature and load and with the decrease in TiCp content. PMID- 28800085 TI - Recent Progress of Development of Optogenetic Implantable Neural Probes. AB - As a cell type-specific neuromodulation method, optogenetic technique holds remarkable potential for the realisation of advanced neuroprostheses. By genetically expressing light-sensitive proteins such as channelrhodopsin-2 (ChR2) in cell membranes, targeted neurons could be controlled by light. This new neuromodulation technique could then be applied into extensive brain networks and be utilised to provide effective therapies for neurological disorders. However, the development of novel optogenetic implants is still a key challenge in the field. The major requirements include small device dimensions, suitable spatial resolution, high safety, and strong controllability. In this paper, I present a concise review of the significant progress that has been made towards achieving a miniaturised, multifunctional, intelligent optogenetic implant. I identify the key limitations of current technologies and discuss the possible opportunities for future development. PMID- 28800086 TI - The Potential for Reassortment between Oropouche and Schmallenberg Orthobunyaviruses. AB - A number of viruses within the Peribunyaviridae family are naturally occurring reassortants, a common phenomenon for segmented viruses. Using a minigenome reporter and virus-like particle (VLP) production assay, we have accessed the potential of Oropouche virus (OROV), Schmallenberg virus (SBV), and other orthobunyaviruses within the Simbu serogroup to reassort. We found that the untranslated region (UTR) in the medium segment is a potential contributing factor for reassortment by the tested viruses. We demonstrate that for promoter activity to occur it was essential that the viral RNA polymerase (L) and nucleocapsid (N) proteins were from the same virus, reinforcing the hypothesis that the large and small segments that encode these proteins segregate together during genome reassortment. Our results indicate that, given the right epidemiological setting, reassortment between SBV and OROV would potentially be feasible and could contribute to the emergence of a new Simbu virus. PMID- 28800087 TI - Imaging Features of Non-Alcoholic Fatty Liver Disease in Children and Adolescents. AB - Non-invasive diagnosis and quantification of liver steatosis is important to overcome limits of liver biopsy, in order to follow up patients during their therapy and to establish a reference standard that can be used in clinical trials and longitudinal studies. Imaging offers several methods in this setting: ultrasound, which is the cheapest technique and easy to perform; magnetic resonance spectroscopy (MRS), which reflects the real content of triglycerides in a specific volume; and proton density fat fraction (PDFF) magnetic resonance, which is a simple method that reflects the distribution of the fat in the whole liver. Other techniques include ultrasound elastography (EUS) and magnetic resonance elastrography (MRE), which can evaluate the progression of non alcoholic fatty liver disease (NAFLD) into non-alcoholic steato-hepatitis (NASH) and cirrhosis, by quantifying liver fibrosis. PMID- 28800088 TI - Upregulation and Identification of Antibiotic Activity of a Marine-Derived Streptomyces sp. via Co-Cultures with Human Pathogens. AB - Marine natural product drug discovery has begun to play an important role in the treatment of disease, with several recently approved drugs. In addition, numerous microbial natural products have been discovered from members of the order Actinomycetales, particularly in the genus Streptomyces, due to their metabolic diversity for production of biologically active secondary metabolites. However, many secondary metabolites cannot be produced under laboratory conditions because growth conditions in flask culture differ from conditions in the natural environment. Various experimental conditions (e.g., mixed fermentation) have been attempted to increase yields of previously described metabolites, cause production of previously undetected metabolites, and increase antibiotic activity. Adult ascidians-also known as tunicates-are sessile marine invertebrates, making them vulnerable to predation and therefore are hypothesized to use host-associated bacteria that produce biologically active secondary metabolites for chemical defense. A marine-derived Streptomyces sp. strain PTY087I2 was isolated from a Panamanian tunicate and subsequently co-cultured with human pathogens including Bacillus subtilis, methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), and Pseudomonas aeruginosa, followed by extraction. Co-culture of Streptomyces sp. PTY087I2 with each of these human pathogens resulted in increased production of three antibiotics: granaticin, granatomycin D, and dihydrogranaticin B, as well as several analogues seen via molecular networking. In addition, co-cultures resulted in strongly enhanced biological activity against the Gram positive human pathogens used in these experiments. Expanded utilization of co-culture experiments to allow for competitive interactions may enhance metabolite production and further our understanding of these microbial interactions. PMID- 28800089 TI - FITNET's Internet-Based Cognitive Behavioural Therapy Is Ineffective and May Impede Natural Recovery in Adolescents with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. A Review. AB - The Dutch Fatigue In Teenagers on the interNET (FITNET) study claimed that after 6 months, internet based cognitive behaviour therapy in adolescents with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), led to a 63% recovery rate compared to 8% after usual care, and that this was maintained at long term follow up (LTFU). Our reanalysis shows that their post-hoc definition of recovery included the severely ill, the unblinded trial had no adequate control group and it used lax selection criteria as well as outcomes assessed via questionnaires rather than objective outcomes, further contributing to exaggerated recovery figures. Their decision not to publish the actometer results might suggest that these did not back their recovery claims. Despite these bias creating methodological faults, the trial still found no significant difference in recovery rates ("~60%") at LTFU, the trial's primary goal. This is similar to or worse than the documented 54-94% spontaneous recovery rates within 3-4 years, suggesting that both FITNET and usual care (consisting of cognitive behaviour and graded exercise therapies) are ineffective and might even impede natural recovery in adolescents with ME/CFS. This has implications for the upcoming costly NHS FITNET trial which is a blueprint of the Dutch study, exposing it to similar biases. PMID- 28800090 TI - The Effect of Buffering High Acid Load Meal with Sodium Bicarbonate on Postprandial Glucose Metabolism in Humans-A Randomized Placebo-Controlled Study. AB - Background: High dietary acid load relates to increased risk of type 2 diabetes in epidemiological studies. We aimed to investigate whether buffering a high acid load meal with an alkalizing treatment changes glucose metabolism post meal. Methods: Non-diabetic participants (n = 32) were randomized to receive either 1680 mg NaHCO3 or placebo, followed by a high acid load meal in a double-blind placebo-controlled crossover (1-4 weeks apart) study. Thirty (20 men) participants completed the study. Venous blood pH, serum bicarbonate, blood glucose, serum insulin, C-peptide, non-esterified fatty acid (NEFA), and plasma glucagon-like peptide-1 (GLP-1) concentrations were measured at baseline (fasting) and at 15-30 min intervals for 3 h post meal. Results: The treatment was well tolerated. Venous blood pH declined in the first 15 min post meal with the placebo (p = 0.001), but not with NaHCO3 (p = 0.86) and remained decreased with the placebo for 3 h (pinteraction = 0.04). On average over the 3 h blood pH iAUC was greater with NaHCO3 compared with placebo (p = 0.02). However, postprandial glucose, insulin, C-peptide, NEFA and GLP-1 were not different between treatments (pinteraction >= 0.07). Conclusions: An alkalizing medication administered pre-meal has no acute effect on glycaemia and insulin response in healthy individuals. Long-term interventions in at-risk populations are necessary to investigate the effect of sustained alkalization on glucose metabolism. PMID- 28800091 TI - Inverse Associations between a Locally Validated Mediterranean Diet Index, Overweight/Obesity, and Metabolic Syndrome in Chilean Adults. AB - Obesity and metabolic syndrome (MetS) are key risk factors for chronic disease. Dietary patterns are critical in the incidence and persistence of obesity and MetS, yet there is few data linking diet to obesity and MetS in Chile. Our objective was to use a locally validated diet index to evaluate adherence to a Mediterranean dietary pattern and its correlations with overweight/obesity (OW/O) and MetS prevalence in Chilean adults. We conducted a nationwide, cross-sectional online survey of Chilean adults with complete self-reported diet and body mass index data (n = 24,882). A subsample of 4348 users (17.5%) had valid MetS data. An inverse association was observed between adherence to Mediterranean diet and OW/O and MetS prevalence. As diet quality decreased from healthy, to moderately healthy, to unhealthy, prevalence increased from 44.8, 51.1, to 60.9% for OW/O and from 13.4, 18.5, to 28.9% for MetS (p-values < 0.001). Adjusted odds ratios for OW/O and MetS were significantly higher in moderately-healthy (OR = 1.58 and 1.54) and unhealthy (OR = 2.20 and 2.49, respectively) diet groups in comparison to the healthy diet group. This study represents the first report on the relationship between Mediterranean diet and chronic disease risk in Chile. It suggests that the Mediterranean diet may be applied to manage chronic disease risk beyond the Mediterranean basin. PMID- 28800092 TI - Induced Aberrant Organisms with Novel Ability to Protect Intestinal Integrity from Inflammation in an Animal Model. AB - : Robust and balanced gut microbiota are required to support health and growth. Overgrowth of gut microbial or pathogens can change ecosystem balance, and compromise gut integrity to initiate gastrointestinal (GI) complications. There is no safe and effective modality against coccidiosis. Antibiotic additives routinely fed to food animals to protect against infection, are entered into the food chain, contaminate food products and pass to the consumers. HYPOTHESIS: induced aberrant organisms possess distinct ultrastructure and are tolerated by immunodeficient-animals yet are non-pathogenic, but immunogenic in various strains of chicks to act as a preventive (vaccine) and eliminating the needs for antibiotic additives. Methods: cyclophosphamide-immunodeficient and immune-intact chicks were inoculated with induced aberrant or normal Coccidal-organisms. Immune intact-chicks were immunized with escalating-doses of organisms. Results: Aberrant organisms showed distinct ultrastructure with 8-free-sporozoites which lacked sporocysts walls and veils. Immunodeficient-chicks inoculated with normal organisms developed severe GI complications but tolerated aberrant-organisms (p < 0.001) while they had no detectable antibodies. Naive-animals challenged with a pathogenic-dose showed GI complications, bloody diarrhea, severe lesions and weight loss. Immune-intact-animals immunized with aberrant forms were protected against high dose normal-pathogenic-challenge infection and gained more weight compared to those immunized with normal-organisms (p < 0.05). Conclusions: Aberrant organisms possess a distinct ultrastructure and are tolerated in immunodeficient-chicks, yet provide novel immune-protection against pathogenic challenges including diarrhea, malnutrition and weight loss in immune-intact animals to warrant further investigations toward vaccine production. PMID- 28800093 TI - Omega-3 Fatty Acids and Cardiovascular Disease: Summary of the 2016 Agency of Healthcare Research and Quality Evidence Review. AB - We summarize the 2016 update of the 2004 Agency of Healthcare Research and Quality's evidence review of omega-3 fatty acids and cardiovascular disease (CVD). The overall findings for the effects of marine oil supplements on intermediate CVD outcomes remain largely unchanged. There is high strength of evidence, based on numerous trials, of no significant effects of marine oils on systolic or diastolic blood pressures, but there are small, yet statistically significant increases in high density lipoprotein and low density lipoprotein cholesterol concentrations. The clinical significance of these small changes, particularly in combination, is unclear. The strongest effect of marine oils is on triglyceride concentrations. Across studies, this effect was dose-dependent and related to studies' mean baseline triglyceride concentration. In observational studies, there is low strength of evidence that increased marine oil intake lowers ischemic stroke risk. Among randomized controlled trials and observational studies, there is evidence of variable strength of no association with increased marine oil intake and lower CVD event risk. Evidence regarding alpha-linolenic acid intake is sparser. There is moderate strength of evidence of no effect on blood pressure or lipoprotein concentrations and low strength of evidence of no association with coronary heart disease, atrial fibrillation and congestive heart failure. PMID- 28800094 TI - Socioeconomic Inequalities in Visits to the Dentist to Receive Professionally Applied Topical Fluoride in a Developing Country. AB - OBJECTIVE: To determine the frequency and associated factors of visits to the dentist in the last year by Nicaraguan schoolchildren to receive professionally applied topical fluoride (PATF). MATERIAL AND METHODS: A cross-sectional study was designed in children from public schools in the city of Leon, Nicaragua, were included. A series of socioeconomic, sociodemographic, and behavioural variables were collected through a questionnaire. The dependent variable was the visit to the dentist to receive professionally applied topical fluoride in the last year, which was dichotomised as (0) Did not receive PATF and (1) Yes received PATF. In the statistical analysis, binary logistic regression was used. RESULTS: The mean age of the students included was 9 years, and 49.9% were girls. The prevalence of visits to the dentist in the last year to receive PATF was 3.1%. In the multivariate model, the associated characteristics (p < 0.05) were: female (OR = 2.73, 95% CI = 1.34-4.50); the positive attitude of the mother to the oral health of her child (OR = 2.15, 95% CI = 1.03-4.50); and the best socioeconomic position (OR = 2.68, 95% CI = 1.36-5.31). CONCLUSIONS: The prevalence of visits to the dentist in the last year to receive professionally applied topical fluoride was very low (3.1%). The results of the socioeconomic position suggest the existence of certain inequalities in oral health. It is necessary to implement policies and programs aimed at improving this scenario. PMID- 28800095 TI - Influence of Polymer-Clay Interfacial Interactions on the Ignition Time of Polymer/Clay Nanocomposites. AB - Metal ions present on smectite clay (montmorillonite) platelets have preferential reactivity towards peroxy/alkoxy groups during polyamide 6 (PA6) thermal decomposition. This changes the decomposition pathway and negatively affects the ignition response of PA6. To restrict these interfacial interactions, high temperature-resistant polymers such as polyetherimide (PEI) and polyimide (PI) were used to coat clay layers. PEI was deposited on clay by solution precipitation, whereas PI was deposited through a solution-imidization precipitation technique before melt blending with PA6. The absence of polymer clay interfacial interactions has resulted in a similar time-to-ignition of PA6/PEI-clay (133 s) and PA6/PI-clay (139 s) composites as neat PA6 (140 s). On the contrary, PA6 with conventional ammonium-based surfactant modified clay has showed a huge drop in time-to-ignition (81 s), as expected. The experimental evidences provided herein reveal the role of the catalytic activity of clay during the early stages of polymer decomposition. PMID- 28800096 TI - An Iterative Closest Points Algorithm for Registration of 3D Laser Scanner Point Clouds with Geometric Features. AB - The Iterative Closest Points (ICP) algorithm is the mainstream algorithm used in the process of accurate registration of 3D point cloud data. The algorithm requires a proper initial value and the approximate registration of two point clouds to prevent the algorithm from falling into local extremes, but in the actual point cloud matching process, it is difficult to ensure compliance with this requirement. In this paper, we proposed the ICP algorithm based on point cloud features (GF-ICP). This method uses the geometrical features of the point cloud to be registered, such as curvature, surface normal and point cloud density, to search for the correspondence relationships between two point clouds and introduces the geometric features into the error function to realize the accurate registration of two point clouds. The experimental results showed that the algorithm can improve the convergence speed and the interval of convergence without setting a proper initial value. PMID- 28800097 TI - Why Do People Like Loud Sound? A Qualitative Study. AB - Many people choose to expose themselves to potentially dangerous sounds such as loud music, either via speakers, personal audio systems, or at clubs. The Conditioning, Adaptation and Acculturation to Loud Music (CAALM) Model has proposed a theoretical basis for this behaviour. To compare the model to data, we interviewed a group of people who were either regular nightclub-goers or who controlled the sound levels in nightclubs (bar managers, musicians, DJs, and sound engineers) about loud sound. Results showed four main themes relating to the enjoyment of loud sound: arousal/excitement, facilitation of socialisation, masking of both external sound and unwanted thoughts, and an emphasis and enhancement of personal identity. Furthermore, an interesting incidental finding was that sound levels appeared to increase gradually over the course of the evening until they plateaued at approximately 97 dBA Leq around midnight. Consideration of the data generated by the analysis revealed a complex of influential factors that support people in wanting exposure to loud sound. Findings were considered in terms of the CAALM Model and could be explained in terms of its principles. From a health promotion perspective, the Social Ecological Model was applied to consider how the themes identified might influence behaviour. They were shown to influence people on multiple levels, providing a powerful system which health promotion approaches struggle to address. PMID- 28800098 TI - Porous Graphene Oxide Prepared on Nickel Foam by Electrophoretic Deposition and Thermal Reduction as High-Performance Supercapacitor Electrodes. AB - A simple electrophoretic deposition method was developed to prepare graphene oxide (GO) films on the frameworks of nickel foam without any conductive agents and polymer binders. Then, GO was transformed into thermally-reduced graphene oxide (RGO) at an appropriate temperature. The effects of deposition voltage and thermal reduction temperature on the electrochemical properties of RGO were investigated by cyclic voltammetry (CV) and galvanostatic charge/discharge. The appropriate combination of deposition voltage and thermal reduction temperature was established. Moreover, scanning electron microscopy, thermal gravimetric analysis, differential thermal analysis, Fourier transform infrared spectroscopy, Raman spectroscopy, and X-ray diffractometry were applied to validate the results, which showed that the highest specific capacitance of RGO was obtained when the deposition voltage was 60 V and the thermal reduction temperature was 300 degrees C. The specific capacitance values calculated by CV and galvanostatic charge/discharge were 139 F.g-1 (0.005 V.s-1) and 151 F.g-1 (1 A.g 1), respectively. The specific capacitance of RGO maintained 55% and 66% of the initial value when the scan rate and the current density were increased up to 0.3 V.s-1 and 10 A.g-1, respectively. RGO also displayed an excellent cycling stability by maintaining 98% of the initial specific capacitance after 500 cycles. PMID- 28800099 TI - Portuguese Honeys from Different Geographical and Botanical Origins: A 4-Year Stability Study Regarding Quality Parameters and Antioxidant Activity. AB - Portuguese honeys (n = 15) from different botanical and geographical origins were analysed regarding their quality parameters (diastase activity, hydroxymethylfurfural content, moisture and pH), colour (L*, a*, b*) and antioxidant profile (total phenolics content, total flavonoids content, DPPH* scavenging activity, and ferric reducing power). The samples were analysed fresh and after 4-years of storage (at 25 degrees C and protected from light). The hydroxymethylfurfural content and diastase activity of the fresh samples were in accordance with the recommended values described in the legislation. In general, the antioxidant activity of the samples correlated more with the bioactive compounds content than with colour. The storage affected differently each individual sample, especially regarding the antioxidant profile. Nevertheless, although in general the lightness of the samples decreased (and the redness increased), after 4 years, 11 samples still presented acceptable diastase activity and hydroxymethylfurfural values. PMID- 28800100 TI - Readily Available Chiral Benzimidazoles-Derived Guanidines as Organocatalysts in the Asymmetric alpha-Amination of 1,3-Dicarbonyl Compounds. AB - The synthesis and the evaluation as organocatalysts of new chiral guanidines derived from benzimidazoles in the enantioselective alpha-amination of 1,3 dicarbonyl compounds using di-t-butylazodicarboxylate as aminating agent is herein disclosed. The catalysts are readily synthesized through the reaction of 2 chlorobezimidazole and a chiral amine in moderate-to-good yields. Among all of them, those derived from (R)-1-phenylethan-1-amine (1) and (S)-1-(2 naphthyl)ethan-1-amine (3) turned out to be the most efficient for such asymmetric transformation, rendering good-to-high yields and moderate-to-good enantioselectivities for the amination products. PMID- 28800102 TI - A Grid Connected Photovoltaic Inverter with Battery-Supercapacitor Hybrid Energy Storage. AB - The power generation from renewable power sources is variable in nature, and may contain unacceptable fluctuations, which can be alleviated by using energy storage systems. However, the cost of batteries and their limited lifetime are serious disadvantages. To solve these problems, an improvement consisting in the collaborative association of batteries and supercapacitors has been studied. Nevertheless, these studies don't address in detail the case of residential and large-scale photovoltaic systems. In this paper, a selected combined topology and a new control scheme are proposed to control the power sharing between batteries and supercapacitors. Also, a method for sizing the energy storage system together with the hybrid distribution based on the photovoltaic power curves is introduced. This innovative contribution not only reduces the stress levels on the battery, and hence increases its life span, but also provides constant power injection to the grid during a defined time interval. The proposed scheme is validated through detailed simulation and experimental tests. PMID- 28800101 TI - Induced Pluripotent Stem Cell Neuronal Models for the Study of Autophagy Pathways in Human Neurodegenerative Disease. AB - Human induced pluripotent stem cells (hiPSCs) are invaluable tools for research into the causes of diverse human diseases, and have enormous potential in the emerging field of regenerative medicine. Our ability to reprogramme patient cells to become hiPSCs, and to subsequently direct their differentiation towards those classes of neurons that are vulnerable to stress, is revealing how genetic mutations cause changes at the molecular level that drive the complex pathogeneses of human neurodegenerative diseases. Autophagy dysregulation is considered to be a major contributor in neural decline during the onset and progression of many human neurodegenerative diseases, meaning that a better understanding of the control of non-selective and selective autophagy pathways (including mitophagy) in disease-affected classes of neurons is needed. To achieve this, it is essential that the methodologies commonly used to study autophagy regulation under basal and stressed conditions in standard cell-line models are accurately applied when using hiPSC-derived neuronal cultures. Here, we discuss the roles and control of autophagy in human stem cells, and how autophagy contributes to neural differentiation in vitro. We also describe how autophagy-monitoring tools can be applied to hiPSC-derived neurons for the study of human neurodegenerative disease in vitro. PMID- 28800103 TI - The Ultrasonic Directional Tidal Breathing Pattern Sensor: Equitable Design Realization Based on Phase Information. AB - Pulmonary ailments are conventionally diagnosed by spirometry. The complex forceful breathing maneuver as well as the extreme cost of spirometry renders it unsuitable in many situations. This work is aimed to facilitate an emerging direction of tidal breathing-based pulmonary evaluation by designing a novel, equitable, precise and portable device for acquisition and analysis of directional tidal breathing patterns, in real time. The proposed system primarily uses an in-house designed blow pipe, 40-kHz air-coupled ultrasound transreceivers, and a radio frequency (RF) phase-gain integrated circuit (IC). Moreover, in order to achieve high sensitivity in a cost-effective design philosophy, we have exploited the phase measurement technique, instead of selecting the contemporary time-of-flight (TOF) measurement; since application of the TOF principle in tidal breathing assessments requires sub-micro to nanosecond time resolution. This approach, which depends on accurate phase measurement, contributed to enhanced sensitivity using a simple electronics design. The developed system has been calibrated using a standard 3-L calibration syringe. The parameters of this system are validated against a standard spirometer, with maximum percentage error below 16%. Further, the extracted respiratory parameters related to tidal breathing have been found to be comparable with relevant prior works. The error in detecting respiration rate only is 3.9% compared to manual evaluation. These encouraging insights reveal the definite potential of our tidal breathing pattern (TBP) prototype for measuring tidal breathing parameters in order to extend the reach of affordable healthcare in rural regions and developing areas. PMID- 28800104 TI - Chemometric Analysis of Lavender Essential Oils Using Targeted and Untargeted GC MS Acquired Data for the Rapid Identification and Characterization of Oil Quality. AB - Standard raw material test methods such as the ISO Standard 11024 are focused on the identification of lavender oil and not the actual class/quality of the oil. However, the quality of the oil has a significant effect on its price at market. As such, there is a need for raw material tests to identify not only the type of oil but its quality. This paper describes two approaches to rapidly identifying and classifying lavender oil. First, the ISO Standard 11024 test method was evaluated in order to determine its suitability to assess lavender oil quality but due to its targeted and simplistic approach, it has the potential to miss classify oil quality. Second, utilizing the data generated by the ISO Standard 11024 test methodology, an untargeted chemometric predicative model was developed in order to rapidly assess and characterize lavender oils (Lavandulaangustifolia L.) for geographical/environmental adulteration that impact quality. Of the 170 compounds identified as per the ISO Standard 11024 test method utilizing GC-MS analyses, 15 unique compounds that greatly differentiate between the two classes of lavender were identified. Using these 15 compounds, a predicative multivariate chemometric model was developed that enabled lavender oil samples to be reliably differentiated based on quality. A misclassification analysis was performed and it was found that the predictions were sound (100% matching rate). Such an approach will enable producers, distributers, suppliers and manufactures to rapidly screen lavender essential oil. The authors concede that the validation and implementation of such an approach is more difficult than a conventional chromatographic assay. However, the rapid, reliable and less problematic screening is vastly superior and easily justifies any early implementation validation difficulties and costs. PMID- 28800105 TI - Anti-Anxiety Effect of (-)-Syringaresnol-4-O-beta-d-apiofuranosyl-(1->2)-beta-d glucopyranoside from Albizzia julibrissin Durazz (Leguminosae). AB - Albizzia julibrissin Durazz, a Chinese Medicine, is commonly used for its anti anxiety effects. (-)-syringaresnol-4-O-beta-d-apiofuranosyl-(1->2)-beta-d glucopyranoside (SAG) is the main ingredient of Albizzia julibrissin Durazz. The present study investigated the anxiolytic effect and potential mechanisms on the HPA axis and monoaminergic systems of SAG on acute restraint-stressed rats. The anxiolytic effect of SAG was examined through an open field test and an elevated plus maze test. The concentration of CRF, ACTH, and CORT in plasma was examined by an enzyme-linked immune sorbent assay (ELISA) kit while neurotransmitters in the cerebral cortex and hippocampus of the brain were examined by High Performance Liquid Chromatography (HPLC). We show that repeated treatment with SAG (3.6 mg/kg, p.o.) significantly increased the number and time spent on the central entries in the open-field test when compared to the vehicle/stressed group. In the elevated plus maze test, 3.6 mg/kg SAG could increase the percentage of entries into and time spent on the open arms of the elevated plus maze. In addition, the concentration of CRF, ACTH, and CORT in plasma and neurotransmitters (NE, 5-HT, DA and their metabolites 5-HIAA, DOPAC, and HVA) in the cerebral cortex and hippocampus of the brain were decreased after SAG treatment, as compared to the repeated acute restraint-stressed rats. These results suggest that SAG is a potential anti-anxiety drug candidate. PMID- 28800107 TI - Sequestration Effect on the Open-Cyclic Switchable Property of Warfarin Induced by Cyclodextrin: Time-Resolved Fluorescence Study. AB - The excited-state lifetimes of the anticoagulant drug warfarin (W) in water and in the absence and presence of methyl-beta-cyclodextrins (Me-beta-CD) were recorded using time-resolved fluorescence measurements. Selective excitation of the open and cyclic protonated isomers of W were acquired with laser emitting diodes (LED) producing 320 and 280 nm excitation pulses, respectively. Formation of the inclusion complex was checked by UV-visible absorption spectroscopy, and the values of binding constants (2.9 * 103 M-1 and 4.2 * 102 M-1 for protonated and deprotonated forms, respectively) were extracted from the spectrophotometric data. Both absorption and time-resolved fluorescence results established that the interior of the macromolecular host binds preferentially the open protonated form, red shifts the maximum of its absorption of light at ~305 nm, extends its excited-state lifetime, and decreases its emission quantum yield (FF). Collectively, sequestration of the open guest molecules decreases markedly their radiative rate constants (kr), likely due to formation of hydrogen-bonded complexes in both the ground and excited states. Due to lack of interactions, no change was observed in the excited-state lifetime of the cyclic form in the presence of Me-beta-CD. The host also increases the excited-state lifetime and FF of the drug deprotonated form (W-). These later findings could be attributed to the increased rigidity inside the cavity of Me-beta-CD. The pKa values extracted from the variations of the UV-visible absorption spectra of W versus the pH of aqueous solution showed that the open isomer is more acidic in both ground and excited states. The positive shifts in pKa values induced by three derivatives of cyclodextrins: HE-beta-CD, Ac-beta-CD, and Me-beta-CD supported the preferential binding of these hosts to open isomers over cyclic. PMID- 28800106 TI - Recent Trends on Electrochemical Sensors Based on Ordered Mesoporous Carbon. AB - The past decade has seen an increasing number of extensive studies devoted to the exploitation of ordered mesoporous carbon (OMC) materials in electrochemistry, notably in the fields of energy and sensing. The present review summarizes the recent achievements made in field of electroanalysis using electrodes modified with such nanomaterials. On the basis of comprehensive tables, the interest in OMC for designing electrochemical sensors is illustrated through the various applications developed to date. They include voltammetric detection after preconcentration, electrocatalysis (intrinsically due to OMC or based on suitable catalysts deposited onto OMC), electrochemical biosensors, as well as electrochemiluminescence and potentiometric sensors. PMID- 28800108 TI - Optical Refractive Index Sensing Based on High-Q Bound States in the Continuum in Free-Space Coupled Photonic Crystal Slabs. AB - High sensitivity (S) and high quality factor (Q) are desirable to achieve low detection limit in label-free optical sensors. In this paper, we theoretically demonstrate that single-layer and coupled bi-layer photonic crystal slabs (PCS) possess simultaneously high S and high Q near the bound states in the continuum (BIC). We theoretically achieved S > 800 nm/RIU and Q > 107 in refractive index sensing in the 1400-1600 nm telecom optical wavelength bands. We experimentally demonstrated an S of 94 nm/RIU and a Q of 1.2 * 104, with a detection limit of 6 * 10-5 refractive index unit. These sensor designs can find applications in biochemical sensing, environmental monitoring, and healthcare. PMID- 28800109 TI - Effects of ZnO Nanoparticle on the Gas Separation Performance of Polyurethane Mixed Matrix Membrane. AB - Polyurethane (PU)-ZnO mixed matrix membranes (MMM) were fabricated and characterized for gas separation. A thermogravimetric analysis (TGA), a scanning electron microscope (SEM) test and an atomic-force microscopy (AFM) revealed that the physical properties and thermal stability of the membranes were improved through filler loading. Hydrogen Bonding Index, obtained from the Fourier transform infrared spectroscopy (FTIR), demonstrate that the degree of phase separation in PU-ZnO 0.5 wt % MMM was more than the neat PU, while in PU-ZnO 1.0 wt % MMM, the phase mixing had increased. Compared to the neat membrane, the CO2 permeability of the MMMs increased by 31% for PU-ZnO 0.5 wt % MMM and decreased by 34% for 1.0 wt % ZnO MMM. The CO2/CH4 and CO2/N2 selectivities of PU-ZnO 0.5 wt % were 18.75 and 64.75, respectively. PMID- 28800110 TI - Response of Dermal Fibroblasts to Biochemical and Physical Cues in Aligned Polycaprolactone/Silk Fibroin Nanofiber Scaffolds for Application in Tendon Tissue Engineering. AB - Silk fibroin (SF) and fiber alignment were introduced into polycaprolactone (PCL) based electrospun nanofibers as chemical and physical cues for tendon tissue engineering applications. The physicochemical properties of random PCL (RP) nanofibers, random PCL/SF (RPSF) nanofibers and aligned PCL/SF (APSF) nanofibers were characterized for fiber orientation and SF blending effects. An in vitro cell culture with rabbit dermal fibroblasts (RDFBs) on nanofibers indicated that SF promotes cell proliferation to a higher extent than fiber alignment. Cells aligned in the direction of fiber axes could be confirmed through scanning electron microscopy (SEM) observation and cytoskeleton staining. The quantitative real-time polymerase chain reaction (qRT-PCR) experiments indicated up-regulated gene expression of tendon marker proteins (type I collagen (Col I), fibronectin and biglycan) on APSF nanofibers and tendon reconstruction was confirmed from Col III gene expression. Animal experiments with Achilles tendon defect repairs in rabbits were carried out with RPSF and APSF scaffolds. The beneficial effects of fiber alignment were verified from histological and immunohistochemical staining, where cell migration and extracellular matrix protein deposition tend to stretch in a parallel direction along the axial direction of APSF nanofibers with enhanced Col I and tenascin C production. Biomechanical testing indicated the tensile stiffness and maximum load of cell-seeded APSF scaffolds were 60.2 and 81.3% of normal tendon values, respectively, which are significantly higher than cell-seeded RPSF or acellular APSF and RPSF scaffolds. These results suggest that APSF nanofiber scaffolds combined with RDFBs have the potential to repair the gap defects of Achilles tendons in vivo and to effectively restore the function and structure of tendons. PMID- 28800111 TI - Translational Imaging Spectroscopy for Proximal Sensing. AB - Proximal sensing as the near field counterpart of remote sensing offers a broad variety of applications. Imaging spectroscopy in general and translational laboratory imaging spectroscopy in particular can be utilized for a variety of different research topics. Geoscientific applications require a precise pre processing of hyperspectral data cubes to retrieve at-surface reflectance in order to conduct spectral feature-based comparison of unknown sample spectra to known library spectra. A new pre-processing chain called GeoMAP-Trans for at surface reflectance retrieval is proposed here as an analogue to other algorithms published by the team of authors. It consists of a radiometric, a geometric and a spectral module. Each module consists of several processing steps that are described in detail. The processing chain was adapted to the broadly used HySPEX VNIR/SWIR imaging spectrometer system and tested using geological mineral samples. The performance was subjectively and objectively evaluated using standard artificial image quality metrics and comparative measurements of mineral and Lambertian diffuser standards with standard field and laboratory spectrometers. The proposed algorithm provides highly qualitative results, offers broad applicability through its generic design and might be the first one of its kind to be published. A high radiometric accuracy is achieved by the incorporation of the Reduction of Miscalibration Effects (ROME) framework. The geometric accuracy is higher than 1 MUpixel. The critical spectral accuracy was relatively estimated by comparing spectra of standard field spectrometers to those from HySPEX for a Lambertian diffuser. The achieved spectral accuracy is better than 0.02% for the full spectrum and better than 98% for the absorption features. It was empirically shown that point and imaging spectrometers provide different results for non-Lambertian samples due to their different sensing principles, adjacency scattering impacts on the signal and anisotropic surface reflection properties. PMID- 28800112 TI - Low-Concentration Tributyltin Decreases GluR2 Expression via Nuclear Respiratory Factor-1 Inhibition. AB - Tributyltin (TBT), which has been widely used as an antifouling agent in paints, is a common environmental pollutant. Although the toxicity of high-dose TBT has been extensively reported, the effects of low concentrations of TBT are relatively less well studied. We have previously reported that low-concentration TBT decreases alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) type glutamate receptor subunit 2 (GluR2) expression in cortical neurons and enhances neuronal vulnerability to glutamate. However, the mechanism of this TBT induced GluR2 decrease remains unknown. Therefore, we examined the effects of TBT on the activity of transcription factors that control GluR2 expression. Exposure of primary cortical neurons to 20 nM TBT for 3 h to 9 days resulted in a decrease in GluR2 mRNA expression. Moreover, TBT inhibited the DNA binding activity of nuclear respiratory factor-1 (NRF-1), a transcription factor that positively regulates the GluR2. This result indicates that TBT inhibits the activity of NRF 1 and subsequently decreases GluR2 expression. In addition, 20 nM TBT decreased the expression of genes such as cytochrome c, cytochrome c oxidase (COX) 4, and COX 6c, which are downstream of NRF-1. Our results suggest that NRF-1 inhibition is an important molecular action of the neurotoxicity induced by low concentration TBT. PMID- 28800114 TI - Fatty Acid Profile Is Modulated by Dietary Resveratrol in Rainbow Trout (Oncorhynchus mykiss). AB - To produce fish of a high quality that are rich in omega-3 fatty acids (n-3 FA) and simultaneously generate more sustainable aquaculture, the combined use of phytochemicals and vegetable oils in fish feed seems to be a promising approach. Resveratrol (RV) potentially induces endogenous fatty acid synthesis, resulting in elevated n-3 FA levels in fish. RV putatively influences ?6-desaturase, the key enzyme in FA metabolism, and serves as a ligand for PPARalpha, a transcription factor regulating beta-oxidation. Rainbow trout (36.35 +/- 0.03 g) were randomly allocated into six groups and fed diets with reduced fish oil levels (F4 = 4%, F2 = 2% and F0 = 0% of dry matter) supplemented with 0.3% (w/w) RV (F4 + RV, F2 + RV and F0 + RV). RV significantly affected FA composition in liver tissue and whole fish homogenates. 20:5n-3 (EPA) and 22:6n-3 (DHA) were significantly increased whereas precursor FA were diminished in fish fed the F2 + RV and F0 + RV diets when compared to F4 + RV and F0. RV significantly elevated ?6-desaturase protein levels in the livers of F0 + RV fed animals. Hepatic mRNA expression of ?6-desaturase, PPARalpha, and its target genes were affected by the dietary fish oil level and not by dietary RV. The results of this study indicated a potential benefit of supplementing RV in fish oil deprived diets elevating n-3 FA levels in rainbow trout. PMID- 28800113 TI - Biomarker Research in Parkinson's Disease Using Metabolite Profiling. AB - Biomarker research in Parkinson's disease (PD) has long been dominated by measuring dopamine metabolites or alpha-synuclein in cerebrospinal fluid. However, these markers do not allow early detection, precise prognosis or monitoring of disease progression. Moreover, PD is now considered a multifactorial disease, which requires a more precise diagnosis and personalized medication to obtain optimal outcome. In recent years, advanced metabolite profiling of body fluids like serum/plasma, CSF or urine, known as "metabolomics", has become a powerful and promising tool to identify novel biomarkers or "metabolic fingerprints" characteristic for PD at various stages of disease. In this review, we discuss metabolite profiling in clinical and experimental PD. We briefly review the use of different analytical platforms and methodologies and discuss the obtained results, the involved metabolic pathways, the potential as a biomarker and the significance of understanding the pathophysiology of PD. Many of the studies report alterations in alanine, branched-chain amino acids and fatty acid metabolism, all pointing to mitochondrial dysfunction in PD. Aromatic amino acids (phenylalanine, tyrosine, tryptophan) and purine metabolism (uric acid) are also altered in most metabolite profiling studies in PD. PMID- 28800115 TI - Intake of Fat-Soluble Vitamins in the Belgian Population: Adequacy and Contribution of Foods, Fortified Foods and Supplements. AB - A key challenge of public health nutrition is to provide the majority of the population with a sufficient level of micronutrients while preventing high consumers from exceeding the tolerable upper intake level. Data of the 2014 Belgian food consumption survey (n = 3200) were used to assess fat-soluble vitamin (vitamins A, D, E and K) intake from the consumption of foods, fortified foods and supplements. This study revealed inadequate intakes for vitamin A, from all sources, in the entire Belgian population and possible inadequacies for vitamin D. The prevalence of inadequate intake of vitamin A was lowest in children aged 3-6 (6-7%) and highest in adolescents (girls, 26%; boys, 34-37%). Except for women aged 60-64 years, more than 95% of the subjects had vitamin D intake from all sources below the adequate intake (AI) of 15 MUg/day. The risk for inadequate intake of vitamins K and E was low (median > AI). Belgian fortification and supplementation practices are currently inadequate to eradicate suboptimal intakes of vitamins A and D, but increase median vitamin E intake close to the adequate intake. For vitamin A, a small proportion (1-4%) of young children were at risk of exceeding the upper intake level (UL), while for vitamin D, inclusion of supplements slightly increased the risk for excessive intakes (% > UL) in adult women and young children. The results may guide health authorities when developing population health interventions and regulations to ensure adequate intake of fat-soluble vitamins in Belgium. PMID- 28800116 TI - Maintaining Traditions: A Qualitative Study of Early Childhood Caries Risk and Protective Factors in an Indigenous Community. AB - In lower middle-income economies (LMIE), the nutrition transition from traditional diets to sugary foods and beverages has contributed to widespread early childhood dental caries. This qualitative study explores perceived risk and protective factors, and overall experiences of early childhood nutrition and oral health in indigenous Ecuadorian families participating in a community-based oral health and nutrition intervention. Dental exams of 698 children age 6 months through 6 years determined each child's caries burden. A convenience sample of 18 "outlier" families was identified: low-caries children with <=2 carious teeth vs. high-caries children with >=10 carious teeth. Semi-structured in-depth interviews with parents/caregivers explored the child's diet, dental habits, and family factors related to nutrition and oral health. Interviews were transcribed and thematically analyzed using grounded theory. In the high-caries families, proximity to highway and stores, consumption of processed-food, and low parental monitoring of child behavior were identified as risk factors for ECC (early childhood caries). In the low-caries families, protective factors included harvesting and consuming food from the family farm, remote geography, and greater parental monitoring of child behavior. The study results suggest that maintaining traditional family farms and authoritative parenting to avoid processed foods/drinks and ensure tooth brushing could improve early childhood nutrition and oral health. PMID- 28800117 TI - Iron Fortification of Lentil (Lens culinaris Medik.) to Address Iron Deficiency. AB - Iron (Fe) deficiency is a major human health concern in areas of the world in which diets are often Fe deficient. In the current study, we aimed to identify appropriate methods and optimal dosage for Fe fortification of lentil (Lens culinaris Medik.) dal with FeSO4.7H2O (ferrous sulphate hepta-hydrate), NaFeEDTA (ethylenediaminetetraacetic acid iron (III) sodium salt) and FeSO4.H2O (ferrous sulphate mono-hydrate). We used a colorimetric method to determine the appearance of the dal fortified with fortificants at different Fe concentrations and under different storage conditions. Relative Fe bioavailability was assessed using an in vitro cell culture bioassay. We found that NaFeEDTA was the most suitable fortificant for red lentil dal, and at 1600 ppm, NaFeEDTA provides 13-14 mg of additional Fe per 100 g of dal. Lentil dal sprayed with fortificant solutions, followed by shaking and drying at 75 degrees C, performed best with respect to drying time and color change. Total Fe and phytic acid concentrations differed significantly between cooked unfortified and fortified lentil, ranging from 68.7 to 238.5 ppm and 7.2 to 8.0 mg g-1, respectively. The relative Fe bioavailability of cooked fortified lentil was increased by 32.2-36.6% compared to unfortified cooked lentil. We conclude that fortification of lentil dal is effective and could provide significant health benefits to dal-consuming populations vulnerable to Fe deficiency. PMID- 28800118 TI - Deep Source Localization with Magnetoencephalography Based on Sensor Array Decomposition and Beamforming. AB - In recent years, the source localization technique of magnetoencephalography (MEG) has played a prominent role in cognitive neuroscience and in the diagnosis and treatment of neurological and psychological disorders. However, locating deep brain activities such as in the mesial temporal structures, especially in preoperative evaluation of epilepsy patients, may be more challenging. In this work we have proposed a modified beamforming approach for finding deep sources. First, an iterative spatiotemporal signal decomposition was employed for reconstructing the sensor arrays, which could characterize the intrinsic discriminant features for interpreting sensor signals. Next, a sensor covariance matrix was estimated under the new reconstructed space. Then, a well-known vector beamforming approach, which was a linearly constraint minimum variance (LCMV) approach, was applied to compute the solution for the inverse problem. It can be shown that the proposed source localization approach can give better localization accuracy than two other commonly-used beamforming methods (LCMV, MUSIC) in simulated MEG measurements generated with deep sources. Further, we applied the proposed approach to real MEG data recorded from ten patients with medically refractory mesial temporal lobe epilepsy (mTLE) for finding epileptogenic zone(s), and there was a good agreement between those findings by the proposed approach and the clinical comprehensive results. PMID- 28800120 TI - Effects of Dilution Systems in Olfactometry on the Recovery of Typical Livestock Odorants Determined by PTR-MS. AB - The present study provides an elaborate assessment of the performance of olfactometers in terms of odorant recovery for a selection of odorants emitted from livestock houses. The study includes three different olfactometer dilution systems, which have been in use at accredited odor laboratories. They consist of: (i) a custom-built olfactometer made of glass tubes, (ii) a TO8 olfactometer, and (iii) an Olfacton dilution system based on a mass flow controller. The odorants include hydrogen sulfide, methanethiol, dimethyl sulfide, acetic acid, butanoic acid, propanoic acid, 3-methylbutanoic acid, 4-methylphenol, and trimethylamine. Furthermore, n-butanol, as the reference gas in the European standard for olfactometry, EN13725, was included. All measurements were performed in real time with proton-transfer-reaction mass spectrometry (PTR-MS). The results show that only dimethyl sulfide was almost completely recovered in all cases, while for the remaining compounds, the performance was found to vary significantly (from 0 to 100%) depending on the chemical properties of the compounds, the concentration levels, the pulse duration, and the olfactometer material. To elucidate the latter, the recovery in different locations of the TO8 olfactometer and in tubes of different materials, that is, poly-tetrafluoroethylene (PTFE), perfluoroalkoxy (PFA), stainless steel and SilcoTek-coated steel, were tested. Significant saturation effects were observed when odorants were in contact with stainless steel. PMID- 28800119 TI - New Insights Contributing to the Development of Effective Vaccines and Therapies to Reduce the Pathology Caused by hRSV. AB - Human Respiratory Syncytial Virus (hRSV) is one of the major causes of acute lower respiratory tract infections (ALRTI) worldwide, leading to significant levels of immunocompromisation as well as morbidity and mortality in infants. Its main target of infection is the ciliated epithelium of the lungs and the host immune responses elicited is ineffective at achieving viral clearance. It is thought that the lack of effective immunity against hRSV is due in part to the activity of several viral proteins that modulate the host immune response, enhancing a Th2-like pro-inflammatory state, with the secretion of cytokines that promote the infiltration of immune cells to the lungs, with consequent damage. Furthermore, the adaptive immunity triggered by hRSV infection is characterized by weak cytotoxic T cell responses and secretion of low affinity antibodies by B cells. These features of hRSV infection have meant that, to date, no effective and safe vaccines have been licensed. In this article, we will review in detail the information regarding hRSV characteristics, pathology, and host immune response, along with several prophylactic treatments and vaccine prototypes. We will also expose significant data regarding the newly developed BCG-based vaccine that promotes protective cellular and humoral response against hRSV infection, which is currently undergoing clinical evaluation. PMID- 28800121 TI - An Energy-Efficient Mobile Sink-Based Unequal Clustering Mechanism for WSNs. AB - Network lifetime and energy efficiency are crucial performance metrics used to evaluate wireless sensor networks (WSNs). Decreasing and balancing the energy consumption of nodes can be employed to increase network lifetime. In cluster based WSNs, one objective of applying clustering is to decrease the energy consumption of the network. In fact, the clustering technique will be considered effective if the energy consumed by sensor nodes decreases after applying clustering, however, this aim will not be achieved if the cluster size is not properly chosen. Therefore, in this paper, the energy consumption of nodes, before clustering, is considered to determine the optimal cluster size. A two stage Genetic Algorithm (GA) is employed to determine the optimal interval of cluster size and derive the exact value from the interval. Furthermore, the energy hole is an inherent problem which leads to a remarkable decrease in the network's lifespan. This problem stems from the asynchronous energy depletion of nodes located in different layers of the network. For this reason, we propose Circular Motion of Mobile-Sink with Varied Velocity Algorithm (CM2SV2) to balance the energy consumption ratio of cluster heads (CH). According to the results, these strategies could largely increase the network's lifetime by decreasing the energy consumption of sensors and balancing the energy consumption among CHs. PMID- 28800122 TI - Increased Expression of Plasma-Induced ABCC1 mRNA in Cystic Fibrosis. AB - The ABCC1 gene is structurally and functionally related to the cystic fibrosis transmembrane conductance regulator gene (CFTR). Upregulation of ABCC1 is thought to improve lung function in patients with cystic fibrosis (CF); the mechanism underlying this effect is unknown. We analyzed the ABCC1 promoter single nucleotide polymorphism (SNP rs504348), plasma-induced ABCC1 mRNA expression levels, and ABCC1 methylation status and their correlation with clinical variables among CF subjects with differing CFTR mutations. We assigned 93 CF subjects into disease severity groups and genotyped SNP rs504348. For 23 CF subjects and 7 healthy controls, donor peripheral blood mononuclear cells (PBMCs) stimulated with plasma underwent gene expression analysis via qRT-PCR. ABCC1 promoter methylation was analyzed in the same 23 CF subjects. No significant correlation was observed between rs504348 genotypes and CF disease severity, but pancreatic insufficient CF subjects showed increased colonization with any form of Pseudomonas aeruginosa (OR = 3.125, 95% CI: 1.192-8.190) and mucoid P. aeruginosa (OR = 5.075, 95% CI: 1.307-28.620) compared to the pancreatic sufficient group. A significantly higher expression of ABCC1 mRNA was induced by CF plasma compared to healthy control plasma (p < 0.001). CF subjects with rs504348 (CC/CG) also had higher mRNA expression compared to those with the ancestral GG genotype (p < 0.005). ABCC1 promoter was completely unmethylated; therefore, we did not detect any association between methylation and CF disease severity. In silico predictions suggested that histone modifications are crucial for regulating ABCC1 expression in PBMCs. Our results suggest that ABCC1 expression has a role in CFTR activity thereby increasing our understanding of the molecular underpinnings of the clinical heterogeneity in CF. PMID- 28800123 TI - Differential Proteomic Analysis Reveals the Effect of Calcium on Malus baccata Borkh. Leaves under Temperature Stress. AB - In the cool apple-producing areas of northern China, air temperature during early spring changes in a rapid and dramatic manner, which affects the growth and development of apple trees at the early stage of the growing season. Previous studies have shown that the treatment of calcium can increase the cold tolerance of Malus baccata Borkh., a widely-used rootstock apple tree in northern China. To better understand the physiological function of calcium in the response of M. baccata to temperature stress, we analyzed the effect of calcium treatment (2% CaCl2) on M. baccata leaves under temperature stress. Physiological analysis showed that temperature stress aggravated membrane lipid peroxidation, reduced chlorophyll content and induced photo-inhibition in leaves, whereas these indicators of stress injuries were alleviated by the application of calcium. An isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomics approach was used in this study. Among the 2114 proteins that were detected in M. baccata leaves, 41, 25, and 34 proteins were differentially regulated by the increasing, decreasing, and changing temperature treatments, respectively. Calcium treatment induced 9 and 15 proteins after increasing and decreasing temperature, respectively, in comparison with non-treated plants. These calcium responsive proteins were mainly related to catalytic activity, binding, and structural molecule activity. Hierarchical cluster analysis indicated that the changes in abundance of the proteins under increasing temperature and changing temperature treatments were similar, and the changes in protein abundance under decreasing temperature and increasing temperature with calcium treatment were similar. The findings of this study will allow a better understanding of the mechanisms underlying the role of calcium in M. baccata leaves under temperature stress. PMID- 28800124 TI - UPLC-QTOF-MS Identification of the Chemical Constituents in Rat Plasma and Urine after Oral Administration of Rubia cordifolia L. Extract. AB - An effective ultra-performance liquid chromatography coupled with the quadrupole time-of-flight tandem mass spectrometry (UPLC/Q-TOF/MS) method was developed for analysing the chemical constituents in rat plasma and urine after the oral administration of Rubia cordifolia L. extract. Under the optimized conditions, nine of 11 prototypes in rat plasma and four prototypes in urine were identified or characterized by comparing the retention time, accurate mass, fragmentation patterns, reference compounds, and literature data. In total, six metabolites, including alizarin-1-O-beta-glucuronide, alizarin-2-O-beta-glucuronide, alizarin 1-O-sulfation, alizarin-2-O-sulfation, purpurin-1-O-beta-glucuronide, and purpurin-3-O-beta-glucuronide, were identified in rat plasma, which were confirmed by lavaging standard solutions. Purpurin was found to be able to be transformed into alizarin based on the results in which alizarin was detected in rat plasma after the oral administration of a purpurin solution. In total, four metabolites were found in rat urine, but their chemical structures were not confirmed. The results indicate that the metabolic pathway of alizarin involves glucuronidation and sulfation, with the purpurins having undergone glucuronidation. The components absorbed into the blood, and the metabolites have the opportunity to become bioactive constituents. The experimental results would supply a helpful chemical basis for further research on the mechanism of actions of Rubia cordifolia L. PMID- 28800125 TI - Large Introns of 5 to 10 Kilo Base Pairs Can Be Spliced out in Arabidopsis. AB - Most of the eukaryotic genes contain introns, which are removed from the pre-RNA during RNA processing. In contrast to the introns in animals, which are usually several kilo base pairs (kb), those in plants generally are very small, which are mostly from dozens of base pairs (bp) to a few hundred bp. According to annotation version 10.0 of the genome of Arabidopsis thaliana, there are 127,854 introns in the nuclear genes; 99.23% of them are less than 1 kb, and only 16 introns are annotated to be larger than 5 kb, which are extremely large introns (ELI) in Arabidopsis. To learn whether these introns are true introns or not and how large introns could be in Arabidopsis, RT-PCR analysis of genes containing these ELIs were carried out. The results indicated that some of these putative introns are indeed ELIs. These ELIs are mainly composed of transposons or transposable elements (TE), excepting one, whose counterparts are also very long in diverse plant species. Thus, this study confirms the existence of introns larger than 5 kb or even 10 kb in Arabidopsis. PMID- 28800126 TI - Human Adenocarcinoma Cell Line Sensitivity to Essential Oil Phytocomplexes from Pistacia Species: a Multivariate Approach. AB - Principal component analysis (PCA) multivariate analysis was applied to study the cytotoxic activity of essential oils from various species of the Pistacia genus on human tumor cell lines. In particular, the cytotoxic activity of essential oils obtained from P. lentiscus, P. lentiscus var. chia (mastic gum), P. terebinthus, P. vera, and P. integerrima, was screened on three human adenocarcinoma cell lines: MCF-7 (breast), 2008 (ovarian), and LoVo (colon). The results indicate that all the Pistacia phytocomplexes, with the exception of mastic gum oil, induce cytotoxic effects on one or more of the three cell lines. PCA highlighted the presence of different cooperating clusters of bioactive molecules. Cluster variability among species, and even within the same species, could explain some of the differences seen among samples suggesting the presence of both common and species-specific mechanisms. Single molecules from one of the most significant clusters were tested, but only bornyl-acetate presented cytotoxic activity, although at much higher concentrations (IC50 = 138.5 ug/mL) than those present in the essential oils, indicating that understanding of the full biological effect requires a holistic vision of the phytocomplexes with all its constituents. PMID- 28800127 TI - Mnt modulates Myc-driven lymphomagenesis. AB - The transcriptional represser Mnt is a functional antagonist of the proto oncoprotein Myc. Both Mnt and Myc utilise Max as an obligate partner for DNA binding, and Myc/Max and Mnt/Max complexes compete for occupancy at E-box DNA sequences in promoter regions. We have previously shown in transgenic mouse models that the phenotype and kinetics of onset of haemopoietic tumours varies with the level of Myc expression. We reasoned that a decrease in the level of Mnt would increase the functional level of Myc and accelerate Myc-driven tumorigenesis. We tested the impact of reduced Mnt in three models of myc transgenic mice and in p53+/- mice. To our surprise, mnt heterozygosity actually slowed Myc-driven tumorigenesis in vavP-MYC10 and EMU-myc mice, suggesting that Mnt facilitates Myc-driven oncogenesis. To explore the underlying cause of the delay in tumour development, we enumerated Myc-driven cell populations in healthy young vavP-MYC10 and EMU-myc mice, expecting that the reduced rate of leukaemogenesis in mnt heterozygous mice would be reflected in a reduced number of preleukaemic cells, due to increased apoptosis or reduced proliferation or both. However, no differences were apparent. Furthermore, when mnt+/+ and mnt+/- pre-B cells from healthy young EMU-myc mice were compared in vitro, no differences were seen in their sensitivity to apoptosis or in cell size or cell cycling. Moreover, the frequencies of apoptotic, senescent and proliferating cells were comparable in vivo in mnt+/- and mnt+/+ EMU-myc lymphomas. Thus, although mnt heterozygosity clearly slowed lymphomagenesis in vavP-MYC10 and EMU myc mice, the change(s) in cellular properties responsible for this effect remain to be identified. PMID- 28800128 TI - Adult cardiac stem cells are multipotent and robustly myogenic: c-kit expression is necessary but not sufficient for their identification. AB - Multipotent adult resident cardiac stem cells (CSCs) were first identified by the expression of c-kit, the stem cell factor receptor. However, in the adult myocardium c-kit alone cannot distinguish CSCs from other c-kit-expressing (c kitpos) cells. The adult heart indeed contains a heterogeneous mixture of c kitpos cells, mainly composed of mast and endothelial/progenitor cells. This heterogeneity of cardiac c-kitpos cells has generated confusion and controversy about the existence and role of CSCs in the adult heart. Here, to unravel CSC identity within the heterogeneous c-kit-expressing cardiac cell population, c kitpos cardiac cells were separated through CD45-positive or -negative sorting followed by c-kitpos sorting. The blood/endothelial lineage-committed (Lineagepos) CD45posc-kitpos cardiac cells were compared to CD45neg(Lineageneg/Linneg) c-kitpos cardiac cells for stemness and myogenic properties in vitro and in vivo. The majority (~90%) of the resident c-kitpos cardiac cells are blood/endothelial lineage-committed CD45posCD31posc-kitpos cells. In contrast, the LinnegCD45negc-kitpos cardiac cell cohort, which represents ?10% of the total c-kitpos cells, contain all the cardiac cells with the properties of adult multipotent CSCs. These characteristics are absent from the c-kitneg and the blood/endothelial lineage-committed c-kitpos cardiac cells. Single Linnegc-kitpos cell-derived clones, which represent only 1-2% of total c kitpos myocardial cells, when stimulated with TGF-beta/Wnt molecules, acquire full transcriptome and protein expression, sarcomere organisation, spontaneous contraction and electrophysiological properties of differentiated cardiomyocytes (CMs). Genetically tagged cloned progeny of one Linnegc-kitpos cell when injected into the infarcted myocardium, results in significant regeneration of new CMs, arterioles and capillaries, derived from the injected cells. The CSC's myogenic regenerative capacity is dependent on commitment to the CM lineage through activation of the SMAD2 pathway. Such regeneration was not apparent when blood/endothelial lineage-committed c-kitpos cardiac cells were injected. Thus, among the cardiac c-kitpos cell cohort only a very small fraction has the phenotype and the differentiation/regenerative potential characteristics of true multipotent CSCs. PMID- 28800129 TI - The combination of reduced MCL-1 and standard chemotherapeutics is tolerable in mice. AB - A common therapeutic strategy to combat human cancer is the use of combinations of drugs, each targeting different cellular processes or vulnerabilities. Recent studies suggest that addition of an MCL-1 inhibitor to such anticancer drug treatments could be an attractive therapeutic strategy. Thus, it is of great interest to understand whether combinations of conventional anticancer drugs with an MCL-1 inhibitor will be tolerable and efficacious. In order to mimic the combination of MCL-1 inhibition with other cancer therapeutics, we treated Mcl 1+/- heterozygous mice, which have a ~50% reduction in MCL-1 protein in their cells, with a broad range of chemotherapeutic drugs. Careful monitoring of treated mice revealed that a wide range of chemotherapeutic drugs had no significant effect on the general well-being of Mcl-1+/- mice with no overt damage to a broad range of tissues, including the haematopoietic compartment, heart, liver and kidney. These results indicate that MCL-1 inhibition may represent a tolerable strategy in cancer therapy, even when combined with select cytotoxic drugs. PMID- 28800130 TI - miR-130a upregulates mTOR pathway by targeting TSC1 and is transactivated by NF kappaB in high-grade serous ovarian carcinoma. AB - Activation of mammalian target of rapamycin (mTOR) signaling pathway is associated with poor prognosis of epithelial ovarian cancer. The TSC1-TSC2 complex is a critical negative regulator of mTOR signaling. Here, we demonstrated that TSC1 was frequently downregulated in high-grade serous ovarian carcinoma (HGSOC) and low TSC1 expression level is associated with advanced tumor stage. We next identified miR-130a to be a negative regulator of TSC1 by targeting its 3'UTR. miR-130a was overexpressed in HGSOC and could drive proliferation and invasion/metastasis of ovarian cancer cells. miR-130a could also attenuate rapamycin/starvation-induced autophagy. Ectopic TSC1 expression could block the effects of miR-130a on cell proliferation, migration and autophagy. Finally, we found that miR-130a expression could be upregulated by inflammatory factors and was transactivated by NF-kappaB. Therefore, our findings establish a crosstalk between inflammation and mTOR signaling that is mediated by miR-130a, which might have a pivotal role in the initiation and progression of HGSOC. PMID- 28800131 TI - Atg2A/B deficiency switches cytoprotective autophagy to non-canonical caspase-8 activation and apoptosis. AB - Autophagosomal membranes are emerging as platforms for various cell survival and death signaling networks beyond autophagy. While autophagy-dependent cell death has been reported in response to a variety of stimuli, the underlying molecular mechanisms remain far from clear. Here, we demonstrate that inhibition of autophagosome completion by Atg2A/B deletion accumulates immature autophagosomal membranes that promote non-canonical caspase-8 activation in response to nutrient starvation via an intracellular death-inducing signaling complex (iDISC). Importantly, iDISC-induced caspase-8 dimerization and activation occurs on accumulated autophagosomal membranes and requires the LC3 conjugation machinery but is independent from the extrinsic pathway of apoptosis. Moreover, we have identified NF-kappaB signaling and c-FLIP as negative regulators of iDISC mediated caspase-8 activation and apoptosis. Collectively, these findings reveal autophagosomal membrane completion as a novel target to switch cytoprotective autophagy to apoptosis. PMID- 28800132 TI - Sphingolipid accumulation causes mitochondrial dysregulation and cell death. AB - Sphingolipids are structural components of cell membranes that have signaling roles to regulate many activities, including mitochondrial function and cell death. Sphingolipid metabolism is integrated with numerous metabolic networks, and dysregulated sphingolipid metabolism is associated with disease. Here, we describe a monogenic yeast model for sphingolipid accumulation. A csg2Delta mutant cannot readily metabolize and accumulates the complex sphingolipid inositol phosphorylceramide (IPC). In these cells, aberrant activation of Ras GTPase is IPC-dependent, and accompanied by increased mitochondrial reactive oxygen species (ROS) and reduced mitochondrial mass. Survival or death of csg2Delta cells depends on nutritional status. Abnormal Ras activation in csg2Delta cells is associated with impaired Snf1/AMPK protein kinase, a key regulator of energy homeostasis. csg2Delta cells are rescued from ROS production and death by overexpression of mitochondrial catalase Cta1, abrogation of Ras hyperactivity or genetic activation of Snf1/AMPK. These results suggest that sphingolipid dysregulation compromises metabolic integrity via Ras and Snf1/AMPK pathways. PMID- 28800133 TI - Adaptive evolution of rhizobial symbiotic compatibility mediated by co-evolved insertion sequences. AB - Mutualism between bacteria and eukaryotes has essential roles in the history of life, but the evolution of their compatibility is poorly understood. Here we show that different Sinorhizobium strains can form either nitrogen-fixing nodules or uninfected pseudonodules on certain cultivated soybeans, while being all effective microsymbionts of some wild soybeans. However, a few well-infected nodules can be found on a commercial soybean using inocula containing a mixed pool of Tn5 insertion mutants derived from an incompatible strain. Reverse genetics and genome sequencing of compatible mutants demonstrated that inactivation of T3SS (type three secretion system) accounted for this phenotypic change. These mutations in the T3SS gene cluster were dominated by parallel transpositions of insertion sequences (ISs) other than the introduced Tn5. This genetic and phenotypic change can also be achieved in an experimental evolution scenario on a laboratory time scale using incompatible wild-type strains as inocula. The ISs acting in the adaptive evolution of Sinorhizobium strains exhibit broader phyletic and replicon distributions than other ISs, and prefer target sequences of low GC% content, a characteristic feature of symbiosis plasmid where T3SS genes are located. These findings suggest an important role of co-evolved ISs in the adaptive evolution of rhizobial compatibility. PMID- 28800134 TI - Bacterial volatile ammonia regulates the consumption sequence of d-pinitol and d glucose in a fungus associated with an invasive bark beetle. AB - Interactions among microbial symbionts have multiple roles in the maintenance of insect-microbe symbiosis. However, signals mediating microbial interactions have been scarcely studied. In the classical model system of bark beetles and fungal associates, fungi increase the fitness of insects. However, not all interactions are mutualistic, some of these fungal symbionts compete for sugars with beetle larvae. How this antagonistic effect is alleviated is unknown, and recent research suggests potential roles of bacterial symbionts. Red turpentine beetle (RTB), Dendroctonus valens LeConte, is an invasive pest in China, and it leads to wide spread, catastrophic mortality to Chinese pines. In the symbiotic system formed by RTB, fungi and bacteria, volatiles from predominant bacteria regulate the consumption sequence of carbon sources d-pinitol and d-glucose in the fungal symbiont Leptographium procerum, and appear to alleviate the antagonistic effect from the fungus against RTB larvae. However, active components of these volatiles are unknown. We detected 67 volatiles by Gas Chromatography-Mass Spectrometer (GC MS). Seven of them were identified as candidate chemicals mediating bacteria fungus interactions, among which ammonia made L. procerum consume its secondary carbon source D-pinitol instead of its preferred carbohydrate D-glucose. In conclusion, ammonia regulated the consumption sequence of these two carbon sources in the fungal symbiont. PMID- 28800135 TI - Network analysis of gut microbiota literature: an overview of the research landscape in non-human animal studies. AB - A wealth of human studies have demonstrated the importance of gut microbiota to health. Research on non-human animal gut microbiota is now increasing, but what insight does it provide? We reviewed 650 publications from this burgeoning field (2009-2016) and determined that animals driving this research were predominantly 'domestic' (48.2%), followed by 'model' (37.5%), with least studies on 'wild' (14.3%) animals. Domestic studies largely experimentally perturbed microbiota (81.8%) and studied mammals (47.9%), often to improve animal productivity. Perturbation was also frequently applied to model animals (87.7%), mainly mammals (88.1%), for forward translation of outcomes to human health. In contrast, wild animals largely characterised natural, unperturbed microbiota (79.6%), particularly in pest or pathogen vectoring insects (42.5%). We used network analyses to compare the research foci of each animal group: 'diet' was the main focus in all three, but to different ends: to enhance animal production (domestic), to study non-infectious diseases (model), or to understand microbiota composition (wild). Network metrics quantified model animal studies as the most interdisciplinary, while wild animals incorporated the fewest disciplines. Overall, animal studies, especially model and domestic, cover a broad array of research. Wild animals, however, are the least investigated, but offer under exploited opportunities to study 'real-life' microbiota. PMID- 28800136 TI - Feathermoss and epiphytic Nostoc cooperate differently: expanding the spectrum of plant-cyanobacteria symbiosis. AB - Dinitrogen (N2)-fixation by cyanobacteria in symbiosis with feathermosses is the primary pathway of biological nitrogen (N) input into boreal forests. Despite its significance, little is known about the cyanobacterial gene repertoire and regulatory rewiring needed for the establishment and maintenance of the symbiosis. To determine gene acquisitions and regulatory changes allowing cyanobacteria to form and maintain this symbiosis, we compared genomically closely related symbiotic-competent and -incompetent Nostoc strains using a proteogenomics approach and an experimental set up allowing for controlled chemical and physical contact between partners. Thirty-two gene families were found only in the genomes of symbiotic strains, including some never before associated with cyanobacterial symbiosis. We identified conserved orthologs that were differentially expressed in symbiotic strains, including protein families involved in chemotaxis and motility, NO regulation, sulfate/phosphate transport, and glycosyl-modifying and oxidative stress-mediating exoenzymes. The physical moss-cyanobacteria epiphytic symbiosis is distinct from other cyanobacteria-plant symbioses, with Nostoc retaining motility, and lacking modulation of N2-fixation, photosynthesis, GS-GOGAT cycle and heterocyst formation. The results expand our knowledge base of plant-cyanobacterial symbioses, provide a model of information and material exchange in this ecologically significant symbiosis, and suggest new currencies, namely nitric oxide and aliphatic sulfonates, may be involved in establishing and maintaining the cyanobacteria-feathermoss symbiosis. PMID- 28800137 TI - Chemical dispersants enhance the activity of oil- and gas condensate-degrading marine bacteria. AB - Application of chemical dispersants to oil spills in the marine environment is a common practice to disperse oil into the water column and stimulate oil biodegradation by increasing its bioavailability to indigenous bacteria capable of naturally metabolizing hydrocarbons. In the context of a spill event, the biodegradation of crude oil and gas condensate off eastern Canada is an essential component of a response strategy. In laboratory experiments, we simulated conditions similar to an oil spill with and without the addition of chemical dispersant under both winter and summer conditions and evaluated the natural attenuation potential for hydrocarbons in near-surface sea water from the vicinity of crude oil and natural gas production facilities off eastern Canada. Chemical analyses were performed to determine hydrocarbon degradation rates, and metagenome binning combined with metatranscriptomics was used to reconstruct abundant bacterial genomes and estimate their oil degradation gene abundance and activity. Our results show important and rapid structural shifts in microbial populations in all three different oil production sites examined following exposure to oil, oil with dispersant and dispersant alone. We found that the addition of dispersant to crude oil enhanced oil degradation rates and favored the abundance and expression of oil-degrading genes from a Thalassolituus sp. (that is, metagenome bin) that harbors multiple alkane hydroxylase (alkB) gene copies. We propose that this member of the Oceanospirillales group would be an important oil degrader when oil spills are treated with dispersant. PMID- 28800139 TI - Functionalized mesoporous silica thin films as a tunable nonlinear optical material. AB - The article is about a novel material for application in optoelectronic devices: mesoporous silica in the form of thin films with vertically aligned channels containing anchored propyl-copper-phosphonate functional groups. We described a synthesis route and carried out characterization of the structure to obtain its nonlinear optical (NLO) properties (second and third order harmonic generation). A quasi phase transition was found in the material resulting from modification of the functional group content. We also demonstrated that it is possible to modify NLO susceptibilities by tuning the distance between active polar units. PMID- 28800138 TI - Phylogenetically conserved resource partitioning in the coastal microbial loop. AB - Resource availability influences marine microbial community structure, suggesting that population-specific resource partitioning defines discrete niches. Identifying how resources are partitioned among populations, thereby characterizing functional guilds within the communities, remains a challenge for microbial ecologists. We used proteomic stable isotope probing (SIP) and NanoSIMS analysis of phylogenetic microarrays (Chip-SIP) along with 16S rRNA gene amplicon and metagenomic sequencing to characterize the assimilation of six 13C-labeled common metabolic substrates and changes in the microbial community structure within surface water collected from Monterey Bay, CA. Both sequencing approaches indicated distinct substrate-specific community shifts. However, observed changes in relative abundance for individual populations did not correlate well with directly measured substrate assimilation. The complementary SIP techniques identified assimilation of all six substrates by diverse taxa, but also revealed differential assimilation of substrates into protein and ribonucleotide biomass between taxa. Substrate assimilation trends indicated significantly conserved resource partitioning among populations within the Flavobacteriia, Alphaproteobacteria and Gammaproteobacteria classes, suggesting that functional guilds within marine microbial communities are phylogenetically cohesive. However, populations within these classes exhibited heterogeneity in biosynthetic activity, which distinguished high-activity copiotrophs from low-activity oligotrophs. These results indicate distinct growth responses between populations that is not apparent by genome sequencing alone. PMID- 28800140 TI - Photoactivatable aggregation-induced emission of triphenylmethanol. AB - Triphenylmethanol (TPOH) is a non-fluorescent compound. Interestingly, after UV irradiation at 254 nm, TPOH showed a strong blue fluorescence on a solid surface. Moreover, the fluorescence can be quenched by UV irradiation at 365 nm, making the photoactivatable fluorescence reversible. TPOH is thus applied for rewritable photopatterning tuned by UV light. PMID- 28800141 TI - Effects of Strong CYP3A Inhibition and Induction on the Pharmacokinetics of Ixazomib, an Oral Proteasome Inhibitor: Results of Drug-Drug Interaction Studies in Patients With Advanced Solid Tumors or Lymphoma and a Physiologically Based Pharmacokinetic Analysis. AB - At clinically relevant ixazomib concentrations, in vitro studies demonstrated that no specific cytochrome P450 (CYP) enzyme predominantly contributes to ixazomib metabolism. However, at higher than clinical concentrations, ixazomib was metabolized by multiple CYP isoforms, with the estimated relative contribution being highest for CYP3A at 42%. This multiarm phase 1 study (Clinicaltrials.gov identifier: NCT01454076) investigated the effect of the strong CYP3A inhibitors ketoconazole and clarithromycin and the strong CYP3A inducer rifampin on the pharmacokinetics of ixazomib. Eighty-eight patients were enrolled across the 3 drug-drug interaction studies; the ixazomib toxicity profile was consistent with previous studies. Ketoconazole and clarithromycin had no clinically meaningful effects on the pharmacokinetics of ixazomib. The geometric least-squares mean area under the plasma concentration-time curve from 0 to 264 hours postdose ratio (90%CI) with vs without ketoconazole coadministration was 1.09 (0.91-1.31) and was 1.11 (0.86-1.43) with vs without clarithromycin coadministration. Reduced plasma exposures of ixazomib were observed following coadministration with rifampin. Ixazomib area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration was reduced by 74% (geometric least-squares mean ratio of 0.26 [90%CI 0.18-0.37]), and maximum observed plasma concentration was reduced by 54% (geometric least-squares mean ratio of 0.46 [90%CI 0.29-0.73]) in the presence of rifampin. The clinical drug-drug interaction study results were reconciled well by a physiologically based pharmacokinetic model that incorporated a minor contribution of CYP3A to overall ixazomib clearance and quantitatively considered the strength of induction of CYP3A and intestinal P-glycoprotein by rifampin. On the basis of these study results, the ixazomib prescribing information recommends that patients should avoid concomitant administration of strong CYP3A inducers with ixazomib. PMID- 28800142 TI - Alcohol-Mediated Missplicing of Mcl-1 Pre-mRNA is Involved in Neurotoxicity. AB - BACKGROUND: Heavy and chronic ethanol (EtOH) exposure can cause significant structural and functional damage to the adult brain. The most devastating consequence of EtOH exposure is the neurotoxicity associated with the depletion of neurons. Regulation of splice variants in the brain can modulate protein functions, which may ultimately affect behaviors associated with alcohol dependence and EtOH-mediated neurotoxicity. As alcohol consumption is associated with neurotoxicity, it is possible that altered splicing of survival and pro survival factors during the development of alcoholism may contribute to the neurotoxicity. METHODS: Primary human neurons and a neuroblastoma cell line were exposed to different concentrations of EtOH for various time periods. Cell viability and neuronal marker expression were analyzed by MTT assay and immunoblotting, respectively. Effect of EtOH exposure on splicing regulatory protein expression and alternative splicing of candidate genes was analyzed by a biochemical approach. Transcriptional activity of serine/arginine-rich splicing factor 1 (SRSF1) gene was determined by reporter gene analysis. RESULTS: Our results suggest that EtOH exposure to neuronal cells at 25 mM and higher concentrations are detrimental. In addition, EtOH exposure caused a dramatic reduction in SRSF1 expression levels. Furthermore, EtOH exposure led to pre-mRNA missplicing of Mcl-1, a pro-survival member of the Bcl-2 family, by down regulating the expression levels of SRSF1. Moreover, ectopic expression of both SRSF1 and Mcl-1L isoform was able to recover EtOH-mediated neurotoxicity. CONCLUSIONS: Our results suggest that EtOH exposure can lead to pre-mRNA missplicing of Mcl-1 in neuronal cells. Our results indicate that EtOH exposure of neurons leads to a decrease in the ratio of Mcl-1L/Mcl-1S by favoring pro apoptotic Mcl-1S splicing over anti-apoptotic Mcl-1L isoform suggesting that Mcl 1S may play a crucial role in neurotoxicity associated with alcohol consumption. PMID- 28800143 TI - Immunohistochemistry reveals an increased proportion of MYC-positive cells in subcutaneous panniculitis-like T-cell lymphoma compared with lupus panniculitis. AB - BACKGROUND: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a malignant primary cutaneous T-cell lymphoma that shares significant clinical, histopathologic and immunophenotypic overlap with lupus erythematosus panniculitis (LEP). METHODS: We performed immunohistochemistry for the MYC oncoprotein on 23 cases of SPTCL (1 CD8 negative) and 12 cases of LEP to evaluate if there are quantitative or qualitative differences in protein expression of this marker in these entities. RESULTS: In SPTCL cases, the percentage of all cells that were c-Myc positive ranged from 0.8% to 16%, with a mean of 5.0% and a median of 4.4%. In contrast, in the LEP cases, the percentage of c-Myc-positive cells in the cases ranged from 0.34% to 3.7%, averaged 1.4% and the median was 0.8%. The difference between the means of these 2 diagnostic categories was statistically significant. Fluorescence in situ hybridization performed on 4 cases of SPTCL with a relatively high level of MYC immunohistochemical staining, however, failed to demonstrate evidence of MYC rearrangement or amplification. CONCLUSIONS: Our work demonstrates that MYC expression levels differ between these 2 histologic mimics and suggests that this important oncoprotein may play a role in the pathogenesis of SPTCL. PMID- 28800144 TI - At least three phenotypes exist among periodontitis patients. AB - AIM: To identify phenotypes of periodontitis patients by the use of an unsupervised modelling technique (clustering), based on pre-treatment radiographic and microbiological characteristics. MATERIALS AND METHODS: This retrospective study included data from 392 untreated periodontitis patients. Co regularized spectral clustering algorithm was used to cluster the patients. The resulting clusters were subsequently characterized based on their demographics, radiographic bone loss patterns and microbial data. RESULTS: The vast majority of patients fitted into one of the three main clusters (accuracy 90%). Cluster A (n = 18) was characterized by high prevalence and high proportions of Aggregatibacter actinomycetemcomitans, a trend for a more localized pattern of alveolar bone loss and young individuals. Clusters B (n = 200) and C (n = 135) differed clearly in disease severity patterns and smoking habits, but not in microbiological characteristics. CONCLUSION: On the basis of alveolar bone loss patterns and microbiological data, untreated periodontitis patients can be clustered into at least three phenotypes. These results should be validated in other cohorts, and the clinical utility needs to be explored on the basis of periodontal treatment outcomes and/or disease progression. PMID- 28800145 TI - Soil handling methods should be selected based on research questions and goals. PMID- 28800146 TI - The relationship between open versus normal contact point and inter-proximal papilla dimensions in periodontally healthy young adults: A controlled clinical trial. AB - AIM: The gingival architecture is determined by the spatial orientation of the gingival zenith (GZ) and the inter-dental papillae (IP). Among the factors commonly associated with the presence and morphology of the IP, the contact point (CP) and the inter-dental distance relationships have been considered the most important. The objective of the present controlled clinical trial was to evaluate the role of the CP in determining the clinical and morphometric parameters of the inter-dental papilla. MATERIALS AND METHODS: The inter-dental papillae of sixty patients with unilateral diastemas were evaluated by means of periodontal probing, transgingival probing, the papilla presence index and morphometric measurement with a digital calliper and were analysed with a paired t-test, with significance set at alpha value of 0.05 or lower. RESULTS: All the papillae exhibited PPI score = 1. Papillary measurements were significantly increased in the experimental (diastema) group. CONCLUSIONS: In patients with gingival health, the dimensions of the IP are significantly increased in teeth without a contact point in comparison with their contra-lateral controls with a contact point. The contact point does not determine the presence and size of the inter-dental papilla, in patients with a healthy gingiva and without periodontal attachment loss. PMID- 28800147 TI - Reduction in bacteremia after brushing with a triclosan/copolymer dentifrice-A randomized clinical study. AB - AIM: The aims of this study were to; 1) test susceptibility to bacteremia in subjects with moderate gingivitis, and 2) compare the effects of brushing with a fluoride toothpaste (control) as compared to a triclosan/copolymer toothpaste (test) on those susceptible to repeated bacteremia. MATERIALS AND METHODS: One hundred and seven adult subjects were tested for repeated bacteremia after eating a hard apple. Twenty-nine bacteremia positive subjects were enrolled in a double blind cross-over study designed to analyse the effects of a test toothpaste. After random toothpaste assignment, subjects brushed for 21 days. Following a wash-out period, subjects completed the study with the alternate toothpaste. Statistical analysis compared bacteremia between groups by analysis of covariance (ANCOVA). RESULTS: Twenty-six adult subjects completed the cross-over study. No statistically significant differences for bacteremia were seen at baseline. Mean bacterial counts at baseline and post-treatment visits were 45.5 and 10.8 counts versus 48.5 and 38.0 counts, respectively (test vs. control group; significant at p < .05). Significant reductions in blood borne bacteria were seen in the test versus control groups in both cultural and DNA data (p < .05). CONCLUSIONS: Thirty percentage of subjects showed repeated bacteremia. Brushing with a triclosan/copolymer dentifrice demonstrated significant reductions in bacteremia as compared to the control toothpaste. PMID- 28800148 TI - For Better or for Worse? Positive and Negative Parental Influences on Young Children's Executive Function. AB - Despite rapidly growing research on parental influences on children's executive function (EF), the uniqueness and specificity of parental predictors and links between adult EF and parenting remain unexamined. This 13-month longitudinal study of 117 parent-child dyads (60 boys; Mage at Time 1 = 3.94 years, SD = 0.53) included detailed observational coding of parent-child interactions and assessed adult and child EF and child verbal ability (VA). Supporting a differentiated view of parental influence, negative parent-child interactions and parental scaffolding showed unique and specific associations with child EF, whereas the home learning environment and parental language measures showed global associations with children's EF and VA. PMID- 28800149 TI - Atrial fibrillation variability on long-term monitoring of implantable cardiac rhythm management devices. AB - BACKGROUND: Atrial fibrillation (AF) burden and duration are predictors of thromboembolic events. The random nature of these measures may affect clinical decision making. The objective of this study was to determine temporal changes in AF burden as detected by continuous monitoring. HYPOTHESIS: AF burden changes over time when detected by continuous monitoring. METHODS: A post hoc analysis of patients enrolled in the TRENDS (A Prospective Study of the Clinical Significance of Atrial Arrhythmias Detected by Implanted Device Diagnostics) study with >=1 stroke risk factor(s) who were implanted with a dual-chamber cardiac rhythm management device (CRMD) and had AF burden data available for >=2 years was performed. AF burden was defined as no AF, low AF (<5.5 hours on any given day), or high AF burden (>=5.5 hours in a day), and was first assessed over the initial 30 days following enrollment and then reassessed at 6-month intervals for 2 years. RESULTS: Among 394 patients included, the average age was 70.2 +/- 10.9 years, 71% were male, and mean CHA2 DS2- VASc (congestive heart failure, hypertension, age >=75 years, diabetes mellitus, prior stroke or TIA, vascular disease, age 65-74 years, sex category) score was 3.7 +/- 1.6. In the 30-day baseline period, 75.1% of patients had no AF, 11.2% had low AF, and 13.7% had high AF. Over the subsequent 2 years, 40.0% of patients initially classified as no AF or low AF experienced periods with high AF, whereas 59.3% of patients initially classified as high AF experienced >=6 consecutive months with no AF or low AF. Advanced age was the sole predictor of AF progression. CONCLUSIONS: Significant temporal variability in AF burden exists when measured continuously with an implantable CRMD. PMID- 28800150 TI - Heterozygosity for P2Y12 receptor gene mutation associated with postoperative hemorrhage in a Greater Swiss Mountain dog. AB - A 3-year-old, female Greater Swiss Mountain dog developed a hemoperitoneum following an exploratory laparotomy and ovariohysterectomy. Platelet count, PT, APTT, and plasma von Willebrand factor antigen concentration were within RIs. A buccal mucosal bleeding time (BMBT) was prolonged. Given the probability of a hereditary thrombopathia, the dog was administered desmopressin, fresh platelet transfusions, and aminocaproic acid to control hemorrhage. Subsequently, DNA testing for the P2Y12 receptor gene mutation identified the dog as being a heterozygote (carrier). Further platelet function testing was performed following complete recovery. Results of a repeat BMBT and a point-of-care screening test using the Platelet Function Analyzer-100 (collagen/adenosine-diphosphate [ADP] test cartridge) were within RIs. Flow cytometric studies demonstrated a marked reduction in fibrinogen binding to the dog's platelets in response to ADP - adenosine diphosphate activation. Likewise, turbidimetric aggregometry revealed a complete absence of platelet aggregation in response to ADP. However, there were a normal aggregation response to the platelet agonist convulxin and a mild reduction in amplitude in response to gamma-thrombin. This is the first report of a dog heterozygous for the P2Y12 receptor gene mutation exhibiting a bleeding tendency and having evidence of impaired platelet function in vitro in response to ADP activation. Given that the mutant allele for the P2Y12 thrombopathia appears to be widespread in the Greater Swiss Mountain dog breed, veterinarians need to be aware that both homozygotes and heterozygotes for this platelet receptor mutation are at risk of developing life-threatening bleeding following trauma or surgery. PMID- 28800151 TI - Cost comparison of prediction-based decision-making for periodontally affected molars. AB - AIM: Tooth loss prediction could improve decision-making for periodontally affected molars. We analysed the costs of removing all, none or only those molars predicted to be at-risk for extraction during supportive periodontal therapy (SPT). METHODS: This is a model-based study using a German private payer perspective. Building mainly on cost and effectiveness data from 2039 molars (301 patients) which received long-term SPT, five (exemplary) prediction/decision strategies were compared: Retaining all molars, removing molars with furcation involvement (FI) >= I/ >= II/ III, or removing all molars. Each strategy came with different proportions of molars correctly or erroneously (false positively) removed. Retaining as well as removing molars had long-term cost implications (via SPT or tooth replacement). Using Monte-Carlo microsimulations, we estimated the lifetime costs of an average population in our cohort and evaluated what accuracy a prediction method needed to have to save costs in different risk groups. RESULTS: Removing only molars with FI III (1188 Euro) and removing no molars (1195 Euro) were significantly less costly than removing all molars (1454 Euro). Prediction methods needed to be highly specific in most populations to avoid unnecessary tooth loss and the associated high costs. CONCLUSIONS: Removing molars prior to SPT should be decided cautiously. PMID- 28800152 TI - Prediction of the reduction potential in transition-metal containing complexes: How expensive? For what accuracy? AB - Accurate computationally derived reduction potentials are important for catalyst design. In this contribution, relatively inexpensive density functional theory methods are evaluated for computing reduction potentials of a wide variety of organic, inorganic, and organometallic complexes. Astonishingly, SCRF single points on B3LYP optimized geometries with a reasonably small basis set/ECP combination works quite well--B3LYP with the BS1 [modified-LANL2DZ basis set/ECP (effective core potential) for metals, LANL2DZ(d,p) basis set/LANL2DZ ECP for heavy nonmetals (Si, P, S, Cl, and Br), and 6-31G(d') for other elements (H, C, N, O, and F)] and implicit PCM solvation models, SMD (solvation model based on density) or IEFPCM (integral equation formalism polarizable continuum model with Bondi atomic radii and alpha = 1.1 reaction field correction factor). The IEFPCM Bondi-B3LYP/BS1 methodology was found to be one of the least expensive and most accurate protocols, among six different density functionals tested (BP86, PBEPBE, B3LYP, B3P86, PBE0, and M06) with thirteen different basis sets (Pople split valence basis sets, correlation consistent basis sets, or Los Alamos National Laboratory ECP/basis sets) and four solvation models (SMD, IEFPCM, IPCM, and CPCM). The MAD (mean absolute deviation) values of SCRF-B3LYP/BS1 of 49 studied species were 0.263 V for SMD and 0.233 V for IEFPCM-Bondi; and the linear correlations had respectable R2 values (R2 = 0.94 for SMD and R2 = 0.93 for IEFPCM-Bondi). These methodologies demonstrate relatively reliable, convenient, and time-saving functional/basis set/solvation model combinations in computing the reduction potentials of transition metal complexes with moderate accuracy. (c) 2017 Wiley Periodicals, Inc. PMID- 28800153 TI - Increased Autolysis of MU-Calpain in Skeletal Muscles of Chronic Alcohol-Fed Rats. AB - BACKGROUND: Proteolysis can proceed via several distinct pathways such as the lysosomal, calcium-dependent, and ubiquitin-proteasome-dependent pathways. Calpains are the main proteases that cleave a large variety of proteins, including the giant sarcomeric proteins, titin and nebulin. Chronic ethanol feeding for 6 weeks did not affect the activities of MU-calpain and m-calpain in the m. gastrocnemius. In our research, changes in MU-calpain activity were studied in the m. gastrocnemius and m. soleus of chronically alcohol-fed rats after 6 months of alcohol intake. METHODS: SDS-PAGE analysis was applied to detect changes in titin and nebulin contents. Titin phosphorylation analysis was performed using the fluorescent dye Pro-Q Diamond. Western blotting was used to determine MU-calpain autolysis as well as MU-calpain and calpastatin contents. The titin and nebulin mRNA levels were assessed by real-time PCR. RESULTS: The amounts of the autolysed isoform (78 kDa) of full-length MU-calpain (80 kDa) increased in the m. gastrocnemius and m. soleus of alcohol-fed rats. The calpastatin content increased in m. gastrocnemius. Decreased intact titin-1 (T1) and increased T2-proteolytic fragment contents were found in the m. gastrocnemius and m. soleus of the alcohol-fed rats. The nebulin content decreased in the rat gastrocnemius muscle of the alcohol-fed group. The phosphorylation levels of T1 and T2 were increased in the m. gastrocnemius and m. soleus, and decreased titin and nebulin mRNA levels were observed in the m. gastrocnemius. The nebulin mRNA level was increased in the soleus muscle of the alcohol-fed rats. CONCLUSIONS: In summary, our data suggest that prolonged chronic alcohol consumption for 6 months resulted in increased autolysis of MU-calpain in rat skeletal muscles. These changes were accompanied by reduced titin and nebulin contents, titin hyperphosphorylation, and development of hindlimb muscle atrophy in the alcohol fed rats. PMID- 28800154 TI - High-Intensity Drinking Versus Heavy Episodic Drinking: Prevalence Rates and Relative Odds of Alcohol Use Disorder Across Adulthood. AB - BACKGROUND: Heavy episodic drinking (HED) or consuming 4+/5+ drinks in 1 occasion for women/men is linked consistently with alcohol-related harms. Recent research suggests that many individuals drink at levels more than twice this cutoff (8+/10+ drinks), commonly referred to as "high-intensity drinking." Prevalence rates of high-intensity drinking and its dynamic association with alcohol use disorder (AUD) across all ages, however, remain unknown. The current study used data from a nationally representative sample to document age-varying prevalence rates of HED-only drinking and high-intensity drinking, prevalence rates of AUD for HED-only drinkers and high-intensity drinkers, and relative odds of experiencing an AUD for high-intensity drinkers as compared to HED-only drinkers. METHODS: Data were from the National Epidemiologic Survey on Alcohol and Related Conditions-III. The final analytic sample consisted of past-year drinkers aged 18 to 64 years (n = 22,776). RESULTS: Time-varying effect modeling revealed that high-intensity drinking and HED-only drinking were equally prevalent during young adulthood and prevalence rates of both types of drinking generally became less common with increasing age. At all ages, high-intensity drinkers were at 3 or more times greater odds of meeting criteria for an AUD than HED-only drinkers. The association between high-intensity relative to HED-only drinking was strongest earlier in adulthood with approximately 83% of 18-year-old high intensity drinkers having AUD relative to 42% of HED-only drinkers. CONCLUSIONS: Future research aiming to identify drinkers most at risk of harms and in need of treatment may benefit from assessing the extent to which an individual exceeds the 8+/10+ threshold of drinking. PMID- 28800156 TI - Quantitative Dextran Trafficking to the Coxiella burnetii Parasitophorous Vacuole. AB - The gram-negative bacterium Coxiella burnetii causes human Q fever, a disease characterized by a debilitating flu-like illness in acute cases and endocarditis in chronic patients. An obligate intracellular pathogen, Coxiella burnetii survives within a large, lysosome-like vacuole inside the host cell. A unique feature of the Coxiella parasitophorous vacuole (PV) is high levels of fusion with the host endocytic pathway, with PV-endosome fusion critical for Coxiella survival within the host cell. This unit describes quantitating PV-endosome fusion by measuring delivery of the fluid phase endosome marker dextran to the PV using live cell imaging. To study the effect of host cell proteins involved in PV endosome fusion, details are provided for using siRNA knockdown host cells. This method is a powerful tool for understanding mechanisms underlying Coxiella's ability to manipulate host cell trafficking pathways. (c) 2017 by John Wiley & Sons, Inc. PMID- 28800155 TI - Epigenetic Analysis of SV40 Minichromosomes. AB - Simian virus 40 (SV40) is one of the best-characterized members of the polyomavirus family of small DNA tumor viruses. It has a small genome of 5243 bp and utilizes cellular proteins for its molecular biology, with the exception of the T-antigen protein, which is coded by the virus and is involved in regulating transcription and directing replication. Importantly, SV40 exists as chromatin in both the virus particle and intracellular minichromosomes. These facts, combined with high yields of virus and minichromosomes following infection and ease of manipulation, have made SV40 an extremely useful model to study all aspects of eukaryotic molecular biology. This unit describes procedures for working with SV40 and preparing SV40 chromatin from infected cells and virus particles, as well as procedures for using SV40 chromatin to study epigenetic regulation. (c) 2017 by John Wiley & Sons, Inc. PMID- 28800158 TI - Using KBase to Assemble and Annotate Prokaryotic Genomes. AB - The DOE Systems Biology Knowledgebase (KBase, http://kbase.us/) is an open-access bioinformatics software and data platform for analyzing plants, microbes, and their communities. KBase enables scientists to create, execute, collaborate on, and share reproducible analyses of their biological data in the context of public data and private collaborator data. For microbiologists researching prokaryotes, KBase offers analysis tools for performing quality control and assessment of Next Generation Sequencing reads, de novo assembly, genome annotation, and tools for analyzing structural and functional features of genomes. This unit demonstrates an example workflow for taking a comparative and iterative approach to assembly and annotation of prokaryotic genomes using KBase that can be used by microbiologists seeking to perform isolate analysis in a rapid and reproducible fashion. (c) 2017 by John Wiley & Sons, Inc. PMID- 28800157 TI - Generating and Maintaining Transgenic Cryptosporidium parvum Parasites. AB - The apicomplexan parasite Cryptosporidium is a leading cause of diarrheal disease and an important contributor to overall global child mortality. We currently lack effective treatment and immune prophylaxis. Recent advances now permit genetic modification of this important pathogen. We expect this to produce rapid advances in fundamental as well as translational research on cryptosporidiosis. Here we outline genetic engineering for Cryptosporidium in sufficient detail to establish transfection in any laboratory that requires access to this key technology. This chapter details the conceptual design consideration, as well as the experimental steps required to transfect, select, and isolate transgenic parasites. We also provide detail on key in vitro and in vivo assays to detect, validate, and quantify genetically modified Cryptosporidium parasites. (c) 2017 by John Wiley & Sons, Inc. PMID- 28800159 TI - Mouse Models of Acinetobacter baumannii Infection. AB - This unit describes basic protocols for infecting mice through intranasal and intraperitoneal routes with Acinetobacter baumannii to induce associated pneumonia and sepsis, the two most common manifestations of clinical infections with this pathogen. By selecting the appropriate protocols and bacterial strains of different virulence, these mouse models provide an opportunity to study the infection pathogenesis and host-immune responses, and to evaluate the efficacies of prophylactic and therapeutic anti-A. baumannii candidates. (c) 2017 by John Wiley & Sons, Inc. PMID- 28800160 TI - Exercise attenuates alveolar bone loss and anxiety-like behaviour in rats with periodontitis. AB - AIM: To evaluate the effects of physical training on inflammatory and behavioural parameters of Wistar rats with periodontal disease (PD). MATERIALS AND METHODS: Twenty four animals were distributed in a 2 * 2 factorial design (with and without exercise, with and without PD). Trained animals swimmed one hour daily during 8 weeks. PD was induced by ligature 14 days before the end of experiment, and in the last week, all animals were submitted to the Marble Burying Test. Histomorphometric analyses of the mandibles and expression of cytokines were conducted by Western blotting. We also evaluated the morphometry of hippocampal astrocytes using anti-glial fibrillary acidic protein antibody. RESULTS: Physical training attenuated bone loss and epithelial attachment loss levels of rats with PD. Trained animals with PD presented lower TNF-alpha expression in periodontal tissues while IL-10 was increased. TNF-alpha/IL-10 ratio was lower in trained animals with PD compared to those with induced periodontitis. PD increased anxiety-like behaviour, and physical training attenuated this parameter. Exercise increased the ramifications of hippocampal astrocytes in rats without PD. CONCLUSIONS: Exercise decreased anxiety behaviour, inflammatory proteins expression and bone loss in rats with PD. PMID- 28800161 TI - Parental Cultural Socialization and Adolescent Private Regard: Exploring Mediating Pathways Through Daily Experiences. AB - Using longitudinal experience sampling data from 214 ethnic/racial minority adolescents (Wave 1 Mage = 15.24), the present study investigated how the longitudinal effect of parental cultural socialization on adolescent private regard was mediated through various daily pathways and novel constructs. Both the mean levels and variability of adolescents' ethnic feelings (i.e., private regard) and social interactions (i.e., intragroup contact) in daily situations, as well as the situational association between intragroup contact and private regard, emerged as mediators. Greater cultural socialization promoted greater and more stable ethnic feelings and interactions, as well as their situational association, all of which promoted private regard over time. This study provides a framework to explore how development occurs in daily lives. PMID- 28800162 TI - Feeding Imprinting: The Extreme Test Case of Premature Infants Born With Very Low Birth Weight. AB - Feeding imprinting, considered a survival-enabling process, is not well understood. Infants born very preterm, who first feed passively, are an effective model for studying feeding imprinting. Retrospective analysis of neonatal intensive care unit (NICU) records of 255 infants (Mgestational age = 29.98 +/- 1.64) enabled exploring the notion that direct breastfeeding (DBF) during NICU stay leads to consumption of more mother's milk and earlier NICU discharge. Results showed that DBF before the first bottle feeding is related to shorter transition into oral feeding, a younger age of full oral feeding accomplishment and earlier discharge. Furthermore, the number of DBF meals before first bottle feeding predicts more maternal milk consumption and improved NICU outcomes. Improved performance in response to initial exposure to DBF at the age of budding feeding abilities supports a feeding imprinting hypothesis. PMID- 28800163 TI - Edoxaban Use in Nonvalvular Atrial Fibrillation With Valvular Heart Disease Insights from ENGAGE AF-TIMI 48. PMID- 28800165 TI - Burnout among Finnish and Chinese university students. AB - In this study the levels of experienced burnout of Finnish and Chinese university students are compared using School Burnout Inventory (SBI). This study is motivated by earlier studies, which suggest that the level of student burnout is different in the culturally distinct Finnish and Chinese university systems, but which are based on different research instruments for the two groups. The sample studied consisted of 3,035 Finnish students and 2,309 Chinese students. Because of the cross-cultural nature of this study the level of structural equivalence of SBI between the cultural groups was examined and the effect of different response styles on the results was taken into account. Both standard and robust statistical methods were used for the analyses. The results showed that SBI with two extracted components is suitable for cross-cultural analysis between Finnish and Chinese university students. Virtually no difference was found in experienced overall burnout between the Finnish and Chinese students, which means that both university systems contain factors causing similar levels of student burnout. This study also verified that controlling for the response styles is important in cross-cultural studies as it was found to have a distinct effect on the results obtained from mean-level comparisons. PMID- 28800164 TI - B cell phenotypes in patients with rheumatoid arthritis relapsing after rituximab: expression of B cell-activating factor-binding receptors on B cell subsets. AB - Serum levels of B cell-activating factor (BAFF) rise following rituximab (RTX) therapy in patients with rheumatoid arthritis (RA). Initiation of naive B cell return to the periphery and autoreactive B cell expansion leading to relapse after RTX may therefore be linked to interactions between BAFF and BAFF-binding receptors (BBR). Relationships between serum BAFF and BBR expression [(BAFFR, calcium signal modulating cyclophilic ligand interactor (TACI) and B cell maturation antigen (BCMA)] were determined on B cell subsets, defined using immunoglobulin (Ig)D/CD38. Twenty pre-RTX and 18 RA patients relapsing after B cell depletion were included. Results were analysed with respect to timing of relapse up to 7 months after peripheral B cell return (>= 5 B cells/MUl) and to serum BAFF levels. After B cell return, B cell populations from relapsing patients had significantly lower BAFFR+ expression compared to HC and pre-RTX patients. The percentage of BAFFR+ B cells increased with time after B cell return and was correlated inversely with serum BAFF levels. BAFFR expression remained reduced. The percentage of TACI+ memory B cells were lower in RA patients after RTX compared with healthy controls (HC). BCMA expression (% and expression) did not differ between patients and HC. Relapse following B cell return appeared largely independent of the percentage of BAFFR+ or percentage of BCMA+ B cells or serum BAFF levels. The lower percentage of TACI+ memory B cells may reduce inhibitory signalling for B cell differentiation. In patients relapsing at longer periods after B cell return, recovery of the B cell pool was more complete, suggesting that selection or expansion of autoreactive B cells may be needed to precipitate relapse. PMID- 28800166 TI - Exposure-Response Analysis of Nivolumab in Patients With Previously Treated or Untreated Advanced Melanoma. PMID- 28800167 TI - A functional imaging study of germinating oilseed rape seed. AB - Germination, the process whereby a dry, quiescent seed springs to life, has been a focus of plant biologist for many years, yet the early events following water uptake, during which metabolism of the embryo is restarted, remain enigmatic. Here, the nature of the cues required for this restarting in oilseed rape (Brassica napus) seed has been investigated. A holistic in vivo approach was designed to display the link between the entry and allocation of water, metabolic events and structural changes occurring during germination. For this, we combined functional magnetic resonance imaging with Fourier transform infrared microscopy, fluorescence-based respiration mapping, computer-aided seed modeling and biochemical tools. We uncovered an endospermal lipid gap, which channels water to the radicle tip, from whence it is distributed via embryonic vasculature toward cotyledon tissues. The resumption of respiration is initiated first in the endosperm, only later spreading to the embryo. Sugar metabolism and lipid utilization are linked to the spatiotemporal sequence of tissue rehydration. Together, this imaging study provides insights into the spatial aspects of key events in oilseed rape seeds leading to germination. It demonstrates how seed architecture predetermines the pattern of water intake, which sets the stage for the orchestrated restart of life. PMID- 28800168 TI - Malodorogenic Sensing of Carbon Monoxide. AB - A thin film of poly-([IrCl(cod)(NHC-onbe)]n -(propyl-onbe)m ) (onbe=oxanorbornene) coated on filter paper reacts quantitatively with CO to yield 1,5-cyclooctadiene, the unpleasant smell of which can be detected by the human olfactory system with very high sensitivity. Odorless, but toxic CO is thus "translated" into the distinct smell of 1,5-cyclooctadiene. Based on malodorogenic sensing it is possible to smell the presence of CO. PMID- 28800169 TI - Global multielectrode contact mapping plus ablation with a single catheter: Preclinical and preliminary experience in humans with atrial fibrillation. AB - INTRODUCTION: One question for the technological advancement of catheter ablation of atrial fibrillation (AF) is whether a creative new concept can combine and even improve the diagnostic mapping options of single-tip and basket catheters with the simplicity of the use of balloon catheters for ablation. Herein, we describe the first in-human experience with a single catheter offering such a complete solution. METHODS AND RESULTS: A new catheter (Globe(r) ) with a distal multielectrode array consisting of 16 ribs with 122 gold-plated electrodes was used. Each electrode can ablate, pace, and can measure tissue contact, temperature, current, and intracardiac electrograms. The Globe was deployed and removed without difficulty in all 3 patients. Complete pulmonary vein isolation (PVI) was achieved in all 12 veins. In 10 veins, PVI was achieved with a single placement in front of the respective vein ("single circle isolation"). In one subject, the device was repositioned due to the esophagus location. In the other subject, a single gap was observed after circumferential ablation of the right inferior PV. After precise gap identification, the device was adjusted slightly for improved contact at that region, and reablation resulted in immediate PVI. CONCLUSIONS: PVI isolation could be performed with the new multielectrode array Globe in all 12 PVs offering the option for easy handling and fast "single-shot" PVI. Several continuously updated mapping types from 122 electrodes even in real time during ablation demonstrate the capability to go beyond PVI for voltage mapping plus substrate modification, and for rotor mapping plus rotor ablation. PMID- 28800170 TI - Ischaemic stroke. AB - There are about 25.7 million stroke survivors worldwide. Ischaemic stroke remains the most common type of stroke. Numerous modifiable risk factors have been identified, including behaviors such as cigarette smoking and sedentary lifestyle and treatable medical comorbidities such as hypertension, hyperlipidemia and atrial fibrillation. Once considered irreversible, acute ischaemic stroke is now amenable to acute medical and endovascular therapies to reduce infarct volume. Many advances are expected in the years to come, particularly in the areas of prevention and recovery. PMID- 28800171 TI - Antioxidant protection by beta-selenoamines against thioacetamide-induced oxidative stress and hepatotoxicity in mice. AB - Thioacetamide (TAA) is a hepatotoxin that rapidly triggers the necrotic process and oxidative stress in the liver. Nevertheless, organic selenium compounds, such as beta-selenoamines, can be used as pharmacological agents to diminish the oxidative damage. Thus, the aim of this study was to investigate the protective effect of the antioxidant beta-selenoamines on TAA-induced oxidative stress in mice. Here, we observed that a single intraperitoneal injection of TAA (200 mg/kg) dramatically elevated some parameters of oxidative stress, such as lipid peroxidation and reactive oxygen species (ROS) production, as well as depleted cellular antioxidant defenses. In addition, TAA-induced edema and morphological changes in the liver, which correlate with high serum aspartate and alanine aminotransferase enzyme activities, and a decrease in cell viability. Conversely, a significant reduction in liver lipid peroxidation, ROS production, and edema was observed in animals that received an intraperitoneal injection of beta selenoamines (15.6 mg/kg) 1 h after TAA administration. PMID- 28800173 TI - Non-invasive brain stimulation might act in synergy with invasive brain stimulation in dystonia. PMID- 28800172 TI - Viscous drag on the flagellum activates Bacillus subtilis entry into the K-state. AB - Bacillus subtilis flagella are not only required for locomotion but also act as sensors that monitor environmental changes. Although how the signal transmission takes place is poorly understood, it has been shown that flagella play an important role in surface sensing by transmitting a mechanical signal to control the DegS-DegU two-component system. Here we report a role for flagella in the regulation of the K-state, which enables transformability and antibiotic tolerance (persistence). Mutations impairing flagellar synthesis are inferred to increase DegU-P, which inhibits the expression of ComK, the master regulator for the K-state, and reduces transformability. Tellingly, both deletion of the flagellin gene and straight filament (hagA233V ) mutations increased DegU phosphorylation despite the fact that both mutants had wild type numbers of basal bodies and the flagellar motors were functional. We propose that higher viscous loads on flagellar motors result in lower DegU-P levels through an unknown signaling mechanism. This flagellar-load based mechanism ensures that cells in the motile subpopulation have a tenfold enhanced likelihood of entering the K state and taking up DNA from the environment. Further, our results suggest that the developmental states of motility and competence are related and most commonly occur in the same epigenetic cell type. PMID- 28800174 TI - Curcumin ameliorates diclofenac sodium-induced nephrotoxicity in male albino rats. AB - Exposure to drugs often results in toxicity in the kidney which represents the major control system maintaining homeostasis of the body and thus is especially susceptible to xenobiotics. Nephrotoxicity is a life-threatening side-effect of nonsteroidal anti-inflammatory drugs (NSAIDs). Diclofenac is one of the most frequently prescribed NSAIDs and have been reported to cause multiple organs damage. Curcumin (CUR) exhibits nephroprotective properties. Therefore, rats were divided into four groups; rats of groups 3 and 4 received diclofenac (100 mg/kg, i.m.), whereas rats of groups 2 and 4 received CUR (100 mg/kg, p.o.) for 3 days. Diclofenac revealed a significant increase in urea and creatinine levels and malondialdehyde concentration and marked reduction in catalase activity and reduced glutathione concentration. Histopathologically, diclofenac produced fatty changes and eosinophilic casts were detected in the renal tubules, those were attenuated by administration of CUR prior diclofenac. PMID- 28800175 TI - Mesenchymal stromal cells contribute to quiescence of therapy-resistant leukemic cells in acute myeloid leukemia. AB - OBJECTIVE: Persistence of leukemic cells after induction therapy has been shown to correlate with poor survival in acute myeloid leukemia (AML). In this study, we tested if human mesenchymal stromal cells (hMSCs) have protective effects on leukemic cells undergoing chemotherapy. METHODS: Persistent disease was used as marker to identify cases with therapy-resistant leukemic cells in 95 patients with AML. Immunophenotyping, cell cycle, and apoptosis assays were assessed by flow cytometry. AML coculture studies were performed with hMSC of healthy donors. RESULTS: Samples from patients with persistent disease had increased fractions of CD34+ CD38- and quiescent leukemic cells. Comparison of sample series collected at time points of diagnosis and blast persistence showed a relative therapy resistance of quiescent leukemic cells. Consistent with these observations, relapsed disease always displayed higher proportions of quiescent cells compared to samples of first diagnosis suggesting that quiescence is an important therapy escape mechanism of resistant cells. Co-culture studies demonstrated that hMSC protect leukemic cells from the effect of AraC treatment by enriching for quiescent cells, mimicking the effects observed in patients. This effect was even detectable when no direct stromal contact was established. CONCLUSIONS: Our data suggest that hMSC contribute to quiescence and therapy resistance of persistent AML cells. PMID- 28800176 TI - Catheter ablation of left atrial arrhythmias on uninterrupted oral anticoagulation with vitamin K antagonists: What is the relationship between international normalized ratio, activated clotting time, and procedure-related complications? AB - BACKGROUND: Ablation of atrial fibrillation (AF) on uninterrupted phenprocoumon reduces periprocedural thromboembolic and bleeding complications. Heparin is administered intraprocedurally to achieve activated clotting times (ACT) of 300 400 seconds. We investigated the effect of international normalized ratio (INR) on ACT and intraprocedural heparin requirements. Moreover, safety of a target ACT of 250-300 seconds was investigated. METHODS AND RESULTS: We studied 949 patients referred for AF or left atrial tachycardia ablation. Patients were divided into Group 1 (n = 249) with an INR <2 and Group 2 (n = 700) with an INR >=2. Mean INR was 1.7 +/- 0.13 in Group 1 and 2.3 +/- 0.25 in Group 2. Baseline, mean, minimum and maximum ACT were significantly lower in Group 1 (138 +/- 17 seconds vs. 145 +/- 21 seconds; 281 +/- 28 seconds vs. 288 +/- 29 seconds; 251 +/- 36 seconds vs. 258 +/- 34 seconds; 307 +/- 32 seconds vs. 316 +/- 40 seconds; P <0.05). Intraprocedural heparin requirements adjusted to body weight were lower in Group 1 (127 +/- 41 U/kg vs. 122 +/- 40 U/kg). Weak correlations between INR and baseline, mean, minimum and maximum ACT as well as intraprocedural heparin requirements were observed. No differences regarding major or minor complications were found. INR and periprocedural anticoagulation parameters had no influence on major complications. No thromboembolic complications were observed in both groups with a target ACT value of 250-300 seconds. CONCLUSIONS: There is only a weak correlation between INR, intraprocedural ACT, and intraprocedural heparin requirements. Periprocedural target ACT of 250-300 seconds seems safe and does not increase periprocedural bleeding and thromboembolic complications in patients undergoing RF ablation on uninterrupted phenprocoumon therapy. PMID- 28800177 TI - Exercise stress test reveals ineligibility for subcutaneous implantable cardioverter defibrillator in patients with Brugada syndrome. AB - BACKGROUND: The eligibility of patients with Brugada syndrome (BrS) for implantation of a subcutaneous implantable cardioverter defibrillator (S-ICD) is not well known. This study aimed to clarify the eligibility of BrS patients for S ICD using electrocardiography (ECG) at rest and during exercise testing. We also analyzed factors associated with ineligibility for S-ICD from standard 12-lead ECG at rest. METHODS: We enrolled 110 consecutive BrS patients who visited Okayama university hospital from December 2015 to December 2016. All patients were assessed for S-ICD eligibility, which required one lead to satisfy the S-ICD screening template. We assessed standard 12-lead ECG parameters in all participants. Of those who passed S-ICD screening, 45 patients were assessed for S-ICD eligibility during treadmill stress test. RESULTS: Mean age of study patients was 54 +/- 13 years and 108 (98%) were men. In total, 89 patients (81%) satisfied S-ICD indications at rest. Existence of complete right bundle branch block (CRBBB) on standard 12-lead ECG was a significant predictor of ineligibility for S-ICD (odds ratio, 5.00; P = 0.03; 95%CI, 1.14-21.98). Of the 45 patients who underwent treadmill stress testing, 11 patients (24%) showed ineligibility for S-ICD during the test. CONCLUSION: CRBBB was a predictor of ineligibility for S-ICD in patients with BrS. Sinus tachycardia changes ECG morphology in some patients and stress testing should be considered before S-ICD implantation. PMID- 28800178 TI - Outcomes of catheter ablation of ventricular tachycardia with mechanical hemodynamic support: An analysis of the Medicare database. AB - INTRODUCTION: There is a paucity of data in favor of mechanical support during catheter ablation of ventricular tachycardia (VT). This study investigated the outcomes of VT ablation associated with mechanical support using percutaneous ventricular assist device (PVAD) versus intra-aortic balloon pump (IABP). METHODS AND RESULTS: We retrospectively examined the outcomes of patients who underwent VT ablation associated with PVAD versus IABP from 2010 to 2013, captured by the Medicare Inpatient Standard Analytic File database. Data from 345 patients (PVAD = 230, IABP = 115) were examined. On admission, the incidence of heart failure was higher in PVAD (84.3% vs. 73.0%; P = 0.01) with similar rates of renal failure in PVAD versus IABP (33.0% vs. 37.4%; P = 0.42). However, PVAD was associated with reduced in-hospital cardiogenic shock (9.1% vs. 23.5%; P < 0.001), renal failure (11.7% vs. 21.7%; P = 0.01), and length of stay (8.4 +/- 7.9 vs. 10.6 +/- 7.5; P < 0.001), but with greater hospital discharges to home/self-care (66.0% vs. 51.6%; P = 0.02). Index mortality (6.5% vs. 19.1%; P = 0.001) and mortality in patients with cardiogenic shock (18.2% vs. 41.2%; P = 0.03) were significantly lower with PVAD versus IABP. Furthermore, PVAD was associated with lower all-cause (27.0% vs. 38.7%; P = 0.04) and heart failure related (21.4% vs. 33.3%; P = 0.03) 30-day hospital readmissions, but with similar redo-VT ablation rates at 1 year (10.2% vs. 14.0%; P = 0.34). CONCLUSION: Among the cases captured by the Medicare database, catheter ablation of VT associated with mechanical support using PVAD was associated with reduced in hospital cardiogenic shock, renal failure, length of stay, hospital readmissions and mortality, but no difference in redo-VT ablation at 1 year. PMID- 28800179 TI - Short-term outcomes of atrial flutter ablation. AB - BACKGROUND: Understanding the factors associated with early readmissions following atrial flutter (AFL) ablation is critical to reduce the cost and improving the quality of life in AFL patients. METHOD: The study cohort was derived from the national readmission database 2013-2014. International Classification of Diseases, 9th Revision (ICD-9-CM) diagnosis code 427.32 and procedure code 37.34 were used to identify AFL and catheter ablation, respectively. The primary and secondary outcomes were 90-day readmission and complications including in-hospital mortality. Cox proportional regression and hierarchical logistic regression were used to generate the predictors of primary and secondary outcomes respectively. Readmission causes were identified by ICD-9 CM code in primary diagnosis field of readmissions. RESULT: Readmission rate of 18.19% (n = 1,010 with 1,396 readmissions) was noted among AFL patients (n = 5552). Common etiologies for readmission were heart failure (12.23%), atrial fibrillation (11.13%), atrial flutter (8.93%), respiratory complications (9.42%), infections (7.4%), bleeding (7.39%, including GI bleed-4.09% and intracranial bleed-0.79%) and stroke/TIA (1.89%). Multivariate predictors of 90-day readmission (hazard ratio, 95% confidence interval, P value) were preexisting heart failure (1.30, 1.13-1.49, P < 0.001), chronic pulmonary disease (1.37, 1.18 1.58, P < 0.001), anemia (1.23, 1.02-1.49, P = 0.035), malignancy (1.87, 1.40 2.49, P < 0.001), weekend admission compared to weekday admission (1.23, 1.02 1.47, P = 0.029), and length of stay (LOS) >=5 days (1.39, 1.16-1.65, P < 0.001). Note that 50% of readmissions happened within 30 days of discharge. CONCLUSION: Cardiac etiologies remain the most common reason for the readmission after AFL ablation. Identifying high risk patients, careful discharge planning, and close follow-up postdischarge can potentially reduce readmission rates in AFL ablation patients. PMID- 28800180 TI - Epithelioid malignant mesothelioma metastatic to the skin: A case report and review of the literature. AB - Malignant mesothelioma (MM) is an aggressive and invasive neoplasm primarily affecting the pleura, peritoneum and pericardium. While mesothelioma commonly metastasizes to visceral organs, it has rarely been documented to involve the skin and subcutaneous tissue. There is a paucity of reports of cutaneous metastatic mesothelioma, and histologic examination is often challenging because the tumor closely mimics other primary and metastatic neoplasms. We report a case of a 75-year-old man presenting with a firm, hard nodule on his upper back, which on initial histologic evaluation resembled metastatic adenocarcinoma. However, upon review of his medical history and immunohistochemical evaluation of the lesion, the diagnosis of epithelioid MM metastatic to the skin was rendered. The purpose of this case report and review of the literature is to summarize the most effective available immunostains to aid in the diagnosis of this challenging entity, highlight the histologic similarities between metastatic epithelioid MM and other primary and metastatic neoplasms of the skin, and provide prognostic information for these rare tumors. PMID- 28800181 TI - Synephrine and phenylephrine act as alpha-amylase, alpha-glycosidase, acetylcholinesterase, butyrylcholinesterase, and carbonic anhydrase enzymes inhibitors. AB - In this paper, synephrine and phenylephrine compounds showed excellent inhibitory effects against human carbonic anhydrase (hCA) isoforms I and II, alpha-amylase, alpha-glycosidase, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). Synephrine and phenylephrine had Ki values of 199.02 +/- 16.01 and 65.01 +/- 5.00 MUM against hCA I and 336.02 +/- 74.01 and 92.04 +/- 18.03 MUM against hCA II, respectively. On the other hand, their Ki values were found to be 169.10 +/- 80.03 and 88.03 +/- 5.01 nM against AChE and 177.06 +/- 6.01 and 78.03 +/- 3.05 nM against BChE, respectively. alpha-Amylase and alpha-glycosidase enzymes were easily inhibited by these compounds. alpha-Glycosidase inhibitors, generally defined to as starch blockers, are anti-diabetic drugs that help to decrease post comestible blood glucose levels. PMID- 28800183 TI - Unknown Intracardiac Electrogram. AB - Watch a video presentation of this article. For additional educational resources, please visit Medtronic Academy . PMID- 28800182 TI - Development and preliminary pilot evaluation of a brief tablet computer intervention to motivate tobacco quitline use among smokers in substance use treatment. AB - BACKGROUND AND OBJECTIVES: The majority of individuals in substance use disorder (SUD) treatment also smoke cigarettes; yet, the availability of smoking cessation services in SUD treatment remains limited. In this study, we developed and piloted a brief intervention for smokers in SUD treatment intended to motivate engagement in tobacco quitline treatment (TIME-TQ). METHODS: First, we interviewed 19 smokers in SUD treatment to inform the development of TIME-TQ (Phase 1). Second, we delivered a prototype TIME-TQ to 16 smokers in the same SUD treatment program and followed them for 3 months post-discharge (Phase 2). RESULTS: Feedback from Phase 1 participants was used to refine response choices and video segments included in the prototype TIME-TQ. Phase 2 participants rated TIME-TQ high on relevance, interest, respectfulness, and helpfulness. Additionally, they reported significant increases in readiness to quit and perceived importance of quitting after receiving TIME-TQ. A total of 8 of the 16 accepted a quitline referral, and 8 of 13 reached for follow-up (four referral acceptors, four decliners) reported efforts to quit or reduce smoking during the follow-up period. However, only three received quitline counseling and none achieved a sustained period of abstinence. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Our results suggest that TIME-TQ activated these patients to quit smoking, but our referral method (standard fax referral) was unsuccessful in helping participants fully engage in quitline treatment or achieving a period of abstinence. SCIENTIFIC SIGNIFICANCE: We are now conducting an RCT to evaluate TIME-TQ with a revised referral procedure intended to increase treatment engagement and, ultimately, abstinence rates. (Am J Addict 2017;26:587-594). PMID- 28800184 TI - Use of non-pharmacological strategies for pain relief in addiction treatment patients with chronic pain. AB - BACKGROUND AND OBJECTIVES: We examined use of non-pharmacological treatments for pain in addiction treatment patients. METHODS: Patients in addiction treatment with chronic pain (N = 501) were classified based on use of non-pharmacological pain treatments. Demographic and clinical correlates were compared. RESULTS: A total of 49% (N = 243) of patients used a non-pharmacological treatment in the past year versus 72% (N = 361) who used opioids. Non-pharmacological treatment users were more likely to use opioids and other pain medications. CONCLUSIONS: Non-pharmacological treatments are less commonly used than opioids by addiction treatment patients. SCIENTIFIC SIGNIFICANCE: Findings highlight the need to better understand pain treatment decision-making among addiction treatment patients. (Am J Addict 2017;26:564-567). PMID- 28800185 TI - Synthesis of Spirocyclic Pyrrolidines: Advanced Building Blocks for Drug Discovery. AB - In the context of drug discovery, novel spirocyclic pyrrolidines have been synthesized in two steps from common three- to seven-membered-ring (hetero)alicyclic ketones. The key transformation is a reaction between an electron-deficient exocyclic alkene and an in situ generated N-benzyl azomethine ylide. The developed method has been used to synthesize the central diamine core of the known antibacterial agents Sitafloxacin and Olamufloxacin. PMID- 28800186 TI - Ameliorative response to detoxification, psychotherapy, and medical management in patients maintained on opioids for pain. AB - BACKGROUND AND OBJECTIVES: The prevalence of opioid-induced hyperalgesia (OIH) among patients maintained on opioids for chronic non-malignant pain has not been estimated. As a contribution toward establishing its prevalence, we report a case series of opioid maintained patients whose pain tolerance was measured by the cold pressor test at baseline. METHODS: A case series of 117 patients who had undergone detoxification was reviewed retrospectively. Most patients (n = 108) and selected non-addicted support persons who accompanied them (controls; n = 37) had cold pressor time (CPT) assessments at baseline. Twenty patients had a repeat CPT after 1 month. RESULTS: When 61 patients completed one month abstinent reported pain was improved (51%), unchanged (46%), or worse (3%). Baseline CPT was 48 sec for patients and 102 sec for controls, suggesting that opioid maintained patients were more pain sensitive than opioid naive controls. CPT increased for 90% of 1-month completers, suggesting improved pain tolerance. Ameliorative response to detoxification, psychotherapy, and medical management, as defined as the absence of worsening pain with removal of opioids, was 97% in this population. CONCLUSION: The difference in CPT between opioid maintained patients and controls, and the response to detoxification, psychotherapy and medical management suggest the possibility that the prevalence of OIH may be high. SCIENTIFIC SIGNIFICANCE: This study adds to the growing evidence that chronic opioid treatment contributes little to the management of chronic pain and in fact appears to frequently make it worse. (Am J Addict 2017;26:738-743). PMID- 28800187 TI - (CF3 )3 Au as a Highly Acidic Organogold(III) Fragment. AB - The Lewis acidity of perfluorinated trimethylgold (CF3 )3 Au was assessed by theoretical and experimental methods. It was found that the (CF3 )3 Au unit is much more acidic than its nonfluorinated analogue (CH3 )3 Au, and probably sets the upper limit of the acidity scale for neutral organogold(III) species R3 Au. The significant acidity increase on fluorination is in line with the CF3 group being more electron-withdrawing than CH3 . The solvate (CF3 )3 Au?OEt2 (1) is presented as a convenient synthon of the unsaturated, 14-electron species (CF3 )3 Au. Thus, the weakly coordinated ether molecule in 1 is readily replaced by a variety of neutral ligands (L) to afford a wide range of (CF3 )3 Au?L compounds, which were isolated and characterized. Most of these mononuclear compounds exhibit marked thermal stability. This enhanced stabilization can be rationalized in terms of substantially stronger [Au]-L interactions with the (CF3 )3 Au unit. An affinity scale of this single-site, highly acidic organogold(III) fragment was calculated by DFT methods and experimentally mapped for various neutral monodentate ligands. The high-energy profile calculated for the fluorotropic [Au] CF3 ?F-[Au]<-CF2 process makes this potential decomposition path unfavorable and adds to the general stabilization of the fragment. PMID- 28800188 TI - Care in the Context of a Chronic Epidemic: Caring for Diabetes in Chicago's Native Community. AB - American Indians have some of the highest rates of diabetes worldwide, and they are disproportionately affected by the secondary complications of the disease. While most research on Native populations focuses on reservations, this study investigates diabetes care in Chicago's Native community. People living with diabetes manage blood sugar levels to prevent the development of secondary complications. As with many diabetics, the majority of their health care work is completed outside of the biomedical setting. In this article, I explore how, in a community facing epidemic rates of disease, care is enmeshed in the everyday lives of not just those living with the disease but also significant others. As care in this context is accomplished across multiple spheres, from inside individual households to community-wide considerations, Chicago's intertribal community ties are strengthened. Care, in this sense, becomes a (perhaps tragic) means of Native American community building tied to cultural identity. PMID- 28800189 TI - Supramolecular Host-Guest Inclusion for Distinguishing Cucurbit[7]uril-Based Pseudorotaxanes from Small-Molecule Ligands in Coordination Assembly with a Uranyl Center. AB - Although the capability of supramolecular pseudorotaxane/rotaxane systems as ligands for coordination with actinides has been identified by the on-going emerging of uranyl-organic polyrotaxane compounds, it is, however, still unknown how supramolecular inclusion affects the coordination assembly of the simple "axle" ligand with uranyl species. Herein, a semi-rigid organic dicarboxylate compound [BzBPCEt]Br2 (L1 ) is selected as a small-molecule "axle" ligand and the corresponding cucurbit[7]uril (CB7)-based [2]pseudorotaxane ligand, [BzBPCEt]Br2 @CB7 (L1 @CB7) has been also synthesized through CB7-based inclusion in this work. A detailed comparison between uranyl complexes from the "axle" ligand L1 and those from pseudorotaxane L1 @CB7 has been conducted, demonstrating the significant role of CB7-based inclusion in distinguishing supramolecular pseudorotaxane ligands from small-molecule dicarboxylates in uranyl coordination assembly. Notably, the impact of supramolecular inclusion on the "axle" linker in the system with cucurbituril macrocycles involved is established for the first time. Detailed structure decipherment suggests that the significant effect of CB7 is attributed to hydrothermal stabilization of the "axle" ligand or increased steric hindrance to the groups nearby originated from the bulky size of macrocyclic CB7. PMID- 28800190 TI - Reductive Eliminations from Diarylpalladium(II) Complexes: A Combined Experimental and Computational Investigation. AB - The diverse mechanisms for the reductive elimination of biaryl compounds from diarylpalladium(II) complexes with a tetradentate ligand were investigated through a combined experimental and computational study. At least four distinct chemical triggers with specific regioselectivity exist for this elimination. Heating of the complexes in inert solvents (e.g., para-xylene) reveals their relatively high thermal stability as reflected by a very high barrier for a unimolecular reductive elimination. In contrast, electron-donor ligands like triphenylphosphine induce a facile reductive elimination via twofold associative ligand exchange as confirmed by kinetic experiments, which are in good agreement with the computational results. Oxidants, such as H2 O2 , can trigger an oxidation-induced reductive elimination via palladium(IV) intermediates at room temperature. Rearrangement of the diarylpalladium(II) complexes can occur in organic acids, facilitating a reductive elimination with distinct regiochemical outcome. PMID- 28800191 TI - An investigation into regional medical practitioners' knowledge of exercise during pregnancy guidelines. PMID- 28800192 TI - Efficacy and safety of driver-guided catheter ablation for atrial fibrillation: A systematic review and meta-analysis. AB - INTRODUCTION: Targeting localized drivers (electrical rotors or focal impulses) during catheter ablation for atrial fibrillation (AF) has been proposed as a strategy to improve procedural success. However, the strength and quality of the evidence to support this approach is unclear. METHODS AND RESULTS: Clinical studies reporting efficacy or safety outcomes of driver-guided ablation for AF were identified in Medline, Embase, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, Pubmed, and conference abstracts from major scientific meetings. Random-effects meta-analysis of efficacy outcomes from controlled studies was performed. Thirty-one reports from 30 studies were included: two randomized controlled trials, five nonrandomized controlled studies, and 23 uncontrolled studies. In controlled studies, driver guided ablation has been associated with higher rates of acute AF termination (RR 2.08, 95% CI 1.43-3.05; P < 0.001) and increased freedom from AF/atrial tachycardia (AT) at >=1 year (RR 1.34, 95% CI 1.05-1.70; P = 0.02). Similar rates of procedural complications have been reported between ablation strategies. Overall, current data on driver-guided ablation are predominantly from nonrandomized studies with considerable heterogeneity in mapping and ablation strategies used and in clinical outcomes reported. CONCLUSION: Pooled data on the efficacy of AF driver-guided catheter ablation suggest increased freedom from AF/AT relative to conventional strategies. However, most studies are nonrandomized and of moderate quality. Though promising data exist, there remains no conclusive evidence for the efficacy of AF driver ablation. Robust data from randomized trials are needed. PMID- 28800193 TI - Citrin deficiency: A rare but important metabolic disorder to consider in infants with faltering growth and hyperbilirubinaemia. PMID- 28800194 TI - A comparison of two endoscopic posterior cordotomy techniques: Laser cordotomy vs diathermy-assisted cordotomy. AB - OBJECTIVES: To compare respiratory function, swallowing and voice quality of bilateral abductor vocal fold paralysis (BAVFP) patients undergoing laser and diathermy-assisted posterior cordotomy. DESIGN: Prospective study. SETTING: Tertiary academic hospital. PARTICIPANTS: Thirty patients were included in the study (groups 1 and 2, 15 patients each). Mean age was 53 +/- 14.27 years with a range of 31-78 years (12 [40%] males, 18 [60%] females). MAIN OUTCOME MEASURES: Sufficient airway, complications, FEV1, FEV1/FVC, peak expiratory flow rate (PEF), voice quality VAS, fundamental frequency, jitter, shimmer, NHR, amplitude perturbation quotient (APQ) and pitch perturbation quotient (PPQ) scores. RESULTS: A sufficient laryngeal airway was achieved in all patients. Six patients (20%) developed postoperative granulation tissue (2 in group 1 and 4 in group 2). There was a statistically significant improvement in FEV1, FEV1/FVC and PEF measurements at the postoperative sixth month compared to preoperative measurements in both of the groups (P < .05). Preoperative median voice quality VAS scores in groups 1 and 2 were 8 (IQR = 1) and 8 (IQR = 3), respectively. Postoperative sixth-month voice quality VAS scores in groups 1 and 2 were 6 (IQR = 1) and 6 (IQR = 0), respectively. Postoperative VAS scores were significantly lower in both groups (P < .05). The postoperative changes in fundamental frequency, NHR, jitter, shimmer, APQ and PPQ were not statistically significant in both of the groups (P > .05). CONCLUSIONS: Laser and diathermy-assisted posterior cordotomy are both minimally invasive, effective techniques with a long term sufficient laryngeal airway. Despite lower quality of voice VAS scores, objective acoustic outcomes were not significantly lower in both of the groups. PMID- 28800195 TI - Pharmacokinetics, Safety, and Tolerability of Glecaprevir and Pibrentasvir in Healthy White, Chinese, and Japanese Adult Subjects. AB - Glecaprevir and pibrentasvir are direct-acting antiviral agents being developed as combination therapy for the treatment of chronic hepatitis C virus infection. The aim of the present studies was to assess the effect of race and ethnicity (white, Han Chinese, Japanese) on the pharmacokinetics and safety of multiple oral doses of glecaprevir and pibrentasvir given alone and in combination. Two multiple-dose, single-center, phase 1 studies were conducted in healthy adult male and female subjects (n = 170) of respective Asian and white race/ethnicity. Glecaprevir (100, 200, 300, or 700 mg once daily) and pibrentasvir (80, 120, or 160 mg once daily) were administered alone for 7 days followed by the combination of both direct-acting antiviral agents for another 7 days. Intensive blood sampling was performed, and pharmacokinetic parameters were estimated by noncompartmental analyses. ANOVA was employed to evaluate for differences of steady-state glecaprevir and pibrentasvir exposures between Asian (Japanese or Han Chinese) and white subjects. Glecaprevir and pibrentasvir exposures in Han Chinese and Japanese were similar to those in whites across dose levels. The nonlinear dose-exposure relationships for glecaprevir and pibrentasvir were similar across Japanese, Han Chinese, and white subjects, and the safety profiles of the agents were comparable across these groups. The results of these studies demonstrate that race/ethnicity has no clinically meaningful impact on direct acting antiviral agent exposures, safety, or tolerability of the glecaprevir and pibrentasvir combination. This is supported in part by the large global registration program of the pangenotypic, coformulated fixed-dose glecaprevir/pibrentasvir regimen and allows for inclusion of diverse ethnic populations. PMID- 28800196 TI - Furthering knowledge of seaweed growth and development to facilitate sustainable aquaculture. AB - Macroalgae (seaweeds) are the subject of increasing interest for their potential as a source of valuable, sustainable biomass in the food, feed, chemical and pharmaceutical industries. Compared with microalgae, the pace of knowledge acquisition in seaweeds is slower despite the availability of whole-genome sequences and model organisms for the major seaweed groups. This is partly a consequence of specific hurdles related to the large size of these organisms and their slow growth. As a result, this basic scientific field is falling behind, despite the societal and economic importance of these organisms. Here, we argue that sustainable management of seaweed aquaculture requires fundamental understanding of the underlying biological mechanisms controlling macroalgal life cycles - from the production of germ cells to the growth and fertility of the adult organisms - using diverse approaches requiring a broad range of technological tools. This Viewpoint highlights several examples of basic research on macroalgal developmental biology that could enable the step-changes which are required to adequately meet the demands of the aquaculture sector. PMID- 28800197 TI - beta-Functionalized Push-Pull opp-Dibenzoporphyrins as Sensitizers for Dye Sensitized Solar Cells. AB - A novel class of beta-functionalized push-pull zinc opp-dibenzoporphyrins were designed, synthesized, and utilized as sensitizers for dye-sensitized solar cells. Spectral, electrochemical, and computational studies were systematically performed to evaluate their spectral coverage, redox behavior, and electronic structures. These porphyrins displayed much broader spectral coverage and more facile oxidation upon extension of the pi conjugation. Free-energy calculations and femtosecond transient absorption studies (charge injection rate in the range of 1011 s-1 ) suggested efficient charge injection from the excited singlet state of the porphyrin to the conduction band of TiO2 . The power conversion efficiency (eta) of YH3 bearing acrylic acid linkers (eta=5.9 %) was close to that of the best ruthenium dye N719 (eta=7.4 %) under similar conditions. The superior photovoltaic performance of YH3 was attributed to its higher light harvesting ability and more favorable electron injection and collection, as supported by electrochemical impedance spectral studies. This work demonstrates the exceptional potential of benzoporphyrins as sensitizers for dye-sensitized solar cells. PMID- 28800198 TI - Identifying the Crystalline Orientation of Black Phosphorus by Using Optothermal Raman Spectroscopy. AB - Current polarized Raman-based techniques for identifying the crystalline orientation of black phosphorus suffer significant uncertainty and unreliability because of the complex interference involving excitation laser wavelength, scattering light wavelength, and sample thickness. Herein, for the first time, we present a new method, optothermal Raman spectroscopy (OT-Raman), for identifying crystalline orientation. With a physical mechanism based on the anisotropic optical absorption of the polarized laser and the resulting heating, the OT-Raman can identify the crystalline orientation explicitly, regardless of excitation wavelength and sample thickness, by Raman frequency-power differential Phi (=?omega/?P). The parameter Phi has the largest (smallest) value when the laser polarization is along the armchair (zigzag) direction. The OT-Raman technique is robust and is able to identify the crystalline orientation of BP samples with thicknesses up to 300 nm at a minimum and potentially as high as 1200 nm. PMID- 28800199 TI - Intracranial elastance is increased in idiopathic intracranial hypertension. AB - BACKGROUND AND PURPOSE: To date, no pathophysiological model has sufficiently accounted for all the findings encountered in patients with idiopathic intracranial hypertension (IIH). Intracranial elastance is an index of volume buffering capacity known to play a role in certain disorders of cerebrospinal fluid (CSF) dynamics, which has not been previously investigated in relation to IIH patients. METHODS: This was a single-center retrospective cohort study from 1 July 2011 to 1 July 2016. Values for opening pressure (PO ), closing pressure (PC ) and volume (V) of CSF removed were collected, as well as demographic and clinical covariates. Intracranial elastance (E) and pressure-volume index (PVI) were calculated according to established equations: E = (PO -PC )/V and PVI = V/log10 (PO /PC ), respectively. Those with an alternative central nervous system pathology, including meningitis, encephalitis and normal pressure hydrocephalus were excluded. Eligible patients were subdivided into two groups based on final diagnosis: a control group and an IIH group. RESULTS: In our cohort (n = 49), a significant association of both E (P < 0.0001) and PVI (P = 0.005) with a diagnosis of IIH was observed. Median E was 0.45 [interquartile range (IQR) 0.29 0.63] in the control group and 1 (IQR 0.59-1.29) in the IIH group, and median PVI was 98.07 (IQR 59.92-135.86) in the control group and 64.1 (IQR 42.4-91.7) in the IIH group. Neither E nor PVI were significantly associated with age, gender or body mass index. PVI was independent of opening pressure. CONCLUSIONS: As calculated by clinically accessible indices, our study provides evidence that intracranial elastance is increased in IIH, reflecting a novel insight into disease pathogenesis. PMID- 28800200 TI - Selective alpha-Oxyamination and Hydroxylation of Aliphatic Amides. AB - Compared to the alpha-functionalization of aldehydes, ketones, even esters, the direct alpha-modification of amides is still a challenge because of the low acidity of alpha-CH groups. The alpha-functionalization of N-H (primary and secondary) amides, containing both an unactived alpha-C-H bond and a competitively active N-H bond, remains elusive. Shown herein is the general and efficient oxidative alpha-oxyamination and hydroxylation of aliphatic amides including secondary N-H amides. This transition-metal-free chemistry with high chemoselectivity provides an efficient approach to alpha-hydroxy amides. This oxidative protocol significantly enables the selective functionalization of inert alpha-C-H bonds with the complete preservation of active N-H bond. PMID- 28800201 TI - Molting drives mortality in foraging populations of Formosan subterranean termites (Isoptera: Rhinotermitidae) baited with a chitin synthesis inhibitor, noviflumuron. AB - BACKGROUND: The lethal time of a chitin synthesis inhibitor (CSI)-baited colony of Coptotermes formosanus Shiraki largely depends on the time taken for workers to molt after consuming a lethal dose. Given that termite molting biology can regulate the time to elimination of a baited termite colony, the objective of this study was to determine how the fasting period (an important element of the worker molting cycle) and acquisition of the lethal dose can impact the total elimination period for a colony. RESULTS: Noviflumuron eliminated the foraging population over a 30 m-long foraging arena within 9 weeks. However, mortality in treatment groups did not begin until day 11. The 10-day lag post treatment corresponds to the fasting period during which workers to prepare for ecdysis on the 11th day, at which time mortality occurs due to the effect of CSI. CONCLUSION: This study shows that, with the exception of successful molting events during the first 10 days after baiting, mortality among workers is inevitable in the next molt with lethal doses of noviflumuron. The 10-day fasting period can comprise at least 22% of a molt cycle (45 days for a fourth worker instar or lower), and can provide a window during which a worker escapes the effect of CSI bait, thereby extending the total time needed for elimination of a colony. (c) 2017 Society of Chemical Industry. PMID- 28800202 TI - The SIGN 104 guideline (2014) for topical antibiotic prophylaxis during grommet insertion: Misguided? PMID- 28800203 TI - Smokers have a higher risk of inflammatory peri-implant disease than non-smokers. AB - AIM: To comparatively evaluate peri-implant health status in smokers and non smokers. MATERIALS AND METHODS: A total of 142 implants (74 implants in non smokers, 68 in smokers) in 43 smoker or non-smoker systemically healthy patients were included in the study. Demographic and clinical periodontal data were recorded and analysed by chi-square and Mann-Whitney U tests. RESULTS: Peri implantitis and mucositis cases were significantly more frequent in the smokers than non-smokers (p = .001). Suppuration, bleeding and plaque scores around the implants were significantly higher in smokers than non-smokers (p = .001; p = .002; p < .0001, respectively). CONCLUSION: The present findings indicate that smokers have a higher risk of inflammatory peri-implant diseases. Therefore, more frequent recalls may be recommended in smokers with dental implants. PMID- 28800204 TI - Comparison of robotic and coblation tongue base resection for obstructive sleep apnoea. AB - OBJECTIVES: To compare the efficacy and safety of transoral robotic surgery (TORS) with endoscope-guided coblation tongue base resection. DESIGN: Retrospective case-control study. SETTING: University-based tertiary care medical center. PARTICIPANTS: Patients with obstructive sleep apnoea (OSA) who underwent endoscope-guided tongue base coblation resection or transoral robotic surgery (TORS) in combination with lateral pharyngoplasty at a single institution in South Korea between April 2013 and December 2016 were investigated. Forty-five patients who had moderate-to-severe OSA with tongue base collapse and a minimum follow-up period of 6 months with postoperative polysomnography (PSG) were enrolled in this study. MAIN OUTCOME MEASURES: All patients underwent pre- and postoperative (at least 4 months after surgery) overnight PSG. Available information on results of the PSG, Epworth sleepiness scale and complications of the TORS and coblation groups were compared. RESULTS: Postoperative PSG studies showed improved sleep quality for most patients. The mean postoperative apnoea hypopnea index (AHI) was reduced significantly from 45.0 to 17.0 events/h (P < .0001) in the TORS group and from 45.6 to 16.2 events/h (P < .0001) in the coblation group. The mean rates of improvement (AHI reduction > 50%) were 75.0% in TORS patients and 62.1% in coblation patients and the difference was not significant. Less frequent postoperative morbidity, including bleeding, taste dysfunction and foreign body sensation, was recorded in TORS patients. CONCLUSIONS: Both the coblation and TORS groups showed similar surgical outcomes, TORS achieved PSG results non-inferior to and complication rates comparable to coblation. PMID- 28800205 TI - Wide-field color imaging of scatter-based tissue contrast using both high spatial frequency illumination and cross-polarization gating. AB - This study characterizes the scatter-specific tissue contrast that can be obtained by high spatial frequency (HSF) domain imaging and cross-polarization (CP) imaging, using a standard color imaging system, and how combining them may be beneficial. Both HSF and CP approaches are known to modulate the sensitivity of epi-illumination reflectance images between diffuse multiply scattered and superficially backscattered photons, providing enhanced contrast from microstructure and composition than what is achieved by standard wide-field imaging. Measurements in tissue-simulating optical phantoms show that CP imaging returns localized assessments of both scattering and absorption effects, while HSF has uniquely specific sensitivity to scatter-only contrast, with a strong suppression of visible contrast from blood. The combination of CP and HSF imaging provided an expanded sensitivity to scatter compared with CP imaging, while rejecting specular reflections detected by HSF imaging. ex vivo imaging of an atlas of dissected rodent organs/tissues demonstrated the scatter-based contrast achieved with HSF, CP and HSF-CP imaging, with the white light spectral signal returned by each approach translated to a color image for intuitive encoding of scatter-based contrast within images of tissue. The results suggest that visible CP-HSF imaging could have the potential to aid diagnostic imaging of lesions in skin or mucosal tissues and organs, where just CP is currently the standard practice imaging modality. PMID- 28800206 TI - Relative Bioavailability of Fixed-Dose Combinations of Tamsulosin and Dutasteride: Results From 2 Randomized Trials in Healthy Male Volunteers. AB - The relative bioavailabilities of dutasteride/tamsulosin hydrochloride 0.5 mg/0.2 mg fixed-dose combination (FDC) capsules compared with coadministered reference products (1 dutasteride 0.5-mg capsule [Avodart(r) ] + 1 tamsulosin hydrochloride 0.2-mg orally disintegrating tablet [Harnal D(r) ]) were investigated in 2 clinical trials under fasted and fed conditions (ClinicalTrials.gov NCT02184585 and NCT02509104). Both trials were open-label, randomized, single-dose, crossover studies in healthy male adults aged 18-65 years. Trial 1 evaluated 2 formulations (FDC1 and FDC2), and trial 2 evaluated a third formulation (FDC3). The primary end points were dutasteride area under the concentration-time curve from time 0 to t (AUC(0-t) ) and peak plasma concentration (Cmax ) and tamsulosin AUC(0 infinity) , AUC(0-t) , and Cmax . The formulations were considered to be bioequivalent if the 90%CIs for the geometric mean ratios for each end point were within the range of 0.80-1.25. For FDC1 in trial 1, bioequivalence criteria were not met for dutasteride Cmax or AUC in the fasted state or for tamsulosin Cmax in the fasted or fed states. For FDC2 in trial 1, all bioequivalence criteria were met except for tamsulosin Cmax in the fasted state. For FDC3 in trial 2, bioequivalence criteria were met for all dutasteride and tamsulosin end points in both the fed and fasted states. Safety profiles were similar for all FDC formulations and combination treatments. PMID- 28800207 TI - Optically derived metabolic and hemodynamic parameters predict hippocampal neurogenesis in the BTBR mouse model of autism. AB - In this study, we made use of dual-wavelength laser speckle imaging (DW-LSI) to assess cerebral blood flow (CBF) in the BTBR-genetic mouse model of autism spectrum disorder, as well as control (C57Bl/6J) mice. Since the deficits in social behavior demonstrated by BTBR mice are attributed to changes in neural tissue structure and function, we postulated that these changes can be detected optically using DW-LSI. BTBR mice demonstrated reductions in both CBF and cerebral oxygen metabolism (CMRO2 ), as suggested by studies using conventional neuroimaging technologies to reflect impaired neuronal activation and cognitive function. To validate the monitoring of CBF by DW-LSI, measurements with laser Doppler flowmetry (LDF) were also performed which confirmed the lowered CBF in the autistic-like group. Furthermore, we found in vivo cortical CBF measurements to predict the rate of hippocampal neurogenesis, measured ex vivo by the number of neurons expressing doublecortin or the cellular proliferation marker Ki-67 in the dentate gyrus, with a strong positive correlation between CBF and neurogenesis markers (Pearson, r = 0.78; 0.9, respectively). These novel findings identifying cortical CBF as a predictive parameter of hippocampal neurogenesis highlight the power and flexibility of the DW-LSI and LDF setups for studying neurogenesis trends under normal and pathological conditions. PMID- 28800208 TI - Palliative care in the Top End: The continuing cancer bias. PMID- 28800209 TI - Using local clinical educators and shared resources to deliver simulation training activities across rural and remote South Australia and south-west Victoria: A distributed collaborative model. AB - PROBLEM: There is a lack of access to simulation-based education (SBE) for professional entry students (PES) and health professionals at rural and remote locations. DESIGN: A descriptive study. SETTING: Health and education facilities in regional South Australia and south-west Victoria. KEY MEASURES FOR IMPROVEMENT: Number of training recipients who participated in SBE; geographical distribution and locations where SBE was delivered; number of rural clinical educators providing SBE. STRATEGIES FOR CHANGE: A distributed model to deliver SBE in rural and remote locations in collaboration with local health and community services, education providers and the general public. Face-to-face meetings with health services and education providers identified gaps in locally delivered clinical skills training and availability of simulation resources. Clinical leadership, professional development and community of practice strategies were implemented to enhance capacity of rural clinical educators to deliver SBE. EFFECTS OF CHANGE: The number of SBE participants and training hours delivered exceeded targets. The distributed model enabled access to regular, localised training for PES and health professionals, minimising travel and staff backfill costs incurred when attending regional centres. The skills acquired by local educators remain in rural areas to support future training. LESSONS LEARNT: The distributed collaborative model substantially increased access to clinical skills training for PES and health professionals in rural and remote locations. Developing the teaching skills of rural clinicians optimised the use of simulation resources. Consequently, health services were able to provide students with flexible and realistic learning opportunities in clinical procedures, communication techniques and teamwork skills. PMID- 28800210 TI - Rates of early intervention services in children born extremely preterm/extremely low birthweight. AB - AIM: To determine the rates of early intervention (EI) service use in extremely preterm (EP, <28 weeks' gestation) or extremely low birthweight (ELBW, <1000 g) infants between 1991 and 2013, and identify biological or socio-economic factors associated with receiving EI. METHODS: Participants comprised consecutive EP or ELBW survivors born in 1991-1992, 1997 or 2005 in Victoria, Australia, and randomly selected, matched term-born controls. The main outcome measure was parent-reported EI participation up to 8 years of age. Neurodevelopmental outcomes and socio-economic risk factors were compared with EI participation to identify associations among the preterm groups. RESULTS: The rates of EI were higher in the preterm groups than the control groups overall (odds ratio 4.29, 95% confidence interval 3.28, 5.59, P < 0.001), and the rates of EI rose significantly over time - from 42% in the 1991-1992 preterm cohort to 64% in the 2005 preterm cohort. Among the preterm groups, post-natal corticosteroid therapy, cystic periventricular leukomalacia and surgery in the newborn period were all independently associated with increased odds of receiving EI. Increased severity of disability was associated with higher rates of EI. The majority (95%) of preterm children with a physical impairment received EI, compared with only 73% of children with a cognitive impairment alone. EI participation rates were independent of social risk. CONCLUSION: EI participation is high in the EP population, and rates of EI use have increased over time. Contrary to previous reports, social risk factors were not found to be associated with EI use. PMID- 28800211 TI - Pharmacokinetics and Bioequivalence of Branded and Generic Formulations of Dofetilide 0.5-mg Capsules After Single-Dose Administration in Healthy Subjects. AB - Class III antiarrhythmics are preferred therapy for managing atrial fibrillation/flutter. Dofetilide 0.5-mg capsules were US Food and Drug Administration (FDA) approved in 1999 to treat atrial fibrillation/flutter. Bioequivalence of generic dofetilide is important for treating arrhythmias because drug concentrations must be consistent to maintain normal sinus rhythm. Generic dofetilide 0.5-mg capsule pharmacokinetics were compared with branded product in 2 open-label, 2-way crossover, single-dose studies - 1 study each in fasted and fed healthy subjects. Blood samples were collected before and up to 48 hours after dosing. Safety was assessed by tabulating adverse events and vital signs. Seventy-three subjects were enrolled; 59 completed the studies. In fasted subjects, the 90% confidence intervals (CIs) for generic dofetilide 0.5 mg versus the reference formulation were 0.996-1.026 for the area under the plasma concentration-time curve from 0 to infinity (AUC) and 0.974-1.066 for the maximum observed concentration (Cmax ). In fed subjects, the 90%CIs for AUC and Cmax were 0.988-1.015 and 0.928-0.992, respectively. All ratios were within the FDA established bioequivalence range. Twenty-six subjects experienced 37 adverse events (generic, 15; reference, 22); all but 1 were mild or moderate in severity. Generic dofetilide 0.5-mg capsules can be considered bioequivalent to the reference product. PMID- 28800212 TI - ABO blood group phenotype frequency estimation using molecular phenotyping in rhesus and cynomolgus macaques. AB - A much larger sample (N = 2369) was used to evaluate a previously reported distribution of the A, AB and B blood group phenotypes in rhesus and cynomolgus macaques from six different regional populations. These samples, acquired from 15 different breeding and research facilities in the United States, were analyzed using a real-time quantitative polymerase chain reaction (qPCR) assay that targets single nucleotide polymorphisms (SNPs) responsible for the macaque A, B and AB phenotypes. The frequency distributions of blood group phenotypes of the two species differ significantly from each other and significant regional differentiation within the geographic ranges of each species was also observed. The B blood group phenotype was prevalent in rhesus macaques, especially those from India, while the frequencies of the A, B and AB phenotypes varied significantly among cynomolgus macaques from different geographic regions. The Mauritian cynomolgus macaques, despite having originated in Indonesia, showed significant (P ? .01) divergence from the Indonesian animals at the ABO blood group locus. Most Mauritian animals belonged to the B blood group while the Indonesian animals were mostly A. The close similarity in blood group frequency distributions between the Chinese rhesus and Indochinese cynomolgus macaques demonstrates that the introgression between these two species extends beyond the zone of intergradation in Indochina. This study underscores the importance of ABO blood group phenotyping of the domestic supply of macaques and their biospecimens. PMID- 28800213 TI - Dynamics of Additive Migration to Form Cathodic Interlayers in Organic Solar Cells. AB - Migration of additives to organic/metal interfaces can be used to self-generate interlayers in organic electronic devices. To generalize this approach for various additives, metals, and organic electronic devices it is first necessary to study the dynamics of additive migration from the bulk to the top organic/metal interface. In this study, we focus on a known cathode interlayer material, polyethylene glycol (PEG), as additive in P3HT:PC71BM blends and study its migration to the blend/Al interface during metal deposition and its effect on organic solar cell (OSC) performance. Using dynamic secondary ion mass spectroscopy (DSIMS) depth profiles and X-ray photoelectron spectroscopy surface analysis (XPS), we quantitatively correlate the initial concentration of PEG in the blend and sequence of thermal annealing/metal deposition processes with the organic/Al interfacial composition. We find that PEG is initially distributed within the film according to the kinetics of the spin coating process, i.e., the majority of PEG accumulates at the bottom substrate, while the minority resides in the film. During electrode evaporation, PEG molecules kinetically "trapped" near the film surface migrate to the organic/Al interface to reduce the interfacial energy. This diffusion-limited process is enhanced with the initial concentration of PEG in the solution and with thermal annealing after metal deposition. In contrast, annealing the film before metal deposition stalls PEG migration. This mechanism is supported by corresponding OSC devices showing that Voc increases with PEG content at the interface, up to a saturation value associated with the formation of a continuous PEG interlayer. Presence of a continuous interlayer excludes the driving force for further migration of PEG to the interface. Revealing this mechanism provides practical insight for judicious selection of additives and processing conditions for interfacial engineering of spontaneously generated interlayers. PMID- 28800214 TI - Highly Nitrogen-Doped Three-Dimensional Carbon Fibers Network with Superior Sodium Storage Capacity. AB - Inspired by the excellent absorption capability of spongelike bacterial cellulose (BC), three-dimensional hierarchical porous carbon fibers doped with an ultrahigh content of N (21.2 atom %) (i.e., nitrogen-doped carbon fibers, NDCFs) were synthesized by an adsorption-swelling strategy using BC as the carbonaceous material. When used as anode materials for sodium-ion batteries, the NDCFs deliver a high reversible capacity of 86.2 mAh g-1 even after 2000 cycles at a high current density of 10.0 A g-1. It is proposed that the excellent Na+ storage performance is mainly due to the defective surface of the NDCFs created by the high content of N dopant. Density functional theory (DFT) calculations show that the defect sites created by N doping can strongly "host" Na+ and therefore contribute to the enhanced storage capacity. PMID- 28800215 TI - C Fibers@WSe2 Nanoplates Core-Shell Composite: Highly Efficient Solar-Driven Photocatalyst. AB - Recently, WSe2 as a typical transition metal dichalcogenide compound has attracted extensive attention due to its potential applications in electronic and optoelectronic devices. However, WSe2 alone cannot be directly used as a photocatalyst due to its inferior performance possibly caused by the strong recombination of photogenerated electron-hole pairs. Here a novel C fibers@WSe2 nanoplates core-shell composite (NPCSC) was successfully synthesized via facile, one-step thermal evaporation, in which numerous WSe2 thin nanoplates were in situ, densely and even vertically grown on the surface of the C fibers. Such composite presents highly solar-driven photocatalytic activity and stability for the degradation of various organic aqueous dyes including methylene blue and rhodamine B, and highly harmful gases like toluene, showing the great potential for environmental remediation by degrading toxic industrial chemicals using sunlight. Under simulated sunlight irradiation, comparing with commercially available WSe2 powder, the as-synthesized C fibers@WSe2 NPCSC presents significantly enhanced reaction rate constants by a factor of approximately 15, 9, and 3 for the degradation of aqueous methylene blue, aqueous rhodamine B, and gaseous toluene, respectively, due to the effective separation of photogenerated electron-hole pairs promoted by the rapid transfer of photogenerated electrons through C fibers. Moreover, this one-step thermal evaporation is an easy handling, environmentally friendly, and low-cost synthesis method, which is suitable for large-scale production. PMID- 28800216 TI - Cross Stacking of Nanopatterned PEDOT Films for Use as Soft Electrodes. AB - Cross stacking of nanopatterned conductive polymer film was explored using a sacrificial soft template made of nanopatterned polystyrene (PS) film as a guide for nanopatterned conductive polymer film. For use as a conductive film, the PS pattern was filled with poly(3,4-ethylenedioxythiophene) (PEDOT), and then completely removed, to generate single-patterned PEDOT (SPDOT) film having a conductivity of 1079 S/cm, which was comparable to the pristine unpatterned PEDOT (UPDOT) film on a glass slide. SPDOT layers were stacked across each other to form double-layered (DPDOT) and multiple-layered patterned PEDOT film on a glass slide or polymeric substrate. The patterned PEDOT film showed enhanced optical and electrochemical activity; specifically as compared to the UPDOT film on a glass slide, the DPDOT film showed an increase in reflectance and an enhanced electrochemically active surface by 23.4% and 32.8%, respectively. The patterned PEDOT film on a polymer substrate showed high bendability up to being completely folded and maintained its conductivity for over 10 000 cycles of bending. The patterned PEDOT layers were applied to dye-sensitized solar cells (DSSCs) as a transparent conductive oxide (TCO)-free counter electrode. An N719-based DSSC with a DPDOT film recorded a photoconversion efficiency of 7.54%, which is one of the highest values among the TCO-free DSSCs based on a PEDOT counter electrode. PMID- 28800218 TI - Efficient Solution-Processed n-Type Small-Molecule Thermoelectric Materials Achieved by Precisely Regulating Energy Level of Organic Dopants. AB - To achieve efficient n-type doping, three dopants, 2-Cyc-DMBI-H, (2-Cyc-DMBI)2, and (2-Cyc-DMBI-Me)2, with precisely regulated electron-donating ability were designed and synthesized. By doping with a small-molecule 2DQTT-o-OD with high electron mobility, an unexpectedly high power factor of 33.3 MUW m-1 K-2 was obtained with the new dopant (2-Cyc-DMBI-Me)2. Notably, with the intrinsically low lateral thermal conductivity of 0.28 W m-1 K-1, the figure of merit was determined to be 0.02 at room temperature. Thus, we have demonstrated that small molecules with high electron mobility and low-lying LUMO energy levels can achieve high doping efficiency and excellent thermoelectric properties by doping with n-type dopants featuring highly matched energy levels and excellent miscibility. PMID- 28800217 TI - Engineering Antibody Reactivity for Efficient Derivatization to Generate NaV1.7 Inhibitory GpTx-1 Peptide-Antibody Conjugates. AB - The voltage-gated sodium channel NaV1.7 is a genetically validated pain target under investigation for the development of analgesics. A therapeutic with a less frequent dosing regimen would be of value for treating chronic pain; however functional NaV1.7 targeting antibodies are not known. In this report, we describe NaV1.7 inhibitory peptide-antibody conjugates as an alternate construct for potential prolonged channel blockade through chemical derivatization of engineered antibodies. We previously identified NaV1.7 inhibitory peptide GpTx-1 from tarantula venom and optimized its potency and selectivity. Tethering GpTx-1 peptides to antibodies bifunctionally couples FcRn-based antibody recycling attributes to the NaV1.7 targeting function of the peptide warhead. Herein, we conjugated a GpTx-1 peptide to specific engineered cysteines in a carrier anti 2,4-dinitrophenol monoclonal antibody using polyethylene glycol linkers. The reactivity of 13 potential cysteine conjugation sites in the antibody scaffold was tuned using a model alkylating agent. Subsequent reactions with the peptide identified cysteine locations with the highest conversion to desired conjugates, which blocked NaV1.7 currents in whole cell electrophysiology. Variations in attachment site, linker, and peptide loading established design parameters for potency optimization. Antibody conjugation led to in vivo half-life extension by 130-fold relative to a nonconjugated GpTx-1 peptide and differential biodistribution to nerve fibers in wild-type but not NaV1.7 knockout mice. This study describes the optimization and application of antibody derivatization technology to functionally inhibit NaV1.7 in engineered and neuronal cells. PMID- 28800219 TI - Machine Learning Using Combined Structural and Chemical Descriptors for Prediction of Methane Adsorption Performance of Metal Organic Frameworks (MOFs). AB - Using molecular simulation for adsorbent screening is computationally expensive and thus prohibitive to materials discovery. Machine learning (ML) algorithms trained on fundamental material properties can potentially provide quick and accurate methods for screening purposes. Prior efforts have focused on structural descriptors for use with ML. In this work, the use of chemical descriptors, in addition to structural descriptors, was introduced for adsorption analysis. Evaluation of structural and chemical descriptors coupled with various ML algorithms, including decision tree, Poisson regression, support vector machine and random forest, were carried out to predict methane uptake on hypothetical metal organic frameworks. To highlight their predictive capabilities, ML models were trained on 8% of a data set consisting of 130,398 MOFs and then tested on the remaining 92% to predict methane adsorption capacities. When structural and chemical descriptors were jointly used as ML input, the random forest model with 10-fold cross validation proved to be superior to the other ML approaches, with an R2 of 0.98 and a mean absolute percent error of about 7%. The training and prediction using the random forest algorithm for adsorption capacity estimation of all 130,398 MOFs took approximately 2 h on a single personal computer, several orders of magnitude faster than actual molecular simulations on high-performance computing clusters. PMID- 28800220 TI - The Secret Life of Collagen: Temporal Changes in Nanoscale Fibrillar Pre-Strain and Molecular Organization during Physiological Loading of Cartilage. AB - Articular cartilage is a natural biomaterial whose structure at the micro- and nanoscale is critical for healthy joint function and where degeneration is associated with widespread disorders such as osteoarthritis. At the nanoscale, cartilage mechanical functionality is dependent on the collagen fibrils and hydrated proteoglycans that form the extracellular matrix. The dynamic response of these ultrastructural building blocks at the nanoscale, however, remains unclear. Here we measure time-resolved changes in collagen fibril strain, using small-angle X-ray diffraction during compression of bovine and human cartilage explants. We demonstrate the existence of a collagen fibril tensile pre-strain, estimated from the D-period at approximately 1-2%, due to osmotic swelling pressure from the proteoglycan. We reveal a rapid reduction and recovery of this pre-strain which occurs during stress relaxation, approximately 60 s after the onset of peak load. Furthermore, we show that this reduction in pre-strain is linked to disordering in the intrafibrillar molecular packing, alongside changes in the axial overlapping of tropocollagen molecules within the fibril. Tissue degradation in the form of selective proteoglycan removal disrupts both the collagen fibril pre-strain and the transient response during stress relaxation. This study bridges a fundamental gap in the knowledge describing time-dependent changes in collagen pre-strain and molecular organization that occur during physiological loading of articular cartilage. The ultrastructural details of this transient response are likely to transform our understanding of the role of collagen fibril nanomechanics in the biomechanics of cartilage and other hydrated soft tissues. PMID- 28800222 TI - Correction to Consensus Outlier Detection Using Sum of Ranking Differences of Common and New Outlier Measures Without Tuning Parameter Selections. PMID- 28800221 TI - Graphene-Paper Pressure Sensor for Detecting Human Motions. AB - Pressure sensors should have an excellent sensitivity in the range of 0-20 kPa when applied in wearable applications. Traditional pressure sensors cannot achieve both a high sensitivity and a large working range simultaneously, which results in their limited applications in wearable fields. There is an urgent need to develop a pressure sensor to make a breakthrough in both sensitivity and working range. In this paper, a graphene-paper pressure sensor that shows excellent performance in the range of 0-20 kPa is proposed. Compared to most reported graphene pressure sensors, this work realizes the optimization of sensitivity and working range, which is especially suitable for wearable applications. We also demonstrate that the pressure sensor can be applied in pulse detection, respiratory detection, voice recognition, as well as various intense motion detections. This graphene-paper pressure sensor will have great potentials for smart wearable devices to achieve health monitoring and motion detection. PMID- 28800223 TI - Green Fabrication of Silkworm Cocoon-like Silicon-Based Composite for High Performance Li-Ion Batteries. AB - Designing yolk-shell nanostructures is an effective way of addressing the huge volume expansion issue for large-capacity anode and cathode materials in Li-ion batteries (LIBs). Previous studies mainly focused on adopting a SiO2 template through HF etching to create yolk-shell nanostructures. However, HF etching is highly corrosive and may result in a significant reduction of Si content in the composite. Herein, a silkworm cocoon-like silicon-based composite is prepared through a green approach in which Al2O3 was selected as a sacrificial template. The void space between the outer nitrogen-doped carbon (NC) shell formed by chemical vapor deposition using a pyridine precursor and the inside porous silicon nanorods (p-Si NRs) synthesized by magnesiothermic reduction of ordered mesoporous silica nanorods can be generated by etching Al2O3 with diluted HCl. The obtained p-Si NRs@void@NC composite is utilized as an anode material for LIBs, which exhibits a large initial discharge capacity of 3161 mAh g-1 at 0.5 A g-1, excellent cycling behavior up to 300 cycles, and super rate performance. Furthermore, a deep understanding of the mechanism for the yolk-shell nanostructure during the Li-alloying process is revealed by in situ transmission electron microscopy and finite element simulation. PMID- 28800224 TI - Ullmann Reaction Catalyzed by Heterogeneous Mesoporous Copper/Manganese Oxide: A Kinetic and Mechanistic Analysis. AB - A heterogeneous copper oxide supported on mesoporous manganese oxide (meso Cu/MnOx) was explored for Ullmann-type cross-coupling reactions. An inverse micelle-templated evaporation-induced self-assembly method with in situ addition of copper was adopted to synthesize the mesoporous catalyst. Broad substrate scope and excellent functional group tolerability in C-O, C-N, and C-S bond formation reactions were observed using the optimized reaction conditions. The catalytic protocol was ligand free, and the catalyst was reusable without any significant loss of activity. The kinetic and Hammett analyses provided evidence for oxidative addition to a Cu(I) reaction center followed by nucleophilic addition and reductive elimination at the active copper oxide surface. Rate acceleration was observed for aryl halides with electron-withdrawing groups. The Hammett analysis determined rho = +1.0, indicative of an oxidative addition, whereas the electronic effect in the phenol ring (rho = -2.9) was indicative of coordination to a metal ion. Theoretically, the oxidative addition of the aryl halides is assisted by the ligand environment of the copper center. Relevant mechanistic implications are discussed on the basis of the experimental and computational results. PMID- 28800225 TI - Automated in Situ Oxygen Profiling at Aquatic-Terrestrial Interfaces. AB - Optical sensing technologies provide opportunities for in situ oxygen sensing capable of capturing the whole range of spatial and temporal variability. We developed a miniaturized Distributed Oxygen Sensor ("mDOS") specifically for long term in situ application in soil and sediment. The mDOS sensor system enables the unattended, repeated acquisition of time series of in situ oxygen profiles at a subcentimeter resolution covering a depth of up to one meter. As compared to existing approaches, this provides the possibility to reveal highly variable and heterogeneous oxygen dynamics at a high, quasi-continuous resolution across both scales. The applicability of the mDOS to capture both intra- and interday fine scale variability of spatiotemporal oxygen dynamics under varying hydrological conditions is exemplarily demonstrated. We specifically aim at estimating the dependency between oxygen dynamics and hydrologic conditions along the measured profiles. The mDOS system enables highly detailed insights into oxygen dynamics in various aquatic and terrestrial environments and in the inherent transition zones between them. It thus represents a valuable tool to capture oxygen dynamics to help disentangling the coupling between underlying hydrological and biogeochemical process dynamics. PMID- 28800226 TI - Systematic Identification of Promoters for Methane Oxidation Catalysts Using Size and Composition-Controlled Pd-Based Bimetallic Nanocrystals. AB - Promoters enhance the performance of catalytic active phases by increasing rates, stability, and/or selectivity. The process of identifying promoters is in most cases empirical and relies on testing a broad range of catalysts prepared with the random deposition of active and promoter phases, typically with no fine control over their localization. This issue is particularly relevant in supported bimetallic systems, where two metals are codeposited onto high-surface area materials. We here report the use of colloidal bimetallic nanocrystals to produce catalysts where the active and promoter phases are colocalized to a fine extent. This strategy enables a systematic approach to study the promotional effects of several transition metals on palladium catalysts for methane oxidation. In order to achieve these goals, we demonstrate a single synthetic protocol to obtain uniform palladium-based bimetallic nanocrystals (PdM, M = V, Mn, Fe, Co, Ni, Zn, Sn, and potentially extendable to other metal combinations) with a wide variety of compositions and sizes based on high-temperature thermal decomposition of readily available precursors. Once the nanocrystals are supported onto oxide materials, thermal treatments in air cause segregation of the base metal oxide phase in close proximity to the Pd phase. We demonstrate that some metals (Fe, Co, and Sn) inhibit the sintering of the active Pd metal phase, while others (Ni and Zn) increase its intrinsic activity compared to a monometallic Pd catalyst. This procedure can be generalized to systematically investigate the promotional effects of metal and metal oxide phases for a variety of active metal-promoter combinations and catalytic reactions. PMID- 28800227 TI - Vertical Leaching of Allelochemicals Affecting Their Bioactivity and the Microbial Community of Soil. AB - Leaching of allelochemicals in soil is one of the fundamental processes that determines allelopathic activities but is often overlooked. In the present study, the vertical leaching of seven putative allelochemicals as well as one pesticide and one herbicide was investigated using polyvinyl chloride columns combined with a bioassay approach. The results indicated that the leachability of pretilachlor and imidacloprid were the best (Lf > 0.8), followed by vanillin and coumarin (Lf > 0.6). The leachability of daidzein, menthol, and m-tyrosine were medium (0.3 < Lf < 0.6). The lowest leachability has been observed on p-coumaric and p hydroxybenzoic acids (Lf < 0.3). The chemicals were classified into three clusters according to the phospholipid fatty acid profile (i.e., vanillin in one cluster, coumarin and menthol in the second cluster, and the rest in the third cluster). Bioactivities of the chemicals changed dramatically. Germination of lettuce seeds was suppressed by imidacloprid and pretilachlor, and the suppression was concentration-dependent. The bioactivity of most of the allelochemicals were progressively decreased with the downward movement of chemicals. The results indicated that leaching mediated the microbial communities and the interactions of chemical-microorganism and modified the bioavailability of allelochemicals in soil. PMID- 28800228 TI - Stoichiometric and Catalytic Aryl-Perfluoroalkyl Coupling at Tri-tert butylphosphine Palladium(II) Complexes. AB - This Communication describes studies of Ph-RF (RF = CF3 or CF2CF3) coupling at Pd complexes of general structure (PtBu3)PdII(Ph)(RF). The CF3 analogue participates in fast Ph-CF3 coupling (<5 min at 80 degrees C). However, the formation of side products limits the yield of this transformation as well as its translation to catalysis. DFT and experimental studies suggest that the side products derive from facile alpha-fluoride elimination at the 3-coordinate PdII complex. Furthermore, they show that this undesired pathway can be circumvented by changing from a CF3 to a CF2CF3 ligand. Ultimately, the insights gained from stoichiometric studies enabled the identification of Pd(PtBu3)2 as a catalyst for the Pd-catalyzed cross-coupling of aryl bromides with TMSCF2CF3 to afford pentafluoroethylated arenes. PMID- 28800229 TI - Fragment-Based Drug Discovery of Phosphodiesterase Inhibitors. AB - Phosphodiesterases are proving to be fruitful targets for drug discovery. At the same time fragment-based drug discovery has matured into a powerful and widely applied technique. In this communication we review the application of fragment based drug discovery for the successful identification of novel 3',5'-cyclic nucleotide phosphodiesterase (PDE) inhibitors, concentrating on both experimental and computational strategies for fragment screening and hit-to-lead development. To this end, we also mine the open access databases ChEMBL and PDB for fragments showing PDE inhibitory activity, as well as SureChEMBL for recent PDE related patents, to provide a wider context for exploring fragment diversity. Together these approaches form an integrated experimental and computational platform to exploit fragment-based drug discovery for this important gene superfamily. PMID- 28800231 TI - Accurate Modeling of Water Clusters with Density-Functional Theory Using Atom Centered Potentials. AB - The ability of atom-centered potentials (ACPs) to improve the modeling of water clusters using density-functional methods is explored. Water-specific ACPs were developed using accurate ab initio reference data to correct the deficiencies of the BHandHLYP density functional in the calculation of absolute and relative binding energies of water clusters. In conjunction with aug-cc-pVTZ basis sets and with or without dispersion corrections, it is possible to obtain absolute binding energies for water clusters containing up to 10 H2O molecules to within 0.44 kcal/mol or 0.04 kcal/mol per water molecule. In contrast, dispersion corrected BHandHLYP/aug-cc-pVTZ predicts binding energies with errors as large as 6 kcal/mol for (H2O)10 in the absence of ACPs. Therefore, the ACPs improve predicted binding energies in these clusters by more than an order of magnitude. The conformers of (H2O)16 and (H2O)17 were used to validate the application of ACPs to larger clusters. ACP-based approaches are able to predict the binding energies in (H2O)16,17 within a range of 0.3-2.2 kcal/mol (less than 1.3%) of recently revised ab initio wave function results. ACPs for basis sets smaller than aug-cc-pVTZ are also presented. However, the ability of the BHandHLYP/ACP approach to predict accurate binding energies deteriorates as the size of the basis sets decreases. Nevertheless, ACPs improve predicted binding energies by as much as a factor of 50 across the range of the basis sets studied. The BHandHLYP/aug-cc-pVTZ-ACP method was applied to (H2O)25 in order to identify the minimum-energy structure of a collection of proposed global minimum-energy structures. The BHandHLYP/aug-cc-pVTZ-ACP approach is an accurate and computationally affordable alternative to wave function theory methods for the prediction of the binding energies and energy ranking of water clusters. PMID- 28800230 TI - Mechanistic Investigations of the Pd(0)-Catalyzed Enantioselective 1,1 Diarylation of Benzyl Acrylates. AB - A mechanistic study of the Pd-catalyzed enantioselective 1,1-diarylation of benzyl acrylates that is facilitated by a chiral anion phase transfer (CAPT) process is presented. Kinetic analysis, labeling, competition, and nonlinear effect experiments confirm the hypothesized general mechanism and reveal the role of the phosphate counterion in the CAPT catalysis. The phosphate was found to be involved in the phase transfer step and in the stereoinduction process, as expected, but also in the unproductive reaction that provides the traditional Heck byproduct. Multivariate correlations revealed the CAPT catalyst's structural features, affecting the production of this undesired byproduct, as well as weak interactions responsible for enantioselectivity. Such putative interactions include pi-stacking and a CH...O electrostatic attraction between the substrate benzyl moiety and the phosphate. Analysis of the computed density functional theory transition structures for the stereodetermining step of the reaction supports the multivariate model obtained. The presented work provides the first comprehensive study of the combined use of CAPT and transition metal catalysis, setting the foundation for future applications. PMID- 28800232 TI - Strategic Design of Bacteriochlorins as Possible Dyes for Photovoltaic Applications. AB - Bacteriochlorin-based dyes, having a push-pull type of configuration similar to that of the YD2 dye, were theoretically designed based on modification of the macrocycle and pi-conjugated bridge for use in dye-sensitized solar cells. Various parameters were assessed to determine its structure-property relationships, such as the absorption profile based on time-dependent density functional theory, nonlinear optical properties from (hyper)polarizability data, ground- and excited-state oxidation potentials, and the electronic properties of the free and adsorbed dyes. On the basis of the results, the most appropriate macrocycle would be 7,7,17,17-tetramethyl-7H,8H,17H,18H-porphyrin and, for its pi conjugated bridge, either thieno[3,2-b]thiophene, dithieno[3,2-b:2',3' d]thiophene, or 4,4-diisopropyl-4H-cyclopenta[2,1-b:3,4-b']dithiophene. These newly designed dyes produced an absorption spectra having a range of 300-800 nm, which could likely increase the light harvesting efficiency. It has better nonlinear properties than the reference, thereby ensuring higher charge-transfer properties. Also, the dye regeneration efficiency is within the optimized value of 0.2 eV, which could minimize the excessive loss of voltage. This shows that through theoretical approach we can deductively design analogues before synthesis to streamline the process in the design of dyes to produce efficient dye sensitized solar cells. PMID- 28800233 TI - Machine Learning Force Field Parameters from Ab Initio Data. AB - Machine learning (ML) techniques with the genetic algorithm (GA) have been applied to determine a polarizable force field parameters using only ab initio data from quantum mechanics (QM) calculations of molecular clusters at the MP2/6 31G(d,p), DFMP2(fc)/jul-cc-pVDZ, and DFMP2(fc)/jul-cc-pVTZ levels to predict experimental condensed phase properties (i.e., density and heat of vaporization). The performance of this ML/GA approach is demonstrated on 4943 dimer electrostatic potentials and 1250 cluster interaction energies for methanol. Excellent agreement between the training data set from QM calculations and the optimized force field model was achieved. The results were further improved by introducing an offset factor during the machine learning process to compensate for the discrepancy between the QM calculated energy and the energy reproduced by optimized force field, while maintaining the local "shape" of the QM energy surface. Throughout the machine learning process, experimental observables were not involved in the objective function, but were only used for model validation. The best model, optimized from the QM data at the DFMP2(fc)/jul-cc-pVTZ level, appears to perform even better than the original AMOEBA force field (amoeba09.prm), which was optimized empirically to match liquid properties. The present effort shows the possibility of using machine learning techniques to develop descriptive polarizable force field using only QM data. The ML/GA strategy to optimize force fields parameters described here could easily be extended to other molecular systems. PMID- 28800234 TI - Synthesis of Benzoxazoles Using Electrochemically Generated Hypervalent Iodine. AB - The indirect ("ex-cell") electrochemical synthesis of benzoxazoles from imines using a redox mediator based on the iodine(I)/iodine(III) redox couple is reported. Tethering the redox-active iodophenyl subunit to a tetra-alkylammonium moiety allowed for anodic oxidation to be performed without supporting electrolyte. The mediator salt can be easily recovered and reused. Our "ex-cell" approach toward the electrosynthesis of benzoxazoles is compatible with a range of redox-sensitive functional groups. An unprecedented concerted reductive elimination mechanism for benzoxazole formation is proposed on the basis of control experiments and DFT calculations. PMID- 28800235 TI - Phase Transitions of Cobalt Oxide Bilayers on Au(111) and Pt(111): The Role of Edge Sites and Substrate Interactions. AB - Well-characterized metal oxides supported on single crystal surfaces serve as valuable model systems to study fundamental chemical properties and reaction mechanisms in heterogeneous catalysis or as new thin film metal oxide catalysts in their own right. Here, we present scanning tunneling microscopy and X-ray photoelectron spectroscopy results for cobalt oxide nanoislands that reveal the detailed atomistic mechanisms leading to transitions between Co-O bilayer and O Co-O trilayer, induced by oxidation in O2 and reductive vacuum annealing treatments, respectively. By comparing between two different noble metal substrates, Au(111) and Pt(111), we further address the influence of the substrate. Overall, nanoisland edges act to initiate both the oxidation and reduction processes on both substrates. However, important influences of the choice of substrate were found, as the progress of oxidation includes intermediate steps on Au(111) not observed on Pt(111), where the oxidation on the other hand takes place at a significantly higher rate. During reductive treatment of trilayer, the bilayer structure gradually reappears on Pt(111), but not on Au(111) where the reduction rather results in the appearance of a stacked cobalt oxide morphology. These observations point to strong differences in the catalytic behavior between Au and Pt supported cobalt oxides, despite the otherwise strong structural similarities. PMID- 28800236 TI - Inorganic Nanoparticle Induced Morphological Transition for Confined Self Assembly of Block Copolymers within Emulsion Droplets. AB - Recently, it has been reported that the incorporation of functional inorganic nanoparticles (NPs) into the three-dimensional (3D) confined self-assembly of block copolymers (BCPs) creates the unique nanostructured hybrid composites, which can not only introduce new functions to BCPs but also induce some interesting morphological transitions of BCPs. In the current study, we systematically investigate the cooperative self-assembly of a series of size controlled and surface chemistry-tunable gold nanoparticles (AuNPs) and polystyrene-b-poly(2-vinylpyridine) (PS-b-P2VP) diblock copolymer within the emulsion droplets. The influences of the size, content, and surface chemistry of the AuNPs on the coassembled nanostructures as well as the spatial distribution of AuNPs in the hybrid particles are examined. It is found that the size and content of the AuNPs are related to the entropic interaction, while the surface chemistry of AuNPs is related to the enthalpic interaction, which can be utilized to tailor the self-assembled morphologies of block copolymer confined in the emulsion droplets. As the content of PS-coated AuNPs increases, the morphology of the resulting AuNPs/PS-b-P2VP hybrid particles changes from the pupa-like particles to the bud-like particles and then to the onion-like particles. However, a unique morphological transition from the pupa-like particles to the mushroom-like particles is observed as the content of P4VP-coated AuNPs increases. More interestingly, it is observed that the large AuNPs are expelled to the surface of the BCP particles to reduce the loss in the conformational entropy of the block segment, which can arrange into the strings of necklaces on the surfaces of the hybrid particles. PMID- 28800237 TI - Nanoscale Effects on Phase Separation. AB - Classical nucleation theory predicts that a binary system which is immiscible in the bulk should become miscible at the nanoscale when lowering its size below a critical size. Here we tackle the problem of miscibility in nanoalloys with a combination of ab initio and atomistic calculations, developing a statistical mechanics approach for the free energy cost of forming phase-separated aggregates. We apply it to the controversial case of AuCo nanoalloys. AuCo is immiscible in the bulk, but a rich variety of nanoparticle configurations, both phase-separated and intermixed, have been obtained experimentally. Our calculations strongly point to the permanence of an equilibrium miscibility gap down to the nanoscale and to the nonexistence of a critical size below which phase separation is impossible. We show that this is due to nanoscale effects of general character, caused by the existence of preferred nucleation sites in nanoparticles, which lower the free-energy cost for phase separation with respect to bulk systems. PMID- 28800238 TI - An Admix Approach To Determine Counter Anion Effects on Metal-Free Arylation Reactions with Diaryliodonium Salts. AB - A method to determine the effect of counter anions in metal-free arylation reactions of diaryliodonium salts is described. This approach avoids the independent synthesis of individual diaryliodonium salts and potentially enables assessment of a large number of different counter anions, including those that are synthetically challenging to install. Diaryliodonium tosylate salts serve as a general precursor for this approach, and an azide arylation reaction was used to develop this strategy. Further optimization and representative scope of azide arylation is demonstrated in yields that range from 74-95% (89% average). The use of this method as a screening tool has also been validated with arylation reactions of three different nucleophiles employing diphenyliodonium tosylate. PMID- 28800239 TI - Rh(I)-Catalyzed Alkylation of ortho-C-H Bonds in Aromatic Amides with Maleimides. AB - An alkylation of C-H bonds with maleimides by a rhodium-catalyzed reaction of aromatic amides containing an 8-aminoquinoline moiety as the directing group is reported. Various N-substituents in the maleimide, including methyl, ethyl, cyclohexyl, benzyl, and phenyl groups and even H, are applicable to the reaction. The reaction is highly regioselective at the less hindered ortho-C-H bond when meta-substituted aromatic amides are used as substrates. PMID- 28800240 TI - An Optically and Electrochemically Decoupled Monolithic Photoelectrochemical Cell for High-Performance Solar-Driven Water Splitting. AB - Photoelectrochemical (PEC) cells have attracted much attention as a viable route for storing solar energy and producing value-added chemicals and fuels. However, the competition between light absorption and electrocatalysis at a restrained cocatalyst area on conventional planar-type photoelectrodes could limit their conversion efficiency. Here, we demonstrate a new monolithic photoelectrode architecture that eliminate the optical-electrochemical coupling by forming locally nanostructured cocatalysts on a photoelectrode. As a model study, Ni inverse opal (IO), an ordered three-dimensional porous nanostructure, was used as a surface-area-controlled electrocatalyst locally formed on Si photoanodes. The optical-electrochemical decoupling of our monolithic photoanodes significantly enhances the PEC performance for the oxygen evolution reaction (OER) by increasing light absorption and by providing more electrochemically active sites. Our Si photoanode with local Ni IOs maintains an identical photolimiting current density but reduces the overpotential by about 120 mV compared to a Si photoanode with planar Ni cocatalysts with the same footprint under 1 sun illumination. Finally, a highly efficient Si photoanode with an onset potential of 0.94 V vs reversible hydrogen electrode (RHE) and a photocurrent density of 31.2 mA/cm2 at 1.23 V vs RHE in 1 M KOH under 1 sun illumination is achieved with local NiFe alloy IOs. PMID- 28800241 TI - Diastereoselective Synthesis of Diquinanes and Triquinanes Bearing Vicinal Quaternary Carbon Stereocenters from Acyclic Allene-based Precursors via a Cascade Reaction. AB - A cascade benzenethiol-mediated intramolecular [3 + 2] cycloaddition reaction between an allene and an alpha,beta-unsaturated aldehyde or ester is developed for the diastereoselective synthesis of [3.3.0] bicyclic system bearing two quaternary atoms at their bridgehead positions. Notably, these structurally complex systems can be found in a wide range of natural products. PMID- 28800242 TI - Cobalt-Catalyzed Silylcarbonylation of Unactivated Secondary Alkyl Tosylates at Low Pressure. AB - A catalytic preparation of silyl enol ethers from unactivated secondary alkyl tosylates is reported. An inexpensive cobalt catalyst is used under mild conditions with low pressures of carbon monoxide. Nucleophilic, anionic cobalt carbonyls facilitate the catalytic activation of a range of alkyl tosylates. The silylcarbonylation offers a practical approach to synthetically valuable silyl enol ethers from simple starting materials. PMID- 28800243 TI - Kinetically-Driven Phase Transformation during Lithiation in Copper Sulfide Nanoflakes. AB - Two-dimensional (2D) transition metal chalcogenides have been widely studied and utilized as electrode materials for lithium ion batteries due to their unique layered structures to accommodate reversible lithium insertion. Real-time observation and mechanistic understanding of the phase transformations during lithiation of these materials are critically important for improving battery performance by controlling structures and reaction pathways. Here, we use in situ transmission electron microscopy methods to study the structural, morphological, and chemical evolutions in individual copper sulfide (CuS) nanoflakes during lithiation. We report a highly kinetically driven phase transformation in which lithium ions rapidly intercalate into the 2D van der Waals-stacked interlayers in the initial stage, and further lithiation induces the Cu extrusion via a displacement reaction mechanism that is different from the typical conversion reactions. Density functional theory calculations have confirmed both the thermodynamically favored and the kinetically driven reaction pathways. Our findings elucidate the reaction pathways of the Li/CuS system under nonequilibrium conditions and provide valuable insight into the atomistic lithiation mechanisms of transition metal sulfides in general. PMID- 28800245 TI - The Respective Roles of Lung Clearance Index and Magnetic Resonance Imaging in the Clinical Management of Patients with Cystic Fibrosis. PMID- 28800244 TI - Exploiting Analysis of Heterogeneity to Increase the Information Content Extracted from Fluorescence Micrographs of Transgenic Zebrafish Embryos. AB - Zebrafish embryos are a near-ideal animal model for drug discovery because of their high genetic and physiological similarity to mammals, small size, high fecundity, and optical transparency. The latter properties make zebrafish at larval stages especially suited for high-content analysis and high throughput screening (HTS). However, inherent biological complexity and the inability to screen multiple specimens in a single well present a challenge for HTS because limiting replicates and high variability often prevent assays from reaching the stringent performance criteria demanded of large-scale screening assays. In this report, we present methodology that overcomes these obstacles. We used our previously developed Tg(lhx1a:EGFP)pt303 line, which expresses a fluorescent transgene that enables live real-time measurements of kidney progenitor cell expansion. Since transgenes are expressed in specific cell populations, whose localization is precisely controlled, both spatially and temporally, we considered the developing embryo to be a "host" for a cell population, analogous to a well of a cell culture microplate, rather than a single specimen. By adopting this view, parameters routinely used to analyze cultured cells became applicable to characterize and quantify zebrafish transgene appearance beyond the overall intensity or area measurements, which are analogous to calculating well average data. Using the pixel-level distribution of transgene intensity as a proxy to cell-level data, we applied population-based intensity and heterogeneity measurements to quantitatively describe and characterize transgene expression in each embryo. Subsequent linear discriminant analysis on eight such parameters captured and condensed this information into a single assay parameter that maximizes the difference between positive and negative responses. The improvements in assay performance resulted in the Tg(lhx1a:EGFP)pt303 assay achieving HTS compatible assay performance in multi-day variability studies, documenting readiness for HTS of compounds that expand kidney progenitor cell populations. PMID- 28800246 TI - Risk of Salmonellosis from Chicken Parts Prepared from Whole Chickens Sold in Flow Pack Wrappers and Subjected to Temperature Abuse. AB - The flow pack wrapper is a popular packaging choice for retail sale of whole chickens. However, it may provide a favorable environment for growth and spread of Salmonella within the package, leading to an outbreak of salmonellosis. To investigate this possibility, a process risk model was developed that predicted the risk of salmonellosis from chicken parts prepared from whole chickens sold in flow pack wrappers and subjected to proper storage (6 h at 4 degrees C) or improper storage (72 h at 15 degrees C) before preparation. The model had four unit operations (pathogen events): (i) preparation (contamination), (ii) cooking (death), (iii) serving (cross-contamination), and (iv) consumption (dose response). Data for prevalence, number, and serotype of Salmonella on chicken parts were obtained by whole sample enrichment, real-time PCR. Improper storage increased (P < 0.05) prevalence of Salmonella on raw chicken parts from 10.6% (17 of 160) to 41.2% (66 of 160) and incidence of cross-contamination of cooked chicken from 10% (4 of 40) to 52.2% (24 of 46). Improper storage also increased (P < 0.05) the number (mean +/- standard deviation) of Salmonella from 0.017 +/- 0.030 to 3.51 +/- 1.34 log per raw chicken part and from 0.048 +/- 0.089 to 3.08 +/- 1.50 log per cooked chicken part. The predominant serotypes isolated (n = 111) were Typhimurium (34.2%), Typhimurium var 5- (20.7%), Kentucky (12.6%), Enteritidis (11.7%), and Heidelberg (8.1%). When chicken was properly stored before preparation, the model predicted that risk of salmonellosis was low and sporadic with only six cases per 100 simulations of 105 chicken parts. However, when 0.1 to 1% of chickens were improperly stored before preparation, the model predicted that salmonellosis would increase (P < 0.05) linearly from a median of 7 (range, 1 to 15) to a median of 72 (range, 52 to 93) cases per 105 chicken parts. These results indicated that the flow pack wrapper provided a favorable environment for growth and spread of Salmonella within the package and that even when only a small percentage of packages were subjected to improper storage before preparation, the risk and size of an outbreak of salmonellosis from chicken parts increased significantly. PMID- 28800247 TI - Reply to Verbanck and Vanderhelst: The Respective Roles of Lung Clearance Index and Magnetic Resonance Imaging in the Clinical Management of Patients with Cystic Fibrosis. PMID- 28800248 TI - How Phenotypic Screening Influenced Drug Discovery: Lessons from Five Years of Practice. AB - Since 2011, phenotypic screening has been a trend in the pharmaceutical industry as well as in academia. This renaissance was triggered by analyses that suggested that phenotypic screening is a superior strategy to discover first-in-class drugs. Despite these promises and considerable investments, pharmaceutical research organizations have encountered considerable challenges with the approach. Few success stories have emerged in the past 5 years and companies are questioning their investment in this area. In this contribution, we outline what we have learned about success factors and challenges of phenotypic screening. We then describe how our efforts in phenotypic screening have influenced our approach to drug discovery in general. We predict that concepts from phenotypic screening will be incorporated into target-based approaches and will thus remain influential beyond the current trend. PMID- 28800249 TI - Reply to Verbanck and Vanderhelst: The Respective Roles of Lung Clearance Index and Magnetic Resonance Imaging in the Clinical Management of Patients with Cystic Fibrosis. PMID- 28800250 TI - Ventilator-induced Lung Injury: Follow the Right Direction! Another Piece of the Puzzle in the Ventilator-induced Lung Injury Epic. PMID- 28800251 TI - Fifty Years of Physiology in Obstructive Sleep Apnea. PMID- 28800252 TI - Progressive Changes in Walking Kinematics and Kinetics After Anterior Cruciate Ligament Injury and Reconstruction: A Review and Meta-Analysis. AB - CONTEXT: Anterior cruciate ligament (ACL) injury and ACL reconstruction (ACLR) result in persistent alterations in lower extremity movement patterns. The progression of lower extremity biomechanics from the time of injury has not been described. OBJECTIVE: To compare the 3-dimensional (3D) lower extremity kinematics and kinetics of walking among individuals with ACL deficiency (ACLD), individuals with ACLR, and healthy control participants from 3 to 64 months after ACLR. DATA SOURCES: We searched PubMed and Web of Science from 1970 through 2013. STUDY SELECTION AND DATA EXTRACTION: We selected only articles that provided peak kinematic and kinetic values during walking in individuals with ACLD or ACLR and comparison with a healthy control group or the contralateral uninjured limb. DATA SYNTHESIS: A total of 27 of 511 identified studies were included. Weighted means, pooled standard deviations, and 95% confidence intervals were calculated for the healthy control, ACLD, and ACLR groups at each reported time since surgery. The magnitude of between-groups (ACLR versus ACLD, control, or contralateral limb) differences at each time point was evaluated using Cohen d effect sizes and associated 95% confidence intervals. Peak knee flexion angle (Cohen d = -0.41) and external knee-extensor moment (Cohen d = 0.68) were smaller in the ACLD than in the healthy control group. Peak knee flexion angle (Cohen d range = -0.78 to -1.23) and external knee-extensor moment (Cohen d range = -1.39 to -2.16) were smaller in the ACLR group from 10 to 40 months after ACLR. Reductions in external knee-adduction moment (Cohen d range = 0.50 to -1.23) were present from 9 to 42 months after ACLR. CONCLUSIONS: Reductions in peak knee-flexion angle, external knee-flexion moment, and external knee-adduction moment were present in the ACLD and ACLR groups. This movement profile during the loading phase of gait has been linked to knee-cartilage degeneration and may contribute to the development of osteoarthritis after ACLR. PMID- 28800253 TI - Targeting Pulmonary Endothelial Hemoglobin alpha Improves Nitric Oxide Signaling and Reverses Pulmonary Artery Endothelial Dysfunction. AB - Pulmonary hypertension is characterized by pulmonary endothelial dysfunction. Previous work showed that systemic artery endothelial cells (ECs) express hemoglobin (Hb) alpha to control nitric oxide (NO) diffusion, but the role of this system in pulmonary circulation has not been evaluated. We hypothesized that up-regulation of Hb alpha in pulmonary ECs contributes to NO depletion and pulmonary vascular dysfunction in pulmonary hypertension. Primary distal pulmonary arterial vascular smooth muscle cells, lung tissue sections from unused donor (control) and idiopathic pulmonary artery (PA) hypertension lungs, and rat and mouse models of SU5416/hypoxia-induced pulmonary hypertension (PH) were used. Immunohistochemical, immunocytochemical, and immunoblot analyses and transfection, infection, DNA synthesis, apoptosis, migration, cell count, and protein activity assays were performed in this study. Cocultures of human pulmonary microvascular ECs and distal pulmonary arterial vascular smooth muscle cells, lung tissue from control and pulmonary hypertensive lungs, and a mouse model of chronic hypoxia-induced PH were used. Immunohistochemical, immunoblot analyses, spectrophotometry, and blood vessel myography experiments were performed in this study. We find increased expression of Hb alpha in pulmonary endothelium from humans and mice with PH compared with controls. In addition, we show up-regulation of Hb alpha in human pulmonary ECs cocultured with PA smooth muscle cells in hypoxia. We treated pulmonary ECs with a Hb alpha mimetic peptide that disrupts the association of Hb alpha with endothelial NO synthase, and found that cells treated with the peptide exhibited increased NO signaling compared with a scrambled peptide. Myography experiments using pulmonary arteries from hypoxic mice show that the Hb alpha mimetic peptide enhanced vasodilation in response to acetylcholine. Our findings reveal that endothelial Hb alpha functions as an endogenous scavenger of NO in the pulmonary endothelium. Targeting this pathway may offer a novel therapeutic target to increase endogenous levels of NO in PH. PMID- 28800254 TI - Sirtuin1 Protects against Systemic Sclerosis-related Pulmonary Fibrosis by Decreasing Proinflammatory and Profibrotic Processes. AB - Pulmonary fibrosis is the leading cause of death in systemic sclerosis (SSc). Sirtuin1 (SIRT1) is a deacetylase with known antiinflammatory and antifibrotic activity in the liver, kidney, and skin. The role of SIRT1 in SSc-related pulmonary fibrosis is unknown. In the present work, we determined that the expression of SIRT1 in peripheral blood mononuclear cells of patients with SSc with pulmonary fibrosis is lower than that in patients with SSc without pulmonary fibrosis. In in vivo studies of bleomycin-induced lung fibrosis in mice, SIRT1 activation with resveratrol reduced collagen production when it was administered either prophylactically during the inflammatory stage or after the development of fibrosis. Furthermore, SIRT1 activation or overexpression inhibited tumor necrosis factor-alpha-induced inflammatory responses in vitro in human fetal lung fibroblasts, depletion of SIRT1 in fibroblasts enhanced inflammation, and these effects were related to changes in the acetylation of NF-kappaB. In addition, SIRT1 activation or exogenous overexpression inhibited collagen production in vitro, and these manipulations also inhibited fibrosis via inactivation of transforming growth factor-beta/mothers against decapentaplegic homolog and mammalian target of rapamycin signaling. Taken together, our results show that a loss of SIRT1 may participate in the pathogenesis of SSc-related pulmonary fibrosis, and that SIRT1 activation is an effective treatment for both the early (inflammatory) and late (fibrotic) stages of pulmonary fibrosis. Thus, SIRT1 may be a promising therapeutic target in the management of SSc-related pulmonary fibrosis. PMID- 28800255 TI - Overexpression of Lymphocyte Activation Gene-3 Inhibits Regulatory T Cell Responses in Osteoarthritis. AB - Lymphocyte activation gene-3 (LAG-3) is a CD4 homologue expressed on the surface of activated conventional T cells and regulatory T (Treg) cells. In conventional T cells, LAG-3 acts as an inhibitory receptor of T cell inflammation. However, the role of LAG-3 in Treg cells remains controversial. In this study, we investigated the effect of LAG-3 on Tregs in osteoarthritis (OA). We observed that the proportion of LAG-3-expressing cells in CD4+CD25+/high T cells and Foxp3+CD4+CD25+/high T cells were significantly upregulated in OA patients. The level of LAG-3-to-Foxp3 ratio was further increased in synovial fluid. Several aspects of Treg responses in LAG-3+ and LAG-3- Treg cells were then examined. First, LAG-3+ Treg cells demonstrated significantly lower proliferation than LAG 3- Treg cells. Second, the increase in interleukin (IL)-10 and transforming growth factor (TGF)-beta expression was significantly lower in LAG-3+ Treg cells than that in LAG-3- Treg cells. Third, LAG-3+ Treg cells were less capable of inhibiting the proliferation of CD4+CD25- conventional T cells than LAG-3- Treg cells. This study suggests that Treg cells in OA may be enriched with a LAG-3 expressing population that exhibits functional impairment, which limits their capacity in suppressing inflammation. PMID- 28800256 TI - The Critical Care Crisis of Opioid Overdoses in the United States. AB - RATIONALE: Opioid abuse is increasing, but its impact on critical care resources in the United States is unknown. OBJECTIVES: We hypothesized that there would be a rising need for critical care among opioid-associated overdoses in the United States. METHODS: We analyzed all adult admissions, using a retrospective cohort study from 162 hospitals in 44 states, discharged between January 1, 2009, and September 31, 2015 to describe the incidence of intensive care unit (ICU) admissions for opioid overdose during this time. Admissions were identified using the Clinical Database/Resource Manager of Vizient, the successor to the University Health System Consortium. RESULTS: Our primary outcome was opioid associated overdose admissions to the ICU. The outcome was defined on the basis of previously validated ICD-9 codes. Our secondary outcomes were in-hospital death and markers of ICU resources. The final cohort included 22,783,628 admissions; 4,145,068 required ICU care. There were 52.4 ICU admissions for overdose per 10,000 ICU admissions over the entire study (95% confidence interval [CI], 51.8-53.0 per 10,000 ICU admissions). During this time period, opioid overdose admissions requiring intensive care increased 34%, from 44 per 10,000 (95% CI, 43-46 per 10,000) to 59 per 10,000 ICU admissions (95% CI, 57-61 per 10,000; P < 0.0001). The mortality rate of patients with ICU admissions with overdoses averaged 7% (95% CI, 7.0-7.6%) but increased to 10% in 2015 (95% CI, 8.8-10.8%). CONCLUSIONS: The number of deaths of ICU patients with opioid overdoses increased substantially in the 7 years of our study, reflecting increases in both the incidence and mortality of this condition. Our findings raise the need for a national approach to developing safe strategies to care for patients with overdose in the ICU, to providing coordinated resources in the hospital for patients and families, and to helping survivors maintain sobriety on discharge. PMID- 28800258 TI - Nasopharyngeal Microbiota: Gatekeepers or Fortune Tellers of Susceptibility to Respiratory Tract Infections? PMID- 28800259 TI - Extraction of primary canines for interceptive orthodontic treatment of palatally displaced permanent canines: A systematic review. AB - OBJECTIVE: To determine whether the successful management of palatally displaced permanent canines (PDCs) can be achieved by the interceptive extraction of primary maxillary canines. MATERIALS AND METHODS: Digital databases (Medline, Scopus, Web of Science, and Cochrane) were searched to retrieve articles published from 1952 to April 2016. The university librarian developed search strategies for each database. Two calibrated reviewers independently reviewed potentially related titles and abstracts. Papers meeting the inclusion and exclusion criteria were read in full. The selected articles were evaluated and scored according to methodological quality criteria. RESULTS: Four randomized clinical trials (RCTs) were included in the systematic review. Compared with two older studies, two more recent RCTs were found to have better study designs, were better conducted, and involved better reporting of the results. The included studies compared intervention groups (children with PDCs undergoing extraction of primary canines) with controls (subjects with PDCs but no primary canine extractions). In three of the four studies, the interceptive extraction of primary canines facilitated eruption of PDCs in more than 65% of cases. Overall, the intervention groups had a markedly higher incidence of successful eruption of PDCs (50%-69%) compared with the control groups (36%-42%). CONCLUSIONS: Based on the available evidence, it is reasonable to conclude that eruption of PDCs can be facilitated by extraction of primary canines. However, further high-quality, randomized clinical trials are warranted in other population groups. It is hoped that this study will help orthodontists make evidence-based decisions about clinically managing PDCs. PMID- 28800257 TI - The Inherent Asymmetry of DNA Replication. AB - Semiconservative DNA replication has provided an elegant solution to the fundamental problem of how life is able to proliferate in a way that allows cells, organisms, and populations to survive and replicate many times over. Somewhat lost, however, in our admiration for this mechanism is an appreciation for the asymmetries that occur in the process of DNA replication. As we discuss in this review, these asymmetries arise as a consequence of the structure of the DNA molecule and the enzymatic mechanism of DNA synthesis. Increasing evidence suggests that asymmetries in DNA replication are able to play a central role in the processes of adaptation and evolution by shaping the mutagenic landscape of cells. Additionally, in eukaryotes, recent work has demonstrated that the inherent asymmetries in DNA replication may play an important role in the process of chromatin replication. As chromatin plays an essential role in defining cell identity, asymmetries generated during the process of DNA replication may play critical roles in cell fate decisions related to patterning and development. PMID- 28800260 TI - Study of response of Swiss Webster mice to light subunit of mushroom tyrosinase. AB - The light subunit of mushroom, Agaricus bisporus, tyrosinase (LSMT), has been identified as an extrinsic component of the enzyme. Its function is unknown, but it can cross an epithelial cell layer, which suggests that it can be absorbed by the intestine. A similar capability has been demonstrated for the HA-33 component of the progenitor toxin from Clostridium botulinum, which is the closest structural homolog of LSMT. Unlike HA-33, LSMT appears to be non-immunogenic as shown by preliminary tests in Swiss Webster mice. We investigated the immunogenicity and histopathology of LSMT in mice to determine its safety in vivo. LSMT did not evoke generation of antibodies after prolonged periods of intraperitoneal administration. Histopathological observations confirmed the absence of responses in organs after twelve weekly administrations of LSMT. We found that LSMT is not toxic and is less immunogenic than the C. botulinum HA-33 protein, which supports further research and development for pharmaceutical application. PMID- 28800261 TI - The Triple Value in Yoga Laboratory for Neuroscience Education. PMID- 28800262 TI - Risk factors predisposing to the development of hypogammaglobulinemia and infections post-Rituximab. AB - Rituximab (RTX) is a monoclonal antibody against CD20, commonly used in the treatment of hematological malignancies and autoimmune diseases. The use of RTX is related to the development of hypogammaglobulinemia and infections. Aim of this review is to summarize the evidence supporting the association of specific risk factors with the development of hypogammaglobulinemia and infections post RTX. Immunological complications are more common in patients with malignant diseases as compared to non-malignant diseases. Moreover, the use of more than one dose of RTX, maintenance regimens, low pre-treatment basal immunoglobulin levels and the association with Mycophenolate and purine analogues represent risk factors for the development of hypogammaglobulinemia. The number of RTX courses, the evidence of low IgG levels for more than 6 months, the use of G-CSF, the occurrence of chronic lung disease, cardiac insufficiency, extra-articular involvement in patients with rheumatoid arthritis, low levels of IgG and older age have been correlated with a higher risk of infections. Even though the heterogeneity of the studies in terms of study population age and underlying disease, RTX schedules as well as differences in pre-treatment or concomitant therapy doesn't allow drawing definitive conclusions, the study of the literature highlight the association of specific risk factors with the occurrence of hypogammaglobulinemia and/or infections. A long term randomized controlled clinical trial could be useful to define a personalized evidence-based risk management plan for patients treated with RTX. PMID- 28800264 TI - ? PMID- 28800263 TI - MicroRNA mediated regulation of immunity against gram-negative bacteria. AB - Evidence over the last couple decades has comprehensively established that short, highly conserved, non-coding RNA species called microRNA (miRNA) exhibit the ability to regulate expression and function of host genes at the messenger RNA (mRNA) level. MicroRNAs play key regulatory roles in immune cell development, differentiation, and protective function. Intrinsic host immune response to invading pathogens rely on intricate orchestrated events in the development of innate and adaptive arms of immunity. We discuss the involvement of miRNAs in regulating these processes against gram negative pathogens in this review. PMID- 28800265 TI - Use of SNOMED CT(r) and LOINC(r) to standardize terminology for primary care asthma electronic health records. AB - OBJECTIVES: The burden of asthma ranks among the highest for chronic diseases. Interoperable electronic health records (EHRs) can improve the management of chronic diseases such as asthma by facilitating sharing of data between health care settings along the continuum of care. Terminology such as SNOMED CT(r) (Systematized Nomenclature of Medicine-Clinical Terms) and LOINC(r) (Logistical Observation Identifier Names and Codes) are prerequisites for interoperability of EHRs. We sought to determine the extent to which data elements in a validated asthma care map (ACM) are congruent with these terminologies. METHODS: A certified asthma educator entered all 169 elements in the ACM into the SNOMED CT(r) browser. Matched elements were assigned a concept name, an identification number, and classified into a hierarchy. LOINC(r) terminology was reviewed for asthma-related pulmonary function tests (PFTs). RESULTS: Forty-two percent of the ACM elements were complete matches to existing SNOMED CT(r) concepts, 24% partial matches, and 34% unmatched. Specific asthma control parameters were either complete (n = 3) or partial (n = 4) matches, but overall "asthma control" was unmatched. There were 92% complete or partial matches for PFT elements to SNOMED CT(r) and 83% to LOINC(r). Conclusions: The majority of ACM elements are congruent with standardized terminology, enabling EHR interoperability. Future requests for new concepts in SNOMED CT(r) and LOINC(r) should be pursued for asthma control parameters paramount to evidence-based practice. PMID- 28800266 TI - Impact of shared decision making on asthma quality of life and asthma control among children. AB - OBJECTIVE: Few studies have examined the effectiveness of shared decision making (SDM) in clinical practice. This study evaluated the impact of SDM on quality of life and symptom control in children with asthma. METHODS: We conducted a prospective 3-year study in six community-based practices serving a low-income patient population. Practices received training on SDM using an evidence-based toolkit. Patients aged 2-17 with a diagnosis of asthma were identified from scheduling and billing data. At approximate 6-month intervals, patients completed a survey consisting of the Mini Pediatric Asthma Quality of Life Questionnaire (range 1-7) and the control domain of the Pediatric Asthma Therapy Assessment Questionnaire (range 0-7). We used propensity scores to match 46 children receiving SDM to 46 children receiving usual care with decision support. Included children had completed a baseline survey and at least one follow-up survey. Random coefficient models incorporated repeated measures to assess the effect of SDM on asthma quality of life and asthma control. RESULTS: The sample was primarily of non-White patients (94.6%) with Medicaid insurance (92.4%). Receipt of SDM using an evidence-based toolkit was associated with higher asthma quality of life [mean difference 0.9; 95% confidence interval (CI) 0.4-1.4] and fewer asthma control problems (mean difference -0.9; 95% CI -1.6--0.2) compared to usual care with decision support. CONCLUSIONS: Implementation of SDM within clinical practices using a standardized toolkit is associated with improved asthma quality of life and asthma control for low-income children with asthma when compared to usual care with decision support. PMID- 28800267 TI - Geographic variation in inhaled corticosteroid use for children with persistent asthma in Medicaid. AB - OBJECTIVE: Geographic variation in the rates of inhaled corticosteroid (ICS) use for children with persistent asthma in Medicaid has been reported, but the source of this variation is unknown. The objective of this study was to quantify the geographic variation in ICS use for children with persistent asthma in Medicaid that remains after adjusting for the characteristics of children in an area. METHODS: Data from the 2005-2007 Medicaid Analytic eXtract files were used. Frequent fills of short-acting beta2-agonist (SABA) were used to identify children 5-18 years of age with persistent asthma across the United States. A child was considered to have used an ICS if the child initially filled an ICS following frequent SABA use. Areas were determined using published methods, and the unadjusted ICS rate and the area treatment ratio for ICS, which adjusted for demographic and clinical characteristics, were calculated for each area. RESULTS: Of 15,917 children, 13% used an ICS. The median unadjusted ICS rate for all areas was 10% but ranged from 0% to 64%. ICS use was less than expected for more than half of the areas based on the characteristics of the children in the area, but use was nearly five times what was expected in some areas. Areas with higher than expected ICS use were found contiguous to areas with lower than expected use. CONCLUSIONS: Geographic variation in ICS not attributable to the demographic and clinical characteristics of the children in an area exists and could prove useful in the struggle to reduce asthma exacerbation rates. PMID- 28800268 TI - Asthma management experiences of Australians who are native Arabic speakers. AB - OBJECTIVE: The aim of this study was to explore the asthma management experiences of people with asthma within the Arabic-speaking community in Australia. METHODS: Semi-structured interviews guided by a schedule of questions were conducted with 25 Arabic-speaking women with asthma?carer of a child with asthma, recruited from medical practices and community centers in Melbourne, Australia. RESULTS: Twenty five Arabic-speaking participants with asthma or caring for those with asthma were interviewed. Interviews lasted on average 25 minutes. Most participants or those they were caring for did not have well-controlled asthma. Thematic analyses of the interview transcripts highlighted five key emergent themes: stigma, health literacy, non-adherence, expectations, and coping styles. Findings indicated that many participants were not conversant about local information avenues or healthcare or facilities such as the Asthma Foundation or availability of Arabic translators during general practitioner (GP) consults. Many recent migrants were generally non-adherent with treatment; preferring to follow traditional folk medicine rather than consulting a GP or pharmacist. Some unrealistic expectations from doctors/treatment goals were expressed by a few participants. Some parents of children with asthma reported disappointment with the fact that their children did not grow out of asthma. CONCLUSION: Low health literacy and in particular knowledge about asthma, cultural beliefs, language, and migration-related issues may all be affecting the level of asthma control in the Arabic-speaking population in Australia. Measures to enhance asthma and health system literacy designed to be culturally concordant with the beliefs, expectations, and experiences of such populations may be key to improving asthma management. PMID- 28800269 TI - The connections among suicidal behavior, lipid profile and low-grade inflammation in patients with major depressive disorder: a specific relationship with the neutrophil-to-lymphocyte ratio. AB - OBJECTIVES: The role of inflammation and lipid metabolism in the pathophysiology of suicidal behavior has received particular attention in recent years. The neutrophil-to-lymphocyte ratio (NLR) has been suggested as a new and more reliable indicator of low-grade inflammation. NLR has been found to be altered in major depressive disorder (MDD) and has been related to various factors, including chronic stress and impulsivity that were previously reported to be related to suicidal behavior. We aimed to explore the roles of NLR, C-reactive protein (CRP) and serum lipid levels on suicidal behavior in patients with MDD. METHODS: The study group consisted of 139 inpatients diagnosed with MDD [37 suicide attempters (SA); 102 suicide non-attempters (NSA)], 50 healthy controls and matched according to age, gender and education. NLR, PLR, CRP and lipid values were obtained from digital inpatient records. RESULTS: CRP levels and NLR were substantially higher in patients with SA than in subjects with NSA and healthy comparison subjects after adjusting the confounding factors. The logistic regression included two predictive variables for suicide status in patients with depressive disorder (A) previous suicidal history; (B) NLR. CONCLUSIONS: This is the first study suggesting that NLR may be a trait marker for suicidal vulnerability via a relationship between NLR and a recent suicide attempt in depressed inpatients. Future prospective studies are needed to determine the exact roles of NLR, and other inflammatory markers on suicidality in MDD. PMID- 28800270 TI - Reply to M. Horiguchi et al. PMID- 28800271 TI - Overall Survival in the Randomized Phase II Study Investigating Pazopanib Versus Weekly Paclitaxel in Relapsed or Progressive Urothelial Cancer. PMID- 28800272 TI - Omalizumab in non-allergic Asthma: A report of 13 cases. AB - BACKGROUND: There are limited data regarding the effectiveness of omalizumab in patients with non-allergic asthma. OBJECTIVE: To evaluate the clinical and functional effectiveness of omalizumab in patients with non-allergic asthma. METHODS: The study was a single-center, retrospective chart review of patients with non-allergic asthma who were treated with add-on omalizumab between February 2014 and March 2016. After omalizumab was started, data of the asthma control test (ACT), pulmonary function test, and daily oral corticosteroid (OCS) dosage were collected at baseline, 16 weeks, 1 year, 2 and 3 years (if available). The number of exacerbations/hospitalizations were collected 1 year prior to and 6 months/1 year after omalizumab. To calculate the total daily dosage of OCS in milligrams, data for 6 months/1 year prior and after omalizumab treatment were recorded. RESULTS: Thirteen patients were included. After omalizumab, the mean ACT was significantly increased at 16 weeks (n = 13, p = 0.002), 1 year (n = 7, p = 0.006), and 2 years (n = 5, p = 0.006). The mean daily OCS dose was significantly decreased at 16 weeks (n = 13, p = 0.001), 1 year (n = 7, p = 0.006), and 2 years (n = 5, p = 0.04). The mean number of exacerbations and hospitalizations were decreased at the 6th month (n = 13; p = 0.001, p = 0.005) and 1st year (n = 7; p = 0.01, p = 0.02). The mean total quantity of OCS decreased 42% from 1.4 to 0.8 g in the six-month period prior to and post omalizumab treatment (n = 6, p = 0.02) and decreased 76% from 3.8 to 0.9 g at 1 year in the pre vs. post-omalizumab treatment comparison (n = 7, p = 0.01). Six (46.2%) patients responded perfectly and seven (53.8%) partially responded to treatment. CONCLUSION: Omalizumab can be effective in non-atopic severe asthma. PMID- 28800273 TI - Assessing the impact of a remote digital coaching engagement program on patient reported outcomes in asthma. AB - BACKGROUND: Low adherence and poor outcomes provide opportunity for digital coaching to engage patients with uncontrolled asthma in their care to improve outcomes. OBJECTIVE(S): To examine the impact of a remote digital coaching program on asthma control and patient experience. METHODS: We recruited 51 adults with uncontrolled asthma, denoted by albuterol use of >2 times per week and/or exacerbations requiring corticosteroids, and applied a 12-week patient-centered remote digital coaching program using a combination of educational pamphlets, symptom trackers, best peak flow establishment, physical activity, and dietary counseling, as well as coaches who implemented emotional enforcement to motivate disease self-management through telephone, text, and email. Baseline and post intervention measures were quality of life (QOL), spirometry, Asthma Control Test (ACT), Asthma Symptom Utility Index (ASUI), rescue albuterol use, and exacerbation history. RESULTS: Among 51 patients recruited, 40 completed the study. Eight subjects required assistance reading medical materials. Significant improvements from baseline were observed for Patient-Reported Outcomes Measurement Information System mental status (p = 0.010), body weight, and outpatient exacerbation frequency (p = 0.028). The changes from baseline in ACT (p = 0.005) were statistically significant but did not achieve the pre-specified minimum clinically important difference (MCID), whereas for ASUI, the MCID and statistical significance were achieved. Spirometry and rescue albuterol use were no different. CONCLUSION: A patient-oriented, remote digital coaching program that utilized trained health coaches and digital materials led to statistically significant improvement in mental status, outpatient exacerbations, body weight, and ASUI. Digital coaching programs may improve some outcomes in adults with uncontrolled asthma. PMID- 28800274 TI - Relationships between self-reported asthma and pulmonary function and various measures of obesity. AB - OBJECTIVE: We explore the association with self-reported asthma and pulmonary function based on spirometry measurements using different measures to determine obesity because body mass index (BMI) is limited in not differentiating fat and muscle mass. METHODS: A multi-year cross-sectional study using Korean National Health and Nutrition Examination Survey data was conducted between July 2008 and May 2011. A total of 9409 subjects were included in the final analysis. RESULTS: Obesity was associated with self-reported asthma and pulmonary function limitations mainly in adult women aged between 40 and 65 years and elderly men aged 65 or older. The association was stronger when the measurement of obesity was based on body fat percentage or waist-to-height ratio (WHtR), compared to BMI. There was a higher self-reported asthma risk among obese women according to the WHtR [odds ratio (OR) = 1.817, 95% CI: (1.208, 2.735)]. There was an increased risk of pulmonary function limitation with abdominal obesity [OR 1.418, 95% CI (1.020, 1.972)], weight-to-height ratio [OR 1.467, 95% CI (1.058, 2.034)], and obesity with regard to body fat percentage [OR 1.753, 95% CI (1.251, 2.457)] in adult women. In elderly men, obesity based on body fat percentage was associated with an increased risk of pulmonary function limitation [OR 1.93, 95% CI (1.098, 3.388)]. CONCLUSIONS: Measures other than BMI should be examined when investigating the effect of obesity on self-reported asthma and pulmonary function limitation. PMID- 28800276 TI - Enhancing Informed Consent for Physician Aid in Dying: Potential Role of Handout on Possible Benefits of Palliative Care. AB - In the United States, physician aid in dying (PAD) is now legal in several states. However, neither a requirement for a palliative care (PC) consultation nor a defined education in PC exists for physicians participating in PAD or patients requesting assistance. Patients with advanced chronic and serious illness often experience complex physical, psychosocial, and spiritual distress. PC focuses on relieving this distress and improving patient quality of life through early identification and intervention in all domains of suffering, including physical, psychological, social, and spiritual. Ideally, we would recommend a PC consult, but unfortunately, PC is not readily available or offered at this time to all those who might benefit from it. We present a case for providing an educational handout to patients who inquire about PAD. This handout explains the potential benefits of PC as an additional procedural safeguard to existing regulations. Such information would help to ensure the integrity of the informed consent process, enhance shared decision making, and improve patient comprehension of the options. PMID- 28800275 TI - Polyphenol-Rich Fraction of Parquetina nigrescens Mitigates Dichlorvos-Induced Cardiorenal Dysfunction Through Reduction in Cardiac Nitrotyrosine and Renal p38 Expressions in Wistar Rats. AB - Parquetina nigrescens is commonly used to treat diseases in humans and animals in developing countries, including Nigeria. This study evaluates the effects of its polyphenol-rich fraction (prf) on dichlorvos-induced cardio- and renal toxicity. There were several factors assessed during this study, including cardiac and renal markers, serum myeloperoxidase and xanthine oxidase, and electrocardiograph (ECG) changes. The changes in electrocardiograph (ECG) were recorded. Immunohistochemistry of cardiac and renal p38 and nitrotyrosine was determined. Dichlorvos exposure caused a significant decrease in L-glutathione (reduced glutathione) and other antioxidant enzymes with increases in malondialdehyde, myeloperoxidase, advanced oxidation protein products, and protein carbonyl levels. It also brought about alterations in microanatomy of the heart and kidneys accompanied by increases in serum creatinine and urea levels. Exposure to dichlorvos induced prolonged QRS interval and shortened QT durations in rats. Immunohistochemistry revealed lower expressions of cardiac nitrotyrosine and renal p38 (mitogen-activated protein kinase; MAPK) in rats treated with prf of P. nigrescens. Combining all, prf of P. nigrescens demonstrated antioxidant as well as protective properties in the heart and kidneys of rats exposed to dichlorvos. It ameliorated dichlorvos-induced cardio- and nephrotoxicity giving credence to its use in ethnomedicine. PMID- 28800277 TI - Inspiring Confidence as a Young Therapist and the Danger of Being Too Transparent. PMID- 28800278 TI - The antidepressant-like effect of Ocimum basilicum in an animal model of depression. AB - We investigated the efficacy of Ocimum basilicum (OB) essential oils for treating depression related behavioral, biochemical and histopathological changes caused by exposure to chronic unpredictable mild stress (CUMS) in mice and to explore the mechanism underlying the pathology. Male albino mice were divided into four groups: controls; CUMS; CUMS plus fluoxetine, the antidepressant administered for pharmacological validation of OB; and CUMS plus OB. Behavioral tests included the forced swim test (FST), elevated plus-maze (EPM) and the open field test (OFT); these tests were performed at the end of the experiment. We assessed serum corticosterone level, protein, gene and immunoexpression of brain-derived neurotropic factor (BDNF) and glucocorticoid receptors (GRs) as well as immunoexpression of glial fibrillary acidic protein (GFAP), Ki67, caspase-3 in the hippocampus. CUMS caused depression in the mice as evidenced by prolonged immobility in the FST, prolonged time spent in the open arms during the EPM test and reduction of open field activity in the OFT. OB ameliorated the CUMS induced depressive status. OB significantly reduced the corticosterone level and up regulated protein and gene expressions of BDNF and GR. OB reduced CUMS induced hippocampal neuron atrophy and apoptosis, and increased the number of the astrocytes and new nerve cells. OB significantly increased GFAP-positive cells as well as BDNF and GR immunoexpression in the hippocampus. PMID- 28800279 TI - More Than a Feeling? An Empirical Analysis of the Dual-Continua Model on a National Sample of Lesbian, Gay, and Bisexual Identified Canadians. AB - The goal of the study is to investigate whether positive mental health complements mental illness within a theoretically informed (the dual-continua model) and psychometrically tested (the Mental Health Continuum-Short Form) framework. National-level, population-based data from the 2012 Canadian Community Health Survey on Mental Health (CCHS-MH) was used, with comparisons between sexual minority and heterosexual adults. Results show that gay, lesbian, and bisexual Canadians have substantially lower rates of positive mental health and are more likely to have been diagnosed with a mental illness, with the disparities between health and illness being the most pronounced among lesbians and bisexual females. Results show considerable support for the dual-continua model, which posits that the absence of health does not automatically translate into the presence of illness, and vice versa. Suggestions are made for practitioners and researchers toward the use of the dual-continua model as a surveillance tool, especially among sexual minority individuals. PMID- 28800280 TI - Evaluations of Antigay Hate Crimes and Hate Crime Legislation: Independent and Differentially Predicted. AB - Minimal studies have investigated individuals' evaluations of antigay hate crimes and hate crime legislation simultaneously, with most research focusing on one or the other. In a sample of 246 heterosexual undergraduates, the present study found that evaluations of antigay hate crimes and hate crime legislation were unrelated. Higher social dominance orientation (SDO) and crime control orientation scores were associated with more positive evaluations of antigay hate crimes. Positive evaluations of hate crime legislation were associated with more positive attitudes toward gay men and lesbians. We also found that the relationship between SDO and evaluations were mediated by crime control beliefs (for hate crimes evaluations) and antigay attitudes (for hate crime legislation evaluations). The present findings have possible implications for the manner in which organizations advocate for the extension of hate crime legislation to include sexual orientation. PMID- 28800281 TI - Attentional Lapses in Attention-Deficit/Hyperactivity Disorder: Blank Rather Than Wandering Thoughts. AB - People with attention-deficit/hyperactivity disorder (ADHD) have difficulties sustaining their attention on external tasks. Such attentional lapses have often been characterized as the simple opposite of external sustained attention, but the different types of attentional lapses, and the subjective experiences to which they correspond, remain unspecified. In this study, we showed that unmedicated children (ages 6-12) with ADHD, when probed during a standard go/no go task, reported more mind blanking (a mental state characterized by the absence of reportable content) than did control participants. This increase in mind blanking happened at the expense of both focused and wandering thoughts. We also found that methylphenidate reverted the level of mind blanking to baseline (i.e., the level of mind blanking reported by control children without ADHD). However, this restoration led to mind wandering more than to focused attention. In a second experiment, we extended these findings to adults who had subclinical ADHD. These results suggest that executive functions impaired in ADHD are required not only to sustain external attention but also to maintain an internal train of thought. PMID- 28800282 TI - Toward a generation free of tuberculosis: TB disease and infection in individuals of college age in the United States. AB - OBJECTIVES: To assess the magnitude of active TB disease and latent TB infection (LTBI) in young adults of college age. PARTICIPANTS: Individuals who were aged 18 24 years in 2011 were used as a proxy for college students. METHODS: Active TB cases reported to the 2011 US National TB Surveillance System (NTSS) were included. LTBI prevalence was calculated from the 2011-2012 National Health and Nutrition Examination Survey. The 2011 American Community Survey was used to calculate population denominators. Analyses were stratified by nativity. RESULTS: Active TB disease incidence among persons aged 18-24 years was 2.82/100,000, 18.8/100,000 among foreign-born individuals and 0.9/100,000 among US-born individuals. In 2011, 878 TB cases were reported; 629 (71.6%) were foreign-born. LTBI prevalence among persons of 18-24 years was 2.5%: 8.7% and 1.3% among foreign-born and US-born, respectively. CONCLUSION: Active screening and treatment programs for foreign-born young adults could identify TB cases earlier and provide an opportunity for prevention efforts. PMID- 28800283 TI - Predator, Pet Lesbian, or Just The Nanny? LGBTQ Parents of Children With Disabilities Describe Categorization. AB - How are lesbian/gay/bisexual/trans/queer (LGBTQ) parents of children with disabilities categorized by service providers, and how do parents anticipate, interpret, and respond to such categorizations? This intersectional study investigated the experiences of LGBTQ parents of children with disabilities with service providers in Toronto, Canada. Parents described pressures to "fit" into providers' limited understanding of family. Some parents described facing overt discrimination, including one parent who was seen as a possible sexual predator. Some described being perceived as representatives of "diversity" for organizations, or "pet lesbians" in the words of one couple. Others described being misread as a non-parent, as in "just the nanny," particularly in conjunction with their racial minority status. Parents described how their experiences of being "outside the mainstream" helped them challenge systems and normative beliefs. Findings suggest that a context of scarce disability resources shapes parents' experiences of how LGBTQ identity comes to matter. PMID- 28800284 TI - Survival After HIV Infection Stage 3 (AIDS) Diagnosis, by Population Density Areas, United States, 2005-2010. AB - OBJECTIVES: We examined the survival rates after diagnosis of HIV infection stage 3 (AIDS) in the United States by population density area of residence at diagnosis. METHODS: We used data from the National HIV Surveillance System to calculate survival rates among people aged >=13 with HIV infection stage 3 (AIDS) diagnosed from 2005 through 2010. We determined survival rates for more than 12, 24, and 36 months after diagnosis; overall and by demographic characteristics; and across 3 population density area categories (large metropolitan statistical areas [MSAs, >=500 000 people], small-to-medium MSAs [50 000 to 499 999 people], and nonmetropolitan areas [<50 000 people]). RESULTS: The survival rates for more than 12, 24, and 36 months after diagnosis were highest among people residing in large MSAs (90.2%, 87.2%, and 84.9%, respectively) and lowest among people residing in nonmetropolitan areas (87.3%, 84.1%, and 81.4%, respectively). With a few exceptions, survival rates were lower in those residing in nonmetropolitan areas than those residing in large MSAs and small-to-medium MSAs across most subgroups by age at diagnosis, race/ethnicity, sex, transmission category, region of residence, and year of diagnosis. Between 2005 and 2010, significant year-to year increases occurred in the proportion of people surviving more than 36 months after diagnosis across all 3 population density area categories (estimated annual percentage change: large MSAs [0.88; 95% confidence interval (CI), 0.56-1.20]; small-to-medium MSAs [0.94; 95% CI, 0.06-1.83]; and nonmetropolitan areas [1.26; 95% CI, 0.07-2.46]). CONCLUSIONS: Although survival rates for those with HIV infection stage 3 (AIDS) improved in all 3 population density area categories, efforts to remove barriers to care and promote treatment adherence in nonmetropolitan areas will be necessary to eliminate survival disparities. PMID- 28800285 TI - Cytogenetic Reconstruction of Gamma-Ray Doses Delivered to Atomic Bomb Survivors: Dealing with Wide Distributions of Photon Energies and Contributions from Hematopoietic Stem/Progenitor Cells. AB - Retrospective estimation of the doses received by atomic bomb (A-bomb) survivors by cytogenetic methods has been hindered by two factors: One is that the photon energies released from the bomb were widely distributed, and since the aberration yield varies depending on the energy, the use of monoenergetic 60Co gamma radiation to construct a calibration curve may bias the estimate. The second problem is the increasing proportion of newly formed lymphocytes entering into the lymphocyte pool with increasing time intervals since the exposures. These new cells are derived from irradiated precursor/stem cells whose radiosensitivity may differ from that of blood lymphocytes. To overcome these problems, radiation doses to tooth enamel were estimated using the electron spin resonance (ESR; or EPR, electron paramagnetic resonance) method and compared with the cytogenetically estimated doses from the same survivors. The ESR method is only weakly dependent on the photon energy and independent of the years elapsed since an exposure. Both ESR and cytogenetic doses were estimated from 107 survivors. The latter estimates were made by assuming that although a part of the cells examined could be lymphoid stem or precursor cells at the time of exposure, all the cells had the same radiosensitivity as blood lymphocytes, and that the A-bomb gamma-ray spectrum was the same as that of the 60Co gamma rays. Subsequently, ESR and cytogenetic endpoints were used to estimate the kerma doses using individual DS02R1 information on shielding conditions. The results showed that the two sets of kerma doses were in close agreement, indicating that perhaps no correction is needed in estimating atomic bomb gamma-ray doses from the cytogenetically estimated 60Co gamma-ray equivalent doses. The present results will make it possible to directly compare cytogenetic doses with the physically estimated doses of the survivors, which would pave the way for testing whether or not there are any systematic trends or factors affecting physically estimated doses. PMID- 28800286 TI - Clinical PET Imaging in Prostate Cancer. AB - Prostate cancer is the second most common cancer in men worldwide, with a wide spectrum of biologic behavior ranging from indolent low-risk disease to highly aggressive castration-resistant prostate cancer. Conventional imaging with computed tomography, magnetic resonance imaging, and bone scintigraphy is limited for the detection of nodal disease and distant bone metastases. In addition, advances in the available therapeutic options, both localized and systemic, drive the requirement for precise diagnostic and prognostic tools to refine the individual therapeutic approach at various times in the management of patients with prostate cancer. Positron emission tomography (PET) has a rapidly evolving role in the assessment of prostate cancer, particularly in the scenario of biochemical relapse. Fluorine 18 (18F) fluorodeoxyglucose, the most widely available PET tracer, has limitations, particularly in indolent prostate cancer. In the past decade, several PET tracers with specific molecular targets have reached the clinical domain. These tracers include 18F-sodium fluoride, which is a bone-specific biomarker of osteoblastic activity; 18F-choline and carbon 11 choline, which are directed at cell membrane metabolism; gallium 68-prostate specific membrane antigen ligands; and, more recently, an amino acid analog, 18F fluciclovine (anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid; also known as FACBC), which is also directed at cell membrane turnover. The mechanisms of actions of the clinically available PET tracers are reviewed, as well as their role in the imaging of prostate cancer with reference to relevant guidelines and the technical and imaging pearls and pitfalls of these tracers. (c)RSNA, 2017. PMID- 28800288 TI - Population-Based Study of the National Implementation of Therapeutic Hypothermia in Infants with Hypoxic-Ischemic Encephalopathy. AB - Data on the incidence of hypoxic-ischemic encephalopathy (HIE) in the first 6 hours of life together with the implementation of therapeutic hypothermia (TH) are relevant to delineate actions to achieve the lowest rates of neonatal mortality, morbidity, and long-term impact on health associated with HIE. This is population-based national survey study, including newborns >=35 weeks of gestation with moderate-to-severe HIE from all level III neonatal care units, to provide the incidence of HIE for the period 2012-2013, and the implementation of TH up to June 2015 in Spain. Incidence rate was 0.77 per 1000 live births (95% confidence interval 0.72-0.83). By June 2015, 63% (57/90) of the units had implemented TH; 95% of them performed servo-controlled whole-body TH. For the 2 year period, 86% of the newborns diagnosed with moderate-to-severe HIE received TH. Active TH increased in use from 78% in 2012 to 85% in 2013 (p = 0.01). The main reasons for not cooling were a delay in the diagnosis (31/682) and the fact that the treatment was not offered (20/682). Interhospital patient transfer was performed using passive hypothermia, by appropriately trained personnel in 61% of centers. Eighteen percent of newborns with moderate or severe HIE died, without significant differences between the 2 years. Up-to-date knowledge of the national coverage of neonatal care of infants with HIE in developed countries is a prerequisite to reducing the load of HIE in this area and to facilitating coordinated, eliminate investigation. PMID- 28800287 TI - Measuring and Establishing the Accuracy and Reproducibility of 3D Printed Medical Models. AB - Despite the rapid growth of three-dimensional (3D) printing applications in medicine, the accuracy and reproducibility of 3D printed medical models have not been thoroughly investigated. Although current technologies enable 3D models to be created with accuracy within the limits of clinical imaging spatial resolutions, this is not always achieved in practice. Inaccuracies are due to errors that occur during the imaging, segmentation, postprocessing, and 3D printing steps. Radiologists' understanding of the factors that influence 3D printed model accuracy and the metrics used to measure this accuracy is key in directing appropriate practices and establishing reference standards and validation procedures. The authors review the various factors in each step of the 3D model printing process that contribute to model inaccuracy, including the intrinsic limitations of each printing technology. In addition, common sources of model inaccuracy are illustrated. Metrics involving comparisons of model dimensions and morphology that have been developed to quantify differences between 3D models also are described and illustrated. These metrics can be used to define the accuracy of a model, as compared with the reference standard, and to measure the variability of models created by different observers or using different workflows. The accuracies reported for specific indications of 3D printing are summarized, and potential guidelines for quality assurance and workflow assessment are discussed. Online supplemental material is available for this article. (c)RSNA, 2017. PMID- 28800290 TI - Factor Structure and Psychometric Properties of the Italian Version of the Homosexuality Scale of the Trueblood Sexual Attitudes Questionnaire. AB - The aim of the present study was to translate the Homosexuality scale of the Trueblood Sexual Attitudes Questionnaire into the Italian language and to assess its factor structure and psychometric properties in Italian psychology students. The questionnaire was originally developed and validated in U.S. college students, and later in Turkish social work students, showing high internal consistency. It measures attitudes toward several sexual practices and behaviors, regarding self and others. Particularly, the Homosexuality scale measures attitudes toward different sexual and romantic practices with people of the same sex. A total of 199 Italian psychology students participated to the study, and they were administered the Italian translation of the scale. We applied exploratory factor analysis and confirmatory factor analysis. Results showed that the scale has high internal consistency, and that the original two-factor model accounting for attitudes toward self and others fits the data well. Implications for education and assessment in student populations are discussed. PMID- 28800291 TI - Therapeutic Hypothermia and Targeted Temperature Management With or Without the "Cold Stress" Response. PMID- 28800289 TI - Fate-Regulating Circuits in Viruses: From Discovery to New Therapy Targets. AB - Current antivirals effectively target diverse viruses at various stages of their life cycles. Nevertheless, curative therapy has remained elusive for important pathogens, such as human immunodeficiency virus type 1 (HIV-1) and herpesviruses, in large part due to viral latency and the evolution of resistance to existing therapies. Here, we review the discovery of viral master circuits: virus-encoded autoregulatory gene networks that autonomously control viral expression programs (i.e., between active, latent, and abortive fates). These circuits offer the opportunity for a new class of antivirals that could lead to intrinsic combination-antiviral therapies within a single molecule-evolutionary escape from such circuit-disrupting antivirals would require simultaneous evolution of both the viral cis regulatory element (e.g., the DNA-binding site) and the trans element (e.g., the transcription factor) in order for the virus to recapitulate a circuit that would not be disrupted. We review the architectures of these fate regulating master circuits in HIV-1 and the human herpesvirus cytomegalovirus along with potential circuit-disruption strategies that may ultimately enable escape-resistant antiviral therapies. PMID- 28800292 TI - Osteoporosis knowledge translation for young adults: new directions for prevention programs. AB - INTRODUCTION: Osteoporosis prevention is heavily reliant on education programs, which are most effective when tailored to their intended audience. Most osteoporosis prevention education is designed for older adults, making application of these programs to younger adults difficult. Designing programs for young adults requires understanding the information-seeking practices of young adults, so that knowledge about osteoporosis can be effectively translated. METHODS: Individual interviews were conducted with 60 men and women-multiethnic, Canadian young adults-to explore both the sources and types of information they search for when seeking information on nutrition or bone health. RESULTS: The results of this study raised themes related to the sources participants use, to their interests and to ways of engaging young adults. Prevention programs should make use of traditional sources, such as peers, family members and medical professionals, as well as emerging technologies, such as social media. Choice of sources was related to the perceived authority of and trust associated with the source. Messaging should relate to young adult interests, such as fitness and food-topics on which young adults are already seeking information-rather than being embedded within specific osteoporosis awareness materials. Engaging young adults means using relatable messages that are short and encourage small changes. Small gender-based differences were found in the information-seeking interests of participants. Differences related to age were not examined. CONCLUSION: Creating short, action-oriented messages that are designed to encourage small changes in behaviour and are packaged with information that young adults are actively seeking is more likely to result in active engagement in prevention behaviours. PMID- 28800294 TI - The 2017 Canadian Chronic Disease Indicators. PMID- 28800295 TI - The Physical Activity, Sedentary Behaviour and Sleep (PASS) Indicator Framework. PMID- 28800293 TI - Rotating shift work associated with obesity in men from northeastern Ontario. AB - INTRODUCTION: While some studies have suggested associations between shift work and obesity, few have been population-based or considered multiple shift schedules. Since obesity is linked with several chronic health conditions, understanding which types of shift work influence obesity is important and additional work with more detailed exposure assessment of shift work is warranted. METHODS: Using multivariate polytomous logistic regression, we investigated the associations between shift work (evening/night, rotating and other shift schedules) and overweight and obesity as measured by body mass index cross-sectionally among 1561 men. These men had previously participated as population controls in a prostate cancer case-control study conducted in northeastern Ontario from 1995 to 1999. We obtained information on work history (including shift work), height and weight from the existing self-reported questionnaire data. RESULTS: We observed an association for ever (vs. never) having been employed in rotating shift work for both the overweight (OR [odds ratio] = 1.34; 95% CI [confidence interval]: 1.05-1.73) and obese (OR = 1.57; 95% CI: 1.12-2.21) groups. We also observed nonsignificant associations for ever (vs. never) having been employed in permanent evening/night shifts. In addition, we found a significant trend of increased risk for both overweight and obesity with increasing duration of rotating shift work. CONCLUSION: Both the positive association between rotating shift work and obesity and the suggested positive association for permanent evening/night shift work in this study are consistent with previous findings. Future population-based research that is able to build on our results while examining additional shift work characteristics will further clarify whether some shift patterns have a greater impact on obesity than others. PMID- 28800297 TI - Different cancers, same target? PMID- 28800296 TI - A contextual analysis of the Suicide Surveillance Indicators. PMID- 28800298 TI - Impact of field number and beam angle on functional image-guided lung cancer radiotherapy planning. AB - To investigate the effect of beam angles and field number on functionally-guided intensity modulated radiotherapy (IMRT) normal lung avoidance treatment plans that incorporate hyperpolarised helium-3 magnetic resonance imaging (3He MRI) ventilation data. Eight non-small cell lung cancer patients had pre-treatment 3He MRI that was registered to inspiration breath-hold radiotherapy planning computed tomography. IMRT plans that minimised the volume of total lung receiving ?20 Gy (V20) were compared with plans that minimised 3He MRI defined functional lung receiving ?20 Gy (fV20). Coplanar IMRT plans using 5-field manually optimised beam angles and 9-field equidistant plans were also evaluated. For each pair of plans, the Wilcoxon signed ranks test was used to compare fV20 and the percentage of planning target volume (PTV) receiving 90% of the prescription dose (PTV90). Incorporation of 3He MRI led to median reductions in fV20 of 1.3% (range: 0.2 9.3%; p = 0.04) and 0.2% (range: 0 to 4.1%; p = 0.012) for 5- and 9-field arrangements, respectively. There was no clinically significant difference in target coverage. Functionally-guided IMRT plans incorporating hyperpolarised 3He MRI information can reduce the dose received by ventilated lung without comprising PTV coverage. The effect was greater for optimised beam angles rather than uniformly spaced fields. PMID- 28800299 TI - Representing the dosimetric impact of deformable image registration errors. AB - Deformable image registration (DIR) is emerging as a tool in radiation therapy for calculating the cumulative dose distribution across multiple fractions of treatment. Unfortunately, due to the variable nature of DIR algorithms and dependence of performance on image quality, registration errors can result in dose accumulation errors. In this study, landmarked images were used to characterize the DIR error throughout an image space and determine its impact on dosimetric analysis. Ten thoracic 4DCT images with 300 landmarks per image study matching the end-inspiration and end-expiration phases were obtained from 'dir labs'. DIR was performed using commercial software MIM Maestro. The range of dose uncertainty (RDU) was calculated at each landmark pair as the maximum and minimum of the doses within a sphere around the landmark in the end-expiration phase. The radius of the sphere was defined by a measure of DIR error which included either the actual DIR error, mean DIR error per study, constant errors of 2 or 5 mm, inverse consistency error, transitivity error or the distance discordance metric (DDM). The RDUs were evaluated using the magnitude of dose uncertainty (MDU) and inclusion rate (IR) of actual error lying within the predicted RDU. The RDU was calculated for 300 landmark pairs on each 4DCT study for all measures of DIR error. The most representative RDU was determined using the actual DIR error with a MDU of 2.5 Gy and IR of 97%. Across all other measures of DIR error, the DDM was most predictive with a MDU of 2.5 Gy and IR of 86%, closest to the actual DIR error. The proposed method represents the range of dosimetric uncertainty of DIR error using either landmarks at specific voxels or measures of registration accuracy throughout the volume. PMID- 28800300 TI - Intraventricular vector flow mapping-a Doppler-based regularized problem with automatic model selection. AB - We propose a regularized least-squares method for reconstructing 2D velocity vector fields within the left ventricular cavity from single-view color Doppler echocardiographic images. Vector flow mapping is formulated as a quadratic optimization problem based on an [Formula: see text]-norm minimization of a cost function composed of a Doppler data-fidelity term and a regularizer. The latter contains three physically interpretable expressions related to 2D mass conservation, Dirichlet boundary conditions, and smoothness. A finite difference discretization of the continuous problem was adopted in a polar coordinate system, leading to a sparse symmetric positive-definite system. The three regularization parameters were determined automatically by analyzing the L hypersurface, a generalization of the L-curve. The performance of the proposed method was numerically evaluated using (1) a synthetic flow composed of a mixture of divergence-free and curl-free flow fields and (2) simulated flow data from a patient-specific CFD (computational fluid dynamics) model of a human left heart. The numerical evaluations showed that the vector flow fields reconstructed from the Doppler components were in good agreement with the original velocities, with a relative error less than 20%. It was also demonstrated that a perturbation of the domain contour has little effect on the rebuilt velocity fields. The capability of our intraventricular vector flow mapping (iVFM) algorithm was finally illustrated on in vivo echocardiographic color Doppler data acquired in patients. The vortex that forms during the rapid filling was clearly deciphered. This improved iVFM algorithm is expected to have a significant clinical impact in the assessment of diastolic function. PMID- 28800301 TI - Simultaneous assessment of blood coagulation and hematocrit levels in dielectric blood coagulometry. AB - BACKGROUND: In a whole blood coagulation test, the concentration of any in vitro diagnostic agent in plasma is dependent on the hematocrit level but its impact on the test result is unknown. OBJECTIVE: The aim of this work was to clarify the effects of reagent concentration, particularly Ca2+, and to find a method for hematocrit estimation compatible with the coagulation test. METHODS: Whole blood coagulation tests by dielectric blood coagulometry (DBCM) and rotational thromboelastometry were performed with various concentrations of Ca2+ or on samples with different hematocrit levels. DBCM data from a previous clinical study of patients who underwent total knee arthroplasty were re-analyzed. RESULTS: Clear Ca2+ concentration and hematocrit level dependences of the characteristic times of blood coagulation were observed. Rouleau formation made hematocrit estimation difficult in DBCM, but use of permittivity at around 3 MHz made it possible. The re-analyzed clinical data showed a good correlation between permittivity at 3 MHz and hematocrit level (R2=0.83). CONCLUSIONS: Changes in the hematocrit level may affect whole blood coagulation tests. DBCM has the potential to overcome this effect with some automated correction using results from simultaneous evaluations of the hematocrit level and blood coagulability. PMID- 28800302 TI - The effect of pain severity on postural stability and dynamic limits of stability in chronic low back pain. AB - BACKGROUND: Deficits of dynamic balance in chronic low back pain patients have been reported by different studies in terms of impaired postural control. However, they excluded the degree of pain as a determinant affecting dynamic balance. OBJECTIVE: To evaluate the effect of pain intensity on dynamic balance control in terms of postural stability indices (PSIs) and limits of stability (LOS) in chronic LBP patients. METHODS: Sixty subjects (38 men, 22 women) participated in the current study, 45 patients with chronic LBP were selected randomly and served as the chronic LBP group while 15 healthy subjects served as the asymptomatic group (AS). The chronic LBP group was further classified in terms of pain intensity into 3 subgroups; low pain (LP), moderate pain (MP) and severe pain (SP) subgroups. The Biodex Balance System was used to measure the dynamic balance control (PSIs and LOS). RESULTS: Statistical significant differences were found among AS group and chronic LBP subgroups in PSIs and LOS. CONCLUSIONS: The intensity of pain has shown to be one of the determinants affecting dynamic balance in chronic LBP patients who showed differences in the impairment of PSIs and LOS with different degrees of pain. PMID- 28800303 TI - Does gender make a difference in knee rotation proprioception and range of motion in healthy subjects? AB - BACKGROUND: Knee proprioception is an integral component of neuromuscular control system that stabilizes the joints, reducing incidence of injury. Knee injuries' incidences differ between genders. Knee rotation is a component of different knee injury mechanisms. Gender differences in knee proprioception in internal (IR) and external (ER) rotations are not sufficiently studied. OBJECTIVE: To check whether proprioceptive acuity in IR and ER directions of knee rotation is inherently lower in women compared to men. Moreover, to assess gender difference in ranges of knee rotation. METHODS: Thirty volunteers (15 women and 15 men) participated. Knee proprioception acuity and ranges of knee rotation were assessed using the knee rotatory kinesthetic device (KRKD). Proprioception was tested using absolute judgment task, subject's ability to discriminate different rotation movements (stimuli) randomly presented, then just notable difference (JND) was calculated; least difference accurately discriminated in 75% of trials. RESULTS: Women had lower proprioception acuity in IR than men (1.70?+/- 0.79? and 1.12?+/- 0.32?, p= 0.011) respectively. Active IR (women: 41.29?+/- 7.46?, men 32.80?+/- 3.64?, p= 0.000), and passive IR (women: 53.43?+/-11.67?, men: 37.94?+/- 5.22?, p= 0.000) were higher in women compared to men. Active ER (women: 49.71?+/- 11.37?, men: 39.16?+/- 5.46?, p= 0.003), and passive ER (women: 62.29?+/- 13.74?, men: 48.89?+/- 7.09?, p= 0.002) were, also, higher in women. CONCLUSION: Gender difference in knee proprioception acuity was found in IR, which is the direction of rotation that anterior cruciate ligament (ACL) stabilize. Women's ranges of knee rotation are greater than men in both IR and ER. PMID- 28800304 TI - Role of upper cervical spine in temporomandibular disorders. AB - BACKGROUND: Temporomandibular disorders (TMDs) are prevalent multifactorial pathologies in which the actual role of the cervical region position is controversial. OBJECTIVE: To analyze the relationship between the position of the upper cervical rachis and the symptoms of TMD. METHODS: Sixty women were recruited to this study. All of them completed a questionnaire and were subjected to a temporomadibular exploration to create two different groups: a TMD Group (n= 30) - women who suffered TMD symptoms according to the evaluation; and a control group (n= 30) - women who were free from TMD symptoms. Two X-ray examinations were performed in all the women: a lateral one and a frontal one with mouth open to assess the C1-C0 distance and the craniocervical angle. RESULTS: ANOVA showed that the TMD and control women had similar C1-C0 distances and craniocervical angles (p> 0.05). Pearson correlation did not indicate any relationship between the craniocervical position and the symptomatology of TMD (r=- 0.070). CONCLUSIONS: TMD symptomatology is unrelated to alterations in craniocervical position (C0-C1 distance and craniocervical angle). Women with and without TMD showed a similar prevalence of alteration in the craniocervical position. PMID- 28800305 TI - Influence of chronic neck pain on cervical joint position error (JPE): Comparison between young and elderly subjects. AB - BACKGROUND: Evaluation of cervical joint position sense in subjects with chronic neck pain has gained importance in recent times. Different authors have established increased joint position error (JPE) in subjects with acute neck pain. However, there is a paucity of studies to establish the influence of chronic neck pain on cervical JPE. OBJECTIVE: The objective of the study was to understand the influence of chronic neck pain on cervical JPE, and to examine the differences in cervical JPE between young and elderly subjects with chronic neck pain. METHODS: Forty-two chronic neck pain patients (mean age 47.4) were compared for cervical JPE with 42 age-matched healthy subjects (mean age 47.8), using a digital inclinometer. The cervical JPE were measured in flexion, extension, and rotation in right and left movement directions. RESULTS: The comparison of JPE showed significantly larger errors in subjects with chronic neck pain when compared to healthy subjects (p< 0.001). The errors were larger in all of the movement directions tested. Comparison between young and older subjects with chronic neck pain revealed no significant differences (P> 0.05) in cervical JPE. CONCLUSIONS: Cervical joint position sense is impaired in subjects with chronic neck pain. PMID- 28800306 TI - Acute effects of Kinesio taping on pain, disability and back extensor muscle endurance in patients with low back pain caused by magnetic resonance imaging confirmed lumbar disc degeneration. AB - BACKGROUND: Individuals with disc degeneration experience associated pain and disability. Considering its safety and affordability, Kinesio tape (KT) may be a viable treatment. However, most KT studies have demonstrated its effects in healthy adults and patients with nonspecific low back pain. The efficacy of KT in patients with disc degeneration is yet to be investigated. OBJECTIVES: To examine the acute effects of KT on patients with lumbar disc degeneration confirmed through magnetic resonance imaging. METHODS: A total of 31 eligible patients (aged 25-64 years) with low back pain caused by lumbar disc degeneration were divided into mild and moderate-to-severe pain groups. KT was applied to the painful lumbar region in a lumbar brace-like pattern for 1 day. A visual analogue scale for pain and the Oswestry disability index were analysed before and after 1 day of taping. The Biering-Sorensen test for trunk muscle endurance was performed before, immediately after, and 1 day after taping as well as immediately after tape removal. RESULTS: After taping, both groups showed significant pain reduction (p< 0.001), but the reduction was of minimal clinical importance in the moderate-to-severe pain group. The magnitude of treatment (i.e. effect size) was higher in the moderate-to-severe pain group. Disability significantly decreased in both groups, particularly in the moderate-to-severe pain group, but the improvement was not clinically worthwhile. Trunk muscle endurance significantly improved in both groups with in situ taping, but it decreased after tape removal. CONCLUSIONS: KT may be adopted as an assistive aid for immediate pain reduction, particularly in lumbar disc degeneration patients with moderate-to-severe pain; however, its effects on disability and trunk muscle endurance are not clinically worthwhile. The long-term effects of KT, with or without active exercise, warrant further assessment. PMID- 28800307 TI - Dynamic trunk muscle endurance profile in adolescents aged 14-18: Normative values for age and gender differences. AB - BACKGROUND: The selection and validation of age- and gender-specific criterion referenced cut-points for abdominal endurance are still unclear. OBJECTIVE: To stablish normative values for abdominal endurance in adolescents by age and gender using the Bench Trunk Curl-up Test (BTC). Additionally, the reliability of the BTC was analyzed. METHODS: Two hundred and sixteen untrained high school students (104 males - 112 females) were grouped into five age strata. Participants performed the BTC twice with a rest period of 72 h. Descriptive statistics and percentile scores were determined for each gender/age strata. RESULTS: Males showed higher BTC scores than females (males: 90.07 +/- 32.65 repetitions; females: 73.43 +/- 27.74 repetitions), but no significant differences between age strata nor age * gender interaction were found. Significant differences for the BTC scores between sessions were found (T1 = 72.06 +/- 26.28 repetitions; T2 = 81.44 +/- 31.27 repetitions). The ICC was 0.82, whereas the typical error was 17.2%. CONCLUSIONS: Gender, but not age, is an important factor when abdominal endurance is compared between adolescents. Finally, the BTC is a reliable test, supporting the findings of this study. However, an extensive familiarization period to reduce the learning effect is necessary. PMID- 28800308 TI - Cancer stem cells as functional biomarkers. AB - According to the American Association of Cancer Research (AACR), a Cancer Stem Cell is a cell within a tumor that possesses the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that constitutes the tumor [1]. Cancer Stem Cells (CSCs) are involved in the metastatic process, in the resistance to therapeutic treatments of many types of human cancers and consequently in the onset of recurrences. Numerous translational studies have been conducted to understand CSC characteristics and evaluate association between CSC-related biomarkers and clinical outcomes. The CSC theory can explain also a tumor relapse after that a tumor has been completely surgically removed (R0 macroscopical zero residual resection) or after an apparently complete response to chemotherapy. CSCs, in fact, showed a marked ability to reduce intracellular accumulation of chemotherapic agents by active drug extrusion, increased chemoresistance and survival, as well as elevated membrane transporter activity. In addition, it is possible that these cancer stem cells may nest in the "secured" (niche) sites of our body, where they may remain undisturbed for a long time, even years, until a stimulus arrives to awaken them, causing the disease to resume. CSCs, in fact, are able to use a variety of cellular pathways to survive to anticancer treatments. More recently CSCs have been described in several solid tumors, expressing specific biomarkers. Another field of research should be focused on the realization of diagnostic instruments to follow up patients after R0 surgical resection or after a complete response for an early detection and management of relapse and metastasis. PMID- 28800309 TI - The prognostic role of preoperative serum CA125 levels in patients with advanced endometrial carcinoma. AB - BACKGROUND: Lifetime risk of developing endometrial cancer is 2.17%. There is controversy regarding the predictive value of Cancer Antigen 125 (CA125) in endometrial cancer as well as the significance of its relationship with prognostic factors and appropriate cut-off value. OBJECTIVE: The aim of the present study was to investigate the prognostic role of CA125 in advanced endometrial carcinoma and determination of the appropriate cut-off value. METHODS: A sample of 91 patients was retrospectively selected from a population of 501 patients suffering from endometrial cancer during 1995 to 2015 in accordance with the inclusion criteria. The relation between clinicopathological variables and CA125 were analyzed. In order to determine sensitivity and specificity of various cut-off levels, receiver operating characteristic (ROC) curve analysis was performed for associated factors confirmed by logistic regression analysis. RESULTS: In 35% of patients, CA125 values were 35 u/ml, and in 52%, the values were equal to or greater than 20 u/ml. High preoperative CA125 was significantly related with advanced stage, ovarian involvement, omental metastasis, and myometrial invasion equal to or greater than 50%. According to the ROC curve, the suitable cut-off value for CA125 in advanced stage (sensitivity = 73%, specificity = 55%, positive predictive value = 18%, negative predictive value = 78%) and myometrial invasion equal to or greater than 50% (sensitivity = 64%, specificity = 61%, positive predictive value = 47%, negative predictive value = 74%) was 20 u/ml. Further, the suitable cut-off value for CA125 in involvement of the ovaries (sensitivity = 77%, specificity = 72%, positive predictive value = 31%, negative predictive value = 95%) and omental involvement (sensitivity = 70%, specificity = 70%, positive predictive value = 22%, negative predictive value = 95%) was 35 u/ml. CONCLUSIONS: In endometrial carcinoma, due to the relationship of CA125 with numerous prognostic factors, it is recommended that CA125 measurement be included in preoperative evaluation. In case of high CA125 levels, complete surgical staging including lymphadenectomy and omentectomy should be considered. PMID- 28800310 TI - Nephroblastoma overexpressed gene expression and its prognostic implications of clinical outcomes in renal cell carcinoma patients. AB - BACKGROUND: The nephroblastoma overexpressed gene (NOV) expressions in tissues and organs has become abnormal during tumorigenesis and progression. This study intended to investigate the correlation between clinical outcomes and NOV expression in renal cell carcinoma (RCC) patients. METHODS: Fifty RCC patients who attended the hospital from January 2013 to January 2015 were enrolled in this study. NOV expression in cancerous tissues and adjacent non-tumor (ANT) renal tissues of RCC patients was detected by immunohistochemistry (IHC). According to the percentage of NOV-positive cells, cases were divided into NOV-positive and NOV-negative groups. The correlations between age, gender, disease course, tumor diameter, pathological grades (WHO/ISUP grading system) or tumor-node-metastasis (TNM) staging and NOV-positive rate were determined. Kaplan-Meier method was utilized for analyzing the 3- and 5-survial rates of RCC patients. The Cox proportional hazards regression model was used for the multivariate analysis. RESULTS: NOV-positive rate was uncorrelated with age, gender, disease course or TNM classification while was negatively correlated with pathological grades. NOV positive rate in RCC tumor and ANT tissues was 58% and 100%, respectively. Five year survival rate in NOV-positive group was significantly lower than that in NOV negative group. CONCLUSION: Our data suggested that NOV down-regulation might be a biomarker for RCC but its positivity might be an indicator of poor prognosis. PMID- 28800311 TI - Prognostic value of combined and individual expression of microRNA-1290 and its target gene nuclear factor I/X in human esophageal squamous cell carcinoma. AB - BACKGROUND: microRNA (miR)-1290 was previously indicated to promote esophageal squamous cell carcinoma (ESCC) progression via regulating its target gene nuclear factor I/X (NFIX). OBJECTIVE: To investigate clinical significance of miR-1290 and NFIX in ESCC. METHODS: Quantitative real-time PCR was performed to detect miR 1290 and NFIX mRNA expression in ESCC tissues. Associations of miR-1290 and/or NFIX mRNA expression with various clinicopathological features and prognosis in ESCC patients were statistically evaluated. RESULTS: Compared to noncancerous esophageal mucosa, miR-1290 expression was upregulated, while NFIX mRNA expression was downregulated in ESCC tissues. There was a significantly negative correlation between miR-1290 and NFIX expression in ESCC tissues (r=-0.427, P= 0.01). Interestingly, miR-1290-high and/or NFIX-low expression were all significantly associated with positive lymph node metastasis and advanced tumor node-metastasis stage of ESCC patients (all P< 0.05). Moreover, miR-1290 upregulation and NFIX downregulation both correlated short overall and disease free survivals of ESCC patients. Importantly, the prognostic value of combined miR-1290 and NFIX expression was more significant than those considered alone. CONCLUSIONS: Our data suggest that the dysregulation of miR-1290-NFIX axis may play crucial roles in esophageal carcinogenesis and progression. We also confirmed miR-1290 and its target gene NFIX as independent prognostic factors for ESCC patients. PMID- 28800312 TI - Circulating endothelial cells and microparticles for prediction of tumor progression and outcomes in advanced non-small cell lung cancer. AB - BACKGROUND: Circulating endothelial cells (CECs) and microparticles (MPs) are proposed as useful biosensors for angiogenesis and membrane damage in cancer. OBJECTIVE: We investigated their predictive value for progression disease (PD) and clinical outcomes in advanced non-small cell lung cancer (NSCLC) patients treated with cytotoxic chemotherapy. METHODS: Peripheral blood samples were obtained from 60 patients. Immunomagnetic separation (IMS) and flow cytometry techniques were used to quantify CECs and MPs, respectively. Receiver operating characteristics (ROC) analysis was used to determine the optimal cutoff values for CECs and MPs counts according to their levels in patients with an objective response (OR) and non-responders after treatment. Baseline serum biomarkers levels and their kinetics after chemotherapy were correlated with tumor response and outcomes in advanced NSCLC patients. RESULTS: Forty-seven patients presented an OR after chemotherapy. Of these, 28 patients progressed within three months. Through an increase in their levels during or after chemotherapy, CECs and MPs correctly predicted PD in 57% and 61% of these patients, respectively. Regarding tumor stage, NSCLC patients with stage IV had significantly higher pretreatment CECs and MPs levels than stage III patients (p= 0.037 and 0.018, respectively). Moreover, progression-free survival (PFS) was significantly longer in patients with high baseline CECs levels than those with low pretreatment CECs values (p= 0.05). Moreover, patients with high percentage change in CECs count after chemotherapy had significantly longer time to progression (TTP) duration (p= 0.018). CONCLUSIONS: Our findings suggest the increase in CECs and MPs number during or after chemotherapy as predictive biomarkers of tumor progression in advanced NSCLC patients. An association of basal CECs and MPs values with tumor stage was also shown in advanced NSCLC patients. However, baseline CECs levels and their kinetics after chemotherapy seem to be prognostic factors in advanced NSCLC. PMID- 28800313 TI - Clinical validation of the CE-IVD marked Therascreen MGMT kit in a cohort of glioblastoma patients. AB - BACKGROUND: Pyrosequencing is recognized as a strong technique to analyze the MGMT status of glioblastoma patients. The most commonly used assay, quantifies the methylation levels of CpGs 74 to 78. A more recent CE-marked In Vitro Diagnostic Medical Device (CE-IVD) assay, Therascreen, analyzes CpGs 76-79. METHODS: We performed a comparison of these two assays to evaluate the potential impact of this shift in analyzed CpGs. Therascreen analysis was centrally performed for 102 glioblastoma patients, who were part of a prospective multicenter trial. RESULTS: A strong correlation was observed for the mean values of the 4 or 5 analyzed CpGs, with lower values recorded using the Therascreen assay, especially for values greater than 20%. When considering a classification in 3 categories (> 12%: methylated; ? 8%: unmethylated; 9-12%: grey zone), 93% of patients were identically classified between the two assays. Using a binary classification, 95% and 97% of patients were identically classified with cut-offs of 8% and 12%, respectively. A strong prognostic significance was observed for both assays: median overall survival were 15.9 months and 34.9 months for respectively unmethylated and methylated patients with either test. CONCLUSION: The results demonstrate that these assays may be used interchangeably. PMID- 28800314 TI - Long noncoding RNA PVT1 promotes hepatocellular carcinoma progression through regulating miR-214. AB - BACKGROUND: Long noncoding RNAs (lncRNA) have been verified to be involved in hepatocellular carcinoma (HCC) progression. However, the potential biologic function of PVT1 in HCC is not still fully known. METHODS: PVT1 and miR-214 were detected by qRT-PCR assays in HCC tissues and adjacent normal tissues. CCK8, cell colony and transwell invasion assays were performed to evaluate cell proliferation and invasion abilities. Western-blot assay was performed to detect the protein of E-cadherin and Vimentin. QRT-PCR, RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP) assays demonstrated PVT1 regulated miR 214 expression. RESULTS: The results showed that PVT1 was increased in HCC tissues and higher PVT1 expression was associated with tumor size, histological differentiation grade and advanced TNM stage. Furthermore, we revealed that PVT1 promoted cell proliferation and invasion in HCC. RIP and ChIP assays demonstrated that PVT1 significantly inhibited miR-214 expression by interacting with enhancer of zeste homolog 2 (EZH2). CONCLUSIONS: Thus, these results demonstrated that PVT1/EZH2/miR-214 regulatory pathway might serve as new target for HCC treatment. PMID- 28800315 TI - MiR-99a suppresses proliferation, migration and invasion of esophageal squamous cell carcinoma cells through inhibiting the IGF1R signaling pathway. AB - miR-99a is down-regulated in esophageal squamous cell carcinoma (ESCC), however the role and underlying mechanism are still unknown. We aim to explore the role and mechanism of miR-99a down-regulation in ESCC. The expression of miR-99a in ESCC tissues and cell lines was detected by Human miRNA Microarrays and Real-time PCR. The effects of miR-99a on cell proliferation, migration and invasion were determined by Cell Counting Kit-8 (CCK-8) assay, transwell migration and invasion assay. Target gene of miR-99a were analyzed by target prediction software and validated by Real-time PCR and Western blotting assay. Our microarray results and four Gene Expression Omnibus (GEO) datasets showed lower expression level of miR 99a in ESCC tissues. Overexpression of miR-99a using mimics significantly suppressed cell proliferation, and decreased expressions of CCND1, CCNA2 and CCNE1. We also found that enhanced miR-99a significantly inhibited migration, invasion and epithelial-mesenchymal transition (EMT) of ESCC cells, and down regulated EMT associated transcription factor Slug, and MMPs including MMP2, MMP7 and MMP13. TargetScan predicted insulin-like growth factor 1 receptor (IGF1R) as the cadidate target gene of miR-99a, and western blotting confirmed the negative correlation between miR-99a and IGF1R. Importantly, we further found that knockdown of IGF1R also significantly inhibited the proliferation, migration, invasion and slug-induced EMT of ESCC cells, and reduced the cell cycle regulatory proteins and MMPs. In conclusion, our findings suggested that loss of miR-99a in ESCC promoted the tumor cell proliferation, migration, invasion and slug-induced EMT through activating IGF1R signaling pathway. PMID- 28800316 TI - Prognostic significance of low miR-144 expression in gastric cancer. AB - BACKGROUND: An overwhelming amount of evidence has emerged suggesting that dysregulated microRNAs (miRNAs) play crucial roles in tumorigenesis. OBJECTIVE: The study was to analyze tissue/serum miR-144 expression in gastric cancer and then evaluate their potential to predict the prognosis of gastric cancer. METHODS: We examined miR-144 levels in tissues and peripheral blood samples from 96 gastric cancer patients using real-time PCR. Then the association between tissue/serum miR-144 levels and clinicopathological parameters was determined. RESULTS: The expression levels of miR-144 were significantly down-regulated in the cancerous tissue and serum samples from gastric cancer patients. Serum miR 144 was able to differentiate the gastric cancer patients from healthy controls with high accuracy. In addition, tissue and serum miR-144 levels were both associated with clinical stage and lymph node metastasis. Moreover, patients with lower tissue or serum miR-144 suffered worse 5 year overall survival and disease free survival. CONCLUSIONS: Taken together, our data support the potential clinical value of tissue and serum miR-144 as prognostic biomarkers in gastric cancer. PMID- 28800317 TI - Identification of prostate cancer hub genes and therapeutic agents using bioinformatics approach. AB - BACKGROUND: Prostate cancer (PCa) is the most common and the second leading cause of cancer-related death among men in America. As the molecular mechanism of PCa has not yet been completely discovered, identification of hub genes and potential drug of this disease is an important area of research that could provide new insights into exploring the mechanisms underlying PCa. OBJECTIVE: The aim of this study was to identify potential biomarkers and novel drug for prostate cancer treatment. METHODS: The differentially expressed genes (DEGs) between prostate cancer and normal cells were screened using microarray data obtained from the Gene Expression Omnibus database. Gene ontology (GO) and pathway enrichment analyses were performed in order to investigate the functions of DEGs, and the protein-protein interaction (PPI) network of the DEGs was constructed using the Cytoscape software. DEGs were then mapped to the connectivity map database to identify molecular agents associated with the underlying mechanisms of PCa. RESULTS: Totally, 359 genes (155 upregulated and 204 downregulated genes) were found to be differentially expressed between prostate cancer and normal cells. The GO terms significantly enriched by DEGs included cell adhesion, protein binding involved in cell-cell adhesion, response to BMP, extracellular region and extracellular region part. KEGG pathway analysis showed that the most significant pathways included cell adhesion molecules (CAMs) and TGF-beta signaling pathway. The PPI network of up-regulated DEGs and down-regulated DEGs were established, respectively. While CDH1, BMP2, NKX3-1, PPARG and PRKAR2B were identified as the hub genes in the PPI network. CONCLUSIONS: The BMP2, PPARG and PRKAR2B genes may therefore be potential biomarkers in the treatment of PCa. Additionally, the small molecular agent phenoxybenzamine may be a potential drug for PCa. PMID- 28800318 TI - MiR-513c suppresses neuroblastoma cell migration, invasion, and proliferation through direct targeting glutaminase (GLS). AB - Neuroblastoma is a brain malignancy of childhood and accounts for 7-10% of childhood cancers, leading to approximately 15% of pediatric cancer deaths. MicroRNAs (miRNAs) are a family of short (about 18-25 nucleotides), noncoding and single stranded endogenous RNAs, which complementarily bind to the 3' untranslated regions of their target genes. Recently, glutamine metabolism has been recognized as an important nutrition source for tumor cells, and hence targeting glutamine metabolism could benefit to development of anti-cancer agents. In this study, we investigate the roles of miR-513c in human neuroblastoma. We report miR-513c is significantly downregulated in human neuroblastoma tissues compared with their adjacent normal tissues. Moreover, miR 513c is significantly downregulated in neuroblastoma cell lines compared with normal neuroblast cells. Overexpression of miR-513c suppresses neuroblastoma cells' migration, invasion, and proliferation. We demonstrate the glutaminase (GLS) is a direct target of miR-513c in human neuroblastoma cells. In addition, we found restoration of GLS expression recovered the neuroblastoma cells' migration, invasion, and proliferation. In summary, this study illustrates a miR 513c mediated neuroblastoma cells suppression, providing a new aspect on the miRNA-based therapeutic approach for the treatments of neuroblastoma. PMID- 28800319 TI - miR-503-3p induces apoptosis of lung cancer cells by regulating p21 and CDK4 expression. AB - Studies have shown that microRNAs (miRNAs) can promote or suppress tumor growth and therefore act as targets for cancer therapy. Hsa-miR-503-5p, a mature miRNA derived from 5' ends of pre-miR-503, has been proved to regulate cell proliferation, transformation, migration and invasion. However, the biological function of miR-503-3p derived from 3' ends of pre-miR-503 has never been reported. In current study, we found that miR-503-3p inhibits lung cancer cell viability and induces cell apoptosis. To better understand the molecular mechanism underlying the miR-503-3p participating in this process, PCR array and RNA-sequencing (RNA-seq) were performed and some differential expression genes were discovered between NC and miR-503-3p treated groups. Biological interaction network showed that p21 and CDK4 are the most important proteins involving miR 503-3p signal pathway. Dual-luciferase assay results shown miR-503-3p directly regulates the expression of p21 by targeting 3'-UTR of its mRNA. These results shed light on the potential roles of miR-503-3p, indicating that it may act as an anti-oncogene factor to inhibit lung cancer cell viability. PMID- 28800320 TI - An ensemble method integrated with miRNA expression data for predicting miRNA targets in stomach adenocarcinoma. AB - OBJECTIVE: It is crucially important to discover the relationships between genes and microRNAs (miRNAs) in cancer. Thus, we proposed a combined bioinformatics method integrating Pearson's correlation coefficient (PCC), Lasso, and causal inference method (IDA) to identify the potential miRNA targets for stomach adenocarcinoma (STAD) using Borda count election. MATERIALS AND METHODS: Firstly, the ensemble method integrating PCC, IDA, and Lasso was used to predict miRNA targets. Subsequently, to validate the performance ability of this ensemble method, comparisons between verified database and predicted miRNA targets were implemented. Pathway analysis for target genes in the top 1000 miRNA-mRNA interactions was implemented to discover significant pathways. Finally, the top 10 target genes were identified based on predicted times > 3. RESULTS: The ensemble approach was confirmed to be a feasible method to predict miRNA targets The 527 target genes of the top 1000 miRNA-mRNA interactions were enriched in 21 pathways. Of note, cell adhesion molecules (CAMs) was the most significant one. The top 10 target genes were identified based on predicted times > 3, such as GABRA3, CSAG1 and PTPN7. These targets were all predicted by 4 times. Moreover, GABRA3 and CSAG1 were simultaneously targeted by miRNA-105-1, miRNA-105-2, and miRNA-767. Significantly, among these top 10 targets, PTPN7 and GABRA3-miRNA interactions owned the highest correlation with 691. CONCLUSION: The combined bioinformatics method integrating PCC, IDA, and Lasso might be a valuable method for miRNA target prediction, and dys-regulated expression of miRNAs and their potential targets might be prominently involved in the pathogenesis of STAD. PMID- 28800321 TI - The impact of chemotherapy-associated hemoglobin on prognosis of colorectal cancer patients receiving adjuvant chemotherapy. AB - BACKGROUND AND OBJECTIVE: The association of chemotherapy-associated hemoglobin and survival of colorectal cancer (CRC) receiving adjuvant chemotherapy is uncertain. We sought to explore the prognostic value of chemotherapy-associated hemoglobin in CRC receiving adjuvant chemotherapy and the best cut point affecting prognosis. METHODS: Three hundred and twenty stage II and III CRC patients receiving adjuvant FOLFOX chemotherapy from March 2003 to March 2012 were enrolled. The associations between chemotherapy-associated hemoglobin (the absolute levels of post-chemotherapy) or chemotherapy-associated hemoglobin change (change between the pre- and post-chemotherapy hemoglobins) and disease free survival (DFS) or overall survival (OS) of CRC, and the best cut point were investigated. RESULTS: Log rank test showed the best cut points for chemotherapy associated hemoglobin and chemotherapy-associated hemoglobin change were respectively 90 g/L, 30 g/L. Cox regression model showed chemotherapy-associated hemoglobin < 90 g/L was the independent prognostic factor for DFS (HR, 2.221; 95% CI = 1.157-4.262), OS (HR, 2.058; 95% CI = 1.009-4.197), respectively, but no association of chemotherapy-associated hemoglobin change ? 30g/L and DFS (HR, 2.063; 95% CI = 0.929-4.583), OS (HR, 1.386; 95% CI = 0.553-3.471) was found. CONCLUSIONS: Chemotherapy-associated hemoglobin < 90 g/L has a significant prognostic value in CRC receiving adjuvant chemotherapy, which is a significant biomarker in the individualized management and may suggest the simple indication for the treatment of anemia in adjuvant chemotherapy in CRC. PMID- 28800322 TI - Relationship between skin blood flow regulation mechanisms and vascular endothelial growth factor in patients with metabolic syndrome. AB - The focus of this paper is the determination of endothelial dysfunction in patients with metabolic syndrome (MetS) and the establishment of a relationship between the traditional biomarkers of endothelial dysfunction and the vascular tone regulation indices obtained from indirect cold tests in MetS patients. Our investigation was conducted on 30 patients aged 45.5+/-9 years. The control group comprised 14 healthy subjects aged 48.2+/-2.4 years. The mechanism of vascular tone regulation was investigated using the wavelet analysis of skin temperature oscillations (WAST). The degrees of microvascular vasoconstriction and vasodilatation were determined during contralateral cold tests in the endothelial (0.02-0.0095 Hz), neurogenic (0.05-0.02 Hz) and myogenic (0.05-0.14 Hz) frequency ranges. In MetS patients, vasoconstriction indices were higher and vasodilatation indices were lower than in the subjects of the control group, which is indicative of disorders in the mechanisms of microvascular tone regulation. These indices correlate with the metabolic parameters and VEGF (vascular endothelial growth factor) levels. The correlation of vasoconstriction and vasodilatation indices with the main factors of the metabolic syndrome testifies that the biological and functional aspects of the endothelial dysfunction are closely related. PMID- 28800323 TI - Platelet activation and erythrocyte lysis during brief exposure of blood to pathophysiological shear stress in vitro. AB - BACKGROUND: Interaction of von Willebrand factor (VWF) with circulating platelets is the trigger for thrombosis in a region of arterial stenosis. These events are typically studied in vitro under conditions where platelets adhere to a VWF coated surface. Our approach assesses platelet responses in the absence of adhesion. OBJECTIVE: To characterize extent of platelet activation and erythrocyte lysis in an artificial stenosis model. METHODS: Whole blood is perfused through a length of polyetheretherketone tubing that includes an artificial stenosis, comprising narrow-bore (89-381 MUm) tubing. Secretion of [14C] serotonin and hemoglobin release was measured to evaluate platelet activation and hemolysis respectively at various perfusion rates and different stenosis dimensions. RESULTS: Platelet activation and erythrocyte lysis increased progressively with increasing perfusion rate and decreasing stenosis diameter; the length of the stenosis had negligible influence. Modest platelet activation (5-10% secretion of [14C] serotonin) occurred without significant erythrocyte lysis under a limited range of perfusion conditions (4-6 mL/min flow through a 127 MUm stenosis). CONCLUSIONS: Our experimental approach mimics conditions in severe arterial stenosis or a mechanical heart valve. It could be a valuable aid in the development of novel drugs to treat arterial thrombosis and in the design of heart valves. PMID- 28800324 TI - Fluid in the tissue channels of vascular adventitia investigated by AFM and TEM. AB - BACKGROUND: Tissue channels as a part of microcirculation system have been proposed over three decades, playing an important role in fluid transportation as reported. Adventitia of inferior vena cava (IVC) is a typical hierarchical porous media with abundant tissue channels. Its fluid transportation behaviors attract massive research interest. However, the mechanism of the driving force and microstructure was lack of deep research. OBJECTIVE: This study was to investigate the microstructural basis of fluid transportation within inferior vena cava (IVC). METHODS: Rat IVC samples were extracted and fixed on a gelatin substrate. Four samples were randomly used as 4 cases: Case 1 with AFM loading and the fluorescent tracer adding; Case 2 with fluorescent tracer adding only; Case 3 with AFM loading only as the control group; Case 4 with no treatment. The movement of fluorescent tracer was observed by two-photon fluorescent microscope and analyzed by self-made Matlab program. The microscopic structure was characterized by high resolution TEM. RESULTS: The fluorescent tracer in Case 1 exhibited faster and longer transportation comparing to other cases, while in Case 2 diffused normally following Fick's law. Case 3 with only AFM loading demonstrated that collagen bundles twisting along the fluid orientation, while the bundles in Case 4 with no treatment were straggling. The brush-like macromolecule structure of collagen microfibril was found on the bundle surfaces under TEM. CONCLUSIONS: Transportation within loose connective tissues is observed ex vivo. AFM loading, as the mechanical stimulation resemblance to muscle constrictions and blood pulsations, can facilitate the transportation as the driving force. The brush-like glycosaminoglycan macromolecules on the surfaces of the collagen bundles can be considered as a type of hierarchical porous media, which might form the transport pathway for fluids. The possible mechanism was conducted regarding the conformation of the superficial macromolecule brushes. PMID- 28800325 TI - Classification of Alzheimer's Disease and Prediction of Mild Cognitive Impairment Conversion Using Histogram-Based Analysis of Patient-Specific Anatomical Brain Connectivity Networks. AB - In this study, we investigated the early detection of Alzheimer's disease (AD) and mild cognitive impairment (MCI) conversion to AD through individual structural connectivity networks using structural magnetic resonance imaging (sMRI) data. In the proposed method, the cortical morphometry of individual gray matter images were used to construct structural connectivity networks. A statistical feature generation approach based on histogram-based feature generation procedure was proposed to represent a statistical-pattern of connectivity networks from a high-dimensional space into low-dimensional feature vectors. The proposed method was evaluated on numerous samples including 61 healthy controls (HC), 42 stable-MCI (sMCI), 45 progressive-MCI (pMCI), and 83 AD subjects at the baseline from the J-ADNI data-set using support vector machine classifier. The proposed method yielded a classification accuracy of 84.17%, 70.38%, and 61.05% in identifying AD/HC, MCIs/HCs, and sMCI/pMCI, respectively. The experimental results show that the proposed method performed in a comparable way to alternative methods using MRI data. PMID- 28800326 TI - Intracerebroventricular Streptozotocin Induces Obesity and Dementia in Lewis Rats. AB - BACKGROUND: Animal models of dementia associated with metabolic abnormalities play an important role in understanding the bidirectional relationships between these pathologies. Rodent strains develop cognitive dysfunctions without alteration of peripheral metabolism following intracerebroventricular administration of streptozotocin (icv-STZ). OBJECTIVE: We aimed to estimate the effect of icv-STZ on cognitive functions and peripheral metabolism in Lewis rats, which are rarely used for the induction of cognitive abnormalities. METHODS: Inbred adult Lewis rats were treated with single icv-STZ (3 mg/kg). Cognitive functions were assessed using Morris water maze (MWM) test and locomotion by the Open Field test. Metabolic alterations were studied using histological and biochemical analysis of brain and peripheral tissues. RESULTS: The icv-STZ induced rapid weight decline during the first two weeks. Thereafter, the rats showed an accelerated weight gain. Three months after the icv-STZ treatment, the rats were severely obese and revealed fatty liver, pancreatic islet hypertrophy, significantly elevated levels of blood insulin, leptin, and adiponectin, but intact peripheral glucose homeostasis. The icv-STZ rats expressed amyloid-beta deposits in blood vessels of leptomeningeal area, microgliosis, astrogliosis, and spongiosis in fimbria-fornix area of hippocampus. Locomotor activities of icv-STZ treated and sham-operated rats were similar. In the MWM test, the icv-STZ treated rats demonstrated severely impaired spatial learning during both acquisition and reversal phases. CONCLUSIONS: Icv-STZ treated Lewis rats develop severe dementia associated with obesity and peripheral metabolic abnormalities. This animal model may be useful for exploring the pathophysiological relationship between obesity and dementia and provides a new tool for development of effective therapy. PMID- 28800328 TI - Effects of Exercise on Cognitive Function in Older People with Dementia: A Randomized Controlled Trial. AB - BACKGROUND: Although physical exercise has been suggested to influence cognitive function, previous exercise studies show inconsistent results in people with dementia. OBJECTIVES: To investigate effects of exercise on cognitive function in people with dementia. METHOD: The Umea Dementia and Exercise (UMDEX) study, a cluster-randomized controlled trial, was set in 16 nursing homes in Umea, Sweden. One hundred-and-forty-one women and 45 men with dementia; mean age of 85 y and mean Mini-Mental State Examination (MMSE) score of 15, were randomized to a High Intensity Functional Exercise program or a seated attention control activity. Blinded assessors measured global cognitive function using the MMSE and the Alzheimer's disease Assessment Scale - Cognitive subscale (ADAS-Cog), and executive function using Verbal fluency (VF) at baseline and 4 months (directly after intervention completion), and MMSE and VF at 7 months. RESULTS: Linear mixed models showed no between-group effects in mean difference from baseline (95% confidence intervals, CI) at 4 months in MMSE (-0.27; 95% CI -1.4 to 0.87, p = 0.644), ADAS-Cog (-1.04, 95% CI -4 to 1.92, p = 0.491), or VF (-0.53, 95% CI 1.42 to 0.35, p = 0.241) or at 7 months in MMSE (-1.15, 95% CI -2.32 to 0.03, p = 0.056) or VF (-0.18, 95% CI -1.09 to 0.74, p = 0.707). CONCLUSION: A 4-month, high-intensity functional exercise program had no superior effects on global cognition or executive function in people with dementia living in nursing homes when compared with an attention control activity. PMID- 28800327 TI - Analytical Strategy to Prioritize Alzheimer's Disease Candidate Genes in Gene Regulatory Networks Using Public Expression Data. AB - Alzheimer's disease (AD) progressively destroys cognitive abilities in the aging population with tremendous effects on memory. Despite recent progress in understanding the underlying mechanisms, high drug attrition rates have put a question mark behind our knowledge about its etiology. Re-evaluation of past studies could help us to elucidate molecular-level details of this disease. Several methods to infer such networks exist, but most of them do not elaborate on context specificity and completeness of the generated networks, missing out on lesser-known candidates. In this study, we present a novel strategy that corroborates common mechanistic patterns across large scale AD gene expression studies and further prioritizes potential biomarker candidates. To infer gene regulatory networks (GRNs), we applied an optimized version of the BC3Net algorithm, named BC3Net10, capable of deriving robust and coherent patterns. In principle, this approach initially leverages the power of literature knowledge to extract AD specific genes for generating viable networks. Our findings suggest that AD GRNs show significant enrichment for key signaling mechanisms involved in neurotransmission. Among the prioritized genes, well-known AD genes were prominent in synaptic transmission, implicated in cognitive deficits. Moreover, less intensive studied AD candidates (STX2, HLA-F, HLA-C, RAB11FIP4, ARAP3, AP2A2, ATP2B4, ITPR2, and ATP2A3) are also involved in neurotransmission, providing new insights into the underlying mechanism. To our knowledge, this is the first study to generate knowledge-instructed GRNs that demonstrates an effective way of combining literature-based knowledge and data-driven analysis to identify lesser known candidates embedded in stable and robust functional patterns across disparate datasets. PMID- 28800329 TI - Chronic Verubecestat Treatment Suppresses Amyloid Accumulation in Advanced Aged Tg2576-AbetaPPswe Mice Without Inducing Microhemorrhage. AB - Verubecestat is a potent BACE1 enzyme inhibitor currently being investigated in Phase III trials for the treatment of mild-to-moderate and prodromal Alzheimer's disease. Multiple anti-amyloid immunotherapies have been dose-limited by adverse amyloid related imaging abnormalities such as vasogenic edema (ARIA-E) and microhemorrhage (ARIA-H) observed in human trials and mice. Verubecestat was tested in a 12-week nonclinical study for the potential to exacerbate microhemorrhage (ARIA-H) profiles in 18-22-month-old post-plaque Tg2576 AbetaPPswe mice. Animals were treated with verubecestat or controls including the anti-Abeta antibody analog of bapineuzumab (3D6) as a positive control for ARIA induction. ARIA-H was measured using in-life longitudinal T2*-MRI and Prussian blue histochemistry at study end. Verubecestat reduced plasma and cerebrospinal fluid Abeta40 and Abeta42 by >90% and 62% to 68%, respectively. The ARIA-H profile of verubecestat-treated mice was not significantly different than controls. Anti-Abeta treatment significantly increased ARIA-H detected by Prussian blue staining; however, anti-Abeta antibody treatment did not impact plaque status. Verubecestat treatment significantly suppressed the accumulation of total levels of brain Abeta40 and Abeta42 and Thioflavin S positive plaque load. Stereological analysis of cortex and hippocampus plaque load similarly revealed significantly reduced area of Abeta immunoreactivity and reduced plaque number in verubecestat-treated animals compared to controls. The absence of elevated ARIA events in verubecestat-treated mice was associated with a significant reduction in the level of accumulated CNS amyloid pathology and brain Abeta peptides; effects consistent with the desired therapeutic mechanism of verubecestat in AD patients. These data will be compared with longitudinal MRI profiles from ongoing clinical trials. PMID- 28800331 TI - Alzheimer's Disease Biomarkers Interactively Influence Physical Activity, Mobility, and Cognition Associations in a Non-Demented Aging Population. AB - BACKGROUND: Alzheimer's disease (AD) risk-reduction strategies (e.g., increasing physical activity, improving mobility) have garnered increasing attention in the literature. However, the effect of such modifiable factors on the preclinical trajectories of brain and cognitive health may be moderated by non-modifiable biomarkers associated with AD. OBJECTIVE: In a longitudinal sample of non demented older adults, we examine the independent predictors everyday physical activity (EPA) and mobility on executive function (EF) performance and change. Next, we test whether these predictions are modified by interactions between age and AD genetic risk. METHODS: This accelerated longitudinal design included adults (n = 532, M age = 70.4, age range 53-95) from the Victoria Longitudinal Study. We tested the independent effects of EPA and Mobility (i.e., gait, balance), moderation by Apolipoprotein E (i.e., APOEE4+, E4-) and age (young-old, middle-old, old-old), and interactions between APOE and age on performance and 9 year change in an EF latent variable. RESULTS: First, higher levels of both EPA and Mobility were associated with better EF performance and less decline. Second, the interaction between age and APOE showed that low EPA and older age was associated with poorer EF performance and steeper EF decline for APOEE4 + carriers, and low mobility was associated with poorer EF performance and steeper EF decline for APOEE4 + carriers than the non-risk carriers. CONCLUSION: In non demented older adults, age moderated the effects of both EPA and Mobility on EF performance and change. However, this moderation occurs differentially across APOE4 status. PMID- 28800330 TI - PET Tau and Amyloid-beta Burden in Mild Alzheimer's Disease: Divergent Relationship with Age, Cognition, and Cerebrospinal Fluid Biomarkers. AB - BACKGROUND: Combining PET amyloid-beta (Abeta) and tau imaging may be critical for tracking disease progression in Alzheimer's disease (AD). OBJECTIVE: We sought to characterize the relationship between Abeta and tau ligands as well as with other measures of pathology. METHODS: We conducted a multi-center observational study in early AD (MMSE >20) participants aged 50 to 85 y. The schedule included cognitive assessments (ADAS-Cog) and CSF measurement of Abeta and tau at baseline and 6 months; PET-CT imaging with Abeta ([18F]AV45) and tau ([18F]AV1451) ligands at baseline. RESULTS: 22 participants took part in the study with 20 completing its 6-month duration and 12 having both tau and amyloid PET. The PET biomarker analysis revealed a strong negative correlation between age and tau in multiple regions. Entorhinal cortex tau and age interacted significantly in terms of cognitive change over 6 months which may have been to older participants deteriorating faster despite lower levels of cortical tau. Cortical Abeta associated with entorhinal cortex tau while CSF tau/Abeta ratio correlated strongly with cortical tau but not Abeta. CONCLUSION: The negative relationship between age and cortical tau whereby younger patients with mild AD had relatively greater tau burden is potentially important. It suggests that younger-age onset AD may be primarily driven by tau pathology while AD developing later may depend on a multitude of pathological mechanisms. These data also suggest that PET-tau performs better than PET-amyloid in predicting the best validated AD diagnostic marker- the CSF total tau/Abeta ratio. PMID- 28800332 TI - Cerebral Oxidative Stress and Microvasculature Defects in TNF-alpha Expressing Transgenic and Porphyromonas gingivalis-Infected ApoE-/- Mice. AB - The polymicrobial dysbiotic subgingival biofilm microbes associated with periodontal disease appear to contribute to developing pathologies in distal body sites, including the brain. This study examined oxidative stress, in the form of increased protein carbonylation and oxidative protein damage, in the tumor necrosis factor-alpha (TNF-alpha) transgenic mouse that models inflammatory TNF alpha excess during bacterial infection; and in the apolipoprotein knockout (ApoE /-) mouse brains, following Porphyromonas gingivalis gingival monoinfection. Following 2,4-dinitrophenylhydrazine derivatization, carbonyl groups were detected in frontal lobe brain tissue lysates by immunoblotting and immunohistochemical analysis of fixed tissue sections from the frontotemporal lobe and the hippocampus. Immunoblot analysis confirmed the presence of variable carbonyl content and oxidative protein damage in all lysates, with TNF-alpha transgenic blots exhibiting increased protein carbonyl content, with consistently prominent bands at 25 kDa (p = 0.0001), 43 kDa, and 68 kDa, over wild-type mice. Compared to sham-infected ApoE-/- mouse blots, P. gingivalis-infected brain tissue blots demonstrated the greatest detectable protein carbonyl content overall, with numerous prominent bands at 25 kDa (p = 0.001) and 43 kDa (p = 0.0001) and an exclusive band to this group between 30-43 kDa* (p = 0.0001). In addition, marked immunostaining was detected exclusively in the microvasculature in P. gingivalis-infected hippocampal tissue sections, compared to sham-infected, wild-type, and TNF-alpha transgenic mice. This study revealed that the hippocampal microvascular structure of P. gingivalis-infected ApoE-/- mice possesses elevated oxidative stress levels, resulting in the associated tight junction proteins being susceptible to increased oxidative/proteolytic degradation, leading to a loss of functional integrity. PMID- 28800333 TI - Pain Assessment in Dementia: Evaluation of a Point-of-Care Technological Solution. AB - Pain is common among people with moderate to severe dementia, but inability of patients to self-report means it often goes undetected and untreated. We developed the electronic Pain Assessment Tool (ePAT) to address this issue. A point-of-care App, it utilizes facial recognition technology to detect facial micro-expressions indicative of pain. ePAT also records the presence of pain related behaviors under five additional domains (Voice, Movement, Behavior, Activity, and Body). In this observational study, we assessed the psychometric properties of ePAT compared to the Abbey Pain Scale (APS). Forty aged care residents (70% females) over the age of 60 years, with moderate to severe dementia and a history of pain-related condition(s) were recruited into the study. Three hundred and fifty-three paired pain assessments (either at rest or post-movement) were recorded and analyzed. The ePAT demonstrated excellent concurrent validity (r = 0.882, 95% CI: 0.857-0.903) and good discriminant validity. Inter-rater reliability score was good overall (weighted kappa= 0.74, 95% CI: 0.68-0.80) while internal consistency was excellent. ePAT has psychometric properties which make it suitable for use in non-communicative patients with dementia. ePAT also has the advantage of automated facial expression assessment which provides objective and reproducible evidence of the presence of pain. PMID- 28800334 TI - Baseline Predictors of Antipsychotic Treatment Continuation and Response at Week 8 in Patients with Alzheimer's Disease with Psychosis or Aggressive Symptoms: An Analysis of the CATIE-AD Study. AB - BACKGROUND/OBJECTIVE: The aim of the present study was to investigate predictors of atypical antipsychotic (AAP) treatment continuation and response by week 8 in patients with Alzheimer's disease (AD) who have psychotic/aggressive symptoms using the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) dataset. METHODS: Clinical data was utilized from 421 AD outpatients with psychotic/aggressive symptoms who needed interventional treatment. Logistic regression analyses were performed to examine which baseline sociodemographic and clinical characteristics contributed to treatment 'continuation' and 'response', the latter of which was evaluated by the Clinical Global Impression of Change (CGI-C), Neuropsychiatric Inventory (NPI), and Brief Psychiatric Scale (BPRS). RESULTS: The treatment continuation rate was 48.7%, and CGI-C, NPI, and BPRS response rate by the last observation carried forward method were 42.7%, 48.6%, and 37.5%, respectively. No significant predictor was identified for treatment continuation in the Caucasian patients (n = 331), while better treatment response was predicted by a lower Mini-Mental State Examination score, treatment with risperidone (versus olanzapine and quetiapine), history of diabetes mellitus, healthier physical status, and more severe initial psychotic symptoms. CONCLUSIONS: Comparatively high intolerability from AAPs in the short term was confirmed. We found that baseline clinical predictors to treatment response in Caucasian AD patients with psychotic/aggressive symptoms include treatment with risperidone (versus quetiapine and olanzapine), diabetes mellitus, global physical status, cognitive impairment, and psychotic symptoms. Going forward, these findings may help to determine treatment strategies or care plans. PMID- 28800336 TI - Development of a New Self-Reporting Instrument Measuring Benefits and Side Effects of Corticosteroids in Duchenne Muscular Dystrophy: Report from a Pilot Study. AB - BACKGROUND: There is no cure for Duchenne Muscular Dystrophy (DMD); treatment is symptomatic and corticosteroids slow the progression. Side effects of corticosteroids - especially the physical effects - have been described, however patients' and caregivers perception on chronic corticosteroid treatment and their side effects is less well known, in particular with regards to cognition, behaviour, and emotional functioning. OBJECTIVE: The primary aim of this pilot study was to (i) construct a self-report questionnaire to assess the perceived benefits and side effects of corticosteroids for patients with DMD and their parents. Furthermore we aimed to (ii) investigate the psychometric qualities of this questionnaire, (iii) whether there was a difference between parents' and patient's perceptions, and finally (iv) to what extent reported side effects may alter over time. METHODS: A 23-item questionnaire (SIDECORT: side effect of corticosteroids) was constructed to assess the perception of these benefits and side effects in a systematic manner. RESULTS: In total, 86 patients (aged 5 - 28 years) and 125 of their parents completed the questionnaire. Internal consistency was good. Using factor analyses on the side effect items as reported by parents, two underlying factors were found, with the first factor describing cognitive, behavioural and emotional functioning, and the second factor describing physical functioning. The potential benefits of corticosteroids were highly rated among both parents and patients, although parents rated the importance of the benefits higher than their sons (p = 0.002). Similarly, parents rated the severity of the side effects generally higher than their sons (p = 0.011), especially with regards to the physical side effects (p = 0.014). Based on the parent's perception, the neurodevelopmental side effects generally appeared to decline the longer corticosteroids were used. CONCLUSIONS: To our knowledge, this is the first explicit study on perceived cognitive-, behavioural-, and emotional side effects and the allocation of benefits to corticosteroids in DMD. On the basis of our research we suggest a short form questionnaire, which proves to be reliable and valid for research- and clinical practice. This questionnaire could provide useful insights for the care of boys and men with DMD. PMID- 28800337 TI - The New Zealand Neuromuscular Disease Patient Registry; Five Years and a Thousand Patients. AB - The New Zealand Neuromuscular Disease Patient Registry has been recruiting for five years. Its primary aim is to enable people with neuromuscular disease to participate in research including clinical trials. It has contributed data to large anonymised cohort studies and many feasibility studies, and has provided practical information and advice to researchers wanting to work with people with neuromuscular conditions. 1019 people have enrolled since the Registry's launch in August 2011 with over 70 different diagnoses. Of these; 8 patients have been involved in clinical trials, 134 in other disease-specific research and 757 have contributed anonymised data to cohort studies. As a result the Registry is now effectively facilitating almost all neuromuscular research currently taking place in New Zealand. PMID- 28800339 TI - Perceptual learning improves contrast sensitivity, visual acuity, and foveal crowding in amblyopia. AB - BACKGROUND: Amblyopic observers present abnormal spatial interactions between a low-contrast sinusoidal target and high-contrast collinear flankers. It has been demonstrated that perceptual learning (PL) can modulate these low-level lateral interactions, resulting in improved visual acuity and contrast sensitivity. OBJECTIVE: We measured the extent and duration of generalization effects to various spatial tasks (i.e., visual acuity, Vernier acuity, and foveal crowding) through PL on the target's contrast detection. METHODS: Amblyopic observers were trained on a contrast-detection task for a central target (i.e., a Gabor patch) flanked above and below by two high-contrast Gabor patches. The pre- and post learning tasks included lateral interactions at different target-to-flankers separations (i.e., 2, 3, 4, 8lambda) and included a range of spatial frequencies and stimulus durations as well as visual acuity, Vernier acuity, contrast sensitivity function, and foveal crowding. RESULTS: The results showed that perceptual training reduced the target's contrast-detection thresholds more for the longest target-to-flanker separation (i.e., 8lambda). We also found generalization of PL to different stimuli and tasks: contrast sensitivity for both trained and untrained spatial frequencies, visual acuity for Sloan letters, and foveal crowding, and partially for Vernier acuity. Follow-ups after 5-7 months showed not only complete maintenance of PL effects on visual acuity and contrast sensitivity function but also further improvement in these tasks. CONCLUSION: These results suggest that PL improves facilitatory lateral interactions in amblyopic observers, which usually extend over larger separations than in typical foveal vision. The improvement in these basic visual spatial operations leads to a more efficient capability of performing spatial tasks involving high levels of visual processing, possibly due to the refinement of bottom-up and top-down networks of visual areas. PMID- 28800338 TI - A Guideline for Parkinson's Disease Nurse Specialists, with Recommendations for Clinical Practice. AB - BACKGROUND: Parkinson's Disease Nurse Specialists (PDNS) play an important role in the care for patients with Parkinson's disease (PD) and their caregivers. Until now, there were no nursing guidelines in PD, and interventions were based solely on daily clinical practice because there is no evidence to support the merits of nursing interventions. Consequently, there is little uniformity in current care delivery. OBJECTIVE: Developing a guideline for PDNS. METHODS: We developed a guideline based on a questionnaire among PDNS and a literature review, supplemented with expert opinion plus the input of patients and caregivers. The questionnaire was filled in by 97 PDNS and 51 generic nurses with knowledge of PD to identify barriers in PD nursing care. Subsequently, we did a systematic literature search and transformed these sources of information into practice recommendations, which were developed according to international standards for guideline development. RESULTS: Based on the results of the questionnaire we identified seven specific core areas: defining the role of PDNS in terms of caseload, education, competences and care coordination; medication adherence; provision of information and education; coping; caregiver support; urogenital function and orthostatic hypotension. The systematic literature search identified 186 studies, of which 33 studies were finally analyzed. Furthermore, we developed practice recommendations based on good clinical practice for the following areas: self-care, mental functioning, mobility, nutrition, sexuality, work, sleep, palliative care and complementary (integrative) care. CONCLUSION: This guideline provide ground to harmonize care delivery by PDNS in clinical practice, and offer a foundation for future research. PMID- 28800340 TI - Reducing the rate of misdiagnosis in patients with chronic disorders of consciousness: Is there a place for audiovisual stimulation? AB - BACKGROUND: The patients with chronic Disorders of Consciousness (DoC) mostly present with extremely challenging differential diagnosis. The advanced analysis of electroencephalographic (EEG) signals induced by brain stimulation paradigms may provide an appropriate approach to differentiate patients with DoC, besides the clinical assessment. OBJECTIVE: This study was performed with an objective of identifying residual brain network perturbations following an innovative, non invasive audiovisual stimulation protocol, which could be related to behavioral responsiveness in patients with DoC. METHODS: The study comprised of ten healthy controls (HC), seven patients with Minimally Conscious State (MCS), and nine patients with Unresponsive Wakefulness Syndrome (UWS). Both synchronous as well as asynchronous transorbital and transauricolar alternating current were employed as stimuli and their effects were measured in terms of functional and effective connectivity. RESULTS: A more noticeable deterioration of long range connectivity patterns were found in patients with UWS than in those with MCS, with an exception of two patients with UWS, who showed connectivity values similar to those of MCS patients. CONCLUSION: The audiovisual stimulation paradigm used in the present study may be employed as a supportive bedside tool for improving the differential diagnosis in patients with DoC. PMID- 28800335 TI - An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge? AB - With increasing survival of patients infected with human immunodeficiency virus type 1 (HIV-1), the manifestation of heterogeneous neurological complications is also increasing alarmingly in these patients. Currently, more than 30% of about 40 million HIV-1 infected people worldwide develop central nervous system (CNS) associated dysfunction, including dementia, sensory, and motor neuropathy. Furthermore, the highly effective antiretroviral therapy has been shown to increase the prevalence of mild cognitive functions while reducing other HIV-1 associated neurological complications. On the contrary, the presence of neurological disorder frequently affects the outcome of conventional HIV-1 therapy. Although, both the children and adults suffer from the post-HIV treatment-associated cognitive impairment, adults, especially depending on the age of disease onset, are more prone to CNS dysfunction. Thus, addressing neurological complications in an HIV-1-infected patient is a delicate balance of several factors and requires characterization of the molecular signature of associated CNS disorders involving intricate cross-talk with HIV-1-derived neurotoxins and other cellular factors. In this review, we summarize some of the current data supporting both the direct and indirect mechanisms, including neuro inflammation and genome instability in association with aging, leading to CNS dysfunction after HIV-1 infection, and discuss the potential strategies addressing the treatment or prevention of HIV-1-mediated neurotoxicity. PMID- 28800341 TI - Robotic-assisted gait training combined with transcranial direct current stimulation in chronic stroke patients: A pilot double-blind, randomized controlled trial. AB - BACKGROUND: Although robotic-assisted gait training (RAGT) is becoming a standard method in stroke rehabilitation, its effect on chronic stroke patients is uncertain. OBJECTIVE: This study aimed to investigate whether anodal transcranial direct current stimulation (tDCS) enhances the effect of RAGT on functional ambulation in chronic stroke patients. METHODS: Chronic hemiplegic stroke patients with a Functional Ambulatory Category (FAC) score<=4 were randomly assigned to either the RAGT with anodal tDCS (Anodal) group the sham tDCS (Sham) group. The patients were provided with RAGT for 45 min after allocated tDCS on the leg motor cortex in the impaired hemisphere for 20 min every weekday for 2 weeks. The primary outcome measure was the FAC, and the secondary outcome measures included 10-m walking test, 6-min walking test, Berg Balance Scale, Fugl Meyer assessment of the lower extremity, Medical Research Council Scale, and motor-evoked potential (MEP) parameters. They were evaluated before treatment (T0), immediately after treatment (T1), and 4 weeks after the end of treatment (T2). RESULTS: Twenty-one patients were finally included. The percentage of participants who achieved improvement in the FAC score was greater in the Anodal group than in the Sham group, and the difference was significant at T2 (66.7% vs. 12.5%, p = 0.024). In secondary outcome measures, the Anodal group showed greater improvement in the 6-min walking test than the Sham group at T2 (56.49+/-38.87 vs. 23.59+/-17.00, p = 0.038). The changes in the MEP parameters were not significantly different between the two groups. CONCLUSION: This pilot study suggested that anodal tDCS on the leg motor cortex in the impaired hemisphere may facilitate the effect of RAGT on functional ambulation in chronic stroke patients. Larger clinical trials will be needed to confirm the effect of RAGT combined with tDCS in chronic stroke patients based on the present study. PMID- 28800342 TI - Use of melatonin versus valproic acid in prophylaxis of migraine patients: A double-blind randomized clinical trial. AB - BACKGROUND: Melatonin is known to be effective in curing migraine. OBJECTIVE: This study aimed to investigate the therapeutic effect of melatonin versus sodium valproate in the prophylaxis of chronic migraine. METHODS: This randomized, double-blind, placebo-controlled clinical trial included patients with chronic migraine who were divided into three equal sized groups, and baseline therapy with nortriptyline (10-25 mg) and propranolol (20-40 mg) was used. Patients in groups A, B, and C were adjunctively treated daily with 3 mg melatonin, 200 mg sodium valproate, and a placebo, respectively. The patients underwent treatment for 2 months and follow-up was done at baseline (baseline), first (I) and second month (II). Attack frequency (AF), attack duration, attack severity, Migraine Disability Assessment (MIDAS) score (within 3 months in two steps), analgesic intake, and drug side effects between the groups and during follow-up were compared. RESULTS: The mean of monthly AF (melatonin: baseline: 4.2, I: 3.1, II: 2.5, p = 0.018; valproate: baseline: 4.3, I: 3.1, II: 2.3, p = 0.001; placebo: baseline: 4.1, I: 3.8, II: 3.8 p = 0.211), attack duration (hr) (melatonin: baseline: 19.8, I: 10.1, II: 8.7, p < 0.001; valproate: baseline: 19.5, I: 10.2, II: 8.8, p < 0.001; placebo: baseline: 19.6, I: 15.4, II: 14.1, p = 0.271), attack severity (melatonin: baseline: 7.3, I: 5.4, II: 3.5, p < 0.001; valproate: baseline: 7.4, I: 5.3, II: 3.4, p = 0.000; placebo: baseline: 7.3, I: 6.4, II: 6, p = 0.321), and MIDAS score (melatonin: baseline: 15.2, II: 8.9, p = 0.005; valproate: baseline: 16.1, II: 8.3, p = 0.001; placebo: baseline: 16, II: 12.1, p = 0.44), were significantly reduced in the melatonin and sodium valproate groups, but not in the placebo groups. Adverse events were reported in 11 patients (10.47%): 2 (5.71%) during melatonin treatment, 8 (22.85%) during valproate, and 1 (2.85%) during placebo. CONCLUSION: The adjuvant treatment with melatonin was found to be superior to the placebo and had the same clinical efficacy as sodium valproate, but with higher tolerability. Melatonin may prove to be an efficient substitute for sodium valproate, as a chronic migraine prophylaxis. PMID- 28800343 TI - Microsaccade dysfunction and adaptation in hemianopia after stroke. AB - BACKGROUND: Besides the reduction of visual field size, hemianopic patients may also experience other poorly understood symptoms such as blurred vision, diplopia, or reduced visual acuity, which may be related to microsaccade function. OBJECTIVE: To determine (i) if microsaccades are altered in hemianopia; (ii) how altered microsaccade features correlate with visual performances; and (iii) how their direction relates to visual field defect topography. METHODS: In this case-control study, microsaccades of hemianopic stroke patients (n = 14) were assessed with high-resolution eye-tracking technique, compared with those of healthy controls (n = 14), and correlated with visual performances, visual field defect parameters and lesion age. RESULTS: Patients' microsaccades had (i) larger amplitude (P = 0.027), (ii) longer duration (P = 0.042), and (iii) impaired binocular microsaccade conjugacy (horizontal: P = 0.002; vertical: P = 0.035). Older lesions were associated with poorer binocular conjugacy (horizontal: r(14) = 0.67, P = 0.009; vertical: r(14) = 0.75, P = 0.002) and larger microsaccade amplitudes (r(14) = 0.55, P = 0.043). (iv) Half of the patients had a microsaccade bias towards the seeing field (monocular: P = 0.002; binocular: P < 0.001) which was associated with faster reactions to super-threshold visual stimuli in areas of residual vision (P = 0.042). Finally, (v) patients with more binocular microsaccades (r(14) = 0.59, P = 0.027) and lower microsaccade velocity (r(14) = -0.66, P = 0.011) had better visual acuity. CONCLUSIONS: Hemianopia leads not only to the loss of visual field but also to microsaccade enlargement and impaired binocular conjugacy, suggesting malfunctioning microsaccade control circuits which worsen over time. But a microsaccade bias towards the seeing field, which suggests greater allocation of attention, accelerates stimulus detection. Microsaccades may play a role to compensate for vision impairment and provide a basis for vision restoration and plasticity, which deserves further exploration. PMID- 28800344 TI - Automatic computer aided analysis algorithms and system for adrenal tumors on CT images. AB - BACKGROUND: The adrenal tumor will disturb the secreting function of adrenocortical cells, leading to many diseases. Different kinds of adrenal tumors require different therapeutic schedules. OBJECTIVE: In the practical diagnosis, it highly relies on the doctor's experience to judge the tumor type by reading the hundreds of CT images. METHODS: This paper proposed an automatic computer aided analysis method for adrenal tumors detection and classification. It consisted of the automatic segmentation algorithms, the feature extraction and the classification algorithms. These algorithms were then integrated into a system and conducted on the graphic interface by using MATLAB Graphic user interface (GUI). RESULTS: The accuracy of the automatic computer aided segmentation and classification reached 90% on 436 CT images. CONCLUSION: The experiments proved the stability and reliability of this automatic computer aided analytic system. PMID- 28800345 TI - Development of a device to prevent the late consequence of non-treated/lately diagnosed glaucoma. AB - People residing in rural and remote areas (worldwide) have substantially worse outcome in early detection and diagnosis of glaucoma than those living in metropolitan areas. This gap can be reduced by improved glaucoma diagnosis activities in primary care, but there is little empirical evidence regarding use of tonometry in rural settings, or the expertise associated with quality of eye care. This article describes a feasibility study of a novel through-eyelid tonometer based on the use of an instrumented form of indentation and applanation tonometry. PMID- 28800346 TI - How should a virtual agent present psychoeducation? Influence of verbal and textual presentation on adherence. AB - BACKGROUND AND OBJECTIVE: With the rise of autonomous e-mental health applications, virtual agents can play a major role in improving trustworthiness, therapy outcome and adherence. In these applications, it is important that patients adhere in the sense that they perform the tasks, but also that they adhere to the specific recommendations on how to do them well. One important construct in improving adherence is psychoeducation, information on the why and how of therapeutic interventions. In an e-mental health context, this can be delivered in two different ways: verbally by a (virtual) embodied conversational agent or just via text on the screen. The aim of this research is to study which presentation mode is preferable for improving adherence. METHODS: This study takes the approach of evaluating a specific part of a therapy, namely psychoeducation. This was done in a non-clinical sample, to first test the general constructs of the human-computer interaction. We performed an experimental study on the effect of presentation mode of psychoeducation on adherence. In this study, we took into account the moderating effects of attitude towards the virtual agent and recollection of the information. Within the paradigm of expressive writing, we asked participants (n= 46) to pick one of their worst memories to describe in a digital diary after receiving verbal or textual psychoeducation. RESULTS AND CONCLUSION: We found that both the attitude towards the virtual agent and how well the psychoeducation was recollected were positively related to adherence in the form of task execution. Moreover, after controlling for the attitude to the agent and recollection, presentation of psychoeducation via text resulted in higher adherence than verbal presentation by the virtual agent did. PMID- 28800347 TI - Neuro-fuzzy method for predicting the viability of stem cells treated at different time-concentration conditions. AB - Dental stem cells isolated for human dental pulp are an excellent source for regenerative medicine and dentistry. Simulation of clinical scenario is one of the crucial challenges for evaluation of the efficacy of DPSCs in various regenerative therapies. In this study we evaluated the viability of DPSCs after treatment with artificial bacterial lipopolysaccharides (LPS) as the main component responsible for inducing inflammatory response in majority of the inflammatory conditions in clinical scenario. Although a number of studies have previously treated stem cells with LPS from bacteria, however the accuracy level of the outcome was not established. Here we have analyzed the outcome using adaptive neuro-fuzzy inferences system (ANFIS) to predict the viability of human DPSCs after treatment with bacterial LPS. PMID- 28800348 TI - Disability management and organizational culture in Australia and Canada. AB - BACKGROUND: Organizational culture has received increasing attention in terms of its influence on workplace health and productivity, yet there has been little research on its relationship with employer-based disability programs. OBJECTIVE: This study explored the relationship between disability management and organizational culture in Australian and Canadian organizations. METHODS: Thematic analysis was conducted on data from semi-structured interviews with 16 employees, including injured workers, human resource managers and disability managers in two Australian and two Canadian large organizations. RESULTS: Seven themes were identified: 1. Consistency between espoused beliefs and artifacts in organization; 2. Genuineness of interest in well-being of injured worker; 3. Level of ongoing support of worker following injury; 4. Communication with injured workers; 5. Level of support from supervisors and co-workers; 6. Promptness in claims processing and covering medical costs and; 7. Focus on wellness and injury prevention. It was found that organizational culture may impact the delivery and perceived value of employer-based disability management programs. CONCLUSIONS: Given the potential relationship between organizational culture and disability management, employers should facilitate a positive workplace culture by ensuring consistency among underlying values, espoused values and actual treatment of employees, including injured workers. PMID- 28800349 TI - Musculoskeletal disorders, personality traits, psychological distress, and accident proneness of Chinese coal miners. AB - BACKGROUND: Human factors comprise one of the important reasons leading to the casualty accidents in coal mines. OBJECTIVE: The aim of this study was to analyze the relationships among musculoskeletal disorders (MSDs), personality traits, psychological distress, and accident proneness of coal miners. PARTICIPANTS: There were 1500 Chinese coal miners surveyed in this study. Among these miners, 992 valid samples were obtained. METHODS: The study surveyed the MSDs, personality traits, psychological distress, and accident proneness of coal miners with MSDs Likert scale, Eysenck personality questionnaire, Symptom Checklist-90 (SCL-90) scale, and accident proneness questionnaire, respectively. RESULTS: The highest MSDs level was found in the waist. The increasing working age of the miners was connected with increased MSDs and psychological distress. Significant differences in MSDs and psychological distress of miners from different types of work were observed. Coal miners with higher MSDs had higher accident proneness. Coal miners with higher neuroticism dimension of Eysenck personality and more serious psychological distress had higher accident proneness. Phobic anxiety, paranoid ideation and psychoticism dimension of psychological distress were the three most important indicators that had significant positive relationships with accident proneness. CONCLUSION: The MSDs, neuroticism dimension, and psychological distress of the coal mine workers are important to work safety and require serious attention. Some implications concerning coal mine safety management in China were provided. PMID- 28800352 TI - Workers' medication as occupational risk at construction site with formworks. AB - BACKGROUND: Accidents in the construction sector are a cause for concern. The influence of many different factors in construction accidents have been studied (age, company size, length of service, deviation, drugs or alcohol consumption, etc.) but the influence of medicinal substances in specific construction activities has not been evaluated until now. OBJECTIVE: The aim of the research presented here is to identify the effect of different medicinal substances on the occupational risk levels of construction activities with formworks. METHODS: An expert panel was selected in order to quantify the individual risk of each medication for each individual construction activity. RESULTS: Results showed that narcotics, antipsychotics, and hypnotics had the highest risk values, and the use of cranes and cutting materials were considered the most dangerous activities for a medicated worker. CONCLUSIONS: Data obtained in this research can help reduce the negative effects of the substances studied on the occupational safety of construction workers. A better knowledge of the risk levels according to the current capabilities of workers under the effects of medication is a powerful tool in planning safer construction activities. PMID- 28800353 TI - How do users design? The case of sugar cane harvester machines. AB - BACKGROUND: Design in use and inventiveness are key concepts in ergonomics. It is well-known that users design but is not explored in the literature how they manage to do that. OBJECTIVE: This paper aims to contribute to the discussion of how users actually design, by showing a research conducted in sugar cane harvesting in Brazil and in Australia. METHODS: Through the methodology of the Ergonomic Work Analysis (EWA), the design modifications made by the harvesting teams were identified as well as their elaboration process. RESULTS: Three categories of modifications in machines' design were identified: structural, functional and operational and they were more numerous in Brazilian situations. It is proposed that two theories underlying the theme are intertwined: the instrument-mediated activity approach and the design as bricolage. CONCLUSIONS: It is argued that users design through the articulation of: a) the operators' activity, b) the mechanical technicians' inventory to practice bricolage as a way of designing and c) the work organisation and the existence of social spaces of interaction between these two subjects. PMID- 28800354 TI - Explaining attrition and decreased effectiveness of experienced teachers: A research synthesis. AB - BACKGROUND: Teacher retention and development of the full potential of teachers is important at a national level in order to be able to belong to the top world economies. A number of studies suggests that part of the group of experienced teachers with more than 20 years of experience perform didactically at a lower level than would be expected and are at a greater risk for attrition. OBJECTIVE: The aim of the present study is to find explanations for this by making use of the Job Demands Resources Model. METHODS: Specific demands of the teaching profession, interpersonal demands related to the developmental stage of experienced teachers, job resources and personal resources in relation to health and motivation are explored by reviewing a vast amount of literature. RESULTS: The proposed conceptual model is an extension of the Job Demands Resources Model with the inclusion of personal demands related to adulthood and personal resources. CONCLUSIONS: The resulting model provides us with clues on how attrition and decreased performance could be counteracted. PMID- 28800355 TI - Work-related stress and role of personality in a sample of Italian bus drivers. AB - BACKGROUND: Several studies have shown that professional drivers are at risk of developing work-related stress. Stress may be responsible for a variety of adverse effects and may also be associated with an increased number of accidents. OBJECTIVE: Perform an integrated, objective and subjective evaluation of work related stress in bus drivers, that also considered the role of personality traits. METHODS: Salivary alpha-amylase and cortisol were measured in 42 bus drivers. Subjective stress evaluation was performed with the Perceived Stress Scale (PSS-10) and Driver Stress Inventory (DSI). To evaluate personality traits, we administered the Eysenck Personality Questionnaire-Revised (EPQ-R) and the Impulsivity Inventory (IVE). RESULTS: Salivary biomarkers showed no associations with PSS-10 and personality traits. Cortisol levels were positively correlated with fatigue (r = 0.44) at the middle of the work-shift and with aggression (r = 0.51) at the end of a day off. At the end of the work-shift, cortisol levels were negatively correlated with hazard monitoring (r = -0.37) and salivary alpha amylase was positively correlated with thrill-seeking (r = 0.36). Neuroticism (beta= 0.44) and impulsiveness (beta= 0.38) were predictors of perceived stress by multiple regression. CONCLUSIONS: An integrated method, considering both objective and subjective indicators, seems adequate to evaluate work-related stress in professional drivers. Personality traits are relevant in determining perception of stress. PMID- 28800356 TI - Factors Associated with Benign Paroxysmal Positional Vertigo: A Chinese Case Control Study. AB - BACKGROUND Benign paroxysmal positional vertigo (BPPV) is one of the most common and most successfully treated vestibular disorders. However, there is a lack of predictive factors for BPPV in clinical practice. We aimed to explore several possible predictive factors for BPPV in the Chinese population. MATERIAL AND METHODS We enrolled 240 patients with BPPV from Beijing Chaoyang Hospital between July 2013 and July 2016. Biochemical and hematological markers were obtained along with the history of cardiovascular and cerebrovascular diseases. RESULTS Serum uric acid (SUA) [279.0+/-84.7 vs. 331.0+/-82.7], hemoglobin A1C (HbA1c) [5.75+/-1.17 vs. 6.61+/-1.00], albumin [38.1+/-3.71 vs. 40.9+/-4.1], and creatinine [68.4+/-19.3 vs. 81.5+/-24.1] were significantly lower in patients with BPPV compared with controls (P<0.05). Multiple logistic regression analysis showed that lower levels of HbA1c and albumin were independently associated with BPPV (P<0.05), with odds ratio (OR) 0.680 (95% CI 0.551-0.839) and 0.338 (95% CI 0.190-0.603), respectively. However, the level of SUA was not independently related with BPPV [OR=0.999 (95% CI 0.991-1.006), P=0.713]. There were no significant differences between the parameters of systolic blood pressure, diastolic blood pressure, blood routine examination, lipid profiles, homocysteine, pre-albumin, and blood urea nitrogen in patients with BPPV vs. controls (P>0.05). CONCLUSIONS Lower levels of HbA1c and albumin were independently associated with BPPV. Although the level of SUA was lower in BPPV patients, SUA was not an independent risk factor for BPPV. PMID- 28800357 TI - Identification of differentially expressed genes through RNA sequencing in goats (Capra hircus) at different postnatal stages. AB - Intramuscular fat (IMF) content and fatty acid composition of longissimus dorsi muscle (LM) change with growth, which partially determines the flavor and nutritional value of goat (Capra hircus) meat. However, unlike cattle, little information is available on the transcriptome-wide changes during different postnatal stages in small ruminants, especially goats. In this study, the sequencing reads of goat LM tissues collected from kid, youth, and adult period were mapped to the goat genome. Results showed that out of total 24 689 Unigenes, 20 435 Unigenes were annotated. Based on expected number of fragments per kilobase of transcript sequence per million base pairs sequenced (FPKM), 111 annotated differentially expressed genes (DEGs) were identified among different postnatal stages, which were subsequently assigned to 16 possible expression patterns by series-cluster analysis. Functional classification by Gene Ontology (GO) analysis was used for selecting the genes showing highest expression related to lipid metabolism. Finally, we identified the node genes for lipid metabolism regulation using co-expression analysis. In conclusion, these data may uncover candidate genes having functional roles in regulation of goat muscle development and lipid metabolism during the various growth stages in goats. PMID- 28800358 TI - Global change in the trophic functioning of marine food webs. AB - The development of fisheries in the oceans, and other human drivers such as climate warming, have led to changes in species abundance, assemblages, trophic interactions, and ultimately in the functioning of marine food webs. Here, using a trophodynamic approach and global databases of catches and life history traits of marine species, we tested the hypothesis that anthropogenic ecological impacts may have led to changes in the global parameters defining the transfers of biomass within the food web. First, we developed two indicators to assess such changes: the Time Cumulated Indicator (TCI) measuring the residence time of biomass within the food web, and the Efficiency Cumulated Indicator (ECI) quantifying the fraction of secondary production reaching the top of the trophic chain. Then, we assessed, at the large marine ecosystem scale, the worldwide change of these two indicators over the 1950-2010 time-periods. Global trends were identified and cluster analyses were used to characterize the variability of trends between ecosystems. Results showed that the most common pattern over the study period is a global decrease in TCI, while the ECI indicator tends to increase. Thus, changes in species assemblages would induce faster and apparently more efficient biomass transfers in marine food webs. Results also suggested that the main driver of change over that period had been the large increase in fishing pressure. The largest changes occurred in ecosystems where 'fishing down the marine food web' are most intensive. PMID- 28800360 TI - Prerequisites for a dry powder inhaler for children with cystic fibrosis. AB - Correct inhalation technique is essential for effective use of dry powder inhalers (DPIs), as their effectiveness largely depends on the patient's inhalation manoeuvre. Children are an especially challenging target population for DPI development due to the large variability in understanding and inspiratory capacities. We previously performed a study in which we determined the prerequisites for a paediatric DPI in a mostly healthy paediatric population, for which we used an empty test inhaler with variable internal airflow resistance and mouthpiece. In the current study we investigated what specifications are required for a DPI for children with cystic fibrosis (CF), for which we expanded on our previous findings. We recorded flow profiles of 35 children with CF (aged 4.7 14.7 years) at three airflow resistances (0.031-0.045 kPa0.5.min.L-1) from which various inspiratory parameters were computed. Obstructions in the mouth during inhalation were recorded with a sinuscope. All children were able to perform a correct inhalation manoeuvre, although video analysis showed that children did not place the inhaler correctly in the mouth in 17% of the cases. No effect was found of medium to high airflow resistance on total inhaled volume, which implies that the whole resistance range tested is suitable for children with CF aged 4-14 years. No effect could be established of either mouthpiece design or airflow resistance on the occurrence of obstructions in the mouth cavity. This study confirms our previous conclusion that the development of DPIs specifically for children is highly desired. Such a paediatric DPI should function well at 0.5 L inhaled volume and a peak inspiratory flow rate of 20 to 30 L/min, depending on the internal airflow resistance. This resistance can be increased up to 0.045 kPa0.5.min.L-1 (medium-high) to reduce oropharyngeal deposition. A higher resistance may be less favourable due to its compromising effect on PIF and thereby on the energy available for powder dispersion. PMID- 28800359 TI - The selective PI3Kalpha inhibitor BYL719 as a novel therapeutic option for neuroendocrine tumors: Results from multiple cell line models. AB - BACKGROUND/AIMS: The therapeutic options for metastatic neuroendocrine tumors (NETs) are limited. As PI3K signaling is often activated in NETs, we have assessed the effects of selective PI3Kp110alpha inhibition by the novel agent BYL719 on cell viability, colony formation, apoptosis, cell cycle, signaling pathways, differentiation and secretion in pancreatic (BON-1, QGP-1) and pulmonary (H727) NET cell lines. METHODS: Cell viability was investigated by WST 1 assay, colony formation by clonogenic assay, apoptosis by caspase3/7 assay, the cell cycle by FACS, cell signaling by Western blot analysis, expression of chromogranin A and somatostatin receptors 1/2/5 by RT-qPCR, and chromogranin A secretion by ELISA. RESULTS: BYL719 dose-dependently decreased cell viability and colony formation with the highest sensitivity in BON-1, followed by H727, and lowest sensitivity in QGP-1 cells. BYL719 induced apoptosis and G0/G1 cell cycle arrest associated with increased p27 expression. Western blots showed inhibition of PI3K downstream targets to a varying degree in the different cell lines, but IGF1R activation. The most sensitive BON-1 cells displayed a significant, and H727 cells a non-significant, GSK3 inhibition after BYL719 treatment, but these effects do not appear to be mediated through the IGF1R. In contrast, the most resistant QGP-1 cells showed no GSK3 inhibition, but a modest activation, which would partially counteract the other anti-proliferative effects. Accordingly, BYL719 enhanced neuroendocrine differentiation with the strongest effect in BON 1, followed by H727 cells indicated by induction of chromogranin A and somatostatin receptor 1/2 mRNA-synthesis, but not in QGP-1 cells. In BON-1 and QGP-1 cells, the BYL719/everolimus combination was synergistic through simultaneous AKT/mTORC1 inhibition, and significantly increased somatostatin receptor 2 transcription compared to each drug separately. CONCLUSION: Our results suggest that the agent BYL719 could be a novel therapeutic approach to the treatment of NETs that may sensitize NET cells to somatostatin analogs, and that if there is resistance to its action this may be overcome by combination with everolimus. PMID- 28800361 TI - Identification of a common Ara h 3 epitope recognized by both the capture and the detection monoclonal antibodies in an ELISA detection kit. AB - Allergy to peanuts has become a common and severe problem, especially in westernized countries. In this study, we evaluated the target and epitope specificity of the capture and detection mouse monoclonal antibodies (mAbs) used in a commercial peanut allergen detection platform. We first identified the target of these antibodies as Ara h 3 and then used an overlapping peptide array of Ara h 3 to determine the antibody-binding epitopes. Further amino acids critical for the binding via alanine substitutions at individual amino acid residues within the epitope were mapped. Finally, inhibition ELISA and inhibition immunoblotting using a recombinant Ara h 3 protein were performed to confirm these results. Surprisingly, the capture and detection mAbs showed identical binding characteristics and were presumed to represent two isolates of the same clone, a notion supported by both isoelectric focusing electrophoresis and Liquid chromatography-mass spectrometry experiments. The simultaneous binding of a pair of identical mAbs to an individual allergen such as Ara h3 is attributed to the multivalency of the analyte and has implications for developing diagnostic assays for additional multimeric allergens. PMID- 28800363 TI - The viability of lytic bacteriophage PhiD5 in potato-associated environments and its effect on Dickeya solani in potato (Solanum tuberosum L.) plants. AB - Dickeya solani is one of the most important pectinolytic phytopathogens responsible for high losses in potato, especially in seed potato production in Europe. Lytic bacteriophages can affect the structure of the host population and may influence spread, survival and virulence of the pathogen and in consequence, infection of the plant. In this study, we aimed to acquire information on the viability of the broad host lytic bacteriophage PhiD5 on potato, as well as to apprehend the specific effect of this bacteriophage on its host D. solani type strain in different settings, as a preliminary step to target co-adaptation of phages and host bacteria in plant environment. Viability of the PhiD5 phage in tuber extract, on tuber surface, in potting compost, in rainwater and on the leaf surface, as well as the effect of copper sulfate, were examined under laboratory conditions. Also, the interaction of PhiD5 with the target host D. solani in vitro and in compost-grown potato plants was evaluated. PhiD5 remained infectious in potato tuber extract and rain water for up to 72 h but was inactivated in solutions containing 50 mM of copper. The phage population was stable for up to 28 days on potato tuber surface and in potting compost. In both, tissue culture and compost-grown potato plants, PhiD5 reduced infection by D. solani by more than 50%. The implications of these findings are discussed. PMID- 28800362 TI - Nucleotide transmitters ATP and ADP mediate intercellular calcium wave communication via P2Y12/13 receptors among BV-2 microglia. AB - Nerve injury is accompanied by a liberation of diverse nucleotides, some of which act as 'find/eat-me' signals in mediating neuron-glial interplay. Intercellular Ca2+ wave (ICW) communication is the main approach by which glial cells interact and coordinate with each other to execute immune defense. However, the detailed mechanisms on how these nucleotides participate in ICW communication remain largely unclear. In the present work, we employed a mechanical stimulus to an individual BV-2 microglia to simulate localized injury. Remarkable ICW propagation was observed no matter whether calcium was in the environment or not. Apyrase (ATP/ADP-hydrolyzing enzyme), suramin (broad-spectrum P2 receptor antagonist), 2-APB (IP3 receptor blocker) and thapsigargin (endoplasmic reticulum calcium pump inhibitor) potently inhibited these ICWs, respectively, indicating the dependence of nucleotide signals and P2Y receptors. Then, we detected the involvement of five naturally occurring nucleotides (ATP, ADP, UTP, UDP and UDP glucose) by desensitizing receptors. Results showed that desensitization with ATP and ADP could block ICW propagation in a dose-dependent manner, whereas other nucleotides had little effect. Meanwhile, the expression of P2Y receptors in BV-2 microglia was identified and their contributions were analyzed, from which we suggested P2Y12/13 receptors activation mostly contributed to ICWs. Besides, we estimated that extracellular ATP and ADP concentration sensed by BV-2 microglia was about 0.3 MUM during ICWs by analyzing calcium dynamic characteristics. Taken together, these results demonstrated that the nucleotides ATP and ADP were predominant signal transmitters in mechanical stimulation-induced ICW communication through acting on P2Y12/13 receptors in BV-2 microglia. PMID- 28800365 TI - The impact of the Orlando mass shooting on fear of victimization and gun purchasing intentions: Not what one might expect. AB - Mass public shootings are typically followed by a spike in gun sales as well as calls for stricter gun control laws. What remains unclear is whether the spike in gun sales is motivated by increased threat perceptions or by concerns about gun control, or whether the sales are mainly driven by non-owners purchasing guns or gun owners adding to their collection. Two surveys of gun owners and non-owners, conducted immediately before and after the Orlando shooting, allowed us to assess its impact on threat perceptions and on gun-purchasing intentions. Although there was a minor impact on threat perceptions of non-owners, neither group reported any increased gun-purchasing intentions or an increased need of a gun for protection and self-defense. We suggest that these responses are representative for the majority of Americans and, therefore, people who are influenced by mass shootings to buy guns are probably an atypical minority. PMID- 28800364 TI - Expression optimization of a cell membrane-penetrating human papillomavirus type 16 therapeutic vaccine candidate in Nicotiana benthamiana. AB - High-risk human papillomaviruses (hr-HPVs) cause cervical cancer, the fourth most common cancer in women worldwide. A HPV-16 candidate therapeutic vaccine, LALF32 51-E7, was developed by fusing a modified E7 protein to a bacterial cell penetrating peptide (LALF): this elicited both tumour protection and regression in pre-clinical immunization studies. In the current study, we investigated the potential for producing LALF32-51-E7 in a plant expression system by evaluating the effect of subcellular localization and usage of different expression vectors and gene silencing suppressors. The highest expression levels of LALF32-51-E7 were obtained by using a self-replicating plant expression vector and chloroplast targeting, which increased its accumulation by 27-fold compared to cytoplasmic localization. The production and extraction of LALF32-51-E7 was scaled-up and purification optimized by affinity chromatography. If further developed, this platform could potentially allow for the production of a more affordable therapeutic vaccine for HPV-16. This would be extremely relevant in the context of developing countries, where cervical cancer and other HPV-related malignancies are most prevalent, and where the population have limited or no access to preventative vaccines due to their typical high costs. PMID- 28800367 TI - A new method for mapping perceptual biases across visual space. AB - How we perceive the environment is not stable and seamless. Recent studies found that how a person qualitatively experiences even simple visual stimuli varies dramatically across different locations in the visual field. Here we use a method we developed recently that we call multiple alternatives perceptual search (MAPS) for efficiently mapping such perceptual biases across several locations. This procedure reliably quantifies the spatial pattern of perceptual biases and also of uncertainty and choice. We show that these measurements are strongly correlated with those from traditional psychophysical methods and that exogenous attention can skew biases without affecting overall task performance. Taken together, MAPS is an efficient method to measure how an individual's perceptual experience varies across space. PMID- 28800366 TI - Proceedings of the ISEV symposium on "HIV, NeuroAIDS, drug abuse & EVs". AB - Extracellular vesicles (EVs) are globular, membrane bound nanovesicles (30-100 nm range) that are shed both during normal cellular functioning and under pathological conditions by most cell types. In recent years, there has been significant interest in the study of these vesicles as conduits for the delivery of information between cells from both analogous and disparate tissues. Their ability to carry specialised cargo including signalling mediators, proteins, messenger RNA and miRNAs characterises these vesicles as primary facilitators of cell-to-cell communication and regulation. EVs have also been demonstrated to play important roles in the field of cancer biology and metastasis. However, significant knowledge gaps exist in the role these vesicles play in the context of HIV infection and drug abuse. To foster discussion in this area a satellite symposium on "HIV, NeuroAIDS, Drug Abuse & EVs", was held in conjunction with the annual meeting of the International Society for Extracellular Vesicles (ISEV) in Bethesda, in April 2015. Experts in HIV and drug abuse fields were invited to share their findings on the role of EVs in HIV-1 infection and drug addiction. Additional discussion included current areas of research in EV biology in HIV infection and drug abuse. PMID- 28800368 TI - Unpredictability does not hamper nonretinotopic motion perception. AB - The motion of parts of an object is usually perceived relative to the object, i.e., nonretinotopically, rather than in retinal coordinates. For example, we perceive a reflector to rotate on the wheel of a moving bicycle even though its trajectory is cycloidal on the retina. The rotation is perceived because the motion of the object (bicycle) is discounted from the motion of its parts (reflector). It seems that the visual system can easily compute the object motion and subtract it from the part motion. Bikes move usually rather predictably. Given the complexity of real-world motion computations, including many ill-posed problems such as the motion correspondence problem, predictability of an object's motion may be essential for nonretinotopic perception. Here, we used the Ternus Pikler display to investigate this question. Performance was not impaired when contrast polarity, shape, and motion trajectories changed unpredictably. Our findings suggest that predictability is not crucial for nonretinotopic motion processing. PMID- 28800369 TI - Feature singletons attract spatial attention independently of feature priming. AB - People perform better in visual search when the target feature repeats across trials (intertrial feature priming [IFP]). Here, we investigated whether repetition of a feature singleton's color modulates stimulus-driven shifts of spatial attention by presenting a probe stimulus immediately after each singleton display. The task alternated every two trials between a probe discrimination task and a singleton search task. We measured both stimulus-driven spatial attention (via the distance between the probe and singleton) and IFP (via repetition of the singleton's color). Color repetition facilitated search performance (IFP effect) when the set size was small. When the probe appeared at the singleton's location, performance was better than at the opposite location (stimulus-driven attention effect). The magnitude of this attention effect increased with the singleton's set size (which increases its saliency) but did not depend on whether the singleton's color repeated across trials, even when the previous singleton had been attended as a search target. Thus, our findings show that repetition of a salient singleton's color affects performance when the singleton is task relevant and voluntarily attended (as in search trials). However, color repetition does not affect performance when the singleton becomes irrelevant to the current task, even though the singleton does capture attention (as in probe trials). Therefore, color repetition per se does not make a singleton more salient for stimulus driven attention. Rather, we suggest that IFP requires voluntary selection of color singletons in each consecutive trial. PMID- 28800370 TI - The Effect of Dynamic Pitch on Speech Recognition in Temporally Modulated Noise. AB - Purpose: This study investigated the effect of dynamic pitch in target speech on older and younger listeners' speech recognition in temporally modulated noise. First, we examined whether the benefit from dynamic-pitch cues depends on the temporal modulation of noise. Second, we tested whether older listeners can benefit from dynamic-pitch cues for speech recognition in noise. Last, we explored the individual factors that predict the amount of dynamic-pitch benefit for speech recognition in noise. Method: Younger listeners with normal hearing and older listeners with varying levels of hearing sensitivity participated in the study, in which speech reception thresholds were measured with sentences in nonspeech noise. Results: The younger listeners benefited more from dynamic pitch for speech recognition in temporally modulated noise than unmodulated noise. Older listeners were able to benefit from the dynamic-pitch cues but received less benefit from noise modulation than the younger listeners. For those older listeners with hearing loss, the amount of hearing loss strongly predicted the dynamic-pitch benefit for speech recognition in noise. Conclusions: Dynamic-pitch cues aid speech recognition in noise, particularly when noise has temporal modulation. Hearing loss negatively affects the dynamic-pitch benefit to older listeners with significant hearing loss. PMID- 28800371 TI - Population Estimates, Health Care Characteristics, and Material Hardship Experiences of U.S. Children With Parent-Reported Speech-Language Difficulties: Evidence From Three Nationally Representative Surveys. AB - Purpose: To provide estimates for the prevalence of parent-reported speech language difficulties in U.S. children, and to describe the levels of health care access and material hardship in this population. Method: We tabulated descriptive and bivariate statistics using cross-sectional data from the 2007 and 2011/2012 iterations of the National Survey of Children's Health, the 2005/2006 and 2009/2010 iterations of the National Survey of Children with Special Health Care Needs, and the 2004 and 2008 panels of the Survey of Income and Program Participation. Results: Prevalence estimates ranged from 1.8% to 5.0%, with data from two of the three surveys preliminarily indicating increased prevalence in recent years. The largest health care challenge was in accessing care coordination, with 49%-56% of children with parent-reported speech-language difficulties lacking full access. Children with parent-reported speech-language difficulties were more likely than peers without any indications of speech language difficulties to live in households experiencing each measured material hardship and participating in each measured public benefit program (e.g., 20%-22% experiencing food insecurity, compared to 11%-14% of their peers without any indications of speech-language difficulties). Conclusions: We found mixed preliminary evidence to suggest that the prevalence of parent-reported speech language difficulties among children may be rising. These children face heightened levels of material hardship and barriers in accessing health care. PMID- 28800372 TI - Alveolar and Postalveolar Voiceless Fricative and Affricate Productions of Spanish-English Bilingual Children With Cochlear Implants. AB - Purpose: This study investigates the production of voiceless alveolar and postalveolar fricatives and affricates by bilingual and monolingual children with hearing loss who use cochlear implants (CIs) and their peers with normal hearing (NH). Method: Fifty-four children participated in our study, including 12 Spanish English bilingual CI users (M = 6;0 [years;months]), 12 monolingual English speaking children with CIs (M = 6;1), 20 bilingual children with NH (M = 6;5), and 10 monolingual English-speaking children with NH (M = 5;10). Picture elicitation targeting /s/, /t?/, and /?/ was administered. Repeated-measures analyses of variance comparing group means for frication duration, rise time, and centroid frequency were conducted for the effects of CI use and bilingualism. Results: All groups distinguished the target sounds in the 3 acoustic parameters examined. Regarding frication duration and rise time, the Spanish productions of bilingual children with CIs differed from their bilingual peers with NH. English frication duration patterns for bilingual versus monolingual CI users also differed. Centroid frequency was a stronger place cue for children with NH than for children with CIs. Conclusion: Patterns of fricative and affricate production display effects of bilingualism and diminished signal, yielding unique patterns for bilingual and monolingual CI users. PMID- 28800373 TI - Dysphagia and Speech-Language Pathology Involvement Following Chemical Ingestion Injury: A Review of 44 Cases Admitted to a Quaternary Australian Hospital (2008 2012). AB - Purpose: This study aimed to explore the clinical characteristics of an adult chemical ingestion population and examine the course of return to oral intake post injury and speech-language pathologist (SLP) involvement during the initial acute-care admission. Method: A retrospective chart review of adults admitted to a quaternary hospital for the treatment of an acute chemical ingestion injury between 2008 and 2012 was conducted. Results: Forty-four adults (23 men, 21 women) were identified as receiving treatment for ingestion injury, of whom 18 (40.91%) required altered oral intake. Of those requiring altered oral intake, 50% were referred to SLPs. Individuals requiring altered oral intake were significantly (p < .05) older, more likely to be men, and present with more severe injuries requiring longer ICU and hospital admissions following intentional chemical ingestions than those who were able to commence a normal oral diet without any alteration or nonoral supplementation. By discharge, 15.91% (n = 7) of the total cohort had not resumed normal oral intake. Conclusions: Return to oral intake post chemical ingestion injury can be protracted and complex. Referrals to SLPs were limited. These data may aid prognostic insight as well as provide (a) collateral information to assist discharge planning and follow-up and (b) background for evaluating the potential for SLP involvement. PMID- 28800375 TI - The Tragic Case of Charlie Gard. PMID- 28800374 TI - Charlie Gard and the Limits of Best Interests. PMID- 28800376 TI - Fetal Bovine Serum (FBS): Past - Present - Future. AB - The supplementation of culture medium with fetal bovine serum (FBS, also referred to as "fetal calf serum") is still common practice in cell culture applications. Due to a number of disadvantages in terms of quality and reproducibility of in vitro data, animal welfare concerns, and in light of recent cases of fraudulent marketing, the search for alternatives and the development of serum-free medium formulations has gained global attention. Here, we report on the 3rd Workshop on FBS, Serum Alternatives and Serum-free Media, where regulatory aspects, the serum dilemma, alternatives to FBS, case-studies of serum-free in vitro applications, and the establishment of serum-free databases were discussed. The whole process of obtaining blood from a living calf fetus to using the FBS produced from it for scientific purposes is de facto not yet legally regulated despite the existing EU Directive 2010/63/EU on the use of animals for scientific purposes. Together with the above-mentioned challenges, several strategies have been developed to reduce or replace FBS in cell culture media in terms of the 3Rs (Refinement, Reduction, Replacement). Most recently, releasates of activated human donor thrombocytes (human platelet lysates) have been shown to be one of the most promising serum alternatives when chemically-defined media are not yet an option. Additionally, new developments in cell-based assay techniques, advanced organ-on-chip and microphysiological systems are covered in this report. Chemically-defined serum free media are shown to be the ultimate goal for the majority of culture systems, and examples are discussed. PMID- 28800377 TI - Antidote to cannabinoid intoxication: the CB1 receptor inverse agonist, AM251, reverses hypothermic effects of the CB1 receptor agonist, CB-13, in mice. AB - BACKGROUND AND PURPOSE: Cannabis is a recreational drug leading to intoxication, following stimulation of cannabinoid CB1 receptors. However, more recently, herbs mixed with synthetic cannabinoids sometimes known as 'Spice' and 'Black Mamba' have been increasingly used, and their high CB1 receptor affinity has led not only to marked intoxication but also life-threatening complications and an increasing number of deaths. Although many studies have indicated that prophylactic treatment with CB1 receptor antagonists can block cannabimimetic effects in animals and humans, the aim of this study was to determine whether CB1 receptor antagonism could reverse physical cannabimimetic effects. EXPERIMENTAL APPROACH: Cannabimimetic effects, measured by the hypothermic response following sedation and hypomotility, were induced by the synthetic CB1 receptor agonist CB 13 (1-naphthalenyl[4-(pentyloxy)-1-naphthalenyl]methanone) in Biozzi Antibody High mice. The CB1 receptor antagonist/inverse agonist AM251 (N-(piperidin-1-yl) 5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) was administered 20 min after the injection of CB-13 and its effects on the cannabimimetic responses were assessed. KEY RESULTS: In this study, the CNS related cannabimimetic effects, as measured by the hypothermic effect, induced by the CB1 receptor agonist were therapeutically treated and were rapidly reversed by the CB1 receptor antagonist/inverse agonist. There was also a subjective reversal of visually evident sedation. CONCLUSIONS AND IMPLICATIONS: Cannabinoid receptor antagonists have been widely used and so may provide an acceptable single-dose antidote to cannabinoid intoxication. This use may save human life, where the life-threatening effects are mediated by cannabinoid receptors and not off-target influences of the synthetic cannabinoids or non-cannabinoids within the recreational drug mixture. PMID- 28800379 TI - Erratum to "A model of exposure to rotavirus from nondietary ingestion iterated by simulated intermittent contacts." By T.R. Julian, R.A. Canales, J.O. Leckie, and A.B. Boehm, in Risk Analysis, 29(5):617-622. PMID- 28800378 TI - Security Events and Vulnerability Data for Cybersecurity Risk Estimation. AB - Current industry standards for estimating cybersecurity risk are based on qualitative risk matrices as opposed to quantitative risk estimates. In contrast, risk assessment in most other industry sectors aims at deriving quantitative risk estimations (e.g., Basel II in Finance). This article presents a model and methodology to leverage on the large amount of data available from the IT infrastructure of an organization's security operation center to quantitatively estimate the probability of attack. Our methodology specifically addresses untargeted attacks delivered by automatic tools that make up the vast majority of attacks in the wild against users and organizations. We consider two-stage attacks whereby the attacker first breaches an Internet-facing system, and then escalates the attack to internal systems by exploiting local vulnerabilities in the target. Our methodology factors in the power of the attacker as the number of "weaponized" vulnerabilities he/she can exploit, and can be adjusted to match the risk appetite of the organization. We illustrate our methodology by using data from a large financial institution, and discuss the significant mismatch between traditional qualitative risk assessments and our quantitative approach. PMID- 28800380 TI - Advances in Risk Analysis with Big Data. AB - With cloud computing, Internet-of-things, wireless sensors, social media, fast storage and retrieval, etc., organizations and enterprises have access to unprecedented amounts and varieties of data. Current risk analysis methodology and applications are experiencing related advances and breakthroughs. For example, highway operations data are readily available, and making use of them reduces risks of traffic crashes and travel delays. Massive data of financial and enterprise systems support decision making under risk by individuals, industries, regulators, etc. In this introductory article, we first discuss the meaning of big data for risk analysis. We then examine recent advances in risk analysis with big data in several topic areas. For each area, we identify and introduce the relevant articles that are featured in the special issue. We conclude with a discussion on future research opportunities. PMID- 28800381 TI - The Phosphinoboration of N-Heterocycles. AB - The addition of phosphinoboronate ester Ph2 PBpin (pin=1,2-O2 C2 Me4 ) (1) to a number of different N-heterocycles has been investigated. Reaction of 1 with pyridine resulted in highly selective formation of the corresponding 1,4-addition product, with addition of the electron-deficient Bpin group to the pyridine nitrogen atom and the phosphido group to the para carbon atom. Conversely, reactions of para-substituted pyridine derivatives occurred predominately to afford 1,2-addition products while quinoline reacted to afford the 1,2-adduct which ultimately isomerized to afford the corresponding 1,4-addition product. Preliminary computational studies have been undertaken to explore possible pathways for these transformations including transfer of the PPh2- anion from [B(PPh2 )2 pin]- to the 4-position of a borenium/boronium activated pyridine and concerted pathways for 1,2-addition via intramolecular nucleophilic attack of PPh2 at C2 of a Ph2 PBpin-coordinated pyridine via a four-centered transition state and intramolecular transfer of PPh2 to the 2-position of a boron-activated pyridine in a phosphido-bridged dimer involving a six-centered transition state. PMID- 28800384 TI - Exploring conditions for redistribution of anti-tumor necrosis factors to reduce spillage: A study on the quality of anti-tumor necrosis factor home storage. AB - BACKGROUND AND AIM: Biologicals are potent drugs for immune-mediated inflammatory diseases. After discontinuation or switch of therapy, many patients have unused biological injectors left. This study aimed to evaluate potential redistribution of unused injectors to prevent spillage of these costly drugs by assessing (i) the quality of transport and home storage through the proportion of injectors stored within the recommended temperature range (2-8 degrees C) and (ii) acceptance of redistribution by patients. METHODS: All golimumab users, irrespective of the indication, at Maastricht University Medical Center were eligible for inclusion. Patients received golimumab in a sealed bag containing a validated temperature sensor, measuring temperature every 5 min. Patients were asked to store their medication as usual. Deviations from the recommended range were defined as any duration below 0 degrees C and > 30 min below 2 degrees C or above 8 degrees C. After 3 months, patients completed a questionnaire on their opinion towards potential redistribution of unused biologicals. RESULTS: Fifty patients (42.0% male, mean age 53.2 +/- 14.3 years) received 276 injectors. The mean storage time was 30.9 +/- 33.1 days. Only 11.6% of the injectors were stored within the recommended temperature range. In addition, 11.2% were stored > 30 min below 0 degrees C and 33.2% were stored > 1 week above 8 degrees C. Of all patients, 95% would accept redistributed medication when product quality is ensured. CONCLUSIONS: During transport and home storage, only one in eight biological injectors was stored within the recommended temperature range. This hinders redistribution of unused injectors but also raises concern regarding drug effectiveness in immune-mediated inflammatory disease patients. PMID- 28800383 TI - Epithelial desquamation observed in a phase I study of an oral cathepsin C inhibitor (GSK2793660). AB - AIMS: Cathepsin C (CTSC) is necessary for the activation of several serine proteases including neutrophil elastase (NE), cathepsin G and proteinase 3. GSK2793660 is an oral, irreversible inhibitor of CTSC that is hypothesized to provide an alternative route to achieve NE inhibition and was tested in a Phase I study. METHODS: Single escalating oral doses of GSK2793660 from 0.5 to 20 mg or placebo were administered in a randomized crossover design to healthy male subjects; a separate cohort received once daily doses of 12 mg or placebo for 21 days. Data were collected on safety, pharmacokinetics, CTSC enzyme inhibition and blood biomarkers. RESULTS: Single, oral doses of GSK2793660 were able to dose dependently inhibit whole blood CTSC activity. Once daily dosing of 12 mg GSK2793660 for 21 days achieved >=90% inhibition (95% CI: 56, 130) of CTSC within 3 h on day 1. Only modest reductions of whole blood enzyme activity of approximately 20% were observed for NE, cathepsin G and proteinase 3. Seven of 10 subjects receiving repeat doses of GSK2793660 manifested epidermal desquamation on palmar and plantar surfaces beginning 7-10 days after dosing commencement. There were no other clinically important safety findings. CONCLUSIONS: GSK2793660 inhibited CTSC activity but not the activity of downstream neutrophil serine proteases. The palmar-plantar epidermal desquamation suggests a previously unidentified role for CTSC or one of its target proteins in the maintenance and integrity of the epidermis at these sites, with some similarities to the phenotype of CTSC-deficient humans. PMID- 28800382 TI - Suboptimal cotrimoxazole prophylactic concentrations in HIV-infected children according to the WHO guidelines. AB - AIMS: A clinical study was conduct in HIV-infected children to evaluate the prophylactic doses of cotrimoxazole [sulfamethoxazole (SMX) and trimethoprim (TMP)] advised by the WHO. METHODS: Children received lopinavir-based antiretroviral therapy with cotrimoxazole prophylaxis (200 mg of SMX/40 mg of TMP once daily). A nonlinear mixed effects modelling approach was used to analyse plasma concentrations. Factors that could impact the pharmacokinetic profile were investigated. The model was subsequently used to simulate individual exposure and evaluate different administration schemes. RESULTS: The cohort comprised 136 children [average age: 1.9 years (range: [0.7-4]), average weight: 9.5 kg (range: [6-16.3])]. A dose per kg was justified by the significant influence of implementing an allometrically scaled body size covariate on SMX and TMP pharmacokinetics. SMX and TPM clearance were estimated at 0.49 l h-1 /9.5 kg and 3.06 l h-1 /9.5 kg, respectively. The simulated exposures obtained after administration of oral dosing recommended by the WHO for children from 10 to 15 kg were significantly lower than in adults for SMX and TMP. This could induce a reduction of effectiveness of cotrimoxazole. Simulations show that regimens of 30 mg kg-1 of SMX and 6 mg kg-1 of TMP in the 5-10 kg group and 25 mg kg-1 of SMX and 5 mg kg-1 of TMP in the 10-15 kg group are more suitable doses. CONCLUSIONS: In this context of high prevalence of opportunistic infections, a lower exposure to cotrimoxazole in children than adults was noted. To achieve comparable exposure to adults, a dosing scheme per kg was proposed. PMID- 28800386 TI - Three-dimensional correlative single-cell imaging utilizing fluorescence and refractive index tomography. AB - Cells alter the path of light, a fact that leads to well-known aberrations in single cell or tissue imaging. Optical diffraction tomography (ODT) measures the biophysical property that causes these aberrations, the refractive index (RI). ODT is complementary to fluorescence imaging and does not require any markers. The present study introduces RI and fluorescence tomography with optofluidic rotation (RAFTOR) of suspended cells, facilitating the segmentation of the 3D correlated RI and fluorescence data for a quantitative interpretation of the nuclear RI. The technique is validated with cell phantoms and used to confirm a lower nuclear RI for HL60 cells. Furthermore, the nuclear inversion of adult mouse photoreceptor cells is observed in the RI distribution. The applications shown confirm predictions of previous studies and illustrate the potential of RAFTOR to improve our understanding of cells and tissues. PMID- 28800385 TI - In vivo and in vitro palatability testing of a new paediatric formulation of valaciclovir. AB - AIMS: The palatability of a new paediatric formulation of valaciclovir was assessed in children and their parents: non-inferiority of the new paediatric formulation (test formulation) compared to the reference formulation was investigated. METHODS: In vivo palatability testing was performed in a randomized, two-period, multicentre, cross-over study. Children and their parents scored the liking of the new paediatric valaciclovir formulation and the reference formulation on a 100 mm visual analogue scale (VAS). To support formulation development and palatability testing, electronic tongue measurements were applied. RESULTS: The electronic tongue measurement indicated taste-masking capabilities for three different formulations in the developmental phase. A glycerol-based formulation was further tested and compared to the reference formulation prepared out of crushed and suspended tablets. The mean difference (95% CI) in VAS scores between both formulations, as indicated by the children (n = 20), was 2.4 (-8.5, 13) mm, in favour of the new paediatric valaciclovir formulation. The mean (95% CI) difference in VAS scores indicated by the parents (n = 20) was -0.9 (-12, 9.8) mm. CONCLUSION: The palatability of the new paediatric valaciclovir formulation was considered non-inferior to the reference formulation prepared out of crushed tablets. We were able to optimize the study design and number of children to be included in the palatability testing by using electronic tongue measurements. PMID- 28800387 TI - Remote meta-C-H Cyanation of Arenes Enabled by a Pyrimidine-Based Auxiliary. AB - An easily removable pyrimidine-based auxiliary has been employed for the remote meta-C-H cyanation of arenes. The scope of this Pd-catalyzed cyanation reaction using copper(I) cyanide as the cyanating agent was demonstrated with benzylsilanes, benzylsulfonates, benzylphophonates, phenethylsulfonates, and phenethyl ether derivatives. The method was utilized for the synthesis of pharmaceutically valuable precursors. PMID- 28800388 TI - Rapid Access to Nanographenes and Fused Heteroaromatics by Palladium-Catalyzed Annulative pi-Extension Reaction of Unfunctionalized Aromatics with Diiodobiaryls. AB - Efficient and rapid access to nanographenes and pi-extended fused heteroaromatics is important in materials science. Herein, we report a palladium-catalyzed efficient one-step annulative pi-extension (APEX) reaction of polycyclic aromatic hydrocarbons (PAHs) and heteroaromatics, producing various pi-extended aromatics. In the presence of a cationic Pd complex, triflic acid, silver pivalate, and diiodobiaryls, diverse unfunctionalized PAHs and heteroaromatics were directly transformed into larger PAHs, nanographenes, and pi-extended fused heteroaromatics in a single step. In the reactions that afford [5]helicene substructures, simultaneous dehydrogenative ring closures occur at the fjord regions to form unprecedented larger nanographenes. This successive APEX reaction is notable as it stiches five aryl-aryl bonds by C-H functionalization in a single operation. Moreover, the unique molecular structures, crystal-packing structures, photophysical properties, and frontier molecular orbitals of the thus formed nanographenes were elucidated. PMID- 28800390 TI - How Ag Nanospheres Are Transformed into AgAu Nanocages. AB - Bimetallic hollow, porous noble metal nanoparticles are of broad interest for biomedical, optical and catalytic applications. The most straightforward method for preparing such structures involves the reaction between HAuCl4 and well formed Ag particles, typically spheres, cubes, or triangular prisms, yet the mechanism underlying their formation is poorly understood at the atomic scale. By combining in situ nanoscopic and atomic-scale characterization techniques (XAFS, SAXS, XRF, and electron microscopy) to follow the process, we elucidate a plausible reaction pathway for the conversion of citrate-capped Ag nanospheres to AgAu nanocages; importantly, the hollowing event cannot be explained by the nanoscale Kirkendall effect, nor by Galvanic exchange alone, two processes that have been previously proposed. We propose a modification of the bulk Galvanic exchange process that takes into account considerations that can only occur with nanoscale particles. This nanoscale Galvanic exchange process explains the novel morphological and chemical changes associated with the typically observed hollowing process. PMID- 28800391 TI - Recent Advances in Asymmetric Hydrogenation of Tetrasubstituted Olefins. AB - The asymmetric hydrogenation of tetrasubstituted olefins provides direct access to very useful biological molecules and intermediates. The development of the technology has been slow, due in part to the synthetic challenges involved in developing chiral catalysts for a successful asymmetric induction. We briefly recount the breakthroughs in functionalized and unfunctionalized tetrasubstituted olefins, from the reports of Zhou and Buchwald for functionalized and unfunctionalized substrates, respectively, to the advent of chiral phosphoramidite ligands. The main emphasis of this Perspective lies in bringing into focus the complexity and challenges of inducing an asymmetric reduction for these substrates, which includes a brief discussion of the mechanism, the latest developed chiral catalysts, and the enormous scientific opportunities that still exist in developing "go to" catalyst systems for the various substrate types. PMID- 28800389 TI - Silicon Micropore-Based Parallel Plate Membrane Oxygenator. AB - Extracorporeal membrane oxygenation (ECMO) is a life support system that circulates the blood through an oxygenating system to temporarily (days to months) support heart or lung function during cardiopulmonary failure until organ recovery or replacement. Currently, the need for high levels of systemic anticoagulation and the risk for bleeding are main drawbacks of ECMO that can be addressed with a redesigned ECMO system. Our lab has developed an approach using microelectromechanical systems (MEMS) fabrication techniques to create novel gas exchange membranes consisting of a rigid silicon micropore membrane (SMUM) support structure bonded to a thin film of gas-permeable polydimethylsiloxane (PDMS). This study details the fabrication process to create silicon membranes with highly uniform micropores that have a high level of pattern fidelity. The oxygen transport across these membranes was tested in a simple water-based bench top set-up as well in a porcine in vivo model. It was determined that the mass transfer coefficient for the system using SuM-PDMS membranes was 3.03 +/- 0.42 mL O2 min-1 m-2 cm Hg-1 with pure water and 1.71 +/- 1.03 mL O2 min-1 m-2 cm Hg-1 with blood. An analytic model to predict gas transport was developed using data from the bench-top experiments and validated with in vivo testing. This was a proof of concept study showing adequate oxygen transport across a parallel plate SuM-PDMS membrane when used as a membrane oxygenator. This work establishes the tools and the equipoise to develop future generations of silicon micropore membrane oxygenators. PMID- 28800392 TI - Coarse-Grained Directed Simulation. AB - Many free-energy sampling and quantum mechanics/molecular mechanics (QM/MM) computations on protein complexes have been performed where, by necessity, a single component is studied isolated in solution while its overall configuration is kept in the complex-like state by either rigid restraints or harmonic constraints. A drawback in these studies is that the system's native fluctuations are lost, both due to the change of environment and the imposition of the extra potential. Yet, we know that having both accurate structure and fluctuations is likely crucial to achieving correct simulation estimates for the subsystem within its native larger protein complex context. In this work, we provide a new approach to this problem by drawing on ideas developed to incorporate experimental information into a molecular simulation by relative entropy minimization to a target system. We show that by using linear biases on coarse grained (CG) observables (such as distances or angles between large subdomains within a protein), we can maintain the protein in a particular target conformation while also preserving the correct equilibrium fluctuations of the subsystem within its larger biomolecular complex. As an application, we demonstrate this algorithm by training a bias that causes an actin monomer (and trimer) in solution to sample the same average structure and fluctuations as if it were embedded within a much larger actin filament. Additionally, we have developed a number of algorithmic improvements that accelerate convergence of the on-the-fly relative entropy minimization algorithms for this type of application. Finally, we have contributed these methods to the PLUMED open source free energy sampling software library. PMID- 28800394 TI - ZnO(1010) Surface Hydroxylation under Ambient Water Vapor. AB - The interaction of water vapor with a single crystal ZnO(1010) surface was investigated using synchrotron-based ambient pressure X-ray photoelectron spectroscopy (APXPS). Two isobaric experiments were performed at 0.3 and 0.07 Torr water vapor pressure at sample temperatures ranging from 750 to 295 K up to a maximum of 2% relative humidity (RH). Below 10-4 % RH the ZnO(1010) interface is covered with ~0.25 monolayers of OH groups attributed to dissociation at nonstoichiometric defect sites. At ~10-4 % RH there is a sharp onset in increased surface hydroxylation attributed to reaction at stoichiometric terrace sites. The surface saturates with an OH monolayer ~0.26 nm thick and occurs in the absence of any observable molecularly bound water, suggesting the formation of a 1 * 1 dissociated monolayer structure. This is in stark contrast to ultrahigh vacuum experiments and molecular simulations that show the optimum structure is a 2 * 1 partially dissociated H2O/OH monolayer. The sharp onset to terrace site hydroxylation at ~10-4 % RH for ZnO(1010) contrasts with APXPS observations for MgO(100) which show a sharp onset at 10-2 % RH. A surface thermodynamic analysis reveals that this shift to lower RH for ZnO(1010) compared to MgO(100) is due to a more favorable Gibbs free energy for terrace site hydroxylation. PMID- 28800393 TI - POVME 3.0: Software for Mapping Binding Pocket Flexibility. AB - We present a substantial update to the open-source POVME binding pocket analysis software. New capabilities of POVME 3.0 include a flexible chemical coloring scheme for feature identification, postanalysis tools for comparing large ensembles of pockets (e.g., from molecular dynamics simulations), and the introduction of scripts and methods that facilitate binding pocket comparison and analysis. We envision the use of this software for visualization of binding pocket dynamics, selection of representative structures for ensemble docking, and incorporation of molecular dynamics results into ligand design efforts. PMID- 28800395 TI - Using Chemistry to Target Neuroblastoma. AB - Neuroblastoma is a cancer of the neural crest almost exclusively seen in childhood. While children with single, small primary tumors are often cured with surgery alone, the 65% of children with neuroblastoma whose disease has metastasized have less than a 50% chance of surviving five years after diagnosis. Innovative pharmacological strategies are critically needed for these children. Efforts to identify novel targets that afford ablation of neuroblastoma with minimal toxicity to normal tissues are underway. Developing approaches to neuroblastoma include those that target the catecholamine transporter, ubiquitin E3 ligase, the ganglioside GD2, the retinoic acid receptor, the protein kinases ALK and Aurora, and protein arginine N-methyltransferases. Here, as examples of the use of chemistry to combat neuroblastoma, we describe targeting of the protein arginine N-methyltransferases and their role in prolonging the half-life of the neuroblastoma oncoprotein N-Myc, redox signaling in neuroblastoma, and developmentally regulated proteins expressed in primitive neuroblastoma cells but not in mature neural crest elements. PMID- 28800396 TI - A Simple and Efficient Protein Structure Refinement Method. AB - Improving the quality of a given protein structure can serve as the ultimate solution for accurate protein structure prediction, and seeking such a method is currently a challenge in computational structural biology. In order to promote and encourage much needed such efforts, CASP (Critical Assessment of Structure Prediction) has been providing an ideal computational experimental platform, where it was reported only recently (since CASP10) that systematic protein structure refinement is possible by carrying out extensive (approximately millisecond) MD simulations with proper restraints generated from the given structure. Using an explicit solvent model and much reduced positional and distance restraints than previously exercised, we propose a refinement protocol that combines a series of short (5 ns) MD simulations with energy minimization procedures. Testing and benchmarking on 54 CASP8-10 refinement targets and 34 CASP11 refinement targets shows quite promising results. Using only a small fraction of MD simulation steps (nanosecond versus millisecond), systematic protein structure refinement was demonstrated in this work, indicating that refinement of a given model can be achieved using a few hours of desktop computing. PMID- 28800397 TI - Association Between the 7-Day Moving Average for Nutrition and Growth in Very Low Birth Weight Infants. AB - BACKGROUND: Very low birth weight (VLBW) infants remain at risk for postnatal growth restriction. Clinicians may have difficulty identifying growth patterns resulting from nutrition interventions, impeding prompt management changes intended to increase growth velocity. This study aimed to quantify the association between growth and nutrition intake through 7-day moving averages (SDMAs). METHODS: The first 6 weeks of daily nutrition intake and growth measurements were collected from VLBW infants admitted to a level 4 neonatal intensive care unit (2011-2014). The association between SDMA for energy and macronutrients and subsequent 7-day growth velocities for weight, length, and head circumference were determined using mixed effects linear regression. Analyses were adjusted for fluid intake, infant characteristics, and comorbid conditions. RESULTS: Detailed enteral and parenteral caloric provisions were ascertained for 115 infants (n = 4643 patient-days). Each 10-kcal/kg/d increase over 7 days was independently associated with increased weight (1.7 g/kg/d), length (0.4 mm/wk), and head circumference (0.9 mm/wk; P < .001, for weight and head circumference; P = .041 for length). Each 1 g/kg/d macronutrient increase was also associated with increased weight (protein, P = .027; fat and carbohydrates, P < .001), increased length (fat, P = .032), and increased head circumference (fat and carbohydrates, P < .001). CONCLUSIONS: The SDMA identifies clinically meaningful associations among total energy, macronutrient dosing, and growth in VLBW infants. Whether SDMA is a clinically useful tool for providing clinicians with prompt feedback to improve growth warrants further attention. PMID- 28800398 TI - A 13-week low glycemic load diet and lifestyle modification program combining low glycemic load protein shakes and targeted nutraceuticals improved weight loss and cardio-metabolic risk factors. AB - An open-label, randomized, exploratory study of 44 healthy overweight subjects with cardio-metabolic syndrome (CMS) risk factors was conducted to assess the safety, tolerability, and efficacy of a proprietary lifestyle modification program without (DIET) and with (PROG) targeted nutraceutical supplementation, including phytosterols, antioxidants, probiotics, fish oil, berberine, and soy, pea, and whey proteins over 13 weeks. Key metrics were recorded at baseline and weeks 9 and 13. For the DIET and PROG groups, compliance was 85% and 86%, respectively, with no adverse events related to the diet or supplements. Twelve subjects discontinued participation before week 9 for reasons unrelated to the study. PROG subjects experienced greater decreases (p < 0.05) than DIET in body mass, fat mass, total cholesterol, LDL cholesterol, TG, cholesterol / HDL ratio, TG/HDL ratio, apolipoprotein B / apolipoprotein A1 ratio, and hs-CRP. The Framingham 10-year cardiovascular disease risk score decreased by 40% (p < 0.01) in the PROG arm versus no change for the DIET arm. As a pilot study, it was not possible to state whether the observed effects were the result of nutraceutical supplementation alone or the result of additive or synergistic interactions among diet, lifestyle modifications, and nutraceutical supplementation. Moreover, individuals with CMS risk factors following a lifestyle modification program received additional health benefits from targeted nutraceutical supplementation. PMID- 28800399 TI - Price and utilisation differences for statins between four countries. AB - INTRODUCTION: Australia, England, France and New Zealand use different policies to regulate their medicines market, which can impact on utilisation and price. OBJECTIVES: To compare the prices and utilisation of statins in Australia, England, France and New Zealand from 2011 to 2013. METHODS: Utilisation of statins in the four countries was compared using Defined Daily Doses (DDD) per 1000 inhabitants per year. Pairwise Laspeyres and Paasche index comparisons were conducted comparing the price and utilisation of statins. RESULTS: The results showed that the price of statins in New Zealand was the cheapest. The price of statins in Australia was most expensive in 2011 and 2012 but France was more expensive in 2013. There were large differences between the Laspeyres index and Paasche index when comparing the price and utilisation of England with Australia and France. DISCUSSION: The policies that regulate the New Zealand and England medicines markets were more effective in reducing the price of expensive statins. The relative utilisation of cheaper statins was greatest in England and had a large effect on the differences between the two index results. The pricing policies in Australia have been only partly effective in reducing the price of statins compared to other countries. PMID- 28800400 TI - Mechanisms of TFAM-mediated cardiomyocyte protection. AB - Although mitochondrial transcription factor A (TFAM) is a protective component of mitochondrial DNA and a regulator of calcium and reactive oxygen species (ROS) production, the mechanism remains unclear. In heart failure, TFAM is significantly decreased and cardiomyocyte instability ensues. TFAM inhibits nuclear factor of activated T cells (NFAT), which reduces ROS production; additionally, TFAM transcriptionally activates SERCA2a to decrease free calcium. Therefore, decreasing TFAM vastly increases protease expression and hypertrophic factors, leading to cardiomyocyte functional decline. To examine this hypothesis, treatments of 1.0 MUg of a TFAM vector and 1.0 MUg of a CRISPR-Cas9 TFAM plasmid were administered to HL-1 cardiomyocytes via lipofectamine transfection. Western blotting and confocal microscopy analysis show that CRISPR-Cas9 knockdown of TFAM significantly increased proteases Calpain1, MMP9, and regulators Serca2a, and NFAT4 protein expression. CRISPR knockdown of TFAM in HL-1 cardiomyocytes upregulates degradation factors, leading to cardiomyocyte instability. Hydrogen peroxide oxidative stress decreased TFAM expression and increased Calpain1, MMP9, and NFAT4 protein expression. TFAM overexpression normalizes pathological hypertrophic factor NFAT4 in the presence of oxidative stress. PMID- 28800401 TI - Lupus nephritis and B-cell targeting therapy. AB - INTRODUCTION: Lupus Nephritis (LN) is a severe manifestation of Systemic Lupus Erythematosus (SLE) with a significant prognostic impact. Over a prolonged course, an exhaustion of treatment alternatives may occur and further therapeutic options are needed. B cells play a pivotal role in disease pathogenesis and represent an attractive therapeutic target. Areas covered: This review provides an update regarding targeting B cells in LN. The rational for this approach, as well as currently available and future targets are discussed. Expert commentary: Despite its wide clinical use and the encouraging results from retrospective studies, a role of rituximab in LN has not been prospectively confirmed. Trial design methodologies as well as intrinsic limitations of this approach may be responsible and rituximab use is currently limited as a rescue treatment or in settings where a strong steroid sparing effect is warranted. Despite belimumab now being licensed for use in SLE, the evidence in LN is weak although prospective trials are on-going. The combination of different targeted approaches as well as a focus on new clinical end-points may be strategies to identify new therapeutic options. PMID- 28800402 TI - Extracellular Matrix Cartilage Allograft and Particulate Cartilage Allograft for Osteochondral Lesions of the Knee and Ankle Joints: A Systematic Review. AB - BACKGROUND: Extracellular matrix cartilage allografts (EMCAs) and particulate cartilage allografts (PCAs) are relatively new biologics that may improve the quality of cartilage regeneration after bone marrow stimulation. The increasing popularity of these novel biologics in the treatment of osteochondral lesions (OCLs) of the knee and ankle joints prompts a systematic evaluation of their efficacies. PURPOSE: The purpose of this systematic review was to clarify the effectiveness of EMCAs and PCAs on cartilage regeneration. STUDY DESIGN: Systematic review; Level of evidence, IV. METHODS: Two reviewers searched MEDLINE and Embase in February 2016 based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Predetermined variables from each study were extracted and analyzed. RESULTS: For EMCAs, 1 in vitro study and 2 clinical studies for OCLs of the ankle joint were found. For PCAs, 3 in vitro studies, 5 clinical studies for OCLs of the knee joint, and 5 clinical studies for OCLs of the ankle joint were found. For all studies, in vitro chondrogenesis and clinical outcomes favored EMCAs and PCAs. However, the highest level of evidence was IV, and the methodological quality of evidence was indicated to be poor. CONCLUSION: Both EMCAs and PCAs have yielded favorable outcomes in both in vitro and clinical studies. However, the available studies were of limited data with significant confounding factors. Therefore, it is unclear whether the effectiveness of these novel biologics is any greater than that of bone marrow stimulation alone in the repair of knee and ankle cartilage. PMID- 28800403 TI - An Exploration of Maternal Satisfaction With Breastfeeding as a Clinically Relevant Measure of Breastfeeding Success. PMID- 28800404 TI - Does Propofol Sedation Contribute to Overall Energy Provision in Mechanically Ventilated Critically Ill Adults? A Retrospective Observational Study. AB - BACKGROUND: Propofol sedation is common in critically ill patients, providing energy of 1.1 kcal/mL when administered as a 1% solution. We aimed to determine the proportion of energy administered as propofol on days 1-5 in the intensive care unit (ICU) and any association with outcomes. METHODS: Retrospective observational study in a quaternary ICU from January-December 2012. Inclusion criteria were length of stay (LOS) >=5 days, age >=18 years, and provision of mechanical ventilation (MV) for >=5 days. Outcome measures included proportion of total daily energy provided as propofol, overall energy balance, hospital mortality, duration of MV, and ICU LOS. RESULTS: Data from 370 patients were analyzed, 87.8% (n = 325) of whom received propofol during days 1-5 in ICU. A median [interquartile range (IQR)] of 119 [50-730] kcal was provided as propofol per patient-day. Proportion of energy provided by propofol as a percentage of total energy delivered was 55.4%, 15.4%, 9.3%, 7.9%, and 9.9% days 1-5, respectively. Patients administered propofol received a greater proportion of their total daily energy prescription compared with those who were not (P < .01). Proportion of energy provided as propofol was not significantly different based on hospital mortality (P = .62), duration of MV (P = .50), or ICU LOS (P = .15). CONCLUSION: Propofol contributes to overall energy intake on days 1-5 of ICU admission. Energy balance was higher in those receiving propofol. No association was found between the proportion of energy delivered as propofol and outcomes. PMID- 28800405 TI - Neonatal Weight Matters: An Examination of Weight Changes in Full-Term Breastfeeding Newborns During the First 2 Weeks of Life. AB - BACKGROUND: Weight changes in the early weeks of life are important indicators of newborn wellness. Yet, little is known about weight loss patterns for breastfeeding newborns. Research aim: This study aimed to compare weight changes and exclusive breastfeeding rates in newborns who lost <= 7% and > 7% of their body weight after birth. METHODS: A prospective, observational cohort study was completed. Newborns who lost <= 7% made up Group 1 and newborns who lost > 7% of birth weight made up Group 2. Mothers used a digital scale to weigh their newborns daily until 14 days of life. Newborn intake and outputs were also recorded. RESULTS: Mean (with standard deviation in parentheses) weight loss for all newborns ( N = 151) was 7.68% (2.35%). Newborns in Group 1 ( n = 67) lost 5.7% (0.99%) and newborns in Group 2 lost 9.3% (1.87%). More than half of healthy, full-term newborns (56%) lost > 7%. On Day 14, the exclusive breastfeeding rate for newborns in Group 2 was significantly less than for those in Group 1 (60% vs. 82%; p = .033). Newborns gained a mean of 1.1% body weight daily; those in Group 1 gained 1.2% daily, and those in Group 2 gained 1.0% daily. CONCLUSION: Weight loss > 7% may be a normal phenomenon among breastfeeding newborns. Newborns who lost > 7% had a lower exclusive breastfeeding rate at 2 weeks of age. After the weight nadir was reached, most newborns gained weight at a similar pace, despite differences in early weight loss. PMID- 28800406 TI - A research-based mantra for compassionate caring. AB - BACKGROUND: The United Kingdom introduced the Six C's strategy to help address deficits in approaching nursing care in a compassionate and caring manner. OBJECTIVE: To identify the book, article, poem, film or play that most influenced nurse educators' understanding of care and compassion and to articulate a clearer understanding of compassionate caring. DESIGN: A qualitative study applying discourse analysis to respondents' questionnaires and their nominated narrative. SETTINGS AND PARTICIPANTS: 41 nurse educators working in 5 universities in the UK (n=3), Republic of Ireland and Canada participated. 39 items (10 books, 2 journal articles, 10 poems, 15 films and 2 plays) were nominated. FINDINGS: The desire to understand others and how to care compassionately characterised choices. Three main themes emerged. Abandonment of, and failure to see, the suffering person was evident in 25 narratives. Connecting with others was shown in 25 narratives as being able to truly seeing the other person. Comforting others was supported by 37 narratives with examples of kindness and compassion. CONCLUSION: Published narratives are valuable in developing compassionate responses. An annotated list is provided with suggestions for educational uses to help develop compassionate caring in student nurses. Compassionate, caring nurses recognise that patients need them to: "See who I am; Be present with me; Do not abandon me." PMID- 28800407 TI - Human brown adipose tissue-function and therapeutic potential in metabolic disease. AB - There has been a resurgence of interest in brown adipose tissue (BAT) over the last decade. Key to this has been our ability to accurately image it, which has improved significantly. The role of BAT in regulating energy expenditure is important, and its pharmacological manipulation may hold therapeutic potential in metabolic disease. There is ample evidence of BAT activation by cold exposure, and pharmacological utilisation of similar pathways, using B3 receptor agonists holds promise since the development of selective agonists with limited cross reactivity has rekindled interest. Endogenous agents like irisin, FGF21 and certain gut hormones may hold value as BAT activators. Other agents such as steroid hormones may also hold therapeutic potential, although short-term worsening of metabolic profile remains problematic. Clearly, pharmacological manipulation of BAT is important, and thanks to recent advances we may one day be able to add such agents to our anti-obesity arsenal. PMID- 28800408 TI - Effects of phenanthrene on early development of the Pacific oyster Crassostrea gigas (Thunberg, 1789). AB - Phenanthnere (PHE) is a polycyclic aromatic hydrocarbon continuously discarded in the marine environment and bioavailable to many aquatic species. Although studies about PHE toxicity have been documented for adult oysters, the effects on early developmental stages are poorly characterized in bivalves. In this study, the effects of PHE (0.02 and 2.0MUg.L-1) were evaluated on the embryogenesis and larval development of Crassostrea gigas. Toxicity bioassays, growth and deformities assessment, analysis of shell calcium abundance and transcript levels of genes related to xenobiotic biotransformation (CYP2AU2, CYP30C1), immune system (Cg-Tal) and tissue growth and shell formation (Ferritin, Insulin-like, Cg Try, Calmodulin and Nacrein) were assayed in D-shape larvae after 24h of PHE exposure. At the highest concentration (2.0MUg.L-1), PHE decreased the frequency of normal development (19.7+/-2.9%) and shell size (53.5+/-2.8mm). Developmental deformities were mostly related to abnormal mantle and shell formation. Lower calcium levels in oyster shells exposed to PHE 2.0MUg.L-1 were observed, suggesting effects on shell structure. At this same PHE concentration, CYP30C1, Cg-Tal, Cg-Tyr, Calmodulin were upregulated and CYP2AU2, Ferritin, Nacrein, and Insulin-Like were downregulated compared to control larvae. At the lowest PHE concentration (0.02MUg.L-1), it was observed a minor decrease in normal larval development (89,6+/-6%) and the remaining parameters were not affected. This is the first study to provide evidences that exposure to PHE can affect early oyster development at the molecular and morphological levels, possibly threatening this bivalve species. PMID- 28800409 TI - Cytotoxic effects of the proton pump inhibitor omeprazole on the non-target marine microalga Tetraselmis suecica. AB - Omeprazole (OMP) is one of the most commonly used drugs for the treatment of gastro-intestinal disorders. Although it is daily consumed in high quantities and commonly detected in waters worldwide, relatively little is known about its ecotoxicity. The aim of this study was to evaluate the potential acute toxicity of increasing concentrations of OMP on the marine microalga Tetraselmis suecica analysing several cytotoxicity biomarkers by flow cytometry after 24h of exposure. Results showed that OMP caused a decrease in growth and autofluorescence, an increase in cellular volume and intracellular complexity, hyperpolarization of cytoplasmic and mitochondrial membranes and intracellular acidification. In addition, large amounts of reactive oxygen species (ROS) were generated which resulted in a decrease in the percentage of the viable population. However, the viable population showed an increase in their metabolic activity as an early response to overcome the stress. In conclusion, OMP may affect proton pumps in non-target organisms such as microalgae; it disturbed pH homeostasis and provoked an early accumulation of ROS that resulted in a rapid cell death in cells exposed to the highest concentration assayed. PMID- 28800410 TI - Incident risk and progression of cerebral microbleeds in healthy adults: a multi occasion longitudinal study. AB - Decline in cerebrovascular health complicates brain aging, and development of cerebral microbleeds (CMBs) is one of its prominent indicators. In a large sample of healthy adults (N = 251, age 18-78 years at baseline, 70% women), the contributions of chronological age and vascular health indicators to the risk of developing a CMB, as well as the change in CMB size and iron content, were examined in a prospective 8-year longitudinal study using susceptibility weighted imaging. Twenty-six persons (10.4%), most of whom were 40 years of age or older, had at least 1 CMB during the study. Older age was associated with greater risk for developing a CMB (odds ratio 1.03). Elevation of combined metabolic syndrome indicators (b = 0.15, p = 0.001) conferred additional risk (odds ratio 1.02). High body mass index exacerbated the risk associated with poor vascular health (b = 0.75, p < 0.001) and frequent exercise mitigated it (b = -0.46, p = 0.03). CMBs persisted over time, yet their volume decreased (mean change = -0.32, p < 0.05), whereas their relative iron content remained stable (mean change = -0.14, p = 0.05). We conclude that although developing a CMB is unlikely during normal aging, risk increases with declining vascular health, which is modifiable via behavioral and pharmaceutical intervention. PMID- 28800411 TI - Antimicrobial resistance and resistance genes in Salmonella strains isolated from broiler chickens along the slaughtering process in China. AB - A total of 189 Salmonella isolates were recovered from 627 samples which were collected from cecal contents of broilers, chicken carcasses, chicken meat after cutting step and frozen broiler chicken products along the slaughtering process at a slaughterhouse in Sichuan province of China. The Salmonella isolates were subjected to antimicrobial susceptibility testing to 10 categories of antimicrobial agents using the Kirby-Bauer disk diffusion method. Those antibiotics-resistant isolates were further investigated for the occurrence of resistance genes, the presence of class 1 integron as well as the associated gene cassettes, and the mutations within the gyrA and parC genes. Consequently, the prevalence of Salmonella was 30.14% (47.96% for cecal content, 18.78% for chicken carcasses, 31.33% for cutting meat and 14.00% for frozen meat, respectively). The predominant serotypes were S. Typhimurium (15.34%) and S. Enteritidis (69.84%). High resistance rates to the following drugs were observed: nalidixic acid (99.5%), ampicillin (87.8%), tetracycline (51.9%), ciprofloxacin (48.7%), trimethoprim/sulfamethoxazole (48.1%), and spectinomycin (34.4%). Antimicrobial resistance profiling showed that 60.8% of isolates were multidrug resistant (MDR), and MDR strains increased from 44.7% to 78.6% along the slaughtering line. 94.6% (n=157) of beta-lactam-resistant isolates harbored at least one resistance gene of blaTEM or blaCTX-M. The relatively low prevalence of aminoglycoside resistance genes (aac(3)-II, aac(3)-IV, and ant(2")-I) was found in 49 (66.2%) of antibiotic-resistant isolates. The tetracycline resistance genes (tet(A), tet(B), tet(C), and tet(G) and sulfonamide resistance genes (sul1, sul2, and sul3) were identified in 84 (85.7%) and 89 (97.8%) antibiotic-resistant isolates respectively. floR was identified in 44 (97.8%) florfenicol-resistant isolates. Class 1 integron was detected in 37.4% (n=43) of the MDR isolates. Two different gene cassettes, blaOXA-30-aadA1 (19 isolates) and blaOXA-30-aadA1/drfA1-orfC (2 isolates), were identified in class 1 integron-positive isolates. 97.9% (184/188) of quinolone-resistant isolates had at least one mutation within gyrA or parC. Overall, antimicrobial resistance showed an increasing trend along the slaughtering process. The results showed that broiler chicken products in the slaughterhouse were contaminated with MDR Salmonella, which might originate from food producing animals to some extent, and cross-contamination during slaughter, and facilitate the dissemination of the resistance genes to consumers along the production chain, which suggests importance of controlling Salmonella during slaughter for public health, underlying strict hygiene method and HACCP management to reduce cross-contamination. PMID- 28800412 TI - Practical issues in suspected venous thrombosis in general practice: A multicentre prospective cohort in primary care. PMID- 28800413 TI - The impact of climate change and emissions control on future ozone levels: Implications for human health. AB - Overwhelming evidence has shown that, from the Industrial Revolution to the present, human activities influence ground-level ozone (O3) concentrations. Past studies demonstrate links between O3 exposure and health. However, knowledge gaps remain in our understanding concerning the impacts of climate change mitigation policies on O3 concentrations and health. Using a hybrid downscaling approach, we evaluated the separate impact of climate change and emission control policies on O3 levels and associated excess mortality in the US in the 2050s under two Representative Concentration Pathways (RCPs). We show that, by the 2050s, under RCP4.5, increased O3 levels due to combined climate change and emission control policies, could contribute to an increase of approximately 50 premature deaths annually nationwide in the US. The biggest impact, however, is seen under RCP8.5, where rises in O3 concentrations are expected to result in over 2,200 additional premature deaths annually. The largest increases in O3 are seen in RCP8.5 in the Northeast, the Southeast, the Central, and the West regions of the US. Additionally, when O3 increases are examined by climate change and emissions contributions separately, the benefits of emissions mitigation efforts may significantly outweigh the effects of climate change mitigation policies on O3 related mortality. PMID- 28800414 TI - Global distribution of perfluorochemicals (PFCs) in potential human exposure source-A review. AB - Human exposure to perfluorochemicals (PFCs) has attracted mounting attention due to their potential harmful effects. Breathing, dietary intake, and drinking are believed to be the main routes for PFC entering into human body. Thus, we profiled PFC compositions and concentrations in indoor air and dust, food, and drinking water with detailed analysis of literature data published after 2010. Concentrations of PFCs in air and dust samples collected from home, office, and vehicle were outlined. The results showed that neutral PFCs (e.g., fluorotelomer alcohols (FTOHs) and perfluorooctane sulfonamide ethanols (FOSEs)) should be given attention in addition to PFOS and PFOA. We summarized PFC concentrations in various food items, including vegetables, dairy products, beverages, eggs, meat products, fish, and shellfish. We showed that humans are subject to the dietary PFC exposure mostly through fish and shellfish consumption. Concentrations of PFCs in different drinking water samples collected from various countries were analyzed. Well water and tap water contained relatively higher PFC concentrations than other types of drinking water. Furthermore, PFC contamination in drinking water was influenced by the techniques for drinking water treatment and bottle originating pollution. PMID- 28800415 TI - Impact of alkaline alterations to a Brazilian soil on cesium retention under low temperature conditions. AB - To be used as backfilling materials in radioactive waste disposal facilities, a natural material must have a suitable permeability, mechanical properties and a high sorption capacity for radionuclides. Also important when considering a material as a backfill is the effect of its interaction with the alkaline solution generated from concrete degradation. This solution promotes mineralogical alterations that result in significant changes in the material key properties influencing its performance as a safety component of the repository. This paper presents results of an investigation on the effect of alkaline interaction under a low temperature on cesium retention properties of a local soil being considered suitable as a backfill for the Brazilian near surface disposal facility. A sample of the Brazilian soil was mixed with an alkaline solution, simulating the pore water leached in the first stage of cement degradation, during 1, 7, 14 and 28 days. The experiments were conducted under low temperature (25 degrees C) aiming to evaluate similar conditions found on a low and intermediate level radioactive waste disposal installation. A non classical isotherm sorption model was fitted to sorption data obtained from batch experiments, for unaltered and altered samples, providing parameters that allowed us to assess the effect of the interaction on material quality as Cs sorbent. The sorption parameters obtained from the data-fitted isotherm were used then to estimate the corresponding retardation factor (R). Alkaline interaction significantly modified the soil sorption properties for Cs. The parameter Q, related to the maximum sorption capacity, as well as the affinity parameter (K) and the retardation coefficients became significantly smaller (about 1000 times for the R coefficient) after pretreatment with the simulated alkaline solutions. Moreover, the increase in n-values, which is related with the energy distribution width and heterogeneity of surface site energies, demonstrated that the adsorbent surface became more homogenous as a consequence of the alkaline alteration. Together these results suggest that cementitious leachate has a profound effect on Cs retention and should be accounted for estimating radionuclide retention in radioactive waste disposal systems containing cementitious materials. PMID- 28800416 TI - The enigma of male eating disorders: A critical review and synthesis. AB - Historically, male presentations of eating disorders (EDs) have been perceived as rare and atypical - a perception that has resulted in the systematic underrepresentation of males in ED research. This underrepresentation has profoundly impacted clinical practice with male patients, in which i) stigmatization and treatment non-engagement are more likely, ii) a distinct array of medical complexities are faced, and iii) symptom presentations differ markedly from female presentations. Further, the marginalization of males from ED research has hindered the assessment and clinical management of these presentations. This critical review provides an overview of the history of male EDs and synthesizes current evidence relating to the unique characteristics of male presentations across the diagnostic spectrum of disordered eating. Further, the emerging body of evidence relating to muscularity-oriented eating is synthesized in relation to the existing nosological framework of EDs. The impact of marginalizing male ED patients is discussed, in light of findings from epidemiological studies suggesting that clinicians will be increasingly likely to see males with ED in their practices. It is suggested that changes to current conceptualizations of ED pathology that better accommodation male ED presentations are needed. PMID- 28800417 TI - Buccal delivery of small molecules and biologics: of mucoadhesive polymers, films, and nanoparticles. AB - Buccal delivery of macromolecules (biologics) sets a great challenge for researchers. Although several niche small molecule products have been approved as simple sprays, tablets and oral films, it is not simply a case of adapting existing technologies to biologics. Buccal delivery of insulin has reached clinical trials with two approaches: oromucosal sprays of the peptide with permeation enhancers, and embedded gold nanoparticles in a dissolvable film. However, neither of these approaches have led to FDA approvals likely due to poor efficacy, submaximal peptide loading in the dosage form, and to wide intra subject variability in pharmacokinetics and pharmacodynamics. It is likely however that printed film designs with lower molecular weight stable biotech payloads including lipophilic glucagon-like 1 (GLP-1) agonists and macrocycles with long half-lives will generate greater efficacy than was achieved to date for insulin. PMID- 28800418 TI - Lighting the shadows: methods that expose nuclear and cytoplasmic gene regulatory control. AB - Within cells, myriad interconnected processes orchestrate the progression of gene expression from chromatin, to mRNA, and to protein. Assessment of DNA methylation, histone modification, transcript isoform abundance, and the proteome are frequently performed to examine this progression, but do not resolve many intermediary steps in the coordinated regulation of gene expression. Here, we consider single and multiplexed technologies that yield genome-wide assessment of gene and mRNA activity, from transcription factor access to DNA to de novo synthesis of protein. An emphasis is placed on methods that can resolve gene regulatory processes in cells of defined identity within multicellular organs at spatial and temporal scales, leading to more effective design of gene regulatory cassettes for biotechnology. PMID- 28800419 TI - Genome editing and plant transformation of solanaceous food crops. AB - During the past decade, the ability to alter plant genomes in a DNA site-specific manner was realized through availability of sequenced genomes and emergence of editing technologies based on complexes that guide endonucleases. Generation of targeted DNA breaks by ZFNs, TALENs, and CRISPR/Cas9, then mending by repair mechanisms, provides a valuable foundation for studies of gene function and trait modification. Genome editing has been successful in several food crops, including those belonging to the Solanaceae, which contains some of the most widely used, economically important ones such as tomato and potato. Application of new breeding technologies has the potential to not only address deficiencies of current crops, but to also transform underutilized species into viable sources to diversify and strengthen our food supply. PMID- 28800421 TI - Lanostane-type triterpenoids from the fruiting body of Ganoderma calidophilum. AB - To search for active anti-cancer constituents in the fruiting body of Ganoderma calidophilum, we have successfully isolated four previously undescribed spiro lactone lanostane triterpenoids (spiroganocalitones A-D), two previously undescribed lanostanoids (ganodecalones A and B) together with twenty-three known ones. The structures of the six previously undescribed compounds were elucidated based on 1D, 2D-NMR, and HRMS analyses. Ganoderone A showed moderate cytotoxic activity against K562, BEL7402, and SGC790 cell lines with IC50 values of 7.62, 6.28, and 3.55 MUM, respectively. PMID- 28800420 TI - Retention in medication-assisted treatment programs in Ukraine-Identifying factors contributing to a continuing HIV epidemic. AB - BACKGROUND: Opioid agonist treatments (OAT) are widely-used, evidence-based strategies for treating opioid dependence and reducing HIV transmission. The positive benefits of OAT are strongly correlated with time spent in treatment, making retention a key indicator for program quality. This study assessed patient retention and associated factors in Ukraine, where OAT was first introduced in 2004. METHODS: Data from clinical records of 2916 patients enrolled in OAT at thirteen sites from 2005 to 2012 were entered into an electronic monitoring system. Survival analysis methods were used to determine the probability of retention and its correlates. RESULTS: Twelve-month retention was 65.8%, improving from 27.7% in 2005, to 70.9% in 2011. In multivariable analyses, the correlates of retention were receiving medium and high doses of medication (compared to low doses, dropout aHR=0.57 for both medium and high doses), having not been tested for HIV and tuberculosis (compared to not being tested, dropout aHR=4.44 and 3.34, respectively), and among those who were tested-a negative TB test result (compared to receiving a positive test result, dropout aHR=0.67). CONCLUSION: Retention in Ukrainian OAT programs, especially in recent years, is comparable to other countries. The results confirm the importance of adequate OAT dosing (>=60mg of methadone, >=8mg of buprenorphine). Higher dosing, however, will require interventions that address negative attitudes toward OAT by patients and providers. Interruption of OAT, in the case developing tuberculosis, should incorporate continuity of OAT for TB patients through integrated care delivery systems. PMID- 28800422 TI - Cytotoxic lanostane triterpenoids from the fruiting bodies of Piptoporus betulinus. AB - Chemical investigation of a bioactive methanolic extract of the fruiting bodies of Piptoporus betulinus led to the isolation of five previously undescribed lanostane triterpenoids named piptolinic acids A-E, as well as five known lanostane triterpenoids. Their structures were elucidated on the basis of 1D and 2D NMR spectroscopic and HRESIMS analysis. Piptolinic acid A with an unusual moiety (3-hydroxy-4-methoxycarbonyl-3-methylbutyryloxy) at C-3 exhibited comparable cytotoxic activity against human promyelocytic leukemia cell line HL 60 (IC50 = 1.77 MUM) and human acute monocytic leukemia cell line THP-1 (IC50 = 8.21 MUM) to those of positive control, fluorouracil (IC50 = 6.38 and 4.41 MUM, respectively). PMID- 28800424 TI - Migration of pentachlorophenol and copper from a preservative treated bridge. AB - The potential for migration of pentachlorophenol (PCP) and copper naphthenate (CuNaph) from Douglas-fir was assessed in a bridge over a stream located in Western Oregon in the United States. All rainfall runoff was collected from a portion of the bridge on 15 occasions over a 27 month period and analyzed for pentachlorophenol or copper. PCP and copper were detected at every time point. PCP concentrations ranged from 0.296 to 6.183 MUg/mL, while those for copper ranged from 0.37 to 7.80 MUg/mL. These data were then used to estimate PCP and Cu inputs in runoff from the entire bridge. Stream flow data were then used to predict the concentrations that would develop in the receiving stream. The results showed that runoff from the bridge would result in PCP and copper concentrations that were 500-1000 times lower than the reported levels of effect for each component. The results are discussed in the context of this location as well as other sites with lower stream flow conditions. PMID- 28800423 TI - Relationship of executive functioning deficits to N-acetyl aspartate (NAA) and gamma-aminobutyric acid (GABA) in youth with bipolar disorder. AB - BACKGROUND: Although cognitive deficits in bipolar disorder (BD) have been repeatedly observed, our understanding of these impairments at a mechanistic level remains limited. Few studies that investigated cognitive impairments in bipolar illness have examined the association with brain biochemistry. This pilot study utilized proton magnetic resonance spectroscopy (1H-MRS) to evaluate the relationship between neurocognitive performance and brain metabolites in youth with BD. METHODS: Thirty participants, twenty depressed BD participants and ten healthy comparison participants, ages 13-21, completed mood and executive function measures. 1H-MRS data were also acquired from the anterior cingulate cortex (ACC) using two-dimensional (2D) J-resolved 1H-MRS sequence. Proton metabolites including N-acetyl aspartate (NAA) and gamma-aminobutyric acid (GABA) were quantified for both groups. RESULTS: Participants with BD performed significantly lower on executive functioning measures than comparison participants. There were significant positive correlations between Wisconsin Card Sorting Test (WCST) performance and NAA (p < .001) and GABA (p < .01) in the ACC in bipolar youth, such that as WCST performance increased, both NAA and GABA levels increased. LIMITATIONS: Small sample size and lack of control for medications. CONCLUSIONS: These findings build on previous observations of biochemical alterations associated with BD and indicate that executive functioning deficits in bipolar youth are correlated with NAA and GABA. These results suggest that cognitive deficits occur early in the course of illness and may reflect risk factors associated with altered neurochemistry. Further investigation of the relationship between brain metabolites and cognition in BD may lead to important information for developing novel, targeted interventions. PMID- 28800425 TI - Implementing the adapted physical education E-learning program into physical education teacher education program. AB - According to the Ministry of Education Korea (2014), the approximately 70.4% of all students with disabilities are included in general schools in Korea. However, studies show that Korean GPE teachers do not feel comforatble or prepared to include students with disabilities (Oh & Lee, 1999; Roh, 2002; Roh & Oh, 2005). The purpose of this study was to explore whether an APE e-learning supplement would have an impact on the level of self-efficacy and content knowledge of pre service teachers related to including students with intellectual disabilities. An APE supplement was developed based on the Instructional Design Model (Dick, Carey, & Carey, 2005) to provide three sources of self-efficacy, mastery experience, vicarious experience, and social persuasions. Three groups of pre service teachers (N=75) took the same content supplement with different delivery system, E-learning group (n=25) with online, traditional group (n=25) with printed handout, and control group (n=25) without supplement. Two instruments, the Physical Educators' Situation-Specific Self-efficacy and Inclusion Student with Disabilities in Physical Education (SE-PETE-D) and the content knowledge test, were given to all participants twice (i.e., pretest and posttest). A 3*2 mixed effect ANOVA revealed that pre-service teachers' perceived self-efficacy (p=0.023) improved after taking the e-learning supplement. However, there was no significant difference in the level of content knowledge (p=0.248) between the learning group and tranditional group. PMID- 28800426 TI - An exploratory study of competition scores and salivary cortisol concentrations in Warmblood horses. AB - The main objective of this explorative study was to describe the relationship between competition scores and salivary cortisol concentrations in young horses during dressage and showjumping competitions. The study also investigated whether the diurnal rhythm of salivary cortisol concentrations was affected by competition over consecutive days compared with the home environment. Saliva samples were collected from 126 dressage horses and showjumpers in their home environment and at 3 different events. The relationship between scores given by judges at the competition and cortisol concentrations at the event was assessed. The results demonstrated that competition scores correlated positively to baseline cortisol concentrations at one of 3 events (r = 0.53, P < 0.001). Salivary cortisol concentrations followed a diurnal rhythm with the highest concentrations measured in the morning and the lowest in the evening, both at home and in the competition environment (P < 0.05). Salivary cortisol concentrations were greater during the competitions than at home (P < 0.05) except at one event where showjumpers did not increase between home and competition. Dressage horses had the highest baseline cortisol concentrations at competition, and exercise caused cortisol concentrations to increase in both showjumpers and dressage horses (P < 0.001). In conclusion, the diurnal rhythm in salivary cortisol concentrations was maintained in the novel environment. Dressage horses demonstrated greater baseline cortisol concentrations at competition than showjumpers, suggesting that they may perceive the novel environment as more stressful. Furthermore, there was no consistent relationship between baseline salivary cortisol concentrations and competition scores across the events. PMID- 28800427 TI - Sibling response to initial antiepileptic medication predicts treatment success. AB - OBJECTIVE: A recent study focusing on a response to antiepileptic drugs (AED) among siblings for epilepsy showed a similar response among epileptic siblings to specific AEDs or AED combinations. Currently, however, family history of treatment response to AEDs is not readily employed in deciding which initial medication to use when treating patients with epilepsy. We tested the hypothesis that sibling response to initial AED predicts treatment success. METHODS: Presumed siblings were identified from a single-center database of patients diagnosed with epilepsy by matching last name, address, and name of parent(s). We identified 28 sibling pairs and two sibling trios with epilepsy. Seventeen of these sibling pairs were started on the same initial AED, with 15 sibling pairs having the same type of epilepsy. The remaining 11 pairs were started on a different initial AED, with 8 of these sibling pairs having the same type of epilepsy. Subjects with seizure freedom for a period of >=1year were classified as a "responder". RESULTS: When at least one of the sibling pair responded to an initial AED, the proportion of the other siblings also responding to the initial AED was significantly higher if the siblings were treated with the same AED (8/11) compared to siblings who were treated with different AED (1/10) (Fisher's exact test, p-value=0.0075). SIGNIFICANCE: These findings suggest that sibling response to initial AED is predictive of the success of AED therapy. This study is limited by a small cohort and retrospective design. Future, larger prospective studies are needed to reproduce and further validate these findings. PMID- 28800428 TI - Socially anxious tendencies affect neural processing of gaze perception. AB - The gaze of others is known to be a particularly common cause of social anxiety. In the current study, we measured event-related potentials (ERPs) during gaze perception among people with or without high socially anxious tendencies (HSA). The experimental stimuli were grayscale images of the eye region of a face, showing direct or averted eye gaze (leftward gaze or rightward gaze) or closed eyes. We found that negative ERPs at a right occipito-temporal site (N170) and positive ERPs at the fronto-central region (P2) were evoked by eye gaze stimuli. While the N170 was not affected by socially anxious tendencies, the amplitude of the P2 was significantly greater in the HSA group than in the low socially anxious tendencies (LSA) group. Furthermore, P2 latency showed a significant interaction between groups and conditions: the HSA group exhibited shorter P2 latencies in response to direct gaze than averted gaze, while the LSA group did not. These results indicate that the neural processing of eye gaze is strongly influenced by socially anxious tendencies. In particular, the attentional processing of direct gaze is more prominent in individuals with HSA tendencies. PMID- 28800429 TI - Bimanual coordination positively predicts episodic memory: A combined behavioral and MRI investigation. AB - Some people remember events more completely and accurately than other people, but the origins of individual differences in episodic memory are poorly understood. One way to advance understanding is by identifying characteristics of individuals that reliably covary with memory performance. Recent research suggests motor behavior is related to memory performance, with individuals who consistently use a single preferred hand for unimanual actions performing worse than individuals who make greater use of both hands. This research has relied on self-reports of behavior. It is unknown whether objective measures of motor behavior also predict memory performance. Here, we tested the predictive power of bimanual coordination, an important form of manual dexterity. Bimanual coordination, as measured objectively on the Purdue Pegboard Test, was positively related to correct recall on the California Verbal Learning Test-II and negatively related to false recall. Furthermore, MRI data revealed that cortical surface area in right lateral prefrontal regions was positively related to correct recall. In one of these regions, cortical thickness was negatively related to bimanual coordination. These results suggest that individual differences in episodic memory may partially reflect morphological variation in right lateral prefrontal cortex and suggest a relationship between neural correlates of episodic memory and motor behavior. PMID- 28800430 TI - Chain length effects on the vibrational structure and molecular interactions in the liquid normal alkyl alcohols. AB - Alkyl alcohols are widely used in academia, industry, and our everyday lives, e.g. as cleaning agents and solvents. Vibrational spectroscopy is commonly used to identify and quantify these compounds, but also to study their structure and behavior. However, a comprehensive investigation and comparison of all normal alkanols that are liquid at room temperature has not been performed, surprisingly. This study aims at bridging this gap with a combined experimental and computational effort. For this purpose, the alkyl alcohols from methanol to undecan-1-ol have been analyzed using infrared and Raman spectroscopy. A detailed assignment of the individual peaks is presented and the influence of the alkyl chain length on the hydrogen bonding network is discussed. A 2D vibrational mapping allows a straightforward visualization of the effects. The conclusions drawn from the experimental data are backed up with results from Monte Carlo simulations using the simulation package Cassandra. PMID- 28800431 TI - Anharmonic vibrational analysis of s-trans and s-cis conformers of acryloyl fluoride using numerical-analytic Van Vleck operator perturbation theory. AB - A new gas-phase infrared (IR) spectrum of acryloyl fluoride (ACRF, CH2CHCFO) with a resolution of 0.1cm-1 in the range 4000-450cm-1 was measured. Theoretical ab initio molecular structures, full quartic potential energy surfaces (PES), and cubic surfaces of dipole moments and polarizability tensor components (electro optical properties, EOP) of the s-trans and s-cis conformers of the ACRF were calculated by the second-order Moller-Plesset electronic perturbation theory with a correlation consistent Dunning triple-zeta basis set. The numerical-analytic implementation of the second-order operator canonical Van Vleck perturbation theory was employed for predicting anharmonic IR and Raman scattering (RS) spectra of ACRF. To improve the anharmonic predictions, harmonic frequencies were replaced by their counterparts evaluated with the higher-level CCSD(T)/cc-pVTZ model, to form a "hybrid" PES. The original operator representation of the Hamiltonian is analytically reduced to a quasi-diagonal form, integrated in the harmonic oscillator basis and diagonalized to account for strong resonance couplings. Double canonical transformations of EOP expansions enabled prediction of integral intensities of both fundamental and multi-quanta transitions in IR/RS spectra. Enhanced band shape analysis reinforced the assignments. A thorough interpretation of the new IR experimental spectra and existing matrix-isolation literature data for the mixture of two conformers of ACRF was accomplished, and a number of assignments clarified. PMID- 28800432 TI - Linear and circular dichroism characterization of thionine binding mode with DNA polynucleotides. AB - The binding mode of thionine (3,7-diamino-5-phenothiazinium) with alternating and non-alternating DNA polynucleotides at low binding ratios was conclusively determined using linear and circular dichroism spectroscopies. The binding to [poly(dG-dC)]2 and poly(dG).poly(dC) was purely intercalative and was insensitive to ionic strength. Intercalative binding to [poly(dA-dT)]2 is observed at low ionic strength, but a shift of some dye to an non-intercalative mode is observed as the background salt concentration increases. With poly(dA).poly(dT), intercalative binding is unfavourable, although some dye molecules may intercalate at low ionic strength, and groove binding is strongly promoted with increasing concentration of background salt. However, stacking with bases is observed with single-stranded poly(dA) and with triplex poly(dT)*poly(dA).poly(dT) which suggests that the unusual structure of poly(dA).poly(dT) precludes intercalation. Thionine behaves similarly to the related dye methylene blue, and small differences may be attributed either to the ability of thionine to form H-bonds that stabilize intercalation or to its improved stacking interactions in the basepair pocket on steric grounds. PMID- 28800433 TI - Global gene expression analysis of the muscle tissues of medaka acclimated to low and high environmental temperatures. AB - Medaka (Oryzias latipes) is a temperate eurythermal fish that is able to survive over a wide range of water temperatures ranging from near zero to over 30 degrees C throughout the year; it maintains its normal physiological and biochemical processes through temperature acclimation. To determine the mechanisms involved in temperature acclimation of fish, the fast skeletal muscle tissues of medaka underwent global gene expression analysis using next-generation sequencing. Ten individuals were placed into two aquariums at 24 degrees C. While the water temperature of one aquarium was decreased to 10 degrees C, that of the other aquarium was increased to 30 degrees C; these temperatures were subsequently maintained for 5weeks. RNA sequencing (RNA-Seq) analyses revealed that 11 genes involved in energy metabolism and muscle atrophy were significantly highly expressed in the 10 degrees C-acclimated fish. Meanwhile, significantly higher expression levels were observed for 20 genes encoding myofibrillar proteins and heat shock proteins in the 30 degrees C-acclimated fish. Moreover, 1103 genes had at least fourfold differential expression between the acclimation groups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses provided important information: although the expression of genes related to metabolic processes were activated, muscle atrophy occurred in the 10 degrees C acclimated fish, and muscle cells divided actively in the 30 degrees C-acclimated fish and avoided thermal stress by expressing heat shock proteins. Therefore, RNA Seq analyses with the available genome database will be useful for better understanding the molecular mechanisms involved in the temperature acclimation of fish. PMID- 28800434 TI - Enhanced photothermal therapy of biomimetic polypyrrole nanoparticles through improving blood flow perfusion. AB - In this study, we reported a strategy to improve delivery efficiency of a long circulation biomimetic photothermal nanoagent for enhanced photothermal therapy through selectively dilating tumor vasculature. By using a simply nanocoating technology, a biomimetic layer of natural red blood cell (RBC) membranes was camouflaged on the surface of photothermal polypyrrole nanoparticles (PPy@RBC NPs). The erythrocyte-mimicking PPy NPs inherited the immune evasion ability from natural RBC resulting in superior prolonged blood retention time. Additionally, excellent photothermal and photoacoustic imaging functionalities were all retained attributing to PPy NPs cores. To further improve the photothermal outcome, the endothelin A (ETA) receptor antagonist BQ123 was jointly employed to regulate tumor microenvironment. The BQ123 could induce tumor vascular relaxation and increase blood flow perfusion through modulating an ET-1/ETA transduction pathway and blocking the ETA receptor, whereas the vessel perfusion of normal tissues was not altered. Through our well-designed tactic, the concentration of biomimetic PPy NPs in tumor site was significantly improved when administered systematically. The study documented that the antitumor efficiency of biomimetic PPy NPs combined with specific antagonist BQ123 was particularly prominent and was superior to biomimetic PPy NPs (P < 0.05) and PEGylated PPy NPs with BQ123 (P < 0.01), showing that the greatly enhanced photothermal treatment could be achieved with low-dose administration of photothermal agents. Our findings would provide a promising procedure for other similar enhanced photothermal treatment by blocking ETA receptor to dramatically increase the delivery of biomimetic photothermal nanomaterials. PMID- 28800435 TI - Reliability of measurement of the carpal tunnel and median nerve in asymptomatic subjects with ultrasound. AB - BACKGROUND: Morphology of the carpal tunnel changes with varying wrist postures and compressive forces applied to the wrist. These changes may affect the morphology and pressure on the median nerve and could be used as part of the treatment of the carpal tunnel syndrome patients. Reliability of the ultrasonographic measurements of the median nerve has been widely studied. However, there is a lack of investigation regarding reliability of ultrasonographic measurements of the carpal tunnel. OBJECTIVE: The purpose of this study was to assess intra-tester and inter-tester reliability of measurement of dimensions of the carpal tunnel and median nerve with ultrasound in asymptomatic volunteers. DESIGN: A cross-sectional methodological study. METHODS: Aspects measured were mediolateral and anteroposterior diameters, flattening ratio, circularity, perimeter and cross-section area of the carpal tunnel and median nerve. RESULTS: Intra-tester reliability was excellent for the carpal tunnel (ICCs from 0.91 to 0.97) and for the median nerve (ICCs from 0.79 to 0.94) measurements. The flattening ratio of the median nerve showed good agreement (ICC = 0.68). Inter-tester reliability was excellent for the carpal tunnel measurements (ICCs from 0.76 to 0.95) and, for the cross sectional area, the perimeter and mediolateral diameter of the median nerve, the ICC values were 0.89, 0.84 and 0.81, respectively. CONCLUSION: In the context of this study, ultrasound was a reliable instrument for measuring carpal tunnel and median nerve dimensions in asymptomatic subjects. LEVEL OF EVIDENCE: 1b. PMID- 28800436 TI - Tactile acuity testing at the neck: A comparison of methods. AB - BACKGROUND: Interest in measurement of tactile acuity in musculoskeletal practice has emerged following its link to functional reorganization of the somatosensory cortex in ongoing pain states. Several tactile acuity measurement methods have been described but have not been thoroughly investigated in the cervical region. OBJECTIVE: This study examined reliability, concurrent validity and responsiveness of four tests of tactile acuity-Two-point discrimination, Point-to point, Graphesthesia, and Localisation tests-at the cervical region. METHOD: Forty-two healthy participants were included. In Part 1 (n = 22), participants' tactile acuity was assessed at two time points, 30 min apart, to determine the test-retest reliability and concurrent validity of each of the tests. In Part 2 (n = 20), participants received five daily tactile training sessions, delivered via a vibro-tactile device. Tactile acuity was assessed pre- and post-training to examine responsiveness of each test. RESULTS: Two-point discrimination demonstrated excellent test-retest reliability (ICC = 0.85, SEM = 3.7 mm), Point to-point and Localisation tests demonstrated good reliability (ICC = 0.60, SEM = 2.8 mm; ICC = 0.60, SEM = 8.8%), and Graphesthesia demonstrated fair reliability (ICC = 0.48, SEM = 1.9/20). There was no significant correlation among measures. Only Graphesthesia failed to show responsiveness to change following training. CONCLUSION: The reliability of Two-point discrimination appears superior to other examined tests of tactile acuity, however measurement variability should be considered. Two-point discrimination, Point-to-point, and Localisation tests appear responsive to change, although testing in clinical samples is needed. The lack of concurrent validity among tests suggests that they cannot be used interchangeably. PMID- 28800437 TI - Beyond the latch: A new approach to breastfeeding. AB - Health professionals supporting breastfeeding play an important role in women successfully achieving their breastfeeding goals. Instrumental knowledge has dominated health professionals' breastfeeding education and practice. Because breastfeeding is a contextual and embodied experience, a relational orientation is required to identify effective strategies to support women. A relational inquiry approach to breastfeeding practice offers a practical way to support women to better achieve their breastfeeding goals within the complexities of their own lives. Incorporating a relational inquiry approach to breastfeeding practice may assist health professionals to more effectively respond and engage with women in practice so that women's breastfeeding goals are protected; women's capacity and self-efficacy are promoted; and women feel and experience the support from health professionals that they require to be successful with breastfeeding. PMID- 28800438 TI - Social exposure and emotion dysregulation: Main effects in relation to nonsuicidal self-injury. AB - We examined the relation of interpersonal and media exposure to nonsuicidal self injury (NSSI) among 340 university students in the southeastern United States (73.5% female, M age = 19.38 years, SD = 1.15). We also assessed interactions and main effects of each exposure and emotion dysregulation in relation to NSSI, testing the social learning hypothesis of NSSI. Most participants endorsed medium to high levels of exposure to NSSI via media sources. More than one-third of participants were somewhat or very familiar with someone who engaged in NSSI. Almost half reported occasional or frequent conversations about NSSI. Both exposure forms were significantly related to NSSI history. However, hurdle regression analyses revealed that interpersonal exposure and emotion dysregulation, but not media exposure, were significantly associated with NSSI history and frequency. We did not find evidence for an emotion dysregulation-by interpersonal-exposure interaction. We discuss implications for theoretical models of NSSI, limitations, and future directions. PMID- 28800439 TI - A simplified parametrised model for lung microstructures capable of mimicking realistic geometrical and mechanical properties. AB - The respiratory zone of mammalian lungs contains several millions of so-called alveoli. The geometrical and mechanical properties of this microstructure are crucial for respiration and influence the macroscopic behaviour of the entire organ in health and disease. Hence, if computational models are sought to gain more insight into lung behaviour, predict lung states in certain scenarios or suggest better treatment options in early stages of respiratory dysfunction, an adequate representation of this microstructure is essential. However, investigating the real alveolar architecture requires complex medical-imaging methods and would be computationally extremely expensive. Even worse, there is currently no way of obtaining the real patient-specific microstructure in vivo. Hence, we present a fast and easy to compute parametrised model of lung microstructures based on tetrakaidecahedra which can represent both geometrical and mechanical properties of the parenchyma. We show that gas transport pathways and stress and strain distributions are comparable to real alveolar microstructures and even capable of capturing variations present in biology. The created parametrised lung microstructure models can be utilized in finite element simulations to study, e.g., alveolar flow phenomena, particle deposition, or alveolar stresses and strains during mechanical ventilation. Due to the simpler geometry of the parametrised microgeometries compared to imaging-based microstructures, remarkable savings in CPU time can be achieved. We show that our model requires a minimum of 10% of the computational time for computing the same strain state in structural mechanics simulations compared to imaging-based alveolar microstructures. PMID- 28800440 TI - Low density lipoprotein transport through patient-specific thoracic arterial wall. AB - BACKGROUND AND AIMS: The distribution of Low density lipoprotein (LDL) within the arterial wall is helpful in understanding the onset and development of atherosclerosis. The objective of the study is to study the transport and LDL distribution within patient-specific arterial wall using computational analysis under normal and hypertensive conditions. METHODS: Patient specific model of the thoracic aorta is computationally examined. The arterial wall is treated macroscopically as homogeneous (one layered) porous media of variable thickness. The interfacial lumen-arterial wall (endothelium) coupling is achieved by the Kedem-Katchalsky equation. RESULTS: High values of LDL are located at areas where WSS values range from 0.4 N/m2 to 1.5 N/m2 for normal conditions. In this case the Pearson correlation coefficient r between LDL values and WSS is equal to 0.655 denoting a strong negative linear correlation. In the case that hypertension takes place, high LDL values are located at areas where WSS values range from 0.59 N/m2 to 1.7 N/m2 and the corresponding Pearson correlation coefficient r is equal to -0.808 denoting a very strong negative linear correlation. For the same parabolic intake flow velocity profile, the luminal surface concentration of LDL is 0.2-2.1% higher than that of the bulk flow for the normal pressure and 0.4-3.4% higher than that of the bulk flow for the hypertensive pressure. For normal conditions, the concentration of LDL at the endothelium/media interface is considerably lower (almost 20 times) than the LDL concentration value at lumen/endothelium interface. For hypertensive conditions, the LDL concentration at the endothelium/media interface is only 4.5 times lower than the corresponding luminal (endothelium side) concentration. The lumen/endothelium side locations (mainly the concave parts) of low WSS - high LDL concentration values coincide with those of high wall-side LDL concentration. CONCLUSIONS: The transport and LDL distribution is affected by elevated transmural pressure which causes higher LDL concentration. Thus, hypertensive conditions theoretically enhance atherosclerosis. PMID- 28800441 TI - Digital image analysis protocol for determining the radiocarpal joint space in the rheumatoid arthritic wrist. AB - This paper describes a simple protocol for measuring the joint space of the rheumatoid arthritic (RA) wrist from projection radiographs. The protocol is implemented using a computer algorithm based upon the Interactive Data Language platform. The computerized algorithm features a user-friendly graphical interface to aid the operator to measure joint space parameters, namely distance and area, of the wrist vertebral morphometry at the radiocarpal region. Dual-energy X-ray absorptiometry (DXA) radiograph of a standard hand and wrist phantom was evaluated using the measurement protocol to determine the accuracy and precision of the protocol. The accuracy, parameterised by the systematic error, returned a mean of 5.20% for distance and is equal to 3.49% for area measurement. The precision of the measurement protocol, parameterised by the coefficient of variation (CV), for distance returned a mean of 1.96%; the CV for area measurement equals 2.1%. Three observers participated to investigate the repeatability (intra-observer) and reproducibility (inter-observer) of the measurement protocol, parameterised by the CV, using DXA radiographs from a healthy volunteer and a RA patient. The inter-observer repeatability for distance measurement for the respective observers returned mean values of 10.9%, 7.7% and 11.4% for the healthy wrist. However, the results revealed improved repeatability for the RA wrist; the CV for the respective observers returned mean values of 7.7% 7.1% and 10.0%. The inter-observer repeatability for area measurement for the respective observers returned mean values of 10.2%, 7.1% and 10.1% for the healthy wrist. However, the results revealed improved repeatability (in two out of the three observers) for the RA wrist; the CV for the respective observers returned mean values of 6.8% 6.5% and 10.8%. Student's t-test analysis of the intra-observer repeatability revealed that the measurements of distance and area were generally not intra-observer sensitive. On the other hand, student's t-test analysis of the inter-observer reproducibility revealed that half of the distance measurements were inter-observer sensitive; whereas the remaining were not. Similar findings were obtained for area measurements. Overall the results reveal that the variabilities in accuracy and precision tests and the repeatability and reproducibility tests were typically 10% or less. These findings, in addition to the versatility and simplicity of the digital image analysis protocol, lend to the potential of using the protocol to complement the acquisition of bone mineral density data derived from DXA for diagnosing the progression of RA in patients. PMID- 28800442 TI - Pre-trained convolutional neural networks as feature extractors for tuberculosis detection. AB - It is estimated that in 2015, approximately 1.8 million people infected by tuberculosis died, most of them in developing countries. Many of those deaths could have been prevented if the disease had been detected at an earlier stage, but the most advanced diagnosis methods are still cost prohibitive for mass adoption. One of the most popular tuberculosis diagnosis methods is the analysis of frontal thoracic radiographs; however, the impact of this method is diminished by the need for individual analysis of each radiography by properly trained radiologists. Significant research can be found on automating diagnosis by applying computational techniques to medical images, thereby eliminating the need for individual image analysis and greatly diminishing overall costs. In addition, recent improvements on deep learning accomplished excellent results classifying images on diverse domains, but its application for tuberculosis diagnosis remains limited. Thus, the focus of this work is to produce an investigation that will advance the research in the area, presenting three proposals to the application of pre-trained convolutional neural networks as feature extractors to detect the disease. The proposals presented in this work are implemented and compared to the current literature. The obtained results are competitive with published works demonstrating the potential of pre-trained convolutional networks as medical image feature extractors. PMID- 28800443 TI - A novel approach to spinal 3-D kinematic assessment using inertial sensors: Towards effective quantitative evaluation of low back pain in clinical settings. AB - This paper presents a novel approach for evaluating LBP in various settings. The proposed system uses cost-effective inertial sensors, in conjunction with pattern recognition techniques, for identifying sensitive classifiers towards discriminate identification of LB patients. 24 healthy individuals and 28 low back pain patients performed trunk motion tasks in five different directions for validation. Four combinations of these motions were selected based on literature, and the corresponding kinematic data was collected. Upon filtering (4th order, low pass Butterworth filter) and normalizing the data, Principal Component Analysis was used for feature extraction, while Support Vector Machine classifier was applied for data classification. The results reveal that non-linear Kernel classification can be adequately employed for low back pain identification. Our preliminary results demonstrate that using a single inertial sensor placed on the thorax, in conjunction with a relatively simple test protocol, can identify low back pain with an accuracy of 96%, a sensitivity of %100, and specificity of 92%. While our approach shows promising results, further validation in a larger population is required towards using the methodology as a practical quantitative assessment tool for the detection of low back pain in clinical/rehabilitation settings. PMID- 28800444 TI - Do parental ADHD symptoms reduce the efficacy of parent training for preschool ADHD? A secondary analysis of a randomized controlled trial. AB - Previous studies have suggested that children with Attention Deficit/Hyperactivity Disorder (ADHD) may benefit less from behavioral parent training (BPT) if their parents have high levels of ADHD symptoms. We conducted a secondary analysis of data from a randomized controlled trial to test the hypothesis that parental ADHD symptoms reduce the efficacy of two BPT programs in a sample of preschoolers with ADHD. One intervention was specifically designed for children with ADHD (NFPP: New Forest Parenting Programme) and one was designed for children with Oppositional Defiant Disorder (ODD) (HNC: Helping the Noncompliant Child). Neither intervention was adapted to address parental ADHD symptoms. This secondary analysis included data from 164 parents and their 3-4 year-old children who were randomly assigned to one of the two programs or a waitlist group. Children were compared on ADHD and ODD outcomes at post intervention and a 6-month follow-up. The presence of parent ADHD symptoms reduced the efficacy of BPT in only one of 16 analyses. Implications and limitations (e.g., low baseline rate of parental ADHD symptoms) of the findings are provided. PMID- 28800445 TI - Enzyme-sensitive gemcitabine conjugated albumin nanoparticles as a versatile theranostic nanoplatform for pancreatic cancer treatment. AB - Development of gemcitabine (GEM) nanocarriers as theranostic agents for pancreatic cancer chemotherapy has received extensive attention in recent years. A novel enzyme-sensitive albumin-based GEM delivery nanoplatform was developed in this research by simple conjugation of GEM to human serum albumin (HSA) via cathepsin B cleavable peptide GFLG and then complexing with near-infrared (NIR) dye IR780, forming a HSA-GEM/IR780 complex. The successful preparation of HSA GEM/IR780 complex was confirmed by Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS), UV-vis-NIR absorption spectra and fluorescent emission spectra. The in vivo performance of HSA-GEM/IR780 complex was carried out on BxPC-3 pancreatic tumor xenografted mice. As revealed by in vivo NIR imaging, HSA-GEM/IR780 exhibited enhanced accumulation and long term retention in tumor tissues compared to free IR780. Meanwhile, compared to free GEM, the deamination of GEM nanovectors into inactive 2',2' difluorodeoxyuridine (dFdU) can be greatly suppressed, while the concentration of the activated form of GEM (gemcitabine triphosphate, dFdCTP) was significantly increased in tumor tissue, thus exhibiting superior tumor inhibition activity with minimal side effects. PMID- 28800446 TI - Synthesis of a hierarchical SnS2 nanostructure for efficient adsorption of Rhodamine B dye. AB - Using Sn2+ instead of Sn4+ as Sn source, H2O2 as oxidizer, and l-cysteine as sulphur source and structure-directing agent, hierarchical SnS2 nanostructure built with the thickness of 10nm nanosheets was successfully synthesized by a green hydrothermal process. The morphology and structure of the products were investigated by means of X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM) with energy-dispersive X-ray spectrometer (EDS) and Elemental mapping, Fourier transform infrared spectroscopy (FT-IR) and X-ray photoelectron spectroscopy (XPS). The as-prepared nanostructured SnS2 nanomaterials were tested for adsorption of Rhodamine B (RhB) from aqueous solution. The effects of contact time, adsorbent dosage and initial concentration were investigated in detail. The adsorption kinetic data were well fitted to the pseudo-second-order model and the equilibrium adsorption data were well described by the Langmuir isotherm model, with a maximum capacity of 200.0mgg-1. This study provides a novel approach to obtain metal sulfide nanostructures using low-valence metal salts. PMID- 28800447 TI - Two-phase displacements in microchannels of triangular cross-section. AB - Varying microfluidic channel cross-sectional geometry can dramatically alter fluid flow behavior, particularly for capillary-driven flow. Most fabrication techniques, however, are planar and therefore incapable of providing depth dependent variations in width. We introduce an ultrafast laser ablation technique that enables the fabrication of microchannels with arbitrary triangular cross sectional geometry. Triangular channels were fabricated with widths ranging from 45 to 116um and aspect ratios between 0.7 and 1.9. This experimental platform was utilized to observe two-phase flow and evaluate the capillary pressures required to initiate flow within triangular capillaries. Applying Mayer, Stowe and Princen (MS-P) theory, critical drainage capillary pressures were predicted for varying cross sections and compared to experimental observations. Results indicate the capability to predict capillary pressures inside triangular channels with perfectly water wet surfaces, providing the first instance of experimental validation of the theory for arbitrary triangular cross sections. This work was extended to intermediate wet conditions, which provides an insight into the prediction of capillary pressure under more realistic conditions. The fabrication techniques and validation of predictive frameworks presented here provide an approach to microfluidic experimental design that will impact a wide range of fundamental and applied technology areas. PMID- 28800448 TI - Biphasic-to-monophasic successive Co-assembly approach to yolk-shell structured mesoporous organosilica nanoparticles. AB - In this work, we report a facile biphasic-to-monophasic successive co-assembly approach to synthesize yolk-shell structured mesoporous organosilica nanoparticles (MONs). The yolk-shell structured MONs possess ethane-bridged frameworks, high surface area (1023m2g-1), radially oriented mesochannels (3.8nm), large pore volume (0.99cm3g-1), and tunable diameter (147-324nm) and shell thickness (23-53nm). The biphasic-to-monophasic successive co-assembly method is intrinsically simple and requires neither sacrificial templates nor multistep coating processes. The key of the method is that the interiors of the mesostructured organosilica nanospheres grown in the biphasic system have a lower condensation degree and Si-C-C-Si species content than the outer shells formed in the monophasic system. Thus, the interior layer is attracted by OH-1 anions and dissolved in the monophasic system, forming the yolk-shell structures. In vitro cytotoxicity and haemolysis assays demonstrate that the ethane-bridged yolk-shell MONs possess excellent biocompatibility. Furthermore, the chemotherapy drug doxorubicin (DOX) is loaded into the yolk-shell MONs to kill drug-resistant MCF 7/ADR human breast cancer cells. Compared with free DOX and DOX-loaded typical MONs, the DOX-loaded yolk-shell MONs have higher chemotherapeutic efficacy against MCF-7/ADR cells, suggesting the great potential of yolk-shell MONs synthesized via the biphasic-to-monophasic successive co-assembly approach in the biomedical field. PMID- 28800449 TI - Enhanced adsorption removal of antibiotics from aqueous solutions by modified alginate/graphene double network porous hydrogel. AB - Alginate/graphene double network hydrogel has recently been demonstrated as a promising adsorbent for water pollutants. To improve the adsorption capacity of the double network hydrogel, physical and chemical modifications are made to obtain an excellent porous structure and more functional groups. As-modified alginate/graphene double network hydrogel has a higher hydroxyl group content under a higher polyvinyl alcohol content and a higher carboxyl group content with a higher oxidation degree. Moreover, the CO2 produced by CaCO3 is used as pore formation agent avoiding the use of toxic organic matters. The modified alginate/graphene double network hydrogel shows a higher specific surface area, a larger mean pore diameter, and a higher pore volume with a higher initial CaCO3. In antibiotics adsorption, the mechanistic understanding shows that hydrogen bonds have greater influence on adsorption than carboxyl groups. The results reported here pave the way for the use of the alginate/graphene double network hydrogel for water treatment. PMID- 28800450 TI - Status inconsistency and mental health: A random effects and instrumental variables analysis using 14 annual waves of cohort data. AB - Status inconsistency refers to a discrepancy between the position a person holds in one domain of their social environment comparative to their position in another domain. For example, the experience of being overeducated for a job, or not using your skills in your job. We sought to assess the relationship between status inconsistency and mental health using 14 annual waves of cohort data. We used two approaches to measuring status inconsistency: 1) being overeducated for your job (objective measure); and b) not using your skills in your job (subjective measure). We implemented a number of methodological approaches to assess the robustness of our findings, including instrumental variable, random effects, and fixed effects analysis. Mental health was assessed using the Mental Health Inventory-5. The random effects analysis indicates that only the subjective measure of status inconsistency was associated with a slight decrease in mental health (beta-1.57, 95% -1.78 to -1.36, p < 0.001). This size of these coefficients was maintained in the instrumental variable analysis. We suggest that status inconsistency might explain some of the relationship between social determinants (such as work and education) and health outcomes. PMID- 28800451 TI - Synthesis, antimicrobial, DNA cleavage and antioxidant activities of tricyclic sultams derived from saccharin. AB - Two series of fused tricyclic sultams (carboxylates, 3a, b and 5a, f, g and anilides 5b-e) were synthesized from saccharin and their chemical structures were confirmed by spectroscopic tools. Then, their antibacterial activities and MIC were evaluated against two strains of gram positive and gram-negative bacteria. The MIC values of the tested compounds are in the of range 8-33 MUg/ml. In addition, their DNA cleavage ability, binding affinity and their anticancer activities against hepatic cancer cell were tested. And their antioxidant activities were also measured. Four carboxylate derivatives (3a, 5a, 5f and 5g) and one anilide (5d) of the tested compounds proved to be the highest activity all over the study. PMID- 28800452 TI - Identification of 3,4-dihydro-2H-thiochromene 1,1-dioxide derivatives with a phenoxyethylamine group as highly potent and selective alpha1D adrenoceptor antagonists. AB - A series of phenoxyethylamine derivatives was designed and synthesized to discover potent and selective human alpha1D adrenoceptor (alpha1D adrenergic receptor; alpha1D-AR) antagonists. Compound 7 was taken from our internal compound collection as an attractive starting point and exhibited moderate binding affinity for alpha1D-AR and high selectivity against alpha1A- and alpha1B ARs. We focused on modifying the 2-methylsulfonylbenzyl group of 7 to discover novel compounds structurally distinct from other reported alpha1-AR antagonists containing the phenoxyethylamine motif. Study of structure activity relationship guided by a targeted ligand-lipophilicity efficiency score led to the discovery of a novel scaffold of 3,4-dihydro-2H-thiochromene 1,1-dioxide for selective alpha1D-AR antagonists. Further optimization studies resulted in the identification of (4S)-N4-[2-(2,5-difluorophenoxy)ethyl]-N6-methyl-3,4-dihydro-2H thiochromene-4,6-diamine 1,1-dioxide, (S)-41, as a novel, highly potent and selective alpha1D-AR antagonist. Herein, we provide details of the structure activity relationship of the phenoxyethylamine analog for the potency and selectivity. PMID- 28800453 TI - Discovery of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific glucokinase activators: Design, synthesis, and biological evaluation. AB - Glucokinase (GK) activators are being developed for the treatment of type 2 diabetes mellitus (T2DM). However, existing GK activators have risks of hypoglycemia caused by over-activation of GK in islet cells and dyslipidemia caused by over-activation of intrahepatic GK. In the effort to mitigate risks of hypoglycemia and dyslipidemia while maintaining the promising efficacy of GK activator, we investigated a series of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific partial GK activators, which led to the identification of compound 72 that showed a good balance between in vitro potency and enzyme kinetic parameters, and protected beta-cells from streptozotocin-induced apoptosis. Chronic treatment of compound 72 demonstrated its potent activity in regulation of glucose homeostasis and low risk of dyslipidemia with diabetic db/db mice in oral glucose tolerance test (OGTT). Moreover, acute treatment of compound 72 did not induce hypoglycemia in C57BL/6J mice even at 200 mg/kg via oral administration. PMID- 28800454 TI - Tau protein aggregation in Alzheimer's disease: An attractive target for the development of novel therapeutic agents. AB - Alzheimer's Disease (AD) is a neurodegenerative brain disorder in which many biological dysfunctions are involved. Among them, two main types of lesions were discovered and widely studied: the amyloid plaques and the neurofibrillary tangles (NFTs). These two lesions are caused by the dysfunction and the accumulation of two proteins which are, respectively, the beta-amyloid peptide and the tau protein. The process that leads these two proteins to aggregate is complex and is the subject of current studies. After a brief description of the aggregation mechanisms, we will provide an overview of new therapeutic agents targeting the different dysfunctions and toxic species found during aggregation. PMID- 28800455 TI - In vitro targeting of colon cancer cells using spiropyrazoline oxindoles. AB - We report on the synthesis and biological evaluation of a library of twenty-three spiropyrazoline oxindoles. The antiproliferative activity of the chemical library was evaluated in HCT-116 p53(+/+) human colon cancer cell line with eight derivatives displaying good activities (IC50<15 MUM). To characterize the molecular mechanisms involved in compound antitumoral activity, two spiropyrazoline oxindoles were selected for further studies. Both compounds were able to induce apoptosis and cell cycle arrest at G0/G1 phase and upregulated p53 steady-state levels, while decreasing its main inhibitor MDM2. Importantly, cytotoxic effects induced by spiropyrazolines oxindoles occurred in cancer cells without eliciting cell death in non-malignant CCD-18Co human colon fibroblasts. Additionally, we demonstrated that the combination of spiropyrazoline oxindole 2e with sub-toxic concentrations of the chemotherapeutic agent 5-fluorouracil (5-FU) exerted a synergistic inhibitory effect on HCT-116 colon cancer cell proliferation. Collectively, our results show the potential of spiropyrazoline oxindoles for development of novel anticancer agents. PMID- 28800456 TI - Synthesis and anticancer properties of ruthenium (II) complexes as potent apoptosis inducers through mitochondrial disruption. AB - A new ligand MHPIP (MHPIP = 2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazo[4,5 f][1,10]phenanthroline) and its three ruthenium (II) complexes [Ru(N N)2(MHPIP)](ClO4)2 (N-N = phen: 1,10-phenanthroline 1; dmp = 2,9-dimethyl-1,10 phenanthroline 2; ttbpy = 4,4'-ditertiarybutyl-2,2'-bipyridine 3) were synthesized and characterized. The cytotoxic activity in vitro was studied by MTT method. The complexes 1-3 show moderate cytotoxic effects on the cell growth in HepG2 cells with an IC50 value of 25.5 +/- 3.5, 35.6 +/- 1.9 and 27.4 +/- 2.3 MUM, respectively. The apoptosis was investigated with AO/EB and Annex V/PI staining methods and comet assay. The reactive oxygen species, mitochondrial membrane potential were investigated under a fluorescent microscope. Autophagy assay shows that the complexes can cause autophagy and up-regulate the expression of Beclin-1 protein. Additionally, the complexes inhibit the cell growth in HepG2 cells at G0/G1 phase, and the complexes can regulate the expression of caspase 3 and Bcl-2 family proteins. The studies demonstrate that the complexes induce apoptosis in HepG2 cells through DNA damage and ROS-mediated mitochondrial dysfunction pathways. PMID- 28800457 TI - Fucosylated chondroitin sulfate oligosaccharides exert anticoagulant activity by targeting at intrinsic tenase complex with low FXII activation: Importance of sulfation pattern and molecular size. AB - Fucosylated chondroitin sulfates (fCSs) are structurally unusual glycosaminoglycans isolated from sea cucumbers that exhibit potent anticoagulant activity. These fCSs were isolated from sea cucumber, Isostichopus badionotus and Pearsonothuria graeffei. Fenton reaction followed by gel filtration chromatography afforded fCS oligosaccharides, with different sulfation patterns identified by mass and NMR spectroscopy, and these were used to clarify the relationship between the structures and the anticoagulant activities of fCSs. In vitro activities were measured by activated partial thromboplastin time (APTT), thrombin time (TT), thrombin and factor Xa inhibition, and activation of FXII. The results showed that free radicals preferentially acted on GlcA residues affording oligosaccharides that were purified from both fCSs. The inhibition of thrombin and factor X activities, mediated through antithrombin III and heparin cofactor II of fCSs oligosaccharides were affected by their molecular weight and fucose branches. Oligosaccharides with different sulfation patterns of the fucose branching had a similar ability to inhibit the FXa by the intrinsic factor Xase (factor IXa-VIIIa complex). Oligosaccharides with 2,4-O-sulfo fucose branches from fCS-Ib showed higher activities than ones with 3,4-O-disulfo branches obtained from fCS-Pg. Furthermore, a heptasaccharide is the minimum size oligosaccharide required for anticoagulation and FXII activation. This activity was absent for fCS oligosaccharides smaller than nonasaccharides. Molecular size and fucose branch sulfation are important for anticoagulant activity and reduction of size can reverse the activation of FXII caused by native fCSs. PMID- 28800458 TI - Quinoline hybrids and their antiplasmodial and antimalarial activities. AB - Malaria, in particular infection with P. falciparum (the most lethal of the human malaria parasite species, responsible for nearly one million deaths every year), is one of the most devastating and common infectious disease throughout the world. Beginning with quinine, quinoline containing compounds have long been used in clinical treatment of malaria and remained the mainstays of chemotherapy against malaria. The emergence of P. falciparum strains resistant to almost all antimalarials prompted medicinal chemists and biologists to study their effective replacement with an alternative mechanism of action and new molecules. Combination with variety of quinolines and other active moieties may increase the antiplasmodial and antimalarial activities and reduce the side effects. Thus, hybridization is a very attractive strategy to develop novel antimalarials. This review aims to summarize the recent advances towards the discovery of antiplasmodial and antimalarial hybrids including quinoline skeleton to provide an insight for rational designs of more active and less toxic quinoline hybrids antimalarials. PMID- 28800459 TI - Novel cinnamamide-dibenzylamine hybrids: Potent neurogenic agents with antioxidant, cholinergic, and neuroprotective properties as innovative drugs for Alzheimer's disease. AB - By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer's disease (AD), a novel series of cinnamamide dibenzylamine hybrids have been designed, synthesized, and evaluated biologically. In vitro assay indicated that most of the target compounds exhibited a significant ability to inhibit ChEs, strong potency inhibitory of self-induced beta-amyloid (Abeta) aggregation and to act as potential antioxidants and biometal chelators. A Lineweaver-Burk plot and molecular modeling study showed that compound 7f targeted both the CAS and PAS of AChE. In addition, compound 7f could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). Overall, all of these outstanding in vitro results in combination with promising in vivo outcomes highlighted derivative 7f as the lead structure worthy of further investigation. PMID- 28800460 TI - Synthesis and biological evaluation of 4-biphenylamino-5-halo-2(5H)-furanones as potential anticancer agents. AB - An efficient route without metal catalyst has been developed for synthesis of 4 biphenylamino-5-halo-2(5H)-furanones. The antitumor activities against various tumor cells of all the compounds have been evaluated by MTT assay. Among them, the compound 3j exhibits significant inhibitory activity against MCF-7 human breast cancer cells with an IC50 value of 11.8 MUM and low toxicity toward HaCaT human normal cells. The mechanism studies confirm that 3j can induce cell cycle arrest at G2/M phase in MCF-7 cells. Compared with compound 3e, 3j has stronger binding affinity to c-myc G-quadruplex (G4) DNA via pi-pi stacking and H-bonding interactions. Western blot analysis also further confirms that compound 3j can down-regulate the expression of c-myc in MCF-7 cells. PMID- 28800461 TI - Design, synthesis, and biological evaluation of novel 3-substituted imidazo[1,2 a]pyridine and quinazolin-4(3H)-one derivatives as PI3Kalpha inhibitors. AB - Phosphatidylinositol 3-kinase (PI3K) is a pivotal regulator of intracellular signaling pathways and considered as a promising target in the development of a therapeutic treatment of cancer. Among the different PI3K subtypes, the PIK3CA gene encoding PI3K p110alpha is frequently mutated and overexpressed in majority of human cancers. Therefore, the inhibition of PI3Kalpha has been considered to be an efficient approach for the treatment of cancer. In this study, two series compounds containing hydrophilic group in imidazo[1,2-a]pyridine and quinazolin 4(3H)-one were synthesized and their antiproliferative activities against five cancer cell lines, including HCT-116, SK-HEP-1, MDA-MB-231, SNU638 and A549, were evaluated. Compound 1i with most potent antiproliferative activity was selected for further biological evaluation. PI3K kinase assay showed that 1i has selectivity for PI3Kalpha distinguished from other isoforms. The western blot assay indicated that 1i is more effective than HS-173, an imidazopyridine-based PI3Ka inhibitor, in reducing the levels of phospho-Akt. All these results suggested that 1i is a potent PI3Kalpha inhibitor and could be considered as a potential candidate for the development of anticancer agents. PMID- 28800462 TI - Imaging, biodistribution and in vitro study of smart 99mTc-PAMAM G4 dendrimer as novel nano-complex. AB - Overexpression of folic acid receptor in various human tumors cells makes it as good candidate for targeting delivery of chemotherapeutic and radiopharmaceutical agents. In this research, FA used for functionalization of PEG modified PAMAM G4 dendrimer as a smart delivery of 5-FU and 99mTc for the breast carcinoma in order to chemotherapeutic and imaging goals. One aim of this research was assess the FA mediated cell viability assay of PEG-PAMAM G4-FA-5FU-99mTc and in vitro uptake of PEG-PAMAM G4-FA-99mTc as the novel nano-complex determined on C2Cl2 (normal cell) and MCF-7 (breast cancer cell) cell lines. Other main goals were studied. Morover, an investigation in to in vivo imaging and biodistribution was carried out via a novel radio tracer by which tumor accumulation and site were obviously detected. The targeted tumor images taken by tail intravenous injection demonstrated that nano-complex can be smartly used in imaging study of the clinical practices. Also, the biodistribution of this nano-complex was investigated and the organ predestination of 99mTc labeled nano-complex (%ID/g) was ascertained. PMID- 28800463 TI - Combination of dexamethasone and Avastin(r) by supramolecular hydrogel attenuates the inflammatory corneal neovascularization in rat alkali burn model. AB - Corneal neovascularization (CNV) is one of the leading causes of vision loss and a high-risk factor for transplant rejection. The present study proposed a supramolecular hydrogel comprised of MPEG-PCL micelles and alpha-cyclodextrin (alpha-CD) for co-delivery of dexamethasone sodium phosphate (Dexp) and Avastin(r) (Ava), and further evaluated its therapeutic efficacy in rat alkali burn model. A physical mixing of Dexp/Ava, MPEG-PCL micelles, and alpha-CD aqueous solution leads to a spontaneous formation of the supramolecular hydrogel via a "host-guest" recognition between MPEG and alpha-CD. The supramolecular hydrogel provides a relatively quick release of Dexp over Ava during the study of the 5-day in vitro release. The results of in vitro cytotoxicity test and wound healing assay illustrated that the proposed supramolecular hydrogel was non-toxic against L-929 and HCEC cells and did not significantly affect the migration of HCEC cells after 24h incubation. The corneal distribution test suggested that the precorneal duration of Ava was significantly extended by the supramolecular hydrogel with respect to its solution formulation. Moreover, the supramolecular hydrogel showed high ocular biocompatibility and was a non-irritant after topical instillation. Furthermore, the Dexp-Ava hydrogel medication, but not by Ava solution and Ava hydrogel medication, could greatly attenuate the alkali burn induced corneal inflammation and remarkably suppress the corneal neovascularization via the downregulation of VEGF, CD31, and alpha-SMA expression in the rat alkali burn model. As a result, the combined Dexp and Ava by supramolecular hydrogel exhibited an advantage over Ava monotherapy approach, which might be a promising alternative therapy for inflammatory CNV. PMID- 28800464 TI - Accelerated biomineralization of graphene oxide - incorporated cellulose acetate nanofibrous scaffolds for mesenchymal stem cell osteogenesis. AB - For bone tissue engineering, it requires that the scaffolds have excellent biocompatibility, proper mechanical and osteoinductive properties. Electrospun nanofibers with extracellular matrices mimicking structure have proven to be good scaffolds for bone tissue repairing. Hybrid nanofibers in particular, endow the nanofibers with specific and multiple functionalities, and therefore have attracted increasing interests in the recent years. In this study, we fabricated graphene oxide (GO)-incorporated cellulose acetate (CA) nanofibrous scaffolds by electrospinning technique for enhancement of biomineralization and osteogenic differentiation of human mesenchymal stem cells (hMSCs). The results displayed the average fiber diameter was decreased from 595 to 285nm with the presence of GO from 0 to 1wt%. Furthermore, with incorporation of GO, the Young's modulus of the nanofibers increased in a dose-dependent manner. More importantly, the incorporation of GO led to significantly enhanced adhesion and proliferation of hMSCs on the scaffolds, mainly due to the good biocompatibility and extracellular matrices mimicking structure of the hybrid nanofibers. Exposure of the nanofibers to the simulated body fluid revealed that the biomineralization was improved significantly with the doping of GO in the nanofibers, possibly owing to the more nucleation sites for calcium phosphate provided by GO. The accelerated biomineralization on the GO-CA nanofibers resulted in a markedly increase in the activity of biomineralization-relevant alkaline phosphatase, and thus induced osteogenic differentiation of hMSCs. The current work demonstrated that the GO-CA nanofibrous scaffolds may find potential applications in bone tissue engineering and other regenerative medicine fields. PMID- 28800465 TI - Oil-based cyclo-oligosaccharide nanodevices for drug encapsulation. AB - New encapsulation nanodevices were synthesized by emulsification of cyclo oligosaccharides fully substituted by hydrophobic palmitic chains. These highly hydrophobic compounds, acquire oily-like behaviour at moderate temperatures (~50 degrees C) and when submitted to ultrasound (US) can undergo emulsification. The improved emulsifying properties of modified cyclo-oligosaccharides are suitable to produce small and narrow sized nanoemulsions with ability to encapsulate amphiphilic molecules. Both encapsulation and delivery of a therapeutic drug, methotrexate (MTX), with amphiphilic character was assessed. The physicochemical properties of the cyclo-oligosaccharide nanoemulsions containing MTX were investigated by nuclear magnetic resonance (NMR), scanning transmission electron microscopy (STEM) and dynamic light scattering (DLS). The results revealed that the modified cyclo-oligosaccharides are potential platforms for the encapsulation of bio compounds for cosmetic and pharmaceutical purposes. PMID- 28800466 TI - Monitoring and modulating ion traffic in hybrid lipid/polymer vesicles. AB - Controlling the traffic of molecules and ions across membranes is a critical feature in a number of biologically relevant processes and highly desirable for the development of technologies based on membrane materials. In this paper, ion transport behavior of hybrid lipid/polymer membranes was studied in the absence and presence of ion transfer agents. A pH-sensitive fluorophore was used to investigate ion (H+/OH-) permeability across hybrid lipid/polymer membranes as a function of the fraction of amphiphilic block copolymer. It was observed that vesicles with intermediate lipid/polymer ratios tend to be surprisingly more permeable to ion transport than the pure lipid or pure polymer vesicles. Hybrid vesicle permeability could be further modulated with valinomycin, nigericin, or gramicidin A, which significantly expedite the dissipation of externally-imposed pH gradients by facilitating the transport of the rate-limiting co-ions (e.g. K+) ions across the membrane. For gramicidin A, ion permeability decreased with increasing polymer mole fraction, and the method of introduction of gramicidin A into the membrane played an important role. Strategies to incorporate biofunctional molecules and facilitate their activity in synthetic systems are highly desirable for developing artificial organelles or other synthetic compartmentalized structures requiring control over molecular traffic across biomimetic membranes. PMID- 28800467 TI - Tympanic membrane pressure buffering function at quasi-static and low-frequency pressure variations. AB - Deformation of the tympanic membrane is known to contribute to the pressure regulation processes in the middle ear cleft. In this paper we investigated pressure variations in the rabbit middle ear in response to sinusoidal varying pressures applied to the ear canal, with frequencies ranging from 0.5 Hz to 50 Hz and pressure amplitudes ranging between 0.25 kPa and 1 kPa. The transtympanic pressure difference was found to be smallest in the quasi-static range, and quickly increased as a function of frequency. The response curves showed asymmetry, with larger transtympanic pressures when positive pressures were applied in the ear canal. Normalized transtympanic pressure amplitudes remained fairly constant as a function of input pressure, with values in the range of 60% 70% relative to the applied pressure. The total harmonic distortion of the middle ear pressure signal was calculated and was found to be very small (<=2%) for low pressure amplitudes and low frequencies. For pressure amplitudes in the order of 0.25 kPa-0.5 kPa, it increased to about 10% at 50 Hz. When a 1 kPa pressure amplitude was applied, variation between animals became large and distortion values up to 30% at 50 Hz were observed. The results showed that pressure buffering due to tympanic membrane displacement was most effective for compensating small transtympanic pressure loads at low frequencies. PMID- 28800468 TI - The MMN as a viable and objective marker of auditory development in CI users. AB - In the present article, we review the studies on the use of the mismatch negativity (MMN) as a tool for an objective assessment of cochlear-implant (CI) functioning after its implantation and as a function of time of CI use. The MMN indexes discrimination of different sound stimuli with a precision matching with that of behavioral discrimination and can therefore be used as its objective index. Importantly, these measurements can be reliably carried out even in the absence of attention and behavioral responses and therefore they can be extended to populations that are not capable of behaviorally reporting their perception such as infants and different clinical patient groups. In infants and small children with CI, the MMN provides the only means for assessing the adequacy of the CI functioning, its improvement as a function of time of CI use, and the efficiency of different rehabilitation procedures. Therefore, the MMN can also be used as a tool in developing and testing different novel rehabilitation procedures. Importantly, the recently developed multi-feature MMN paradigms permit the objective assessment of discrimination accuracy for all the different auditory dimensions (such as frequency, intensity, and duration) in a short recording time of about 30 min. Most recently, such stimulus paradigms have been successfully developed for an objective assessment of music perception, too. PMID- 28800469 TI - Immunotherapy in ovarian, endometrial and cervical cancer: State of the art and future perspectives. AB - The tumors of the female genital tract represent a leading cause of morbidity and mortality among women worldwide. Substantial progresses have been made in ovarian cancer, with the increasing knowledge about BRCA mutated tumors and the recent development of PARP inhibitors, and in cervical cancer, thanks to extensive screening and widespread of vaccination against Human Papilloma Virus. Nevertheless many needs remain unmet, advanced stage diseases are still incurable and cervical and endometrial carcinoma, as well as platinum-resistant ovarian carcinoma, can certainly be classifiable among the cancers with poor sensitivity to conventional chemotherapy. Immunotherapy, including a number of approaches, checkpoint inhibitors, adoptive cellular transfer, vaccines, has experienced a remarkable growth in the last few years and it is already an available option in melanoma, lung and renal malignancies. We reviewed the main findings about the immune microenvironment in ovarian, endometrial and cervical cancer with a special focus on the clinical data, the therapeutic implications and the most promising novel agents. PMID- 28800470 TI - 210Pb and 137Cs as tracers of recent sedimentary processes in two water reservoirs in Cuba. AB - Hanabanilla and Paso Bonito Reservoirs are the main fresh water sources for about half a million inhabitants in central Cuba. Prior to this investigation precise information about the losses of storage capacity was not available. Sedimentation is the dominant process leading to reduction in water storage capacity. We investigated the sedimentation process in both reservoirs by analyzing environmental radionuclides (e.g. 210Pb, 226Ra and 137Cs) in sediment cores. In the shallow Paso Bonito Reservoir (mean depth of 6.5 m; water volume of 8 * 106 m3), we estimated a mean mass accumulation rate (MAR) of 0.4 +/- 0.1 g cm-2y-1 based on 210Pb chronologies. 137Cs was detected in the sediments, but due to the recent construction of this reservoir (1975), it was not possible to use it to validate the 210Pb chronologies. The estimated MAR in this reservoir is higher than the typical values reported in similar shallow fresh water reservoirs worldwide. Our results highlight a significant loss of water storage capacity during the past 30 years. In the deeper and larger Hanabanilla Reservoir (mean depth of 15.5 m; water volume of 292 * 106 m3), the MAR was investigated in three different sites of the reservoir. The mean MARs based on the 210Pb chronologies varied between 0.15 and 0.24 g cm-2y-1. The MARs calculated based on the 137Cs profiles further validated these values. We show that the sediment accumulation did not change significantly over the last 50 years. A simple empirical mixing and sedimentation model that assumes 137Cs in the water originated from both, direct atmospheric fallout and the catchment area, was applied to interpret the 137Cs depth profiles. The model consistently reproduced the measured 137Cs profiles in the three cores (R2 > 0.9). Mean residence times for 137Cs in the water and in the catchment area of 1 y and 35-50 y, respectively were estimated. The model identified areas where the catchment component was higher, zones with higher erosion in the catchment, and sites where the fallout component was quantitatively recorded in the sediments. PMID- 28800471 TI - Microplastic ingestion by Mullus surmuletus Linnaeus, 1758 fish and its potential for causing oxidative stress. AB - A total of 417 striped red mullet, Mullus surmuletus, were analyzed to study microplastic ingestion and livers of fish were assessed to study effects of microplastics. Nearly one third (27.30%) of the individuals were quantified to ingest microplastics although there was no evidence of oxidative stress or cellular damage in the liver of fish which had ingested microplastics. A small increase in the activity of glutathione S-transferase (GST) of M. surmuletus was detected which could be suggesting an induction of the detoxification systems but these findings should be tested in laboratory conditions under a controlled diet and known concentration of microplastics. Fish from trammel fisheries, operating closer to land and targeting larger individuals, showed higher mean ingestion values than fish from trawling fisheries, and were related to body size, as microplastics ingested increased with total fish length. Consequently, ingestion values of microplastics were not related to sampling distance from land giving further evidence of the ubiquity of microplastics in the marine environment. Finally, Fourier Transform Infrared Spectroscopy (FTIR) analysis showed that the vast majority of microplastics were filament type and polyethylene terephthalate (PET) was the main identified component. PMID- 28800473 TI - Public health risk of mercury in China through consumption of vegetables, a modelling study. AB - Sample measurement of mercury (Hg) contents is a common method for health risk assessment of Hg through vegetable consumption in China. In the present work, we undertook the first modelling study which produced consistent health-risk maps for the whole eastern China. Regional maps of Probable Daily Intake (PDI) of Total mercury (THg) and Methylmercury (MeHg) over the studied area were produced, which were important for the researchers and policy-makers to evaluate the risk and to propose mitigation measures if necessary. The model predictions of air borne Hg(0) concentrations agreed well with the observations and simulated Hg distribution over China as reported elsewhere. Our calculated PDIs of THg in vegetables were also comparable to those reported in the literature. There was 19% of the studied area with PDIs > 0.08ugkg-1 bw d-1 [half of the reference dose (RfD)]. The PDI for THg (MeHg) varied from 0.034 (0.007) to 0.162 (0.035)ugkg-1 bw d-1 with an average of 0.058 (0.013)ugkg-1 bw d-1. The highest calculated PDIs of THg over China was equal to the RfD, while the calculated PDIs of MeHg were well below the RfD of 0.1ugkg-1 bw d-1. The health risk was of concern through consumption of THg in leafy vegetables, rice/wheat and fish in Liaoning Provinces, Hunan, Zhejiang and Guizhou Provinces, with the associated PDIs exceeding the RfD. Despite this, the heath risk of MeHg exposure for the general population in southern China from the same foodstuff consumption was not a concern. The contribution of consumption through leafy vegetation should be considered when THg and MeHg exposures to the population are evaluated. The results improve our understanding in managing public health risk in China especially in large cities with high population, and thus have important contribution to enhance sustainable urbanization as one of the principle goals under the framework of the Nature-Based Solution (NBS). PMID- 28800472 TI - Phthalate and bisphenol A exposure during in utero windows of susceptibility in relation to reproductive hormones and pubertal development in girls. AB - BACKGROUND: Over the past several decades, the age of pubertal onset in girls has shifted downward worldwide. As early pubertal onset is associated with increased risky behavior and psychological issues during adolescence and cardiometabolic disease and cancer in adulthood, this is an important public health concern. Exposure to endocrine disrupting chemicals during critical windows of in utero development may play a role in this trend. Our objective was to investigate trimester-specific phthalate and BPA exposure in relation to pubertal development among girls in the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) birth cohort. METHODS: We measured maternal urinary phthalate metabolites and BPA in samples collected during the first, second, and third trimesters of pregnancy. To assess reproductive development among their female children, we measured serum testosterone, estradiol, dehydroepiandrosterone sulfate (DHEA-S), inhibin B, and sex hormone-binding globulin (SHBG), and assessed sexual maturation, including Tanner staging for breast and pubic hair development and menarche status, at age 8-13 years (n = 120). We used linear and logistic regression to examine measures of trimester-specific in utero exposure as predictors of peripubertal hormone levels and pubertal onset, respectively. In secondary analyses, we evaluated estimated exposure at the midpoint of the first trimester and rates of change in exposure across pregnancy in relation to outcomes. RESULTS: Several phthalate metabolites measured throughout in utero development were associated with higher serum testosterone concentrations, while a number of metabolites measured in the third trimester were associated with higher DHEA-S. For example, an interquartile range (IQR) increase in mean monoethyl phthalate (MEP) levels across pregnancy was associated with 44% higher peripubertal testosterone (95% CI: 13-83%), while an IQR increase in di-2 ethylhexyl phthalate metabolites (SigmaDEHP) specifically in the third trimester was associated with 25% higher DHEA-S (95%CI: 4.7-47%). In IQR increase in mean mono-2-ethylhexyl phthalate (MEHP) levels across pregnancy was associated with lower odds of having a Tanner Stage >1 for breast development (OR = 0.32, 95%CI: 0.11-0.95), while MEHP in the third trimester was associated with higher odds of having a Tanner Stage >1 for pubic hair development (OR = 3.76, 95%CI: 1.1-12.8). Results from secondary analyses were consistent with findings from our main analysis. CONCLUSION: These findings suggest that female reproductive development may be more vulnerable to the effects of phthalate or BPA exposure during specific critical periods of in utero development. This highlights the need for comprehensive characterizations of in utero exposure and consideration of windows of susceptibility in developmental epidemiological studies. Future research should consider repeated measures of in utero phthalate and BPA exposure within each trimester and across pregnancy. PMID- 28800474 TI - NPS 2143, a selective calcium-sensing receptor antagonist inhibits lipopolysaccharide-induced pulmonary inflammation. AB - NPS 2143, a novel and selective antagonist of calcium-sensing receptor (CaSR) has been reported to possess anti-inflammatory activity. In the present study, we examined the protective effect of NPS 2143 on lipopolysaccharide (LPS)-induced acute lung injury (ALI). NPS 2143 pretreatment significantly inhibited the influx of inflammatory cells and the expression of monocyte chemoattractant protein-1 (MCP-1) in the lung of mice with LPS-induced ALI. NPS 2143 decreased the levels of neutrophil elastase (NE) and protein concentration in the bronchoalveolar lavage fluid (BALF). NPS 2143 also reduced the production of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL 6) in the BALF and serum. In addition, NPS 2143 attenuated the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and increased the activation of AMP-activated protein kinase (AMPK) in the lung. NPS 2143 also downregulated the activation of nuclear factor-kappa B (NF-kappaB) in the lung. In LPS-stimulated H292 airway epithelial cells, NPS 2143 attenuated the releases of IL-6 and MCP-1. Furthermore, NPS 2143 upregulated the activation of AMPK and downregulated the activation of NF-kappaB. These results suggest that NPS 2143 could be potential agent for the treatment of inflammatory diseases including ALI. PMID- 28800475 TI - Biological, immunological and functional properties of two novel multi-variant chimeric recombinant proteins of CSP antigens for vaccine development against Plasmodium vivax infection. AB - The circumsporozoite protein (CSP) of the malaria parasite Plasmodium vivax is a major pre-erythrocyte vaccine candidate. The protein has a central repeat region that belongs to one of repeat families (VK210, VK247, and the P. vivax-like). In the present study, computer modelling was employed to select chimeric proteins, comprising the conserved regions and different arrangements of the repeat elements (VK210 and VK247), whose structure is similar to that of the native counterparts. DNA encoding the selected chimeras (named CS127 and CS712) were synthetically constructed based on E. coli codons, then cloned and expressed. Mouse monoclonal antibodies (mAbs; anti-Pv-210-CDC and -Pv-247-CDC), recognized the chimeric antigens in ELISA, indicating correct conformation and accessibility of the B-cell epitopes. ELISA using IgG from plasma samples collected from 221 Iranian patients with acute P. vivax showed that only 49.32% of the samples reacted to both CS127 and CS712 proteins. The dominant subclass for the two chimeras was IgG1 (48% of the positive responders, OD492=0.777+/-0.420 for CS127; 48.41% of the positive responders, OD492=0.862+/-0.423 for CS712, with no statistically significant difference P>0.05; Wilcoxon signed ranks test). Binding assays showed that both chimeric proteins bound to immobilized heparan sulphate and HepG2 hepatocyte cells in a concentration-dependent manner, saturable at 80MUg/mL. Additionally, anti-CS127 and -CS712 antibodies raised in mice recognized the native protein on the surface of P. vivax sporozoite with high intensity, confirming the presence of common epitopes between the recombinant forms and the native proteins. In summary, despite structural differences at the molecular level, the expression levels of both chimeras were satisfactory, and their conformational structure retained biological function, thus supporting their potential for use in the development of vivax-based vaccine. PMID- 28800476 TI - Neighborhood heterogeneity in health and well-being among the elderly in India - Evidence from Study on global AGEing and adult health (SAGE). AB - We establish a rationale for a multilevel approach in examining health among older adults. Using data on a nationally representative sample of 6560 Indian adults aged 50 years and older, we examine the extent of contextual variation between neighborhoods, after accounting for the compositional effect of individuals' background characteristics, across multiple dimensions of elderly health. The variance apportioned to neighborhoods in null intercept-only models varied widely across different health outcomes examined in the elderly - while neighborhoods accounted for only 4% of the total variation in high blood pressure at exam, 23% of the total variation in self-rated poor quality of life could be attributed to neighborhood-level differences. In models that accounted for state, place of residence, and demographic and socioeconomic characteristics of individuals, the contribution of neighborhood to the total variation for most health outcomes was attenuated (2-11%) but persisted to exist. Our findings underscore the importance of neighborhoods in studying the health and well-being of the elderly in India. PMID- 28800477 TI - Visualization of suppressed intraventricular flow by constrictive pericarditis. PMID- 28800478 TI - Use of dexmedetomidine to attenuate acute kidney injury after cardiac surgery. PMID- 28800479 TI - Thrombolysis for acute pulmonary embolism after major hepatic surgery. PMID- 28800480 TI - Frail elderly with and without cognitive impairment at the end of life: Their emotional state and the wellbeing of their family caregivers. AB - PURPOSE OF THE STUDY: (1) To identify the main predictors of the emotional state of the frail elderly at the end-of-life and that of their primary family caregivers, taking into consideration the presence/absence of significant cognitive impairment in the patient and (2) to analyse the relationship between the emotional state of the patient and that of their primary family caregiver. METHODS: Our study is cross-sectional. 85 frail elderly patients at the end-of life and their primary family caregivers participated. Information on the following aspects was collected: (1) From the patients: Socio-demographics, Functional independence, and Cognitive and Emotional state; (2) From the caregivers: Socio-demographics, Emotional state and Overburden (according to Zarit Scale). Descriptive, correlational and linear regression analyses were computed using SPSS. RESULTS: The models that best predict the observed variance in the emotional state of patients (with or without significant cognitive impairment) include the same variables: functional independence of the patient and caregiver's overburden. Similarly, the models that best predict the observed variance in the emotional state of family caregivers include: cognitive state of the patient and caregiver's overburden. IMPLICATIONS: The overburden of the family caregiver stands out as a key factor in the reduction of the emotional distress of frail elder patients -whether or not they present significant cognitive impairment- and that of their family caregivers. Our results suggest that reducing overburden of the family caregiver may also reduce the emotional distress of the patient and that of their family caregiver. PMID- 28800481 TI - Effects of whole-body vibration on postural control in elderly: An update of a systematic review and meta-analysis. AB - The aim of this systematic review and meta-analysis was to offer an updated overview of the current studies on all types of whole-body vibration (WBV), to determine the effects of WBV on balance in Go-Go (active, independent), Slow-Go (some physical activity limitations) and No-Go (in need of care) elderly and to provide recommendations on available evidence on WBV for clinicians and researchers. An electronic literature search was conducted in PubMed, Cochrane Register of Controlled Trials, Physiotherapy Evidence Database (PEDro) and CINAHL (Ebsco Host) to identify studies on WBV therapy in Go-Goes, Slow-Goes and No Goes. Outcomes were static, dynamic and functional balance. Thirty-tree studies were included in this systematic review. Pooling was possible for static balance and dynamic balance. Effect size (SMD) of WBV on static balance was 0.34 (95% CI 0.18, 0.49) in Go-Goes. Effect size (SMD) of WBV on dynamic balance was -0.15 (95% CI -0.44, 0.15) in Slow-Go and -0.90 (95% CI -1.63, -0.17) in No-Go elderly people respectively. The results of this current meta-analysis suggest that WBV can be used for improving static balance in Go-Go elderly and that it has the potential to positively influence dynamic balance in Slow-Go and No-Go elderly. PMID- 28800483 TI - Assessment of AOD variability over Saudi Arabia using MODIS Deep Blue products. AB - The aim of this study is to investigate the variability of aerosol over The Kingdom of Saudi Arabia. For this analysis, Moderate Resolution Imaging Spectroradiometer (MODIS) Deep Blue (DB) Aerosol Optical Depth (AOD) product from Terra and Aqua satellites for the years 2000-2013 is used. The product is validated using AERONET data from ground stations, which are situated at Solar Village Riyadh and King Abdullah University of Science and Technology (KAUST) Jeddah. The results show that both Terra and Aqua satellites exhibit a tendency to show the spatial variation of AOD with Aqua being better than Terra to represent the ground based AOD measurements over the study region. The results also show that the eastern, central, and southern regions of the country have a high concentration of AOD during the study period. The validation results show the highest correlation coefficient between Aqua and KAUST data with a value of 0.79, whilst the Aqua and Solar Village based AOD indicates the lowest Root Mean Square Error (RMSE) and Mean Absolute Error (MAE) values which are, 0.17 and 0.12 respectively. Furthermore, the Relative Mean Bias (RMB) based analysis show that the DB algorithm overestimates the AOD when using Terra and Solar Village data, while it underestimates the AOD when using Aqua with Solar Village and KAUST data. The RMB value for Aqua and Solar Village data indicates that the DB algorithm is close to normal in the study region. PMID- 28800484 TI - Characteristics of elemental and Pb isotopic compositions in aerosols (PM10-2.5) at the Ieodo Ocean Research Station in the East China Sea. AB - A total of 82 aerosol samples (PM10-2.5) were collected from June 18, 2015 to October 1, 2016 at the remote sea site, the Ieodo Ocean Research Station (IORS), in the East China Sea. Samples were analyzed for 10 elements (Al, Fe, Cu, Zn, As, Mo, Cd, Sb, Tl, and Pb) as well as Pb isotopic composition to characterize temporal variations in elemental concentration levels, and to identify the potential source regions of atmospheric pollutants transported over the remote East China Sea. The results showed that the annual average element concentrations were lowest compared to those at different sites in East Asia, suggesting a very clean background area of IORS, with values ranging from 114 ng m-3 for Al to 0.045 ng m-3 for Tl. Concentrations averaged seasonally for all the elements revealed the highest levels occurring between winter and spring, and the lowest levels in summer. High enrichment factors (EF) of more than 100 for trace elements suggest that these elements originated mostly from anthropogenic sources. Coupling the Pb isotopic composition with a back trajectory analysis identified the potential source regions for each sample. Our approach identified China as a dominant contributor affecting atmospheric composition changes at IORS, the remote area of the East China Sea. As the largest anthropogenic emission source in East Asia, China contributed to almost 100% of the elemental concentration levels in winter and spring, ~53% in summer and ~63% in autumn. Because IORS's ambient air is sensitive to even slight changes in pollutant loading due to the significantly low pollution levels, long-term monitoring of air quality at IORS will provide invaluable information on the progress and efforts of atmospheric pollution management linked to emission controls in East Asian countries, especially China. PMID- 28800482 TI - Targeting phenotypic heterogeneity in benign prostatic hyperplasia. AB - Benign prostatic hyperplasia and associated lower urinary tract symptoms remain difficult to treat medically, resulting in hundreds of thousands of surgeries performed annually in elderly males. New therapies have not improved clinical outcomes since alpha blockers and 5 alpha reductase inhibitors were introduced in the 1990s. An underappreciated confounder to identifying novel targets is pathological heterogeneity. Individual patients display unique phenotypes, composed of distinct cell types. We have yet to develop a cellular or molecular understanding of these unique phenotypes, which has led to failure in developing targeted therapies for personalized medicine. This review covers the strategic experimental approach to unraveling the cellular pathogenesis of discrete BPH phenotypes and discusses how to incorporate these findings into the clinic to improve outcomes. PMID- 28800485 TI - Validation of site-specific soil Ni toxicity thresholds with independent ecotoxicity and biogeochemistry data for elevated soil Ni. AB - The Existing Substances Regulation Risk Assessments by the European Union (EU RA) generated new toxicity data for soil organisms exposed to Ni added to sixteen field-collected soils with low background concentration of metals and varying physico-chemical soil characteristics. Using only effective cation exchange capacity (eCEC) as a bioavailability correction, chronic toxicity of Ni in soils with a wide range of characteristics could be predicted within a factor of two. The objective of the present study was to determine whether this was also the case for three independent data sets of Ni toxicity thresholds. Two of the data sets were from Community Based Risk Assessments in Port Colborne ON, and Sudbury ON (Canada) for soils containing elevated concentrations of Ni, Co and Cu arising from many decades of Ni mining, smelting and refining. The third data set was the Metals in Asia study of soluble Ni added to field soils in China. These data yielded 72 leached and aged EC10/NOEC values for soil Ni, for arthropods, higher plants and woodlot structure and function. These were reduced to nine most sensitive single or geometric mean species/function endpoints, none of which were lower than the HC5 predicted for a soil with an eCEC of 20 cmol/kg. Most of these leached and aged EC10/NOEC values were from soils co-contaminated with Cu, in some cases at its median HC5 as predicted by the EU RA from soil characteristics. We conclude that the EU RA is protective of Ni toxicity to higher-tier ecological endpoints, including in mixture with Cu, before the assessment factor of 2 is applied. We suggest that for prospective risk assessment, the bioavailability based PNEC (HC5/2) be used as a conservative screen, but for retrospective and site-specific risk assessment, the bioavailability based HC5 is sufficient. PMID- 28800486 TI - The influence of e-waste recycling on the molecular ecological network of soil microbial communities in Pakistan and China. AB - Primitive electronic waste (e-waste) recycling releases large amounts of organic pollutants and heavy metals into the environment. As crucial moderators of geochemical cycling processes and pollutant remediation, soil microbes may be affected by these contaminants. We collected soil samples heavily contaminated by e-waste recycling in China and Pakistan, and analyzed the indigenous microbial communities. The results of this work revealed that the microbial community composition and diversity, at both whole and core community levels, were affected significantly by polycyclic aromatic hydrocarbons (PAHs), polybrominated diphenyl ethers (PBDEs) and heavy metals (e.g., Cu, Zn, and Pb). The geographical distance showed limited impacts on microbial communities compared with geochemical factors. The constructed ecological network of soil microbial communities illustrated microbial co-occurrence, competition and antagonism across soils, revealing the response of microbes to soil properties and pollutants. Two of the three main modules constructed with core operational taxonomic units (OTUs) were sensitive to nutrition (total organic carbon and total nitrogen) and pollutants. Five key OTUs assigned to Acidobacteria, Proteobacteria, and Nitrospirae in ecological network were identified. This is the first study to report the effects of e-waste pollutants on soil microbial network, providing a deeper understanding of the ecological influence of crude e-waste recycling activities on soil ecological functions. PMID- 28800487 TI - Development of atmospheric acid deposition in China from the 1990s to the 2010s. AB - Atmospheric acid deposition is a global environmental issue. China has been experiencing serious acid deposition, which is anticipated to become more severe with the country's economic development and increasing consumption of fossil fuels in recent decades. We explored the spatiotemporal variations of acid deposition (wet acid deposition) and its influencing factors by collecting nationwide data on pH and concentrations of sulfate (SO42-) and nitrate (NO3-) in precipitation between 1980 and 2014 in China. Our results showed that average precipitation pH values were 4.59 and 4.70 in the 1990s and 2010s, respectively, suggesting that precipitation acid deposition in China has not seriously worsened. Average SO42- deposition declined from 40.54 to 34.87 kg S ha-1 yr-1 but average NO3- deposition increased from 4.44 to 7.73 kg N ha-1 yr-1. Specifically, the area of severe precipitation acid deposition in southern China has shrunk to some extent as a result of controlling the pollutant emissions; but the area of moderate precipitation acid deposition has expanded in northern China, associated with rapid industrial and transportation development. Furthermore, we found significant positive correlations between precipitation acid deposition, energy consumption, and rainfall. Our findings provide a relatively comprehensive evaluation of the spatiotemporal dynamics of precipitation acid deposition in China over past three decades, and confirm the idea that strategies implemented to save energy and control pollutant emissions in China have been effective in alleviating precipitation acid deposition. These findings might be used to demonstrate how developing countries could achieve economic development and environmental protection through the implementation of advanced technologies to reduce pollutant emissions. PMID- 28800488 TI - Benzo(a)pyrene-induced a mitochondria-independent apoptosis of liver in juvenile Chinese rare minnows (Gobiocypris rarus). AB - To examine the effects of BaP on tissue apoptosis, laboratory studies were conducted using juvenile Chinese rare minnows (Gobiocypris rarus) exposed to 1, 5, 20, and 80 MUg/L of BaP for 28 days. The post-treatment pathological findings in the liver were associated with hepatocyte swelling, karyopyknosis, and karyorrhexis. Moreover, an increase in the goblet cells in the intestine, epithelial hyperplasia of the gills and fusion of gill lamellae were observed. Significant increases in hepatocyte apoptosis using the TUNEL stain were observed in the liver tissue but not in the intestine and gills. In addition, BaP exposure significantly up-regulated the mRNA levels of cyp1a1, p53, bax, bcl-2, and caspase-9 in the liver following the 5, 20, and 80 MUg/L treatments, whereas the apaf-1 was significantly down-regulated following all treatments. Moreover, the activities of caspase 3 and caspase 8 were markedly elevated, whereas the protein expression levels of Apaf-1 were down-regulated following the 20 and 80 MUg/L treatments. Taken together, our results suggested that BaP strongly induces tissue-specific apoptosis in vivo, leading to significant pathological changes. The responsiveness of apoptotic-related genes demonstrates that BaP induced apoptosis in the liver may be through a mitochondria-independent pathway. PMID- 28800489 TI - Polioviruses that bind a chimeric Pvr-nectin-2 protein identify capsid residues involved in receptor interaction. AB - Amino acid changes in the C'C"D region in poliovirus receptor domain 1 disrupt poliovirus binding. To examine further the role of the C'C"D region in poliovirus infection, we substituted this region of Pvr into the corresponding region of a murine homolog, nectin-2. The chimeric receptor, nectin-2Pvr(c'c"d), rendered transformed L cells susceptible to infection with poliovirus P1/Mahoney, but not with polioviruses P2/Lansing and P3/Leon, due to lack of binding. Twenty-four variants of P2/Lansing were selected that replicate in nectin-2Pvr(c'c"d) producing cell lines. Sequence analysis revealed 30 amino acid changes at 28 capsid residues. One change, K1103R, is found in nearly all isolates and is located at one end of the VP1 BC loop. Other alterations are located on the canyon surface, at the protomer interface, and along the perimeter of the canyon south wall. Unlike poliovirus-Pvr binding, the VP1 BC loop is required for infection of cells producing nectin-2Pvr(c'c"d). PMID- 28800490 TI - Oxytocin secretion is pulsatile in men and is related to social-emotional functioning. AB - : The hypothalamic hormone oxytocin (OXT) plays an important role in a range of physiological processes and social-emotional functioning in both sexes. In women, physiological stimuli, such as suckling and parturition, result in pulsatile release of OXT into the peripheral circulation via the posterior pituitary gland. However, data regarding OXT secretory patterns in men during a state of rest are limited. Further, the relationship between secretory dynamics of OXT and emotional measures has never been evaluated. We hypothesized a pulsatile pattern of OXT secretion in men, and explored the relationship between OXT secretory patterns and social-emotional functioning. METHODS: Deconvolution analysis was performed on serum OXT levels obtained every 5min over a period of 10h in 5 healthy normal weight men. Area under the curve (AUC), average OXT values, and pulse characteristics [pulse number, inter-pulse interval, pulse height and mass (area under each pulse)] were calculated. State Adult Attachment Measure (SAAM) assessed types of human attachment. Interpersonal Support Evaluation List (ISEL) assessed perception of social support. Toronto Alexithymia Scale (TAS-20) measured the ability to express and identify one's own emotions. RESULTS: Mean age was 22.8+/-1.2years, and BMI was 21.7+/-0.4kg/m2 (mean+/-SEM). Assuming a basal secretion of zero and a half life of five to seven minutes, we demonstrated the following: OXT AUC: 5421+/-1331pg/ml, mean OXT level: 9.1pg/ml, mean pulse number: 22+/-3/10hr, mean pulse height: 1.81+/-0.48pg/ml, mean pulse mass: 30.34+/-10.29pg/ml and mean inter-pulse interval: 27+/-4min. The SAAM Avoidant scale correlated negatively with mean OXT pulse height (r=-0.90, p=0.04) and pulse mass (r=-0.95, p=0.01). The ISEL Belonging score correlated positively with OXT AUC (r=0.89, p=0.04) and average OXT (r=0.93, p=0.02). ISEL Appraisal score also had a positive association with mean OXT pulse height (r=0.99, p=0.0006) and pulse mass (r=0.98, p=0.003). Finally, ISEL total score had a significant correlation with average OXT values (r=0.90, p=0.04). While none of the subjects had a score in the alexithymia range, TAS-20 Difficulty describing feelings score had an inverse correlation with OXT pulse height (r=-0.96, p=0.01) and pulse mass (r=-0.99, p=0.001). TAS-20 total score also had an inverse correlation with OXT pulse height (r=-0.94, p=0.02) and pulse mass (r=-0.96, p=0.009). CONCLUSION: We demonstrate a pulsatile pattern of peripheral OXT secretion in healthy men at rest. Subjects with lower OXT pulse height and pulse mass had a more avoidant style of attachment, felt less supported, and expressed greater difficulty in describing their feelings. Our findings support the concept that OXT is a key mediator of social-emotional functioning. Future studies to determine causality are warranted. PMID- 28800491 TI - Survival for patients with rare haematologic malignancies: Changes in the early 21st century. AB - INTRODUCTION: Population-level survival has improved for common haematologic malignancies in the early 21st century. However, relatively few population-level data are available for rare haematologic malignancies. METHODS: Data were extracted from 12 cancer registries in Germany and the Surveillance, Epidemiology and End Results database in the United States (US). Cases of haematologic malignancies with an incidence of less than 1 per 100,000 were selected for analysis. Period analysis was used to determine 5-year relative survival (RS) for the years 2003-2012, and modelled period analysis was used to determine changes in survival between 2003-2007 and 2008-2012. RESULTS: Seven individual haematologic malignancies which met criteria were identified. Overall 5-year age adjusted RS was 62.4% in Germany and 57.0% in the US in 2003-2012, with a good deal of variability by individual haematologic malignancy, ranging from less than 30% for chronic monomyeloid leukaemia to greater than 85% for hairy cell leukaemia and mycosis fungoides. Five-year RS increased significantly between 2003-2007 and 2008-2012 for patients with mantle cell lymphoma, Burkitt's lymphoma and hairy cell leukaemia in Germany and for patients with mantle cell lymphoma and anaplastic large-cell kinase+ anaplastic lymphoma in the US. CONCLUSIONS: Survival for rare haematologic malignancies varied considerably by cancer entity. Overall 5-year RS was slightly higher in Germany compared to the US. Survival estimates increased for a minority of haematologic malignancies between 2003-2007 and 2008-2012. Further research into the best treatment options for rare malignancies is needed to further improve survival. PMID- 28800493 TI - Efficient simulation of elastic guided waves interacting with notches, adhesive joints, delaminations and inclined edges in plate structures. AB - This paper presents an approach to model transmission and reflection phenomena of elastic guided waves in plates. The formulation is applied to plate structures containing notches, inclined edges, delaminations or (adhesive) joints. For these cases, only the thickness direction of the structure needs to be discretized at several locations, while the direction of propagation is described analytically. Consequently, the number of degrees of freedom is very small. Semi-infinite domains can be modeled, in which case the radiation condition is fulfilled exactly. Traction boundary conditions are introduced on the plate surface without requiring a mesh along the surface. Results are validated against conventional finite element implementations, showing the accuracy of the proposed approach and a reduction of the computational costs by typically 2-3 orders of magnitude. PMID- 28800492 TI - Adding abiraterone to androgen deprivation therapy in men with metastatic hormone sensitive prostate cancer: A systematic review and meta-analysis. AB - BACKGROUND: There is a need to synthesise the results of numerous randomised controlled trials evaluating the addition of therapies to androgen deprivation therapy (ADT) for men with metastatic hormone-sensitive prostate cancer (mHSPC). This systematic review aims to assess the effects of adding abiraterone acetate plus prednisone/prednisolone (AAP) to ADT. METHODS: Using our framework for adaptive meta-analysis (FAME), we started the review process before trials had been reported and worked collaboratively with trial investigators to anticipate when eligible trial results would emerge. Thus, we could determine the earliest opportunity for reliable meta-analysis and take account of unavailable trials in interpreting results. We searched multiple sources for trials comparing AAP plus ADT versus ADT in men with mHSPC. We obtained results for the primary outcome of overall survival (OS), secondary outcomes of clinical/radiological progression free survival (PFS) and grade III-IV and grade V toxicity direct from trial teams. Hazard ratios (HRs) for the effects of AAP plus ADT on OS and PFS, Peto Odds Ratios (Peto ORs) for the effects on acute toxicity and interaction HRs for the effects on OS by patient subgroups were combined across trials using fixed effect meta-analysis. FINDINGS: We identified three eligible trials, one of which was still recruiting (PEACE-1 (NCT01957436)). Results from the two remaining trials (LATITUDE (NCT01715285) and STAMPEDE (NCT00268476)), representing 82% of all men randomised to AAP plus ADT versus ADT (without docetaxel in either arm), showed a highly significant 38% reduction in the risk of death with AAP plus ADT (HR = 0.62, 95% confidence interval [CI] = 0.53-0.71, p = 0.55 * 10-10), that translates into a 14% absolute improvement in 3-year OS. Despite differences in PFS definitions across trials, we also observed a consistent and highly significant 55% reduction in the risk of clinical/radiological PFS (HR = 0.45, 95% CI = 0.40-0.51, p = 0.66 * 10-36) with the addition of AAP, that translates to a 28% absolute improvement at 3 years. There was no evidence of a difference in the OS benefit by Gleason sum score, performance status or nodal status, but the size of the benefit may vary by age. There were more grade III-IV acute cardiac, vascular and hepatic toxicities with AAP plus ADT but no excess of other toxicities or death. INTERPRETATION: Adding AAP to ADT is a clinically effective treatment option for men with mHSPC, offering an alternative to docetaxel for men who are starting treatment for the first time. Future research will need to address which of these two agents or whether their combination is most effective, and for whom. PMID- 28800494 TI - A time-domain model and experimental validation of the acoustic field radiated by air-coupled transducers. AB - This paper presents a time-domain model for the prediction of an acoustic field in an air-coupled, non-contact, ultrasonic setup, which includes an air-coupled Emitter, the Propagation space and an air-coupled Receiver (EPR). The model takes into account the finite size of the aperture receiver, attenuation in air, and the electric response of the emitter-receiver set he. The attenuation is characterized by a causal time-domain Green's function, allowing the wideband attenuation of a lossy medium obeying the power law alpha(omega)=alpha0omegaeta,1?eta?2 to be included. The electrical response is recovered experimentally using a procedure which includes the deconvolution of air absorption effects. The model is implemented numerically using a discrete representation approach. In order to study the influence of receiver size and attenuation, five different computational approaches are proposed; each of these is evaluated quantitatively, by comparing the predicted acoustic field with the experimentally measured signal. The prediction error is studied in both the near and far fields, for three typical field features: the system's impulse response, the on-axis field distribution, and the directivity pattern, for the case of air coupled transducers operating at two different central frequencies, namely 50kHz and 350kHz, with a 10mm diameter wideband receiver. It is shown that when the attenuation in air, the receiver size, and the accurately recovered electric response he, are correctly taken into account, the model allows the system's impulse response to be accurately predicted, with on-axis errors ranging between 0.2% in the far field and 1% in the near field. In the near-field area and within the far field -3dB beam spread width, the error is generally greater than on the axis, but globally remains smaller than 1%. Inclusion of the size of the receiver dimension in the model appears to be crucial to the accuracy of the near field predictions, and an approximate criterion is proposed for the evaluation of the influence of receiver. The procedure used to recover the electric response he is also presented in detail. The results obtained from this study are used to formulate various recommendations related to EPR modelling. PMID- 28800495 TI - The explanatory effect of a label: Explanations with named categories are more satisfying. AB - Can opium's tendency to induce sleep be explained by appeal to a "dormitive virtue"? If the label merely references the tendency being explained, the explanation seems vacuous. Yet the presence of a label could signal genuinely explanatory content concerning the (causal) basis for the property being explained. In Experiments 1 and 2, we find that explanations for a person's behavior that appeal to a named tendency or condition are indeed judged to be more satisfying than equivalent explanations that differ only in omitting the name. In Experiment 3, we find support for one proposal concerning what it is about a name that drives a boost in explanatory satisfaction: named categories lead people to draw an inference to the existence of a cause underlying the category, a cause that is responsible for the behavior being explained. Our findings have implications for theories of explanation and point to the central role of causation in explaining behavior. PMID- 28800496 TI - Goal commitment predicts treatment outcome for adolescents with alcohol use disorder. AB - OBJECTIVE: Commitment to change is an innovative potential mediator and mechanism of behavior change (MOBC) that has not been examined in adolescents with substance use disorders (SUD). The Adolescent Substance Abuse Goal Commitment (ASAGC) questionnaire is a reliable and valid 2-scale measure developed to assess the adolescent's commitment to either abstinence or harm reduction (HR) that includes consumption reduction as a stated treatment goal. The objective of this study was to examine the ASAGC's ability to predict alcohol use treatment outcome. METHOD: During sessions three and nine of a 10-week treatment program, therapists completed the ASAGC for 170 adolescents 13-18years of age with alcohol use disorder (AUD). Drinking behaviors were assessed during and after a continued care phase until 12-month from study onset. RESULTS: Analysis of Variance results indicated that adolescents who reported no alcohol use had significantly higher scores on the commitment to abstinence scale than adolescents who reported alcohol use. None of the ANOVA models were significant for commitment to HR. When treatment outcome was examined, commitment to abstinence consistently predicted number of drinking days, number of heavy drinking days, and the maximum number of drinks post-treatment. In contrast, commitment to HR did not predict any of the drinking outcomes. These results suggest that the more adolescents were committed to abstinence during treatment, the less they used and abused alcohol after treatment completion. CONCLUSIONS: In addition to the ASAGC's ability to differentiate between commitment to abstinence and commitment to HR, study findings demonstrate that goal commitment consistently predicts AUD treatment outcome. PMID- 28800497 TI - Glycoconjugate probes containing a core-fucosylated N-glycan trisaccharide for fucose lectin identification and purification. AB - Glyco-PAMAM dendrimers and glyco-agarose beads bearing a core-fucosylated N glycan trisaccharide GlcNAcbeta1,4(Fucalpha1,6)GlcNAc or a non-fucose disaccharide GlcNAcbeta1,4GlcNAc were successfully synthesized and characterized by monosaccharide analysis with HPAEC-PAD technique. These glycoconjugates as fucose lectin probes were applied in fucose-specific lectin detection and purification. The model fucose lectin AAL indicated binding activity with the FITC-labeled PAMAM carrying core-fucose trisaccharide. An affinity chromatography column stuffed with the agarose beads carrying core-fucosylated trisaccharide exhibited a good specificity in purification of AAL than non-fucose disaccharide agarose beads. These novel glycoconjugates bearing the precise and simplified core-fucose N-glycan structure provided a potential application for core-fucose specific lectin discovery. PMID- 28800498 TI - Erylosides F8, V1-V3, and W-W2 - New triterpene oligoglycosides from the Carribean sponge Erylus goffrilleri. AB - Seven new triterpene glycosides, erylosides F8 (1), V1 (2), V2 (3), V3 (4), W (5), W1 (6) and W2 (7), were isolated from a Carribean sponge Erylus goffrilleri collected from the Carribean Sea near the Arrecife-Seco reef (Cuba). Structures of the glycosides were determined using 1H and 13C NMR spectroscopy, including 2D NMR procedures (1H-1H COSY, 1H-13S HMBC, 1H-13S HSQC and NOESY) and HR ESI mass spectrometry. Erylosides 1 and 4 have 14-carboxy-24,25-dimethyllanost-8(9)-en 3beta,25-diol as aglycone whereas glycosides 2, 3, 5, 6 and 7 are 14-carboxy-24 acetoxy-24-methyllanost-8(9)-en-3beta-ol glycoconjugates. Cytotoxic activities of the isolated compounds against Ehrlich carcinoma cells and hemolysis were examined and their dependence on eryloside structure was evaluated. PMID- 28800499 TI - Effects of preimplantation factor on interleukin-6 and prostaglandin F2alpha and E2 in the bovine endometrium. AB - Preimplantation factor (PIF) is a pregnancy specific peptide with immune modulatory properties exerted on the human endometrium. Viable bovine embryos secrete PIF, but its effect on the bovine endometrial immune response is unknown, both in native and inflammatory stimulated endometrial tissue. An ex vivo bovine endometrial tissue culture model was used with lipopolysaccharide (LPS) as an inflammatory stimulant. The effect of synthetic PIF (sPIF) was assessed, in three separate experiments, on the secretion or mRNA expression of essential prostaglandins and cytokines. Radioimmunoassays were used to assess prostaglandin secretion and ELISA for IL-6 secretion from endometrial explants. mRNA expression of IL6 and IL8 was analysed from endometrial explants with real-time PCR. Synthetic PIF reduced native IL-6 secretion from explants when pre-treated for 24 h. There was no effect of sPIF on IL-6 secretion from LPS challenged explants; however, sPIF increased IL6 mRNA expression when challenged with 500 ng/mL LPS. There was no effect of sPIF on prostaglandin secretion or mRNA expression of IL8. Therefore, sPIF is able to modulate the native IL-6 production pathway in the bovine endometrium, yet demonstrates no effect on prostaglandin secretion or IL8 expression. Unlike in human studies, effects of sPIF were minimal, thus sPIF is not an effective modulator of the immune targets investigated in the bovine endometrium. PMID- 28800500 TI - SB223412, a neurokinin-3 receptor-selective antagonist, suppresses testosterone secretion in male guinea pigs. AB - Guinea pigs are important zoo animals and have been recommended for animal assisted activities or therapy, however there are problems concerning testosterone inducing aggressive or sexual behaviors in male guinea pigs. Testicular testosterone secretion is regulated by pulsatile gonadotropin releasing hormone (GnRH)/luteinizing hormone (LH) release in mammals. The mechanism generating GnRH/LH pulses is thought to be governed by kisspeptin neurons, which coexpress neurokinin B (NKB) and dynorphin A (Dyn), in the arcuate nucleus (ARC). Kisspeptin neurons in the ARC are frequently referred to as KNDy neurons. The purpose of this study was to examine whether the antagonization of NKB-neurokinin-3 receptor (NK3R) signaling can manipulate testosterone secretion in male guinea pigs. A single subcutaneous administration or 7 days of oral administration of an NK3R-selective antagonist, SB223412 (50 mg/body), significantly decreased plasma testosterone levels in male guinea pigs. In vitro binding assays confirmed that SB223412 has a high affinity to guinea pig NK3R. These results suggest that SB223412 could be used as an orally-available compound to suppress testosterone levels in male guinea pigs. Double labeling in situ hybridization of kisspeptin and either NKB or Dyn showed that kisspeptin expressing neurons contained NKB (77.9%) or Dyn (62.3%) in the ARC, suggesting the presence of KNDy neurons in the ARC of guinea pigs. In conclusion, the present study shows that SB223412 could be a candidate compound to suppress testosterone secretion in male guinea pigs for controlling sexual and aggressive behaviors in the species. PMID- 28800501 TI - Learning effects of dynamic postural control by auditory biofeedback versus visual biofeedback training. AB - Augmented sensory biofeedback (BF) for postural control is widely used to improve postural stability. However, the effective sensory information in BF systems of motor learning for postural control is still unknown. The purpose of this study was to investigate the learning effects of visual versus auditory BF training in dynamic postural control. Eighteen healthy young adults were randomly divided into two groups (visual BF and auditory BF). In test sessions, participants were asked to bring the real-time center of pressure (COP) in line with a hidden target by body sway in the sagittal plane. The target moved in seven cycles of sine curves at 0.23Hz in the vertical direction on a monitor. In training sessions, the visual and auditory BF groups were required to change the magnitude of a visual circle and a sound, respectively, according to the distance between the COP and target in order to reach the target. The perceptual magnitudes of visual and auditory BF were equalized according to Stevens' power law. At the retention test, the auditory but not visual BF group demonstrated decreased postural performance errors in both the spatial and temporal parameters under the no-feedback condition. These findings suggest that visual BF increases the dependence on visual information to control postural performance, while auditory BF may enhance the integration of the proprioceptive sensory system, which contributes to motor learning without BF. These results suggest that auditory BF training improves motor learning of dynamic postural control. PMID- 28800502 TI - Spotlight on equality of employment opportunities: A qualitative study of job seeking experiences of graduating nurses and physiotherapists from black and minority ethnic backgrounds. AB - BACKGROUND: There is growing attention in the UK and internationally to the representation of black and minority ethnic groups in healthcare education and the workplace. Although the NHS workforce is very diverse, ethnic minorities are unevenly spread across occupations, and considerably underrepresented in senior positions. Previous research has highlighted that this inequality also exists at junior levels with newly qualified nurses from non-White/British ethnic groups being less likely to get a job at graduation than their White/British colleagues. Although there is better national data on the scale of inequalities in the healthcare workforce, there is a gap in our understanding about the experience of job seeking, and the factors that influence disadvantage in nursing and other professions such as physiotherapy. AIM: This qualitative study seeks to fill that gap and explores the experience of student nurses (n=12) and physiotherapists (n=6) throughout their education and during the first 6-months post qualification to identify key experiences and milestones relating to successful employment particularly focusing on the perspectives from different ethnic groups. PARTICIPANTS: Participants were purposively sampled from one university to ensure diversity in ethnic group, age and gender. METHODS: Using a phenomenological approach, in-depth semi-structured interviews were conducted at course completion and 6 months later. RESULTS: Two main themes were identified. The 'proactive self' ('It's up to me') theme included perceptions of employment success being due to student proactivity and resilience; qualities valued by employers. The second theme described the need to 'fit in' with organisational culture. Graduates described accommodating strategies where they modified aspects of their identity (clothing, cultural markers) to fit in. At one extreme, rather than fitting in, participants from minority ethnic backgrounds avoided applying to certain hospitals due to perceptions of discriminatory cultures, 'I wouldn't apply there 'cos you know, it's not really an ethnic hospital'. In contrast, some participants recognised that other graduates (usually white) did not need to change and aspects of their identity brought unsolicited rewards 'if your face fits then the barriers are reduced'. CONCLUSIONS: The findings indicate that success in getting work is perceived as determined by individual factors, and fitting in is enabled by strategies adopted by the individual rather than the workplace. Demands for change are more acute for graduates from black and minority ethnic backgrounds. This is an issue for healthcare organisations seeking to be inclusive and challenges employers and educators to acknowledge inequalities and take action to address them. PMID- 28800504 TI - Survival outcomes and patterns of failure in women with stage IIIC2 endometrial carcinoma. AB - OBJECTIVES: Para-aortic lymph node involvement in women with endometrial carcinoma (EC) is a poor prognostic factor. Many studies have included women with stage IIIC2 in cohorts of patients with advanced stage disease. The aim of this study was to analyze survival outcomes and patterns of failure in women with solely stage IIIC2 EC. METHODS: We identified women with FIGO stage IIIC2 EC who underwent surgical staging at our institution. In addition to descriptive analyses of patient demographics, tumor characteristics, and adjuvant treatment received, univariate log-rank analyses and Cox regression multivariate analyses (MVA) were performed to identify predictors of recurrence-free (RFS), disease specific (DSS) and overall survival (OS). RESULTS: A total of 72 women were included in this study cohort. The median follow-up time was 43 months. The median number of positive para-aortic lymph nodes was one. Of the 61 women (84.7%) who received adjuvant therapy, 40 women (65.6%) received chemotherapy and radiation therapy (CRT), 17 women (27.9%) received chemotherapy alone (CT), and only 4 women (6.6%) received radiation therapy alone. Thirty-seven women (51.4%) experienced disease recurrence. Distant metastasis was the most common pattern of failure (73%). Five-year RFS, DSS, and OS were 48%, 51%, and 48%, respectively. Due to small study size, our exploratory multivariate analysis demonstrated that histologic grade was the only significant prognostic factor for DSS (p=0.03) and OS (p=0.02). The type of adjuvant therapy did not sustain its independent predictive significance for RFS, DSS and OS. CONCLUSIONS: Our findings suggest that almost half of women with stage IIIC2 can be cured with surgical staging and adjuvant therapies. The most common pattern of failure was distant metastasis calling for further optimization of systemic therapy. PMID- 28800503 TI - Intravenous heroin use in Haiphong, Vietnam: Need for comprehensive care including methamphetamine use-related interventions. AB - BACKGROUND: The aim of this study was to describe patterns among people who inject drugs (PWID), risk-related behaviours and access to methadone treatment, in order to design a large-scale intervention aiming to end the HIV epidemic in Haiphong, Vietnam. METHODS: A respondent-driven sampling (RDS) survey was first conducted to identify profiles of drug use and HIV risk-related behaviour among PWID. A sample of PWID was then included in a one-year cohort study to describe access to methadone treatment and associated factors. RESULTS: Among the 603 patients enrolled in the RDS survey, 10% were female, all were injecting heroin and 24% were using methamphetamine, including 3 (0.5%) through injection. Different profiles of risk-related behaviours were identified, including one entailing high-risk sexual behaviour (n=37) and another involving drug-related high-risk practices (n=22). High-risk sexual activity was related to binge drinking and methamphetamine use. Among subjects with low sexual risk, sexual intercourse with a main partner with unknown serostatus was often unprotected. Among the 250 PWID included in the cohort, 55.2% initiated methadone treatment during the follow-up (versus 4.4% at RDS); methamphetamine use significantly increased. The factors associated with not being treated with methadone after 52 weeks were fewer injections per month and being a methamphetamine user at RDS. CONCLUSION: Heroin is still the main drug injected in Haiphong. Methamphetamine use is increasing markedly and is associated with delay in methadone initiation. Drug-related risks are low but sexual risk behaviours are still present. Comprehensive approaches are needed in the short term. PMID- 28800505 TI - Electrochemical aptasensor for thrombin using co-catalysis of hemin/G-quadruplex DNAzyme and octahedral Cu2O-Au nanocomposites for signal amplification. AB - In this work, novel octahedral Cu2O-Au nanocomposites were synthesized and first applied in an electrochemical aptasensor to detect thrombin (TB) with the aid of a DNAzyme for signal amplification. The octahedral Cu2O-Au nanocomposites have not only simultaneously served as signal amplifying molecules but have also been utilized as an ideal loading platform to immobilize a large number of electroactive substances and recognition probes. Gold nanoparticles (AuNPs) were grown directly on the surface of the octahedral Cu2O nanocrystals, and the Cu2O Au nanocomposites obtained had the advantages of large surface areas and excellent biocompatibilities. The hemin/G-quadruplex, which was formed by intercalating hemin into the amino terminated thrombin binding aptamer (NH2-TBA), and the electroactive toluidine blue (Tb) were immobilized onto the Cu2O-Au nanocomposite surfaces through a stable Au-N bond. AuNPs, Cu2O and hemin/G quadruplex co-catalyse the H2O2 in the working buffer to promote the electron transfer of Tb as a multiple signal amplification strategy in order to improve the performance of the electrochemical aptasensor. Under optimal conditions, the designed aptasensor exhibited sensitive detection of TB from 100 fM to 20nM with a lower detection limit of 23fM. This proposed aptasensor exhibited good sensitivity, high specificity and acceptable reproducibility and could be widely applied in bioassay analysis. PMID- 28800506 TI - Ni(OH)2/NGQDs-based electrochemiluminescence immunosensor for prostate specific antigen detection by coupling resonance energy transfer with Fe3O4@MnO2 composites. AB - An efficient quenching electrochemiluminescence (ECL) immunosensor based on ECL resonance energy transfer (ECL-RET) was studied for sensitive analysis of prostate specific antigen (PSA). In this protocol, nitrogen-doped graphene quantum dots (NGQDs) which could produce excellent ECL emission, were loaded onto Ni(OH)2 with the three-dimensional (3D) hierarchical and stacked lamellar structure. Taking advantages of high conductivity and large specific surface area of Ni(OH)2, the better electrochemical and ECL behavior of Ni(OH)2/NGQDs were presented. As another part of immunosensor, the Fe3O4@MnO2 composites with wider ultraviolet absorption range were successfully assembled. The absorption spectra of Fe3O4@MnO2 precisely overlapped with the ECL spectra of NGQDs, leading to the significant decrement of ECL signal. Herein, the sandwich-type immunosensor was developed based on the quenching mechanism between NGQDs (ECL donor) and Fe3O4@MnO2 (ECL acceptor). The system was optimized to realize reliable determination of PSA concentration within the linear range of 10-5-10ng/mL and a detection limit of 5 fg/mL (S/N = 3). Eminently, the developed method was successfully applied in real serum samples with good recoveries in a range from 94.0% to 102%, indicating the good accuracy of the proposed method for PSA detection. PMID- 28800507 TI - Ultrasensitive electrochemiluminescence immunoassay for simultaneous determination of CA125 and CA15-3 tumor markers based on PAMAM-sulfanilic acid Ru(bpy)32+ and PAMAM-CdTe@CdS nanocomposite. AB - A multiplex ultrasensitive electrochemiluminescence (ECL) immunoassay was developed for the simultaneous determination of two different tumor markers, cancer antigen 153 (CA 15-3) and cancer antigen 125 (CA 125) using polyamidoamine dendrimer-quantum dots (PAMAM-QDs) and PAMAM-sulfanilic acid-Ru(bpy)32+ as the signal probes and Fe3O4-SiO2 as a magnetic bead. The CdTe@CdS- QDs and Ru(bpy)32+ at the presence of tripropyl amine (TPA) as coreactant generate ECL at an applied voltage of + 1.2V (vs Ag/AgCl) in two different wavelengths 500 and 620nm, respectively. Based on this strategy, the simultaneous detection of two tumor markers in single run carried out. This dual signal amplification technique was achieved by employing Fe3O4@SiO2-dendrimer as immunosensing platform and PAMAM as the carrier for immobilizing CdTe@CdS and Ru(bpy)32+ probes. Experimental results illustrated that the designed immunosensor can be used to sequentially detection of CA 125 and CA 15-3 markers with the wide linear ranges of 1uU/mL to 1U/mL and 0.1mU/mL to 100U/mL with very low detection limits of 0.1uU/mL and 10uU/mL, respectively. The application of the immunosensor for simultaneous detection of CA125 and CA15-3 in human serum samples was evaluated and the obtained results were found to be in acceptable agreement with the those obtained with an ELISA assay as reference method. The proposed ECL immunosensor can provide a simple, sensitive and reliable approach for the simultaneous detection of tumor markers in clinical samples. PMID- 28800508 TI - A suspending-droplet mode paper-based microfluidic platform for low-cost, rapid, and convenient detection of lead(II) ions in liquid solution. AB - A paper-based microfluidic device based on unconventional principle was developed and used to detect lead ions through a two-step process including heated incubation and subsequent mixing. The device was made by generating a superhydrophobic pattern, which defines channel and reservoir barriers, on a water-impermeable paper substrate, followed by loading and drying the reagents in the defined reservoirs. Different from the conventional paper-based devices that are made of water-permeable paper, the as-prepared device holds water drops in discrete reservoirs, and the water drops will not move unless the device is titled along the direction of the predefined channels. In this way, the liquid samples applied onto the device are handled as individual drops and could be stored, transported, and mixed on demand. Different from the conventional paper based devices that use capillary force to drive liquid, our new device uses wetting and gravity as driving force. We name this operation principle suspending droplet mode paper-based device (SD-MUPAD). The use of a Teflon contact-printing stamp makes the production of such devices rapid, cost efficient, and mass productive. Utilizing a G-quadruplex-based luminescence switch-on assay, we demonstrated rapid, convenient, highly sensitive, and low cost detection of lead(II) ions in water samples, using a custom made battery-powered portable device, and a smart phone as the detector. PMID- 28800509 TI - Polyethylene glycol modified ORMOSIL theranostic nanoparticles for triggered doxorubicin release and deep drug delivery into ovarian cancer spheroids. AB - A novel pegylated multifunctional probe of Ormosil nanoparticles (PEGCDSIR820) loaded with Near Infrared dye (NIR; IR820) and a chemotherapeutic drug, Doxorubicin (DOX) was developed for cancer theranostic applications. PEGCDSIR820 nanoparticles had an average diameter of 58.2+/-3.1nm, zeta potential of -6.9+/ 0.1mV in cell culture media and stability against aggregation in physiological buffers. The encapsulation efficiency of DOX was 65.0+/-3.0%, and that of IR820 was 76.0+/-2.1%. PEGCDSIR820 showed no cytotoxicity in ovarian cancer cells (Skov 3). The cytotoxicity markedly increased when Skov-3 cells incubated with PEGCDSIR820 particles were exposed to 808nm laser due to the combination of adjuvant hyperthermia (43 degrees C) and enhanced DOX release. Exposure to laser enhanced the release of DOX, 45% of DOX release was observed in 3h compared to 23% without laser exposure. Confocal imaging in Skov-3 cells showed that the combination of hyperthermia due to NIR exposure and release of DOX caused cell necrosis. Furthermore, in spheroids exposed to NIR laser penetration of DOX was deeper compared to the absence of laser exposure. Skov-3 spheroids incubated with pegylated nanoparticles for 24h and exposed to laser showed 94% reduction in cell viability. Encapsulation of IR820 in PEGCDSIR820 increased the in-vivo elimination half-life to 41.0+/-7.2h from 30.5+/-0.5h of free IR820. PMID- 28800510 TI - Medication adherence in schizophrenia: The role of insight, therapeutic alliance and perceived trauma associated with psychiatric care. AB - Medication non adherence in schizophrenia is a major cause of relapse and hospitalization and remains for clinicians an important challenge. This study investigates the associations between insight, therapeutic alliance, perceived trauma related to psychiatric treatment and medication adherence in patients with schizophrenia. In this multicenter study, 72 patients were assessed regarding symptomatology, self-reported adherence with medication, insight, medication side effects, therapeutic alliance and perceived trauma related to psychiatric treatment. Structural Equation Modeling (SEM) was used to test predicted paths among these variables. The data fit a model in which medication adherence was directly predicted by insight, therapeutic alliance and perceived trauma related to psychiatric treatment. Perceived trauma moderates the role of insight on medication adherence. The final model showed good fit, based on four reliable indices. Greater adherence was correlated with higher insight, higher therapeutic alliance and lower perceived trauma. These three variables appear to be important determinants of patient's medication adherence. Medication adherence could be enhanced by reducing perceived trauma and by increasing insight. The need for mental health providers to acknowledge patients' potentially traumatic experience with psychiatric treatment and the need to encourage greater involvement in care are discussed. PMID- 28800511 TI - The serotonin transporter promoter variant (5-HTTLPR) and childhood adversity are associated with the personality trait openness to experience. AB - There is evidence supporting an association between the serotonin-transporter linked polymorphic region (5-HTTLPR) and the Five Factor Model (FFM) of human personality. 5-HTTLPR has also been found to interact with stressful life events to increase risk of psychopathology. In the present study, by taking into account stressful life events in the form of childhood adversity, we examined the association between 5-HTTLPR and FFM traits using an adult Swedish cohort (N = 3112). We found that 5-HTTLPR was significantly associated with openness (to experience). Specifically, homozygote carriers of the short allele had lower levels of openness compared to carriers of the long allele. In addition, childhood adversity was found to influence openness. These findings support a previously reported association of 5-HTTLPR with openness in a younger cohort and may provide insights into the neurobiological basis of human personality. PMID- 28800512 TI - Metabotropic glutamate receptors as emerging research targets in bipolar disorder. AB - Glutamatergic dysregulation is implicated in the neuropathology of bipolar disorder (BD). There is increasing interest in investigating the role of metabotropic glutamate receptors (mGluRs) in BD and as a target for treatment intervention. Bipolar mGluR studies (published January 1992-April 2016) were identified via PubMed, Embase, Web of Science, and Scopus. Full-text screening, data extraction, and quality appraisal were conducted in duplicate, with strict inclusion and exclusion criteria. The initial literature search for mGluRs in BD, including non-bipolar mood disorders and primary psychotic disorders, identified 1544 articles. 61 abstracts were selected for relevance, 16 articles met full inclusion criteria, and three additional articles were found via citations. Despite limited literature, studies demonstrated: single nucleotide polymorphisms (SNPs) associated with BD, including a GRM3 SNP associated with greater likelihood of psychosis (rs6465084), mRNA binding protein Fragile X Mental Retardation Protein associated with altered mGluR1/5 activity in BD populations, and lithium decreasing mGluR5 expression and mGluR-mediated intracellular calcium signaling. Limited research has been performed on the role of mGluRs in BD, but results highlight the importance of ongoing study. Future directions for research of mGluRs in BD include GRM polymorphisms, epigenetic regulation, intracellular proteins, and pharmacologic interactions. PMID- 28800513 TI - Serum TNF-related weak inducer of apoptosis (TWEAK) and TNF-related apoptosis inducing ligand (TRAIL) levels of patients with bipolar disorder in manic episode, in remission and healthy controls. AB - TNF-related weak inducer of apoptosis (TWEAK) and TNF-related apoptosis-inducing ligand (TRAIL) are members of TNF superfamily, which has various roles in immunologic and inflammatory reactions in the organism. Pathophysiology in bipolar disorder is still under investigation and altered serum levels of cytokines are often encountered. Aim of this study is to detect serum TWEAK and TRAIL levels of patients with bipolar disorder and healthy controls. For this purpose, 55 patients with bipolar disorder -27 manic episode (ME), 28 remission (RE) and 29 healthy controls (HC) were included. TWEAK levels of ME and RE groups were significantly lower than HC. TWEAK levels of bipolar patients (BP) were also lower than HC. TRAIL levels of ME, RE, HC groups and BP, HC groups were statistically similar. In our knowledge, this is the first study concerning about TWEAK and TRAIL levels in bipolar disorder and our results pointed that TWEAK related immune response might be impaired in bipolar disorder, but our study fails to eradicate the confounders such as medication, smoking and body mass index. Studies having larger samples and limited confounders are needed to be able to evaluate these changes better and detect possible alterations about TRAIL and other TNF superfamily members. PMID- 28800515 TI - Development and validation study of the Smartphone Overuse Screening Questionnaire. AB - The aim of this study was to develop a screening questionnaire that could distinguish individuals at high risk of smartphone overuse from casual users. The reliability, validity, and diagnostic ability of the Smartphone Overuse Screening Questionnaire (SOS-Q) were evaluated. Preliminary items were assessed by 50 addiction experts on-line, and 28 questions were selected. A total of 158 subjects recruited from six community centers for internet addiction participated in this study. The SOS-Q, Young's internet addiction scale, Korean scale for internet addiction, and Smartphone Scale for Smartphone Addiction (S-Scale) were used to assess the concurrent validity. Construct validity was supported by a six factor model using an exploratory factor analysis. The internal consistency and the item-total correlations were favorable (alpha = 0.95, r = 0.35-0.81). The test-retest reliability was moderate (r = 0.70). The SOS-Q showed superior concurrent validity with the highest correlation between the S-Scale (r = 0.76). Receiver operating characteristic curve analysis revealed an area under the curve of 0.877. A cut-off point of 49 effectively categorized addiction high-risk group with a sensitivity of 0.81 and specificity of 0.86. Overall, the current study supports the use of SOS-Q as both a primary and supplementary measurement tool in a variety of settings. PMID- 28800516 TI - Repetitive vs. occasional non-suicidal self-injury and school-related factors among Israeli high school students. AB - The current study explored the relationship between non-suicidal self-injuries (NSSI) and students' perceptions of school among adolescents. A sample of 594 high-school students (54.4% male; mean age 14.96) completed validated self reported measures. Students were divided into three groups: repetitive-NSSI (more than 6 occasions), occasional-NSSI (at least once but less than 6), and no-NSSI. Multi-nominal regression, controlling for gender, age, and depression symptoms, indicated that teachers' psychological support, a sense of school belongingness, and negative perceptions of peer climate were significantly different between repetitive-NSSI and non-NSSI groups. These school-related factors should be considered as risk factors for NSSI behaviors. PMID- 28800514 TI - The relationship between executive functions and fluid intelligence in euthymic Bipolar Disorder patients. AB - Distinct cognitive deficits have been described in Bipolar disorder (BD), including executive impairments, commonly attributed to frontal dysfunction. However, recent attention has been paid to the heterogeneity of cognitive functioning in this population, suggesting that the executive deficits observed in BD might be due to a loss in fluid intelligence (g). Following our previous line of investigation in multiple neurological and psychiatric conditions we aimed at determining the role of g in frontal deficits in BD. Euthymic BD patients (n = 51) and healthy controls (n = 37) were assessed with Wisconsin Card Sorting Test (WCST), Verbal Fluency, Trail Making Test B (TMTB), a multitasking test, and a theory of mind test. A general cognitive battery was used to derive a measure of g. As in other neuropsychiatric conditions, significant patient control differences in WCST, Verbal Fluency and TMTB were removed when g was introduced as a covariate. Deficits remained significant in the multitasking test. We suggest that neuropsychological assessment in BD should include tests of general intelligence, together with one or more specific tasks that allow for the assessment of residual frontal deficits, putatively associated with anterior frontal functioning. PMID- 28800517 TI - Efficient inactivation of MS-2 virus in water by hydrodynamic cavitation. AB - The aim of this study was to accurately quantify the impact of hydrodynamic cavitation on the infectivity of bacteriophage MS2, a norovirus surrogate, and to develop a small scale reactor for testing the effect of hydrodynamic cavitation on human enteric viruses, which cannot be easily prepared in large quantities. For this purpose, 3 mL scale and 1 L scale reactors were constructed and tested. Both devices were efficient in generating hydrodynamic cavitation and in reducing the infectivity of MS2 virus. Furthermore, they reached more than 4 logs reductions of viral infectivity, thus confirming the scalability of hydrodynamic cavitation for this particular application. As for the mechanism of page inactivation, we suspect that cavitation generated OH- radicals formed an advanced oxidation process, which could have damaged the host's recognition receptors located on the surface of the bacteriophage. Additional damage could arise from the high shear forces inside the cavity. Moreover, the effectiveness of the cavitation was higher for suspensions containing low initial viral titers that are in similar concentration to the ones found in real water samples. According to this, cavitation generators could prove to be a useful tool for treating virus-contaminated wastewaters in the future. PMID- 28800518 TI - The implications of drought and water conservation on the reuse of municipal wastewater: Recognizing impacts and identifying mitigation possibilities. AB - As water agencies continue to investigate opportunities to increase resilience and local water supply reliability in the face of drought and rising water scarcity, water conservation strategies and the reuse of treated municipal wastewater are garnering significant attention and adoption. Yet a simple water balance thought experiment illustrates that drought, and the conservation strategies that are often enacted in response to it, both likely limit the role reuse may play in improving local water supply reliability. For instance, as a particular drought progresses and agencies enact water conservation measures to cope with drought, influent flows likely decrease while influent pollution concentrations increase, particularly salinity, which adversely affects wastewater treatment plant (WWTP) costs and effluent quality and flow. Consequently, downstream uses of this effluent, whether to maintain streamflow and quality, groundwater recharge, or irrigation may be impacted. This is unfortunate since reuse is often heralded as a drought-proof mechanism to increase resilience. The objectives of this paper are two-fold. First, we illustrate-using a case study from Southern California during its most recent drought- how drought and water conservation strategies combine to reduce influent flow and quality and, subsequently, effluent flow and quality. Second, we use a recently developed regional water reuse decision support model (RWRM) to highlight cost-effective strategies that can be implemented to mitigate the impacts of drought on effluent water quality. While the solutions we identify cannot increase the flow of influent or effluent coming into or out of a treatment plant, they can improve the value of the remaining effluent in a cost effective manner that takes into account the characteristics of its demand, whether it be for landscaping, golf courses, agricultural irrigation, or surface water augmentation. PMID- 28800519 TI - Emerging poly- and perfluoroalkyl substances in the aquatic environment: A review of current literature. AB - Poly- and perfluoroalkyl substances (PFASs) comprise a group of synthetic organic surfactants with a wide range of industrial and commercial applications. A few PFASs such as perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are now known to be ubiquitously present in the aquatic environment. They have become a global concern because of the toxicity and bioaccumulative properties. With the increasing availability of high-resolution mass spectrometers, many novel PFASs have been identified. Studies published between 2009 and 2017 have discovered 455 new PFASs (including nine fully and 446 partially fluorinated compounds), 45%, 29%, 17%, and 8% of which are anions, zwitterions, cations, and neutrals, respectively. They have been identified in natural waters, fish, sediments, wastewater, activated sludge, soils, aqueous film-forming foams, and commercial fluoropolymer surfactants. This article integrates and critically evaluates what is known about these newly identified PFASs. It discusses the different aspects of detection methodologies. It also surveys the removal of these compounds during conventional and advanced drinking-water and wastewater treatment, predicts the relevant physicochemical properties by means of four software programs, and identifies major knowledge gaps. Notably, a number of these newly identified PFASs are potential precursor compounds of PFOS and PFOA. Studies are critically needed to understand the removal and transformation of these compounds in natural and engineered environmental systems and their contribution, if any, to the secondary formation of PFOS and PFOA in these systems. PMID- 28800520 TI - A modified Delphi process to identify clinical and research priorities in patient and family centred critical care. AB - PURPOSE: To identify elements which enable patient and family centred care (PFCC) in the intensive care unit (ICU) and priorities for PFCC research. MATERIALS AND METHODS: We engaged a panel of multidisciplinary stakeholders in a modified Delphi process. Items generated from a literature review and panelist suggestions were rated in 3 successive rounds on a scale from 1 to 7. Median score was used to rate each item's priority, with 5 or more indicating "essential priority," 4 or 5 "moderate priority" and 3 or less "low priority." Interquartile range (IQR) was used to measure consensus, with IQR of 1 indicating "high" consensus, 2 "moderate" consensus, and 3 or greater "low" consensus. RESULTS: Six items were rated essential elements for facilitating PFCC with high consensus (flexible visiting hours, family participation in bedside care, trained family support person, interventions to facilitate continuity of care, staff education to support families, continuity of staff assignments). Three items were rated essential research topics: interventions to facilitate continuity of care following ICU discharge (moderate consensus), family participation in bedside care (low consensus), and decision aids for end of life decision-making (low consensus). CONCLUSIONS: Stakeholders identified clear and distinct priorities for PFCC in clinical care and research, though there was greater consensus for clinical care. PMID- 28800521 TI - Potassium deficiency alters growth, photosynthetic performance, secondary metabolites content, and related antioxidant capacity in Sulla carnosa grown under moderate salinity. AB - Salinity and K+ deficiency are two environmental constraints that generally occur simultaneously under field conditions, resulting in severe limitation of plant growth and productivity. The present study aimed at investigating the effects of salinity, either separately applied or in combination with K+ deficiency, on growth, photosynthetic performance, secondary metabolites content, and related antioxidant capacity in Sulla carnosa. Seedlings were grown hydroponically under sufficient (6000 MUM) or low (60 MUM) K+ supply with 100 mM NaCl (C + S and D + S treatments, respectively). Either alone or combined with K+ deficiency, salinity significantly restricted the plant growth. K+ deficiency further increased salt impact on the photosynthetic activity of S. carnosa, but this species displayed mechanisms that play a role in protecting photosynthetic machinery (including non photochemical quenching and antioxidant activity). In contrast to plants subjected to salt stress alone, higher accumulation of phenolic compounds was likely related to antioxidative defence mechanism in plants grown under combined effects of two stresses. As a whole, these data suggest that K+ deficiency increases the deleterious effects of salt stress. The quantitative and qualitative alteration of phenolic composition and the enhancement of related antioxidant capacity may be of crucial significance for S. carnosa plants growing under salinity and K+ deficient conditions. PMID- 28800522 TI - Screening for infectious diseases among asylum seekers newly arrived in Germany in 2015: a systematic single-centre analysis. AB - OBJECTIVES: During the migrant crisis in 2015, Germany was the largest single recipient of new asylum seekers in Europe. The German asylum law requires a screening examination for certain infectious diseases in asylum seekers upon arrival. The aim of this work was to analyse the rate of certain infectious diseases among asylum seekers screened at a reception centre in Southern Germany. STUDY DESIGN: Retrospective medical record review. METHODS: Medical records of 2602 asylum seekers screened by a local public health authority in Germany in 2015 were systematically analysed. RESULTS: The majority of screened subjects came from Afghanistan and Syria. The mean age was 22.1 (+/-12.0) years. The majority of subjects were male (75.4%). Most individuals were of normal weight or overweight, more subjects were obese than underweight. A total of 78 (3.9%) individuals were infected with hepatitis B and eight (0.4%) with HIV. In 31 cases, chest radiographs suggested active tuberculosis (1.6%), which was confirmed in four cases (0.2%). The physical examination uncovered 44 (1.7%) cases of scabies, nine (0.3%) cases of lice, eight (0.3%) of upper respiratory tract infections, two (0.1%) of varicella and 13 (0.5%) of other skin infections. CONCLUSIONS: In the majority of subjects none of the screened infectious diseases were found. No evidence was found that the overall prevalence of certain infectious diseases screened for in the present analysis was considerably higher than in previous migration studies. PMID- 28800523 TI - Quantification of cyclocreatine in mouse and rat plasma using hydrophilic interaction ultra-performance liquid chromatography-tandem mass spectrometry. AB - An accurate, rapid and selective method was developed to quantify cyclocreatine in mouse and rat plasma using hydrophilic interaction (HILIC) ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The plasma samples were prepared by protein precipitation with acetonitrile:methanol (70:30). Chromatographic separation was performed on a HILIC BEH amide column (2.1mm*50mm, 1.7MUm) with a 3min gradient elution at a flow rate of 0.5mL/min. For mass spectrometric detection, selected reaction monitoring (SRM) was used; the SRM transitions were m/z 144->98 and m/z 144->56 for cyclocreatine and m/z 148->102 for the internal standard (D4-cyclocreatine) in the positive ionization mode. No endogenous components interfered with the analysis of cyclocreatine and the internal standard in mouse and rat plasma. Plasma calibration curves were constructed in the range of 0.01-25MUM. The correlation coefficient of the calibration curves was greater than 0.99. The mean intraday assay accuracy for all quality control (QC) replicates was between 93 and 105%. The mean intraday assay precision (CV%) was 1.9-11% for all QC levels. The HILIC-UPLC-MS/MS method was successfully applied in pharmacokinetic (PK) studies of cyclocreatine in mice and rats for the first time. After a single 30mg/kg oral administration in mice and rats, the AUC0-infinity (area under the curve) was 84.1MUgh/mL and 91.7+/ 18.0MUgh/mL, respectively. PMID- 28800524 TI - Degradation and metabolite formation of estrogen conjugates in an agricultural soil. AB - Estrogen conjugates are precursors of free estrogens such as 17beta-estradiol (E2) and estrone (E1), which cause potent endocrine disrupting effects on aquatic organisms. In this study, microcosm laboratory experiments were conducted at 25 degrees C in an agricultural soil to investigate the aerobic degradation and metabolite formation kinetics of 17beta-estradiol-3-glucuronide (E2-3G) and 17beta-estradiol-3-sulfate (E2-3S). The aerobic degradation of E2-3G and E2-3S followed first-order kinetics and the degradation rates were inversely related to their initial concentrations. The degradation of E2-3G and E2-3S was extraordinarily rapid with half of mass lost within hours. Considerable quantities of E2-3G (7.68ng/g) and E2-3S (4.84ng/g) were detected at the end of the 20-d experiment, particularly for high initial concentrations. The major degradation pathway of E2-3G and E2-3S was oxidation, yielding the primary metabolites 17beta-estrone-3-glucuronide and 17beta-estrone-3-sulfate, respectively. Common metabolites were E2, the second primary metabolite, and E1, the secondary metabolite. Additionally, ring B unsaturated estrogens and their sulfate conjugates were tentatively proposed as minor metabolites. The persistence of E2-3G and E2-3S (up to 20 d) suggests that the high rate of application of conjugated estrogen-containing substances could be responsible for the frequent detection of free estrogens in surface and subsurface water. PMID- 28800525 TI - Chemical analysis and potential endocrine activities of aluminium coatings intended to be in contact with cosmetic water. AB - The objective of the work was to check the presence of Non-Intended Added Substances (NIAS) with hormonal activities in aluminium coatings extracts coded: AA, BBF, MC and RR, furnished by four different suppliers. Water samples were prepared at room temperature or at 40 degrees C for three months to verify the storage effect on the coatings. Solid phase extraction was used to concentrate and to extract coating substances. Hormonal activities were checked in vitro using reporter gene bioassays. Except BBF, all extracts induced a weak but significant estrogenic agonist activity in the human cell line. Using an estrogenic antagonist (ICI-182, 780), the answer was demonstrated specific in the bioassay. RR was the only extract to induce a concentration dependent anti androgenic response in the MDA-KB2 cell line. Analysis performed using GC-MS and HPLC-MS detected 12 substances in most of the extracts. 8 NIAS were present. Among them, 4 were identified with certainty: HMBT, BGA, DCU and BPA. Estrogenic potency was BPA>DCU>BGA>HMBT. HMBT was also anti-androgenic at high concentration. Combining chemical analysis and bioassays data, we demonstrated that in the RR and the RR40 extracts, the observed estrogenic response was mainly due to BPA, the anti-androgenic activity of RR could be due to a synergism between HMBT and BPA. For MC and AA, estrogenic responses appear to be due to the presence of DCU. Except BBF, storage conditions tended to increase estrogenic activities in all extracts. However, in term of risk assessment, activities observed were negligible. This work demonstrated that sensitive bioassays are pertinent tools in complement to chemical analysis to monitor and check the presence of NIAS with hormonal activity in coating extracts. PMID- 28800526 TI - Identification and determination of related substances of ceftaroline fosamil in medicinal product by high performance liquid chromatography with diode array detection and tandem mass spectrometry. AB - Ceftaroline fosamil, the prodrug of ceftaroline, is an advanced-generation cephalosporin antibacterial agent approved for treatment in the European Union in 2012. The drug is dedicated to curing complicated skin and soft tissue infections and community-acquired pneumonia. The developed analytical method of high performance liquid chromatography (HPLC) followed by diode array detector (DAD) set at 243nm was used to identify and determine degradation products of ceftaroline fosamil. The elaborated method demonstrated good selectivity and linearity [r>0.998 for the range 0.8-1.2mg/mL (80-120%) and r>0.997 for the range 0.005-0.015mg/mL (0.5-1.5%)]. Limit of detection (LOD) and limit of quantification (LOQ) values were equal to 0.15MUg/mL and 0.5MUg/mL, respectively. The forced decomposition of ceftaroline fosamil carried out under acidic, basic, oxidative, photolytic and thermal conditions revealed the high sensitivity of ceftaroline on photodegradation and thermolysis processes. Representative ceftaroline samples were selected and analysed by LC coupled with electrospray ionisation time-of-flight mass spectrometry (LC-ESI-Q-TOF-MS) to identify the related substances that appeared under stress conditions. The LC-DAD method was transferred without any modification to LC-MS/MS system, allowing it to correlate results back to the LC-DAD method. Eight unknown signals were detected in the photolytic and thermal stress solutions for ceftaroline fosamil. The evaluated method was applied to the analysis of a medicinal product containing ceftaroline fosamil - ZinforoTM, 600mg, powder for concentrate for solution for infusion. Moreover, the optimised conditions allowed for the successful separation of eight cephalosporin antibiotics possessing a molecular structure similar to ceftaroline (cefepime, cefapirin, ceftazidime, cefpirome, cefalonium, cefotaxime, cefquinome, cefalotin). PMID- 28800527 TI - Quantification of concentrated Chinese medicine granules by quantitative polymerase chain reaction. AB - Determination of the amount of constituent in a multi-herb product is important for quality control. In concentrated Chinese medicine granules (CCMG), no dregs are left after dissolution of the CCMG. This study is the first to examine the feasibility of using quantitative polymerase chain reaction (qPCR) to find the amount of CCMG in solution form. DNA was extracted from Hirudo and Zaocys CCMG mixed at different ratios and amplified in qPCR using species-specific primers. The threshold cycle (CT) obtained was compared with the respective standard curves. Results showed that reproducible quantification results could be obtained (1) for 5-50mg CCMG using a modified DNA extraction protocol, (2) amongst DNA extracted from the same batch of CCMG and (3) amongst different batches of CCMG from the same company. This study demonstrated the constitute amount of CCMG in a mixture could be determined using qPCR. This work has extended the application of DNA techniques for the quantification of herbal products and this approach may be developed for quality assurance in the CCMG industry. PMID- 28800528 TI - Comparison of three officinal species of Callicarpa based on a biochemome profiling strategy with UHPLC-IT-MS and chemometrics analysis. AB - Traditional Chinese medicine (TCM) materials with closely related species are frequently fungible in clinical use. Therefore, holistic comparison of the composition in bioactive compounds is essential to evaluate whether they are equivalent in efficacy. Taking three officinal species of Callicarpa as a case, we proposed and validated a standardized strategy for the discrimination of closely related TCM materials, which focused on the extraction, profiling and multivariate statistical analysis of their biochemome. Firstly, serial liquid liquid extractions were utilized to prepare different batches of Callicarpa biochemome, and the preparation yields were utilized for the normalization of sampling quantity prior to UHPLC-IT-MS analysis. Secondly, 34 compounds, including 19 phenylethanoid glycosides, 10 flavonoids and 5 terpenoids, were identified based on an untargeted UHPLC-IT-MS method. Thirdly, method validation of linearity, precision and stability showed that the UHPLC-IT-MS system was qualified (R2>0.995, RSD<15%) for subsequent biochemome profiling. After PCA and PLS-DA analysis, 30 marker compounds were screened and demonstrated to be of good predictability using genetic algorithm optimized support vector machines. Finally, a heatmap visualization was employed for clarifying the distribution of marker compounds, which could be helpful to determine whether the three Callicarpa species are, in fact, equivalent substitutes. This study provides a standardized biochemome profiling strategy for systemic comparison analysis of closely related TCM materials, which shows promising perspectives in tracking the supply chain of pharmaceutical suppliers. PMID- 28800529 TI - Mental health stigma and barriers to mental health care for first responders: A systematic review and meta-analysis. AB - OBJECTIVE: It is unclear how many first responders experience barriers to care and stigma regarding mental health care, and how this influences their help seeking. A systematic review and meta-analysis was conducted on barriers to care and mental health stigma in first responders and their empirical relationship with psychosocial and psychiatric variables. METHODS: The databases Medline, Embase PsycINFO, CINAHL, PILOTS, LILACS, Sociological Abstracts, SocINDEX, and Social Citation Index were searched to identify relevant studies. A quality assessment and meta-analysis was performed. RESULTS: Fourteen articles met inclusion criteria, from which data from 12 samples were extracted for meta analyses. All studies measured stigma regarding mental health care and 33.1% of first responders (95% CI 26.7-40.1; 12 individual samples) endorsed stigma items. The systematic review revealed that the most frequently endorsed items were fears regarding confidentiality and negative career impact. Five of 14 studies measured barriers to mental health care and 9.3% of first responders (95% CI 7.0-12.3; 4 individual samples) endorsed barriers to care items. The most frequently endorsed barriers were scheduling concerns and not knowing where to get help. Indications were found for more stigma and barriers in individuals with mental health problems. CONCLUSIONS: Stigma and barriers to care are experienced by a significant proportion of firs responders, which can potentially lead to delayed presentation in mental health care and therefore, increased risk of chronicity of post-trauma psychopathology for these groups. The current systematic review draws attention to the paucity of research in this area, particularly in non-Western samples. PMID- 28800530 TI - Comparative ecotoxicity of polystyrene nanoparticles in natural seawater and reconstituted seawater using the rotifer Brachionus plicatilis. AB - The impact of nanoplastics using model polystyrene nanoparticles (PS NPs), anionic (PS-COOH) and cationic (PS-NH2), has been investigated on the marine rotifer Brachionus plicatilis, a major component of marine zooplanktonic species. The role of different surface charges in affecting PS NP behaviour and toxicity has been considered in high ionic strength media. To this aim, the selected media were standardized reconstituted seawater (RSW) and natural sea water (NSW), the latter resembling more natural exposure scenarios. Hatched rotifer larvae were exposed for 24h and 48h to both PS NPs in the range of 0.5-50MUg/ml using PS NP suspensions made in RSW and NSW. No effects on lethality upon exposure to anionic NPs were observed despite a clear gut retention was evident in all exposed rotifers. On the contrary, cationic NPs caused lethality to rotifer larvae but LC50 values resulted lower in rotifers exposed in RSW (LC50=2.75+/-0.67ug/ml) compared to those exposed in NSW (LC50=6.62+/-0.87ug/ml). PS NPs showed similar pattern of aggregation in both high ionic strength media (RSW and NSW) but while anionic NPs resulted in large microscale aggregates (Z-average 1109 +/- 128nm and 998+/-67nm respectively), cationic NP aggregates were still in nano-size forms (93.99 +/- 11.22nm and 108.3 +/- 12.79nm). Both PDI and Z-potential of PS NPs slightly differed in the two media suggesting a role of their different surface charges in affecting their behaviour and stability. Our findings confirm the role of surface charges in nanoplastic behaviour in salt water media and provide a first evidence of a different toxicity in rotifers using artificial media (RSW) compared to natural one (NSW). Such evidence poses the question on how to select the best medium in standardized ecotoxicity assays in order to properly assess their hazard to marine life in natural environmental scenarios. PMID- 28800531 TI - Changes on lipid peroxidation,enzymatic activities and gene expression in planarian (Dugesia japonica) following exposure to perfluorooctanoic acid. AB - We investigated perfluorooctanoic acid (PFOA)-induced stress response in planarians. We administered different concentrations of PFOA to planarians for up to 10 d. PFOA exposure resulted in significant concentration-dependent elevations in lipid peroxidation, glutathione S-transferase and caspase-3 protease activities, and a significant decline in glutathione peroxidase activities compared with control groups. Exposure to PFOA significantly up-regulated the heat shock proteins hsp70 and hsp90, and p53, and down-regulated hsp40 compared with controls. PFOA exposure also increased HSP70 protein levels, as demonstrated by western blot analysis. These alterations indicated that PFOA exposure induced a stress response and affected the regulation of oxidative stress, enzymatic activities and gene expression. These results suggest that these sensitive parameters, together with other biomarkers, could be used for evaluating toxicity, for ecological risk assessment of PFOA in freshwaters. PMID- 28800532 TI - Cell cycle arrest mediated by Cd-induced DNA damage in Arabidopsis root tips. AB - Accumulating evidence demonstrates that the aberrant expression of cell cycle regulation and DNA repair genes can result in abnormal cell proliferation and genomic instability in eukaryotic cells under different stresses. Herein, Arabidopsis thaliana (Arabidopsis) seedlings were grown hydroponically on 0.5 * MS media containing cadmium (Cd) at 0-2.5mgL-1 for 5d of treatment. Real time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis revealed that expression of DNA damage repair and cell cycle regulation genes, including BRCA1, MRE11, WEE1, CDKA;1 and PCNA1, showed an inverted U-shaped dose response. In contrast, notably reduced expression was observed for G1-to-S transition-related genes, Histone H4, E2Fa and PCNA2; DSB end processing, GR1; G2 to-M transition-related gene, CYCB1;1; and DNA mismatch repair, MSH2, MSH6 and MLH1 genes in root tips exposed to 0.125-2.5mg/L Cd for 5d. Flow cytometry (FCM) analysis revealed significant increases of cells with a 2C nuclear content and with a 4C and 8C nuclear content under Cd stresses of 0.125 and 1-2.5mgL-1, respectively. Our results suggest that 0.125mgL-1 Cd-induced DNA damage induced the marked G1/S arrest, leading to accelerated growth in root tips, while 1.0 2.5mgL-1 Cd-induced DNA damage caused a notable G2/M arrest in root tips, leading to reduced growth in root tips. This may be a protective mechanism that prevents cells with damaged DNA from dividing under Cd stress. PMID- 28800533 TI - Deficiency and toxicity of boron: Alterations in growth, oxidative damage and uptake by citrange orange plants. AB - Boron (B) deficiency and toxicity are the major factors that affect plant growth and yield. The present study revealed the effect of B deficiency and toxicity on plant growth, morphology, physiology, and cell structure. A hydroponic culture experiment was conducted with five B levels, B deficient (B0), sufficient (B20, B10, B40) and toxic (B100). Our results show that both B deficient as well as excess level inhibit plant growth. In B deficiency, the major visible symptoms were appeared in roots, while B excess burned the leaf margin of older leaves. The antioxidant enzymes including superoxide dismutase (SOD), peroxidase (POD), catalase (CAT) and ascorbate peroxidase (APX) decreased at B deficiency and also decreased up to some extent at B excess, while in sufficient treatments, the higher antioxidant enzymes were found at B20. In addition, the MDA concentration decreased at B deficiency and increased with B concentration. Moreover, the photosynthetic rate, transpiration rate, stomatal conductance, leaf gas exchange and intercellular CO2 were reduced at both B deficiency as well as excess and higher at sufficient B20 treatment significantly. The chlorophyll and carotenoid content increased at B20 treatment, while decreased at B deficiency and excess. The middle lamellae of cell wall were found thick at B excess and normal at B20. The current study revealed that B deficiency as well as excess concentration affect plant growth and various morpho-physiological processes. PMID- 28800534 TI - Molecular understanding of the interaction of methyl hydrogen sulfate with ammonia/dimethylamine/water. AB - Theoretical calculations at the B3LYP-D3/aug-cc-pVTZ (aug-cc-pV(T+d)Z for sulfur) level were used to investigate the contribution of methyl hydrogen sulfate (MHS) to new particle formation with the common atmospheric aerosol nucleation precursors including water (H2O), ammonia (NH3), and dimethylamine (DMA). A typical characteristic feature of the MHS-containing complexes is the formation of six- or eight-membered ring structures via SOH?O (MHS donor), OH?O/N (H2O donor) and NH?O/N (NH3/DMA donor). The stability of the complexes was evaluated based on the calculated binding energies. The molecular interactions between three molecules are found to be more thermodynamically favorable than the complexes consisting two molecules. The red shifts of the SOH-stretching (MHS donor) vibrational transitions with respect to the isolated monomers are much larger than the red shifts of the OH (H2O donor) and NH-stretching (NH3/DMA donor) vibrational transitions. Topological analysis shows that the electron density and Laplacian at the bond critical points beyond the range of hydrogen bonding criteria for most of the complexes. This is due to the strong acid-base interaction between MHS and DMA or NH3, thus leads to a proton transfer from MHS to DMA or NH3. Remarkably, the atmospheric relevance of the MHS-containing complexes is much higher than H2SO4, which is evaluated by combining the calculated thermodynamic data and the concentrations of the reactant species. This study reveals the environmental fate of MHS could serve as nucleation centers in new particle formation. PMID- 28800535 TI - Computational investigation of the nitrosation mechanism of piperazine in CO2 capture. AB - Quantum chemistry calculations and kinetic modeling were performed to investigate the nitrosation mechanism and kinetics of diamine piperazine (PZ), an alternative solvent for widely used monoethanolamine in postcombustion CO2 capture (PCCC), by two typical nitrosating agents, NO2- and N2O3, in the presence of CO2. Various PZ species and nitrosating agents formed by the reactions of PZ, NO2-, and N2O3 with CO2 were considered. The results indicated that the reactions of PZ species having NH group with N2O3 contribute the most to the formation of nitrosamines in the absorber unit of PCCC and follow a novel three-step nitrosation mechanism, which is initiated by the formation of a charge-transfer complex. The reactions of all PZ species with NO2- proceed more slowly than the reactions of PZ species with ONOCO2-, formed by the reaction of NO2- with CO2. Therefore, the reactions of PZ species with ONOCO2- contribute more to the formation of nitrosamines in the desorber unit of PCCC. In view of CO2 effect on the nitrosation reaction of PZ, the effect through the reaction of PZ with CO2 shows a completely different tendency for different nitrosating agents. More importantly, CO2 can greatly accelerate the nitrosation reactions of PZ by NO2- through the formation of ONOCO2- in the reaction of CO2 with NO2-. This work can help to better understand the nitrosation mechanism of diamines and in the search for efficient methods to prevent the formation of carcinogenic nitrosamines in CO2 capture unit. PMID- 28800536 TI - Fate of metals before and after chemical extraction of incinerated sewage sludge ash. AB - Chemical extraction of incinerated sewage sludge ash (ISSA) can effectively recycle P, but it may change the speciation and mobility of the remaining metals. This study investigated the changes of the leaching potential and distribution of metals in the chemically extracted ISSA. Batch extraction experiments with different extractants, including inorganic acids, organic acids, and chelating agents, were conducted on the ISSA collected from a local sewage sludge incinerator. The extraction of Zn, Cu, Pb, Ni, Cd, Ba, Cr and As from the ISSA and the corresponding changes of the mobility and speciation were examined. The results showed that the metals in ISSA were naturally stable because large portions of metals were associated with the residual fraction. The inorganic (HNO3 and H2SO4) and organic acids (citric acid and oxalic acid) significantly co dissolved the metals through acid dissolution, but the reduction in the total concentrations did not tally the leaching potential of the residual metals. The increase in the exchangeable fraction due to destabilization by the extractants significantly enhanced the mobility and leachability of the metals in the residual ISSA. Chelating agents (EDTA and EDTMP) only extracted a small quantity of metals and had a marginal effect on the fate of the residual metals, but they significantly reduced the Fe/Mn oxide-bound fraction. In comparison, the bioaccessibility of residual metals were reduced to varying extent. Therefore, the disposal or reuse of chemically extracted ISSA should be carefully evaluated in view of possible increase in mobility of residual metals in the environment. PMID- 28800537 TI - Lead exposure in raptors from Japan and source identification using Pb stable isotope ratios. AB - Lead (Pb) poisoning is widespread among raptors and water birds. In Japan, fragments of Pb ammunition are still found in endangered eagles although more than 10 years have passed since legislation regarding use of Pb ammunition was introduced. This study was performed to investigate Pb exposure in raptors from various locations in Japan. We measured hepatic and renal Pb concentrations and hepatic Pb isotope ratios of Steller's sea eagles (Haliaeetus pelagicus), white tailed sea eagles (Haliaeetus albicilla), golden eagles (Aquila chrysaetos), and 13 other species (total 177 individuals) that were found dead, as well as blood samples from three eagles found in a weakened state during 1993-2015 from Hokkaido (northern part), Honshu (the main island), and Shikoku (a southern island) of Japan. In the present study in Hokkaido, one quarter of the sea eagles showed a high Pb concentration, suggesting exposure to abnormally high Pb levels and Pb poisoning. Pb isotope ratios indicated that endangered Steller's sea eagle and white-tailed sea eagle were poisoned by Pb ammunition that was used illegally in Hokkaido. In other areas of Japan, both surveillance and regulations were less extensive than in Hokkaido, but Pb poisoning in raptors was also noted. Therefore, Pb poisoning is still a serious problem in raptors in various areas of Japan due to accidental ingestion of materials containing Pb, especially Pb ammunition. PMID- 28800538 TI - Characterization of the metabolic transformation of thiamethoxam to clothianidin in Helicoverpa armigera larvae by SPE combined UPLC-MS/MS and its relationship with the toxicity of thiamethoxam to Helicoverpa armigera larvae. AB - In order to characterize the metabolic transformation of thiamethoxam (TMX) to clothianidin (CLO) in Helicoverpa armigera larvae and clarify its relationship with the insecticidal toxicity of TMX, method for determination of TMX and its metabolite clothianidin (CLO) residues in H. armigera larvae by solid phase extraction (SPE) combined UPLC-MS/MS was established. Following acetonitrile extraction and purification by SPE on florisil cartridge and C18 cartridge sequently, and cleanup by PSA adsorption, TMX and CLO residues in H. armigera larvae were successfully determined by UPLC-MS/MS. By using the established method, the concentration-time curves of TMX and its metabolite CLO in H. armigera larvae in vivo and metabolism of TMX by microsome of H. armigera larvae midguts in vitro were studied. TMX was quickly eliminated from H. armigera larvae with the elimination half-life as 4.2h. Meanwhile, only a small amount of CLO was formed from TMX metabolism, with the maximum CLO level in H. armigera larvae only accounts for the metabolic transformation of 7.99% of TMX, at 10h after intravenous TMX administration. Our results suggested that the low insecticidal efficacy of TMX against H. armigera larvae was related with the rapidly elimination of TMX from H. armigera larvae, meanwhile, CLO as TMX metabolite at a very low level in vivo didn't contribute to TMX toxicity to H. armigera larvae. In H. armigera larvae, TMX didn't act as proinsecticide for CLO in insecticidal efficacy of TMX. PMID- 28800539 TI - Development of a rapid and sensitive multiple reaction monitoring proteomic approach for quantification of transporters in human liver tissue. AB - With increasing knowledge on the role of hepatic transporters in drug disposition, numerous efforts have been described to quantify the expression of human hepatic transporters. However, reported quantitative proteomic approaches often require long analysis times. Additionally, greater assay sensitivity is still necessary for less abundant transporters or limited quantity of samples (e.g. hepatocytes and liver tissue). In the present study, an LC-MS/MS method for rapid and simultaneous quantification of 12 hepatic transporters (BCRP, BSEP, MATE1, MRP2, MRP3, MRP4, NTCP, OATP1B1, 1B3, 2B1, OCT1, and P-gp) was developed. Using a high LC flow rate (1.5mL/min) and fast LC gradient (4min total cycle time), the run time was markedly reduced to 4min, which was much shorter than most previously published assays. Chromatographic separation was achieved using ACE UltraCore SuperC18 50mm*2.1mm 5-MUm HPLC column. In addition, greater analytical sensitivity was achieved with both high LC flow rate/fast LC gradient and post-column infusion of ethylene glycol. The on-column LLOQ for signature peptides in this method ranged from 0.194 to 0.846 femtomoles. The impact of five protein solubilizers, including extraction buffer II of ProteoExtract Native Membrane Protein Extraction Kit, 3% (w/v) sodium deoxycholate, 20% (v/v) Invitrosol, 0.2% (w/v) RapiGest SF, and 10% (w/v) formamide on total membrane protein extraction and trypsin digestion was investigated. Sodium deoxycholate was chosen because of good total membrane protein extraction and trypsin digestion efficiency, as well as no significant MS interference. Good precision (within 15% coefficient of variation) and accuracy (within +/-15% bias), and inter-day trypsin digestion efficiency (within 28% coefficient of variation) was observed for quality controls. This method can quantify human hepatic transporter expression in a high-throughput manner and due to the increased sensitivity can be used to investigate the down-regulation of hepatic transporter protein (e.g., different ethnic groups and liver disease patients). PMID- 28800540 TI - Rapid extraction of Amomum tsao-ko essential oil and determination of its chemical composition, antioxidant and antimicrobial activities. AB - A simple, green and efficient extraction method named modified-solvent free microwave extraction (M-SFME) was employed for the extraction of essential oils (EOs) from Amomun tsao-ko. The process of M-SFME was optimized with the prominent preponderance of such higher extraction yield (1.13%) than those of solvent free microwave extraction (SFME, 0.91%) and hydrodistillation (HD, 0.84%) under the optimal parameters. Thirty-four volatile substances representing 95.4% were identified. The IC50 values of EOs determined by DPPH radical scavenging activity and beta-carotene/linoleic acid bleaching assay were 5.27 and 0.63mg/ml. Furthermore, the EOs exhibited moderate to potent broad-spectrum antimicrobial activity against all tested strains including five gram-positive and two gram negative bacteria (MIC: 2.94-5.86mg/ml). In general, M-SFME is a potential and desirable alternative for the extraction of EOs from aromatic herbs, and the EOs obtained from A. tsao-ko can be explored as a potent natural antimicrobial and antioxidant preservative ingredient in food industry from the technological and economical points of view. PMID- 28800541 TI - An experimental study of the protective effect of simvastatin on sepsis-induced myocardial depression in rats. AB - Many patients with sepsis died of heart failure caused by sepsis-induced myocardial depression. Patients with cardiovascular diseases treated by statins have a lower incidence and mortality of sepsis, although the mechanisms remain elusive. To investigate the protective effect of simvastatin on sepsis-induced myocardial depression and to explore possible mechanisms of action. Thirty six adult male Wistar rats were pretreated with simvastatin (0.2MUg/g, q12h) for one week before cecal ligation and puncture (CLP). It was found that in simvastatin treated rats, cardiac function indices, including left ventricular systolic pressure (LVESP) and maximal rate of rise and fall of left ventricular pressure (+/-dp/dtmax) and mean arterial pressure(MAP) markedly improved. Myocardial cells examined with hematoxylin and eosin (HE) were only partially swollen and degenerated and with fewer inflammatory cells infiltrating. Expressions of TLR4 and NF-kappaB p65 protein were significantly lower in simvastatin-treated rats than that in sepsis rats at the same time point. Levels of TNF-alpha, IL-1beta, IL-6, MCP-1 and NO in myocardial tissues, together with levels of CTnI in serum were significantly declined in simvastatin-treated rats. Simvastatin has a protective effect on myocardial depression caused by sepsis. The effect may be mediated by the inhibition of TLR4-NF-kappaB signaling pathway, which leads to reduced levels of downstream inflammatory factors such as TNF-alpha, IL-1beta, IL 6, MCP-1 and NO. PMID- 28800542 TI - Digitoflavone (DG) attenuates LPS-induced acute lung injury through reducing oxidative stress and inflammatory response dependent on the suppression of TXNIP/NLRP3 and NF-kappaB. AB - Acute lung injury is a severe disease with a high rate of mortality. Digitoflavone (DG) was suggested to possess bioactivities to reduce oxidative stress, inflammation and to regulate apoptosis. In our study, the normal saline, a low dose of DG (12.5mg/kg), a medium dose of DG (25mg/kg) and a high dose of DG (50mg/kg) were administered to male C57BL/6 mice by gavage. And then, the mice were intratracheally injected with either normal saline or lipopolysaccharide (LPS). We found that DG ameliorated LPS-induced lung injury and platelets activation, accompanied with reduced CD41 expression and neutrophil platelet aggregates (NPAs). Further, pulmonary myeloperoxidase (MPO) activity and neutrophil infiltration in the lung tissues induced by LPS were abolished by DG dose-dependently. Additionally, LPS-triggered oxidative stress and secretion of pro-inflammatory cytokines were reduced by DG administration through suppressing thioredoxin-interacting protein (TXNIP) and nuclear factor-kappaB (NF-kappaB) signaling pathways, and their down-streaming and up-streaming signals, including xanthine oxidase (XO), NLR family, pyrin domain-containing 3 (NLRP3), ASC, Caspase-1, as well as IkappaB kinase-alpha (IKK-alpha), and IkappaBalpha. Moreover, mitogen-activated protein kinases (MAPKs) pathway was also inactivated by DG in LPS-induced mice. The in vitro study further confirmed that DG ameliorated LPS-induced inflammation and oxidative stress, which was associated with reduction of ROS. In conclusion, our data suggested that DG treatment could be considered as a promising therapy for treating acute lung injury. PMID- 28800543 TI - Hypoglycemic and hypolipidemic effects of aqueous extract of phaseolus vulgaris pods in streptozotocin-diabetic rats. AB - The present investigation was carried out to evaluate the reduction potential of aqueous extract of casing of pods of phaseolus vulgaris in blood glucose and lipids levels among hyperglycemic streptozotocin (STZ)-induced rats. Oral administration of 150mg/kg of aqueous oral administration of aqueous pod extract of phaseolus vulgaris to diabetic rats for 40days resulted in a significant decrease in blood glucose (p<001), cholesterol (P<0.01) and triglycerides (P<0.01). In addition, glibenclamide reduced blood glucose, cholesterol and triglycerides. It is concluded that both aqueous extract of casing of pods of phaseolus vulgaris and glibenclamide reduced the blood levels of glucose and lipids. In addition, aqueous extract of phaseolus vulgaris pods was more effective than glibenclamide in reducing blood glucose. PMID- 28800544 TI - Protease loaded permeation enhancer liposomes for treatment of skin fibrosis arisen from second degree burn. AB - Cysteine protease (papain) is a plant derived enzyme and due to its collagenolytic activity has potential in fibrosis reduction. However, a major hurdle in its use as fibrosis reducing agent is to overcome stratum corneum skin barrier via topical application, owing to its hydrophilic and high molecular weight and protein nature which is prone to degradation. The aim of the present study was to develop a penetration enhancer incorporated drug delivery system, i.e. propylene glycol (PG) liposomes, loaded with papain for application in fibrosis therapy. Papain loaded PG-liposomes were prepared by the solvent injection method and characterized by size, shape, zeta potential, entrapment efficiency, drug release and stability. Papain conformational changes due to process stress were evaluated by electrophoresis and fluorescence spectroscopy. Biological evaluation was carried out in rodents by skin irritation and percent fibrosis reduction assays following induction of fibrosis arisen due to controlled second degree burn. Papain loaded PG-liposomes had mean vesicle size 180+/-30.3, zeta potential -25+/-1, polydispersity index 0.181 and 85+/-4.3% entrapment efficiency. Cumulative drug release after 8h was found to be 74.26+/ 3.0%. SDS-PAGE and fluorescence spectroscopic studies confirmed the stability of papain after incorporation in PG-liposomes. Fibrosis reduction studies in animal models revealed that PG-liposomes incorporated papain improved fibrosis reduction significantly in comparison to conventional liposomes and free papain solution (p <0.05). Data suggest that propylene glycol incorporated liposomal system enhances papain proteolytic and collagenolytic activity along with a reduction in skin irritancy via preventing direct contact of papain with skin, improves papain therapeutic fibrosis reduction potential, an approach that may provide an efficient alternative for protease mediated fibrosis reduction in a variety of demanding circumstances. PMID- 28800545 TI - Liver toxicity of chemotherapy and targeted therapy for breast cancer patients with hepatitis virus infection. AB - BACKGROUND: Chemotherapy has greatly improved the prognosis of breast cancer patients. However, it may also result in undesirable side effects such as hepatitis virus reactivation. Little information is available on the liver toxicity of chemotherapy and targeted therapy for breast cancer patients with hepatitis virus (HBV/HCV) infection. METHODS: We performed a retrospective survey of 835 patients diagnosed with breast cancer between January 2010 and December 2015 at our institution. All patients had been screened for HBV/HCV infection at the time of breast cancer diagnosis. We retrospectively investigated the toxicity of chemotherapy and the changes in HBV/HCV load based on a medical record review. RESULTS: 52 patients with positive anti-HBV antibody test and 21 patients with positive anti-HCV antibody tests received chemotherapy. 762 patients without HBV and HCV infection served as the control group. The morbidity of liver toxicity and disruptions in chemotherapy attributable to liver toxicity were not significantly different among control group, HBV group and HCV groups (27.7% vs 34.6% vs 42.9%, P = 0.189 and 5.0% vs 9.6% vs 9.5%, P = 0.173, respectively). No patients presented with HBV/HCV reactivation. CONCLUSION: Breast cancer patients with HCV can be treated with chemotherapy and targeted therapy with trastuzumab. Breast cancer patients with HBV who accept antiviral therapy can be treated with chemotherapy and targeted therapy with trastuzumab and patients can benefit from prophylactic antiviral therapy before chemotherapy. However, a multidisciplinary cooperation and closely monitoring liver function during the course of chemotherapy may benefit patients. PMID- 28800546 TI - MR-based respiratory and cardiac motion correction for PET imaging. AB - PURPOSE: To develop a motion correction for Positron-Emission-Tomography (PET) using simultaneously acquired magnetic-resonance (MR) images within 90 s. METHODS: A 90 s MR acquisition allows the generation of a cardiac and respiratory motion model of the body trunk. Thereafter, further diagnostic MR sequences can be recorded during the PET examination without any limitation. To provide full PET scan time coverage, a sensor fusion approach maps external motion signals (respiratory belt, ECG-derived respiration signal) to a complete surrogate signal on which the retrospective data binning is performed. A joint Compressed Sensing reconstruction and motion estimation of the subsampled data provides motion resolved MR images (respiratory + cardiac). A 1-POINT DIXON method is applied to these MR images to derive a motion-resolved attenuation map. The motion model and the attenuation map are fed to the Customizable and Advanced Software for Tomographic Reconstruction (CASToR) PET reconstruction system in which the motion correction is incorporated. All reconstruction steps are performed online on the scanner via Gadgetron to provide a clinically feasible setup for improved general applicability. The method was evaluated on 36 patients with suspected liver or lung metastasis in terms of lesion quantification (SUVmax, SNR, contrast), delineation (FWHM, slope steepness) and diagnostic confidence level (3-point Likert-scale). RESULTS: A motion correction could be conducted for all patients, however, only in 30 patients moving lesions could be observed. For the examined 134 malignant lesions, an average improvement in lesion quantification of 22%, delineation of 64% and diagnostic confidence level of 23% was achieved. CONCLUSION: The proposed method provides a clinically feasible setup for respiratory and cardiac motion correction of PET data by simultaneous short-term MRI. The acquisition sequence and all reconstruction steps are publicly available to foster multi-center studies and various motion correction scenarios. PMID- 28800547 TI - Dinuclear silver(I)-N-heterocyclic carbene complexes: Synthesis, characterization and larvicidal activity of bis-imidazolium dinuclear silver(I)-N-heterocyclic carbene complexes. AB - New synthesized bis-imidazolium salts that are linked by xylyl derivatives moiety, 1-4 was reacted with Ag2O to facilitate the formation of dinuclear Ag(I) N-heterocyclic carbene (NHC) complexes, 5-8, respectively. All the synthesized ligand salts and complexes were characterized by 1H and 13C NMR, FTIR spectroscopy and elemental analysis. Molecular structures of compounds 3, 5, and 7 were elucidated by single crystal X-ray diffraction analyses. Larvicidal studies against the Aedes aegypti and Culex quinquefasciatus were carried out on all synthesized compounds following the World Health Organization standard larval susceptibility test. All the imidazolium salts were found inactive while the activity of the dinuclear Ag(I)-NHC complexes on mosquito larvae are varies with the nature of the ligands. Complex 7 has high activity on Ae. aegypti and Cx. quinquefasciatus, emphasising its potential as a larvicidal compound. PMID- 28800548 TI - Postmortem blood sampling-Comparison of drug concentrations at different sample sites. AB - Drug concentrations in postmortem blood samples can differ considerably, depending on the sample site - a phenomenon named postmortem redistribution. In this study, blood samples from 48 cases of suspected intoxications were collected during autopsy at the Department of Forensic Medicine in Stockholm, Sweden. Samples were collected from the right and left heart, the carotid artery, jugular vein, external iliac artery and external iliac vein. The mean ratio of right heart/iliac vein was 1.3, which confirms the results from previous studies that drug concentrations in central blood are generally higher than in peripheral blood. The mean ratio of the ext iliac artery/ext iliac vein and the ratio of the carotid artery/jugular vein were 1.3 and 1.4, respectively, suggesting that drug concentrations are higher in arterial than in venous blood. Drugs with a low volume of distribution had a lower ratio of central/peripheral blood than drugs with a high volume of distribution (1.2 vs 1.4) and also a lower ratio of arterial/venous blood (1.3 vs 1.4). In cases with a short postmortem interval (PMI) there were no significant concentration differences in central and peripheral blood, but in cases with medium and long PMI, the ratios increased (1.2 and 1.4). Cases with a long PMI had an arterial/venous concentration ratio of 2.0. The results suggest that postmortem blood sampling should be performed as soon as possible after death and that peripheral venous blood, if available, should be used for analysis. PMID- 28800549 TI - Simultaneous determination of bentazone and its metabolites in postmortem whole blood using liquid chromatography-tandem mass spectrometry. AB - A liquid chromatography-tandem mass spectrometry method with solid-phase extraction (SPE) was developed and validated for the detection and quantitation of bentazone and its two hydroxylated metabolites, 6-hydroxybentazone and 8 hydroxybentazone, in postmortem blood. Sample cleanup was performed using a hydrophilic-lipophilic balanced (HLB) SPE cartridge and then separated on a C18 LC column using a gradient elution of 0.1% formic acid in distilled water and 0.1% formic acid in methanol. The identification of bentazone and its hydroxylated metabolites was performed using tandem mass spectrometry with electrospray ionization in negative ion mode with selective reaction monitoring. The retention times of bentazone, 6-hydroxybentazone, 8-hydroxybentazone, and 2 methyl-4-chlorophenoxyacetic acid (MCPA, internal standard) appeared separately in the chromatogram. The matrix effect, recovery, and process efficiency of bentazone were 75.3%, 103.6% and 77.9%, respectively. In addition, good accuracy (88.2-110.5%), precision (0.5-7.5%, bias), and linearity (5-500ng/mL) were obtained with this method. The limit of detection (LOD) of bentazone, 6 hydroxybentazone, and 8-hydroxybentazone were 0.05, 0.5, and 0.5ng/mL, respectively. The method developed herein was applied to authentic samples from three fatal cases from 2016 for the determination of the corresponding bentazone and its metabolites levels. The concentration ranges of bentazone, 6 hydroxybentazone, and 8-hydroxybentazone in the heart blood from the three victims were 46.0-91.8, 4.2-6.2, and 0.2-0.6MUg/mL, respectively. PMID- 28800550 TI - Protein-based medicines analysis by Raman spectroscopy for the detection of counterfeits. AB - Protein-based medicines, or large molecule medicines, are innovative products used to treat various diseases like hepatitis or cancer. This new generation of molecules are usually expensive, and thus represents an attractive target for the counterfeiters. Due to the complexity of their chemical structure, their analysis for counterfeit detection is more difficult than small molecule medicines. The aim of the article is to demonstrate that Raman spectroscopy and microscopy can be used for the fast analysis of counterfeits of protein-based medicines. Twelve types of medicines, under liquid or lyophilized form, have been analyzed by a Raman spectrometer through their glass packaging and ten of them also by a Raman microscope with drop deposition on a gold plate. The optimization of the acquisition parameters has first been described. Then the identification of the studied products has been presented with the attribution of the protein bands observed on the spectra. Finally the methods were successfully applied to seven counterfeits of these products and their chemical composition identified by spectral analysis. Counterfeits can indeed be detected if the excipient profile differs, if no protein is present, or if the genuine sample has been strongly diluted by the counterfeiters. Raman spectroscopy and microscopy have thus proved efficient for the fast analysis of counterfeits of protein-based medicines. PMID- 28800551 TI - Using transgenic plants and modified plant viruses for the development of treatments for human diseases. AB - Production of proteins in plants for human health applications has become an attractive strategy attributed by their potentials for low-cost production, increased safety due to the lack of human or animal pathogens, scalability and ability to produce complex proteins. A major milestone for plant-based protein production for use in human health was achieved when Protalix BioTherapeutics produced taliglucerase alfa (Elelyso(r)) in suspension cultures of a transgenic carrot cell line for the treatment of patients with Gaucher's disease, was approved by the USA Food and Drug Administration in 2012. In this review, we are highlighting various approaches for plant-based production of proteins and recent progress in the development of plant-made therapeutics and biologics for the prevention and treatment of human diseases. PMID- 28800552 TI - Utilization of engineered resistance to viruses in crops of the developing world, with emphasis on sub-Saharan Africa. AB - Viral diseases in crop plants constitute a major obstacle to food security in the developing world. Subsistence crops, including cassava, sweetpotato, potato, banana, papaya, common bean, rice and maize are often infected with RNA and/or DNA viruses that cannot be controlled with pesticides. Hence, healthy planting materials and virus-resistant cultivars are essential for high yields of good quality. However, resistance genes are not available for all viral diseases of crop plants. Therefore, virus resistance engineered in plants using modern biotechnology methods is an important addition to the crop production toolbox. PMID- 28800553 TI - Effects of different biofilm carriers on biogas production during anaerobic digestion of corn straw. AB - This study investigated the performance of anaerobic digestion systems using four types of fibrous biofilm carriers, a polypropylene, a polyester, a polyamide, and a polyurethane fiber material. The biogas and methane production, pH, chemical oxygen demand, total solids content, volatile solids content, residual coenzyme F420, and microbial community compositions were determined during the experimental runs. Furthermore, scanning electron microscopy was employed to identify the microbial consortium and examine their attachment onto the surface of the four fibrous biofilm carriers. The polypropylene fiber system maintained the highest biogas and methane production in the reactor, which was 44.80% and 49.84% higher than that noted in the control, respectively, during the entire anaerobic fermentation cycle. Meanwhile, the polypropylene fiber system exhibited the highest TS, VS, and COD removal efficiency. The results of high-throughput sequencing indicated that the dominant species in the polypropylene fiber system were Methanoregula and Methanobacterium. PMID- 28800554 TI - Anthraquinone-2-sulfonate immobilized to conductive polypyrrole hydrogel as a bioanode to enhance power production in microbial fuel cell. AB - In this study, anthraquinone-2-sulfonate (AQS), a redox mediator, was covalently bound to conductive polypyrrole hydrogel (CPH) via electrochemical reduction of the in-situ-generated AQS diazonium salts. The porous structure and hydrophilic surface of this CPH/AQS anode enhanced biofilm formation while the AQS bound on the CPH/AQS anode worked as a redox mediator. The CPH/AQS bioanode reduced the charge transfer resistance from 28.3Omega to 4.1Omega while increased the maximum power density from 762+/-37mW/m2 to 1919+/-69mW/m2, compared with the bare anode. These results demonstrated that the facile synthesis of the CPH/AQS anode provided an efficient route to enhance the power production of microbial fuel cell (MFC). PMID- 28800555 TI - Simultaneous nitrogen and organics removal using membrane aeration and effluent ultrafiltration in an anaerobic fluidized membrane bioreactor. AB - Dissolved methane and a lack of nutrient removal are two concerns for treatment of wastewater using anaerobic fluidized bed membrane bioreactors (AFMBRs). Membrane aerators were integrated into an AFMBR to form an aeration membrane fluidized bed membrane bioreactor (AeMFMBR) capable of simultaneous removal of organic matter and ammonia without production of dissolved methane. Good effluent quality was obtained with no detectable suspended solids, 93+/-5% of chemical oxygen demand (COD) removal to 14+/-11mg/L, and 74+/-8% of total ammonia (TA) removal to 12+/-3mg-N/L for domestic wastewater (COD of 193+/-23mg/L and TA of 49+/-5mg-N/L) treatment. Nitrate and nitrite concentrations were always low (<1mg N/L) during continuous flow treatment. Membrane fouling was well controlled by fluidization of the granular activated carbon (GAC) particles (transmembrane pressures maintained <3kPa). Analysis of the microbial communities suggested that nitrogen removal was due to nitrification and denitrification based on the presence of microorganisms associated with these processes. PMID- 28800556 TI - Supplementation of lycopene in maturation media improves bovine embryo quality in vitro. AB - This study sought to modulate factors that reduce embryo quality in in vitro culture (IVC) systems. Over eight replicates, 3075 oocytes were cultured in in vitro maturation media containing various concentrations of lycopene, followed by in vitro fertilization and culture. The percentages of MII-stage oocytes, the presumptive zygotes that underwent cleavage and developed into blastocysts were significantly (P < 0.05) higher, the intracellular ROS concentrations reduced significantly (P < 0.05) in oocytes/blastocysts, TUNEL assay demonstrates reduced apoptosis and increased total cell number per blastocyst (P < 0.05), Immunocytochemistry confirmed that diminished protein expression of nuclear factor kappa B (NFkappaB), cyclooxygenase-2 (COX2), and 8-oxoguanine (indicated by ROS) and relative mRNA expression of the Caspase-3, NFkappaB, COX2, iNOS and BCL2-associated X (BAX) was significantly (P < 0.05) lower whereas the anti apoptotic gene BCL2 was significantly (P < 0.05) higher in the 0.2 MUM lycopene supplemented group than the control. In conclusion, lycopene improves blastocyst quality by overcoming unfavorable conditions in in vitro culture systems. PMID- 28800557 TI - Predicting and experimental evaluating bio-electrochemical synthesis - A case study with Clostridium kluyveri. AB - Microbial electrosynthesis is a highly promising application of microbial electrochemical technologies for the sustainable production of organic compounds. At the same time a multitude of questions need to be answered and challenges to be met. Central for its further development is using appropriate electroactive microorganisms and their efficient extracellular electron transfer (EET) as well as wiring of the metabolism to EET. Among others, Clostridia are believed to represent electroactive microbes being highly promising for microbial electrosynthesis. We investigated the potential steps and challenges for the bio electrochemical fermentation (electro-fermentation) of mid-chain organic acids using Clostridium kluyveri. Starting from a metabolic model the potential limitations of the metabolism as well as beneficial scenarios for electrochemical stimulation were identified and experimentally investigated. C. kluyveri was shown to not be able to exchange electrons with an electrode directly. Therefore, exogenous mediators (2-hydroxy-1,4-naphthoquinone, potassium ferrocyanide, neutral red, methyl viologen, methylene blue, and the macrocyclic cobalt hexaamine [Co(trans-diammac)]3+) were tested for their toxicity and electro fermentations were performed in 1L bioreactors covering 38 biotic and 8 abiotic runs. When using C. kluyveri and mediators, maximum absolute current densities higher than the abiotic controls were detected for all runs. At the same time, no significant impact on the cell metabolism (product formation, carbon recovery, growth rate) was found. From this observation, we deduce general potential limitations of electro-fermentations with C. kluyveri and discuss strategies to successfully overcome them. PMID- 28800558 TI - AQDS immobilized solid-phase redox mediators and their role during bioelectricity generation and RR2 decolorization in air-cathode single-chamber microbial fuel cells. AB - The application of immobilized redox mediators (RMs) in microbial fuel cells (MFCs) is an emerging technology for electricity generation with simultaneous azo dye decolorization due to facilitated electrons transfer from bacteria to anodes and azo dyes. The use of immobilized RMs avoids the requirement of their continuous dosing in MFCs, which has been the main limitation for practical applications. Two strategies of anthraquinones-2,6-disulphonic salt (AQDS) immobilization, AQDS immobilized with polyvinyl alcohol particles and AQDS immobilized on anodes by electropolymerization, were evaluated and compared to achieve simultaneous reactive red 2 (RR2) dye reduction and bioelectricity generation. The AQDS immobilized by electropolymerization showed the highest power density (816+/-2mW/m2) and extent of RR2 decolorization (89+/-0.6%). This power density is one of the highest values yet achieved in the presence of a recalcitrant pollutant, suggesting that immobilization was important for enabling current generation in the presence of RR2. PMID- 28800559 TI - Assessment of health literacy among outpatient clinics attendees at Ain Shams University Hospitals, Egypt: a cross-sectional study. AB - OBJECTIVES: The aim of conducting this study is to measure health literacy (HL) and to investigate the factors associated with inadequate HL in a sample of outpatient clinics attendees (i.e. patients and companions) at Ain Shams University (ASU) Hospitals. STUDY DESIGN: It is a cross-sectional study. METHODS: The study was conducted on 805 attendees of the outpatient clinics at El Demerdash University Hospital of ASU Hospitals. The Arabic versions of the Swedish Functional Health Literacy Scale and the European Health Literacy Survey Questionnaire-short version-were used to assess HL. The level of HL and factors influencing it were analyzed using correlation and binary logistic regression tests. RESULTS: It was found that 81% of the participants had limited comprehensive health literacy (CHL; 34.3% inadequate and 46.7% problematic), while only 18.9% had sufficient CHL. Regarding functional health literacy (FHL), it was found that 84% had limited FHL (50.6% inadequate and 33.4% problematic), while only 16.1% had sufficient FHL. Females were more likely to have inadequate FHL. On the other hand, males, individuals with low educational levels, and attendees identified as patients as well as participants with inadequate FHL were more likely to have inadequate CHL. CONCLUSION: The majority of our study population has limited HL. Extensive research is warranted to explore the extent of the problem on multi-institutional and national levels and to investigate more explanatory factors. PMID- 28800561 TI - Vaccination is fundamental but can it escape from a more insightful and critical information about its action? PMID- 28800560 TI - Molecular basis for the functions of a bacterial MutS2 in DNA repair and recombination. AB - Bacterial MutS2 proteins, consisting of functional domains for ATPase, DNA binding, and nuclease activities, play roles in DNA recombination and repair. Here we observe a mechanism for generating MutS2 expression diversity in the human pathogen Helicobacter pylori, and identify a unique MutS2 domain responsible for specific DNA-binding. H. pylori strains differ in mutS2 expression due to variations in the DNA upstream sequence containing short sequence repeats. Based on Western blots, mutS2 in some strains appears to be co translated with the upstream gene, but in other strains (e.g. UA948) such translational coupling does not occur. Accordingly, strain UA948 had phenotypes similar to its DeltamutS2 derivative, whereas expression of MutS2 at a separate locus in UA948 (the genetically complemented strain) displayed a lower mutation rate and lower transformation frequency than did DeltamutS2. A series of truncated HpMutS2 proteins were purified and tested for their specific abilities to bind 8-oxoG-containing DNA (GO:C) and Holiday Junction structures (HJ). The specific DNA binding domain was localized to an area adjacent to the Smr nuclease domain, and it encompasses 30-amino-acid-residues containing a "KPPKNKFKPPK" motif. Gel shift assays and competition assays supported that a truncated version of HpMutS2-C12 (~12kDa protein containing the specific DNA-binding domain) has much greater capacity to bind to HJ or GO:C DNA than to normal double stranded DNA. By studying the in vivo roles of the separate domains of HpMutS2, we observed that the truncated versions were unable to complement the DeltamutS2 strain, suggesting the requirement for coordinated function of all the domains in vivo. PMID- 28800562 TI - Underlying challenges of public health insurance enrollment and use among Latino adults: insights from the largest safety-net institution in Los Angeles. PMID- 28800563 TI - A novel polymer inclusion membrane based method for continuous clean-up of thiocyanate from gold mine tailings water. AB - Thiocyanate is present in gold mine tailings waters in concentrations up to 1000mgL-1 and this has a serious environmental impact by not allowing water reuse in the flotation of gold ore. This significantly increases the consumption of fresh water and the amount of wastewater discharged in tailings dams. At the same time thiocyanate in tailings waters often leads to groundwater contamination. A novel continuous membrane-based method for the complete clean-up of thiocyanate in concentrations as high as 1000mgL-1 from its aqueous solutions has been developed. It employs a flat sheet polymer inclusion membrane (PIM) of composition 70wt% PVC, 20wt% Aliquat 336 and 10wt% 1-tetradecanol which separates counter-current streams of a feed thiocyanate solution and a 1M NaNO3 receiving solution. The PIM-based system has been operated continuously for 45days with 99% separation efficiency. The volume of the receiving solution has been drastically reduced by recirculating it and continuously removing thiocyanate by precipitating it with in-situ generated Cu(I). The newly developed PIM-based thiocyanate clean-up method is environmentally friendly in terms of reagent use and inexpensive with respect to both equipment and running costs. PMID- 28800564 TI - Interplay between flow and bioturbation enhances metal efflux from low permeability sediments. AB - Understanding the interplay effects between processes such as hydrodynamic forcing, sediment resuspension, and bioturbation is key to assessment of contaminated sediments. In the current study, effects of hydrodynamic forcing, sediment resuspension, and bioturbation by the marine polychaete Nereis virens were evaluated both independently and together in a six-month flume experiment. The results show that hydrodynamic forcing without resuspension or worm action slightly enhanced efflux of dissolved Cu to the water column, sediment resuspension released considerable amounts of dissolved Cu, and interactions between hydrodynamics and worm burrowing further enhanced Cu efflux. In non bioturbated sediments, fine particles were only resuspended to the overlying water under the highest imposed shear stress, 0.58Pa. However, bioturbated sediments were resuspended under all shear stresses tested (0.11-0.58Pa), indicating that bioturbation destabilized the sediment bed. Further, increases in fluid shear following bioturbation caused rapid releases of dissolved Cu to the overlying water within a few hours. Cu efflux under fluid shears of 0.47Pa and 0.58Pa were 360* and 15* greater after the introduction of worms compared with the same flow conditions without their presence. Overall, our results indicate that the release of metals from low-permeability sediments is greatly enhanced by interactions between flow and bioturbation. PMID- 28800565 TI - In vitro toxicity evaluation of new silane-modified clays and the migration extract from a derived polymer-clay nanocomposite intended to food packaging applications. AB - The clay montmorillonite (Mt) is among the nanofillers more frequently used for food packaging applications. The organomodification of clays with different modifiers, such as silanes, is an important step in the preparation of improved polymer/clay materials known as nanocomposites. However, the toxicological data about these nanofillers is still scarce. In the present study, an in vitro toxicological evaluation in Caco-2 cells of two silane-modified clays based on Mt, Clay3 and Clay4 (0-250MUg/ml), was performed. The cytotoxicity, cell death, genotoxicity and oxidative stress produced by both organoclays were evaluated after 24 and 48h of exposure. Moreover, the migration extracts obtained from nanocomposites of polypropylene (PP) + Clay3 and only PP were also investigated. Only Clay4 induced cytotoxicity, showing a reduction of cell viability to 63% of the control, as well as oxidative stress in a concentration-dependent manner. Regarding the PP-Clay3 migration extract, no cytotoxic effects were observed after exposure to the tested concentrations (0-100%). Moreover, significant differences in the presence of Ca, Mg and Si compared to the PP extract were obtained, although migration levels were in accordance with the food contact materials regulation. These findings indicate that a case-by-case toxicological assessment of organoclays should be performed. PMID- 28800566 TI - Highly selective adsorption of CO over CO2 in a Cu(I)-chelated porous organic polymer. AB - Cu(I) species were successfully chelated to nitrogen atoms in a nitrogen-rich porous organic polymer (SNW-1) by mixing with a CuCl solution (Scheme 1). Although pristine SNW-1 adsorbs CO2 better than CO, Cu(I)-incorporated SNW-1 (nCu(I)@SNW-1) shows selective CO adsorption over CO2 because of the pi complexation of CO with Cu(I). To the best of our knowledge, this is the first CO/CO2 selectivity observed for POP-based materials. 1.3Cu(I)@SNW-1 exhibits high CO/CO2 selectivity (23) at 1bar and a large CO working capacity (0.6mmol/g) at 0.1-1bar. Moreover, the breakthrough and thermogravimetric experiments show that 1.3Cu(I)@SNW-1 can effectively separate CO from CO2 under dynamic mixture conditions and can be easily regenerated under mild regeneration conditions without heating the column. Furthermore, 1.3Cu(I)@SNW-1 exhibited a good stability under exposure to atmospheric air for 3h or 9h. These results suggest that chelating Cu(I) species to a nitrogen-rich porous organic polymer can be an efficient strategy to separate and recover CO from CO/CO2 mixtures. PMID- 28800567 TI - A comparative evaluation of anaerobic dechlorination of PCB-118 and Aroclor 1254 in sediment microcosms from three PCB-impacted environments. AB - Aroclor 1254 (A1254) is the most toxic commercial PCB mixture produced, primarily due to its relatively high concentrations of dioxin-like congeners. This study demonstrates a comparative evaluation of dechlorination of A1254 and PCB-118 by indigenous organohalide respiring bacteria enriched from three PCB impacted sites: Grasse River (GR), NY; Fox River (FR), WI; and Baltimore Harbor (BH), MD. PCB-118 dechlorination rates in GR, BH, and FR was 0.0308, 0.015, and 0.0006 Cl /biphenyl/day, respectively. A1254 dechlorination rates in GR, FR, and BH were 0.0153, 0.0144, and 0.0048 Cl-/biphenyl/day, respectively. A1254 dechlorination was achieved through the removal of doubly-/singly-flanked chlorines in meta and para positions of mostly penta- followed by hexa- and hepta-chlorinated congeners by 88%, 69%, and 51% in GR, and 88%, 87%, and 83% in FR, respectively, while in BH mostly hepta- (70%) followed by hexa-chlorinated congeners (66%) were dechlorinated. A previously developed Anaerobic Dechlorination Model (ADM) quantified a total of 17 toxicity-related dechlorination pathways in all three sediment microcosms. The toxic equivalency of A1254 based on seven dioxin-like congeners decreased by about 53%, 45% and 21%, in GR, FR and BH microcosms, respectively. The dechlorination products were generally tetra- and tri chlorinated congeners with unflanked chlorines, all of which is susceptible to further degradation by aerobic bacteria. Concerning the toxic congeners, ADM can be useful to initiate further research focusing on the stimulation of the toxicity reducing pathways for risk assessment and effective remediation strategies. PMID- 28800569 TI - Surgery for Refractory Coccygodynia: Operative Versus Nonoperative Treatment. AB - STUDY DESIGN: This is a retrospective cohort study. OBJECTIVE: To evaluate the long-term outcomes for patients with refractory coccygodynia treated with coccygectomy compared to a nonsurgical regimen of sitting aids, physical therapy, medications, and injections. SUMMARY OF BACKGROUND DATA: The surgical treatment of coccygodynia remains controversial. To date, there has only been one small comparative study of surgical versus nonsurgical treatment. METHODS: From 2004 to 2014, 109 patients presenting with coccygodynia were treated with either total coccygectomy or a nonsurgical course of sitting aids, physical therapy, anti inflammatory medications, and injections. All had at least 2 years of symptoms before surgery. The patient principally made the treatment decision, counseled by the treating physician. Before surgery, all subjects underwent at least 2 years of conservative treatment and three-dimensional imaging (computed tomography and/or magnetic resonance imaging). Subjects completed visual analog pain scales, EuroQol five-dimension, components of the PROMIS measure, and a novel Coccygodynia Disability Index evaluation. Work status, complications, and satisfaction were recorded. RESULTS: A total of 61 patients received nonsurgical care; eight declined participation and five could not be located. Forty-eight patients underwent total coccygectomy; three declined participation and five could not be located. At an average 4.8 years of follow-up (range: 2-9), the nonsurgical visual analog pain scales was 5 and the surgical 2 (P = 0.001); 79% of surgically treated patients were improved at 2 years versus 43% for the nonsurgical group. EuroQol five-dimension (P = 0.002), Coccygodynia Disability Index (0.01), and PROMIS Pain interference scores (0.02) were also significantly improved in the surgical group. Eleven surgical patients (26%) had complications, all wound related with successful resolution; seven treated with dressing changes and four with surgical debridement. CONCLUSION: Total coccygectomy is a safe and effective surgical treatment of coccygodynia refractory to nonoperative care. Patient-reported outcome measures were improved after surgery compared with nonsurgical management. Postoperative wound care remains a concern. LEVEL OF EVIDENCE: 4. PMID- 28800568 TI - Causes and consequences of gestational diabetes in South Asians living in Canada: results from a prospective cohort study. AB - BACKGROUND: The reasons for the increased risk of gestational diabetes among South Asian women are not well understood. We sought to identify the determinants of gestational diabetes and its impact on newborn health in a prospective birth cohort of South Asian women and their babies. METHODS: As part of the South Asian Birth Cohort (START) prospective birth cohort study in Ontario, we recruited 1012 South Asian women with singleton pregnancies in the second trimester of pregnancy between July 11, 2011, and Nov. 10, 2015. We collected health information and physical measurements and administered an oral glucose tolerance test. Birth weight and skinfold thickness measurements were obtained from their newborns, and cord blood glucose and insulin levels were measured. RESULTS: The incidence of gestational diabetes was 36.3% (95% confidence interval [CI] 33.3%-39.3%); the age-standardized rate was 40.7%. Factors associated with gestational diabetes included maternal age (odds ratio [OR] 1.08 [95% CI 1.04-1.12]), family history of diabetes (OR 1.65 [95% CI 1.26-2.17]), prepregnancy weight (OR 1.025 [95% CI 1.01-1.04]) and low diet quality (OR 1.57 [95% CI 1.16-2.12]). Maternal height was protective against gestational diabetes (OR 0.97 [95% CI 0.95-0.99]). The population attributable risk due to prepregnancy body mass index and low diet quality was 37.3%. Compared to newborns of women without gestational diabetes, those of women with gestational diabetes had a significantly higher birth weight (3267 [standard error (SE) 23] g v. 3181 [SE 17] g, p = 0.005), greater skinfold thickness (11.7 [SE 0.1] mm v. 11.2 [SE 0.1] mm, p = 0.007) and lower insulin sensitivity (glucose/insulin ratio 0.092 [SE 0.009] mmol/pmol v. 0.129 [SE 0.006] mmol/pmol, p = 0.001). INTERPRETATION: The modifiable risk factors of prepregnancy weight and low diet quality accounted for 37% of the population attributable risk of gestational diabetes in our cohort. Intervention studies to lower prepregnancy weight and to prevent gestational diabetes among South Asian women in high-income countries are needed. PMID- 28800570 TI - Clinical Evaluation of the Spinal Instability Neoplastic Score in Patients Treated With Radiotherapy for Symptomatic Spinal Bone Metastases. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To determine the predictive value of the Spinal Instability Neoplastic Score (SINS) in a cohort of patients treated with radiotherapy for spinal bone metastases. SUMMARY OF BACKGROUND DATA: Assessment of spinal stability in metastatic disease is challenging and is mostly done by relying on clinical experience, in the absence of validated guidelines or an established predetermined set of risk factors. The SINS provides clinicians with a tool to assess tumor-related spinal instability. METHODS: A total of 110 patients were included in this retrospective study. Time to event was calculated as the difference between start of radiotherapy and date of occurrence of an adverse event or last follow-up, with death being considered a competing event. A competing risk analysis was performed to estimate the effect of the SINS on the cumulative incidence of the occurrence of an adverse event. RESULTS: Sixteen patients (15%) experienced an adverse event during follow-up. The cumulative incidence for the occurrence of an adverse event at 6 and 12 months was 11.8% (95% confidence interval 5.1%-24.0%) and 14.5% (95% confidence interval 6.9% 22.2%), respectively. Competing risk analysis showed that the final SINS classification was not significantly associated with the cumulative incidence of an adverse event within the studied population. CONCLUSION: The clinical applicability of the SINS as a tool to assess spinal instability seems limited. LEVEL OF EVIDENCE: 3. PMID- 28800571 TI - Long-term Pulmonary Function After Open Anterior Thoracolumbar Surgery in Thoracolumbar/Lumbar Idiopathic Adolescent Scoliosis. AB - STUDY DESIGN: A prospectively updated, long-term case series analysis. OBJECTIVE: The aim of this study was to report the effect of thoracolumbar anterior open surgery performed during adolescence on adult pulmonary function. SUMMARY OF BACKGROUND DATA: There seems to be subclinical impairment of pulmonary function in the mid-term (2-5 years) in patients who underwent thoracotomy or thoraco phreno-laparotomy after adolescent idiopathic scoliosis (AIS) surgery. However, long-term results when patients reach adulthood are lacking. METHODS: Prospective data of pulmonary function tests (PFTs) on adult patients who underwent anterior open surgery during adolescence due to main thoracolumbar/lumbar curves were collected. Forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and the Tiffeneau index (TI: FEV1/FVC) with a 12-year minimum follow-up were recorded. These figures were compared with reference (predicted) values and preoperative data. RESULTS: Twenty-four patients were included. All patients had undergone a thoraco-phreno-laparotomy. None of the patients had pulmonary disease. Mean age was 15.83 years at the time of surgery and the mean follow-up was 18.26 years (12-29 years).Long-term results of the 24 operated patients (mean +/- SD: FVC = 3.3 +/- 0.39; FEV1 = 2.6 +/- 0.38; TI = 80.3 +/- 5.7) showed a similar FVC and slightly worse FEV1 than reference values (FVC = 3.4 +/- 0.48; FEV1 = 3.03 +/- 0.42; TI = 82.4 +/- 1.3), (P = 0.21; P = 0.02; P = 0.3, respectively). Nevertheless, the values were within the normal percent predicted range for FVC (93.5% +/- 11.2) and FEV1 (91.4% +/- 12.8). In 14 patients, long-term figures (median +/- IQR): FVC = 3.2 +/- 0.6; FEV1 = 2.54 +/- 0.42; TI = 81.5 +/- 11.2) were compared with preoperative values (median +/- IQR: FVC = 2.9 +/- 0.8; FEV1 = 2.47 +/- 0.93; TI = 84.8 +/- 34.2), (P = 0.08, P = 0.92, P = 0.026, respectively). Only the TI showed significant differences due to disproportionate improvement of FVC and FEV1 during the follow-up years. CONCLUSION: Thoracolumbar/lumbar AIS patients who underwent a thoraco-phreno laparotomy during adolescence showed, in the long-term (18 years follow-up), a similar FVC compared with the reference values that was slightly superior than the values before surgery. Despite the lower FEV1 than the reference values and taking into consideration our limitations, the percent-predicted values were within the normal range, indicating no major pulmonary impairment in the long run. LEVEL OF EVIDENCE: 4. PMID- 28800573 TI - Lumbar Degenerative Spondylolisthesis: Changes in Surgical Indications and Comparison of Instrumented Fusion with Two Surgical Decompression Procedures: Erratum. PMID- 28800572 TI - Do Demographic Factors of Spine Surgeons Affect the Rate at Which Spinal Fusion Is Performed on Patients? AB - STUDY DESIGN: Retrospective study. OBJECTIVE: The purpose of this study was to evaluate associations between spine surgeon demographics and the rate at which elective spine fusion is performed. SUMMARY OF BACKGROUND DATA: Rapidly increasing rates of elective spinal fusion in the United States have given rise to important questions about what factors may drive spine surgeon decision making. METHODS: Publicly available spine surgeon practice pattern data from Centers for Medicare and Medicaid Services were reviewed retrospectively. Fusion rate was defined as the number of fusion procedures performed on Medicare beneficiaries by a surgeon per total number of unique Medicare beneficiaries seen. Inclusion criteria were neurological or orthopedic spine surgeons who performed 11 or more separate spine fusion procedures on Medicare patients between 2011 and 2013 as defined by this database. Demographic information was collected from public record. The increased probability of a surgeon performing spine fusion was assessed using a relative risk (RR) and corresponding 95% confidence interval (CI). RESULTS: A total of 3979 spine surgeons who practice in the United States and performed spine fusion on 171,676 Medicare patients from 2011 to 2013 met the inclusion criteria. The average rate of spine fusion for surgeons in this database was 7.5%. Surgeons with higher fusion rates practiced in an academic versus private setting (RR = 1.44, 95% CI [1.35-1.53]; P < 0.0001), were more likely neurological versus orthopedic surgeons (RR = 1.10, 95% CI [1.05-1.15]; P < 0.0001), and practiced in the West versus Midwest, South, and Northeast region of the United States (RR = 1.20, 95% CI [1.14-1.27]; P < 0.0001). Number of years in practice was significantly associated negatively with fusion rate (P < 0.0001). CONCLUSION: Significant variation in the rate of spine fusion based on practice type, training, region, and experience suggests poor consensus on indications for this procedure. Knowledge of these relationships may help identify underlying reasons for variations in surgical care and improve surgical outcomes. LEVEL OF EVIDENCE: 3. PMID- 28800574 TI - Outcome of Micropulse Laser Transscleral Cyclophotocoagulation on Pediatric Versus Adult Glaucoma Patients. AB - PURPOSE: To study and compare the outcome of micropulse transscelral cyclophotocoagulation in pediatric glaucoma patients to that in adult glaucoma patients. METHODS: Consecutive pediatric and adult patients who received micropulse transscelral cyclophotocoagulation between July 2015 and December 2016 at University of California, San Francisco were retrospectively analyzed. All cases had at least 12 months of follow-up. RESULTS: Nine eyes from 9 pediatric patients and 27 eyes from 25 adult patients were included. The sample size in pediatric group is small because MP-TCP was not offered to pediatric patients after unsatisfactory results in initial cases. Preoperatively, the mean intraocular pressure (IOP) was 28.41+/-8.32 mm Hg in adult patients and 34.28+/ 9.92 mm Hg in pediatric patients. Postoperatively, the mean IOP in adult patients significantly decreased at all follow-up points (P<0.001). In pediatric patients, the mean IOP decreased to 20.44+/-13.41 mm Hg at 1 month (P=0.021), 23.56+/-10.10 mm Hg at 3 months (P=0.093), 23.00+/-8.31 mm Hg (P=0.018) at 6 months, and 27.20+/-15.68 mm Hg (P=0.15) at 12 months. No significant complications were noted in either group. The success rate in adults was 72.22% versus 22.22% in pediatric patients at 12 months (P=0.02). Seven of 9 pediatric patients required reoperation during the 12 months of follow-up. CONCLUSIONS: Micropulse transscelral cyclophotocoagulation is a safe procedure for pediatric as well as adult glaucoma patients. Its effect seems to be short lived in pediatric patients and the rate of reoperation was high. PMID- 28800575 TI - Disruption of frontal-parietal connectivity during conscious sedation by propofol administration. AB - The sedative state is a transitional state from wakefulness to general anesthesia. However, little is understood regarding the mechanism of conscious sedation, different from general anesthesia while maintaining wakefulness. In this study, we aimed to investigate changes in functional connectivity of the parietal-frontal network, implicated in wakefulness during conscious sedation induced by propofol infusion. The electroencephalography was obtained at the frontal and parietal areas of adult volunteers who maintain wakefulness during low-dose propofol infusion (1.5 mg/kg/h) over 1 h. Spectral Granger causality (GC) (delta, theta, alpha, beta, and gamma frequency bands) and time-domain GC were calculated during each stage of awake (before propofol administration), sedation, and recovery (after discontinuation of propofol). We also calculated the phase-locking index and compared it with GC during each stage. A decrease in GC from the frontal to parietal areas was observed particularly in the low frequency bands during propofol administration. Contrary to the GC changes in the frontoparietal direction, GC from the parietal to frontal areas was increased in the high-frequency bands during propofol administration and significantly decreased after discontinuation of propofol. In summary, we showed that frontal parietal neural networks were significantly changed differently by the frequency of the brain rhythm and the directions of connections during sedation by propofol administration. Our result suggests that the alteration of brain interaction may induce sedative state lying between awake and general anesthesia. PMID- 28800576 TI - Heterotopic Pregnancy Including Intrauterine Normal Gestation and Tubal Complete Hydatidiform Mole: A Case Report and Review of the Literature. AB - We report a rare case of heterotopic pregnancy with intrauterine normal gestation alongside tubal complete hydatidiform mole (CHM) that resulted in a viable pregnancy after removal of molar tissue. Because of their rarity and inherent complexity, such cases represent a significant challenge in diagnosis and management. A 34-year-old female in her 10th week of gestation presented with nausea, vomiting, and intermittent abdominal pain that progressively worsened. Imaging studies revealed a normal intrauterine fetus and an 11-cm heterogenous mass in the left adnexal region. The patient's serum human chorionic gonadotropin was higher than the reference range. Diagnostic laparoscopy revealed a large hemorrhagic mass involving the left adnexa that was removed completely. The mass was composed of blood clots admixed with necrotic tissue of vesicular appearance on gross inspection. Microscopic examination revealed large chorionic villi with circumferential trophoblastic proliferation and cisterns, all of which are characteristic of CHM. An implantation site was identified at the tubal fimbriae. Immunohistochemistry p57 demonstrated negative staining in the villous stromal and cytotrophoblastic cells, supporting the diagnosis of CHM. Chromosomal karyotyping and cytogenetic analysis were performed on chorionic villi samples from the intrauterine gestation and reported as normal (46, XX). The patient elected to continue the intrauterine pregnancy, delivering a healthy female infant at 39 weeks. Our case reaffirms that to successfully manage this rare yet life-threatening condition, heterotopic pregnancy should be included in the differential diagnosis for any gravid women presenting with persistent abdominal pain and/or extrauterine mass. PMID- 28800577 TI - Case Report: Use of Tumor and Germline Y Chromosomal Analysis to Guide Surgical Management in a 46, XX Female Presenting With Gonadoblastoma With Dysgerminoma. AB - Gonadoblastomas are rare mixed gonadal tumors that are almost always found in individuals with 46, XY karyotype or some other form of Y chromosome mosaicism. It is extremely rare to diagnose gonadoblastoma in phenotypically normal 46, XX females. Herein, we present a 20-year-old 46, XX female diagnosed with gonadoblastoma and dysgerminoma. Use of cytogenetic and molecular analyses to identify the presence of Y chromosome material in peripheral blood, gonadal, and tumor tissue can exclude mosaicism to provide reassurance to undertake conservative surgical management and preserve fertility. PMID- 28800578 TI - Angiomyofibroblastoma of the Broad Ligament: A Case Report. AB - Angiomyofibroblastoma (AMF) is a distinctive, rare, benign mesenchymal tumor that often occurs in the lower genital region of women. The most commonly reported location of an AMF is in the vulvovaginal area. We describe a rare case of an AMF located in the broad ligament in a 47-yr-old woman. The patient experienced menorrhagia, dysmenorrhea, and subsequent menstrual spotting. She sought help at the National Cheng Kung University Hospital. Ultrasonography showed an echo complex mass in the left adnexal area. The patient underwent laparoscopic surgery to remove the soft tissue mass located in the left broad ligament. The final pathology of the mass was reported as an AMF. We reviewed all of the AMF cases reported in the English-language literature found in Pubmed. This case is the first of AMF located in the broad ligament. PMID- 28800579 TI - Primary Vaginal Melanoma With Rhabdoid Features: A Case Report and Literature Review. AB - Primary vaginal melanoma is a rare mucosal neoplasm, which is more aggressive than cutaneous melanoma. Information regarding its morphologic patterns is limited. In particular, the rhabdoid phenotype, mostly observed in metastatic or recurrent cutaneous melanomas, has yet to be reported at this anatomic location. Hence, a potential diagnostic difficulty may arise because of the inability to recognize this unusual histologic variant and its immunohistochemical aberrance. In this report, we describe the case of a primary vaginal melanoma in a 62-year old woman, who exhibited both rhabdoid and small blue round cell morphologies, absence of S100 protein, and aberrant expression of desmin, CD56, and FLI-1. This report can facilitate the task of expanding the morphologic spectrum of vaginal melanoma, and prevent misdiagnosis and inadequate medical treatment. PMID- 28800580 TI - Establishing a Classification System for High Fall-Risk Among Inpatients Using Support Vector Machines. AB - We constructed a model using a support vector machine to determine whether an inpatient will suffer a fall on a given day, depending on patient status on the previous day. Using fall report data from our own facility and intensity-of nursing-care-needs data accumulated through hospital information systems, a dataset comprising approximately 1.2 million patient-days was created. Approximately 50% of the dataset was used as training and testing data. A multistep grid search was conducted using the semicomprehensive combination of three parameters. A discriminant model for the testing data was created for each parameter to identify which parameter had the highest score by calculating the sensitivity and specificity. The score of the model with the highest score had a sensitivity of 64.9% and a specificity of 69.6%. By adopting a method that relies on daily data recorded in the electronic medical record system and accurately predicts unknown data, we were able to overcome issues described in previous studies while simultaneously constructing a discriminant model for patients' fall risk that does not burden nurses and patients with information gathering. PMID- 28800581 TI - Implementation of Electronic Health Records in US Nursing Homes. AB - While electronic health records have emerged as promising tools to help improve quality of care, nursing homes have lagged behind in implementation. This study assessed electronic health records implementation, associated facility characteristics, and potential impact on quality indicators in nursing homes. Using national Centers for Medicare & Medicaid Services and survey data for nursing homes, a cross-sectional analysis was conducted to identify variations between nursing homes that had and had not implemented electronic health records. A difference-in-differences analysis was used to estimate the longitudinal effect of electronic health records on commonly used quality indicators. Data from 927 nursing homes were examined, 49.1% of which had implemented electronic health records. Nursing homes with electronic health records were more likely to be nonprofit/government owned (P = .04) and had a lower percentage of Medicaid residents (P = .02) and higher certified nursing assistant and registered nurse staffing levels (P = .002 and .02, respectively). Difference-in-differences analysis showed greater quality improvements after implementation for five long stay and two short-stay quality measures (P = .001 and .01, respectively) compared with those who did not implement electronic health records. Implementation rates in nursing homes are low compared with other settings, and better-resourced facilities are more likely to have implemented electronic health records. Consistent with other settings, electronic health records implementation improves quality in nursing homes, but further research is needed to better understand the mechanism for improvement and how it can best be supported. PMID- 28800582 TI - The Sexting Phenomenon in Spanish Nursing Students. AB - One of the adverse effects arising among young people who engage in various social practices is the phenomenon of sexting. Sexting involves the production and delivery of sexual content voluntarily and freely and, in many cases, without the consent of the recipient. The aim of this study was to describe the presence of sexting in undergraduate students at the College of Nursing of the University of Almeria in Spain. It is a descriptive cross-sectional quantitative study. A total of 105 undergraduate nursing students completed the sexuality and technology questionnaire. The questionnaire consists of seven dimensions with 59 items. Depending on size, statistically significant differences between the use of social networks and the dimension "sexting actions completed" and the dimension "position on statements about sexting" were found. No statistically significant differences between gender and the practice of sexting were found. The three main reasons for sexting match in both genders, these being "to draw attention," "as a sexy gift," and "to feel sexy." Nursing students associated behaviors to show sexting, being a standard practice, common in both genders. Future research should consider the possible influence of this behavior on future professionals and on the field of nursing. PMID- 28800583 TI - The nucleoid protein Dps binds genomic DNA of Escherichia coli in a non-random manner. AB - Dps is a multifunctional homododecameric protein that oxidizes Fe2+ ions accumulating them in the form of Fe2O3 within its protein cavity, interacts with DNA tightly condensing bacterial nucleoid upon starvation and performs some other functions. During the last two decades from discovery of this protein, its ferroxidase activity became rather well studied, but the mechanism of Dps interaction with DNA still remains enigmatic. The crucial role of lysine residues in the unstructured N-terminal tails led to the conventional point of view that Dps binds DNA without sequence or structural specificity. However, deletion of dps changed the profile of proteins in starved cells, SELEX screen revealed genomic regions preferentially bound in vitro and certain affinity of Dps for artificial branched molecules was detected by atomic force microscopy. Here we report a non-random distribution of Dps binding sites across the bacterial chromosome in exponentially growing cells and show their enrichment with inverted repeats prone to form secondary structures. We found that the Dps-bound regions overlap with sites occupied by other nucleoid proteins, and contain overrepresented motifs typical for their consensus sequences. Of the two types of genomic domains with extensive protein occupancy, which can be highly expressed or transcriptionally silent only those that are enriched with RNA polymerase molecules were preferentially occupied by Dps. In the dps-null mutant we, therefore, observed a differentially altered expression of several targeted genes and found suppressed transcription from the dps promoter. In most cases this can be explained by the relieved interference with Dps for nucleoid proteins exploiting sequence-specific modes of DNA binding. Thus, protecting bacterial cells from different stresses during exponential growth, Dps can modulate transcriptional integrity of the bacterial chromosome hampering RNA biosynthesis from some genes via competition with RNA polymerase or, vice versa, competing with inhibitors to activate transcription. PMID- 28800584 TI - Expression of the RNA-binding protein RBP10 promotes the bloodstream-form differentiation state in Trypanosoma brucei. AB - In nearly all eukaryotes, cellular differentiation is governed by changes in transcription, and stabilized by chromatin and DNA modification. Gene expression control in the pathogen Trypanosoma brucei, in contrast, relies almost exclusively on post-transcriptional mechanisms, so RNA binding proteins must assume the burden that is usually borne by transcription factors. T. brucei multiply in the blood of mammals as bloodstream forms, and in the midgut of Tsetse flies as procyclic forms. We show here that a single RNA-binding protein, RBP10, promotes the bloodstream-form trypanosome differentiation state. Depletion of RBP10 from bloodstream-form trypanosomes gives cells that can grow only as procyclic forms; conversely, expression of RBP10 in procyclic forms converts them to bloodstream forms. RBP10 binds to procyclic-specific mRNAs containing an UAUUUUUU motif, targeting them for translation repression and destruction. Products of RBP10 target mRNAs include not only the major procyclic surface protein and enzymes of energy metabolism, but also protein kinases and stage specific RNA-binding proteins: this suggests that alterations in RBP10 trigger a regulatory cascade. PMID- 28800585 TI - Comparative pathogenomics of Clostridium tetani. AB - Clostridium tetani and Clostridium botulinum produce two of the most potent neurotoxins known, tetanus neurotoxin and botulinum neurotoxin, respectively. Extensive biochemical and genetic investigation has been devoted to identifying and characterizing various C. botulinum strains. Less effort has been focused on studying C. tetani likely because recently sequenced strains of C. tetani show much less genetic diversity than C. botulinum strains and because widespread vaccination efforts have reduced the public health threat from tetanus. Our aim was to acquire genomic data on the U.S. vaccine strain of C. tetani to better understand its genetic relationship to previously published genomic data from European vaccine strains. We performed high throughput genomic sequence analysis on two wild-type and two vaccine C. tetani strains. Comparative genomic analysis was performed using these and previously published genomic data for seven other C. tetani strains. Our analysis focused on single nucleotide polymorphisms (SNP) and four distinct constituents of the mobile genome (mobilome): a hypervariable flagellar glycosylation island region, five conserved bacteriophage insertion regions, variations in three CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated) systems, and a single plasmid. Intact type IA and IB CRISPR/Cas systems were within 10 of 11 strains. A type IIIA CRISPR/Cas system was present in two strains. Phage infection histories derived from CRISPR-Cas sequences indicate C. tetani encounters phages common among commensal gut bacteria and soil-borne organisms consistent with C. tetani distribution in nature. All vaccine strains form a clade distinct from currently sequenced wild type strains when considering variations in these mobile elements. SNP, flagellar glycosylation island, prophage content and CRISPR/Cas phylogenic histories provide tentative evidence suggesting vaccine and wild type strains share a common ancestor. PMID- 28800586 TI - The potential role of kelp forests on iodine speciation in coastal seawater. AB - Kelps have a major role in marine and atmospheric iodine cycling in the coastal zone of temperate regions, with potential wide-ranging impacts on ozone destruction in the coastal marine boundary layer. However, little is known about the impact of kelp forests on iodine speciation in coastal sea water. To address this, we examined iodide and iodate concentrations in seawater in and around a giant kelp forest near San Diego, CA, USA, and a nearby site that was not influenced by kelp biology. Our data shows that while both iodide and iodate concentrations remained unchanged during the year at the nearby site, these concentrations changed significantly in and around the kelp forest, and were strongly related to changes in kelp canopy biomass. In particular, iodide reached its highest concentration and iodate reached its lowest concentration during the summer when the kelp canopies were near their maximum, while the opposite pattern was observed during the winter and spring when the kelp canopies were near their minimum. Further, comparisons of these changes with corresponding changes in seawater temperature and wind speed indicated that these relationships were relatively small compared to those with changes in kelp biomass. Together, our data show a strong relationship between kelp biomass and iodine metabolism. PMID- 28800587 TI - Highly efficient gene inactivation by adenoviral CRISPR/Cas9 in human primary cells. AB - Phenotypic assays using human primary cells are highly valuable tools for target discovery and validation in drug discovery. Expression knockdown (KD) of such targets in these assays allows the investigation of their role in models of disease processes. Therefore, efficient and fast modes of protein KD in phenotypic assays are required. The CRISPR/Cas9 system has been shown to be a versatile and efficient means of gene inactivation in immortalized cell lines. Here we describe the use of adenoviral (AdV) CRISPR/Cas9 vectors for efficient gene inactivation in two human primary cell types, normal human lung fibroblasts and human bronchial epithelial cells. The effects of gene inactivation were studied in the TGF-beta-induced fibroblast to myofibroblast transition assay (FMT) and the epithelial to mesenchymal transition assay (EMT), which are SMAD3 dependent and reflect pathogenic mechanisms observed in fibrosis. Co-transduction (co-TD) of AdV Cas9 with SMAD3-targeting guide RNAs (gRNAs) resulted in fast and efficient genome editing judged by insertion/deletion (indel) formation, as well as significant reduction of SMAD3 protein expression and nuclear translocation. This led to phenotypic changes downstream of SMAD3 inhibition, including substantially decreased alpha smooth muscle actin and fibronectin 1 expression, which are markers for FMT and EMT, respectively. A direct comparison between co TD of separate Cas9 and gRNA AdV, versus TD with a single "all-in-one" Cas9/gRNA AdV, revealed that both methods achieve similar levels of indel formation. These data demonstrate that AdV CRISPR/Cas9 is a useful and efficient tool for protein KD in human primary cell phenotypic assays. The use of AdV CRISPR/Cas9 may offer significant advantages over the current existing tools and should enhance target discovery and validation opportunities. PMID- 28800588 TI - Non-lethal genotyping of Tribolium castaneum adults using genomic DNA extracted from wing tissue. AB - The red flour beetle Tribolium castaneum has become the second most important insect model organism and is frequently used in developmental biology, genetics and pest-associated research. Consequently, the methodological arsenal increases continuously, but many routinely applied techniques for Drosophila melanogaster and other insect species are still unavailable. For example, a protocol for non lethal genotyping has not yet been adapted but is particularly useful when individuals with known genotypes are required for downstream experiments. In this study, we present a workflow for non-lethal genotyping of T. castaneum adults based on extracting genomic DNA from wing tissue. In detail, we describe a convenient procedure for wing dissection and a custom method for wing digestion that allows PCR-based genotyping of up to fifty adults in less than an afternoon with a success rate of about 86%. The amount of template is sufficient for up to ten reactions while viability and fertility of the beetles are preserved. We prove the applicability of our protocol by genotyping the white / scarlet gene pair alleles from the black-eyed San Bernadino wild-type and white-eyed Pearl recessive mutant strains spanning four generations. Non-lethal genotyping has the potential to improve and accelerate many workflows: Firstly, during the establishment process of homozygous cultures or during stock keeping of cultures that carry recessively lethal alleles, laborious test crossing is replaced by non lethal genotyping. Secondly, in genome engineering assays, non-lethal genotyping allows the identification of appropriate founders before they are crossed against wild-types, narrowing the efforts down to only the relevant individuals. Thirdly, non-lethal genotyping simplifies experimental strategies, in which genotype and behavior should be correlated, since the genetic configuration of potential individuals can be determined before the actual behavior assays is performed. PMID- 28800589 TI - Prognostic factors and outcomes in Japanese lung transplant candidates with interstitial lung disease. AB - OBJECTIVE: Young patients with advanced interstitial lung disease (ILD) are potential candidates for cadaveric lung transplantation. This study aimed to examine clinical features, outcomes, and prognostic factors in Japanese ILD patients awaiting lung transplantation. METHODS: We investigated the clinical features and outcomes of 77 consecutive candidates with ILD who were referred to Kyoto University Hospital and subsequently actively listed for lung transplant in the Japan Organ Transplant Network between 2010 and 2014. RESULTS: Of the 77 candidates, 33 had idiopathic pulmonary fibrosis (IPF) and 15 had unclassifiable ILD. During the observational period, 23 patients (30%) received lung transplantations and 49 patients (64%) died before transplantation. Of the 33 patients with IPF, 13 (39%) had a family history of ILD and 13 (39%) had an "inconsistent with usual interstitial pneumonia pattern" on high-resolution computed tomography (HRCT). The median survival time from registration was 16.7 months, and mortality was similar among patients with IPF, unclassifiable ILD, and other ILDs. Using a multivariate stepwise Cox proportional hazards model, 6 min walking distance was shown to be an independent prognostic factor in candidates with ILD (per 10 m, hazard ratio (HR): 0.97; 95% confidence interval (CI): 0.95-0.99, p<0.01), while lower body mass index (HR: 0.83; 95% CI: 0.72 0.95, p < 0.01) independently contributed to mortality in patients with IPF. CONCLUSIONS: Japanese patients with ILD awaiting transplantation had very poor outcomes regardless of their specific diagnosis. A substantial percentage of IPF patients had an atypical HRCT pattern. 6-min walking distance in ILD patients and body mass index in IPF patients were independent predictors of mortality. PMID- 28800590 TI - Assessment and optimization of Theileria parva sporozoite full-length p67 antigen expression in mammalian cells. AB - Delivery of various forms of recombinant Theileria parva sporozoite antigen (p67) has been shown to elicit antibody responses in cattle capable of providing protection against East Coast fever, the clinical disease caused by T. parva. Previous formulations of full-length and shorter recombinant versions of p67 derived from bacteria, insect, and mammalian cell systems are expressed in non native and highly unstable forms. The stable expression of full-length recombinant p67 in mammalian cells has never been described and has remained especially elusive. In this study, p67 was expressed in human-derived cells as a full-length, membrane-linked protein and as a secreted form by omission of the putative transmembrane domain. The recombinant protein expressed in this system yielded primarily two products based on Western immunoblot analysis, including one at the expected size of 67 kDa, and one with a higher than expected molecular weight. Through treatment with PNGase F, our data indicate that the larger product of this mammalian cell-expressed recombinant p67 cannot be attributed to glycosylation. By increasing the denaturing conditions, we determined that the larger sized mammalian cell-expressed recombinant p67 product is likely a dimeric aggregate of the protein. Both forms of this recombinant p67 reacted with a monoclonal antibody to the p67 molecule, which reacts with the native sporozoite. Additionally, through this work we developed multiple mammalian cell lines, including both human and bovine-derived cell lines, transduced by a lentiviral vector, that are constitutively able to express a stable, secreted form of p67 for use in immunization, diagnostics, or in vitro assays. The recombinant p67 developed in this system is immunogenic in goats and cattle based on ELISA and flow cytometric analysis. The development of a mammalian cell system that expresses full-length p67 in a stable form as described here is expected to optimize p67-based immunization. PMID- 28800591 TI - Frequencies of decision making and monitoring in adaptive resource management. AB - Adaptive management involves learning-oriented decision making in the presence of uncertainty about the responses of a resource system to management. It is implemented through an iterative sequence of decision making, monitoring and assessment of system responses, and incorporating what is learned into future decision making. Decision making at each point is informed by a value or objective function, for example total harvest anticipated over some time frame. The value function expresses the value associated with decisions, and it is influenced by system status as updated through monitoring. Often, decision making follows shortly after a monitoring event. However, it is certainly possible for the cadence of decision making to differ from that of monitoring. In this paper we consider different combinations of annual and biennial decision making, along with annual and biennial monitoring. With biennial decision making decisions are changed only every other year; with biennial monitoring field data are collected only every other year. Different cadences of decision making combine with annual and biennial monitoring to define 4 scenarios. Under each scenario we describe optimal valuations for active and passive adaptive decision making. We highlight patterns in valuation among scenarios, depending on the occurrence of monitoring and decision making events. Differences between years are tied to the fact that every other year a new decision can be made no matter what the scenario, and state information is available to inform that decision. In the subsequent year, however, in 3 of the 4 scenarios either a decision is repeated or monitoring does not occur (or both). There are substantive differences in optimal values among the scenarios, as well as the optimal policies producing those values. Especially noteworthy is the influence of monitoring cadence on valuation in some years. We highlight patterns in policy and valuation among the scenarios, and discuss management implications and extensions. PMID- 28800592 TI - CX3CR1 knockout aggravates Coxsackievirus B3-induced myocarditis. AB - Studies on inflammatory disorders elucidated the pivotal role of the CX3CL1/CX3CR1 axis with respect to the pathophysiology and diseases progression. Coxsackievirus B3 (CVB3)-induced myocarditis is associated with severe cardiac inflammation, which may progress to heart failure. We therefore investigated the influence of CX3CR1 ablation in the model of acute myocarditis, which was induced by inoculation with 5x105 plaque forming units of CVB3 (Nancy strain) in either CX3CR1-/- or C57BL6/j (WT) mice. Seven days after infection, myocardial inflammation, remodeling, and titin expression and phosphorylation were examined by immunohistochemistry, real-time PCR and Pro-Q diamond stain. Cardiac function was assessed by tip catheter. Compared to WT CVB3 mice, CX3CR1-/- CVB3 mice exhibited enhanced left ventricular expression of inflammatory cytokines and chemokines, which was associated with an increase of immune cell infiltration/presence. This shift towards a pro-inflammatory immune response further resulted in increased cardiac fibrosis and cardiomyocyte apoptosis, which was reflected by an impaired cardiac function in CX3CR1-/- CVB3 compared to WT CVB3 mice. These findings demonstrate a cardioprotective role of CX3CR1 in CVB3 infected mice and indicate the relevance of the CX3CL1/CX3CR1 system in CVB3 induced myocarditis. PMID- 28800593 TI - In vivo functional and morphological characterization of bone and striated muscle microcirculation in NSG mice. AB - Organ-specific microcirculation plays a central role in tumor growth, tumor cell homing, tissue engineering, and wound healing. Mouse models are widely used to study these processes; however, these mouse strains often possess unique microhemodynamic parameters, making it difficult to directly compare experiments. The full functional characterization of bone and striated muscle microcirculatory parameters in non-obese diabetic-severe combined immunodeficiency/y-chain; NOD Prkds IL2rg (NSG) mice has not yet been reported. Here, we established either a dorsal skinfold chamber or femur window in NSG mice (n = 23), allowing direct analysis of microcirculatory parameters in vivo by intravital fluorescence microscopy at 7, 14, 21, and 28 days after chamber preparation. Organ-specific differences were observed. Bone had a significantly lower vessel density but a higher vessel diameter than striated muscle. Bone also showed higher effective vascular permeability than striated muscle. The centerline velocity values were similar in the femur window and dorsal skinfold chamber, with a higher volumetric blood flow in bone. Interestingly, bone and striated muscle showed similar tissue perfusion rates. Knowledge of physiological microhemodynamic values of bone and striated muscle in NSG mice makes it possible to analyze pathophysiological processes at these anatomic sites, such as tumor growth, tumor metastasis, and tumor microcirculation, as well as the response to therapeutic agents. PMID- 28800594 TI - Species identification and molecular typing of human Brucella isolates from Kuwait. AB - Brucellosis is a zoonotic disease of major concern in Kuwait and the Middle East. Human brucellosis can be caused by several Brucella species with varying degree of pathogenesis, and relapses are common after apparently successful therapy. The classical biochemical methods for identification of Brucella are time-consuming, cumbersome, and provide information limited to the species level only. In contrast, molecular methods are rapid and provide differentiation at intra species level. In this study, four molecular methods [16S rRNA gene sequencing, real-time PCR, enterobacterial repetitive intergenic consensus (ERIC)-PCR and multilocus variable-number tandem-repeat analysis (MLVA)-8, MLVA-11 and MLVA-16 were evaluated for the identification and typing of 75 strains of Brucella isolated in Kuwait. 16S rRNA gene sequencing of all isolates showed 90-99% sequence identity with B. melitensis and real-time PCR with genus- and species- specific primers identified all isolates as B. melitensis. The results of ERIC PCR suggested the existence of 75 ERIC genotypes of B. melitensis with a discriminatory index of 0.997. Cluster classification of these genotypes divided them into two clusters, A and B, diverging at ~25%. The maximum number of genotypes (n = 51) were found in cluster B5. MLVA-8 analysis identified all isolates as B. melitensis, and MLVA-8, MLVA-11 and MLVA-16 typing divided the isolates into 10, 32 and 71 MLVA types, respectively. Furthermore, the combined minimum spanning tree analysis demonstrated that, compared to MLVA types discovered all over the world, the Kuwaiti isolates were a distinct group of MLVA 11 and MLVA-16 types in the East Mediterranean Region. PMID- 28800595 TI - Elderly road collision injury outcomes associated with seat positions and seatbelt use in a rapidly aging society-A case study in South Korea. AB - INTRODUCTION: Aging has long been regarded as one of the most critical factors affecting crash injury outcomes. In South Korea, where the elderly population is projected to reach 35.9% by 2050, the implications of an increasing number of elderly vehicle users on road safety are evident. In this research, the confounding effect of occupant age in a vehicle in terms of seat position and seatbelt use was investigated. In addition, elderly occupants were divided into a younger-old group aged between 65 and 74 years and an older-old group aged 75 years and older in an effort to assess whether the conventional elderly age standard of 65 years should be reconsidered. METHODS: A multinomial logit framework was adopted to predict two-level injury severity using collision data between 2008 and 2015. Predictor variables included gender, age group, seat position, seatbelt, road type, road slope, road surface, road line, and type of vehicle. Five models, a base model with no interactions and four interaction models which were combinations of age group, seatbelt use and seat position, were devised and evaluated. RESULTS: With no interacting term, age was the most prominent predictor. Elderly occupants were most likely to suffer from severe injury without a seatbelt in all seat positions, and the use of a seatbelt reduced this likelihood the most in the elderly group as well. Front passenger seats had the highest risk to elderly occupants, while the driver seat was statistically insignificant. When the elderly group was divided into the younger old group and the older-old group, the older-olds were found to be much more vulnerable compared to the younger-olds. In particular, older drivers were five times more likely to suffer a severe injury without a seatbelt. CONCLUSIONS: The degree of injury severity of elderly occupants was reduced the most with the use of a seatbelt, demonstrating the importance of using seat restraints. The sharp increase in the risk of injury of the older-old group suggests that the age standard of 65 years as the elderly group with regard to traffic safety may require reconsideration due to the growing number of elderly vehicle users on the road. Our results provide practical evidence with which to formulate new safety policies, including mandatory seatbelt use, driving age limits and insurance pricing. PMID- 28800596 TI - Fungal genome and mating system transitions facilitated by chromosomal translocations involving intercentromeric recombination. AB - Species within the human pathogenic Cryptococcus species complex are major threats to public health, causing approximately 1 million annual infections globally. Cryptococcus amylolentus is the most closely known related species of the pathogenic Cryptococcus species complex, and it is non-pathogenic. Additionally, while pathogenic Cryptococcus species have bipolar mating systems with a single large mating type (MAT) locus that represents a derived state in Basidiomycetes, C. amylolentus has a tetrapolar mating system with 2 MAT loci (P/R and HD) located on different chromosomes. Thus, studying C. amylolentus will shed light on the transition from tetrapolar to bipolar mating systems in the pathogenic Cryptococcus species, as well as its possible link with the origin and evolution of pathogenesis. In this study, we sequenced, assembled, and annotated the genomes of 2 C. amylolentus isolates, CBS6039 and CBS6273, which are sexual and interfertile. Genome comparison between the 2 C. amylolentus isolates identified the boundaries and the complete gene contents of the P/R and HD MAT loci. Bioinformatic and chromatin immunoprecipitation sequencing (ChIP-seq) analyses revealed that, similar to those of the pathogenic Cryptococcus species, C. amylolentus has regional centromeres (CENs) that are enriched with species specific transposable and repetitive DNA elements. Additionally, we found that while neither the P/R nor the HD locus is physically closely linked to its centromere in C. amylolentus, and the regions between the MAT loci and their respective centromeres show overall synteny between the 2 genomes, both MAT loci exhibit genetic linkage to their respective centromere during meiosis, suggesting the presence of recombinational suppressors and/or epistatic gene interactions in the MAT-CEN intervening regions. Furthermore, genomic comparisons between C. amylolentus and related pathogenic Cryptococcus species provide evidence that multiple chromosomal rearrangements mediated by intercentromeric recombination have occurred during descent of the 2 lineages from their common ancestor. Taken together, our findings support a model in which the evolution of the bipolar mating system was initiated by an ectopic recombination event mediated by similar repetitive centromeric DNA elements shared between chromosomes. This translocation brought the P/R and HD loci onto the same chromosome, and further chromosomal rearrangements then resulted in the 2 MAT loci becoming physically linked and eventually fusing to form the single contiguous MAT locus that is now extant in the pathogenic Cryptococcus species. PMID- 28800597 TI - Confirmation bias in human reinforcement learning: Evidence from counterfactual feedback processing. AB - Previous studies suggest that factual learning, that is, learning from obtained outcomes, is biased, such that participants preferentially take into account positive, as compared to negative, prediction errors. However, whether or not the prediction error valence also affects counterfactual learning, that is, learning from forgone outcomes, is unknown. To address this question, we analysed the performance of two groups of participants on reinforcement learning tasks using a computational model that was adapted to test if prediction error valence influences learning. We carried out two experiments: in the factual learning experiment, participants learned from partial feedback (i.e., the outcome of the chosen option only); in the counterfactual learning experiment, participants learned from complete feedback information (i.e., the outcomes of both the chosen and unchosen option were displayed). In the factual learning experiment, we replicated previous findings of a valence-induced bias, whereby participants learned preferentially from positive, relative to negative, prediction errors. In contrast, for counterfactual learning, we found the opposite valence-induced bias: negative prediction errors were preferentially taken into account, relative to positive ones. When considering valence-induced bias in the context of both factual and counterfactual learning, it appears that people tend to preferentially take into account information that confirms their current choice. PMID- 28800598 TI - An in silico evaluation of treatment regimens for recurrent Clostridium difficile infection. AB - BACKGROUND: Clostridium difficile infection (CDI) is a significant nosocomial infection worldwide, that recurs in as many as 35% of infections. Risk of CDI recurrence varies by ribotype, which also vary in sporulation and germination rates. Whether sporulation/germination mediate risk of recurrence and effectiveness of treatment of recurring CDI remains unclear. We aim to assess the role of sporulation/germination patterns on risk of recurrence, and the relative effectiveness of the recommended tapered/pulsing regimens using an in silico model. METHODS: We created a compartmental in-host mathematical model of CDI, composed of vegetative cells, toxins, and spores, to explore whether sporulation and germination have an impact on recurrence rates. We also simulated the effectiveness of three tapered/pulsed vancomycin regimens by ribotype. RESULTS: Simulations underscored the importance of sporulation/germination patterns in determining pathogenicity and transmission. All recommended regimens for recurring CDI tested were effective in reducing risk of an additional recurrence. Most modified regimens were still effective even after reducing the duration or dosage of vancomycin. However, the effectiveness of treatment varied by ribotype. CONCLUSION: Current CDI vancomycin regimen for treating recurrent cases should be studied further to better balance associated risks and benefits. PMID- 28800599 TI - Extracting information from free-text electronic patient records to identify practice-based evidence of the performance of coronary stents. AB - BACKGROUND AND OBJECTIVE: Percutaneous coronary intervention (PCI) using drug eluting stents (DES) is an indispensable treatment for coronary artery disease. However, to evaluate the performance of various types of stents for PCI, numerous resources are required. We extracted clinical information from free-text records and, using practice-based evidence, compared the efficacy of various DES. MATERIALS AND METHODS: We developed a text mining tool based on regular expression and applied it to PCI reports stored in the electronic health records (EHRs) of Ajou University Hospital from 2010-2014. The PCI data were extracted from EHRs with a sensitivity of 0.996, a specificity of 1.000, and an F-measure of 0.995 when compared with a sample of 200 reports. Using these data, we compared the performance of stents by Kaplan-Meier analysis and the Cox hazard proportional regression. RESULTS: In the self-validation analysis comparing the first-generation to the second-generation DES, the second-generation DES was superior to the first-generation DES (hazard ratio [HR]: 0.423, 95% confidence interval [CI]: 0.284-0.630) in terms of target vessel revascularization (TVR), showing similar findings to the established results of previous studies. Among the second-generation DES, the biodegradable-polymer DES tended to be superior, with a risk of TVR (HR: 0.568, 95% CI: 0.281-1.147) falling below than that for the durable-polymer DES approximately 1 year after the index procedure. The Endeavor stent had the highest TVR risk among the newer generation DES (HR: 2.576, 95% CI: 1.273-5.210). CONCLUSIONS: In this study, we demonstrated how to construct a PCI data warehouse of PCI-related parameters obtained from free-text electronic records with high accuracy for use in the post surveillance of coronary stents in a time- and cost effective manner. Post surveillance of the practice based evidence in the PCI data warehouse indicated that the biodegradable-polymer DES might have a lower risk of TVR than the durable-polymer DES. PMID- 28800600 TI - Botulinum neurotoxin C mutants reveal different effects of syntaxin or SNAP-25 proteolysis on neuromuscular transmission. AB - Botulinum neurotoxin serotype C (BoNT/C) is a neuroparalytic toxin associated with outbreaks of animal botulism, particularly in birds, and is the only BoNT known to cleave two different SNARE proteins, SNAP-25 and syntaxin. BoNT/C was shown to be a good substitute for BoNT/A1 in human dystonia therapy because of its long lasting effects and absence of neuromuscular damage. Two triple mutants of BoNT/C, namely BoNT/C S51T/R52N/N53P (BoNT/C alpha-51) and BoNT/C L200W/M221W/I226W (BoNT/C alpha-3W), were recently reported to selectively cleave syntaxin and have been used here to evaluate the individual contribution of SNAP 25 and syntaxin cleavage to the effect of BoNT/C in vivo. Although BoNT/C alpha 51 and BoNT/C alpha-3W toxins cleave syntaxin with similar efficiency, we unexpectedly found also cleavage of SNAP-25, although to a lesser extent than wild type BoNT/C. Interestingly, the BoNT/C mutants exhibit reduced lethality compared to wild type toxin, a result that correlated with their residual activity against SNAP-25. In spite of this, a local injection of BoNT/C alpha-51 persistently impairs neuromuscular junction activity. This is due to an initial phase in which SNAP-25 cleavage causes a complete blockade of neurotransmission, and to a second phase of incomplete impairment ascribable to syntaxin cleavage. Together, these results indicate that neuroparalysis of BoNT/C at the neuromuscular junction is due to SNAP-25 cleavage, while the proteolysis of syntaxin provides a substantial, but incomplete, neuromuscular impairment. In light of this evidence, we discuss a possible clinical use of BoNT/C alpha-51 as a botulinum neurotoxin endowed with a wide safety margin and a long lasting effect. PMID- 28800601 TI - Sequence homology between HLA-bound cytomegalovirus and human peptides: A potential trigger for alloreactivity. AB - Human cytomegalovirus (hCMV) reactivation may often coincide with the development of graft-versus-host-disease (GVHD) in stem cell transplantation (SCT). Seventy seven SCT donor-recipient pairs (DRP) (HLA matched unrelated donor (MUD), n = 50; matched related donor (MRD), n = 27) underwent whole exome sequencing to identify single nucleotide polymorphisms (SNPs) generating alloreactive peptide libraries for each DRP (9-mer peptide-HLA complexes); Human CMV CROSS (Cross-Reactive Open Source Sequence) database was compiled from NCBI; HLA class I binding affinity for each DRPs HLA was calculated by NetMHCpan 2.8 and hCMV- derived 9-mers algorithmically compared to the alloreactive peptide-HLA complex libraries. Short consecutive (>=6) amino acid (AA) sequence homology matching hCMV to recipient peptides was considered for HLA-bound-peptide (IC50<500nM) cross reactivity. Of the 70,686 hCMV 9-mers contained within the hCMV CROSS database, an average of 29,658 matched the MRD DRP alloreactive peptides and 52,910 matched MUD DRP peptides (p<0.001). In silico analysis revealed multiple high affinity, immunogenic CMV-Human peptide matches (IC50<500 nM) expressed in GVHD-affected tissue-specific manner. hCMV+GVHD was found in 18 patients, 13 developing hCMV viremia before GVHD onset. Analysis of patients with GVHD identified potential cross reactive peptide expression within affected organs. We propose that hCMV peptide sequence homology with human alloreactive peptides may contribute to the pathophysiology of GVHD. PMID- 28800602 TI - MEFV M694V mutation has a role in susceptibility to ankylosing spondylitis: A meta-analysis. AB - OBJECTIVE: The aim of the current study was to determine the contributions of several common mutations in the Mediterranean fever (MEFV) gene, namely, E148Q, M680I, M694V and V726A, to ankylosing spondylitis (AS) susceptibility. METHODS: Two investigators independently searched the literature regarding the association of MEFV with AS in the PubMed, EMBASE, Web of Science, and Scopus databases. They independently selected eligible articles and then extracted data from the included studies. The associations between MEFV mutations and AS risk were assessed with odds ratios (ORs) and 95% confidence intervals (95% CI). Further analyses were conducted with STATA 12.0 software (Stata Corp.; College Station, Texas, USA). RESULTS: Four mutations (E148Q, M680I, M694V and V726A) were genotyped in 869 AS cases and 879 controls from the 8 eligible studies. Of the four mutations, M694V (pooled OR: 3.330, 95% CI: 2.129-5.208) was found to be associated with AS through overall analysis. However, the other mutations demonstrated no relation with AS (pooled ORs: 1.295, 1.258, 1.778; 95% CI: 0.886 1.891, 0.688-2.298 and 0.938-3.371). No significant publication bias was discovered in the meta-analysis. CONCLUSIONS: The present study indicates that the MEFV M694V mutation may contribute to the pathogenesis of AS. The associations between the other mutations and AS need to be validated with more relevant and well-designed studies. PMID- 28800604 TI - The scaling of crime concentration in cities. AB - Crime is a major threat to society's well-being but lacks a statistical characterization that could lead to uncovering some of its underlying mechanisms. Evidence of nonlinear scaling of urban indicators in cities, such as wages and serious crime, has motivated the understanding of cities as complex systems-a perspective that offers insights into resources limits and sustainability, but that usually neglects details of the indicators themselves. Notably, since the nineteenth century, criminal activities have been known to occur unevenly within a city; crime concentrates in such way that most of the offenses take place in few regions of the city. Though confirmed by different studies, this concentration lacks broad analyses on its characteristics, which hinders not only the comprehension of crime dynamics but also the proposal of sounding counter measures. Here, we developed a framework to characterize crime concentration which divides cities into regions with the same population size. We used disaggregated criminal data from 25 locations in the U.S. and the U.K., spanning from 2 to 15 years of longitudinal data. Our results confirmed that crime concentrates regardless of city and revealed that the level of concentration does not scale with city size. We found that the distribution of crime in a city can be approximated by a power-law distribution with exponent alpha that depends on the type of crime. In particular, our results showed that thefts tend to concentrate more than robberies, and robberies more than burglaries. Though criminal activities present regularities of concentration, we found that criminal ranks have the tendency to change continuously over time-features that support the perspective of crime as a complex system and demand analyses and evolving urban policies covering the city as a whole. PMID- 28800603 TI - Genetic variants specific to aging-related verbal memory: Insights from GWASs in a population-based cohort. AB - Verbal memory is typically studied using immediate recall (IR) and delayed recall (DR) scores, although DR is dependent on IR capability. Separating these components may be useful for deciphering the genetic variation in age-related memory abilities. This study was conducted to (a) construct individual trajectories in IR and independent aspects of delayed recall, or residualized-DR (rDR), across older adulthood; and (b) identify genetic markers that contribute to four estimated phenotypes: IR and rDR levels and changes after age 60. A cognitively intact sample (N = 20,650 with 125,164 observations) was drawn from the U.S. Health and Retirement Study, a nationally representative study of adults aged 50 and older. Mixed effects regression models were constructed using repeated measures from data collected every two years (1996-2012) to estimate level at age 60 and change in memory post-60 in IR and rDR. Genome-wide association scans (GWAS) were conducted in the genotypic subsample (N = 7,486) using ~1.2 million single nucleotide polymorphisms (SNPs). One SNP (rs2075650) in TOMM40 associated with rDR level at the genome-wide level (p = 5.0x10-08), an effect that replicated in an independent sample from the English Longitudinal Study on Ageing (N = 6,898 with 41,328 observations). Meta-analysis of rDR level confirmed the association (p = 5.0x10-11) and identified two others in TOMM40 (rs71352238 p = 1.0x10-10; rs157582 p = 7.0x10-09), and one in APOE (rs769449 p = 3.1 x10-12). Meta-analysis of IR change identified associations with three of the same SNPs in TOMM40 (rs157582 p = 8.3x10-10; rs71352238 p = 1.9x10-09) and APOE (rs769449 p = 2.2x10-08). Conditional analyses indicate GWAS signals on rDR level were driven by APOE, whereas signals on IR change were driven by TOMM40. Additionally, we found that TOMM40 had effects independent of APOE e4 on both phenotypes. Findings from this first U.S. population-based GWAS study conducted on both age-related immediate and delayed verbal memory merit continued examination in other samples and additional measures of verbal memory. PMID- 28800605 TI - Stroke survivors with severe mental illness: Are they at-risk for increased non psychiatric hospitalizations? AB - BACKGROUND: This study examined outcomes for two groups of stroke survivors treated in Veteran Health Administration (VHA) hospitals, those with a severe mental illness (SMI) and those without prior psychiatric diagnoses, to examine risk of non-psychiatric medical hospitalizations over five years after initial stroke. METHODS: This retrospective cohort study included 523 veterans who survived an initial stroke hospitalization in a VHA medical center during fiscal year 2003. The survivors were followed using administrative data documenting inpatient stroke treatment, patient demographics, disease comorbidities, and VHA hospital admissions. Multivariate Poisson regression was used to examine the relationship between patients with and without SMI diagnosis preceding the stroke and their experience with non-psychiatric medical hospitalizations after the stroke. RESULTS: The study included 100 patients with SMI and 423 without SMI. Unadjusted means for pre-stroke non-psychiatric hospitalizations were higher (p = 0.0004) among SMI patients (1.47 +/- 0.51) compared to those without SMI (1.00 +/ 1.33), a difference which persisted through the first year post-stroke (SMI: 2.33 +/- 2.46; No SMI: 1.74 +/- 1.86; p = 0.0004). Number of non-psychiatric hospitalizations were not significantly different between the two groups after adjustment for patient sociodemographic, comorbidity, length of stay and inpatient stroke treatment characteristics. Antithrombotic medications significantly lowered risk (OR = 0.61; 95% CI: 0.49-0.73) for stroke-related readmission within 30 days of discharge. CONCLUSIONS: No significant differences in medical hospitalizations were present after adjusting for comorbid and sociodemographic characteristics between SMI and non-SMI stroke patients in the five-year follow-up. However, unadjusted results continue to draw attention to disparities, with SMI patients experiencing more non-psychiatric hospitalizations both prior to and up to one year after their initial stroke. Additionally, stroke survivors discharged on antithrombotic medications were at lower risk of re admission within 30 days suggesting the VHA should continue to focus on effective stroke management irrespective of SMI. PMID- 28800606 TI - Whole exome sequencing as a diagnostic tool for patients with ciliopathy-like phenotypes. AB - Ciliopathies are a group of rare disorders characterized by a high genetic and phenotypic variability, which complicates their molecular diagnosis. Hence the need to use the latest powerful approaches to faster identify the genetic defect in these patients. We applied whole exome sequencing to six consanguineous families clinically diagnosed with ciliopathy-like disease, and for which mutations in predominant Bardet-Biedl syndrome (BBS) genes had previously been excluded. Our strategy, based on first applying several filters to ciliary variants and using many of the bioinformatics tools available, allowed us to identify causal mutations in BBS2, ALMS1 and CRB1 genes in four families, thus confirming the molecular diagnosis of ciliopathy. In the remaining two families, after first rejecting the presence of pathogenic variants in common cilia-related genes, we adopted a new filtering strategy combined with prioritisation tools to rank the final candidate genes for each case. Thus, we propose CORO2B, LMO7 and ZNF17 as novel candidate ciliary genes, but further functional studies will be needed to confirm their role. Our data show the usefulness of this strategy to diagnose patients with unclear phenotypes, and therefore the success of applying such technologies to achieve a rapid and reliable molecular diagnosis, improving genetic counselling for these patients. In addition, the described pipeline also highlights the common pitfalls associated to the large volume of data we have to face and the difficulty of assigning a functional role to these changes, hence the importance of designing the most appropriate strategy according to each case. PMID- 28800607 TI - RNA-sequencing-based transcriptome and biochemical analyses of steroidal saponin pathway in a complete set of Allium fistulosum-A. cepa monosomic addition lines. AB - The genus Allium is a rich source of steroidal saponins, and its medicinal properties have been attributed to these bioactive compounds. The saponin compounds with diverse structures play a pivotal role in Allium's defense mechanism. Despite numerous studies on the occurrence and chemical structure of steroidal saponins, their biosynthetic pathway in Allium species is poorly understood. The monosomic addition lines (MALs) of the Japanese bunching onion (A. fistulosum, FF) with an extra chromosome from the shallot (A. cepa Aggregatum group, AA) are powerful genetic resources that enable us to understand many physiological traits of Allium. In the present study, we were able to isolate and identify Alliospiroside A saponin compound in A. fistulosum with extra chromosome 2A from shallot (FF2A) and its role in the defense mechanism against Fusarium pathogens. Furthermore, to gain molecular insight into the Allium saponin biosynthesis pathway, high-throughput RNA-Seq of the root, bulb, and leaf of AA, MALs, and FF was carried out using Illumina's HiSeq 2500 platform. An open access Allium Transcript Database (Allium TDB, http://alliumtdb.kazusa.or.jp) was generated based on RNA-Seq data. The resulting assembled transcripts were functionally annotated, revealing 50 unigenes involved in saponin biosynthesis. Differential gene expression (DGE) analyses of AA and MALs as compared with FF (as a control) revealed a strong up-regulation of the saponin downstream pathway, including cytochrome P450, glycosyltransferase, and beta-glucosidase in chromosome 2A. An understanding of the saponin compounds and biosynthesis-related genes would facilitate the development of plants with unique saponin content and, subsequently, improved disease resistance. PMID- 28800608 TI - Minimum variance rooting of phylogenetic trees and implications for species tree reconstruction. AB - Phylogenetic trees inferred using commonly-used models of sequence evolution are unrooted, but the root position matters both for interpretation and downstream applications. This issue has been long recognized; however, whether the potential for discordance between the species tree and gene trees impacts methods of rooting a phylogenetic tree has not been extensively studied. In this paper, we introduce a new method of rooting a tree based on its branch length distribution; our method, which minimizes the variance of root to tip distances, is inspired by the traditional midpoint rerooting and is justified when deviations from the strict molecular clock are random. Like midpoint rerooting, the method can be implemented in a linear time algorithm. In extensive simulations that consider discordance between gene trees and the species tree, we show that the new method is more accurate than midpoint rerooting, but its relative accuracy compared to using outgroups to root gene trees depends on the size of the dataset and levels of deviations from the strict clock. We show high levels of error for all methods of rooting estimated gene trees due to factors that include effects of gene tree discordance, deviations from the clock, and gene tree estimation error. Our simulations, however, did not reveal significant differences between two equivalent methods for species tree estimation that use rooted and unrooted input, namely, STAR and NJst. Nevertheless, our results point to limitations of existing scalable rooting methods. PMID- 28800610 TI - Anticoagulant action of low, physiologic, and high albumin levels in whole blood. AB - Albumin is the most abundant plasma protein. Critical illness is often associated with altered, predominately decreased, serum albumin levels. This hypoalbuminaemia is usually corrected by administration of exogenous albumin. This study aimed to track the concentration-dependent influence of albumin on blood coagulation in vitro. Whole blood (WB) samples from 25 volunteers were prepared to contain low (19.3 +/- 7.7 g/L), physiological (45.2 +/- 7.8 g/L), and high (67.5 +/- 18.1 g/L) levels of albumin. Haemostatic profiling was performed using a platelet function analyzer (PFA) 200, impedance aggregometry, a Cone and Platelet analyzer (CPA), calibrated automated thrombogram, and thrombelastometry (TEM). Platelet aggregation-associated ATP release was assessed via HPLC analysis. In the low albumin group, when compared to the physiological albumin group, we found: i) shortened PFA 200-derived closure times indicating increased primary haemostasis; ii) increased impedance aggregometry-derived amplitudes, slopes, ATP release, as well as CPA-derived average size indicating improved platelet aggregation; iii) increased TEM-derived maximum clot firmness and alpha angles indicating enhanced clot formation. TEM measurements indicated impaired clot formation in the high albumin group compared with the physiological albumin group. Thus, albumin exerted significant anticoagulant action. Therefore, low albumin levels, often present in cancer or critically ill patients, might contribute to the frequently occurring venous thromboembolism. PMID- 28800609 TI - The Trypomastigote Small Surface Antigen (TSSA) regulates Trypanosoma cruzi infectivity and differentiation. AB - BACKGROUND: TSSA (Trypomastigote Small Surface Antigen) is an antigenic, adhesion molecule displayed on the surface of Trypanosoma cruzi trypomastigotes. TSSA displays substantial sequence identity to members of the TcMUC gene family, which code for the trypomastigote mucins (tGPI-mucins). In addition, TSSA bears sequence polymorphisms among parasite strains; and two TSSA variants expressed as recombinant molecules (termed TSSA-CL and TSSA-Sy) were shown to exhibit contrasting features in their host cell binding and signaling properties. METHODS/PRINCIPLE FINDINGS: Here we used a variety of approaches to get insights into TSSA structure/function. We show that at variance with tGPI-mucins, which rely on their extensive O-glycoslylation to achieve their protective function, TSSA seems to be displayed on the trypomastigote coat as a hypo-glycosylated molecule. This has a functional correlate, as further deletion mapping experiments and cell binding assays indicated that exposition of at least two peptidic motifs is critical for the engagement of the 'adhesive' TSSA variant (TSSA-CL) with host cell surface receptor(s) prior to trypomastigote internalization. These motifs are not conserved in the 'non-adhesive' TSSA-Sy variant. We next developed transgenic lines over-expressing either TSSA variant in different parasite backgrounds. In strict accordance to recombinant protein binding data, trypomastigotes over-expressing TSSA-CL displayed improved adhesion and infectivity towards non-macrophagic cell lines as compared to those over expressing TSSA-Sy or parental lines. These phenotypes could be specifically counteracted by exogenous addition of peptides spanning the TSSA-CL adhesion motifs. In addition, and irrespective of the TSSA variant, over-expression of this molecule leads to an enhanced trypomastigote-to-amastigote conversion, indicating a possible role of TSSA also in parasite differentiation. CONCLUSION/SIGNIFICANCE: In this study we provided novel evidence indicating that TSSA plays an important role not only on the infectivity and differentiation of T. cruzi trypomastigotes but also on the phenotypic variability displayed by parasite strains. PMID- 28800611 TI - Using local chromatin structure to improve CRISPR/Cas9 efficiency in zebrafish. AB - Although the CRISPR/Cas9 has been successfully applied in zebrafish, considerable variations in efficiency have been observed for different gRNAs. The workload and cost of zebrafish mutant screening is largely dependent on the mutation rate of injected embryos; therefore, selecting more effective gRNAs is especially important for zebrafish mutant construction. Besides the sequence features, local chromatin structures may have effects on CRISPR/Cas9 efficiency, which remain largely unexplored. In the only related study in zebrafish, nucleosome organization was not found to have an effect on CRISPR/Cas9 efficiency, which is inconsistent with recent studies in vitro and in mammalian cell lines. To understand the effects of local chromatin structure on CRISPR/Cas9 efficiency in zebrafish, we first determined that CRISPR/Cas9 introduced genome editing mainly before the dome stage. Based on this observation, we reanalyzed our published nucleosome organization profiles and generated chromatin accessibility profiles in the 256-cell and dome stages using ATAC-seq technology. Our study demonstrated that chromatin accessibility showed positive correlation with CRISPR/Cas9 efficiency, but we did not observe a clear correlation between nucleosome organization and CRISPR/Cas9 efficiency. We constructed an online database for zebrafish gRNA selection based on local chromatin structure features that could prove beneficial to zebrafish homozygous mutant construction via CRISPR/Cas9. PMID- 28800612 TI - Burnout, associated comorbidities and coping strategies in French community pharmacies-BOP study: A nationwide cross-sectional study. AB - BACKGROUND: Work-related stress and burnout syndromes are unfortunately common comorbidities found in health professionals. However, burnout syndrome has only been partly and episodically assessed for community pharmacists whereas these professionals are exposed to patients' demands and difficulties every day. Prevalence of burnout, associated comorbidities and coping strategies were assessed in pharmacy teams (pharmacists and pharmacy technicians) in French community pharmacies. METHODS: This online survey was performed by emails sent to all French community pharmacies over 3 months. The survey assessed the prevalence of burnout (Maslach Burnout Inventory-MBI-questionnaire), anxiety, depression and strategies for coping with work-related stress. RESULTS: Of the 1,339 questionnaires received, 1,322 were completed and useable for the analysis. Burnout syndrome was detected in 56.2% of respondents and 10.5% of them presented severe burnout syndrome. Severe burnout syndrome was significantly associated with men, large urban areas and the number of hours worked. Depression and anxiety were found in 15.7% and 42.4% of respondents, respectively. These co morbidities were significantly associated with severe burnout syndrome. Higher MBI scores were significantly associated with medical consultations and medicinal drug use. Conversely, respondents suffering from burnout syndrome declared they resorted less to non-medical strategies to manage their work-related stress (leisure, psychotherapy, holidays and time off). CONCLUSION: This study demonstrated that community pharmacists and pharmacy technicians presented high prevalence of burnout syndrome, such as many healthcare professionals. Unfortunately, burnout syndrome was associated with several comorbidities (anxiety, depression and alcohol abuse) and the consumption of health resources. The psychological suffering of these healthcare professionals underlines the necessity to deploy a strategy to detect and manage burnout in community pharmacy. PMID- 28800613 TI - Ongoing slow oscillatory phase modulates speech intelligibility in cooperation with motor cortical activity. AB - Neural oscillation is attracting attention as an underlying mechanism for speech recognition. Speech intelligibility is enhanced by the synchronization of speech rhythms and slow neural oscillation, which is typically observed as human scalp electroencephalography (EEG). In addition to the effect of neural oscillation, it has been proposed that speech recognition is enhanced by the identification of a speaker's motor signals, which are used for speech production. To verify the relationship between the effect of neural oscillation and motor cortical activity, we measured scalp EEG, and simultaneous EEG and functional magnetic resonance imaging (fMRI) during a speech recognition task in which participants were required to recognize spoken words embedded in noise sound. We proposed an index to quantitatively evaluate the EEG phase effect on behavioral performance. The results showed that the delta and theta EEG phase before speech inputs modulated the participant's response time when conducting speech recognition tasks. The simultaneous EEG-fMRI experiment showed that slow EEG activity was correlated with motor cortical activity. These results suggested that the effect of the slow oscillatory phase was associated with the activity of the motor cortex during speech recognition. PMID- 28800614 TI - Optimization of recombinant bacteria expressing dsRNA to enhance insecticidal activity against a lepidopteran insect, Spodoptera exigua. AB - Double-stranded RNA (dsRNA) has been applied to control insect pests due to its induction of RNA interference (RNAi) of a specific target gene expression. However, developing dsRNA-based insecticidal agent has been a great challenge especially against lepidopteran insect pests due to variations in RNAi efficiency. The objective of this study was to screen genes of chymotrypsins (SeCHYs) essential for the survival of the beet armyworm, Spodoptera exigua, to construct insecticidal dsRNA. In addition, an optimal oral delivery method was developed using recombinant bacteria. At least 7 SeCHY genes were predicted from S. exigua transcriptomes. Subsequent analyses indicated that SeCHY2 was widely expressed in different developmental stages and larval tissues by RT-PCR and its expression knockdown by RNAi caused high mortality along with immunosuppression. However, a large amount of dsRNA was required to efficiently kill late instars of S. exigua because of high RNase activity in their midgut lumen. To minimize dsRNA degradation, bacterial expression and formulation of dsRNA were performed in HT115 Escherichia coli using L4440 expression vector. dsRNA (300 bp) specific to SeCHY2 overexpressed in E. coli was toxic to S. exigua larvae after oral administration. To enhance dsRNA release from E. coli, bacterial cells were sonicated before oral administration. RNAi efficiency of sonicated bacteria was significantly increased, causing higher larval mortality at oral administration. Moreover, targeting young larvae possessing weak RNase activity in the midgut lumen significantly enhanced RNAi efficiency and subsequent insecticidal activity against S. exigua. PMID- 28800615 TI - Pitx3 and En1 determine the size and molecular programming of the dopaminergic neuronal pool. AB - Mesodiencephalic dopaminergic (mdDA) neurons are located in the ventral midbrain. These neurons form the substantia nigra (SNc) and the ventral tegmental area (VTA). Two transcription factors that play important roles in the process of terminal differentiation and subset-specification of mdDA neurons, are paired like homeodomain transcription factor 3 (Pitx3), and homeobox transcription factor Engrailed 1 (En1). We previously investigated the single Pitx3KO and En1KO and observed important changes in the survival of mdDA neurons of the SNc and VTA as well as altered expression of pivotal rostral- and caudal-markers, Ahd2 and Cck, respectively. To refine our understanding of the regional-specific relationships between En1 and Pitx3 and their (combined) role in the programming mdDA neurons on the rostral-to-caudal axis, we created double En1tm1Alj/tm1Alj;Pitx3gfp/gfp (En1KO;Pitx3GFP/GFP) animals. Here we report, that in absence of En1 and Pitx3, only a limited number of mdDA neurons are present at E14.5. These mdDA neurons have a rudimentary dopaminergic cell fate, as they express Nurr1, Pbx3 and Otx2 but have lost their rostral or caudal subset identity. Furthermore, we report that the expression of Cck depends on En1 expression, while (in contrast) both Pitx3 and En1 are involved in the initiation of Ahd2 expression. Thus we reveal in this manuscript that regulated levels of Pitx3 and En1 control the size and rostral/caudal-identity of the mdDA neuronal population. PMID- 28800617 TI - Improved usability of a multi-infusion setup using a centralized control interface: A task-based usability test. AB - The objective of this study was to assess the usability benefits of adding a bedside central control interface that controls all intravenous (IV) infusion pumps compared to the conventional individual control of multiple infusion pumps. Eighteen dedicated ICU nurses volunteered in a between-subjects task-based usability test. A newly developed central control interface was compared to conventional control of multiple infusion pumps in a simulated ICU setting. Task execution time, clicks, errors and questionnaire responses were evaluated. Overall the central control interface outperformed the conventional control in terms of fewer user actions (40+/-3 vs. 73+/-20 clicks, p<0.001) and fewer user errors (1+/-1 vs. 3+/-2 errors, p<0.05), with no difference in task execution times (421+/-108 vs. 406+/-119 seconds, not significant). Questionnaires indicated a significant preference for the central control interface. Despite being novice users of the central control interface, ICU nurses displayed improved performance with the central control interface compared to the conventional interface they were familiar with. We conclude that the new user interface has an overall better usability than the conventional interface. PMID- 28800616 TI - Seroprevalence of IgA anti Epstein-Barr virus is high among family members of nasopharyngeal cancer patients and individuals presenting with chronic complaints in head and neck area. AB - Epstein-Barr (EBV) infection and presence of a nasopharyngeal cancer (NPC) case in the family increases the risk of developing NPC. Aberrant anti-EBV immunoglobulin A (IgA) antibodies (EBV-IgA) may be present in the sera of non cancer individuals and predict NPC. Limited studies report the presence of EBV IgA antibodies within non-cancer individuals in Indonesia where the disease is prevalent. This study aimed at exploring whether EBV-IgA was found more frequently among first degree relatives of NPC patients and individuals presenting with chronic symptoms in the head and neck area compared to healthy controls. A total of 967 non-cancer subjects were recruited, including 509 family members of NPC cases, 196 individuals having chronic complaints in the head and neck region, and 262 healthy donors of the local blood bank. Sera were analyzed using a standardized peptide-based EBV-IgA ELISA. Overall, 61.6% of all individuals had anti-EBV IgA reactivity equal to or below cut off value (CoV). Seroreactivity above CoV was significantly higher in females (38.7%) compared to males (28.7%) (p = 0.001). Older individuals had more seroreactivity above CoV (42.5%) than the younger ones (26.4%) (p< 0.001). Seroprevalence was significantly higher in family members of NPC patients (41.7%), compared to 32.7% of individuals with chronic head and neck problems (p = 0.028) and 16.4% healthy blood donors (p< 0.001). As conclusion, this study showed a significant higher seroprevalence in healthy family members of NPC cases and subjects presenting with chronic symptoms in the head and neck area compared to healthy individuals from the general community. This finding indicates that both groups have elevated risk of developing NPC and may serve as targets for a regional NPC screening program. PMID- 28800618 TI - The workforce trends of nurses in Lebanon (2009-2014): A registration database analysis. AB - BACKGROUND: Analysis of the nursing registration databases is a highly informative approach that provides accurate and reliable information supporting evidence based decisions relevant to the nursing workforce planning, management and development. This study presents the first systematic analysis of the nursing registration database in Lebanon. It Reports on the workforce distribution and trends using an updated version of the Order of Nurses in Lebanon (ONL) databases. METHODS: This study presents a secondary data analysis of a de identified subset of the updated ONL registration database. The workforce participation status of ONL registered nurses was categorized as active and eligible. For active nurses sectors and sub-sectors of employment were defined. Eligible nurses were categorized as unemployed, working outside nursing and working abroad. SPSS was used to conduct descriptive analysis to present workforce trends of Lebanese nurses for year 2009-2014 as frequencies, percentages and percentage changes. RESULTS: Increases in the size of the Active (35%) and Eligible (86%) nurses were observed over the past six years. The majority of nurses fell in the below 35 years age group (60% in 2014). The hospital sector remained the principle employer, with 87% of Lebanese nurses working in hospitals in 2014. A 173% increases was reported for nurses working abroad. DISCUSSION: Despite the growth of the Active nursing workforce, the skewed distribution of nurses in the below 35 age group and the growth in the Eligible category, especially for nurses living abroad, raise concerns on the longevity of nurses in the profession and the reasons for their attrition from the workforce. CONCLUSION: There is a need to investigate the push and pull factors that are affecting nurses and the design of policies and interventions that would encourage nurses to remain active in Lebanon. Furthermore, policies and interventions that would create employment opportunities outside hospitals, especially in the Community sector, are recommended. PMID- 28800619 TI - "What is relevant in a text document?": An interpretable machine learning approach. AB - Text documents can be described by a number of abstract concepts such as semantic category, writing style, or sentiment. Machine learning (ML) models have been trained to automatically map documents to these abstract concepts, allowing to annotate very large text collections, more than could be processed by a human in a lifetime. Besides predicting the text's category very accurately, it is also highly desirable to understand how and why the categorization process takes place. In this paper, we demonstrate that such understanding can be achieved by tracing the classification decision back to individual words using layer-wise relevance propagation (LRP), a recently developed technique for explaining predictions of complex non-linear classifiers. We train two word-based ML models, a convolutional neural network (CNN) and a bag-of-words SVM classifier, on a topic categorization task and adapt the LRP method to decompose the predictions of these models onto words. Resulting scores indicate how much individual words contribute to the overall classification decision. This enables one to distill relevant information from text documents without an explicit semantic information extraction step. We further use the word-wise relevance scores for generating novel vector-based document representations which capture semantic information. Based on these document vectors, we introduce a measure of model explanatory power and show that, although the SVM and CNN models perform similarly in terms of classification accuracy, the latter exhibits a higher level of explainability which makes it more comprehensible for humans and potentially more useful for other applications. PMID- 28800620 TI - Experimental study of ASCs combined with POC-PLA patch for the reconstruction of full-thickness chest wall defects. AB - To explore the repairing effect of combination of adipose stem cells (ASCs) and composite scaffolds on CWR, the electrospun Poly 1, 8-octanediol-co-citric acid (POC)-poly-L-lactide acid (PLA) composite scaffolds were prepared, followed by in vitro and in vivo biocompatibility evaluation of the scaffolds. Afterwards, ASCs were seeded on POC-PLA to construct the POC-PLA-ASCs scaffolds, and the POC-PLA, POC-PLA-ASCs, and traditional materials expanded polytetrafluoroethylene (ePTFE) were adopt for CWR in New Zealand white (NZW) rabbit models. As results, the POC PLA-ASCs patches possessed good biocompatibility as the high proliferation ability of cells surrounding the patches. Rabbits in POC-PLA-ASCs groups showed better pulmonary function, less pleural adhesion, higher degradation rate and more neovascularization when compared with that in other two groups. The results of western blot indicated that POC-PLA-ASCs patches accelerated the expression of VEGF and Collagen I in rabbit models. From the above, our present study demonstrated that POC-PLA material was applied for CWR successfully, and ASCs seeded on the sheets could improve the pleural adhesions and promote the reparation of chest wall defects. PMID- 28800621 TI - Chimeric proteins tagged with specific 3xHA cassettes may present instability and functional problems. AB - Epitope-tagging of proteins has become a widespread technique for the analysis of protein function, protein interactions and protein localization among others. Tagging of genes by chromosomal integration of PCR amplified cassettes is a widely used and fast method to label proteins in vivo. Different systems have been developed during years in the yeast Saccharomyces cerevisiae. In the present study, we analysed systematically a set of yeast proteins that were fused to different tags. Analysis of the tagged proteins revealed an unexpected general effect on protein level when some specific tagging module was used. This was due in all cases to a destabilization of the proteins and caused a reduced protein activity in the cell that was only apparent in particular conditions. Therefore, an extremely cautious approach is required when using this strategy. PMID- 28800622 TI - Microbial profile comparisons of saliva, pooled and site-specific subgingival samples in periodontitis patients. AB - OBJECTIVES: The purpose of this study was to compare microbial profiles of saliva, pooled and site-specific subgingival samples in patients with periodontitis. We tested the hypotheses that saliva can be an alternative to pooled subgingival samples, when screening for presence of periopathogens. DESIGN: Site specific subgingival plaque samples (n = 54), pooled subgingival plaque samples (n = 18) and stimulated saliva samples (n = 18) were collected from 18 patients with generalized chronic periodontitis. Subgingival and salivary microbiotas were characterized by means of HOMINGS (Human Oral Microbe Identification using Next Generation Sequencing) and microbial community profiles were compared using Spearman rank correlation coefficient. RESULTS: Pronounced intraindividual differences were recorded in site-specific microbial profiles, and site-specific information was in general not reflected by pooled subgingival samples. Presence of Porphyromonas gingivalis, Treponema denticola, Prevotella intermedia, Filifactor alocis, Tannerella forsythia and Parvimona micra in site specific subgingival samples were detected in saliva with an AUC of 0.79 (sensitivity: 0.61, specificity: 0.94), compared to an AUC of 0.76 (sensitivity: 0.56, specificity: 0.94) in pooled subgingival samples. CONCLUSIONS: Site specific presence of periodontal pathogens was detected with comparable accuracy in stimulated saliva samples and pooled subgingival plaque samples. Consequently, saliva may be a reasonable surrogate for pooled subgingival samples when screening for presence of periopathogens. Future large-scale studies are needed to confirm findings from this study. PMID- 28800623 TI - Quantifying immediate and delayed effects of anthelmintic exposure on ecosystem functioning supported by a common dung beetle species. AB - Dung beetles (Coleoptera: Scarabaeoidea) support numerous ecosystem functions in livestock-grazed pastures. Exposure to veterinary anthelmintic residues in livestock dung can have lethal and sublethal effects on dung beetles, and can reduce rates of dung removal, but the immediate and longer-term consequences for other dung beetle mediated functions have rarely been studied. We investigated the consequences of anthelmintic exposure on survival of the dung beetle Aphodius fossor and its delivery of four ecosystems functions that underpin pasture production: dung removal, soil fauna feeding activity, primary productivity, and reduction of soil compaction. We tested whether anthelmintic exposure had immediate or delayed effects on these functions individually and simultaneously (i.e., ecosystem multifunctionality). We found no evidence that ivermectin residues had a lethal effect on adult beetles. For dung removal, we found a significant interaction between the timing of exposure and functioning: while dung removal was impaired by concurrent exposure to high levels of ivermectin, functioning was unaffected when beetles that had been exposed previously to the same concentration of anthelmintic later interacted with untreated dung. Other ecosystem functions were not affected significantly by anthelmintic exposure, and there was no evidence to suggest any persistent impact of anthelmintic exposure on ecosystem multifunctionality. While anthelmintic residues remain a significant threat to dung beetle populations, for adult beetles, we found no evidence that residues have detrimental consequences for ecosystem functioning beyond the immediate point of exposure. PMID- 28800624 TI - Destabilizing polymorphism in cervid prion protein hydrophobic core determines prion conformation and conversion efficiency. AB - Prion diseases are infectious neurodegenerative disorders of humans and animals caused by misfolded forms of the cellular prion protein PrPC. Prions cause disease by converting PrPC into aggregation-prone PrPSc. Chronic wasting disease (CWD) is the most contagious prion disease with substantial lateral transmission, affecting free-ranging and farmed cervids. Although the PrP primary structure is highly conserved among cervids, the disease phenotype can be modulated by species specific polymorphisms in the prion protein gene. How the resulting amino-acid substitutions impact PrPC and PrPSc structure and propagation is poorly understood. We investigated the effects of the cervid 116A>G substitution, located in the most conserved PrP domain, on PrPC structure and conversion and on 116AG-prion conformation and infectivity. Molecular dynamics simulations revealed structural de-stabilization of 116G-PrP, which enhanced its in vitro conversion efficiency when used as recombinant PrP substrate in real-time quaking-induced conversion (RT-QuIC). We demonstrate that 116AG-prions are conformationally less stable, show lower activity as a seed in RT-QuIC and exhibit reduced infectivity in vitro and in vivo. Infectivity of 116AG-prions was significantly enhanced upon secondary passage in mice, yet conformational features were retained. These findings indicate that structurally de-stabilized PrPC is readily convertible by cervid prions of different genetic background and results in a prion conformation adaptable to cervid wild-type PrP. Conformation is an important criterion when assessing transmission barrier, and conformational variants can target a different host range. Therefore, a thorough analysis of CWD isolates and re assessment of species-barriers is important in order to fully exclude a zoonotic potential of CWD. PMID- 28800625 TI - Variability in quantitative analysis of atherosclerotic plaque inflammation using 18F-FDG PET/CT. AB - BACKGROUND: 18F-FDG-PET(/CT) is increasingly used in studies aiming at quantifying atherosclerotic plaque inflammation. Considerable methodological variability exists. The effect of data acquisition and image analysis parameters on quantitative uptake measures, such as standardized uptake value (SUV) and target-to-background ratio (TBR) has not been investigated extensively. OBJECTIVE: The goal of this study was to explore the effect of several data acquisition and image analysis parameters on quantification of vascular wall 18F FDG uptake measures, in order to increase awareness of potential variability. METHODS: Three whole-body emission scans and a low-dose CT scan were acquired 38, 60 and 90 minutes after injection of 18F-FDG in six rheumatoid arthritis patients with high cardiovascular risk profiles.Data acquisition (1 and 2) and image analysis (3, 4 and 5) parameters comprised:1. 18F-FDG uptake time, 2. SUV normalisation, 3. drawing regions/volumes of interest (ROI's/VOI's) according to: a. hot-spot (HS), b. whole-segment (WS) and c. most-diseased segment (MDS), 4. Background activity, 5. Image matrix/voxel size.Intraclass correlation coefficients (ICC's) and Bland Altman plots were used to assess agreement between these techniques and between observers. A linear mixed model was used to determine the association between uptake time and continuous outcome variables. RESULTS: 1. Significantly higher TBRmax values were found at 90 minutes (1,57 95%CI 1,35-1,80) compared to 38 minutes (1,30 95%CI 1,21-1,39) (P = 0,024) 2. Normalising SUV for BW, LBM and BSA significantly influences average SUVmax (2,25 (+/-0,60) vs 1,67 (+/-0,37) vs 0,058 (+/-0,013)). 3. Intraclass correlation coefficients were high in all vascular segments when SUVmax HS was compared to SUVmax WS. SUVmax HS was consistently higher than SUVmax MDS in all vascular segments. 4. Blood pool activity significantly decreases in all (venous and arterial) segments over time, but does not differ between segments. 5. Image matrix/voxel size does not influence SUVmax. CONCLUSION: Quantitative measures of vascular wall 18F-FDG uptake are affected mainly by changes in data acquisition parameters. Standardization of methodology needs to be considered when studying atherosclerosis and/or vasculitis. PMID- 28800626 TI - Targeting lysyl oxidase reduces peritoneal fibrosis. AB - BACKGROUND: Abdominal surgery and disease cause persistent abdominal adhesions, pelvic pain, infertility and occasionally, bowel obstruction. Current treatments are ineffective and the aetiology is unclear, although excessive collagen deposition is a consistent feature. Lysyl oxidase (Lox) is a key enzyme required for crosslinking and deposition of insoluble collagen, so we investigated whether targeting Lox might be an approach to reduce abdominal adhesions. METHODS: Female C57Bl/6 mice were treated intraperitoneally with multiwalled carbon nanotubes (NT) to induce fibrosis, together with chemical (beta-aminoproprionitrile-BAPN) or miRNA Lox inhibitors, progesterone or dexamethasone. Fibrotic lesions on the diaphragm, and expression of fibrosis-related genes in abdominal wall peritoneal mesothelial cells (PMC) were measured. Effects of BAPN and dexamethasone on collagen fibre alignment were observed by TEM. Isolated PMC were cultured with interleukin-1 alpha (IL-1alpha) and progesterone to determine effects on Lox mRNA in vitro. RESULTS: NT-induced fibrosis and collagen deposition on the diaphragm was ameliorated by BAPN, Lox miRNA, or steroids. BAPN and dexamethasone disrupted collagen fibres. NT increased PMC Lox, Col1a1, Col3a1 and Bmp1 mRNA, which was inhibited by steroids. Progesterone significantly inhibited IL-1alpha induced Lox expression by PMC in vitro. CONCLUSION: Our results provide proof-of-concept that targeting peritoneal Lox could be an effective approach in ameliorating fibrosis and adhesion development. PMID- 28800627 TI - Suppressive effects of RXR agonist PA024 on adrenal CYP11B2 expression, aldosterone secretion and blood pressure. AB - The effects of retinoids on adrenal aldosterone synthase gene (CYP11B2) expression and aldosterone secretion are still unknown. We therefore examined the effects of nuclear retinoid X receptor (RXR) pan-agonist PA024 on CYP11B2 expression, aldosterone secretion and blood pressure, to elucidate its potential as a novel anti-hypertensive drug. We demonstrated that PA024 significantly suppressed angiotensin II (Ang II)-induced CYP11B2 mRNA expression, promoter activity and aldosterone secretion in human adrenocortical H295R cells. Human CYP11B2 promoter functional analyses using its deletion and point mutants indicated that the suppression of CYP11B2 promoter activity by PA024 was in the region from -1521 (full length) to -106 including the NBRE-1 and the Ad5 elements, and the Ad5 element may be mainly involved in the PA024-mediated suppression. PA024 also significantly suppressed the Ang II-induced mRNA expression of transcription factors NURR1 and NGFIB that bind to and activate the Ad5 element. NURR1 overexpression demonstrated that the decrease of NURR1 expression may contribute to the PA024-mediated suppression of CYP11B2 transcription. PA024 also suppressed the Ang II-induced mRNA expression of StAR, HSD3beta2 and CYP21A2, a steroidogenic enzyme group involved in aldosterone biosynthesis. Additionally, the PA024-mediated CYP11B2 transcription suppression was shown to be exerted via RXRalpha. Moreover, the combination of PPARgamma agonist pioglitazone and PA024 caused synergistic suppressive effects on CYP11B2 mRNA expression. Finally, PA024 treatment significantly lowered both the systolic and diastolic blood pressure in Tsukuba hypertensive mice (hRN8-12 x hAG2-5). Thus, RXR pan-agonist PA024 may be a candidate anti-hypertensive drugs that acts via the suppression of aldosterone synthesis and secretion. PMID- 28800628 TI - GENomE wide analysis of sotalol-induced IKr inhibition during ventricular REPOLarization, "GENEREPOL study": Lack of common variants with large effect sizes. AB - : Many drugs used for non-cardiovascular and cardiovascular purposes, such as sotalol, have the side effect of prolonging cardiac repolarization, which can trigger life-threatening cardiac arrhythmias by inhibiting the potassium-channel IKr (KCNH2). On the electrocardiogram (ECG), IKr inhibition induces an increase in QTc and Tpeak-Tend (TpTe) interval and a decrease of T wave maximal amplitude (TAmp). These changes vary markedly between subjects, suggesting the existence of predisposing genetic factors. 990 healthy individuals, prospectively challenged with an oral 80mg sotalol dose, were monitored for changes in ventricular repolarization on ECG between baseline and 3 hours post dosing. QTc and TpTe increased by 5.5+/-3.5% and 15+/-19.6%, respectively, and TAmp decreased by 13.2+/-15.5%. A principal-component analysis derived from the latter ECG changes was performed. A random subsample of 489 individuals were subjected to a genome wide-association analysis where 8,306,856 imputed single nucleotide polymorphisms (SNPs) were tested for association with QTc, TpTe and TAmp modulations, as well their derived principal-components, to search for common genetic variants associated with sotalol-induced IKr inhibition. None of the studied SNPs reached the statistical threshold for genome-wide significance. This study supports the lack of common variants with larger effect sizes than one would expect based on previous ECG genome-wide-association studies. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT00773201. PMID- 28800630 TI - Measuring single constructs by single items: Constructing an even shorter version of the "Short Five" personality inventory. AB - The aim of this study was to construct a short, 30-item personality questionnaire that would be, in terms of content and meaning of the scores, as comparable as possible with longer, well-established inventories such as NEO PI-R and its clones. To do this, we shortened the formerly constructed 60-item "Short Five" (S5) by half so that each subscale would be represented by a single item. We compared all possibilities of selecting 30 items (preserving balanced keying within each domain of the five-factor model) in terms of correlations with well established scales, self-peer correlations, and clarity of meaning, and selected an optimal combination for each domain. The resulting shortened questionnaire, XS5, was compared to the original S5 using data from student samples in 6 different countries (Estonia, Finland, UK, Germany, Spain, and China), and a representative Finnish sample. The correlations between XS5 domain scales and their longer counterparts from well-established scales ranged from 0.74 to 0.84; the difference from the equivalent correlations for full version of S5 or from meta-analytic short-term dependability coefficients of NEO PI-R was not large. In terms of prediction of external criteria (emotional experience and self-reported behaviours), there were no important differences between XS5, S5, and the longer well-established scales. Controlling for acquiescence did not improve the prediction of criteria, self-peer correlations, or correlations with longer scales, but it did improve internal reliability and, in some analyses, comparability of the principal component structure. XS5 can be recommended as an economic measure of the five-factor model of personality at the level of domain scales; it has reasonable psychometric properties, fair correlations with longer well-established scales, and it can predict emotional experience and self reported behaviours no worse than S5. When subscales are essential, we would still recommend using the full version of S5. PMID- 28800631 TI - Lack of spacing effects during piano learning. AB - Spacing effects during retention of verbal information are easily obtained, and the effect size is large. Relatively little evidence exists on whether motor skill retention benefits from distributed practice, with even less evidence on complex motor skills. We taught a 17-note musical sequence on a piano to individuals without prior formal training. There were five lags between learning episodes: 0-, 1-, 5-, 10-, and 15-min. After a 5-min retention interval, participants' performance was measured using three criteria: accuracy of note playing, consistency in pressure applied to the keys, and consistency in timing. No spacing effect was found, suggesting that the effect may not always be demonstrable for complex motor skills or non-verbal abilities (timing and motor skills). Additionally, we taught short phrases from five songs, using the same set of lags and retention interval, and did not find any spacing effect for accuracy of song reproduction. Our findings indicate that although the spacing effect is one of the most robust phenomena in the memory literature (as demonstrated by verbal learning studies), the effect may vary when considered in the novel realm of complex motor skills such as piano performance. PMID- 28800629 TI - Protective effects on the retina after ranibizumab treatment in an ischemia model. AB - Retinal ischemia is common in eye disorders, like diabetic retinopathy or retinal vascular occlusion. The goal of this study was to evaluate the potential protective effects of an intravitreally injected vascular endothelial growth factor (VEGF) inhibitor (ranibizumab) on retinal cells in an ischemia animal model via immunohistochemistry (IF) and quantitative real-time PCR (PCR). A positive binding of ranibizumab to rat VEGF-A was confirmed via dot blot. One eye underwent ischemia and a subgroup received ranibizumab. A significant VEGF increase was detected in aqueous humor of ischemic eyes (p = 0.032), whereas VEGF levels were low in ranibizumab eyes (p = 0.99). Ischemic retinas showed a significantly lower retinal ganglion cell number (RGC; IF Brn-3a: p<0.001, IF RBPMS: p<0.001; PCR: p = 0.002). The ranibizumab group displayed fewer RGCs (IF Brn-3a: 0.3, IF RBPMS: p<0.001; PCR: p = 0.007), but more than the ischemia group (IF Brn-3a: p = 0.04, IF RBPMS: p = 0.03). Photoreceptor area was decreased after ischemia (IF: p = 0.049; PCR: p = 0.511), while the ranibizumab group (IF: p = 0.947; PCR: p = 0.122) was comparable to controls. In the ischemia (p<0.001) and ranibizumab group (p<0.001) a decrease of ChAT+ amacrine cells was found, which was less prominent in the ranibizumab group. VEGF-receptor 2 (VEGF-R2; IF: p<0.001; PCR: p = 0.021) and macroglia (GFAP; IF: p<0.001; PCR: p<0.001) activation was present in ischemic retinas. The activation was weaker in ranibizumab retinas (VEGF-R2: IF: p = 0.1; PCR: p = 0.03; GFAP: IF: p = 0.1; PCR: p = 0.015). An increase in the number of total (IF: p = 0.003; PCR: p = 0.023) and activated microglia (IF: p<0.001; PCR: p = 0.009) was detected after ischemia. These levels were higher in the ranibizumab group (Iba1: IF: p<0.001; PCR: p = 0.018; CD68: IF: p<0.001; PCR: p = 0.004). Our findings demonstrate that photoreceptors and RGCs are protected by ranibizumab treatment. Only amacrine cells cannot be rescued. They seem to be particularly sensitive to ischemic damage and need maybe an earlier intervention. PMID- 28800632 TI - RADAR: A novel fast-screening method for reading difficulties with special focus on dyslexia. AB - Dyslexia is a developmental learning disorder of single word reading accuracy and/or fluency, with compelling research directed towards understanding the contributions of the visual system. While dyslexia is not an oculomotor disease, readers with dyslexia have shown different eye movements than typically developing students during text reading. Readers with dyslexia exhibit longer and more frequent fixations, shorter saccade lengths, more backward refixations than typical readers. Furthermore, readers with dyslexia are known to have difficulty in reading long words, lower skipping rate of short words, and high gaze duration on many words. It is an open question whether it is possible to harness these distinctive oculomotor scanning patterns observed during reading in order to develop a screening tool that can reliably identify struggling readers, who may be candidates for dyslexia. Here, we introduce a novel, fast, objective, non invasive method, named Rapid Assessment of Difficulties and Abnormalities in Reading (RADAR) that screens for features associated with the aberrant visual scanning of reading text seen in dyslexia. Eye tracking parameter measurements that are stable under retest and have high discriminative power, as indicated by their ROC (receiver operating characteristic) curves, were obtained during silent text reading. These parameters were combined to derive a total reading score (TRS) that can reliably separate readers with dyslexia from typical readers. We tested TRS in a group of school-age children ranging from 8.5 to 12.5 years of age. TRS achieved 94.2% correct classification of children tested. Specifically, 35 out of 37 control (specificity 94.6%) and 30 out of 32 readers with dyslexia (sensitivity 93.8%) were classified correctly using RADAR, under a circular validation condition (see section Results/Total Reading Score) where the individual evaluated was not included in the test construction group. In conclusion, RADAR is a novel, automated, fast and reliable way to identify children at high risk of dyslexia that is amenable to large-scale screening. Moreover, analysis of eye movement parameters obtained with RADAR during reading will likely be useful for implementing individualized treatment strategies and for monitoring objectively the success of chosen interventions. We envision that it will be possible to use RADAR as a sensitive, objective, and quantitative first pass screen to identify individuals with reading disorders that manifest with abnormal oculomotor reading strategies, like dyslexia. PMID- 28800634 TI - Utilizing the R/V Marcus G. Langseth's streamer to measure the acoustic radiation of its seismic source in the shallow waters of New Jersey's continental shelf. AB - Shallow water marine seismic surveys are necessary to understand a range of Earth processes in coastal environments, including those that represent major hazards to society such as earthquakes, tsunamis, and sea-level rise. Predicting the acoustic radiation of seismic sources in shallow water, which is required for compliance with regulations designed to limit impacts on protected marine species, is a significant challenge in this environment because of variable reflectivity due to local geology, and the susceptibility of relatively small bathymetric features to focus or shadow acoustic energy. We use data from the R/V Marcus G. Langseth's towed hydrophone streamer to estimate the acoustic radiation of the ship's seismic source during a large survey of the shallow shelf off the coast of New Jersey. We use the results to estimate the distances from the source to acoustic levels of regulatory significance, and use bathymetric data from the ship's multibeam system to explore the relationships between seafloor depth and slope and the measured acoustic radiation patterns. We demonstrate that existing models significantly overestimate mitigation radii, but that the variability of received levels in shallow water suggest that in situ real-time measurements would help improve these estimates, and that post-cruise revisions of received levels are valuable in accurately determining the potential acoustic impact of a seismic survey. PMID- 28800633 TI - Feeding-fasting dependent recruitment of membrane microdomain proteins to lipid droplets purified from the liver. AB - Lipid droplets (LDs) are cellular stores of neutral fat that facilitate lipid and protein trafficking in response to metabolic cues. Unlike other vesicles, the phospholipid membrane on the LD is a monolayer. Interestingly, this monolayer membrane has free cholesterol, and may therefore contain lipid microdomains that serve as a platform for assembling proteins involved in signal transduction, cell polarity, pathogen entry etc. In support of this, cell culture studies have detected microdomain-associated "raftophilic" proteins on LDs. However, the physiological significance of this observation has been unclear. Here we show that two proteins (Flotillin-1 and SNAP23) that bind to membrane microdomains associate differently with LDs purified from rat liver depending on the feeding/fasting state of the animal. Flotillin-1 increases on LDs in the fed state, possibly because LDs interact with the endoplasmic reticulum (ER), facilitating supply of flotillin-1 from ER to LDs. Interestingly, this increase in flotillin-1 is correlated with an increase in free cholesterol on the LDs in fed state. In opposite behaviour to flotillin-1, SNAP23 increases on LDs in the fasted state and this appears to mediate LD-mitochondria interactions. Such LD mitochondria interactions may provide fatty acids to mitochondria for promoting beta-oxidation in hepatocytes in response to fasting. Our work brings out physiologically relevant aspects of lipid droplet biology that are different from, and may not be entirely possible to replicate and study in cell culture. PMID- 28800635 TI - Design of a cosmetic glove stiffness compensation mechanism for toddler-sized hand prostheses. AB - The addition of a cosmetic glove to an upper limb prosthesis has a distinct effect on the cosmetic value, but its viscoelastic behaviour adds a substantial amount of stiffness and hysteresis to the system. As a result, the overall usability of the prosthesis is degraded. A novel negative stiffness element is designed to compensate for the cosmetic glove's stiffness. A combination of linear helical springs and the concept of rolling link mechanisms has resulted in a Rolling Stiffness Compensation Mechanism (RSCM). Results show that the RSCM is capable of exerting a progressive negative stiffness characteristic and can be built small enough to fit inside a 33 mm diameter wrist. Using the RSCM, an otherwise voluntary opening toddler-sized prosthesis is converted into a voluntary closing device, reducing maximum operation forces down to 40 N with a combined efficiency of 52%. Further adjustments to the design are possible to further improve the efficiency of the mechanism. Moreover, changes in geometric relations of the mechanism offers possibilities for a wide range of prostheses and other applications. PMID- 28800636 TI - Combined sprint and resistance training abrogates age differences in somatotropic hormones. AB - The aim of this investigation was to compare serum growth hormone (GH), insulin like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-3 (IGFBP-3) in response to a combined sprint and resistance training (CSRT) program in young and middle-aged men.Thirty-eight healthy, moderately trained men participated in this study. Young and middle-aged men were randomly assigned to, a young training group (YT = 10, 21.4+/-1.2yrs) ora young control group (YC = 9, 21.6+/-1.8 yrs), a middle-aged training group (MAT = 10, 40.4+/-2.1 yrs) or a middle-aged control group (MAC = 9, 40.5+/-1.8 yrs). Participants performed the Wingate Anaerobic Test (WAnT) before and after a 13-week CSRT program (three sessions per week). Blood samples were collected at rest, after warm-up, immediately post-WAnT, and 10 min post-WAnT. CSRT induced increases in GH at rest and in response to the WAnT in YT and MAT (P<0.05). CSRT-induced increases were observed for IGF-1 and IGFBP-3 at rest in MAT only (P<0.05). Pre-training, GH, IGF-1 and IGFBP-3 were significantly higher at rest and in response to the WAnT in young participants as compared to their middle-aged counterparts (P<0.05). Post-training, YT and MAT had comparable basal GH (P>0.05). In response to the WAnT, amelioration of the age-effect was observed between YT and MAT for IGF-1 and IGF-1/IGFBP-3 ratio following CSRT (P>0.05). These data suggest that CSRT increases the activity of the GH/IGF-1 axis at rest and in response to the WAnT in young and middle-aged men. In addition, CSRT reduces the normal age-related decline of somatotropic hormones in middle-age men. PMID- 28800638 TI - Exact correspondence between walk in nucleotide and protein sequence spaces. AB - In the course of evolution, genes traverse the nucleotide sequence space, which translates to a trajectory of changes in the protein sequence in protein sequence space. The correspondence between regions of the nucleotide and protein sequence spaces is understood in general but not in detail. One of the unexplored questions is how many sequences a protein can reach with a certain number of nucleotide substitutions in its gene sequence. Here I propose an algorithm to calculate the volume of protein sequence space accessible to a given protein sequence as a function of the number of nucleotide substitutions made in the protein-coding sequence. The algorithm utilizes the power of the dynamic programming approach, and makes all calculations within a couple of seconds on a desktop computer. I apply the algorithm to green fluorescence protein, and get the number of sequences four times higher than estimated before. However, taking into account the astronomically huge size of the protein sequence space, the previous estimate can be considered as acceptable as an order of magnitude estimation. The proposed algorithm has practical applications in the study of evolutionary trajectories in sequence space. PMID- 28800637 TI - Biologically active recombinant human erythropoietin expressed in hairy root cultures and regenerated plantlets of Nicotiana tabacum L. AB - Hairy root culture is a potential alternative to conventional mammalian cell culture to produce recombinant proteins due to its ease in protein recovery, low costs and absence of potentially human pathogenic contaminants. The current study focussed to develop a new platform of a hairy root culture system from Nicotiana tabacum for the production of recombinant human EPO (rhEPO), which is regularly produced in mammalian cells. The human EPO construct was amplified with C terminal hexahistidine tag from a cDNA of Caco-2 cells. Two versions of rhEPO clones, with or without the N-terminal calreticulin (cal) fusion sequence, were produced by cloning the amplified construct into gateway binary vector pK7WG2D. Following Agrobacterium rhizogenes mediated transformation of tobacco explants; integration and expression of constructs in hairy roots were confirmed by several tests at DNA, RNA and protein levels. The amount of intracellular rhEPO from hairy root cultures with cal signal peptide was measured up to 66.75 ng g-1 of total soluble protein. The presence of the ER signal peptide (cal) was essential for the secretion of rhEPO into the spent medium; no protein was detected from hairy root cultures without ER signal peptide. The addition of polyvinylpyrrolidone enhanced the stabilization of secreted rhEPO leading to a 5.6 fold increase to a maximum concentration of 185.48 pg rhEPOHR g-1 FW hairy root cultures. The rhizo-secreted rhEPO was separated by HPLC and its biological activity was confirmed by testing distinct parameters for proliferation and survival in retinal pigment epithelial cells (ARPE). In addition, the rhEPO was detected to an amount 14.8 ng g-1 of total soluble leaf protein in transgenic T0 generation plantlets regenerated from hairy root cultures with cal signal peptide. PMID- 28800639 TI - Mitochondrial impairment and melatonin protection in parkinsonian mice do not depend of inducible or neuronal nitric oxide synthases. AB - MPTP-mouse model constitutes a well-known model of neuroinflammation and mitochondrial failure occurring in Parkinson's disease (PD). Although it has been extensively reported that nitric oxide (NO?) plays a key role in the pathogenesis of PD, the relative roles of nitric oxide synthase isoforms iNOS and nNOS in the nigrostriatal pathway remains, however, unclear. Here, the participation of iNOS/nNOS isoforms in the mitochondrial dysfunction was analyzed in iNOS and nNOS deficient mice. Our results showed that MPTP increased iNOS activity in substantia nigra and striatum, whereas it sharply reduced complex I activity and mitochondrial bioenergetics in all strains. In the presence of MPTP, mice lacking iNOS showed similar restricted mitochondrial function than wild type or mice lacking nNOS. These results suggest that iNOS-dependent elevated nitric oxide, a major pathological hallmark of neuroinflammation in PD, does not contribute to mitochondrial impairment. Therefore, neuroinflammation and mitochondrial dysregulation seem to act in parallel in the MPTP model of PD. Melatonin administration, with well-reported neuroprotective properties, counteracted these effects, preventing from the drastic changes in mitochondrial oxygen consumption, increased NOS activity and prevented reduced locomotor activity induced by MPTP. The protective effects of melatonin on mitochondria are also independent of its anti-inflammatory properties, but both effects are required for an effective anti parkinsonian activity of the indoleamine as reported in this study. PMID- 28800640 TI - Knockdown of the Plasmodium falciparum SURFIN4.1 antigen leads to an increase of its cognate transcript. AB - The genome of the malaria parasite Plasmodium falciparum contains the surf gene family which encodes large transmembrane proteins of unknown function. While some surf alleles appear to be expressed in sexual stages, others occur in asexual blood stage forms and may be associated to virulence-associated processes and undergo transcriptional switching. We accessed the transcription of surf genes along multiple invasions by real time PCR. Based on the observation of persistent expression of gene surf4.1, we created a parasite line which expresses a conditionally destabilized SURFIN4.1 protein. Upon destabilization of the protein, no interference of parasite growth or morphological changes were detected. However, we observed a strong increase in the transcript quantities of surf4.1 and sometimes of other surf genes in knocked-down parasites. While this effect was reversible when SURFIN4.1 was stabilized again after a few days of destabilization, longer destabilization periods resulted in a transcriptional switch away from surf4.1. When we tested if a longer transcript half-life was responsible for increased transcript detection in SURFIN4.1 knocked-down parasites, no alteration was found compared to control parasite lines. This suggests a specific feedback of the expressed SURFIN protein to its transcript pointing to a novel type of regulation, inedited in Plasmodium. PMID- 28800641 TI - High RBM3 expression is associated with an improved survival and oxaliplatin response in patients with metastatic colorectal cancer. AB - BACKGROUND: High expression of the RNA-binding motif protein 3 (RBM3) has been shown to correlate, with prolonged survival in several malignant diseases and with the benefit of platinum-based chemotherapy in ovarian cancer. The aim of this study was to evaluate RBM3 in metastatic colorectal cancer (mCRC) as a prognostic factor for overall survival and in relation to benefit of first-line chemotherapy. METHODS: Immunohistochemical staining was conducted and evaluated in tumours from 455 mCRC patients. Kaplan-Meier analysis and Cox regression proportional hazards models were used to access the impact of RBM3 expression on overall survival (OS) and progression-free survival (PFS). RESULTS: High RBM3 expression, both nuclear and cytoplasmic, was an independent prognostic factor for prolonged OS (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.50-0.90 and HR 0.66, 95% CI 0.48-0.91, respectively). PFS was significantly longer in patients with high RBM3 expression who had received first-line oxaliplatin based treatment, compared to those who had received irinotecan based treatment, both regarding nuclear and cytoplasmic expression (p-value 0.020 and 0.022 respectively). CONCLUSION: High RBM3 expression is an independent predictor of prolonged survival in mCRC patients, in particular in patients treated with first line oxaliplatin based chemotherapy. PMID- 28800642 TI - Cost-effectiveness evaluation of bovine tuberculosis surveillance in wildlife in France (Sylvatub system) using scenario trees. AB - Bovine tuberculosis (bTB) is a common disease in cattle and wildlife, with health, zoonotic and economic implications. Infected wild animals, and particularly reservoirs, could hinder eradication of bTB from cattle populations, which could have an important impact on international cattle trade. Therefore, surveillance of bTB in wildlife is of particular importance to better understand the epidemiological role of wild species and to adapt the control measures. In France, a bTB surveillance system for free-ranging wildlife, the Sylvatub system, has been implemented since 2011. It relies on three surveillance components (SSCs) (passive surveillance on hunted animals (EC-SSC), passive surveillance on dead or dying animals (SAGIR-SSC) and active surveillance (PSURV-SSC)). The effectiveness of the Sylvatub system was previously assessed, through the estimation of its sensitivity (i.e. the probability of detecting at least one case of bTB infection by each SSC, specie and risk-level area). However, to globally assess the performance of a surveillance system, the measure of its sensitivity is not sufficient, as other factors such as economic or socio economic factors could influence the effectiveness. We report here an estimation of the costs of the surveillance activities of the Sylvatub system, and of the cost-effectiveness of each surveillance component, by specie and risk-level, based on scenario tree modelling with the same tree structure as used for the sensitivity evaluation. The cost-effectiveness of the Sylvatub surveillance is better in higher-risk departments, due in particular to the higher probability of detecting the infection (sensitivity). Moreover, EC-SSC, which has the highest unit cost, is more efficient than the surveillance enhanced by the SAGIR-SSC, due to its better sensitivity. The calculation of the cost-effectiveness ratio shows that PSURV-SSC remains the most cost-effective surveillance component of the Sylvatub system, despite its high cost in terms of coordination, sample collection and laboratory analysis. PMID- 28800643 TI - Social disadvantage and the black-white disparity in spontaneous preterm delivery among California births. AB - We examined the contribution of social disadvantage to the black-white disparity in preterm birth. Analyses included linked vital and hospital discharge records from 127,358 black and 615,721 white singleton California births from 2007-11. Odds ratios (OR) were estimated by 4 logistic regression models for 2 outcomes: early (<32 wks) and moderate (32-36 wks) spontaneous preterm birth (ePTB, mPTB), stratified by 2 race-ethnicity groups (blacks and whites). We then conducted a potential impact analysis. The OR for less than high school education (vs. college degree) was 1.8 (95% confidence interval 1.6, 2.1) for ePTB among whites but smaller for the other 3 outcome groups (ORs 1.3-1.4). For all 4 groups, higher census tract poverty was associated with increased odds (ORs 1.03-1.05 per 9% change in poverty). Associations were less noteworthy for the other variables (payer, and tract percent black and Gini index of income inequality). Setting 3 factors (education, poverty, payer) to 'favorable' values was associated with lower predicted probability of ePTB (25% lower among blacks, 31% among whites) but a 9% higher disparity, compared to probabilities based on observed values; for mPTB, respective percentages were 28% and 13% lower probability, and 17% lower disparity. Results suggest that social determinants contribute to preterm delivery and its disparities, and that future studies should focus on ePTB and more specific factors related to social circumstances. PMID- 28800644 TI - Cytokine and hormonal regulation of bone marrow immune cell Wnt10b expression. AB - BACKGROUND & AIMS: Wnt10b is a crucial regulator of bone density through its ability to promote osteoblastogenesis. Parathyroid hormone has been shown to regulate Wnt10b expression in CD8+ T cells. However, the relative expression and other source(s) of Wnt10b in the bone marrow immune cells (BMICs) is unknown. Sex hormones and cytokines such as, estrogen and TNFalpha are critical regulators of bone physiology but whether they regulate BMIC Wnt10b expression is unclear. To determine the potential regulation of Wnt10b by estrogen and TNFalpha, we assessed Wnt10b expression by flow cytometry under estrogen- and TNFalpha deficient conditions. METHODS: Effects of TNFalpha was determined in male and female C57BL/6 wildtype and TNFalpha knockout mice. Effect of estrogen was investigated 4, 6 and 8 weeks post-surgery in ovariectomized Balb/c mice. Intracellular Wnt10b was detected using goat anti-mouse Wnt10b and a conjugated secondary antibody and analyzed by flow cytometry. RESULTS: Wnt10b expression was sex- and lineage-specific. Females had 1.8-fold higher Wnt10b signal compared to males. Percent of Wnt10b+ myeloid cells was higher in females than males (8.9% Vs 5.4%) but Wnt10b+ lymphoid cells was higher in males than females (6.3% Vs 2.5%). TNFalpha ablation in males increased total BM Wnt10b expression 1.5-fold but significantly reduced the percentage of BM Wnt10b+ CD4+ T cells (65%), CD8+ T cells (59%), dendritic cells (59%), macrophages (56%) and granulocytes (52%). These effects of TNFalpha on Wnt10b were observed only in males. In contrast to TNFalpha, estrogen-deficiency had indirect effects on BMIC Wnt10b levels; reducing the average percentage of BM Wnt10b+ CD8+ T cells (25%) and granulocytes (26%) across an 8-week time course. CONCLUSION: Our results demonstrate unique cell type- and sex-dependent effects on BMIC Wnt10b expression. Together, our results reveal myeloid cells in the bone marrow as an important source of Wnt10b under complex hormonal and cytokine regulation. PMID- 28800646 TI - Heritability of Retinal Vascular Fractals: A Twin Study. AB - Purpose: To determine the genetic contribution to the pattern of retinal vascular branching expressed by its fractal dimension. Methods: This was a cross-sectional study of 50 monozygotic and 49 dizygotic, same-sex twin pairs aged 20 to 46 years. In 50 degrees , disc-centered fundus photographs, the retinal vascular fractal dimension was measured using the box-counting method and compared within monozygotic and dizygotic twin pairs using Pearson correlation coefficients. Falconer's formula and quantitative genetic models were used to determine the genetic component of variation. Results: The mean fractal dimension did not differ statistically significantly between monozygotic and dizygotic twin pairs (1.505 vs. 1.495, P = 0.06), supporting that the study population was suitable for quantitative analysis of heritability. The intrapair correlation was markedly higher (0.505, P = 0.0002) in monozygotic twins than in dizygotic twins (0.108, P = 0.46), corresponding to a heritability h2 for the fractal dimension of 0.79. In quantitative genetic models, dominant genetic effects explained 54% of the variation and 46% was individually environmentally determined. Conclusions: In young adult twins, the branching pattern of the retinal vessels demonstrated a higher structural similarity in monozygotic than in dizygotic twin pairs. The retinal vascular fractal dimension was mainly determined by genetic factors, which accounted for 54% of the variation. The genetically predetermination of the retinal vasculature may affect the retinal response to potential vascular disease in later life. PMID- 28800645 TI - Analysis of endogenous lipids during intestinal wound healing. AB - Intestinal wound healing is a new therapeutic goal for inflammatory bowel disease (IBD) as complete healing of the mucosa is the key element of clinical remission in IBD. Previous studies showed that termination of inflammation can be achieved by adding pro-resolving lipids like DHA and EPA exogenously. However, the roles of these lipids in mucosal healing have not been investigated. To recapitulate intestinal healing process, mice were received dextran sodium sulfate (DSS) for 7 days in the drinking water followed by regular tap water for 5 additional days. DSS-induced intestinal inflammation featuring body weight loss, histological tissue damage, increased cytokine production and infiltration of inflammatory cells was gradually reduced upon switching to water. To investigate whether endogenous lipids play a role in mucosal healing, the lipidomics analysis of mouse serum was performed. Reduced levels of arachidonic acid, the biosynthetic precursor of prostaglandin F (PGF)2alpha, 19H-PGF1alpha, the metabolite of prostacyclin, and 20H-PGF2alpha, the metabolite of PGF2alpha, suggest subsiding inflammation. In contrast, increased levels of an active metabolite of resolvin D1 along with decreased levels of its precursor DHA as well as decreased levels of the precursor of resolvin E, 18-hydroxy-eicosapentaenoic acid, suggest inauguration of mucosal healing by endogenous lipids. Furthermore, exogenously supplied fish oil enhanced the process even further. These results suggest the presence of mucosal healing regulated by endogenous pro-healing lipids and also indicate that the remission state of IBD could be prolonged by enhancing the levels of these lipids. PMID- 28800647 TI - Effects of Vitrectomy and Lensectomy on Older Rhesus Macaques: Oxygen Distribution, Antioxidant Status, and Aqueous Humor Dynamics. AB - Purpose: The purpose of this study is to evaluate effects of vitrectomy (PPV) and lens extraction with intraocular lens implantation (PE/IOL) on molecular oxygen (pO2) distribution, aqueous humor antioxidant-oxidant balance, aqueous humor dynamics, and histopathologic changes in the trabecular meshwork (TM) in the older macaque monkey. Methods: Six rhesus monkeys underwent PPV followed by PE/IOL. pO2, outflow facility, and intraocular pressure (IOP) were measured. Aqueous and vitreous humor specimens were analyzed for antioxidant status and 8 hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative damage. TM specimens were obtained for immunohistochemical and quantitative PCR analysis. Results: pO2 at baseline revealed steep gradients in the anterior chamber and low levels in the posterior chamber (PC) and around the lens. Following PPV and PE/IOL, pO2 significantly increased in the PC, around the IOL, and angle. IOP increased following both surgical interventions, with no change in outflow facility. Histopathologic analysis did not show changes in TM cell quantification, but there was an increase in 8-OHdG. Quantitative PCR did not reveal significant differences in glaucoma-related gene expression. Aqueous and vitreous humor analysis revealed decreased ascorbate and total reactive antioxidant potential and increased 8-OHdG in the aqueous humor only in the surgical eyes. Conclusions: Oxygen distribution in the older rhesus monkey is similar to humans at baseline and following surgical interventions. Our findings of histopathologic changes of TM oxidative damage and alterations in the oxidant-antioxidant balance suggest a potential correlation of increased oxygen exposure with oxidative stress/damage and the development of open angle glaucoma. PMID- 28800648 TI - Fundus Autofluorescence Findings in Eyes With Birdshot Chorioretinitis. AB - Purpose: The purpose of this study was to describe fundus autofluorescence (FAF) findings in eyes with birdshot chorioretinitis (BSCR) and to compare findings to demographic, medical, and clinical characteristics. Methods: In this multicenter, prospective, cross-sectional study, 172 eyes (86 patients) with BSCR were investigated. Participants underwent a standardized evaluation including collection of demographic data, ophthalmic and treatment history, and ophthalmologic examination. Using a standardized protocol, hypo- and hyperautofluorescence in macular and extramacular regions and specific patterns of abnormal FAF could be scored for 167 eyes. Images were scored by two independent, masked graders. Measures of visual function included best-corrected visual acuity (BCVA), contrast sensitivity (CS), color vision, and Humphrey visual field mean deviation (HVF-MD). Results: Any abnormal FAF finding was observed in 132 eyes (79.0%); macular abnormalities were observed in 84 eyes (49.1%). The most common findings were peripapillary confluent hypoautofluorescence (122 eyes [73.1%]); extramacular granular hypoautofluorescence (100 eyes [59.9%]); and macular granular hypoautofluorescence (67 eyes [40.1%]). Confluent hypoautofluorescence was related to longer median disease duration (8.7 years) than granular hypoautofluorescence (7.9 years) or hyperautofluorescence (5.6 years). Macular confluent hypoautofluorescence was associated with BCVA <=20/25 (odds ratio [OR] = 7.83, P = 0.007), BCVA <=20/50 (OR = 4.94, P = 0.002), and abnormal CS (OR = 4.56, P = 0.009). Presence of macular or extramacular hypoautofluorescence was related to HVF-MD <=-3 dB (OR = 2.43, P = 0.01 and OR = 2.89, P = 0.003, respectively). Conclusions: In this large cohort, various FAF abnormalities were found, indicating that disorders of the retinal pigment epithelium are features of BSCR. Abnormal FAF is a marker of visual dysfunction in the disease. PMID- 28800649 TI - Birdshot Chorioretinitis and Fundus Autofluorescence: Novel Insights Into Disease Pathogenesis. PMID- 28800650 TI - Peptide Nucleic Acid-Fluorescence In Situ Hybridization for Detection of Staphylococci From Endophthalmitis Isolates: A Proof-of-Concept Study. AB - Purpose: Rapid identification of pathogens causing endophthalmitis may improve treatment outcomes through early administration of species-specific medication. The current study reports a new molecular application of peptide nucleic acid fluorescence in situ hybridization (PNA-FISH) with Staphylococcus-specific molecular PNA probes for the potential rapid detection of common pathogens causing endophthalmitis. Methods: An experimental study was designed to evaluate the proof of concept at the microbiology laboratory of the Bascom Palmer Eye Institute. Stored culture-positive staphylococci endophthalmitis isolates obtained from prior vitreous samples (n = 15), along with broth as negative controls (n = 5) were used. Inoculum was prepared to a final concentration of 1 * 105 colony-forming units/mL to ensure that the isolates were viable. Smears of samples were fixed and hybridized using QuickFISH protocol with probes for Staphylococcus. Results: With PNA-FISH technique, Staphylococcus aureus was identified in 9 of 10 samples and coagulase-negative staphylococci were identified in 10 of 10 samples. Detection time was 20 minutes. Conclusions: This study serves a proof of concept using a new microbial detection system with FISH probes, and may have the potential for clinical use in the rapid and accurate identification of isolates from patients with endophthalmitis. PMID- 28800652 TI - [Hypothenar hammer syndrome as incidental finding in hand surgery]. PMID- 28800651 TI - Vertical Macular Asymmetry Measures Derived From SD-OCT for Detection of Early Glaucoma. AB - Purpose: To test the hypothesis that vertical asymmetry in macular ganglion cell/inner plexiform layer (GCIPL) thickness can improve detection of early glaucoma. Methods: Sixty-nine normal eyes and 101 glaucoma eyes had macular imaging with spectral-domain optical coherence tomography (OCT; 200 * 200 cube). The resulting GCIPL thickness matrix was grouped into a 20 * 20 superpixel array and superior superpixels were compared to their inferior counterparts. A global asymmetry index (AI) was defined as the grand mean of the asymmetry ratios. To measure local asymmetry, the corresponding thickness measurements of three rows above and below the horizontal raphe were compared individually and in combinations. Global and local AIs were compared to the best-performing GCIPL thickness parameters with area under the receiver operating curves (AUC) and sensitivity/specificities. Results: Age or axial length did not influence AIs in normal subjects (P >= 0.08). Global and local AIs were significantly higher in the glaucoma group compared to normal eyes. Minimum (AUC = 0.962, 95% confidence interval [CI]: 0.936-0.989) and inferotemporal thickness (AUC = 0.944, 95% CI: 0.910-0.977; P = 0.122) performed best for detection of early glaucoma. The AUC for global AI was 0.851 (95% CI: 0.792-0.909) compared to 0.916 (95% CI: 0.874 0.958) for the best local AI. Combining minimum or inferotemporal GCIPL thickness and the best local AI led to higher partial AUCs (0.088 and 0.085, 90% specificity, P = 0.120 and 0.130, respectively) than GCIPL thickness measures. Conclusions: Macular vertical thickness asymmetry measures did not perform better than sectoral or minimum GCIPL thickness for detection of early glaucoma. Combining local asymmetry parameters with the best sectoral GCIPL thickness measures enhanced this task. PMID- 28800654 TI - ? PMID- 28800655 TI - [Further Development of Modern Refractive Lens Surgery]. PMID- 28800656 TI - [Interpretation of the Intraocular Lens Constants for the Haigis Formula]. AB - Background The Haigis formula uses a linear regression with three IOL constants for the prediction of the effective lens position (ELP) of the intraocular lens (IOL), ELP ~ a0 + a1 ACD + a2 L. It is based on the preoperative anterior chamber depth (ACD) and axial length (L). Material and Methods Differences between IOL constant triplets can be judged based on their statistical measurement uncertainty. To investigate, if the estimation of the average ELP with the help of the average ACD and average L according to ~ a0 + a1 + a2 provides a possible alternative, we have compared both methods. The results based on two different strategies for optimisation of the IOL constants a0, a1, a2 are used for illustration. Results The estimation of the average ELP is suitable for basic categorisation of the IOL constants. The confidence-volumes in shape of ellipsoids based on the statistical measurement uncertainties of the IOL constant optimisations allow a better comparison between IOL constant triplets a0, a1, a2. PMID- 28800657 TI - ? PMID- 28800658 TI - Spontaneous Labor Onset and Outcomes in Obese Women at Term. AB - OBJECTIVE: The objective of this study was to compare the rates of spontaneous labor onset and its progression in obese and nonobese women after 37 weeks. STUDY DESIGN: We performed a secondary analysis of a retrospective cohort of all women who were admitted for delivery at >= 37 weeks of gestation at a university-based tertiary care center between 2004 and 2010. The cohort was stratified by weeks of gestation at which the patient presented for delivery. The rates of spontaneous labor, vaginal delivery, and augmentation with oxytocin were compared between obese (body mass index [BMI] >= 30) and nonobese (BMI < 30) women. RESULTS: Obese women had lower rates of spontaneous labor than nonobese women at every gestational week (37 weeks, 6.1 vs. 9.3%, p < 0.001; 38 weeks, 12.8 vs. 19.2%, p < 0.001; 39 weeks 26.0 vs. 37.0%, p < 0.001; 40 weeks, 39.6 vs. 50.2%, p < 0.001; 41 weeks, 30.8 vs. 38.0%, p < 0.012). Among women who presented in spontaneous labor, obesity was associated with higher rates of augmentation with oxytocin and lower rates of vaginal delivery. CONCLUSION: Obese women at or beyond 37 weeks are less likely to experience spontaneous labor compared with nonobese women. In addition, obese women presenting in spontaneous labor are less likely that nonobese women to have a vaginal delivery at 37 to 40 weeks, even after oxytocin augmentation. PMID- 28800659 TI - Neonatal-Onset Recurrent Guillain-Barre Syndrome-Like Disease: Clues for Inherited CD59 Deficiency. PMID- 28800660 TI - [Eye Drops Instead of Intravitreal Injections? The Dream of Treating Macular Diseases by Topically Administered Drugs]. AB - Background The introduction of VEGF inhibitors revolutionized treatment for age related macular degeneration. However, it requires regular intravitreal (IVT) injections. Hence, replacement of IVT injections by topical, non-invasive eye drop treatment is subject to intensive research. Material and Methods Literature and database research on topical therapies for neovascular AMD. Results Several clinical projects with topical inhibitors of the VEGF pathway were initiated recently. Several candidate molecules were investigated and should have an efficacy potential in neovascular AMD given their ability to block the VEGF pathway. Preclinical experiments were quite promising. Still, translation into the clinical application has not been successful thus far. Differences in preclinical and clinical pharmacokinetics are assumed to be the major barrier to successful translation. In addition, specific algorithms for monitoring of disease activity are required for successful clinical implementation; otherwise, a topical therapy may reduce the IVT injection number, but patients would not gain independence through fewer office visits. Discussion It is required to refine the scientific basis including preclinical models and screening cascades. This will enable targeted selection of future candidates for clinical development. PMID- 28800662 TI - Jugular Foramen Meningioma with Transverse and Sigmoid Sinuses Invasion and Jugular Vein Extension. PMID- 28800661 TI - Cytotoxic Flavones from the Stem Bark of Bougainvillea spectabilis Willd. AB - Five new flavones possessing a fully substituted A-ring with C-6 and C-8 methyl groups, bougainvinones I - M (1: -5: ), along with three known congeners, 2' hydroxydemethoxymatteucinol (6: ), 5,7,3',4'-tetrahydroxy-3-methoxy-6,8 dimethylflavone (7: ) and 5,7,4'-trihydroxy-3-methoxy-6,8-dimethylflavone (8: ), were isolated from the EtOAc extract of the stem bark of Bougainvillea spectabilis. Their structures were established by means of spectroscopic data (ultraviolet, infrared, high-resolution electrospray ionization mass spectrometry, and one-dimensional and two-dimensional nuclear magnetic resonance) and single-crystal X-ray crystallographic analysis. The in vitro cytotoxicity of all isolated compounds against five cancer cell lines (KB, HeLa S-3, MCF-7, HT 29, and HepG2) was evaluated. Compound 5: showed promising cytotoxic activity against the KB and HeLa S-3 cell lines, with IC50 values of 7.44 and 6.68 uM. The other compounds exhibited moderate cytotoxicity against the KB cell line. PMID- 28800663 TI - Computational Fluid Dynamics of a Fatal Ruptured Anterior Communicating Artery Aneurysm. PMID- 28800664 TI - Outcomes of Cranioplasty with Preformed Titanium versus Freehand Molded Polymethylmethacrylate Implants. AB - OBJECTIVE: Cranioplasty reshapes the neurocranium and viscerocranium after craniectomy. Different materials have been used for cranioplasty. However, no consistent data are yet available comparing these different materials regarding indications, complications, and outcome. We report our experience with preformed titanium implants and freehand molded polymethylmethacrylate (PMMA) implants for cranioplasty. METHODS: This retrospective single-center analysis included 120 consecutive cranioplasty patients who had been operated between 2006 and 2013. A total of 60 patients (27 women, 33 men; mean age: 54 years) had received a preformed titanium implant and 60 patients (22 women, 38 men; mean age: 46 years) a freehand molded PMMA implant. We evaluated all demographic and procedure related data, indications, and outcome. The longest follow-up was 5.5 years. RESULTS: The most frequent indications for cranioplasty were trauma (n = 48 [40%]), malignant infarction (n = 27 [23%]), tumor (n = 22 [18%]), spontaneous intracerebral or aneurysmal subarachnoid hemorrhage (n = 16 [13%]), revision surgery (n = 5 [4%]), and empyema (n = 2 [2%]). PMMA implants were more often associated with wound-healing disorders (p < 0.023; odds ratio [OR]: 10.53) and epidural hematoma (p < 0.03; OR: 8.46), resulting in a significantly higher re operation rate (p < 0.005). Precise fitting was radiologically confirmed in 98% of titanium implants but in only 71% of PMMA implants (p < 0.001). Magnetic resonance imaging of patients with titanium implants (n = 4) did not show any relevant artifacts. CONCLUSION: Cranioplasty with preformed titanium implants seems to be superior to freehand molded PMMA implants regarding surgical morbidity, revision rate, and aesthetic results. PMID- 28800665 TI - Fusion Rates of Intervertebral Polyetheretherketone and Titanium Cages without Bone Grafting in Posterior Interbody Lumbar Fusion Surgery for Degenerative Lumbar Instability. PMID- 28800666 TI - Full Percutaneous Lumbar Interbody Fusion: Technical Note. PMID- 28800667 TI - [Not Available]. PMID- 28800668 TI - [Epidemiology, Risk Factors and Risk Stratification of Venous Thromboembolism in Pregnancy and the Puerperium]. AB - Venous thromboembolism (VTE) remains a leading cause of direct maternal deaths in the developed countries. The incidence of VTE has increased significantly during the past two decades. The absolute risk of VTE is estimated 0.6-2.2 per 1000 deliveries. Compared with age-matched non-pregnant women, the daily risk of VTE is increased 7- to 10-fold for antepartum VTE, but it is 15- to 35-fold for postpartum VTE. The incidence of pulmonary embolism (PE) during the first 6 weeks postpartum is nearly 15-fold higher compared to the incidence in pregnancy, and remains significantly increased up to 12 weeks postpartum. The case fatality rate of PE ranges from 2.2 to 6.6%.The basis of VTE prevention is careful assessment of individual risk factors of VTE and proper risk stratification.It is necessary to differentiate preexisting maternal from transient pregnancy-specific risk factors. Women with previous VTE or hereditary high-risk thrombophilias or with the antiphospholipid syndrome have the highest risk for VTE in pregnancy and the puerperium.Other most important pregnancy-specific risk factors in the antenatal period are severe ovarian hyperstimulation syndrome, hyperemesis, major surgery, severe comorbidities (e.g., systemic lupus erythematodes), hospitalization in women with a body mass index > 25 kg/m2, and inflammatory bowel diseases.Heart diseases, stillbirth, systemic infections, severe postpartum hemorrhage in combination with blood product replacement and/or surgery and emergency caesarean section are predominant risk factors in the postpartum period.Recommendations for risk stratification vary among current international guidelines. According to the SOGC (Society of Obstetricians and Gynaecologists of Canada) 2014, pharmacologic VTE prophylaxis is recommended if the estimated absolute risk of one or multiple risk factors is greater than 1%.The ACCP (American College of Chest Physicians) Guideline 2012 presents specific recommendations only for post-caesarean risk factor-based prophylaxis.The recent RCOG (Royal College of Obstetricians and Gynaecologists) Guideline No. 37a 2015 recommends risk stratification for VTE prophylaxis on the basis of a special risk scoring system weighting individual risk factors between one point (low risk) to a maximum of 4 points (very high risk).A check list of important risk factors and a management plan for thromboprophylaxis based on current guidelines should be readily available in each obstetric unit. PMID- 28800669 TI - ? AB - Fetal cardiac myxomas are very rare. To date there has been no representative description of fetal cardiac myxomas. The aim of this study is to highlight the clinical features, possible outcomes and the disparities from the adult cardiac myxomas and other fetal cardiac tumors.A comprehensive literature review yielded 27 reports including 32 cases of fetal cardiac myxomas.Apart from the same pedunculated and solitary nature and echogenic appearance, fetal cardiac myxomas differ from those in adults in many aspects, including tumor location, clinical manifestation and malignant potential. Fetal cardiac myxomas are the most common in the left ventricle and the least common in the left atrium. Tumor size and tumor site could be predictive risk factors of adverse cardiac events of fetuses.Their clinical courses are often benign with fewer cases of adverse cardiac events. Prenatal echocardiography is a reliable diagnostic technique, which can detect cardiac myxomas at as early as 18 weeks gestation. Differential diagnosis should be made from other types of fetal cardiac tumors. Postnatal cardiac myxoma resection may provide a good prognosis. PMID- 28800670 TI - [Oral Health and Pregnancy - Patient Survey using a Questionnaire]. AB - Introduction and Hypothesis This study investigated how well pregnant patients were informed about the causes and effects of gingivitis during pregnancy. Factors such as age, level of education and nationality were taken into account. Data was collected for the overall oral hygiene of the patients and differences between outpatient and inpatient pregnancies were shown. Possible risk factors in terms of birth results were also defined. Methods With the use of a questionnaire, 83 patients (40 outpatients/43 inpatients) were asked about their oral hygiene, as well as their knowledge pertaining to the causes and effects of gingivitis. Additionally, birth outcome data for 50 patients was collected for the purposes of this study. Results When the 2 groups were compared in terms of their knowledge about the effects of gingivitis, the inpatient participants were significantly better informed than the outpatient participants. The factor of education had a p-value of 0.016, meaning that this factor had a significant influence on the birth result. 24% of the participants were informed about good oral hygiene practices by their doctor or dentist. More than half of the participants subjectively perceived signs of an infection, such as bleeding gums while brushing their teeth. Furthermore, 31% of participants experienced nausea and vomiting, which is one of the common symptoms of morning sickness. 24% of participants stated that they improved their oral hygiene during pregnancy by using extra measures. 27% of participants had not had a dental check-up in over a year. Conclusion According to the present study, only 1 out of 4 women is informed by their gynaecologist about the importance of regular dental check-ups during pregnancy. This low rate of patients being informed about oral hygiene likely has to do with the gynaecologists being less informed about periodontal diseases, which therefore receive less attention and are less likely to be diagnosed. Thus, it would make sense for gynaecologists to recommend during the first pregnancy check-up that patients schedule an appointment with their dentist. The higher risk groups should be informed early on so as to motivate them to improve their oral hygiene. It is here that the collaboration between gynaecologists and dentists becomes especially important. PMID- 28800671 TI - [Outcomes of Planned Out-of-Hospital and Low-Risk Hospital Births in Lower Saxony]. AB - Introduction Internationally, there is debate on the safety of different birth settings inside and outside of hospitals. Low-risk women in Germany can choose where they give birth, and out-of-hospital births are especially necessary in regions lacking infrastructure. To date, national studies are required. Materials and Methods We investigated planned out-of-hospital (OH) and hospital births in Lower Saxony, Germany, in 2005. Women with a singleton fetus in the vertex position were included once they reached 34+0 gestational weeks. 1 273 out of 4 424 births were included via risk assessment. Outcomes were compared using Pearson's chi-squared test, the Mann-Whitney test, and logistic regression. Results 152 (36.6%) nulliparae (NP) and 263 (63.4%) multiparae (MP) gave birth out of hospital, 439 (51.2%) nulliparae and 419 (48.8%) multiparae in a hospital. 10.1% of women whose care started outside of the hospital needed a transfer to the hospital. Women who planned OH were older and had a higher level of education. Women without a migration background displayed an increased rate of out-of-hospital birth. A higher proportion received their antenatal care from midwives rather than medical doctors. Induction of labor was less likely for women with planned out-of-hospital births, as were other intrapartum interventions. In hospital births, fetal monitoring was more likely performed via cardiotocograph instead of intermittent auscultation. Duration of labor was significantly longer in OH births (median: NP: 9.01 h vs. 7.38 h; MP: 4.53 h vs. 4.25 h). Nulliparae had more spontaneous births out-of-hospital (94.7%) than in hospital (73.6%). There was no difference in adverse fetal outcomes, blood loss, and severe perineal lacerations. The perineum was less frequently intact in hospital births. Retained placenta was more often documented in out-of-hospital births. Conclusions In an out-of-hospital setting, fewer interventions were performed, spontaneous births occurred more often, and there was no difference in neonatal outcomes. OH birth appears reasonably safe with thorough pre-labor risk assessment and good transfer management. Some beneficial aspects of OH birth care (like continuity of care and restriction of routine interventions) could be adopted by hospital labor wards, leading to a higher rate of vaginal births and improved care. PMID- 28800672 TI - ? PMID- 28800674 TI - The genetic encoded toolbox for electron microscopy and connectomics. AB - Developments in bioengineering and molecular biology have introduced a palette of genetically encoded probes for identification of specific cell populations in electron microscopy. These probes can be targeted to distinct cellular compartments, rendering them electron dense through a subsequent chemical reaction. These electron densities strongly increase the local contrast in samples prepared for electron microscopy, allowing three major advances in ultrastructural mapping of circuits: genetic identification of circuit components, targeted imaging of regions of interest and automated analysis of the tagged circuits. Together, the gains from these advances can decrease the time required for the analysis of targeted circuit motifs by over two orders of magnitude. These genetic encoded tags for electron microscopy promise to simplify the analysis of circuit motifs and become a central tool for structure-function studies of synaptic connections in the brain. We review the current state-of-the art with an emphasis on connectomics, the quantitative analysis of neuronal structures and motifs. WIREs Dev Biol 2017, 6:e288. doi: 10.1002/wdev.288 For further resources related to this article, please visit the WIREs website. PMID- 28800673 TI - M-type K+ channels in peripheral nociceptive pathways. AB - : Pathological pain is a hyperexcitability disorder. Since the excitability of a neuron is set and controlled by a complement of ion channels it expresses, in order to understand and treat pain, we need to develop a mechanistic insight into the key ion channels controlling excitability within the mammalian pain pathways and how these ion channels are regulated and modulated in various physiological and pathophysiological settings. In this review, we will discuss the emerging data on the expression in pain pathways, functional role and modulation of a family of voltage-gated K+ channels called 'M channels' (KCNQ, Kv 7). M channels are increasingly recognized as important players in controlling pain signalling, especially within the peripheral somatosensory system. We will also discuss the therapeutic potential of M channels as analgesic drug targets. LINKED ARTICLES: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc/. PMID- 28800675 TI - Discovery and pharmacological characterization of a novel series of highly selective inhibitors of cyclin-dependent kinases 4 and 6 as anticancer agents. AB - BACKGROUND AND PURPOSE: Cyclin D-dependent kinases 4 and 6 (CDK4/6) are crucial regulators of the G1 to S phase transition of the cell cycle and are actively pursued as therapeutic targets in cancer. We sought to discover a novel series of orally bioavailable and highly selective small molecule inhibitors of CDK4/6. EXPERIMENTAL APPROACH: The discovery of pharmacological inhibitors and optimization for potency, selectivity and drug properties were achieved by iterative chemical synthesis, biochemical screening against a panel of kinases, cell-based assays measuring cellular viability, cell cycle distribution, induction of apoptosis and the level of retinoblastoma tumour suppressor protein (Rb) phosphorylation and E2 factor (E2F)-regulated gene expression and in vitro biopharmaceutical and in vivo pharmacokinetic profiling. KEY RESULTS: We discovered several lead compounds that displayed >1000-fold selectivity for CDK4/6 over other members of the CDK family. The lead compounds, 82, 91 and 95, potently inhibited the growth of cancer cells by inducing G1 arrest with a concomitant reduction in the phosphorylation of Rb at S780 and in E2F-regulated gene expression. With a remarkable selectivity for CDK4 over 369 human protein kinases, 91 was identified as a highly potent and orally bioavailable drug candidate. CONCLUSIONS AND IMPLICATIONS: We have identified unique and new inhibitors of CDK4/6 as potential drug candidates. Compound 91 represents an ideal candidate for further development as targeted cancer therapy. PMID- 28800676 TI - Development and Evaluation of Heartbeat: A Machine Perfusion Heart Preservation System. AB - Static cold storage is accompanied with a partial safe ischemic interval for donor hearts. In this current study, a machine perfusion system was built to provide a better preservation for the donor heart and assessment for myocardial function. Chinese mini-swine (weight 30-35 kg, n = 16) were randomly divided into HTK, Celsior, and Heartbeat groups. All donor hearts were respectively preserved for 8 hours under static cold storage or machine perfusion. The perfusion solution is aimed to maintain its homeostasis based on monitoring the Heartbeat group. The ultrastructure of myocardium suggests better myocardial protection in the Heartbeat group compared with HTK or Celsior-preserved hearts. The myocardial and coronary artery structural and functional integrity was evaluated by immunofluorescence and Western blots in the Heartbeat. In the Heartbeat group, donor hearts maintained a high adenosine triphosphate level. Bcl-2 and Beclin-1 protein demonstrates high expression in the Celsior group. The Heartbeat system can be used to preserve donor hearts, and it could guarantee the myocardial and endothelial function of hearts during machine perfusion. Translating Heartbeat into clinical practice, it is such as to impact on donor heart preservation for cardiac transplantation. PMID- 28800677 TI - Levothyroxine enhances glucose clearance and blunts the onset of experimental type 1 diabetes mellitus in mice. AB - BACKGROUND AND PURPOSE: Thyroid hormones induce several changes in whole body metabolism that are known to improve metabolic homeostasis. However, adverse side effects have prevented its use in the clinic. In view of the promising effects of thyroid hormones, we investigated the effects of levothyroxine supplementation on glucose homeostasis. EXPERIMENTAL APPROACH: C57BL/6 mice were treated with levothyroxine from birth to 24 weeks of age, when mice were killed. The effects of levothyroxine supplementation on metabolic health were determined. C57BL/6 mice treated with levothyroxine for 2 weeks and then challenged with streptozotocin to monitor survival. Mechanistic experiments were conducted in the pancreas, liver and skeletal muscle. RIP-B7.1 mice were treated with levothyroxine for 2 weeks and were subsequently immunized to trigger experimental autoimmune diabetes (EAD). Metabolic tests were performed. Mice were killed and metabolic tissues were extracted for immunohistological analyses. KEY RESULTS: Long-term levothyroxine supplementation enhanced glucose clearance and reduced circulating glucose in C57BL/6 mice. Levothyroxine increased simultaneously the proliferation and apoptosis of pancreatic beta cells, promoting the maintenance of a highly insulin-expressing beta cell population. Levothyroxine increased circulating insulin levels, inducing sustained activation of IRS1-AKT signalling in insulin-target tissues. Levothyroxine-treated C57BL/6 mice challenged with streptozotocin exhibited extended survival. Levothyroxine blunted the onset of EAD in RIP-B7.1 mice by inducing beta cell proliferation and preservation of insulin-expressing cells. CONCLUSIONS AND IMPLICATIONS: Interventions based on the use of thyroid hormones or thyromimetics could be explored to provide therapeutic benefit in patients with type 1 diabetes mellitus. PMID- 28800678 TI - New perspectives on the neurophysiology of primate amygdala emerging from the study of naturalistic social behaviors. AB - A major challenge of primate neurophysiology, particularly in the domain of social neuroscience, is to adopt more natural behaviors without compromising the ability to relate patterns of neural activity to specific actions or sensory inputs. Traditional approaches have identified neural activity patterns in the amygdala in response to simplified versions of social stimuli such as static images of faces. As a departure from this reduced approach, single images of faces were replaced with arrays of images or videos of conspecifics. These stimuli elicited more natural behaviors and new types of neural responses: (1) attention-gated responses to faces, (2) selective responses to eye contact, and (3) selective responses to touch and somatosensory feedback during the production of facial expressions. An additional advance toward more natural social behaviors in the laboratory was the implementation of dyadic social interactions. Under these conditions, neurons encoded similarly rewards that monkeys delivered to self and to their social partner. These findings reinforce the value of bringing natural, ethologically valid, behavioral tasks under neurophysiological scrutiny. WIREs Cogn Sci 2018, 9:e1449. doi: 10.1002/wcs.1449 This article is categorized under: Psychology > Emotion and Motivation Neuroscience > Cognition Neuroscience > Physiology. PMID- 28800681 TI - Time-frequency dynamics of the sum of intra- and extracerebral hemodynamic functional connectivity during resting-state and respiratory challenges assessed by multimodal functional near-infrared spectroscopy. PMID- 28800679 TI - Butyrate protects against disruption of the blood-milk barrier and moderates inflammatory responses in a model of mastitis induced by lipopolysaccharide. AB - BACKGROUND AND PURPOSE: Short-chain fatty acids are fermentation end products produced by gut bacteria, which have been shown to ameliorate inflammatory bowel diseases and allergic asthma. However, the mechanism involved remains largely unknown. Here, we investigate the protective effects and mechanisms of sodium butyrate (SB) on LPS-induced mastitis model. EXPERIMENTAL APPROACH: Effects of increasing doses of SB on blood-milk barrier function and inflammation are studied in BALB/c mice with LPS-induced mastitis. The underlying mechanisms of anti-inflammatory effects of SB were further investigated in LPS-stimulated mouse mammary epithelial cells (mMECs). KEY RESULTS: The results show that SB decreased LPS-induced disruption in mammary tissues, infiltration of inflammatory cells and the levels of TNF-alpha, IL-6 and IL-1beta. SB up-regulated the tight junction proteins occludin and claudin-3 and reduced blood-milk barrier permeability in LPS-induced mastitis. Studies in vitro revealed that SB inhibited LPS-induced inflammatory response by inhibition of the NF-kappaB signalling pathway and histone deacetylases in LPS-stimulated mMECs. CONCLUSIONS AND IMPLICATIONS: In our model, SB protected against LPS-induced mastitis by preserving blood-milk barrier function and depressing pro-inflammatory responses, suggesting the potential use of SB as a prophylactic agent to protect blood-milk barrier function in mastitis. PMID- 28800680 TI - Pharmacological inhibition of focal segmental glomerulosclerosis-related, gain of function mutants of TRPC6 channels by semi-synthetic derivatives of larixol. AB - BACKGROUND AND PURPOSE: Gain of function mutations in TRPC6 channels can cause autosomal dominant forms of focal segmental glomerulosclerosis (FSGS). Validated inhibitors of TRPC6 channels that are biologically active on FSGS-related TRPC6 mutants are eagerly sought. EXPERIMENTAL APPROACH: We synthesized new TRPC6 inhibiting modulators from larixol, a resiniferous constituent of Larix decidua, and tested the potency and selectivity in cell lines stably expressing various TRPC channel isoforms. Channel activation was followed by Ca2+ influx analyses and electrophysiological recordings. The most promising compound larixyl carbamate (LC) was tested on native TRPC6 channels and TRPC6 constructs carrying FSGS-related point mutations. KEY RESULTS: LC exhibited an about 30-fold preference for TRPC6 over TRPC3 channels and a fivefold preference for TRPC6 over TRPC7 channels. Six FSGS-related TRPC6 mutants, including the highly active M132T and R175Q variants, were strongly inhibited by 1 MUM LC. Surprisingly, no TRPC6 related Ca2+ signals were detectable in primary murine podocytes, or in acutely isolated glomeruli. in these preparations. Quantitative PCR revealed a 20-fold to 50-fold lower abundance of TRPC6 transcripts in rat or mouse podocytes, compared with pulmonary artery smooth muscle cells from the same species. Accordingly, electrophysiological recordings demonstrated that DAG-induced currents in murine podocytes are very small, but sensitive to LC. CONCLUSIONS AND IMPLICATIONS: In spite of their low abundance in native podocytes, native TRPC6 channels are targetable using larixol-derived TRPC6 inhibitors. As observed with wild-type TRPC6 channels, FSGS-related TRPC6 mutants were sensitive to the newly developed inhibitors, paving the way for experimental therapies. PMID- 28800682 TI - Corrigendum to "Neural activation in speech production and reading aloud in native and non-native languages" [J. Neuroimage 112 (2015) 208-217]. PMID- 28800683 TI - Erratum to "Subfields of the hippocampal formation at 7T MRI: In vivo volumetric assessment" [NeuroImage 61 (2012) 1043-1049]. PMID- 28800684 TI - Sediment Zn-release during post-drought re-flooding: Assessing environmental risk to Hyalella azteca and Daphnia magna. AB - Hydrologic variability exacerbated by climate change affects biogeochemical cycling in sediments through changes in pH, redox, and microbial activity. These alterations affect the lability and speciation of metals, such that toxicity may be observed in otherwise non-toxic sediments. In this study, we investigate the effects of drought and reflooding on metal bioavailability in sediments with low to moderate concentrations of Zn (18-270 mg kg-1). Sediments were collected from coastal wetlands in Michigan, dried (36-days) and re-inundated in lab microcosms. We investigated the relationships between key parameters, for surface/porewater (dissolved and particulate metals, dissolved oxygen, redox (Eh), reduced iron, and temperature) and sediment (simultaneously extracted metals (SEM), acid volatile sulfide (AVS), Fe/Mn-oxyhydroxide, organic carbon, water content analyses, and diffusive gradient in thin films (DGTs) metal concentrations). Porewater Zn increased with inundation of dried sediments for all sediment types, exceeding United States Environmental Protection Agency (U.S. EPA) chronic criteria for freshwater organisms, and decreased as sediments became reduced. Effects on Hyalella azteca (7-day exposure) and Daphnia magna (10-day exposure) were quantified. Results show decreased growth of H. azteca for sites with elevated Zn and increased Zn-body concentration (BCZn) in the most contaminated sediment type. Further, BCZn was negatively correlated with H. azteca growth. D. magna survival, growth, and reproduction were not affected. DGT metal concentrations were more reflective of porewater than organism bioaccumulation. Outcomes of predictive toxicology methods are compared to toxicity test results and suggestions are provided for model improvements. This study demonstrates that post-drought re-flooding of sediments affects Zn biogeochemical cycling with potentially adverse effects on benthic organisms, even in sediments with only moderately elevated concentrations (>150 mg kg-1). PMID- 28800685 TI - Occurrence and ecological hazard assessment of selected antibiotics in the surface waters in and around Lake Honghu, China. AB - The occurrence and temporal-spatial distributions of 13 antibiotics (tetracyclines, sulfonamides, and fluoroquinolones) in the water of a high intensity aquaculture lake, Honghu Lake, and its associated river network and ponds were investigated. Tetracycline, oxytetracycline, chlortetracycline, and sulfadiazine are the four dominant antibiotics in this region, with maximum and median concentrations of 1454.8 and 304.8ng/L, 2796.6 and 161.9ng/L, 1431.3 and 349.9ng/L, and 499.5 and 106.5ng/L, respectively. The median concentrations of the other nine antibiotics are lower than 57.1ng/L. The highest contaminated sites are located in the Four-lake main canal and its lake inlets. Antibiotic concentrations were higher in November than in May and the concentrations were strongly correlated with water temperature, dissolved oxygen, and nitrates according to redundancy analysis. The source analysis indicated that besides untreated domestic and husbandry sewage, the aquaculture in the lake and ponds is a main source of antibiotics in the study region. The environmental hazards posed by the selected antibiotics were assessed by using the methods of hazard quotient and mixture hazard quotient. The results suggested that tetracycline, oxytetracycline, sulfadiazine, and ciprofloxacin pose medium to high ecological hazard to algae in almost all of the water samples, and the high combination ecological hazards of antibiotics are mainly posed by the high individual hazard quotient of tetracycline in the study area. PMID- 28800686 TI - Functionality of surfactants in waste-activated sludge treatment: A review. AB - Proper treatment of waste-activated sludge (WAS) involves three pivotal processes, dewatering, anaerobic digestion, and pollutants removal, which need to be re-assessed urgently. Although many traditional sludge treatments have been developed, it is prudent to enhance the efficiency of sludge treatment using multifunctional, flexible, and environmentally friendly surfactants. With regard to sludge dewatering, surfactants can weaken the binding interaction between sludge flocs and promote the dissolution of extracellular polymeric substances (EPSs), resulting in the release of bound water. Using surfactants in anaerobic digestion promotes the release of enzymes trapped in sludge and improves the activity of enzymes during hydrolysis. Owing to their characteristic encapsulation of hydrophobes into self-assembled aggregates (micelles), surfactants can form host-guest complexes with polycyclic aromatic hydrocarbons (PAHs). Additionally, surfactants can enhance the desorption of heavy metals and prevent the emergence of heavy metal residue. This review summarizes the current surfactant-based sludge treatment technologies according to their roles in sludge disposal solutions. Then, possible mechanisms of surfactants in sludge dewatering, anaerobic digestion, and the removal of organic pollutants and heavy metals are analysed systemically. Finally, changes to sludge treatment via the aid of surfactants are highlighted. This review presents the comprehensive advances in the use of surfactants in WAS reduction, recycling, and risk relief, underscoring their roles in increasing economic efficiency and ensuring environmental quality. PMID- 28800687 TI - The profound effect of harmful cyanobacterial blooms: From food-web and management perspectives. AB - Sustainable and effective water management plans must have a reliable risk assessment strategies for harmful cyanobacterial blooms (HABs) that would enable timely decisions to be made, thus avoiding the trespassing of ecological thresholds, leading to the collapse of ecosystem structure and function. Such strategies are usually based on cyanobacterial biomass and/or on the monitoring of known toxins, which may, however, in many cases, under- or over-represent the actual toxicity of the HAB. Therefore, in this study, by the application of growth-inhibition assays using different bacteria, algae, zooplankton and fish species, we assessed the toxicological potential of two cyanobacterial blooms that differed in total cyanobacterial biomass, species composition and cyanopeptide profiles. We demonstrated that neither cyanobacterial community composition nor its relative abundance, nor indeed concentrations of known toxins reflected the potential risk of HAB based on growth-inhibition assays. We discuss our findings in the context of food-web dynamics and ecosystem management, and suggest that toxicological tests should constitute a key element in the routine monitoring of water bodies so as to prevent under-/over-estimation of potential HAB risk for both ecosystem and public health. PMID- 28800688 TI - Monitoring of air pollution levels related to Charilaos Trikoupis Bridge. AB - Charilaos Trikoupis bridge is the longest cable bridge in Europe that connects Western Greece with the rest of the country. In this study, six air pollution monitoring campaigns (including major regulated air pollutants) were carried out from 2013 to 2015 at both sides of the bridge, located in the urban areas of Rio and Antirrio respectively. Pollution data were statistically analyzed and air quality was characterized using US and European air quality indices. From the overall campaign, it was found that air pollution levels were below the respective regulatory thresholds, but once at the site of Antirrio (26.4 and 52.2MUg/m3 for PM2.5 and RhoMU10, respectively) during the 2nd winter period. Daily average PM10 and PM2.5 levels from two monitoring sites were well correlated to gaseous pollutant (CO, NO, NO2, NOx and SO2) levels, meteorological parameters and factor scores from Positive Matrix Factorization during the 3-year period. Moreover, the elemental composition of PM10 and PM2.5 was used for source apportionment. That analysis revealed that major emission sources were sulfates, mineral dust, biomass burning, sea salt, traffic and shipping emissions for PM10 and PM2.5, for both Rio and Antirrio. Seasonal variation indicates that sulfates, mineral dust and traffic emissions increased during the warm season of the year, while biomass burning become the dominant during the cold season. Overall, the contribution of the Charilaos Trikoupis bridge to the vicinity air pollution is very low. This is the result of the relatively low daily traffic volume (~10,000 vehicles per day), the respective traffic fleet composition (~81% of the traffic fleet are private vehicles) and the speed limit (80km/h) which does not favor traffic emissions. In addition, the strong and frequent winds further contribute to the rapid dispersion of the emitted pollutants. PMID- 28800689 TI - Evaluation of EDAR vehicle emissions remote sensing technology. AB - Despite much work in recent years, vehicle emissions remain a significant contributor in many areas where air quality standards are under threat. Policy makers are actively exploring options for next generation vehicle emission control and local fleet management policies, and new monitoring technologies to aid these activities. Therefore, we report here on findings from two separate but complementary blind evaluation studies of one new-to-market real-world monitoring option, HEAT LLC's Emission Detection And Reporting system or EDAR, an above-road open path instrument that uses Differential Absorption LIDAR to provide a highly sensitive and selective measure of passing vehicle emissions. The first study, by Colorado Department of Public Health and Environment and Eastern Research Group, was a simulated exhaust gas test exercise used to investigate the instrumental accuracy of the EDAR. Here, CO, NO, CH4 and C3H8 measurements were found to exhibit high linearity, low bias, and low drift over a wide range of concentrations and vehicle speeds. Instrument accuracy was high (R2 0.996 for CO, 0.998 for NO; 0.983 for CH4; and 0.976 for C3H8) and detection limits were 50 to 100ppm for CO, 10 to 30ppm for NO, 15 to 35ppmC for CH4, and, depending on vehicle speed, 100 to 400ppmC3 for C3H8. The second study, by the Universities of Birmingham and Leeds and King's College London, used the comparison of EDAR, on board Portable Emissions Measurement System (PEMS) and car chaser (SNIFFER) system measurements collected under real-world conditions to investigate in situ EDAR performance. Given the analytical challenges associated with aligning these very different measurements, the observed agreements (e.g. EDAR versus PEMS R2 0.92 for CO/CO2; 0.97 for NO/CO2; ca. 0.82 for NO2/CO2; and, 0.94 for PM/CO2) were all highly encouraging and indicate that EDAR also provides a representative measure of vehicle emissions under real-world conditions. PMID- 28800690 TI - Community airborne particulate matter from mining for sand used as hydraulic fracturing proppant. AB - Field and laboratory studies were conducted to evaluate the impact of proppant sand mining and processing activities on community particulate matter (PM) concentrations. In field studies outside 17 homes within 800m of sand mining activities (mining, processing, and transport), respirable (PM4) crystalline silica concentrations were low (<0.4MUg/m3) with crystalline silica detected on 7 samples (2% to 4% of mass). In long-term monitoring at 6 homes within 800m of sand mining activities, the highest daily mean PM concentrations observed were 14.5MUg/m3 for PM2.5 and 37.3MUg/m3 for PM10, although infrequent (<3% of time), short-term elevated PM concentrations occurred when wind blew over the facility. In laboratory studies, aerosolized sand was shown to produce respirable-sized particles, containing 6% to 19% crystalline silica. Dispersion modeling of a mine and processing facility indicated that PM10 can exceed standards short distances (<40m) beyond property lines. Lastly, fence-line PM and crystalline silica concentrations reported to state agencies were substantially below regulatory or guideline values, although several excursions were observed for PM10 when winds blew over the facility. Taken together, community exposures to airborne particulate matter from proppant sand mining activities at sites similar to these appear to be unlikely to cause chronic adverse health conditions. PMID- 28800691 TI - The landscape model: A model for exploring trade-offs between agricultural production and the environment. AB - We describe a model framework that simulates spatial and temporal interactions in agricultural landscapes and that can be used to explore trade-offs between production and environment so helping to determine solutions to the problems of sustainable food production. Here we focus on models of agricultural production, water movement and nutrient flow in a landscape. We validate these models against data from two long-term experiments, (the first a continuous wheat experiment and the other a permanent grass-land experiment) and an experiment where water and nutrient flow are measured from isolated catchments. The model simulated wheat yield (RMSE 20.3-28.6%), grain N (RMSE 21.3-42.5%) and P (RMSE 20.2-29% excluding the nil N plots), and total soil organic carbon particularly well (RMSE3.1 13.8%), the simulations of water flow were also reasonable (RMSE 180.36 and 226.02%). We illustrate the use of our model framework to explore trade-offs between production and nutrient losses. PMID- 28800692 TI - Does the developmental stage and composition of riparian forest stand affect ecosystem functioning in streams? AB - A common watershed restoration practice to improve water quality and stream ecosystem functions and services is replanting riparian corridors with plant species that may differ from those of natural communities. This restoration practice may have consequences on the aquatic ecosystem processes because organisms obtain energy from leaf litter inputs of the riparian zones. Leaf litter decomposition in streams is a vital ecosystem-level process, which depends on the activity of microorganisms and invertebrates. In the current study, we examined whether the type and developmental stage of riparian forest affect stream ecosystem functioning. We selected three widespread tree species in the Northwest Portugal, namely alder (Alnus glutinosa (L.) Gaertn.), oak (Quercus robur L.) and eucalyptus (Eucalyptus globulus Labill.) and conducted stream litter decomposition experiments with leaf litter from trees differing in developmental stage to assess leaf mass loss, fungal and invertebrate biomass and diversity. Both type and developmental stage of riparian stand significantly affected leaf mass loss, biomass of fungi and benthic invertebrates, sporulation of fungi, and abundance of invertebrates. However, only developmental stage of the riparian stand had an impact on the richness and diversity of fungi, whereas invertebrate diversity and richness was influenced by both stage and type classes. Overall our study provides the novel information that stream ecosystem processes are dictated not only by the composition but also by the developmental stage of the riparian stand. Moreover, this study provides an insight into how by altering riparian forest community composition through restoration practices may have an impact on a key ecosystem process and may have implications for successfully implementing future management strategies. PMID- 28800693 TI - A modified SINTACS method for groundwater vulnerability and pollution risk assessment in highly anthropized regions based on NO3- and SO42- concentrations. AB - Groundwater vulnerability and risk assessment are worldwide tools in supporting groundwater protection and land planning. In this study, we used three of these different methodologies applied to the Campanian Plain located in southern Italy: SINTACS, AVI and LOS. However, their capability to describe the observed chemical pollution of the area has resulted quite poor. For such a reason, a modified SINTACS method has been then implemented in the area in order to get a more reliable view of groundwater vulnerability. NO3- and SO42- from more than 400 monitoring wells were used for specific vulnerability assessment. Land use was chosen as key parameter to infer the risk of groundwater pollution in our area. The new methodology seems to show a higher correlation with observed NO3- concentrations and a more reliable identification of aquifer's pollution hot spots. The main sources of NO3- were found in sub-urban areas, where vulnerability and risk are higher than in other areas. Otherwise due to reducing conditions triggered by the presence of elevated sedimentary organic matter and peat, concentrations below agricultural areas were lower than in sub-urban areas. The SO42- specific vulnerability map showed a positive correlation with observed concentrations, due to geogenic and anthropogenic SO42- sources present in the area. The combination of both NO3- and SO42- derived risk maps becomes essential to improve the conceptual model of aquifer pollution in this severely anthropized area. The application of this new and original approach shed light on the strengths and weaknesses of each of the described previous methods and clearly showed how anthropogenic activities have to be taken into account in the assessment process. PMID- 28800694 TI - Variability, drivers, and effects of atmospheric nitrogen inputs across an urban area: Emerging patterns among human activities, the atmosphere, and soils. AB - Atmospheric deposition of nitrogen (N) is a major input of N to the biosphere and is elevated beyond preindustrial levels throughout many ecosystems. Deposition monitoring networks in the United States generally avoid urban areas in order to capture regional patterns of N deposition, and studies measuring N deposition in cities usually include only one or two urban sites in an urban-rural comparison or as an anchor along an urban-to-rural gradient. Describing patterns and drivers of atmospheric N inputs is crucial for understanding the effects of N deposition; however, little is known about the variability and drivers of atmospheric N inputs or their effects on soil biogeochemistry within urban ecosystems. We measured rates of canopy throughfall N as a measure of atmospheric N inputs, as well as soil net N mineralization and nitrification, soil solution N, and soil respiration at 15 sites across the greater Boston, Massachusetts area. Rates of throughfall N are 8.70+/-0.68kgNha-1yr-1, vary 3.5-fold across sites, and are positively correlated with rates of local vehicle N emissions. Ammonium (NH4+) composes 69.9+/-2.2% of inorganic throughfall N inputs and is highest in late spring, suggesting a contribution from local fertilizer inputs. Soil solution NO3 is positively correlated with throughfall NO3- inputs. In contrast, soil solution NH4+, net N mineralization, nitrification, and soil respiration are not correlated with rates of throughfall N inputs. Rather, these processes are correlated with soil properties such as soil organic matter. Our results demonstrate high variability in rates of urban throughfall N inputs, correlation of throughfall N inputs with local vehicle N emissions, and a decoupling of urban soil biogeochemistry and throughfall N inputs. PMID- 28800696 TI - Making Sense of the Mountains of New Cancer Data. PMID- 28800695 TI - Long-term impact of manuring and fertilization on enrichment, stability and quality of organic carbon in Inceptisol under two potato-based cropping systems. AB - Soil organic matter (SOM) stability is a prerequisite for long-term C sequestration. The long-term effect of manuring and fertilization on stability of SOM in rice-potato-wheat (R-P-W) and maize-potato-onion (M-P-O) cropping systems was studied in an Inceptisol of semi-arid subtropical India. Soil samples were collected (0-15 and 15-30cm soil depths) from the following treatments: control, 100% NPK-Fertilizer, 100% N-Vermicompost (VC), 50% NPK-Fertilizer+50%N Vermicompost (VC), 100%NPK-Fertilizer+crop residue (CR), 100% N-VC+CR. The stability of SOM was studied by correlating the ammonium oxalate extractable Fe, Al and Si with stable soil organic C (SOC). Application of 100% N-VC and 100% N VC+CR increased the SOC stock by 66% and 32%, respectively over 100% NPK in R-P-W cropping system, while in M-P-O system, the above treatments increased the SOC stock by 28% and 12%. As compared to 100%NPK, the integrated use of 50%NPK+50%N VC increased the SOC stock by 58% and 35% in R-P-W and M-P-O system, respectively. The extractable Fe, Al and Si significantly correlated with stable OC and the multiple regression model developed between these parameters could well predict the stable OC in soil. Complete or partial substitution of chemical fertilizer N with VC could be a promising nutrient management strategy for enhancing the SOC stock in Inceptisol under potato-based cropping systems of semi arid sub-tropical India. However, the integrated use of 50%NPK+50%N-VC could be promising due to lowest yield reductions and moderate SOC sequestration potential. The enrichment (47%), as well as quality (81%) of SOC was higher in R P-W system than in M-P-O system. The organic treatments like 100%NPK+CR and 100%N VC+CR showed higher stability of SOC in R-P-W (31% and 26%) than in M-P-O cropping system. The stability of SOC could well be predicted by extractable amorphous and poorly crystalline Fe, Al and Si and SOC in both the cropping systems. PMID- 28800697 TI - Improving Children's Access to Cancer Clinical Trials. PMID- 28800698 TI - PDQ (Physician Data Query). PMID- 28800699 TI - Risk of Heart Disease in Breast Cancer Patients Receiving Estrogen-Deprivation Therapy. PMID- 28800700 TI - Reducing Risk of Suicide in Cancer Patients. PMID- 28800701 TI - A New Indole Derivative Decreased SALL4 Gene Expression in Acute Promyelocytic Leukemia Cell Line (NB4) AB - Background: Acute myeloblastic leukemia (AML) is a clonal disorder due to bone marrow failure and uncontrolled proliferation of myeloid lineage. Acute promyelocytic leukemia (APL) is a subtype of AML. Heterocyclic compounds, such as indole, are considered as attractive candidates for cancer therapy, due to their abundance in nature and known biological activity. Sal-like protein (SALL4) is a zinc finger transcription factor involving in the multi-potency of stem cells, in the NB4 cell line. This study was aimed to evaluate the effects of basal indole and its new derivative, 2-(1-((2, 4-Aril)imino)-2,2,2-trifluoroethyl) phenyl-1H Indole-3- carbaldehyde (TFPHC), on the expression of SALL4. Methods: Cells were cultured and treated with different concentrations (75, 150, and 300 ug/mL) of the new indole derivative and DMSO, as a vehicle control, for 24 and 48 hours. Cell proliferation was evaluated by using Trypan blue exclusion and MTT assays. The percentage of apoptotic cells was determined by flowcytometry analysis using the Annexin V/PI apoptosis detection kit; mRNA expression of SALL4 was studied using absolute quantitative RT-PCR. Data were analyzed by student's t-test. P<0.05 were considered statistically significant. Results: Our findings demonstrated the effects of new indole derivatives on SALL4 mRNA expression. Expression of SALL4 mRNA was significantly decreased at 75, 150, and 300 ug/mL concentrations. Conclusion: SALL4 plays a role in the survival of APL cells. SALL4 expression could be suppressed by the novel indole derivative. Additionally, SALL4 gene suppression can serve as a target in APL therapy. PMID- 28800702 TI - Single Mo Atom Supported on Defective Boron Nitride Monolayer as an Efficient Electrocatalyst for Nitrogen Fixation: A Computational Study. AB - The production of ammonia (NH3) from molecular dinitrogen (N2) under mild conditions is one of the most attractive and challenging processes in chemistry. Here by means of density functional theory (DFT) computations, we systematically investigated the potential of single transition metal atoms (Sc to Zn, Mo, Ru, Rh, Pd, and Ag) supported on the experimentally available defective boron nitride (TM-BN) monolayer with a boron monovacancy as a N2 fixation electrocatalyst. Our computations revealed that the single Mo atom supported by a defective BN nanosheet exhibits the highest catalytic activity for N2 fixation at room temperature through an enzymatic mechanism with a quite low overpotential of 0.19 V. The high spin-polarization, selective stabilization of N2H* species, or destabilizing NH2* species are responsible for the high activity of the Mo embedded BN nanosheet for N2 fixation. This finding opens a new avenue of NH3 production by single-atom electrocatalysts under ambient conditions. PMID- 28800703 TI - Mechanism of Reduction in IgG and IgE Binding of beta-Lactoglobulin Induced by Ultrasound Pretreatment Combined with Dry-State Glycation: A Study Using Conventional Spectrometry and High-Resolution Mass Spectrometry. AB - Bovine beta-lactoglobulin (beta-Lg) is one of major allergens in cow's milk. Previous study showed that ultrasound treatment induced the conformational changes of beta-Lg and promoted the glycation in aqueous solutions, which is, however, less efficient compared with dry-state. In this work, the effect of ultrasound pretreatment combined with dry-state glycation on the IgG and IgE binding of beta-Lg was studied. Dry-state glycation with mannose after ultrasound pretreatment at 0-600 W significantly reduced the IgG and IgE binding of beta-Lg, with the lowest values observed at 400 W. The decrease in the IgG and IgE binding of beta-Lg was attributed to the increase in glycation extent and the changes of secondary and tertiary structure, which reflected in the increase of UV absorbance, alpha-helix and beta-sheet contents, as well as the decrease of intrinsic fluorescence intensity, surface hydrophobicity, beta-turn, and random coil contents. Moreover, ultrasound pretreatment promoted the reduction of IgG and IgE binding abilities by improving glycation, reflecting in the increase of the glycation sites and the degree of substitution per peptide (DSP) value determined by Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS). Ultrasound pretreatment at 400 W showed the most significantly enhanced glycation extent. Besides, the results suggested FTICR-MS could provide insights into the glycation at molecular level, which was conducive to the understanding of the mechanism of the reduction in the IgG and IgE binding of beta-Lg. Therefore, ultrasound pretreatment combined with dry-state glycation may be a promising method for beta-Lg hyposensitization. PMID- 28800704 TI - Qualitative and Quantitative Analysis of Carbohydrate Modification on Glycoproteins from Seeds of Ginkgo biloba. AB - Recent progress in the relationship between carbohydrate cross-reactive determinants (CCDs) and allergic response highlights the importance of carbohydrate moieties in the innate immune system. Previous research pointed out that the protein allergen in Ginkgo biloba seeds is glycosylated, and the oligosaccharides conjugated to these proteins might also contribute to the allergy. The aim of this study was to analyze carbohydrate moieties, especially N linked glycans, of glycoproteins from Ginkgo seeds originating from different places for detailed structures, to enable further research on the role played by N-glycans in Ginkgo-caused allergy. Results of monosaccharide composition and immunoblotting assays indicated the existence of N-glycans. Detailed structural elucidation of the N-glycans was further carried out by means of hydrophilic interaction ultraperformance liquid chromatography (HILIC-UPLC) and matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). In total, 14 out of 16 structures detected by UPLC were confirmed by MALDI TOF-MS and tandem mass spectrometry, among which complex-type N-glycans bearing Lewis A determinants and high-mannose-type N-glycans were identified from Ginkgo seeds for the first time. Precise quantification of N-glycans was performed by use of an external standard, and both the absolute amount of each N-glycan and the percentage of different types of N-glycan showed significant diversity among the samples without any pattern of geographic variation. PMID- 28800705 TI - Two-Photon Imaging of 3D Organization of Bimetallic AuAg Nanoclusters in DNA Matrix. AB - We report on two-photon excitation properties of small silver-doped gold nanoclusters (AuAgNCs) and on their three-dimensional arrangement in a hybrid system composed of DNA liquid crystals (LCs) and AuAgNCs. UV-vis and fluorescence spectroscopy, transmission electron microscopy (TEM), and multiphoton excitation spectroscopy were used to characterize the nanoparticles. We show that AuAgNCs exhibit two-photon excited luminescence (2PL) emission and second-harmonic generation (SHG) and that these properties remain the same in liquid crystalline matrix. The results are described in detail and discussed in the context of possible imaging application of AuAgNC and specific AuAgNCs organization induced by liquid crystalline ordering of DNA molecules. PMID- 28800706 TI - Parsing the Hypomanic Personality: Explicating the Nature of Specific Dimensions Defining Mania Risk. AB - Considerable research has used the Hypomanic Personality Scale (HPS) to assess traits conferring risk for hypomanic and manic episodes. Although the HPS has been shown to be defined by several distinct sets of content, most research has continued to rely exclusively on HPS total scores, due to (a) little research having examined its structure and (b) the discrepant structural results obtained in the few available studies. Therefore, we examined the structure and relations of the HPS in a large sample of community adults ( N = 737) receiving psychiatric treatment. Our structural results indicated a five-factor structure of Activation, Charisma, Intellectual Confidence, Lability, and Modesty. Subscales modeling these emergent factors showed divergent patterns of relations with personality and other forms of psychopathology. These findings underscore the importance of examining HPS subscale relations in addition to HPS total scores in future research. PMID- 28800707 TI - Radiographic Results and Return to Activity After Sesamoidectomy for Fracture. AB - BACKGROUND: Limited data are available comparing the results of lateral sesamoidectomy and medial sesamoidectomy for the treatment of fractures recalcitrant to nonoperative treatment interventions. The hypothesis of this study was that sesamoidectomy for either lateral or medial sesamoid fractures would not change radiographic alignment of the first ray given the use of identical reconstruction of the plantar plate, intersesamoid ligament, and plantar ligament complex at the time of surgery. METHODS: This retrospective cohort study compared the outcomes of 46 consecutive patients treated with sesamoidectomy (24 lateral, 22 medial). Patient demographics, mechanisms of injury, and outcomes were recorded. Preoperative, postoperative, and changes in both hallux valgus angle (HVA) and intermetatarsal angle (IMA) were measured. RESULTS: No statistically significant difference could be detected for age ( P = .577), sex ( P = .134), return to activity ( P = 1.000), likelihood to undergo the procedure again ( P = 1.000), orthotic use postoperatively ( P = 1.000), perioperative complications ( P = .497), duration of symptoms ( P = .711), or length of follow-up ( P = .609). While statistically significant changes in preoperative and postoperative alignment were detected for both medial and lateral sesamoidectomy, these changes were not clinically significant. Patients undergoing medial sesamoidectomy had higher preoperative and postoperative HVA and IMA compared with those undergoing lateral sesamoidectomy. Medial sesamoidectomy patients had a net increase in both HVA and IMA, while patients undergoing lateral sesamoidectomy had a net decrease in both HVA and IMA. CONCLUSION: Although statistically significant changes in both HVA and IMA were detected, these values were too small to be considered clinically significant. Patient outcomes did not differ between the 2 groups, and sesamoidectomy was used with low patient morbidity for both medial and lateral sesamoid fractures that failed to respond to nonoperative modalities. These data suggest that the underlying mechanics of the foot may be different in patients who sustain medial and lateral sesamoid stress injury, suggesting a possible etiologic difference between medial and lateral sesamoid injuries. LEVEL OF EVIDENCE: Level III, retrospective cohort study. PMID- 28800708 TI - Multiplanar Correction of the Lesser Digital Deviation and Indirect Plantar Plate Rupture Repair Using a Braided Polyethylene Nylon Suture: A Technique Guide. AB - : Forefoot and lesser digital pathology continues to be a challenging area of surgical correction for foot and ankle surgeons. Many techniques for the correction of digital deformities secondary to plantar plate rupture, regardless of planal dominance, have been described including direct repair and metatarsal shortening osteotomies for repair. The authors present a new technique for multiplanar correction of deformed lesser digits without direct repair of the plantar plate rupture utilizing a specialty suture. The technique utilizes a braided synthetic polyethylene Nylon suture, which has been traditionally used for open or arthroscopic shoulder labrum repair, for the stabilization of the lesser metatarsophalangeal joint. This novel technique guide for the correction of transverse and sagittal plane deformities of the digit at the metatarsophalangeal joint negates the need for a plantar incisional approach for plantar plate repair or metatarsal head osteotomy from a dorsal approach with augmented stabilization. LEVELS OF EVIDENCE: Level V: Expert opinion. PMID- 28800709 TI - The Major Outer Membrane Protein MopB Is Required for Twitching Movement and Affects Biofilm Formation and Virulence in Two Xylella fastidiosa strains. AB - MopB is a major outer membrane protein (OMP) in Xylella fastidiosa, a bacterial plant pathogen that causes losses on many economically important crops. Based on in silico analysis, the uncharacterized MopB protein of X. fastidiosa contains a beta-barrel structure with an OmpA-like domain and a predicted calcium-binding motif. Here, MopB function was studied by mutational analysis taking advantage of the natural competence of X. fastidiosa. Mutants of mopB were constructed in two different X. fastidiosa strains, the type strain Temecula and the more virulent WM1-1. Deletion of the mopB gene impaired cell-to-cell aggregation, surface attachment, and biofilm formation in both strains. Interestingly, mopB deletion completely abolished twitching motility. Electron microscopy of the bacterial cell surface revealed that mopB deletion eliminated type IV and type I pili formation, potentially caused by destabilization of the outer membrane. Both mopB mutants showed reduced virulence using tobacco (Nicotiana tabacum) as a host under greenhouse conditions. These results suggest that MopB has pleiotropic functions in biofilm formation and twitching motility and is important for virulence of X. fastidiosa. PMID- 28800710 TI - Synergistic Effect of Different Plant Cell Wall-Degrading Enzymes Is Important for Virulence of Fusarium graminearum. AB - Endo-polygalacturonases (PGs) and xylanases have been shown to play an important role during pathogenesis of some fungal pathogens of dicot plants, while their role in monocot pathogens is less defined. Pg1 and xyr1 genes of the wheat pathogen Fusarium graminearum encode the main PG and the major regulator of xylanase production, respectively. Single- and double-disrupted mutants for these genes were obtained to assess their contribution to fungal infection. Compared with wild-type strain, the ?pg mutant showed a nearly abolished PG activity, slight reduced virulence on soybean seedlings, but no significant difference in disease symptoms on wheat spikes; the ?xyr mutant was strongly reduced in xylanase activity and moderately reduced in cellulase activity but was as virulent as wild type on both soybean and wheat plants. Consequently, the DeltapgDeltaxyr double mutant was impaired in xylanase, PG, and cellulase activities but, differently from single mutants, was significantly reduced in virulence on both plants. These findings demonstrate that the concurrent presence of PG, xylanase, and cellulase activities is necessary for full virulence. The observation that the uronides released from wheat cell wall after a F. graminearum PG treatment were largely increased by the fungal xylanases suggests that these enzymes act synergistically in deconstructing the plant cell wall. PMID- 28800711 TI - Getting Better or Getting Well? The Patient Acceptable Symptom State (PASS) Better Predicts Patient's Satisfaction than the Decrease of Pain, in Knee Osteoarthritis Subjects Treated with Viscosupplementation. AB - Background In the management of knee osteoarthritis (OA), patient-reported outcomes (PROs) are being developed for relevant assessment of pain. The patient acceptable symptom state (PASS) is a relevant cutoff, which allows classifying patients as being in "an acceptable state" or not. Viscosupplementation is a therapeutic modality widely used in patients with knee OA that many patients are satisfied with despite meta-analyses give conflicting results. Objectives To compare, 6 months after knee viscosupplementation, the percentage of patients who reached the PASS threshold (PASS +) with that obtained from other PROs. Methods Data of 53 consecutive patients treated with viscosupplementation (HANOX-M-XL) and followed using a standardized procedure, were analyzed at baseline and month 6. The PROs were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function, patient's global assessment of pain (PGAP), patient's self-assessment of satisfaction, PASS for WOMAC pain and PGAP. Results At baseline, WOMAC pain and PGAP (range 0-10) were 4.6 (1.1) and 6.0 (1.1). At month 6, they were 1.9 (1.2) and 3.1 (5) ( P < 0.0001). At 6 months, 83% of patients were "PASS + pain," 100% "PASS + function," 79% "PASS + PGAP," 79% were satisfied, and 73.6% experienced a >=50% decrease in WOMAC pain. Among "PASS + pain" and "PASS + PGAP" subjects, 90% and 83.3% were satisfied with the treatment, respectively. Conclusion In daily practice, clinical response to viscosupplementation slightly varies according to PROs. "PASS + PGAP" was the most related to patient satisfaction. PMID- 28800712 TI - Outcomes Achieved With Use of a Prefabricated Roll-On Total Contact Cast. AB - BACKGROUND: The total contact cast (TCC) is considered the gold standard for offloading of plantar diabetic foot ulcerations, yet its use remains suboptimal for a variety of reasons. Prefabricated TCC systems have been developed to help enhance TCC use. The primary objective of this study was to determine if healing rates obtained with use of a prefabricated roll-on TCC were similar to those reported with conventional TCC use. Secondary outcomes measured were the incidence of iatrogenic ulceration, amputation, and recurrent ulceration, and patient tolerance of the device. METHODS: A retrospective chart review was performed on all patients in whom TCC was used for treatment of an ulceration at our institution from April 2013 to December 2016. Seventy patients (132 ulcerations) were identified. RESULTS: An 85.6% healing rate was achieved. Five subjects (7.1%) sustained 11 iatrogenic ulcerations. All resolved with local treatment and continued casting. Thirteen subjects (18.6%) underwent amputation. No amputation occurred because of TCC application technique or use. Fifteen ulcerations (12 subjects, 17.1%) recurred. Greater than 70% resolved with re initiation of TCC use. Forty-three subjects (61.4%) tolerated use of the prefabricated roll-on TCC. CONCLUSION: Similar healing rates and reduced rates of iatrogenic ulceration, amputation, and recurrent ulceration were attained with use of a prefabricated roll-on TCC. These results, good patient tolerance, and the reduced administrative and clinical time related to supply acquisition, training, and proper application supports use of this device as a viable alternative to a conventional TCC for treatment of plantar neuropathic foot ulcerations. LEVEL OF EVIDENCE: Level IV, case series. PMID- 28800714 TI - Sagittal Subtalar and Talocrural Joint Assessment During Ambulation With Controlled Ankle Movement (CAM) Boots. AB - BACKGROUND: The purpose of the current study was to determine sagittal plane talocrural and subtalar kinematic differences between barefoot and controlled ankle movement (CAM) boot walking. This study used fluoroscopic images to determine talar motion relative to tibia and calcaneal motion relative to talus. METHODS: Fourteen male subjects (mean age 24.1 +/- 3.5 years) screened for normal gait were tested. A fluoroscopy unit was used to collect images at 200 Hz during stance. Sagittal motion of the talocrural and subtalar joints were analyzed barefoot and within short and tall CAM boots. RESULTS: Barefoot talocrural mean maximum plantar and dorsiflexion were 9.2 +/- 5.4 degrees and -7.5 +/- 7.4 degrees, respectively; short CAM boot mean maximum plantar and dorsiflexion were 3.2 +/- 4.0 degrees and -4.8 +/- 10.2 degrees, respectively; and tall CAM boot mean maximum plantar and dorsiflexion were -0.2 +/- 3.5 degrees and -2.4 +/- 5.1 degrees, respectively. Talocrural mean range of motion (ROM) decreased from barefoot (16.7 +/- 5.1 degrees) to short CAM boot (8.0 +/- 4.9 degrees) to tall CAM boot (2.2 +/- 2.5 degrees). Subtalar mean maximum plantarflexion angles were 5.3 +/- 5.6 degrees for barefoot walking, 4.1 +/- 5.9 degrees for short CAM boot walking, and 3.0 +/- 4.7 degrees for tall CAM boot walking. Mean minimum subtalar plantarflexion angles were 0.7 +/- 3.2 degrees for barefoot walking, 0.7 +/- 2.9 degrees for short CAM boot walking, and 0.1 +/- 4.8 degrees for tall CAM boot walking. Subtalar mean ROM decreased from barefoot (4.6 +/- 3.9 degrees) to short CAM boot (3.4 +/- 3.8 degrees) to tall CAM boot (2.9 +/- 2.6 degrees). CONCLUSION: Tall and short CAM boot intervention was shown to limit both talocrural and subtalar motion in the sagittal plane during ambulation. The greatest reductions were seen with the tall CAM boot, which limited talocrural motion by 86.8% and subtalar motion by 37.0% compared to barefoot. Short CAM boot intervention reduced talocrural motion by 52.1% and subtalar motion by 26.1% compared to barefoot. CLINICAL RELEVANCE: Both short and tall CAM boots reduced talocrural and subtalar motion during gait. The short CAM boot was more convenient to use, whereas the tall CAM boot more effectively reduced motion. In treatments requiring greater immobilization of the talocrural and subtalar joints, the tall CAM boot should be considered. PMID- 28800713 TI - Application of High-Speed Dual Fluoroscopy to Study In Vivo Tibiotalar and Subtalar Kinematics in Patients With Chronic Ankle Instability and Asymptomatic Control Subjects During Dynamic Activities. AB - BACKGROUND: Abnormal angular and translational (ie, kinematic) motion at the tibiotalar and subtalar joints is believed to cause osteoarthritis in patients with chronic ankle instability (CAI). METHODS: In this preliminary study the investigators quantified and compared in vivo tibiotalar and subtalar kinematics in 4 patients with CAI (3 women) and 10 control subjects (5 men) using dual fluoroscopy during a balanced, single-leg heel-rise and treadmill walking at 0.5 and 1.0 m/s. RESULTS: During balanced heel-rise, 69%, 54%, and 66% of mean CAI tibiotalar internal rotation/external rotation (IR/ER), subtalar inversion/eversion, and subtalar IR/ER angles, respectively, were outside the 95% confidence intervals of control subjects. During 0.5-m/s gait, 50% and 60% of mean CAI tibiotalar dorsi/plantarflexion and subtalar IR/ER angles, respectively, were outside the 95% confidence intervals of control subjects. During 1.0-m/s gait, 62%, 65%, and 73% of mean CAI subtalar dorsi/plantarflexion, inversion/eversion, and IR/ER, respectively, were outside the 95% confidence intervals of control subjects. Patients with CAI exhibited less tibiotalar and subtalar translational motion during gait; no clear differences in translations were noted during balanced heel-rise. CONCLUSION: Overall, the balanced heel-rise activity exposed more tibiotalar and subtalar kinematic variation between patients with CAI and control subjects. Therefore, weight-bearing activities involving large range of motion, balance, and stability may be best for studying kinematic adaptations in patients with CAI. CLINICAL RELEVANCE: These preliminary results suggest that patients with CAI require more tibiotalar external rotation, subtalar eversion, and subtalar external rotation during weight-bearing stability exercises, all with less overall joint translation. PMID- 28800715 TI - An EEG Study of Children With and Without ADHD Symptoms: Between-Group Differences and Associations With Sluggish Cognitive Tempo Symptoms. AB - OBJECTIVE: We examined differences between those with and without ADHD symptoms on resting state electroencephalography (EEG) indices and unique relations with sluggish cognitive tempo (SCT) symptoms. METHOD: Children with ADHD symptoms ( n = 21) and healthy controls ( n = 20) were assessed using rating scales, a neuropsychological task measuring sustained attention and inhibitory control, and EEG activity during a resting state period. Between-group, correlational, and regression analyses were conducted. RESULTS: Large differences (particularly for theta/beta ratio in frontal and frontocentral regions) were found on EEG measures between those with and without ADHD symptoms. While ADHD and SCT symptoms both related to sustained attention on a computerized task, only ADHD symptoms were related to frontal and frontocentral theta/beta ratio. CONCLUSION: Results support the conclusion that ADHD symptoms are strongly associated with theta/beta ratio in frontal and frontocentral regions. Future studies should explore unique neurophysiological correlates of SCT. PMID- 28800716 TI - Co-Occurrence of ASD and ADHD Traits in an Adult Population. AB - OBJECTIVE: ADHD and autism spectrum disorder (ASD) can be viewed as the extreme end of traits found in the general population. Clinical and genetic studies suggest that ADHD and ASD often co-occur and share genetic susceptibility. The aim of this study was to examine co-occurrence of ADHD and ASD traits in the general population. METHOD: In total, 334 participants were recruited from a population-based sample. Four questionnaires assessing current and retrospective ADHD and ASD traits were administered online: the Adult ADHD Self-Report Scale (ASRS) Symptom Checklist, the Wender Utah Rating Scale (WURS-25), the Broad Autism Phenotype Questionnaire (BAPQ), and the Autism Spectrum Quotient (AQ). RESULTS: A significant correlation was found between ADHD and autistic traits. In particular, higher inattention and overall ADHD scores were associated with self reported deficits in communication and social skills. CONCLUSION: Our findings are similar to results from studies on clinical populations, suggesting that ADHD and ASD might share common etiology. PMID- 28800717 TI - Multidimensional Inventory of Hypochondriacal Traits: An Examination of a Bifactor Model and Measurement Invariance Between Those With and Without a Self Reported Medical Condition. AB - The Multidimensional Inventory of Hypochondriacal Traits (MIHT) is a self-report measure that assesses four interrelated domains of health anxiety (i.e., Cognitive, Behavioral, Perceptual, Affective). Prior research has supported a correlated four-factor model, as well as a hierarchical model, in which each of the four factors load onto the higher order health anxiety construct. However, a bifactor modeling approach has yet to be used to examine the factor structure of the MIHT. Results supported a bifactor model of the MIHT in three different samples (i.e., unselected based on current medical status [ n = 824], and those with [ n = 348] and without [ n = 354] a self-reported medical condition). The MIHT appears to be strongly multidimensional, with three of the four subscales providing substantive value. Confirmatory factor analysis supported the configural and metric/scalar invariance of the bifactor model between those with and without a self-reported medical condition. Results provide support for a bifactor conceptualization of the MIHT and the invariance of that model across levels of current health status. PMID- 28800718 TI - Sex Differences in the Meaning of Parent and Teacher Ratings of ADHD Behaviors: An Observational Study. AB - OBJECTIVE: To test explanations for the underrecognition of female ADHD by examining differences in adult ratings of boys and girls matched for levels of directly observed ADHD behaviors. METHOD: In a secondary analysis of a population based sample, 3- to 4-year-olds ( n = 153, 79 male) and 8- to 9-year-olds ( n = 144, 75 male) were grouped according to levels of directly observed ADHD behaviors (low/moderate/high). Groups were then compared with parent/teacher ADHD ratings. RESULTS: There were no sex differences in levels of directly observed ADHD behaviors within groups. For preschoolers, parents' ratings of males, but not females, significantly increased across groups-mirroring levels of observed behaviors. For older children, both parent and teacher mean ratings were significantly higher for males than females across groups. CONCLUSION: Identified differences in adult ratings of males and females matched for directly observed behaviors may contribute to understanding the substantial ADHD underrecognition in females. PMID- 28800719 TI - Total Ankle Arthroplasty: Comparing Perioperative Outcomes When Performed at an Orthopaedic Specialty Hospital Versus an Academic Teaching Hospital. AB - BACKGROUND: The number of total ankle arthroplasties (TAAs) performed in the United States has risen significantly in recent years, as has utilization of orthopaedic specialty hospital (OSH) to treat healthy patients undergoing elective surgery. The purpose of this study was to compare postoperative outcomes following TAA at an OSH when compared with a matching population of patients undergoing TAA at an academic teaching hospital (ATH). METHODS: We identified all TAA from January 2014 to December 2014 at the OSH and January 2010 to January 2016 at the ATH. Each OSH patient was manually matched with a corresponding ATH patient by clinical variables. Outcomes analyzed were length of stay (LOS), 30 day readmissions, mortality, reoperation, and inpatient rehabilitation utilization. RESULTS: There were 40 TAA patients in each group. OSH and ATH patients were similar in age, body mass index, age-adjusted Charlson Comorbidity Index, and gender. Average LOS for TAA at the OSH was 1.28 +/- 0.51 compared with 2.03 +/- 0.89 (P < .001) at the ATH. There were no OSH patients readmitted within 30 days, compared with 2 ATH patients readmitted (5.0%; P = .15). Two OSH patients (5.0%) and 2 ATH patients (5.0%; P = 1.00) required reoperation. There were no mortalities in either group. There were no OSH patients requiring transfer. CONCLUSIONS: Primary TAA performed at an OSH had significantly shorter LOS when compared with a matched patient treated at an ATH with no significant difference in readmission or reoperation rates and may offer a potential source of significant health care savings. LEVELS OF EVIDENCE: Level III: Retrospective cohort study. PMID- 28800720 TI - JC Virus-Related Progressive Multifocal Leukoencephalopathy After Living-Donor Liver Transplant: A Rare Case. AB - Progressive multifocal leukoencephalopathy caused by polyoma JC virus is a rare and severe demyelinating disease of the central nervous system. It occurs in immunocompromised patients and is scarcely reported in liver transplant recipients. Brain biopsy demonstrating demyelination with presence of foamy macrophages, relative preservation of axons, astrogliosis, and typical polyomavirus inclusions in the enlarged oligodendroglial nuclei is essential for diagnosis. Here, we report a case of JC virus-associated progressive multifocal leukoencephalopathy in a living-donor liver transplant recipient who was transplanted for hepatitis C virus-related decompensated cirrhosis. Brain biopsy with immunohistochemistry confirmed the diagnosis of progressive multifocal leukoencephalopathy secondary to JC virus. JC virus related-progressive multifocal leukoencephalopathy is associated with extremely poor prognosis. Awareness and consideration of this entity in liver transplant recipients who present with sudden progressive neurologic manifestations can help in prompt diagnosis and timely treatment. PMID- 28800721 TI - MicroRNA expression in bone marrow-derived human multipotent Stromal cells. AB - BACKGROUND: Multipotent stromal cells (MSCs) are being studied in the field of regenerative medicine for their multi-lineage differentiation and immunoregulatory capacity. MicroRNAs (miRNAs) are short non-coding RNAs that are responsible for regulating gene expression by targeting transcripts, which can impact MSC functions such as cellular proliferation, differentiation, migration and cell death. miRNAs are expressed in MSCs; however, the impact of miRNAs on cellular functions and donor variability is not well understood. Eight MSC lines were expanded to passages 3, 5 and 7, and their miRNA expression was evaluated using microarray technology. RESULTS: Statistical analyses of our data revealed that 71 miRNAs out of 939 examined were expressed by this set of MSC lines at all passages and the expression of 11 miRNAs were significantly different between passages 3 and 7, while the expression of 7 miRNAs was significantly different between passages 3 and 5. The expression of these identified miRNAs was evaluated using RT-qPCR for both the first set of MSC lines (n = 6) and a second set of MSC lines (n = 7) expanded from passages 4 to 8. By RT-qPCR only 2 miRNAs, miR-638 and miR-572 were upregulated at passage 7 compared to passage 3 in the first set of MSC lines by 1.71 and 1.54 fold, respectively; and upregulated at passage 8 compared to passage 4 in the second set of MSC lines, 1.35 and 1.59 fold, respectively. CONCLUSIONS: The expression of miR-638 and miR-572 can distinguish MSCs from two different passages of cell culture. These results may be useful in establishing critical quality attributes of MSCs and determining whether changes in these two miRNAs impact cellular functions. PMID- 28800722 TI - Randomized comparison of sevoflurane versus propofol-remifentanil on the cardioprotective effects in elderly patients with coronary heart disease. AB - BACKGROUND: It is skeptical about cardioprotective property of sevoflurane in patients undergoing noncardiac surgery, especially in the elderly patients with coronary heart disease. We hypothesized that long duration of sevoflurane inhalation in noncardiac surgery could ameliorate myocardial damage in such patients. METHODS: This was a randomized, prospective study. One hundred twenty one elderly patients with coronary heart disease were randomly allocated into two groups. Maintenance of anesthesia was achieved by sevoflurane inhalation (Group S) or propofol-remifentanil respectively (Group PR). Serum cardiac troponin I (cTnI) and brain natriuretic peptide (BNP) were measured before anesthesia induction (T0), 8 h (T1) and 24 h (T2) after anesthesia respectively. The perioperative cardiac output, complications and postoperative 3-month follow-up from end of surgery were recorded. RESULTS: Between the two groups, there were no statistical differences in the values of cTnI and BNP during the study. However, The area under the curve of cTnI values over 24 h after operation was less in Group S. Group PR had lower cardiac output and consumed more amount of phenylephrine during the study (P < 0.05). CONCLUSIONS: Compared with the group PR, sevoflurane had no benefit in the myocardial protection for the elderly patients with CHD. However, Sevoflurane showed advantage in maintaining hemodynamic stability during the operative period. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-IPR-16008871 , 21 July 2016. PMID- 28800723 TI - A CLCA regulatory protein present in the chemosensory cilia of olfactory sensory neurons induces a Ca2+-activated Cl- current when transfected into HEK293. AB - BACKGROUND: CLCA is a family of metalloproteases that regulate Ca2+-activated Cl- fluxes in epithelial tissues. In HEK293 cells, CLCA1 promotes membrane expression of an endogenous Anoctamin 1 (ANO1, also termed TMEM16A)-dependent Ca2+-activated Cl- current. Motif architecture similarity with CLCA2, 3 and 4 suggested that they have similar functions. We previously detected the isoform CLCA4L in rat olfactory sensory neurons, where Anoctamin 2 is the principal chemotransduction Ca2+-activated Cl- channel. We explored the possibility that this protein plays a role in odor transduction. RESULTS: We cloned and expressed CLCA4L from rat olfactory epithelium in HEK293 cells. In the transfected HEK293 cells we measured a Cl--selective Ca2+-activated current, blocked by niflumic acid, not present in the non-transfected cells. Thus, CLCA4L mimics the CLCA1 current on its ability to induce the ANO1-dependent Ca2+-activated Cl- current endogenous to these cells. By immunocytochemistry, a CLCA protein, presumably CLCA4L, was detected in the cilia of olfactory sensory neurons co-expressing with ANO2. CONCLUSION: These findings suggests that a CLCA isoform, namely CLCA4L, expressed in OSN cilia, might have a regulatory function over the ANO2-dependent Ca2+-activated Cl- channel involved in odor transduction. PMID- 28800724 TI - A comparison of machine learning and Bayesian modelling for molecular serotyping. AB - BACKGROUND: Streptococcus pneumoniae is a human pathogen that is a major cause of infant mortality. Identifying the pneumococcal serotype is an important step in monitoring the impact of vaccines used to protect against disease. Genomic microarrays provide an effective method for molecular serotyping. Previously we developed an empirical Bayesian model for the classification of serotypes from a molecular serotyping array. With only few samples available, a model driven approach was the only option. In the meanwhile, several thousand samples have been made available to us, providing an opportunity to investigate serotype classification by machine learning methods, which could complement the Bayesian model. RESULTS: We compare the performance of the original Bayesian model with two machine learning algorithms: Gradient Boosting Machines and Random Forests. We present our results as an example of a generic strategy whereby a preliminary probabilistic model is complemented or replaced by a machine learning classifier once enough data are available. Despite the availability of thousands of serotyping arrays, a problem encountered when applying machine learning methods is the lack of training data containing mixtures of serotypes; due to the large number of possible combinations. Most of the available training data comprises samples with only a single serotype. To overcome the lack of training data we implemented an iterative analysis, creating artificial training data of serotype mixtures by combining raw data from single serotype arrays. CONCLUSIONS: With the enhanced training set the machine learning algorithms out perform the original Bayesian model. However, for serotypes currently lacking sufficient training data the best performing implementation was a combination of the results of the Bayesian Model and the Gradient Boosting Machine. As well as being an effective method for classifying biological data, machine learning can also be used as an efficient method for revealing subtle biological insights, which we illustrate with an example. PMID- 28800725 TI - A novel thermal compression device for perioperative warming: a randomized trial for feasibility and efficacy. AB - BACKGROUND: Inadvertent perioperative hypothermia (IPH) leads to surgical complications and increases length of stay. IPH rates are high with the current standard of care, forced air warming (FAW). Our hypothesis is that a prototype thermal compression device that heats the popliteal fossa and soles of the feet, with lower leg compression, increases perioperative temperatures and reduces IPH compared to the current standard of care. METHODS: Thirty six female breast surgery patients, at a tertiary academic hospital, were randomized to the device or intraoperative FAW (stage I) with a further 18 patients randomized to the device with a single heating area only (stage II, popliteal fossa or sole of the feet). Stage I: 37 patients recruited (final 36). Stage II: 18 patients recruited (final 18). INCLUSION CRITERIA: general anesthesia with esophageal monitoring for over 30 min, legs available and able to fit the device and no contraindications to leg heating or compression. The intervention was: Stage I: Investigational prototype thermal compression device (full device group) or intraoperative FAW. Stage II: Device with only a single heating location. Primary outcomes were perioperative temperatures and incidence of IPH. Secondary outcomes were local skin temperature, general and thermal comfort scores and presence of perioperative complications, including blood loss. RESULTS: Mean temperatures in the full device group were significantly higher than the FAW group in the pre operative (36.7 vs 36.4 degrees C, p < 0.001), early intraoperative (36.3 vs 35.9 degrees C, p < 0.001), intraoperative (36.6 vs 36.2 degrees C, p < 0.001) and postoperative periods (36.8 vs 36.5 degrees C, p < 0.001). The incidence of IPH in the device group was also significantly lower (16.7% vs 72.0%, p = 0.001). Thermal comfort scores were significantly higher in the full device group and hypothermia associated wound complications were higher in the FAW group. CONCLUSIONS: The thermal compression device is feasible and has efficacy over the FAW. Further studies are recommended to investigate clinically significant outcomes. TRIAL REGISTRATION: clinicaltrials.gov ( NCT02155400 ). PMID- 28800726 TI - Incidence and risk factors of chronic pain following hysterectomy among Southern Jiangsu Chinese Women. AB - BACKGROUND: Chronic post-surgical pain (CPSP) after hysterectomy has been recognized as a major clinical problem in the Western World. Reports on post hysterectomy pain are relatively scarce in China. The aim of the current study was to prospectively investigate the incidence and the potential risk factors of CPSP at 3 months following hysterectomy in Chinese population. METHODS: We assessed and collected data on preoperative socio-demographic characteristics, preexisting pain, anxiety and depression, sexual satisfaction, intra-operative variables, and acute postoperative pain intensity in a cohort of 870 women undergoing hysterectomy. The participants were interviewed to determine their suitability to diagnostic criteria of CPSP 3 months later. Logistic regression analyses were subsequently performed to identify predictors for CPSP. RESULTS: The incidence of CPSP at 3 months after hysterectomy was 27.7%. Most of the women with CPSP suffered from mild pain and had a slight impact on daily life with sleep and emotion functional limitation. Risk factors for CPSP after hysterectomy were preoperative anxiety, depression, pelvic pain, preexisting pain, very moderate sexual dissatisfaction, and acute postoperative pain at movement. Intra operative dexmedetomidine infusion with 0.5 MUg/kg/h was associated with a decreased incidence rate of chronic post-hysterectomy pain. CONCLUSION: Twenty eight percent of patients after hysterectomy in southern Jiangsu china had CPSP with 92% of those women describing it as mild with sleep and emotion functional limitation. Patients with preoperative anxiety and depression, poor sexual satisfaction, preexisting pain, and acute postoperative pain on movement have been identified to be at risk to develop CPSP. PMID- 28800727 TI - A phased SNP-based classification of sickle cell anemia HBB haplotypes. AB - BACKGROUND: Sickle cell anemia causes severe complications and premature death. Five common beta-globin gene cluster haplotypes are each associated with characteristic fetal hemoglobin (HbF) levels. As HbF is the major modulator of disease severity, classifying patients according to haplotype is useful. The first method of haplotype classification used restriction fragment length polymorphisms (RFLPs) to detect single nucleotide polymorphisms (SNPs) in the beta-globin gene cluster. This is labor intensive, and error prone. METHODS: We used genome-wide SNP data imputed to the 1000 Genomes reference panel to obtain phased data distinguishing parental alleles. RESULTS: We successfully haplotyped 813 sickle cell anemia patients previously classified by RFLPs with a concordance >98%. Four SNPs (rs3834466, rs28440105, rs10128556, and rs968857) marking four different restriction enzyme sites unequivocally defined most haplotypes. We were able to assign a haplotype to 86% of samples that were either partially or misclassified using RFLPs. CONCLUSION: Phased data using only four SNPs allowed unequivocal assignment of a haplotype that was not always possible using a larger number of RFLPs. Given the availability of genome-wide SNP data, our method is rapid and does not require high computational resources. PMID- 28800728 TI - Feasibility and diagnostic accuracy of point-of-care handheld echocardiography in acute ischemic stroke patients - a pilot study. AB - BACKGROUND: Standard echocardiography (SE) is an essential part of the routine diagnostic work-up after ischemic stroke (IS) and also serves for research purposes. However, access to SE is often limited. We aimed to assess feasibility and accuracy of point-of-care (POC) echocardiography in a stroke unit (SU) setting. METHODS: IS patients were recruited on the SU of the University Hospital Wurzburg, Germany. Two SU team members were trained in POC echocardiography for a three-month period to assess a set of predefined cardiac parameters including left ventricular ejection fraction (LVEF). Diagnostic agreement was assessed by comparing POC with SE executed by an expert sonographer, and intraclass correlation coefficient (ICC) or kappa (kappa) with 95% confidence intervals (95% CI) were calculated. RESULTS: In the 78 patients receiving both POC and SE agreement for cardiac parameters was good, with ICC varying from 0.82 (95% CI 0.71-0.89) to 0.93 (95% CI 0.87-0.96), and kappa from 0.39 (-95% CI 0.14-0.92) to 0.79 (95% CI 0.67-0.91). Detection of systolic dysfunction with POC echocardiography compared to SE was very good, with an area under the curve of 0.99 (0.96-1.00). Interrater agreement for LVEF measured by POC echocardiography was good with kappa 0.63 (95% CI 0.40-0.85). CONCLUSIONS: POC echocardiography in a SU setting is feasible enabling reliable quantification of LVEF and preliminary assessment of selected cardiac parameters that might be used for research purposes. Its potential clinical utility in triaging stroke patients who should undergo or do not necessarily require SE needs to be investigated in larger prospective diagnostic studies. PMID- 28800729 TI - accD nuclear transfer of Platycodon grandiflorum and the plastid of early Campanulaceae. AB - BACKGROUND: Campanulaceae species are known to have highly rearranged plastid genomes lacking the acetyl-CoA carboxylase (ACC) subunit D gene (accD), and instead have a nuclear (nr)-accD. Plastid genome information has been thought to depend on studies concerning Trachelium caeruleum and genome announcements for Adenophora remotiflora, Campanula takesimana, and Hanabusaya asiatica. RNA editing information for plastid genes is currently unavailable for Campanulaceae. To understand plastid genome evolution in Campanulaceae, we have sequenced and characterized the chloroplast (cp) genome and nr-accD of Platycodon grandiflorum, a basal member of Campanulaceae. RESULTS: We sequenced the 171,818 bp cp genome containing a 79,061 bp large single-copy (LSC) region, a 42,433 bp inverted repeat (IR) and a 7840 bp small single-copy (SSC) region, which represents the cp genome with the largest IR among species of Campanulaceae. The genome contains 110 genes and 18 introns, comprising 77 protein-coding genes, four RNA genes, 29 tRNA genes, 17 group II introns, and one group I intron. RNA editing of genes was detected in 18 sites of 14 protein-coding genes. Platycodon has an IR containing a 3' rps12 operon, which occurs in the middle of the LSC region in four other species of Campanulaceae (T. caeruleum, A. remotiflora, C. takesimana, and H. asiatica), but lacks accD, clpP, infA, and rpl23, as has been found in these four species. Platycodon nr-accD contains about 3.2 kb intron between nr-accD.e1 and nr-accD.e2 at the same insertion point as in other Campanulaceae. The phylogenies of the plastid genomes and accD show that Platycodon is basal in the Campanulaceae clade, indicating that IR disruption in Campanulaceae occurred after the loss of accD, clpP, infA, and rpl23 in the cp genome, which occurred during plastid evolution in Campanulaceae. CONCLUSIONS: The plastid genome of P. grandiflorum lacks the rearrangement of the IR found in T. caeruleum, A. remotiflora, C. takesimana, and H. asiatica. The absence of accD, clpP, infA, and rpl23 in the plastid genome is a synapomorphic characteristic of Campanulaceae. The chloroplast genome phylogeny supports the hypothesis that chloroplast genomic arrangement occurred after accD nuclear transfer and loss of the four genes in the plastid of early Campanulaceae as a lineage of asterids. PMID- 28800730 TI - Genotypes of hepatitis a virus in Turkey: first report and clinical profile of children infected with sub-genotypes IA and IIIA. AB - BACKGROUND: Hepatitis A virus (HAV) is a food and water-borne virus causing clinical (mainly hepatitis) and subclinical disease in humans. It is important to characterize circulating strains of HAV in order to prevent HAV infections using efficacious vaccines. The aim of this study was the detection and characterization of the circulating strains of HAV in Turkey by performing serology, RT-PCR, sequencing and phylogenetic analysis. METHODS: In this study, 355 HAV suspected cases were analysed by ELISA for the presence of antibodies to HAV. RNA was extracted from 54 HAV IgM positive human sera. None of the suspect cases were vaccinated against HAV and they never received blood transfusions. Samples found positive by RT-PCR using primers targeting the VP1/VP2A junction and VP1/VP3 capsid region of HAV, were subjected to sequencing and phylogenetic analyses. RESULTS: IgM type antibodies to HAV were detected in 54 patients. Twenty one of them were students. The age of IgM positive cases was between 3 and 60 years. IgM positivity differed in age groups and was higher in the age group 3 to 10 years. Phylogenetic analysis showed that the majority of HAV strains detected in this study belong to the "HAV 1B" cluster. In addition, the HAV sub genotypes IA (KT874461.1) and IIIA (KT222963.1) were found in 2 children. These sub-genotypes were not previously reported in Turkey. The child who carried sub genotype IIIA travelled to Afghanistan and presented with abdominal pain, icterus and vomitus. He was positive for anti-HAV IgM and IgG but negative for hepatitis B and C. Liver enzymes like aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase and lactate dehydrogenase were severely elevated. Bilirubin levels were also increased. White blood cells, neutrophils and hemoglobin were decreased while lymphocytes and monocytes were increased. Similar clinical signs and laboratory findings were reported for the child infected with sub-genotype IA but aspartate aminotransferase and alanine aminotransferase were not severely elevated. CONCLUSIONS: The results indicate that molecular studies determining the HAV genotype variation in Turkey are timely and warranted. The majority of IgM positive cases in 3-10 year old patients indicate that childhood vaccination is important. Sub-genotype IB is the most prevalant genotype in Turkey. Surprisingly, sub-genotype IA and IIIA are also present in Turkey; future diagnostic efforts need to include diagnostic methods which can identify this emerging HAV genotypes. Our results also show that one important risk factor for contracting hepatitis A virus is international travel since genotype IIIA was detected in a child who had travelled to Afghanistan. PMID- 28800731 TI - The analysis of APOL1 genetic variation and haplotype diversity provided by 1000 Genomes project. AB - BACKGROUND: The APOL1 gene variants has been shown to be associated with an increased risk of multiple kinds of diseases, particularly in African Americans, but not in Caucasians and Asians. In this study, we explored the single nucleotide polymorphism (SNP) and haplotype diversity of APOL1 gene in different races provided by 1000 Genomes project. METHODS: Variants of APOL1 gene in 1000 Genome Project were obtained and SNPs located in the regulatory region or coding region were selected for genetic variation analysis. Total 2504 individuals from 26 populations were classified as four groups that included Africa, Europe, Asia and Admixed populations. Tag SNPs were selected to evaluate the haplotype diversities in the four populations by HaploStats software. RESULTS: APOL1 gene was surrounded by some of the most polymorphic genes in the human genome, variation of APOL1 gene was common, with up to 613 SNP (1000 Genome Project reported) and 99 of them (16.2%) with MAF >= 1%. There were 79 SNPs in the URR and 92 SNPs in 3'UTR. Total 12 SNPs in URR and 24 SNPs in 3'UTR were considered as common variants with MAF >= 1%. It is worth noting that URR-1 was presents lower frequencies in European populations, while other three haplotypes taken an opposite pattern; 3'UTR presents several high-frequency variation sites in a short segment, and the differences of its haplotypes among different population were significant (P < 0.01), UTR-1 and UTR-5 presented much higher frequency in African population, while UTR-2, UTR-3 and UTR-4 were much lower. APOL1 coding region showed that two SNP of G1 with higher frequency are actually pull down the haplotype H-1 frequency when considering all populations pooled together, and the diversity among the four populations be widen by the G1 two mutation (P 1 = 3.33E 4 vs P 2 = 3.61E-30). CONCLUSIONS: The distributions of APOL1 gene variants and haplotypes were significantly different among the different populations, in either regulatory or coding regions. It could provide clues for the future genetic study of APOL1 related diseases. PMID- 28800732 TI - The Duffy binding protein (PkDBPalphaII) of Plasmodium knowlesi from Peninsular Malaysia and Malaysian Borneo show different binding activity level to human erythrocytes. AB - BACKGROUND: The zoonotic Plasmodium knowlesi is a major cause of human malaria in Malaysia. This parasite uses the Duffy binding protein (PkDBPalphaII) to interact with the Duffy antigen receptor for chemokines (DARC) receptor on human and macaque erythrocytes to initiate invasion. Previous studies on P. knowlesi have reported distinct Peninsular Malaysia and Malaysian Borneo PkDBPalphaII haplotypes. In the present study, the differential binding activity of these haplotypes with human and macaque (Macaca fascicularis) erythrocytes was investigated. METHODS: The PkDBPalphaII of Peninsular Malaysia and Malaysian Borneo were expressed on the surface of COS-7 cells and tested with human and monkey erythrocytes, with and without anti-Fy6 (anti-Duffy) monoclonal antibody treatment. Binding activity level was determined by counting the number of rosettes formed between the transfected COS-7 cells and the erythrocytes. RESULTS: Anti-Fy6 treatment was shown to completely block the binding of human erythrocytes with the transfected COS-7 cells, thus verifying the specific binding of human DARC with PkDBPalphaII. Interestingly, the PkDBPalphaII of Peninsular Malaysia displayed a higher binding activity with human erythrocytes when compared with the Malaysian Borneo PkDBPalphaII haplotype (mean number of rosettes formed = 156.89 +/- 6.62 and 46.00 +/- 3.57, respectively; P < 0.0001). However, no difference in binding activity level was seen in the binding assay using M. fascicularis erythrocytes. CONCLUSION: This study is the first report of phenotypic difference between PkDBPalphaII haplotypes. The biological implication of this finding is yet to be determined. Therefore, further studies need to be carried out to determine whether this differential binding level can be associated with severity of knowlesi malaria in human. PMID- 28800733 TI - Integrative and quantitive evaluation of the efficacy of his bundle related pacing in comparison with conventional right ventricular pacing: a meta-analysis. AB - BACKGROUND: Long-term RVP could bring adverse problems to cardiac electro mechanics and result in inter- and intra-ventricular asynchrony, impaired labor force, and aggravation of cardiac function. HBRP including direct His bundle pacing and para-His bundle pacing was regarded as a novel physiological pacing pattern to avoid devastating cardiac function. This synthetic study was conducted to integratively and quantitatively evaluate the efficacy of His bundle related pacing (HBRP) in comparison with conventional right ventricular pacing (RVP). METHODS: Published studies on comparison of left ventricular ejection fraction (LVEF), left ventricular end diastolic volume (LVEDV), left ventricular end systolic volume (LVESV), New York Heart Association (NYHA) class, inter ventricular asynchrony, and QRS duration, etc. between HBRP and RVP were collected and for meta-analysis. RESULTS: HBRP showed higher LVEF (WMD = 3.9%, 95% CI: 1.6% - 6.1%), lower NYHA class (WMD = -0.5, 95% CI: -0.7 - -0.3), WMD of LVESV = -0.1 ml, 95% CI: -3.0 - 2.8 ml), less inter-ventricular asynchrony (WMD = -13.2 ms, 95% CI: -16.4 - -10.0 ms), and shorter QRS duration for long-term (WMD = -36.9 ms, 95% CI: -40.0 - -33.8 ms), however, no significant difference of ventricular volume (WMDLVEDV = -2.4 ml, 95% CI: -5.0 - 0.2 ml; WMDLVESV = -0.1 ml, 95% CI: -3.0 - 2.8 ml) compared to RVP. CONCLUSIONS: The efficacy of HBRP was firstly verified by meta-analysis to date. Compared with RVP, HBRP markedly preserve LVEF, NYHA class, and QRS duration. However, it seemed to have less effect on ventricular volume. PMID- 28800734 TI - A T-type channel-calmodulin complex triggers alphaCaMKII activation. AB - Calmodulin (CaM) is an important signaling molecule that regulates a vast array of cellular functions by activating second messengers involved in cell function and plasticity. Low voltage-activated calcium channels of the Cav3 family have the important role of mediating low threshold calcium influx, but were not believed to interact with CaM. We find a constitutive association between CaM and the Cav3.1 channel at rest that is lost through an activity-dependent and Cav3.1 calcium-dependent CaM dissociation. Moreover, Cav3 calcium influx is sufficient to activate alphaCaMKII in the cytoplasm in a manner that depends on an intact Cav3.1 C-terminus needed to support the CaM interaction. Our findings thus establish that T-type channel calcium influx invokes a novel dynamic interaction between CaM and Cav3.1 channels to trigger a signaling cascade that leads to alphaCaMKII activation. PMID- 28800735 TI - Life-span of in vitro differentiated Plasmodium falciparum gametocytes. AB - BACKGROUND: The sexual stages (gametocytes) of Plasmodium falciparum do not directly contribute to the pathology of malaria but are essential for transmission of the parasite from the human host to the mosquito. Mature gametocytes circulate in infected human blood for several days and their circulation time has been modelled mathematically from data of previous in vivo studies. This is the first time that longevity of gametocytes is studied experimentally in vitro. METHODS: The in vitro longevity of P. falciparum gametocytes of 1 clinical isolate and 2 laboratory strains was assessed by three different methods: microscopy, flow cytometry and reverse transcription quantitative real-time PCR (RT-qPCR). Additionally, the rate of gametocytogenesis of the used P. falciparum strains was compared. RESULTS: The maximum in vitro lifespan of P. falciparum gametocytes reached almost 2 months (49 days by flow cytometry, 46 days by microscopy, and at least 52 days by RT-qPCR) from the starting day of gametocyte culture to death of last parasite in the tested strains with an average 50% survival rate of 6.5, 2.6 and 3.5 days, respectively. Peak gametocytaemia was observed on average 19 days after initiation of gametocyte culture followed by a steady decline due to natural decay of the parasites. The rate of gametocytogenesis was highest in the NF54 strain. CONCLUSIONS: Plasmodium falciparum mature gametocytes can survive up to 16-32 days (at least 14 days for mature male gametocytes) in vitro in absence of the influence of host factors. This confirms experimentally a previous modelling estimate that used molecular tools for gametocyte detection in treated patients. The survival time might reflect the time the parasite can be transmitted to the mosquito after clearance of asexual parasites. These results underline the importance of efficient transmission blocking agents in the fight against malaria. PMID- 28800736 TI - Using computer, mobile and wearable technology enhanced interventions to reduce sedentary behaviour: a systematic review and meta-analysis. AB - BACKGROUND: High levels of sedentary behaviour (SB) are associated with negative health consequences. Technology enhanced solutions such as mobile applications, activity monitors, prompting software, texts, emails and websites are being harnessed to reduce SB. The aim of this paper is to evaluate the effectiveness of such technology enhanced interventions aimed at reducing SB in healthy adults and to examine the behaviour change techniques (BCTs) used. METHODS: Five electronic databases were searched to identify randomised-controlled trials (RCTs), published up to June 2016. Interventions using computer, mobile or wearable technologies to facilitate a reduction in SB, using a measure of sedentary time as an outcome, were eligible for inclusion. Risk of bias was assessed using the Cochrane Collaboration's tool and interventions were coded using the BCT Taxonomy (v1). RESULTS: Meta-analysis of 15/17 RCTs suggested that computer, mobile and wearable technology tools resulted in a mean reduction of -41.28 min per day (min/day) of sitting time (95% CI -60.99, -21.58, I2 = 77%, n = 1402), in favour of the intervention group at end point follow-up. The pooled effects showed mean reductions at short (<= 3 months), medium (>3 to 6 months), and long-term follow up (>6 months) of -42.42 min/day, -37.23 min/day and -1.65 min/day, respectively. Overall, 16/17 studies were deemed as having a high or unclear risk of bias, and 1/17 was judged to be at a low risk of bias. A total of 46 BCTs (14 unique) were coded for the computer, mobile and wearable components of the interventions. The most frequently coded were "prompts and cues", "self-monitoring of behaviour", "social support (unspecified)" and "goal setting (behaviour)". CONCLUSION: Interventions using computer, mobile and wearable technologies can be effective in reducing SB. Effectiveness appeared most prominent in the short-term and lessened over time. A range of BCTs have been implemented in these interventions. Future studies need to improve reporting of BCTs within interventions and address the methodological flaws identified within the review through the use of more rigorously controlled study designs with longer-term follow-ups, objective measures of SB and the incorporation of strategies to reduce attrition. TRIAL REGISTRATION: The review protocol was registered with PROSPERO: CRD42016038187. PMID- 28800737 TI - Anaemia in pregnancy and associated factors: a cross sectional study of antenatal attendants at the Sunyani Municipal Hospital, Ghana. AB - BACKGROUND: Anaemia in pregnancy is an important health issue resulting in high maternal morbidity and mortality. The purpose of the current study was to identify factors associated with anaemia among pregnant women receiving antenatal care at the Sunyani Municipal Hospital in Ghana. METHODS: A cross-sectional study involving pregnant women seeking antenatal care at the Sunyani Municipal Hospital was conducted between May and June, 2015. It involved the collection of data on socio demographic and obstetric variables, medical interventions and malaria infection, consumption of iron containing foods and supplements using a case record form and a structured questionnaire. Also, data on haemoglobin concentrations at first and current antenatal visit were collected. Bivariate and multivariate statistical analysis were done to determine factors associated with anaemia. RESULTS: Out of the 316 participants, 129 (40.8%) were found to be anaemic (Hb <11.0 g/dl) at the time of their first ANC visit (mean Hb: 11.21 g/dl, range 6.8-15.1 g/dl). Seventy-nine (61.2%) of them had mild anemia (Hb 9.0 10.9 g/dl), 48 (37.2%) had moderate anemia (Hb 7.0-8.9 g/dl) whilst 2 (1.6%) had severe anemia (Hb <7.0 g/dl). During their most recent ANC visit, the prevalence of anaemia was found to be similar to that of the first visit with 131 (41.5%) of them being anaemic [mean Hb: 11.24 g/dl, range 8.10-14.5 g/dl]. The haemoglobin levels however improved significantly during the most recent visit compared to the first with none of the women being severely anaemic (Hb <7.0 g/dl). The prevalence of moderate anaemia reduced from 37.2% (CI 28.9-46.2) during the first visit to 19.1% (12.7-26.9) during the most recent visit, a reduction of 48.7%. Malaria infection, frequency at which one consumed fish/snails and gestational age at first ANC visit were the main factors found to be associated with anaemia among the pregnant women. CONCLUSIONS: Malaria infection, fish/snails intake and gestational age at first ANC visit were significantly associated with anaemia. Addressing these factors can reduce the incidence of anaemia in pregnancy. PMID- 28800738 TI - Advances in closed-loop deep brain stimulation devices. AB - BACKGROUND: Millions of patients around the world are affected by neurological and psychiatric disorders. Deep brain stimulation (DBS) is a device-based therapy that could have fewer side-effects and higher efficiencies in drug-resistant patients compared to other therapeutic options such as pharmacological approaches. Thus far, several efforts have been made to incorporate a feedback loop into DBS devices to make them operate in a closed-loop manner. METHODS: This paper presents a comprehensive investigation into the existing research-based and commercial closed-loop DBS devices. It describes a brief history of closed-loop DBS techniques, biomarkers and algorithms used for closing the feedback loop, components of the current research-based and commercial closed-loop DBS devices, and advancements and challenges in this field of research. This review also includes a comparison of the closed-loop DBS devices and provides the future directions of this area of research. RESULTS: Although we are in the early stages of the closed-loop DBS approach, there have been fruitful efforts in design and development of closed-loop DBS devices. To date, only one commercial closed-loop DBS device has been manufactured. However, this system does not have an intelligent and patient dependent control algorithm. A closed-loop DBS device requires a control algorithm to learn and optimize the stimulation parameters according to the brain clinical state. CONCLUSIONS: The promising clinical effects of open-loop DBS have been demonstrated, indicating DBS as a pioneer technology and treatment option to serve neurological patients. However, like other commercial devices, DBS needs to be automated and modernized. PMID- 28800739 TI - Sources of variability in quantification of cardiovascular magnetic resonance infarct size - reproducibility among three core laboratories. AB - BACKGROUND: Acute myocardial infarct (AMI) size depicted by late gadolinium enhancement cardiovascular magnetic resonance (CMR) is increasingly used as an efficacy endpoint in randomized trials comparing AMI therapies. Infarct size is quantified using manual planimetry (MANUAL), visual scoring (VISUAL), or automated techniques using signal-intensity thresholding (AUTO). Although AUTO is considered the most reproducible, prior studies did not account for the subjective determination of endocardial/epicardial borders, which all methods require. For MANUAL and VISUAL, prior studies did not address how to treat intermediate signal intensities due to partial volume. METHODS: To assess sources of variability, AMI size was measured in 30 patients and 12 controls by 3 core laboratories using 8 methods, each separated by more than 2 months time (n = 720 evaluations). The methods were: (1,2) AUTOSegment, AUTOFWHM (using Segment software or the full-width-at-half-maximum algorithm, respectively); (3,4) AUTO UCSegment, AUTO-UCFWHM (user correction for endocardial border pixels, no-reflow, etc.); (5) MANUAL; (6) MANUAL-ISI (adjustment for intermediate signal intensities); (7) VISUAL; (8) VISUAL-ISI. RESULTS: Mean infarct size varied between 16.8% and 27.2% of LV mass depending on method. Even automated techniques with no user interaction for infarct borders resulted in significant within patient variability given the need to subjectively trace endocardial/epicardial contours. The coefficient-of-variation (CV) was 10.6% and 14.6% for AUTOSegment and AUTOFWHM, respectively. For manual and visual categories, reproducibility was improved when intermediate signal-intensities were considered (MANUAL-ISI vs MANUAL: CV = 8.3% vs 14.4%; p = 0.03; VISUAL-ISI vs VISUAL: CV = 8.4% vs 10.9%; p = 0.01). For AUTO-UCSegment, MANUAL-ISI, and VISUAL-ISI (best technique in each category) within-patient variability due to the quantification method was less than 10% of total variability, and the required sample sizes for detecting a 5% absolute difference in infarct size were 62, 63, and 62 patients, respectively. CONCLUSION: Among CMR core-laboratories, an important source of variability in infarct size quantification is the subjective delineation of endocardial/epicardial borders. When intermediate signal intensities are considered in manual planimetry and visual scoring, reproducibility and impact on sample size are similar to automated techniques. PMID- 28800740 TI - Neurocognitive sparing of desktop microbeam irradiation. AB - BACKGROUND: Normal tissue toxicity is the dose-limiting side effect of radiotherapy. Spatial fractionation irradiation techniques, like microbeam radiotherapy (MRT), have shown promising results in sparing the normal brain tissue. Most MRT studies have been conducted at synchrotron facilities. With the aim to make this promising treatment more available, we have built the first desktop image-guided MRT device based on carbon nanotube x-ray technology. In the current study, our purpose was to evaluate the effects of MRT on the rodent normal brain tissue using our device and compare it with the effect of the integrated equivalent homogenous dose. METHODS: Twenty-four, 8-week-old male C57BL/6 J mice were randomly assigned to three groups: MRT, broad-beam (BB) and sham. The hippocampal region was irradiated with two parallel microbeams in the MRT group (beam width = 300 MUm, center-to-center = 900 MUm, 160 kVp). The BB group received the equivalent integral dose in the same area of their brain. Rotarod, marble burying and open-field activity tests were done pre- and every month post-irradiation up until 8 months to evaluate the cognitive changes and potential irradiation side effects on normal brain tissue. The open-field activity test was substituted by Barnes maze test at 8th month. A multilevel model, random coefficients approach was used to evaluate the longitudinal and temporal differences among treatment groups. RESULTS: We found significant differences between BB group as compared to the microbeam-treated and sham mice in the number of buried marble and duration of the locomotion around the open field arena than shams. Barnes maze revealed that BB mice had a lower capacity for spatial learning than MRT and shams. Mice in the BB group tend to gain weight at the slower pace than shams. No meaningful differences were found between MRT and sham up until 8-month follow-up using our measurements. CONCLUSIONS: Applying MRT with our newly developed prototype compact CNT-based image-guided MRT system utilizing the current irradiation protocol can better preserve the integrity of normal brain tissue. Consequently, it enables applying higher irradiation dose that promises better tumor control. Further studies are required to evaluate the full extent effects of this novel modality. PMID- 28800741 TI - Erythrocyte depletion from bone marrow: performance evaluation after 50 clinical scale depletions with Spectra Optia BMC. AB - BACKGROUND: Red blood cell (RBC) depletion is a standard graft manipulation technique for ABO-incompatible bone marrow (BM) transplants. The BM processing module for Spectra Optia, "BMC", was previously introduced. We here report the largest series to date of routine quality data after performing 50 clinical-scale RBC-depletions. METHODS: Fifty successive RBC-depletions from autologous (n = 5) and allogeneic (n = 45) BM transplants were performed with the Spectra Optia BMC apheresis suite. Product quality was assessed before and after processing for volume, RBC and leukocyte content; RBC-depletion and stem cell (CD34+ cells) recovery was calculated there from. Clinical engraftment data were collected from 26/45 allogeneic recipients. RESULTS: Median RBC removal was 98.2% (range 90.8 99.1%), median CD34+ cell recovery was 93.6%, minimum recovery being 72%, total product volume was reduced to 7.5% (range 4.7-23.0%). Products engrafted with expected probability and kinetics. Performance indicators were stable over time. DISCUSSION: Spectra Optia BMC is a robust and efficient technology for RBC depletion and volume reduction of BM, providing near-complete RBC removal and excellent CD34+ cell recovery. PMID- 28800742 TI - An intramedullary Echidna pin for fixation of comminuted clavicle fractures: a biomechanical study. AB - BACKGROUND: Intramedullary fixation of comminuted mid-shaft clavicle fractures has traditionally been employed with satisfactory clinical outcomes; however, pins with smooth surfaces may protrude from the bone and are prone to migration, while some threaded pins are difficult to remove post-operatively. The aim of this proof-of-concept study was to develop and evaluate the biomechanical strength of a novel intramedullary Echidna pin device designed to maintain fracture reduction, resist migration and facilitate ease of post-operative removal. METHODS: Thirty human clavicle specimens were harvested and fractured in a comminuted mid-shaft butterfly configuration. Each specimen was randomly allocated to three surgical repair groups including intramedullary fixation using the Echidna pin and Herbert Cannulated Bone Screw System, as well as plate fixation using bi-cortical locking screws. Using a biomechanical testing apparatus, construct bending and torsional stiffness were measured, as well as ultimate bending strength. RESULTS: There was no significant difference in torsional stiffness and ultimate bending moment between the Echidna pin and Herbert screw repair constructs (p > 0.05); however, the Echidna pin construct demonstrated a significantly greater bending stiffness compared to that of the Herbert screw construct (mean difference 0.55 Nm/deg., p = 0.001). The plate construct demonstrated significantly greater torsional stiffness, bending stiffness and ultimate bending moment compared to those of the Herbert screw and Echidna pin (p < 0.05). CONCLUSIONS: An intramedullary Echidna pin device was designed to stabilize comminuted fractures of the clavicle, maintain fracture compression and provide ease of removal post-operatively. Since the results suggest equivalent or superior torsional and bending stability in the Echidna pin compared to that of the Herbert screw, the Echidna pin concept may represent an alternative fixation device to conventional intramedullary screws, nails and pins; however, superior plating using bi-cortical locking screws provides substantially higher construct structural rigidity than intramedullary devices, and may therefore be useful in cases of osteoporotic bone, or where high fracture stability is required. PMID- 28800743 TI - An iTRAQ-based proteomic analysis reveals dysregulation of neocortical synaptopodin in Lewy body dementias. AB - Lewy body dementias are the second most common cause of neurodegenerative dementia in the elderly after Alzheimer's disease (AD). The two clinical subgroups of Lewy body dementias, namely, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), are differentiated by the chronology of cognitive symptoms relative to parkinsonism. At present, there remains a debate on whether DLB and PDD are separate disease entities, or fall within the same spectrum of Lewy body dementias. In this study, we compared the detergent-soluble proteome via an 8-plex isobaric tag for relative and absolute quantitation (iTRAQ) analysis of pooled lysates from the prefrontal cortex (BA9) of DLB (n = 19) and PDD (n = 21) patients matched a priori for amyloid (total Abeta42) burden, semi-quantitative scores for Lewy bodies and neurofibrillary tangles together with age-matched control (n = 21) subjects. A total of 1914 proteins were confidently identified by iTRAQ (false discovery rate = 0%). None of the proteins showed a significant yet opposite regulation in between DLB and PDD when compared to aged controls in the proteomic data set as well as following immunoblot analysis of the pooled and individual lysates involving all 61 subjects. The postsynaptic protein, synaptopodin (SYNPO) was significantly down regulated in both DLB and PDD subgroups, suggesting a defective synaptic transmission in the demented patients. In conclusion, the largely similar proteome of DLB and PDD matched for amyloid burden suggests that variations in concomitant AD-related pathology, abnormal post-translational modifications or protein-protein interactions, defective intracellular trafficking or misfolding of proteins could play a part in driving the clinically observed differences between these two subgroups of Lewy body dementias. This further indicates that amyloid-targeting therapeutic strategies may show different efficacies in DLB versus PDD. PMID- 28800745 TI - Retraction Note: Intracytoplasmic morphologically selected sperm injection versus conventional intracytoplasmic sperm injection: a randomized controlled trial. PMID- 28800744 TI - Physiological artifacts in scalp EEG and ear-EEG. AB - BACKGROUND: A problem inherent to recording EEG is the interference arising from noise and artifacts. While in a laboratory environment, artifacts and interference can, to a large extent, be avoided or controlled, in real-life scenarios this is a challenge. Ear-EEG is a concept where EEG is acquired from electrodes in the ear. METHODS: We present a characterization of physiological artifacts generated in a controlled environment for nine subjects. The influence of the artifacts was quantified in terms of the signal-to-noise ratio (SNR) deterioration of the auditory steady-state response. Alpha band modulation was also studied in an open/closed eyes paradigm. RESULTS: Artifacts related to jaw muscle contractions were present all over the scalp and in the ear, with the highest SNR deteriorations in the gamma band. The SNR deterioration for jaw artifacts were in general higher in the ear compared to the scalp. Whereas eye blinking did not influence the SNR in the ear, it was significant for all groups of scalps electrodes in the delta and theta bands. Eye movements resulted in statistical significant SNR deterioration in both frontal, temporal and ear electrodes. Recordings of alpha band modulation showed increased power and coherence of the EEG for ear and scalp electrodes in the closed-eyes periods. CONCLUSIONS: Ear-EEG is a method developed for unobtrusive and discreet recording over long periods of time and in real-life environments. This study investigated the influence of the most important types of physiological artifacts, and demonstrated that spontaneous activity, in terms of alpha band oscillations, could be recorded from the ear-EEG platform. In its present form ear-EEG was more prone to jaw related artifacts and less prone to eye-blinking artifacts compared to state-of-the-art scalp based systems. PMID- 28800746 TI - Artery of Percheron infarction: a case report. AB - BACKGROUND: The artery of Percheron is a rare anatomic variant of arterial supply to the paramedian thalamus and rostral midbrain, and occlusion of the artery of Percheron results in bilateral paramedian thalamic infarcts with or without midbrain involvement. Acute artery of Percheron infarcts represent 0.1 to 2% of total ischemic stroke. However, of thalamic strokes, occlusion of artery of Percheron is the cause in 4 to 35% of cases. Early diagnosis of artery of Percheron infarction can be challenging because it is infrequent and early computed tomography or magnetic resonance imaging may be negative. Thus, it can be confused with other neurological conditions such as tumors and infections. CASE PRESENTATION: This is a retrospective case study of a 56-year-old white man admitted to Umea University Hospital and diagnosed with an artery of Percheron infarction. Medical records and the neuroradiological database were reviewed, and the diagnosis was made based on typical symptoms and radiological findings of artery of Percheron infarction. We report the case of a 56-year-old man with a history of overconsumption of alcohol who was found in his home unconscious and hypothermic. He had a Reaction Level Scale-85 score of 4. He developed ventricular fibrillation on arrival at our emergency department, and cardiopulmonary resuscitation successfully restored sinus rhythm within an estimated 2 minutes of onset. He was then put on cardiopulmonary bypass for rewarming. The initial head computed tomography performed on admission was wrongly assessed as unremarkable. Bilateral ischemia in the paramedian thalamic nuclei and pons were first documented on a follow-up computed tomography on day 24 after hospitalization. He died on day 35 after hospitalization. CONCLUSIONS: Artery of Percheron infarcts are rare. The radiological diagnosis can initially often be judged as normal and in combination with variability in the neurological symptoms it is a rather difficult condition to diagnose. For these reasons few clinicians have much experience with this type of infarct, which may delay diagnosis and initiation of appropriate treatment. PMID- 28800747 TI - Bovine cryptosporidiosis: impact, host-parasite interaction and control strategies. AB - Gastrointestinal disease caused by the apicomplexan parasite Cryptosporidium parvum is one of the most important diseases of young ruminant livestock, particularly neonatal calves. Infected animals may suffer from profuse watery diarrhoea, dehydration and in severe cases death can occur. At present, effective therapeutic and preventative measures are not available and a better understanding of the host-pathogen interactions is required. Cryptosporidium parvum is also an important zoonotic pathogen causing severe disease in people, with young children being particularly vulnerable. Our knowledge of the immune responses induced by Cryptosporidium parasites in clinically relevant hosts is very limited. This review discusses the impact of bovine cryptosporidiosis and describes how a thorough understanding of the host-pathogen interactions may help to identify novel prevention and control strategies. PMID- 28800748 TI - Short-term treatment with taurolidine is associated with liver injury. AB - BACKGROUND: Taurolidine has been used for peritonitis, oncological and catheter lock treatment because of its anti-inflammatory properties. It has been suggested that taurolidine has no severe side-effects, but after long-term use morphological and functional changes of the liver were reported. The aim of this study was to investigate the effect of short-term use of taurolidine on the liver. METHODS: In HepaRG cell cultures and on a novel liver biochip dose dependent effects of taurolidine treatment on hepatocyte adherence and cell viability was investigated. Furthermore, liver enzymes and interleukin- (IL-) 6 were measured in supernatants. Male rats were treated with low- or high-dose taurolidine, respectively, and compared to controls with physiological saline solution administration regarding blood serum parameters and histology. RESULTS: In HepaRG cell cultures, hepatocyte adherence was significantly decreased, cell death and cleaved caspase-3 were significantly increased after administration of taurolidine in a dose-dependent manner. High-dose application of taurolidine led to elevated liver enzymes and IL-6 secretion in hepatic organoid. After 24 h a significant increase of serum GLDH and ASAT was observed in rats treated with high-dose taurolidine treatment. CONCLUSIONS: Our results suggest that taurolidine caused liver injury after short-term use in in vitro and in vivo models probably due to direct toxic effects on hepatocytes. Therefore, the taurolidine dose should be titrated in further investigations regarding liver injury and inflammation. PMID- 28800749 TI - Palliative external beam radiotherapy for the treatment of tumor bleeding in inoperable advanced gastric cancer. AB - BACKGROUND: To assess the outcomes and prognostic factors associated with palliative external beam radiotherapy (EBRT), administered to patients with advanced gastric cancer. METHODS: Forty-two patients with bleeding gastric tumors that received EBRT for palliation were analyzed. The response to EBRT was assessed by the palliation of tumor bleeding. Patients were classified as either responders, or non-responders to EBRT. The prognostic utility of clinical and dosimetric variables was examined in a multivariate logistic regression model. The optimal dose cutoff to classify the two groups was determined with receiver operating characteristic analysis. RESULTS: The palliation of gastric tumor bleeding after EBRT was achieved in 29 patients (69.0%). The time to resolve tumor bleeding ranged from 1 to 84 days (median, 15 days). The median duration of palliation was 14.9 weeks. The median EBRT dose was 40 Gy in responders vs. 21 Gy in non-responders, with the difference being significant (p < 0.001). The biologically effective dose (using alpha/beta = 10, BED10) for responders was significantly higher than the BED10 for non-responders (median 48 Gy vs. 26.4 Gy, p < 0.001), and the optimal cut off value to separate the two groups was 36 Gy (p < 0.001). The absence of distant metastasis and the use of concurrent chemotherapy generally showed a better EBRT response (p = 0.079 and p = 0.079, respectively). In the multivariate analysis, BED10 >= 36 Gy was the most significant factor associated with EBRT response (p = 0.001). Overall survival (OS) and re-bleeding-free survival was median 12.6 weeks and 14.9 weeks. The responders to EBRT showed superior OS (16.6 vs. 5.1 months, p < 0.001). Neither acute nor chronic toxicities of grade 3 or higher were observed. CONCLUSIONS: EBRT is an effective method for treating tumor bleeding in advanced gastric cancer, and does not induce severe toxicity. PMID- 28800750 TI - Angiopoietin-1 deficiency increases tumor metastasis in mice. AB - BACKGROUND: Angipoietin-1 activation of the tyrosine kinase receptor Tek expressed mainly on endothelial cells leads to survival and stabilization of endothelial cells. Studies have shown that Angiopoietin-1 counteracts permeability induced by a number of stimuli. Here, we test the hypothesis that loss of Angiopoietin-1/Tek signaling in the vasculature would increase metastasis. METHODS: Angiopoietin-1 was deleted in mice just before birth using floxed Angiopoietin-1 and Tek mice crossed to doxycycline-inducible bitransgenic ROSA-rtTA/tetO-Cre mice. By crossing Angiopoietin-1 knockout mice to the MMTV PyMT autochthonous mouse breast cancer model, we investigated primary tumor growth and metastasis to the lung. Furthermore, we utilized B16F10 melanoma cells subcutaneous and experimental lung metastasis models in Angiopoietin-1 and Tek knockout mice. RESULTS: We found that primary tumor growth in MMTV-PyMT mice was unaffected, while metastasis to the lung was significantly increased in Angiopoietin-1 knockout MMTV-PyMT mice. In addition, angiopoietin-1 deficient mice exhibited a significant increase in lung metastasis of B16F10 melanoma cells, compared to wild type mice 3 weeks after injection. Additional experiments showed that this was likely an early event due to increased attachment or extravasation of tumor cells, since seeding of tumor cells was significantly increased 4 and 24 h post tail vein injection. Finally, using inducible Tek knockout mice, we showed a significant increase in tumor cell seeding to the lung, suggesting that Angiopoietin-1/Tek signaling is important for vascular integrity to limit metastasis. CONCLUSIONS: This study show that loss of the Angiopoietin-1/Tek vascular growth factor system leads to increased metastasis without affecting primary tumor growth. PMID- 28800751 TI - Prevalence, awareness, treatment and control of dyslipidemia in older persons in urban and rural population in the Astana region, Kazakhstan. AB - BACKGROUND: Despite high cardiovascular mortality in Central Asian republics of the former Soviet Union, there is limited information about major risk factors, including blood lipids. We investigated the prevalence of impaired concentrations of blood lipids, the awareness, treatment and control of hypercholesterolemia, and factors associated with these indicators in urban and rural populations in Kazakhstan. METHODS: We conducted a cross-sectional study of random urban and rural population samples (the state capital Astana and Akmol village). Men and women aged 50-74 years were examined; a total of 954 adults participated (response rate 59%). Serum concentrations of total, LDL and HDL cholesterol and triglycerides and a range of other cardiovascular risk factors were measured. RESULTS: The overall prevalence of hypercholesterolemia (total cholesterol >=6.2 mmol/l) was 37%; among subjects with hypercholesterolemia, 57% were aware of their condition, 41% took medication and 23% had total cholesterol <6.2 mmol/l (4.5% <5 mmol/l). The prevalence, awareness, treatment, and control of hypercholesterolemia were all higher in the urban than the rural area. Similarly, the proportions of subjects with impaired concentrations of specific lipids fractions were also considerably higher in the urban population. Most associations with other covariates were in the expected direction. CONCLUSIONS: This study found relatively high prevalence of dyslipidemia in the Kazakh population, and the blood lipid profile was less favourable in the urban area. These pronounced urban-rural differences may be related to urbanization, the associated nutrition transition and to access to health care. PMID- 28800752 TI - A type I combi-targeting approach for the design of molecules with enhanced potency against BRCA1/2 mutant- and O6-methylguanine-DNA methyltransferase (mgmt) expressing tumour cells. AB - BACKGROUND: Mutations of the DNA repair proteins BRCA1/2 are synthetically lethal with the DNA repair enzyme poly(ADP-ribose) polymerase (PARP), which when inhibited, leads to cell death due to the absence of compensatory DNA repair mechanism. The potency of PARP inhibitors has now been clinically proven. However, disappointingly, acquired resistance mediated by the reactivation of wild type BRCA1/2 has been reported. In order to improve their efficacy, trials are ongoing to explore their combinations with temozolomide (TMZ). Here, in order to enhance potency in BRCA1/2-mutant cells, we report on the design of single molecules termed "combi-molecules" capable of not only inhibiting PARP but also damaging DNA like TMZ, which is known to induce a large number of DNA adducts. The majority of these lesions are processed through PARP-dependent base-excision repair machinery. Paradoxically, the least abundant lesion, the O6-methylguanine adduct is the most cytotoxic. Its repair by the O6-methylguanine DNA methyl transferase (MGMT) confers robust resistance to TMZ. Thus, we surmise that a combi-molecule designed to generate the same DNA adducts as TMZ, with an additional ability to block PARP, could induce BRCA1/2 mutant selective potency and a growth inhibitory profile independent of MGMT status. METHODS: The hydrolysis of EG22 and its stabilized form ZSM02 was analyzed by HPLC and fluorescence spectroscopy. Growth inhibitory potency was determined by SRB assay. PARP inhibition was determined by an enzyme assay and DNA damage by the comet assay. Subcellular distribution was visualized by confocal microscopy. RESULTS: Studies on EG22 showed that: (a) it inflicted anomalously higher levels of DNA damage than TMZ (b) it induced PARP inhibitory potency in the same range as ANI, a known PARP inhibitor (IC50 = 0.10 MUM) (c) it showed strong potency in both BRCA1/2 wild type and mutated cells with 6-fold selectivity for the mutants and it was 65-303-fold more potent than TMZ and 4-63-fold than ANI alone and 3-47 fold than their corresponding equimolar combinations and (d) its potency was independent of MGMT expression. CONCLUSION: The results in toto suggest that a combi-molecular approach directed at blocking PARP and damaging DNA can lead to single molecules with selective and enhanced potency against BRCA1/2 mutant and with activity independent of MGMT, the major predictive biomarker for resistance to TMZ. PMID- 28800753 TI - Efficacy of a prevention program for eating disorders in schools: a cluster randomized controlled trial. AB - BACKGROUND: Previous prevention programs in the school context have not addressed both genders, have been time-consuming, or have had deficits in the evaluation method. The aim of the present study was to evaluate the impact of a universal prevention program for female and male adolescents on eating disorder pathology and related risk factors. METHODS: Between February 2012 and July 2014, 2515 students in 23 schools from 8th or 11th grade were assessed for eligibility in this longitudinal cluster-randomized controlled trial with a six months follow up. Of those students, 2342 were cluster-randomized to the intervention condition which received a six school hours universal prevention program or to the no treatment control condition. RESULTS: The complete case population comprised 724 students in the intervention (54.3% female, M = 14.3 years, SD = 1.61) and 728 in the control condition (57.0% female, M = 14.7 years, SD = 1.63). Random-effects analysis of covariance on the primary outcome showed no significant differences between the intervention and control groups in their eating disorder pathology change scores six months after the intervention. Regarding secondary outcomes, participants in the intervention group showed a greater increase in knowledge about eating disorders both after the intervention (p < .001, ES = 1.06) and six months later (p = .01, ES = 0.40). Greater reductions in anxiety severity were observed in the intervention group post-intervention (p = .02, ES = 0.22) which was not maintained at the six months follow-up. Results differed between participants from grade 8 and 11. CONCLUSION: The present universal prevention program can be particularly recommended for adolescents from grade 11. TRIAL REGISTRATION: ISRCTN 97989348. PMID- 28800755 TI - The influence of 3 months of physical exercises and verbal stimulation on functional efficiency and use of free time in an older population under institutional care: study protocol for a randomized controlled trial. AB - BACKGROUND: In recent years, there has been a significant change in the demographics of developed countries, including an increase in the number of older people. This aging population and the associated need for medical care and assistance places great strain on health care systems worldwide. In older populations, improved knowledge and understanding of the relationship between moderate exercise and health might result in greater motivation to engage in such activity; thus improving the overall health of this population. The aim of the proposed project is to assess the degree of improvement in functional performance through physical training with verbal stimulation, as well as the possibility of changing habitual ways of spending free time, in older people under institutional care. METHODS: Study participants aged 65-85 years, who are living a sedentary lifestyle in care homes in Southeast Poland, will be invited to participate in this randomized controlled trial. Those who meet the eligibility criteria and are enrolled in the study will be assigned at random to one of four parallel groups: (1) basic exercises combined with verbal stimulation, (2) basic exercises without verbal stimulation, (3) functional exercise training with verbal stimulation, and (4) functional exercise training without verbal stimulation. Participants will engage in 30-min workouts, twice per week, for 12 weeks. Tests will be done: (1) before exercises, (2) after 12 weeks of exercises, (3) 12 weeks after the end of the exercises, and (4) 24 weeks after the exercises. Primary outcome measures will include the Short Physical Performance Battery (SPPB). Secondary outcomes will include the Physical Activity Scale for the Elderly (PASE), the Timed Up and Go (TUG) test, the 10-Meter Walk test (10MWT), the Back Scratch (BS) test, the Chair Sit and Reach (CSR) test, the Grip Strength (GS), and the Berg Balance Scale (BBS). Other outcomes will include results regarding postural stability from the stabilometric platform and quality of life (SF-36). DISCUSSION: Our study will help to determine the effectiveness of the training programs, particularly in relation to participants' motivation to exercise. TRIAL REGISTRATION: The Sri Lanka Clinical Trials Registry, ID: SLCTR/2016/004 . Registered on 12 February 2016. PMID- 28800756 TI - Lawsonia intracellularis in the feces of wild rodents and stray cats captured around equine farms. AB - BACKGROUND: Proliferative enteropathy is a global enteric disease of particular importance in pigs. The causative bacterium, Lawsonia intracellularis, has a wide range of susceptible host species. Recently, L. intracellularis has been recognized as an etiologic agent of an emerging enteric disease in foals called equine proliferative enteropathy (EPE). The presence of L. intracellularis in nonruminant wildlife has raised questions regarding the role of these species in EPE transmission. RESULTS: This study investigated exposure to L. intracellularis in wild rodents and feral cats from eight farms with confirmed EPE. Serum (42) and fecal (40) samples from resident foals and fecal samples (131), intestinal mucosa tissues (14), and mesenteric lymph nodes (14) from wild and feral animals were collected for the evaluation of the farm status and the molecular detection of L. intracellularis following the diagnosis of EPE in index cases. Fresh feces from wild rodents and feral cats were collected from the ground while walking the premises or after trapping the animals using live traps. A total of 3 brown rats, 7 house mice, 1 striped field mouse, 2 grey red-backed voles, and 3 feral cats showed evidence of prior exposure to L. intracellularis. CONCLUSIONS: Our data add to increasing evidence demonstrating the potential for L. intracellularis transmission and infection in wild rodents and feral cats and provide possible evidence of interspecies transmission. The exposure of wild rodents and feral cats provides potential evidence for the spillover of L. intracellularis to wildlife species and raises the question of spillback to horses. Additionally, these animals may represent an indicator of environmental exposure or may be actively involved in the transmission of L. intracellularis to foals by acting as potential reservoir/amplifier hosts. This study is the first to demonstrate the magnitude of L. intracellularis shedding in the feces of wild rodents and feral cats and to indicate the significant infection risk that wild rodents and feral cats pose to naive horses in South Korea. PMID- 28800754 TI - Current concepts in bone metastasis, contemporary therapeutic strategies and ongoing clinical trials. AB - BACKGROUND: Elucidation of mechanisms regulating bone metastasis has progressed significantly in recent years and this has translated to many new therapeutic options for patients with bone metastatic cancers. However, the rapid rate of progress in both the basic science literature and therapies undergoing clinical trials makes staying abreast with current developments challenging. This review seeks to provide an update on the current state of the science in bone metastasis research and give a snap shot of therapies in clinical trials for bone metastatic cancer. MAIN BODY: Bone metastasis represents a difficult to treat clinical scenario due to pain, increased fracture risk, decreased quality of life and diminished overall survival outcomes. Multiple types of cancer have the specific ability to home to the bone microenvironment and cause metastatic lesions. This osteotropism was first described by Stephen Paget nearly 100 years ago as the 'seed and soil' hypothesis. Once cancer cells arrive at the bone they encounter a variety of cells native to the bone microenvironment which contribute to the establishment of bone metastatic lesions. In the first part of this review, the 'seed and soil' hypothesis is revisited while emphasizing recent developments in understanding the impact of native bone microenvironment cells on the metastatic process. Next, approved therapies for treating bone metastasis at the systemic level as well as those that target the bone microenvironment are discussed and current National Comprehensive Cancer Network (NCCN) guidelines relating to treatment of bone metastases are summarized. Finally, all open interventional clinical trials for therapies relating to treatment of bone metastasis have been complied and categorized. CONCLUSION: Understanding the recent advancements in bone metastasis research is important for continued development of novel bone targeted therapies. The plethora of ongoing clinical trials will hopefully translate into improved treatments options for patients suffering from bone metastatic cancers. PMID- 28800757 TI - Anthelminthic properties of Methylene chloride-methanol (1:1) extracts of two Cameroonians medicinal plants on Heligmosomoides bakeri (Nematoda: Heligmosomatidea). AB - BACKGROUND: The resistance of some medico-veterinary parasite strains as well as the unavailability and toxicity of synthetic anthelminthics on humans, animals and the impacts of their residues in the environment have pushed scientists to turn to plants with anthelminthic properties. Hence, the aim of this work was to contribute to the fight against helminths of medical and veterinary importance in general, and also to clear the environment of their free living stages. METHODS: Fresh eggs of Heligmosomoides bakeri were obtained from the faeces of experimentally infected mice. L1 and L2 larval stages were obtained after 48 and 72 h of coproculture respectively. Methylene Chloride-Methanol (1:1) extracts of Annona senegalensis and Nauclea latifolia were diluted in DMSO or Tween 80 to prepare the following concentrations: 625, 1250, 2500, 3750 and 5000 MUg/ml. The effects of extract solutions were evaluated on the embryonation of eggs, egg hatching and on L1 and L2 survival after 48, 10 and 24 h of incubation. Negative controls were 1.5% DMSO, 4% Tween 80 and a mixture of these solvents. The TLC was carried out and the profiles of secondary metabolites were made. RESULTS: Negative controls had no effect on the embryonation, eggs hatching and on larval mortality. However, it was found that, the extracts affected the free living stages of H. bakeri in a concentration-dependant manner. At the highest concentration (5000 MUg/ml), the rate of inhibition of embryonation obtained were 20.80%, 38.15% and 84.83% for Methylene Chloride-Methanol of Annona senegalensis (MCM As), Nauclea latifolia (MCM Nl) extracts and mixture of Annona senegalensis and Nauclea latifolia (MCM As-Nl) extract respectively. For egg hatch, the inhibition rate was 16.10%, 46.24% and 87.07% for the above three extracts respectively at the same concentration of 5000 MUg/ml. On L1 and L2 larval stages after 24 h of exposure to extracts, the mortality rates of 100%, 54.76% and 96.77% against 98%, 51.44% and 100% were obtained for MCM As, MCM Nl and MCM As Nl respectively at the highest concentration. The Methylene Chloride-Methanol of A.senegalensis, N. latifolia extracts showed the presence of alkaloids except in N. latifolia extract, flavonoids, sterols, triterpens, tanins, polyphenols, anthraquinons, saponins and terpenoids. CONCLUSION: These findings suggest that, the mixture of the two plant extracts showed an additive (synergetic effect) ovicidal effect and a slight larval mortality on L1 as compared to the effect of MCM As extract alone. These effects were due to the presence ao secondary metabolites identifies in the plant extracts. Thus, they may be used as possible "disinfectants" for soil transmitted nematodes. PMID- 28800758 TI - Validation of verbal autopsy: determination of cause of deaths in Malaysia 2013. AB - BACKGROUND: Mortality statistics by age, sex and cause are the foundation of basic health data required for health status assessment, epidemiological research and formation of health policy. Close to half the deaths in Malaysia occur outside a health facility, are not attended by medical personnel, and are given a lay opinion as to the cause of death, leading to poor quality of data from vital registration. Verbal autopsy (VA) is a very useful tool in diagnosing broad causes of deaths for events that occur outside health facilities. This article reports the development of the VA methods and our principal finding from a validation study. METHODS: A cross sectional study on nationally representative sample deaths that occurred in Malaysia during 2013 was used. A VA questionnaire suitable for local use was developed. Trained field interviewers visited the family members of the deceased at their homes and conducted face to face interviews with the next of kin. Completed questionnaires were reviewed by trained physicians who assigned multiple and underlying causes. Reference diagnoses for validation were obtained from review of medical records (MR) available for a sample of the overall study deaths. RESULTS: Corresponding MR diagnosis with matched sample of the VA diagnosis were available in 2172 cases for the validation study. Sensitivity scores were good (>75%) for transport accidents and certain cancers. Moderate sensitivity (50% - 75%) was obtained for ischaemic heart disease (64%) and cerebrovascular disease (72%). The validation sample for deaths due to major causes such as ischaemic heart disease, pneumonia, breast cancer and transport accidents show low cause-specific mortality fraction (CSMF) changes. The scores obtained for the top 10 leading site-specific cancers ranged from average to good. CONCLUSION: We can conclude that VA is suitable for implementation for deaths outside the health facilities in Malaysia. This would reduce ill-defined mortality causes in vital registration data, and yield more accurate national mortality statistics. PMID- 28800759 TI - Quantitative reproducibility analysis for identifying reproducible targets from high-throughput experiments. AB - BACKGROUND: High-throughput assays are widely used in biological research to select potential targets. One single high-throughput experiment can efficiently study a large number of candidates simultaneously, but is subject to substantial variability. Therefore it is scientifically important to performance quantitative reproducibility analysis to identify reproducible targets with consistent and significant signals across replicate experiments. A few methods exist, but all have limitations. METHODS: In this paper, we propose a new method for identifying reproducible targets. Considering a Bayesian hierarchical model, we show that the test statistics from replicate experiments follow a mixture of multivariate Gaussian distributions, with the one component with zero-mean representing the irreproducible targets. RESULTS: A target is thus classified as reproducible or irreproducible based on its posterior probability belonging to the reproducible components. We study the performance of our proposed method using simulations and a real data example. CONCLUSION: The proposed method is shown to have favorable performance in identifying reproducible targets compared to other methods. PMID- 28800760 TI - Perceptions of patients and providers on myocardial perfusion imaging for asymptomatic patients, choosing wisely, and professional liability. AB - BACKGROUND: Despite efforts by professional societies to reduce low value care, many reports indicate that unnecessary tests, such as nuclear myocardial perfusion imaging (MPI), are commonly used in contemporary practice. The degree to which lack of awareness and professional liability concerns drive these behaviors warrants further study. We sought to investigate patient and provider perceptions about MPI in asymptomatic patients, the Choosing Wisely (CW) campaign, and professional liability concerns. METHODS: We administered an anonymous, paper-based survey with both discrete and open-response queries to subjects in multiple outpatient settings at our facilities. The survey was completed by 456 respondents including 342 patients and 114 physicians and advanced practice providers between May and August 2014. Our outcome was to compare patient and provider perceptions about MPI in asymptomatic patients and related factors. RESULTS: Patients were more likely than providers to report that MPI was justified for asymptomatic patients (e.g. asymptomatic with family history of heart disease 75% versus 9.2%, p < 0.0001). In free responses to the question "What would be an inappropriate reason for MPI?" many responses echoed the goals of CW (for example, "If you don't have symptoms", "If the test is too risky", "For screening or in asymptomatic patients"). A minority of providers were aware of CW while even fewer patients were aware (37.2% versus 2.7%, p < 0.0001). Over one third of providers (38.9%) admitted to ordering MPI out of concern for professional liability including 48.3% of VA affiliated providers. CONCLUSIONS: While some patients and providers are aware of the low value of MPI in patients without symptoms, others are enthusiastic to use it for a variety of scenarios. Concerns about professional liability likely contribute, even in the VA setting. Awareness of the Choosing Wisely campaign is low in both groups. PMID- 28800761 TI - Development of the Adolescent Preoccupation with Screens Scale. AB - BACKGROUND: Although public health concerns have been raised regarding the detrimental health effects of increasing rates of electronic screen use among adolescents, such effects have been small. Instruments currently available tend to be lengthy, have a clinical research focus, and assess young people's screen use on specific screen-based activities (e.g., TV, computer, or internet). None appear to address screen use across a broad range of screens, including mobile devices and screen-based activities. The objective was to develop a new and short self-report scale for investigating adolescents' screen use across all screens and screen-based activities in non-clinical settings. METHODS: The Adolescent Preoccupation with Screens Scale (APSS) was developed over a three stage process. First, a review of the current literature and existing instruments was undertaken and suitable items identified. Second, the draft APSS was piloted with adolescents and item affectivity and discrimination indices were calculated. Third, a cross sectional school based online survey of 1967 Australian adolescents in grades 5 (10 years old), 7 (13 years) and 9 (15 years) from 25 randomly selected schools was conducted. RESULTS: Factor Analysis on a sub-sample of the data (n = 782) and Confirmatory Factor Analysis on the remaining sub sample (n = 1185), supported a two-factor model. The first factor reflects adolescents' mood management with screen use, and the second reflects a behavioural preoccupation. The measure demonstrated strong invariance across sex and across Grades 5, 7, and 9. Both factors displayed good internal consistency (alpha = .91 and .87, respectively). Sex and grade differences on both scales were investigated and boys in Grade 5 reported higher levels of both mood management and behavioural preoccupation with screens. There were no sex differences on mood management in Grades 7 and 9, but girls reported higher behavioural preoccupation in both these later grades. CONCLUSION: The APSS provides researchers with a new, brief and robust measure of potentially problematic screen use across a wide array of screens, including mobile devices, so readily accessed during adolescence. PMID- 28800762 TI - The novel cannabinoid receptor GPR55 mediates anxiolytic-like effects in the medial orbital cortex of mice with acute stress. AB - The G protein-coupled receptor 55 (GPR55) is a novel cannabinoid receptor, whose exact role in anxiety remains unknown. The present study was conducted to explore the possible mechanisms by which GPR55 regulates anxiety and to evaluate the effectiveness of O-1602 in the treatment of anxiety-like symptoms. Mice were exposed to two types of acute stressors: restraint and forced swimming. Anxiety behavior was evaluated using the elevated plus maze and the open field test. We found that O-1602 alleviated anxiety-like behavior in acutely stressed mice. We used lentiviral shRNA to selective ly knockdown GPR55 in the medial orbital cortex and found that knockdown of GPR55 abolished the anxiolytic effect of O 1602. We also used Y-27632, a specific inhibitor of ROCK, and U73122, an inhibitor of PLC, and found that both inhibitors attenuated the effectiveness of O-1602. Western blot analysis revealed that O-1602 downregulated the expression of GluA1 and GluN2A in mice. Taken together, these results suggest that GPR55 plays an important role in anxiety and O-1602 may have therapeutic potential in treating anxiety-like symptoms. PMID- 28800763 TI - Causes, trends and severity of musculoskeletal injuries in Ghana. AB - BACKGROUND: Musculoskeletal [MSK] injuries are common causes of long-term pain and physical disability which affect many people worldwide. The economic and social impacts on the individual, society and national health systems are enormous making a matter of public health concern. Therefore, this study examined the causes and extent of MSK injuries in a referral hospital in Ghana. METHODS: A prospective study design with consecutive sampling method was used to recruit patients admitted at Trauma Unit as well as those receiving orthopaedic reviews at St. Joseph's Orthopaedic Hospital over a ten-month period. A structured questionnaire, Visual Analogue Scale (VAS) and Abbreviated Injury Scale (AIS) were used to collect data which were analysed descriptively using SPSS version 20. RESULTS: A total of 269 MSK injury patients were identified - of these, 137 (50.9%) males with an average age of 38 years (SD = 19.88). Nearly half (49.1%) of the injuries sustained were fractures, and common causes were vehicular crash 113 (42.0%) and fall 68 (25.3%). Body parts affected most were the knee (19.62) and the mean levels of pain for all injuries were 6.04 +/- 2.44 and 3.25 (+/ 1.50) respectively. CONCLUSION: Ghana needs a healthy population to steer its development trajectory. Policy makers in Ghana should pay attention to both preventive as well as management of MSK injuries, or else, most of the country's working class could live with lasting effects of injuries which may have significant impacts on the economy. PMID- 28800764 TI - Lrp, a global regulator, regulates the virulence of Vibrio vulnificus. AB - BACKGROUND: An attenuated mutant (designated NY303) of Vibrio vulnificus, which causes serious wound infection and septicemia in humans, was isolated fortuitously from a clinical strain YJ016. This mutant was defective in cytotoxicity, migration on soft agar and virulence in the mouse. The purpose of this study was to map the mutation in this attenuated mutant and further explore how the gene thus identified is involved in virulence. METHODS: The whole genome sequence of mutant NY303 determined by next-generation sequencing was compared with that of strain YJ016 to map the mutations. By isolating and characterizing the specific gene-knockout mutants, the gene associated with the phenotype of mutant NY303 was identified. This gene encodes a global regulator, Lrp. A mutant, YH01, deficient in Lrp was isolated and examined in vitro, in vivo and ex vivo to find the affected virulence mechanisms. The target genes of Lrp were further identified by comparing the transcriptomes, which were determined by RNA-seq, of strain YJ016 and mutant YH01. The promoters bound by Lrp were identified by genome footprinting-sequencing, and those related with virulence were further examined by electrophoretic mobility shift assay. RESULTS: A mutation in lrp was shown to be associated with the reduced cytotoxicity, chemotaxis and virulence of mutant NY303. Mutant YH01 exhibited a phenotype resembling that of mutant NY303, and was defective in colonization in the mouse and growth in mouse serum, but not the antiphagocytosis ability. 596 and 95 genes were down- and up-regulated, respectively, in mutant YH01. Many of the genes involved in secretion of the MARTX cytotoxin, chemotaxis and iron-acquisition were down-regulated in mutant YH01. The lrp gene, which was shown to be negatively autoregulated, and 7 down regulated virulence-associated genes were bound by Lrp in their promoters. A 14 bp consensus sequence, mkCrTTkwAyTsTG, putatively recognized by Lrp was identified in the promoters of these genes. CONCLUSIONS: Lrp is a global regulator involved in regulation of cytotoxicity, chemotaxis and iron-acquisition in V. vulnificus. Down-regulation of many of the genes associated with these properties may be responsible, at least partly, for loss of virulence in mutant NY303. PMID- 28800765 TI - Therapeutic effects of flurbiprofen axetil on mesenteric traction syndrome: randomized clinical trial. AB - BACKGROUND: This study aimed to reveal the appropriate timing for the intravenous administration of flurbiprofen axetil for preventing mesenteric traction syndrome (MTS), caused by prostacyclin release. METHODS: In this prospective, randomized, clinical study, forty-five patients who were undergoing elective surgery for colorectal cancer via laparotomy were enrolled. Patients were randomly divided into 3 groups: a preoperative group (n = 16) receiving flurbiprofen axetil directly before surgery; a post-MTS group (n = 14) receiving following MTS onset; and a control group (n = 15) who were not administered flurbiprofen axetil. 6 keto-PGF1alpha, a stable metabolite of prostacyclin, levels were measured and mean blood pressures were recorded. RESULTS: In the preoperative group, 6-keto PGF1alpha levels did not increase, blood pressure levels did not decrease, and no facial flushing was observed. In both the post-MTS and control groups, 6-keto PGF1alpha levels increased markedly after mesenteric traction and blood pressure decreased significantly. The post-MTS group exhibited a faster decreasing trend in 6-keto-PGF1alpha levels and quick restore of the mean blood pressure, and the use of vasopressors and phenylephrine were lower than that in the control group. CONCLUSIONS: Even therapeutic administration of flurbiprofen axetil after the onset of MTS has also effects on MTS by suppressing prostacyclin production. TRIAL REGISTRATION: Clinical trial number: UMIN000009111 . (Registered 14 October 2012). PMID- 28800766 TI - Examining non-LTR retrotransposons in the context of the evolving primate brain. AB - Researchers have long sought to understand the genetic basis of the cognitive differences between primates, with particular focus on the human brain. Although all mutational types have worked in concert with evolutionary forces to generate the current human brain, in this review we will explore the impact of mobile elements, specifically non-LTR retrotransposons. Non-LTR retrotransposons have contributed coding and regulatory sequences to the genome throughout evolution. During primate evolution there have been multiple waves of LINE retrotransposition as well as the birth of new mobile elements such as the SINEs Alu and SVA and we will explore what kinds of impacts these may have had on the evolving human brain. PMID- 28800767 TI - Cell adhesion heterogeneity reinforces tumour cell dissemination: novel insights from a mathematical model. AB - BACKGROUND: Cancer cell invasion, dissemination, and metastasis have been linked to an epithelial-mesenchymal transition (EMT) of individual tumour cells. During EMT, adhesion molecules like E-cadherin are downregulated and the decrease of cell-cell adhesion allows tumour cells to dissociate from the primary tumour mass. This complex process depends on intracellular cues that are subject to genetic and epigenetic variability, as well as extrinsic cues from the local environment resulting in a spatial heterogeneity in the adhesive phenotype of individual tumour cells. Here, we use a novel mathematical model to study how adhesion heterogeneity, influenced by intrinsic and extrinsic factors, affects the dissemination of tumour cells from an epithelial cell population. The model is a multiscale cellular automaton that couples intracellular adhesion receptor regulation with cell-cell adhesion. RESULTS: Simulations of our mathematical model indicate profound effects of adhesion heterogeneity on tumour cell dissemination. In particular, we show that a large variation of intracellular adhesion receptor concentrations in a cell population reinforces cell dissemination, regardless of extrinsic cues mediated through the local cell density. However, additional control of adhesion receptor concentration through the local cell density, which can be assumed in healthy cells, weakens the effect. Furthermore, we provide evidence that adhesion heterogeneity can explain the remarkable differences in adhesion receptor concentrations of epithelial and mesenchymal phenotypes observed during EMT and might drive early dissemination of tumour cells. CONCLUSIONS: Our results suggest that adhesion heterogeneity may be a universal trigger to reinforce cell dissemination in epithelial cell populations. This effect can be at least partially compensated by a control of adhesion receptor regulation through neighbouring cells. Accordingly, our findings explain how both an increase in intra-tumour adhesion heterogeneity and the loss of control through the local environment can promote tumour cell dissemination. REVIEWERS: This article was reviewed by Hanspeter Herzel, Thomas Dandekar and Marek Kimmel. PMID- 28800768 TI - 3D printing-assisted preoperative plan of pedicle screw placement for middle upper thoracic trauma: a cohort study. AB - BACKGROUND: This study aimed to evaluate the application of 3D printing in assisting preoperative plan of pedicle screw placement for treating middle-upper thoracic trauma. METHODS: A preoperative plan was implemented in seven patients suffering from middle-upper thoracic (T3-T7) trauma between March 2013 and February 2016. In the 3D printing models, entry points of 56 pedicle screws (Magerl method) and 4 important parameters of the pedicle screws were measured, including optimal diameter (phi, mm), length (L, mm), inclined angle (alpha), head-tilting angle (+beta), and tail-tilting angle (-beta). In the surgery, bare hands fixation of pedicle screws was performed using 3D printing models and the measured parameters as guidance. RESULTS: A total of seven patients were enrolled, including five men and two women, with the age of 21-62 years (mean age of 37.7 years). The position of the pedicle screw was evaluated postoperatively using a computerized tomography scan. Totally, 56 pedicle screws were placed, including 33 pieces of level 0, 18 pieces of level 1, 4 pieces of level 2 (pierced lateral wall), and 1 piece of level 3 (pierced lateral wall, no adverse consequences), with a fine rate of 91.0%. CONCLUSIONS: 3D printing technique is an intuitive and effective assistive technology to pedicle screw fixation for treating middle-upper thoracic vertebrae, which improve the accuracy of bare hands screw placement and reduce empirical errors. TRIAL REGISTRATION: The trial was approved by the Ethics Committee of the Fujian Provincial Hospital. It was registered on March 1st, 2013, and the registration number was K2013-03-001. PMID- 28800769 TI - Maternal sleep and small for gestational age infants in the Japan Environment and Children's Study: a cohort study. AB - OBJECTIVES: Small for gestational age infants have an increased risk of immediate complications, short-term morbidity and mortality, and long-term neurologic and metabolic disorders in adulthood. Previous research has shown that reduced sleep duration is a risk factor for SGA birth. However, only a few studies have evaluated maternal sleep as a risk factor for SGA birth. In the present study, we investigated the relationship between the amount and quality of mothers' sleep and infants' birth weight. RESULTS: This cohort study (n = 8631) used data from the Japan Environment and Children's Study, an ongoing cohort study that began in January 2011. Data on sleep status (sleep duration and one indicator of sleep quality) and potential confounding factors were recorded. A log-binomial regression model was used to estimate the risk of small for gestational age birth, and the results were expressed as risk ratios and their respective 95% confidence interval. No significant results were observed for sleep duration or tiredness upon waking. Neither the amount nor the quality of mothers' sleep was associated with the risk of small for gestational age birth. PMID- 28800770 TI - Knowledge of pharmacy students about doping, and the need for doping education: a questionnaire survey. AB - BACKGROUND: Anti-doping activities are carried out on a global scale. Based on these activities, the specialty of "sports pharmacist," which entails a deeper comprehension of doping, use of supplements, and appropriate drug use for athletes, was established in 2009 in Japan. It is difficult to say whether the education on doping is adequate for pharmacy students who will be eligible to become sports pharmacists. It is also unclear how well these students understand doping. Therefore, the aim of this study was to investigate pharmacy students' current knowledge of appropriate drug use, doping and use of supplements, and to explore the need for further education on these topics. METHODS: A questionnaire survey was conducted from July 3rd to August 2nd in 2014 at Showa University in Japan. A total of 406 respondents (2nd- to 6th-year students) were assessed as eligible. Group comparison was used to compare those who had attended a lecture about doping and those who had not. RESULTS: Most of the students only knew the word doping and had not attended a lecture on the subject, but 72% of them expressed a desire to attend one. Over half did not know that the most common doping violation in Japan is unintentional doping, and were unfamiliar with certain past cases of doping. In addition, 41% did not know that over-the-counter medicines and dietary supplements might contain prohibited substances, and 87% were unaware that names of prohibited substances might not appear on the ingredient labels of dietary supplements. In contrast, attending a lecture on doping was effective in facilitating the acquisition of all these types of knowledge. CONCLUSIONS: It is important to provide more opportunities for appropriate education of pharmacy students on the topic of doping, given that interest exists and attending a lecture on the topic appears to be useful. More education about doping for pharmacy students would be as effective for anti doping activities as is education of athletes. PMID- 28800771 TI - Perceived confidence to use female condoms among students in Tertiary Institutions of a Metropolitan City, Southwestern, Nigeria. AB - BACKGROUND: Latex condoms for men have been documented to offer high efficacy as both a contraceptive and protection against sexually transmitted diseases. This equally establishes the importance of continued research on female condoms. This study aims to investigate the perceived confidence to use the female condoms amongst undergraduate female students from selected tertiary institutions from Ibadan Southwestern Nigeria. METHODS: The study was a descriptive cross-sectional survey involving 388 female undergraduate students selected through a multistage sampling technique. The survey was carried using pre-tested semi-structured questionnaires. Quantitative data were analyzed using the Statistical Package for the Social Sciences to generate frequencies, cross tabulations of variables at 5% level of significance. RESULTS: Mean age of respondents 18.26 +/- 3.45 with most students being 20-24 years (55.2%), single (92.8%), Yorubas (85.6%) and from the polytechnic institutions (41.0%). Only 10.8% had good perceived confidence to use a female condom. Perceived confidence was significantly higher amongst other ethnicities (19.59 +/- 3.827) compared to Yoruba ethnicity (18.04 +/- 3.337) (F = 9.935; p < 0.05). Likewise, students from the Polytechnic campuses exhibited significantly higher mean scores (18.81 +/- 3.187) compared to others (F = 3.724; p < 0.05). Perception towards the condom was a significant factor that influenced the confidence to use a female condom (F = 9.896; p < 0.000). CONCLUSIONS: Concerted efforts are advocated to improve the low perception exhibited towards the use of female condoms and the low perceived confidence to its utilization. This would help to transfer the decision making and control to women thus contributing to their empowerment and increased protection from unplanned pregnancies and sexually transmitted diseases. PMID- 28800772 TI - Endurance training lowers ribosome density despite increasing ribosome biogenesis markers in rodent skeletal muscle. AB - OBJECTIVE: The purpose of this study was to examine if: (a) high sugar/high fat Western diet (WD)-feeding affects skeletal muscle ribosome biogenesis markers in hyperphagic, diabetic-prone Otsuka Long-Evans Tokushima Fatty (OLETF) rats, and (b) 12 weeks of treadmill training rescued potential detriments that WD feeding exerted on these markers. METHODS: Eight week-old male OLETF rats were fed a low fat control diet (O-CON, n = 10) or high/sucrose/cholesterol Western diet (WD). At weeks 20-32 of age, WD-fed rats were divided into WD sedentary (O-WD/SED, n = 16), or WD treadmill trained (5 days/week, 60 min/day) (O-WD/EX, n = 10) conditions. RESULTS: Interestingly, total RNA (i.e., ribosome density) was 2.3 fold greater in O-WD/SED versus O-WD/EX rats (p = 0.003) despite levels of upstream binding factor protein, RNA polymerase I protein and pre-45S rRNA being greater in O-WD/EX rats. Ribophagy (USP10 and G3BP1) and TRAMP-exosome rRNA degradation pathway (EXOSC10 and SKIV2L2) proteins were assayed to determine if these pathways were involved with lower ribosome density in O-WD/EX rats. While USP10 was higher in O-CON versus O-WD/SED and O-WD/EX rats (p < 0.001 and p < 0.001, respectively), G3BP1, EXOSC10 and SKIV2L2 did not differ between groups. Nop56 and Ncl mRNAs, ribosome assembly markers, were highest in O-WD/EX rats. However, Fbl mRNA and 28S rRNA, downstream ribosome processing markers, were lowest in O-WD/EX rats. Collectively these data suggest that, in WD-fed rats, endurance training increases select skeletal muscle ribosome biogenesis markers. However, endurance training may reduce muscle ribosome density by interfering with rRNA processing and/or export through mechanisms independent of ribophagy or rRNA degradation. PMID- 28800773 TI - Rattus norvegicus BN/SHR liver and heart left ventricle ribosomal RNA depleted directional RNA sequencing. AB - OBJECTIVE: The spontaneously hypertensive rat strain is a frequently used disease model. In a previous study, we measured translational efficiency from this strain and BN-Lx animals. Here, we describe long RNA sequencing reads from ribosomal RNA depleted samples from the same animals. This data can be used to investigate splicing-related events. RESULTS: RNA was extracted from rat liver and heart left ventricle from BN-Lx and SHR/Ola rats in biological replicates. Ribosomal RNA was removed and the samples subjected to directional high-throughput RNA-sequencing. Read and alignment statistics indicate high quality of the data. The raw sequencing reads are freely available on the NCBI short read archive and can be used for further research on tissue and strain differences, or analysed together with other published high-throughput data from the same animals. PMID- 28800774 TI - Angiostrongylus vasorum in wolves in Italy: prevalence and pathological findings. AB - BACKGROUND: Angiostrongylus vasorum is a nematode residing in the heart and pulmonary vessels of dogs and wild carnivores. In Europe the red fox is its reservoir, while only three records from wolves have been published. Angiostrongylus vasorum has a worldwide distribution, and many pieces of evidence demonstrate that it is spreading from endemic areas to new ones. In Italy, A. vasorum was reported with increasing frequency in dogs and foxes in the last decades, and now it is considered endemic throughout the country. Angiostrongylus vasorum can be asymptomatic or cause respiratory and circulatory disorders, at times causing severe disseminated infections. METHODS: Between February 2012 and December 2016, 25 wolves found dead in central Italy were submitted to the Istituto Zooprofilattico del Lazio e della Toscana for post-mortem examination. Samples of lungs, heart, liver, spleen, kidneys, mediastinic lymph nodes and brain were collected from each animal for histological examination. When adult and larval nematodes were microscopically seen in lungs, the other organs were processed, and five histological sections for each organ were examined. To confirm parasite identification, lung samples were submitted to a PCR-sequencing protocol targeting the ITS2 region of A. vasorum. RESULTS: Seven wolves (28.0%) harboured nematode larvae in lung sections. In two of the positive wolves, adult nematodes were visible in pulmonary arteries, in four animals larvae were also detected in other organs. DNA sequencing reactions confirmed parasite identification as A. vasorum in all the cases. CONCLUSIONS: As a result of the high prevalence of A. vasorum reported in wolves in the present study, a focus of high circulation could be hypothesised in central Italy. Nevertheless, the similarly high prevalence in foxes originating from the same areas were reported in previous papers. Histopathological evidence highlights the pathogenic potential of A. vasorum in the wolf, especially in juvenile animals. PMID- 28800776 TI - Revisiting clinico-epidemiological pattern of human rickettsial infections in the central region of Sri Lanka: a hospital based descriptive study. AB - BACKGROUND: This study revisits the clinico-epidemiology and serological patterns of rickettsioses in the central region of Sri Lanka and highlights the need of advanced diagnostics for precise identification of species responsible for rickettsioses. METHODS: The patients treated for rickettsioses between November 2009 and October 2011 were recruited for the study from Teaching Hospital, Peradeniya. Clinical characteristics and serology results were used for diagnosis. RESULTS: Study included 210 patients (mean age 44 years +/- 3.2) and of them 188 (90%) had positive IgG and/or IgM sero-reactivity for spotted fever group (SFG). Of them, 134 had IgG titre >=1/256 for SFG and presented with fever and skin rash. They also had headache [n = 119 (89%)], myalgia [n = 103 (77%)], arthralgia [n = 89 (66%)] of large joints, conjunctival injections [n = 83 (62%)], thrombocytopenia (n = 78.58%), anaemia (n = 14.10%), leukocytosis [n = 35 (26%)], leucopenia [n = 17 (13%)], elevated aspartate transaminase [n = 69 (52%)] and alanine transaminase [n = 73 (55%)]. CONCLUSIONS: Predominance of SFG rickettsioses are reiterated, possibly transmitted by ticks. Joint disease is common with occasional fern leaf skin necrosis. Changing socio-economic conditions, vegetations, contact with domestic and wild animals, abundance of vectors would have contributed for emergence and sustenance of SFG in the region. Further research is needed to identify the causative agents and the mode of transmission. PMID- 28800775 TI - Lack of high BMI-related features in adipocytes and inflammatory cells in the infrapatellar fat pad (IFP). AB - BACKGROUND: Obesity is associated with the development and progression of osteoarthritis (OA). Although the infrapatellar fat pad (IFP) could be involved in this association, due to its intracapsular localization in the knee joint, there is currently little known about the effect of obesity on the IFP. Therefore, we investigated cellular and molecular body mass index (BMI)-related features in the IFP of OA patients. METHODS: Patients with knee OA (N = 155, 68% women, mean age 65 years, mean (SD) BMI 29.9 kg/m2 (5.7)) were recruited: IFP volume was determined by magnetic resonance imaging in 79 patients with knee OA, while IFPs and subcutaneous adipose tissue (SCAT) were obtained from 106 patients undergoing arthroplasty. Crown-like structures (CLS) were determined using immunohistochemical analysis. Adipocyte size was determined by light microscopy and histological analysis. Stromal vascular fraction (SVF) cells were characterized by flow cytometry. RESULTS: IFP volume (mean (SD) 23.6 (5.4) mm3) was associated with height, but not with BMI or other obesity-related features. Likewise, volume and size of IFP adipocytes (mean 271 pl, mean 1933 MUm) was not correlated with BMI. Few CLS were observed in the IFP, with no differences between overweight/obese and lean individuals. Moreover, high BMI was not associated with higher SVF immune cell numbers in the IFP, nor with changes in their phenotype. No BMI-associated molecular differences were observed, besides an increase in TNFalpha expression with high BMI. Macrophages in the IFP were mostly pro-inflammatory, producing IL-6 and TNFalpha, but little IL-10. Interestingly, however, CD206 and CD163 were associated with an anti-inflammatory phenotype, were the most abundantly expressed surface markers on macrophages (81% and 41%, respectively) and CD163+ macrophages had a more activated and pro inflammatory phenotype than their CD163- counterparts. CONCLUSIONS: BMI-related features usually observed in SCAT and visceral adipose tissue could not be detected in the IFP of OA patients, a fat depot implicated in OA pathogenesis. PMID- 28800777 TI - Bortezomib treatment induces a higher mortality rate in lupus model mice with a higher disease activity. AB - BACKGROUND: Bortezomib (Bz) is a proteasome inhibitor that directly targets antibody-producing plasma cells. We recently reported the first randomized control trial that evaluated the effects of Bz in patients with systemic lupus erythematosus (SLE). In that study, we demonstrated that Bz treatment is associated with many adverse reactions in patients with refractory disease. In the present study, we examine the therapeutic and toxic effects of Bz on MRL/MpJ lpr/lpr (MRL/lpr) mice with severe disease activity. METHODS: Female MRL/lpr mice at 10 and 14 weeks of age were treated with phosphate buffered saline (PBS) (n = 19), Bz (750 MUg/kg twice weekly) (n = 27), or cyclophosphamide (Cyc) (1 mg/body, once in 2 weeks) (n = 20). Cellular subsets, serum immunoglobulin, anti-double stranded DNA (anti-dsDNA) antibody titer, and a pathological index of glomerulonephritis were then analyzed at 22 weeks of age. Survival curves of the 10-week-old and 14-week-old Bz-treated groups were compared. Blood counts, creatinine, liver enzymes, and serum cytokine levels were measured 1 week after Bz treatment. Gene expression profiling of spleens from Bz and Cyc treatment mice were compared with those from control mice. RESULTS: The anti-dsDNA antibody levels were significantly higher in 14-week-old than in 10-week-old mice, indicating a higher disease activity at 14 weeks. A significant decrease in the number of splenic cells and glomerulonephritis index was observed in Bz-treated and Cyc-treated mice. Bz, but not Cyc, significantly decreased serum immunoglobulin and anti-dsDNA antibody titer levels. Survival curve analysis revealed a significantly higher mortality rate in 14-week-old than in 10-week-old Bz-treated and control groups. Following two injections of Bz, serum IL-6 and TNF alpha levels were significantly more elevated in 14-week-old than in 10-week-old mice. Potentially immunogenic molecules, such as heat shock proteins, were characteristically upregulated in spleens of Bz-treated but not Cyc-treated mice. CONCLUSIONS: In spite of its therapeutic effect, Bz treatment had more toxic effects associated with increased proinflammatory cytokine levels in mice with a higher disease activity. Understanding the mechanism of the toxicity and developing preventive strategies against it is important for the safe clinical application of Bz in human SLE. PMID- 28800778 TI - Effects of intraoperative PEEP optimization on postoperative pulmonary complications and the inflammatory response: study protocol for a randomized controlled trial. AB - BACKGROUND: Patients undergoing general anesthesia and mechanical ventilation during major abdominal surgery commonly develop pulmonary atelectasis and/or hyperdistention of the lungs. Recent studies show benefits of lung-protective mechanical ventilation with the use of low tidal volumes, a moderate level of positive end-expiratory pressure (PEEP) and regular alveolar recruitment maneuvers during general anesthesia, even in patients with healthy lungs. The purpose of this clinical trial is to evaluate the effects of intraoperative lung protective mechanical ventilation, using individualized PEEP values, on postoperative pulmonary complications and the inflammatory response. METHODS/DESIGN: A total number of 40 patients with bladder cancer undergoing open radical cystectomy and urinary diversion (ileal conduit or orthotopic bladder substitute) will be enrolled and randomized into a study (SG) and a control group (CG). Standard lung-protective ventilation with a PEEP of 6 cmH2O will be applied in the CG and an optimal PEEP value determined during a static pulmonary compliance (Cstat)-directed PEEP titration procedure will be used in the SG. Low tidal volumes (6 mL/Kg ideal bodyweight) and a fraction of inspired oxygen of 0.5 will be applied in both groups. After surgery both groups will receive standard postoperative management. Primary endpoints are postoperative pulmonary complications and serum procalcitonin kinetics during and after surgery until the third postoperative day. Secondary and tertiary endpoints will be: organ dysfunction as monitored by the Sequential Organ Failure Assessment Score, in hospital stay, 28-day and in-hospital mortality. DISCUSSION: This trial will assess the possible benefits or disadvantages of an individualized lung protective mechanical ventilation strategy during open radical cystectomy and urinary diversion regarding postoperative pulmonary complications and the inflammatory response. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02931409 . Registered on 5 October 2016. PMID- 28800779 TI - Proinflammatory MG-63 cells response infection with Enterococcus faecalis cps2 evaluated by the expression of TLR-2, IL-1beta, and iNOS mRNA. AB - OBJECTIVE: We have previously demonstrated that unencapsulated Enterococcus faecalis cps2 inhibits biofilm formation of Candida albicans, a fungus commonly found with E. faecalis in periapical lesion. In this study, we compared encapsulated and unencapsulated E. faecalis cps2 strains relationship with osteoblastic (MG-63) cells, whereas E. faecalis ATCC 29212 were used as a reference strain. RESULTS: The binding capacity of E. faecalis to MG-63 cells as shown by each tested strain was comparable, but the unencapsulated strain was less invasive compared to the encapsulated and the reference strains. Moreover, quantitative real time-PCR (qPCR) results showed that infecting unencapsulated E. faecalis cps2 is a stronger stimulator for toll like receptor 2 (TLR2) and interleukin-1beta (IL-1beta) mRNAs, but not for inducible nitric oxide synthase (iNOS) mRNA in osteoblastic cells. In conclusion, the performance of unencapsulated E. faecalis cps2 when the bacterium interacts with osteoblastic cells is quite different from that of encapsulated E. faecalis cps2 and reference strains. It appears that the unencapsulated strain might contribute to the persistence of the periapical inflammatory response, depending on down-regulation of iNOS mRNA expression. PMID- 28800780 TI - A novel scoring system based on common laboratory tests predicts the efficacy of TNF-inhibitor and IL-6 targeted therapy in patients with rheumatoid arthritis: a retrospective, multicenter observational study. AB - BACKGROUND: Currently, although several categories of biological disease modifying antirheumatic drugs (bDMARDs) are available, there are few data informing selection of initial treatment for individual patients with rheumatoid arthritis (RA). Therefore, tumor necrosis factor inhibitor (TNF-i) and tocilizumab (TCZ) are treated as equivalent treatments in the recent disease management recommendations. We focused on two anticytokine therapies, TCZ and TNF i, and aimed to develop a scoring system that predicts a better treatment for each RA patient before starting an IL-6 or a TNF-i. METHODS: The expression of IL 6 and TNF-alpha mRNA in peripheral blood from 45 newly diagnosed RA patients was measured by DNA microarrays to evaluate cytokine activation. Next, laboratory indices immediately before commencing treatment and disease activity score improvement ratio after 6 months in 98 patients treated with TCZ or TNF-i were retrospectively analyzed. Some indices correlated with TCZ efficacy were selected and their cutoff values were defined by receiver operating characteristic (ROC) analysis to develop a scoring system to discriminate between individuals more likely to respond to TCZ or TNF-i. The validity of the scoring system was verified in these 98 patients and an additional 228 patients. RESULTS: There was significant inverse correlation between the expression of IL-6 and TNF-alpha mRNA in newly diagnosed RA patients. The analysis of 98 patients revealed significant correlation between TCZ efficacy and platelet counts, hemoglobin, aspartate aminotransferase, and alanine aminotransferase; in contrast, there was no similar correlation in the TNF-i group. The cutoff values were defined by ROC analysis to develop a scoring system (1 point/item, maximum of 4 points). A good TCZ response was predicted if the score was >=2; in contrast, TNF-i seemed to be preferable if the score was <=1. Similar results were obtained in a validation study of an additional 228 patients. If the case scored >=3, the good responder rates of TCZ/TNF-i were 75.0%/37.9% (p < 0.01) and the non-responder rates were 3.1%/27.6% (p < 0.01), respectively. CONCLUSIONS: The score is easily calculated from common laboratory results. It appears useful for identifying a better treatment at the time of selecting either an IL-6 or a TNF inhibitor. PMID- 28800781 TI - Knowledge-guided gene prioritization reveals new insights into the mechanisms of chemoresistance. AB - BACKGROUND: Identification of genes whose basal mRNA expression predicts the sensitivity of tumor cells to cytotoxic treatments can play an important role in individualized cancer medicine. It enables detailed characterization of the mechanism of action of drugs. Furthermore, screening the expression of these genes in the tumor tissue may suggest the best course of chemotherapy or a combination of drugs to overcome drug resistance. RESULTS: We developed a computational method called ProGENI to identify genes most associated with the variation of drug response across different individuals, based on gene expression data. In contrast to existing methods, ProGENI also utilizes prior knowledge of protein-protein and genetic interactions, using random walk techniques. Analysis of two relatively new and large datasets including gene expression data on hundreds of cell lines and their cytotoxic responses to a large compendium of drugs reveals a significant improvement in prediction of drug sensitivity using genes identified by ProGENI compared to other methods. Our siRNA knockdown experiments on ProGENI-identified genes confirmed the role of many new genes in sensitivity to three chemotherapy drugs: cisplatin, docetaxel, and doxorubicin. Based on such experiments and extensive literature survey, we demonstrate that about 73% of our top predicted genes modulate drug response in selected cancer cell lines. In addition, global analysis of genes associated with groups of drugs uncovered pathways of cytotoxic response shared by each group. CONCLUSIONS: Our results suggest that knowledge-guided prioritization of genes using ProGENI gives new insight into mechanisms of drug resistance and identifies genes that may be targeted to overcome this phenomenon. PMID- 28800784 TI - Upregulation of MicroRNA-4262 Targets Kaiso (ZBTB33) to Inhibit the Proliferation and EMT of Cervical Cancer Cells. AB - More and more studies have reported that dysregulation of microRNAs (miRNAs) leads to the proliferation and EMT of multiple cancers. Recently, several reports have demonstrated that dysregulation of miR-4262 occurs in numerous cancers. However, its role and precise mechanism in human cervical cancer (CC) have not been well clarified. Hence, this study aimed to explore the biological roles and precise mechanisms of miR-4262 in CC cell lines. The level of miR-4262 was found to be significantly decreased in CC tissues and cell lines. Moreover, decreased expression of miR-4262 was closely related to increased expression of Kaiso (ZBTB33), which belongs to the BTB/POZ family, in CC tissues and cell lines. The proliferation and EMT of CC cells were inhibited by a miR-4262 mimic. However, downregulation of miR-4262 enhanced the proliferation and EMT of CC cells. Next, bioinformatics analysis predicted that miR-4262 might directly target the Kaiso gene. Besides, luciferase reporter assay had confirmed this result. Moreover, introduction of Kaiso in CC cells partially blocked the effects of miR-4262 mimic. In conclusion, miR-4262 suppressed the proliferation and EMT of CC cells by directly downregulating Kaiso. PMID- 28800782 TI - Effects of Chinese medicinal herbs on expression of brain-derived Neurotrophic factor (BDNF) and its interaction with human breast cancer MDA-MB-231 cells and endothelial HUVECs. AB - BACKGROUND: Our previous study demonstrated that an up-regulation of the Brain Derived Neurotrophic Factor (BDNF) signaling pathway is involved the mechanism causing the recurrence of triple negative breast cancer. The aim of this study is to investigate the effects of commonly used Chinese medicinal herbs on MDA-MB-231 and HUVEC cells and how they interact with BDNF. METHODS: Human TNBC MDA-MB-231 cells and human endothelial HUVEC cells were used to explore the effect of commonly used Chinese herbal medicines on cancer cells alone, on endothelial cells alone and on cancer cell/endothelial cell interactions; this was done via functional studies, including migration and invasion assays. Furthermore, Western blot analysis and real-time PCR investigations were also used to investigate migration signal transduction, invasion signal transduction, and angiogenic signal transduction in these systems. Finally, the effect of the Chinese medicinal herbs on cancer cell/endothelial cell interactions was assessed using co-culture and ELISA. RESULTS: In terms of autoregulation, BDNF up-regulated TrkB gene expression in both MDA-MB-231 and HUVEC cells. Furthermore, BDNF enhanced migration by MDA-MB-231 cells via Rac, Cdc42 and MMP, while also increasing the migration of HUVEC cells via MMP and COX-2 expression. As measured by ELISA, the Chinese herbal medicinal herbs A. membranaceus, P. lactiflora, L. chuanxiong, P. suffruticosa and L. lucidum increased BDNF secretion by MDA-MB-231 cells. Similarly, using a co-culture system with MDA-MB-231 cells, A. membranaceus and L. lucidum modulated BDNF-TrkB signaling by HUVEC cells. CONCLUSION: We conclude that BDNF plays an important role in the metastatic interaction between MDA-MB 231 and HUVEC cells. Some Chinese medicinal herbs are able to enhance the BDNF related metastatic potential of the interaction between cancer cells and endothelial cells. These findings provide important information that should help with the development of integrated medical therapies for breast cancer patients. PMID- 28800783 TI - Bioprospecting saline gradient of a Wildlife Sanctuary for bacterial diversity and antimicrobial activities. AB - OBJECTIVE: Antibiotic-resistant bacteria are becoming a global crisis, causing death of thousands of people and significant economic impact. The discovery of novel antibiotics is crucial to saving lives and reducing healthcare costs. To address the antibiotic-resistant crisis, in collaboration the Small World Initiative, which aims to crowdsource novel antibiotic discovery, this study aimed to identify antimicrobial producing bacteria and bacterial diversity in the soil of the Stimpson Wildlife Sanctuary, an inland area with a soil salt gradient. RESULTS: Approximately 4500 bacterial colonies were screened for antimicrobial activity and roughly 100 bacteria were identified as antimicrobial producers, which belong to Entrococcaceae (74%), Yersiniaceae (19%), and unidentified families (7%). Several bacterial isolates showed production of broad spectrum inhibitory compounds, while others were more specific to certain pathogens. The data obtained from the current study provide a resource for further characterization of the soil bacteria with antimicrobial activity, with an aim to discover novel ones. The study showed no correlation between soil salt level and the presence of bacteria with antimicrobial activities. However, most of the identified antimicrobial producing bacteria do not belong to actinomycetes, the most common phyla of antibiotic producing bacteria and this could potentially lead to the discovery of novel antibiotics. PMID- 28800785 TI - MiR-26b Mimic Inhibits Glioma Proliferation In Vitro and In Vivo Suppressing COX 2 Expression. AB - Glioma is the most common malignant tumor of the nervous system. Studies have shown the microRNA (miR)-26b/cyclooxygenase (COX)-2 axis in the development and progression in many tumor cells. Our study aims to investigate the effect and mechanism of miR-26b/COX-2 axis in glioma. Decreased expression of miR-26b with increased level of COX-2 was found in glioma tissues compared with matched normal tissues. A strong negative correlation was observed between the level of miR-26b and COX-2 in 30 glioma tissues. The miR-26b was then overexpressed by transfecting miR-26b mimic into U-373 cells. The invasive cell number and wounld closing rate were reduced in U-373 cells transfected with miR-26b mimic. Besides, COX2 siRNA enhanced the effect of miR-26b mimic in suppressing the expression of p-ERK1 and p-JNK. Finally, the in vivo experiment revealed that miR-26b mimic transfection strongly reduced the tumor growth, tumor volume and the expression of matrix metalloproteinase (MMP)-2, MMP-9). Taken together, our research indicated a miR-26b/COX-2/ERK/JNK axis in regulating the motility of glioma in vitro and in vivo, providing a new sight for treatment of glioma. PMID- 28800786 TI - Knockdown of Long Noncoding RNA LINC00152 Suppresses Cellular Proliferation and Invasion in Glioma Cells by Regulating miR-4775. AB - Long noncoding RNAs (lncRNAs) play an important role in various biological properties of glioma cells. Herein we aimed to elucidate the function and the possible molecular mechanisms of long intergenic noncoding RNA 152 (LINC00152) in glioma cells. Relative expressions of LINC00152, miR-4775, and CDK6 in U-118 MG cells were regulated by transfections. Thereafter, cell viability, migration, invasion, and apoptosis were analyzed by CCK-8, Transwell, and flow cytometry assays. Dual-Luciferase Reporter Assay was conducted to validate the target genes of LINC00152 and miR-4775. Expression of components of the signal pathways were detected by Western blot. The results showed that LINC00152 knockdown significantly suppressed cell viability, migration, and invasion and induced apoptosis in vitro. Additionally, LINC00152 functioned as a molecular sponge for miR-4775, and inhibition of miR-4775 reversed the tumor-suppressive effects of LINC00152 knockdown on glioma cells. Furthermore, CDK6 was confirmed to be a target of miR-4775, and overexpression of CDK6 reduced apoptosis and abolished the inhibitory effects of miR-4775 overexpression on cell viability, migration, and invasion. Overexpression of CDK6 activated the PI3K/AKT/MAPK and Notch signal pathways. Overall, these findings demonstrate that LINC00152 plays an oncogenic role in glioma cells by regulation of miR-4775, which may therefore be a potential therapeutic target for glioma. PMID- 28800787 TI - miR-449a Suppresses LDHA-Mediated Glycolysis to Enhance the Sensitivity of Non Small Cell Lung Cancer Cells to Ionizing Radiation. AB - MicroRNA dysregulation contributes to malignant progression, dissemination, and profound treatment resistance in multiple cancers. miR-449a is recognized as a tumor suppresser. However, the roles of miR-449a in lung cancer initiation and progression are largely unknown. Our study aims to investigate the roles and underlying mechanism of miR-449a in modulating sensitivity to ionizing radiation (IR) in non-small cell lung cancer (NSCLC). Lung cancer cells were transfected with miR-449a mimics or negative control and exposed to IR; the levels of target protein, glycolysis, cell viability, apoptosis, and DNA damage were examined. miR 449a was suppressed in lung cancer tissues and cancer cells (A549 and H1299). IR exposure significantly increased the expression of miR-449a in A549 cells at doses ranging from 4 to 8 Gy at 24 h, whereas no significant change in miR-449a was found in H1299 cells after IR. When A549 cells were exposed to IR at a dose of 8 Gy, the miR-449a level only had an acute increase within 12 h. miR-449a restoration dramatically suppressed IR-induced cell apoptosis and DNA damage in both A549 and H1299 cells. Bioinformatics analysis indicated that lactate dehydrogenase A (LDHA) was a potential target of miR-449a. miR-449a mimic transfection substantially suppressed the LDHA expression and production of lactate catalyzed by LDHA as well as glucose uptake. We confirmed that miR-449a could bind to the 3'-UTR of LDHA mRNA using luciferase reporter assay. LDHA siRNA transfected cells showed enhanced cell apoptosis and DNA damage in response to IR exposure. miR-449a upregulation enhanced IR sensitivity of lung cancer cells by suppressing LDHA and the subsequent glycolysis. PMID- 28800788 TI - miR-204 Regulates Cell Proliferation and Invasion by Targeting EphB2 in Human Cervical Cancer. AB - MicroRNAs (miRNAs) are small noncoding RNAs that are involved in human carcinogenesis and progression. miR-204 has been reported to be a tumor suppressor in several cancer types. However, the function and underlying molecular mechanism of miR-204 in cervical cancer (CC) are still unclear. In the present study, the expression level of miR-204 was measured using the qRT-PCR method in 30 paired CC clinical samples and in 6 CC cell lines. We found that the expression of miR-204 was significantly downregulated in CC tissues and cell lines compared to normal cervical tissues and cell line. miR-204 was overexpressed by transfection with the miR-204 mimic in HeLa and C33A cell lines in the following experiments. The results showed that overexpression of miR-204 dramatically suppressed cell proliferation, migration, and invasion, caused cell cycle arrest at the G0/G1 phase, promoted cell apoptosis in vitro, and inhibited tumor growth in vivo. Western blot results indicated that overexpressing miR-204 decreased the expressions of CDK2, cyclin E, MMP2, MMP9, Bcl2, whereas it enhanced Bax expression and suppressed the activation of the PI3K/AKT signaling pathways in CC cells. Ephrin type B receptor 2 (EphB2) was identified as a direct target of miR-204 in CC cells according to bioinformatics analysis and luciferase reporter assay. Furthermore, knockdown of EphB2 mimicked the inhibitory effect of miR-204 on the proliferation, invasion, and migration of CC cells. These findings suggested that miR-204 might serve as a tumor suppressor in the development of CC by directly targeting EphB2. PMID- 28800789 TI - Indicators of poorly controlled asthma and health-related quality of life among school-age children in the United States. AB - BACKGROUND: Poorly controlled asthma has far-reaching effects on school-age children and their parents, but little is known about the national impact on health-related quality of life (HRQoL). OBJECTIVE: To examine HRQoL associated with asthma and indicators of poorly controlled asthma in the United States. METHODS: This was a cross-sectional analysis of HRQoL among school-age children (age range, 6-17 years) with asthma in the nationally representative 2007-2013 Medical Expenditure Panel Survey (MEPS). Indicators of poor asthma control included the following: exacerbation in the previous 12 months, use of more than three canisters of short-acting beta agonist in 3 months, and annual asthma specific emergency department or inpatient visits. Health status and HRQoL instruments included the following: the Columbia Impairment Scale (CIS), Child Health Questionnaire (CHQ), Children with Special Health Care Needs Screener (CSHCN), and self-perceived physical and mental health. Ordered logistic regression was used for ordered categorical variables, and logistic regression was used for binary variables. All regressions controlled for sociodemographics and other covariates. RESULTS: There were 44,320 school-age children in the MEPS, of whom 5890 had asthma. School-age children with indicators of poorly controlled asthma had higher odds of feeling unhappy and/or sad or nervous and/or afraid, and of having problems with sports and/or hobbies and schoolwork on the CIS. Results from the CHQ showed that parents of school-age children with asthma and indicators of poorly controlled asthma had higher odds of worrying about their child's health and future. Results from the CSHCN showed that school-age children with asthma and indicators of poorly controlled asthma were more likely to have special health care needs. School-age children with asthma and indicators of poorly controlled asthma had higher odds of having poor perceived physical health. CONCLUSION: This nationally representative study provided novel information on the burden of poorly controlled asthma on emotional problems, school-related and activity limitations, general health status, and worry among school-age children and their families as measured by validated instruments. PMID- 28800790 TI - miR-641 Functions as a Tumor Suppressor by Targeting MDM2 in Human Lung Cancer. AB - Lung cancer is the leading cause of deaths due to cancer. Studies suggest an important role of microRNAs (miRNAs) in a variety of cancers, including lung cancer. In the present study, we evaluated the role of miR-641 in human lung cancer A549 cells. Quantitative RT-PCR and Western blot were used to measure mRNA and protein expression, respectively. Cell viability and cell apoptosis were respectively measured by MTT assay and flow cytometry. In addition, luciferase activity assay was used to identify the target of miR-641. The expression of miR 641 was downregulated in lung cancer tissues and lung cancer cell lines (p < 0.05 or p < 0.01). Overexpression of miR-641 significantly inhibited proliferation and induced apoptosis of lung cancer cells (p < 0.05, p < 0.01, or p < 0.001). MDM2 was identified as a direct target of miR-641. Overexpression of miR-641 decreased the expression of MDM2 and increased the expression of p53 in lung cancer cells. PMID- 28800791 TI - MicroRNA-154 Inhibits the Growth and Invasion of Gastric Cancer Cells by Targeting DIXDC1/WNT Signaling. AB - MicroRNAs (miRNAs) have emerged as pivotal regulators of the development and progression of gastric cancer. Studies have shown that miR-154 is a novel cancer associated miRNA involved in various cancers. However, the role of miR-154 in gastric cancer remains unknown. Here we aimed to investigate the biological function and the potential molecular mechanism of miR-154 in gastric cancer. We found that miR-154 was significantly downregulated in gastric cancer tissues and cell lines. The overexpression of miR-154 significantly repressed the growth and invasion of gastric cancer cells. Bioinformatics analysis and Dual-Luciferase Reporter Assay data showed that miR-154 directly targeted the 3'-untranslated region of Dishevelled-Axin domain containing 1 (DIXDC1). Real-time quantitative polymerase chain reaction and Western blot analyses showed that miR-154 overexpression inhibited DIXDC1 expression. An inverse correlation of miR-154 and DIXDC1 was also demonstrated in gastric cancer specimens. Overexpression of miR 154 also significantly suppressed the activation of WNT signaling. Moreover, restoration of DIXDC1 expression significantly reversed the inhibitory effect of miR-154 overexpression on the cell proliferation, invasion, and WNT signaling in gastric cancer cells. Overall, these results suggest that miR-154 inhibits gastric cancer cell growth and invasion by targeting DIXDC1 and could serve as a potential therapeutic target for the treatment of gastric cancer. PMID- 28800792 TI - MicroRNA-125a-5p Inhibits Cell Proliferation and Induces Apoptosis in Hepatitis B Virus-Related Hepatocellular Carcinoma by Downregulation of ErbB3. AB - MicroRNAs, a class of endogenous non-coding RNAs, regulate gene expression at post-transcriptional level, thus taking part in multiple biological processed. Increasing miRNAs are found to be dysregulated in hepatocellular carcinoma (HCC) and are involved in liver tumorigenesis. In this study, miR-125a-5p was found to obviously downregulate much more in hepatitis B virus (HBV)-related HCC. To investigate the effects of miR-125a-5p, miR-125a-5p was overexpressed in HepG2.2.15 and HepG3X cells, respectively. The findings have indicated that overexpression of miR-125a-5p dramatically inhibited cell proliferation and induced cell apoptosis. Furthermore, overexpression of miR-125a-5p could significantly decrease the secretion of HBsAg and HBeAg. In concordance to this, the expression of ErbB3 was up-regulated in human HBV-related HCC tissue, HepG2.2.15 and HepG3X cells. MiR-125a-5p directly targeted ErbB3, and reduced both mRNA and protein levels of ErbB3 which promoted cell proliferation and suppressed cell apoptosis in HCC cells. Our results provide new insight into the function of miR-125a-5p in HBV-related HCC. It is beneficial to insight into the mechanism of HBV infection and pathophysiology of HBV-related HCC. PMID- 28800793 TI - WITHDRAWN: Upregulation of HINT2 Inhibits Non-Small Cell Lung Cancer Cell Invasion Via COX-2/PGE2-Mediated Activation of beta-catenin Signaling. AB - Histidine triad nucleotide binding protein 2 (HINT2) belongs to a HIT superfamily. It is ubiquitous and can be detectedin all forms of life. Recently, this protein has been reported to function as a tumor suppressor in some kind of cancers. However, little is known about its precise role in non-small cell lung cancer (NSCLC). In the present study, we explored the effects of HINT2 on the invasive potential of NSCLC cells. Our results showed that the expression of HINT2 was reduced in NSCLC tissues and cell lines. Up-regulation of HINT2 inhibited NSCLC cell invasion in vitro and tumor metastasis in vivo. We also found that the inhibitory effect of HINT2 on NSCLC cell invasion was associated with reduction of COX-2 expression. In addition, our further investigation on the underlying mechanisms demonstrated that up-regulation of HINT2 inhibited NSCLC cell invasion via COX-2/PGE2-mediated activation of beta-catenin signaling. In conclusion, we presented evidence that HINT2 exerted a tumor-suppression effect on the progression of NSCLC. Thus, HINT2 might be a promising molecular target for treatment of NSCLC. PMID- 28800794 TI - Long Intergenic Noncoding RNA 319 (linc00319) Promotes Cell Proliferation and Invasion in Lung Cancer Cells by Directly Downregulating the Tumor Suppressor MiR 32. AB - Long non-coding RNAs (lncRNAs) have been shown to play important regulatory roles in the pathogenesis and progression of multiple cancers. Here, we investigated the role of long intergenic non coding RNA 319 (linc00319) in the proliferation and invasion of lung cancer cells. We found that, compared with normal lung cell line HBE, linc00319 was increased in low metastatic lung cancer cell lines PAa and AgiY-83a, and further increased in high metastatic lung cancer cell lines A549 and Anip-973. Then, different concentrations of pcDNA-linc00319 expression vector and different concentrations of linc00319 siRNA were respectively transfected into A549 lung cancer cells. The results showed that linc00319 increased the proliferation and invasion of A549 cells, and suppressed cell apoptosis, in a dose-dependent manner. In contrast, linc00319 siRNA suppressed A549 cell proliferation and invasion, and promoted cell apoptosis, in a dose dependent manner. The online bioinformatic tool RNAhybrid revealed that linc00319 potentially bound with the miR-32, which functioned as a tumor suppressor in lung cancer. Luciferase acitivity and RNA pull-down assays comfirmed that linc00319 directly bound with miR-32. Linc00319 could negatively regulate the expression of miR-32 and positively regulate the protein levels of miR-32 target genes, including AURKA, SOX9 and TWIST1. In conclusion, linc00319 promotes cell proliferation and invasion in lung cancer cells by directly binding with and downregulating the tumor suppressor miR-32. PMID- 28800795 TI - Evaluation of Depression and Suicidal Patients in the Emergency Room. AB - Depression is the leading cause of disability globally, and more than one-half of those suffering with depression are not receiving effective treatment. Untreated or undertreated depression poses a significant risk for suicide. Suicide is the 10th leading cause of death in the United States. The emergency room provides an essential opportunity to screen for depression as well as suicide and to provide important and evidence-based interventions. The Basic Suicide Assessment Five step Evaluation (B-SAFE) model provides a structure for all physicians to assess suicide risk and intervene. PMID- 28800796 TI - Difficult Patients in the Emergency Department: Personality Disorders and Beyond. AB - Physician-patient encounters in clinical settings, especially in the emergency department, can be of varying degrees of difficulty. Medically complicated, challenging cases can be paradoxically rewarding, whereas psychologically driven difficulty is frustrating and counterproductive for patient care. This article presents 3 different complementary perspectives on difficult patients: clinical presentations, manifestations of personality traits and disorders in clinical settings, and how physician feelings may affect care. Management strategies are discussed. PMID- 28800797 TI - A Modern-Day Fight Club? The Stabilization and Management of Acutely Agitated Patients in the Emergency Department. AB - This article is an overview of the treatment and management of acutely agitated patients as they present in the emergency department or emergency psychiatric facility. This article focuses on how a patient encounter may unfold and what issues need to be considered along the way. Verbal de-escalation is emphasized as a standard of care, including the offering of environmental changes and medications when indicated. Approved medications are reviewed as well as the proper use of restraints. PMID- 28800798 TI - Emergency Department Medical Clearance of Patients with Psychiatric or Behavioral Emergencies, Part 1. AB - Patients presenting to the emergency department with mental illness or behavioral complaints merit workup for underlying physical conditions that can trigger, mimic, or worsen psychiatric symptoms. However, interdisciplinary consensus on medical clearance is lacking, leading to wide variations in quality of care and, quite often, poor medical care. Psychiatry and emergency medicine specialty guidelines support a tailored, customized approach. This article summarizes best practice approaches to the medical clearance of patients with psychiatric illness, tips on history taking, system reviews, clinical or physical examination, and common pitfalls in the medical clearance process. PMID- 28800799 TI - Emergency Department Medical Clearance of Patients with Psychiatric or Behavioral Emergencies, Part 2: Special Psychiatric Populations and Considerations. AB - Patients who present to the emergency department (ED) with mental illness or behavioral complaints merit workup for underlying physical conditions that can trigger, mimic, or worsen psychiatric symptoms. However, there are wide variations in quality of care for these individuals. Psychiatry and emergency medicine specialty guidelines support a tailored, customized approach to patients. Our group has long advocated a dynamic comanagement approach for medical clearance in the ED, and this article summarizes best-practice approaches to the medical clearance of patients with psychiatric illness, tips on history taking, system reviews, clinical/physical examination, and common pitfalls in the medical clearance process. PMID- 28800800 TI - Behavioral Emergencies: Special Considerations in the Pregnant Patient. AB - This article describes psychiatric emergencies in pregnant women. The perinatal period is a time of psychiatric vulnerability. Up to 1 in 6 pregnant women experience major depressive disorder, and 1 in 4 pregnant women with bipolar disorder experience mood exacerbation. We discuss the management of severe mental illness in pregnancy, risk to mother and child of untreated psychiatric illness in pregnancy, risk of relapse of psychiatric disorders in pregnancy with medication discontinuation, psychopharmacologic considerations of teratogenicity and other fetal adverse effects, acute agitation in the pregnant patient, suicidality in pregnancy, and emergency considerations related to substance use disorders. PMID- 28800801 TI - Behavioral Emergencies: Special Considerations in the Geriatric Psychiatric Patient. AB - This article reviews psychiatric considerations and common psychiatric emergencies in the elderly. The elderly are vulnerable to medication side-effects because of pharmacokinetic changes from aging, and require lower doses and slower titration. They are a high-risk group for suicide, with more serious intent, fewer warning signs, and more lethality. Prompt diagnosis and treatment of delirium in emergency settings is essential, given association with worse outcomes when undiagnosed. Pharmacologic options with demonstrable efficacy for agitation in dementia are limited to antipsychotics, which are, however, associated with an increased risk of mortality; behavioral interventions are universally recommended as first-line measures. PMID- 28800802 TI - Special Considerations in the Pediatric Psychiatric Population. AB - Youth with psychiatric and behavioral complaints commonly present to emergency departments (EDs), which often lack dedicated mental health staff. This article addresses techniques EDs can use to better care for children in need of psychiatric assessment and medical clearance, specifically addressing the evaluation of youth with suicidal ideation and coexisting medical and psychiatric needs. The evaluation and management of youth with agitation and aggression are also discussed. The article concludes with a discussion of systems changes needed to truly improve emergency care for psychiatrically ill youth. PMID- 28800803 TI - Addictive Disorders in Adolescents. AB - Addictive disorders in youth represent a dynamic field characterized by shifting patterns of substance use and high rates of experimentation, while retaining the risky behaviors and negative outcomes associated with established drug classes. Youth/adolescents are also at the forefront of use of new technologies, and non substance-related disorders are pertinent. These disorders present with similar pictures of impairment, and can be diagnosed following the same principles. An underlying mental disorder and the possibility of a dual diagnosis need to be assessed carefully, and optimal treatment includes psychosocial treatments with applicable pharmacologic management, the latter representing an expanding field. PMID- 28800804 TI - Intensive Care and its Discontents: Psychiatric Illness in the Critically Ill. AB - Critically ill patients can develop a host of cognitive and psychiatric complaints during their intensive care unit (ICU) stay, many of which persist for weeks or months following discharge from the ICU and can seriously affect their quality of life, including their ability to return to work. This article describes some common psychiatric problems encountered by clinicians in the ICU, including their assessment and management. A comprehensive approach is needed to decrease patient suffering, improve morbidity and mortality, and ensure that critically ill patients can return to the highest quality of life after an ICU stay. PMID- 28800805 TI - Drugs of Abuse. AB - Drug abuse and its consequences remain a significant public health issue. An increasing number of individuals are present in the emergency room with life threatening drug intoxication. It is imperative that emergency room physicians are cognizant of the signs, symptoms, and treatment to improve the chances of early recognition and treatment. As a result, the proportion of lives saved will increase significantly. In this article, we present some of the most prevalent life-threatening drugs that lead to emergency room admission. The signs, symptoms, and treatment modalities are discussed. PMID- 28800806 TI - Toxicologic Emergencies in Patients with Mental Illness: When Medications Are No Longer Your Friends. AB - Patients with psychiatric disorders are at risk for toxicologic emergencies. Psychotropic medications have numerous effects on the neurologic, cardiac, and other organ systems and interact with other medications, potentially leading to further side effects. It is important to become familiar with accepted psychiatric practice guidelines, common toxidromes, medical sequelae associated with prescribed medications, and the specific workup and treatment of overdoses of frequently prescribed psychotropics. PMID- 28800807 TI - The Changing Health Policy Environment and Behavioral Health Services Delivery. AB - Deinstitutionalization has left an inadequate supply of inpatient psychiatric beds. Simultaneous cuts to public funding and insurance coverage for outpatient mental health treatment have increased the frequency of acute psychiatric crises. The resulting lack of available options has shifted the burden of treatment to emergency departments and the criminal justice system. Recent legislation has improved insurance access, but rules are not always enforced and there are still few options for care. Discussion of mental health care delivery must acknowledge that many emergent behavioral health crises arise in the context of acute substance intoxication, withdrawal, or dependence. PMID- 28800808 TI - Legal and Ethical Challenges, Part 1: General Population. AB - Several federal and state laws and regulations, as well as ethical medical principles, govern the emergency clinician's practice of care. Although some common legal-medical and ethical principles are shared with other medical specialties, emergency medicine and emergency psychiatry have unique legal and ethical challenges. This article presents and discusses these challenges, including the physician-patient relationship, malpractice, confidentiality and privilege, duty to report, decision-making capacity and vicarious decision making, the Emergency Medical Treatment and Labor Act, right to treatment, hospital admissions, involuntary commitment, forced medication administration, and child and elder abuse. PMID- 28800809 TI - Legal and Ethical Challenges in Emergency Psychiatry, Part 2: Management of Inmates. AB - Psychiatrists and clinicians encounter unique situations, challenges, and requirements in the treatment of jail and prison inmates in the emergency department. This article reviews the historical legal highlights pertaining to medical and psychiatric care of inpatients, as well as the professional, ethical, and legal aspects that allow clinicians to evaluate, treat, and properly disposition their inmate patients. In particular, this article discusses the specific suicide risk factors related to inmates and correctional facilities that should be ascertained and managed in a clinician's suicide risk assessment and intervention planning in this special high suicide risk patient population. PMID- 28800810 TI - International Emergency Psychiatry Challenges: Disaster Medicine, War, Human Trafficking, Displaced Persons. AB - Mental health disorders are a major cause of morbidity and a growing burden in low-income and middle-income countries; but there is little existing literature on the detailed epidemiology, diagnosis, and treatment in low-resource settings. Special situations with vulnerable populations, such as those created by international humanitarian emergencies, refugees or internally displaced people, and victims of human trafficking, are increasing in prevalence. These victims are often resettled in developed countries and come to the emergency department seeking care. To better care for these populations, knowledge of specialized psychosocial and cultural considerations should inform the comprehensive psychiatric assessment and treatment plan. PMID- 28800811 TI - Violence in the Emergency Department: A Global Problem. AB - Violence against health care workers is an unfortunately common event. Because of several inherent factors, emergency departments are particularly vulnerable. Once an incident occurs, it often goes unreported and leads to both physical and mental trauma. Health care workers should learn to recognize the cues that patients are escalating toward violence and be familiar with various options for sedating agitated patients. If sedation is not successful, physical restraint may become necessary. There are measures that can be taken that may help minimize the likelihood of violence toward health care workers. These measures include legislation, physical design, and increased security. PMID- 28800812 TI - Highlight in Telepsychiatry and Behavioral Health Emergencies. AB - Carolinas HealthCare System is one of the largest freestanding psychiatric emergency departments in the country. It has grown from a small community mental health center in the 1930s, to one of the largest providers of emergency mental health services in the country. It offers services in person and via telepsychiatry to other emergency departments and primary care clinics. It decreased emergency room wait times and revolutionized where and how patients get their care. This has been the work of several groups from many disciplines. The transition from community mental health center to large-scale mental health emergency department has been a model for the rest of the country. PMID- 28800813 TI - Emergency Psychiatry: Ten Years Later. PMID- 28800815 TI - Corrigendum to "Palmitoylation of the TPbeta isoform of the human thromboxane A2 receptor. Modulation of G protein: Effector coupling and modes of receptor internalization." [Cell Signal. 19(5) (2007) 1056-1070]. PMID- 28800814 TI - Phthalates impact human health: Epidemiological evidences and plausible mechanism of action. AB - Disregarding the rising alarm on the hazardous nature of various phthalates and their metabolites, ruthless usage of phthalates as plasticizer in plastics and as additives in innumerable consumer products continues due low their cost, attractive properties, and lack of suitable alternatives. Globally, in silico computational, in vitro mechanistic, in vivo preclinical and limited clinical or epidemiological human studies showed that over a dozen phthalates and their metabolites ingested passively by man from the general environment, foods, drinks, breathing air, and routine household products cause various dysfunctions. Thus, this review addresses the health hazards posed by phthalates on children and adolescents, epigenetic modulation, reproductive toxicity in women and men; insulin resistance and type II diabetes; overweight and obesity, skeletal anomalies, allergy and asthma, cancer, etc., coupled with the description of major phthalates and their general uses, phthalate exposure routes, biomonitoring and risk assessment, special account on endocrine disruption; and finally, a plausible molecular cross-talk with a unique mechanism of action. This clinically focused comprehensive review on the hazards of phthalates would benefit the general population, academia, scientists, clinicians, environmentalists, and law or policy makers to decide upon whether usage of phthalates to be continued swiftly without sufficient deceleration or regulated by law or to be phased out from earth forever. PMID- 28800816 TI - An investigation of vtx2 bacteriophage transduction to different Escherichia coli patho-groups in food matrices and nutrient broth. AB - This study investigated bacteriophage (phage) mediated transfer of the vtx2 gene from a donor Escherichia coli (C600phi3538(Deltavtx2::cat)) to enteropathogenic (EPEC), enterotoxigenic (ETEC), enteroaggregative (EAEC), enteroinvasive (EIEC) and diffusely adherent (DAEC) E. coli strains in LB broth, milk, ground beef and lettuce. Two bacterial concentrations for both the E. coli donor and recipient strains, 3 and 5 log10 CFU/ml (LB broth and milk)/g (beef) or/cm2 (lettuce), were used. When transductants were obtained, the location of insertion of the phage (insertion sites wrbA, yehA, sbcB, yecE and/or Z2577) in the E. coli chromosome was investigated by PCR. The vtx2 gene was readily transferred to EAEC O104:H4 (E99518) in all matrices and inserted into the chromosome at the sbcB locus. At higher cell concentrations, transductants were also obtained with ETEC E4683, ETEC E8057 (insertion site unknown) and DAEC O75:H- E66438 (insertion site unknown) in LB broth and milk. It was concluded that the vtx2 gene may be transferred by bacteriophage to different E. coli pathotypes in laboratory and food matrices, resulting in the spread of the vtx2 gene and the emergence of novel foodborne pathogens. PMID- 28800817 TI - Selection of reference genes to quantify relative expression of ochratoxin A related genes by Penicillium nordicum in dry-cured ham. AB - Penicillium nordicum is an important and consistent producer of ochratoxin A (OTA) in NaCl-rich foods such as dry-cured ham. OTA is a toxic secondary metabolite which provokes negative effects on consumer health. Once OTA is produced in ham, this mycotoxin is difficult to remove. Since gene expression always precedes OTA production, analysis of expression of OTA-related genes by reverse transcription real-time PCR (RT-qPCR) could be a valuable tool to predict OTA contamination in ham. However scarce RT-qPCR protocols are properly validated leading to inconsistent data analyses. The objective of this study was to examine reference genes suitable for normalisation in designing and developing new RT qPCR methods for quantifying the relative expression of genes involved in OTA biosynthesis (otapks and otanps) by P. nordicum on a dry-cured ham model system after 7 days of incubation. Firstly, primers based on three housekeeping genes commonly found in moulds, beta-tubulin, COI and ITS, and on the otapks gene were designed. The primer pair F/R-npstr previously developed on the otanps gene was also used. Although most of the designed primers met the requirements needed to be used in qPCR assays, the primer pairs beta-tubF1/R1, COI-F1/R1, ITSF2/R2 and otapksF3/R3 for the beta-tubulin, COI, ITS and otapks genes, respectively, were selected due to their lowest Cq value. Next, the two assumptions of the 2 DeltaDeltaCT method to evaluate the relative expression of the otapks and otanps genes were fulfilled for two of the three endogenous genes tested, beta-tubulin and COI. However, beta-tubulin was considered more proper as reference gene than COI under the environmental conditions assayed since its expression values by day 7 were more related to OTA production. Therefore, the two RT-qPCR methods for the analysis of the relative expression of the otapks and otanps genes have been properly validated and can be used as control tools to avoid or minimise the presence of OTA in ham. PMID- 28800818 TI - Characterization of a novel endolysin LysSA11 and its utility as a potent biocontrol agent against Staphylococcus aureus on food and utensils. AB - Here we show that the LysSA11 endolysin, derived from the virulent Staphylococcus aureus phage SA11, has lytic activity against staphylococcal strains. Bioinformatics analysis revealed an enzymatically active CHAP (cysteine, histidine-dependent amidohydrolases/peptidases) domain at the N-terminus of LysSA11 that showed amidase activity. A novel cell wall binding domain (CBD) in the C-terminus could bind to a broad spectrum of staphylococcal cells. The bactericidal activity of LysSA11 was determined in food and utensils artificially contaminated with methicillin-resistant S. aureus (MRSA). The amounts of MRSA bacteria in milk and on ham were significantly reduced by 1.44-log CFU/mL and 3.12-log CFU/cm3, respectively, within 15 min at refrigeration temperature (4 degrees C) and by 2.02-log CFU/mL and 3.37-log CFU/cm2, respectively, within 15 min at room temperature (25 degrees C). Moreover, a polypropylene plastic cutting board and a stainless steel knife artificially contaminated with approximately 4-log CFU/cm2 of MRSA also showed complete bacterial elimination after a 30-min treatment with 1.35 MUM of LysSA11. The data presented here strongly suggest that the novel CBD-containing staphylococcal endolysin LysSA11 can be used both as a food antimicrobial and as a practical sanitizer for utensils. PMID- 28800819 TI - Estimation of the probability of bacterial population survival: Development of a probability model to describe the variability in time to inactivation of Salmonella enterica. AB - Despite the development of numerous predictive microbial inactivation models, a model focusing on the variability in time to inactivation for a bacterial population has not been developed. Additionally, an appropriate estimation of the risk of there being any remaining bacterial survivors in foods after the application of an inactivation treatment has not yet been established. Here, Gamma distribution, as a representative probability distribution, was used to estimate the variability in time to inactivation for a bacterial population. Salmonella enterica serotype Typhimurium was evaluated for survival in a low relative humidity environment. We prepared bacterial cells with an initial concentration that was adjusted to 2 * 10n colony-forming units/2 MUl (n = 1, 2, 3, 4, 5) by performing a serial 10-fold dilution, and then we placed 2 MUl of the inocula into each well of 96-well microplates. The microplates were stored in a desiccated environment at 10-20% relative humidity at 5, 15, or 25 degrees C. The survival or death of bacterial cells for each well in the 96-well microplate was confirmed by adding tryptic soy broth as an enrichment culture. The changes in the death probability of the 96 replicated bacterial populations were described as a cumulative Gamma distribution. The variability in time to inactivation was described by transforming the cumulative Gamma distribution into a Gamma distribution. We further examined the bacterial inactivation on almond kernels and radish sprout seeds. Additionally, we described certainty levels of bacterial inactivation that ensure the death probability of a bacterial population at six decimal reduction levels, ranging from 90 to 99.9999%. Consequently, the probability model developed in the present study enables us to estimate the death probability of bacterial populations in a desiccated environment over time. This probability model may be useful for risk assessment to estimate the amount of remaining bacteria in a given sample. PMID- 28800820 TI - Bacterial diversity of the Colombian fermented milk "Suero Costeno" assessed by culturing and high-throughput sequencing and DGGE analysis of 16S rRNA gene amplicons. AB - "Suero Costeno" (SC) is a traditional soured cream elaborated from raw milk in the Northern-Caribbean coast of Colombia. The natural microbiota that characterizes this popular Colombian fermented milk is unknown, although several culturing studies have previously been attempted. In this work, the microbiota associated with SC from three manufacturers in two regions, "Planeta Rica" (Cordoba) and "Caucasia" (Antioquia), was analysed by means of culturing methods in combination with high-throughput sequencing and DGGE analysis of 16S rRNA gene amplicons. The bacterial ecosystem of SC samples was revealed to be composed of lactic acid bacteria belonging to the Streptococcaceae and Lactobacillaceae families; the proportions and genera varying among manufacturers and region of elaboration. Members of the Lactobacillus acidophilus group, Lactocococcus lactis, Streptococcus infantarius and Streptococcus salivarius characterized this artisanal product. In comparison with culturing, the use of molecular in deep culture-independent techniques provides a more realistic picture of the overall bacterial communities residing in SC. Besides the descriptive purpose, these approaches will facilitate a rational strategy to follow (culture media and growing conditions) for the isolation of indigenous strains that allow standardization in the manufacture of SC. PMID- 28800821 TI - Listeria monocytogenes incidence changes and diversity in some Brazilian dairy industries and retail products. AB - Listeria monocytogenes can cause listeriosis, a severe foodborne disease. In Brazil, despite very few reported cases of listeriosis, the pathogen has been repeatedly isolated from dairies. This has led the government to implement specific legislation to reduce the hazard. Here, we determined the incidence of L. monocytogenes in five dairies and retail products in the Southeast and Midwest regions of Brazil over eight months. Of 437 samples, three samples (0.7%) from retail and only one sample (0.2%) from the dairies were positive for L. monocytogenes. Thus, the contamination rate was significantly reduced as compared to previous studies. MultiLocus Sequence Typing (MLST) was used to determine if contamination was caused by new or persistent clones leading to the first MLST profile of L. monocytogenes from the Brazilian dairy industry. The processing environment isolate is of concern being a sequence-type (ST) 2, belonging to the lineage I responsible for the majority of listeriosis outbreaks. Also, ST3 and ST8 found in commercialized cheese have previously been reported in outbreaks. Despite the lower incidence, dairy products still pose a potential health risk and the occurrence of L. monocytogenes in dairies and retail products emphasize the need for continuous surveillance of this pathogen in the Brazilian dairy industry. PMID- 28800823 TI - Detection and quantification of Alicyclobacillus acidoterrestris by electrical impedance in apple juice. AB - Alicyclobacillus acidoterrestris is a thermotolerant bacterium able to grow in fruit juices and drinks, as the spoilage by Alicyclobacillus in the final product does not product any gas, but leads to a "medicine flavor" due to the formation of guaicol. Also, its detection is a challenge for the quality control departments, because it takes several days to get the results of traditional microbiology methods. This study aimed at developing a more accurate electrical impedance technique for the detection of A. acidoterrestris in concentrated apple juice. Samples of apple juice were inoculated with A. acidoterrestris spores isolated from a peach and grape juice. For the spore germination, several heat shock treatments were tested (80 degrees C/10 min, 70 degrees C/20 min and 60 degrees C/30 min). Direct and indirect electrical impedance was applied to detect and quantify the microorganism in the inoculated apple juice, using BAT broth and Bimedia 002A (pH 4). The 80 degrees C/10 min treatment was selected for spore activation. The valid electrical impedance technique was the indirect method in BAT broth, which measured the changes in the impedance through the formation of CO2. In addition, a positive correlation (r = 0.98, R2 = 0.97) was observed between the classical microbiology (BAM agar) and the indirect impedance method. PMID- 28800822 TI - Escherichia coli transfer from simulated wildlife feces to lettuce during foliar irrigation: A field study in the Northeastern United States. AB - Wildlife intrusion has been associated with pathogen contamination of produce. However, few studies have examined pathogen transfer from wildlife feces to pre harvest produce. This study was performed to calculate transfer coefficients for Escherichia coli from simulated wildlife feces to field-grown lettuce during irrigation. Rabbit feces inoculated with a 3-strain cocktail of non-pathogenic E. coli were placed in a lettuce field 2.5-72 h before irrigation. Following irrigation, the E. coli concentration on the lettuce was determined. After exclusion of an outlier with high E. coli levels (Most Probable Number = 5.94*108), the average percent of E. coli in the feces that transferred to intact lettuce heads was 0.0267% (Standard Error [SE] = 0.0172). Log-linear regression showed that significantly more E. coli transferred to outer leaves compared to inner leaves (Effect = 1.3; 95% Confidence Interval = 0.4, 2.1). Additionally, the percent of E. coli that transferred from the feces to the lettuce decreased significantly with time after fecal placement, and as the distance between the lettuce and the feces, and the lettuce and the sprinklers increased. These findings provide key data that may be used in future quantitative risk assessments to identify potential intervention strategies for reducing food safety risks associated with fresh produce. PMID- 28800824 TI - Assessing the antimicrobial potential of aerosolised electrochemically activated solutions (ECAS) for reducing the microbial bio-burden on fresh food produce held under cooled or cold storage conditions. AB - The main aim of this study was to assess the antimicrobial efficacy of electrochemically activated fog (ECAF) for reducing the microbial bio-burden on artificially inoculated fresh produce held under cooled (cucumber and vine tomatoes) or cold (rocket and broccoli) storage conditions. The ECAF treatment (1100 +/- 5 mV ORP; 50 +/- 5 mg L-1 free chlorine; 2.7 +/- 0.1 pH) resulted in a significant log reduction in the potential pathogen E. coli recovered from rocket (2.644 Log10 CFU g-1), broccoli (4.204 Log10 CFU g-1), cucumber (3.951 Log10 CFU g-1) and tomatoes (2.535 Log10 CFU g-1) after 5 days. ECAF treatment also resulted in a significant log reduction in potential spoilage organisms, whereby a 3.533 Log10 CFU g-1, 2.174 Log10 CFU g-1 and 1.430 Log10 CFU g-1 reduction in presumptive Pseudomonads was observed for rocket, broccoli and cucumber respectively, and a 3.527 Log10 CFU g-1 reduction in presumptive Penicillium spp. was observed for tomatoes (after 5 days). No adverse visual effects on produce were recorded. The results of this study will inform industrial scale-up trials within commercial facilities (assessing shelf-life, microbial quality and organoleptic assessment) to assess the developed ECAF technology platform within a real food processing environment. PMID- 28800825 TI - Efficacy evaluation of a new water sanitizer for increasing the shelf life of Southern Australian King George Whiting and Tasmanian Atlantic Salmon fillets. AB - The bacterial species and specific spoilage organisms associated with the Southern Australian King George Whiting (KGW) and Tasmanian Atlantic Salmon (TAS), and the efficacy of a HOCl-containing water-based sanitization product (Electro-Chemically Activated Solution, by ECAS4) in extending the shelf life of KGW and TAS fillets were evaluated. Fillets were washed with an ECAS4 solution containing either 45 ppm or 150 ppm of free chlorine and bacterial species enumerated on selective and non-selective media, followed by identification of pure isolates by 16 S rRNA gene sequencing. The dominant spoilage microbiota in KGW and TAS fillets stored at 4 +/- 1 degrees C were Pseudomonas spp. and Shewanella spp. At either concentration, ECAS4 significantly reduced total bacterial load and specific spoilage organisms on KGW and TAS fillets (approx. 1 2 log colony-forming units) during storage and significantly extended the shelf life of the fillets by 2 and 4 days, respectively. The significant increase in shelf life and quality of fillets was corroborated by raw and cooked sensory evaluation. ECAS4 sanitization could have a significant impact on the overall food industry, translating into health and economic benefits through reduction of food spoilage bacteria and potentially, foodborne pathogens without many of the disadvantages of currently approved biocides. PMID- 28800826 TI - Effect of thyme essential oil and Lactococcus lactis CBM21 on the microbiota composition and quality of minimally processed lamb's lettuce. AB - The main aim of this work was to evaluate, at pilot scale in an industrial environment, the effects of the biocontrol agent Lactococcus lactis CBM21 and thyme essential oil compared to chlorine, used in the washing step of fresh-cut lamb's lettuce, on the microbiota and its changes in relation to the time of storage. The modification of the microbial population was studied through pyrosequencing in addition to the traditional plate counts. In addition, the volatile molecule and sensory profiles were evaluated during the storage. The results showed no significant differences in terms of total aerobic mesophilic cell loads in relation to the washing solution adopted. However, the pyrosequencing data permitted to identify the genera and species able to dominate the spoilage associations over storage in relation to the treatment applied. Also, the analyses of the volatile molecule profiles of the samples during storage allowed the identification of specific molecules as markers of the spoilage for each different treatment. The sensory analyses after 3 and 5 days of storage showed the preference of the panelists for samples washed with the combination thyme EO and the biocontrol agent. These samples were preferred for attributes such as flavor, acceptability and overall quality. These results highlighted the effect of the innovative washing solutions on the quality of lettuce through the shift of microbiota towards genera and species with lower potential in decreasing the sensory properties of the product. PMID- 28800827 TI - Modelling the effect of water activity reduction by sodium chloride or glycerol on conidial germination and radial growth of filamentous fungi encountered in dairy foods. AB - Water activity (aw) is one of the most influential abiotic factors affecting fungal development in foods. The effects of aw reduction on conidial germination and radial growth are generally studied by supplementing culture medium with the non-ionic solute glycerol despite food aw can also depend on the concentration of ionic solutes such as sodium chloride (NaCl). The present study aimed at modelling and comparing the effects of aw, either modified using NaCl or glycerol, on radial growth and/or conidial germination parameters for five fungal species occurring in the dairy environment. The estimated cardinal values were then used for growth prediction and compared to growth kinetics observed on commercial fresh cheese. Overall, as compared to glycerol, NaCl significantly increased the fungistatic effect resulting from aw reduction by extending latency and/or reducing radial growth rates of Paecilomyces niveus, Penicillium brevicompactum, Penicillium expansum and Penicillium roqueforti but not of Mucor lanceolatus. Besides, NaCl significantly reduced aw range for conidial germination and delayed median germination time of P. expansum but not of P. roqueforti. Despite these observations, cardinal aw values obtained on glycerol medium yielded similar predictions of radial growth and germination time in commercial fresh cheese as those obtained with NaCl. Thus, it indicates that, for the studied species and aw range used for model validation, the use of NaCl instead of glycerol as a aw depressor had only limited impact for fungal behavior prediction. PMID- 28800828 TI - Culture-dependent and culture-independent assessment of spoilage community growth on VP lamb meat from packaging to past end of shelf-life. AB - Packaging and storage temperature are important factors that influence the shelf life of vacuum packed (VP) meat. In this study the shelf-life of VP bone-in lamb hind shanks stored at 8 degrees C and -1.2 degrees C was determined in parallel to analyses of starting and eventual spoilage bacterial communities via Illumina MiSeq based 16S rRNA amplicon sequencing. The mean total viable counts (TVC) and lactic acid bacterial viable counts (LAB) were observed to increase to log 7.5 CFU/cm2 and 7 CFU/cm2 after 6 and 42 days at 8 degrees C and -1.2 degrees C and stayed stable until shelf-life termination after 13 and 124 days, respectively. The sequence data showed initial communities were patchily distributed and were mainly derived from skin microbiome taxa likely prevalent within the abattoir. A broad diversity of VP meat associated specific spoilage organisms (SSO) were comparatively abundant in this initial population. Overtime meat spoilage communities developed a distinctive and stable microbiome. At -1.2 degrees C SSO included mainly Carnobacterium, Yersinia and Clostridium spp. while at 8 degrees C SSO expanded to include Hafnia, Lactococcus, Providencia spp. Growth curves inferred from the sequence data after taking into account rRNA copy number suggested that SSO growth rates were consistent with overall growth rates determined from TVC and LAB data and are predictable. PMID- 28800829 TI - Combination of endolysins and high pressure to inactivate Listeria monocytogenes. AB - Outbreaks of listeriosis are often related to the consumption of low-processed ready-to-eat food products (e.g. soft cheeses or smoked fish) contaminated with Listeria monocytogenes. Traditional preservation techniques, such as heat treatment, cannot eliminate Listeria from these products without strongly affecting the quality of the foods. We therefore investigated the use of endolysin (PlyP40, Ply511, or PlyP825) in combination with high hydrostatic pressure processing to kill L. monocytogenes in buffer. The results demonstrated a more than additive effect when both treatments were combined. For example, whereas 0.16 MUg/mL PlyP825 or 300 MPa (1 min, 30 degrees C) applied individually reduced the cell count by 0.2 and 0.3 log cfu, respectively, a combined treatment resulted in a reduction of 5.5 log cfu. Similar results were obtained for the other endolysins combined with high pressure processing. We also showed that the synergistic inactivation of cells by endolysin and HHP is possible at a pressure level of only 200 MPa (2 min, 30 degrees C). Thus, the application of endolysins did not only substantially increase the bactericidal effect of high pressure, but it also enabled the inactivation of bacterial cells at much lower pressure levels. This shows the potential of using such combined processes for the inactivation of L. monocytogenes and food preservation. PMID- 28800830 TI - Modeling carbon dioxide effect in a controlled atmosphere and its interactions with temperature and pH on the growth of L. monocytogenes and P. fluorescens. AB - The effect of carbon dioxide, temperature, and pH on growth of Listeria monocytogenes and Pseudomonas fluorescens was studied, following a protocol to monitor microbial growth under a constant gas composition. In this way, the CO2 dissolution didn't modify the partial pressures in the gas phase. Growth curves were acquired at different temperatures (8, 12, 22 and 37 degrees C), pH (5.5 and 7) and CO2 concentration in the gas phase (0, 20, 40, 60, 80, 100% of the atmospheric pressure, and over 1 bar). These three factors greatly influenced the growth rate of L. monocytogenes and P. fluorescens, and significant interactions have been observed between the carbon dioxide and the temperature effects. Results showed no significant effect of the CO2 concentration at 37 degrees C, which may be attributed to low CO2 solubility at high temperature. An inhibitory effect of CO2 appeared at lower temperatures (8 and 12 degrees C). Regardless of the temperature, the gaseous CO2 is sparingly soluble at acid pH. However, the CO2 inhibition was not significantly different between pH 5.5 and pH 7. Considering the pKa of the carbonic acid, these results showed the dissolved carbon under HCO3- form didn't affect the bacterial inhibition. Finally, a global model was proposed to estimate the growth rate vs. CO2 concentration in the aqueous phase. This dissolved concentration is calculated according to the physical equations related to the CO2 equilibriums, involving temperature and pH interactions. This developed model is a new tool available to manage the food safety of MAP. PMID- 28800831 TI - Characterization of Enterococcus durans 152 bacteriocins and their inhibition of Listeria monocytogenes in ham. AB - Listeria monocytogenes is a nonfastidious, widely occurring foodborne pathogen that is a major challenge to the food industry. Enterococcus durans 152, a confirmed L. monocytogenes-control microorganism, was isolated from floor drain samples from a food processing facility. In this study, the two bacteriocins produced by E. durans 152 were characterized and identified as Dur 152A (an enterocin L50A derivative with two amino acid substitutions of I->M) and enterocin L50B. The bacteriocins were then partially purified and evaluated for inhibitory activity to L. monocytogenes in deli ham. Results revealed that at 400 AU/ml, the bacteriocins prevented growth of listeria in deli ham for at least 10 weeks at 8 degrees C and at least 30 days at 15 degrees C. For comparison, 500 ppm Nisin controlled listeria growth for up to 6 weeks at 8 degrees C and up to 18 days at 15 degrees C. These findings reveal the potential for the bacteriocins of E. durans 152 to serve as anti-listerial agents in deli meat. PMID- 28800832 TI - Knowledge of Appropriate Outpatient Pediatric Echocardiogram Ordering in Primary Care Physicians and Trainees. AB - Appropriate Use Criteria (AUC) for the initial use of outpatient pediatric echocardiography were established to aid all clinicians in the evaluation of children with possible heart disease, and limit low diagnostic yield studies. We sought to (1) assess PCPs' and trainees' awareness of the AUC document; (2) compare their knowledge of appropriate echocardiogram ordering with that of pediatric cardiologists; and (3) identify additional medical and nonmedical factors affecting PCP echocardiogram ordering. An online survey with clinical scenarios derived from the AUC guidelines was distributed to PCPs and trainees in Arkansas, and pediatric cardiologists from Arkansas Children's Hospital and Cincinnati Children's Hospital Medical Center. Respondents were also asked to rate whether additional medical and nonmedical factors have "no," "mild," "moderate," or "major" impact on PCP echocardiogram ordering. Survey data were collected from 148 respondents. Awareness of the AUC was significantly lower in PCPs (21.4%) and trainees (14%) than in pediatric cardiologists (90.5%, p <0.001). For all rarely appropriate clinical scenarios, cardiologists had stronger agreement with the AUC document (90.9%) than did the PCP group (50.3%) and trainees (53.3%, p <0.001). The strongest additional factors affecting PCP echocardiogram ordering were parental anxiety, difficulty distinguishing innocent from pathologic murmurs, and legal implications of a missed diagnosis. In conclusion, PCPs and trainees are largely unaware of the existence of the pediatric echocardiogram AUC. Educational strategies to improve appropriate echocardiogram ordering should address not only increasing awareness of AUC, but also other factors affecting decision-making. PMID- 28800833 TI - Bleeding Risk Scores in Atrial Fibrillation and Venous Thromboembolism. AB - Patients receiving oral anticoagulant (OAC) therapy for stroke prevention in atrial fibrillation (AF) and prevention of venous thromboembolism (VTE) face an increased risk of bleeding with OAC treatment. Clinicians need to weigh the benefits of OAC treatment against the risk of bleeding. To help formalize bleeding risk assessment, various bleeding risk scores have been developed to help predict the risk of bleeding in AF and VTE patients receiving OAC therapy. This review summarizes the literature involving original studies deriving bleeding risk scores and validation studies of these scores for stroke prevention in AF and treatment/prevention of VTE. To date, there are 10 bleeding risk scores, 6 for use in AF populations, 3 in VTE cohorts, and 1 for mixed indications; they differ markedly in the number of, and risk factors for, bleeding and complexity. In conclusion, many clinical prediction tools to assess bleeding risk prior to starting OAC treatment for either stroke prevention in AF or treatment of VTE are available and should be used in clinical practice to identify and manage modifiable risk factors. PMID- 28800834 TI - Benefits and Harms of Sacubitril in Adults With Heart Failure and Reduced Left Ventricular Ejection Fraction. AB - The quality of evidence regarding patient-centered outcomes in adults with heart failure (HF) after sacubitril combined with valsartan has not been systematically appraised. We searched 4 databases in February 2017 and graded the quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation working group approach. We reviewed 1 meta-analysis and multiple publications of 2 randomized controlled trials (RCT) and 1 unpublished RCT. In adults with HF and reduced ejection fraction, low-quality evidence from 1 RCT of 8,432 patients suggests that sacubitril combined with valsartan reduces all-cause (number needed to treat [NNT] to prevent 1 event [NNTp] = 35) and cardiovascular mortality (NNTp = 32), hospitalization (NNTp = 11), emergency visits (NNTp = 69), and serious adverse effects, leading to treatment discontinuation (NNTp = 63) and improves quality of life when compared with enalapril. In adults with HF and preserved ejection fraction, very low-quality evidence from 1 RCT of 301 patients suggests that there are no differences in mortality, morbidity, or adverse effects between sacubitril combined with valsartan and valsartan alone. In conclusion, in adults with HF and reduced ejection fraction, to reduce cardiovascular mortality and hospitalizations and improve quality of life, clinicians may recommend sacubitril combined with valsartan over angiotensin converting enzyme inhibitors. PMID- 28800835 TI - Deployed women's illness behaviors while managing genitourinary symptoms: An exploratory theoretical synthesis of two qualitative studies. AB - BACKGROUND: The recent removal of United States military combat exclusion rules resulted in more women serving in forward deployed austere conditions. In the deployed setting, women were diagnosed with genitourinary (GU) conditions five times greater than men. PURPOSE: Describe deployed military women's GU illness behaviors. METHOD: Two qualitative descriptive studies interviewing military women and enlisted medics were synthesized using the Illness Behavior Model. DISCUSSION: Similar and divergent views on the impact of the military culture of the illness behaviors were described by women and medics. Both agreed appropriate attention on managing GU symptoms must continue; however differing strategies were appraised. One agreed option was to offer a health care mentor. CONCLUSION: The Illness Behavior Model provided an excellent framework for evaluation of military women's illness behaviors exposing areas for comparing and contrasting the perspectives provided. While significant changes have been made, additional strategies will continue to improve the women's deployed health care quality. PMID- 28800836 TI - [Convulsions associated with Neocodion(r) abuse (codeine camphosulfonate, sulfogaiacol, grindelia extract)]. PMID- 28800837 TI - Outcomes of invasive mediastinal nodal staging versus positron emission tomography staging alone for early-stage non-small cell lung cancer treated with stereotactic body radiation therapy. AB - BACKGROUND: The benefit of invasive mediastinal nodal staging (IMNS) in addition to positron emission tomography-computed tomography (PET/CT) is undefined for early stage non-small cell lung cancer (NSCLC). This multi-institutional investigation aimed to evaluate outcomes and patterns of failure in patients staged with PET/CT with or without additional IMNS. METHODS: Two academic centers assessed all consecutive patients staged with PET/CT for early-stage, primary lung NSCLC (cT1-2aN0M0) treated with SBRT. Local recurrence-free survival (LRFS), nodal recurrence-free survival (NRFS), distant metastasis-free survival (DMFS), and overall survival (OS) were calculated using Kaplan-Meier methodology. Univariate and multivariate Cox proportional hazards modeling addressed factors associated with outcomes. RESULTS: Overall, 180 patients (199 lesions) were staged with PET/CT alone and 56 patients (58 lesions) underwent additional IMNS. Among patients receiving IMNS, 52 (93%) underwent EBUS and 4 (7%) underwent mediastinoscopy. At a median follow-up of 33.5 months (range, 1.9-80.9 months), there was no significant difference in LRFS (37 vs. 47 months, p=0.309), NRFS (34 vs. 42 months p=0.370), DMFS (36 vs. 47 months, p=0.234) or OS (37 vs. 47 months, p=0.236) between patients undergoing PET/CT-only versus PET/CT+IMNS staging, respectively. Receipt of IMNS did not correlate with any outcome on either univariate or multivariate analysis (p>0.05). Patterns of failure in both groups were similar, including crude isolated nodal failure rates (8% PET/CT-only versus 14% PET+IMNS group, p=0.202). CONCLUSIONS: Patients undergoing IMNS had similar survival and patterns of recurrence as those receiving PET/CT alone. Further study, ideally prospectively, is needed to determine which subgroups might benefit from IMNS. PMID- 28800838 TI - Noncompliance with surgical antimicrobial prophylaxis guidelines: A Jordanian experience in cesarean deliveries. AB - BACKGROUND: Surgical site infections are common, especially in developing countries. Nevertheless, up to 60% of surgical site infections can be prevented with appropriate perioperative care, which includes among other measures using suitable surgical antimicrobial prophylaxis (SAP). METHODS: After a short interview with patients and retrospective review of medical charts, compliance with 6 SAP parameters was assessed for appropriateness; those parameters are indication, choice, dose, time of administration, intraoperative redosing interval, and duration of prophylaxis in 1,173 operations. RESULTS: Overall compliance was poor; nevertheless, certain components showed high compliance rates, such as indication and choice of antibiotics. The most frequent error noted was extended administration of prophylactic antibiotics, which was observed in 88.2% of the study population. Emergency operations were associated with a lower risk of noncompliance in administering the correct dose at the correct time (odds ratio, 0.63; 95% confidence interval, 0.47-0.83 and odds ratio, 0.21; 95% confidence interval, 0.14-0.3, respectively). On the other hand, women who underwent an emergency operation were associated with a 6-fold higher risk of receiving prophylactic therapy following surgery. CONCLUSIONS: The present study demonstrated the existence of a surprisingly low level of overall compliance with the hospital-adapted SAP guidelines. Factors implicated in noncompliance were investigated, and the present results create a starting point to improve the current practice. PMID- 28800839 TI - Outcomes of intervention for cephalic arch stenosis in brachiocephalic arteriovenous fistulas. AB - BACKGROUND: Development of recalcitrant stenotic lesions of the cephalic arch is a significant cause of dysfunction of brachiocephalic access arteriovenous fistulas (AVFs). Endovascular and surgical therapy can be used to treat cephalic arch stenosis. The aim of this study was to evaluate the outcomes of endovascular and surgical interventions for cephalic arch stenosis. METHODS: A retrospective review of all patients during a 16-year period with a compromised but not occluded brachiocephalic AVF due to cephalic arch stenosis was undertaken. Patency, reintervention, infection, and functional dialysis rates were examined. RESULTS: From January 2000 to December 2015, 219 patients (67% female; mean age, 58 +/- 20 years) with a failing brachiocephalic AVF underwent intervention at the cephalic arch. These interventions included angioplasty, primary stent placement, transposition, and bypass. The average time to intervention for cephalic arch stenosis was 1.7 years after primary access placement. The average number of percutaneous interventions before the decision to intervene surgically on the cephalic arch was three (range, two to six). Technical success was superior in the surgical groups (70% and 80% compared with 96% and 100% for balloon angioplasty, stenting, transposition, and bypass, respectively; P = .02). Major adverse cardiovascular events were overall low but significantly higher in the surgical groups (1%, 1%, 0.3%, and 0.3% for transposition, bypass, balloon angioplasty, and stenting, respectively; P = .02). Both surgical options carried significantly superior patency rates at 2 years for transposition, bypass, balloon angioplasty, and stenting, respectively (63%, 59%, 90%, and 92%; P = .04). There was a lower rate of interventions per person-year of follow-up in the surgical groups compared with the endovascular groups (1.9, 1.4, 3.5, and 3.1 for transposition, bypass, balloon angioplasty, and stenting, respectively; P = .04). Functional dialysis durations were significantly superior in the surgical groups compared with the endovascular group (P = .03). CONCLUSIONS: Cephalic arch stenosis is a significant cause of brachiocephalic AVF malfunction. Surgical options offer superior long-term patency and functional results and should be considered earlier in the treatment of this disease. PMID- 28800840 TI - Comparing Low-income Mothers' and Fathers' Concern for Young Children's Weight. AB - PURPOSE: The objectives of this study were to compare the relationship of mother and father (1) perceived child weight and child body mass index (BMI) z-score, (2) concern for child's current weight and child BMI z-score, and (3) concern for child's future weight and child BMI z-score. DESIGN AND METHODS: This cross sectional study included low-income mothers (n=30) and fathers (n=30) with a young child (3 to 10years old) from the same household. Each parent completed select items from the Child Feeding Questionnaire (CFQ) with a trained interviewer. Child BMI z-score was calculated. RESULTS: There was a significant, positive relationship between fathers' perceived child weight and child BMI z score (p=0.006) and between fathers' concern for a child's future weight and child BMI z-score (p=0.001) but not among mothers. CONCLUSIONS: Cohabitating low income parents of young children may have conflicting appraisals of their child's BMI z-score and concerns for their child's future weight, and low-income fathers may be more accurate and concerned about their children's weight. PRACTICE IMPLICATIONS: Based on findings from this study, healthcare providers including physicians and nurses should attempt to include fathers in discussions regarding their child's weight for obesity prevention, especially in low-income families. PMID- 28800841 TI - Translational Research-The Multidimensional Challenges of Pediatric Nursing and the Linkage With Improved Health Outcomes for Children and Families. PMID- 28800842 TI - Treatment outcome in orthognathic surgery-A prospective randomized blinded case controlled comparison of planning accuracy in computer-assisted two- and three dimensional planning techniques (part II). AB - PURPOSE: The aim of the present study was to compare the accuracy of two dimensional (2D) and three-dimensional (3D) prediction methods. The hypothesis was that a 3D technique would give a more accurate outcome of the postoperative result. MATERIAL AND METHODS: Patients with severe class III occlusion were included and planed with both a 2D and 3D prediction technique. They were there after randomly subdivided into a control (2D) and test (3D) group and treated according to the technique randomized for. Cephalometric measurements from 2D and 3D predictions were compared with 12-month follow-up respectively. Together with an analysis of tracing error, placements of 3580 cephalometric markers, 2460 measurements, 680 intra-individual analyses and 1200 preop/postop comparisons were performed in 57 individuals. RESULTS: Statistically significant differences for accuracy between the two groups were seen for 11/NSL-112/NSL2 and for A-A2 (p < 0.05). Both groups showed a high level of accuracy for SNA and SNB. The test group also showed a relatively high level of accuracy for 11/NSL and for the A point. No prediction method achieves a perfect accuracy. As expected from this, measuring accuracy within each group showed statistically significant difference for all markers and cephalometric measurements (p < 0.001). Mandibular markers showed greater differences than maxillary markers. CONCLUSION: The present study indicates an equal high accuracy in predicting facial outcome for both studied techniques. However, in patients with asymmetry the three-dimensional technique has an obvious advantage. PMID- 28800843 TI - Discectomy without replacement improves function in patients with internal derangement of the temporomandibular joint. AB - PURPOSE: Treatment of internal derangement is controversial. This study assessed the effectiveness of discectomy without replacement in improving jaw function and decreasing pain. MATERIALS AND METHODS: A retrospective cohort study sample of subjects with internal derangement underwent discectomy without replacement by one surgeon at a single academic medical center. The primary predictor variables were preoperative maximal incisal opening (MIO) and Helkimo Clinical Dysfunction Index (CDI) score. The primary outcome variable was postoperative MIO and CDI score. A paired student's t-test assessed the difference between pre- and post operative MIO and CDI scores. RESULTS: Preoperatively, all patients had a clinical dysfunction index of DiIII, indicating severe dysfunction. Postoperatively 14 of 17 subjects (82%) showed marked improvement in mandibular function, and reduction in pain characterized as clinically symptom-free or only small dysfunction (DiO or DiI). One subject improved to DiII and two remained DiIII due to poor compliance. Preoperatively all subjects had an anamnestic index of AiII, representing TMJ locking or severe TMJ or muscle pain. Postoperatively 15 of 17 patients (88%) improved to AiO or AiI, and the two patients with poor compliance remained at AiII, but with marked pain reduction. Of the 17 subjects, the mean pre- and post-operative MIO was 24.2 mm and 34.9 mm, respectively (p < 0.001). There was a significant difference in pre- and post-operative MIO in subjects with Wilkes III (p = 0.005) and Wilkes IV (p = 0.008), but not Wilkes V (p = 0.7). Mean pre- and post-CDI scores were 17.3 and 3.8, respectively (p < 0.001). When stratifying by Wilkes stage, there was a significant difference in pre- and post-operative CDI in subjects with Wilkes III (p < 0.001) and Wilkes IV (p < 0.001), but not Wilkes V (p = 0.1). CONCLUSIONS: In Wilkes III and IV subjects, discectomy without replacement is effective in improving MIO based upon improvement in objective and subjective assessments. PMID- 28800844 TI - First comparative analysis concerning the plasma platelet contamination during MNC collection. AB - BACKGROUND AND OBJECTIVES: Monocytes can be cultured into dendritic cells with addition of autologous plasma, which is highly prone to platelet contamination due to the apheresis process. Since platelets affect the maturation process of monocytes into dendritic cells and might even lead to a diminished harvest of dendritic cells, it is very important to reduce the platelet contamination. A new collection device (Spectra Optia) was analyzed, compared to two established devices (COM.TEC, Cobe Spectra) and evaluated regarding the potential generation of source plasma. MATERIALS AND METHODS: Concurrent plasma collected during leukapheresis was analyzed for residual cell contamination in a prospective study with the new Spectra Optia apheresis device (n=24) and was compared with COM.TEC and Cobe Spectra data (retrospective analysis, n=72). Donor pre-donation counts of platelets were analyzed for their predictive value of contaminating PLTs in plasma harvests. RESULTS: The newest apheresis device showed the lowest residual platelet count of the collected concurrent plasma (median 3.50*109/l) independent of pre-donation counts. The other two devices and sets had a higher platelet contamination. The contamination of the plasma with leukocytes was very low (only 2.0% were higher than 0.5*109/l). CONCLUSIONS: This study showed a significant reduction of platelet contamination of the concurrent plasma collected with the new Spectra Optia device. This plasma product with low residual platelets and leukocytes might also be used as plasma for fractionation. PMID- 28800845 TI - Assessment of stability of CD34+ cell products enriched by immunoselection from peripheral blood mononuclear cells during refrigerated storage. AB - Durable engraftment of transplanted CD34+ cells largely depends on the quality of the cell product. Limited data are currently available about extended storage of immunoselected CD34+ cells. The aim of our study was to assess the stability of CD34+ cell product with the cells stored in high concentration (80*106 in 6mL) in small bags intended for cell implantation. Cell products were prepared by leukapheresis and immunoselection (Clinimacsplus procedure) from 13 patients with chronic dilated cardiomyopathy. CD34+ cell products were stored at 2-8 degrees C and analyzed at time 0 (fresh products), 24, 48h, 4 and 6 days. Product viability, absolute number of viable CD34+ cells and apoptosis were determined by flow cytometry. Microbiological contamination of the cell products was tested by BACTEC system. The mean viability of CD34+ cells decreased by 2.7% within 24h, by 13.4% within 48h and by 37.5% within 6 days. The mean recovery of viable CD34+ cells was 91.1%, 74.8%, 66.3% and 56.2% at 24, 48h, 4 and 6 days, respectively. The mean fraction of early apoptotic cells in fresh and stored products was 4.9+/ 3.5% at 0h, 5.9+/-3.8% at 24h, 4.2+/-3.1% at 48h, 6.3+/-2.6% at 4 days and 9.3+/ 4.6% at 6 days. All products were negative for microbial contamination. PMID- 28800846 TI - Saprotrophic proteomes of biotypes of the witches' broom pathogen Moniliophthora perniciosa. AB - Nine geographically diverse Moniliophthora perniciosa (witches' broom disease pathogen) isolates were cultured in vitro. They included six C-biotypes differing in virulence on cacao (Theobroma cacao), two S-biotypes (solanaceous hosts), and an L-biotype (liana hosts). Mycelial growth rates and morphologies differed considerably, but no characters were observed to correlate with virulence or biotype. In plant inoculations using basidiospores, one C-biotype caused symptoms on tomato (an S-biotype host), adding to evidence of limited host adaptation in these biotypes. Mycelial proteomes were analysed by two-dimensional gel electrophoresis (2-DE), and 619 gel spots were indexed on all replicate gels of at least one strain. Multivariate analysis of gel spots discriminated the L biotype, but not the S-biotypes, from the remaining strains. The proteomic similarity of the S- and C-biotypes is consistent with their reported lack of phylogenetic distinction. Sequences from tandem mass spectrometry of tryptic peptides from major 2-DE spots were matched with Moniliophthora genome and transcript sequences on NCBI and WBD Transcriptome Atlas databases. Protein-spot identifications indicated that M. perniciosa saprotrophic mycelial proteomes expressed functions potentially connected with a 'virulence life-style', including peroxiredoxin, heat-shock proteins, nitrilase, formate dehydrogenase, a prominent complement of aldo-keto reductases, mannitol-1-phosphate dehydrogenase, and central metabolism enzymes with proposed pathogenesis functions. PMID- 28800847 TI - Heterotrimeric G protein alpha subunit controls growth, stress response, extracellular protease activity, and cyclopiazonic acid production in Penicillium camemberti. AB - The fungus Penicillium camemberti is widely used in the ripening of various bloomy-rind cheeses. Several properties of P. camemberti are important in cheese ripening, including conidiation, growth and enzyme production, among others. However, the production of mycotoxins such as cyclopiazonic acid during the ripening process by P. camemberti has raised concerns among consumers that demand food with minimal contamination. Here we show that overexpressing an alpha subunit from the subgroup I of the heterotrimeric G protein (Galphai) influences several of these processes: it negatively affects growth in a media-dependent manner, triggers conidial germination, reduces the rate of sporulation, affects thermal and osmotic stress resistance, and also extracellular protease and cyclopiazonic acid production. Our results contribute to understanding the biological determinants underlying these biological processes in the economically important fungus P. camemberti. PMID- 28800848 TI - Cold generation of smoke flavour by the first phenolic acid decarboxylase from a filamentous ascomycete - Isaria farinosa. AB - A decarboxylase (IfPAD) from the ascomycete Isaria farinosa converted ferulic acid to 4-vinylguaiacol (4-VG), a volatile which imparts the distinct "smoke flavor" of pyrolized wood. The activity was enhanced by adding (E)-ferulic acid to the culture medium and peaked with 3.6 U g-1 mycelium (1 MUmol 4-VG min-1). The coding sequence of 543 bp was translated into a 25 kDa protein with a homology of 91 % to putative phenolic acid decarboxylases of its teleomorph, Cordyceps militaris, and Beauveria bassiana, the anamorph of Cordyceps bassiana. Cold shock expression in Escherichia coli yielded 411 U g-1 wet mass. Substrate conversion required a hydroxyl substituent para to a trans-unsaturated C3-side chain of the aromatic ring. Km and kcat/Km values were determined to 0.3 mM and 78.4 mM-1s-1 for p-coumaric acid and 1.9 mM and 45.1 mM-1s-1 for (E)-ferulic acid, respectively. The native enzyme and its recombinant counterpart showed pH optima at pH 6.0 and pH 5.5, and low temperature optima of 19 degrees C and 14 degrees C, respectively. IfPAD produced 4-VG from destarched wheat bran and sugar beet fiber, confirming activity on complex plant biomass. This is the first report on the biochemical characterization of a phenolic acid decarboxylase from a filamentous ascomycete. PMID- 28800849 TI - RNAi-mediated silencing of MAP kinase signalling genes (Fmk1, Hog1, and Pbs2) in Fusarium oxysporum reduces pathogenesis on tomato plants. AB - Fusarium oxysporum is a soil-borne plant fungal pathogen, and causes colossal losses in several crop plants including tomato. Effective control measures include the use of harmful fungicides and resistant cultivars, but these methods have shown limited success. Conventional methods to validate fungal pathogenic genes are labour intensive. Therefore, an alternative strategy is required to efficiently characterize unknown pathogenic genes. RNA interference (RNAi) has emerged as a potential tool to functionally characterize novel fungal pathogenic genes and also to control fungal diseases. Here, we report an efficient method to produce stable RNAi transformants of F. oxysporum using Agrobacterium-mediated transformation (AMT). We have transformed F. oxysporum spores using RNAi constructs of Fmk1, Hog1, and Pbs2 MAP kinase signalling genes. Fmk1 RNAi fungal transformants showed loss of surface hydrophobicity, reduced invasive growth on tomato fruits and hypo-virulence on tomato seedlings. Hog1 and Pbs2 RNAi transformants showed altered conidial size, and reduced invasive growth and pathogenesis. These results showed that AMT using RNAi constructs is an effective approach for dissecting the role of genes involved in pathogenesis in F. oxysporum and this could be extended for other fungal systems. The obtained knowledge can be easily translated for developing fungal resistant crops by RNAi. PMID- 28800850 TI - Characterization of the autophagy-related gene BmATG8 in Bipolaris maydis. AB - Autophagy is involved in cellular development and the maintenance of viability under nutrient deprivation in a wide range of eukaryotes. A filamentous ascomycete Bipolaris maydis, responsible for southern corn leaf blight, is also studied as a model fungus for sexual reproduction in filamentous ascomycetes that form filiform ascospores. In order to clarify the roles of autophagy in various stages of the life cycle of B. maydis, we constructed null mutants of BmATG8, an orthologue of the Saccharomyces cerevisiae autophagy gene ATG8 in B. maydis. Deletion of BmATG8 impaired localization of cytosolic components to the vacuole under nitrogen starvation, suggesting that autophagy was deficient in the null mutants. Additionally, fluorescent microscopic observations on a eGFP-fused BmATG8 expressing strain showed that BmATG8 is associated with autophagy-related structures. In vegetative growth, DeltaBmATG8 strains showed a reduction in conidiation and aerial mycelial growth. Interestingly, the mutant conidia indicated loss of the germination rate under starvation conditions and affected longevity. However, germinated mutant conidia were still capable of infecting the host plant via appressoria. In sexual reproduction, ascospores with DeltaBmATG8 genetic background were aborted. Our results revealed that autophagy plays a crucial role in the function of conidia, not in host infection via appressoria in B. maydis. In addition, conservation of the importance of autophagy in ascospore development is suggested among ascomycetes including species that form bitunicate ascus. PMID- 28800851 TI - A revised family-level classification of the Polyporales (Basidiomycota). AB - Polyporales is strongly supported as a clade of Agaricomycetes, but the lack of a consensus higher-level classification within the group is a barrier to further taxonomic revision. We amplified nrLSU, nrITS, and rpb1 genes across the Polyporales, with a special focus on the latter. We combined the new sequences with molecular data generated during the PolyPEET project and performed Maximum Likelihood and Bayesian phylogenetic analyses. Analyses of our final 3-gene dataset (292 Polyporales taxa) provide a phylogenetic overview of the order that we translate here into a formal family-level classification. Eighteen clades are assigned a family name, including three families described as new (Cerrenaceae fam. nov., Gelatoporiaceae fam. nov., Panaceae fam. nov.) and fifteen others (Dacryobolaceae, Fomitopsidaceae, Grifolaceae, Hyphodermataceae, Incrustoporiaceae, Irpicaceae, Ischnodermataceae, Laetiporaceae, Meripilaceae, Meruliaceae, Phanerochaetaceae, Podoscyphaceae, Polyporaceae, Sparassidaceae, Steccherinaceae). Three clades are given informal names (/hypochnicium,/climacocystis and/fibroporia + amyloporia). Four taxa (Candelabrochete africana, Mycoleptodonoides vassiljevae, Auriporia aurea, and Tyromyces merulinus) cannot be assigned to a family within the Polyporales. The classification proposed here provides a framework for further taxonomic revision and will facilitate communication among applied and basic scientists. A survey of morphological, anatomical, physiological, and genetic traits confirms the plasticity of characters previously emphasized in taxonomy of Polyporales. PMID- 28800852 TI - Growth of Amanita caesarea in the presence of Pseudomonas fluorescens and Bacillus cereus. AB - The ectomycorrhizal (ECM) fungus Amanita caesarea CECT 20127 was tested in vitro with two potentially mycorrhizal-promoting bacterial strains, Pseudomonas fluorescens CECT 844 and Bacillus cereus CECT 148. Although P. fluorescens showed spatial and temporal compatibility with A. caesarea, it did not affect growth of the fungus. Conversely, B. cereus exhibited no such compatibility and also inhibited fungal growth. The expression pattern of the A. caesarea gene AcMST-1 was analysed using real-time quantitative polymerase chain reaction (qPCR) at three time points. This gene displays a high degree of homology with two genes, possible orthologues to AcMST-1, previously described in Amanita muscaria (AmMST 1) and Laccaria bicolor (LbMST-1) and encoding monosaccharide transporter proteins. The transcription levels of AcMST1 increased shortly after initial contact between A. caesarea and B. cereus, but expression of the gene was inhibited in the presence of P. fluorescens. Our results show that A. caesarea may possess orthologous genes of similar ECM fungal species that would allow it to adapt in nature to optimize sugar uptake from the environment depending on the presence of different microorganisms. PMID- 28800853 TI - The anterolateral ligament: Anatomic implications for its reconstruction. AB - BACKGROUND: The purpose of this study was to define the best anatomic parameters with which to perform an accurate anterolateral ligament (ALL) reconstruction. These parameters were anatomical insertions, allowing favorable isometry, length variation during flexion, and anthropometric predictors of ALL lengths. METHODS: A total of 84 fresh-frozen cadaver knees were dissected to analyze the ALL, focusing on its femoral insertion. The ALL length was measured in different degrees of flexion (extension, 30 degrees , 60 degrees , and 90 degrees of flexion) and rotation (neutral, internal or external rotation). The ALL width and thickness were measured. A correlation between ALL length, the general knee size and individual characteristics was investigated. RESULTS: The ALL was present in 80 specimens (95%). The femoral footprint was always posterior (5.52+/-0.93 mm, range 3.83-6.94) and slightly proximal (1.51+/-0.75mm, range 0.63-2.37) to the lateral femoral epicondyle. The mean ALL length increased with internal rotation and decreased with external rotation (P<0.05). The maximum ALL length was found at 30 degrees of flexion, and the minimum at 90 degrees . There was a significant correlation between the ALL length and height, sex, and proximal femur dimensions. CONCLUSION: In order to get an anatomical reconstruction with favorable isometry, it is recommended that the ALL femoral graft is implanted posterior and slightly proximal to the epicondyle. It is also suggested that the tension be adjusted by fixing the graft between 0 and 30 degrees of flexion, being tighter near extension. This will allow good rotational stability without implying any stiffness. PMID- 28800854 TI - Up to seven years' follow-up of short cemented stems in complex primary total knee arthroplasty: A prospective study. AB - BACKGROUND: Although primary total knee arthroplasty (TKA) shows good clinical, functional and radiological results, it can be complicated by certain conditions or pathologies. The main objective of this study was to evaluate the global performance of short cemented metaphyseal stem components in patients undergoing complex primary TKA. METHODS: This is a single-surgeon prospective case series of 91 patients who underwent complex primary TKA requiring short stem fixation between January 2009 and October 2014. Knee Society Scores, physical examinations, and radiological assessments were performed pre- and postoperatively at six weeks, three months, six months, 12months, and annually thereafter. RESULTS: There were 40 females (46 TKAs) and 40 males (45 TKAs) in the study cohort. The left knee accounted for 52.7% of the surgeries. The average body-mass index (BMI) was 31.8kg/m2. Knee Society Scores obtained at the latest follow-up showed 96.4% and 95.5% good-to-excellent results respectively for the Knee and Function sub-scores. Radiological assessment showed that all Knee Society roentgenographic scores were below 10, without any evidence of impending or possible failure. Only one revision was required in this cohort for a patient suffering a deep chronic infection. At seven years, the Kaplan-Meier survivorship analysis revealed a 100% survivorship for aseptic loosening and a 98.9% survivorship for infection and revision of the components for any reason. CONCLUSION: This study demonstrated that TKA with short cemented stems resulted in good functional, clinical, and radiological outcomes for up to seven years for patients requiring complex TKA. PMID- 28800855 TI - Radiographic analysis of the lower limbs using the hip-calcaneus line in healthy individuals and in patients with varus knee osteoarthritis. AB - BACKGROUND: Several recent reports define the line from the centre of the femoral head to the lowest point of the calcaneus. The purpose of this study was to comparatively examine the usefulness of the hip-calcaneus (HC) line and hip-ankle (HA) line for the evaluation of lower-limb alignment in healthy individuals and in patients with osteoarthritis (OA). METHODS: Participants included 34 healthy individuals (mean age, 26.4years) and 34 patients with OA (mean age, 74.2years). Frontal radiographs of the entire lower limb were taken in single- and double-leg stances. For each group, the hip-knee-ankle (HKA) and hip-knee-calcaneus (HKC) angles were assessed and compared within and between stances. In addition, the HA line and HC line were assessed as the passing line in the knee, and were similarly compared. RESULTS: Significant differences between the HKA and HKC angles, and between the HA line and HC line were observed in both groups during both stances. In addition, significant stance-related differences in the HKA and HKC angles, HA line, and HC line were found in the OA group, but not in the healthy group. CONCLUSIONS: Our results suggest that the HC line of the lower limb differs from the HA line. Furthermore, single- and double-leg stances should also be considered, especially in patients with OA. These considerations may affect preoperative planning for high tibial osteotomies and TKA. PMID- 28800856 TI - [Impact of mitral annuloplasty combined with surgical revascularization in ischemic mitral regurgitation]. AB - INTRODUCTION: Ischemic Mitral Regurgitation (IMR) is a serious complication of coronary artery disease and is associated with a poor prognosis. The optimal surgical treatment of IMR involves controversies in its indications and modalities. OBJECTIVES: To determine whether mitral annuloplasty associated with surgical revascularization improved short and mid terms outcomes compared with revascularization alone in patients with IMR. METHODS: Between January 2007 and January 2011, 81 patients operated on Department of Cardiovascular Surgery "B" were included in this study divided into 3 groups. Group 1: 28 patients with IMR had mitral valve surgery associated with surgical revascularization. Group 2: 26 patients with IMR had surgical revascularization without mitral valve surgery. Group 3: 27 patients without IMR had isolated revascularization. Clinical end points were operative mortality, late mortality, postoperative functional status (NYHA), and the Effective Regurgitant Orifice (ERO) at last follow-up. The mean follow-up was 5 years for groups 1 and 2 and 4 years for group 3. RESULTS: There was no difference between the 3 groups regarding age, sex, cardiovascular risk factors, and extension of coronary artery disease. The Left Ventricle End Diastolic Diameter (LVEDD) and the Left Ventricle Ejection Fraction (LVEF) were slightly different. Late and operative mortality were higher in group 2 compared to groups 1 and 3. Postoperative functional status (NYHA) improved both in groups 1 and 2. In group 1, there was a decrease in ERO. CONCLUSION: Mitral annuloplasty combined to revascularization improves symptoms, postoperative ERO and short- and mid-term survival compared with revascularization alone. PMID- 28800857 TI - Treatment algorithm proposal for patients with drug resistant overactive bladder syndrome. PMID- 28800858 TI - Diagnostic Value of Synovial White Blood Cell Count and Serum C-Reactive Protein for Acute Periprosthetic Joint Infection After Knee Arthroplasty. AB - BACKGROUND: The diagnosis of periprosthetic joint infection (PJI) remains difficult, particularly in acute postoperative stage. The purpose of this study was to investigate the optimal cutoff value of synovial white blood cell (WBC) count, percentage of polymorphonuclear cells, erythrocyte sedimentation rate, and C-reactive protein (CRP) for diagnosing early postoperative infection after knee joint arthroplasty. METHODS: We retrospectively reviewed primary total knee arthroplasties and unicompartmental knee arthroplasties, with a knee aspiration within 3 weeks of surgery, from January 2006 to November 2016. Twelve infected cases and 185 uninfected cases met the inclusion criteria of our study. We compared the laboratory parameters (synovial WBC count, percentage of polymorphonuclear cells, erythrocyte sedimentation rate, and CRP levels) between the 2 groups. Receiver operating characteristic curves were constructed to determine the optimal cutoff values for each parameter. Each parameter was studied to determine its sensitivity, specificity, and positive and negative predictive values (PPV and NPV) in diagnosing acute PJI. RESULTS: There were 2 optimal cutoff values for synovial WBC count and CRP levels. With the cutoff value of synovial WBC set at 11,200 cells/MUL, acute PJI could be diagnosed with the highest sensitivity (100%) and specificity (98.9%); with the cutoff value set at 16,000 cells/MUL, the best PPV and NPV were found (100% and 99.5%, respectively). Similarly, the CRP level >34.9 mg/L had the best sensitivity (100%) and specificity (90.3%), whereas the CRP level >74.5 mg/L had the best PPV (100%) and NPV (99.2%). CONCLUSION: Synovial WBC count and CRP levels are useful in diagnosing acute PJI between 1 and 3 weeks after primary knee arthroplasty. PMID- 28800859 TI - The Role of Psychiatric Diagnoses for Outcome After Hip and Knee Arthroplasty. AB - BACKGROUND: Surgical patients receiving psychopharmacologic treatment have been associated with adverse outcomes in total hip and knee arthroplasty (THA and TKA). The purpose of this study was to investigate whether a specific high-risk group of patients receiving psychopharmacologic treatment could be identified based upon a nationwide psychiatric diagnosis register. METHODS: From 7 different orthopedic centers, 8288 THA and TKA patients were included from January 2010 to November 2012 of which 943 (11.4%) received psychopharmacologic treatment. Patients receiving preoperative psychopharmacologic treatment were divided into 2 groups based on the presence or absence of a psychiatric diagnosis in a nationwide administrative database and analyzed with respect to length of hospital stay (LOS >4 days) and 30- and 90-day readmissions using multivariable logistic regression models. RESULTS: A total of 191 patients receiving psychopharmacologic treatment were registered with a psychiatric diagnosis while 752 patients received psychopharmacologic treatment without a registered psychiatric diagnosis. No significantly increased risk was found in patients with a preoperative registered psychiatric diagnosis compared to patients without, with regard to LOS >4 days (odds ratio [OR], 1.19; P = .51), 30-day readmission (OR, 0.56; P = .086), or 90-day readmission (OR, 0.81; P = .446), respectively. However, both groups had an increased risk of LOS >4 days and readmissions compared to a control population without psychopharmacologic treatment or any registered psychiatric diagnoses. CONCLUSION: No further risk was found for psychopharmacologically treated THA/TKA patients with an additional hospital related psychiatric diagnosis compared to patients without, suggesting that the psychopharmacologic treatment per se is an outcome risk factor independent of severity of the psychiatric disorder. PMID- 28800860 TI - Correction to Lancet Oncol 2017; 18: e429. PMID- 28800862 TI - NICE guidance on cabozantinib for previously treated advanced renal cell carcinoma. PMID- 28800861 TI - Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. AB - BACKGROUND: The oral AKT inhibitor ipatasertib is being investigated in cancers with a high prevalence of PI3K/AKT pathway activation, including triple-negative breast cancer. The LOTUS trial investigated the addition of ipatasertib to paclitaxel as first-line therapy for triple-negative breast cancer. METHODS: In this randomised, placebo-controlled, double-blind, phase 2 trial, women aged 18 years or older with measurable, inoperable, locally advanced or metastatic triple negative breast cancer previously untreated with systemic therapy were recruited from 44 hospitals in South Korea, the USA, France, Spain, Taiwan, Singapore, Italy, and Belgium. Enrolled patients were randomly assigned (1:1) to receive intravenous paclitaxel 80 mg/m2 (days 1, 8, 15) with either ipatasertib 400 mg or placebo once per day (days 1-21) every 28 days until disease progression or unacceptable toxicity. Randomisation was by stratified permuted blocks (block size of four) using an interactive web-response system with three stratification criteria: previous (neo)adjuvant therapy, chemotherapy-free interval, and tumour PTEN status. The co-primary endpoints were progression-free survival in the intention-to-treat population and progression-free survival in the PTEN-low (by immunohistochemistry) population. This ongoing trial is registered with ClinicalTrials.gov (NCT02162719). FINDINGS: Between Sept 2, 2014, and Feb 4, 2016, 166 patients were assessed for eligibility and 124 patients were enrolled and randomly assigned to paclitaxel plus ipatasertib (n=62) or paclitaxel plus placebo (n=62). Median follow-up was 10.4 months (IQR 6.5-14.1) in the ipatasertib group and 10.2 months (6.0-13.6) in the placebo group. Median progression-free survival in the intention-to-treat population was 6.2 months (95% CI 3.8-9.0) with ipatasertib versus 4.9 months (3.6-5.4) with placebo (stratified hazard ratio [HR] 0.60, 95% CI 0.37-0.98; p=0.037) and in the 48 patients with PTEN-low tumours, median progression-free survival was 6.2 months (95% CI 3.6-9.1) with ipatasertib versus 3.7 months (1.9-7.3) with placebo (stratified HR 0.59, 95% CI 0.26-1.32, p=0.18). The most common grade 3 or worse adverse events were diarrhoea (14 [23%] of 61 ipatasertib-treated patients vs none of 62 placebo-treated patients), neutrophil count decreased (five [8%] vs four [6%]), and neutropenia (six [10%] vs one [2%]). No colitis, grade 4 diarrhoea, or treatment-related deaths were reported with ipatasertib. One treatment-related death occurred in the placebo group. Serious adverse events were reported in 17 (28%) of 61 patients in the ipatasertib group and nine (15%) of 62 patients in the placebo group. INTERPRETATION: Progression-free survival was longer in patients who received ipatasertib than in those who received placebo. To our knowledge, these are the first results supporting AKT-targeted therapy for triple-negative breast cancer. Ipatasertib warrants further investigation for the treatment of triple-negative breast cancer. FUNDING: F Hoffmann-La Roche. PMID- 28800863 TI - Targeting PI3K/AKT pathway in triple-negative breast cancer. PMID- 28800864 TI - Prospective study of sexual dysfunction after proctectomy for rectal cancer. AB - BACKGROUND: Although rectal cancer is a common malignancy and has an improved cure rate in response to oncological treatment, research on rectal-cancer survivors' sexual function remains limited. OBJECTIVE: The aim of this prospective study is to assess sexual dysfunction after rectal cancer surgery. PATIENTS AND METHODS: Patients undergoing curative rectal cancer surgery were included in the study. Sexual function before and 6 months after the operation was measured using the validated questionnaires. Primary outcome was to determine the rates of Sexual dysfunction after rectal cancer surgery. Furthermore, the factors which can have an impact on sexual function after radical treatment have been assessed. RESULTS: A total of 187 patients [117 (63%) men and 70 (37%) women] with rectal cancer who underwent radical resection were included in the study. Sexual function has significantly decreased after surgery. Among male patients, sexual dysfunction increased from the baseline 4% (n = 5) up to 41% (n = 48) after the operation. Among female patients, sexual dysfunction increased from the baseline 53% (n = 37) up to 77% (n = 54) after the operation. A significant lower rate of laparoscopic surgery has been found in both males and females who reported sexual dysfunction after surgery. The patients who have locally advanced disease and those who received postoperative chemotherapy or radiotherapy have higher rates of sexual dysfunction. CONCLUSION: This study, showed that sexual dysfunction is common in patients with rectal cancer after radical treatment. However, patients who underwent laparoscopic surgery have lower rates of sexual dysfunction than those who underwent open surgery. PMID- 28800865 TI - Anaphylaxis. AB - Anaphylaxis is a systemic, life-threatening disorder triggered by mediators released by mast cells and basophils activated via allergic (IgE-mediated) or nonallergic (non-IgE-mediated) mechanisms. It is a rapidly evolving, multisystem process involving the integumentary, pulmonary, gastrointestinal, and cardiovascular systems. Anaphylaxis and angioedema are serious disorders that can lead to fatal airway obstruction and culminate in cardiorespiratory arrest, resulting in hypoxemia and/or shock. Often, these disorders can be appropriately managed in an outpatient setting; however, these conditions can be severe enough to warrant evaluation of the patient in the ED and in some cases, hospitalization, and management in an ICU. Reports suggest that underdiagnosis and undertreatment of anaphylaxis are common. Several new syndromes have been described recently including bird-egg, pork-cat, delayed allergy to mammalian meat and a diverse group of mast cell activation disorders. Conditions such as postural orthostatic tachycardia syndrome, carcinoid syndrome, Munchausen stridor, and factitious anaphylaxis can present similarly and need to be included in the differential diagnosis. Anaphylaxis is a clinical diagnosis, but plasma tryptase and urinary histamine levels are often elevated, allowing diagnostic confirmation; however, diagnostic testing should not delay treatment as results may not be immediately available. The sine qua non of treatment is avoidance of any known triggers and epinephrine, which should never be delayed if this disorder is suspected. Secondary treatments include fluids, bronchodilators, antihistamines, and glucocorticoids. Patients with cardiopulmonary arrest or airway or vascular compromise require mechanical ventilation, vasopressors, and other advanced life support in the ICU. PMID- 28800866 TI - Five-Year Trends of Critical Care Practice and Outcomes. AB - BACKGROUND: Longitudinal analyses of large, detailed adult critical care datasets provide insights into practice trends and generate useful outcome and process benchmarks. METHODS: Data representing 991,571 consecutive critical care visits to 160 US adult ICUs from 2009 to 2013 from the eICU Research Institute clinical practice database were used to quantitate patient characteristics, APACHE IV based acuity predictions, treatments, and outcomes. Analyses for changes over time were performed for patient characteristics, entry and discharge locations, primary admission diagnosis, treatments, adherence to consensus ICU best practices, length of stay (LOS), and inpatient mortality. RESULTS: We detected significant trends for increasing age, BMI, and risk of mortality, higher frequency of admission from an ED and stepdown unit, and more frequent hospital discharge to substance abuse centers and skilled nursing facilities. Significantly more patients were admitted for sepsis, emphysema, coma, congestive heart failure, diabetic ketoacidosis, and fewer were admitted for asthma, unspecified chest pain, coronary artery bypass graft, and stroke care. The frequency of noninvasive mechanical ventilation and adherence to critical care best practices significantly increased, whereas the duration of renal replacement therapies, frequency of transfusions, antimicrobial use, critical care complications, LOS, and inpatient mortality decreased. CONCLUSIONS: Analyses of patients, practices, and outcomes from a large geographically dispersed sample of adult ICUs revealed trends of increasing age and acuity, higher rates of adherence to best practice, use of noninvasive mechanical ventilation, and decreased use of antimicrobials, transfusions, and duration of renal replacement therapies. Acuity-adjusted LOS and in hospital mortality decreased. PMID- 28800867 TI - Impact of Timing of Lobectomy on Survival for Clinical Stage IA Lung Squamous Cell Carcinoma. AB - BACKGROUND: Because the relationship between the timing of surgery following diagnosis of lung cancer and survival has not been precisely described, guidelines on what constitutes a clinically meaningful delay of resection of early-stage lung cancer do not exist. This study tested the hypothesis that increasing the time between diagnosis and lobectomy for stage IA squamous cell carcinoma (SCC) would be associated with worse survival. METHODS: The association between timing of lobectomy and survival for patients with clinical stage IA SCC in the National Cancer Data Base (2006-2011) was assessed using multivariable Cox proportional hazards analysis and restricted cubic spline (RCS) functions. RESULTS: The 5-year overall survival of 4,984 patients who met study inclusion criteria was 58.3% (95% CI, 56.3-60.2). Surgery was performed within 30 days of diagnosis in 1,811 (36%) patients, whereas the median time to surgery was 38 days (interquartile range, 23, 58). In multivariable analysis, patients who had surgery 38 days or more after diagnosis had significantly worse 5-year survival than patients who had surgery earlier (hazard ratio, 1.13 [95% CI, 1.02-1.25]; P = .022). Multivariable RCS analysis demonstrated the hazard ratio associated with time to surgery increased steadily the longer resection was delayed; the threshold time associated with statistically significant worse survival was ~90 days or greater. CONCLUSIONS: Longer intervals between diagnosis of early-stage lung SCC and surgery are associated with worse survival. Although factors other than the timing of treatment may contribute to this finding, these results suggest that efforts to minimize delays beyond those needed to perform a complete preoperative evaluation may improve survival. PMID- 28800868 TI - NOR-TEST-ing tenecteplase in acute ischaemic stroke. PMID- 28800869 TI - The role of CA3 GABAB receptors on anxiolytic-like behaviors and avoidance memory deficit induced by D-AP5 with respect to Ca2+ ions. AB - Glutamatergic and GABAergic systems play key roles in the hippocampus and affect the pathogenesis of anxiety- and memory-related processes. Some investigations have assessed the role of balancing the function of these two systems in different areas of the central nervous system (CNS) as an approach to manage the related disorders. We investigated the anxiety and avoidance memory states using the test-retest protocol in the elevated plus maze to understand the role of GABAB receptors (GABABRs) in relation to the NMDA receptor blockade by D-AP5 (an NMDA receptor antagonist). Also, we examined the function of Ca2+ ions by blocking its entrance to the cell using SKF96365 (a Ca2+ channel blocker). The drugs were injected into the CA3 region before the test. Our data showed that D AP5 induced anxiolytic-like behaviors and impaired the avoidance memory. Injection of baclofen (a GABABR agonist), but not phaclofen (a GABABR antagonist) induced anxiolytic-like behaviors. Neither baclofen nor phaclofen altered avoidance memory-related behaviors. When baclofen was injected before D-AP5, it potentiated the anxiolytic-like behaviors induced by D-AP5, but counteracted its effect on avoidance memory. Phaclofen pretreatment attenuated D-AP5-induced anxiolytic-like behaviors, but potentiated its effect on avoidance memory. The effect of baclofen application before D-AP5 on anxiety and phaclofen application before D-AP5 on avoidance memory at the heist doses were accompanied by a decrease in locomotion. The application of SKF96365 did not alter anxiety-like behaviors but induced avoidance memory impairment. SKF96365 application before the combination of baclofen and D-AP5 counteracted the effects produced by the combination of baclofen and D-AP5 on anxiety and memory states. Our findings showed that the CA3 GABABRs had a critical role in anxiolytic-like behaviors and avoidance memory deficit induced by D-AP5 and confirmed the role of Ca2+ ions in the observed results. PMID- 28800870 TI - Recent advances in HER2 positive breast cancer epigenetics: Susceptibility and therapeutic strategies. AB - HER2 amplification/overexpression accounts for aggressive clinical features of HER2 positive breast cancer. Epigenetic changes including DNA methylation, histone modifications and ncRNAs/miRNAs are associated with regulation of DNA chromatin and specifically, gene transcription. Hence, these produce eminent effects upon proto-oncogenes, tumor-suppressors and key cancer-regulatory signaling pathways. Understanding of epigenomic regulation of HER2 overexpression and signaling may help uncover the unmatchable physiology of HER2 gene/protein. Moreover, this may also aid in resolving the major issue of resistance development towards HER2 targeted agents (trastuzumab and lapatinib), since epigenetic alterations are important therapeutic markers and modulate the response towards HER2 targeted therapy. Therefore, in this review the information regarding various epigenetic markers implicated in HER2 positive breast cancer susceptibility and therapeutic-strategies has been compiled. PMID- 28800872 TI - Oxysterols and phytosterols in human health. PMID- 28800871 TI - Malignant Pleural Mesothelioma: State of the art and advanced cell therapy. AB - Malignant Pleural Mesothelioma (MPM) is an aggressive malignancy highly resistant to chemotherapy, with a response rate of 20% of patients and for this reason an efficient treatment is still a challenge. Platinum-based chemotherapy in association with a third-generation antifolate is the front-line standard of care whereas any second-line treatment was approved for MPM thus making it a pathology that evokes the need for new therapeutic agents. Different platinum-drugs were synthesised and tested as an option for patients who are not candidates to cisplatin-based therapy. Among these, monofunctional cationic antineoplastic platinum compounds received a special attention in the last decade. Alternative strategies to the commonly used combination-therapy resulted from the use of Mesenchymal Stromal Cells (MSC) widely used in the field of regenerative medicine and recently proposed as natural carriers for a selective delivery of chemotherapeutic agents and from the use of immune checkpoint and kinase inhibitors. The present short review shed light on the recent state of art and the future perspectives relative to MPM therapy. PMID- 28800874 TI - The synthesis, characterization and in vivo study of mineral substituted hydroxyapatite for prospective bone tissue rejuvenation applications. AB - Minerals substituted apatite (M-HA) nanoparticles were prepared by the precipitation of minerals and phosphate reactants in choline chloride-Thiourea (ChCl-TU) deep eutectic solvent (DESs) as a facile and green way approach. After preparation of nanoparticles (F-M-HA (F=Fresh solvent)), the DESs was recovered productively and reprocess for the preparation of R-M-HA nanoparticles (R=Recycle solvent).The functional groups, phase, surface texture and the elemental composition of the M-HA nanoparticles were evaluated by advance characterization methods. The physicochemical results of the current work authoritative the successful uses of the novel (ChCl-TU) DESs as eco-friendly recuperate and give the medium for the preparation of M-HA nanoparticles. Moreover, the as synthesized both M-HA nanoparticles exhibit excellent biocompatibility, consisting of cell co-cultivation and cell adhesion, in vivo according to surgical implantation of Wistar rats. PMID- 28800873 TI - Transbronchial lung cryobiopsy: Associated complications. AB - INTRODUCTION: Transbronchial lung cryobiopsy (TBC) has emerged as a diagnostic alternative to surgical lung biopsy in interstitial lung disease (ILD). Despite its less invasive nature, some associated complications have been described. OBJECTIVE: To evaluate complications of TBC and associated factors. METHODS: Prospective evaluation of all patients with ILD submitted to TBC in our centre. Clinicodemographic variables and factors associated to TBC complications were analyzed. The effect of the variables on the complication risk was evaluated by a logistic regression model. RESULTS: Ninety patients were included (mean age 60+/ 13 years; 58.9% male). Twenty-two patients presented pneumothorax, 18 (81.8%) of which were treated with chest tube drainage [median air leak time: 1 day (IQR=2)]. Grade 2 and 3 bleeding was observed in 13 (14.4%) cases. Presence of visceral pleura in the sample accounted for almost more than 10 times the odds of pneumothorax (OR=9.59, 95% CI 2.95-31.17, p<0.001). Increased body mass index (BMI) was associated with bleeding (16% additional odds for each BMI unit increase (OR=1.16, 95% CI 1.01-1.34, p=0.049). CONCLUSION: The most frequent complication of TBC was pneumothorax, although rapidly reversible. There was a positive association between pneumothorax and the presence of pleura in the biopsy samples as well as between bleeding and increased BMI. More studies about TBC complications are needed to improve the selection of the candidates for this procedure. PMID- 28800875 TI - Local delivery of siRNA-loaded calcium phosphate nanoparticles abates pulmonary inflammation. AB - The local interference of cytokine signaling mediated by siRNA-loaded nanoparticles might be a promising new therapeutic approach to dampen inflammation during pulmonary diseases. For the local therapeutic treatment of pulmonary inflammation, we produced multi-shell nanoparticles consisting of a calcium phosphate core, coated with siRNAs directed against pro-inflammatory mediators, encapsulated into poly(lactic-co-glycolic acid), and coated with a final outer layer of polyethylenimine. Nasal instillation of nanoparticles loaded with a mixture of siRNAs directed against different cytokines to mice suffering from TH1 cell-mediated lung inflammation, or of siRNA directed against NS-1 in an influenza infection model led to a significant reduction of target gene expression which was accompanied by distinct amelioration of lung inflammation in both models. Thus, this study provides strong evidence that the specific and local modulation of the inflammatory response by CaP/PLGA nanoparticle-mediated siRNA delivery could be a promising approach for the treatment of inflammatory disorders of the lung. PMID- 28800876 TI - The Effects of red Blood Cell Transfusion on Tissue Oxygenation and the Microcirculation in the Intensive Care Unit: A Systematic Review. AB - The transfusion of red blood cells (RBCs) is a common intervention in intensive care unit (ICU) patients, yet the benefits are far from clear in patients with moderate anemia (eg, hemoglobin (Hb) levels of 7-10 g/dL). Determining which of these patients benefit, and how to even define benefit, from transfusion is challenging. As the intended physiological benefit underpinning RBC transfusion is to improve tissue oxygenation, several studies utilizing a wide range of assessment techniques have attempted to study the effects of transfusion on tissue oxygenation and microcirculatory function. The objective of this systematic review was to determine whether RBC transfusion improves tissue oxygenation/microcirculatory indices in the ICU population, and to provide an introduction to the techniques used in these studies. Eligible studies published between January 1996 and February 2017 were identified from searches of PubMed, Embase, Cinahl, ScienceDirect, Web of Science, and The Cochrane Library. Seventeen studies met inclusion criteria, though there was significant heterogeneity in study design, patient population, assessment techniques and outcomes reported. Overall, the majority of studies (11 of 17) concluded that transfusion did not generally improve tissue oxygenation or microcirculation. Inter-individual effects were highly variable, however, and closer review of sub groups available in 9 studies revealed that patients with abnormal tissue oxygenation or microcirculatory indices prior to transfusion had improvement in these indices with transfusion, irrespective of assessment method. This finding suggests a new strategy for future trials in the ICU: utilizing tissue oxygenation/microcirculatory parameters to determine the need for transfusion rather than largely arbitrary hemoglobin concentrations. PMID- 28800877 TI - Reply to: "Interferon-free therapy of hepatitis C during wait list and post transplant risk of hepatocellular carcinoma recurrence". PMID- 28800878 TI - Developing PreDICT - a fully integrated data platform for preclinical in vivo data: learning from experience. AB - In vivo models have been crucial for developing our understanding of key processes associated with human disease and developing novel therapeutics. These in vivo studies are becoming increasingly complex, requiring long-term efficacy data and additional supportive datasets such as pharmacokinetic profiles and analysis of multiple biomarkers of pharmacodynamic response and efficacy. Moreover, a new agent will be investigated in many different models and often in combination with other drugs. Despite advances across the industry integrating and analysing complex datasets, management of in vivo data remains an ongoing challenge across the industry. Here, we describe a project that has successfully delivered a working solution to integrate pharmacokinetic, biomarker and efficacy data, independent of therapy area. PMID- 28800879 TI - The Association Between Fruit and Vegetable Consumption and Fruit and Vegetable Stage of Change in Underserved Communities Engaging With Cooperative Extension Services. AB - OBJECTIVE: To compare differences in fruit and vegetable (FV) intake and FV stage of change in 2 diverse communities engaging with cooperative extension services (Extension). METHODS: Cross-sectional study of FV behaviors of community members enrolled in a team-based challenge offered by Extension. t test and chi-square analyses examined differences in FV intake and FV stage of change. Linear regression examined the relationship between FV stage of change and FV intake, adjusting for demographics. RESULTS: There was a significant (P = .01) difference in staging between the African American and Hispanic communities. Of individuals in the African American community, 60% were in the preparation stage; in the Hispanic community, 55% were in the precontemplation/contemplation stage. The FV stage of change was significantly associated with daily FV intake (beta = .53; P < .001). CONCLUSIONS AND IMPLICATIONS: To promote consumption of FVs better, nutrition education programs such as Extension should differentiate based on stages of change among subpopulations. PMID- 28800880 TI - Radioactive iodine 131I uptake in an ovarian teratoma. PMID- 28800881 TI - Incidental pituitary adenoma detected by 18F-FDG PET/CT and 18F-choline PET/CT in the same patient. PMID- 28800882 TI - Salvianolic acid B inhibits intermittent high glucose-induced INS-1 cell apoptosis through regulation of Bcl-2 proteins and mitochondrial membrane potential. AB - Blood glucose fluctuations, also referred to as intermittent high glucose, have been validated to be more harmful than sustained high glucose in exacerbating pancreatic dysfunction by inducing beta cell apoptosis. Salvianolic acid B (Sal B), an aqueous component of Salvia miltiorrhiza, has been proved beneficial to pancreatic islet function in diabetes, but the underlying mechanisms remain to be elucidated. The present study investigated the protective effect of Sal B on INS 1 cells exposed to intermittent high glucose and the possible mechanisms implicated. The results indicated that Sal B was able to restore cell viability and suppress INS-1 cell apoptosis induced by intermittent high glucose. Preincubation with Sal B led to a significant decrease of caspase-9 and caspase-3 activity and poly ADP-ribose polymerase (PARP) cleavage. Exposure to intermittent high glucose induced significant up-regulation of proapoptotic proteins, down regulation of antiapoptotic protein and depolarization of mitochondrial membrane potential (MMP) in INS-1 cells, while these changes were reversed effectively in Sal B treated groups. In addition, Sal B markedly attenuated intermittent high glucose-induced oxidative stress as manifested by notably decreased levels of intracellular reactive oxygen species and malondialdehyde (MDA). Taken together, these results indicate that Sal B is able to suppress intermittent high glucose induced INS-1 cell apoptosis, which might be ascribed to regulation of Bcl-2 family protein expression and preservation of mitochondrial membrane potential. PMID- 28800883 TI - Gene expression profiling and pathway network analysis of anti-tumor activity by Jaridon 6 in esophageal cancer. AB - Jaridon 6, a novel ent-kaurene diterpenoid derived from Rabdosia rubescens (Hemsl.) Hara, possesses strong anti-tumor activity in esophageal cancer cells. In this study, we explored the underlying molecular events of the anti-tumor activity of Jaridon 6. Cell viability and apoptosis results obtained by flow cytometry confirmed the tumor inhibitory effect of Jaridon 6 in esophageal cancer cells. A cDNA microarray was performed and the observations were validated using quantitative reverse transcription polymerase chain reaction. The microarray data showed that 151 genes were differentially expressed between the untreated group and the Jaridon 6-treated group, among these were 57 upregulated genes, and 94 downregulated genes (P < 0.01, fold change threshold: 2). These included genes such as Wnt, peroxisome, and genes involved in chemokine signaling pathways. In addition, Western blot analysis demonstrated that Jaridon 6 regulated the expression of Wnt pathway proteins, including reduced levels of Dvl 2, survivin and cyclin D1, and increased levels of p-beta-catenin, and AXIN2 in EC109 and EC9706 esophageal cancer cells. In addition, recombinant murine Wnt3a could change the regulation of Jaridon 6 on Wnt pathway proteins. Immunohistochemical analysis indicated that the anti-tumor activity of Jaridon 6 was closely related to the Wnt signaling pathway in esophageal cancer cells. PMID- 28800884 TI - Ionic mechanisms of the action of anaesthetics on sinoatrial node automaticity. AB - Although various general anaesthetics affect the heart rate in clinical settings, their precise mechanisms remain to be fully elucidated. Because the heart rate is determined by automaticity of the cardiac pacemaker sinoatrial node and its regulation by autonomic nervous system, it is important to clarify the effect of anaesthetics on sinoatrial node automaticity. The spontaneous electrical activity of sinoatrial node is generated by a complex but coordinated interaction of multiple ionic currents, such as the hyperpolarisation-activated cation current (If), T-type and L-type Ca2+ currents (ICa,T and ICa,L), Na+/Ca2+ exchange current (INCX), and rapidly and slowly activating delayed rectifier K+ currents (IKr and IKs). Patch-clamp studies have revealed the direct inhibitory effects of various anaesthetics on sinoatrial node automaticity and its underlying ionic mechanisms. Sevoflurane, desflurane and propofol directly suppress the sinoatrial node automaticity by inhibiting multiple ionic channels and transporter, such as If, ICa,T, ICa,L, IKs and INCX. By incorporating these inhibitory effects of anaesthetics on multiple ion channels and transporter into sinoatrial node model, suppression of sinoatrial node activity is well reproduced in computer simulation. The inhibitory effect of anaesthetics on sinoatrial node automaticity can be exaggerated under some pathophysiological conditions, such as aging, heart failure and arrhythmias, where the function and/or expression of ion channels involved in sinoatrial node automaticity are modulated. This review focuses on molecular, ionic and cellular mechanisms underlying the regulation of sinoatrial node automaticity by anaesthetics, which will provide an electrophysiological and molecular basis for understanding the changes in heart rate during perioperative period. PMID- 28800885 TI - Methyl farnesoate epoxidase (mfe) gene expression and juvenile hormone titers in the life cycle of a highly eusocial stingless bee, Melipona scutellaris. AB - In social insects, juvenile hormone (JH) has acquired novel functions related to caste determination and division of labor among workers, and this is best evidenced in the honey bee. In contrast to honey bees, stingless bees are a much more diverse group of highly eusocial bees, and the genus Melipona has long called special attention due to a proposed genetic mechanism of caste determination. Here, we examined methyl farnesoate epoxidase (mfe) gene expression, encoding an enzyme relevant for the final step in JH biosynthesis, and measured the hemolymph JH titers for all life cycle stages of Melipona scutellaris queens and workers. We confirmed that mfe is exclusively expressed in the corpora allata. The JH titer is high in the second larval instar, drops in the third, and rises again as the larvae enter metamorphosis. During the pupal stage, mfe expression is initialy elevated, but then gradually drops to low levels before adult emergence. No variation was, however, seen in the JH titer. In adult virgin queens, mfe expression and the JH titer are significantly elevated, possibly associated with their reproductive potential. For workers we found that JH titers are lower in foragers than in nurse bees, while mfe expression did not differ. Stingless bees are, thus, distinct from honey bee workers, suggesting that they have maintained the ancestral gonadotropic function for JH. Hence, the physiological circuitries underlying a highly eusocial life style may be variable, even within a monophyletic clade such as the corbiculate bees. PMID- 28800886 TI - Corrigendum to "Towards in vitro DT/DNT testing: Assaying chemical susceptibility in early differentiating NT2 cells" [Toxicology 338 (2015) 69-76]. PMID- 28800887 TI - Evaluation of the Boussignac Cardiac arrest device (B-card) during cardiopulmonary resuscitation in an animal model. AB - AIM OF THE STUDY: The purpose of this study was to examine continuous oxygen insufflation (COI) in a swine model of cardiac arrest. The primary hypothesis was COI during standard CPR (S-CPR) should result in higher intrathoracic pressure (ITP) during chest compression and lower ITP during decompression versus S-CPR alone. These changes with COI were hypothesized to improve hemodynamics. The second hypothesis was that changes in ITP with S-CPR+COI would result in superior hemodynamics compared with active compression decompression (ACD) + impedance threshold device (ITD) CPR, as this method primarily lowers ITP during chest decompression. METHODS: After 6min of untreated ventricular fibrillation, S-CPR was initiated in 8 female swine for 4min, then 3min of S-CPR+COI, then 3min of ACD+ITD CPR, then 3min of S-CPR+COI. ITP and hemodynamics were continuously monitored. RESULTS: During S-CPR+COI, ITP was always positive during the CPR compression and decompression phases. ITP compression values with S-CPR+COI versus S-CPR alone were 5.5+/-3 versus 0.2+/-2 (p<0.001) and decompression values were 2.8+/-2 versus -1.3+/-2 (p<0.001), respectively. With S-CPR+COI versus ACD+ITD the ITP compression values were 5.5+/-3 versus 1.5+/-2 (p<0.01) and decompression values were 2.8+/-2 versus -4.7+/-3 (p<0.001), respectively. CONCLUSION: COI during S-CPR created a continuous positive pressure in the airway during both the compression and decompression phase of CPR. At no point in time did COI generate a negative intrathoracic pressures during CPR in this swine model of cardiac arrest. PMID- 28800888 TI - Clinical classification of post anoxic myoclonic status. AB - INTRODUCTION: Despite decades of research into the prognostic significance of post anoxic myoclonic status (MS), no consistent definition has been used to describe its clinical appearance. We set out to characterize the clinical features of MS and hypothesized that there are distinct clinical subtypes that may have prognostic implications. METHODS: Video EEG reports from 2008 to 2016 were searched to identify adult patients with post anoxic MS defined as persistent myoclonus for >30min beginning within 3days of cardiac arrest in a comatose patient. Forty-three patients met inclusion and exclusion criteria. To generate definitions of the clinical features of MS, we reviewed videos of 23 cases and characterized 3 distinct clinical semiologies. An additional 20 cases were independently reviewed and categorized by 3 raters to evaluate inter-rater agreement (IRA). All 43 patients were assigned to a group based on consensus review for the first 23 patients and majority agreement for IRA patients. We also examined the relationship between semiology and outcome. RESULTS: Three distinct clinical semiologies of MS were identified: Type 1: distal, asynchronous, variable; type 2: axial or axial and distal, asynchronous, variable; and type 3: axial, synchronous, stereotyped. For IRA, Gwet's kappa was 0.64 indicating substantial agreement. Two of 3 type 1 patients (66.6%) and 7.4% of type 2 followed commands whereas none of type 3 followed commands (p=0.03). CONCLUSION: We defined and validated a classification system of post anoxic MS based on clinical semiology. This classification may be a useful bedside prognostication tool. PMID- 28800890 TI - Creating a lung adenocarcinoma canvas, one brush stroke at a time. PMID- 28800889 TI - Spatio-temporal expression patterns of Wnt signaling pathway during the development of temporomandibular condylar cartilage. AB - There is a growing body of evidence supporting the involvement of the Wnt signaling pathway in various aspects of skeletal and joint development; however, it is unclear whether it is involved in the process of temporomandibular joint development. In order to clarify this issue, we examined the spatio-temporal distribution of mRNAs and proteins of the Wnt family during the formation of the mandibular condylar cartilage at the prenatal and postnatal stages. An in situ hybridization test revealed no mRNAs of beta-catenin and Axin2 during early mesenchymal condensation; the ligands surveyed in this study (including Wnt-4, 5a, and 9a) were clearly detected at various ranges of expression, mainly in the condylar blastema and later distinct cartilaginous layers. Apart from beta catenin and Axin2, the Wnt family members surveyed in this study, including Lef 1, were found to be immunopositive during early chondrogenesis in the condylar cartilage at E14.5. After distinct chondrocyte layers were identified within the cartilage at E16.5, the expression of the Wnt signaling members was different and mainly restricted to proliferating cells and mineralized hypertrophic chondrocytes. In the adult mandibular condylar cartilage, the Wnt-4 mRNA, as well as the Wnt-4 and Wnt-9a proteins, was not observed. Our findings demonstrated that the Wnt signaling pathway was associated with the development of mandibular condylar cartilage. PMID- 28800891 TI - Concomitant mitral repair and continuous-flow left ventricular assist devices: Is it warranted? AB - BACKGROUND: Pre-existing mitral pathology is common in patients undergoing continuous-flow left ventricular assist device implantation. We sought to investigate whether concurrent mitral repair confers any advantage. METHODS: From March 2004 to October 2014, 374 patients received a continuous-flow left ventricular assist device. Of these, a total of 115 patients with pre-existing mitral regurgitation (MR) greater than moderate were identified and included in the analysis. Outcomes were compared between patients with concurrent mitral repair (n = 52 [45.2%]; Group A) and without repair (n = 63 [54.8%]; Group B). RESULTS: The mean age was 56.8 years and 25 (21.5%) were women. Patients in Group A were more likely to have undergone destination therapy (48.1% vs 11.1%; P < .001) and had a greater cardiopulmonary bypass time (125 vs 89 minutes; P < .001) than did patients in Group B. Longitudinal analysis using a generalized mixed effects model demonstrated the odds of developing moderate or severe MR during device support were 86% lower for Group A patients (P < .001). Among those who were discharged alive, 9 (8.6%)-consisting of 1 (2.2%) in Group A and 8 (13.6%) in Group B (P = .039)-developed late right heart failure requiring a total of 13 readmissions (0.03 vs 0.15 readmissions per patient-year; P = .011). Multivariable competing risks regression revealed mitral repair to be a protective factor (hazard ratio, 0.16; 95% confidence interval, 0.03-0.94; P = .042) for late right heart failure occurrence. CONCLUSIONS: Concurrent mitral repair appears to be efficacious in controlling MR after device implant. The fact that repaired patients developed late right heart failure less frequently than did patients without repair challenges the notion that concurrent mitral repair is unwarranted. PMID- 28800892 TI - Peace at the interface of human and machine. PMID- 28800893 TI - Should the risk of a permanent pacemaker be considered when choosing a procedure for aortic stenosis? PMID- 28800895 TI - A randomized trial of a web-based platform to help families manage dementia related behavioral symptoms: The WeCareAdvisorTM. AB - Dementia-related behavioral symptoms are challenging clinical features occurring across etiologies and disease progression. They are associated with increased healthcare utilization, nursing home placement, family upset and burden. Families typically manage behavioral symptoms without requisite knowledge, skills and guidance. We designed WeCareAdvisorTM as an easy-to-use, evidence-informed web based platform. It provides families knowledge about dementia, daily tips, and a systematic approach to describe behaviors, investigate modifiable contributors, create treatment plans (WeCareAdvisorTM Prescription) consisting of management tips tailored to symptom presentation, and evaluate effectiveness. WeCareAdvisorTM is being tested in a randomized trial to assess acceptability, usability and immediate impact on caregiver confidence managing and upset with behavioral symptoms, and secondarily, frequency of behavioral occurrences. Fifty seven caregivers will be enrolled from communities and medical clinics at two sites (University of Michigan; Johns Hopkins University). Families reporting behavioral symptoms in a telephone screen are consented and interviewed at home. Following the interview, an envelope is opened by interviewers to reveal group assignment (immediate vs one-month delayed treatment group). Those receiving WeCareAdvisorTM immediately are provided an iPad and instruction in its use; those in the delayed treatment group are informed of next study steps. All caregivers are reassessed at home one month from baseline. The delayed treatment group then receives iPad instructions and are re-interviewed one month thereafter. During treatment phase, participants receive 3 weekly check-in calls to encourage tool use and troubleshoot. Key outcomes include number of times using WeCareAdvisorTM and for which behaviors, self-efficacy and upset managing behavioral symptoms, and frequency of behavioral occurrences. Clinical trial registration #: NCT02420535. PMID- 28800897 TI - Special Issue on "Frontier Biomechanical Challenges in Cardiovascular Physiopathology". PMID- 28800896 TI - Antimicrobial susceptibility of Clostridium difficile isolates from ICU colonized patients revealed alert to ST-37 (RT 017) isolates. AB - Seventy Clostridium difficile isolates from ICU colonized patients were tested for antimicrobial susceptibility and screened for resistance determinants. We found that multilocus sequence type 37 (ribotype 017) toxin A-negative/B-positive isolates were more likely resistant to moxifloxacin than toxin A-positive/B positive isolates (41.7% versus 9.3%) with major variations in both GyrA (Thr82Ile) and GyrB (Ser366Ala), suggesting that the use of quinolone should be more strictly regulated. PMID- 28800898 TI - The association of bradykinesia and balance control in patients with Alzheimer's disease? PMID- 28800899 TI - Lycopene spray probably does not improve the symptoms of drug-induced xerostomia in older adults. PMID- 28800894 TI - Examining unanswered questions about the home environment and childhood obesity disparities using an incremental, mixed-methods, longitudinal study design: The Family Matters study. AB - There are disparities in the prevalence of childhood obesity for children from low-income and minority households. Mixed-methods studies that examine home environments in an in-depth manner are needed to identify potential mechanisms driving childhood obesity disparities that have not been examined in prior research. The Family Matters study aims to identify risk and protective factors for childhood obesity in low-income and minority households through a two-phased incremental, mixed-methods, and longitudinal approach. Individual, dyadic (i.e., parent/child; siblings), and familial factors that are associated with, or moderate associations with childhood obesity will be examined. Phase I includes in-home observations of diverse families (n=150; 25 each of African American, American Indian, Hispanic/Latino, Hmong, Somali, and White families). In-home observations include: (1) an interactive observational family task; (2) ecological momentary assessment of parent stress, mood, and parenting practices; (3) child and parent accelerometry; (4) three 24-hour child dietary recalls; (5) home food inventory; (6) built environment audit; (7) anthropometry on all family members; (8) an online survey; and (9) a parent interview. Phase I data will be used for analyses and to inform development of a culturally appropriate survey for Phase II. The survey will be administered at two time points to diverse parents (n=1200) of children ages 5-9. The main aim of the current paper is to describe the Family Matters complex study design and protocol and to report Phase I feasibility data for participant recruitment and study completion. Results from this comprehensive study will inform the development of culturally-tailored interventions to reduce childhood obesity disparities. PMID- 28800900 TI - Insufficient evidence to claim good outcomes of lithium disilicate implant supported single crowns after 5 years. PMID- 28800901 TI - Dentifrices specifically formulated for tooth whitening reduce extrinsic tooth surface discoloration. PMID- 28800902 TI - Inconclusive evidence about whether the addition of enamel matrix derivatives to bone substitutes yields better clinical outcomes for treatment of intrabony defects. PMID- 28800903 TI - Endodontically treated teeth that receive nonsurgical periodontal treatment are more likely to develop apical periodontitis than periodontally healthy teeth. PMID- 28800904 TI - Osteoporosis may result in a small increase in marginal bone loss around dental implants in osteoporotic women. PMID- 28800905 TI - Treat-and-Extend Therapy Using Aflibercept for Neovascular Age-Related Macular Degeneration: A Prospective Clinical Trial. PMID- 28800906 TI - Solid-phase analytical derivatization for gas-chromatography-mass-spectrometry based metabolomics. AB - A novel derivatization method for gas chromatography/mass spectrometry (GC/MS) based metabolomics was developed, based on solid-phase analytical derivatization (SPAD) with methoximation followed by trimethylsilylation. This SPAD method realized derivatization on solid phases combining strong anion exchange with strong cation exchange. To omit a sample condensation process, GC/MS injection was performed using a large-volume injection mode. This mode uses a stomach shaped insert, and enables a large quantity of sample to be vaporized and introduced into the GC/MS system. In the present study, several parameters were investigated for each SPAD step. The optimal derivatization conditions were determined to be 3-min-methoximation with 5 MUL of >5% methoxyamine solution, and 10-min-trimethylsilylation with 25 MUL of N-methyl-N-trimethylsilyl trifluoroacetamide (MSTFA). Derivatized analytes were effectively eluted with 25 MUL of n-hexane. The influences of coexisting substances were also investigated. Coexisting saccharides did not significantly affect the derivatization of analytes. Moreover, saccharides were efficiently washed out using 80% (v/v) acetonitrile in water. The influences of coexisting sodium chloride were negated by dilution of the sample solution with water. The developed method enables the derivatization of both anionic and cationic metabolites, and high-throughput sample preparation. The coverage of detectable metabolites for the developed method was similar to that of the conventional method. This is the first report of a SPAD-based human plasma metabolome analysis protocol. PMID- 28800907 TI - Biochemical characterization of Aspergillus oryzae recombinant alpha-l rhamnosidase expressed in Pichia pastoris. AB - An alpha-l-rhamnosidase-encoding gene from Aspergillus oryzae, which belongs to the glycoside hydrolase family 78, was cloned and expressed in Pichia pastoris. SDS-PAGE of the purified recombinant alpha-l-rhamnosidase protein revealed smeared bands with apparent molecular mass of 90-130 kDa. After N deglycosylation, the recombinant enzyme showed a molecular mass of 70 kDa. The enzyme exhibited optimal activity at a pH of 5.0 and a temperature of 70 degrees C. Specific activity of the enzyme was higher toward hesperidin than toward naringin, which consist of alpha-1,6 and alpha-1,2 linkages, respectively. The activity was also higher toward hesperidin than toward rutin, which consist of 7 O- and 3-O-glycosyl linkages of flavonoids, respectively. Kinetic analysis of the enzyme showed that the Michaelis constant (Km) was lowest toward rutin, moderate toward naringin, and higher toward p-nitrophenyl-alpha-l-rhamnopyranoside and hesperidin. Its high catalytic efficiency (kcat/Km) toward rutin was results of its low Km value while its high catalytic efficiency toward hesperidin was results of a considerably high kcat value. PMID- 28800908 TI - Stimulation of d- and l-lactate dehydrogenases transcriptional levels in presence of diammonium hydrogen phosphate resulting to enhanced lactic acid production by Lactobacillus strain. AB - The present study revealed the effect of nitrogen sources on lactic acid production and stimulation of d- and l-lactate dehydrogenases (LDH) of parent Lactobacillus lactis NCIM 2368 and its mutant RM2-24 generated after UV mutagenesis. Both the parent and mutant strains were evaluated for d-lactic acid production in control and modified media. The modified media did not show remarkable effect on lactic acid production in case of parent whereas mutant exhibited significant enhancement in d-lactic acid production along with the appearance of l-lactic acid in the broth. Both LDH activities and specific activities were found to be higher in mutant than the parent strain. These results suggested that the diammonium hydrogen phosphate in modified media triggered the expression of LDH genes leading to enhanced lactic acid production. This observation has been proved by studying the expression levels of d- and l LDH genes of parent and mutant in control and modified media using quantitative RT-PCR technique. In case of mutant, the transcriptional levels of d-LDH and l LDH increased ~17 fold and ~1.38 fold respectively in modified medium compared to the values obtained with control medium. In case of parent, no significant change in transcriptional levels of d- and l-LDH was found when the cells were grown in either control medium or modified medium. This study suggested that the mutant, RM2-24 has l-LDH gene which is expressed in presence of (NH4)2HPO4 resulting in l lactic acid production. Co-production of l-lactic acid in d-lactic acid fermentation may be detrimental in the PLA production. PMID- 28800909 TI - Comment on: New onset of lupus nephritis in two patients with SLE shortly after initiation of treatment with belimumab. PMID- 28800910 TI - Chronology of anthropogenic impacts reconstructed from sediment records of trace metals and Pb isotopes in Todos os Santos Bay (NE Brazil). AB - The evolution of the impacts of anthropogenic activities in Todos os Santos Bay was evaluated by profiles of trace metals and Pb isotopes determined in sediment cores. Fluxes of metals increased up to 12, 4 and 2 times for Cu, Pb, and Zn, respectively, compared to those recorded in the beginning of the 20th century. Stable Pb isotopes identified a decommissioned lead smelter and burning of fossil fuels as the main sources of Pb. Most metals showed minor to moderate enrichment factors (EF<4), but Cu and Pb were highly enriched (EF=28 and 6, respectively) at the Aratu harbor. Temporal changes in sediments were associated to different activities, namely Pb smelting, burning of fossil fuels, maritime traffic, petroleum related activities, inputs of domestic effluents, and changes in land uses. The effects of the implementation of environmental policies to improve the waters of the bay could not be identified in the evaluated cores. PMID- 28800911 TI - Distribution profiles of per- and poly fluoroalkyl substances (PFASs) and their re-regulation by ocean currents in the East and South China Sea. AB - We investigated the distribution of 17 individual per- and polyfluoroalkyl substances (PFASs) in 42 surface water samples collected from the East and South China Seas (7.0-36.0 degrees N, 110.0 degrees N-123.0 degrees E). Concentrations of 7 individual PFASs, including perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS), perfluoropentanoic acid (PFPA), perfluorohexanoate (PFHxA), perfluoroheptanoate (PFHpA), perfluorooctanoic acid (PFOA), and perfluorooctane sulfonamide (FOSA), were quantified in the East China Sea, but only concentrations of PFOA and FOSA were quantified in the South China Sea. The total concentrations of the 17 PFASs ranged from 181 to 2658pg/L in the East China Sea and from 62 to 494pg/L in the South China Sea. We also show that river fluxes and ocean currents had a strong influence on the distribution of PFASs in the East China Sea. Using ArcGIS 10.1, we show how ocean currents control the spatial distribution of PFOA in the central South China Sea. PMID- 28800912 TI - Colonoscopy and Endocarditis: A Compromised Relationship. PMID- 28800913 TI - [Prevalence of hypovitaminosis D and associated factors in Spanish population of school children and adolescents]. AB - OBJECTIVE: To analyse the prevalence of hypovitaminosisD and associated factors in school children and adolescents living in a region of northern Spain. DESIGN: Cross-sectional study (convenience sampling). SETTING: Primary Health Care. PARTICIPANTS: A total of 602 Caucasian individuals (aged 3.1 to 15.4years) were included in the study. MAIN MEASUREMENTS: Prevalence of hypovitaminosisD were calculated (dependent variable). HypovitaminosisD is defined according to the US Endocrine Society criteria: deficiency (calcidiol <20ng/mL), insufficiency (calcidiol: 20-29ng/mL), and sufficiency (calcidiol >=30ng/mL). Gender, age, body mass index, residence, and season of the year were recorded (independent variables), and their association with hypovitaminosisD was analysed by multiple regression. RESULTS: The prevalence of hypovitaminosisD was 60.4% (insufficiency: 44.6%; deficiency: 15.8%). Multivariate analysis showed that factors associated to hypovitaminosisD were being female (OR: 1.6; 95%CI: 1.1-2.3), pubertal age (OR: 1.8; 95%CI: 1.2-2.6), autumn (OR: 9.5; 95%CI: 4.8-18.7), winter (OR: 8.8; 95%CI: 4.5-17.5) and spring time (OR: 13.2; 95%CI: 6.4-27.5), living in urban areas (OR:1.6; CI95%: 1.1-2.2), and severe obesity (OR: 4.4; 95%CI: 1.9-10.3). CONCLUSIONS: There is a high prevalence of hypovitaminosisD in juvenile populations. being female, pubertal age, autumn, winter and spring seasons, severe obesity, and living in urban areas are factors associated to hypovitaminosisD. Consideration should be given to the administration of vitamin supplements and/or the increase in the ingestion of natural vitaminD dietary sources. PMID- 28800914 TI - Aneuploidy Police Detect Chromosomal Imbalance Triggering Immune Crackdown! AB - Aneuploidy is ubiquitous in cancer and plays a pivotal, early role in tumor evolution. It must therefore be avoided, and two recent papers highlight the roles of p53, senescence, and the immune system in preventing the outgrowth of aneuploid clones in tissue culture. These mechanisms are likely to synergize to maintain diploid cell populations. PMID- 28800915 TI - Transposable Elements Direct The Coevolution between Plants and Microbes. AB - Transposable elements are powerful drivers of genome evolution in many eukaryotes. Although they are mostly considered as 'selfish' genetic elements, increasing evidence suggests that they contribute to genetic variability; particularly under stress conditions. Over the past few years, the role of transposable elements during host-microbe interactions has been recognised. It has been proposed that many pathogenic microbes have evolved a 'two-speed' genome with regions that show increased variability and that are enriched in transposable elements and pathogenicity-related genes. Plants similarly display structured genomes with transposable-element-rich regions that mediate accelerated evolution. Immune receptor genes typically reside in such regions. Various mechanisms have recently been identified through which transposable elements contribute to the coevolution between plants and their associated microbes. PMID- 28800916 TI - [Particulate contamination associated with the manipulation of drugs in glass ampules: A literature review]. AB - OBJECTIVES: The manipulation of drugs from glass ampules can generate particles when the ampule is broken. Several authors recommend the use of filter needle to withdraw the drug content. The aim of this study is to make an assessment of the presence of particles during the manipulation of glass ampules and to discuss the current practices. METHODS: Literature review based on a search strategy (Pubmed, Google Scholar) and a summary table of available data. Analysis to evaluate the efficacy of the filtration when data are available. RESULTS: Eighteen articles have been included. Most of study shows the presence of particles in glass ampules. Important discrepancies reported regarding the number of particles per ampule. Analysis of data from seven studies: decrease of 83% of the total number of particles (>10MUm) identified when drugs are removed with filter needle. All studies but two confirm the efficacy of filter needles. CONCLUSIONS: Studies show the presence of particles when drugs are removed from glass ampules. They do not allow to make a conclusion on human clinical consequences associated with the presence of particles. It is necessary to evaluate in human the risks associated with particle contamination to determine the optimal use of filter needle. PMID- 28800917 TI - Thyrotoxic rubber antioxidants, 2-mercaptobenzimidazole and its methyl derivatives, cause both inhibition and induction of drug-metabolizing activity in rat liver microsomes after repeated oral administration. AB - We examined the effects of thyrotoxic rubber antioxidants, 2 mercaptobenzimidazole (MBI, 0.3 mmol/kg/day) and its methyl derivatives, methyl MBIs [4-methyl-MBI (4-MeMBI, 0.6 mmol/kg/day), 5-methyl-MBI (5-MeMBI, 0.6 mmol/kg/day), and 4(or 5)-methyl-MBI (4(5)-MeMBI, 0.6 or 1.2 mmol/kg/day)], on the drug-metabolizing activity in male rat liver microsomes by 8-day repeated oral administration. The weight of liver and thyroid were increased by all the test chemicals; MBI was most potent, and there was no additive or synergistic effect between 4-MeMBI and 5-MeMBI. MBI decreased the cytochrome P450 (CYP) content, NADPH-cytochrome P450 reductase (POR) activity, 7-ethoxycoumarin O deethylation (ECOD) activity, and flavin-containing monooxygenase (FMO) activity, but increased the 7-pentoxyresorufin O-depentylation (PROD) activity, suggesting inhibition of the drug-metabolizing activity on the whole but induce some activities such as the CYP2B activity. On the contrary, all the methyl-MBIs increased the CYP content, CYB5 content, ECOD activity, 7-ethoxyresorufin O deethylation (EROD) activity, and PROD activity, indicating that they are mostly inducible of the CYP activity. However, the methyl-MBIs decreased the FMO activity, and 5-MeMBI and 4(5)-MeMBI appeared inhibitory for CYPs 2C11 and 2C13. Between 4-MeMBI and 5-MeMBI, there was no additive or synergistic effect on the drug-metabolizing activity, but was counteraction. It was concluded that MBI and methyl-MBIs had both inhibitory and inducible effects on the drug-metabolizing activity in rat liver microsomes at thyrotoxic doses. The effects of 4(5)-MeMBI indicated that the increased liver weight alone can be a hepatotoxic sign but not an adaptive no-adverse response in toxicity studies. The present results were related to the toxicokinetic profiles of MBI and 4(5)-MeMBI in the repeated toxicity studies. PMID- 28800918 TI - The Timing of Hip Arthroscopy After Intra-articular Hip Injection Affects Postoperative Infection Risk. AB - PURPOSE: To evaluate the association of preoperative intra-articular hip injection with surgical site infection after hip arthroscopy. METHODS: A large administrative database was used to identify all patients undergoing hip arthroscopy from 2007 to 2015 within a single private insurer and from 2005 to 2012 within Medicare in the United States. Those that received an ipsilateral preoperative intra-articular hip injection were identified. The patients were then divided into the following groups based on the interval between preoperative injection and ipsilateral hip arthroscopy: (1) <3 months, (2) 3 to 6 months, and (3) 6 to 12 months. These groups were compared to a control group composed of patients with no history or a remote history (>12 months) of preoperative hip injection. Patients developing a surgical site infection within 6 months following hip arthroscopy were identified using International Classification of Diseases, Ninth Revision, and Current Procedural Terminology codes associated with infection. Groups were compared using a multivariate logistic regression analysis to control for age, gender, body mass index, smoking status, alcohol usage, and multiple medical comorbidities including diabetes mellitus, hemodialysis use, inflammatory arthritis, and peripheral vascular disease. RESULTS: In total, 19% of privately insured and 6% of Medicare patients received a hip injection within 12 months of hip arthroscopy. The overall infection rate in privately insured and Medicare patients was 1.19% and 1.10%, respectively. Preoperative hip injection within 3 months of surgery was associated with a significantly higher risk of postoperative infection versus controls (2.16%, odds ratio [OR] 6.1, P < .001, for privately insured group; 2.80%, OR 1.99, P = .037, for Medicare group). In contrast, preoperative hip injection given after more than 3 months of surgery was not associated with an increased risk of postoperative infection versus controls. CONCLUSIONS: Risk of infection after hip arthroscopy increased when preoperative intra-articular hip injections were given within 3 months of surgery. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 28800919 TI - Similar Outcomes After Osteochondral Allograft Transplantation in Anterior Cruciate Ligament-Intact and -Reconstructed Knees: A Comparative Matched-Group Analysis With Minimum 2-Year Follow-Up. AB - PURPOSE: To compare failure rates and clinical outcomes of osteochondral allograft transplantation (OCA) in anterior cruciate ligament (ACL)-intact versus ACL-reconstructed knees at midterm follow-up. METHODS: After a priori power analysis, a prospective registry of patients treated with OCA for focal chondral lesions >=2 cm2 in size with minimum 2-year follow-up was used to match ACL reconstructed knees with ACL-intact knees by age, sex, and primary chondral defect location. Exclusion criteria included meniscus transplantation, realignment osteotomy, or other ligamentous injury. Complications, reoperations, and patient responses to validated outcome measures were reviewed. Failure was defined by any procedure involving allograft removal/revision or conversion to arthroplasty. Kaplan-Meier analysis and multivariate Cox regression were performed to evaluate the association of ACL reconstruction (ACLR) with failure. RESULTS: A total of 50 ACL-intact and 25 ACL-reconstructed (18 prior, 7 concomitant) OCA patients were analyzed. The mean age was 36.2 years (range, 14 62 years). Mean follow-up was 3.9 years (range, 2-14 years). Patient demographics and chondral lesion characteristics were similar between groups. ACL reconstructed patients averaged 2.2 +/- 1.9 prior surgeries on the ipsilateral knee compared with 1.4 +/- 1.4 surgeries for ACL-intact patients (P = .014). Grafts used for the last ACLR included bone-patellar tendon-bone autograft, hamstring autograft, Achilles tendon allograft, and tibialis allograft (data available for only 11 of 25 patients). At final follow-up, 22% of ACL-intact and 32% of ACL-reconstructed patients had undergone reoperation. OCA survivorship was 90% and 96% at 2 years and 79% and 85% at 5 years in ACL-intact and ACL reconstructed patients, respectively (P = .774). ACLR was not independently associated with failure. Both groups demonstrated clinically significant improvements in the Short Form-36 pain and physical functioning, International Knee Documentation Committee subjective, and Knee Outcome Survey-Activities of Daily Living scores at final follow-up (P < .001), with no significant differences in preoperative, postoperative, and change scores between groups. CONCLUSIONS: OCA in the setting of prior or concomitant ACLR does not portend higher failure rates or compromise clinical outcomes. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 28800920 TI - Does Platelet-Rich Plasma Lead to Earlier Return to Sport When Compared With Conservative Treatment in Acute Muscle Injuries? A Systematic Review and Meta analysis. AB - PURPOSE: To compare the time to return to sport and reinjury rate after platelet rich plasma (PRP) injection versus control therapy (i.e., physiotherapy or placebo injection) in patients with acute grade I or II muscle strains. METHODS: All eligible studies comparing PRP against a control in the treatment of acute (<=7 days) grade I or II muscle strains were identified. The primary outcome was time to return to play. The secondary outcome was the rate of reinjury at a minimum of 6 months of follow-up. Subgroup analysis was performed to examine the efficacy of PRP in hamstring muscle strains alone. The checklist to evaluate a report of a nonpharmacologic trial (CLEAR-NPT) was used to assess the quality of studies. RESULTS: Five randomized controlled trials including a total of 268 patients with grade I and II acute muscle injuries were eligible for review. The pooled results revealed a significantly earlier return to sport for the PRP group when compared with the control group (mean difference, -5.57 days [95% confidence interval, -9.57 to -1.58]; P = .006). Subgroup analysis showed no difference in time to return to sport when comparing PRP and control therapy in grade I and II hamstring muscle strains alone (P = .19). No significant difference was noted in the rate of reinjury between the 2 groups (P = .50) at a minimum of 6 months of follow-up. CONCLUSIONS: Evidence from the current literature, although limited, suggests that the use of PRP may result in an earlier return to sport among patients with acute grade I or II muscle strains without significantly increasing the risk of reinjury at 6 months of follow-up. However, no difference in time to return to sport was revealed when specifically evaluating those with a grade I or II hamstring muscle strain. LEVEL OF EVIDENCE: Level II, meta-analysis of level I and II studies. PMID- 28800921 TI - Sodium corrected to normoglycemia: Time to re-evaluate? PMID- 28800923 TI - [Squamous cell carcinoma associated with use of skin-lightening cream]. AB - BACKGROUND: Women widely use skin-lightening products for cosmetic purposes in sub-Saharan Africa despite numerous reported cutaneous and systemic complications. The occurrence of epidermoid carcinoma has long been reported, but only three cases have been published so far. We report the first case in Mali. PATIENTS AND METHODS: A 30-year old woman with no noteworthy medical history was seen at our outpatient center for cervical ulceration that had been present for the last 5 years. She had used cosmetic bleaching cream over a period of around ten years. Physical examination revealed extensive ulceration on the left side of her neck. Blood tests for viral hepatitis and human immunodeficiency virus were negative. The pathological examination of the skin biopsy confirmed the diagnosis of squamous cell carcinoma. After failure of the initial excision with early relapse, multiple surgical ablations were performed 3 months later. DISCUSSION: The high prevalence of skin-lightening cosmetic use contrasts with the rarity of epidermoid carcinoma in depigmented skin. However, a large chronic ulcer on uncovered parts of the upper body, particularly the neck, should prompt physicians to consider skin cancer. Appropriate preventive measures include the promotion of educational messages for the general population, the use of sun protection devices, and routine skin biopsy for all women presenting chronic cervical ulceration after long-term use of skin-lightening products. PMID- 28800922 TI - Inhibition of H3K4 demethylation induces autophagy in cancer cell lines. AB - Epigenetic factors and related small molecules have emerged to be strongly involved in autophagy process. Here we report that 2-PCPA and GSK-LSD1, two inhibitors of histone H3K4 demethylase KDM1A/LSD1, induce autophagy in multiple mammalian cell lines. The two small molecules induce accumulation of LC3II, formation of autophagosome and autolysosome, and SQSTM1/p62 degradation. 2-PCPA treatment inhibits cell proliferation through cell cycle arrest but does not inducing cell death. Exogenous expression of KDM1A/LSD1 impaired the autophagic phenotypes triggered by 2-PCPA. The autophagy induced by 2-PCPA requires LC3-II processing machinery. But depletion of BECN1 and ULK1 with siRNA did not affect the LC3-II accumulation triggered by 2-PCPA. 2-PCPA treatment induces the change of global gene expression program, including a series of autophagy-related genes, such as SQSTM1/p62. Taken together, our data indicate that KDM1A/LSD1 inhibitors induce autophagy through affecting the expression of autophagy-related genes and in a BECN1-independent manner. PMID- 28800925 TI - Resveratrol increases phagocytosis and lipopolysaccharide-induced interleukin 1beta production, but decreases surface expression of Toll-like receptor 2 in THP 1 monocytes. AB - THP-1 monocytes were used to evaluate the effects of physiological levels of resveratrol aglycone, resveratrol-3-O-glucuronide, resveratrol-4'-O-glucuronide, and resveratrol-3-O-sulfate on phagocytosis, IL-1beta, IL-1alpha, and IL-18 production, viability, and TLR2 and TLR4 expression. THP-1 cells were treated with 1, 5, 10, and 15MUM resveratrol or metabolites. Resveratrol-3-O-glucuronide, resveratrol-4'-O-glucuronide, and resveratrol-3-O-sulfate had no effect on the functional parameters tested. Resveratrol aglycone increased phagocytosis at concentrations of 5, 10, and 15MUM and LPS-induced IL-1beta production at concentrations of 10 and 15MUM. Expression of TLR4 increased slightly after resveratrol treatment, but surface expression of TLR2 was reduced as resveratrol concentrations increased. Our data suggest that resveratrol may be effective in modulating monocyte function in an environment where there is direct exposure to the aglycone, such as at the gut epithelium. PMID- 28800926 TI - Corrigendum to "Expression of mutant DISC1 in Purkinje cells increases their spontaneous activity and impairs cognitive and social behaviors in mice" [Neurobiol. Dis. 103 (2017) 144-153]. PMID- 28800927 TI - Oligomeric Proantho Cyanidins provides neuroprotection against early brain injury following subarachnoid hemorrhage possibly via anti-oxidative, anti-inflammatory and anti-apoptotic effects. PMID- 28800924 TI - The influence of macrophage growth factors on Theiler's Murine Encephalomyelitis Virus (TMEV) infection and activation of macrophages. AB - Macrophages are common targets for infection and innate immune activation by many pathogenic viruses including the neurotropic Theiler's Murine Encephalomyelitis Virus (TMEV). As both infection and innate activation of macrophages are key determinants of viral pathogenesis especially in the central nervous system (CNS), an analysis of macrophage growth factors on these events was performed. C3H mouse bone-marrow cells were differentiated in culture using either recombinant macrophage colony stimulating factor (M-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF), inoculated with TMEV (BeAn) and analyzed at various times thereafter. Cytokine RNA and protein analysis, virus titers, and flow cytometry were performed to characterize virological parameters under these culture conditions. GM-CSF-differentiated macrophages showed higher levels of TMEV viral RNA and proinflammatory molecules compared to infected M-CSF differentiated cells. Thus, GM-CSF increases both TMEV infection and TMEV-induced activation of macrophages compared to that seen with M-CSF. Moreover, while infectious viral particles decreased from a peak at 12h to undetectable levels at 48h post infection, TMEV viral RNA remained higher in GM-CSF- compared to M-CSF differentiated macrophages in concert with increased proinflammatory gene expression. Analysis of a possible basis for these differences determined that glycolytic rates contributed to heightened virus replication and proinflammatory cytokine secretion in GM-CSF compared to M-CSF-differentiated macrophages. In conclusion, we provide evidence implicating a role for GM-CSF in promoting virus replication and proinflammatory cytokine expression in macrophages, indicating that GM-CSF may be a key factor for TMEV infection and the induction of chronic TMEV-induced immunopathogenesis in the CNS. PMID- 28800928 TI - Post-operative bracing after pedicle screw fixation for thoracolumbar burst fractures: A cost-effectiveness study. AB - PURPOSE: While frequently prescribed to patients following fixation for spine trauma, the utility of spinal orthoses during the post-operative period is poorly described in the literature. In this study, we calculated rates of reoperation and performed a decision analysis to determine the utility of bracing following pedicle screw fixation for thoracic and lumbar burst fractures. METHODS: Pubmed was searched for articles published between 2005 and 2015 for terms related to pedicle screw fixation of thoracolumbar fractures. Additionally, a database of neurosurgical patients operated on within the authors institution was also used in the analysis. Incidences of significant adverse events (wound revision for either dehiscence or infection or re-operation for non-union or instability due to hardware failure) were determined. Pooled means and variances of reported parameters were obtained using a random-effects, inverse variance meta-analytic model for observational data. Utilities for surgical outcome and complications were assigned using previously published values. RESULTS: Of the 225 abstracts reviewed, 48 articles were included in the study, yielding a total of 1957 patients. After including patients from the institutional registry, together a total of 2081 patients were included in the final analysis, 1328 of whom were braced. Non-braced patients were older then braced patients, although this only approached significance (p=0.051). Braced patients had significantly lower rates of re-operation for non-union or clinically significant hardware failure (1.3% vs. 1.8%, p<0.001) although the groups had comparable rates of operative wound dehiscence and infection (p=1.000). These two approaches yielded comparable utility scores (p=0.120). Costs between braced and non-braced patients were comparable excluding the cost of the brace (p=0.256); hence, the added cost of the brace suggests that bracing post-operatively is not a cost effective measure. CONCLUSIONS: Bracing following operative stabilization of thoracolumbar fracture does not significantly improve stability, nor does it increase wound complications. Moreover, our data suggests that post-operative bracing may not be a cost-effective measure. PMID- 28800930 TI - Fashioning blood vessels by ROS signalling and metabolism. AB - Formation and maturation of a functional vascular network is a process called angiogenesis. This is a crucial biological event in all vertebrates. Precise morphogenetic and cellular mechanisms act in endothelial cells (ECs) to drive angiogenesis during growth and throughout adulthood. Reactive oxygen species (ROS) and their metabolism are proving to be crucial participants in the shaping and stabilizing of blood vessels. Often, the same mechanisms are responsible for the insurgence of vascular-associated pathologies. In this review we discuss how ROS-mediated signalling events and distinctive metabolic pathways drive the biology of endothelial cells. We support the use of alternative anti-angiogenic therapy based on the manipulation of ROS signalling and metabolism to solve angiogenesis-related diseases. PMID- 28800929 TI - Directing T cell fate: How thymic antigen presenting cells coordinate thymocyte selection. AB - The development of a self-tolerant and effective T cell receptor repertoire is dependent on interactions coordinated by various antigen presenting cells (APC) within the thymus. T cell receptor-self-peptide-MHC interactions are essential for determining T cell fate, however different cytokine and co-stimulatory signals provided by the diverse APCs within the thymus are also critical. Here, we outline the different localization and functional capabilities of thymic APCs. We also discuss how these distinct APCs work collectively to facilitate the establishment of a diverse T cell receptor repertoire that is tolerant to an array of different self-antigens. PMID- 28800932 TI - Is Type 2 Diabetes in Adults Associated With Impaired Capacity for Weight Loss? PMID- 28800933 TI - Stepwise Intervention for Small Vessel Chronic Total Occlusion. PMID- 28800934 TI - Is the Risk of Postoperative Atrial Fibrillation Predictable in Patients Undergoing Surgery Due to Primary Lung Cancer? AB - BACKGROUND: Atrial fibrillation (AF) is a type of cardiac arrhythmia which is commonly seen following lung resection. There is currently no algorithm which can predict which patients will develop postoperative AF (PAF). The present study aims to identify the risk factors for the development of PAF and high-risk patients with PAF along with multiple risk factors. MATERIALS AND METHODS: A total of 887 patients, who underwent lung resection due to primary lung malignancy at our clinic between January 2000 and December 2016, were retrospectively analysed. Group 1 (n=44) consisted of the patients who developed PAF and Group 2 (n=843) consisted of the patients without PAF. Age and sex of the patients, comorbidities, previous diagnosis of malignancy, and surgery-related variables were evaluated using statistical methods for their effects on the development of AF. A score was assigned to each identified risk factor and scores of the patients were calculated. The risk of developing PAF was evaluated based on this scoring system. RESULTS: We found that >=60 years of age and the diagnosis of chronic obstructive pulmonary disease (COPD) were significant risk factors for the development of PAF (p<0.05). The risk of developing PAF was not associated with male sex, previous history of malignancy, presence of comorbidities, and the type of surgery applied. There was an increased risk of AF with increasing scores in the risk calculation system. CONCLUSION: Advanced age and the presence of COPD were found to be associated with an increased risk of developing PAF. In addition we found a significant increase in the risk of developing PAF in the presence of multiple factors, although they did not reach statistical significance alone. PMID- 28800931 TI - Molecular signatures of longevity: Insights from cross-species comparative studies. AB - Much of the current research on longevity focuses on the aging process within a single species. Several molecular players (e.g. IGF1 and MTOR), pharmacological compounds (e.g. rapamycin and metformin), and dietary approaches (e.g. calorie restriction and methionine restriction) have been shown to be important in regulating and modestly extending lifespan in model organisms. On the other hand, natural lifespan varies much more significantly across species. Within mammals alone, maximum lifespan differs more than 100 fold, but the underlying regulatory mechanisms remain poorly understood. Recent comparative studies are beginning to shed light on the molecular signatures associated with exceptional longevity. These include genome sequencing of microbats, naked mole rat, blind mole rat, bowhead whale and African turquoise killifish, and comparative analyses of gene expression, metabolites, lipids and ions across multiple mammalian species. Together, they point towards several putative strategies for lifespan regulation and cancer resistance, as well as the pathways and metabolites associated with longevity variation. In particular, longevity may be achieved by both lineage specific adaptations and common mechanisms that apply across the species. Comparing the resulting cross-species molecular signatures with the within species lifespan extension strategies will improve our understanding of mechanisms of longevity control and provide a starting point for novel and effective interventions. PMID- 28800935 TI - Two Stage Interventional Management of Tube Thoracostomy Induced Pulmonary Artery Perforation in a Patient with Parapneumonic Pleural Effusion Associated With Oesophageal Squamous Cell Carcinoma. PMID- 28800936 TI - Associations between dietary salt, potassium and blood pressure in South African adults: WHO SAGE Wave 2 Salt & Tobacco. AB - BACKGROUND & AIMS: In June 2016, South Africa implemented legislation mandating maximum sodium levels in a range of processed foods with a goal of reducing population salt intake and disease burden from hypertension. Our aim was to explore the relationship between salt and blood pressure (BP) in a subsample of the World Health Organization Study on global AGEing and adult health (SAGE) Wave 2 before implementation of legislation in South Africa. METHODS & RESULTS: Blood pressure (BP) was measured in triplicate (n = 2722; median age 56 years; 33% male) and 24-h urine collected in a nested subsample (n = 526) for sodium, potassium and creatinine analysis. Hypertension prevalence was 55% in older adults (50-plus years) and 28% in younger adults (18-49 years). Median salt intake (6.8 g/day) was higher in younger than older adults (8.6 g vs 6.1 g/day; p < 0.001), and in urban compared to rural populations (7.0 g vs 6.0 g/day; p = 0.033). Overall, 69% of participants had salt intakes above 5 g/day. Potassium intakes were generally low (median 35 mmol/day) with significantly lower intakes in rural areas and older adults. Overall, 91% of adults failed to meet the daily potassium recommendation of 90 mmol/d. Salt intakes above 5 g/day, and to a greater extent, a dietary sodium-to-potassium (Na:K) ratio above 2 mmol/mmol, were associated with significantly steeper regression slopes of BP with age. CONCLUSION: These preliminary results indicate that high dietary Na:K ratio may lead to a greater increase in BP and hypertension risk with age. Interventions to increase potassium intakes alongside sodium reduction initiatives may be warranted. PMID- 28800937 TI - Vortioxetine: A new alternative for the treatment of major depressive disorder. AB - Major Depressive Disorder (MDD) is a serious psychiatric condition. Its treatment remains a challenge nowadays. Vortioxetine is a novel antidepressant with a unique profile, as it acts as a multimodal serotoninergic agent. Its efficacy in MDD has been established in many short- and long-term studies, with 7 positive, 4 negative and 1 failed randomized controlled trials. Moreover, its ability to modulate a wide range of neurotransmitters (serotonin, dopamine, norepinephrine, histamine, glutamate or GABA) confers vortioxetine pro-cognitive effects. Side effects are also different from conventional antidepressants, according to its low incidence of sexual dysfunction, weight gain or cardiovascular alterations. The aim of this systematic review is to describe the pharmacology, clinical efficacy and safety profile of vortioxetine, as well as its potential effectiveness in improving cognitive symptoms. PMID- 28800938 TI - Using hospital use trends to improve transitional care. AB - BACKGROUND: This study evaluates the Northwestern Medicine Group Transitional Care clinic (NMG-TC), which transitions patients from an urban hospital to primary care at partner community clinics. We evaluate change over the 55 month study period in emergency department, observation or inpatient use within 90 days of an initial NMG-TC visit. METHODS: Electronic health records were used to determine patient demographic, insurance and clinical characteristics, including inflation-adjusted total hospital charges in the 90 days prior and the 90 days after an initial NMG-TC visit. Multiple logistic regression was used to estimate the likelihood of any 90-day post-NMG-TC visit hospital use, controlled for the simultaneous effects of patient characteristics and pre-visit hospital use level. RESULTS: There were 3318 patients with 90-day follow-up of whom 28.5% had 90 day post-visit hospital encounters. Patients with cancer, infectious disease or pain diagnoses at the time of a NMG-TC visit had the highest 90-day post-visit hospital use. The level of pre-NMG-TC visit hospital charges, the number of NMG TC visit diagnostic categories and the number of NMG-TC visits all showed a sharply graded effect on subsequent hospital use. Patients with a first NMG-TC visit in the last nine months of the study (2015-2016) had a 38% lower likelihood of any 90-day hospital use (OR = 0.62, 95% CI = 0.45-0.84) as compared to patients seen in 2011-2012. CONCLUSION AND IMPLICATIONS: Reduced post-visit hospital use is likely related to increased clinic resources, Affordable Care Act insurance expansions, and improved clinical and community social service expertise. LEVEL OF EVIDENCE: Cohort study, Level 2. PMID- 28800939 TI - Serving people with severe mental illness who are dually eligible for Medicare and Medicaid. PMID- 28800940 TI - Neoadjuvant chemotherapy and chemotherapy cycle number: A national multicentre study. AB - OBJECTIVES: Six cycles of consolidation chemotherapy have become the standard for ovarian cancer treatment regimen following primary cytoreduction, yet with neoadjuvant chemotherapy (NAC), only 3 consolidation cycles are used. This study examines the effects of number of chemotherapy cycles in women with ovarian cancer that are being treated with neoadjuvant chemotherapy. In addition, we examined the effect of number of cycles on survival on consolidation and total chemotherapy. METHODS: All patients with stage IIIC and IV high grade serous carcinoma (HGSC) were identified at 4 major Canadian cancer centers treated with NAC. A retrospective chart review was conducted using the medical charts and registry databases. RESULTS: 403 NAC patients were identified. 47% had zero residual disease. Chemotherapy cycles were divided into <3cycles or >=4cycles for NAC and consolidation treatments and analyzed with multivariate analysis. 139/403 (34.5%) received >=4cycles of NAC and had a worse prognosis than <3cycles (p=0.011). 70/403 (17.4%) received >=4cycles of consolidation treatment and there was no difference in survival (p=0.33) CONCLUSION: Women with advanced HGSC are managed with a combination of surgery and chemotherapy. This is a study of a homogenous cohort of patients with stage IIIC or IV high grade serous cancers who received NAC. >=4cycles of NAC had a worse outcome than <3cycles likely due to poor prognostic factors or poor response. The number of consolidation cycles did not appear to make a difference in overall survival. PMID- 28800941 TI - Survival and safety associated with aggressive surgery for stage III/IV epithelial ovarian cancer: A single institution observation study. AB - OBJECTIVE: We evaluated the efficacy and safety of aggressive surgery for advanced ovarian cancer at a non-high-volume center. MATERIALS AND METHODS: We evaluated consecutive patients with stage III/IV ovarian, fallopian, and peritoneal cancer undergoing elective aggressive surgery from January 2008 to December 2012, which encompassed the first 5years after implementing an aggressive surgery protocol. After receiving appropriate training for 9months, a gynecological surgical team began performing multi-visceral resections. Primary debulking surgery was chosen when the team considered that optimal surgery was achievable on the initial laparotomy, otherwise interval debulking surgery was chosen (the protocol treatments). Analysis was performed on an intention-to-treat basis (full-set analysis), and outcomes were compared to those of patients who underwent standard surgery between 2000 and 2007. RESULTS: Of 106 consecutive patients studied, 87 (82%) underwent aggressive surgery per protocol and 19 were excluded. Serous carcinoma was the most common disease (78%), followed by clear cell carcinoma (7%), and 32% of the patients had stage IV disease. The respective median progression-free and overall survival rates increased from 14.6 and 38.1months before implementation, respectively, to 25.0 and 68.5months after implementation, respectively. Complete resection was achieved in 83 of the 106 patients (78%), and the surgical complexity score was high (>8) in 61 patients (58%); although there was no mortality within 12weeks of surgery, major complications occurred in 8 patients. CONCLUSIONS: We confirmed that outcomes improved after implementing aggressive surgery for advanced ovarian cancer, without causing a significant increase in mortality. Factors enhancing survival outcomes are discussed. PMID- 28800942 TI - Plasma and ovarian tissue sphingolipids profiling in patients with advanced ovarian cancer. AB - PURPOSE: The role of lipids in carcinogenesis through induction of abnormal cell lines in the human body is currently undisputable. Based on the literature, bioactive sphingolipids play an essential role in the development and progression of cancer and are involved in the metastatic process. The aim of this study was to determine the concentration of selected sphingolipids in patients with advanced ovarian cancer (AOC, FIGO III/IV, high grade ovarian cancer). METHODS: Seventy-four patients with ovarian cancer were enrolled. Plasma concentrations of C16-Cer, C18:1-Cer and C18-Cer were assessed by LC/MS/MS. The content of tissue sphingolipids was measured using a UHPLC/MS/MS. RESULTS: Plasma concentration of 3 ceramides: C16-Cer, C18:1-Cer and C18-Cer was significantly elevated in women with advanced ovarian cancer compared to control group (P=0.031; 0.022; 0.020; respectively). There were increases in concentration of 5 ceramides: C16-Cer, C18:1-Cer, C18-Cer, C24:1-Cer, C24-Cer (P=0.025; 0.049; 0.032; 0.005; 0.013, respectively) and S1P (P=0.004) in ovarian tissue of women with advanced ovarian cancer compared to healthy individuals. Importantly, significantly higher risk of ovarian cancer when the plasma concentration of C16-Cer>311.88ng/100MUl (AUC: 0.76, P=0.0261); C18:1-Cer>4.75ng/100MUl (AUC: 0.77, P=0.0160) and C18 Cer>100.76ng/100MUl (AUC:0.77, P=0.0136) was noticed. CONCLUSIONS: Bioactive sphingolipids play an essential role in the development and progression of cancer and they also take part in the process of metastasizing. This study suggests that some sphingolipids can be used as potential biomarkers of advanced ovarian cancer and that they can play an important role in the pathogenesis of this disease. PMID- 28800943 TI - Genetic consultation embedded in a gynecologic oncology clinic improves compliance with guideline-based care. AB - OBJECTIVE: Analyze the impact of embedding genetic counseling services in gynecologic oncology on clinician referral and patient uptake of cancer genetics services. METHODS: Data were reviewed for a total of 737 newly diagnosed epithelial ovarian cancer patients seen in gynecologic oncology at a large academic medical center including 401 from 11/2011-7/2014 (a time when cancer genetics services were provided as an off-site consultation). These data were compared to data from 8/2014-9/2016 (n=336), when the model changed to the genetics embedded model (GEM), incorporating a cancer genetic counselor on-site in the gynecologic oncology clinic. RESULTS: A statistically significant difference in proportion of patients referred pre- and post-GEM was observed (21% vs. 44%, p<0.0001). Pre-GEM, only 38% of referred patients were actually scheduled for genetics consultation and post-GEM 82% were scheduled (p<0.00001). The difference in the time from referral to scheduling in genetics was also statistically significant (3.92months pre-GEM vs. 0.79months post-GEM, p<0.00001) as was the time from referral to completion of genetics consultation (2.52months pre-GEM vs. 1.67months post-GEM, p<0.01). Twenty-five percent of patients referred post GEM were seen by the genetic counselor on the same day as the referral. CONCLUSIONS: Providing cancer genetics services on-site in gynecologic oncology and modifying the process by which patients are referred and scheduled significantly increases referral to cancer genetics and timely completion of genetics consultation, improving compliance with guideline-based care. Practice changes are critical given the impact of genetic test results on treatment and familial cancer risks. PMID- 28800944 TI - Systematic review: Tumor-associated antigen autoantibodies and ovarian cancer early detection. AB - OBJECTIVES: Tumor-associated autoantibodies (AAbs), produced as an immune response to tumor-associated antigens (TAAs), are a novel pathway of early detection markers. METHODS: We conducted a systematic review on AAbs and ovarian cancer to summarize the diagnostic performance of individual AAbs and AAb panels. A total of 29 studies including 85 AAbs were included; 27 of the studies were conducted in prevalent cases and cancer-free controls and 2 investigations included pre-diagnosis samples. The majority of studies were hypothesis-driven, evaluating AAbs to target TAAs; 10 studies used screening approaches such as serological expression cloning (SEREX) and nucleic acid-programmable protein arrays (NAPPA). RESULTS: The highest sensitivities for individual AAbs were reported for RhoGDI-AAbs (89.5%) and TUBA1C-AAbs (89%); however, specificity levels were relatively low (80% and 75%, respectively). High sensitivities at high specificities were reported for HOXA7-AAbs for detection of moderately differentiated ovarian tumors (66.7% sensitivity at 100% specificity) and IL8 AAbs in stage I-II ovarian cancer (65.5% sensitivity at 98% specificity). A panel of 11 AAbs (ICAM3, CTAG2, p53, STYXL1, PVR, POMC, NUDT11, TRIM39, UHMK1, KSR1, and NXF3) provided 45% sensitivity at 98% specificity for serous ovarian cancer, when at least 2 AAbs were above a threshold of 95% specificity. Twelve of the AAbs identified in this review were investigated in more than one study. Data on diagnostic discrimination by tumor histology and stage at diagnosis are sparse. Limited data suggest select AAb markers improve diagnostic discrimination when combined with markers such as CA125 and HE4. CONCLUSIONS: AAbs for ovarian cancer early detection is an emerging area, and large-scale, prospective investigations considering histology and stage are required for discovery and validation. However, data to date suggests panels of AAbs may eventually reach sufficient diagnostic discrimination to allow earlier detection of disease as a complement to existing markers and transvaginal ultrasound. PMID- 28800945 TI - Impact of age at diagnosis on racial disparities in endometrial cancer patients. AB - INTRODUCTION: Although black patients with endometrial cancer (EC) have worse survival compared with white patients, the interaction between age/race has not been examined. The primary objective was to evaluate the impact of age at diagnosis on racial disparities in disease presentation and outcome in EC. METHODS: We evaluated women diagnosed with EC between 1991 and 2010 from the Surveillance, Epidemiology, and End Results. Mutation status for TP53 or PTEN, or with the aggressive integrative, transcript-based, or somatic copy number alteration-based molecular subtype were acquired from the Cancer Genome Atlas. Logistic regression model was used to estimate the interaction between age and race on histology. Cox regression model was used to estimate the interaction between age and race on survival. RESULTS: 78,184 white and 8518 black patients with EC were analyzed. Median age at diagnosis was 3-years younger for black vs. white patients with serous cancer and carcinosarcoma (P<0.0001). The increased presentation of non-endometrioid histology with age was larger in black vs. white patients (P<0.0001). The racial disparity in survival and cancer-related mortality was more prevalent in black vs. white patients, and in younger vs. older patients (P<0.0001). Mutations in TP53, PTEN and the three aggressive molecular subtypes each varied by race, age and histology. CONCLUSIONS: Aggressive histology and molecular features were more common in black patients and older age, with greater impact of age on poor tumor characteristics in black vs. white patients. Racial disparities in outcome were larger in younger patients. Intervention at early ages may mitigate racial disparities in EC. PMID- 28800946 TI - Three Tctn proteins are functionally conserved in the regulation of neural tube patterning and Gli3 processing but not ciliogenesis and Hedgehog signaling in the mouse. AB - Tctn1, Tctn2, and Tctn3 are membrane proteins that localize at the transition zone of primary cilia. Tctn1 and Tctn2 mutations have been reported in both humans and mice, but Tctn3 mutations have been reported only in humans. It is also not clear whether the three Tctn proteins are functionally conserved with respect to ciliogenesis and Hedgehog (Hh) signaling. In the present study, we report that loss of Tctn3 gene function in mice results in a decrease in ciliogenesis and Hh signaling. Consistent with this, Tctn3 mutant mice exhibit holoprosencephaly and randomized heart looping and lack the floor plate in the neural tube, the phenotypes similar to those of Tctn1 and Tctn2 mutants. We also show that overexpression of Tctn3, but not Tctn1 or Tctn2, can rescue ciliogenesis in Tctn3 mutant cells. Similarly, replacement of Tctn3 with Tctn1 or Tctn2 in the Tctn3 gene locus results in reduced ciliogenesis and Hh signaling, holoprosencephaly, and randomized heart looping. Surprisingly, however, the neural tube patterning and the proteolytic processing of Gli3 (a transcription regulator for Hh signaling) into a repressor, both of which are usually impaired in ciliary gene mutants, are normal. These results suggest that Tctn1, Tctn2, and Tctn3 are functionally divergent with respect to their role in ciliogenesis and Hh signaling but conserved in neural tube patterning and Gli3 processing. PMID- 28800947 TI - [From pathogenesis of giant cell arteritis to new therapeutic targets]. AB - Giant cell arteritis (GCA) is the most common vasculitis in adults. GCA is a granulomatous large-vessel vasculitis involving the aorta and its major branches in people>50 years. Glucocorticoids (GC) remain the cornerstone of GCA treatment. Prednisone is usually started at 0.7 or 1mg/kg/day depending on the occurrence of ischemic complications. Then, GC are progressively tapered and stopped after a mean duration of 18 months. GC are very efficient but relapses often occur during their tapering. Moreover, GC-related side effects are very common during this long term GC therapy. Thus, it can be assumed that GC are not the ideal treatment for GCA and that GC-sparing strategies have to be developed. The pathogenesis of GCA is not fully understood but major advances have been achieved in the recent years. If the trigger of GCA, which is suspected to be infectious, is still not identified, mechanisms triggering the granulomatous inflammation of the arterial wall and the progressive vascular remodeling leading to the occurrence of ischemic events have been better and better deciphered. Thanks to these advances in the knowledge of GCA pathogenesis, new therapeutic targets have emerged such as blockade of the activation of T cells or inhibition of the interleukin-6 (IL 6), IL-12/23 or IL-1beta pathways. PMID- 28800948 TI - Comparative effects of intraduodenal fat and glucose on the gut-incretin axis in healthy males. AB - BACKGROUND: The interaction of nutrients with the small intestine stimulates the secretion of numerous enteroendocrine hormones that regulate postprandial metabolism. However, differences in gastrointestinal hormonal responses between the macronutrients are incompletely understood. In the present study, we compared blood glucose and plasma hormone concentrations in response to standardised intraduodenal (ID) fat and glucose infusions in healthy humans. METHODS: In a parallel study design, 16 healthy males who received an intraduodenal fat infusion were compared with 12 healthy males who received intraduodenal glucose, both at a rate of 2kcal/min over 120min. Venous blood was sampled at frequent intervals for measurements of blood glucose, and plasma total and active glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon. RESULTS: Plasma concentrations of the incretin hormones (both total and active GLP-1 and GIP) and glucagon were higher, and plasma insulin and blood glucose concentrations lower, during intraduodenal fat, when compared with intraduodenal glucose, infusion (treatment by time interaction: P<0.001 for each). CONCLUSIONS: Compared with glucose, intraduodenal fat elicits substantially greater GLP-1, GIP and glucagon secretion, with minimal effects on blood glucose or plasma insulin in healthy humans. These observations are consistent with the concept that fat is a more potent stimulus of the 'gut incretin' axis than carbohydrate. PMID- 28800949 TI - Pulmonary sinus cusp mapping and ablation: A new concept and approach for idiopathic right ventricular outflow tract arrhythmias. AB - BACKGROUND: Right ventricular outflow tract (RVOT) ventricular arrhythmias (VAs) may originate from the pulmonary sinus cusps (PSCs) far more frequently than previously recognized. OBJECTIVE: The purpose of this study was to assess whether mapping and ablation in PSCs might be an appropriate first-choice treatment in unselected patients with idiopathic RVOT VAs. METHODS: Ninety consecutive patients with VAs of RVOT-type origin were prospectively enrolled at our institution between August 2015 and September 2016. Pulmonary valve (PV) and PSCs were precisely localized by pulmonary arteriography. Activation and pace-mapping were performed in the PSCs and RVOT region below the PV, and ablation was preferentially performed in PSCs. RESULTS: In 81 patients (90%), earliest activation of VAs was found in PSCs, and ablation resulted in elimination of VAs without any additional ablation in the RVOT region underneath the PV. The best pace-map was obtained at successful ablation sites in PSCs in 96.3% of patients. In the remaining 9 patients, final successful ablation sites were in the aortic coronary cusps in 5 and at the lowest and most posterior part of the RVOT in 4. During mean follow-up of 15.2 +/- 9.5 months, single procedural success rate was 96.7%. CONCLUSION: In this single-center, prospective study, a strategy based on PSC mapping and ablation eliminated 90% (81/90) of unselected idiopathic RVOT type VAs with favorable mid-term effectiveness. PMID- 28800950 TI - Added Value of Bone Subtraction in Dual-energy Digital Radiography in the Detection of Pneumothorax: Impact of Reader Expertise and Medical Specialty. AB - RATIONALE AND OBJECTIVES: This study aimed to determine the value of dual-energy thoracic radiography in the diagnosis of pneumothorax considering the reader's experience. MATERIALS AND METHODS: Forty patients with a suspected pneumothorax, imaged with dual-energy chest radiographs, were divided into two groups: those with pneumothorax as the final diagnosis (n = 19) and those without (n = 21). The images were analyzed by 36 readers (5 interns, 16 residents, 15 senior physicians) for the presence or absence of pneumothorax during three readout sessions at 2-week intervals: standard images alone (session 1), dual-energy images with bone subtraction alone (session 2), and a combination of the two (session 3). RESULTS: The number of correct responses increased 13.3% between sessions 1 and 2 (P < .001) and 9.4% between sessions 1 and 3 (P < .001). The mean sensitivity for pneumothorax detection was higher in sessions 2 (82%) and 3 (79%) compared to session 1 (70%). There was no statistically significant difference in specificity between the sessions. The number of correct responses for small volume pneumothoraces was higher in sessions 2 (10.6 +/- 1.8) and 3 (10.1 +/- 2.0) than in session 1 (8.9 +/- 2.3), with a statistically significant difference between sessions 1 and 2 (P = .002) and between sessions 1 and 3 (P = .048). CONCLUSION: Bone subtracted dual-energy thoracic radiographs improve the detection sensitivity of pneumothorax, including in cases of small pneumothoraces, regardless of the reader's level or expertise. PMID- 28800951 TI - Evaluation of a High Concentrated Contrast Media Injection Protocol in Combination with Low Tube Current for Dose Reduction in Coronary Computed Tomography Angiography: A Randomized, Two-center Prospective Study. AB - RATIONALE AND OBJECTIVES: The study aimed to prospectively evaluate the radiation dose reduction potential and image quality (IQ) of a high-concentration contrast media (HCCM) injection protocol in combination with a low tube current (mAs) in coronary computed tomography angiography. MATERIALS AND METHODS: Eighty-one consecutive patients (mean age: 62 years; 34 females; body mass index: 18-31) were included and randomized-assigned into two groups. All computed tomography (CT) examinations were performed in two groups with the same tube voltage (100 kV), flow rate of contrast medium (5.0 mL/s), and iodine dose (22.8 g). An automatic mAs and low concentration contrast medium (300 mgI/mL) were used in group A, whereas effective mAs was reduced by a factor 0.6 along with HCCM (400 mgI/mL) in group B. Radiation dose was assessed (CT dose index [CTDIvol] and dose length product), and vessel-based objective IQ for various regions of interest (enhancement, noise, signal-to-noise ratio, and contrast-to-noise ratio), subjective IQ, noise, and motion artifacts were analyzed overall and vessel-based with a 5-point Likert scale. RESULTS: The CT attenuation of coronary arteries and image noise in group B were significantly higher than those in group A (ranges: 507.5-548.1 Hounsfield units vs 407.5-444.5 Hounsfield units; and 20.3 +/- 8.6 vs 17.7 +/- 8.0) (P <= 0.0166). There was no significant difference between the two groups in signal-to-noise ratio, contrast-to-noise ratio, and subjective IQ of coronary arteries (29.4-31.7, 30.0-37.0, and medium score of 5 in group A vs 29.4 32.4, 27.7-36.3, and medium score of 5 in group B, respectively, P >= 0.1859). Both mean CTDIvol and dose length product in group B were 58% of those of group A. CONCLUSIONS: HCCM combined with low tube current allows dose reduction in coronary computed tomography angiography and does not compromise IQ. PMID- 28800952 TI - The Best Single Measurement for Assessing Splenomegaly in Patients with Cirrhotic Liver Morphology. AB - RATIONALE AND OBJECTIVES: There is little agreement within the radiology literature as to the best single measurement for assessing splenomegaly. In this study, we evaluate the correlation of multiple unidirectional measurements of the spleen with splenic volume in patients with cirrhotic liver morphology on computed tomography (CT). MATERIALS AND METHODS: Splenic volume was retrospectively calculated from CT examinations of 179 adult patients, 47 of whom were approved as renal donors, and 132 of whom were referred for various other indications, and were found to have cirrhotic liver morphology on CT. Seven unidimensional measurements (long-axis, cranial-caudal, width, and four measures of thickness) of each spleen were evaluated to identify which most closely correlated with the calculated volume. RESULTS: The splenic width had the best correlation with splenic volume for mild-to-moderate splenomegaly, and the splenic cranial-caudal measurement had the best correlation with splenic volume for massive splenomegaly. Receiver operating characteristic analysis demonstrates that a splenic width measurement of approximately 10.5 cm has a sensitivity of 89% and a specificity of 78% for mild-to-moderate splenomegaly, and a cranial caudal measurement of 14.6 cm has a sensitivity of 92% and a specificity of 91% for massive splenomegaly. CONCLUSIONS: A splenic width threshold of 10.5 cm is the most sensitive (89%) and specific (78%) single measurement for mild-to moderate splenomegaly in patients with cirrhotic liver morphology, whereas a cranial-caudal height threshold of 14.6 cm is the most sensitive (92%) and specific (91%) single measurement for massive splenomegaly. PMID- 28800954 TI - A TIM-3 Oligonucleotide Aptamer Enhances T Cell Functions and Potentiates Tumor Immunity in Mice. AB - T cell immunoglobulin-3 (TIM-3) is a negative regulator of interferon-gamma (IFN gamma) secreting CD4+ T cells and CD8+ T cytotoxic cells. Recent studies have highlighted the role of TIM-3 as an important mediator of CD8+ T cell exhaustion in the setting of chronic viral infections and cancer. In murine tumor models, antibody blockade of TIM-3 with anti-TIM-3 antibodies as monotherapy has no or minimal antitumor activity, suggesting that TIM-3 signaling exerts an accessory or amplifying effect in keeping immune responses in check. Using a combined bead and cell-based systemic evolution of ligands by exponential enrichment (SELEX) protocol, we have isolated nuclease-resistant oligonucleotide aptamer ligands that bind to cell-associated TIM-3 with high affinity and specificity. A trimeric form of the TIM-3 aptamer blocked the interaction of TIM-3 with Galectin-9, reduced cell death, and enhanced survival, proliferation, and cytokine secretion in vitro. In tumor-bearing mice, the aptamer delayed tumor growth as monotherapy and synergized with PD-1 antibody in prolonging the survival of the tumor-bearing mice. Both in vitro and in vivo, the trimeric aptamer displayed superior activity compared to the currently used RMT3-23 monoclonal antibody. This study suggests that multi-valent aptamers could represent an alternative platform to generate potent ligands to manipulate the function of TIM-3 and other immune modulatory receptors. PMID- 28800956 TI - Adult hippocampal neurogenesis: Is it the alpha and omega of antidepressant action? AB - It is now well established that all clinically available antidepressants share a common aptitude: they increase the production of adult-generated neurons in the dentate gyrus of the hippocampus. This was first observed in animal models and subsequently in human populations, highlighting the clinical relevance of this finding. Later, it was suggested that hippocampal neurogenesis was not an epiphenomenal correlate of antidepressant action but was causally involved. Indeed, when neurogenesis is suppressed, antidepressant compounds can no longer achieve remission. This action of adult-born neurons seems necessary to achieve remission, but less evidence exists to show that it is sufficient alone. In the following decades, a new generation of putative antidepressants that act through different non-monoaminergic mechanisms were proposed in preclinical research as potential therapies. Interestingly, these treatments all increased neurogenesis in animal models of pathological states: this was observed with drugs acting through peptidergic or glutamatergic mechanisms and with neurostimulation strategies not targeting the hippocampus. However, the involvement of neurogenesis was not always causal. To advance further in this field, an understanding of how adult-generated neurons induce therapeutic effects and how this is related to the pathophysiology of depression are required. PMID- 28800953 TI - COL7A1 Editing via CRISPR/Cas9 in Recessive Dystrophic Epidermolysis Bullosa. AB - Designer nucleases allow specific and precise genomic modifications and represent versatile molecular tools for the correction of disease-associated mutations. In this study, we have exploited an ex vivo CRISPR/Cas9-mediated homology-directed repair approach for the correction of a frequent inherited mutation in exon 80 of COL7A1, which impairs type VII collagen expression, causing the severe blistering skin disease recessive dystrophic epidermolysis bullosa. Upon CRISPR/Cas9 treatment of patient-derived keratinocytes, using either the wild-type Cas9 or D10A nickase, corrected single-cell clones expressed and secreted similar levels of type VII collagen as control keratinocytes. Transplantation of skin equivalents grown from corrected keratinocytes onto immunodeficient mice showed phenotypic reversion with normal localization of type VII collagen at the basement membrane zone, compared with uncorrected keratinocytes, as well as fully stratified and differentiated skin layers without indication of blister development. Next-generation sequencing revealed on-target efficiency of up to 30%, whereas nuclease-mediated off-target site modifications at predicted genomic loci were not detected. These data demonstrate the potential of the CRISPR/Cas9 technology as a possible ex vivo treatment option for genetic skin diseases in the future. PMID- 28800957 TI - Insight into the mode of action and selectivity of PBRM, a covalent steroidal inhibitor of 17beta-hydroxysteroid dehydrogenase type 1. AB - 17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is involved in the biosynthesis of estradiol, the major bioactive endogenous estrogen in mammals, and constitutes an interesting therapeutic target for estrogen-dependent diseases. A steroidal derivative, 3-{[(16beta,17beta)-3-(2-bromoethyl)-17 hydroxyestra-1,3,5(10)-trien-16-yl]methyl} benzamide (PBRM), has recently been described as a non-estrogenic, irreversible inhibitor of 17beta-HSD1. However, the mode of action of this inhibitor and its selectivity profile have not yet been elucidated. We assessed PBRM potency via in vitro kinetic measurements. The mechanism of enzyme inactivation was also investigated using interspecies (human, mouse, pig and monkey) comparisons via both in vitro assays and in silico analysis. Mouse and human plasma protein binding of PBRM was determined, whereas its selectivity of action was studied using a wide range of potential off-targets (e.g. GPCR, hERG, CYPs, etc.). The affinity constant (Ki=368nM) and the enzyme inactivation rate (kinact=0.087min-1) values for PBRM were determined with purified 17beta-HSD1. PBRM was found to be covalently linked to the enzyme. A long delay period (i.e. 3-5days) is required to recover 17beta-HSD1 activity following a pretreatment of breast and placenta cell lines with PBRM. Mechanistic analyses showed important interspecies differences of 17beta-HSD1 inhibition which support the importance of inactivation for PBRM effect. Evidences of the potency and selectivity of action presented herein for this first non-estrogenic and steroidal covalent irreversible inhibitor of 17beta-HSD1 warrant its further development as a potential drug candidate for estrogen-dependent disorders. PMID- 28800958 TI - The pharmacology of neurogenesis: Conceptual advances and remaining challenges. PMID- 28800959 TI - MYBPH inhibits vascular smooth muscle cell migration and attenuates neointimal hyperplasia in a rat carotid balloon-injury model. AB - Vascular smooth muscle cell (VSMC) migration is implicated in restenosis. Myosin binding protein H (MYBPH) is capable of reducing cell motility and metastasis. In this study, we sought to determine whether MYBPH is involved in VSMC migration and neointima formation in response to vascular injury. To determine the expression of MYBPH in injured artery, we used a standard rat carotid artery balloon-injury model. In vivo studies have demonstrated that MYBPH is upregulated after vascular injury. VSMCs treated with platelet-derived growth factor (PDGF) BB displayed increased MYBPH mRNA and protein levels. PDGF-induced VSMC migration was inhibited by adenovirus-mediated expression of MYBPH whereas it was enhanced by small interfering RNA knockdown of MYBPH. The activation of ROCK1 was repressed by MYBPH. Luminal delivery of MYBPH adenovirus to carotid arteries decreased neointimal hyperplasia in vivo. MYBPH may, therefore, serve as a novel therapeutic target for postangioplasty restenosis. PMID- 28800961 TI - Functional consequences of inducible genetic elements from the p53 SOS response in a mammalian organ system. AB - In response to DNA damage from ultraviolet (UV) radiation, bacteria deploy the SOS response in order to limit cell death. This bacterial SOS response is characterized by an increase in the recA gene that transactivates expression of multiple DNA repair genes. The current series of experiments demonstrate that a mammalian organ system (the cochlea) that is not evolutionarily conditioned to UV radiation can elicit SOS responses that are reminiscent of that of bacteria. This mammalian SOS response is characterized by an increase in the p53 gene with activation of multiple DNA repair genes that harbor p53 response elements in their promoters. Furthermore, the experimental results provide support for the notion of a convergent trigger paradox, where independent SOS triggers facilitate disparate physiologic sequelae (loss vs. recovery of function). Therefore, it is proposed that the mammalian SOS response is multifunctional and manipulation of this endogenous response could be exploited in future biomedical interventions. PMID- 28800960 TI - ETS transcription factor ELF5 induces lumen formation in a 3D model of mammary morphogenesis and its expression is inhibited by Jak2 inhibitor TG101348. AB - The loss of expression of a single gene can revert normal tissue to a malignant phenotype. For example, while normal breast has high lumenal expression of CEACAM1, the majority of breast cancers exhibit the early loss of this gene with the concurrent loss of their lumenal phenotype. MCF7 cells that lack CEACAM1 expression and fail to form lumena in 3D culture, regain the normal phenotype when transfected with CEACAM1. In order to probe the mechanism of this gain of function, we treated these cells with the clinically relevant Jak2 inhibitor TG101348 (TG), expecting that disruption of the prolactin receptor signaling pathway would interfere with the positive effects of transfection of MCF7 cells with CEACAM1. Indeed, lumen formation was inhibited, resulting in the down regulation of a set of genes, likely involved in the complex process of lumen formation. As expected, inhibition of the expression of many of these genes also inhibited lumen formation, confirming their involvement in a single pathway. Among the genes identified by the inhibition assay, ETS transcription factor ELF5 stood out, since it has been identified as a master regulator of mammary morphogenesis, and is associated with prolactin receptor signaling. When ELF5 was transfected into the parental MCF7 cells that lack CEACAM1, lumen formation was restored, indicating that ELF5 can replace CEACAM1 in this model system of lumenogenesis. We conclude that the event(s) that led to the loss of expression of CEACAM1 is epistatic in that multiple genes associated with a critical pathway were affected, but that restoration of the normal phenotype can be achieved with reactivation of certain genes at various nodal points in tissue morphogenesis. PMID- 28800962 TI - Contacting co-culture of human retinal microvascular endothelial cells alters barrier function of human embryonic stem cell derived retinal pigment epithelial cells. AB - Here we evaluated the effects of human retinal microvascular endothelial cells (hREC) on mature human embryonic stem cell (hESC) derived retinal pigment epithelial (RPE) cells. The hESC-RPE cells (Regea08/017, Regea08/023 or Regea11/013) and hREC (ACBRI 181) were co-cultured on opposite sides of transparent membranes for up to six weeks. Thereafter barrier function, small molecule permeability, localization of RPE and endothelial cell marker proteins, cellular fine structure, and growth factor secretion of were evaluated. After co culture, the RPE specific CRALBP and endothelial cell specific von Willebrand factor were appropriately localized. In addition, the general morphology, pigmentation, and fine structure of hESC-RPE cells were unaffected. Co-culture increased the barrier function of hESC-RPE cells, detected both with TEER measurements and cumulative permeability of FD4 - although the differences varied among the cell lines. Co-culturing significantly altered VEGF and PEDF secretion, but again the differences were cell line specific. The results of this study showed that co-culture with hREC affects hESC-RPE functionality. In addition, co culture revealed drastic cell line specific differences, most notably in growth factor secretion. This model has the potential to be used as an in vitro outer blood-retinal barrier model for drug permeability testing. PMID- 28800963 TI - Young adults' internet addiction: Prediction by the interaction of parental marital conflict and respiratory sinus arrhythmia. AB - The aim of the current study was to address the potential moderating roles of respiratory sinus arrhythmia (RSA; baseline and suppression) and participant sex in the relation between parents' marital conflict and young adults' internet addiction. Participants included 105 (65 men) Chinese young adults who reported on their internet addiction and their parents' marital conflict. Marital conflict interacted with RSA suppression to predict internet addiction. Specifically, high RSA suppression was associated with low internet addiction, regardless of parental marital conflict; however, for participants with low RSA suppression, a positive relation between marital conflict and internet addiction was found. Internet addiction also was predicted by a significant three-way interaction among baseline RSA, marital conflict, and participant sex. Specifically, for men, marital conflict positively predicted internet addiction under conditions of low (but not high) baseline RSA. For women, marital conflict positively predicted internet addiction under conditions of high (but not low) baseline RSA. Findings highlight the importance of simultaneous consideration of physiological factors, in conjunction with family factors, in the prediction of young adults' internet addiction. PMID- 28800964 TI - The effect of metal ions released from different dental implant-abutment couples on osteoblast function and secretion of bone resorbing mediators. AB - OBJECTIVES: The etiology of the reduced marginal bone loss observed around platform-switched implant-abutment connections is not clear but could be related to the release of variable amounts of corrosion products. The present study evaluated the effect of different concentrations of metal ions released from different implant abutment couples on osteoblastic cell viability, apoptosis and expression of genes related to bone resorption. METHODS: Osteoblastic cells were exposed to five conditions of culture media prepared containing metal ions (titanium, aluminum, vanadium, cobalt, chromium and molybdenum) in different concentrations representing the amounts released from platform-matched and platform-switched implant-abutment couples as a result of an earlier accelerated corrosion experiment. Cell viability was evaluated over 21days using the Alamar Blue assay. Induction of apoptosis was measured after 24h of exposure using flow cytometry. Expression of interleukin-6, interleukin-8, cyclooxygenase-2, caspase 8, osteoprotegerin and receptor activator of nuclear factor kappa-B ligand (RANKL) by osteoblastic cells were analysed after exposure for 1, 3 and 21days using real-time quantitative polymerase chain reaction assay RESULTS: Metal ions in concentrations representing the platform-matched groups led to a reduction in cell viability (P<0.01) up to 7days of exposure. Stimulated cells showed higher rates of early apoptosis (P<0.01) compared to non-treated cells. Metal ions up regulated the expression of interleukin-6, interleukin-8, cyclooxygenase-2 and RANKL in a dose dependent manner after 1day of exposure (P<0.05). The up regulation was more pronounced in the groups containing the corrosion products of platform-matched implant-abutment couples. CONCLUSION: Osteoblastic cell viability, apoptosis, and regulation of bone resorbing mediators were significantly altered in the presence of metal ions. The change in cytokine levels expressed was directly proportional to the metal ion concentration. CLINICAL SIGNIFICANCE: The observed biological responses to decreased amounts of metal ions released from platform-switched implant-abutment couples compared to platform-matched couples may partly explain the positive radiographic findings in respect to crestal bone level when utilising the "platform-switching" concept, which highlights the possible role of corrosion products in the mediation of crestal bone loss around dental implants. PMID- 28800965 TI - The CRISPR/Cas9-facilitated multiplex pathway optimization (CFPO) technique and its application to improve the Escherichia coli xylose utilization pathway. AB - One of the most important research subjects of metabolic engineering is the pursuit of balanced metabolic pathways, which requires the modulation of expression of many genes. However, simultaneously modulating multiple genes on the chromosome remains challenging in prokaryotic organisms, including the industrial workhorse - Escherichia coli. In this work, the CRISPR/Cas9 facilitated multiplex pathway optimization (CFPO) technique was developed to simultaneously modulate the expression of multiple genes on the chromosome. To implement it, two plasmids were employed to target Cas9 to regulatory sequences of pathway genes, and a donor DNA plasmid library was constructed containing a regulator pool to modulate the expression of these genes. A modularized plasmid construction strategy was used to enable the assembly of a complex donor DNA plasmid library. After genome editing using this technique, a combinatorial library was obtained with variably expressed pathway genes. As a demonstration, the CFPO technique was applied to the xylose metabolic pathway genes in E. coli to improve xylose utilization. Three transcriptional units containing a total of four genes were modulated simultaneously with 70% efficiency, and improved strains were selected from the resulting combinatorial library by growth enrichment. The best strain, HQ304, displayed a 3-fold increase of the xylose utilization rate. Finally, the xylose-utilization pathway of HQ304 was analyzed enzymologically to determine the optimal combination of enzyme activities. PMID- 28800966 TI - Reconstruction of a metabolic regulatory network in Escherichia coli for purposeful switching from cell growth mode to production mode in direct GABA fermentation from glucose. AB - gamma-aminobutyric acid (GABA) is a drug and functional food additive and is used as a monomer for producing the biodegradable plastic, polyamide 4. Recently, direct GABA fermentation from glucose has been developed as an alternative to glutamate-based whole cell bioconversion. Although total productivity in fermentation is determined by the specific productivity and cell amount responsible for GABA production, the optimal metabolic state for GABA production conflicts with that for bacterial cell growth. Herein, we demonstrated metabolic state switching from the cell growth mode based on the metabolic pathways of the wild type strain to a GABA production mode based on a synthetic metabolic pathway in Escherichia coli through rewriting of the metabolic regulatory network and pathway engineering. The GABA production mode was achieved by multiple strategies such as conditional interruption of the TCA and glyoxylate cycles, engineering of GABA production pathway including a bypass for precursor metabolite supply, and upregulation of GABA transporter. As a result, we achieved 3-fold improvement in total GABA production titer and yield (4.8g/L, 49.2% (mol/mol glucose)) in batch fermentation compared to the case without metabolic state switching (1.6g/L, 16.4% (mol/mol glucose)). This study reports the highest GABA production performance among previous reports on GABA fermentation from glucose using engineered E. coli. PMID- 28800967 TI - Role of Prion protein in premature senescence of human fibroblasts. AB - Prion protein (PrP) is essentially known for its capacity to induce neurodegenerative prion diseases in mammals caused by a conformational change in its normal cellular isoform (PrPC) into an infectious and disease-associated misfolded form, called scrapie isoform (PrPSc). Although its sequence is highly conserved, less information is available on its physiological role under normal conditions. However, increasing evidence supports a role for PrPC in the cellular response to oxidative stress. In the present study, a new link between PrP and senescence is highlighted. The role of PrP in premature senescence induced by copper was investigated. WI-38 human fibroblasts were incubated with copper sulfate (CuSO4) to trigger premature senescence. This induced an increase of PrP mRNA level, an increase of protein abundance of the normal form of PrP and a nuclear localization of the protein. Knockdown of PrP expression using specific small interfering RNA (siRNA) gave rise to appearance of several biomarkers of senescence as a senescent morphology, an increase of senescence associated beta galactosidase activity and a decrease of the cellular proliferative potential. Overall these data suggest that PrP protects cells against premature senescence induced by copper. PMID- 28800968 TI - Routine beta-Human Chorionic Gonadotropin Monitoring for Single-Dose Methotrexate Treatment in Ectopic Pregnancy. AB - STUDY OBJECTIVE: To evaluate an alternative monitoring protocol without day 4 beta-human chorionic gonadotropin (beta-hCG) measurement for predicting the need for a repeated methotrexate (MTX) dose in patients undergoing single-dose MTX therapy for ectopic pregnancy (EP). DESIGN: Single-center retrospective study (Canadian Task Force classification II-3). SETTING: University-affiliated hospital. PATIENTS: Included in the study were 184 EP patients treated with MTX between January 2009 and December 2016. INTERVENTIONS: Single-dose MTX treatment (50 mg/m2). MEASUREMENTS AND MAIN RESULTS: The patients were treated with repeated doses of MTX every 7 days, if necessary, according to Stovall's protocol, or with laparoscopic surgery in cases of tubal rupture. The success of a single-dose of MTX according to the alternative measure was defined as a >50% decrease in the beta-hCG level between days 1 and 7 in clinically stable patients. The sensitivity, specificity, false-negative rate, false-positive rate, and attributable risk of this new monitoring measure were calculated and compared with the traditional regimen. The new protocol had a sensitivity and specificity of 100% and 88.7%, respectively, for predicting a required second dose in patients whose day 1 beta-hCG levels were <2000 mIU/mL. For patients with day 1 beta-hCG level >=2000 mIU/mL, both monitoring regimens had the same efficiency. CONCLUSIONS: The new monitoring model without the day 4 beta-hCG measurement may offer both patients and clinicians multiple options to monitor single-dose MTX therapy for selected EP patients, with a comparable clinical efficiency to Stovall's protocol and less expense and follow-up burden to patients. PMID- 28800969 TI - New guidelines for the diagnosis of fibromyalgia. AB - OBJECTIVE: To establish guidelines based on scientific evidence for the diagnosis of fibromyalgia. MATERIAL AND METHODS: Evidence collection was performed based on 9 questions regarding the diagnosis of fibromyalgia, structured using the Patient, Intervention or Indicator, Comparison and Outcome (P.I.C.O.), with searches in the main, primary databases of scientific information. After defining the potential studies to support the recommendations, they were graded according to evidence and degree of recommendation. PMID- 28800970 TI - Guidelines of the Brazilian Society of Rheumatology for the diagnosis and treatment of osteoporosis in men. AB - Osteoporosis, a metabolic disease characterized by low bone mass, deterioration of the bone tissue microarchitecture and increased susceptibility to fractures, is commonly regarded as a women's health problem. This point of view is based on the fact that compared with men, women have lower bone mineral density and longer lifespans and lose bone mass faster, especially after menopause, due to a marked decrease in serum estrogen levels. However, in the last 20 years, osteoporosis in men has become recognized as a public health problem due to the occurrence of an increasingly higher number of fragility fractures. Approximately 30% of all hip fractures occur in men. Recent studies show that the probability of fracture due to hip, vertebral or wrist fragility in Caucasian men older than fifty years, for the rest of their lives, is approximately 13% versus a 40% probability of fragility fractures in women. Men show bone mass loss and fractures later than women. Although older men have a higher risk of fracture, approximately half of all hip fractures occur before the age of 80. Life expectancy is increasing for both sexes in Brazil and worldwide, albeit at a higher rate for men than for women. This Guideline was based on a systematic review of the literature on the prevalence, etiology, diagnosis and treatment of osteoporosis in men. PMID- 28800971 TI - Perkinsus infection is associated with alterations in the level of global DNA methylation of gills and gastrointestinal tract of the oyster Crassostrea gasar. AB - : Bivalves are filter feeders that obtain food from seawater that may contain infectious agents, such as the protozoan parasites Perkinsus marinus and P. olseni that are associated with massive mortalities responsible for losses in the aquaculture industry. Despite all physical and chemical barriers, microorganisms cross epithelia and infect host tissues to cause pathologies. Epigenetics mechanisms play important roles in a variety of human processes, from embryonic development to cell differentiation and growth. It is currently emerging as crucial mechanism involved in modulation of host-parasite interactions and pathogenesis, promoting discovery of targets for drug treatment. In bivalves, little is known about epigenetic mechanism in host parasite interactions. The objective of the present study was to evaluate the effect of Perkinsus sp. infections on DNA methylation levels in tissues of Crassostrea gasar oysters. Samples were collected in 2015 and 2016 in the Mamanguape River estuary (PB). Oyster gills were removed and used for Perkinsus sp. DIAGNOSIS: Gills (G) and gastrointestinal tract (GT), as well as cultured P. marinus trophozoites were preserved in 95% ethanol for DNA extractions. DNA methylation levels were estimated from G and GT tissues of uninfected (n=60) and infected oysters (n=60), and from P. marinus trophozoites, by ELISA assays. Results showed that the mean prevalence of Perkinsus sp. infections was high (87.3%) in 2015 and moderate (59.6%) in 2016. DNA methylation levels of G and GT tissues were significantly lower in infected oyster than in uninfected oysters, suggesting that infections are associated with hypomethylation. Methylation level was significantly higher in G than in GT tissues, indicating a likely tissue-specific mechanism. P. marinus trophozoites showed 33% methylation. This was the first study that confirms alterations of DNA methylation in two tissues of C. gasar oysters in association with Perkinsus sp. infections. PMID- 28800972 TI - Intranasal oxytocin and the neural correlates of infant face processing in non parent women. AB - Event-related potentials (ERPs) have been widely employed to identify different stages of face processing, with recent research probing the neural dynamics of adult's processing of infant faces. Infant faces represent a salient category of visual stimuli, especially in parents, likely prioritized for processing through activity of the oxytocinergic system. Here we employed a randomized, double blind, and within-subject crossover study of 24 non-parent women to examine the impact of intranasal oxytocin administration, relative to placebo, on processing infant and adult faces. Our main finding was that, relative to placebo, the P300 ERP elicited by infant faces was greater than the P300 elicited by adult faces in the oxytocin condition. Therefore, oxytocin administration may enhance the allocation of attention towards infant cues, even in non-parent women. PMID- 28800973 TI - Critical evaluation of dipolar, acid-base and charge interactions I. Electron displacement within and between molecules, liquids and semiconductors. AB - Specific dipolar, acid-base and charge interactions involve electron displacements. For atoms, single bonds and molecules electron displacement is characterized by electronic potential, absolute hardness, electronegativity and electron gap. In addition, dissociation, bonding, atomization, formation, ionization, affinity and lattice enthalpies are required to quantify the electron displacement in solids. Semiconductors are characterized by valence and conduction band energies, electron gaps and average Fermi energies which in turn determine Galvani potentials of the bulk, space charge layer and surface states. Electron displacement due to interaction between (probe) molecules, liquids and solids are characterized by parameters such as Hamaker constant, solubility parameter, exchange energy density, surface tension, work of adhesion and immersion. They are determined from permittivity, refractive index, enthalpy of vaporization, molar volume, surface pressure and contact angle. Moreover, acidic and basic probes may form adducts which are adsorbed on target substrates in order to establish an indirect measure of polarity, acidity, basicity or hydrogen bonding. Acidic acceptor numbers (AN), basic donor numbers (DN), acidic and basic "electrostatic" (E) and "covalent" (C) parameters determined by enthalpy of adduct formation are considered as general acid-base scales. However, the formal grounds for assignments as dispersive, Lifshitz-van der Waals, polar, acid, base and hydrogen bond interactions are inconsistent. Although correlations are found no of the parameters are mutually fully compatible and moreover the enthalpies of acid-base interaction do not correspond to free energies. In this review the foundations of different acid-base parameters relating to electron displacement within and between (probe) molecules, liquids and (semiconducting) solids are thoroughly investigated and their mutual relationships are evaluated. PMID- 28800974 TI - Advances in the synthesis, molecular architectures and potential applications of gemini surfactants. AB - Gemini surfactants have been the subject of intensive scrutiny by virtue of their unique combination of physical and chemical properties and being used in ordinary household objects to multifarious industrial processes. In this review, we summarize the recent developments of gemini surfactants, highlighting the classification of gemini surfactants based on the variation in headgroup polarity, flexibility/rigidity of spacer, hydrophobic alkyl chain and counterion along with potential applications of gemini surfactants, depicting the truly remarkable journey of gemini surfactants that has just come of age. We have focused on those objectives which will act as suitable candidates to take the field forward. The preceding information will permit us to estimate the effect of structural variation on the aggregation behavior of gemini surfactants for nanoscience and biological applications like antimicrobial, anti-fungal agent, better gene and drug delivery agent with low cytotoxicity and biodegradability, which makes them more advantageous for a number of technological processes and hence reduces the impact of these gemini surfactants on the environment. PMID- 28800976 TI - Genome characterization, antigenicity and pathogenicity of a novel infectious bronchitis virus type isolated from south China. AB - In 2014, three infectious bronchitis virus (IBV) strains, designated as gammaCoV/ck/China/I0111/14, gammaCoV/ck/China/I0114/14 and gammaCoV/ck/China/I0118/14, were isolated and identified from chickens suspected to be infected with IBV in Guangxi province, China. Based upon data arising from S1 sequence and phylogenetic analyses, the three IBV isolates were genetically different from other known IBV types, which represented a novel genotype (GI-29). Virus cross-neutralization tests, using gammaCoV/ck/China/I0111/14 as a representative, showed that genotype GI-29 was antigenically different from all other known IBV types, thus representing a novel serotype. Complete genomic analysis showed that GI-29 type viruses were closely related to and might originate from a GX-YL5-like virus by accumulation of substitutions in multiple genes. These GI-29 viral genomes are still evolving and diverging, particularly in the 3' region, although we cannot rule out the possibility of recombination events occurring. For isolate gammaCoV/ck/China/I0114/14, we found that recombination events had occurred between nsps 2 and 3 in gene 1 which led to the introduction of a 4/91 gene fragment into the gammaCoV/ck/China/I0114/14 viral genome. In addition, we found that the GI-29 type gammaCoV/ck/China/I0111/14 isolate was a nephropathogenic strain and high pathogenic to 1-day-old specific pathogen-free (SPF) chickens although cystic oviducts were not observed in the surviving layer chickens challenged with gammaCoV/ck/China/I0111/14 isolate. PMID- 28800975 TI - Exopolysaccharides from Lactobacillus delbrueckii OLL1073R-1 modulate innate antiviral immune response in porcine intestinal epithelial cells. AB - Previous studies demonstrated that the extracellular polysaccharides (EPSs) produced by Lactobacillus delbrueckii OLL1073R-1 (LDR-1) improve antiviral immunity, especially in the systemic and respiratory compartments. However, it was not studied before whether those EPSs are able to beneficially modulate intestinal antiviral immunity. In addition, LDR-1-host interaction has been evaluated mainly with immune cells while its interaction with intestinal epithelial cells (IECs) was not addressed before. In this work, we investigated the capacity of EPSs from LDR-1 to modulate the response of porcine IECs (PIE cells) to the stimulation with the Toll-like receptor (TLR)-3 agonist poly(I:C) and the role of TLR2, TLR4, and TLR negative regulators in the immunoregulatory effect. We showed that innate immune response triggered by TLR3 activation in porcine IECs was differentially modulated by EPS from LDR-1. EPSs treatment induced an increment in the expression of interferon (IFN)-alpha and IFN-beta in PIE cells after the stimulation with poly(I:C) as well as the expression of the antiviral factors MxA and RNase L. Those effects were related to the reduced expression of A20 in EPS-treated PIE cells. EPS from LDR-1 was also able to reduce the expression of IL-6 and proinflammatory chemokines. Although further in vivo studies are needed, our results suggest that these EPSs or a yogurt fermented with LDR-1 have potential to improve intestinal innate antiviral response and protect against intestinal viruses. PMID- 28800977 TI - Severe Noncardiac Chest Pain Responds to Interdisciplinary Chronic Pain Rehabilitation. PMID- 28800978 TI - Modelling landscape dynamics with LST in protected areas of Western Ghats, Karnataka. AB - Forest ecosystems sustain biota on the earth as they are habitat to diverse biotic species, arrests soil erosion, play a crucial role in water cycle, sequester carbon, and helps in mitigating the impacts of global warming. Large scale land use land cover (LULC) change leading to deforestation is one of the drivers of global climate changes and alteration of biogeochemical cycles with significant consequences in ecosystem services and biodiversity. This has necessitated the investigation of LULC by mapping, monitoring and modelling spatio-temporal patterns and evaluating these in the context of human-environment interactions. The current work investigates LULC changes with temperature dynamics of select protected areas in Western Ghats. The land use analyses reveal changes in the forest cover across Kudremukh National Park (KNP), Rajiv Gandhi Tiger Reserve (RTR), Bandipur Tiger Reserve (BTR). KNP region has lost evergreen forest cover during 1973-2016 from 33.46 to 27.22%, while BTR lost deciduous cover from 61.69 to 47.3% due to mining, horticulture plantations, human habitations, etc. The LST increase has impacted regeneration of species with the induced water stress, etc. CA-Markov modelling was used for forecasting the likely land uses in 2026 and validation was done through Kappa indices. Results highlight decline of evergreen cover in KNP (9%) and deciduous cover in RTR (2%) followed by BTR (3%) with further expansion of plantations, which will impact biodiversity, hydrology and ecology. Insights of LULC dynamics help natural resource managers in evolving appropriate strategies to ensure conservation of threatened biota in Western Ghats. PMID- 28800979 TI - Advancing Cerebral Oximetry Research One Small Step at a Time. PMID- 28800980 TI - Pain in the ICU; Can We Adequately Treat What We Can't Hear? PMID- 28800981 TI - Near-Infrared Spectroscopy in Adult Cardiac Surgery Patients: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: To identify the normal baseline preoperative range of cerebral tissue oxygen saturation (SctO2) derived using near-infrared spectroscopy (NIRS) and the efficacy of perioperative interventions designed to modulate SctO2 in cardiac surgical patients. DESIGN: Systematic review and meta-analysis of relevant randomized controlled trials (RCTs) extracted from the Medline, Embase, and Cochrane Central Register of Controlled Trials databases. SETTING: Hospitals performing cardiac surgery. PARTICIPANTS: The study comprised 953 participants from 11 RCTs. INTERVENTIONS: Interventions included the following: (1) SctO2 monitoring protocol compared with no monitoring; (2) use of cardiopulmonary bypass (CPB) compared with no CPB; (3) normothermic CPB compared with hypothermic CPB; (4) glyceryl trinitrate during surgery compared with placebo; (5) midazolam during induction of anesthesia compared with propofol; (6) sevoflurane anesthesia compared with total intravenous anesthesia; (7) sevoflurane anesthesia compared with propofol-based anesthesia; and (8) norepinephrine during CPB compared with phenylephrine. MEASUREMENTS AND MAIN RESULTS: Eleven RCTs with 953 participants measured baseline preoperative SctO2 using NIRS. The pooled mean baseline SctO2 was 66.4% (95% CI 65.0-67.7), generating a reference range of 51.0% to 81.8%. Four interventions (1, 3, 4, and 6 described in the Interventions section above) increased intraoperative SctO2 across the majority of reported time points. Postoperative follow-up of SctO2 occurred in only 1 study, and postoperative cognitive assessment correlating SctO2 with cognitive function was applied in only 4 studies using variable methodology. CONCLUSIONS: The authors have established that reference values for baseline NIRS-derived SctO2 in cardiac surgery patients are varied and have identified interventions that modulate SctO2. This information opens the door to standardized research and interventional studies in this field. PMID- 28800982 TI - Pain Measurement in Mechanically Ventilated Patients After Cardiac Surgery: Comparison of the Behavioral Pain Scale (BPS) and the Critical-Care Pain Observation Tool (CPOT). AB - OBJECTIVES: The Behavioral Pain Scale (BPS) and Critical-Care Pain Observation Tool (CPOT) are behavioral pain assessment tools for sedated and unconscious critically ill patients. The aim of this study was to compare the reliability, internal consistency, and discriminant validation of the BPS and the CPOT simultaneously in mechanically ventilated patients after cardiac surgery. DESIGN: A prospective, observational cohort study. SETTING: A 20-bed closed-format intensive care unit with mixed medical, surgical, and cardiac surgery patients in a teaching hospital in Amsterdam, The Netherlands. PARTICIPANTS: The study comprised 72 consecutive intubated and mechanically ventilated patients after cardiac surgery who were not able to self-report pain. MEASUREMENTS AND MAIN RESULTS: Two nurses assessed the BPS and CPOT simultaneously and independently at the following 4 moments: rest, a nonpainful procedure (oral care), rest, and a painful procedure (turning). Both scores showed a significant increase of 2 points between rest and turning. The median BPS score of nurse 1 showed a significant increase of 1 point between rest and the nonpainful procedure (oral care), whereas both median CPOT scores did not change. The interrater reliability of the BPS and CPOT showed fair-to-good agreement of 0.74 overall. During the periods of rest 1 and rest 2, values ranged from 0.24 to 0.46. Cronbach's alpha values for the BPS were 0.62 (nurse 1) and 0.59 (nurse 2) compared with 0.65 and 0.58, respectively, for the CPOT. CONCLUSIONS: The BPS and CPOT are reliable and valid pain assessment tools in a daily clinical setting. However, the discriminant validation of both scores seems less satisfactory in sedated or agitated patients and this topic requires further investigation. PMID- 28800983 TI - Gastrointestinal Complications After Cardiac Surgery: A Nationwide Population Based Analysis of Morbidity and Mortality Predictors. AB - OBJECTIVE: The authors aimed to evaluate the incidence, risk factors, and outcomes of gastrointestinal (GI) complications in cardiac and aortic surgery using recent versions of the National (Nationwide) Inpatient Sample (NIS) to provide clinicians with a better understanding of these uncommon but potentially serious complications. DESIGN: Population-based study. SETTING: NIS database 2010 2012. PARTICIPANTS: Patients undergoing cardiac and aortic aneurysm repair surgeries. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: The most common GI complication was postoperative ileus, which also had the lowest mortality, followed by GI hemorrhage. Mesenteric ischemia demonstrated the highest mortality, followed by intestinal perforation. Mortality was highest in those with infective endocarditis (16.02%), followed by myocardial infarction (12.48%). GI complications were highest in patients undergoing repair of abdominal aortic aneurysm, followed by off-pump coronary artery bypass grafting. CONCLUSION: In conclusion, this study demonstrated that GI complications after cardiac surgery occurred at a rate of 4.17%, which is similar to that reported in the NIS database from 1998 to 2002 in coronary artery bypass grafting patients, but higher than that previously described in single-center studies. GI complications after cardiac surgery increased inpatient mortality 3-fold and more than doubled length of stay. Improved recognition and understanding of the predisposing risk factors and complications elucidated in this study could serve to increase the necessity for timely diagnosis and treatment of patients at high risk for GI complications after cardiac surgery. PMID- 28800984 TI - Identifying Predictors of Gastrointestinal Complications After Cardiovascular Surgery: How Do We Digest the Data? PMID- 28800986 TI - Are Transthoracic and Transesophageal Echocardiography Equal "PARTNERS" in the Assessment of Paravalvular Leak After TAVR? PMID- 28800985 TI - Assessment of Paravalvular Leak After Transcatheter Aortic Valve Replacement: Transesophageal Echocardiography Compared With Transthoracic Echocardiography. AB - OBJECTIVES: Determine whether moderate or greater paravalvular leak (PVL) after transcatheter aortic valve replacement quantified using intraoperative transesophageal echocardiography (TEE) is associated with mortality and investigate the correlation between PVL grading using intraoperative TEE and postoperative transthoracic echocardiography (TTE). DESIGN: Retrospective, observational study. SETTING: Single academic institution. PARTICIPANTS: The study comprised adult patients undergoing elective transcatheter aortic valve replacement between April 2011 and February 2014. INTERVENTIONS: Patients were grouped by amount of PVL on intraoperative TEE into "significant" (moderate or greater) and "nonsignificant" (no, trivial, or mild) PVL groups. Demographics and patient characteristics were compared. Continuous variables were assessed with t tests or Wilcoxon rank sum tests and categorical variables with the chi-square or Fisher exact test. A Cox proportional hazards model adjusted for EuroSCORE was used to test the independent association of PVL with late mortality, and covariate-adjusted survival curves were constructed. A Fleiss-Cohen-weighted kappa value was used to assess agreement between PVL grading using intraoperative TEE and postoperative TTE. MEASUREMENTS AND MAIN RESULTS: One hundred ninety-six patients were grouped into the "significant" (n = 22) or "nonsignificant" (n = 174) PVL group. Twenty patients (10%) died during the follow-up period. Significant PVL on either TTE (p = 0.62, hazard ratio 1.68, 95% confidence interval [CI] 0.22-12.85) or TEE (p = 0.49, hazard ratio 0.49; 95% CI 0.06-3.68) was not associated with a survival difference. Modest agreement was found between PVL on intraoperative TEE and postoperative TTE (kappa = 0.47, CI 0.37-0.57, p < 0.0001). CONCLUSIONS: Larger studies are needed to evaluate the association of PVL graded on intraoperative TEE with survival. There is modest agreement between the degree of PVL found on TEE and TTE. PMID- 28800987 TI - Dynamic Three-Dimensional Geometry of the Aortic Valve Apparatus-A Feasibility Study. AB - OBJECTIVE: To provide (1) an overview of the aortic valve (AV) apparatus anatomy and nomenclature, and (2) data regarding the normal AV apparatus geometry and dynamism during the cardiac cycle obtained from three-dimensional transesophageal echocardiography (3D TEE). DESIGN: Retrospective feasibility study. SETTING: A single-center university teaching hospital. PARTICIPANTS: The study was performed on data of 10 patients with a nonregurgitant, nonstenotic aortic valve undergoing cardiac surgery. INTERVENTIONS: Intraoperative 3D TEE was performed on all the participants using the Siemens ACUSON SC2000 ultrasound system and Z6Ms transducer (Siemens Medical Systems, Mountainview, CA). MEASUREMENTS AND MAIN RESULTS: Dynamic offline analyses were performed with Siemens eSie valve analytical software in a semiautomated fashion. Forty-five parameters were exported of which 13 were selected and analyzed. The cardiac cycle was divided into 4 quartiles to account for frame-rate variations. The annulus, sinus of Valsalva (SoV) and sinotubular junction (STJ) areas, diameter, perimeter and height, aortic leaflet height, leaflet coaptation height, and aortic valve-mitral valve angle changed significantly during the cardiac cycle (p < 0.001). STJ expanded more than both the annulus and the SoV (p < 0.001). The maximum aortic valve leaflet height change was greater in the left and right versus noncoronary leaflet (p < 0.001). CONCLUSIONS: The semiautomated AV apparatus dynamic assessment using eSie valve software is a clinically feasible technique and can be performed readily in the operating room. It has the potential to significantly impact intraoperative decision-making in cases suitable for AV repair. The AV apparatus is a dynamic structure and demonstrates significant changes during the cardiac cycle. PMID- 28800988 TI - 3D Geometry of the Aortic Valve: The Future of Aortic Valve Repair or Just Another Measurement? PMID- 28800989 TI - A Prospective Comparison of Intraluminal and Extraluminal Placement of the 9 French Arndt Bronchial Blocker in Adult Thoracic Surgery Patients. AB - OBJECTIVE: To compare the standard intraluminal approach with the placement of the 9-French Arndt endobronchial blocker with an extraluminal approach by measuring the time to positioning and other relevant intraoperative and postoperative parameters. DESIGN: A prospective, randomized, controlled trial. SETTING: University hospital. PARTICIPANTS: The study comprised 41 patients (20 intraluminal, 21 extraluminal) undergoing thoracic surgery. INTERVENTION: Placement of a 9-French Arndt bronchial blocker either intraluminally or extraluminally. Comparisons between the 2 groups included the following: (1) time for initial placement, (2) quality of isolation at 1-hour intervals during one lung ventilation, (3) number of repositionings during one-lung ventilation, and (4) presence or absence of a sore throat on postoperative days 1 and 2 and, if present, its severity. MEASUREMENTS AND MAIN RESULTS: Median time to placement (min:sec) in the extraluminal group was statistically faster at 2:42 compared with 6:24 in the intraluminal group (p < 0.05). Overall quality of isolation was similar between groups, even though a significant number of blockers in both groups required repositioning (extraluminal 47%, intraluminal 40%, p > 0.05), and 1 blocker ultimately had to be replaced intraoperatively. No differences in the incidence or severity of sore throat postoperatively were observed. CONCLUSIONS: A statistically significant reduction in time to placement using the extraluminal approach without any differences in the rate of postoperative sore throat was observed. Whether placed intraluminally or extraluminally, a significant percentage of Arndt endobronchial blockers required at least one intraoperative repositioning. PMID- 28800990 TI - Thinking Outside the Tube: Expanding the Armamentarium of the Thoracic Anesthesiologist. PMID- 28800991 TI - Supraglottic Airway Device for Transbronchial Lung Cryobiopsy. PMID- 28800992 TI - New Approaches to Airway Management in Tracheal Resections-A Systematic Review and Meta-analysis. AB - OBJECTIVES: Although endotracheal intubation, surgical crossfield intubation, and jet ventilation are standard techniques for airway management in tracheal resections, there are also reports of new approaches, ranging from regional anesthesia to extracorporeal support. The objective was to outline the entire spectrum of new airway techniques. DESIGN: The literature databases PubMed/Medline and the Cochrane Library were searched systematically for prospective and retrospective trials as well as case reports on tracheal resections. SETTING: No restrictions applied to hospital types or settings. PARTICIPANTS: Adult patients undergoing surgical resections of noncongenital tracheal stenoses with end-to-end anastomoses. INTERVENTIONS: Airway management techniques were divided into conventional and new approaches and analyzed regarding their potential risks and benefits. MEASUREMENTS AND MAIN RESULTS: A total of 59 publications (n = 797 patients) were included. The majority of publications (71.2%) describe conventional airway techniques. Endotracheal tube placement after induction of general anesthesia and surgical crossfield intubation after incision of the trachea were used most frequently without major complications. A total of 7 new approaches were identified, including 4 different regional anesthetic techniques (25 cases), supraglottic airways (4 cases), and new forms of extracorporeal support (25 cases). Overall failure rates of new techniques were low (1.8%). Details on patient selection and procedural specifics are provided. CONCLUSIONS: New approaches have several theoretical benefits, yet further research is required to establish criteria for patient selection and evaluate procedural safety. Given the low level of evidence, it currently is impossible to compare methods of airway management regarding outcome-related risks and benefits. PMID- 28800993 TI - Bridging the Educational Gap in Thoracic Anesthesia. PMID- 28800994 TI - Perioperative Management of Endovascular Thoracoabdominal Aortic Aneurysm Repair. PMID- 28800995 TI - Cardiovascular Anesthesia and Critical Care Services in the Federal Democratic Republic of Nepal. PMID- 28800996 TI - Con: Preinduction Pulmonary Artery Catheter Placement Is Advisable in Patients With Right Ventricular Dysfunction Secondary to Severe Pulmonary Hypertension. PMID- 28800997 TI - Palliative Care and Human Rights: A Decade of Evolution in Standards. AB - CONTEXT: Human rights standards to address palliative care have developed over the last decade. OBJECTIVES: This article aims to examine key milestones in the evolution of human rights standards to address palliative care, relevant advocacy efforts, and areas for further growth. METHODS: The article provides an analysis of human rights standards in the context of palliative care through the lens of the right to health, freedom from torture and ill treatment, and the rights of older persons and children. RESULTS: Significant developments include the following: 1) the first human rights treaty to explicitly recognize the right to palliative care, the Inter-American Convention on the Rights of Older Persons; 2) the first World Health Assembly resolution on palliative care; 3) a report by the UN Special Rapporteur on Torture with a focus on denial of pain treatment; 4) addressing the availability of controlled medicines at the UN General Assembly Special Session on the World Drug Problem. CONCLUSION: Development of human rights standards in relation to palliative care has been most notable in the context of the right to health, freedom from torture and ill treatment, and the rights of older persons. More work is needed in the context of the rights of children, and human rights treaty bodies are still not consistently addressing state obligations with regards to palliative care. PMID- 28800998 TI - International Children's Palliative Care Network: A Global Action Network for Children With Life-Limiting Conditions. AB - The International Children's Palliative Care Network (ICPCN) is a global network of individuals and organizations working together to reach the estimated 21 million children with life-limiting conditions and life-threatening illnesses. The drive to establish the ICPCN was born from the recognition of the gaps in service provision for children's palliative care and the need to collaborate, network, and share resources. Established in 2005 during a meeting in Seoul, South Korea, the ICPCN has developed over the years into an established network with a global membership. The history of the organization is described, including some of the key events since its inception. Working in collaboration with others, ICPCN has five key focus areas: Communication; Advocacy; Research; Education; and Strategic development, and is the only international charity working globally for the rights of children with palliative care needs. Activities in these areas are discussed, along with the inter-connection between the five areas. Without the ICPCN, palliative care for children would not have developed as far as it has over the years and the organization is committed to ongoing work in this area until all children requiring palliative care have access to quality services, wherever they live around the world. PMID- 28800999 TI - Promoting Palliative Care Internationally: Building Leaders to Promote Education, Practice, and Advocacy. AB - In February 2000, nine nursing educators, practitioners, and researchers met in Nashville, Tennessee, to develop a palliative care curriculum specifically for nurses. The following month, 22 advisors from nursing organizations across the United States convened in Washington, DC to review the recommended curriculum development and dissemination plans for end-of-life care throughout nursing schools, hospitals, hospices, home care, and geriatric settings. The Robert Wood Johnson Foundation provided funding for curriculum and competency development and for six national train-the-trainer courses to be held from 2001 to 2003. The curriculum entitled the End-of-Life Nursing Education Consortium was designed to meet the needs of nurses caring for patients with serious and complex illnesses at the end of their lives. This work, beginning in 2000 with the development of the End-of-Life Nursing Education Consortium curriculum, has been taught in every state across America and in 91 countries around the world and has been translated into eight languages. Over 21,400 trainers have returned to their institutions and educated over 642,000 colleagues. PMID- 28801000 TI - Palliative Care Development in Ukraine. PMID- 28801001 TI - Effects of a Home-Based Palliative Heart Failure Program on Quality of Life, Symptom Burden, Satisfaction and Caregiver Burden: A Randomized Controlled Trial. AB - CONTEXT: Provision of home-based palliative care (PC) for seriously ill patients is important, yet few home-based PC services specifically or exclusively focus on end-stage heart failure (ESHF) patients. OBJECTIVES: This study aimed to examine the effect of a home-based palliative heart failure (HPHF) program on quality of life (QOL), symptoms burden, functional status, patient satisfaction, and caregiver burden among patients with ESHF. METHODS: This study was a two-group randomized controlled trial undertaken in three hospitals. We recruited a total of 84 hospitalized ESHF patients who were referred to PC. They were randomized to the intervention or control group. The intervention group received a 12-week structured program with regular home visits/telephone calls provided by the nurse case managers. Data were collected at baseline (T1) and at four (T2) and 12 weeks (T3) after discharge. RESULTS: A statistically significant between-group effect was found, with the HPHF group having significantly higher McGill QOL total score than the control group (P = 0.016) and there was significant group * time interaction effect (P = 0.032). There was no significant between-group effects detected for the measures of symptom distress or functional status at 12 weeks. The intervention group had higher satisfaction (P = 0.001) and lower caregiver burden (P = 0.024) than the control group at 12 weeks. CONCLUSION: The HPHF program is effective in enhancing the QOL of ESHF patients, satisfaction with care, and caregiver burden. The program has potential to reduce distress for some of the symptoms. PMID- 28801002 TI - Legal Support for Palliative Care Patients. AB - CONTEXT: Palliative care patients face legal issues that impact their quality of life. Legal support, embedded in holistic palliative care services, has developed globally over the last decade to address this. OBJECTIVES: This article aims to trace the origins of legal support for palliative care patients, detail models of legal support, and describe achievements and challenges. METHODS: The article draws on years of work in this area and the available literature. RESULTS: Common legal issues include disposing of property and drafting wills, planning for children, dealing with debt and securing social benefits, and addressing discrimination. Diverse approaches to integrating legal support include developing paralegal skills, accessing skilled legal advice, empowering patients and families, and building awareness of rights among health care workers. CONCLUSION: There is robust and growing acceptance of legal support as a key component of holistic palliative care, and many palliative care professionals are identifying and addressing the legal needs they encounter through mediation, guidance on basic rights, or referrals to a lawyer. Addressing legal problems can contribute to peace of mind, well-being, and the health of patients. PMID- 28801003 TI - World Health Organization Public Health Model: A Roadmap for Palliative Care Development. AB - The Open Society Foundation's International Palliative Care Initiative (IPCI) began to support palliative care development in Central and Eastern Europe and the Former Soviet Union in 1999. Twenty-five country representatives were invited to discuss the need for palliative care in their countries and to identify key areas that should be addressed to improve the care of adults and children with life-limiting illnesses. As a public health concern, progress in palliative care requires integration into health policy, education and training of health care professionals, availability of essential pain relieving medications, and health care services. IPCI created the Palliative Care Roadmap to serve as a model for government and/or nongovernment organizations to use to frame the necessary elements and steps for palliative care integration. The roadmap includes the creation of multiple Ministry of Health-approved working groups to address: palliative care inclusion in national health policy, legislation, and finance; availability of essential palliative care medications, especially oral opioids; education and training of health care professionals; and the implementation of palliative care services at home or in inpatient settings for adults and children. Each working group is tasked with developing a pathway with multiple signposts as indicators of progress made. The roadmap may be entered at different signposts depending upon the state of palliative care development in the country. The progress of the working groups often takes place simultaneously but at variable rates. Based on our experience, the IPCI Roadmap is one possible framework for palliative care development in resource constrained countries but requires both health care professional engagement and political will for progress to be made. PMID- 28801004 TI - The Palliative Care Journey in Kenya and Uganda. AB - Palliative care is an approach that improves the quality of life of patients and their families facing the problems associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other physical, psychosocial, and spiritual problems. This update is aimed at examining palliative care development/achievements and challenges in Kenya and Uganda and the role of various actors in palliative care establishment in the region. It assesses the policy environment, progress in education, access to essential medicines, palliative care implementation efforts, and legal and human rights work. East African nations have huge disease burdens, both communicable and noncommunicable. HIV and cancer are the major causes of mortality in Kenya and Uganda and put huge demands on the health care system and on the country's economies. All these conditions will require palliative care services as the disease burden increases. Unfortunately, for many African countries, accessing palliative care services, including access to pain relief, remains very limited resulting in serious suffering for patients and their families. The interventions in Kenya and Uganda help palliative care organizations engage with their respective governments to ensure that the social and legal barriers impeding access to palliative care services are removed. PMID- 28801005 TI - Pain and Policy Studies Group: Two Decades of Working to Address Regulatory Barriers to Improve Opioid Availability and Accessibility Around the World. AB - For two decades, the Pain & Policy Studies Group (PPSG), a global research program at the University of Wisconsin Carbone Cancer Center, has worked passionately to fulfill its mission of improving pain relief by achieving balanced access to opioids worldwide. PPSG's early work highlighted the conceptual framework of balance leading to the development of the seminal guidelines and criteria for evaluating opioid policy. It has collaborated at the global level with United Nations agencies to promote access to opioids and has developed a unique model of technical assistance to help national governments assess regulatory barriers to essential medicines for pain relief and amend existing or develop new legislation that facilitates appropriate and adequate opioid prescribing according to international standards. This model was initially applied in regional workshops and individual country projects and then adapted for PPSG's International Pain Policy Fellowship, which provides long-term mentoring and support for several countries simultaneously. The PPSG disseminates its work online in several ways, including an extensive Web site, news alerts, and through several social media outlets. PPSG has become the focal point for expertise on policy governing drug control and medicine and pharmacy practice related to opioid availability and pain relief. PMID- 28801006 TI - Palliative Care in Kazakhstan. AB - In Kazakhstan, like most ex-Soviet Union countries palliative care began in the late 1990s with the opening of the Almaty Hospice in 1999. Since that time, several palliative care services have opened in urban centers, but there is little coverage in rural areas. Palliative care has grown because of the collaborative work of Parliament leaders, Ministry of Health, local governments officials, Public Health Higher School, National Center for Health Development, academic medical institutions, oncology and palliative care experts, NGOs, Soros Foundation Kazakhstan, and international experts. A National Palliative Care Strategy provides the legislative framework that mandates the components of palliative that must be available at no cost for patients living with cancer. Palliative care courses are provided in several of the medical universities and nursing schools with practical training in local hospices who also offer seminars each year to practicing health care professionals. There is no "palliative care" or "palliative medicine" specialty in the national classifier of specialties. There are a number of palliative care specialists who participated in various training courses outside Kazakhstan. Oral morphine is not registered or available in the country, and patients must depend on injectable opioids or patches. Going forward, additional policies, increased public awareness, education of health care professionals, access to oral opioids, and more inpatient, home care, and day care services are needed. PMID- 28801007 TI - A Survey to Evaluate Facilitators and Barriers to Quality Measurement and Improvement: Adapting Tools for Implementation Research in Palliative Care Programs. AB - CONTEXT: Although critical for improving patient outcomes, palliative care quality indicators are not yet widely used. Better understanding of facilitators and barriers to palliative care quality measurement and improvement might improve their use and program quality. OBJECTIVES: Development of a survey tool to assess palliative care team perspectives on facilitators and barriers to quality measurement and improvement in palliative care programs. METHODS: We used the adapted Consolidated Framework for Implementation Research to define domains and constructs to select instruments. We assembled a draft survey and assessed content validity through pilot testing and cognitive interviews with experts and frontline practitioners for key items. We analyzed responses using a constant comparative process to assess survey item issues and potential solutions. We developed a final survey using these results. RESULTS: The survey includes five published instruments and two additional item sets. Domains include organizational characteristics, individual and team characteristics, intervention characteristics, and process of implementation. Survey modules include Quality Improvement in Palliative Care, Implementing Quality Improvement in the Palliative Care Program, Teamwork and Communication, Measuring the Quality of Palliative Care, and Palliative Care Quality in Your Program. Key refinements from cognitive interviews included item wording on palliative care team members, programs, and quality issues. CONCLUSION: This novel, adaptable instrument assesses palliative care team perspectives on barriers and facilitators for quality measurement and improvement in palliative care programs. Next steps include evaluation of the survey's construct validity and how survey results correlate with findings from program quality initiatives. PMID- 28801008 TI - The course of quality of life and neurocognition in newly diagnosed patients with glioblastoma. AB - BACKGROUND: The importance of QoL and neurocognitive functions in patients with glioblastoma (GB) is above controversy by now. We followed newly diagnosed GB patients treated with radio-chemotherapy during their course of disease by continuously evaluating their quality of life (QoL) and cognitive functions. METHODS: We included consecutive patients with newly diagnosed GB from 2010 to 2013 at the Medical University of Vienna. To assess QoL the EORTC QLQ C30 and BN20 questionnaire were used. Neurocognition was measured with the NeuroCog FX. The evaluations were done 6 times every three months, beginning at the beginning of radio-chemotherapy. RESULTS: 42 patients participated in this study. We also recorded QoL and neurocognition in 23 patients after the first disease progression. Patients maintained their cognitive summary score until relapse. Patients with left-sided tumors showed significant lower scores in the subscale verbal fluency than patients with right-sided tumors. The global health score of QoL decreased after the fifth evaluation (13months after diagnosis) whereas a peak of fatigue symptoms was obtained at the third evaluation. Furthermore, fatigue symptoms increased strongly 7months after diagnosis and patients' financial difficulties were mentioned more frequently by younger patients and in patients with lower education levels. CONCLUSIONS: QoL and cognitive long-term assessments are feasible also in some patients with GB after a symptomatic progression. Our study demonstrates maintenance of QoL and cognitive summary scales before tumor progression. Moreover, it highlights subgroups according to tumor location and socioeconomic factors. PMID- 28801009 TI - Management of Radiation Side Effects to the Skin. AB - Radiation therapy (RT) is an essential component for management of many cancers. Veterinary health care professionals must counsel owners about the potential side effects of RT, the anticipated management plan, and associated costs. For most veterinary patients treated with RT, acute radiation side effects are mild; however, careful radiation treatment planning and appropriate management of acute side effects are essential to try to prevent chronic sequelae and the need for ongoing wound care. This article reviews acute and late side effects to the skin and their management. PMID- 28801010 TI - Corrigendum to "Salivary levels of nickel, chromium, iron, and copper in patients treated with metal or esthetic fixed orthodontic appliances: A retrospective cohort study" [J. Trace Elem. Med. Biol. 40 (2017) 67-71]. PMID- 28801011 TI - Paraneoplastic Pemphigus. A Life-Threatening Autoimmune Blistering Disease. AB - Paraneoplastic pemphigus (PNP), a subset of pemphigus, is a unique autoimmune blistering condition that can affect multiple organs other than the skin. It is a life-threatening disease associated with an underlying malignancy, most commonly of lymphoproliferative origin. The clinical picture may resemble pemphigus, pemphigoid, erythema multiforme, graft-versus-host disease, or lichen planus. The earliest and most consistent finding is a painful, severe, chronic and often recalcitrant stomatitis. Treatment of PNP is difficult. Immunosuppressive agents are required to decrease blistering, and treating the underlying tumor may control autoantibody production. In this review, we included essential diagnostic aspects of PNP and the most useful treatment options in the dermatologist practice. PMID- 28801013 TI - Psoriasis Protects Against a Low Minimal Erythema Dose. PMID- 28801012 TI - Use of Lymph Node Ultrasound Prior to Sentinel Lymph Node Biopsy in 384 Patients with Melanoma: A Cost-Effectiveness Analysis. AB - BACKGROUND AND OBJECTIVES: Locoregional lymph node ultrasound is not typically included in guidelines as part of the staging process prior to sentinel lymph node biopsy (SLNB). The objective of the present study was to make a clinical and economic analysis of lymph node ultrasound prior to SLNB. MATERIALS AND METHODS: We performed a retrospective study of 384 patients with clinical stage I-II primary melanoma who underwent locorregional lymph node ultrasound (with or without ultrasound-guided biopsy) prior to SLNB between 2004 and 2015. We evaluated the reliability and cost-effectiveness of the strategy. RESULTS: Use of locorregional lymph node ultrasound avoided SLNB in 23 patients (6%). Ultrasound had a sensitivity of 46% and specificity of 76% for the detection of metastatic lymph nodes that were not clinically palpable. False negatives were significantly more common in patients aged over 60 years and in tumors with a thickness of less than 2mm. The staging process using SLNB and ultrasound with ultrasound-guided biopsy produced an increase of ?16.30 in the unit price. Our cost-effectiveness analysis identified the staging protocol with ultrasound and SLNB as the dominant strategy, with a lower cost-effectiveness ratio than the alternative, consisting of SLNB alone (8,095.24 vs. ?28,605.00). CONCLUSIONS: Ultrasound with ultrasound guided biopsy for the diagnostic staging of melanoma prior to SLNB is a useful and cost-effective tool. This procedure does not substitute SLNB, though it does allow to avoid SLNB in a not insignificant proportion of patients. PMID- 28801014 TI - Addressing the Nation's Opioid Epidemic: Lessons from an Unsanctioned Supervised Injection Site in the U.S. PMID- 28801015 TI - Food allergen extracts to diagnose food-induced allergic diseases: How they are made. AB - OBJECTIVE: To review the manufacturing procedures of food allergen extracts and applicable regulatory requirements from government agencies, potential approaches to standardization, and clinical application of these products. The effects of thermal processing on allergenicity of common food allergens are also considered. DATA SOURCES: A broad literature review was conducted on the natural history of food allergy, the manufacture of allergen extracts, and the allergenicity of heated food. Regulations, guidance documents, and pharmacopoeias related to food allergen extracts from the United States and Europe were also reviewed. STUDY SELECTIONS: Authoritative and peer-reviewed research articles relevant to the topic were chosen for review. Selected regulations and guidance documents are current and relevant to food allergen extracts. RESULTS: Preparation of a food allergen extract may require careful selection and identification of source materials, grinding, defatting, extraction, clarification, sterilization, and product testing. Although extractions for all products licensed in the United States are performed using raw source materials, many foods are not consumed in their raw form. Heating foods may change their allergenicity, and doing so before extraction may change their allergenicity and the composition of the final product. CONCLUSION: The manufacture of food allergen extracts requires many considerations to achieve the maximal quality of the final product. Allergen extracts for a select number of foods may be inconsistent between manufacturers or unreliable in a clinical setting, indicating a potential area for future improvement. PMID- 28801016 TI - Adult-onset food allergies. PMID- 28801017 TI - Uptake of EpiPen and Allerject (Auvi-Q) epinephrine auto-injectors in Manitoba children. PMID- 28801018 TI - Author's response. PMID- 28801019 TI - Drug-device interaction for systemic effects of fluticasone in patients with asthma. PMID- 28801020 TI - Author's response. PMID- 28801021 TI - Immunotherapy and systemic reactions. PMID- 28801022 TI - Understanding the biology of disease in underserved children with asthma: The missing piece of the health disparity puzzle. PMID- 28801023 TI - Thermoluminescence of metallic oxides. Development and applications in Mexico: An overview. AB - Interest in the study of the thermoluminescence of metallic oxides doped with various elements has been steadily increasing due to the characteristics of these materials and their possible applications in the dosimetry of ionizing radiation. Metal oxides such as zirconium oxide (ZrO2), aluminum oxide Al2O3, titanium oxide (TiO2), hafnium oxide (HfO2) and beryllium oxide (BeO) are very interesting semiconductor materials having a wide band gap with different important applications. Since 1998, in our country we have developed these materials un doped and doped with various elements, using different preparation methods. These materials have been obtained in powder form, thin films or in pellets made by mixing the TL powder with PTFE. Thermoluminescent and dosimetric characteristics of these materials have been studied and have been used successfully in various applications. It is presented an overview of the development of these materials in Mexico for the past 20 years. PMID- 28801024 TI - Understanding the role of SOCS signaling in neurodegenerative diseases: Current and emerging concepts. AB - Suppressor of cytokine signaling proteins (SOCS) are a family of intracellular cytokine inducible proteins, consisting of eight members. They are involved in the complex control of the inflammatory response through their actions on various signaling pathways, including the JAK/STAT and NF-kappaB pathways. A series of studies has shown that SOCS proteins are involved in the regulation and progression of immune responses in microglia cells. The accumulated data suggest that modulation of SOCS expression could be a target for drug development aimed at controlling inflammation in the brain. This review focuses on the current understanding of SOCS proteins involvement in inflammation-based neurodegenerative diseases and their role as therapeutic targets in future approaches. PMID- 28801025 TI - Toward an MRI-based nomogram for the prediction of transperineal prostate biopsy outcome: A physician and patient decision tool. AB - PURPOSE: To develop and internally validate a nomogram using biparametric magnetic resonance imaging (B-MRI)-derived variables for the prediction of prostate cancer at transperineal sector-guided prostate biopsy (TPSB). SUBJECTS/PATIENTS AND METHODS: Consecutive patients referred to our institution with raised prostate-specific antigen (PSA), abnormal prostate examination, or persistent suspicion of prostate cancer after previous transrectal biopsy between July 2012 and November 2015 were reviewed from a prospective database. All patients underwent prebiopsy B-MRI with T2-weighted and diffusion-weighted imaging sequences, followed by 24 to 40 core TPSB with additional targeted cores using cognitive registration. Univariable and multivariable logistic regression analysis was used to determine predictors of prostate cancer outcomes. Multivariable coefficients were used to construct 2 MRI-based nomograms to predict any and significant (Gleason 4 or maximum cancer core length >=6mm) prostate cancer at TPSB. Bootstrap resamples were used for internal validation. Accuracy was assessed by calculating the concordance index. RESULTS: In total, 615 men were included in the study. Prostate cancer was diagnosed in 317 (51.5%) men with significant cancer diagnosed in 237 (38.5%) men. Age, Prostate Imaging Reporting and Data System (PI-RADS) score, PSA, PSA density, and primary biopsy were predictors of prostate cancer at TPSB on univariable analysis (P<0.0001). PSA showed strong correlation with PSA density and was excluded. The remaining variables were all independent predictors of prostate cancer on multivariable analysis (P<0.0001) and used to generate the nomograms. Both nomograms showed good discrimination for prostate cancer, with a concordance index of 87% for any cancer and 92% for significant disease. Using a nomogram-derived probability threshold of<15%, 111 (18.0%) biopsies can be saved, at the expense of 3 missed significant prostate cancers. CONCLUSIONS: These internally validated MR-based nomograms were able to accurately predict TPSB outcomes for prostate cancer, especially significant disease. Our findings support the combination of prebiopsy MRI results and clinical factors as part of the biopsy decision-making process. PMID- 28801026 TI - Quadruple immunotherapy of Bacillus Calmette-Guerin, interferon, interleukin-2, and granulocyte-macrophage colony-stimulating factor as salvage therapy for non muscle-invasive bladder cancer. AB - BACKGROUND: Bacillus Calmette-Guerin (BCG) is the most effective initial intravesical therapy for high-grade non-muscle invasive bladder cancer, but many patients still fail. Combination intravesical BCG and interferon (IFN) will salvage some patients but results remain suboptimal. OBJECTIVE: We hypothesized that further immunostimulation with intravesical interleukin-2 and subcutaneous granulocyte-macrophage colony-stimulating factor may improve response to intravesical BCG and IFN in patient with prior BCG failure(s). METHODS: A retrospective review was performed. Patients received 6 treatments of quadruple immunotherapy (intravesical solution with one-third dose BCG, 50 million units IFN, and 22 million units interleukin-2, along with a 250-mcg subcutaneous sargramostim injection). Surveillance began 4 to 6 weeks after treatment completion. Patients received maintenance if recurrence-free. Success was defined as no recurrence (bladder or extravesical) and bladder preservation. Analysis was performed by Kaplan-Meier method (P<0.05). RESULTS: Fifty-two patients received treatment with a median recurrence follow-up of 16.3 months and overall follow-up of 41.8 months. All patients had at least 1 prior BCG failure and 13% had 2 or more prior failures. Only 3 patients (6%) were unable to tolerate full induction. Treatment success was 55% at 1 year, and 53% at 2 years. Thirteen patients (25%) underwent cystectomy at a median time of 17.3 months with disease progression to T2 in 1 patient and T3 in 2 patients. No patients had positive surgical margins or positive lymph nodes. CONCLUSIONS: In patients with non-muscle-invasive bladder cancer with prior BCG failure, quadruple immunotherapy demonstrated good treatment success in some patients and warrants further evaluation. PMID- 28801027 TI - Lymph node dissection should not be dismissed in case of localized renal cell carcinoma in the presence of larger diseases. AB - OBJECTIVE: To assess whether even in the group of localized renal cell carcinoma (RCC), some patients might harbor a disease with a predilection for lymph node invasion (LNI) and/or lymph node (LN) progression and might deserve lymph node dissection (LND) at the time of surgery. MATERIALS AND METHODS: Between 1990 and 2014, 2,010 patients with clinically defined T1-T2N0M0 RCC were treated with nephrectomy and standardized LND at a single tertiary care referral center. The endpoint consists of the presence of LNI and/or nodal progression, defined as the onset of a new clinically detected lymphadenopathy (>10mm) in the retroperitoneal lymphatic area with associated systemic progression or histological confirmation or both. We tested the association between clinical characteristics and the endpoint of interest. Predictors consisted of age at surgery, clinical tumor size, preoperative hemoglobin, and platelets levels. Multivariable logistic regression model and smoothed Lowess method were used. RESULTS: LNI was recorded in 14 cases (2.2%). The median follow-up after surgery was 68 months. During the study period, 23 patients (1.1%) experienced LN progression; 91% of those patients experienced LN progression within 3 years after surgery. Combining the 2 endpoints, 36 patients (1.8%) had LNI and/or LN progression. Clinical tumor size was the only independent predictors of LNI and/or LN progression (OR = 1.25). A significant increase of the risk of LNI and/or LN progression was observed in RCC larger than 7cm (cT2a or higher). CONCLUSIONS: LNI and/or LN progression is a rare entity in patients with localized RCC. Nonetheless, patients with larger tumors might still benefit from LND because of a non-negligible risk of LNI and/or LN progression. PMID- 28801028 TI - Convergent evolution of germ granule nucleators: A hypothesis. AB - Germ cells have been considered "the ultimate stem cell" because they alone, during normal development of sexually reproducing organisms, are able to give rise to all organismal cell types. Morphological descriptions of a specialized cytoplasm termed 'germ plasm' and associated electron dense ribonucleoprotein (RNP) structures called 'germ granules' within germ cells date back as early as the 1800s. Both germ plasm and germ granules are implicated in germ line specification across metazoans. However, at a molecular level, little is currently understood about the molecular mechanisms that assemble these entities in germ cells. The discovery that in some animals, the gene products of a small number of lineage-specific genes initiate the assembly (also termed nucleation) of germ granules and/or germ plasm is the first step towards facilitating a better understanding of these complex biological processes. Here, we draw on research spanning over 100years that supports the hypothesis that these nucleator genes may have evolved convergently, allowing them to perform analogous roles across animal lineages. PMID- 28801029 TI - Cardiovascular disease in familial hypercholesterolemia: Validation and refinement of the Montreal-FH-SCORE. AB - BACKGROUND: Familial hypercholesterolemia (FH) is a disease characterized by increased low-density lipoprotein cholesterol and premature cardiovascular disease (CVD) but there is marked individuality in the occurrence of CVD events. Recently, the Montreal-FH-SCORE (MFHS) has been shown to stratify CVD frequency in FH subjects, but this score has not yet been validated. OBJECTIVE: The aims of the present study were to conduct an independent external validation of the MFHS in a retrospective cohort of heterozygous FH and to identify additional variables that could significantly improve the prediction of prevalent CVD. METHODS: The MFHS calculation is based on 5 variables: age, high-density lipoprotein cholesterol, gender, hypertension, and smoking status. This score was validated in a cohort of 718 adult FH using receiver operating characteristic (ROC) curves analysis to determine the discriminatory ability of the MFHS. The performance of the MFHS was compared to a novel Combined-FH-SCORE in 1388 FH. RESULTS: The MFHS had an excellent discrimination for prevalent CVD events in the validation cohort, with an area under the receiver operating characteristic curve of 0.799 (0.766-0.832, P < .0001). Patients with a high MFHS score presented a significant 8.8-fold increased odd of CVD events compared with patients with a low score (95% confidence interval 5.8-13.3, P < .0001). The addition of lipoprotein(a) to the score did not improve the prediction of CVD events (area under the receiver operating characteristic curve 0.823 vs 0.817, P = .11). CONCLUSION: This study confirmed that the MFHS is a strong predictor of prevalent CVD in FH and that the addition of lipoprotein(a) offers a minor improvement in the discrimination of the score. PMID- 28801030 TI - Lipoprotein(a) screening in patients with controlled traditional risk factors undergoing percutaneous coronary intervention. AB - BACKGROUND: Lipoprotein(a) [Lp(a)] is an inherited atherogenic lipoprotein and an independent risk factor for atherosclerotic cardiovascular disease; however, its clinical role remains limited. OBJECTIVE: We hypothesized that Lp(a) screening in high cardiovascular risk patients could provide insight into disease pathogenesis and modify physician behavior for treatment intensification targeting traditional risk factors when Lp(a)-related risk was identified. METHODS: We screened 113 patients presenting electively for percutaneous coronary intervention (PCI) for Lp(a) who met any of the following criteria: (1) premature coronary artery disease (male age <55 years, female age <65 years); (2) family history of premature coronary artery disease; (3) progression to PCI despite well-controlled traditional risk factors (blood pressure <140/90 mm Hg, and low-density lipoprotein cholesterol <100 mg/dL, and HbA1c <7%, and nonsmoker); or (4) progression to PCI despite at least moderate intensity statin use (simvastatin 40, atorvastatin 40-80, or rosuvastatin 20-40 mg daily). RESULTS: In this high risk cohort, Lp(a) was elevated in nearly half of all subjects, including those with seemingly well-controlled lipids by prior guidelines, suggesting a role for Lp(a) in conferring residual cardiovascular risk. In our cohort, when screened positive, knowledge of an elevated Lp(a) did not influence referring physicians' treatment intensification targeting traditional modifiable cardiovascular risk factors (P = .18). CONCLUSION: When screened judiciously, elevated levels of Lp(a) are highly prevalent in high cardiovascular risk patients, including at a young age, presenting for PCI and may contribute to previously unappreciated residual cardiovascular risk. PMID- 28801031 TI - Substitution of doctors with physiotherapists in the management of common musculoskeletal disorders: a systematic review. AB - BACKGROUND: There is large variation in models-of-care involving the professional substitution of doctors with physiotherapists. OBJECTIVE: To establish the impact upon patients and health services, of substituting doctors with physiotherapists in the management of common musculoskeletal disorders. DATA SOURCES: Medline, CINAHL and ABI Complete databases, and hand-searching of related studies. STUDY SELECTION: Randomised and non-randomised clinical trials, inter-rater reliability and comparative studies comparing the outcomes of usual care from doctors, with outcomes when the doctor was substituted with a physiotherapist. STUDY APPRAISAL AND SYNTHESIS METHODS: Two reviewers evaluated all studies using the Downs and Black Instrument. Meta-analysis was not possible due to study heterogeneity. A descriptive review was undertaken. RESULTS: 14 studies of moderate to low quality met the inclusion criteria. Professional substitution with a physiotherapist causes no significant change to health outcomes and inconsistent variation in the use of healthcare resources. There is insufficient health economic data to determine overall efficiency. In the selected presentations studied, physiotherapists made similar diagnostic and management decisions to orthopaedic surgeons and patients are as, or more satisfied with a physiotherapist. LIMITATIONS: Further high quality health and economic research is needed, in less selective patient populations, to determine the optimal role for physiotherapists. CONCLUSION AND IMPLICATIONS OF KEY FINDINGS: Physiotherapists provide a professional alternative to doctors for musculoskeletal disorders but the health economic implications of this model are presently unclear. Systematic Review Registration Number PROSPERO (Registration number CRD42015027671). PMID- 28801032 TI - Physiotherapy for patients with shoulder pain in primary care: a descriptive study of diagnostic- and therapeutic management. AB - BACKGROUND: Shoulder pain is one of the three main musculoskeletal complaints and more than 50% of the patients have symptoms longer than 6 months. Until now, limited data exist about the content of physiotherapy for patients with shoulder pain in primary care. OBJECTIVE: Describe current physiotherapeutic diagnostic- and therapeutic management, including the use of diagnostic ultrasound, in patients with shoulder pain in primary care. DESIGN AND SETTING: A prospective cohort study in primary care physiotherapy with a 12 week follow-up. METHODS: Descriptive data from physiotherapists was collected, such as: the diagnostic hypotheses after patient history and physical examination, the use of specific tests and diagnostic ultrasound, the interventions used and possible changes in treatment plan. RESULTS: Subacromial impingement syndrome was the most common hypothesis after patient history (48%) as well as physical examination (39%). Diagnostic ultrasound was used in 31% and of these patients the clinical diagnosis changed in 29%. Various interventions were used in all clinical diagnoses. After 12 weeks 41% of patients still received physiotherapy treatment. CONCLUSIONS: Patients with shoulder pain in physiotherapy practice frequently show signs of subacromial impingement syndrome. The interventions used by the physiotherapists were generally in line with the guideline for subacromial impingement syndrome however a small proportion of physiotherapists used massage and tape/bracing techniques. A large proportion of patients were still receiving treatment after 12 weeks when no improvement was observed. If treatment for patients with subacromial impingement shows no benefit patients should be referred back to the general practitioner or orthopedic surgeon. Conclusions from this study might be slightly biased because of the selection of physiotherapists. PMID- 28801033 TI - Development and delivery of an exercise programme for falls prevention: the Prevention of Falls Injury Trial (PreFIT). AB - OBJECTIVE: This paper describes the development and implementation of an exercise intervention to prevent falls within The Prevention of Fall Injury Trial (PreFIT), which is a large multi-centred randomised controlled trial based in the UK National Health Service (NHS). DESIGN: Using the template for intervention description and replication (TIDieR) checklist, to describe the rationale and processes for treatment selection and delivery of the PreFIT exercise intervention. PARTICIPANTS: Based on the results of a validated falls and balance survey, participants were eligible for the exercise intervention if they were at moderate or high risk of falling. INTERVENTIONS: Intervention development was informed using the current evidence base, published guidelines, and pre-existing surveys of clinical practice, a pilot study and consensus work with therapists and practitioners. The exercise programme targets lower limb strength and balance, which are known, modifiable risk factors for falling. Treatment was individually tailored and progressive, with seven recommended contacts over a six month period. Clinical Trials Registry (ISCTRN 71002650). PMID- 28801034 TI - Impact of pelvic floor muscle training on sexual function of women with urinary incontinence and a comparison of electrical stimulation versus standard treatment (IPSU trial): a randomised controlled trial. AB - AIMS: To evaluate the clinical and cost-effectiveness of electric stimulation plus standard pelvic floor muscle training compared to standard pelvic floor muscle training alone in women with urinary incontinence and sexual dysfunction. METHODS: Single centre two arm parallel group randomised controlled trial conducted in a Teaching hospital in England. Participants were women presenting with urinary incontinence and sexual dysfunction. The interventions compared were electric stimulation versus standard pelvic floor muscle training. OUTCOME MEASURES: included Prolapse and Incontinence Sexual function Questionnaire (PISQ) physical function dimension at post-treatment (primary); other dimensions of PISQ, SF-36; EQ-5D, EPAQ, resource use, adverse events and cost-effectiveness (secondary outcomes). RESULTS: 114 women were randomised (Intervention n=57; Control group n=57). 64/114 (56%). PARTICIPANTS: had valid primary outcome data at follow-up (Intervention 30; Control 34). The mean PISQ-PF dimension scores at follow-up were 33.1 (SD 5.5) and 32.3 (SD 5.2) for the Intervention and Control groups respectively; with the Control group having a higher (better) score. After adjusting for baseline score, BMI, menopausal status, time from randomisation and baseline oxford scale score the mean difference was -1.0 (95% CI: -4.0 to 1.9; P=0.474). There was no differences between the groups in any of the secondary outcomes at follow-up. Within this study, the use of electrical stimulation was cost-effective with very small incremental costs and quality adjusted life years (QALYs). CONCLUSIONS: In women presenting with urinary incontinence in conjunction with sexual dysfunction, physiotherapy is beneficial to improve overall sexual function. However no specific form of physiotherapy is beneficial over another. Trial registration ISRCTN09586238. PMID- 28801035 TI - [Creation of a complete organised care network allowing facilitated access to ophthalmological care for patients living in socially "at-risk" situations, feasibility study]. AB - BACKGROUND: Currently, renouncement to healthcare by socially "at-risk" patients continues to increase and access to ophthalmological care is complex. The main objective of this study is to test the feasibility of a complete organised care network allowing facilitated access to ophthalmological care for patients living in socially "at-risk" situations. METHOD: A prospective interventional study was conducted within four social housing infrastructures to screen for vision problems in the "at-risk" socially population in question. Partnering with the ophthalmological department of the CHRU de Nancy, an interventional and supportive care trial for the affected population was conducted with the assistance of social workers, nursing aides, opticians, and the author. RESULTS: Ten screening sessions were conducted between December 2015 and April 2016 allowing a vision exam of sixty-five patients living in social housing. Twenty five patients benefited from specialised care within a three-month time frame provided by the ophthalmological department, of which nineteen patients received corrective lenses. The remaining six patients received other types of ophthalmological care. CONCLUSION: The study allowed to demonstrate that the cooperation of willing actors makes it possible to improve access to visual healthcare for patients living in socially "at-risk" situations, in particular in the frame of ophthalmological care, often taking second place in a general medical consultation. PMID- 28801036 TI - [Bilateral acute arteritic anterior ischemic optic neuropathy during chronic steroid therapy]. PMID- 28801037 TI - Genome modularity and synthetic biology: Engineering systems. AB - Whole genome sequencing projects running in various laboratories around the world has generated immense data. A systematic phylogenetic analysis of this data shows that genome complexity goes on decreasing as it evolves, due to its modular nature. This modularity can be harnessed to minimize the genome further to reduce it with the bare minimum essential genes. A reduced modular genome, can fuel progress in the area of synthetic biology by providing a ready to use plug and play chassis. Advances in gene editing technology such as the use of tailor made synthetic transcription factors will further enhance the availability of synthetic devices to be applied in the fields of environment, agriculture and health. PMID- 28801038 TI - QRS duration reflects underlying changes in conduction velocity during increased intraventricular pressure and heart failure. AB - Pressure overload and heart failure electrophysiological remodeling (HF-ER) in pigs are associated with decreased conduction velocity (CV) and dispersion of repolarization, which lead to higher risk of ventricular arrhythmia. This work aimed to establish the correlation between QRS complex duration and underlying changes in CV during increased intraventricular pressure (IVP) and/or HF-ER ex vivo, and to determine whether QRS duration could be sensitive to an acute increase in left ventricular (LV) afterload in-vivo. HF-ER was induced in 7 pigs by high-rate ventricular pacing. Seven weight-matched animals were used as controls. Isolated Langendorff-perfused hearts underwent programmed ventricular stimulation to study QRS complex duration and CV under low/high IVP, using volume conducted ECG and epicardial optical mapping, respectively. Four additional pigs underwent open-chest surgery to increase LV afterload by partially clamping the ascending aorta, while measuring QRS complex duration during sinus rhythm (SR). In 13 hearts included for analysis, both HF-ER and increased IVP showed significantly slower epicardial CV (-40% and -15%, p < 0.001 and p = 0.004, respectively), which correlated with similar widening of the QRS complex (+41% and +17%, p = 0.005 and p < 0.001, respectively). HF-ER hearts shower larger prolongation of the QRS complex than controls upon increasing the IVP (+21% vs. +12%, respectively. HF-ER*IVP interaction: p = 0.004). QRS complex widened after increasing LV afterload in-vivo (n=3), with correlation between QRS duration and aortic diastolic pressures (R = 0.58, p < 0.001). In conclusion, high IVP and/or HF-ER significantly decrease CV, which correlates with QRS widening on the ECG during ventricular pacing. Increased myocardial wall stress also widens the QRS complex during SR in-vivo. PMID- 28801039 TI - Kohler's disease presenting as acute foot injury. AB - Kohler's disease is rare cause of foot pain and limping in the pediatric population. The exact etiology of Kohler's disease is unknown. It usually presents as sudden and unexplained foot pain and limping. We report a case of a 5 year-old male who presented to the Pediatric Emergency Department with foot pain and inability to bear weight for two days after overactivity and acute foot injury. The patient was eventually diagnosed with Kohler's disease (avascular necrosis of the navicular bone). Although Kohler's disease is not very common, it should be considered in the differential diagnosis of foot pain in the pediatric population, as it may prevent unnecessary tests and treatments. PMID- 28801040 TI - Extracorporeal cardiopulmonary resuscitation for blunt cardiac rupture. AB - Extracorporeal cardiopulmonary resuscitation (ECPR) followed by operating room sternotomy, rather than resuscitative thoracotomy, might be life-saving for patients with blunt cardiac rupture and cardiac arrest who do not have multiple severe traumatic injuries. A 49-year-old man was injured in a vehicle crash and transferred to the emergency department. On admission, he was hemodynamically stable, but a plain chest radiograph revealed a widened mediastinum, and echocardiography revealed hemopericardium. A computed tomography scan revealed hemopericardium and mediastinal hematoma, without other severe traumatic injuries. However, the patient's pulse was lost soon after he was transferred to the intensive care unit, and cardiopulmonary resuscitation was initiated. We initiated ECPR using femorofemoral veno-arterial extracorporeal membrane oxygenation (ECMO) with heparin administration, which achieved hemodynamic stability. He was transferred to the operating room for sternotomy and cardiac repair. Right ventricular rupture and pericardial sac laceration were identified intraoperatively, and cardiac repair was performed. After repairing the cardiac rupture, the cardiac output recovered spontaneously, and ECMO was discontinued intraoperatively. The patient recovered fully and was discharged from the hospital on postoperative day 7. In this patient, ECPR rapidly restored brain perfusion and provided enough time to perform operating room sternotomy, allowing for good surgical exposure of the heart. Moreover, open cardiac massage was unnecessary. ECPR with sternotomy and cardiac repair is advisable for patients with blunt cardiac rupture and cardiac arrest who do not have severe multiple traumatic injuries. PMID- 28801041 TI - Diagnosis of delayed diffuse axonal Injury. AB - Diffuse axonal injury is usually caused by head trauma, and patients have significant clinical symptoms during admission to the emergency department. In our case, we present a five-year-old patient who was involved in a car accident. During admission to the emergency department, the patient had no symptoms of trauma. However, 6 h after admission to emergency service, neurological symptoms occurred, and mental status changed. Diffuse axonal injury (DAI) is characterized by diffuse nerve axon injury in the brain and brainstem. This is one of the worst results of a head trauma and occurs in one-third of the patients admitted to the hospital with head trauma. In some studies, it has been reported that diffuse axonal injury is permanent in accelerated and decelerated head traumas without accompanying loss of consciousness. Neurological sequels have occurred in the recovery phase of some patients with diffuse axonal damage. In this study, we present a delayed diffuse axonal injury case accompanying a head trauma. PMID- 28801042 TI - Triacylglycerols in edible oils: Determination, characterization, quantitation, chemometric approach and evaluation of adulterations. AB - Vegetable oils are a dietary source of lipids that constitute an essential component of a healthy diet. The commonly used vegetable oils differ significantly for their triacylglycerol (TAG) profile. TAGs represent the principal components of oils and may contain different fatty acids (FA) esterified with glycerol leading to several positional isomers. To differentiate individual TAGs species in edible oils, advanced analysis systems and innovative methods are therefore required. TAGs can be considered as good fingerprints for quality control and many studies have been performed to develop rapid and low cost analytical methods to determinate the authenticity, origin and eventually evidence frauds or adulterations. The present manuscript provides a general overview on the most common vegetable oils TAGs compositions and on the related analytical methodologies recently used. Finally, the chemometric applications developed to assess the authenticity, quality and botanical origin of various edible oils are discussed. PMID- 28801043 TI - Rapid identification of herbal compounds derived metabolites using zebrafish larvae as the biotransformation system. AB - Metabolites derived from herbal compounds are becoming promising sources for discovering new drugs. However, the rapid identification of metabolites from biological matrixes is limited by massive endogenous interference and low abundance of metabolites. Thus, by using zebrafish larvae as the biotransformation system, we herein proposed and validated an integrated strategy for rapid identification of metabolites derived from herbal compounds. Two pivotal steps involved in this strategy are to differentiate metabolites from herbal compounds and match metabolites with their parent compounds. The differentiation step was achieved by cross orthogonal partial least-squares discriminant analysis. Automatic matching analysis was performed on R Project based on a self-developed program, of which the number of matched ionic clusters and its corresponding percentage between metabolite and parent compound were taken into account to assess their similarity. Using this strategy, 46 metabolites screened from incubation water samples of zebrafish treated with total Epimedium flavonoids (EFs) could be matched with their corresponding parent compounds, 37 of them were identified and validated by the known metabolic pathways and fragmentation patterns. Finally, 75% of the identified EFs metabolites were successfully detected in urine samples of rats treated with EFs. These experimental results indicate that the proposed strategy using zebrafish larvae as the biotransformation system will facilitate the rapid identification of metabolites derived from herbal compounds, which shows promising perspectives in providing additional resources for pharmaceutical developments from natural products. PMID- 28801045 TI - Mathematical modelling and evaluation of performance of cuboid packed-bed devices for chromatographic separations. AB - In a recent paper, box-shaped or cuboid packed bed devices have been proposed as alternative to columns for chromatographic separations. We first propose a mathematical model for residence time distribution in such devices. Based on it, we examine factors likely to affect separation performance, and verify the predictions of our mathematical model by conducting tracer experiments. We then compare the performance of two commercial columns with their respective equivalent cuboid packed-bed devices, i.e. containing the same chromatographic media, and having the same bed-height and bed-volume. Parameters compared include the number of theoretical plates, attributes of flow-through and eluted protein peaks, and resolution in model binary protein separations. For each of these metrics examined, the cuboid packed-bed device outperformed its equivalent commercial column. Other potential advantages likely to be gained from using a cuboid packed-bed instead of a column are elucidated. PMID- 28801044 TI - Cationic ionic liquid surfactant-polyacrylamide gel electrophoresis for enhanced separation of acidic and basic proteins with single-step ribonuclease b glycoforms separation. AB - Cationic ionic liquids-based surfactants (ILS), such as 4-methyl pyridinium bromide (CnPBr, where n=4,6,8), were used in preparation of polyacrylamide gels, sample buffer, and running buffer for cationic ILS polyacrylamide gel electrophoresis (ILS-PAGE). These ILS are liquids in the pure state and were selected for improved separation of ribonuclease b (Rib b) glycoforms in a single step and a protein mixture containing bovine serum albumin (BSA, pI-4.8, 66.5kDa), ovalbumin (Ova, pI-4.6, 44.3kDa), alpha-chymotrypsinogen (alpha-Chy, pI 8.8, 25.7kDa), myoglobin (Myo, pI-6.8, 16.9kDa), and cytochrome c (Cyt c, pI 10.0, 12.3kDa). Results acquired for Rib b glycoform separation by use of ILS were compared with conventional non-ILS surfactants-PAGE: sodium dodecylsulfate (SDS)-PAGE, cetyltrimethylammonium bromide (CTAB)-PAGE, and benzyldimethyl-n hexadecylammonium chloride (16-BAC)-PAGE. A single protein band was observed with relatively short migration time in all the conventional PAGE techniques tested. In contrast, ILS-PAGE showed multiple bands with two distinct bands for Rib b protein. The two distinct bands of Rib b from ILS-PAGE were further analyzed using MALDI-MS. Examination of MALDI-MS spectral data revealed the presence of Rib b glycoforms. Furthermore, a two-dimensional isoelectric focusing (IEF)/SDS PAGE map of Rib b protein revealed negative charge heterogeneity on the protein, which is a common observation for glycoproteins. This overall discovery greatly enhances the capability of using cationic ILS-PAGE for Rib b protein separation. Among all ILS tested, excellent protein separations were observed using C4PBr ILS at concentrations of 0.05% (w/v) in polyacrylamide gels, 0.01% (w/v) in protein sample buffer, and 0.1% (w/v) in running buffer. Under these optimum conditions, all other tested proteins were separated as sharp bands with good resolution. PMID- 28801046 TI - CON4EI: Short Time Exposure (STE) test method for hazard identification and labelling of eye irritating chemicals. AB - Assessment of ocular irritancy is an international regulatory requirement in the safety evaluation of industrial and consumer products. Although many in vitro ocular irritation assays exist, alone they are incapable of fully categorizing chemicals. Therefore, the CEFIC-LRI-AIMT6-VITO CON4EI consortium was developed to assess the reliability of eight in vitro test methods and establish an optimal tiered-testing strategy. One assay selected was the Short Time Exposure (STE) assay. This assay measures the viability of SIRC rabbit corneal cells after 5min exposure to 5% and 0.05% solutions of test material, and is capable of categorizing of Category 1 and No Category chemicals. The accuracy of the STE test method to identify Cat 1 chemicals was 61.3% with 23.7% sensitivity and 95.2% specificity. If non-soluble chemicals and unqualified results were excluded, the performance to identify Cat 1 chemicals remained similar (accuracy 62.2% with 22.7% sensitivity and 100% specificity). The accuracy of the STE test method to identify No Cat chemicals was 72.5% with 66.2% sensitivity and 100% specificity. Excluding highly volatile chemicals, non-surfactant solids and non qualified results resulted in an important improvement of the performance of the STE test method (accuracy 96.2% with 81.8% sensitivity and 100% specificity). Furthermore, it seems that solids are more difficult to test in the STE, 71.4% of the solids resulted in unqualified results (solubility issues and/or high variation between independent runs) whereas for liquids 13.2% of the results were not qualified, supporting the restriction of the test method regarding the testing of solids. PMID- 28801047 TI - The Ribosome Holds the RNA Polymerase on Track in Bacteria. AB - The central dogma of molecular biology comprises two fundamental mechanistic steps of gene expression (transcription and translation), which, in bacteria, are coupled. A recent study provides structural insights into a supercomplex between the RNA polymerase and the ribosome, thus highlighting the synergy between two key macromolecular machineries in the cell. PMID- 28801048 TI - The key role of glutamate 172 in the mechanism of type II NADH:quinone oxidoreductase of Staphylococcus aureus. AB - Type II NADH:quinone oxidoreductases (NDH-2s) are membrane bound enzymes that deliver electrons to the respiratory chain by oxidation of NADH and reduction of quinones. In this way, these enzymes also contribute to the regeneration of NAD+, allowing several metabolic pathways to proceed. As for the other members of the two-Dinucleotide Binding Domains Flavoprotein (tDBDF) superfamily, the enzymatic mechanism of NDH-2s is still little explored and elusive. In this work we addressed the role of the conserved glutamate 172 (E172) residue in the enzymatic mechanism of NDH-2 from Staphylococcus aureus. We aimed to test our earlier hypothesis that E172 plays a key role in proton transfer to allow the protonation of the quinone. For this we performed a complete biochemical characterization of the enzyme's variants E172A, E172Q and E172S. Our steady state kinetic measurements show a clear decrease in the overall reaction rate, and our substrate interaction studies indicate the binding of the two substrates is also affected by these mutations. Interestingly our fast kinetic results show quinone reduction is more affected than NADH oxidation. We have also determined the X-ray crystal structure of the E172S mutant (2.55A) and compared it with the structure of the wild type (2.32A). Together these results support our hypothesis for E172 being of central importance in the catalytic mechanism of NDH-2, which may be extended to other members of the tDBDF superfamily. PMID- 28801049 TI - A four state parametric model for the kinetics of the non-photochemical quenching in Photosystem II. AB - The phenomenon of non-photochemical quenching (NPQ) was studied in spinach chloroplasts using pulse amplitude modulated (PAM) fluorometry. We present a new analysis method which describes the observed fluorescence quantum yield as the sum of the product of four different states of PSII and their corresponding quantum yields. These four distinct states are PSII in the quenched or unquenched state, and with its reaction center either open or closed depending upon the reduction of the QA site. With this method we can describe the dynamics of the NPQ induction and recovery as well as quantify the percentage of photoinactivated RC throughout the measurement. We show that after one cycle of quenching followed by a period of recovery, approximately 8-9% of the RC are photoinactivated, after two cycles of illumination this number becomes 15-17%. The recovery from the quenching appeared with rates of (50s)-1 and (1h)-1. The new analysis method presented here is flexible, allowing it to be applied to any type of PAM fluorometry protocol. The method allows to quantitatively compare qualitatively different PAM curves on the basis of statistically relevant fitting parameters and to quantify quenching dynamics and photoinactivation. Moreover, the results presented here demonstrate that the analysis of a single PAM fluorometry quenching experiment can already provide information on the relative quantum yield of the four different states of PSII for the intact chloroplasts - something no other form of spectroscopy could provide in a single measurement. PMID- 28801052 TI - Accompaniment of second-trimester abortions: the model of the feminist Socorrista network of Argentina. AB - OBJECTIVE: Legal restrictions on abortion access impact the safety and timing of abortion. Women affected by these laws face barriers to safe care that often result in abortion being delayed. Second-trimester abortion affects vulnerable groups of women disproportionately and is often more difficult to access. In Argentina, where abortion is legally restricted except in cases of rape or threat to the health of the woman, the Socorristas en Red, a feminist network, offers a model of accompaniment wherein they provide information and support to women seeking second-trimester abortions. This qualitative analysis aimed to understand Socorristas' experiences supporting women who have second-trimester medication abortion outside the formal health care system. STUDY DESIGN: We conducted 2 focus groups with 16 Socorristas in total to understand experiences accompanying women having second-trimester medication abortion who were at 14-24 weeks' gestational age. We performed a thematic analysis of the data and present key themes in this article. RESULTS: The Socorristas strived to ensure that women had the power of choice in every step of their abortion. These cases required more attention and logistical, legal and medical risks than first-trimester care. The Socorristas learned how to help women manage the possibility of these risks and were comfortable providing this support. They understood their work as activism through which they aim to destigmatize abortion and advocate against patriarchal systems denying the right to abortion. CONCLUSION: Socorrista groups have shown that they can provide supportive, women-centered accompaniment during second trimester medication abortions outside the formal health care system in a setting where abortion access is legally restricted. IMPLICATIONS: Second-trimester self use of medication abortion outside of the formal health system supported by feminist activist groups could provide an alternative model for second-trimester care worldwide. More research is needed to document the safety and effectiveness of this accompaniment service-provision model. PMID- 28801050 TI - Electron transfer through arsenite oxidase: Insights into Rieske interaction with cytochrome c. AB - Arsenic is a widely distributed environmental toxin whose presence in drinking water poses a threat to >140 million people worldwide. The respiratory enzyme arsenite oxidase from various bacteria catalyses the oxidation of arsenite to arsenate and is being developed as a biosensor for arsenite. The arsenite oxidase from Rhizobium sp. str. NT-26 (a member of the Alphaproteobacteria) is a heterotetramer consisting of a large catalytic subunit (AioA), which contains a molybdenum centre and a 3Fe-4S cluster, and a small subunit (AioB) containing a Rieske 2Fe-2S cluster. Stopped-flow spectroscopy and isothermal titration calorimetry (ITC) have been used to better understand electron transfer through the redox-active centres of the enzyme, which is essential for biosensor development. Results show that oxidation of arsenite at the active site is extremely fast with a rate of >4000s-1 and reduction of the electron acceptor is rate-limiting. An AioB-F108A mutation results in increased activity with the artificial electron acceptor DCPIP and decreased activity with cytochrome c, which in the latter as demonstrated by ITC is not due to an effect on the protein protein interaction but instead to an effect on electron transfer. These results provide further support that the AioB F108 is important in electron transfer between the Rieske subunit and cytochrome c and its absence in the arsenite oxidases from the Betaproteobacteria may explain the inability of these enzymes to use this electron acceptor. PMID- 28801051 TI - The mechanism for oxygen reduction in cytochrome c dependent nitric oxide reductase (cNOR) as obtained from a combination of theoretical and experimental results. AB - Bacterial NO-reductases (NOR) belong to the heme-copper oxidase (HCuO) superfamily, in which most members are O2-reducing, proton-pumping enzymes. This study is one in a series aiming to elucidate the reaction mechanisms of the HCuOs, including the mechanisms for cellular energy conservation. One approach towards this goal is to compare the mechanisms for the different types of HCuOs, cytochrome c oxidase (CcO) and NOR, reducing the two substrates O2 and NO. Specifically in this study, we describe the mechanism for oxygen reduction in cytochrome c dependent NOR (cNOR). Hybrid density functional calculations were performed on large cluster models of the cNOR binuclear active site. Our results are used, together with published experimental information, to construct a free energy profile for the entire catalytic cycle. Although the overall reaction is quite exergonic, we show that during the reduction of molecular oxygen in cNOR, two of the reduction steps are endergonic with high barriers for proton uptake, which is in contrast to oxygen reduction in CcO, where all reduction steps are exergonic. This difference between the two enzymes is suggested to be important for their differing capabilities for energy conservation. An additional result from this study is that at least three of the four reduction steps are initiated by proton transfer to the active site, which is in contrast to CcO, where electrons always arrive before the protons to the active site. The roles of the non-heme metal ion and the redox-active tyrosine in the active site are also discussed. PMID- 28801053 TI - Cervical mucus and contraception: what we know and what we don't. AB - OBJECTIVES: Cervical mucus varies in response to both natural and artificial hormonal changes. It is commonly believed that cervical mucus thinning is associated with normal fertility and that progestogen-induced thickening is an essential contraceptive mechanism. This review aims to broadly summarize our current knowledge about cervical mucus from both a clinical and basic research perspective. STUDY DESIGN: We reviewed published literature pertinent to cervical mucus and contraception across scientific disciplines. We first present the most current understanding of the composition of cervical mucus, how it is hormonally regulated, and examine the role of mucus as an immune barrier. We then critically assess the current clinical tests used as surrogate markers for a contraceptive effect. Finally, we review contraceptive studies that have specifically focused on cervical mucus changes. RESULTS: Existing research suggests that cervical mucus has potential to be a contraceptive target with unique, multipurpose characteristics. However, methodologic limitations associated with clinical assessments of cervical mucus complicate our understanding of contraceptive treatment effects. Key pathways involved in cervical mucus production with potential as novel nonhormonal contraceptive targets have been identified. CONCLUSIONS: More research is needed to clarify the role of cervical mucus in current hormonal contraceptives and to support the development of novel nonhormonal cervix-based methods. PMID- 28801054 TI - "Without bodily autonomy we are not free": exploring women's concerns about future access to contraception following the 2016 US presidential election. AB - OBJECTIVE: Following the 2016US presidential election, social media posts and news stories amplified concerns about the potential for reduced access to contraception under the incoming administration and urged women to seek long acting reversible contraception. We aimed to describe women's concerns about future access to contraception, in their own words. STUDY DESIGN: A social-media based, anonymous online survey assessing thoughts and concerns about future access to contraception was distributed to reproductive-aged US women for 1 week in mid-January 2017. Participants who were concerned about future access to contraception could share their thoughts and feelings in an open-ended comments box. We qualitatively analyzed 449 written responses for content and themes, with the goal of characterizing key concerns. RESULTS: Women who provided written comments had a mean age of 28years; 85% were white, 88% had at least a college degree, and 93% identified as Democratic or Democratic-leaning. Women were highly concerned about future affordability of contraceptive methods due to potential loss of insurance, reduced insurance coverage for contraceptive methods and reduced access to low-cost care at Planned Parenthood. Many also worried about increased restrictions on abortion. Participants' concerns regarding access to contraception and abortion centered around themes of reproductive and bodily autonomy, which women described as fundamental rights. CONCLUSIONS: Women in this study expressed considerable fear and uncertainty regarding their future access to contraception and abortion following the 2016US presidential election. The potential for restricted access to affordable contraception and abortion was viewed as an unacceptable limitation on bodily autonomy. IMPLICATIONS: As the future of US health care policy is debated, many women are concerned about the impact of policy changes on their ability to access affordable contraception and abortion, which many view as essential to the preservation of bodily and reproductive autonomy. PMID- 28801055 TI - Therapy with mesenchymal stromal cells or conditioned medium reverse cardiac alterations in a high-fat diet-induced obesity model. AB - BACKGROUND: Obesity is associated with numerous cardiac complications, including arrhythmias, cardiac fibrosis, remodeling and heart failure. Here we evaluated the therapeutic potential of mesenchymal stromal cells (MSCs) and their conditioned medium (CM) to treat cardiac complications in a mouse model of high fat diet (HFD)-induced obesity. METHODS: After obesity induction and HFD withdrawal, obese mice were treated with MSCs, CM or vehicle. Cardiac function was assessed using electrocardiography, echocardiography and treadmill test. Body weight and biochemical parameters were evaluated. Cardiac tissue was used for real time (RT)-polymerase chain reaction (PCR) and histopathologic analysis. RESULTS/DISCUSSION: Characterization of CM by protein array showed the presence of different cytokines and growth factors, including chemokines, osteopontin, cystatin C, Serpin E1 and Gas 6. HFD-fed mice presented cardiac arrhythmias, altered cardiac gene expression and fibrosis reflected in physical exercise incapacity associated with obesity and diabetes. Administration of MSCs or CM improved arrhythmias and exercise capacity. This functional improvement correlated with normalization of GATA4 gene expression in the hearts of MSC- or CM-treated mice. The gene expression of connexin 43, troponin I, adiponectin, transforming growth factor (TGF) beta, peroxisome proliferator activated receptor gamma (PPARgamma), insulin-like growth factor 1 (IGF-1), matrix metalloproteinase 9 (MMP9) and tissue inhibitor of metalloproteinases 1 (TIMP1) were significantly reduced in MSCs, but not in CM-treated mice. Moreover, MSC or CM administration reduced the intensity of cardiac fibrosis. CONCLUSION: Our results suggest that MSCs and CM have a recovery effect on cardiac disturbances due to obesity and corroborate to the paracrine action of MSCs in heart disease models. PMID- 28801056 TI - Clinical evaluation of the new Roche platform of serological and molecular cytomegalovirus-specific assays in the diagnosis and prognosis of congenital cytomegalovirus infection. AB - Clinical evaluation of the Elecsys(r) CMV IgM, IgG, IgG Avidity and COBAS AmpliPrep/COBAS TaqMan CMV (COBAS CMV) assays (Roche Diagnostics AG) in the diagnosis and prognosis of congenital CMV infection was performed. In this study, 150 preselected clinical samples (50 primary infection sera, 50 amniotic fluid [AF] and 50 newborn urine) were processed using Roche serological/molecular CMV specific tests. Results were compared with those obtained by routine assays (comparator assays). The Elecsys(r) CMV IgM and IgG assays showed a perfect agreement (100%) with the comparator assays. Using the combination of the Elecsys(r) CMV IgM and IgG Avidity assays results, a primary infection was identified in 100% of cases. Inappropriate avidity CMV IgG values in two samples with very low IgG values (<6 AU/mL) were observed. COBAS CMV assay showed an agreement equal to 98% and 100% with comparator assays by processing AF and urine samples, respectively. Among AF with quantitative results, Lin's concordance correlation was 0.933 and comparator-COBAS CMV assays gave CMV-DNA loads differing by <0.5 log10 DNA. Finally, higher CMV-DNA levels in AF samples were associated with a symptomatic outcome (p=0.003). The Roche CMV-specific assays compared well with the comparator assays, thus providing to be suitable for clinical use. PMID- 28801058 TI - Critical appraisal of Salari et al. case-control study. PMID- 28801059 TI - Editorial overview: Cryo Electron Microscopy: Exciting advances in CryoEM Herald a new era in structural biology. PMID- 28801057 TI - Mothers' loss of control over eating during pregnancy in relation to their infants' appetitive traits. PMID- 28801060 TI - Prognostic markers in well differentiated papillary and follicular thyroid cancer (WDTC). AB - OBJECTIVES: WDTC (papillary and follicular thyroid cancer) make up around 90% of all thyroid tumours. Overall, the prognosis in patients with WDTC is excellent. However, there are small cohorts of patients who experience a more aggressive form of disease which is often associated with certain poor prognostic factors. Identifying these patients at an early stage is imperative for guiding treatment decisions. With recent developments in this area we plan to discuss the current evidence surrounding prognostic markers. METHODS: The literature regarding prognostic factors in WDTC was reviewed using an electronic database Medline - Pubmed. Using the MeSH search engine specific prognostic factors including age, size, grade, lymph node involvement, distant metastasis, extension/invasion, ethnic background, radioactive iodine avidity, and thyroglobulin level and their association with WDTC were evaluated. A broader search of prognostic markers in thyroid cancer was also carried out to avoid missing other pertinent markers. RESULTS: Multiple clinical and pathologic variables have been shown to be poor prognostic factors in WDTC with statistical significance. Extensive extrathyroidal extension and age may be the most important factors when predicting clinical outcomes in WDTC, although the age threshold may be increased from 45 to 55 years in due course. CONCLUSIONS: Management of WDTC has changed considerably over the last two years as reflected in evolving British and American Thyroid Guidelines. In all cases a combined multi-disciplinary approach, with consideration of the available guidelines and stratification systems should be utilised when planning an individualised treatment program to offer the best contemporary care to WDTC patients. PMID- 28801061 TI - European temporal trends in the use of lymph node dissection in patients with renal cancer. AB - BACKGROUND: The role of lymph node dissection (LND) in renal cell carcinoma (RCC) is still under debate. We aimed to assess the utilization rates of LND over time in Europe. METHODS: A multi-institutional database of 13,581 RCC patients who underwent radical nephrectomy (RN) or nephron sparing surgery (NSS) between 1988 and 2014 was created within an European consortium. We analysed temporal trends in the frequency of LND by using Joinpoint regression. Logistic regression models were used to identify predictors of LND. RESULTS: Overall, 5114 patients (42.7%) underwent LND. Lymph node invasion was recorded in 566 cases (11% of LND patients) which represents 4.7% of the whole study cohort. A gradual decline in the use of LND started in the 1990s. After 2008 LND decreased significantly by 21.5% per year (95%CI -33.3 to -7.5, p < 0.01) until 2011 and stabilized thereafter (Annual Percentage Change 4.9%, 95%CI -3.4 to 13.8, p = 0.2). At multivariable analyses, patient age (OR 0.98, p < 0.0001), type of surgery (RN vs. NSS: OR 5.46, p < 0.0001), surgical approach (open vs. minimally invasive: OR 1.75, p < 0.0001), T stage (T2 vs. T1: OR 1.57; T3-4 vs. T1: OR 1.44, p < 0.0001), clinical tumour size (OR 1.14, p < 0.0001), and year of surgery (OR 0.95, p < 0.0001) were associated with higher probability of LND at nephrectomy. CONCLUSIONS: A trend towards lower LND was observed over time for RCC patients who underwent RN or NSS. LND is more frequently performed in younger patients, locally advanced diseases and in case of open surgery. PMID- 28801062 TI - Perineural invasion through the sheath in posttherapy esophagectomy specimens predicts poor survival in patients with esophageal squamous cell carcinoma. AB - BACKGROUND: The prognostic impact of perineural invasion (PNI) in patients with esophageal cancer who receive neoadjuvant chemoradiotherapy (nCRT) remains unclear. METHODS: A thorough pathological review of PNI was performed on post nCRT esophagectomy specimens obtained from non-ypT0 patients with esophageal squamous cell carcinoma (ESCC). When PNI was identified, it was classified according to the presence or absence of penetration through the nerve sheath (i.e., PNI surrounding the nerve sheath [PNI-SS] versus PNI penetrating through the nerve sheath [PNI-TS]). The impact of PNI on overall survival (OS) was assessed in combination with clinical and pathological risk factors. RESULTS: A total of 177 eligible patients were identified between 1998 and 2008. PNI was identified in 43.5% (77/177) of participants. Of them, 33 and 44 had PNI-SS and PNI-TS, respectively. The 5-year OS rate of patients with PNI-TS was significantly lower (6.7%) than that observed in those without PNI (30.6%, P < 0.001). However, the 5-year OS observed in the latter group did not differ significantly from that of patients with PNI-SS (26%, P = 0.68). Multivariate analysis identified PNI-TS (hazard ratio [HR] = 1.965, P = 0.02), LVI (HR = 1.514, P = 0.048), and ypN2 stage (HR = 2.39, P = 0.007) as independent adverse prognostic factors for OS. CONCLUSIONS: The presence of PNI-TS after nCRT is associated with poor survival. A thorough assessment of distinct PNI patterns (i.e., PNI-TS versus PNI-SS) should be part of the routine post-nCRT histopathological work-up of ESCC patients. PMID- 28801063 TI - Chondroitin sulfates do not impede axonal regeneration in goldfish spinal cord. AB - Chondroitin sulfate proteoglycans produced in glial scar tissue are a major inhibitory factor for axonal regeneration after central nervous system injury in mammals. The inhibition is largely due to chondroitin sulfates, whose effects differ according to the sulfation pattern. In contrast to mammals, fish nerves spontaneously regenerate beyond the scar tissue after spinal cord injury, although the mechanisms that allow for axons to pass through the scar are unclear. Here, we used immunohistochemistry to examine the expression of two chondroitin sulfates with different sulfation variants at the lesion site in goldfish spinal cord. The intact spinal cord was immunoreactive for both chondroitin sulfate-A (CS-A) and chondroitin sulfate-C (CS-C), and CS-A immunoreactivity overlapped extensively with glial processes positive for glial fibrillary acidic protein. At 1week after inducing the spinal lesion, CS-A immunoreactivity was observed in the cell bodies and extracellular matrix, as well as in glial processes surrounding the lesion center. At 2weeks after the spinal lesion, regenerating axons entering the lesion center overtook the CS-A abundant area. In contrast, at 1week after lesion induction, CS-C immunoreactivity was significantly decreased, and at 2weeks after lesion induction, CS-C immunoreactivity was observed along the regenerating axons entering the lesion center. The present findings suggest that after spinal cord injury in goldfish, chondroitin sulfate proteoglycans are deposited in the extracellular matrix at the lesion site but do not form an impenetrable barrier to the growth of regenerating axons. PMID- 28801064 TI - Can different mechanisms underpin the "Geschwind syndrome" in temporal lobe epilepsy and in temporal lobe variant of frontotemporal degeneration? PMID- 28801065 TI - Multimodal mental imagery. AB - When I am looking at my coffee machine that makes funny noises, this is an instance of multisensory perception - I perceive this event by means of both vision and audition. But very often we only receive sensory stimulation from a multisensory event by means of one sense modality, for example, when I hear the noisy coffee machine in the next room, that is, without seeing it. The aim of this paper is to bring together empirical findings about multimodal perception and empirical findings about (visual, auditory, tactile) mental imagery and argue that on occasions like this, we have multimodal mental imagery: perceptual processing in one sense modality (here: vision) that is triggered by sensory stimulation in another sense modality (here: audition). Multimodal mental imagery is not a rare and obscure phenomenon. The vast majority of what we perceive are multisensory events: events that can be perceived in more than one sense modality - like the noisy coffee machine. And most of the time we are only acquainted with these multisensory events via a subset of the sense modalities involved - all the other aspects of these multisensory events are represented by means of multisensory mental imagery. This means that multisensory mental imagery is a crucial element of almost all instances of everyday perception. PMID- 28801066 TI - Identification of pyrazolopyrimidine arylsulfonamides as CC-chemokine receptor 4 (CCR4) antagonists. AB - A novel 4-aminoindazole sulfonamide hit (13) was identified as a human CCR4 antagonists from testing a focussed library of compounds in the primary GTPgammaS assay. Replacing the indazole core with a pyrazolopyrimidine, and introduction of a methoxy group adjacent to the sulfonamide substituent, resulted in the identification of pyrazolopyrimidine 37a, which exhibited good binding affinity in the GTPgammaS assay (pIC50=7.2), low lipophilicity (clogP=2.2, chromlogD7.4=2.4), high LE (0.41), high solubility (CLND solubility >=581uM), and an excellent PK profile in both the rat (F=62%) and the dog (F=100%). Further SAR investigation of the pyrazolopyrimidine suggested that substitution at N1 is tolerated, providing a suitable vector to modulate the properties, and increase the potency in a lead optimisation campaign. PMID- 28801067 TI - DNA methylation in CHO cells. AB - Chinese hamster ovary (CHO) cells account for the production of the majority of biopharmaceutical molecules - however, the molecular basis for their versatile properties is not entirely understood yet and the underlying cellular processes need to be characterized in detail. One such process that is supposed to contribute significantly to CHO cell phenotype is methylation of DNA at cytosine residues. DNA methylation was shown to be involved in several central biological processes in humans and to contribute to diseases like cancer. Early studies of DNA methylation in CHO mostly focused on methylation of single recombinant genes and promoters and proved a correlation between DNA methylation status and recombinant gene expression or production stability. More recent publications utilized the CHO genomic and transcriptomic data available since 2011 and provided first insights into the CHO DNA methylation landscape and DNA methylation changes in response to effector molecules or culture conditions. Generally, further genome-wide studies of DNA methylation in CHO will be required to shed light on the relevance of this process regarding biopharmaceuticals production and might, e.g., address a potential link between CHO cell metabolism and DNA methylation or provide novel targets for rational cell line engineering. PMID- 28801068 TI - LEPR polymorphism may affect energy balance during weight loss among Brazilians obese adolescents. AB - OBJECTIVE: Leptin is an adipokine released mainly by adipose tissue, with many functions including regulation of energy balance. However, little is known about the effect of LEPR polymorphism on orexigenic and anorexigenic neuropeptides. Thus, the aim of the present study is to verify the influence of LEPR polymorphism (rs2767485) on serum orexigenic (NPY, MCH and AgRP) and anorexigenic (Leptin and alpha-MSH) neuropeptides levels among obese adolescents submitted to 1year of multicomponent weight loss therapy. METHODS: Seventy-six adolescents with obesity were enrolled in 1year of weight loss therapy including clinical, nutritional, psychological and exercise-related. Blood samples were collected to analyze neuropeptides (NPY, MCH, AgRP and leptin) and LEPR genotyping. Visceral fat was measured by ultrasound and body composition was measured by plethysmography. The parameters were measured at baseline and after one year. Adolescents were grouped according to genotype (TT or CT+CC group). Effect of the weight loss therapy was analyzed through ANOVA and Wilcox, according to normality. Statistic value was set at <0.05. RESULTS: C-allele carriers have the orexigenic neuropeptides (NPY, AgRP and MCH) levels statistically higher when compared with TT group, at baseline. Furthermore, TT group seems to respond better to the therapy by a greater delta on BMI. Indeed, the data suggest a concomitant increased of AgRP levels in CT+CC genotypes, after weight loss therapy. CONCLUSION: Both groups responded to the weight loss intervention, however wildtypes (TT) appear to respond to the intervention most optimally with C carries, where post intervention reduction in BMI was significantly greater in wildtypes. The leptin receptor polymorphism seems to affect neuroendocrine regulation of energy balance among adolescents with obesity. PMID- 28801070 TI - Methodological Considerations for the Temporal Summation of Second Pain. AB - : Temporal summation of second pain (TSSP) is a psychophysical indication of a central pain encoding mechanism, potentially enhanced in pathological pain conditions. Low-frequency repetitive stimulation of unmyelinated (C) nociceptors results in a progressive increase of pain intensity when thermal stimulation intensity remains constant. However, when using different methods of nociceptive delivery to the skin, regularity as well as rate of pain enhancement with repetition varies between experiments. Specifically, repetitive ramping up and down from a neutral to a painful temperature has produced weak and inconsistent pain summation. In contrast, repetitive contact of the skin with a preheated probe has generated substantial pain summation. In the present study, TSSP by the intermittent contact with a preheated thermode and constant contact, ramp and hold methods were compared during 10 iterations of stimulation of glabrous skin of the hand or hairy forearm skin, with an onset to onset interval of 3.3 seconds and stimulus interval of .8 seconds. Significantly greater TSSP was observed for intermittent contact stimulation at both sites (P < .001). Differential activation of myelinated and unmyelinated nociceptors by ramping and tapping may account for different rates of temporal summation of heat pain. PERSPECTIVE: This article presents direct evidence suggesting the constant contact, ramp and hold stimulus may underestimate the level of TSSP. This evidence suggests the re evaluation of stimulation techniques used for temporal summation tests, especially within clinical models. PMID- 28801072 TI - Irinotecan chemotherapy-induced intestinal oxidative stress: Underlying causes of disturbed mucosal water and electrolyte transport. AB - Irinotecan, a chemotherapy drug, can cause acute diarrhea immediately after administration. Hence, the present study was designed to investigate the gastrointestinal (GI) disturbances after an intraperitoneal (IP) administration of irinotecan in rats.Twenty Wistar rats were separated into two groups of ten. Group A was considered as a control group (NaCl, 0.9%). Group B was treated with irinotecan at a single dose of 200mgkg-1. The rats were observed for defecation. For the enteropooling test, the animals were sacrificed by decapitation 1h post treatment. The small intestine was excised and the fluid was milked into a graduated tube and the volume was measured. After centrifugation of intraluminal liquid, the electrolyte concentrations in the supernatants were measured by flame photometry. Oxidative stress parameters and intracellular mediators as well as the MPO activity were determined in intestinal mucosa by colorimetric methods Our result indicated that irinotecan produces an intestinal fluid accumulation and electrolyte transport disorders. These effects were associated with augmented intestinal MPO activity and oxidative damage such as an elevation of MDA production and a depletion of enzymatic and non-enzymatic antioxidants. More than that, drug administration provoked intracellular mediator disturbances such as a free iron, H2O2 and calcium levels. In conclusion, the data suggest that irinotecan caused a gastrointestinal stress via oxidative stress-induced disturbances in water and electrolyte transport in the intestinal mucosa in rats. PMID- 28801071 TI - Comparison of 2 Lumbar Manual Therapies on Temporal Summation of Pain in Healthy Volunteers. AB - : The purpose of this study was to compare the immediate change in temporal summation of heat pain (TSP) between spinal manipulation (SMT) and spinal mobilization (MOB) in healthy volunteers. Ninety-two volunteers (24 male; 23.8 +/ 5.3 years) were randomized to receive SMT, MOB, or no treatment (REST) for 1 session. Primary outcomes were changes in TSP, measured at the hand and foot, immediately after the session. A planned subgroup analysis investigated effects across empirically derived TSP clusters. For the primary outcome there were no differences in the immediate change in TSP measured at the foot between SMT and MOB, however, both treatments were superior to the REST condition. In the subgroup analysis the response to a standard TSP protocol was best characterized by 3 clusters: 52% no change (n = 48, 52%); facilitatory response (n = 24, 26%), and inhibitory response (n = 20, 22%). There was a significant Time * Treatment group * Cluster interaction for TSP measured at the foot. The inhibitory cluster showed the greatest attenuation of TSP after SMT and MOB compared with REST. These data suggest lumbar manual therapies of different velocities produce a similar localized attenuation of TSP, compared with no treatment. Attenuation of localized pain facilitatory processes by manual therapies was greatest in pain free individuals who show an inhibitory TSP response. PERSPECTIVE: The attenuation of pain facilitatory measures may serve an important underlying role in the therapeutic response to manual therapies. Identifying patients in pain who still have an inhibitory capacity (ie, an inhibitory response subgroup) may be useful clinically in identifying the elusive "manual therapy" responder. PMID- 28801069 TI - HSC Niche Biology and HSC Expansion Ex Vivo. AB - Hematopoietic stem cell (HSC) transplantation can restore a new functional hematopoietic system in recipients in cases where the system of the recipient is not functional or for example is leukemic. However, the number of available donor HSCs is often too low for successful transplantation. Expansion of HSCs and thus HSC self-renewal ex vivo would greatly improve transplantation therapy in the clinic. In vivo, HSCs expand significantly in the niche, but establishing protocols that result in HSC expansion ex vivo remains challenging. In this review we discuss current knowledge of niche biology, the intrinsic regulators of HSC self-renewal in vivo, and introduce novel niche-informed strategies of HSC expansion ex vivo. PMID- 28801074 TI - Rational Heart Transplant From a Hepatitis C Donor: New Antiviral Weapons Conquer the Trojan Horse. AB - BACKGROUND: Donors with hepatitis C (HCV) viremia are rarely used for orthotopic heart transplantation (HT) owing to post-transplantation risks. New highly effective HCV antivirals may alter the landscape. METHODS: An adult patient unsuitable for bridging mechanical support therapy accepted a heart transplant offer from a donor with HCV viremia. On daily logarithmic rise in HCV viral load and adequate titers to ensure successful genotyping, once daily sofosbuvir (400 mg)-velpatasvir (100 mg) (Epclusa; Gilead) was initiated empirically pending HCV genotype (genotype 3a confirmed after initiation of therapy). RESULTS: We report the kinetics of acute hepatitis C viremia and therapeutic response to treatment with a new pangenotypic antiviral agent after donor-derived acute HCV infection transmitted incidentally with successful cardiac transplantation to an HCV negative recipient. Prompt resolution of viremia was noted by the 1st week of a 12 week course of antiviral therapy. Sustained virologic remission continued beyond 12 weeks after completion of HCV therapy (SVR-12). CONCLUSIONS: The availability of effective pangenotypic therapy for HCV may expand donor availability. The feasibility of early versus late treatment of HCV remains to be determined through formalized protocols. We hypothesize pharmacoeconomics to be the greatest limitation to widespread availability of this promising tool. PMID- 28801073 TI - Newborn screening for carnitine palmitoyltransferase II deficiency using (C16+C18:1)/C2: Evaluation of additional indices for adequate sensitivity and lower false-positivity. AB - BACKGROUND: Carnitine palmitoyltransferase (CPT) II deficiency is one of the most common forms of mitochondrial fatty acid oxidation disorder (FAOD). However, newborn screening (NBS) for this potentially fatal disease has not been established partly because reliable indices are not available. METHODS: We diagnosed CPT II deficiency in a 7-month-old boy presenting with hypoglycemic encephalopathy, which apparently had been missed in the NBS using C16 and C18:1 concentrations as indices. By referring to his acylcarnitine profile from the NBS, we adopted the (C16+C18:1)/C2 ratio (cutoff 0.62) and C16 concentration (cutoff 3.0nmol/mL) as alternative indices for CPT II deficiency such that an analysis of a dried blood specimen collected at postnatal day five retroactively yielded the correct diagnosis. Thereafter, positive cases were assessed by measuring (1) the fatty acid oxidation ability of intact lymphocytes and/or (2) CPT II activity in the lysates of lymphocytes. The diagnoses were then further confirmed by genetic analysis. RESULTS: The disease was diagnosed in seven of 21 newborns suspected of having CPT II deficiency based on NBS. We also analyzed the false-negative patient and five symptomatic patients for comparison. Values for the NBS indices of the false-negative, symptomatic patient were lower than those of the seven affected newborns. Although it was difficult to differentiate the false-negative patient from heterozygous carriers and false-positive subjects, the fatty acid oxidation ability of the lymphocytes and CPT II activity clearly confirmed the diagnosis. Among several other indices proposed previously, C14/C3 completely differentiated the seven NBS-positive patients and the false-negative patient from the heterozygous carriers and the false-positive subjects. Genetic analysis revealed 16 kinds of variant alleles. The most prevalent, detected in ten alleles in nine patients from eight families, was c.1148T>A (p.F383Y), a finding in line with those of several previous reports on Japanese patients. CONCLUSIONS: These findings suggested that CPT II deficiency can be screened by using (C16+C18:1)/C2 and C16 as indices. An appropriate cutoff level is required to achieve adequate sensitivity albeit at the cost of a considerable increase in the false-positive rate, which might be reduced by using additional indices such as C14/C3. PMID- 28801075 TI - Doppler Assessment of Diastolic Function Reflect the Severity of Injury in Rats With Chronic Heart Failure. AB - OBJECTIVE: For chronic heart failure (CHF), more emphasis has been placed on evaluation of systolic as opposed to diastolic function. Within the study of diastology, measurements of left ventricular (LV) longitudinal myocardial relaxation have the most validation. Anterior wall radial myocardial tissue relaxation velocities along with mitral valve inflow (MVI) patterns are applicable diastolic parameters in the differentiation between moderate and severe disease in the ischemic rat model of CHF. Myocardial tissue relaxation velocities correlate with traditional measurements of diastolic function (ie, hemodynamics, Tau, and diastolic pressure-volume relationships). METHODS AND RESULTS: Male Sprague-Dawley rats underwent left coronary artery ligation or sham operation. Echocardiography was performed at 3 and 6 weeks after coronary ligation to evaluate LV ejection fraction (EF) and LV diastolic function through MVI patterns (E, A, and E/A) and Doppler imaging of the anterior wall (e' and a'). The rats were categorized into moderate or severe CHF according to their LV EF at 3 weeks postligation. Invasive hemodynamic measurements with solid-state pressure catheters were obtained at the 6-week endpoint. Moderate (N = 20) and severe CHF (N = 22) rats had significantly (P < .05) different EFs, hemodynamics, and diastolic pressure-volume relationships. Early diastolic anterior wall radial relaxation velocities as well as E/e' ratios separated moderate from severe CHF and both diastolic parameters had strong correlations with invasive hemodynamic measurements of diastolic function. CONCLUSION: Radial anterior wall e' and E/e' can be used for serial assessment of diastolic function in rats with moderate and severe CHF. PMID- 28801076 TI - Early Development of Right Ventricular Ischemic Lesions in a Novel Large Animal Model of Acute Right Heart Failure in Chronic Thromboembolic Pulmonary Hypertension. AB - BACKGROUND: Our aim was to develop a model of acute right heart failure (ARHF) in the setting of pulmonary hypertension and to characterize acute right ventricular lesions that develop early after hemodynamic restoration. METHODS AND RESULTS: We used a described piglet model of chronic pulmonary hypertension (cPH) induced by pulmonary artery occlusions. We induced ARHF in animals with cPH (ARHF-cPH group, n = 9) by volume loading and iterative acute pulmonary embolism until hemodynamic compromise followed by dobutamine infusion for hemodynamic restoration before sacrifice for right ventricular tissue evaluation. The median duration of ARHF before sacrifice was 162 (135-189) minutes. Although ventriculoarterial coupling (measured with multibeat pressure-volume loops) and stroke volume decreased after iterative pulmonary embolism and improved with dobutamine, relative pulmonary to systemic pressure increased by 2-fold and remained similarly increased with dobutamine. Circulating high-sensitivity troponin I increased after hemodynamic restoration. We found an increase in right ventricular subendocardial and subepicardial focal ischemic lesions and in expression of autophagy-related protein LC3-II (Western blot) in the ARHF-cPH group compared with the cPH (n = 5) and control (n = 5) groups. CONCLUSIONS: We developed and phenotyped a novel large animal model of ARHF on cPH in which right ventricular ischemic lesions were observed early after hemodynamic restoration. PMID- 28801078 TI - On position/force tracking control problem of cooperative robot manipulators using adaptive fuzzy backstepping approach. AB - In this paper, the position and force tracking control problem of cooperative robot manipulator system handling a common rigid object with unknown dynamical models and unknown external disturbances is investigated. The universal approximation properties of fuzzy logic systems are employed to estimate the unknown system dynamics. On the other hand, by defining new state variables based on the integral and differential of position and orientation errors of the grasped object, the error system of coordinated robot manipulators is constructed. Subsequently by defining the appropriate change of coordinates and using the backstepping design strategy, an adaptive fuzzy backstepping position tracking control scheme is proposed for multi-robot manipulator systems. By utilizing the properties of internal forces, extra terms are also added to the control signals to consider the force tracking problem. Moreover, it is shown that the proposed adaptive fuzzy backstepping position/force control approach ensures all the signals of the closed loop system uniformly ultimately bounded and tracking errors of both positions and forces can converge to small desired values by proper selection of the design parameters. Finally, the theoretic achievements are tested on the two three-link planar robot manipulators cooperatively handling a common object to illustrate the effectiveness of the proposed approach. PMID- 28801077 TI - Myocardial Amyloid Quantification with Look-Locker Magnetic Resonance Sequence in Cardiac Amyloidosis. Diagnostic Accuracy in Clinical Practice and Histological Validation. AB - BACKGROUND: Cardiac magnetic resonance (CMR) has demonstrated its utility in the noninvasive diagnosis of cardiac amyloidosis (CA). Our aim was to evaluate the ability of standard Look-Locker sequences to quantify amyloid deposition in CA. METHODS AND RESULTS: Consecutive patients referred for CMR for possible CA were retrospectively evaluated. Positive cardiac biopsy and/or typical pattern of late gadolinium enhancement were required for the diagnosis of CA. Postcontrast T1 values were obtained from Look-Locker sequences and correlated with markers of severity of disease and major events. When cardiac biopsies were available, histological validation was determined. A total of 174 patients were included. A final diagnosis of CA was reached in 37.4%. Myocardial and endocardial T1 times, as well as the respective ratios with blood and skeletal muscle, were lower among patients with CA and demonstrated good diagnostic performance. The best parameters were myocardial/blood (area under the curve 0.83; P < .001) and endocardial/blood (area under the curve 0.84; P < .001) T1 ratios. Among patients with CA, no associations were found between T1 ratios either with markers of amyloid burden or with prognostic variables. However, all T1 indexes showed significant correlations with histological quantification of amyloid deposition. CONCLUSIONS: Look-Looker derived postcontrast T1 shows good diagnostic accuracy to detect CA and correlation with histological amyloid burden. PMID- 28801079 TI - Re-raising muscle flaps: A randomised controlled animal study. AB - BACKGROUND: In the experience of our centre, 33% of reconstructed compound lower limb injuries will need an orthopaedic revision.1 A flap may be re-raised through numerous methods, and historically, the approach of choice has been based on the principle of protecting the vascular pedicle rather than the inset. Our aim was to determine whether a marginal versus a split approach to re-raising inferred a higher risk of flap necrosis and whether more attention should be paid to protecting the inset of the flap, particularly at the distal portion. METHOD: A pedicled pectoralis profundus muscle flap was raised in 32 Sprague-Dawley rats and transposed to the lateral chest wall. After 21 days, the flaps were randomised into one of four treatment groups according to the surgical approach and whether or not the anatomical vascular pedicle was ligated. Necrosis was assessed 48 h later, both clinically and through the analysis of digital photographs. RESULTS: The rate of necrosis in the marginal group was higher than that in the split group (63% vs 0%, p < 0.001, McNemar). More necrosis occurred in the former when the pedicle was ligated (p < 0.001, Fisher's exact test). Measured necrosis was also higher in the marginal group (18% vs 0%, p = 0.002, Wilcoxon signed-rank test). Twenty-nine percent more flap could be raised using the split approach (p = 0.001, Mann-Whitney U test). CONCLUSIONS: Splitting a muscle flap produces significantly less necrosis than incising the inset, regardless of whether the pedicle is in flow. It also offers wider exposure of structures deep to the flap. These findings provide a detailed model for human trials, which is presented as a proposed management algorithm. It also highlights conditions that must be met for translation to a human population. PMID- 28801080 TI - Reprint of "Anticancer activity of hydroxy- and sulfonamide-azobenzene platinum(II) complexes in cisplatin-resistant ovarian cancer cells". AB - The syntheses of three platinum(II) complexes bearing sulfonamide-((E)-2-(4 methylphenylsulfonamido)-2',6'-difluoroazobenzene, HL1) and hydroxy-azo-2,6 difluorobenzene ((E)-2-((2,6-difluorophenyl)diazenyl)phenol, HL2) bidentate ligands is described. These complexes, [Pt(L1)(DMSO)Cl] (1), [Pt(L2)(DMSO)Cl] (2), and [Pt(L2)2] (3), were characterized by multinuclear NMR spectroscopy, mass spectrometry, and X-ray crystallography. Despite bearing azobenzene functional groups, none of the three complexes undergo photoisomerization. The anticancer activities of these complexes were evaluated in wild-type (A2780) and cisplatin resistant (A2780CP70) ovarian cancer cells. All three complexes exhibited IC50 values below 10MUM and displayed similar activity in both A2780 and A2780CP70 cell lines, indicating that they are not cross-resistant with cisplatin. The DNA binding properties of 1-3 were investigated by circular dichroism spectroscopy and by agarose gel electrophoresis. Both studies suggest that 1 and 2 form monofunctional DNA adducts. PMID- 28801081 TI - Effects of Therapeutic Touch on Healing of the Skin in Rats. AB - CONTEXT: Therapeutic touch is a complementary treatment directed toward the balance of the energy field surrounding living beings. OBJECTIVE: This study's aim was to investigate the effect of therapeutic touch on wound area contraction and fibroblast proliferation in rat skin. DESIGN: This study was conducted using 24 male Wistar rats with dorsal wounds of diameter 8mm. The rats were divided into the following two groups: a control group: in this, the wounds were sanitized with filtered water and neutral-pH soap and a treatment group: in this, the wounds were sanitized as in the control group but the rats also underwent to daily sessions of therapeutic touch. Wound area was measured on days 1, 4, and 7 using imagelab software, version 2.4 R.C. On days 4 and 7, six animals in each group were euthanized so that the lesioned tissue could be collected for fibroblast counts and histological evaluations. RESULTS: On days 1 and 4, wound areas were similar in both groups. Moreover, no significant differences in fibroblast counts were observed on day 4. On day 7, however, fibroblast counts were significantly higher in the treated group than in the control group, with a subsequent wound shrinkage. CONCLUSION: These data indicate that therapeutic touch may accelerate wound repair, possibly by increasing fibroblast activity. PMID- 28801082 TI - "How To" Videos Improve Residents Performance of Essential Perioperative Electronic Medical Records and Clinical Tasks. AB - OBJECTIVE: The ability to use electronic medical records (EMR) is an essential skill for surgical residents. However, frustration and anxiety surrounding EMR tasks may detract from clinical performance. We created a series of brief, 1-3 minutes "how to" videos demonstrating 7 key perioperative EMR tasks: booking OR cases, placing preprocedure orders, ordering negative-pressure wound dressing supplies, updating day-of-surgery history and physical notes, writing brief operative notes, discharging patients from the postanesthesia care unit, and checking vital signs. Additionally, we used "Cutting Insights"-a locally developed responsive mobile application for surgical trainee education-as a platform for providing interns with easy access to these videos. We hypothesized that exposure to these videos would lead to increased resident efficiency and confidence in performing essential perioperative tasks, ultimately leading to improved clinical performance. METHODS: Eleven surgery interns participated in this initiative. Before watching the "how to" videos, each intern was timed performing the aforementioned 7 key perioperative EMR tasks. They also underwent a simulated perioperative emergency requiring the performance of 3 of these EMR tasks in conjunction with 5 other required interventions (including notifying the chief resident, the anesthesia team, and the OR coordinator; and ordering fluid boluses, appropriate laboratories, and blood products). These simulations were scored on a scale from 0 to 8. The interns were then directed to watch the videos. Two days later, their times for performing the 7 tasks and their scores for a similar perioperative emergency simulation were once again recorded. Before and after watching the videos, participants were surveyed to assess their confidence in performing each EMR task using a 5-point Likert scale. We also elicited their opinions of the videos and web-based mobile application using a 5 point scale. Statistical analyses to assess for statistical significance (p <= 0.05) were conducted using paired t-test for parametric variables and a Wilcoxon matched-pair test for nonparametric variables. SETTING: Hospital of the University of Pennsylvania, Philadelphia, PA (a quaternary teaching hospital within the University of Pennsylvania Health System). PARTICIPANTS: Eleven out of 15 interns (12 entered and 11 completed the study) from our categorical and preliminary general surgery residency programs during the 2016 academic year. RESULTS: Before exposure to the brief "how to" videos, 6 of 11 interns were unable to complete all 7 EMR tasks; after exposure, all 11 interns were able to complete all 7 EMR tasks. Moreover, interns' times for each task improved following exposure. Interns self-reported improved confidence in booking an OR case (4 +/- 0.9 vs. 4.7 +/- 0.6, p = 0.05), ordering negative-pressure wound therapy supplies (3.1 +/- 1.6 vs. 4.5 +/- 0.7, p < 0.05), writing a brief operative note (3.7 +/- 1.2 vs. 4.6 +/- 0.7, p = 0.05), discharging patients from the postanesthesia care unit (3.3 +/- 1.0 vs. 4.4 +/- 0.8, p < 0.05), checking vital signs (2.5 +/- 1.4 vs. 4.5 +/- 0.8, p <= 0.01), and performing necessary EMR tasks during an emergency situation (2.4 +/- 0.8 vs. 4.6 +/- 0.7, p <= 0.0001). Participants also demonstrated a significant improvement in average clinical score on the emergency simulations (5.2 +/- 1.7 vs. 6.6 +/- 0.9, p < 0.05). Interns' opinions of the videos and the mobile phone application were favorable. CONCLUSIONS: In our group of 11 surgery interns, exposure to a series of short "how to" videos led to increased confidence and shortened times in performing 7 essential EMR tasks. Additionally, during a simulated perioperative emergency, EMR tasks were performed significantly faster. Clinical performance also improved significantly following exposure to the videos. This just-in-time educational intervention could improve workflow efficiency and clinical performance, both of which may ultimately enhance perioperative patient safety. PMID- 28801083 TI - Halsted's "See One, Do One, and Teach One" versus Peyton's Four-Step Approach: A Randomized Trial for Training of Laparoscopic Suturing and Knot Tying. AB - BACKGROUND: This study aimed to compare the effectiveness of Halsted's method "see one, do one, and teach one" with Peyton's Four-Step Approach for teaching intracorporal suturing and knot tying (ICKT). METHODS: Laparoscopically naive medical students (n = 60) were randomized to teaching of ICKT with either Halsted's (n = 30) or Peyton's method (n = 30) for 60 minutes. Each student's first 3 and final sutures were evaluated using Objective Structured Assessment of Technical Skills (OSATS), procedural implementation, knot quality, total time, and suture placement accuracy. RESULTS: Performance score and OSATS-PSC always differed significantly in favor of Peyton's group (p = 0.001). OSATS-GRS (p = 0.01) and task time (p = 0.03) differed only in the summary of the first 3 sutures in favor of Peyton's group. There were no significant intergroup differences in knot quality and accuracy. CONCLUSIONS: Peyton's Four-Step Approach is the preferable method for learning complex laparoscopic skills like ICKT. PMID- 28801084 TI - The diagnostic trial of iron replacement therapy even in normocytic anaemia. PMID- 28801085 TI - Measuring in vivo cerebral maturation using age-related T2 relaxation times at 3T. AB - OBJECTIVE: To examine age-related changes in T2 relaxation times during infancy and childhood in order to assess T2 values obtained from routine MRI as a biomarker. METHODS: From our pool of clinical pediatric MRI examinations at 3T all patients with normal conventional MRI scans were retrospectively selected. Depending on their clinical findings the identified 99 patients (0-199months) were divided into 43 healthy controls and 56 diseased children with various clinical abnormalities (developmental delay, epilepsy, prematurity, and deafness). T2 maps based on routinely performed triple echo turbo spin echo sequences were created. T2 values were measured in 22 brain regions to determine age-related changes. We also investigated whether such changes differ between healthy and diseased children. RESULTS: Age significantly reduced T2 relaxation times across all regions (p<0.05), but health status had no impact. With increasing age, T2 values decreased continuously, with declines faster over the first 10months and slower thereafter. Early rapid and later slow decline was similar in healthy and diseased groups. CONCLUSIONS: Using T2 maps based on clinical MRI data we could determine age-related T2 relaxation times in 22 brain regions during infancy and childhood. Our data have relevance for future investigator independent T2 relaxation time measurements in determining whether T2 values are within the normal range or should be considered as potentially pathologic. PMID- 28801086 TI - Slowly progressive leukodystrophy in an adolescent male with phosphoglycerate kinase deficiency. AB - We report the case of an 18-year-old man with a phosphoglycerate kinase (PGK) deficiency who had slowly progressive leukodystrophy during adolescence. The patient had a history of severe neonatal jaundice, hemolytic crisis with rhabdomyolysis triggered by febrile viral infections, dysarthria, and intellectual disability during early childhood. Clumsiness in walking and writing became obvious at ~10years of age. Evaluations performed by us on the 18-year-old patient confirmed the presence of pyramidal tract signs, increased muscle tone, and generalized dystonia. Brain magnetic resonance (MR) imaging revealed leukodystrophy in the periventricular white matter, posterior limbs of the internal capsule, dorsal pons, and middle cerebellar peduncles. Compared to MR images acquired at 9years of age, MR images acquired at 18years of age showed that the white matter atrophy had progressed. The PGK deficiency was diagnosed by identifying a known missense mutation in PGK1 (c.1060G>C) through comprehensive target capture sequencing and by observing low PGK activity in his red blood cells. The patient underwent a ketogenic diet for 2weeks, which we expected would increase adenosine triphosphate levels through sources other than the PGK associated glycolytic pathway. The diet was not tolerated owing to the unexpected emergence of hemolysis. Hemolytic anemia, neurological dysfunction, and myopathy are often associated with PGK deficiencies. However, leukodystrophy as a symptom of PGK deficiency has not been reported previously. Our case highlights the progressive nature of the neurological complications related to PGK deficiencies. Therefore, long-term follow-up is recommended, even if neurological impairments are not obvious during childhood. PMID- 28801087 TI - Cause of acute encephalitis/encephalopathy in Japanese children diagnosed by a rapid and comprehensive virological detection system and differences in their clinical presentations. AB - BACKGROUND: Acute encephalitis/encephalopathy (AE/E) is a rare and severe complication of common childhood infections; however, a treatment strategy based on clinical and pathological evidence has not been established. METHODS: The clinical data and aetiological results using a rapid and comprehensive virological detection system of 62 Japanese children diagnosed with AE/E from 2010 to 2014 were collected. We assessed clinical differences between causes and effectiveness of our multiplex PCR system to establish a pathogen-based treatment strategy for AE/E. RESULTS: Suspected causes were detected in 84% of patients, and our multiplex PCR system contributed to diagnosing 38% of the patients. Furthermore, a negative virus PCR might be important for inferring underlying disease. Most cases were triggered by human herpes virus (HHV) 6/7 (32%) and influenza virus (24%). The causes of AE/E depended on age (p=0.00089) but not on sex (p=0.94). The median age of HHV6/7-associated AE/E was 2.3years, which is lower than the median ages of AE/E associated with other viruses. Major initial treatments were pulse steroid therapy (83.9%) and acyclovir (71%). Most of the patients in this study had good prognoses: 77% recovered without neurological sequalae. CONCLUSIONS: Our virological detection system was useful for detecting the cause of AE/E, and may also contribute to construction of pathogen-based treatment strategies for AE/E. Our data indicated the possibility that early intervention with pulse steroid therapy could be effective for treating AE/E. Further investigation for selection of antiepileptic drugs and additional therapies might be required to prevent progression of AE/E. PMID- 28801089 TI - Clinical and microbiological characteristics of patients with bacteremia caused by Campylobacter species with an emphasis on the subspecies of C. fetus. AB - OBJECTIVES: This study was intended to investigate the clinical and microbiological characteristics of patients with bacteremia caused by Campylobacter species. METHODS: From April 1998 to May 2014, 56 adults with bacteremia caused by Campylobacter species were evaluated. These Campylobacter species isolates were confirmed to the species level using 16S rRNA gene sequencing (all isolates) and multiplex PCR analysis (for C. fetus only). The performance of identification for Campylobacter species by the Bruker Biotyper MALDI-TOF MS was evaluated. The genetic relatedness of C. fetus isolates was analyzed by multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE). RESULTS: The leading underlying medical conditions of these patients were malignancy (46.4%), hypertension (35.7%), and liver cirrhosis (23.2%). The overall 30-day mortality rate was 5.4%. Using 16S rRNA sequencing analysis, 26 isolates of C. coli, 11 of C. jejuni, and 19 of C. fetus, including 15 C. fetus subsp. fetus and five C. fetus subsp. venerealis, were identified. Among the five C. fetus subsp. venerealis isolates recognized by 16S rRNA gene sequencing, only two isolates were C. fetus subsp. venerealis by multiplex PCR method. The Bruker Biotyper MALDI-TOF MS failed to correctly identify C. fetus subsp. venerealis isolates. MLST analysis of C. fetus isolates revealed three STs: ST20 (n = 12), ST11 (n = 5), and ST57 (n = 2), which were compatible with three major PFGE clusters. CONCLUSION: Database expansion of MALDI-TOF MS for the correct identification of C. fetus to subspecies levels is needed. A novel clone of ST57-PFGE Cluster C of C. fetus subsp. venerealis was noted. PMID- 28801088 TI - Characteristics of severe asthma with fungal sensitization. AB - BACKGROUND: Some patients with severe asthma also have fungal sensitization and are considered to have severe asthma with fungal sensitization. However, there is limited information on the clinical features of SAFS. OBJECTIVE: To investigate the clinical characteristics of severe asthma with fungal sensitization. METHODS: The present study enrolled 124 patients with severe asthma. We evaluated clinical aspects, such as various serum cytokines, fractional exhaled nitric oxide, pulmonary function, and serum immunoglobulin E (IgE). Fungal sensitization was assessed by determining serum levels of IgE specific to fungal allergens (Aspergillus, Alternaria, Candida, Cladosporium, Penicillium, and Trichophyton species and Schizophyllum commune). The protocol was registered at a clinical trial registry (www.umin.ac.jp/ctr/index-j.htm; UMIN 000002980). RESULTS: Thirty six patients (29%) showed sensitization to at least 1 fungal allergen. The most common species were Candida (16%), Aspergillus (11%), and Trichophyton (11%). The rate of early-onset asthma (<16 years of age) was higher in patients with fungal sensitization than in those without fungal sensitization (45% vs 25%; P = .02). Interleukin-33 levels were higher in patients with fungal sensitization than in those without fungal sensitization. Of patients with atopic asthma, Asthma Control Test scores were worse in patients with multiple fungal sensitizations than in patients with a single fungal sensitization or those without fungal sensitization. CONCLUSION: Severe asthma with fungal sensitization is characterized by early onset of disease and high serum levels of interleukin-33. Multiple fungal sensitizations are associated with poor asthma control. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN-CTR; www.umin.ac.jp/ctr/index j.htm): UMIN 000002980. PMID- 28801090 TI - Leptin concentrations and SCD-1 indices in classical homocystinuria: Evidence for the role of sulfur amino acids in the regulation of lipid metabolism. AB - BACKGROUND: We describe body composition, lipid metabolism and Stearoyl-CoA desaturase-1 (SCD-1) indices in patients with classical homocystinuria (HCU). METHODS: Eleven treated HCU patients and 16 healthy controls were included. Body composition and bone mineral density were assessed by dual X-ray absorptiometry. Sulfur amino acids (SAA) and their derivatives (total homocysteine, cysteine, methionine, S-adenosylmethionine, S-adenosylhomocysteine, and glutathione), lipids (free fatty acids, acylcarnitines, triglycerides and lipoproteins), glucose, insulin, leptin, adiponectin, and isoprostanes were measured in plasma. Insulin resistance was evaluated by HOMA-IR. To estimate liver SCD-1 activity, SCD-16 [16:1(n-7)/16:0] and SCD-18 [18:1(n-9)/18:0] desaturation indices were determined. RESULTS: In HCU patients, SCD-16 index was significantly reduced (p=0.03). A trend of an association of SCD-16 index with cysteine was observed (r=0.624, p=0.054). HCU patients displayed lower lean mass (p<0.05), with no differences in fat mass percentage. Leptin and low-density lipoprotein concentrations were lower in HCU patients (p<0.05). Femur bone mineral density Z scores were correlated with plasma cysteine (r=0.829; p=0.04) and total homocysteine (r=-0.829; p=0.04) in HCU patients. CONCLUSIONS: We report alterations in leptin and SCD-1 in HCU patients. These results agree with previous findings from epidemiologic and animal studies, and support a role for SAA on lipid homeostasis. PMID- 28801091 TI - How much is too much? Two contrasting cases of excessive vitamin D supplementation. AB - BACKGROUND: In this report, we describe 2 contrasting cases of hypervitaminosis D. CASE PRESENTATION: Patient 1 was a 75-y old man who developed symptomatic hypercalcemia (peak serum calcium concentration of 15.3mg/dl; reference range: 8.5-10.6mg/dl), cardiac injury, and a high total serum vitamin D concentration of 243ng/ml (30-80ng/ml) as a result of daily consumption of prescribed 50,000IU ergocalciferol (vitamin D2) and 500mg calcium-citrate for 1y. Patient 2 was a 60 y old woman who consumed 40,000IU of cholecalciferol (vitamin D3) daily for >10months with a peak total serum vitamin D concentration of 479ng/ml (30 80ng/ml), but did not present with symptoms related to vitamin D toxicity. CONCLUSION: These cases demonstrate that individual responses to supraphysiologic concentrations of vitamin D for extended periods of time vary widely, and that defining a toxic concentration of this vitamin is difficult. The different outcomes in these two patients, despite months of high-dose vitamin D therapy, demonstrates that individual patient pharmacodynamics determine clinical sequelae. PMID- 28801092 TI - Anterior segment optical coherence tomography for the diagnosis of corneal dystrophies according to the IC3D classification. AB - Corneal dystrophies are categorized according to the International Committee for Classification of Corneal Dystrophies (IC3D) classification, and their treatment depends on the affected structures and layer of the cornea. Therefore, estimating the depth and extent of the morphological changes due to the specific dystrophy is crucial when deciding between different treatment options. Besides superficial laser treatments and penetrating keratoplasty, minimal invasive lamellar keratoplasties such as Descemet membrane endothelial keratoplasty, deep anterior lamellar keratoplasty, or Descemet stripping automated keratoplasty have become increasingly popular to exchange the specific opaque layers in dystrophic eyes. To determine the morphological changes of the cornea in the different dystrophies, in addition to slit-lamp examination, anterior segment optical coherence tomography has become an important tool with nearly histological resolution. Nonetheless, only a few case series describe the characteristics of changes seen on anterior segment optical coherence tomography. Therefore, we summarize anterior segment optical coherence tomography signs and correlate with slit-lamp examination, as well as the histopathological findings, of corneal dystrophies according to the IC3D classification. PMID- 28801093 TI - Current developments and applications of microfluidic technology toward clinical translation of nanomedicines. AB - Nanoparticulate drug delivery systems hold great potential for the therapy of many diseases, especially cancer. However, the translation of nanoparticulate drug delivery systems from academic research to industrial and clinical practice has been slow. This slow translation can be ascribed to the high batch-to-batch variations and insufficient production rate of the conventional preparation methods, and the lack of technologies for rapid screening of nanoparticulate drug delivery systems with high correlation to the in vivo tests. These issues can be addressed by the microfluidic technologies. For example, microfluidics can not only produce nanoparticles in a well-controlled, reproducible, and high throughput manner, but also create 3D environments with continuous flow to mimic the physiological and/or pathological processes. This review provides an overview of the microfluidic devices developed to prepare nanoparticulate drug delivery systems, including drug nanosuspensions, polymer nanoparticles, polyplexes, structured nanoparticles and theranostic nanoparticles. We also highlight the recent advances of microfluidic systems in fabricating the increasingly realistic models of the in vivo milieu for rapid screening of nanoparticles. Overall, the microfluidic technologies offer a promise approach to accelerate the clinical translation of nanoparticulate drug delivery systems. PMID- 28801094 TI - Effect of gamma irradiation on the physicochemical and structural properties of plant seed gums. AB - The objective of the study was to evaluate the effect of irradiation (0-5 kGy) on the physicochemical properties of two seed gums (guar and locust bean gum). The Hunter color parameters changed upon irradiation, namely "L" value decreased, whereas "a" and "b" values, i.e. redness and yellowness, increased. Irradiation reduced the final viscosity of gums at neutral and acidic pH. Increase in irradiation dose (0-5 kGy) increased the water absorption in the range of 11.75 14.61g/g and 20.04-23.99g/g in guar gum and locust bean gum, respectively. Rheological study of the gums revealed their gel behaviour with higher values of G' than G". G' in native guar gum was observed to increase in the range of 880.39 1332.29Pa while G" increased in the range of 194.21-239.77Pa as the test frequency was raised from 14.6-100s-1. In native locust bean gum, the G' and G" varied in the range of 476.50-1230.50Pa and 300.65-380.30Pa, respectively, under the applied frequency sweep. FT-IR revealed the presence of CH, COOH and CO groups in the guar as well as locust bean gum, in addition to the uronic acid and pyranose rings. The absorption of the functional groups declined upon irradiation. PMID- 28801095 TI - Fabrication of chitosan/poly(lactic acid)/graphene oxide/TiO2 composite nanofibrous scaffolds for sustained delivery of doxorubicin and treatment of lung cancer. AB - In this work, the synthesized graphene oxide/TiO2/doxorubicin (GO/TiO2/DOX) composites were loaded into the chitosan/poly(lactic acid) (PLA) solutions to fabricate the electrospun chitosan/PLA/GO/TiO2/DOX nanofibrous scaffolds via electrospinning process. The synthesized composites and nanofibers were characterized using X-ray powder diffraction (XRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analysis. Three-factor three level central composite design was used to determine the influence of PLA to chitosan ratio, TiO2/DOX content and GO/TiO2/DOX content on the release of DOX from nanofibrous scaffolds. Drug loading efficiency and drug release behavior from nanofibers were investigated. The higher sustained release rate of DOX following the small burst release were achieved from nanofibrous scaffolds with 30 and 50MUm thicknesses within two weeks incubation time. The faster DOX release rate from nanofibers was obtained in pH 5.3 compared to pH 7.4. Korsmayer-Peppas kinetic model was used to determine the DOX release mechanism from nanofibers. The cell viability results showed the higher proliferation inhibition effect of nanofibers on target lung cancer cells in the presence of magnetic field. PMID- 28801096 TI - A comparative study of the properties and self-aggregation behavior of collagens from the scales and skin of grass carp (Ctenopharyngodon idella). AB - Collagens were extracted from the scales and skin of Ctenopharyngodon idella (C. idella) as raw materials using an acid-enzyme hybrid method. The structural properties of the extracted collagens were compared using ultraviolet-visible spectrophotometry, Fourier transform infrared spectroscopy, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and differential scanning calorimetry. Additionally, the in vitro self-aggregation behaviors of the two types of collagens (fish skin- and scale-derived collagens) were compared using turbidimetric assays, aggregation assays, and scanning electron microscopy (SEM). The results showed that both types of extracted collagen were typical type I collagen with two alpha chains and intact triple-helical structures. The denaturation temperatures of the collagens from fish scales and skin were 34.99 degrees C and 39.75 degrees C, respectively. Both types of collagens were capable of self-aggregation in neutral salt solution at 30 degrees C, with aggregation degrees of 28% and 27.33% for the scale and skin collagens, respectively. SEM analysis revealed that both types of collagens could self-aggregate into interwoven fibers, and the fish scale-derived collagen had a more pronounced reticular fiber structure with a striped periodic D-band pattern of collagen fibrils, whereas the collagen fibers from the self-aggregation of fish skin derived collagen had a certain degree of disruption without any D-band pattern. PMID- 28801097 TI - Chicken feathers as a natural source of sulphur to develop sustainable protein films with enhanced properties. AB - In this work, the effect of hydrolyzed keratin on the properties of soy protein based films was analyzed when different manufacture processes were employed. It is widely known that the processing method selected can affect the film properties as a function of the structure obtained during the film formation. Therefore, the assessment of hydrolyzed keratin/soy protein films processed by casting and compression moulding was carried out by means of the analysis of physicochemical, thermal, mechanical, optical and surface properties. It was observed that the incorporation of hydrolyzed keratin, obtained from a simpler, environmentally friendlier and more sustainable extraction method, resulted in the improvement of the thermal stability of the films, irrespective of the processing method employed. Moreover, the films processed by compression moulding showed enhanced tensile strength, which increased with the incorporation of hydrolyzed keratin due to the formation of disulfide bonds. PMID- 28801098 TI - Synthesis and in vitro evaluation of Ca2+ channel blockers 1,4-dihydropyridines analogues against Trypanosoma cruzi and Leishmania amazonensis: SAR analysis. AB - Drugs containing the1,4-dihydropyridine (DHP) core have recently attracted attention concerning their antiparasitic effect against various species of Leishmania and Trypanosoma. This approach named drugs repositioning led to interesting results, which have prompted us to prepare 21 DHP's analogues. The 1,4-DHP scaffold was decorated with different function groups at tree points including the nitrogen atom (NH and N-phenyl), the aryl group attached to C-4 (various substituted aryl residues) and the carbon atoms 2 and 6 (bearing Ph or Me groups). Moreover, the products were evaluated for their cytotoxicity on three cancer and a non-tumoral cell lines. Only 6 of them were antiproliferative and their weak effect (CC50 comprised between 27 and 98MUM) suggested these DHPs as good candidates against the intracellular amastigote forms of L. amazonensis and T. cruzi. L. amazonensis was sensitive to DHPs 5, 11 and 15 (IC50 values at 15.11, 45.70 and 53.13MUM, respectively) while 12 of them displayed significant to moderate trypanocidal activities against T. cruzi. The best trypanocidal activities were obtained with compounds 2, 18 and 21 showing IC50 values at 4.95, 5.44, and 6.64MUM, respectively. A part of the N-phenylated DHPs showed a better selectivity than their NH analogues towards THP-1 cells. 4-Chlorophenyl, 4 nitrophenyl and 3-nitrophenyl residues attached to the carbon atom 4 turned to be important sub-structures for the antitrypanosomal activity. PMID- 28801099 TI - Immediate reduction of serum citrulline but no change of steroid profile after initiation of metformin in individuals with type 2 diabetes. AB - Metformin is the most important first-line treatment for type 2 diabetes mellitus (T2DM) but its exact mode of action remains unknown. In this study, we used targeted metabolomics to gain new insights into the metabolic effects of metformin in humans with T2DM. We also examined changes in the serum steroid hormone profile. We quantified 167 serum metabolites and 19 steroid hormones using liquid chromatography-tandem mass spectrometry at three time points in individuals with previously untreated T2DM: before the start of metformin therapy (time point A), after the first dose (B) and after short-term therapy for 4-6 weeks (C). For metabolite analysis, we split the study cohort into a discovery and a replication study of 88 and 45 subjects, respectively. The statistical analysis was done using linear mixed-effects models. Among the metabolites quantified, citrulline showed the most pronounced changes. Compared to its baseline serum concentration, citrulline was reduced by 17% after the first dose of metformin (p=1.34E-07) and by 24% after short-term therapy (p=2.84E-08) in the discovery study. These results were confirmed in the replication study. The only other metabolite significantly changed after correction for multiple testing was PC ae C36:4 between baseline and 4-6 weeks. The serum steroid hormone profile showed no significant changes after metformin intake. In summary, we observed an immediate and sustained reduction of serum citrulline by metformin in humans. This may be relevant for some of the wanted or unwanted effects of the drug. PMID- 28801101 TI - Calcium signaling and cell cycle: Progression or death. AB - Cytosolic Ca2+ concentration levels fluctuate in an ordered manner along the cell cycle, in line with the fact that Ca2+ is involved in the regulation of cell proliferation. Cell proliferation should be an error-free process, yet is endangered by mistakes. In fact, a complex network of proteins ensures that cell cycle does not progress until the previous phase has been successfully completed. Occasionally, errors occur during the cell cycle leading to cell cycle arrest. If the error is severe, and the cell cycle checkpoints work perfectly, this results into cellular demise by activation of apoptotic or non-apoptotic cell death programs. Cancer is characterized by deregulated proliferation and resistance against cell death. Ca2+ is a central key to these phenomena as it modulates signaling pathways that control oncogenesis and cancer progression. Here, we discuss how Ca2+ participates in the exogenous and endogenous signals controlling cell proliferation, as well as in the mechanisms by which cells die if irreparable cell cycle damage occurs. Moreover, we summarize how Ca2+ homeostasis remodeling observed in cancer cells contributes to deregulated cell proliferation and resistance to cell death. Finally, we discuss the possibility to target specific components of Ca2+ signal pathways to obtain cytostatic or cytotoxic effects. PMID- 28801102 TI - Editorial overview: Chemical genetics and epigenetics. PMID- 28801103 TI - Melanocortin receptors. PMID- 28801100 TI - Neuroendocrine disruption in animal models due to exposure to bisphenol A analogues. AB - Animal and human studies provide evidence that exposure to the endocrine disrupting chemical (EDC), bisphenol A (BPA), can lead to neurobehavioral disorders. Consequently, there is an impetus to identify safer alternatives to BPA. Three bisphenol compounds proposed as potential safer alternatives to BPA are bisphenol S (BPS), bisphenol F (BPF), and bisphenol AF (BPAF). However, it is not clear whether these other compounds are safer in terms of inducing less endocrine disrupting effects in animals and humans who are now increasingly coming into contact with these BPA-substitutes. In the past few years, several animal studies have shown exposure to these other bisphenols induce similar neurobehavioral disruption as BPA. We will explore in this review article the current studies suggesting these other bisphenols result in neuroendocrine disruptions that may be estrogen receptor-dependent. Current work may aide in designing future studies to test further whether these BPA-substitutes can act as neuroendocrine disruptors. PMID- 28801105 TI - Rectal swab screening assays of public health importance in molecular diagnostics: Sample adequacy control. AB - Rectal swabs are routinely used by public health authorities to screen for multi drug resistant enteric bacteria including vancomycin-resistant enterococci (VRE) and carbapenem-resistant enterobacteriaceae (CRE). Screening sensitivity can be influenced by the quality of the swabbing, whether performed by the patient (self swabbing) or a healthcare practitioner. One common exclusion criterion for rectal swabs is absence of "visible soiling" from fecal matter. In our institution, this criterion excludes almost 10% of rectal swabs received in the microbiology laboratory. Furthermore, over 30% of patients in whom rectal swabs are cancelled will not be re-screened within the next 48h, resulting in delays in removing infection prevention measures. We describe two quantitative polymerase chain reaction (qPCR)-based assays, human RNAse P and eubacterial 16S rDNA, which might serve as suitable controls for sampling adequacy. However, lower amounts of amplifiable human DNA make the 16s rDNA assay a better candidate for sample adequacy control. PMID- 28801104 TI - n-Alcohol Length Governs Shift in Lo-Ld Mixing Temperatures in Synthetic and Cell Derived Membranes. AB - A persistent challenge in membrane biophysics has been to quantitatively predict how membrane physical properties change upon addition of new amphiphiles (e.g., lipids, alcohols, peptides, or proteins) in order to assess whether the changes are large enough to plausibly result in biological ramifications. Because of their roles as general anesthetics, n-alcohols are perhaps the best-studied amphiphiles of this class. When n-alcohols are added to model and cell membranes, changes in membrane parameters tend to be modest. One striking exception is found in the large decrease in liquid-liquid miscibility transition temperatures (Tmix) observed when short-chain n-alcohols are incorporated into giant plasma membrane vesicles (GPMVs). Coexisting liquid-ordered and liquid-disordered phases are observed at temperatures below Tmix in GPMVs as well as in giant unilamellar vesicles (GUVs) composed of ternary mixtures of a lipid with a low melting temperature, a lipid with a high melting temperature, and cholesterol. Here, we find that when GUVs of canonical ternary mixtures are formed in aqueous solutions of short-chain n-alcohols (n <= 10), Tmix increases relative to GUVs in water. This shift is in the opposite direction from that reported for cell-derived GPMVs. The increase in Tmix is robust across GUVs of several types of lipids, ratios of lipids, types of short-chain n-alcohols, and concentrations of n alcohols. However, as chain lengths of n-alcohols increase, nonmonotonic shifts in Tmix are observed. Alcohols with chain lengths of 10-14 carbons decrease Tmix in ternary GUVs of dioleoyl-PC/dipalmitoyl-PC/cholesterol, whereas 16 carbons increase Tmix again. Gray et al. observed a similar influence of the length of n alcohols on the direction of the shift in Tmix. These results are consistent with a scenario in which the relative partitioning of n-alcohols between liquid ordered and liquid-disordered phases evolves as the chain length of the n-alcohol increases. PMID- 28801106 TI - Comparison of caged and native blue mussels (Mytilus edulis spp.) for environmental monitoring of PAH, PCB and trace metals. AB - Contaminant bioaccumulation was studied in blue mussels (Mytilus edulis spp.) using the harbor waters of Kristiansand (Norway) as a case study. A suite of chemical contaminants (trace metals, PAHs and PCBs) was analyzed in caged and native mussels as well as in passive samplers (Diffusive Gradients in Thin films (DGT)-devices and silicone rubbers) placed alongside the mussels for estimation of contaminant concentrations in water and uptake rates and bioaccumulation factors (BAFs) in mussels during a six-months deployment period. Estimated logBAFs were in the ranges 2.3-5.5, 3.8-5.2 and 3.2-4.4 for metals, PCBs and PAHs, respectively. Contaminant levels in caged mussels increased rapidly to stable levels for trace metals, whereas for hydrophobic organic contaminants the increase was steady but slow and for many compounds did not reach the levels observed in native mussels. Some key issues related to mussel caging design, such as mussel deployment time and confounding influence from seasonal fluctuations, are discussed herein. PMID- 28801107 TI - Nanoprecipitation process: From encapsulation to drug delivery. AB - Drugs encapsulation is a suitable strategy in order to cope with the limitations of conventional dosage forms such as unsuitable bioavailability, stability, taste, and odor. Nanoprecipitation technique has been used in the pharmaceutical and agricultural research as clean alternative for other drug carrier formulations. This technique is based on precipitation mechanism. Polymer precipitation occurs after the addition of a non-solvent to a polymer solution in four steps mechanism: supersaturation, nucleation, growth by condensation, and growth by coagulation that leads to the formation of polymer nanoparticles or aggregates. The scale-up of laboratory-based nanoprecipitation method shows a good reproducibility. In addition, flash nanoprecipitation is a good strategy for industrial scale production of nanoparticles. Nanoprecipitation is usually used for encapsulation of hydrophobic or hydrophilic compounds. Nanoprecipitation was also shown to be a good alternative for the encapsulation of natural compounds. As a whole, process and formulation related parameters in nanoprecipitation technique have critical effect on nanoparticles characteristics. Biodegradable or non-biodegradable polymers have been used for the preparation of nanoparticles intended to in vivo studies. Literature studies have demonstrated the biodistribution of the active loaded nanoparticles in different organs after administration via various routes. In general, in vitro drug release from nanoparticles prepared by nanoprecipitation includes two phases: a first phase of "burst release" which is followed by a second phase of prolonged release. Moreover, many encapsulated active molecules have been commercialized in the pharmaceutical market. PMID- 28801108 TI - Breaching barriers in glioblastoma. Part II: Targeted drug delivery and lipid nanoparticles. AB - Tailored nanocarriers have gained huge research focus for brain drug delivery, aimed at combating several neuro-oncological conditions, such as the glioblastoma multiforme (GBM). The progress of knowledge on the pathogenesis of GBM has allowed identifying the major hurdles for efficient treatment, encompassing biological interfaces (blood-brain barrier and blood-brain tumour barrier), specificities of tumour microenvironment, as well as both bulk and glioma stem cell subpopulations. These findings provided new insights into the molecular basis of GBM, being a strong driving force behind development of targeted nanomedicines in this area. Diversified nanoparticles have been designed to target GBM surface markers, overexpressed receptors, aberrant genes and signalling pathways, in addition to contemplating barriers targeting strategies. Among the nanocarriers explored, lipid nanoparticles claim important and unique features, including the versatility in promoting both passive and active drug targeting, making them excellent candidates for brain drug delivery and one of the most appealing to overcome the obstacles of the current GBM treatment. PMID- 28801109 TI - Modelling and understanding powder flow properties and compactability of selected active pharmaceutical ingredients, excipients and physical mixtures from critical material properties. AB - The development of solid dosage forms and manufacturing processes are governed by complex physical properties of the powder and the type of pharmaceutical unit operation the manufacturing processes employs. Suitable powder flow properties and compactability are crucial bulk level properties for tablet manufacturing by direct compression. It is also generally agreed that small scale powder flow measurements can be useful to predict large scale production failure. In this study, predictive multilinear regression models were effectively developed from critical material properties to estimate static powder flow parameters from particle size distribution data for a single component and for binary systems. A multilinear regression model, which was successfully developed for ibuprofen, also efficiently predicted the powder flow properties for a range of batches of two other active pharmaceutical ingredients processed by the same manufacturing route. The particle size distribution also affected the compactability of ibuprofen, and the scope of this work will be extended to the development of predictive multivariate models for compactability, in a similar manner to the approach successfully applied to flow properties. PMID- 28801111 TI - Luminescence resonance energy transfer spectroscopy of ATP-binding cassette proteins. AB - The ATP-binding cassette (ABC) superfamily includes regulatory and transport proteins. Most human ABC exporters pump substrates out of cells using energy from ATP hydrolysis. Although major advances have been made toward understanding the molecular mechanism of ABC exporters, there are still many issues unresolved. During the last few years, luminescence resonance energy transfer has been used to detect conformational changes in real time, with atomic resolution, in isolated ABC nucleotide binding domains (NBDs) and full-length ABC exporters. NBDs are particularly interesting because they provide the power stroke for substrate transport. Luminescence resonance energy transfer (LRET) is a spectroscopic technique that can provide dynamic information with atomic resolution of protein conformational changes under physiological conditions. Using LRET, it has been shown that NBD dimerization, a critical step in ABC proteins catalytic cycle, requires binding of ATP to two nucleotide binding sites. However, hydrolysis at just one of the sites can drive dissociation of the NBD dimer. It was also found that the NBDs of the bacterial ABC exporter MsbA reconstituted in a lipid bilayer membrane and studied at 37 degrees C never separate as much as suggested by crystal structures. This observation stresses the importance of performing structural/functional studies of ABC exporters under physiologic conditions. This article is part of a Special Issue entitled: Beyond the Structure-Function Horizon of Membrane Proteins edited by Ute Hellmich, Rupak Doshi and Benjamin McIlwain. PMID- 28801110 TI - Risk factors for 30-day readmission in patients with congestive heart failure. AB - BACKGROUND: Risk of readmission is elevated in patients congestive heart failure (CHF), and clinical decision makers need to better understand risk factors for 30 day readmissions. OBJECTIVE: To identify risk factors for readmission in patients with CHF. METHODS: We studied all admissions for patients with CHF during 2011 using a statewide discharge data set from Pennsylvania. The primary outcome was readmission to any Pennsylvania hospital within 30 days of discharge. RESULTS: Of 155,146 CHF patients admitted, 35,294 (22.8%) were readmitted within 30 days. Male sex, black race, coverage by Medicare, comorbidities, discharge to a skilled nursing facility or with a home nurse, a longer length of stay (LOS), admission from another facility, and emergent admission (all p < 0.001) were significant risk factors. CONCLUSIONS: Comorbidities, sociodemographic factors including male sex, age, black race and Medicare coverage, and prolonged length of stay are associated with increased risk of readmission in patients with CHF. PMID- 28801112 TI - Clinical efficacies of coracoclavicular ligament reconstruction using suture anchor versus hook plate in the treatment of distal clavicle fracture. AB - INTRODUCTION: Comparison of clinical efficacies between coracoclavicular ligament reconstruction using autologous gracilis tendon with suture anchor and clavicular hook plate for the treatment of acute Neer type II distal clavicle fracture. HYPOTHESIS: Both coracoclavicular reconstruction with autologous gracilis tendon and clavicular hook plate could achieve satisfactory results for treating acute Neer type II distal clavicle fracture. METHODS: Acute Neer type II distal clavicle fracture patients enrolled in this prospective randomized study were divided into the coracoclavicular ligament reconstruction group (using autologous gracilis tendon and suture anchor) and the hook plate group. Clinical outcomes were evaluated by shoulder X-ray, forward flexion, abduction and external rotation angle, Constant-Murley shoulder score and pain Visual Analogue Scale (VAS) at each follow-up for up to 24 months. RESULTS: The current study enrolled a total of 42 acute Neer type II distal clavicle fracture patients attended our hospital from March 2010 to December 2013. All patients had achieved complete healing and followed up for an average of 26 months (range, 24-38 months). At 3 month and 6-month follow-ups, Constant-Murley score in the ligament reconstruction group was significantly higher (93.8+/-2.6 vs. 88.7+/-8.7; 95.9+/ 2.7 vs. 93.0+/-7.0, P<0.05), while VAS score was poorer than those in the hook plate group (1.6+/-0.8 vs. 2.5+/-1.9; 1.1+/-1.0 vs. 1.6+/-1.7, P<0.05). DISCUSSION: Reconstruction with autologous gracilis tendon improved VAS pain score in early postoperation follow-up; while Constant-Murley score and VAS score were significantly improved in the hook plate group after the implant was removed. These suggested that both coracoclavicular reconstruction with autologous gracilis tendon and clavicular hook plate could achieve satisfactory results. LEVEL OF EVIDENCE: Level II, low-powered prospective randomized trial. PMID- 28801113 TI - Internet Delivery and Peer Support: New Venues for Psychosocial Interventions of Late-Life Depression. PMID- 28801114 TI - Effects of curcumin on short-term spatial and recognition memory, adult neurogenesis and neuroinflammation in a streptozotocin-induced rat model of dementia of Alzheimer's type. AB - Curcumin is a natural polyphenol with evidence of antioxidant, anti-inflammatory and neuroprotective properties. Recent evidence also suggests that curcumin increases cognitive performance in animal models of dementia, and this effect would be related to its capacity to enhance adult neurogenesis. The aim of this study was to test the hypothesis that curcumin treatment would be able to preserve cognition by increasing neurogenesis and decreasing neuroinflammation in the model of dementia of Alzheimer's type induced by an intracerebroventricular injection of streptozotocin (ICV-STZ) in Wistar rats. The animals were injected with ICV-STZ or vehicle and curcumin treatments (25, 50 and 100mg/kg, gavage) were performed for 30days. Four weeks after surgery, STZ-lesioned animals exhibited impairments in short-term spatial memory (Object Location Test (OLT) and Y maze) and short-term recognition memory (Object Recognition Test - ORT), decreased cell proliferation and immature neurons (Ki-67- and doublecortin positive cells, respectively) in the subventricular zone (SVZ) and dentate gyrus (DG) of hippocampus, and increased immunoreactivity for the glial markers GFAP and Iba-1 (neuroinflammation). Curcumin treatment in the doses of 50 and 100mg/kg prevented the deficits in recognition memory in the ORT, but not in spatial memory in the OLT and Y maze. Curcumin treatment exerted only slight improvements in neuroinflammation, resulting in no improvements in hippocampal and subventricular neurogenesis. These results suggest a positive effect of curcumin in object recognition memory which was not related to hippocampal neurogenesis. PMID- 28801115 TI - Incidence and prediction of seed migration to the chest after iodine-125 brachytherapy for hepatocellular carcinoma. AB - PURPOSE: The aims were to determine the incidence of seed migration to the chest and to analyze the predictive factors after iodine-125 brachytherapy for hepatocellular carcinoma. METHODS AND MATERIALS: Three hundred ninety-nine patients with hepatocellular carcinoma underwent iodine-125 seed brachytherapy. After seed implantation, chest X-ray radiograph or computerized tomography were undertaken to assess the occurrence and location of seed migration at 3 months after brachytherapy. The incidence of seed migration to the lung and heart was calculated. A statistical analysis of the influences of seed loss to the chest was performed between patients with and without seed migration. RESULTS: A total of 13,977 seeds were implanted in 399 patients. One hundred fifty of the 13,977 (1.07%) seeds migrated to the chest in 81 of the 399 (20.30%) patients. Of all the migrated seeds, 112 (74.67%) migrated to the lungs in 59 (67.82%) patients, and 38 (25.33%) seeds migrated to the heart in 28 (47.46%) patients. No case exhibited clinical symptoms related to the migrated seeds. The number of seeds implanted and the number of seed implantations were significantly associated with seed migration. CONCLUSIONS: The occurrence of seed migration to the lungs and heart was evaluated. Furthermore, the number of seeds implanted and the number of seed implantation procedures are significant predictors of seed migration. PMID- 28801116 TI - Comparative results of three short brachytherapy schedules as exclusive treatment in postoperative endometrial carcinoma. AB - PURPOSE: To compare vaginal control and treatment toxicity of three different high-dose-rate brachytherapy schedules as exclusive treatment in postoperative endometrial carcinoma. METHODS AND MATERIALS: From 2003 to 2015, three different schedules were used as postoperative treatment for 146 patients (p) with intermediate-risk endometrial carcinoma. Group 1 (41 p): six fractions of 4-6 Gy, 3-4 fractions per week; Group 2 (59 p): four fractions of 5-6 Gy administered daily; Group 3 (46 p): 6 Gy * 3 fractions in three consecutive days. The dose was prescribed at 5 mm of applicator surface using an active treatment length of 2.5 cm. Toxicity scores were evaluated using the Radiation Therapy Oncology Group scores for bladder and rectum and the objective criteria of late effects of normal tissues-subjective, objective, management, analytic for vagina. Statistics used were group descriptions calculating their means, medians, and ranges. Bivariate analysis was evaluated using variance models and chi2 tests. RESULTS: The mean followup was as follows: Group 1: 88 months, Group 2: 75 months, and 41 months in Group 3. No vaginal relapses were found. Late toxicity >= G2: rectum: 0 p in the three groups (0%). Bladder: Group 1: 1 p (2.4%), Group 2: 0%, and Group 3: 0%. Vagina: Group 1: 4 p (9.5%); Group 2: 9 p (15.3%); and Group 3:10 p (21.8%). There were no differences in late toxicity among the three groups of patients for rectum (p = 0.83), bladder (p = 0.58), and vagina (p = 0.67); the expected global risk of complications for rectum, bladder, and vagina is 0.8%, 0.8%, and 28.8%, respectively. CONCLUSIONS: Similar results in vaginal control and complications were achieved with the three schedules. The use of three fractions of 6 Gy administered daily is the best option for patient comfort and convenience and use of resources. Nonetheless, specific studies are needed to demonstrate the best cost-efficacy regime. PMID- 28801118 TI - [Value of gastric fluid to start antibiotics in premature babies suspected of having early neonatal bacterial infection]. AB - : The objective of this study was to evaluate the value of direct examination and culture of gastric fluid in the treatment of early neonatal bacterial infections (INBP) in pre-term infants. MATERIALS AND METHODS: Observational study conducted over 6 months in a Type III center. All hospitalized premature babies who had routine gastric fluid sampling at birth during the period of the study were included. They were classified into two groups: premature infants with probable or suspected infection and treated as such (Group 1) and premature infants with no infection or only having colonization (Group 2). RESULTS AND DISCUSSION: In total, 255 pre-term infants were included in the study. Group 1 consisted of 127 newborns and group 2 consisted of 128 newborns. The direct gastric fluid examination was positive in 51 newborns in Group 1 and in 46 newborns in group 2. The culture was positive in 25 newborns in group 1 and eight newborns in group 2. Direct examination of gastric fluid of the 255 children studied had low sensitivity (40.1%) and low specificity (64%) of INBP, with 52.6% positive predictive value (PPV) and 51.8% negative predictive value (NPV). The gastric fluid culture was specific (93.7%) of the INBP, sensitivity was low (19.6%), with PPV at 75.7% and NPV at 54%. CONCLUSION: These results undermine the relevance of the direct examination of gastric fluid in the delicate diagnosis of INBP. This direct examination has a low PPV and NPV. It is advisable not to start or stop antibiotic therapy solely on this argument; however, it can guide the choice of antibiotic therapy and remains useful for this reason. The culture of gastric fluid has very good specificity (93.7%). PMID- 28801119 TI - Stability and efficacy of frozen and lyophilized fecal microbiota transplant (FMT) product in a mouse model of Clostridium difficile infection (CDI). AB - Freezing donor fecal microbiota has simplified fecal microbiota transplantation (FMT) in the treatment of recurrent C. difficile infection (CDI). However, the optimal storage time for the frozen FMT products remains unknown. Using an established murine model of CDI, stability and efficacy of frozen and lyophilized FMT product was studied at time points from 2 months to 15 months. DNA was extracted from fecal samples from the mice with identification of specific bacterial species by real-time quantitative PCR (qPCR). FMT product stability and efficacy were measured by occurrence of diarrhea in the challenged mice together with stability of the microbiota composition. The results were analyzed and compared by SAS statistical software. All mice treated with only C. difficile developed diarrhea within 72 h. Mice treated with frozen (n = 5/group), lyophilized (n = 5/group) products stored for <= 7-month or fresh FMT product (n = 22) were protected from post C. difficile challenge diarrhea. There was no difference between frozen and lyophilized products (n = 5/group) stored for <= 7 months 95% CI 1.00 (0.38-2.64) and 1.00 (0.38-2.64), respectively. Prevention if CDI by frozen and lyophilized product was not different for storage of 9-, 11- and 15-months. qPCR results demonstrated there were no significant quantitative change in Bacteroides and Clostridium species during any of the storage times (P > 0.05). In the present study, frozen and lyophilized FMT products were stored up to 7 months without losing microbiota composition and therapeutic efficacy. The animal model described may be useful to study stability of human microbiota designed for FMT. PMID- 28801117 TI - Incidence and Outcomes of Infectious and Noninfectious Endophthalmitis after Intravitreal Injections for Age-Related Macular Degeneration. AB - PURPOSE: To assess the incidence, cumulative rate, and long-term outcomes of infectious and noninfectious endophthalmitis after intravitreal injections (IVTs) of anti-vascular endothelial growth factor (VEGF) agents. DESIGN: Database study, prospectively designed. PARTICIPANTS: Treatment-naive eyes with neovascular age related macular degeneration (nAMD) tracked by the Fight Retinal Blindness! (FRB!) registry that commenced anti-VEGF therapy between January 1, 2006, and November 30, 2016. METHODS: Cumulative rate of endophthalmitis and survival curves were measured using Cox-proportional hazards models. Locally weighted scatterplot smoothing curves were used to display visual acuity (VA). MAIN OUTCOME MEASURES: Incidence and cumulative rate of endophthalmitis, and change in VA 12 months after endophthalmitis. RESULTS: Infectious endophthalmitis developed in 18 of 88 150 injections (1/4897 injections [0.020%]; 95% confidence interval [CI], 0.012-0.032) with no difference found between types of anti-VEGF medications (P = 0.896). The cumulative rate of infectious endophthalmitis per patient was 0.055%, 0.183%, 0.360%, 0.360%, 0.555%, and 0.843% after 10, 20, 30, 40, 50, and 60 IVTs, respectively. However, the "risk" of infectious endophthalmitis did not increase with each successive injection (P = 0.202). Noninfectious endophthalmitis developed in 11 of 88 150 injections (1/8013 injections [0.012%]; 95% CI, 0.006-0.022). The cumulative rate of noninfectious endophthalmitis per patient was 0.087% and 0.228% after 10 and 20 IVTs, respectively, and then remained stable up to 60 IVTs. The incidence of noninfectious endophthalmitis was higher for bevacizumab (8/9931, 0.081%) compared with ranibizumab (3/54 776, 0.005%; P = 0.005) and aflibercept (0/23 425; P = 0.016), and no differences were observed between ranibizumab and aflibercept (P = 1.0). The 12-month VA in infectious and noninfectious endophthalmitis was within +/-2 lines of before endophthalmitis in 53% and 75% of eyes, respectively; a loss >2 lines was observed in 31% and 25% of eyes, respectively. CONCLUSIONS: The incidences of infectious and noninfectious endophthalmitis after IVT were low, and the risk did not increase with each successive injection. We found higher rates of noninfectious endophthalmitis with bevacizumab compared with ranibizumab or aflibercept. Three quarters of cases with infectious and two thirds of cases with noninfectious endophthalmitis retained vision within 10 letters of the pre-endophthalmitis level. PMID- 28801120 TI - Establishment of valnemulin susceptibility breakpoint against Clostridium perfringens in rabbits. AB - Susceptibility breakpoints provide fundamental information for rational administration of antibiotics. The present investigation reports the first valnemulin susceptibility breakpoint (MIC<0.25 MUg/mL) against Clostridium perfringens infections in rabbits based on the wild-type cutoff (COWT) and the pharmacokinetics/pharmacodynamic (PK/PD) cutoff (COPD). The established susceptibility breakpoint of valnemulin might be useful in resistance surveillance of pleuromutilins and development of clinical breakpoints. PMID- 28801121 TI - Impact of Hyperuricemia on Long-term Outcomes of Kidney Transplantation: Analysis of the FAVORIT Study. AB - BACKGROUND: Elevated uric acid concentration is associated with higher rates of cardiovascular (CV) morbidity and mortality in the general population. It is not known whether hyperuricemia increases the risk for CV death or transplant failure in kidney transplant recipients. STUDY DESIGN: Post hoc cohort analysis of the FAVORIT Study, a randomized controlled trial that examined the effect of homocysteine-lowering vitamins on CV disease in kidney transplantation. SETTING & PARTICIPANTS: Adult recipients of kidney transplants in the United States, Canada, or Brazil participating in the FAVORIT Study, with hyperhomocysteinemia, stable kidney function, and no known history of CV disease. PREDICTOR: Uric acid concentration. OUTCOMES: The primary end point was a composite of CV events. Secondary end points were all-cause mortality and transplant failure. Risk factors included in statistical models were age, sex, race, country, treatment assignment, smoking history, body mass index, presence of diabetes mellitus, history of CV disease, blood pressure, estimated glomerular filtration rate (eGFR), donor type, transplant vintage, lipid concentrations, albumin-creatinine ratio, and uric acid concentration. Cox proportional hazards models were fit to examine the association of uric acid concentration with study end points after risk adjustment. RESULTS: 3,512 of 4,110 FAVORIT participants with baseline uric acid concentrations were studied. Median follow-up was 3.9 (IQR, 3.0-5.3) years. 503 patients had a primary CV event, 401 died, and 287 had transplant failure. In unadjusted analyses, uric acid concentration was significantly related to each outcome. Uric acid concentration was also strongly associated with eGFR. The relationship between uric acid concentration and study end points was no longer significant in fully adjusted multivariable models (P=0.5 for CV events; P=0.09 for death, and P=0.1 for transplant failure). LIMITATIONS: Unknown use of uric acid-lowering agents among study participants. CONCLUSIONS: Following kidney transplantation, uric acid concentrations are not independently associated with CV events, mortality, or transplant failure. The strong association between uric acid concentrations with traditional risk factors and eGFR is a possible explanation. PMID- 28801123 TI - A New Mouse Model of APOL1-Associated Kidney Diseases: When Traffic Gets Snarled, the Podocyte Suffers. PMID- 28801122 TI - Deoxycholic Acid, a Metabolite of Circulating Bile Acids, and Coronary Artery Vascular Calcification in CKD. AB - BACKGROUND: Vascular calcification is common among patients with chronic kidney disease (CKD), and it is associated with all-cause and cardiovascular disease mortality. Deoxycholic acid, a metabolite of circulating bile acids, is elevated in CKD and induces vascular mineralization and osteogenic differentiation in animal models. STUDY DESIGN: Cohort analysis of clinical trial participants. SETTING & PARTICIPANTS: 112 patients with moderate to severe CKD (estimated glomerular filtration rate, 20-45mL/min/1.73m2) who participated in a randomized controlled study to examine the effects of phosphate binders on vascular calcification. PREDICTOR: Serum deoxycholic acid concentration. OUTCOMES: Baseline coronary artery calcification (CAC) volume score and bone mineral density (BMD) and change in CAC volume score and BMD after 9 months. MEASUREMENTS: Deoxycholic acid was assayed in stored baseline serum samples using liquid chromatography-tandem mass spectrometry, CAC was measured using a GE Imitron C150 scanner, and BMD was determined using computed tomographic scans of the abdomen with calibrated phantom of known density. RESULTS: Higher serum deoxycholic acid concentrations were significantly correlated with greater baseline CAC volume and lower baseline BMD. After adjusting for demographics, coexisting illness, body mass index, estimated glomerular filtration rate, and concentrations of circulating markers of mineral metabolism, including serum calcium, phosphorus, vitamin D, parathyroid hormone, and fibroblast growth factor 23, a serum deoxycholic acid concentration > 58ng/mL (the median) was positively associated with baseline CAC volume (beta=0.71; 95% CI, 0.26-1.16; P=0.003) and negatively associated with baseline BMD (beta = -20.3; 95% CI, -1.5 to -39.1; P=0.04). Serum deoxycholic acid concentration > 58ng/mL was not significantly associated with change in CAC volume score after 9 months (beta=0.06; 95% CI, 0.09 to 0.21; P=0.4). The analysis for the relationship between baseline deoxycholic acid concentrations and change in BMD after 9 months was not statistically significant, but was underpowered. LIMITATIONS: The use of nonfasting serum samples is a limitation because deoxycholic acid concentrations may vary based on time of day and dietary intake. Few trial participants with complete data to evaluate the change in CAC volume score (n=75) and BMD (n=59). No data for changes in deoxycholic acid concentrations over time. CONCLUSIONS: Among patients with moderate to severe CKD, higher serum deoxycholic acid concentrations were independently associated with greater baseline CAC volume score and lower baseline BMD. PMID- 28801125 TI - Re: Sungmin Woo, Chong Hyun Suh, Sang Youn Kim, Jeong Yeon Cho, Seung Hyup Kim. Diagnostic Performance of Prostate Imaging Reporting and Data System Version 2 for Detection of Prostate Cancer: A Systematic Review and Diagnostic Meta analysis. Eur Urol 2017;72:177-88. PMID- 28801124 TI - Changing our Approach to Stage D Heart Failure. AB - Despite the tremendous progress made in the management of heart failure (HF), many patients reach advanced stages. This paper aims to present a practical approach to the stage D HF patient who is no longer responding to optimal medical therapy. We discuss all available therapies for this patient population. We also offer some important caveats with regard to identification, risk stratification, evaluation and treatment including early patient referral to a center with an advanced HF program. Given the changing landscape of heart transplantation and an impending change in the allocation system, we also intend to engage a discussion on the need for a paradigm shift towards left ventricular assist device therapy in this population. PMID- 28801126 TI - Abiraterone or Docetaxel for Castration-sensitive Metastatic Prostate Cancer? That Is the Question! PMID- 28801127 TI - Reply to Ugo De Giorgi, Vincenza Conteduca, and Emanuela Scarpi's Letter to the Editor re: Marzia Del Re, Elisa Biasco, Stefania Crucitta, et al. The Detection of Androgen Receptor Splice Variant 7 in Plasma-derived Exosomal RNA Strongly Predicts Resistance to Hormonal Therapy in Metastatic Prostate Cancer Patients. Eur Urol 2017;71:680-7. PMID- 28801128 TI - Reply to Bora Lee and Jae Heon Kim's Letter to the Editor re: Alan D. Uren, Nikki Cotterill, Christopher Harding, et al. Qualitative Exploration of the Patient Experience of Underactive Bladder. Eur Urol 2017;72:402-7. PMID- 28801129 TI - Re: Alan D. Uren, Nikki Cotterill, Christopher Harding, et al. Qualitative Exploration of the Patient Experience of Underactive Bladder. Eur Urol 2017;72:402-7. PMID- 28801130 TI - Prospective Implementation of Enhanced Recovery After Surgery Protocols to Radical Cystectomy. AB - BACKGROUND: Multimodal enhanced recovery after surgery (ERAS) regimens have improved outcomes from colorectal surgery. OBJECTIVE: We report the application of ERAS to patients undergoing radical cystectomy (RC). DESIGN, SETTING, AND PARTICIPANTS: Prospective collection of outcomes from consecutive patients undergoing RC at a single institution. INTERVENTION: Twenty-six components including prehabilitation exercise, same day admission, carbohydrate fluid loading, targeted intraoperative fluid resuscitation, regional local anaesthesia, cessation of nasogastric tubes, omitting oral bowel preparation, avoiding drain use, early mobilisation, chewing gum use, and audit. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcomes were length of stay and readmission rate. Secondary outcomes included intraoperative blood loss, transfusion rates, survival, and histopathological findings. RESULTS AND LIMITATIONS: Four hundred and fifty-three consecutive patients underwent RC, including 393 (87%) with ERAS. Length of stay was shorter with ERAS (median [interquartile range]: 8 [6-13] d) than without (18 [13-25], p<0.001). Patients with ERAS had lower blood loss (ERAS: 600 [383-969] ml vs 1050 [900-1575] ml for non-ERAS, p<0.001), lower transfusion rates (ERAS: 8.1% vs 25%, chi-square test, p<0.001), and fewer readmissions (ERAS: 15% vs 25%, chi-square test, p=0.04) than those without. Histopathological parameters (eg, tumour stage, node count, and margin state) and survival outcomes did not differ with ERAS use (all p>0.1). Multivariable analysis revealed ERAS use was (p=0.002) independently associated with length of stay. CONCLUSIONS: The use of ERAS pathways was associated with lower intraoperative blood loss and faster discharge for patients undergoing RC. These changes did not increase readmission rates or alter oncological outcomes. PATIENT SUMMARY: Recovery after major bladder surgery can be improved by using enhanced recovery pathways. Patients managed by these pathways have shorter length of stays, lower blood loss, and lower transfusion rates. Their adoption should be encouraged. PMID- 28801131 TI - Health care demand elasticities by type of service. AB - We estimate within-year price elasticities of demand for detailed health care services using an instrumental variable strategy, in which individual monthly cost shares are instrumented by employer-year-plan-month average cost shares. A specification using backward myopic prices gives more plausible and stable results than using forward myopic prices. Using 171 million person-months spanning 73 employers from 2008 to 2014, we estimate that the overall demand elasticity by backward myopic consumers is -0.44, with higher elasticities of demand for pharmaceuticals (-0.44), specialists visits (-0.32), MRIs (-0.29) and mental health/substance abuse (-0.26), and lower elasticities for prevention visits (-0.02) and emergency rooms (-0.04). Demand response is lower for children, in larger firms, among hourly waged employees, and for sicker people. Overall the method appears promising for estimating elasticities for highly disaggregated services although the approach does not work well on services that are very expensive or persistent. PMID- 28801133 TI - [Toward new modalities of surveillance in lung cancer patients?] PMID- 28801132 TI - In-vivo imaging of the sentinel vein using the near-infrared vascular imaging system in hallux valgus patients. AB - BACKGROUND: A high incidence of dorsomedial cutaneous nerve (DMCN) damage in hallux valgus surgery has been reported. Identification of the vein around 1st metatarsal head is reported to be helpful to reduce the DMCN damage during surgery. The near-infrared (NIR) vascular imaging system, the VeinViewer(r) Flex, projects the vein onto the skin. The purpose of this study was to investigate the difference of the vein course between normal and hallux valgus foot using the VeinViewer(r) Flex, and to validate that the DMCN was accompanied with its vein. METHODS: Twenty-seven feet with the hallux valgus and 27 feet in healthy subjects were included. The vein was projected onto the skin at the metatarsal head by the VeinViewer(r) Flex. The distance between the vein and the mid-line of the metatarsal head was measured. The correlation of the distance and hallux valgus angle or 1-2 intermetatarsal angle (IMA) was analyzed. The vein depicted by the VeinViewer(r) Flex and operative findings was compared in 4 patients during surgery. RESULTS: The vein in the hallux valgus patients shifted toward the dorsolateral side on the metatarsal bone head compared to that in healthy subjects. The distance from the midline of the 1st metatarsal bone to the vein in the hallux valgus (12.1 mm) was significantly higher than that in healthy subjects (2.7 mm) (p < 0.05). There was a significant correlation between the shift of the vein course toward dorsolateral and IMA. Surgical exploration revealed that the vein depicted by VeinViewer(r) Flex could be easily identified and the nerve was along with this vein in all 4 surgical cases. CONCLUSIONS: The vein in the hallux valgus patients shifted toward the dorsolateral on the metatarsal bone and it could be a landmark to identify DMCN. The NIR vascular imaging system would be useful to reduce the risk of nerve damage in great toe surgery. PMID- 28801134 TI - Wellens' syndrome. PMID- 28801135 TI - Pyrrolo[2,1-f][1,2,4]triazines: From C-nucleosides to kinases and back again, the remarkable journey of a versatile nitrogen heterocycle. AB - Pyrrolo[2,1-f][1,2,4]triazine, a unique NN bond-containing heterocycle with a bridgehead nitrogen, was first synthesized in the late 1970s but did not find utility until more than a decade later in the early 1990s when it was incorporated into C-nucleosides as a novel purine-like mimetic. This heterocycle remained at the fringes of medicinal chemistry until a confluence of events spurred by the explosion of the kinase inhibitor field in the early 2000s and the pressing need for novel, druggable scaffolds to occupy that exciting space led to numerous applications against diverse therapeutic targets. This digest will explore the history of this scaffold and the importance of chemistry in propelling drug discovery. The varied uses of this scaffold will be detailed as it progressed from C-nucleosides, to kinase inhibitors, to recognition as a "privileged" template, and finally reemergence in the C-nucleoside field. PMID- 28801136 TI - Outcomes of Pharmacomechanical Catheter-directed Thrombolysis for Acute and Subacute Inferior Vena Cava Thrombosis: A Retrospective Evaluation in a Single Institution. AB - OBJECTIVE/BACKGROUND: The objective was to assess the mid-term results of pharmacomechanical catheter-directed thrombolysis (PCDT) for symptomatic acute and subacute inferior vena cava (IVC) thrombosis; the risk factors of early thrombosis recurrence and iliocaval patency were also evaluated. METHODS: From January 2010 to December 2015, 54 patients (33 men; mean age 47.1 years) with symptomatic acute and subacute IVC thrombosis were treated with PCDT. Primary technical success (clot lysis >= 50% after PCDT), stent-assisted technical success (residual stenosis < 30% after stenting), clinical success (freedom from thrombosis recurrence within 30 days), complications, frequency of post thrombotic syndrome (PTS; Villalta score >= 5), and iliocaval patency were recorded at follow-up evaluation. A multivariate regression model was used to determine predictors of early thrombosis reoccurrence and iliocaval patency. RESULTS: The primary technical success and the stent-assisted technical success were 63% (n = 34/54) and 100% (n = 54/54) respectively. There were 11 patients (20%) with immediate recurrent thrombosis requiring repeat PCDT. Minor bleeding complications occurred in seven patients, and one patient with major bleeding needed a blood transfusion. The occurrence of PTS at a mean of 26 months (range 1 60 months) was 13% (7/54). The 3-year primary and secondary iliocaval patency was 63% and 81%, respectively. On multivariate analysis, active malignancy was predictive of immediate IVC thrombosis recurrence (hazard ratio [HR] 5.8, 95% confidence interval [CI] 1.7-19.8; p = .01), whereas the pre-existing filter played a protective role against iliocaval re-occlusion (HR 0.3, 95% CI 0.1-0.8; p = .01). CONCLUSIONS: PCDT is safe and effective in managing symptomatic acute and subacute IVC thrombosis. Active malignancy is predictor of thrombosis re occurrence, whereas the presence of a filter is associated with a higher rate of iliocaval patency at mid-term follow-up. PMID- 28801138 TI - Cadmium exposure in newborn rats ovary induces developmental disorders of primordial follicles and the differential expression of SCF/c-kit gene. AB - Since the 1990s, the rising problem that gonad reproductive toxicity on adult female after exposing to cadmium (Cd), an environmental endocrine disruptor, has attracted high attention at home and abroad,and was systematically studied. Our research focuses on a further problem is that early cadmium exposure (during birth to before puberty) impact on development and function of ovarian cells and its possible mechanism. Our research focuses on the changes of ovarian cells growth and development after the newborn rat ovaries with cadmium exposure in vitro, and different expression of ovarian cells development-related factors, SCF/c-kit and changes of their DNA methylation status. We obtained ovaries from 4 day-old SD rats and cultured them in DMEM/F12 mixed with alpha-MEM media in vitro. Different doses of cadmium were designed as control, 0.5, 5, 10 and 50MUM, and then the constituent ratio of ovarian follicle and follicular oocytes diameter were observed with microscope after 4-h exposure. We found that the increased constituent ratio of original follicle and decreased diameter of all levels of follicular oocytes(compared with control, with statistically significant differences, P<0.01).After the measurement of expression of SCF/c-kit by qRT-PCR and Western Blotting, the mRNA and protein expression of SCF/c-kit in ovarian were both decreased. We further found that the increased constituent ratio of growth follicle and increased diameter of oocytes under the treatment of adding SCF in cell culture media. Finally, MALDI-TOF-MS method showed DNA-low methylation status of SCF/c-kit promoter region after Cd exposure. Overall, we concluded that the exposure of cadimium (5-50MUM) on newborn rats ovaries could inhibit follicle development.SCF/c-kit system might mediate follicle development damage caused by cadmium, which is associated with DNA hypomethylation of SCF/c kit promoter region may be worthy of further study. PMID- 28801137 TI - The challenges of treating recurrent polymorphic ventricular tachycardia due to coronary vasospasm: Lessons from an interesting case. AB - Coronary artery vasospasm can cause recurrent anginal episodes with ST-segment elevation. Vasospasm induced myocardial ischemia can lead to arrhythmias including life threatening ventricular tachycardia (VT). Percutaneous coronary intervention (PCI), although not routinely recommended for treating vasospastic angina, can be considered for discrete coronary spasm that is not amenable to vasodilator therapy. We present a challenging case of a 41-year-old lady with recurrent episodes of vasospastic angina and VT refractory to medical therapy, which was successfully treated with PCI and an implantable cardioverter defibrillator. PMID- 28801140 TI - The therapeutic effects of Longikaurin A, a natural ent-kauranoid, in esophageal squamous cell carcinoma depend on ROS accumulation and JNK/p38 MAPK activation. AB - Effective treatments for esophageal squamous cell carcinoma (ESCC), one of the most common cancers in China, are lacking. Longikaurin A (LK-A), an ent-kauranoid diterpenoid isolated from Isodon ternifolius, has been shown to have potent cytotoxic effects on ESCC cells both in vivo and in vitro, mainly by inducing apoptosis. In this study, LK-A inhibited ESCC cells viability and induced G2/M cell cycle arrest. Moreover, LK-A was also highly effective in a KYSE-30 xenograft nude mouse model. Treatment with Z-VAD(OMe)-FMK partially attenuated LK A-induced apoptosis. LK-A significantly induced reactive oxygen species (ROS) production in ESCC cells, and LK-A-induced apoptosis was attenuated by the ROS scavenger N-acetyl cysteine (NAC). Furthermore, we found that treatment with LK-A activated both the JNK and p38 MAPK signaling pathways, resulting in increases in ROS levels and apoptosis induction. Taken together, these findings indicate that LK-A exerts novel anti-tumor effects in ESCC cells by activating the JNK and p38 MAPK pathways and inducing increases in ROS production, which suggest that the compound may have potential as a clinical therapeutic agent. PMID- 28801141 TI - Middle meningeal artery aneurysm associated with diffuse calvarial metastases: A case report and review of the literature. PMID- 28801142 TI - Synergistic experimental and numerical characterization of a dry-heat, fluid warming device. AB - Fluids that are infused into the human body must be at a temperature that is compatible with the internal thermal state of the body. Since infusants are typically stored at temperatures that are too low for compatibility, a heating means is required to achieve the appropriate infusion temperature. This paper sets forth a synergistic investigation involving coupled experimentation and numerical simulation of the characteristics of one of the main categories of body fluid heating means. The methodology developed here serves equally well as a design optimization tool. The paper encompasses two stages: (a) an experimental and numerical evaluation of a generic warming device in common use and (b) a redesign utilizing the same tools to elevate the performance of devices of this category. The numerical simulation dealt with steady and unsteady three dimensional fluid flow and heat transfer which are endemic to devices of this kind. The two-pronged approach developed here was shown to be capable of coping with an operating feature called stopflow wherein an officiating physician orders an immediate cessation of fluid flow. The thermal events following stopflow are well described by the numerical simulations. PMID- 28801143 TI - Corrigendum to "Native language experience shapes neural basis of addressed and assembled phonologies" [Neuroimage 114 (2015) 38-48]. PMID- 28801144 TI - Corrigendum to "Long-term experience with Chinese language shapes the fusiform asymmetry of English reading" [NeuroImage 110 (2015) 3-10]. PMID- 28801145 TI - Body image dissatisfaction and dietary patterns according to nutritional status in adolescents. AB - OBJECTIVE: There is a lack of data on the association between body self perception and eating patterns in Brazil. Thus, this study aimed to explore the relationship between body image dissatisfaction and eating patterns by the anthropometric status in adolescents. METHODS: A cross-sectional study of 1496 adolescents was conducted. The participants completed the Body Shape Questionnaire. Demographic, anthropometric, and socioeconomic data were collected, as well as information regarding the pubertal development and dietary intake. Logistic regression was performed to evaluate the associations of interest. RESULTS: Body image dissatisfaction was identified in 19.5% of the adolescents. Three dietary patterns were identified: (1) the Western pattern was composed of sweets and sugars, soft drinks, typical dishes, pastries, fast food, beef, milk, and dairy products; (2) the Traditional pattern was composed of oils, chicken, fish, eggs, processed meat products, cereals (rice, cassava flour, pasta, etc.), baked beans, and bread; and (3) the Restrictive pattern was composed of granola, roots, vegetables, and fruit. Among overweight/obese adolescents, the data indicated a negative association of slight body image dissatisfaction (OR: 0.240 [0.100; 0.576]) and moderate body image dissatisfaction (OR: 0.235 [0.086; 0.645]) with the Western dietary pattern. Additionally, in this group, there was a positive association between high body image dissatisfaction and the Restrictive pattern (OR: 2.794 [1.178; 6.630]). CONCLUSION: Amongst overweight/obese adolescents, those with slight and moderate body image dissatisfaction were less likely to follow a Western-like dietary pattern when compared with those satisfied with their body image. Additionally, in this group, adolescents with high body image dissatisfaction was more likely to follow a restrictive pattern. PMID- 28801146 TI - BH4 deficiency identified in a neonatal screening program for hyperphenylalaninemia. AB - OBJECTIVES: To show the general prevalence and to characterize tetrahydrobiopterin (BH4) deficiencies with hyperphenylalaninemia, identified by the Neonatal Screening Program of the State of Minas Gerais. METHODS: Descriptive study of patients with BH4 deficiency identified by the Neonatal Screening Program of the State of Minas Gerais. RESULTS: The prevalence found was 2.1 for 1,000,000 live births, with a frequency of 1.71% among hyperphenylalaninemias. There were four cases (40%) with 6-pyruvoyl-tetrahydropterin synthase deficiency, three with GTP cyclohydrolase I - autosomal recessive form deficiency, and three with dihydropteridine reductase deficiency (30% each). Six patients were diagnosed due to clinical suspicion and four cases due to systematic screening in neonatal screening. After the start of the treatment, patients identified by neonatal screening had rapid improvement and improved neuropsychomotor development compared to those diagnosed by the medical history. CONCLUSIONS: The prevalence of BH4 deficiencies in Minas Gerais was slightly higher than that found in the literature, but the frequency among hyperphenylalaninemias was similar. Although rare, they are severe diseases and, if left untreated, lead to developmental delays, abnormal movements, seizures, and premature death. Early treatment onset (starting before 5 months of age) showed good results in preventing intellectual disability, justifying the screening of these deficiencies in newborns with hyperphenylalaninemia identified at the neonatal screening programs for phenylketonuria. PMID- 28801147 TI - Variability in split-thickness skin graft depth when using an air-powered dermatome: A paediatric cohort study. AB - AIM: Split-thickness skin grafts (STSG) taken using calibrated powered dermatomes are assumed to yield a graft of uniform thickness, though this assumption has never been analysed statistically. This study aims to test that assumption in a paediatric population. METHOD: STSGs from a consecutive cohort of paediatric patients were analysed for mean thickness, measured from a central biopsy. All STSGs were taken from the thigh at a dialled thickness of 0.007in. Data were analysed using non-parametric methods. RESULTS: There were 140 STSGs taken from 91 children. The median thickness was 6.94 thousandths of an inch, with a spread of thicknesses about this median (IQR 5.05-9.28). There were no significant differences when results were analysed by surgeon, patient age or gender, swipe number within the case, or the number of previous passes with the same blade. CONCLUSION: STSG thickness is inconsistent, with a broad spread about a median value. This study provides no data to suggest there are pre-operative predictors of STSG thickness being significantly more or less than that dialled on a powered dermatome. PMID- 28801148 TI - Assessing and addressing the problem of pain and distress during wound care procedures in paediatric patients with burns. AB - OBJECTIVE: While the prevalence of burns in children is highest in low and middle income countries, most research on burn-related pain intensity and distress is carried out in high-income countries. In this study we assessed pain intensity and distress in paediatric patients with burns undergoing wound care procedures without distraction and parental presence in a South-African children's hospital and sought to identify predictors for the outcomes. METHODS: This observational study, carried out as part of a randomized controlled trial, took place at a burns unit in Cape Town, South Africa and included patients between the ages of 0 and 13 years undergoing their first or second wound care procedure. We measured pain intensity and distress using the COMFORT Behavioural scale (COMFORT-B) across four distinct phases of wound care procedures: removal of bandage; washing the wound; administering wound care; putting on new dressings. COMFORT-B scores >=21 indicate severe pain intensity and distress. RESULTS: 124 patients were included, median age 21.2 months (IQR 14.9-39.5 months), 90% suffered scalds, and median total body surface 8% (IQR 5-14%). Assessment scores for the majority of patients were indicative of severe pain intensity and distress during wound care procedures. Median COMFORT-B scores across the four phases were 24, 25, 25 and 22 respectively. Across the four phases respectively 76%; 89%; 81% and 62% of the patients were indicated with severe pain intensity and distress. Age was a predictor for pain intensity and distress as younger children were assigned higher scores than older children (Unstandardized B -.052; 95% CI -.071 to -.032 p<0.001). CONCLUSIONS: In this study children received wound care procedures without distraction or parental presence and were assessed to have high pain intensity and distress. There is a correlation between age and COMFORT-B scores: younger children show higher distress, indicating a great need for better pain and distress control during wound care procedures. It is difficult to identify whether pain or distress is the specific primary cause for the high COMFORT-B scores. PMID- 28801149 TI - Hypnosis for reduction of background pain and pain anxiety in men with burns: A blinded, randomised, placebo-controlled study. AB - INTRODUCTION: 'Background pain' and 'pain anxiety' are among the numerous problems of patients with burns. Non-pharmacological and pharmacological interventions have been used to reduce background pain and pain anxiety. This study compared the effectiveness of hypnosis and 'neutral hypnosis' (as a placebo in the control group) in decreasing the background burn pain and pain anxiety of adult male survivors with burns. DESIGN: This is a blinded, randomised, placebo controlled study. METHODS: Sixty men with burns were included in the minimisation method (30 individuals in the intervention group and 30 individuals in the control group). Four hypnotherapy sessions were performed every other day for each participant in the intervention group. Four neutral hypnosis sessions were performed every other day in the control group. Burn pain and pain anxiety of the patients in both groups were measured at the end of the second and fourth sessions. Repeated measures ANOVA was used for data analysis. RESULTS: There was no significant difference between the groups in the reduction in background pain intensity. There was a significant reduction in background pain quality and pain anxiety in the intervention group during the four hypnosis sessions. After two hypnotherapy sessions, a significant reduction was observed in the level of background pain quality and pain anxiety of participants. CONCLUSION: Hypnosis is effective in reducing background pain quality and pain anxiety of men with burns. PMID- 28801150 TI - Three-dimensional wound mapping software compared to expert opinion in determining wound area. AB - INTRODUCTION: New technologies in the field of burn wound and scar assessment are continually being evaluated. Accurate estimation of total body surface area (TBSA) burn wound is of paramount importance in fluid resuscitation to prevent complications which are associated with morbidity and mortality. Estimating the TBSA is performed by a multitude of different methods, however a gold standard would be ideal. The aim of this study was to compare the estimation of burned TBSA% between 3D photography by Panasonic FZ-M1 Toughpad in conjunction with WoundCare Lite software and expert opinion volunteered by burns doctors. METHODS: Two life sized mannequins were used to simulate burns; an adult and a child. The burn was drawn to mimic real life burn patterns. Burns were measured prior to specialist assessment on the 3D camera. Burns doctors were asked to estimate the TBSA% of the burn. 10 burn sizes were assessed on the adult mannequin, and 8 on the child. RESULTS: Wound size as estimated from the camera varied from 0.42% to 18.23%, with a mean of 5.246%. Each burn was assessed by a median of 3 assessors (ranging from 2 to 8). Burn TBSA assessments from the 3D camera and specialist assessment (compared using ICC) showed excellent agreement, 0.985 (95% CI 0.905, 0.996). CONCLUSIONS: This study has demonstrated that the wound mapping software WoundCare Lite in conjunction with the Panasonic FZ-M1 Toughpad 3D camera compares well with expert opinion in determining burn surface area on a mannequin. Further research is needed to establish whether this is the case in burns on patients in an acute setting. PMID- 28801151 TI - Correlation between desiccation stress response and epigenetic modifications of genes in Drosophila melanogaster: An example of environment-epigenome interaction. AB - Animals from different phyla including arthropods tolerate water stress to different extent. This tolerance is accompanied by biochemical changes which in turn are due to transcriptional alteration. The changes in transcription can be an indirect effect on some of the genes, ensuing from the effect of stress on the regulators of transcription including epigenetic regulators. Within this paradigm, we investigated the correlation between stress response and epigenetic modification underlying gene expression modulation during desiccation stress in Canton-S. We report altered resistance of flies in desiccation stress for heterozygote mutants of PcG and TrxG members. Pc/+ mutant shows lower survival, while ash1/+ mutants show higher survival under desiccation stress as compared to Canton-S. We detect expression alteration in stress related genes as well the genes of the Polycomb and trithorax complex in Canton-S subjected to desiccation stress. Concomitant with this, there is an altered enrichment of H3K27me3 and H3K4me3 at the upstream regions of the stress responsive genes. The enrichment of activating mark, H3K4me3, is higher in non-stress condition. H3K27me3, the repressive mark, is more pronounced under stress condition, which in turn, can be correlated with the binding of Pc. Our results show that desiccation stress induces dynamic switching in expression and enrichment of PcG and TrxG in the upstream region of genes, which correlates with histone modifications. We provide evidence that epigenetic modulation could be one of the mechanisms to adapt to the desiccation stress in Drosophila. Thus, our study proposes the interaction of epigenome and environmental factors. PMID- 28801152 TI - Reply to: Increased risk of thromboembolic events in adult congenital heart disease patients with atrial tachyarrhythmias: Bias due to the data sparsity. PMID- 28801153 TI - Trends, causes and timing of 30-day readmissions after hospitalization for heart failure: 11-year population-based analysis with linked data. AB - BACKGROUND: Reliable data are necessary if the burden of early readmissions following hospitalization for heart failure (HF) is to be addressed. We studied unplanned 30-day readmissions, their causes and timing over an 11-year period, using population-based linked data. METHODS: All hospitalizations from 2003 to 2013 were analyzed by using administrative linked data based on the Minimum Basic Set discharge registry of the Department of Health (Region of Murcia, Spain). Index hospitalizations with HF as principal diagnosis (n=27,581) were identified. Transfers between centers were merged into one discharge. Readmissions were defined as unplanned admissions to any hospital within 30-days after discharge. RESULTS: In the 2003-2013 period, 30-day readmission rates had a relative mean annual growth of +1.36%, increasing from 17.6% to 22.1%, with similar trends for cardiovascular and non-cardiovascular causes. The figure of 22.1% decreased to 19.8% when only same-hospital readmissions were considered. Most readmissions were due to cardiovascular causes (60%), HF being the most common single cause (34%). The timing of readmission shows an early peak on the fourth day post discharge (+13.29%) due to causes other than HF, followed by a gradual decline ( 3.32%); readmission for HF decreased steadily from the first day (-2.22%). Readmission for HF (12.7%) or non-cardiovascular causes (13.3%) had higher in hospital mortality rates than the index hospitalization (9.2%, p<0.001). Age and comorbidity burden were the main predictors of any readmission, but the performance of a predictive model was poor. CONCLUSION: These findings support the need for population-based strategies to reduce the burden of early-unplanned readmissions. PMID- 28801154 TI - Progress in prophylactic human papillomavirus (HPV) vaccination in 2016: A literature review. AB - Prophylactic human papillomavirus (HPV) vaccine represents a revolutionary step forward in preventing HPV-related cancers, especially cervical carcinoma. Alongside appropriate screening, it has the potential to dramatically reduce cervical cancer incidence and even eradicate it. Following extensive evaluations in clinical trials, the first decade of routine HPV vaccine use provides overwhelming evidence of the vaccines' safety and their real-life effectiveness. In 2016, further clinical trials showed high vaccine efficacy in adult women, especially those that were HPV DNA-negative at baseline, and indicated possible protection from HPV-related diseases after treatment of precancerous cervical lesions. The recommendation for a two-dose schedule in individuals under 15 is further supported for all three licensed vaccines by immunogenicity studies that show non-inferior immune responses and similar clinical efficacy compared to the three-dose schedule. So far, natural competition between HPV types has not been confirmed and therefore vaccine-induced clinically significant type replacement is unlikely. The real-world effectiveness data showed cross-sectional reduction in the prevalence/incidence of vaccine-related HPV types, genital warts and precancerous cervical lesions in countries and regions with HPV vaccination coverage. These declines were evident not only in vaccinated females, but also in unvaccinated females and males, strongly suggesting herd protection. Despite an excellent safety profile consistently demonstrated in clinical trials and confirmed in real-life settings, recently invented controversial syndromes allegedly linked to HPV vaccines temporarily compromised some previously very successful vaccination programs and significantly contributed to the failure of HPV vaccine implementation in some countries with the highest prevalence of cervical cancer. However, several safety studies failed to confirm any association of these syndromes with HPV vaccination in various settings and geographic locations. The main challenges remain implementing HPV vaccination in national vaccination programs, especially in low-and middle-income countries with the highest burden of cervical cancer, and achieving and sustaining high vaccine coverage rates. PMID- 28801156 TI - Alarming Burden of Triple-Negative Breast Cancer in India. AB - Breast cancer is the most prevalent cancer among women worldwide. Among the different breast cancer subtypes, triple-negative breast cancer (TNBC), which is more prevalent among younger age women, is the most aggressive form. Numerous clinicopathologic studies performed throughout the world strongly support the utterly poor prognoses and high recurrence rate of TNBC. The present report details a thorough data survey from Google and PubMed on the burden of TNBC worldwide and other associated factors, with special emphasis on its ever increasing incidence among Indian women. Our analysis revealed that the proportion of TNBC ranges from 6.7% to 27.9% in different countries, with the highest reported percentage in India among all, followed by Indonesia, Algeria, and Pakistan. Most of the other countries (Netherlands, Italy, London, Germany) had a TNBC incidence less than the mean level (ie, 15%). The high incidence of TNBC in the Indian population is associated with vivid risk factors, which primarily include lifestyle, deprivation status, obesity, family history, high mitotic indexes, and BRCA1 mutations. The treatment of TNBC is greatly hampered due to the lack of targeted therapies. Hence, it requires earnest attention towards extensive research for the prevention and development of treatment modalities with high efficacy. PMID- 28801155 TI - Vaccinations in the first year of life and risk of atopic disease - Results from the KiGGS study. AB - BACKGROUND: The study focused on the question of whether and - if so - to what direction and extent immunisations in the 1st year may be associated with the risk of being diagnosed with atopic diseases after the 1st year of life. METHODS: Data from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS, 2003-2006) were analysed. For analyses of potential associations between vaccination status and risk of hay fever, atopic dermatitis or asthma, sample sizes of 15254, 14297, and 15262, respectively, were available. RESULTS: Children with a sufficient TDPHiHeP vaccination at the end of the 1st year of life had a lower risk of being diagnosed with hay fever after the 1st year of life (adjusted prevalence ratio 0.85, 95% confidence interval 0.76-0.96). Analyses for associations between TDPHiHeP vaccination and risk of atopic dermatitis or asthma, or between age at onset of vaccination or of the number of antigens vaccinated in the 1st year of life and risk of atopic disease failed to yield statistical significance. CONCLUSIONS: Our results provide no evidence that immunisations in the 1st year of life may increase the risk of atopic disease. If any association exists at all, our results may be interpreted as weakly supportive of the hypothesis that immunisations may slightly decrease the risk of atopy in later life. PMID- 28801157 TI - Toxin production, growth kinetics and molecular characterization of Ostreopsis cf. ovata isolated from Todos os Santos Bay, tropical southwestern Atlantic. AB - The toxin profile and hemolytic activity of a strain of Ostreopsis cf. ovata (UFBA013) isolated from Todos os Santos Bay (northeastern Brazil) were evaluated under different levels of N and P. Phylogenetic analyses based on ITS rDNA region (ITS1-5.8S-ITS2) placed UFBA013 within the Atlantic/Mediterranean/Pacific clade of O. cf. ovata. Growth experiments were conducted in f/2 medium modified by adding N and P (P: 0-36 MUM; N: 0-882 MUM). The growth kinetics was adequately described by logistic equations. The best growth (highest Gm) was recorded under levels of N/P = 0/18, 129/5 and 441/36, while one of the lowest Gm was obtained under P-depletion. The maximum and specific maximum growth rates (as vm; cells mL 1 d-1 and MUm; d-1) were achieved with N limitation (N/P = 441/36) and P limitation/depletion (753/5.3 and 441/0) and are the highest values reported in the literature, most similar to isolates from Pacific and Mediterranean areas. The control experiment (N/P = 441/18) also yielded similar values to those from some Mediterranean isolates, but higher than formerly reported for Brazilian isolates. In all conditions assayed, no palytoxin (PLTX) was detected. The ovatoxins (OVTXs) a, b, c, d and e did not show significant differences in cell quota between exponential and stationary phases. A significant relationship was detected between OVTXs concentration and hemolytic activity. PMID- 28801158 TI - Similarities between obstetric anesthesia and the service industry. PMID- 28801159 TI - Re: Tawfik M.M., et al. "Circulatory collapse in a parturient undergoing cesarean delivery: a diagnostic dilemma." PMID- 28801160 TI - The videolaryngoscope as a first-line intubation device in women with hypertensive disease of pregnancy. PMID- 28801161 TI - ? PMID- 28801162 TI - ? PMID- 28801163 TI - Anaesthesia for abnormally invasive placenta: cell salvage and tranexamic acid. PMID- 28801164 TI - Anaesthetic management of an obstetric patient with cleidocranial dysplasia. PMID- 28801165 TI - Child Care Health Consultation Improves Infant and Toddler Care. AB - INTRODUCTION: Many families enroll their infants and toddlers in early education and child care programs. The Pennsylvania Chapter of the American Academy of Pediatrics recruited 32 child care centers that care for infants and toddlers to be linked with a child care health consultant (CCHC). METHOD: Project staff assigned the centers alternately to an immediate intervention or a 1-year delayed intervention (contrast) group. At entry into the project, and then 1 and 2 years later, an evaluator assessed center compliance with 13 standards for infants and toddler care selected from Caring for Our Children: National Health and Safety Performance Standards (3rd ed.). Project staff linked the Immediate Intervention centers with a CCHC in Year 1. In Year 2, in a crossover comparison, project staff linked Contrast centers with a CCHC. RESULTS: Working with a CCHC effectively improved compliance with some selected health and safety standards. PMID- 28801167 TI - Corrigendum to "Rapid PD-L1 detection in tumors with PET using a highly specific peptide" [Biochemical and Biophysical Research Communications 483/1 (2017) 258 263]. PMID- 28801168 TI - Please Don't Move-Evaluating Motion Artifact From Peripheral Quantitative Computed Tomography Scans Using Textural Features. AB - Most imaging methods, including peripheral quantitative computed tomography (pQCT), are susceptible to motion artifacts particularly in fidgety pediatric populations. Methods currently used to address motion artifact include manual screening (visual inspection) and objective assessments of the scans. However, previously reported objective methods either cannot be applied on the reconstructed image or have not been tested for distal bone sites. Therefore, the purpose of the present study was to develop and validate motion artifact classifiers to quantify motion artifact in pQCT scans. Whether textural features could provide adequate motion artifact classification performance in 2 adolescent datasets with pQCT scans from tibial and radial diaphyses and epiphyses was tested. The first dataset was split into training (66% of sample) and validation (33% of sample) datasets. Visual classification was used as the ground truth. Moderate to substantial classification performance (J48 classifier, kappa coefficients from 0.57 to 0.80) was observed in the validation dataset with the novel texture-based classifier. In applying the same classifier to the second cross-sectional dataset, a slight-to-fair (kappa = 0.01-0.39) classification performance was observed. Overall, this novel textural analysis-based classifier provided a moderate-to-substantial classification of motion artifact when the classifier was specifically trained for the measurement device and population. Classification based on textural features may be used to prescreen obviously acceptable and unacceptable scans, with a subsequent human-operated visual classification of any remaining scans. PMID- 28801166 TI - Nuclear factor (erythroid-derived 2)-like 2 (NRF2) drug discovery: Biochemical toolbox to develop NRF2 activators by reversible binding of Kelch-like ECH associated protein 1 (KEAP1). AB - Mechanisms that activate innate antioxidant responses, as a way to mitigate oxidative stress at the site of action, hold much therapeutic potential in diseases, such as Parkinson's disease, Alzheimer's disease and Huntington's disease, where the use of antioxidants as monotherapy has not yielded positive results. The nuclear factor NRF2 is a transcription factor whose activity upregulates the expression of cell detoxifying enzymes in response to oxidative stress. NRF2 levels are modulated by KEAP1, a sensor of oxidative stress. KEAP1 binds NRF2 and facilitates its ubiquitination and subsequent degradation. Recently, compounds that reversibly disrupt the NRF2-KEAP1 interaction have been described, opening the field to a new era of safer NRF2 activators. This paper describes a set of new, robust and informative biochemical assays that enable the selection and optimization of non-covalent KEAP1 binders. These include a time resolved fluorescence resonance energy transfer (TR-FRET) primary assay with high modularity and robustness, a surface plasmon resonance (SPR) based KEAP1 direct binding assay that enables the quantification and analysis of full kinetic binding parameters and finally a 1H-15N heteronuclear single quantum coherence (HSQC) NMR assay suited to study the interaction surface of KEAP1 with residue specific information to validate the interaction of ligands in the KEAP1 binding site. PMID- 28801169 TI - A single high dose of dexamethasone increases GAP-43 and synaptophysin in the hippocampus of aged rats. AB - The administration of dexamethasone, a synthetic glucocorticoid receptor agonist, has been reported to modulate cognitive performance in both animals and humans. In the present study, we demonstrate the effects of a single high dose of dexamethasone on the expression and distribution of synaptic plasticity-related proteins, growth-associated protein-43 (GAP-43) and synaptophysin, in the hippocampus of 6-, 12-, 18- and 24-month-old rats. Acute dexamethasone treatment significantly altered the expression of GAP-43 at the posttranslational level by modulating the levels of phosphorylated GAP-43 and proteolytic GAP-43-3 fragment. The effect was the most pronounced in the hippocampi of the aged animals. The total GAP-43 protein was increased only in 24-month-old dexamethasone-treated animals, and was concomitant with a decrease in calpain-mediated proteolysis. Moreover, by introducing the gray level co-occurrence matrix method, a form of texture analysis, we were able to reveal the subtle differences in the expression pattern of both GAP-43 and synaptophysin in the hippocampal subfields that were not detected by Western blot analysis alone. Therefore, the current study demonstrates, through a novel combined approach, that dexamethasone treatment significantly affects both GAP-43 and synaptophysin protein expression in the hippocampus of aged rats. PMID- 28801170 TI - PGC-1alpha in aging and lifelong exercise training-mediated regulation of UPR in mouse liver. AB - Aging is associated with changes in several metabolic pathways affecting liver function including the adaptive unfolded protein response (UPR). On the other hand, exercise training has been shown to exert beneficial effects on metabolism in the liver and exercise training has been reported to affect hepatic UPR. PGC 1alpha is a transcriptional coactivator involved in exercise training-induced adaptations in skeletal muscle and liver. Therefore, the aim of the present study was to examine the impact of PGC-1alpha in aging and lifelong exercise training induced hepatic UPR in mice. Liver was obtained from young (3months old), aged (15months old) and lifelong exercise trained aged wild-type (WT) and whole-body PGC-1alpha knockout (KO) mice. Hepatic BiP, IRE1alpha and cleaved ATF6 protein content increased, whereas PERK protein content was reduced with aging indicating both increased and decreased capacity of specific UPR pathways and increased activity of the ATF6 pathway in the liver with aging. Lifelong exercise training prevented the age-associated change in BiP and IRE1alpha protein, but not cleaved ATF6 protein and resulted in further decreased PERK protein. Taken together, the present study provides evidence that the capacity and activity of the three UPR pathways are differentially regulated in the liver with aging and lifelong exercise training. In addition, PGC-1alpha does not seem to regulate the activity of hepatic UPR in response to exercise training, but to influence the capacity of the liver to induce UPR in a pathway specific manner. PMID- 28801171 TI - Microorganisms-based methods for harmful algal blooms control: A review. AB - Harmful algal blooms (HABs) are a worldwide problem with numerous negative effects on water systems, which have prompted researchers to study applicable measures to inhibit and control them. This review summarized the current microorganisms-based methods or technologies aimed at controlling HABs. Based on their characteristics, these methods can be divided into two categories: methods based on single-species microorganisms and methods based on microbial aggregates, and four types: methods for rapid decrease of algal cells density (e.g., alga bacterium and alga-fungus bioflocculation), inhibition of harmful algal growth, lysis of harmful algae (e.g. algicidal bacteria, fungi, and actinomycete), and methods based on microbial aggregates (periphytons and biofilms). An integrative process of "flocculation-lysis-degradation-nutrients regulation" is proposed to control HABs. This review not only offers a systematic understanding of HABs control technologies based on microorganisms but also elicits a re-thinking of HABs control based on microbial aggregates. PMID- 28801172 TI - The inhibitory effects of free ammonia on ammonia oxidizing bacteria and nitrite oxidizing bacteria under anaerobic condition. AB - The free ammonia (FA) inhibition on ammonia oxidizing bacteria (AOB) and nitrite oxidizing bacteria (NOB) under anaerobic condition was investigated in this study. The results indicated that NOB was more sensitive to the FA anaerobic treatment than AOB. The FA anaerobic inhibition on nitrifier gradually heightened with the increase of FA concentration. Accompanied with FA concentration increase from 0 to 16.82mgNH3-N.L-1 (the highest concentration adopted in this study), the activity of AOB reduced by 15.9%, while NOB decreased by 29.2%. After FA anaerobic treatment, nitrite was accumulated during nitrification. However, the nitrite accumulation disappeared on the sixth cycle of activity recovery tests with excessive aeration. Based on this result, a novel strategy for achieving nitritation is proposed, which involves recirculating a portion of the activated sludge through a side-line sludge treatment unit, where the sludge is subjected to treatment with FA under anaerobic condition. PMID- 28801173 TI - Impacts of silver nanoparticles on the nutrient removal and functional bacterial community in vertical subsurface flow constructed wetlands. AB - The widespread utilization of silver nanoparticles (AgNPs) in industrial and commercial products inevitably raises the release into wastewater. In this study, the influences of AgNPs (0, 50 and 200MUg/L) on the performance and microbial community of CWs were evaluated. Compared with the control system (without AgNPs), the COD removal was not affected, whereas the TN, NH4+-N, and TP removals were evidently affected in presence of AgNPs, and the effects had a positive relation with AgNPs concentration. In addition, AgNPs were effectively removed from wastewater and mainly accumulated in the soil layer and plant tissues. The illumina high-throughput sequencing results indicated that there were obvious variations in the microbial community at different AgNPs concentrations, associated with the variations of CW performance. Sequencing analyses also showed that Proteobacteria, Acidobacteria, Bacteroidetes were the dominant phyla. These results may provide valuable information and reference for evaluating the effect of AgNPs on constructed wetlands. PMID- 28801174 TI - The cerebral collateral circulation: Relevance to pathophysiology and treatment of stroke. AB - The brain's collateral circulation consists of arterial anastomotic channels capable of providing nutrient perfusion to brain regions whose normal sources of flow have become compromised, as occurs in acute ischemic stroke. Modern CT-based neuroimaging is capable of providing detailed information as to collateral extent and sufficiency and is complemented by magnetic resonance-based methods. In the present era of standard-of-care IV thrombolysis for acute ischemic stroke, and following the recent therapeutic successes of randomized clinical trials of acute endovascular intervention, the sufficiency of the collateral circulation has been convincingly established as a key factor influencing the likelihood of successful reperfusion and favorable clinical outcome. This article reviews the features of the brain's collateral circulation; methods for its evaluation in the acute clinical setting; the relevance of collateral circulation to prognosis in acute ischemic stroke; the specific insights into the collateral circulation learned from recent trials of endovascular intervention; and the major influence of genetic factors. Finally, we emphasize the need to develop therapeutic approaches to augment collateral perfusion as an adjunctive strategy to be employed along with, or prior to, thrombolysis and endovascular interventions, and we highlight the possible potential of inhaled nitric oxide, albumin, and other approaches. This article is part of the Special Issue entitled 'Cerebral Ischemia'. PMID- 28801175 TI - MDMA and brain activity during neurocognitive performance: An overview of neuroimaging studies with abstinent 'Ecstasy' users. AB - MDMA/Ecstasy has had a resurgence in popularity, with recent supplies comprising higher strength MDMA, potentially leading to increased drug-related harm. Neurocognitive problems have been widely reported in ecstasy users, equally some studies report null findings, and it remains unclear which factors underlie the development of neurocognitive impairments. This review covers the empirical research into brain activity during neurocognitive performance, using fMRI, fNIRS, and EEG. Our main conclusion is that chronic repeated use of recreational ecstasy can result in haemodynamic and electrophysiological changes that reflect recruitment of additional resources to perform cognitive tasks. Findings are consistent with serotonergic system changes, although whether this reflects neurotoxicity or neuroadaptation, cannot be answered from these data. There is a degree of heterogeneity in the methodologies and findings, limiting the strengths of current conclusions. Future research with functional neuroimaging paired with molecular imaging, genetics or pharmacological challenges of the serotonin system may help to decipher the link between serotonergic and cognitive changes in ecstasy users. PMID- 28801176 TI - Caffeine use in the neonatal intensive care unit. AB - Caffeine is the most frequently used medication in the neonatal intensive care unit. It is used for the prevention and treatment of apnea, although this has been associated with lower incidence of bronchopulmonary dysplasia (BPD) and patent ductus arteriosus as well as intact survival at 18-21 months of life. Although neurodevelopmental advantage was no longer statistically significant at age 5 years, caffeine was associated with sustained improvement in co-ordination and less gross motor impairment than placebo. The mechanism of action of caffeine on prevention of apnea and activation of breathing seems to be through central inhibition of adenosine receptors. However, its impact on BPD and neurodevelopmental outcomes might be induced through its effects as anti inflammatory mediator, protection of white matter, and induction of surfactant protein B. Whereas long-term studies have documented the safety of caffeine as used in current practice, further studies are clearly needed to identify optimum dosing, and time of starting and discontinuing caffeine. PMID- 28801177 TI - Uses and misuses of sodium bicarbonate in the neonatal intensive care unit. AB - Over the past several decades, bicarbonate therapy continues to be used routinely in the treatment of acute metabolic acidosis in critically ill neonates despite the lack of evidence for its effectiveness in the treatment of acid-base imbalance, and evidence indicating that it may be detrimental. Clinicians often feel compelled to use bicarbonate since acidosis implies a need for such therapy and thus the justification for its use is based on hearsay rather than science. This review summarizes the evidence and refutes the clinical practice of administering sodium bicarbonate to treat metabolic acidosis associated with several specific clinical syndromes in neonates. PMID- 28801178 TI - Impact of head and neck radiotherapy on the mechanical behavior of composite resins and adhesive systems: A systematic review. AB - OBJECTIVES: To analyze the evidence regarding the impact of head and neck radiotherapy (HNRT) on the mechanical behavior of composite resins and adhesive systems. METHODS: Searches were conducted on PubMed, Embase, Scopus and ISI Web of Science databases using "Radiotherapy", "Composite resins" and "Adhesive systems" as keywords. Selected studies were written in English and assessed the mechanical behavior of composite resins and/or adhesive systems when bonding procedure was conducted before and/or after a maximum radiation dose >=50Gy, applied under in vitro or in vivo conditions. RESULTS: In total, 115 studies were found but only 16 were included, from which five evaluated the effect of in vitro HNRT on microhardness, wear resistance, diametral tensile and flexural strength of composite resins, showing no significant negative effect in most of reports. Regarding bond strength of adhesive systems, 11 studies were included from which five reported no meaningful negative effect when bonding procedure was conducted before simulated HNRT. Conversely, five studies showed that bond strength diminished when adhesive procedure was done after in vitro radiation therapy. Only two studies about dental adhesion were conducted after in vivo radiotherapy but the results were not conclusive. SIGNIFICANCE: The mechanical behavior of composite resins and adhesive systems seems not to be affected when in vitro HNRT is applied after bonding procedure. However, bond strength of adhesive systems tends to decrease when simulated radiotherapy is used immediately before bonding procedure. Studies assessing dentin bond strength after in-vivo HNRT were limited and controversial. PMID- 28801179 TI - Family history of gastric cancer is associated with the risk of colorectal neoplasia in Korean population. AB - BACKGROUND: Family history of cancers at different sites except for colorectum has not been evaluated as a risk factor for colorectal neoplasia (CRN). AIMS: To investigate CRN risk according to family history of cancers at 12 different sites, including stomach and colorectum. METHODS: A cross-sectional study was performed on 139,497 asymptomatic Koreans who underwent colonoscopy as part of a health check-up. RESULTS: The mean age of the study population was 41.6 and the prevalence of CRN was 16.3%. Multivariate analyses revealed that family histories of CRC (adjusted odds ratio; confidence interval, 1.26; 1.17-1.35) and gastric cancer (1.07; 1.01-1.13) were independent risk factors for CRN. Notably, the risk of CRN increased even more for participants with family histories of both CRC and gastric cancer (1.38; 1.12-1.70). Family history of CRC was associated with risk of CRN in participants aged both <50 and >=50 years, whereas family history of gastric cancer was associated with risk of CRN in participants aged <50 years (1.22; 1.14-1.30), but not in participants aged >=50 years (1.08; 0.99-1.18). CONCLUSIONS: Family history of gastric cancer was an independent risk factor for CRN, especially in those aged <50years. Persons with family histories of gastric cancer and CRC, especially those with family histories of both, may need to begin colonoscopy earlier. PMID- 28801180 TI - Obesity as predictor of postoperative outcomes in liver transplant candidates: Review of the literature and future perspectives. AB - BACKGROUND: Current American and European guidelines consider a pre-transplant BMI >=40kg/m2 as a relative contraindication for liver transplantation but this recommendation is graded as uncertain and requires further research. Moreover, conflicting results are reported on the predictive value of BMI 30-39.9kg/m2 on post-transplant complication and mortality risk. AIM: This study analyzed the data of the literature on the effect of all three BMI classes of obesity on postoperative outcomes in liver transplantation. MATERIALS AND METHODS: A PubMed and Cochrane Library search was conducted from inception to October 2015. RESULTS: Analysis of the literature demonstrates that discrepancies among studies are mainly either due to limitations of BMI per se, the different BMI cut-offs used to select patients with obesity or reference group and the different outcomes considered. Moreover, the evaluation of visceral adipose tissue and the detrimental effect of muscle mass reduction in presence of obesity are never considered. CONCLUSIONS: BMI assessment should be used as a preliminary method to evaluate obesity. Subsequently, the assessment of visceral adipose tissue and muscle mass should complete the preoperative evaluation of liver transplant candidates. This innovative approach could represent a new field of research in liver transplantation. PMID- 28801182 TI - Prediction of regioselectivity and preferred order of metabolisms on CYP1A2 mediated reactions. Part 2: Solving substrate interactions of CYP1A2 with non-PAH substrates on the template system. AB - In our previous paper (Drug Metabolism Parmacokinet31: 363, 2016), a simulation system for ligand interactions of human CYP1A2 was developed using "Template" composed of hexagonal grids focusing on polyaromatic hydrocarbons (PAHs). The system has been expanded for the application of non-PAH chemicals including medical drugs, industrial chemicals and natural products in the present study. Additions of two Templates C and D around Ring C/E and Ring B, respectively, perpendicular each to Template A, offered the accommodation of non-PAH substrates. The size and shape of Templates C and D were defined from the reciprocal comparison of experimental data of ligands with simulation on Templates. The requirements of occupancies at Trigger region (Ring B) and at region of Facial-side Movement (Ring C) as well as Site of Oxidation were found to be mutual throughout CYP1A2 good substrates tested for over the 450 reactions, irrespective of their shapes and flexibilities. The CYP1A2 Template system was also verified with distinct types of poor substrates (47 chemicals) and inhibitors (37 inhibitors) and found to offer the information on probable structural causes. Present CYP1A2 Template system offers a unified evaluation of human CYP1A2 ligands, which aids for toxicological assessments as well as drug metabolism studies. PMID- 28801181 TI - The use of oral corticosteroids in inflammatory bowel diseases in Italy: An IG IBD survey. AB - AIM: To evaluate how Italian gastroenterologists use corticosteroids in clinical practice for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). MATERIAL AND METHODS: All members of the Italian Group for Inflammatory Bowel Disease (IG-IBD) were invited to fill in a web-based questionnaire. RESULTS: 131/448 (29.2%) members completed the survey. In mild-to-moderate UC and CD relapses, low-bioavailability steroids (LBS) are first-line therapy for 37% and 42% of clinicians, respectively. In case of failure, immediate step-up to biologics or immunosuppressants is considered by 23% and 29%. Regarding conventional corticosteroids (CCS), a fixed starting dose is prescribed by 50%, and a weight-based dose by 22%. Tapering is started after 7-10days by 41% and after 14days by 32%. The preferred tapering schedule is 5mg/week. In case of CCS failure, 47% switch to parenteral steroids before considering shifting to different drug classes. In case of symptoms recurrence during tapering, 14% re increase the dose and try tapering again. Before prescribing steroids, 72% do not prescribe any specific evaluation whereas during treatment some evaluation is performed by 85%. Vitamin D and calcium supplements are routinely prescribed along with steroids by 38%. CONCLUSIONS: Several discrepancies and some deviation from the available guidelines were recorded among Italian gastroenterologists regarding corticosteroids use in IBD patients. PMID- 28801183 TI - Paired Phase II Studies of Erlotinib/Bevacizumab for Advanced Bronchioloalveolar Carcinoma or Never Smokers With Advanced Non-Small-cell Lung Cancer: SWOG S0635 and S0636 Trials. AB - BACKGROUND: Before mutation testing of the epidermal growth factor receptor (EGFR) gene was recognized as highly associated with the activity of EGFR tyrosine kinase inhibitors (TKIs), clinically defined patient populations with bronchioloalveolar carcinoma (BAC) and never smokers were identified as likely to benefit from EGFR TKIs. From preclinical and clinical data suggesting potentially improved efficacy with a combination of an EGFR TKI and the antiangiogenic agent bevacizumab, the Southwestern Oncology Group (SWOG) initiated paired phase II trials to evaluate the combination of erlotinib/bevacizumab in patients with advanced BAC (SWOG S0635) or never smokers with advanced lung adenocarcinoma (SWOG S0636). MATERIALS AND METHODS: Eligible patients with BAC or adenocarcinoma with BAC features (SWOG S0635) or never smokers with advanced lung adenocarcinoma (SWOG S0636) received erlotinib 150 mg/day with bevacizumab 15 mg/kg until progression or prohibitive toxicity. Never smokers with BAC were preferentially enrolled to SWOG S0636. The primary endpoint for both trials was overall survival. RESULTS: A total of 84 patients were enrolled in the SWOG S0635 trial and 85 in the SWOG S0636 trial. The objective response rate was 22% (3% complete response) in the SWOG S0635 trial and 50% (38% confirmed; 3% complete response) in the SWOG S0636 trial. The median progression-free survival was 5 and 7.4 months in the S0635 and S0636 trials, respectively. The median overall survival was 21 and 29.8 months, respectively. Toxicity consisted mainly of rash and diarrhea in both trials. CONCLUSION: Although the field has moved toward molecular, rather than clinical, selection of patients as optimal candidates for EGFR TKI therapy, these results support the hypothesis that a subset of patients in whom erlotinib is particularly active could receive an incremental benefit from the addition of bevacizumab. PMID- 28801184 TI - Fatal Colloid Cysts: A Systematic Review. AB - OBJECTIVE: To accurately describe patient characteristics and the clinical presentation of fatal colloid cysts. METHODS: A systematic literature search of 3 popular databases was performed. Inclusion criteria were individuals with sudden onset death and colloid cysts identified on imaging and/or autopsy. The cause of death must have been ascribed to the colloid cyst to be eligible for data extraction. Deaths precipitated by lumbar puncture were excluded. Clinical data were extracted and descriptive statistics were ascertained. Subgroup analyses were performed to compare adults with pediatric patients. RESULTS: A total of 107 patients were included in the quantitative synthesis. The mean age was 28.5 years (standard deviation 13.3, range 6-79 years). Male and female patients were affected equally. Headache was the most frequent symptom (n = 86, 80%). There were 6 patients (5 adults and 1 child) who reported positional headaches. The mean duration of signs and symptoms was shorter in adults versus pediatric patients (2.1 days vs. 6.5 days, P = 0.02), and more adults presented with signs and symptoms for less than 24 hours than did pediatric patients (38% vs. 6%, P = 0.01). Colloid cyst mean diameter was 2.0 cm (standard deviation 1.1, range 0.5 7.9 cm) and 96% measured 1 cm or larger. CONCLUSIONS: Our data suggests that the prodrome preceding sudden death in the setting of a colloid cyst may be shorter in adults. Also, most fatal colloid cysts measured 1 cm or larger. PMID- 28801185 TI - Neuroimaging Epigenetics: Challenges and Recommendations for Best Practices. AB - Neuroimaging epigenetics is an interdisciplinary application of epigenetics to cognitive neuroscience that seeks to identify molecular and neural predictors of human behavior. This approach can be sensitive to the dynamic interaction between biological predisposition and environmental influences, and is potentially more informative than an approach using static genetic code. Recent work in this field has generated considerable enthusiasm, yet caution is warranted since any novel cross-disciplinary approach lacks a set of established conventions or standards. In this paper we review existing research in the field of imaging epigenetics, outline important caveats and considerations, and suggest a set of guidelines for researchers conducting this work. PMID- 28801187 TI - Benefit with adjuvant chemotherapy in anaplastic astrocytoma. PMID- 28801186 TI - Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. AB - BACKGROUND: The role of temozolomide chemotherapy in newly diagnosed 1p/19q non co-deleted anaplastic gliomas, which are associated with lower sensitivity to chemotherapy and worse prognosis than 1p/19q co-deleted tumours, is unclear. We assessed the use of radiotherapy with concurrent and adjuvant temozolomide in adults with non-co-deleted anaplastic gliomas. METHODS: This was a phase 3, randomised, open-label study with a 2 * 2 factorial design. Eligible patients were aged 18 years or older and had newly diagnosed non-co-deleted anaplastic glioma with WHO performance status scores of 0-2. The randomisation schedule was generated with the electronic EORTC web-based ORTA system. Patients were assigned in equal numbers (1:1:1:1), using the minimisation technique, to receive radiotherapy (59.4 Gy in 33 fractions of 1.8 Gy) alone or with adjuvant temozolomide (12 4-week cycles of 150-200 mg/m2 temozolomide given on days 1-5); or to receive radiotherapy with concurrent temozolomide 75 mg/m2 per day, with or without adjuvant temozolomide. The primary endpoint was overall survival adjusted for performance status score, age, 1p loss of heterozygosity, presence of oligodendroglial elements, and MGMT promoter methylation status, analysed by intention to treat. We did a planned interim analysis after 219 (41%) deaths had occurred to test the null hypothesis of no efficacy (threshold for rejection p<0.0084). This trial is registered with ClinicalTrials.gov, number NCT00626990. FINDINGS: At the time of the interim analysis, 745 (99%) of the planned 748 patients had been enrolled. The hazard ratio for overall survival with use of adjuvant temozolomide was 0.65 (99.145% CI 0.45-0.93). Overall survival at 5 years was 55.9% (95% CI 47.2-63.8) with and 44.1% (36.3-51.6) without adjuvant temozolomide. Grade 3-4 adverse events were seen in 8-12% of 549 patients assigned temozolomide, and were mainly haematological and reversible. INTERPRETATION: Adjuvant temozolomide chemotherapy was associated with a significant survival benefit in patients with newly diagnosed non-co-deleted anaplastic glioma. Further analysis of the role of concurrent temozolomide treatment and molecular factors is needed. FUNDING: Schering Plough and MSD. PMID- 28801188 TI - Journal of Environmental Radioactivity special issue: II International Conference on Radioecological Concentration Processes. (50 years later). AB - An international conference on Radioecological Concentration Processes was held in Seville, Spain, 6-9 November 2016 at the Centro Nacional de Aceleradores. It was attended by 160 participants from 35 different countries. This was the 2nd conference on this item since 1966, 50 years ago. The conference covered aspects of radiological important radionuclides on terrestrial, marine and freshwater environments and has allowed obtaining a clear picture of the status of the Radioecology as a consolidated discipline in the 21st century. PMID- 28801189 TI - Comparison of femoral nerve block and fascia iliaca block for pain management in total hip arthroplasty: A meta-analysis. PMID- 28801190 TI - How will we get there? How will we know? PMID- 28801191 TI - Household survey of HIV incidence in Rwanda: a national observational cohort study. AB - BACKGROUND: In Rwanda, HIV prevalence among adults aged 15-49 years has been stable at 3% since 2005. The aim of this study was to characterise HIV incidence across Rwanda. METHODS: We did a nationally representative, prospective HIV incidence survey for the period of 2013-14, which used two-stage sampling. We randomly selected 492 villages in the first sampling stage and 14 households per village in the second stage. Participants completed a questionnaire and 14 140 people were tested for HIV. 13 728 participants were HIV negative, and were enrolled in the incidence cohort. Participants were retested and surveyed again after 12 months. Weights were calculated as the inverse of the probability to select the villages and the households. FINDINGS: The study period was from Nov 5, 2013, to Nov 15, 2014. Among 14 222 respondents from 6792 households, 14 140 were tested for HIV and 13 728 were HIV negative. Of 12 593 people who participated in the endpoint data collection activities, 5965 (47.4%) were men and the mean age was 30 years (SD 10.8). 11 237 (89.2%) participants lived in rural areas, 4826 (38.3%) were single, and 7140 (56.7%) were married or cohabitating. During the year, 35 participants had seroconversion, including 13 men and 22 women, resulting in an overall incidence of 0.27 per 100 person-years (95% CI 0.18-0.35). Incidence was 0.21 per 100 person-years (0.10-0.32) in men and 0.32 per 100 person-years (0.19-0.45) in women. Our findings suggested multiple breakouts, with multiple seroconversions occurring in three villages and two households. Incidence was higher in adults aged 36-45 years (0.37 per 100 person-years, 0.12-0.62; adjusted hazard ratio [aHR] 4.49, 95% CI 1.30-14.70) relative to those aged 16-25, higher in western province (0.57 per 100 person years, 0.31-0.87; aHR 5.90, 1.33-25.28) relative to the northern province, and higher in urban areas (0.65 per 100 person-years, 0.23-1.07; aHR 3.10, 1.28-6.99) than in rural areas. INTERPRETATION: The incidence of HIV in Rwanda was higher than that previously estimated from models, with outbreaks seeming to contribute to the ongoing epidemic. Characterisation of incident infections can help the national HIV programmes to plan for preventive interventions tailored to the most at risk populations. FUNDING: Global Fund to Fight HIV, Tuberculosis and Malaria, WHO Rwanda, UNAIDS Rwanda, and the Government of Rwanda. PMID- 28801193 TI - Re: Current thinking about the management of dysfunction of the temporomandibular joint: a review. PMID- 28801192 TI - Evaluating FINDRISC as a screening tool for type 2 diabetes among overweight adults in the PREVIEW:NZ cohort. AB - AIMS: This study aimed to evaluate the efficacy of a high (>=12) Finnish diabetes risk (FINDRISC) score in identifying undiagnosed prediabetes and type 2 diabetes (T2D) in an New Zealand population of overweight and obese individuals, across a variety of ethnic groups. METHODS: We estimated the efficacy of elevated FINDRISC scores in predicting prediabetes and T2D in 424 overweight adults with no prior diagnosis recruited for the PREVention of diabetes through lifestyle Interventions in Europe and Worldwide (PREVIEW) study. All participants who completed the FINDRISC questionnaire during a pre-screening phase with a score of >=12 were then screened using a 2h oral glucose tolerance test (2h-OGTT) to identify undiagnosed dysglycaemia. RESULTS: Of the 424 participants, 65% (n=280) were pre-diabetic and 7% (n=32) had undiagnosed T2D. A higher FINDRISC score was significantly associated with prediabetes and T2D (P=0.02). There was a significant association between ethnicity and glycaemic status (normal vs prediabetes/T2D, P=0.02). Increasing the FINDRISC cut-off to >=15 resulted in a non-significant increase in the proportion of participants correctly classified with dysglycaemia. ROC-AUC=0.6 with sensitivity=0.6026 (95% CI: 0.5459-0.6573) and specificity=0.5536 (95% CI: 0.4567-0.6476). Isolated impaired fasting glucose (IFG) was more efficient in predicting dysglycaemia than isolated impaired glucose tolerance (IGT). CONCLUSIONS: The FINDRISC questionnaire is a useful and efficacious screening tool to identify unknown prediabetes and T2D in overweight New Zealanders, particularly in Maori individuals. PMID- 28801194 TI - Medial septum modulates hippocampal gamma activity and prepulse inhibition in an N-methyl-d-aspartate receptor antagonist model of schizophrenia. AB - We reviewed the participation of the septohippocampal system in an animal model of schizophrenia that was acutely induced by systemic injection of an N-methyl-d aspartate (NMDA) receptor antagonist such as phencyclidine, MK-801 and ketamine. The NMDA receptor antagonist-induced model of schizophrenia is characterized by behavioral and electrophysiological disruptions, including a decrease in prepulse inhibition of the acoustic startle response (PPI), hyperlocomotion, decrease in gating of hippocampal auditory evoked potentials and robust increase in hippocampal gamma (30-100Hz) oscillations. Similar disruptions were also induced by a single electrographic seizure in the hippocampus. The behavioral and electrophysiological disruptions induced by an NMDA receptor antagonist can be reduced by inactivation or lesion of GABAergic neurons in the medial septum, deep brain stimulation of the medial septum or nucleus accumbens, or positive modulation of GABAB receptors. Our results suggest a close association between high-amplitude hippocampal gamma oscillations and psychosis-relevant behaviors including PPI loss, behavioral hyperactivity and loss in auditory gating. Abnormal electrophysiology suggests a disruption of somatic and apical dendritic inhibition in the hippocampus, resulting in distorted sensory integration, and impaired cognitive and memory processing. The hippocampus is suggested to be a hub in a brain network that participates in psychosis-relevant behaviors, through its direct projection to the nucleus accumbens, or through indirect connections via the entorhinal, cingulate and prefrontal cortices. PMID- 28801195 TI - Avoidance of accelerated aging in schizophrenia?: Clinical and biological characterization of an exceptionally high functioning individual. AB - OBJECTIVE: To determine the clinical and biological characteristics of an exceptionally high functioning index person (IP) with schizophrenia in her mid 50s, which may represent compensatory mechanisms, and potentially, avoidance of the accelerated aging typically associated with schizophrenia. METHOD: IP, 11 other women with schizophrenia, and 11 non-psychiatric comparison (NC) women were assessed with standard ratings of psychopathology, neurocognitive function, decisional capacity, and functional brain imaging. IP was also compared to a sample of demographically similar NCs (N=45) and persons with schizophrenia (N=42) on a set of blood-based biomarkers of aging related to metabolic function, oxidative stress, and inflammation. RESULTS: IP's scores on working memory, and levels of brain activation during an affective face matching task in the left fusiform, right lingual, and left precentral gyri, exceeded NCs. IP was similar to NCs in severity of negative symptoms, most neurocognitive functions, decisional capacity, and brain activation in the left inferior occipital gyrus during a selective stopping task. IP's levels on 11 of 14 metabolic and inflammatory biomarkers of aging were better than NCs and the schizophrenia group. CONCLUSION: Although speculative, results suggest a possible model in which superior working memory permits a person to be aware of the potentially psychotic nature of a thought or perception, and adjust response accordingly. Compensatory overactivity of brain regions during affective processing may also reflect heightened meta-awareness in emotional situations. Biomarker levels raise the possibility that IP partially avoided the accelerated biological aging associated with schizophrenia. PMID- 28801197 TI - Kinase inhibitors in clinical practice: An expanding world. PMID- 28801196 TI - Prenatal fine particulate exposure and early childhood asthma: Effect of maternal stress and fetal sex. AB - BACKGROUND: The impact of prenatal ambient air pollution on child asthma may be modified by maternal stress, child sex, and exposure dose and timing. OBJECTIVE: We prospectively examined associations between coexposure to prenatal particulate matter with an aerodynamic diameter of less than 2.5 microns (PM2.5) and maternal stress and childhood asthma (n = 736). METHODS: Daily PM2.5 exposure during pregnancy was estimated using a validated satellite-based spatiotemporally resolved prediction model. Prenatal maternal negative life events (NLEs) were dichotomized around the median (high: NLE >= 3; low: NLE < 3). We used Bayesian distributed lag interaction models to identify sensitive windows for prenatal PM2.5 exposure on children's asthma by age 6 years, and determine effect modification by maternal stress and child sex. RESULTS: Bayesian distributed lag interaction models identified a critical window of exposure (19-23 weeks' gestation, cumulative odds ratio, 1.15; 95% CI, 1.03-1.26; per interquartile range [1.7 MUg/m3] increase in prenatal PM2.5 level) during which children concomitantly exposed to prenatal PM2.5 and maternal stress had increased risk of asthma. No significant association was seen in children born to women reporting low prenatal stress. When examining modifying effects of prenatal stress and fetal sex, we found that boys born to mothers with higher prenatal stress were most vulnerable (19-21 weeks' gestation; cumulative odds ratio, 1.28; 95% CI, 1.15-1.41; per interquartile range increase in PM2.5). CONCLUSIONS: Prenatal PM2.5 exposure during sensitive windows is associated with increased risk of child asthma, especially in boys concurrently exposed to elevated maternal stress. PMID- 28801198 TI - In response to the letter to the editor regarding: Resting pectoralis minor muscle length: An accurate way to determine if the muscle is shortened? PMID- 28801199 TI - Repositioning the scapula with taping following distal radius fracture: Kinematic analysis using 3-dimensional motion system. AB - STUDY DESIGN: Cross-sectional and controlled laboratory study using pretest posttest design. INTRODUCTION: Patients with distal radius fracture (DRfx) report proximal segment problems. Taping is commonly recommended because it provides improved posture and function. PURPOSE OF THE STUDY: This study aimed to investigate the 3-dimensional scapular kinematics and the effect of taping on the kinematics in participants with DRfx. METHODS: Twenty participants with a unilateral history of DRfx and 20 healthy controls participated. Scapular kinematics was assessed using an electromagnetic system. Three separate strips of elastic taping were applied for participants with DRfx over the arm, scapula, and middle and lower trapezius muscles through the paravertebral muscles. Afterward, the scapular kinematics was reassessed in taped condition. RESULTS: When participants with DRfx and healthy controls compared, the scapula was more downwardly rotated at 120 degrees of humerothoracic elevation (mean difference [MD], 9.06 degrees ) and at 120 degrees (MD, 9.04 degrees ), 90 degrees (MD, 5.6 degrees ) of humerothoracic lowering, more upwardly rotated at 30 degrees of humerothoracic lowering (MD, 5.1 degrees ). Taping showed a significant effect on kinematics; specifically, the scapula was more externally rotated (38.9 degrees untaped vs 31.1 degrees taped) and posteriorly tilted (-9.2 degrees untaped vs 4.8 degrees taped) during humerothoracic elevation and lowering for participants with DRfx. DISCUSSION: Participants with DRfx showed different scapular kinematics and taping resulted in changes on tested kinematic parameters during humeral movements. Differences in scapular motion during elevation with taping showed a specific pattern. CONCLUSIONS: Overall, taping maintained a position likely to produce optimal rotator cuff function during early rehabilitation of patients with DRfx. LEVEL OF EVIDENCE: N/A. PMID- 28801200 TI - Perioperative mortality for patients with a hip fracture. AB - INTRODUCTION: Studies on mortality following hip fracture surgery have hitherto focused on the 30 day to 1 year period and beyond. This study focuses on the immediate perioperative period. It examines mortality rates, patient characteristics, operative details and post-operative complications. PATIENTS AND METHODS: A retrospective study of a hip fracture database in a large District General Hospital in the United Kingdom, from 1986 to 2015. A dataset of 9393 patients was identified, including patients undergoing surgery for curative and palliative purposes, over fifteen years of age and with no upper age limit imposed. It compared patients who survived the first 48h from start of surgery with those who died within this perioperative period. RESULTS: 9393 patients were treated surgically and included within this study, with a mean age of 80.13 and consisting of 7130 female and 2263 male patients. The all cause mortality within 48h from start of surgery was 0.8% (72 patients). Increased risk of perioperative mortality was associated with increasing age, ASA grade 3 and above, in-hospital falls, impaired mobility prior to the fall and a reduced mental test score on admission. For the patient with a perioperative death, the most common circumstances identified in this study involved being found dead in bed by attending staff within 48h of surgery. DISCUSSION: There has been significant attention paid to the optimization of patient management leading up to hip fracture surgery and its attendant impact on medium and longer term survival. The information from this study may be used to identify patients most at risk of death in the 48h after surgery. The importance of this dataset is that it provides large numbers, which are needed in order to look for associations, given the low 48h mortality rate found. CONCLUSION: We are unable to highlight any correctable or alterable factors associated with mortality. Further studies with detailed collection of data on a national scale may be needed to assess the impact of levels of postoperative care for hip fracture patients and perioperative mortality. PMID- 28801201 TI - Effectiveness of controlled telescoping system for lateral hip pain caused by sliding of blade following intramedullary nailing of trochanteric fracture. AB - INTRODUCTION: The purpose of this study was to demonstrate the effectiveness of controlled telescoping system for lateral hip pain caused by sliding of the blade following intramedullary nailing of trochanteric fractures. MATERIALS AND METHODS: A retrospective cohort study was performed to compare the controlled telescoping system (Compression Hip Nail; CHN) with the conventional sliding system (Proximal Femoral Nail Antirotation; PFNA) for trochanteric fractures. 74 cases in the PFNA group and 77 cases in the CHN group were included from two university hospitals in this study. All patients had a minimum of 12-month follow up period. Lateral hip pain was evaluated and operation time and blood loss during the surgery were measured. The fracture classification was evaluated. The quality of postoperative reduction and other complications after surgery were also evaluated and tip-apex distance (TAD), telescoping and lateral protrusion of the blade and lag screw were measured. RESULTS: The mean age was 78.5 years in the PFNA group and 74.7 years in the CHN group (p=0.25). The mean telescoping was 19.2mm in the PFNA group and 10.7mm in the CHN group (p<0.001). The mean length of lateral protrusion was 10.5mm in the PFNA group and 2.5mm in the CHN group (p<0.001). Twenty-eight patients in the PFNA group complained of lateral hip pain, whereas 12 patients in the CHN group did (p=0.002). These four variables showed statistically significant differences between the PFNA and CHN groups (p<0.05). The length of lateral protrusion was the only variable significantly related to lateral hip pain through multivariate logistic regression analysis (p=0.045). CONCLUSIONS: The degree of lateral protrusion was mainly related to lateral hip pain. Therefore, controlled telescoping would help to decrease lateral hip pain by decreasing the lateral protrusion beyond the lateral femoral cortex. PMID- 28801202 TI - A biomechanical study comparing proximal femur nail and proximal femur locking compression plate in fixation of reverse oblique proximal femur fractures. AB - BACKGROUND: The reverse oblique trochanteric fractures are common fractures and its treatment poses a challenge. The purpose of this study was to compare the biomechanical parameters of the construct using proximal femoral nail (PFN) and proximal femoral locking compression plates (PFLCP) in these fractures using cadaveric specimens. MATERIALS AND METHODS: Twenty freshly harvested cadaveric femoral specimens were randomly assigned to two groups after measuring bone mineral density, ten of which were implanted with PFN and the other ten with PFLCP. The constructs were made unstable to simulate reverse oblique trochanteric fracture (AO type 31A3.3) by removing a standard size posteromedial wedge. These constructs were tested in a computer controlled cyclic compressive loading with 200kg at a frequency of 1 cycle/s (1Hz) and test was observed for 50,000 cycles or until implant failure, whichever occurred earlier. Peak displacements were measured and analysis was done to determine axial stiffness and subsidence in axial loading. RESULTS: All the specimens in PFN group completed 50,000 cycles and in PFLCP group, seven specimens completed 50,000 cycles. Average subsidence in PFN group was 1.24+/-0.22mm and in PFLCP group was 1.48+/-0.38mm. The average stiffness of PFN group (72.6+/-6.8N/mm) was significantly higher than of PFLCP group (62.4+/-4.9N/mm) (P=0.04). The average number of cycles sustained by PFLCP was 46634 and for PFN group was 50,000 (P=0.06). CONCLUSION: The PFN is biomechanically superior to PFLCP in terms of axial stiffness, subsidence and number of specimens failed for the fixation of reverse oblique trochanteric fractures of femur. PMID- 28801204 TI - Improved post-processing strategy for MOLLI based tissue characterization allows application in patients with dyspnoe and impaired left ventricular function. AB - : Contrast and non-contrast MRI based characterization of myocardium by T1 mapping will be of paramount importance to obtain biomarkers, e.g. fibrosis, which determines the risk of heart failure patients. T1-mapping by the standard post-processing of the modified look-locker inversion recovery (MOLLI) lacks of accuracy when trying to reduce its duration, which on the other hand, is highly desirable in patients with heart failure. The recently suggested inversion group fitting (IGF) technique, which considers more parameters for fitting, has a superior accuracy for long T1 times despite a shorter duration. However, for short T1 values, the standard method has a superior precision. A conditional fitting routine is proposed which ideally takes advantage of both algorithms. MATERIALS AND METHODS: All measurements were performed on a 1.5T clinical scanner (ACHIEVA, Philips Healthcare, The Netherlands) using a MOLLI 5(n)3(n)3 prototype with n(heart beats) being a variable waiting time between inversion experiments. Phantom experiments covered a broad range of T1 times, waiting times and heart rates. A saturation recovery experiment served as a gold standard for T1 measurement. All data were analyzed with the standard MOLLI, the IGF fit and the conditional fitting routine and the obtained T1 values were compared with the gold standard. In vivo measurements were performed in a healthy volunteer and a total of 34 patients with normal findings, dilative cardiomyopathy and amyloidosis. RESULTS: Theoretical analysis and phantom experiments provided a threshold value for an apparent IGF T1* determining processing with IGF post processing for values above, or switching to the standard technique for values below. This was validated in phantoms and patients measurements. A reduction of the waiting time to 1 instead of 3 heart beats between the inversion experiments showed reliable results. The acquisition time was reduced from 17 to 13 heart beats. The in vivo measurements showed ECV values between 25% (18-33%; SD 0.03) in the healthy, 30% (22-40%; SD 0.04) in patients with DCM and 45% (30-60%; SD 0.9) in patients with amyloidosis. CONCLUSION: The adopted post-processing algorithm determines long T1 values with high accuracy and short T1 values while maintaining a high precision. Based on reduction of waiting time, and independence of heart rate, it shortens breath hold duration and allows fast T1 mapping, which is frequently a prerequisite in patients with cardiac diseases. PMID- 28801203 TI - Echocardiographic Prediction of Cardiac Resynchronization Therapy Response Requires Analysis of Both Mechanical Dyssynchrony and Right Ventricular Function: A Combined Analysis of Patient Data and Computer Simulations. AB - BACKGROUND: Pronounced echocardiographically measured mechanical dyssynchrony is a positive predictor of response to cardiac resynchronization therapy (CRT), whereas right ventricular (RV) dysfunction is a negative predictor. The aim of this study was to investigate how RV dysfunction influences the association between mechanical dyssynchrony and left ventricular (LV) volumetric remodeling following CRT. METHODS: One hundred twenty-two CRT candidates (mean LV ejection fraction, 19 +/- 6%; mean QRS width, 168 +/- 21 msec) were prospectively enrolled and underwent echocardiography before and 6 months after CRT. Volumetric remodeling was defined as percentage reduction in LV end-systolic volume. RV dysfunction was defined as RV fractional area change < 35%. Mechanical dyssynchrony was assessed as time to peak strain between the septum and LV lateral wall, interventricular mechanical delay, and septal systolic rebound stretch. Simulations of heart failure with an LV conduction delay in the CircAdapt computer model were used to investigate how LV and RV myocardial contractility influence LV dyssynchrony and acute CRT response. RESULTS: In the entire patient cohort, higher baseline septal systolic rebound stretch, time to peak strain between the septum and LV lateral wall, and interventricular mechanical delay were all associated with LV volumetric remodeling in univariate analysis (R = 0.599, R = 0.421, and R = 0.410, respectively, P < .01 for all). The association between septal systolic rebound stretch and LV volumetric remodeling was even stronger in patients without RV dysfunction (R = 0.648, P < .01). However, none of the mechanical dyssynchrony parameters were associated with LV remodeling in the RV dysfunction subgroup. The computer simulations showed that low RV contractility reduced CRT response but hardly affected mechanical dyssynchrony. In contrast, LV contractility changes had congruent effects on mechanical dyssynchrony and CRT response. CONCLUSIONS: Mechanical dyssynchrony parameters do not reflect the negative impact of reduced RV contractility on CRT response. Echocardiographic prediction of CRT response should therefore include parameters of mechanical dyssynchrony and RV function. PMID- 28801205 TI - Recombinant laminin fragments endowed with collagen-binding activity: A tool for conferring laminin-like cell-adhesive activity to collagen matrices. AB - Laminins are major components of basement membranes that sustain a wide variety of stem cells. Among 15 laminin isoforms, laminin-511 and its E8 fragment (LM511E8) have been shown to strongly promote the adhesion and proliferation of human pluripotent stem cells. The aim of this study was to endow the cell adhesive activity of laminin-511 on collagen matrices, thereby fabricating collagen-based culture scaffolds for stem cells with defined composition. To achieve this goal, we utilized the collagen-binding domain (CBD) of fibronectin to immobilize LM511E8 on collagen matrices. CBD was attached to the N-termini of individual laminin chains (alpha5E8, beta1E8, gamma1E8), producing LM511E8s having one, two, or three CBDs. While LM511E8 did not bind to collagen, CBD attached LM511E8s (CBD-LM511E8s) exhibited significant collagen-binding activity, dependent on the number of attached CBDs. Human iPS cells were cultured on collagen-coated plates preloaded with CBD-LM511E8s. Although iPS cells did not attach or grow on collagen, they robustly proliferated on CBD-LM511E8-loaded collagen matrices, similar to the case with LM511E8-coated plates. Importantly, iPS cells proliferated and yielded round-shaped colonies even on collagen gels preloaded with CBD-LM511E8s. These results demonstrate that CBD-attached laminin E8 fragments are promising tools for fabrication of collagen-based matrices having the cell-adhesive activity of laminins. PMID- 28801206 TI - Response to: Ultrasonographic assessment of tonsillar volume in children. PMID- 28801207 TI - CredibleMeds.org: What does it offer? AB - Since the 1990s, when numerous non-cardiac drugs were first recognized to have the potential to prolong the QT interval and cause torsades de pointes (TdP), clinicians, drug regulators, drug developers, and clinical investigators have become aware of the complexities of assessing evidence and determining TdP causality for the many drugs being marketed or under development. To facilitate better understanding, the Arizona Center for Education and Research on Therapeutics, known as AZCERT, has developed the CredibleMeds.org website which includes QTdrugs, a listing of over 220 drugs placed in four risk categories based on their association with QT prolongation and TdP. Since the site was launched in 1999, it has become the single and most reliable source of information of its kind for patients, healthcare providers, and research scientists. Over 96,000 registered users rely on the QTdrugs database as their primary resource to inform their medication use, their prescribing or their clinical research into the impact of QT-prolonging drugs and drug-induced arrhythmias. The QTdrugs lists are increasingly used as the basis for clinical decision support systems in healthcare and for metrics of prescribing quality by healthcare insurers. A free smartphone app and an application program interface enable rapid and mobile access to the lists. Also, the CredibleMeds website offers numerous educational resources for patients, educators and healthcare providers that foster the safe use of medications. PMID- 28801208 TI - Projected increase in total knee arthroplasty in the United States - an alternative projection model. AB - OBJECTIVE: The purpose of our study was to estimate the future incidence rate (IR) and volume of primary total knee arthroplasty (TKA) in the United States from 2015 to 2050 using a conservative projection model that assumes a maximum IR of procedures. Furthermore, our study compared these projections to a model assuming exponential growth, as done in previous studies, for illustrative purposes. METHODS: A population based epidemiological study was conducted using data from US National Inpatient Sample (NIS) and Census Bureau. Primary TKA procedures performed between 1993 and 2012 were identified. The IR, 95% confidence intervals (CI), or prediction intervals (PI) of TKA per 100,000 US citizens over the age of 40 years were calculated. The estimated IR was used as the outcome of a regression modelling with a logistic regression (i.e., conservative model) and Poisson regression equation (i.e., exponential growth model). RESULTS: Logistic regression modelling suggests the IR of TKA is expected to increase 69% by 2050 compared to 2012, from 429 (95%CI 374-453) procedures/100,000 in 2012 to 725 (95%PI 121-1041) in 2050. This translates into a 143% projected increase in TKA volume. Using the Poisson model, the IR in 2050 was projected to increase 565%, to 2854 (95%CI 2278-4004) procedures/100,000 IR, which is an 855% projected increase in volume compared to 2012. CONCLUSIONS: Even after using a conservative projection approach, the number of TKAs in the US, which already has the highest IR of knee arthroplasty in the world, is expected to increase 143% by 2050. PMID- 28801210 TI - The longitudinal relationship between hand, hip and knee osteoarthritis and cardiovascular events: a population-based cohort study. AB - OBJECTIVE: In this population-based cohort study, we examined the association between the presence of symptomatic osteoarthritis (OA) and risk for cardiovascular (CV) events. METHOD: A cohort aged >=55 years recruited from 1996 to 98 was followed through provincial health administrative data to 2014. Demographics, joint complaints and functional limitations were collected. Hip, knee and hand OA were defined using a validated definition. Using Cox regressions, the relationship between OA and a composite CV outcome (myocardial infarction (MI), stroke, angina, heart failure, revascularization) was assessed controlling for age, body mass index (BMI), sex, pre-existing metabolic factors, comorbidities, income status, primary care exposure and functional limitations. RESULTS: 18,490 participants were included: median age was 68 years, 60.3% were female; 24.4% met criteria for OA (10.0% hip, 15.3% knee, 16.0% hand), 16.3% self reported limitation in grip and 25.4% in walking. Over a median 13.4 years, 31.9% experienced a CV event. Controlling for all but walking limitation, a dose response relationship was observed between number of joints affected by knee/hip OA and CV risk (HR 2 hips/knees vs none: 1.13, 95% CI 1.03-1.23; 3+ hips/knees: 1.22, 95% CI 1.09-1.36). This relationship became non-significant additionally controlling for difficulty walking. Self-reported difficulty walking was associated with a 30% increased hazard for CV events. The effect of hand OA was not significant. CONCLUSION: In a large population cohort, a greater burden of hip/knee OA was associated with higher CV risk; the relationship was explained by OA-related difficulty walking. Increased attention to management of OA with a view to improving mobility has potential to reduce CV events. PMID- 28801211 TI - Parkin clearance of dysfunctional mitochondria regulates ROS levels and increases survival of human chondrocytes. AB - OBJECTIVE: Mitochondrial dysfunction, oxidative stress and chondrocyte death are important contributors to the development and pathogenesis of osteoarthritis (OA). In this study, we determined the expression and role of Parkin in the clearance of damaged/dysfunctional mitochondria, regulation of reactive oxygen species (ROS) levels and chondrocyte survival under pathological conditions. METHODS: Human chondrocytes were from the unaffected area of knee OA cartilage (n = 12) and were stimulated with IL-1beta to mimic pathological conditions. Mitochondrial membrane depolarization and ROS levels were determined using specific dyes and flow cytometry. Autophagy was determined by Western blotting for ATG5, Beclin1, immunofluorescence staining and confocal microscopy. Gene expression was determined by RT-qPCR. siRNA, wild-type and mutant Parkin plasmids were transfected using Amaxa system. Apoptosis was determined by PI staining of chondrocytes and TUNEL assay. RESULTS: IL-1beta-stimulated OA chondrocytes showed high levels of ROS generation, mitochondrial membrane damage, accumulation of damaged mitochondria and higher incidence of apoptosis. IL-1beta stimulation of chondrocytes with depleted Parkin expression resulted in sustained high levels of ROS, accumulation of damaged/dysfunctional mitochondria and enhanced apoptosis. Parkin translocation to depolarized/damaged mitochondria and recruitment of p62/SQSTM1 was required for the elimination of damaged/dysfunctional mitochondria in IL-1beta-stimulated OA chondrocytes. Importantly we demonstrate that Parkin elimination of depolarized/damaged mitochondria required the Parkin ubiquitin ligase activity and resulted in reduced ROS levels and inhibition of apoptosis in OA chondrocytes under pathological conditions. CONCLUSIONS: Our data demonstrates that Parkin functions to eliminate depolarized/damaged mitochondria in chondrocytes which is necessary for mitochondrial quality control, regulation of ROS levels and chondrocyte survival under pathological conditions. PMID- 28801209 TI - Compromised autophagy precedes meniscus degeneration and cartilage damage in mice. AB - OBJECTIVE: Autophagy is a cellular homeostasis mechanism that facilitates normal cell function and survival. Objectives of this study were to determine associations between autophagic responses with meniscus injury, joint aging, and osteoarthritis (OA), and to establish the temporal relationship with structural changes in menisci and cartilage. METHODS: Constitutive activation of autophagy during aging was measured in GFP-LC3 transgenic reporter mice between 6 and 30 months. Meniscus injury was created by surgically destabilizing the medial meniscus (DMM) to induce posttraumatic OA in C57BL/6J mice. Levels of autophagy proteins and activation were analyzed by confocal microscopy and immunohistochemistry. Associated histopathological changes, such as cellularity, matrix staining, and structural damage, were graded in the meniscus and compared to changes in articular cartilage. RESULTS: In C57BL/6J mice, basal autophagy was lower in the meniscus than in articular cartilage. With increasing age, expression of the autophagy proteins ATG5 and LC3 was significantly reduced by 24 months. Age-related changes included abnormal Safranin-O staining and reduced cellularity, which preceded structural damage in the meniscus and articular cartilage. In mice with DMM, autophagy was induced in the meniscus while it was suppressed in cartilage. Articular cartilage exhibited the most profound changes in autophagy and structure that preceded meniscus degeneration. Systemic administration of rapamycin to mice with DMM induced autophagy activation in cartilage and reduced degenerative changes in both meniscus and cartilage. CONCLUSION: Autophagy is significantly affected in the meniscus during aging and injury and precedes structural damage. Maintenance of autophagic activity appears critical for meniscus and cartilage integrity. PMID- 28801212 TI - Intraoperative validation of quantitative T2 mapping in patients with articular cartilage lesions of the knee. AB - OBJECTIVE: The aim of this study was to compare T2 relaxation times of knee cartilage with intraoperative results for the assessment of early osteoarthritis (OA) and to define T2 values for the differentiation between healthy and degenerated cartilage. DESIGN: Twenty-one patients with cartilage lesions or moderate OA were examined using 3T magnetic resonance imaging (MRI). In this prospective study, a total of 882 regions of interest (ROIs) were examined by a sagittal, multi-echo, spin-echo T2 sequence and a morphological high-resolution three-dimensional, fat-saturated proton-density space sequence. Cartilage lesions were identified arthroscopically, graded by the International Cartilage Repair Society (ICRS) score in 42 defined ROIs per patient and consecutively compared with mean T2 values using analysis of variance and Spearman's rank correlation test. Receiver operating characteristics (ROC) curves were developed to identify threshold T2 values to differentiate between the ICRS grades. RESULTS: A total of 882 ROIs were examined and graduated in ICRS score 0 (67.3%), 1 (25.2%), 2 (6.2%) and the merged ICRS 3 and 4 (1.0%). T2 values increased with increasing grade of cartilage damage with a statistically significant positive correlation between T2 values and ICRS scores. A T2 value threshold of 47.6 ms was identified to differentiate between ICRS score 0 (normal) and all other grades (ROC curve analysis). CONCLUSION: T2 mapping might provide a diagnostic tool for the detection of early knee-joint cartilage damage and for the non-invasive differentiation between ICRS grades by MRI in clinical practice. PMID- 28801213 TI - Response to the comments on "Effects of high intensity aquatic resistance training on body composition and walking speed in women with mild knee osteoarthritis: a 4-month RCT with 12-month follow-up". PMID- 28801214 TI - Lobar Hemorrhage Induced by Acquired Factor XIII Deficiency in a Patient with Cerebral Amyloid Angiopathy. AB - A 68-year-old man presented with intracranial hemorrhage in the right frontal lobe, which rapidly increased the day after admission. We performed hematoma removal with a biopsy of the cortex around the hematoma. The day after the operation, a subcutaneous hematoma over the craniotomy appeared, and the computed tomography showed a recurrent hemorrhage with an acute subdural hematoma. We were aware of a bleeding tendency, and a detailed hematologic examination by hematologists revealed autoimmune acquired factor XIII deficiency due to an antifactor XIII antibody. Specimens taken around the hematomas were pathologically diagnosed as cerebral amyloid angiopathy (CAA) on immunohistochemical examination. We considered that acquired factor XIII deficiency had induced lobar hemorrhage in the frontal lobe affected with CAA, and the coagulation disorder induced postoperative rebleeding. The patient died from repeated lobar hemorrhage 3 years after the surgery. There is no routine screening coagulation test including the active partial thromboplastin time and the prothrombin time for factor XIII deficiency. It is important for neurologists and neurosurgeons to be aware of this rare disease in patients with a bleeding tendency. PMID- 28801215 TI - Nitrogen removal from digested slurries using a simplified ammonia stripping technique. AB - This study assessed a novel technique for removing nitrogen from digested organic waste based on a slow release of ammonia that was promoted by continuous mixing of the digestate and delivering a continuous air stream across the surface of the liquid. Three 10-day experiments were conducted using two 50-L reactors. In the first two, nitrogen removal efficiencies were evaluated from identical digestates maintained at different temperatures (30 degrees C and 40 degrees C). At the start of the first experiment, the digestates were adjusted to pH 9 using sodium hydroxide, while in the second experiment pH was not adjusted. The highest ammonia removal efficiency (87%) was obtained at 40 degrees C with pH adjustment. However at 40 degrees C without pH adjustment, removal efficiencies of 69% for ammonia and 47% for total nitrogen were obtained. In the third experiment two different digestates were tested at 50 degrees C without pH adjustment. Although the initial chemical characteristics of the digestates were different in this experiment, the ammonia removal efficiencies were very similar (approximately 85%). Despite ammonia removal, the pH increased in all experiments, most likely due to carbon dioxide stripping that was promoted by temperature and mixing. The technique proved to be suitable for removing nitrogen following anaerobic digestion of livestock manure because effective removal was obtained at natural pH (~8) and 40 degrees C, common operating conditions at typical biogas plants that process manure. Furthermore, the electrical energy requirement to operate the process is limited (estimated to be 3.8kWhm-3digestate). Further improvements may increase the efficiency and reduce the processing time of this treatment technique. Even without these advances slow-rate air stripping of ammonia is a viable option for reducing the environmental impact associated with animal manure management. PMID- 28801217 TI - Evaluation of Unplanned Hospital Readmissions After Major Urologic Inpatient Surgery in the Era of Accountable Care. AB - OBJECTIVE: To provide a multi-institutional analysis of clinical factors predicting unplanned hospital readmission after major inpatient urologic surgery. MATERIALS AND METHODS: The American College of Surgeons National Surgical Quality Improvement Program is a risk-adjusted data collection mechanism for analyzing clinical outcomes data including 30-day perioperative readmissions and complications. We identified 23,108 patients who underwent major inpatient urologic surgery from 2011 to 2012. Readmission rates were determined and stratified by procedure type. Multiple logistic regression was used to determine independent risk factors for 30-day unplanned hospital readmissions. RESULTS: Of a total of 23,108 patients undergoing urologic surgery, 1329 patients (5.8%) had unplanned readmissions. Upper tract reconstruction and urinary diversion without cystectomy (21/102) and with cystectomy (291/1662) had the highest rates of readmission of all procedures analyzed. Readmitted patients had a 64.2% (853/1329) and 64.4% (855/1329) rate of major and minor complications, respectively, compared with 6.7% (1459/21,779) and 15.9% (3462/21,779) for patients not readmitted (P <.02). Organ space infection (odds ratio [OR] 15.23), pulmonary embolism (OR 12.14), deep venous thrombosis (OR 10.96), and return to the operating room (OR 8.46) were the most substantial predictors of readmission. Laparoscopic-robotic procedures had significantly lower readmission rates compared with open procedures for prostatectomy, partial nephrectomy, and nephrectomy (P <.01). CONCLUSION: Readmission after inpatient urologic surgery occurs at a rate of 5.8%, with cystectomy and urinary diversion demonstrating the highest rates. Major and minor postoperative complications were the most substantial predictors of readmission. These results may guide risk reduction initiatives to prevent readmissions after major urologic surgery. PMID- 28801216 TI - A novel process for separation of hazardous poly(vinyl chloride) from mixed plastic wastes by froth flotation. AB - A novel method, calcium hypochlorite (CHC) treatment, was proposed for separation of hazardous poly(vinyl chloride) (PVC) plastic from mixed plastic wastes (MPWs) by froth flotation. Flotation behavior of single plastic indicates that PVC can be separated from poly(ethylene terephthalate) (PET), poly(acrylonitrile-co butadiene-co-styrene) (ABS), polystyrene (PS), polycarbonate (PC) and poly(methyl methacrylate) (PMMA) by froth flotation combined with CHC treatment. Mechanism of CHC treatment was examined by contact angle measurement, scanning electron microscopy, Fourier transform infrared and X-ray photoelectron spectroscopy. Under the optimum conditions, separation of PVC from binary plastics with different particle sizes is achieved efficiently. The purity of PC, ABS, PMMA, PS and PET is greater than 96.8%, 98.5%, 98.8%, 97.4% and 96.3%, respectively. Separation of PVC from multi-plastics was further conducted by two-stage flotation. PVC can be separated efficiently from MPWs with residue content of 0.37%. Additionally, reusing CHC solution is practical. This work indicates that separation of hazardous PVC from MPWs is effective by froth flotation. PMID- 28801218 TI - Urology Residents' Experience and Attitude Toward Surgical Simulation: Presenting our 4-Year Experience With a Multi-institutional, Multi-modality Simulation Model. AB - OBJECTIVE: To evaluate the Urological resident's attitude and experience with surgical simulation in residency education using a multi-institutional, multi modality model. MATERIALS AND METHODS: Residents from 6 area urology training programs rotated through simulation stations in 4 consecutive sessions from 2014 to 2017. Workshops included GreenLight photovaporization of the prostate, ureteroscopic stone extraction, laparoscopic peg transfer, 3-dimensional laparoscopy rope pass, transobturator sling placement, intravesical injection, high definition video system trainer, vasectomy, and Urolift. Faculty members provided teaching assistance, objective scoring, and verbal feedback. Participants completed a nonvalidated questionnaire evaluating utility of the workshop and soliciting suggestions for improvement. RESULTS: Sixty-three of 75 participants (84%) (postgraduate years 1-6) completed the exit questionnaire. Median rating of exercise usefulness on a scale of 1-10 ranged from 7.5 to 9. On a scale of 0-10, cumulative median scores of the course remained high over 4 years: time limit per station (9; interquartile range [IQR] 2), faculty instruction (9, IQR 2), ease of use (9, IQR 2), face validity (8, IQR 3), and overall course (9, IQR 2). On multivariate analysis, there was no difference in rating of domains between postgraduate years. Sixty-seven percent (42/63) believe that simulation training should be a requirement of Urology residency. Ninety seven percent (63/65) viewed the laboratory as beneficial to their education. CONCLUSION: This workshop model is a valuable training experience for residents. Most participants believe that surgical simulation is beneficial and should be a requirement for Urology residency. High ratings of usefulness for each exercise demonstrated excellent face validity provided by the course. PMID- 28801219 TI - Renal Forniceal Rupture: Is Conservative Management Safe? AB - OBJECTIVE: To outline treatment considerations and outcomes for a cohort of patients with forniceal rupture with the aim of adding to a very limited body of literature regarding clinical practice in this area. METHODS: We retrospectively searched all radiographic records for patients treated at our institution between January 2009 and January 2016 with forniceal rupture. We compiled demographic data, etiology, clinical factors, treatments, and outcomes. RESULTS: Of the 103 patients analyzed, the median age at presentation was 64 years (interquartile range 52-73), and 56 (54%) were female. The etiology of forniceal rupture was most commonly urolithiasis (73%), with cancer being the next most common cause (11%). Most cases (61%) were caused by small (1-5 mm) stones in the distal ureter. Thirty-one patients (30%) were treated surgically with ureteral stent placement upfront; 27 of those patients had a ureteral stone, and most had some clinical factors making them higher risk. There was only 1 operative complication during the study period. Only 1 patient developed an abscess. Forty-three patients (42%) were sent home from the emergency room. Of the patients who were admitted, the average hospital stay was 3 days (interquartile range 2-6). For the entire cohort, there were 6 (6%) readmissions in the study period. CONCLUSION: Very limited data exist in the literature regarding clinical practice in the treatment of forniceal rupture. Clinical practice at our institution is conservative treatment of forniceal rupture in the absence of infection, kidney failure, or other risk factors with few complications or readmissions. PMID- 28801221 TI - The aminoacyl-tRNA synthetases had only a marginal role in the origin of the organization of the genetic code: Evidence in favor of the coevolution theory. AB - The coevolution theory of the origin of the genetic code suggests that the organization of the genetic code coevolved with the biosynthetic relationships between amino acids. The mechanism that allowed this coevolution was based on tRNA-like molecules on which-this theory-would postulate the biosynthetic transformations between amino acids to have occurred. This mechanism makes a prediction on how the role conducted by the aminoacyl-tRNA synthetases (ARSs), in the origin of the genetic code, should have been. Indeed, if the biosynthetic transformations between amino acids occurred on tRNA-like molecules, then there was no need to link amino acids to these molecules because amino acids were already charged on tRNA-like molecules, as the coevolution theory suggests. In spite of the fact that ARSs make the genetic code responsible for the first interaction between a component of nucleic acids and that of proteins, for the coevolution theory the role of ARSs should have been entirely marginal in the genetic code origin. Therefore, I have conducted a further analysis of the distribution of the two classes of ARSs and of their subclasses-in the genetic code table-in order to perform a falsification test of the coevolution theory. Indeed, in the case in which the distribution of ARSs within the genetic code would have been highly significant, then the coevolution theory would be falsified since the mechanism on which it is based would not predict a fundamental role of ARSs in the origin of the genetic code. I found that the statistical significance of the distribution of the two classes of ARSs in the table of the genetic code is low or marginal, whereas that of the subclasses of ARSs statistically significant. However, this is in perfect agreement with the postulates of the coevolution theory. Indeed, the only case of statistical significance-regarding the classes of ARSs-is appreciable for the CAG code, whereas for its complement-the UNN/NUN code-only a marginal significance is measurable. These two codes codify roughly for the two ARS classes, in particular, the CAG code for the class II while the UNN/NUN code for the class I. Furthermore, the subclasses of ARSs show a statistical significance of their distribution in the genetic code table. Nevertheless, the more sensible explanation for these observations would be the following. The observation that would link the two classes of ARSs to the CAG and UNN/NUN codes, and the statistical significance of the distribution of the subclasses of ARSs in the genetic code table, would be only a secondary effect due to the highly significant distribution of the polarity of amino acids and their biosynthetic relationships in the genetic code. That is to say, the polarity of amino acids and their biosynthetic relationships would have conditioned the evolution of ARSs so that their presence in the genetic code would have been detectable. Even if the ARSs would not have-on their own-influenced directly the evolutionary organization of the genetic code. In other words, the role that ARSs had in the origin of the genetic code would have been entirely marginal. This conclusion would be in perfect accord with the predictions of the coevolution theory. Conversely, this conclusion would be in contrast-at least partially-with the physicochemical theories of the origin of the genetic code because they would foresee an absolutely more active role of ARSs in the origin of the organization of the genetic code. PMID- 28801220 TI - Multiple Reflex Pathways Contribute to Bladder Activation by Intraurethral Stimulation in Persons With Spinal Cord Injury. AB - OBJECTIVE: To measure the urodynamic effects of electrical co-stimulation of 2 individual sites in the proximal and distal urethra in persons with spinal cord injury (SCI). This work was motivated by preclinical findings that selective co stimulation of the cranial urethral sensory nerve and the dorsal genital nerve, which innervate the proximal and distal portions of the urethra, respectively, increased reflex bladder activation and voiding efficiency. MATERIALS AND METHODS: Electrical co-stimulation of urethral afferents was conducted in persons with chronic SCI during urodynamics. The effects of different frequencies of intraurethral stimulation at multiple urethral locations on bladder pressure and pelvic floor electromyographic activity were measured. RESULTS: Electromyographic activity indicated that multiple reflex pathways were recruited through stimulation that contributed to bladder activation. The size of reflex bladder contractions evoked by stimulation was dependent on stimulation location or reflex activated and stimulation frequency. CONCLUSION: Pudendal nerve afferents are a promising target to restore lost bladder control, as stimulation with different frequencies may be used to treat urinary incontinence and increase continent volumes or to generate stimulation-evoked bladder contractions for on demand voiding. This work identified that co-stimulation of multiple afferent reflex pathways can enhance activation of spinal circuits and may enable improved bladder emptying in SCI when stimulation of a single pathway is not sufficient. PMID- 28801222 TI - Inferring incomplete lineage sorting, duplications, transfers and losses with reconciliations. AB - Gene trees and species trees can be discordant due to several processes. Standard models of reconciliations consider macro-evolutionary events at the gene level: duplications, losses and transfers of genes. However, another common source of gene tree-species tree discordance is incomplete lineage sorting (ILS), whereby gene divergences corresponding to speciations occur "out of order". However, ILS is seldom considered in reconciliation models. In this paper, we devise a unified formal IDTL reconciliation model which includes all the above mentioned processes. We show how to properly cost ILS under this model, and then give a fixed-parameter tractable (FPT) algorithm which calculates the most parsimonious IDTL reconciliation, with guaranteed time-consistency of transfer events. Provided that the number of branches in contiguous regions of the species tree in which ILS is allowed is bounded by a constant, this algorithm is linear in the number of genes and quadratic in the number of species. This provides a formal foundation to the inference of ILS in a reconciliation framework. PMID- 28801223 TI - Limited benefits of presymptomatic cord blood transplantation in neurovisceral acid sphingomyelinase deficiency (ASMD) intermediate type. AB - Acid sphingomyelinase (ASM) deficient Niemann-Pick disease is a lysosomal storage disorder resulting from mutations in the SMPD1 gene. The clinical spectrum distinguishes a severe infantile neurological form (type A), a non-neurological visceral form (type B) and a rare intermediate neurovisceral form. We report the first case of presymptomatic cord blood transplantation in a child with the intermediate type of ASM deficiency due to a homozygous Tyr369Cys mutation, whose affected elder brother had developed neurodevelopmental delay from 19 months of age, and had died from severe visceral complications at the age of 3. In the transplanted propositus, neurological deterioration became evident by 4 years of age; the child was alive at age 8, although severely disabled. Whereas the transplant prevented visceral progression and early death, it could only delay neurocognitive deterioration. PMID- 28801224 TI - Celiac Disease and Increased Risk of Pneumococcal Infection: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Celiac disease has been associated with hyposplenism, and multiple case reports link celiac disease and pneumococcal infections; however, increased risk of pneumococcal infection in celiac disease has not been confirmed. The purpose of this study was to conduct a systematic review to determine the risk of pneumococcal infections in celiac disease. METHODS: Relevant studies were identified using electronic bibliographic searches of PubMed, OVID, Medline, and EMBASE (1980 to February 2017) and reviewing abstracts from major conferences in gastroenterology. Using number of events in celiac patients and referent patients, we calculated a summary relative risk of pneumococcal infections. All analyses were conducted in Comprehensive Meta-Analysis software using random effects assumptions. RESULTS: Of a total of 156 articles, 3, representing 3 large databases (the Swedish National Inpatient Register; the Oxford Record Linkage Study; and the English National Hospital Episode Statistics) were included. Each compared patients with celiac disease and confirmed pneumococcal infection to a specific reference group: inpatients and/or the general population. Overall, the odds of pneumococcal infection were higher among hospitalized celiac patients compared with controls (odds ratio 1.66; 95% confidence interval 1.43-1.92). There was no evidence of heterogeneity (Q[1] = 1.17, P = .56, I2 = 0%). CONCLUSIONS: Celiac disease is associated with an increased risk of pneumococcal infection. Preventive pneumococcal vaccination should be considered for those with celiac disease, with special attention to those aged 15-64 years who have not received the scheduled pneumococcal vaccination series as a child. PMID- 28801225 TI - Temporal Trends in the Clinical Acuity of Patients with ST-Segment Elevation Myocardial Infarction. AB - BACKGROUND: Despite advances in ST-segment elevation myocardial infarction (STEMI) systems of care over the last decade, studies have shown no improvement in risk-adjusted mortality. It has been hypothesized that the population presenting to the catheterization laboratory has become sicker over time, in ways not accurately captured by current mortality models. The objective of this study was to examine changes in the clinical characteristics and in-hospital case fatality rate of the STEMI population treated with early percutaneous coronary intervention (PCI). METHODS: We conducted a retrospective analysis of a nationwide inpatient database for the period 2004-2012. All patients with a diagnosis of STEMI who underwent PCI within 24 hours of admission were identified. The primary outcome was in-hospital mortality. RESULTS: From 2004 to 2012 there was a consistent increase in unadjusted in-hospital mortality (3.9% in 2004 and 4.7% in 2012, odds ratioyear 1.03; 95% confidence interval 1.01-1.04). During this time there was an increase in the proportion of patients with >=3 Elixhauser comorbidities (14.8% vs 29.0%, Ptrend < .001). Intubation or cardiac arrest on presentation increased from 3.2% to 7.8% (Ptrend < .001) and had a strong, independent association with mortality. After multivariable adjustment using a model that incorporated the increasing trend in intubation/cardiac arrest, mortality decreased over time (odds ratioyear 0.95; 95% confidence interval 0.94-0.97). CONCLUSIONS: During a period that corresponds to improvement in STEMI quality of care, risk-adjusted in-hospital mortality declined. An increase in comorbidities, and more importantly in the proportion of patients presenting with extreme-risk features, may explain the overall "null" effect regarding in-hospital mortality despite improvements in timely reperfusion. PMID- 28801226 TI - Decreasing Clostridium difficile-Associated Fatality Rates Among Hospitalized Patients in the United States: 2004-2014. AB - BACKGROUND: Clostridium difficile infection has emerged as a major public health problem in the United States over the last 2 decades. We examined the trends in the C. difficile-associated fatality rate, hospital length of stay, and hospital charges over the last decade. METHODS: We used data from the National Inpatient Sample to identify patients with a principal diagnosis of C. difficile infection from 2004 to 2014. Outcomes included in-hospital fatality rate, hospital length of stay, and hospital charges. For each outcome, trends were also stratified by age categories because the risk of infection and associated mortality increases with age. RESULTS: Clostridium difficile infection discharges increased from 19.9 per 100,000 persons in 2004 to 33.8 per 100,000 persons in 2014. Clostridium difficile-associated fatality decreased from 3.6% in 2004 to 1.6% in 2014 (P < .001). Among patients aged 45-64 years, fatality decreased from 1.2% in 2004 to 0.7% in 2014 (P < .001). Among patients aged 65-84 years, fatality decreased from 4.3% in 2004 to 2.0% in 2014 (P < .001). Among patients aged >=85 years, fatality decreased from 6.9% in 2004 to 3.6% in 2014 (P < .001). The mean length of hospital stay decreased from 6.9 days in 2004 to 5.8 days in 2014 (P < .001). The mean hospital charges increased from 2004 ($24,535) to 2014 ($35,898) (P < .001). CONCLUSION: In-hospital fatality associated with C. difficile infection in the United States has decreased more than 2-fold in the last decade, despite increasing infection rates. PMID- 28801227 TI - Estrogen directly stimulates LHb expression at the pituitary level during puberty in female zebrafish. AB - The LHb expression is up-regulated during puberty in female zebrafish. However, the molecular mechanism underlying how LHb expression is regulated during puberty remains largely unknown. In this study, we found that the mRNA expression levels of lhb, fshb and cyp19a1b were up-regulated along with the puberty onset in zebrafish. Among the three nuclear estrogen receptors (nERs), the esr2b is the only type whose expression is significantly up-regulated during puberty onset in the pituitary. However, in situ hybridization results revealed that lhb mRNA was colocalized with esr1 and esr2a but not esr2b. Exposure to estradiol (E2) significantly stimulates LHb expression in both wild-type and kiss1-/-;kiss2-/ ;gnrh3-/- triple knockout pubertal zebrafish. Moreover, exposure of cultured pituitary cells to E2 increased the LHb expression, indicating that the estrogenic effect on LHb expression could be acted at the pituitary level. Finally, we cloned and analyzed the promoter of lhb by luciferase assay. Our results indicated that the E2 responsive regions of lhb promoter for ERalpha and ERbeta2 are identical, suggesting that ERalpha and ERbeta2 could bind to the same half ERE region of the promoter of lhb, exhibiting a classical ERE-dependent pathway. In summary, we demonstrate that E2 could directly act on the pituitary level to stimulate LHb transcription during puberty in zebrafish. PMID- 28801228 TI - Identification of the first cathelicidin gene from skin of Chinese giant salamanders Andrias davidianus with its potent antimicrobial activity. AB - Cathelicidins, as effector molecules, play important roles against infections and represent a crucial component of the innate immune system in vertebrates. They are widely studied in mammals, but little is known in amphibians. In the present study, we report the identification and characterization of a novel cathelicidin from Chinese giant salamander Andrias davidianus, which is the first study in Caudata amphibian. The cDNA sequence encodes a predicted 148-amino-acid polypeptide, which composed of a 20-residue signal peptide, a 94-residue conserved cathelin domain and a 34-residue mature peptide. From the multiple sequence alignments and phylogenetic analysis, AdCath shared conserved structure with other orthologs and clustered with other amphibian peptides. The tissue expression profiles revealed AdCath was highly expressed in skin. To study the function of AdCath gene, the AdCath precursor protein and mature peptide were recombinantly expressed and chemical synthesized respectively. The rAdCath protein could bind to LPS in a dose-dependent manner. When the concentrations of rAdCath protein and mature peptide were up to 22 MUg/mL, they showed significantly cytotoxicity to human 293T cell lines. The rAdCath protein and synthetic peptide could exhibit antibacterial activities detected by the minimum inhibitory concentrations assay. From the SEM assay, the synthetic mature peptide could destroy the membrane of bacteria and cause loss of membrane integrity. Collectively, these findings characterized the first cathelicidin from A. davidianus, and highlighted its potential antimicrobial activities, indicating its important roles in the skin immune response against different bacteria. PMID- 28801229 TI - Immunomodulation: A definitive role of microRNA-142. AB - Majority of microRNAs are evolutionarily conserved in vertebrates. This is suggestive of their similar roles in regulation of gene networks. In addition to their conserved mature sequences and regulatory roles, a few microRNAs show very cell or tissue specific expression. These microRNAs are highly enriched in some cell types or organs. One such microRNA is microRNA-142 (miR-142). The classical stem-loop structure of miR142 encodes for two species of mature microRNAs; miR142 5p and miR142-3p. MiR-142 is abundant in cells of hematopoietic origin, and therefore, aptly plays a role in lineage differentiation of hematopoietic cells. Interestingly, over the years, miR-142 has gained considerable attention for its quintessential role in regulating immune response. This mini-review discusses the important functional roles of miR-142 in inflammatory and immune response in different physiological and disease setting. PMID- 28801230 TI - A mitochondrial proteomics view of complex I deficiency in Candida albicans. AB - : Proteomic analyses were carried out on isolated mitochondrial samples of C. albicans from gene-deleted mutants (nuo1Delta, nuo2Delta and goa1Delta) as well as the parental strain in order to better understand the contribution of these three fungal-specific mitochondrial ETC complex I (CI) subunits to cellular activities. Herein, we identify 2333 putative proteins from four strains, in which a total of 663 proteins (28.5%) are putatively located in mitochondria. Comparison of protein abundances between mutants and the parental strain reveal 146 differentially-expressed proteins, of which 78 are decreased and 68 are increased in at least one mutant. The common changes across the three mutants include the down-regulation of nuclear-encoded CI subunit proteins as well as phospholipid, ergosterol and cell wall mannan synthesis, and up-regulated proteins in CIV and the alternative oxidase (AOX2). As for gene-specific functions, we find that NUO1 participates in nucleotide synthesis and ribosomal biogenesis; NUO2 is involved in vesicle trafficking; and GOA1 appears to regulate membrane transporter proteins, ROS removal, and substrates trafficking between peroxisomes and mitochondria. The proteomic view of general as well as mutant specific proteins further extends our understanding of the functional roles of non-mammalian CI-specific subunit proteins in cell processes. Particularly intriguing is the confirmation of a regulatory role for GOA1 on ETC function, a protein found almost exclusively in Candida species. SIGNIFICANCE: Fungal mitochondria are critical for fungal pathogenesis. The absence of any of the three fungal specific CI subunits in mitochondria causes an avirulence phenotype of C. albicans in a murine model of invasive disease. As model yeast (Saccharomyces cerevisiae) lacks a CI and is rarely a pathogen of humans, C. albicans is a better choice for establishing a link between mitochondrial CI and pathogenesis. Apart from the general effects of CI mutants on respiration, previous phenotyping of these mutants were quite similar to each other or to CI conservative subunit. By comparison to transcriptional data, the proteomic data obtained in this study indicate that biosynthetic events in each mutant such as cell wall and cell membrane phospholipids and ergosterol are generally decreased in both transcriptomal and translational levels. However, in the case of mitochondrial function, glycolysis/gluconeogenesis, and ROS scavengers, often gene changes are opposite that of proteomic data in mutants. We hypothesize that the loss of energy production in mutants is compensated by increases in protein levels of glycolysis, gluconeogenesis, and anti-ROS scavengers that at least extend mutant survival. PMID- 28801231 TI - Anti-Inflammatory Chromatinscape Suggests Alternative Mechanisms of Glucocorticoid Receptor Action. AB - Despite the widespread use of glucocorticoids (GCs), their anti-inflammatory effects are not understood mechanistically. Numerous investigations have examined the effects of glucocorticoid receptor (GR) activation prior to inflammatory challenges. However, clinical situations are emulated by a GC intervention initiated in the midst of rampant inflammatory responses. To characterize the effects of a late GC treatment, we profiled macrophage transcriptional and chromatinscapes with Dexamethasone (Dex) treatment before or after stimulation by lipopolysaccharide (LPS). The late activation of GR had a similar gene-expression profile as from GR pre-activation, while ameliorating the disruption of metabolic genes. Chromatin occupancy of GR was not predictive of Dex-regulated gene expression, contradicting the "trans-repression by tethering" model. Rather, GR activation resulted in genome-wide blockade of NF-kappaB interaction with chromatin and directly induced inhibitors of NF-kappaB and AP-1. Our investigation using GC treatments with clinically relevant timing highlights mechanisms underlying GR actions for modulating the "inflamed epigenome." PMID- 28801232 TI - Nlrp6- and ASC-Dependent Inflammasomes Do Not Shape the Commensal Gut Microbiota Composition. AB - The gut microbiota regulate susceptibility to multiple human diseases. The Nlrp6 ASC inflammasome is widely regarded as a hallmark host innate immune axis that shapes the gut microbiota composition. This notion stems from studies reporting dysbiosis in mice lacking these inflammasome components when compared with non littermate wild-type animals. Here, we describe microbial analyses in inflammasome-deficient mice while minimizing non-genetic confounders using littermate-controlled Nlrp6-deficient mice and ex-germ-free littermate-controlled ASC-deficient mice that were all allowed to shape their gut microbiota naturally after birth. Careful microbial phylogenetic analyses of these cohorts failed to reveal regulation of the gut microbiota composition by the Nlrp6- and ASC dependent inflammasomes. Our results obtained in two geographically separated animal facilities dismiss a generalizable impact of Nlrp6- and ASC-dependent inflammasomes on the composition of the commensal gut microbiota and highlight the necessity for littermate-controlled experimental design in assessing the influence of host immunity on gut microbial ecology. PMID- 28801233 TI - T Cell Zone Resident Macrophages Silently Dispose of Apoptotic Cells in the Lymph Node. AB - In lymph nodes (LNs), dendritic cells (DCs) are thought to dispose of apoptotic cells, a function pertaining to macrophages in other tissues. We found that a population of CX3CR1+ MERTK+ cells located in the T cell zone of LNs, previously identified as DCs, are efferocytic macrophages. Lineage-tracing experiments and shield chimeras indicated that these T zone macrophages (TZM) are long-lived macrophages seeded in utero and slowly replaced by blood monocytes after birth. Imaging the LNs of mice in which TZM and DCs express different fluorescent proteins revealed that TZM-and not DCs-act as the only professional scavengers, clearing apoptotic cells in the LN T cell zone in a CX3CR1-dependent manner. Furthermore, similar to other macrophages, TZM appear inefficient in priming CD4 T cells. Thus, efferocytosis and T cell activation in the LN are uncoupled processes designated to macrophages and DCs, respectively, with implications to the maintenance of immune homeostasis. PMID- 28801234 TI - Dendritic Cells but Not Macrophages Sense Tumor Mitochondrial DNA for Cross priming through Signal Regulatory Protein alpha Signaling. AB - Inhibition of cytosolic DNA sensing represents a strategy that tumor cells use for immune evasion, but the underlying mechanisms are unclear. Here we have shown that CD47-signal regulatory protein alpha (SIRPalpha) axis dictates the fate of ingested DNA in DCs for immune evasion. Although macrophages were more potent in uptaking tumor DNA, increase of DNA sensing by blocking the interaction of SIRPalpha with CD47 preferentially occurred in dendritic cells (DCs) but not in macrophages. Mechanistically, CD47 blockade enabled the activation of NADPH oxidase NOX2 in DCs, which in turn inhibited phagosomal acidification and reduced the degradation of tumor mitochondrial DNA (mtDNA) in DCs. mtDNA was recognized by cyclic-GMP-AMP synthase (cGAS) in the DC cytosol, contributing to type I interferon (IFN) production and antitumor adaptive immunity. Thus, our findings have demonstrated how tumor cells inhibit innate sensing in DCs and suggested that the CD47-SIRPalpha axis is critical for DC-driven antitumor immunity. PMID- 28801235 TI - Cost-Effectiveness of a Proactive Primary Care Program for Frail Older People: A Cluster-Randomized Controlled Trial. AB - BACKGROUND: A proactive integrated approach has shown to preserve daily functioning among older people in the community. The aim is to determine the cost effectiveness of a proactive integrated primary care program. METHODS: Economic evaluation embedded in a single-blind, 3-armed, cluster-randomized controlled trial with 12 months' follow-up in 39 general practices in the Netherlands. General practices were randomized to one of 3 trial arms: (1) an electronic frailty screening instrument using routine medical record data followed by standard general practitioner (GP) care; (2) this screening instrument followed by a nurse-led care program; or (3) usual care. Health resource utilization data were collected using electronic medical records and questionnaires. Associated costs were calculated. A cost-effectiveness analysis from a societal perspective was undertaken. The incremental cost per quality-adjusted life-year was calculated comparing proactive screening arm with usual care, and screening plus nurse-led care arm with usual care, as well as the screening arm with screening plus nurse-led care arm. RESULTS: Out of 7638 potential participants, 3092 (40.5%) older adults participated. Whereas effect differences were minor, the total costs per patient were lower in both intervention groups compared with usual care. The probability of cost-effectiveness at ?20,000 per QALY threshold was 87% and 91% for screening plus GP care versus usual care and for screening plus nurse-led care compared to usual care, respectively. For screening plus nurse-led care vs screening plus standard GP care, the probability was 55%. CONCLUSION: A proactive screening intervention has a high probability of being cost-effective compared to usual care. The combined intervention showed less value for money. PMID- 28801236 TI - Frailty Status in Older Adults Is Related to Alterations in Indoleamine 2,3 Dioxygenase 1 and Guanosine Triphosphate Cyclohydrolase I Enzymatic Pathways. AB - BACKGROUND: Frailty is a multidimensional syndrome correlated to the loss of homeostasis and increased vulnerability to stressors, which is associated with increase in the risk of disability, comorbidity, hospitalization, and death in the elderly. It is based on the interplay of physiological, psychological, social, and environmental factors. OBJECTIVES: Because aging involves a detrimental immune response, this work aimed to assess the possible role of chronic low-grade immune stimulation on frailty status in the elderly. METHODS: Biomarkers involved in indoleamine 2,3-dioxygenase 1 and guanosine triphosphate cyclohydrolase I enzymatic pathways (namely neopterin, tryptophan, kynurenine, phenylalanine, tyrosine, and nitrite) were analyzed in a population of Spanish older adults aged 65 years and above, and their relationships with frailty status were evaluated. RESULTS: Significant increases in neopterin levels, kynurenine/tryptophan ratio, and phenylalanine/tyrosine ratio, and significant decreases in tryptophan, nitrite and tyrosine concentrations in frail individuals compared with nonfrail persons were obtained. Significant correlations were also observed between immune biomarkers, indicating they change in parallel, thus, pointing to interrelated causes. Besides, reference ranges for a number of immune biomarkers in the population of robust older adults were established for the first time. CONCLUSIONS: Results obtained in the present study are consistent with the idea that frailty status in the elderly is associated with an additional degree of immune stimulation, manifested in a more intense disturbance of indoleamine 2,3-dioxygenase 1 and guanosine triphosphate cyclohydrolase I pathways than in nonfrail or prefrail older adults. PMID- 28801237 TI - Tissue is the Issue: Duodenal Biopsies to Elucidate Gut Structure and Function Among Undernourished Children in Low-Resource Settings. PMID- 28801238 TI - A Co-Inhibitory Alliance in Myeloid Leukemia: TIM-3/Galectin-9 Complex as a New Target for Checkpoint Blockade Therapy. PMID- 28801239 TI - Salsalate Activates Skeletal Muscle Thermogenesis and Protects Mice from High-Fat Diet Induced Metabolic Dysfunction. AB - Salsalate plays beneficial roles for ameliorating hyperglycemia and dyslipidemia in type 2 diabetes patients, but the underlying mechanisms are still poorly understood. In this study, by administering salsalate to mice fed with high fat diet and examining how salsalate rectifies metabolic dysfunction in these obese mice, we found that salsalate stimulated body temperature and attenuated body weight gain without affecting food intake. Our results showed that salsalate application decreased lipid accumulation in liver and epididymal white adipose tissue (eWAT), inhibited hepatic gluconeogenesis and improved insulin signaling transduction in eWAT. In addition, salsalate increased the expression of genes related to glucose and fatty acid transport and oxidation in skeletal muscle. Our results also showed that expression of genes in mitochondrial uncoupling and mitochondrial electron transport are strengthened by salsalate. Moreover, sarcolipin (Sln) and sarcoplasmic reticulum Ca2+ ATPase 2 (Serca2) in skeletal muscle were enhanced in salsalate-treated mice. Together, our data suggest that the beneficial metabolic effects of salsalate may depend, at least in part, on skeletal muscle thermogenesis via activation of mitochondrial uncoupling and the axis of Sln/Serca2a. PMID- 28801240 TI - Exploring All Avenues for Radiotherapy in Oligorecurrent Prostate Cancer Disease Limited to Lymph Nodes: A Systematic Review of the Role of Stereotactic Body Radiotherapy. AB - CONTEXT: Stereotactic body radiotherapy (SBRT) is emerging as a treatment option in patients affected by oligorecurrent prostate cancer disease limited to lymph nodes, a subgroup of patients who would otherwise be treated only with androgen deprivation therapy (ADT). OBJECTIVE: To perform a systematic review of SBRT for oligorecurrent prostate cancer limited to lymph nodes. EVIDENCE ACQUISITION: We performed a systematic review of PubMed/Medline in October 2016 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA). We searched for studies reporting on biochemical or clinical progression and/or toxicity or complications of SBRT. Reports were excluded if these end points could not be ascertained or separately analyzed, or if insufficient details were provided. EVIDENCE OF SYNTHESIS: A total of 363 patients from nine studies were collected. Of these patients, 211 were treated with SBRT for a total of 270 lymph nodes. With an alpha-beta ratio of 3 Gy, the biologically effective dose in fractionated SBRT was >100 Gy in all studies (range, 88-216 Gy). With a median follow-up of 19.23 mo, local control was achieved in 98.1% of patients. Median progression-free survival (defined as biochemical and/or radiological progression) was 22.5 mo (range, 11-30 mo). Information about ADT during SBRT was available in 281 patients, of whom 114 (40.5%) were on ADT during SBRT, and the duration of hormone therapy ranged from 1 to 17.5 mo. Median ADT-free survival was 32.8 mo (range, 25-44 mo). About toxicity, Common Terminology Criteria for Adverse Events toxicity scale was most used. Acute and/or late grade >=2 toxicity was reported in only 5.6% of patients, and no patient developed grade 4 toxicity. CONCLUSIONS: SBRT seems to be promising in lymph node oligorecurrent prostate cancer, although there is a weak level of evidence to support such investigational treatment, which is currently based on retrospective studies of single-institution or pooled experiences. ADT-free survival is an interesting end point, which needs to be investigated. PATIENT SUMMARY: We performed a systematic review to assess outcomes and toxicity of stereotactic body radiotherapy (SBRT) for patients affected by oligorecurrent prostate cancer limited to lymph nodes. We concluded that SBRT is a promising therapy in this setting, but it needs to be validated in randomized controlled trials. PMID- 28801241 TI - Trends in Radical Prostatectomy Risk Group Distribution in a European Multicenter Analysis of 28 572 Patients: Towards Tailored Treatment. AB - BACKGROUND: Active surveillance (AS) has been increasingly proposed as the preferential initial management strategy for low-risk prostate cancer (PC), while in high-risk PC the indication for surgery has widened. OBJECTIVE: To evaluate the development of risk group distribution of patients undergoing radical prostatectomy (RP). DESIGN, SETTING, AND PARTICIPANTS: Retrospective database review of combined RP databases (2000-2015) of four large European centers (Creteil, Paris; San Rafaele, Milan; Martini Klinik, Hamburg; NKI, AvL, Amsterdam). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinical and pathological characteristics per year of surgery. Eligibility for AS was defined according to Prostate Cancer Research International Active Surveillance criteria: cT<=2c, cN0/X, cM0/X, PSA <=10ng/ml, prostate-specific antigen density <0.2ng/ml/ml, one to two positive biopsies, and Gleason score <=6, high-risk disease as: cT>=3, c N1, cM1, PSA >20ng/ml, and/or Gleason >=8. RESULTS AND LIMITATIONS: In total, 28572 patients had complete clinical and 24790 complete pathological data available. The absolute number of RPs increased: 401, 975, 2344, and 2504 in 2000, 2005, 2010, and 2015, respectively. The proportion of cases considered suitable for AS decreased: 31%, 32%, 18%, and 5%, while the cases considered high risk increased: 10%, 8%, 16%, and 30%. The percentage of patients having only localized Gleason 6 disease after RP decreased: 46%, 34%, 14%, and 8% for all patients (p<0.01), as well as for AS-suitable patients: 70%, 54%, 41%, and 38% (p<0.01). Comparisons between centers were outside the scope of this article. Developments in diagnostics may have impacted on results. CONCLUSIONS: This European analysis confirmed the risk profile of patients undergoing RP shifting away of the most favorable disease spectrum. Patients with PC clinically considered suitable for AS and men having only localized Gleason 6 disease pathologically comprised a decreasing share of all RP performed. High risk disease comprised an increasing share of all RPs. PATIENT SUMMARY: The databases of four large European centers of prostate cancer surgery were analyzed. In recent years, the risk profile of patients shifted away of low-risk cancer, while high-risk cancer comprised a larger part of cases. This confirms the introduction of active surveillance for low-risk prostate cancer and increase in potentially curative options for high-risk disease. PMID- 28801242 TI - Oxidant species are involved in T/B-mediated ERK1/2 phosphorylation that activates p53-p21 axis to promote KSHV lytic cycle in PEL cells. AB - KSHV is a gammaherpesvirus strongly associated to human cancers such as Primary Effusion Lymphoma (PEL) and Kaposi's Sarcoma. The naturally virus-infected tumor cells usually display latent infection since a minority of cells undergoes spontaneous viral replication. The lytic cycle can be induced in vitro upon appropriate stimuli such as TPA (T), alone or in combination with butyrate (B), (T/B). In previous studies, Protein Kinase C (PKC) delta, Extracellular Signal regulated Kinase1/2 (ERK1/2) and p53-p21 axis have been separately reported to play a role in KSHV reactivation from latency. Here, we found that these pathways were interconnected to induce KSHV lytic cycle in PEL cells treated with T/B. T/B also increased H2O2 that played an important role in the activation of these pathways. Oxidant specie production correlated with PKC delta activation, as the PKC delta inhibitor rottlerin reduced both H2O2 and KSHV lytic antigen expression. H2O2 contributed to T/B-mediated ERK1/2 activation that mediated p53 phosphorylation at serine 15 (Ser15) and increased p21 expression. Oxidant specie inhibition by quercetin indeed strongly reduced the activation of these pathways, lytic antigen expression and interestingly it also increased T/B-induced cell death. The use of ERK inhibitor PD98059 or p53 silencing demonstrated the importance of p53Ser15 phosphorylation and of p53-p21 axis in KSHV lytic cycle activation. Understanding the role of oxidant species and the molecular mechanisms involved in KSHV lytic cycle induction is particularly important since oxidant species represent the most physiological stimulus for viral reactivation in vivo and it is known that viral production contributes to the maintenance/progression of KSHV associated malignancies. PMID- 28801243 TI - Peroxiredoxin-2 plays a pivotal role as multimodal cytoprotector in the early phase of pulmonary hypertension. AB - Pulmonary-artery-hypertension (PAH) is a life-threatening and highly invalidating chronic disorder. Chronic oxidation contributes to lung damage and disease progression. Peroxiredoxin-2 (Prx2) is a typical 2-cysteine (Cys) peroxiredoxin but its role on lung homeostasis is yet to be fully defined. Here, we showed that Prx2-/- mice displayed chronic lung inflammatory disease associated with (i) abnormal pulmonary vascular dysfunction; and (ii) increased markers of extracellular-matrix remodeling. Hypoxia was used to induce PAH. We focused on the early phase PAH to dissect the role of Prx2 in generation of PAH. Hypoxic Prx2-/-mice showed (i) amplified inflammatory response combined with cytokine storm; (ii) vascular activation and dysfunction; (iii) increased PDGF-B lung levels, as marker of extracellular-matrix deposition and remodeling; and (iv) ER stress with activation of UPR system and autophagy. Rescue experiments with in vivo the administration of fused-recombinant-PEP-Prx2 show a reduction in pulmonary inflammatory vasculopathy and in ER stress with down-regulation of autophagy. Thus, we propose Prx2 plays a pivotal role in the early stage of PAH as multimodal cytoprotector, targeting oxidation, inflammatory vasculopathy and ER stress with inhibition of autophagy. Collectively, our data indicate that Prx2 is able to interrupt the hypoxia induced vicious cycle involving oxidation inflammation-autophagy in the pathogenesis of PAH. PMID- 28801244 TI - Corrigendum to 'Redox and pH dual responsive poly(amidoamine) dendrimer poly(ethylene glycol) conjugates for intracellular delivery of doxorubicin' [Acta Biomater. 36 (2016) 241-253]. PMID- 28801245 TI - Episodic future thinking and future-based decision-making in a case of retrograde amnesia. AB - We investigated episodic future thinking (EFT) and future-based cognition and decision-making in patient SG, who developed a dense retrograde amnesia following hypoxia due to a cardiac arrest. Despite intact general cognitive and executive functioning, SG was unable to remember events from his entire lifetime. He had, however, relatively spared anterograde memory and general semantic knowledge. Voxel-based morphometry detected a reduction of gray matter in the thalamus, cerebellum and fusiform gyrus bilaterally, and, at a reduced threshold, in several regions of the autobiographical memory network, including the hippocampi. We show that SG is unable to imagine personal future events, but can imagine fictitious events not self-relevant and not located in subjective time. Despite severely impaired EFT, SG shows normal attitudes towards the future time, and normal delay discounting rates. These findings suggest that retrieval of autobiographical information from long-term memory is necessary for EFT. However, relatively spared anterograde memory and general semantic knowledge may be sufficient to allow construction of fictitious experiences. As well, EFT is not necessary to drive future-oriented cognition and choice. These findings highlight the relation between autobiographical memory and EFT, and the fractionation of human temporal consciousness. Moreover, they contribute to our understanding of retrograde amnesia as an impairment of memory as well as future thinking. PMID- 28801246 TI - Time-optimal control strategies in SIR epidemic models. AB - We investigate the time-optimal control problem in SIR (Susceptible-Infected Recovered) epidemic models, focusing on different control policies: vaccination, isolation, culling, and reduction of transmission. Applying the Pontryagin's Minimum Principle (PMP) to the unconstrained control problems (i.e. without costs of control or resource limitations), we prove that, for all the policies investigated, only bang-bang controls with at most one switch are admitted. When a switch occurs, the optimal strategy is to delay the control action some amount of time and then apply the control at the maximum rate for the remainder of the outbreak. This result is in contrast with previous findings on the unconstrained problems of minimizing the total infectious burden over an outbreak, where the optimal strategy is to use the maximal control for the entire epidemic. Then, the critical consequence of our results is that, in a wide range of epidemiological circumstances, it may be impossible to minimize the total infectious burden while minimizing the epidemic duration, and vice versa. Moreover, numerical simulations highlighted additional unexpected results, showing that the optimal control can be delayed also when the control reproduction number is lower than one and that the switching time from no control to maximum control can even occur after the peak of infection has been reached. Our results are especially important for livestock diseases where the minimization of outbreaks duration is a priority due to sanitary restrictions imposed to farms during ongoing epidemics, such as animal movements and export bans. PMID- 28801247 TI - Object categorization by wild ranging birds-Winter feeder experiments. AB - The object categorization is only scarcely studied using untrained wild ranging animals and relevant stimuli. We tested the importance of the spatial position of features salient for categorization of a predator using wild ranging birds (titmice) visiting a winter feeder. As a relevant stimulus we used a dummy of a raptor, the European sparrowhawk (Accipiter nisus), placed at the feeding location. This dummy was designed to be dismantled into three parts and rearranged with the head in the correct position, in the middle or at the bottom of the dummy. When the birds had the option of visiting an alternative feeder with a dummy pigeon, they preferred this option to visiting the feeder with the dummy sparrowhawk with the head in any of the three positions. When the birds had the option of visiting an alternative feeder with an un-rearranged dummy sparrowhawk, they visited both feeders equally often, and very scarcely. This suggests that the titmice considered all of the sparrowhawk modifications as being dangerous, and equally dangerous as the un-rearranged sparrowhawk. The position of the head was not the most important cue for categorization. The presence of the key features was probably sufficient for categorization, and their mutual spatial position was of lower importance. PMID- 28801248 TI - Clinical value of ctDNA in upper-GI cancers: A systematic review and meta analysis. AB - BACKGROUND: The recent expanding technical possibilities to detect tumor derived mutations in blood, so-called circulating tumor DNA (ctDNA), has rapidly increased the interest in liquid biopsies. This review and meta-analysis explores the clinical value of ctDNA in malignancies of the upper gastro-intestinal tract. METHODS: PubMed, Cochrane and Embase databases were searched to identify studies reporting the diagnostic, prognostic or predictive value of ctDNA in patients with esophageal, gastric and pancreatic cancer, until January 2017. The diagnostic accuracy and, using random-effect pair-wise meta-analyses, the prognostic value of ctDNA was assessed. RESULTS: A total of 34 studies met the inclusion criteria. For esophageal and gastric cancer, amplification of oncogenes in blood, such as HER2 and MYC, can be relevant for diagnostic purposes, and to predict treatment response in certain patient subpopulations. Given the limited number of studies assessing the role of ctDNA in esophageal and gastric cancer, the meta-analysis estimated the diagnostic accuracy and predictive value of ctDNA in pancreatic cancer only (n=10). The pooled sensitivity and specificity of ctDNA as a diagnostic tool in pancreatic cancer were 28% and 95%, respectively. Patients with pancreatic cancer and detectable ctDNA demonstrated a worse overall survival compared to patients with undetectable ctDNA (HR 1.92, 95% confidence interval (CI) 1.15-3.22, p=0.01). CONCLUSION: The presence of ctDNA is significantly associated with a poor prognosis in patients with pancreatic cancer. The use of ctDNA in clinical practice is promising, although standardization of sequencing techniques and further development of high sensitive detection methods is needed. PMID- 28801250 TI - Decoding fMRI activity in the time domain improves classification performance. AB - Most current functional Magnetic Resonance Imaging (fMRI) decoding analyses rely on statistical summaries of the data resulting from a deconvolution approach: each stimulation event is associated with a brain response. This standard approach leads to simple learning procedures, yet it is ill-suited for decoding events with short inter-stimulus intervals. In order to overcome this issue, we propose a novel framework that separates the spatial and temporal components of the prediction by decoding the fMRI time-series continuously, i.e. scan-by-scan. The stimulation events can then be identified through a deconvolution of the reconstructed time series. We show that this model performs as well as or better than standard approaches across several datasets, most notably in regimes with small inter-stimuli intervals (3-5s), while also offering predictions that are highly interpretable in the time domain. This opens the way toward analyzing datasets not normally thought of as suitable for decoding and makes it possible to run decoding on studies with reduced scan time. PMID- 28801251 TI - Modeling correlated noise is necessary to decode uncertainty. AB - Brain decoding algorithms form an important part of the arsenal of analysis tools available to neuroscientists, allowing for a more detailed study of the kind of information represented in patterns of cortical activity. While most current decoding algorithms focus on estimating a single, most likely stimulus from the pattern of noisy fMRI responses, the presence of noise causes this estimate to be uncertain. This uncertainty in stimulus estimates is a potentially highly relevant aspect of cortical stimulus processing, and features prominently in Bayesian or probabilistic models of neural coding. Here, we focus on sensory uncertainty and how best to extract this information with fMRI. We first demonstrate in simulations that decoding algorithms that take into account correlated noise between fMRI voxels better recover the amount of uncertainty (quantified as the width of a probability distribution over possible stimuli) associated with the decoded estimate. Furthermore, we show that not all correlated variability should be treated equally, as modeling tuning-dependent correlations has the greatest impact on decoding performance. Next, we examine actual noise correlations in human visual cortex, and find that shared variability in areas V1-V3 depends on the tuning properties of fMRI voxels. In line with our simulations, accounting for this shared noise between similarly tuned voxels produces important benefits in decoding. Our findings underscore the importance of accurate noise models in fMRI decoding approaches, and suggest a statistically feasible method to incorporate the most relevant forms of shared noise. PMID- 28801249 TI - p53 stability is regulated by diverse deubiquitinating enzymes. AB - The tumor suppressor protein p53 has a variety of roles in responses to various stress signals. In such responses, p53 activates specific transcriptional targets that control cell cycle arrest, DNA repair, angiogenesis, autophagy, metabolism, migration, aging, senescence, and apoptosis. Since p53 has been identified as the most frequently altered gene in human cancers, regulation and stabilization of its normal functions are important. Stability of p53 is regulated by the ubiquitin-proteasome pathway (UPP). Furthermore, it is readjusted by deubiquitination via deubiquitinating enzymes (DUBs) that can eliminate ubiquitin from p53. Diverse DUBs directly or indirectly affect the ubiquitination of p53 and, consequently, regulate various cellular processes associated with p53. As maintenance of p53 is regulated by a variety of DUBs, the interaction of DUBs and p53 can affect diseases such as cancer. Currently, DUBs have a central role in our understanding of various cancers, and some have potential in the development of effective therapeutic strategies. This review summarizes the current knowledge of p53 and of the interconnection between p53 and DUBs. PMID- 28801252 TI - Measuring the effects of attention to individual fingertips in somatosensory cortex using ultra-high field (7T) fMRI. AB - Attention to sensory information has been shown to modulate the neuronal processing of that information. For example, visuospatial attention acts by modulating responses at retinotopically appropriate regions of visual cortex (Puckett and DeYoe, 2015; Tootell et al. 1998). Much less, however, is known about the neuronal processing associated with attending to other modalities of sensory information. One reason for this is that visual cortex is relatively large, and therefore easier to access non-invasively in humans using tools such as functional magnetic resonance imaging (fMRI). With high-resolution fMRI, however, it is now possible to access smaller cortical areas such as primary somatosensory cortex (Martuzzi et al., 2014; Sanchez-Panchuelo et al., 2010; Schweisfurth et al. 2014; Schweizer et al. 2008). Here, we combined a novel experimental design and high-resolution fMRI at ultra-high field (7T) to measure the effects of attention to tactile stimulation in primary somatosensory cortex, S1. We find that attention modulates somatotopically appropriate regions of S1, and importantly, that this modulation can be measured at the level of the cortical representation of individual fingertips. PMID- 28801253 TI - Investigating the maturation of microstructure and radial orientation in the preterm human cortex with diffusion MRI. AB - Preterm birth disrupts and alters the complex developmental processes in the cerebral cortex. This disruption may be a contributing factor to widespread delay and cognitive difficulties in the preterm population. Diffusion-weighted magnetic resonance imaging (DW MRI) is a noninvasive imaging technique that makes inferences about cellular structures, at scales smaller than the imaging resolution. One established finding is that DW MRI shows a transient radial alignment in the preterm cortex. In this study, we quantify this maturational process with the "radiality index", a parameter that measures directional coherence, which we expect to change rapidly in the perinatal period. To measure this index, we used structural T2-weighted MRI to segment the cortex and generate cortical meshes. We obtained normal vectors for each face of the mesh and compared them to the principal diffusion direction, calculated by both the DTI and DIAMOND models, to generate the radiality index. The subjects included in this study were 89 infants born at fewer than 34 weeks completed gestation, each imaged at up to four timepoints between 27 and 42 weeks gestational age. In this manuscript, we quantify the longitudinal trajectory of radiality, fractional anisotropy and mean diffusivity from the DTI and DIAMOND models. For the radiality index and fractional anisotropy, the DIAMOND model offers improved sensitivity over the DTI model. The radiality index has a consistent progression across time, with the rate of change depending on the cortical lobe. The occipital lobe changes most rapidly, and the frontal and temporal least: this is commensurate with known developmental anatomy. Analysing the radiality index offers information complementary to other diffusion parameters. PMID- 28801255 TI - Decoding naturalistic experiences from human brain activity via distributed representations of words. AB - Natural visual scenes induce rich perceptual experiences that are highly diverse from scene to scene and from person to person. Here, we propose a new framework for decoding such experiences using a distributed representation of words. We used functional magnetic resonance imaging (fMRI) to measure brain activity evoked by natural movie scenes. Then, we constructed a high-dimensional feature space of perceptual experiences using skip-gram, a state-of-the-art distributed word embedding model. We built a decoder that associates brain activity with perceptual experiences via the distributed word representation. The decoder successfully estimated perceptual contents consistent with the scene descriptions by multiple annotators. Our results illustrate three advantages of our decoding framework: (1) three types of perceptual contents could be decoded in the form of nouns (objects), verbs (actions), and adjectives (impressions) contained in 10,000 vocabulary words; (2) despite using such a large vocabulary, we could decode novel words that were absent in the datasets to train the decoder; and (3) the inter-individual variability of the decoded contents co-varied with that of the contents of scene descriptions. These findings suggest that our decoding framework can recover diverse aspects of perceptual experiences in naturalistic situations and could be useful in various scientific and practical applications. PMID- 28801254 TI - The effect of visual parameters on neural activation during nonsymbolic number comparison and its relation to math competency. AB - Nonsymbolic numerical comparison task performance (whereby a participant judges which of two groups of objects is numerically larger) is thought to index the efficiency of neural systems supporting numerical magnitude perception, and performance on such tasks has been related to individual differences in math competency. However, a growing body of research suggests task performance is heavily influenced by visual parameters of the stimuli (e.g. surface area and dot size of object sets) such that the correlation with math is driven by performance on trials in which number is incongruent with visual cues. Almost nothing is currently known about whether the neural correlates of nonsymbolic magnitude comparison are also affected by visual congruency. To investigate this issue, we used functional magnetic resonance imaging (fMRI) to analyze neural activity during a nonsymbolic comparison task as a function of visual congruency in a sample of typically developing high school students (n = 36). Further, we investigated the relation to math competency as measured by the preliminary scholastic aptitude test (PSAT) in 10th grade. Our results indicate that neural activity was modulated by the ratio of the dot sets being compared in brain regions previously shown to exhibit an effect of ratio (i.e. left anterior cingulate, left precentral gyrus, left intraparietal sulcus, and right superior parietal lobe) when calculated from the average of congruent and incongruent trials, as it is in most studies, and that the effect of ratio within those regions did not differ as a function of congruency condition. However, there were significant differences in other regions in overall task-related activation, as opposed to the neural ratio effect, when congruent and incongruent conditions were contrasted at the whole-brain level. Math competency negatively correlated with ratio-dependent neural response in the left insula across congruency conditions and showed distinct correlations when split across conditions. There was a positive correlation between math competency in the right supramarginal gyrus during congruent trials and a negative correlation in the left angular gyrus during incongruent trials. Together, these findings support the idea that performance on the nonsymbolic comparison task relates to math competency and ratio-dependent neural activity does not differ by congruency condition. With regards to math competency, congruent and incongruent trials showed distinct relations between math competency and individual differences in ratio-dependent neural activity. PMID- 28801256 TI - New innovative ecosystems in France to develop the Bioeconomy. AB - The cluster's policy initiated in France in 2005 was a formidable opportunity to boost innovation in the bioeconomy and to develop innovation platforms allowing industrial demonstration and feasibility at technology readiness level (TRL) from 5 to 9. The IAR Cluster (Industries and Agro-Resources), based in the Hauts-de France and Grand Est regions is completely dedicated to the bioeconomy. IAR's work has contributed to build a complete innovation ecosystem on bioeconomy by opening up relationships between actors along the full value chain. It also facilitated investments in new platforms and programs through public-private partnerships. The Biorefinery of Pomacle is a good illustration of such a collective approach. The role of regional and national public partners is essential to succeed in this development which requires a long term strategy and support. PMID- 28801257 TI - Editorial Comment. PMID- 28801258 TI - Editorial Comment. PMID- 28801259 TI - Editorial Comment. PMID- 28801260 TI - Editorial Comment. PMID- 28801262 TI - The physiological and pathophysiological roles of taurine in adipose tissue in relation to obesity. AB - Obesity is caused by an imbalance between energy intake and energy expenditure. It is established that obesity is a state of low-grade chronic inflammation, which is characterized by enlarged hypertrophied adipocytes, increased infiltration by macrophages and marked changes in the secretion of adipokines and free fatty acids. The effects of taurine on the pathogenesis of obesity have been reported in animals and humans. Although the mechanisms underlying the anti obesity action of taurine remain to be defined, taurine seems to ameliorate obesity through stimulation of energy expenditure, modulation of lipid metabolism, anorexic effect, anti-inflammatory and anti-oxidative effects. Recent studies revealed that taurine supplementation reduces the infiltration of macrophages and modulates the polarization of adipose tissue macrophages in high fat diet-induced obese mice. In addition, taurine downregulates the production of pro-inflammatory cytokines by adipocytes, suggesting that taurine plays an anti inflammatory role in adipose tissue. This article reviews the effects and mechanisms of taurine on the development of obesity, focusing on the role of taurine in white adipose tissue. PMID- 28801261 TI - Long-wavelength (red) light produces hyperopia in juvenile and adolescent tree shrews. AB - In infant tree shrews, exposure to narrow-band long-wavelength (red) light, that stimulates long-wavelength sensitive cones almost exclusively, slows axial elongation and produces hyperopia. We asked if red light produces hyperopia in juvenile and adolescent animals, ages when plus lenses are ineffective. Animals were raised in fluorescent colony lighting (100-300 lux) until they began 13days of red-light treatment at 11 (n=5, "infant"), 35 (n=5, "juvenile") or 95 (n=5, "adolescent") days of visual experience (DVE). LEDs provided 527-749 lux on the cage floor. To control for the higher red illuminance, a fluorescent control group (n=5) of juvenile (35 DVE) animals was exposed to ~975 lux. Refractions were measured daily; ocular component dimensions at the start and end of treatment and end of recovery in colony lighting. These groups were compared with normals (n=7). In red light, the refractive state of both juvenile and adolescent animals became significantly (P<0.05) hyperopic: juvenile 3.9+/-1.0 diopters (D, mean+/-SEM) vs. normal 0.8+/-0.1D; adolescent 1.6+/-0.2D vs. normal 0.4+/-0.1D. The fluorescent control group refractions (0.6+/-0.3D) were normal. In red treated juveniles the vitreous chamber was significantly smaller than normal (P<0.05): juvenile 2.67+/-0.03mmvs. normal 2.75+/-0.02mm. The choroid was also significantly thicker: juvenile 77+/-4MUmvs. normal 57+/-3MUm (P<0.05). Although plus lenses do not restrain eye growth in juvenile tree shrews, the red light induced slowed growth and hyperopia in juvenile and adolescent tree shrews demonstrates that the emmetropization mechanism is still capable of restraining eye growth at these ages. PMID- 28801263 TI - Glucocorticoids regulate MiR-29c levels in vascular smooth muscle cells through transcriptional and epigenetic mechanisms. AB - AIMS: The objective of this study was to determine the underlying mechanism by which glucocorticoids (GCs) induce of miR-29c expression in vascular smooth muscle cells. MAIN METHODS: QRT-PCR was used for miR-29c detection. Protein levels were determined by western blotting. Knockdown of SP1, DNMT1 and DNMT3A was achieved through transfection with their specific respective siRNAs. The effect of GCs on SP1 activity was determined by luciferase reporter assay and the methylation status in miR-29c promoter was detected by methylation specific PCR. CHIP assay was used to determine the binding ability of SP1 and glucocorticoid receptor (GR) in miR-29c promoter. KEY FINDINGS: Treatment of RASMC with SP1 siRNA or SP1 inhibitor, mithramycin A, as well as DNMT1 and DNMT3A siRNAs and an inhibitor of DNMTs, Decitabine, resulted in increased expression of miR-29c (P<0.05). Treatment RASMC with dexamethasone (DEX, 0.1MUM) for 24h reduced the expression of SP1 and phosphorylated SP1 at threonine 453 protein levels, repressed SP1 activity, and inhibited the expression of DNMT1 and DNMT3A proteins (P<0.05). Treatment with mifepristone, a GR antagonist, blocked the inhibitory effect of DEX on DNMT1 and DNMT3A protein expression. DEX also suppressed SP1 binding ability in miR-29c promoter and inhibited methylation of miR-29c promoter (P<0.05). Treatment of RASMC with DEX (0.1MUM) significantly (P<0.05) increased the binding of GR to the miR-29c promoter. SIGNIFICANCE: The stimulatory effect of GCs on miR-29c expression is mediated by these three mechanisms: transcriptionally regulated by SP1, and epigenetically through a methylation dependent process and GR. PMID- 28801264 TI - Vasoactive properties of antihypertensive lactoferrin-derived peptides in resistance vessels: Effects in small mesenteric arteries from SHR rats. AB - AIMS: Bovine lactoferrin (LF) hydrolysates and peptides identified thereof have shown antihypertensive effects in rat models, mainly but not exclusively by angiotensin-converting enzyme inhibition. In this study we aimed to assess the vasoactive effects and mechanisms of an ultrafiltered (<3kDa) pepsin LF hydrolysate (LFH) and a heptapeptide identified in a LF hydrolysate produced by yeast proteolysis (DPYKLRP) in peripheral resistance arteries from spontaneously hypertensive rats (SHRs). MAIN METHODS: We used a myograph system for isometric tension recording in isolated small mesenteric arteries from SHRs. Direct vasoactive effects of LFH (30-100MUg/mL) and DPYKLRP (30-100MUM) were assessed in arteries precontracted with phenylephrine (PE, 10MUM) or KCl (120mM), and in PE precontracted arteries preincubated (10min) with the NO synthase inhibitor L-NAME (0.1mM) or the cyclooxygenase inhibitor indomethacin (10MUM). Indirect vasoactive effects of LFH (30-100MUg/mL) or DPYKLRP (30-100MUM) preincubation (10min) on the relaxant responses to the NO donor sodium nitroprusside (SNP, 0.01-10MUM) or acetylcholine (Ach, 1-100MUM) were also studied in PE-precontracted arteries. KEY FINDINGS: Both LHF and DPYKLRP elicited direct relaxation of mesenteric arteries, by a mechanism involving NO release, counteracting modulation by prostanoids and K+ efflux. Moreover, LF-derived peptides also showed indirect vasoactive effects by enhancing endothelium-dependent relaxation to Ach and endothelium-independent relaxation to SNP. SIGNIFICANCE: In conclusion, LF-derived peptides show ex vivodirect and indirect relaxing effects in small mesenteric arteries from SHRs. These vasoactive effects would reduce vascular peripheral resistance in vivo, and thus contribute to their antihypertensive effects. PMID- 28801265 TI - Fluoxetine coupled with zinc in a chronic mild stress model of depression: Providing a reservoir for optimum zinc signaling and neuronal remodeling. AB - BACKGROUND: Recently, depression has been envisioned as more than an alteration in neurotransmitters centered around receptor signaling pathways. Consequently, the precise mechanisms of selective serotonin reuptake inhibitor (SSRI) antidepressant drugs such as fluoxetine are being revisited. Zinc is a trace element that has been long implicated in the psychopathology and therapy of depression. Zinc has been found to be sequestered and dispensed during stress and inflammation through a family of proteins called metallothioneins (MTs). In addition, MTs are well known for their antioxidant and therefore cytoprotective action. Changes in MTs, their upstream regulators and downstream effectors in response to fluoxetine have not been yet studied. The aim of the present study is to examine whether depression-induced changes in protein levels and mRNA levels of nuclear factor-erythroid 2-related factor 2 (Nrf2), MTs, antioxidant defensive enzyme heme oxygenase (HO-1), zinc-specific receptor GPR39 and brain derived neurotrophic factor (BDNF) in the hippocampus can be reversed by fluoxetine treatment, zinc supplementation or a combination of the two. MATERIAL AND METHODS: The present study investigated the effect of chronic (4weeks) combined treatment with zinc hydroaspartate (15mg/kg) and fluoxetine (10mg/kg) on a chronic mild stress model (CMS) in male Sprague-Dawley rats. RESULTS: Hippocampal mRNA and protein levels of Nrf2, HO-1, MTs, GPR39 (protein level only) and BDNF were significantly higher in response to a combined therapy of fluoxetine and zinc than to either monotherapy. Additionally, HO-1 and MTs gene expression was correlated with that of Nrf2 in the FLX-only group. CONCLUSION: Fluoxetine therapy activated the expression of MTs and HO-1 through an Nrf2-dependent pathway. When FLX was escorted by zinc, activated MTs had a positive impact on BDNF through the zinc signaling receptor GPR39, resulting in general improvement in neuronal plasticity as well as reduction of neuronal atrophy and neuronal cell loss. PMID- 28801266 TI - Lipogels responsive to near-infrared light for the triggered release of therapeutic agents. AB - : Here we report a composite system based on fibrin hydrogels that incorporate in their structure near-infrared (NIR) responsive nanomaterials and thermosensitive liposomes (TSL). Polymerized fibrin networks entrap simultaneously gold-based nanoparticles (NPs) capable of transducing NIR photon energy into heat, and lysolipid-incorporated TSL (LTSL) loaded with doxorubicin hydrochloride (DOX). NIR irradiation of the resulting hydrogels (referred to as "lipogels") with 808nm laser light increased the temperature of the illuminated areas, leading to the release of the liposomal cargo. Levels of DOX that release from the "smart" composites were dependent on the concentration of NIR nanotransducers loaded in the lipogel, the intensity of the electromagnetic energy deposited and the irradiation regime. Released DOX retained its bioactivity, as shown in cultures of epithelial carcinoma cells. Finally, the developed drug delivery platform was refined by using NIR-photoabsorbers based on copper sulfide NPs to generate completely biodegradable composites as well as through the incorporation of cholesterol (Ch) in LTSL formulation, which lessens leakiness of the liposomal cargo at physiological temperature. This remotely controlled system may suit well for those therapies that require precise control over the dose of delivered drug in a defined spatiotemporal framework. STATEMENT OF SIGNIFICANCE: Hydrogels composed of fibrin embedding nanoparticles responsive to near infrared (NIR) energy and thermosensitive liposomes loaded with doxorubicin hydrochloride (DOX), were prepared by in situ polymerization. NIR-light irradiation of these constructs, referred to as "NIR responsive lipogels", results in the controlled release of DOX to the surrounding medium. This technology may use fully degradable components and can preserve the bioactivity of liposomal cargo after remote triggering to finely regulate the dose and bioavailability of delivered payloads. NIR responsive lipogels technology overcomes the limitations of drug release systems based on the combination of liposomes and degradable polymeric materials, which in many cases lead to insufficient release at therapy onset or to overdose during high degradation period. PMID- 28801267 TI - Primum non nocere - The effects of sodium hypochlorite on dentin as used in endodontics. AB - : The medical literature is replete with the maxim 'primum non nocere', cautioning health care providers to avoid doing any harm to human subjects in their delivery of medical care. Sodium hypochlorite (NaOCl) is a well-established irrigant for root canal treatment because of its antimicrobial and organic tissue remnant dissolution capability. However, little is known about the deleterious effect of this strong oxidizing agent on the integrity of human mineralized dentin. Iatrogenically-induced loss of dentin integrity may precipitate post treatment root fracture and has potential medico-legal complications. In the present work, transmission electron microscopy provided evidence for collagen destruction in the surface/subsurface of dentin treated with high NaOCl concentrations and long contact times. Size exclusion chromatography showed that the hypochlorite anion, because of its small size, penetrated the water compartments of apatite-encapsulated collagen fibrils, degraded the collagen molecules and produced a 25-35um thick, non-uniform "ghost mineral layer" with enlarged, coalesced dentinal tubules and their lateral branches. Fourier transform-infrared spectroscopy identified increases in apatite/collagen ratio in NaOCl-treated dentin. The apatite-rich, collagen-sparse dentin matrix that remained after NaOCl treatment is more brittle, as shown by the reductions in flexural strength. Understanding the deleterious effects of NaOCl on mineralized dentin enables one to balance the risks and benefits in using high NaOCl concentrations for lengthy periods in root canal debridement. Delineating the mechanism responsible for such a phenomenon enables high molecular weight, polymeric antimicrobial and tissue dissolution irrigants to be designed that abides by the maxim of 'primum non nocere' in contemporary medical practices. STATEMENT OF SIGNIFICANCE: The antimicrobial and tissue-dissolution capacities of NaOCl render it a well-accepted agent for root canal debridement. These highly desirable properties, however, appear to be intertwined with the untoward effect of collagen matrix degradation within mineralized dentin. Because of its small size, the hypochlorite anion is capable of infiltrating mineralized collagen and destroying the collagen fibrils, producing a mineral-rich, collagen sparse ghost mineral matrix with reduced flexural strength. Findings from the present work challenge the biosafety of NaOCl when it is used in high concentrations and for lengthy time periods during root canal treatment, and laid the background work for future biomaterials design in debridement of the canal space. PMID- 28801268 TI - Positron emission tomography (PET) guided glioblastoma targeting by a fullerene based nanoplatform with fast renal clearance. AB - : Various carbonaceous nanomaterials, including fullerene, carbon nanotube, graphene, and carbon dots, have attracted increasing attention during past decades for their potential applications in biological imaging and therapy. In this study, we have developed a fullerene-based tumor-targeted positron emission tomography (PET) imaging probe. Water-soluble functionalized C60 conjugates were radio-labeled with 64Cu and modified with cyclo (Arg-Gly-Asp) peptides (cRGD) for targeting of integrin alphavbeta3 in glioblastoma. The specificity of fluorescein labeled C60 conjugates against cellular integrin alphavbeta3 was evaluated in U87MG (integrin alphavbeta3 positive) and MCF-7 cells (integrin alphavbeta3 negative) by confocal fluorescence microscopy and flow cytometry. Our results indicated that cRGD-conjugated C60 derivatives showed better cellular internalization compared with C60 derivatives without the cRGD attachment. Moreover, an interesting finding on intra-nuclei transportation of cRGD conjugated C60 derivatives was observed in U87MG cells. In vivo serial PET studies showed preferential accumulation of cRGD-conjugated C60 derivatives at in U87MG tumors. In addition, the pharmacokinetic profiles of these fullerene-based nanoparticles conjugated with cRGD and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) fit well with the three compartment model. The renal clearance of C60 based nanoparticles is remarkably fast, which makes this material very promising for safer cancer theranostic applications. STATEMENT OF SIGNIFICANCE: Safety is one of the major concerns for nanomedicine and nanomaterials with fast clearance profile are highly desirable. Fullerene is a distinct type of zero-dimensional carbon nanomaterial with ultrasmall size, uniform dispersity, and versatile reactivity. Here we have developed a fullerene-based tumor-targeted positron emission tomography imaging probe using water-soluble functionalized C60 conjugates radio-labeled with 64Cu and modified with cyclo (Arg-Gly-Asp) peptides (cRGD) for glioblastoma targeting. The improved tumor targeting property along with fast renal clearance behavior of C60-based nanoparticles makes this material very promising for future safer cancer theranostic applications. PMID- 28801270 TI - Immunomodulatory effects and anti-Candida activity of lactobacilli in macrophages and in invertebrate model of Galleria mellonella. AB - Due to the growing number of multi-resistant Candida spp., adjuvant treatments that may help combat these fungal pathogens are relevant and useful. This study evaluated the immunomodulation and anti-Candida activity of Lactobacillus rhamnosus (LR), Lactobacillus acidophilus and Lactobacillus paracasei suspensions, either single- or multiple-strain, in mouse macrophages (RAW 264.7) and Galleria mellonella (GM). Mouse macrophages were activated by different lactobacilli suspensions and challenged with C. albicans (CA). Tumor necrosis factor (TNF)-alpha, interleukin IL-1beta, IL-6 and IL-17 production and cell viability were investigated. LR was the best suspension for stimulating all evaluated cytokines and thus was used in subsequent in vivo assays. Two C. albicans clinical strains, CA21 and CA60, were then added to the GM assays to further confirm the results. LR suspension was injected into the larvae 24 h before challenging with CA. Survival curve, CFU per larva and hemocytes were counted. In the GM, the LR suspension increased the survival rate and hemocyte counts and decreased the CFU per larva counts for all groups. Lactobacilli suspensions presented strain-dependent immunomodulation; however, single suspensions showed better results. Anti-Candida activity was demonstrated by decreased Candida counts in the GM with the use of LR. PMID- 28801271 TI - Comparative evaluation of microbial translocation products (LPS, sCD14, IgM Endocab) in HIV-1 infected Indian individuals. AB - BACKGROUND: Microbial translocation of lipopolysaccharides (LPS), soluble CD14 (sCD14) and IgM Endocab levels have been reported to be associated with disease progression in HIV-1 infection. In this longitudinal study, plasma levels of different microbially translocated products (LPS, sCD14, Endocab) was investigated in HIV-1 infected Indian Individuals stratified as Rapid (R), Viremic slow (VS), Slow progressors (S) and healthy controls. METHOD: Ten healthy and twenty HIV-1 infected individuals were enrolled. Plasma levels of LPS, sCD14, Endocab was examined using commercially available Limulus Amebocyte assay and enzyme-linked immunosorbent assay (ELISA) enzyme linked immunosorbant assay. RESULTS: Elevated levels of sCD14, IgM EndoCab and LPS were observed during HIV-1 infection compared to healthy controls. Rapid progressors had higher levels of sCD14, IgM EndoCab, LPS (median% 1553, 3596, 202.2) compared to viremic slow, slow progressors and healthy controls both at baseline and follow up visits. At baseline, LPS correlated positively with IgM Endocab and negatively with sCD14 levels while at follow-up, significant positive correlation was observed between IgM Endocab and sCD14 (IgM EndoCab r = 0.490, p = 0.05; sCD14 r = 0.051, p = 0.830). Plasma levels of sCD14 correlated positively with viral load in rapid, viremic slow and slow progressors while CD + T cell count correlated positively with sCD14 and IgM EndoCab levels in viremic slow and slow progressors. CONCLUSION: Our findings indicate that elevated levels of sCD14, IgM EndoCab and LPS in HIV-1 infected individuals are strong predictors of disease progression and could be considered as candidate biomarkers for disease monitoring. PMID- 28801269 TI - Elastin-PLGA hybrid electrospun nanofiber scaffolds for salivary epithelial cell self-organization and polarization. AB - : Development of electrospun nanofibers that mimic the structural, mechanical and biochemical properties of natural extracellular matrices (ECMs) is a promising approach for tissue regeneration. Electrospun fibers of synthetic polymers partially mimic the topography of the ECM, however, their high stiffness, poor hydrophilicity and lack of in vivo-like biochemical cues is not optimal for epithelial cell self-organization and function. In search of a biomimetic scaffold for salivary gland tissue regeneration, we investigated the potential of elastin, an ECM protein, to generate elastin hybrid nanofibers that have favorable physical and biochemical properties for regeneration of the salivary glands. Elastin was introduced to our previously developed poly-lactic-co glycolic acid (PLGA) nanofiber scaffolds by two methods, blend electrospinning (EP-blend) and covalent conjugation (EP-covalent). Both methods for elastin incorporation into the nanofibers improved the wettability of the scaffolds while only blend electrospinning of elastin-PLGA nanofibers and not surface conjugation of elastin to PLGA fibers, conferred increased elasticity to the nanofibers measured by Young's modulus. After two days, only the blend electrospun nanofiber scaffolds facilitated epithelial cell self-organization into cell clusters, assessed with nuclear area and nearest neighbor distance measurements, leading to the apicobasal polarization of salivary gland epithelial cells after six days, which is vital for cell function. This study suggests that elastin electrospun nanofiber scaffolds have potential application in regenerative therapies for salivary glands and other epithelial organs. STATEMENT OF SIGNIFICANCE: Regenerating the salivary glands by mimicking the extracellular matrix (ECM) is a promising approach for long term treatment of salivary gland damage. Despite their topographic similarity to the ECM, electrospun fibers of synthetic polymers lack the biochemical complexity, elasticity and hydrophilicity of the ECM. Elastin is an ECM protein abundant in the salivary glands and responsible for tissue elasticity. Although it's widely used for tissue regeneration of other organs, little is known about its utility in regenerating the salivary tissue. This study describes the use of elastin to improve the elasticity, hydrophilicity and biochemical complexity of synthetic nanofibers and its potential in directing in vivo-like organization of epithelial salivary cells which helps the design of efficient salivary gland regeneration scaffolds. PMID- 28801272 TI - Low serum uric acid levels in chronic insomnia patients: A case-control study. AB - Recent studies have demonstrated the presence of oxidative stress in insomnia patients. Uric acid (UA) is regarded as one of the most important antioxidants that may attenuate oxidative stress. The aim of our study was to investigate whether there is an alteration of serum UA levels in chronic insomnia patients. The association between sleep quality and serum UA in chronic insomnia patients was also investigated. We recruited 300 chronic insomnia patients and 300 age- and gender-matched normal controls. The uricase-PAP method was used to measure the concentration of UA both in patient and normal control subjects. The Pittsburgh Sleep Quality Index (PSQI) was used to assess the sleep quality of chronic insomniac participants. As a result, significantly lower serum UA levels were observed in patients with chronic insomnia when compared with normal control subjects (279.56+/-65.80 vs. 299.10+/-61.17MUmol/L, t=-3.991, p<0.001). Low serum UA levels were correlated with high PSQI scores in multiple linear regression models (beta=-0.322, p<0.001). Our results suggested that low serum UA levels were associated with the presence and severity of chronic insomnia. PMID- 28801273 TI - Building concepts one episode at a time: The hippocampus and concept formation. AB - Concepts organize our experiences and allow for meaningful inferences in novel situations. Acquiring new concepts requires extracting regularities across multiple learning experiences, a process formalized in mathematical models of learning. These models posit a computational framework that has increasingly aligned with the expanding repertoire of functions associated with the hippocampus. Here, we propose the Episodes-to-Concepts (EpCon) theoretical model of hippocampal function in concept learning and review evidence for the hippocampal computations that support concept formation including memory integration, attentional biasing, and memory-based prediction error. We focus on recent studies that have directly assessed the hippocampal role in concept learning with an innovative approach that combines computational modeling and sophisticated neuroimaging measures. Collectively, this work suggests that the hippocampus does much more than encode individual episodes; rather, it adaptively transforms initially-encoded episodic memories into organized conceptual knowledge that drives novel behavior. PMID- 28801274 TI - Mannich base approach to 5-methoxyisatin 3-(4-isopropylphenyl)hydrazone: A water soluble prodrug for a multitarget inhibition of cholinesterases, beta-amyloid fibrillization and oligomer-induced cytotoxicity. AB - Targeting protein aggregation for the therapy of neurodegenerative diseases remains elusive for medicinal chemists, despite a number of small molecules known to interfere in amyloidogenesis, particularly of amyloid beta (Abeta) protein. Starting from previous findings in the antiaggregating activity of a class of indolin-2-ones inhibiting Abeta fibrillization, 5-methoxyisatin 3-(4 isopropylphenyl)hydrazone 1 was identified as a multitarget inhibitor of Abeta aggregation and cholinesterases with IC50s in the low MUM range. With the aim of increasing aqueous solubility, a Mannich-base functionalization led to the synthesis of N-methylpiperazine derivative 2. At acidic pH, an outstanding solubility increase of 2 over the parent compound 1 was proved through a turbidimetric method. HPLC analysis revealed an improved stability of the Mannich base 2 at pH2 along with a rapid release of 1 in human serum as well as an outstanding hydrolytic stability of the parent hydrazone. Coincubation of Abeta1 42 with 2 resulted in the accumulation of low MW oligomers, as detected with PICUP assay. Cell assays on SH-SY5Y cells revealed that 2 exerts strong cytoprotective effects in both cell viability and radical quenching assays, mainly related to its active metabolite 1. These findings show that 2 drives the formation of non-toxic, off-pathway Abeta oligomers unable to trigger the amyloid cascade and toxicity. PMID- 28801275 TI - Air blood barrier phenotype correlates with alveolo-capillary O2 equilibration in hypobaric hypoxia. AB - The O2 diffusion limitation across the air blood barrier (DO2 and subcomponents Dm and Vc) was evaluated in 17 healthy participants exposed to hypobaric hypoxia (HA, 3840m, PIO2 ~90mmHg). A 10% decrease in alveolar volume (VA) in all participants suggested the development of sub-clinical interstitial lung edema. In >80% of participants DO2/VA increased, reflecting an individual strategy to cope with the hypoxia stimulus by remodulating Vc or Dm. Opposite changes in Dm/Vc ratio were observed and participants decreasing Vc showed reduced alveolar blood capillary transit time. The interplay between diffusion and perfusion (cardiac output) was estimated in order to investigate the individual adaptive response to hypoxia. It appears remarkable that despite individual differences in the adaptive response to HA, diffusion limitation did not exceed ~11% of the alveolar-venous PO2 gradient, revealing an admirable functional design of the air blood barrier to defend the O2 diffusion/perfusion function when facing hypobaric hypoxia corresponding to 50mmHg decreased PAO2. PMID- 28801276 TI - Transferability of antimicrobial resistance from multidrug-resistant Escherichia coli isolated from cattle in the USA to E. coli and Salmonella Newport recipients. AB - OBJECTIVES: This study aimed to evaluate conjugative transfer of cephalosporin resistance among 100 strains of multidrug-resistant Escherichia coli (MDRE) to Salmonella enterica serotype Newport and E. coli DH5alpha recipients. METHODS: Phenotypic and genotypic profiles were determined for MDRE as well as for Salmonella Newport (trSN) and E. coli DH5alpha (trDH) transconjugants. RESULTS: Of 95 MDRE donor isolates, 26 (27%) and 27 (28%) transferred resistance to trSN and trDH recipients, respectively. A total of 27 MDRE (27%) were confirmed as extended-spectrum beta-lactamase (ESBL)-producers based on the double-disk synergy assay and whole-genome sequencing (WGS). WGS was performed on 25 of the ESBL-producing isolates, showing that 2 isolates carried blaCTX-M-6, 22 possessed blaCTX-M-32 and 1 was negative for blaCTX-M genes. Fourteen of the ESBLs sequenced were qnrB19. Differential transfer of IncA/C and IncN from MDRE32 was observed between trSN32 and trDH32. IncN-positive trDH32 displayed an ESBL phenotype, whereas IncA/C-positive trSN32 displayed an AmpC phenotype. The rate of ESBL transfer to trSN and trDH recipients was 11% and 96%, respectively. CONCLUSIONS: Twenty-seven MDRE were phenotypically identified as ESBL-producers. WGS of 25 MDRE revealed that 2 and 22 isolates carried blaCTX-M-6 and blaCTX-M 32, respectively. One multidrug-resistant isolate exhibited conversion from an AmpC phenotype to an ESBL phenotype with the transfer of only the IncN plasmid. The rate of resistance transfer to Salmonella or E. coli recipients was nearly identical. However, the ESBL phenotype was transferred with significantly greater prevalence to E. coli compared with Salmonella Newport (96% and 11%, respectively). PMID- 28801278 TI - [A rare case of spontaneous coronary artery dissection after emotional stress in a postmenopausal woman]. AB - OBJECTIVE: Spontaneous coronary artery dissection (SCAD) is a rare cause of acute myocardial infarction. While its etiology and pathogenesis remain not fully understood, SCAD occurs most frequently in patients at a young age and of a female gender. We report a case of SCAD in a 52-year-old healthy postmenopausal woman who developed acute myocardial infarction and subsequent ventricular aneurysm after emotional stress. This case may provide valuable insight into this rare disease and highlights the importance of psychological factors as contributing factors of SCAD in postmenopausal women with acute onset of chest pain. PMID- 28801277 TI - [Pioglitazone ameliorates atherosclerosis in apoE knockout mice through transforming growth factor-beta/Smad signaling and adaptive T cell immunity]. AB - OBJECTIVE: To examine whether transforming growth factor-beta (TGF-beta) pathway and adaptive T cell immunity play roles in the anti-atherosclerotic effects of pioglitazone (PIO) in ApoE-/- mice. METHODS: ApoE-/- mice with atherosclerosis induced by high-fat feeding were treated daily with PIO (20 mg/kg) or vehicle for 8 weeks. The protein expressions of TGF-beta pathway in the atheromatous lesions of the aorta and the percentages of IFN-gamma+ and Foxp3+ cells in the spleen of the mice were examined with immunohistochemical staining. In the in vitro experiment, primary cultured splenocytes were stimulated with oxidized low density lipoproteins (oxLDL) and treated with PIO either alone or in combination with the PPARgamma antagonist GW9662, after which the changes in percentages of CD4+IFN-gamma+ cells and CD4+CD25+Foxp3+ cells were analyzed with flow cytometry. RESULTS: PIO treatment of ApoE-/- mice with high-fat feeding significantly attenuated the progression of atheromatous lesions (P<0.05) and resulted in increased expressions of TGFbeta1 (P<0.01), TGFbetaRII (P<0.05), and p-Smad3 (P<0.05) and a decreased expression of Smad7 (P<0.05) in the lesions. PIO treatment also led to decreased percentage of IFN-gamma+ cells (P<0.05) and increased percentage of Foxp3+ cells (P<0.01) in the spleen of the mice. In primary cultured splenocytes, PIO treatment caused significant down-regulation of IFN-gamma mRNA (P<0.05) and up-regulation of Foxp3 mRNA (P<0.05) and obviously increased the percentages of CD4+IFN-gamma+ cells (P<0.05) and CD4+CD25+Foxp3+ (P<0.05); the effects of PIO on CD4+IFN-gamma+ and CD4+CD25+Foxp3+ cells were abolished by treatment of the cells with GW9662. CONCLUSION: The anti atherosclerotic effect of PIO is probably mediated by the TGF-beta/Smad signaling pathway and PPAR-gamma-dependent modulation of Th1/Treg population. PMID- 28801279 TI - [High-frequency echocardiography for assessment of regional wall motion abnormality and cardiac function in mice with myocardial infarction]. AB - OBJECTIVE: To evaluate the value of high-frequency echocardiography in assessing cardiac structure and function in a mouse model of myocardial infarction. METHODS: Twenty-five C57BL/6 mice were randomly divided into sham-operated group (n=10) and myocardial infarction model group (n=15) established by ligation of the left anterior descending artery. The cardiac structure, regional wall motion and cardiac function of mice were examined with pulsed wave Doppler (PWD), tissue Doppler imaging (TDI), EKV and M-mode echocardiography 3 days before and at 1 week after the operation. The histological changes and myocardial structure of the heart were observed at 1 week after the operation. RESULTS: High-frequency echocardiography and HE staining detected obvious myocardial infarction in the mice in the model group. Compared with the sham-operated mice, the mice with myocardial infarction showed significant left ventricular expansion, obvious thinning of the ventricular wall, and significantly decreased ventricular systolic function and diastolic function with regional wall motion abnormality and ventricular remodeling. CONCLUSION: s 2D-type echocardiography combined with M-mode, PWD, TDI and EKVTM for allows accurate and sensitive detection of the loci and severity of myocardial infarction to provide important evidence for clinical diagnosis and treatment of myocardial infarction. PMID- 28801280 TI - [Regression analysis of red cell distribution width and mean platelet volume in patients with acute myocardial infarction]. AB - OBJECTIVE: To investigate clinical implications of changes in red cell distribution width (RDW) and mean platelet volume (MPV) in patients with acute myocardial infarction. METHODS: A total of 127 patients (90 men and 37 women) were enrolled in this analysis, including 66 with acute myocardial infarction (AMI) and 61 with unstable angina (UA). The patients' baseline demographic and clinical data were compared between the two groups including age, hypertension, diabetes, smoking, BMI, blood biochemical profiles, cardiac functions and platelet and red blood cell parameters. The patients were further divided into subgroups according to the RDW 50% cumulative frequency, and the MPV, P-LCR, hsCRP, NT-proBNP, RBC, Dimer and MCV were compared. The correlations between platelet and erythrocyte test results were evaluated in both the AMI and UA patients. Regression analysis was performed to identify the factors affecting the RDW in the AMI group and a regression model was established. RESULTS: The platelet and red blood cell test results, P-LCR, MPV, and RDW differed significantly between AMI and UA groups (P<0.01 or 0.05). Correlation analysis showed a significant positive correlation between RDW and MPV in AMI group (r=0.34, P<0.01). Between the subgroups with different RDW 50% cumulative frequencies, MPV, P-LCR, hsCRP, D-Dimer, and NT-proBNP all differed significantly (P<0.05 or 0.01). In AMI group, with RDW as the dependent variable, we established a multivariate regression model of RDW=0.19MPV+10.83. CONCLUSION: RDW and MPV are closely correlated in patients with AMI. In multiple regression analysis, MPV can explain the changes in RDW in patients with AMI. PMID- 28801281 TI - [Effect of endomorphin-1 postconditioning against myocardial ischemia-reperfusion injury in rats and the role of Erk1/2 signaling pathway]. AB - OBJECTIVE: To investigate the effect of postischemic treatment with endomorphin-1 (EM-1) against myocardial ischemia/reperfusion (IR) injury in rats and on extracellular signal regulated kinase 1/2 (Erk1/2)-dependent signaling pathway. METHODS: Sprague-Dawley rats were randomly divided into 5 groups, namely the sham operated group, IR group, EM-1 post-treatment group (EM50 group), EM-1 post treatment group with PD98059 treatment (EM50+PD group), and PD98059 post treatment group (PD group). The hemodynamic indexes of the rats were recorded. After reperfusion, CK-MB, LDH, CTnI, MDA, IL-6, TNF-alpha, and SOD activities or contents were measured, the infarct size was determined, and the expression levels of Erk1/2, P-Erk1/2 and cleaved caspase-3 were detected using Western blotting. RESULTS: Compared with the sham group, the IR group showed significantly decreased heart rate and mean arterial pressure (P<0.05), which were increased obviously by EM-1 post-treatment (P<0.05). EM-1 post-treatment also resulted in significantly decreased LDH, CK-MB, CTnI, MDA, IL-6, and TNF alpha activities or contents (P<0.05), increased SOD activity (P<0.05), reduced the infarct size (P<0.05), and increased the expression level of P-Erk protein (P<0.05). Compared with EM50 group, EM50+PD group showed significantly decreased heart rate and mean arterial pressure (P<0.05), increased LDH, CK-MB, CTnI, MDA, IL-6, and TNF-alpha activities or contents (P<0.05), decreased SOD activity, increased infarct size (P<0.05), and lowered expression of P-Erk protein (P<0.05). CONCLUSION: Postischemic treatment with EM-1 protects the heart against IR injury by improving the cardiac function, inhibiting inflammation, and inhibiting oxidative stress and myocardial apoptosis, and Erk1/2 signaling pathway may be involved in this process. PMID- 28801282 TI - [SOST knockdown promotes differentiation of osteoblasts MG63 and mesenchymal stem cells C3H10 in an in vitro model of bone metastasis of breast cancer]. AB - OBJECTIVE: To investigate whether SOST is involved in breast cancer MDA-MB-231 cells-induced suppression of differentiation of osteoblast MG63 cells and mesenchymal stem C3H10 cells. METHODS: SOST-specific small interfering RNA (siRNA) was transfected into breast cancer MDA-MB-231 cells, and the interfering efficiency was verified by RT-PCR. The supernatants were collected from MDA-MB 231 cells in routine culture, cells transfected with SOST siRNA via adenovirus, and cells transfected with empty adenoviral vectors and added in MG63 or C3H10 cell cultures. The changes in the expressions of OPG, OCN, OPN and IBSP in MG63 and C3H10 cells were detected using quantitative real-time PCR, and ALP activity was detected with ALP reading and ALP staining with the cells cultured in routine culture medium and cells in osteogenic induction medium as the negative and positive controls. RESULTS: The adenovirus Ad-siSOST effectively knocked down the expression of SOST in MDA-MB-231 cells. MG63 cells and C3H10 cells cultured in osteogenic medium showed significantly upregulated expressions of the osteoblast markers OPG, OPN, OCN and IBSP (P<0.01), while co-culture with the supernatant of MDA-MB-231 cells obviously reduced the expressions of the osteoblast markers (P<0.01); the expression of the markers increased again in MG63 and C3H10 cells after treatment with the supernatant of MDA-MB-231 cells transfected with ad siSOST (P<0.01). ALP activity in MG63 and C3H10 cells exhibited a similar pattern of variations in response to the treatments (P<0.01). CONCLUSION: In the in vitro model of bone metastasis of breast cancer, the differentiation of MG63 or C3H10 cells is suppressed, which can be partly reversed by knocking down the expression of SOST in the bone metastasis microenvironment. PMID- 28801283 TI - [Expression of MIER3 in colorectal cancer and bioinformatic analysis of MIER3- interacting proteins]. AB - OBJECTIVE: To explore role of MIER3 gene in the development and progression of human colorectal carcinoma (CRC) and analyze the proteins that interact with MIER3 using bioinformatic techniques. METHODS: MIER3 mRNA and protein expressions were detected in 8 CRC biopsy samples and paired adjacent tissues using real-time PCR and Western blotting. A recombinant eukaryotic expression vector pcDNA3-MIER3 was constructed and its effect on the proliferation and invasion of CRC cells were tested using CCK8 assay and Transwell migration assay. Bioinformatic methods were used to predict and analyze MIER3-interacting proteins. RESULTS: MIER3 was obviously down-regulated in the 8 CRC tissues as compared with the paired adjacent tissues. In human CRC cell line DLD1, MIER3 overexpression induced by transfection of the cells with pcDNA3-MIER3 significantly inhibited the cell proliferation and suppressed cell invasiveness in vitro. Bioinformatics analyses indicated that NAT9 was a potential MIER3-interacting protein and MIER3 was probably associated with tumor susceptibility. CONCLUSION: MIER3, which is obviously down-regulated in CRC tissues, is closely associated with the proliferation and invasion of CRC, and NAT9 protein is a probable MIER3 interacting protein. PMID- 28801284 TI - [Yiqihuoxue prescription promotes nerve regeneration by miR-124-mediated regulation of Wnt signaling in rats]. AB - OBJECTIVE: To investigate the effect of Yiqihuoxue prescription (NLXT) on nerve regeneration in MCAO-R rat models of qi deficiency and blood stasis syndrome and explore the underlying mechanisms. METHODS: The rats were randomized into 4 groups, namely the control group, model group, NLXT group and TXL group. The rats in NLXT group and TXL group were treated with gavage of NLXT and TXL solutions, respectively. The NFDS, QDSS and BSSS of the rats were evaluated. The regional cerebral blood flow (rCBF) were dynamically monitored with laser Doppler scanning, and the volume of cerebral infarction was detected with TTC-dye; the expression levels of nestin and BrdU were assayed with immunohistochemistry and mmunofluorescent staining. The expressions of miRNA-124, Wnt3a, GSK3beta and beta catenin in the rat brain tissue were detected with PCR or Western blotting. RESULTS: NLXT and TXL both improved the neurological functions of the model rats, reduced NFDS, QDSS, and BSSS scores, decreased the volume of cerebral infarction, and promoted the recovery of the rCBF (P<0.01). Nestin and BrdU expression levels were significantly increased in the rat brain tissue in NLXT group and TXL group. NLXT significantly inhibited high expressions of miRNA-124 and Wnt3a in response to stress, and increased beta-catenin expression level (P<0.01). NLXT and TXL produced no obvious effect on GSK3beta expression in the model rats (P>0.05). CONCLUSION: NLXT can activate Wnt signaling by affecting miRNA-124 expression to offer neuroprotection and promote nerve regeneration in rats with cerebral ischemia with qi deficiency and blood stasis syndrome. PMID- 28801285 TI - [Clinical analysis of 939 patients with adrenal lesions detected by abdominal computed tomography]. AB - OBJECTIVE: To investigate the prevalence, etiology and clinical characteristics of adrenal lesions detected by abdominal computed tomography (CT). METHODS: This retrospective study was conducted in patients with adrenal lesions detected by abdominal CT examinations in Nanfang Hospital between July, 2014 and June, 2015. The clinical data of the patients were collected for analysis of the demographics, comorbidities, imaging characteristics, biochemical profiles, clinical diagnosis and intervention. RESULTS: A total of 939 patients with adrenal lesions were identified from 19 004 patients undergoing abdominal CT scan over the defined period. The mean age of the patients was 53.2 years and 560 of the patients were male. Among the total cases with adrenal lesions, the percentages of cases with adrenal masses tended to increase progressively with age. Endocrine studies were done in 270 of the total patients, which identified non-functioning masses in 38.9%, primary aldosteronism in 16.3%, Cushing's syndrome in 4.1%, subclinical Cushing's syndrome in 7.0%, and pheochromocytomas in 7.0% of the cases. Adrenal incidentalomas was detected in 191 patients, with a detection rate of 1.0% among the overall patients undergoing abdominal CT scans. Imaging study detected adenomas (70.3%), cortical carcinomas (2.4%), and metastases (0.5%). Of 191 patients with adrenal incidentalomas, only 76 (39.8%) underwent endocrine evaluation, including 34 with nonfunctioning adrenal masses, 17 with pheochromocytoma, 7 with primary aldosteronism, and 5 with subclinical Cushing's syndrome. CONCLUSION: s The overall detection rates of adrenal lesions and adrenal incidentalomas by abdominal CT were 4.9% and 1.0%, respectively, in our cohort of patients undergoing the examination over the defined period. Although most of the lesions were benign and nonfunctioning, malignant and functional lesions were also detected. As many as 60% of the patients with adrenal incidentalomas did not have hormonal testing. Clinicians need to have greater awareness of adrenal incidentalomas and standard protocol for its management should be established. PMID- 28801286 TI - [Value of detection of serum glypican-3 level in diagnosis and therapeutic effect evaluation of primary hepatocellular carcinoma]. AB - OBJECTIVE: To explore the clinical value of detecting serum glypican-3 in the diagnosis and therapeutic effect evaluation of primary hepatocellular carcinoma (PHC). METHODS: Using sandwich ELISA, we detected serum glypican-3 levels in 60 patients with PHC, 60 with metastatic liver cancer, 50 with liver cirrhosis, 50 with chronic viral hepatitis, 20 with hepatic cyst, 20 with fatty liver, 20 with hepatic hemangioma and 20 with drug-induced hepatitis as well as in 40 healthy subjects (control). We also analyzed the changes in serum levels of glypican-3 and alpha fetoprotein (AFP) in PHC patients after treatment. RESULTS: PHC patients had significantly higher serum levels of glypican-3 than patients with other liver diseases and the control subjects (P<0.05). The levels of serum glypican-3 were significantly higher in patients with metastatic liver cancer, liver cirrhosis and viral hepatitis than in those with other benign liver diseases and the control subjects (P<0.05). Glypican-3 level was not associated with AFP level or liver function in PHC patients, in whom the positivity rates for glypican-3 and AFP were 65% and 56.7%, respectively. The detection rate of PHC increased to 85% by a combined detection of AFP and glypican-3. In the 23 PHC patients who responded positively to treatments, serum glypican-3 level showed a steady decline compared with that in 15 patients before treatment, while serum AFP level showed a similar decrease only in 10 patients. CONCLUSION: Combined detection of glypican-3 and AFP is expected to improve the early diagnosis rate of PHC. The different thresholds of serum glypican-3 may play a role in the differential diagnosis of PHC and other various liver diseases. Glypican-3 may serve as a better marker than AFP with a high specificity and sensitivity for evaluating the therapeutic effect in PHC patients. PMID- 28801287 TI - [Th1/Th2 and Treg/Th17 cell balance in peripheral blood of patients with ovarian cancer]. AB - OBJECTIVE: To investigate the changes in the percentages and balance of CD4+T cell subsets including T helper cells (Thl, Th2, and Thl7) and T regulatory cells (Treg) in patients with ovarian cancer. METHODS: Peripheral blood samples were collected from 30 patients with ovarian cancer and 20 healthy subjects for analysis of the percentages of Thl, Th2, Thl7 and Treg using flow cytometry. RESULTS: Compared with the control subjects, the patients with ovarian cancer showed significantly increased percentages of Th2, Thl7 and Treg (P<0.05) but significantly decreased percentage of Th1 in the peripheral blood of patients with ovarian cancer (P<0.05). The changes in CD4+ T cell subsets were significantly correlated with the clinical stage of the tumor (P<0.05) but not with the histological type or cell differentiation (P>0.05). The Th1/Th2 ratio was significantly decreased in ovarian cancer patients (P<0.05) with obvious Th2 polarization compared with control group. The Treg/Th17 ratio was significantly increased in ovarian cancer patients (P<0.05). CONCLUSION: Patients with in ovarian cancer have abnormal expressions of CD4+T cell subsets in the peripheral blood with Th1/Th2 and Treg/Th17 imbalance, and these findings provide evidence for clinical immunotherapy of ovarian cancer. PMID- 28801288 TI - [Expression of Wnt5b in patients with HBV-related hepatocellular carcinoma and its clinical significance]. AB - OBJECTIVE: To investigate the expression of Wnt5b in hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) tissues and its correlation with the clinicopathological parameters. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical staining were employed to measure Wnt5b mRNA and protein expressions in two groups of HBV-related HCC patients (100 cases in each) selected from a cohort of 289 cases with HBV-related HCC using simple random sampling method. The correlation of Wnt5b expression with the clinicopathological parameters and the prognosis of HCC patients was analyzed. RESULTS: Wnt5b mRNA expression was significantly higher in HCC tissues than that of adjacent noncancerous tissues in 65.0% (65/100) of the cases, and the positivity rate of Wnt5b protein was significantly higher in HCC tissues than that of adjacent noncancerous tissues (58.0% vs 22.0%, P<0.05). Wnt5b expression was significantly correlated with the tumor size (P<0.05), tumor number (P<0.01, only at the protein level), tumor differentiation (P<0.01, only at the protein level), TNM stage (P<0.05), BCLC stage (P<0.05), metastasis (P<0.05) and recurrence (P<0.01). The patients with up-regulated Wnt5b mRNA and protein had a shorter relapse-free survival (P<0.01). CONCLUSION: s Up-regulated Wnt5b might contribute to the progression of HBV-related HCC and predicts a poor prognosis. PMID- 28801289 TI - [LKB1 regulates epithelial-mesenchymal transition in Peutz-Jeghers hamartoma and intestinal epithelial cells]. AB - OBJECTIVE: To investigate the molecular mechanism by which LKB1 regulates epithelial-mesenchymal transition (EMT) in Peutz-Jeghers hamartoma and intestinal epithelial cells. METHODS: Immunohistochemistry was used to detect gene expression of LKB1, E-cadherin, and vimentin in 20 hamartoma tissues and 10 normal intestinal tissues, and collagen fiber deposition was analyzed using Masson trichrome staining. Normal intestinal epithelial NCM460 cells were transfected with LKB1 shRNA plasmid or negative control via lentiviral vectors, and the role of LKB1 in cell polarization and migration were determined using CCK8 and Transwell assays. Western blotting, quantitative real-time PCR (qPCR) and immunofluorescence were used to assess the alterations of EMT markers in the cells with LKB1 knockdown. RESULTS: Compared with normal intestinal tissues, hamartoma polyps showed significantly decreased LKB1 and E-cadherin expressions and increased vimentin expression with increased collagen fiber deposition. The cells with LKB1 knockdown exhibited enhanced cell proliferation and migration activities (P<0.01). Western blot analysis, qPCR and immunofluorescence all detected decreased E-cadherin and increased N-cadherin, vimentin, Snail, and Slug expressions in the cells with LKB1 knockdown. CONCLUSION: s LKB1 deficiency triggers EMT in intestinal epithelial cells and Peutz-Jeghers hamartoma, suggesting that EMT can serve as the therapeutic target for treatment of Peutz Jeghers syndrome. PMID- 28801290 TI - [Quinalizarin induces apoptosis in gastric cancer AGS cells via MAPK and Akt signaling pathway]. AB - OBJECTIVE: To investigate quinalizarin-induced apoptosis in gastric cancer cells in vitro and explore the molecular mechanisms. METHODS: MTT assay was used to determine the cytotoxic effects of quinalizarin on human gastric cancer AGS, MKN 28 and MKN-45 cells. Annexin V-FITC/PI staining and flow cytometry were used to assess quinalizarin-induced apoptosis in AGS cells and its effect on intracellular ROS levels; the expression levels of apoptotic proteins in the cells were determined with Western blotting. RESULTS: Quinalizarin dose dependently reduced the cell viabilities of the 3 gastric cancer cells (P<0.05). The IC50 values of quinalizarin in AGS, MKN-28 and MKN-45 cells were 7.07 umol/L, 22.55 umol/L and 14.18 umol/L, respectively. Quinalizarin time-dependently induced apoptosis of AGS cells and potentiated the generation of intracellular reactive oxygen species (ROS) levels. Pretreatment with NAC, a scavenger of ROS, inhibited quinalizarin-induced apoptosis (P<0.001). Western blotting results showed that quinalizarin also up-regulated the expression levels of the apoptotic proteins including p-p38, p-JNK, Bad, cleaved caspase-3, and cleaved PARP-1 (P<0.05), and down-regulated the expression of the anti-apoptotic proteins p-Akt, p-ERK, and Bcl-2 (P<0.05). CONCLUSION: Quinalizarin inhibits the proliferation and induces apoptosis in gastric cancer cells in vitro through regulating intracellular ROS levels via the MAPK and Akt signaling pathways. PMID- 28801291 TI - [Value of PI-RADS v2 scores combined with prostate specific antigen in diagnosis of peripheral zone prostate cancer: a logistic regression analysis]. AB - OBJECTIVE: To assess the value of Prostate Imaging and Reporting and Data System: Version 2 (PI-RADS v2) combined with prostate specific antigen (PSA) in the diagnosis of peripheral zone (PZ) prostate cancer (PCa). METHODS: The preoperative magnetic resonance imaging and PSA data were ananlyzed for 69 patients with pathologically confirmed PCa and 109 non-PCa patients. PI-RADS v2 scores (1-5) was used to evaluate the risk of PZ PCa. The total PSA (tPSA) level, free to total PSA ratio (f/t PSA), PSA density (PSAD), PZ-PSAD and PI-RADS v2 scores were compared between the PCa and non-PCa patients. Logistic regression models were established with parameters that differed significantly the two groups. The receiver opearting characteristics (ROC) curve was constructed based on the P values derived from the logical regression models and PI-RADS scores to assess the diagnostic efficiency. RESULTS: PI-RADS v2 score, tPSA, f/t PSA, PSAD and PZ-PSAD differed significantly between the two groups (P<0.01). Four predictive multivariate models were established: Logit P=-6.825+1.024PI-RADS v2+ 0.223tPSA (A), Logit P=-4.354+1.586PI-RADS v2-12.7841f/tPSA (B), Logit P= 8.993+1.630PI-RADS v2+17.091PSAD (C), and Logit P=-9.434+1.596PI-RADS v2+10.494PZ PSAD (D), whose area under the ROC curves was 0.908, 0.891, 0.944, and 0.961, respectively, all significantly greater than that of PI-RADS v2 score (P<0.05). CONCLUSION: Compared with PI-RADS v2 score alone, the combination of PI-RADS v2 score and PSA in the logistic regression model can improve the diagnostic efficiency of PZ PCa and offers better confidence in the decision of biopsy in suspected cases. PMID- 28801292 TI - [Oxidized low-density lipoprotein modulates differentiation of murine memory CD8+ T cell subpopulations]. AB - OBJECTIVE: To investigate effect of oxidized low-density lipoprotein (ox-LDL) on memory CD8+ T cell subpopulation differentiation in mice with autoimmune diabetes. METHODS: Cultured splenic CD8+ T cells from pre-diabetic NOD mice isolated with magnetic beads were treated with 30 ug/mL ox-LDL and 10 U/mL interleukin-2 (IL-2) for 24 h and the control cells were treated with IL-2 only. Flow cytometry was used to determine the percentage of splenic CD8+IFN-gamma+ T cells, expressions of CD8, CD44 and CD62L on the T cells, and the activation of T cell factor-1 (TCF-1) and STAT-3. The CD127+ memory T cells were purified and transplanted into the pre-diabetic NOD mice via the tail vein, and the blood glucose was recorded weekly and survival time of the mice was monitored. RESULTS: Treatment with ox-LDL significantly reduced islet beta cell-specific cytotoxic CD8+T cells as compared with the control group [(0.7?0.03)% vs (2.7?0.14)%, P<0.01]. The percentage of effector memory CD8+T cells (Tem) in the total memory CD8+T cells was reduced [(10.3?0.71)% vs (30.3?1.36)%, P<0.01] and that of stem cell-like memory T cells was significantly increased [(72.3?3.8)% vs (55.1?2.61)%, P<0.05] following ox-LDL treatment, which also resulted in significantly decreased activation of TCF-1 [(14.5?0.82)% vs (34.2?1.23)%, P<0.01] and pSTAT-3 [(3.3?0.12)% vs (22.1?1.1)%, P<0.01]. Transplantation of ox LDL-treated memory T cells in pre-diabetic NOD mice obviously inhibited the increase of blood glucose and prolonged the survival time of the mice (P<0.05). CONCLUSION: Ox-LDL decreases the activation of transcriptional factors TCF-1 and phosphorylation of STAT-3, inhibits the formation of effector memory CD8+ T cells with long-term cytotoxicity, but promote the generation of stem cell-like memory CD8+ T cells, which result in suppression of islet beta cell-specific effector cytotoxic CD8+ T cell differentiation to lessen autoimmune injury to the islet beta cells. PMID- 28801293 TI - [Effect of macrophage inflammatory protein-1beta on proliferation and apoptosis of human tongue squamous cell carcinoma CAL-27 cells in vitro]. AB - OBJECTIVE: To detect CCR5 protein expression in different human tongue squamous cell carcinoma cells and observe the effect of macrophage inflammatory protein 1beta (MIP-1beta) on the proliferation and apoptosis of CAL-27 cells. METHODS: Western blotting and immunofluorescence staining were used to detect the expression of the CCR5, the receptor of MIP-1beta, in 3 human tongue squamous cell carcinoma cells UM-1, CAL-27, and Tca-8113. CCK-8 assay was used to assess the proliferation of CAL-27 cells stimulated with 10, 20, and 40 ng/mL MIP-1beta for 12, 24, or 48 h. The apoptosis of the cells stimulated with MIP-1beta (10, 20, and 40 ng/mL) for 24 h was analyzed using flow cytometry with Annexin V/PI double staining. RESULTS: CCR5 expression was detected both on the membrane and in the cytoplasm in all the 3 tongue squamous cell carcinoma cell lines. At the concentrations of 10, 20, and 40 ng/mL, MIP-1beta stimulation for 12 and 24 h significantly promoted the proliferation of CAL-27 cells (P<0.05); MIP-1beta stimulation for 48 h at the concentrations 10 and 20 ng/mL, but not at 40 ng/mL, promoted the proliferation of CAL-27 cells (P<0.05). MIP-1beta stimulation at 40 ng/mL for 24 produced the most obvious apoptosis-inducing effect in CAL -27 cells (P<0.05), while MIP-1beta at 10 or 20 ng/mL did not induce obvious apoptosis in the cells (P>0.05). CONCLUSION: CCR5 is expressed in all the 3 human tongue squamous cell carcinoma cells. MIP-1beta can promote the proliferation of CAL-27 cells but high concentrations of MIP-1beta also induced cell apoptosis. Prolonged stimulation of the cells with a high concentration of MIP-1beta shows attenuated effect in promoting cell proliferation probably as a result of cell apoptosis induced by MIP-1beta. PMID- 28801294 TI - [Early intervention of BK virus replication promotes stabilization of renal graft function]. AB - OBJECTIVE: To investigate the optimal time window for intervention of BK virus (BKV) replication and its effect on the outcomes of kidney transplant recipients (KTRs). METHODS: A retrospective analysis of the clinical data and treatment regimens was conducted among KTRs whose urine BKV load was >=1.0*104 copies/mL following the operation between April, 2000 and April, 2015. KTRs with urine BKV load <1.0*104 copies/mL matched for transplantation time served as the control group. RESULTS: A total of 54 recipients positive for urine BKV were included in the analysis. According to urine BKV load, the recipients were divided into 3 groups: group A with urine BKV load of 1.0*104-1.0*107 copies/mL (n=22), group B with urine BKV load >1.0*107 copies/mL (n=24), and group C with plasma BKV load >=1.0*104 copies/mL (n=8); 47 recipients were included in the control group. During the follow-up for 3.2-34.5 months, the urine and plasma BKV load was obviously lowered after intervention in all the 54 BKV-positive recipients (P<0.05). Eighteen (81.82%) of the recipients in group A and 19 (79.17%) in group B showed stable or improved estimated glomerular filtration rate (eGFR) after the intervention; in group C, 4 recipients (50%) showed stable eGFR after the intervention. In the last follow-up, the recipients in groups A and B showed similar eGFR with the control group (P>0.05), but in group C, eGFR was significantly lower than that of the control group (P=0.001). The recipients in group A and the control group had the best allograft outcome with stable or improved eGFR. CONCLUSION: Early intervention of BKV replication (urine BKV load >=1.0*104 copies/mL) in KTRs with appropriate immunosuppression reduction can be helpful for stabilizing the allograft function and improving the long-term outcomes. PMID- 28801295 TI - [Foshouningshen decoction improves sleeping via the serotonergic system in a rat model of insomnia]. AB - OBJECTIVE: To evaluate the sedative and hypnotic effects of Foshouningshen decoction (FSNSD) and study its effects on expressions of 5-hydroxy tryptamine (5 HT) and 5-HT1A receptor (5-HT1AR) in the hippocampus in a rat model of insomnia. METHODS: Male KM mice were divided into control group, estazolam (0.4 mg/kg daily) group, and low-, moderate-, and high-dose FSNSD groups (daily dose of 12, 24, and 48 g/kg, respectively). After corresponding treatments for 1 week, the mice underwent sleep-inducing test with subthreshold and threshold doses of sodium pentobarbital. Forty-eight male SD rats were randomized into control group, insomnia model group, estazolam group (0.2 mg/kg daily), and low-, moderate-, and high-dose FSNSD groups (with daily dose of 6, 12, and 24 g/kg, respectively). Rat models of insomnia were established by intraperitoneal injection of 4-cholro-dl-phenylalanine (PCPA) at the daily dose of 350 mg/kg for 3 days, after which the rats received corresponding treatments via gavage for 1 week. The performance of the rats in open field test was recorded and the hippocampal expression of 5-HT was detected using ELISA; the expressions of 5 HT1AR protein and mRNA in the hippocampus were detected using immunohistochemistry and real-time PCR, respectively. RESULTS: In the sleep inducing test with a subthreshold dose of sodium pentobarbital, the mice treated with high-dose FSNSD showed a significantly higher rate of sleep onset than the control mice (P<0.05); in the test with a threshold dose of sodium pentobarbital, treatment with moderate- and high-dose FSNSD resulted in significantly prolonged sleeping time (P<0.01) and shortened sleep latency (P<0.05) in the mice. The rats in insomnia model group showed increased total distance in open field test (P<0.05) with significantly decreased content of 5-HT (P<0.01) and expressions of 5-HT1AR protein and mRNA in the hippocampus (P<0.01). Treatment of the rats with estazolam or high-dose FSNSD obviously decreased the total distance in open field test (P<0.05) and increased the content of 5-HT (P<0.05) and expressions of 5 HT1AR (P<0.01) in the hippocampus of rats with insomnia. CONCLUSION: FSNSD can produce therapeutic effects on insomnia possibly by increasing 5-HT content and expressions of 5-HT1AR in the hippocampus. PMID- 28801296 TI - [Efficacy of ultrasound-guided vacuum-assisted Mammotome excision for management of benign breast diseases: analysis of 1267 cases]. AB - OBJECTIVE: To assess the clinical value of ultrasound-guided vacuum-assisted Mammotome (MMT) system for surgical resection of benign breast disease. METHODS: This retrospective study was conducted among 1267 patients who underwent minimally invasive surgery with ultrasound-guided MMT system for benign breast disease at our center between January, 2009 and January, 2014. The resection rate, incidence of complication, recurrence rate, patients' satisfaction, clinical follow-up results and risk factors were analyzed. The patients were followed up at 1 month, 6 months and every 6 months thereafter for up to 2 years with a median follow-up of 22 months. RESULTS: Of the total of 1267 patients, 1259 (99.36%) had complete resection of the breast lesions, and residual lesions were found in 8 cases 1 month after the operation. The resection rate was significantly associated with lesion size (P=0.003) but not with the patients'age, pathology, BI-RADS classification, or the number or location of the lesions (P>0.05). Eighty-nine (7.02%) patients showed postoperative complications, and hematoma occurred in 70 (5.52%) patients after the operation. The complication rate was significantly associated with the number and location of lesions (P=0.000) but not with age, pathology, BI-RADS classification or the lesion size (P>0.05). A total of 193 (15.23%) patients had recurrence after the operation, including 65 (5.13%) with in situ recurrence and 128 (10.1%) with new lesions. The recurrence rate was significantly associated with the number and size of lesions (P=0.000) but not with age, pathology, BI-RADS classification or location of lesions(P>0.05). Six patients were not satisfied with the appearance of the incision, and the overall satisfaction rate of the patients was 99.52%. CONCLUSION: s Ultrasound-guided vacuum-assisted MMT excision is a safe and effective procedure for benign breast disease with a low surgical complication rate, a high resection rate and a low recurrence rate. This technique results in good postoperative appearance for treatment of benign and high-risk breast lesions, especially multiple benign breast lesions. PMID- 28801297 TI - [Effect of metformin on insulin resistance during catch-up growth in mice with fetal growth restriction]. AB - OBJECTIVE: To study the efficacy of metformin intervention on insulin resistance during catch-up growth in mice with fetal growth restriction (FGR). METHODS: Mouse models of FGR were established by low protein diet feeding of the pregnant mice. Both the newborn female mice with FGR and normal control (NC) mice were randomized for feeding with a standard diet (SF) or a high-fat diet (HF) after weaning and treatment with gavage of either metformin or normal saline. The mice were examined for vaginal opening time and the estrous cycle at the age of 8 weeks. At the age of 12 weeks, 6 mice in anestrus from each group were fasted for 12 h for measurement of body weight, height, poundera index (PI), fasting blood glucose (FBG), fasting insulin (Fins), follicle stimulating hormone (FSH) and anti-Mullerian hormone (AMH), and the HOMA-IR was calculated. The reproductive capacity of female mice was assessed by mixing them with male mice at the ratio of 2:1. The 3 * 2 factorial analysis was conducted to determine the interactions between FGR, high-fat feeding and metformin. RESULTS: Factorial analysis showed that FGR and high-fat feeding had significant effects on the PI index, Fins, HOMA IR, vaginal opening time, and AMH (P<0.05). Metformin significantly affected the factors related to high-fat feeding including weight, PI, FPG, Fins, HOMA-IR and estrous cycle (P<0.05) and the factors related to FGR with the exception of height and FSH (P<0.05). FGR significantly affected the factors tested except for body weight (P<0.05); high-fat feeding affected all the factors but the FSH (P<0.05); metformin affected all the factors but the height and FSH (P<0.05). In the female mice treated with saline, the pregnancy rates differed significantly between FGR mice with high-fat feeding and control mice with standard feeding, and between FGR mice with standard feeding and high-fat feeding (P<0.05). CONCLUSION: FGR mice can present with delayed puberty with rare ovulation and adulthood insulin resistance, and high-fat feeding after birth can promote the catch-up growth of FGR mice. Metformin intervention is effective for improving insulin resistance and reproductive-endocrine disorders in FGR mice during catch up growth. PMID- 28801298 TI - [Application of 3D visualization technique in breast cancer surgery with immediate breast reconstruction using laparoscopically harvested pedicled latissimus dorsi muscle flap]. AB - OBJECTIVE: To study the value of 3D visualization technique in breast-preserving surgery for breast cancer with immediate breast reconstruction using laparoscopically harvested pedicled latissimus dorsi muscle flap. METHODS: From January, 2015 to May, 2016, 30 patients with breast cancer underwent breast preserving surgery with immediate breast reconstruction using pedicled latissimus dorsi muscle flap. The CT data of the arterial phase and venous phase were collected preoperatively and imported into the self-developed medical image 3D visualization system for image segmentation and 3D reconstruction. The 3D models were imported into the simulation surgery platform for virtual surgery to prepare for subsequent surgeries. The cosmetic outcomes of the patients were evaluated 6 months after the surgery. Another 18 patients with breast cancer who underwent laparoscopic latissimus dorsi muscle breast reconstruction without using 3D visualization technique from January to December, 2014 served as the control group. The data of the operative time, intraoperative blood loss and postoperative appearance of the breasts were analyzed. RESULTS: The reconstructed 3D model clearly displayed the anatomical structures of the breast, armpit, latissimus dorsi muscle and vessels and their anatomical relationship in all the 30 cases. Immediate breast reconstruction was performed successfully in all the cases with median operation time of 226 min (range, 210 to 420 min), a median blood loss of 95 mL (range, 73 to 132 mL). Evaluation of the appearance of the breast showed excellent results in 22 cases, good appearance in 6 cases and acceptable appearance in 2 cases. In the control group, the median operation time was 283 min (range, 256 to 313 min) and the median blood loss was 107 mL (range, 79 to 147 mL) with excellent appearance of the breasts in 10 cases, good appearance in 4 cases and acceptable appearance in 4 cases. CONCLUSION: 3D reconstruction technique can clearly display the morphology of the latissimus dorsi and the thoracic dorsal artery, allows calculation of the volume of the breast and the latissimus dorsi, and helps in defining the scope of resection of the latissimus dorsi to avoid injuries of the pedicled vessels. This technique also helps to shorten the operation time, reduce intraoperative bleeding, and improve the appearance of the reconstructed breast using pedicled latissimus dorsi muscle flap. PMID- 28801299 TI - [Effect of bortezomib in inducing apoptosis of imatinib-resistant K562 cells and the mechanism]. AB - OBJECTIVE: To investigate the effect of bortezomib in inducing apoptosis in imatinib-resistant K562 (K562R) cells and its possible mechanism. METHODS: K562 cells were cultured in gradient concentrations of imatinib for several months to generate imatinib-resistant K562 cells. The viability of K562R cells treated with bortezomib was measured using CCK-8 cell proliferation assay, and the cell apoptosis was analyzed by flow cytometry with annexin V/PI dual staining. Western blotting was used to detect the protein expressions of Mcl-1,Bcl-2 and Bcr/Abl. RESULTS: K562R cell line was successfully established, which showed 31.8 folds of imatinib resistance compared with the na?ve cells. Bortezomib treatment produced dose- and time-dependent inhibitory effect on the proliferation of both K562 cells and K562R cells and dose-dependently induced apoptosis in K562R cells. Combination of bortezomib with imatinib significantly enhanced the apoptosis of the cells. Western blotting showed that bortezomib treatment dose-dependently decreased the protein levels of both Mcl-1and Bcr/Abl in K562R cells without affecting bcl-2 protein expression. CONCLUSION: Bortezomib can inhibit the proliferation of K562R cells and induce cell apoptosis possibly by down regulating Mcl-1 and Bcr/Abl expression and enhancing Mcl-1 cleavage. PMID- 28801300 TI - [Carotid artery stenosis treated with modified carotid endarterectomy: report of two cases]. AB - OBJECTIVE: Based on standard carotid endarterectomy, we performed modified carotid endarterectomy in two cases of carotid artery stenosis by changing the direction of the carotid artery incision to avoid restenosis of the internal carotid artery without using a patch. The two patients recovered smoothly without any complications. Compared with eversion or patch endarterectomy, this modified carotid endarterectomy avoids restenosis of the carotid artery and shortens operation time. PMID- 28801301 TI - Exploring User Learnability and Learning Performance in an App for Depression: Usability Study. AB - BACKGROUND: Mental health apps tend to be narrow in their functioning, with their focus mostly being on tracking, management, or psychoeducation. It is unclear what capability such apps have to facilitate a change in users, particularly in terms of learning key constructs relating to behavioral interventions. Thought Challenger (CBITs, Chicago) is a skill-building app that engages users in cognitive restructuring, a core component of cognitive therapy (CT) for depression. OBJECTIVE: The purpose of this study was to evaluate the learnability and learning performance of users following initial use of Thought Challenger. METHODS: Twenty adults completed in-lab usability testing of Thought Challenger, which comprised two interactions with the app. Learnability was measured via completion times, error rates, and psychologist ratings of user entries in the app; learning performance was measured via a test of CT knowledge and skills. Nonparametric tests were conducted to evaluate the difference between individuals with no or mild depression to those with moderate to severe depression, as well as differences in completion times and pre- and posttests. RESULTS: Across the two interactions, the majority of completion times were found to be acceptable (5 min or less), with minimal errors (1.2%, 10/840) and successful completion of CT thought records. Furthermore, CT knowledge and skills significantly improved after the initial use of Thought Challenger (P=.009). CONCLUSIONS: The learning objectives for Thought Challenger during initial uses were successfully met in an evaluation with likely end users. The findings therefore suggest that apps are capable of providing users with opportunities for learning of intervention skills. PMID- 28801302 TI - Improving Patient-Centered Care for Young People in General Practice With a Codesigned Screening App: Mixed Methods Study. AB - BACKGROUND: Despite experiencing a high prevalence and co-occurrence of mental health disorders and health-compromising behaviors, young people tend not to seek professional help for these concerns. However, they do regularly attend primary care, making primary care providers ideally situated to identify and discuss mental health and lifestyle issues as part of young people's routine health care. OBJECTIVE: The aim was to investigate whether using a codesigned health and lifestyle-screening app, Check Up GP, in general practice influenced young people's assessment of the quality of their care (measures of patient-centered care and youth friendliness), and their disclosure of sensitive issues. In addition, this study aimed to explore young people's acceptance and experience of using a screening app during regular health care. METHODS: This was a mixed methods implementation study of Check Up GP with young people aged 14 to 25 years attending a general practice clinic in urban Melbourne, Australia. A 1-month treatment-as-usual group was compared to a 2-month intervention group in which young people and their general practitioners (GPs) used Check Up GP. Young people in both groups completed an exit survey immediately after their consultation about disclosure, patient-centered and youth-friendly care, and judgment. In addition, participants in the intervention group were surveyed about app acceptability and usability and their willingness to use it again. Semistructured interviews with participants in the intervention group expanded on themes covered in the survey. RESULTS: The exit survey was completed by 30 young people in the treatment-as-usual group and 85 young people in the intervention group. Young people using Check Up GP reported greater disclosure of health issues (P<.001), and rated their GP higher in patient-centered care: communication and partnership (P=.01), personal relationship (P=.01), health promotion (P=.03), and interest in effect on life (P<.001). No differences were found on core indicators of youth friendly care: trust, level of comfort, expectations met, and time to ask questions. In all, 86% (73/85) of young people felt the app was a "good idea" and only 1% (1/85) thought it a "bad idea." Thematic analysis of qualitative interviews with 14 participants found that Check Up GP created scope to address unmet health needs and increased sense of preparedness, with use moderated by honesty, motivation, app content and functionality, and app administration. CONCLUSIONS: Integrating a health and lifestyle-screening app into face-to-face care can enrich young people's experience of seeing their GP, create scope to identify and address unmet health needs, and increase patient-centered care. Further research is needed to investigate the effect of using a health and lifestyle-screening app in a diverse range of clinic types and settings, and with a diverse range of GPs and youth. PMID- 28801303 TI - Health Care Providers' Knowledge of HPV Vaccination, Barriers, and Strategies in a State With Low HPV Vaccine Receipt: Mixed-Methods Study. AB - BACKGROUND: Human papillomavirus (HPV) vaccination is below national goals in the United States. Health care providers are at the forefront of improving vaccination in the United States, given their close interactions with patients and parents. OBJECTIVE: The objective of this study was to assess the associations between demographic and practice characteristics of the health care providers with the knowledge of HPV vaccination and HPV vaccine guidelines. Furthermore, our aim was to contextualize the providers' perceptions of barriers to HPV vaccination and strategies for improving vaccination in a state with low HPV vaccine receipt. METHODS: In this mixed-methods study, participating providers (N=254) were recruited from statewide pediatric, family medicine, and nursing organizations in Utah. Participants completed a Web-based survey of demographics, practice characteristics, HPV vaccine knowledge (<=10 correct vs 11 12 correct answers), and knowledge of HPV vaccine guidelines (correct vs incorrect). Demographic and practice characteristics were compared using chi square and Fisher exact tests for HPV knowledge outcomes. Four open-ended questions pertaining to the barriers and strategies for improving HPV vaccination were content analyzed. RESULTS: Family practice providers (52.2%, 71/136; P=.001), institutional or university clinics (54.0%, 20/37; P=.001), and busier clinics seeing 20 to 29 patients per day (50.0%, 28/56; P=.04) had the highest proportion of respondents with high HPV vaccination knowledge. Older providers aged 40 to 49 years (85.1%, 57/67; P=.04) and those who were a Vaccines for Children provider (78.7%, 133/169; P=.03) had the highest proportion of respondents with high knowledge of HPV vaccine recommendations. Providers perceived the lack of parental education to be the main barrier to HPV vaccination. They endorsed stronger, consistent, and more direct provider recommendations for HPV vaccination delivered to parents through printed materials available in clinical settings and public health campaigns. Hesitancy to recommend the HPV vaccine to patients persisted among some providers. CONCLUSIONS: Providers require support to eliminate barriers to recommending HPV vaccination in clinical settings. Additionally, providers endorsed the need for parental educational materials and instructions on framing HPV vaccination as a priority cancer prevention mechanism for all adolescents. PMID- 28801304 TI - How Accurate Is Your Activity Tracker? A Comparative Study of Step Counts in Low Intensity Physical Activities. AB - BACKGROUND: As commercially available activity trackers are being utilized in clinical trials, the research community remains uncertain about reliability of the trackers, particularly in studies that involve walking aids and low-intensity activities. While these trackers have been tested for reliability during walking and running activities, there has been limited research on validating them during low-intensity activities and walking with assistive tools. OBJECTIVE: The aim of this study was to (1) determine the accuracy of 3 Fitbit devices (ie, Zip, One, and Flex) at different wearing positions (ie, pants pocket, chest, and wrist) during walking at 3 different speeds, 2.5, 5, and 8 km/h, performed by healthy adults on a treadmill; (2) determine the accuracy of the mentioned trackers worn at different sites during activities of daily living; and (3) examine whether intensity of physical activity (PA) impacts the choice of optimal wearing site of the tracker. METHODS: We recruited 15 healthy young adults to perform 6 PAs while wearing 3 Fitbit devices (ie, Zip, One, and Flex) on their chest, pants pocket, and wrist. The activities include walking at 2.5, 5, and 8 km/h, pushing a shopping cart, walking with aid of a walker, and eating while sitting. We compared the number of steps counted by each tracker with gold standard numbers. We performed multiple statistical analyses to compute descriptive statistics (ie, ANOVA test), intraclass correlation coefficient (ICC), mean absolute error rate, and correlation by comparing the tracker-recorded data with that of the gold standard. RESULTS: All the 3 trackers demonstrated good-to-excellent (ICC>0.75) correlation with the gold standard step counts during treadmill experiments. The correlation was poor (ICC<0.60), and the error rate was significantly higher in walker experiment compared to other activities. There was no significant difference between the trackers and the gold standard in the shopping cart experiment. The wrist worn tracker, Flex, counted several steps when eating (P<.01). The chest tracker was identified as the most promising site to capture steps in more intense activities, while the wrist was the optimal wearing site in less intense activities. CONCLUSIONS: This feasibility study focused on 6 PAs and demonstrated that Fitbit trackers were most accurate when walking on a treadmill and least accurate during walking with a walking aid and for low-intensity activities. This may suggest excluding participants with assistive devices from studies that focus on PA interventions using commercially available trackers. This study also indicates that the wearing site of the tracker is an important factor impacting the accuracy performance. A larger scale study with a more diverse population, various activity tracker vendors, and a larger activity set are warranted to generalize our results. PMID- 28801305 TI - Peter Joseph Wilkinson Monks. PMID- 28801306 TI - Inducible Activation of MyD88 and CD40 in CAR T Cells Results in Controllable and Potent Antitumor Activity in Preclinical Solid Tumor Models. AB - Adoptive immunotherapy with T cells expressing chimeric antigen receptors (CAR) has had limited success for solid tumors in early-phase clinical studies. We reasoned that introducing into CAR T cells an inducible costimulatory (iCO) molecule consisting of a chemical inducer of dimerization (CID)-binding domain and the MyD88 and CD40 signaling domains would improve and control CAR T-cell activation. In the presence of CID, T cells expressing HER2-CARzeta and a MyD88/CD40-based iCO molecule (HER2zeta.iCO T cells) had superior T-cell proliferation, cytokine production, and ability to sequentially kill targets in vitro relative to HER2zeta.iCO T cells without CID and T cells expressing HER2 CAR.CD28zeta. HER2zeta.iCO T cells with CID also significantly improved survival in vivo in two xenograft models. Repeat injections of CID were able to further increase the antitumor activity of HER2zeta.iCO T cells in vivo Thus, expressing MyD88/CD40-based iCO molecules in CAR T cells has the potential to improve the efficacy of CAR T-cell therapy approaches for solid tumors.Significance: Inducible activation of MyD88 and CD40 in CAR T cells with a small-molecule drug not only enhances their effector function, resulting in potent antitumor activity in preclinical solid tumors, but also enables their remote control post infusion. Cancer Discov; 7(11); 1306-19. (c)2017 AACR.This article is highlighted in the In This Issue feature, p. 1201. PMID- 28801307 TI - Loss of MutL Disrupts CHK2-Dependent Cell-Cycle Control through CDK4/6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer. AB - Significant endocrine therapy-resistant tumor proliferation is present in >=20% of estrogen receptor-positive (ER+) primary breast cancers and is associated with disease recurrence and death. Here, we uncover a link between intrinsic endocrine therapy resistance and dysregulation of the MutL mismatch repair (MMR) complex (MLH1/3, PMS1/2), and demonstrate a direct role for MutL complex loss in resistance to all classes of endocrine therapy. We find that MutL deficiency in ER+ breast cancer abrogates CHK2-mediated inhibition of CDK4, a prerequisite for endocrine therapy responsiveness. Consequently, CDK4/6 inhibitors (CDK4/6i) remain effective in MutL-defective ER+ breast cancer cells. These observations are supported by data from a clinical trial where a CDK4/6i was found to strongly inhibit aromatase inhibitor-resistant proliferation of MutL-defective tumors. These data suggest that diagnostic markers of MutL deficiency could be used to direct adjuvant CDK4/6i to a population of patients with breast cancer who exhibit marked resistance to the current standard of care.Significance: MutL deficiency in a subset of ER+ primary tumors explains why CDK4/6 inhibition is effective against some de novo endocrine therapy-resistant tumors. Therefore, markers of MutL dysregulation could guide CDK4/6 inhibitor use in the adjuvant setting, where the risk benefit ratio for untargeted therapeutic intervention is narrow. Cancer Discov; 7(10); 1168-83. (c)2017 AACR.This article is highlighted in the In This Issue feature, p. 1047. PMID- 28801310 TI - Waiting list for elective surgery tops four million for first time since 2007. PMID- 28801309 TI - Determining the mechanisms of dietary turnip rapeseed oil on cholesterol metabolism in men with metabolic syndrome. AB - We have earlier reported the reduction of total cholesterol, low-density lipoprotein (LDL) cholesterol and oxidized LDL caused by short-term modification of diet with cold-pressed turnip rapeseed oil (CPTRO) instead of butter. The aim of this supplementary study was to determine whether the beneficial effects resulted from altered cholesterol metabolism during the intervention.Thirty-seven men with metabolic syndrome (MetS) completed an open, randomized and balanced crossover study. Subjects' usual diet was supplemented with either 37.5 g of butter or 35 mL of CPTRO for 6-8 weeks. Otherwise normal dietary habits and physical activity were maintained without major variations. Serum non-cholesterol sterols were assayed with gas-liquid chromatography and used as surrogate markers of whole-body cholesterol synthesis and absorption efficiency. Serum proprotein convertase subtilisin/kexin type 9 (PCSK9) concentration was analyzed with Quantikine ELISA Immunoassay. Serum cholesterol synthesis markers and serum cholestanol (absorption marker), all as ratios to cholesterol, did not differ between the periods. Serum campesterol and sitosterol ratios to cholesterol were significantly increased after the administration of CPTRO resulting from the increased intake of 217 mg/day of plant sterols in CPTRO. Serum PCSK9 concentration did not differ between CPTRO and butter periods.The reduction in serum cholesterol by 7.2% after consumption of rapeseed oil could not be explained by changes in cholesterol absorption, synthesis or PCSK9 metabolism in MetS.ClinicalTrials.gov NCT01119690. PMID- 28801311 TI - Ethical issues when modelling brain disorders innon-human primates. AB - Non-human animal models of human diseases advance our knowledge of the genetic underpinnings of disease and lead to the development of novel therapies for humans. While mice are the most common model organisms, their usefulness is limited. Larger animals may provide more accurate and valuable disease models, but it has, until recently, been challenging to create large animal disease models. Genome editors, such as Clustered Randomised Interspersed Palindromic Repeat (CRISPR), meet some of these challenges and bring routine genome engineering of larger animals and non-human primates (NHPs) well within reach. There is growing interest in creating NHP models of brain disorders such as autism, depression and Alzheimer's, which are very difficult to model or study in other organisms, including humans. New treatments are desperately needed for this set of disorders. This paper is novel in asking: Insofar as NHPs are being considered for use as model organisms for brain disorders, can this be done ethically? The paper concludes that it cannot. Notwithstanding ongoing debate about NHPs' moral status, (1) animal welfare concerns, (2) the availability of alternative methods of studying brain disorders and (3) unmet expectations of benefit justify a stop on the creation of NHP model organisms to study brain disorders. The lure of using new genetic technologies combined with the promise of novel therapeutics presents a formidable challenge to those who call for slow, careful, and only necessary research involving NHPs. But researchers should not create macaques with social deficits or capuchin monkeys with memory deficits just because they can. PMID- 28801312 TI - Bioethics and multiculturalism: nuancing the discussion. AB - In his recent analysis of multiculturalism, Tom Beauchamp has argued that those who implement multicultural reasoning in their arguments against common morality theories, such as his own, have failed to understand that multiculturalism is neither a form of moral pluralism nor ethical relativism but is rather a universalistic moral theory in its own right. Beauchamp's position is indeed on the right track in that multiculturalists do not consider themselves ethical relativists. Yet, Beauchamp tends to miss the mark when he argues that multiculturalism is in effect a school of thought that endorses a form of moral universalism that is akin to his own vision of a common morality. As a supporter of multiculturalism, I would like to discuss some aspects of Beauchamp's comments on multiculturalism and clarify what a multicultural account of public bioethics might look like. Ultimately, multiculturalism is purported as a means of managing diversity in the public arena and should not be thought of as endorsing either a version of moral relativism or a universal morality. By simultaneously refraining from the promotion of a comprehensive common moral system while it attempts to avoid a collapse into relativism, multiculturalism can serve as the ethico political framework in which diverse moralities can be managed and in which opportunities for ethical dialogue, debate and deliberation on the prospects of common bioethical norms are made possible. PMID- 28801308 TI - EGFR Mutations Compromise Hypoxia-Associated Radiation Resistance through Impaired Replication Fork-Associated DNA Damage Repair. AB - EGFR signaling has been implicated in hypoxia-associated resistance to radiation or chemotherapy. Non-small cell lung carcinomas (NSCLC) with activating L858R or DeltaE746-E750 EGFR mutations exhibit elevated EGFR activity and downstream signaling. Here, relative to wild-type (WT) EGFR, mutant (MT) EGFR expression significantly increases radiosensitivity in hypoxic cells. Gene expression profiling in human bronchial epithelial cells (HBEC) revealed that MT-EGFR expression elevated transcripts related to cell cycle and replication in aerobic and hypoxic conditions and downregulated RAD50, a critical component of nonhomologous end joining and homologous recombination DNA repair pathways. NSCLCs and HBEC with MT-EGFR revealed elevated basal and hypoxia-induced gamma H2AX-associated DNA lesions that were coincident with replication protein A in the S-phase nuclei. DNA fiber analysis showed that, relative to WT-EGFR, MT-EGFR NSCLCs harbored significantly higher levels of stalled replication forks and decreased fork velocities in aerobic and hypoxic conditions. EGFR blockade by cetuximab significantly increased radiosensitivity in hypoxic cells, recapitulating MT-EGFR expression and closely resembling synthetic lethality of PARP inhibition.Implications: This study demonstrates that within an altered DNA damage response of hypoxic NSCLC cells, mutant EGFR expression, or EGFR blockade by cetuximab exerts a synthetic lethality effect and significantly compromises radiation resistance in hypoxic tumor cells. Mol Cancer Res; 15(11); 1503-16. (c)2017 AACR. PMID- 28801313 TI - Seven day service doesn't improve clinical outcomes, researchers find. PMID- 28801315 TI - Changing gender in medical records needs to be made easier. PMID- 28801316 TI - Barriers to the use of buccal and intranasal fentanyl for breakthrough pain in paediatric palliative care: an exploratory survey. PMID- 28801314 TI - Macrophage Migration Inhibitory Factor Limits Renal Inflammation and Fibrosis by Counteracting Tubular Cell Cycle Arrest. AB - Renal fibrosis is a common underlying process of progressive kidney diseases. We investigated the role of macrophage migration inhibitory factor (MIF), a pleiotropic proinflammatory cytokine, in this process. In mice subjected to unilateral ureteral obstruction, genetic deletion or pharmacologic inhibition of MIF aggravated fibrosis and inflammation, whereas treatment with recombinant MIF was beneficial, even in established fibrosis. In two other models of progressive kidney disease, global Mif deletion or MIF inhibition also worsened fibrosis and inflammation and associated with worse kidney function. Renal MIF expression was reduced in tubular cells in fibrotic compared with healthy murine and human kidneys. Bone marrow chimeras showed that Mif expression in bone marrow-derived cells did not affect fibrosis and inflammation after UUO. However, Mif gene deletion restricted to renal tubular epithelial cells aggravated these effects. In LPS-stimulated tubular cell cultures, Mif deletion led to enhanced G2/M cell cycle arrest and increased expression of the CDK inhibitor 1B (p27Kip1) and of proinflammatory and profibrotic mediators. Furthermore, MIF inhibition reduced tubular cell proliferation in vitro In all three in vivo models, global Mif deletion or MIF inhibition caused similar effects and attenuated the expression of cyclin B1 in tubular cells. Mif deletion also resulted in reduced tubular cell apoptosis after UUO. Recombinant MIF exerted opposing effects on tubular cells in vitro and in vivo Our data identify renal tubular MIF as an endogenous renoprotective factor in progressive kidney diseases, raising the possibility of pharmacologic intervention with MIF pathway agonists, which are in advanced preclinical development. PMID- 28801317 TI - Responses to assisted suicide requests: an interview study with Swiss palliative care physicians. AB - OBJECTIVES: Assisted suicide in Switzerland is mainly performed by right-to-die societies. Medical involvement is limited to the prescription of the drug and certification of eligibility. Palliative care has traditionally been perceived as generally opposed to assisted suicide, but little is known about palliative care physicians' involvement in assisted suicide practices. This paper aims to describe their perspectives and involvement in assisted suicide practices. METHODS: A qualitative interview study was conducted with 23 palliative care physicians across Switzerland. Thematic analysis was used to interpret data. RESULTS: Swiss palliative care physicians regularly receive assisted suicide requests while none reported having received specific training in managing these requests. Participants reported being involved in assisted suicide decision making most were not willing to prescribe the lethal drug. After advising patients of the limits on their involvement in assisted suicide, the majority explored the origins of the patient's request and offered alternatives. Many participants struggled to reconcile their understanding of palliative care principles with patients' wishes to exercise their autonomy. The majority of participants had no direct contact with right-to-die societies, many desired better collaboration. A desire was voiced for a more structured debate on assisted suicide availability in hospitals and clearer legal and institutional frameworks. CONCLUSIONS: The Swiss model of assisted suicide gives palliative care physicians opportunities to develop roles which are compatible with each practitioner's values, but may not correspond to patients' expectations. Specific education for all palliative care professionals and more structured ways to manage communication about assisted suicide are warranted. PMID- 28801318 TI - From DNA binding to transcriptional activation: Is the TALE complete? AB - How transcription factors (TFs) control enhancer and promoter functions to effect changes in gene expression is an important question. In this issue, Hau et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201701154) show that the TALE TF MEIS recruits the histone modifier PARP1/ARTD1 at promoters to decompact chromatin and activate transcription. PMID- 28801320 TI - In stable COPD, long-acting muscarinic antagonist plus long-acting beta-agonists resulted in less exacerbations, pneumonia and larger improvement in FEV 1 than long-acting beta-agonists plus inhaled corticosteroids. PMID- 28801321 TI - Massive ascites, pelvic mass, elevated CA-125 and weight loss: think outside the 'ovaries'. AB - A 44-year-old woman presented with 3 months' history of painless progressive abdominal distension and weight loss of more than 15 kg. Clinically a pelviabdominal mass with ascites was detected. CT scan of the pelvis and abdomen showed a subserosal leiomyoma with huge amount of ascites. Cancer Antigen (CA) 125 was 546 kU/L. Exploratory laparotomy with myomectomy was done and this was followed by dramatic improvement postoperatively. PMID- 28801322 TI - Portal vein aneurysm in thalassaemia. AB - Arterial aneurysms are more common than visceral venous aneurysms. Portal vein aneurysms being the most common type of visceral venous aneurysms. Here, we present an 18-year-old young woman with thalassaemia major, who presented with headache, palpitation, shortness of breath and a recent increase in blood transfusion rate. On clinical examination, she had hepatosplenomegaly. Ultrasonography revealed hepatosplenomegaly with fusiform dilatation of extrahepatic portal vein, which was confirmed to be portal vein aneurysm on contrast enhanced CT. Though portal vein aneurysms were previously thought to be rare, recently they are increasingly diagnosed with the use of cross-sectional imaging. Recognition of this finding can help to avoid potential confusion with other periportal cystic masses of different aetiologies, especially on sonography. PMID- 28801323 TI - Transvaginal postpartum manual removal of a prolapsed submucous leiomyoma, initially diagnosed hybrid predominantly intramural. AB - We present a rare case of a large infarcted submucous fibroid removed manually after a normal vaginal delivery. This patient was known to have a large postero fundal hybrid predominantly intramural uterine fibroid, measuring 11 x 10 cm in diameter and diagnosed 2 years prior to last conception. Thirty-five days postpartum, she presented with severe lower abdominal pain and foul smell per vaginum. Abdominal examination revealed a very tender bulky uterus at 24 weeks size, and vaginal examination revealed a big fleshy smelly mass with friable surface just bulging from a dilated cervix. Examination under anaesthesia revealed a very foul smelly large pedunculated submucous fibroid that was felt through a dilated cervix. It was deliverable vaginally, so the submucous leiomyoma was removed manually, a procedure similar to manual removal of placenta. Histopathology examination confirmed an infarcted massive fibroid. PMID- 28801319 TI - Pet10p is a yeast perilipin that stabilizes lipid droplets and promotes their assembly. AB - Pet10p is a yeast lipid droplet protein of unknown function. We show that it binds specifically to and is stabilized by droplets containing triacylglycerol (TG). Droplets isolated from cells with a PET10 deletion strongly aggregate, appear fragile, and fuse in vivo when cells are cultured in oleic acid. Pet10p binds early to nascent droplets, and their rate of appearance is decreased in pet10Delta Moreover, Pet10p functionally interacts with the endoplasmic reticulum droplet assembly factors seipin and Fit2 to maintain proper droplet morphology. The activity of Dga1p, a diacylglycerol acyltransferase, and TG accumulation were both 30-35% lower in the absence of Pet10p. Pet10p contains a PAT domain, a defining property of perilipins, which was not previously known to exist in yeast. We propose that the core functions of Pet10p and other perilipins extend beyond protection from lipases and include the preservation of droplet integrity as well as collaboration with seipin and Fit2 in droplet assembly and maintenance. PMID- 28801324 TI - Mechanical thrombectomy for repeated cerebral tumor embolism from a thoracic sarcomatoid carcinoma. AB - Cerebral embolism originating from intracardiac tumors represents a rare cause of stroke and has been documented in both adult and pediatric populations. We present a patient recently diagnosed with a right pulmonary hilum tumor, invading the pulmonary veins and the left atrium. Two consecutive episodes of large cerebral vessel occlusion in separate vascular territories occurred in the same day and were treated by mechanical thrombectomy. Embolic material retrieved on both occasions contained tumor fragments with peripheral endothelialization. To our knowledge, this is the first report with histological confirmation of cerebral embolism from an invasive extracardiac tumor. PMID- 28801325 TI - Aluminium phosphide poisoning with severe cardiac dysfunction and the role of digoxin. AB - Aluminium phosphide (ALP) is a common cause of suicidal poisoning in India where it is easily available and commonly known as 'rice tablet'. In rural areas of India, it is still used to protect rice and stored grains from rodents and pests. 1 There is no specific antidote for phosphide poisoning and treatment involves meticulous supportive care. Ingestion can lead to severe cardiac suppression and cardiogenic shock. For patients poisoned with ALP who continue to have refractory shock with persistent myocardial suppression despite the use of adrenergic inotropic agents, the addition of digoxin may be beneficial. We present a case where digoxin was utilised with beneficial patient outcomes. PMID- 28801326 TI - Sternal cleft malformation in a newborn. PMID- 28801327 TI - Insulin-mediated lipohypertrophy: an uncommon cause of diabetic ketoacidosis. PMID- 28801328 TI - Cytomegalovirus-related transverse myelitis in an immunocompetent host: a subacute onset of an immune-mediated disease? AB - We report a case of transverse myelitis in an immunocompetent host with an atypical long onset of symptoms. A 56-year-old man was admitted to the hospital reporting 5 months of progressive ascending lower extremity weakness and numbness, inability to walk, bowel incontinence,urinary retention and several episodes of nausea and vomiting. MRI showed moderate spinal swelling and multiple hyperintense signal changes on cervical levels C2-C5 and thoracic levels T1-T3. Cerebrospinal fluid (CSF) showed pleocytosis and was positive for anti cytomegalovirus (CMV) IgG intrathecal antibodies, but the CSF PCR for CMV was negative. The diagnosis of immune-mediated CMV-related transverse myelitis was established and the patient was treated with methylprednisolone and valgancyclovir. The patient had poor recovery and remained paraplegic at discharge. PMID- 28801329 TI - Postcardiac injury syndrome and stroke following permanent pacemaker insertion. AB - An 80-year-old woman initially presented with an episode of pleuritic chest pain 10 days after implantation of a dual chamber permanent pacemaker. She returned to hospital a day later with vomiting and fever. She was found to have new atrial fibrillation in addition to right-sided weakness and dysarthria. An infarct in the left anterior inferior cerebellar artery territory was later confirmed on CT. She continued to have recurrent febrile episodes associated with vomiting and dyspnoea. Extensive investigations for infection were negative, and her symptoms were initially attributed to aspiration pneumonia. The patient gradually deteriorated despite antibiotics and became progressively short of breath, with development of large pleural and pericardial effusions. A diagnosis of postcardiac injury syndrome was made after exclusion of other differentials. The patient recovered well after pleurocentesis, pericardiocentesis and a pericardial window, with resolution of symptoms without further medical therapy. PMID- 28801330 TI - Anterior cervical osteophytosis as a cause of dyspnoea and stridor. PMID- 28801331 TI - Autoimmune gastrointestinal dysmotility due to small cell lung cancer. AB - The diagnosis of autoimmune gastrointestinal dysmotility requires a high level of clinical suspicion when standard work-up is unrevealing. We report the case of a 56-year-old male patient with history of tobacco use and a subacute presentation of weight loss, vomiting and cerebellar ataxia. The discovery of paraneoplastic type 1 antineuronal nuclear antibodies and neuronal acetylcholine receptor antibodies led to further directed imaging and diagnostic studies in spite of prior negative chest imaging. Bronchoscopy with endobronchial ultrasound was used to confirm a diagnosis of small cell lung cancer and paraneoplastic syndrome as the cause of the presenting upper gastrointestinal symptoms. PMID- 28801333 TI - Valsalva haemorrhagic retinopathy in pregnancy after yoga. AB - A 35-year-old pregnant Caucasian woman at 27 weeks gestation presented with sudden onset painless loss of vision and a large floater in her left eye while doing yoga. She was found to have a dense vitreous haemorrhage with a small preretinal haemorrhage. Ultrasound imaging confirmed the haemorrhage and showed no other retinal damage. She was diagnosed with valsalva haemorrhagic retinopathy and was treated conservatively. After 5 months of follow-up, this woman had had a normal delivery and her haemorrhages and vision loss had resolved. PMID- 28801332 TI - Acute myeloid leukaemia masquerading as a primary CNS tumour. AB - In children with newly diagnosed acute myeloid leukaemia (AML), myeloid sarcomas (MS) of the central nervous system (CNS) are rare. Since MS involving the CNS are potentially curable, timely recognition is paramount. Establishing a diagnosis may be problematic as they can easily mimic primary CNS neoplasms. We report the case of a 5-year-old boy with AML with t(8;21)(q22;q22) rearrangement who presented with a massive intracranial MS and rapid clinical deterioration suggestive of a meningioma or a primitive neuroectodermal tumour. The peripheral smear showed blasts with Auer rods. Urgent chemotherapy was started for AML with presumptive CNS MS. The mass resolved with chemotherapy, and treatment was consolidated with radiotherapy. Although exceedingly rare, this case highlights the potential for MS to present similarly to a primary CNS tumour. MS should be part of the differential diagnosis as part of a CNS mass, particularly if the complete blood count is abnormal. PMID- 28801334 TI - Family with clots: antithrombin deficiency. PMID- 28801335 TI - Hypercapnia-induced cerebral oedema in a patient with COPD exacerbation: a rare and under-recognised entity. PMID- 28801336 TI - Isolated clival metastasis: a rare presentation of renal cell carcinoma. AB - Renal cell carcinoma accounts for 3% of all adult malignancies. Usual sites of metastasis are lymph nodes, lungs, bone, liver and brain. We describe a patient who presented with complaints of holocranial headache and diplopia. MRI of the head showed a clival-based lesion with associated bony erosion. With suspicion of a metastatic lesion, an ultrasonogram of the abdomen was done which showed a left renal mass that enhanced on contrast-enhanced CT. There were no other metastatic foci. Patient underwent radiotherapy for the clival lesion. This case report emphasises on the evaluation of clival lesion with cranial neuropathies for a possibility of a renal primary tumour. PMID- 28801337 TI - Stabbing pain in the throat after teeth cleaning. PMID- 28801339 TI - Rare disease levels of evidence: Time for a new bar? PMID- 28801338 TI - Rituximab as treatment for anti-MuSK myasthenia gravis: Multicenter blinded prospective review. AB - OBJECTIVE: To evaluate the efficacy of rituximab in treatment of anti-muscle specific kinase (MuSK) myasthenia gravis (MG). METHODS: This was a multicenter, blinded, prospective review, comparing anti-MuSK-positive patients with MG treated with rituximab to those not treated with rituximab. The primary clinical endpoint was the Myasthenia Gravis Status and Treatment Intensity (MGSTI), a novel outcome that combines the Myasthenia Gravis Foundation of America (MGFA) postintervention status (PIS) and the number and dosages of other immunosuppressant therapies used. A priori, an MGSTI of level <=2 was used to define a favorable outcome. Secondary outcomes included modified MGFA PIS of minimal manifestations or better, mean/median prednisone dose, and mean/median doses of other immunosuppressant drugs. RESULTS: Seventy-seven of 119 patients with anti-MuSK MG evaluated between January 1, 2005, and January 1, 2015, at 10 neuromuscular centers were selected for analysis after review of limited clinical data by a blinded expert panel. An additional 22 patients were excluded due to insufficient follow-up. Baseline characteristics were similar between the rituximab-treated patients (n = 24) and the controls (n = 31). Median follow-up duration was >3.5 years. At last visit, 58% (14/24) of rituximab-treated patients reached the primary outcome compared to 16% (5/31) of controls (p = 0.002). Number needed to treat for the primary outcome is 2.4. At last visit, 29% of rituximab-treated patients were taking prednisone (mean dose 4.5 mg/day) compared to 74% of controls (mean dose 13 mg/day) (p = 0.001 and p = 0.005). CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with anti-MuSK MG, rituximab increased the probability of a favorable outcome. PMID- 28801340 TI - Rare case of ribose 5 phosphate isomerase deficiency with slowly progressive leukoencephalopathy. PMID- 28801341 TI - Tetrabenazine and subthalamic stimulation in graft-induced dyskinesias. PMID- 28801342 TI - Terence John Cain. PMID- 28801343 TI - Trainee GP who was warned over falsifying timesheets to get new sanction after GMC appeal. PMID- 28801344 TI - Frontline Science: Macrophage-derived exosomes promote neutrophil necroptosis following hemorrhagic shock. AB - Hemorrhagic shock (HS) renders patients susceptible to development of systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) through mechanisms that are, as yet, unclear. Cell necroptosis, a form of regulated inflammatory cell death, is one of the mechanisms that controls cell release of inflammatory mediators from innate immune cells, such as polymorphonuclear neutrophils (PMNs), and critically regulates the progress of inflammation. In this study, we investigated the mechanisms of alveolar macrophage (AMphi) effects on PMN necroptosis following HS. With the use of in vivo and ex vivo HS models, we reveal a novel function of shock-activated AMphi in promoting PMN necroptosis. We demonstrate that exosomes released from HS activated AMphi induce mainly NADPH oxidase-derived reactive oxygen species (ROS) production inside PMNs and subsequent promotion of necroptosis. These findings explore a previously unidentified pathway of AMphi-PMN cross-talk, which causes enhanced PMN necroptosis and subsequent exaggerated post-HS lung inflammation. The targeting of this PMN death pathway may serve as a new therapeutic strategy for treatment of post-HS SIRS. PMID- 28801345 TI - Molecular basis for increased susceptibility of Indigenous North Americans to seropositive rheumatoid arthritis. AB - OBJECTIVE: The pathogenetic mechanisms by which HLA-DRB1 alleles are associated with anticitrullinated peptide antibody (ACPA)-positive rheumatoid arthritis (RA) are incompletely understood. RA high-risk HLA-DRB1 alleles are known to share a common motif, the 'shared susceptibility epitope (SE)'. Here, the electropositive P4 pocket of HLA-DRB1 accommodates self-peptide residues containing citrulline but not arginine. HLA-DRB1 His/Phe13beta stratifies with ACPA-positive RA, while His13betaSer polymorphisms stratify with ACPA-negative RA and RA protection. Indigenous North American (INA) populations have high risk of early-onset ACPA positive RA, whereby HLA-DRB1*04:04 and HLA-DRB1*14:02 are implicated as risk factors for RA in INA. However, HLA-DRB1*14:02 has a His13betaSer polymorphism. Therefore, we aimed to verify this association and determine its molecular mechanism. METHODS: HLA genotype was compared in 344 INA patients with RA and 352 controls. Structures of HLA-DRB1*1402-class II loaded with vimentin-64Arg59-71, vimentin-64Cit59-71 and fibrinogen beta-74Cit69-81 were solved using X-ray crystallography. Vimentin-64Cit59-71-specific and vimentin59-71-specific CD4+ T cells were characterised by flow cytometry using peptide-histocompatibility leukocyte antigen (pHLA) tetramers. After sorting of antigen-specific T cells, TCRalpha and beta-chains were analysed using multiplex, nested PCR and sequencing. RESULTS: ACPA+ RA in INA was independently associated with HLA DRB1*14:02. Consequent to the His13betaSer polymorphism and altered P4 pocket of HLA-DRB1*14:02, both citrulline and arginine were accommodated in opposite orientations. Oligoclonal autoreactive CD4+ effector T cells reactive with both citrulline and arginine forms of vimentin59-71 were observed in patients with HLA DRB1*14:02+ RA and at-risk ACPA- first-degree relatives. HLA-DRB1*14:02 vimentin59-71-specific and HLA-DRB1*14:02-vimentin-64Cit59-71-specific CD4+ memory T cells were phenotypically distinct populations. CONCLUSION: HLA DRB1*14:02 broadens the capacity for citrullinated and native self-peptide presentation and T cell expansion, increasing risk of ACPA+ RA. PMID- 28801347 TI - A simple algorithmic approach using histology and immunohistochemistry for the current classification of adult diffuse glioma in a resource-limited set-up. AB - AIMS: The WHO 2016 classification of diffuse gliomas combines histological and molecular parameters for diagnosis. However, in view of cost constraints for molecular testing, an economical working formula is essential to reach a meaningful diagnosis in a resource-limited setting. The aim of this study was to establish a practical algorithmic approach using histology and immunohistochemistry (IHC) in the classification of diffuse gliomas in such a set up. METHODS: Diffuse gliomas of WHO grade II and III diagnosed in our institute in the year 2016 were analysed for histological and IHC features, using the markers isocitrate dehydrogenase 1 (IDH1R132H) and alpha thalassemia/mental retardation syndrome X-linked gene (ATRX). Fluorescence in situ hybridisation (FISH) for 1p/19q co-deletion was performed when requested. RESULTS: 449 diffuse gliomas (grades II/III) were included in the study. Integrating histology and IHC features, as per the WHO 2016 guidelines, we derived the following groups: Astrocytoma, IDH-mutant (A,IDH-mt, 37.2%); astrocytoma, not otherwise specified (A,NOS, 12.7%); oligoastrocytoma, NOS (OA,NOS, 4.5%); and oligodendroglioma, NOS (ODG,NOS, 45.6%). FISH was performed in a subset of ODG,NOS, OA,NOS and A,NOS gliomas. This revealed 1p/19q co-deletion in all cases of ODG,NOS, 15.8% of OA,NOS and 37.5% of A,NOS. Sequencing for rare IDH 1/2 mutations was not carried out in this study. CONCLUSION: In a resource-limited set-up, histology with IHC (IDH1(R132H) and ATRX) form the baseline to reasonably derive four histomolecular subgroups of diffuse glioma. Of these, we recommend, OA,NOS and IDH1(R132H)-non mt ODG,NOS to be our priority for performing 1p/19q co-deletion studies in comparison to IDH-mt ODG,NOS, and it would not be mandatory for astrocytoma. Sequencing for rare IDH mutations is advised for A,NOS and OA,NOS groups, but not for the IDH1(R132H)-non-mutant diffuse gliomas with 1p/19q co-deletion. PMID- 28801348 TI - Incidental detection of germline variants of potential clinical significance by massively parallel sequencing in haematological malignancies. AB - Massively parallel sequencing (MPS) technology has become routinely available for diagnosis, prognostication and therapeutic decision-making in haematological malignancies. However, increased throughput and wider coverage of genes can have unintended consequences. Germline variants of potential clinical significance (GVPCSs) detected during cancer testing may have implications for patients and families beyond the biological evaluation of a specific tumour. 721 reports generated from MPS panels used in the routine testing of myeloid and lymphoid malignancies were reviewed and variants within genes of potential germline relevance (TP53, RUNX1, GATA2 and WT1 in all contexts and CBL, KRAS and NRAS in the setting of juvenile myelomonocytic leukaemia) were analysed. A variant allele fraction threshold of >=33.09% for considering germline origin of variants within cancer samples was established. The detection rate of incidental, pathogenic germline variants was 0.42%. Patient education and confirmatory germline sample testing of GVPCSs in appropriate circumstances are recommended. PMID- 28801346 TI - Pan-PPAR agonist IVA337 is effective in experimental lung fibrosis and pulmonary hypertension. AB - OBJECTIVE: To evaluate the antifibrotic effects of the pan-peroxisome proliferator-activated receptor (PPAR) agonist IVA337 in preclinical mouse models of pulmonary fibrosis and related pulmonary hypertension (PH). METHODS: IVA337 has been evaluated in the mouse model of bleomycin-induced pulmonary fibrosis and in Fra-2 transgenic mice, this latter being characterised by non-specific interstitial pneumonia and severe vascular remodelling of pulmonary arteries leading to PH. Mice received two doses of IVA337 (30 mg/kg or 100 mg/kg) or vehicle administered by daily oral gavage up to 4 weeks. RESULTS: IVA337 demonstrated at a dose of 100 mg/kg a marked protection from the development of lung fibrosis in both mouse models compared with mice receiving 30 mg/kg of IVA337 or vehicle. Histological score was markedly reduced by 61% in the bleomycin model and by 50% in Fra-2 transgenic mice, and total lung hydroxyproline concentrations decreased by 28% and 48%, respectively, as compared with vehicle-treated mice. IVA337 at 100 mg/kg also significantly decreased levels of fibrogenic markers in lesional lungs of both mouse models. In addition, IVA337 substantially alleviated PH in Fra-2 transgenic mice by improving haemodynamic measurements and vascular remodelling. In primary human lung fibroblasts, IVA337 inhibited in a dose-dependent manner fibroblast to myofibroblasts transition induced by TGF-beta and fibroblast proliferation mediated by PDGF. CONCLUSION: We demonstrate that treatment with 100 mg/kg IVA337 prevents lung fibrosis in two complementary animal models and substantially attenuates PH in the Fra-2 mouse model. These findings confirm that the pan-PPAR agonist IVA337 is an appealing therapeutic candidate for these cardiopulmonary involvements. PMID- 28801349 TI - C-myc expression in adrenocortical tumours. AB - AIMS: Widespread use of high-resolution imaging techniques and thus increased prevalence of adrenal lesions has made diagnostics of adrenocortical tumours an increasingly important clinical issue. In non-metastatic tumours, diagnosis is based on histology. New or enhanced information for clinicopathological diagnosis, revealing the malignant potential of the tumour, could emerge by means of biomarkers. The connection of proto-oncogene c-myc to adrenocortical neoplasias is poorly known, although the Wnt/beta-catenin pathway, one of the signalling pathways leading to induction of c-myc expression, has been connected to development of adrenocortical neoplasias. We studied c-myc expression in adrenocortical tumours and investigated molecules associated with the signalling pathway of c-myc, including cell cycle-related proteins p27, cyclin E and cyclin D1. METHODS: We studied 195 consecutive adult patients with 197 primary adrenocortical tumours. Histopathological diagnosis was determined by Weiss score and the novel Helsinki score. C-myc, cyclin D1, cyclin E and p27 expressions were determined by immunohistochemistry. RESULTS: Benign adenomas showed prominent nuclear c-myc expression comparable to that of normal adrenocortical cells, whereas carcinomas showed increased cytoplasmic expression. Strong cytoplasmic and weak nuclear c-myc expressions associated with malignancy and adverse outcome. C-myc staining did not correlate with cyclin E. Cyclin D1 correlated with cytoplasmic c-myc expression and to a lesser extent with nuclear c-myc. P27 correlated with cytoplasmic c-myc, but not with nuclear c-myc. P27 correlated with cyclin E. CONCLUSIONS: Strong cytoplasmic c-myc expression and weak nuclear expression in adrenocortical tumours associated with malignancy and shorter survival. PMID- 28801351 TI - Calcium-induced calpain mediates apoptosis via caspase-3 in a mouse photoreceptor cell line. PMID- 28801350 TI - Combined effect of anti-BAG3 and anti-PD-1 treatment on macrophage infiltrate, CD8+ T cell number and tumour growth in pancreatic cancer. PMID- 28801352 TI - Mechanism of Rv2837c from Mycobacterium tuberculosis remains controversial. PMID- 28801353 TI - Reply to Valadares and Woo: Mechanism of Rv2837c from Mycobacterium tuberculosis remains controversial. PMID- 28801354 TI - Following the fate of endocytosed fibrils. AB - Cell-to-cell transmission of intracellular protein aggregates is considered a central event in many neurodegenerative diseases, but little is known about the underlying molecular mechanisms. A new study employs fluorescence quenching to examine the fate of alpha-synuclein, a key molecule in the pathology of Parkinson's disease and related disorders, in primary cultured neurons, finding that endocytosis and lysosomal processing of exogenous fibrils may explain the transmission of alpha-synuclein pathology. PMID- 28801355 TI - Healthcare providers need to address misconceptions young women have around IUDs and their fertility. PMID- 28801356 TI - David Cosgrove. PMID- 28801357 TI - The Autoimmune Risk Variant PTPN22 C1858T Alters B Cell Tolerance at Discrete Checkpoints and Differentially Shapes the Naive Repertoire. AB - A common genetic variant in the gene encoding the protein tyrosine phosphatase nonreceptor type 22 (PTPN22 C1858T) has been linked to a wide range of autoimmune disorders. Although a B cell-intrinsic role in promoting disease has been reported, the mechanism(s) through which this variant functions to alter the preimmune B cell repertoire remains unknown. Using a series of polyclonal and transgenic self-reactive models harboring the analogous mutation in murine Ptpn22, we show evidence for enhanced BCR, B cell-activating factor receptor, and CD40 coreceptor programs, leading to broadly enhanced positive selection of B cells at two discrete checkpoints in the bone marrow and spleen. We further identified a bias for selection of B cells into the follicular mature versus marginal zone B cell compartment. Using a biomarker to track a self-reactive H chain in peripheral blood, we found evidence of similarly enhanced positive selection in human carriers of the PTPN22 C1858T variant. Our combined data support a model whereby the risk variant augments the BCR and coreceptor programs throughout B cell development, promoting enrichment of self-reactive specificities into the follicular mature compartment and thereby likely increasing the risk for seeding of autoimmune B cell responses. PMID- 28801360 TI - Erratum. Association Between Long-term Exposure to Air Pollution and Biomarkers Related to Insulin Resistance, Subclinical Inflammation, and Adipokines. Diabetes 2016;65:3314-3326. PMID- 28801358 TI - IL-4/IL-13 Heteroreceptor Influences Th17 Cell Conversion and Sensitivity to Regulatory T Cell Suppression To Restrain Experimental Allergic Encephalomyelitis. AB - IL-4 and IL-13 have been defined as anti-inflammatory cytokines that can counter myelin-reactive T cells and modulate experimental allergic encephalomyelitis. However, it is not known whether endogenous IL-4 and IL-13 contribute to the maintenance of peripheral tolerance and whether their function is coordinated with T regulatory cells (Tregs). In this study, we used mice in which the common cytokine receptor for IL-4 and IL-13, namely the IL-4Ralpha/IL-13Ralpha1 (13R) heteroreceptor (HR), is compromised and determined whether the lack of signaling by endogenous IL-4 and IL-13 through the HR influences the function of effector Th1 and Th17 cells in a Treg-dependent fashion. The findings indicate that mice deficient for the HR (13R-/-) are more susceptible to experimental allergic encephalomyelitis than mice sufficient for the HR (13R+/+) and develop early onset and more severe disease. Moreover, Th17 cells from 13R-/- mice had reduced ability to convert to Th1 cells and displayed reduced sensitivity to suppression by Tregs relative to Th17 effectors from 13R+/+ mice. These observations suggest that IL-4 and IL-13 likely operate through the HR and influence Th17 cells to convert to Th1 cells and to acquire increased sensitivity to suppression, leading to control of immune-mediated CNS inflammation. These previously unrecognized findings shed light on the intricacies underlying the contribution of cytokines to peripheral tolerance and control of autoimmunity. PMID- 28801359 TI - CCR7 Deficiency Allows Accelerated Clearance of Chlamydia from the Female Reproductive Tract. AB - Immune mechanisms responsible for pathogen clearance from the female reproductive tract (FRT) are incompletely defined; in particular, the contribution of lymphocyte trafficking to this process is unclear. CCR7-deficient mice have profoundly altered lymphocyte recirculation and display ectopic formation of lymphocyte aggregates within mucosal nonlymphoid tissues, including the FRT. In this study, we investigated how altered lymphocyte distribution in CCR7-deficient mice would affect host responses to Chlamydia muridarum within the reproductive tract. As expected, CCR7-deficient mice exhibited reduced lymphocyte trafficking to lymph nodes and a corresponding increase in T cell populations within the FRT. After intravaginal infection with Chlamydia, CCR7-deficient mice displayed markedly reduced Ag-specific CD4 T cell responses within the local draining iliac lymph nodes, yet robust Th1 and Th17 responses were prominent in the FRT. In addition, Chlamydia-specific Ab responses were dysregulated in CCR7-deficient mice, displaying an unexpected increase in the systemic IgA responses. Importantly, prominent mucosal immune responses in CCR7-deficient mice increased the efficiency of bacteria clearance from the FRT while reducing tissue associated inflammation and pathology. Thus, increased numbers of lymphocytes within the FRT result in pathogen clearance with reduced immune-mediated pathology. PMID- 28801361 TI - One level up: abnormal proteolytic regulation of IGF activity plays a role in human pathophysiology. AB - The discovery of a mutation in a specific gene can be very important for determining the pathophysiology underlying the disease of a patient and may also help to decide the best treatment protocol on an individual basis. However, sometimes the discovery of mutations in new proteins advances our comprehension in a more widespread manner. The growth hormone (GH)/insulin-like growth factor (IGF)-1 axis is fundamental for systemic growth, but is also involved in many other important processes. Our understanding of this system in physiology and pathophysiology has advanced throughout the years with each discovery of mutations in members of this axis. This review focuses on the most recent discovery: mutations in the metalloproteinase pregnancy-associated plasma protein A2 (PAPP-A2), one of the proteases involved in liberating IGF-1 from the complexes in which it circulates, in patients with delayed growth failure. We also discuss the advances in the stanniocalcins (STC1 and STC2), proteins that modulate PAPP-A2, as well as PAPP-A. These new advances not only bring us one step closer to understanding the strict spatial and temporal control of this axis in systemic growth and maturation, but also highlight possible therapeutic targets when this system goes awry. PMID- 28801362 TI - Trends in cigarette consumption and time to first cigarette on awakening from 2002 to 2015 in the USA: new insights into the ongoing tobacco epidemic. AB - OBJECTIVE: The current study estimates trends in the number of cigarettes smoked per day (CPD) and percentage of smokers having their first CPD within 30 min of waking (time to first cigarette (TTFC)<30 min) among smokers from 2002 to 2015 in the USA overall, and adjusting for demographics. Trends in TTFC<30 min were also estimated by varying levels of cigarette consumption. METHODS: Data were drawn from the National Household Survey on Drug Use, an annual nationally representative cross-sectional study of the US population aged 12 and older (n=54 079-58 397 per year). Linear time trend analyses of CPD and TTFC<30 min were conducted adjusting for age, gender and income; linear time trend analyses of TTFC among those at varying levels of CPD were then performed. RESULTS: Estimates suggest that CPD declined overall from 2002 to 2015, and that the prevalence of TTFC<30 min declined overall among smokers (p<0.0001). The proportion of smokers consuming fewer (ie, 1-5, 6-15) CPD has increased while the number consuming 16+ CPD has decreased overall. Among those smoking 1-5 (p=0.0006) and 6-15 (p<0.0001) CPD, TTFC<30 min has increased significantly, but TTFC<30 min has remained unchanged among those smoking 16 or more CPD (p=0.5838). CONCLUSIONS: Findings suggest that smokers today are consuming fewer CPD, yet are increasingly likely to have their first cigarette earlier on awakening than they were a decade ago. Intervention and outreach efforts aimed at moving the prevalence lower may benefit from evaluating and addressing nicotine dependence even among lighter smokers. PMID- 28801363 TI - L-selectin Promotes the Maturation of Dendritic Cells via Up-regulation the Expression of TLR4 in vitro. AB - The relationship between dendritic cells (DCs) and L-selectin in the progress of atherosclerosis is unclear. Here, we used L-selectin co-cultured with DCs to investigate the effect of L-selectin on the maturation of DCs in vitro Monocytes derived DCs were isolated and cultured from human peripheral blood. After being stimulated with L-selectin and/or its antagonist for 24-48 hours, the feather of cells was observed by the electron microscope. The expression of mature antigens CD1a, CD80, CD83, and CD86 were investigated by flow cytometric analysis (FACS). RT-PCR and FACS were used to detect the mRNA and protein expression of Toll-like receptor 4(TLR-4). We found that only the cells of giving L-selectin have the mature special feature for irregular shapes. DCs which were stimulated by L selectin have a larger number of expressing CD1a, CD80, CD83, and CD86 compared with non-stimulated and cultured with L-selectin antagonist. The transcript levels of TLR4 were significantly higher after L-selectin and lipopolysaccharide (LPS) stimulated. And the antagonist of L-selectin can deeply decrease the expression of CD1a, CD80, CD83, and CD86 on DCs appeared to coincide with the level of TLR4 transcription. The results demonstrate L-selectin can promote the maturation of DCs via up-regulation the expression of TLR4. PMID- 28801364 TI - CD47 is not Over-Expressed in Fibrolamellar Hepatocellular Carcinoma. AB - OBJECTIVES: CD47 is a transmembrane receptor that inhibits phagocytosis. Over expression of CD47 is associated with an increased risk of tumor growth and metastasis. Clinical trials based on anti-CD47 therapy in adults are underway in a variety of malignancies. CD47 has been shown to be over-expressed in conventional hepatocellular carcinoma (HCC), a common liver tumor in adults. To our knowledge, there have been no studies to evaluate CD47 expression in the fibrolamellar subtype of HCC (FL-HCC), common in children and young adults. This study will evaluate CD47 expression in FL-HCC and shed light on its suitability for anti-CD47 therapy. METHODS: Using immunohistochemistry, 10 samples of FL-HCC from 8 patients were evaluated for CD47 (anti-phagocytic) and calreticulin (pro phagocytic) expression. By direct comparison, CD47 and calreticulin expression were evaluated in 21 samples of conventional HCC. Additionally, transcriptome sequencing to detect CD47 mRNA expression was performed on fresh tissue from 1 FL HCC institutional patient and previously published sequencing data from 20 additional samples was reviewed. RESULTS: Immunohistochemistry showed only weak CD47 expression in 20% of FL-HCC samples. In contrast, 57% of conventional HCC samples showed CD47 expression. All (100%) FL-HCC samples showed moderate or strong calreticulin expression. The difference between CD47 and calreticulin expression in FL-HCC is statistically significant (p=0.0007). Transcriptome sequencing revealed no difference in CD47 expression between FL-HCC and normal liver samples. CONCLUSIONS: CD47 is not over-expressed in FL-HCC. Our studies provide no support for expanding ongoing clinical trials in adults to include children and young adults with FL-HCC. PMID- 28801366 TI - Fullerenes May Cause eIF Mediated Perturbation in Translational Machinery: Evidence from in-silico Analysis. AB - GOALS: Fullerenes have tremendous potential for human biological studies which may further lead to their therapeutic applications. Hence, it has become necessary to explore the possibility of their interference with various important cellular processes. The current study was designed to explore how the presence of fullerenes can affect the binding of DNA with different enzymes and factors involved in transcription and translation process. METHODS: Various bioinformatics approaches and software programs were used to study the effect of fullerenes on the binding pattern of DNA with different enzymes and factors involved in transcription and translation process. RESULTS: Fullerenes of different molecular weights were interacted with various transcription enzymes and factors and no significant effects were observed on transcription machinery. On the contrary, the factors involved in translation process when docked with their functional partners in the presence/absence of fullerenes display reduced activity of eIF2, eIF4A, eIF4H, eIF4G, eIF4B, eIF5B, and eEF1 with fullerenes of different molecular weights. CONCLUSIONS: We conclude that these molecules mostly control the translation of a number of genes. The reduced expression of these factors may cause a number of clinical pathological conditions including neurodegenerative disorders like Alzheimer's, Parkinson's, and Huntington's diseases. PMID- 28801365 TI - Overexpression of SATB1 Gene Inhibits the Immunosuppressive Function of Regulatory T Cells in Chronic Hepatitis B. AB - Special AT-rich sequence-binding protein 1 (SATB1) is a class of nuclear matrix binding protein expressed by T cells and plays an important role in regulatory T cells (Tregs) mediated immune regulation. The immunosuppressive function of Tregs in chronic hepatitis B (CHB) being inhibited by SATB1 has been shown in our previous studies. The objective of this study was to learn the impact of SATB1 on the cellular immune function of CHB. SATB1 isolated from human peripheral blood mononuclear cells (PBMCs) was used as a template of PCR and its product was connected to vector PLV-EF1alpha-EGFP-N. Reconstructed vector PLV-EF1alpha SATB1/EGFP was used to create highly infectious virions and then transduced to Tregs isolated from the CHB patients. Cytokine secreted by Tregs with and without SATB1 overexpression were determined. The results showed that there was a significant increase of Th1 (IFN-gamma) and Th2 (IL-4 and IL-5) cytokines following SATB1 overexpression in CHB derived Tregs. It means that overexpression of SATB1 can promote the conversion from Tregs to effector T cells (Teffs) that lose suppressive function and stimulate the secretion of effective cytokines. These data provide the basis for further research on the mechanism of SATB1 in regulating specific immune response of CHB patients. PMID- 28801367 TI - Comparison of Hematological Aspects between Neuroblastoma Patients with and without Bone Marrow Infiltration. AB - Bone marrow involvement in neuroblastoma indicates an advanced stage of the disease. In this study, we retrospectively analyzed the bone marrow infiltration status and hematological parameters of 111 cases of neuroblastoma. Among the 111 cases, 62 (55.9%) exhibited marrow infiltration. Erythrocytopenia, anemia, and thrombocytopenia were significantly (p<0.05) associated with marrow infiltration of >10% malignant cells. The evaluation of blood cell count parameters with receiver operating characteristic curves indicated that erythrocytopenia can substantially improve the accurate prediction of the risk of bone marrow involvement with a Youden index of 0.60. The sensitivity and specificity were 90% and 70%, respectively, which correspond to a cut-off value of 4.015*10^12/L. Hematological aspects with diagnostic value are different among neuroblastoma patients with and without bone marrow infiltration. PMID- 28801368 TI - Analysis of Separation of White Blood Cells in Peripheral Blood as an Indicator of MPO Deficiency. AB - The purpose of this study was to analyze the white blood cell (WBC) percentage pattern of patients with myeloperoxidase disorder. During the 18 months of routine work, 36 blood samples were found with disorders of myeloperoxidase activity: 12 cases of total myeloperoxidase (MPOt) deficiency and 24 cases of partial myeloperoxidase (MPOp) deficiency. In the group with MPOp, according to the results, monocytes (MONO) were the dominant population 33.2%+/-21.3; however, the microscopic evaluation of leucocytes showed the dominance of neutrophil (NEUT). The average NEUT value was 66.63%+/-12.31; LYMPH 23.33%+/-10.08; MONO 6.00%+/-3.20; EOS 2.04%+/-2.20; BASO 0.29%+/-0.62; ATYP 0.83%+/-1.09. In the group with MPOt, the results of automated leukocyte analysis showed that the dominant group consisted of large unstained cells (LUC) 72.6%+/-8.64. LUC category reflects large immature cells such as blusts. In the microscopic evaluation: NEUT 67% +/-11.40; LYMPH 23%+/-8.94; MONO 6.17%+/-3.47; EOS 1.25%+/ 1.06; BASO 0.08%+/-0.29; ATYP 0.92%+/-1.38. During microscopic verification, no LUC cells were found. Results of the evaluation of automatic WBC separation according to morphology and functionality of cells led to the conclusion that monocyte dominance in the differential WBC count is associated with a high likelihood of MPOp, and the domination of large unstained cells with MPOt. PMID- 28801369 TI - Hepatitis B Virus Upregulates the Expression of C-reactive Protein Both in vivo and in vitro. AB - Hepatitis B virus (HBV) infection induces immune-mediated inflammatory responses. The C-reactive protein (CRP) is an inflammatory marker that is synthesized by the liver. The aim of the present study was to investigate the effect of HBV infection on the expression of CRP and its clinical significance. A reverse transcription-polymerase chain reaction (RT-PCR) analysis was employed to examine the expression of CRP mRNA in the human hepatocellular carcinoma (HCC) cell lines HepG2 and HepG2.2.15. A fully automatic biochemical analyzer was used to examine the serum levels of CRP in patients with chronic HBV infections and in healthy controls. The differences in the serum CRP levels between patients with chronic hepatitis B (CHB), liver cirrhosis (LC), and HCC were compared and analyzed. Our results showed that the expression level of CRP mRNA was higher in HepG2.2.15 cells than in HepG2 cells. The CRP serum level was significantly elevated in individuals with hepatitis B infection (P<0.05). These CRP levels were significantly higher in patients with LC and HCC than in patients with CHB. This study provides new inflammation-related aspects of investigation for understanding HCC oncogenesis caused by HBV. PMID- 28801370 TI - Impact of TLR 2, TLR 4-activation on the Expression of ABCA1 and ABCG1 in Raw Cells. AB - Toll-like receptors (TLR) activation is thought to modulate the macrophage cholesterol efflux and contribute to the atherosclerosis progression; however, the precise pathophysiological mechanism remains unclear. We investigated the effects of TLR2- and TLR4-activation on the expression of the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 in a mouse macrophage cell line, Raw 264.7. Both TLR2- and TLR4-activation upregulated the expression of ABCA1 mRNA but downregulated that of ABCG1 mRNA. These alterations may be mainly regulated by the following 3 cascades: (1) the TLR/myeloid differentiation primary-response protein 88/Liver X receptor pathway, which upregulated the ABCA1 mRNA; (2) NF kappaB pathway, which downregulated the ABCG1 mRNA, and (3) the p38 pathway, which upregulated and stabilized ABCA1 mRNA. These cascades are involved in a complex crosstalk and result in the upregulation of ABCA1 mRNA without a change in ABCA1 protein and the down-regulation of ABCG1 mRNA leading to the increase in ABCG1 protein. These alterations, especially the induction of ABCG1 protein, may be closely involved with the development of atherosclerosis. PMID- 28801371 TI - Small Intestinal Bacterial Overgrowth May Increase the Likelihood of Lactose and Sorbitol but not Fructose Intolerance False Positive Diagnosis. AB - BACKGROUND: Small intestinal bacterial overgrowth (SIBO) is defined as a bacterial count of more than 105 colony-forming units per milliliter in duodenal aspirate. It shares many symptoms with carbohydrate intolerance, which makes the clinical distinction of the disorders difficult. The aim of the study was to examine the relationship between a positive carbohydrate breath test and the presence of SIBO suggested by a positive lactulose hydrogen breath test. METHODS: The electronic database of the gastroenterology laboratory of a tertiary medical center was searched for all patients clinically tested for SIBO in 2012-2013 for whom previous results for lactose, fructose, and/or sorbitol breath test were available. The correlation between positive findings for carbohydrate intolerance and for SIBO was statistically analyzed. RESULTS: The study group included 349 patients, 231 female and 118 male, of mean age 53+/-19 years. All had symptoms of abdominal bloating and gas. There was a statistically significant difference in rates of a positive breath test for lactose and sorbitol at <=90 minutes between patients who were positive and negative for SIBO [chi2(1)=12.8, p<0.01 and chi2(1)=9.5, p<0.01 respectively]. Findings for fructose were not significant. There was no effect of age or gender. CONCLUSIONS: SIBO may represent an important reversible cause of carbohydrate intolerance. It may be especially prudent to exclude SIBO patients with an early peak (<=90 minutes) in H2 excretion. PMID- 28801372 TI - Multi-variant Genetic Panel for Genetic Risk of Opioid Addiction. AB - Over 116 million people worldwide have chronic pain and prescription dependence. In the US, opioids account for the majority of overdose deaths, and in 2014, almost 2 million Americans abused or were dependent on prescription opioids. Genetic factors may play a key role in opioid prescription addiction. Herein, we describe genetic variations between opioid addicted and non-addicted populations and derive a predictive model determining risk of opioid addiction. This case cohort study compares the frequency of 16 single nucleotide polymorphisms involved in the brain reward pathways in patients with and without opioid addiction. Data from 37 patients with prescription opioid or heroin addiction and 30 age and gender matched controls were used to design the predictive score. The predictive score was then tested on an additional 138 samples to determine generalizabilty. Results for Method Derivation of Observed data: ROC statistic=0.92, sensitivity=82% (95% CI: 66-90), specificity=75% (95% CI:56-87). TreeNet "learn" data: ROC statistic=0.92, sensitivity=92%, specificity=90%, precision=92%, and overall correct=91%. Results of Generalizability data: Sensitivity=97% (95% CI: 90 to 100), specificity=87% (95% CI: 86 to 93), positive likelihood ratio=7.3 (95% CI: 4.0 to 13.5), and negative likelihood ratio=0.03 (95% CI: 0.01 to 0.13). This negative likelihood ratio can be used as an evidence based measure to exclude patients with a high risk of opioid addicition or substance use disorder. By identifying patients with a lower risk for opioid addiction, our model may inform therapeutic decisions. PMID- 28801373 TI - Metformin and Melatonin in Adrenocortical Carcinoma: Morphoproteomics and Biomedical Analytics Provide Proof of Concept in a Case Study. AB - Metformin has been proposed as a novel anti-cancer drug for adrenocortical carcinoma (ACC) based upon Poli's recent preclinical studies that 1. "in vitro" metformin modulates the ACC cell model H295R and 2. "in vivo" metformin inhibits tumor growth in a xenograft model as confirmed by a significant reduction of Ki67 [1]. Here we report on our prior clinical case study that provides proof of concept for Poli's studies. We were requested to perform morphoproteomic analysis to further define the biology of, and raise targeted therapeutic options, for a case of post-treatment and chemoresistant ACC metastatic to the liver and the lung. Profiling the patient's ACC from the liver resulted in the recommendation of metformin as a maintenance therapy, which was supported by biomedical data analysis. The patient remains on maintenance therapy with metformin and melatonin and is free of disease some 7 years post diagnosis, thus underscoring the recommendation for clinical trials employing these therapeutic agents. PMID- 28801374 TI - Myeloid Sarcoma in a Patient with Myelodysplastic Syndrome Associated with del(5q ): Case Report and Literature Review. AB - OBJECTIVE: Myeloid sarcoma (MS) is defined in the World Health Organization classification as a tumor mass consisting of myeloblasts with or without maturation and involving any anatomic site other than the bone marrow. We present a case of MS developing in a patient with 5q- myelodysplastic syndrome (MDS) and review the relevant literature. METHODS: A 77-year-old woman with recent diagnosis of MDS associated with del(5q) presented with symptoms and signs attributable to a mass involving the T8 vertebra. Biopsy of the spinal mass was performed and the specimen was analyzed using routine hematoxylin-eosin stain, immunohistochemical methods, and fluorescence in situ hybridization (FISH). RESULTS: Microscopic examination revealed an infiltrate of intermediate-large cells with basophilic cytoplasm and nuclei containing occasional prominent nucleoli. Immunohistochemical analysis showed that the neoplastic cells were positive for CD4, CD43, CD45, CD68, and CD117, and negative for B- and T-cell antigens supporting the diagnosis of MS. Fluorescence in situ hybridization of the spinal mass showed del(5q) in the neoplastic cells. CONCLUSION: Although the 5q- syndrome is a clinically indolent form of MDS, a small subset of patients may develop MS as illustrated in this patient. The relevant literature is also reviewed. PMID- 28801376 TI - Cellular Blue Nevus of Perilimbal Conjunctiva: A Case Report and Review of Literature. AB - Cellular blue nevus is an uncommon neoplasm in the conjunctiva. Here we present an unusual case of a cellular blue nevus that clinically resembled conjunctival melanoma. A 29-year-old Chinese male was found to have a giant pigmented lesion of the conjunctiva around the limbal area of right eye from birth. Excisional biopsy with no-touch technique, lamellar corneal transplantation, amniotic membrane transplantation and adjuvant cryotherapy were performed. Histopathology revealed a nodular, well-defined tumor, which was composed of heavily pigmented dendritic cells and less pigmented spindle cells. There was no recurrence during eight years follow-up. Cellular blue nevus of conjunctiva can be wrongly diagnosed as conjunctival melanoma due to atypia criteria. Therefore, it is important to understand its clinical and pathological characteristics to avoid an overtreatment. PMID- 28801375 TI - Primary Pure Endometrial Primitive Neuroectodermal Tumors with EWSR1 Gene Rearrangement: Report of 2 Cases. AB - Primary Primitive Neuroectodermal Tumor (PNET) of the female genital tract is very rare. The majority has been described in ovaries, and the endometrium is an even rarer site. Herein we describe 2 cases of primary uterine corpus PNET cases with EWSR1 FISH confirmation. To the best of our knowledge, there are four cases reported in the English literature. The knowledge of these tumors' incidence in the endometrium is important to keep in mind, to differentiate it from poorly differentiated and undifferentiated adenocarcinomas, should such pattern of growth be encountered. PMID- 28801377 TI - Ethnic Differences in Genetic Ion Channelopathies Associated with Sudden Cardiac Death: A Systematic Review and Meta-Analysis. AB - BACKGROUND AND AIMS: Reports of allele frequencies encoding ion channel, or their interacting proteins associated with sudden cardiac death among different ethnic groups have been inconsistent. Here, we aimed to characterize the distribution of these genes and their alleles among various ethnicities through meta-analysis. METHODS: We conducted a systematic review and meta-analysis to assess the mean allele frequencies of channelopathy genes SCN5A, NOS1AP, KCNH2, KCNE1, and KCNQ1 among the Black, Caucasian, Asian, and Hispanic ethnicities. Searches in PubMed, Google Scholar, and Web of Science resulted in 18 reports published before July 2015 that met the eligible criteria. Allele frequencies were averaged by weight, and pooled values were calculated by inverse variance. Fixed-effects and random effects models were used to pool effect sizes within each study and across different studies, respectively. Moreover, to extend our findings, we used sequenced genomic data from the Exome Aggregation Consortium to compare allele frequencies between different ethnicities. RESULTS: Meta-analysis of published studies supports that Asians had the highest overall mean allele frequencies of NOS1AP (0.36%, 95% CI: 0.30, 0.43; P<0.001), and SCN5A frequencies (0.17%, 95% CI: 0.07, 0.27, P=0.001), and whereas Caucasians had the highest KCNH2 frequency (0.21%, 95% CI: 0.16, 0.25; P<0.001), and Hispanics the highest KCNQ1 frequency (0.16%). Analysis of the Exome Aggregation Consortium also provided consistent data in agreement the meta-analysis. CONCLUSION: Overall, Asians carried the most alleles of genes associated with sudden cardiac death. The meta-analysis reveals significant differences in allele distribution of channelopathy-associated genes among different ethnic groups. PMID- 28801378 TI - Relationship between miR-146a rs2910164 (G>C) Polymorphism and Digestive System Cancer Susceptibility: A Meta-Analysis. AB - MicroRNAs (miRNAs) are identified negatively regulating gene expression and acting as oncogenes or tumor suppressors in tumorigenesis. The association between miR-146a rs2910164 (G>C) polymorphism and susceptibility to digestive system cancers was contradictory and inconsistent in previously published studies. Presently, we performed a comprehensive literature retrieve on PubMed, Web of Science, Embase, Wanfang and CNKI databases to identify all relevant studies published before July 30, 2016. Odds ratio (OR) and 95% confidential interval (95%CI) were used to calculate the relationship between miR-146a rs2910164 (G>C) polymorphism and digestive system cancers susceptibility. Finally, a total of 45 publications comprising 47 separate case-control studies were enrolled in the present updated meta-analysis including 20,281 cases and 26,099 controls. However, no significant association was uncovered for miR-146a rs2910164 polymorphism and digestive system cancers susceptibility in all the genetic models. Moreover, in the stratification analyses by cancer type, the source of control, ethnicity and Hardy-Weinberg Equilibrium (HWE) status, we also revealed a negative result. To conclude, our work suggests that miR-146a rs2910164 (G>C) polymorphism is not a susceptibility factor for digestive system cancers. PMID- 28801379 TI - Historical Perspectives, Current Status, and Ethical Issues in Granulocyte Transfusion. AB - The goal of this commentary is to provide a historical aspect of granulocyte transfusion, present practices in granulocyte transfusion, accentuate the complexity of the issue, and foster contemplation of ethical issues assimilated with this practice. Clinical aspects of granulocyte transfusion in the light of ethical issues are also discussed. PMID- 28801380 TI - Vitamin D and Immunomodulation: Is It Time to Change the Reference Values? AB - The term "vitamin D" refers to two chemical compounds - ergosterol, or vitamin D2, and cholecalciferol, or vitamin D3. Active vitamin D3 is correctly regarded as a neurohormone due to its pleiotropic biological activities. Although the relation between vitamin D and calcium-phosphorus metabolism has never been discussed, the knowledge on many other roles vitamin D plays is growing fast. Briefly, vitamin D immunomodulation includes attenuation and stimulation of Th1 and Th2 cell proliferation, respectively. Similarly, vitamin D can induce or inhibit the synthesis, secretion, and release of anti- inflammatory (IL-4 and IL 10) and pro-inflammatory (IL-1, TNF-alpha, IFN-gamma) cytokines, respectively. Redefining vitamin D reference values seems to be either a critical or urgent issue. There is not so far a univocal consensus on the reference values of vitamin D status, mainly because of such reference value rates on the basis of the parathyroid hormone (PTH) plasma response. The optimal serum concentration of vitamin D has been considered to lead not to a PTH elevation. Such criterion is clearly resulted from a partial knowledge of the biology of vitamin D so that it can be considered at least obsolete.Based on the distribution of vitamin D levels among healthy individuals and inflammatory/autoimmune patients, an appropriate review of vitamin D reference values is required, following adequate standardization and harmonization of the cut-off, as well as taking into account the ethnic/cultural/geographical features influencing vitamin D status. PMID- 28801381 TI - Fluoroquinolone Resistance Mechanisms by Molecular Epidemiologic Study of Ciprofloxacin-Nonsusceptible Escherichia coli Sequence Types Isolated from Clinical Specimens in a Tertiary Care University Hospital in Korea: Emergence of Clone ST131, 2006-2008. AB - To investigate the sequence types (STs) and fluoroquinolone resistance related mutations among ciprofloxacin (CIP)-non-susceptible extended-spectrum beta lactamase (ESBL)-producing E. coli isolated from Korean patients from 2006-2008. The prevalence of fluoroquinolone resistance-determining region (QRDR) mutations in gyrA, gyrB, parC, and parE and plasmid-mediated quinolone resistance (PMQR) genes were also studied. Multilocus sequence typing (MLST) was performed to identify STs. The most common ST was ST131 (33/51, 64.7%). All isolates, except one isolate, showed three mutations at codons 83 (S83L) and 87 (S87N) in gyrA and 80 (S80I) in parC The prevalence of ST131 in our hospital was much higher than reported in other Asian studies during a similar time period. The mutations found in ST131 were concordant with other studies. PMID- 28801382 TI - False Positive HIV Result and Low CD4 in Babesiosis. PMID- 28801384 TI - Causes of and contributors to infant mortality in a rural community of North India: evidence from verbal and social autopsy. AB - OBJECTIVE: To identify the medical causes of death and contribution of non biological factors towards infant mortality by a retrospective analysis of routinely collected data using verbal and social autopsy tools. SETTING: The study site was Health and Demographic Surveillance System (HDSS), Ballabgarh, North India PARTICIPANTS: All infant deaths during the years 2008-2012 were included for verbal autopsy and infant deaths from July 2012 to December 2012 were included for social autopsy. OUTCOME MEASURES: Cause of death ascertained by a validated verbal autopsy tool and level of delay based on a three-delay model using the INDEPTH social autopsy tool were the main outcome measures. The level of delay was defined as follows: level 1, delay in identification of danger signs and decision making to seek care; level 2, delay in reaching a health facility from home; level 3, delay in getting healthcare at the health facility. RESULTS: The infant mortality rate during the study period was 46.5/1000 live births. Neonatal deaths contributed to 54.3% of infant deaths and 39% occurred on the first day of life. Birth asphyxia (31.5%) followed by low birth weight (LBW)/prematurity (26.5%) were the most common causes of neonatal death, while infection (57.8%) was the most common cause of post-neonatal death. Care-seeking was delayed among 50% of neonatal deaths and 41.2% of post-neonatal deaths. Delay at level 1 was most common and occurred in 32.4% of neonatal deaths and 29.4% of post-neonatal deaths. Deaths due to LBW/prematurity were mostly followed by delay at level 1. CONCLUSION: A high proportion of preventable infant mortality still exists in an area which is under continuous health and demographic surveillance. There is a need to enhance home-based preventive care to enable the mother to identify and respond to danger signs. Verbal autopsy and social autopsy could be routinely done to guide policy interventions aimed at reduction of infant mortality. PMID- 28801383 TI - Long-term outcomes after acute myocardial infarction in countries with different socioeconomic environments: an international prospective cohort study. AB - BACKGROUND: Hospital-based data on the impact of socioeconomic environment on long-term survival after myocardial infarction (MI) are lacking. We compared outcome and quality of secondary prevention in patients after MI living in three different socioeconomic environments including patients from three tertiary-care teaching hospitals with similar service population size in Switzerland, Poland and Ukraine. METHODS: This is a prospective cohort study of patients with a first MI in three different tertiary-care teaching hospitals in Bern (Switzerland), Gdansk (Poland) and Lutsk (Ukraine) during the acute phase in the year 2010 and follow-up of these patients with a questionnaire and, if necessary, telephone interviews 3.5 years after the acute event. The study cohort comprises all consecutive patients hospitalised in every one of the three study centres during the year 2010 for a first MI in the age <=75 years who survived >=30 days. RESULTS: The proportion of patients with ST-segment elevation myocardial infarction (STEMI) was high in Gdansk (Poland) (80%) and in Lutsk (Ukraine) (74%), while the ratio of STEMIs to non-STEMIs was nearly 50:50 in Bern (Switzerland) (50.6% STEMIs). Percutaneous coronary intervention (PCI) was the first choice therapy both in Bern (Switzerland) (100%) and in Gdansk (Poland) (92%), while it was not performed at all in Lutsk (Ukraine). We found substantial differences in treatment and also in secondary prevention interventions including cardiac rehabilitation. All-cause mortality at 3.5 year follow-up was 4.6% in Bern (Switzerland), 8.5% in Gdansk (Poland) and 14.6% in Lutsk (Ukraine). CONCLUSION: Substantial differences in treatment and secondary prevention measures according to low-income, middle-income and high-income socioeconomic situation are associated with a threefold difference in mortality 3.5 years after the acute event. Countries with low socioeconomic environment should increase efforts and be supported to improve care including secondary prevention in particular for MI patients. A greater number of PCIs per million inhabitants itself does not guarantee lower mortality scores. PMID- 28801385 TI - Diagnostic barriers for somatic symptom disorders in primary care: study protocol for a mixed methods study in Germany. AB - INTRODUCTION: Somatoform or somatic symptom disorders ((S)SD) are common and have a negative impact on the patients' health-related quality of life, healthcare use and costs. In primary care, which is central to the management of (S)SD, diagnosis and treatment tend to be delayed. There is a significant lack of evidence regarding the barriers in the diagnostic process of (S)SD in primary care and how interventions should be tailored to address them. The aim of this study is to analyse the diagnostic process in primary care that results in the diagnosis or non-diagnosis of a (S)SD. METHODS AND ANALYSIS: This mixed methods study will investigate the topic with qualitative methods, subsequently proceeding to a quantitative phase where the initial results will be validated and/or generalised. First, focus groups will explore meanings and patterns, inconsistencies and conflicts in general practitioners' (GPs) thoughts and behaviours when diagnosing (S)SD. Second, the results of these focus groups will be used to develop interview guidelines for subsequent face-to-face interviews. Patients and their treating GPs will be interviewed separately on how they experience the history of illness, the diagnostic process and treatment. Third, based on the results of the first two study parts, a questionnaire will be derived and a nationwide survey among German GPs will be conducted, quantifying the barriers and difficulties identified before. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Ethics Committee of the Hamburg Medical Association, Germany (approval number PV4763). The results of this study will be disseminated through conference presentation and publications in peer-reviewed journals. TRIAL REGISTRATION NUMBER: The study is registered in the German Clinical Trial Register (DRKS), DRKS-ID DRKS00009736. PMID- 28801386 TI - Gender differences in infant survival: a secondary data analysis in rural North India. AB - OBJECTIVE: To examine gender differences in infant survival on the first day of life, in the first week of life, and in the neonatal and post-neonatal periods by socio-demographic and economic variables. DESIGN: Secondary data analysis was performed on data from a cluster randomised trial on the effect of implementation of the Integrated Management of Neonatal and Childhood Illness programme, India. SETTINGS: The study setting was Palwal and Faridabad, districts of Haryana, a state in North India. MEASURES: Multiple logistic regression models taking the cluster design into account were used to estimate gender differences in mortality in different periods of infancy. RESULTS: A total of 60 480 infants were included in these analyses. Of 4060 infant deaths, 2054 were female (7.2% of all females born) and 2006 were male (6.3% of all males born). The death rate was significantly higher in females in the post-neonatal period but not during the neonatal period. The odds of death at 29-180 days and at 181-365 days were 1.4 (95% CI 1.3 to 1.6) and 1.7 (95% CI: 1.4 to 2.0) higher in females compared with males, respectively. This increase was seen across all socio-demographic and economic strata. CONCLUSION: Gender differences during the post-neonatal period are a major threat to the survival and health of female infants in India. Programmes need to identify measures that can specifically reduce female mortality. TRIAL REGISTRATION: Clinical trials NCT00474981. PMID- 28801387 TI - Microbubbles and UltraSound-accelerated Thrombolysis (MUST) for peripheral arterial occlusions: protocol for a phase II single-arm trial. AB - INTRODUCTION: Acute peripheral arterial occlusions can be treated with intra arterial catheter-directed thrombolysis as an alternative to surgical thromboembolectomy. Although less invasive, this treatment is time-consuming and carries a significant risk of haemorrhagic complications. Contrast-enhanced ultrasound using microbubbles could accelerate dissolution of thrombi by thrombolytic medications due to mechanical effects caused by oscillation; this could allow for lower dosages of thrombolytics and faster thrombolysis, thereby reducing the risk of haemorrhagic complications. In this study, the safety and practical applicability of this treatment will be investigated. METHODS AND ANALYSIS: A single-arm phase II trial will be performed in 20 patients with acute peripheral arterial occlusions eligible for thrombolytic treatment. Low-dose catheter-directed thrombolysis with urokinase will be used. The investigated treatment will be performed during the first hour of thrombolysis, consisting of intravenous infusion of 4 Luminity phials (6 mL in total, diluted with saline 0.9% to 40 mL total) of microbubbles with the use of local ultrasound at the site of occlusion. Primary end points are the incidence of complications and technical feasibility. Secondary end points are angiographic and clinical success, duration of thrombolytic infusion, treatment-related mortality, amputations, additional interventions and quality of life. ETHICS AND DISSEMINATION: Ethical approval for this study was obtained in 2015 from the Medical Ethics Committee of the VU University Medical Center, Amsterdam, the Netherlands. A statement of consent for this study was given by the Dutch national competent authority. Data will be presented at national and international conferences and published in a peer reviewed journal. TRIAL REGISTRATION NUMBERS: Dutch National Trial Registry: NTR4731; European Clinical Trials Database of the European Medicines Agency: 2014 003469-10; Pre-results. PMID- 28801389 TI - The role of rehabilitation measures in reintegration of children with brain tumours or leukaemia and their families after completion of cancer treatment: a study protocol. AB - INTRODUCTION: For ill children as well as for their parents and siblings, childhood cancer poses a major challenge. Little is known about the reintegration into daily life of childhood cancer survivors and their families. The aim of this prospective observational study is to further the understanding of the role of rehabilitation measures in the reintegration process of childhood leukaemia or brain tumour survivors and their family members after the end of cancer treatment. METHODS AND ANALYSIS: This prospective observational study consists of three study arms: a quantitative study in cooperation with three German paediatric oncological study registries (study arm 1), a quantitative study in cooperation with a rehabilitation clinic that offers a family-oriented paediatric oncological rehabilitation programme (study arm 2) and a qualitative study at 12 month follow-up including families from the study arms 1 and 2 (study arm 3). In study arm 1, children, parents and siblings are surveyed after treatment (baseline), 4-6 months after baseline measurement and at 12-month follow-up. In study arm 2, data are collected at the beginning and at the end of the rehabilitation measure and at 12-month follow-up. Families are assessed with standardised questionnaires on quality of life, emotional and behavioural symptoms, depression, anxiety, fear of progression, coping and family functioning. Furthermore, self-developed items on rehabilitation aims and reintegration into daily life are used. Where applicable, users and non-users of rehabilitation measures will be compared regarding the outcome parameters. Longitudinal data will be analysed by means of multivariate analysis strategies. Reference values will be used for comparisons if applicable. Qualitative data will be analysed using thematic analysis. ETHICS AND DISSEMINATION: This study has been approved by the medical ethics committee of the Medical Chamber of Hamburg. Data will be published in peer-reviewed journals and presented at conferences. PMID- 28801390 TI - The benefits of hardware removal in patients with pain or discomfort after fracture healing of the ankle: a systematic review protocol. AB - INTRODUCTION: For any orthopaedic surgeon working with trauma; ankle fractures are one of the most common injuries treated. The treatment of ankle fractures can be conservative, using external fixation, but more commonly the fractures are treated with open reduction and internal fixation. Residual pain and discomfort are common in patients after surgical treatment of fractures of the ankle. Sometimes it is difficult to determine whether the pain or discomfort is due to the implants left in situ or the primary injury itself. In many cases, the decision is made to remove the implants. Extraction of internal fixation material from the ankle is a common procedure in many orthopaedic clinics. There are no evidence-based guidelines or consensus regarding the effect of hardware removal from the ankle. The aim of this protocol is to describe the method that will be used to collect, describe and analyse the current evidence regarding hardware removal after fracture healing of the ankle. METHODS AND ANALYSIS: We will conduct a systematic review of studies that were published after 1967 regarding the benefits of hardware removal in patients with pain or discomfort after fracture healing of the ankle. Study selection will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. We will make a predefined search strategy and use it in several databases. We will include both randomised controlled trials (RCTs) and non-RCT studies. We will use descriptive statistics to summarise the studies collected. If more than one RCT is collected then a meta-analysis will be conducted. The quality of evidence will be assessed using Grading of Recommendations Assessment, Development and Evaluation guidelines. ETHICS AND DISSEMINATION: No ethics approval is required as no primary data will be collected. Once complete, the results will be made available by peer-reviewed publication. TRIAL REGISTRATION NUMBER: PROSPERO registration number CRD42016039186. PMID- 28801388 TI - Facilitation roles and characteristics associated with research use by healthcare professionals: a scoping review. AB - BACKGROUND: Implementing research findings into practice is a complex process that is not well understood. Facilitation has been described as a key component of getting research findings into practice. The literature on facilitation as a practice innovation is growing. This review aimed to identify facilitator roles and to describe characteristics of facilitation that may be associated with successful research use by healthcare professionals. METHODS: We searched 10 electronic databases up to December 2016 and used predefined criteria to select articles. We included conceptual papers and empirical studies that described facilitator roles, facilitation processes or interventions, and that focused on healthcare professionals and research use. We used content and thematic analysis to summarise data. Rogers' five main attributes of an innovation guided our synthesis of facilitation characteristics. RESULTS: Of the 38 488 articles identified from our online and manual search, we included 195 predominantly research studies. We identified nine facilitator roles: opinion leaders, coaches, champions, research facilitators, clinical/practice facilitators, outreach facilitators, linking agents, knowledge brokers and external-internal facilitators. Fifteen facilitation characteristics were associated with research use, which we grouped into five categories using Rogers' innovation attributes: relative advantage, compatibility, complexity, trialability and observability. CONCLUSIONS: We found a diverse and broad literature on the concept of facilitation that can expand our current thinking about facilitation as an innovation and its potential to support an integrated, collaborative approach to improving healthcare delivery. PMID- 28801391 TI - Primary Sjogren's syndrome and the risk of acute pancreatitis: a nationwide cohort study. AB - OBJECTIVE: Studies on the risk of acute pancreatitis in patients with primary Sjogren's syndrome (pSS) are limited. We evaluated the effects of pSS on the risk of acute pancreatitis in a nationwide, population-based cohort in Taiwan. STUDY DESIGN: Population-based retrospective cohort study. SETTING: We studied the claims data of the >97% Taiwan population from 2002 to 2012. PARTICIPANTS: We identified 9468 patients with pSS by using the catastrophic illness registry of the National Health Insurance Database in Taiwan. We also selected 37 872 controls that were randomly frequency matched by age (in 5 year bands), sex and index year from the general population. PRIMARY OUTCOME MEASURE: We analysed the risk of acute pancreatitis by using Cox proportional hazards regression models including sex, age and comorbidities. RESULTS: From 23.74 million people in the cohort, 9468 patients with pSS (87% women, mean age=55.6 years) and 37 872 controls were followed-up for 4.64 and 4.74 years, respectively. A total of 44 cases of acute pancreatitis were identified in the pSS cohort versus 105 cases in the non-pSS cohort. Multivariate Cox regression analysis indicated that the incidence rate of acute pancreatitis was significantly higher in the pSS cohort than in the non-pSS cohort (adjusted HR (aHR) 1.48, 95% CI 1.03 to 2.12). Cyclophosphamide use increased the risk of acute pancreatitis (aHR 5.27, 95% CI 1.16 to 23.86). By contrast, hydroxychloroquine reduced the risk of acute pancreatitis (aHR 0.23, 95% CI 0.09 to 0.55). CONCLUSION: This nationwide, retrospective cohort study demonstrated that the risk of acute pancreatitis was significantly higher in patients with pSS than in the general population. PMID- 28801394 TI - The role of nurse specialists in the delivery of integrated diabetes care: a cross-sectional survey of diabetes nurse specialist services. AB - OBJECTIVES: International evidence suggests the diabetes nurse specialist (DNS) has a key role in supporting integrated management of diabetes. We examine whether hospital and community DNS currently support the integration of care, examine regional variation in aspects of the service relevant to the delivery of integrated care and identify barriers to service delivery and areas for improvement. DESIGN: A cross-sectional survey of hospital and community-based DNS in Ireland. METHODS: Between September 2015 and April 2016, a 67-item online survey, comprising closed and open questions on their clinical role, diabetes clinics, multidisciplinary working, and barriers and facilitators to service delivery, was administered to all eligible DNS (n=152) in Ireland. DNS were excluded if they were retired or on maternity leave or extended leave. RESULTS: The response rate was 66.4% (n=101): 60.6% (n=74) and 89.3% (n=25) among hospital and community DNS, respectively. Most DNS had patients with stable (81.8%) and complicated type 2 diabetes mellitus (89.9%) attending their service. The majority were delivering nurse-led clinics (81.1%). Almost all DNS had a role liaising with (91%), and providing support and education to (95%), other professionals. However, only a third reported that there was local agreement on how their service should operate between the hospital and primary care. Barriers to service delivery that were experienced by DNS included deficits in the availability of specialist staff (allied health professionals, endocrinologists and DNS), insufficient space for clinics, structured education and issues with integration. CONCLUSIONS: Delivering integrated diabetes care through a nurse specialist-led approach requires that wider service issues, including regional disparities in access to specialist resources and formalising agreements and protocols on multidisciplinary working between settings, be explicitly addressed. PMID- 28801393 TI - Protocol for the mWellcare trial: a multicentre, cluster randomised, 12-month, controlled trial to compare the effectiveness of mWellcare, an mHealth system for an integrated management of patients with hypertension and diabetes, versus enhanced usual care in India. AB - INTRODUCTION: Rising burden of cardiovascular disease (CVD) and diabetes is a major challenge to the health system in India. Innovative approaches such as mobile phone technology (mHealth) for electronic decision support in delivering evidence-based and integrated care for hypertension, diabetes and comorbid depression have potential to transform the primary healthcare system. METHODS AND ANALYSIS: mWellcare trial is a multicentre, cluster randomised controlled trial evaluating the clinical and cost-effectiveness of a mHealth system and nurse managed care for people with hypertension and diabetes in rural India. mWellcare system is an Android-based mobile application designed to generate algorithm based clinical management prompts for treating hypertension and diabetes and also capable of storing health records, sending alerts and reminders for follow-up and adherence to medication. We recruited a total of 3702 participants from 40 Community Health Centres (CHCs), with >=90 at each of the CHCs in the intervention and control (enhanced care) arms. The primary outcome is the difference in mean change (from baseline to 1 year) in systolic blood pressure and glycated haemoglobin (HbA1c) between the two treatment arms. The secondary outcomes are difference in mean change from baseline to 1 year in fasting plasma glucose, total cholesterol, predicted 10-year risk of CVD, depression, smoking behaviour, body mass index and alcohol use between the two treatment arms and cost-effectiveness. ETHICS AND DISSEMINATION: The study has been approved by the institutional Ethics Committees at Public Health Foundation of India and the London School of Hygiene and Tropical Medicine. Findings will be disseminated widely through peer-reviewed publications, conference presentations and other mechanisms. TRIAL REGISTRATION: mWellcare trial is registered with Clinicaltrial.gov (Registration number NCT02480062; Pre-results) and Clinical Trial Registry of India (Registration number CTRI/2016/02/006641). The current version of the protocol is Version 2 dated 19 October 2015 and the study sponsor is Public Health Foundation of India, Gurgaon, India (www.phfi.org). PMID- 28801392 TI - Can promoting awareness of fetal movements and focusing interventions reduce fetal mortality? A stepped-wedge cluster randomised trial (AFFIRM). AB - BACKGROUND: In 2013, the stillbirth rate in the UK was 4.2 per 1000 live births, ranking 24th out of 49 high-income countries, with an annual rate of reduction of only 1.4% per year. The majority of stillbirths occur in normally formed infants, with (retrospective) evidence of placental insufficiency the most common clinical finding. Maternal perception of reduced fetal movements (RFM) is associated with placental insufficiency and increased risk of subsequent stillbirth.This study will test the hypothesis that the introduction of a package of care to increase women's awareness of the need for prompt reporting of RFM and standardised management to identify fetal compromise with timely delivery in confirmed cases, will reduce the rate of stillbirth. Following the introduction of a similar intervention in Norway the odds of stillbirth fell by 30%, but the efficacy of this intervention (and possible adverse effects and implications for service delivery) has not been tested in a randomised trial. METHODS: We describe a stepped-wedge cluster trial design, in which participating hospitals in the UK and Ireland will be randomised to the timing of introduction of the care package. Outcomes (including the primary outcome of stillbirth) will be derived from detailed routinely collected maternity data, allowing us to robustly test our hypothesis. The degree of implementation of the intervention will be assessed in each site. A nested qualitative study will examine the acceptability of the intervention to women and healthcare providers and identify process issues including barriers to implementation. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Scotland A Research Ethics Committee (Ref 13/SS/0001) and from Research and Development offices in participating maternity units. The study started in February 2014 and delivery of the intervention completed in December 2016. Results of the study will be submitted for publication in peer-reviewed journals and disseminated to local investigating sites to inform education and care of women presenting with RFM. TRIAL REGISTRATION NUMBER: www.clinicaltrials.gov NCT01777022. VERSION: Protocol Version 4.2, 3 February 2017. PMID- 28801395 TI - The involvement of early stage breast cancer patients during oncology consultations in Italy: a multi-centred, randomized controlled trial of a question prompt sheet versus question listing. AB - OBJECTIVES: To investigate, prior to an oncology consultation, the use of a pre prepared list of evidence based questions, Question Prompt Sheet (QPS), compared with a Question List (QL), a patient self-generated list of questions. DESIGN: Multi-centred, randomised controlled trial. SETTING: Secondary-care patients attending three outpatient oncology clinics in Northern Italy. PARTICIPANTS: 308 women completed the study. Inclusion criteria were an age between 18 and 75 years, a recent diagnosis of early stage, non-metastatic breast cancer, adequate Italian language skills, no previous oncology visits and no evidence of cognitive impairment. INTERVENTION: Patients received the QPS or the QL prior to the consultation, completed it without suggestion or coaching session and delivered back before the visit.The consultations were audio-recorded and analysed for the number and content of questions. Multilevel linear models were used to compare the two groups. OUTCOME MEASURES: The primary outcome was the comparison of questions asked between QPS and QL group. Secondary outcomes included satisfaction about questions asked, satisfaction with decision, and level of anxiety. RESULTS: Patients in the QPS and QL group asked 13 and 16 questions respectively. The difference was not significant (b=1.7, CI -0.3 to 3.6, p=0.10). A mean of 22 questions was selected in the QPS, while a mean of 2 questions was written in the QL. Patients in the QPS group were significantly less satisfied (t=3.60, p<0.01) with questions asked but wanted less additional information (t=2.20, p<0.05). Levels of patient decisional satisfaction were equivalent between groups. Similarly, anxiety levels were equal between groups prior to the consultation and decreased in similar way after the consultation. CONCLUSIONS: Both interventions have similar impact on patients' participation in terms of question asking during the consultation. Future research is needed in order to explore which components of the interventions are really useful and efficacious. TRIAL REGISTRATION: ClinicalTrials.gov NCT01510964. PMID- 28801397 TI - Getting the right balance? A mixed logit analysis of the relationship between UK training doctors' characteristics and their specialties using the 2013 National Training Survey. AB - OBJECTIVE: To analyse how training doctors' demographic and socioeconomic characteristics vary according to the specialty that they are training for. DESIGN: Descriptive statistics and mixed logistic regression analysis of cross sectional survey data to quantify evidence of systematic relationships between doctors' characteristics and their specialty. SETTING: Doctors in training in the United Kingdom in 2013. PARTICIPANTS: 27 530 doctors in training but not in their foundation year who responded to the National Training Survey 2013. MAIN OUTCOME MEASURES: Mixed logit regression estimates and the corresponding odds ratios (calculated separately for all doctors in training and a subsample comprising those educated in the UK), relating gender, age, ethnicity, place of studies, socioeconomic background and parental education to the probability of training for a particular specialty. RESULTS: Being female and being white British increase the chances of being in general practice with respect to any other specialty, while coming from a better-off socioeconomic background and having parents with tertiary education have the opposite effect. Mixed results are found for age and place of studies. For example, the difference between men and women is greatest for surgical specialties for which a man is 12.121 times more likely to be training to a surgical specialty (relative to general practice) than a woman (p-value<0.01). Doctors who attended an independent school which is proxy for doctor's socioeconomic background are 1.789 and 1.413 times more likely to be training for surgical or medical specialties (relative to general practice) than those who attended a state school (p-value<0.01). CONCLUSIONS: There are systematic and substantial differences between specialties in respect of training doctors' gender, ethnicity, age and socioeconomic background. The persistent underrepresentation in some specialties of women, minority ethnic groups and of those coming from disadvantaged backgrounds will impact on the representativeness of the profession into the future. Further research is needed to understand how the processes of selection and the self-selection of applicants into specialties gives rise to these observed differences. PMID- 28801396 TI - The SIMS trial: adjustable anchored single-incision mini-slings versus standard tension-free midurethral slings in the surgical management of female stress urinary incontinence. A study protocol for a pragmatic, multicentre, non inferiority randomised controlled trial. AB - INTRODUCTION: Single-incision mini-slings (SIMS) represent the third generation of midurethral slings. They have been developed with the aim of offering a true ambulatory procedure for treatment of female stress urinary incontinence (SUI) with reduced morbidity and earlier recovery while maintaining similar efficacy to standard midurethral slings (SMUS). The aim of this study is to determine the clinical and cost-effectiveness of adjustable anchored SIMS compared with tension free SMUS in the surgical management of female SUI, with 3-year follow-up. METHODS AND ANALYSIS: A pragmatic, multicentre, non-inferiority randomised controlled trial. PRIMARY OUTCOME MEASURE: The primary outcome measure is the patient-reported success rate measured by the Patient Global Impression of Improvement at 12 months. The primary economic outcome will be incremental cost per quality-adjusted life year gained at 12 months. SECONDARY OUTCOME MEASURES: The secondary outcomes measures include adverse events, objective success rates, impact on other lower urinary tract symptoms, health-related quality of life profile and sexual function, and reoperation rates for SUI. Secondary economic outcomes include National Health Service and patient primary and secondary care resource use and costs, incremental cost-effectiveness and incremental net benefit. STATISTICAL ANALYSIS: The statistical analysis of the primary outcome will be by intention-to-treat and also a per-protocol analysis. Results will be displayed as estimates and 95% CIs. CIs around observed differences will then be compared with the prespecified non-inferiority margin. Secondary outcomes will be analysed similarly. ETHICS AND DISSEMINATION: The North of Scotland Research Ethics Committee has approved this study (13/NS/0143). The dissemination plans include HTA monograph, presentation at international scientific meetings and publications in high-impact, open-access journals. The results will be included in the updates of the National Institute for Health and Care Excellence and the European Association of Urology guidelines; these two specific guidelines directly influence practice in the UK and worldwide specialists, respectively. In addition, plain English-language summary of the main findings/results will be presented for relevant patient organisations. TRIAL REGISTRATION NUMBER: ISRCTN93264234. The SIMS study is currently recruiting in 20 UK research centres. The first patient was randomised on 4 February 2014, with follow-up to be completed at the end of February 2020. PMID- 28801398 TI - HIV prevalence and factors associated with HIV infection among transgender women in Cambodia: results from a national Integrated Biological and Behavioral Survey. AB - OBJECTIVE: To examine factors associated with HIV infection among transgender women in Cambodia. DESIGN: Cross-sectional study. SETTINGS: HIV high-burden sites including the capital city and 12 provinces. PARTICIPANTS: This study included 1375 sexually active transgender women with a mean age of 25.9 years (SD 7.1), recruited by using respondent-driven sampling for structured questionnaire interviews and rapid finger-prick HIV testing. PRIMARY OUTCOME MEASURE: HIV infection detected by using Determine antibody test. RESULTS: HIV prevalence among this population was 5.9%. After adjustment for other covariates, participants living in urban areas were twice as likely to be HIV infected as those living in rural areas. Participants with primary education were 1.7 times as likely to be infected compared with those with high school education. HIV infection increased with age; compared with those aged 18-24 years, the odds of being HIV infected were twice as high among transgender women aged 25-34 years and 2.8 times higher among those aged >=35 years. Self-injection of gender affirming hormones was associated with a fourfold increase in the odds of HIV infection. A history of genital sores over the previous 12 months increased the odds of HIV infection by threefold. Transgender women with stronger feminine identity, dressing as a woman all the time, were twice as likely to be HIV infected compared with those who did not dress as a woman all the time. Having never used online services developed for transgender women in the past six months was also associated with higher odds of being HIV infected. CONCLUSIONS: Transgender women in Cambodia are at high risk of HIV. To achieve the goal of eliminating HIV in Cambodia, effective combination prevention strategies addressing the above risk factors among transgender women should be strengthened. PMID- 28801399 TI - A randomised controlled pilot trial evaluating feasibility and acceptability of a computer-based tool to identify and reduce harmful and hazardous drinking among adolescents with alcohol-related presentations in Canadian pediatric emergency departments. AB - OBJECTIVE: This study piloted procedures and obtained data on intervention acceptability to determine the feasibility of a definitive randomised controlled trial (RCT) of the effectiveness of a computer-based brief intervention in the emergency department (ED). DESIGN: Two-arm, multi-site, pilot RCT. SETTING AND PARTICIPANTS: Adolescents aged 12-17 years presenting to three Canadian pediatric EDs from July 2010 to January 2013 for an alcohol-related complaint. INTERVENTIONS: Standard medical care plus computer-based screening and personalised assessment feedback (experimental group) or standard care plus computer-based sham (control group). ED and research staff, and adolescents were blinded to allocation. OUTCOMES: Main: change in alcohol consumption from baseline to 1- and 3 months post-intervention. Secondary: recruitment and retention rates, intervention acceptability and feasibility, perception of group allocation among ED and research staff, and change in health and social services utilisation. RESULTS: Of the 340 adolescents screened, 117 adolescents were eligible and 44 participated in the study (37.6% recruitment rate). Adolescents allocated to the intervention found it easy, quick and informative, but were divided on the credibility of the feedback provided (agreed it was credible: 44.4%, disagreed: 16.7%, unsure: 16.7%, no response: 22.2%). We found no evidence of a statistically significant relationship between which interventions adolescents were allocated to and which interventions staff thought they received. Alcohol consumption, and health and social services data were largely incomplete due to modest study retention rates of 47.7% and 40.9% at 1- and 3 months post-intervention, respectively. CONCLUSIONS: A computer-based intervention was acceptable to adolescents and delivery was feasible in the ED in terms of time to use and ease of use. However, adjustments are needed to the intervention to improve its credibility. A definitive RCT will be feasible if protocol adjustments are made to improve recruitment and retention rates; and increase the number of study sites and research staff. TRIAL REGISTRATION: clinicaltrials.gov NCT01146665. PMID- 28801400 TI - Protein misfolding, amyotrophic lateral sclerosis and guanabenz: protocol for a phase II RCT with futility design (ProMISe trial). AB - INTRODUCTION: Recent studies suggest that endoplasmic reticulum stress may play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through an altered regulation of the proteostasis, the cellular pathway-balancing protein synthesis and degradation. A key mechanism is thought to be the dephosphorylation of eIF2alpha, a factor involved in the initiation of protein translation. Guanabenz is an alpha-2-adrenergic receptor agonist safely used in past to treat mild hypertension and is now an orphan drug. A pharmacological action recently discovered is its ability to modulate the synthesis of proteins by the activation of translational factors preventing misfolded protein accumulation and endoplasmic reticulum overload. Guanabenz proved to rescue motoneurons from misfolding protein stress both in in vitro and in vivo ALS models, making it a potential disease-modifying drug in patients. It is conceivable investigating whether its neuroprotective effects based on the inhibition of eIF2alpha dephosphorylation can change the progression of ALS. METHODS AND ANALYSES: Protocolised Management In Sepsis is a multicentre, randomised, double-blind, placebo-controlled phase II clinical trial with futility design. We will investigate clinical outcomes, safety, tolerability and biomarkers of neurodegeneration in patients with ALS treated with guanabenz or riluzole alone for 6 months. The primary aim is to test if guanabenz can reduce the proportion of patients progressed to a higher stage of disease at 6 months compared with their baseline stage as measured by the ALS Milano-Torino Staging (ALS-MITOS) system and to the placebo group. Secondary aims are safety, tolerability and change in at least one biomarker of neurodegeneration in the guanabenz arm compared with the placebo group. Findings will provide reliable data on the likelihood that guanabenz can slow the course of ALS in a phase III trial. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of IRCCS 'Carlo Besta Foundation' of Milan (Eudract no. 2014-005367-32 Pre-results) based on the Helsinki declaration. PMID- 28801401 TI - Satisfaction with rehabilitative health care services among German and non-German nationals residing in Germany: a cross-sectional study. AB - OBJECTIVES: Rehabilitation following medical conditions is largely offered as in patient service in Germany. Foreign-national residents use rehabilitative services less often than Germans and attain less favourable treatment outcomes. These differences are independent of demographic, socioeconomic and health characteristics. Satisfaction with different aspects of rehabilitative care presumably affects the effectiveness of rehabilitative services. We compared the degree of satisfaction with different domains of the rehabilitative care process between Germans and non-German nationals residing in Germany. METHODS: We used data from a cross-sectional rehabilitation patient survey annually conducted by the German Statutory Pension Insurance Scheme. The sample comprises 274 513 individuals undergoing medical rehabilitation in 642 hospitals during the years 2007-2011. Participants rated their satisfaction with different domains of rehabilitation on multi-item scales. We dichotomised each scale to low/moderate and high satisfaction. For each domain, a multilevel adjusted logistic regression analysis was conducted to examine differences in the levels of satisfaction between German and non-German nationals. Average marginal effects (AMEs) and 99.5% CI were computed as effect estimates. AMEs represent differences in the probability for the occurrence of the outcome. RESULTS: Turkish nationals had a higher probability for being less satisfied with most aspects of their rehabilitation, with AMEs ranging between 0.05 (99.5% CI 0.00 to 0.09) for 'satisfaction with psychological care' and 0.11 (99.5% CI 0.08 to 0.14) for 'satisfaction with treatments during rehabilitation'. Patients from former Yugoslavia and from Portugal/Spain/Italy/Greece were as satisfied as Germans with most aspects of their rehabilitation. CONCLUSIONS: Turkish nationals are less satisfied with their rehabilitative care than other population groups. This may be attributable to the diversity of the population in terms of its expectations towards rehabilitation. Rehabilitative care institutions need to provide services that are sensitive to the needs of all clients. Diversity management can contribute to this process. PMID- 28801402 TI - Reasons for non-adherence to cardiometabolic medications, and acceptability of an interactive voice response intervention in patients with hypertension and type 2 diabetes in primary care: a qualitative study. AB - OBJECTIVES: This study explored the reasons for patients' non-adherence to cardiometabolic medications, and tested the acceptability of the interactive voice response (IVR) as a way to address these reasons, and support patients, between primary care consultations. DESIGN, METHOD, PARTICIPANTS AND SETTING: The study included face-to-face interviews with 19 patients with hypertension and/or type 2 diabetes mellitus, selected from primary care databases, and presumed to be non-adherent. Thirteen of these patients pretested elements of the IVR intervention few months later, using a think-aloud protocol. Five practice nurses were interviewed. Data were analysed using multiperspective, and longitudinalthematic analysis. RESULTS: Negative beliefs about taking medications, the complexity of prescribed medication regimens, and the limited ability to cope with the underlying affective state, within challenging contexts, were mentioned as important reasons for non-adherence. Nurses reported time constraints to address each patient's different reasons for non-adherence, and limited efficacy to support patients, between primary care consultations. Patients gave positive experiential feedback about the IVR messages as a way to support them take their medicines, and provided recommendations for intervention content and delivery mode. Specifically, they liked the voice delivering the messages and the voice recognition software. For intervention content, they preferred messages that were tailored, and included messages with 'information about health consequences', 'action plans', or simple reminders for performing the behaviour. CONCLUSIONS: Patients with hypertension and/or type 2 diabetes, and practice nurses, suggested messages tailored to each patient's reasons for non-adherence. Participants recommended IVR as an acceptable platform to support adherence to cardiometabolic medications between primary care consultations. Future studies could usefully test the acceptability, and feasibility, of tailored IVR interventions to support medication adherence, as an adjunct to primary care. PMID- 28801403 TI - Equipping community pharmacy workers as agents for health behaviour change: developing and testing a theory-based smoking cessation intervention. AB - OBJECTIVE: To develop a complex intervention for community pharmacy staff to promote uptake of smoking cessation services and to increase quit rates. DESIGN: Following the Medical Research Council framework, we used a mixed-methods approach to develop, pilot and then refine the intervention. METHODS: Phase I: We used information from qualitative studies in pharmacies, systematic literature reviews and the Capability, Opportunity, Motivation-Behaviour framework to inform design of the initial version of the intervention. Phase II: We then tested the acceptability of this intervention with smoking cessation advisers and assessed fidelity using actors who visited pharmacies posing as smokers, in a pilot study. Phase III: We reviewed the content and associated theory underpinning our intervention, taking account of the results of the earlier studies and a realist analysis of published literature. We then confirmed a logic model describing the intended operation of the intervention and used this model to refine the intervention and associated materials. SETTING: Eight community pharmacies in three inner east London boroughs. PARTICIPANTS: 12 Stop Smoking Advisers. INTERVENTION: Two, 150 min, skills-based training sessions focused on communication and behaviour change skills with between session practice. RESULTS: The pilot study confirmed acceptability of the intervention and showed preliminary evidence of benefit; however, organisational barriers tended to limit effective operation. The pilot data and realist review pointed to additional use of Diffusion of Innovations Theory to seat the intervention in the wider organisational context. CONCLUSIONS: We have developed and refined an intervention to promote smoking cessation services in community pharmacies, which we now plan to evaluate in a randomised controlled trial. TRIAL REGISTRATION NUMBER: UKCRN ID 18446, Pilot. PMID- 28801404 TI - Systematic review of preoperative physical activity and its impact on postcardiac surgical outcomes. AB - OBJECTIVES: The objective of this systematic review was to study the impact of preoperative physical activity levels on adult cardiac surgical patients' postoperative: (1) major adverse cardiac and cerebrovascular events (MACCEs), (2) adverse events within 30 days, (3) hospital length of stay (HLOS), (4) intensive care unit length of stay (ICU LOS), (5) activities of daily living (ADLs), (6) quality of life, (7) cardiac rehabilitation attendance and (8) physical activity behaviour. METHODS: A systematic search of MEDLINE, Embase, AgeLine and Cochrane library for cohort studies was conducted. RESULTS: Eleven studies (n=5733 patients) met the inclusion criteria. Only self-reported physical activity tools were used. Few studies used multivariate analyses to compare active versus inactive patients prior to surgery. When comparing patients who were active versus inactive preoperatively, there were mixed findings for MACCE, 30 day adverse events, HLOS and ICU LOS. Of the studies that adjusted for confounding variables, five studies found a protective, independent association between physical activity and MACCE (n=1), 30-day postoperative events (n=2), HLOS (n=1) and ICU LOS (n=1), but two studies found no protective association for 30-day postoperative events (n=1) and postoperative ADLs (n=1). No studies investigated if activity status before surgery impacted quality of life or cardiac rehabilitation attendance postoperatively. Three studies found that active patients prior to surgery were more likely to be inactive postoperatively. CONCLUSION: Due to the mixed findings, the literature does not presently support that self-reported preoperative physical activity behaviour is associated with postoperative cardiac surgical outcomes. Future studies should objectively measure physical activity, clearly define outcomes and adjust for clinically relevant variables. REGISTRATION: Trial registration number NCT02219815. PROSPERO number CRD42015023606. PMID- 28801405 TI - Prevalence of hepatitis C virus infection and its correlates in a rural area of southwestern China: a community-based cross-sectional study. AB - OBJECTIVES: Hepatitis C virus (HCV) infection is a major public health problem in southwestern China. Our aim of the study was to assess the prevalence of HCV infection and its correlates in the Yi population of this region. METHODS: A community-based survey was conducted to investigate sociodemographic characteristics and other associated factors for HCV infection in a rural area of southwestern China. Blood samples were collected and tested for antibodies to HCV. Anti-HCV positive samples were further assessed for HCV RNA. RESULTS: A total of 2558 participants aged >=14 years were included in our analysis. Of them, 2.8% (95% CI 2.2% to 3.5%) were positive for HCV antibody. Multiple logistic regression analysis revealed that sex (male vs female: adjusted OR (aOR)=3.30, 95% CI 1.80 to 6.07), marital status (unmarried vs married: aOR=0.27, 95% CI 0.09 to 0.80), ever using injection drug (aOR=28.65, 95% CI 15.9 to 51.64) and ever having blood transfusion (aOR=7.64, 95% CI 1.94 to 30.16) were significantly associated with HCV infection (indicated by positive HCV antibody). Stratified analysis by HIV infection found that in HIV-negative individuals, sex (male vs female: aOR=3.84, 95% CI 1.88 to 7.85), ever using injection drug (aOR=22.15, 95% CI 8.45 to 58.04), having multiple sexual partners (aOR=2.57, 95% CI 1.26 to 5.23), and ever having blood transfusion (aOR=16.54, 95% CI 4.44 to 61.58) were significantly associated with HCV infection and in HIV-positive individuals, ever using injection drug (aOR=8.96, 95% CI 3.16 to 25.38) was associated with HCV infection. CONCLUSION: The data suggested a higher risk of HCV infection in this area when compared with the rest of China and some unique associated factors. Rapid scale-up of targeted interventions are needed to prevent further transmission and consequent morbidities. PMID- 28801407 TI - The boundaries of mild chronic obstructive pulmonary disease (COPD): design of the searching clinical COPD onset (SOON) study. AB - INTRODUCTION: Clinical onset of chronic obstructive pulmonary disease (COPD) is the point at which the disease is first identifiable by physicians. It is a poorly defined stage which seems to include both mild spirometric and non spirometric disease, and could be described as early grade COPD, for practical purposes. While dyspnoea; chronic bronchitis and CT imaging evidence of emphysema and airway disease may be present very early, the lone significance of dyspnoea, the most relevant symptom in COPD in identifying these individuals, has been scarcely assessed.The Searching Clinical COPD Onset (SOON) Study was designed primarily to detect clinical, physiological and structural differences between dyspnoeic and non-dyspnoeic individuals with early grade COPD. It is hypothesised that presence of dyspnoea in early disease may identify a subtype of individuals with reduced exercise capacity, notwithstanding of their spirometry results. In addition, dyspnoeic individuals will share worse quality of life, lower physical activity, greater lung hyperinflation greater emphysema and airway thickness and reduced peripheral muscle mass than their non-dyspnoeic counterpart. METHODS AND ANALYSIS: SOON is a monocentric study, with a cross sectional design aimed at obtaining representative samples of current or ex-smoker-adults aged >=45 and <=80 years. Two hundred and forty participants will be enrolled into four strata, according to normal spirometry or mild spirometric obstruction and presence or not of dyspnoea modified Medical Research Council score >=1. The primary outcome will be the difference between dyspnoeic and non-dyspnoeic individuals on the 6 min walk test performance, regardless of their spirometry results. To account for the confounding effect of heart failure on dyspnoea, stress echocardiography will be also performed. Secondary outcomes will include clinical (quality of life, physical activity), physiological (exercise testing) and structural characteristics (emphysema, airway disease and peripheral muscle mass by CT imaging). ETHICS AND DISSEMINATION: The Institutional Ethics Committee from Pontificia Universidad Catolica de Chile has approved the study protocol and signed informed consent will be obtained from all participants. The findings of the trial will be disseminated through relevant peer-reviewed journals and international conference presentations. TRIAL REGISTRATION NUMBER: NCT03026439. PMID- 28801406 TI - Speak-up culture in an intensive care unit in Hong Kong: a cross-sectional survey exploring the communication openness perceptions of Chinese doctors and nurses. AB - OBJECTIVES: Despite growing recognition of the importance of speaking up to protect patient safety in critical care, little research has been performed in this area in an intensive care unit (ICU) context. This study explored the communication openness perceptions of Chinese doctors and nurses and identified their perceptions of issues in ICU communication, their reasons for speaking up and the possible factors and strategies involved in promoting the practice of speaking up. DESIGN: A mixed-methods design with quantitative and sequential qualitative components was used. SETTING AND PARTICIPANTS: Eighty ICU staff members from a large public hospital in Hong Kong completed a questionnaire regarding their perceptions of communication openness. Ten clinicians whose survey responses indicated support for open communication were then interviewed about their speak-up practices. RESULTS: The participating ICU staff members had similar perceptions of their openness to communication. However, the doctors responded more positively than the nurses to many aspects of communication openness. The two groups also had different perceptions of speaking up. The interviewed ICU staff members who indicated a high level of communication openness reported that their primary reasons for speaking up were to seek and clarify information, which was achieved by asking questions. Other factors perceived to influence the motivation to speak up included seniority, relationships and familiarity with patient cases. CONCLUSIONS: Creating an atmosphere of safety and equality in which team members feel confident in expressing their personal views without fear of reprisal or embarrassment is necessary to encourage ICU staff members, regardless of their position, to speak up. Because harmony and saving face is valued in Chinese culture, training nurses and doctors to speak up by focusing on human factors and values rather than simply addressing conflict management is desirable in this context. PMID- 28801409 TI - What is the prevalence of and associations with forced labour experiences among male migrants from Dolakha, Nepal? Findings from a cross-sectional study of returnee migrants. AB - OBJECTIVES: Growing numbers of people are migrating outside their country for work, and many experience precarious conditions, which have been linked to poor physical and mental health. While international dialogue on human trafficking, forced labour and slavery increases, prevalence data of such experiences remain limited. METHODS: Men from Dolakha, Nepal, who had ever migrated outside of Nepal for work were interviewed on their experiences, from predeparture to return (n=194). Forced labour was assessed among those who returned within the past 10 years (n=140) using the International Labour Organization's forced labour dimensions: (1) unfree recruitment; (2) work and life under duress; and (3) impossibility to leave employer. Forced labour is positive if any one of the dimensions is positive. RESULTS: Participants had worked in India (34%), Malaysia (34%) and the Gulf Cooperation Council countries (29%), working in factories (29%), as labourers/porters (15%) or in skilled employment (12%). Among more recent returnees (n=140), 44% experienced unfree recruitment, 71% work and life under duress and 14% impossibility to leave employer. Overall, 73% experienced forced labour during their most recent labour migration.Forced labour was more prevalent among those who had taken loans for their migration (PR 1.23) and slightly less prevalent among those who had migrated more than once (PR 0.87); however the proportion of those who experienced forced labour was still high (67%). Age, destination and duration of stay were associated with only certain dimensions of forced labour. CONCLUSION: Forced labour experiences were common during recruitment and at destination. Migrant workers need better advice on assessing agencies and brokers, and on accessing services at destinations. As labour migration from Nepal is not likely to reduce in the near future, interventions and policies at both source and destinations need to better address the challenges migrants face so they can achieve safer outcomes. PMID- 28801408 TI - A cross-sectional study of travel patterns of older adults in the USA during 2015: implications for mobility and traffic safety. AB - BACKGROUND: With an ever increasing population of older adults (65+ years) in the USA, a better understanding of this population's travel patterns is needed to improve travel mobility and transportation safety. OBJECTIVE: In this study, we described the travel patterns of older adults in the USA during 2015. METHODS: Travel patterns of older adults (65-74 and 75+ years) were compared with younger adults (25-64 years) by frequency and proportion of daily trips. The daily trips of various age groups were estimated using the 2015 American Time Use Survey. RESULTS: The percentage of daily travellers was 88% for adults (25-64 years), 75% for adults (65-74 years) and 68% for adults (75+ years). While the percentage of privately owned vehicle (POV) drivers and average time of driving POVs decreased, the percentage of POV passengers increased as adults aged. Females were less likely to drive POVs and had decreased average daily driving time, but they were more likely to ride in POVs as passengers and had longer average daily riding times than their male counterparts across all age groups. Older adults were more likely to travel in the mornings and early afternoons (from 8:00 to 15:59) while younger adults were more likely to travel in the late afternoons and early evenings (from 16:00 to 19:59). CONCLUSIONS: POV use is the predominant mode of transit in the USA. As adults age, the percentages of daily travellers and POV drivers decrease. This pattern is more apparent among females than males. This study delineated travel patterns of older adults using a 2015 national survey, and the findings facilitate traffic systems designers and policy-makers to develop and implement initiatives to accommodate older adults' mobility needs and improve traffic safety. PMID- 28801410 TI - Radiographic features of importance in the National Institute for Occupational Safety and Health-administered Coal Workers' Health Surveillance Program: characterising the use of the 'other symbols'. AB - OBJECTIVE: The National Institute for Occupation Safety and Health-administered Coal Workers' Health Surveillance Program (CWHSP) provides radiographic pneumoconiosis screening for US coal miners. Radiographs are classified by readers according to International Labour Office criteria. In addition to pneumoconiotic parenchymal and pleural lung abnormalities, readers document radiographic features of importance (other symbols). Other symbols are not meant to imply a diagnosis or interpretation but are relevant as they provide information beyond a pneumoconiosis classification for features related to dust exposure and other aetiologies. Our objective was to summarise other symbol data from 48 years of CWHSP participants. METHODS: Chest radiograph classifications obtained from CWHSP participants between July 1968 and July 2016 were analysed. Any 'other symbol' indication from any of the readings were counted. Frequencies were tabulated by individual reader and those identified by any reader. RESULTS: Of the 469 922 radiographs included in this study, nearly 15% had at least one reader identify a radiographic feature of importance. The most commonly identified other symbol was cancer (excluding mesothelioma) (6.83%), followed by emphysema (1.68%). Some features were rarely identified over the 48 years of data collection such as rheumatoid pneumoconiosis (n=46), pneumothorax (n=32), mesothelioma (n=12) and rounded atelectasis (n=4). CONCLUSIONS: This is the largest study to date describing radiographic features of importance as part of routine chest radiographic surveillance. While these symbols are not diagnostic they can be used to describe features associated with dust exposure. One of the most commonly identified radiographic features in our population is emphysema which is associated with respirable dust exposure. These results can be compared with other dust exposed populations. PMID- 28801411 TI - Exploring newly qualified doctors' workplace stressors: an interview study from Australia. AB - PURPOSE: Postgraduate year 1 (PGY1) doctors suffer from high levels of psychological distress, yet the contributory factors are poorly understood. This study used an existing model of workplace stress to explore the elements most pertinent to PGY1 doctors. In turn, the data were used to amend and refine the conceptual model to better reflect the unique experiences of PGY1 doctors. METHOD: Focus groups were undertaken with PGY1 doctors working at four different health services in Victoria, Australia. Transcripts were coded using Michie's model of workplace stress as the initial coding template. Remaining text was coded inductively and the supplementary codes were used to modify and amplify Michie's framework. RESULTS: There were 37 participants in total. Key themes included stressors intrinsic to the job, such as work overload and long hours, as well as those related to the context of work such as lack of role clarity and relationships with colleagues. The main modification to Michie's framework was the addition of the theme of uncertainty. This concept related to most of the pre existing themes in complex ways, culminating in an overall sense of anxiety. CONCLUSIONS: Michie's model of workplace stress can be effectively used to explore the stressors experienced by PGY1 doctors. Pervasive uncertainty may help to explain the high levels of psychological morbidity in this group. While some uncertainty will always remain, the medical education community must seek ways to improve role clarity and promote mutual respect. PMID- 28801412 TI - Health practitioners' perceptions of adopting clinical prediction rules in the management of musculoskeletal pain: a qualitative study in Australia. AB - OBJECTIVES: To investigate health practitioners' understanding and practice behaviours with regards to clinical prediction rules (CPRs) and explore their perceptions of adopting a new whiplash CPR. DESIGN: Qualitative study using six semistructured focus groups. SETTING: Primary and secondary care in New South Wales and Queensland, Australia. PARTICIPANTS: Physiotherapists (n=19), chiropractors (n=6) and osteopaths (n=3) were purposively sampled to include health practitioners who provide routine treatment to people with whiplash associated disorders. METHODS: Focus group discussions (n=6) were audio-recorded, transcribed verbatim and analysed using an inductive thematic approach. RESULTS: Health practitioners' understanding and use of CPRs were mixed. Clinicians considered components relating to acceptability ('whether I agree with it') and implementation ('how I'll use it') when deciding on whether to adopt a new CPR. Acceptability was informed by four themes: knowledge and understanding, CPR type, congruence and weighted value. Consideration of matters that promote implementation occurred once a CPR was deemed to be acceptable. Three themes were identified as potentially enhancing whiplash CPR implementation: the presence of an external driver of adoption, flexibility in how the CPR could be administered and guidance regarding communication of CPR output to patients. CONCLUSIONS: Education on CPR purpose and fit with practice is needed to enhance the perceived acceptability of CPRs. Strategies that facilitate practitioner motivation, enable administrative flexibility and assist clinicians in communicating the results of the whiplash CPR could promote adoption of the whiplash CPR. PMID- 28801413 TI - Effectiveness of rehabilitation after a total hip arthroplasty: a protocol for an observational study for the comparison of usual care in the Netherlands versus Germany. AB - INTRODUCTION: Osteoarthritis is the most common joint disorder worldwide. Total hip arthroplasty (THA) is considered one of the most effective treatments for end stage hip osteoarthritis. The number of THAs is expected to increase dramatically in the coming decades. Usual postoperative rehabilitation after primary THA differs between the German and the Dutch system. In the Netherlands, patients undergo fast-track surgery and are discharged into their home environment within a few days without receiving any aftercare. In Germany, patients stay in the hospital for about 12 days before being transferred to a rehabilitation centre for a period of 3 weeks. The superficially more cost-effective Dutch system of usual care after THA is judged critically in both countries due to suboptimal rehabilitation outcomes. The aim of this study is therefore to compare the Dutch with the German usual care rehabilitation after primary THA. It is hypothesised that the German procedure is more effective in terms of functional outcomes and patient satisfaction than the Dutch procedure and that in the long run the German approach is more cost-effective than the Dutch system. METHODS AND ANALYSIS: Medical effectiveness will be assessed at four different time points by means of patient self-reported questionnaires and functional tests. Assessments include the Hip disability and Osteoarthritis Outcome Score, Patient Acceptable Symptom State, Short Form 36, EuroQol 5 Dimensions 3 Level Questionnaire, Timed Up & Go Test and Five Times Sit-to-Stand Test. Additionally, long-term economic aspects in both countries will be assessed from a societal perspective, to get a first impression on whether cutting costs for rehabilitation, as practised in the Netherlands, really disburdens the healthcare system efficiently. ETHICS AND DISSEMINATION: The study is approved by the Institutional Review Boards of both University Medical Center Groningen (METc2015/483) and Hannover Medical School (no 2874-2015) and will be conducted according to the principles of the Declaration of Helsinki (64th, 2013). The results of the study will be published in international peer-reviewed scientific journals. Patient data will be presented anonymously in any publication or scientific journal. TRIAL REGISTRATION NUMBER: DRKS00011345; Pre-results. PMID- 28801414 TI - Transformation of mortality in a remote Australian Aboriginal community: a retrospective observational study. AB - OBJECTIVES: To describe trends in ages and causes of death in a remote-living Australian Aboriginal group over a recent 50-year period. DESIGN: A retrospective observational study, from 1960 to 2010, of deaths and people starting dialysis, using data from local clinic, parish, dialysis and birthweight registers. SETTING: A remote island community in the Top End of Australia's Northern Territory, where a Catholic mission was established in 1911. The estimated Aboriginal population was about 800 in 1960 and 2260 in 2011. PARTICIPANTS: All Aboriginal residents of this community whose deaths had been recorded. OUTCOME MEASURES: Annual frequencies and rates of terminal events (deaths and dialysis starts) by age group and cause of death. RESULTS: Against a background of high rates of low birth weight, 223 deaths in infants and children and 934 deaths in adults (age > 15 years) were recorded; 88% were of natural causes. Most deaths in the 1960s were in infants and children. However, over time these fell dramatically, across the birthweight spectrum, while adult deaths progressively increased. The leading causes of adult natural deaths were chronic lung disease, cardiovascular disease and, more recently, renal failure, and rates were increased twofold in those of low birth weight. However, rates of natural adult deaths have been falling briskly since 1986, most markedly among people of age >=45 years. The population is increasing and its age structure is maturing. CONCLUSIONS: The changes in death profiles, the expression of the Barker hypothesis and the ongoing increases in adult life expectancy reflect epidemiological and health transitions of astonishing rapidity. These probably flow from advances in public health policy and healthcare delivery, as well as improved inter-sectoral services, which are all to be celebrated. Other remote communities in Australia are experiencing the same phenomena, and similar events are well advanced in many developing countries. PMID- 28801415 TI - Randomised feasibility trial into the effects of low-frequency electrical muscle stimulation in advanced heart failure patients. AB - OBJECTIVES: Low-frequency electrical muscle stimulation (LF-EMS) may have the potential to reduce breathlessness and increase exercise capacity in the chronic heart failure population who struggle to adhere to conventional exercise. The study's aim was to establish if a randomised controlled trial of LF-EMS was feasible. DESIGN AND SETTING: Double blind (participants, outcome assessors), randomised study in a secondary care outpatient cardiac rehabilitation programme. PARTICIPANTS: Patients with severe heart failure (New York Heart Association class III-IV) having left ventricular ejection fraction <40% documented by echocardiography were eligible. INTERVENTIONS: Participants were randomised (remotely by computer) to 8 weeks (5*60 mins per week) of either LF-EMS intervention (4 Hz, continuous, n=30) or sham placebo (skin level stimulation only, n=30) of the quadriceps and hamstrings muscles. Participants used the LF EMS straps at home and were supervised weekly OUTCOME MEASURES: Recruitment, adherence and tolerability to the intervention were measured during the trial as well as physiological outcomes (primary outcome: 6 min walk, secondary outcomes: quadriceps strength, quality of life and physical activity). RESULTS: Sixty of 171 eligible participants (35.08%) were recruited to the trial. 12 (20%) of the 60 patients (4 LF-EMS and 8 sham) withdrew. Forty-one patients (68.3%), adhered to the protocol for at least 70% of the sessions. The physiological measures indicated no significant differences between groups in 6 min walk distance(p=0.13) and quality of life (p=0.55) although both outcomes improved more with LF-EMS. CONCLUSION: Patients with severe heart failure can be recruited to and tolerate LF-EMS studies. A larger randomised controlled trial (RCT) in the advanced heart failure population is technically feasible, although adherence to follow-up would be challenging. The preliminary improvements in exercise capacity and quality of life were minimal and this should be considered if planning a larger trial. TRIAL REGISTRATION NUMBER: ISRCTN16749049. PMID- 28801417 TI - Optic nerve sheath diameter sonography for the diagnosis of increased intracranial pressure: a systematic review and meta-analysis protocol. AB - INTRODUCTION: Increased intracranial pressure (ICP) is a significant neurological issue that may lead to permanent neurological sequelae. When evaluating patients with traumatic brain injury, it is crucial to identify those with high ICP in order to expedite ICP lowering measures and maintain adequate cerebral perfusion. Several measures are used to recognise patients with increased ICP including CT scan, MRI, ICP monitor, and lumbar puncture (LP). However, these tests can be invasive, associated with radiation exposure, contraindicated, or not readily available. Ultrasonography measurement of the optic nerve sheath diameter (ONSD) is proposed as a non-invasive and quick measure to identify high ICP. The aim of this systematic review and meta-analysis will be to examine the accuracy of ONSD sonography for increased ICP diagnosis. METHODS AND ANALYSES: We will include published and unpublished randomised controlled trials, observational studies, and abstracts, with no publication type or language restrictions. Search strategies will be designed to peruse the MEDLINE, Embase, Web of Science, WHO Clinical Trials, ClinicalTrials.gov, CINAHL, and the Cochrane Library databases. We will also implement strategies to search grey literature. Two reviewers will independently complete data abstraction and conduct quality assessment. Included studies will be assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. We will construct the hierarchical summary receiver operating characteristic curve for included studies and pool sensitivity and specificity using the bivariate model. We also plan to conduct prespecified subgroup analyses to explore heterogeneity. The overall quality of evidence will be rated using Grading of Recommendations, Assessment, Development and Evaluations (GRADE). ETHICS AND DISSEMINATION: Research ethics board approval is not required for this study as it draws from published data and raises no concerns related to patient privacy. This review will provide a comprehensive assessment of the evidence on ONSD sonography diagnostic accuracy and is directed to a wide audience. Results from the review will be disseminated extensively through conferences and submitted to a peer-reviewed journal for publication. PROSPERO REGISTRATION NUMBER: CRD42017055485. CLINICAL TRIAL NUMBER: Trial registration number is NCT00783809. PMID- 28801416 TI - Outcome of revascularisation in stable coronary artery disease without ischaemia: a Danish registry-based follow-up study. AB - OBJECTIVES: In stable coronary artery disease (CAD), coronary revascularisation may reduce mortality of patients with a certain amount of left ventricular myocardial ischaemia. However, revascularisation does not always follow the guidance suggested by ischaemia testing. We compared outcomes in patients without ischaemia who had either revascularisation or medical treatment. DESIGN AND POPULATION: Based on registries, 1327 consecutive patients with normal myocardial perfusion scintigraphy (MPS) and 278 with fixed perfusion defects were followed for a median of 6.1 years. Most patients received medical therapy alone (Med), but 26 (2%) with a normal MPS and 15 (5%) with fixed perfusion defects underwent revascularisation (Revasc). OUTCOME MEASURES: Incidence rates of all-cause death (ACD) and rates of cardiac death/myocardial infarction (CD/MI). RESULTS: With a normal MPS, the ACD rate was 6.2%/year in the Revasc group versus 1.9%/year in the Med group (p=0.01); the CD/MI rates were 6.9%/year and 0.6%/year, respectively (p<0.00001). Results persisted after adjustment for predictors of revascularisation, in particular angina score, and in comparisons of matched Revasc and Med patients. With fixed defects, the ACD rate was 9.1%/year in the Revasc group and 6.7%/year in the Med group (p=0.44); the CD/MI rate was 5.0%/year versus 4.2%/year, respectively (p=0.69). If adjusted for angiographic variables or analysed in matched subsets, differences remained insignificant. CONCLUSIONS: With normal MPS, revascularisation conferred a higher risk, even after adjustment for predictors of revascularisation. With fixed defects, the Revascversus Med difference was close to equipoise. Hence, in patients with stable CAD without ischaemia, we could not find evidence to justify exceptional revascularisation. PMID- 28801418 TI - Value of light microscopy to diagnose urogenital gonorrhoea: a diagnostic test study in Indonesian clinic-based and outreach sexually transmitted infections services. AB - INTRODUCTION: Gonorrhoea is a common sexually transmitted disease caused by Neisseria gonorrhoeae (Ng) infection. Light microscopy of urogenital smears is used as a simple tool to diagnose urogenital gonorrhoea in many resource-limited settings. We aimed to evaluate the accuracy of light microscopy to diagnose urogenital gonorrhoea as compared with a PCR-based test. METHODS: In 2014, we examined 632 male urethral and 360 endocervical smears in clinic-based and outreach settings in Jakarta, Yogyakarta and Denpasar, Indonesia. Using the detection of Ng DNA by a validated PCR as reference test, we evaluated the accuracy of two light microscopic criteria to diagnose urogenital gonorrhoea in genital smears: (1) the presence of intracellular Gram-negative diplococci (IGND) and (2) >=5 polymorphonuclear leucocytes (PMNL)/oil-immersion field (oif) in urethral or >=20 PMNL/oif in endocervical smears. RESULTS: In male urethral smears, IGND testing had a sensitivity (95% CI), specificity (95% CI) and kappa+/ SE of 59.0% (50.1 to 67.4), 89.4% (86.3 to 91.9) and 0.49+/-0.04, respectively. For PMNL count, these were 59.0% (50.1 to 67.4), 83.7% (80.2 to 86.9) and 0.40+/ 0.04, respectively. The accuracy of IGND in the clinic-based settings (72.0% (57.5 to 83.3), 95.2% (91.8 to 97.5) and 0.68+/-0.06, respectively) was better than in the outreach settings (51.2% (40.0 to 62.3), 83.4% (78.2 to 87.8) and 0.35+/-0.06, respectively). In endocervical smears, light microscopy performed poorly regardless of the setting or symptomatology, with kappas ranging from 0.09 to 0.24. CONCLUSION: Light microscopy using IGND and PMNL criteria can be an option with moderate accuracy to diagnose urethral gonorrhoea among males in a clinic-based setting. The poor accuracy in detecting endocervical infections indicates an urgent need to implement advanced methods, such as PCR. Further investigations are needed to identify the poor diagnostic outcome in outreach services. PMID- 28801419 TI - SSRI antidepressant use potentiates weight gain in the context of unhealthy lifestyles: results from a 4-year Australian follow-up study. AB - OBJECTIVE: To examine the association between antidepressant use and weight gain, as well as the interaction with lifestyle factors. DESIGN: Longitudinal study. SETTING AND PARTICIPANTS: We used data from 2334 adults from two stages (4.4 years apart) of the North West Adelaide Health Study, including validated diet and lifestyle questionnaires, measured body weight and linked pharmaceutical prescription data. MAIN OUTCOME MEASURES: Body weight change. RESULTS: 188 (8.1%) participants had a mean annual number of 1-2 antidepressant prescriptions, and 212 (9.1%) had over two prescriptions. The mean annual weight gain was 0.12, 0.18 and 0.28 kg in non-users, low (1-2 prescriptions/year) and high (>2 prescriptions/year) antidepressant users, respectively. In multivariable regression models, antidepressant use was positively associated with weight gain: high antidepressant users gained an extra 0.22 (95% CI 0.00 to 0.44) kg per year. This association was mainly due to selective serotonin reuptake inhibitor (SSRI) use. High SSRI users gained 0.48 (95% CI 0.20 to 0.76) kg more than non-users. There was no association between tricyclic or other antidepressant use and weight gain. The association between SSRI use and weight gain was stronger among those with high intake of Western diet, greater sedentary activity, and who smoked. CONCLUSIONS: SSRIs use was associated with weight gain in the presence of unhealthy behaviours including Western diet, sedentarism and smoking. PMID- 28801420 TI - Protocol study for a randomised, controlled, double-blind, clinical trial involving virtual reality and anodal transcranial direct current stimulation for the improvement of upper limb motor function in children with Down syndrome. AB - INTRODUCTION: Down syndrome results in neuromotor impairment that affects selective motor control, compromising the acquisition of motor skills and functional independence. The aim of the proposed study is to evaluate and compare the effects of multiple-monopolar anodal transcranial direct current stimulation and sham stimulation over the primary motor cortex during upper limb motor training involving virtual reality on motor control, muscle activity, cerebral activity and functional independence. METHODS AND ANALYSIS: A randomised, controlled, double-blind, clinical trial is proposed. The calculation of the sample size will be defined based on the results of a pilot study involving the same methods. The participants will be randomly allocated to two groups. Evaluations will be conducted before and after the intervention as well as 1 month after the end of the intervention process. At each evaluation, three dimensional analysis of upper limb movement muscle activity will be measured using electromyography, cerebral activity will be measured using an electroencephalogram system and intellectual capacity will be assessed using the Wechsler Intelligence Scale for Children. Virtual reality training will be performed three times a week (one 20 min session per day) for a total of 10 sessions. During the protocol, transcranial stimulation will be administered concomitantly to upper limb motor training. The results will be analysed statistically, with a p value<=0.05 considered indicative of statistical significance. ETHICAL ASPECTS AND PUBLICITY: The present study received approval from the Institutional Review Board of Universidade Nove de Julho (Sao Paulo,Brazil) under process number 1.540.113 and is registered with the Brazilian Registry of Clinical Trials (N degrees RBR3PHPXB). The participating institutions have presented a declaration of participation. The volunteers will be permitted to drop out of the study at any time with no negative repercussions. The results will be published and will contribute evidence regarding the use of this type of intervention on children. PMID- 28801422 TI - 'It's trying to manage the work': a qualitative evaluation of recruitment processes within a UK multicentre trial. AB - OBJECTIVES: To explore trial site staff's perceptions regarding barriers and facilitators to local recruitment. DESIGN: Qualitative semi-structured interviews with a range of trial site staff from four trial sites in the UK. Interviews were analysed thematically to identify common themes across sites, barriers that could be addressed and facilitators that could be shared with other sites. PARTICIPANTS: 11 members of staff from four trial sites: clinical grant Co applicant (n=1); Principal Investigators (n=3); Consultant Urologist (n=1); Research Nurses (n=5); Research Assistant (n=1). SETTING: Embedded within an ongoing randomised controlled trial (the TISU trial). TISU is a UK multicentre trial comparing therapeutic interventions for ureteric stones. RESULTS: Our study draws attention to the initial and ongoing burden of trial work that is involved throughout the duration of a clinical trial. In terms of building and sustaining a research culture, trial staff described the ongoing work of engagement that was required to ensure that clinical staff were both educated and motivated to help with the process of identifying and screening potential participants. Having adequate and sufficient organisational and staffing resources was highlighted as being a necessary prerequisite to successful recruitment both in terms of accessing potentially eligible patients and being able to maximise recruitment after patient identification. The nature of the research study design can also potentially generate challenging communicative work for recruiting staff which can prove particularly problematic. CONCLUSIONS: Our paper adds to existing research highlighting the importance of the hidden and complex work that is involved in clinical trial recruitment. Those designing and supporting the operationalisation of clinical trials must recognise and support the mitigation of this 'work'. While much of the work is likely to be contextually sensitive at the level of local sites and for individual trials, some aspects are ubiquitous issues for delivery of trials more generally. TRIAL REGISTRATION NUMBER: ISRCTN No 92289221; Pre-results. PMID- 28801421 TI - Electroacupuncture for treating insomnia in patients with cancer: a study protocol for a randomised pilot clinical trial. AB - INTRODUCTION: Although insomnia is one of the most prevalent and disturbing symptoms among patients with cancer, it has not been properly managed. Electroacupuncture (EA) has received attention as a promising intervention for insomnia, and a few previous studies have reported that this intervention may be beneficial for treating insomnia in patients with cancer. The aim of this pilot study is to explore the feasibility and preliminary effectiveness of EA on the sleep disturbance of patients with cancer with insomnia using a subjective method, patient-reported questionnaires and an objective tool, actigraphy, to measure the quality of sleep. METHODS AND ANALYSIS: This is a study protocol for a randomised, three-arm, multicentre, pilot clinical trial. A total of 45 patients with cancer who have continuous insomnia related to cancer treatment or cancer itself will be randomly allocated to an EA group, sham EA group or usual care group in equal proportions. The EA group will receive 10 sessions of EA treatment over 4 weeks. The sham EA group will receive sham EA at non-acupoints using non-penetrating Streitberger acupuncture needles with mock EA. The usual care group will not receive EA treatment. All participants will be provided a brochure on the management of sleep disorders regardless of their group assignment. The primary outcome measure is the mean change in the insomnia severity index from the baseline to week 5. Information related to sleep quality will also be obtained through the Pittsburgh Sleep Quality Index, a sleep diary and actigraphy. Participants will complete the trial by visiting the research centre at week 9 for follow-up assessment. ETHICS AND DISSEMINATION: This study protocol was approved by the institutional review boards of each research centre. Written informed consent will be obtained from all participants. The result of this study will be published in peer-reviewed journals or presented at academic conferences. TRIAL REGISTRATION NUMBER: KCT0002162; Pre-results. PMID- 28801423 TI - Comparative efficacy and acceptability of antidepressants, psychological interventions, and their combination for depressive disorder in children and adolescents: protocol for a network meta-analysis. AB - INTRODUCTION: Depressive disorder is common in children and adolescents, with important consequences and serious impairments in terms of personal and social functioning. While both pharmacological and psychological interventions have been shown to be effective, there is still uncertainty about the balance between these and what treatment strategy should be preferred in clinical practice. Therefore, we aim to compare and rank in a network meta-analysis (NMA) the commonly used psychological, pharmacological and combined interventions for depressive disorder in children and adolescents. METHODS AND ANALYSIS: We will update the literature search of two previous NMAs for the identification of trials of antidepressant and psychotherapy alone for depressive disorder in children and adolescents. For identification of trials of combination interventions, seven databases (PubMed, EMBASE, CENTRAL (Cochrane Central Register of Controlled Trials), Web of Science, PsycINFO, CINAHL, LiLACS) will be searched from date of inception. We will also search ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform and check relevant reports on the US Food and Drug Administration website for unpublished data. Building on our previous findings in the field, we will include any commonly prescribed oral antidepressants and any manualised or structured psychotherapies, as well as their combinations. Randomised controlled trials assessing any active intervention against active comparator or pill placebo/psychological controls in acute treatment for depressive disorder in children and adolescents will be included. The primary outcomes will be efficacy (mean change in depressive symptoms), and acceptability of treatment (dropout rate due to any cause). The secondary outcomes will be remission rate, tolerability of treatment (dropouts for adverse events), as well as suicide related outcomes (suicidal behaviour or ideation). We will perform Bayesian NMAs for all relative outcome measures. Subgroup analyses and sensitivity analyses will be conducted to assess the robustness of the findings. DISSEMINATION: This NMA will provide the most up to date and clinically useful information about the comparative efficacy and acceptability of antidepressants, psychological intervention and their combination in the acute treatment of children and adolescents with depressive disorder. This is the newest NMA and therefore these results are very important in terms of evidence-based medicine. The results will be disseminated through peer-reviewed publication. PROTOCOL REGISTRATION: PROSPERO CRD42015020841. PMID- 28801424 TI - A cost-effectiveness comparison of the NICE 2015 and WHO 2013 diagnostic criteria for women with gestational diabetes with and without risk factors. AB - OBJECTIVES: To compare the cost-effectiveness (CE) of the National Institute for Health and Care Excellence (NICE) 2015 and the WHO 2013 diagnostic thresholds for gestational diabetes mellitus (GDM). SETTING: The analysis was from the perspective of the National Health Service in England and Wales. PARTICIPANTS: 6221 patients from four of the Hyperglycaemia and Adverse Pregnancy Outcomes (HAPO) study centres (two UK, two Australian), 6308 patients from the Atlantic Diabetes in Pregnancy study and 12 755 patients from UK clinical practice. PRIMARY AND SECONDARY OUTCOME MEASURES PLANNED: The incremental cost per quality adjusted life year (QALY), net monetary benefit (NMB) and the probability of being cost-effective at CE thresholds of L20 000 and L30 000 per QALY. RESULTS: In a population of pregnant women from the four HAPO study centres and using NICE defined risk factors for GDM, diagnosing GDM using NICE 2015 criteria had an NMB of L239 902 (relative to no treatment) at a CE threshold of L30 000 per QALY compared with WHO 2013 criteria, which had an NMB of L186 675. NICE 2015 criteria had a 51.5% probability of being cost-effective compared with the WHO 2013 diagnostic criteria, which had a 27.6% probability of being cost-effective (no treatment had a 21.0% probability of being cost-effective). For women without NICE risk factors in this population, the NMBs for NICE 2015 and WHO 2013 criteria were both negative relative to no treatment and no treatment had a 78.1% probability of being cost-effective. CONCLUSION: The NICE 2015 diagnostic criteria for GDM can be considered cost-effective relative to the WHO 2013 alternative at a CE threshold of L30 000 per QALY. Universal screening for GDM was not found to be cost-effective relative to screening based on NICE risk factors. PMID- 28801425 TI - Non-pharmacological self-management for people living with migraine or tension type headache: a systematic review including analysis of intervention components. AB - OBJECTIVES: To assess the effect of non-pharmacological self-management interventions against usual care, and to explore different components and delivery methods within those interventions PARTICIPANTS: People living with migraine and/or tension-type headache INTERVENTIONS: Non-pharmacological educational or psychological self-management interventions; excluding biofeedback and physical therapy.We assessed the overall effectiveness against usual care on headache frequency, pain intensity, mood, headache-related disability, quality of life and medication consumption in meta-analysis.We also provide preliminary evidence on the effectiveness of intervention components and delivery methods. RESULTS: We found a small overall effect for the superiority of self-management interventions over usual care, with a standardised mean difference (SMD) of -0.36 (-0.45 to -0.26) for pain intensity; -0.32 (-0.42 to -0.22) for headache-related disability, 0.32 (0.20 to 0.45) for quality of life and a moderate effect on mood (SMD=0.53 (-0.66 to -0.40)). We did not find an effect on headache frequency (SMD=-0.07 (-0.22 to 0.08)).Assessment of components and characteristics suggests a larger effect on pain intensity in interventions that included explicit educational components (-0.51 (-0.68 to -0.34) vs -0.28 (-0.40 to -0.16)); mindfulness components (-0.50 (-0.82 to -0.18) vs 0.34 (-0.44 to -0.24)) and in interventions delivered in groups vs one-to-one delivery (0.56 (-0.72 to -0.40) vs -0.39 (-0.52 to -0.27)) and larger effects on mood in interventions including a cognitive-behavioural therapy (CBT) component with an SMD of -0.72 (-0.93 to 0.51) compared with those without CBT -0.41 (-0.58 to -0.24). CONCLUSION: Overall we found that self-management interventions for migraine and tension-type headache are more effective than usual care in reducing pain intensity, mood and headache-related disability, but have no effect on headache frequency. Preliminary findings also suggest that including CBT, mindfulness and educational components in interventions, and delivery in groups may increase effectiveness. TRIAL REGISTRATION NUMBER: PROSPERO 2016:CRD42016041291. PMID- 28801426 TI - Patient preferences for venous thromboembolism prophylaxis after injury: a discrete choice experiment. AB - OBJECTIVE: Limited evidence for the optimal venous thromboembolism (VTE) prophylaxis regimen in orthopaedic trauma leads to variability in regimens. We sought to delineate patient preferences towards cost, complication profile, and administration route (oral tablet vs. subcutaneous injection). DESIGN: Discrete choice experiment (DCE). SETTING: Level 1 trauma center in Baltimore, USA. PARTICIPANTS: 232 adult trauma patients (mean age 47.9 years) with pelvic or acetabular fractures or operative extremity fractures. PRIMARY AND SECONDARY OUTCOME MEASURES: Relative preferences and trade-off estimates for a 1% reduction in complications were estimated using multinomial logit modelling. Interaction terms were added to the model to assess heterogeneity in preferences. RESULTS: Patients preferred oral tablets over subcutaneous injections (marginal utility, 0.16; 95% CI: 0.11 - 0.21, P<0.0001). Preferences changed in favor of subcutaneous injections with an absolute risk reduction of 6.98% in bleeding, 4.53% in wound complications requiring reoperation, 1.27% in VTE, and 0.07% in death from pulmonary embolism (PE). Patient characteristics (sex, race, type of injury, time since injury) affected patient preferences (P<0.01). CONCLUSIONS: Patients preferred oral prophylaxis and were most concerned about risk of death from PE. Furthermore, the findings estimated the trade-offs acceptable to patients and heterogeneity in preferences for VTE prophylaxis. PMID- 28801427 TI - Effect of Community ART Groups on retention-in-care among patients on ART in Tete Province, Mozambique: a cohort study. AB - OBJECTIVES: Estimate the effect of participation in Community ART Groups (CAG) versus individual care on retention-in-care (RIC) on antiretroviral therapy (ART). DESIGN: Retrospective cohort study. SETTING: High levels of attrition (death or loss-to-follow-up (LTFU) combined) on ART indicate that delivery models need to adapt in sub-Saharan Africa. In 2008, patients more than 6 months on ART began forming CAG, and took turns to collect ART refills at the health facility, in Tete Province, Mozambique,. PARTICIPANTS: 2406 adult patients, retained in care for at least 6 months after starting ART, during the study period (date of CAG introduction at the health facility-30 April 2012). METHODS: Data up to 30 April 2012 were collected from patient records at eight health facilities. Survival analysis was used to compare RIC among patients in CAG and patients in individual care, with joining a CAG treated as an irreversible time-dependent variable. Multivariable Cox regression was used to estimate the effect of CAG on RIC, adjusted for age, sex and health facility type and stratified by calendar cohort. RESULTS: 12-month and 24-monthRIC from the time of eligibility were, respectively, 89.5% and 82.3% among patients in individual care and 99.1% and 97.5% among those in CAGs (p<0.0001). CAG members had a greater than fivefold reduction in risk of dying or being LTFU (adjusted HR: 0.18, 95% CI 0.11 to 0.29). CONCLUSIONS: Among patients on ART, RIC was substantially better among those in CAGs than those in individual care. This study confirms that patient driven ART distribution through CAGs results in higher RIC among patients who are stable on ART. PMID- 28801428 TI - Relationship between estimated cardiovascular disease risk and insulin resistance in a black African population living with HIV: a cross-sectional study from Cameroon. AB - OBJECTIVES: Cardiovascular disease (CVD) and metabolic diseases are growing concerns among patients with HIV infection as a consequence of the improving survival of this population. We aimed to assess the relationship between CVD risk and insulin resistance in a group of black African individuals with HIV infection. METHODS: This cross-sectional study involved patients with HIV infection aged 30-74 years and followed up at the Yaounde Central Hospital, Cameroon. Absolute CVD risk was calculated using the Framingham and the DAD CVD risk equations while the HOMA-IR index was used to assess insulin resistance (index >=2.1). RESULTS: A total of 452 patients (361 women; 80%) were screened. The mean age was 44.4 years and most of the respondents were on antiretroviral therapy (88.5%). The median 5-year cardiovascular risk was 0.7% (25th-75th percentiles: 0.2-2.0) and 0.6% (0.3-1.3) according to the Framingham and DAD equations respectively. Of all participants, 47.3% were insulin resistant. The Framingham equation derived absolute CVD risk was significantly associated with insulin resistance; while no linear association was found using the DAD equation. CONCLUSION: The relationship between cardiovascular risk and insulin resistance in black African patients with HIV infection seems to depend on the cardiovascular risk equation used. PMID- 28801431 TI - Socioeconomic and geographical variation in general practitioner consultations for allergic rhinitis in England, 2003-2014: an observational study. AB - OBJECTIVE: Allergic rhinitis (AR) is a global health problem, potentially impacting individuals' sleep, work and social life. We aimed to use a surveillance network of general practitioners (GPs) to describe the epidemiology of AR consultations in England. SETTING: A large GP surveillance network covering approximately 53% of the English population. METHODS: GP consultations for AR across England between 30 December 2002 and 31 December 2014 were analysed. Using more granular data available between 2 April 2012 and 31 December 2014 rates and rate ratios (RR) of AR were further analysed in different age groups, gender, rural-urban classification and index of multiple deprivation score quintile of location of GP. RESULTS: The mean weekly rate for AR consultations was 19.8 consultations per 100 000 GP registered patients (range 1.13-207), with a regular peak occurring during June (weeks 24-26), and a smaller peak during April. Between 1 April 2012 and 31 December 2014, the highest mean daily rates of consultations per 1 00 000 were: in age group 5-14 years (rate=8.02, RR 6.65, 95% CI 6.38 to 6.93); females (rate=4.57, RR 1.12 95% CI 1.12 to 1.13); persons registered at a GP in the most socioeconomically deprived quintile local authority (rate=5.69, RR 1.48, 95% CI 1.47 to 1.49) or in an urban area with major conurbation (rate=5.91, RR 1.78, 95% CI 1.69 to 1.87). CONCLUSIONS: AR rates were higher in those aged 5-14 years, females and in urban and socioeconomically deprived areas. This needs to be viewed in the context of this study's limitations but should be considered in health promotion and service planning. PMID- 28801429 TI - Multicentric randomised study of Helicobacter pylori eradication and pepsinogen testing for prevention of gastric cancer mortality: the GISTAR study. AB - INTRODUCTION: Population-based eradication of Helicobacter pylori has been suggested to be cost-effective and is recommended by international guidelines. However, the potential adverse effects of widespread antibiotic use that this would entail have not been sufficiently studied. An alternative way to decrease gastric cancer mortality is by non-invasive search for precancerous lesions, in particular gastric atrophy; pepsinogen tests are the best currently available alternative. The primary objective of GISTAR is to determine whether H pylori eradication combined with pepsinogen testing reduces mortality from gastric cancer among 40-64-year-old individuals. The secondary objectives include evaluation of H pylori eradication effectiveness in gastric cancer prevention in patients with precancerous lesions and evaluation of the potential adverse events, including effects on microbiome. METHODS AND ANALYSIS: Individuals are recruited from general population (50% men) in areas with high gastric cancer risk in Europe and undergo detailed lifestyle and medical history questionnaire before being randomly allocated to intervention or control groups. The intervention group undergoes H pylori testing and is offered eradication therapy if positive; in addition, pepsinogen levels are detected in plasma and those with decreased levels are referred for upper endoscopy. All participants are offered faecal occult blood testing as an incentive for study participation. Effectiveness of eradication and the spectrum of adverse events are evaluated in study subpopulations. A 35% difference in gastric cancer mortality between the groups is expected to be detectable at 90% power after 15 years if 30 000 individuals are recruited. Biological materials are biobanked for the main and ancillary studies. The study procedure and assumptions will be tested during the pilot phase. ETHICS AND DISSEMINATION: The study was approved by the respective ethics committees. An independent Data Safety and Monitoring Board has been established. The findings will be published in peer-reviewed journals and presented at scientific meetings. TRIAL REGISTRATION NUMBER: NCT02047994. PMID- 28801430 TI - Association between pregravid physical activity and family history of stroke and risk of stillbirth: population-based cohort study. AB - OBJECTIVES: To evaluate whether family history of disease and pregravid lifestyle and cardiovascular risk factors are associated with subsequent stillbirth delivery. DESIGN: Prepregnancy cohort study. SETTING: Cohort Norway regional health surveys (1994-2003) linked to Medical Birth Registry of Norway for deliveries through 2012. PARTICIPANTS: 13 497 singleton births (> 22 weeks gestation) in 8478 women. MAIN OUTCOME MEASURE: Risk of stillbirth evaluated by Poisson regression. RESULTS: Mean (SD) length of follow-up was 5.5 (3.5) years. In analyses adjusting for baseline age and length of follow-up, >=3 hours of baseline past-year vigorous physical activity per week (resulting in shortness of breath/sweating) was associated with increased risk of stillbirth compared with <1 hour/week of vigorous activity (incidence rate ratio, IRR 2.46; 95% CI 1.23 to 4.90). In contrast, baseline past-year light physical activity of >=3 hours per week associated with reduced risk of stillbirth compared with <3 hours of light physical activity per week (IRR 0.53; 95% CI 0.30 to 0.93). A family history of stroke associated with increased risk of stillbirth delivery (IRR 2.53; 95% CI 1.06 to 6.01). Because overweight/obese women may experience shortness of breath and sweating with less physical exertion than normal weight women, a sensitivity analysis was conducted limited to women with a normal BMI (> 18.5 and <25 kg/m2). Vigorous activity of >=3 hours per week (IRR of 4.50; 95% CI 1.72 to 11.79) and a family history of stroke (IRR of 3.81; 95% CI 1.31 to 11.07) were more strongly related to stillbirth risk among women with a normal BMI than that observed for all women combined. Established risk factors also associated with stillbirth risk. CONCLUSIONS: The study identified physical activity and family history of stroke as potential new risk factors for stillbirth delivery. PMID- 28801432 TI - Psychiatric disorders among people with cancer in low- and lower-middle-income countries: study protocol for a systematic review and meta-analysis. AB - INTRODUCTION: Cancer is a rapidly growing public health problem in low- and lower middle-income countries (LLMICs). There is evidence from upper-income countries that comorbid mental illness is common and can adversely impact cancer outcomes. Little is known about this burden in LLMICs. This systematic review has two aims. The first is to review the prevalence and patterns of psychiatric comorbidity in adults with cancer in LLMICs. The second is to review psychiatric treatment outcomes in this population. METHODS AND ANALYSIS: The review will be reported according to the Preferred Reporting Items for Systematic Review and Meta Analysis (PRISMA) guidelines. A systematic search of electronic databases (MEDLINE, PsycInfo, Embase and CINAHL) will be conducted. Studies will be included if they report the prevalence of psychiatric comorbidity, or if they evaluate psychiatric treatment outcomes, in adults with cancer living in LLMICs. The search will be limited to studies published in peer-reviewed journals between March 2002 and March 2017. The reference lists of included studies will be hand searched. Critical appraisal will be performed using Quality Assessment Tools from the National Institute of Health. Pooled prevalence meta-analysis is planned. ETHICS AND DISSEMINATION: Ethics approval is not required as no primary data will be collected. The results will be presented at conferences and published in a peer-reviewed journal. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017057103. PMID- 28801433 TI - Developing core economic outcome sets for asthma studies: a protocol for a systematic review. AB - INTRODUCTION: Core outcome sets are standardised lists of outcomes, which should be measured and reported in all clinical studies of a specific condition. This study aims to develop core outcome sets for economic evaluations in asthma studies. Economic outcomes include items such as costs, resource use or quality adjusted life years. The starting point in developing core outcome sets will be conducting a systematic literature review to establish a preliminary list of reporting items to be considered for inclusion in the core outcome set. METHODS AND ANALYSIS: We will conduct literature searches of peer-reviewed studies published from January 1990 to January 2017. These will include any comparative or observational studies (including economic models) and systematic reviews reporting economic outcomes. All identified economic outcomes will be tabulated together with the major study characteristics, such as population, study design, the nature and intensity of the intervention, mode of data collection and instrument(s) used to derive an outcome. We will undertake a 'realist synthesis review' to analyse the identified economic outcomes. The outcomes will be summarised in the context of evaluation perspectives, types of economic evaluation and methodological approaches. Parallel to undertaking a systematic review, we will conduct semistructured interviews with stakeholders (including people with personal experience of asthma, health professionals, researchers and decision makers) in order to explore additional outcomes which have not been considered, or used, in published studies. The list of outcomes generated from the systematic review and interviews with stakeholders will form the basis of a Delphi survey to refine the identified outcomes into a core outcome set. ETHICS AND DISSEMINATION: The review will not involve access to individual-level data. Findings from our systematic review will be communicated to a broad range of stakeholders including clinical guideline developers, research funders, trial registries, ethics committees and other regulators. PMID- 28801434 TI - Comparative effectiveness of six Chinese herb formulas for acute exacerbation of chronic obstructive pulmonary disease: protocol for systematic review and network meta-analysis. AB - INTRODUCTION: Chinese medicine is commonly used to combine with pharmacotherapy for the treatment of acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Six Chinese herb formulas involving Weijing decoction, Maxingshigan decoction, Yuebijiabanxia decoction, Qingqihuatan decoction, Dingchuan decoction and Sangbaipi decoction are recommended in Chinese medicine clinical guideline or textbook, to relieve patients with phlegm-heat according to Chinese syndrome differentiation. However, the comparative effectiveness among these six formulas has not been investigated in published randomised controlled trials. We plan to summarise the direct and indirect evidence for these six formulas combined with pharmacotherapy to determine the relative merits options for the management of AECOPD. METHODS AND ANALYSIS: We will perform the comprehensive search for the randomised controlled trials to evaluate the effectiveness of six Chinese herb formulas recommended in Chinese medicine clinical guideline or textbook. The combination of pharmacotherapy includes bronchodilators, antibiotics and corticosteroids that are routinely prescribed for AECOPD. The primary outcome will be lung function, arterial blood gases and length of hospital stay. The data screening and extraction will be conducted by two different reviewers. The quality of RCT will be assessed according to the Cochrane handbook risk of bias tool. The Bayes of network meta-analysis (NMA) will be conducted with WinBUGS to compare the effectiveness of six formulas. We will also use the surface under the cumulative ranking curve (SUCRA) to obtain the comprehensive rank for these treatments. ETHICS AND DISSEMINATION: This review does not require ethics approval and the results of NMA will be submitted to a peer-review journal. TRIAL REGISTRATION NUMBER: PROSPERO (CRD42016052699). PMID- 28801435 TI - Differences in the pregnancy gestation period and mean birth weights in infants born to Indian, Pakistani, Bangladeshi and white British mothers in Luton, UK: a retrospective analysis of routinely collected data. AB - OBJECTIVE: To compare mean birth weights and gestational age at delivery of infants born to Indian, Pakistani, Bangladeshi and white British mothers in Luton, UK. DESIGN: Retrospective analysis using routinely recorded secondary data in Ciconia Maternity information System, between 2008 and 2013. SETTING: Luton, UK. PARTICIPANTS: Mothers whose ethnicity was recorded as white British, Bangladeshi, Pakistani or Indian and living in Luton, aged over 16, who had a live singleton birth over 24 weeks of gestation were included in the analysis (n=14 871). OUTCOME MEASURES: Primary outcome measures were mean birth weight and gestational age at delivery. RESULTS: After controlling for maternal age, smoking, diabetes, gestation age, parity and maternal height and body mass index at booking, a significant difference in infants' mean birth weight was found between white British and Indian, Pakistani and Bangladeshi infants, F(3, 12 287)=300.32, p<0.0001. The partial Eta-squared for maternal ethnicity was eta2=0.067. The adjusted mean birth weight for white British infants was found to be 3377.89 g (95% CI 3365.34 to 3390.44); Indian infants, 3033.09 g (95% CI 3038.63 to 3103.55); Pakistani infants, 3129.49 g (95% CI 3114.5 to 3144.48); and Bangladeshi infants, 3064.21 g (95% CI 3041.36 to 3087.06). There was a significant association in preterm delivery found in primipara Indian mothers, compared with Indian mothers (Wald=8.192, df 1, p<0.005). CONCLUSIONS: Results show important differences in adjusted mean birth weight between Indian, Pakistani, Bangladeshi and white British women. Moreover, an association was found between primipara Indian mothers and preterm delivery, when compared with Pakistani, Bangladeshi and white British women. PMID- 28801436 TI - Effect of endoscopic transpapillary biliary drainage with/without endoscopic sphincterotomy on post-endoscopic retrograde cholangiopancreatography pancreatitis in patients with biliary stricture (E-BEST): a protocol for a multicentre randomised controlled trial. AB - INTRODUCTION: The effect of endoscopic sphincterotomy prior to endoscopic biliary stenting to prevent post-endoscopic retrograde cholangiopancreatography pancreatitis remains to be fully elucidated. The aim of this study is to prospectively evaluate the non-inferiority of non-endoscopic sphincterotomy prior to stenting for naive major duodenal papilla compared with endoscopic sphincterotomy prior to stenting in patients with biliary stricture. METHODS AND ANALYSIS: We designed a multicentre randomised controlled trial, for which we will recruit 370 patients with biliary stricture requiring endoscopic biliary stenting from 26 high-volume institutions in Japan. Patients will be randomly allocated to the endoscopic sphincterotomy group or the non-endoscopic sphincterotomy group. The main outcome measure is the incidence of pancreatitis within 2 days of initial transpapillary biliary drainage. Data will be analysed on completion of the study. We will calculate the 95% confidence intervals (CIs) of the incidence of pancreatitis in each group and analyse weather the difference in both groups with 95% CIs is within the non-inferiority margin (6%) using the Wald method. ETHICS AND DISSEMINATION: This study has been approved by the institutional review board of Hokkaido University Hospital (IRB: 016-0181). Results will be submitted for presentation at an international medical conference and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: The University Hospital Medical Information Network ID: UMIN000025727 Pre-results. PMID- 28801437 TI - Patient experience of NHS health checks: a systematic review and qualitative synthesis. AB - OBJECTIVE: To review the experiences of patients attending NHS Health Checks in England. DESIGN: A systematic review of quantitative and qualitative studies with a thematic synthesis of qualitative studies. DATA SOURCES: An electronic literature search of Medline, Embase, Health Management Information Consortium, Cumulative Index of Nursing and Allied Health Literature, Global Health, PsycInfo, Web of Science, OpenGrey, the Cochrane Library, National Health Service (NHS) Evidence, Google Scholar, Google, Clinical Trials.gov and the ISRCTN registry to 09/11/16 with no language restriction and manual screening of reference lists of all included papers. INCLUSION CRITERIA: Primary research reporting experiences of patients who have attended NHS Health Checks. RESULTS: 20 studies met the inclusion criteria, 9 reporting quantitative data and 15 qualitative data. There were consistently high levels of reported satisfaction in surveys, with over 80% feeling that they had benefited from an NHS Health Check. Data from qualitative studies showed that the NHS Health Check had been perceived to act as a wake-up call for many who reported having gone on to make substantial lifestyle changes which they attributed to the NHS Health Check. However, some had been left with a feeling of unmet expectations, were confused about or unable to remember their risk scores, found the lifestyle advice too simplistic and non personalised or were confused about follow-up. CONCLUSIONS: While participants were generally very supportive of the NHS Health Check programme and examples of behaviour change were reported, there are a number of areas where improvements could be made. These include greater clarity around the aims of the programme within the promotional material, more proactive support for lifestyle change and greater appreciation of the challenges of communicating risk and the limitations of relying on the risk score alone as a trigger for facilitating behaviour change. PMID- 28801438 TI - Associations between polypharmacy and treatment intensity for hypertension and diabetes: a cross-sectional study of nursing home patients in British Columbia, Canada. AB - OBJECTIVES: Describe nursing home polypharmacy prevalence in the context of prescribing for diabetes and hypertension and determine possible associations between lower surrogate markers for treated hypertension and diabetes (overtreatment) and polypharmacy. DESIGN: Cross-sectional study. SETTING: 6 nursing homes in British Columbia, Canada. PARTICIPANTS: 214 patients residing in one of the selected facilities during data collection period. PRIMARY AND SECONDARY OUTCOME MEASURES: Polypharmacy was defined as >=9 regular medications. Overtreatment of diabetes was defined as being prescribed at least one hypoglycaemic medication and a glycosylated haemoglobin (HbA1c) <=7.5%. Overtreatment of hypertension required being prescribed at least one hypertension medication and having a systolic blood pressure <=128 mm Hg. Polypharmacy prescribing, independent of overtreatment, was calculated by subtracting condition-specific medications from total medications prescribed. RESULTS: Data gathering was completed for 214 patients, 104 (48%) of whom were prescribed >=9 medications. All patients were very frail. Patients with polypharmacy were more likely to have a diagnosis of hypertension (p=0.04) or congestive heart failure (p=0.003) and less likely to have a diagnosis of dementia (p=0.03). Patients with overtreated hypertension were more likely to also experience polypharmacy (Relative Risk (RR))1.77 (1.07 to 2.96), p=0.027). Patients with overtreated diabetes were prescribed more non-diabetic medications than those with a higher HbA1c (11.0+/-3.7vs 7.2+/-3.1, p=0.01). CONCLUSION: Overtreated diabetes and hypertension appear to be prevalent in nursing home patients, and the presence of polypharmacy is associated with more aggressive treatment of these risk factors. The present study was limited by its small sample size and cross-sectional design. Further study of interventions designed to reduce overtreatment of hypertension and diabetes is needed to fully understand the potential links between polypharmacy and potential of harms of condition-specific overtreatment. PMID- 28801440 TI - Baseline data from a planned RCT on attitudes to female genital cutting after migration: when are interventions justified? AB - OBJECTIVES: To present the primary outcomes from a baseline study on attitudes towards female genital cutting (FGC) after migration. DESIGN: Baseline data from a planned cluster randomised, controlled trial. Face-to-face interviews were used to collect questionnaire data in 2015. Based on our hypothesis that established Somalis could be used as facilitators of change among those newly arrived, data were stratified into years of residency in Sweden. SETTING: Sweden. PARTICIPANTS: 372 Somali men and women, 206 newly arrived (0-4 years), 166 established (>4 years). PRIMARY OUTCOME MEASURES: Whether FGC is acceptable, preferred for daughter and should continue, specified on anatomical extent. RESULTS: The support for anatomical change of girls and women's genitals ranged from 0% to 2% among established and from 4% to 8% among newly arrived. Among those supporting no anatomical change, 75%-83% among established and 53%-67% among newly arrived opposed all forms of FGC, with the remaining supporting pricking of the skin with no removal of tissue. Among newly arrived, 37% stated that pricking was acceptable, 39% said they wanted their daughter to be pricked and 26% reported they wanted pricking to continue being practised. Those who had lived in Sweden <= 2 years had highest odds of supporting FGC; thereafter, the opposition towards FGC increased over time after migration. CONCLUSION: A majority of Somali immigrants, including those newly arrived, opposed all forms of FGC with increased opposition over time after migration. The majority of proponents of FGC supported pricking. We argue that it would have been unethical to proceed with the intervention as it, with this baseline, would have been difficult to detect a change in attitudes given that a majority opposed all forms of FGC together with the evidence that a strong attitude change is already happening. Therefore, we decided not to implement the planned intervention. TRIAL REGISTRATION NUMBER: Trial registration number NCT02335697;Pre-results. PMID- 28801439 TI - Validation of asthma recording in the Clinical Practice Research Datalink (CPRD). AB - OBJECTIVES: The optimal method of identifying people with asthma from electronic health records in primary care is not known. The aim of this study is to determine the positive predictive value (PPV) of different algorithms using clinical codes and prescription data to identify people with asthma in the United Kingdom Clinical Practice Research Datalink (CPRD). METHODS: 684 participants registered with a general practitioner (GP) practice contributing to CPRD between 1 December 2013 and 30 November 2015 were selected according to one of eight predefined potential asthma identification algorithms. A questionnaire was sent to the GPs to confirm asthma status and provide additional information to support an asthma diagnosis. Two study physicians independently reviewed and adjudicated the questionnaires and additional information to form a gold standard for asthma diagnosis. The PPV was calculated for each algorithm. RESULTS: 684 questionnaires were sent, of which 494 (72%) were returned and 475 (69%) were complete and analysed. All five algorithms including a specific Read code indicating asthma or non-specific Read code accompanied by additional conditions performed well. The PPV for asthma diagnosis using only a specific asthma code was 86.4% (95% CI 77.4% to 95.4%). Extra information on asthma medication prescription (PPV 83.3%), evidence of reversibility testing (PPV 86.0%) or a combination of all three selection criteria (PPV 86.4%) did not result in a higher PPV. The algorithm using non-specific asthma codes, information on reversibility testing and respiratory medication use scored highest (PPV 90.7%, 95% CI (82.8% to 98.7%), but had a much lower identifiable population. Algorithms based on asthma symptom codes had low PPVs (43.1% to 57.8%)%). CONCLUSIONS: People with asthma can be accurately identified from UK primary care records using specific Read codes. The inclusion of spirometry or asthma medications in the algorithm did not clearly improve accuracy. ETHICS AND DISSEMINATION: The protocol for this research was approved by the Independent Scientific Advisory Committee (ISAC) for MHRA Database Research (protocol number15_257) and the approved protocol was made available to the journal and reviewers during peer review. Generic ethical approval for observational research using the CPRD with approval from ISAC has been granted by a Health Research Authority Research Ethics Committee (East Midlands-Derby, REC reference number 05/MRE04/87).The results will be submitted for publication and will be disseminated through research conferences and peer reviewed journals. PMID- 28801441 TI - Changes in prevalence of workplace violence against doctors in all medical specialties in Norway between 1993 and 2014: a repeated cross-sectional survey. AB - OBJECTIVES: The aim of this study was to investigate whether reported prevalence of experienced threats, real acts of violence and debilitating fear of violence among Norwegian doctors have increased over the last two decades. DESIGN: Repeated cross-sectional survey. SETTING: All healthcare levels and medical specialties in Norway. PARTICIPANTS: Representative samples of Norwegian doctors in 1993 (n=2628) and 2014 (n=1158). MAIN OUTCOME MEASURES: Relative risk (RR) of self-reported prevalence of work-time experiences of threats and real acts of violence, and of being physically or psychologically unfit during the last 12 months due to fear of violence, in 2014 compared with 1993, adjusted by age, gender and medical specialty. RESULTS: There were no differences in self-reported threats (adjusted RR=1.01, 95% CI 0.95 to 1.08) or real acts (adjusted RR=0.90, 95% CI 0.80 to 1.03) of violence when comparing 2014 with 1993. The proportion of doctors who had felt unfit due to fear of violence decreased from 1993 to 2014 (adjusted RR=0.53, 95% CI 0.39 to 0.73). Although still above average, the proportion of doctors in psychiatry who reported real acts of violence decreased substantially from 1993 to 2014 (adjusted RR=0.75, 95% CI 0.60 to 0.95). CONCLUSIONS: A substantial proportion of doctors experience threats and real acts of violence during their work-time career, but there was no evidence that workplace violence has increased over the last two decades. Still, the issue needs to be addressed as part of the doctors' education and within work settings. PMID- 28801442 TI - Bangladesh Environmental Enteric Dysfunction (BEED) study: protocol for a community-based intervention study to validate non-invasive biomarkers of environmental enteric dysfunction. AB - INTRODUCTION: Environmental enteric dysfunction (EED) is a subacute inflammatory condition of the small intestinal mucosa with unclear aetiology that may account for more than 40% of all cases of stunting. Currently, there are no universally accepted protocols for the diagnosis, treatment and ultimately prevention of EED. The Bangladesh Environmental Enteric Dysfunction (BEED) study is designed to validate non-invasive biomarkers of EED with small intestinal biopsy, better understand disease pathogenesis and identify potential therapeutic targets for interventions designed to control EED and stunting. METHODS AND ANALYSIS: The BEED study is a community-based intervention where participants are recruited from three cohorts: stunted children aged 12-18 months (length for age Z-score (LAZ) <-2), at risk of stunting children aged 12-18 months (LAZ <-1 to -2) and malnourished adults aged 18-45 years (body mass index <18.5 kg/m2). After screening, participants eligible for study provide faecal, urine and plasma specimens to quantify the levels of candidate EED biomarkers before and after receiving a nutritional intervention. Participants who fail to respond to nutritional therapy are considered as the candidates for upper gastrointestinal endoscopy with biopsy. Histopathological scoring for EED will be performed on biopsies obtained from several locations within the proximal small intestine. Candidate EED biomarkers will be correlated with nutritional status, the results of histochemical and immunohistochemical analyses of epithelial and lamina propria cell populations, plus assessments of microbial community structure. ETHICS AND DISSEMINATION: Ethics approval was obtained in all participating institutes. Results of this study will be submitted for publication in peer reviewed journals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov ID: NCT02812615. Registered on 21 June 2016. PMID- 28801443 TI - The provision of medical assistance in dying: protocol for a scoping review. AB - INTRODUCTION: Medical assistance in dying (MAID), a term encompassing both euthanasia and assisted suicide, was decriminalised in Canada in 2015. Although Bill C-14 legislated eligibility criteria under which patients could receive MAID, it did not provide guidance regarding the technical aspects of providing an assisted death. Therefore, we propose a scoping review to map the characteristics of the existing medical literature describing the medications, settings, participants and outcomes of MAID, in order to identify knowledge gaps and areas for future research. METHODS AND ANALYSIS: We will search electronic databases (MEDLINE, EMBASE, CINAHL, CENTRAL, PsycINFO), clinical trial registries, conference abstracts, and professional guidelines and recommendations from jurisdictions where MAID is legal, up to June 2017. Eligible report types will include technical summaries, institutional policies, practice surveys, practice guidelines and clinical studies. We will include all descriptions of MAID provision (either euthanasia or assisted suicide) in adults who have provided informed consent for MAID, for any reason, including reports where patients have provided consent to MAID in advance of the development of incapacity (eg, dementia). We will exclude reports in which patients receive involuntary euthanasia (eg, capital punishment). Two independent investigators will screen and select retrieved reports using pilot-tested screening and eligibility forms, and collect data using standardised data collection forms. We will summarise extracted data in tabular format with accompanying descriptive statistics and use narrative format to describe their clinical relevance, identify knowledge gaps and suggest topics for future research. ETHICS AND DISSEMINATION: This scoping review will map the range and scope of the existing literature on the provision of MAID in jurisdictions where the practice has been decriminalised. The review will be disseminated through conference presentations and publication in a peer reviewed journal. These results will be useful to clinicians, policy makers and researchers involved with MAID. PMID- 28801445 TI - Correction: Efficacy and safety of gelatine tannate for the treatment of acute gastroenteritis in children: protocol of a randomised controlled trial. PMID- 28801444 TI - Radical cystectomy (bladder removal) against intravesical BCG immunotherapy for high-risk non-muscle invasive bladder cancer (BRAVO): a protocol for a randomised controlled feasibility study. AB - INTRODUCTION: High-risk non-muscle invasive bladder cancer (HRNMIBC) is a heterogeneous disease that can be difficult to predict. While around 25% of cancers progress to invasion and metastases, the remaining majority of tumours remain within the bladder. It is uncertain whether patients with HRNMIBC are better treated with intravesical maintenance BCG (mBCG) immunotherapy or primary radical cystectomy (RC). A definitive randomised controlled trial (RCT) is needed to compare these two different treatments but may be difficult to recruit to and has not been attempted to date. Before undertaking such an RCT, it is important to understand whether such a comparison is possible and how best to achieve it. METHODS AND ANALYSIS: BRAVO is a multi-centre, parallel-group, mixed-methods, individually randomised, controlled, feasibility study for patients with HRNMIBC. Participants will be randomised to receive either mBCG immunotherapy or RC. The primary objective is to assess the feasibility and acceptability of performing the definitive phase III trial via estimation of eligibility and recruitment rates, assessing uptake of allocated treatment and compliance with mBCG, determining quality-of-life questionnaire completion rates and exploring reasons expressed by patients for declining recruitment into the study. We aim to recruit 60 participants from six centres in the UK. Surgical trials with disparate treatment options find recruitment challenging from both the patient and clinician perspective. By building on the experiences of other similar trials through implementing a comprehensive training package aimed at clinicians to address these challenges (qualitative substudy), we hope that we can demonstrate that a phase III trial is feasible. ETHICS AND DISSEMINATION: The study has ethical approval (16/YH/0268). Findings will be made available to patients, clinicians, the funders and the National Health Service through traditional publishing and social media. TRIAL REGISTRATION NUMBER: ISRCTN12509361; Pre results. PMID- 28801446 TI - Correction: EUropean prospective cohort study on Enterobacteriaceae showing REsistance to CArbapenems (EURECA): a protocol of a European multicentre observational study. PMID- 28801447 TI - Correction: Screening for cancer in patients with unprovoked venous thromboembolism: protocol for a systematic review and individual patient data meta-analysis. PMID- 28801448 TI - Long-term results of a phase 2 study of rituximab and bendamustine for mucosa associated lymphoid tissue lymphoma. PMID- 28801449 TI - Engraftment and in vivo proliferation advantage of gene-corrected mobilized CD34+ cells from Fanconi anemia patients. AB - Previous Fanconi anemia (FA) gene therapy studies have failed to demonstrate engraftment of gene-corrected hematopoietic stem and progenitor cells (HSPCs) from FA patients, either after autologous transplantation or infusion into immunodeficient mice. In this study, we demonstrate that a validated short transduction protocol of G-CSF plus plerixafor-mobilized CD34+ cells from FA-A patients with a therapeutic FANCA-lentiviral vector corrects the phenotype of in vitro cultured hematopoietic progenitor cells. Transplantation of transduced FA CD34+ cells into immunodeficient mice resulted in reproducible engraftment of myeloid, lymphoid, and CD34+ cells. Importantly, a marked increase in the proportion of phenotypically corrected, patient-derived hematopoietic cells was observed after transplantation with respect to the infused CD34+ graft, indicating the proliferative advantage of corrected FA-A hematopoietic repopulating cells. Our data demonstrate for the first time that optimized protocols of hematopoietic stem cell collection from FA patients, followed by the short and clinically validated transduction of these cells with a therapeutic lentiviral vector, results in the generation of phenotypically corrected HSPCs capable of repopulating and developing proliferation advantage in immunodeficient mice. Our results suggest that clinical approaches for FA gene therapy similar to those used in this study will facilitate hematopoietic repopulation in FA patients with gene corrected HSPCs, opening new prospects for gene therapy of FA patients. PMID- 28801450 TI - Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations. AB - Classical hairy cell leukemia (cHCL) is characterized by a near 100% frequency of the BRAFV600E mutation, whereas ~30% of variant HCLs (vHCLs) have MAP2K1 mutations. However, recurrent genetic alterations cooperating with BRAFV600E or MAP2K1 mutations in HCL, as well as those in MAP2K1 wild-type vHCL, are not well defined. We therefore performed deep targeted mutational and copy number analysis of cHCL (n = 53) and vHCL (n = 8). The most common genetic alteration in cHCL apart from BRAFV600E was heterozygous loss of chromosome 7q, the minimally deleted region of which targeted wild-type BRAF, subdividing cHCL into those hemizygous versus heterozygous for the BRAFV600E mutation. In addition to CDKN1B mutations in cHCL, recurrent inactivating mutations in KMT2C (MLL3) were identified in 15% and 25% of cHCLs and vHCLs, respectively. Moreover, 13% of vHCLs harbored predicted activating mutations in CCND3 A change-of-function mutation in the splicing factor U2AF1 was also present in 13% of vHCLs. Genomic analysis of de novo vemurafenib-resistant cHCL identified a novel gain-of function mutation in IRS1 and losses of NF1 and NF2, each of which contributed to resistance. These data provide further insight into the genetic bases of cHCL and vHCL and mechanisms of RAF inhibitor resistance encountered clinically. PMID- 28801452 TI - Correction for Nechama et al., "An Unusual Two-Step Control of CPEB Destruction by Pin1". PMID- 28801453 TI - Correction for Szilagyi et al., "Cyclin-Dependent Kinase 8 Regulates Mitotic Commitment in Fission Yeast". PMID- 28801451 TI - Adult high-grade B-cell lymphoma with Burkitt lymphoma signature: genomic features and potential therapeutic targets. AB - The adult high-grade B-cell lymphomas sharing molecular features with Burkitt lymphoma (BL) are highly aggressive lymphomas with poor clinical outcome. High resolution structural and functional genomic analysis of adult Burkitt lymphoma (BL) and high-grade B-cell lymphoma with BL gene signature (adult-molecularly defined BL [mBL]) revealed the MYC-ARF-p53 axis as the primary deregulated pathway. Adult-mBL had either unique or more frequent genomic aberrations (del13q14, del17p, gain8q24, and gain18q21) compared with pediatric-mBL, but shared commonly mutated genes. Mutations in genes promoting the tonic B-cell receptor (BCR)->PI3K pathway (TCF3 and ID3) did not differ by age, whereas effectors of chronic BCR->NF-kappaB signaling were associated with adult-mBL. A subset of adult-mBL had BCL2 translocation and mutation and elevated BCL2 mRNA and protein expression, but had a mutation profile similar to mBL. These double hit lymphomas may have arisen from a tumor precursor that acquired both BCL2 and MYC translocations and/or KMT2D (MLL2) mutation. Gain/amplification of MIR17HG and its paralogue loci was observed in 50% of adult-mBL. In vitro studies suggested miR-17~92's role in constitutive activation of BCR signaling and sensitivity to ibrutinib. Overall integrative analysis identified an interrelated gene network affected by copy number and mutation, leading to disruption of the p53 pathway and the BCR->PI3K or NF-kappaB activation, which can be further exploited in vivo by small-molecule inhibitors for effective therapy in adult mBL. PMID- 28801454 TI - Correction for Xu and Davis, "c-Jun NH2-Terminal Kinase Is Required for Lineage Specific Differentiation but Not Stem Cell Self-Renewal". PMID- 28801455 TI - Correction for Chen et al., "Nuclear Export of Smads by RanBP3L Regulates Bone Morphogenetic Protein Signaling and Mesenchymal Stem Cell Differentiation". PMID- 28801456 TI - Correction for Yang et al., "Cross Talk between Histone Deacetylase 4 and STAT6 in the Transcriptional Regulation of Arginase 1 during Mouse Dendritic Cell Differentiation". PMID- 28801457 TI - Correction for Yu et al., "A Mouse PRMT1 Null Allele Defines an Essential Role for Arginine Methylation in Genome Maintenance and Cell Proliferation". PMID- 28801458 TI - Correction for Lu et al., "Nuclear GIT2 Is an ATM Substrate and Promotes DNA Repair". PMID- 28801460 TI - Multiplexed silicon photonic sensor arrays enable facile characterization of coagulation protein binding to nanodiscs with variable lipid content. AB - Interactions of soluble proteins with the cell membrane are critical within the blood coagulation cascade. Of particular interest are the interactions of gamma carboxyglutamic acid-rich domain-containing clotting proteins with lipids. Variability among conventional analytical methods presents challenges for comparing clotting protein-lipid interactions. Most previous studies have investigated only a single clotting protein and lipid composition and have yielded widely different binding constants. Herein, we demonstrate that a combination of lipid bilayer nanodiscs and a multiplexed silicon photonic analysis technology enables high-throughput probing of many protein-lipid interactions among blood-clotting proteins. This approach allowed direct comparison of the binding constants of prothrombin, factor X, activated factor VII, and activated protein C to seven different binary lipid compositions. In a single experiment, the binding constants of one protein interacting with all lipid compositions were simultaneously determined. A simple surface regeneration then facilitated similar binding measurements for three other coagulation proteins. As expected, our results indicated that all proteins exhibit tighter binding (lower Kd ) as the proportion of anionic lipid increases. Interestingly, at high proportions of phosphatidylserine, the Kd values of all four proteins began to converge. We also found that although koff values for all four proteins followed trends similar to those observed for the Kd values, the variation among the proteins was much lower, indicating that much of the variation came from the kinetic binding (kon) of the proteins. These findings indicate that the combination of silicon photonic microring resonator arrays and nanodiscs enables rapid interrogation of biomolecular binding interactions at model cell membrane interfaces. PMID- 28801461 TI - Structural basis of human PR/SET domain 9 (PRDM9) allele C-specific recognition of its cognate DNA sequence. AB - PRDM9 is the only mammalian gene that has been associated with speciation. The PR/SET domain 9 (PRDM9) protein is a major determinant of meiotic recombination hot spots and acts through sequence-specific DNA binding via its C2H2 zinc finger (ZF) tandem array, which is highly polymorphic within and between species. The most common human variant, PRDM9 allele A (PRDM9a), contains 13 fingers (ZF1-13). Allele C (PRDM9c) is the second-most common among African populations and differs from PRDM9a by an arginine-to-serine change (R764S) in ZF9 and by replacement of ZF11 with two other fingers, yielding 14 fingers in PRDM9c. Here we co crystallized the six-finger fragment ZF8-13 of PRDM9c, in complex with an oligonucleotide representing a known PRDM9c-specific hot spot sequence, and compared the structure with that of a characterized PRDM9a-specific complex. There are three major differences. First, Ser764 in ZF9 allows PRDM9c to accommodate a variable base, whereas PRDM9a Arg764 recognizes a conserved guanine. Second, the two-finger expansion of ZF11 allows PRDM9c to recognize three-base-pair-longer sequences. A tryptophan in the additional ZF interacts with a conserved thymine methyl group. Third, an Arg-Asp dipeptide immediately preceding the ZF helix, conserved in two PRDM9a fingers and three PRDM9c fingers, permits adaptability to variations from a C:G base pair (G-Arg interaction) to a G:C base pair (C-Asp interaction). This Arg-Asp conformational switch allows identical ZF modules to recognize different sequences. Our findings illuminate the molecular mechanisms for flexible and conserved binding of human PRDM9 alleles to their cognate DNA sequences. PMID- 28801462 TI - Protein glutaminylation is a yeast-specific posttranslational modification of elongation factor 1A. AB - Ribosomal translation factors are fundamental for protein synthesis and highly conserved in all kingdoms of life. The essential eukaryotic elongation factor 1A (eEF1A) delivers aminoacyl tRNAs to the A-site of the translating 80S ribosome. Several studies have revealed that eEF1A is posttranslationally modified. Using MS analysis, site-directed mutagenesis, and X-ray structural data analysis of Saccharomyces cerevisiae eEF1A, we identified a posttranslational modification in which the alpha amino group of mono-l-glutamine is covalently linked to the side chain of glutamate 45 in eEF1A. The MS analysis suggested that all eEF1A molecules are modified by this glutaminylation and that this posttranslational modification occurs at all stages of yeast growth. The mutational studies revealed that this glutaminylation is not essential for the normal functions of eEF1A in S. cerevisiae However, eEF1A glutaminylation slightly reduced growth under antibiotic-induced translational stress conditions. Moreover, we identified the same posttranslational modification in eEF1A from Schizosaccharomyces pombe but not in various other eukaryotic organisms tested despite strict conservation of the Glu45 residue among these organisms. We therefore conclude that eEF1A glutaminylation is a yeast-specific posttranslational modification that appears to influence protein translation. PMID- 28801465 TI - An American Sickness: How Healthcare Became Big Business and How You Can Take It Back. PMID- 28801463 TI - Shaping Health Policy for Low-Income Populations: An Assessment of Public Comments in a New Medicaid Waiver Process. AB - Since the Supreme Court decided that the Affordable Care Act's (ACA) Medicaid expansion is optional for the states, several have obtained federal approval to use Section 1115 waivers to expand Medicaid while changing its coverage and benefits design. There has long been concern that policy making for Medicaid populations may lack meaningful engagement with low-income constituents, and therefore the ACA established a new process under which the public can submit comments on pending Medicaid waiver applications. We analyzed 291 comment letters submitted to federal regulators pertaining to Medicaid Section 1115 waiver applications in the first five states to seek such waivers: Arkansas, Indiana, Iowa, Michigan, and Pennsylvania. We found that individual citizens, including those who identified as Medicaid-eligible, submitted a sizable majority of the comment letters. Comment letters tended to mention controversial provisions of the waivers and reflected the competing political rhetoric of "personal responsibility" versus "vulnerable populations." Despite the fact that the federal government seemed likely to approve the waiver applications, we found robust public engagement, reflecting the salience of the issue of Medicaid expansion under the ACA. Our findings are consistent with the argument that Medicaid is a program of growing centrality in US health politics. PMID- 28801464 TI - Partisan Responses to Public Health Messages: Motivated Reasoning and Sugary Drink Taxes. AB - This study examines the public's motivated reasoning of competitive messages about sugary drink taxes, a public health policy approach attempted with some recent success in the United States. In an experiment embedded in a nationally representative survey fielded in the fall of 2012, we randomized participants (N = 5,147) to receive one of four messages: control, a strong protax message, a two sided message, or a message refuting arguments made in soda company antitax messages. The protax message showed no effects on tax support, while the two sided message depressed Republicans' support. The refutation message boosted independents' support but produced backlash among Republicans. This motivated response was pronounced among Republicans who were plausibly previously exposed to the sugary drink tax debate. These findings reinforce the communication challenges in an increasingly politicized US health policy discourse. PMID- 28801467 TI - Minors, Moral Psychology, and the Harm Reduction Debate: The Case of Tobacco and Nicotine. AB - Harm reduction debates are important in health policy. Although it has been established that morality affects policy, this article proposes that perspectives from moral psychology help to explain the challenges of developing evidence-based policy on prohibition-only versus tobacco/nicotine harm reduction for minors. Protecting youth from tobacco is critical, especially since tobacco/nicotine products are legal for adults, who usually begin using when young. Although cigarettes and other combustibles are the deadliest tobacco products, other products such as smokeless tobacco and electronic cigarettes, though unsafe, are upward of 90 percent less harmful than cigarettes. Disgust at contaminating the "purity" of youth, especially "good," low-risk youth, with any tobacco/nicotine products opposes harm reduction, as does contempt for violating so-called community values and disrespecting authority. Support for harm reduction arises from anger at failing to provide reduced harm to "bad," high-risk individuals and denying them the "liberty" to decide. Fast-thinking, moral-emotional intuitions are supported by rationalizations arising from slow-thinking processes. The recognition of such moral psychological influences and the efforts to minimize their impact may help lead to amelioration and compromise. This example from tobacco control, with divided concerns for low-risk and high-risk youth, can be applied to other harm reduction versus prohibition-only policies directed at minors. PMID- 28801466 TI - Statewide Payment and Delivery Reform: Do States Have What It Takes? AB - States' role in payment as well as coverage will be subject to debate as the administration and the Congress decide how to address the Affordable Care Act (ACA) and otherwise reshape the nation's health policies. Acting as stewards of health care for the entire state population and stimulated by concern about rising costs and federal support under the ACA, the elected and administrative leaders of some states have been using their political influence and authority to improve their state's overall systems of care regardless of who pays the bill. In early 2015 we conducted on-site interviews with key stakeholders in five states to explore their strategies for payment and delivery reform. We found that despite these states' similar goals, differences in their statutory authority and purchasing power, along with their leaders' willingness to use them, significantly influence a state's ability to achieve reform objectives. We caution federal and state policy makers to recognize the reality that state leaders' political desire to exercise stewardship may not be enough to achieve it. PMID- 28801468 TI - Minnesota Integrated Health Partnership Demonstration: Implementation of a Medicaid ACO Model. AB - In recent years, accountable care organizations (ACOs) have become more prevalent in the United States. This study describes the origins, implementation, and early results of Minnesota's Medicaid ACO payment model, the Integrated Health Partnership (IHP) demonstration project. We describe the structure of the program and present preliminary evaluation results to document the state's important work and to provide lessons for other states interested in implementing Medicaid ACOs. The IHP program has expanded in size over time, the state has reported significant savings, and evidence exists of capacity building among participating providers. We identify factors that may have contributed to the program's early success, but more work is needed to investigate the specific drivers of quality improvement and savings within Minnesota's ACO program and to compare the design and effects of the IHP with other Medicaid and Medicare ACO programs. We conclude with comments about the future of the state's Medicaid ACO program and situate Minnesota's findings within the context of the broader ACO movement. PMID- 28801469 TI - The Politics of Autism: Navigating the Contested Spectrum. PMID- 28801470 TI - Litigation Provides Clues to Ongoing Challenges in Implementing Insurance Parity. AB - Over the past twenty-five years, thirty-seven states and the US Congress have passed mental health and substance use disorder (MH/SUD) parity laws to secure nondiscriminatory insurance coverage for MH/SUD services in the private health insurance market and through certain public insurance programs. However, in the intervening years, litigation has been brought by numerous parties alleging violations of insurance parity. We examine the critical issues underlying these legal challenges as a framework for understanding the areas in which parity enforcement is lacking, as well as ongoing areas of ambiguity in the interpretation of these laws. We identified all private litigation involving federal and state parity laws and extracted themes from a final sample of thirty seven lawsuits. The primary substantive topics at issue include the scope of services guaranteed by parity laws, coverage of certain habilitative therapies such as applied behavioral analysis for autism spectrum disorders, credentialing standards for MH/SUD providers, determinations regarding the medical necessity of MH/SUD services, and the application of nonquantitative treatment limitations under the 2008 federal parity law. Ongoing efforts to achieve nondiscriminatory insurance coverage for MH/SUDs should attend to the major issues subject to private legal action as important areas for facilitating and monitoring insurer compliance. PMID- 28801471 TI - Editor's Note. PMID- 28801472 TI - Breast Cancer Immunotherapy: Facts and Hopes. AB - Immunotherapy is revolutionizing the management of multiple solid tumors, and early data have revealed the clinical activity of programmed cell death 1/programmed death ligand-1 (PD-1/PD-L1) antagonists in small numbers of patients with metastatic breast cancer. Clinical activity appears more likely if the tumor is triple negative, PD-L1+, and/or harbors higher levels of tumor-infiltrating leukocytes. Responses to atezolizumab and pembrolizumab appear to be durable in metastatic triple-negative breast cancer (TNBC), suggesting that these agents may transform the lives of responding patients. Current clinical efforts are focused on developing immunotherapy combinations that convert nonresponders to responders, deepen those responses that do occur, and surmount acquired resistance to immunotherapy. Identifying biomarkers that can predict the potential for response to single-agent immunotherapy, identify the best immunotherapy combinations for a particular patient, and guide salvage immunotherapy in patients with progressive disease are high priorities for clinical development. Smart clinical trials testing rational immunotherapy combinations that include robust biomarker evaluations will accelerate clinical progress, moving us closer to effective immunotherapy for almost all patients with breast cancer. Clin Cancer Res; 24(3); 511-20. (c)2017 AACR. PMID- 28801474 TI - Association Between Adherence to Pharmacotherapy and Outcomes in Type 2 Diabetes: A Meta-analysis. AB - OBJECTIVE: A previous study suggests an association between poor medication adherence and excess mortality in chronic disease. The purpose of this study was to assess the association between medication adherence and risk of cardiovascular disease (CVD), all-cause mortality, and hospitalization in type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted an electronic search on many electronic databases from inception to 27 April 2016. We selected randomized controlled trials and case-control and cohort studies reporting on CVD, all-cause mortality, or hospitalization outcomes by adherence in adults with type 2 diabetes. Two reviewers independently screened for eligible studies and extracted outcome data. Pooled relative risks (RRs) were calculated using a random-effects meta-analysis; risk of bias in each of the included studies was assessed using the GRADE approach. RESULTS: Eight observational studies were included (n = 318,125). The mean rate of poor adherence was 37.8% (95% CI 37.6-38.0). Adjusted estimates were provided by five studies only. The RRs of good (>=80%) versus poor adherence to medication were 0.72 (95% CI 0.62-0.82, I2 = 0%, three studies) for all-cause mortality and 0.90 (0.87-0.94, I2 = 63%, seven studies) for hospitalization. No evidence of small study bias was observed. Only one study reported CVD outcomes by adherence. CONCLUSIONS: We identified no trials reporting on outcomes by adherence, suggesting a systematic failure to include this information. Pooled estimates from available observational studies suggest that good medication adherence is associated with reduced risk of all-cause mortality and hospitalization in people with type 2 diabetes, although bias cannot be excluded as an explanation for these findings. PMID- 28801473 TI - Type 2 Diabetes in the Real World: The Elusive Nature of Glycemic Control. AB - Despite U.S. Food and Drug Administration (FDA) approval of over 40 new treatment options for type 2 diabetes since 2005, the latest data from the National Health and Nutrition Examination Survey show that the proportion of patients achieving glycated hemoglobin (HbA1c) <7.0% (<53 mmol/mol) remains around 50%, with a negligible decline between the periods 2003-2006 and 2011-2014. The Healthcare Effectiveness Data and Information Set reports even more alarming rates, with only about 40% and 30% of patients achieving HbA1c <7.0% (<53 mmol/mol) in the commercially insured (HMO) and Medicaid populations, respectively, again with virtually no change over the past decade. A recent retrospective cohort study using a large U.S. claims database explored why clinical outcomes are not keeping pace with the availability of new treatment options. The study found that HbA1c reductions fell far short of those reported in randomized clinical trials (RCTs), with poor medication adherence emerging as the key driver behind the disconnect. In this Perspective, we examine the implications of these findings in conjunction with other data to highlight the discrepancy between RCT findings and the real world, all pointing toward the underrealized promise of FDA-approved therapies and the critical importance of medication adherence. While poor medication adherence is not a new issue, it has yet to be effectively addressed in clinical practice-often, we suspect, because it goes unrecognized. To support the busy health care professional, innovative approaches are sorely needed. PMID- 28801475 TI - Understanding the Gap Between Efficacy in Randomized Controlled Trials and Effectiveness in Real-World Use of GLP-1 RA and DPP-4 Therapies in Patients With Type 2 Diabetes. AB - OBJECTIVE: The objective of this study was to estimate and explain the gap between clinical efficacy and real-world (RW) effectiveness of type 2 diabetes medications. RESEARCH DESIGN AND METHODS: This mixed-methods quasi-experimental study used retrospective claims (Optum/Humedica) to compare the change in HbA1c of RW patients with type 2 diabetes 12 months after starting a glucagon-like peptide 1 receptor agonist (GLP-1 RA) or dipeptidyl peptidase 4 (DPP-4) inhibitor with published findings from randomized controlled trials (RCTs) evaluating these drugs. Selected RW patients were similar to RCT patients, and regression analysis was used in the RW data to adjust for differences between poorly adherent and adherent patients to explain why RCT and RW findings may differ. RESULTS: RW patients initiating a GLP-1 RA (n = 221) or a DPP-4 (n = 652) experienced smaller reductions in HbA1c (GLP-1 RA: -0.52% [-6 mmol/mol], DPP-4: -0.51% [-6 mmol/mol])than reported in RCTs (-1.30% [-14 mmol/mol] from seven GLP-1 RA RCTs, n = 2,600; -0.68% [-8 mmol/mol] from four DPP-4 RCTs, n = 1,889). Baseline HbA1c, additional medications, and adherence were significant explanatory factors in the RW HbA1c change. Modeled estimates of RCT efficacy (-1.04% GLP-1 RA [-12 mmol/mol], -0.69% DPP-4 [-8 mmol/mol]) were within the RCTs' reported range (GLP 1 RA: -0.84% to -1.60% [-9 to -18 mmol/mol], DPP-4: -0.47% to -0.90% [-5 to -10 mmol/mol]). Poor medication adherence accounted for approximately three-fourths of the gap between RW and expected RCT results (gap = 0.51% [6 mmol/mol] GLP-1 RA; 0.18% [3 mmol/mol] DPP-4). CONCLUSIONS: Poor medication adherence is primarily why RW effectiveness is significantly less than RCT efficacy, suggesting an urgent need to effectively address adherence among patients with type 2 diabetes. PMID- 28801476 TI - Warfarin Use in Patients With Atrial Fibrillation Undergoing Hemodialysis: A Nationwide Population-Based Study. AB - BACKGROUND AND PURPOSE: The aim of this study is to elucidate the effects of warfarin use in patients with atrial fibrillation undergoing dialysis using a population-based Korean registry. METHODS: Data were extracted from the Health Insurance Review and Assessment Service, which is a nationwide, mandatory social insurance database of all Korean citizens enrolled in the National Health Information Service between 2009 and 2013. Thromboembolic and hemorrhagic outcomes were analyzed according to warfarin use. Overall and propensity score matched cohorts were analyzed by Cox proportional hazards models. RESULTS: Among 9974 hemodialysis patients with atrial fibrillation, the mean age was 66.6+/-12.2 years, 5806 (58.2%) were men, and 2921 (29.3%) used warfarin. After propensity score matching to adjust for all described baseline differences, 5548 subjects remained, and differences in baseline variables were distributed equally between warfarin users and nonusers. During a mean follow-up duration of 15.9+/-11.1 months, ischemic and hemorrhagic stroke occurred in 678 (6.8%) and 227 (2.3%) patients, respectively. In a multiple Cox model, warfarin use was significantly associated with an increased risk of hemorrhagic stroke (hazard ratio, 1.44; 95% confidence interval, 1.09-1.91; P=0.010) in the overall cohort. Furthermore, a significant relationship between warfarin use and hemorrhagic stroke was found in propensity-matched subjects (hazard ratio, 1.56; 95% confidence interval, 1.10 2.22; P=0.013). However, the ratios for ischemic stroke were not significantly different in either the propensity-matched (hazard ratio, 0.95; 95% confidence interval, 0.78-1.15; P=0.569) or overall cohort (hazard ratio, 1.06; 95% confidence interval, 0.90-1.26; P=0.470). CONCLUSIONS: Our findings suggest that warfarin should be used carefully in hemodialysis patients, given the higher risk of hemorrhagic events and the lack of ability to prevent thromboembolic complications. PMID- 28801477 TI - Type 2 Diabetes Mellitus and Impaired Renal Function Are Associated With Brain Alterations and Poststroke Cognitive Decline. AB - BACKGROUND AND PURPOSE: Type 2 diabetes mellitus (T2DM) is associated with diseases of the brain, kidney, and vasculature. However, the relationship between T2DM, chronic kidney disease, brain alterations, and cognitive function after stroke is unknown. We aimed to evaluate the inter-relationship between T2DM, impaired renal function, brain pathology on imaging, and cognitive decline in a longitudinal poststroke cohort. METHODS: The TABASCO (Tel Aviv brain acute stroke cohort) is a prospective cohort of stroke/transient ischemic attack survivors. The volume and white matter integrity, ischemic lesions, and brain and hippocampal volumes were measured at baseline using 3-T MRI. Cognitive tests were performed on 507 patients, who were diagnosed as having mild cognitive impairment, dementia, or being cognitively intact after 24 months. RESULTS: At baseline, T2DM and impaired renal function (estimated creatinine clearance [eCCl] <60 mL/min) were associated with smaller brain and hippocampal volumes, reduced cortical thickness, and worse white matter microstructural integrity. Two years later, both T2DM and eCCl <60 mL/min were associated with poorer cognitive scores, and 19.7% of the participants developed cognitive decline (mild cognitive impairment or dementia). Multiple analysis, controlling for age, sex, education, and apolipoprotein E4, showed a significant association of both T2DM and eCCl <60 mL/min with cognitive decline. Having both conditions doubled the risk compared with patients with T2DM or eCCl <60 mL/min alone and almost quadrupled the risk compared with patients without either abnormality. CONCLUSIONS: T2DM and impaired renal function are independently associated with abnormal brain structure, as well as poorer performance in cognitive tests, 2 years after stroke. The presence of both conditions quadruples the risk for cognitive decline. T2DM and lower eCCl have an independent and additive effect on brain atrophy and the risk of cognitive decline. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01926691. PMID- 28801478 TI - Phosphatases and solid tumors: focus on glioblastoma initiation, progression and recurrences. AB - Phosphatases and cancer have been related for many years now, as these enzymes regulate key cellular functions, including cell survival, migration, differentiation and proliferation. Dysfunctions or mutations affecting these enzymes have been demonstrated to be key factors for oncogenesis. The aim of this review is to shed light on the role of four different phosphatases (PTEN, PP2A, CDC25 and DUSP1) in five different solid tumors (breast cancer, lung cancer, pancreatic cancer, prostate cancer and ovarian cancer), in order to better understand the most frequent and aggressive primary cancer of the central nervous system, glioblastoma. PMID- 28801481 TI - Errata for vol. 313, p. PMID- 28801480 TI - GFI1 functions in transcriptional control and cell fate determination require SNAG domain methylation to recruit LSD1. PMID- 28801482 TI - Errata for vol. 313, p. PMID- 28801479 TI - The role of interactions of long non-coding RNAs and heterogeneous nuclear ribonucleoproteins in regulating cellular functions. AB - Long non-coding RNAs (lncRNAs) are emerging as critical regulators of various biological processes and human diseases. The mechanisms of action involve their interactions with proteins, RNA and genomic DNA. Most lncRNAs display strong nuclear localization. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are a large family of RNA-binding proteins that are important for multiple aspects of nucleic acid metabolism. hnRNPs are also predominantly expressed in the nucleus. This review discusses the interactions of lncRNAs and hnRNPs in regulating gene expression at transcriptional and post-transcriptional levels or by changing genomic structure, highlighting their involvements in glucose and lipid metabolism, immune response, DNA damage response, and other cellular functions. Toward the end, several techniques that are used to identify lncRNA binding partners are summarized. There are still many questions that need to be answered in this relatively new research area, which might provide novel targets to control the biological outputs of cells in response to different stimuli. PMID- 28801483 TI - Characteristics of youth agreeing to electronic sexually transmitted infection risk assessment in the emergency department. AB - OBJECTIVES: Adolescents and young adults are at high risk for sexually transmitted infections (STIs). We previously reported an increase in STI testing of adolescents in our ED by obtaining a sexual history using an Audio-enhanced Computer-Assisted Self-Interview (ACASI). We now examine associations among demographics, sexual behaviour, chief complaint and willingness to be tested. METHODS: This was a prospective study conducted in a paediatric ED between April and December 2011. After triage, eligible patients between 15 and 21 years presenting with non-life-threatening conditions were asked to participate in the study. Consenting participants used an ACASI to provide their demographic data and answer questions about their sexual history and willingness to be tested. Our primary outcome was the association of demographics, chief complaint and ACASI recommendation with the participant's willingness to be tested. RESULTS: We approached 1337 patients, of whom 800 (59%) enrolled and completed the ACASI. Eleven who did not answer questions related to their sexual history were excluded from analysis. Of 789 participants, 461 (58.4%) were female and median age was 16.9 years (IQR 16.0-17.8); 509 (64.5%) endorsed a history of anal, oral and/or vaginal intercourse. Disclosing a sexual history and willingness to be tested did not differ significantly by gender. 131 (16.6%) had a chief complaint potentially referable to an STI; among the 658 participants with non-STI-related complaints, 412 (62.6%) were sexually active, many of whom disclosed risky behaviours, including multiple partners (46.4%) and inconsistent condom use (43.7%). The ACASI identified 419 patients as needing immediate STI testing; the majority (81%) did not have a chief complaint potentially related to STIs. 697 (88.3%) participants were willing to receive STI testing. Most (94.6%) of the patients with STI-related complaints were willing to be tested, and 92.1% of patients with a recommendation for immediate testing by the ACASI indicated a willingness to be tested. CONCLUSIONS: Adolescents were willing to disclose sexual activity via electronic questionnaires and were willing to receive STI testing, even when their chief complaint was not STI related. The ACASI facilitated identification of adolescent ED patients needing STI testing regardless of chief complaint. PMID- 28801484 TI - Predicting outcomes in traumatic out-of-hospital cardiac arrest: the relevance of Utstein factors. AB - BACKGROUND: Given low survival rates in cases of traumatic out-of-hospital cardiac arrest (OHCA), there is a need to identify factors associated with outcomes. We aimed to investigate Utstein factors associated with achieving return of spontaneous circulation (ROSC) and survival to hospital in traumatic OHCA. METHODS: The Victorian Ambulance Cardiac Arrest Registry (VACAR) was used to identify cases of traumatic OHCA that received attempted resuscitation and occurred between July 2008 and June 2014. We excluded cases aged <16 years or with a mechanism of hanging or drowning. RESULTS: Of the 660 traumatic OHCA patients who received attempted resuscitation, ROSC was achieved in 159 patients (24%) and 95 patients (14%) survived to hospital (ROSC on hospital handover). Factors that were positively associated with achieving ROSC in multivariable logistic regression models were age >=65 years (adjusted OR (AOR)=1.56, 95% CI: 1.01 to 2.43) and arresting rhythm (shockable (AOR=3.65, 95% CI: 1.64 to 8.11) and pulseless electrical activity (AOR=2.15, 95% CI: 1.36 to 3.39) relative to asystole). Similarly, factors positively associated with survival to hospital were arresting rhythm (shockable (AOR=3.92, 95% CI: 1.64 to 9.41) relative to asystole), and the mechanism of injury (falls (AOR=2.16, 95% CI: 1.03 to 4.54) relative to motor vehicle collisions), while trauma type (penetrating (AOR=0.27, 95% CI: 0.08 to 0.91) relative to blunt trauma) and event region (rural (AOR=0.39, 95% CI: 0.19 to 0.80) relative to urban) were negatively associated with survival to hospital. CONCLUSIONS: Few patient and arrest characteristics were associated with outcomes in traumatic OHCA. These findings suggest there is a need to incorporate additional information into cardiac arrest registries to assist prognostication and the development of novel interventions in these trauma patients. PMID- 28801485 TI - Identifying discordance between senior physicians and trainees on the root cause of ED revisits. AB - OBJECTIVE: Analysis of 72-hour ED revisits is a common emergency medicine quality assurance (QA) practice. Our aim was to compare the perceived root cause for 72 hour ED revisits between senior physicians (attendings) and trainees. We proposed that discordance in perception of why the revisit occurred would guide improvements in 72-hour revisits QA and elucidate innovative educational opportunities. METHODS: Questionnaire-based observational study conducted in an urban academic paediatric ED. Treating attendings and trainees independently completed questionnaires on revisit cases. The primary outcome was the revisit's perceived root cause, dichotomised into 'potential medical deficiency' or 'not potential medical deficiency'. Discordance between provider pairs was measured, stratified by revisit disposition. RESULTS: During the study period, 31 630 patients were treated in the ED, 559 returned within 72 hours and 218 met inclusion criteria for paired analysis. The proportion of cases assigned 'potential medical deficiency' by the attending and trainee was 13% and 9%, respectively. Discordance in the dichotomised root cause between attendings and trainees was 17% (38/218, 95% CI 12% to 22%). Revisit cases requiring admission revealed attending-trainee discordance of 25% (23/92, 95% CI 16% to 34%). CONCLUSIONS: Attendings and trainees frequently disagree on whether a potential medical deficiency was the root cause for an ED revisit, with more disagreement noted for cases requiring admission. These findings support the premise that there may be opportunities to improve 72-hour revisits QA systems through trainee integration. Finally, reuniting attending-trainee pairs around revisit cases may be a novel educational opportunity. PMID- 28801488 TI - Panorama showed 'anti agenda'. PMID- 28801489 TI - L529M EMA relocation could have 'far reaching consequences' for vets. PMID- 28801490 TI - M bovis in badgers in Cumbrian TB hotspot triggers new measures. PMID- 28801492 TI - Horse vets shouldn't give in to pressure to break the law. PMID- 28801494 TI - Sheep farmers not feeling the lynx effect. PMID- 28801495 TI - An audience with Stephen May. AB - RCVS President Stephen May talks to Veterinary Record editor Adele Waters about education reform. PMID- 28801496 TI - Hunting for a needle in a haystack: investigating inherited diseases of sheep. PMID- 28801497 TI - Veterinary student competence in equine lameness recognition and assessment: a mixed methods study. AB - The development of perceptual skills is an important aspect of veterinary education. The authors investigated veterinary student competency in lameness evaluation at two stages, before (third year) and during (fourth/fifth year) clinical rotations. Students evaluated horses in videos, where horses were presented during trot on a straight line and in circles. Eye-tracking data were recorded during assessment on the straight line to follow student gaze. On completing the task, students filled in a structured questionnaire. Results showed that the experienced students outperformed inexperienced students, although even experienced students may classify one in four horses incorrectly. Mistakes largely arose from classifying an incorrect limb as lame. The correct detection of sound horses was at chance level. While the experienced student cohort primarily looked at upper body movement (head and sacrum) during lameness assessment, the inexperienced cohort focused on limb movement. Student self assessment of performance was realistic, and task difficulty was most commonly rated between 3 and 4 out of 5. The inexperienced students named a considerably greater number of visual lameness features than the experienced students. Future dedicated training based on the findings presented here may help students to develop more reliable lameness assessment skills. PMID- 28801500 TI - Raw feeding and the risks to people. PMID- 28801498 TI - Comparison of veterinary drugs and veterinary homeopathy: part 1. AB - For many years after its invention around 1796, homeopathy was widely used in people and later in animals. Over the intervening period (1796-2016) pharmacology emerged as a science from Materia Medica (medicinal materials) to become the mainstay of veterinary therapeutics. There remains today a much smaller, but significant, use of homeopathy by veterinary surgeons. Homeopathic products are sometimes administered when conventional drug therapies have not succeeded, but are also used as alternatives to scientifically based therapies and licensed products. The principles underlying the veterinary use of drug-based and homeopathic products are polar opposites; this provides the basis for comparison between them. This two-part review compares and contrasts the two treatment forms in respect of history, constituents, methods of preparation, known or postulated mechanisms underlying responses, the legal basis for use and scientific credibility in the 21st century. Part 1 begins with a consideration of why therapeutic products actually work or appear to do so. PMID- 28801501 TI - Welfare at slaughter. PMID- 28801502 TI - Use of animals in research. PMID- 28801503 TI - Providing water for animals at slaughter. PMID- 28801504 TI - Providing water for animals at slaughter. PMID- 28801506 TI - My week. AB - Kara Brand joined PawSquad in January this year. Here she talks about her week, delivering convenient and stress-free home visits to pet owners in Devon. PMID- 28801507 TI - Diary of a parliamentary intern. AB - How the loss of non-UK EU vets could threaten animal welfare, public health and our ability to trade was discussed at a BVA/RCVS reception in Parliament in June. Parliamentary intern Anthony Ridge reports how the discussions will influence the Government's future immigration policy. PMID- 28801508 TI - Intricate and Cell Type-Specific Populations of Endogenous Circular DNA (eccDNA) in Caenorhabditis elegans and Homo sapiens. AB - Investigations aimed at defining the 3D configuration of eukaryotic chromosomes have consistently encountered an endogenous population of chromosome-derived circular genomic DNA, referred to as extrachromosomal circular DNA (eccDNA). While the production, distribution, and activities of eccDNAs remain understudied, eccDNA formation from specific regions of the linear genome has profound consequences on the regulatory and coding capabilities for these regions. Here, we define eccDNA distributions in Caenorhabditis elegans and in three human cell types, utilizing a set of DNA topology-dependent approaches for enrichment and characterization. The use of parallel biophysical, enzymatic, and informatic approaches provides a comprehensive profiling of eccDNA robust to isolation and analysis methodology. Results in human and nematode systems provide quantitative analysis of the eccDNA loci at both unique and repetitive regions. Our studies converge on and support a consistent picture, in which endogenous genomic DNA circles are present in normal physiological states, and in which the circles come from both coding and noncoding genomic regions. Prominent among the coding regions generating DNA circles are several genes known to produce a diversity of protein isoforms, with mucin proteins and titin as specific examples. PMID- 28801510 TI - Therapeutic options for bleeding oesophageal varices: cyanoacrylate and balloon occluded retrograde obliteration (BRTO). AB - A 56-year-old male with cirrhosis presented with acute bleeding from cardiofundal gastroesophageal varices (GOV) and was treated with endoscopic cyanoacrylate glue. Glue therapy achieved stabilisation of the patient in the emergent setting. Three months later, the patient suffered rebleeding. At that time, he underwent retreatment with balloon-occluded retrograde obliteration (BRTO), with no recurrence at a follow-up of 14 months.Available treatments for bleeding GOV include methods to (a) directly obstruct the varices (endoscopic variceal ligation , sclerotherapy and cyanoacrylate glue, BRTO) or to (b) decrease portal pressure (surgical portacaval shunts; transportal intrahepatic portosystemic shunt). No precise guidelines are available regarding when to use which modality, and few centres have experience with all of them. This case report illustrates a setting in which both options of cyanoacrylate glue therapy and BRTO were used for acute gastric variceal bleeding. PMID- 28801509 TI - Exosome cofactor hMTR4 competes with export adaptor ALYREF to ensure balanced nuclear RNA pools for degradation and export. AB - The exosome is a key RNA machine that functions in the degradation of unwanted RNAs. Here, we found that significant fractions of precursors and mature forms of mRNAs and long noncoding RNAs are degraded by the nuclear exosome in normal human cells. Exosome-mediated degradation of these RNAs requires its cofactor hMTR4. Significantly, hMTR4 plays a key role in specifically recruiting the exosome to its targets. Furthermore, we provide several lines of evidence indicating that hMTR4 executes this role by directly competing with the mRNA export adaptor ALYREF for associating with ARS2, a component of the cap-binding complex (CBC), and this competition is critical for determining whether an RNA is degraded or exported to the cytoplasm. Together, our results indicate that the competition between hMTR4 and ALYREF determines exosome recruitment and functions in creating balanced nuclear RNA pools for degradation and export. PMID- 28801511 TI - Paraneoplastic mucous membrane pemphigoid with ocular and laryngeal involvement. AB - A 73-year-old woman was treated 8 years previously for synchronous breast and uterine neoplasms. She presented with a severe sore throat, odynophagia, dysphonia, dyspnoea, ocular irritation and weight loss over the last 3 months. Physical examination revealed ulcerations in the oral cavity, posterior pharyngeal wall and supraglottic larynx, nasal crusting, bilateral conjunctivitis and three cutaneous blisters. A diagnosis of anti-laminin 5 mucous membrane pemphigoid was retained, based on skin biopsy, direct immunofluorescence and immunoprecipitation. A positron emission tomography (PET)-CT detected multiple adenopathies. Cytology revealed adenocarcinoma with an immunocytology compatible with a breast origin and this was considered as a late metastatic recurrence of her previous breast cancer. A treatment of prednisone, dapsone and hormonotherapy was introduced, but intravenous immunoglobulin and rituximab were added due to new mucosal lesions. Despite treatment, a posterior laryngeal scar and bilateral symblepharon were developed. After 3 years, the patient is still alive and reports a satisfactory quality of life. PMID- 28801512 TI - Unresectable squamous cell carcinoma of upper trachea with long-term survival after concurrent chemoradiotherapy. AB - Upper tracheal malignancies are rare, and long-term survival is even rarer, especially among the unresectable malignancies. A 66-year-old chronic smoker was diagnosed as a locally advanced, non-metastatic squamous cell carcinoma of the upper trachea. Being unresectable, he was treated with six cycles of concurrent weekly cisplatin and three-dimensional conformal radiotherapy to a dose of 60 Gy in 30 fractions over 6 weeks. Follow-up imaging at 6 and 12 months revealed no disease. Our patient is presently 36 months post-treatment and is disease free without tracheal necrosis, fistula or radiation pneumonitis but developed hypothyroidism and is presently euthyroid. Concurrent chemoradiotherapy appears safe up to 3 years at least without any necrosis and is effective in controlling local disease. Meticulous planning obviates the need for higher technology like motion management techniques or intensity-modulated radiotherapy. PMID- 28801513 TI - Isolated intraductal variant of hepatocellular carcinoma. PMID- 28801514 TI - Bilateral painful tic convulsif. AB - 'Painful tic convulsif' (PTC) describes the coexistence of hemifacial spasm and trigeminal neuralgia. In this report, we describe a unique presentation of bilateral PTC in a man with bilateral hemifacial spasm and trigeminal neuralgia secondary to neurovascular conflict of all four cranial nerves. Following failed medical and radiofrequency therapy, microvascular decompression of three of the four involved nerves was performed, where the offending vessels were mobilised and Teflon used to prevent conflict recurrence. He continues to respond to Botox for right hemifacial spasm. Since surgery, he remains pain free bilaterally and spasm free on the left. PMID- 28801515 TI - Lenalidomide-associated arterial thrombosis in a patient with JAK2 positive atypical myeloproliferative neoplasm. PMID- 28801516 TI - Right hepatic artery 'caterpillar hump' and dual cystic arteries: relevance of critical view of safety in a 'straightforward' cholecystectomy. PMID- 28801517 TI - Effect of densely ionizing radiation on cardiomyocyte differentiation from human induced pluripotent stem cells. AB - The process of human cardiac development can be faithfully recapitulated in a culture dish with human pluripotent stem cells, where the impact of environmental stressors can be evaluated. The consequences of ionizing radiation exposure on human cardiac differentiation are largely unknown. In this study, human-induced pluripotent stem cell cultures (hiPSCs) were subjected to an external beam of 3.7 MeV alpha-particles at low mean absorbed doses of 0.5, 3, and 10 cGy. Subsequently, the hiPSCs were differentiated into beating cardiac myocytes (hiPSC CMs). Pluripotent and cardiac markers and morphology did not reveal differences between the irradiated and nonirradiated groups. While cell number was not affected during CM differentiation, cell number of differentiated CMs was severely reduced by ionizing radiation in a dose-responsive manner. beta adrenergic stimulation causes calcium (Ca2+) overload and oxidative stress. Although no significant increase in Ca2+ transient amplitude was observed in any group after treatment with 1 MUmol/L isoproterenol, the incidence of spontaneous Ca2+ waves/releases was more frequent in hiPSC-CMs of the irradiated groups, indicating arrhythmogenic activities at the single cell level. Increased transcript expression of mitochondrial biomarkers (LONP1, TFAM) and mtDNA-encoded genes (MT-CYB, MT-RNR1) was detected upon differentiation of hiPSC-CMs suggesting increased organelle biogenesis. Exposure of hiPSC-CM cultures to 10 cGy significantly upregulated MT-CYB and MT-RNR1 expression, which may reflect an adaptive response to ionizing radiation. Our results indicate that important aspects of differentiation of hiPSCs into cardiac myocytes may be affected by low fluences of densely ionizing radiations such as alpha-particles. PMID- 28801518 TI - Effects of plyometric and isometric training on muscle and tendon stiffness in vivo. AB - The purpose of this study was to compare the effects of plyometric and isometric training on tendon properties during ramp and ballistic contractions and muscle stiffness under passive and active conditions. Eleven subjects completed 12 weeks (3 days/week) of a unilateral training program for the plantar flexors. They performed plyometric training on one side (PLY) and isometric training on the other side (ISO). Active muscle stiffness in the medial gastrocnemius muscle was calculated according to changes in estimated muscle force and fascicle length during fast stretching after submaximal isometric contractions. Passive muscle stiffness was also calculated from estimated passive muscle force and fascicle length during slow passive stretching. Stiffness and hysteresis of tendon structures were measured using ultrasonography during ramp and ballistic contractions. Passive muscle stiffness and tendon hysteresis did not change for PLY or ISO Active muscle stiffness significantly increased for PLY, but not for ISO Tendon stiffness during ramp and ballistic contractions increased significantly for ISO, but not for PLY In addition, tendon elongation values at force production levels beyond 100 N during ballistic contractions increased for PLY These results suggest that plyometric training (but not isometric training) enhances the extensibility of tendon structures during ballistic contractions and active muscle stiffness during fast stretching, and these changes may be related to improved performances during stretch-shortening cycle exercises. PMID- 28801519 TI - XOR inhibition with febuxostat accelerates pulmonary endothelial barrier recovery and improves survival in lipopolysaccharide-induced murine sepsis. AB - Sepsis is a leading cause of death among patients in the intensive care unit, resulting from multi-organ failure. Activity of xanthine oxidoreductase (XOR), a reactive oxygen species (ROS) producing enzyme, is known to be elevated in nonsurvivors of sepsis compared to survivors. We have previously demonstrated that XOR is critical for ventilator-induced lung injury. Using febuxostat, a novel nonpurine inhibitor of XOR, we sought to determine the role of XOR inhibition in a murine model of sepsis-induced lung injury and mortality. C57BL/6J mice were subjected to intravenous (IV) lipopolysaccharide (LPS) for various time points, and lungs were harvested for analyses. Subsets of mice were treated with febuxostat, pre or post LPS exposure, or vehicle. Separate groups of mice were followed up for mortality after LPS exposure. After 24 hr of IV LPS, mice exhibited an increase in XOR activity in lung tissue and a significant increase in pulmonary endothelial barrier disruption. Pretreatment of animals with febuxostat before exposure to LPS, or treatment 4 h after LPS, resulted in complete abrogation of XOR activity. Inhibition of XOR with febuxostat did not prevent LPS-induced pulmonary vascular permeability at 24 h, however, it accelerated recovery of the pulmonary endothelial barrier integrity in response to LPS exposure. Furthermore, treatment with febuxostat resulted in significant reduction in mortality. Inhibition of XOR with febuxostat accelerates recovery of the pulmonary endothelial barrier and prevents LPS-induced mortality, whether given before or after exposure to LPS. PMID- 28801520 TI - Evidence that central pathways that mediate defecation utilize ghrelin receptors but do not require endogenous ghrelin. AB - In laboratory animals and in human, centrally penetrant ghrelin receptor agonists, given systemically or orally, cause defecation. Animal studies show that the effect is due to activation of ghrelin receptors in the spinal lumbosacral defecation centers. However, it is not known whether there is a physiological role of ghrelin or the ghrelin receptor in the control of defecation. Using immunohistochemistry and immunoassay, we detected and measured ghrelin in the stomach, but were unable to detect ghrelin by either method in the lumbosacral spinal cord, or other regions of the CNS In rats in which the thoracic spinal cord was transected 5 weeks before, the effects of a ghrelin agonist on colorectal propulsion were significantly enhanced, but defecation caused by water avoidance stress (WAS) was reduced. In knockout rats that expressed no ghrelin and in wild-type rats, WAS-induced defecation was reduced by a ghrelin receptor antagonist, to similar extents. We conclude that the ghrelin receptors of the lumbosacral defecation centers have a physiological role in the control of defecation, but that their role is not dependent on ghrelin. This implies that a transmitter other than ghrelin engages the ghrelin receptor or a ghrelin receptor complex. PMID- 28801521 TI - Role of pattern recognition receptors of the neurovascular unit in inflamm-aging. AB - Aging is associated with chronic inflammation partly mediated by increased levels of damage-associated molecular patterns, which activate pattern recognition receptors (PRRs) of the innate immune system. Furthermore, many aging-related disorders are associated with inflammation. PRRs, such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-like receptors (NLRs), are expressed not only in cells of the innate immune system but also in other cells, including cells of the neurovascular unit and cerebral vasculature forming the blood-brain barrier. In this review, we summarize our present knowledge about the relationship between activation of PRRs expressed by cells of the neurovascular unit-blood-brain barrier, chronic inflammation, and aging-related pathologies of the brain. The most important damage-associated molecular pattern-sensing PRRs in the brain are TLR2, TLR4, and NLR family pyrin domain-containing protein-1 and pyrin domain-containing protein-3, which are activated during physiological and pathological aging in microglia, neurons, astrocytes, and possibly endothelial cells and pericytes. PMID- 28801523 TI - Dietary modulation of oxylipins in cardiovascular disease and aging. AB - Oxylipins are a group of fatty acid metabolites generated via oxygenation of polyunsaturated fatty acids and are involved in processes such as inflammation, immunity, pain, vascular tone, and coagulation. As a result, oxylipins have been implicated in many conditions characterized by these processes, including cardiovascular disease and aging. The best characterized oxylipins in relation to cardiovascular disease are derived from the omega-6 fatty acid arachidonic acid. These oxylipins generally increase inflammation, hypertension, and platelet aggregation, although not universally. Similarly, oxylipins derived from the omega-6 fatty acid linoleic acid generally have more adverse than beneficial cardiovascular effects. Alternatively, most oxylipins derived from 20- and 22 carbon omega-3 fatty acids have anti-inflammatory, antiaggregatory, and vasodilatory effects that help explain the cardioprotective effects of these fatty acids. Much less is known regarding the oxylipins derived from the 18 carbon omega-3 fatty acid alpha-linolenic acid, but clinical trials with flaxseed supplementation have indicated that these oxylipins can have positive effects on blood pressure. Normal aging also is associated with changes in oxylipin levels in the brain, vasculature, and other tissues, indicating that oxylipin changes with aging may be involved in age-related changes in these tissues. A small number of trials in humans and animals with interventions that contain either 18 carbon or 20- and 22-carbon omega-3 fatty acids have indicated that dietary induced changes in oxylipins may be beneficial in slowing the changes associated with normal aging. In summary, oxylipins are an important group of molecules amenable to dietary manipulation to target cardiovascular disease and age-related degeneration.NEW & NOTEWORTHY Oxylipins are an important group of fatty acid metabolites amenable to dietary manipulation. Because of the role they play in cardiovascular disease and in age-related degeneration, oxylipins are gaining recognition as viable targets for specific dietary interventions focused on manipulating oxylipin composition to control these biological processes. PMID- 28801522 TI - Vascular niche contribution to age-associated neural stem cell dysfunction. AB - Neural stem cells (NSCs) persist throughout life in the dentate gyrus and the ventricular-subventricular zone, where they continuously provide new neurons and some glia. These cells are found in specialized niches that regulate quiescence, activation, differentiation, and cell fate choice. A key aspect of the regulatory niche is the vascular plexus, which modulates NSC behavior during tissue homeostasis and regeneration. During aging, NSCs become depleted and dysfunctional, resulting in reduced neurogenesis and poor brain repair. In this review, we discuss the emerging evidence that changes in the vascular niche both structurally and functionally contribute to reduced neurogenesis during aging and how this might contribute to reduced plasticity and repair in the aged brain. PMID- 28801524 TI - Muscle contraction induced arterial shear stress increases endothelial nitric oxide synthase phosphorylation in humans. AB - We determined if local increases in brachial artery shear during repetitive muscle contractions induce changes in protein expression of endothelial nitric oxide synthase (eNOS) and/or phosphorylated (p-)eNOS at Ser1177, the primary activation site on eNOS, in endothelial cells (ECs) of humans. Seven young male subjects (25 +/- 1 yr) performed 20 separate bouts (3 min each) of rhythmic forearm exercise at 20% of maximum over a 2-h period. Each bout of exercise was separated by 3 min of rest. An additional six male subjects (24 +/- 1 yr) served as time controls (no exercise). ECs were freshly isolated from the brachial artery using sterile J-wires through an arterial catheter at baseline and again after the 2-h exercise or time control period. Expression of eNOS or p-eNOS Ser1177 in ECs was determined via immunofluorescence. Brachial artery mean shear rate was elevated compared with baseline and the time control group throughout the 2-h exercise protocol (P < 0.001). p-eNOS Ser1177 expression was increased 57% in ECs in the exercise group [0.06 +/- 0.01 vs. 0.10 +/- 0.02 arbitrary units (au), P = 0.02] but not in the time control group (0.08 +/- 0.01 vs. 0.07 +/- 0.01 au, P = 0.72). In contrast, total eNOS expression did not change in either the exercise (0.13 +/- 0.04 vs. 0.12 +/- 0.03 au) or time control (0.12 +/- 0.03 vs. 0.11 +/- 0.03 au) group (P > 0.05 for both). Our novel results suggest that elevations in brachial artery shear increase eNOS Ser1177 phosphorylation in the absence of changes in total eNOS in ECs of young healthy male subjects, suggesting that this model is sufficient to alter posttranslational modification of eNOS activity in vivo in humans.NEW & NOTEWORTHY Elevations in brachial artery shear in response to forearm exercise increased endothelial nitric oxide synthase Ser1177 phosphorylation in brachial artery endothelial cells of healthy humans. Our present study provides the first evidence in humans that muscle contraction induced increases in conduit arterial shear lead to in vivo posttranslational modification of endothelial nitric oxide synthase activity in endothelial cells. PMID- 28801525 TI - Exercise of obese mice induces cardioprotection and oxygen sparing in hearts exposed to high-fat load. AB - Exercise training is a potent therapeutic approach in obesity and diabetes that exerts protective effects against the development of diabetic cardiomyopathy and ischemic injury. Acute increases in circulating fatty acids (FAs) during an ischemic insult can challenge the heart, since high FA load is considered to have adverse cardiac effects. In the present study, we tested the hypothesis that exercise-induced cardiac effects in diet-induced obese mice are abrogated by an acute high FA load. Diet-induced obese mice were fed a high-fat diet (HFD) for 20 wk. They were exercised using moderate- and/or high-intensity exercise training (MIT and HIT, respectively) for 10 or 3 wk, and isolated perfused hearts from these mice were exposed to a high FA load. Sedentary HFD mice served as controls. Ventricular function and myocardial O2 consumption were assessed after 10 wk of HIT and MIT, and postischemic functional recovery and infarct size were examined after 3 wk of HIT. In addition to improving aerobic capacity and reducing obesity and insulin resistance, long-term exercise ameliorated the development of diet induced cardiac dysfunction. This was associated with improved mechanical efficiency because of reduced myocardial oxygen consumption. Although to a lesser extent, 3-wk HIT also increased aerobic capacity and decreased obesity and insulin resistance. HIT also improved postischemic functional recovery and reduced infarct size. Event upon the exposure to a high FA load, short-term exercise induced an oxygen-sparing effect. This study therefore shows that exercise-induced cardioprotective effects are present under hyperlipidemic conditions and highlights the important role of myocardial energetics during ischemic stress.NEW & NOTEWORTHY The exercise-induced cardioprotective effects in obese hearts are present under hyperlipidemic conditions, comparable to circulating levels of FA occurring with an ischemic insult. Myocardial oxygen sparing is associated with this effect, despite the general notion that high fat can decrease cardiac efficiency. This highlights the role of myocardial energetics during ischemic stress. PMID- 28801526 TI - An update on hormone therapy in postmenopausal women: mini-review for the basic scientist. AB - The worlds of observational, clinical, and basic science collided in 2002 with the publication of results of the Women's Health Initiative (WHI), a large-scale, prospective, blinded, randomized-controlled trial designed to provide evidence regarding use of hormone treatment to prevent cardiovascular disease in menopausal women. The results of the WHI dramatically changed clinical practice, negatively impacted funding for hormone research, and left scientists to unravel the "why" of the results. Now over a decade and a half since the initial publication of the WHI results, basic and clinical scientists often do not interpret the results of the WHI with the precision needed to move the science forward. This review will 1) describe the historical background leading up to the WHI, 2) list the outcomes from the WHI, and put them in perspective with results of subsequent analysis of the WHI data and results from other prospective menopausal hormone treatment trials addressing cardiovascular effects of menopausal hormone use, and 3) articulate how the collective results are influencing current clinical care with the intent to provide guidance for designing and evaluating relevant new hormonal studies. PMID- 28801527 TI - Circulating Antibodies against Thrombospondin Type-I Domain-Containing 7A in Chinese Patients with Idiopathic Membranous Nephropathy. AB - BACKGROUND AND OBJECTIVES: Thrombospondin type-I domain-containing 7A (THSD7A) was recently identified as the target antigen in about 10% of patients with M type phospholipase A2 receptor (PLA2R)-negative membranous nephropathy in European and North American populations. The prevalence of THSD7A in other populations and their clinical associations deserve further clarification. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Immunofluorescence assay was performed to investigate anti-THSD7A antibodies in 578 consecutive patients with biopsy-proven idiopathic membranous nephropathy, 114 patients with secondary membranous nephropathy, 64 disease controls, and 20 healthy controls. Glomerular expression of THSD7A antigen was examined by immunohistochemistry. Anti-PLA2R antibodies and glomerular PLA2R expression were also screened. RESULTS: Among the 578 patients with idiopathic membranous nephropathy, 12 (2%) patients were identified as THSD7A-positive: ten patients were THSD7A-positive alone, which accounted for 16% (ten of 64) of PLA2R-negative patients; two patients were dual positive for both anti-THSD7A and anti-PLA2R antibodies and showed enhanced expression of both antigens colocalized in glomeruli. Among the 114 patients with secondary membranous nephropathy, one among 44 (2%) patients with cancer had anti THSD7A antibodies, whereas 18 of 44 (41%) had anti-PLA2R antibodies. No anti THSD7A antibody was detected in other disease controls or healthy individuals. Clinical features were comparable between the patients with and without THSD7A. During follow-up, two patients who achieved remission had a clearance of circulating antibodies against THSD7A, whereas antibodies increased in parallel with proteinuria in a patient with a relapse. CONCLUSIONS: THSD7A-associated membranous nephropathy has a low prevalence in Chinese patients. The double positive patients suggest dual autoimmune responses. PMID- 28801528 TI - Epidemiology and Natural History of the Cardiorenal Syndromes in a Cohort with Echocardiography. AB - BACKGROUND AND OBJECTIVES: It is unknown whether echocardiographic parameters are independently associated with the cardiorenal syndrome. No direct comparison of the natural history of various cardiorenal syndrome types has been conducted. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Our retrospective cohort study enrolled adult patients with at least one transthoracic echocardiography between 2004 and 2014 at a single health care system. Information on comorbidities was extracted using condition-specific diagnostic codes. All-cause mortality was the primary outcome among patients with cardiorenal syndrome types 1-4. Myocardial infarction and stroke were the secondary outcomes. RESULTS: In total, 30,681 patients were included, and 2512 (8%) developed at least one of the cardiorenal syndromes: 1707 patients developed an acute form of the syndrome (type 1 or 3), 128 patients developed type 2, and 677 patients developed type 4. In addition, 16% of patients with type 2 and 20% of patients with type 4 also developed an acute cardiorenal syndrome, whereas 14% of patients with acute cardiorenal progressed to CKD or chronic heart failure. Decreasing left ventricular ejection fraction, increasing pulmonary artery pressure, and higher right ventricular diameter were independently associated with higher incidence of a cardiorenal syndrome. Acute cardiorenal syndrome was associated with the highest risk of death compared with patients with CKD without cardiorenal syndrome (hazard ratio, 3.13; 95% confidence interval, 2.72 to 3.61; P<0.001). Patients with cardiorenal type 4 had better survival than patients with acute cardiorenal syndrome (hazard ratio, 0.48; 95% confidence interval, 0.37 to 0.61; P<0.001). Patients with acute cardiorenal syndrome and type 4 had increased risk of myocardial infarction and stroke compared with patients with CKD without cardiorenal syndrome. CONCLUSIONS: Up to 19% of patients with a chronic form of cardiorenal syndrome will subsequently develop an acute syndrome. Development of acute or type 4 cardiorenal syndrome is independently associated with mortality, the acute form having the worst prognosis. PMID- 28801531 TI - Correction. PMID- 28801529 TI - Silencing of Repetitive DNA Is Controlled by a Member of an Unusual Caenorhabditis elegans Gene Family. AB - Repetitive DNA sequences are subject to gene silencing in various animal species. Under specific circumstances repetitive DNA sequences can escape such silencing. For example, exogenously added, extrachromosomal DNA sequences that are stably inherited in multicopy repetitive arrays in the nematode Caenorhabditis elegans are frequently silenced in the germline, whereas such silencing often does not occur in the soma. This indicates that somatic cells might utilize factors that prevent repetitive DNA silencing. Indeed, such "antisilencing" factors have been revealed through genetic screens that identified mutant loci in which repetitive transgenic arrays are aberrantly silenced in the soma. We describe here a novel locus, pals-22 (for protein containing ALS2CR12 signature), required to prevent silencing of repetitive transgenes in neurons and other somatic tissue types. pals-22 deficiency also severely impacts animal vigor and confers phenotypes reminiscent of accelerated aging. We find that pals-22 is a member of a large family of divergent genes (39 members), defined by homology to the ALS2CR12 protein family. While gene family members are highly divergent, they show striking patterns of chromosomal clustering. The family expansion appears C. elegans-specific and has not occurred to the same extent in other nematode species for which genome sequences are available. The transgene-silencing phenotype observed upon loss of PALS-22 protein depends on the biogenesis of small RNAs. We speculate that the pals gene family may be part of a species specific cellular defense mechanism. PMID- 28801530 TI - Rhythmic Behavior Is Controlled by the SRm160 Splicing Factor in Drosophila melanogaster. AB - Circadian clocks organize the metabolism, physiology, and behavior of organisms throughout the day-night cycle by controlling daily rhythms in gene expression at the transcriptional and post-transcriptional levels. While many transcription factors underlying circadian oscillations are known, the splicing factors that modulate these rhythms remain largely unexplored. A genome-wide assessment of the alterations of gene expression in a null mutant of the alternative splicing regulator SR-related matrix protein of 160 kDa (SRm160) revealed the extent to which alternative splicing impacts on behavior-related genes. We show that SRm160 affects gene expression in pacemaker neurons of the Drosophila brain to ensure proper oscillations of the molecular clock. A reduced level of SRm160 in adult pacemaker neurons impairs circadian rhythms in locomotor behavior, and this phenotype is caused, at least in part, by a marked reduction in period (per) levels. Moreover, rhythmic accumulation of the neuropeptide PIGMENT DISPERSING FACTOR in the dorsal projections of these neurons is abolished after SRm160 depletion. The lack of rhythmicity in SRm160-downregulated flies is reversed by a fully spliced per construct, but not by an extra copy of the endogenous locus, showing that SRm160 positively regulates per levels in a splicing-dependent manner. Our findings highlight the significant effect of alternative splicing on the nervous system and particularly on brain function in an in vivo model. PMID- 28801532 TI - Activation of the Nkx2.5-Calr-p53 signaling pathway by hyperglycemia induces cardiac remodeling and dysfunction in adult zebrafish. AB - Hyperglycemia is an independent risk factor for diabetic cardiomyopathy in humans; however, the underlying mechanisms have not been thoroughly elucidated. Zebrafish (Danio rerio) was used in this study as a novel vertebrate model to explore the signaling pathways of human adult cardiomyopathy. Hyperglycemia was induced by alternately immersing adult zebrafish in a glucose solution or water. The hyperglycemic fish gradually exhibited some hallmarks of cardiomyopathy such as myocardial hypertrophy and apoptosis, myofibril loss, fetal gene reactivation, and severe arrhythmia. Echocardiography of the glucose-treated fish demonstrated diastolic dysfunction at an early stage and systolic dysfunction at a later stage, consistent with what is observed in diabetic patients. Enlarged hearts with decreased myocardial density, accompanied by decompensated cardiac function, indicated that apoptosis was critical in the pathological process. Significant upregulation of the expression of Nkx2.5 and its downstream targets calreticulin (Calr) and p53 was noted in the glucose-treated fish. High-glucose stimulation in vitro evoked marked apoptosis of primary cardiomyocytes, which was rescued by the p53 inhibitor pifithrin-MU. In vitro experiments were performed using compound treatment and genetically via cell infection. Genetically, knockout of Nkx2.5 induced decreased expression of Nkx2.5, Calr and p53 Upregulation of Calr resulted in increased p53 expression, whereas the level of Nkx2.5 remained unchanged. An adult zebrafish model of hyperglycemia-induced cardiomyopathy was successfully established. Hyperglycemia-induced myocardial apoptosis was mediated, at least in part, by activation of the Nkx2.5-Calr-p53 pathway in vivo, resulting in cardiac dysfunction and hyperglycemia-induced cardiomyopathy. PMID- 28801533 TI - Glibenclamide induces apoptosis by activating reactive oxygen species dependent JNK pathway in hepatocellular carcinoma cells. AB - Glibenclamide (Gli) is a widely employed drug in the treatment of type 2 diabetes and many lines of evidence have described its anti-tumor effects in some neoplasms. The aim of the present study was to investigate the effect of Gli on apoptosis of human hepatocellular carcinoma (HCC) cells and to analyze the underlying pathway involved in this action. Two HCC cell lines, HepG-2 and Huh7 were used as the cell models. We found that Gli treatment significantly inhibited cell viability, induced a significant cell-cycle arrest in G2/M-phase and induced apoptosis in both HepG-2 and Huh7 cells. We further verified that apoptosis induction by Gli was accompanied by increase in ROS levels and activation of the JNK pathway. Scavenging of the intracellular ROS with its blocker N-acetyl-L cysteine (NAC) could mitigate the Gli-induced apoptosis and JNK activation in the two HCC cell lines. Furthermore, inhibition of JNK pathway by its inhibitor SP100625 effectively reduced Gli-induced apoptosis in HCC cells. In conclusion, Gli treatment significantly induced cell apoptosis by promoting ROS-dependent JNK pathway activation in HCC cells. Gli may be a potential clinical anti-tumor drug for HCC. PMID- 28801534 TI - cGAS is activated by DNA in a length-dependent manner. AB - Cytosolic DNA stimulates innate immune responses, including type I interferons (IFN), which have antiviral and immunomodulatory activities. Cyclic GMP-AMP synthase (cGAS) recognizes cytoplasmic DNA and signals via STING to induce IFN production. Despite the importance of DNA in innate immunity, the nature of the DNA that stimulates IFN production is not well described. Using low DNA concentrations, we show that dsDNA induces IFN in a length-dependent manner. This is observed over a wide length-span of DNA, ranging from the minimal stimulatory length to several kilobases, and is fully dependent on cGAS irrespective of DNA length. Importantly, in vitro studies reveal that long DNA activates recombinant human cGAS more efficiently than short DNA, showing that length-dependent DNA recognition is an intrinsic property of cGAS independent of accessory proteins. Collectively, this work identifies long DNA as the molecular entity stimulating the cGAS pathway upon cytosolic DNA challenge such as viral infections. PMID- 28801536 TI - Structure Annotation and Quantification of Wheat Seed Oxidized Lipids by High Resolution LC-MS/MS. AB - Lipid oxidation is a process ubiquitous in life, but the direct and comprehensive analysis of oxidized lipids has been limited by available analytical methods. We applied high-resolution liquid chromatography-mass spectrometry (LC-MS) and tandem mass spectrometry (MS/MS) to quantify oxidized lipids (glycerides, fatty acids, phospholipids, lysophospholipids, and galactolipids) and implemented a platform-independent high-throughput-amenable analysis pipeline for the high confidence annotation and acyl composition analysis of oxidized lipids. Lipid contents of 90 different naturally aged wheat (Triticum aestivum) seed stocks were quantified in an untargeted high-resolution LC-MS experiment, resulting in 18,556 quantitative mass-to-charge ratio features. In a posthoc liquid chromatography-tandem mass spectrometry experiment, high-resolution MS/MS spectra (5 mD accuracy) were recorded for 8,957 out of 12,080 putatively monoisotopic features of the LC-MS data set. A total of 353 nonoxidized and 559 oxidized lipids with up to four additional oxygen atoms were annotated based on the accurate mass recordings (1.5 ppm tolerance) of the LC-MS data set and filtering procedures. MS/MS spectra available for 828 of these annotations were analyzed by translating experimentally known fragmentation rules of lipids into the fragmentation of oxidized lipids. This led to the identification of 259 nonoxidized and 365 oxidized lipids by both accurate mass and MS/MS spectra and to the determination of acyl compositions for 221 nonoxidized and 295 oxidized lipids. Analysis of 15-year aged wheat seeds revealed increased lipid oxidation and hydrolysis in seeds stored in ambient versus cold conditions. PMID- 28801537 TI - Closure of Secundum Atrial Septal Defects With the AMPLATZER Septal Occluder: A Prospective, Multicenter, Post-Approval Study. AB - BACKGROUND: Prospective data on the medium-term safety and effectiveness of the AMPLATZER Septal Occluder in clinical practice are not available. The objective of this study was to prospectively evaluate the risk of hemodynamic compromise and obtain medium-term survival data on patients implanted with the AMPLATZER Septal Occluder for percutaneous closure of secundum atrial septal defects. METHODS AND RESULTS: Subjects were enrolled prospectively at 50 US sites and followed for 2 years. Between 2008 and 2012, atrial septal defect closure with the AMPLATZER Septal Occluder was attempted in 1000 patients (aged 0.3-83.6 years, mean 21+/-22 years). Procedural closure occurred in 97.9%, with 1-month and 2-year closure 98.5% and 97.9%, respectively. Hemodynamic compromise occurred in 6 subjects (0.65%), because of dysrhythmia in 2, device embolization in 1, and cardiac erosion in 3. The rate of cardiac erosion was 0.3% (average 83, range 12 171 days from implant). CONCLUSIONS: Closure of atrial septal defect with the AMPLATZER Septal Occluder is safe and effective. The rate of hemodynamic compromise and cardiac erosion is rare. The risk factors for cardiac erosion after device closure are not yet clear. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00650936. PMID- 28801538 TI - Comparison of Acute Thrombogenicity for Metallic and Polymeric Bioabsorbable Scaffolds: Magmaris Versus Absorb in a Porcine Arteriovenous Shunt Model. AB - BACKGROUND: A comparison in acute thrombogenicity between the Magmaris sirolimus eluting bioabsorbable magnesium scaffold and the Absorb bioresorbable vascular scaffold has not been performed. This study assessed acute thrombogenicity of Magmaris compared with Absorb and the Orsiro hybrid drug-eluting stent in a porcine arteriovenous shunt model. METHODS AND RESULTS: An ex vivo porcine carotid jugular arteriovenous shunt was established and connected to SYLGARD tubing containing the Magmaris, Absorb, and Orsiro scaffolds/stents and allowed to run in the shunt for a maximum of 1 hour. Twelve shunts (2 shunt runs per pig) were run comparing the 3 scaffolds in alternating order. Nested generalized linear mixed models were used to compare variables between scaffold groups while adjusting for variability between shunt runs. Confocal fluorescent microscopy costaining CD61/CD42b demonstrated that both Magmaris (3.0%) and Orsiro (4.6%) had less platelet coverage of the total scaffold compared with Absorb (21.8%). Scanning electron microscopy demonstrated significantly less thrombus deposition to Magmaris as a percentage of the total scaffold compared with Absorb (5.0% versus 16.1%, P=0.02). Magmaris had significantly less PM-1-positive neutrophil and CD14-positive monocyte adherence compared with both Orsiro and Absorb. Orsiro had significantly less monocyte deposition compared with Absorb. CONCLUSIONS: Despite a similar scaffold strut thickness, the Magmaris sirolimus-eluting bioabsorbable magnesium scaffold was significantly less thrombogenic compared with the Absorb bioresorbable vascular scaffold in an ex vivo porcine arteriovenous shunt model. Further studies are needed to determine whether the reduced thrombogenicity of Magmaris will result in reductions in major cardiovascular events. PMID- 28801535 TI - Expansion of the ISWI chromatin remodeler family with new active complexes. AB - ISWI chromatin remodelers mobilize nucleosomes to control DNA accessibility. Complexes isolated to date pair one of six regulatory subunits with one of two highly similar ATPases. However, we find that each endogenously expressed ATPase co-purifies with every regulatory subunit, substantially increasing the diversity of ISWI complexes, and we additionally identify BAZ2B as a novel, seventh regulatory subunit. Through reconstitution of catalytically active human ISWI complexes, we demonstrate that the new interactions described here are stable and direct. Finally, we profile the nucleosome remodeling functions of the now expanded family of ISWI chromatin remodelers. By revealing the combinatorial nature of ISWI complexes, we provide a basis for better understanding ISWI function in normal settings and disease. PMID- 28801539 TI - Cangrelor in Older Patients Undergoing Percutaneous Coronary Intervention: Findings From CHAMPION PHOENIX. AB - BACKGROUND: Older patients treated with percutaneous coronary intervention are at increased risk of periprocedural events. METHODS AND RESULTS: CHAMPION (cangrelor versus standard therapy to achieve optimal management of platelet inhibition) PHOENIX randomized 11 145 patients to cangrelor or clopidogrel. We sought to determine the outcomes in the prespecified subgroup of patients >=75 years old (n=2010; 18%). Cangrelor resulted in directionally consistent effects on the primary end point (death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis) in patients >=75 years old (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.50-1.02) and in those <75 years old (OR, 0.81; 95% CI, 0.67-0.98; P [interaction]=0.55). Age >=75 years was an independent predictor of GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate/severe bleeding (1.0% versus 0.3%; adjusted OR, 2.94; 95% CI, 1.28-6.77; P=0.01) when compared with patients <75 years old. There was no significant difference in GUSTO moderate/severe bleeding with cangrelor versus clopidogrel (1.1% versus 1.0%; OR, 1.07; 95% CI 0.45-2.53) in patients >=75 years old or in those <75 years old (0.4% versus 0.2%; OR, 2.24; 95% CI, 1.02-4.93; P [interaction]=0.21). For the net composite end point of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis plus GUSTO moderate/severe bleeding, the OR for cangrelor in those >=75 years old was 0.75 (6.4% versus 8.3%; 95% CI, 0.54-1.05; P=0.09). The effects were similar in those <75 years old (4.9% versus 5.8%; OR, 0.85; 95% CI, 0.70-1.02; P=0.08; P [interaction]=0.53). CONCLUSIONS: Patients >=75 years old have an overall ~3-fold increased odds of moderate/severe bleeding. Cangrelor, when compared with clopidogrel, provides similar efficacy and in patients >=75 years old as in those <75 years old but does not increase the risk of major bleeding. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01156571. PMID- 28801541 TI - Letter by Calabro and Gragnano Regarding Article, "Dual Antiplatelet Therapy Continuation Beyond 1 Year After Drug-Eluting Stents: A Meta-Analysis of Randomized Trials". PMID- 28801540 TI - Time-Course Reduction in Patient Exposure to Radiation From Coronary Interventional Procedures: The Greater Paris Area Percutaneous Coronary Intervention Registry. AB - BACKGROUND: The frequency of complex percutaneous coronary interventions (PCIs) has increased in the last few years, with a growing concern on the radiation dose received by the patients. Multicenter data from large unselected populations on patients' radiation doses during coronary angiography (CA) and PCI and temporal trends are lacking. This study sought to evaluate the temporal trends in patients' exposure to radiation from CA and PCI. METHODS AND RESULTS: Data were taken from the CARDIO-ARSIF registry that prospectively collects data on all CAs and PCIs performed in the 36 catheterization laboratories in the Greater Paris Area, the most populated regions in France with about 12 million inhabitants. Kerma area product and Fluoroscopy time from 152 684 consecutive CAs and 103 177 PCIs performed between 2009 and 2013 were analyzed. A continuous trend for a decrease in median [interquartile range] Kerma area product was observed, from 33 [19-55] Gy cm2 in 2009 to 27 [16-44] Gy cm2 in 2013 for CA (P<0.0001), and from 73 [41-125] to 55 [31-91] Gy cm2 for PCI (P<0.0001). Time-course differences in Kerma area product remained highly significant after adjustment on Fluoroscopy time, PCI procedure complexity, change of x-ray equipment, and other patient- and procedure-related covariates. CONCLUSIONS: In a large patient population, a steady temporal decrease in patient radiation exposure during CA and PCI was noted between 2009 and 2013. Kerma area product reduction was consistent in all types of procedure and was independent of patient-related factors and PCI procedure complexity. PMID- 28801542 TI - Rather Thick, Yet Antithrombogenic: Is the Magmaris Scaffold a New Hope for Bioresorbable Coronary Scaffold? PMID- 28801543 TI - Radiation Exposure in Cardiac Catheterization: Operator Behavior Matters. PMID- 28801544 TI - Editorial on 'Assessing the association between thinking dispositions and clinical error'. PMID- 28801545 TI - Cardiotoxicity and Mechanism of Particulate Matter 2.5 (PM2.5) Exposure in Offspring Rats During Pregnancy. AB - BACKGROUND The aim of this study was to investigate the cardiotoxicity and mechanism of particulate matter 2.5 (PM2.5) exposure on offspring rats during pregnancy. MATERIAL AND METHODS Wistar rats were used to establish a PM2.5 exposure animal model during pregnancy, and they were divided into a control group, a low-dose group, a middle-dose group, and a high-dose group according to PM2.5 exposure dose. The pathological changes of heart tissue, the rate of myocardial cell apoptosis, the levels of LDH, AST, and CM-KB in serum, and the difference in mitochondrial fusion genes (OPA1 and Mfn1) and mitochondrial genes (Drp1 and Fis1) were compared among groups. RESULTS The arrangement of myocardial fibers in offspring mice of PM2.5 exposure groups became disordered, the shape of some cardiomyocytes became irregular, and some staining darker nuclei appeared. The apoptotic rates of myocardium in offspring rats exposed to PM2.5 were (12.61+/-0.93)% in the low-dose group, (25.14+/-1.53)% in the middle-dose group, and (30.13+/-1.50)% in the high-dose group, which were all significantly higher than in the control group (9.12+/-0.80)% (P<0.05). The levels of LDH, AST, and CM KB and the expression of OPA1, Mfn1, Drp1, and Fis1 in offspring mice of PM2.5 exposure groups increased with the increase of PM2.5 exposure dose, and were significantly higher than that of the control group (P<0.05). CONCLUSIONS The mitochondria of the offspring mice were damaged due to the abnormal expression of mitochondrial fusion/splicing gene by PM2.5 exposure during pregnancy, and the hearts of offspring mice were damaged due to damaged mitochondria. PMID- 28801546 TI - Incoherent scattering can favorably influence energy filtering in nanostructured thermoelectrics. AB - Investigating in detail the physics of energy filtering through a single planar energy barrier in nanostructured thermoelectric generators, we reinforce the non trivial result that the anticipated enhancement in generated power at a given efficiency via energy filtering is a characteristic of systems dominated by incoherent scattering and is absent in ballistic devices. In such cases, assuming an energy dependent relaxation time tau(E) = kE r , we show that there exists a minimum value r min beyond which generation can be enhanced by embedding nanobarriers. For bulk generators with embedded nanobarriers, we delve into the details of inter sub-band scattering and show that it has finite contribution to the enhancement in generation. We subsequently discuss the realistic aspects, such as the effect of smooth transmission cut-off and show that for r > r min , the optimized energy barrier is just sufficiently wide enough to scatter off low energy electrons, a very wide barrier being detrimental to the performance. Analysis of the obtained results should provide general design guidelines for enhancement in thermoelectric generation via energy filtering. Our non equilibrium approach is typically valid in the absence of local quasi-equilibrium and hence sets the stage for future advancements in thermoelectric device analysis, for example, Peltier cooling near a barrier interface. PMID- 28801547 TI - Early changes in plasma DNA levels of mutant KRAS as a sensitive marker of response to chemotherapy in pancreatic cancer. AB - Pancreatic cancer (PDAC) is still lacking of reliable markers to monitor tumor response. CA 19-9 is the only biomarker approved, despite it has several limitations in sensitivity and specificity. Since mutations of KRAS occur in more than 90% of tumors, its detection in circulating free tumor DNA (cftDNA) could represent a biomarker to monitor chemotherapy response. Twenty-seven advanced PDAC patients given first-line 5-fluorouracil, irinotecan and oxaliplatin or gemcitabine and nab-paclitaxel were enrolled. Three ml of plasma were collected: 1) before starting chemotherapy (baseline); 2) at day 15 of treatment; and 3) at each clinical follow-up. cftDNA was extracted and analysed for KRAS mutations (mutKRAS) by digital droplet PCR. Nineteen patients displayed a mutKRAS in baseline plasma samples. There was a statistically significant difference in progression-free survival (PFS) and overall survival (OS) in patients with increase vs. stability/reduction of cftDNA in the sample collected at day 15 (median PFS 2.5 vs 7.5 months, p = 0.03; median OS 6.5 vs 11.5 months, p = 0.009). The results of this study demonstrate that cftDNA mutKRAS changes are associated with tumor response to chemotherapy and support the evidence that mutKRAS in plasma may be used as a new marker for monitoring treatment outcome and disease progression in PDAC. PMID- 28801548 TI - Virtual cardiac monolayers for electrical wave propagation. AB - The complex structure of cardiac tissue is considered to be one of the main determinants of an arrhythmogenic substrate. This study is aimed at developing the first mathematical model to describe the formation of cardiac tissue, using a joint in silico-in vitro approach. First, we performed experiments under various conditions to carefully characterise the morphology of cardiac tissue in a culture of neonatal rat ventricular cells. We considered two cell types, namely, cardiomyocytes and fibroblasts. Next, we proposed a mathematical model, based on the Glazier-Graner-Hogeweg model, which is widely used in tissue growth studies. The resultant tissue morphology was coupled to the detailed electrophysiological Korhonen-Majumder model for neonatal rat ventricular cardiomyocytes, in order to study wave propagation. The simulated waves had the same anisotropy ratio and wavefront complexity as those in the experiment. Thus, we conclude that our approach allows us to reproduce the morphological and physiological properties of cardiac tissue. PMID- 28801550 TI - Active neutron and gamma-ray imaging of highly enriched uranium for treaty verification. AB - The detection and characterization of highly enriched uranium (HEU) presents a large challenge in the non-proliferation field. HEU has a low neutron emission rate and most gamma rays are low energy and easily shielded. To address this challenge, an instrument known as the dual-particle imager (DPI) was used with a portable deuterium-tritium (DT) neutron generator to detect neutrons and gamma rays from induced fission in HEU. We evaluated system response using a 13.7-kg HEU sphere in several configurations with no moderation, high-density polyethylene (HDPE) moderation, and tungsten moderation. A hollow tungsten sphere was interrogated to evaluate the response to a possible hoax item. First, localization capabilities were demonstrated by reconstructing neutron and gamma ray images. Once localized, additional properties such as fast neutron energy spectra and time-dependent neutron count rates were attributed to the items. For the interrogated configurations containing HEU, the reconstructed neutron spectra resembled Watt spectra, which gave confidence that the interrogated items were undergoing induced fission. The time-dependent neutron count rate was also compared for each configuration and shown to be dependent on the neutron multiplication of the item. This result showed that the DPI is a viable tool for localizing and confirming fissile mass and multiplication. PMID- 28801551 TI - Fault reactivation and earthquakes with magnitudes of up to Mw4.7 induced by shale-gas hydraulic fracturing in Sichuan Basin, China. AB - This paper presents a timely and detailed study of significant injection-induced seismicity recently observed in the Sichuan Basin, China, where shale-gas hydraulic fracturing has been initiated and the aggressive production of shale gas is planned for the coming years. Multiple lines of evidence, including an epidemic-type aftershock sequence model, relocated hypocenters, the mechanisms of 13 large events (M W > 3.5), and numerically calculated Coulomb failure stress results, convincingly suggest that a series of earthquakes with moment magnitudes up to M W 4.7 has been induced by "short-term" (several months at a single well pad) injections for hydraulic fracturing at depths of 2.3 to 3 km. This, in turn, supports the hypothesis that they represent examples of injection-induced fault reactivation. The geologic reasons why earthquake magnitudes associated with hydraulic fracturing operations are so high in this area are discussed. Because hydraulic fracturing operations are on the rise in the Sichuan Basin, it would be beneficial for the geoscience, gas operator, regulator, and academic communities to work collectively to elucidate the local factors governing the high level of injection-induced seismicity, with the ultimate goal of ensuring that shale gas fracking can be carried out effectively and safely. PMID- 28801549 TI - Great cormorants (Phalacrocorax carbo) as potential vectors for the dispersal of Vibrio cholerae. AB - Vibrio cholerae is the cause of cholera, a devastating epidemic and pandemic disease. Despite its importance, the way of its global dissemination is unknown. V. cholerae is abundant in aquatic habitats and is known to be borne by copepods, chironomids and fishes. Our aim was to determine if fish-eating birds act as vectors in the spread of V. cholerae by consuming infected fish. We determined the existence of V. cholerae in the microbiome of 5/7 wild cormorants' intestine. In three of these V. cholerae-positive wild cormorants, the presence of a gene for cholera toxin (ctxA) was detected. We subsequently tested eight captive, hand reared cormorants, divided into two equal groups. Prior to the experiment, the feces of the cormorants were V. cholerae-negative. One group was fed exclusively on tilapias, which are naturally infected with V. cholerae, and the other was fed exclusively on goldfish or on koi that were V. cholerae-negative. We detected V. cholerae in the feces of the tilapia-fed, but not in the goldfish/koi-fed, cormorants. Hence, we demonstrate that fish-eating birds can be infected with V. cholerae from their fish prey. The large-scale movements of many fish-eating birds provide a potential mechanism for the global distribution of V. cholerae. PMID- 28801552 TI - Gene Location, Expression, and Function of FNDC5 in Meishan Pigs. AB - Irisin is a new muscular regulatory factor that is generated by the cleavage of its precursor protein fibronectin type III domain-containing protein 5 (FNDC5). Irisin promotes fat consumption due to its stimulatory role in the browning of the adipocytes in mice. Currently, there is no report on FNDC5 functions in pigs as model animals. In this study, we investigated the expression patterns and functions of FNDC5 in Meishan pigs. Our results showed that FNDC5 gene in Meishan pigs contains five transcripts, all of which can be translated into functional intact irisin proteins. Porcine FNDC5 is mainly expressed in skeletal muscle, with the expression level being significantly higher during the embryonic and juvenile periods than in the adulthood stage. In vitro study showed that FNDC5 stimulates the proliferation and adipogenic differentiation of primary adipocytes isolated from Meishan pigs, and FNDC5 enhances the expression of browning marker genes during adipogenic differentiation. Our study was the first report on FNDC5 expression patterns and functions in pigs. Data from this study provide valuable information related to the study on FNDC5 functions and future development of novel treatment for obesity. PMID- 28801553 TI - Dead-end complex, lipid interactions and catalytic mechanism of microsomal glutathione transferase 1, an electron crystallography and mutagenesis investigation. AB - Microsomal glutathione transferase 1 (MGST1) is a detoxification enzyme belonging to the Membrane Associated Proteins in Eicosanoid and Glutathione Metabolism (MAPEG) superfamily. Here we have used electron crystallography of two dimensional crystals in order to determine an atomic model of rat MGST1 in a lipid environment. The model comprises 123 of the 155 amino acid residues, two structured phospholipid molecules, two aliphatic chains and one glutathione (GSH) molecule. The functional unit is a homotrimer centered on the crystallographic three-fold axes of the unit cell. The GSH substrate binds in an extended conformation at the interface between two subunits of the trimer supported by new in vitro mutagenesis data. Mutation of Arginine 130 to alanine resulted in complete loss of activity consistent with a role for Arginine 130 in stabilizing the strongly nucleophilic GSH thiolate required for catalysis. Based on the new model and an electron diffraction data set from crystals soaked with trinitrobenzene, that forms a dead-end Meisenheimer complex with GSH, a difference map was calculated. The map reveals side chain movements opening a cavity that defines the second substrate site. PMID- 28801554 TI - Delayed fractional dose regimen of the RTS,S/AS01 malaria vaccine candidate enhances an IgG4 response that inhibits serum opsonophagocytosis. AB - A recent study of the RTS,S malaria vaccine, which is based on the circumsporozoite protein (CSP), demonstrated an increase in efficacy from 50-60% to 80% when using a delayed fractional dose regimen, in which the standard 0-1-2 month immunization schedule was modified to a 0-1-7 month schedule and the third immunization was delivered at 20% of the full dose. Given the role that antibodies can play in RTS,S-induced protection, we sought to determine how the modified regimen alters IgG subclasses and serum opsonophagocytic activity (OPA). Previously, we showed that lower CSP-mediated OPA was associated with protection in an RTS,S study. Here we report that the delayed fractional dose regimen resulted in decreased CSP-mediated OPA and an enhanced CSP-specific IgG4 response. Linear regression modeling predicted that CSP-specific IgG1 promote OPA, and that CSP-specific IgG4 interferes with OPA, which we subsequently confirmed by IgG subclass depletion. Although the role of IgG4 antibodies and OPA in protection is still unclear, our findings, combined with previous results that the delayed fractional dose increases CSP-specific antibody avidity and somatic hypermutation frequency in CSP-specific B cells, demonstrate how changes in vaccine regimen alone can significantly alter the quality of antibody responses to improve vaccine efficacy. PMID- 28801555 TI - Electrochemically anodized porous silicon: Towards simple and affordable anode material for Li-ion batteries. AB - Silicon is being increasingly studied as the next-generation anode material for Li-ion batteries because of its ten times higher gravimetric capacity compared with the widely-used graphite. While nanoparticles and other nanostructured silicon materials often exhibit good cyclability, their volumetric capacity tends to be worse or similar than that of graphite. Furthermore, these materials are commonly complicated and expensive to produce. An effortless way to produce nanostructured silicon is electrochemical anodization. However, there is no systematic study how various material properties affect its performance in LIBs. In the present study, the effects of particle size, surface passivation and boron doping degree were evaluated for the mesoporous silicon with relatively low porosity of 50%. This porosity value was estimated to be the lowest value for the silicon material that still can accommodate the substantial volume change during the charge/discharge cycling. The optimal particle size was between 10-20 um, the carbide layer enhanced the rate capability by improving the lithiation kinetics, and higher levels of boron doping were beneficial for obtaining higher specific capacity at lower rates. Comparison of pristine and cycled electrodes revealed the loss of electrical contact and electrolyte decay to be the major contributors to the capacity decay. PMID- 28801556 TI - Collective modes in simple melts: Transition from soft spheres to the hard sphere limit. AB - We study collective modes in a classical system of particles with repulsive inverse-power-law (IPL) interactions in the fluid phase, near the fluid-solid coexistence (IPL melts). The IPL exponent is varied from n = 10 to n = 100 to mimic the transition from moderately soft to hard-sphere-like interactions. We compare the longitudinal dispersion relations obtained using molecular dynamic (MD) simulations with those calculated using the quasi-crystalline approximation (QCA) and find that this simple theoretical approach becomes grossly inaccurate for [Formula: see text]. Similarly, conventional expressions for high-frequency (instantaneous) elastic moduli, predicting their divergence as n increases, are meaningless in this regime. Relations of the longitudinal and transverse elastic velocities of the QCA model to the adiabatic sound velocity, measured in MD simulations, are discussed for the regime where QCA is applicable. Two potentially useful freezing indicators for classical particle systems with steep repulsive interactions are discussed. PMID- 28801557 TI - Controlling the thermoelectric effect by mechanical manipulation of the electron's quantum phase in atomic junctions. AB - The thermoelectric voltage developed across an atomic metal junction (i.e., a nanostructure in which one or a few atoms connect two metal electrodes) in response to a temperature difference between the electrodes, results from the quantum interference of electrons that pass through the junction multiple times after being scattered by the surrounding defects. Here we report successfully tuning this quantum interference and thus controlling the magnitude and sign of the thermoelectric voltage by applying a mechanical force that deforms the junction. The observed switching of the thermoelectric voltage is reversible and can be cycled many times. Our ab initio and semi-empirical calculations elucidate the detailed mechanism by which the quantum interference is tuned. We show that the applied strain alters the quantum phases of electrons passing through the narrowest part of the junction and hence modifies the electronic quantum interference in the device. Tuning the quantum interference causes the energies of electronic transport resonances to shift, which affects the thermoelectric voltage. These experimental and theoretical studies reveal that Au atomic junctions can be made to exhibit both positive and negative thermoelectric voltages on demand, and demonstrate the importance and tunability of the quantum interference effect in the atomic-scale metal nanostructures. PMID- 28801558 TI - Visceral adiposity index, lipid accumulation product and intracranial atherosclerotic stenosis in middle-aged and elderly Chinese. AB - We investigated the association of the newly established lipid accumulation product (LAP) and visceral adiposity index (VAI) with intracranial atherosclerotic stenosis (ICAS) in middle-aged and elderly Chinese. From June 2012 to January 2013, consecutive patients >=40 years of age who underwent cerebral vascular imaging for various medical reasons were enrolled in this study. Multivariate logistic regression models were used to evaluate the correlation of VAI and LAP with the risk of ICAS. In total, 845 patients were included in the study. The prevalence of ICAS gradually increased in females and in all patients with advancing tertiles of VAI or LAP. After adjusting for potential risks, both the VAI and LAP were related to ICAS in females [VAI: odds ratio (OR) = 3.25, 95% confidence interval (95%CI) = 1.17-9.03, P = 0.024; LAP: OR = 4.11, 95%CI = 1.39-12.12, P = 0.011; tertiles 3 vs. 1]. The sensitivity, specificity, and positive predictive value (PPV) were 74.7%, 45.5%, and 84.4% for VAI (cut-off: 1.71) and 79.3%, 40.5%, and 84.1% for LAP (cut-off: 23.99). The same relationships in males were not significant. Both VAI and LAP were closely associated with an increased risk of ICAS in middle-aged and elderly Chinese females. PMID- 28801559 TI - Differential Effects of Linagliptin on the Function of Human Islets Isolated from Non-diabetic and Diabetic Donors. AB - Linagliptin is a dipeptidyl Peptidase-4 (DPP-4) inhibitor that inhibits the degradation of glucagon-like peptide 1 (GLP-1), and has been approved for the treatment of type 2 diabetes (T2D) in clinic. Previous studies have shown linagliptin improves beta cell function using animal models and isolated islets from normal subjects. Since beta cell dysfunction occurs during diabetes development, it was not clear how human islets of T2D patients would respond to linagliptin treatment. Therefore, in this study we employed human islets isolated from donors with and without T2D and evaluated how they responded to linagliptin treatment. Our data showed that linagliptin significantly improved glucose stimulated insulin secretion for both non-diabetic and diabetic human islets, but its effectiveness on T2D islets was lower than on normal islets. The differential effects were attributed to reduced GLP-1 receptor expression in diabetic islets. In addition, linagliptin treatment increased the relative GLP-1 vs glucagon production in both non-diabetic and diabetic islets, suggesting a positive role of linagliptin in modulating alpha cell function to restore normoglycemia. Our study indicated that, from the standpoint of islet cell function, linagliptin would be more effective in treating early-stage diabetic patients before they develop severe beta cell dysfunction. PMID- 28801560 TI - Imaging Active Infection in vivo Using D-Amino Acid Derived PET Radiotracers. AB - Occult bacterial infections represent a worldwide health problem. Differentiating active bacterial infection from sterile inflammation can be difficult using current imaging tools. Present clinically viable methodologies either detect morphologic changes (CT/ MR), recruitment of immune cells (111In-WBC SPECT), or enhanced glycolytic flux seen in inflammatory cells (18F-FDG PET). However, these strategies are often inadequate to detect bacterial infection and are not specific for living bacteria. Recent approaches have taken advantage of key metabolic differences between prokaryotic and eukaryotic organisms, allowing easier distinction between bacteria and their host. In this report, we exploited one key difference, bacterial cell wall biosynthesis, to detect living bacteria using a positron-labeled D-amino acid. After screening several 14C D-amino acids for their incorporation into E. coli in culture, we identified D-methionine as a probe with outstanding radiopharmaceutical potential. Based on an analogous procedure to that used for L-[methyl-11C]methionine ([11C] L-Met), we developed an enhanced asymmetric synthesis of D-[methyl-11C]methionine ([11C] D-Met), and showed that it can rapidly and selectively differentiate both E. coli and S. aureus infections from sterile inflammation in vivo. We believe that the ease of [11C] D-Met radiosynthesis, coupled with its rapid and specific in vivo bacterial accumulation, make it an attractive radiotracer for infection imaging in clinical practice. PMID- 28801561 TI - Inflammation-mediated SOD-2 upregulation contributes to epithelial-mesenchymal transition and migration of tumor cells in aflatoxin G1-induced lung adenocarcinoma. AB - : Tumor-associated inflammation plays a critical role in facilitating tumor growth, invasion and metastasis. Our previous study showed Aflatoxin G1 (AFG1) could induce lung adenocarcinoma in mice. Chronic lung inflammation associated with superoxide dismutase (SOD)-2 upregulation was found in the lung carcinogenesis. However, it is unclear whether tumor-associated inflammation mediates SOD-2 to contribute to cell invasion in AFG1-induced lung adenocarcinoma. Here, we found increased SOD-2 expression associated with vimentin, alpha-SMA, Twist1, and MMP upregulation in AFG1-induced lung adenocarcinoma. Tumor-associated inflammatory microenvironment was also elicited, which may be related to SOD-2 upregulation and EMT in cancer cells. To mimic an AFG1-induced tumor-associated inflammatory microenvironment in vitro, we treated A549 cells and human macrophage THP-1 (MPhi-THP-1) cells with AFG1, TNF-alpha and/or IL-6 respectively. We found AFG1 did not promote SOD-2 expression and EMT in cancer cells, but enhanced TNF-alpha and SOD-2 expression in MPhi-THP-1 cells. Furthermore, TNF-alpha could upregulate SOD-2 expression in A549 cells through NF kappaB pathway. Blocking of SOD-2 by siRNA partly inhibited TNF-alpha-mediated E cadherin and vimentin alteration, and reversed EMT and cell migration in A549 cells. Thus, we suggest that tumor-associated inflammation mediates SOD-2 upregulation through NF-kappaB pathway, which may contribute to EMT and cell migration in AFG1-induced lung adenocarcinoma. INTRODUCTION: PMID- 28801562 TI - Explosive death induced by mean-field diffusion in identical oscillators. AB - We report the occurrence of an explosive death transition for the first time in an ensemble of identical limit cycle and chaotic oscillators coupled via mean field diffusion. In both systems, the variation of the normalized amplitude with the coupling strength exhibits an abrupt and irreversible transition to death state from an oscillatory state and this first order phase transition to death state is independent of the size of the system. This transition is quite general and has been found in all the coupled systems where in-phase oscillations co exist with a coupling dependent homogeneous steady state. The backward transition point for this phase transition has been calculated using linear stability analysis which is in complete agreement with the numerics. PMID- 28801563 TI - The global burden of lower urinary tract symptoms suggestive of benign prostatic hyperplasia: A systematic review and meta-analysis. AB - Benign prostatic hyperplasia is a common non-malignant condition among older men, but the epidemiology is poorly characterised. We summarised and determined the global prevalence of benign prostatic hyperplasia. A systematic search on PubMed, EMBASE and CENTRAL was performed up until 31st July 2016. Studies that described the epidemiology of benign prostatic hyperplasia were included and cumulative plots of prevalence estimates were calculated. A total of 31 prevalence rate estimates from 25 countries were identified. The combined prevalence estimates showed that the lifetime prevalence of BPH was 26.2% (95% CI: 22.8-29.6%). We found that there was an increasing prevalence of BPH with age. However, we found no significant difference between (a) rural, urban or mixed sites, (b) different countries, (c) respondent representativeness. (d) sample size or (e) study quality. We also found no significant change in the prevalence over the past 20 years. While there is substantial variation between sites estimates, results suggest that nearly 1 in 4 men will suffer from BPH over their lifetime. The study revealed there are significant gaps in knowledge, which provides opportunities for future research to further enrich the epidemiological landscape with data. PMID- 28801564 TI - Evolution of Hemoglobin Genes in Codfishes Influenced by Ocean Depth. AB - Understanding the genetic basis of adaptation is one of the main enigmas of evolutionary biology. Among vertebrates, hemoglobin has been well documented as a key trait for adaptation to different environments. Here, we investigate the role of hemoglobins in adaptation to ocean depth in the diverse teleost order Gadiformes, with species distributed at a wide range of depths varying in temperature, hydrostatic pressure and oxygen levels. Using genomic data we characterized the full hemoglobin (Hb) gene repertoire for subset of species within this lineage. We discovered a correlation between expanded numbers of Hb genes and ocean depth, with the highest numbers in species occupying shallower, epipelagic regions. Moreover, we demonstrate that the Hb genes have functionally diverged through diversifying selection. Our results suggest that the more variable environment in shallower water has led to selection for a larger Hb gene repertoire and that Hbs have a key role in adaptive processes in marine environments. PMID- 28801565 TI - Dual gene expression cassette is superior than single gene cassette for enhancing sheath blight tolerance in transgenic rice. AB - Sheath blight, caused by the necrotrophic fungal pathogen Rhizoctonia solani, is a serious and destructive disease of the rice. In order to improve sheath blight resistance, we developed three different kinds of transgenic rice lines. The first transgenic line overexpresses the rice chitinase gene (OsCHI11); the second contains the Arabidopsis NPR1 (AtNPR1) gene and, the third has pyramided constructs with both the genes (OsCHI11 and AtNPR1). This is a comparative study between the single-gene transgenic lines and the double gene transgenic in terms of their ability to activate the plant defense system. Rice plants of each individual construct were screened via PCR, Southern hybridization, activity assays, and expression analysis. The best transgenic lines of each construct were chosen for comparative study. The fold change in qRT-PCR and activity assays revealed that the pyramided transgenic rice plants show a significant upregulation of defense-related genes, PR genes, and antioxidant marker genes as compared to the single transgene. Simultaneous co-expression of both the genes was found to be more efficient in tolerating oxidative stress. In R. solani (RS) toxin assay, mycelial agar disc bioassay, and in vivo plant bioassay, pyramided transgenic plant lines were more competent at restricting the pathogen development and enhancing sheath blight tolerance as compared to single gene transformants. PMID- 28801566 TI - Influence of temperature on methane hydrate formation. AB - During gas hydrate formation process, a phase transition of liquid water exists naturally, implying that temperature has an important influence on hydrate formation. In this study, methane hydrate was formed within the same media. The experimental system was kept at 1.45, 6.49, and 12.91 degrees C respectively, and then different pressurization modes were applied in steps. We proposed a new indicator, namely the slope of the gas flow rates against time (dnu g /dt), to represent the intrinsic driving force for hydrate formation. The driving force was calculated as a fixed value at the different stages of formation, including initial nucleation/growth, secondary nucleation/growth, and decay. The amounts of gas consumed at each stage were also calculated. The results show that the driving force during each stage follows an inverse relation with temperature, whereas the amount of consumed gas is proportional to temperature. This opposite trend indicates that the influences of temperature on the specific formation processes and final amounts of gas contained in hydrate should be considered separately. Our results also suggest that the specific ambient temperature under which hydrate is formed should be taken into consideration, when explaining the formation of different configurations and saturations of gas hydrates in natural reservoirs. PMID- 28801568 TI - Atomic Force Microscopy Reveals the Dynamic Morphology of Fenestrations in Live Liver Sinusoidal Endothelial Cells. AB - Here, we report an atomic force microscopy (AFM)-based imaging method for resolving the fine nanostructures (e.g., fenestrations) in the membranes of live primary murine liver sinusoidal endothelial cells (LSECs). From data on topographical and nanomechanical properties of the selected cell areas collected within 1 min, we traced the dynamic rearrangement of the cell actin cytoskeleton connected with the formation or closing of cell fenestrations, both in non stimulated LSECs as well as in response to cytochalasin B and antimycin A. In conclusion, AFM-based imaging permitted the near real-time measurements of dynamic changes in fenestrations in live LSECs. PMID- 28801567 TI - Effectiveness of a multimodal pain management concept for patients with cervical radiculopathy with focus on cervical epidural injections. AB - Cervical radiculopathy has become an increasing problem worldwide. Conservative treatment options have been recommended in many reviews on cervical radiculopathy, ranging from different types of physiotherapy to waiting for remission by natural history. No multimodal pain management concept (MPM) on an inpatient basis has been evaluated. This study aimed at showing the positive short-term effects of an inpatient multimodal pain management concept with focus on cervical translaminar epidural steroid injection for patients with cervical radiculopathy. 54 patients who had undergone inpatient MPM for 10 days were evaluated before and after 10-days treatment. The NRS (0-10) value for arm pain could be reduced from 6.0 (IQR 5.7-6.8) to 2.25 (IQR 2.0-3.1) and from 5.9 (IQR 4.8-6.0) to 2.0 (IQR 1.7-2.6) for neck pain. Neck pain was reduced by 57.4% and arm pain by 62.5%. 2 days after epidural steroid injection, pain was reduced by 40.1% in the neck and by 43.4% in the arms. MPM seems to be an efficient short term approach to treating cervical radiculopathy. Cervical translaminar epidural steroid injection is an important part of this concept. In the absence of a clear indication for surgery, MPM represents a treatment option. PMID- 28801569 TI - Global assessment of flood and storm extremes with increased temperatures. AB - There is overwhelming consensus that the intensity of heavy precipitation events is increasing in a warming world. It is generally expected such increases will translate to a corresponding increase in flooding. Here, using global data sets for non-urban catchments, we investigate the sensitivity of extreme daily precipitation and streamflow to changes in daily temperature. We find little evidence to suggest that increases in heavy rainfall events at higher temperatures result in similar increases in streamflow, with most regions throughout the world showing decreased streamflow with higher temperatures. To understand why this is the case, we assess the impact of the size of the catchment and the rarity of the event. As the precipitation event becomes more extreme and the catchment size becomes smaller, characteristics such as the initial moisture in the catchment become less relevant, leading to a more consistent response of precipitation and streamflow extremes to temperature increase. Our results indicate that only in the most extreme cases, for smaller catchments, do increases in precipitation at higher temperatures correspond to increases in streamflow. PMID- 28801570 TI - The buckling instability of aggregating red blood cells. AB - Plasma proteins such as fibrinogen induce the aggregation of red blood cells (RBC) into rouleaux, which are responsible for the pronounced shear thinning behavior of blood, control the erythrocyte sedimentation rate (ESR) - a common hematological test - and are involved in many situations of physiological relevance such as structuration of blood in the microcirculation or clot formation in pathological situations. Confocal microscopy is used to characterize the shape of RBCs within rouleaux at equilibrium as a function of macromolecular concentration, revealing the diversity of contact zone morphology. Three different configurations that have only been partly predicted before are identified, namely parachute, male-female and sigmoid shapes, and quantitatively recovered by numerical simulations. A detailed experimental and theoretical analysis of clusters of two cells shows that the deformation increases nonlinearly with the interaction energy. Models indicate a forward bifurcation in which the contacting membrane undergoes a buckling instability from a flat to a deformed contact zone at a critical value of the interaction energy. These results are not only relevant for the understanding of the morphology and stability of RBC aggregates, but also for a whole class of interacting soft deformable objects such as vesicles, capsules or cells in tissues. PMID- 28801572 TI - Facile fabrication of complex networks of memristive devices. AB - We describe the memristive properties of cluster-assembled gold films. We show that resistive switching is observed in pure metallic nanostructured films at room temperature and atmospheric pressure, in response to applied voltage inputs. In particular, we observe resistance changes up to 400% and archetypal switching events that have remarkable symmetry with the applied voltage. We associated this symmetry with 'potentiation' and 'anti-potentiation' processes involving the activation of synapses and of pathways comprising multiple synapses. The stability and reproducibility of the resistance switching, which lasted over many hours, make these devices ideal test-beds for exploration of the basic mechanisms of the switching processes, and allow convenient fabrication of devices that may have neuromorphic properties. PMID- 28801571 TI - CRP-level-associated polymorphism rs1205 within the CRP gene is associated with 2 hour glucose level: The SAPPHIRe study. AB - C-reactive protein (CRP) encoded by CRP gene is a reflection of systemic inflammation. Many studies associated CRP level with diabetes and glucose levels, but the association of CRP gene with these traits is unclear. We conducted a cross-sectional study consisting of 945 siblings from 330 families collected by the Stanford Asian Pacific Program in Hypertension and Insulin Resistance (SAPPHIRe) to investigate associations between CRP polymorphisms, circulating CRP, diabetes, and glucose levels. Five single-nucleotide polymorphisms were analyzed: rs3093059, rs2794521, rs1417938, rs1800947, and rs1205. The generalized estimating equation approach was used to deal with correlated data within families. CRP level was positively correlated with diabetes prevalence and levels of fasting and 2-hour glucose (each P < 0.008). Alleles C at rs3093059 and G at rs1205 were associated with elevated CRP level (each P < 1.2 * 10-6). Allele C at rs3093059 was associated with fasting glucose (beta = 0.20, P = 0.045) and G at rs1205 was associated with 2-hour glucose (beta = 0.46, P = 0.00090) post oral glucose tolerance test, but only the latter passed Bonferroni correction. No polymorphism was associated with diabetes. Since 2-hour glucose is an indicator of glucose tolerance, this study indicated CRP gene is associated with glucose intolerance. PMID- 28801573 TI - A structural and mechanistic study of pi-clamp-mediated cysteine perfluoroarylation. AB - Natural enzymes use local environments to tune the reactivity of amino acid side chains. In searching for small peptides with similar properties, we discovered a four-residue pi-clamp motif (Phe-Cys-Pro-Phe) for regio- and chemoselective arylation of cysteine in ribosomally produced proteins. Here we report mutational, computational, and structural findings directed toward elucidating the molecular factors that drive pi-clamp-mediated arylation. We show the significance of a trans conformation prolyl amide bond for the pi-clamp reactivity. The pi-clamp cysteine arylation reaction enthalpy of activation (DeltaH?) is significantly lower than a non-pi-clamp cysteine. Solid-state NMR chemical shifts indicate the prolyl amide bond in the pi-clamp motif adopts a 1:1 ratio of the cis and trans conformation, while in the reaction product Pro3 was exclusively in trans. In two structural models of the perfluoroarylated product, distinct interactions at 4.7 A between Phe1 side chain and perfluoroaryl electrophile moiety are observed. Further, solution 19F NMR and isothermal titration calorimetry measurements suggest interactions between hydrophobic side chains in a pi-clamp mutant and the perfluoroaryl probe. These studies led us to design a pi-clamp mutant with an 85-fold rate enhancement. These findings will guide us toward the discovery of small reactive peptides to facilitate abiotic chemistry in water. PMID- 28801574 TI - Intestinal transepithelial permeability of oxytocin into the blood is dependent on the receptor for advanced glycation end products in mice. AB - Plasma oxytocin (OT) originates from secretion from the pituitary gland into the circulation and from absorption of OT in mother's milk into the blood via intestinal permeability. However, the molecular mechanism underlying the absorption of OT remains unclear. Here, we report that plasma OT concentrations increased within 10 min after oral delivery in postnatal day 1-7 mice. However, in Receptors for Advanced Glycation End Products (RAGE) knockout mice after postnatal day 3, an identical OT increase was not observed. In adult mice, plasma OT was also increased in a RAGE-dependent manner after oral delivery or direct administration into the intestinal tract. Mass spectrometry evaluated that OT was absorbed intact. RAGE was abundant in the intestinal epithelial cells in both suckling pups and adults. These data highlight that OT is transmitted via a receptor-mediated process with RAGE and suggest that oral OT supplementation may be advantageous in OT drug development. PMID- 28801575 TI - Limits of radiomic-based entropy as a surrogate of tumor heterogeneity: ROI-area, acquisition protocol and tissue site exert substantial influence. AB - Entropy is a promising quantitative imaging biomarker for characterizing cancer imaging phenotype. Entropy has been associated with tumor gene expression, tumor metabolism, tumor stage, patient prognosis, and treatment response. Our hypothesis states that tumor-specific biomarkers such as entropy should be correlated between synchronous metastases. Therefore, a significant proportion of the variance of entropy should be attributed to the malignant process. We analyzed 112 patients with matched/paired synchronous metastases (SM#1 and SM#2) prospectively enrolled in the MOSCATO-01 clinical trial. Imaging features were extracted from Regions Of Interest (ROI) delineated on CT-scan using TexRAD software. We showed that synchronous metastasis entropy was correlated across 5 Spatial Scale Filters: Spearman's Rho ranged between 0.41 and 0.59 (P = 0.0001, Bonferroni correction). Multivariate linear analysis revealed that entropy in SM#1 is significantly associated with (i) primary tumor type; (ii) entropy in SM#2 (same malignant process); (iii) ROI area size; (iv) metastasis site; and (v) entropy in the psoas muscle (reference tissue). Entropy was a logarithmic function of ROI area in normal control tissues (aorta, psoas) and in mathematical models (P < 0.01). We concluded that entropy is a tumor-specific metric only if confounding factors are corrected. PMID- 28801576 TI - Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer. AB - Pancreatic cancer is a lethal disease with poor prognosis. Gemcitabine has been the first line systemic treatment for pancreatic cancer. However, the rapid development of drug resistance has been a major hurdle in gemcitabine therapy leading to unsatisfactory patient outcomes. With the recent renewed understanding of glutamine metabolism involvement in drug resistance and immuno-response, we investigated the anti-tumor effect of a glutamine analog (6-diazo-5-oxo-L norleucine) as an adjuvant treatment to sensitize chemoresistant pancreatic cancer cells. We demonstrate that disruption of glutamine metabolic pathways improves the efficacy of gemcitabine treatment. Such a disruption induces a cascade of events which impacts glycan biosynthesis through Hexosamine Biosynthesis Pathway (HBP), as well as cellular redox homeostasis, resulting in global changes in protein glycosylation, expression and functional effects. The proteome alterations induced in the resistant cancer cells and the secreted exosomes are intricately associated with the reduction in cell proliferation and the enhancement of cancer cell chemosensitivity. Proteins associated with EGFR signaling, including downstream AKT-mTOR pathways, MAPK pathway, as well as redox enzymes were downregulated in response to disruption of glutamine metabolic pathways. PMID- 28801577 TI - Effects of disulfide bridges and backbone connectivity on water sorption by protein matrices. AB - Understanding the water sorption behavior of protein powders is important in applications such as the preservation of protein-based pharmaceuticals. Most globular proteins exhibit a characteristic sigmoidal water adsorption isotherm at ambient conditions. However, it is not well understood how water sorption behavior is influenced by intrinsic factors that are related to structural properties of proteins. We investigate computationally how structural constraints on proteins influence the water sorption isotherms of amorphous protein powders. Specifically, we study the effects of non-local disulfide linkages and backbone connectivity using pheromone ER-23 and lysozyme as model proteins. We find that non-local disulfide linkages can significantly restrict structural changes during hydration and dehydration, and this in turn greatly reduces the extent of hysteresis between the adsorption and desorption branches. Upon removing the backbone connectivity by breaking all peptide bonds in lysozyme, we find that the hysteresis shifts towards the lower humidity regime, and the water uptake capacity is significantly enhanced. We attribute these changes to the higher aggregation propensity of the constraint-free amino acids in dehydrated condition, and the formation of a spanning water network at high hydration levels. PMID- 28801578 TI - Basophils contribute to pristane-induced Lupus-like nephritis model. AB - Lupus nephritis (LN), one of the most severe outcomes of systemic lupus erythematosus (SLE), is initiated by glomerular deposition of immune-complexes leading to an inflammatory response and kidney failure. Autoantibodies to nuclear antigens and autoreactive B and T cells are central in SLE pathogenesis. Immune mechanisms amplifying this autoantibody production drive flares of the disease. We previously showed that basophils were contributing to LN development in a spontaneous lupus-like mouse model (constitutive Lyn -/- mice) and in SLE subjects through their activation and migration to secondary lymphoid organs (SLOs) where they amplify autoantibody production. In order to study the basophil specific mechanisms by which these cells contribute to LN development, we needed to validate their involvement in a genetically independent SLE-like mouse model. Pristane, when injected to non-lupus-prone mouse strains, induces a LN-like disease. In this inducible model, basophils were activated and accumulated in SLOs to promote autoantibody production. Basophil depletion by two distinct approaches dampened LN-like disease, demonstrating their contribution to the pristane-induced LN model. These results enable further studies to decipher molecular mechanisms by which basophils contribute to lupus progression. PMID- 28801579 TI - TNFalpha induced up-regulation of Na+,K+,2Cl- cotransporter NKCC1 in hepatic ammonia clearance and cerebral ammonia toxicity. AB - The devastating consequences of hepatic failure include hepatic encephalopathy, a severe, life threatening impairment of neuronal function. Hepatic encephalopathy is caused by impaired hepatic clearance of NH4+. Cellular NH4+ uptake is accomplished mainly by the Na+,K+,2Cl- cotransporter. Here we show that hepatic clearance of NH4+ is impaired in TNFalpha deficient as well as TNFR1&TNFR2 double knockout mice, which both develop hyperammonemia. Despite impaired hepatic clearance of NH4+, TNFalpha deficient mice and TNFR1 deficient mice were protected against acute ammonia intoxication. While 54% of the wild-type mice and 60% of TNFR2 deficient mice survived an NH4+ load, virtually all TNFalpha deficient mice and TNFR1 deficient mice survived the treatment. Conversely, TNFalpha treatment of wild type mice sensitized the animals to the toxic effects of an NH4+ load. The protection of TNFalpha-deficient mice against an NH4+ load was paralleled by decreased cerebral expression of NKCC1. According to the present observations, inhibition of TNFalpha formation and/or NKCC1 may be strategies to favorably influence the clinical course of hepatic encephalopathy. PMID- 28801580 TI - Immune responses against Helicobacter pylori-specific antigens differentiate relapsing remitting from secondary progressive multiple sclerosis. AB - To assess whether Helicobacter pylori (Hp) antibody (ab) reactivity against individual Hp antigens is pathogenetically relevant to multiple sclerosis (MS), we systematically investigated prevalence and clinical significance of abs against 14 immunodominant and subdominant Hp antigens by ELISA and immunoblotting in 139 consecutive MS patients with relapsing-remitting (RRMS, n = 102) or secondary progressive (SPMS, n = 37). Sera from 39 patients with Parkinson's disease (PD), 21 with Alzheimer's disease (ALZ) and 68 healthy controls (HCs), were also tested. Anti-flagellin (18.3%) and anti-p41 (25.0%) abs in MS were less frequent than in HCs (39.4%, 48.5%, respectively). Abs against 5 of the 14 antigens were less frequent in RRMS than HCs, including p41, p54-flagellin, p29 UreA, p67-FSH, and p120-CagA. Anti-VacA abs were more frequent in SPMS than in HCs (42.1 vs 12.1%, p = 0.019). Anti-p54, anti-p29-UreA and anti-p26 correlated with extended disability status scale (EDSS) (p = 0.017, p = 0.005, p = 0.002, respectively). Anti-p26 and anti-p17 correlated with the number of relapses (p = 0.037 and p = 0.047, respectively). This is the first comprehensive analysis of ab reactivities against most Hp antigens in MS patients. Ab responses differ between MS and HCs and between RRMS and SPMS, being more prevalent in SPMS than RRMS, thus suggesting an association between anti-Hp and the former type of MS. PMID- 28801581 TI - Bpifcl modulates kiss2 expression under the influence of 11-ketotestosterone in female zebrafish. AB - The bactericidal/permeability-increasing (BPI) fold-containing (BPIF) superfamily of genes expressed in the brain are purportedly involved in modulating brain function in response to stress, such as inflammation. Kisspeptin, encoded by kiss, is affected by inflammation in the brain; therefore, BPIF family genes might be involved in the modulation of kisspeptin in the brain. In this study, we investigated the expression of BPIF family C, like (bpifcl) in zebrafish brain and its involvement in kiss2 regulation. The identified, full-length sequence of a bpifcl isoform expressed in the zebrafish brain contained the BPI fold shared by BPIF family members. bpifcl mRNA expression in female zebrafish brains was significantly higher than that in males. Exposure of female zebrafish to 11 ketotestosterone decreased bpifcl and kiss2 mRNA expression. bpifcl knockdown by bpifcl-specific small interfering RNA administration to female zebrafish brain decreased kiss2 mRNA expression. bpifcl expression was widely distributed in the brain, including in the dorsal zone of the periventricular hypothalamus (Hd). Furthermore, bpifcl was also expressed in KISS2 neurons in the Hd. These results suggest that the Bpifcl modulates kiss2 mRNA expression under the influence of testosterone in the Hd of female zebrafish. PMID- 28801582 TI - Percutaneous Placement of Iliosacral Screws Under the Guidance of Axial View Projection of the S1 Pedicle: a Case Series. AB - The aim of this study was to evaluate the safety and efficacy of percutaneous placement of iliosacral screws under the guidance of axial view projection of the S1 pedicle clinically. This case series includes 58 consecutive unstable pelvic injury patients, which were treated with iliosacral screws between July 2011 and July 2016. Patients were divided into two groups: normal sacrum (n = 31) and dysmorphic sacrum (n = 27). A single orthopedic surgeon operated on all patients, with percutaneous placement of iliosacral screws under the guidance of axial view projection of the S1 pedicle. The time needed for screw insertion and the radiation exposure time were recorded. Chi-squared test and Student t-test were used to analyze the differences between the two groups. Sacral dysmorphism was present in 47% of patients. The median time for screw insertion and radiation exposure time in these two groups showed no statistical difference (P > 0.05). No clinical complications or malpositioned screws occurred in any case. Preoperative pelvic CT is necessary to determine the sacral osseous anatomy. In patients with either a normal or dysmorphic sacrum, iliosacral screws can be placed by this method with less radiation exposure and complications than in the conventional method. PMID- 28801583 TI - Effect of X-ray irradiation on hepatocarcinoma cells and erythrocytes in salvaged blood. AB - The broad clinical acceptance of intraoperative blood salvage and its applications in cancer surgery remain controversial. Until now, a method that can safely eliminate cancer cells while preserving erythrocytes does not exist. Here, we investigated whether X-ray generated from linear accelerator irradiation at a certain dose can kill hepatocarcinoma cells while preserving erythrocytes. HepG2, SK-Hep1 or Huh7 cells were mixed into the aliquots of erythrocytes obtained from healthy volunteers. After the mixed cells were exposed to 30 Gy and 50 Gy X-rays irradiation, the viability, clonogenicity, DNA synthesis and tumorigenicity of the tumor cells were determined by the MTT assay, plate colony formation, 5 ethynyl-2'-deoxyuridine incorporation, and subcutaneous xenograft implantation into immunocompromised mice. The ATP, 2,3-DPG, free Hb, osmotic fragility, blood gas variables in erythrocytes and morphology of erythrocytes at 0 h, 12 h, 24 h, 48 h, 72 h after irradiation were analyzed. X-ray irradiation at 30 Gy effectively inhibited the viability, proliferation, and tumorigenicity of HepG2, SK-Hep1 and Huh7 cells without noticeably damaging the ability of oxygen carrying, membrane integrity and morphology of erythrocytes. Theses results suggest that X-ray at 30 Gy irradiation might be safe to eliminate hepatocarcinoma cells while preserving erythrocytes in salvaged blood. PMID- 28801585 TI - Inputs of humic fluorescent dissolved organic matter via submarine groundwater discharge to coastal waters off a volcanic island (Jeju, Korea). AB - The abundance of fluorescent dissolved organic matter (FDOM) in the surface ocean plays a critical role in the growth of marine microorganisms and corals by affecting the optical properties (i.e., the penetration of UV radiation) of seawater. In general, it is known that rivers are the main source of FDOM to surface ocean waters. Here, however, we show that the concentrations of FDOM in coastal seawater off a volcanic island, Jeju, Korea, are dependent primarily on submarine groundwater discharge (SGD). Based on a significant correlation between 222Rn and salinity in seawater, fresh groundwater was found to be the main source of groundwater as well as fresh water in the bay. The addition of dissolved organic carbon (DOC) and protein-like FDOM to the bay via SGD was generally negligible or negative. However, SGD enhanced the inventory of humic-like FDOM (FDOMH) in seawater by 2-3 times over all seasons, with conservative behavior of FDOMH in bay seawater. These results suggest that SGD-driven fluxes of FDOM regulate its inventory in seawater and consequently play a significant role in determining the optical properties of coastal waters off islands and associated coastal ecosystems (i.e., corals). PMID- 28801584 TI - Differences of protein expression profiles, KRAS and BRAF mutation, and prognosis in right-sided colon, left-sided colon and rectal cancer. AB - To compare protein expression levels, gene mutation and survival among Right Sided Colon Cancer (RSCC), Left-Sided Colon Cancer (LSCC) and rectal cancer patients, 57 cases of RSCC, 87 LSCC and 145 rectal cancer patients were included retrospectively. Our results demonstrated significant differences existed among RSCC, LSCC and rectal cancer regarding tumor diameter, differentiation, invasion depth and TNM stage. No significant difference was identified in expression levels of MLH1, MSH2, MSH6, PMS2, beta-Tubulin III, P53, Ki67 and TOPIIalpha, and gene mutation of KRAS and BRAF among three groups. Progression Free Survival (PFS) of RSCC was significantly lower than that of LRCC and rectal cancer. In univariate analyses, RSCC, preoperative chemoradiotherapy, poor differentiation, advanced TNM stage, elevated serum CEA and CA19-9 level, tumor deposit, perineural and vascular invasion were found to be predictive factors of shorter PFS. In multivariate analyses, only differentiation and TNM stages were found to be independent predictors of PFS. In conclusion, compared with LSCC and rectal cancer, RSCC has larger tumor size, poor differentiation, advanced TNM stage and shorter survival. The shorter survival in RSCC might be attributed to the advanced tumor stage caused by its inherent position feature of proximal colon rather than genetic difference. PMID- 28801586 TI - Identification of mega-environments and rice genotypes for general and specific adaptation to saline and alkaline stresses in India. AB - In the present study, a total of 53 promising salt-tolerant genotypes were tested across 18 salt-affected diverse locations for three years. An attempt was made to identify ideal test locations and mega-environments using GGE biplot analysis. The CSSRI sodic environment was the most discriminating location in individual years as well as over the years and could be used to screen out unstable and salt sensitive genotypes. Genotypes CSR36, CSR-2K-219, and CSR-2K-262 were found ideal across years. Overall, Genotypes CSR-2K-219, CSR-2K-262, and CSR-2K-242 were found superior and stable among all genotypes with higher mean yields. Different sets of genotypes emerged as winners in saline soils but not in sodic soils; however, Genotype CSR-2K-262 was the only genotype that was best under both saline and alkaline environments over the years. The lack of repeatable associations among locations and repeatable mega-environment groupings indicated the complexity of soil salinity. Hence, a multi-location and multi-year evaluation is indispensable for evaluating the test sites as well as identifying genotypes with consistently specific and wider adaptation to particular agro climatic zones. The genotypes identified in the present study could be used for commercial cultivation across edaphically challenged areas for sustainable production. PMID- 28801587 TI - Temozolomide arrests glioma growth and normalizes intratumoral extracellular pH. AB - Gliomas maintain an acidic extracellular pH (pHe), which promotes tumor growth and builds resistance to therapy. Given evidence that acidic pHe beyond the tumor core indicates infiltration, we hypothesized that imaging the intratumoral pHe in relation to the peritumoral pHe can provide a novel readout of therapeutic influence on the tumor microenvironment. We used Biosensor Imaging of Redundant Deviation in Shifts (BIRDS), which utilizes chemical shifts of non-exchangeable protons from macrocyclic chelates (e.g., DOTP8-) complexed with paramagnetic thulium (Tm3+), to generate pHe maps in rat brains bearing U251 tumors. Following TmDOTP5- infusion, T2-weighted MRI provided delineation of the tumor boundary and BIRDS was used to image the pHe gradient between intratumoral and peritumoral regions (DeltapHe) in both untreated and temozolomide treated (40 mg/kg) rats bearing U251 tumors. Treated rats had reduced tumor volume (p < 0.01), reduced proliferation (Ki-67 staining; p < 0.03) and apoptosis induction (cleaved Caspase 3 staining; p < 0.001) when compared to untreated rats. The DeltapHe was significantly higher in untreated compared to treated rats (p < 0.002), suggesting that temozolomide, which induces apoptosis and hinders proliferation, also normalizes intratumoral pHe. Thus, BIRDS can be used to map the DeltapHe in gliomas and provide a physiological readout of the therapeutic response on the tumor microenvironment. PMID- 28801588 TI - Both Nuclear Size and DNA Amount Contribute to Midblastula Transition Timing in Xenopus laevis. AB - During early Xenopus laevis embryogenesis both nuclear and cell volumes decrease with the nuclear-to-cytoplasmic (N/C) volume ratio reaching a maximum at the midblastula transition (MBT). At the MBT, embryonic transcription is upregulated and cell cycles lengthen. Early studies demonstrated a role for the DNA-to cytoplasmic ratio in the control of MBT timing. By altering nuclear size, we previously showed that the N/C volume ratio also contributes to proper MBT timing. Here we examine the relative contributions of nuclear size and DNA amount to MBT timing by simultaneously altering nuclear size and ploidy in X. laevis embryos. Compared to diploid embryos, haploids exhibited a delay in both zygotic gene expression and cell cycle lengthening, while diploid embryos with increased N/C volume ratios showed early expression of zygotic genes and premature lengthening of cell cycles. Interestingly, haploids with increased N/C volume ratios exhibited an intermediate effect on the timing of zygotic gene expression and cell cycle lengthening. Decreasing nuclear size in post-MBT haploid embryos caused a further delay in cell cycle lengthening and the expression of some zygotic genes. Our data suggest that both the N/C volume ratio and DNA amount contribute to the regulation of MBT timing with neither parameter being dominant. PMID- 28801589 TI - Plasma GDF15 level is elevated in psychosis and inversely correlated with severity. AB - Accumulating evidence suggests that GDF15 is a biomarker for ageing and morbidity of many somatic disorders such as cancer and inflammatory disorders. Recently, elevated serum GDF15 level was proposed as a marker for mood disorder. However, psychosis severity was not investigated in relation to plasma GDF15 levels. In the present study we measured GDF15 levels in plasma of 120 psychosis patients compared to 120 age and gender matched healthy controls. Within the patient cohort GDF15 levels were evaluated for association with age, gender, lifestyle factors, C-reactive protein levels, psychosis severity and metabolic disorder. Psychosis patients had elevated GDF15 levels compared to controls (medianPsychosis = 744 ng/mL, mediancontrols = 516 ng/mL, p < 0.001). Within the psychosis cohort, GDF15 levels, when corrected for age, metabolic health and lifestyle factors, were negatively correlated with psychosis severity (beta = 0.218, p = 0.012). While GDF15 levels were elevated in patients versus healthy controls, the negative correlation between psychosis severity and GDF15 suggests a loss of anti-inflammatory GDF15 mediated functionality in severe psychosis. Study replication in larger cohorts will be necessary to assess the potential of GDF15 as a prognostic biomarker in psychosis. PMID- 28801590 TI - SNAP-25 phosphorylation at Ser187 regulates synaptic facilitation and short-term plasticity in an age-dependent manner. AB - Neurotransmitter release is mediated by the SNARE complex, but the role of its phosphorylation has scarcely been elucidated. Although PKC activators are known to facilitate synaptic transmission, there has been a heated debate on whether PKC mediates facilitation of neurotransmitter release through phosphorylation. One of the SNARE proteins, SNAP-25, is phosphorylated at the residue serine-187 by PKC, but its physiological significance has been unclear. To examine these issues, we analyzed mutant mice lacking the phosphorylation of SNAP-25 serine-187 and found that they exhibited reduced release probability and enhanced presynaptic short-term plasticity, suggesting that not only the release process, but also the dynamics of synaptic vesicles was regulated by the phosphorylation. Furthermore, it has been known that the release probability changes with development, but the precise mechanism has been unclear, and we found that developmental changes in release probability of neurotransmitters were regulated by the phosphorylation. These results indicate that SNAP-25 phosphorylation developmentally facilitates neurotransmitter release but strongly inhibits presynaptic short-term plasticity via modification of the dynamics of synaptic vesicles in presynaptic terminals. PMID- 28801591 TI - New variant and expression studies provide further insight into the genotype phenotype correlation in YAP1-related developmental eye disorders. AB - YAP1, which encodes the Yes-associated protein 1, is part of the Hippo pathway involved in development, growth, repair and homeostasis. Nonsense YAP1 mutations have been shown to co-segregate with autosomal dominantly inherited coloboma. Therefore, we screened YAP1 for variants in a cohort of 258 undiagnosed UK patients with developmental eye disorders, including anophthalmia, microphthalmia and coloboma. We identified a novel 1 bp deletion in YAP1 in a boy with bilateral microphthalmia and bilateral chorioretinal coloboma. This variant is located in the coding region of all nine YAP1 spliceforms, and results in a frameshift and subsequent premature termination codon in each. The variant is predicted to result in the loss of part of the transactivation domain of YAP1, and sequencing of cDNA from the patient shows it does not result in nonsense mediated decay. To investigate the role of YAP1 in human eye development, we performed in situ hybridisation utilising human embryonic tissue, and observed expression in the developing eye, neural tube, brain and kidney. These findings help confirm the role of YAP1 and the Hippo developmental pathway in human eye development and its associated anomalies and demonstrate its expression during development in affected organ systems. PMID- 28801592 TI - Dietary arginine affects the insulin signaling pathway, glucose metabolism and lipogenesis in juvenile blunt snout bream Megalobrama amblycephala. AB - This study evaluated the mechanisms governing insulin resistance, glucose metabolism and lipogenesis in juvenile fish fed with graded levels of dietary arginine. The results showed that, compared with the control group (0.87%), 2.31% dietary arginine level resulted in the upregulation of the relative gene expression of IRS-1, PI3K and Akt in the insulin signaling pathway, while 2.70% dietary arginine level led to inhibition of these genes. 1.62% dietary arginine level upregulated glycolysis by increasing GK mRNA level; 2.70% dietary arginine level upregulated gluconeogenesis and resulted in high plasma glucose content by increasing PEPCK and G6P mRNA level. Furthermore, 2.70% dietary arginine level significantly lowered GLUT2 and increased PK mRNA levels. 1.62% dietary arginine level significantly upregulated ACC, FAS and G6PDH mRNA levels in the fat synthesis pathway and resulted in high plasma TG content. These results indicate that 1.62% dietary arginine level improves glycolysis and fatty acid synthesis in juvenile blunt snout bream. However, 2.70% dietary arginine level results in high plasma glucose, which could lead to negative feedback of insulin resistance, including inhibition of IRS-1 mRNA levels and activation of gluconeogenesis related gene expression. This mechanism seems to be different from mammals at the molecular level. PMID- 28801593 TI - Genetic variations of HvP5CS1 and their association with drought tolerance related traits in barley (Hordeum vulgare L.). AB - Delta-1-pyrroline-5-carboxylate synthase gene1 (P5CS1) is the key gene involved in the biosynthesis of proline and is significantly induced by drought stress. The exploration of genetic variation in HvP5CS1 may facilitate a better understanding of the mechanism of drought adaptation in barley. In the current study, 41 polymorphisms including 16 single nucleotide polymorphisms (SNPs) and 25 insertions/deletions (indels) were detected in HvP5CS1 among 287 barley (Hordeum vulgare L.) accessions collected worldwide, with 13 distinct haplotypes identified in the barley collection. Five polymorphisms in HvP5CS1 were significantly (P < 0.001) associated with drought tolerance related traits in barley. The phenotypic variation of a given trait explained by each associated polymorphism ranged from 4.43% to 9.81%. Two sequence variations that were significantly (P < 0.0001) associated with grain yield had marginally significant positive Tajima's D values in the sliding window, so they might have been selected for environmental adaptation. Meanwhile, two haplotypes HvP5CS1_H1 and HvP5CS1_H4, which contained desired alleles of the two variations mentioned above, were significantly (P < 0.001) associated with drought tolerance related traits, and explained 5.00~11.89% of the phenotypic variations. These variations associated with drought tolerance related traits can be used as potential markers for improving drought tolerance in barley. PMID- 28801594 TI - Deficiency in catechol-o-methyltransferase is linked to a disruption of glucose homeostasis in mice. AB - 2-methoxyestradiol (2-ME), an estrogen metabolite generated via catechol-o methyltransferase (COMT), is multifunctional methoxy-catechol. Here, we report that COMT deficiency leads to glucose intolerance and 2-ME rescues COMT-deficient associated metabolic defects. Liver COMT protein was suppressed in high fat diet (HFD)-fed or in pregnant mice. COMT suppression, by Ro41-0960 or siRNA, in HFD fed mice or in pregnant mice exacerbated glucose intolerance; 2-ME intervention ameliorated these defects. 2-ME effects on glucose tolerance were associated with AMPK phosphorylation in the liver and in islet cells. Metformin restored liver COMT protein levels, and metformin-induced liver AMPK phosphorylation was abolished by COMT inhibition. The amelioration in glucose tolerance by 2-ME was associated with biphasic insulin secretion in an environment-dependent manner. 2 ME-induced insulin secretion was associated with the AMPK phosphorylation, PDX-1 phosphorylation, and MST-1 suppression in MIN-6 cells. Furthermore 2-ME displayed PPARgamma agonist-like activity. These results suggest that COMT is an enzyme to maintain glucose homeostasis and 2-ME is a potential endogenous multi-target anti diabetic candidate. PMID- 28801595 TI - Spectral characteristics of voltage-sensitive indocyanine green fluorescence in the heart. AB - Indocyanine green (ICG) fluorescent dye has been approved by the FDA for use in medical diagnostics. Recently, we demonstrated that ICG dye has voltage-sensitive properties with a dual-component (fast and slow) response in the Langendorff perfused rabbit heart. Here, we extended our studies by showing the different spectral properties of both components for analysis of the fractional change in ICG fluorescence in response to voltage changes. We used light from four LEDs to obtain excitation; emission was measured using an EMCCD camera with band-pass filters and a spectrometer. We applied a graphical model with Gaussian functions to construct and evaluate the individual emission curves and calculated the voltage-sensitive portion of each component of the ICG fluorescence in the rabbit heart. The results revealed that each isolated component (fast and slow) emanates from a unique ICG pool in a different environment within the cell membrane and that each component is also composed of two constituents (ICG-monomeric and ICG aggregated). We propose the existence of different voltage-sensitive mechanisms for the components: (I) electrochromism and field-induced reorientation for the fast component; and (II) field-induced dye squeezing that amplifies intermolecular interactions, resulting in self-quenching of the dye fluorescence, for the slow component. PMID- 28801596 TI - A synthesis of soil carbon and nitrogen recovery after wetland restoration and creation in the United States. AB - Wetland restoration and creation efforts have been widely attempted as a way to compensate for wetland losses and to recover wetland functions; however, to date, there has been no comprehensive evaluation of the efficacy of soil carbon (C) and nitrogen (N) content recovery at a regional scale. This meta-analysis synthesizes 48 articles to identify the general patterns of soil C and N change after wetland restoration and creation in the United States. Our results indicate that, after 11-20 years, soil C and N in restored and created wetlands are still significantly lower by 51.7% and 50.3%, respectively, than those in natural wetlands. The soil C and N in restored wetlands recovered faster than in created wetlands. Furthermore, the soil C in restored organic flat and created depressional wetlands recovered more rapidly than in restored and created hydrologically open wetlands (riverine and tidal), respectively. Mean annual temperature and soil texture were recognized as two crucial abiotic factors affecting soil C and N recovery. Linear regression analysis revealed a positive relationship between the restoration and creation effect sizes on soil C and N, indicating that wetlands may alleviate N limitations intrinsically during C recovery processes. PMID- 28801597 TI - MoS2@rGO Nanoflakes as High Performance Anode Materials in Sodium Ion Batteries. AB - A simple one-pot hydrothermal method is developed for fabrication of MoS2@rGO nanoflakes using the economical MoO3 as the molybdenum source. Benefiting from the unique nanoarchitecture, high MoS2 loading (90.3 wt%) and the expanded interlayer spacing, the as-prepared MoS2@rGO nanoflakes exhibit greatly enhanced sodium storage performances including a high reversible specific capacity of 441 mAh g-1 at a current density of 0.2 A g-1, high rate capability, and excellent capacity retention of 93.2% after 300 cycles. PMID- 28801598 TI - Conductance fluctuations in InAs quantum wells possibly driven by Zitterbewegung. AB - The highly successful Dirac equation predicts peculiar phenomena such as Klein tunnelling and Zitterbewegung (ZB) of electrons. From its conception by Erwin Schrodinger, ZB has been considered key in understanding relativistic quantum mechanics. However, observing the ZB of electrons has proved difficult, and instead various emulations of the phenomenon have been proposed producing several successes. Concerning charge transport in semiconductors and graphene, expectations were high but little has been reported. Here, we report a surprisingly large ZB effect on charge transport in a semiconductor nanostructure playing "flat pinball". The setup is a narrow strip of InAs two-dimensional electron gas with strong Rashba spin-orbit coupling. Six quantum point contacts act as pinball pockets. In transiting between two contacts, ZB appears as a large reproducible conductance fluctuation that depends on the in-plane magnetic field. Numerical simulations successfully reproduced our experimental observations confirming that ZB causes this conductance fluctuation. PMID- 28801599 TI - Mating-type genes of the anamorphic fungus Ulocladium botrytis affect both asexual sporulation and sexual reproduction. AB - Ulocladium was thought to be a strictly asexual genus of filamentous fungi. However, Ulocladium strains were shown to possess both MAT1-1-1 and MAT1-2-1 genes as observed in homothallic filamentous Ascomycetes. Here, we demonstrate that the U. botrytis MAT genes play essential roles for controlling asexual traits (conidial size and number). Using reciprocal genetic transformation, we demonstrate that MAT genes from the related heterothallic species Cochliobolus heterostrophus can also influence U. botrytis colony growth, conidial number and size, and have a strong effect on the range of the number of septa/conidium. Moreover, U. botrytis MAT genes can also affect similar aspects of asexual reproduction when expressed in C. heterostrophus. Heterologous complementation using C. heterostrophus MAT genes shows that they have lost the ability to regulate sexual reproduction in U. botrytis, under the conditions we employed, while the reciprocal heterologous complementation demonstrates that U. botrytis MAT genes have the ability to partially induce sexual reproduction in C. heterostrophus. Thus, the genetic backgrounds of C. heterostrophus and U. botrytis play significant roles in determining the function of MAT genes on sexual reproduction in these two fungi species. These data further support the role of MAT genes in controlling asexual growth in filamentous Ascomycetes but also confirm that heterothallic and homothallic Dothideomycete fungi can be interconverted by the exchange of MAT genes. PMID- 28801600 TI - CaV1.3 L-type Ca2+ channel contributes to the heartbeat by generating a dihydropyridine-sensitive persistent Na+ current. AB - The spontaneous activity of sinoatrial node (SAN) pacemaker cells is generated by a functional interplay between the activity of ionic currents of the plasma membrane and intracellular Ca2+ dynamics. The molecular correlate of a dihydropyridine (DHP)-sensitive sustained inward Na+ current (I st), a key player in SAN automaticity, is still unknown. Here we show that I st and the L-type Ca2+ current (I Ca,L) share CaV1.3 as a common molecular determinant. Patch-clamp recordings of mouse SAN cells showed that I st is activated in the diastolic depolarization range, and displays Na+ permeability and minimal inactivation and sensitivity to I Ca,L activators and blockers. Both CaV1.3-mediated I Ca,L and I st were abolished in CaV1.3-deficient (CaV1.3-/-) SAN cells but the CaV1.2 mediated I Ca,L current component was preserved. In SAN cells isolated from mice expressing DHP-insensitive CaV1.2 channels (CaV1.2DHP-/-), I st and CaV1.3 mediated I Ca,L displayed overlapping sensitivity and concentration-response relationships to the DHP blocker nifedipine. Consistent with the hypothesis that CaV1.3 rather than CaV1.2 underlies I st, a considerable fraction of I Ca,L was resistant to nifedipine inhibition in CaV1.2DHP-/- SAN cells. These findings identify CaV1.3 channels as essential molecular components of the voltage dependent, DHP-sensitive I st Na+ current in the SAN. PMID- 28801601 TI - Spray-cast multilayer perovskite solar cells with an active-area of 1.5 cm2. AB - We utilise spray-coating under ambient conditions to sequentially deposit compact TiO2, mesoporous-TiO2, CH3NH3PbI(3-x)Clx perovskite and doped spiro-OMeTAD layers, creating a mesoporous standard architecture perovskite solar cell (PSC). The devices created had an average power conversion efficiency (PCE) of 9.2% and a peak PCE of 10.2%; values that compare favourably with control-devices fabricated by spin-casting that had an average efficiency of 11.4%. We show that our process can be used to create devices having an active-area of 1.5 cm2 having an independently verified efficiency of 6.6%. This work demonstrates the versatility of spray-coating as well as its potential as a method of manufacturing low-cost, large-area, efficient perovskite devices. PMID- 28801603 TI - Identifying the tilt angle and correcting the orbital angular momentum spectrum dispersion of misaligned light beam. AB - The axis tilt of light beam in optical system would introduce the dispersion of orbital angular momentum (OAM) spectrum. To deal with it, a two-step method is proposed and demonstrated. First, the tilt angle of optical axis is identified with a deduced relation between the tilt angle and the variation of OAM topological charges with different reference axes, which is obtained with the help of a charge coupled device (CCD) camera. In our experiments, the precision of measured tilt angle is about 10-4 rad with topological charges of -3~3. With the measured angle value, the additional phase delay due to axis tilt can be calculated so that the dispersion of OAM spectrum can be corrected with a simple formula while the optical axis is not aligned. The experimental results indicate that the original OAM spectrum has been successfully extracted for not only the pure state but also the superposed OAM states. PMID- 28801602 TI - Fermentative hydrogen production from Jerusalem artichoke by Clostridium tyrobutyricum expressing exo-inulinase gene. AB - Clostridium tyrobutyricum ATCC25755 has been reported as being able to produce significant quantities of hydrogen. In this study, the exo-inulinase encoding gene cloned from Paenibacillus polymyxa SC-2 was into the expression plasmid pSY6 and expressed in the cells of C. tyrobutyricum. The engineered C. tyrobutyricum strain efficiently fermented the inulin-type carbohydrates from Jerusalem artichoke, without any pretreatment being necessary for the production of hydrogen. A comparatively high hydrogen yield (3.7 mol/mol inulin-type sugar) was achieved after 96 h in a batch process with simultaneous saccharification and fermentation (SSF), with an overall volumetric productivity rate of 620 +/- 60 mL/h/L when the initial total sugar concentration of the inulin extract was increased to 100 g/L. Synthesis of inulinase in the batch SSF culture was closely associated with strain growth until the end of the exponential phase, reaching a maximum activity of 28.4 +/- 0.26 U/mL. The overall results show that the highly productive and abundant biomass crop Jerusalem artichoke can be a good substrate for hydrogen production, and that the application of batch SSF for its conversion has the potential to become a cost-effective process in the near future. PMID- 28801604 TI - Recombineering using RecET in Corynebacterium glutamicum ATCC14067 via a self excisable cassette. AB - Gene manipulation is essential for metabolic engineering and synthetic biology, but the current general gene manipulation methods are not applicable to the non model strain Corynebacterium glutamicum (C. glutamicum) ATCC14067, which is used for amino acid production. Here, we report an effective and sequential deletion method for C. glutamicum ATCC14067 using the exonuclease-recombinase pair RecE + RecT (RecET) for recombineering via a designed self-excisable linear double strand DNA (dsDNA) cassette, which contains the Cre/loxP system, to accomplish markerless deletion. To the best of our knowledge, this is the first effective and simple strategy for recombination with markerless deletion in C. glutamicum ATCC14067. This strategy provides a simple markerless deletion strategy for C. glutamicum and builds a solid basis for producer construction. PMID- 28801605 TI - Luteolin, a natural flavonoid, inhibits methylglyoxal induced apoptosis via the mTOR/4E-BP1 signaling pathway. AB - Methylglyoxal (MG) accumulation has been observed in human cerebrospinal fluid and body tissues under hyperglycaemic conditions. Recent research has demonstrated that MG-induces neuronal cell apoptosis, which promotes the development of diabetic encephalopathy. Our previous animal study has shown that luteolin, a natural flavonoid, attenuates diabetes-associated cognitive dysfunction. To further explore the neuroprotective properties of luteolin, we investigated the inhibitive effect of luteolin on MG-induced apoptosis in PC12 neuronal cells. We found that MG inhibited cell viability in a dose-dependent manner and induced apoptosis in PC12 cells. Pretreatment with Luteolin significantly elevated cell viability, reduced MG-induced apoptosis, inhibited the activation of the mTOR/4E-BP1 signaling pathway, and decreased pro-apoptotic proteins, Bax, Cytochrome C as well as caspase-3. Furthermore, we found that pretreatment with the mTOR inhibitor, rapamycin, significantly reduced the expression of the pro-apoptotic protein Bax. Therefore, these observations unambiguously suggest that the inhibitive effect of Luteolin against MG-induced apoptosis in PC12 cells is associated with inhibition of the mTOR/4E-BP1 signaling pathway. PMID- 28801606 TI - Linkage mapping aided by de novo genome and transcriptome assembly in Portunus trituberculatus: applications in growth-related QTL and gene identification. AB - A high-resolution genetic linkage map is an essential tool for decoding genetics and genomics in non-model organisms. In this study, a linkage map was constructed for the swimming crab (Portunus trituberculatus) with 10,963 markers; as far as we know, this number of markers has never been achieved in any other crustacean. The linkage map covered 98.85% of the whole genome with a mean marker interval of 0.51 cM. The de novo assembly based on genome and transcriptome sequencing data enabled 2,378 explicit annotated markers to be anchored to the map. Quantitative trait locus (QTL) mapping revealed 10 growth-related QTLs with a phenotypic variance explained (PVE) range of 12.0-35.9. Eight genes identified from the growth-related QTL regions, in particular, RE1-silencing transcription factor and RNA-directed DNA polymerase genes with nonsynonymous substitutions, were considered important growth-related candidate genes. We have demonstrated that linkage mapping aided by de novo assembly of genome and transcriptome sequencing could serve as an important platform for QTL mapping and the identification of trait-related genes. PMID- 28801607 TI - Enhancing NK cell-mediated cytotoxicity to cisplatin-resistant lung cancer cells via MEK/Erk signaling inhibition. AB - Major progress has been made clinically in inhibiting the programmed death receptor 1 (PD-1)/PD-L1 interaction to enhance T cell-mediated immune function, yet the effectiveness of anti-PD-L1/PD-1 agents in enhancing natural killer (NK) cell's function remains largely unknown. Susceptibilities of cisplatin-resistant A549CisR and H157CisR cells vs. parental cells to the cytotoxic action of NK cells were examined. We found cisplatin-resistant cells more resistant to NK cell cytotoxicity than parental cells. There were constitutively higher expressions of PD-L1 in A549CisR and H157CisR cells than in parental cells in vitro, as well as in H157CisR cell-derived tumors than H157P cell-derived tumors. In contrast, we observed that the expression of PD-1 in NK cells was induced after co-culture with cisplatin-resistant cells. We also observed increased susceptibility of cisplatin-resistant cells to NK cell cytotoxicity when neutralizing antibody of PD-1 or PD-L1 was added. Further, we found that the NK group 2, member D (NKG2D) ligand levels were lower in A549CisR and H157CisR cells than in parental cells. Meanwhile, we discovered that the MEK/Erk signaling pathway played a significant role in this regulation, and the addition of a MEK/Erk pathway inhibitor significantly enhanced the PD-L1 Ab effect in enhancing NK cell cytotoxicity to cisplatin-resistant cells. PMID- 28801608 TI - Broadband Surface Plasmon Lasing in One-dimensional Metallic Gratings on Semiconductor. AB - We report surface plasmon (SP) lasing in metal/semiconductor nanostructures, where one-dimensional periodic silver slit gratings are placed on top of an InGaAsP layer. The SP nature of the lasing is confirmed from the emission wavelength governed by the grating period, polarization analysis, spatial coherence, and comparison with the linear transmission. The excellent performance of the device as an SP source is demonstrated by its tunable emission in the 400 nm-wide telecom wavelength band at room temperature. We show that the stimulated emission enhanced by the Purcell effect enables successful SP lasing at high energies above the gap energy of the gain. We also discuss the dependence of the lasing efficiency on temperature, grating dimension, and type of metal. PMID- 28801609 TI - Micro-to-nano scale filling behavior of PMMA during imprinting. AB - The filling behavior of polymers in narrow gaps or small pores is important for the dynamics of polymeric micro/nanostructure fabrication. Here, the filling behavior, the mechanical properties, and the stress versus strain relationship of 996 kD poly (methyl methacrylate) (PMMA) at a scale from micron to molecular confinement are measured. It has been found that the solid polymer exhibits elastic-plastic dominant deformation behavior at micron scale. As the scale reduces to submicron, the resistance to deformation of the polymeric solid has a pronounced reduction. A softening effect and the visco-dominant behavior which is always exhibited by melt flow is observed. In confinement conditions, an anomalous hardening effect is found. The modulus and the hardness of 996 kD PMMA have been found to increase dramatically. The stress-strain curve also exhibits an obvious hardening phenomenon which is contrary to the conventional shear thinning and deformation acceleration results. The results of this paper show that the PMMA can exhibit a change of "solid-fluid-solid" in mechanical character at micron to molecular confinement scale. PMID- 28801610 TI - CREB3L2-mediated expression of Sec23A/Sec24D is involved in hepatic stellate cell activation through ER-Golgi transport. AB - Hepatic fibrosis is caused by exaggerated wound healing response to chronic injury, which eventually leads to hepatic cirrhosis. Differentiation of hepatic stellate cells (HSCs) to myofibroblast-like cells by inflammatory cytokines is the critical step in fibrosis. This step is accompanied by enlargement of the endoplasmic reticulum (ER) and Golgi apparatus, suggesting that protein synthesis and secretion are augmented in the activated HSCs. However, the process of rearrangement of secretory organelles and their functions remain to be fully elucidated. Here, we revealed that differentiation alters early secretory gene expression. We observed significant isoform-specific upregulation of the inner coat protein complex II (COPII) components, Sec23A and Sec24D, via the transmembrane bZIP transcription factor, CREB3L2/BBF2H7, during HSC activation. Moreover, knockdown of these components abrogated the activation, suggesting that Sec23A/Sec24D-mediated ER to Golgi trafficking is required for HSC activation. PMID- 28801611 TI - Pseudolaric acid B attenuates atopic dermatitis-like skin lesions by inhibiting interleukin-17-induced inflammation. AB - Pseudolaric acid B (PB), isolated from the extract of the root bark of Pseudolarix kaempferi Gordon, has been used as a traditional remedy for the treatment of skin diseases. However, the information of PB on atopic dermatitis (AD) remains largely unknown. In the present study, oral administration with PB improved the severity scores of AD-like skin lesions dose-dependently in NC/Nga mice through reducing serum IgE, pro-inflammatory cytokines, and the infiltration of inflammatory cells. In addition, PB significantly attenuated the levels of IL 17 and IL-22, and the proportion of Th17 cells in NC/Nga mice, as well as decreased IL-17-induced inflammation in RAW264.7 cells. Moreover, PB inhibited the phosphorylation of IkappaBalpha and miR-155 expression both in NC/Nga mice and in IL-17-stimulated RAW264.7 cells, which could be reversed by GW9662, a specific antagonist for PPARgamma. The incorporation of GW9662 reversed the inhibitory effect of PB on the RORgamma-mediated activation of the Il17 promoter. Transfection with PPARgamma luciferase reporter gene further demonstrated the enhancement of PB on PPARgamma transactivation. These findings indicate that PB could ameliorate AD-like skin lesions by inhibiting IL-17-induced inflammation in a PPARgamma-dependent manner, which would provide experimental evidence of PB for the therapeutic potential on AD and other inflammatory skin diseases. PMID- 28801612 TI - Temperature-induced oligomerization of polycyclic aromatic hydrocarbons at ambient and high pressures. AB - Temperature-induced oligomerization of polycyclic aromatic hydrocarbons (PAHs) was found at 500-773 K and ambient and high (3.5 GPa) pressures. The most intensive oligomerization at 1 bar and 3.5 GPa occurs at 740-823 K. PAH carbonization at high pressure is the final stage of oligomerization and occurs as a result of sequential oligomerization and polymerization of the starting material, caused by overlapping of pi-orbitals, a decrease of intermolecular distances, and finally the dehydrogenation and polycondensation of benzene rings. Being important for building blocks of life, PAHs and their oligomers can be formed in the interior of the terrestrial planets with radii less than 2270 km. PMID- 28801613 TI - Selective effects of non-thermal atmospheric plasma on triple-negative breast normal and carcinoma cells through different cell signaling pathways. AB - Non-thermal atmospheric plasma (NTP) has shown its selective anticancer effects in many types of tumors in vitro and one of the main mechanisms is that the different increase of intracellular ROS in cancer and homologous normal cells. In this study, we report that NTP treatment reduces the proliferation in triple negative breast cancer (TNBC) and normal cell lines. Simultaneously, STAT3 pathway is inhibited by NTP effects. However, it is observed that normal cells MCF10A are more sensitive to ROS toxicity induced by NTP than cancer cells MDA-MB 231. When 5 mM of ROS inhibitor N-acetyl cysteine (NAC) is employed in NTP treatments, the proliferation of normal breast cells MCF10A recovers. Meanwhile, NTP effects remain significant inhibition of MDA-MB-231 cells. Our results further reveal that NTP can induce apoptosis in MDA-MB-231 cells through inhibiting interleukin-6 receptor (IL-6R) pathway. Moreover, the mechanism of NTP anti-cancer selectivity relates to constantly HER2/Akt activation induced by NTP especially in MCF10A cells but not in MDA-MB-231 cells. Therefore, these two different cell signaling pathways induced by NTP treatments in TNBC and homologous normal cells make NTP becoming a potential tool in future therapy. PMID- 28801614 TI - Palladium nanoparticles entrapped in a self-supporting nanoporous gold wire as sensitive dopamine biosensor. AB - Traced dopamine (DA) detection is critical for the early diagnosis and prevention of some diseases such as Parkinson's, Alzheimer and schizophrenia. In this research, a novel self-supporting three dimensional (3D) bicontinuous nanoporous electrochemical biosensor was developed for the detection of dopamine by Differential Pulse Voltammetry (DPV). This biosensor was fabricated by electrodepositing palladium nanoparticles (Pd) onto self-supporting nanoporous gold (NPG) wire. Because of the synergistic effects of the excellent catalytic activity of Pd and novel structure of NPG wire, the palladium nanoparticles decorated NPG (Pd/NPG) biosensor possess tremendous superiority in the detection of DA. The Pd/NPG wire biosensor exhibited high sensitivity of 1.19 MUA MUMU-1, broad detection range of 1-220 MUM and low detection limit up to 1 MUM. Besides, the proposed dopamine biosensor possessed good stability, reproducibility, reusability and selectivity. The response currents of detection in the fetal bovine serum were also close to the standard solutions. Therefore the Pd/NPG wire biosensor is promising to been used in clinic. PMID- 28801615 TI - Choroidal Remodeling in Age-related Macular Degeneration and Polypoidal Choroidal Vasculopathy: A 12-month Prospective Study. AB - Choroid thinning occurs in age-related macular degeneration (AMD). However, it remains unclear whether the reduction is due to reduction in choroidal vessels or shrinkage of choroidal stroma, or both. The purpose of this study was to evaluate the changes of the choroidal vascular and stromal area in 118 patients with typical AMD (t-AMD) and polypoidal choroidal vasculopathy (PCV) over a 12-month period. We used spectral-domain optical coherence tomography (SD-OCT) with enhanced depth imaging (EDI) mode to measure the subfoveal choroidal thickness (CT), central retinal thickness (CRT) and choroidal vascularity index (CVI - ratio of luminal area to total choroidal area). At baseline, PCV eyes had higher CRT (471.6 um vs 439.1 um, p = 0.02), but comparable subfoveal CT and CVI, compared to t-AMD. Eyes with high CVI at baseline showed marked reduction in stromal area compared with eyes with average or low CVI. Over 12 months, CRT and subfoveal CT significantly decreased (p < 0.001) in both subtypes. Eyes with high baseline CVI showed significant CVI reduction from baseline to month 12 (p < 0.001), whereas eyes with average to low baseline CVI showed increase in CVI. These differences in choroidal vascularity may reflect different predominant pathogenic processes and remodeling in AMD eyes with varying spectrum. PMID- 28801616 TI - Circulating CD40 and sCD40L Predict Changes in Renal Function in Subjects with Chronic Kidney Disease. AB - Soluble CD40 ligand (sCD40L) has been implicated in the development of renal injury. The CD40 receptor exists in a soluble form, sCD40R, and has been shown to function as a competitive antagonist against CD40 activation. We analyzed whether plasma levels of sCD40L and sCD40R predict changes in renal function in an all cause chronic kidney disease (CKD) cohort. Stratification of subjects based on sCD40L and sCD40R individually, as well as in combination, demonstrated that sCD40L was directly associated with declines in estimated glomerular filtration rate (eGFR). sCD40R was negatively associated with declines in eGFR. Baseline characteristics following stratification, including systolic blood pressure, history of diabetes mellitus or peripheral vascular disease, primary renal disease classification, and angiotensin converting enzyme inhibitor or angiotensin receptor blocker usage were not significantly different. High sCD40L and low sCD40R were both found to be independent predictors of a decline in eGFR at 1-year follow-up (-7.57%, p = 0.014; -6.39%, p = 0.044). Our data suggest that circulating levels of sCD40L and sCD40R are associated with changes in renal function in patients with CKD. The CD40 decoy receptor, sCD40R, may serve as a potential therapeutic target to attenuate renal function decline. PMID- 28801617 TI - G protein stoichiometry dictates biased agonism through distinct receptor-G protein partitioning. AB - Biased agonism at G protein coupled receptors emerges as an opportunity for development of drugs with enhanced benefit/risk balance making biased ligand identification a priority. However, ligand biased signature, classically inferred from ligand activity across multiple pathways, displays high variability in recombinant systems. Functional assays usually necessity receptor/effector overexpression that should be controlled among assays to allow comparison but this calibration currently fails. Herein, we demonstrate that Galpha expression level dictates the biased profiling of agonists and, to a lesser extent of beta blockers, in a Galpha isoform- and receptor-specific way, depending on specific G protein activity in different membrane territories. These results have major therapeutic implications since they suggest that the ligand bias phenotype is not necessarily maintained in pathological cell background characterized by fluctuations in G protein expression. Thus, we recommend implementation of G protein stoichiometry as a new parameter in biased ligand screening programs. PMID- 28801618 TI - Optically Isotropic, Colorless, and Flexible PITEs/TiO2 and ZrO2 Hybrid Films with Tunable Refractive Index, Abbe Number, and Memory Properties. AB - A series of novel polyimidothioethers (PITEs) and the respective polymer hybrids of titania or zirconia with fantastic thermal stability and optical properties have been successfully prepared. These colorless PITEs with high transparency were synthesized by Michael polyaddition from commercially available dithiol and bismaleimides monomers. The PITE with sulfide and hydroxyl groups (S-OH) and the corresponding hybrid films declare ultra-lowest birefringence value of 0.002 and tunable refractive index (1.65-1.81 for S-OH/titania and 1.65-1.80 for S OH/zirconia), implying large potential to the optical applications in the future. Moreover, the S-OH/zirconia hybrid films exhibit higher Abbe's number and optical transparency than those of S-OH/titania system because larger energy band gap of ZrO2. Furthermore, by adding titania and zirconia as electron acceptor into S-OH system, the charge transfer complex can be facilitated and stabilized caused by the lower LUMO energy level of hybrid materials. Consequently, the devices of memory prepared from these polymer films of hybrid showed interesting and adjustable memory behavior from DRAM, SRAM, to WORM at various titania or zirconia contents with a large ON/OFF ratio (108), denoting that the memory devices derived from these highly transparent novel S-OH/TiO2 and S-OH/ZrO2 hybrid films are attractive for the electrical applications. PMID- 28801619 TI - Repetitive motor cortex stimulation reinforces the pain modulation circuits of peripheral neuropathic pain. AB - Recent evidence indicates that motor cortex stimulation (MCS) is a potentially effective treatment for chronic neuropathic pain. However, the neural mechanisms underlying the attenuated hyperalgesia after MCS are not completely understood. In this study, we investigated the neural mechanism of the effects of MCS using an animal model of neuropathic pain. After 10 daily sessions of MCS, repetitive MCS reduced mechanical allodynia and contributed to neuronal changes in the anterior cingulate cortex (ACC). Interestingly, inhibition of protein kinase M zeta (PKMzeta), a regulator of synaptic plasticity, in the ACC blocked the effects of repetitive MCS. Histological and molecular studies showed a significantly increased level of glial fibrillary acidic protein (GFAP) expression in the ACC after peripheral neuropathy, and neither MCS treatment nor ZIP administration affected this increase. These results suggest that repetitive MCS can attenuate the mechanical allodynia in neuropathic pain, and that the activation of PKMzeta in the ACC may play a role in the modulation of neuropathic pain via MCS. PMID- 28801620 TI - A Novel Aldosterone Antagonist Limits Renal Injury in 5/6 Nephrectomy. AB - Aldosterone antagonists slow the progression of chronic kidney disease (CKD), but their use is limited by hyperkalemia, especially when associated with RAS inhibitors. We examined the renoprotective effects of Ly, a novel non-steroidal mineralocorticoid receptor (MR) blocker, through two experimental protocols: In Protocol 1, male Munich-Wistar rats underwent 5/6 renal ablation (Nx), being divided into: Nx+V, receiving vehicle, Nx+Eple, given eplerenone, 150 mg/kg/day, and Nx+Ly, given Ly, 20 mg/kg/day. A group of untreated sham-operated rats was also studied. Ly markedly raised plasma renin activity (PRA) and aldosterone, and exerted more effective anti-albuminuric and renoprotective action than eplerenone. In Protocol 2, Nx rats remained untreated until Day 60, when they were divided into: Nx+V receiving vehicle; Nx+L treated with losartan, 50 mg/kg/day; Nx+L+Eple, given losartan and eplerenone, and Nx+L+Ly, given losartan and Ly. Treatments lasted for 90 days. As an add-on to losartan, Ly normalized blood pressure and albuminuria, and prevented CKD progression more effectively than eplerenone. This effect was associated with strong stimulation of PRA and aldosterone. Despite exhibiting higher affinity for the MR than either eplerenone or spironolactone, Ly caused no hyperkalemia. Ly may become a novel asset in the effort to detain the progression of CKD. PMID- 28801621 TI - Efficient generation of conditional knockout mice via sequential introduction of lox sites. AB - Conditional knockout using Cre/lox is essential for functional analysis of genes. CRISPR/Cas in combination with two sets of guide RNAs and a single-stranded oligonucleotide enables simultaneous insertion of two lox sequences. However, this method induces double-strand breaks at two sites on the same chromosome, which causes an undesirable chromosomal deletion and reduces the flanked lox (flox) rate. To solve this problem, we investigated a method that sequentially introduces each lox sequence at the 1-cell and 2-cell embryonic stages, respectively. The sequential method was applied to both microinjection and electroporation systems. Sequential electroporation improved the flox efficiency compared with ordinary simultaneous microinjection, leading to a high yield of offspring with floxed alleles. Finally, we directly produced Cre/lox mice containing both the Cre transgene and floxed allele via sequential electroporation using Cre zygotes, which accelerated the generation of conditional knockout mice compared with the ordinary method. PMID- 28801622 TI - Decoupling Frequencies, Amplitudes and Phases in Nonlinear Optics. AB - In linear optics, light fields do not mutually interact in a medium. However, they do mix when their field strength becomes comparable to electron binding energies in the so-called nonlinear optical regime. Such high fields are typically achieved with ultra-short laser pulses containing very broad frequency spectra where their amplitudes and phases are mutually coupled in a convolution process. Here, we describe a regime of nonlinear interactions without mixing of different frequencies. We demonstrate both in theory and experiment how frequency domain nonlinear optics overcomes the shortcomings arising from the convolution in conventional time domain interactions. We generate light fields with previously inaccessible properties by avoiding these uncontrolled couplings. Consequently, arbitrary phase functions are transferred linearly to other frequencies while preserving the general shape of the input spectrum. As a powerful application, we introduce deep UV phase control at 207 nm by using a conventional NIR pulse shaper. PMID- 28801623 TI - Social contact patterns relevant to the spread of respiratory infectious diseases in Hong Kong. AB - The spread of many respiratory infections is determined by contact patterns between infectious and susceptible individuals in the population. There are no published data for quantifying social contact patterns relevant to the spread of respiratory infectious diseases in Hong Kong which is a hotspot for emerging infectious diseases due to its high population density and connectivity in the air transportation network. We adopted a commonly used diary-based design to conduct a social contact survey in Hong Kong in 2015/16 using both paper and online questionnaires. Participants using paper questionnaires reported more contacts and longer contact duration than those using online questionnaires. Participants reported 13 person-hours of contact and 8 contacts per day on average, which decreased over age but increased with household size, years of education and income level. Prolonged and frequent contacts, and contacts at home, school and work were more likely to involve physical contacts. Strong age assortativity was observed in all age groups. We evaluated the characteristics of social contact patterns relevant to the spread of respiratory infectious diseases in Hong Kong. Our findings could help to improve the design of future social contact surveys, parameterize transmission models of respiratory infectious diseases, and inform intervention strategies based on model outputs. PMID- 28801624 TI - Stingray venom activates IL-33 producing cardiomyocytes, but not mast cell, to promote acute neutrophil-mediated injury. AB - One of the hallmarks of acute inflammation is neutrophil infiltration of tissues. We investigated molecular mechanisms implicated in acute neutrophilic inflammation induced by the venom of a freshwater stingray (Potamotrygon cf. henlei) in mice. Ray venom induced early mobilization of neutrophil in the microvasculature of cremaster mice and infiltration of the peritoneal cavity 2 hours after injury, in a dose-response manner. IL-1beta, IL-6, TNF-alpha, and KC were produced. The neutrophilic infiltration did not occur in mice with ST2 receptor and MyD88 adapters neutralized, or in those with PI3K and p38 MAPK signaling blocked. Drastic reduction of neutrophil infiltration to peritoneal cavities was observed in ST2-/-, TLR2/TLR4-/-, MyD88-/-, TRIF-/- and IL-17A-/- mice, and a partial reduction was observed in IL-18R-/- mice. Mast cell Kit W(sh)/W(sh)-, AHR-, NLRP3-, ICE-, IL-1beta-, P2RX7-, CD39-, IL-17RA-, and TBX21 KO mice retain the ability to induce neutrophilia in peritoneal cavity after ray venom injection. IL-6 and TNF-alpha alone were insufficient for promote neutrophilia in the absence of ST2 signaling. Finally, abundant production of IL 33 by cardiomyocytes was observed. These results refine our understanding of the importance of the IL-33/ST2 axis and IL-33-producing cardiomyocytes in the early acute neutrophilia induced by freshwater stingray venoms. PMID- 28801625 TI - The tomato histone deacetylase SlHDA1 contributes to the repression of fruit ripening and carotenoid accumulation. AB - Histone deacetylation is one of the well characterized post-translational modifications related to transcriptional repression in eukaryotes. The process of histone deacetylation is achieved by histone deacetylases (HDACs). Over the last decade, substantial advances in our understanding of the mechanism of fruit ripening have been achieved, but the role of HDACs in this process has not been elucidated. In our study, an RNA interference (RNAi) expression vector targeting SlHDA1 was constructed and transformed into tomato plants. Shorter fruit ripening time and decreased storability were observed in SlHDA1 RNAi lines. The accumulation of carotenoid was increased through an alteration of the carotenoid pathway flux. Ethylene content, ethylene biosynthesis genes (ACS2, ACS4 and ACO1, ACO3) and ripening-associated genes (RIN, E4, E8, Cnr, TAGL1, PG, Pti4 and LOXB) were significantly up-regulated in SlHDA1 RNAi lines. In addition, the expression of fruit cell wall metabolism genes (HEX, MAN, TBG4, XTH5 and XYL) was enhanced compared with wild type. Furthermore, SlHDA1 RNAi seedlings displayed shorter hypocotyls and were more sensitive to ACC (1-aminocyclopropane-1-carboxylate) than the wild type. The results of our study indicate that SlHDA1 functions as a negative regulator of fruit ripening by affecting ethylene synthesis and carotenoid accumulation. PMID- 28801626 TI - HIF1alpha regulates glioma chemosensitivity through the transformation between differentiation and dedifferentiation in various oxygen levels. AB - Chemotherapy plays a significant role in glioma treatment; however, it has limited effectiveness in extending the life expectancies of glioma patients. Traditional studies have attributed this lack of efficacy to glioma stem cells (GSCs) and their high resistance to chemotherapy, and hypoxia worsens this issue. In contrast, hyperoxia effectively alleviates hypoxia in glioma and sensitizes glioma cells to chemotherapy. In a summary of traditional studies, the majority of researchers overlooked the influence of hypoxia on differentiated cells because they only focused on the maintenance of GSCs stemness, which thus resulted in chemoresistance. Because of this background, we hypothesized that GSCs may be induced through dedifferentiation under hypoxic conditions, and hypoxia maintains GSCs stemness, which thus leads to resistance to chemotherapy. In contrast, hyperoxia inhibits the dedifferentiation process and promotes GSCs differentiation, which increases the sensitization of glioma cells to chemotherapy. Hypoxia-inducible factor-1alpha (HIF1alpha) contributes substantially to the stemness maintenance of GSCs and resistance of glioma to chemotherapy; thus, we investigated whether HIF1alpha regulates the resistance or sensitization of glioma cells to chemotherapy in different oxygen levels. It highlights a novel viewpoint on glioma chemosensitivity from the transformation between dedifferentiation and differentiation in different oxygen levels. PMID- 28801628 TI - Colossal piezomagnetic response in magnetically pressed Zr+4 substituted cobalt ferrites. AB - A remarkable 111% increase in magnetostriction (lambda) and 435% increase in strain sensitivity (dlambda/dH) (compared to normally compacted (NC) unsubstituted CoFe2O4 (CFO)) of Zr+4 doped CFO sample, Co1.2Zr0.2Fe1.6O4, prepared by magnetic field assisted compaction, have been reported in this study. Magnetic field assisted compaction (MC) has been employed to process Zr-doped cobalt ferrites, Co1+xZrxFe2-2xO4 (0 <= * <= 0.4), to further improve the magnetoelastic properties. Saturation magnetization (M S ) and coercivity (H C ) increase from ~426 kA/m and ~4.4 kA/m respectively, for x = 0, to ~552 kA/m and ~7.11 kA/m respectively for x = 0.2. Dramatic increase in lambda was observed for MC samples (~ -360 ppm and ~-380 ppm for x = 0 and x = 0.2 respectively) compared to the NC samples (~-181 ppm and ~-185 ppm for x = 0 and x = 0.2 respectively). A remarkable quadruple increase in dlambda/dH was observed in Zr-doped (x = 0.2) cobalt-ferrite (~4.3 * 10-9 A-1m) compared to that of unsubstituted cobalt ferrite (~1.24 * 10-9 A-1m), while a fivefold increase in dlambda/dH was observed for magnetically compacted (MC) Zr doped cobalt ferrite (x = 0.2) (~4.3 * 10-9 A 1m) compared to normal compacted (NC) unsubstituted cobalt ferrite (~0.8 * 10-9 A 1m). PMID- 28801627 TI - Increased risk of low birth weight in women with placental malaria associated with P. falciparum VAR2CSA clade. AB - Pregnancy associated malaria (PAM) causes adverse pregnancy and birth outcomes owing to Plasmodium falciparum accumulation in the placenta. Placental accumulation is mediated by P. falciparum protein VAR2CSA, a leading PAM-specific vaccine target. The extent of its antigen diversity and impact on clinical outcomes remain poorly understood. Through amplicon deep-sequencing placental malaria samples from women in Malawi and Benin, we assessed sequence diversity of VAR2CSA's ID1-DBL2x region, containing putative vaccine targets and estimated associations of specific clades with adverse birth outcomes. Overall, var2csa diversity was high and haplotypes subdivided into five clades, the largest two defined by homology to parasites strains, 3D7 or FCR3. Across both cohorts, compared to women infected with only FCR3-like variants, women infected with only 3D7-like variants delivered infants with lower birthweight (difference: -267.99 g; 95% Confidence Interval [CI]: -466.43 g,-69.55 g) and higher odds of low birthweight (<2500 g) (Odds Ratio [OR] 5.41; 95% CI:0.99,29.52) and small-for gestational-age (OR: 3.65; 95% CI: 1.01,13.38). In two distinct malaria-endemic African settings, parasites harboring 3D7-like variants of VAR2CSA were associated with worse birth outcomes, supporting differential effects of infection with specific parasite strains. The immense diversity coupled with differential clinical effects of this diversity suggest that an effective VAR2CSA based vaccine may require multivalent activity. PMID- 28801629 TI - Condition-Dependent Trade-Off Between Weapon Size and Immunity in Males of the European Earwig. AB - Investigating the expression of trade-offs between key life-history functions is central to our understanding of how these functions evolved and are maintained. However, detecting trade-offs can be challenging due to variation in resource availability, which masks trade-offs at the population level. Here, we investigated in the European earwig Forficula auricularia whether (1) weapon size trades off with three key immune parameters - hemocyte concentration, phenoloxidase and prophenoloxidase activity - and whether (2) expression and strength of these trade-offs depend on male body condition (body size) and/or change after an immune challenge. Our results partially confirmed condition dependent trade-offs between weapon size and immunity in male earwigs. Specifically, we found that after an immune challenge, weapon size trades off with hemocyte concentrations in low-condition, but not in good-condition males. Contrastingly, weapon size was independent of pre-challenge hemocyte concentration. We also found no trade-off between weapon size and phenoloxidase activity, independent of body condition and immune challenge. Overall, our study reveals that trade-offs with sexual traits may weaken or disappear in good condition individuals. Given the importance of weapon size for male reproductive success, our results highlight how low-condition individuals may employ alternative life-history investment strategies to cope with resource limitation. PMID- 28801630 TI - The role of Snell's law for a magnonic majority gate. AB - In the fifty years since the postulation of Moore's Law, the increasing energy consumption in silicon electronics has motivated research into emerging devices. An attractive research direction is processing information via the phase of spin waves within magnonic-logic circuits, which function without charge transport and the accompanying heat generation. The functional completeness of magnonic logic circuits based on the majority function was recently proved. However, the performance of such logic circuits was rather poor due to the difficulty of controlling spin waves in the input junction of the waveguides. Here, we show how Snell's law describes the propagation of spin waves in the junction of a Psi shaped magnonic majority gate composed of yttrium iron garnet with a partially metallized surface. Based on the analysis, we propose a magnonic counterpart of a core-cladding waveguide to control the wave propagation in the junction. This study has therefore experimentally demonstrated a fundamental building block of a magnonic logic circuit. PMID- 28801631 TI - Rhodoterpenoids A-C, Three New Rearranged Triterpenoids from Rhododendron latoucheae by HPLC-MS-SPE-NMR. AB - Rhodoterpenoids A-C (1-3), three new rearranged triterpenoids, together with one new biogenetically related compound, rhodoterpenoid D (4), were isolated and efficiently elucidated from Rhododendron latoucheae by high-performance liquid chromatography-mass spectrometry-solid-phase extraction-nuclear magnetic resonance (HPLC-MS-SPE-NMR). Compounds 1 and 2 possess an unprecedented skeleton with a 5/7/6/6/6-fused pentacyclic ring system, while compound 3 contains a unique 6/7/6/6/6-fused pentacyclic carbon backbone. Their structures were determined by extensive spectroscopic methods and electronic circular dichroism (ECD) analyses. Plausible biogenetic pathways for 1-4 were proposed. Compounds 1 and 4 showed potential activity against herpes simplex virus 1 (HSV-1) with IC50 values of 8.62 and 6.87 MUM, respectively. PMID- 28801632 TI - Stimulation in primary and secondary metabolism by elevated carbon dioxide alters green tea quality in Camellia sinensis L. AB - Rising CO2 concentration, a driving force of climate change, is impacting global food security by affecting plant physiology. Nevertheless, the effects of elevated CO2 on primary and secondary metabolism in tea plants (Camellia sinensis L.) still remain largely unknown. Here we showed that exposure of tea plants to elevated CO2 (800 umol mol-1 for 24 d) remarkably improved both photosynthesis and respiration in tea leaves. Furthermore, elevated CO2 increased the concentrations of soluble sugar, starch and total carbon, but decreased the total nitrogen concentration, resulting in an increased carbon to nitrogen ratio in tea leaves. Among the tea quality parameters, tea polyphenol, free amino acid and theanine concentrations increased, while the caffeine concentration decreased after CO2 enrichment. The concentrations of individual catechins were altered differentially resulting in an increased total catechins concentration under elevated CO2 condition. Real-time qPCR analysis revealed that the expression levels of catechins and theanine biosynthetic genes were up-regulated, while that of caffeine synthetic genes were down-regulated in tea leaves when grown under elevated CO2 condition. These results unveiled profound effects of CO2 enrichment on photosynthesis and respiration in tea plants, which eventually modulated the biosynthesis of key secondary metabolites towards production of a quality green tea. PMID- 28801633 TI - Evaluation of novel factor Xa inhibitors from Oxya chinensis sinuosa with anti platelet aggregation activity. AB - The edible grasshopper Oxya chinensis sinuosa is consumed worldwide for its various medicinal effects. The purpose of this study was to investigate potential bioactive antithrombotic and antiplatelet compounds from O. chinensis sinuosa. Five N-acetyldopamine dimers (1-5) were isolated from O. chinensis sinuosa and compounds 1 and 2 were identified as new chemicals with chiral centers at H-2 and H-3 of the benzo-1,4-dioxane structure. Compounds 1-4 were found to have both FXa and platelet aggregation inhibitory activities. These compounds inhibited the catalytic activity of FXa toward its synthetic substrate, S-2222, by noncompetitive inhibition, and inhibited platelet aggregation induced by ADP and U46619. Furthermore, compounds 1-4 showed enhanced antithrombotic effects, which were assessed using in vivo models of pulmonary embolism and arterial thrombosis. The isolated compounds also showed anticoagulant effects in mice. However, compounds 1-4 did not prolong bleeding time in mice, as shown by tail clipping. N Acetyldopamine dimers, including two new stereoisomers 1 and 2, are novel antithrombotic compounds showing both FXa inhibition and antiplatelet aggregation activity with a low bleeding risk. Collectively, these results suggest that compounds 1-4 could serve as candidates and provide scaffolds for development of new antithrombotic drugs. PMID- 28801634 TI - Mapping physiological inputs from multiple photoreceptor systems to dopaminergic amacrine cells in the mouse retina. AB - In the vertebrate retina, dopamine is synthesized and released by a specialized type of amacrine cell, the dopaminergic amacrine cell (DAC). DAC activity is stimulated by rods, cones, and melanopsin-expressing intrinsically photosensitive retinal ganglion cells upon illumination. However, the relative contributions of these three photoreceptor systems to the DAC light-induced response are unknown. Here we found that rods excite dark-adapted DACs across a wide range of stimulation intensities, primarily through connexin-36-dependent rod pathways. Similar rod-driven responses were observed in both ventral and dorsal DACs. We further found that in the dorsal retina, M-cones and melanopsin contribute to dark-adapted DAC responses with a similar threshold intensity. In the ventral retina, however, the threshold intensity for M-cone-driven responses was two log units greater than that observed in dorsal DACs, and melanopsin-driven responses were almost undetectable. We also examined the DAC response to prolonged adapting light and found such responses to be mediated by rods under dim lighting conditions, rods/M-cones/melanopsin under intermediate lighting conditions, and cones and melanopsin under bright lighting conditions. Our results elucidate the relative contributions of the three photoreceptor systems to DACs under different lighting conditions, furthering our understanding of the role these cells play in the visual system. PMID- 28801635 TI - Thermally-assisted Magma Emplacement Explains Restless Calderas. AB - Many calderas show repeated unrest over centuries. Though probably induced by magma, this unique behaviour is not understood and its dynamics remains elusive. To better understand these restless calderas, we interpret deformation data and build thermal models of Campi Flegrei caldera, Italy. Campi Flegrei experienced at least 4 major unrest episodes in the last decades. Our results indicate that the inflation and deflation of magmatic sources at the same location explain most deformation, at least since the build-up of the last 1538 AD eruption. However, such a repeated magma emplacement requires a persistently hot crust. Our thermal models show that this repeated emplacement was assisted by the thermal anomaly created by magma that was intruded at shallow depth ~3 ka before the last eruption. This may explain the persistence of the magmatic sources promoting the restless behaviour of the Campi Flegrei caldera; moreover, it explains the crystallization, re-melting and mixing among compositionally distinct magmas recorded in young volcanic rocks. Our model of thermally-assisted unrest may have a wider applicability, possibly explaining also the dynamics of other restless calderas. PMID- 28801636 TI - Inhibition of hypoxic response decreases stemness and reduces tumorigenic signaling due to impaired assembly of HIF1 transcription complex in pancreatic cancer. AB - Pancreatic tumors are renowned for their extremely hypoxic centers, resulting in upregulation of a number of hypoxia mediated signaling pathways including cell proliferation, metabolism and cell survival. Previous studies from our laboratory have shown that Minnelide, a water-soluble pro-drug of triptolide (anti-cancer compound), decreases viability of cancer cells in vitro as well as in vivo. However, its mechanism of action remain elusive. In the current study we evaluated the effect of Minnelide, on hypoxia mediated oncogenic signaling as well as stemness in pancreatic cancer. Minnelide has just completed Phase 1 trial against GI cancers and is currently awaiting Phase 2 trials. Our results showed that upon treatment with triptolide, HIF-1alpha protein accumulated in pancreatic cancer cells even though hypoxic response was decreased in them. Our studies showed even though HIF-1alpha is accumulated in the treated cells, there was no decrease in HIF-1 binding to hypoxia response elements. However, the HIF-1 transcriptional activity was significantly reduced owing to depletion of co activator p300 upon treatment with triptolide. Further, treatment with triptolide resulted in a decreased activity of Sp1 and NF-kB the two major oncogenic signaling pathway in pancreatic cancer along with a decreased tumor initiating cell (TIC) population in pancreatic tumor. PMID- 28801637 TI - Effect of GOLPH3 on cumulus granulosa cell apoptosis and ICSI pregnancy outcomes. AB - Previous studies have shown that GOLPH3 mediates cell growth, proliferation and differentiation and inhibits cell apoptosis; however, the role of GOLPH3 in cumulus granulosa cells and the value of GOLPH3 in predicting ICSI pregnancy outcomes remain unknown until now. Our findings showed higher positive expression rate, score of staining intensity, and immunohistochemical score of GOLPH3 in the cumulus granulosa cells of the pregnant women relative to non-pregnant women, and a higher apoptotic rate of cumulus granulosa cells was detected in non-pregnant women than in pregnant women. Pearson correlation analyses revealed that pregnancy correlated negatively with GOLPH3 expression and apoptosis of cumulus granulosa cells, and positively with the number of follicles punctured, number of grade III oocytes, number of eggs retrieved for ICSI, number of zygotes, number of cleavage-stage embryos, number of top-quality embryos, number of blastocysts, number of top-quality blastocysts, and number of frozen embryos. GOLPH3 may be involved in the apoptosis of cumulus granulosa cells, which may correlate with oocyte maturation and egg development. GOLPH3 expression in cumulus granulosa cells may facilitate the selection of top-quality eggs and embryos, the prediction of the clinical pregnancy outcomes of ICSI, and the increase of the pregnancy rate. PMID- 28801638 TI - In-situ, time resolved monitoring of uranium in BFS:OPC grout. Part 1: Corrosion in water vapour. AB - Uranium encapsulated in grout was exposed to water vapour for extended periods of time. Through synchrotron x-ray powder diffraction and tomography measurements, uranium dioxide was determined the dominant corrosion product over a 50-week time period. The oxide growth rate initiated rapidly, with rates comparable to the U + H2O reaction. Over time, the reaction rate decreased and eventually plateaued to a rate similar to the U + H2O + O2 reaction. This behaviour was not attributed to oxygen ingress, but instead the decreasing permeability of the grout, limiting oxidising species access to the metal surface. PMID- 28801639 TI - Investigation into the stability and culturability of Chinese enterotypes. AB - Although many gut microbial enterotypes have been reported in Europe, Africa and the U.S., their effects on human health are still not yet clear. Culturing gut microbial enterotypes in vitro will be helpful to study their effects and applications. Here, fecal samples from 13 healthy Chinese volunteers were collected and subjected to next-generation sequencing. The results showed that seven of these samples belong to the Bacteroides enterotype and another six to the Prevotella enterotype. Stability of these Chinese gut microbial enterotypes was also evaluated. Results showed that most of the tested volunteer gut microbiota to be very stable. For one volunteer, the bacterial community returned to the state it was in before intestinal lavage and antibiotics treatment after four months. XP medium was found effective for simulating the Bacteroides enterotype independent of the original gut microbial community in an in vitro chemostat culture system. Although, the Prevotella enterotype was not very well simulated in vitro, different culture elements selectively enriched different gut bacteria. Pectin and xylan were found to be related to the enrichment of the genera Bacteroides, Sutterella, and Flavonifractor in this chemostat culture system. PMID- 28801640 TI - Spectroscopic observation of oxygen dissociation on nitrogen-doped graphene. AB - Carbon nanomaterials' reactivity towards oxygen is very poor, limiting their potential applications. However, nitrogen doping is an established way to introduce active sites that facilitate interaction with gases. This boosts the materials' reactivity for bio-/gas sensing and enhances their catalytic performance for the oxygen reduction reaction. Despite this interest, the role of differently bonded nitrogen dopants in the interaction with oxygen is obscured by experimental challenges and has so far resisted clear conclusions. We study the interaction of molecular oxygen with graphene doped via nitrogen plasma by in situ high-resolution synchrotron techniques, supported by density functional theory core level simulations. The interaction leads to oxygen dissociation and the formation of carbon-oxygen single bonds on graphene, along with a band gap opening and a rounding of the Dirac cone. The change of the N 1 s core level signal indicates that graphitic nitrogen is involved in the observed mechanism: the adsorbed oxygen molecule is dissociated and the two O atoms chemisorb with epoxy bonds to the nearest carbon neighbours of the graphitic nitrogen. Our findings help resolve existing controversies and offer compelling new evidence of the ORR pathway. PMID- 28801641 TI - Polymertropism of rod-shaped bacteria: movement along aligned polysaccharide fibers. AB - In nature, bacteria often live in surface-associated communities known as biofilms. Biofilm-forming bacteria typically deposit a layer of polysaccharide on the surfaces they inhabit; hence, polysaccharide is their immediate environment on many surfaces. In this study, we examined how the physical characteristics of polysaccharide substrates influence the behavior of the biofilm-forming bacterium Myxococcus xanthus. M. xanthus responds to the compression-induced deformation of polysaccharide substrates by preferentially spreading across the surface perpendicular to the axis of compression. Our results suggest that M. xanthus is not responding to the water that accumulates on the surface of the polysaccharide substrate after compression or to compression-induced changes in surface topography such as the formation of troughs. These directed surface movements do, however, consistently match the orientation of the long axes of aligned and tightly packed polysaccharide fibers in compressed substrates, as indicated by behavioral, birefringence and small angle X-ray scattering analyses. Therefore, we suggest that the directed movements are a response to the physical arrangement of the polymers in the substrate and refer to the directed movements as polymertropism. This behavior might be a common property of bacteria, as many biofilm-forming bacteria that are rod-shaped and motile on soft surfaces exhibit polymertropism. PMID- 28801642 TI - Extreme anoxia tolerance in crucian carp and goldfish through neofunctionalization of duplicated genes creating a new ethanol-producing pyruvate decarboxylase pathway. AB - Without oxygen, most vertebrates die within minutes as they cannot meet cellular energy demands with anaerobic metabolism. However, fish of the genus Carassius (crucian carp and goldfish) have evolved a specialized metabolic system that allows them to survive prolonged periods without oxygen by producing ethanol as their metabolic end-product. Here we show that this has been made possible by the evolution of a pyruvate decarboxylase, analogous to that in brewer's yeast and the first described in vertebrates, in addition to a specialized alcohol dehydrogenase. Whole-genome duplication events have provided additional gene copies of the pyruvate dehydrogenase multienzyme complex that have evolved into a pyruvate decarboxylase, while other copies retained the essential function of the parent enzymes. We reveal the key molecular substitution in duplicated pyruvate dehydrogenase genes that underpins one of the most extreme hypoxic survival strategies among vertebrates and that is highly deleterious in humans. PMID- 28801644 TI - Intrusion of the Kuroshio into the South and East China Seas. AB - The northward-flowing Kuroshio often intrudes westward and modulates the water masses of the South and East China Seas. These intrusions transcend multiple scales in time and space, which we demonstrate here using various independent data sets. There are two hot spots of intrusion, one in the Luzon Strait and the other off northeast Taiwan, which occur synchronously when the upstream Kuroshio weakens during winter. Beyond seasonal time scales, the two intrusions were not synchronous during 1993-2013. While intrusions into the South China Sea echoed the Pacific Decadal Oscillation, the intrusion northeast of Taiwan decreased markedly before 2002 but regularly reached the shelf thereafter. This change was due to the influence of westward impingements of cyclonic eddies from the open ocean on the Kuroshio main stream in place of anticyclonic eddies. During 1993 2001, decreasing cyclonic eddy impingements moved the Kuroshio away from northeast Taiwan, weakening the Kuroshio intrusion onto the East China Sea shelf. Thereafter, enhanced cyclonic eddy impingement during 2002-2013 weakened the Kuroshio transport, moving it closer to the shelf and enhancing its intrusion into the East China Sea. PMID- 28801643 TI - The Role of PGE2 in Alveolar Epithelial and Lung Microvascular Endothelial Crosstalk. AB - Disruption of the blood-air barrier, which is formed by lung microvascular endothelial and alveolar epithelial cells, is a hallmark of acute lung injury. It was shown that alveolar epithelial cells release an unidentified soluble factor that enhances the barrier function of lung microvascular endothelial cells. In this study we reveal that primarily prostaglandin (PG) E2 accounts for this endothelial barrier-promoting activity. Conditioned media from alveolar epithelial cells (primary ATI-like cells) collected from BALB/c mice and A549 cells increased the electrical resistance of pulmonary human microvascular endothelial cells, respectively. This effect was reversed by pretreating alveolar epithelial cells with a cyclooxygenase-2 inhibitor or by blockade of EP4 receptors on endothelial cells, and in A549 cells also by blocking the sphingosine-1-phosphate1 receptor. Cyclooxygenase-2 was constitutively expressed in A549 cells and in primary ATI-like cells, and was upregulated by lipopolysaccharide treatment. This was accompanied by enhanced PGE2 secretion into conditioned media. Therefore, we conclude that epithelium-derived PGE2 is a key regulator of endothelial barrier integrity via EP4 receptors under physiologic and inflammatory conditions. Given that pharmacologic treatment options are still unavailable for diseases with compromised air-blood barrier, like acute lung injury, our data thus support the therapeutic potential of selective EP4 receptor agonists. PMID- 28801645 TI - Chronic Intermittent Hypobaric Hypoxia Improves Cardiac Function through Inhibition of Endoplasmic Reticulum Stress. AB - We investigated the role of endoplasmic reticulum stress (ERS) in chronic intermittent hypobaric hypoxia (CIHH)-induced cardiac protection. Adult male Sprague-Dawley rats were exposed to CIHH treatment simulating 5000 m altitude for 28 days, 6 hours per day. The heart was isolated and perfused with Langendorff apparatus and subjected to 30-min ischemia followed by 60-min reperfusion. Cardiac function, infarct size, and lactate dehydrogenase (LDH) activity were assessed. Expression of ERS molecular chaperones (GRP78, CHOP and caspase-12) was assayed by western blot analysis. CIHH treatment improved the recovery of left ventricular function and decreased cardiac infarct size and activity of LDH after I/R compared to control rats. Furthermore, CIHH treatment inhibited over expression of ERS-related factors including GRP78, CHOP and caspase-12. CIHH induced cardioprotection and inhibition of ERS were eliminated by application of dithiothreitol, an ERS inducer, and chelerythrine, a protein kinase C (PKC) inhibitor. In conclusion CIHH treatment exerts cardiac protection against I/R injury through inhibition of ERS via PKC signaling pathway. PMID- 28801646 TI - A New Treatment-integrated Prognostic Nomogram of the Barcelona Clinic Liver Cancer System for Hepatocellular Carcinoma. AB - The nomogram of the Barcelona Clinic Liver Cancer (BCLC) has accurate outcome prediction. This study aims to propose a treatment-integrated nomogram derived from BCLC for patients with hepatocellular carcinoma (HCC). A total of 3,371 patients were randomly grouped into derivation (n = 2,247) and validation (n = 1,124) sets. Multivariate Cox proportional hazards model was used to generate the nomogram from tumor burden, cirrhosis, performance status (PS) and primary anti cancer treatments. Concordance indices and calibration plots were used to evaluate the performance of nomogram. The derivation and validation sets had the same concordance index of 0.774 (95% confidence intervals: 0.717-0.826 and 0.656 0.874, respectively). In calibration plots, survival distributions predicted by the nomogram and observed by the Kaplan-Meier method were similar at 3- and 5 year for patients from derivation and validation sets. Validation group patients divided into 10 subgroups by the original and new treatment-integrated BCLC nomogram were used to evaluate the prognostic performance of integrating primary anti-cancer treatments. Compared to the nomogram of original BCLC system, the treatment-integrated nomogram of BCLC system had larger linear trend and likelihood ratio X2. In conclusion, based on the results of concordance index tests, integrating primary anti-cancer treatments into the BCLC system provides similar discriminatory ability. PMID- 28801647 TI - Reconstruction of a Genome-scale Metabolic Network of Komagataeibacter nataicola RZS01 for Cellulose Production. AB - Bacterial cellulose (BC) is widely used in industries owing to its high purity and strength. Although Komagataeibacter nataicola is a representative species for BC production, its intracellular metabolism leading to BC secretion is unclear. In the present study, a genome-scale metabolic network of cellulose-producing K. nataicola strain RZS01 was reconstructed to understand its metabolic behavior. This model iHZ771 comprised 771 genes, 2035 metabolites, and 2014 reactions. Constraint-based analysis was used to characterize and evaluate the critical intracellular pathways. The analysis revealed that a total of 71 and 30 genes are necessary for cellular growth in a minimal medium and complex medium, respectively. Glycerol was identified as the optimal carbon source for the highest BC production. The minimization of metabolic adjustment algorithm identified 8 genes as potential targets for over-production of BC. Overall, model iHZ771 proved to be a useful platform for understanding the physiology and BC production of K. nataicola. PMID- 28801648 TI - An effective combination of whole-exome sequencing and runs of homozygosity for the diagnosis of primary ciliary dyskinesia in consanguineous families. AB - Primary ciliary dyskinesia (PCD) is clinically characterized by neonatal respiratory distress, chronic sinusitis, bronchiectasis and infertility, and situs inversus in 50% of the patients. PCD is a result of mutations in genes encoding proteins involved in ciliary function, and is primarily inherited in an autosomal recessive fashion. Diagnosis of PCD is often a challenging task due to its high clinical and genetic heterogeneities. In the present study, we attempted to use whole-exome sequencing (WES) combined with runs of homozygosity (ROH) approaches to identify the genetic defects in four Chinese consanguineous families with clinical PCD. We successfully identified three recently acknowledged PCD genes: DYX1C1, CCNO and ARMC4, and one well-characterized PCD gene, DNAI1. Our study provides compelling evidence that WES in combination with ROH analysis is an efficient diagnostic tool for identifying genetic causes of PCD in consanguineous families. Furthermore, our work expands the genetic mutation spectrum in PCD, and provides the additional tools to better serve the counseling of the families with PCD. PMID- 28801649 TI - Protein O-mannosylation deficiency increases LprG-associated lipoarabinomannan release by Mycobacterium tuberculosis and enhances the TLR2-associated inflammatory response. AB - Protein O-mannosylation is crucial for the biology of Mycobacterium tuberculosis but the key mannosylated protein(s) involved and its(their) underlying function(s) remain unknown. Here, we demonstrated that the M. tuberculosis mutant (Deltapmt) deficient for protein O-mannosylation exhibits enhanced release of lipoarabinomannan (LAM) in a complex with LprG, a lipoprotein required for LAM translocation to the cell surface. We determined that LprG is O-mannosylated at a unique threonine position by mass spectrometry analyses of the purified protein. However, although replacement of this amino acid by an alanine residue completely abolished LprG O-mannosylation, the increased release of the LAM/LprG complex was preserved. We found that the increased secretion of this complex is due to enhanced LAM production in the Deltapmt M. tuberculosis and M. smegmatis mutants relative to their wild-type counterparts. This abnormal release of LAM/LprG has functional consequences on the induction of inflammatory responses and provides a possible explanation for the reduced virulence of the M. tuberculosis Deltapmt mutant. PMID- 28801650 TI - Regulation of the Human Phosphatase PTPN4 by the inter-domain linker connecting the PDZ and the phosphatase domains. AB - Human protein tyrosine phosphatase non-receptor type 4 (PTPN4) has been shown to prevent cell death. The active form of human PTPN4 consists of two globular domains, a PDZ (PSD-95/Dlg/ZO-1) domain and a phosphatase domain, tethered by a flexible linker. Targeting its PDZ domain abrogates this protection and triggers apoptosis. We previously demonstrated that the PDZ domain inhibits the phosphatase activity of PTPN4 and that the mere binding of a PDZ ligand is sufficient to release the catalytic inhibition. We demonstrate here that the linker connecting the PDZ domain and the phosphatase domain is involved in the regulation of the phosphatase activity in both PDZ-related inhibition and PDZ ligand-related activation events. We combined bioinformatics and kinetic studies to decipher the role of the linker in the PTPN4 activity. By comparing orthologous sequences, we identified a conserved patch of hydrophobic residues in the linker. We showed that mutations in this patch affect the regulation of the PTPN4 bidomain indicating that the PDZ-PDZ ligand regulation of PTPN4 is a linker mediated mechanism. However, the mutations do not alter the binding of the PDZ ligand. This study strengthens the notion that inter-domain linker can be of functional importance in enzyme regulation of large multi-domain proteins. PMID- 28801651 TI - Discovery of novel highly active and stable aspartate dehydrogenases. AB - Aspartate family amino acids (AFAAs) have important commercial values due to their wide spectrum of applications. Most if not all AFAAs are produced under aerobic conditions which is energy-intensive. To establish a cost-effective anaerobic process for production of AFAAs, it holds great promise to develop a new pathway enabling the conversion of oxoloacetate into aspartate through direct amination which is catalyzed by aspartate dehydrogenase (AspDH). Compared with the well studied aspartate aminotransferase and aspartate ammonia-lyase, only a few AspDHs are characterized till date, and failure to reproduce the high activity of AspDH from Rastonia eutropha documented in the literature encouraged us to screen and characterize novel AspDHs from different origins. Interestingly, the AspDHs from Klebsiella pneumoniae 34618 (KpnAspDH) and Delftia sp. Cs1-4 (DelAspDH) showed successful soluble expression. KpnAspDH and DelAspDH containing C-terminal hexa-histidine tags were purified and characterized for their catalytic properties. Notably, in addition to its high reductive amination activity, DelAspDH exhibited considerable stability as compared to the other source of AspDHs. This work thus provides novel enzyme resource for engineering strains capable of producing AFAAs under anaerobic conditions. PMID- 28801652 TI - Assessment of Three New Loci from Genome-wide Association Study in Essential Tremor in Chinese population. AB - Essential tremor (ET) is the most common tremor disorder. Evidences indicated that genetics plays an essential role in the researches of etiology. A new genome wide association study (GWAS) from European population identified three novel loci in ET, which were rs10937625 in STK32B, rs17590046 in PPARGC1A, and rs12764057, rs10822974 and rs7903491 in CTNNA3. Due to the different genetic background in different population, we performed a case-control study to investigate these variants in a cohort of 533 subjects in Chinese population. We found a significant difference in the distributions of genotypes and alleles frequencies between ET and control groups of rs10937625 (genotype p = 0.037, OR = 0.69[0.48-0.98]; allele p = 0.033, OR = 0.82[0.69-0.99]) and rs7903491 (genotype p = 0.030, OR = 1.34[1.03-1.74]; allele p = 0.029, OR = 1.16[1.02-1.32]) after adjusted for age and gender. And no associations were detected between rs17590046 (genotype p = 0.794; allele p = 0.791), rs12764057 (genotype p = 0.337; allele p = 0.337), rs10822974 (genotype p = 0.102; allele p = 0.100) and ET in Chinese population individually. Our research supports that C allele of rs10937625 in STK32B is a protective factor and G allele of rs7903491 in CTNNA3 is a risk factor for ET in Chinese population. PMID- 28801653 TI - Fluorescent hydrogel waveguide for on-site detection of heavy metal ions. AB - Hydrogels have great applications in tissue engineering and drug delivery. Recently, there have been intense interests in developments and applications of nanocomposite hydrogels by incorporating nanomaterials into polymer matrix, which endows the hydrogels with new functionalities. Here, we report on the first carbon dots (CDs) doped hydrogel waveguide for selective, on-site detection of heavy metal ions in aqueous solutions. The CDs-doped hydrogel waveguide exhibits efficient light confinement in water due to the refractive index contrast. The smooth waveguide surfaces lead to low light scattering loss. Real-time spectra measurement of the CDs-doped hydrogel waveguide with a compact interrogation setup demonstrates that the novel design can be used as a portable, robust sensing platform for on-site analysis and assessment of heavy metal ions. PMID- 28801654 TI - Perceptions of asthma control in the United Kingdom: a cross-sectional study comparing patient and healthcare professionals' perceptions of asthma control with validated ACT scores. AB - : Perceptions of asthma control often vary between patients and physicians. This cross-sectional survey provided UK-specific data on actual and perceived asthma control in patients (18-75 years) attending routine asthma reviews in primary, secondary and tertiary settings. Differences between healthcare professionals' (HCP) and patients' perceptions of asthma control were evaluated via an online questionnaire and compared to a control-the validated asthma control test (ACT) which patients completed. Treated patients (at least a short acting beta-agonist) with a documented diagnosis of asthma were enroled and consented within a month of their last appointment. Patients were grouped according to the British Thoracic Society (BTS)/Scottish Intercollegiate Guidelines Network (SIGN) 2014 treatment guidelines (BTS/SIGN steps 1-5). A total of 260 patients were screened: 234 were eligible for enrolment: 33, 52, 50, 49 and 50 patients in steps 1-5, respectively. Seventy per cent (164) were women. The percentage of patients aged 45-64 years was 47.4%. HCPs classed 70% (164) as non-smokers. 84.2% of patients and 73.9% of HCPs perceived that asthma was controlled but ACT results suggest that asthma was only controlled in 54.7% of patients (ACT score >=20). Patients in steps 4 and 5 had the highest levels of uncontrolled asthma. Correct agreement between ACT score with perceptions of controlled or uncontrolled asthma occurred in 67.9% of patients and 68.8% of HCPs; the poorest levels of agreement occurred in patients in steps 4 and 5. Uncontrolled asthma is common in UK patients. High proportions of patients and HCPs have incorrect perceptions of asthma control, especially in relation to patients with asthma in steps 4 and 5. ASTHMA: MISPERCEPTIONS OF CONTROL ABOUND AMONG UK PATIENTS AND DOCTORS: Asthma patients and their doctors often misperceive whether the disease is under control, according to a British study. Andrew Menzies-Gow from Royal Brompton Hospital in London and Gavin Chiu from Boehringer Ingelheim UK in Bracknell used an online questionnaire to assess perceptions of asthma control among 234 patients and their healthcare providers. All participants had at least intermittent asthma that required occasional treatment; many had more severe disease. The researchers found that 84% of patients and 74% of doctors thought the asthma was well controlled, but results of the Asthma Control Test indicated only 55% of patients objectively achieved disease control. Correct agreement between the validated test and more subjective perceptions occurred in only 68 % of patients and 69% of doctors. Addressing this mismatch could go a long way to improving asthma control among British patients. PMID- 28801655 TI - beta1-adrenergic receptor O-glycosylation regulates N-terminal cleavage and signaling responses in cardiomyocytes. AB - beta1-adrenergic receptors (beta1ARs) mediate catecholamine actions in cardiomyocytes by coupling to both Gs/cAMP-dependent and Gs-independent/growth regulatory pathways. Structural studies of the beta1AR define ligand-binding sites in the transmembrane helices and effector docking sites at the intracellular surface of the beta1AR, but the extracellular N-terminus, which is a target for post-translational modifications, typically is ignored. This study identifies beta1AR N-terminal O-glycosylation at Ser37/Ser41 as a mechanism that prevents beta1AR N-terminal cleavage. We used an adenoviral overexpression strategy to show that both full-length/glycosylated beta1ARs and N-terminally truncated glycosylation-defective beta1ARs couple to cAMP and ERK-MAPK signaling pathways in cardiomyocytes. However, a glycosylation defect that results in N terminal truncation stabilizes beta1ARs in a conformation that is biased toward the cAMP pathway. The identification of O-glycosylation and N-terminal cleavage as novel structural determinants of beta1AR responsiveness in cardiomyocytes could be exploited for therapeutic advantage. PMID- 28801657 TI - Crack-induced Ag nanowire networks for transparent, stretchable, and highly sensitive strain sensors. AB - Crack-based strain sensor systems have been known for its high sensitivity, but suffer from the small fracture strain of the thin metal films employed in the sensor which results in its negligible stretchability. Herein, we fabricated a transparent (>90% at 550 nm wavelength), stretchable (up to 100%), and sensitive (gauge factor (GF) of 30 at 100% strain) strain gauge by depositing an encapsulated crack-induced Ag nanowire (AgNW) network on a hydroxylated poly(dimethylsiloxane) (PDMS) film. Stretching the encapsulated AgNWs/PDMS resulted in the formation of a percolation network of nanowire ligaments with abundant percolation paths. The encapsulating polymer was designed to adhere strongly to both the AgNW and PDMS. The improved adhesion ensured the resistance of the crack-induced network of AgNWs varied reversibly, stably, and sensitively when stretched and released, at strains of up to 100%. The developed sensor successfully detected human motions when applied to the skin. PMID- 28801656 TI - Comprehensive miRNA expression profiling in human T-cell acute lymphoblastic leukemia by small RNA-sequencing. AB - T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease that can be classified into different molecular genetic subtypes according to their mRNA gene expression profile. In this study, we applied RNA sequencing to investigate the full spectrum of miRNA expression in primary T-ALL patient samples, T-ALL leukemia cell lines and healthy donor thymocytes. Notably, this analysis revealed that genetic subtypes of human T-ALL also display unique miRNA expression signatures, which are largely conserved in human T-ALL cell lines with corresponding genetic background. Furthermore, small RNA-sequencing also unraveled the variety of isoforms that are expressed for each miRNA in T-ALL and showed that a significant number of miRNAs are actually represented by an alternative isomiR. Finally, comparison of CD34+ and CD4+CD8+ healthy donor thymocytes and T-ALL miRNA profiles allowed identifying several novel miRNAs with putative oncogenic or tumor suppressor functions in T-ALL. Altogether, this study provides a comprehensive overview of miRNA expression in normal and malignant T cells and sets the stage for functional evaluation of novel miRNAs in T-ALL disease biology. PMID- 28801658 TI - Relationship between long working hours and periodontitis among the Korean workers. AB - We aimed to investigate the association between long working hours and periodontitis, and whether such an association constitutes an exposure-response relationship. Data for this study were collected from the Korea National Health and Nutrition Examination Surveys conducted from 2007 to 2014; 17,533 workers (9,483 of men and 8,050 of women) were included. The odds ratios (OR) and 95% confidence intervals (CI) for the analysis of periodontitis defined as positive of Community Periodontal Index in relation to working hours were calculated using multiple logistic regression models with various stratifications. Compared to participants who worked <=40 hours per week, the prevalence ratio (95% CI) for the periodontitis was 1.19 (1.14-1.24) and full adjusted OR (95% CI) was 1.09 (1.02-1.18) in participants who worked over 40 hours per week. The OR (95% CI) for periodontitis were 1.09 (0.99-1.19) in working group of 40< and >=52 and 1.10 (1.01-1.20) in working group of >52 hours per week with a significant trend (p = 0.0233) even after adjusting for age, socioeconomic status, healthy behaviour, chronic disease, and dental care status. Long working hours are associated with periodontitis among Korean workers in an exposure-response manner. PMID- 28801660 TI - BiVO4-rGO with a novel structure on steel fabric used as high-performance photocatalysts. AB - A high-performance and novel photocatalyst of BiVO4-reduced Graphene Oxide (BiVO4 rGO) nanocomposite was prepared by a facile hydrothermal method. The photocatalyst was characterized by X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy, transmission electronic microscopy, UV-Vis diffusion reflectance spectroscopy, photoluminescence spectroscopy and UV Vis adsorption spectroscopy, respectively. The visible-light photocatalytic activity was evaluated by oxidation of methyl orange (MO) under simulated sunlight irradiation. The results show that the BiVO4-rGO nanocomposites exhibit enhanced photocatalytic performance for the degradation of MO with a maximum removal rate of 98.95% under visible light irradiation as compared with pure BiVO4 (57.55%) due to the increased light absorption intensity and the degradation of electron-hole pair recombination in BiVO4 with the introduction of the rGO. PMID- 28801659 TI - Relationship between higher-order wavefront aberrations and natural progression of myopia in schoolchildren. AB - This study investigated the relationship between higher-order aberrations (HOAs) and myopia progression as well as axial elongation in schoolchildren. We examined cycloplegic refraction, axial length, and wavefront aberrations prospectively in 71 myopic children. Changes in cycloplegic refraction and axial length during a 2 year study period were assessed, and their correlations with HOA components were analyzed. Sixty-four subjects ([mean +/- SD] 9.2 +/- 1.6 years) completed the 2 year examinations. Cycloplegic refraction was significantly changed after 2 years (P < 0.0001), and the average change (myopia progression) was -1.60 +/- 1.04 D. Axial length also increased significantly (P < 0.0001), and the average increase (axial elongation) was 0.77 +/- 0.40 mm. Myopia progression and axial elongation showed significant correlations with many components of corneal HOA (P < 0.0001 to P = 0.0270). Multivariate analysis showed that the total HOA of the cornea was the most relevant variable to myopia progression and axial elongation (P < 0.0001). Eyes with larger amounts of corneal HOAs showed less myopia progression and smaller axial elongation, suggesting that corneal HOAs play a role in the refractive and ocular developments in children. PMID- 28801661 TI - Statistical characterization of therapeutic protein modifications. AB - Peptide mapping with liquid chromatography-tandem mass spectrometry (LC-MS/MS) is an important analytical method for characterization of post-translational and chemical modifications in therapeutic proteins. Despite its importance, there is currently no consensus on the statistical analysis of the resulting data. In this manuscript, we distinguish three statistical goals for therapeutic protein characterization: (1) estimation of site occupancy of modifications in one condition, (2) detection of differential site occupancy between conditions, and (3) estimation of combined site occupancy across multiple modification sites. We propose an approach, which addresses these goals in terms of summarizing the quantitative information from the mass spectra, statistical modeling, and model based analysis of LC-MS/MS data. We illustrate the approach using an LC-MS/MS experiment from an antibody-drug conjugate and its monoclonal antibody intermediate. The performance was compared to a 'naive' data analysis approach, by using computer simulation, evaluation of differential site occupancy in positive and negative controls, and comparisons of estimated site occupancy with orthogonal experimental measurements of N-linked glycoforms and total oxidation. The results demonstrated the importance of replicated studies of protein characterization, and of appropriate statistical modeling, for reproducible, accurate and efficient site occupancy estimation and differential analysis. PMID- 28801663 TI - Acrodictys-like wood decay fungi from southern China, with two new families Acrodictyaceae and Junewangiaceae. AB - During our continuous survey (2012-2016) of saprobic hyphomycetes from dead branches in the forest ecosystems of southern China, we collected several acrodictys-like species. Acrodictys-like species are characterized by darkly pigmented and muriform conidia produced from holoblastic conidiogenous cells on macronematous, mononematous, cylindrical and unbranched or infrequently branched conidiophores. Phylogenetic analyses of ncLSU, ncSSU, ITS and tub2 sequence data lead us to propose two novel families in Sordariomycetes, Acrodictyaceae and Junewangiaceae. In addition, a new species, Acrodictys hainanensis, two new combinations, Junewangia queenslandica and Distoseptispora martinii, three new Chinese records, Acrodictys liputii, A. peruamazonensis and Junewangia sphaerospora are introduced. Two names, Acrodictys globulosa and A. malabarica, are resurrected. PMID- 28801662 TI - Nanometer size silicon particles for hyperpolarized MRI. AB - Hyperpolarized silicon particles have been shown to exhibit long spin-lattice relaxation times at room temperature, making them interesting as novel MRI probes. Demonstrations of hyperpolarized silicon particle imaging have focused on large micron size particles (average particle size (APS) = 2.2 MUm) as they have, to date, demonstrated much larger polarizations than nanoparticles. We show that also much smaller silicon-29 particles (APS = 55 +/- 12 nm) can be hyperpolarized with superior properties. A maximum polarization of 12.6% in the solid state is reported with a spin-lattice relaxation time of 42 min at room temperature thereby opening a new window for MRI applications. PMID- 28801664 TI - STAT3-induced long noncoding RNAs in multiple myeloma cells display different properties in cancer. AB - Interleukin-6 (IL-6)-activated Signal Transducer and Activator of Transcription 3 (STAT3) facilitates survival in the multiple myeloma cell line INA-6 and therefore represents an oncogenic key player. However, the biological mechanisms are still not fully understood. In previous studies we identified microRNA-21 as a STAT3 target gene with strong anti-apoptotic potential, suggesting that noncoding RNAs have an impact on the pathogenesis of human multiple myeloma. Here, we describe five long noncoding RNAs (lncRNAs) induced by IL-6-activated STAT3, which we named STAiRs. While STAiRs 1, 2 and 6 remain unprocessed in the nucleus and show myeloma-specific expression, STAiRs 15 and 18 are spliced and broadly expressed. Especially STAiR2 and STAiR18 are promising candidates. STAiR2 originates from the first intron of a tumor suppressor gene. Our data support a mutually exclusive expression of either STAiR2 or the functional tumor suppressor in INA-6 cells and thus a contribution of STAiR2 to tumorigenesis. Furthermore, STAiR18 was shown to be overexpressed in every tested tumor entity, indicating its global role in tumor pathogenesis. Taken together, our study reveals a number of STAT3-induced lncRNAs suggesting that the interplay between the coding and noncoding worlds represents a fundamental principle of STAT3-driven cancer development in multiple myeloma and beyond. PMID- 28801665 TI - Pulsed Laser Beam Welding of Pd43Cu27Ni10P20 Bulk Metallic Glass. AB - We used pulsed laser beam welding method to join Pd43Cu27Ni10P20 (at.%) bulk metallic glass and characterized the properties of the joint. Fusion zone and heat-affected zone in the weld joint can be maintained completely amorphous as confirmed by X-ray diffraction and differential scanning calorimetry. No visible defects were observed in the weld joint. Nanoindentation and bend tests were carried out to determine the mechanical properties of the weld joint. Fusion zone and heat-affected zone exhibit very similar elastic moduli and hardness when compared to the base material, and the weld joint shows high ductility in bending which is accomplished through the operation of multiple shear bands. Our results reveal that pulsed laser beam welding under appropriate processing parameters provides a practical viable method to join bulk metallic glasses. PMID- 28801666 TI - Small secreted proteins from the necrotrophic conifer pathogen Heterobasidion annosum s.l. (HaSSPs) induce cell death in Nicotiana benthamiana. AB - The basidiomycete Heterobasidion annosum sensu lato (s.l.) is considered to be one of the most destructive conifer pathogens in the temperate forests of the northern hemisphere. H. annosum is characterized by a dual fungal lifestyle. The fungus grows necrotrophically on living plant cells and saprotrophically on dead wood material. In this study, we screened the H. annosum genome for small secreted proteins (HaSSPs) that could potentially be involved in promoting necrotrophic growth during the fungal infection process. The final list included 58 HaSSPs that lacked predictable protein domains. The transient expression of HaSSP encoding genes revealed the ability of 8 HaSSPs to induce cell chlorosis and cell death in Nicotiana benthamiana. In particular, one protein (HaSSP30) could induce a rapid, strong, and consistent cell death within 2 days post infiltration. HaSSP30 also increased the transcription of host-defence-related genes in N. benthamiana, which suggested a necrotrophic-specific immune response. This is the first line of evidence demonstrating that the H. annosum genome encodes HaSSPs with the capability to induce plant cell death in a non-host plant. PMID- 28801667 TI - Microscopic Live Electrooptic Imaging. AB - Live electrooptic imaging (LEI) in the microscopic range has been successfully demonstrated for the first time. The finest resolution achieved in the present study is 2.7 MUm, which is finer than the previous record by more than an order of magnitude. This drastic improvement in the resolution record has been achieved through comprehensive improvement of the limiting factors of the conventional LEI system. Residual limiting factors in the improved system have been systematically analyzed and ideas for even finer resolution have also been presented. PMID- 28801668 TI - Exercise leads to unfavourable cardiac remodelling and enhanced metabolic homeostasis in obese mice with cardiac and skeletal muscle autophagy deficiency. AB - Autophagy is stimulated by exercise in several tissues; yet the role of skeletal and cardiac muscle-specific autophagy on the benefits of exercise training remains incompletely understood. Here, we determined the metabolic impact of exercise training in obese mice with cardiac and skeletal muscle disruption of the Autophagy related 7 gene (Atg7h&mKO). Muscle autophagy deficiency did not affect glucose clearance and exercise capacity in lean adult mice. High-fat diet in sedentary mice led to endoplasmic reticulum stress and aberrant mitochondrial protein expression in autophagy-deficient skeletal and cardiac muscles. Endurance exercise training partially reversed these abnormalities in skeletal muscle, but aggravated those in the heart also causing cardiac fibrosis, foetal gene reprogramming, and impaired mitochondrial biogenesis. Interestingly, exercise trained Atg7h&mKO mice were better protected against obesity and insulin resistance with increased circulating fibroblast growth factor 21 (FGF21), elevated Fgf21 mRNA and protein solely in the heart, and upregulation of FGF21 target genes involved in thermogenesis and fatty acid oxidation in brown fat. These results indicate that autophagy is essential for the protective effects of exercise in the heart. However, the atypical remodelling elicited by exercise in the autophagy deficient cardiac muscle enhances whole-body metabolism, at least partially, via a heart-brown fat cross-talk involving FGF21. PMID- 28801669 TI - Balance between Estrogens and Proinflammatory Cytokines Regulates Chemokine Production Involved in Thymic Germinal Center Formation. AB - The early-onset form of Myasthenia Gravis (MG) is prevalent in women and associates with ectopic germinal centers (GCs) development and inflammation in the thymus. we aimed to investigate the contribution of estrogens in the molecular processes involved in thymic GCs formation. We examined expression of genes involved in anti-acetylcholine receptor (AChR) response in MG, MHC class II and alpha-AChR subunit as well as chemokines involved in GC development (CXCL13, CCL21and CXCL12). In resting conditions, estrogens have strong regulatory effects on thymic epithelial cells (TECs), inducing a decreased protein expression of the above molecules. In knockout mouse models for estrogen receptor or aromatase, we observed that perturbation in estrogen transduction pathway altered MHC Class II, alpha-AChR, and CXCL13 expression. However, in inflammatory conditions, estrogen effects were partially overwhelmed by pro-inflammatory cytokines. Interestingly, estrogens were able to control production of type I interferon and therefore play dual roles during inflammatory events. In conclusion, we showed that estrogens inhibited expression of alpha-AChR and HLA-DR in TECs, suggesting that estrogens may alter the tolerization process and favor environment for an autoimmune response. By contrast, under inflammatory conditions, estrogen effects depend upon strength of the partner molecules with which it is confronted to. PMID- 28801670 TI - Ectodomain shedding of Limbic System-Associated Membrane Protein (LSAMP) by ADAM Metallopeptidases promotes neurite outgrowth in DRG neurons. AB - IgLONs are members of the immunoglobulin superfamily of cell adhesion proteins implicated in the process of neuronal outgrowth, cell adhesion and subdomain target recognition. IgLONs form homophilic and heterophilic complexes on the cell surface that repress or promote growth depending on the neuronal population, the developmental stage and surface repertoire of IgLON family members. In the present study, we identified a metalloproteinase-dependent mechanism necessary to promote growth in embryonic dorsal root ganglion cells (DRGs). Treatment of embryonic DRG neurons with pan-metalloproteinase inhibitors, tissue inhibitor of metalloproteinase-3, or an inhibitor of ADAM Metallopeptidase Domain 10 (ADAM10) reduces outgrowth from DRG neurons indicating that metalloproteinase activity is important for outgrowth. The IgLON family members Neurotrimin (NTM) and Limbic System-Associated Membrane Protein (LSAMP) were identified as ADAM10 substrates that are shed from the cell surface of DRG neurons. Overexpression of LSAMP and NTM suppresses outgrowth from DRG neurons. Furthermore, LSAMP loss of function decreases the outgrowth sensitivity to an ADAM10 inhibitor. Together our findings support a role for ADAM-dependent shedding of cell surface LSAMP in promoting outgrowth from DRG neurons. PMID- 28801671 TI - The CpG-sites of the CBX3 ubiquitous chromatin opening element are critical structural determinants for the anti-silencing function. AB - Suppression of therapeutic transgene expression from retroviral gene therapy vectors by epigenetic defence mechanisms represents a problem that is particularly encountered in pluripotent stem cells (PSCs) and their differentiated progeny. Transgene expression in these cells, however, can be stabilised by CpG-rich ubiquitous chromatin opening elements (UCOEs). In this context we recently demonstrated profound anti-silencing properties for the small (679 bp) CBX3-UCO element and we now confirmed this observation in the context of the defined murine chromosomal loci ROSA26 and TIGRE. Moreover, since the structural basis for the anti-silencing activity of UCOEs has remained poorly defined, we interrogated various CBX3 subfragments in the context of lentiviral vectors and murine PSCs. We demonstrated marked though distinct anti-silencing activity in the pluripotent state and during PSC-differentiation for several of the CBX3 subfragments. This activity was significantly correlated with CpG content as well as endogenous transcriptional activity. Interestingly, also a scrambled CBX3 version with preserved CpG-sites retained the anti-silencing activity despite the lack of endogenous promoter activity. Our data therefore highlight the importance of CpG-sites and transcriptional activity for UCOE functionality and suggest contributions from different mechanisms to the overall anti-silencing function of the CBX3 element. PMID- 28801672 TI - Sample entropy reveals an age-related reduction in the complexity of dynamic brain. AB - Dynamic reconfiguration of the human brain is characterized by the nature of complexity. The purpose of this study was to measure such complexity and also analyze its association with age. We modeled the dynamic reconfiguration process by dynamic functional connectivity, which was established by resting-state functional magnetic resonance imaging (fMRI) data, and we measured complexity within the dynamic functional connectivity by sample entropy (SampEn). A brainwide map of SampEn in healthy subjects shows larger values in the caudate, the olfactory gyrus, the amygdala, and the hippocampus, and lower values in primary sensorimotor and visual areas. Association analysis in healthy subjects indicated that SampEn of the amygdala-cortical connectivity decreases with advancing age. Such age-related loss of SampEn, however, disappears in patients with schizophrenia. These findings suggest that SampEn of the dynamic functional connectivity is a promising indicator of normal aging. PMID- 28801673 TI - Photosensitizer in lipid nanoparticle: a nano-scaled approach to antibacterial function. AB - Photosensitization-based antimicrobial therapy (PAT) is an alternative therapy aimed at achieving bacterial inactivation. Researchers use various photosensitizers to achieve bacterial inactivation. However, the most widely used approach involves the use of photosensitizers dispersed in aqueous solution, which could limit the effectiveness of photodynamic inactivation. Therefore, the approaches to encapsulate the photosensitizer in appropriate vehicles can enhance the delivery of the photosensitizer. Herein, Toluidine Blue O (TBO) was the photosensitizer, and lipid nanoparticles were used for its encapsulation. The lipid nanoparticle-based delivery system has been tailor-made for decreasing the average size and viscosity and increasing the formulation stability as well as the wettability of skin. Usage of an appropriate vehicle will also increase the cellular uptake of the photosensitizer into the bacterial cells, leading to the damage on cell membrane and genomic DNA. Evidence of effectiveness of the developed PAT on planktonic bacteria and biofilms was examined by fluorescence microscopy and scanning electron microscopy. Lipid nanoparticles protected the photosensitizer from aggregation and made the application easy on the skin as indicated in data of size distribution and contact angle. The use of lipid nanoparticles for encapsulating TBO could enhance photosensitization-based antimicrobial therapy as compared to the aqueous media for delivering photosensitizers. PMID- 28801674 TI - A new scoring model for the prediction of mortality in patients with acute kidney injury. AB - Currently, little information is available to stratify the risks and predict acute kidney injury (AKI)-associated death. In this present cross-sectional study, a novel scoring model was established to predict the probability of death within 90 days in patients with AKI diagnosis. For establishment of predictive scoring model, clinical data of 1169 hospitalized patients with AKI were retrospectively collected, and 731 patients of them as the first group were analyzed by the method of multivariate logistic regression analysis to create a scoring model and further predict patient death. Then 438 patients of them as the second group were used for validating this prediction model according to the established scoring method. Our results showed that Patient's age, AKI types, respiratory failure, central nervous system failure, hypotension, and acute tubular necrosis-individual severity index (ATN-ISI) score are independent risk factors for predicting the death of AKI patients in the created scoring model. Moreover, our scoring model could accurately predict cumulative AKI and mortality rate in the second group. In conclusion, this study identified the risk factors of 90-day mortality for hospitalized AKI patients and established a scoring model for predicting 90-day prognosis, which could help to interfere in advance for improving the quality of life and reduce mortality rate of AKI patients. PMID- 28801675 TI - Targeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancer. AB - P-glycoprotein (P-gp) is a drug transporter that effluxes chemotherapeutic drugs and is implicated in the development of resistance of cancer cells to chemotherapeutic drugs. To date, no drug has been approved to inhibit P-gp and restore chemotherapy efficacy. Moreover, majority of the reported inhibitors have high molecular weight and complex structures, making it difficult to understand the basic structural requirement for P-gp inhibition. In this study, two structurally simple, low molecular weight piperine analogs Pip1 and Pip2 were designed and found to better interact with P-gp than piperine in silico. A one step, acid-amine coupling reaction between piperic acid and 6,7 dimethoxytetrahydroisoquinoline or 2-(3,4-dimethoxyphenyl)ethylamine afforded Pip1 and Pip2, respectively. In vitro testing in drug resistant P-gp overexpressing KB (cervical) and SW480 (colon) cancer cells showed that both analogs, when co-administered with vincristine, colchicine or paclitaxel were able to reverse the resistance. Moreover, accumulation of P-gp substrate (rhodamine 123) in the resistant cells, a result of alteration of the P-gp efflux, was also observed. These investigations suggest that the natural product analog - Pip1 ((2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-1-(6,7-dimethoxy-3,4 dihydroisoquinolin-2(1 H)-yl)penta-2,4-dien-1-one) - is superior to piperine and could inhibit P-gp function. Further studies are required to explore the full potential of Pip1 in treating drug resistant cancer. PMID- 28801676 TI - Hyaluronic acid coatings as a simple and efficient approach to improve MSC homing toward the site of inflammation. AB - A major challenge in regenerative medicine is to improve therapeutic cells' delivery and targeting using an efficient and simple protocol. Mesenchymal stem cells (MSC) are currently employed for the treatment of inflammatory-based diseases, due to their powerful immunosoppressive potential. Here we report a simple and versatile method to transiently overexpress the hyaluronic acid (HA) receptor, CD44, on MSC membranes, to improve their homing potential towards an inflammatory site without affecting their behavior. The effect of HA-coatings on murine MSC was functionally determined both, in vitro and in vivo as a consequence of the transient CD44 overexpression induced by HA. Data obtained from the in vitro migration assay demonstrated a two-fold increase in the migratory potential of HA-treated MSC compared to untreated cells. In an LPS induced inflamed ear murine model, HA-treated MSC demonstrated a significantly higher inflammatory targeting as observed at 72 hrs as compared to untreated cells. This increased accumulation for HA-treated MSC yielded a substantial reduction in inflammation as demonstrated by the decrease in the expression of pro-inflammatory markers and by the induction of a pro-regenerative environment. PMID- 28801677 TI - Polyacrylamide-Phytic Acid-Polydopamine Conducting Porous Hydrogel for Efficient Removal of Water-Soluble Dyes. AB - Removal of toxic dyes from wastewater has become a hot topic in both academic and industrial fields since there is growing concern about the threat of sewage to human health. Herein, we demonstrate that the three-dimensional porous polyacrylamide-phytic acid-polydopamine (termed as PAAM/PA/PDA) hydrogel can be served as reusable adsorbent with high efficiency for either anionic or cationic dyes. Using methyl blue (MB), methylene blue (YMB), methyl violet (MV) and neutral red (NR) as model dyes, we investigate the effect of pH, temperature, dye concentration, and PAAM/PA/PDA hydrogel mass on the adsorption. The experimental maximum adsorption capacities are more than 350.67 mg g-1 for four selected dyes. Adsorption kinetic and thermodynamic analysis suggests that the dyes are adsorbed on the PAAM/PA/PDA hydrogel through the strong pi-pi stacking and anion-cation interaction, and the adsorption process satisfies a pseudo-second-order model. Furthermore, the free-standing PAAM/PA/PDA hydrogel can be easily removed from water after adsorption process, and regenerated by adjusting solution pH values. PMID- 28801678 TI - Ultra-fast Hygrometer based on U-shaped Optical Microfiber with Nanoporous Polyelectrolyte Coating. AB - Real-time measurement of the relative humidity of air has applications ranging from process control to safety. By using a microfiber form-factor, we demonstrate a miniature and fast-response hygrometer with the shortest-ever response time (3 ms). The sensor head consists of an optical microfiber of 10 um diameter and 2 mm length configured to form a compact U-shaped probe, and functionalized with a polyelectrolyte multilayer coating of 1.0 bilayer. The sensing mechanism is primarily water-absorption-based optical loss. We have measured a response time of 3 ms and a recovery time of 36 ms. The sensitivity is as high as 0.4%/%RH, and the detection limit is as low as 1.6%RH. The maximum relative humidity is 99%RH, before reaching a recoverable dew-point. PMID- 28801680 TI - Population pharmacokinetics of peginterferon alpha2a in patients with chronic hepatitis B. AB - There were significant differences in response and pharmacokinetic characteristics to the peginterferon alpha2a treatment among Chronic Hepatitis B (CHB) patients. The aim of this study is to identify factors which could significantly impact the peginterferon alpha2a pharmacokinetic characteristics in CHB patients. There were 208 blood samples collected from 178 patients who were considered as CHB and had been treated with peginterferon alpha2a followed by blood concentration measurement and other laboratory tests. The covariates such as demographic and clinical characteristics of the patients were retrieved from medical records. Nonlinear mixed-effects modeling method was used to develop the population pharmacokinetic model with NONMEM software. A population pharmacokinetic model for peginterferon alpha2a has been successfully developed which shows that distribution volume (V) was associated with body mass index (BMI), and drug clearance (CL) had a positive correlation with creatinine clearance (CCR). The final population pharmacokinetic model supports the use of BMI and CCR-adjusted dosing in hepatitis B virus patients. PMID- 28801679 TI - Improvement of a rapid diagnostic application of monoclonal antibodies against avian influenza H7 subtype virus using Europium nanoparticles. AB - The development of a sensitive and rapid diagnostic test is needed for early detection of avian influenza (AI) H7 subtype. In this study, novel monoclonal antibodies (mAbs) against influenza A H7N9 recombinant hemagglutinin (rHA)1 were developed and applied to a Europium nanoparticle-based rapid fluorescent immunochromatographic strip test (FICT) to improve the sensitivity of the rapid diagnostic system. Two antibodies (2F4 and 6D7) exhibited H7 subtype specificity in a dot-FICT assay by optimization of the conjugate and the pH of the lysis buffer. The subtype specificity was confirmed by an immunofluorescence assay and Western blot analysis. The limit of detection of the FICT employing novel mAbs 31 ng/mL for H7N9 rHA1 and 40 hemagglutination units/mL for H7 subtype virus. Sensitivity was improved 25-fold using Europium as confirmed by comparison of colloidal gold-based rapid diagnostic kit using the 2F4 and 6D7 mAbs. PMID- 28801681 TI - NRF1 and ZSCAN10 bind to the promoter region of the SIX1 gene and their effects body measurements in Qinchuan cattle. AB - The SIX1 homeobox gene belongs to the six homeodomain family and is widely thought to play a principal role in mediating of skeletal muscle development. In the present study, we determined that the bovine SIX1 gene was highly expressed in the longissimus thoracis and physiologically immature individuals. DNA sequencing of 428 individual Qinchuan cattle identified nine single nucleotide polymorphisms (SNPs) in the promoter region of the SIX1 gene. Using a series of 5' deletion promoter plasmid luciferase reporter assays and 5'-rapid amplification of cDNA end analysis (RACE), two of these SNPs were found to be located in the proximal minimal promoter region -216/-28 relative to the transcriptional start site (TSS). Correlation analysis showed the combined haplotypes H1-H2 (-GG-GA-) was significantly greater in the body measurement traits (BMTs) than the others, which was consistent with the results showing that the transcriptional activity of Hap2 was higher than the others in Qinchuan cattle myoblast cells. Furthermore, the electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation assay (ChIP) demonstrated that NRF1 and ZSCAN10 binding occurred in the promoter region of diplotypes H1-H2 to regulate SIX1 transcriptional activity. This information may be useful for molecular marker-assisted selection (MAS) in cattle breeding. PMID- 28801682 TI - Water ingestion decreases cardiac workload time-dependent in healthy adults with no effect of gender. AB - Ingestion of water entails a variety of cardiovascular responses. However, the precise effect remains elusive. We aimed to determine in healthy adults the effect of water on cardiac workload and to investigate potential gender differences. We pooled data from two controlled studies where blood pressure (BP) and heart rate (HR) were continuously recorded before and after the ingestion of 355 mL of tap water. Additionally, we calculated double product by multiplying systolic BP with HR and evaluated spectral parameters referring to vagal tone. All parameters were investigated for potential differences based on gender. In response to water, HR, systolic BP, and double product decreased significantly during the first 30 min. However, these effects were attenuated for HR and double product and even abolished for systolic BP over the subsequent 30 min. Over the entire post-drink period (60 min), decreases in HR and double product (all P < 0.05) were observed. Spectral markers for vagal tone increased with the on-set of the water drink and remained elevated until the end (P < 0.005). No significant gender difference in cardiac workload parameters was observed. We provide evidence that drinking water decreases, in a time-dependent fashion, cardiac workload and that these responses appear not to be influenced by gender. PMID- 28801685 TI - Investigation on Ti6Al4V-V-Cr-Fe-SS316 Multi-layers Metallic Structure Fabricated by Laser 3D Printing. AB - Joining titanium alloy and stainless steel is becoming an urgent need since their outstanding mechanical properties can be utilized integratedly. However, direct fusion joining of Ti6Al4V to SS316 can cause brittle Ti-Fe intermetallics which compromise join bonds' mechanical properties. In this research, Laser 3D Printing was applied to explore a new Ti6Al4V to SS316 multi-metallic structure. A novel filler transition route was introduced (Ti6Al4V -> V -> Cr -> Fe -> SS316) to avoid the Ti-Fe intermetallics. Two experimental cases were performed for comparison to evaluate this novel route's effect. In the first case, SS316 layer was directly deposited on Ti6Al4V substrate by laser 3D printing, but the sample cracked in the printing process. Then fracture morphology, phase identification, and micro-hardness were analyzed. In the second case, a multi-metallic structure was fabricated via laser 3D printing following the transition route. Microstructure characterization and composition distribution were analyzed via scanning electron microscope(SEM) and energy dispersive spectrometry(EDS). x-ray diffraction(XRD) tests demonstrated the intermetallics were effectively avoided following the transition route. Vickers hardness number(VHN) showed no significant hard brittle phases in the sample. Comparing with directly depositing SS316 on Ti6Al4V, the usage of the novel transition route can eliminate the intermetallics effectively. These research results are good contributions in joining titanium alloy and stainless steel. PMID- 28801683 TI - Regulation of tumour related genes by dynamic epigenetic alteration at enhancer regions in gastric epithelial cells infected by Epstein-Barr virus. AB - Epstein-Barr virus (EBV) infection is associated with tumours such as Burkitt lymphoma, nasopharyngeal carcinoma, and gastric cancer. We previously showed that EBV(+) gastric cancer presents an extremely high-methylation epigenotype and this aberrant DNA methylation causes silencing of multiple tumour suppressor genes. However, the mechanisms that drive EBV infection-mediated tumorigenesis, including other epigenomic alteration, remain unclear. We analysed epigenetic alterations induced by EBV infection especially at enhancer regions, to elucidate their contribution to tumorigenesis. We performed ChIP sequencing on H3K4me3, H3K4me1, H3K27ac, H3K27me3, and H3K9me3 in gastric epithelial cells infected or not with EBV. We showed that repressive marks were redistributed after EBV infection, resulting in aberrant enhancer activation and repression. Enhancer dysfunction led to the activation of pathways related to cancer hallmarks (e.g., resisting cell death, disrupting cellular energetics, inducing invasion, evading growth suppressors, sustaining proliferative signalling, angiogenesis, and tumour promoting inflammation) and inactivation of tumour suppressive pathways. Deregulation of cancer-related genes in EBV-infected gastric epithelial cells was also observed in clinical EBV(+) gastric cancer specimens. Our analysis showed that epigenetic alteration associated with EBV-infection may contribute to tumorigenesis through enhancer activation and repression. PMID- 28801684 TI - Structural Properties of Human IAPP Dimer in Membrane Environment Studied by All Atom Molecular Dynamics Simulations. AB - The aggregation of human islet amyloid polypeptide (hIAPP) can damage the membrane of the beta-cells in the pancreatic islets and induce type 2 diabetes (T2D). Growing evidences indicated that the major toxic species are small oligomers of IAPP. Due to the fast aggregation nature, it is hard to characterize the structures of IAPP oligomers by experiments, especially in the complex membrane environment. On the other side, molecular dynamics simulation can provide atomic details of the structure and dynamics of the aggregation of IAPP. In this study, all-atom bias-exchange metadynamics (BE-Meta) and unbiased molecular dynamics simulations were employed to study the structural properties of IAPP dimer in the membranes environments. A number of intermediates, including alpha-helical states, beta-sheet states, and fully disordered states, are identified. The formation of N-terminal beta-sheet structure is prior to the C terminal beta-sheet structure towards the final fibril-like structures. The alpha helical intermediates have lower propensity in the dimeric hIAPP and are off pathway intermediates. The simulations also demonstrate that the beta-sheet intermediates induce more perturbation on the membrane than the alpha-helical and disordered states and thus pose higher disruption ability. PMID- 28801686 TI - miR-12 and miR-124 contribute to defined early phases of long-lasting and transient memory. AB - MicroRNAs (miRNAs) are important epigenetic regulators of mRNA translation implicated in long-lasting synaptic plasticity and long-term memory (LTM). Since recent findings demonstrated a role of epigenetic regulation of gene expression in early memory phases we investigated whether epigenetic regulation by miRNAs also contributes to early memory phases. We used the olfactory associative learning paradigm in honeybees and addressed the contribution of miRNAs depending on the conditioning strength. We selected miR-12, miR-124, and miR-125 that have been implicated in processes of neuronal plasticity and analysed their contribution to non-associative and associative learning using miRNA inhibitors. Blocking miR-12, miR-124, or miR125 neither affects gustatory sensitivity nor habituation nor sensitization. Blocking the function of miR-12 and miR-124 during and shortly after 3-trial conditioning impairs different early memory phases. Although different, the function of miR-12 and miR-124 is also required for early phases of transient memory that is induced by 1-trial conditioning. Blocking miR 125 has no effect on early memory independent of the conditioning strength. These findings demonstrate that distinct miRNAs contribute to early phases of both, transient memories as well as long-lasting memories. PMID- 28801687 TI - Human Mesenchymal Stromal Cell Sheet Enhances Allograft Repair in a Mouse Model. AB - To determine whether cell sheets generated with long-term passaged (P10) aging human mesenchymal stromal cells (MSCs) could be used for bone tissue regeneration as tissue engineered periosteum in a femoral allograft mouse model similar to fresh passaged (P3) young MSCs. At 3 weeks after transplantation of MSC sheets, results showed more bony callus formed between allograft and host bone ends in both young P3 MSC and aged P10 MSC sheet-wrapped groups when compared to allograft alone. At 6 weeks, while both MSC sheet-wrapped allografts showed more bony callus formation when compared to allograft alone groups, the bony callus size in aged P10 MSC sheet groups was significantly less than young P3 MSC sheet groups. Biomechanical testing confirmed that P3 MSC sheet-grafted femurs had the highest biomechanical strength in the three groups. Histology sections showed that the area of the chondriod callus in the aged P10 MSC sheet groups was significantly larger than in P3 MSC sheet groups. Finally, a significant increase of chondro-osteoclast activity was observed in the P3 MSC sheet-grafted femur. Our data demonstrates that extensive long-term culture-induced MSC aging impaired their osteogenic ability and subsequent bony callus formation, and could be used to induce cartilaginous callus formation. PMID- 28801689 TI - A child with macroscopic crystalluria: Questions. PMID- 28801688 TI - [Tricuspid valve regurgitation : Indications and operative techniques]. AB - Functional tricuspid valve (TV) regurgitation secondary to left heart disease (e.g. mitral insufficiency and stenosis) is observed in 75% of the patients with TV regurgitation and is thus the most common etiology; therefore, the majority of patients who require TV surgery, undergo concomitant mitral and/or aortic valve surgery. Uncorrected moderate and severe TV regurgitation may persist or even worsen after mitral valve surgery, leading to progressive heart failure and death. Patients with moderate to severe TV regurgitation show a 3-year survival rate of 40%. Surgery is indicated in patients with severe TV regurgitation undergoing left-sided valve surgery and in patients with severe isolated primary regurgitation without severe right ventricular (RV) dysfunction. For patients requiring mitral valve surgery, tricuspid valve annuloplasty should be considered even in the absence of significant regurgitation, when severe annular dilatation (>=40 mm or >21 mm/m2) is present. Functional TV regurgitation is primarily treated with valve reconstruction which carries a lower perioperative risk than valve replacement. Valve replacement is rarely required. Tricuspid valve repair with ring annuloplasty is associated with better survival and a lower reoperation rate than suture annuloplasty. Long-term results are not available. The severity of the heart insufficiency and comorbidities (e.g. renal failure and liver dysfunction) are the essential determinants of operative mortality and long-term survival. Tricuspid valve reoperations are rarely necessary and associated with a considerable mortality. PMID- 28801691 TI - A new data processing routine facilitating the identification of surface adhered proteins from bacterial conditioning films via QCM-D/MALDI-ToF/MS. AB - Conditioning films are an important factor in the initiation and development of microbial biofilms, which are the leading cause of chronic infections associated with medical devices. Here, we analyzed the protein content of conditioning films formed after exposure to supernatants of cultures of the human pathogen Pseudomonas aeruginosa PAO1. Adhesion of substances from the supernatant was monitored using quartz crystal microbalance with dissipation monitoring (QCM-D) sensor chips modified with the commonly used implant material titanium dioxide (TiO2). Attached proteins were identified after on-chip digestion using matrix assisted laser desorption/ionization (MALDI) time of flight (ToF) mass spectrometry (MS), and a new data processing tool consisting of an XML-database with theoretical tryptic peptides of every PAO1 protein and PHP scripts. Sub databases containing only proteins, that we found in all replicates, were created and used for MS/MS precursor selection. The obtained MS/MS peaklists were then matched against theoretical fragmentations of the expected peptide sequences to verify protein identification. Using this approach we were able to identify 40 surface-associated proteins. In addition to extracellular proteins such as adhesins, a number of intra-cellular proteins were identified which may be involved in conditioning film formation, suggesting an as-yet unidentified role for these proteins, possibly after cell lysis. Graphical Abstract Flowchart of the method. PMID- 28801690 TI - Ethical issues in obesity prevention for school children: a systematic qualitative review. AB - OBJECTIVES: Planning and conducting preventive measures against obesity for school children is beset with ethical issues which should be known to make well informed decisions. The goal of this study was to provide a comprehensive spectrum of these ethical issues by means of a systematic review. In this context, the study also assesses the value of different search strategies for ethical literature in public health. METHODS: Literature was searched in Medline, EBSCO and others. Three different search strategies with varied scopes were applied and their output was compared. Qualitative content analysis was used for extracting and categorizing ethical issues. RESULTS: 109 publications (published from 1995 to 2015) were finally included. The qualitative analysis resulted in 60 potentially relevant ethical issues. The three search strategies showed substantial differences regarding their search results. CONCLUSIONS: The presented spectrum provides an initial evidence base for dealing with ethical issues adequately. The findings of the study further suggest that a broader scope is more fruitful for systematic reviews on ethical issues in the field of public health. PMID- 28801692 TI - [Urethral centralization and pseudo-glans formation after partial penectomy]. AB - The management of penile cancer has altered dramatically over the last decade. Confidence to excise lesions safely with smaller margins has led to the adoption of penile-preserving techniques and in turn improved the functional and cosmetic results. Patients undergoing partial penectomy (PP) find that the urethral meatus is located in an abnormal ventral position. In addition, there is a high risk of meatal stenosis. We describe our novel technique that allows the urethral meatus to be centralised after PP and creation of a pseudo-glans and wide meatus and therefore maintain the cosmetic appearance of the penis after split thickness skin grafting. The UCAPP technique allows the restoration of the normal meatal location and creation of a pseudo-glans in case of partial penectomy and therefore can improve the overall cosmetic appearance and reduce the psychological morbidity. PMID- 28801693 TI - Grading of diffuse astrocytic gliomas: Broders, Kernohan, Zulch, the WHO... and Shakespeare. PMID- 28801694 TI - Work overcommitment: Is it a trait or a state? AB - PURPOSE: Effort-reward imbalance (ERI) is a well-tested work-related stress model with three components, the two extrinsic components "efforts" and "rewards" and the one intrinsic component "overcommitment". While an imbalance between "efforts" and "rewards" leads to strain reactions, "work-related overcommitment" (OC) has been described as a personal characteristic with a set of attitudes, behaviours, and emotions reflecting excessive striving combined with a strong desire for approval. However, the question whether OC is a personality trait or a response pattern sensitive to changes in the work context (state) is still open. METHODS: 2940 Swedish industrial employees were included in this longitudinal analysis of the WOLF-Norrland data over 5 years. A change of OC index or its subscales were regressed against a change of freedom of choice at work, extra work, and ERI adjusted for age, sex, and education. RESULTS: While OC was insensitive to changes in freedom of choice at work and extra work, it was clearly associated with changes of work-related stress over time. Three of four OC subscales exhibited statistically significant associations with ERI. CONCLUSIONS: For the first time, we studied fundamental characteristics of OC as an independent personality variable (trait) or an outcome variable subject to changes in the work environment (state). The association between external ERI and OC over time supports our hypothesis of OC being a state. Further investigations are needed to establish OC as a trait or a state. PMID- 28801695 TI - A child with macroscopic crystalluria: Answers. PMID- 28801696 TI - Clonorchis sinensis infection and co-infection with the hepatitis B virus are important factors associated with cholangiocarcinoma and hepatocellular carcinoma. AB - To evaluate the contributions of Clonorchis sinensis and hepatitis B virus to the development of cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC), C. sinensis and hepatitis B virus infections in 20 clinical liver cancer cases from a C. sinensis- and hepatitis B virus-epidemic region were detected. Eight cases of ICC, 11 cases of HCC and one mixed ICC and HCC case were verified by CT, pathological section and (or) observations during surgery. The C. sinensis infection was detected by stool microscopy and ELISA, and the worms and eggs found during surgery and in pathological sections also allowed for diagnoses. Hepatitis B virus infections were detected by ELISA. In the 20 cases, 18 patients were diagnosed with C. sinensis infections. Eight of the 20 patients were infected with the hepatitis B virus, and seven were co-infected with C. sinensis. In the eight ICC patients, seven were diagnosed with C. sinensis infection, and two had mixed infections with the hepatitis B virus. In the 11 HCC patients, 10 were diagnosed with C. sinensis, four had mixed infections with the hepatitis B virus, and only one HCC patient presented a single infection by the hepatitis B virus. These clinical observations revealed that C. sinensis infection and C. sinensis co-infection with the hepatitis B virus are important factors in ICC and HCC. PMID- 28801697 TI - Low Hartmann's procedure or intersphincteric proctectomy for distal rectal cancer: a retrospective comparative cohort study. AB - PURPOSE: Two non-restorative options for low rectal cancer not invading the sphincter are the low Hartmann's procedure (LH) or intersphincteric proctectomy (IP). The aim of this study was to compare postoperative morbidity with emphasis on pelvic abscesses after LH and IP. METHODS: All patients that had LH or IP for low rectal cancer were included in three centres between 2008 and 2014 in this retrospective cohort study. Follow-up was performed for at least 12 months. RESULTS: A total of 52 patients were included: 40 LH and 12 IP. Median follow-up was 29 months (IQR 23). There were no differences between groups in gender, age and ASA classification. Seven patients in the LH group (18%) and four patients in the IP group (33%) developed a complication within 30-day postoperative with a Clavien-Dindo classification grade III or higher (P = 0.253). Four out of 40 patients (10%) in the LH group and two out of 12 patients (17%) in the IP group developed a pelvic abscess (P = 0.612). Reinterventions were performed in 11 (28%) patients in the LH group and five (42%) patients in the IP group (P = 0.478), with a total number of reinterventions of 13 and 20, respectively. Six and 15 interventions were related to pelvic abscesses, respectively. CONCLUSION: Pelvic abscesses seem to occur in a similar rate after both LH and IP. Previous reports from the literature suggesting that IP might be associated with less infectious pelvic complications compared to LH are not supported by this study, although numbers are small. PMID- 28801698 TI - Association between dementia and reduced walking ability and 30-day mortality in patients with extended-spectrum beta-lactamase-producing Escherichia coli bacteremia. AB - Previous studies have shown controversial results of factors associated with short-term mortality in patients with extended-spectrum beta-lactamase (ESBL) producing E. coli bacteremia and no research has investigated the impact of the geriatric assessment criteria on short-term mortality. Our objective was to determine whether dementia and walking ability are associated with 30-day mortality in patients with ESBL-producing E. coli bacteremia. All blood bottle cultures, analyzed from January 2008 to April 2015, in the Bacteriology Department of a 2,600-bed, university-affiliated center, Nantes, France, were retrospectively extracted. Factors associated with short-term mortality in patients with ESBL-producing E. coli bacteremia: 140 patients with an ESBL producing E. coli bloodstream infection were included; 22 (15.7%) patients died within 30 days following the first positive blood bottle culture of ESBL producing E.coli. In multivariate analysis, a reduced ability to walk (OR = 0.30; p = 0.021), presence of dementia (OR = 54.51; p = 0.040), a high Sepsis-related Organ Failure Assessment (SOFA) score (OR = 1.69; p < 0.001), presence of neutropenia (OR = 12.94; p = 0.049), and presence of a urinary tract infection (OR = 0.07; p = 0.036), were associated with 30-day mortality. Our findings provide new data showing an independent association between 30-day mortality with dementia and reduced walking ability, in patients with ESBL-producing E. coli bacteremia. These criteria should be considered in the therapeutic management of patients with ESBL-producing E. coli bacteremia. PMID- 28801699 TI - Use of subconjunctival injections of 5-fluorouracil to rescue and prolong intraocular pressure reduction for a failing Ahmed glaucoma implant. PMID- 28801701 TI - The overexpression of Hsp90B1 is associated with tumorigenesis of canine mammary glands. AB - Heat shock proteins (Hsp) are molecular chaperones that are responsible for protein folding and maintenance of cellular homeostasis. Hsp90, an important member of HSP family, has an important role in breast cancer. Glucose-regulated protein 94 (Grp94) is the endoplasmic reticulum paralog of Hsp90 encoded by Hsp90B1 gene. To test if this protein is overexpressed in dogs with mammary tumor, we estimated and compared its serum levels in healthy dogs and that of dogs with mammary tumors. Hsp90B1 mRNA expression was measured in tumorous and healthy mammary tissues (from age- and breed-matched dogs) by real-time PCR. The gene was found to be overexpressed in mammary tumors (3.586 +/- 0.067 times). Further, it was heterologously expressed in a prokaryotic system as 90 kDa protein. A recombinant Grp94-based sandwich ELISA was developed to quantify serum Grp94 in dogs with mammary tumors. Based on receiver-operating characteristics' analysis, the assay was found to be 90.62% sensitive and 93.75% specific for a cutoff value of 0.35 with respect to histopathological staining in diagnosing the disease. The t test showed that serum Grp94 levels were significantly elevated (92.97 +/- 3.62 ng/ml) in dogs with mammary tumors compared with healthy controls (10.30 +/- 0.79 ng/ml) (p < 0.0001). These findings suggest that Grp94 might act as a potential biomarker for prognosis of canine mammary tumors and monitoring its therapy. PMID- 28801700 TI - Evaluation of the learning curve of non-penetrating glaucoma surgery. AB - PURPOSE: To evaluate the learning curve of non-penetrating glaucoma surgery (NPGS). METHODS: The study included 32 eyes of 27 patients' (20 male and 7 female) with medically uncontrolled glaucoma. Non-penetrating glaucoma surgeries performed by trainees under control of an experienced surgeon between 2005 and 2007 at our tertiary referral hospital were evaluated. Residents were separated into two groups. Humanistic training model applied to the one in the first group, he studied with experimental models before performing NPGS. Two residents in the second group performed NPGS after a conventional training model. Surgeries of the residents were recorded on video and intraoperative parameters were scored by the experienced surgeon at the end of the study. Postoperative intraocular pressure, absolute and total success rates were analyzed. RESULTS: In the first group 19 eyes of 16 patients and in the second group 13 eyes of 11 patients had been operated by residents. Intraoperative parameters and complication rates were not statistically significant between groups (p > 0.05, Chi-square). The duration of surgery was 32.7 +/- 5.6 min in the first group and 45 +/- 3.8 min in the second group. The difference was statistically significant (p < 0.001, Student's t test). Absolute and total success was 68.8 and 93.8% in the first group and 62.5 and 87.5% in the second group, respectively. The difference was not statistically significant. CONCLUSIONS: Humanistic and conventional training models under control of an experienced surgeon are safe and effective for senior residents who manage phacoemulsification surgery in routine cataract cases. Senior residents can practice these surgical techniques with reasonable complication rates. PMID- 28801702 TI - Paeonol attenuates aging MRC-5 cells and inhibits epithelial-mesenchymal transition of premalignant HaCaT cells induced by aging MRC-5 cell-conditioned medium. AB - Senescence-associated secretory phenotype (SASP) factors, such as IL-6 and IL-8, are extremely critical in tissue microenvironment. Senescent human fibroblasts facilitate epithelial-mesenchymal transition (EMT) in premalignant epithelial cells mainly through the secretion of SASP factors. Meanwhile, premalignant human HaCaT Keratinocyte (HaCaT) cells as immortal epithelial cells are susceptible to malignant transformation. Paeonol, an herbal phenolic component found in peonies, exerts anti-aging and anti-tumor efficacies, while the molecular mechanisms of paeonol on EMT in premalignant HaCaT cells induced by SASP factors are unclear. In this study, we first established a senescent human fetal lung fibroblast MRC-5 cell model using hydrogen peroxide evaluated by senescence-associated beta galactosidase assay. Upon paeonol treatment, intracellular reactive oxygen species levels in aging MRC-5 cells were significantly decreased via regulation of nuclear translocation of Nrf2. Then we curiously studied whether the aging MRC 5 cell-conditioned medium could induce EMT in premalignant HaCaT cells, and the results showed that paeonol significantly reduced the clonogenic, migratory, and invasive capacities of premalignant HaCaT cells potentially induced by IL-6 and IL-8. Moreover, we found that paeonol notably altered pluripotency of EMT associated markers via the modulation of ERK and TGF-beta1/Smad pathway in premalignant HaCaT cells. These findings suggest that paeonol may be used as an adjuvant therapy for SASP factor-mediated EMT in premalignant lesion. PMID- 28801703 TI - The Long-Term Effects of Bariatric Surgery on Type 2 Diabetes Remission, Microvascular and Macrovascular Complications, and Mortality: a Systematic Review and Meta-Analysis. AB - This systematic review aimed to evaluate the long-term (>= 5 years) outcomes of bariatric surgery on diabetes remission, microvascular and macrovascular events, and mortality among type 2 diabetes (T2D) patients. Ten articles (one randomized controlled trial and nine cohorts) met the inclusion criteria and were included in this review. Pooled estimates of nine cohort studies showed that surgery significantly increased the diabetes remission (relative risk (RR) = 5.90; 95% CI 3.75-9.28), reduced the microvascular (RR = 0.37; 95% CI = 0.30-0.46) and macrovascular events (RR = 0.52; 95% CI 0.44-0.61), and mortality (RR = 0.21; 95% CI 0.20-0.21) as compared to non-surgical treatment. Available evidence suggests better remission and lower risks of microvascular and macrovascular disease and mortality in the surgery group as compared to non-surgical treatment group in T2D patients after at least 5 years of follow-up. PMID- 28801705 TI - Gastrointestinal motility in people with type 1 diabetes and peripheral neuropathy. PMID- 28801704 TI - No clinical differences between anteromedial portal and transtibial technique for femoral tunnel positioning in anterior cruciate ligament reconstruction: a prospective randomized, controlled trial. AB - PURPOSE: The anteromedial (AMP) portal technique was introduced to position the femoral tunnel in anterior cruciate ligament (ACL) reconstruction to more closely replicate the original ACL footprint compared to the transtibial (TT) approach. Few randomized trials have evaluated differences in these techniques with respect to clinical outcomes. The purpose of this study was to determine if there are any differences in clinical outcome between the AMP and TT approaches. METHODS: This is a single-blinded, prospective, randomized controlled trial. Participants were randomized to undergo ACL reconstruction using the AMP or TT approach. The primary outcome measure was the ACL quality of life (ACL-QOL), and secondary outcomes were the IKDC knee assessment, side-to-side difference in anterior posterior knee laxity (KT-1000) and tunnel orientation (X-ray findings) at preoperative, 3, 6, 12, and 24 months postoperative. Statistical comparisons were performed using a series of t tests for independent groups with equal variance. RESULTS: Ninety-six participants were consented and randomized between 2007 and 2011 with eight excluded postrandomization. Mean (SD) preoperative ACL-QOL was 33 (13) for TT and 36 (17) for AMP and improved significantly (p < 0.001) in both groups to 79 (18) and 78 (18) at 24 months postoperative, respectively. The preoperative median IKDC grade for both groups was C and improved similarly in both groups at 24 months (n.s.). There was no side-to-side difference in knee laxity based on KT-1000 measurements with a mean (SD) 1 (3) mm between affected and unaffected limbs in the TT group compared to 1 (3) mm for the AMP group. A significant difference was found in femoral tunnel orientation with the AMP group at 43 degrees (7) and the TT group 58 degrees (8) in the coronal plane (p < 0.001). CONCLUSION: No differences in clinical outcome were found when comparing AMP to TT in primary ACL reconstruction using a STG graft. This prospective randomized controlled trial suggests surgeons can use either method without significantly compromising clinical outcome. LEVEL OF EVIDENCE: I. PMID- 28801706 TI - Seasonal Distribution, Source Identification, and Toxicological Risk Assessment of Polycyclic Aromatic Hydrocarbons (PAHs) in Sediments from Wadi El Bey Watershed in Tunisia. AB - Surface sediments were collected from the Watershed of Wadi El Bey in Tunisia to evaluate the degree of polycyclic aromatic hydrocarbons (PAHs) contamination. Sediments were collected during different seasons in 14 sites that received wastes from domestic effluent, industrial discharge, and agricultural drainage wastes. Twenty-six individual PAHs were analyzed. The total PAH contents (Sigma PAHs) in surface sediments showed wide variability, ranging from 6.89 +/- 0.05 to 340 +/- 0.1 ng g-1. The 4-, 5-, and 6-ring compounds were the most abundant PAHs detected at the majority of sites. Diagnostic concentration ratios between pairs of PAHs and molecular indices, calculated with the purpose of drawing information about pollution sources, indicated that PAHs were of both petrogenic and pyrolytic origins. Toxic contaminants concentrations were determined according to the numerical effect-based sediment quality guidelines (SQGs). PAH levels did not exceed the SQGs, indicating that PAHs seem to pose low and occasional toxicity risks. Total carcinogenicity and mutagenicity (TEQBaP and MEQBaP) ranged from 0.08 to 65 ng and from 0.02 to 135.0 ng g-1 of dry weight, respectively. Among the seven carcinogenic PAHs, BaP accounted for the majority of the potency and could potentially be used as a unique indicator of PAH toxicity. This study provides a baseline to promote environmental protection programs and pollution monitoring/control in Watershed and coastal areas. PMID- 28801707 TI - Association Between Anticholinergic Drug Use and Health-Related Quality of Life in Community-Dwelling Older Adults. AB - BACKGROUND: The use of drugs with anticholinergic properties (AC drugs) has been associated with decreased functioning and impaired cognition in older adults. Studies assessing the association between AC-drug use and health-related quality of life (HRQoL) show conflicting results. OBJECTIVE: The aim was to evaluate the association between AC-drug use and HRQoL in community-dwelling older adults. METHODS: The NuAge cohort study enrolled 1793 men and women aged 68-82 years. The participants were free of disabilities in activities of daily living, not cognitively impaired at recruitment and followed annually for 3 years (December 2003-May 2005). AC-drug exposure was assessed using the Anticholinergic Cognitive Burden Scale (ACBS). HRQoL was assessed using the physical (PCS) and mental (MCS) component summaries of the 36-item Short Form Survey (SF-36) questionnaire. The association between AC drug and HRQoL was determined by a mixed model analysis using four annual time points. RESULTS: At recruitment the mean age was 74.4 +/- 4.2 years, 52% were female and 33% of participants were prescribed at least one AC drug. The mean PCS and MCS (/100) scores were 49.0 +/- 8.2 and 54.9 +/- 8.1, respectively. In the mixed model analysis, an increase of 1 on the ACBS was associated with a decrease of -0.50 (95% CI -0.68 to -0.31) in the PCS and an increase of 0.19 (95% CI 0.01-0.37) in the MCS. CONCLUSIONS: In a cohort of generally healthy community-dwelling older adults, AC-drug exposure was associated with a statistically significant decrease in the PCS and increase in the MCS throughout the entire follow-up period. However, the effects on the PCS and MCS were small and likely not clinically relevant. PMID- 28801708 TI - Characterizing Particulate Matter Exfiltration Estimates for Alternative Cookstoves in a Village-Like Household in Rural Nepal. AB - Alternative stoves are an intervention option to reduce household air pollution. The amount of air pollution exiting homes when alternative stoves are utilized is not known. In this paper, particulate matter exfiltration estimates are presented for four types of alternative stoves within a village-like home, which was built to reflect the use of local materials and common size, in rural Nepal. Four alternative stoves with chimneys were examined, which included an alternative mud brick stove, original Envirofit G3355 model, manufacture altered Envirofit G3355, and locally altered Envirofit G3355. Multiple linear regression was utilized to determine estimates of PM2.5 exfiltration. Overall exfiltration fraction average (converted to a percent) for the four stoves were: alternative mud brick stove with chimney 56%, original Envirofit G3355 model with chimney 87%, manufacture altered Envirofit G3355 model with chimney 69%, and locally altered Envirofit G3355 model with chimney 69%. Alternative cookstoves resulted in higher overall average exfiltration due to direct and indirect ventilation relative to traditional, mud-based stoves. This contrast emphasizes the need for an improved understanding of the climate and health implications that are believed to come from implementing alternative stoves on a large scale and the resultant shift of exposure burden from indoors to outdoors. PMID- 28801709 TI - DEX implant intravitreal injection, sustained intraocular hypertension, and steroid-induced glaucoma in patients with no risk factors. PMID- 28801710 TI - Randomized controlled trial of EndoWrist-enabled robotic versus human laparoendoscopic single-site access surgery (LESS) in the porcine model. AB - INTRODUCTION: A robotic laparoendoscopic single-site access surgery (R-LESS) platform that incorporates the EndoWrist function of robotic instruments may provide better triangulation and retraction during LESS. The aim of the study is to assess if R-LESS is feasible with standard robotic instruments via a single incision and whether the approach could reduce the difficulty of the procedure and confer additional benefits over conventional LESS. METHODS: This was a prospective randomized controlled study investigating the workload performance, efficacy, and risks of performing R-LESS when compared with human LESS (H-LESS) in a survival porcine model for cholecystectomy and gastrojejunostomy. The primary outcome is the NASA task load index. Secondary outcomes included the difficulty of the procedures, procedural time, morbidities, and mortalities. RESULTS: Twenty-four cholecystectomies and gastrojejunostomies using the R-LESS or H-LESS approach (12:12) were performed. None of the swine suffered from procedural adverse events and none of the procedures required conversion. In both the cholecystectomy and gastrojejunostomy groups, R-LESS was associated with significantly lower NASA task load index (P < 0.001) and reduced difficulties in various steps of the procedures. No differences in the overall procedure times of the two procedures were observed (P = 0.315). CONCLUSION: The R-LESS approach significantly reduced the workload and difficulties of LESS cholecystectomies and gastrojejunostomies. A dedicated single-site platform that could reduce instrument clashing while retaining the EndoWrist function is eagerly awaited. PMID- 28801711 TI - Safety of Onyx Transarterial Embolization of Skull Base Dural Arteriovenous Fistulas from Meningeal Branches of the External Carotids also Fed by Meningeal Branches of Internal Carotid or Vertebral Arteries. AB - PURPOSE: To analyze the angiographic and clinical results of transarterial embolization with Onyx (Medtronic-Covidien, Irvine, CA) in dural arteriovenous fistulas (DAVFs) partially fed by arteries arising from the carotid siphon or the vertebral arteries. METHODS: We isolated 40 DAVFs supplied by either the tentorial artery of the internal carotid artery (ICA) or the posterior meningeal artery of the vertebral artery. These DAVFs were embolized with Onyx through the middle meningeal artery or the occipital artery. We reviewed the occurrence of reflux into the arteries of carotid or vertebral origin. RESULTS: In all the cases, reflux occurred into the first millimeters of the DAVF arterial feeders arising from carotid or vertebral arteries but slowly enough to be controlled by interruption of Onyx injection. Reflux was always minimal and Onyx never reached the ostium of the arteries. No cerebral ischemic complications occurred in our series. CONCLUSION: The behavior of Onyx is clearly different from that of cyanoacrylate glue, resulting in superior control during injection. Reflux into arteries arising from the ICA or vertebral artery during DAVF treatment always carries a risk of unintentional non-target embolization of normal cerebral vasculature but Onyx appears to be safe in this situation. PMID- 28801712 TI - Design and characterization of alcalase-chitosan conjugates as potential biocatalysts. AB - In this study, alcalase (protease from Bacillus licheniformis) immobilization by adsorption, enzyme crosslinking and covalent enzyme binding to activated chitosan microbeads were examined. The biocatalysts highest activity was obtained by covalent immobilization of alcalase onto a solid support. The alcalase covalent immobilization onto different types of chitosan beads obtained by inverse emulsion technique and electrostatic extrusion was studied. Parameters examined under different conditions were beads diameter, enzyme loading, enzyme capacity yield, and biocatalyst activity. The highest activity and enzyme loading of 23.6 IU/mg protein and 340.2 mg/g, respectively, were achieved by the enzyme immobilized onto chitosan microbeads obtained by the electrostatic extrusion technique. FT-IR analysis was used to confirm formation of alcalase-chitosan conjugates. The activity of optimally produced alcalase-chitosan microbeads was then verified in the industrially feasible reaction systems of egg white and soy protein hydrolysis. The high degree of hydrolysis of 29.85 +/- 0.967% after 180 min and five successive reuses obtained under real conditions (50 degrees C, pH 8) verified the covalently bound alcalase to chitosan beads a promising candidate for use in industrial egg white protein hydrolysis process. PMID- 28801713 TI - Cross-reactivity profiles of legumes and tree nuts using the xMAP(r) multiplex food allergen detection assay. AB - The homology between proteins in legumes and tree nuts makes it common for individuals with food allergies to be allergic to multiple legumes and tree nuts. This propensity for allergenic and antigenic cross-reactivity means that commonly employed commercial immunodiagnostic assays (e.g., dipsticks) for the detection of food allergens may not always accurately detect, identify, and quantitate legumes and tree nuts unless additional orthogonal analytical methods or secondary measures of analysis are employed. The xMAP(r) Multiplex Food Allergen Detection Assay (FADA) was used to determine the cross-reactivity patterns and the utility of multi-antibody antigenic profiling to distinguish between legumes and tree nuts. Pure legumes and tree nuts extracted using buffered detergent displayed a high level of cross-reactivity that decreased upon dilution or by using a buffer (UD buffer) designed to increase the stringency of binding conditions and reduce the occurrence of false positives due to plant-derived lectins. Testing for unexpected food allergens or the screening for multiple food allergens often involves not knowing the identity of the allergen present, its concentration, or the degree of modification during processing. As such, the analytical response measured may represent multiple antigens of varying antigenicity (cross-reactivity). This problem of multiple potential analytes is usually unresolved and the focus becomes the primary analyte, the antigen the antibody was raised against, or quantitative interpretation of the content of the analytical sample problematic. The alternative solution offered here to this problem is the use of an antigenic profile as generated by the xMAP FADA using multiple antibodies (bead sets). By comparing the antigenic profile to standards, the allergen may be identified along with an estimate of the concentration present. Cluster analysis of the xMAP FADA data was also performed and agreed with the known phylogeny of the legumes and tree nuts being analyzed. Graphical abstract The use of cluster analysis to compare the multi-antigen profiles of food allergens. PMID- 28801714 TI - Parthenolide attenuates 7,12-dimethylbenz[a]anthracene induced hamster buccal pouch carcinogenesis. AB - Over the decades, the survival rates for oral cancer have not improved despite development in novel diagnostic and therapeutic strategies. Therefore, the present study is aimed at investigating the chemopreventive potential of parthenolide in DMBA-induced hamster buccal pouch carcinogenesis. The hamsters were divided into 4 groups (n = 6/group). Group I was treated as control. Groups II and III were painted with a solution of 0.5% DMBA three times per week for 14 weeks on the left buccal pouches. In addition, group III were orally administrated with parthenolide 2 mg/kg b.w on days alternate to the DMBA application. Group IV received only parthenolide. At the end of 14th week all hamsters were sacrificed. Buccal tissues from all hamsters were evaluated for histopathology. Biochemical studies were carried out using plasma, liver, and buccal mucosa of control and experimental hamsters. Gene and protein expression studies of apoptotic markers p53, Bcl-2, and Bax were performed. The results showed 100% tumor formation and marked alterations in histopathology, status of detoxification enzymes, lipid peroxidation, and antioxidant profile in group II hamsters. Oral administration of parthenolide completely prevented tumor formation and significantly reduced the severity of histopathological changes in group III hamsters. The status of detoxification enzymes, lipid peroxidation, and antioxidants were significantly restored in parthenolide treated group compared to group II hamsters. The apoptotic gene p53 and antiapoptotic gene Bcl-2 were significantly down regulated; whereas, pro-apoptotic gene Bax was up regulated in group III hamsters compared to group II. The results of the present study suggest that parthenolide have potent chemopreventive, antioxidant, and apoptotic effect in DMBA-induced oral carcinogenesis. PMID- 28801715 TI - Spiritual Care in the ICU: Perspectives of Dutch Intensivists, ICU Nurses, and Spiritual Caregivers. AB - Since there are no scientific data available about the role of spiritual care (SC) in Dutch ICUs, the goal of this quantitative study was twofold: first, to map the role of SC as a part of daily adult ICU care in The Netherlands from the perspective of intensivists, ICU nurses, and spiritual caregivers and second, to identify similarities and differences among these three perspectives. This study is the quantitative part of a mixed methods approach. To conduct empirical quantitative cohort research, separate digital questionnaires were sent to three different participant groups in Dutch ICUs, namely intensivists, ICU nurses, and spiritual caregivers working in academic and general hospitals and one specialist oncology hospital. Overall, 487 participants of 85 hospitals (99 intensivists, 290 ICU nurses, and 98 spiritual caregivers) responded. The majority of all respondents (>70%) considered the positive effects of SC provision to patients and relatives: contribution to mental well-being, processing and channeling of emotions, and increased patient and family satisfaction. The three disciplines diverged in their perceptions of how SC is currently evolving in terms of information, assessment, and provision. Nationwide, SC is not implemented in daily ICU care. The majority of respondents, however, attached great importance to interdisciplinary collaboration. In their view SC contributes positively to the well-being of patients and relatives in the ICU. Further qualitative research into how patients and relatives experience SC in the ICU is required in order to implement and standardize SC as a scientifically based integral part of daily ICU care. PMID- 28801716 TI - [Plastic surgery reconstruction of the adult buried penis : Option or obligation?] AB - The adult buried penis afflicts the patient with shame and is also potentially associated with considerable urogenital complications. Due to obesity, chronic urogenital lymphedema or subsequent inflammatory urogenital conditions, such as a lichen sclerosus et atrophicus, the clinical appearance of the adult buried penis is extremely variable. Epidemiological data are non-existent. Therapeutically, a combination of various plastic surgery procedures is often necessary for the best esthetic and functional results. The therapeutic strategy is highly individual and the therapy itself is interdisciplinary. This article provides an overview of the plastic surgery reconstruction of the adult buried penis. PMID- 28801717 TI - Vitamin B6 is essential for serine de novo biosynthesis. AB - Pyridoxal 5'-phosphate (PLP), the metabolically active form of vitamin B6, plays an essential role in brain metabolism as a cofactor in numerous enzyme reactions. PLP deficiency in brain, either genetic or acquired, results in severe drug resistant seizures that respond to vitamin B6 supplementation. The pathogenesis of vitamin B6 deficiency is largely unknown. To shed more light on the metabolic consequences of vitamin B6 deficiency in brain, we performed untargeted metabolomics in vitamin B6-deprived Neuro-2a cells. Significant alterations were observed in a range of metabolites. The most surprising observation was a decrease of serine and glycine, two amino acids that are known to be elevated in the plasma of vitamin B6 deficient patients. To investigate the cause of the low concentrations of serine and glycine, a metabolic flux analysis on serine biosynthesis was performed. The metabolic flux results showed that the de novo synthesis of serine was significantly reduced in vitamin B6-deprived cells. In addition, formation of glycine and 5-methyltetrahydrofolate was decreased. Thus, vitamin B6 is essential for serine de novo biosynthesis in neuronal cells, and serine de novo synthesis is critical to maintain intracellular serine and glycine. These findings suggest that serine and glycine concentrations in brain may be deficient in patients with vitamin B6 responsive epilepsy. The low intracellular 5-mTHF concentrations observed in vitro may explain the favourable but so far unexplained response of some patients with pyridoxine-dependent epilepsy to folinic acid supplementation. PMID- 28801718 TI - Stentless endoscopic repair of congenital choanal atresia: is it enough for maintaining choanal patency? AB - The aim of choanal atresia (CA) surgery is to achieve bilateral nasal patency. Among the different methods of CA repair, the endoscopic transnasal approach has gained recent popularity with the advent of endoscopic instruments and techniques. This article describes our experience regarding CA repair that was done either using or not using a stent in different periods of time in our department. Between February 2006 and February 2016, a total of 29 patients aged 2 days-53 years underwent endoscopic transnasal CA repair. While in early years stents were used to maintain nasal patency, since 2010, all cases were repaired endoscopically without stenting. Of the 29 patients, 8 were excluded because of inadequate follow-up data. The mean follow-up time for the remaining 21 patients after surgery averaged 53 months (range 12-111 months). Intranasal stents were used in 5 of 21 patients for 8 out of 32 operative sides. Of the 8 stented neochoanae, 6 (75%), restenosed at a mean time of 15.2 weeks (5-24). The restenosis rate was 25% (6/24 nasal sides) in 16 patients who underwent stentless repair. In unilateral CA, 2 of 10 (20%) patients underwent atresia repair using stents and only these cases restenosed after surgery in this group. Of the 11 patients with bilateral disease, 5 (45.4%) underwent revision surgeries. In the bilateral group, 2 of 3 (66.6%) stented patients required revision surgeries, whereas 3 of 8 (37.5%) patients who underwent stentless repair relapsed. In one patient, we have experienced an alar cartilage injury intraoperatively caused by drilling. The transnasal endoscopic repair has proved to be effective and yielded long-term satisfactory results. The use of stent seems to have no advantage over a stentless repair regarding maintenance of a patent nasal airway. Patients experienced restenosis more frequently with stenting. PMID- 28801719 TI - The Phospholipid Composition of Kangaroo Spermatozoa Verified by Mass Spectrometric Lipid Analysis. AB - Cryopreservation of kangaroo sperm has not been successful so far, and yet there is no promising cryopreservation protocol for these cells available. However, conservation of gametes is extremely important, particularly in the context of preserving endangered species. As spermatozoa are comprised of different membrane systems, the composition of these membranes might account for difficulties in cryopreservation. Lipids, as the main components, affect the physical properties of biological membranes and play a major role in sperm maturation. Therefore, knowledge of the lipid composition is crucial for any further step toward the preservation of the species. We used MALDI-TOF, ESI-IT, tandem mass spectrometry, and thin layer chromatography to investigate the lipid composition of epididymal spermatozoa of four different kangaroo species. Spectra of these species were very similar with respect to the identified lipid species. Tremendous changes in the lipid composition during the transit of sperm from caput to cauda epididymis could be seen, specifically an increase in poly-unsaturated fatty acids, ether lipids, and plasmalogens, as well as a reduction in mono- and di-unsaturated fatty acids. Additionally, phosphatidylcholines containing docosatrienoic acid (22:3), a heretofore unknown fatty acid for sperm membranes, showed the highest abundance in kangaroo sperm. PMID- 28801720 TI - Functionalized hydrothermal carbon derived from waste pomelo peel as solid-phase extractant for the removal of uranyl from aqueous solution. AB - To develop a high-performance solid-phase extractant for the separation of uranyl f, pomelo peel, a kind of waste biomass, has been employed as carbon source to prepare carbonaceous matrix through low-temperature hydrothermal carbonization (200 degrees C, 24 h). After being oxidized by Hummers method, the prepared hydrothermal carbon matrix was functionalized with carboxyl and phenolic hydroxyl groups (1.75 mmol g-1). The relevant characterizations and batch studies had demonstrated that the obtained carbon material possessed excellent affinity toward uranyl (436.4 mg g-1) and the sorption process was a spontaneous, endothermic and rapid chemisorption. The selective sorption of U(VI) from the simulated nuclear effluent demonstrated that the sorbent displayed a desirable selectivity (56.14% at pH = 4.5) for the U(VI) ions over the other 11 competitive cations from the simulated industrial nuclear effluent. The proposed synthetic strategy in the present work had turned out to be effective and practical, which provides a novel approach to prepare functional materials for the recovery and separation of uranyl or other heavy metals from aqueous environment. PMID- 28801721 TI - Surgery is essential in squamous cell cancer of the rectum. AB - PURPOSE: Squamous cell cancer (SCC) is a rare histological subtype of rectal cancer. It is unclear whether SCC should be treated by multimodal therapy, including surgery, or by chemoradiation alone. The objective of the study was to define an optimal treatment strategy. METHODS: Patients with rectal cancer and SCC histology were identified in the Surveillance Epidemiology and End Results Database between 1990 and 2013. According to treatment, three groups were defined: radiotherapy and surgery (RT/SX), radiotherapy (RT), and surgery (SX). Overall survival (OS) and disease-specific survival (DSS) for localized, regional, and distant disease were assessed using a multivariable Cox regression model. RESULTS: Out of 856,435 colorectal cancer patients, 1747 with SCC of the rectum were eligible. Four hundred and fifty-five were treated with RT/SX, 994 with RT, and 298 with SX. Adjusted hazard ratios (HR) did not differ for OS and DSS in localized disease. In regional disease, OS and DSS were improved for RT/SX compared to RT (HR 0.751, 95% CI 0.566-0.997, P = 0.048 and HR 0.679, 95% CI 0.478-0.966, P = 0.031). In distant disease, OS and DSS were not different. CONCLUSIONS: Multimodal therapy including surgery improved OS and DSS compared to receiving a treatment without surgery for regional disease in rectal SCC. No difference was observed in localized and distant disease. The findings contradict with recent reports favoring definitive chemoradiation. PMID- 28801722 TI - Effect of Disturbances of Zinc and Copper on the Physical and Mental Health Status of Patients with Alcohol Dependence. AB - The concentrations of copper and zinc in the tissues of alcohol-addicted people can significantly correlate with the variables describing their mental state. Studies on the homeostasis of zinc in alcohol-dependent patients have often been characterized by low hypozincemia detection. This may be caused by a low content of zinc in blood serum (1%) compared to the average zinc level in the body. Unfortunately, most authors have identified extracellular zinc in their studies. In the available literature, data on the level of copper in patients suffering from alcohol dependence are inconsistent. Our study included 100 alcohol-addicted patients (the study group) and 50 healthy subjects (the control group). Mental state was measured using appropriate psychometric scales. We used inductively coupled plasma mass spectrometry (ICP-MS) to determine copper and zinc content. Our results confirm the purposefulness of the use of zinc concentration in erythrocytes as a diagnostic parameter for low zinc status in alcohol-dependent patients. Alcohol-dependent patients with reduced concentrations of zinc in erythrocytes/copper in blood plasma differed significantly from alcohol-dependent patients with normal concentrations in terms of clinical parameters. With regard to zinc in blood plasma and copper in erythrocytes, this situation has not been found. The clinical symptoms of hypozincemia and copper deficiency in patients addicted to alcohol usually relate to disorders in central nervous system functioning, and they result in a decreased quality of physical and mental life. PMID- 28801723 TI - A review of the role of immune cells in acute kidney injury. AB - Acute kidney injury (AKI) is a systemic disease occurring commonly in patients who are critically ill. Etiologies of AKI can be septic or aseptic (nephrotoxic, or ischemia-reperfusion injury). Recent evidence reveals that innate and adaptive immune responses are involved in mediating damage to renal tubular cells and in recovery from AKI. Dendritic cells, monocytes/macrophages, neutrophils, T lymphocytes, and B lymphocytes all contribute to kidney injury. Conversely, M2 macrophages and regulatory T cells are essential in suppressing inflammation, tissue remodeling and repair following kidney injury. AKI itself confers an increased risk for developing infection owing to increased production and decreased clearance of cytokines, in addition to dysfunction of immune cells themselves. Neutrophils are the predominant cell type rendered dysfunctional by AKI. In this review, we describe the bi-directional interplay between the immune system and AKI and summarize recent developments in this field of research. PMID- 28801724 TI - Pneumococcal meningitis and endocarditis in an infant: possible improved survival with factor V Leiden mutation. AB - : Streptococcus pneumoniae infections continue to remain associated with high morbidity and mortality. Although the incidence of invasive meningeal and/or lung disease are not uncommon, Streptococcus pneumoniae endocarditis is rare especially in healthy pediatric population. New studies have suggested a strong association between factor V leiden (FVL) mutation and favorable outcomes in critically ill children. A healthy 10 month old presented with sepsis and meningeal signs, was later confirmed to have Streptococcus pneumoniae meningitis and endocarditis. She was found to have factor V leiden mutation and made a complete recovery despite initial complications. CONCLUSION: Presence of factor V leiden mutation in critically ill children with severe septicaemia possibly contributes to better outcomes. What is known: * Mortality and morbidity remain high with invasive pneumococcal disease. * Pneumococcal endocarditis is rare in healthy pediatric population and results in significant morbidity and mortality What is new: * New studies have suggested a strong association between factor V leiden (FVL) mutation and favorable outcomes in critically ill children. * The presence of factor V mutation in children with extensive invasive pneumococcal disease possibly contributes to a better outcome. PMID- 28801725 TI - Optimization of Soluble Expression and Purification of Recombinant Human Rhinovirus Type-14 3C Protease Using Statistically Designed Experiments: Isolation and Characterization of the Enzyme. AB - Human rhinovirus (HRV) 3C protease is widely used in recombinant protein production for various applications such as biochemical characterization and structural biology projects to separate recombinant fusion proteins from their affinity tags in order to prevent interference between these tags and the target proteins. Herein, we report the optimization of expression and purification conditions of glutathione S-transferase (GST)-tagged HRV 3C protease by statistically designed experiments. Soluble expression of GST-HRV 3C protease was initially optimized by response surface methodology (RSM), and a 5.5-fold increase in enzyme yield was achieved. Subsequently, we developed a new incomplete factorial (IF) design that examines four variables (bacterial strain, expression temperature, induction time, and inducer concentration) in a single experiment. The new design called Incomplete Factorial Strain/Temperature/Time/Inducer (IF-STTI) was validated using three GST-tagged proteins. In all cases, IF-STTI resulted in only 10% lower expression yields than those obtained by RSM. Purification of GST-HRV 3C was optimized by an IF design that examines simultaneously the effect of the amount of resin, incubation time of cell lysate with resin, and glycerol and DTT concentration in buffers, and a further 15% increase in protease recovery was achieved. Purified GST-HRV 3C protease was active at both 4 and 25 degrees C in a variety of buffers. PMID- 28801726 TI - Mortality associated with candidemia in non-neutropenic cancer patients is not less compared to a neutropenic cohort of cancer patients. PMID- 28801729 TI - [Plastic reconstruction of external genitalia after Fournier's gangrene]. AB - Fournier's gangrene is a rapidly progressing necrotizing fasciitis restricted to the perineal and genital regions. Although rare, it is an acute life-threatening disease, requiring rapid radical surgical debridement and antibiotic treatment, resulting in large soft tissue defects. Various reconstructive methods for defect coverage are applied to satisfactorily reconstitute functionality and esthetics. PMID- 28801728 TI - Arctium minus crude extract presents antinociceptive effect in a mice acute gout attack model. AB - Gout is a disorder that triggers a severe inflammatory reaction which generates episodes of intense pain and discomfort to the patient. Arctium minus (Hill) Bernh. (Asteraceae) is known as "burdock" and displays anti-inflammatory, antinociceptive, against rheumatic pain and radical-scavenging activities. Species of the genus Arctium have been used in assistant therapy of gout and other inflammatory processes. We investigated the antinociceptive and anti edematogenic effects of the crude extract of A. minus seeds in an acute gout attack model induced by intra-articular injection of monosodium urate (MSU) crystals in adult male Swiss mice (25-30 g). The crude extract of A. minus (100 mg/kg, p.o.) reduced the mechanical allodynia induced by the injection of MSU (1.25 mg/site, i.a.) from 4 until 8 h after its administration. A. minus seeds crude extract prevented mechanical allodynia at doses of 30 and 100 mg/kg, but not 10 mg/kg. Allopurinol (10 ug/mL) and A. minus crude extract (10-300 ug/mL) inhibited the xanthine oxidase activity in vitro. The A. minus seeds crude extract did not cause adverse effects since did not change the toxicological parameters evaluated. A. minus crude extract can be used as an assistant therapy of gout pain, supporting its traditional use, without causing adverse effects. PMID- 28801727 TI - Inflammation Induced by Candida parapsilosis in THP-1 Cells and Human Peripheral Blood Mononuclear Cells (PBMCs). AB - Candida parapsilosis is one of the most prevalent Candida species; however, the inflammation response induced by C. parapsilosis and related mechanism received few studies. In this study, we analyzed the pro-inflammatory cytokine responses evoked by C. parapsilosis in human peripheral blood mononuclear cells (PBMCs) and THP-1 cells, determined the signal pathways related to the inflammation response and investigated the expression of dectin-1 modified with C. parapsilosis. Exposure of PBMCs and THP-1 cells to C. parapsilosis led to the increased gene expression and production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). C. parapsilosis induced TNF-alpha and IL-6 release in a time- and dose-dependent manner. Western blotting was used to analyze p38, ERK1/2 mitogen-activated protein kinases (MAPKs) and IkappaB-alpha phosphorylation and degradation. Nuclear translocation of NF-kappaB was detected by confocal microscopy. THP-1 cells challenged by C. parapsilosis resulted in the activation of NF-kappaB and phosphorylation of p38 and ERK1/2 MAPKs. The expression of dectin-1 was up-regulated after the stimulation of C. parapsilosis. Our results suggest that C. parapsilosis could stimulate the inflammatory response, increase the expression of dectin-1 and activate NF-kappaB and MAPKs signaling pathways in macrophages. PMID- 28801730 TI - Prospective changes in neural alcohol cue reactivity in at-risk adolescents. AB - Adolescence represents an ideal time for elucidating the etiology of cue reactivity profiles. This study examined the influence of three risk factors consistently associated with heavy adolescent drinking on alcohol cue reactivity. Youth were first assessed while still naive to alcohol (12-14 years old) and followed after transitioning into alcohol use (17-21 years old). The effects of family history of substance use disorder, sex, and history of early of dating (i.e., before 14 years of age) on BOLD response contrast to alcohol picture cues were examined in a linear mixed model, controlling for age and alcohol use patterns at follow-up. Activation to alcohol picture cues differed as a function of risk factor and time. At baseline, family history positive youth showed greater activation to alcohol cues than family history negative peers in the right middle occipital and anterior cingulate gyri. Youth with a history of early dating showed greater activation to alcohol cues, compared to non-early daters, in the left anterior cingulate/white matter region. Girls showed greater activation to alcohol than boys at baseline in left middle frontal gyrus. At follow-up, after drinking started, patterns reversed for each risk factor. These results indicate that even prior to initiating alcohol use, adolescents showed differences in activation to alcohol cues based on their family history, dating history, and sex. PMID- 28801732 TI - Evaluation of the Relationship between Alopecia Areata and Viral Antigen Exposure. AB - BACKGROUND: Alopecia areata (AA) is an autoimmune disease characterized by non scarring alopecia with T-cell infiltration at the affected hair follicle. OBJECTIVE: Our aim was to study the potential link between hepatitis B virus (HBV) antigen exposure and AA. METHODS: Two pediatric patients with AA following hepatitis B vaccination were identified in a general dermatology clinic. A bioinformatics analysis and an electronic medical record (EMR) database query were performed at the University of Rochester Medical Center to identify patients with AA, coexisting viral infections, vaccinations, or interferon (IFN) therapy in order to determine if the presence of AA and these conditions was higher than in AA patients without these associated conditions or therapy. RESULTS: An increased frequency of AA among those who received the HBV surface protein antigen [odds ratio (OR) 2.7, p < 0.0001] was identified, and an independent analysis revealed an increased frequency of AA in those receiving IFN-beta treatment (OR 8.1, p < 0.05). One potential antigenic target identified was SLC45A2, a melanosomal transport protein important in skin and hair pigmentation. The longest potential vaccine peptide fragment match (8-mer) was to a segment of natural killer (NK) cell inhibitory receptors, KIR3DL2 and KIR3DL1. Predictive modeling of major histocompatibility complex (MHC)-peptide binding demonstrated potential binding of this peptide to MHC relevant to AA. LIMITATIONS: The results will need to be verified in additional patient databases allowing analysis of temporal relationships, and with molecular experiments of the identified antigens. CONCLUSIONS: Our data confirm associations between viral infection and IFN treatment with AA. It establishes that the hepatitis B surface protein antigen has shared epitopes with human killer immunoglobulin-like receptors. PMID- 28801735 TI - [Viewpoint of the VAV-clinics is lacking]. PMID- 28801736 TI - [Do not forget clinics on other levels]. PMID- 28801731 TI - Molecular mapping and genomics of soybean seed protein: a review and perspective for the future. AB - KEY MESSAGE: Genetic improvement of soybean protein meal is a complex process because of negative correlation with oil, yield, and temperature. This review describes the progress in mapping and genomics, identifies knowledge gaps, and highlights the need of integrated approaches. Meal protein derived from soybean [Glycine max (L) Merr.] seed is the primary source of protein in poultry and livestock feed. Protein is a key factor that determines the nutritional and economical value of soybean. Genetic improvement of soybean seed protein content is highly desirable, and major quantitative trait loci (QTL) for soybean protein have been detected and repeatedly mapped on chromosomes (Chr.) 20 (LG-I), and 15 (LG-E). However, practical breeding progress is challenging because of seed protein content's negative genetic correlation with seed yield, other seed components such as oil and sucrose, and interaction with environmental effects such as temperature during seed development. In this review, we discuss rate limiting factors related to soybean protein content and nutritional quality, and potential control factors regulating seed storage protein. In addition, we describe advances in next-generation sequencing technologies for precise detection of natural variants and their integration with conventional and high throughput genotyping technologies. A syntenic analysis of QTL on Chr. 15 and 20 was performed. Finally, we discuss comprehensive approaches for integrating protein and amino acid QTL, genome-wide association studies, whole-genome resequencing, and transcriptome data to accelerate identification of genomic hot spots for allele introgression and soybean meal protein improvement. PMID- 28801734 TI - Fibrinogen promotes malignant biological tumor behavior involving epithelial mesenchymal transition via the p-AKT/p-mTOR pathway in esophageal squamous cell carcinoma. AB - PURPOSE: Hyperfibrinogenemia is associated with unfavorable prognosis and advanced tumor behavior in various malignancies, including esophageal squamous cell carcinoma (ESCC). However, its biological function in ESCC is unknown. The present study was designed to further validate the prognostic value of preoperative plasma hyperfibrinogenemia and evaluate the biological role of fibrinogen, as well as the underlying mechanism in ESCC. METHODS: Data from 452 cases with newly diagnosed ESCC followed by curative surgery between 2006 and 2010 were retrospectively evaluated. The Clauss method was utilized to measure the preoperative plasma fibrinogen level. Correlations between the fibrinogen level and clinicopathologic characteristics and survival analysis were performed. The effects of fibrinogen on malignant behaviors, including tumor cell viability, colony formation, migration, and invasion, were also investigated. RESULTS: The optimal cut-off value for plasma fibrinogen level was defined as 4.0 g/L according to recommendations. Thus, the proportion of hyperfibrinogenemia was 24.8% (112/452). Preoperative plasma hyperfibrinogenemia was significantly associated with advanced tumor length, deep tumor invasion, advanced tumor-node metastasis stage, alcohol consumption, a higher white blood cell count, a higher platelet count, and high globulin levels. Univariate survival analysis revealed that compared to those with normal plasma fibrinogen levels, patients with hyperfibrinogenemia tended to have poorer disease-free survival (DFS) [hazard ratio (HR), 1.692; 95% confidence interval (CI), 1.304-2.196; P < 0.001] and overall survival (OS) (HR 1.864; 95% CI 1.424-2.440; P < 0.001). In the multivariate Cox regression models, these factors remained independent predictors for impaired DFS (HR 1.491; 95% CI 1.138-1.955; P = 0.004) and OS (HR 1.648; 95% CI 1.246-2.180; P < 0.001) after adjusting for other confounding variables. In addition, fibrinogen could significantly promote cell migration and invasion but not proliferation. Moreover, it could also induce epithelial-mesenchymal transition (EMT) and increase the levels of p-PTEN, p-AKT, and p-mTOR in ESCC cell lines. CONCLUSIONS: Preoperative plasma hyperfibrinogenemia might serve as an independent predictor of unfavorable survival in ESCC. Furthermore, fibrinogen may promote cell motility by inducing EMT via the p-AKT/p-mTOR pathway. PMID- 28801737 TI - How is light interception efficiency related to shoot structure in tall canopy species? AB - Coexistence of multiple species is a fundamental aspect of plant and forest ecology. Although spatial arrangement of leaves within crowns is an important determinant of light interception and productivity, shoot structure varies considerably among coexisting canopy species. We investigated the relative importance of structural traits in determining the light availability of leaves (I) and light interception efficiency at the current-year shoot level (LIECS; the total light interception of leaves divided by shoot biomass) at the top of crowns of 11 canopy species in a cool-temperate forest in Japan. In accordance with Corner's rules, the total mass, stem mass, total mass of leaf laminae, individual leaf area, and stem cross-sectional area of current-year shoot were positively correlated with each other, and branching intensity (the number of current-year shoots per branch unit of 1-m length) was inversely correlated with these traits across species. In contrast, I was correlated not with these traits, but with leaf elevation angle (a L). Moreover, variation in LIECS across species was caused by variation in I (thus in a L). Thus, a L is a key parameter for the leaf light interception of canopy shoots in this cool-temperate forest. Differences in a L across species might be related to different physiological strategies that developed in the high light and water-limited environment of forest canopies. Small variation in the length of current-year shoots among species implies that variations in I and LIECS would be important for the coexistence of these canopy species. PMID- 28801738 TI - [Alterations in the WHO classification of brain tumors from 2016]. AB - BACKGROUND: The World Health Organization (WHO) provides uniform definitions and a uniform nomenclature for tumors of various organs. OBJECTIVE: What changes resulted from the 2016 WHO classification of tumors of the central nervous system? MATERIAL AND METHODS: Changes in the definition and classification of brain tumors of the revised WHO classification are presented. Most changes evolve from the results of molecular pathology that were generated during the last decade. RESULTS: For the first time the WHO classification of brain tumors is not based exclusively on histology. Molecular parameters add to the definition of a number of tumor entities. Especially the chapters of gliomas, medulloblastomas and other embryonal tumors have been restructured. CONCLUSION: Advances in molecular pathology require a modular diagnostics scheme that integrates histological and molecular parameters into a final diagnosis. This approach will result in more precise tumor groups with respect to prognosis and therapy. PMID- 28801739 TI - [The new treatment procedures of the DGUV from the perspective of an injury type procedure (VAV) clinic]. AB - The new treatment procedures of the German Statutory Accident Insurance (DGUV) have ramifications for the injury type procedure clinics (VAV) from medical, economic and structural aspects. Whereas the latter can be assessed as positive, the medical and economical aspects are perceived as being negative. Problems arise from the partially unclear formulation of the injury type catalogue, which results in unpleasant negotiations with the occupational insurance associations with respect to financial remuneration for services rendered. Furthermore, the medical competence of the VAV clinics will be reduced by the preset specifications of the VAV catalogue, which opens up an additional field of tension between medical treatment, fulfillment of the obligatory training and acquisition of personnel as well as the continually increasing economic pressure. From the perspective of the author, the relinquence of medical competence imposed by the regulations of the new VAV catalogue is "throwing the baby out with the bathwater" because many VAV clinics nationwide also partially have competence in the severe injury type procedure (SAV). A concrete "competence-based approval" for the individual areas of the VAV procedure would be sensible and would maintain the comprehensive care of insured persons and also increase or strengthen the willingness of participating VAV hospitals for unconditional implementation of the new VAV procedure. PMID- 28801740 TI - A Statistical Classifier to Support Diagnose Meningitis in Less Developed Areas of Brazil. AB - This paper describes the development of statistical classifiers to help diagnose meningococcal meningitis, i.e. the most sever, infectious and deadliest type of this disease. The goal is to find a mechanism able to determine whether a patient has this type of meningitis from a set of symptoms that can be directly observed in the earliest stages of this pathology. Currently, in Brazil, a country that is heavily affected by meningitis, all suspected cases require immediate hospitalization and the beginning of a treatment with invasive tests and medicines. This procedure, therefore, entails expensive treatments unaffordable in less developed regions. For this purpose, we have gathered together a dataset of 22,602 records of suspected meningitis cases from the Brazilian state of Bahia. Seven classification techniques have been applied from input data of nine symptoms and other information about the patient such as age, sex and the area they live in, and a 10 cross-fold validation has been performed. Results show that the techniques applied are suitable for diagnosing the meningococcal meningitis. Several indexes, such as precision, recall or ROC area, have been computed to show the accuracy of the models. All of them provide good results, but the best corresponds to the J48 classifier with a precision of 0.942 and a ROC area over 0.95. These results indicate that our model can indeed help lead to a non-invasive and early diagnosis of this pathology. This is especially useful in less developed areas, where the epidemiologic risk is usually high and medical expenses, sometimes, unaffordable. PMID- 28801741 TI - Scleral suture fixation technique for dislocated plate haptic toric IOL. AB - Purpose We describe a scleral suture fixation technique for dislocated plate haptic toric intraocular lens (IOL) implantation. Materials and methods A double armed 10-0 straight polypropylene suture was passed into the eye from the sclera (2 mm away from the limbus). A suture needle was passed through the hole on the corner of the IOL and pulled out from the paracentesis with a 27-gauge needle. Afterward, the suture needle was reinserted from the same paracentesis and then removed from the eye with the help of a 27-gauge needle entering the eye from a nearby point to the first scleral entrance. The needle was passed through the end of the loop and pulled slightly to initiate the formation of a cow-hitch knot. The same procedure was applied to the other hole on the plate haptic. Both sutures were adjusted and fixed to the sclera with a Z suture. Results No complications were observed and at the follow-up visits, uncorrected visual acuity was 0.8 with decimal. Conclusion Axial, sagittal, and rotational stability rules are taken into consideration, scleral fixation surgery for a dislocated plate haptic foldable toric IOL is an alternative method to eliminate astigmatic refractive error. PMID- 28801742 TI - The cyclic lipopeptide orfamide induces systemic resistance in rice to Cochliobolus miyabeanus but not to Magnaporthe oryzae. AB - KEY MESSAGE: The Pseudomonas- derived cyclic lipopeptide orfamide can induce resistance to Cochliobolus miyabeanus but not to Magnaporthe oryzae in rice. Abscisic acid signaling is involved in the induced systemic resistance response triggered by orfamide. Diverse natural products produced by beneficial Pseudomonas species have the potential to trigger induced systemic resistance (ISR) in plants, and thus may contribute to control of diseases in crops. Some beneficial Pseudomonas spp. can produce cyclic lipopeptides (CLPs), amphiphilic molecules composed of a fatty acid tail linked to an oligopeptide which is cyclized. CLPs can have versatile biological functions, but the capacity of Pseudomonas-derived CLPs in triggering ISR responses has barely been studied. Pseudomonas protegens and related species can produce orfamide-type CLPs. Here we show that in rice, orfamides can act as ISR elicitors against the necrotrophic fungus Cochliobolus miyabeanus, the causal agent of brown spot disease, but are not active against the blast fungus Magnaporthe oryzae. Orfamide A can trigger early defensive events and activate transcripts of defense-related genes in rice cell suspension cultures, but does not cause cell death. Further testing in rice cell suspension cultures and rice plants showed that abscisic acid signaling, the transcriptional activator OsWRKY4 and pathogenesis-related protein PR1b are triggered by orfamide A and may play a role in the ISR response against C. miyabeanus. PMID- 28801743 TI - Investigation of an optimal cell lysis method for the study of the zinc metalloproteome of Histoplasma capsulatum. AB - This work sought to assess optimal extraction conditions in the study of the metalloproteome of the dimorphic fungus Histoplasma capsulatum. One of the body's responses to H. capsulatum infection is sequestration of zinc within host macrophage (MO), as reported by Vignesh et al. (Immunity 39:697-710, 2013) and Vignesh et al. (PLOS Pathog 9:E1003815, 2013). Thus, metalloproteins containing zinc were of greatest interest as it plays a critical role in survival of the fungus. One challenge in metalloproteomics is the preservation of the native structure of proteins to retain non-covalently bound metals. Many of the conventional cell lysis, separation, and identification techniques in proteomics are carried out under conditions that could lead to protein denaturation. Various cell lysis techniques were investigated in an effort to both maintain the metalloproteins during lysis and subsequent analysis while, at the same time, serving to be strong enough to break the cell wall, allowing access to cytosolic metalloproteins. The addition of 1% Triton x-100, a non-ionic detergent, to the lysis buffer was also studied. Seven lysis methods were considered and these included: Glass Homogenizer (H), Bead Beater (BB), Sonication Probe (SP), Vortex with 1% Triton x-100 (V, T), Vortex with no Triton x-100 (V, NT), Sonication Bath, Vortex, and 1% Triton x-100 (SB, V, T) and Sonication Bath, Vortex, and no Triton x-100 (SB, V, NT). A Qubit(r) Assay was used to compare total protein concentration and inductively coupled plasma-mass spectrometry (ICP-MS) was utilized for total metal analysis of cell lysates. Size exclusion chromatography coupled to ICP-MS (SEC-HPLC-ICP-MS) was used for separation of the metalloproteins in the cell lysate and the concentration of Zn over a wide molecular weight range was examined. Additional factors such as potential contamination sources were also considered. A cell lysis method involving vortexing H. capsulatum yeast cells with 500 MUm glass beads in a 1% Triton x-100 lysis buffer (V, T) was found to be most advantageous to extract intact zinc metalloproteins as demonstrated by the highest Zn to protein ratio, 1.030 ng Zn/MUg protein, and Zn distribution among high, mid, and low molecular weights suggesting the least amount of protein denaturation. Graphical abstract In this work, several cell lysis techniques and two lysis buffers were investigated to evaluate the preservation of the zinc metalloproteome of H. capsulatum while maintaining compatibility with the analytical techniques employed. PMID- 28801744 TI - The relevance of data driven motion correction in diagnostic PET. PMID- 28801745 TI - An undefined acute respiratory failure: a peculiar case of lymphoma presentation. PMID- 28801746 TI - Laparoscopic Nissen Fundoplication Plus Mid-gastric Plication for Treatment of Obese Patients with Gastroesophageal Reflux Disease. AB - BACKGROUND: Gastroesophageal reflux disease (GERD) is commonly associated with obesity, and its surgical management is debatable. OBJECTIVE: The objective of this study was to prove the safety and feasibility of laparoscopic Nissen's fundoplication (LNF) combined with mid-gastric plication (MGP) for treatment of obese patients with GERD. METHODS: LNF combined with MGP was done for 18 patients. All interventions were performed under general anesthesia. The follow up protocol included body mass index (BMI), percentage of excess weight loss (%EWL), percentage of excess BMI loss (%EBMIL), and clinical assessment using the Gastro-esophageal Reflux Health-Related Quality-of-Life (GERD-HRQOL) scale at 6 and 12 months. RESULTS: The period of follow-up ranged from 12 to 33 months with a mean of 17.74 +/- 3.73 months. The operation time was 1.40 +/- 0.27 h. No serious procedure-related complications occurred. GERD-related symptoms resolved in all patients (p < 0.001). There was a significant improvment in endoscopic findings at 6 months compared to properatively (p = 0.001). There was a significant patient satisfaction score using GERD-HRQOL at 6 and 12 months (p = 0.000). The 1-year follow-up excess weight was significantly less than the baseline excess weight (p < 0.001). The average BMI decreased from 37.59 +/- 1.89 kg/m2 at baseline to 30.61 +/- 1.57 kg/m2 at 1 year (p < 0.001). CONCLUSIONS: LNF combined with MGP for treatment of obese patients with GERD is technically safe, feasible, and promising with no serious procedure-related complications. The technique is effective in terms of weight loss and cure of GERD. However, future larger studies are required to demonstrate the safety, effectiveness, and long term durability of the procedure. PMID- 28801747 TI - Comparison of outcomes of thoracoscopic primary repair of gross type C esophageal atresia performed by qualified and non-qualified surgeons. AB - PURPOSE: Although thoracoscopic repair of esophageal atresia has become widespread, most studies are based on operations performed by expert surgeons. Therefore, the outcomes of operations performed by non-expert surgeons are not well known. The aim of this study was to compare outcomes based on operator skill level. METHODS: We retrospectively reviewed the demographics and outcomes of patients with Gross type C esophageal atresia, who underwent primary thoracoscopic repair at our hospital between January 2014 and August 2016. Outcomes of surgeries performed by qualified surgeons, as determined by the Japanese Society for Endoscopic Surgery were compared with those of non-qualified surgeons. All operations were performed by or under the supervision of one qualified surgeon. RESULTS: Nine operations were performed by qualified surgeons and six operations by non-qualified surgeons with >10 years of experience in surgery. None of the patients developed anastomotic leakage or recurrent tracheoesophageal fistula. However, the operative time and rate of stricture formation at the beginning of the weaning period were significantly higher in the latter group (P = 0.008 and 0.044). CONCLUSIONS: Although supervision of experts would improve results in thoracoscopic repair of esophageal atresia, the results indicate that good skill is necessary to avoid anastomotic stricture. PMID- 28801748 TI - Molecular and phenotypic characterization of transgenic wheat and sorghum events expressing the barley alanine aminotransferase. AB - MAIN CONCLUSION: The expression of a barley alanine aminotransferase gene impacts agronomic outcomes in a C3 crop, wheat. The use of nitrogen-based fertilizers has become one of the major agronomic inputs in crop production systems. Strategies to enhance nitrogen assimilation and flux in planta are being pursued through the introduction of novel genetic alleles. Here an Agrobacterium-mediated approach was employed to introduce the alanine aminotransferase from barley (Hordeum vulgare), HvAlaAT, into wheat (Triticum aestivum) and sorghum (Sorghum bicolor), regulated by either constitutive or root preferred promoter elements. Plants harboring the transgenic HvAlaAT alleles displayed increased alanine aminotransferase (alt) activity. The enhanced alt activity impacted height, tillering and significantly boosted vegetative biomass relative to controls in wheat evaluated under hydroponic conditions, where the phenotypic outcome across these parameters varied relative to time of year study was conducted. Constitutive expression of HvAlaAT translated to elevation in wheat grain yield under field conditions. In sorghum, expression of HvAlaAT enhanced enzymatic activity, but no changes in phenotypic outcomes were observed. Taken together these results suggest that positive agronomic outcomes can be achieved through enhanced alt activity in a C3 crop, wheat. However, the variability observed across experiments under greenhouse conditions implies the phenotypic outcomes imparted by the HvAlaAT allele in wheat may be impacted by environment. PMID- 28801749 TI - Cancer Risk Assessment of Polycyclic Aromatic Hydrocarbons in the Soils and Sediments of India: A Meta-Analysis. AB - A carcinogenic risk assessment of polycyclic aromatic hydrocarbons in soils and sediments was conducted using the probabilistic approach from a national perspective. Published monitoring data of polycyclic aromatic hydrocarbons present in soils and sediments at different study points across India were collected and converted to their corresponding BaP equivalent concentrations. These BaP equivalent concentrations were used to evaluate comprehensive cancer risk for two different age groups. Monte Carlo simulation and sensitivity analysis were applied to quantify uncertainties of risk estimation. The analysis denotes 90% cancer risk value of 1.770E-5 for children and 3.156E-5 for adults at heavily polluted site soils. Overall carcinogenic risks of polycyclic aromatic hydrocarbons in soils of India were mostly in acceptance limits. However, the food ingestion exposure route for sediments leads them to a highly risked zone. The 90% risk values from sediments are 7.863E-05 for children and 3.999E-04 for adults. Sensitivity analysis reveals exposure duration and relative skin adherence factor for soil as the most influential parameter of the assessment, followed by BaP equivalent concentration of polycyclic aromatic hydrocarbons. For sediments, biota to sediment accumulation factor of fish in terms of BaP is most sensitive on the total outcome, followed by BaP equivalent and exposure duration. Individual exposure route analysis showed dermal contact for soils and food ingestion for sediments as the main exposure pathway. Some specific locations such as surrounding areas of Bhavnagar, Raniganj, Sunderban, Raipur, and Delhi demand potential strategies of carcinogenic risk management and reduction. The current study is probably the first attempt to provide information on the carcinogenic risk of polycyclic aromatic hydrocarbons in soil and sediments across India. PMID- 28801752 TI - Biosimilar G-CSF versus filgrastim and lenograstim in healthy unrelated volunteer hematopoietic stem cell donors. AB - The World Marrow Donor Organization recommends original granulocyte-colony stimulating factor (G-CSF) for the mobilization of stem cells in healthy unrelated hematopoietic stem cell donors. We report the comparison of a biosimilar G-CSF (Zarzio) with two original G-CSFs (filgrastim and lenograstim) in mobilization in unrelated donors. We included data of 313 consecutive donors who were mobilized during the period from October 2014 to March 2016 at the Medical University of Warsaw. The primary endpoints of this study were the efficiency of CD34+ cell mobilization to the circulation and results of the first apheresis. The mean daily dose of G-CSF was 9.1 MUg/kg for lenograstim, 9.8 MUg/kg for biosimilar filgrastim, and 9.3 MUg/kg for filgrastim (p < 0.001). The mean CD34+ cell number per microliter in the blood before the first apheresis was 111 for lenograstim, 119 for biosimilar filgrastim, and 124 for filgrastim (p = 0.354); the mean difference was even less significant when comparing CD34+ number per dose of G-CSF per kilogram (p = 0.787). Target doses of CD34+ cells were reached with one apheresis in 87% donors mobilized with lenograstim and in 93% donors mobilized with original and biosimilar filgrastim (p = 0.005). The mobilized apheresis outcomes (mean number of CD34+ cells/kg of donor collected during the first apheresis) was similar with lenograstim, biosimilar filgrastim, and filgrastim: 6.2 * 106, 7.6 * 106, and 7.3 * 106, respectively, p = 0.06. There was no mobilization failure in any of the donors. Biosimilar G-CSF is as effective in the mobilization of hematopoietic stem cells in unrelated donors as original G-CSFs. Small and clinically irrelevant differences seen in the study can be attributed to differences in G-CSF dose and collection-related factors. Active safety surveillance concurrent to clinical use and reporting to donor outcome registry (e.g., EBMT donor outcome registry or WMDA SEAR/SPEAR) might help to evaluate the possible short- and long-term complications of biosimilar G CSF. PMID- 28801751 TI - Activity Demands During Multi-Directional Team Sports: A Systematic Review. AB - BACKGROUND: Late-stage rehabilitation programs often incorporate 'sport-specific' demands, but may not optimally simulate the in-game volume or intensity of such activities as sprinting, cutting, jumping, and lateral movement. OBJECTIVE: The aim of this review was to characterize, quantify, and compare straight-line running and multi-directional demands during sport competition. DATA SOURCES: A systematic review of PubMed, CINAHL, SPORTDiscus, and Cochrane Central Register of Controlled Trials databases was conducted. STUDY ELIGIBILITY CRITERIA: Studies that reported time-motion analysis data on straight-line running, accelerations/decelerations, activity changes, jumping, cutting, or lateral movement over the course of an entire competition in a multi-directional sport (soccer, basketball, lacrosse, handball, field hockey, futsal, volleyball) were included. STUDY APPRAISAL AND SYNTHESIS METHODS: Data was organized based on sport, age level, and sex and descriptive statistics of the frequency, intensity, time, and volume of the characteristics of running and multi-directional demands were extracted from each study. RESULTS: Eighty-one studies were included in the review (n = 47 soccer, n = 11 basketball, n = 9 handball, n = 7 field hockey, n = 3 futsal, n = 4 volleyball). Variability of sport demand data was found across sports, sexes, and age levels. Specifically, soccer and field hockey demanded the most volume of running, while basketball required the highest ratio of high intensity running to sprinting. Athletes change activity between 500 and 3000 times over the course of a competition, or once every 2-4 s. Studies of soccer reported the most frequent cutting (up to 800 per game), while studies of basketball reported the highest frequency of lateral movement (up to 450 per game). Basketball (42-56 per game), handball (up to 90 per game), and volleyball (up to 35 per game) were found to require the most jumping. LIMITATIONS: These data may provide an incomplete view of an athlete's straight-line running load, considering that only competition and not practice data was provided. CONCLUSIONS: Considerable variability exists in the demands of straight-line running and multi-directional demands across sports, competition levels, and sexes, indicating the need for sports medicine clinicians to design future rehabilitation programs with improved specificity (including the type of activity and dosage) to these demands. PMID- 28801750 TI - Cutaneous Drug Reactions in the Elderly. AB - Cutaneous adverse drug reactions comprise a significant proportion of all adverse drug reactions. They may mimic other dermatologic or systemic illnesses and may cause significant morbidity or mortality. Seven morphologic groups encompass the most commonly encountered cutaneous drug reaction syndromes: exanthematous (maculopapular), dermatitic/eczematous, urticarial, pustular, blistering, purpuric, and erythrodermic. Drug reactions may have significant downstream consequences for the older individual. PMID- 28801753 TI - The corpus callosum as anatomical marker of intelligence? A critical examination in a large-scale developmental study. AB - Intellectual abilities are supported by a large-scale fronto-parietal brain network distributed across both cerebral hemispheres. This bihemispheric network suggests a functional relevance of inter-hemispheric coordination, a notion which is supported by a series of recent structural magnetic resonance imaging (MRI) studies demonstrating correlations between intelligence scores (IQ) and corpus callosum anatomy. However, these studies also reveal an age-related dissociation: mostly positive associations are reported in adult samples, while negative associations are found in developing samples. In the present study, we re-examine the association between corpus callosum and intelligence measures in a large (734 datasets from 495 participants) developmental mixed cross-sectional and longitudinal sample (6.4-21.9 years) using raw test scores rather than deviation IQ measures to account for the ongoing cognitive development in this age period. Analyzing mid-sagittal measures of regional callosal thickness, a positive association in the splenium of the corpus callosum was found for both verbal and performance raw test scores. This association was not present when the participants' age was considered in the analysis. Thus, we did not reveal any association that cannot be explained by a temporal co-occurrence of overall developmental trends in intellectual abilities and corpus callosum maturation in the present developing sample. PMID- 28801754 TI - Expression profiling of Tas2r genes reveals a complex pattern along the mouse GI tract and the presence of Tas2r131 in a subset of intestinal Paneth cells. AB - The chemical variability of the intestinal lumen requires the presence of molecular receptors detecting the various substances naturally occurring in the diet and as a result of the activity of the microbiota. Despite their early discovery, intestinal bitter taste receptors (Tas2r) have not yet been assigned an unambiguous physiological function. Recently, using a CRE-recombinant approach we showed that the Tas2r131 gene is expressed in a subset of mucin-producing goblet cells in the colon of mice. Moreover, we also demonstrated that the expression of the Tas2r131 locus is not restricted to this region. In the present study we aimed at characterizing the presence of positive cells also in other gastrointestinal regions. Our results show that Tas2r131+ cells appear in the jejunum and the ileum, and are absent from the stomach and the duodenum. We identified the positive cells as a subpopulation of deep-crypt Paneth cells in the ileum, strengthening the notion of a defensive role for Tas2rs in the gut. To get a broader perspective on the expression of bitter taste receptors in the alimentary canal, we quantified the expression of all 35 Tas2r genes along the gastrointestinal tract by qRT-PCR. We discovered that the number and expression level of Tas2r genes profoundly vary along the alimentary canal, with the stomach and the colon expressing the largest subsets. PMID- 28801755 TI - A cross-national comparison of violence among young men in China and the UK: psychiatric and cultural explanations. AB - PURPOSE: Public health psychiatry has a key role in violence prevention. Cross national comparisons of violence and associated psychiatric morbidity can indicate targets for preventive interventions. METHOD: Data on young adult men in households, 18-34 years, were drawn from the Second Men's Modern Lifestyles survey in Great Britain (n = 2046) and from a corresponding survey in Chengdu, China (n = 4132), using a translated questionnaire. Binary logistic regression models were carried out to estimate the cross-national differences for different types of violence and to identify explanatory variables. RESULTS: Chinese men were less likely to report violence in the past 5 years (AOR 0.59, 95% CI 0.48 0.72, P < 0.001). All levels of violence were lower among Chinese men except intimate partner violence (AOR 2.43, 95% CI 1.65-3.59, P < 0.001) and a higher proportion of Chinese men were only violent towards their partners (AOR 7.90, 95% CI 3.27-19.07, P < 0.001). CONCLUSIONS: Cross-national differences were explained by British men's reports of early violence persisting into adulthood, confidence in fighting ability, perception that violence is acceptable behaviour, and experience of violent victimization. More British men screened positive for antisocial personality disorder and substance misuse. Attitudes which condone violence and a serious problem of alcohol-related, male-on-male violence are key targets for preventive interventions among British men. The higher prevalence of life course-persistent antisocial behaviour among British men is of concern and requires further investigation. Higher prevalence of intimate partner violence among Chinese men reflects patriarchal approaches to conflict resolution and confirms an important public health problem in China which requires further cross national investigation. PMID- 28801756 TI - Segregation distortion and genome-wide digenic interactions affect transmission of introgressed chromatin from wild cotton species. AB - KEY MESSAGE: This study reports transmission genetics of chromosomal segments into Gossypium hirsutum from its most distant euploid relative, Gossypium mustelinum . Mutilocus interactions and structural rearrangements affect introgression and segregation of donor chromatin. Wild allotetraploid relatives of cotton are a rich source of genetic diversity that can be used in genetic improvement, but linkage drag and non-Mendelian transmission genetics are prevalent in interspecific crosses. These problems necessitate knowledge of transmission patterns of chromatin from wild donor species in cultivated recipient species. From an interspecific cross, Gossypium hirsutum * Gossypium mustelinum, we studied G. mustelinum (the most distant tetraploid relative of Upland cotton) allele retention in 35 BC3F1 plants and segregation patterns in BC3F2 populations totaling 3202 individuals, using 216 DNA marker loci. The average retention of donor alleles across BC3F1 plants was higher than expected and the average frequency of G. mustelinum alleles in BC3F2 segregating families was less than expected. Despite surprisingly high retention of G. mustelinum alleles in BC3F1, 46 genomic regions showed no introgression. Regions on chromosomes 3 and 15 lacking introgression were closely associated with possible small inversions previously reported. Nonlinear two-locus interactions are abundant among loci with single-locus segregation distortion, and among loci originating from one of the two subgenomes. Comparison of the present results with those of prior studies indicates different permeability of Upland cotton for donor chromatin from different allotetraploid relatives. Different contributions of subgenomes to two-locus interactions suggest different fates of subgenomes in the evolution of allotetraploid cottons. Transmission genetics of G. hirsutum * G. mustelinum crosses reveals allelic interactions, constraints on fixation and selection of donor alleles, and challenges with retention of introgressed chromatin for crop improvement. PMID- 28801757 TI - DFT study of the interactions between thiophene-based corrosion inhibitors and an Fe4 cluster. AB - Understanding the physicochemical properties of corrosion inhibitors and their chemical interactions with metal surfaces is crucial to the design of improved (i.e., more efficient) corrosion inhibitors. In this work, the physicochemical properties of six thiophene-based corrosion inhibitors (2-acetylthiophene (AT), 2 formylthiophene (FT), thiophene (Th), 2-methyl-3-thiophenthiol (MTT), 2 pentylthiophene (PT), and 2-thenylthiol (TT)) were systematically studied by performing ab initio calculations at the MP2(full)/6-31G(2df,p) level of theory. Adsorption of the inhibitors on an iron surface was also modeled by investigating the interactions of these molecules with a tetrahedral Fe4 cluster using the B3LYP method and the 6-311G(d,p) basis set or the LanL2DZ basis set. The calculated results indicate that the nature of the substituent group present has a significant impact on the geometric and electronic structures of the thiophene based molecules. The presence of an electron-donating group causes the electron density in the thiophene ring to increase, while the presence of an electron withdrawing group has the opposite effect. Accordingly, the examined molecules were ranked in order of corrosion inhibition efficiency as follows: FT ~ AT < Th < PT < TT < MTT. The calculated binding energies demonstrated that the pi-1Fe and pi-3Fe interaction configurations dominated over the S-1Fe configuration for all the compounds. Natural bond orbital analysis revealed that all of the thiophene based compounds donate electrons from the pi and sigma orbitals of high-electron density regions such as C2-S1-C5 and C3-C4 or from two lone pairs on S1 to the Fe4 cluster. Although electron donation from the thiophene-based compounds is always the dominant electron transfer process during adsorption, the backdonation of electrons from the 3d orbital of iron to sigma*-antibonding orbitals of the thiophene compounds is also observed, especially in the case of pi-3Fe parallel adsorption. Graphical abstract Optimized geometry, HOMO and LUMO for the pi-3Fe interaction configuration of 2-pentylthiophene and Fe4 cluster. PMID- 28801759 TI - ? PMID- 28801758 TI - PRKAG2 mutations presenting in infancy. AB - PRKAG2 encodes the gamma2 subunit of AMP-activated protein kinase (AMPK), which is an important regulator of cardiac metabolism. Mutations in PRKAG2 cause a cardiac syndrome comprising ventricular hypertrophy, pre-excitation, and progressive conduction-system disease, which is typically not diagnosed until adolescence or young adulthood. However, significant variability exists in the presentation and outcomes of patients with PRKAG2 mutations, with presentation in infancy being underrecognized. The diagnosis of PRKAG2 can be challenging in infants, and we describe our experience with three patients who were initially suspected to have Pompe disease yet ultimately diagnosed with mutations in PRKAG2. A disease-causing PRKAG2 mutation was identified in each case, with a novel missense mutation described in one patient. We highlight the potential for patients with PRKAG2 mutations to mimic Pompe disease in infancy and the need for confirmatory testing when diagnosing Pompe disease. PMID- 28801760 TI - The Need for Authenticity-Based Autonomy in Medical Ethics. AB - The notion of respect for autonomy dominates bioethical discussion, though what qualifies precisely as autonomous action is notoriously elusive. In recent decades, the notion of autonomy in medical contexts has often been defined in opposition to the notion of autonomy favoured by theoretical philosophers. Where many contemporary theoretical accounts of autonomy place emphasis on a condition of "authenticity", the special relation a desire must have to the self, bioethicists often regard such a focus as irrelevant to the concerns of medical ethics, and too stringent for use in practical contexts. I argue, however, that the very condition of authenticity that forms a focus in theoretical philosophy is also essential to autonomy and competence in medical ethics. After tracing the contours of contemporary authenticity-based theories of autonomy, I consider and respond to objections against the incorporation of a notion of authenticity into accounts of autonomy designed for use in medical contexts. By looking at the typical problems that arise when making judgments concerning autonomy or competence in a medical setting, I reveal the need for a condition of authenticity-as a means of protecting choices, particularly high-stakes choices, from being restricted or overridden on the basis of intersubjective disagreement. I then turn to the treatment of false and contestable beliefs, arguing that it is only through reference to authenticity that we can make important distinctions in this domain. Finally, I consider a potential problem with my proposed approach; its ability to deal with anorexic and depressive desires. PMID- 28801761 TI - Milonine, a Morphinandienone Alkaloid, Has Anti-Inflammatory and Analgesic Effects by Inhibiting TNF-alpha and IL-1beta Production. AB - Milonine is a morphinandienone alkaloid from Cissampelos sympodialis Eichl (Menispermaceae), a plant used in Brazil to treat inflammatory disorders. In this study, we evaluated the anti-inflammatory and analgesic activity of milonine (MIL) by using classical experimental models of inflammation and nociception. The results showed that MIL reduced the paw edema formation induced by lipopolysaccharide, prostaglandin E2, and bradykinin, without interfering with the serotonin-induced edema. With respect to the nociception experiments, MIL decreased the exudate into the peritoneum induced by acetic acid, maintaining the tissue morphology. The alkaloid was able to inhibit the peritonitis induced by carrageenan, decreasing mainly the migration of polymorphonuclear cells, without altering the mononuclear cell number, and reduced the levels of TNF-alpha and IL 1beta in the peritoneum. In addition, MIL was able to decrease the frequency of abdominal writhing induced by acetic acid but did not increase the latency time of the animals in the hot plate test. MIL significantly reduced the nociceptive behavior of paw licking induced by formalin only at the second phase of the test. In conclusion, we demonstrate that milonine has anti-inflammatory and anti nociceptive activities by inhibiting mediators essential for the inflammatory process. PMID- 28801763 TI - A situational analysis of breast cancer early detection services in Trinidad and Tobago. AB - PURPOSE: A situational analysis of breast cancer (BC) early detection services was carried out to investigate whether Trinidad and Tobago (T&T) has the framework for successful organized national screening. METHODS: An online survey was designed to assess the availability, accessibility, quality control and assurance (QC&A), and monitoring and evaluation (M&E) mechanisms for public and private BC early detection. A focus group with local radiologists (n = 3) was held to identify unaddressed challenges and make recommendations for improvement. RESULTS: Major public hospitals offer free detection services with wait times of 1-6 months for an appointment. Private institutions offer mammograms for TTD$240 (USD$37) at minimum with same day service. Both sectors report a lack of trained staff. Using 1.2 mammograms per 10,000 women >=40 years as sufficient, the public sector's rate of 0.19 mammograms per 10,000 women >=40 years for screening and diagnosis is inadequate. Program M&E mechanisms, QC&A guidelines for machinery use, delays in receipt of pathology reports, and unreliable drug access are further unaddressed challenges. CONCLUSION: T&T must first strengthen its human and physical resources, implement M&E and QC&A measures, strengthen cancer care, and address other impediments to BC early detection before investing in nationally organized BC screening. PMID- 28801762 TI - Does the use of the proportional shortfall help align the prioritisation of health services with public preferences? AB - It has been proposed that equity may be included in the economic evaluation of health services using the 'proportional shortfall' (PS)-the proportion of a person's QALY expectation that they would lose because of an illness. The present paper reports the results of a population survey designed to test whether PS helped to explain people's preferences for health services and whether it did this better than the absolute shortfall or the equity related variables that PS seeks to replace. Survey respondents were asked to allocate 100 votes between 13 scenarios and a standard scenario. Variation in the allocation of votes was explained by health gain and different combinations of the equity variables. Differences in votes for the comparisons were significantly related to differences in PS but the relationship was weaker than between votes and the age related variables. Cases were identified where PS suggested a priority ordering of services which was strongly rejected by respondents. It is concluded that the use of PS is unlikely to improve the alignment of priorities with public preferences. PMID- 28801766 TI - Absence of cardiotoxicity with prolonged treatment and large accumulating doses of pegylated liposomal doxorubicin. AB - BACKGROUND: Pegylated liposomal doxorubicin (PLD) is used as a second-line therapy for gynecologic cancers, with a better short-term toxicity profile compared to doxorubicin or other anthracyclines. METHODS: We screened 14 patients with recurrent gynecologic cancers, who underwent prolonged treatment with large cumulative doses of PLD for overt or subtle signs of cardiotoxicity (CTX) using standard and advanced echocardiography techniques [3D volumetric method for left ventricular ejection fraction (LVEF) and left ventricular/right ventricular global longitudinal strain]. Half the patients had previous echocardiographic studies available for comparison. RESULTS: The average PLD treatment duration was 23.6 +/- 10.8 months (range 13-57), accumulating dose of 1387 +/- 483 mg (range 780-2538 mg). The study group had a normal LVEF both by 2D-echo (60 +/- 5%, range 50-67) and 3D echo (58 +/- 5%, range 46-63). Two patients (14%) were found to have minimally reduced ejection fraction by 2D and 3D echo (50%/46% and 51%/49%, respectively) that did not meet the current definition of CTX. For the seven patients who had consecutive echocardiography studies, the average LVEF remained stable between studies (59 +/- 7, 60 +/- 9 and 58 +/- 10.5% for the latest study, previous, p < 0.79, and most remote study p < 0.9); No change was found in average left ventricular/right ventricular global longitudinal strain as well: 20.8 +/- 4.6% at the latest study and -19.3 +/- 2.6% for the previous (p < 0.51). CONCLUSION: No prevalent or incident cases of cardiotoxicity were found despite prolonged treatment with large cumulative doses of PLD, adding to previous reports on shorter treatment duration. PMID- 28801767 TI - Experimental validation of predicted application accuracies for computer-assisted (CAS) intraoperative navigation with paired-point registration. AB - PURPOSE: The target registration error (TRE) is a crucial parameter to estimate the potential usefulness of computer-assisted navigation intraoperatively. Both image-to-patient registration on base of rigid-body registration and TRE prediction methods are available for spatially isotropic and anisotropic data. This study presents a thorough validation of data obtained in an experimental operating room setting with CT images. METHODS: Optical tracking was used to register a plastic skull, an anatomic specimen, and a volunteer to their respective CT images. Plastic skull and anatomic specimen had implanted bone fiducials for registration; the volunteer was registered with anatomic landmarks. Fiducial localization error, fiducial registration error, and total target error (TTE) were measured; the TTE was compared to isotropic and anisotropic error prediction models. Numerical simulations of the experiment were done additionally. RESULTS: The user localization error and the TTE were measured and calculated using predictions, both leading to results as expected for anatomic landmarks and screws used as fiducials. TRE/TTE is submillimetric for the plastic skull and the anatomic specimen. In the experimental data a medium correlation was found between TRE and target localization error (TLE). Most of the predictions of the application accuracy (TRE) fall in the 68% confidence interval of the measured TTE. For the numerically simulated data, a prediction of TTE was not possible; TRE and TTE show a negligible correlation. CONCLUSION: Experimental application accuracy of computer-assisted navigation could be predicted satisfactorily with adequate models in an experimental setup with paired-point registration of CT images to a patient. The experimental findings suggest that it is possible to run navigation and prediction of navigation application accuracy basically defined by the spatial resolution/precision of the 3D tracker used. PMID- 28801768 TI - The influence of particle size and feedstock of biochar on the accumulation of Cd, Zn, Pb, and As by Brassica chinensis L. AB - Biochar produced from rice straw (RC) and maize stalk (MC) was amended to the heavy metal-contaminated soil to investigate the effects of different biochar feedstock and particle size (fine, moderate, coarse) on the accumulation of Cd, Zn, Pb, and As in Brassica chinensis L. (Chinese cabbage). The concentrations of Cd, Zn, and Pb in shoot were decreased by up to 57, 75, and 63%, respectively, after biochar addition (4%). Only MC decreased As concentration in B. chinensis L. shoots by up to 61%. Biochar treatments significantly decreased NH4NO3 extractable concentrations of Cd, Zn, and Pb in soil by 47-62, 33-66, and 38-71%, respectively, yet increased that of As by up to 147%. Amendment of RC was more effective on immobilizing Cd, Zn, and Pb, but mobilizing soil As, than MC. A decrease in biochar particle size greatly contributed to the immobilization of Cd, Zn, and Pb in soil and thereby the reduction of their accumulations in B. chinensis L. shoots, especially RC. Increases in soil pH and extractable P induced by biochar addition contributed to the sequestration of Cd, Zn, and Pb and the mobilization of As. Shoot biomass, root biomass, and root system of B. chinensis L. were enhanced with biochar amendments, especially RC. This study indicates that biochar addition could potentially decrease Cd, Zn, Pb, and As accumulations in B. chinensis L., and simultaneously increase its yield. A decrease in biochar particle size is favorable to improve the immobilization of heavy metals (except As). The reduction in Cd, Zn, Pb, and As levels in B. chinensis L. shoots by biochar amendment could be mainly attributed to a function of heavy metal mobility in soil, plant translocation factor, and root uptake. PMID- 28801769 TI - Illusory limb movements activate different brain networks than imposed limb movements: an ALE meta-analysis. AB - Proprioceptive information allows us to perform smooth coordinated movements by constantly updating us with knowledge of the position of our limbs in space. How this information is combined and processed to form conscious perceptions of limb position is still relatively unknown. Several functional neuroimaging studies have attempted to tease out the brain areas responsible for proprioceptive processing in the human brain. Yet there still exists some disagreement in the specific brain regions involved. In order to consolidate the current knowledge in the field, we performed a systematic review of the literature and an activation likelihood estimation (ALE) meta-analysis of functional neuroimaging studies of proprioception. We identified 12 studies that used a proprioceptive stimulus of the upper extremity for ALE analysis (n = 141 participants). Two types of stimuli (illusion of movement induced through muscle tendon vibration and passive/imposed movements) were found to be most commonly used to probe proprioceptive networks in the brain. ALE analysis of these two stimulus types revealed that both were associated with activation in the left precentral, postcentral, and anterior cingulate gyri. Interestingly, different patterns of activation were also observed between illusions of movement and imposed movement. In the left hemisphere, imposed movements resulted in activations that were more inferior in the post-central gyrus. In the right hemisphere, imposed movements resulted in two clusters of activation in the inferior aspect of the precentral gyrus and the hand area of the post-central gyrus, while illusions of movement resulted in a single cluster of activation in the inferior parietal lobule. These results suggest that illusions of movement without limb displacement may activate different brain areas compared with actual limb displacement. Careful consideration should be made in future studies when selecting a proprioceptive stimulus to probe these brain networks. PMID- 28801770 TI - Nutrient composition of culture media induces different patterns of CO2 fixation from biogas and biomass production by the microalga Scenedesmus obliquus U169. AB - Microalgae are considered as a promising biotechnological strategy to capture CO2 from biogas, producing biomass with valuable energetic compounds. This study has evaluated the biotechnological potential to fix CO2 from biogas and biomass production by Scenedesmus obliquus cultured in four different formulations of culture media, C30, Bristol, Bold 3N, and C30+M, as well as the effect of methane (CH4) of biogas during CO2 fixation and biomass production. The results obtained showed that different nutrient composition and concentration of culture media, mainly micronutrient and vitamin concentrations, induced different patterns of CO2 fixation from biogas and biomass production in S. obliquus. The highest CO2 fixation (23.03 +/- 0.24%) and biomass production (4.63 +/- 0.31 g L-1) were attained in the microalgae growing in C30+M medium, accumulating mainly proteins. Moreover, these results demonstrated that the CH4 of biogas did not affect CO2 fixation from biogas and biomass production by S. obliquus. Overall, these results demonstrated that a culture medium with a balanced nutrient supply is crucial to increasing the biotechnological potential of microalgae to fix CO2 from biogas. PMID- 28801771 TI - Morphology and ultrastructure of the tarsal adhesive organs of the Madagascar hissing cockroach Gromphadorhina portentosa. AB - The present transmission and scanning electron microscopic study of the ultramorphology of the pliable attachment pads (arolium, euplantulae) of the Madagascar hissing cockroach Gromphadorhina portentosa reveals structural evidence for their function in producing, storing, and secreting an adhesion mediating secretion and releasing it to the exterior. The exocrine epidermal tissue of both the arolium and the euplantula is significantly enlarged by numerous invaginations stretching into the hemolymph cavity. Its cells show large nuclei, numerous mitochondria, Golgi complexes, and a prominent rough-surfaced endoplasmic reticulum integrated within an electron-dense cytoplasm that contains numerous vesicles of diverse electron density and size. Invaginations of the cell membrane provide evidence for strong membrane turnover. The glandular epithelium of both the arolium and the euplantula releases the adhesion-mediating secretion into a subcuticular void from which it has to permeate the thick cuticle of the adhesive pads. The subcuticular void is compartmentalized by cuticle bands through which the adhesion-mediating secretion permeates via small canals. The secretion subsequently enters a larger storage reservoir before being received by a prominent sponge-like cuticle. The structural differences between the arolium and the euplantula consist of the number and length of the interdigitations spanning the hemolymph cavity, of the subdivision of the subcuticular reservoir by cuticle bands, and of the thickness of the sponge-like cuticle. The structural results are discussed with respect to the production of a chemically complex (emulsion-like) adhesive, its controlled release to the exterior, and the micromechanical properties of the cuticle of the pliable pad. PMID- 28801772 TI - CORR Insights(r): What Factors Predict Conversion to THA After Arthroscopy? PMID- 28801773 TI - Growth Performance, Mineral Digestibility, and Blood Characteristics of Ostriches Receiving Drinking Water Supplemented with Varying Levels of Chelated Trace Mineral Complex. AB - The effects of water supplementation of chelated trace minerals (CTM, which is named Bonzaplex designed with chelate compounds technology) on growth performance, apparent total tract digestibility (ATTD) of minerals, and some blood metabolites, TM, and antioxidant enzyme values in African ostriches were investigated from 8 to 12 months of age. A total of 20 8-month-old ostriches (five birds in five replicate pens) was randomly allocated into one of the following four treatments: (1) control (basal diet + tap water), (2) low CTM (basal diet +100 mg/bird/day CTM powder in tap water), (3) medium CTM (basal diet +1 g/bird/day CTM powder in tap water), and (4) high CTM (basal diet +2 g/bird/day CTM powder in tap water). Compared with control, medium CTM improved (P < 0.05) daily weight gain and ATTD of phosphorous, zinc, and copper in 12 month-old ostriches. Furthermore, the feed conversion ratio was lower, and ATTD of magnesium was higher in the medium- and high-CTM groups than that in the control group (P < 0.05). At the end of the trial, ostriches receiving high-CTM treatment exhibited the lower (P < 0.05) serum triglyceride and very low-density lipoprotein cholesterol concentrations and higher copper levels compared to those of the control treatment. Supplementation of higher amounts of CTM (medium and high CTM) also increased the activity of serum superoxide dismutase (P < 0.05). No differences were detected for other blood parameters including glucose, total protein, albumin, cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, iron, magnesium, and glutathione peroxidase values. In conclusion, supplementation of CTM at the level of 1 g/bird/day to the drinking water can be recommended for improving growth performance, mineral absorption, and antioxidant status of ostriches fed diets containing the recommended levels of inorganic TM. PMID- 28801774 TI - Bcl-2 antigen expression in luminal A and triple-negative breast cancer. AB - Biomarkers for the prognosis of breast cancer have been routinely used in clinical practice, including the expression of hormone receptors, Ki-67 and HER 2. More recently, Bcl-2 has been recognized as an important prognostic factor in breast cancer, although controversies persist with respect to the significance of its expression. The aim of the present study was to evaluate Bcl-2 antigen expression in luminal A and triple-negative breast cancer. Sixty women with invasive ductal carcinoma were included in the study and divided into two groups: Group A (luminal A) and Group B (triple-negative), with 30 cases in each group. Immunohistochemistry was performed on tissue sections to evaluate Bcl-2 antigen expression. Fisher's exact test was used to compare the proportions of cases with cells expressing Bcl-2 between the two subtype cancer groups, with statistical significance being established at p < 0.05. The number of cases with cells expressing Bcl-2 in Groups A and B was 26 (86.7%) and 12 (40.0%), respectively (p < 0.0003). In the present study, the expression of the anti-apoptotic protein Bcl 2 was greater in luminal A breast cancer tissue samples compared to triple negative breast cancer. PMID- 28801775 TI - Plasticizers and bisphenol A, in packaged foods sold in the Tunisian markets: study of their acute in vivo toxicity and their environmental fate. AB - Today, processed and packaged foods are considered as among the major sources of human exposure to plasticizers and bisphenol which migrate from plastic packing. In the present study, a wide range of food products sold on the Tunisian market such as grain and grain products, milk and dairy products, fats and oil, drink, fish, and sweets have been analyzed firstly in order to identify the presence of phthalates and bisphenol. Then, the identified chemical molecules were studied for their environmental fate and tested in vivo for its toxicity in mice models. The food products analyzed using GC-MS/MS indicated the presence of the benzyl butyl phthalate (BBP), dibutyl phthalate (DBP), bis(2-ethylhexyl) phthalate (DEHP), diisodecyl phthalate (DiDP), diisononyl phthalate (DiNP), and 1,2 cyclohexane dicarboxylic acid diisononyl ester (DINC) and which using UPLC-MS/MS demonstrated the presence of bisphenol A of all food products. However, compared to other phthalates, BBP was found at high concentrations in the puff pastry (123 mg/kg), milk (2.59 mg/kg), butter (1.5 mg/kg), yogurt (2.23 mg/kg), oil (6.94 mg/kg), water (0.57 mg/kg), candy 1 (2.35 mg/kg), candy 2 (0.81 mg/kg), orange juice (1.25 mg/kg), peach juice (1.26 mg/kg), fruit juices (0.4 mg/kg), and chocolate (0.884 mg/kg). The obtained data in vivo clearly showed that the acute administration of BBP caused hepatic and renal damage as demonstrated by an increase in biochemical parameters as well as the activities of plasma marker enzymes such as alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, blood urea nitrogen, glucose, urea, creatinine, and uric acid when compared to the control group. By the same occurrence, the histopathological study revealed that BBP strongly modified the structure of hepatic and renal tissues. In addition, the plasticizers and BBP will therefore discharge via wastewater treatment plants in aquatic system and could reach marine organisms such as fish. We have followed the fate of BBP in bream Sparus aurata. In fact, chemical analysis showed the contamination of wild S. aurata by BBP from Sousse Coast (1.5 mg/kg) and wild S. aurata from Monastir Coast (0.33 mg/kg). PMID- 28801776 TI - Effects of training status on PDH regulation in human skeletal muscle during exercise. AB - Pyruvate dehydrogenase (PDH) is the gateway enzyme for carbohydrate-derived pyruvate feeding into the TCA cycle. PDH may play a central role in regulating substrate shifts during exercise, but the influence of training state on PDH regulation during exercise is not fully elucidated. The purpose of this study was to investigate the impact of training state on post-translational regulation of PDHa activity during submaximal and exhaustive exercise. Eight untrained and nine endurance exercise-trained healthy male subjects performed incremental exercise on a cycle ergometer: 40 min at 50% incremental peak power output (IPPO), 10 min at 65% (IPPO), followed by 80% (IPPO) until exhaustion. Trained subjects had higher (P < 0.05) PDH-E1alpha, PDK1, PDK2, PDK4, and PDP1 protein content as well as PDH phosphorylation and PDH acetylation. Exercising at the same relative intensity led to similar muscle PDH activation in untrained and trained subjects, whereas PDHa activity at exhaustion was higher (P < 0.05) in trained than untrained. Furthermore, exercise induced similar PDH dephosphorylation in untrained and trained subjects, while PDH acetylation was increased (P < 0.05) only in trained subjects. In conclusion, PDHa activity and PDH dephosphorylation were well adjusted to the relative exercise intensity during submaximal exercise. In addition, higher PDHa activity in trained than untrained at exhaustion seemed related to differences in glycogen utilization rather than differences in PDH phosphorylation and acetylation state, although site-specific contributions cannot be ruled out. PMID- 28801777 TI - An internally validated new clinical and inflammation-based prognostic score for patients with advanced hepatocellular carcinoma treated with sorafenib. AB - BACKGROUND: Sorafenib is a standard treatment for patients (pts) with advanced hepatocellular carcinoma (aHCC), although the clinical benefit is heterogeneous between different pts groups. Among novel prognostic factors, a low baseline neutrophil-to-lymphocyte ratio (bNLR) and early-onset diarrhoea have been linked with a better prognosis. PURPOSE: To identify prognostic factors in pts with aHCC treated with 1st-line sorafenib and to develop a new prognostic score to guide management. MATERIALS AND METHODS: Retrospective review of 145 pts bNLR, overall toxicity, early toxicity rates and overall survival (OS) were assessed. Univariate and multivariate analysis of prognostic factors for OS was performed. The prognostic score was calculated from the coefficients found in the Cox analysis. ROC curves and pseudoR2 index were used for internal validation. Discrimination ability and calibration were tested by Harrel's c-index (HCI) and Akaike criteria (AIC). RESULTS: The optimal bNLR cut-off for the prediction of OS was 4 (AUC 0.62). Independent prognostic factors in multivariate analysis for OS were performance status (PS) (p < .0001), Child-Pugh (C-P) score (p = 0.005), early-onset diarrhoea (p = 0.006) and BNLR (0.011). The prognostic score based on these four variables was found efficient (HCI = 0.659; AIC = 1.180). Four risk groups for OS could be identified: a very low-risk (median OS = 48.6 months), a low-risk (median OS = 11.6 months), an intermediate-risk (median OS = 8.3 months) and a high-risk group (median OS = 4.4 months). CONCLUSIONS: PS and C-P score were the main prognostic factors for OS, followed by early-onset diarrhoea and bNLR. We identified four risk groups for OS depending on these parameters. This prognostic model could be useful for patient stratification, but an external validation is needed. PMID- 28801779 TI - TOF MS Investigation of Nickel Oxide CVD. AB - NiO layers were deposited by metal-organic chemical vapor deposition using bis (ethylcyclopentadienyl) nickel (EtCp)2Ni and oxygen or ozone. As a continuation of kinetic study of NiO MOCVD the gas-phase, transformations of (EtCp)2Ni were studied in the temperature range of 380-830 K. Time of reactions corresponding to the residence time of the gas stream in hot zone of the reactor was about 0.1 s under conditions studied. The interaction of (EtCp)2Ni with oxygen started at 450 K and its conversion rate reached the maximum at 700 K. The interaction of (EtCp)2Ni with ozone started at 400 K and its conversion rate reached the maximum at 600 K. Transformations of the gas phase with the temperature in the reaction zone were studied, the model reaction schemes illustrating (EtCp)2Ni transformations in the reaction systems containing oxygen and ozone have developed. In the reaction system (EtCp)2Ni-O2-Ar the main gas-phase products at 380-500 K were CO, CO2, HCO, C2H5OH, CpCOOH, and CpO. Formation of the C2H2O, C3H4O, and C5H8O was found at 630-830 K. The same gas-phase species, (C4H3O)2Ni and dialdehydes was formed in the reaction system (EtCp)2Ni-O3-O2-Ar. Graphical Abstract ?. PMID- 28801780 TI - A case of acetaminophen-induced acute tubulointerstitial nephritis in adult. AB - We report a case of allergic acute tubulointerstitial nephritis (TIN) induced by acetaminophen in a 48-year-old Japanese man with no past medical history. Two days after receiving the non-steroidal anti-inflammatory drug (NSAID) loxoprofen for left shoulder pain, he developed cold symptoms such as fever and sore throat. He then took a 300 mg dose of acetaminophen three times a day and a 100 mg dose of minocycline hydrochloride twice a day for 7 days. Because there was no improvement in his symptoms, he consulted a local clinic again, where blood tests revealed renal insufficiency, and he was, then, referred to our hospital for evaluation of kidney function. Renal biopsy revealed acute TIN, and Ga-67 scintigraphy showed diffuse uptake in bilateral kidneys. A drug-induced lymphocyte stimulation test (DLST) was positive for acetaminophen and negative for loxoprofen and minocycline. Based on these findings, we made a diagnosis of acetaminophen-induced TIN. We treated the patient with three courses of semi pulse steroid therapy, after which his fever went down, and his serum creatinine level recovered from 2.09 to 1.43 mg/dL. Although we medical doctors think that therapeutic dose of acetaminophen retains high safety, it is important to keep in mind that acetaminophen can cause allergic acute TIN. PMID- 28801778 TI - Knockdown of eukaryotic translation initiation factor 3 subunit D (eIF3D) inhibits proliferation of acute myeloid leukemia cells. AB - Various eukaryotic translation initiation factors (eIFs) have been implicated in carcinoma development. Eukaryotic translation initiation factor 3 subunit D (eIF3D) has recently been shown to regulate the growth of several types of human cancer cells. However, the function of eIF3D in acute myeloid leukemia (AML) remains unclear. In this study, we investigated the expression of eIF3D in three AML cell lines and a lymphoblast cell line, and found that eIF3D was expressed in all four leukemia cell lines. To explore the role of eIF3D in AML cell proliferation, lentivirus-mediated RNA interference was applied to knock down the expression of eIF3D in U937 cells. The expression of eIF3D was significantly downregulated in U937 cells after eIF3D knockdown, as confirmed by quantitative real-time PCR (qRT-PCR) and Western blot analysis. Knockdown of eIF3D significantly inhibited proliferation of U937 cells. Furthermore, flow cytometry analysis revealed that eIF3D silencing induced cell cycle arrest at the G2/M phase, ultimately leading to apoptosis. Our results indicate that eIF3D plays a key role in the proliferation of AML cells, and suggest that eIF3D silencing might be a potential therapeutic strategy for leukemia. PMID- 28801781 TI - Acute pain crisis in a patient with sickle cell disease undergoing ovarian simulation for fertility preservation prior to curative stem cell transplantation: case report and literature review. AB - PURPOSE: Hematopoietic stem cell transplantation (HSCT) is a cure for sickle cell disease (SCD) but frequently results in permanent sterility. The complications associated with oocyte cryopreservation and risks of future pregnancy are increased in SCD patients. This case report discusses risk reduction strategies and includes a literature review of pregnancy after HSCT. CASE: A 23-year-old woman underwent ovarian stimulation for fertility preservation resulting in cancelation due to acute pain crisis. She underwent a successful oocyte retrieval after exchange transfusion to decrease her hemoglobin S to 30%. This is the second report of a pain crisis in a woman with SCD undergoing oocyte banking. CONCLUSION(S): Women with SCD undergoing fertility preservation may be at increased risk of complications from ovarian stimulation. Risks in pregnancy after HSCT should also be considered before proceeding with fertility preservation. PMID- 28801782 TI - Common Pediatric Medical Emergencies in Office Practice. AB - General Practitioners frequently see children with medical conditions that may evolve into an emergency if not promptly attended to. The most common emergencies encountered in pediatric office practice are respiratory distress, dehydration, anaphylaxis, seizures and trauma. Assessment of children is sometimes difficult as the signs and symptoms might be subtle and not markedly expressed. Also, normal value of vital signs vary with age, thus their interpretation requires discrete knowledge of age appropriate values. Initial approach to a sick child involves formation of initial impression, doing primary assessment, proper history taking and classifying the condition into following categories: Respiratory distress, Respiratory failure, Compensated shock, Decompensated shock and Primary brain dysfunction. Initial management of any pediatric emergency involves assessment of airway, breathing and circulation and providing relevant adequate support. Majority of cardiac arrests in pediatric practice are secondary to progressive respiratory failure and thus, if intervened timely and effectively, will prevent fatal outcome. In a child with shock, compensated state can rapidly evolve to decompensated state, thus necessitating its early recognition and rapid intervention. Anaphylaxis should be suspected in any child with sudden onset of skin or mucosal symptoms along with respiratory, circulatory or gastro-intestinal involvement and adrenaline should be given by intra-muscular route. PMID- 28801783 TI - Screening of additives and other chemicals in polyurethanes by direct analysis in real time mass spectrometry (DART-MS). AB - Direct analysis in real time mass spectrometry (DART-MS) was used to characterize commercial polyurethane (PUR) samples without sample pretreatment. More than 50 substances, such as catalysts, stabilizers, antioxidants, flame retardants, plasticizers, chain extenders, chain terminators, polyols, solvents, degradation products and contaminants, a few of them presumably toxic, were detected and identified in 18 PUR items. The identification of 16 compounds was further confirmed by DART MS/MS experiments. Catalysts were the largest class of compounds detected in the PURs by DART-MS. In each of the 18 PUR samples, at least one catalyst residue was identified. In addition, DART-MS was able to detect the migration of hazardous chemicals from the PURs to other objects. The collision-induced dissociation (CID) properties of two PUR catalysts, such as the protonated bis[2-(dimethylamino)ethyl] ether (DMAEE) and the protonated 2,2 dimorpholinodiethylether (DMDEE), as well as those of two PUR antioxidants (Antioxidant 1135 and Antioxidant 1076), were explored. PMID- 28801784 TI - Prior Repeated Stress Attenuates Cold-Induced Immunomodulation Associated with "Browning" in Mesenteric Fat of Rats. AB - Continuous exposure to cold leads to activation of adaptive thermogenesis in brown adipose tissue but also to induction of brown/beige cell phenotype in white adipose tissue. The aim of this work was to investigate whether prior exposure to immobilization (IMO) stress may affect immune response associated with adipocyte "browning" in mesenteric adipose tissue (mWAT). In the first experiment, Sprague Dawley rats were exposed to acute (3 h) or prolonged (7 days) cold exposure (4 +/ 1 degrees C). 7-day cold stimulated gene expression of uncoupling protein 1 and other "browning"-associated factors. In the second experiment, rats were immobilized for 7 days (2 h daily) followed by exposure to continuous cold for 1 or 7 days. Prior IMO exaggerated cold-induced sympathetic response manifested by elevated tyrosine hydroxylase (TH) protein and norepinephrine in mWAT. Induction of non-sympathetic catecholamine production demonstrated by elevated TH and PNMT (phenylethanolamine N-methyltransferase) mRNAs was observed after 7-day cold; however, prior IMO attenuated this response. 7-day cold-induced gene expression of anti-inflammatory mediators (IL-4, IL-13, IL-10, adiponectin), markers of M2 macrophages (Arg1, Retnlalpha), and eosinophil-associated molecules (eotaxin, IL 5), while inhibited expression of pro-inflammatory cytokines (IFNgamma, IL-1b, IL 6, IL-17) and monocytes (MCP-1, Ly6C). This immune response was accompanied by elevated expression of uncoupling protein-1 and other thermogenic factors. Rats exposed to prior IMO exhibited inhibition of cold-induced immune and "browning" related expression pattern. Overall, we demonstrated that 7-day cold-induced browning"-associated changes in rat mWAT, while prior history of repeated stress prevented this response. PMID- 28801785 TI - [Treatment strategies for mass casualty incidents and terrorist attacks in trauma and vascular surgery : Presentation of a treatment concept]. AB - The treatment of patients in the context of mass casualty incidents (MCI) represents a great challenge for the participating rescue workers and clinics. Due to the increase in terrorist activities it is necessary to become familiar with this new kind of threat to civilization with respect to the medical treatment of victims of terrorist attacks. There are substantial differences between a "normal" MCI and a terrorist MCI with respect to injury patterns (blunt trauma vs. penetrating/perforating trauma), the type and form of the incident (MCI=static situation vs. terrorist attack MCI= dynamic situation) and the different security positions (rescue services vs. police services). This article is concerned with question of which changes in the surgical treatment of patients are made necessary by these new challenges. In this case it is necessary that physicians are familiar with the different injury patterns, whereby priority must be given to gunshot and explosion (blast) injuries. Furthermore, altered strategic and tactical approaches (damage control surgery vs. tactical abbreviated surgical care) are necessary to ensure survival for as many victims of terrorist attacks as possible and also to achieve the best possible functional results. It is only possible to successfully counter these new challenges by changing the mindset in the treatment of terrorist MCI compared to MCI incidents. An essential component of this mindset is the acquisition of a maximum of flexibility. This article would like to make a contribution to this problem. PMID- 28801788 TI - Overview of the experimental and computational approaches to protein design session at the 19th IUPAB congress and 11th EBSA congress. PMID- 28801786 TI - The grapevine VvCAX3 is a cation/H+ exchanger involved in vacuolar Ca2+ homeostasis. AB - MAIN CONCLUSION: The grapevine VvCAX3 mediates calcium transport in the vacuole and is mostly expressed in green grape berries and upregulated by Ca 2+ , Na + and methyl jasmonate. Calcium is an essential plant nutrient with important regulatory and structural roles in the berries of grapevine (Vitis vinifera L.). On the other hand, the proton-cation exchanger CAX proteins have been shown to impact Ca2+ homeostasis with important consequences for fruit integrity and resistance to biotic/abiotic stress. Here, the CAX gene found in transcriptomic databases as having one of the highest expressions in grapevine tissues, VvCAX3, was cloned and functionally characterized. Heterologous expression in yeast showed that a truncated version of VvCAX3 lacking its NNR autoinhibitory domain (sCAX3) restored the ability of the yeast strain to grow in 100-200 mM Ca2+, demonstrating a role in Ca2+ transport. The truncated VvCAX3 was further shown to be involved in the transport of Na+, Li+, Mn2+ and Cu2+ in yeast cells. Subcellular localization studies using fluorescently tagged proteins confirmed VvCAX3 as a tonoplast transporter. VvCAX3 is expressed in grapevine stems, leaves, roots, and berries, especially at pea size, decreasing gradually throughout development, in parallel with the pattern of calcium accumulation in the fruit. The transcript abundance of VvCAX3 was shown to be regulated by methyl jasmonate (MeJA), Ca2+, and Na+ in grape cell suspensions, and the VvCAX3 promotor contains several predicted cis-acting elements related to developmental and stress response processes. As a whole, the results obtained add new insights on the mechanisms involved in calcium homeostasis and intracellular compartmentation in grapevine, and indicate that VvCAX3 may be an interesting target towards the development of strategies for enhancement of grape berry properties. PMID- 28801787 TI - Reduction of 68Ga-PSMA renal uptake with mannitol infusion: preliminary results. AB - PURPOSE: Urea-based prostate-specific membrane antigen (PSMA) ligands labelled with 68Ga or 177Lu are new tracers with great potential for theranostic approaches in prostate cancer. However, clinical studies have shown that the kidneys are one of the off-target organs along with the salivary and lacrimal glands. In the kidneys, PSMA is physiologically expressed in the apical epithelium of the proximal tubules, and mannitol acts as an osmotic diuretic in these tubules. We investigated the potential of mannitol to reduce renal uptake of 68Ga-PSMA. METHODS: Kidney uptake (SUVmax) was calculated in nine patients undergoing 68Ga-PSMA PET/CT at baseline (b-PET/CT) and after intravenous infusion of 500 ml of 10% mannitol (m-PET/CT). Two different infusion schemes for mannitol were used: (1) 500 ml mannitol was infused over 40 min after 68Ga-PSMA administration (A-infusion) and (2) 250 ml mannitol was infused over 15 min before and again after 68Ga-PSMA administration (B-infusion). RESULTS: In patients receiving the A-infusion, mean SUVmax increased by 11.9% and 7.4% in the right and left kidney, respectively. In patients receiving the B-infusion, mean SUVmax decreased by 24.3% and 22.4% in the right and left kidney, respectively. CONCLUSION: Our preliminary findings indicate that mannitol may play a role in reducing off-target 68Ga-PSMA renal uptake. Administration of the osmotic diuretic should be rapid and start before 68Ga-PSMA injection. These results warrant dosimetric studies in patients treated with 177Lu-PSMA to find the best scheme for mannitol administration. PMID- 28801789 TI - Multimodal laser ablation/desorption imaging analysis of Zn and MMP-11 in breast tissues. AB - Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases. The main functions of these metalloproteinases are the degradation of the stromal connective tissue and basement membrane components. Recent data from model systems suggest that MMPs are involved in breast cancer (BC) initiation, invasion, and metastasis. Particularly, MMP-11 (stromelysin-3) is expressed in stromal fibroblasts adjacent to epithelial tumor cells, and high levels of this metalloproteinase were associated with tumor progression and poor prognosis of BC. Consequently, MMP-11 involved in these processes can be a candidate as a new potential prognostic biomarker in BC. Bioimaging techniques based on laser ablation/desorption and mass spectrometry are rapidly growing in biology and medicine for studies of biological systems to provide information of biomolecules (such as proteins, metabolites, and lipids) and metals with lateral resolution at the micrometer scale. In this study, matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) has been used for the first time to investigate the distribution of MMP-11 in human breast cancer tissues in order to show a possible correlation between cancerous and healthy samples, by differential proteomics and using such differences for possible cancer diagnosis and/or prognosis. Additionally, those human breast tissue samples were analyzed in parallel by laser ablation inductively coupled plasma mass spectrometry (LA ICP-MS) in order to gather additional information about the elemental distribution of Zn and its possible associations with MMPs. PMID- 28801791 TI - Effectiveness of Healthcare Coordination in Patients with Chronic Respiratory Diseases. AB - Coordination of healthcare effectively prevents exacerbations and reduces the number of hospitalizations, emergency visits, and the mortality rate in patients with chronic respiratory diseases. The purpose of this study was to determine clinical effectiveness of ambulatory healthcare coordination in chronic respiratory patients and its effect on the level of healthcare services as an indicator of direct medical costs. We conducted a retrospective health record survey, using an online database of 550 patients with chronic respiratory diseases. There were decreases in breathing rate, heart rate, and the number of cigarettes smoked per day, and forced vital capacity (FVC) and forced expired volume in 1 s (FEV1) increased after the implementation of the coordinated healthcare structure. These benefits were accompanied by increases in the number of visits to the pulmonary outpatient clinic (p < 0.001), diagnostic costs (p < 0.001), and referrals to other outpatient clinics (p < 0.003) and hospitals (p < 0.001). The advantageous effects of healthcare coordination on clinical status of respiratory patients above outlined persisted over a 3-year period being reviewed. PMID- 28801790 TI - Cardiovascular Disease, the Nitric Oxide Pathway and Risk of Cognitive Impairment and Dementia. AB - PURPOSE OF REVIEW: In this review, we summarise the evidence on the association between cardiovascular disease (CVD) and cognitive impairment and explore the role of the nitric oxide (NO) pathway as a causal mechanism. RECENT FINDINGS: Evidence from epidemiological studies suggests that the presence of CVD and its risk factors in midlife is associated with an increased risk of later life cognitive impairment and dementia. It is unclear what is driving this association but risk may be conveyed via an increase in neurodegeneration (e.g. amyloid deposition), vascular changes (e.g. small vessel disease) and mechanistically due to increased levels of oxidative stress and inflammation as well as changes in NO bioavailability. CVDs and dementia are major challenges to global health worldwide. The NO pathway may be a promising biological candidate for future studies focused on reducing not only CVD but also risk of cognitive decline and dementia. PMID- 28801792 TI - Electronic Cigarettes and Awareness of Their Health Effects. AB - The use of electronic cigarettes or e-cigarettes is strongly on the rise. The literature confirms that in the process of quitting smoking using an electronic device dispensing nicotine should be a transitional stage before the complete cessation of smoking. The aim of the present study was to assess the popularity of e-cigarettes, the underlying reasons for use of such nicotine products, and the level of awareness of health hazards associated with e-cigarettes. The study is of a survey type. The material consisted of data collected from an anonymous survey distributed among 46 female and 23 male users of e-cigarettes in 2015. We used a questionnaire of our own design. The findings demonstrate that the main reason for a recourse to e-cigarettes is a desire to use fashionable technological innovations, and the conviction that such cigarettes are less harmful than the traditional tobacco products. Some respondents used e-cigarettes to quit smoking; others to minimize the harmful effects of smoking. Most respondents acquired information about e-cigarettes from friends or from the Internet. There was a high awareness of the chemical composition of substances contained in e-cigarettes. An interest in e-cigarettes is caused by an increased knowledge on the negative effects of traditional smoking. Currently, the e cigarettes remains a technological novelty, so that the exact health effects of their long-term use are open to conjecture. PMID- 28801793 TI - Robotic technique improves entry point alignment for intramedullary nailing of femur fractures compared to the conventional technique: a cadaveric study. AB - We aimed to test whether a robotic technique would offer more accurate access to the proximal femoral medullary cavity for insertion of an intramedullary nail compared to the conventional manual technique. The medullary cavity of ten femur specimens was accessed in a conventional fashion using fluoroscopic control. In ten additional femur specimens, ISO-C 3D scans were obtained and a computer program calculated the ideal location of the cavity opening based on the trajectory of the medullary canal. In both techniques, the surgeon opened the cavity using a drill and inserted a radiopaque tube that matched the diameter of the cavity. The mean difference in angle between the proximal opening and the medullary canal in the shaft of the femur was calculated for both groups. Robotic cavity opening was more accurate than the manual technique, with a mean difference in trajectory between the proximal opening and the shaft canal of 2.0 degrees (95% CI 0.6 degrees -3.5 degrees ) compared to a mean difference of 4.3 degrees (95% CI 2.11 degrees -6.48 degrees ) using the manual technique (P = 0.0218). The robotic technique was more accurate than the manual procedure for identifying the optimal location for opening the medullary canal for insertion of an intramedullary nail. Additional advantages may include a reduction in total radiation exposure, as only one ISO-C 3D scan is needed, as opposed to multiple radiographs when using the manual technique. PMID- 28801795 TI - Storage lipid and polysaccharide metabolism in Yarrowia lipolytica and Umbelopsis isabellina. AB - Complex biochemical mechanisms are being involved in oleaginous microorganisms during storage lipid and polysaccharide metabolism. Detailed biochemical analyses and monitoring of key enzymes involved in carbon metabolism were performed in Yarrowia lipolytica and Umbelopsis isabellina, which are often used as model oleaginous microorganisms. It was found that during the early oleaginous phase, the carbon source (glucose) was channeled to lipid accumulation, but also to polysaccharide biosynthesis. However, during transition from the early to the late oleaginous phase, glucose was exclusively converted to lipids, while in U. isabellina, but not in Y. lipolytica, an additional conversion of cellular polysaccharides into lipids was observed. After glucose depletion in the growth medium, cellular storage material was degraded either for generating maintenance energy or for supporting further microbial growth, depending on the availability of essential nutrients in the growth medium. We demonstrated that in both microorganisms, reserve lipids were exclusively used as an intra-cellular carbon source in order to generate energy for maintenance purpose. When cellular storage material degradation was related to new cell mass production, a bioconversion of lipids into new lipid-free material, consisting of polysaccharides and proteins, was observed in Y. lipolytica, while new lipid-free material in U. isabellina was richer in proteins. Lipid and polysaccharide remodeling may occur in some cases in both microorganisms. This study revealed some new biochemical features of oleaginous microorganisms that may be crucial for the design of new biotechnological processes, such as the production of bio-molecules of industrial, technological, and medical interest. PMID- 28801794 TI - Management of congenital tracheal stenosis in the neonatal period. AB - PURPOSE: Few reports have focused on the management of congenital tracheal stenosis (CTS) in the neonatal period. The aim of this study was to determine appropriate management strategies for CTS in the neonatal period. METHODS: The medical records of eight neonatal patients with CTS at a single institution between January 2007 and December 2016 were retrospectively reviewed. RESULTS: Three patients with frequent ventilatory insufficiency despite assisted ventilation underwent surgical intervention (balloon tracheoplasty: n = 1, slide tracheoplasty: n = 2). Ventilatory insufficiency improved after surgery in all three patients. One patient who underwent slide tracheoplasty died due to non airway-related causes. Observation or conservative management was performed in five patients with minimal respiratory symptoms or stable ventilation under assisted ventilation. All five patients were safely managed non-operatively in the neonatal period. CONCLUSION: Depending on the severity of ventilatory insufficiency, there are two management strategies for CTS in the neonatal period. Surgical intervention, such as balloon tracheoplasty or slide tracheoplasty, is indicated for patients with unstable ventilatory status despite assisted ventilation. Observation or conservative management is a more suitable option for neonates with stable ventilation. PMID- 28801796 TI - Immobilization of lead by application of soil amendment produced from vinegar residue, stainless steel slag, and weathered coal. AB - This paper presents a new soil amendment used for immobilization of soil Pb, produced from vinegar residue, stainless steel slag, and weathered coal. The pH value measuring, granulation and adsorption experiments were carried out to determine the optimal composition of soil amendment. Optimizing soil amendment B2 was composed of vinegar residue, weathered coal (humic acid 61.53 wt%), and stainless steel slag with the ratio of 80?16?4, and particle size was in the range of 2-4 mm. In the leaching column experiment, B2 addition reduced the Pb release from the soil as well as increasing leachate pH and decreasing the bioavailable Pb concentration. The leachate Pb concentration decreased with lengthened leaching time under lower pH, but such a phenomenon disappeared in the rebounding period. Compared to control, the DTPA extractable Pb content in soil decreased by 12.41, 13.20, and 8.78% with the B2 addition amount of 1.00, 2.00, and 2.00 wt%, respectively. In addition, the total Pb content of each soil layer generally rose as B2 addition increased. It was concluded that application of B2 led to lower transport and transformation of Pb in soil. Based on the single chemical extraction, the environmental risk of Pb was decreased after application of B2. Meanwhile, soil amendment was also a new way to recycle vinegar residue, stainless steel slag, and weathered coal. PMID- 28801797 TI - Planar covariance of upper and lower limb elevation angles during hand-foot crawling in healthy young adults. AB - Habitual quadrupeds have been shown to display a planar covariance of segment elevation angle waveforms in the fore and hind limbs during many forms of locomotion. The purpose of the current study was to determine if humans generate similar patterns in the upper and lower limbs during hand-foot crawling. Nine healthy young adults performed hand-foot crawling on a treadmill at speeds of 1, 2, and 3 km/h. A principal component analysis (PCA) was applied to the segment elevation angle waveforms for the upper (upper arm, lower arm, and hand) and lower (thigh, shank, and foot) limbs separately. The planarity of the elevation angle waveforms was determined using the sum of the variance explained by the first two PCs and the orientation of the covariance plane was quantified using the direction cosines of the eigenvector orthogonal to the plane, projected upon each of the segmental semi-axes. Results showed that planarity of segment elevation angles was maintained in the upper and lower limbs (explained variance >97%), although a slight decrease was present in the upper limb when crawling at 3 km/h. The orientation of the covariance plane was highly limb-specific, consistent with animal studies and possibly related to the functional neural control differences between the upper and lower limbs. These results may suggest that the motor patterns stored in the central nervous system for quadrupedal locomotion may be retained through evolution and may still be exploited when humans perform such tasks. PMID- 28801798 TI - Downregulation of Paralemmin-3 Ameliorates Lipopolysaccharide-Induced Acute Lung Injury in Rats by Regulating Inflammatory Response and Inhibiting Formation of TLR4/MyD88 and TLR4/TRIF Complexes. AB - Previous studies have demonstrated paralemmin-3 (PALM3) participates in Toll-like receptor (TLR) signaling. This study investigated the effect of PALM3 knockdown on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and its underlying mechanisms. We constructed a recombinant adenoviral vector containing short hairpin RNA for PALM3 to knockdown PALM3 expression. A transgene-free adenoviral vector was used as a negative control. The ALI rat model was established by LPS peritoneal injection at 48-h post-transfection. Results showed that downregulation of PALM3 improved the survival rate, attenuated lung pathological changes, alleviated pulmonary edema, lung vascular leakage and neutrophil infiltration, inhibited the production of proinflammatory cytokines and activation of nuclear factor kappaB and interferon beta regulatory factor 3, and promoted the secretion of anti-inflammatory cytokine interleukin-10 and expression of suppressor of cytokine signaling-3 in the ALI rat model. However, PALM3 knockdown had no effect on TLR4, myeloid differentiation factor 88 (MyD88), and Toll-interleukin-1 receptor domain-containing adaptor inducing interferon beta (TRIF) expression. Moreover, PALM3 knockdown reduced the interaction of TLR4 with MyD88 or TRIF induced by LPS in rat lungs. Therefore, the downregulation of PALM3 protected rats from LPS-induced ALI and its mechanisms were partially associated with the modulation of inflammatory responses and inhibition of TLR4/MyD88 and TLR4/TRIF complex formation. PMID- 28801799 TI - Double versus single source left-sided coronary revascularization using bilateral internal thoracic artery graft alone. AB - Left-sided coronary revascularization with bilateral internal thoracic artery (BITA) graft is performed usually either with an in situ (double source) or Y graft configuration (single source). Two hundred fifty-three (mean age, 67.1 +/- 9.5 years) patients underwent isolated left-sided coronary revascularization with BITA graft alone at the present authors' institution (2000-2015). Skeletonized BITA grafts were used either in an in situ (n = 199) or Y-graft configuration (n = 54). Forty pairs were identified with the propensity score-matching. Outcomes of the two groups were compared both in unmatched and matched series. Cardiopulmonary exercise testing was performed in five pairs of selected, asymptomatic matched patients having patent BITA grafts at coronary computed tomography angiography. BITA in situ patients had lower risk profiles than BITA Y graft patients (median EuroSCORE II, 1.9 vs. 2.9%, p = 0.051). In-hospital mortality (5.6 vs. 0, p = 0.0093) and the rates of postoperative complications except deep sternal wound infection were higher in BITA Y-graft patients. However, these differences were not confirmed in matched groups. During the follow-up period (mean, 5.9 +/- 4.3 years), between BITA in situ and BITA Y-graft matched patients, there were no differences in non-parametric estimates of freedom from cardiac death (p = 0.6), major adverse cardiac and cerebrovascular events (MACCEs, p = 0.65), and repeat coronary revascularization (p = 0.44). Adjusted risk estimates of MACCEs according to BITA configuration confirmed no superiority of the one configuration over the other (p >= 0.44). No significant differences were found at the cardiopulmonary exercise testing. Results of left sided coronary revascularization with BITA graft alone are independent from BITA configuration, even after stress testing. PMID- 28801800 TI - The horizontal plane appearances of scoliosis: what information can be obtained from top-view images? AB - PURPOSE: A posterior-anterior vertebral vector is proposed to facilitate visualization and understanding of scoliosis. The aim of this study was to highlight the interest of using vertebral vectors, especially in the horizontal plane, in clinical practice. METHODS: We used an EOS two-/three-dimensional (2D/3D) system and its sterEOS 3D software for 3D reconstruction of 139 normal and 814 scoliotic spines-of which 95 cases were analyzed pre-operatively and post operatively, as well. Vertebral vectors were generated for each case. Vertebral vectors have starting points in the middle of the interpedicular segment, while they are parallel to the upper plate, ending in the middle of the segment joining the anterior end plates points, thus defining the posterior-anterior axis of vertebrae. To illustrate what information could be obtained from vertebral vector based top-view images, representative cases of a normal spine and a thoracic scoliosis are presented. RESULTS: For a normal spine, vector projections in the transverse plane are aligned with the posterior-anterior anatomical axis. For a scoliotic spine, vector projections in the horizontal plane provide information on the lateral decompensation of the spine and the lateral displacement of vertebrae. In the horizontal plane view, vertebral rotation and projections of the sagittal curves can also be analyzed simultaneously. CONCLUSIONS: The use of posterior-anterior vertebral vector facilitates the understanding of the 3D nature of scoliosis. The approach used is simple. These results are sufficient for a first visual analysis furnishing significant clinical information in all three anatomical planes. This visualization represents a reasonable compromise between mathematical purity and practical use. PMID- 28801802 TI - Does Dose Modification Affect Efficacy of First-Line Pazopanib in Metastatic Renal Cell Carcinoma? AB - BACKGROUND: Pazopanib is a standard treatment for metastatic renal cell carcinoma (mRCC), and 800 mg/daily is considered the optimal dose. However, some patients require dose modification because of toxicity. Whether a reduced dose of pazopanib is as effective as the standard dose in achieving clinical benefit remains unclear. OBJECTIVES: Our objective was to conduct a retrospective analysis to investigate the clinical effect of different therapeutic doses of first-line pazopanib in patients with mRCC. METHODS: Consecutive patients with mRCC treated with first-line pazopanib between 2011 and 2016 at the Istituto Nazionale Tumori of Milan were retrospectively analysed for demographics, response, outcomes, and toxicity. Three patient groups were compared: group 1 received the standard dose of 800 mg/day; group 2 started with 800 mg/day and then reduced the dose to 400 or 600 mg/day because of toxicity; and group 3 received a reduced starting dose of 400 or 600 mg/day because they had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 and/or comorbidities. RESULTS: In total, 69 patients were evaluated: 34 in group 1, 19 in group 2, and 16 in group 3. After a median follow-up of 13.9 months (range 0.3 43.8), 27 (39.1%) patients had progressive disease (PD) and three (4.3%) patients had died. The incidence rate of PD or death per 100 person-months was 2.5 [95% confidence interval (CI) 0.6-4.4; hazard ratio (HR) 1] in group 1 and 3.9 (95% CI 0-14.3; HR 1.43) in the combined group (2 + 3). The discontinuation rate due to PD was 28% in group 1, 42% in group 2, and 44% in group 3. The objective response rate was 44, 11, and 19% in groups 1, 2, and 3, respectively. CONCLUSIONS: Our results may suggest that patients with mRCC receiving a lower dose of first-line pazopanib might not have a meaningful progression-free survival advantage compared with those receiving a standard dose. These data highlight that proper management of treatment-related side effects may lead to optimal drug exposure. PMID- 28801803 TI - The adsorption of NO, NH3, N2 on carbon surface: a density functional theory study. AB - To explore the adsorption mechanism of NO, NH3, N2 on a carbon surface, and the effect of basic and acidic functional groups, density functional theory was employed to investigate the interactions between these molecules and carbon surfaces. Molecular electrostatic potential, Mulliken population analyses, reduced density gradient, and Mayer bond order analyses were used to clarify the adsorption mechanism. The results indicate that van der Waals interactions are responsible for N2 physisorption, and N2 is the least likely to adsorb on a carbon surface. Modification of carbon materials to decorate basic or acidic functional groups could enhance the NH3 physisorption because of hydrogen bonding or electrostatic interactions, however, NO physisorption on a carbon surface is poor. Zig-zag sites are more reactive than armchair sites when these gas molecules absorb on the edge sites of carbon surface. Graphical abstract NH3, N2, NO adsortion on carbon surface. PMID- 28801804 TI - A comparison of the characteristics and precision of needle driving for right handed pediatric surgeons between right and left driving using a model of infant laparoscopic diaphragmatic hernia repair. AB - PURPOSE: We compared the characteristics and precision of right and left needle driving for right-handed pediatric surgeons using a laparoscopic diaphragmatic repair model. METHODS: Eighteen right-handed pediatric surgeons performed three needle driving maneuvers using both hands. We evaluated the required time and conducted an image analysis. The total path length, velocity, and acceleration of the needle driving were also evaluated. RESULTS: Obtained results show the findings for the required time (s, Rt 310.78 +/- 148.93 vs. Lt 308.61 +/- 122.53, p = 0.93), sum of needle driving balances (mm, Rt 5.23 +/- 2.44 vs. Lt 5.05 +/- 3.17, p = 0.83), the gap of the needle driving interval (Rt 1.2 +/- 0.93 vs. Lt 2.17 +/- 1.67, p = 0.04), total path length (mm, Rt 594.03 +/- 205.29 vs. Lt 1641.07 +/- 670.68, p < 0.01), and average velocity (mm/s, Rt 1.92 +/- 0.54 vs. Lt 5.3 +/- 1.39, p < 0.01). CONCLUSION: For right-handed pediatric surgeons, left needle driving showed almost same quality of right needle driving as regarding the precision. But left needle driving also showed too fast but not economical movement unfortunately, implying rough and risky forceps manipulation. Non dominant hand training is necessary to avoid organ injury. PMID- 28801806 TI - Editorial Report. PMID- 28801805 TI - Pulmonary CTA in sickle cell patients: quantitative assessment of enhancement quality. AB - PURPOSE: The purpose of this study was to validate the observation that pulmonary artery (PA) enhancement is often decreased in sickle cell disease (SCD) patients imaged with MDCT for suspected pulmonary embolism and determine whether contrast infusion parameters are accountable for lower enhancement levels. MATERIALS AND METHODS: Retrospective comparison of 35 adult SCD patients imaged for suspected pulmonary embolism (PE) in our emergency department using 128-slice dual source MDCT scanner to 34 age and weight matched adult controls. Bolus tracking data was recorded, and enhancement levels of the main PA and descending aorta were measured. Electronic records were reviewed for demographics, imaging and lab correlation, and infusion parameters. RESULTS: Age, weight, contrast infusion rate, and contrast volume were similar for both SCD and control patients. SCD patients had significantly lower main PA enhancement (mean 233 HU, range 151-361 HU) than the control subjects (mean 290 HU, range 138-487 HU) (p < 0.001). Most (74%) SCD subjects had PA enhancement that was <250 HU, while most (68%) control patients had PA enhancement >=250 HU. Change in PA enhancement per second during bolus tracking was lower in SCD patients (12 HU/s, range -24 to 91 HU/s) than control patients (mean 30 HU/s, range -37 to 138 HU/s), although the difference was not statistically significant (p = 0.08). Hemoglobin levels were significantly lower in the SCD cohort (p < 0.001). CONCLUSION: In this series of adult SCD patients with suspected PE imaged with MDCT, main PA enhancement level was lower than controls. Quality improvement investigations should focus on protocol optimization to improve enhancement quality and likelihood of a definitive diagnosis. PMID- 28801801 TI - Nuclear envelope: a new frontier in plant mechanosensing? AB - In animals, it is now well established that forces applied at the cell surface are propagated through the cytoskeleton to the nucleus, leading to deformations of the nuclear structure and, potentially, to modification of gene expression. Consistently, altered nuclear mechanics has been related to many genetic disorders, such as muscular dystrophy, cardiomyopathy and progeria. In plants, the integration of mechanical signals in cell and developmental biology has also made great progress. Yet, while the link between cell wall stresses and cytoskeleton is consolidated, such cortical mechanical cues have not been integrated with the nucleoskeleton. Here, we propose to take inspiration from studies on animal nuclei to identify relevant methods amenable to probing nucleus mechanics and deformation in plant cells, with a focus on microrheology. To identify potential molecular targets, we also compare the players at the nuclear envelope, namely lamina and LINC complex, in both plant and animal nuclei. Understanding how mechanical signals are transduced to the nucleus across kingdoms will likely have essential implications in development (e.g. how mechanical cues add robustness to gene expression patterns), in the nucleoskeleton-cytoskeleton nexus (e.g. how stress is propagated in turgid/walled cells), as well as in transcriptional control, chromatin biology and epigenetics. PMID- 28801808 TI - Validation study of accelerometer in measuring some sleep parameters in adults. PMID- 28801807 TI - Hyaluronan-mediated mononuclear leukocyte binding to gingival fibroblasts. AB - OBJECTIVES: Binding of mononuclear leukocytes to hyaluronan cable structures is a well-known pathomechanism in several chronic inflammatory diseases, but has not yet described for chronic oral inflammations. The aim of this study was to evaluate if and how binding of mononuclear leukocytes to pathologic hyaluronan cable structures can be induced in human gingival fibroblasts. MATERIAL AND METHODS: Experiments were performed with human gingival fibroblasts and peripheral blood mononuclear cells (PBMCs) from three healthy blood donors. Gingival fibroblasts were stimulated with (1) tunicamycin, (2) polyinosinic/polycytidylic acid (Poly:IC), and (3) lipopolysaccharides (LPS) to simulate (1) ER stress and (2) viral and (3) bacterial infections, respectively. Fibroblasts were then co-incubated with PBMCs, and the number of bound and fluorescently labeled PBMCs was assessed using a fluorescence reader and microscopy. For data analysis, a linear mixed model was used. RESULTS: Hyaluronan mediated binding of PBMCs to gingival fibroblasts was increased by tunicamycin and Poly(I:C) but not by LPS. Hyaluronidase treatment and co-incubation with hyaluronan transport inhibitors reduced this binding. CONCLUSIONS: Results suggest that hyaluronan-mediated binding of blood cells might play a role in oral inflammations. A potential superior role of viruses needs to be confirmed in further clinical studies. CLINICAL RELEVANCE: The linkage between pathological hyaluronan matrices and oral infections opens up potential applications of hyaluronan transport inhibitors in the treatment of chronic oral inflammations. PMID- 28801809 TI - [Establishment of a trauma surgical department at the Diospi Suyana missionary hospital in Curahuasi, Peru]. AB - The confusingly structured and in many areas corrupt health system in Peru even today provides only a fragmentary and insufficient medical treatment especially for the indigenous population (mainly Quechua Indians). Since October 2007 the Diospi Suyana missionary hospital in Curahuasi (State of Apurimac) has provided an affordable medical treatment at a high level mainly for these indigenous people of Peru; however, so far the hospital could only insufficiently meet the traumatological needs of the region. The establishment of a surgical trauma department aims to meet those needs but is also encumbered by special problems and challenges. Some patients, for example only present at the hospital after the fractures have already incorrectly healed, sometimes many weeks or even months after the trauma either due to a long journey through the country to different hospitals where treatment was not possible or they could not pay for the treatment and sometimes because of inadequate prior treatment, for example by traditional healers. Cultural and infrastructural particularities of the country must be included in the process of choosing the right method of treatment. PMID- 28801810 TI - Effects of PBM in different energy densities and irradiance on maintaining cell viability and proliferation of pulp fibroblasts from human primary teeth. AB - This study aimed to compare the effects of photobiomodulation (PBM) in different energy densities and irradiances on maintaining cell viability, and proliferation of pulp fibroblasts from human primary teeth (HPF) were cultured in DMEM and used between the fourth and eighth passages. Then, HPF were irradiated with the following different energy densities: 1.25 J/cm2 (a), 2.50 J/cm2 (b), 3.75 J/cm2 (c), 5.00 J/cm2 (d), and 6.25 J/cm2 (e); but varying either the time of irradiation (groups 1a-1e) or the output power (groups 2a-2e). Positive (groups 1f and 2f) and negative controls (groups 1g and 2g), respectively, comprised non irradiated cells grown in regular nutritional conditions (10% fetal bovine serum [FBS]) and under nutritional deficit (1% FBS). Cell viability and proliferation were respectively assessed through MTT and crystal violet (CV) assays at 24, 48, and 72 h after irradiation. Statistical analysis was performed by two-way ANOVA, followed by Tukey test (P < 0.05). The negative controls showed significantly lower viability in relation to most of the corresponding subgroups, both for MTT and CV assays. For both assays, the intragroup comparison showed that the periods of 24 h exhibited lower viability than the periods of 48 and 72 h for most of the subgroups, except the negative controls with lower viability. The different irradiation protocols (equal energy densities applied with different irradiances) showed no statistically significant differences on cell viability and proliferation at the evaluated periods. The proposed PBM in different energy densities and irradiance did not affect the viability and proliferation of pulp fibroblasts from human primary teeth. PMID- 28801811 TI - Association of variably expressed KIR3dl1 alleles with psoriatic disease. AB - The purpose of this study is to examine the genetic interaction of variably expressed killer cell immunoglobulin-like receptor (KIR) 3DL1 alleles with their cognate ligand, human leukocyte antigen (HLA)-Bw4, in susceptibility to psoriatic disease (PsD). A novel allelic typing system was developed to differentiate KIR3DL1 alleles (*High, *Low, *Null expression, and 3DS1), in PsD patients, including those with psoriatic arthritis (PsA) and cutaneous psoriasis without arthritis (PsC) and healthy controls. Frequencies of each KIR3DL1 allele, Bw4-80I and Bw4-80T, as well as the genetic interaction between the KIR3DL1 alleles and the Bw4 epitope were analyzed. KIR3DL1 alleles were successfully genotyped in 392 PsA, 260 PsC, and 371 control subjects. Only the KIR3DL1*Null allele was associated with PsD (OR = 0.69, p = 0.008), both in the PsA (OR = 0.69, p = 0.02) and PsC patients (OR = 0.70, p = 0.04) compared to control subjects. No difference in the frequency of KIR3DL1*Null was found between the PsA and PsC patients. The presence of the HLA-Bw4 epitope was significantly associated with PsD, particularly in the PsA patients compared to controls. Bw4-80I was increased in PsD and PsA subjects, but not in PsC patients compared to controls. Bw4-80T was increased in PsA compared to both PsC patients or to controls. No interaction was detected between any of the KIR3DL1 alleles and HLA-Bw4, Bw4-80I, or Bw4-80T. The novel qPCR technique successfully identified the four variably expressed KIR3DL1 alleles. The HLA-Bw4 epitope was associated with psoriatic disease, particularly with PsA, but no genetic interactions with KIR3DL1 alleles were detected. PMID- 28801812 TI - A synopsis of the history of Hansen's disease. AB - Leprosy is a contagious infectious disease caused by the bacillus Mycobacterium leprae. This microorganism was discovered by Dr. Gerhard Hansen, and the illness was then baptized as Hansen's disease. For a long time, Hansen's disease was thought to be hereditary-a curse or a punishment from God. The disease affects skin and nerves and can cause severe damage. Due to its destructive effects, leprosy has caused fear, segregation, and prejudice in all societies since Biblical times. Patients with Hansen's disease have not been treated humanely around the world throughout the ages. This article is a summary of curious and interesting facts about the history and cultural aspects of Hansen's disease, which has chastised humanity for centuries. These facts are about the discovery of the disease, its propagation, the evolution of treatments, and the prejudice of society towards patients. PMID- 28801813 TI - Detection of QTL for greasy fleece weight in sheep using a 50 K single nucleotide polymorphism chip. AB - Genome-wide association studies (GWAS) have introduced an influential tool in the search for quantitative trait loci (QTL) influencing economically important traits in sheep. To identify QTL associated with greasy fleece weight, a GWAS with 50 K single nucleotide polymorphisms (SNPs) was performed in a Baluchi sheep population. Association with greasy fleece weights was tested using the software Plink. The results of our GWAS provided three novel SNP markers and candidate genes associated with greasy fleece weight. A total of three chromosome-wide significant associations were detected for SNP on chromosomes 17 and 20 affecting greasy fleece weight across the four shearing. One of the significant SNP markers was located within ovine known genes namely FAM101A. Further investigation of these identified regions in validation studies will facilitate the identification of strong candidate genes for wool production in sheep. PMID- 28801814 TI - Serum amyloid A as a marker of disease activity and treatment response in Takayasu arteritis. AB - Assessment of disease activity in Takayasu arteritis (TA) is challenging. We aimed to study utility of serum amyloid A (SAA) to assess disease activity and its association with SAA gene polymorphisms, if any, in our TA patients. Serum of 99 consecutive adult TA patients and 40 healthy controls were assayed for SAA. Depending on the ITAS2010 and ITAS-CRP score, patients were designated as having active disease if ITAS2010 >= 2 or ITAS-CRP >= 3 and stable disease if ITAS2010 = 0 or ITAS-CRP is <=1. Clinical ITAS of 0 with raised inflammatory markers scoring a ITAS-CRP of 2 was considered as indeterminate for disease activity assessment. Repeat SAA levels for active group was measured after 6 months from baseline. SAA levels between active and stable disease as well as serial levels were compared. DNA of 40 patients and controls were genotyped for SAA polymorphisms (rs12218, rs2468844) and the allele frequencies were compared. At baseline, SAA levels were higher in patients as compared to controls (137.4 vs 100.8 ng/ml, p = 0.001) and higher in patients with active disease (166.4 ng/ml) than those with stable disease (98.2 ng/ml), p = 0.001. SAA decreased during follow-up in treatment responders (189.9 ng/ml at baseline vs 119.0 ng/ml at follow-up, p = 0.008); in contrast, there was no significant change among non-responders during follow-up. Allelic frequencies of SAA gene polymorphisms did not differ between cases and controls. SAA may be a reliable biomarker to assess disease activity and treatment response in TA. PMID- 28801815 TI - Plasma levels of complement activation fragments C3b and sC5b-9 significantly increased in patients with thrombotic microangiopathy after allogeneic stem cell transplantation. AB - Transplantation-associated thrombotic microangiopathy (TA-TMA) is an uncommon but severe complication in patients undergoing allogeneic stem cell transplantation (allo-SCT). However, the mechanism is unclear. From 2011 to 2014, 20 patients with TA-TMA, 20 patients without, and 54 patients with various other complications, including veno occlusive disease (VOD), graft-versus-host disease (GVHD), and infection, were recruited in the study. Plasma vWF antigen (vWFAg), vWF activity (vWFAc), and ADAMTS13 activity were determined in these patients by ELISAs and FRETS-vWF73 assay, respectively. Plasma C3b, sC5b-9, and CH50 were also determined by ELISAs. Plasma levels of C3b were significantly increased in patients with either TA-TMA (p < 0.0001) or GVHD (p < 0.01). Plasma sC5b-9 and CH50 levels in patients with TA-TMA were also significantly increased (p < 0.001). Plasma ADAMTS13 activity was lower in patients with VOD, but normal with other complications. Both plasma vWFAg and vWFAc levels were not elevated in patients with TA-TMA or VOD compared with those of other groups. Complement activation likely via an alternative pathway (increased C3b, sC5b-9, and CH50) may play a role in the pathogenesis of TA-TMA. ADAMTS13 activity is reduced in VOD, but the ADAMTS13/vWF axis appears to be unaffected in patients with TA-TMA. PMID- 28801816 TI - Are TKAs Performed in High-volume Hospitals Less Likely to Undergo Revision Than TKAs Performed in Low-volume Hospitals? AB - BACKGROUND: High-volume hospitals have achieved better outcomes for THAs and unicompartmental knee arthroplasties (UKAs). However, few studies have analyzed implant survival after primary TKA in high-volume centers. QUESTIONS/PURPOSES: Is the risk of revision surgery higher when receiving a TKA in a low-volume hospital than in a high-volume hospital? METHODS: Using nationwide billing data of the largest German healthcare insurer for inpatient hospital treatment, we identified 45,165 TKAs in 44,465 patients insured by Allgemeine Ortskrankenkasse who had undergone knee replacement surgery between January 2012 and December 2012. Revision rates were calculated at 1 and 2 years in all knees. The hospital volume was calculated using volume quintiles of the number of all knee arthroplasties performed in each center. We used multiple logistic regression to model the odds of revision surgery as a function of hospital volume. Age, sex, 31 comorbidities, and variables for socioeconomic status were included as independent variables in the model. RESULTS: After controlling for socioeconomic factors, patient age, sex, and comorbidities, we found that having surgery in a high-volume hospital was associated with a decreased risk of having revision TKA within 2 years of the index procedure. The odds ratio for the 2-year revision was 1.6 (95% CI, 1.4-2.0; p < 0.001) for an annual hospital volume of 56 or fewer cases, 1.5 (95% CI, 1.3 1.7; p < 0.001) for 57 to 93 cases, 1.2 (95% CI, 1.0-1.3; p = 0.039) for 94 to 144 cases, and 1.1 (95% CI, 0.9-1.2; p = 0.319) for 145 to 251 cases compared with a hospital volume of 252 or more cases. CONCLUSIONS: We found a clear association of higher risk for revision surgery when undergoing a TKA in a hospital where less than 145 arthroplasties per year were performed. The study results could help practitioners to guide potential patients in hospitals that perform more TKAs to reduce the overall revision and complication rates. Furthermore, this study underscores the importance of a minimum hospital threshold of arthroplasty cases per year to get permission to perform an arthroplasty. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 28801817 TI - Contour segmentation of the intima, media, and adventitia layers in intracoronary OCT images: application to fully automatic detection of healthy wall regions. AB - PURPOSE: Quantitative and automatic analysis of intracoronary optical coherence tomography images is useful and time-saving to assess cardiovascular risk in the clinical arena. METHODS: First, the interfaces of the intima, media, and adventitia layers are segmented, by means of an original front propagation scheme, running in a 4D multi-parametric space, to simultaneously extract three non-crossing contours in the initial cross-sectional image. Second, information resulting from the tentative contours is exploited by a machine learning approach to identify healthy and diseased regions of the arterial wall. The framework is fully automatic. RESULTS: The method was applied to 40 patients from two different medical centers. The framework was trained on 140 images and validated on 260 other images. For the contour segmentation method, the average segmentation errors were [Formula: see text] for the intima-media interface, [Formula: see text] for the media-adventitia interface, and [Formula: see text] for the adventitia-periadventitia interface. The classification method demonstrated a good accuracy, with a median Dice coefficient equal to 0.93 and an interquartile range of (0.78-0.98). CONCLUSION: The proposed framework demonstrated promising offline performances and could potentially be translated into a reliable tool for various clinical applications, such as quantification of tissue layer thickness and global summarization of healthy regions in entire pullbacks. PMID- 28801818 TI - [Branch duct intraductal papillary mucinous neoplasm - surgical approach]. AB - Due to increasing precision of modern imaging modalities, intraductal papillary mucinous neoplasms (IPMN) of the pancreas are found with increasing prevalence. Despite their malignant potential IPMN are often kept under surveillance and are not immediately resected. The 2012 International Consensus Guidelines of Fukuoka have been widely accepted for the management of IPMN. They recommend surgical resection for branch duct IPMN with "high risk stigmata", while branch duct IPMN with "worrisome features" should undergo observation without immediate resection. Consequently, patients with asymptomatic branch duct IPMN and a presumed low malignant potential mostly undergo primary surveillance to avoid surgery-related morbidity and mortality following pancreatic resection; however, with respect to the cumulative risk of malignant transformation over time, surgical resection might also be indicated for patients with branch duct IPMN with "worrisome features". This article discusses the indications for surgery and different options of resection of branch duct IPMN. PMID- 28801819 TI - Treadmill Exercise Prevents Increase of Neuroinflammation Markers Involved in the Dopaminergic Damage of the 6-OHDA Parkinson's Disease Model. AB - Parkinson's disease (PD) involves loss of dopaminergic neurons in the substantia nigra (SN), which can be correlated to neuroinflammatory changes with the aging of the nervous system. On the other hand, exercise can reduce the deleterious effects promoted by age, but the mechanism involved is still unclear. This study investigated the preventive exercise-induced changes on neuroinflammatory processes in a rat model of PD induced by unilateral striatal injections of 6 hydroxydopamine (6-OHDA). Adult male Wistar rats were divided into two groups: (1) sedentary (SED) or (2) exercised (EX), animals that did treadmill exercise three times per week, every other day, for 4 weeks prior to 6-OHDA or saline injection. The rats were then divided into four sub-groups: (1) sedentary saline (SED), (2) sedentary 6-OHDA (SED + 6-OHDA), (3) exercised saline (EX), and (4) exercised 6-OHDA (EX + 6-OHDA). Seven and 30 days after surgery, brains were collected for immunohistochemistry and immunoblotting for dopaminergic and neuroinflammatory markers into SN and striatum. The SED + 6-OHDA animals presented an increase in the astrocyte, microglial, and oxidative species activation. On the other hand, EX + 6-OHDA animals did not present neuroinflammatory responses and performed better apormorphine test. Our data suggest that treadmill exercise throughout life can markedly reduce the chances of dopamine decrease, reinforcing studies that showed a lower incidence of Parkinson's disease in patients who were active during life. PMID- 28801820 TI - Lymph Node Evaluation in Robot-Assisted Versus Video-Assisted Thoracoscopic Esophagectomy for Esophageal Squamous Cell Carcinoma: A Propensity-Matched Analysis. AB - OBJECTIVE: Radical lymph node dissection (LND) along the bilateral recurrent laryngeal nerve (RLN) is a surgically challenging procedure with a high rate of morbidity. Here, we assessed in a retrospective manner the adequacy of LND along the RLN performed with robot-assisted thoracoscopic esophagectomy (RATE) versus video-assisted thoracoscopic esophagectomy (VATE) in patients with esophageal squamous cell carcinoma (ESCC). METHODS: This was a single-center, retrospective, propensity-matched study. ESCC patients who underwent McKeown esophagectomy and bilateral RLN LND with a minimally invasive approach were divided into two groups according to the use of robot-assisted surgery or not (RATE vs VATE, respectively). Using propensity score matching, 34 balanced matched pairs were identified. The number of dissected nodes as well as the rates of RLN palsy and perioperative complications served as the main outcome measures. RESULTS: No conversion to open thoracotomy occurred in either group. Intraoperative blood loss and the need of blood transfusions did not show significant intergroup differences. The mean number of dissected nodes was similar in the two study groups, the only exception being the left RLN area. Specifically, the mean number of nodes removed from this region was 5.32 in the RATE group and 3.38 in patients who received VATE (p = 0.007). Notably, the RATE and VATE groups did not differ significantly with regard to rates of both RLN palsy (20.6 vs 29.4%, respectively, p = 0.401) and pulmonary complications (5.9 vs 17.6%, respectively, p = 0.259). CONCLUSIONS: Compared with VATE, RATE resulted in a higher lymph node yield along the left RLN without increasing morbidity. PMID- 28801821 TI - [Optimal margins for breast-conserving surgery with whole-breast irradiation in ductal carcinoma in situ : Results of the ASTRO, ASCO, and SSO consensus guideline]. PMID- 28801822 TI - Simultaneous Quantification of Free Cholesterol, Cholesteryl Esters, and Triglycerides without Ester Hydrolysis by UHPLC Separation and In-Source Collision Induced Dissociation Coupled MS/MS. AB - We demonstrate the application of in-source nitrogen collision-induced dissociation (CID) that eliminates the need for ester hydrolysis before simultaneous analysis of esterified cholesterol (EC) and triglycerides (TG) along with free cholesterol (FC) from human serum, using normal phase liquid chromatography (LC) coupled to atmospheric pressure chemical ionization (APCI) tandem mass spectrometry (MS/MS). The analysis requires only 50 MUL of 1:100 dilute serum with a high-throughput, precipitation/evaporation/extraction protocol in one pot. Known representative mixtures of EC and TG species were used as calibrators with stable isotope labeled analogs as internal standards. The APCI MS source was operated with nitrogen source gas. Reproducible in-source CID was achieved with the use of optimal cone voltage (declustering potential), generating FC, EC, and TG lipid class-specific precursor fragment ions for multiple reaction monitoring (MRM). Using a representative mixture of purified FC, CE, and TG species as calibrators, the method accuracy was assessed with analysis of five inter-laboratory standardization materials, showing -10% bias for Total-C and -3% for Total-TG. Repeated duplicate analysis of a quality control pool showed intra-day and inter-day variation of 5% and 5.8% for FC, 5.2% and 8.5% for Total-C, and 4.1% and 7.7% for Total-TG. The applicability of the method was demonstrated on 32 serum samples and corresponding lipoprotein sub fractions collected from normolipidemic, hypercholesterolemic, hypertriglyceridemic, and hyperlipidemic donors. The results show that in-source CID coupled with isotope dilution UHPLC-MS/MS is a viable high precision approach for translational research studies where samples are substantially diluted or the amounts of archived samples are limited. Graphical Abstract ?. PMID- 28801823 TI - Quantification of light screening by anthocyanins in leaves of Berberis thunbergii. AB - MAIN CONCLUSION: Up to 40% of incident light was screened in red Berberis leaves in vivo by anthocyanins, resulting also in up to 40% reduction of light-limited photosynthesis. The biological function of anthocyanins in leaves has been strongly discussed, but the hypothesis of a screening function is favored by most authors. For an evaluation of the function as photoprotective pigments, a quantification of their screening of the mesophyll is important. Here, chlorophyll fluorescence excitation of leaves of a red and a green variety of Berberis thunbergii was used to estimate the extent of screening by anthocyanins at 545 nm and over the whole photosynthetically active wavelength range. Growth at high light (430 umol m-2 s-1) resulted in 90% screening at 545 nm corresponding to 40-50% screening over the whole wavelength range, depending on the light source. The concomitant reduction of photosynthetic quantum yield was of the same size as the calculated reduction of light reaching the chloroplasts. The induction of anthocyanins in the red variety also enhanced the epoxidation state of the violaxanthin cycle under growth conditions, indicating that red leaves were suffering less from excessive irradiance. Pool sizes of violaxanthin cycle carotenoids indicated a shade acclimation of the light harvesting complexes in red leaves. The observed reduction of internal light in anthocyanic leaves has by necessity a photoprotective effect. PMID- 28801824 TI - Two-dimensional capillary zone electrophoresis-mass spectrometry for the characterization of intact monoclonal antibody charge variants, including deamidation products. AB - Capillary zone electrophoresis (CZE) is a powerful tool that is progressively being applied for the separation of monoclonal antibody (mAb) charge variants. Mass spectrometry (MS) is the desired detection method concerning identification of mAb variants. In biopharmaceutical applications, there exist optimized and validated electrolyte systems for mAb variant quantification. However, these electrolytes interfere greatly with the electrospray ionization (ESI) process. Here, a heart-cut CZE-CZE-MS setup with an implemented mechanical four-port valve interface was developed that used a generic epsilon-aminocaproic acid based background electrolyte in the first dimension and acetic acid in the second dimension. Interference-free, highly precise mass data (deviation less than 1 Da) of charge variants of trastuzumab, acting as model mAb system, were achieved. The mass accuracy obtained (low parts per million range) is discussed regarding both measured and calculated masses. Deamidation was detected for the intact model antibody, and related mass differences were significantly confirmed on the deglycosylated level. The CZE-CZE-MS setup is expected to be applicable to a variety of antibodies and electrolyte systems. Thus, it has the potential to become a compelling tool for MS characterization of antibody variants separated in ESI-interfering electrolytes. Graphical Abstract Two-dimensional capillary zone electrophoresis mass spectrometry for the characterization of intact monoclonal antibody (mAb) charge variants. A generic, but highly electrospray interfering electrolyte system was used as first dimension for mAb charge variant separation and coupled to a volatile electrolyte system as second dimension via a four-port nanoliter valve. In this way, interference-free and precise mass spectrometric data of separated mAb charge variants, including deamidation products, were obtained. PMID- 28801825 TI - Intractable Constipation in the Elderly. AB - OPINION STATEMENT: Chronic constipation is a common gastrointestinal disorder disproportionately affecting the elderly. Immobility, polypharmacy, and physiologic changes contribute to its increased prevalence in this population. Unidentified and undertreated constipation leads to a significant negative impact on quality of life and an increase in healthcare spending. Careful physical examination and exploration of the clinical history can unmask primary and secondary forms of constipation, guiding diagnostic and therapeutic considerations. Non-pharmacologic treatment options include bowel training and biofeedback as well as the addition of fiber. Laxatives are safe and can be used long term; thus, they remain the mainstay of therapy. Newer agents with specific physiologic targets have proven to be effective in adults with chronic constipation, but data is lacking for safety profile in the elderly. Consideration for surgery in medically refractory cases should be entertained, while use of neuromodulation is not ready for prime time. This is a review of the currently available treatment options for chronic constipation in adults and specifically tailored towards the elderly. PMID- 28801826 TI - Brain Activity Changes in Somatosensory and Emotion-Related Areas With Medial Patellofemoral Ligament Deficiency. AB - BACKGROUND: Patellar instability with medial patellofemoral ligament (MPFL) deficiency is a common sports injury among young people. Although nonoperative and surgical treatment can provide stability of the patella, patients often have anxiety related to the knee. We speculate that neural dysfunction may be related to anxiety in these patients; however, the mechanism in the brain that generates this anxiety remains unknown. QUESTIONS/PURPOSES: (1) How does brain activity in patients with MPFL deficiency change in the areas related to somatic sensation against lateral shift of the patella? (2) How does patella instability, which can lead to continuous fear or apprehension for dislocation, influence brain activity in the areas related to emotion? METHODS: Nineteen patients with MPFL deficiency underwent surgical reconstruction in our hospital from April 2012 to March 2014. Excluding seven patients with osteochondral lesions, 12 patients (five males and seven females; mean age, 20 years) with MPFL deficiency were sequentially included in this study. Eleven control subjects (four males and seven females; mean age, 23 years) were recruited from medical students who had no history of knee injury. Diagnosis of the MPFL deficiency was made with MR images, which confirmed the rupture, and by proving the instability with a custom-made biomechanical device. Brain activity during passive lateral stress to the patella was assessed by functional MRI. Functional and anatomic images were analyzed using statistical parametric mapping. Differences in functional MRI outcome measures from the detected activated brain regions between the patients with MPFL deficiency and controls were assessed using t tests. RESULTS: Intergroup analysis showed less activity in several sensorimotor cortical areas, including the contralateral primary somatosensory areas (% signal change for MPFL group 0.49% versus 1.1% for the control group; p < 0.001), thalamus (0.2% versus 0.41% for the MPFL versus control, respectively; p < 0.001), ipsilateral thalamus (0.02% versus 0.27% for the MPFL versus control, respectively; p < 0.001), and ipsilateral cerebellum (0.82% versus 1.25% for the MPFL versus control, respectively; p < 0.001) in the MPFL deficiency group than in the control group. In contrast, the MPFL deficiency group showed more activity in several areas, including the contralateral primary motor area (1.06% versus 0.6% for the MPFL versus control, respectively; p < 0.001), supplementary motor area (0.89% versus 0.52% for the MPFL versus control, respectively; p < 0.001), prefrontal cortex (1.09% versus 1.09% for the MPFL versus control, respectively; p < 0.001), inferior parietal lobule (0.89% versus 0.62% for the MPFL versus control, respectively; p < 0.001), anterior cingulate cortex (0.84% versus 0.08% for the MPFL versus control, respectively; p < 0.001), visual cortex (0.86% versus 0.14% for the MPFL versus control, respectively; p < 0.001), vermis (1.18% versus 0.37% for the MPFL versus control, respectively; p < 0.001), and ipsilateral prefrontal cortex (1.1% versus 0.75% for the MPFL versus control, respectively; p < 0.001) than did the control group. CONCLUSIONS: Less activity in the contralateral somatosensory cortical areas suggested that MPFL deficiency may lead to diminished somatic sensation against lateral shift of the patella. In contrast, increased activity in the anterior cingulate cortex, prefrontal cortex, and inferior parietal lobule may indicate anxiety or fear resulting from patellar instability, which is recognized as an aversion similar to that toward chronic pain. CLINICAL RELEVANCE: This study suggests that specific brain-area activity is increased in patients with MPFL deficiency relative to that in controls. Further longitudinal research to assess brain activity and proprioception between patients pre- and postreconstructive knee surgery may reveal more regarding how patella instability is related to brain function. We hope that based on such research, a neural approach to improve patella-instability-related brain function can be developed. PMID- 28801827 TI - Rapid screening and identification of ACE inhibitors in snake venoms using at line nanofractionation LC-MS. AB - This study presents an analytical method for the screening of snake venoms for inhibitors of the angiotensin-converting enzyme (ACE) and a strategy for their rapid identification. The method is based on an at-line nanofractionation approach, which combines liquid chromatography (LC), mass spectrometry (MS), and pharmacology in one platform. After initial LC separation of a crude venom, a post-column flow split is introduced enabling parallel MS identification and high resolution fractionation onto 384-well plates. The plates are subsequently freeze dried and used in a fluorescence-based ACE activity assay to determine the ability of the nanofractions to inhibit ACE activity. Once the bioactive wells are identified, the parallel MS data reveals the masses corresponding to the activities found. Narrowing down of possible bioactive candidates is provided by comparison of bioactivity profiles after reversed-phase liquid chromatography (RPLC) and after hydrophilic interaction chromatography (HILIC) of a crude venom. Additional nanoLC-MS/MS analysis is performed on the content of the bioactive nanofractions to determine peptide sequences. The method described was optimized, evaluated, and successfully applied for screening of 30 snake venoms for the presence of ACE inhibitors. As a result, two new bioactive peptides were identified: pELWPRPHVPP in Crotalus viridis viridis venom with IC50 = 1.1 MUM and pEWPPWPPRPPIPP in Cerastes cerastes cerastes venom with IC50 = 3.5 MUM. The identified peptides possess a high sequence similarity to other bradykinin potentiating peptides (BPPs), which are known ACE inhibitors found in snake venoms. PMID- 28801828 TI - A New Classification System is Helpful in Diagnosing Intracranial Complications of Acute Mastoiditis in CT. AB - PURPOSE: To assess the usefulness of the new computed tomography (CT) classification criteria proposed by Horowitz et al. and their effect on inter observer agreement when estimating intracranial complications of acute mastoiditis. METHODS: In this study 53 contrast-enhanced CT scans of patients with acute mastoiditis were each retrospectively reviewed by two radiologists, using two different assessment criteria for intracranial complications. According to the new criteria, intracranial CT findings in the perisinuous area were graded into four classes (I normal, II linear halo, III nodular halo <=4 mm thick and IV nodular halo >4 mm thick), where classes III and IV indicate a high risk for epidural abscesses. Inter-reader agreement was estimated by weighted kappa analysis for both methods. RESULTS: With the old method, epidural abscesses were suspected in six and venous sinus thrombosis in five patients. With the new method, high-risk perisinuous lesions (classes III or IV) were detected in 11 patients, and sinus thrombosis outside the perisinuous area in 3 patients. All epidural abscesses were in the perisinuous area. Of the patients four, in whom intracranial pathology was not suspected with the old method, fell into the high risk group (class III) according to the new method. All class IV lesions were also determined to be pathological with the old method. The inter-observer agreement (weighted kappa) rose from 0.21 (old method) to 0.80 (new method) when assessing epidural abscesses and from 0.44 (old method) to 0.85 (new method) when assessing sinus thrombosis. CONCLUSION: The new assessment method raised the inter-observer agreement for detection of intracranial acute mastoiditis complications, namely epidural abscesses and venous sinus thrombosis. PMID- 28801829 TI - Cloning and characterization of Halomonas elongata L-asparaginase, a promising chemotherapeutic agent. AB - L-asparaginase has been used in the treatment of patients with acute lymphoblastic leukemia (ALL) for more than 30 years. Rapid clearance of the enzyme from blood stream and its L-glutaminase-dependent neurotoxicity has led to searching for new L-asparaginases with more desirable properties. In the present study, L-asparaginase coding gene of Halomonas elongata was isolated, expressed in Escherichia coli, purified, and characterized. The purified protein was found to have a molecular mass of 39.5 kDa and 1000-folds more activity towards L asparagine than L-glutamine. Enzyme-specific activity towards L-asparagine was determined to be 1510 U/mg, which is among the highest reported values for microbial L-asparaginases. K m , Vmax, and k cat values were 5.6 mM, 2.2 MUmol/min, and 1.96 * 103 1/S, respectively. Optimum temperature was found to be 37 degrees C while the enzyme showed maximum activity at a wide pH range (from 6 to 9). Enzyme half-life in the presence of human serum at 37 degrees C was 90 min which is three times higher when compared with reported values for E. coli L asparaginase. Enzyme showed cytotoxic effects against Jurkat and U937 cell lines with an IC50 of 2 and 1 U/ml, respectively. Also, no toxic effects on human erythrocytes and Chinese hamster ovary cell lines were detected, and just minor inhibitory effects on human umbilical vein endothelial cells were observed. This is the first report describing the therapeutic potentials of a recombinant L asparaginase isolated from a halophilic bacterium as an anticancer agent. PMID- 28801831 TI - Response regarding involvement of the cerebral veins in MELAS syndrome. PMID- 28801830 TI - Cloning and Expression Analysis of Human Amelogenin in Nicotiana benthamiana Plants by Means of a Transient Expression System. AB - Enamel is the covering tissue of teeth, made of regularly arranged hydroxyapatite crystals deposited on an organic matrix composed of 90% amelogenin that is completely degraded at the end of the enamel formation process. Amelogenin has a biomineralizing activity, forming nanoparticles or nanoribbons that guide hydroxyapatite deposit, and regenerative functions in bone and vascular tissue and in wound healing. Biotechnological products containing amelogenin seem to facilitate these processes. Here, we describe the production of human amelogenin in plants by transient transformation of Nicotiana benthamiana with constructs carrying synthetic genes with optimized human or plant codons. Both genes yielded approximately 500 ug of total amelogenin per gram of fresh leaf tissue. Two purification procedures based on affinity chromatography or on intrinsic solubility properties of the protein were followed, yielding from 12 to 150 ug of amelogenin per gram of fresh leaf tissue, respectively, at different purity. The identity of the plant-made human amelogenin was confirmed by MALDI-TOF-MS analysis of peptides generated following chymotrypsin digestion. Using dynamic light scattering, we showed that plant extracts made in acetic acid containing human amelogenin have a bimodal distribution of agglomerates, with hydrodynamic diameters of 22.8 +/- 3.8 and 389.5 +/- 86.6 nm. To the best of our knowledge, this is the first report of expression of human amelogenin in plants, offering the possibility to use this plant-made protein for nanotechnological applications. PMID- 28801832 TI - Simultaneous measurement of total estradiol and testosterone in human serum by isotope dilution liquid chromatography tandem mass spectrometry. AB - Reliable measurement of total testosterone and estradiol is critical for their use as biomarkers of hormone-related disorders in patient care and translational research. We developed and validated a mass spectrometry method to simultaneously quantify these analytes in human serum without chemical derivatization. Serum is equilibrated with isotopic internal standards and treated with acidic buffer to release hormones from their binding proteins. Lipids are isolated and polar impurities are removed by two serial liquid-liquid extraction steps. Total testosterone and estradiol are measured using liquid chromatography tandem mass spectrometry (LC-MS/MS) in combination of positive and negative electrospray ionization modes. The method shows broad analytical measurement range for both testosterone 0.03-48.5 nM (0.75-1400 ng/dL) and estradiol 11.0-5138 pM (2.99-1400 pg/mL) and excellent agreement with certified reference materials (mean bias less than 2.1% to SRM 971, BCR 576, 577, and 578) and a high order reference method (mean bias 1.25% for testosterone and -0.84% for estradiol). The high accuracy of the method was monitored and certified by CDC Hormone Standardization (HoSt) Program for 2 years with mean bias -0.7% (95% CI -1.6% to 0.2%) for testosterone and 0.1% (95% CI -2.2% to 2.3%) for estradiol. The method precision over a 2-year period for quality control pools at low, medium, and high concentrations was 2.7 2.9% for testosterone and 3.3-5.3% for estradiol. With the consistently excellent accuracy and precision, this method is readily applicable for high-throughput clinical and epidemiological studies. PMID- 28801833 TI - Concentrations, input prediction and probabilistic biological risk assessment of polycyclic aromatic hydrocarbons (PAHs) along Gujarat coastline. AB - A comprehensive investigation was conducted in order to assess the levels of PAHs, their input prediction and potential risks to bacterial abundance and human health along Gujarat coastline. A total of 40 sediment samples were collected at quarterly intervals within a year from two contaminated sites-Alang-Sosiya Shipbreaking Yard (ASSBRY) and Navlakhi Port (NAV), situated at Gulf of Khambhat and Gulf of Kutch, respectively. The concentration of SigmaPAHs ranged from 408.00 to 54240.45 ng g-1 dw, indicating heavy pollution of PAHs at both the contaminated sites. Furthermore, isomeric ratios and principal component analysis have revealed that inputs of PAHs at both contaminated sites were mixed-pyrogenic and petrogenic. Pearson co-relation test and regression analysis have disclosed Nap, Acel and Phe as major predictors for bacterial abundance at both contaminated sites. Significantly, cancer risk assessment of the PAHs has been exercised based on incremental lifetime cancer risks. Overall, index of cancer risk of PAHs for ASSBRY and NAV ranged from 4.11 * 10-6-2.11 * 10-5 and 9.08 * 10 6-4.50 * 10-3 indicating higher cancer risk at NAV compared to ASSBRY. The present findings provide baseline information that may help in developing advanced bioremediation and bioleaching strategies to minimize biological risk. PMID- 28801834 TI - Current characteristics and management of congenital esophageal stenosis: 40 consecutive cases from a multicenter study in the Kyushu area of Japan. AB - PURPOSE: Congenital esophageal stenosis (CES) is rare, and the available clinical data are limited. We explored the current diagnosis, treatment and outcomes of CES. METHODS: A questionnaire survey was performed using medical records at pediatric surgical centers in the Kyushu area. RESULTS: Over 10 years, 40 patients (24 males) had CES. The incidence of associated anomalies was 52.5% (21/40), and that of esophageal atresia was 20.0% (8/40). The mean age at the diagnosis was 12.0 months (range, 1 day-8.8 years). Seven (17.5%) patients were diagnosed in the neonatal period. Ten (25.0%) developed CES due to tracheobronchial remnants, 27 (67.5%) due to fibromuscular stenosis (FMS) and 1 (2.5%) due to membranous stenosis + FMS. Thirty-six (90.0%) were treated by balloon dilatation (mean, 3 times; range, 1-20). Perforation at dilatation occurred in 7 (17.5%) patients, and all were diagnosed with FMS. Eighteen (45.0%) patients underwent radical operation (3 primary, 15 secondary to dilatation). CONCLUSIONS: Our study clarified the characteristics and outcomes of CES, including neonatal diagnoses. CES occurred in 1 in every 33,000 births in the Kyushu area. Careful attention should be paid, even in cases of dilatation for FMS. CES requires long-term follow-up for symptom persistence after adequate and repeated treatment. PMID- 28801836 TI - Optimization of Sample Preparation and Instrumental Parameters for the Rapid Analysis of Drugs of Abuse in Hair samples by MALDI-MS/MS Imaging. AB - Matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) has been employed to rapidly screen longitudinally sectioned drug user hair samples for cocaine and its metabolites using continuous raster imaging. Optimization of the spatial resolution and raster speed were performed on intact cocaine contaminated hair samples. The optimized settings (100 * 150 MUm at 0.24 mm/s) were subsequently used to examine longitudinally sectioned drug user hair samples. The MALDI-MS/MS images showed the distribution of the most abundant cocaine product ion at m/z 182. Using the optimized settings, multiple hair samples obtained from two users were analyzed in approximately 3 h: six times faster than the standard spot-to-spot acquisition method. Quantitation was achieved using longitudinally sectioned control hair samples sprayed with a cocaine dilution series. A multiple reaction monitoring (MRM) experiment was also performed using the 'dynamic pixel' imaging method to screen for cocaine and a range of its metabolites, in order to differentiate between contaminated hairs and drug users. Cocaine, benzoylecgonine, and cocaethylene were detectable, in agreement with analyses carried out using the standard LC-MS/MS method. Graphical Abstract ?. PMID- 28801835 TI - Fabrication of acyclovir-loaded flexible membrane vesicles (FMVs): evidence of preclinical efficacy of antiviral activity in murine model of cutaneous HSV-1 infection. AB - The present investigation focuses on the development and evaluation of acyclovir loaded flexible membrane vesicles (ACY-FMVs) and evaluates their targeting potential to localize the drug into skin layers. The drug-loaded FMVs were prepared by thin-film hydration method and characterized for various attributes including micromeritics, entrapment efficiency, vesicle shape, size, and degree of deformability. The values of particle size and zeta potential of the developed carrier system were found to be 453.7 nm and - 11.62 mV, respectively. The system was further incorporated into a hydrogel and evaluated for skin permeability and retention characteristics in comparison to marketed formulation. The developed formulation demonstrated enhanced retention of drug deep inside the skin layers which can probably decrease the frequency of application of the drug, thereby reducing its adverse effects. Skin irritancy studies performed on Laca mice skin proved the safety and non-irritant nature of ACY-FMVs. The pharmacodynamic studies on murine model for HSV-1 infection demonstrated immense potential and safety of topically applied ACY-FMVs. However, more intensive studies need to be pursued to explore and exploit the potential of lipid-based systems in anti-viral therapeutics. These preclinical findings provide a hope for corroborating the efficacy in clinical situations. PMID- 28801837 TI - Blunt injuries related to equestrian sports: results from an international prospective trauma database analysis. AB - INTRODUCTION: The objective of this study was to investigate the nature, management, and outcome of major injuries related to equestrian sports and to define the at-risk groups for serious and life-threatening injuries. METHODS: We analyzed demographic, pre-hospital, clinical, and outcome data from an international population-based prospective trauma database (TraumaRegister DGU(r)). Patients with major injuries (Injury Severity Score [ISS] >=9 points) related to equestrian sports activities were included (January 1, 1993, to December 31, 2012). Clinical and outcome parameters were stratified for four different types of injury mechanisms: fall from horse (FFH), horse-kick (HK), horse crush (HC), and carriage-related accidents (CRA). Participating countries included Germany, Austria, Switzerland, Finland, Slovenia, Belgium, Luxembourg, and The Netherlands. Statistical analyses were performed with SPSS (Version 22, IBM Inc., Armonk, NY). RESULTS: The Database identified 122,000 documented patients, of whom 679 were equestrian incidents. Among these, the four major injury mechanisms were: FFH (n = 427), HK (n = 188), HC (n = 34), and the CRA (n = 30). Females were more likely to sustain FFH (75.5%, p < 0.001), leading to head injuries (n = 204, 47.8%) and spinal fractures (n = 109, 25.5%). HK injuries often resulted in facial fractures (29.3%, p < 0.001). Individuals sustaining HC injuries had a high risk for pelvic (32.4%, p < 0.001) and abdominal injuries (35.2%, p < 0.001). In contrast to the FFH cohort, the CRA cohort involved older males (57 +/- 13 years), with chest (63.3% p = 0.001), and extremity injuries, resulting in significant injury severity (ISS 20.7 +/- 10.6). In the CRA cohort, 16% were in haemorrhagic shock on scene, and also the highest in-hospital mortality (14.8%, p = 0.006) was observed. CONCLUSIONS: Young female riders are at risk from falling, horse-kicks, and crush-injuries. Older males in carriage related accidents sustained the highest injury severity and mortality rate, and must specifically be targeted by future prevention initiatives. Level of evidence Descriptive Epidemiologic Study, Level II. PMID- 28801838 TI - Erratum to: Imaging for planning of transcatheter aortic valve implantation. PMID- 28801839 TI - Biotransformation with cellulase, hemicellulase and Yarrowia lipolytica boosts health benefits of okara. AB - Okara (soybean residue) is a highly perishable food processing by-product from soymilk and tofu manufacture. It contains a large proportion of insoluble dietary fibre (40-60% on a dry basis), as well as digestion-resistant proteins, trypsin inhibitors and phytic acid. These factors contribute lead to the under utilisation of okara. To improve the overall nutritional quality of okara, sequential saccharification of okara by Celluclast(r) 1.5L (cellulase) or Viscozyme(r) L (cellulase and hemicellulase) and fermentation by the yeast Yarrowia lipolytica were performed. The changes in the antioxidant capacity, amino acids, phenolic acids, isoflavones, phytic acid and dietary fibre during biotransformation were studied. Carbohydrase pre-treatment increased the amounts of monosaccharides, trans-cinnamic acid and aglycone isoflavones in okara. After fermentation, the okara had higher antioxidant activity and greater amounts of total amino acids and ferulic acid. Some positive interactions between the carbohydrase and Y. lipolytica were hypothesised: the carbohydrase and Y. lipolytica proteases could have synergised with each other to break down the okara secondary cell wall more efficiently. After 52 h, Celluclast(r) 1.5 L and Viscozyme(r) L significantly reduced the insoluble dietary fibre content from 61.9 +/- 0.6 to 45.6 +/- 3.0% and 24.7 +/- 0.3%, respectively (all w/w, dry basis), while increasing the soluble dietary fibre content by about onefold. Both carbohydrases also increased the amounts of monosaccharides, trans-cinnamic acid, and aglycone isoflavones in okara. The addition of Y. lipolytica led to a higher antioxidant capacity and greater amounts of total amino acids and ferulic acid in okara. The overall improvements in the digestibility and potential health benefits of okara highlight the promising applicability of biotransformation in okara valorisation. PMID- 28801840 TI - Tobacco-related carcinogenesis in head and neck cancer. AB - Head and neck cancer (head and neck squamous cell carcinoma (HNSCC)) is a devastating disease. Patients require intensive treatment that is often disfiguring and debilitating. Those who survive are often left with poor speech articulation, difficulties in chewing and swallowing, and cosmetic disfigurement, as well as loss of taste. Furthermore, given that HNSCC survivors are frequently disabled and unable to return to work, the economic and societal costs associated with HNSCC are massive. HNSCC is one of many cancers that are strongly associated with tobacco use. The risk for HNSCC in smokers is approximately ten times higher than that of never smokers, and 70-80% of new HNSCC diagnoses are associated with tobacco and alcohol use. Tobacco products have been used for centuries; however, it is just within the last 60-70 years that we have developed an understanding of their damaging effects. This relatively recent understanding has created a pathway towards educational and regulatory efforts aimed at reducing tobacco use. Understanding the carcinogenic components of tobacco products and how they lead to HNSCC is critical to regulatory and harm reduction measures. To date, nitrosamines and other carcinogenic agents present in tobacco products have been associated with cancer development. The disruption of DNA structure through DNA adduct formation is felt to be a common mutagenic pathway of many carcinogens. Intense work pertaining to tobacco product constituents, tobacco use, and tobacco regulation has resulted in decreased use in some parts of the world. Still, much work remains as tobacco continues to impart significant harm and contribute to HNSCC development worldwide. PMID- 28801842 TI - Precision Medicine Core: Progress in Prognostication-Populations to Patients. PMID- 28801841 TI - The use of aortic balloon occlusion in traumatic shock: first report from the ABO trauma registry. AB - PURPOSE: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a technique for temporary stabilization of patients with non-compressible torso hemorrhage. This technique has been increasingly used worldwide during the past decade. Despite the good outcomes of translational studies, clinical studies are divided. The aim of this multicenter-international study was to capture REBOA specific data and outcomes. METHODS: REBOA practicing centers were invited to join this online register, which was established in September 2014. REBOA cases were reported, both retrospective and prospective. Demographics, injury patterns, hemodynamic variables, REBOA-specific data, complications and 30-days mortality were reported. RESULTS: Ninety-six cases from 6 different countries were reported between 2011 and 2016. Mean age was 52 +/- 22 years and 88% of the cases were blunt trauma with a median injury severity score (ISS) of 41 (IQR 29-50). In the majority of the cases, Zone I REBOA was used. Median systolic blood pressure before balloon inflation was 60 mmHg (IQR 40-80), which increased to 100 mmHg (IQR 80-128) after inflation. Continuous occlusion was applied in 52% of the patients, and 48% received non-continuous occlusion. Occlusion time longer than 60 min was reported as 38 and 14% in the non-continuous and continuous groups, respectively. Complications, such as extremity compartment syndrome (n = 3), were only noted in the continuous occlusion group. The 30-day mortality for non continuous REBOA was 48%, and 64% for continuous occlusion. CONCLUSIONS: This observational multicenter study presents results regarding continuous and non continuous REBOA with favorable outcomes. However, further prospective studies are needed to be able to draw conclusions on morbidity and mortality. PMID- 28801843 TI - Sex estimation of infants through geometric morphometric analysis of the ilium. AB - In archeology or forensics, the analysis of the ilia is often used to determine the age and sex of unknown individuals. However, sex determination using the skeletal remains of individuals who did not develop secondary sexual characteristics remains controversial. Accurately estimating the sex of subadults is hampered by a small number of studies based on identified skeletal collections of juvenile individuals. Here, we analyzed the sexual dimorphism of the subadult ilia using geometric morphometric techniques and individuals from the osteological collection of identified subadults from San Jose's graveyard (Granada). Seventy-one left ilia from 40 males and 31 females aged between birth and 1 year were included in the analysis. Three landmarks and 27 semi-landmarks of the ilia were placed. By principal component analysis, we found that the size and shape of the ilia could be used to differentiate males and females. PMID- 28801845 TI - Accurate analytical method for human plasma glucagon levels using liquid chromatography-high resolution mass spectrometry: comparison with commercially available immunoassays. AB - Accurate quantification of plasma glucagon levels in humans is necessary for understanding the physiological and pathological importance of glucagon. Although several immunoassays for glucagon are available, they provide inconsistent glucagon values owing to cross-reactivity of the antibodies with peptides other than glucagon. To overcome this limitation, we developed a novel method to measure glucagon levels by a liquid chromatography (LC)-high-resolution mass spectrometry (HRMS) assay via parallel reaction monitoring (PRM) without immunoaffinity enrichment. Using stable isotope-labeled glucagon as an internal standard and 200 MUL of plasma, the lower limit of quantification was 0.5 pM. This method was applied to measure plasma glucagon levels during the oral glucose tolerance test (OGTT) and meal tolerance test (MTT) in healthy volunteers, and its results were compared with those of sandwich enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA). During the OGTT, this method showed significant suppression of plasma glucagon levels, and similar patterns were observed with sandwich ELISA and RIA. In contrast, during the MTT, plasma glucagon levels were slightly elevated according to the LC-MS/MS and sandwich ELISA results and were reduced according to RIA results. Our newly developed LC MS/MS method overcomes a lack of specificity among currently available immunoassays for glucagon and may contribute to a better understanding of the importance of glucagon. Graphical abstract Flowchart for the extraction and quantification of glucagon in human plasma, and plasma glucagon responses in healthy volunteers quantified by the present LC-MS/MS, sandwich ELISA, and RIA during OGTT and MTT. PMID- 28801844 TI - Brg1 inhibits E-cadherin expression in lung epithelial cells and disrupts epithelial integrity. AB - : Brahma-related gene-1 (Brg1), a key chromatin remodeling factor, is associated with cell proliferation and migration in kidney and heart cells, but few reports have examined its role in airway epithelial cell. Airway epithelial injury, which is involved in the entire pathological process of asthma, is an important cause of recurrent asthma. Here, we studied the function of Brg1 in an ovalbumin (OVA) induced asthma model (lung-specific conditional Brg1 (Brg1-/-) knockdown mice) and human bronchial epithelial 16HBE cells stably expressing Brg1 shRNA. Our results showed that high expression of Brg1 was detected in asthmatic children and in mouse models. Brg1-/- mice showed improved airway hyperresponsiveness (AHR) and bronchial epithelial integrity, along with reduced inflammatory cell infiltration and airway mucus secretion, when challenged with OVA. Furthermore, cell proliferation, migration, and expression of E-cadherin increased in 16HBE cells in which Brg1 was silenced. We further demonstrated that Brg1 bound to and inactivated a critical region (-86/+60 bp) within the E-cadherin promoter in bronchial epithelial cells. Thus, Brg1 might act as an important regulator of airway epithelial integrity in asthma progression and might be a novel therapeutic target. KEY MESSAGES: * Depletion of Brg1 improves the integrity of airway epithelium in asthma by regulating E-cadherin expression in lung epithelial cells. * Knockdown of Brg1 increased the cell proliferation and migration by human bronchial epithelial 16HBE cells. * Brg1 might bLLe a novel therapeutic target in asthma. PMID- 28801846 TI - Vascular function in breast cancer survivors on aromatase inhibitors: a pilot study. AB - PURPOSE: Aromatase inhibitors (AI) have been shown to reduce breast cancer related mortality in women with estrogen positive (ER+) breast cancer. The use of AIs, however, has been associated with higher rates of hypertension, hyperlipidemia, and cardiovascular (CV) events. METHODS: A cross-sectional study of 25 healthy postmenopausal women and 36 women with curative intent breast cancer on an AI was performed to assess endothelial dysfunction, an indicator of risk for CV events. Consented subjects underwent vascular testing using the HDI/Pulse Wave CR-2000 Cardiovascular Profiling System and the EndoPAT2000 system. RESULTS: Mean age was 61.7 and 59.6 years (cases, controls). Most subjects were Caucasian and overweight. Controls had a lower mean systolic blood pressure (128.6 mmHg vs. 116.2 mmHg, p = 0.004). Median estradiol levels were reduced in cases (2 vs. 15 pg/ml, p < 0.0001). EndoPAT ratio (0.8 vs. 2.7, p < 0.0001) was significantly reduced in cases as compared to controls. Median large artery elasticity (12.9 vs. 14.6 ml/mmHg * 10, p = 0.12) and small artery elasticity (5.2 vs. 7.0 ml/mmHg * 100, p = 0.07) were also reduced though not statistically significant. There was no correlation between use of chemotherapy, radiation therapy, type of AI, or duration of AI use and endothelial function. When adjusting for differences in blood pressure, results remained significant. CONCLUSION: Breast cancer cases on AIs have reductions in endothelial function, a predictor of adverse CV disease. IMPACT: Vascular function changes in breast cancer cases on AIs compared to postmenopausal women. Further work is needed to evaluate vascular changes over time. PMID- 28801848 TI - Structural phase transition of BeTe: an ab initio molecular dynamics study. AB - Beryllium telluride (BeTe) with cubic zinc-blende (ZB) structure was studied using ab initio constant pressure method under high pressure. The ab initio molecular dynamics (MD) approach for constant pressure was studied and it was found that the first order phase transition occurs from the ZB structure to the nickel arsenide (NiAs) structure. It has been shown that the MD simulation predicts the transition pressure P T more than the value obtained by the static enthalpy and experimental data. The structural pathway reveals MD simulation such as cubic -> tetragonal -> orthorhombic -> monoclinic -> orthorhombic -> hexagonal, leading the ZB to NiAs phase. The phase transformation is accompanied by a 10% volume drop and at 80 GPa is likely to be around 35 GPa in the experiment. In the present study, our obtained values can be compared with the experimental and theoretical results. Graphical abstract The energy-volume relation and ZB phase for the BeTe. PMID- 28801847 TI - Assessment of functioning and disability in patients with schizophrenia using the WHO Disability Assessment Schedule 2.0 in a large-scale database. AB - Schizophrenia is a common mental disorder characterized by deficits in multiple domains of functioning. This study is arguably the first of its kind in Taiwan to examine, in a multifaceted and objective manner, the disability of patients with schizophrenia and the factors affecting it. A cross-sectional design was adopted to gather data from 24,299 patients with schizophrenia who were listed in the Taiwan Databank of Persons with Disabilities. The level of disability in these patients was measured using the World Health Organization Disability Assessment Schedule 2.0. Statistical analyses were conducted through the chi 2 statistic and Poisson regression. The highest level of disability was in participation and the lowest was in self-care. An analysis of disability in all six domains of functioning on the basis of sex, age, type of residence, and socioeconomic status (SES) showed significant differences (P < 0.05). Significant factors (P < 0.05) affecting disability in these domains were female gender, age, educational attainment, SES, type of residence, and employment status. The overall degree of disability in schizophrenia patients was moderate. Six domains were measured in this study. The degrees of disability in mobility and self-care were mild while cognition, getting along, life activities, and participation were moderate. Moreover, female gender, an age of 45 or older, low educational attainment, middle to low SES, staying at healthcare institutions, and unemployment were crucial factors affecting disability of the participants. Preventive and rehabilitation programs should be developed to delay disability and functional degeneration in schizophrenic patients with these characteristics. PMID- 28801849 TI - Bevacizumab in Colorectal Cancer: Current Role in Treatment and the Potential of Biosimilars. AB - Colorectal cancer (CRC) is a leading cause of tumor-related morbidity and mortality worldwide, with mortality most often attributable to metastatic disease. Bevacizumab, a humanized monoclonal antibody targeting vascular endothelial growth factor, has a significant role in the treatment of metastatic CRC (mCRC). However, patient access to bevacizumab may be limited in some regions or circumstances, owing to factors related to insurance coverage, reimbursement, patient out-of-pocket costs, or availability. As a result, outcomes for patients with mCRC may be worsened. Additionally, counterfeit bevacizumab has infiltrated legitimate supply chains, exposing patients to risk. Oncologists may also be affected detrimentally, since resolving access issues can be time-consuming and demoralizing. The imminent expiry of patents protecting bevacizumab provides other manufacturers with the opportunity to produce highly similar versions known as biosimilars. High-quality, safe, and effective biosimilars have the potential to expand access to bevacizumab. Most of the bevacizumab biosimilars currently in development are in clinical trials in patients with non-small-cell lung cancer, and future authorization for mCRC indications will, therefore, be based on extrapolation. This article reviews the current role of bevacizumab in the management of mCRC, the possible barriers associated with diminished access to bevacizumab, and the potential bevacizumab biosimilars in development. How biosimilars may impact the treatment of mCRC is also discussed. PMID- 28801850 TI - Amisulpride in the prevention of nausea and vomiting induced by cisplatin-based chemotherapy: a dose-escalation study. AB - PURPOSE: The purpose of this study was to investigate the antiemetic effect of the dopamine D2- and dopamine D3-receptor antagonist, amisulpride, in patients receiving cisplatin-based chemotherapy. METHODS: This dose-finding, non comparative study investigated the antiemetic effect and safety of increasing doses (2.5, 7.5 and 20 mg) of amisulpride against acute nausea and vomiting in the period 0-24 h after initiation of cisplatin-based chemotherapy. The 20 mg dose was also investigated in combination with the 5-HT3-receptor antagonist, ondansetron. The primary parameter was complete response (0-24 h), defined as no emesis and no need for rescue antiemetics. Secondary parameters were number of emetic episodes, severity of nausea and time to first emetic episode and start of nausea. RESULTS: A total of 51 patients were enrolled and evaluable. None of the 10 patients in the 2.5 and 7.5 mg groups obtained a CR. In the 20 mg monotherapy cohort, two of the 18 subjects (11%) had a CR, 3/18 (17%) had no emesis and 12/18 (67%) had no significant nausea. Seven subjects (39%) had no nausea at all (a VAS score < 5 mm). In the combination (ondansetron plus amisulpride) cohort, 19/23 (83%; 90% confidence interval: 65-94%) had a CR and 14/23 (61%) had no nausea at all. CONCLUSIONS: Amisulpride has antiemetic effect against cisplatin-induced acute nausea and vomiting. The effect against nausea is of particular interest. Randomised studies are warranted to further explore the effect and safety of amisulpride. PMID- 28801851 TI - Vertical distribution of soil extractable organic C and N contents and total C and N stocks in 78-year-old tree plantations in subtropical Australia. AB - Few studies have focused on the effects of long-term forest plantations on the soil profile of carbon (C) and nitrogen (N) stocks. In this study, we selected 78 year-old tree plantations that included three coniferous tree species (i.e., slash pine, hoop pine and kauri pine) and a Eucalyptus species in subtropical Australia. We measured soil extractable organic C (EOC) and N (EON) contents and total C and N stocks under different tree species on the forest floor and along a soil profile to 100 cm depth. The results showed that Eucalyptus had significantly higher soil EOC contents (3.3 Mg ha-1) than the other tree species (EOC of 1.9-2.3 Mg ha-1) and had significantly higher EON (156 kg ha-1) contents than slash pine (107 kg ha-1). Eucalyptus had significantly higher soil C (58.9 Mg ha-1) and N (2.03 Mg ha-1) stocks than the other tree species (22.3-27.6 Mg C ha-1 and 0.71-1.23 Mg N ha-1) at 0-100 cm depth. There were no differences in soil C stocks at the 0-100 cm depth among the coniferous tree species. Forest floor C stocks had stronger effects on mineral soil total N stocks than fine root biomass, whereas fine root biomass exerted stronger effects on soil total C stocks at the 0-100 cm depth than forest floor C and N stocks. Our results addressed large differences in soil C and N stocks under different tree species, which can provide useful information for local forest management practices in this region. PMID- 28801852 TI - Phase 1 study of darolutamide (ODM-201): a new-generation androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer. AB - PURPOSE: This trial assessed the safety, pharmacokinetics, and efficacy of darolutamide (ODM-201), a new-generation nonsteroidal androgen receptor antagonist, in Japanese patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: In this open-label, nonrandomized, two-cohort, dose escalating phase 1 study, Japanese patients with mCRPC were enrolled after a screening period. In the single-dose period (~1 week), darolutamide was administered at 300 mg (Cohort 1) or 600 mg (Cohort 2) on day -5 (fasting state) and day -2 (fed condition). In the subsequent multiple-dose period (fed condition), patients received darolutamide 300 mg twice daily (Cohort 1) or 600 mg twice daily (Cohort 2) for 12 weeks. Primary endpoints: evaluate safety and pharmacokinetics of darolutamide. RESULTS: Of 12 patients enrolled, 9 received darolutamide (Cohort 1, n = 3; Cohort 2, n = 6). All 9 patients experienced >=1 treatment-emergent adverse event (TEAE; majority Grade 1/2). Incidence of drug related TEAEs (DR-TEAEs) was 44% (all grades; n = 4); most common DR-TEAE was decreased appetite (22%), and 1 serious DR-TEAE (Grade 3 nausea) was observed. No Grade >=4 DR-TEAEs or new safety signals were observed. C max and AUC (0-t last) were dose-dependent; pharmacokinetics of each dose appeared to be linear over time. Prostate-specific antigen response was observed in 11% (1/9) of patients. Compared with fasting status, geometric mean C max increased 2.5-fold after 300 mg and 2.8-fold after 600 mg; geometric mean AUC (0-t last) increased 2.5-fold after both doses under fed conditions. CONCLUSIONS: Darolutamide was well tolerated at the examined doses in Japanese patients with mCRPC, without differences in safety and pharmacokinetics relative to Western patients. PMID- 28801853 TI - Tumor-associated macrophage infiltration is highly associated with PD-L1 expression in gastric adenocarcinoma. AB - BACKGROUND: Programmed death ligand 1 (PD-L1) is a key protein upregulated by tumor cells to suppress immune responses. Tumor-associated macrophages (TAMs) play a major role in this immunosuppression, but the relationship between PD-L1 expression and TAMs remains unclear in gastric adenocarcinoma (GAC). We simultaneously examined expression of PD-L1 and TAMs in GAC. METHODS: We performed immunohistochemical staining for PD-L1, CD68 (pan-macrophage), and CD163 (M2-like macrophage) in 217 GAC samples using a tissue microarray. Expression of PD-L1 and CD68- and CD163-positive cells was evaluated using the Cytoplasmic V2.0 algorithm in Aperio ImageScope software, and logistic regression analysis was used to compare expression patterns between groups. RESULTS: Thirty one samples (14%) were positive for PD-L1 expression. The mean (+/- standard error) rates of infiltration were 6.83 +/- 0.38% for CD68-positive cells and 6.16 +/- 0.29% for CD163-positive cells. The mean rate of CD163-positive cell infiltration was significantly higher in diffuse GAC than in intestinal GAC (diffuse n = 111, 6.91%; intestinal n = 91, 5.26%; p = 0.006), but the mean rate of CD68-positive cell infiltration was similar between these types (p = 0.38). The mean infiltration rates of CD68- and CD163-positive cells in PD-L1-positive GAC were significantly higher than in PD-L1-negative GAC (CD68 p = 0.0002; CD163 p < 0.0001). In multivariate logistic regression analyses, CD163-positive cell infiltration was associated with PD-L1 expression (odds ratio 1.13; 95% confidence interval 1.02-1.25; p = 0.021). CONCLUSION: M2-like macrophage infiltration is highly associated with PD-L1 expression in GAC cells, suggesting that macrophage infiltration can serve as a potential therapeutic target. PMID- 28801854 TI - How do red and infrared low-level lasers affect folliculogenesis cycle in rat's ovary tissue in comparison with clomiphene under in vivo condition. AB - Folliculogenesis is a cycle that produces the majority of oocyte. Any disruption to this cycle leads to ovulation diseases, like polycystic ovarian syndrome (PCOS). Treatments include drugs and surgery; lasers have also been used complementarily. Meanwhile, still there is no definite treatment for PCOS. This study investigated the photo-bio stimulation effect of near-infrared and red low level laser on producing follicles and compared the result with result of using common drug, clomiphene. Therefore, the aim of this study was to propose the use of lasers autonomously treatment. So, there was one question: how do lasers affect folliculogenesis cycle in rat's ovary tissue? In this study, 28 rats were assigned to four groups as follows: control (CT), clomiphene drug (D), red laser (RL), and near-infrared laser (NIRL). Afterwards, 14 rats of RL and NIRL groups received laser on the first 2 days of estrous cycle, each 6 days, for 48 days. During treatment period, each rat received energy density of 5 J/cm2. Seven rats in D group received clomiphene. After the experiment, lasers' effects at two wavelengths of 630 and 810 nm groups have been investigated and compared with clomiphene and CT groups. Producing different follicles to complement folliculogenesis cycle increased in NIRL and RL groups, but this increase was significant only in the NIRL group. This indicates that NIRL increases ovarian activity to produce oocyte that certainly can be used in future studies for finding a cure to ovarian negligence to produce more oocyte and treat diseases caused by it like PCOS. PMID- 28801855 TI - [The AMDS system for the documentation of symptoms and signs associated with pain]. AB - The authors present a system for nomenclature and documentation of symptoms and signs associated with pain. The system was compiled in a staged process by the study group for methods and documentation of pain-associated symptoms and signs (Arbeitsgemeinschaft fur Methodik und Dokumentation von Schmerzbefunden [AMDS]). The suggested items were elaborated from terms used in current national and international guidelines and classifications and in part integrated into superordinate terms. The items that were built up by this approach aim to reflect the broad spectrum of pain diseases. The items for the description of pain associated symptoms and signs are divided into the areas of algesiomotor, psychoalgesiological and somatoalgesiological findings. The aim is the documentation of a multidimensional algesiological description of findings with defined terminology, which can serve as a comparable and unified standard, particularly in the field of pain assessment. The AMDS system should enable a systematic description of pain, which is a reliable foundation for diagnostics, therapy planning and expert case evaluation. PMID- 28801856 TI - The effects of supplementing Acacia mearnsii tannin extract on dairy cow dry matter intake, milk production, and methane emission in a tropical pasture. AB - The study assessed the effect of Acacia mearnsii tannin extract supplementation grazing dairy cows on dry matter (DM) intake, enteric methane (CH4) emission, and performance. Twelve Holstein cows were divided into two groups and subjected to two treatments that consisted of millet pasture (Pennisetum glaucum L.) plus supplementation with 6 kg of concentrate (750-g/kg ground corn and 250-g/kg soybean meal) including or excluding 120-g tannin extract. The trial design was a double reversal using three periods of 28 days each, with 21 days for the adaption period, and 7 days for sample collection. Herbage intake was measured using the n-alkane technique, and daily CH4 emission was measured with the sulfur hexafluoride tracer gas technique. Individual total DM intake (mean = 17.1 kg/day), herbage DM intake (mean = 11.8 kg/day), and milk production (mean = 19.2 kg/day) were similar between treatments. CH4 emission significantly decreased (32%, P < 0.05) in the animals supplemented with tannin extract, compared to non supplemented animals. On the other hand, as proportion of DM intake or milk production, methane emission tended to decrease in tannin-supplemented animals. Supplementing dairy cows grazing a millet pasture with 120-g tannin extract reduced daily CH4 emission without affecting animal performance. PMID- 28801857 TI - Simultaneous addition of zero-valent iron and activated carbon on enhanced mesophilic anaerobic digestion of waste-activated sludge. AB - The performance of biogas generation and sludge degradation was studied under different zero-valent iron/activated carbon (ZVI/AC) ratios in detail in mesophilic anaerobic digestion of sludge. A good enhancement of methane production was obtained at the 10:1 ZVI/AC ratio, and the cumulative methane production was 132.1 mL/g VS, 37.6% higher than the blank. The methane content at the 10:1 ZVI/AC ratio reached 68.8%, which was higher than the blank (55.2%) and the sludge-added AC alone (59.6%). For sludge degradation, the removal efficiencies of total chemical oxygen demand (TCOD), proteins, and polysaccharides were all the highest at the 10:1 ZVI/AC ratio. The concentration of available phosphorus (AP) decreased after anaerobic digestion process. On the other hand, the concentrations of available nitrogen (AN) and available potassium (AK) increased after the anaerobic digestion process and showed a gradually decreasing trend with increasing ZVI/AC ratio. The concentrations of AN and AK were 2303.1-4200.3 and 274.7-388.3 mg/kg, showing a potential for land utilization. PMID- 28801858 TI - Prediction of nitrogen release from sigmoid-type controlled release fertilizers in greenhouse production of strawberry and cucumber. PMID- 28801859 TI - Cross-cultural adaption and psychometric properties of the Chinese version of the Diabetes Behavior Rating Scale: a pilot study. AB - Self-care behavior plays a major role in diabetic management. However, in China, a satisfactory instrument has not yet been developed to evaluate the compliance of self-care behavior for young patients with type 1 diabetes mellitus (T1DM). The Diabetes Behavior Rating Scale (DBRS) has a potential to be the first mature instrument. The purpose of this study is to cross-culturally adapt the DBRS, and preliminarily evaluate its psychometric properties. The instrument translation included translation, back translation and culture adaptation. Psychometric properties were assessed in a sample of 116 young patients with T1DM adapting insulin injection therapy. The Chinese version of the DBRS was divided to four subscales. Cronbach's alpha for the total scale was 0.92. The mean inter-item and item-total correlations were 0.35 and 0.54 respectively. Test-retest reliability showed good temporal stability (r=0.81, P=0.001). Negative correlations were found between DBRS scores with the Diabetes Distress Scale scores (r=-0.32, P=0.003) and hemoglobin A1c (HbA1c) levels (r=-0.36, P=0.002). Higher DBRS scores correlated with better glycemic control. The Chinese insulin injection therapy version of the DBRS is well translated and culturally adapted. It shows good overall reliability and validity and appears to be a valuable tool for assessing the diabetic self-care behaviors for young patients with T1DM. PMID- 28801860 TI - Towards a one-stop solution for large-scale proteomics data analysis. PMID- 28801861 TI - Human PIWI (HIWI) is an azoospermia factor. PMID- 28801862 TI - Feasibility, comparability, and reliability of the standard gamble compared with the rating scale and time trade-off techniques in Korean population. AB - PURPOSE: The standard gamble (SG) method is the gold standard for valuing health states as a utility, although it is accepted that it is difficult to valuate health states. This study was conducted in order to compare the SG with the rating scale (RS) and time trade-off (TTO) techniques in terms of their feasibility, comparability, and reliability in a valuation survey of the general Korean population. METHODS: Five-hundred members of the general Korean population were recruited using a multi-stage quota sampling method in Seoul and its surrounding areas, Korea. Respondents evaluated 9 EQ-5D-5L health states using a visual analogue scale (VAS), SG, and TTO during a personal interview. Feasibility was assessed in aspects of the level of difficulty, administration time, and inconsistent responses. Comparability was evaluated using intraclass correlation coefficient (ICC) and the Bland-Altman approach. Test-retest reliability was analyzed using the ICC. RESULTS: Of the three methods, VAS was the easiest and quickest method to respond. The SG method did not differ significantly compared to the TTO method in administration time as well as the level of difficulty. The SG and TTO values were highly correlated (r = 0.992), and the average mean difference between the SG and the TTO values was 0.034. The ICCs of the VAS, SG, and TTO scores were 0.906, 0.841, and 0.827, respectively. CONCLUSIONS: This study suggests that the SG method compared with the VAS and TTO method was feasible and offered a reliable tool for population-based, health state valuation studies in Korea. PMID- 28801863 TI - Pedicle screw fixation in thoracolumbar and lumbar spine assisted by lateral fluoroscopic imaging: a study to evaluate the accuracy of screw placement. AB - BACKGROUND: The purpose of this study was to evaluate the accuracy of pedicle screw placement, its advantages, and limitations in posterior instrumentation of thoracolumbar and lumbar burst fractures assisted only by lateral fluoroscopic imaging. MATERIALS AND METHODS: Pre- and postoperative computerized tomographic (CT) scans of 117 patients with thoracolumbar and lumbar burst fractures, who underwent posterior instrumentation with pedicle screw fixation, were prospectively analyzed. Accuracy of screw placement, reconstruction of the vertebral height, and correction of the kyphotic angle were studied. Position of the pedicle screws were determined, and cortical breach was graded on the postoperative axial CT scans. Percentage of vertebral height reconstruction and kyphotic angle correction were calculated from the postoperative midsagittal CT scans. RESULTS: Four hundred and sixty-eight pedicle screws in 234 motion segments were included in this study. 427 screws were centrally placed with an accuracy rate of 91.24%. Out of the 41 (8.76%) screws that breached the pedicle wall, 32 (6.84%) screws had violated the medial wall, while 9 (1.92%) screws breached the lateral wall. There were no "air-ball" screws. No screw penetrated the anterior wall. Postoperatively, none of the patients deteriorated neurologically, and no screw required revision. Postoperatively, there was significant restoration of vertebral height and correction of kyphosis (P < 0.05). CONCLUSION: Pedicle fixation performed on a Relton-Hall frame is relatively simple and, when performed carefully using only lateral fluoroscopic imaging, has a lower potential for complications due to cortical breach. PMID- 28801864 TI - Isolation and characterization of iron chelators from turmeric (Curcuma longa): selective metal binding by curcuminoids. AB - Iron overload disorders may be treated by chelation therapy. This study describes a novel method for isolating iron chelators from complex mixtures including plant extracts. We demonstrate the one-step isolation of curcuminoids from turmeric, the medicinal food spice derived from Curcuma longa. The method uses iron nitrilotriacetic acid (NTA)-agarose, to which curcumin binds rapidly, specifically, and reversibly. Curcumin, demethoxycurcumin, and bisdemethoxycurcumin each bound iron-NTA-agarose with comparable affinities and a stoichiometry near 1. Analyses of binding efficiencies and purity demonstrated that curcuminoids comprise the primary iron binding compounds recovered from a crude turmeric extract. Competition of curcuminoid binding to the iron resin was used to characterize the metal binding site on curcumin and to detect iron binding by added chelators. Curcumin-Iron-NTA-agarose binding was inhibited by other metals with relative potency: (>90% inhibition) Cu2+ ~ Al3+ > Zn2+ >= Ca2+ ~ Mg2+ ~ Mn2+ (<20% inhibition). Binding was also inhibited by pharmaceutical iron chelators (desferoxamine or EDTA) or by higher concentrations of weak iron chelators (citrate or silibinin). Investigation of the physiological effects of iron binding by curcumin revealed that curcumin uptake by cultured cells was reduced >80% by addition of iron to the media; uptake was completely restored by desferoxamine. Ranking of metals by relative potencies for blocking curcumin uptake agreed with their relative potencies in blocking curcumin binding to iron NTA-agarose. We conclude that curcumin can selectively bind toxic metals including iron in a physiological setting, and propose inhibition of curcumin binding to iron-NTA-agarose for iron chelator screening. PMID- 28801865 TI - Faecal lactoferrin and calprotectin in patients with Clostridium difficile infection: a case-control study. AB - Calprotectin and lactoferrin are released by the gastrointestinal tract in response to infection and mucosal inflammation. Our objective was to assess the usefulness of quantifying faecal lactoferrin and calprotectin concentrations in Clostridium difficile infection (CDI) patients with or without free toxins in the stools. We conducted a single-centre 22-month case-control study. Patients with a positive CDI diagnosis were compared to two control groups: group 1 = diarrhoeic patients negative for C. difficile and matched (1:1) to CDI cases on the ward location and age, and group 2 = diarrhoeic patients colonised with a non toxigenic strain of C. difficile. Faecal lactoferrin and calprotectin concentrations in faeces were determined for patients with CDI and controls. Of 135 patients with CDI, 87 (64.4%) had a positive stool cytotoxicity assay (free toxin) and 48 (35.6%) had a positive toxigenic culture without detectable toxins in the stools. The median lactoferrin values were 26.8 MUg/g, 8.0 MUg/g and 15.8 MUg/g in CDI patients and groups 1 and 2, respectively. The median calprotectin values were 218.0 MUg/g, 111.5 MUg/g and 111.3 MUg/g, respectively. Among patients with CDI, faecal lactoferrin and calprotectin levels were higher in those with free toxins in their stools (39.2 vs. 10.2 MUg/g, p = 0.003 and 274.0 vs. 166.0 MUg/g, p = 0.051, respectively). Both faecal calprotectin and lactoferrin were higher in patients with CDI, especially in those with detectable toxin in faeces, suggesting a correlation between intestinal inflammation and toxins in stools. PMID- 28801866 TI - Neurosecretion: what can we learn from chromaffin cells. AB - Many of the molecular players in the stimulus-secretion chain are similarly active in neurosecretion and catecholamine release. Therefore, studying chromaffin cells uncovered many details of the processes of docking, priming, and exocytosis of vesicles. However, morphological specializations at synapses, called active zones (AZs), confer extra speed of response and another layer of control to the fast release of vesicles by action potentials. Work at the Calyx of Held, a glutamatergic nerve terminal, has shown that in addition to such rapidly released vesicles, there is a pool of "Slow Vesicles," which are held to be perfectly release-competent, but lack a final step of tight interaction with the AZ. It is argued here that such "Slow Vesicles" have many properties in common with chromaffin granules. The added complexity in the AZ-dependent regulation of "Fast Vesicles" can lead to misinterpretation of data on neurosecretion. Therefore, the study of Slow Vesicles and of chromaffin granules may provide a clearer picture of the early steps in the highly regulated process of neurosecretion. PMID- 28801867 TI - Regulation of the aggregation behavior of human islet amyloid polypeptide fragment by titanocene complexes. AB - The aggregation of human islet amyloid polypeptide (hIAPP) is associated with type II diabetes. The misfolding of hIAPP induces amyloid deposition and causes beta-cell dysfunction. Metal complexes are potential metallodrugs that may reverse the aggregation of amyloid peptides. hIAPP19-37 is a crucial fragment of the full-length hIAPP1-37 and contains typical aromatic residues and a core hydrophobic region. In this work, we studied the effects of titanocene complexes titanocene dichloride (1), titanocene salicylic acid complex (2), and titanocene methionine complex (3) on the aggregation behavior of hIAPP19-37. We also explored the possible interactions of these complexes with hIAPP19-37. Results demonstrated that the titanocene complexes could effectively inhibit the aggregation of hIAPP19-37. The complexes bound with hIAPP19-37 in a spontaneous and exothermic process through hydrophobic interaction. Moreover, complex 3 could significantly decrease the cytotoxicity of hIAPP19-37 and improve cell survival. These data provide a basis for the use of titanocene complexes as potential agents against amyloidosis. PMID- 28801868 TI - Resilience in Women who Experience Domestic Violence. AB - Violence in the family constitutes a serious social and psychological problem with harmful consequences leading, among others, to changes in the psychological functioning of the victim and, secondarily, also the perpetrator. The aim of this study was to examine resilience in women experiencing domestic violence. The "Ego Resiliency Scale" (ERS) was used to study the group of women suffering domestic violence. The study group included 52 women aged 30-65 years (mean age: 40.15) using assistance of the Crisis Intervention Centre due to experienced domestic violence. They most often reported suffering psychological and physical violence, with the husband or intimate partner being the most common perpetrator. Study women experiencing domestic violence obtained significantly lower scores on the ERS. The lowest scores on the ERS were achieved by women suffering paternal violence, while the highest - by women experiencing violence on the part of the intimate partner. Resilience of study women suffering domestic violence was lower than resilience of the general population, i.e. individuals not experiencing domestic violence. Suffered violence inflicted by the father exerted the greatest adverse impact on resilience. It seems advisable to consider resilience in the process of providing women experiencing domestic violence with psychosocial help. PMID- 28801870 TI - Letter regarding "Effect of laser on pain relief and wound healing of recurrent aphthous stomatitis: a systematic review". PMID- 28801871 TI - Pediatric Delirium: Evaluation, Management, and Special Considerations. AB - Delirium describes a syndrome of acute brain dysfunction with severe consequences on patient outcomes, medical cost, morbidity, and mortality. It represents a final common pathway of numerous pathophysiologic disturbances disrupting cerebral homeostasis. The diagnosis is predicated on recognition of the clinical features of the syndrome through ongoing clinical assessment. Early identification can be aided by routine screening, particularly in high-risk populations. Evaluation and management are continuous and simultaneous processes involving a multidisciplinary care team including child psychiatry consultation. Prevention, early identification and management are critical in alleviating symptoms, improving outcomes, and reducing distress for patients, families, and care teams. This review highlights our current understanding regarding pediatric delirium, its mechanisms, clinical manifestations, detection and management. PMID- 28801872 TI - New hybrid nanocomposite of copper terephthalate MOF-graphene oxide: synthesis, characterization and application as adsorbents for toxic metal ion removal from Sungun acid mine drainage. AB - The application of a hybrid Cu(tpa).GO (Cu(tpa) copper terephthalate metal organic framework, GO graphene oxide) composite as a new adsorbent for the removal of toxic metal ions was reported. New hybrid nanocomposite with excellent dispersibility and stability was successfully fabricated by the simple and effective ultrasonication method. The synthesized composite was characterized by scanning electron microscopy (SEM), UV-Vis and Fourier-transform infrared (FT-IR) techniques. The characterization results concluded that the binding mechanism of the Cu(tpa) and GO was related to both pi-pi packing and hydrogen bonding. For scrutinizing the sorption activity, the prepared adsorbents were assessed for the removal of Mn2+, Cu2+, Zn2+, Cd2+, Pb2+ and Fe3+ metal ions from aqueous synthetic solution and also acid mine drainage (AMD) wastewater. The sorption experiments demonstrated that the removal efficiency was significantly improved by modified hybrid Cu(tpa).GO composite, owing to the significant number of active binding sites and unique structure formed based on pi-conjugated networks. Also, it was shown that the adsorption reaction was mainly attributed to the chemical interactions between metal ions and the surface functional groups. Moreover, kinetic and adsorption studies clarified that the adsorption process onto the Cu(tpa).GO follows a pseudo-second-order kinetics and fits the Langmuir and Freundlich adsorption models. Holistically, the results of this research represent that applying Cu(tpa).GO can be remarked as an effective adsorbent with high possibility at conventional water treatment. PMID- 28801869 TI - The role of vitamin D in hepatic metastases from colorectal cancer. AB - Colorectal cancer (CRC) represents a significant health burden worldwide, comprising approximately 10% of annual cancer cases globally. Hepatic metastases are the most common site of CRC metastasis, and are the leading cause of death in CRC patients. There is strong epidemiologic evidence for an inverse association between vitamin D status and risk of CRC; however, the role of vitamin D in the natural history of liver metastases has not yet been investigated. Several researchers have proposed hallmarks of metastases; crucially, metastases can be blocked by interrupting just one rate-limiting step. Vitamin D status has been implicated in each proposed hallmark of metastasis. The aim of this review is to examine the potential role for vitamin D in reducing the development of hepatic metastases from CRC and outline the candidate mechanisms by which vitamin D may mediate these effects. The results of ongoing randomised intervention trials are eagerly awaited to determine whether addressing vitamin D insufficiency in CRC patients could reduce the occurrence of liver metastases, and the consequent morbidity and mortality. PMID- 28801874 TI - EAPD Interim Seminar in Turin, Italy. PMID- 28801873 TI - Transgenic silkworms secrete the recombinant glycosylated MRJP1 protein of Chinese honeybee, Apis cerana cerana. AB - Major royal jelly protein-1 (MRJP1) is the most abundant glycoprotein of royal jelly (RJ) and is considered a potential component of functional foods. In this study, we used silkworm transgenic technology to obtain five transgenic silkworm lineages expressing the exogenous recombinant Chinese honeybee, Apis cerana cerana, protein-1 (rAccMRJP1) under the control of a fibroin light chain (Fib-L) promoter in the posterior silk glands. The protein was successfully secreted into cocoons; specifically, the highest rAccMRJP1 protein content was 0.78% of the dried cocoons. Our results confirmed that the protein band of the exogenous rAccMRJP1 protein expressed in the transgenic silkworm lineages was a glycosylated protein. Therefore, this rAccMRJP1 protein could be used as an alternative standard protein sample to measure the freshness of RJ. Moreover, we also found that the overall trend between the expression of the endogenous and exogenous genes was that the expression level of the endogenous Fib-L gene declined as the expression of the exogenous rAccMRJP1 gene increased in the transgenic silkworm lineages. Thus, by employing genome editing technology to reduce silk protein expression levels, a silkworm bioreactor expression system could be developed as a highly successful system for producing various valuable heterologous proteins, potentially broadening the applications of the silkworm. PMID- 28801875 TI - Nanoparticles in explosives detection - the state-of-the-art and future directions. PMID- 28801876 TI - Tumor DNA: an emerging biomarker in head and neck cancer. AB - Head and neck cancer (HNC) includes a diverse range of malignancies arising commonly from mucosal epithelia of the upper aerodigestive tract. Head and neck squamous cell carcinoma (HNSCC), the most common form of HNC, develops in the oral cavity, pharynx, and larynx and is associated with tobacco exposure, alcohol abuse, and infection with oncogenic viruses. Despite global advances in cancer care, HNSCC often presents with advanced disease and is associated with poor 5 year survival of ~50%. Genotyping tumor tissue to guide clinical decision-making is becoming commonplace in modern oncology, but in the management of HNSCC, tissue biopsies with cytopathology or histopathology remain the mainstay for diagnosis. Furthermore, conventional biopsies are temporally and spatially limited, often providing a brief snapshot of a single region of a heterogeneous tumor. In the absence of a useful biomarker, both primary and recurrent HNSCCs are diagnosed with conventional imaging and clinical examination. As a result, many patients are diagnosed with advanced disease. Tumor DNA is an emerging biomarker in HNSCC. DNA fragments are constantly being shed from tumors and metastatic lesions, and can therefore be detected in blood and other bodily fluids. Utilizing next-generation sequencing techniques, these tumor DNA can be characterized and quantified. This can serve as a minimally invasive liquid biopsy allowing for specific tumor profiling, dynamic tumor burden monitoring, and active surveillance for disease recurrences. In HNSCC, analysis of tumor DNA has the potential to enhance tumor profiling, aid in determining patient prognosis, and guide treatment decisions. PMID- 28801877 TI - Are Barbed Sutures Associated With 90-day Reoperation Rates After Primary TKA? AB - BACKGROUND: Studies have suggested that barbed sutures for wound closure in TKAs are an acceptable alternative to standard methods. However others have observed a higher risk of wound-related complications with barbed sutures. QUESTIONS/PURPOSES: (1) Do 90-day TKA reoperation rates differ between patients undergoing a barbed suture arthrotomy closure compared with a traditional interrupted closure? (2) Do the 90-day reoperation rates of wound-related, deep infection, and arthrotomy failure complications differ between barbed suture and traditional closures? METHODS: A retrospective analysis of a longitudinally maintained institutional primary TKA database was conducted on all TKAs performed between April 2011 and September 2015. We compared 884 primary TKAs, where the arthrotomy was closed with a barbed suture, with 1598 primary TKAs closed with the standard interrupted suture. After barbed sutures were introduced at our institution in 2012, the majority of surgeons gradually switched to barbed suture closures, with many using them exclusively by the end of the data collection period. We confirmed in-person followups and available data past 90 days for 97.4% (1556 of 1598) of the knees in patients with standard sutures and 94.8% (838 of 884) of the knees in patients with barbed sutures. Our primary endpoint was all-cause 90-day reoperation; our secondary endpoints considered: wound related reoperation, as defined by previous studies; deep infection per Musculoskeletal Infection Society guidelines; and arthrotomy failure, defined intraoperatively as an opening or dehiscence through the previous arthrotomy closure. T tests and chi-square analyses were used to determine differences between the suture cohorts, and bivariate logistic regression was used to determine associations with our 90-day reoperation outcomes. RESULTS: With the numbers available, there was no association between suture type and 90-day all cause reoperation (odds ratio [OR], 1.70; 95% CI, 0.82-3.53; p = 0.156). Suture type was not associated with wound-related reoperation (OR, 2.73; 95% CI, 0.97 7.69; p = 0.058). A 0.6% (five of 884) arthrotomy failure rate was observed in the barbed cohort while no (0 of 1598) arthrotomy failures were noted in the traditional group (p = 0.003). Deep infections were rare in both groups (two of 884 barbed sutures, 0 of 1598 standard sutures) and could not be compared. CONCLUSIONS: Although we saw no difference in overall and wound-related 90-day reoperation rates by suture type with the numbers available, we observed a higher frequency in our secondary question of arthrotomy failures when barbed sutures are used for arthrotomy closure during TKA. Given the widespread use of this closure technique, our preliminary pilot results warrant further investigation in larger multicenter cohorts. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 28801878 TI - Pulse Waveform Analysis: Is It Ready for Prime Time? AB - PURPOSE OF REVIEW: Arterial pulse waveform analysis has a long tradition but has not pervaded medical routine yet. This review aims to answer the question whether the methodology is ready for prime time use. The current methodological consensus is assessed, existing technologies for waveform measurement and pulse wave analysis are discussed, and further needs for a widespread use are proposed. RECENT FINDINGS: A consensus document on the understanding and analysis of the pulse waveform was published recently. Although still some discrepancies remain, the analysis using both pressure and flow waves is favoured. However, devices which enable pulse wave measurement are limited, and the comparability between devices is not sufficiently given. Pulse waveform analysis has the potential for prime time. It is currently on a way towards broader use, but still needs to overcome challenges before settling its role in medical routine. PMID- 28801880 TI - Effects of Educational Intervention on Nurses' Knowledge and Attitude Towards Providing Cervical Cancer Screening Information in Selected Health Facilities in Ibadan, Nigeria. AB - Cervical cancer is a major cause of death among women especially in developing nations. It can be prevented through screening yet many women are unaware of screening options. Nurses are in vantage position to provide cervical cancer screening (CCS) information and services especially in antenatal clinics. The purpose of this study is to evaluate the effects of an educational intervention (EI) on nurses' knowledge and attitude towards providing CCS information. This quasi-experimental study was conducted in eight health facilities in Ibadan, Nigeria. The facilities were randomly divided into intervention group (IG) and control group (CG). A total of 133 consenting nurses (60 in the IG and 73 in the CG) participated. Baseline data were collected using self-administered questionnaire. The nurses in the IG received the EI and both groups were administered with a post-test questionnaire after 6 months. Data were analysed using chi square and Student's t test at p = 0.05. Nurses' mean age was 41.7 years. Knowledge scores for the IG (11.8 +/- 3.3) and CG (11.7 +/- 3.3) were comparable at baseline (p = 0.901) but was significantly higher among nurses in the IG (14.63 +/- 3.12) than CG (12.7 +/- 3.5) at 6 months PI (p = 0.01). More nurses in the IG had high level of knowledge than CG. There was no significant difference in their attitude at baseline and at PI. There was a significant association between knowledge and attitude towards providing cervical cancer screening information (p < 0.000). Education improved knowledge of nurses on cervical cancer screening. Regular education programmes for nurses may result in improved counselling on major health issues like cancer. PMID- 28801879 TI - Charging and Release Mechanisms of Flexible Macromolecules in Droplets. AB - We study systematically the charging and release mechanisms of a flexible macromolecule, modeled by poly(ethylene glycol) (PEG), in a droplet by using molecular dynamics simulations. We compare how PEG is solvated and charged by sodium Na+ ions in a droplet of water (H2O), acetonitrile (MeCN), and their mixtures. Initially, we examine the location and the conformation of the macromolecule in a droplet bearing no net charge. It is revealed that the presence of charge carriers do not affect the location of PEG in aqueous and MeCN droplets compared with that in the neutral droplets, but the location of the macromolecule and the droplet size do affect the PEG conformation. PEG is charged on the surface of a sodiated aqueous droplet that is found close to the Rayleigh limit. Its charging is coupled to the extrusion mechanism, where PEG segments leave the droplet once they coordinate a Na+ ion or in a correlated motion with Na+ ions. In contrast, as PEG resides in the interior of a MeCN droplet, it is sodiated inside the droplet. The compact macro-ion transitions through partially unwound states to an extended conformation, a process occurring during the final stage of desolvation and in the presence of only a handful of MeCN molecules. For charged H2O/MeCN droplets, the sodiation of PEG is determined by the H2O component, reflecting its slower evaporation and preference over MeCN for solvating Na+ ions. We use the simulation data to construct an analytical model that suggests that the droplet surface electric field may play a role in the macro-ion-droplet interactions that lead to the extrusion of the macro-ion. This study provides the first evidence of the effect of the surface electric field by using atomistic simulations. Graphical Abstract ?. PMID- 28801881 TI - Transgenic Analysis Reveals 5' Abbreviated OsRGLP2 Promoter(s) as Responsive to Abiotic Stresses. AB - Germins and germin-like proteins are ubiquitous, expressed at various developmental stages and in response to various abiotic and biotic stresses. In this study, to functionally validate the OsRGLP2 promoter, 5' deletion analysis of the promoter sequences was performed and the deletion fragments fused with the beta-glucuronidase (GUS) and green fluorescent protein reporter genes were used for transient expression in tobacco as well as for generating stable transgenic Arabidopsis plants. Very high level of GUS activity was observed in agroinfiltrated tobacco leaves by the construct carrying the P-1063 and P-565 when subjected to abiotic stresses. Histochemical analysis of transgenic Arabidopsis plants revealed expression of reporter gene in root, leaf and stem sections of plants harboring P-1063 and P-565. Real-time qPCR analysis of transiently expressed tobacco leaves and transgenic Arabidopsis plants subjected to several abiotic stresses supported histochemical data and showed that P-565 responded to all the stresses to which the full-length promoter was responsive. The data suggest that P-565 may be a good alternative to full-length promoter region that harbors the necessary cis-elements in providing stable and high level of expression in response to wound, salt and temperature stresses. PMID- 28801882 TI - Patients with Non-invasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features are Unlikely to have Malignant Preoperative Cytology. AB - BACKGROUND: The newly termed tumor 'noninvasive follicular thyroid neoplasm with papillary-like nuclear features' (NIFTP) acts in an indolent manner and can likely be safely managed with a thyroid lobectomy. Preoperative fine-needle aspiration (FNA) is the cornerstone of surgical planning, but the ability of FNA to distinguish NIFTP from other variants of papillary thyroid carcinoma (PTC) has not been well-evaluated. METHODS: A 9-year retrospective review of the preoperative cytology and surgical pathology of PTC patients who underwent a thyroidectomy at our tertiary referral center. RESULTS: Overall, 174 patients with 177 PTCs had a preoperative FNA followed by a thyroidectomy, and met our inclusion criteria. Of the 21 patients with NIFTP, the preoperative cytology was read as malignant in three (14%), suspicious for malignancy in three (14%), follicular neoplasm in ten (48%), atypia of undetermined significance in four (19%), and benign in one (5%) nodule. When comparing patients with NIFTP with other variants of PTC, patients with NIFTP were younger (p = 0.023) and less likely to have malignant cytology (p < 0.001). On multivariable regression modeling, malignant cytology was independently associated with a decreased risk of a final diagnosis of NIFTP (odds ratio 0.064, 95% confidence interval 0.018 0.233, p < 0.001). CONCLUSIONS: Patients with a final diagnosis of NIFTP are less likely to have preoperative FNA diagnosis of malignancy than those with final pathology of classical or other variants of PTC. Surgeons should take this into consideration when considering between a lobectomy and total thyroidectomy for patients with suspected PTC. PMID- 28801883 TI - Prognostic Utility of Fatty Acid-Binding Protein 4 in Patients with Type 2 Diabetes and Acute Ischemic Stroke. AB - The role of fatty acid-binding proteins (FABPs) in atherosclerosis has been investigated. The aim of this study was to verify the hypothesis that higher levels of serum fatty acid-binding protein 4 (FABP4) could be a prognostic factor in Chinese patients with type 2 diabetes (T2DM) and acute ischemic stroke (AIS). From September 2015 to August 2016, consecutive first-ever AIS patients combined with T2DM were included in this study. FABP4, NIH stroke scale (NIHSS), and conventional risk factors were evaluated to determine their value to predict functional outcomes within 3 months. Multivariate analyses were performed using logistic regression models. We measured FABP4 in 329 patients. The median age of patients included in this study was 63 (IQR, 56-72) years and 45.9% were women. FABP4 serum levels were obtained at a median of 8.5 h (IQR, 4.0-14.0 h) after the stroke onset with a median value of 21.4 ng/ml (IQR, 15.6-28.2 ng/ml). In multivariable models, FABP4 remained an independent stroke severity predictor with an adjusted OR of 1.05 (95% CI, 1.02-1.09). In multivariate models comparing the third (odd ratio (OR), 2.25; 95% confidence interval (CI), 1.59-3.54) and fourth quartiles (OR, 3.75; 95% CI, 2.48-5.03) against the first quartile of the FABP4, levels of FABP4 were associated with poor functional outcome. At 3 months, 38 patients (11.6%; 95%CI, 8.1-15.0%) had died. The mortality distribution across the FABP4 quartiles ranged between 3.7% (first quartile) and 20.7% (fourth quartile). Elevation of FABP4 is associated with an increased risk of death and poor functional outcome events in patients with type 2 diabetes and acute ischemic stroke and is independent of other established clinical risk predictors and biomarkers. PMID- 28801884 TI - Identification and Partial Structural Characterization of Mass Isolated Valsartan and Its Metabolite with Messenger Tagging Vibrational Spectroscopy. AB - Recent advances in the coupling of vibrational spectroscopy with mass spectrometry create new opportunities for the structural characterization of metabolites with great sensitivity. Previous studies have demonstrated this scheme on 300 K ions using very high power free electron lasers in the fingerprint region of the infrared. Here we extend the scope of this approach to a single investigator scale as well as extend the spectral range to include the OH stretching fundamentals. This is accomplished by detecting the IR absorptions in a linear action regime by photodissociation of weakly bound N2 molecules, which are attached to the target ions in a cryogenically cooled, rf ion trap. We consider the specific case of the widely used drug Valsartan and two isomeric forms of its metabolite. Advantages and challenges of the cold ion approach are discussed, including disentangling the role of conformers and the strategic choices involved in the selection of the charging mechanism that optimize spectral differentiation among candidate structural isomers. In this case, the Na+ complexes are observed to yield sharp resonances in the high frequency NH and OH stretching regions, which can be used to easily differentiate between two isomers of the metabolite. Graphical Abstract ?. PMID- 28801885 TI - Active Surveillance for Intermediate Risk Prostate Cancer. AB - PURPOSE OF REVIEW: Active surveillance is now widely utilized for the management of low-risk prostate cancer (PCa). The limits of surveillance for men with intermediate risk cancer are controversial. While there is a broad consensus that men with low-risk disease can be safely managed with AS, many potential candidates, including those with Gleason 3 + 4 disease, PSA >10, younger men and African-Americans are often excluded. RECENT FINDINGS: Outcome data for intermediate-risk patients managed by active surveillance demonstrate reasonable outcomes, but these men clearly are at higher risk for progression to metastatic disease. The use of biomarkers and multiparametric MRI will enable a more precise and personalized risk assessment. Literature describing the effects of young age on outcomes is limited, but the experience reported in prospective series with 15 20 year follow-up suggests it is a safe approach. African-American men are at greater risk for occult co-existent higher-grade disease, but in the absence of this their outcome is favorable. Patients with intermediate-risk PCa should not be excluded from active surveillance based on a single criterion. Treatment decisions should be based on multiple parameters, including percent Gleason 4, PSA density, cancer volume on biopsy, MRI findings, and patient age and co morbidity. Genetic tissue-based biomarkers are also likely to play a role in enhancing decision making. PMID- 28801886 TI - Effects of 3-Nitro-1,2,4-triazol-5-one on Survival, Growth and Metamorphosis in the Northern Leopard Frog, Lithobates pipiens. AB - New explosive formulations are being developed to be less sensitive to impact and inadvertent explosion, increasing safety for the warfighter. Since testing and training make environmental releases imminent, the toxicity of 3-nitro-1,2,4 triazol-5-one (NTO), a component of Insensitive Munitions eXplosive (IMX) formulations, was assessed in a one-generation study to the northern leopard frog (Lithobates ( = Rana) pipiens). Because NTO in water creates acidic conditions, acute studies were conducted with non-pH-adjusted NTO, while a long-term (70-d) study was conducted with neutralized NTO. In the acute study, 48-h and 7-d LC50s were ~250 mg NTO/L. In the long-term study, tadpoles were dead by day 2 in 11,350 mg/L NTO, and by day 63 in 8382 mg/L. The 70-d LC50 was 3670 mg (neutralized) NTO/L. The number of organisms reaching complete metamorphosis was reduced by NTO; the lowest IC25 was 1999 mg NTO/L for the Number Completing Metamorphosis. The NOECs for Time to Front Limb Eruption or Time to Metamorphosis were the same at 1346 mg/L. Histopathology did not significantly distinguish between NTO exposed and unexposed animals, although possible effects on the density of spermatogonia in NTO-exposed males was suggested. The test data indicate that acute toxicity to ambient NTO can be attributed primarily to its acidic nature; relatively low chronic toxicity of neutralized NTO is due to delays in metamorphosis. The consequence from this latter observation may be ecologically significant as delays of even a few days could increase mortality through predation and/or loss of the aquatic medium in temporary water bodies. PMID- 28801887 TI - Degradation of 5,5-diphenylhydantoin by chlorination and UV/chlorination: kinetics, transformation by-products, and toxicity assessment. AB - This study investigated the reaction kinetics and mechanism of the degradation of 5,5-diphenylhydantoin (DPH) during conventional chlorination and UV/chlorination. DPH is one of the antiepileptic drugs, which has frequently been detected in the aquatic environment. For chlorination, the second-order rate constant for the reaction between DPH and free active chlorine (FAC) was determined at pH 5 to 8. At pH 6 to 8, the efficiency of chlorination in the removal of DPH was found to be dominated by the reaction involving hypochlorous acid (HOCl). The result also showed that anionic species of DPH was more reactive toward FAC as compared with neutral DPH. For UV/chlorination, the effect of FAC dosage and pH on the degradation of DPH was evaluated. UV/chlorination is a more effective method for removing DPH as compared with conventional chlorination and UV irradiation. The DPH degradation rate was found to increase with increasing FAC concentration. On the other hand, the degradation of DPH was found to be more favorable under the acidic condition. Based on the identified transformation by-products, DPH was found to be degraded through the reaction at imidazolidine-2,4-dione moiety of DPH for both chlorination and UV/chlorination. Toxicity study on the chlorination and UV/chlorination-treated DPH solutions suggested that UV/chlorination is a more efficient method for reducing the toxicity of DPH. PMID- 28801888 TI - Utilization and Effectiveness of a Peer Advocate Program for Medical Students. PMID- 28801890 TI - Application of Grading of Recommendations Assessment, Development, and Evaluation (GRADE) to the guideline development for clinical practice with acupuncture and moxibustion. AB - Grading of Recommendations Assessment, Development, and Evaluation (GRADE) offers a worldwide approach to guideline development for clinical practice. For the clinical practice of acupuncture therapy, 18 evidence-based guidelines have been developed in China using GRADE. In this study, we review the advantages and limitations of the GRADE approach in the guideline development for acupuncture and moxibustion and propose some solutions to these limitations. Scientific advantages of rating the quality of evidence, outcome-centric direction, overall progression to develop recommendations, and strength of recommendations providing specific clinical guidance are the advantages of GRADE. The limitations of GRADE in the development of guidelines for acupuncture and moxibustion include rating the quality of evidence for ancient literature and literature on famous traditional Chinese medicine experts' experiences and specific guidelines for formulating recommendations from evidence. In the guideline development for clinical practice with acupuncture and moxibustion, we suggest that a specific method should be explored based on the GRADE approach and the characteristics of acupuncture therapy. PMID- 28801889 TI - Strategies of minimally invasive treatment for intrahepatic and extrahepatic bile duct stones. AB - Cholelithiasis is a kind of common and multiple diseases. In recent years, traditional laparotomy has been challenged by a minimally invasive surgery. Through literature review, the therapeutic method, effect, and complications of minimally invasive treatment of intrahepatic and extrahepatic bile duct stones by combining our practical experience were summarized as follows. (1) For intrahepatic bile duct stones, the operation may be selected by laparoscopic liver resection, laparoscopic common bile duct exploration (LCBDE), or percutaneous transhepatic cholangioscopy. (2) For concomitant gallstones and common bile duct stones, the surgical approach can be selected as follows: laparoscopic cholecystectomy (LC) combined with endoscopic sphincterotomy (EST) or endoscopic papillary balloon dilatation, LC plus laparoscopic transcystic common bile duct exploration, LC plus LCBDE, and T-tube drainage or primary suture. (3) For concomitant intrahepatic and extrahepatic bile duct stones, laparoscopic liver resection, choledochoscopy through the hepatic duct orifice on the hepatectomy cross section, LCBDE, EST, and percutaneous transhepatic cholangioscopic lithotripsy could be used. According to the abovementioned principle, the minimally invasive treatment approach combined with the surgical technique and equipment condition will be significant in improving the therapeutic effect and avoiding the postoperative complications or hidden dangers of intrahepatic and extrahepatic bile duct stones. PMID- 28801892 TI - Adaptive neuro-fuzzy inference system-applied QSAR with bond dissociation energy for antioxidant activities of phenolic compounds. AB - The aim of this study was to develop quantitative structure-activity relationship (QSAR) models for predicting antioxidant activities of phenolic compounds. The bond dissociation energy of O-H bond (BDE) was calculated by semi-empirical quantum chemical methods. As a new parameter for QSAR models, sum of reciprocals of BDE of enol and phenol groups (X BDE ) was calculated. Significant correlations were observed between X BDE and antioxidant activities, and X BDE was introduced as a parameter for developing QSAR models. Linear regression applied QSAR models and adaptive neuro-fuzzy inference system (ANFIS)-applied QSAR models were developed. QSAR models by both of linear regression and ANFIS achieved high prediction accuracies. Among the developed models, ANFIS-applied models achieved better prediction accuracies than linear regression-applied models. From these results, the proposed parameter of X BDE was confirmed as an appropriate variable for predicting and analysing antioxidant activities of phenolic compounds. Also, the ANFIS could be applied on QSAR models to improve prediction accuracy. PMID- 28801891 TI - Monitoring of Busulphan Concentrations in Children Undergone Hematopoietic Stem Cell Transplantation: Unicentric Experience over 10 years. AB - BACKGROUND AND OBJECTIVES: The aim of this report is to describe the experience in the management of busulphan-based conditioning regimen administered before hematopoietic stem cell transplantation (HSCT) in children. METHODS: We report the values of the first dose AUC (area under the concentration-time curve, normal target between 3600 and 4800 ng.h/mL) in children treated with oral and intravenous busulphan, and we analyze the impact of some clinical variables in this cohort of patients. RESULTS: 82 children treated with busulphan before HSCT were eligible for the study: 57 received oral busulphan with a mean AUC of 3586 ng.h/mL, while 25 received intravenous busulphan with a mean AUC of 4158 ng.h/mL. Dose adjustment was based on first dose AUC. The dose was increased in 36 children (43.9%) and decreased in 26 patients (31.7%). Age at HSCT (P = 0.015), cumulative dose of busulphan as mg/m2 (P < 0.001), busulphan dose prescribed as mg/Kg (P = 0.001), intravenous busulphan administration (P < 0.001), type of stem source cells (P = 0.016), and type of HSCT (P = 0.03) were associated with AUC levels. No statistically significant differences were found between transplant related toxicity, acute and chronic graft versus host disease, engraftment, and AUC levels. CONCLUSIONS: We concluded that older age at HSCT, intravenous administration of busulphan, cumulative, and prescribed dose of busulphan are associated with higher AUC levels. The absence of significant correlations between toxic events, graft failure, and AUC suggests the efficacy of busulphan concentrations monitoring in our patients. PMID- 28801894 TI - Increased apical rotation in patients with severe aortic stenosis assessed by three-dimensional speckle tracking imaging. AB - BACKGROUND: Two-dimensional (2D) speckle tracking imaging (STI) is a non-invasive method used to assess subtle changes in left ventricular (LV) function such as strain and rotational dynamics. However, 2D methodology is complicated by issues such as the out-of-plane problem inherent in short-axis imaging. In addition, circumferential rotation contributes to three-dimensional (3D) wall deformations and affects tracking accuracy. By using 3D-STI technique, we evaluated LV global longitudinal strain (GLS) and apical rotation in severe aortic stenosis (AS) patients with preserved LV ejection fraction (EF). METHODS: LV GLS and apical rotation were evaluated using 3D-STI in 20 severe AS patients (79 +/- 8 years old; aortic valve area 0.7 +/- 0.2 cm2) with preserved LVEF (68 +/- 7%). Data were compared with those of 11 hypertensive LV hypertrophy (LVH) patients (75 +/- 10 years old, EF = 66 +/- 4%) and 12 controls (healthy individuals: 30 +/- 14 years old, EF = 63 +/- 6%). RESULTS: Compared with LVH patients, severe AS patients had significantly decreased values of GLS (-13.0 +/- 2.4 vs. -10.4 +/- 2.0%, p = 0.008). In contrast, LV rotation was significantly higher in AS than LVH patients (13.9 +/- 3.0 degrees vs. 10.8 +/- 2.5 degrees , p = 0.007). There was no significant difference in stroke volume index among three groups. In these three groups, severe AS patients had significantly decreased values of GLS [analysis of variance (ANOVA), p < 0.001] and increased LV rotation (ANOVA, p < 0.001). CONCLUSIONS: In severe AS patients, impaired GLS existed although LVEF was preserved. However, LV rotation was increased in patients with severe AS probably to maintain the LV stroke volume. PMID- 28801893 TI - Variation in soil aggregate-size distribution affects the dissipation of polycyclic aromatic hydrocarbons in long-term field-contaminated soils. AB - Soil organic matter (SOM) is the main adsorbent for polycyclic aromatic hydrocarbons (PAHs) and the principal aggregating agent for soil aggregation that can affect PAH bioavailability and bioaccessibility in soils. The objective of this study was to analyze the relationship between PAH dissipation and variation in soil aggregate-size distribution in two field-contaminated soils with different soil organic C (SOC) content (Anthrosols, 1.41% SOC; Phaeozems, 8.51% SOC) in phytoremediation with alfalfa. The results showed that there were significant reductions of 10.2 and 15.4% of the total PAHs in unplanted and planted treatments, respectively, for Anthrosols. However, there was no significant reduction of total PAHs in either unplanted or planted treatment for Phaeozems. For Anthrosols, mass percentages of coarse sand and fine sand were significantly reduced while coarse silt and fine silt were significantly increased for the planted soil compared to the initial soil (p < 0.05). For Phaeozems, there was no significant variation in aggregate-size distribution among different treatments except that coarse silt in planted and unplanted soil was slightly reduced. The main reason for the dissipation of PAHs in Anthrosols could be that macroaggregates were broken into microaggregates, which made some trapped PAHs become bioaccessible to soil microorganisms. PMID- 28801895 TI - Initial Considerations Before Designing a Promoter Construct. AB - Before designing a synthetic promoter, it can be helpful to think about its final application. Is the study purely an in vitro exercise in monitoring short-term promoter activity from an episomal vector, or does the promoter eventually need to be permanently active and be integrated into the genome or perhaps even to function in vivo? The final application will have a bearing on promoter design and vector of choice from the start of the study. In this chapter I highlight some of the vector attributes to consider and features that should be thought about. PMID- 28801896 TI - Demonstrating Interactions of Transcription Factors with DNA by Electrophoretic Mobility Shift Assay. AB - Confirming the binding of a transcription factor with a particular DNA sequence may be important in characterizing interactions with a synthetic promoter. Electrophoretic mobility shift assay is a powerful approach to demonstrate the specific DNA sequence that is bound by a transcription factor and also to confirm the specific transcription factor involved in the interaction. In this chapter we describe a method we have successfully used to demonstrate interactions of endogenous transcription factors with sequences derived from endogenous and synthetic promoters. PMID- 28801897 TI - Chromatin Immunoprecipitation and Quantitative Real-Time PCR to Assess Binding of a Protein of Interest to Identified Predicted Binding Sites Within a Promoter. AB - Chromatin immunoprecipitation (ChIP) has become a widely used methodology for assessment of protein/DNA interactions. The technique allows the analysis of direct binding of transcription factors to gene promoters, identification of histone modifications, and localization of DNA modifying enzymes. Antibodies conjugated to agarose beads can be utilized to immunoprecipitate specific proteins, cross-linked to sheared chromatin regions to which they are bound endogenously. With downstream applications including quantitative real-time polymerase chain reaction (qRT-PCR), genome-wide sequencing (ChIP-seq), microarray analysis (ChIP-chip), and mass spectrometry (ChIP-MS), the technique enables comprehensive assessment of protein/DNA interactions. Here I describe ChIP, followed by qRT-PCR, to assess direct binding of a single protein to multiple predicted binding sites within a gene promoter. PMID- 28801898 TI - Secreted Reporters for Monitoring Multiple Promoter Function. AB - Secreted reporter proteins are reliable modalities for monitoring of different biological processes, which can be measured longitudinally in conditioned medium of cultured cells or body fluids such as blood and urine, ex vivo. In this chapter, we will explore established secreted reporters and their applications and limitations for monitoring of promoter function. We will also describe both cell-based and blood-based assays for detecting three commonly used reporters: secreted alkaline phosphatase (SEAP ), Gaussia luciferase (Gluc), and Vargula luciferase (Vluc). PMID- 28801899 TI - Bioluminescence Monitoring of Promoter Activity In Vitro and In Vivo. AB - The application of luciferase reporter genes to provide quantitative outputs for the activation of promoters is a well-established technique in molecular biology. Luciferase catalyzes an enzymatic reaction, which in the presence of the substrate luciferin produces photons of light relative to its molar concentration. The luciferase transgene can be genetically inserted at the first intron of a target gene to act as a surrogate for the gene's endogenous expression in cells and transgenic mice. Alternatively, promoter sequences can be excised and/or amplified from genomic sources or constructed de novo and cloned upstream of luciferase in an expression cassette transfected into cells. More recently, the development of synthetic promoters where the essential components of an RNA polymerase binding site and transcriptional start site are fused with various upstream regulatory sequences are being applied to drive reporter gene expression. We have developed a high-throughput cloning strategy to develop lentiviral luciferase reporters driven by transcription factor activated synthetic promoters. Lentiviruses integrate their payload cassette into the host cell genome, thereby facilitating the study of gene expression not only in the transduced cells but also within all subsequent daughter cells. In this manuscript we describe the design, vector construction, lentiviral transduction, and luciferase quantitation of transcription factor activated reporters (TFARs) in vitro and in vivo. PMID- 28801900 TI - Monitoring Promoter Activity by Flow Cytometry. AB - Genetic reporters have become invaluable tools for indirectly monitoring promoter activities. The quantitative measurement of promoter activities using reporter gene systems is fundamental for pharmaceutical, biomedical, and molecular biology research. Genetic reporters are used not only for measuring promoter activities but also for understanding the mechanisms controlling gene transcription and in the identification, and characterization of cis-acting regulatory elements. Fluorescent reporter proteins including enhanced green fluorescent protein (EGFP ) are reliable for monitoring quantitative underlying differences in promoter activities. The emitted fluorescence intensity of the expressed reporter is measured at the single-cell level by flow cytometry and represents a readout for the promoter activities. In this chapter, the protocol for measurement and analyzing of transfected cells expressing the reporter gene EGFP is thoroughly described and fully illustrated. PMID- 28801902 TI - Bioinformatically Informed Design of Synthetic Mammalian Promoters. AB - Synthetic promoters have been developed in a number of different organisms and are capable of mediating specific and enhanced levels of gene expression. Typically, cis-regulatory regions from a few genes are randomly combined to generate a synthetic promoter library, and the sequences with the highest activity are selected for in target cell lines. Here we describe a novel approach that can be employed in the construction of synthetic promoters . Specifically, we use gene expression profiles obtained from microarray datasets to select the cis-regulatory elements that comprise the synthetic promoter library. By adopting this approach, we were able to construct several promoters that could specifically mediate gene expression in colorectal cancer cells. We develop a new selection criteria based on the observed transcriptome of target cells, the frequency that identified cis-regulatory sequences occur in identified gene modules, and the length of identified cis-regulatory regions. Our method allows for the generation of synthetic promoter libraries with increased level of specificity and facilitates the selection of promoters that are highly active only under predefined gene expression profiles. PMID- 28801901 TI - Functional Screening of Core Promoter Activity. AB - The core promoter is the DNA sequence that recruits the basal transcription machinery and directs accurate initiation of transcription. It is an active contributor to gene expression that can be rationally designed to manipulate the levels of expression. Core promoter function can be analyzed using different experimental approaches. Here, we describe the qualitative and quantitative analysis of engineered core promoter functions using the EGFP reporter gene that is driven by distinct core promoters. Expression plasmids are transfected into different mammalian cell lines, and the resulting fluorescence is monitored by live cell imaging , as well as by flow cytometry. In order to verify that the transcriptional activity of the examined core promoters is indeed a function of their activity, as opposed to differences in DNA uptake, real-time quantitative PCR analysis is performed. Importantly, the described methodology for functional screening of core promoter activity has enabled the analysis of engineered potent core promoters for extended time periods. PMID- 28801903 TI - Synthetic Tumor-Specific Promoters for Transcriptional Regulation of Viral Replication. AB - Here we describe a collection of methods that have been adapted to isolate and modify tumor-specific promoters (TSPs ) to drive viral replication for cancer therapy and other uses. We will describe as examples the secreted protein acidic and rich in cysteine (SPARC ) and the protease-activated receptor-1 (PAR-1) promoter. We outline strategies to select appropriate TSPs using bioinformatics resources and the methods utilized in their subsequent cloning, assessment of transcriptional activity, and their use in conditionally replicative oncolytic adenoviruses . PMID- 28801904 TI - Constructing Strong Cell Type-Specific Promoters Through Informed Design. AB - Promoter functionality is highly context dependent, as exemplified by gene specific expression profiles across different tissues and cell types. Cell type specific promoter regulation is a function of each cell's unique complement of transcriptional machinery components. Accordingly, to achieve high levels of transcriptional activity within a particular cell type, synthetic promoters must be specifically designed to harness those cells discrete repertoire of available transcription factors . Here, we describe a method for constructing very strong cell type-specific synthetic promoters for use in any given mammalian host cell. Transcription factor regulatory elements (TFREs; or transcription factor binding sites) that can independently mediate activation of recombinant gene transcription in the chosen host cells by using available transcription factor activity are identified and utilized as building blocks to construct novel promoter sequences with varying activities. Bioinformatics analysis of synthetic promoter 's TFRE compositions is then performed to determine how differing relative TFRE abundances explain variations in relative promoter activities . This information is used to derive an optimal second-generation promoter library construction design space, such that promoters with maximal transcriptional activity in the host cell type can be created. PMID- 28801905 TI - PCR Assembly of Synthetic Promoters. AB - In this chapter, we describe a two-step assembly PCR method to construct synthetic promoters. Essentially, this method takes advantage of specific annealing between complimentary DNA sequences to build random TFBS combinations within the assembled PCR products. A DNA polymerase is then employed to fill in the unpaired nucleotides in the generated sequences and also to amplify the assembled PCR products. We have used this method to generate synthetic promoters whereby the orientation of the TFBS can be controlled, the spacing between TFBS can be predetermined, and also the full diversity of the consensus TFBS can be covered through the use of degenerate oligonucleotides . PMID- 28801906 TI - The Tetracycline Responsive System. AB - Constitutive gene expression is not always the appropriate expression system because the unphysiological levels of expressed protein could be detrimental in studies examining biological roles of proteins, or continued expression may be unnecessary after therapeutic effects have been achieved in gene therapy . We have utilized pharmacologically regulated gene expression systems to achieve fine control of gene expression levels which facilitate research in basic biology and translates to use in experimental gene therapy studies. In this chapter, we outline the application of a tightly controlled tetracycline responsive gene expression system. PMID- 28801907 TI - Light-Responsive Promoters. AB - Recent advances in the development of light-inducible transgene expression systems have overcome many inherent drawbacks of conventional chemically regulated systems. The latest generation of those light-regulated systems that are specifically responsive to different wavelengths allows spatiotemporal control of gene expression in a so far unprecedented manner.In this chapter, we first describe the available light-inducible gene expression systems compatible with mammalian cells and explain their underlying mechanisms. Afterward, we give a detailed protocol for the implementation of a UVB light-inducible expression system in mammalian cells. PMID- 28801908 TI - A Simple Method for Constructing Artificial Promoters Activated in Response to Ultrasound Stimulation. AB - It has been pointed out that ultrasound could be used as a controller for bioprocesses including gene expression since its energy can noninvasively reach deep in the body. Gene expression may be timely and spatially controlled by ultrasound, thus providing necessary bioactive proteins for the targeted tissue in a timely fashion. Although there are many processes involved in gene expression control, one of the most important processes is transcription, and the promoter plays an essential role in it. There are several promoters known to be activated in response to ultrasound irradiation . However, in our opinion, an artificial promoter is more suitable for clinical use. We herein describe simple methods to construct promoters that are responsive to ultrasound irradiation by randomly combining cis-elements (transcription factor binding motifs) and thereby improve its reactivity to ultrasound irradiation . PMID- 28801909 TI - Promoter Activation with Electromagnetism. AB - Gene expression can be modified by physical factors, such as heat, electricity and magnetic fields , and several types of ionizing and non-ionizing radiation. Promoter activation with extremely low-frequency electromagnetic fields is possible with an appropriate promoter, containing electromagnetic field response elements. Here, we describe how to examine promoter activation with extremely low frequency electromagnetic fields, and we provide a step-by-step guide to the assembly of a solenoid suitable for promoter activation. PMID- 28801910 TI - Application of Synthetic Tumor-Specific Promoters Responsive to the Tumor Microenvironment. AB - Activity of endogenous promoters can be altered by including additional responsive elements (REs). These elements can be responsive to features of the tumor environment or alternatively to signaling pathways specifically activated in cancer cells. These REs incorporated into tumor-specific promoters can improve cancer targeting, the replicative capacity, and lytic activity of conditionally replicative adenovirus. Here we outline an approach to incorporate hypoxia and inflammation REs into a specific fragment of the SPARC promoter and the steps to clone a nucleosome positioning sequence (NPS ) identified in the osteocalcin promoter that contains a Wnt RE upstream of a heterologous synthetic promoter. PMID- 28801911 TI - A Modular Approach to Building Complex Synthetic Circuits. AB - Efficient assembly of genetic circuits is a critical element in synthetic biology for implementing complex gene expression systems. Here we present an assembly framework that integrates recent developments in DNA recombination technologies and unique nucleotide sequences for modular and reliable construction of complex genetic circuits. All relevant protocols are described in detail. Implementing these protocols relies on readily available reagents and basic molecular biology techniques without the need for specialized equipment. PMID- 28801912 TI - Computational Sequence Design with R2oDNA Designer. AB - Recently developed DNA assembly methods have enabled the rapid and simultaneous assembly of multiple parts to create complex synthetic gene circuits. A number of groups have proposed the use of computationally designed orthogonal spacer sequences to guide the ordered assembly of parts using overlap-directed or homologous recombination-based methods. This approach is particularly useful for assembling multiple parts with repetitive elements. Orthogonal spacer sequences (sometimes called UNSs-unique nucleotide sequences) also have a number of other potential uses including in the design of synthetic promoters regulated by novel regulatory elements. PMID- 28801913 TI - Design of Synthetic Promoters for Gene Circuits in Mammalian Cells. AB - Synthetic biology, the synthesis of engineering and biology, has rapidly matured and has dramatically increased the complexity of artificial gene circuits in recent years. The deployment of intricate synthetic gene circuits in mammalian cells requires the establishment of very precise and orthogonal control of transgene expression. In this chapter, we describe methods of modulating the expression of transgenes at the transcriptional level. Using cAMP-response element-binding protein (CREB)-dependent promoters as examples, a tool for the precise tuning of gene expression by using different core promoters and by varying the binding affinity of transcription factor operator sites is described. PMID- 28801914 TI - Blockade of transforming growth factor-beta signaling enhances oncolytic herpes simplex virus efficacy in patient-derived recurrent glioblastoma models. AB - Despite the current standard of multimodal management, glioblastoma (GBM) inevitably recurs and effective therapy is not available for recurrent disease. A subset of tumor cells with stem-like properties, termed GBM stem-like cells (GSCs), are considered to play a role in tumor relapse. Although oncolytic herpes simplex virus (oHSV) is a promising therapeutic for GBM, its efficacy against recurrent GBM is incompletely characterized. Transforming growth factor beta (TGF beta) plays vital roles in maintaining GSC stemness and GBM pathogenesis. We hypothesized that oHSV and TGF-beta inhibitors would synergistically exert antitumor effects for recurrent GBM. Here we established a panel of patient derived recurrent tumor models from GBMs that relapsed after postsurgical radiation and chemotherapy, based on GSC-enriched tumor sphere cultures. These GSCs are resistant to the standard-of-care temozolomide but susceptible to oHSVs G47Delta and MG18L. Inhibition of TGF-beta receptor kinase with selective targeted small molecules reduced clonogenic sphere formation in all tested recurrent GSCs. The combination of oHSV and TGF-betaR inhibitor was synergistic in killing recurrent GSCs through, in part, an inhibitor-induced JNK-MAPK blockade and increase in oHSV replication. In vivo, systemic treatment with TGF betaR inhibitor greatly enhanced the antitumor effects of single intratumoral oHSV injections, resulting in cures in 60% of mice bearing orthotopic recurrent GBM. These results reveal a novel synergistic interaction of oHSV therapy and TGF beta signaling blockade, and warrant further investigations aimed at clinical translation of this combination strategy for GBM patients. PMID- 28801915 TI - Manganese- and 1-methyl-4-phenylpyridinium-induced neurotoxicity display differences in morphological, electrophysiological and genome-wide alterations: implications for idiopathic Parkinson's disease. AB - Idiopathic Parkinson's disease and manganese-induced atypical parkinsonism are characterized by movement disorder and nigrostriatal pathology. Although clinical features, brain region involved and responsiveness to levodopa distinguish both, differences at the neuronal level are largely unknown. We studied the morphological, neurophysiological and molecular differences in dopaminergic neurons exposed to the Parkinson's disease toxin 1-methyl-4-phenylpyridinium ion (MPP+ ) and manganese (Mn), followed by validation in the 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine and Mn mouse models. Morphological analysis highlighted loss of neuronal processes in the MPP+ and not the Mn model. Cellular network dynamics of dopaminergic neurons characterized by spike frequency and inter-spike intervals indicated major neuronal population (~ 93%) with slow discharge rates (0-5 Hz). While MPP+ exposure suppressed the firing of these neurons, Mn neither suppressed nor elevated the neuronal activity. High throughput transcriptomic analysis revealed up-regulation of 694 and 603 genes and down-regulation of 428 and 255 genes in the MPP+ and Mn models respectively. Many differentially expressed genes were unique to either models and contributed to neuroinflammation, metabolic/mitochondrial function, apoptosis and nuclear function, synaptic plasticity, neurotransmission and cytoskeleton. Analysis of the Janus kinase-signal transducer and activator of transcription pathway with implications for neuritogenesis and neuronal proliferation revealed contrasting profile in both models. Genome-wide DNA methylomics revealed differences between both models and substantiated the epigenetic basis of the difference in the Janus kinase-signal transducer and activator of transcription pathway. We conclude that idiopathic Parkinson's disease and atypical parkinsonism have divergent neurotoxicological manifestation at the dopaminergic neuronal level with implications for pathobiology and evolution of novel therapeutics. Cover Image for this issue: doi. 10.1111/jnc.13821. PMID- 28801916 TI - Adenosine and dopamine oppositely modulate a hyperpolarization-activated current Ih in chemosensory neurons of the rat carotid body in co-culture. AB - KEY POINTS: Adenosine and dopamine (DA) are neuromodulators in the carotid body (CB) chemoafferent pathway, but their mechanisms of action are incompletely understood. Using functional co-cultures of rat CB chemoreceptor (type I) cells and sensory petrosal neurons (PNs), we show that adenosine enhanced a hyperpolarization-activated cation current Ih in chemosensory PNs via A2a receptors, whereas DA had the opposite effect via D2 receptors. Adenosine caused a depolarizing shift in the Ih activation curve and increased firing frequency, whereas DA caused a hyperpolarizing shift in the curve and decreased firing frequency. Acute hypoxia and isohydric hypercapnia depolarized type I cells concomitant with increased excitation of adjacent PNs; the A2a receptor blocker SCH58261 inhibited both type I and PN responses during hypoxia, but only the PN response during isohydric hypercapnia. We propose that adenosine and DA control firing frequency in chemosensory PNs via their opposing actions on Ih . ABSTRACT: Adenosine and dopamine (DA) act as neurotransmitters or neuromodulators at the carotid body (CB) chemosensory synapse, but their mechanisms of action are not fully understood. Using a functional co-culture model of rat CB chemoreceptor (type I) cell clusters and juxtaposed afferent petrosal neurons (PNs), we tested the hypothesis that adenosine and DA act postsynaptically to modulate a hyperpolarization-activated, cyclic nucleotide-gated (HCN) cation current (Ih ). In whole-cell recordings from hypoxia-responsive PNs, cAMP mimetics enhanced Ih whereas the HCN blocker ZD7288 (2 MUm) reversibly inhibited Ih . Adenosine caused a potentiation of Ih (EC50 ~ 35 nm) that was sensitive to the A2a blocker SCH58261 (5 nm), and an ~16 mV depolarizing shift in V1/2 for voltage dependence of Ih activation. By contrast, DA (10 MUm) caused an inhibition of Ih that was sensitive to the D2 blocker sulpiride (1-10 MUm), and an ~11 mV hyperpolarizing shift in V1/2 . Sulpiride potentiated Ih in neurons adjacent to, but not distant from, type I cell clusters. DA also decreased PN action potential frequency whereas adenosine had the opposite effect. During simultaneous paired recordings, SCH58261 inhibited both the presynaptic hypoxia-induced receptor potential in type I cells and the postsynaptic PN response. By contrast, SCH58261 inhibited only the postsynaptic PN response induced by isohydric hypercapnia. Confocal immunofluorescence confirmed the localization of HCN4 subunits in tyrosine hydroxylase-positive chemoafferent neurons in tissue sections of rat petrosal ganglia. These data suggest that adenosine and DA, acting through A2a and D2 receptors respectively, regulate PN excitability via their opposing actions on Ih . PMID- 28801917 TI - Attention-Deficit/Hyperactivity Disorder (ADHD): Interaction between socioeconomic status and parental history of ADHD determines prevalence. AB - BACKGROUND: Many studies have reported a higher prevalence of Attention Deficit/Hyperactivity Disorder (ADHD) among disadvantaged populations, but few have considered how parental history of ADHD might modify that relationship. We evaluated whether the prevalence of ADHD varies by socioeconomic status (SES) and parental history of ADHD in a population-sample of elementary school children age 6-14 years. METHODS: We screened all children in grades 1-5 in 17 schools in one North Carolina (U.S.) county for ADHD using teacher rating scales and 1,160 parent interviews, including an ADHD structured interview (DISC). We combined parent and teacher ratings to determine DSM-IV ADHD status. Data analysis was restricted to 967 children with information about parental history of ADHD. SES was measured by family income and respondent education. RESULTS: We found an interaction between family income and parental history of ADHD diagnosis (p = .016). The SES gradient was stronger in families without a parental history and weaker among children with a parental history. Among children without a parental history of ADHD diagnosis, low income children had 6.2 times the odds of ADHD (95% CI 3.4-11.3) as high income children after adjusting for covariates. Among children with a parental history, all had over 10 times the odds of ADHD as high income children without a parental history but the SES gradient between high and low income children was less pronounced [odds ratio (OR) = 1.4, 95% CI 0.6-3.5]. CONCLUSIONS: Socioeconomic status and parental history of ADHD are each strong risk factors for ADHD that interact to determine prevalence. More research is needed to dissect the components of SES that contribute to risk of ADHD. Future ADHD research should evaluate whether the strength of other environmental risk factors vary by parental history. Early identification and interventions for children with low SES or parental histories of ADHD should be explored. PMID- 28801918 TI - Motion compensation in the region of the coronary arteries based on partial angle reconstructions from short-scan CT data. AB - PURPOSE: In order to mitigate motion-induced artifacts, several motion compensation (MoCo) methods have been developed, which are either able to (a) compensate for severe artifacts, but utilize the data for the reconstruction of several cardiac phases, or (b) improve image quality of a single reconstruction with only moderate motion artifacts. We propose a method combining both benefits: dose efficiency by utilizing only the data needed for a single short-scan reconstruction while still being able to compensate for severe artifacts. METHODS: We introduce a MoCo method, which we call PAMoCo, to improve the visualization of the coronary arteries of a standard coronary CT angiography exam by reducing motion artifacts. As a first step, we segment a region of interest covering a chosen coronary artery. We subdivide a volume covering the whole heart into several stacks, which are sub-volumes, reconstructed from phase-correlated short-scan data acquired during different heart cycles. Motion-compensated reconstruction is performed for each stack separately, based on partial angle reconstructions, which are derived by dividing the data corresponding to the segmented stack volume into several double-overlapping sectors. We model motion along the coronary artery center line obtained from segmentation and the temporal dimension by a low-degree polynomial and create a dense 3D motion vector field (MVF). The parameters defining the MVF are estimated by optimizing an image artifact measuring cost function and we employ a semi-global optimization routine by re-initializing the optimization multiple times. The algorithm was evaluated on the basis of a phantom measurement and clinical data. For the phantom measurement an artificial vessel equipped with calcified lesions mounted on a moving robot arm was measured, where typical coronary artery motion patterns for 70 bpm and 90 bpm have been applied. For analysis, we calculated the calcified volume V inside an ROI and measured the maximum vessel diameter d based on cross sectional views to compare the performances of standard reconstructions obtained via filtered backprojection (FBP) and PAMoCo reconstructions between 20% and 80% of the cardiac cycle. Further, the new algorithm was applied to six clinical cases of patients with heart rates between 50 bpm and 74 bpm. Standard FBP, PAMoCo reconstructions were performed and compared to best phase FBP reconstructions and another MoCo algorithm, which is based on motion artifact metrics (MAM), via visual inspection. RESULTS: In case of the phantom measurement we found a strong dependence of V and d on the cardiac phase in case of the FBP reconstructions. When applying PAMoCo, V and d became almost constant due to a better discrimination from calcium to vessel and water background and values close to the ground truth have been derived. In the clinical study we chose reconstructions showing strong motion artifacts and observed a substantially improved delineation of the coronary arteries in PAMoCo reconstructions compared to the standard FBP reconstructions and also the MAM images, confirming the findings of the phantom measurement. CONCLUSIONS: Due to the fast reconstruction of PAMoCo images and the introduction of a new motion model, we were able to re initialize the optimization routine at pre-selected parameter sets and thereby increase the potential of the MAM algorithm. From the phantom measurement we conclude that PAMoCo performed almost equally well in all cardiac phases and suggest applying the PAMoCo algorithm for single source systems in case of patients with high or irregular heart rates. PMID- 28801920 TI - Restoration of thalamo-cortical connectivity after brain injury: recovery of consciousness, complex behavior, or passage of time? AB - In 2000, a landmark case report described the concurrent restoration of consciousness and thalamo-frontal connectivity after severe brain injury (Laureys et al., ). Being a single case however, this study could not disambiguate whether the result was specific to the restoration of consciousness per se as opposed to the return of complex cognitive function in general or simply the temporal evolution of post-injury pathophysiological events. To test whether the restoration of thalamo-cortical connectivity is specific to consciousness, 20 moderate-to-severe brain injury patients (from a recruited sample of 42) underwent resting-state functional magnetic resonance imaging within a week after injury and again six months later. As described in the single case report, we find thalamo-frontal connectivity to be increased at the chronic, compared with the acute, time-point. The increased connectivity was independent of whether patients had already recovered consciousness prior to the first assessment or whether they recovered consciousness in-between the two. Conversely, we did find an association between restoration of thalamo-frontal connectivity and the return of complex cognitive function. While we did replicate the findings of Laureys et al. (), our data suggests that the restoration of thalamo-frontal connectivity is not as tightly linked to the reemergence of consciousness per se. However, the degree to which the return of connectivity is linked to the return of complex cognitive function, or to the evolution of other time-dependent post-injury mechanisms, remains to be understood. PMID- 28801919 TI - Familial associations of female breast cancer with other cancers. AB - Familial risks of breast cancer (BC) are well established but whether BC clusters with other, i.e. discordant, cancers is less certain but of interest for the identification of common genetic and possible environmental factors contributing to a general cancer susceptibility. We apply a novel approach to search for familial associations of BC with other (discordant) cancers based on the Swedish Family-Cancer Database. Relative risks (RRs) were calculated for BC in families with increasing numbers of patients with discordant cancer X, and conversely, familial RRs for cancer X in families with increasing numbers of BC patients. Joint p-values were calculated from independent analyses. The total number of familial BCs was 12,266, 14.9% with one first-degree relative with BC and 1.2% with at least 2 affected relatives. Ovarian and prostate cancers showed the strongest associations with BC (p-value <10-11 ). The p-value for melanoma was <10-6 , for stomach and male colorectal cancer <2.5 * 10-6 , for cancer of unknown primary <2.5 * 10-5 and for lung cancer <5 * 10-5 . Significance level <5 * 10-4 was reached with pancreatic cancer. The remaining associations (p < 0.0025) included thyroid, endometrial, testicular, eye cancers (uveal melanoma), nervous system and endocrine tumors and non-Hodgkin lymphoma. The RR for BC increased by increasing numbers of patients with any cancer in family members and it reached 1.62 when three or more family members were affected. The results suggest that BC shares susceptibility with a number of other cancers. This might alert genetic counselors and challenge approaches for gene and gene-environment identification. PMID- 28801921 TI - Autophagy impairment by caspase-1-dependent inflammation mediates memory loss in response to beta-Amyloid peptide accumulation. AB - beta-Amyloid peptide accumulation in the cortex and in the hippocampus results in neurodegeneration and memory loss. Recently, it became evident that the inflammatory response triggered by beta-Amyloid peptides promotes neuronal cell death and degeneration. In addition to inflammation, beta-Amyloid peptides also induce alterations in neuronal autophagy, eventually leading to neuronal cell death. Thus, here we evaluated whether the inflammatory response induced by the beta-Amyloid peptides impairs memory via disrupting the autophagic flux. We show that male mice overexpressing beta-Amyloid peptides (5XFAD) but lacking caspase 1, presented reduced beta-Amyloid plaques in the cortex and in the hippocampus; restored brain autophagic flux and improved learning and memory capacity. At the molecular level, inhibition of the inflammatory response in the 5XFAD mice restored LC3-II levels and prevented the accumulation of oligomeric p62 and ubiquitylated proteins. Furthermore, caspase-1 deficiency reinstates activation of the AMPK/Raptor pathway while down-regulating AKT/mTOR pathway. Consistent with this, we found an inverse correlation between the increase of autophagolysosomes in the cortex of 5XFAD mice lacking caspase-1 and the presence of mitochondria with altered morphology. Together our results indicate that beta Amyloid peptide-induced caspase-1 activation, disrupts autophagy in the cortex and in the hippocampus resulting in neurodegeneration and memory loss. PMID- 28801922 TI - Prophylaxis with enoxaparin for prevention of venous thromboembolism after lung transplantation: a retrospective study. AB - Venous thromboembolism (VTE) is a frequent complication after solid organ transplantation (SOT) and, specifically, after lung transplantation (LT). The objectives of this study were to evaluate prophylaxis with enoxaparin and to describe risk factors for VTE after LT. We retrospectively reviewed the clinical records of 333 patients who underwent LT in our institution between 2009 and 2014. We compared two consecutive cohorts: one that received enoxaparin only during post-transplant hospital admissions and a second cohort that received 90 day extended prophylaxis with enoxaparin. Cumulative incidence function for competing risk analysis was used to determine incidence of VTE during the first year after transplantation. Risk factors were analyzed using a Cox proportional hazards regression model. The cumulative incidence of VTE was 15.3% (95% CI: 11.6 19.4). Median time from transplant to the event was 40 (p25-p75, 14-112) days. Ninety-day extended prophylaxis did not reduce the incidence of VTE. In this study, the risk factors associated with VTE were male gender and interstitial lung disease. VTE is a major complication after LT, and 90-day extended prophylaxis was not able to prevent it. Large, multicenter, randomized clinical trials should be performed to define the best strategy for preventing VTE. PMID- 28801923 TI - Sensitive liquid chromatography/tandem mass spectrometry method for the determination of two novel highly lipophilic anticancer drug candidates in rat plasma and tissues. AB - A simple and sensitive liquid chromatography/electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method was developed and validated for determination of two highly lipophilic anticancer drug candidates, LG1980 and GH501, in rat plasma and tissues (liver, kidney and femur bones). LG1980 and GH501 were extracted from rat plasma and tissue homogenates using liquid-liquid extraction. The method provided a linear range of 1.0-200.0 ng/mL for GH501 in plasma and LG1980 in plasma and liver. For both analytes in other tissue homogenates the linear range was 2.0-400.0 ng/mL. The method was validated with precision within 15% relative standard deviation, accuracy within 15% relative error and a consistent recovery. This method has been successfully applied in two preclinical studies for LG1980 and GH501 to determine their concentrations in rat plasma, liver, kidney and bone over 24 h after intravenous injection of compounds. PMID- 28801924 TI - Foramen epiploicum mesh closure (FEMC) through a ventral midline laparotomy. AB - BACKGROUND: Preventive laparoscopic closure of the epiploic foramen (EF) has previously been described, but methods for EF closure during laparotomy for treatment of colic are lacking. OBJECTIVES: To describe the foramen epiploicum mesh closure (FEMC) technique through a ventral midline laparotomy in horses under general anaesthesia and its outcome. STUDY DESIGN: Terminal surgical experiment and in vivo study. METHODS: In a pilot study, a standard ventral midline laparotomy was performed under general anaesthesia in 10 experimental horses and a three-dimensional expandable diabolo-shaped mesh construct was manually introduced through the EF into the omental vestibule. The laparotomy incision was routinely closed after which the horses were subjected to euthanasia. Subsequently, the cadavers were extensively manipulated and finally mesh position was verified during necropsy. Thereafter, a ventral midline laparotomy, with simulation of abdominal manipulations during colic surgery was performed on six experimental horses. A three-dimensional expandable diabolo shaped mesh with a radiological marker was introduced as in the pilot study. Clinical and laboratory parameters were recorded during the post-operative period. Four weeks after the intervention, abdominal radiography and laparoscopy were performed in all six horses. RESULTS: Insertion of all 16 diabolo-shaped mesh constructs during laparotomy was uneventful. The 10 mesh constructs of the pilot study were positioned correctly at necropsy. No post-operative clinical or laboratory parameter alterations were noticed in the other six horses, apart from a transient leucocytosis and an increase in serum amyloid A. Abdominal radiography at 4 weeks revealed consistent positioning of the mesh marker. Laparoscopy confirmed that all six EFs were closed, without intestinal adhesions. MAIN LIMITATIONS: Mesh insertion in clinical cases and during clean contaminated surgery was not investigated. CONCLUSION: The FEMC technique via laparotomy provides a fast, simple and reliable procedure to obliterate the EF and may be useful during EFE surgery to prevent recurrence of the disease, avoiding a subsequent laparoscopic procedure. PMID- 28801925 TI - Rare complication of treated immune thrombocytopenia. PMID- 28801926 TI - Internet-delivered eating disorder prevention: A randomized controlled trial of dissonance-based and cognitive-behavioral interventions. AB - OBJECTIVE: The current study evaluated two web-based programs for eating disorder prevention in high-risk, predominantly ethnic minority women. METHOD: Two hundred and seventy-one women with elevated weight concerns were randomized to Internet dissonance-based intervention (DBI-I), Internet cognitive-behavioral intervention (CBI-I), or no intervention (NI). Both interventions consisted of four weekly online sessions. Participants were assessed at pre- and post intervention. Outcome measures included eating pathology, body dissatisfaction, dieting, thin ideal internalization, and depression. RESULTS: At postintervention, DBI-I and CBI-I led to greater reductions in body dissatisfaction, thin-ideal internalization, and depression than NI. In addition, CBI-I was effective at reducing dieting and composite eating pathology relative to NI. No outcome differences were found between the active conditions. Moderation analyses suggested that both active conditions were more effective for ethnic minorities than Whites relative to NI. DISCUSSION: Results suggest that both DBI-I and CBI-I are effective at reducing eating disorder risk factors in a high-risk, predominantly minority population relative to no intervention. PMID- 28801927 TI - Mediating burden and stress over time: Caregivers of patients with primary brain tumor. AB - : There is a growing literature on the effects of cancer caregiving on the well being of informal family caregivers. However, there has been little longitudinal research on caregivers of patients with the complex, rapidly-changing disease of primary malignant brain tumor. OBJECTIVE: Our objective was to model longitudinal relationships between caregiver burden, social support, and distress within caregivers of patients with primary brain tumor. METHODS: Caregiver participants were recruited from a neuro-oncology clinic. Caregiver questionnaire data, including sociodemographics, social support, depression, anxiety, and caregiving burden, were collected at 4 time points (diagnosis, +4, +8, and +12 mo). Using the stress process model as a guide, we hypothesized that early burden would predict later depression and anxiety, and this would be mediated by social support. RESULTS: Using data from 147 participants, we found support for the stress process model in caregivers of patients with primary brain tumor. Greater burden at diagnosis was associated with lower social support at 4 months, and lower social support was related to higher depression and anxiety at 8 months, as well as to changes in anxiety between 8 and 12 months. CONCLUSION: We found evidence of the stress process model in caregivers of primary brain tumor patients unfolding over the course of a year after diagnosis. Our findings emphasize the potential importance of early programs for caregivers to ensure low initial levels of burden, which may have a positive effect on social support, depression, and anxiety. PMID- 28801930 TI - Conformationally Flexible Bis(9-fluorenylidene)porphyrin Diradicaloids. AB - A stable 5,10-bis(9-fluorenylidene)porphyrin (Por-Fl) diradicaloid was synthesized. It shows a quinoidal, saddle-shaped geometry in the single crystal but can be thermally populated to a triplet diradical both in solution and in the solid state. Coordination with the Ni2+ ion (Por-Fl-Ni) does not significantly change the contorted conformation but reduces the singlet-triplet gap. Heat induced geometric change can explain the observed paramagnetic properties as well as unusual hysteresis in SQUID measurements. On the other hand, protonation (Por Fl-2H+ ) dramatically changes the conformation while maintains the closed-shell electronic structure. Our studies demonstrate how heat, coordination, and protonation affect the geometry, diradical character, and physical properties of conformationally flexible open-shell singlet diradicaloids. PMID- 28801929 TI - Validation and application of a novel integrated genetic screening method to a cohort of 1,112 men with idiopathic azoospermia or severe oligozoospermia. AB - Microdeletions of the Y chromosome (YCMs), Klinefelter syndrome (47,XXY), and CFTR mutations are known genetic causes of severe male infertility, but the majority of cases remain idiopathic. Here, we describe a novel method using single molecule Molecular Inversion Probes (smMIPs), to screen infertile men for mutations and copy number variations affecting known disease genes. We designed a set of 4,525 smMIPs targeting the coding regions of causal (n = 6) and candidate (n = 101) male infertility genes. After extensive validation, we screened 1,112 idiopathic infertile men with non-obstructive azoospermia or severe oligozoospermia. In addition to five chromosome YCMs and six other sex chromosomal anomalies, we identified five patients with rare recessive mutations in CFTR as well as a patient with a rare heterozygous frameshift mutation in SYCP3 that may be of clinical relevance. This results in a genetic diagnosis in 11-17 patients (1%-1.5%), a yield that may increase significantly when more genes are confidently linked to male infertility. In conclusion, we developed a flexible and scalable method to reliably detect genetic causes of male infertility. The assay consolidates the detection of different types of genetic variation while increasing the diagnostic yield and detection precision at the same or lower price compared with currently used methods. PMID- 28801928 TI - Cyclic oligomer design with de novo alphabeta-proteins. AB - We have previously shown that monomeric globular alphabeta-proteins can be designed de novo with considerable control over topology, size, and shape. In this paper, we investigate the design of cyclic homo-oligomers from these starting points. We experimented with both keeping the original monomer backbones fixed during the cyclic docking and design process, and allowing the backbone of the monomer to conform to that of adjacent subunits in the homo-oligomer. The latter flexible backbone protocol generated designs with shape complementarity approaching that of native homo-oligomers, but experimental characterization showed that the fixed backbone designs were more stable and less aggregation prone. Designed C2 oligomers with beta-strand backbone interactions were structurally confirmed through x-ray crystallography and small-angle X-ray scattering (SAXS). In contrast, C3-C5 designed homo-oligomers with primarily nonpolar residues at interfaces all formed a range of oligomeric states. Taken together, our results suggest that for homo-oligomers formed from globular building blocks, improved structural specificity will be better achieved using monomers with increased shape complementarity and with more polar interfaces. PMID- 28801931 TI - Immunomodulatory Effects of Adipose Stromal Vascular Fraction Cells Promote Alternative Activation Macrophages to Repair Tissue Damage. AB - The pathogenesis of many diseases is driven by the interactions between helper T (TH ) cells and macrophages. The phenotypes of these cells are functional dichotomies that are persuaded according to the surrounding milieu. In both multiple sclerosis and the experimental autoimmune encephalomyelitis (EAE) model, TH 1 and TH 17 cells propagate autoimmune signaling and inflammation in the peripheral lymphoid tissues. In turn, this proinflammatory repertoire promotes the classical activation, formerly the M1-type, macrophages. Together, these cells infiltrate into the central nervous system (CNS) tissues and generate inflammatory and demyelinating lesions. Our most recent report demonstrated the immunomodulatory and anti-inflammatory effects of adipose stromal vascular fraction (SVF) cells and adipose-derived stem cells (ASCs) that led to functional, immunological, and pathological improvements in the EAE model. Here, a deeper investigation revealed the induction of regulatory T cells and alternative activation, or M2-type, macrophages in the periphery followed by the presence of alternative activation macrophages, reduced cellular infiltrates, and attenuation of neuroinflammation in CNS tissues following intraperitoneal administration of these treatments. Spleens from treated EAE mice revealed diminished TH 1 and TH 17 cell activities and were markedly higher in the levels of anti-inflammatory cytokine interleukin-10. Interestingly, SVF cells were more effective than ASCs at mediating these beneficial changes, which were attributed to their localization to the spleens after administration. Together, SVF cells rapidly and robustly attenuated the propagation of autoimmune signaling in the periphery that provided a permissive milieu in the CNS for repair and possibly regeneration. Stem Cells 2017;35:2198-2207. PMID- 28801932 TI - Introduction, comparison, and validation of Meta-Essentials: A free and simple tool for meta-analysis. AB - We present a new tool for meta-analysis, Meta-Essentials, which is free of charge and easy to use. In this paper, we introduce the tool and compare its features to other tools for meta-analysis. We also provide detailed information on the validation of the tool. Although free of charge and simple, Meta-Essentials automatically calculates effect sizes from a wide range of statistics and can be used for a wide range of meta-analysis applications, including subgroup analysis, moderator analysis, and publication bias analyses. The confidence interval of the overall effect is automatically based on the Knapp-Hartung adjustment of the DerSimonian-Laird estimator. However, more advanced meta-analysis methods such as meta-analytical structural equation modelling and meta-regression with multiple covariates are not available. In summary, Meta-Essentials may prove a valuable resource for meta-analysts, including researchers, teachers, and students. PMID- 28801933 TI - MALDI Imaging-Guided Microproteomic Analyses of Heterogeneous Breast Tumors-A Pilot Study. AB - Matrix-assisted laser desorption/ionization (MALDI) imaging is an ideal tool to study intratumor heterogeneity (ITH) and its implication in prognostic stratification of patients. However, there are some drawbacks concerning protein identification. On the other hand, laser microdissection (LMD)-based microproteomics allows retrieving thousands of protein identifications from small tissue pieces. As a proof of concept, the authors combine these two complementary approaches to analyze heterogeneous regions in breast tumors. Invasive ductal breast cancer FFPE tissue sections from five patients are analyzed by MALDI imaging and the dataset is processed by segmentation. Heterogeneous regions within tumors are processed by LMD-based microproteomics, in duplicates. Liquid chromatography-tandem mass spectrometry data are classified by hierarchical clustering. Heterogeneous tissue regions are discriminated on the basis of their actual molecular heterogeneity. The dataset is correlated with MALDI imaging to identify m/z values discriminating heterogeneous regions. The molecular characterization of cell clones in tumors related to bad patient outcome could have great impact for pathology. A combined application of LMD-based microproteomics and MALDI imaging for ITH studies is presented. PMID- 28801934 TI - Dual Effect in Fluorine-Doped Hematite Nanocrystals for Efficient Water Oxidation. AB - Herein, excellent light absorption and oxygen-evolving activity were simultaneously achieved by doping fluorine anions into hematite nanocrystals. Upon anion doping, the band structure of hematite can be effectively regulated, leading to the generation of defect levels between the band gap and remarkably increased visible light absorption. The activity for electrocatalytic oxygen evolution reaction (OER) of the hematite nanocrystals is enhanced after fluorine doping, where the doped hematite assists as an effective catalyst for photoelectrochemical water splitting. The optimization strategy proposed herein may shed light on the future design of photocatalysts for energy-related applications. PMID- 28801935 TI - Biocidal Potential and Chemical Composition of Industrial Essential Oils from Hyssopus officinalis, Lavandula * intermedia var. Super, and Santolina chamaecyparissus. AB - This work presents the biocidal (insecticidal, ixodicidal, nematicidal, and phytotoxic) effects and chemical compositions of three essential oils obtained from the industrial steam distillation (IEOs) of hyssop (Hyssopus officinalis L.), lavandin (Lavandula * intermedia or L. * hybrida var. Super), and cotton lavender (Santolina chamaecyparissus L.). Their chemical composition analyzed by gas chromatography coupled to mass spectrometry showed 1,8-cineole (53%) and beta pinene (16%) as the major components of H. officinalis, linalyl acetate (38%) and linalool (29%) of L. * intermedia; and 1,8-cineole (10%) and 8-methylene-3 oxatricyclo[5.2.0.02,4 ]nonane (8%) in S. chamaecyparissus. The biocidal tests showed that L. * intermedia IEO was the most active against the insect Spodoptera littoralis and toxic to the tick Hyalomma lusitanicum, IEO of H. officinalis was strongly active against S. littoralis, and finally, S. chamaecyparissus IEO was a strong antifeedant against the aphid Rhopalosiphum padi, toxic to H. lusitanicum and with moderate effects against Leptinotarsa decemlineata, S. littoralis, and Lolium perenne. PMID- 28801936 TI - Normative data and psychometric properties of a farsi translation of the strange stories test. AB - BACKGROUND AND OBJECTIVE: The Strange Stories test is one of the most commonly used tests to evaluate advanced "theory of mind," i.e. attribution of mental states. Normative data and psychometric properties of a new Farsi translation of this test were evaluated in a large community-based sample of Iranian school-aged children. METHODS: Through randomized cluster sampling, 398 children aged 9-11 years studying at 20 elementary schools were recruited from 4 central regions of Tehran, Iran. The mean age of the students was 9.96 years (SD = 0.92), and 51% were girls (n = 202). The Child Behavior Checklist (CBCL) was completed by parents. The Strange Stories test was completed by all children and repeated for 20% of them after 2-4 weeks to assess the test-retest reliability. FINDINGS: Students in upper grades had higher scores (P < .01); age predicted 2% of variance on the mental state score. Girls had significantly higher mentalizing scores than boys (P = .003). The split-half internal reliability coefficient was good (0.73). The test-retest reliability was fair to good. Item-scale score correlations were all significant (P < .01). CONCLUSION: This new translation of the Strange Stories test is a reliable and valid instrument to evaluate higher level theory of mind abilities in community samples of Farsi speaking children. Autism Res 2017, 10: 1960-1967. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: "Mentalizing" or "theory of mind," the ability to recognize others' mental states, is a key aspect of social understanding. Mentalizing problems are characteristic of some clinical conditions such as autism. The Strange Stories is a test evaluating mentalizing in every day social situations. It was translated into Farsi language and administered to a group of Iranian school-aged children. The instrument was useful in assessing children's mind reading. Older children and girls were better in mentalizing ability. PMID- 28801937 TI - In situ liver splitting under extracorporeal membrane oxygenation in brain-dead donor. AB - Hemodynamic instability is generally considered as a contraindication to liver splitting, in particular when using an in situ technique. We describe the cases of two young donors with brain death in whom refractory cardiac arrest and hemodynamic instability were supported by veno-arterial extracorporeal membrane oxygenation (VA-ECMO), allowing uneventful in situ splitting. Two adult and two pediatric liver recipients were successfully transplanted with immediate graft function. Favorable outcomes were also observed for the other transplanted organs, including one heart, two lungs, and four kidneys. Refractory cardiac arrest and hemodynamic instability corrected by VA-ECMO should not be considered as a contraindication to in situ liver splitting. PMID- 28801938 TI - Factors in Variability of Serial Gabapentin Concentrations in Elderly Patients with Epilepsy. AB - OBJECTIVES: To characterize and quantify the variability of serial gabapentin concentrations in elderly patients with epilepsy. METHODS: This study included 83 patients (age >= 60 yrs) from an 18-center randomized double-blind double-dummy parallel study from the Veterans Affairs Cooperative 428 Study. All patients were taking 1500 mg/day gabapentin. Within-person coefficient of variation (CV) in gabapentin concentrations, measured weekly to bimonthly for up to 52 weeks, then quarterly, was computed. Impact of patient characteristics on gabapentin concentrations (linear mixed model) and CV (linear regression) were estimated. RESULTS: A total of 482 gabapentin concentration measurements were available for analysis. Gabapentin concentrations and intrapatient CVs ranged from 0.5 to 22.6 MUg/ml (mean 7.9 MUg/ml, standard deviation [SD] 4.1 MUg/ml) and 2% to 79% (mean 27.9%, SD 15.3%), respectively, across all visits. Intrapatient CV was higher by 7.3% for those with a body mass index of >= 30 kg/m2 (coefficient = 7.3, p=0.04). CVs were on average 0.5% higher for each 1-unit higher CV in creatinine clearance (coefficient = 0.5, p=0.03) and 1.2% higher for each 1-hour longer mean time after dose (coefficient = 1.2, p=0.04). CONCLUSIONS: Substantial intrapatient variability in serial gabapentin concentration was noted in elderly patients with epilepsy. Creatinine clearance, time of sampling relative to dose, and obesity were found to be positively associated with variability. PMID- 28801939 TI - Assessment of advanced hepatic MR elastography methods for susceptibility artifact suppression in clinical patients. AB - PURPOSE: To assess the success rate, image quality, and the ability to stage liver fibrosis of a standard 2D gradient-recalled echo (GRE) and four different spin-echo (SE) magnetic resonance elastography (MRE) sequences in patients with different liver iron concentrations. MATERIALS AND METHODS: A total of 332 patients who underwent 3T MRE examinations that included liver fat and iron quantification were enrolled, including 136 patients with all five MRE techniques. Thirty-four patients had biopsy results for fibrosis staging. The liver stiffness, region of interest area, image quality, and success rate of the five sequences were compared in 115/136 patients. The area under the receiver operating characteristic curves (AUCs) and the accuracies for diagnosing early stage fibrosis and advanced fibrosis were compared. The effect of BMI (body mass index), the R2* relaxation time, and fat fraction on the image quality and liver stiffness measurements were analyzed. RESULTS: The success rates were significantly higher in the four SE sequences (99.1-100%) compared with GRE MRE (85.3%) (all P < 0.001). There were significant differences of the mean ROI area between every pair of sequences (all P < 0.0001). There were no significant differences in the AUC of the five MRE sequences for discriminating advanced fibrosis (10 P-values ranging from 0.2410-0.9171). R2* had a significant effect on the success rate and image quality for the noniron 2D echo-planar imaging (EPI), 3D EPI and 2D GRE (all P < 0.001) sequences. BMI had a significant effect on the iron 2D EPI (P = 0.0230) and iron 2D SE (P = 0.0040) sequences. CONCLUSION: All five techniques showed good diagnostic performance in staging liver fibrosis. The SE MRE sequences had higher success rates and better image quality than GRE MRE in 3T clinical hepatic imaging. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018;47:976-987. PMID- 28801940 TI - Examining the association between depression and obesity during a weight management programme. AB - The prevalence of depression in those with obesity is reported to be as high as double that in individuals of normal weight. There is potentially a bi directional relationship between obesity and depression. Some research has suggested that depression results in weight gain and obesity, and other studies have suggested that those with obesity are more likely to develop depression at a later stage. The aim of this study was to investigate the association of depression symptoms with weight change over a 12-month study. Seventy participants undertook a 3-month lifestyle (diet and exercise) weight loss intervention, and were followed up as part of a 12-month study. Participants completed the Beck Depression Inventory-II (BDI-II) and had their body weight measured throughout the study. Baseline body mass index (BMI) of participants (mean +/- standard deviation [SD]) was 31.1 +/- 3.9 kg m-2 , body weight was 89.4 +/- 16.1 kg, and age was 45.4 +/- 11.1 years; 63% of the cohort were female. The mean weight change from baseline to 3 months was -5.2% (+/-SD 4.3%), and from baseline to 12 months was -4.2% (+/-SD 6.1%). There was a significant decrease in BDI-II scores over the 12-month study, and a 1-unit decrease in BDI-II score was associated with a further decrease in body weight of -0.4%. The current study indicated that weight loss was associated with improvements in mood for non clinically depressed individuals with obesity, and these improvements persisted during a period of 3-12 months of follow-up. PMID- 28801941 TI - Step it up! Using the good behavior game to increase physical activity with elementary school students at recess. AB - We evaluated the effects of a modified version of the Good Behavior Game (GBG) on the number of steps taken by students during school recess. We divided a class into two teams, and awarded the team with the highest step counts at the end of each game raffle tickets for a school-wide lottery. The GBG was compared to recess periods without the game using an alternating-treatments design. Students took more steps while playing the GBG than they did during recess periods without the game. PMID- 28801942 TI - Cancer risk in different generations of Middle Eastern immigrants to California, 1988-2013. AB - The objective of this study is to compare cancer risk among different generations of Middle Eastern immigrants (ME) and non-Hispanic whites (NHW) in California between 1988 and 2013. We used data from the California Cancer Registry to identify invasive primary incident cancer cases in three population groups: (i) first-generation ME immigrants, (ii) second- or subsequent-generations ME immigrants, and (iii) NHW. Proportional incidence ratio (PIR) was used to compare cancer risk of the 15 selected most common cancers in the 3 population groups taking into consideration time since immigration for first-generation ME immigrants. First generation ME immigrants were more likely to be at increased risk of stomach (PIR= 3.13) and hepatobiliary (PIR = 2.27) cancers in females and thyroid (PIR = 2.19) and stomach (PIR = 2.13) cancers in males in comparison with NHW. Second- or subsequent-generations ME immigrants were at increased risk of thyroid cancer (PIR = 1.43 in females and 2.00 in males) in comparison with NHW, and malignant melanoma cancer (PIR = 4.53 in females and 4.61 in males) in comparison with first-generation ME immigrants. The risk levels of breast, thyroid and bladder cancers in ME first generation were significantly higher compared to NHW regardless of time spent in the United States suggesting the role of genetic predisposition, and/or cultural characteristics associated with these cancers. The results suggest that differences in cancer risk between ME first generation immigrants and NHW change in second or subsequent generations, approaching the risk level of NHW and indicating the impact of acculturation in this immigrant population. PMID- 28801943 TI - Utilizing Telehealth to deliver family-based treatment for adolescent anorexia nervosa. AB - OBJECTIVE: The purpose of this study was to test the feasibility and preliminary effect size on the main outcome measure (weight gain) of family-based treatment (FBT) for adolescents with anorexia nervosa (AN) and their families delivered via a Telehealth platform (i.e., an HIPAA compliant videoconferencing format). METHOD: Ten adolescents, mean age of 16.08 years (SD = 1.99), meeting DSM-5 criteria for AN or atypical AN, were enrolled in the study and offered FBT via a Telehealth platform. Feasibility and acceptability were evaluated by rates of recruitment and retention. Treatment outcome was determined utilizing percent median body mass index (%mBMI), the eating disorder examination (EDE), and measures for depression and self-esteem. RESULTS: Recruitment target was achieved within allotted time, and all participants were retained for the course of treatment. Percent mBMI improved significantly from baseline to the end-of treatment (p = .013) and from baseline to the 6-month follow-up (p = .032). Similar results were achieved for the EDE Global Score (p = .002 and .001, respectively). DISCUSSION: These findings provide preliminary evidence that it is feasible to deliver FBT via Telehealth and that satisfactory clinical outcomes are achievable. PMID- 28801944 TI - The Emergence of Second-Generation Lethal Injection Protocols: A Brief History and Review. AB - The history of capital punishment in the United States is long and controversial. In many cases, lethal injection has brought medical personnel, ethically and professionally charged with preserving life, into the arena of assisting the state in taking life. U.S. Supreme Court decisions, including Baze v. Rees (2008) and Glossip v. Gross (2015), have evaluated and condoned lethal injection protocols. Despite the judicial validation of some midazolam-containing protocols, controversy exists about the level of unconsciousness provided due to the ceiling effects of the drug. Drug shortages, induced in part by manufacturers under pressure by death penalty opponents and governments opposed to capital punishment, have forced states to sometimes use creative means to obtain medications for use in lethal injection, even proposing to allow inmates to supply their own drugs for use in execution. Others have resorted to using compounding pharmacies and enacting tougher execution secrecy laws to protect the identities of those involved in the process. Professional organizations representing health care team members, including nursing, medicine, and pharmacy, among others, have roundly denounced the medicalization of capital punishment. Legal challenges continue to mount at all levels, leading to an uncertain future for lethal injection. PMID- 28801945 TI - Bullying Victimization Trajectories for Sexual Minority Adolescents: Stable Victims, Desisters, and Late-Onset Victims. AB - Sexual minority adolescents are bullied more frequently than heterosexual peers. Research is lacking on their rates of general and sexual orientation bullying victimization. The present study identified (1) the rate, onset, and desistance of general and sexual orientation bullying victimization, (2) the rate of bullying victimization trajectories, and (3) risk and protective factors across trajectories. A life history calendar method and thematic analysis were employed with a sexual minority adolescent sample (N = 52, 14-20 y/o). General bullying began at age 5 and declined after age 12, with sexual orientation bullying increasing throughout adolescence. Late-onset victim (34.6%) was the most common trajectory, followed by stable victim (28.9%), desister (23.1%), and nonvictim (13.5%). Differences in risk and protective factors were found across trajectories. PMID- 28801946 TI - Imitation inhibition in children with Tourette syndrome. AB - OBJECTIVE: Echopraxia, that is, the open and automatic imitation of other peoples' actions, is common in patients with Gilles de la Tourette syndrome, autism spectrum disorder, and also those with frontal lobe lesions. While systematic reaction time tasks have confirmed increased automatic imitation in the latter two groups, adult patients with Tourette syndrome appear to compensate for automatic imitation tendencies by an overall slowing in response times. However, whether children with Tourette syndrome are already able to inhibit automatic imitation tendencies has not been investigated. METHOD: Fifteen children with Tourette syndrome and 15 healthy children (aged 7-12 years) performed an imitation inhibition paradigm. Participants were asked to respond to an auditory cue by lifting their index finger or their little finger. Participants were simultaneously presented with either compatible or incompatible visual stimuli. RESULTS: Overall responses in children with Tourette syndrome were slower than in healthy children. Although responses were faster in compatible than in incompatible trials in both groups, this 'interference effect' was smaller in children with Tourette syndrome. CONCLUSIONS: Children with Tourette syndrome have a smaller interference effect than healthy children, indicating an enhanced ability to behaviourally control automatic imitation tendencies at the cost of reacting slower. The results suggest that children with Tourette syndrome already employ different or additional inhibition strategies compared to healthy children. PMID- 28801947 TI - How will transitioning from cytology to HPV testing change the balance between the benefits and harms of cervical cancer screening? Estimates of the impact on cervical cancer, treatment rates and adverse obstetric outcomes in Australia, a high vaccination coverage country. AB - Primary HPV screening enables earlier diagnosis of cervical lesions compared to cytology, however, its effect on the risk of treatment and adverse obstetric outcomes has not been extensively investigated. We estimated the cumulative lifetime risk (CLR) of cervical cancer and excisional treatment, and change in adverse obstetric outcomes in HPV unvaccinated women and cohorts offered vaccination (>70% coverage in 12-13 years) for the Australian cervical screening program. Two-yearly cytology screening (ages 18-69 years) was compared to 5 yearly primary HPV screening with partial genotyping for HPV16/18 (ages 25-74 years). A dynamic model of HPV transmission, vaccination, cervical screening and treatment for precancerous lesions was coupled with an individual-based simulation of obstetric complications. For cytology screening, the CLR of cervical cancer diagnosis, death and treatment was estimated to be 0.649%, 0.198% and 13.4% without vaccination and 0.182%, 0.056% and 6.8%, in vaccinated women, respectively. For HPV screening, relative reductions of 33% and 22% in cancer risk for unvaccinated and vaccinated women are predicted, respectively, compared to cytology. Without the implementation of vaccination, a 4% increase in treatment risk for HPV versus cytology screening would have been expected, implying a possible increase in pre-term delivery (PTD) and low birth weight (LBW) events of 19 to 35 and 14 to 37, respectively, per 100,000 unvaccinated women. However, in vaccinated women, treatment risk will decrease by 13%, potentially leading to 4 to 41 fewer PTD events and from 2 more to 52 fewer LBW events per 100,000 vaccinated women. In unvaccinated women in cohorts offered vaccination as 12-13 year olds, no change to lifetime treatment risk is expected with HPV screening. In unvaccinated women in cohorts offered vaccination as 12-13 year olds, no change to lifetime treatment risk is expected with HPV screening. HPV screening starting at age 25 in populations with high vaccination coverage, is therefore expected to both improve the benefits (further decrease risk of cervical cancer) and reduce the harms (reduce treatments and possible obstetric complications) associated with cervical cancer screening. PMID- 28801948 TI - A proteomics method using immunoaffinity fluorogenic derivatization-liquid chromatography/tandem mass spectrometry (FD-LC-MS/MS) to identify a set of interacting proteins. AB - Biological functions in organisms are usually controlled by a set of interacting proteins, and identifying the proteins that interact is useful for understanding the mechanism of the functions. Immunoprecipitation is a method that utilizes the affinity of an antibody to isolate and identify the proteins that have interacted in a biological sample. In this study, the FD-LC-MS/MS method, which involves fluorogenic derivatization followed by separation and quantification by HPLC and finally identification of proteins by HPLC-tandem mass spectrometry, was used to identify proteins in immunoprecipitated samples, using heat shock protein 90 (HSP90) as a model of an interacting protein in HepaRG cells. As a result, HSC70 protein, which was known to form a complex with HSP90, was isolated, together with three different types of HSP90-beta. The results demonstrated that the proposed immunoaffinity-FD-LC-MS/MS method could be useful for simultaneously detecting and identifying the proteins that interact with a certain protein. PMID- 28801949 TI - The relationship between learning mathematics and general cognitive ability in primary school. AB - Three relationships between learning mathematics and general cognitive ability have been hypothesized: The educational hypothesis that learning mathematics develops general cognitive skills, the psychometric hypothesis that differences in general cognitive ability cause differences in mathematical attainment, and the reciprocal influence hypothesis that developments in mathematical ability and general cognitive ability influence each other. These hypotheses are assessed with a sample of 948 children from the Twins Early Development Study who were assessed at 7, 9, and 10 years on mathematics, English, and general cognitive ability. A cross-lagged path analysis with mathematics and general cognitive ability measures supports the reciprocal influence hypothesis between 7 and 9 and between 9 and 10. A second analysis including English assessments only provides evidence of a reciprocal relationship between 7 and 9. Statement of Contribution What is already known on this subject? The correlations between mathematical attainment, literacy, and measures of general cognitive skills are well established. The role of literacy in developing general cognitive skills is emerging. What the present study adds? Mathematics contributes to the development of general cognitive skills. General cognitive ability contributes to mathematical development between 7 and 10. These findings support the hypothesis of reciprocal influence between mathematics and general cognitive ability, at least between 7 and 9. PMID- 28801950 TI - Can chronic stretching change the muscle-tendon mechanical properties? A review. AB - It is recognized that stretching is an effective method to chronically increase the joint range of motion. However, the effects of stretching training on the muscle-tendon structural properties remain unclear. This systematic review with meta-analysis aimed to determine whether chronic stretching alter the muscle tendon structural properties. Published papers regarding longitudinal stretching (static, dynamic and/or PNF) intervention (either randomized or not) in humans of any age and health status, with more than 2 weeks in duration and at least 2 sessions per week, were searched in PubMed, PEDro, ScienceDirect and ResearchGate databases. Structural or mechanical variables from joint (maximal tolerated passive torque or resistance to stretch) or muscle-tendon unit (muscle architecture, stiffness, extensibility, shear modulus, volume, thickness, cross sectional area, and slack length) were extracted from those papers. A total of 26 studies were selected, with a duration ranging from 3 to 8 weeks, and an average total time under stretching of 1165 seconds per week. Small effects were seen for maximal tolerated passive torque, but trivial effects were seen for joint resistance to stretch, muscle architecture, muscle stiffness, and tendon stiffness. A large heterogeneity was seen for most of the variables. Stretching interventions with 3- to 8-week duration do not seem to change either the muscle or the tendon properties, although it increases the extensibility and tolerance to a greater tensile force. Adaptations to chronic stretching protocols shorter than 8 weeks seem to mostly occur at a sensory level. PMID- 28801951 TI - Modeling ion recombination in liquid ionization chambers - Improvement and analysis of the two-dose-rate method. AB - PURPOSE: The use of liquid ionization chambers can provide useful information to endeavors with radiation dosimetry for highly modulated beams. Liquid ionization chambers may be particularly suitable for computed tomography applications where conventional ionization chambers do not present a high enough sensitivity for the spatial resolution required to characterize common X-ray beams. Due to the sensitivity, which leads to high charge densities, liquid ionization chambers can suffer from large recombination losses leading to degradation in signal to dose rate linearity. To solve this problem, a two-dose-rate method for general recombination correction has been proposed for liquid ionization chambers. However, the valid range of recombination losses that the method can accurately account for has been found to vary depending on radiation quality. The present work provides an in-depth analysis of the performance of the two-dose-rate method. Furthermore, the soundness of applying gas theory to liquids is investigated by using the two-dose-rate method. METHODS: In the present work, the two-dose-rate method for general recombination correction of liquid ionization chambers used in continuous beams is studied by employing theory for gas-filled ionization chambers. An approximate relation for the general collection efficiency containing a material-specific parameter that is traceable to liquids has been derived for theoretical and experimental investigation alongside existing theory. Furthermore, the disassociation between initial and general recombination in the method is analyzed both theoretically and experimentally. RESULTS: The results indicate that liquids and gases share general recombination characteristics, where the liquids investigated (isooctane and tetramethylsilane) to a large extent mimic the behavior theoretically expected in gases. Furthermore, it is shown that the disassociation between initial and general recombination in the two-dose-rate method is an approximation that depends on the relation between initial recombination and the collecting electric field strength at the dose rates used. CONCLUSIONS: Due to the approximation used to separate initial and general recombination the valid range of collection efficiencies for the two-dose-rate method will not only depend on the model used to describe general recombination but also on the type of liquid and radiation beam quality. As there is no robust theory for initial recombination in liquids to apply, the valid range of general collection efficiencies for the two-dose-rate method should be experimentally evaluated for each radiation dosimetry application. PMID- 28801952 TI - Positioning, telling, and performing a male illness: Chronic prostatitis/chronic pelvic pain syndrome. AB - OBJECTIVES: There is a paucity of illness accounts of men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), despite a significant level of prevalence and burden of disease. This qualitative study thus elicited twelve accounts from men suffering with CP/CPPS. METHODS: Narrative analysis was employed, focusing primarily on narrative content. RESULTS: Three major narrative themes were identified: (1) Medical stories: Blame and shame; (2) The Erratic nature of CP/CPPS; and (3) Ongoing struggles for coping and cures and the Search for meaning. CONCLUSIONS: Recommendations were made for health care providers and increasing the internal agency, support and activism of men with this debilitating condition. Statement of contribution What is already known on this subject? One qualitative account of this male illness (CP/CPPS) exists: an IPA study. Five cross-sectional themes: (1) Need for repeated confirmation - disease not life-threatening nor leading inexorably towards cancer; (2) Disturbed sleep and fatigue; (3) Concealing pain and problems - 'normalizing'; (4) Enduring pain by performing activities; and (5) Abrupt mood swings and limited sociality. What does this study add? Narrative analysis adds information as to how this illness is managed and survived over time. It challenges the findings (above) by providing an insider perspective. Novel narrative themes include meaning-making amongst others. Masculine performance and experiences are also crucial to this stigmatized illness. PMID- 28801953 TI - Response to "Minimization of Ischemic Cholangiopathy in Donation After Cardiac Death Liver Transplantation: Is it Thrombolytic Therapy or Warm Ischemic Time Stringency and Donor Bile Duct Flush?" PMID- 28801954 TI - An analysis of inpatient pediatric sickle cell disease: Incidence, costs, and outcomes. AB - OBJECTIVE: To identify characteristics of pediatric sickle cell disease (SCD) hospitalizations and to examine admission demographics and medical expenditures. METHODS: Admissions with SCD were identified from the 2009 and 2012 releases of the Healthcare and Cost Utilization Project's Kids Inpatient Database. Disease specific secondary diagnoses including acute chest syndrome (ACS), vaso-occlusive pain crisis (VOC), splenic sequestration, and stroke/transient ischemic attack were analyzed for patient and hospital demographics. Analytical endpoints included total healthcare expenditures and mortality. RESULTS: We reviewed 75,234 inpatient hospitalizations with a diagnosis of SCD. Over $900,000,000 was spent annually in associated healthcare expenditure. The median length of hospitalization stay (LOS) for all admissions was 3 days (interquartile range [IQR] 2-5 days). VOC was the most frequent secondary diagnosis, recording 48,698 total hospitalizations and a median LOS of 3 days (IQR 2-6 days). Of the 8,490 hospitalizations with ACS, the infant population had a significantly higher mortality rate compared to other age groups (2% vs. 0.3%, P < 0.001). Cerebral vascular accidents incurred the second highest median hospitalization cost ($18,956), behind ACS ($22,631). A high proportion of Caucasian patients died during hospitalization for VOC (0.4% vs. 0.1%, P = 0.014) and ACS (4% vs. 0.2%, P < 0.001) when compared to non-Caucasians. CONCLUSION: Inpatient hospitalizations for secondary manifestations of pediatric SCD were associated with significant healthcare expenditures. Patients with an increased statistical risk for death during hospitalization included Caucasians with SCD complications of ACS and VOC, and patients <1-year-old with ACS. Further research is needed to substantiate the associated clinical significance of these findings. PMID- 28801955 TI - Single layer centrifugation of fresh dromedary camel semen improves sperm quality and in vitro fertilization capacity compared with simple sperm washing. AB - Single layer centrifugation (SLC) through a colloid is a tool for selecting viable mammalian spermatozoa but has not been used previously for fresh dromedary camel sperm. Semen from six camels (2 ejaculates/male) was diluted 1:5 (v:v) or 1:10 (v:v) in a Tris-citrate-fructose buffer for mechanical liquefaction by gentle pipetting. Following liquefaction, semen was processed either by SLC or by centrifugation without a colloid (control). Total and progressive motilities, CASA kinematics, vitality and acrosome integrity (eosin-nigrosin) and plasma membrane integrity (Hypo-osmotic swelling test; HOST), and fertilizing ability in a heterologous assay (zona-free goat oocytes) were evaluated. Both total (p = .003) and progressive motilities (p = .003) were higher in SLC-processed than in control semen samples, irrespective of dilution. Positive HOST values increased when using colloid in 1:5 (p = .001) and 1:10 dilution (p = .010). Colloid selected sperm had higher penetration rates than controls (p < .001 and p = .02 for 1:5 and 1:10 dilutions, respectively). However, only the SLC sperm at 1:5 dilution showed higher percentages of pronuclear formation (p = .02) than controls. Dilution effect was only significant for total motility before in vitro fertilization, with higher values for the 1:5 dilution (p = .033). The recovery rates of motile sperm between dilutions were similar (26.1% vs 35.4%; p = .226). In conclusion, SLC is a promising tool for selecting functional dromedary camel sperm and warrants more research. PMID- 28801956 TI - Evidence of er stress and upr activation in patients with brody disease and brody syndrome. AB - Brody disease (BD, OMIM #601003) is an inherited skeletal muscle disease clinically characterized by exercise-induced impairment of muscle relaxation and stiffness due to the delay in the Ca2+ re-uptake in the sarcoplasmic reticulum (SR)[1, 2]. The delayed muscle relaxation mainly affects legs, harms, hands and eyelids and usually improves after a few minutes rest [1-3]. Patients frequently report myalgia, painless or mildly painful cramps whereas recurrent rhabdomyolysis have been described in a few cases [2, 3]. A reduction in sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity characterizes the skeletal muscle of these patients [2-5]. This article is protected by copyright. All rights reserved. PMID- 28801957 TI - Monitoring and depth of strategy use in computer-based learning environments for science and history. AB - BACKGROUND: Self-regulated learning (SRL) models position metacognitive monitoring as central to SRL processing and predictive of student learning outcomes (Winne & Hadwin, 2008; Zimmerman, 2000). A body of research evidence also indicates that depth of strategy use, ranging from surface to deep processing, is predictive of learning performance. AIMS: In this study, we investigated the relationships among the frequency of metacognitive monitoring and the utilization of deep and surface-level strategies, and the connections between these SRL processes and learning outcomes across two academic domains, science and history. SAMPLE: This was a secondary data analysis of two studies. The first study sample was 170 undergraduate students from a University in the south-eastern United States. The second study sample consisted of 40 US high school students in the same area. METHODS: We collected think-aloud protocol SRL and knowledge measure data and conducted both structural equation modelling and path analysis to investigate our research questions. RESULTS: Findings showed across both studies and two distinct academic domains, students who enacted more frequent monitoring also enacted more frequent deep strategies resulting in better performance on academic evaluations. CONCLUSIONS: These findings suggest the importance of measuring not only what depth of strategies learners use, but also the degree to which they monitor their learning. Attention to both is needed in research and practice. PMID- 28801958 TI - Virtual reality jogging as a novel exposure paradigm for the acute urge to be physically active in patients with eating disorders: Implications for treatment. AB - The acute urge to be physically active is a relevant clinical phenomenon in patients suffering from eating disorders. In this study with n = 20 female patients with anorexia nervosa and n = 10 female patients with bulimia nervosa, a virtual reality (VR) jogging paradigm was applied as a novel highly immersive 3D exposure paradigm. Patients were asked to rate their acute urge to be physically active during the exposure procedure. A 10-item self-report questionnaire (smQ) was developed to capture the cognitive, emotional, and behavioral aspects of the acute urge to move. We hypothesized that exposure would lead to habituation of the urge to be physically active. We also hypothesized that leptin levels would be associated with the degree of the subjective urge to be physically active, while habituation would be associated with a decrease in stress hormones (alpha amylase, cortisol, and cortisone in saliva). A statistically significant change in subjective scores in the smQ from baseline to postexposure was seen. Our novel VR paradigm may serve as a therapeutic tool for exposure and habituation of the urge of acutely engaging in physical activity in patients with eating disorders. PMID- 28801959 TI - Outcomes of patients with atypical haemolytic uraemic syndrome with native and transplanted kidneys treated with eculizumab: a pooled post hoc analysis. AB - Atypical haemolytic uraemic syndrome (aHUS) often leads to end-stage renal disease (ESRD) and kidney transplantation; graft loss rates are high due to disease recurrence. A post hoc analysis of four prospective clinical trials in aHUS was performed to evaluate eculizumab, a terminal complement inhibitor, in patients with native or transplanted kidneys. The trials included 26-week treatment and extension periods. Dialysis, transplant and graft loss were evaluated. Study endpoints included complete thrombotic microangiopathy (TMA) response, TMA event-free status, haematologic and renal parameters and adverse events. Of 100 patients, 74 had native kidneys and 26 in the transplant subgroup had a collective history of 38 grafts. No patients lost grafts and only one with pre-existing ESRD received a transplant on treatment. Efficacy endpoints were achieved similarly in both subgroups. After 26 weeks, mean absolute estimated glomerular filtration rate increased from baseline to 61 and 37 ml/min/1.73 m2 in native (n = 71; P < 0.0001) and transplanted kidney (n = 25; P = 0.0092) subgroups. Two patients (one/subgroup) developed meningococcal infections; both recovered, one continued therapy. Eculizumab was well tolerated. Eculizumab improved haematologic and renal outcomes in both subgroups. In patients with histories of multiple graft losses, eculizumab protected kidney function. PMID- 28801960 TI - MRI characterization of brown adipose tissue under thermal challenges in normal weight, overweight, and obese young men. AB - PURPOSE: To implement quantitative Dixon magnetic resonance imaging (MRI) methods for brown adipose tissue (BAT) characterization at inactive and cold-activated states in normal weight, overweight, and obese subjects. The hypotheses are that MRI characteristics of BAT would differentiate between nonobese and obese subjects, and activation of BAT in response to thermal challenges that are detected by MRI would be correlated with BAT activity measured by positron emission tomography / computed tomography (PET/CT). MATERIALS AND METHODS: Fifteen male subjects (20.7 +/- 1.5 years old) including six normal weight, five overweight, and four obese subjects participated in the study. A multiecho Dixon MRI sequence was performed on a 1.5T scanner. MRI was acquired under thermoneutral, nonshivering thermogenesis, and subsequent warm-up conditions. Fat fraction (FF), R2*, and the number of double bonds (ndb) were measured by solving an optimization problem that fits in- and out-of-phase MR signal intensities to the fat-water interference models. Imaging acquisition and postprocessing were performed by two MRI physicists. In each subject, Dixon MRI measurements of FF, R2*, and ndb were calculated for each voxel within all BAT regions of interest (ROIs) under each thermal condition. Mean FF, R2*, and ndb were compared between nonobese (ie, normal-weight/overweight) and obese subjects using the two-sample t test. Receiver operating characteristic (ROC) analyses were performed to differentiate nonobese vs. obese subjects. BAT MRI measurement changes in response to thermal condition changes were compared with hypermetabolic BAT volume/activity measured by PET/CT using the Pearson's correlation. In addition, BAT MRI measurements were compared with body adiposity using the Pearson's correlation. P < 0.05 was considered statistically significant. RESULTS: Obese subjects showed higher FF and lower R2* than nonobese subjects under all three thermal conditions (P < 0.01). ROC analyses demonstrated that FF and R2* were excellent predictors for the differentiation of nonobese from obese subjects (100% specificity and 100% sensitivity). FF changes under thermal challenges were correlated with hypermetabolic BAT volume (r = -0.55, P = 0.04 during activation, and r = 0.72, P = 0.003 during deactivation), and with BAT activity (r = 0.69, P = 0.006 during deactivation), as measured by PET/CT. FF and R2* under all three thermal conditions were highly correlated with body adiposity (P <= 0.002). CONCLUSION: MRI characteristics of BAT differentiated between nonobese and obese subjects in both inactivated and activated states. BAT activation detected by Dixon MRI in response to thermal challenges were correlated with glucose uptake of metabolically active BAT. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:936-947. PMID- 28801961 TI - Recent advances in microscale separation. AB - This review focuses on the recent advances on microscale separation technology, particularly on the new development on column and detection technologies in electrophoretic and chromatographic separation modes (i.e., CE, CEC, cLC, etc.). Representative examples illustrate also applications on the small molecules, peptides, proteins, polysaccharides, chiral and so on. 246 relevant articles are cited covering the literature published from 2013 to May 2017. PMID- 28801962 TI - The Charge Transfer Approach to Heavier Main-Group Element Radicals in Transition Metal Complexes. AB - The CoII and FeII complexes 1Co and 1Fe with a coordinated phosphorus radical were easily obtained through a charge-transfer approach from the MI precursors LMI (tol) (M=Co, Fe; L=CH(MeC=NDipp)2 , Dipp=2,6-iPr2 C6 H3 ) to the diazafluorenylidene-substituted phosphaalkene 1. Structural, magnetic, and computational studies on 1Co and 1Fe indicate a weak antiferromagnetic interaction between the high-spin MII ion and the phosphorus radical, resulting in a triplet and quartet ground state, respectively. Complexes 1Co and 1Fe are the first examples of phosphorus-radical-coordinated transition-metal complexes synthesized by charge transfer, providing a new approach to access radicals of heavier main-group elements. PMID- 28801963 TI - A preliminary study of static and dynamic balance in sedentary obese young adults: the relationship between BMI, posture and postural balance. AB - The aim of this study was to evaluate the postural control of obese young adults with normal body mass index during different static (bipedic and unipedic support) and dynamic postural conditions (gait velocity and limits of stability) in order to compare the static and dynamic balance of these individuals. A cross sectional quantitative study was carried out to evaluate static and dynamic balance in 25 sedentary individuals. The sample was divided into two groups, 10 in the normal-weight group (24.70 +/- 3.89 years and 21.5 +/- 1.66 kg m-2 ) and 15 in the obese group (26.80 +/- 5.16 years and 35.66 +/- 4.29 kg m-2 ). Postural evaluation was performed through visual inspection, and balance analyses were performed using the Timed Up & Go test (TUGT) and Balance System (Biodex). Descriptive analyses, Fisher's exact test and Mann Whitney U-tests were performed using the Statistical Package for Social Sciences (SPSS - 20.0, Armonk, NY) software. Most of the obese volunteers presented postural alterations, such as head protrusion (47.6%), hyperkyphosis (46.7%) and hyperlordosis (26.7%). Medial lateral dynamic displacement, risk of falls and mean time to perform the limits of stability test and TUGT were higher for obese subjects (P < 0.05), while there were no significant differences between the groups (P > 0.05) for static balance tests for either bipedal or unipedal tasks. The disadvantage presented by the young obese subjects occurs in dynamic activities, representing worse balance and an increase in time needed to accomplish these activities. PMID- 28801964 TI - Changes in pulmonary vascular responsiveness to hypoxia. PMID- 28801965 TI - Improved electron collimation system design for Elekta linear accelerators. AB - Prototype 10 * 10 and 20 * 20-cm2 electron collimators were designed for the Elekta Infinity accelerator (MLCi2 treatment head), with the goal of reducing the trimmer weight of excessively heavy current applicators while maintaining acceptable beam flatness (+/-3% major axes, +/-4% diagonals) and IEC leakage dose. Prototype applicators were designed initially using tungsten trimmers of constant thickness (1% electron transmission) and cross-sections with inner and outer edges positioned at 95% and 2% off-axis ratios (OARs), respectively, cast by the upstream collimating component. Despite redefining applicator size at isocenter (not 5 cm upstream) and reducing the energy range from 4-22 to 6-20 MeV, the designed 10 * 10 and 20 * 20-cm2 applicator trimmers weighed 6.87 and 10.49 kg, respectively, exceeding that of the current applicators (5.52 and 8.36 kg, respectively). Subsequently, five design modifications using analytical and/or Monte Carlo (MC) calculations were applied, reducing trimmer weight while maintaining acceptable in-field flatness and mean leakage dose. Design Modification 1 beveled the outer trimmer edges, taking advantage of only low energy beams scattering primary electrons sufficiently to reach the outer trimmer edge. Design Modification 2 optimized the upper and middle trimmer distances from isocenter for minimal trimmer weights. Design Modification 3 moved inner trimmer edges inward, reducing trimmer weight. Design Modification 4 determined optimal X ray jaw positions for each energy. Design Modification 5 adjusted middle and lower trimmer shapes and reduced upper trimmer thickness by 50%. Design Modifications 1->5 reduced trimmer weights from 6.87->5.86->5.52->5.87->5.43 >3.73 kg for the 10 * 10-cm2 applicator and 10.49->9.04->8.62->7.73->7.35->5.09 kg for the 20 * 20-cm2 applicator. MC simulations confirmed these final designs produced acceptable in-field flatness and met IEC-specified leakage dose at 7, 13, and 20 MeV. These results allowed collimation system design for 6 * 6-25 * 25 cm2 applicators. Reducing trimmer weights by as much as 4 kg (25 * 25-cm2 applicator) should result in easier applicator handling by the radiotherapy team. PMID- 28801967 TI - Retreatment and prolonged therapy with subcutaneous bortezomib in patients with relapsed multiple myeloma: A randomized, controlled, phase III study. AB - OBJECTIVES: This randomized, international, multicenter, open-label phase III study investigated the effects of experimental retreatment with subcutaneous bortezomib plus dexamethasone (VD) followed by prolonged bortezomib therapy vs standard VD retreatment in patients with relapsed/refractory multiple myeloma. METHODS: Patients were randomized (2:1) to receive either experimental (n = 53) or standard (n = 27) retreatment, stratified by the number of prior therapy lines. RESULTS: The study was terminated prematurely with insufficient enrollment to adequately compare the retreatment therapies; results should be considered descriptive. After a median follow-up of 21.2 and 20.0 months in the experimental and standard arms, respectively, the median progression-free survival (primary endpoint) was 7.2 months (95% confidence interval 5.7-9.0) vs 7.8 months (4.9 11.7). The overall response rate was 66% and 52% for experimental and standard retreatment regimens, respectively. Thrombocytopenia was the most common and most differentially observed grade >=3 adverse event (experimental: 9% vs standard: 22%). Any-grade peripheral neuropathies (including peripheral sensory neuropathies) were reported in 23% vs 37% of patients. CONCLUSIONS: This study showed no significant benefit with experimental vs standard VD retreatment therapy. Further investigations are required to determine whether the experimental retreatment regimen is a suitable alternative to the current standard retreatment regimen. PMID- 28801968 TI - Warming of Subarctic waters accelerates development of a key marine zooplankton Calanus finmarchicus. AB - Recent observations confirm the rising temperatures of Atlantic waters transported into the Arctic Ocean via the West Spitsbergen Current (WSC). We studied the overall abundance and population structure of the North Atlantic keystone zooplankton copepod Calanus finmarchicus, which is the main prey for pelagic fish and some seabirds, in relation to selected environmental variables in this area between 2001 and 2011, when warming in the Arctic and Subarctic was particularly pronounced. Sampling within a 3-week time window each summer demonstrated that trends in the overall abundance of C. finmarchicus varied between years, with the highest values in "extreme" years, due to high numbers of nauplii and early copepodite stages in colder years (2001, 2004, 2010), and contrary to that, the fifth copepodite stage (C5) peaking in warm years (2006, 2007, 2009). The most influential environmental variable driving C. finmarchicus life cycle was temperature, which promoted an increased C5 abundance when the temperature was above 6 degrees C, indicating earlier spawning and/or accelerated development, and possibly leading to their development to adults later in the summer and spawning for the second time, given adequate food supply. Based on the presented high interannual and spatial variability, we hypothesize that under a warmer climate, C. finmarchicus may annually produce two generations in the southern part of the WSC, what in turn could lead to food web reorganization of important top predators, such as little auks, and induce northward migrations of fish, especially the Norwegian herring. PMID- 28801966 TI - Ursolic Acid, a Natural Nutraceutical Agent, Targets Caspase3 and Alleviates Inflammation-Associated Downstream Signal Transduction. AB - SCOPE: Ursolic acid (UA) is a pentacyclicterpenoid carboxylic acid that is present in a wide variety of plant foods. There are many beneficial health effects that are attributed to the properties of UA. However, the specific cellular targets of UA and the mechanism underlying downstream signal transduction processes linked to the anti-inflammation pathway have not been thoroughly elucidated to date. METHODS AND RESULTS: Chemical biology strategies such as target fishing, click reaction synthesis of a UA probe and molecular imaging were used to identify potential target proteins of UA. Cysteinyl aspartate specific proteinase 3 (CASP3) and its downstream signaling pathway were verified as potential targets by molecular docking, intracellular enzyme activity evaluation and accurate pathway analysis. The results indicated that UA acted on CASP3, ERK1 and JNK2 targets, alleviated inflammation-associated downstream multiple signal transduction factors, including ERK1, NF-kappaB and STAT3, and exhibited anti-inflammation activities. CONCLUSION: As a natural dietary supplement, UA demonstrated anti-inflammation activity via inhibition of CASP3 and shows the potential to improve the therapy effect of several inflammation associated diseases. PMID- 28801969 TI - Anesthetic management for intestinal transplantation: A decade of experience. AB - BACKGROUND: Intestinal transplantation (ITx) is the definitive therapy for patients suffering from intestinal failure. Previously published reports suggest that these cases should be managed perioperatively with the same intensive monitors and techniques as in liver transplantation. METHODS: We retrospectively reviewed the anesthetic management of 67 isolated intestinal, intestinal pancreas, and intestinal-kidney transplants over the previous decade (2005-2015) in our tertiary care institution. RESULTS: Patients were typically managed with a single arterial line, a single central venous catheter, and rarely intensive modalities such as a pulmonary artery catheter, a transesophageal echocardiography, a second arterial catheter or central venous catheter, a rapid infusion system, a cell salvage device, or viscoelastic testing. Significant hemodynamic derangements were rare, and the rate of postreperfusion syndrome was 8.96%. Our fluid administration type and volume and transfusion type and volume were similar to previous reports in which more intensive anesthetic management was employed. CONCLUSION: We demonstrate that ITx can safely occur without utilizing the intensive resources requisite for a liver transplant. PMID- 28801970 TI - Lysozyme oxidation by singlet molecular oxygen: Peptide characterization using [18 O]-labeling oxygen and nLC-MS/MS. AB - Singlet molecular oxygen (1 O2 ) is generated in biological systems and reacts with different biomolecules. Proteins are a major target for 1 O2 , and His, Tyr, Met, Cys, and Trp are oxidized at physiological pH. In the present study, the modification of lysozyme protein by 1 O2 was investigated using mass spectrometry approaches. The experimental findings showed methionine, histidine, and tryptophan oxidation. The experiments were achieved using [18 O]-labeled 1 O2 released from thermolabile endoperoxides in association with nano-scale liquid chromatography coupled to electrospray ionization mass spectrometry. The structural characterization by nLC-MS/MS of the amino acids in the tryptic peptides of the proteins showed addition of [18 O]-labeling atoms in different amino acids. PMID- 28801972 TI - Brief Report: A Differential Transcriptomic Profile of Ex Vivo Expanded Adult Human Hematopoietic Stem Cells Empowers Them for Engraftment Better than Their Surface Phenotype. AB - Transplantation of small cord blood (CB) units, or of autologous ex vivo genetically modified adult hematopoietic stem cells (HSC), face the common challenge of suboptimal HSC doses for infusion and impaired engraftment of the transplanted cells. Ex vivo expansion of HSCs, using either cell-based coculture approaches or especially small molecules have been successfully tested mainly in CB and in prolonged cultures. Here, we explored whether innovative combinations of small molecules can sufficiently, after short culture, expand adult HSCs while retaining their functionality in vivo. We found that 5-day cultured cells, in the presence of the small molecule combinations tested, achieved higher engraftment levels in NSG mice than both their uncultured and their cytokine only-cultured counterparts. Surprisingly, the engraftment levels were neither concordant to the numbers of phenotypically similar HSCs expanded under different small molecule combinations, nor explained by their distinct companion cells present. Transcriptomic comparative analysis of sorted, phenotypically similar, ex vivo generated HSCs transplanted in equal numbers, suggested that HSCs generated under expansion conditions that maintain low expression of the Rap1/Ras/PI3K-AKT pathway exhibit a superior functional profile in vivo. Stem Cells Translational Medicine 2017;6:1852-1858. PMID- 28801971 TI - Pharmacokinetics and metabolism of olerciamide A from Portulaca oleracea L. in rats by UHPLC-UV and UHPLC-ESI-Q-TOF/MS. AB - The aim of this study was to elucidate the pharmacokinetics of olerciamide A in rats after oral and intravenous administration of Portulaca oleracea L. extract by a simple and rapid ultra high-performance liquid chromatography method with bergapten as internal standard. The pharmacokinetic results indicated that olerciamide A was rapidly distributed with a time to peak concentration of 30 min after oral administration and presented a low oral absolute bioavailability of 4.57%. The metabolism of olerciamide A in rats was also investigated using ultra high-performance liquid chromatography electrospray coupled with quadrupole-time of flight mass spectrometry to elucidate the reason for the low absolute bioavailability of olerciamide A and seven metabolites of oleraciamide A were found in rat plasma and urine. PMID- 28801973 TI - Cognitive functioning in children with self-limited epilepsy with centrotemporal spikes: A systematic review and meta-analysis. AB - OBJECTIVE: It is now well appreciated that benign epilepsy with centrotemporal spikes (BECTS, or more recently, ECTS) is associated with a range of cognitive and behavioral disturbances. Despite our improved understanding of cognitive functioning in ECTS, there have been to date no efforts to quantitatively synthesize the available literature within a comprehensive cognitive framework. METHODS: The present systematic review and meta-analysis was conducted according to PRISMA guidelines. Forty-two case-control samples met eligibility criteria comprising a total of 1,237 children with ECTS and 1,137 healthy control children. Univariate, random-effects meta-analyses were conducted on eight cognitive factors in accordance with the Cattell-Horn-Carroll model of intelligence. RESULTS: Overall, children with ECTS demonstrated significantly lower scores on neuropsychological tests across all cognitive factors compared to healthy controls. Observed effects ranged from 0.42 to 0.81 pooled standard deviation units, with the largest effect for long-term storage and retrieval and the smallest effect for visual processing. SIGNIFICANCE: The results of the present meta-analysis provide the first clear evidence that children with ECTS display a profile of pervasive cognitive difficulties and thus challenge current conceptions of ECTS as a benign disease or of limited specific or localized cognitive effect. PMID- 28801974 TI - Heritability estimates of endurance-related phenotypes: A systematic review and meta-analysis. AB - The aim of this study was to clarify heritability estimates for endurance-related phenotypes and the underlying factors affecting these estimates. A systematic literature search was conducted for studies reporting heritability estimates of endurance-related phenotypes using the PubMed database (up to 30 September 2016). Studies that estimated the heritability of maximal oxygen uptake (VO2max), submaximal endurance phenotypes, and endurance performance were selected. The weighted mean heritability for endurance-related phenotypes was calculated using a random-effects model. A total of 15 studies were selected via a systematic review. Meta-analysis revealed that the weighted means of the heritability of VO2max absolute values and those adjusted for body weight and for fat-free mass were 0.68 (95% CI: 0.59-0.77), 0.56 (95% CI: 0.47-0.65), and 0.44 (95% CI: 0.13 0.75), respectively. There was a significant difference in the weighted means of the heritability of VO2max across these different adjustment methods (P < .05). Moreover, there was evidence of statistical heterogeneity in the heritability estimates among studies. Meta-regression analysis revealed that sex could partially explain the heterogeneity in the VO2max heritability estimates adjusted by body weight. For submaximal endurance phenotypes and endurance performance, the weighted mean heritabilities were 0.49 (95% CI: 0.33-0.65) and 0.53 (95% CI: 0.27-0.78), respectively. There was statistically significant heterogeneity in the heritability estimates reported among the studies, and we could not identify the specific factors explaining the heterogeneity. Although existing studies indicate that genetic factors account for 44%-68% of the variability in endurance related phenotypes, further studies are necessary to clarify these values. PMID- 28801975 TI - Trends in Aging-Related Services During Nephrectomy: Implications for Surgery in an Aging Population. AB - OBJECTIVES: To characterize the extent to which geriatric and related healthcare services are provided to older adults undergoing surgery for kidney cancer, a potential growth area in geriatrics and oncology. DESIGN: Population-based observational study. SETTING: Surveillance, Epidemiology, and End Results cancer data linked with Medicare claims. PARTICIPANTS: Adults aged 65 and older with kidney cancer treated surgically from 2000 to 2009 (N = 19,129). MEASUREMENTS: Receipt of geriatric consultation, medical comanagement during the surgical hospitalization, inpatient physical or occupational therapy (PT/OT), and postacute PT/OT during the surgical care episode. Multivariable, mixed-effects models were used to identify associated participant and hospital characteristics, examine trends over time, and characterize hospital-level variation. RESULTS: Geriatric consultation occurred rarely in the perioperative period (2.6%). Medical comanagement (15.8%), inpatient PT/OT (34.2%), and postacute PT/OT (15.6%) occurred more frequently. In our mixed-effects models, participant age and comorbidity burden appeared to be consistent determinants of use of services, although hospital-level variation was also noted (P < .001). Use of geriatric consultation increased modestly in the latter years of the study period (P < .05). In contrast, medical comanagement (183%), inpatient PT/OT (73%), and postacute PT/OT (71%) increased substantially over the study period (P < .001). CONCLUSION: Although geriatric consultation remained sparse, use of medical comanagement and rehabilitation services has grown considerably for older adults undergoing surgery for kidney cancer. Efforts to reorganize cancer and surgery care should explore reasons for variation and the potential for these service elements to meet the health needs of an aging population. PMID- 28801976 TI - Implications of fetoplacental mosaicism on cell-free DNA testing for sex chromosome aneuploidies. AB - OBJECTIVE: The unique biological behavior of sex chromosomes has implications for cell-free DNA (cfDNA) testing. Our purpose is to predict the (1) false positive/negative rates of cfDNA testing consequent to fetoplacental mosaicism for any sex chromosome aneuploidies (SCA) and (2) positive predictive value (PPV) and negative predictive values of a high-risk and low-risk cfDNA result for any SCA. METHOD: This is a retrospective analysis of 67 030 chorionic villus sampling karyotypes, including fetoplacental mosaicism cases. RESULTS: Non-mosaic 45, X is associated with cystic hygroma/increased nuchal translucency and fetal anomalies. The false positive rate consequent to confined placental mosaicism is predicted to be 0.05%. The estimated false negative rate is in the range of 0% to 5.7% for all non-mosaic SCAs; it is 70% for mosaic 45, X with normal ultrasound. The predicted PPV on amniocytes is very high for most SCAs (94.4-99.4%). However, the stratified analysis shows that the PPV is much lower for 45, X without ultrasound anomalies compared with 45, X with abnormal scan (51% or 71%, vs 99%, respectively). CONCLUSION: Mosaicism is a major issue for SCA cfDNA testing, and prenatal confirmation, preferentially with amniocentesis if there are no ultrasound anomalies, remains important in counseling. As PPV varies on the basis of the presence of an ultrasound anomaly, skilled evaluation is critical. (c) 2017 John Wiley & Sons, Ltd. PMID- 28801977 TI - Isolation, identification and characterization of lignin-degrading bacteria from Qinling, China. AB - AIMS: Lignin is an aromatic heteropolymer forming a physical barrier and it is a big challenge in biomass utilization. This paper first investigated lignin degradation bacteria from rotten wood in Qinling Mountain. METHODS AND RESULTS: Nineteen potential strains were selected and ligninolytic enzyme activities were determined over 84 h. Strains that had higher enzyme activities were selected. Further, the biodegradation of wheat straw lignin and alkali lignin was evaluated indicating that Burkholderia sp. H1 had the highest capability. It was confirmed by gel permeation chromatography and field emission scanning electron microscope that alkali lignin was depolymerized into small fragments. The degraded products were analysed using gas chromatography-mass spectrometry. The total ion chromatograph of products treated for 7 days showed the formation of aromatic compounds, an important intermediate from lignin degradation. Interestingly, they disappeared in 15 days while the aldehyde and ester compounds increased. CONCLUSIONS: The results suggest that the lignin-degrading bacteria are abundant in rotten wood and strain H1 has high potential to break down lignin. SIGNIFICANCE AND IMPACT OF THE STUDY: The diversity of lignin-degrading bacteria in Qinling Mountain is revealed. The study of Burkholderia sp. H1 expands the range of bacteria for lignin degradation and provides novel bacteria for application to lignocellulosic biomass. PMID- 28801979 TI - Germanium-Bridged 2-Phenylbenzoheteroles as Luminophores Exhibiting Highly Efficient Solid-State Fluorescence. AB - [1]Benzogermolo[3,2-b]indoles, [1]benzogermolo[3,2-b]benzofuran, [1]benzogermolo[3,2-b]benzothiophene, and [1]benzogermolo[3,2-b]benzothiophene S,S-dioxide were synthesized from the corresponding 3-bromo-2-(2 bromophenyl)benzoheteroles and characterized. A comparison of the absorption spectra of the Ph2 Ge- and Ph2 Si-bridged 2-phenylindoles reveals that the Ge bridge has the effect of slightly widening the HOMO-LUMO energy gap of the bridged 2-phenylindole pi-system with regard to the Si-bridged system. Replacement of the indole ring by benzofuran or benzothiophene rings induces blueshifts in the absorption spectrum, whereas the absorption spectrum of the benzothiophene-S,S-dioxide derivative was redshifted with respect to the indole derivative. These results are consistent with the changes in the HOMO-LUMO energy gaps calculated by using density functional theory. The Ph2 Ge-bridged indole, benzofuran, and benzothiophene-S,S-dioxide derivatives exhibit brilliant fluorescence in the violet-to-blue region with good-to-excellent quantum yields in toluene (lambdaem =376-439 nm, Phi=0.62-0.99) and powder form (lambdaem =401 451 nm, Phi=0.64-0.80). PMID- 28801978 TI - Mindfulness of voices, self-compassion, and secure attachment in relation to the experience of hearing voices. AB - OBJECTIVES: Developing compassion towards oneself has been linked to improvement in many areas of psychological well-being, including psychosis. Furthermore, developing a non-judgemental, accepting way of relating to voices is associated with lower levels of distress for people who hear voices. These factors have also been associated with secure attachment. This study explores associations between the constructs of mindfulness of voices, self-compassion, and distress from hearing voices and how secure attachment style related to each of these variables. DESIGN: Cross-sectional online. METHOD: One hundred and twenty-eight people (73% female; Mage = 37.5; 87.5% Caucasian) who currently hear voices completed the Self-Compassion Scale, Southampton Mindfulness of Voices Questionnaire, Relationships Questionnaire, and Hamilton Programme for Schizophrenia Voices Questionnaire. RESULTS: Results showed that mindfulness of voices mediated the relationship between self-compassion and severity of voices, and self-compassion mediated the relationship between mindfulness of voices and severity of voices. Self-compassion and mindfulness of voices were significantly positively correlated with each other and negatively correlated with distress and severity of voices. CONCLUSION: Mindful relation to voices and self-compassion are associated with reduced distress and severity of voices, which supports the proposed potential benefits of mindful relating to voices and self-compassion as therapeutic skills for people experiencing distress by voice hearing. PRACTITIONER POINTS: Greater self-compassion and mindfulness of voices were significantly associated with less distress from voices. These findings support theory underlining compassionate mind training. Mindfulness of voices mediated the relationship between self-compassion and distress from voices, indicating a synergistic relationship between the constructs. Although the current findings do not give a direction of causation, consideration is given to the potential impact of mindful and compassionate approaches to voices. PMID- 28801980 TI - Effects of proton pump inhibitors and famotidine on elimination of plasma methotrexate: Evaluation of drug-drug interactions mediated by organic anion transporter 3. AB - Methotrexate (MTX) is an antifolate agent used in the treatment of numerous types of cancer, and eliminated by active tubular secretion via organic anion transporter 3 (OAT3). Gastric antisecretory drugs, such as proton pump inhibitors (PPIs) and histamine H2 receptor antagonists, are widely used among patients with cancer in clinical practice. The aim of the present study was to analyse the potential drug-drug interactions between MTX and gastric antisecretory drugs in high-dose MTX (HD-MTX) therapy. The impact of PPIs on the plasma MTX concentration on 73 cycles of HD-MTX therapy was analysed retrospectively in 43 patients. Also investigated was the involvement of OAT3 in PPI-MTX drug interaction in an in vitro study using human OAT3 expressing HEK293 cells. In a retrospective study, patients who received a PPI had significantly higher MTX levels at 48 h (0.38 vs. 0.15 MUmol l-1 , respectively, p = 0.000018) and 72 h (0.13 vs. 0.05 MUmol l-1 , respectively, p = 0.0002) compared with patients who did not receive a PPI (but received famotidine). Moreover, in vitro experiments demonstrated that PPIs (esomeprazole, lansoprazole, omeprazole and rabeprazole) inhibited hOAT3-mediated uptake of MTX in a concentration-dependent manner (IC50 values of 0.40-5.5 MU m), with a rank order of lansoprazole > esomeprazole > rabeprazole > omeprazole. In contrast to PPIs, famotidine showed little inhibitory effect on hOAT3-mediated MTX uptake. These results demonstrated that co-administration of PPI, but not famotidine, could result in a pharmacokinetic interaction that increases the plasma MTX levels, at least in part, via hOAT3 inhibition. PMID- 28801981 TI - Pregnancy outcomes in mothers of offspring with inherited bone marrow failure syndromes. AB - BACKGROUND: Children with inherited bone marrow failure syndromes (IBMFSs) may be symptomatic in utero, resulting in maternal and fetal problems during the pregnancy. Subsequent pregnancies by their mothers should be considered "high risk". METHODS: We retrospectively analyzed outcomes of 575 pregnancies in 165 unaffected mothers of offspring with Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS) for events noted during pregnancy, labor, and delivery. We compared outcomes of pregnancies with affected and unaffected offspring within each group of mothers and with the general population. RESULTS: The rates of miscarriage (12-20%), elective abortion (5-10%), and live birth (68-78%) among mothers of all IBMFS groups were similar and comparable with general population rates but recurrent miscarriages (>=2) were significantly more common in mothers of offspring with DBA and SDS. Offspring with FA were more frequently born small for gestational age (SGA) than unaffected babies (39% vs. 4%) and had fetal malformations (46%) with 18% having three or more, often necessitating early delivery and surgery; offspring with DC had higher rates of SGA (39% vs. 8%) and fetal distress (26% vs. 3%); and offspring with DBA had fetal hypoxia (19% vs. 1%) leading to preterm and emergency cesarean deliveries (26% vs. 6%). Offspring with early-onset severe phenotypes had the most prenatal and peripartum adverse events. CONCLUSION: We identified the high-risk nature of pregnancies in mothers with IBMFS-affected fetuses, suggesting the need for prepregnancy counseling and monitoring of subsequent pregnancies by high-risk fetal-maternal specialists. PMID- 28801982 TI - Influence of practitioner expertise during early pregnancy diagnosis on pregnancy loss rate: A controlled, blinded trial. AB - A controlled field trial was conducted to assess the potential influence of practitioner inexperience during early pregnancy diagnosis with ultrasound (PD US) on the risk of pregnancy loss. A veterinarian with more than 10 years' experience in PD-US (Vet-A) and a veterinarian with fewer than 12 months' experience at the start of the study (Vet-B) visited the same dairy farm once a week for 33 and 26 weeks, respectively. The two veterinarians did not interact with each other at any time during the study, nor did they know that their data would later be used in this study. Using the same farm scanner, they performed PD US at 28-34 day after breeding, together diagnosing 915 pregnancies. All cows were re-checked at 49-56 day after artificial insemination, and cows no longer pregnant were recorded as having suffered pregnancy loss. Although Vet-A and Vet B diagnosed a similar proportion of pregnancies (58.44 +/- 16% vs 56.96 +/- 18%, p > .05), the rate of pregnancy loss was significantly higher among cows diagnosed by Vet-B (10.41 +/- 11.2% vs 4.87 +/- 9.0, p = .029). In addition, among cows diagnosed by Vet-B, the rate of pregnancy loss was significantly higher among cows diagnosed, while he had fewer than 12 months' PD-US experience (11.17 +/- 12.14%) than among cows that he diagnosed later (7.14 +/- 11.01%, p = .038); in fact, this latter loss rate was comparable to that among cows diagnosed by Vet-A during the same period (3.51 +/- 9.83%, p = .620). These results suggest that inexperience with PD-US during the late embryonic period can increase risk of early pregnancy loss, supporting the need for proper training. PMID- 28801983 TI - Body weight status and health-care expenditure among university retirees in Beijing, China. AB - OBJECTIVE: This study examined the impact of overweight and obesity on health care expenditure among university retirees in Beijing, China. METHODS: Annual health surveys of retirees were conducted at Tsinghua University during 2011 2016. Individual random-effect regressions were performed to estimate incremental health-care expenditures attributable to overweight/obesity, adjusting for various individual characteristics. RESULTS: Compared to their normal-weight counterparts, obesity was associated with an increase in annual out-of-pocket expenditure on outpatient care by 27%, inpatient care 19% and medication 15%, and an increase in annual total out-of-pocket health-care expenditure by 33%. Overweight was associated with an increase in annual out-of-pocket expenditure on inpatient care by 13%, and an increase in annual total out-of-pocket health-care expenditure by 13%. The impact of obesity on health-care expenditure was statistically significant among men but not women. CONCLUSION: Overweight, and obesity in particular, was associated with substantial increases in out-of-pocket health-care expenditures among Chinese older adults. PMID- 28801984 TI - Low-dose bortezomib and dexamethasone as primary therapy in elderly patients with Waldenstrom macroglobulinemia. AB - OBJECTIVE: This retrospective study was designed to determine the efficacy and safety of low-dose bortezomib and dexamethasone (lBD) in elderly Chinese patients with Waldenstrom macroglobulinemia (WM). METHODS: Ten patients with WM aged over 60 years received first-line treatment with lBD. RESULTS: The median age was 70 years (range, 61-77 years). The overall response rate was 80%, including 1 patient who achieved a complete response, 1 patient with very good partial response, and 6 patients with a partial response. Median time to response was 1.8 months after treatment with lBD. Six (60%) patients achieved a partial response, including 2 (20%) patients who had a more than 75% reduction in serum immunoglobulin M levels. A rapid reduction in paraprotein was observed in three patients who received plasmapheresis. After a median follow-up period of 36 months, all patients were still alive and six had no disease progression. The estimated median time to progression was 39 months (range, 15-60 months). The most common adverse events were anemia, thrombocytopenia, neuropathy, and neutropenia. Peripheral neuropathy was the most common non-hematological toxicity in six (60%) patients, but did not result in the discontinuation of bortezomib. CONCLUSIONS: Our findings show that lBD is an effective and tolerable treatment regimen for elderly patients with WM. PMID- 28801985 TI - Between-day reliability of local thermal hyperemia in the forearm and index finger using single-point laser Doppler flowmetry. AB - OBJECTIVE: To assess between-day reliability for LTH in glabrous and nonglabrous index finger skin and nonglabrous forearm skin, with single-point laser Doppler flowmetry. METHODS: Part-1: In healthy, habitually active males (n=10), LTH was examined twice (~7-10 days apart) for both skin types on the index finger. Part 2: Identical testing was performed on the volar forearm. Local heating (33-42 degrees C at 1 degrees C.20 s-1 + 20 minutes at 44 degrees C) was performed at all skin sites and baseline, initial peak, and plateau phases were identified. Data were expressed as raw CVC (laser-Doppler flux/MAP), and as CVC normalized to baseline (%CVC33 degrees C ) and maximum heating (%CVC44 degrees C ). Reliability was assessed using between-day mean difference, %CV, and ICC. RESULTS: Reliability (%CV) was poor at baseline for all forms of data presentation and for other phases with %CVC33 degrees C . At the initial peak and plateau, reliability was moderate-poor (20%-26%) for CVC and good-moderate (6%-18%) for %CVC44 degrees C . Reliability was good-moderate for vasodilatory onset time (10%-23%) and time to initial peak (6%-13%). CONCLUSIONS: For all sites, LTH reliability was acceptable for the timing, and for the initial peak and plateau using CVC or %CVC44 degrees C . PMID- 28801986 TI - Persistent detection of alternatively spliced BCR-ABL variant results in a failure to achieve deep molecular response. AB - Treatment with tyrosine kinase inhibitors (TKI) may sequentially induce TKI resistant BCR-ABL mutants in chronic myeloid leukemia (CML). Conventional PCR monitoring of BCR-ABL is an important indicator to determine therapeutic intervention for preventing disease progression. However, PCR cannot separately quantify amounts of BCR-ABL and its mutants, including alternatively spliced BCR ABL with an insertion of 35 intronic nucleotides (BCR-ABLIns35bp ) between ABL exons 8 and 9, which introduces the premature termination and loss of kinase activity. To assess the clinical impact of BCR-ABL mutants, we performed deep sequencing analysis of BCR-ABL transcripts of 409 samples from 37 patients with suboptimal response to frontline imatinib who were switched to nilotinib. At baseline, TKI-resistant mutations were documented in 3 patients, whereas BCR ABLIns35bp was detected in all patients. After switching to nilotinib, both BCR ABL and BCR-ABLIns35bp became undetectable in 3 patients who attained complete molecular response (CMR), whereas in the remaining all 34 patients, BCR ABLIns35bp was persistently detected, and minimal residual disease (MRD) fluctuated at low but detectable levels. PCR monitoring underestimated molecular response in 5 patients whose BCR-ABLIns35bp was persisted, although BCR ABLIns35bp does not definitively mark TKI resistance. Therefore, quantification of BCR-ABLIns35bp is useful for evaluating "functional" MRD and determining the effectiveness of TKI with accuracy. PMID- 28801987 TI - Predictors of long-term outcomes in patients with acute severe colitis: A northern Indian cohort study. AB - BACKGROUND AND AIM: Knowledge of long-term outcomes following an index episode of acute severe colitis (ASC) can help informed decision making at a time of acute exacerbation especially when colectomy is an option. We aimed to identify long term outcomes and their predictors after a first episode of ASC in a large North Indian cohort. METHODS: Hospitalized patients satisfying Truelove and Witts' criteria under follow-up at a single center from January 2003 to December 2013 were included. Patients avoiding colectomy at index admission were categorized as complete (<= 3 non bloody stool per day) or incomplete responders, based upon response to corticosteroids at day 7. Random Forest-based machine learning models were constructed to predict the long-term risk of colectomy or steroid dependence following an index episode of ASC. RESULTS: Of 1731 patients with ulcerative colitis, 179 (10%) had an index episode of ASC. Nineteen (11%) patients underwent colectomy at index admission and 42 (26%) over a median follow-up of 56 (1-159) months. Hazard ratio for colectomy for incomplete responder was 3.6 (1.7-7.5, P = 0.001) compared with complete responder. Modeling based on four variables, response at day 7 of hospitalization, steroid use during the first year of diagnosis, longer disease duration before ASC, and number of extra-intestinal manifestations, was able to predict colectomy with an accuracy of 77%. CONCLUSIONS: Disease behavior of ASC in India is similar to the West, with a third undergoing colectomy at 10 years. Clinical features, especially response at day 7 hospitalization for index ASC, can predict both colectomy and steroid dependence with reasonable accuracy. PMID- 28801988 TI - Prompt sonographic scanning and quantification of lumbar muscles: Seeing the butterfly. PMID- 28801989 TI - Determination of higenamine and coclaurine levels in human urine after the administration of a throat lozenge containing Nandina domestica fruit. AB - Higenamine is a key component of traditional Chinese herbal medicine. The fruit of Nandina domestica (which contains this component) is available as an ingredient in the so-called Nanten-nodo-ame throat lozenge found on the Japanese market, which is an over-the-counter pharmaceutical and is easy to purchase for Japanese athletes. However, higenamine is a non-selective beta2-agonist, which is exemplified in the prohibited list of the World Anti-Doping Agency (WADA). Therefore, some have raised a concern regarding the potential cause of increased unintentional higenamine doping cases in the Asian region. This study aimed to investigate components of throat lozenges and develop a mass-spectrometry method for the quantification of higenamine and coclaurine in human urine. Moreover, a population study of Japanese subjects (n = 246) and an excretion study (n = 4) of the corresponding throat-lozenge recipients were performed to test the applicability of the current reporting threshold (i.e., 10 ng/mL) of higenamine set by WADA. The estimates of higenamine and coclaurine were 2.2 +/- 0.1 MUg/drop (mean of n = 12) and 0.5 +/- 0.01 MUg/drop (mean of n = 12), respectively. The maximum concentrations of higenamine and coclaurine were 0.2-0.4 and 0.3-1.0 ng/mL, respectively, at 10-12 h after administration of higenamine (nine drops); however, the concentrations in all four volunteers did not reach the positivity criterion of 10 ng/mL. No higenamine and coclaurine could be detected in the Japanese subjects. Therefore, there is no risk of detecting unintentional higenamine doping when the WADA reporting threshold is used. PMID- 28801990 TI - Degradation of euptox A by tannase-producing rumen bacteria from migratory goats. AB - AIMS: The gut microbiota capable of degrading plant biomass and antinutritional phytometabolites are of immense importance. This study reports isolation and characterization of tannase-producing rumen bacteria that could also degrade euptox A (9-oxo-10,11-dehydroageraphorone) present in Eupatorium adenophorum (Spreng). METHODS AND RESULTS: Migratory Gaddi goats were selected as source of inoculums for isolating rumen bacteria with ability to produce tannase which catalyses degradation of hydrolysable tannins (HTs). Three rumen bacterial isolates producing tannase were studied, and identified as Klebsiella variicola strain PLP G-17 LC, K. variicola strain PLP S-18 and Klebsiella pneumoniae strain PLP G-17 SC. The isolates exhibited optimal tannase activity at 40 degrees C, and pH 6.0. The bacteria could also degrade euptox A, a potent hepatotoxin in E. adenophorum Spreng, a widely distributed noxious weed. CONCLUSIONS: The rumen bacteria could degrade antinutritional HTs and euptox A. Culture-independent metagenomic interventions are envisioned to completely decipher the rumen microbial ecology and exploit its genetic and metabolic potential. SIGNIFICANCE AND IMPACT OF THE STUDY: The bacteria producing tannase which catalyses degradation of HTs, and concurrently degrading euptox A, may have potential as microbial feed additives to increase utilization of plant biomass containing antinutritional phytometabolites. PMID- 28801991 TI - Early autism symptoms in infants with tuberous sclerosis complex. AB - : Tuberous sclerosis complex (TSC) is a rare, autosomal dominant genetic syndrome that confers significantly increased risk for autism spectrum disorder (ASD), with 50-60% of infants with TSC meeting criteria for ASD by 3 years of age. In a previous study of the current longitudinal cohort, we found that infants with TSC who develop ASD (TSC/ASD) evidence decreased cognitive abilities that diverge from infants with TSC and no ASD (TSC/no ASD). We extended this work by asking whether TSC/ASD infants (n = 13) differed from TSC/no ASD infants (n = 10) and infants with low developmental risk and no ASD (LR; n = 21) in their social communication functioning during the first year of life. We measured early ASD symptoms with the Autism Observation Scale for Infants (AOSI) at 9 and 12 months of age. At both ages, infants in the TSC/ASD group had significantly higher AOSI total scores than infants in the TSC/no ASD and LR groups, which were not fully explained by differences in cognitive abilities. Several items on the AOSI at both ages were predictive of ASD outcome, particularly those representing core social communication deficits (e.g., social referencing). Our findings signal the need for further study of this population within the first year and provide strong justification for early identification and early intervention targeting social communication skills in infants with TSC. Autism Res 2017, 10: 1981-1990. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We examined early signs of autism spectrum disorder (ASD) in infants with tuberous sclerosis complex (TSC), approximately 50% of whom will meet criteria for ASD by age 3. Infants with TSC and ASD showed deficits in social communication behaviors by 9 months of age that were clearly distinguishable from behaviors in infants with TSC who do not develop ASD and low risk infants. Results support the importance of early ASD screening and intervention for infants with TSC. PMID- 28801992 TI - Associations between behaviours that challenge in adults with intellectual disability, parental perceptions and parental mental health. AB - OBJECTIVES: This study examined parental perceptions of behaviours that challenge (CB) in their adult children with intellectual disability (ID), and explored whether perceptions mediated associations between CB and parental psychological distress. DESIGN: A within-group correlational design was employed. METHODS: Sixty-five parents reported on individuals with genetic syndromes and ID who had chronic CB. Parents completed the Illness Perception Questionnaire-Revised (IPQ R) adapted to measure perceptions of self-injury, aggression or property destruction, alongside assessments of parental locus of control, attributions about behaviour, parental psychological distress, and CB. RESULTS: A high proportion of parents evidenced anxiety and depression at clinically significant levels (56.9% and 30.8%, respectively). Contrary to predictions, psychological distress was not significantly associated with CB. The perception that the adult with ID exerted control over the parent's life mediated the association between CB and parental psychological distress. Few parents endorsed operant reinforcement as a cause of CB (< 10%). CONCLUSIONS: The high levels of psychological distress in parents is notable and of concern. Further research should consider the reasons why parents have causal attributions that might be inconsistent with contemporary interventions. PRACTITIONER POINTS: Parents experience high levels of psychological distress while supporting adults with ID who engage in chronic behaviours that challenge. A stronger belief that the adult with ID exerts control over the parent's life may mediate an association between CB exhibited by the individual with ID and parental psychological distress. Few parents endorsed operant reinforcement as a cause of behaviours that challenge. PMID- 28801993 TI - Effects of service number on conception rate in Japanese Black cattle. AB - The conception rate (CR) of Japanese Black cattle has been decreasing since 1990. The objectives of this study were to compare CR by artificial insemination (AI) number, and to assess the interaction between AI number and possible factors related to CR in Japanese Black cattle. Records of 11,182 AI records for 6,741 heifers and 61,302 AI records for 13,139 cows on 977 farms were analysed. The average CR of heifers was 47.0%, and CR at the first, second and third AI was higher than at the fourth or subsequent AI (p < 0.05). The average CR of cows was 47.8%, and their CR at first and second AI was higher than the fourth or subsequent AI (p < 0.05). Data analysis with CR as the dependent variable revealed significant interactions of AI number with interval from calving to first AI and AI season. Cows first serviced at <=48 days post-partum had lower CR than those at >=90 days at first AI (p < 0.05), but the interval from calving to first AI did not affect CR at second AI. Cows serviced in the autumn had a higher CR at first AI than those serviced in the spring and winter (p < 0.05); however, there was no seasonal difference in CR at the second AI. In summary, CR began to decrease from the fourth AI in heifers and the third AI in cows. The AI season and the interval from calving to first AI significantly affected CR only at the first AI. PMID- 28801994 TI - Influence of feeding hematocrit and perfusion pressure on hematocrit reduction (Fahraeus effect) in an artificial microvascular network. AB - OBJECTIVE: Hct in narrow vessels is reduced due to concentration of fast-flowing RBCs in the center, and of slower flowing plasma along the wall of the vessel, which in combination with plasma skimming at bifurcations leads to the striking heterogeneity of local Hct in branching capillary networks known as the network Fahraeus effect. We analyzed the influence of feeding Hct and perfusion pressure on the Fahraeus effect in an AMVN. METHODS: RBC suspensions in plasma with Hcts between 20% and 70% were perfused at pressures of 5-60 cm H2 O through the AMVN. A microscope and high-speed camera were used to measure RBC velocity and Hct in microchannels of height of 5 MUm and widths of 5-19 MUm. RESULTS: Channel Hcts were reduced compared with Hctfeeding in 5 and 7 MUm microchannels, but not in larger microchannels. The magnitude of Hct reduction increased with decreasing Hctfeeding and decreasing DeltaP (flow velocity), showing an about sevenfold higher effect for 40% Hctfeeding and low pressure/flow velocity than for 60% Hctfeeding and high pressure/flow velocity. CONCLUSIONS: The magnitude of the network Fahraeus effect in an AMVN is inversely related to Hctfeeding and DeltaP. PMID- 28801996 TI - Updating the guidelines for data transparency in the British Journal of Pharmacology - data sharing and the use of scatter plots instead of bar charts. PMID- 28801995 TI - INST OX-05-024: first line gemcitabine, oxaliplatin, and erlotinib for primary hepatocellular carcinoma and bile duct cancers: a multicenter Phase II trial. AB - Hepatocellular Carcinoma (HCC) incidence is increasing in the USA. Gemcitabine (G) and oxaliplatin (O) are active in HCC and biliary duct cancer (BDC). Erlotinib (E) is an EGFR tyrosine kinase inhibitor (TKI) with known activity against both. We sought to evaluate the efficacy of the combination G+O+E. Patients with either of the two diagnosis were treated in a phase II trial. Simons 2 stage design was used. A disease-control rate (DCR), complete response (CR) + partial response (PR)+ stable disease (SD) at 24 weeks of <=20% and >40% (P0 and P1 of 0.2 and 0.4, respectively) were set as undesirable (null) and desirable results. 26 HCC and 7 BDC patients were accrued. In HCC, 1 PR, 10 SD, and 9 PDs were seen. DCR in HCC was 42%. Among seven (7) patients with BDC, one patient was not evaluable; one achieved a long lasting PR, and five patients had SD and DCR was 86%. Median overall survival (OS) times and progression-free survivals (PFS) were 196 and 149 days in HCC and 238 days and not reached in BDC. PFS at 26 weeks in HCC was 41% and at 21 weeks in BDC was 60%. Grade 3 toxicities in >5% of patients were fatigue (12.9%), neutropenia (9.6%), thrombocytopenia (9.6%), and diarrhea (6.4%). G+O+E exceeded both preset P0a and P1 of the primary objective with a PFS of 41% at 26 weeks for HCC and preliminary BDC data may warrant further investigations. PMID- 28801997 TI - Prevalence of low bone mass among adolescents with nontransfusion-dependent hemoglobin E/beta-thalassemia and its relationship with anemia severity. AB - BACKGROUND: Low bone mass is common among adolescents with transfusion-dependent beta-thalassemia despite adequate transfusion and iron chelation. However, there are few reports regarding bone mineral density (BMD) among adolescents with nontransfusion-dependent thalassemia (NTDT). Indeed, only BMD data in patients with nontransfusion-dependent (NTD) beta-thalassemia intermedia have been reported. No previous study has investigated BMD among adolescents with NTD hemoglobin (Hb) E/beta-thalassemia. OBJECTIVE: To determine the prevalence of low bone mass among adolescents with NTD Hb E/beta-thalassemia and factors relating to low bone mass. METHODS: We investigated BMD of lumbar spine (L2-L4; BMDLS) and total body (BMDTB), as measured by dual-energy X-ray absorptiometry, in 22 adolescents (aged 13.2-20 years) with NTD Hb E/beta-thalassemia. RESULTS: Low bone mass was found to be 18.2% and 22.7% at the lumbar spine (BMDLS Z-score adjusted for bone age and height age) and 13.6% and 9.1% at the total body (BMDTB Z-score adjusted for bone age and height age). Patients with mean Hb level <8 g/dl were more likely to have low bone mass (BMDLS and BMDTB Z-scores adjusted for bone age) compared to those with Hb level >= 8 g/dl. Mean Hb level correlated with BMDLS and BMDTB Z-scores adjusted for bone age. CONCLUSION: We demonstrated that a low Hb level was associated with low bone mass among adolescents with NTD Hb E/beta-thalassemia. A significant proportion of low bone mass among these patients highlights the importance of appropriate management, including red cell transfusion, vitamin D and calcium supplementation for improved long-term bone health. PMID- 28801999 TI - Nanostructured materials as separation media. PMID- 28802000 TI - Pmepa1 induced by RANKL-p38 MAPK pathway has a novel role in osteoclastogenesis. AB - Osteoclasts are multinucleated cells formed by fusion of preosteoclasts (POCs) derived from cells of the monocyte/macrophage lineage. We have reported a culture system that supports the formation of POCs from stroma-depleted rat bone marrow cells. Global gene expression analysis of this culture system identified genes highly expressed in POCs. Here, we have analyzed the expression and function of one of these highly expressed genes, prostate transmembrane protein androgen induced 1 (Pmepa1), a target of TGF-beta and binds Nedd4 ubiquitin ligase, which plays a role in intracellular trafficking. We show here that the expression of Pmepa1 was strongly induced by RANKL in mouse bone marrow macrophage and in the osteoclast precursor cell line RAW-D. The expression of Pmepa1 was increased at 24 hr of culture, but was decreased at 72 hr. Pmepa1 protein was localized to intracellular vesicle membrnane of mononuclear cells, some of which were cathepsin-K positive. RANKL-induced expression of Pmepa1 was significantly reduced by inhibitors of p38 MAPK signaling. Pmepa1 siRNA suppressed the formation of osteoclasts in RAW-D cells, and inhibited the expression of cathepsin K and c-fos but not RANK. In addition, inhibition of Pmepa1 expression reduced the surface expression of RANK in RAW-D cells induced by RANKL. These results demonstrate that Pmepa1 is induced by RANK-p38 MAPK pathway signaling, and upregulates cell surface expression of RANK, suggesting that Pmepa1 plays a role in osteoclastogenesis and osteoclast signaling. PMID- 28801998 TI - Resistin-Like Molecule Beta (RELM-beta) Regulates Proliferation of Human Diabetic Nephropathy Mesangial Cells via Mitogen-Activated Protein Kinases (MAPK) Signaling Pathway. AB - BACKGROUND Resistin-like molecule beta (RELM-beta) has been reported to be associated with diabetic nephropathy (DN). However, the role of RELM-beta in DN is poorly understood. This study was conducted to delineate the underlying mechanisms of action and to investigate the role of RELM-beta in the primitive development of DN via MAPK signaling pathways. MATERIAL AND METHODS Lentivirus mediated vectors and RNAi technology were used to establish the model of RELM beta up-regulated and down-regulated expression in human mesangial cells (HMCs). The proliferation of HMCs was detected through CCK-8 method. The cell cycle and cell proliferation of HMCs was detected through flow cytometry. The MAPKs pathway protein activity was detected through Western blotting. RESULTS The HMCs with up regulated and down-regulated expression of RELM-beta increased or decreased significantly at 2-3 days. The HMCs with high glucose intervention reversed the proliferation inhibition. The HMCs with exogenous glucose or RELM-beta protein intervention partially reversed the cell cycle inhibition. Among the MAPKs pathway, the phosphorylation activity of p38MAPK and JNK increased or decreased and ERK1/2 did not change in the overexpression or inhibition of RELM-beta. The p38 MAPK pathway inhibitor SB202190 significantly inhibited the proliferation of HMCs caused by overexpression of RELM-beta. Up-regulated expression of RELM-b induced the phosphorylation of p38 MAPK, JNK in HMCs and promoted HMCs proliferation and participated in early DN through the MAPKs pathway. CONCLUSIONS The results provide evidence that RELM-b is a potential molecular target for the treatment of DN. PMID- 28802001 TI - A simple, time-saving, microwave-assisted periodic acid-Schiff's staining of glycoproteins on 1D electrophoretic gels. AB - We introduce an optimized periodic acid-Schiff's staining of glycoproteins on 1D electrophoretic gels. Thanks to heating in a household microwave oven the protocol of standard periodic acid-Schiff's staining has been accelerated from 6 h to below 10 min employing standard chemistry. At the same time, we show that the microwave-assisted glycoprotein staining is at least as sensitive as the conventional approach. All glycoproteins stained by the microwave-accelerated procedure were successfully identified using MALDI TOF/TOF mass spectrometry. The ensuing reduction in gel staining time and simplification of the staining protocol should significantly increase laboratory throughput when glycoprotein detection on electrophoretic gels is required in large numbers. PMID- 28802002 TI - Congenital neurocristic cutaneous hamartoma with poliosis: A case report. AB - Neurocristic cutaneous hamartomas (NCH) are rare, pigmented skin lesions derived from the abnormal migration of neural crest cells. We report the case of a 57 year-old female with a congenital localized area of poliosis and underlying pigmented patch on her scalp. Analysis of 2 punch biopsies yielded features consistent with NCH. Histopathology revealed schwannian-differentiated spindle cells and melanocytic components in the dermis. The spindle cells stained positively for S-100 and the stroma showed a prominent CD34 staining. The melanocytes were positive for melanoma triple stain (HMB-45, Melan A, Tyrosinase) and S-100. As the presentation of NCH and focal poliosis has yet to be described, we will present a literature review of NCH and discuss common features and associations of poliosis. PMID- 28802003 TI - Recombinant Lactococcus lactis for efficient conversion of cellodextrins into L lactic acid. AB - Lactic acid bacteria (LAB) are among the most interesting organisms for industrial processes with a long history of application as food starters and biocontrol agents, and an underexploited potential for biorefineries converting biomass into high-value compounds. Lactic acid (LA), their main fermentation product, is among the most requested chemicals owing to its broad range of applications. Notably, LA polymers, that is, polylactides, have high potential as biodegradable substitutes of fossil-derived plastics. However, LA production by LAB fermentation is currently too expensive for polylactide to be cost competitive with traditional plastics. LAB have complex nutritional requirements and cannot ferment inexpensive substrates such as cellulose. Metabolic engineering could help reduce such nutritional requirements and enable LAB to directly ferment low-cost polysaccharides. Here, we engineered a Lactococcus lactis strain which constitutively secretes a beta-glucosidase and an endoglucanase. The recombinant strain can grow on cellooligosaccharides up to at least cellooctaose and efficiently metabolizes them to L-LA in single-step fermentation. This is the first report of a LAB able to directly metabolize cellooligosaccharides longer that cellohexaose and a significant step toward cost sustainable consolidated bioprocessing of cellulose into optically pure LA. PMID- 28802005 TI - Reply from Michael J. Tipton, Joseph T. Costello and Julian F. R. Paton. PMID- 28802004 TI - Comparison of antimicrobial peptide purification via free-flow electrophoresis and gel filtration chromatography. AB - Antimicrobial peptides (AMPs) are usually small and cationic biomolecules with broad-spectrum antimicrobial activities against pathogens. Purifying them from complex samples is essential to study their physiochemical properties. In this work, free-flow zone electrophoresis (FFZE) was utilized to purify AMPs from yeast fermentation broth. Meanwhile, gel filtration chromatography (GFC) was conducted for comparison. The separation efficiency was evaluated by SDS-PAGE analysis of the fractions from both methods. Our results demonstrated as follows: (i) FFZE had more than 30-fold higher processing capacity as compared with GFC; (ii) FFZE could achieve 87% purity and 89% recovery rate while in GFC these parameters were about 93 and 82%, respectively; (iii) the former had ~2-fold dilution but the latter had ~13-fold dilution. Furthermore, Tricine-SDS-PAGE, Native-PAGE, and gel IEF were carried out to characterize the purified AMPs. We found that two peptides existed as a pair with the molecular mass of ~5.5 and 7.0 kDa, while the same pI 7.8. These two peptides were proved to have the antimicrobial activity through the standardized agar diffusion method. Therefore, FFZE could be used to continuously purify AMPs with high bioactivity, which will lead to its wide application in the clinical and pharmaceutical fields. PMID- 28802006 TI - The role of satellite cells in activity-induced adaptations: breathing new life into the debate. PMID- 28802007 TI - Characterization of intrinsic material properties of a model lipoproteic emulsion gel by oscillatory and creep compliance rheometry. AB - : The effects of varying formulation and processing parameters on rheological properties in a model lipid/protein-based emulsion gel were studied. Heat-set model lipoproteic emulsion gels were prepared with varying levels of protein, lipid, and NaCl contents and high pressure homogenization treatments. Small deformation oscillatory rheometry, creep compliance, and pore size analysis experiments were used to characterize intrinsic structural properties, matrix interactions, and microstructure. Creep compliance behavior of the gel system was successfully modeled by a four-component Burgers model. Shear storage and loss moduli and Newtonian viscosity increased while instantaneous compliance, retarded compliance, and pore size decreased with increasing protein or fat content or homogenization pressure. The data obtained in this study provide information on factors affecting protein network structure and strength, properties may be useful for creating desirable attributes in lipid/protein-based foods with a further optimization process. PRACTICAL APPLICATIONS: This research evaluates the effects of formulation and processing factors on the properties of a protein/fat based food system. These properties may be related to sodium mobility and salty taste perception. This research provides information on strategies that can be used to control factors influencing the physical properties of protein/fat-based food systems targeting sodium reduction. PMID- 28802009 TI - Duration of tracheostomy dependence and development of tracheocutaneous fistula in children. AB - OBJECTIVE: To determine whether the risk of developing a tracheocutaneous fistula (TCF) increases with longer tracheostomy dependence times in children. STUDY DESIGN: Retrospective review of medical records. METHOD: A retrospective chart review was conducted for all children who both underwent tracheotomy and were decannulated between 2002 and 2011 at a tertiary children's hospital. Charts were analyzed for duration of tracheostomy and evidence of TCF up to 12 months. Data for these criteria was available on 164 out of 182 patients. RESULTS: A significant difference in the duration of tracheostomy dependence between children with and without resultant TCF was determined by the Wilcoxon signed rank test (P = 0.0003). The relative risk (RR) of a persistent TCF was significantly increased when the duration of tracheostomy dependence was greater than 24 months (RR = 2.5217, P < 0.005) when compared to those decannulated before 12 months. The mean tracheostomy dependence times for children with and without TCF were 33.1 and 23.4 months, respectively. Overall, 94 children (57.3%) developed a TCF. CONCLUSION: To our knowledge, this study represents the largest collection of data for children who have been decannulated following tracheostomy placement. These data demonstrate that the risk of developing a TCF increases with longer tracheostomy dependence times in children. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2709-2712, 2017. PMID- 28802008 TI - Mechanism study of multimode ultrasound pretreatment on the enzymolysis of wheat gluten. AB - BACKGROUND: Ultrasound pretreatment could improve the angiotensin-I converting enzyme (ACE) inhibitory activity of hydrolysates of wheat gluten (WG). The working mode of ultrasound has an important effect on the enzymatic hydrolysis of protein. RESULTS: The results showed that the optimum working mode of ultrasound was alternate dual-frequency mode (20/35 kHz), substrate concentration was 30 g L 1 , initial temperature of the suspension was 30 degrees C, ultrasound pretreatment time was 10 min and power density was 150 W L-1 . Under optimised conditions, ACE inhibitory activity of WG hydrolysates reached to its maximum value in advance. The surface hydrophobicity (H0 ) of WG and the content of small peptides at the beginning of the enzymolysis were improved by the ultrasound pretreatment. The structure of WG was destroyed by the ultrasound pretreatment. The enzymatic residue of ultrasound pretreated WG were damaged greater than control. CONCLUSION: It was concluded that alternate dual-frequency ultrasound pretreatment improved the ACE inhibitory activity. Ultrasonic pretreatment may loosen the tissue of WG aggregate, and help the enzyme alcalase to attack the interior of WG aggregate easily, which resulted in the release of low molecular weight peptides from WG aggregate. (c) 2017 Society of Chemical Industry. PMID- 28802010 TI - Quality control in mass spectrometry-based proteomics. AB - Mass spectrometry is a highly complex analytical technique and mass spectrometry based proteomics experiments can be subject to a large variability, which forms an obstacle to obtaining accurate and reproducible results. Therefore, a comprehensive and systematic approach to quality control is an essential requirement to inspire confidence in the generated results. A typical mass spectrometry experiment consists of multiple different phases including the sample preparation, liquid chromatography, mass spectrometry, and bioinformatics stages. We review potential sources of variability that can impact the results of a mass spectrometry experiment occurring in all of these steps, and we discuss how to monitor and remedy the negative influences on the experimental results. Furthermore, we describe how specialized quality control samples of varying sample complexity can be incorporated into the experimental workflow and how they can be used to rigorously assess detailed aspects of the instrument performance. PMID- 28802011 TI - Evaluation of poly([2-(acryloyloxy)ethyl]trimethylammonium chloride) cationic polymer capillary coating for capillary electrophoresis and electrokinetic chromatography separations. AB - Capillary electrophoresis and electrokinetic chromatography are typically carried out in unmodified fused-silica capillaries under conditions that result in a strong negative zeta potential at the capillary wall and a robust cathodic electroosmotic flow. Modification of the capillary wall to reverse the zeta potential and mask silanol sites can improve separation performance by reducing or eliminating analyte adsorption, and is essential when conducting electrokinetic chromatography separations with cationic latex nanoparticle pseudo stationary phases. Semipermanent modification of the capillary walls by coating with cationic polymers has proven to be facile and effective. In this study, poly([2-(acryloyloxy)ethyl]trimethylammonium chloride) polymers were synthesized by reversible addition-fragmentation chain transfer polymerization and used as physically adsorbed semipermanent coatings for capillary electrophoresis and electrokinetic chromatography separations. An initial synthesis of poly([2 (acryloyloxy)ethyl]trimethylammonium chloride) polymer coating produced strong and stable anodic electroosmotic flow of -5.7 to -5.4 * 10-4 cm2 /V?s over the pH range of 4-7. Significant differences in the magnitude of the electroosmotic flow and effectiveness were observed between synthetic batches, however. For electrokinetic chromatography separations, the best performing batches of poly([2 (acryloyloxy)ethyl]trimethylammonium chloride) polymer performed as well as the commercially available cationic polymer polyethyleneimine, whereas polydiallylammonium chloride and hexadimethrine bromide did not perform well. PMID- 28802012 TI - The inhibitory effect of 5,7-DMF on pancreatic sphere-forming cell function mediated by FoxM1 gene expression. AB - Pancreatic cancer is one of the major human malignant tumors severely endangering human health and life with high mortality due to the concealment of early symptoms and lack of effective therapies during advanced stages. The identification of pancreatic cancer stem cell functions has been as important strategy for understanding of pancreatic cancer biology and novel drug and therapy development. In the present study, we successfully isolated the pancreatic sphere-forming cells from pancreatic cancer cell line PANC-1 by sphere forming method and we found that the sphere-forming ability and the cell migration rate of pancreatic sphere-forming cells were significantly inhibited by 5,7-DMF treatment, which was supported by the corresponding changes of several EMT biomarkers after being treated with 5,7-DMF. Moreover, we revealed here that the inhibition of pancreatic sphere-forming cells was mediated by the expression of FoxM1 gene, and also the expression of SOX2 gene was regulated by FoxM1 in pancreatic sphere-forming cells and involved in the inhibitory role of 5,7-DMF. These results provided important basis for the application of 5,7-DMF as a novel drug candidate for the pancreatic cancer treatment. PMID- 28802013 TI - Effects of levan-type fructan on growth performance, nutrient digestibility, diarrhoea scores, faecal shedding of total lactic acid bacteria and coliform bacteria, and faecal gas emission in weaning pigs. AB - BACKGROUND: The use of antibiotics as growth promoters in feed has been fully or partially banned in several countries. The objective of this study was to evaluate effects of levan-type fructan on growth performance, nutrient digestibility, faecal shedding of lactic acid bacteria and coliform bacteria, diarrhoea scores, and faecal gas emission in weaning pigs. A total of 144 weaning pigs [(Yorkshire * Landrace) * Duroc] were randomly allocated to four diets: corn soybean meal-based diets supplemented with 0, 0.1, 0.5, or 1.0 g kg-1 levan-type fructan during this 42-day experiment. RESULTS: During days 0 to 21 and 0 to 42, average daily gain and average daily feed intake were linearly increased (P < 0.01) with increasing dietary levan-type fructan inclusion. The apparent total tract digestibility of dry matter, crude protein, and gross energy were linearly increased (P < 0.001) with increasing dietary levan-type fructan content. With increasing levels of levan-type fructan, faecal lactic acid bacteria counts were linearly increased (P = 0.001). CONCLUSION: The results indicate that dietary supplementation with increasing levan-type fructan enhanced growth performance, improved nutrient digestibility, and increased faecal lactic acid bacteria counts in weaning pigs linearly. (c) 2017 Society of Chemical Industry. PMID- 28802014 TI - Flow-covariate prediction of stream pesticide concentrations. AB - Potential peak functions (e.g., maximum rolling averages over a given duration) of annual pesticide concentrations in the aquatic environment are important exposure parameters (or target quantities) for ecological risk assessments. These target quantities require accurate concentration estimates on nonsampled days in a monitoring program. We examined stream flow as a covariate via universal kriging to improve predictions of maximum m-day (m = 1, 7, 14, 30, 60) rolling averages and the 95th percentiles of atrazine concentration in streams where data were collected every 7 or 14 d. The universal kriging predictions were evaluated against the target quantities calculated directly from the daily (or near daily) measured atrazine concentration at 32 sites (89 site-yr) as part of the Atrazine Ecological Monitoring Program in the US corn belt region (2008-2013) and 4 sites (62 site-yr) in Ohio by the National Center for Water Quality Research (1993 2008). Because stream flow data are strongly skewed to the right, 3 transformations of the flow covariate were considered: log transformation, short term flow anomaly, and normalized Box-Cox transformation. The normalized Box-Cox transformation resulted in predictions of the target quantities that were comparable to those obtained from log-linear interpolation (i.e., linear interpolation on the log scale) for 7-d sampling. However, the predictions appeared to be negatively affected by variability in regression coefficient estimates across different sample realizations of the concentration time series. Therefore, revised models incorporating seasonal covariates and partially or fully constrained regression parameters were investigated, and they were found to provide much improved predictions in comparison with those from log-linear interpolation for all rolling average measures. Environ Toxicol Chem 2018;37:260 273. (c) 2017 SETAC. PMID- 28802016 TI - Involvement of sperm acetylated histones and the nuclear isoform of Glutathione peroxidase 4 in fertilization. AB - We previously demonstrated that the nuclear form of Glutathione peroxidase 4 (nGPx4) has a peculiar distribution in sperm head, being localized to nuclear matrix and acrosome and that sperm lacking nGPx4 are more prone to decondensation in vitro. In this study we have hypothesized that sperm retained acetylated histones and nGPx4 are implicated in paternal chromatin decondensation and male pronucleus formation at fertilization. Indeed, significant higher amounts of acetylated histone H4 and acetylated histone H3 were observed by both immunofluorescence and western blotting in nGPx4-KO sperm vs WT ones. In vitro fertilization of zona pellucida-deprived oocytes by WT sperm in the presence of trichostatin (TSA) also demonstrated that paternal histone acetylation was inversely related to the timing of sperm nucleus decondensation at fertilization. In contrast, TSA had no effect on nGPx4-KO sperm, indicating they had a maximal level of histone acetylation. Moreover the paternally imprinted gene Igf2/H19 was hypomethylated in KO sperm compared to WT ones. The lack of nGPx4 negatively affected male fertility, causing a marked decrease in total pups and pregnancies with delivery, a significant reduction in pronuclei (PN) embryos in in vitro fertilization assays and an approximately 2 h delay in egg fertilization in vivo. Because the zona pellucida binding and fusion to oolemma of nGPx4-KO and WT sperm were similar, the subfertility of nGPx4 sperm reflected a decreased sperm progression through egg cumulus/zona pellucida, pinpointing a defective acrosome in line with acrosomal nGPx4 localization. We conclude that paternal acetylated histones and acrosomal nGPx4 are directly involved in fertilization. PMID- 28802015 TI - Identification and characterization of metformin on peptidomic profiling in human visceral adipocytes. AB - To gain insight into the effect of metformin on losing weight from peptidomic perspective and to screen potential active peptides for reducing fat lipid deposition. After determining the proper concentration of metformin on human primary visceral adipocytes, we constructed a comparative peptidomic profiling between control and metformin treatment group (n = 3) using a stable isobaric labeling strategy involving tandem mass tag reagents, followed by liquid chromatography tandem mass spectrometry. We identified and quantified 3065 non redundant peptides, 304 of which were differentially expressed after metformin treatment, 206 peptides were up regulated and 98 peptides were down regulated significantly. Gene ontology (GO) enrichment and pathway analysis were performed to study differentially peptides though their precursor proteins. We concluded three peptides located within the functional domains of their precursor proteins could be candidate bioactive peptides for obesity. On one hand, these results confirmed the versatile effects of metformin on adipocyte and advance our current understanding of metformin, on the other hand, these identified peptides might play putative roles in treatment of obesity. PMID- 28802017 TI - Volatile composition and sensory profile of shiitake mushrooms as affected by drying method. AB - BACKGROUND: One of the best preservation method for long-term storage is drying. In this work, the influence of different drying methods on aroma and sensory profile of shiitake mushroom was evaluated. The drying methods tested were: convective drying (CD), freeze-drying (FD), vacuum-microwave drying (VMD), and a combination of convective pre-drying and vacuum-microwave finish-drying (CPD VMFD). RESULTS: The volatile composition of fresh and dried shiitake mushrooms was analysed by SPME, GC-MS and GC-FID, and showed the presence of 71 volatile compounds, most of them present in all dried samples but with quantitative variation. The major volatile compounds in fresh shiitake were 1-octen-3-ol (20.2%), 2-octanone (20.7%), 1,2,4-trithiolane (9.8%), and 1,2,3,5,6 pentathiepane (8.2%). Drying of shiitake mushrooms caused significant losses of C8 compounds and cyclic sulfur compounds, such as 1,2,4-trithiolane (V31) and 1,2,4,5-tetrathiane (V57). Samples dried at CD 80 degrees C implied a relative short drying time (120 min), had the highest contents of total volatiles (1594 MUg 100 g-1 ) and cyclic sulfur compounds (e.g. V57 126 MUg 100 g-1 ), and the highest intensity of most of the key positive sensory attributes, such as inner colour (7.0), fresh shiitake flavour (6.7), and sponginess (6.2). CONCLUSION: The best dehydration methods, resulting in the highest total concentrations of volatile compounds and high intensity of key sensory attributes were FD (if vacuum and liquid nitrogen facilities are available) and CD at 80 degrees C (for companies with vacuum and liquid nitrogen facilities). (c) 2017 Society of Chemical Industry. PMID- 28802018 TI - Characterization of two catalase-peroxidase-encoding genes in Fusarium verticillioides reveals differential responses to in vitro versus in planta oxidative challenges. AB - Catalase-peroxidases (KatGs) are a superfamily of reactive oxygen species (ROS) degrading enzymes believed to have been horizontally acquired by ancient Ascomycota from bacteria. Subsequent gene duplication resulted in two KatG paralogues in ascomycetes: the widely distributed intracellular KatG1 group and the phytopathogen-dominated extracellular KatG2 group. To functionally characterize FvCP01 (KatG1) and FvCP02 (KatG2) in the maize pathogen Fusarium verticillioides, single and double gene deletion mutants were examined in response to hydrogen peroxide (H2 O2 ). Both DeltaFvCP01 and DeltaFvCP02 were more sensitive to H2 O2 than the wild-type in vitro, although their sensitivity differed depending on the type of inoculum. Inoculations using mycelial agar plugs demonstrated an additive effect of the mutants, with the DeltaFvCP01/DeltaFvCP02 double deletion being the most sensitive to H2 O2 . In general, conidia were much more sensitive than agar plugs to H2 O2 , and conidial inoculations indicated that FvCP01 conferred more H2 O2 tolerance than FvCP02. Transcriptional analysis showed the induction of FvCP01, but decreased expression of FvCP02, in both mycelia and spores in the wild-type after H2 O2 exposure, but this trend was reversed when the fungus was grown on germinating maize seeds. This interaction with the plant increased the expression of FvCP02, but not FvCP01, indicating that FvCP02 may be responsive to plant-derived H2 O2 . Yet, FvCP01 was induced more than three-fold in the DeltaFvCP02 mutant grown on germlings, suggesting that FvCP01 can compensate for the loss of FvCP02. Given the differential responses of these two F. verticillioides genes to in vitro versus in planta challenges, a model is proposed to illustrate the differing roles of FvCP01 and FvCP02 in protective responses against H2 O2 -derived oxidative stress. PMID- 28802019 TI - Effects of ultrasound treatment on physico-chemical, functional properties and antioxidant activity of whey protein isolate in the presence of calcium lactate. AB - BACKGROUND: The aim of this study was to investigate the effects of ultrasound applied at various powers (0, 200, 400, 600 or 800 W) and for different times (20 or 40 min) on the physico-chemical, functional properties and antioxidant activities of whey protein isolate (WPI) dispersions in the presence of 1.20 mmol L-1 calcium lactate. RESULTS: Surface hydrophobicity and free sulfhydryl group of the WPI dispersions containing 1.2 mmol L-1 calcium lactate were significantly enhanced after sonication. Furthermore, particle size of WPI dispersions containing 1.20 mmol L-1 calcium lactate was minimised after sonication. Scanning electron microscopy of sonicated WPI suspensions containing 1.20 mmol L-1 calcium lactate showed that WPI microstructure had significantly changed. After WPI dispersions were treated by sonication assisted with calcium lactate, its gel strength enhanced and solubility decreased. Gel strength of sonicated WPI dispersions (600 W, 40 min) was the maximum among all the WPI treatments. Emulsification activity of sonicated WPI dispersions reduced while its emulsion stability increased. The DPPH radical scavenging activity and ferrous reducing power of sonicated WPI dispersions mostly increased. CONCLUSION: Ultrasound treatments induced structural changes in WPI molecules, leading to different microstructure and improved gel strength of WPI in the presence of calcium lactate. (c) 2017 Society of Chemical Industry. PMID- 28802020 TI - Investigation of the diversity of effector genes in the banana pathogen, Fusarium oxysporum f. sp. cubense, reveals evidence of horizontal gene transfer. AB - It is hypothesized that the virulence of phytopathogenic fungi is mediated through the secretion of small effector proteins that interfere with the defence responses of the host plant. In Fusarium oxysporum, one family of effectors, the Secreted In Xylem (SIX) genes, has been identified. We sought to characterize the diversity and evolution of the SIX genes in the banana-infecting lineages of F. oxysporum f. sp. cubense (Foc). Whole-genome sequencing data were generated for the 23 genetic lineages of Foc, which were subsequently queried for the 14 known SIX genes (SIX1-SIX14). The sequences of the identified SIX genes were confirmed in a larger collection of Foc isolates. Genealogies were generated for each of the SIX genes identified in Foc to further investigate the evolution of the SIX genes in Foc. Within Foc, variation of the SIX gene profile, including the presence of specific SIX homologues, correlated with the pathogenic race structure of Foc. Furthermore, the topologies of the SIX gene trees were discordant with the topology of an infraspecies phylogeny inferred from EF 1alpha/RPB1/RPB2 (translation elongation factor-1alpha/RNA polymerase II subunit I/RNA polymerase II subunit II). A series of topological constraint models provided strong evidence for the horizontal transmission of SIX genes in Foc. The horizontal inheritance of pathogenicity genes in Foc counters previous assumptions that convergent evolution has driven the polyphyletic phylogeny of Foc. This work has significant implications for the management of Foc, including the improvement of diagnostics and breeding programmes. PMID- 28802021 TI - Acute exposure to an environmentally relevant concentration of diclofenac elicits oxidative stress in the culturally important galaxiid fish Galaxias maculatus. AB - Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) of growing concern in aquatic environments worldwide; nevertheless, knowledge of its effects on aquatic biota is restricted to a few model species with limited information regarding its mechanisms of impact. In the present study, diclofenac accumulation, its effects on metabolic rate, ionoregulation, and oxidative stress were examined at environmentally relevant (0.17 ug L-1 ) and elevated (763 ug L-1 ) concentrations in a culturally and economically important galaxiid fish, inanga (Galaxias maculatus), from the Southern Hemisphere. This species is among the most widespread freshwater fish in the world but its sensitivity to emerging contaminants is unknown. Following an acute 96-h exposure, bioconcentration of diclofenac was measured in the inanga whole-body, resulting in an estimated bioconcentration factor of 87 for the 0.17-ug L-1 exposure concentration, approaching values where transfer through the food chain should be considered. Lipid peroxidation in the liver was significantly elevated at both 0.17- and 763 ug L-1 exposure concentrations but lipid peroxidation in the kidney and gill decreased after diclofenac exposure. Catalase activity was also elevated in the liver of inanga but activity decreased in the gill. There were no effects of diclofenac on metabolic rate or ion (sodium and calcium) influx rates. These data indicate that toxicologically relevant adverse outcomes and bioconcentration of diclofenac at environmentally relevant levels warrant additional study in this important fish. Environ Toxicol Chem 2018;37:224-235. (c) 2017 SETAC. PMID- 28802022 TI - MicroRNA-492 overexpression involves in cell proliferation, migration, and radiotherapy response of cervical squamous cell carcinomas. AB - MicroRNAs (miRNAs) are small non-coding RNA that target protein-coding mRNAs at the post-transcriptional level. The aim of this study was to define the role of miR-492 in cervical squamous cell carcinomas. After microRNA profiling and comparison, we firstly detected miR-492 expression in 104 tumor tissues biopsies derived from advanced staged (FIGO IIB-IIIB) cervical squamous cell carcinoma patients before receiving concomitant chemoradiotherapy and found miR-492 expression was significantly higher in the specimens that were sensitive to concomitant chemoradiotherapy, as compared with insensitive cancer specimens (P < 0.05). Moreover, higher expression of miR-492 was associated with pelvic lymph node metastasis (LNM) (P < 0.05). Further studies illustrated ectopic miR-492 overexpression in SiHa cells promoted cell proliferation, migration, and enhanced the sensitivity of cervical cancer cells to irradiation by promoting apoptosis. In addition, we identified TIMP2 as a direct miR-492 target, which has been shown to be critical in modulating cancer cell migration and invasion. We also confirmed that miR-492 expression levels in positive pelvic LNM were much higher than negative LNM and miR-492 played a vital role in pelvic lymph node metastasis via regulating miR-492/TIMP2/MMP10 axis. In particular, miR-492 was correlated with prognosis in the subgroup of patients with negative pelvic LNM (P < 0.05) and had a promising value in predicting treatment response in the subgroup of patients with positive pelvic LNM (an AUC of 85%, 75.00% specificity, and 95.24% sensitivity). Taken together, the results suggested that miR-492 may serve as a potential biomarker for cervical cancer treatment and prognosis. PMID- 28802023 TI - The Agrobacterium VirE2 effector interacts with multiple members of the Arabidopsis VIP1 protein family. AB - T-DNA transfer from Agrobacterium to its host plant genome relies on multiple interactions between plant proteins and bacterial effectors. One such plant protein is the Arabidopsis VirE2 interacting protein (AtVIP1), a transcription factor that binds Agrobacterium tumefaciens C58 VirE2, potentially acting as an adaptor between VirE2 and several other host factors. It remains unknown, however, whether the same VirE2 protein has evolved to interact with multiple VIP1 homologues in the same host, and whether VirE2 homologues encoded by different bacterial strains/species recognize AtVIP1 or its homologues. Here, we addressed these questions by systematic analysis (using the yeast two-hybrid and co-immunoprecipitation approaches) of interactions between VirE2 proteins encoded by four major representatives of known bacterial species/strains with functional T-DNA transfer machineries and eight VIP1 homologues from Arabidopsis and tobacco. We also analysed the determinants of the VirE2 sequence involved in these interactions. These experiments showed that the VirE2 interaction is degenerate: the same VirE2 protein has evolved to interact with multiple VIP1 homologues in the same host, and different and mutually independent VirE2 domains are involved in interactions with different VIP1 homologues. Furthermore, the VIP1 functionality related to the interaction with VirE2 is independent of its function as a transcriptional regulator. These observations suggest that the ability of VirE2 to interact with VIP1 homologues is deeply ingrained into the process of Agrobacterium infection. Indeed, mutations that abolished VirE2 interaction with AtVIP1 produced no statistically significant effects on interactions with VIP1 homologues or on the efficiency of genetic transformation. PMID- 28802024 TI - The cereal pathogen Fusarium pseudograminearum produces a new class of active cytokinins during infection. AB - The fungal pathogen Fusarium pseudograminearum causes important diseases of wheat and barley. During a survey of secondary metabolites produced by this fungus, a novel class of cytokinins, herein termed Fusarium cytokinins, was discovered. Cytokinins are known for their growth-promoting and anti-senescence activities, and the production of a cytokinin mimic by what was once considered as a necrotrophic pathogen that promotes cell death and senescence challenges the simple view that this pathogen invades its hosts by employing a barrage of lytic enzymes and toxins. Through genome mining, a gene cluster in the F. pseudograminearum genome for the production of Fusarium cytokinins was identified and the biosynthetic pathway was established using gene knockouts. The Fusarium cytokinins could activate plant cytokinin signalling, demonstrating their genuine hormone mimicry. In planta analysis of the transcriptional response to one Fusarium cytokinin suggests extensive reprogramming of the host environment by these molecules, possibly through crosstalk with defence hormone signalling pathways. PMID- 28802025 TI - Simple and rapid determination of zaltoprofen in human plasma by manual-shaking assisted dispersive liquid-liquid microextraction followed by liquid chromatography with ultraviolet detection. AB - A readily applicable method was developed to determine the concentration level of zaltoprofen, a non-steroidal antiinflammatory drug from the propionic acid family, in human plasma. This method is based on manual-shaking-assisted dispersive liquid-liquid microextraction coupled with liquid chromatography with ultraviolet detection. Factors affecting the extraction efficiency were screened and optimized by experimental design using fractional factorial and central composite designs, respectively. Optimal conditions were: 220 MUL of C2 H4 Cl2 (extraction solvent), 5 mL of 3.75% w/v NaCl aqueous solution at pH 2.0, and manual shaking for 13 s (65 times). The resulting extraction method yielded a reasonable enrichment factor of 18.0 (+/-0.6, n = 3) and extraction recovery of 86.0% (+/-3.3%, n = 3). The established method was validated for selectivity, linearity, precision, accuracy, matrix effect, recovery, dilution integrity, and stability, and it met the acceptable criteria for all of the tested parameters. Specifically, the method was linear in the range of 0.16-50.0 mg/L, precise (< 8.8% RSD), accurate (-7.5-5.6% deviation), and showed negligible matrix effects (96.1-106.4%) with high absolute recovery (94.5-97.7%). Compared with previous methods involving labor-intensive liquid-liquid extraction or non-specific protein precipitation, our method allows the simple, rapid, and efficient determination of zaltoprofen using the most affordable analytical instrument, liquid chromatography with ultraviolet detection. PMID- 28802026 TI - Reversible immune abnormality and regulatory T cells in offspring of Der p 1 exposed female mice. AB - BACKGROUND: Maternal allergic diseases have an important influence on the origin of allergic rhinitis (AR) in offspring, but the mechanism and the duration of the maternal effect are unknown. Previous researches prompted the important roles of Tregs and Foxp3 DNA methylation in the development of allergic diseases. OBJECTIVE: To investigate the immune state and Tregs in the offspring of Der p 1 exposed female mice. METHOD: BALB/c female mice were exposed to Der p1 to construct the mouse AR model, then mated with normal male mice. Offspring were kept in an allergen-free environment after birth. At postnatal weeks 3, 5 and 8, mice were culled for testing. RESULT: Compared with the offspring of PBS-exposed female mice (N-N), the offspring of Der p 1-exposed female mice (A-N) showed increased IL-4 and decreased IL-10 levels in serum at postnatal weeks 3 and 5. Correspondingly, the percentage of Tregs in spleen CD4+ cells declined significantly at postnatal week 5 in A-N. Further analysis of the methylation status of spleen lymphocytes revealed hypermethylation of the Foxp3 promoter in A N mice at postnatal weeks 3 and 5. However, by 8 weeks of age, all abnormalities in cytokines, Treg counts and Foxp3 DNA methylation in A-N mice had returned to normal levels. CONCLUSION: Under the influence of maternal AR, offspring have an abnormal immune state at birth. However, without exposure to allergens, the immune state in AR offspring recovered by maturity. Changes in Tregs and Foxp3 DNA methylation may be the mechanism for this reversible immune abnormality in AR offspring. PMID- 28802027 TI - Performance Evaluation of the Bioneer AccuPower(r) HIV-1 Quantitative RT-PCR kit: Comparison with the Roche COBAS(r) AmpliPrep/COBAS TaqMan(r) HIV-1 Test Ver.2.0 for Quantification of HIV-1 Viral Load in Indonesia. AB - BACKGROUND: Measurement of viral load in human immunodeficiency virus type 1 (HIV 1) infected patients is essential for the establishment of a therapeutic strategy. Several assays based on qPCR are available for the measurement of viral load; they differ in sample volume, technology applied, target gene, sensitivity and dynamic range. The Bioneer AccuPower(r) HIV-1 Quantitative RT-PCR is a novel commercial kit that has not been evaluated for its performance. OBJECTIVE: This study aimed to evaluate the performance of the Bioneer AccuPower(r) HIV-1 Quantitative RT-PCR kit. METHODS: In total, 288 EDTA plasma samples from the Dharmais Cancer Hospital were analyzed with the Bioneer AccuPower(r) HIV-1 Quantitative RT-PCR kit and the Roche COBAS(r) AmpliPrep/COBAS(r) TaqMan(r) HIV-1 version 2.0 (CAP/CTM v2.0). The performance of the Bioneer assay was then evaluated against the Roche CAP/CTM v2.0. RESULTS: Overall, there was good agreement between the two assays. The Bioneer assay showed significant linear correlation with CAP/CTM v2.0 (R2=0.963, p<0.001) for all samples (N=118) which were quantified by both assays, with high agreement (94.9%, 112/118) according to the Bland-Altman model. The mean difference between the quantitative values measured by Bioneer assay and CAP/CTM v2.0 was 0.11 Log10 IU/mL (SD=0.26). CONCLUSION: Based on these results, the Bioneer assay can be used to quantify HIV 1 RNA in clinical laboratories. PMID- 28802028 TI - H5N1 NS genomic segment distinctly governs the influenza virus infectivity and cytokine induction in monocytic cells. AB - BACKGROUND: The level of virulence of H5N1 highly pathogenic avian influenza (HPAI) virus was higher than those of the other virus subtypes. It has been suggested that the nonstructural (NS) gene might be a factor contributing to H5N1 HPAI virulence. OBJECTIVES: To determine the efficiency of the NS genomic segment of H5N1 HPAI virus on governing viral infectivity and cytokine induction in monocytic cells compared to other virus strain/subtypes. METHODS: By reverse genetics, five reassortant influenza viruses carrying the NS genomic segment derived from seasonal influenza A(H1N1), 2009 pandemic A(H1N1), A(H3N2) or H5N1 HPAI virus in the backbone of A/Puerto Rico/8/34 H1N1 (PR8) virus were constructed together with the reassorted PR8 virus control, i.e., rgH1N1sea-NS, rgH1N1pdm-NS, rgH3N2-NS, rgH5N1-NS and rgPR8 viruses, respectively. These reverse genetics-derived viruses (rg-viruses) were used to infect monocytic cells for 24 hours prior to determining intracellular influenza nucleoprotein (NP) levels and cytokine induction by flow cytometry. RESULTS: U937 cells were significantly more susceptible to rgPR8 control virus than THP-1 cells; thus, U937 cells were chosen for further study. The number of U937-infected cells (NP+ cells) and the numbers of infected cells that expressed IFN-alpha (NP+IFN-alpha+ cell) obtained with rgH5N1-NS virus infection were significantly higher than the others, except for cells infected with the rgH1N1pdm-NS virus. Nevertheless, the numbers of U937 cells that expressed NP+IL-1beta+ were comparable upon infection with any of the rg-viruses; almost none expressed TNF-alpha. CONCLUSIONS: The H5N1 NS genomic segment distinctly up-regulated the viral infectivity and induction of IFN-alpha compared to the rgPR8, rgH1N1sea-NS and rgH3N2-NS viruses. PMID- 28802029 TI - Immediate hypersensitivity reaction to Ketamine in children with history of atopic disease. AB - Many investigators have demonstrated that a large number of patients who experience anaphylaxis during anesthesia have a history of atopic disease or allergy to a specific substance. Here, we review a hypersensitivity reaction to ketamine in a nine-year-old child with a history of atopic disease. PMID- 28802030 TI - Solenopsis geminata (tropical fire ant) anaphylaxis among Thai patients: its allergens and specific IgE-reactivity. AB - BACKGROUND: Specific IgE against Solenopsis invicta (imported fire ant) remains the current diagnostic tool for allergy to ants worldwide. However, S. invicta may not be the only cause of ant anaphylaxis in Thai patients. OBJECTIVE: To characterize ant species causing anaphylaxis in Thai patients and to test allergenic reactivity to whole body extracts (WBE) of S. geminata (tropical fire ants) in patients with evidence of IgE-mediated ant anaphylaxis. METHODS: Thirty two patients with ant anaphylaxis were identified. The causative ants collected by the patients were subjected to species identification. Twelve patients with ant anaphylaxis and showed positive skin test or serum specific IgE to S. invicta and 14 control subjects were recruited. Whole body extraction from S. geminata was performed for protein characterization using SDS-PAGE and protein staining. IgE-immunoblotting and ELISA-specific IgE binding assays were performed on patients' sera and compared with controls. RESULTS: Of 32 patients with ant anaphylaxis, the most common causative ant identified was S. geminata (37.5%). Western blot analysis of crude S. geminata revealed 13 refined protein components that bound to patients' serum IgE. Three major allergens with molecular masses of 26, 55 and 75 kDa were identified. All 12 patients gave positive results for specific IgE to S. geminata with statistically significant higher absorbance units of 0.390 +/- 0.044, compared to healthy control group (0.121 +/- 0.010), P < 0.01. CONCLUSIONS: S. geminata is identified as the most common causative ant anaphylaxis in Thai patients. Its WBE comprises of 13 IgE-binding components and 3 major allergens (26, 55 and 75 kDa), which supported possible IgE-mediated mechanism. PMID- 28802031 TI - Quality of life among caregivers and growth in children with parent-reported food allergy. AB - BACKGROUND: Some caregivers who believe their children have food allergy avoid feeding certain foods to their children without proper allergy tests. Such actions made without a proper diagnosis can negatively impact the child's health and impose an unnecessary burden on the caregivers. OBJECTIVE: This study aimed to evaluate the caregiver quality of life (QoL) and growth in children with a parent-reported food allergy. METHODS: An observational cross-sectional study was performed in 200 children younger than five years who had a parent-reported food allergy. The caregivers' QoL was evaluated by two questionnaires: the Food Allergy Quality of Life -Parental Burden and the Scale of Psychosocial Factors in Food Allergy. Growth of the children was evaluated by their weight-for-age and length/height-for-age percentiles. RESULTS: Among the caregivers, 50% expressed worry that their children might be allergic to some foods and 30% were concerned about leaving their children in the care of others. According to the QoL scores, caregivers whose children underwent an oral food challenge (OFC) test were significantly less stressed, while caregivers whose children had multiple food allergies and had experienced at least one anaphylactic reaction were significantly more stressed. The distributions of both weight-for-age and length/height-for-age percentiles were 50th comparable to the general population. CONCLUSIONS: Parent-reported food allergy could put caregivers under high stress, but the OFC test could reduce stress among anxious, over-parenting caregivers. Parent-reported food allergy had no impact on a child's growth in our study. PMID- 28802032 TI - Deciphering critical amino acid residues to modify and enhance the binding affinity of ankyrin scaffold specific to capsid protein of human immunodeficiency virus type 1. AB - BACKGROUND: AnkGAG1D4 is an artificial ankyrin repeat protein which recognizes the capsid protein (CA) of the human immunodeficiency virus type 1 (HIV-1) and exhibits the intracellular antiviral activity on the viral assembly process. Improving the binding affinity of AnkGAG1D4 would potentially enhance the AnkGAG1D4-mediated antiviral activity. OBJECTIVE: To augment the affinity of AnkGAG1D4 scaffold towards its CA target, through computational predictions and experimental designs. METHOD: Three dimensional structure of the binary complex formed by AnkGAG1D4 docked to the CA was used as a model for van der Waals (vdW) binding energy calculation. The results generated a simple guideline to select the amino acids for modifications. Following the predictions, modified AnkGAG1D4 proteins were produced and further evaluated for their CA-binding activity, using ELISA-modified method and bio-layer interferometry (BLI). RESULTS: Tyrosine at position 56 (Y56) in AnkGAG1D4 was experimentally identified as the most critical residue for CA binding. Rational substitutions of this residue diminished the binding affinity. However, vdW calculation preconized to substitute serine for tyrosine at position 45. Remarkably, the affinity for the viral CA was significantly enhanced in AnkGAG1D4-S45Y mutant, with no alteration of the target specificity. CONCLUSIONS: The S-to-Y mutation at position 45, based on the prediction of interacting amino acids and on vdW binding energy calculation, resulted in a significant enhancement of the affinity of AnkGAG1D4 ankyrin for its CA target. AnkGAG1D4-S45Y mutant represented the starting point for further construction of variants with even higher affinity towards the viral CA, and higher therapeutic potential in the future. PMID- 28802033 TI - Formidable Defenses In Utero. AB - A developing human embryo encounters a multitude of threatening scenarios in the womb. How does the fetus defend itself throughout gestation? A new study by McGovern et al. provides remarkable insight into maternal-fetal immunotolerance. PMID- 28802034 TI - Keeping the Rhythm while Changing the Lyrics: Circadian Biology in Aging. AB - Aging and circadian rhythms have been linked for decades, but their molecular interplay has remained obscure. Sato et al. and Solanas et al. now reveal that, while core clock components remain nearly unaltered, aging is associated with tissue-specific rewiring, which can be prevented by calorie restriction. PMID- 28802035 TI - The MutAnts Are Here. AB - The development of CRISPR/Cas9-mediated gene knockout in two ant species opens a new window into exploring how social insects use olfactory cues to organize their collective behavior. PMID- 28802036 TI - Transcription-Replication Conflicts: Orientation Matters. AB - Interference between DNA replication and transcription represents a major source of genomic instability. In this issue of Cell, Lang et al. and Hamperl et al. show that head-on collisions, but not codirectional collisions, impede fork progression in bacteria and in human cells by promoting the formation of RNA-DNA hybrids known as R-loops. PMID- 28802038 TI - TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease. AB - Elevated risk of developing Alzheimer's disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering, and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2 deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth-factor limitation or endoplasmic reticulum (ER) stress. Combined metabolomics and RNA sequencing (RNA-seq) linked this anomalous autophagy to defective mammalian target of rapamycin (mTOR) signaling, which affects ATP levels and biosynthetic pathways. Metabolic derailment and autophagy were offset in vitro through Dectin-1, a receptor that elicits TREM2-like intracellular signals, and cyclocreatine, a creatine analog that can supply ATP. Dietary cyclocreatine tempered autophagy, restored microglial clustering around plaques, and decreased plaque-adjacent neuronal dystrophy in TREM2-deficient mice with amyloid-beta pathology. Thus, TREM2 enables microglial responses during AD by sustaining cellular energetic and biosynthetic metabolism. PMID- 28802039 TI - Circadian Reprogramming in the Liver Identifies Metabolic Pathways of Aging. AB - The process of aging and circadian rhythms are intimately intertwined, but how peripheral clocks involved in metabolic homeostasis contribute to aging remains unknown. Importantly, caloric restriction (CR) extends lifespan in several organisms and rewires circadian metabolism. Using young versus old mice, fed ad libitum or under CR, we reveal reprogramming of the circadian transcriptome in the liver. These age-dependent changes occur in a highly tissue-specific manner, as demonstrated by comparing circadian gene expression in the liver versus epidermal and skeletal muscle stem cells. Moreover, de novo oscillating genes under CR show an enrichment in SIRT1 targets in the liver. This is accompanied by distinct circadian hepatic signatures in NAD+-related metabolites and cyclic global protein acetylation. Strikingly, this oscillation in acetylation is absent in old mice while CR robustly rescues global protein acetylation. Our findings indicate that the clock operates at the crossroad between protein acetylation, liver metabolism, and aging. PMID- 28802040 TI - Aged Stem Cells Reprogram Their Daily Rhythmic Functions to Adapt to Stress. AB - Normal homeostatic functions of adult stem cells have rhythmic daily oscillations that are believed to become arrhythmic during aging. Unexpectedly, we find that aged mice remain behaviorally circadian and that their epidermal and muscle stem cells retain a robustly rhythmic core circadian machinery. However, the oscillating transcriptome is extensively reprogrammed in aged stem cells, switching from genes involved in homeostasis to those involved in tissue-specific stresses, such as DNA damage or inefficient autophagy. Importantly, deletion of circadian clock components did not reproduce the hallmarks of this reprogramming, underscoring that rewiring, rather than arrhythmia, is associated with physiological aging. While age-associated rewiring of the oscillatory diurnal transcriptome is not recapitulated by a high-fat diet in young adult mice, it is significantly prevented by long-term caloric restriction in aged mice. Thus, stem cells rewire their diurnal timed functions to adapt to metabolic cues and to tissue-specific age-related traits. PMID- 28802041 TI - Cryo-EM Structure of the TOM Core Complex from Neurospora crassa. AB - The TOM complex is the main entry gate for protein precursors from the cytosol into mitochondria. We have determined the structure of the TOM core complex by cryoelectron microscopy (cryo-EM). The complex is a 148 kDa symmetrical dimer of ten membrane protein subunits that create a shallow funnel on the cytoplasmic membrane surface. In the core of the dimer, the beta-barrels of the Tom40 pore form two identical preprotein conduits. Each Tom40 pore is surrounded by the transmembrane segments of the alpha-helical subunits Tom5, Tom6, and Tom7. Tom22, the central preprotein receptor, connects the two Tom40 pores at the dimer interface. Our structure offers detailed insights into the molecular architecture of the mitochondrial preprotein import machinery. PMID- 28802042 TI - orco Mutagenesis Causes Loss of Antennal Lobe Glomeruli and Impaired Social Behavior in Ants. AB - Life inside ant colonies is orchestrated with diverse pheromones, but it is not clear how ants perceive these social signals. It has been proposed that pheromone perception in ants evolved via expansions in the numbers of odorant receptors (ORs) and antennal lobe glomeruli. Here, we generate the first mutant lines in the clonal raider ant, Ooceraea biroi, by disrupting orco, a gene required for the function of all ORs. We find that orco mutants exhibit severe deficiencies in social behavior and fitness, suggesting they are unable to perceive pheromones. Surprisingly, unlike in Drosophila melanogaster, orco mutant ants also lack most of the ~500 antennal lobe glomeruli found in wild-type ants. These results illustrate that ORs are essential for ant social organization and raise the possibility that, similar to mammals, receptor function is required for the development and/or maintenance of the highly complex olfactory processing areas in the ant brain. VIDEO ABSTRACT. PMID- 28802037 TI - The PI3K Pathway in Human Disease. AB - Phosphoinositide 3-kinase (PI3K) activity is stimulated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is considered a hallmark of cancer. Many PI3K pathway-targeted therapies have been tested in oncology trials, resulting in regulatory approval of one isoform-selective inhibitor (idelalisib) for treatment of certain blood cancers and a variety of other agents at different stages of development. In parallel to PI3K research by cancer biologists, investigations in other fields have uncovered exciting and often unpredicted roles for PI3K catalytic and regulatory subunits in normal cell function and in disease. Many of these functions impinge upon oncology by influencing the efficacy and toxicity of PI3K-targeted therapies. Here we provide a perspective on the roles of class I PI3Ks in the regulation of cellular metabolism and in immune system functions, two topics closely intertwined with cancer biology. We also discuss recent progress developing PI3K-targeted therapies for treatment of cancer and other diseases. PMID- 28802043 TI - An Engineered orco Mutation Produces Aberrant Social Behavior and Defective Neural Development in Ants. AB - Ants exhibit cooperative behaviors and advanced forms of sociality that depend on pheromone-mediated communication. Odorant receptor neurons (ORNs) express specific odorant receptors (ORs) encoded by a dramatically expanded gene family in ants. In most eusocial insects, only the queen can transmit genetic information, restricting genetic studies. In contrast, workers in Harpegnathos saltator ants can be converted into gamergates (pseudoqueens) that can found entire colonies. This feature facilitated CRISPR-Cas9 generation of germline mutations in orco, the gene that encodes the obligate co-receptor of all ORs. orco mutations should significantly impact olfaction. We demonstrate striking functions of Orco in odorant perception, reproductive physiology, and social behavior plasticity. Surprisingly, unlike in other insects, loss of OR functionality also dramatically impairs development of the antennal lobe to which ORNs project. Therefore, the development of genetics in Harpegnathos establishes this ant species as a model organism to study the complexity of eusociality. PMID- 28802044 TI - The Neuropeptide Corazonin Controls Social Behavior and Caste Identity in Ants. AB - Social insects are emerging models to study how gene regulation affects behavior because their colonies comprise individuals with the same genomes but greatly different behavioral repertoires. To investigate the molecular mechanisms that activate distinct behaviors in different castes, we exploit a natural behavioral plasticity in Harpegnathos saltator, where adult workers can transition to a reproductive, queen-like state called gamergate. Analysis of brain transcriptomes during the transition reveals that corazonin, a neuropeptide homologous to the vertebrate gonadotropin-releasing hormone, is downregulated as workers become gamergates. Corazonin is also preferentially expressed in workers and/or foragers from other social insect species. Injection of corazonin in transitioning Harpegnathos individuals suppresses expression of vitellogenin in the brain and stimulates worker-like hunting behaviors, while inhibiting gamergate behaviors, such as dueling and egg deposition. We propose that corazonin is a central regulator of caste identity and behavior in social insects. PMID- 28802045 TI - Transcription-Replication Conflict Orientation Modulates R-Loop Levels and Activates Distinct DNA Damage Responses. AB - Conflicts between transcription and replication are a potent source of DNA damage. Co-transcriptional R-loops could aggravate such conflicts by creating an additional barrier to replication fork progression. Here, we use a defined episomal system to investigate how conflict orientation and R-loop formation influence genome stability in human cells. R-loops, but not normal transcription complexes, induce DNA breaks and orientation-specific DNA damage responses during conflicts with replication forks. Unexpectedly, the replisome acts as an orientation-dependent regulator of R-loop levels, reducing R-loops in the co directional (CD) orientation but promoting their formation in the head-on (HO) orientation. Replication stress and deregulated origin firing increase the number of HO collisions leading to genome-destabilizing R-loops. Our findings connect DNA replication to R-loop homeostasis and suggest a mechanistic basis for genome instability resulting from deregulated DNA replication, observed in cancer and other disease states. PMID- 28802048 TI - Biology Gone Wild. PMID- 28802047 TI - Dual ifgMosaic: A Versatile Method for Multispectral and Combinatorial Mosaic Gene-Function Analysis. AB - Improved methods for manipulating and analyzing gene function have provided a better understanding of how genes work during organ development and disease. Inducible functional genetic mosaics can be extraordinarily useful in the study of biological systems; however, this experimental approach is still rarely used in vertebrates. This is mainly due to technical difficulties in the assembly of large DNA constructs carrying multiple genes and regulatory elements and their targeting to the genome. In addition, mosaic phenotypic analysis, unlike classical single gene-function analysis, requires clear labeling and detection of multiple cell clones in the same tissue. Here, we describe several methods for the rapid generation of transgenic or gene-targeted mice and embryonic stem (ES) cell lines containing all the necessary elements for inducible, fluorescent, and functional genetic mosaic (ifgMosaic) analysis. This technology enables the interrogation of multiple and combinatorial gene function with high temporal and cellular resolution. PMID- 28802049 TI - SnapShot: Cellular Senescence Pathways. AB - Cellular senescence is a fundamental cell fate, playing important physiological and pathophysiological roles. This SnapShot focuses on major signaling pathways and transcriptional control mechanisms that consolidate the senescence phenotype. PMID- 28802046 TI - Replication-Transcription Conflicts Generate R-Loops that Orchestrate Bacterial Stress Survival and Pathogenesis. AB - Replication-transcription collisions shape genomes, influence evolution, and promote genetic diseases. Although unclear why, head-on transcription (lagging strand genes) is especially disruptive to replication and promotes genomic instability. Here, we find that head-on collisions promote R-loop formation in Bacillus subtilis. We show that pervasive R-loop formation at head-on collision regions completely blocks replication, elevates mutagenesis, and inhibits gene expression. Accordingly, the activity of the R-loop processing enzyme RNase HIII at collision regions is crucial for stress survival in B. subtilis, as many stress response genes are head-on to replication. Remarkably, without RNase HIII, the ability of the intracellular pathogen Listeria monocytogenes to infect and replicate in hosts is weakened significantly, most likely because many virulence genes are head-on to replication. We conclude that the detrimental effects of head-on collisions stem primarily from excessive R-loop formation and that the resolution of these structures is critical for bacterial stress survival and pathogenesis. PMID- 28802050 TI - Distinct DC subsets regulate adaptive Th1 and 2 responses during Trichuris muris infection. AB - Low- and high-dose infections with the murine large intestinal nematode Trichuris muris are associated with induction of adaptive Th1 and Th2 responses, respectively, in mesenteric lymph nodes (MLN). Classical dendritic cells (cDC) accumulate in the large intestinal mucosa and MLN upon T. muris infection, yet their role in driving adaptive responses to infection remains largely unknown. We performed low- and high-dose T. muris infections of mice deficient in defined cDC subsets to investigate their role in induction of adaptive immune responses. Mice lacking IRF4-dependent cDC failed to clear a high-dose infection and displayed impaired Th2 responses. Conversely, mice lacking IRF8-dependent cDC cleared a low dose infection and displayed an impaired Th1 response while increased production of Th2 cytokines. Finally, mice lacking both IRF4- and IRF8-dependent cDC were able to generate a Th2 response and clear a low-dose infection. Collectively, these results suggest that IRF4- and IRF8-dependent cDC act antagonistically during T. muris infection, and demonstrate that intestinal Th2 responses can be generated towards T. muris in the absence of IRF4-dependent cDC. PMID- 28802051 TI - Extraneural ganglion cyst as a rare cause for footdrop. PMID- 28802052 TI - Tax policy and tax protest in 20 rich democracies, 1980-2010. AB - Why are some policies protested more than others? New data on protest against eight categories of taxation in twenty rich democracies from 1980 to 2010 reveal that economically and socially concentrated taxes are protested most, whereas taxes that confer entitlement to benefits are protested least. Other features of policy design often thought to affect the salience or visibility of costs are unimportant for explaining the frequency of protest. These findings overturn a folk theory that political sociology has inherited from classical political economy; clarify the conditions under which policy threats provoke protest; and shed light on how welfare states persist. PMID- 28802053 TI - Gene-panel testing of breast and ovarian cancer patients identifies a recurrent RAD51C duplication. AB - Gene-panel sequencing allows comprehensive analysis of multiple genes simultaneously and is now routinely used in clinical mutation testing of high risk breast and ovarian cancer patients. However, only BRCA1 and BRCA2 are often analyzed also for large genomic changes. Here, we have analyzed 10 clinically relevant susceptibility genes in 95 breast or ovarian cancer patients with gene panel sequencing including also copy number variants (CNV) analysis for genomic changes. We identified 12 different pathogenic BRCA1, BRCA2, TP53, PTEN, CHEK2, or RAD51C mutations in 18 of 95 patients (19%). BRCA1/2 mutations were observed in 8 patients (8.4%) and CHEK2 protein-truncating mutations in 7 patients (7.4%). In addition, we identified a novel duplication encompassing most of the RAD51C gene. We further genotyped the duplication in breast or ovarian cancer families (n = 1149), in unselected breast (n = 1729) and ovarian cancer cohorts (n = 553), and in population controls (n = 1273). Seven additional duplication carries were observed among cases but none among controls. The duplication associated with ovarian cancer risk (3/590 of all ovarian cancer patients, 0.5%, P = .032 compared with controls) and was found to represent a large fraction of all identified RAD51C mutations in the Finnish population. Our data emphasizes the importance of comprehensive mutation analysis including CNV detection in all the relevant genes. PMID- 28802054 TI - A dyadic typology of social desires in couples. AB - OBJECTIVE: Employing a couple-centered approach to social motivation in intimate relationships, we developed a dyadic typology based on the ABC model of communal and agentic social desires. METHOD: Using latent profile analysis, 631 heterosexual couples (age women: M = 39.7, SD = 13.6; age men: M = 42.0, SD = 14.1) were categorized regarding both partners' self-reported desires for closeness with partner, for affiliation with friends, and for being alone. Couple types were described using self-reported indicators of relationship functioning. Relationship stability was assessed after 1 year, and in stable couples, social desires were reassessed to examine continuity and change. RESULTS: We identified four motivational couple types. Three profiles showed similar orientations between partners and were labeled the communion, closeness, and distance couple types. Additionally, the distanced-man type was characterized by a low desire for closeness and a high desire for being alone in men, but not women. The communion and closeness types showed better relationship functioning than the other types, and the distanced-man type showed an increased rate of relationship break-up. CONCLUSIONS: A couple-centered, typological approach provides a viable way of studying complex dyadic motivational constellations and their consequences. This is beneficial for researchers as well as practitioners. PMID- 28802055 TI - Effect of storage temperatures and stresses on the survival of Salmonella spp. in halva. AB - : The presence of Salmonella spp. in halva has been associated with foodborne illnesses and product recalls from the markets. This study investigated the effect of environmental stresses on the survival of Salmonella spp. in halva during storage for 12 months at 10 and 25 degrees C (log (N0 /N) g-1 ). Halva samples were inoculated with a cocktail of four strains of unstressed, desiccation stressed or heat stressed Salmonella (106 -107 CFU per gram). In general, survival of Salmonella spp. in halva decreased significantly (P ? 0.05) as storage time and temperature increased. At the end of halva shelf life at 10 degrees C, the initial populations of unstressed, desiccation stressed or heat stressed Salmonella spp. decreased by 2.7, 2.6 or 2.8 log CFU per gram (reduction rate c. 0.2 log CFU per month), respectively. While at 25 degrees C, the populations decreased 5.2, 6.7 or 6.3 log CFU per gram, respectively (reduction rate c. 0.4-0.5 log CFU per month). The populations of stressed Salmonella spp. in halva samples were not significantly different (P >= 0.05) from populations of unstressed cells during storage at 10 and 25 degrees C, except during the last 3 months of storage at 25 degrees C when populations of unstressed cells were higher (P < 0.05). Exposing Salmonella spp. to desiccation or heat stress prior product contamination may play a role in Salmonella spp. survival in halva during storage. SIGNIFICANCE AND IMPACT OF THE STUDY: Contamination of halva (tahini halva) with Salmonella from raw materials or during production was documented. Halva and tahini have been involved in salmonellosis outbreaks in different countries. The study demonstrated enhanced survivability of stressed and unstressed Salmonella spp. in halva over a 12-month storage period at 10 and 25 degrees C with lower log reductions than expected. Exposing Salmonella spp. to desiccation or heat stress prior product contamination may play a role in microbial survival in halva during storage. These findings serve as a model to halva producers to implement control measures to prevent Salmonella spp. contamination in halva. PMID- 28802056 TI - Different nerve ultrasound patterns in charcot-marie-tooth types and hereditary neuropathy with liability to pressure palsies. AB - INTRODUCTION: Nerve ultrasound in Charcot-Marie-Tooth (CMT) disease has focused mostly on the upper limbs. We performed an evaluation of a large cohort of CMT patients in which we sonographically characterized nerve abnormalities in different disease types, ages, and nerves. METHODS: Seventy patients affected by different CMT types and hereditary neuropathy with liability to pressure palsies (HNPP) were evaluated, assessing median, ulnar, fibular, tibial, and sural nerves bilaterally. Data were correlated with age. RESULTS: Nerve dimensions were correlated with CMT type, age, and nerve site. Nerves were larger in demyelinating than in axonal neuropathies. Nerve involvement was symmetric. DISCUSSION: CMT1 patients had larger nerves than did patients with other CMT types. Patients with HNPP showed enlargement at entrapment sites. Our study confirms the general symmetry of ultrasound nerve patterns in CMT. When compared with ultrasound studies of nerves of the upper limbs, evaluation of the lower limbs did not provide additional information. Muscle Nerve 57: E18-E23, 2018. PMID- 28802057 TI - High-mobility group box 1 released by autophagic cancer-associated fibroblasts maintains the stemness of luminal breast cancer cells. AB - Cancer stem cells/cancer-initiating cells (CICs) and their microenvironmental niche play a vital role in malignant tumour recurrence and metastasis. Cancer associated fibroblasts (CAFs) are major components of the niche of breast cancer initiating cells (BCICs), and their interactions may profoundly affect breast cancer progression. Autophagy has been considered to be a critical process for CIC maintenance, but whether it is involved in the cross-talk between CAFs and CICs to affect tumourigenesis and pathological significance has not been determined. In this study, we found that the presence of CAFs containing high levels of microtubule-associated protein 1 light chain 3 (LC3II), a marker of autophagosomes, was associated with more aggressive luminal human breast cancer. CAFs in human luminal breast cancer tissues with high autophagy activity enriched BCICs with increased tumourigenicity. Mechanistically, autophagic CAFs released high-mobility group box 1 (HMGB1), which activated its receptor, Toll-like receptor (TLR) 4, expressed by luminal breast cancer cells, to enhance their stemness and tumourigenicity. Furthermore, immunohistochemistry of 180 luminal breast cancers revealed that high LC3II/TLR4 levels predicted an increased relapse rate and a poorer prognosis. Our findings demonstrate that autophagic CAFs play a critical role in promoting the progression of luminal breast cancer through an HMGB1-TLR4 axis, and that both autophagy in CAFs and TLR4 on breast cancer cells constitute potential therapeutic targets. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28802058 TI - Postantibiotic effect and postantibiotic sub-MIC effect of LTX-109 and mupirocin on Staphylococcus aureus blood isolates. AB - : The development of new synthetic antimicrobial peptides like LTX-109 provides a new class of drugs for the treatment of Staphylococcus aureus infections. We evaluated LTX-109 and mupirocin for pharmacodynamic parameters against 10 methicillin-resistant S. aureus isolates. The postantibiotic effect (PAE) is defined as the length of time that bacterial growth is suppressed following a brief exposure to an antibiotic. We also determined the sub-MIC effect (SME) which measures the direct effect of subinhibitory levels on strains that have not previously been exposed to antibiotics. The postantibiotic sub-MIC effect (PA SME) is a combination of the PAE and SME. LTX-109 had an average PAE of 5.51 h vs 1.04 h for mupirocin. The PA-SME of LTX-109 ranged from 2.51 to 9.33 h as the concentration increased from 0.2 to 0.4 times the minimal inhibitory concentration (MIC). The PA-SME range for mupirocin was 0.93-2.58 h. LTX-109, as compared to mupirocin, demonstrated prolonged time of effect for these pharmacodynamic parameters, which supports persistent activity for several hours after the drug is no longer present or is below the MIC. The pharmacodynamic parameters studied here suggest that LTX-109 is less likely than mupirocin to generate resistance to S. aureus. SIGNIFICANCE AND IMPACT OF THE STUDY: Resistant bacterial infections continue to be a challenge for clinicians. Identification of antibiotics with pharmacodynamic advantages may be beneficial in the treatment of these infections. An antibiotic with a longer postantibiotic effect may be able to be administered less frequently resulting in improved adherence. In this study, a new synthetic antimicrobial peptide, LTX-109, demonstrated a more prolonged time for LTX-109 than mupirocin against methicillin-resistant Staphylococcus aureus. PMID- 28802059 TI - Overlap of acute mydriasis and acute pharyngeal weakness associated with anti GQ1b antibodies. PMID- 28802061 TI - Eulogy John Ludbrook: Surgeon, physiologist and biostatistician. PMID- 28802060 TI - Taurine up-regulated gene 1 functions as a master regulator to coordinate glycolysis and metastasis in hepatocellular carcinoma. AB - : Cancer cells display altered glucose metabolism characterized by a preference for aerobic glycolysis. The aerobic glycolytic phenotype of hepatocellular carcinoma (HCC) is often correlated with tumor progression and poorer clinical outcomes. However, the issue of whether glycolytic metabolism influences metastasis in HCC remains unclear. In the current study, we showed that knockdown of taurine up-regulated gene 1 (TUG1) induces marked inhibition of cell migration, invasion, and glycolysis through suppression of microRNA (miR)-455-3p. MiR-455-3p, which is transcriptionally repressed by p21, directly targets the 3' untranslated region of adenosine monophosphate-activated protein kinase subunit beta 2 (AMPKbeta2). The TUG1/miR-455-3p/AMPKbeta2 axis regulates cell growth, metastasis, and glycolysis through regulation of hexokinase 2 (HK2). TUG1 is clearly associated with HK2 overexpression and unfavorable prognosis in HCC patients. CONCLUSION: Our data collectively highlight that novel regulatory associations among TUG1, miR-455-3p, AMPKbeta2, and HK2 are an important determinant of glycolytic metabolism and metastasis in HCC cells and support the potential utility of targeting TUG1/HK2 as a therapeutic strategy for HCC. (Hepatology 2018;67:188-203). PMID- 28802062 TI - Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. AB - : Nonalcoholic fatty liver disease (NAFLD) and resulting nonalcoholic steatohepatitis (NASH) are highly prevalent in the United States, where they are a growing cause of cirrhosis and hepatocellular carcinoma (HCC) and increasingly an indicator for liver transplantation. A Markov model was used to forecast NAFLD disease progression. Incidence of NAFLD was based on historical and projected changes in adult prevalence of obesity and type 2 diabetes mellitus (DM). Assumptions were derived from published literature where available and validated using national surveillance data for incidence of NAFLD-related HCC. Projected changes in NAFLD-related cirrhosis, advanced liver disease, and liver-related mortality were quantified through 2030. Prevalent NAFLD cases are forecasted to increase 21%, from 83.1 million (2015) to 100.9 million (2030), while prevalent NASH cases will increase 63% from 16.52 million to 27.00 million cases. Overall NAFLD prevalence among the adult population (aged >=15 years) is projected at 33.5% in 2030, and the median age of the NAFLD population will increase from 50 to 55 years during 2015-2030. In 2015, approximately 20% of NAFLD cases were classified as NASH, increasing to 27% by 2030, a reflection of both disease progression and an aging population. Incidence of decompensated cirrhosis will increase 168% to 105,430 cases by 2030, while incidence of HCC will increase by 137% to 12,240 cases. Liver deaths will increase 178% to an estimated 78,300 deaths in 2030. During 2015-2030, there are projected to be nearly 800,000 excess liver deaths. CONCLUSION: With continued high rates of adult obesity and DM along with an aging population, NAFLD-related liver disease and mortality will increase in the United States. Strategies to slow the growth of NAFLD cases and therapeutic options are necessary to mitigate disease burden. (Hepatology 2018;67:123-133). PMID- 28802063 TI - Hepatitis B Virus Pregenomic RNA in Hepatocellular Carcinoma: A Nosological and Prognostic Determinant. AB - : Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). However, very little is known about the replication of HBV in HCC tissues. We analyzed viral and cellular parameters in HCC (T) and nontumor liver (NT) samples from 99 hepatitis B surface antigen (HBsAg)-positive, virologically suppressed patients treated by tumor resection or liver transplantation. We examined total HBV DNA and RNA as well as covalently closed circular DNA (cccDNA) and pregenomic RNA (pgRNA), which are considered as markers of active HBV replication. Total HBV DNA and RNA were detected in both T and NT samples in a majority of cases, but only a subset of tumors harbored detectable levels of HBV cccDNA and pgRNA (39% and 67%) compared to NT livers (66% and 90%; P < 0.01). Further evidence for HBV replication in tumor tissues was provided by sequencing of the X gene derived from episomal forms, showing that HBV genotypes differed between T and matched NT samples in 11 cases. The detection of pgRNA and cccDNA in tumors was correlated to the absence of tumorous microvascular invasion and to better patient survival. Analysis of gene expression profiles by Agilent microarrays revealed that pgRNA positive HCCs were characterized by low levels of cell cycle and DNA repair markers and expression of the HBV receptor, sodium taurocholate cotransporting polypeptide, indicating well-differentiated tumors. CONCLUSION: HCC replicating HBV represents a subtype of weakly invasive HCC with a transcriptomic signature. pgRNA originating from nonintegrated, complete HBV genomes is a sensitive marker for viral replication and prognosis. (Hepatology 2018;67:86-96). PMID- 28802064 TI - Neurokinin 3 receptor antagonism decreases gonadotropin and testosterone secretion in healthy men. AB - OBJECTIVE: Patients with mutations of neurokinin B (NKB) and its receptor show hypogonadotrophic hypogonadism, but there is little evidence for the importance of this pathway in reproductive function in normal men, or its functional hierarchy with kisspeptin. DESIGN: An open label study wherein men (n = 6) were administered the NK3R antagonist MLE4901 40 mg orally twice a day for 7 days. Kisspeptin-10 (0.3 MUg/kg iv bolus) was given before and on day 7 of NK3R antagonist treatment. PATIENTS: Subjects were healthy men. MEASUREMENTS: Reproductive hormones were measured before and during the NK3R antagonist administration, including frequent sampling on two occasions for analysis of pulsatile LH secretion. RESULTS: LH, FSH and testosterone secretion were decreased during NK3R antagonist administration. LH showed a biphasic response, being reduced after 24 hours of treatment (4.5 +/- 0.6 IU/L pretreatment to 1.7 +/- 0.2 IU/L, P < .05), with partial recovery thereafter, but it was again decreased on day 7 (2.5 +/- 0.6 IU/L, P < .05 vs pretreatment). FSH secretion was also suppressed, with a similar temporal pattern to that of LH. Testosterone secretion was decreased from 24 hours (18.4 +/- 1.6 pretreatment vs 5.6 +/- 1.5 nmol/L, P < .01) and remained suppressed throughout the treatment period. Analysis of LH pulsatility showed that both basal and pulsatile LH secretion were markedly suppressed but there was no detected change in LH pulse frequency. Kisspeptin-10 stimulated LH secretion, with similar responses before and during NK3R antagonist administration. CONCLUSIONS: These data demonstrate a central role for NKB/NK3R in the physiological regulation of reproductive function in men, and that this is functionally upstream of kisspeptin-mediated GnRH secretion. PMID- 28802065 TI - Quercetin reverses experimental cirrhosis by immunomodulation of the proinflammatory and profibrotic processes. AB - The ability of quercetin to reverse an established cirrhosis has not yet been investigated. Therefore, the aim of this study was to examine the efficacy of this flavonoid in reversing experimental cirrhosis. Cirrhosis was induced by intraperitoneal administration of TAA (200 mg/kg of body weight) three times per week for 8 weeks or by intraperitoneal petrolatum-CCl4 (400 mg/kg of body weight) administration three times per week for 8 weeks. To determine the capacity of quercetin to prevent liver fibrosis, the flavonoid (50 mg/kg of body weight, p.o.) was administered daily to rats during the CCl4 or TAA treatment. To evaluate the ability of quercetin to reverse the previously induced cirrhosis, we first treated rats with CCl4 for 8 weeks, as previously described and then the flavonoid was administered for four more weeks. We found that the liver anti inflammatory and antinecrotic effects of quercetin are associated with its antioxidant properties, to the ability of the flavonoid to block NF-kappaB activation and in consequence to reduce cytokine IL-1. The ability of quercetin to reverse fibrosis may be associated with the capacity of the flavonoid to decrease TGF-beta levels, hepatic stellate cell activation, and to promote degradation of the ECM by increasing metalloproteinases. The main conclusion is that quercetin, in addition to its liver protective activity against TAA chronic intoxication, is also capable of reversing a well-stablished cirrhosis by blocking the prooxidant processes and by downregulating the inflammatory and profibrotic responses. PMID- 28802067 TI - Corticotrophin-releasing hormone stimulation tests for the infants with relative adrenal insufficiency. AB - BACKGROUND: Very low birthweight (VLBW) infants are considered to be vulnerable to relative adrenal insufficiency (RAI); however, diagnosis is difficult in some clinical settings. Considering this background, it is necessary to establish a diagnosis of RAI in preterm infants. OBJECTIVE: In this study, we attempted to clarify the difference in response to CRH stimulation tests for preterm infants with or without RAI. METHODS: Between June 2009 and December 2015, we performed CRH stimulation tests for preterm infants born at a gestational age of <30 weeks at around 2 weeks of age. Retrospectively, subjects were classified into two groups: infants with RAI (n = 9) or without RAI (n = 17) based on the clinical symptoms and responsiveness to hydrocortisone. RESULTS: We found no difference in base or peak serum cortisol levels related to CRH stimulation tests between the two groups; however, delta cortisol levels and responsive ratio (peak-to-base ratio) were significantly reduced in infants with RAI. 140 nmol/L for delta cortisol or 1.5 times for peak-to-base ratio may be cut-off levels in preterm infants. CONCLUSION: This study provides evidence that base cortisol levels of preterm infants with RAI were not different from those without RAI; however, CRH stimulation tests may be a useful tool for the diagnosis of RAI in preterm infants. PMID- 28802066 TI - Targeting senescent cholangiocytes and activated fibroblasts with B-cell lymphoma extra large inhibitors ameliorates fibrosis in multidrug resistance 2 gene knockout (Mdr2-/- ) mice. AB - : Cholangiocyte senescence has been linked to primary sclerosing cholangitis (PSC). Persistent secretion of growth factors by senescent cholangiocytes leads to the activation of stromal fibroblasts (ASFs), which are drivers of fibrosis. The activated phenotype of ASFs is characterized by an increased sensitivity to apoptotic stimuli. Here, we examined the mechanisms of apoptotic priming in ASFs and explored a combined targeting strategy to deplete senescent cholangiocytes and ASFs from fibrotic tissue to ameliorate liver fibrosis. Using a coculture system, we determined that senescent cholangiocytes promoted quiescent mesenchymal cell activation in a platelet-derived growth factor (PDGF)-dependent manner. We also identified B-cell lymphoma-extra large (Bcl-xL) as a key survival factor in PDGF-activated human and mouse fibroblasts. Bcl-xL was also up regulated in senescent cholangiocytes. In vitro, inhibition of Bcl-xL by the small molecule Bcl-2 homology domain 3 mimetic, A-1331852, or Bcl-xL-specific small interfering RNA induced apoptosis in PDGF-activated fibroblasts, but not in quiescent fibroblasts. Likewise, inhibition of Bcl-xL reduced the survival and increased apoptosis of senescent cholangiocytes, compared to nonsenescent cells. Treatment of multidrug resistance 2 gene knockout (Mdr2-/- ) mice with A-1331852 resulted in an 80% decrease in senescent cholangiocytes, a reduction of fibrosis inducing growth factors and cytokines, decrease of alpha-smooth muscle actin positive ASFs, and finally in a significant reduction of liver fibrosis. CONCLUSION: Bcl-xL is a key survival factor in ASFs as well as in senescent cholangiocytes. Treatment with the Bcl-xL-specific inhibitor, A-1331852, reduces liver fibrosis, possibly by a dual effect on activated fibroblasts and senescent cholangiocytes. This mechanism represents an attractive therapeutic strategy in biliary fibrosis. (Hepatology 2018;67:247-259). PMID- 28802068 TI - Dietary citrate and plasma ionized calcium: Implications for platelet donors. AB - BACKGROUND: Platelet donors receive 40 mmol or more of IV citrate anion during donation. When plasma ionized calcium ([Ca2+ ]) falls by ~20%, half of the donors report symptoms of hypocalcemic toxicity. Citrus juices contain clinically relevant amounts of citrate anion. We asked whether citrus juice can lower [Ca2+ ] thus potentially contributing to hypocalcemic toxicity. METHOD: Six volunteers were given 20.4 mmol of citrate anion as grapefruit juice or orange juice. Capillary blood obtained by fingerstick was analyzed for [Ca2+ ] using an iSTAT point-of-care blood analyzer. [Ca2+ ] was measured at baseline and then 30, 60, 120, and 180 minutes after drinking juice. Subjects were tested with the alternative juice on a subsequent day. The outcome measure was the percent change in plasma [Ca2+ ] from baseline. RESULTS: [Ca2+ ] fell -2.2% to -11.5% in four of six subjects 30 minutes after drinking grapefruit juice. The effect persisted up to 3 hours. [Ca2+ ] fell -2.1% to -12.2% in four of six subjects 30-60 minutes after drinking orange juice. The effect abated after 2 hours. We could not correlate gender or body surface area to these findings. SUMMARY AND CONCLUSIONS: Citrus juice may lower [Ca2+ ] for 2-3 hours. This could add to the effect of IV citrate infusion during platelet donation, thus worsening the expected fall in [Ca2+ ]. This, in turn, would likely increase the rate and severity of hypocalcemic toxicity. It is prudent to advise platelet donors to avoid high citrate anion beverages, such as citrus juice, for at least 4 hours prior to donation. PMID- 28802069 TI - Reply. PMID- 28802070 TI - Memantine for the treatment of general neuropathic pain: a narrative review. AB - Neuropathic pain (NP) is difficult to treat and is associated with a decline in quality of life. NP aetiologies are numerous and a number of pathologies display neuropathic characteristics. Of the various N-methyl-d-aspartate antagonists that are alternatives to be recommended in first-line NP treatment, memantine has the safest side-effect profile and has long been approved in Alzheimer's disease. The review covers memantine studies in postherpetic neuralgia, diabetic pain, postoperative pain, complex regional pain syndrome, chronic phantom limb pain, opioid-refractory pain and fibromyalgia. Results were inconclusive because of studies with poor levels of evidence, paucity of trials and small samples. Two recent randomized trials, however, showed significant efficacy of memantine: one demonstrated prophylactic effects against postoperative neuralgia and pain associated psychological impairment; in the other, memantine improved pain and cognition in fibromyalgia. Both studies found no side effects or adverse events. Given the high rate of therapeutic failure in chronic states, often because of adverse events, the excellent benefit/risk ratio of memantine in these pilot studies encourages further exploration of this drug in NP prevention and in fibromyalgia in larger-scale studies. PMID- 28802071 TI - MicroRNA-137 and microRNA-195* inhibit vasculogenesis in brain arteriovenous malformations. AB - OBJECTIVE: Brain arteriovenous malformations (AVMs) are the most common cause of nontraumatic intracerebral hemorrhage in young adults. The genesis of brain AVM remains enigmatic. We investigated microRNA (miRNA) expression and its contribution to the pathogenesis of brain AVMs. METHODS: We used a large-scale miRNA analysis of 16 samples including AVMs, hemangioblastoma, and controls to identify a distinct AVM miRNA signature. AVM smooth muscle cells (AVMSMCs) were isolated and identified by flow cytometry and immunohistochemistry, and candidate miRNAs were then tested in these cells. Migration, tube formation, and CCK-8 induced proliferation assays were used to test the effect of the miRNAs on phenotypic properties of AVMSMCs. A quantitative proteomics approach was used to identify protein expression changes in AVMSMCs treated with miRNA mimics. RESULTS: A distinct AVM miRNA signature comprising a large portion of lowly expressed miRNAs was identified. Among these miRNAs, miR-137 and miR-195* levels were significantly decreased in AVMs and constituent AVMSMCs. Experimentally elevating the level of these microRNAs inhibited AVMSMC migration, tube formation, and survival in vitro and the formation of vascular rings in vivo. Proteomics showed the protein expression signature of AVMSMCs and identified downstream proteins regulated by miR-137 and miR-195* that were key signaling proteins involved in vessel development. INTERPRETATION: Our results indicate that miR-137 and miR-195* act as vasculogenic suppressors in AVMs by altering phenotypic properties of AVMSMCs, and that the absence of miR-137 and miR-195* expression leads to abnormal vasculogenesis. Ann Neurol 2017;82:371-384. PMID- 28802072 TI - Fifty Years of (Benz)oxaphospholene Chemistry. AB - The first synthesis of benzoxaphospholenes dates back to the 1960s. Since then, the structural variety of reported (benz)oxaphospholenes has steadily increased. Organophosphorus compounds have caught the interest of synthetic chemists for a couple of decades now because of their interesting biological properties. Oxaphospholenes, in particular, could serve as carbohydrate mimetics, and benzoxaphospholenes have been reported to possess bactericidal, insecticidal, herbicidal, and fungistatical properties. Transesterification reactions and addition of phosphorus nucleophiles to carbonyl compounds were reaction types that led to the production of the first (benz)oxaphospholenes. When it was discovered that allenylphosphonates could easily be obtained from propargyl alcohols and dialkyl halophosphites, the electrophile-induced cyclization reaction of these allenylphosphonate precursors resulted in a huge boom in the amount of reports on oxaphospholene synthesis. To this day, this method is still frequently used. Ring-closing metathesis and Horner-Wadsworth-Emmons reactions have also proven their potential for the preparation of oxaphospholenes. In recent years, Pd, Rh and Au-catalysis have made their entry, generating (benz)oxaphospholenes from a wide variety of simple substrates. A couple of miscellaneous methods are summarized at the end of the Review. PMID- 28802073 TI - Species delimitation with gene flow: A methodological comparison and population genomics approach to elucidate cryptic species boundaries in Malaysian Torrent Frogs. AB - Accurately delimiting species boundaries is a nontrivial undertaking that can have significant effects on downstream inferences. We compared the efficacy of commonly used species delimitation methods (SDMs) and a population genomics approach based on genomewide single-nucleotide polymorphisms (SNPs) to assess lineage separation in the Malaysian Torrent Frog Complex currently recognized as a single species (Amolops larutensis). First, we used morphological, mitochondrial DNA and genomewide SNPs to identify putative species boundaries by implementing noncoalescent and coalescent-based SDMs (mPTP, iBPP, BFD*). We then tested the validity of putative boundaries by estimating spatiotemporal gene flow (fastsimcoal2, ABBA-BABA) to assess the extent of genetic isolation among putative species. Our results show that the A. larutensis complex runs the gamut of the speciation continuum from highly divergent, genetically isolated lineages (mean Fst = 0.9) to differentiating populations involving recent gene flow (mean Fst = 0.05; Nm > 5). As expected, SDMs were effective at delimiting divergent lineages in the absence of gene flow but overestimated species in the presence of marked population structure and gene flow. However, using a population genomics approach and the concept of species as separately evolving metapopulation lineages as the only necessary property of a species, we were able to objectively elucidate cryptic species boundaries in the presence of past and present gene flow. This study does not discount the utility of SDMs but highlights the danger of violating model assumptions and the importance of carefully considering methods that appropriately fit the diversification history of a particular system. PMID- 28802075 TI - Overcoming severe adverse reactions to venom immunotherapy using anti-IgE antibodies in combination with a high maintenance dose. AB - BACKGROUND: An omalizumab treatment and a high maintenance venom dose may both help to prevent recurrent systemic allergic reactions (SAR) to venom immunotherapy (VIT). The effectiveness of this combination therapy, however, is unclear. OBJECTIVE: We wanted to explore the possibility whether a temporary treatment with the anti-IgE antibody omalizumab combined with a VIT using an elevated maintenance dose of >100 MUg venom may establish a permanent tolerance of maintenance VIT. METHODS: For this retrospective case series, we scoured our institutional data base for patients who had had an insect venom allergy, and in whom it had not been possible to continue VIT because of repeated unstoppable SAR during maintenance VIT. Patients were divided into those who had received the combination therapy (omalizumab group) and those who had not received omalizumab because its costs could not be covered (controls). Guided by the total IgE level and by body weight, omalizumab had been given subcutaneously 5, 3 and 1 weeks before VIT had been restarted. Three to 6 months after an elevated maintenance dose (200-300 MUg venom) had been reached, omalizumab had been stopped. RESULTS: Between 2006 and 2011, 15 patients had qualified for an off-label use of omalizumab: 10 patients had received the combination therapy, and 5 patients had remained without such a therapy. The combination therapy leads to a durable tolerance of VIT in all patients even after omalizumab had been discontinued (median of follow-up time 5.8 years, IQR 2.7-8.6 years). Sting challenge tests were tolerated by all of the re-stung omalizumab patients (n = 8). In all controls, VIT had to be stopped permanently due to repeated SARs (P < .001 vs omalizumab group). CONCLUSIONS AND CLINICAL RELEVANCE: Combining a temporary omalizumab therapy with an elevated maintenance dose seems a promising approach to achieve a tolerance of treatment in patients with a recurrent SAR to VIT. PMID- 28802074 TI - Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance. AB - : Plasma concentrations of amino acids (AAs), in particular, branched chain AAs (BCAAs), are often found increased in nonalcoholic fatty liver disease (NAFLD); however, if this is due to increased muscular protein catabolism, obesity, and/or increased insulin resistance (IR) or impaired tissue metabolism is unknown. Thus, we evaluated a) if subjects with NAFLD without obesity (NAFLD-NO) compared to those with obesity (NAFLD-Ob) display altered plasma AAs compared to controls (CTs); and b) if AA concentrations are associated with IR and liver histology. Glutamic acid, serine, and glycine concentrations are known to be altered in NAFLD. Because these AAs are involved in glutathione synthesis, we hypothesized they might be related to the severity of NAFLD. We therefore measured the AA profile of 44 subjects with NAFLD without diabetes and who had a liver biopsy (29 NAFLD-NO and 15 NAFLD-Ob) and 20 CTs without obesity, by gas chromatography-mass spectrometry, homeostasis model assessment of insulin resistance, hepatic IR (Hep IR; Hep-IR = endogenous glucose production * insulin), and the new glutamate serine-glycine (GSG) index (glutamate/[serine + glycine]) and tested for an association with liver histology. Most AAs were increased only in NAFLD-Ob subjects. Only alanine, glutamate, isoleucine, and valine, but not leucine, were increased in NAFLD-NO subjects compared to CTs. Glutamate, tyrosine, and the GSG index were correlated with Hep-IR. The GSG-index correlated with liver enzymes, in particular, gamma-glutamyltransferase (R = 0.70), independent of body mass index. Ballooning and/or inflammation at liver biopsy were associated with increased plasma BCAAs and aromatic AAs and were mildly associated with the GSG index, while only the new GSG-index was able to discriminate fibrosis F3-4 from F0-2 in this cohort. CONCLUSION: Increased plasma AA concentrations were observed mainly in subjects with obesity and NAFLD, likely as a consequence of increased IR and protein catabolism. The GSG-index is a possible marker of severity of liver disease independent of body mass index. (Hepatology 2018;67:145-158). PMID- 28802076 TI - Single-cell sequencing unveils the lifestyle and CRISPR-based population history of Hydrotalea sp. in acid mine drainage. AB - Acid mine drainage (AMD) is characterized by an acid and metal-rich run-off that originates from mining systems. Despite having been studied for many decades, much remains unknown about the microbial community dynamics in AMD sites, especially during their early development, when the acidity is moderate. Here, we describe draft genome assemblies from single cells retrieved from an early-stage AMD sample. These cells belong to the genus Hydrotalea and are closely related to Hydrotalea flava. The phylogeny and average nucleotide identity analysis suggest that all single amplified genomes (SAGs) form two clades that may represent different strains. These cells have the genomic potential for denitrification, copper and other metal resistance. Two coexisting CRISPR-Cas loci were recovered across SAGs, and we observed heterogeneity in the population with regard to the spacer sequences, together with the loss of trailer-end spacers. Our results suggest that the genomes of Hydrotalea sp. strains studied here are adjusting to a quickly changing selective pressure at the microhabitat scale, and an important form of this selective pressure is infection by foreign DNA. PMID- 28802078 TI - Geographical features are the predominant driver of molecular diversification in widely distributed North American whipsnakes. AB - Allopatric divergence following the formation of geographical features has been implicated as a major driver of evolutionary diversification. Widespread species complexes provide opportunities to examine allopatric divergence across varying degrees of isolation in both time and space. In North America, several geographical features may play such a role in diversification, including the Mississippi River, Pecos River, Rocky Mountains, Cochise Filter Barrier, Gulf of California and Isthmus of Tehuantepec. We used thousands of nuclear single nucleotide polymorphisms (SNPs) and mitochondrial DNA from several species of whipsnakes (genera Masticophis and Coluber) distributed across North and Central America to investigate the role that these geographical features have played on lineage divergence. We hypothesize that these features restrict gene flow and separate whipsnakes into diagnosable genomic clusters. We performed genomic clustering and phylogenetic reconstructions at the species and population levels using Bayesian and likelihood analyses and quantified migration levels across geographical features to assess the degree of genetic isolation due to allopatry. Our analyses suggest that (i) major genetic divisions are often consistent with isolation by geographical features, (ii) migration rates between clusters are asymmetrical across major geographical features, and (iii) areas that receive proportionally more migrants possess higher levels of genetic diversity. Collectively, our findings suggest that multiple features of the North American landscape contributed to allopatric divergence in this widely distributed snake group. PMID- 28802077 TI - Helicobacter pylori and its secreted immunomodulator VacA protect against anaphylaxis in experimental models of food allergy. AB - BACKGROUND: Food allergy is an increasingly common health problem in Western populations. Epidemiological studies have suggested both positive and negative associations between food allergy and infection with the gastric bacterium Helicobacter pylori. OBJECTIVE: The objective of this work was to investigate whether experimental infection with H. pylori, or prophylactic treatment with H. pylori-derived immunomodulatory molecules, affects the onset and severity of food allergy, either positively or negatively. METHODS: We infected neonatal C57BL/6 or C3H mice with H. pylori or treated animals with H. pylori components (bacterial lysate or the immunomodulator VacA) and subsequently subjected them to four different protocols for food allergy induction, using either ovalbumin or peanut extract as allergens for sensitization and challenge. Readouts included anaphylaxis scoring, quantification of allergen-specific serum IgE and IgG1 and of the mast cell protease MCPT1, as well as splenic T-helper-2 cell-derived cytokine production. Mesenteric lymph node CD4+ FoxP3+ regulatory T cells were subjected to flow cytometric quantification and sorting followed by qRT-PCR, and to DNA methylation analyses of the Treg-specific demethylated region (TSDR) within the FOXP3 locus. RESULTS: Mice that had been infected with H. pylori or treated with H. pylori-derived immunomodulators showed reduced anaphylaxis upon allergen sensitization and challenge, irrespective of the allergen used. Most of the immunologic assays confirmed a protective effect of H. pylori. CD4+ FoxP3+ T cells were more abundant in protected mice and exhibited a stable Treg phenotype characterized by FOXP3 TSDR demethylation. CONCLUSIONS AND CLINICAL RELEVANCE: Helicobacter pylori confers protection against the anaphylaxis associated with ovalbumin and peanut allergy and affects the epigenome of T cells, thereby promoting stable Treg differentiation and functionality. Prophylactic treatment with H. pylori-derived immunomodulators appears to be a promising strategy for food allergy prevention. PMID- 28802079 TI - Multiple introductions, admixture and bridgehead invasion characterize the introduction history of Ambrosia artemisiifolia in Europe and Australia. AB - Admixture between differentiated populations is considered to be a powerful mechanism stimulating the invasive success of some introduced species. It is generally facilitated through multiple introductions; however, the importance of admixture prior to introduction has rarely been considered. We assess the likelihood that the invasive Ambrosia artemisiifolia populations of Europe and Australia developed through multiple introductions or were sourced from a historical admixture zone within native North America. To do this, we combine large genomic and sampling data sets analysed with approximate Bayesian computation and random forest scenario evaluation to compare single and multiple invasion scenarios with pre- and postintroduction admixture simultaneously. We show the historical admixture zone within native North America originated before global invasion of this weed and could act as a potential source of introduced populations. We provide evidence supporting the hypothesis that the invasive populations established through multiple introductions from the native range into Europe and subsequent bridgehead invasion into Australia. We discuss the evolutionary mechanisms that could promote invasiveness and evolutionary potential of alien species from bridgehead invasions and admixed source populations. PMID- 28802080 TI - Segmental allotetraploidy generates extensive homoeologous expression rewiring and phenotypic diversity at the population level in rice. AB - Allopolyploidization, that is, concomitant merging and doubling of two or more divergent genomes in a common nucleus/cytoplasm, is known to instantly alter genomewide transcriptome dynamics, a phenomenon referred to as "transcriptomic shock." However, the immediate effects of transcriptomic alteration in generating phenotypic diversity at the population level remain underinvestigated. Here, we employed the MassARRAY-based Sequenom platform to assess and compare orthologous, allelic and homoeologous gene expression status in two tissues (leaf and root) of a set of randomly chosen individuals from populations of parental rice subspecies (indica and japonica), in vitro "hybrids" (parental mixes), reciprocal F1 hybrids and reciprocal tetraploids at the 5th-selfed generation (S5). We show that hybridization and whole genome duplication (WGD) have opposing effects on allelic and homoeologous expression in the F1 hybrids and tetraploids, respectively. Whereas hybridization exerts strong attenuating effects on allelic expression differences in diploid hybrids, WGD augments the intrinsic parental differences and generates extensive and variable homoeolog content which triggers diversification in expression patterning among the tetraploid plants. Coupled with the vast phenotypic diversity observed among the tetraploid individuals, our results provide experimental evidence in support of the notion that allopolyploidy catalyses rapid phenotypic diversification in higher plants. Our data further suggest that largely stochastic homoeolog content reshuffling rather than alteration in total expression level may be an important feature of evolution in young segmental allopolyploids, which underlies rapid expression diversity at the population level. PMID- 28802081 TI - Creativity and physical fitness in primary school-aged children. AB - BACKGROUND: The aim of this study was to analyze the relationship between creativity and physical fitness in elementary school children. METHOD: Data were collected from 308 primary school students in southern Spain, ranging in age from 8 to 12 years (mean, 9.72 +/- 1.25 years). They completed a fitness test battery, and the Prueba de Imaginacion Creativa para Ninos (PIC-N; Creative Imagination Test for Children) to analyze creativity. RESULTS: Significant differences were found between the sexes. Boys had better physical fitness but there were no sex differences in creativity. On clusters analysis, the highly creative groups had better physical fitness. Creativity was correlated with physical fitness. Aerobic capacity was a predictor of creativity. CONCLUSION: There is an association between creativity and physical fitness in primary school children that may have important implications for academic achievement. PMID- 28802082 TI - Ketamine or Ketofol: Do We Have Enough Evidence to Know Which One to Use? PMID- 28802083 TI - Phase-contrast hard X-ray microscopy using synchrotron radiation for the properties of skeletal muscle in mouse hind limbs. AB - Radiation beam interface contrast X-ray microscopy provides resolution of a few dozen nanometers from fixed whole muscle biopsies, allowing better reconstruction of the microstructure of the muscle than is currently possible with classic histological techniques. Fixed soleus muscle biopsies have been evaluated from the walk-in mouse model using phase-contrast X-ray microscopy, and results presented that corroborate the accuracy of the method used, and its potential for application in physiotherapy and occupational therapy studies. We believe that this method will enhance existing morphometric methods of analysis, leading to accurate reconstruction of other thick specimens that would otherwise require thin sectioning and reconstruction through deconvolution algorithms. PMID- 28802085 TI - Recovery and mood disorders. PMID- 28802084 TI - Parameters that help to differentiate biliary atresia from other diseases. AB - BACKGROUND: The diagnosis of biliary atresia (BA) is still challenging. The aim of this study was to analyze the clinical features and parameters that contribute to a diagnosis of BA. METHODS: From January 2000 to December 2013, 37 patients who underwent operative cholangiography were evaluated retrospectively. The patients were divided into two groups: a BA group, and a group with other cholestatic diseases (non-BA group). The demographic data and preoperative liver function test results were analyzed. RESULTS: Of the 37 patients, 29 patients were confirmed to have BA. Age at operation was not significantly different between the two groups (P = 0.77). On preoperative liver function tests, only the level of gamma-glutamyl transpeptidase (gamma-GTP) was significantly higher in the BA group (P = 0.015). The predominant non-BA disease was inspissated bile syndrome (IBS). In the IBS patients, the jaundice was relieved after lavage of the biliary tree. CONCLUSION: The preoperative differentiation of cholestasis is difficult based on laboratory data and imaging. Preoperative gamma-GTP may be useful for diagnosing BA, but operative cholangiography should be performed when BA is suspected and cannot be ruled out by other methods, given that the most common non-BA disease may be IBS. PMID- 28802086 TI - Acute kidney injury is common with intravenous abuse of extended-release oral oxymorphone and delayed renal recovery rates are associated with increased KDIGO staging. AB - AIM: Prescription opioid abuse poses a serious problem in the United States, representing 615 per 100 000 deaths annually. Extended-release oxymorphone (Opana ER) is an oral opioid pain medication that has recently been found to cause thrombotic microangiopathy when intravenously abused. In this retrospective study, we attempted to determine the prevalence and outcomes of acute kidney injury (AKI) among patients intravenously abusing extended-release oral oxymorphone. METHODS: A query of electronic medical records for 'drug abuse' at an academic medical centre during January 2012 to December 2015 was performed and yielded 2350 patients. Patients were further identified by documented intravenous abuse of extended-release oxymorphone. Patients were stratified based on multiple renal indices and outcomes. Potential confounders were also identified. RESULTS: One hundred and sixty-five patients were found to have a documented history of intravenous abuse of extended-release oral oxymorphone. Prevalence of AKI in this population was a 47.8%. KDIGO stage-I patients consisted of 17.8% of patients with AKI, 40.5% were classified as KDIGO stage-II AKI, and 41.8% were classified as KDIGO stage-III AKI. Among patients with AKI, average age was found to be 37.5 years, 59.4% experienced renal recovery, 56.9% required intensive care unit admission, 13.9% progressed to end-stage renal disease (ESRD), and 7.6% expired during admission. CONCLUSION: Clinicians should be educated to help recognize intravenous abuse of extended-release oral oxymorphone and its associated effects. Our data suggests AKI is common in these patients; higher KDIGO staging appears to be associated with slower rates of renal recovery, increased comorbidities and progression to both CKD and ESRD. PMID- 28802088 TI - Screening bioactive quality control markers of QiShenYiQi dripping pills based on the relationship between the ultra-high performance liquid chromatography fingerprint and vascular protective activity. AB - Traditional Chinese medicine consists of complex phytochemical constituents. Selecting appropriate analytical markers of traditional Chinese medicine is a critical step in quality control. Currently, the combination of fingerprinting and efficacy evaluation is considered as a useful method for screening active ingredients in complex mixtures. This study was designed to develop an orthogonal partial least squares model for screening bioactive quality control markers of QishenYiqi dripping pills based on the fingerprint-efficacy relationship. First, the chemical fingerprints of 49 batches of QishenYiqi dripping pill samples were established by ultra-high performance liquid chromatography coupled with a photodiode array detector. Second, ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry was exploited to systematically investigate the 36 copossessing fingerprint components in QishenYiqi dripping pills. The vascular protective activity of QishenYiqi dripping pills was determined by using a cell counting kit-8 assay. Finally, fingerprint-efficacy relationship was established by orthogonal partial least squares model. The results indicated that ten components exhibited strong correlation with vascular protective activity, and these were preliminarily screened as quality control markers. The present study provided a novel idea for the study of the pharmacodynamic material basis and quality evaluation of QishenYiqi dripping pills. PMID- 28802087 TI - Variant histology, IgD and CD30 expression in low-risk pediatric nodular lymphocyte predominant Hodgkin lymphoma: A report from the Children's Oncology Group. AB - BACKGROUND: Histologic prognostic factors have been described for nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). This study examines histologic and immunophenotypic variants in a clinical trial for pediatric NLPHL. PROCEDURE: One hundred sixty-eight cases of localized NLPHL were examined for histologic variants, CD30 and immunoglobulin D (IgD) expression, and outcome. Histologic types were scored categorically as 0 = 0, 1 <= 25%, and 2 > 25% of the sample. RESULTS: Fifty-eight (35.1%) cases showed only typical nodular with or without serpiginous histology (types A and B). The remainder showed mixtures of histologies. The numbers of patients with score 2 are 85 (50.6%) type A, 21 (12.5%) type B, 46 (27.4%) with extranodular large B cells (type C), 3 with T cell-rich nodular pattern (type D), 55 (32.7%) with diffuse T-cell-rich (type E) pattern, and 2 (1.2%) with diffuse B-cell pattern (type F). Higher level of types C (P = 0.048) and D (P = 0.033) resulted in lower event-free survival (EFS). Cytoplasmic IgD was found in 65 of 130 tested (50%), did not significantly associate with EFS but positively correlated with types C and E histology (P < 0.0001) and negatively correlated with types A (P = 0.0003) and B (P = 0.006). Seventeen (10%) expressed CD30, with no adverse effect. CONCLUSIONS: Variant histology is common in pediatric NLPHL, especially types C and E, which are associated with IgD expression. Type C variant histology and possibly type D are associated with decreased EFS, but neither IgD nor CD30 are adverse features. Variant histology may warrant increased surveillance, but did not affect overall survival. PMID- 28802089 TI - Chilblain lupus and steroid-responsive pancytopenia precede monosomy 7-linked AML as manifestation of rasopathy. PMID- 28802090 TI - Assessment of the dynamics of human glymphatic system by near-infrared spectroscopy. AB - Fluctuations in brain water content has attracted increasing interest, particularly as regards studies of the glymphatic system, which is connected with the complex organization of dural lymphatic vessels, responsible for cleaning tissue. Disturbances of glymphatic circulation are associated with several brain disorders, including dementia. This article introduces an approach to noninvasive measurement of water dynamics in the human brain utilizing near-infrared spectroscopy (NIRS). We demonstrate the possibility to sense dynamic variations of water content between the skull and grey matter, for instance, in the subarachnoid space. Measured fluctuations in water content, especially in the cerebrospinal fluid (CSF), are assumed to be correlated with the dynamics of glymphatic circulation. The sampling volume for the NIRS optode was estimated by Monte Carlo modelling for the wavelengths of 660, 740, 830 and 980 nm. In addition, using combinations of these wavelengths, this article presents the calculation models for quantifying water and haemodynamics. The presented NIRS technique allows long-term functional brain monitoring, including sleeping time. Furthermore, it is used in combination with different magnetic neuroimaging techniques, particularly magnetic resonance encephalography. Using the combined setup, we report the preliminary results on the interaction between CSF and blood oxygen level-dependent fluctuations. PMID- 28802091 TI - Cyclic and intermittent very low-protein diet can have beneficial effects against advanced diabetic nephropathy in Wistar fatty (fa/fa) rats, an animal model of type 2 diabetes and obesity. AB - A low-protein diet (LPD), particularly, very low-protein diet (VLPD) is expected for reno-protection in advanced chronic kidney disease, including diabetic nephropathy. We previously also demonstrated that a VLPD clearly improved advanced diabetic nephropathy in a type 2 diabetes and obesity rat. However, clinically, an everyday long-term VLPD contributes to poor adherence, which may be related to controvertial results of an LPD on the suppression for diabetic nephropathy, and has nutritional issues, such as sarcopenia or protein-energy wasting. The aim of this study is to elucidate the reno-protective effect of a cyclic and intermittent VLPD, not an everyday VLPD, against the advanced experimental diabetic nephropathy. Diabetic male Wistar fatty (fa/fa) rats (WFRs) were treated with a standard diet (STD; 23.84% protein) or a cyclic and intermittent VLPD (5.77% protein) consisting of an STD for 3 days and a VLPD for 4 days a week for 20 weeks beginning at 24 weeks of age. A cyclic and intermittent VLPD significantly improved renal hypertrophy, and significantly decreased urinary albumin and liver-type fatty acid binding protein (L-FABP) excretion without changes in body weight or exacerbation of HbA1c levels in diabetic rats. Additionally, diabetes-induced renal injuries including fibrosis, tubular cell damage and inflammation were significantly ameliorated by a cyclic and intermittent VLPD in diabetic rats. Thus, based on our experimental data, a cyclic and intermittent VLPD may be a dietary regimen that is easy to continue and has less risk of malnutrition, compared to an everyday long-term VLPD, against advanced diabetic nephropathy. PMID- 28802092 TI - Utility of Capture-Recapture Methodology to Estimate Prevalence of Congenital Heart Defects Among Adolescents in 11 New York State Counties: 2008 to 2010. AB - BACKGROUND: Congenital heart defects (CHDs) are the most common birth defects in the United States, and the population of individuals living with CHDs is growing. Though CHD prevalence in infancy has been well characterized, better prevalence estimates among children and adolescents in the United States are still needed. METHODS: We used capture-recapture methods to estimate CHD prevalence among adolescents residing in 11 New York counties. The three data sources used for analysis included Statewide Planning and Research Cooperative System (SPARCS) hospital inpatient records, SPARCS outpatient records, and medical records provided by seven pediatric congenital cardiac clinics from 2008 to 2010. Bayesian log-linear models were fit using the R package Conting to account for dataset dependencies and heterogeneous catchability. RESULTS: A total of 2537 adolescent CHD cases were captured in our three data sources. Forty-four cases were identified in all data sources, 283 cases were identified in two of three data sources, and 2210 cases were identified in a single data source. The final model yielded an estimated total adolescent CHD population of 3845, indicating that 66% of the cases in the catchment area were identified in the case identifying data sources. Based on 2010 Census estimates, we estimated adolescent CHD prevalence as 6.4 CHD cases per 1000 adolescents (95% confidence interval: 6.2-6.6). CONCLUSION: We used capture-recapture methodology with a population based surveillance system in New York to estimate CHD prevalence among adolescents. Future research incorporating additional data sources may improve prevalence estimates in this population. Birth Defects Research 109:1423-1429, 2017.(c) 2017 Wiley Periodicals, Inc. PMID- 28802093 TI - Clinical Aspects of Opium Adulterated with Lead in Iran: A Review. AB - Adulteration of drugs with poisonous substances during production or consumption has caused numerous health problems. Among contaminants that have the potential of producing poisonous effects are the heavy metals lead, arsenic and thallium that make up an important group of toxic substances. The emergence of these new health problems related to opioid abuse has precipitated this MiniReview on the status of the most hazardous and common opioid adulterants. In fact, adulterated opium is a major public health problem and can threaten the health of users. In this study, we searched for information on opium, opiates, lead poisoning, toxicity, intoxication, Iran and heavy metals in the TUMS Digital Library, PubMed, Scopus, EMBASE and Google Scholar bibliographical databases. This MiniReview primarily included articles on lead poisoning, signs and symptoms, and management in opioid-dependent individuals. Exclusion criteria were articles dealing with animal studies, specific paediatric studies, adulterants other than heavy metals and substances other than opioids. Adulterated opium is one of the new sources of exposure to lead and has precipitated an increase in lead-poisoned cases owing to the widespread use of opium. The toxicology of lead and general guidelines on diagnosis and treatment of lead poisoning is briefly reviewed. The symptoms of lead toxicity mimic several diseases often leading to unnecessary diagnostic methods, misdiagnoses and even surgery. Finally, owing to the fact that lead toxicity shows non-specific signs and symptoms, screening for this disease, by taking blood samples and assessing blood lead levels in high-risk people, should be given an utmost priority. It is recommended that screening tests are adopted and applied for any drug-abusing patient with non-specific subacute signs and symptoms like abdominal pain, constipation and anaemia. PMID- 28802094 TI - Oncocytic variant of medullary thyroid carcinoma; a rare tumor with numerous diagnostic mimics by fine needle aspiration. AB - Oncocytic variant of medullary thyroid carcinoma is rare form of thyroid carcinoma that is easily misdiagnosed on fine needle aspiration specimens due to it is low incidence and cytomorphologic overlap with other more common Hurtle cell lesions. A correct initial diagnosis by fine needle aspiration is imperative as the clinical treatment for medullary carcinoma differs significantly from the mimickers. We present a case of this rare variant tumor that on initial fine needle aspiration was described as a Hurthle cell lesion and was subsequently correctly classified on the resection specimen. In this brief review, we describe the cytomorphologic features of medullary carcinoma, oncocytic variant of medullary carcinoma and it is most common mimickers, and we discuss the ancillary studies required to confirm the diagnosis. This case highlights the importance of a complete clinical history and radiologic correlation, which in conjunction with a careful attention to the cytologic features of the fine needle aspiration sample, should in most cases ensure a correct initial diagnosis. PMID- 28802095 TI - The diagnostic utility of Merkel cell polyomavirus immunohistochemistry in a fine needle aspirate of metastatic Merkel cell carcinoma of unknown primary to the pancreas. AB - Merkel cell carcinoma (MCC) is an aggressive skin tumor with a high tendency for metastases. We report a case of MCC initially presenting as axillary and pancreatic metastases. A 33-year-old HIV-positive Hispanic male presented with a history of a rapidly growing axillary mass. A needle core biopsy demonstrated an epithelioid neoplasm composed of small to medium-sized cells with high nuclear cytoplasmic ratio, nuclear molding, and frequent mitotic figures. A subsequent PET scan revealed a 1.5 cm FDG avid mass in the pancreas. Endoscopic ultrasound guided FNA of the pancreatic mass showed neoplastic cells with similar morphology to those of the axillary mass. The tumor cells were positive with pancytokeratin AE1/AE3, CK20, CD56, synatophysin, chromogranin, and Merkel cell polyomavirus (MCPyV). This case of MCC most likely originated from a resolved primary skin lesion drained by the involved axillary lymph node with subsequent metastases to the pancreas and distant lymph nodes. PMID- 28802096 TI - Comparison of cleaning methods for delicate insect specimens for scanning electron microscopy. AB - The objective of the present study was to compare cleaning methods for delicate insect specimens for investigations with scanning electron microscopy (SEM). As typical specimens we used aquatic larvae of mosquitoes, springtails, larvae of mayflies and caterpillars because they are very fragile and large parts of their body consist of soft tissue. Additionally their cuticle is very often covered with dirt, soil particles or other materials. Cleaning with ultrasonic sound, as the most common cleaning method used for SEM, will destroy fragile insects. Therefore we tested different procedures to remove the dirt particles. In a first approach we compared cleaning with Potassium hydroxide (KOH), Proteinase K, and Triton X in aquatic larvae of flies, which were available in numbers and kept under the same conditions. As our results showed that the treatment with KOH gives the best results we treated in a second approach springtails, larvae of mayflies and caterpillars only with KOH. The springtails and caterpillars were largely free of particles after treatment with KOH; however, the larvae of mayflies were still covered with remnants of diatoms and precipitates of calcium carbonate of the algae. KOH dissolves organic impurities, on the other hand silicon dioxide and lime crusts are not solved. With this limitation, treatment with KOH is a simple technique for routine use as cleaning method for fragile insect specimens for SEM. PMID- 28802097 TI - Heat shock protein 47 effects on hepatic stellate cell-associated receptors in hepatic fibrosis of Schistosoma japonicum-infected mice. AB - The study aimed to explore the regulation of heat shock protein 47 (HSP47) on expressions of receptors associated with hepatic stellate cell (HSC) in liver fibrosis mouse models induced by Schistosoma japonicum (S. japonicum). Mouse fibroblasts (NIH/3T3) were transfected with HSP47 shRNA plasmid by lipofectamine transfection, and experimental fibrosis in HSCs was studied in S. japonicum mouse models treated with HSP47 shRNA in vivo. HSP47 expression was assessed using Western blot and real-time PCR. Flow cytometry was adopted to determine the expression of cell membrane receptors. HSP47-shRNA could markedly down-regulate the expression of collagen (Col1a1 and Col3a1). The expressions of HSP47, endothelin receptor A (ETAR) and endothelin receptor B (ETBR) significantly increased in the liver tissue of infected mice. However, the expressions of ETAR and HSP47 and ETBR remarkably decreased after the administration of HSP47 shRNA in vitro and in vivo. ETAR and ETBR levels were found to be positively correlated with HSP47 expression. HSP47 might exert influence on liver fibrosis via the regulation of ETAR and ETBR. PMID- 28802098 TI - Response time of indirectly accessed gas exchange depends on measurement method. AB - Noninvasive techniques are routinely used for assessment of tissue effects of lung ventilation. However, comprehensive studies of the response time of the methods are scarce. The aim of this study was to compare the response time of noninvasive methods for monitoring of gas exchange to sudden changes in the composition of the inspired gas. A prospective experimental study with 16 healthy volunteers was conducted. A ventilation circuit was designed that enabled a fast change in the composition of the inspiratory gas mixture while allowing spontaneous breathing. The volunteers inhaled a hypoxic mixture, then a hypercapnic mixture, a hyperoxic mixture and finally a 0.3% CO mixture. The parameters with the fastest response to the sudden change of O2 in inhaled gas were peripheral capillary oxygen saturation (SpO2) and regional tissue oxygenation (rSO2). Transcutaneous oxygen partial pressure (tcpO2) had almost the same time of reaction, but its time of relaxation was 2-3 times longer. End-tidal carbon dioxide (EtCO2) response time to change of CO2 concentration in inhaled gas was less than half in comparison with transcutaneous carbon dioxide partial pressure (tcpCO2). All the examined parameters and devices reacted adequately to changes in gas concentration in the inspiratory gas mixture. PMID- 28802100 TI - Influence of IL-6, IL-33, and TNF-alpha on human mast cell activation: Lessons from single cell analysis by flow cytometry. AB - BACKGROUND: Mechanisms that govern priming and degranulation of human mast cells (MCs) remain elusive. Besides, most of our knowledge is based on experiments from which data only reflect an average of all stimulated cells. This study aims at investigating the effects of proinflammatory cytokines IL-6, IL-33, and TNF-alpha on IgE-dependent and IgE-independent activation of individual MCs. METHODS: MCs were derived from CD34+ progenitors isolated from 50 mL whole blood from 4 healthy controls and 5 birch pollen allergic patients. Passively sensitized MCs were preincubated with IL-6, IL-33, or TNF-alpha and stimulated with anti IgE/birch pollen allergen or substance P, the latter being a ligand for the G protein-coupled MRGPRX2-receptor. Activation-i.e., upregulation of CD203c-and anaphylactic degranulation-i.e., appearance of CD63-were measured using flow cytometry. RESULTS: Preincubation with IL-33 demonstrated upregulated CD203c density without degranulation. Subsequent IgE-dependent stimulation (anti IgE/birch pollen allergen) resulted in higher appearance of CD63 as compared to cells without preincubation, indicating IL-33 to exert a priming effect (P = 0.04). IL-6 only increased allergen-specific responses but to a lesser extent than IL-33. Combination of IL-33/IL-6 had a synergistic effect, demonstrating more degranulation in response to allergen. TNF-alpha had no effect on IgE mediated activation, nor synergistic effects with IL-33. Stimulation with substance P resulted in degranulation that could not be enhanced by preincubation. CONCLUSIONS: In conclusion, IL-33, and in a lesser extent IL-6, prime individual MCs for subsequent IgE-mediated activation. Moreover, this priming effect is synergistic. In contrast, none of the cytokines had a priming effect on MRGPRX2-mediated activation of MCs. (c) 2017 International Clinical Cytometry Society. PMID- 28802099 TI - Cancer-Associated Fibroblasts Autophagy Enhances Progression of Triple-Negative Breast Cancer Cells. AB - BACKGROUND Cancer-associated fibroblasts (CAFs) are key factors in malignant tumor initiation, progression, and metastasis. However, the effect of CAFs autophagy on triple-negative breast cancer (TNBC) cells is not clear. In this study, the growth effect of TNBC cells regulated by CAFs autophagy was evaluated. MATERIAL AND METHODS CAFs were obtained from invasive TNBC tumors and identified by Western blot and immunofluorescence staining assay. CAFs were co-cultured with TNBC cells, and migration and invasion were evaluated by Matrigel-coated Transwell and Transwell inserts. TNBC cells growth was detected by MTT assay, and epithelial-mesenchymal transition (EMT) regulated by CAFs was evaluated by Western blot assay. RESULTS CAFs were identified by the high expression of alpha smooth muscle actin (alpha-SMA) protein. Autophagy-relevant Beclin 1 and LC3-II/I protein conversion levels in CAFs were higher than those in NFs (P<0.05). TNBC cells migration, invasion, and proliferation levels were significantly improved in the CAFs-conditioned medium (CAFs-CM) group, compared with the other 3 groups (P<0.05). TNBC cells vimentin and N-cadherin protein levels were upregulated and E-cadherin protein level was downregulated in the CAFs-CM group compared with the control group (P<0.05). Further study indicated b-catenin and P-GSK-3beta protein levels, which are the key proteins in the Wnt/beta-catenin pathway, were upregulated in the CAFs-CM group compared with the control group (P<0.05). CONCLUSIONS Our data demonstrated CAFs autophagy can enhance TNBC cell migration, invasion, and proliferation, and CAFs autophagy can induce TNBC cells to engage in the EMT process through the Wnt/beta-catenin pathway. PMID- 28802101 TI - Flexible biodegradable citrate-based polymeric step-index optical fiber. AB - Implanting fiber optical waveguides into tissue or organs for light delivery and collection is among the most effective ways to overcome the issue of tissue turbidity, a long-standing obstacle for biomedical optical technologies. Here, we report a citrate-based material platform with engineerable opto-mechano biological properties and demonstrate a new type of biodegradable, biocompatible, and low-loss step-index optical fiber for organ-scale light delivery and collection. By leveraging the rich designability and processibility of citrate based biodegradable polymers, two exemplary biodegradable elastomers with a fine refractive index difference and yet matched mechanical properties and biodegradation profiles were developed. Furthermore, we developed a two-step fabrication method to fabricate flexible and low-loss (0.4 db/cm) optical fibers, and performed systematic characterizations to study optical, spectroscopic, mechanical, and biodegradable properties. In addition, we demonstrated the proof of concept of image transmission through the citrate-based polymeric optical fibers and conducted in vivo deep tissue light delivery and fluorescence sensing in a Sprague-Dawley (SD) rat, laying the groundwork for realizing future implantable devices for long-term implantation where deep-tissue light delivery, sensing and imaging are desired, such as cell, tissue, and scaffold imaging in regenerative medicine and in vivo optogenetic stimulation. PMID- 28802102 TI - PNIPAAm-co-Jeffamine(r) (PNJ) scaffolds as in vitro models for niche enrichment of glioblastoma stem-like cells. AB - Glioblastoma (GBM) is the most common adult primary brain tumor, and the 5-year survival rate is less than 5%. GBM malignancy is driven in part by a population of GBM stem-like cells (GSCs) that exhibit indefinite self-renewal capacity, multipotent differentiation, expression of neural stem cell markers, and resistance to conventional treatments. GSCs are enriched in specialized niche microenvironments that regulate stem phenotypes and support GSC radioresistance. Therefore, identifying GSC-niche interactions that regulate stem phenotypes may present a unique target for disrupting the maintenance and persistence of this treatment resistant population. In this work, we engineered 3D scaffolds from temperature responsive poly(N-isopropylacrylamide-co-Jeffamine M-1000(r) acrylamide), or PNJ copolymers, as a platform for enriching stem-specific phenotypes in two molecularly distinct human patient-derived GSC cell lines. Notably, we observed that, compared to conventional neurosphere cultures, PNJ cultured GSCs maintained multipotency and exhibited enhanced self-renewal capacity. Concurrent increases in expression of proteins known to regulate self renewal, invasion, and stem maintenance in GSCs (NESTIN, EGFR, CD44) suggest that PNJ scaffolds effectively enrich the GSC population. We further observed that PNJ cultured GSCs exhibited increased resistance to radiation treatment compared to GSCs cultured in standard neurosphere conditions. GSC radioresistance is supported in vivo by niche microenvironments, and this remains a significant barrier to effectively treating these highly tumorigenic cells. Taken in sum, these data indicate that the microenvironment created by synthetic PNJ scaffolds models niche enrichment of GSCs in patient-derived GBM cell lines, and presents tissue engineering opportunities for studying clinically important behaviors such as radioresistance in vitro. PMID- 28802103 TI - Where you are affects what you can easily imagine: Environmental geometry elicits sensorimotor interference in remote perspective taking. AB - Imagined perspective switches are notoriously difficult, a fact often ascribed to sensorimotor interference between one's to-be-imagined versus actual orientation. Here, we demonstrate similar interference effects, even if participants know they are in a remote environment with unknown spatial relation to the learning environment. Participants learned 15 target objects irregularly arranged in an office from one orientation (0 degrees , 120 degrees , or 240 degrees ). Participants were blindfolded and disoriented before being wheeled to a test room of similar geometry (exp.1) or different geometry (exp.2). Participants were seated facing 0, 120 degrees , or 240 degrees , and asked to perform judgments of relative direction (JRD, e.g., imagine facing "pen", point to "phone"). JRD performance was improved when participants' to-be-imagined orientation in the learning room was aligned with their physical orientation in the current (test) room. Conversely, misalignment led to sensorimotor interference. These concurrent reference frame facilitation/interference effects were further enhanced when the current and to-be-imagined environments were more similar. Whereas sensorimotor alignment improved absolute and relative pointing accuracy, sensorimotor misalignment predominately increased response times, supposedly due to increased cognitive demands. These sensorimotor facilitation/interference effects were sustained and could not be sufficiently explained by initial retrieval and transformation costs. We propose that facilitation/interference effects occurred between concurrent egocentric representations of the learning and test environment in working memory. Results suggest that merely being in a rectangular room might be sufficient to automatically re-anchor one's representation and thus produce orientation-specific interference. This should be considered when designing perspective-taking experiments to avoid unintended biases and concurrent reference frame alignment effects. PMID- 28802104 TI - Results of the second national forest soil inventory in Germany - Interpretation of level and stock profiles for PCDD/F and PCB in terms of vegetation and humus type. AB - Polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and polychlorinated biphenyls (PCBs) were detected in 86 humic topsoil layers and in a subset of 11 randomly selected top mineral forest soils at the depths of 0 5cm and 5-10cm collected from different federal states of Germany. The distribution of these persistent organic pollutants (POPs) in humic topsoils with respect to vegetation cover (coniferous vs. deciduous vs. mixed), total organic carbon (TOC), altitude and latitude data was investigated. There is cross correlation between the contents and TOC while the correlation with latitude indicates higher abundances of POPs in central Germany where there is high population density accompanied with industrial activities. The calculated stocks suggest that humus type (mor, mull, or moder) in conjunction with forest type can explain the relative POPs abundances in different soil layers. Generally, humic topsoils show highest contents of POPs compare to the two mineral soils with a ratio of 100:10:1. However, the stock humic layers of coniferous stands contribute about 50% to the total stock, whereas at deciduous stands the stock is mainly located in the upper mineral soil layer (0-5cm). The soil-water distribution coefficients (Kd) were calculated to estimate the potential translocation in the different soil types. The Kd values vary among the PCBs and PCDD/Fs congeners and are most variable for humic topsoils. There is pronounced chemical abundance in the top mineral soils with increasing Kd and this points to non-water bound transport processes for superlipophilic compounds. PMID- 28802105 TI - Combined influence of multiple climatic factors on the incidence of bacterial foodborne diseases. AB - Information regarding the relationship between the incidence of foodborne diseases (FBD) and climatic factors is useful in designing preventive strategies for FBD based on anticipated future climate change. To better predict the effect of climate change on foodborne pathogens, the present study investigated the combined influence of multiple climatic factors on bacterial FBD incidence in South Korea. During 2011-2015, the relationships between 8 climatic factors and the incidences of 13 bacterial FBD, were determined based on inpatient stays, on a monthly basis using the Pearson correlation analyses, multicollinearity tests, principal component analysis (PCA), and the seasonal autoregressive integrated moving average (SARIMA) modeling. Of the 8 climatic variables, the combination of temperature, relative humidity, precipitation, insolation, and cloudiness was significantly associated with salmonellosis (P<0.01), vibriosis (P<0.05), and enterohemorrhagic Escherichia coli O157:H7 infection (P<0.01). The combined effects of snowfall, wind speed, duration of sunshine, and cloudiness were not significant for these 3 FBD. Other FBD, including campylobacteriosis, were not significantly associated with any combination of climatic factors. These findings indicate that the relationships between multiple climatic factors and bacterial FBD incidence can be valuable for the development of prediction models for future patterns of diseases in response to changes in climate. PMID- 28802106 TI - Mapping the environment. PMID- 28802108 TI - Do environmental factors affect male fathead minnow (Pimephales promelas) response to estrone? Part 2. Temperature and food availability. AB - Fish are subject to constantly changing environmental conditions and food availability, factors that may impact their response to endocrine disruptors (EDs). This may, in part, explain outcome discrepancies between field studies and laboratory exposures to EDs. This study assessed whether standard laboratory conditions for fish exposures adequately represent effects of ED exposure at two environmentally realistic temperatures. The impact of temperature and food availability on male fathead minnow response to estrone (E1) exposure was studied in two experiments (3*2*2 factorial design) with three E1 concentrations (range 0 135ng/L); two temperatures (18 degrees C and 26 degrees C, the latter the prescribed laboratory temperature), and two feeding treatments (full fed vs. 25% of full fed) in a 21-day flow-through system. Morphometric endpoints [including body condition factor, somatic index of gonad (GSI) and liver (HSI), and secondary sex characteristics (SSC)], blood parameters [hematocrit (HCT), blood glucose, cortisol, and vitellogenin (VTG) concentrations], and histology of liver and testis were determined on day 22. High E1 consistently increased VTG, though interactions among E1, temperature and/or food on liver weight, HSI, and HCT were inconsistent between experiments. High temperature impacted the greatest number of parameters, independent of E1 treatment. Three sex-linked parameters were lower at high temperature (testis weight, GSI and VTG), and in Exp. 2SSC and gonad maturity rating were lower. At 26 degrees C, in Exp. 1 HSI and HCT decreased, and in Exp. 2 length, body and liver weight, and body condition factor were lower. Food restriction decreased GSI in Exp. 1, and blood glucose and liver weight in Exp. 2. At 26 degrees C several parameters were altered independent of E1 exposure, including three out of four measurements of sperm differentiation. Concordance between laboratory and field investigations of the biological effects of EDs may improve if environmentally-relevant exposure conditions, especially temperature, are employed. PMID- 28802107 TI - Historical and future trends in global source-receptor relationships of mercury. AB - Growing concern about the risk associated with increasing environmental mercury (Hg) concentrations has resulted in a focus on the relationships between intercontinental emitted and accumulated Hg. We use a global biogeochemical Hg model with 8 continental regions and a global ocean to evaluate the legacy impacts of historical anthropogenic releases (2000BCE to 2008AD) on global source receptor relationships of Hg. Legacy impacts of historical anthropogenic releases are confirmed to be significant on the source-receptor relationships according to our results. Historical anthropogenic releases from Asia account for 8% of total soil Hg in North America, which is smaller than the proportion (~17%) from previous studies. The largest contributors to the global oceanic Hg are historical anthropogenic releases from North America (26%), Asia (16%), Europe (14%) and South America (14%). Although anthropogenic releases from Asia have exceeded North America since the 1970s, source contributions to global Hg receptors from Asia have not exceeded North America so far. Future projections indicate that if Hg emissions are not effectively controlled, Asia will exceed North America as the largest contributor to the global ocean in 2019 and this has a long-term adverse impact on the future environment. For the Arctic Ocean, historical anthropogenic release from North America contributes most to the oceanic Hg reservoir and future projections reveal that the legacy impacts of historical releases from mid-latitudes would lead to the potential of rising Hg in the Arctic Ocean in the future decades, which calls for more effective Hg controls on mid-latitude releases. PMID- 28802109 TI - Influence of the properties of granitic rocks on their bioreceptivity to subaerial phototrophic biofilms. AB - As any stone substrate is susceptible to biological colonisation, the choice of lithotype used for construction is a key strategy for preventing biodeterioration. For this purpose, a comprehensive evaluation of the primary bioreceptivity to phototrophic biofilms of eleven varieties of granitic rocks, commonly used as building material, was carried out. Blocks were inoculated with a multi-species phototrophic culture and subjected to standardised growth conditions for three months. Biofilm formation was assessed by chlorophyll (chl) fluorescence, colour measurements and extracellular polymeric substances (EPS) quantification. Relationships between the biofilm growth indicators and the properties of the different rocks studied were then analysed. Results showed that the bioreceptivity of the granites is more strongly affected by the physical characteristics of the stones than by their chemical and mineralogical properties, possibly because of the similar composition of the rocks studied. Growth of phototrophic biofilms was enhanced by high open porosity, capillary water content and surface roughness, and the bioreceptivity of weathered granites was higher than that of sound granites. The results obtained can therefore help in the selection of appropriate lithotypes for building purposes. The amounts of EPS produced by subaerial biofilms primarily depended on the requirements and/or characteristics of the biofilm-forming microorganisms, rather than on the bioreceptivity of the substratum, and microorganisms produce the amounts of EPS required at the initial stage of establishment on the stone surface, independently of the subsequent biomass development. These findings are especially important from the point of view of biodeterioration, in which the EPS matrix plays a central role. PMID- 28802110 TI - Application of a microbial source tracking based on bacterial and chemical markers in headwater and coastal catchments. AB - This study identified sources of fecal contamination in three different French headwater and coastal catchments (the Justicou, Pen an Traon, and La Fresnaye) using a combination of microbial source tracking tools. The tools included bacterial markers (three host-associated Bacteroidales) and chemical markers (six fecal stanols), which were monitored monthly over one or two years in addition to fecal indicator bacteria. 168 of the 240 freshwater and marine water samples had Escherichia coli (E. coli) or enterococci concentrations higher than "excellent" European water quality threshold. In the three catchments, the results suggested that the fecal contamination appeared to be primarily from an animal origin and particularly from a bovine origin in 52% (Rum2Bac) and 46% (Bstanol) of the samples and to a lesser extent from a porcine origin in 19% (Pig2Bac) and 21% (Pstanol) of the samples. Our results suggested a human fecal contamination in 56% (HF183) and 32% (Hstanol) of the samples. Rainfall also impacted the source identification of microbial contamination. In general, these findings could inform effective implementation of microbial source tracking strategies, specifically that the location of sampling points must include variability at the landscape scale. PMID- 28802111 TI - Letter to the Editor Re: Yu Qing, Wang Hai-Jun, Wang Hong-Zhu, Li Yan, Liang Xiao Min, Xu Chi, Jeppesen Erik Does the responses of Vallisneria natans (Lour.) Hara to high nitrogen loading differ between the summer high-growth season and the low growth season? Science of the Total Environment 601-602(2017)1513-1521. AB - Yu et al.'s paper showed very interesting effects of high nitrogen (N) on the submerged macrophytes Vallisneria natans: active growth in the growing season enabled the macrophytes partly to overcome the ammonium stress. This result was evident in an experiment using ten pond ecosystems; however, their conclusion that shading induced by high phytoplankton biomass together with the toxicity of high ammonium contributed to the decrease of macrophytes growth was not strongly supported by the data provided in the paper. Three factors influencing how submerged macrophytes respond to high ammonium, not addressed by Yu et al.'s paper, are toxicity of ammonium/ammonia (NH4+/NH3), the precise extent of shading in water and species-specific characteristics of macrophytes. In conclusion, a comprehensive consideration of abiotic and biotic factors that involve in the responses of submerged macrophytes to high N is urged in future studies of the role of high N on the growth of submerged macrophytes. PMID- 28802112 TI - Evaluation of alpha-linolenic acid for freezability and in vivo fertility of Nili Ravi (Bubalus bubalis) buffalo semen. AB - Alpha linolenic acid (ALA) is integral component of cell membrane that protects the cell in stressful events and involves in many metabolic pathways. It was hypothesized that ALA have the ability to protect the structural and functional integrity of buffalo spermatozoa during freeze-thawing. Therefore, study was designed to evaluate ALA supplementation (0, 5, 10 and 20 ng/mL) in extender on freezability and in vivo fertility of buffalo bull spermatozoa. Semen from three adult Nili-Ravi buffalo bulls of similar age was collected with artificial vagina (42 degrees C) for five weeks (replicates; N = 30). Qualified semen ejaculates (>1 mL volume, >60% motility; >0.5 billion/mL concentration) were diluted with tris-citric acid extender containing 0.0 (control), 5.0, 10.0 and 20.0 ng/mL ALA at 37 degrees C and cryopreserved following established protocol. Sperm motility and plasma membrane integrity were recorded higher (P < 0.05) in extender containing 5.0 ng/mL of ALA compared to control. Nevertheless, sperm viability, live dead ratio and chromatin integrity were observed higher (P < 0.05) in all experimental extenders with ALA compared to control. The number of abnormal sperm reduced significantly in all experimental extenders having ALA. A total of 539 artificial inseminations were performed with the best evolved extender having ALA (5.0 ng/mL; 272 inseminations) and control (267 inseminations). In vivo fertility rates of buffalo semen were recorded higher (P < 0.05) with extender containing ALA (5.0 ng/mL) (58%) compared to control (46%). In conclusion, supplementing 5.0 ng/mL ALA in extender improved the post-thaw quality and in vivo fertility of cryopreserved Nili-Ravi buffalo bull semen. PMID- 28802113 TI - L-carnitine enhances oocyte maturation and improves in vitro development of embryos in dromedary camels (Camelus dromedaries). AB - The aim of the present study was to investigate the effect of L-carnitine (LC) addition during either IVM or IVC on the developmental potential of camel oocytes. In Experiment 1; camel oocytes were matured in the absence (control) or presence of different concentrations of LC (0.25 mg, 0.5 mg, 0.75 mg and 1 mg/ml) for 30 h followed by in vitro fertilization and culture up to blastocyst stage. Our results demonstrated that oocytes treated with 0.5 mg/ml LC showed higher (P < 0.05) rates of maturation (74.7%) and fertilization (62.2%) compared with control group, 0.25 and 1 mg/ml of LC (60.2, 63.9, 59.7; 46.2, 48.7, 47.6%, respectively). Addition of 0.5 mg/ml of LC to IVM medium improved the rates of cleavage and embryo development (morula and blastocyst) than those obtained in the control group, 0.25 and 1 mg/ml of LC. No significant differences were noticed between 0.5 and 0.75 mg/ml of LC supplemented groups in term of maturation, fertilization and culture. In Experiment 2; zygotes resulting from in vitro matured (without LC) and fertilized were cultured in embryo culture medium supplemented with different concentrations of LC (0.25 mg, 0.5 mg, 0.75 mg and 1 mg/ml) or without LC (control). Also, the results showed a higher developmental rates to morula and blastocyst stages while adding L-carnitine at a level of 0.5 or 0.75 mg/ml concentration in the culture medium during IVC when compared with other groups. In conclusion, the results demonstrated the usefulness of L carnitine supplementation at the level of 0.5 mg/ml during IVM or IVC after on the developmental potential of camel oocytes. PMID- 28802114 TI - Embryonic and fetal morphology in the lowland paca (Cuniculus paca): A precocial hystricomorph rodent. AB - In mammals, the embryonic and fetal development of a species has evolved to maximize neonatal survival. In this study, we use a sample of 132 embryos/fetuses of wild lowland paca (Cuniculus paca), obtained over a period of 15 years through collaborative methods with local hunters in the Amazon to describe the intrauterine development of external and internal morphology of this Neotropical rodent. We also compare the newborn survival strategy in this species with other rodents. The crown-rump length (CRL) ranged between 0.6 and 24.6 cm. External features appeared in the following chronological order: limbs, eyelid buds, fusioned eyelids, genitalia, outer ear, tactile pelage, claws, skin, skin spots, covering pelage, teeth and open eyelids. Fetuses with CRL >19.5 cm presented all external features fully developed. The growth formula of fetal age was calculated as ?W = 0.082 (t - 37.25), and age was accurately associated with CRL. We described the relationship between CRL and external and internal biometry. The liver declined in proportion within the internal cavity, while the relative volume of tubular gastrointestinal organs increased significantly along the embryo/fetal development. All organs, except the heart and the thymus, had similar relative volumes in advanced fetuses and adults. Our comparison of the intrauterine development in several rodent species indicates that the paca's reproductive strategy is comparable to species that are subject to low natural predation. Given that C. paca is perhaps the most hunted animal in Latin America, sustainable hunting throughout its range must take into account its relative reproductive performance. PMID- 28802116 TI - Corrigendum to "Physical activity and sedentary behavior in people with major depressive disorder: A systematic review and meta-analysis" [J. Affect. Disord. 210 (2017) 139-150]. PMID- 28802115 TI - Production of high purity alveolar-like cells from iPSCs through depletion of uncommitted cells after AFE induction. AB - Protocols to differentiate induced pluripotent stem cells (iPSCs) into specialized cells are continually evolving. iPSCs can be differentiated to alveolar cells with protocols that focus on development, specifically by inducing differentiation into definitive endoderm (DE), anterior foregut endoderm (AFE) and then lung bud progenitor intermediaries. However, current protocols result in a relatively low yield of the desired alveolar cells. The aim of this study was to evaluate whether depleting uncommitted cells after AFE induction would have a beneficial effect on alveolar cell yield. iPSCs were differentiated on Matrigel coated plates for 25days. At each stage, phenotype was assessed using flow cytometry, immunofluorescence and qRT-PCR. Additionally, samples were dissociated in trypsin following AFE induction to improve the purity of the cells for the subsequent lung differentiation phase. Finally, the efficacy of dissociating the samples was confirmed comparing the expression of markers indicative of pluripotency and apoptosis. The ability to differentiate iPSCs to DE was 96% and to AFE was 97% utilizing our current protocol. After depletion of uncommitted cells and 12 days in culture, the purity of lung bud progenitors was 99%. Finally, the percentage of alveolar types I and II at the end of differentiation was 74% as compared to 31% in control cultures that had not been depleted of uncommitted cells after AFE induction. In conclusion, depletion of uncommitted cells after AFE induction, improves terminal differentiation of alveolar cells from 31% to 74%. PMID- 28802117 TI - Intolerance of Uncertainty, anxiety, and worry in children and adolescents: A meta-analysis. AB - BACKGROUND: Intolerance of uncertainty (IU) has been implicated in the development and maintenance of worry and anxiety in adults and there is an increasing interest in the role that IU may play in anxiety and worry in children and adolescents. METHOD: We conducted a systematic review and meta-analysis to summarize existing research on IU with regard to anxiety and worry in young people, and to provide a context for considering future directions in this area of research. The systematic review yielded 31 studies that investigated the association of IU with either anxiety or worry in children and adolescents. RESULTS: The meta-analysis showed that IU accounted for 36.00% of the variance in anxiety and 39.69% in worry. Due to the low number of studies and methodological factors, examination of potential moderators was limited; and of those we were able to examine, none were significant moderators of either association. Most studies relied on questionnaire measures of IU, anxiety, and worry; all studies except one were cross-sectional and the majority of the studies were with community samples. LIMITATIONS: The inclusion of eligible studies was limited to studies published in English that focus on typically developing children. CONCLUSIONS: There is a strong association between IU and both anxiety and worry in young people therefore IU may be a relevant construct to target in treatment. To extend the existing literature, future research should incorporate longitudinal and experimental designs, and include samples of young people who have a range of anxiety disorders. PMID- 28802119 TI - Gambling with antibiotics: a novel approach for exploring antibiotic consumption decision-making. PMID- 28802118 TI - Associations of relative deprivation and income rank with depressive symptoms among older adults in Japan. AB - INTRODUCTION: Income is hypothesized to affect health not just through material pathways (i.e., the ability to purchase health-enhancing goods) but also through psychosocial pathways (e.g., social comparisons with others). Two concepts relevant to the psychosocial effects of income are: relative deprivation (for example expressed by the Yitzhaki Index, measuring the magnitude of difference in income among individuals) and Income Rank. This study examined whether higher relative deprivation and lower income rank are associated with depressive symptoms in an older population independently of absolute income. METHOD: Using cross-sectional data of 83,100 participants (40,038 men and 43,062 women) in the Japan Gerontological Evaluation Study (JAGES), this study applied multiple logistic regression models to calculate the odds ratios (OR) of depression associated with relative deprivation/Income Rank. The Japanese Geriatric Depression Scale (GDS-15) was used to assess depressive symptoms, and subjects with a score of >=5 were categorized as depressed. Reference groups for calculating the Yitzhaki Index and income rank were constructed based on same gender, age-group, and municipality of residence. RESULTS: The findings indicated that after controlling for demographic factors, each 100,000 yen increase in relative deprivation and 0.1 unit decrease in relative rank was associated with a 1.07 (95% CI = 1.07, 1.08) and a 1.15 (95% CI = 1.14, 1.16) times higher odds of depression, respectively, in men. The corresponding ORs in women were 1.05 (95% CI = 1.05, 1.06) and 1.12 (95% CI = 1.11, 1.13), respectively. After adjustment for other covariates and stratification by income quartiles, the results remained statistically significant. Women in the highest income quartile appeared to be more susceptible to the adverse mental health effects of low income rank, while among men the associations were reversed. Low income rank appeared to be more toxic for the poor. CONCLUSION: Concepts of relative income appear to be relevant for mental health over and above the effects of absolute income. PMID- 28802120 TI - Discovery of pentacyclic triterpene 3beta-ester derivatives as a new class of cholesterol ester transfer protein inhibitors. AB - A series of pentacyclic triterpene 3beta-ester derivatives were designed, synthesized and evaluated as a new class of cholesteryl ester transfer protein (CETP) inhibitors for the treatment of dyslipidemia. In vitro screening assay showed that 5 out of 30 compounds displayed moderate inhibiting human CETP activity with IC50s less than 10 MUM. Among them, compound 20 (IC50 = 2.3 MUM) had the most potent biological activity, and effectively ameliorated plasma lipid levels of human adipose tissue specific CETP transgenic (ap2-CETPTg) mice and guinea pigs. Additional safety evaluation (no blood pressure elevation in guinea pigs) and pharmacokinetics studies indicated that the potential druggability for compound 20 which is a promising lead for development of a new class of CETP inhibitors for the treatment of dyslipidemia. PMID- 28802121 TI - Identification of highly potent N-acylethanolamine acid amidase (NAAA) inhibitors: Optimization of the terminal phenyl moiety of oxazolidone derivatives. AB - N-acylethanolamine acid amidase (NAAA) is a cysteine hydrolase that participates in the deactivation of fatty acid ethanolamides, such as palmitoylethanolamide (PEA). NAAA inhibition may provide a potential therapeutic strategy for the treatment of diseases in which higher PEA level is desired. In the present study, we reported the structure-activity relationship (SAR) studies for oxazolidone derivatives as NAAA inhibitors. A series of substituents or alkyl replacements for the terminal phenyl ring of oxazolidone derivatives were examined. The results showed that the inhibition potency of these oxazolidone derivatives towards NAAA depends on the sizes, flexibility, and lipophilicity of the terminal groups. SAR results suggested that small lipophilic 3-phenyl substituents or hydroxy-containing 4-phenyl substituents were preferable for optimal potency. Furthermore, the distal aliphatic replacement is also preferred for high inhibitory potency. Rapid dilution and kinetic analysis suggested that oxazolidone derivatives with different terminal phenyl moieties inhibited NAAA via different mechanisms. This study identified several highly potent NAAA inhibitors, including 1a (F215, IC50 = 0.009 MUM), 1o (IC50 = 0.061 MUM) and 2e (IC50 = 0.092 MUM), and also determined structural requirements of oxazolidone derivatives for potent inhibition against NAAA. PMID- 28802122 TI - Piperlongumine B and analogs are promising and selective inhibitors for acetylcholinesterase. AB - Piperlongumine B (19), an alkaloid previously isolated from long pepper (Piper longum) has been synthesized for the first time in a short sequence and in good yield together with 19 analogs. Screening of these compounds in Ellman's assays showed several of them to be good inhibitors of acetylcholinesterase while being less active for butyrylcholinesterase. Activity of the compounds increased with the ring size of the heterocycle, and a maximum of activity was observed for an analog holding 12 methylene groups in the aliphatic side chain. These compounds may be regarded as promising candidates for the development of efficient inhibitors of acetylcholinesterase being useful for the treatment of Alzheimer's disease. PMID- 28802123 TI - Clathrodin, hymenidin and oroidin, and their synthetic analogues as inhibitors of the voltage-gated potassium channels. AB - We have prepared three alkaloids from the Agelas sponges, clathrodin, hymenidin and oroidin, and a series of their synthetic analogues, and evaluated their inhibitory effect against six isoforms of the Kv1 subfamily of voltage-gated potassium channels, Kv1.1-Kv1.6, expressed in Chinese Hamster ovary (CHO) cells using automated patch clamp electrophysiology assay. The most potent inhibitor was the (E)-N-(3-(2-amino-1H-imidazol-4-yl)allyl)-4,5-dichloro-1H-pyrrole-2 carboxamide (6g) with IC50 values between 1.4 and 6.1 MUM against Kv1.3, Kv1.4, Kv1.5 and Kv1.6 channels. All compounds tested displayed selectivity against Kv1.1 and Kv1.2 channels. For confirmation of their activity and selectivity, compounds were additionally evaluated in the second independent system against Kv1.1-Kv1.6 and Kv10.1 channels expressed in Xenopus laevis oocytes under voltage clamp conditions where IC50 values against Kv1.3-Kv1.6 channels for the most active analogues (e.g. 6g) were lower than 1 MUM. Because of the observed low sub micromolar IC50 values and fairly low molecular weights, the prepared compounds represent good starting points for further optimisation towards more potent and selective voltage-gated potassium channel inhibitors. PMID- 28802124 TI - Design, synthesis and bioevaluation of antitubulin agents carrying diaryl-5,5 fused-heterocycle scaffold. AB - A series of 3,6-diaryl-1H-pyrazolo[5,1-c][1,2,4]triazoles (I) and 3,6-diaryl [1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (II) as antitubulin agents were designed, synthesized and bioevaluated. Compounds (II) 4a, 4d, 4f, 4j, 4l and 4n showed potent antiproliferative activity at sub-micromolar or nanomolar concentrations against SGC-7901, A549 and HT-1080 cell lines, indicating that the bioisosteric replacement of the carbonyl group and B-ring of SMART and ABI with a 5,5-fused-heterocycle scaffold successfully maintained potent antiproliferative activity. Compound 4f exhibited the most excellent antiproliferative activity against the three cancer cell lines (IC50 = 0.022-0.029 MUM). Consistent with its potent antiproliferative activity, 4f also displayed excellent antitubulin activity (IC50 = 0.77 MUM). Furthermore, compound 4f could dramatically affect cell morphology and microtubule networking, while cell cycle studies demonstrated that 4f significantly induced SGC-7901 cells arrest in G2/M phase. In addition, molecular docking studies supported the biological assay data and suggested that 4f may be a potential antitubulin agent. PMID- 28802125 TI - Novel 4/3-((4-oxo-5-(2-oxoindolin-3-ylidene)thiazolidin-2-ylidene)amino) benzenesulfonamides: Synthesis, carbonic anhydrase inhibitory activity, anticancer activity and molecular modelling studies. AB - Herein we report the synthesis of two series of novel 4/3-((4-oxo-5-(2-oxoindolin 3-ylidene)thiazolidin-2-ylidene)amino)benzenesulfonamides (4a-m and 7a-g). All the newly prepared sulfonamides were in vitro investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IV and IX, using a stopped-flow CO2 hydrase assay. In particular, hCA isoforms II and IX (tumor-associated) were more susceptible to inhibition by the synthesized derivatives, with KIs in the range of 2.6-598.2 nM for hCA II, and of 16.1-321 nM for hCA IX. All compounds (4a-m and 7a-g) were evaluated for their anti proliferative activity against breast cancer MCF-7 and colorectal cancer Caco-2 cell lines. Compound 4c was found to be the most potent derivative against MCF-7 (IC50 = 3.96 +/- 0.21 MUM), while 4j was the most active member against Caco-2 cells (IC50 = 5.87 +/- 0.37 MUM). Compound 4c induced the intrinsic apoptotic mitochondrial pathway in MCF-7 cells; evidenced by the enhanced expression of the pro-apoptotic protein Bax and the reduced expression of the anti-apoptotic protein Bcl-2, and the up-regulated active caspase-9 and caspase-3 levels. PMID- 28802127 TI - Investigations on the molecular mode of action of the novel immunostimulator ZelNate: Activation of the cGAS-STING pathway in mammalian cells. AB - Bovine respiratory disease (BRD) is usually prevented or treated with vaccines and/or antibiotics. The use of antibiotics is, however, of concern due to the potential promotion of microbial resistance and the occurrence of residues. Recently an alternative aid in the treatment of BRD, the cationic lipid/bacterial plasmid DNA liposome-based immunomodulator ZelNate, has entered the veterinary market. In the present study, we provide data on the molecular mode of action of ZelNate. Despite the presence of numerous non-methylated CpG motifs in its plasmid DNA, ZelNate proved to be inactive on human and mouse toll-like receptor 9 (TLR9) in cell culture, in both recombinant and natural cellular receptor settings. However, in the human monocyte cell line THP1 and in the mouse melanoma cell line B16, ZelNate activates strongly the stimulator of interferon genes (STING) pathway, which is known to lead predominantly to interferon response factor 3 (IRF3) activation. Further analysis in THP1 cells suggests that the ZelNate plasmid DNA activates STING via interaction with cyclic guanylate adenylate synthase (cGAS), but not via interferon induced gene 16 (IFI16). Our in vitro observations suggest that ZelNate may act predominantly via the cGAS/STING/IRF3 pathway. PMID- 28802126 TI - Derp1-modified dendritic cells attenuate allergic inflammation by regulating the development of T helper type1(Th1)/Th2 cells and regulatory T cells in a murine model of allergic rhinitis. AB - The CD4+CD25+Foxp3+ regulatory T cells (Tregs) are known to regulate Th2-induced allergic rhinitis (AR). In this study, we evaluated the efficacy of Derp1 modified dendritic cells (DCs) in AR immunotherapy. Derp1 was synthesized and transfected into DCs to generate Derp1-modified DCs. Phenotypes of Derp1-modified DCs were analyzed with flow cytometry using antibodies against DC markers CD11c, CD11b, CD59, CD103 and Toll-like receptor 1(TLR1). Four groups of subject mice were formed; the controls were treated with immature DCs, while the AR mice models were sensitized with Derp1(AR) and treated with DCs(DC-AR) or Derp1 modified DCs (Derp1DC-AR). The frequency of sneezing and scratching, eosinophil cell count, and Th1/Th2 ratio in the spleen were measured for all groups. The percentage of CD4+CD25+Foxp3+ Tregs in peripheral blood mononuclear cells was measured using flow cytometry; serum IgE, IgG1, and histamine were measured using enzyme-linked immunosorbent assay; expression levels of transcription factors T bet, GATA3, Foxp3+ and IL-10 were analyzed using reverse transcription-polymerase chain reaction, and Western blot used in analyzed expression of Foxp3+ and IL-10 in nasal mucosa. Treatment with Derp1-modified DCs ameliorated the allergic response. The Derp1DC-AR group had significantly lower eosinophil cell count and the IgE, IgG1, and histamine levels than the AR and DC-AR groups, and higher mRNA levels of Th1 transcription factors T-bet, IL-10 and Foxp3 in nasal mucosa than DC-AR mice, but Th2 transcription factors GATA3 mRNA expression level has the opposite results. Furthermore, the Th1/Th2 ratio and percentage of CD4+CD25+Foxp3+ Tregs was significantly lower in the AR group (p<0.05), but higher in the Derp1DC-AR group than in the control group (p<0.01). Thus, the Derp1-modified DCs increased the percentage of CD4+CD25+Foxp3+Tregs and influenced the balance of Th1/Th2, showing an immunotherapeutic effect against AR. PMID- 28802128 TI - Sorption potential of alkaline treated straw and a soil for sulfonylurea herbicide removal from aqueous solutions: An environmental management strategy. AB - The adsorption potential of alkaline treated straw (wheat and corn) in mixture with soil, has been investigated for the removal of sulfonylurea molecules from an aqueous solutions. The surface characteristics were investigated by scanning electron microscopy and Fourier Transform Infrared - FTIR, while the adsorbent capacity was evaluated using batch sorption tests and liquid chromatography coupled with mass spectrometry. Surface analysis of alkaline treated straw samples by scanning electron microscopy - SEM showed the increasing of the surface roughness improving their functional surface activity. An increase (337.22 mg g-1) of adsorption capacity of sulfonylurea molecules was obtained for all studied straw. The Langmuir isotherm model was the best model for the mathematical description of the adsorption process indicating the forming of a surface sorption monolayer with a finite number of identical sites. The kinetics of sulfonylurea herbicide followed the pseudo-second order mechanism corresponding to strong chemical interactions. The results sustained that the alkaline treated straw have biosorption characteristics, being suitable adsorbent materials. PMID- 28802129 TI - Interactions of two novel stabilizing amendments with sunflower plants grown in a contaminated soil. AB - Several efficient stabilizing amendments have been recently proposed for the remediation of metal(loid)-contaminated soils. However, information on their interactions with plants, which is a crucial factor in soil environments, are still scarce. An amorphous manganese oxide (AMO) synthesized from organic compounds and nano zerovalent iron (nZVI) have been previously tested as promising stabilizing agents usable both for the stabilization of metals and As. Experiments with rhizoboxes were performed in order to evaluate their influence on the mobility of metal(loid)s in the bulk soil and rhizosphere of sunflower (Helianthus annuus L.) together with their impact on metal uptake and biomass yield. Generally, AMO proved more efficient than nZVI in all stages of experiment. Furthermore, the AMO effectively reduced water- and 0.01 M CaCl2 extractable fractions of Cd, Pb and Zn. The decreased bioavailability of contaminating metal(loid)s resulted in significant increase of microbial activity in AMO-amended soil. Together with metal(loid) extractability, the AMO was also able to significantly reduce the uptake of metals and ameliorate plant growth, especially in the case of Zn, since this metal was taken up in excessive amounts from the control soil causing strong phytotoxicity and even death of young seedlings. On the other hand, AMO application lead to significant release of Mn that was readily taken up by plants. Resulting Mn concentrations in biomass exceeded toxicity thresholds while plants were showing emergent Mn phytotoxicity symptoms. We highlight the need of such complex studies involving plants and soil biota when evaluating the efficiency of stabilizing amendments in contaminated soils. PMID- 28802130 TI - Trends in the recovery of phosphorus in bioavailable forms from wastewater. AB - Addressing food security issues arising from phosphorus (P) scarcity is described as one of the greatest global challenges of the 21st Century. Dependence on inorganic phosphate fertilisers derived from limited geological sources of P creates an urgent need to recover P from wastes and treated waters, in safe forms that are also effective agriculturally - the established process of P removal by chemical precipitation using Fe or Al salts, is effective for P removal but leads to residues with limited bioavailability and contamination concerns. One of the greatest opportunities for P recovery is at wastewater treatment plants (WWTPs) where the crystallisation of struvite and Ca-P from enhanced biological P removal (EBPR) sludge is well developed and already shown to be economically and operationally feasible in some WWTPs. However, recovery through this approach can be limited to <25% efficiency unless chemical extraction is applied. Thermochemical treatment of sludge ash produces detoxified residues that are currently utilised by the fertiliser industry; wet chemical extraction can be economically feasible in recovering P and other by-products. The bioavailability of recovered P depends on soil pH as well as the P-rich material in question. Struvite is a superior recovered P product in terms of plant availability, while use of Ca-P and thermochemically treated sewage sludge ash is limited to acidic soils. These technologies, in addition to others less developed, will be commercially pushed forward by revised fertiliser legislation and foreseeable legislative limits for WWTPs to achieve discharges of <1 mg P/L. PMID- 28802131 TI - Food contamination by PCBs and waste disposal crisis: Evidence from goat milk in Campania (Italy). AB - AIM: The study aims at investigating whether, and if so, to what extent the strong presence of urban and industrial waste in a territory may cause PCB contamination in goat milk produced therein. METHODS: We compared PCB concentrations in goat milk from three different locations in the Campania region (Italy). One of the three locations, together with its surrounding area, has long suffered from illegal waste disposal and burning mainly by the so-called Ecomafia. The other locations, not involved in these illegal activities, allowed us to create a control group of goats with characteristics very similar to those of main interest. RESULTS: In milk from the waste contaminated area we identified high PCB concentrations (six indicator PCBs amounted to 170 ng g-1 on lipid weight, on average), whereas there was an almost total absence of such pollutants in milk from the control group. Concentrations of the six indicator PCBs were above the current European maximum residue limit fixed by the EU. At the same time, we found a lower average value of lipid content and a negative relationship between lipid content and PCB concentrations. CONCLUSION: Evidence indicates the potential health risk for consumers living in areas involved in illegal dumping of waste. PMID- 28802132 TI - Importance of intra- and interspecific plant interactions for the phytomanagement of semiarid mine tailings using the tree species Pinus halepensis. AB - The objective of this work was to evaluate the effects of plant interactions (intra- and interspecific) on the growth and metal(loid) uptake of the tree species Pinus halepensis to determine its suitability for the phytomanagement of semiarid mine tailings. The pioneer tailings colonizer grass Piptatherum miliaceum was selected for assessing interspecific interactions. The experiment was conducted following a pot experimental design employing mine tailings soil. Pots containing single individuals of P. halepensis or P. miliaceum and pots containing combinations with pines (two pines per pot, or one pine and one grass per pot) were used. The analyses included the determination of plant biomass, foliar element status and stable isotope composition, metal(loid) uptake and its translocation to different plant organs. P. halepensis strongly favoured the growth of P. miliaceum by increasing 9-fold the latter's biomass and alleviating its P limitation. In this interspecific treatment P. halepensis showed a strong N limitation (N/P = 7), which negatively affected its growth, (to about half the biomass of that obtained for the other treatments) and exhibited a significant increase in some metals translocation (especially Cd) into aerial parts. Interestingly, P. miliaceum showed a decrease in the root to leaves translocation factor for most of metals when growing together with pines. The effects of the intraespecific combination on growth and metal uptake in P. halepensis were less relevant than those obtained for the interspecific one. Further research should be focused on testing the behaviour of plant co-cultures under the addition of N or P amendments which could alleviate the negative effects of plant competition. PMID- 28802133 TI - Sorptive removal of ionizable antibiotic sulfamethazine from aqueous solution by graphene oxide-coated biochar nanocomposites: Influencing factors and mechanism. AB - Significant concerns have been raised over antibiotics pollution in aquatic environments in recent years. In this study, sorption of sulfamethazine (SMT) by novel graphene oxide-coated biochar nanocomposites (GO-BC) based on graphene oxide (GO) with bamboo sawdust biochar (BC) was investigated. In comparison with the original BC, the sorption capacity of GO-BC for SMT increased by 1.14 times. Sorption of SMT onto GO-BC was proved to be dominantly by chemisorption, and Freundlich isotherm described the sorption adequately. It was found that variation of pH and ionic strength obviously affected the sorption of SMT, and GO BC had a good sorption effect on SMT at pH 3.0-6.0 and lower ionic strength. Obvious enhancement (by 30%) in sorption of SMT on GO-BC was observed, which might be attributed to the increase of functional groups on the surface of GO-BC. Moreover, the main sorption mechanism for SMT was pi-pi electron-donor-acceptor interaction, while auxiliary sorption mechanisms were inferred as pore-filling, cation exchange, hydrogen bonding interaction and electrostatic interaction. The results indicated that GO-BC sorption was an efficient way for the removal of SMT. PMID- 28802134 TI - Investigating the features in differential absorbance spectra of NOM associated with metal ion binding: A comparison of experimental data and TD-DFT calculations for model compounds. AB - In this study, seven model compounds containing typical functional groups (phenolic and carboxylic groups) present in nature organic matter (NOM) were used to ascertain the nature of the characteristic bands in differential absorbance spectra (DAS) of NOM that are induced by metal ion binding. Some similarities were found between the DAS of the examined model compounds, caffeic acid, ferulic acid, sinapic acid, terephthalic acid, isophthalic acid, esculetin and myricetin and those of NOM. The binding of Cu(II) with carboxylic group might produce two peaks, A1 and A2, while the binding of Cu(II) with phenolic group might produce all four Gaussian peaks, from A1 to A4 displayed in the DAS of NOM. The UV visible spectra predicted using time-dependent density functional theory (TD-DFT) based methods met well with the experimental DAS of model compounds at different stages of Cu(II) binding. It demonstrates that the features in absorbance spectra are chiefly caused by HOMO (Highest Occupied Molecular Orbital) - LUMO (Lowest Unoccupied Molecular Orbital) transitions in the molecule and that the appearance of peaks in DAS reflects the changes of the molecular orbitals around reactive functional groups in a molecule before and after metal ion binding. The basis of the DAS features of NOM that are induced by metal ion binding could be identified primarily by the frontier molecular orbital theory. PMID- 28802135 TI - Environmental drivers that influence microalgal species in fullscale wastewater treatment high rate algal ponds. AB - In the last decade, studies have focused on identifying the most suitable microalgal species for coupled high rate algal pond (HRAP) wastewater treatment and resource recovery. However, one of the challenges facing outdoor HRAP systems is maintaining microalgal species dominance. By increasing our understanding of the environmental drivers of microalgal community composition within the HRAP environment, it may be possible to manipulate the system in such a way to favour the growth of desirable species. In this paper, we investigate the microalgal community composition in two full-scale HRAPs over a 23-month period. We compare wastewater treatment performance between dominant species and identify the environmental drivers that trigger change in community composition. A total of 33 microalgal species were identified over the 23-month period but species richness (the number of species present at any given time) was low and was not related to either productivity or nutrient removal efficiency. Species turnover of the dominant microalgae happened rapidly, typically <1 week. Changes in the influent NH4-N concentration and zooplankton grazer numbers were significantly associated with species turnover, accounting for 80% of the changes in dominant species throughout the 23-month study period. Both nutrient removal and biomass production did not differ between the two HRAPs when the dominant species was the same or differed in the two ponds. These results suggest that microalgal functional groups are more important than individual species for full-scale HRAP performance. This study has increased our understanding of some of the environmental drivers of the microalgae within the HRAP environment, which may assist with improving wastewater treatment and resource recovery. PMID- 28802136 TI - The role of sulfate in aerobic granular sludge process for emerging sulfate-laden wastewater treatment. AB - Sulfate-rich wastewaters pose a major threat to mainstream wastewater treatment due to the unpreventable production of sulfide and associated shift in functional bacteria. Aerobic granular sludge could mitigate these challenges in view of its high tolerance and resilience against changes in various environmental conditions. This study aims to confirm the feasibility of aerobic granular sludge in the treatment of sulfate containing wastewater, investigate the impact of sulfate on nutrient removal and granulation, and reveal metabolic relationships in the above processes. Experiments were conducted using five sequencing batch reactors with different sulfate concentrations operated under alternating anoxic/aerobic condition. Results showed that effect of sulfate on chemical oxygen demand (COD) removal is negligible, while phosphate removal was enhanced from 12% to 87% with an increase in sulfate from 0 to 200 mg/L. However, a long acclimatization of the biomass (more than 70 days) is needed at a sulfate concentration of 500 mg/L and a total deterioration of phosphate removal at 1000 mg/L. Batch tests revealed that sulfide promoted volatile fatty acids (VFAs) uptake, producing more energy for phosphate uptake when sulfate concentrations were beneath 200 mg/L. However, sulfide detoxification became energy dominating, leaving insufficient energy for Polyhydroxyalkanoate (PHA) synthesis and phosphate uptake when sulfate content was further increased. Granulation accelerated with increasing sulfate levels by enhanced production of N-Acyl homoserine lactones (AHLs), a kind of quorum sensing (QS) auto-inducer, using S Adenosyl Methionine (SAM) as primer. The current study demonstrates interactions among sulfate metabolism, nutrients removal and granulation, and confirms the feasibility of using the aerobic granular sludge process for sulfate-laden wastewaters treatment with low to medium sulfate content. PMID- 28802137 TI - Development of novel polysulfone membranes with embedded zirconium sulfate surfactant micelle mesostructure for phosphate recovery from water through membrane filtration. AB - We prepared novel membranes that could adsorb phosphate from water through membrane filtration for use in a phosphate recovery system. Zirconium sulfate surfactant micelle mesostructure (ZS), which was the phosphate adsorbent, was embedded in a polysulfone matrix and flat sheet ultrafiltration membranes were made by nonsolvent induced phase separation. Scanning electron microscopy showed that the ZS particles existed on both the top surface and in the internal surface of the membrane. Increases in ZS content led to greater pure water flux because of increases in the surface porosity ratio. The amount of phosphate adsorbed on the membrane made from the polymer solution containing 10.5 wt% ZS was 0.071 mg P/cm2 (64.8 mg P/g-ZS) during filtration of 50 mg P/L synthetic phosphate solution. The membrane could be repeatedly used for phosphate recovery after regeneration by filtration of 0.1 M NaOH solution to desorb the phosphate. We applied the membrane to treat the effluent from an anaerobic membrane bioreactor as a real sample and successfully recovered phosphate. PMID- 28802138 TI - Inhibition of bioenergetic metabolism by the combination of metformin and 2 deoxyglucose highly decreases viability of feline mammary carcinoma cells. AB - Feline mammary carcinoma (FMC) is a highly aggressive pathology that has been proposed as an interesting model of breast cancer disease, especially for the hormone refractory subgroup. Recently, cancer cell metabolism has been described as a hallmark of cancer cells. Here, we investigate the effects and mechanism of metabolic modulation by metformin (MET, anti-diabetic drug), 2-deoxyglucose (2DG, hexokinase inhibitor) or a combination of both drugs, MET/2DG on two established FMC cells lines: AlRB (HER2 (3+) and Ki67<5%) and AlRATN (HER2 (-) and Ki67>15%). We found that treatments significantly decreased both FMC cells viability by up to 80%. AlRB resulted more sensitive to 2DG than AlRATN (IC50: 3.15 vs 6.32mM, respectively). The combination of MET/2DG potentiated the effects of the individually added drugs on FMC cells. In addition, MET/2DG caused an increased in intracellular oxidants, autophagic vesicles and completely inhibited colony formation. Conversely, only MET significantly altered plasma membrane integrity, presented late apoptotic/necrotic cells and increased both glucose consumption and lactate concentration. Our results support further studies to investigate the potential use of this metabolic modulation approach in a clinical veterinary setting. PMID- 28802139 TI - Analysis of neurobehavioural data by chemometric methods in ecotoxicological studies. AB - Incorporation of chemometric tools in behavioural data management workflows allows for the early identification of most relevant endpoints complementarily to statistical confirmatory approaches. In this work, the effects of two model neurotoxicants, chlorpyrifos (CPF) and nicotine, exposures on behavioural profiles of adult zebrafish at three different times (2, 6 and 24h) were evaluated using open field test (OFT) paradigm experiments. Two chemometric methods like Principal Component Analysis (PCA) and Analysis of Variance Simultaneous Component Analysis (ASCA) have been used to interpret the changes observed in the obtained behavioural data. A decreased of the locomotor activity, an anxiolytic effect and an altered exploratory behaviour were the most affected behavioural endpoints in the CPF exposures. However, an increase of the locomotor activity and an anxiogenic effect were observed in the nicotine exposures. Finally, an excellent correlation between the ASCA results and the results obtained using traditional statistical procedures for both compounds were encountered. PMID- 28802140 TI - Cell density dependence of Microcystis aeruginosa responses to copper algaecide concentrations: Implications for microcystin-LR release. AB - Along with mechanistic models, predictions of exposure-response relationships for copper are often derived from laboratory toxicity experiments with standardized experimental exposures and conditions. For predictions of copper toxicity to algae, cell density is a critical factor often overlooked. For pulse exposures of copper-based algaecides in aquatic systems, cell density can significantly influence copper sorbed by the algal population, and consequent responses. A cyanobacterium, Microcystis aeruginosa, was exposed to a copper-based algaecide over a range of cell densities to model the density-dependence of exposures, and effects on microcystin-LR (MC-LR) release. Copper exposure concentrations were arrayed to result in a gradient of MC-LR release, and masses of copper sorbed to algal populations were measured following exposures. While copper exposure concentrations eliciting comparable MC-LR release ranged an order of magnitude (24-h EC50s 0.03-0.3mg Cu/L) among cell densities of 106 through 107 cells/mL, copper doses (mg Cu/mg algae) were similar (24-h EC50s 0.005-0.006mg Cu/mg algae). Comparisons of MC-LR release as a function of copper exposure concentrations and doses provided a metric of the density dependence of algal responses in the context of copper-based algaecide applications. Combined with estimates of other site-specific factors (e.g. water characteristics) and fate processes (e.g. dilution and dispersion, sorption to organic matter and sediments), measuring exposure-response relationships for specific cell densities can refine predictions for in situ exposures and algal responses. These measurements can in turn decrease the likelihood of amending unnecessary copper concentrations to aquatic systems, and minimize risks for non-target aquatic organisms. PMID- 28802141 TI - Adsorption of the herbicides diquat and difenzoquat on polyurethane foam: Kinetic, equilibrium and computational studies. AB - This work reports a study about the adsorption of the herbicides diquat and difenzoquat from aqueous medium employing polyurethane foam (PUF) as the adsorbent and sodium dodecylsulfate (SDS) as the counter ion. The adsorption efficiency was shown to be dependent on the concentration of SDS in solution, since the formation of an ion-associate between cationic herbicides (diquat and difenzoquat) and anionic dodecylsulfate is a fundamental step of the process. A computational study was carried out to identify the possible structure of the ion associates that are formed in solution. They are probably formed by three units of dodecylsulfate bound to one unit of diquat, and two units of dodecylsulfate bound to one unit of difenzoquat. The results obtained also showed that 95% of both herbicides present in 45mL of a solution containing 5.5mgL-1 could be retained by 300mg of PUF. The experimental data were well adjusted to the Freundlich isotherm (r2 >= 0.95) and to the pseudo-second-order kinetic equation. Also, the application of Morris-Weber and Reichenberg equations indicated that an intraparticle diffusion process is active in the control of adsorption kinetics. PMID- 28802143 TI - Extrinsic control of Wnt signaling in the intestine. AB - The canonical Wnt/beta-catenin signaling pathway is a central regulator of development and tissue homeostasis. In the intestine, Wnt signaling is primarily known as the principal organizer of epithelial stem cell identity and proliferation. Within the last decade, numerous scientific breakthroughs have shed light on epithelial self-organization in the gut, and organoids are now routinely used to study stem cell biology and intestinal pathophysiology. The contribution of non-epithelial cells to Wnt signaling in the gut has received less attention. However, there is mounting evidence that stromal cells are a rich source of Wnt pathway activators and inhibitors, which can dynamically shape Wnt signaling to control epithelial proliferation and restitution. Elucidating the extent and mechanisms of paracrine Wnt signaling in the intestine has the potential to broaden our understanding of epithelial homeostasis, and may be of particular relevance for disorders such as inflammatory bowel diseases and colitis-associated cancers. PMID- 28802142 TI - Overexpression of HO-1 assisted PM2.5-induced apoptosis failure and autophagy related cell necrosis. AB - Severe smog/haze events accompanied by extremely high concentrations of airborne fine particulate matter (PM2.5) have emerged frequently in China and the potential health risks have attracted ever-growing attention. During these episodes, a surge in hospital visits for acute respiratory symptoms and respiratory diseases exacerbation has been reported to be associated with acute exposure to high-levels of particulate matters. To investigate cell fate determination and the underlying pathogenic mechanisms during severe haze episodes or smog events, we exposed human lung epithelial cells (BEAS-2B) to PM2.5 (0-400MUg/mL) for 24h and found that high doses of PM2.5 caused cell necrosis and autophagy dysfunction, while co-treatment with the autophagy inhibitor 3-MA could partially reduce PM2.5-induced cell necrosis. Exposure to PM2.5 also increased the expression and mitochondrial transposition of heme oxygenase 1 (HO-1), which consequently reduced the release of cytochrome C from mitochondria to cytosol. Knockdown of HO-1 by siRNA attenuated the mitochondrial accumulation of HO-1, reversed HO-1-induced the reduction of cytochrome C release and promoted PM2.5-induced cell apoptosis. In contrast to necrosis, PM2.5-induced autophagy was independent of HO-1. In conclusion, our results demonstrate that acute exposure to high PM2.5 concentrations causes autophagy-related cell necrosis. The decrease in cytochrome C release and apoptosis by upregulation of HO-1 maybe assist PM2.5-induced autophagy-related cell necrosis. Further, this study reveals dual roles for HO-1 in PM2.5-induced cytotoxicity and presents a possible explanation for the onset of acute respiratory symptoms under extreme particulate air pollution. PMID- 28802144 TI - The effect of CYP2C19 genetic polymorphism and non-genetic factors on clopidogrel platelets inhibition in East Asian coronary artery disease patients. PMID- 28802145 TI - Ensemble of expert deep neural networks for spatio-temporal denoising of contrast enhanced MRI sequences. AB - Dynamic contrast-enhanced MRI (DCE-MRI) is an imaging protocol where MRI scans are acquired repetitively throughout the injection of a contrast agent. The analysis of dynamic scans is widely used for the detection and quantification of blood-brain barrier (BBB) permeability. Extraction of the pharmacokinetic (PK) parameters from the DCE-MRI concentration curves allows quantitative assessment of the integrity of the BBB functionality. However, curve fitting required for the analysis of DCE-MRI data is error-prone as the dynamic scans are subject to non-white, spatially-dependent and anisotropic noise. We present a novel spatio temporal framework based on Deep Neural Networks (DNNs) to address the DCE-MRI denoising challenges. This is accomplished by an ensemble of expert DNNs constructed as deep autoencoders, where each is trained on a specific subset of the input space to accommodate different noise characteristics and curve prototypes. Spatial dependencies of the PK dynamics are captured by incorporating the curves of neighboring voxels in the entire process. The most likely reconstructed curves are then chosen using a classifier DNN followed by a quadratic programming optimization. As clean signals (ground-truth) for training are not available, a fully automatic model for generating realistic training sets with complex nonlinear dynamics is introduced. The proposed approach has been successfully applied to full and even temporally down-sampled DCE-MRI sequences, from two different databases, of stroke and brain tumor patients, and is shown to favorably compare to state-of-the-art denoising methods. PMID- 28802146 TI - Epigenetic manipulation of host chromatin by Kaposi sarcoma-associated herpesvirus: a tumor-promoting factor? AB - Molecular and epidemiological evidence links Kaposi sarcoma-associated herpesvirus (KSHV) to a number of malignancies of endothelial or B cell origin. As for most virus-associated cancers, however, the tumor initiating and promoting events remain poorly understood. Given the emerging role of epigenetic alterations as drivers of human cancers, an interesting (and as of yet under explored) hypothesis is that viral manipulation of host cell chromatin may contribute to the pathogenesis of KSHV-associated tumors. We here review the current knowledge regarding the interplay between KSHV-encoded factors and host chromatin and discuss how epigenetic alterations may contribute to the pathogenesis of KSHV-associated tumors. PMID- 28802147 TI - Generation of novel resistance genes using mutation and targeted gene editing. AB - Classical breeding for virus resistance is a lengthy process and is restricted by the availability of resistance genes. Precise genome editing is a 'dream technology' to improve plants for virus resistance and these tools have opened new and very promising ways to generate virus resistant plants by disrupting host susceptibility genes, or by increasing the expression of viral resistance genes. However, precise targets must be identified and their roles understood to minimize potential negative effects on the plant. Nonetheless, the opportunities for genome editing are expanding, as are the technologies to generate effective and broad-spectrum resistance against plant viruses. Here we provide insights into recent progress related to gene targets and gene editing technologies. PMID- 28802148 TI - Inattentional blindness in anesthesiology: A simulation study. AB - STUDY OBJECTIVES: Inattentional blindness is the psychological phenomenon of inability to see the unexpected even if it is in plain view. We hypothesized that anesthesiologists may overlook unexpected intraoperative events whereas medical students, lacking in intraoperative monitoring experience and knowledge, may be more likely to notice such events. DESIGN: A simulation study using a video of a simulated septic patient undergoing abdominal surgery. SETTING: A large academic center. PARTICIPANTS: 31 certified anesthesiologists and 46 upper-year medical students. INTERVENTIONS: None. Participants watched a video of a simulated surgery and scored the abnormalities they saw. MEASUREMENTS: These abnormalities included abnormal physiologic parameters consistent with the condition of the simulated septic patient, and two unexpected but plausible events: head movement and a leaky central line catheter. MAIN RESULTS: Students were significantly more likely than anesthesiologists to notice head movement (p<0.001). PMID- 28802149 TI - Ultrasound-guided pectoral nerves (PECS) block: Complications observed in 498 consecutive cases. PMID- 28802150 TI - MiR-let-7a regulates anti-citrullinated protein antibody-induced macrophage activation and correlates with the development of experimental rheumatoid arthritis. AB - Anti-citrullinated protein antibodies (ACPAs) are a key serological marker of rheumatoid arthritis (RA). To investigate whether miR-let7a downregulated ACPA induced macrophage activation and arthritis, miR-let7a levels were assessed in the synovial fluid from patients with RA or osteoarthritis (OA). In addition, expression of the pro-inflammatory genes HMGA2, PI3K, and IRF5 was examined in ACPA-induced macrophages and a collagen antibody-induced mouse model of arthritis. As expected, miR-let7a expression in synovial fluid macrophages was substantially lower in patients with RA than in those with OA. Moreover, ACPAs treatment (160IU/mL) suppressed miR-let7a expression in macrophages isolated from patients with RA. Mechanistic studies revealed that miR-let7a directly targets HMGA2 to suppress ACPA-induced IRF5 expression through PI3K in macrophages. Further, miR-let7a expression was markedly decreased in swollen ankle tissue and splenocytes isolated from arthritic mice, whereas HMGA2, PI3K, and IRF5 expression positively correlated with disease severity. However, injection miR let7a agomir was unable to mitigate the development of experimental arthritis in model mice. Collectively, these data demonstrated that miR-let7a directly targets HMGA2 to downregulate ACPAs-induced macrophage activation, and correlated with experimental RA severity. PMID- 28802151 TI - Sodium butyrate inhibits the NF-kappa B signaling pathway and histone deacetylation, and attenuates experimental colitis in an IL-10 independent manner. AB - Butyrate is a bacterial metabolite of dietary fiber in the colon that has been used to treat inflammatory disease. However, the effect of oral supplementation with butyrate on colitis has not been fully explored. We evaluated the effects of and mechanisms underlying oral supplementation with butyrate on experimental murine colitis. In an in vitro study, we found that LPS induced the secretion of cytokines (i.e., IL-8 in COLO 205; TNF-alpha, IL-6, IL-12, and IL-10 in RAW 264.7; and TNF-alpha, IL-6 and IL-12 in peritoneal macrophages obtained from IL 10-deficient [IL-10-/-] mice). Butyrate (100MUM and 500MUM) inhibited pro inflammatory cytokine production (i.e., IL-8 in COLO205 and TNF-alpha, IL-6 and IL-12 in macrophages) but promoted anti-inflammatory cytokine (i.e., IL-10) production in RAW264.7 cells. Butyrate attenuated both the LPS-induced degradation/phosphorylation of IkappaBalpha and DNA binding of NF-kappaB and enhanced histone H3 acetylation. To confirm that butyrate played a protective role in colitis, an acute colitis model was induced using dextran sulfate sodium (DSS) and a chronic colitis model was induced in IL-10-/- mice. The administration of oral butyrate (100mg/kg) significantly improved histological scores in both colitis models, including the IL-10-/- mice. In immunohistochemical staining, IkappaBalpha phosphorylation was attenuated, and histone H3 acetylation was reversed in the treated colons of both colitis models. Our results indicate that oral supplementation with butyrate attenuates experimental murine colitis by blocking NF-kappaB signaling and reverses histone acetylation. These anti-colitic effects of butyrate were IL-10-independent. Butyrate may therefore be a therapeutic agent for colitis. PMID- 28802152 TI - Comparison and analysis of the structures and binding modes of antifungal SE and CYP51 inhibitors. AB - With the abuse of clinical broad-spectrum antimicrobial agents, immunosuppressive agents, chemotherapy drugs, the emergence of pathogenic fungi resistance is more and more frequent. However, there is still no effective treatment for the fungal resistance. Squalenee epoxidase (SE) and 14 alpha-demethylase (CYP51) are important antifungal drug targets. In order to achieve a deeper insight into the structural characteristics and the action modes of SE and CYP51inhibitors, the homology model of SE (Candida albicans) was constructed using monooxygenase of Pseudomonas aeruginosa as template, and the reliability of model was confirmed by Ramachandran plots and Verify 3D. Subsequently, the molecular superimposition and molecular docking were performed, and the pharmacophore model based on the CYP51 receptor structure was constructed. The results indicate that SE and CYP51 inhibitors have common structural feature with two parts of essential fragments, which are mainly composed of aromatic groups. In addition, the fragment structures of inhibitors are combined in the similar hydrophobic pockets through the hydrophobic forces. The present study provides a deeper perspective to understand the characteristics and docking modes of SE and CYP51 inhibitors. It can be used to guide the optimization and design of SE and CYP51 inhibitors. In addition, it also provides the oretical support for the development of dual target antifungal inhibitors (SE and CYP51), which can help us solve the problem of fungi resistance. PMID- 28802153 TI - A theoretical exploration of the effect of fluorine and cyano substitutions in diketopyrrolopyrrole-based polymer donor for organic solar cells. AB - A series of polymer donor materials 1-5 based on diketopyrrolopyrrole and thiophene unit which have been widely used in organic solar cells (OSCs) were investigated based on quantum chemical calculations. The effect of fluorine and cyano substitutions in polymer donor materials was focused on. Based on the investigation on electronic structures and optical properties of the reported molecules 1 and 2 and the analysis on some parameters relevant to charge dissociation ability at donor/acceptor interface constituted by 1 and 2 with PC61BM such as intermolecular charge transfer and recombination, driving force and Coulombic bound energy, we explained why fluorine substitution can improve OPV efficiency through strengthening eletron-withdrawing ability from a theoretical perspective. Then we designed cyano-substituted polymers 3-5 with the aim of obtaining better photovoltaic donor materials. The results reveal that our attempt to design donor materials which can balance large open-circuit voltage (Voc) and high short-circuit current (Jsc) in OSCs has worked out. It is worth noting that the substitutions of fluorine and cyano groups synergistically reduce energy gap and HOMO energy level of polymers 3 and 4. Moreover, 3/PC61BM and 4/PC61BM heterojunctions show over 107 and 104 times higher than 1/PC61BM on the ratios of intermolecular charge transfer and recombination rates (kinter CT/kinter-CR). Thus, our work here may provide an efficient strategy to design promising donor materials in OPVs and we hope it could be useful in the future experimental synthesis. PMID- 28802154 TI - Optimization of the sensitivity/doses relationship for a bench-top EDXRF system used for in vivo quantification of gold nanoparticles. AB - The present work is devoted to optimizing the sensitivity-doses relationship of a bench-top EDXRF system, with the aim of achieving a detection limit of 0.010mg/ml of gold nanoparticles in tumor tissue (clinical values expected), for doses below 10mGy (value fixed for in vivo application). Tumor phantoms of 0.3cm3 made of a suspension of gold nanoparticles (15nm AurovistTM, Nanoprobes Inc.) were studied at depths of 0-4mm in a tissue equivalent cylindrical phantom. The optimization process was implemented configuring several tube voltages and aluminum filters, to obtain non-symmetrical narrow spectra with fixed FWHM of 5keV and centered among the 11.2-20.3keV. The used statistical figure of merit was the obtained sensitivity (with each spectrum at each depth) weighted by the delivered surface doses. The detection limit of the system was determined measuring several gold nanoparticles concentrations ranging from 0.0010 to 5.0mg/ml and a blank sample into tumor phantoms, considering a statistical fluctuation within 95% of confidence. The results show the possibility of obtaining a detection limit for gold nanoparticles concentrations around 0.010mg/ml for surface tumor phantoms requiring doses around 2mGy. PMID- 28802155 TI - Energy distribution of the neutron flux measurements at the Chilean Reactor RECH 1 using multi-foil neutron activation and the Expectation Maximization unfolding algorithm. AB - We present a methodology to obtain the energy distribution of the neutron flux of an experimental nuclear reactor, using multi-foil activation measurements and the Expectation Maximization unfolding algorithm, which is presented as an alternative to well known unfolding methods such as GRAVEL. Self-shielding flux corrections for energy bin groups were obtained using MCNP6 Monte Carlo simulations. We have made studies at the at the Dry Tube of RECH-1 obtaining fluxes of 1.5(4)*1013cm-2s-1 for the thermal neutron energy region, 1.9(5)*1012cm 2s-1 for the epithermal neutron energy region, and 4.3(11)*1011cm-2s-1 for the fast neutron energy region. PMID- 28802156 TI - Neutron spectrum unfolding using radial basis function neural networks. AB - Neutron energy spectrum unfolding has been the subject of research for several years. The Bayesian theory, Monte Carlo simulation, and iterative methods are some of the methods that have been used for neutron spectrum unfolding. In this study, the radial basis function (RBF), multilayer perceptron, and artificial neural networks (ANNs) were used for the unfolding of neutron spectrum, and a comparison was made between the networks' results. Both neural network architectures were trained and tested using the same data set for neutron spectrum unfolding from the response of LiI detectors with Eu impurity. Advantages of each ANN method in the unfolding of neutron energy spectrum were investigated, and the performance of the networks was compared. The results obtained showed that RBF neural network can be applied as an effective method for unfolding neutron spectrum, especially when the main target is the neutron dosimetry. PMID- 28802157 TI - Droplet digital PCR for rapid enumeration of viral genomes and particles from cells and animals infected with orthopoxviruses. AB - Droplet digital polymerase chain reaction (ddPCR) was adapted for quantifying the number of orthopoxviral genomes in purified virus samples, infected cell lysates and tissues of infected animals. In contrast to the more commonly used qPCR, the newer ddPCR provides absolute numbers of DNA copies in samples without need for standard curves and has the ability to detect rare mutants in a population. The genome/infectious unit ratio for several sucrose gradient-purified orthopoxviruses varied from 5 to 10, which correlated well with values obtained using the Virocyt, a dedicated fluorescence flow cytometer. By employing a nuclease step to digest unencapsulated DNA, the genome/infectious unit ratios of virus in crude cell lysates approached that of purified virus particles. The speed, accuracy, sensitivity, and dynamic range of less than one to millions of infectious units in a sample make this semi-automated method well suited to a variety of laboratory, animal and clinical studies. PMID- 28802158 TI - Lipidation increases antiviral activities of coronavirus fusion-inhibiting peptides. AB - Coronaviruses (CoVs) can cause life-threatening respiratory diseases. Their infectious entry requires viral spike (S) proteins, which attach to cell receptors, undergo proteolytic cleavage, and then refold in a process that catalyzes virus-cell membrane fusion. Fusion-inhibiting peptides bind to S proteins, interfere with refolding, and prevent infection. Here we conjugated fusion-inhibiting peptides to various lipids, expecting this to secure peptides onto cell membranes and thereby increase antiviral potencies. Cholesterol or palmitate adducts increased antiviral potencies up to 1000-fold. Antiviral effects were evident after S proteolytic cleavage, implying that lipid conjugates affixed the peptides at sites of protease-triggered fusion activation. Unlike lipid-free peptides, the lipopeptides suppressed CoV S protein-directed virus entry taking place within endosomes. Cell imaging revealed intracellular peptide aggregates, consistent with their endocytosis into compartments where CoV entry takes place. These findings suggest that lipidations localize antiviral peptides to protease-rich sites of CoV fusion, thereby protecting cells from diverse CoVs. PMID- 28802160 TI - The Computerized Perceptual Motor Skills Assessment: A new visual perceptual motor skills evaluation tool for children in early elementary grades. AB - Visual perceptual motor skills have been proposed as underlying courses of handwriting difficulties. However, there is no evaluation tool currently available to assess these skills comprehensively and to serve as a sensitive measure. The purpose of this study was to validate the Computerized Perceptual Motor Skills Assessment (CPMSA), a newly developed evaluation tool for children in early elementary grades. Its test-retest reliability, concurrent validity, discriminant validity, and responsiveness were examined in 43 typically developing children and 26 children with handwriting difficulty. The CPMSA demonstrated excellent reliability across all subtests with intra-class correlation coefficients (ICCs)>=0.80. Significant moderate correlations between the domains of the CPMSA and corresponding gold standards including Beery VMI, the TVPS-3, and the eye-hand coordination subtest of the DTVP-2 demonstrated good concurrent validity. In addition, the CPMSA showed evidence of discriminant validity in samples of children with and without handwriting difficulty. This article provides evidence in support of the CPMSA. The CPMSA is a reliable, valid, and promising measure of visual perceptual motor skills for children in early elementary grades. Directions for future study and improvements to the assessment are discussed. PMID- 28802159 TI - Increased beta-catenin accumulation and nuclear translocation are associated with concentric hypertrophy in cardiomyocytes. AB - Defective Wnt/beta-Catenin signaling, activated under various pathological conditions, can result in cardiac and vascular abnormalities. In the present study, the possible role of beta-catenin over expression during cardiac hypertrophy was investigated. Ten samples from hearts of human patients with acute infarction, and granulation tissue from 20 patients and 10 from normal ones were collected in order to investigate roles of beta-catenin in cardiac hypertrophy. H9c2 cardiomyoblast cells and Wistar rat primary neonatal cardiomyocytes were overexpressed with beta-catenin. Expression levels of beta catenin protein were increased in human acute infarction tissues and rat hypertension heart tissues. Overexpression of this transcription factor induced actin filament formation and increased hypertrophic marker protein levels via MAPK pathway. In addition, beta-catenin overexpression also resulted in increased elevation of NFATc3 and p-GATA4. Therefore, acute infarction resulted in beta catenin overexpression mediated hypertrophy in cardiomyocytes regulated through MAPK pathway. PMID- 28802161 TI - Physicochemical analysis of Permian coprolites from Brazil. AB - In this paper we performed the study of two coprolites (fossilized feces) collected from the exposed levels of the Pedra de Fogo Formation, Parnaiba Sedimentary Basin, and Rio do Rasto Formation, Parana Sedimentary Basin, both of the Palaeozoic era (Permian age). They were characterized using X-ray diffractometry, infrared, Raman and energy dispersive spectroscopy techniques in order to aid our understanding of the processes of fossilization and to discuss issues related to the feeding habits of the animals which generated those coprolites, probably cartilaginous fishes. The results obtained using a multitechnique approach showed that although these coprolites are from different geological formations, 3000km away from each other, they show the same major crystalline phases and elemental composition. The main phases found were hydroxyapatite, silica, calcite and hematite, which lead to infer that those coprolites were formed under similar conditions and produced by a similar group of carnivore or omnivore fishes. PMID- 28802162 TI - Efficient dynamic graph construction for inductive semi-supervised learning. AB - Most of graph construction techniques assume a transductive setting in which the whole data collection is available at construction time. Addressing graph construction for inductive setting, in which data are coming sequentially, has received much less attention. For inductive settings, constructing the graph from scratch can be very time consuming. This paper introduces a generic framework that is able to make any graph construction method incremental. This framework yields an efficient and dynamic graph construction method that adds new samples (labeled or unlabeled) to a previously constructed graph. As a case study, we use the recently proposed Two Phase Weighted Regularized Least Square (TPWRLS) graph construction method. The paper has two main contributions. First, we use the TPWRLS coding scheme to represent new sample(s) with respect to an existing database. The representative coefficients are then used to update the graph affinity matrix. The proposed method not only appends the new samples to the graph but also updates the whole graph structure by discovering which nodes are affected by the introduction of new samples and by updating their edge weights. The second contribution of the article is the application of the proposed framework to the problem of graph-based label propagation using multiple observations for vision-based recognition tasks. Experiments on several image databases show that, without any significant loss in the accuracy of the final classification, the proposed dynamic graph construction is more efficient than the batch graph construction. PMID- 28802163 TI - Obstructive mobile small intestinal tumor without radiographic stigmata of bezoar. AB - INTRODUCTION: Gastrointestinal leiomyomas are often clinically silent until they bleed or grow large enough to cause local mass effect. PRESENTATION OF CASE: We report the unique case of an otherwise healthy 69-year-old male who developed a small bowel obstruction secondary to a mobile small intestinal leiomyoma. During initial evaluation, computed tomography did not demonstrate the cause of obstruction. Because of worsening clinical status with conservative management, the patient required emergency laparotomy. Operative findings were significant for an intraluminal leiomyoma that had detached from its pedicle, traveled to the tight lumen of the distal ileum and acted as an obstructive "bezoar" composed of native tissue. Removal of the mass resulted in rapid metabolic stabilization and relief of symptoms. DISCUSSION: This case report illustrates the complexity of diagnosing obstruction secondary to intraluminal native tissue. Clinicians must be aware that such masses may clinically present as but not have corresponding radiographic stigmata of typical bezoars. CONCLUSION: In the absence of clear clinical or radiographic etiology for obstruction, developing a heightened degree of suspicion for native tissue "bezoar" may allow quick and appropriate management of similar cases and limit complications associated with prolonged obstruction. To our knowledge, this is the first reported case of mobile intraluminal leiomyoma causing small bowel obstruction. PMID- 28802164 TI - Agenesis of gall bladder in laparoscopic cholecystectomy-A case report. AB - INTRODUCTION: Agenesis of gallbladder is a rare congenital anomaly of biliary tree that may be associated with other biliary and extra biliary congenital anomalies. CASE PRESENTATION: A 43- year- old female presented with a 4 months history of upper abdominal pain associated with nausea and vomiting. It was associated with dyspeptic symptoms and become worse following ingestion of high fat meal contents. Clinically, a differential of gall stone disease was considered. Ultrasonography of abdomen revealed a contracted gallbladder with multiple stones with normal wall thickness, so the fact of clinical diagnosis considering finding cholithiasis. She was submitted to laparoscopic exploration which revealed that the gall bladder was absent within gall bladder fossa. DISCUSSION: In this case, the differential of cholithiasis symptoms considered support by ultrasonography, symptomatic gall stones presented more than half of cases of gall bladder agenesis, Diagnosis of gall bladder disease usually done by ultrasound modality, it must be done by expert one. Awareness of this entity by clinicians, surgeons and radiologists are essential because many of these patients present with biliary symptoms and have unnecessary operations. CONCLUSION: Agenesis of gallbladder should be kept in mind whenever the gall bladder was improperly visualized in routine imaging methods. Ultrasonography operated dependent we must not depend on single one or even multiple done by the same person. Avoid a needless surgical exploration, which might be risky. Non visualized gall bladder during laparoscopic cholecystectomy is challenging should not convert to open unless sure that the gall bladder was present. PMID- 28802165 TI - The world according to GARP transcription factors. AB - Plant specific GARP transcription factor family (made of ARR-B and G2-like) contains genes with very diverse in planta functions: nutrient sensing, root and shoot development, floral transition, chloroplast development, circadian clock oscillation maintenance, hormonal transport and signaling. In this work we review: first, their structural but distant relationships with MYB transcription factors, second, their role in planta, third, the diversity of their Cis regulatory elements, fourth, their potential protein partners. We conclude that the GARP family may hold keys to understand the interactions between nutritional signaling pathways (nitrogen and phosphate at least) and development. Understanding how plant nutrition and development are coordinated is central to understand how to adapt plants to an ever-changing environment. Consequently GARPs are likely to attract increasing research attentions, as they are likely at the crossroads of these fundamental processes. PMID- 28802166 TI - Design, synthesis and alpha-amylase inhibitory activity of novel chromone derivatives. AB - Quercetin is one of the naturally occurring polyphenol flavonoid predominantly known for antidiabetic activity. In the present study, by considering the structural requirements, twenty two novel chromone derivatives (5-26) as alpha amylase inhibitor were designed and subsequently in silico evaluated for drug likeness behavior. Designed compounds were synthesized, characterized by spectral analysis and finally evaluated for the inhibition of alpha-amylase activity by in vitro assay. Tested compounds exhibited significant to weak activity with IC50 range of 12-125uM. Among the tested compounds, analogues 5, 8, 12, 13, 15, 17 and 22 exhibited significant human alpha-amylase inhibitory activity with IC50 values <25uM, which can be further explored as anti-hyperglycemic agents. Putative binding mode of the significant and least active alpha-amylase inhibitors with the target enzyme was also explored by the docking studies. PMID- 28802167 TI - Induction of senescence in cancer cells by 5'-Aza-2'-deoxycytidine: Bioinformatics and experimental insights to its targets. AB - 5'-Aza-2'-deoxycytidine (5-Aza-dC) is a demethylating drug that causes genome wide hypomethylation resulting in the expression of several tumor suppressor genes causing growth arrest of cancer cells. Cancer is well established as a multifactorial disease and requires multi-module therapeutics. Search for new drugs and their approval by FDA takes a long time. Keeping this in view, research on new functions of FDA-approved anticancer drugs is desired to expand the list of multi-module functioning drugs for cancer therapy. In this study, we conducted an analysis for new functions of 5-Aza-dC by applying bio-chemo-informatics approach. The potential of 5-Aza-dC bioactivity was analyzed by PASS online and Molinspiration. Target proteins were predicted by SuperPred. The protein networks and biological processes were analyzed by Biological Networks using Gene Ontology tool, BINGO, based on BIOGRID database. Interactions between 5-Aza-dC and targeted proteins were examined by Autodoc Vina integrated into pyrx software. Induction of p53 by 5-Aza-dC was tested in vitro using cancer cells. Bioinformatics analyses predicted that 5-Aza-dC functions as a p53 inducer, radiosensitizer, and inhibitor of some enzymes. It was predicted to target proteins including MDM2, POLA1, POLB, and CXCR4 that are involved in the induction of DNA damage response and p53-HDM2-p21 signaling. In this study, we provide experimental evidence showing HDM2 is one of the targets of 5-AZA-dC leading to activation of p53 pathway and growth arrest of cells. Furthermore, we found that the combinatorial treatment of 5-AZA-dC with three other drugs caused drug resistance. We discuss that 5-Aza-dC-induced senescence is a multi-module drug that controls cell proliferation phenotype not only by proteins but also by noncoding miRNAs. Further studies are warranted to dissect these mechanisms and establish 5-Aza-dC as an effective multi-module anticancer reagent. PMID- 28802168 TI - Impact of hepatitis B vaccination on HBsAg kinetics, interferon-inducible protein 10 level and recurrence of viremia. AB - BACKGROUND AND AIMS: Persistent HBs antigenemia >1000IU/ml has a possibility of viral reactivation and HCC in 8%, so we investigated the effect of HBV vaccine on HBsAg, IP-10, and recurrence of viremia. METHODS: Group I: inactive carriers(n=100). Group II: CHB exposed to nucleos(t)ides (n=120) till 1year after HBe seroconversion and HBV DNA disappearance in HBeAg positive (n=60) or3years after DNA disappearance in HBeAg negativepatients (n=60). All showed persistent HBs antigenemia. A control group (n=100) did not receive HBV vaccine. 30ug of HBV vaccine initiated at the determined points of time. 3months after the last vaccine dose; IP-10, HBsAb, HOMA-IR and liver stiffness by fibroscanwere evaluated. HBV DNA and HBsAg were detected every 6months for 3years post vaccination. RESULTS: 46 patients (20.9%) were vaccine nonresponders. 174 patients were responders (79.1%). 62 patients (28.2%)cleared HBsAg, 143 patients showed marked reduction of HBsAg (65%). Recurrence of viremia occurred in 4 vaccinated patients (7.8%) vs. 30 patients in the control group (30%,p=0.000). The vaccine enhanced IP-10 which at a cutoff 350pg/ml helped in HBsAg reduction to a favorable level. The vaccine had no significant effect on HOMA-IR nor fibroscan value. CONCLUSIONS: HBV vaccine was efficient in enhancing IP-10 level with HBsAg clearance, or reduction to a favorable level. ClinicalTrials.gov Identifier: NCT03193775. PMID- 28802169 TI - Human health risk assessment on the consumption of fruits and vegetables containing residual pesticides: A cancer and non-cancer risk/benefit perspective. AB - Pesticide residues in food is a public health concern. This study aimed to evaluate health risk and benefit associated with chronic consumption of fruits and vegetables (F&V) containing residual pesticides in the province of Quebec, Canada. Based on a representative sample of Quebecers (n=4727, aged 1-79) enrolled in the Canadian nutrition survey, population's mean chronic dietary exposure through consumption of F&V was evaluated for 169 different pesticide active ingredients (PAI), including 135 for which toxicological reference values (TRV) were available in the literature. Total lifetime cancer risk was estimated to be 3.3*10-4 considering the 28 substances for which an oral slope factor was also available. Non-cancer risk quotients greater than 1 were obtained at the 95th percentile of children's exposure for 10 of the 135 PAIs, and considering the most severe pesticide-specific TRV. Dithiocarbamates and imazalil are the authorized PAI that contribute the most to cancer and non cancer risk; they are therefore identified as "priority" PAI. For each estimated case of cancer triggered by PAI exposure, at least 88 cases were deemed prevented by the consumed F&V, based on the population's etiological fraction of the cancer risk that F&V prevent. Concluding, chronic health risks investigated are low and health benefits of F&V consumption by far outweigh the PAI-related risk. However, risk estimates are not negligeable and uncertainties remain. Thus, reducing PAI exposure through F&V consumption with a particular focus on "priority" PAI mentionned above, while maintaining an abundant and varied F&V diet, is desirable. PMID- 28802170 TI - Airborne particles in indoor environment of homes, schools, offices and aged care facilities: The main routes of exposure. AB - It has been shown that the exposure to airborne particulate matter is one of the most significant environmental risks people face. Since indoor environment is where people spend the majority of time, in order to protect against this risk, the origin of the particles needs to be understood: do they come from indoor, outdoor sources or both? Further, this question needs to be answered separately for each of the PM mass/number size fractions, as they originate from different sources. Numerous studies have been conducted for specific indoor environments or under specific setting. Here our aim was to go beyond the specifics of individual studies, and to explore, based on pooled data from the literature, whether there are generalizable trends in routes of exposure at homes, schools and day cares, offices and aged care facilities. To do this, we quantified the overall 24h and occupancy weighted means of PM10, PM2.5 and PN - particle number concentration. Based on this, we developed a summary of the indoor versus outdoor origin of indoor particles and compared the means to the WHO guidelines (for PM10 and PM2.5) and to the typical levels reported for urban environments (PN). We showed that the main origins of particle metrics differ from one type of indoor environment to another. For homes, outdoor air is the main origin of PM10 and PM2.5 but PN originate from indoor sources; for schools and day cares, outdoor air is the source of PN while PM10 and PM2.5 have indoor sources; and for offices, outdoor air is the source of all three particle size fractions. While each individual building is different, leading to differences in exposure and ideally necessitating its own assessment (which is very rarely done), our findings point to the existence of generalizable trends for the main types of indoor environments where people spend time, and therefore to the type of prevention measures which need to be considered in general for these environments. PMID- 28802171 TI - Parental occupational exposure to benzene and the risk of childhood cancer: A census-based cohort study. AB - BACKGROUND: Previous studies on occupational exposures in parents and cancer risks in their children support a link between solvents and paints with childhood leukaemia. Few studies have focused specifically on benzene. OBJECTIVES: To examine whether parental occupational exposure to benzene is associated with an increased cancer risk in a census-based cohort of children. METHODS: From a census-based cohort study in Switzerland, we included children aged <16years at national censuses (1990, 2000). We retrieved parental occupations reported at census and assessed exposure to benzene using a job exposure matrix. We identified incident cancer cases through record linkage with the Swiss Childhood Cancer Registry. We fitted Cox proportional-hazards models to assess associations between exposures and the following outcomes: any cancer, leukaemia, acute lymphoid leukaemia (ALL), acute myeloid leukaemia (AML), lymphoma, non-Hodgkin lymphoma, central nervous system (CNS) tumours, and glioma. We adjusted models for a range of socio-economic, perinatal and environmental factors. RESULTS: Analyses of maternal (paternal) exposure were based on 9.0 (13.2)millionperson years at risk and included 1004 (1520) cases of cancer, of which 285 (438) had leukaemia, 186 (281) lymphoma, 227 (339) a CNS tumour. Maternal exposure was associated with an increased risk of childhood leukaemia (hazard ratio 1.73, 95% CI 1.12-2.67) and ALL (1.88, 1.16-3.04). We found little evidence of an association for other outcomes or for paternal exposure. Adjusting for potential confounders did not materially affect the results. CONCLUSIONS: This nationwide cohort study suggests an increased risk of leukaemia among children whose mothers were exposed to benzene at work. PMID- 28802173 TI - Fungicidal activity of copper-sputtered flexible surfaces under dark and actinic light against azole-resistant Candida albicans and Candida glabrata. AB - Candida spp. are able to survive on hospital surfaces and causes healthcare associated infections (HCAIs). Since surface cleaning and disinfecting interventions are not totally effective to eliminate Candida spp., new approaches should be devised. Copper (Cu) has widely recognized antifungal activity and the use of Cu-sputtered surfaces has recently been proposed to curb the spread of HCAIs. Moreover, the activity of Cu under the action of actinic light remains underexplored. We investigated the antifungal activity of Cu-sputtered polyester surfaces (Cu-PES) against azole-resistant Candida albicans and Candida glabrata under dark and low intensity visible light irradiation (4.65mW/cm2). The surface properties of Cu-PES photocatalysts were characterized by diffuse reflectance spectroscopy (DRS) and X-ray fluorescence (XRF). Under dark, Cu-PES showed a fungicidal activity (>=3log10CFU reduction of the initial inoculum) against both C. albicans DSY296 and C. glabrata DSY565 leading to a reduction of the starting inoculum of 3.1 and 3.0log10CFU, respectively, within 60min of exposure. Under low intensity visible light irradiation, Cu-PES exhibited an accelerated fungicidal activity against both strains with a reduction of 3.0 and 3.4log10CFU, respectively, within 30min of exposure. This effect was likely due to the semiconductor Cu2O/CuO charge separation. The decrease in cell viability of the two Candida strains under dark and light conditions correlated with the progressive loss of membrane integrity. These results indicate that Cu-PES represent a promising strategy for decreasing the colonization of surfaces by yeasts and that actinic light can improve its self-disinfecting activity. PMID- 28802172 TI - Interaction of phenazinium-based photosensitizers with the 'N' and 'B' isoforms of human serum albumin: Effect of methyl substitution. AB - The present work is focused on exploring the interaction of two phenazinium-based biological photosensitizers, phenosafranin (PSF) and safranin-O (SO), with human serum albumin (HSA), with particular emphasis on the physiologically significant NB conformational transition of the protein on the dye:HSA interaction. In addition, the presence of methyl substitution on the planar phenazinium ring in SO paves way for looking into the effect of simple chemical manipulation (that is, methyl substitution on the dye nucleus) on the dye:protein interaction behavior as a function of various (pH-induced) isoforms of HSA. Our results reveal a significantly stronger binding interaction of SO with the B isoform of HSA (at pH9.0) compared to that with the N isoform (at pH7.4). On the contrary, the PSF:HSA interaction is found to be reasonably insensitive to the aforesaid conformational transition of HSA. However, the probable binding location of both the dye molecules (PSF and SO) is found to be within the protein scaffolds (domain IB). This is further quantified from the modulation of fluorescence decay behavior of the dyes within the protein scaffolds. It is important to note that the rotational relaxation behavior of the protein-bound dyes reveals an unusual 'dip-rise-dip', an observation not reported earlier. Such unusual anisotropy decay is meticulously analyzed by an associated (or multicomponent) exponential decay model which emphasizes on the fractional contributions from differential classes of fluorophore populations characterized by the fast (due to unbound or solvent exposed part of the fluorophore) and slow (due to embedded or bound part) motions, in combination with their different local mobilities. Furthermore, the translational diffusion of the dye molecules in the presence of the protein in different isoforms (N-form or B-form) at a single molecule level is also measured by Fluorescence Correlation Spectroscopy (FCS). PMID- 28802174 TI - Synthesis and characterization of MnO2/NiO nanocomposites for photocatalysis of tetracycline antibiotic and modification with guanidine for carriers of Caffeic acid phenethyl ester-an anticancer drug. AB - In the present studies, modified NiO nanoparticles and MnO2/NiO nanocomposites with guanidine were synthesized by anchoring method for carriers of anticancer drug "Caffeic acid phenethyl ester". The prepared nanocomposites were characterized by using Scanning Electron Microscopy, Raman and Fourier transform infrared spectroscopy, X-ray diffraction, Vibrating sample magnetometer. The results from XRD indicated that the crystalline size of NiO nanoparticles and MnO2/NiO nanocomposites are 12 and 15nm, respectively. Saturation magnetization (Ms) for NiO NPs and MnO2/NiO nanocomposites was to be 0.60, and 0.68emu/g indicating that these are superparamagnetic and ferromagnetic properties in nature. The prepared nanocomposites were evaluated as catalyst for degradation of antibiotics in photocatalysis process. Particularly, the MnO2/NiO composite demonstrated the higher degradation rate (89.55%) of tetracycline antibiotic under UV light irradiation than the NiO (67.80%). Drug load on and release from nanopowders was investigated by using UV-Vis spectroscopy method. Time of drug loading was 100min and the drug release in 1-10h with 20-80% drug release were found, and then, it's applicable to in-vivo drug delivery. Therefore, the NiO nanoparticles and MnO2/NiO nanocomposites are promising for targeted Caffeic acid phenethyl ester anticancer drug delivery applications. The anticancer drug loaded on guanidine-NiO and guanidine-MnO2/NiO in high concentration has an antioxidant property. PMID- 28802176 TI - A rapid and simple protocol to prepare a living biocomposite that mimics electroactive biofilms. AB - A living material was formed by self-assembly of bacterial cells (Shewanella oneidensis MR-1 or Pseudomonas fluorescens) with carbon nanotubes in the presence of cytochrome c from a bovine heart with the goal to mimic electroactive biofilms. The role of cytochrome c on self-assembly, cell viability and extracellular electron transfer was studied. Scanning electron microscopy and dynamic light scattering experiments highlighted its role on the self-assembly of bacteria-carbon nanotube aggregates within only 2h in solution. The deposition of these aggregates on glassy carbon surfaces led to a homogenous composite film in which the bacteria were embedded in a carbon nanotube network. A comparable cell density of 1cellMUm-2 was achieved in the presence or in the absence of cytochrome c, but this protein allowed maintaining a higher bacterial viability. Electrochemical characterization demonstrated the role of cytochrome c on electron transfer reactions, leading to a current density of up to 300MUAcm-2 in the presence of 50mM formate when a porous carbon felt electrode is used as support for the biocomposite. PMID- 28802175 TI - Conjugate of biotin with silicon(IV) phthalocyanine for tumor-targeting photodynamic therapy. AB - In order to improve the efficacy of photodynamic therapy (PDT), biotin was axially conjugated with silicon(IV) phthalocyanine (SiPc) skeleton to develop a new tumor-targeting photosensitizer SiPc-biotin. The target compound SiPc-biotin showed much higher binding affinity toward BR-positive (biotin receptor overexpressed) HeLa human cervical carcinoma cells than its precursor SiPc-pip. However, when the biotin receptors of HeLa cells were blocked by free biotin, >50% uptake of SiPc-biotin was suppressed, demonstrating that SiPc-biotin could selectively accumulate in BR-positive cancer cells via the BR-mediated internalization. The confocal fluorescence images further confirmed the target binding ability of SiPc-biotin. As a consequence of specificity of SiPc-biotin toward BR-positive HeLa cells, the photodynamic effect was also largely dependent on the BR expression level of HeLa cells. The photodynamic activities of SiPc biotin against HeLa cells were dramatically reduced when the biotin receptors were blocked by the free biotin (IC50: 0.18MUM vs. 0.46MUM). It is concluded that SiPc-biotin can selectively damage BR-positive cancer cells under irradiation. Furthermore, the dark toxicity of SiPc-biotin toward human normal liver cell lines LO2 was much lower than that of its precursor SiPc-pip. The targeting photodynamic activity and low dark toxicity suggest that SiPc-biotin is a promising photosensitizer for tumor-targeting photodynamic therapy. PMID- 28802177 TI - DNA biosensors based on gold nanoparticles-modified graphene oxide for the detection of breast cancer biomarkers for early diagnosis. AB - Two different DNA (ERBB2c and CD24c) modified gold nanoparticles and graphene oxide loaded on glassy carbon electrodes were prepared for early detection of breast cancer markers by electrochemical detection of HER2. Comparative study of ERBB2c and CD24c for the detection was carried out. A "sandwich-type" detection strategy was employed in this electrochemical DNA biosensor and its response was measured by amperometric detection. The electrochemical signal enhancement achieved via gold nanoparticles and grapheme oxide system allowed for sensitive detection of the breast cancer biomarker ERBB2 and the control marker CD24. The modified graphene oxide was characterised using Raman spectroscopy, UV-visible spectroscopy, Fourier transform infrared spectroscopy transmission electron microscopy, scanning electron microscopy and energy-dispersive X-ray spectroscopy. The various steps involved in the modification of a glassy carbon electrode with graphene oxide, gold nanoparticles and DNA probes, target and reporter probe were electrochemically characterised using cyclic voltammetry and electrochemical impedance spectroscopy. Using amperometric detection of a horse radish peroxidase label, detection limits of 0.16nM and 0.23nM were obtained with sensitivity 378nA/nM and 219nA/nM for ERBB2 andCD24 respectively. PMID- 28802178 TI - Cardiac arrest due to ventricular fibrillation in a 23-year-old woman with broken heart syndrome. AB - Broken heart syndrome, also known as takotsubo cardiomyopathy, is a syndrome characterized by a transient regional systolic dysfunction of the left ventricle associated to a psychological stress. We herein describe a case of a 23-year-old female habitual marijuana user who was resuscitated after cardiac arrest and then diagnosed with midventricular stress cardiomyopathy complicated by subendocardial hemorrhage. We discuss this unique pathological finding, the incidence of arrhythmias in this syndrome, and the possible relation with chronic cannabis and tobacco use. Unfortunately, the patient did not survive, but had she survived, the management of the patient for secondary prevention would have been challenging considering the risk of recurrence with this disease. PMID- 28802180 TI - New episode of Middle East Respiratory Syndrome Coronavirus outbreak in Saudi Arabia: an emerging public health threat. PMID- 28802179 TI - Prevalence of population smoking cessation by electronic cigarette use status in a national sample of recent smokers. AB - INTRODUCTION: Amid decreasing rates of cigarette smoking and a rise in e cigarette use, there is a need to understand population patterns of use to inform tobacco control efforts and evaluate whether e-cigarettes may play a role in tobacco harm reduction. METHODS: This study merged data from the 2014 and 2015 National Health Interview Survey (NHIS) and restricted the sample to recent smokers [i.e., current smokers and former smokers who quit in 2010 or later (n=15,532)]. Log-binomial regression estimated adjusted prevalence ratios (aPR) for being quit by e-cigarette use status (i.e., daily, some day, former trier, never). All analyses controlled for factors traditionally correlated with smoking cessation. RESULTS: A quarter of the sample (25.2%) were former smokers. The prevalence of being quit was significantly higher among daily e-cigarette users compared to those who had never used e-cigarettes [52.2% vs. 28.2%, aPR: 3.15 (2.66, 3.73)]. Those who used e-cigarettes on some days were least likely to be former smokers (12.1%). These relationships held even after accounting for making a quit attempt and use of other tobacco products. CONCLUSIONS: Among those with a recent history of smoking, daily e-cigarette use was the strongest correlate of being quit at the time of the survey, suggesting that some smokers may have quit with frequent e-cigarette use or are using the products regularly to prevent smoking relapse. However, the low prevalence of cessation among infrequent e cigarette users highlights the need to better understand this subgroup, including the individual factors and/or product characteristics that may inhibit cessation. PMID- 28802181 TI - Temporal change to self-rated health in the Swiss population from 1997 to 2012: the roles of age, gender, and education. AB - OBJECTIVES: Our study aimed to describe the temporal changes in self-rated health status (SRH) from 1997 to 2012 in adults aged 25 to 84 residing in Switzerland, with a view to identifying groups at risk for declining health. STUDY DESIGN: Secondary analysis of population-based cross-sectional health surveys. METHODS: Data were collected from the cross-sectional, population-based, five-year Swiss Health Survey, from 1997, 2002, 2007 and 2012. A total of 63,861 individuals' data were included. Multilevel mixed-effect logistic regression analysis was employed to estimate the probability of very good and good health within the framework of a hierarchical cross-classified age-period-cohort model (HAPC), adjusting for education level, gender, civil status, smoking status and body mass index. RESULTS: Individuals with higher education were substantially more likely than those with primary education to report good SRH (OR = 2.12; 95% CI = 1.93 2.33 for secondary education and OR = 3.79; 95% CI = 3.39-4.23 for tertiary education). The education effect depended on birth cohort and age: higher proportions of good SRH were reported by secondary (8%-17%) and tertiary (10% 22%) compared with primary educated individuals from the 1940 birth cohort onward; the proportion of secondary/tertiary (compared to primary) educated people reporting good SRH increased with age (by 10/11% at 45-50 years and 25/36% at 80-84 years). Gender health equality was achieved by the 1955 (primary educated) and 1960 (secondary educated) birth cohorts, while these women overtook men in reporting good SRH from the 1975 birth cohort onward. Tertiary educated younger women were significantly less likely to report good SRH than men but parity was achieved at around pension age. Similarly, gender inequality in those with primary and secondary education reduced in the younger ages to not be significant at around age 55, with women overtaking men from age 65. CONCLUSIONS: Younger birth cohorts with lower education levels appear most vulnerable in terms of their SRH. The education effect cumulatively increases when attaining incrementally higher education levels. While women report lower health than men, gender inequality in SRH has declined and even reversed over time and is substantially linked to differences in educational status. Swiss public health strategies should particularly target the younger adults with only primary school education of both genders; for women, to combat health burdens in their early life, and men, to mitigate issues in their later life. PMID- 28802182 TI - Inflammatory markers as risk factors for infection with multidrug-resistant microbes in diabetic foot subjects. AB - BACKGROUND: Diabetic foot ulcers (DFUs), a dreadful microvascular complication of diabetes is responsible for substantial increase in morbidity and mortality. Infection, not a cause, but a consequence in DFUs that accounts for minor or major limb loss. The current study aimed to evaluate the microbial etiology of infected diabetic foot ulcers in northern tertiary care hospital, assessment of risk factors and role of inflammatory markers involved in colonization of multidrug-resistant organisms (MDROs) and their impact on the outcome. METHODS: Pus aspirates and soft tissue samples from 65 patients with infected DFUs were collected and processed for aerobic culture analysis. Serum concentrations of IL 6 and TNF-alpha were determined by enzyme linked immuno-sorbent assay. RESULTS: Aerobic gram-negative isolates were more commonly present (74.7%), followed by gram-positive aerobes (25.2%). Fifty-seven percent patients were positive for MDROs. IL-6 (pg/mL) was significantly lower in diabetic patients with MDROs infected foot ulcers than without (47.0+/-17.2 vs. 78.3+/-22.1 vs. p=<0.001) and TNF-alpha (pg/mL) was also significantly diminished in MDROs infected subjects than without (144.2+/-25.8 vs. 168.7+/-20.9, p<0.001) respectively. CONCLUSIONS: In this study diabetic foot wounds harbored by MDROs were associated with longer duration of ulcer and increased ulcer size. Poor glycemic control was also a confounding factor in mounting MDROs infected ulcers. The declined levels WBCs and neutrophils as well as of cytokines IL-6 and TNF-alpha explains compromised immune responses of host in multi drug resistant infections. PMID- 28802183 TI - Very low birth weight is associated with brain structure abnormalities and cognitive function impairments: A systematic review. AB - Very low birth weight (VLBW) children are at risk of structural brain abnormalities and neurocognitive deficits. Since survival rate of the very low birth weight infants has increased over the past decade, a better understanding of the long-term neurocognitive outcomes is needed. The present systematic review investigated the association between VLBW and cognitive function as well as brain structure. PubMed/Medline, Google Scholar, Scopus and Web of Science databases were searched up from January 2000 to January 2015. The study was restricted to the articles that were about VLBW and its association with cognitive function and brain structure. The initial search yielded 721 articles. There were 44 studies eligible for inclusion after applying the exclusion criteria: 24 follow-up, 14 cohort, and 6 longitudinal studies. Based on this systematic review, we suggest that VLBW is positively related to several cognitive problems and brain structure abnormalities. These findings provide evidence about the importance of early assessment of cognitive development and brain structure to identify at-risk children and provide their specific requirements as early as possible. PMID- 28802184 TI - Functional neural bases of numerosity judgments in healthy adults born preterm. AB - High rates of mathematics learning disabilities among individuals born preterm (<37weeksGA) have spurred calls for a greater understanding of the nature of these weaknesses and their neural underpinnings. Groups of healthy, high functioning young adults born preterm and full term (n=20) completed a symbolic and non-symbolic magnitude comparison task while undergoing functional MRI scanning. Collectively, participants showed activation in superior and inferior frontal and parietal regions previously linked to numeric processing when comparing non-symbolic magnitude arrays separated by small numeric distances. Simultaneous deactivation of the default mode network also was evident during these trials. Individuals born preterm showed increased signal change relative to their full term peers in right inferior frontal and parietal regions when comparing the non-symbolic magnitude arrays. Elevated signal change during non symbolic task blocks was associated with poorer performance on a calculation task administered outside of the scanner. These findings indicate that healthy, high functioning adults born preterm may recruit fronto-parietal networks more extensively when processing non-symbolic magnitudes, suggesting that approximate number system training may be an inroad for early intervention to prevent mathematics difficulties in this population. PMID- 28802185 TI - Diagnostic yield and clinical impact of routine cell culture for respiratory viruses among children with a negative multiplex RT-PCR result. AB - BACKGROUND: Polymerase chain reaction (PCR) is the reference standard for respiratory virus testing. However, cell culture may still have added value in identifying viruses not detected by PCR. OBJECTIVES: We aimed to estimate the yield and clinical impact of routine respiratory virus culture among children with a negative PCR result. STUDY DESIGN: A retrospective cohort study was performed from Jan. 2013 to Sept. 2015. Respiratory samples from hospitalized or immunocompromised patients <18years old were routinely inoculated on traditional tube cell culture monolayers if they tested negative by a PCR assay for 12 respiratory viruses. We studied patients with a respiratory specimen negative by PCR and positive by culture. Duplicates and samples of sold services were excluded. Data on demographics, clinical history, laboratory findings, and patient management were collected from patients' charts. Descriptive and multivariate statistics were performed. RESULTS: Overall, 4638 PCR-negative samples were inoculated in cell culture. Of those, 196 (4.2%) were cell culture positive, and 144 met study inclusion criteria. Most subjects (81.9%) were hospitalized. Mean age was 2.4+/-3.4years. The viruses most frequently isolated were cytomegalovirus (33.3%) and enteroviruses (19.4%). Cell culture results prompted a change in management in 5 patients (3.5%), all of whom had acyclovir initiated for localized HSV-1 infection. Four of these had skin or mucosal lesions that could be sampled to establish a diagnosis. CONCLUSION: In children, routine viral culture on respiratory specimens that were negative by PCR has low yield and minimal clinical impact. PMID- 28802186 TI - A L-type lectin gene is involved in the response to hormonal treatment and water deficit in Volkamer lemon. AB - Combination of biotic and abiotic stress is a major challenge for crop and fruit production. Thus, identification of genes involved in cross-response to abiotic and biotic stress is of great importance for breeding superior genotypes. Lectins are glycan-binding proteins with a functions in the developmental processes as well as in the response to biotic and abiotic stress. In this work, a lectin like gene, namely ClLectin1, was characterized in Volkamer lemon and its expression was studied in plants exposed to either water stress, hormonal elicitors (JA, SA, ABA) or wounding to understand whether this gene may have a function in the response to multiple stress combination. Results showed that ClLectin1 has 100% homology with a L-type lectin gene from C. sinensis and the in silico study of the 5'UTR region showed the presence of cis-responsive elements to SA, DRE2 and ABA. ClLectin1 was rapidly induced by hormonal treatments and wounding, at local and systemic levels, suggesting an involvement in defence signalling pathways and a possible role as fast detection biomarker of biotic stress. On the other hand, the induction of ClLectin1 by water stress pointed out a role of the gene in the response to drought. The simultaneous response of ClLectin1 expression to water stress and SA treatment could be further investigated to assess whether a moderate drought stress may be useful to improve citrus performance by stimulating the SA-dependent response to biotic stress. PMID- 28802187 TI - Radiotherapy access in Belgium: How far are we from evidence-based utilisation? AB - INTRODUCTION: Underutilisation of radiotherapy has been observed worldwide. To evaluate the current situation in Belgium, optimal utilisation proportions (OUPs) adopted from the European SocieTy for Radiotherapy and Oncology - Health Economics in Radiation Oncology (ESTRO-HERO) project were compared to actual utilisation proportions (AUPs) and with radiotherapy advised during the multidisciplinary cancer team (MDT) meetings. In addition, the impact of independent variables was analysed. MATERIALS AND METHODS: AUPs and advised radiotherapy were calculated overall and by cancer type for 110,810 unique cancer diagnoses in 2009-2010. Radiotherapy utilisation was derived from reimbursement data and distinguished between palliative and curative intent external beam radiotherapy (EBRT) and/or brachytherapy (BT). Sensitivity analyses regarding the influence of the follow-up period, the survival length and patient's age were performed. Advised radiotherapy was calculated based on broad treatment categories as reported at MDT meetings. RESULTS: The overall AUP of 37% (39% including BT) was lower than the OUP of 53%, but in line with advised radiotherapy (35%). Large variations by tumour type were observed: in some tumours (e.g. lung and prostate cancer) AUP was considerably lower than OUP, whereas in others there was reasonable concordance (e.g. breast and rectal cancer). Overall, 84% of treatments started within 9 months following diagnosis. Survival time influenced AUP in a cancer type-dependent way. Elderly patients received less radiotherapy. CONCLUSION: Although the actually delivered radiotherapy in Belgium aligns well to MDT advices, it is lower than the evidence based optimum. Further analysis of potential barriers is needed for radiotherapy forecasting and planning, and in order to promote adequate access to radiotherapy. PMID- 28802188 TI - Risk of uterine cancer for BRCA1 and BRCA2 mutation carriers. AB - BACKGROUND: Whether BRCA1 and BRCA2 mutation carriers have a clinically relevant elevated risk of uterine cancer has implications for risk-reducing surgery. AIM: This multicentre, prospective cohort study assessed uterine cancer risk for mutation carriers compared with the general population. METHODS: Eligible mutation carriers were enrolled in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) cohort study, had a uterus present and no history of uterine cancer at cohort entry. Epidemiological, lifestyle and clinical data were collected at cohort entry and updated three yearly. Cancer events were verified using pathology reports. Follow-up was censored at death or last contact. Relative risk of uterine cancer was estimated using the standardised incidence ratio (SIR), with the expected number of cases determined using population-based data for Australia. RESULTS: Of 1,111 mutation carriers in kConFab, 283 were excluded due to prior hysterectomy (N = 278), prior uterine cancer (N = 2) or being non-residents (N = 3). After a median follow-up of 9.0 years, five incident uterine cancers were reported in the 828 eligible women (419 had prior breast cancer and 160 had prior tamoxifen use), compared to 2.04 expected (SIR = 2.45; 95% confidence interval [CI]: 0.80-5.72; P = 0.11). In 438 BRCA1 mutation carriers and 390 BRCA2 mutation carriers, three and two incident cases of uterine cancer were reported, respectively, compared to 1.04 expected (SIR = 2.87; 95% CI: 0.59-8.43; P = 0.18) and 0.99 expected (SIR = 2.01; 95% CI: 0.24-7.30; P = 0.52), respectively. All cases were endometrioid subtype, International Federation of Gynaecology and Obstetrics stage I-II disease. No serous uterine cancers were reported. CONCLUSIONS: Our findings are consistent with those from most other reports and do not support routine risk-reducing hysterectomy for BRCA1 and BRCA2 mutation carriers. PMID- 28802189 TI - pT but not pN stage of the 8th TNM classification significantly improves prognostication in pancreatic ductal adenocarcinoma. AB - The UICC TNM (tumour-node-metastasis) staging system for pancreatic ductal adenocarcinoma (PDAC) has been a matter of debate over decades because survival prediction based on T stages was weak and unreliable. To improve staging, the recently published 8th TNM edition (2016) introduced a conceptually completely changed strictly size-based T staging system and a refined N stage for PDAC. To investigate the clinical value of the novel TNM classification, we compared the prognostic impact of pT and pN stage between the 7th and 8th edition in two well characterised independent German PDAC cohorts from different decades, including a total number of 523 patients. Former UICC T staging (7th edition 2009) resulted in a clustering of pT3 cases (72% and 85% of cases per cohort, respectively) and failed to show significant prognostic differences between the four stages in one of the investigated cohorts (p = 0.074). Application of the novel size-based T stage system resulted in a more equal distribution of cases between the four T categories with a predominance of pT2 tumours (65% and 60% of cases). The novel pT staging algorithm showed greatly improved discriminative power with highly significant overall differences between the four pT stages in both investigated cohorts in univariate and multivariate analyses (p < 0.001, each). In contrast, no prognostic differences were observed between the recently introduced pN1 and pN2 categories in both cohorts (p = 0.970 and p = 0.061). pT stage of resected PDAC patients according to the novel UICC staging protocol (8th edition) significantly improves patient stratification, whereas introduction of an extended N stage protocol does not demonstrate high clinical relevance in our cohorts. PMID- 28802190 TI - Alcohol use and bipolar disorders: Risk factors associated with their co occurrence and sequence of onsets. AB - BACKGROUND: Little is known about the sequence of onsets in patients affected by comorbid alcohol use and bipolar disorder. This study examines the risk factors associated with their co-occurrence and order of onset. METHOD: The demographic, clinical, and temperament characteristics as well as the course of illness were analyzed within our sample of 1090 DSM-IV bipolar I manic patients. Our sample was categorized according to the presence of comorbid alcohol use disorder and the sequence of onsets of bipolar and alcohol use disorders i.e., alcohol first (AUD-BD) and bipolar first (BD-AUD). RESULTS: Regression analyses revealed that alcohol use disorder (52.5%) was associated with the male gender, additional substance use disorders, as well as an irritable and a hyperthymic temperament. The AUD-BD group (6.6%) was older than the BD-AUD group (45.8%) and showed higher rates of comorbid sedative use, organic, and anxiety disorders with higher levels of irritable temperament, and a bipolar subtype characterized by depressive polarity at onset. The BD-AUD group had high levels of hyperthymic temperament with higher rates of comorbid stimulant use disorder and a manic polarity at onset. CONCLUSIONS: In the AUD-BD group, alcohol might have been used to reduce stress and tension caused by the presence of an irritable temperament as well as anxious and organic disorders, leading to first depressive episode. In the BD-AUD group, stimulant use might have triggered the first manic episode, and alcohol abuse result from mania severity. PMID- 28802191 TI - A novel method for sex estimation using 3D computed tomography models of tooth roots: A volumetric analysis. AB - Advances in technologies such as computed tomography (CT) scanning have allowed for further examination of dental sexual dimorphism in modern and archaeological populations. PMID- 28802192 TI - Soft-diet feeding impairs neural transmission between mitral cells and interneurons in the mouse olfactory bulb. AB - (Objective) The subventricular zone in mice generates a lot of neuroblasts even during adulthood. These neuroblasts migrate to the olfactory bulb and differentiate into inhibitory interneurons such as granule cells and periglomerular cells. Olfactory sensory neurons receive information from various odorants and transmit it to the olfactory bulb. Our previous study showed that soft-diet feeding impairs neurogenesis in the subventricular zone, in turn leading to the reduction of odor-induced behaviors and Fos-immunoreactivities, the latter of which are markers of neural activity, at the olfactory bulb after exposure to odors. Release of GABA from inhibitory interneurons at the olfactory bulb induces inhibitory currents at the mitral cells, which are output neurons from the olfactory bulb. (Design) In the present study, we measured spontaneous inhibitory postsynaptic currents (sIPSCs) at the mitral cells of mice fed a soft diet in order to explore the effects of changes in texture of diets on neural function at the olfactory bulb. (Results) The soft-diet feeding extended the intervals between sIPSCs and reduced their peak amplitudes. (Conclusions) The present results suggest that soft-diet feeding in mice attenuates the neural functions of inhibitory interneurons at the olfactory bulb. PMID- 28802193 TI - Preparation of bismuth stannate/silver@silver chloride film samples with enhanced photocatalytic performance and self-cleaning ability. AB - We report a novel technique to fabricate bismuth stannate/silver@silver chloride (Bi2Sn2O7/Ag@AgCl) films on conventional glass substrates. The film exhibited a remarkable self-cleaning capability against organic dyes under visible light. Porous Bi2Sn2O7 (BSO) film was first sintered on a glass substrate, followed by implantation of AgCl in it and photo-induction to produce Ag@AgCl. The degradation of organic dyes and photoelectrochemical studies indicate that, compared with BSO film, Bi2Sn2O7/Ag@AgCl film had a much improved photocatalytic ability, probably due to the enhanced electron transfer efficiency and synergistic effect of visible light absorption of the two semiconductors. The possible mechanism of this marked improvement was investigated and interpreted in terms of electrons and holes separation efficiency and charge circulation routes at the interfaces within the Bi2Sn2O7/Ag@AgCl composite film. The film provided in this study may well have practical applications due to its simplicity of preparation, excellent photocatalytic ability and reasonable stability. PMID- 28802194 TI - Direct laser writing of micro-supercapacitors on thick graphite oxide films and their electrochemical properties in different liquid inorganic electrolytes. AB - In this article we demonstrate a simple approach to fabricate interdigitated in plane electrodes for flexible micro-supercapacitors (MSCs). A nanosecond ultraviolet laser treatment is used to reduce and pattern the electrodes on thick graphite oxide (GO) freestanding films. These laser-treated regions obtained by direct writing provide the conducting channels for electrons in the capacitors. The electrochemical performance of the MSCs was evaluated in the presence of two different electrolytes and they exhibit characteristics of nearly electrical double layer capacitors. The MSCs have areal capacitances as 2.40, 2.23 and 1.62MUF/cm2 for NaOH, Na2SO4 and KCl electrolytes respectively, for measurements performed at the scan rate of 50mV/s. They retain ~93.1% of their initial capacitances after 3500 cycles (scan rate=80mV/s) in NaOH electrolyte. The proposed laser treatment approach enables facile and fast fabrication of flexible MSCs without the need for tedious processing methods such as photolithographic micro-patterning and deposition of porous carbon or metallic current collectors. PMID- 28802195 TI - Measurements and simulation of liquid films during drainage displacements and snap-off in constricted capillary tubes. AB - When a wetting liquid is displaced by air in a capillary tube, a wetting film develops between the tube wall and the air that is responsible for the snap-off mechanism of the gas phase. By dissolving a dye in the wetting phase it is possible to relate a measure of the absorbance in the capillary to the thickness of liquid films. These data could be used to compare with cutting edge numerical simulations of the dynamics of snap-off for which experimental and numerical data are lacking. Drainage experiments in constricted capillary tubes were performed where a dyed wetting liquid is displaced by air for varying flow rates. We developed an optical method to measure liquid film thicknesses that range from 3 to 1000MUm. The optical measures are validated by comparison with both theory and direct numerical simulations. In a constricted capillary tube we observed, both experimentally and numerically, a phenomenon of snap-off coalescence events in the vicinity of the constriction that bring new insights into our understanding and modeling of two-phase flows. In addition, the good agreement between experiments and numerical simulations gives confidence to use the numerical method for more complex geometries in the future. PMID- 28802196 TI - Template-free synthesis of hierarchical hollow NiSx microspheres for supercapacitor. AB - Hierarchical nickel sulfide (NiSx) hollow microspheres can be successfully synthesized with a template-free method using alpha-Ni(OH)2 microspheres as a precursor by calcination and sulfidation. The intermediate Ni hollow spheres, formed at different calcination temperatures (300 degrees C and 400 degrees C) under H2/N2 atmosphere, can be easily transformed into NiSx with similar morphology and mixed phases of Ni3S2 and NiS during the followed sulfidation process. The formation processes for the hollow structure of NiSx are also discussed in this work. Particularly, the NiSx prepared from Ni intermediate spheres at 300 degrees C show a high specific capacity of 153.6mAhg-1 at 0.5Ag-1 at high mass loading due to its small crystal size, hierarchically porous structure and high electrical conductivity. A hybrid capacitor was assembled by using it as positive electrode and activated carbon as negative electrode to examine their practical applications in a full-cell configuration. The hybrid capacitor exhibited excellent comprehensive performances in 1.6V. The hybrid capacitor also showed good cycling stability, with 81.25% of the initial specific capacitance after 1000 cycles at 2Ag-1. Above results indicate the great potential of the NiSx hollow spheres as a promising electrode material for supercapacitor applications. PMID- 28802197 TI - Enhanced electrochemical performance of nickel-cobalt-oxide@reduced graphene oxide//activated carbon asymmetric supercapacitors by the addition of a redox active electrolyte. AB - Supercapacitors are an emerging energy-storage system with a wide range of potential applications. In this study, highly porous nickel-cobalt-oxide@reduced graphene oxide (Ni-Co-O@RGO-s) nanosheets were synthesized as an active material for supercapacitors using a surfactant-assisted microwave irradiation technique. The RGO-modified nanocomposite showed a larger specific area, better conductivity, and lower resistivity than the unmodified nanocomposite because the RGO facilitated faster ion diffusion/transport for improved redox activity. The synergistic effect of Ni-Co-O@RGO-s resulted in a high capacitance of 1903Fg-1 (at 0.8Ag-1) in a mixed KOH/redox active K3Fe(CN)6 electrolyte. The asymmetric Ni Co-O@RGO-s//AC supercapacitor device yielded a high energy density and power density of 39Whkg-1 and 7500Wkg-1, respectively. The porous structure and combination of redox couples from both the electrode and electrolyte provided a highly synergistic effect, which improved the performance of the supercapacitor device. PMID- 28802199 TI - Precarious manhood and muscularity: Effects of threatening men's masculinity on reported strength and muscle dissatisfaction. AB - The precarious manhood perspective proposes that men respond with aggression when they experience threats to their masculinity. Consistent with this view, we hypothesized that men would represent themselves as stronger and more formidable after their masculinity was threatened. A recent study, however, found that men reported less physical strength when threatened (Hunt, Gonsalkorale, & Murray, 2013). In the current two studies (Ns=193; 450), men were given false feedback about whether they were substantially less masculine (masculinity threatened) or more masculine than average (masculinity reassured). Men reported how much weight they could curl, how many push-ups they could complete, and/or measures of satisfaction with muscularity. In most analyses, threatened men reported greater strength than reassured men. Effects of masculinity threat on muscle dissatisfaction varied by outcome measure. The studies highlight the importance of replication studies, and of using experimental approaches to understand connections between precarious manhood and male body image. PMID- 28802198 TI - Body image in emerging adults: The protective role of self-compassion. AB - Self-compassion is thought to protect from body image concerns. However, the mechanisms of this effect remain unclear. This study examined three positive dimensions of self-compassion as moderators of the mediated relationship between perceived overweight status, appearance comparison, and appearance esteem. A sample of 232 youth aged 13-18 years, mean=18.36 (SD=1.5) years, reported on appearance esteem, appearance comparison, perceived weight status, and self compassion dimensions including self-kindness, common humanity, and mindfulness. Among boys, mindfulness and common humanity moderated the perceived weight status to appearance comparison pathway of the mediation (ps=.01), such that this relationship was weaker among boys with higher levels of these dimensions of self compassion. These findings were not replicated among girls. None of the self compassion dimensions moderated the appearance comparison to appearance esteem pathway. Self-compassion dimensions that decrease the focus on the self may protect against body image concerns among boys. PMID- 28802200 TI - Seasonal variations in the fatty acid composition of Greek wild rabbit meat. AB - The fatty acid (FA) profile of the Longissimus thoracis et lumborum muscle (LL) was used to investigate seasonal variation (September, November and March) in wild rabbits from Lemnos Island (Greece). The n-3 FA were particularly high during early March in comparison (P<0.05) with late September and late November. Thrombogenicity index (TI) values were lower in March (P<0.05) compared to the other periods. High concentrations of odd- and branched-chain FA were found in the meat of wild rabbits; however, they were not different among the considered periods of the year. The present results showed that wild rabbit meat has a desirable FA profile, particularly during early spring, and it could be a good source of bioactive FA in human nutrition. PMID- 28802201 TI - Biomimetic Surfaces Supporting Dissociated Pancreatic Islet Cultures. AB - This study describes a method to screen biomimetic surfaces based on intracellular insulin content of either fully or partly dissociated primary endocrine islet tissue. It is challenging to maintain endocrine pancreatic islets and more so, dissociated ones. Physiological activity of isolated islet cells in vitro declines due to loss of cell-to-cell and cell-to-extracellular matrix interactions. An in vitro model was developed to evaluate specific extracellular binding components potentially affecting islet biology, with the intention to identify in vivo-like peptides promoting survival and function. Synthetic peptides were bound to low-fouling carboxy-methyl-dextran surfaces, effectively presenting defined surfaces while minimizing non-specific interactions. These biomimetic surfaces were screened based on intracellular insulin content of applied mouse primary islet tissue by analysis with an anti-insulin cell-ELISA. Three active biomimetic surfaces were identified, two laminin- (IKLLI and PDSGR) and one cadherin (HAVDI)-derived, which supported adhesion and survival of insulin-containing cultures for 5days, respectively suggesting a benefit from both cell-extracellular matrix and cell-cell interactions. Cells from dissociated islets show progression over 10days on the HAVDI-biomimetic for the insulin immunoreactivity and cell density. The three surfaces did not act additively or synergistically. A favorable reaction to glucose-stimulated insulin secretion on the cadherin-biomimetic indicated the cultures were physiologically functional. This supportive role of biomimetic peptides represents initial progress in defining minimal extracellular binding requirements influencing islet cell physiology. This will influence further optimization of growth surfaces and promote the basic understanding of islet biology. Low-fouling biomimetics are predicted to be applicable to additional diverse culture systems. PMID- 28802202 TI - A thermosensitive drug delivery system prepared by blend electrospinning. AB - In this study, the thermosensitive polymer poly(di(ethylene glycol) methyl ether methacrylate) (PDEGMA) was synthesized and electrospun into fibers by blending with ethyl cellulose (EC). Fibers were additionally prepared loaded with ketoprofen (KET) as a model drug. Smooth cylindrical fibers could generally be observed by electron microscopy, although there were some beads and fused fibers visible in the KET-loaded materials. KET was found to be amorphously distributed in the fibers on the basis of X-ray diffraction data. From water contact angle measurements, it was clear that the wettability of the EC/PDEGMA systems changed as the temperature increased, with the fibers becoming markedly more hydrophobic. In vitro drug release studies showed that KET was released over a prolonged period of time with the fibers having different profiles at 25 and 37 degrees C, reflecting their thermosensitive properties. Furthermore, the materials were found to have good biocompatibility towards L929 fibroblasts. Thus, the fibers prepared in this work have potential as smart stimuli-responsive drug delivery systems. PMID- 28802203 TI - Disentangling the origins of virophages and polintons. AB - Virophages and polintons are part of a complex system that also involves eukaryotes, giant viruses, as well as other viruses and transposable elements. Virophages are cosmopolitan, being found in environments ranging from the Amazon River to Antarctic hypersaline lakes, while polintons are found in many single celled and multicellular eukaryotes. Virophages and polintons have a shared ancestry, but their exact origins are unknown and obscured by antiquity and extensive horizontal gene transfer (HGT). Paleovirology can help disentangle the complicated gene flow between these two, as well as their giant viral and eukaryotic hosts. We outline the evidence and theoretical support for polintons being descended from viruses and not vice versa. In order to disentangle the natural history of polintons and virophages, we suggest that there is much to be gained by embracing rigorous metagenomics and evolutionary analyses. Methods from paleovirology will play a pivotal role in unravelling ancient relationships, HGT and patterns of cross-species transmission. PMID- 28802205 TI - Evaluation of electrospinning parameters on the tensile strength and suture retention strength of polycaprolactone nanofibrous scaffolds through surface response methodology. AB - Scaffolds should provide sufficient biomechanical support during tissue regeneration for tissue engineering (TE) applications. Electrospun scaffolds are commonly applied in TE applications due to their tunable physical, chemical, and mechanical properties as well as their similarity to extracellular matrix. Although the mechanical properties of electrospun scaffolds are highly dependent on processing parameters, a limited number of studies have systematically investigated this subject. The present study has investigated the effects of the main electrospinning parameters on tensile and suture retention strength of polycaprolactone (PCL) scaffolds using response surface methodology. Scaffolds morphology and cell-scaffold interaction were also investigated in this study. According to the fitted model, polymer concentration and feed rate have the most significant positive effect on both the tensile and suture retention strength. Whereas applied voltage negatively affected both the tensile and suture retention strength. The effect of distance on tensile strength was not significant while its effect on suture retention was different depending on its values. Changes in biomechanical properties were associated with gross alterations in morphology of the fibers and cell-scaffold interaction. Scaffolds with lowest tensile strength presented a beaded morphology while scaffolds with higher tensile strength presented beadless morphology with worm-like fibers. The increase in tensile strength was correlated with the increase in average diameter of the fibers and pore size. The results of cell culture study showed that fibroblasts stretched and proliferated more on scaffolds with lower tensile strength. The generated model might be helpful when PCL scaffold with desirable tensile and suture retention strength are required. Furthermore, the results suggest that changes in morphology and subsequent cell-scaffold interaction should be considered when these biomechanical properties are optimized. PMID- 28802204 TI - Humanized mouse models to study human cell-mediated and humoral responses to dengue virus. AB - Several candidate dengue virus vaccines are in clinical trials and show promise as an effective measure to control dengue. However, it is becoming clear that additional vaccine candidates may be needed as there is concern about the durability of the immune response to all four serotypes of vaccine components and efficacy varies dependent on the immune status of the individual. The lack of an appropriate animal model to mimic human dengue has deterred the development of vaccines and anti-viral therapies to dengue virus. The focus of this review is to discuss advances in the development of humanized animal models and to highlight how they could be used for antiviral and dengue vaccine testing if limitations with cell-mediated immunity and seroconversion to IgG are overcome. PMID- 28802206 TI - Perfluoroalkyl substance exposure and urine CC16 levels among asthmatics: A case control study of children. AB - BACKGROUND: Studies have reported an association between serum perfluoroalkyl substances (PFASs) and asthma. However, few studies have examined the possible associations between PFASs and the 16-kDa club cell secretory protein (Clara) (CC16) level, a prominent biomarker of asthma, among adolescents. METHODS: We recruited a total of 231 asthmatic children and 225 non-asthmatic controls in the Genetic and Biomarkers study for Childhood Asthma (GBCA) in northern Taiwan from 2009 to 2010. Structured questionnaires were administered by face-to-face interview. Urine CC16 was determined by an enzyme-link immunoassay kit. Multiple general linear models were employed to examine the associations between PFASs and urinary CC16 levels. RESULTS: Asthmatic participants had significantly higher serum PFAS concentrations overall than the healthy controls. After adjusting for confounding factors, urinary CC16 was significantly, negatively associated with PFASs, especially PFOS, PFOA, PFDA and PFNA, and especially among males, as follows: PFOS (beta = -0.003, 95% confidence interval [CI]: -0.004, -0.002), PFOA (beta = -0.045, 95% CI: -0.086, -0.004), and PFHxA (beta = -0.310, 95% CI: 0.455, -0.165) among asthmatic boys, and PFDA (beta = -0.126, 95%CI: -0.241, 0.012) and PFNA (beta = -0.329, 95% CI: -0.526, -0.132) among non-asthmatic boys. Among girls, PFDA (beta = -0.088, 95% CI: -0.172, -0.004), was the only PFAS significantly associated with CC16. Significant interaction effects (p < 0.15) on CC16 levels were found between asthma and PFOS, PFOA, PFBS and PFHxA in all participants. CONCLUSION: Our overall results showed that serum PFASs were significantly, inversely associated with CC16 levels. Associations were stronger among males. PMID- 28802207 TI - The effect of aluminium and sodium impurities on the in vitro toxicity and pro inflammatory potential of cristobalite. AB - BACKGROUND: Exposure to crystalline silica (SiO2), in the form of quartz, tridymite or cristobalite, can cause respiratory diseases, such as silicosis. However, the observed toxicity and pathogenicity of crystalline silica is highly variable. This has been attributed to a number of inherent and external factors, including the presence of impurities. In cristobalite-rich dusts, substitutions of aluminium (Al) for silicon (Si) in the cristobalite structure, and impurities occluding the silica surface, have been hypothesised to decrease its toxicity. This hypothesis is tested here through the characterisation and in vitro toxicological study of synthesised cristobalite with incremental amounts of Al and sodium (Na) dopants. METHODS: Samples of synthetic cristobalite with incremental amounts of Al and Na impurities, and tridymite, were produced through heating of a silica sol-gel. Samples were characterised for mineralogy, cristobalite purity and abundance, particle size, surface area and surface charge. In vitro assays assessed the ability of the samples to induce cytotoxicity and TNF-alpha production in J774 macrophages, and haemolysis of red blood cells. RESULTS: Al-only doped or Al+Na co-doped cristobalite contained between 1 and 4 oxide wt% Al and Na within its structure. Co-doped samples also contained Al- and Na-rich phases, such as albite. Doping reduced cytotoxicity to J774 macrophages and haemolytic capacity compared to non-doped samples. Al-only doping was more effective at decreasing cristobalite reactivity than Al+Na co doping. The reduction in the reactivity of cristobalite is attributed to both structural impurities and a lower abundance of crystalline silica in doped samples. Neither non-doped nor doped crystalline silica induced production of the pro-inflammatory cytokine TNF-alpha in J774 macrophages. CONCLUSIONS: Impurities can reduce the toxic potential of cristobalite and may help explain the low reactivity of some cristobalite-rich dusts. Whilst further work is required to determine if these effects translate to altered pathogenesis, the results have potential implications for the regulation of crystalline silica exposures. PMID- 28802208 TI - Acute effects of visits to urban green environments on cardiovascular physiology in women: A field experiment. AB - BACKGROUND: Epidemiological studies have reported positive associations between the amount of green space in the living environment and mental and cardiovascular human health. In a search for effect mechanisms, field studies have found short term visits to green environments to be associated with psychological stress relief. Less evidence is available on the effect of visits on cardiovascular physiology. OBJECTIVES: To evaluate whether visits to urban green environments, in comparison to visits to a built-up environment, lead to beneficial short-term changes in indicators of cardiovascular health. METHODS: Thirty-six adult female volunteers visited three different types of urban environments: an urban forest, an urban park, and a built-up city centre, in Helsinki, Finland. The visits consisted of 15min of sedentary viewing, and 30min of walking. During the visits, blood pressure and heart rate were measured, and electrocardiogram recorded for the determination of indicators of heart rate variability. In addition, levels of respirable ambient particles and environmental noise were monitored. RESULTS: Visits to the green environments were associated with lower blood pressure (viewing period only), lower heart rate, and higher indices of heart rate variability [standard deviation of normal-to-normal intervals (SDNN), high frequency power] than visits to the city centre. In the green environments, heart rate decreased and SDNN increased during the visit. Associations between environment and indicators of cardiovascular health weakened slightly after inclusion of particulate air pollution and noise in the models. CONCLUSIONS: Visits to urban green environments are associated with beneficial short-term changes in cardiovascular risk factors. This can be explained by psychological stress relief with contribution from reduced air pollution and noise exposure during the visits. Future research should evaluate the amount of exposure to green environments needed for longer-term benefits for cardiovascular health. PMID- 28802209 TI - Commentary on current changes of the SoHT 2016 consensus on alcohol markers in hair and further background information. AB - The consensus on alcohol markers in hair was revised for the fourth time by an expert group of the Society of Hair Testing based on current state of research. This revision was adopted by the members of the Society during the business meeting in Brisbane on August 29th 2016. For both markers, ethyl glucuronide (EtG) and fatty acid ethyl esters (FAEEs), two cut-off values for discrimination between teetotalers or occasional low amount consumption and moderate alcohol drinking (low cut-off), and between non-excessive (abstinence up to moderate alcohol intake) and chronic excessive drinking (high cut-off value) were critically examined. For the current revision, the cut-off values for EtG (7pg/mg and 30pg/mg, respectively) remained unchanged despite different findings or discussions published in the meantime. This was mainly due to the lack of broader data collections from new studies with great numbers of volunteers following thorough study concepts. In contrast, an essential change of the consensus was accepted for the FAEEs, where the concentration of ethyl palmitate (E16:0) can be used autonomously for interpretation instead of the concentration sum (SigmaFAEE) of the four esters ethyl myristate, ethyl palmitate, ethyl oleate and ethyl stearate, as previously applied. After evaluation of the data from seven laboratories, the E16:0 cut-off for abstinence assessment was defined at 0.12ng/mg for the 0-3cm segment and at 0.15ng/mg for the 0-6cm segment. The cut off for chronic excessive drinking was fixed at 0.35ng/mg for the 0-3cm segment and at 0.45ng/mg for the 0-6cm segment. The use of E16:0 with these cut-offs in place of SigmaFAEE for alcohol intake assessment produces only a minor loss in discrimination power, leads to no essential difference in the interpretation concerning chronic excessive alcohol consumption and is suitable to confirm EtG results in abstinence assessment if ethanol containing hair sprays or lotions are excluded. PMID- 28802210 TI - The adoption of children from out-of-home care: The understandings of key decision makers in Victoria, Australia. AB - Adoption is one of a range of options that can provide children in out-of-home care with permanency when they are unable to be reunified with their birth parents. This paper reports on how the adoption of children from out-of-home care is understood by professionals involved in making decisions about the permanent placement of children in out-of-home care in Victoria, Australia, where adoption is rarely used. Data were collected through a single, face-to-face semi structured interview with 21 professionals; eight child welfare specialists, eight adoption and permanent care specialists and five judicial officers. The adoption of children from out-of-home care was primarily understood as a child centered practice that can afford children stability and a sense of belonging. Adoption was largely viewed as a voluntary process dependent upon the consent of a child's birth parents. Adoption and permanent care specialists were the only group to refer to the dispensation of parental consent as a means of obtaining an adoption order. Most decision makers understood that contact between children and their birth parents is possible following adoption, but this was not understood by all judicial officers or all child welfare specialists. Children's connection to their cultural heritage was viewed as important to the consideration of adoption for children in out-of-home care. This research provides insight into the foundations upon which decision makers may appraise adoption, within a hierarchy of options, as a potential outcome for children in need of permanency. PMID- 28802211 TI - Research priority setting for integrated early child development and violence prevention (ECD+) in low and middle income countries: An expert opinion exercise. AB - Child development in low and middle income countries (LMIC) is compromised by multiple risk factors. Reducing children's exposure to harmful events is essential for early childhood development (ECD). In particular, preventing violence against children - a highly prevalent risk factor that negatively affects optimal child development - should be an intervention priority. We used the Child Health and Nutrition Initiative (CHNRI) method for the setting of research priorities in integrated Early Childhood Development and violence prevention programs (ECD+). An expert group was identified and invited to systematically list and score research questions. A total of 186 stakeholders were asked to contribute five research questions each, and contributions were received from 81 respondents. These were subsequently evaluated using a set of five criteria: answerability; effectiveness; feasibility and/or affordability; applicability and impact; and equity. Of the 400 questions generated, a composite group of 50 were scored by 55 respondents. The highest scoring research questions related to the training of Community Health Workers (CHW's) to deliver ECD+ interventions effectively and whether ECD+ interventions could be integrated within existing delivery platforms such as HIV, nutrition or mental health platforms. The priority research questions can direct new research initiatives, mainly in focusing on the effectiveness of an ECD+ approach, as well as on service delivery questions. To the best of our knowledge, this is the first systematic exercise of its kind in the field of ECD+. The findings from this research priority setting exercise can help guide donors and other development actors towards funding priorities for important future research related to ECD and violence prevention. PMID- 28802212 TI - Pharmacophore based design of some multi-targeted compounds targeted against pathways of diabetic complications. AB - Diabetic complications is a complex metabolic disorder developed primarily due to prolonged hyperglycemia in the body. The complexity of the disease state as well as the unifying pathophysiology discussed in the literature reports exhibited that the use of multi-targeted agents with multiple complementary biological activities may offer promising therapy for the intervention of the disease over the single-target drugs. In the present study, novel thiazolidine-2,4-dione analogues were designed as multi-targeted agents implicated against the molecular pathways involved in diabetic complications using knowledge based as well as in silico approaches such as pharmacophore mapping, molecular docking etc. The hit molecules were duly synthesized and biochemical estimation of these molecules against aldose reductase (ALR2), protein kinase Cbeta (PKCbeta) and poly (ADP ribose) polymerase 1 (PARP-1) led to identification of compound 2 that showed good potency against PARP-1 and ALR2 enzymes. These positive results support the progress of a low cost multi-targeted agent with putative roles in diabetic complications. PMID- 28802214 TI - The relationship between physical activity, meaning in life, and subjective vitality in community-dwelling older adults. AB - The present study examined the potential contribution of meaning in life to the relationship between physical activity and subjective vitality in older adults. Two-hundred and fifty community-dwelling elders completed the instruments assessing physical activity, meaning in life, and subjective vitality. Results from structural equation modeling indicated that physical activity was positively associated with both meaning in life and subjective vitality. Further, the relationship between physical activity and vitality was partially mediated by meaning in life. Although previous studies have consistently found a positive impact of physical activity on vitality, the current study suggested that it is more productive to focus not only on physical activity, but also on meaning in life, in order to vitalize elders. Further, a focus on meaning in life can be a productive way to continue to vitalize older adults who are unable to engage in regular physical activity. PMID- 28802213 TI - Influence of nitrogen doping in sumanene framework toward hydrogen storage: A computational study. AB - Two conditions are important to obtain appropriate substances for hydrogen storage; high surface area and fitting binding energy (BE). Doping is a key strategy that improves BE. We investigated hydrogen adsorption onto twenty six nitrogen disubstituted isomers of sumanene (C19N2H12) by MP2/6 311++G(d,p)//B3LYP/6-31+G(d) and M06-2X/6-31+G(d) levels of theory. Effect of nitrogen doping in different positions of sumanene was checked. To obtain better BE, basis set superposition error (BSSE) and zero point energy (ZPE) corrections were used. Anticipating of adsorption sites and extra details about adsorption process was done by molecular electrostatic potential (MEP) surfaces. Various types of density of state (DOS) diagrams such as total DOS (TDOS), projected DOS (PDOS) and overlap population DOS (OPDOS) and natural bond orbital (NBO) analysis were used to find better insight on the adsorption properties. In addition of temperature depending of the BE, HOMO-LUMO gap (HLG), dipole moment, reactivity and stability, bowl depth and natural population analysis (NPA) of the isomers were studied. A physisorption mechanism for adsorption was proposed and a trivial change was seen. Place of nitrogen atoms in sumanene frame causes to binding energy increases or decreases compared with pristine sumanene. The best and the worst isomers and category of isomers were suggested. PMID- 28802215 TI - Predictors of self-reported knee osteoarthritis in community-dwelling older women in Japan: A cross-sectional and longitudinal cohort study. AB - PURPOSE: This study aimed to determine the predictors of knee osteoarthritis in community-dwelling elderly Japanese women. METHODS: In this prospective cohort study, The Tokyo Metropolitan Institute of Gerontology collected baseline data in 2008 and follow-up data in 2012 for participants from the Itabashi Ward of Tokyo, Japan. Participants were asked at each time point if they had been diagnosed with knee osteoarthritis. The baseline evaluation was conducted with 1289 community dwelling women aged 75-85 years, of which 992 reported no history of knee osteoarthritis. The follow-up survey targeted these 992 participants; we obtained history of knee osteoarthritis from 867 of these participants. The baseline evaluation also included collection of anthropometric, fitness, hematologic, and lifestyle data. RESULTS: We performed logistic regression analysis of the cross sectional data at baseline. Participants who reported fewer light exercise sessions (<=2-4days/week) had lower odds ratios for history of self-reported knee osteoarthritis than those who reported more frequent exercise (>=5-6days/week). Logistic regression analysis of the longitudinal data revealed that slow walking speed (<65.22m/min), low serum albumin levels (<4.10g/dL), and low frequency of soy product consumption (<=1 time per 2days) at baseline resulted in higher odds ratios for incidence of self-reported knee osteoarthritis during the 4-year follow-up period. CONCLUSIONS: The results suggest that slow walking speed, low serum albumin, and insufficient consumption of soy products are predictors for knee osteoarthritis in elderly Japanese women. These results could help in the design of knee osteoarthritis prevention programs for elderly women. PMID- 28802216 TI - Knowledge regarding advance care planning: A systematic review. AB - BACKGROUND: Lack of knowledge is one of the main reasons for the low rates of completion of Advance Care Planning (ACP). OBJECTIVE: The purpose of this study was to systematically review the existing literature on knowledge regarding Advance Care Planning. METHODS: A systematic search of the literature was made in CINHAL, AgeLine, PubMed, PsyINFO and SocINDEX, from 1994 till May 2016. RESULTS: We identified 37 articles that satisfied the inclusion criteria: 35 were quantitative, one was qualitative and one used mixed methods. Most of the studies (n=23) were conducted in the United States and participants in most of the studies (n=22) were professionals. A variety of aspects of ACP were examined, regarding subjective and objective knowledge. Seventeen studies found that participants knew some aspects of ACP, but didn't know others. Inconsistencies were found in the types of instruments and the number of items used to assess knowledge. CONCLUSIONS: More effort should be invested in increasing knowledge regarding ACP among professionals and lay people. Developing validated tools to measure objective and subjective knowledge in both populations might be a first step in this direction. PMID- 28802217 TI - Comparatively evaluating the pharmacokinetic of fifteen constituents in normal and blood deficiency rats after oral administration of Xin-Sheng-Hua Granule by UPLC-MS/MS. AB - Xin-Sheng-Hua Granule (XSHG), a famous traditional Chinese medicine prescription, are clinically applied for the treatment of postpartum disease through nourishing blood and promoting blood circulation. In this investigation, a multi constituents (trigonelline, stachydrine hydrochloride, hydroxysafflor yellow A, chlorogenic acid, amygdalin, leonurine, liquiritin, ferulic acid, senkyunolide I, senkyunolide H, glycyrrhizic acid, senkyunolide A, ligustilide, butylidenephthalide and glycyrrhetinic acid) pharmacokinetic study of XSHG was conducted for the first time. These fifteen constituents in both normal and blood deficiency rat plasma were monitored by using the established and validated ultra high-performance liquid chromatography coupled with a triple quadrupole electrospray tandem mass spectrometry (UPLC-TQ-MS/MS) method. The samples were prepared through removing protein from plasma with three volumes of methanol. Sufficient separation of target constituents and internal standards (chloramphenicol and clarithromycin) was obtained on a Thermo Scientific Hypersil GOLD column (100mm*3mm, 1.9MUm) within a 20min gradient elution (0.1% formic acid aqueous - acetonitrile). Multiple reaction monitoring (MRM) mode was applied to monitor target analytes in both positive and negative electrospray ionization. For the fifteen selected target analytes, this method was fully validated with excellent linearity (r>=0.9925), satisfactory intra- and inter-day precisions (RSD<=11.87%), as well as good accuracies (RE, between -12.84 and 11.69). And the stabilities, matrix effects and extraction recoveries of the rat plasma samples were also within acceptable limits (RSD<15%). Compared to normal group, the pharmacokinetics of major active constituents (except liquiritin and glycyrrhetinic acid) had significant differences (P<0.05) in the model rats, indicated that several metabolite enzymes activities could be altered at disease condition. PMID- 28802218 TI - Pharmaceutical and biomedical applications of dispersive liquid-liquid microextraction. AB - Sample treatment is so crucial in pharmaceutical and biomedical analysis. Proper sample preparation protects the analytical instrument, increases the sensitivity, and enhances the selectivity by removing probable interfering substances. Dispersive liquid-liquid microextraction (DLLME) is one of the most important approaches in sample treatment. In normal DLLME, the organic droplet of the extractant is mixed with a dispersing solvent before being injected into the sample. After manual or mechanical shaking, the cloudy solution is centrifuged to break the formed emulsion. The organic phase is then separated and transferred to the analytical instrument. The dispersion process employed in DLLME dramatically increases the contact surface between the extractant and the sample, which enhances the extraction kinetics and efficiency. DLLME can be classified based on the dispersion technique or the density of the extractant. Accordingly, different modes of DLLME have evolved and been applied for drug analysis in biological fluids. This review discusses the principle of DLLME, the requirements of organic solvents used as extractants in each mode and the different factors affecting the extraction efficiency. Selected applications of the different DLLME modes in bio pharmaceutical analysis have also been presented. PMID- 28802219 TI - Development and validation of a high-performance liquid chromatography-tandem mass spectrometry method to quantify LY-354,740 in rat and marmoset plasma. AB - LY-354,740 (eglumegad) is a selective and potent agonist of the metabotropic glutamate group II receptors (mGluR2,3) that has already entered clinical trials as a potential anti-psychotic agent and therefore has well-documented pharmacokinetic (PK), safety and tolerability profiles in human. Whereas its development as an anti-psychotic agent has not been pursued, LY-354,740 may have potential in other neuroscience-related fields, notably anxiety and neuro protection. The common marmoset is a small primate that has long been used in neuroscience. However, given its small size and small circulating blood volume, conducting PK studies to determine the therapeutic effectiveness of LY-354,740 at clinically-relevant doses is challenging. Here, we have developed and validated a simple, sensitive and selective analytical method that enables quantification of LY-354,740 using a small volume of plasma. The analytical method consisted of protein precipitation followed by high-performance liquid chromatography with heat assisted electrospray ionisation mass spectrometry (UHPLC-HESI-MS/MS). The chromatographic separation was achieved using gradient elution with a mobile phase consisting of acetonitrile and 10mM ammonium formate (pH 3) on a Thermo Scientific Acclaim Trinity P1 analytical column (100x3.0mm I.D., 3MUm) operating at 45 degrees C and at a flow rate of 900MUl/min. The method displays a linear relationship ranging from 20.0 to 5000ng/ml. Intra- and inter-day relative standard deviations are less than 5.7% and 7.0%, respectively and the accuracy ranged from 91.0 to 106.0%. The UHPLC-HESI-MS/MS analytical method we describe here is simple, sensitive, specific and capable of quantifying LY-354,740 in both rat and marmoset plasma, and is suitable to conduct PK studies after a single sub cutaneous dose of 1.0mg/kg or lower in both species. PMID- 28802220 TI - Comparison of lower limb muscle strength between diabetic neuropathic and healthy subjects using OpenSim. AB - Diabetes neuropathy and vasculopathy are the two major complications of diabetes mellitus, leading to diabetic foot disease, of which the worst consequences are plantar ulcers and amputations. Motor impairments like joint stiffness and loss of balance are distinctive effects of diabetes and they have been extensively explored. However, while altered muscle function has been also assessed through experimentally measured surface electromyography, little is known about muscle forces. The objective of this study was to estimate muscle forces in subjects with diabetes and to use these data to identify differences with respect to a population of healthy subjects matched for age and BMI. This was obtained by generating musculoskeletal models of 10 diabetic and 10 control subjects in OpenSim starting from experimentally recorded data. Dynamic simulations of motion were run and hence muscle forces calculated. Student T test (p<0.05) was used to compare joints kinematics, kinetics and muscle forces between the two populations. Significant changes were observed between lower limb muscle forces and activation of diabetic and healthy subjects, as well as between joints kinematics and kinetics. In particular muscles related to foot movements proved to be stronger in the healthy population. The typical ankle rigidity of the diabetic population was confirmed by a lower range of motion registered at the ankle plantar/flexion angle associated with weaker dorsal-plantar flexor muscles. The information provided by this methodology can help planning specific training programs aiming at augmenting muscle strength and joints mobility, and they can also improve the evaluation of the potential benefits. PMID- 28802221 TI - In vivo mechanical behaviour of the anterior cruciate ligament: A study of six daily and high impact activities. AB - The anterior cruciate ligament (ACL) plays a key role in the stability of the knee joint restricting the rotation and anterior tibial translation. However, there is a lack of knowledge of the in vivo ACL mechanical behaviour during high impact manoeuvres. The motion of 12 young participants with healthy knees was captured while they performed the following activities: walking, running, cross over cutting, sidestep cutting, jumping and jumping with one leg. The in vivo ACL length and strain were estimated using experimental kinematic data and three degree of freedom (DOF) knee model. The in vivo ACL tensile forces were determined with a well-established force/strain relationship obtained through ACL tensile tests. Statistical regression models between ACL length with respect to angles for each activity have been performed in order to better understand the ACL failure mechanisms. The maximum ACL tensile force was observed during jumping vertically at maximum effort with two legs (1.076+/-0.113 N/BW). Surprisingly, the peak tensile ACL force for all subjects during crossover cutting (0.715+/ 0.2647 N/BW) was lower than during walking (0.774+/-0.064 N/BW). Regression coefficients for crossover cutting indicated that excessive knee rotation and abduction angles contribute more significantly to the ACL elongation than in activities such as walking or running. These findings suggested that the ACL is subjected to multidirectional loading; further studies will be performed to investigate torsion, tensile and shear force on the ligament. PMID- 28802222 TI - Impact of the corrin framework of vitamin B12 on the electrochemical carbon skeleton rearrangement in comparison to an imine/oxime planar ligand; tuning selectivity in 1,2-migration of a functional group by controlling electrolysis potential. AB - Among the coenzyme B12-dependent enzymes, methylmalonyl-CoA mutase (MMCM) catalyzes the carbon-skeleton rearrangement reaction between R-methylmalonyl-CoA and succinyl-CoA. Diethyl 2-bromomethyl-2-phenylmalonate, an alkyl bromide substrate having two different migrating groups (phenyl and carboxylic ester groups) on the beta-carbon, was applied to the electrolysis mediated by a hydrophobic vitamin B12 model complex, heptamethyl cobyrinate perchlorate in this study. The electrolysis of the substrate at -1.0V vs. Ag-AgCl by light irradiation afforded the simple reduced product (diethyl 2-methyl-2 phenylmalonate) and the phenyl migrated product (diethyl 2-benzyl-2 phenylmalonate), as well as the electrolysis of the substrate at -1.5V vs. Ag AgCl in the dark. The electrolysis of the substrate at -2.0V vs. Ag-AgCl afforded the carboxylic ester migrated product (diethyl phenylsuccinate) as the major product. The selectivity for the migrating group was successfully tuned by controlling the electrolysis potential. We clarified that the cathodic chemistry of the Co(III) alkylated heptamethyl cobyrinate is critical for the selectivity of the migrating group through mechanistic investigations and comparisons to the simple vitamin B12 model complex, an imine/oxime-type cobalt complex. PMID- 28802223 TI - Silver and gold in the Protein Data Bank. AB - The structural features of the silver and gold sites in protein crystal structures extracted from the Protein Data Bank have been investigated. It is observed that both cations have nearly always low oxidations states (+1) and low coordination numbers, adopt standard stereochemistries, and interact preferentially (particularly gold) with sulfur donor atoms of cysteine and methionine side-chains. Interestingly, gold cation have been very often refined with occupancy minor than 1.0 and are very often "naked", in the sense that no donor atoms are sufficiently close to the metal cation. This apparently strange observation points out towards the need to develop specific and efficient validation tools for these elements when they are coordinated to proteins. PMID- 28802224 TI - Speciation of the trivalent f-elements Eu(III) and Cm(III) in digestive media. AB - In case radioactive materials are released into the environment, their incorporation into our digestive system would be a significant concern. Trivalent f-elements, i.e., trivalent actinides and lanthanides, could potentially represent a serious health risk due to their chemo- and radiotoxicity, nevertheless the biochemical behavior of these elements are mostly unknown even to date. This study, therefore, focuses on the chemical speciation of trivalent f elements in the human gastrointestinal tract. To simulate the digestive system artificial digestive juices (saliva, gastric juice, pancreatic juice and bile fluid) were prepared. The chemical speciation of lanthanides (as Eu(III)) and actinides (as Cm(III)) was determined experimentally by time-resolved laser induced fluorescence spectroscopy (TRLFS) and the results were compared with thermodynamic modeling. The results indicate a dominant inorganic species with phosphate/carbonate in the mouth, while the aquo ion is predominantly formed with a minor contribution of the enzyme pepsin in the stomach. In the intestinal tract the most significant species are with the protein mucin. We demonstrated the first experimental results on the chemical speciation of trivalent f-elements in the digestive media by TRLFS. The results highlight a significant gap in chemical speciation between experiments and thermodynamic modeling due to the limited availability of thermodynamic stability constants particularly for organic species. Chemical speciation strongly influences the in vivo behavior of metal ions. Therefore, the results of this speciation study will help to enhance the assessment of health risks and to improve decorporation strategies after ingestion of these (radio-)toxic heavy metal ions. PMID- 28802225 TI - The value of ultrasound-guided surgery for breast cancer. AB - OBJECTIVE: An increasing number of breast-conserving surgeries (BCS) has lead clinicians to the dilemma how to provide patients with the best pathological, short-term and long-term outcomes, while at the same time improving the cosmetic outcome and the patients' quality of life. A proposed solution is the use of intraoperative ultrasound (IOUS) for lesion resection in palpable as well as non palpable breast cancer. METHODS: This review identifies and compares evidence on palpation-guided/wire-guided vs. US-guided localization as well as stand-alone observational IOUS studies published between June 2001 and July 2017, indexed in Medline. A cornerstone of this review is the discussion on technology advancement as well as alternative IOUS approaches and their feasibility in treatment of patients with calcifications and multifocal lesions currently not treated with IOUS localization. RESULTS: In comparison to other available methods, IOUS provided in most studies better rates of clear margins, lower rates of re excisions as well as better cosmetic outcomes. Currently, there is a lack of available multicenter data on method comparisons as well as several limitations to the use of IOUS. CONCLUSIONS: With a comparable follow-up rate of loco regional recurrences and a higher reported long-term quality of life, IOUS should be a highly regarded method of localization in the planning of BCS. PMID- 28802226 TI - Taraxerol, a pentacyclic triterpenoid, from Abroma augusta leaf attenuates diabetic nephropathy in type 2 diabetic rats. AB - Persistent hyperglycaemia coupled with inflammation plays an important role in the pathogenesis of diabetic nephropathy (DN). Present study examined the therapeutic potential of taraxerol isolated from the methanol extract of Abroma augusta leaf against DN using rodent model of type 2 diabetes (T2D). T2D was experimentally induced by high fat diet and a single low-single dose of streptozotocin (35mg/kg, i.p.). Accumulation of serum creatinine, urea, and uric acid, activation of lactate dehydrogenase and creatinin kinase, and release of urinary albumin represented the glomerular damage and the progression of nephropathy in T2D rats. Taraxerol (20mg/kg, p.o.) treatment significantly reinstated the aforementioned changes in biochemical parameters near to normalcy. Molecular mechanism studies demonstrated an impaired signaling cascade, IRS1/PI3K/Akt/AMPK/GLUT4/GSK3beta, of glucose metabolism in the skeletal muscle and increase in serum levels of pro-inflammatory cytokines, CRP and MCP1 in T2D rats. Activation of polyol pathway, enhanced production of AGEs, up-regulation of NF-kappaB/PKCs/PARP signaling, and renal fibrosis was also observed in T2D rats. Taraxerol (20mg/kg, p.o.) treatment stimulated glucose metabolism in skeletal muscle, regulated blood glycaemic status and lipid profile in the sera, reduced the secretion of pro-inflammatory cytokines, and restored the renal physiology in T2D rats. Histological assessments were also in agreement with the above findings. Molecular docking study again supported the probable interactions of taraxerol with PKCbeta, PKCdelta, NF-kappaB, PARP, PI3K, IRS, Akt and AMPK. In silico ADME study predicted the drug-likeness character of taraxerol. Results suggest a possibility of taraxerol to be a new therapeutic agent for DN in future. PMID- 28802227 TI - Anti-inflammatory effects of Shufengjiedu capsule for upper respiratory infection via the ERK pathway. AB - BACKGROUND: Shufengjiedu Capsule (SFJD) is a type of Chinese traditional medicine compound for the treatment of acute upper respiratory tract infection. The present work aims to decipher the mechanism of SFJD. METHODS: In this study, we used target prediction and RNA sequence (RNA-Seq) based on transcriptome analysis to clarify the inflammation-eliminating mechanism of SFJD. Firstly, Pseudomonas aeruginosa (PAK) was used to induce acute lung injury in KM mice. After being treated by SFJD, the differently expressed genes were analyzed by RNA-Seq. Secondly, the chemical constituents of SFJD were identified by ultra-performance liquid chromatography quadrupole/time of flight mass spectrometry (UPLC/Q-TOF-MS) and submitted to PharmMapper to predict targets. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and String 9.1 websites were employed to establish the interaction network of inflammation of these targets. RESULTS: The results indicated that SFJD alleviated PAK induced lung injury in KM mice. We infer that the mechanism is a complex network containing 15 pathways related to inflammation regulated by 16 types of components from six types of herbs via 29 proteins. The ERK signaling pathway was a key pathway among them, which was predicted to be regulated by 14 types of components in SFJD. Phillyrin, emodin, and verbenalin were screened out by binding capacity, and the synergistic effect of them was further confirmed. CONCLUSIONS: Various components of SFJD ameliorated PAK induced upper respiratory tract infection via multiple targets, of which ERK phosphorylation might be the key event regulated specifically by verbenalin, phillyrin and emodin. PMID- 28802228 TI - MTDH and MAP3K1 are direct targets of apoptosis-regulating miRNAs in colorectal carcinoma. AB - Artificially designed miRNAs mimics and inhibitors that specifically target known oncogenes have attracted significant research attention. Herein, we aimed to explore whether MIR-375, MIR-145, and MIR-224 are involved in induction of apoptosis of CRC cells by regulating apoptosis-mediating genes MTDH, MAP3K1, PDK1, BAX, and BCL-XL. MTT assay was used to assess cell growth. Apoptosis was determined in terms of caspase activity measurement and phosphatidylserine detection using annexin V staining by flow cytometry. Quantitative real time PCR, Western blotting, and luciferase reporter assay were carried out to validate genes regulation and targeting by miRNAs. We found that ectopic expression of MIR 375 and MIR-145, and inhibition of MIR-224 can decrease cell growth and induce cell ability to undergo early apoptosis. At mRNA level, transfected cells displayed down-regulation of MTDH, PDK1 and BCL-XL, while BAX and MAP3K1 were up regulated. Protein expression of MTDH was decreased in cells transfected with MIR 145 mimic and MIR-224 inhibitor but remained unchanged in MIR-375 mimic transfected cells. Furthermore, MAP3K1 protein expression exibited a decreased level after MIR-375 transient expression with no significant change after MIR-145 mimic or MIR-224 inhibitor transfection. Luciferase reporter assay revealed that MIR-375 and MIR-145 can bind to 3'UTR of MTDH, supporting that MTDH is directly targeted by both miRNAs. Similarly, MAP3K1 was found to be directly regulated by MIR-375. The study concluded that the expression modulation of tumor suppressors MIR-375 and MIR-145, and oncomiR MIR-224 have the ability to induce apoptosis of CRC cells through regulation of apoptosis mediating genes MTDH, MAP3K1, PDK1, BCL XL and BAX. PMID- 28802229 TI - TGF-beta-mediated repression of MST1 by DNMT1 promotes glioma malignancy. AB - Human gliomas are related to high rates of morbidity and mortality. TGF-beta promotes the growth of glioma cells, and correlate with the degree of malignancy of human gliomas. However, the molecular mechanisms involved in the malignant function of TGF-beta are not fully elucidated. Here, we showed that TGF-beta induced the downregulation of MST1 expression in U87 and U251 glioma cells. Treatment of glioma cells with the DNA methylation inhibitor 5-aza-2' deoxycytidine (5-AzadC) prevented the loss of MST1 expression. Addition of 5 AzadC also reduced the TGF-beta-stimulated proliferation, migration and invasiveness of glioma cells. Furthermore, Knockdown of DNMT1 upregulated MST1 expression in gliomas cells. In addition, the inhibition of DNMT1 blocked TGF beta-induced proliferation, migration and invasiveness in glioma cells. These results suggest that TGF-beta promotes glioma malignancy through DNMT1-mediated loss of MST1 expression. PMID- 28802230 TI - Syzygium mundagam bark methanol extract restores skin to normal in diabetic wounded rats. AB - Diabetic wounds have been identified as one of the major complications associated with diabetes. This study features the use of Syzygium mundagam bark methanol (SMBM) extract in the treatment of wounds in Streptozotocin-Nicotinamide induced diabetic rats. The extract ointment base, at 1 and 2% respectively, was applied to the wounded areas on the rats and monitored for 21days. The wound closure, epithelialization period and histopathology of the wounds were evaluated during the study. Both the concentrations of the extract (1% and 2%) healed the wounds even under diabetic conditions induced in rats on day 21 (99.69% and 100% respectively). The 2% SMBM treated animals showed a higher rate of epithelialization of the wound (15+/-0.49days). The histopathology of the wounded skin on day 10 revealed that the rats treated with SMBM extract could initiate the healing and re-epithelialization. This was evident from the migration of neutrophils and proliferation of fibroblasts. On the 21st day, complete healing of the skin could be observed in the rats treated with 2% extract which was evident from the newly formed epidermis, collagen fibers and fibroblast. The results compared well with those treated with betadine (5%). The results of this study will support the use of this plant extract for diabetic healing over the use of commercially available synthetic drugs. PMID- 28802231 TI - Phytochemical properties and pharmacological effects of Quercus ilex L. aqueous extract on gastrointestinal physiological parameters in vitro and in vivo. AB - INTRODUCTION: Several research studies have reported on the pharmacological relevance of the medicinal plants used for treating various gastrointestinal disorders and controlling the dietary glucose uptake in the intestinal tract. METHODS: Male rats were used to investigate the pharmacological effects of green oak acorn aqueous extract (GOAE) on gastrointestinal physiological parameters in vivo and in vitro. In this respect, the gastro-intestinal motility and hypersecretion essays were evaluated using a simple test meal (10% charcoal in 5% gum arabic) and castor oil induced diarrhea. However, the effect of GOAE on glucose absorption and homeostasis was assessed by the Ussing chamber system and oral glucose tolerance test (OGTT) measures. RESULTS: Various doses of the Quercus ilex aqueous extract (125, 250 and 500mgkg-1) administered orally produced a significantly dose-related inhibition of gut meal travel distance in normal rat. The highest intestinal transit reduction of 49.34% was obtained with 500mgkg-1 compared to 58.33% caused by reference drug (clonidine, 1mgkg-1). In castor oil induced diarrhea in rat, Q. ilex extract reduced the frequency of defecation, fluid accumulation and electrolyte transport. These effects were associated with decreased histopathological damage and regulation of intracellular mediators disturbance in the intestinal mucosa. In addition, GOAE treatment improved glucose tolerance and significantly and dose-dependently reduced (>50%) the glucose absorption via intestinal epithelium. Phytochemical screening revealed the presence of many bioactive natural compounds. CONCLUSION: These results suggest that the extract was effective towards reducing diarrhea, fluid accumulation, electrolyte transport and glucose absorption, and no toxic effects of the GOAE presented on this study. PMID- 28802232 TI - The activity of Hou-Po-Da-Huang-Tang is improved through intestinal bacterial metabolism and Hou-Po-Da-Huang-Tang selectively stimulate the growth of intestinal bacteria associated with health. AB - Hou-Po-Da-Huang Tang (HPDHT) was used for the treatment of intestinal tract diseases in China. However, the underlying mechanisms via the intestinal bacteria remain largely unclear. Therefore, the aim of this study was to evaluate the metabolism of HPDHT by the human intestinal bacteria and its modulating effect on the intestinal bacteria. As a result, a total of 34 compounds were identified in HPDHT and transformed HPDHT (T-HPDHT). Among them, 12 metabolites were proved to be transformed by human intestinal bacteria. In vitro assays showed that T-HPDHT exhibited more significant elevation of free radical scavenging activity and suppression on the production of nitric oxide (NO) and TNF-alpha when comparing to HPDHT. Additionally, in vivo experiment confirmed that HPDHT significantly increased activity of superoxide dismutase (SOD), attenuated the malondialdehyde (MDA) and TNF-alpha levels in the conventional rats compared with that of pseudo germ-free (PGF) rats. In addition, HPDHT could significantly enhance the mean counts of Bifidobacterium and Lactobacillus and inhibit the growth of Clostridium, and Enterobacteriaceae, relative to controls. Due to the transformation of HPDHT being dependent on the bacterial strain, the effect of HPDHT on the selective growth of Bifidobacterium bifidum 29521 and Lactobacillus plantarum 8014 was evaluated. The kinetic parameters of microbial growth and prebiotic activity scores indicated that HPDHT could selectively stimulate the growth of the strains Bifidobacterium bifidum 29521 and Lactobacillus plantarum 8014. Taken together, metabolism of HPDHT by intestinal bacteria is a critical step towards the emergence of their anti-oxidation, anti-inflammation and prebiotic activities. This study provided valuable information for further pharmacological research on HPDHT. PMID- 28802233 TI - 1H-Tetrazol-5-amine and 1,3-thiazolidin-4-one derivatives containing 3 (trifluoromethyl)phenyl scaffold: Synthesis, cytotoxic and anti-HIV studies. AB - On the basis of recently reported biologically active 3 (trifluoromethyl)phenylthioureas, a series of diaryl derivatives incorporating 1H tetrazol-5-yl (1a-11a, 1a'-11a') and 1,3-thiazolidin-4-one (1b-11b) scaffolds were synthesized. The synthesis pathway was confirmed by an X-ray crystallographic studies of 3a', 6a, 8a, 6b and 8b. The cytotoxicity against MT-4 cells and anti-HIV properties of new derivatives were evaluated. As compared to initial thiourea connections, the cyclisation reduced the cytotoxicity of compounds by 2-15 times. The most promising N-(4-nitrophenyl)-1H-tetrazol-5-amine 7a was found to be more active than the origin thiourea. Its cytotoxicity was evaluated on A549, HTB-140 and HaCaT cell lines using MTT assay. The compound shows significant influence on cancer, but not on normal cells. Obtained results can provide some constructive data for further designing of novel family of potentially bioactive analogs. PMID- 28802234 TI - PAQR3 overexpression suppresses the aggressive phenotype of esophageal squamous cell carcinoma cells via inhibition of ERK signaling. AB - Progestin and adipoQ receptor family member 3 (PAQR3) has exhibited anticancer activity in multiple malignancies. However, its expression and function in esophageal squamous cell carcinoma (ESCC) is still elusive. In this work, we examined the expression of PAQR3 in 40 surgically resected ESCC specimens and their adjacent normal tissues. The expression of PAQR3 in ESCC cell lines was measured after treatment with the demethylating agent 5-aza-2'-deoxycytidine (5 Aza-CdR). The effects of overexpression of PAQR3 on cell proliferation, colony formation, invasion, and tumorigenesis were investigated. It was found that the PAQR3 mRNA level was significantly lower in ESCC than that in adjacent normal tissues (P=0.0318). Low PAQR3 expression was significantly associated with more advanced TNM stage (P=0.0093) and absent lymph node involvement (P=0.0324). Compared to normal esophageal epithelial cells, ESCC cells had significantly lower levels of PAQR3. 5-Aza-CdR treatment led to an induction of PAQR3 in ESCC cells. Enforced expression of PAQR3 significantly inhibited ESCC cell proliferation, colony formation and invasion. Moreover, PAQR3 overexpression blocked cell cycle transition from G1 to S phase, which was associated with induction of p27 and p21 and reduction of cyclin D1, CDK4, and CDK2. Mechanistically, overexpression of PAQR3 suppressed the phosphorylation of ERK1/2 in ESCC cells. In vivo tumorigenic studies confirmed that PAQR3 overexpression retarded the growth of ECA-109 xenograft tumors and inhibited the activation of ERK signaling. Taken together, PAQR3 is epigenetically silenced in ESCC and restoration of PAQR3 suppresses the aggressive phenotype of ESCC cells. Therefore, PAQR3 may represent a potential target for the treatment of ESCC. PMID- 28802235 TI - Steviol stabilizes polycystin 1 expression and promotes lysosomal degradation of CFTR and beta-catenin proteins in renal epithelial cells. AB - Malfunction of polycystin 1 (PC1) is linked to abnormally high epithelial cell proliferation and fluid secretion, eventually leading to renal cyst development and declined renal function as found in autosomal dominant polycystic kidney disease (ADPKD). Currently, there is no effective therapy for ADPKD. Recent studies report PC1 regulates CFTR chloride channels and beta-catenin levels in normal renal epithelial cells. Concurrently, our previous study found steviol retarded renal cyst enlargement in an in vitro and in an in vivo models by reducing CFTR expression and activity. Therefore, a potential relationship between steviol and PC1 is worthy of exploration. The present study was aimed to determine the effect of steviol on PC1, CFTR, and beta-catenin levels in renal epithelial cells with defective PC1 biogenesis and expression (Prkcsh-/- cell) and postnatal Pkd1 homozygous cell (Pkd1-/- cells). Using western blot analysis, it was found that steviol treatment at 100MUM for 24-48h substantially enhanced and stabilized PC1 C-terminal expression, while decreasing CFTR and beta-catenin protein expression in both Prkcsh-/- and Pkd1-/- cells. In addition, steviol promoted LAMP2 expression, a lysosomal enzyme marker. Interestingly, hydroxychloroquine (a lysosome inhibitor) treatment abolished steviol's effect in reducing CFTR and beta-catenin protein expression. Taken together, these findings suggest steviol slows cyst progression in cells and animal models of PKD, in part, by enhancing and stabilizing PC1 protein expression as well as by promoting lysosomal degradation of CFTR and beta-catenin. Therefore, steviol may represent a promising compound for treatment of polycystic kidney disease. PMID- 28802236 TI - Tetramethylpyrazine alleviates neural apoptosis in injured spinal cord via the downregulation of miR-214-3p. AB - OBJECTIVE: To evaluate the regulation effect of tetramethylpyrazine on microRNA 214-3p (miR-214-3p) in the spinal cord injury (SCI) rats model and to elucidate the neuroprotective effect and its mechanism of tetramethylpyrazine after SCI. METHODS: Ten Sprague-Dawley rats were used to establish the SCI rats model, and the expression levels of miR-214-3p and Bcl2l2 were detected by qRT-PCR and Western blotting at 7 days post-SCI. BBB scoring test was performed to evaluate the motor functional recovery at 21 days post-SCI. Twenty-five SCI rats were randomly assigned to five groups: SCI negative control (NC) group, tetramethylpyrazine (TMP) group, miR-214-3p agomir group, TMP/agomir group and the sham group. The rats were given a two-week injection treatment with or without TMP. The expression levels of miR-214-3p, Bcl2l2, Bax and caspase 3 were measured by qRT-PCR and Western blotting at 7 days after injection. Terminal deoxynucleotidyl transferase (TdT) -mediated dUTP Nick-End Labeling (TUNEL) assay was performed to detect cell apoptosis in vivo. Luciferase activity was measured to verify the miR-214-3p target site in the 3'-UTR of Bcl2l2 mRNA. TMP treatment was also performed to injure primary cultured neuron cells and cell apoptosis in vitro was determined by flow cytometry. RESULTS: MiR-214-3p was up-regulated while anti-apoptotic protein Bcl2l2 was downregulated post-SCI. TMP inhibited the apoptosis in vivo via decreasing the levels of miR-214-3p and increasing the expression level of Bcl2l2. A potential target site of miR-214-3p in the 3'UTR of Bcl2l2 mRNA was identified and validated by luciferase reporter assay. Furthermore, TMP could effectively inhibit neuron cells apoptosis in vitro. CONCLUSIONS: TMP alleviated neural apoptosis in injured spinal cord via down regulation of miR-214-3p. PMID- 28802237 TI - Umbelliferon-alpha-d-glucopyranosyl-(2I->1II)-alpha-Dglucopyranoside ameliorates Diethylnitrosamine induced precancerous lesion development in liver via regulation of inflammation, hyperproliferation and antioxidant at pre-clinical stage. AB - It is well documented that anomalous production of inflammatory proteins linked with most of the toxic expression and genesis of diverse chronic disease including cancer. Diethylnitrosamine (DEN) a well-known hepatotoxin and hepatocarcinogen, can induce oxidative stress and inflammatory reaction in it. Umbelliferone, secondary metabolites, is present in different plants and widely consumed by humans as medicine and food supplements. The aim of the current study was to scrutinize the chemoprotective potential of umbelliferon-alpha-d glucopyranosyl-(2I->1II)-alpha-d-glucopyranoside (UFD) against DEN-induced hepatocellular carcinoma (HCC) in experimental rats. Single intraperitoneal injection of DEN (200mg/kg) was used for induction of HCC in rats and rats were grouped and orally treated with UFD (5, 10 and 20mg/kg) dose for 22 weeks. Parameters under investigation included hepatic, non-hepatic enzymes, oxidative stress, pro-inflammatory cytokines, COX-2 and NF-kappaB level along with histopathological examination in HCC rats. UFD exerted protective effect via reduction of oxidative stress, liver and non-liver parameters in a dose-dependent manner. It also reduced the expression of TNF-alpha, IL-1beta, IL-6 and COX-2 in diseased rats. Our result revealed the essential repression of the inflammation cascade through modulation of nuclear factor-kappa B (NF-kappaB) signaling pathway. PMID- 28802238 TI - Expression and clinical significance of absent in melanoma 2 in colorectal cancer. AB - Increasing research has indicated that absent in melanoma 2 (AIM2) is aberrantly expressed in several tumor types. However, the association between AIM2 expression and clinicopathological factors or prognosis of patient with colorectal cancer (CRC) remains elusive. In the present study, we first examined the protein and mRNA expression of AIM2 in CRC cell lines by western blotting and quantitative RT-PCR (qRT-PCR). Then, we detected AIM2 expression in CRC tissue using western blotting and immunohistochemistry (IHC) respectively to evaluate its clinicopathological characteristics and prognosis in CRC. Our cytological experiments showed that there was low AIM2 expression in most of the CRC cell lines. Western blotting and IHC indicated that AIM2 expression was obviously lower in the primary CRC tissue than the adjacent normal tissue (P<0.01 and P<0.001). Clinicopathological analysis revealed that low AIM2 expression was significantly associated with some clinicopathological features such as depth of invasion (P=0.020), TNM clinical stage (P=0.013) and lymph node metastasis (P=0.026). Spearman analysis indicated that there was a negative correlation between AIM2 expression and preoperative serum carcino-embryonic antigen (CEA) levels in CRC patients (r=-0.217, P=0.009). Moreover, Kaplan-Meier analysis showed that low expression of AIM2 could lead to a significantly shorter overall survival rate (P=0.001). Cox's proportional hazards model also indicated that the low expression of AIM2 could serve as an independent and significant prognostic factor for survival. Taken together, our findings identify AIM2 as a valuable biomarker for prognosis and a potential therapeutic target for CRC. PMID- 28802239 TI - Synergistic antinociceptive interaction of Syzygium aromaticum or Rosmarinus officinalis coadministered with ketorolac in rats. AB - Syzygium aromaticum (L.) Merr. & L.M. Perry (Mirtaceae) and Rosmarinus officinalis L. (Lamiaceae) are both medicinal plants used for centuries to alleviate pain. The aim of the study was to demonstrate the therapeutic potential utility of herb-drug association of S. aromaticum essential oil or R. officinalis ethanolic extract coadministered with ketorolac. Antinociceptive pharmacological interaction was investigated by an isbolographic study using the formalin test in rats. Both alone and in combination with ketorolac; S. aromaticum and R. officinalis produced a dose-dependent antinociceptive response. To plot the isobologram, we used the effective dose 50 of each one component in a fixed 1:1 ratio. The isobolographic analysis showed that, in both combinations, ketorolac plus essential oil S. aromaticum and ketorolac plus ethanolic extract R. officinalis, the experimental value (Zexp) was lower than the theoretical value (Zadd). In addition, this study shows that eugenol, a metabolite present in S. aromaticum, and ursolic acid, a metabolite present in R. officinalis, also synergized the antinociceptive effect of ketorolac. While, the oleanolic acid present in both medicinal species did not show a synergistic antinociceptive effect in combination with ketorolac. No adverse effects were observed with these herb-drug interactions. These findings suggest that essential oil S. aromaticum and ethanolic extract R. officinalis could be useful in combination with ketorolac for the treatment of inflammatory pain. PMID- 28802240 TI - Late summer photosynthesis and storage carbohydrates in walnut (Juglans regia L.): Feed-back and feed-forward effects. AB - The effect of late summer - autumn limitation of phloem export on growth, photosynthesis and storage carbohydrate accumulation, was evaluated in walnut (Juglans regia L.). This was done by girdling current years shoots, with either all or with only a third of the leaves left in place. Nineteen days after girdling, photosynthesis was greatly reduced and after 46 days, it was about 70% lower in both girdling treatments compared to the control (ungirdled shoots). This reduction is consistent with a feed-back effect of an increased carbohydrate content of the leaves. At the end of the experiment (46 days after girdling), the radial growth of girdled shoots was increased at their base but not at their apical part compared to the control. Girdling increased the accumulation of sucrose in the bark at the base of the shoot and of starch in the bark and in the wood of the shoot apical part. The activity of ADP-glucose pyrophosphorylase in wood increased in the apical part of girdled shoots. The results suggest that a high availability of carbohydrates elicits a feed-forward action on the shoot sink size and activity (radial growth and storage carbohydrate accumulation). Further, for the first time in tree wood we found an increased total activity of AGP induced by an increased assimilate availability. Moreover, the results indicated that, in late summer - autumn, CO2 uptake by leaves of the deciduous tree walnut is strongly dependent on export of photosynthates from the crown. Therefore, carbon uptake in this period depends largely on the availability of effective storage sinks where newly produced assimilates can be accumulated. PMID- 28802241 TI - The 9-d CIDR-PG protocol II: Characterization of endocrine parameters, ovarian dynamics, and pregnancy rates to fixed-time AI following use of long-term CIDR based estrus synchronization among mature beef cows. AB - An experiment was designed to evaluate endocrine parameters, ovarian dynamics, and pregnancy rates to fixed-time artificial insemination (FTAI) following the 9 d CIDR-PG protocol in comparison to the 14-d CIDR-PG protocol. While both are long-term protocols using CIDR treatment for presynchronization, the 9-d CIDR-PG protocol differs from the 14-d CIDR-PG protocol in that prostaglandin F2alpha (PG) is administered at CIDR insertion and removal to facilitate a decreased length of progestin treatment and potentially enhance response to the presynchronization treatment. Estrus was synchronized for 393 mature beef cows across five locations. Treatments were represented in each location, and cows within each location were randomly assigned to one of the two protocols based on age, days postpartum (DPP), and body condition score (BCS). Cows assigned to the 14-d CIDR-PG treatment received a CIDR insert (1.38 g progesterone) on Day 0 with removal of CIDR on Day 14, and 25 mg PG 16 d after CIDR removal on Day 30. Cows assigned the 9-d CIDR-PG treatment received 25 mg PG and a CIDR insert (1.38 g progesterone) on Day 5; 25 mg PG and removal of CIDR on Day 14; and 25 mg PG 16 d after CIDR removal on Day 30. In both treatments, cows received FTAI on Day 33, 72 h after PG. All cows were administered 100 MUg gonadotropin-releasing hormone (GnRH) concurrent with insemination. For a subset of animals in each treatment, ovarian ultrasound was performed and blood samples were collected for determination of serum estradiol concentrations at CIDR removal, PG administration, and FTAI. Protocols were compared on the basis of estrous response and pregnancy rate resulting from FTAI. Serum estradiol concentrations, follicle size, and estrous response did not differ based on treatment. However, cows assigned to the 9-d CIDR-PG protocol tended to achieve greater FTAI pregnancy rates than cows assigned to the 14-d CIDR-PG protocol (62% versus 52%; P = 0.07). Across treatments, greater pregnancy rates tended (P = 0.10) to be achieved by cows that expressed estrus prior to FTAI (69% for 9-d CIDR-PG, 58% for 14-d CIDR-PG) than by cows that failed to express estrus (55% for 9-d CIDR PG, 47% for 14-d CIDR-PG). In summary, the 9-d CIDR-PG protocol is an effective protocol for synchronization of estrus among mature beef cows, and pregnancy rates to FTAI tended to be improved through use of the 9-d CIDR-PG compared to the 14-d CIDR-PG protocol. PMID- 28802242 TI - An LC-MS/MS method for simultaneous determination of nine steroidal saponins from Paris polyphylla var. in rat plasma and its application to pharmacokinetic study. AB - Paris polyphylla var is an herbal plant herb widely used in Traditional Chinese Medicine. The purpose of this study is to develop an Ultra Performance Liquid Chromatography-tandem mass spectrometer (UPLC-MS) method to quantify the major components (i.e., nine saponins) from P. polyphylla in plasma samples. A UItra BiPh column (100*2.1mm, 5MUm) was used with acetonitrile/0.1% formic acid in water as mobile phases. The analytes were quantified using a Waters XEVO TQ mass spectrometer via multiple reaction monitoring (MRM) with positive scan mode. A protein precipitation method was used to extract the analytes from rat plasma. The inter/intra-day precision, accuracy, recovery, matrix effect, and stability were evaluated per the FDA guidance. The method showed linearity in the concentration ranges of 2.4-1250ng/mL. The intra-day and inter-day precisions (RSD) of these analytes at three different levels were less than 15.0%. The extraction recoveries of these analytes were from 83.8% to 109.4% and the matrix effects ranged from 87.4% to 105.4%. The stabilities of these compounds in plasma were evaluated by analyzing three different concentrations following storage at 25 degrees C for 6h, and -80 degrees C for 30days. All the samples displayed less than 15.0% variations. The validated method was successfully used to a pharmacokinetic (PK) study using Sprague Dawley (SD) rats with intravenous (i.v.) and oral (p.o.) administration of P. polyphylla extract. The applications revealed that this method can be used to analyze major steroidal saponins from P. polyphylla in biological samples. PMID- 28802243 TI - Pulsed triple electron resonance (TRIER) for dipolar correlation spectroscopy. AB - A new pulse sequence is presented for correlating dipolar frequencies in molecules with more than two paramagnetic centers. This triple electron resonance experiment (TRIER) is an extension the double electron-electron resonance (DEER) experiment, which is widely used for distance determination in the nanometer range. We use linear chirp pulses with smoothed edges to create a refocused observer echo, and two hyperbolic secant pulses with distinct excitation windows to excite two other subsets of spins. These pumped spins are coupled to the observed spin through the dipole-dipole interaction. A two-dimensional dipolar modulation pattern is recorded by variation of the position of the two pump pulses. By two-dimensional Fourier transform of the echo integral, a plot is obtained that correlates dipolar frequencies within the same molecule. Such correlation patterns can be used in conjunction with DEER, with which distance distributions are usually determined for several doubly labeled molecules with different spin-labeling sites. In the presence of two conformers, DEER traces give two distances and assignment to an individual conformer is not trivial and usually requires a trial and error approach. TRIER can potentially provide the missing connection between distances as correlations between dipolar frequencies. PMID- 28802244 TI - Detoxification of diphenyl ether herbicide lactofen by Bacillus sp. Za and enantioselective characteristics of an esterase gene lacE. AB - A bacterial strain Za capable of degrading diphenyl ether herbicide lactofen was isolated and identified as Bacillus sp. This strain could degrade 94.8% of 50mgL 1 lactofen after 4days of inoculation in flasks. It was revealed that lactofen was initially hydrolyzed to desethyl lactofen, which was further transformed to acifluorfen, followed by the reduction of the nitro group to yield aminoacifluorfen. The phytotoxicity of the transformed product aminoacifluorfen to maize was decreased significantly compared with the lactofen. A gene lacE, encoding an esterase responsible for lactofen hydrolysis to desethyl lactofen and acifluorfen continuously, was cloned from Bacillus sp. Za. The deduced amino acid belonging to the esterase family VII contained a typical Ser-His-Asp/Glu catalytic triad and the conserved motifs GXSXG. The purified recombinant protein LacE displayed maximal esterase activity at 40 degrees C and pH 7.0. Additionally, LacE had broad substrate specificity and was capable of hydrolyzing p-nitrophenyl esters. The enantioselectivity of LacE during lactofen degradation was further studied, and the results indicated that the (S)-(+)-lactofen was degraded faster than the (R)-(-)-lactofen, which could illustrate the reported phenomenon that (S)-(+)-lactofen was preferentially degraded in soil and sediment. PMID- 28802245 TI - Hyphospheric impacts of earthworms and arbuscular mycorrhizal fungus on soil bacterial community to promote oxytetracycline degradation. AB - A two-compartment microcosm was used to investigate the role of arbuscular mycorrhizal fungus (AMF) hyphae and earthworm in altering soil microbial community and OTC degradation. Treatments comprised OTC-contaminated hyphal compartments with or without AMF hyphae and with or without earthworms. Results indicated both AMF hyphae and earthworms accelerated OTC degradation; two degradation products were identified as 4-epi-oxytetracycline (EOTC) and 2-acetyl 2-decarboxamido-oxytetracycline (ADOTC). Q-PCR results indicated that both earthworms and AMF hyphae increased 16s rDNA gene, enhancing OTC degradation consequently. Illumina sequencing of the 16S rRNA genes showed that AMF hyphae and earthworm altered bacterial community. Earthworms stimulated the growth of class Anaerolineae, family Flavobacteriaceae, Genus Pseudomonas, reducing OTC residues. AMF hyphae significantly increased the abundance of family Pirellulaceae, genus Glycomyces, and Nonomuraea which had a negative correlation with EOTC, accelerating OTC degradation. When used together, AMF hyphae and earthworms enhanced OTC degradation by stimulating class Anaerolineae and family Flavobacteriaceae. PMID- 28802246 TI - Preparation and adsorption characteristics of an ion-imprinted polymer for fast removal of Ni(II) ions from aqueous solution. AB - A novel Ni(II) ion-imprinted polymer (IIP) was synthesized by bulk polymerization for fast removal of Ni(II) ions from aqueous solution. Effects of preparation conditions on adsorption performance were investigated. Diphenylcarbazide (DPC) and N,N-azobisisobutyronitrile (AIBN) were used as ligand and initiator, respectively. Various monomers, solvents, cross-linking agents and molar ratios of template, monomer and cross-linking agent for polymerization were studied to obtain the largest adsorption capacity. The prepared Ni(II)-IIPs were characterized using Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), energy dispersive X-ray spectroscopy (EDX) and thermogravimetric analysis (TGA). The elution process has no influence on the three-dimension network structure observed on the surfaces of Ni(II)-IIPs. Ni(II) ions could be eluted from IIPs successfully with HCl solution. Effects of operating time, pH and initial concentration of Ni(II) in aqueous solution on adsorption performance were investigated too. The adsorption equilibrium was reached within 30min. The maximum adsorption capacity of Ni(II)-IIPs was 86.3mgg 1 at pH 7.0 with initial Ni(II) concentration of 500mgL-1. The adsorption by Ni(II)-IIPs followed a pseudo-second-order kinetic and Freundlich isotherm models. The selectivity coefficients for all Ni(II)/interfering ions are larger than one because of the imprinting effect. The Ni(II)-IIPs also showed high reusability and stability. PMID- 28802247 TI - Effect of lead speciation on its oral bioaccessibility in surface dust and soil of electronic-wastes recycling sites. AB - We measured bioaccessible lead (Pb) in simulated gastrointestinal fluids containing Pb-contaminated soil or dust from electronic waste (e-waste) recycling sites to assess the risk of Pb ingestion. The physiologically based extraction test (PBET) was used as in vitro bioaccessibility assay. Pb speciation was determined using X-ray absorption spectroscopy. The total Pb concentrations in dusts (n=8) and soils (n=4) were in the range of 1630-131,000 and 239-7800mg/kg, respectively. Metallic Pb, a common component of e-waste, was ubiquitous in the samples. We also found Pb adsorbed onto goethite and as oxides and carbonate, implying soil mixing and weathering influences. Pb phosphate and organic species were only found in the soil samples, suggesting that formation was soil-specific. We identified other Pb compounds in several samples, including Pb silicate, Pb chromate, and Pb(II) hydrogen phosphate. A correlation analysis indicated that metallic Pb decreased bioaccessibility in the stomach, while a Pb speciation analysis revealed a low bioaccessibility for Pb phosphates and high bioaccessibility for organic Pb species. The health risk based on bioaccessible Pb was estimated to be much lower than that of total Pb due to the lower concentrations. PMID- 28802248 TI - Utility of rapid whole-exome sequencing in the diagnosis of Niemann-Pick disease type C presenting with fetal hydrops and acute liver failure. AB - Rapid whole-exome sequencing (rWES) is used in critically ill newborn infants to inform about diagnosis, clinical management, and prognosis. Here we report a male newborn infant with hydrops, pancytopenia, and acute liver failure who was listed for liver transplantation. Given the acuity of the presentation, the procedure related morbidity and mortality, and lack of diagnosis, we used rWES in the proband and both parents with a turnaround time of 10 business days. rWES returned one maternally inherited, likely pathogenic and one paternally inherited, likely pathogenic variant in NPC1, suggestive of a diagnosis of Niemann-Pick disease type C (NPC). Interestingly, a diagnosis of NPC was entertained prior to rWES, but deemed unlikely in light of absent cholesterol storage on liver biopsy and near-normal oxysterol levels in dried blood. The diagnosis of NPC was confirmed on filipin stain in fibroblasts demonstrating defective cholesterol trafficking. NPC is a slowly progressive neurodegenerative disorder that may also affect the liver with overall poor prognosis. It was decided to take the infant off the transplant list and transfer to palliative care, where he died after 4 wk. This case highlights the utility of rWES in an acute clinical setting for several domains of precision medicine including (1) diagnosis, (2) prognosis and outcome, (3) management and therapy, and (4) utilization of resources. PMID- 28802250 TI - A Population-Based Study of Abdominal Aortic Aneurysm Treatment in Finland 2000 to 2014. AB - BACKGROUND: In the event of rupture of an abdominal aortic aneurysm (AAA), mortality is very high. AAA prevalence and incidence of ruptures have been reported to be decreasing. The treatment of AAA has also undergone a change in recent decades with a shift toward endovascular aneurysm repair (EVAR). Our aim was to evaluate how these changes have affected the elective and emergency treatment of AAA and their results in Finland. METHODS: All patients treated for AAA in Finland, a country with a population of 5.5 million, during 2000 to 2014 were searched from the registry of the Finnish Institute for Health and Welfare. Data on all patients who had died of AAA during the same time period were obtained from Statistics Finland. The data were combined and analyzed. RESULTS: The annual incidence of ruptured AAA was 16.4 per 100 000 population over 50 years and decreased significantly during the study period. Over half of the 4949 patients who had a ruptured AAA died outside the hospital. Thirty-day mortality after emergency repair was 39.4%. Intact AAA repairs numbered 4956. The absolute number of annual repairs increased during the study period, and the use of EVAR became the dominant method of elective repair. Thirty-day mortality in elective AAA repair dropped significantly from 6.3% in 2000 to 2004 to 2.7% in 2010 to 2014 mostly because of the increased number of EVAR procedures with lower mortality. Long-term mortality in patients treated with EVAR was higher than in patients treated with open repair. Mortality after elective AAA repair was primarily attributable to cardiovascular causes, but there was a slightly higher proportion of AAA-related late deaths in patients treated with EVAR. CONCLUSIONS: Ruptured AAA incidence for men >65 years has declined by nearly 30% in Finland, likely because of the decrease in AAA prevalence. The treatment results have improved as well for both elective and emergency repair. Increased use of EVAR has resulted in a decrease of mortality after elective AAA repair, but results of open repair have improved as well. However, late mortality from elective EVAR is surprisingly high in comparison with open repair, which may have been exaggerated by patient selection. PMID- 28802249 TI - High-Resolution Mapping of Chromatin Conformation in Cardiac Myocytes Reveals Structural Remodeling of the Epigenome in Heart Failure. AB - BACKGROUND: Cardiovascular disease is associated with epigenomic changes in the heart; however, the endogenous structure of cardiac myocyte chromatin has never been determined. METHODS: To investigate the mechanisms of epigenomic function in the heart, genome-wide chromatin conformation capture (Hi-C) and DNA sequencing were performed in adult cardiac myocytes following development of pressure overload-induced hypertrophy. Mice with cardiac-specific deletion of CTCF (a ubiquitous chromatin structural protein) were generated to explore the role of this protein in chromatin structure and cardiac phenotype. Transcriptome analyses by RNA-seq were conducted as a functional readout of the epigenomic structural changes. RESULTS: Depletion of CTCF was sufficient to induce heart failure in mice, and human patients with heart failure receiving mechanical unloading via left ventricular assist devices show increased CTCF abundance. Chromatin structural analyses revealed interactions within the cardiac myocyte genome at 5 kb resolution, enabling examination of intra- and interchromosomal events, and providing a resource for future cardiac epigenomic investigations. Pressure overload or CTCF depletion selectively altered boundary strength between topologically associating domains and A/B compartmentalization, measurements of genome accessibility. Heart failure involved decreased stability of chromatin interactions around disease-causing genes. In addition, pressure overload or CTCF depletion remodeled long-range interactions of cardiac enhancers, resulting in a significant decrease in local chromatin interactions around these functional elements. CONCLUSIONS: These findings provide a high-resolution chromatin architecture resource for cardiac epigenomic investigations and demonstrate that global structural remodeling of chromatin underpins heart failure. The newly identified principles of endogenous chromatin structure have key implications for epigenetic therapy. PMID- 28802251 TI - MicroRNA-720 Regulates E-cadherin-alphaE-catenin Complex and Promotes Renal Cell Carcinoma. AB - miRNAs are implicated in regulating cancer progression and metastasis. Here, we show that miR-720 is positively associated with renal cell carcinoma (RCC). Elevated levels of miR-720 were observed in a panel of RCC cell lines and clinical tissues compared with nonmalignant cell line and normal samples. Loss of miR-720 function inhibited proliferation, migration, and invasion and induced apoptosis in RCC cell lines in vitro and repressed tumor growth in xenograft mouse models. Conversely, gain of miR-720 function in nonmalignant HK-2 cells induced procancerous characteristics. Silencing of miR-720 caused a marked induction in the levels of endogenous alphaE-catenin and E-cadherin protein levels in anti720 transfected cells compared with control, whereas miR-720 overexpression in RCC cell lines reduced activity of a luciferase reporter gene fused to the wild-type alphaE-catenin or E-cadherin 3'UTR compared with nonspecific 3'UTR control, indicating that alphaE-catenin-E-cadherin complex is a direct and functional target of miR-720 in RCC. We also observed attenuation of beta-catenin, CD44, and Akt expression in RCC cells transfected with miR-720 inhibitor compared with control. Furthermore, miR-720 exhibited clinical significance in RCC. Expression of miR-720 significantly distinguished malignant from normal samples. Elevated miR-720 levels positively correlated with higher Fuhrman grade, pathologic stage, and poor overall survival of RCC patients. These findings uncover a new regulatory network in RCC involving metastasis-promoting miR-720 that directly targets expression of key metastasis-suppressing proteins E cadherin and alphaE-catenin complex. These results suggest that therapeutic regulation of miR-720 may provide an opportunity to regulate EMT and metastasis in RCC. Mol Cancer Ther; 16(12); 2840-8. (c)2017 AACR. PMID- 28802252 TI - Exploiting Radiation-Induced Signaling to Increase the Susceptibility of Resistant Cancer Cells to Targeted Drugs: AKT and mTOR Inhibitors as an Example. AB - Implementing targeted drug therapy in radio-oncologic treatment regimens has greatly improved the outcome of cancer patients. However, the efficacy of molecular targeted drugs such as inhibitory antibodies or small molecule inhibitors essentially depends on target expression and activity, which both can change during the course of treatment. Radiotherapy has previously been shown to activate prosurvival pathways, which can help tumor cells to adapt and thereby survive treatment. Therefore, we aimed to identify changes in signaling induced by radiation and evaluate the potential of targeting these changes with small molecules to increase the therapeutic efficacy on cancer cell survival. Analysis of "The Cancer Genome Atlas" database disclosed a significant overexpression of AKT1, AKT2, and MTOR genes in human prostate cancer samples compared with normal prostate gland tissue. Multifractionated radiation of three-dimensional-cultured prostate cancer cell lines with a dose of 2 Gy/day as a clinically relevant schedule resulted in an increased protein phosphorylation and enhanced protein protein interaction between AKT and mTOR, whereas gene expression of AKT, MTOR, and related kinases was not altered by radiation. Similar results were found in a xenograft model of prostate cancer. Pharmacologic inhibition of mTOR/AKT signaling after activation by multifractionated radiation was more effective than treatment prior to radiotherapy. Taken together, our findings provide a proof-of concept that targeting signaling molecules after activation by radiotherapy may be a novel and promising treatment strategy for cancers treated with multifractionated radiation regimens such as prostate cancer to increase the sensitivity of tumor cells to molecular targeted drugs. Mol Cancer Ther; 17(2); 355-67. (c)2017 AACRSee all articles in this MCT Focus section, "Developmental Therapeutics in Radiation Oncology." PMID- 28802253 TI - The Combination of Metformin and Valproic Acid Induces Synergistic Apoptosis in the Presence of p53 and Androgen Signaling in Prostate Cancer. AB - We investigated the potential of combining the hypoglycemic drug metformin (MET) and the antiepileptic drug valproic acid (VPA), which act via different biochemical pathways, to provide enhanced antitumor responses in prostate cancer. Prostate cancer cell lines (LNCaP and PC-3), normal prostate epithelial cells (PrEC), and patient-derived prostate tumor explants were treated with MET and/or VPA. Proliferation and apoptosis were assessed. The role of p53 in response to MET + VPA was assessed in cell lines using RNAi in LNCaP (p53+) and ectopic expression of p53 in PC-3 (p53-). The role of the androgen receptor (AR) was investigated using the AR antagonist enzalutamide. The combination of MET and VPA synergistically inhibited proliferation in LNCaP and PC-3, with no significant effect in PrEC. LNCaP, but not PC-3, demonstrated synergistic intrinsic apoptosis in response to MET + VPA. Knockdown of p53 in LNCaP (p53+, AR+) reduced the synergistic apoptotic response as did inhibition of AR. Ectopic expression of p53 in PC-3 (p53-, AR-) increased apoptosis in response to MET + VPA. In patient derived prostate tumor explants, MET + VPA also induced a significant decrease in proliferation and an increase in apoptosis in tumor cells. In conclusion, we demonstrate that MET + VPA can synergistically kill more prostate cancer cells than either drug alone. The response is dependent on the presence of p53 and AR signaling, which have critical roles in prostate carcinogenesis. Further in vivo/ex vivo preclinical studies are required to determine the relative efficacy of MET + VPA as a potential treatment for prostate cancer. Mol Cancer Ther; 16(12); 2689-700. (c)2017 AACR. PMID- 28802254 TI - TDP1 is Critical for the Repair of DNA Breaks Induced by Sapacitabine, a Nucleoside also Targeting ATM- and BRCA-Deficient Tumors. AB - 2'-C-cyano-2'-deoxy-1-beta-d-arabino-pentofuranosylcytosine (CNDAC) is the active metabolite of the anticancer drug, sapacitabine. CNDAC is incorporated into the genome during DNA replication and subsequently undergoes beta-elimination that generates single-strand breaks with abnormal 3'-ends. Because tyrosyl-DNA phosphodiesterase 1 (TDP1) selectively hydrolyzes nonphosphorylated 3'-blocking ends, we tested its role in the repair of CNDAC-induced DNA damage. We show that cells lacking TDP1 (avian TDP1-/- DT40 cells and human TDP1 KO TSCER2 and HCT116 cells) exhibit marked hypersensitivity to CNDAC. We also identified BRCA1, FANCD2, and PCNA in the DNA repair pathways to CNDAC. Comparing CNDAC with the chemically related arabinosyl nucleoside analog, cytosine arabinoside (cytarabine, AraC) and the topoisomerase I inhibitor camptothecin (CPT), which both generate 3'-end blocking DNA lesions that are also repaired by TDP1, we found that inactivation of BRCA2 renders cells hypersensitive to CNDAC and CPT but not to AraC. By contrast, cells lacking PARP1 were only hypersensitive to CPT but not to CNDAC or AraC. Examination of TDP1 expression in the cancer cell line databases (CCLE, GDSC, NCI-60) and human cancers (TCGA) revealed a broad range of expression of TDP1, which was correlated with PARP1 expression, TDP1 gene copy number and promoter methylation. Thus, this study identifies the importance of TDP1 as a novel determinant of response to CNDAC across various cancer types (especially non-small cell lung cancers), and demonstrates the differential involvement of BRCA2, PARP1, and TDP1 in the cellular responses to CNDAC, AraC, and CPT. Mol Cancer Ther; 16(11); 2543-51. (c)2017 AACR. PMID- 28802255 TI - Simultaneous Targeting of Two Distinct Epitopes on MET Effectively Inhibits MET- and HGF-Driven Tumor Growth by Multiple Mechanisms. AB - Increased MET activity is linked with poor prognosis and outcome in several human cancers currently lacking targeted therapies. Here, we report on the characterization of Sym015, an antibody mixture composed of two humanized IgG1 antibodies against nonoverlapping epitopes of MET. Sym015 was selected by high throughput screening searching for antibody mixtures with superior growth inhibitory activity against MET-dependent cell lines. Synergistic inhibitory activity of the antibodies comprising Sym015 was observed in several cancer cell lines harboring amplified MET locus and was confirmed in vivo Sym015 was found to exert its activity via multiple mechanisms. It disrupted interaction of MET with the HGF ligand and prompted activity-independent internalization and degradation of the receptor. In addition, Sym015 induced high levels of CDC and ADCC in vitro The importance of these effector functions was confirmed in vivo using an Fc effector function-attenuated version of Sym015. The enhanced effect of the two antibodies in Sym015 on both MET degradation and CDC and ADCC is predicted to render Sym015 superior to single antibodies targeting MET. Our results demonstrate strong potential for use of Sym015 as a therapeutic antibody mixture for treatment of MET-driven tumors. Sym015 is currently being tested in a phase I dose escalation clinical trial (NCT02648724). Mol Cancer Ther; 16(12); 2780-91. (c)2017 AACR. PMID- 28802256 TI - Stochastic feeding dynamics arise from the need for information and energy. AB - Animals regulate their food intake in response to the available level of food. Recent observations of feeding dynamics in small animals showed feeding patterns of bursts and pauses, but their function is unknown. Here, we present a data driven decision-theoretical model of feeding in Caenorhabditis elegans Our central assumption is that food intake serves a dual purpose: to gather information about the external food level and to ingest food when the conditions are good. The model recapitulates experimentally observed feeding patterns. It naturally implements trade-offs between speed versus accuracy and exploration versus exploitation in responding to a dynamic environment. We find that the model predicts three distinct regimes in responding to a dynamical environment, with a transition region where animals respond stochastically to periodic signals. This stochastic response accounts for previously unexplained experimental data. PMID- 28802257 TI - Oxidation of alkyl benzenes by a flavin photooxidation catalyst on nanostructured metal-oxide films. AB - We describe here a surface-bound, oxide-based procedure for the photooxidation of a family of aromatic hydrocarbons by a phosphate-bearing flavin mononucleotide (FMN) photocatalyst on high surface area metal-oxide films. PMID- 28802258 TI - Human blood Tfr cells are indicators of ongoing humoral activity not fully licensed with suppressive function. AB - Germinal center (GC) responses are controlled by T follicular helper (Tfh) and T follicular regulatory (Tfr) cells and are crucial for the generation of high affinity antibodies. Although the biology of human circulating and tissue Tfh cells has been established, the relationship between blood and tissue Tfr cells defined as CXCR5+Foxp3+ T cells remains elusive. We found that blood Tfr cells are increased in Sjogren syndrome, an autoimmune disease with ongoing GC reactions, especially in patients with high autoantibody titers, as well as in healthy individuals upon influenza vaccination. Although blood Tfr cells correlated with humoral responses, they lack full B cell-suppressive capacity, despite being able to suppress T cell proliferation. Blood Tfr cells have a naive like phenotype, although they are absent from human thymus or cord blood. We found that these cells were generated in peripheral lymphoid tissues before T-B interaction, as they are maintained in B cell-deficient patients. Therefore, blood CXCR5+Foxp3+ T cells in human pathology indicate ongoing humoral activity but are not fully competent circulating Tfr cells. PMID- 28802259 TI - Cis-regulatory elements explain most of the mRNA stability variation across genes in yeast. AB - The stability of mRNA is one of the major determinants of gene expression. Although a wealth of sequence elements regulating mRNA stability has been described, their quantitative contributions to half-life are unknown. Here, we built a quantitative model for Saccharomyces cerevisiae based on functional mRNA sequence features that explains 59% of the half-life variation between genes and predicts half-life at a median relative error of 30%. The model revealed a new destabilizing 3' UTR motif, ATATTC, which we functionally validated. Codon usage proves to be the major determinant of mRNA stability. Nonetheless, single nucleotide variations have the largest effect when occurring on 3' UTR motifs or upstream AUGs. Analyzing mRNA half-life data of 34 knockout strains showed that the effect of codon usage not only requires functional decapping and deadenylation, but also the 5'-to-3' exonuclease Xrn1, the nonsense-mediated decay genes, but not no-go decay. Altogether, this study quantitatively delineates the contributions of mRNA sequence features on stability in yeast, reveals their functional dependencies on degradation pathways, and allows accurate prediction of half-life from mRNA sequence. PMID- 28802261 TI - How do different brands of size 1 laryngeal mask airway compare with face mask ventilation in a dedicated laryngeal mask airway teaching manikin? AB - BACKGROUND: International neonatal resuscitation guidelines recommend the use of laryngeal mask airway (LMA) with newborn infants (>=34 weeks' gestation or >2 kg weight) when bag-mask ventilation (BMV) or tracheal intubation is unsuccessful. Previous publications do not allow broad LMA device comparison. OBJECTIVE: To compare delivered ventilation of seven brands of size 1 LMA devices with two brands of face mask using self-inflating bag (SIB). DESIGN: 40 experienced neonatal staff provided inflation cycles using SIB with positive end expiratory pressure (PEEP) (5 cmH2O) to a specialised newborn/infant training manikin randomised for each LMA and face mask. All subjects received prior education in LMA insertion and BMV. RESULTS: 12 415 recorded inflations for LMAs and face masks were analysed. Leak detected was lowest with i-gel brand, with a mean of 5.7% compared with face mask (triangular 42.7, round 35.7) and other LMAs (45.5 65.4) (p<0.001). Peak inspiratory pressure was higher with i-gel, with a mean of 28.9 cmH2O compared with face mask (triangular 22.8, round 25.8) and other LMAs (14.3-22.0) (p<0.001). PEEP was higher with i-gel, with a mean of 5.1 cmH2O compared with face mask (triangular 3.0, round 3.6) and other LMAs (0.6-2.6) (p<0.001). In contrast to other LMAs examined, i-gel had no insertion failures and all users found i-gel easy to use. CONCLUSION: This study has shown dramatic performance differences in delivered ventilation, mask leak and ease of use among seven different brands of LMA tested in a manikin model. This coupled with no partial or complete insertion failures and ease of use suggests i-gel LMA may have an expanded role with newborn resuscitation as a primary resuscitation device. PMID- 28802260 TI - The essential functions of KREPB4 are developmentally distinct and required for endonuclease association with editosomes. AB - Uridine insertion and deletion RNA editing generates functional mitochondrial mRNAs in Trypanosoma brucei, and several transcripts are differentially edited in bloodstream (BF) and procyclic form (PF) cells correlating with changes in mitochondrial function. Editing is catalyzed by three ~20S editosomes that have a common set of 12 proteins, but are typified by mutually exclusive RNase III KREN1, N2, and N3 endonucleases with distinct cleavage specificities. KREPB4 is a common editosome protein that has a degenerate RNase III domain lacking conserved catalytic residues, in addition to zinc-finger and Pumilio/fem-3 mRNA binding factor (PUF) motifs. Here we show that KREPB4 is essential for BF and PF growth, in vivo RNA editing, and editosome integrity, but that loss of KREPB4 has differential effects on editosome components and complexes between BF and PF cells. We used targeted mutagenesis to investigate the functions of the conserved PUF and RNase III domains in both life-cycle stages and show that the PUF motif is not essential for function in BF or PF. In contrast, specific mutations in the RNase III domain severely inhibit BF and PF growth and editing, and disrupt ~20S editosomes, while others indicate that the RNase III domain is noncatalytic. We further show that KREPB4, specifically the noncatalytic RNase III domain, is required for the association of KREN1, N2, and N3 with PF editosomes. These results, combined with previous studies, support a model in which KREPB4 acts as a pseudoenzyme to form the noncatalytic half of an RNase III heterodimer with the editing endonucleases. PMID- 28802262 TI - Small noncoding RNA expression during extreme anoxia tolerance of annual killifish (Austrofundulus limnaeus) embryos. AB - Small noncoding RNAs (sncRNA) have recently emerged as specific and rapid regulators of gene expression, involved in a myriad of cellular and organismal processes. MicroRNAs, a class of sncRNAs, are differentially expressed in diverse taxa in response to environmental stress, including anoxia. In most vertebrates, a brief period of oxygen deprivation results in severe tissue damage or death. Studies on sncRNA and anoxia have focused on these anoxia-sensitive species. Studying sncRNAs in anoxia-tolerant organisms may provide insight into adaptive mechanisms supporting anoxia tolerance. Embryos of the annual killifish Austrofundulus limnaeus are the most anoxia-tolerant vertebrates known, surviving over 100 days at their peak tolerance at 25 degrees C. Their anoxia tolerance and physiology vary over development, such that both anoxia-tolerant and anoxia sensitive phenotypes comprise the species. This allows for a robust comparison to identify sncRNAs essential to anoxia-tolerance. For this study, RNA sequencing was used to identify and quantify expression of sncRNAs in four embryonic stages of A. limnaeus in response to an exposure to anoxia and subsequent aerobic recovery. Unique stage-specific patterns of expression were identified that correlate with anoxia tolerance. In addition, embryos of A. limnaeus appear to constitutively express stress-responsive miRNAs. Most differentially expressed sncRNAs were expressed at higher levels during recovery. Many novel groups of sncRNAs with expression profiles suggesting a key role in anoxia tolerance were identified, including sncRNAs derived from mitochondrial tRNAs. This global analysis has revealed groups of candidate sncRNAs that we hypothesize support anoxia tolerance. PMID- 28802263 TI - Symposium on single cell analysis and genomic approaches, Experimental Biology 2017 Chicago, Illinois, April 23, 2017. AB - Emerging technologies for the analysis of genome-wide information in single cells have the potential to transform many fields of biology, including our understanding of cell states, the response of cells to external stimuli, mosaicism, and intratumor heterogeneity. At Experimental Biology 2017 in Chicago, Physiological Genomics hosted a symposium in which five leaders in the field of single cell genomics presented their recent research. The speakers discussed emerging methodologies in single cell analysis and critical issues for the analysis of single cell data. Also discussed were applications of single cell genomics to understanding the different types of cells within an organism or tissue and the basis for cell-to-cell variability in response to stimuli. PMID- 28802264 TI - Crystal Structure and Substrate Specificity Modification of Acetyl Xylan Esterase from Aspergillus luchuensis. AB - Acetyl xylan esterase (AXE) catalyzes the hydrolysis of the acetyl bonds present in plant cell wall polysaccharides. Here, we determined the crystal structure of AXE from Aspergillus luchuensis (AlAXEA), providing the three-dimensional structure of an enzyme in the Esterase_phb family. AlAXEA shares its core alpha/beta-hydrolase fold structure with esterases in other families, but it has an extended central beta-sheet at both its ends and an extra loop. Structural comparison with a ferulic acid esterase (FAE) from Aspergillus niger indicated that AlAXEA has a conserved catalytic machinery: a catalytic triad (Ser119, His259, and Asp202) and an oxyanion hole (Cys40 and Ser120). Near the catalytic triad of AlAXEA, two aromatic residues (Tyr39 and Trp160) form small pockets at both sides. Homology models of fungal FAEs in the same Esterase_phb family have wide pockets at the corresponding sites because they have residues with smaller side chains (Pro, Ser, and Gly). Mutants with site-directed mutations at Tyr39 showed a substrate specificity similar to that of the wild-type enzyme, whereas those with mutations at Trp160 acquired an expanded substrate specificity. Interestingly, the Trp160 mutants acquired weak but significant type B-like FAE activity. Moreover, the engineered enzymes exhibited ferulic acid-releasing activity from wheat arabinoxylan.IMPORTANCE Hemicelluloses in the plant cell wall are often decorated by acetyl and ferulic acid groups. Therefore, complete and efficient degradation of plant polysaccharides requires the enzymes for cleaving the side chains of the polymer. Since the Esterase_phb family contains a wide array of fungal FAEs and AXEs from fungi and bacteria, our study will provide a structural basis for the molecular mechanism of these industrially relevant enzymes in biopolymer degradation. The structure of the Esterase_phb family also provides information for bacterial polyhydroxyalkanoate depolymerases that are involved in biodegradation of thermoplastic polymers. PMID- 28802266 TI - Functional Analysis of Genes Comprising the Locus of Heat Resistance in Escherichia coli. AB - The locus of heat resistance (LHR) is a 15- to 19-kb genomic island conferring exceptional heat resistance to organisms in the family Enterobacteriaceae, including pathogenic strains of Salmonella enterica and Escherichia coli The complement of LHR-comprising genes that is necessary for heat resistance and the stress-induced or growth-phase-induced expression of LHR-comprising genes are unknown. This study determined the contribution of the seven LHR-comprising genes yfdX1GI, yfdX2, hdeDGI, orf11, trxGI, kefB, and psiEGI by comparing the heat resistances of E. coli strains harboring plasmid-encoded derivatives of the different LHRs in these genes. (Genes carry a subscript "GI" [genomic island] if an ortholog of the same gene is present in genomes of E. coli) LHR-encoded heat shock proteins sHSP20, ClpKGI, and sHSPGI are not sufficient for the heat resistance phenotype; YfdX1, YfdX2, and HdeD are necessary to complement the LHR heat shock proteins and to impart a high level of resistance. Deletion of trxGI, kefB, and psiEGI from plasmid-encoded copies of the LHR did not significantly affect heat resistance. The effect of the growth phase and the NaCl concentration on expression from the putative LHR promoter p2 was determined by quantitative reverse transcription-PCR and by a plasmid-encoded p2:GFP promoter fusion. The expression levels of exponential- and stationary-phase E. coli cells were not significantly different, but the addition of 1% NaCl significantly increased LHR expression. Remarkably, LHR expression in E. coli was dependent on a chromosomal copy of evgA In conclusion, this study improved our understanding of the genes required for exceptional heat resistance in E. coli and factors that increase their expression in food.IMPORTANCE The locus of heat resistance (LHR) is a genomic island conferring exceptional heat resistance to several foodborne pathogens. The exceptional level of heat resistance provided by the LHR questions the control of pathogens by current food processing and preparation techniques. The function of LHR-comprising genes and their regulation, however, remain largely unknown. This study defines a core complement of LHR-encoded proteins that are necessary for heat resistance and demonstrates that regulation of the LHR in E. coli requires a chromosomal copy of the gene encoding EvgA. This study provides insight into the function of a transmissible genomic island that allows otherwise heat-sensitive enteric bacteria, including pathogens, to lead a thermoduric lifestyle and thus contributes to the detection and control of heat resistant enteric bacteria in food. PMID- 28802265 TI - Syntrophomonas wolfei Uses an NADH-Dependent, Ferredoxin-Independent [FeFe] Hydrogenase To Reoxidize NADH. AB - Syntrophomonas wolfei syntrophically oxidizes short-chain fatty acids (four to eight carbons in length) when grown in coculture with a hydrogen- and/or formate using methanogen. The oxidation of 3-hydroxybutyryl-coenzyme A (CoA), formed during butyrate metabolism, results in the production of NADH. The enzyme systems involved in NADH reoxidation in S. wolfei are not well understood. The genome of S. wolfei contains a multimeric [FeFe]-hydrogenase that may be a mechanism for NADH reoxidation. The S. wolfei genes for the multimeric [FeFe]-hydrogenase (hyd1ABC; SWOL_RS05165, SWOL_RS05170, SWOL_RS05175) and [FeFe]-hydrogenase maturation proteins (SWOL_RS05180, SWOL_RS05190, SWOL_RS01625) were coexpressed in Escherichia coli, and the recombinant Hyd1ABC was purified and characterized. The purified recombinant Hyd1ABC was a heterotrimer with an alphabetagamma configuration and a molecular mass of 115 kDa. Hyd1ABC contained 29.2 +/- 1.49 mol of Fe and 0.7 mol of flavin mononucleotide (FMN) per mole enzyme. The purified, recombinant Hyd1ABC reduced NAD+ and oxidized NADH without the presence of ferredoxin. The HydB subunit of the S. wolfei multimeric [FeFe]-hydrogenase lacks two iron-sulfur centers that are present in known confurcating NADH- and ferredoxin-dependent [FeFe]-hydrogenases. Hyd1ABC is a NADH-dependent hydrogenase that produces hydrogen from NADH without the need of reduced ferredoxin, which differs from confurcating [FeFe]-hydrogenases. Hyd1ABC provides a mechanism by which S. wolfei can reoxidize NADH produced during syntrophic butyrate oxidation when low hydrogen partial pressures are maintained by a hydrogen-consuming microorganism.IMPORTANCE Our work provides mechanistic understanding of the obligate metabolic coupling that occurs between hydrogen-producing fatty and aromatic acid-degrading microorganisms and their hydrogen-consuming partners in the process called syntrophy (feeding together). The multimeric [FeFe] hydrogenase used NADH without the involvement of reduced ferredoxin. The multimeric [FeFe]-hydrogenase would produce hydrogen from NADH only when hydrogen concentrations were low. Hydrogen production from NADH by Syntrophomonas wolfei would likely cease before any detectable amount of cell growth occurred. Thus, continual hydrogen production requires the presence of a hydrogen-consuming partner to keep hydrogen concentrations low and explains, in part, the obligate requirement that S. wolfei has for a hydrogen-consuming partner organism during growth on butyrate. We have successfully expressed genes encoding a multimeric [FeFe]-hydrogenase in E. coli, demonstrating that such an approach can be advantageous to characterize complex redox proteins from difficult-to-culture microorganisms. PMID- 28802267 TI - Transient MutS-Based Hypermutation System for Adaptive Evolution of Lactobacillus casei to Low pH. AB - This study explored transient inactivation of the gene encoding the DNA mismatch repair enzyme MutS as a tool for adaptive evolution of Lactobacillus casei MutS deletion derivatives of L. casei 12A and ATCC 334 were constructed and subjected to a 100-day adaptive evolution process to increase lactic acid resistance at low pH. Wild-type parental strains were also subjected to this treatment. At the end of the process, the DeltamutS lesion was repaired in representative L. casei 12A and ATCC 334 DeltamutS mutant isolates. Growth studies in broth at pH 4.0 (titrated with lactic acid) showed that all four adapted strains grew more rapidly, to higher cell densities, and produced significantly more lactic acid than untreated wild-type cells. However, the adapted DeltamutS derivative mutants showed the greatest increases in growth and lactic acid production. Further characterization of the L. casei 12A-adapted DeltamutS derivative revealed that it had a significantly smaller cell volume, a rougher cell surface, and significantly better survival at pH 2.5 than parental L. casei 12A. Genome sequence analysis confirmed that transient mutS inactivation decreased DNA replication fidelity in both L. casei strains, and it identified genetic changes that might contribute to the lactic acid-resistant phenotypes of adapted cells. Targeted inactivation of three genes that had acquired nonsense mutations in the adapted L. casei 12A DeltamutS mutant derivative showed that NADH dehydrogenase (ndh), phosphate transport ATP-binding protein PstB (pstB), and two-component signal transduction system (TCS) quorum-sensing histidine protein kinase (hpk) genes act in combination to increase lactic acid resistance in L. casei 12A.IMPORTANCE Adaptive evolution has been applied to microorganisms to increase industrially desirable phenotypes, including acid resistance. We developed a method to increase the adaptability of Lactobacillus casei 12A and ATCC 334 through transient inactivation of the DNA mismatch repair enzyme MutS. Here, we show this method was effective in increasing the resistance of L. casei to lactic acid at low pH. Additionally, we identified three genes that contribute to increased acid resistance in L. casei 12A. These results provide valuable insight on methods to enhance an organism's fitness to complex phenotypes through adaptive evolution and targeted gene inactivation. PMID- 28802268 TI - Ornithine Decarboxylase-Mediated Production of Putrescine Influences Ganoderic Acid Biosynthesis by Regulating Reactive Oxygen Species in Ganoderma lucidum. AB - Putrescine is an important polyamine that participates in a variety of stress responses. Ornithine decarboxylase (ODC) is a key enzyme that catalyzes the biosynthesis of putrescine. A homolog of the gene encoding ODC was cloned from Ganoderma lucidum In the ODC-silenced strains, the transcript levels of the ODC gene and the putrescine content were significantly decreased. The ODC-silenced strains were more sensitive to oxidative stress. The content of ganoderic acid was increased by approximately 43 to 46% in the ODC-silenced strains. The content of ganoderic acid could be recovered after the addition of exogenous putrescine. Additionally, the content of reactive oxygen species (ROS) was significantly increased by approximately 1.3-fold in the ODC-silenced strains. The ROS content was significantly reduced after the addition of exogenous putrescine. The gene transcript levels and the activities of four major antioxidant enzymes were measured to further explore the effect of putrescine on the intracellular ROS levels. Further studies showed that the effect of the ODC-mediated production of putrescine on ROS might be a factor influencing the biosynthesis of ganoderic acid. Our study reports the role of putrescine in large basidiomycetes, providing a basis for future studies of the physiological functions of putrescine in microbes.IMPORTANCE It is well known that ODC and the ODC-mediated production of putrescine play an important role in resisting various environmental stresses, but there are few reports regarding the mechanisms underlying the effect of putrescine on secondary metabolism in microorganisms, particularly in fungi. G. lucidum is gradually becoming a model organism for studying environmental regulation and metabolism. In this study, a homolog of the gene encoding ODC was cloned in Ganoderma lucidum We found that the transcript level of the ODC gene and the content of putrescine were significantly decreased in the ODC-silenced strains. The content of ganoderic acid was significantly increased in the ODC silenced strains. Further studies showed that the effect of the ODC-mediated production of putrescine on ROS might be a factor influencing the biosynthesis of ganoderic acid. Our study reports the role of putrescine in large basidiomycetes, providing a basis for future studies of the physiological functions of putrescine in microbes. PMID- 28802269 TI - Removal of Soluble Strontium via Incorporation into Biogenic Carbonate Minerals by Halophilic Bacterium Bacillus sp. Strain TK2d in a Highly Saline Solution. AB - Radioactive strontium (90Sr) leaked into saline environments, including the ocean, from the Fukushima Daiichi Nuclear Power Plant after a nuclear accident. Since the removal of 90Sr using general adsorbents (e.g., zeolite) is not efficient at high salinity, a suitable alternative immobilization method is necessary. Therefore, we incorporated soluble Sr into biogenic carbonate minerals generated by urease-producing microorganisms from a saline solution. An isolate, Bacillus sp. strain TK2d, from marine sediment removed >99% of Sr after contact for 4 days in a saline solution (1.0 * 10-3 mol liter-1 of Sr, 10% marine broth, and 3% [wt/vol] NaCl). Transmission electron microscopy and energy-dispersive X ray spectroscopy showed that Sr and Ca accumulated as phosphate minerals inside the cells and adsorbed at the cell surface at 2 days of cultivation, and then carbonate minerals containing Sr and Ca developed outside the cells after 2 days. Energy-dispersive spectroscopy revealed that Sr, but not Mg, was present in the carbonate minerals even after 8 days. X-ray absorption fine-structure analyses showed that a portion of the soluble Sr changed its chemical state to strontianite (SrCO3) in biogenic carbonate minerals. These results indicated that soluble Sr was selectively solidified into biogenic carbonate minerals by the TK2d strain in highly saline environments.IMPORTANCE Radioactive nuclides (134Cs, 137Cs, and 90Sr) leaked into saline environments, including the ocean, from the Fukushima Daiichi Nuclear Power Plant accident. Since the removal of 90Sr using general adsorbents, such as zeolite, is not efficient at high salinity, a suitable alternative immobilization method is necessary. Utilizing the known concept that radioactive 90Sr is incorporated into bones by biomineralization, we got the idea of removing 90Sr via incorporation into biominerals. In this study, we revealed the ability of the isolated ureolytic bacterium to remove Sr under high-salinity conditions and the mechanism of Sr incorporation into biogenic calcium carbonate over a longer duration. These findings indicated the mechanism of the biomineralization by the urease-producing bacterium and the possibility of the biomineralization application for a new purification method for 90Sr in highly saline environments. PMID- 28802270 TI - An Intramolecular Salt Bridge in Bacillus thuringiensis Cry4Ba Toxin Is Involved in the Stability of Helix alpha-3, Which Is Needed for Oligomerization and Insecticidal Activity. AB - Bacillus thuringiensis three-domain Cry toxins kill insects by forming pores in the apical membrane of larval midgut cells. Oligomerization of the toxin is an important step for pore formation. Domain I helix alpha-3 participates in toxin oligomerization. Here we identify an intramolecular salt bridge within helix alpha-3 of Cry4Ba (D111-K115) that is conserved in many members of the family of three-domain Cry toxins. Single point mutations such as D111K or K115D resulted in proteins severely affected in toxicity. These mutants were also altered in oligomerization, and the mutant K115D was more sensitive to protease digestion. The double point mutant with reversed charges, D111K-K115D, recovered both oligomerization and toxicity, suggesting that this salt bridge is highly important for conservation of the structure of helix alpha-3 and necessary to promote the correct oligomerization of the toxin.IMPORTANCE Domain I has been shown to be involved in oligomerization through helix alpha-3 in different Cry toxins, and mutations affecting oligomerization also elicit changes in toxicity. The three-dimensional structure of the Cry4Ba toxin reveals an intramolecular salt bridge in helix alpha-3 of domain I. Mutations that disrupt this salt bridge resulted in changes in Cry4Ba oligomerization and toxicity, while a double point reciprocal mutation that restored the salt bridge resulted in recovery of toxin oligomerization and toxicity. These data highlight the role of oligomer formation as a key step in Cry4Ba toxicity. PMID- 28802271 TI - Antibiofilm effect of poly(vinyl alcohol-co-ethylene) (PVA-co-PE) halamine film against Listeria innocua and Escherichia coli O157:H7. AB - Bacterial biofilm formation is linked to several infections and foodborne disease outbreaks. To address this challenge, there is an unmet need to develop rechargeable antimicrobial materials that can provide continuous sanitation of contact surfaces especially in the food industry. This study was aimed at evaluating a novel rechargeable antimicrobial polymer formed using PVA-co-PE with halamine functionality to prevent biofilm formation with repeated exposure to high loads of bacteria and organic content and also aid in inactivation of pre formed biofilms upon contact with this novel material. Antibiofilm activity of this rechargeable antimicrobial material was evaluated using a combination of fluorescence and scanning electron microscopies and biofilm metabolic activity analyses. The results based on imaging and metabolic activity measurements demonstrated that halamine functionalized polymer films significantly reduced L. innocua and E. coli O157:H7 biofilms formation. This novel polymeric material maintained its antibiofilm activity with repeated cycles of extended exposure to high levels of bacterial load. These polymeric films were recharged using bleach and cleaned using mechanical sonication after each cycle of extended incubation with bacteria. Halamine functionalized polymeric material also exhibited significant antibacterial activity against pre-formed biofilms on a model surface. In summary, results demonstrate potential of this antimicrobial material to provide continuous sanitation surfaces and applications for inactivating pre formed biofilms without extensive use of resources including water and heat. This polymeric material may be used as a replacement for existing polymeric materials or used as a coating on diverse materials.IMPORTANCE Conventional sanitizers can have limited efficacy in inactivating biofilms in areas with limited accessibility and buildup of organic biomass. Furthermore, none of the current approaches provide continuous sanitation of surfaces. There is a significant unmet need to develop and validate materials that can prevent biofilm formation as well as inactivate pre-formed biofilms. In this study the efficacy of a copolymer film containing N-halamine against the biofilms of L. innocua and E. coli O157:H7 was evaluated. The polymer film showed a strong biofilm inhibitory activity against pre-grown biofilm or prevented the growth of a new biofilm. The polymer film also maintained its anti-biofilm activity revealed after multiple cycles of exposure to high titer of bacterial load with recharging of the polymer film using bleach at intermediate steps between the cycles. Overall, the results demonstrate potential of a novel antimicrobial material to inhibit and treat biofilms in food industry applications. PMID- 28802272 TI - Transcriptional Analysis of an Ammonium-Excreting Strain of Azotobacter vinelandii Deregulated for Nitrogen Fixation. AB - Biological nitrogen fixation is accomplished by a diverse group of organisms known as diazotrophs and requires the function of the complex metalloenzyme nitrogenase. Nitrogenase and many of the accessory proteins required for proper cofactor biosynthesis and incorporation into the enzyme have been characterized, but a complete picture of the reaction mechanism and key cellular changes that accompany biological nitrogen fixation remain to be fully elucidated. Studies have revealed that specific disruptions of the antiactivator-encoding gene nifL result in the deregulation of the nif transcriptional activator NifA in the nitrogen-fixing bacterium Azotobacter vinelandii, triggering the production of extracellular ammonium levels approaching 30 mM during the stationary phase of growth. In this work, we have characterized the global patterns of gene expression of this high-ammonium-releasing phenotype. The findings reported here indicated that cultures of this high-ammonium-accumulating strain may experience metal limitation when grown using standard Burk's medium, which could be amended by increasing the molybdenum levels to further increase the ammonium yield. In addition, elevated levels of nitrogenase gene transcription are not accompanied by a corresponding dramatic increase in hydrogenase gene transcription levels or hydrogen uptake rates. Of the three potential electron donor systems for nitrogenase, only the rnf1 gene cluster showed a transcriptional correlation to the increased yield of ammonium. Our results also highlight several additional genes that may play a role in supporting elevated ammonium production in this aerobic nitrogen-fixing model bacterium.IMPORTANCE The transcriptional differences found during stationary-phase ammonium accumulation show a strong contrast between the deregulated (nifL-disrupted) and wild-type strains and what was previously reported for the wild-type strain under exponential-phase growth conditions. These results demonstrate that further improvement of the ammonium yield in this nitrogenase-deregulated strain can be obtained by increasing the amount of available molybdenum in the medium. These results also indicate a potential preference for one of two ATP synthases present in A. vinelandii as well as a prominent role for the membrane-bound hydrogenase over the soluble hydrogenase in hydrogen gas recycling. These results should inform future studies aimed at elucidating the important features of this phenotype and at maximizing ammonium production by this strain. PMID- 28802273 TI - Evidence for Borrelia bavariensis infections of Ixodes uriae within seabird colonies of the North Atlantic Ocean. AB - The first report of members of the spirochete genus Borrelia in the seabird tick, Ixodes uriae, and seabird colonies occurred during the early 1990s. Since then, Borrelia spp. have been detected in these ticks and seabird colonies around the world. To-date, the primary species detected has been B. garinii, with rare occurrences of B. burgdorferi sensu stricto and B. lusitaniae. During our research on Borrelia and I. uriae in seabird colonies of Newfoundland and Labrador, Canada, we have identified B. bavariensis in I. uriae To our knowledge, B. bavariensis has previously only been found in the Eurasian tick species, I. persulcatus and I. ricinus, and it was believed to be a rodent-specific Borrelia ecotype. We found B. bavariensis within I. uriae from three seabird colonies, over three calendar years. We also reanalyzed B. garinii sequences collected from I. uriae from Eurasian seabird colonies, and determined that sequences from two Russian seabird colonies likely also represent B. bavariensis The Canadian B. bavariensis sequences from I. uriae analysed in this study cluster with previously described sequences from Asia. Overall, this is an important discovery that illustrates and expands the range of hosts and vectors for B. bavariensis and it raises questions regarding the possible mechanisms of pathogen dispersal from Asia to North America.Importance To our knowledge this is the first documentation of B. bavariensis outside Eurasia. Additionally, the bacterium was found in a marine ecosystem involving the seabird tick, I. uriae, and its associated seabird hosts. This indicates the epizootiology of B. bavariensis transmission is much different from what was previously described, with this species previously believed to be a rodent-specific ecotype, and indicates that this pathogen is established, or establishing, much more widely. PMID- 28802274 TI - Horizontal Dissemination of Antimicrobial Resistance Determinants in Multiple Salmonella Serotypes following Isolation from the Commercial Swine Operation Environment after Manure Application. AB - The aim of this study was to characterize the plasmids carrying antimicrobial resistance (AMR) determinants in multiple Salmonella serotypes recovered from the commercial swine farm environment after manure application on land. Manure and soil samples were collected on day 0 before and after manure application on six farms in North Carolina, and sequential soil samples were recollected on days 7, 14, and 21 from the same plots. All environmental samples were processed for Salmonella, and their plasmid contents were further characterized. A total of 14 isolates including Salmonella enterica serotypes Johannesburg (n = 2), Ohio (n = 2), Rissen (n = 1), Typhimurium var5- (n = 5), Worthington (n = 3), and 4,12:i:- (n = 1), representing different farms, were selected for plasmid analysis. Antimicrobial susceptibility testing was done by broth microdilution against a panel of 14 antimicrobials on the 14 confirmed transconjugants after conjugation assays. The plasmids were isolated by modified alkaline lysis, and PCRs were performed on purified plasmid DNA to identify the AMR determinants and the plasmid replicon types. The plasmids were sequenced for further analysis and to compare profiles and create phylogenetic trees. A class 1 integron with an ANT(2")-Ia-aadA2 cassette was detected in the 50-kb IncN plasmids identified in S Worthington isolates. We identified 100-kb and 90-kb IncI1 plasmids in S Johannesburg and S Rissen isolates carrying the blaCMY-2 and tet(A) genes, respectively. An identical 95-kb IncF plasmid was widely disseminated among the different serotypes and across different farms. Our study provides evidence on the importance of horizontal dissemination of resistance determinants through plasmids of multiple Salmonella serotypes distributed across commercial swine farms after manure application.IMPORTANCE The horizontal gene transfer of antimicrobial resistance (AMR) determinants located on plasmids is considered to be the main reason for the rapid proliferation and spread of drug resistance. The deposition of manure generated in swine production systems into the environment is identified as a potential source of AMR dissemination. In this study, AMR gene carrying plasmids were detected in multiple Salmonella serotypes across different commercial swine farms in North Carolina. The plasmid profiles were characterized based on Salmonella serotype donors and incompatibility (Inc) groups. We found that different Inc plasmids showed evidence of AMR gene transfer in multiple Salmonella serotypes. We detected an identical 95-kb plasmid that was widely distributed across swine farms in North Carolina. These conjugable resistance plasmids were able to persist on land after swine manure application. Our study provides strong evidence of AMR determinant dissemination present in plasmids of multiple Salmonella serotypes in the environment after manure application. PMID- 28802275 TI - Response of Methylocystis sp. Strain SC2 to Salt Stress: Physiology, Global Transcriptome, and Amino Acid Profiles. AB - Soil microorganisms have to rapidly respond to salt-induced osmotic stress. Type II methanotrophs of the genus Methylocystis are widely distributed in upland soils, but are known to have a low salt tolerance. Here, we tested the ability of Methylocystis sp. strain SC2 to adapt to increased salinity. When exposed to 0.75% NaCl, methane oxidation was completely inhibited for 2.25 h and fully recovered within 6 h. Growth was inhibited for 23.5 h and then fully recovered. Its transcriptome was profiled after 0 min (control), 45 min (early response) and 14 h (late response) of stress exposure. Physiological and transcriptomic stress response corresponded well. Salt stress induced differential expression of 301 genes, with sigma factor sigma32 being a major controller of the transcriptional stress response. The transcript levels of nearly all the genes involved in oxidizing CH4 to CO2 remained unaffected, while gene expression involved in energy-yielding reactions (nuoEFGHI) recovered concomitantly with methane oxidation from salt stress shock. Glutamate acted as an osmoprotectant. Its accumulation in late response corresponded to increased production of glutamate dehydrogenase 1. Chromosomal genes whose products (stress-induced protein, DNA binding protein from starved cells, and CsbD family protein) are known to confer stress tolerance showed increased expression. On plasmid pBSC2-1, genes encoding type IV secretion system and single-strand DNA-binding protein were upregulated in late response, suggesting stress-induced activation of the plasmid-borne conjugation machinery. Collectively, our results show that Methylocystis sp. strain SC2 is able to adapt to salt stress, but only within a narrow range of salinities.Importance Besides the oxic interface of methanogenic environments, Methylocystis spp. are widely distributed in upland soils where they may contribute to the oxidation of atmospheric methane. However, little is known about their ability to cope with changes in moisture content and soil salinity. Growth and methane oxidation of Methylocystis sp. strain SC2 was not affected by the presence of 0.5% NaCl, while 1% NaCl completely inhibited its activities. This places strain SC2 into the low salt tolerance range reported for other Methylocystis spp. Our results show that, albeit in a narrow range, strain SC2 is able to respond and adapt to salinity changes. It possesses various stress response mechanisms, which allows for a full resumption of its activities within 23.5 hours when exposed to 0.75% NaCl. Presumably, these mechanisms allow Methylocystis spp., such as strain SC2, to thrive in upland soils and to adapt to certain fluctuations in soil salinity. PMID- 28802276 TI - On Losing Paddy Johnston. PMID- 28802277 TI - Microbiome in lung explants of idiopathic pulmonary fibrosis: a case-control study in patients with end-stage fibrosis. AB - The microbiome has been proposed to play a role in the progression of idiopathic pulmonary fibrosis (IPF) based on bronchoalveolar lavage analyses, but the microbiome of lung tissue in IPF has not been explored. In a case-control study of lung explants analysed by 16S rRNA gene sequencing, we could not reliably detect bacterial DNA in basilar tissue samples from patients with either chronic or acute exacerbations of IPF, in contrast to control candidate-donor lungs or cystic fibrosis explants. Thus, our data do not indicate microbiome alterations in regions of IPF lung with advanced fibrosis. PMID- 28802278 TI - GDF11: a fountain of youth for the ageing COPD lung? PMID- 28802279 TI - Rare adult presentation of fixed airways obstruction: remember aortic arch abnormalities. PMID- 28802280 TI - Detection and molecular identification of Cryptosporidium species in laboratory rats (Rattus norvegicus) in Ibadan, Nigeria AB - To study the occurrence of Cryptosporidium infection in laboratory rats (Rattus norvegicus) raised for experimental usage, 134 faecal samples were obtained from two rearing houses in Ibadan and examined for the presence of Cryptosporidium oocyst using the modified acid fast staining technique. Cryptosporidium species in 2 samples positive for microscopy were further characterized by a nested polymerase chain reaction (PCR) amplifying the 18S rRNA gene. Two of 134 samples were positive for the Cryptosporidium oocysts. Sequencing of the small-subunit rRNA amplicons identified the species in the two PCR positive samples as Cryptosporidium andersoni and Cryptosporidium rat genotype. These findings showed that laboratory rat is a potential reservoir for diverse Cryptosporidium species and suggests that laboratory rats should be screened for Cryptosporidium infection prior to experiments, especially where pathogen free animals are not available. This the first report to identify Cryptosporidium species infecting laboratory rats in Nigeria. PMID- 28802282 TI - Evolution of Mediterranean diets and cuisine: concepts and definitions. AB - BACKGROUND AND OBJECTIVES: The Mediterranean diet has been demonstrated to provide a range of health benefits in observational and clinical trials and adopted by various dietary guidelines. However, a broad range of definitions exist impeding synthesis across trials. This review aims to provide a historical description of Mediterranean diets, from the ancient to the modern, to inform future educational and diet index tool development representing the 'traditional' Mediterranean diet. METHODS AND STUDY DESIGN: Nine databases were searched from inception to July 2015 to identify papers defining the Mediterranean diet. The definition accepted by the United Nations Educational, Scientific and Cultural Organization (UNESCO) was also reviewed. RESULTS: The 'traditional' Mediterranean diet is described as high in unprocessed plant foods (grains, vegetables, fruits, legumes, nuts/seeds and extra virgin olive oil), moderate in fish/shellfish and wine and low in meat, dairy, eggs, animal fats and discretionary foods. Additional elements relating to cuisine and eating habits identified in this review include frequent intake of home cooked meals; use of moist, lower temperature, cooking methods; eating main meals in company; reduced snacking occasions; fasting practice; ownership of a vegetable garden; use of traditional foods and combinations; and napping after the midday meal. CONCLUSIONS: Scope exists for future tools to incorporate additional elements of the 'traditional' Mediterranean diet to improve the quality, consistency, and synthesis of ongoing research on the Mediterranean diet. PMID- 28802281 TI - High concordance of Pfdhfr and Pfdhps genotypes between matched peripheral and placental isolates of delivered women in Bobo-Dioulasso, Burkina Faso AB - Whether maternal peripheral parasites constitute a representative sample of the overall population infecting the individual, remains unknown in Burkina Faso. We therefore compared Pfdhfr and Pfdhps genotypes between matched peripheral and placental isolates. PCR-restriction fragment length polymorphism (PCR RFLP)analysis of polymorphic codons of the Pfdhfr gene (51, 59, 108 and 164) and the Pfdhps gene (437 and 540) was performed in 18 matched peripheral and placental dried blood spots of delivered women in Bobo-Dioulasso. Both Pfdhfr and Pfdhps genes were successfully genotyped in 94.4% (17/18) of the matched samples. Only 8.8% (3/34) of genotypes were of the wild type, while 20.6% (7/34), 20.6% (7/34), 23.5% (8/34) and 26.5% (9/34) comprised one, two, three and four mutations, respectively. None of the samples carried both Pfdhfr I164L and Pfdhps K540E mutations. A concordance of 82.4% was observed in matched samples for both the Pfdhfr and Pfdhps genes. Setting placental alleles as the reference, a concordance of 100% was obtained with Pfdhfr mutation S108N, Pfdhfr mutation C59R+S108N, and Pfdhfr mutation N51I+C59R +S108N, respectively. Likewise, a concordance of 85.7% was observed with the Pfdhps mutation A437G. For epidemiological purposes, peripheral blood Pfdhfr and Pfdhps genotyping is sufficient for monitoring SP resistant molecular markers in pregnant women. PMID- 28802283 TI - Uyghur food culture. AB - Uyghur food culture has a long history. It is rich in resources, with the strong characteristics of being "green" and healthy, and having high nutritional value. We analyze the development and current status of Uyghur food culture, and explore the value of developing this food culture's resources. Traditional Uyghur food culture formed with influences from many ethnic groups, and has evolved into an intangible element of cultural heritage. It has several components with different healthy and therapeutic functions and is widely utilized in local communities. Overall, Uyghur food is rich in nutrients and beneficial for health. We propose strategies to address issues associated with Uyghur food culture and cultural resources, and specific measures for the development of these resources. PMID- 28802284 TI - Simple questions in salt intake behavior assessment: comparison with urinary sodium excretion in Japanese adults. AB - BACKGROUND AND OBJECTIVES: To clarify whether six conventional 'high-risk' behaviors toward excess salt intake captured by simple questions such as frequency of salty food consumption are related to actual salt intake. Also, to examine the relationship of nutrition knowledge, food label use, and food preparation with actual salt intake. METHODS AND STUDY DESIGN: Study participants were 742 subjects (370 men and 372 women) aged 20-69 years from 20 areas of Japan. Salt intake and dietary knowledge/behavior were evaluated with two 24-hour urine collections and a questionnaire, respectively. Multivariable linear regression analyses by sex included sodium excretion as a dependent variable, each knowledge/behavior item as an independent variable, and with age, body mass index, education, and smoking as covariates. RESULTS: Four 'high-risk' behaviors (frequency of miso soup and salty foods consumption, proportion of consumed noodle soup, and amount of seasoning/condiment use) were associated with higher sodium excretion in men (p for trend <=0.04) and were marginally associated in women (p for trend <=0.06). Combination of these behaviors elevated the odds ratios for excess salt intake (sodium excretion: >136 mmol/day). Most of the other nine dietary factors were not associated with sodium excretion. Interestingly, women who decided to purchase foods after referring to the salt/sodium content information on food label, had significant lower sodium excretion than other women (p for trend=0.03). CONCLUSIONS: High-risk behaviors toward excess salt intake captured by simple questions were actually related to excess salt intake. Specific and practical advice based on answers to these questions might contribute to salt reduction in Japanese population. PMID- 28802285 TI - A nutrition care process knowledge, attitudes, practices, and perceived barriers questionnaire. AB - BACKGROUND AND OBJECTIVES: Assessment of the nutrition care process (NCP) knowledge, attitudes, practices, and perceived barriers (KAPB) of dietetics practitioners is imperative before NCP is implemented completely in dietetics practice. No questionnaire assessing NCP KAPB has been developed and validated. Hence, we developed an NCP KAPB questionnaire called the KAPB-NCP and established its content validity. METHODS AND STUDY DESIGN: A total of 116 items associated with sociodemographic characteristics (7 items), professional development (3 items), organisational culture's support for the NCP (2 items), knowledge (27 items), attitudes (39 items), practices (20 items), and perceived barriers to implementing the NCP (14 items) were generated for potential inclusion in the KAPB-NCP questionnaire. The questionnaire was reviewed online by an expert panel for its content validity. An in-depth review was conducted by the research team for evaluating the overall comprehensiveness of the questionnaire. RESULTS: In total, 87 of 100 items of the KAPB sections showed an excellent content validity index (CVI; k* >0.74), whereas 10 showed a satisfactory CVI (k*=0.60-0.74). Only 3 items had a low CVI (k* <0.40). According to the expert panel revisions and the in-depth review, 72 items were incorporated into the questionnaire. CONCLUSIONS: The KAPB-NCP questionnaire is a content-valid instrument that can assess NCP KAPB. PMID- 28802286 TI - Urine color for assessment of dehydration among college men students in Hebei, China - a cross-sectional study. AB - BACKGROUND AND OBJECTIVES: To examine the association between quantified urine color and urine osmolality, and its validity in distinguishing hydration status among college men in Hebei, China. METHODS AND STUDY DESIGN: Sixty-eight college men aged 18~25 years completed a cross-sectional study. All participants were asked to complete a 24-h fluid intake record to estimate fluid intake from beverages after anthropometric measurements. The foods eaten by participants were weighed to assess fluid intake from foods. All urine samples for the day were collected by participants to determine urine osmolality and urine color by chromatogram spectrophotometry (in accord with the Commission Internationale de l'Eclarige (CIE) notation L*a*b*). RESULTS: A total 413 urine samples from 68 participants were collected and 151 (36.6%) samples indicated dehydration according to urine osmolality. The dehydrated group versus hydrated group had a smaller urine color L* (94.88 vs 98.06) and a* (- 2.39 vs -1.91), bigger b* (30.41 vs 15.15), and higher osmolality (958 mOsm/kg vs 486 mOsm/kg). Urine color and osmolality were closely correlated, especially for b* (0.86, p<0.0001). The percentage variance in urine osmolality (R2) explained by a partial least squares (PLS) model was 79%. Urine color b* contributed most substantially to the PLS model, with variable importance for projection of 1.35. The cutoff for b* for adequate hydration was 17.78 (area under the curve=0.899). CONCLUSIONS: Differences in urine color between dehydrated and hydrated status related to urine osmolality. Urine color quantification is a reliable method to assess hydration status among young Chinese men. PMID- 28802287 TI - Energy expenditure in severe sepsis or septic shock in a Thai Medical Intensive Care Unit. AB - BACKGROUND AND OBJECTIVES: Energy expenditure in severe sepsis/septic shock patients was measured by indirect calorimetry and the correlation of energy expenditure between indirect calorimetry and predictive equations was determined. METHODS AND STUDY DESIGN: This was a prospective, observational analytical study. Severe sepsis or septic shock patients were measured for energy expenditure over 72 hours by indirect calorimetry that was measured by a mechanical ventilator (EngstromCarestation, GE Healthcare). Predictive equations for energy expenditure by the Harris-Benedict equation (HBE), Ireton-Jones 1992 equation (IRE) and ACCP equation (ACCP) were calculated and then correlations and agreement between indirect calorimetry and predictive equations were tested. RESULTS: The 16 patients had a mean age of 71.6+/-5.5 years and a mean APACHE II score of 26.9+/ 4.0. The average energy expenditure by indirect calorimetry over 72 hours per kilogram body weight was 26.7+/-5.3 kcal/kg/day. For predictive equations, IRE was moderately significantly correlated with indirect calorimetry over 72 hours (intraclass correlation 0.46, 95% CI -0.01 to 0.77, p=0.028), but the HBE and ACCP equations were not significantly correlated (intraclass correlation for HBE 0.52, 95% CI -0.8 to -0.06, p=0.985 and intraclass correlation for ACCP 0.29, 95% CI -0.21 to 0.68, p=0.121). CONCLUSIONS: Energy expenditure over 72 hours in severe sepsis or septic shock was about 26.7+/-5.3 kcal/kg/day. The use of predictive equations should be further examined in future studies. PMID- 28802288 TI - Efficacy and safety of pectin-supplemented enteral nutrition in intensive care: a randomized controlled trial. AB - BACKGROUND AND OBJECTIVES: Enteral nutrition (EN) can improve clinical outcomes as an important treatment in critically ill patients. However, when patients suffer from gastrointestinal function disorders, intestinal intolerance occurs and EN administration may be delayed and even fails to perform. Pectin, a structural heteropolysaccharide, could protect gastrointestinal function from disorders in many gastrointestianl diseases. The present study aimed to determine whether pectin-supplemented EN was safe and improved clinical outcomes in intensive care unit (ICU) patients. METHODS AND STUDY DESIGN: Patients enrolled in ICU from August 2014 to January 2015 were randomized to EN group and pectin supplemented EN group (PEC/EN group). Both group received isonitrogenous, isocaloric EN support within 36 hours after ICU admission, and last for 6 days. The primary endpoints were 30-day mortality and gastrointestinal intolerance. RESULTS: There were 125 patients included in this study (63 in EN group, and 62 in PEC/EN group). The results showed that the 30-day mortality was 4.8% in EN group and 1.61% in PEC/EN group (p=0.317). PEC/EN group had a smaller gastrointestinal intolerance rate than EN group (41.3% vs 27.4%, p=0.04). Furthermore, there were shorter times to reach full EN (13.0+/-5.12 vs 9.99+/ 1.91, p=0.05), length of ICU stay (17.9+/-9.72 vs 13.8+/-8.59, p<0.001), and length of hospital stay (32.9+/-19.0 vs 23.4+/-13.2, p<0.001) in EN group than those in PEC/EN group. CONCLUSIONS: These results revealed that pectin- supplemented EN was safe, and could improve clinical outcomes in ICU patients. PMID- 28802289 TI - Home enteral nutrition's effects on nutritional status and quality of life after esophagectomy. AB - BACKGROUND AND OBJECTIVES: We aimed to characterize the effect of home enteral nutrition (HEN) on the nutritional status and the quality of life (QOL) of esophageal cancer patients who underwent Ivor Lewis esophagectomy for cancer. METHODS AND STUDY DESIGN: Sixty patients with esophageal cancer were assigned to receive either HEN (n=30) or standard care only (n=30) from 1 week to 24 weeks following surgery. Nutritional status was evaluated using The Mini Nutritional Assessment at 1 week preoperatively and at 12 and 24 weeks postoperatively. QOL related parameters were analyzed in all patients using the QOL-core 30 questionnaire and the supplemental QOL-esophageal module 18 questionnaire for patients with esophageal cancer from 1-24 weeks after surgery. RESULTS: At 12 weeks after surgery, the incidence of malnutrition or latent malnutrition in the HEN group was lower than that in the control group despite the absence of a significant difference between the two groups before surgery. Compared to the control group, the HEN group achieved higher Global QOL scores, and most of their functional index scores were better. Most of the symptomatic index scores were more reduced at 4 weeks and 12 weeks postoperatively in the HEN group. However, at 24 weeks after surgery, the incidence of malnutrition or latent malnutrition and most of the QOL indexes did not differ significantly between the two groups. CONCLUSIONS: HEN can reduce the incidence of malnutrition or latent malnutrition and help restore the QOL in the patients with esophageal cancer in the early period (24 weeks) after surgery. PMID- 28802290 TI - Postoperative oral nutritional supplementation after major gastrointestinal surgery: a randomized controlled clinical trial. AB - BACKGROUND AND OBJECTIVES: This study aimed to evaluate the efficacy of post operative oral nutrition supplementation after major gastrointestinal surgery. METHODS AND STUDY DESIGN: A prospective randomized controlled trial was conducted to evaluate 174 subjects who were discharged within 2 weeks after major gastrointestinal surgery. The subjects in the study group were prescribed 400 ml/day of Encover(r) from the day of discharge for 8 weeks, but no supplementation was allowed in the control group. The primary endpoint was the weight loss rate at 8 weeks after discharge compared with the pre-operative weight, and the secondary endpoints included changes in body weight, body mass index, Patient-Generated Subjective Global Assessment score/grade, hematological/ biochemical parameters, and adverse events evaluated at 2, 4, and 8 weeks after discharge. RESULTS: The weight loss rate at 8 weeks after discharge did not differ between two groups (4.23+/-5.49% vs 4.80+/-4.84%, p=0.481). The total lymphocyte count, the level of total cholesterol, total protein, and albumin were significantly higher in the study group after discharge. Diarrhea was the most frequent adverse event, and the incidence of adverse events with a severity score of >=3 did not differ between groups (2.3% vs 1.2%). CONCLUSIONS: The utility of routine oral nutritional support after major gastrointestinal surgery was not proven in terms of weight loss at 8 weeks after discharge. However, it can be beneficial for early recovery of biochemical parameters. PMID- 28802291 TI - Metoclopramide for preventing nosocomial pneumonia in patients fed via nasogastric tubes: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND AND OBJECTIVES: Metoclopramide, a prokinetic agent, has been recommended to reduce incidence of pneumonia, but its efficacy is controversial. Thus, this systematic review aimed to evaluate the effectiveness of metoclopramide for pneumonia in patients fed via nasogastric tube. METHODS AND STUDY DESIGN: Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and OVID were searched from their inception to March 31th 2015. Randomized controlled trials (RCTs) of metoclopramide against placebo in patients fed via nasogastric tube were identified. The Cochrane risk of bias assessment tool was used for quality assessment. RESULTS: Four trials involving 694 patients fed via nasogastric tube were identified. Compared with placebo, metoclopramide showed no significant effects in reducing pneumonia (n=694; risk ratio [RR]: 0.79; 95% CI: 0.45 to 1.38, p=0.40) or mortality (n=694; RR: 0.93; 95% CI: 0.78 to 1.11, p=0.44). In two trials using continuous data, metoclopramide significantly delayed the development of nosocomial pneumonia (n=80; weighted mean difference [WMD]: 1.74 days; 95% CI: 1.03 to 2.46 days, p<0.00001). However, in two other trials using dichotomous data, metoclopramide increased the proportion of cases showing early-onset nosocomial pneumonia (n=103; RR: 1.32; 95% CI: 1.10 to 1.58, p=0.003). Adverse effects monitoring was reported in one included trial, No significant adverse reactions were noted in this study. CONCLUSIONS: Because of the poor methodological quality and high risk of bias in the included studies, this systematic review revealed no definite conclusion about the application of metoclopramide for the reduction of nosocomial pneumonia. Therefore, more high quality studies with larger sample sizes are required. PMID- 28802292 TI - Even minimal polishing of an Indian parboiled brown rice variety leads to increased glycemic responses. AB - BACKGROUND AND OBJECTIVES: To evaluate the effect of polishing on the glycemic properties of Indian parboiled brown rice. METHODS AND STUDY DESIGN: We evaluated the effect of different degrees of polishing on the glycemic and insulinemic responses of Bapatla (BPT-5204), Indian parboiled Indica rice variety. Brown rice (BR), under milled rice (UMR) and white rice (WR) with 2.3% and 9.7% degree of polishing (DOP), respectively, were prepared and evaluated for the glycemic properties. Incremental Area Under the Curves (IAUC) were estimated for both glycemic index (GI) in 12 healthy participants (6 men, 6 women) and 24 hr glycemic response studies in 13 overweight participants (5 men, 8 women) using continuous glucose monitoring (CGM) system with ~2000 kcal/day rice diets. Differences in pre and post meal insulin (Delta) were assessed. RESULTS: The GI of WR (GI=79.6) and UMR (GI=73) were significantly higher than BR (GI=57.6) (p<0.01). Similar results were obtained for 24 hr glycemic responses [IAUC: WR=58.4, UMR=55.5, BR=34.7 mg*5 min/dL, respectively]. The Delta Insulin responses were lower with BR meals compared with UMR and WR (p=0.025; p=0.003). CONCLUSIONS: Both UMR and WR had a high GI while BR had a medium GI. This could have influenced the 24 h glycaemic and insulinemic responses of BR which had the lowest responses as compared with UMR and WR, and the latter two had similar higher responses. Thus any degree of polishing leads to higher glycaemic responses. PMID- 28802293 TI - Overall nutrient and total fat intake among Japanese people: The INTERLIPID Study Japan. AB - BACKGROUND AND OBJECTIVES: Total fat intake is linked to the intake of other nutrients. Little data are available on the extent to which total fat affects diet quality in Japanese people. We investigated the relationship between total fat intake and other nutrient intake using INTERLIPID/ INTERMAP data on Japanese people living in Japan. METHODS AND STUDY DESIGN: The participants included 371 men and 401 women with a healthy body mass index and between the ages of 40 and 59 from 4 population samples in Japan. Nutrient intake data were based on four in depth 24-hour dietary recalls per person. RESULTS: Analysis of covariance adjusted for age revealed that total fat intake was positively related to intakes of calcium, thiamine, riboflavin, meat, eggs, and milks and dairy products for both sexes. Total fat intake was inversely associated with carbohydrate and cereals intake for both sexes. On average, men with total fat intake between 25.0 and 27.4% of total energy had saturated fatty acids above 7%, which is the upper limit recommended for preventing lifestyle-related diseases. Men with total fat intake less than 20% of total energy had a higher risk of not meeting the Dietary Reference Intakes for Japanese (2015) for some nutrients. CONCLUSIONS: Total fat intake was positively associated with calcium, thiamine, and riboflavin intakes and inversely associated with carbohydrate intake. Our results suggest that in 40 59-year-old men with a healthy body mass index, total fat intake between 20 and 27% of total energy may best support adequate intake of other nutrients. PMID- 28802294 TI - Serum 25-hydroxyvitamin D and elderly skeletal muscle mass and function in urban north China. AB - BACKGROUND AND OBJECTIVES: To investigate the association of serum 25 hydroxyvitamin D (25(OH)D) with skeletal muscle mass (SMM) and function among the elderly in an urban area in northern China. METHODS AND STUDY DESIGN: A total of 912 participants (316 men, 596 women) aged more than 60 years from 4 communities in Beijing were enrolled. Serum concentrations of 25(OH)D were measured through radioimmunoassay. SMM was assessed through bioelectrical impendence analysis, whereas skeletal muscle function was assessed through grip strength and 4-m regular gait speed measurements. On the basis of expert consensus of the Asian Working Group for Sarcopenia, low muscle mass was defined as relative skeletal mass index (RSMI) <7.0 kg/m2 for men and <5.7 kg/m2 for women. A noncondition logistical regression model was employed to explore the association between vitamin D and both muscle mass and function. RESULTS: Serum 25(OH)D was positively associated with grip strength (beta=0.16, SE=0.05). The upper quartile of 25(OH)D was negatively associated with loss of grip strength (OR=0.05, 95% CI: 0.01-0.48) in men but not in women. No significant associations were noted between 25(OH)D and appendicular skeletal muscle mass, RSMI, and gait speed. CONCLUSIONS: The present study demonstrated a positive association between vitamin D and skeletal muscle strength in elderly Chinese men but not women. PMID- 28802295 TI - Food acceptance and anthropometry in relation to 6-n-propylthiouracil sensitivity in Japanese college women. AB - BACKGROUND AND OBJECTIVES: Differences in anthropometry and food acceptance among tasters and non-tasters of 6-n-propylthiouracil has been well studied in Western countries. However, reports on this issue from Asian countries are still limited. METHODS AND STUDY DESIGN: Healthy Japanese students attending Nara Women's University (n=153) were recruited and classified into 3 groups based on taste sensitivity to a 0.32 mM 6-npropylthiouracil solution as scored on a labeled magnitude scale. Accordingly, the study population consisted of 34 non-tasters, 78 medium-tasters, and 41 super-tasters. Self-reported food intake was assessed using a food frequency questionnaire. Self-reported food preferences were established using a food checklist listing 63 food items. RESULTS: Although subjects in the 6-n-propylthiouracil non-taster group showed a significantly higher body height and weight than subjects in the taster groups, body mass index was comparable among three groups. Intakes of calories, 3 macronutrients, beta carotene and vitamin C did not differ significantly between groups, but the intake of green and yellow vegetables was significantly lower in the taster groups. Among the 5 factors defined by a factor analysis performed with 277 age- and BMI-matched Japanese female students, the taster groups showed a significantly reduced preference for green and cruciferous vegetables alone. CONCLUSIONS: To the best of our knowledge, this is the first comprehensive report investigating associations between anthropometry, food intake, and food preference in relation to 6-n-propylthiouracil sensitivity in Asian countries. The effect of this tendency towards an aversion to vegetables including cruciferous ones among females on living a healthy life remains to be investigated. PMID- 28802296 TI - Iodine status among pregnant women in rural Sabah, Malaysia. AB - BACKGROUND AND OBJECTIVES: In 2000, legislation on mandatory universal salt iodisation was enacted in Sabah, Malaysia, to reduce the incidence of iodine deficiency disorders among its population. To evaluate the iodine levels among pregnant women from selected rural divisions in Sabah 13 years after the enactment of the universal salt iodisation programme. METHODS AND STUDY DESIGN: This cross-sectional study was conducted from 1 May to 30 June, 2013, in three rural divisions of Sabah (the Interior, the West Coast, and Kudat). Data regarding domestic iodised salt use and iodine-containing supplement consumption were obtained from respondents through face-to-face interviews; goitre enlargement was examined through palpation and graded according to the World Health Organization classification. Spot urine samples were also obtained to assess urinary iodine levels by using an in-house modified micromethod. RESULTS: In total, 534 pregnant women participated. The prevalence of goitre was 1.0% (n=5), noted only in the West Coast and Kudat divisions. Although all pregnant women consumed iodised salt, overall median urinary iodine concentration was only 106 MUg/L, indicating insufficient iodine intake, with nearly two-thirds of the women (60%) having a median urinary iodine concentrations of <150 MUg/L. CONCLUSIONS: Pregnant women from the rural divisions in Sabah still exhibit iodine deficiency disorder despite the mandatory universal salt iodisation programme. Iodine supplementation programmes targeting pregnant women are warranted. PMID- 28802297 TI - Breastfeeding and early childhood caries: a meta-analysis of observational studies. AB - BACKGROUND AND OBJECTIVES: The associations of breastfeeding and early childhood caries (ECC) risk have been evaluated in several epidemiological studies with conflicting results. We performed an update meta-analysis to estimate the association of feeding patterns, breastfeeding durations and ECC risk. METHODS AND STUDY DESIGN: Studies were identified through searching Pubmed, Web of Science, and Embase from January 1990 to December 2015. RESULTS: Thirty-five studies involving 73,401 participants aged 0-71 months were included. The overall analysis showed children ever breastfed had a reduced risk of ECC compared with those never breastfed (OR=0.77, 95% CI: 0.61-0.97, p=0.026). Subgroup analysis revealed ever breastfeeding significantly reduced ECC risk for the studies with 3 6 years old children (OR=0.70, 95% CI: 0.54-0.90, p=0.005), with sample size >500 subjects (OR=0.63, 95% CI: 0.46-0.87, p=0.004), with Newcastle-Ottawa Scale (NOS) score >=6 (OR=0.66, 95% CI: 0.46-0.94, p=0.023), published after 2010 (OR=0.50, 95% CI: 0.30-0.82, p=0.006), with adjusted OR (OR=0.40, 95% CI: 0.18-0.88, p=0.023). Exclusive breastfeeding did not significantly decrease ECC risk compared with bottle feeding (OR=0.68, 95% CI: 0.35-1.31, p=0.248). The children breastfed >=12 months significantly increased ECC risk compared with those breastfed <12 months (OR=1.86, 95% CI: 1.37-2.52, p<0.001). Whereas, children breastfed >=6 months did not significantly increase ECC risk compared with those breastfed <6 months (OR=1.13, 95% CI: 0.83-1.53, p=0.428). CONCLUSIONS: Our analysis suggests ever breastfeeding may protect children from ECC, and breastfeeding duration >=12 months is associated with higher ECC risk. Additional large cohort studies are required to illustrate the relationship in further study. PMID- 28802298 TI - Increased pre-school overweight and obesity prevalence between 2004 and 2013 is associated with appetite, eating frequency and supportive facilities: the Jiaxing Birth Cohort in China. AB - BACKGROUND AND OBJECTIVES: Childhood obesity is increasing. However, little is known about the changes in di-etary factors and supportive facilities associated with childhood obesity. We aimed to document the changes in various dietary factors and supportive facilities and their associations with obesity among pre school children. METHODS AND STUDY DESIGN: Among 42,531 children 4-5 years old, recruited between 2004 and 2013 in the Jiax-ing Birth Cohort, we examined the changes in the prevalence of various dietary factors and supportive facilities and overweight/obesity over 10 years. We used logistic regression to investigate the cross-sectional association between these factors and childhood overweight/obesity risk, adjusting for potential confounders. RESULTS: The prevalence of childhood overweight/obesity increased steadily from 11.8% (boy: 14.8%; girl: 9%) during 2004-2005 to 18% (boy: 21.4%%; girl: 15%) during 2012 2013. The prevalence of meal/snack frequency 3 times /day decreased substantially from 23% during 2004-2005 to 8% during 2012-2013, with more children having 5 times /day: from 32% to 45.6%. Children with a fair/bad appetite, compared with those with a good appetite, had a 45% (OR: 0.55; 95% CI: 0.49, 0.62) lower risk of overweight/obesity. Children with a meal frequency >=6 times/day (compared with 3 times/day) had a 0.12 (95% CI: 0.03, 0.2) higher BMI-z-score. CONCLUSIONS: The prevalence of childhood overweight/obesity has increased substantially within a decade in southeast China. A better appetite and greater eating frequency were associated with the increased prevalence. PMID- 28802299 TI - Child and parental perspectives on diet and physical activity decisions: implications for childhood obesity prevention in China. AB - BACKGROUND AND OBJECTIVES: Obesity has become a global epidemic. In China, 42% of adults and about onefifth of children are overweight or obese. In major cities, about one-third of boys are overweight or obese. This study aimed to understand how children and parents in China make eating and physical activity (PA) decisions, considering individual, family, community, social, and environmental factors, and to collect parents' recommendations for interventions to promote healthy eating and physical activity. METHODS AND STUDY DESIGN: Children (n=41, aged 10-15 years) and their parents (n=41) participated in eight semi-structured focus groups (FGs) in Beijing (in North China) and Nanjing (South China). Each site conducted two FGs with children and two FGs with parents. A framework analysis of FG data was conducted with NVivo. RESULTS: Three main themes were identified: Children chose food based on flavor, and consumption of unhealthy snacks was prevalent; there were inconsistent standards and practices of school lunch services across schools; students had limited PA time due to academic demand. Students favored high-calorie snacks over fruits or vegetables. Students' and parents' perceptions of school lunch services varied among schools in terms of operation, price, quality, nutritious options, and food taste. Most students reported enjoying PA but spent little time in PA, due to study burdens. Parents made recommendations for improving school food services and increasing PA during and after school. CONCLUSIONS: These findings will help develop family- and school-targeted health promotion interventions. Intervention framing must consider the unique Chinese social and cultural context. PMID- 28802300 TI - Media exposure and parental mediation on fast-food consumption among children in metropolitan and suburban Indonesia AB - BACKGROUND AND OBJECTIVES: Fast-food companies have been reproached for rising obesity levels due to aggressive marketing tactics targeted at children. They have countered that parents should be held responsible considering their critical role as nutritional gatekeepers. This study examined the comparative effects of media exposure and parental mediation on Indonesian children's fast food consumption and how the effects compare in the metropolitan versus suburban areas. METHODS AND STUDY DESIGN: The sample consisted of 394 child-mother pairs comprising grade three and four children and their mothers from two schools each in Jakarta and Bogor representing 40.9% metropolitan sample and 59.1% suburban sample, respectively. The children completed a guided inclass survey, while the mothers completed a paper-and-pen survey at home. Measures comprised children's weekly media exposure to broadcast media, computer and mobile games, print media, and online and social media, active and restrictive parental mediation strategies, children's fast food consumption and nutrition knowledge. The relationship of media exposure and parental mediation with children's fast food consumption was analyzed using Structural Equation Modelling. RESULTS: Fast food consumption was positively influenced by exposure to broadcast media among metropolitan children, and by exposure to online and social media among suburban children. Active parental mediation was related to lower fast food consumption, but only for suburban children. CONCLUSIONS: Active parental mediation is critical in preventing fast food consumption. The media play a key role in influencing fast food consumption, and hence, literacy education is important to alleviate the adverse effects of exposure to junk food marketing. PMID- 28802301 TI - Sleep duration's association with diet, physical activity, mental status, and weight among Korean high school students. AB - BACKGROUND AND OBJECTIVES: Sleep deprivation is a critical public health problem, especially in Korean adolescents. This study aimed to identify the association between sleep duration and dietary behaviors, physical activity, mental status, and nutritional status among high school students in South Korea. METHODS AND STUDY DESIGN: Based on the data collected from the 2014 Korea Youth Risk Behavior Web-based Survey, 31,407 high school students who met the inclusion criteria were selected and the association between sleep duration and selected health risk factors was identified using multivariable logistic regression models. RESULTS: The average daily sleep duration was 5.7 hours, and the mean BMI was 21.3 kg/m2. Participants with shorter durations of sleep (<7 hours versus >=7 hours of sleep) were more likely to feel sad or hopeless (adjusted OR, 1.09; 95% CI, 1.00-1.18), have suicidal ideation (adjusted OR, 1.13; 95% CI, 1.01-1.27), and feel much or very much stressed (adjusted OR, 1.82; 95% CI, 1.66-2.00). Moreover, shorter sleep was associated with less frequent muscle-strengthening exercises, >=3 times per week (adjusted OR, 0.86; 95% CI, 0.78-0.94), and more frequent cracker consumption, >=3 times per week (adjusted OR, 1.24; 95% CI, 1.13-1.35). CONCLUSIONS: High school students in South Korea suffer from extreme sleep deprivation; only 16% of the students were found to have >=7 hours of sleep during weekdays. Sleep education should be provided to students to improve their physical and mental health. PMID- 28802302 TI - Kimchi intake and atopic dermatitis in Korean aged 19-49 years: The Korea National Health and Nutrition Examination Survey 2010-2012. AB - BACKGROUND AND OBJECTIVES: Many studies have reported that fermented foods have favorable effects in preventing and managing atopic dermatitis (AD). Although kimchi, a major fermented food, is an important part of the traditional diet in Korea, only a few studies have investigated the relationship between AD and kimchi. This study aimed to examine the association between the risk of AD and kimchi intake among Korean adults aged 19 to 49 years. METHODS AND STUDY DESIGN: We conducted a population-based, cross-sectional study among a total of 7,222 adults who participated in the 2010-2012 Korea National Health and Nutrition Examination Surveys. We defined AD based on responses to a health interview and assessed kimchi intake using a 24-hour recall method administered by well-trained interviewers. RESULTS: In the multivariable logistic regression analysis, we observed a significantly decreased odds ratio (OR) of having AD according to kimchi consumption after adjustment for confounding factors. In particular, subjects in the third quartile of kimchi consumption (85.0-158 g) had a 32% lower presence of AD than those in the first quartile of kimchi consumption (0-36.0 g) (Odds ratio: 0.68, 95% confidence interval: 0.50-0.92). CONCLUSIONS: We found that consuming 85.0-158 g/day of kimchi was significantly associated with a lower presence of AD. Considering that one serving size of kimchi is 40 g, this corresponds to about 2-4 servings per day. This finding suggests that adequate amount of kimchi intake might have a protective effect against AD. PMID- 28802303 TI - Body image, weight management behavior, nutritional knowledge and dietary habits in high school boys in Korea and China. AB - BACKGROUND: Adolescence is an important period with rapid physical growth transitioning from childhood to adulthood. Distorted body image can result in eating disorders or inadequate nutrient intakes in adolescence. Limited research has been done with high school boys in both Korea and China. OBJECTIVES: To examine body image, weight control behaviors, nutritional knowledge, and dietary habits in Korean and Chinese teenage boys, and to evaluate any differences in these measures between two countries. METHODS AND STUDY DESIGN: High school boys in Yongin of Korea and Weihai region of China (n=201 Korean and n=196 Chinese) participated in a selfreport survey. A previously validated questionnaire assessed height and weight, body image, nutritional knowledge, and dietary habits. Descriptive statistics, t-test, Chi-square, and Pearson correlations were used for data analysis. RESULTS: About 41.4% of Korean students and 40.8% of Chinese students desired to be thinner. The majority of the students from both countries showed a perception gap between ideal body image and current body image. Korean students had a higher frequency of weight control attempts compared with Chinese students (p=0.004). Overall, Korean students had higher scores in nutritional knowledge (p<0.001), while Chinese students had higher scores in dietary habits (p<0.001). Nutrition knowledge in Korean students and dietary habit in Chinese students showed positive correlation with body shape satisfaction (p<0.01). CONCLUSIONS: The findings of this study support that developing proper body image among high school boys is important in Korea and China. Different educational strategies might be beneficial to Korean or Chinese students. PMID- 28802304 TI - Coffee consumption and coronary heart disease risk using the Framingham risk score. AB - BACKGROUND AND OBJECTIVES: Although concerns regarding the influence of coffee consumption on human health have accompanied the massive increase in coffee consumption, the effects of coffee intake on the risk for coronary heart disease (CHD) remain controversial. Therefore, we evaluated the association between coffee consumption and CHD risk as estimated using the Framingham risk model in Korean adults. METHODS AND STUDY DESIGN: This cross-sectional study involved 3,987 participants aged 30-74 years who participated in the fifth Korea National Health and Nutrition Examination Survey conducted in 2010. The frequency of coffee consumption was self-reported and classified into 4 categories (non drinker, 1, 2, and >=3 cups/day). The 10-year risk for CHD was determined from the Framingham risk score. RESULTS: Across the levels of coffee consumption, there were significant differences in the frequency of smoking among men and advanced age, low high-density lipoprotein cholesterol level, diabetes, and smoking among women. In the multiple logistic regression analyses, the adjusted odds ratios (95% CI) for >=20% 10-year CHD risk was 0.211 (0.060-0.745) for women who consumed >=3 cups of coffee per day compared with women who consumed <1 cup per day. For women, a significant dose-response inverse association between the level of coffee consumption and 10-year CHD risk persisted even after adjusting for multiple confounding factors. For the men, however, there was no significant association between coffee consumption and 10-year CHD risk. CONCLUSIONS: Coffee consumption is associated with a lower risk for CHD in Korean women. PMID- 28802305 TI - Fish, long chain omega-3 polyunsaturated fatty acids consumption, and risk of all cause mortality: a systematic review and dose-response meta-analysis from 23 independent prospective cohort studies. AB - BACKGROUND AND OBJECTIVES: The consumption of fish and long chain omega-3 polyunsaturated fatty acids (n-3 PUFA) may influence the risk of all-cause mortality, but the findings have been inconsistent. The current systematic review and meta-analysis is to clarify the association between fish and long chain n-3 PUFA consumption with risk of all-cause mortality. METHODS AND STUDY DESIGN: Studies published before March 2017 were identified through electronic searches using PubMed, Scopus and Web of Science database. We included prospective cohort studies that reported relative risks with 95% CI of all-cause mortality for fish and long chain n-3 PUFA consumption. Results were combined using a random effects model. RESULTS: Twenty-three prospective cohorts with a total of 1,035,416 participants were included. Twenty-two pooled studies involving 985,126 participants indicated that fish intake was associated with 6% (RR: 0.94; 95% CI: 0.90, 0.98) reduction in risk of all-cause mortality. Six studies with 430,579 participants investigated the association between long chain n-3 PUFA and all cause mortality risk, the relative risk for highest versus lowest category was 0.86 (95% CI: 0.80, 0.93). Doseresponse analysis suggested that the risk of all cause mortality was reduced by 7% (RR: 0.93; 95% CI: 0.88, 0.99) for every 0.2 g per day increment in long chain n-3 PUFA consumption. CONCLUSIONS: Current meta analysis indicates that both fish and long chain n-3 PUFA consumption are inversely associated with risk of all-cause mortality. These findings could have public health implications with regard to lowering risk of all-cause mortality through dietary interventions. PMID- 28802306 TI - ILSI Southeast Asia Region conference proceedings: The gut, its microbes and health: relevance for Asia. AB - BACKGROUND AND OBJECTIVES: The human being is a complex entity, involving interaction between microbes and the human host. Evidence shows that the nutritional value of food is influenced in part by the structure and operations of an individual's gut microbial community, and food in turn shapes the individual's microbiome. A conference was held to promote understanding of the intestinal microbiome and its implications for health and disease, particularly among Asian populations. METHODS AND STUDY DESIGN: Papers describing 1) the intestinal ecosystem in Asian populations, 2) changes in intestinal microbiota through life and its effects, 3) the Asian gut microbiota in disease conditions, 4) indigenous probiotics to maintain a healthy gut microbiota, 5) probiotic regulation in an Asian country, and 6) the results of a panel discussion are included in this report. CONCLUSIONS: The gut microbial inhabitants of Asian people differ from those of Europe and North America. Geographic location, diet, and ethnic background influence intestinal microbial composition. Urbanization and economic development have brought changes in traditional Asian diets, which in turn affected the gut microbiome, contributing to a shift in the region's health burden from infectious diseases to non-communicable chronic diseases. Novel probiotic strains of Indonesian origin demonstrated significant enhancement of humoral immune response in human studies. Knowledge gaps and implications for research to further understand the Asian gut microbiome were discussed. PMID- 28802307 TI - Optimal dietary macronutrient distribution in China (ODMDC): a randomised controlled-feeding trial protocol. AB - BACKGROUND AND OBJECTIVES: Findings from observational studies in China show that increased dietary fat consumption might be a contributor to the developing obesity epidemic. However, some cohort studies suggest that carbohydrate intake, especially from white rice, is a risk factor for obesity, type 2 diabetes and coronary heart disease in China. Our study aims to determine whether the traditional lower-fat, higher-carbohydrate Chinese or the Western higher-fat, lower-carbohydrate dietary pattern is more effective for weight control and the related cardiometabolic profiles increasingly found among contemporary Chinese. METHODS AND STUDY DESIGN: The Optimal Dietary Macronutrient Distribution in China (ODMDC) trial is a 6-month, multi-centre, three-arm controlled feeding study. Based on the macronutrient transition in the past 30 years in China, three isoenergetic diets with a spectrum of fat and carbohydrate intake, but same protein contents, have been formulated. Percentages of fat, carbohydrate, and protein energy are one of 20, 66 and 14%; 30, 56 and 14%; 40, 46 and 14%, respectively. Participants will be provided with all their food and most beverages for 6 months. RESULTS: The study population is planned to be 300 healthy non-obese adults aged 18 to 35 years. The primary outcome is body weight and the secondary variables are waist circumference and cardiometabolic risk factors. CONCLUSIONS: The ODMDC trial will have implications for nutrition policy in regard to weight control and related cardiometabolic disturbances among otherwise healthy non-obese Chinese. PMID- 28802309 TI - List of Standards. PMID- 28802308 TI - Vitreous amyloidosis with autonomic neuropathy of the digestive tract associated with a novel transthyretin p.Gly87Arg variant in a Bangladeshi patient: a case report. AB - BACKGROUND: Hereditary transthyretin amyloidosis is an autosomal dominant inherited disorder, first described in families with sensorimotor and autonomic neuropathy. Since its first description, more than 120 amyloidogenic transthyretin mutations have been reported with various geographic distributions and associated with a wide range of phenotypes involving the peripheral nerve, the heart, the gastrointestinal tract, the eyes, the central nervous system, or the kidneys. In some cases of transthyretin amyloidosis, the first clinical manifestation is vitreous opacity. CASE PRESENTATION: A 46-year-old Bangladeshi woman presented with vitreous amyloidosis and progressive autonomic neuropathy of the digestive tract as initial clinical manifestations, with no clinical evidence of cardiac, renal, central nervous system, or peripheral nerve dysfunction. A novel transthyretin mutation, p.Gly87Arg, was identified in the heterozygous state in this proband of Bangladeshi origin. Histological examination of accessory salivary glands and gastric biopsies revealed Congo-red-positive deposits. Laser microdissection of salivary gland Congo-red deposits and tandem mass spectrometry-based proteomic analysis identified the mutated transthyretin peptide containing the arginine residue at position 87 of the mature protein. CONCLUSIONS: Vitreous amyloidosis should be considered a differential diagnosis of uveitis, in particular transthyretin amyloidosis. Proteomics data from our case, consistent with the genetic findings, highly suggests that this new p.Gly87Arg variant is amyloidogenic. Here, we described the second case of transthyretin amyloidosis reported in a Bangladeshi patient. PMID- 28802310 TI - Quantification of Whey Protein Content in Infant Formulas by Sodium Dodecyl Sulfate-Capillary Gel Electrophoresis (SDS-CGE): Single-Laboratory Validation, First Action 2016.15. PMID- 28802311 TI - AOAC SMPR(r) 2015.016. Standard Method Performance Requirements (SMPRs) for Determination of Vitamin D in Dietary Supplement Finished Products and Ingredients. PMID- 28802312 TI - AOAC SMPR(r) 2017.009. Standard Method Performance Requirements (SMPRs) for Quantitation of Aloe Vera Characteristic Water-Soluble Main Constituents in Dietary Supplements. PMID- 28802313 TI - AOAC SMPR(r) 2017.010. Standard Method Performance Requirements (SMPRs) for Identification of Aloe Vera in Dietary Supplements and Dietary Ingredients. PMID- 28802314 TI - AOAC SMPR(r) 2017.012. Standard Method Performance Requirements (SMPRs) for Quantitation of Select Nonvolatile Ginger Constituents. PMID- 28802315 TI - AOAC SMPR(r) 2017.013. Standard Method Performance Requirements (SMPRs) for Determination of Vitamins K1 and K2 in Dietary Supplements and Dietary Ingredients. PMID- 28802316 TI - AOAC SMPR(r) 2017.001. Standard Method Performance Requirements (SMPRs) for Quantitation of Cannabinoids in Cannabis Concentrates. PMID- 28802317 TI - AOAC SMPR(r) 2017.002. PMID- 28802318 TI - AOAC SMPR(r) 2017.003. PMID- 28802319 TI - AOAC SMPR(r) 2017.004. PMID- 28802320 TI - AOAC SMPR(r) 2011.006. PMID- 28802321 TI - AOAC SMPR(r) 2017.005. PMID- 28802322 TI - AOAC SMPR(r) 2017.006. PMID- 28802323 TI - AOAC SMPR(r) 2017.007. PMID- 28802324 TI - AOAC SMPR(r) 2017.008. PMID- 28802325 TI - SNOMED2HL7: A tool to normalize and bind SNOMED CT concepts to the HL7 Reference Information Model. AB - BACKGROUND: Current clinical research and practice requires interoperability among systems in a complex and highly dynamic domain. There has been a significant effort in recent years to develop integrative common data models and domain terminologies. Such efforts have not completely solved the challenges associated with clinical data that are distributed among different and heterogeneous institutions with different systems to encode the information. Currently, when providing homogeneous interfaces to exploit clinical data, certain transformations still involve manual and time-consuming processes that could be automated. OBJECTIVES: There is a lack of tools to support data experts adopting clinical standards. This absence is especially significant when links between data model and vocabulary are required. The objective of this work is to present SNOMED2HL7, a novel tool to automatically link biomedical concepts from widely used terminologies, and the corresponding clinical context, to the HL7 Reference Information Model (RIM). METHODS: Based on the recommendations of the International Health Terminology Standards Development Organisation (IHTSDO), the SNOMED Normal Form has been implemented within SNOMED2HL7 to decompose and provide a method to reduce the number of options to store the same information. The binding of clinical terminologies to HL7 RIM components is the core of SNOMED2HL7, where terminology concepts have been annotated with the corresponding options within the interoperability standard. A web-based tool has been developed to automatically provide information from the normalization mechanisms and the terminology binding. RESULTS: SNOMED2HL7 binding coverage includes the majority of the concepts used to annotate legacy systems. It follows HL7 recommendations to solve binding overlaps and provides the binding of the normalized version of the concepts. The first version of the tool, available at http://kandel.dia.fi.upm.es:8078, has been validated in EU funded projects to integrate real world data for clinical research with an 88.47% of accuracy. CONCLUSIONS: This paper presents the first initiative to automatically retrieve concept-centered information required to transform legacy data into widely adopted interoperability standards. Although additional functionality will extend capabilities to automate data transformations, SNOMED2HL7 already provides the functionality required for the clinical interoperability community. PMID- 28802326 TI - A biological inspired fuzzy adaptive window median filter (FAWMF) for enhancing DNA signal processing. AB - BACKGROUND AND OBJECTIVE: Digital signal processing techniques commonly employ fixed length window filters to process the signal contents. DNA signals differ in characteristics from common digital signals since they carry nucleotides as contents. The nucleotides own genetic code context and fuzzy behaviors due to their special structure and order in DNA strand. Employing conventional fixed length window filters for DNA signal processing produce spectral leakage and hence results in signal noise. A biological context aware adaptive window filter is required to process the DNA signals. METHODS: This paper introduces a biological inspired fuzzy adaptive window median filter (FAWMF) which computes the fuzzy membership strength of nucleotides in each slide of window and filters nucleotides based on median filtering with a combination of s-shaped and z-shaped filters. Since coding regions cause 3-base periodicity by an unbalanced nucleotides' distribution producing a relatively high bias for nucleotides' usage, such fundamental characteristic of nucleotides has been exploited in FAWMF to suppress the signal noise. RESULTS: Along with adaptive response of FAWMF, a strong correlation between median nucleotides and the Pi shaped filter was observed which produced enhanced discrimination between coding and non-coding regions contrary to fixed length conventional window filters. The proposed FAWMF attains a significant enhancement in coding regions identification i.e. 40% to 125% as compared to other conventional window filters tested over more than 250 benchmarked and randomly taken DNA datasets of different organisms. CONCLUSION: This study proves that conventional fixed length window filters applied to DNA signals do not achieve significant results since the nucleotides carry genetic code context. The proposed FAWMF algorithm is adaptive and outperforms significantly to process DNA signal contents. The algorithm applied to variety of DNA datasets produced noteworthy discrimination between coding and non-coding regions contrary to fixed window length conventional filters. PMID- 28802327 TI - Three dimensional motion capture applied to violin playing: A study on feasibility and characterization of the motor strategy. AB - BACKGROUND AND OBJECTIVE: Playing string instruments requires advanced motor skills and a long training that is often spent in uncomfortable postures that may lead to injuries or musculoskeletal disorders. Thus, it is interesting to objectively characterize the motor strategy adopted by the players. In this work, we implemented a method for the quantitative analysis of the motor performance of a violin player. METHODS: The proposed protocol takes advantage of an optoelectronic system and some infra-red reflecting markers in order to track player's motion. The method was tested on a professional violin player performing a legato bowing task. The biomechanical strategy of the upper limb and bow positioning were described by means of quantitative parameters and motion profiles. Measured quantities were: bow trajectory, angles, tracks, velocity, acceleration and jerk. RESULTS: A good repeatability of the bowing motion (CV < 2%) and high smoothness (jerk < 5 m/s3) were observed. Motion profiles of shoulder, elbow and wrist were repeatable (CV < 7%) and comparable to the curves observed in other studies. Jerk and acceleration profiles demonstrated high smoothness in the ascending and descending phases of bowing. High variability was instead observed for the neck angle (CV ~56%). CONCLUSIONS: "Quantitative" measurements, instead of "qualitative" observation, can support the diagnosis of motor disorders and the accurate evaluation of musicians' skills. The proposed protocol is a powerful tool for the description of musician's performance, that may be useful to document improvements in playing abilities and to adjust training strategies. PMID- 28802328 TI - Hybrid PET/MRI co-segmentation based on joint fuzzy connectedness and graph cut. AB - BACKGROUND AND OBJECTIVE: Tumor segmentation from hybrid PET/MRI scans may be highly beneficial in radiotherapy treatment planning. Indeed, it gives for both modalities the suitable information that could make the delineation of tumors more accurate than using each one apart. We aim in this work to propose a co segmentation method that deals with several challenges, notably the lack of one to-one correspondence between tumors of the two modalities and the boundaries' smoothing. METHODS: The proposed method is designed to surpass these limits, we propose a segmentation method based on the GCsummax technique. The method takes the advantage of Iterative Relative Fuzzy Connectedness (IRFC) on seeds initialization, and the standard min-cut/max-flow technique for the boundary smoothing. Seed initialization was accurately performed thanks to high uptake regions on PET. Besides, a visibility weighting scheme was adapted to achieve the task of co-segmentation using the IRFC algorithm. Then, given the co-segmented regions, we introduce a morphological-based technique that provides object seeds to standard Graph Cut (GC) allowing it to avoid the shrinking problem. Finally, for each modality, the segmentation task is formulated as an energy minimization problem which is resolved by a min-cut/max-flow technique. RESULTS: The overlap ratio (denoted DSC) between our segmentation results and the ground-truth for PET images is 92.63 +/- 1.03, while the DSC for MRI images is 90.61 +/- 3.70. CONCLUSIONS: The proposed method was tested on different types of diseases and it outperformed the state-of-the-art methods. We show its superiority in terms of assymetric relation between PET and MRI and tumors heterogeneity. PMID- 28802329 TI - Skin lesion computational diagnosis of dermoscopic images: Ensemble models based on input feature manipulation. AB - BACKGROUND AND OBJECTIVES: The number of deaths worldwide due to melanoma has risen in recent times, in part because melanoma is the most aggressive type of skin cancer. Computational systems have been developed to assist dermatologists in early diagnosis of skin cancer, or even to monitor skin lesions. However, there still remains a challenge to improve classifiers for the diagnosis of such skin lesions. The main objective of this article is to evaluate different ensemble classification models based on input feature manipulation to diagnose skin lesions. METHODS: Input feature manipulation processes are based on feature subset selections from shape properties, colour variation and texture analysis to generate diversity for the ensemble models. Three subset selection models are presented here: (1) a subset selection model based on specific feature groups, (2) a correlation-based subset selection model, and (3) a subset selection model based on feature selection algorithms. Each ensemble classification model is generated using an optimum-path forest classifier and integrated with a majority voting strategy. The proposed models were applied on a set of 1104 dermoscopic images using a cross-validation procedure. RESULTS: The best results were obtained by the first ensemble classification model that generates a feature subset ensemble based on specific feature groups. The skin lesion diagnosis computational system achieved 94.3% accuracy, 91.8% sensitivity and 96.7% specificity. CONCLUSIONS: The input feature manipulation process based on specific feature subsets generated the greatest diversity for the ensemble classification model with very promising results. PMID- 28802330 TI - Fast detection of the main anatomical structures in digital retinal images based on intra- and inter-structure relational knowledge. AB - BACKGROUND AND OBJECTIVE: The anatomical structure detection in retinal images is an open problem. However, most of the works in the related literature are oriented to the detection of each structure individually or assume the previous detection of a structure which is used as a reference. The objective of this paper is to obtain simultaneous detection of the main retinal structures (optic disc, macula, network of vessels and vascular bundle) in a fast and robust way. METHODS: We propose a new methodology oriented to accomplish the mentioned objective. It consists of two stages. In an initial stage, a set of operators is applied to the retinal image. Each operator uses intra-structure relational knowledge in order to produce a set of candidate blobs that belongs to the desired structure. In a second stage, a set of tuples is created, each of which contains a different combination of the candidate blobs. Next, filtering operators, using inter-structure relational knowledge, are used in order to find the winner tuple. A method using template matching and mathematical morphology is implemented following the proposed methodology. RESULTS: A success is achieved if the distance between the automatically detected blob center and the actual structure center is less than or equal to one optic disc radius. The success rates obtained in the different public databases analyzed were: MESSIDOR (99.33%, 98.58%, 97.92%), DIARETDB1 (96.63%, 100%, 97.75%), DRIONS (100%, n/a, 100%) and ONHSD (100%, 98.85%, 97.70%) for optic disc (OD), macula (M) and vascular bundle (VB), respectively. Finally, the overall success rate obtained in this study for each structure was: 99.26% (OD), 98.69% (M) and 98.95% (VB). The average time of processing per image was 4.16 +/- 0.72 s. CONCLUSIONS: The main advantage of the use of inter-structure relational knowledge was the reduction of the number of false positives in the detection process. The implemented method is able to simultaneously detect four structures. It is fast, robust and its detection results are competitive in relation to other methods of the recent literature. PMID- 28802331 TI - Preliminary physician and pharmacist survey of the National Health Insurance PharmaCloud system in Taiwan. AB - BACKGROUND: The PharmaCloud system, a cloud-based medication system, was launched by the Taiwan National Health Insurance Administration (NHIA) in 2013 to integrate patients' medication lists among different medical institutions. The aim of the preliminary study was to evaluate satisfaction with this system among physicians and pharmacists at the early stage of system implementation. METHODS: A questionnaire was developed through a review of the literature and discussion in 6 focus groups to understand the level of satisfaction, attitudes, and intentions of physicians and pharmacists using the PharmaCloud system. It was then administered nationally in Taiwan in July to September 2015. Descriptive statistics and multiple regression were performed to identify variables influencing satisfaction and intention to use the system. RESULTS: In total, 895 pharmacist and 105 physician questionnaires were valid for analysis. The results showed that satisfaction with system quality warranted improvement. Positive attitudes toward medication reconciliation among physicians and pharmacists, which were significant predictors of the intention to use the system (beta= 0.223, p < 0.001). Most physicians and pharmacists agreed that obtaining signed patient consent was needed but preferred that it be conducted by the NHIA rather than by individual medical institutions (4.02 +/- 1.19 vs. 3.49 +/- 1.40, p < 0.01). CONCLUSIONS: The preliminary study results indicated a moderate satisfaction toward the PharmaCloud system. Hospital pharmacists had a high satisfaction rate, but neither are physicians and community pharmacists. Continuously improvement on system quality has been performing based on the results of this preliminary survey. Policies and standardization processes, including privacy protection, are still warranted further actions to make the Taiwan PharmaCloud system a convenient platform for medication reconciliation. PMID- 28802332 TI - New algorithms for processing time-series big EEG data within mobile health monitoring systems. AB - BACKGROUND AND OBJECTIVES: Recent advances in miniature biomedical sensors, mobile smartphones, wireless communications, and distributed computing technologies provide promising techniques for developing mobile health systems. Such systems are capable of monitoring epileptic seizures reliably, which are classified as chronic diseases. Three challenging issues raised in this context with regard to the transformation, compression, storage, and visualization of big data, which results from a continuous recording of epileptic seizures using mobile devices. METHODS: In this paper, we address the above challenges by developing three new algorithms to process and analyze big electroencephalography data in a rigorous and efficient manner. The first algorithm is responsible for transforming the standard European Data Format (EDF) into the standard JavaScript Object Notation (JSON) and compressing the transformed JSON data to decrease the size and time through the transfer process and to increase the network transfer rate. The second algorithm focuses on collecting and storing the compressed files generated by the transformation and compression algorithm. The collection process is performed with respect to the on-the-fly technique after decompressing files. The third algorithm provides relevant real-time interaction with signal data by prospective users. It particularly features the following capabilities: visualization of single or multiple signal channels on a smartphone device and query data segments. RESULTS: We tested and evaluated the effectiveness of our approach through a software architecture model implementing a mobile health system to monitor epileptic seizures. The experimental findings from 45 experiments are promising and efficiently satisfy the approach's objectives in a price of linearity. Moreover, the size of compressed JSON files and transfer times are reduced by 10% and 20%, respectively, while the average total time is remarkably reduced by 67% through all performed experiments. CONCLUSIONS: Our approach successfully develops efficient algorithms in terms of processing time, memory usage, and energy consumption while maintaining a high scalability of the proposed solution. Our approach efficiently supports data partitioning and parallelism relying on the MapReduce platform, which can help in monitoring and automatic detection of epileptic seizures. PMID- 28802333 TI - Solving the adoption bottleneck to streamline application of medical informatics. PMID- 28802334 TI - Has Quality Improvement Really Improved Outcomes for Babies in the Neonatal Intensive Care Unit? AB - During the past decade, the emergence of outcome measurement and quality improvement in the neonatal intensive care unit, far more than the introduction of new research approaches or novel therapies, has had a profound effect on improving outcomes for premature neonates. Collection of outcome data, review of those data, and strategies to identify and resolve problems using continuous quality improvement methods can dramatically improve patient outcomes. It is likely that further initiatives in quality improvement will continue to have additional beneficial effects for the neonate. PMID- 28802335 TI - National Quality Measures in Perinatal Medicine. AB - There are numerous measures of perinatal quality endorsed by national agencies such as the National Quality Forum (NQF). The sheer number of metrics may lead to confusion about what these measures truly assess, and how to interpret variation in these measures across hospitals, health care systems, and geographic regions. This review presents a conceptual model for the numerous validated measures, an overview of the types of measures endorsed for perinatal quality by NQF in 2016, and potential measures absent from endorsement by these national bodies. PMID- 28802336 TI - The Hard Work of Improving Outcomes for Mothers and Babies: Obstetric and Perinatal Quality Improvement Initiatives Make a Difference at the Hospital, State, and National Levels. AB - Quality improvement efforts are an increasingly expanding focus for perinatal care providers across the United States. From successful hospital-level initiatives, there has been a growing effort to use and implement quality improvement work in substantive and meaningful ways. This article summarizes the foundations of maternal-focused, birth-focused, and neonatal-focused quality improvement initiatives to highlight the underpinnings and potential future directions of current state-level perinatal quality care collaboratives. PMID- 28802337 TI - Eliminating Undesirable Variation in Neonatal Practice: Balancing Standardization and Customization. AB - Consistency of care and elimination of unnecessary and harmful variation are underemphasized aspects of health care quality. This article describes the prevalence and patterns of practice variation in health care and neonatology; discusses the potential role of standardization as a solution to eliminating wasteful and harmful practice variation, particularly when it is founded on principles of evidence-based medicine; and proposes ways to balance standardization and customization of practice to ultimately improve the quality of neonatal care. PMID- 28802339 TI - Family Involvement in Quality Improvement: From Bedside Advocate to System Advisor. AB - Family involvement in newborn intensive care quality improvement dates back to the 1980s. In recent years, there has been an evolution of support for family partnerships at the bedside, transforming parents from being passively present to being active and engaged caregivers and team members. Through those same efforts, a transformational understanding of the power of the family perspective in system design and improvement has occurred. Even with the progression and deepening of this involvement, opportunities exist to learn from families and to improve the quality of neonatal care as a result of the unique family perspective. PMID- 28802338 TI - Context in Quality of Care: Improving Teamwork and Resilience. AB - Quality improvement in health care is an ongoing challenge. Consideration of the context of the health care system is of paramount importance. Staff resilience and teamwork climate are key aspects of context that drive quality. Teamwork climate is dynamic, with well-established tools available to improve teamwork for specific tasks or global applications. Similarly, burnout and resilience can be modified with interventions such as cultivating gratitude, positivity, and awe. A growing body of literature has shown that teamwork and burnout relate to quality of care, with improved teamwork and decreased burnout expected to produce improved patient quality and safety. PMID- 28802340 TI - Improving Neonatal Care: A Global Perspective. AB - Each year, approximately 2.7 million babies die during the neonatal period; more than 90% of these deaths occur in developing countries, largely from preventable causes. The known, evidence-based, simple, low-cost interventions that may improve neonatal survival often have low or unknown baseline coverage rates. Gaps in coverage of essential interventions and in quality of care may be amenable to improvement strategies. However, often these gaps are not easily identified. A variety of international organizations have recommended key indicators of quality and established roadmaps for improving neonatal outcomes. Quality improvement at the facility level is an area for future investment. PMID- 28802341 TI - Using Health Information Technology to Improve Safety in Neonatal Care: A Systematic Review of the Literature. AB - Health information technology (HIT) interventions may improve neonatal patient safety but may also introduce new errors. The objective of this review was to evaluate the evidence for use of HIT interventions to improve safety in neonatal care. Evidence for improvement exists for interventions like computerized provider order entry in the neonatal population, but is lacking for several other interventions. Many unique applications of HIT are emerging as technology and use of the electronic health record expands. Future research should focus on the impact of these interventions in the neonatal population. PMID- 28802343 TI - Using Statistical Process Control to Drive Improvement in Neonatal Care: A Practical Introduction to Control Charts. AB - Quality improvement (QI) is based on measuring performance over time, and variation in data measured over time must be understood to guide change and make optimal improvements. Common cause variation is natural variation owing to factors inherent to any process; special cause variation is unnatural variation owing to external factors. Statistical process control methods, and particularly control charts, are robust tools for understanding data over time and identifying common and special cause variation. This review provides a practical introduction to the use of control charts in health care QI, with a focus on neonatology. PMID- 28802342 TI - Improving Value in Neonatal Intensive Care. AB - Work within the US health care system has sought to improve outcomes, decrease costs, and improve the patient experience. Combining those three elements leads to value-added care. Quality improvement within neonatology has focused primarily on the improvement of clinical outcomes without explicit consideration of cost. Future improvement efforts in neonatology should consider opportunities to decrease or eliminate waste, and improve outcomes. Consideration of how a change affects all stakeholders reveals potential cost-saving opportunities, and developing aims with value in mind facilitates understanding and goal-setting with senior administrative leaders. PMID- 28802344 TI - Creating a Highly Reliable Neonatal Intensive Care Unit Through Safer Systems of Care. AB - Neonates requiring intensive care are at high risk for medical errors due to their unique characteristics and high acuity. Designing a safer work environment begins with safe processes. Creating a culture of safety demands the involvement of all organizational levels and an interdisciplinary approach. Adverse events can result from suboptimal communication and lack of a shared mental model. This chapter describes tools to promote better patient safety in the NICU through monitoring adverse events, improving communication and using information technology. Unplanned extubation is an example of a neonatal safety concern that can be reduced by employing quality improvement methodology. PMID- 28802346 TI - Reducing Incidence of Necrotizing Enterocolitis. AB - Necrotizing enterocolitis (NEC) is a multifactorial disease that occurs when multiple risk factors and/or stressors overlap, leading to profound inflammation and intestinal injury. Due to its multifactorial nature, there has been much uncertainty in identifying clear strategies for prevention of NEC. Despite these obstacles, the incidence of NEC has gradually been decreasing over the past 10 years, in part due to quality improvement (QI) initiatives to prevent NEC. Current QI strategies primarily target the various predisposing conditions. This article reviews the evidence on which QI interventions to prevent NEC have been based and provides examples of successful QI interventions. PMID- 28802345 TI - Tackling Quality Improvement in the Delivery Room. AB - Implementation of standardized practices in the delivery room fosters a safe environment to ensure that newborn infants are cared for optimally, whether or not they require extensive resuscitation. Quality improvement (QI) is an excellent methodology for implementation of standardized practices due to the multidisciplinary nature of the delivery room, complexity of tasks involved, and opportunities to track processes and outcomes. This article discusses how the delivery room is a unique environment and presents examples on how to approach delivery room QI. Key areas of potential focus for teams pursuing delivery QI include thermal regulation, optimizing respiratory support, and facilitating team communication. PMID- 28802347 TI - Using Quality Improvement Tools to Reduce Chronic Lung Disease. AB - Rates of chronic lung disease (CLD) in very low birthweight infants have not decreased at the same pace as other neonatal morbidities over the past 20 years. Multifactorial causes of CLD make this common morbidity difficult to reduce, although there have been several successful quality improvement (QI) projects in individual neonatal intensive care units. QI projects have become a mainstay of neonatal care over the past decade, with an increasing number of publications devoted to this topic. A specific QI project for CLD must be based on best available evidence in the medical literature, expert recommendations, or based on work by previous QI initiatives. PMID- 28802349 TI - Quality Improvement: The Journey Continues! PMID- 28802348 TI - Alarm Safety and Alarm Fatigue. AB - Clinical alarm systems have received significant attention in recent years following warnings from hospital accrediting and health care technology organizations regarding patient harm caused by unsafe practices. Alarm desensitization or fatigue from frequent, false, or unnecessary alarms, has led to serious events and even patient deaths. Other concerns include settings inappropriate to patient population or condition, inadequate staff training, and improper use or disabling. Research on human factors in alarm response and of functionality of medical devices will help clinicians develop appropriate policies, practices, and device settings for clinical alarms in neonatal intensive care units. PMID- 28802350 TI - Improving Quality Improvement in Neonatal-Perinatal Care. PMID- 28802351 TI - Exome sequencing identifies a novel missense mutation of WFS1 as the cause of non syndromic low-frequency hearing loss in a Chinese family. AB - OBJECTIVE: Autosomal dominant non-syndromic low-frequency sensorineural hearing loss (LFSNHL) DFNA6/14/38 is an uncommon type of hearing loss that classically affects low frequencies of 2000 Hz and below, demonstrating an ascending configuration. The current study aimed to investigate the cause of LFSNHL in a five-generation Chinese family. METHODS: The phenotype of the Chinese family was characterized using audiologic testing and pedigree analysis. The combined approach of array screening and whole-exome sequencing was used to identify the disease-causing gene in this family. RESULTS: This pedigree, in which the affected subjects presented isolated low-frequency sensorineural hearing impairment with childhood onset, was associated with autosomal dominant inheritance of the c.2591A > G mutation in exon 8 of the Wolframin syndrome 1 (WFS1) gene which was not present in 286 unrelated controls with matched ancestry and is highly conserved across species. In addition, several mutations affecting the Glu864 residue have been previously identified in different populations, suggesting that this site is likely to be a mutational hot spot. CONCLUSIONS: We identified a novel substitution, Glu864Gly, of WFS1 as the causative variant for this pedigree. Our data extend the mutation spectrum of the WFS1 gene in Chinese individuals and may contribute to establishing a better genotype-phenotype correlation for LFSNHL. PMID- 28802352 TI - Assessment of weight gain following adenotonsillectomy in children with Down syndrome. AB - INTRODUCTION: Adenotonsillectomy (T&A) has been associated with postoperative weight gain in children. The purpose of this study is to determine whether a similar association exists in children with Down syndrome (DS). METHODS: The medical records of 311 DS patients were reviewed. Subjects were classified into either a control group or surgical group based on whether they had undergone adenotonsillectomy (T&A). Subjects were excluded if they only had one recorded BMI. Cases were analyzed in a pairwise fashion to maximize available data. 113 total patients with DS were identified: 84 (74.3%) in the control group and 29 (25.7%) in the T&A group. Height, weight, BMI, and Z-score data were compared between the control and T&A groups at 6-month intervals over a 24-month period. RESULTS: Children with DS who underwent T&A were comparable by demographics to children with DS who did not undergo T&A. Mean weight gain at 24 months for the T&A group was 8.07 +/- 5.66 kg compared with 5.76 +/- 13.20 kg in controls. The median Z-score at 24 months for the T&A group was 1.11 (0.10-1.88) compared with 1.17 (0.80-1.75) in controls. Children undergoing T&A had a stable median Z-score change of 0.09 at 24 months (p = 0.861, compared to baseline) while children who did not undergo T&A had a significantly increased median Z-score of 0.52 (p = 0.035, compared to baseline). Despite this, there were no significant intergroup differences between weight change, BMI, nor Z-score at any interval (p > 0.05). CONCLUSIONS AND RELEVANCE: Children with DS did not have an increased rate of weight gain or increased BMI after T&A. BMI Z-scores were shown to stabilize over 24 months in the T&A group and increase in the control group. While this suggests that T&A provides an added benefit of weight control in patients with DS, the results should be interpreted with caution due to the small sample size and the fact that not all patients had complete follow up across a 24-month period. PMID- 28802353 TI - Hearing loss in children with growth hormone deficiency. AB - OBJECTIVE: Although insulin-like growth factor 1 (IGF-1) has been shown to be important for inner-ear development in animal models, little is known about the otologic and audiologic findings of children with growth hormone deficiency (GHD). The goal of this study is to evaluate the prevalence, type, and severity of hearing impairment in children with GHD. METHODS: Audiologic, otologic, and demographic data were recorded for children with a diagnosis of GHD in the AudGen database. Data for each patient were selected based on the first encounter with available complete audiometric data or the first encounter with a type of hearing loss documented. The patients were then stratified by type and severity of hearing loss, and otologic issues were documented. A separate cohort comprised of children with GHD without hearing loss was compared as a control. RESULTS: 209 children with GHD met inclusion criteria. 173 (83%) of these patients had hearing loss. 79% of losses were bilateral and 21% were unilateral (309 total ears with hearing loss). 293 of the 309 ears with hearing loss had audiograms with ear specific thresholds; 47 had conductive, 24 had sensorineural, 65 had mixed and 157 had undefined hearing loss with incomplete audiograms. Pure-tone averages (PTA) were higher among patients with mixed hearing loss compared to patients with all other loss types. CONCLUSION: Hearing loss is prevalent in children with GHD with a predisposition to be bilateral. These findings suggest the need for increased awareness and routine hearing screening for patients with GHD. Further studies may elucidate the etiology of the hearing impairment in children with GHD to better aid pediatricians, endocrinologists, otolaryngologists and audiologists when assessing and managing these children. PMID- 28802354 TI - A novel management of streptococcal pharyngotonsillar infections by laser activated silver nanoparticles and methylene blue conjugate, in vitro study. AB - INTRODUCTION: Species of Streptococcus are classified based on their hemolytic properties into alpha and beta types. And, since antimicrobial drug resistance is an increasingly problematic issue, the efforts to develop modalities that would overcome this obstacle and avoid antibiotic side effects is an ongoing challenge. METHODS AND MATERIALS: 20 patients from both sexes were selected. The isolated organisms were identified according to standard laboratory methods. Bacterial Cultures were subjected to the low-level diode laser (660 nm), methylene blue (MB) as a photosensitizing agent and for silver nanoparticles. RESULTS: All the experimental groups showed statistically lower values of CFU/ml than the positive control group. CONCLUSION: The photoactivated MB, silver nanoparticles conjugate showed the maximum inhibitory effect on Streptococci, which opens a gate to further investigation of such a promising protocol to establish a safe and efficient method of management for resistant cases of streptococcal tonsillar infections. PMID- 28802355 TI - Effects of residual hearing on cochlear implant outcomes in children: A systematic-review. AB - OBJECTIVES: to investigate if preoperative residual hearing in prelingually deafened children can interfere on cochlear implant indication and outcomes. METHODS: a systematic-review was conducted in five international databases up to November-2016, to locate articles that evaluated cochlear implantation in children with some degree of preoperative residual hearing. Outcomes were auditory, language and cognition performances after cochlear implant. The quality of the studies was assessed and classified according to the Oxford Levels of Evidence table - 2011. Risk of biases were also described. RESULTS: From the 30 articles reviewed, two types of questions were identified: (a) what are the benefits of cochlear implantation in children with residual hearing? (b) is the preoperative residual hearing a predictor of cochlear implant outcome? Studies ranged from 04 to 188 subjects, evaluating populations between 1.8 and 10.3 years old. The definition of residual hearing varied between studies. The majority of articles (n = 22) evaluated speech perception as the outcome and 14 also assessed language and speech production. CONCLUSION: There is evidence that cochlear implant is beneficial to children with residual hearing. Preoperative residual hearing seems to be valuable to predict speech perception outcomes after cochlear implantation, even though the mechanism of how it happens is not clear. More extensive researches must be conducted in order to make recommendations and to set prognosis for cochlear implants based on children preoperative residual hearing. PMID- 28802356 TI - Intracranial complications of CSOM in pediatric patients: A persisting problem in developing countries. AB - BACKGROUND: Intracranial complications (ICC) of chronic suppurative otitis media (CSOM) occur even in the antibiotic area. These complications are commonly seen in pediatric patients due to poor hygiene and low immunity. They are more prevalent in developing countries due to illiteracy, low socioeconomic status and lack of access to health care facilities. OBJECTIVE: To study the incidence, clinical profile, treatment and outcome of pediatric patients presenting with intracranial complications of chronic suppurative otitis media. METHODS: A retrospective analysis of intracranial complications of CSOM in pediatric patients was conducted over a period of 15 years at a tertiary level institute. Data regarding age, sex, clinical presentation, laboratory and radiological investigations, management, duration of hospitalization, and outcomes were recorded. RESULTS: There were 142 patients, in the pediatric age group, diagnosed as having intracranial complications due to chronic otitis media during the study period. There was a decline in the incidence of ICC of CSOM. The most frequent intracranial complication seen was brain abscess (58.5%). All patients were administered intravenous antibiotics for 4-6 weeks and underwent canal wall down mastoidectomy. Neurosurgical intervention was considered in the required patients. The case fatality rate in our study was 2.8% (4 patients). CONCLUSION: Otogenic intracranial complications can be fatal if not managed appropriately and timely. Broad spectrum intravenous antibiotics are usually required for 4-6 weeks with or without neurosurgical intervention and mastoid exploration. A high index of suspicion is required in all patients presenting with danger symptoms. PMID- 28802357 TI - Evaluation of ototoxicity of intratympanic administration of Methotrexate in rats. AB - OBJECTIVE: Methotrexate is a dihydrofolate reductase enzyme inhibitor with very high selectivity, and it is an antiproliferative folic acid antagonist used for the treatment of autoimmune diseases. In this study, our objective was to evaluate the effect of intratympanic Methotrexate application in the inner ear. METHODS: This study was planned as an animal study. This study performed in a tertiary referral center. 24 healthy female rats were used in our study. They were separated into three groups. 0.2 cc intratympanic saline was applied to both ears of Group 1. Paracentesis was applied to the tympanic membrane in both ears of Group 2. 0.2 cc intratympanic Methotrexate was applied to both ears of Group 3. At the beginning of the study, Distortion-product otoacoustic emissions (DPOAE) and Auditory brainstem response (ABR) of all rats were measured and then again on the 5th, 10th and 15th day. Histologic examinations of all groups were compared. RESULTS: There was not any significant difference between basal DPOAE and ABR measurement values of the groups and the results were measured again on the 5th, 10th and 15th day (p > 0.05). There was no difference between the groups in terms of histology. CONCLUSION: The intratympanic Methotrexate injection does not have any ototoxic effect on inner ear. We assume that intratympanic Methotrexate could be used safely on inner ear diseases in which steroid treatment is contraindicated or not effective. PMID- 28802358 TI - Guillotine vs. classic dissection adenotonsillectomy: What's the ideal technique for children in Tanzania? AB - OBJECTIVES: Adenotonsillectomy (ATE) is one of the most performed surgeries in children. Extensive research on which operation technique is the best in terms of minimal pain and complications, operative time and duration of hospital stay is being done mostly in highly resourced developing countries. In developing countries a need for cost effective and time saving operation techniques is essential due to the low-resource setting. This study aims to investigate whether the Guillotine Sluder operation techniques is ideal in a limited resource developing country setting. METHODS: A retrospective cohort study was conducted on children below 12 years of age who underwent ATE at the Kilimanjaro Christian Medical Center, a tertiary hospital in Northern Tanzania, in a period of 2 years to compare the guillotine Sluder and classic dissection ATE techniques. All procedures were done by the same surgeon. Incomplete patient information and congenital syndromes were exclusion criteria for the study. RESULTS: Both operative time and duration of hospital stay were significantly shorter in the guillotine Sluder group (3,5 min with 95% CI 1,1 to 5,9 min, and 0,4 days with 95% CI 0,2 to 0,6 days respectively). The rate of complications was not statistically different between the two groups. The overall rate of complications was comparable to that of Western countries. No difference was found in mean amount of blood loss during operation. CONCLUSIONS: Our results conclude that guillotine Sluder tonsillectomy is a safe procedure that has some advantages compared to classic dissection in children in Tanzania. The shorter operative time and time in hospital stay combined with the low complication rate makes the guillotine Sluder technique a very suitable technique for children in Tanzania and comparable limited resource developing country settings. PMID- 28802359 TI - Transmission analysis of TGFB1 gene polymorphisms in non-syndromic cleft lip with or without cleft palate. AB - OBJECTIVES: Transforming growth factor beta1 (TGF-beta1) plays a significant role in craniofacial development. Previous linkage studies reported that the TGF-beta1 locus at 19q13.1 harbour predisposing genes for non-syndromic oral clefts. In the present study case parents triads were evaluated to find the transmission effects of genetic variants in TGF- beta1 towards non-syndromic cleft lip or palate (NSCL/P). METHODS: Using allelic discrimination method148 families (case-parent triads) were assessed for single nucleotide polymorphisms (SNPs) in TGF-beta1 gene. The SNPs were checked for mendelian errors and Hardy-Weinberg equilibrium (HWE). Transmission disequilibrium test and haplotype frequencies were estimated. RESULTS: The TGF-beta1 SNPs showed very low minor allele frequencies (MAFs) and observed heterozygosity (Hobs). The transmission disequilibrium test (TDT) and parent-of-origin likelihood ratio tests (PO-LRT) were not significant for any of the SNPs tested. Strong linkage disequilibrium (r2 = 0.722) was found between rs1800469 and rs1800470 SNPs. Haplotype analysis ignoring parent of origin showed strong evidence of excess transmission but it is not significant (p-value = 0.293). CONCLUSION: Transmission of minor alleles were not observed from either parent indicating that the TGF-beta1 gene polymorphisms by themselves do not confer risk for non-syndromic oral clefts but, rather, modify the stability and the activation process of TGF-beta1. As the number of families included in the study are less, results must be considered still preliminary and require replication using more families. PMID- 28802360 TI - Resolution of bilateral sensorineural hearing loss following ventriculoperitoneal shunt and literature review. AB - OBJECTIVE: The purpose of this study is to highlight the relationship between obstructive hydrocephalus, changes in intracranial pressure, and sensorineural hearing loss. METHODS: A case of a 10-month old infant with sensorineural hearing loss secondary to obstructive hydrocephalus is reported. A literature review, with a focus on sensorineural hearing loss in the setting of changes in intracranial pressure, was performed. RESULTS: The authors report the case of a 10-month old infant with metopic and bicoronal craniosynostosis who presented with bilateral moderately severe sensorineural hearing loss after failing newborn hearing screening. Imaging subsequently demonstrated obstructive hydrocephalus, which was treated with the insertion of a VP shunt. The patient had immediate improvement of her hearing post-operatively, with repeat hearing tests showed resolution of her hearing loss. CONCLUSION: Sensorineural hearing loss is a rare complication of hydrocephalus, but changes in intracranial pressure should be considered in the differential diagnosis. We put forth a flow diagram illustrating the hypothesized relationship between intracranial pressures, alterations in the levels of cochlear fluid, and hearing. PMID- 28802361 TI - Functional endoscopic sinus surgery improves the quality of life in children suffering from chronic rhinosinusitis with nasal polyps. AB - OBJECTIVE: To evaluate the impact of FESS in children with chronic rhinosinusitis with nasal polyps, regarding their overall postoperative quality-of-life (QoL) and constituent QoL domains. Potential differences between cystic fibrosis (CF) sufferers and non-sufferers, or cases with recurrent sinonasal polyposis versus single-operations were also explored. METHODS: 39 children were studied. The mean patient age was 10.9 years; four children suffered from cystic fibrosis. The children (or parents) completed the Glasgow Benefit Inventory for Children (GCBI) at least six months after their operation. The Mann-Whitney test compared the GCBI scores between non- and CF sufferers, as well as children with and without recurrent polyposis. RESULTS: The median overall QoL score was 98. There were no statistically significant differences between CF sufferers and non-sufferers regarding their overall QoL, or the respective individual QoL domains, apart from their physical postoperative activity (p = 0.04). Twelve children demonstrated recurrent polyposis (30.7%); among them three were cystic fibrosis sufferers. No statistically significant differences were identified in the overall QoL score, or individual GCBI subscale scores between children with recurrent polyposis versus single-operations. Children with recurrent polyposis but not CF performed better regarding their overall QoL (p = 0.021) and medical status (p = 0.015), compared to their CF counterparts. CONCLUSION: FESS performed for chronic rhinosinusitis with nasal polyps in children is associated with improved postoperative QoL, irrespective of the presence of CF (although the latter needs to be confirmed in larger patient cohorts). The absence of appreciable differences in the overall QoL, or its constituent domains, between single and re operated children, indicate that the positive effect of FESS outweighed the burden of re-operation. Appropriate preoperative informed consent in cases of recurrent sinonasal polyposis necessitates acknowledging worse respective outcomes in CF sufferers. PMID- 28802362 TI - Kallmann syndrome in pediatric otorhinolaryngology practice - Case report and literature review. AB - BACKGROUND: Kallmann syndrome (KS) is an isolated form of hypogonadotrophic hypogonadism (HH) in combination with a defect in olfactory function. The diagnosis of KS before maturation is often difficult to make due to the broad spectrum of presentation and genetic heterogeneities. ENT examination including smell test is essential for proper diagnosis of olfactory disturbances and non olfactory abnormalities in craniofacial region which may also be existent in KS. CASE: A 17-year-old girl admitted to ENT Department because of the olfactory sense disturbances since two years. The patient reported also amenorrhea caused by primary HH. A diagnostic work-up using double-checked Sniffin' Sticks test and 6-items olfactory test confirmed serious hyposmia and identified the presence of KS. CONCLUSION: Usually anosmia is not recognized by the affected individuals, so it is recommended to perform olfactory screening tests and obligatory ENT examination in the event of a HH even when patient reports a normal sense of smell. It leads to early diagnosis of KS and will benefit the relevant patient care.The KS diagnosis should be done at an early stage, but symptoms and clinical manifestations are not always evident both in ENT and pediatric field. In this article we would like to highlight the need for a multidisciplinary assessment and awareness for KS symptoms in pediatric practice as a hole. PMID- 28802364 TI - The reliability of flexible nasolaryngoscopy in the identification of vocal fold movement impairment in young infants. AB - OBJECTIVE: Flexible nasolaryngoscopy (FNL) is considered the gold standard for evaluation of vocal fold mobility but there has been no data on the reliability of interpretation in the infant population. Visualization may be limited by excessive movement, secretions, or floppy supraglottic structures that prevent accurate diagnosis of vocal fold movement impairment (VFMI). We sought to evaluate the inter- and intra-rater reliability of FNL for the evaluation of VFMI in young infants. STUDY TYPE: Case-control. METHODS: Twenty infants were identified: 10 with VFMI and 10 normal as seen on FNL. Three pediatric otolaryngologists reviewed the video without sound and rated the presence and/or degree of vocal fold mobility. Twelve videos were repeated to assess intra-rater reliability. RESULTS: There was substantial agreement between the reviewers regarding the identification normal vs. any type of VFMI (kappa = 0.67) but only moderate agreement regarding the degree of vocal fold movement (kappa = 0.49). Intra-rater reliability ranges from moderate to perfect agreement (kappa = 0.48 1). CONCLUSION: FNL in infants is an extremely challenging procedure. Clinically, physicians frequently use the quality of the cry and the past medical and surgical history to help make a judgment of vocal fold movement when the view is suboptimal. These other factors, however, may bias the interpretation of the FNL. Without sound, there is only moderate inter-rater and variable intra-rater reliability for the identification of degree of movement on FNL. Otolaryngologists must be cognizant of the limitations of FNL when using it as a clinical tool or as a "gold standard" against which other modalities are measured. PMID- 28802363 TI - Epidemiology of cerumen impaction among municipal kindergartens children in Wuhan, China. AB - OBJECTIVE: To investigate the epidemiology of cerumen impaction among children of municipal kindergartens in Wuhan. METHODS: The ear canal of children of municipal kindergartens in Wuhan was examined using an electric otoscope by the same otologist in 2005, 2006 and 2012, with age, gender, ears and the nature of cerumen (dry cerumen or wet cerumen) recorded. A chi-square test was performed to investigate for significant differences between cerumen impaction rates and the recorded variables. RESULTS: A total of 1,214, 1863 and 5205 children were examined in 2005, 2006 and 2012, and cerumen impaction prevalence rates for each year were 17.2%, 15.4% and 10%, respectively. Prevalence of cerumen impaction was significantly lower in 2012 than in 2005 or 2006. In 2005, dry cerumen impaction accounted for 22.2% of the total dry cerumen, while wet cerumen impaction only accounted for 5% of the total wet cerumen, showing a statistically significant difference. CONCLUSION: The prevalence of cerumen impaction among children of kindergartens in Wuhan is higher than 10%, and children with dry cerumen are more prone to cerumen impaction. Annual otological examination of kindergarten children is recommended. And improved community ear health promotion activities should reduce the avoidable prevalence of cerumen impaction in pediatric population. PMID- 28802365 TI - Exploring reasons for late identification of children with early-onset hearing loss. AB - INTRODUCTION: Several studies have shown that early identification of childhood hearing loss leads to better language outcomes. However, delays in the confirmation of hearing loss persist even in the presence of well-established universal newborn hearing screening programs (UNHS). The objective of this population-based study was to document the proportion of children who experienced delayed confirmation of congenital and early onset hearing loss in a UNHS program in one region of Canada. The study also sought to determine the reasons for delayed confirmation of hearing loss in children. METHODS: Population level data related to age of first assessment, age of identification and clinical characteristics were collected prospectively for all children identified through the UNHS program. We documented the number of children who experienced delay (defined as more than 3 months) from initial audiologic assessment to confirmation of hearing loss. A detailed chart review was subsequently performed to examine the reasons for delay to confirmation. RESULTS: Of 418 children identified from 2003 to 2013, 182 (43.5%) presented with congenital or early onset hearing loss, of whom 30 (16.5%) experienced more than 3 months delay from initial audiologic assessment to confirmation of their hearing disorder. The median age of first assessment and confirmation of hearing loss for these 30 children was 3.7 months (IQR: 2.0, 7.6) and 13.8 months (IQR: 9.7, 26.1) respectively. Close examination of the factors related to delay to confirmation revealed that for the overwhelming majority of children, a constellation of factors contributed to late diagnosis. Several children (n = 22; 73.3%) presented with developmental/medical issues, 15 of whom also had middle ear dysfunction at assessment, and 9 of whom had documented family follow-up concerns. For the remaining eight children, additional reasons included ongoing middle ear dysfunction for five children, complicated by family follow-up concerns (n = 3) and mild hearing loss (n = 1) and the remaining three children had isolated reasons related to family follow-up (n = 1) or mild hearing loss (n = 2). CONCLUSION: Despite the progress made in the early detection of pediatric hearing loss since UNHS, a substantial number of children referred for early assessment can experience late confirmation and intervention. In particular, infants with developmental and/or medical issues including middle ear disorders are at particular risk for longer time to confirmation of hearing loss. PMID- 28802366 TI - Formula for the prediction of apnea / hypopnea index in children with obstructive sleep apnea without polysomnography according to the clinical parameters: Is it reliable? AB - PURPOSE OF THE STUDY: The aim of the study was to propose "the risk formula" for obstructive sleep apnea in children according to the general and local clinical parameters and findings relevant for obstructive sleep apnea (OSA) severity. The unmet need for this formula arises from the economic burden of polysomnography (device, staff, training, special sleep centers, etc) as the golden standard for the diagnostics. MATERIALS AND METHODS USED: The study was performed from January 2013 until January 2016 in the Sleep Center, Department for Neuroscience, School of Medicine of the University of Split, Department of Pediatrics, University Hospital Split, Croatia and ENT Dept. University Hospital in Split, Croatia. Inclusion criteria were: age > two years, AHI >1 diagnosed by polysomnography. Exclusion criteria were: chronic lung disease, active tonsillitis/pharyngitis at the time of the physical exam and syndromes that affect breathing. All polysomnograms were scored by a qualified sleep technologist and interpreted by two board certified sleep physicians independently. Age, sex, BMI, Mallampati score, tonsillar size and adenoids size were recorded. All statistical calculations were performed using SPSS 20. RESULTS: In total 60 children were included in the study. The median of age was 5 years (range 2-9). There were 19 (32%) girls and 41 (68%) boys. Of all evaluated predictors, there were statistically significant differences in the values of AHI among children with different modified Mallampati score (chi2 = 28.2; p < 0.001), different size of tonsils (chi2 = 25.3; p < 0.001) and different size of adenoids (z = 2.7; p = 0,006) in univariate regression analysis. Strong positive association of AHI with modified Mallampati score (standardized B = 0.51; partial correlation = 0.542, r = 0.631) was found, as well as positive correlation of AHI with tonsillar size (standardized B = 0.246; partial correlation = 0.295,R = 0.489) in the multivariate forward stepwise regression analysis. CONCLUSION: Even though we are aware that PSG is the gold standard for diagnostics of SDB there is a significant financial burden for this diagnostic procedure. That is why there is a necessity for establishing good clinical standards and possible formula for OSA severity evaluation. We propose formula which includes Mallampati score and tonsillar size for OSA -risk calculation in order to perform early therapeutic intervention thereby reducing the risk of long-term negative consequences. We recommend this formula as the screening formula in circumstances where PSG is not available, in cases when the "waiting list" is too long or when a child can not cooperate to perform it. In developing countries like Croatia on time intervention with reduced procedure-associated costs is of the utmost importance. PMID- 28802367 TI - Impact of pneumococcal conjugate vaccines on otitis media: A review of measurement and interpretation challenges. AB - Acute otitis media (AOM) is among the most frequent childhood diseases and is caused by various bacterial and viral etiological agents. In this article, we provide an overview of published studies assessing the impact of higher-valent pneumococcal conjugate vaccines (PCVs) on AOM. In some instances, reports of PCV impact on complications of AOM have been included. While randomized controlled trials (RCTs) allow for the most precise assessment of vaccine efficacy against AOM, observational studies provide answers to questions regarding the public health value of these vaccines in real-life settings. We discuss the challenges that arise when measuring PCV impact on AOM in observational studies: the local variability of viral and bacterial etiology, differences in case ascertainment, care-seeking behavior, standards of care and diagnosis of AOM (e.g. use of incisions), as well as declining baseline AOM incidence that can already be in place before PCV introduction, and how these factors can impact the results and their interpretation. PMID- 28802368 TI - Study of the effects of hearing on static and dynamic postural function in children using cochlear implants. AB - OBJECTIVE: The present study aimed to evaluate the postural control perturbations by the center of pressure parameters in two main approaches, cochlear implant turned "on" and "off". METHODS: We included 25 children aged 8-10 years with unilateral cochlear implants and bilateral vestibular hypofunction deficit. To evaluate the postural function, each children was asked to stand on the force plate under 3 different conditions and cochlear implant turned "on" and "off": Condition (A) double stance from open eyes to closed eyes, Condition (B) double stance with open eyes engaging in the dual task and Condition (C) From double leg stance to one leg stance with open eyes for assessment of dynamic postural control. Also to calculate the center of pressure parameters, we designed new software for the force plate RESULTS: In condition A: although the results demonstrated an overall reduction in the mean of center of pressure parameters when the cochlear implant was "on", only the significant differences were seen in mean and standard deviations for anterior-posterior displacement, mediolateral displacement, area and mean velocity (P =0.00, P=0.04, P=0.02 and P=0.00, respectively) in open eyes In condition B: no significant difference was found between "on" and "off" cochlear implant in single or dual-task situations. In condition C: mean velocity variable demonstrated a significant difference (P=0.00) in the cochlear implant "on" condition in double leg stance only. Also, anterior-posterior displacement demonestrated a significant difference (P=0.00) when the cochlear implant was turned "on" in one leg stance situation. CONCLUSION: The results of our study show that auditory information can improve postural stability and reduce body sways in different situations as an underlying system for reinforcement of the postural control in children without complete normal balance subsystems. PMID- 28802369 TI - The first sporadic case of DFNA11 identified by next-generation sequencing. AB - We report the first sporadic case of nonsyndromic autosomal dominant hearing loss (DFNA11). The patient was a 5-year-old boy with moderate bilateral hearing loss. Targeted next-generation sequencing analysis of patient DNA identified a known heterozygous DFNA11 mutation, c.689C > T, in MYO7A, encoding p.Ala230Val. The mutation was not detected in the parents of the patient and is considered to be de novo. This mutation is identical to the one reported previously in an Italian family. Accumulation of mutation data increases the feasibility of identifying autosomal dominant mutations in sporadic sensorineural hearing loss. PMID- 28802370 TI - A systematic review including an additional pediatric case report: Pediatric cases of mammary analogue secretory carcinoma. AB - IMPORTANCE: Mammary Analogue Secretory Carcinoma (MASC) is a newly characterized salivary gland carcinoma resembling secretory carcinoma of the breast. Prior to being described, MASC was most commonly misdiagnosed as Acinic Cell Carcinoma. Though MASC is predominantly an adult neoplasm, cases have been reported in the pediatric population. Reporting and summarizing of known cases is imperative to understand the prognosis and clinical behavior of MASC. OBJECTIVE: EVIDENCE REVIEW: Web of Science, Medline, EMBASE, and The Cochrane Library were searched for studies that included pediatric cases of MASC. Data on clinical presentation, diagnosis and management, and pathology were collected from all pediatric cases. FINDINGS: CONCLUSIONS AND RELEVANCE: Since the first case of MASC in the pediatric population was described in 2011, only 12 cases, including this one, have been described in the literature. With this paucity of information, much remains unknown regarding this new pathologic diagnosis. The collection of clinical outcomes data of children with MASC is needed to better understand the behavior of this malignancy as well as determine optimal treatment regimens. PMID- 28802371 TI - How can we improve medical adherence to intranasal corticosteroids in children? AB - OBJECTIVE: To evaluate the factors which may be related to nonadherence to intranasal corticosteroids (ICS) in the treatment of allergic rhinitis (AR) in children. METHODS: A prospective study was conducted on children with AR diagnosis in a tertiary referral hospital. All participants were provided with mometasone furoate nasal sprays for 30 days after the diagnosis. Caregivers were called back when the therapy was over and completed a questionnaire about the factors that may influence the adherence to the treatment. Afterwards each caregiver completed the Turkish language validated Morisky Medical Adherence Scale (MMAS-8) form. Each factor was evaluated according to MMAS-8 score and all variables were analyzed statistically. RESULTS: A total number of 76 children with a mean age of 7.82 years were included in the study. The mean overall MMAS-8 score was 2.80. There was only one factor significantly related to low adherence; the number of dependent children to the caregiver (p = 0.011). Besides this 71.51% of the answers to MMAS-8 scale were compatible with good adherence. CONCLUSION: The clinician must consider the factors which may lead to non adherence while setting up a treatment plan. The demographic and sociocultural factors must be taken into consideration and treatment schedule should be made in respect of daily activities of the children. Moreover the father can be involved in the therapy plan and back up the mother as they are usually the responsible parent for children's medical therapy. PMID- 28802372 TI - Phonological awareness in German-speaking preschool children with cochlear implants - 3 case examples. AB - OBJECTIVE: The aim was to explore PA skills German-speaking preschool children with cochlea implants (CIs) and how these skills may be related to their speech and language skills. METHODS: Three monolingual German-speaking pre-school children aged 5;04-6;01 with bilateral CIs were tested. Their cognitive, speech and language skills were assessed. Six subtests of a standardized PA test battery were administered (i.e. rhyme identification, rhyme production; phoneme identification- input and -output; phoneme blending-input and -output). RESULTS: All three children showed distinctive PA profiles. One boy, who had no spoken language deficits, struggled to complete the rhyme tasks but performed well on three phoneme tasks. However, he showed a discrepancy between expressive and receptive phoneme blending skills, scoring poorly on the expressive subtest. The second boy, who displayed grammar comprehension and expressive vocabulary difficulties, showed a mixed profile, with a below average performance on rhyme production. The girl who had significant speech and language deficits scored below average on all six PA subtests. CONCLUSIONS: PA profiles in children with CI vary considerably and PA testing should include a range of different PA tasks. The assumed link between spoken language deficits and PA difficulties shown in children with normal hearing could be confirmed. PMID- 28802373 TI - Clinical curative effect and safety of balloon sinuplasty in children with chronic rhinosinusitis. AB - OBJECTIVE: Balloon Sinuplasty for the management of paranasal sinus inflammatory diseases was introduced in otolaryngology in 2005. Over the past decade, evidence strongly supports its safety and efficacy for the treatment of chronic rhinosinusitis (CRS) in adults. Because it requires no bone or tissue removal, this procedure could be suitable in children. We present our initial experience of its use for the treatment of CRS in children. MATERIALS AND METHODS: A prospective study was performed of 30 children with failed medical therapy, who were scheduled for surgery. They underwent treatment by balloon sinuplasty of selected sinuses. Data were collected, including age, VAS score, CT score, and nasal endoscopy findings. RESULTS: The procedure was successful in 61/65 sinuses (93.84%). Balloon sinuplasty improved sinus-related quality of life scores as well as computed tomography (CT) and endoscopic findings for up to 1 year after operation (p < 0.05). CONCLUSION: In this initial study, balloon sinuplasty showed a clinical curative effect in the treatment of children with refractory CRS, and was relatively safe. Structural abnormalities in sinus ostia and hypoplastic sinuses may not be amenable to balloon catheter sinuplasty. PMID- 28802374 TI - Secondary encephalocele in infant following subdural empyema repaired endoscopically-A case report. AB - Subdural empyema (SDE) is an uncommon entity, mostly associated with meningitis and can be life threatening in infants. Rarely, a subdural empyema can lead to nasal encephalocele which can be challenging situation to manage especially in infant. We present a case of 7 month old infant who presented with subdural empyema that led to formation of nasal encaphalocele after 4 months which was managed endoscopic route. PMID- 28802375 TI - Post-tonsillectomy hemorrhagic outcomes in children with bleeding disorders at a single institution. AB - OBJECTIVE: To report on the post-tonsillectomy bleeding outcomes and factors associated with hemorrhage among children with pre- or post-operatively diagnosed bleeding disorders treated with an institutional protocol. METHODS: Retrospective cohort study of patients with hematologic disorders who underwent tonsillectomy between 2003 and 2016 and were treated with perioperative desmopressin or factor replacement and/or aminocaproic acid. Postoperative outcomes were compared to controls matched for age, sex, and indication for surgery. Analysis of factors associated with hemorrhage was performed in patients with bleeding disorders using Mann-Whitney U or chi-squared tests. RESULTS: 45 patients with hematologic disorders met inclusion criteria. Platelet dysfunction, including von Willebrand Disease (vWD), was the most common diagnosis (77.8%). Most patients had a preoperative diagnosis of a bleeding disorder and received perioperative hematologic medications (86.7%). Compared to matched controls, patients with hematologic disorders experienced more postoperative bleeding (15.5%; 12 bleeds, 7 patients vs. 1.7%; 1 bleed, 1 patient, p = 0.05) and had longer postoperative stays (1.3 days vs. 0.4 days, p < 0.001). Among the patients with hematologic disorders, patients who experienced a postoperative bleed were significantly more likely to have a factor deficiency (e.g. Hemophilia over vWD) and have a postoperative diagnosis (compared to preoperative diagnosis) for which they did not receive perioperative hematologic medication. Of patients with a postoperative bleed, all those diagnosed postoperatively required at least one surgical intervention to control bleeding compared to 33% of patients with a preoperative diagnosis. A history of post-surgical bleeding, male sex, age at surgery, and pharyngitis as surgical indication were not associated with higher hemorrhage rates in this group. CONCLUSIONS: This study suggests a clinically important magnitude of increased bleeding risk in patients with hematologic disease. This risk appears to decrease with the use of an institutional protocol consisting of desmopressin or factor replacement and an antifibrinolytic agent extending through postoperative day 10. PMID- 28802376 TI - Hypovolemic shock after labial and lingual frenulectomy: A report of two cases. AB - Lingual and labial frenulectomy are commonly performed as an outpatient procedure, either in an office setting or under general anesthesia. Frenulectomy is generally regarded by both otolaryngologists and dentists as a straightforward and low-risk procedure with limited evidence-based indications and similarly few contraindications. We describe two cases of hypovolemic shock occurring after outpatient frenulectomy requiring emergent interventions of cardiopulmonary resuscitation and blood transfusion. These rare, but life-threatening outcomes warrant recognition as potential complications for the presumed benign labial and lingual frenulectomy. We additionally briefly review indications for upper labial and lingual frenulectomy. PMID- 28802377 TI - An innovative approach to improve ear, nose and throat surgical access for remote living Cape York Indigenous children. AB - INTRODUCTION: On a background of high rates of severe otitis media (OM) with associated hearing loss, children from the Torres Strait and Cape York region requiring ear, nose and throat (ENT) surgery, faced waiting times exceeding three years. After numerous clinical safety incidents were raised, indicating a failure of the current system to deliver appropriate care, the governing Hospital and Health service opted to deliver surgical care through an alternate process. ENT surgeries were performed on 16 consented children from two remote locations via the private health care system, funded by a health provider partnership. METHODS: We examined the collaboration processes alongside clinical findings from this ENT surgery. Collated patient data, included patient demographics, clinical and audiometry presentation features were reviewed and compared pre and post operatively. Cost savings associated with the use of TeleHealth post-operatively were briefly examined. RESULTS: Surgeries were successfully completed in all 16 children. The reported mean waitlist time for ENT surgery was 1.2 years. Pre surgery pure-tone average hearing thresholds were reported at left: 30.9 dB, right: 38.2 dB. The majority of presentations were for bilateral OM with Effusion (69%). Post-surgical follow up indicated successful clinical outcomes in 80% of patients and successful hearing outcomes in 88% of patients. Mean difference pure tone average hearing thresholds, left: 8.4 dB and right: 11.2 dB. Furthermore, the majority of patients reported improved hearing and breathing. The use of TeleHealth for post-operative review enabled a minimum cost saving of AUD$21,664 for these 16 children. Overall, a high level of staffing resources was required to successfully coordinate this intense surgical activity. CONCLUSION: This innovative approach to a health system crisis enabled successful ENT surgical and hearing outcomes in 16 children, whose waitlisted time grossly exceeded state health recommendations. Using private health facilities funded by a health partnership, while unlikely to be a suitable model of care for routine service delivery; may be applied as an adjunct service model when blockages and delays lead to sub-standard service provision. This approach may be applicable to other health care facilities when facing extended elective surgery wait times in ENT or other specialty areas. PMID- 28802378 TI - Auditory, visual and auditory-visual memory and sequencing performance in typically developing children. AB - OBJECTIVE: The study evaluated whether there exists a difference/relation in the way four different memory skills (memory score, sequencing score, memory span, & sequencing span) are processed through the auditory modality, visual modality and combined modalities. METHODS: Four memory skills were evaluated on 30 typically developing children aged 7 years and 8 years across three modality conditions (auditory, visual, & auditory-visual). Analogous auditory and visual stimuli were presented to evaluate the three modality conditions across the two age groups. RESULTS: The children obtained significantly higher memory scores through the auditory modality compared to the visual modality. Likewise, their memory scores were significantly higher through the auditory-visual modality condition than through the visual modality. However, no effect of modality was observed on the sequencing scores as well as for the memory and the sequencing span. A good agreement was seen between the different modality conditions that were studied (auditory, visual, & auditory-visual) for the different memory skills measures (memory scores, sequencing scores, memory span, & sequencing span). A relatively lower agreement was noted only between the auditory and visual modalities as well as between the visual and auditory-visual modality conditions for the memory scores, measured using Bland-Altman plots. CONCLUSIONS: The study highlights the efficacy of using analogous stimuli to assess the auditory, visual as well as combined modalities. The study supports the view that the performance of children on different memory skills was better through the auditory modality compared to the visual modality. PMID- 28802379 TI - The multivariate analysis of indications of rigid bronchoscopy in suspected foreign body aspiration. AB - OBJECTIVE: Foreign body aspiration (FBA) could be a serious life-threatening condition in children. Patients usually underwent bronchoscopy with suspicious of FBA alone. In this study, we aimed to determine which patients need to go to bronchoscopy based on pre-operative findings. METHODS: Retrospective analysis of patients underwent bronchoscopy between 1999 and 2015 was performed. Clinical symptoms, witnessed aspiration event (WAE), physical examination findings (PEFs) and radiological findings (RFs) were analyzed by multivariate analysis to evaluate the indications of bronchoscopy. RESULTS: 431 patients (266M, 165F) underwent bronchoscopy with a median age of 2 years (7 months-16 years). A foreign body was detected in 68% of the patients. Univariate analysis demonstrated that wheeze was the sole distinctive clinical symptom for detection of FBA (p<0.001). The rates of positive WAE, PEFs and RFs were 83%, 71.7% and 36.9%, respectively. All of them were identified as independent predictive parameters in the detection of FBA by univariate analysis (p = 0.003&p<0.001&p = 0.015). Multivariate analysis was performed with considering the association between them. The rate of positive bronchoscopy was 91.3% in patients with positive WAE, PEFs and RFs together(84/92). In patients with a positive WAE alone who had not got PEFs and RFs, the rate of positive bronchoscopy was 34.2% (25/73). A foreign body was detected in 84% of the patients who had not got a WAE but positive PEFs and RFs together(21/25). Bronchial laceration was occurred in one patient during bronchoscopy. Pneumothorax was not seen in any of the other patients. The rate of mortality was 0.4% in the overall group (2 patients). CONCLUSION: The indications of bronchoscopy in suspected FBA are usually based on clinical suspicious. The definition of " suspicous" could be a WAE or positive PEFs and RFs. The association of these factors increase the rate of positive bronchoscopies. In the light of our study, the classical indication for suspected FBA is still valid as "suspicious requires bronchoscopy". PMID- 28802380 TI - Can telemetry data obviate the need for sleep studies in Pierre Robin Sequence? AB - OBJECTIVE: This study looks to correlate telemetry data gathered on patients with Pierre Robin Sequence (PRS) with sleep study data. Strong correlation might allow obstructive sleep apnea (OSA) to be reasonably predicted without the need for sleep study. METHODS: Charts from forty-six infants with PRS who presented to our children's hospital between 2005 and 2015 and received a polysomnogram (PSG) prior to surgical intervention were retrospectively reviewed. Correlations and scatterplots were used to compare average daily oxygen nadir, overall oxygen nadir, and average number of daily desaturations from telemetry data with apnea hypopnea index (AHI) and oxygen nadir on sleep study. Results were also categorized into groups of AHI >= or <10 and oxygen nadir >= or <80% for chi squared analysis. RESULTS: Our data did not show significant correlations between telemetry data and sleep study data. Patients with O2 nadir below 80% on telemetry were not more likely to have an O2 nadir below 80% on sleep study. Patients with an average O2 nadir below 80% did show some correlation with having an AHI greater than 10 on sleep study but this relationship did not reach significance. Of 22 patients who did not have any desaturations on telemetry below 80%, 16 (73%) had an AHI >10 on sleep study. CONCLUSIONS: In the workup of infants with PRS, the index of suspicion is high for OSA. In our series, telemetry data was not useful in ruling out severe OSA. Thus our data do not support forgoing sleep study in patients with PRS and concern for OSA despite normal telemetry patterns. PMID- 28802381 TI - Diagnosing subtle palatal anomalies: Validation of video-analysis and assessment protocol for diagnosing occult submucous cleft palate. AB - INTRODUCTION: Submucous cleft palate (SMCP) classically involves bifid uvula, zona pellucida, and notched hard palate. However, patients may present with more subtle anatomic abnormalities. The ability to detect these abnormalities is important for surgeons managing velopharyngeal dysfunction (VPD) or considering adenoidectomy. OBJECTIVES: Validate an assessment protocol for diagnosis of occult submucous cleft palate (OSMCP) and identify physical examination features present in patients with OSMCP in the relaxed and activated palate positions. METHODS: Study participants included patients referred to a pediatric VPD clinic with concern for hypernasality or SMCP. Using an appropriately encrypted iPod touch, transoral video was obtained for each patient with the palate in the relaxed and activated positions. The videos were reviewed by two otolaryngologists in normal speed and slow-motion, as needed, and a questionnaire was completed by each reviewer pertaining to the anatomy and function of the palate. RESULTS: 47 patients, with an average age of 4.6 years, were included in the study over a one-year period. Four videos were unusable due to incomplete view of the palate. The most common palatal abnormality noted was OSMCP, diagnosed by each reviewer in 26/43 and 30/43 patients respectively. Using the assessment protocol, agreement on palatal diagnosis was 83.7% (kappa = 0.68), indicating substantial agreement, with the most prevalent anatomic features being vaulted palate elevation (96%) and visible notching of hard palate (75%). CONCLUSION: The diagnosis of subtle palatal anomalies is difficult and can be subjective. Using the proposed video-analysis method and assessment protocol may improve reliability of diagnosis of OSMCP. PMID- 28802382 TI - Evaluation of the possible protective role of naringenin on gentamicin-induced ototoxicity: A preliminary study. AB - OBJECTIVES: The purpose of this study is to evaluate the possible protective role of naringenin in gentamicin-induced ototoxicity through an audiological, biochemical and histopathological evaluation. METHODS: This study was conducted on 32 adult male rats that were randomized into 4 groups(control, gentamicin, naringenin + gentamicin, and naringenin). Naringenin was given to the rats via oral gavage in a dose of 50 mg/kg/day during the 14 day study period. Gentamicin was given by the intraperitoneal route in a dose of 120 mg/kg/day. Audiological assessment was performed by the distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) measurements, applied to all rats at the beginning of the study, and also on day 14. Biochemical parameters were calculated on day 14 to evaluate the oxidative and antioxidative status. Their cochleae were removed and examined histopathologically, also on day 14. The cochlea of animals were evaluated with the terminal deoxynucleotidyl transferase mediated dUTPbiotin nick end labeling (TUNEL) method for apoptosis. RESULTS: On days 14, DPOAE values and ABR thresholds were preserved in group 3(naringenin + gentamicin) when compared with group 2(gentamicin)(p < 0.008). The total oxidant status values and oxidative stress index values were significantly higher in group 2(gentamicin) than in other groups (p < 0.008). The total antioxidant status value was significantly higher in group 3(naringenin + gentamicin) and group 4(naringenin) than in group 2(gentamicin)(p < 0.008). The number of TUNEL positive cells in both the organ of Corti and the stria vascularis were found to be statistically lower in group 3(naringenin + gentamicin) than in group 2(gentamicin)(p < 0.05). CONCLUSION: Our study has demonstrated that the ototoxic effect generated by gentamicin could be ameliorated with the concurrent use of naringenin. PMID- 28802383 TI - Absence of KCNQ4 mutation in Bengali families with ADNSHL originated from West Bengal, India. AB - OBJECTIVE: Autosomal Dominant Non-Syndromic Hearing Loss (ADNSHL) is extremely heterogeneous in nature. More than 60 loci with 30 different genes have been identified linked to ADNSHL. Mutation in KCNQ4 is considered as one of the most common causative factor responsible for ADNSHL. No study focused on the genetic alteration of KCNQ4 gene among hearing loss patients in India. The present study for the first time was carried out to determine the mutation spectrum of KCNQ4 gene in ADNSHL patients of West Bengal state, India. METHOD: Twenty nine individuals from 10 independent ADNSHL family (with two or more generation affected) were studied both clinically and genetically. Most of the patients showed moderate progressive sensorineural hearing loss. Mutation analysis was conducted for KCNQ4 gene using polymerase chain reaction followed by direct sequencing. RESULTS: Neither any reported nor a novel pathogenic mutation in KCNQ4was detected in our studied group, in contrast to the findings among East Asians. CONCLUSION: The result of the present study suggests that mutations in KCNQ4 gene are unlikely to be a major causative factor of ADNSHL in our studied patients from West Bengal, India, pointing to other genes might be responsible for ADNSHL in our studied patients. PMID- 28802385 TI - Comparison of home sleep apnea testing versus laboratory polysomnography for the diagnosis of obstructive sleep apnea in children. AB - INTRODUCTION: Obstructive sleep apnea (OSA) affects 1-5% of pediatric patients. Laboratory polysomnography is expensive, not always available, and is inconvenient for patients. Our study investigates the diagnostic ability of an unattended ambulatory monitor for the diagnosis of pediatric OSA. METHODS: A prospective study was conducted in children, ages 2-17. Subjects completed in-lab polysomnography simultaneously with ambulatory monitoring. Caregivers attempted home studies on two subsequent nights to compare the home monitor and the laboratory polysomnogram (PSG). RESULTS: Thirty-three subjects completed simultaneous laboratory polysomnogram with portable monitoring. Twenty patients completed home studies, with 16 completing 2 nights of monitoring. The measurement of AHI by the portable monitor was different than that obtained by the PSG with statistical significance for the comparisons of PSG vs. In-Lab (p = 0.0026), PSG vs. Home 1 (p = 0.033), and PSG vs. Home 2 (p = 0.033). The sensitivity of the portable monitor for diagnosing OSA was best for the In-lab use at 81%, but only 69% and 70% for the uses at home on the 2 nights respectively. Interestingly, the comparison of AHI and lowest oxygen saturation measurements from the home sleep test in children age 6 and older did not differ significantly from the PSG. CONCLUSIONS: This pilot study demonstrated differences between home sleep testing and in-lab polysomnography for the diagnosis of pediatric sleep apnea. These differences were predominantly found to exist in younger children. Larger prospective studies are needed prior to widespread use, but home studies may alleviate issues of access to care and higher costs of laboratory polysomnography. PMID- 28802384 TI - Retrospective study of intranasal dexmedetomidine as a prophylactic against emergence delirium in pediatric patients undergoing ear tube surgery. AB - OBJECTIVES: This study evaluated the effect of intranasal dexmedetomidine on emergence delirium (ED) in pediatric patients who underwent ear tube surgeries. Due to the brief nature of the surgery and low levels of pain experienced, an IV is rarely needed, limiting the medications available to anesthesiologists to manage postoperative delirium that may arise during recovery from inhalational anesthesia. Intravenous dexmedetomidine is an alpha-2 agonist anesthetic that is used in pediatric patients for the management of ED in various surgical procedures. However, intranasal medication has not been evaluated specifically in ear tube surgeries for ED prevention. METHODS: We conducted a retrospective chart review of pediatric patients at Nemours Children's Hospital who had undergone ear tube insertion or removal surgery between 2013 and 2015, controlling for confounding variables such as age, surgery duration, and anesthesiologist. We used the post anesthesia emergence delirium (PAED) tool, an instrument created to assess ED in the clinical setting. We analyzed the data for significant differences in PAED score and time in the post anesthesia care unit (PACU) between patients treated with intranasal dexmedetomidine and the control group that did not receive the medication. RESULTS: We found no significant difference between the PAED scores of those patients treated with intranasal dexmedetomidine prior to ear tube surgeries and those who did not receive the medication, and no difference in the duration of PACU stay. CONCLUSION: These results conflict with other research on intranasal dexmedetomidine and its potential to prevent ED in pediatric patients. This information should prompt further prospective investigation into the most efficacious use of dexmedetomidine for ED prevention, both in terms of timing and dosage required. PMID- 28802386 TI - Otoplasty for prominent ears - demographics and surgical timing in different populations. AB - INTRODUCTION: Prominent ears are seen in approximately 5% of the population. This benign condition can be treated surgically to reduce or prevent psychological and social problems, most commonly in children before the start of school. Our aim was to examine the demographic characteristics of patients undergoing prominent ear surgery in Finland, and compare findings with international data. METHODS: A retrospective study of all the patients treated for prominent ears in our academic tertiary care referral center during 2007-2011 was performed to gather demographic details of operated patients. A systematic review of published series of prominent ear surgery after the year 2000 was performed to gather demographic details for international comparison. RESULTS: A total of 180 patients were operated in our institution for prominent ears, most of the cases (78.9%) were bilateral. Age at operation ranged between 3 and 36 years, with mean of 9.2 y and median of 7 y. The most common reason for seeking operative treatment was aesthetic complaint, followed by bullying. Review process gathered 20 publications, describing a total of 4433 patients who had been operated for prominent ears. There was wide variation the mean age at operation, ranging 7-38 y while the mean overall was 15.0y. Gender distribution of patient samples was also very variable, with percentage of females ranging from 38 to 71% (overall 52%). There was also considerable variation in the tendency to perform unilateral operations: from 0% up to 21% of the reported population. There were no statistically significant correlations linking these demographic variables, though there was a trend that females are more likely to have this operation performed at an older age. CONCLUSIONS: The treatment culture of prominent ear surgery varies substantially in international comparison. The age at which this operation is performed showed most variation. Omitting some of the basic demographic variables while reporting the results of surgery was common in the reviewed publications. PMID- 28802387 TI - Sleep quality and communication aspects in children. AB - OBJECTIVES: To correlate quality of life of children in terms of sleep, with their oral language skills, auditory processing and orofacial myofunctional aspects. METHODS: Nineteen children (12 males and seven females, in the mean age 9.26) undergoing otorhinolaryngological and speech evaluations participated in this study. The OSA-18 questionnaire was applied, followed by verbal and nonverbal sequential memory tests, dichotic digit test, nonverbal dichotic test and Sustained Auditory Attention Ability Test, related to auditory processing. The Phonological Awareness Profile test, Rapid Automatized Naming and Phonological Working Memory were used for assessment of the phonological processing. Language was assessed by the ABFW Child Language Test, analyzing the phonological and lexical levels. Orofacial myofunctional aspects were evaluated through the MBGR Protocol. Statistical tests used: the Mann-Whitney Test, Fisher's exact test and Spearman Correlation. RESULTS: Relating the performance of children in all evaluations to the results obtained in the OSA-18, there was a statistically significant correlation in the phonological working memory for backward digits (p = 0.04); as well as in the breathing item (p = 0.03), posture of the mandible (p = 0.03) and mobility of lips (p = 0.04). CONCLUSION: A correlation was seen between the sleep quality of life and the skills related to the phonological processing, specifically in the phonological working memory in backward digits, and related to orofacial myofunctional aspects. PMID- 28802388 TI - Adenotonsillectomy outcomes in children with sleep apnea and narcolepsy. AB - OBJECTIVE: To identify improvements in daytime sleepiness following adenotonsillectomy in children with non-severe obstructive sleep apnea and narcolepsy. STUDY DESIGN: Case series with chart review over 15 years. SETTING: Tertiary Children's Hospital. SUBJECTS AND METHODS: Children between 6 and 17 years of age with narcolepsy that underwent adenotonsillectomy for non-severe obstructive sleep apnea (OSA) were included. Narcolepsy was diagnosed based on clinical assessment and the Multiple Sleep Latency Test (MSLT) results. A standardized instrument, the pediatric Epworth Sleepiness Scale (ESS), was used to assess daytime sleepiness before and after adenotonsillectomy. RESULTS: Nine children with a mean age of 12.1 years were included. The majority of the subjects (78%, n = 7) were African American and six children (66.7%) were obese. Four children (44%) were treated with wake promoting agents during the study. The mean preoperative apnea hypopnea index on polysomnography was 4.89 (SD 1.86), while the mean sleep latency on MSLT was 6.32 min (SD 3.14). The mean preoperative ESS was 16.10 and the postoperative ESS was 10.80 (SD 3.96). There was significant improvement (p = 0.02) in the ESS following adenotonsillectomy with seven children (78%) reporting diminished daytime sleepiness. CONCLUSIONS: Children with non-severe OSA and narcolepsy experience significant improvement in daytime sleepiness following adenotonsillectomy. Future studies are needed to determine the incidence and clinical significance of non-severe OSA in children with narcolepsy. PMID- 28802389 TI - Cholesteatoma as a complication of Langerhans Cell Histiocytosis of the temporal bone: A nationwide cross-sectional analysis. AB - OBJECTIVE: To determine if patients with Langerhans Cell Histiocytosis (LCH) of the temporal bone have a higher risk of developing cholesteatoma. METHODS: Review of literature and cross-sectional weighted analysis of patients under 19 with a diagnosis of LCH from the National Inpatient Sample (NIS) and Kids' Inpatient Database (KID) from 2000 to 2013. ICD-9 codes and demographics were analyzed; pairwise comparisons and multivariate analyses were performed. RESULTS: Only seven cases of cholesteatoma after the treatment for LCH of the temporal bone have been documented in the literature. No significant association between cholesteatoma and LCH was seen (OR 0.747 [0.149-3.751]). Patients with LCH did have a higher incidence of chronic otitis media, chronic otitis externa, chronic sinusitis, hearing loss, and otitis media with effusion. CONCLUSION: Our results show that patients with Langerhans Cell Histiocytosis do not appear to have a higher risk of developing cholesteatoma. However they are more likely to be diagnosed with chronic otitis externa which should be differentiated from cholesteatoma or recurrence of LCH. PMID- 28802390 TI - Pediatric head and neck bone sarcomas: An analysis of 204 cases. AB - OBJECTIVES: To analyze the demographics, survival, and treatment efficacy of pediatric sarcomas of the facial skeleton and skull. METHODS: Retrospective study of cases from the US National Cancer Institute's Surveillance, Epidemiology, and End Results database. Pediatric patients between the ages of 0 and 18 diagnosed with a malignant sarcoma of either the mandible or the bones of skull, face, and associated joints from 1973 to 2013 were studied. RESULTS: In total, 204 patients were included in the analysis. The average age at diagnosis was 11.39 (+/-5.15) years with a male-to-female ratio of 1.4:1. Whites were the most commonly affected race (76.0%). Malignant mandible sarcomas accounted for 29.9% of the cohort (n = 61). The most common pathology was osteosarcoma, which accounted for 43.6% of the cohort (n = 89). Among patients with known histologic grade (n = 95), 26.0% were AJCC stage III or IV. Overall, 5-year disease-specific survival (DSS) was 80.6%. When stratified by treatment modality, 5-year DSS was 86.0% for surgery alone, 67.9% for radiation alone, and 75.3% for surgery with adjuvant radiotherapy (p = 0.041). CONCLUSIONS: Osteosarcoma, Ewing's sarcoma, and chondrosarcoma are the most common subtypes of pediatric head and neck bone sarcoma. Such sarcomas more commonly affect whites and males during pubertal ages. Disease-specific survival is not affected by primary site. Surgery alone is the mainstay of treatment, and demonstrates higher 5-year disease-specific survival compared to radiotherapy alone. Adjuvant radiotherapy does not seem to increase survival, but further investigation is warranted. PMID- 28802391 TI - Pathophysiology of esophageal impairment due to button battery ingestion. AB - BACKGROUND: The increased use of button batteries with high energy densities in devices of daily life presents a high risk of injury, especially for toddlers and young children. If an accidental ingestion of a button battery occurs, this foreign body can become caught in the constrictions of the esophagus and cause serious damage to the adjacent tissue layers. The consequences can be ulcerations, perforations with fistula formation and damage to the surrounding anatomical structures. In order to gain a better understanding of the pathophysiology after ingestion, we carried out systematic studies on fresh preparations of porcine esophagi. METHODS: The lithium button battery type CR2032, used most frequently in daily life, was exposed in preparations of porcine esophagi and incubated under the addition of artificial saliva at 37 degrees C. A total of eight esophagi were analysed by different methods. Measurements of the pH value around the battery electrodes and histological studies of the tissue damage were carried out after 0.5-24 h exposure time. In addition, macroscopic time-lapse images were recorded. Measurements of the battery voltage and the course of the electric current supplemented the experiments. FINDINGS: The investigations showed that the batteries caused an electrolysis reaction in the moist environment. The positive electrode formed an acidic and the negative electrode a basic medium. Consequently, a coagulation necrosis at the positive pole, and a deep colliquation necrosis at the minus pole occurred. After an exposure time of 12 h, tissue damage caused by the lye corrosion was observed on the side of the negative electrode up to the lamina muscularis. The corrosion progressed up to the final exposure time of 24 h, but the batteries still had sufficient residual voltage, such that further advancing damage would be expected. CONCLUSIONS: Button battery ingestion in humans poses an acute life-threatening danger and immediate endoscopic removal of the foreign body is essential. After only 2 h exposure time, significant damage to the tissue could be detected, which progressed continuously to complete esophageal perforation. The primary prevention of battery ingestion is therefore of particular importance. PMID- 28802392 TI - Utilization and trends in surgical instrument use in pediatric adenotonsillectomy. AB - OBJECTIVE: Examine trends in surgical instrument usage for pediatric adenotonsillectomy. METHODS: An online survey asking questions about current and previous surgical instrument use was created by the authors and distributed to 517 members of the American Society of Pediatric Otolaryngology in October 2015. The survey was designed to assess trends in the use of surgical instruments in pediatric adenotonsillectomy by comparing the results of our 2015 survey to data from a previously published 2005 study. RESULTS: 133 surveys were returned. The most common instruments for total tonsillectomy in 2015 were monopolar electrocautery (57.0%) and coblation (22.7%). The most common subtotal tonsillectomy instruments in 2015 were microdebrider with monopolar electrocautery (41.3%) and coblation (37.0%). The most common adenoidectomy instruments in 2015 were monopolar electrocautery alone (41.3%), coblation (15.1%), and microdebrider with electrocautery (15.1%). CONCLUSION: As compared to our 2005 study, our 2015 study demonstrates that the instrument choice for total tonsillectomy, sub-total tonsillectomy, and adenoidectomy have shifted away from cold techniques toward monopolar electrocautery and coblation. PMID- 28802393 TI - Paediatric injection medialisation laryngoplasty: Recent Great Ormond Street Hospital experience. AB - INTRODUCTION: Unilateral vocal fold paresis may significantly impair the vocal quality and laryngeal competence of a child. Relatively little literature relates to injection medialisation laryngoplasty (IML) in children and previous reports have involved small numbers of heterogenous cases. METHODS: A retrospective review was conducted of paediatric patients managed by our multidisciplinary specialist voice clinic undergoing IML for unilateral vocal fold paresis. Cases of bilateral paresis, those characterised by vocal fold fixation, and patients without formal pre and post-operative voice evaluation were excluded. RESULTS: Eighteen IML procedures were performed in 12 children eligible for inclusion between 2005 and 2015. The average age at time of procedure was 12 years (range 9 15 years). Autologous fat was used in 5 procedures, succeeded by calcium hydroxylapatite (Radiesse(r) Voice) from 2011 (n = 13). A significant improvement in median GRBAS score components was observed after calcium hydroxylapatite injection in terms of grade (p = 0.008), breathiness (p = 0.002) and aesthenia (p = 0.016). A pre- and post-procedural Voice Handicap Index was self-completed by 6 patients receiving calcium hydroxylapatite injection; the median change in score was an improvement of 19 points (interquartile range 36.5). CONCLUSION: We describe the outcomes of a comparatively large paediatric series and have found IML using calcium hydroxylapatite to be a reliable technique associated with improved subjective outcome measures. Management of UVCP in the child is a challenge with particular investigative and interventional considerations. Further study supported by high quality subjective and, where possible, objective outcome measures, is required to better inform patient selection, timing of intervention and choice of injection material. PMID- 28802394 TI - Assessment of complete unilateral cleft lip and palate treatment outcome using EUROCRAN index and associated factors. AB - OBJECTIVES: Assessment of treatment outcome is the only non-invasive approach to identify the effects of cleft lip and palate repair and modify management accordingly. Here the aim is to assess the outcome of complete unilateral cleft lip and palate (CUCLP) patients using EUROCRAN index and to check whether there are any factors associated with the treatment outcome. MATERIALS AND METHODS: It is a retrospective cross sectional study. Dental models were collected from archives of two cleft referral centers in Pakistan. Five blinded examiners scored 101 models twice at two week interval. The primary outcome was mean EUROCRAN scores based on dental arch relationships and palatal surface morphology. RESULTS: A mean(SD) score of 2.72 (0.76) and 2.20 (0.73) was determined based on dental arch relationships and palatal surface morphology, respectively. According to the final logistic regression model, modified Millard technique (cheiloplasty) and Veau-Wardill-Kilners' method (palatoplasty) had higher odds of producing unfavorable treatment outcome. CONCLUSIONS: Present study determined a fair and a fair to poor treatment outcome based on dental arch relationships and palatal surface morphology, respectively. Our study suggests a significant association between treatment outcome and primary surgical techniques for lip and palate. These findings could warrant a modification of management protocols to ensure improvement in future cleft outcomes. PMID- 28802395 TI - Changes in pediatric tracheostomy tubes exposed to home dishwashing. AB - OBJECTIVE: Determine the effects of household dishwashing on Tracheostomy Tube safety. INTRODUCTION: Tracheostomy tubes accumulate biofilms, which may limit their lifespan. Frequent cleaning of the tubes is a method for biofilm prevention. Cleaning practices vary widely. Some families prefer dishwashing of tubes, but its effects are currently unknown. We hypothesize that dishwashing has no significant effect on the physical properties of tracheostomy tubes and can be recommended as a safe way to clean tracheostomy tubes. METHODS: Twenty 4.0 ShileyTM pediatric tracheostomy tubes were randomly assigned into dishwashed (DW) and non-dishwashed (NDW) groups, 10/group. DW tubes were subjected to 12 wash cycles. Each tube's hardness along with the surface spectra were analyzed to assess for chemical composition changes. Three cannula samples from each group were also randomly assessed with scanning-electron microscopy and scored by blinded examiners to assess for changes in surface heterogeneity. RESULTS: Hardness testing revealed a statistically significant difference (p = 0.0009) between the NDW and the DW group indicating increased fragility in the dishwashed tubes. Spectral analysis revealed loss of plasticizers, indicating decreased flexibility. Blinded electron microscopy scoring revealed increased surface heterogeneity in the DW group (p = 0.00007). CONCLUSION: A significant decrease in tube hardness and increased surface heterogeneity were found with dishwashing. The spectral analysis demonstrated increasing fragility. We believe these effects could potentially lead to decreased mechanical safety. With increased surface heterogeneity there is a greater potential for biofilm formation. At this time, dishwashing cannot be recommended as a tracheostomy tube cleaning method. PMID- 28802396 TI - Host genetics in susceptibility to and severity of mycobacterial diseases. AB - The genetic analysis of susceptibility to infections has proven to be extremely useful for identification of key cells, molecules, pathways, and genes involved in the battle between two genomes - the essence of the infectious process. This is particularly true for tuberculosis and other mycobacterial infections which traditionally attracted much attention from both immunologists and geneticists. In this short review, we observe results of genetic studies performed in human populations and in animal models and compare relative input of forward and reverse genetic approaches in our knowledge about genetic control of and immune responses to mycobacterial infections. PMID- 28802398 TI - A mycobacterial growth inhibition assay (MGIA) for bovine TB vaccine development. AB - Human tuberculosis remains a significant cause of mortality and morbidity throughout the world. The global economic impact of bovine TB is considerable. An effective vaccine would be the most cost-effective way to control both epidemics, particularly in emerging economies. TB vaccine research would benefit from the identification of an immune correlate of protection with which vaccines could be gated at both preclinical and clinical levels. In-vitro mycobacterial growth inhibition assays (MGIA) are functional assays that include most aspects of the complex host immune response to mycobacteria, and they may serve as functional immune correlates for vaccine development. We applied to cattle an MGIA that was developed for use with human and murine samples. Several technical difficulties were encountered while transferring it to the cattle model. However, our data demonstrate that the assay was not discriminatory in cattle and further work is needed before using it for bovine TB vaccine development. PMID- 28802397 TI - lysX gene is differentially expressed among Mycobacterium tuberculosis strains with different levels of virulence. AB - Antimicrobial peptides (AMPs) are mainly produced by epithelial cells and macrophages to eliminate infecting mycobacteria through direct antimicrobial activity and immunomodulation. Indeed, it has been described that this line of defense is essential to control infection. However, Mycobacterium tuberculosis (Mtb) has developed mechanisms to avoid AMPs activity, for instance lysX adds lysine residues to surface phospholipids changing their net charge, leading to the repelling of the AMPs. In the present study, we determined that lysX gene is differentially expressed among Mtb strains. To achieve this aim we used several well-characterized Mtb clinical isolates, lysX mutated strains and reference strains. Our results showed that in the presence of AMPs, lysX expression increased significantly. Strains with higher lysX expression showed increased levels of intracellular survival in vivo and in vitro and induced more severe lesion related with pneumonia. Results showed that ability of Mtb to replicate intracellularly was directly correlated to the level of lysX expression showing that the amount of lysX produced by the bacterial cell is an important variable for the modulation of Mtb virulence. PMID- 28802399 TI - Edoardo Maragliano (1849-1940): The unfortunate fate of a real pioneer in the fight against tuberculosis. PMID- 28802400 TI - Mycobacterium tuberculosis MymA is a TLR2 agonist that activate macrophages and a TH1 response. AB - Cell wall of Mycobacterium tuberculosis (M.tb) is a major source of immunogenic proteins that can be tested as vaccine candidates. MymA (Rv3083), a 55 kDa M.tb flavin containing monooxygenase, is involved in modification of mycolic acids during acidic shock following M.tb internalization in macrophage. In this study, we have investigated the role of this cell wall associated protein in activation of macrophages by toll like receptor (TLRs) engagement and subsequent signaling. Our results showed that MymA stimulation of THP1 cells and human monocyte derived macrophages (MDM) lead to upregulation of TLR2 and co-stimulatory molecules CD40, CD80, CD86 and HLA-DR. This upregulation is partially reduced by TLR2 blocking antibodies. The activation of macrophage following MymA stimulation also resulted in release of proinflammatory cytokines, TNF-alpha and IL-12. Moreover, MymA also polarized the immune response towards TH1 as shown by an increased IFN-gamma level in the supernatant of stimulated peripheral blood mononuclear cells (PBMC). In consensus with the TLR2 signaling involving MyD88 and NF-kappaB, we also observed several fold increase in mRNA for TLR2, MyD88 and NF-kappaB on MymA induction of THP-1 and MDM by qRT-PCR. The increased production of NF-kappaB following recognition of MymA by TLR2 was further confirmed by HEK-TLR2 reporter cell line colorimetric assay. In conclusion, immunological evaluation revealed that MymA is a TLR2 agonist that upregulates signaling via MyD88 and NF-kappaB in macrophages to stimulate the release of proinflammatory cytokines. The MymA protein should be investigated further for expression in recombinant BCG as a pre exposure vaccine or as a post-exposure subunit vaccine candidate. PMID- 28802401 TI - Differences in IgG responses against infection phase related Mycobacterium tuberculosis (Mtb) specific antigens in individuals exposed or not to Mtb correlate with control of TB infection and progression. AB - Tuberculosis (TB) occurs in only 3-10% of Mycobacterium tuberculosis (Mtb) infected individuals, suggesting that natural immunity can contain Mtb infection, although this remains poorly understood. Next to T-cells, a potentially protective role for B-cells and antibodies has emerged recently. However, the Mtb antigens involved remain ill-defined. Here, we investigated in a TB-endemic setting IgG levels against 15 Mtb antigens, representing various phases of Mtb infection and known to be potent human T-cell antigens. IgG levels against ESAT6/CFP10, Rv0440, Rv0867c, Rv1737c, Rv2029c, Rv2215, Rv2389c, Rv3616c and Mtb purified protein derivative (PPD) were higher in TB patients than in endemic and non-endemic controls. The only exception was Rv1733c that was preferentially recognized by antibodies from endemic controls compared to TB patients and non endemic controls, suggesting a potential correlation with control of TB infection and progression. In patients, IgG levels against Ag85B and Rv2029c correlated with Mtb loads, while immunoglobulins against Rv0440 differed between genders. Our results support the potential role of certain Mtb antigen-(Rv1733c) specific antibodies in the control of TB infection and progression, while other Mtb antigen-specific antibodies correlate with TB disease activity and bacillary loads. The findings for Rv1733c agree with previous T-cell results and have implications for including antibody-mediated immunity in designing new strategies to control TB. PMID- 28802402 TI - Sustained expression of DevR/DosR during long-term hypoxic culture of Mycobacterium tuberculosis. AB - DevR/DosR is a key mediator of 'dormancy' adaptation in Mycobacterium tuberculosis in response to gaseous stresses such as hypoxia that inhibit aerobic mode of respiration. In the present study, a temporal analysis over a 1 year period has revealed robust expression of representative DevR regulon genes devR, hspX and tgs1, during long-term 'dormancy' adaptation to hypoxia. Notably, a predominant proportion of long-term hypoxia-adapted bacteria were characterized by their inability to grow on solid media, accumulation of triacylglycerols and recovery of growth in liquid media. Persistent expression of HspX and the accumulation of triacylglycerols reveal a previously underappreciated role of DevR during adaptation to extended hypoxia, and endorse DevR as an effective target for thwarting the sustained survival of 'dormant' subpopulation of M. tuberculosis. PMID- 28802403 TI - Analytical evaluation of QuantiFERON- Plus and QuantiFERON- Gold In-tube assays in subjects with or without tuberculosis. AB - The QuantiFERON-TB Gold Plus (QFT-Plus) represents the new QuantiFERON-TB Gold In tube (QFT-GIT) to identify latent tuberculosis infection (LTBI). The main differences is the addition of a new tube containing shorter peptides stimulating CD8 T-cells. Aim of this study is to evaluate the accuracy of QFT-Plus compared with QFT-GIT in a cross sectional study of individuals with or without tuberculosis (TB). We enrolled 179 participants: 19 healthy donors, 58 LTBI, 33 cured TB and 69 active TB. QFT-Plus and QFT-GIT were performed. The two tests showed a substantial agreement. Moreover we found a similar sensitivity in active TB and same specificity in healthy donors. A higher proportion of the LTBI subjects responded to both TB1 and TB2 compared to those with active TB (97% vs 81%). Moreover, a selective response to TB2 was associated with active TB (9%) and with a severe TB disease, suggesting that TB2 stimulation induces a CD8 T cell response in absence of a CD4-response. In conclusion, QFT-Plus and QFT-GIT assays showed a substantial agreement and similar accuracy for active TB detection. Interestingly, a higher proportion of the LTBI subjects responded concomitantly to TB1 and TB2 compared to those with active TB, whereas a selective TB2 response associated with active TB. PMID- 28802404 TI - Enabling faster Go/No-Go decisions through secondary screens in anti mycobacterial drug discovery. AB - Management of tuberculosis, already a global health emergency, is becoming increasingly challenging with extensive misuse of second line drugs and their inaccessibility to eighty percent of the eligible patients. Rising statistics of antimicrobial resistance underscores the need for a set of completely new and more effective class of compounds with novel mechanisms of action that can be administered in combination to replace and shorten the present intensive six months regimen. In this review, we stress on the importance and the successes of phenotypic screening for discovery of anti-mycobacterial compound and discuss the importance of performing secondary screens and counter screens to get early estimate on compound's potentials for a successful development. We also highlight the recent advances and the related caveats in the assays that have been developed and discuss new screening modalities that can be incorporated during hit-selection to gain a quick insight into the mechanism of action, thus enabling quicker decisions in a hit triage. PMID- 28802405 TI - Detection of Mycobacterium tuberculosis from paraffin-embedded tissues by GeneXpert MTB/RIF. AB - GeneXpert MTB/RIF (Xpert) assay, a rapid and automated system based on real-time PCR and molecular beacon technology, proved to be a sensitive and specific tool capable of detecting Mycobacterium tuberculosis and rifampin resistance in clinical specimens. In this study we provide a Xpert-dedicated successful protocol for processing paraffin-embedded tissue and assess the feasibility of the Xpert assay-based tuberculosis (TB) diagnosis on these specimens, thus proving the Xpert assay as a valuable TB diagnostic tool in supporting conventional histopathological methods. PMID- 28802406 TI - Real-time PCR followed by high-resolution melting curve analysis: A rapid and pragmatic approach for screening of multidrug-resistant extrapulmonary tuberculosis. AB - INTRODUCTION: Multidrug resistance (MDR) in extrapulmonary tuberculosis (EPTB) is a diagnostic challenge in an endemic country like India. Timely detection of MDR TB can contribute to a better patient outcome. OBJECTIVE: To perform real-time PCR (qPCR) using rpoB, mpb64 and IS6110 gene on a variety of EPTB samples and to compare the performance of different gene targets. All qPCR positive samples were subjected to high resolution melt-curve analysis (HRM analysis) for rpoB and katG gene to evaluate its potential for MDR screening among different sample types. METHODS: Real-time PCR using rpoB, mpb64 and IS6110 genes was carried out on 200 cases of study group and 100 cases of non-TB control group. The study group consisted of 100 culture-confirmed and 100 clinically suspected cases of EPTB. Phenotypic drug susceptibility testing (DST) for culture isolates was performed by the 1% indirect agar proportion method. DNA extracted from all qPCR positive samples was subjected to rpoB and katG HRM analysis for screening of MDR. Sequencing was used to confirm the results of HRM analysis and the results were also compared with phenotypic DST in all culture positive cases. RESULTS: The sensitivity of qPCR using rpoB, mpb64 and IS6110 was 86.5%, 86.5% and 76.5%, respectively. All isolates from the control group were negative by all the three targets, giving a specificity of 100%. HRM analysis detected MDR in 22/200 (11%) isolates. 3/200 (1.5%) had mono-rifampicin resistance while 8/200 (4%) had mono isoniazid resistance. HRM analysis identified an additional 4 MDR cases directly from the samples which were negative by culture. On sequencing, mutations were observed at codon 531 (60%); 533 (16%); 516 (12%) and 526 (12%) of the rpoB gene and at codon 315 (100%) of the katG gene. There was 100% concordance in the results of phenotypic DST, HRM analysis and sequencing. CONCLUSION: The HRM analysis can play a promising role in the reliable and rapid screening of EPTB samples for detection of MDR. PMID- 28802408 TI - Down-regulation of malate synthase in Mycobacterium tuberculosis H37Ra leads to reduced stress tolerance, persistence and survival in macrophages. AB - Malate synthase is a condensing enzyme responsible for conversion of glyoxylate to malate in the presence of acetyl-CoA. This reaction helps in bypassing the TCA cycle reactions involving carbon loss and leads to diverting some of the carbon skeletons to gluconeogenic events while rest can continue to provide TCA cycle intermediates. Malate synthase (GlcB) is encoded by MRA_1848 of Mycobacterium tuberculosis H37Ra (Mtb-Ra). We developed a knockdown (KD) Mtb-Ra strain by down regulating GlcB. The survival studies suggested increased susceptibility to oxidative and nitrosative stress as well as to rifampicin. The susceptibility profile was reversed in the presence of free radical scavengers. Also, KD showed reduced biofilm maturation, failed to enter persistent state, and showed reduced growth inside macrophages. The study of post-endocytosis events showed differences in late stage endosomal maturation behavior in macrophages infected with KD compared to WT. Increased iNOS, LAMP1 and cathepsin D expression was observed in macrophages infected with KD compared to WT. PMID- 28802407 TI - Immunological characterization of latent tuberculosis infection in a low endemic country. AB - The diagnosis of a latent tuberculosis infection (LTBI) is based on detection of immunity against Mycobacterium tuberculosis (Mtb). The tuberculin skin test (TST), the Quantiferon (QFT) and a prolonged lymphocyte stimulation test using either ESAT-6/CFP-10 (LST-EC) or PPD (LST-PPD) were evaluated in a cohort of 495 individuals, suspected to have LTBI, in a low endemic country. While the TST and LST-PPD were both positive in the majority (75%) of individuals, only one third responded in the LST-EC and in the QFT. The choice for LTBI treatment was significantly associated with ESAT6/CFP10 recognition, however the LST-EC detected considerably more individuals (21%) with immunity against Mtb, who might also be at risk for development of active TB, although none of them did during follow up. Follow-up for 2 years showed 7% conversions and 32% reversions for the QFT. The LST-EC showed higher conversion rates (~45%), although the percentage of individuals positive in the LST-EC did not change significantly within the follow up period. LTBI treatment did not alter immune recognition of Mtb antigens. In conclusion, the sensitivity of tests for detection of cellular immunity to Mtb specific antigens depends on test methodology and may vary considerably over time in a low endemic region. PMID- 28802409 TI - Exploring the potential of T7 bacteriophage protein Gp2 as a novel inhibitor of mycobacterial RNA polymerase. AB - Over the past six decades, there has been a decline in novel therapies to treat tuberculosis, while the causative agent of this disease has become increasingly resistant to current treatment regimens. Bacteriophages (phages) are able to kill bacterial cells and understanding this process could lead to novel insights for the treatment of mycobacterial infections. Phages inhibit bacterial gene transcription through phage-encoded proteins which bind to RNA polymerase (RNAP), thereby preventing bacterial transcription. Gp2, a T7 phage protein which binds to the beta prime (beta') subunit of RNAP in Escherichia coli, has been well characterized in this regard. Here, we aimed to determine whether Gp2 is able to inhibit RNAP in Mycobacterium tuberculosis as this may provide new possibilities for inhibiting the growth of this deadly pathogen. Results from an electrophoretic mobility shift assay and in vitro transcription assay revealed that Gp2 binds to mycobacterial RNAP and inhibits transcription; however to a much lesser degree than in E. coli. To further understand the molecular basis of these results, a series of in silico techniques were used to assess the interaction between mycobacterial RNAP and Gp2, providing valuable insight into the characteristics of this protein-protein interaction. PMID- 28802410 TI - Evaluation of 24-locus MIRU-VNTR genotyping in Mycobacterium tuberculosis cluster investigations in four jurisdictions in the United States, 2006-2010. AB - The U.S. Centers for Disease Control and Prevention (CDC) uses a combination of spacer oligonucleotide typing (spoligotyping) and mycobacterial interspersed repetitive units-variable number of tandem repeats (MIRU-VNTR) analyses as part of the National TB Genotyping Service (NTGS). The NTGS expansion from 12-locus MIRU-VNTR (MIRU12) to 24-locus MIRU-VNTR (MIRU24) in 2009 enhanced the ability to discriminate Mycobacterium tuberculosis strains. In the current study, we investigated the MIRU24 concordance among epidemiologic-linked tuberculosis (TB) patients in four U.S. health jurisdictions. We also evaluated the programmatic benefits of combining MIRU24 and spoligotyping with epidemiologic evidence in identifying potential recent TB transmission. We examined 342 TB patients in 42 spoligotype/MIRU12 (PCRType) clusters (equivalent to 46 spoligotype/MIRU24 [GENType] clusters) to identify epidemiologic links among cases. GENType clusters, when compared to PCRType clusters, had 12 times higher odds of epidemiologic links being identified if patients were younger than 25 years and 3 times higher odds if patients resided in the same zip code, or had HIV infection. Sixty (18%) fewer PCRType-clustered patients would need investigations if clusters are defined using GENType instead of PCRType. An important advantage of defining clusters by MIRU24 is resource savings related to the reduced number of clustered cases needing investigation. PMID- 28802411 TI - The minipig as an animal model to study Mycobacterium tuberculosis infection and natural transmission. AB - In endemic countries more than 20% of tuberculosis (TB) cases are in infants and children. Current animal models study TB during adulthood but animal models for infant TB are scarce. Here we propose that minipigs can be used as an animal model to study adult, adolescent and infant TB including natural transmission. In these studies, two-month old minipigs (representing infant age in humans) and six month old minipigs (representing adolescence in humans) were infected via the aerosol route with hyper-virulent clinical strain W-Beijing Mycobacterium tuberculosis (Mtb) HN878 and were monitored for 11 or 36 weeks post-challenge, respectively. In the same studies, infected and unchallenged animals were housed together. Viable bacteria were recovered from pulmonary and thoracic lymph nodes from both -infected and their initially unchallenged natural contacts. Bacillary load, gross lesions and histopathology revealed similarities to the spectrum of disease observed in human TB. The study did not reach terminal end point, thus it was not possible to annotate definitive clinical symptoms of active TB. The results demonstrated that minipigs are experimental hosts of Mtb HN878, and the pathology developed in their lungs resembles pathological findings described in human TB. Importantly, within communities of Mtb infected minipigs natural transmission occurs. PMID- 28802413 TI - Newer trends in complex trauma and fracture nonunion. PMID- 28802412 TI - Mycobacterium tuberculosis sigE mutant ST28 used as a vaccine induces protective immunity in the guinea pig model. AB - With more than 9 million new infections and 1.5 million deaths claimed every year, tuberculosis remains one of the major scourges of humankind. The only vaccine available against this disease, the attenuated strain Mycobacterium bovis, BCG is effective against severe forms of the disease in infants, but scarcely effective in protecting adults from the pulmonary form of the disease, thus not stopping transmission. Consequently, the development of an effective anti-tuberculosis vaccine is a major goal for improving global health. The most common concept is that a more effective vaccine should include a first immunization with a live vaccine followed by the administration of an acellular boosting vaccine. In this approach, the live vaccine might be either BCG or a different, more efficient attenuated strain. Recently, we showed that a Mycobacterium tuberculosis mutant missing the gene encoding for the extracellular function sigma factor SigE, is strongly attenuated and is able to induce a more effective protection from M. tuberculosis infection compared to BCG in mice. We now further characterize the protective potential of this novel strain in the guinea pig model of tuberculosis. In the guinea pig, it had limited growth but induced a Th1 immune response and was able to significantly reduce the number of colony forming units as well as prolong survival. Taken together these data provide evidence for the use of the M. tuberculosis sigE mutant as the basis for further development as a vaccine against infection. PMID- 28802414 TI - Management of resistant distal femur non-unions with allograft strut and autografts combined with osteosynthesis in a series of 22 patients. AB - INTRODUCTION AND PURPOSE: Challenges to the surgeon in managing cases of resistant non-union of the distal femur include poor bone stock, disuse osteopenia and joint contractures. Procedures varying from simple bone grafting to megaprosthesis revision have been described. We successfully managed such cases using our technique of combining cortical allograft struts to augment the defect in the femoral condyle coupled with autogenous iliac crest bone grafting and locking plate osteosynthesis. MATERIALS AND METHODS: Between April 2012 and May 2014, 22 patients who presented with resistant nonunions of the distal femur following initial surgery were managed using this technique. Cortical allograft struts were taken from the tissue bank of our institution. All patients were followed up post operatively and their time to union was noted. Functional outcome was calculated using LEFS (Lower extremity functional score). The average follow up of all our patients was 24 months. RESULTS: All patients went on to achieve complete bony union. The average union time was 6.2 months (5 to 8 months). One patient who was a diabetic had superficial infection post operatively which was treated successfully with IV antibiotics. Average knee flexion was 110 degrees (80 to 130 degrees). The mean LEFS score was 72 (59 to 79). CONCLUSION: Combing a locking plate fixation with the bone grafting technique of using an allograft strut to support the metaphyseal medial bone defect and autografts gives a good union and a good functional outcome in the management of resistant non-unions of the distal femur by enhancing the biology and providing a good structural support to the distal femur. PMID- 28802415 TI - Augmentation of intramedullary nailing in unstable intertrochanteric fractures using cerclage wire and lag screws: a comparative study. AB - BACKGROUND: Unstable intertrochanteric fractures present a challenge to orthopaedic surgeons, with varied geometry of the fractures and a wide choice of implants and techniques. The patients are usually osteoporotic, with multiple co morbidities and poor tolerance for complications and re-operations. Lateral wall reconstruction and stability of the trochanteric fragments are considered important in providing a better outcome of these difficult injuries. We present a technique of lateral wall and trochanteric reconstruction using Cerclage wires and lag screws in the greater trochanter in addition to intramedullary nailing, and the radiological and functional outcome of this technique of augmentation. MATERIALS AND METHODS: This prospective study includes 154 patients from 2010 to 2015 presenting to the institute with an unstable intertrochanteric fracture. They were sequentially operated with intramedullary nailing (IMN) and augmentation with cerclage wire and/or Anteroposterior screw in greater trochanter, and 77 patients with IMN only. Operating time and need for blood transfusion post-surgery were documented. Patients were followed up for minimum of 12 months and radiological union time, complications and functional outcome using Harris Hip Score were noted at 1 year. Statistical analysis was performed to compare the results in both groups RESULTS: The mean union was 3.6 months in group A and 4.1 months in group B, with no statistically significant difference. The operating time needed for augmentation was 10 minutes more than IMN only. Blood transfusion was not required in any case. The incidence of complications like screw cut out, back out and non-union was lower in augmented group, and good functional outcome was greater in the augmented group which was statistically significant. The reoperation rate was lower in augmented group. CONCLUSIONS: This new technique of augmentation of fixation of intramedullary nail in unstable trochanteric fractures using cerclage wires and lag screws for lateral wall reconstruction is useful in reducing complications of the procedure and provides good radiological and functional outcome. It requires little additional operating time with minimal blood loss and soft tissue injury. PMID- 28802416 TI - Accuracy of valgus osteotomy using dynamic hip screw. AB - BACKGROUND: Non-union of neck femur is a common but difficult situation to manage especially in young adults. There are two main options of arthroplasty or osteotomy. The aim of this study was to assess the results of intertrochanteric valgus osteotomy in non-union femoral neck fractures. PATIENTS AND METHODS: We present a study of 44 cases of neck femur non-union including untreated fractures, late presentations (more than 3 weeks), treated with compression screw, DHS. From 2006-2016, 44 patients presented to our institute and we analyzed them prospectively on the following criteria: Pauwel's angle, Garden classification, union at fracture site, union at osteotomy site, osteoporosis and AVN changes. Inclusion criteria were age<65, neck not reabsorbed, no AVN. Powel's angle was calculated using the anatomic axis of femur. Wedge angle is equal to Powel's angle minus 30 degree. Entry point of DHS was at the base of greater trochanter and tip of the screw was in the inferior quadrant. Y osteotomy was done in the distal half of the lesser trochanter with a proximal straight cut. RESULTS: Complete union was noted in 93% of the cases. One patient with uncontrolled diabetes developed severe infection and was treated with excision arthoplasty. AVN occurred in 3 cases. The Powell's angle was reduced to mean 30 (22-39). The neck shaft angle was increased to mean 140 (130-150). Limp was noted in almost all patients but they were able to walk full weight bearing with or without the support of a stick. CONCLUSION: Valgus intertrochanteric osteotomy achieved good union rates and good functional outcome with minimal complications. PMID- 28802417 TI - Augmentation plating in management of failed femoral nailing. AB - INTRODUCTION: Non-union following interlocking nailing is a troubling complication in treatment of shaft femur fractures. There is no clear consensus on the treatment of this problem. This research was undertaken to study the role of augmentation plating combined with exchange nailing in such cases. PATIENTS AND METHODS: A prospective clinical study was undertaken from January 2010 to December 2015. Patients with aseptic femoral shaft non-union, with or without implant failure following intramedullary nailing were included in the study. Augmentation plating combined with Exchange Nailing with a 4.5mm LCP was done. RESULTS: Fifteen patients (nine male and six female) with an average age of 43.7 years (range 18-67 years) were treated. Average timing from the first surgery was 7.3 months. Complete clinical and radiological union was achieved in all cases in a mean duration of 5.2 months. Average duration of follow up was 12.6 months. All the patients retained the preoperative hip and knee range of motion till the last follow up. CONCLUSION: Augmentation plating combined with exchange nailing in non unions following intramedullary nailing of femur shaft fractures is a reasonably good and effective procedure with a very high success rate. PMID- 28802418 TI - Delayed presentation or delayed diagnosis? A retrospective study of prospectively collected data of 482 foot and ankle injuries. AB - BACKGROUND: Delayed presentation of injury cases is common in developing countries like India. It is prudent to study reasons for delayed presentations to focus preventive measures towards responsible factors. Since foot and ankle orthopaedics is in its infancy in India, it was deemed to be worthwhile to study reasons for delayed presentations of foot and ankle injuries. METHODS: Retrospective analysis of prospectively collected data from 482 foot and ankle injuries treated at our three foot and ankle centres over past three years was undertaken. Delayed presentation was defined as cases presenting to us at or after 3 weeks of injury, but with complete records. Reasons for delayed presentations were analysed. RESULTS: There were ninety eight such cases who fulfilled the delayed presentation criteria and within this group there were twenty different varieties of foot and ankle injuries. Of these twenty six cases were never treated by qualified orthopaedic surgeons and were labelled as direct delayed presentations, and the remaining 72 cases who were treated by qualified orthopaedic surgeons, but could not be diagnosed and presented late, were labelled as indirect delayed presentations. Failure to suspect injury (5 cases) or failure to diagnose injury (67 cases) were reasons for indirect delayed presentations. Failure to diagnose injury on part of clinicians was either due to failure of clinical and radiological analysis (analytical failure - 15 cases) or due to failure to investigate case with further radiological investigations (investigative failure - 10 cases). Forty-two cases had combined failures. CONCLUSIONS: In developing countries like India, patients did neglect their foot and ankle injuries and presented late. In fact, by way of delayed diagnosis, clinicians were more responsible for indirect delayed presentations of foot and ankle injuries. This is contrary to the common belief that in developing countries like India, only patients would be solely responsible for delayed presentations after injury. Because delayed diagnosis by clinicians seemed more alarming than delayed presentation by patients, focus of prevention of foot and ankle injuries in developing countries should shift more towards educating clinicians than patients. PMID- 28802419 TI - Recalcitrant aseptic atrophic non-union of the shaft of the humerus after failure of surgical treatment: management by excision of non-union, bone grafting and stabilization by LCP in different modes. AB - Non-union of the humeral shaft is infrequently noticed after surgical fixation. Sixty eight patients whose osteosynthesis of humeral shaft had failed leading to non-union were identified over a duration of 10 years from (January 2006 to December 2015). Clinical and radiographical follow-up was available for 64 patients (4 patients were lost for follow-up), with a mean age of 58 years (range 25-78 years). All patients had aseptic atrophic non-union of either: proximal shaft (n=12), mid shaft (n=38), and lower shaft (n=14). All these patients had failure of primary fixation, with a minimum duration from 36 to 110 weeks. Non unions were operated by excision of non-union, autogenous bone grafting and osteosynthesis by locking compression plating. Adequate fixation of non-union with bone grafting was achieved in all patients. All non-unions healed well at an average of 16 weeks (range 6-36 weeks). The mean length of follow-up was 120 weeks (range 60-250 weeks). The mean range of movements following healing of non union was forward flexion of 140 degrees , external rotation and internal rotation of 30 degrees at shoulder and average fixed flexion deformity of 10 degrees and flexion of 130 degrees at elbow. Two patients had postoperative radial nerve palsy because of neuropraxia, which recovered in eight weeks. Three patient developed superficial infections at the iliac crest, which settled with antibiotics, dressings in 3 weeks time and two patients had some discomfort over the fibular graft harvest site. In all patients complete clinical and radiological union was achieved with satisfactory outcome in terms of relief of symptoms and functional improvement in the range of movements. The main points in surgical treatment were complete excision of non-union, correction of deformity, use of plenty of corticocancellous graft, furthermore the use of intramedullary fibula and osteosynthesis by long locking compression plating in different modes of fixation provided good to excellent results and clinical outcome. PMID- 28802420 TI - DHS osteosynthesis with internal bone grafting in unstable delayed presented intracapsular neck femur fractures. AB - OBJECTIVES: The aim of this study was to assess fracture union and complications following use of dynamic hip screw (DHS) with internal bone grafting in treatment of unstable delayed presented intracapsular neck femur fractures in patients younger than 65 years of age. MATERIAL AND METHODS: Thirty two patients with displaced intracapsular neck femur fractures(Garden III and IV, Pauwels III, with comminution) with delayed presentation (15-60 days) in the 45-65 year age group (mean 54.4+/-10.2 years) were included in this study. All patients were treated with dynamic sliding hip screw with closed cancellous bone grafting through a tunnel of a triple reamer. The average time to union was 3.8 months (3-5 months). Satisfactory union was achieved in all patients except two. One case developed avascular necrosis of the femoral head. Other complications were coxa vara in two, shortening of less than 10mm in three cases but there were no cases of infection or implant failure. Excellent results were achieved in 27, good/fair in 4 and poor in 1 patient. CONCLUSION: Osteosynthesis with DHS and primary cancellous bone grafting in indicated cases is a simple, providing biological stimulation for early union. Failure in a particular case can be treated with any appropriate second procedure. PMID- 28802421 TI - Symptomatic medial humeral epicondylar fracture non-union- rare presentation of a relatively common injury. AB - BACKGROUND: Symptomatic non-union of medial humeral epicondylar fractures is a limited entity. Some studies recommend surgical excision of the fragment, but the results are controversial. The purpose of this study is to evaluate the outcome of open reduction and internal fixation of a medial epicondyle non-union fragment. MATERIALS AND METHODS: A retrospective study was conducted in all the patients, who were operated in our hospital between the year 2010 and 2015 for symptomatic medial humeral epicondyle non-union. Inclusion criteria were open reduction and internal fixation of symptomatic medial epicondyle non-union and minimum one year of follow-up from time of surgery. Exclusion criteria included other associated musculoskeletal disorders of the affected limb. Open reduction and internal fixation of the fragment was done in all patients and the ulnar nerve was decompressed and anteriorly transposed in cases where symptomatology was present. Outcome was assessed with radiograph, range/arc of motion, Visual analogue pain scoring and two functional outcome tools. RESULTS: Study sample consisted of 14 patients, with mean age at presentation of 14.9 years (range 6 to 50 years) with mean time since injury of 7.7 months (range 3 to 24 months). Patients presented with medial elbow pain and prominence, limited range of motion, valgus instability, and ulnar nerve compression. After open reduction and internal fixation, at a mean of three years after surgery (range 1.5 to 5 years), patients reported an improvement in visual analogue pain score from a mean of 7.29+/-1.3 to 0.21+/-0.4, and the difference was statistically significant (p=0.001). Mean postoperative Quick DASH (Disability of Arm, Shoulder, and Hand) score was 5.21+/-7.2. Mean Mayo Elbow Performance Score was 96.7+/-6.1. Improvement in arc of motion was statistically significant (p=0.001). Radiographic union was achieved in all patients except one who had fibrous union. Functional elbow range of motion was achieved in 13 out of 14 cases (92.8%) and ulnar nerve recovered in five patients and one patient required tendon transfer. CONCLUSION: Open reduction and internal fixation of symptomatic medial humeral epicondyle non-union gives excellent clinical and functional outcome in the majority of cases. PMID- 28802422 TI - Management of neglected ACL avulsion fractures: a case series and systematic review. AB - INTRODUCTION: Neglected tibial eminence avulsion fractures of the anterior cruciate ligament (ACL) are uncommonly seen in modern times, but are fairly common due to a missed diagnosis/mismanagement in developing countries. OBJECTIVES: To determine the outcomes after open reduction and internal fixation of late presenting ACL avulsion fractures, and to review the literature for similar cases, in an attempt to evaluate the ideal surgical management in this unique scenario. STUDY DESIGN: Retrospective observational study and systematic review MATERIALS: The study included 10 male and 2 female cases (mean age 29.9 years). Patients were assessed for the pre-operative knee range-of-motion (ROM), flexion deformity and stability; functional assessment was conducted using the Lysholm scale, both pre and post-operatively. Open reduction and internal fixation with two partially threaded screws (via a mini anterior approach) was performed in all 12 cases. All patients were clinically followed up for a minimum duration of 12 months. We searched PubMed, Embase and Cochrane databases from the period of inception to January 15, 2017 for similar case series/reports involving management of chronic/neglected ACL avulsion fractures and systematically reviewed these studies following standard PRISMA guidelines. RESULTS: The median duration of presentation after injury was 12 months (range 3 to 312 months; mean 45.3 months). The mean follow-up duration was 24.1 months (range 12-48 months). All patients achieved normal knee extension except one patient who had a residual 5 degrees flexion contracture. On physical examination, Lachman and pivot-shift tests were negative in all but 1 patient. No case required ACL reconstruction, and the fractures united radiologically within 12 weeks; all patients regained former activity levels. DISCUSSION: Eleven published studies, mainly case reports, reported on the management of chronic/neglected ACL avulsion fractures. Arthroscopic suture/wire fixation, arthroscopic debridement of avulsed fragment and open reduction, internal fixation (ORIF) with screws are the described techniques for this uncommon entity. However, anatomic reduction of ACL avulsion fractures is difficult arthroscopically as crater depth assessment and repositioning of the avulsed fragment become a problem; the avulsed fragment may also hypertrophy, and some contractures in ACL may develop. A mini-open procedure does not add to the morbidity, overcomes reduction obstacles and allows easy fixation with screws, and can be done even in centers that do not have arthroscopic experience. The key point is accurate reduction and rigid fixation, ensuring no impingement on full extension CONCLUSIONS: Mini-open fixation allows accurate, anatomic reduction and stable fixation with screws, and should be the preferred method of fixation for late presenting ACL avulsion fractures; embedding the fragment deep into the crater or size reduction are key to preventing extension deficits. PMID- 28802423 TI - Effectiveness of exchange K-nail and augmented plating in aseptic femoral diaphyseal non-union. AB - BACKGROUND: Femoral diaphyseal non-unions present difficult scenario to manage. There are multiple options but most of them still report varying incidences of failure. We combined the principles of augmented plating and exchange nailing and aim to study the effectiveness of this technique. METHOD: A retrospective study at a tertiary trauma centre was conducted. Seventy patients (60 men, 10 women), average age 40.7+/-15.27 years (range 18-81 years) with diaphyseal femoral fracture non-unions treated between July 2010 and January 2015 were reviewed. The average interval between first and the last surgery was 18.07+/-17.65 months (range 4-96 months). Forty six patients had hypertrophic non-union and 24 patients had atrophic non-union. Twenty one patients had undergone a prior surgery for non-union, 13 dynamisation, 4 bone grafting, 1 augmented plating and 3 exchange nailing. Non-unions were treated with implant removal, freshening of bone edges and exchange K-nailing and augmented plating. Autologous bone grafting and raising of osteoperiosteal flaps was done in all cases. Outcome measures were radiographic evidence of fracture union at minimum three out of four cortices, knee range of motion as compared to opposite knee, and study of complications. RESULTS: All patients demonstrated radiographic evidence of fracture union with an average time of 16.77+/-2.38 weeks (range 12-26 weeks). Mean knee range of motion of unaffected limb was 126+/-9.76 degrees (range 90-140 degrees ) while in operated limb it was 121.1+/-11.36 degrees (range 80-140 degrees ), p>0.01. Patients with hypertrophic non-unions, prior surgery for non-union and supra- or infra-isthmal non-unions had shorter union time. Two patients had superficial infection which was managed by superficial debridement and two patients had pain at proximal nail tip site which was managed by anti-inflammatory medication. None of the patients required additional surgery for implant removal. CONCLUSION: Exchange K nailing with Bone graft and additional plating technique for non-union diaphyseal femur fracture achieved good union rates with minimal complication. In our series none of the patient required revision and the technique probably will further minimise the revision rates compared to current options for non-union femur. PMID- 28802424 TI - Can antibiotic impregnated cement nail achieve both infection control and bony union in infected diaphyseal femoral non-unions? AB - BACKGROUND: Infected non-union is complex and debilitating disorder affecting orthopaedic surgeon and patient in terms of cost and time. Many methods are described in the literature for treatment of infected non-union. Local high concentration of antibiotic and mechanical stability of antibiotic cement impregnated intramedullary nail (ACIIN) proves cost and time effective. Recently it was suggested that ACIIN can achieve both union and infection control in infected non-unions with bone gap less than 4cm. The aim of our study was to investigate this hypothesis and study the outcome of antibiotic cement impregnated intramedullary nail in term of both infection control and osseous union. MATERIALS AND METHODS: We retrospectively studied 21 patients with infected diaphyseal femoral non-union. Inclusion criteria were bone gap less than 4cm after debridement and more than 1 year follow-up of the case. ACIIN prepared using K nail was used as primary procedure after adequate debridement. Infection control and osseous union was judged on the basis of clinical, radiological and haematological parameters. All patients were followed up with an average follow up of 20.23+/-3.65 months (range 14-28 months). RESULTS: Infection control was achieved in all 21 patients at end of 12 months follow-up, out of which 16 patients had osseous union and infection control without any secondary procedure. Of the remaining 5 patients: two patients had good infection control but had broken ACCIN due to non-compliance to weight bearing protocol. One patient underwent exchange nailing and plate augmentation whilst the other underwent simple exchange nailing, One more patient who had infection control but had persistent non-union had to undergo exchange nailing and augmented plating to achieve union. One other patient required debridement and implant removal and attained union and fifth patient required two additional debridements to control infection after which the fracture united. Apart from above 5 cases there were two further complications of knee stiffness. CONCLUSION: In infected non-union with bone gap less than 4cm, ACIIN can achieve both infection control and osseous union in significant number of cases. All such cases should be primarily operated with aim to achieve this outcome and use of thicker nail and ensuring proper compliance from patients regarding weight bearing will improve the outcomes. PMID- 28802425 TI - Outcomes of dynamic hip screw augmented with trochanteric wiring for treatment of unstable type A2 intertrochanteric femur fractures. AB - BACKGROUND: Posteromedial and greater trochanteric fragments are a major cause of telescoping and medialization of the femoral shaft in an unstable intertrochanteric fracture. This leads to significant limb shortening, fracture collapse in varus position and implant failure, which can be prevented by trochanteric wiring in addition to dynamic hip screw (DHS) fixation. The purpose of our study is to assess the outcomes of DHS augmented with trochanteric wiring in unstable type A2 intertrochanteric fractures. MATERIALS AND METHODS: One hundred and two retrospective cases of unstable intertrochanteric fractures treated with DHS between January 2010 and December 2015 with a minimum follow-up period of 12 months were reviewed. Out of 102 cases, 28 were treated with DHS and derotation screw alone (Group A), while in rest 74 cases trochanteric wiring was used as an augmentation to DHS and derotation screw (Group B). Patients were evaluated clinically for range of motion, Harris hip score and Oxford hip score. Radiologically, fracture reduction, change in neck shaft angle and neck length ratio in comparison to opposite hip and union status of greater trochanter were assessed. RESULTS: The mean age of the patients at the time of surgery was 72 years (range 23-94 years) with 48 males and 54 females. The mean follow-up period was 20 months (range 12-48 months). The Harris hip score, Oxford hip score, shortening, attainment of weight bearing and change in neck shaft angle was not significantly different between the two groups (all p values >0.05). Incidence of greater trochanter nonunion was greater in group A (17.85%) as compared to group B (6.75%). We found significant association between occurrence of limp with varus change in neck shaft angle, decrease in neck length ratio and greater trochanteric non-union (all p values <0.05). We had 7 complications, one superficial infection, one deep vein thrombosis, 4 screw cut out and one deep infection treated with implant removal. CONCLUSION: DHS augmented with trochanteric wiring in unstable intertrochanteric fractures gives similar result to group without no wiring, although greater trochanter non-union rate was more in the latter group. Limp can be prevented by anatomical or valgus fixation, augmentation of DHS to support posteromedial and greater trochanteric fragments and delayed weight bearing. PMID- 28802426 TI - Comparison between antegrade intramedullary nailing (IMN), open reduction plate osteosynthesis (ORPO) and minimally invasive plate osteosynthesis (MIPO) in treatment of humerus diaphyseal fractures. AB - INTRODUCTION: The three currently used methods of treatment: namely open reduction plate osteosynthesis (ORPO), Minimally invasive plate osteosynthesis (MIPO), antegrade intramedullary nailing(IMN) are all reported as satisfactory procedures for treatment of humeral shaft fractures. However none of the published reports have a comparison of superiority of one procedure over the other. We evaluated the clinical, radiological and functional outcome of the three procedures. MATERIALS AND METHODS: We studied adult patients with humerus shaft fractures over a period of 2 years from May 2014 to May 2016 in a level 1 trauma center. Forty-four were treated with IMN, 34 treated with ORPO, and 34 with MIPO. The null hypothesis tested in this study is that there is no difference between IMN, ORPO, MIPO with respect to union time, surgical time, complication rate, non-union rate and functional outcome. Functional outcome was studied by comparing the UCLA shoulder and MEP scores in the three groups. RESULTS: 112 patients were studied consisting of 83 males and 29 females with mean age of 39 years (range 18-70). IMN group showed early union with mean of 12.73 weeks compared to MIPO (14.45 weeks) and ORPO(13.58 weeks), (p<0.05). MIPO had no events of non-union, as compared to ORPO (5 non-unions) and IMN (10 non unions), (p=0.04). The range of movement at the shoulder with the UCLA score was significantly better with a score of 32.26 in MIPO as compared to 27.54 in IMN and 28.82 in ORPO (p<0.05). The difference in MEPS score in the three groups was not significant (p=0.31). IMN required a mean of 117.95 minutes intraoperatively as compared to 131 and 150.58 mins in MIPO, ORPO respectively. CONCLUSION: MIPO is overall better with respect to non-union, functional outcome and complications rate. The surgical time depends on the surgeons' skill and learning curve. Thus considering the advantages and risks involved in the various procedure and surgical acumen, each case should be individualized to have a good outcome. We advocate that MIPO can be safely used as an alternative in treating these fractures. PMID- 28802427 TI - Experimental study on visual detection for fatigue of fixed-position staff. AB - Fatigue can lead to decreased work performance and poorer safety and health condition. Fatigue is ubiquitous in production and in life, while the research on it is mainly concentrated in the automotive driving, aircraft piloting and other fields, and it is insufficient to study on the fatigue of fixed-position staff. This paper puts forward a non-contact visual image method, which can monitor the extent of fatigue of fixed-position staff. Fatigue threshold used in judgment is obtained by processing the recorded data of visual images of the experimental subjects when fatiguing and by analyzing eye closure time, percentage of eyelid closure (PERCLOS) value, frequency and number of blinks. The results show that there is significant difference among the four indicators before and after experiment subjects undergo fatigue. The fatigue of experimental subjects is obvious when eye closure time is 3.5 s/min, PERCLOS value 6%, and blink frequency 0.4 times/s. This provides a reference for a wider range of detection of fatigue and a method for avoiding mistakes and accidents. PMID- 28802428 TI - Changes in trunk sway of quay crane operators during work shift: A possible marker for fatigue? AB - This study investigated changes in task-induced trunk sway of quay crane operators during a four-hour shift performed in a dedicated simulator as an indicator of postural control system effectiveness. Using a pressure sensitive mat placed on the seat pan, center-of-pressure (COP) time series were acquired and processed to calculate sway area, path length and COP displacements and velocities. The results show a well-defined linear trend for sway path and area, with significant increases starting from 65 to 155 min of work respectively. This indicates non-optimized trunk control most likely originated by the combination of physical and cognitive workload and suggests a possible role of long-term monitoring of trunk sway of crane operators as a useful tool in detecting non optimized movements potentially associated with deteriorating performance. PMID- 28802430 TI - Digital, analogue, or redundant speedometers for truck driving: Impact on visual distraction, efficiency and usability. AB - Existing literature does not draw conclusions as to which speedometer type is better for truck driving. A digital speedometer would be more beneficial when obtaining absolute and relative readings, while an analogue speedometer would be more efficient and less distracting when detecting dynamic speed changes. Redundant speedometers, which simultaneously present digital and analogue speedometers, appear increasingly in vehicles, but no information is available on their ergonomic qualities. This study compared three speedometers: digital speedometers, analogue speedometers, and redundant speedometers. This study compared the efficiency, usability and visual distraction measures for all three types of speedometers in a simulated truck driving setting. The task-dependant results were confirmed for the digital and analogue speedometer. The redundant speedometer combined the benefits of each type presented separately, which highlights interesting theoretical and applied implications. PMID- 28802429 TI - Paramedics' working strategies while loading a stretcher into an ambulance. AB - For paramedics, loading a stretcher into an ambulance is an activity with a high risk of back injury and accidents. The objective of this study was to document strategies paramedics use at work while loading a powered stretcher into an ambulance. A total of 249 stretcher loading operations performed by 58 paramedics, and 51 semistructured post-intervention interviews were analyzed. Almost three quarters of loading operations required additional actions (e.g., raising the shoulders and additional lifting) to insert the stretcher into the cot fastener system in the ambulance. Some strategies that were necessary to complete the stretcher loading operation seemed to have negative impacts on the workers' health, such as repositioning the stretcher. This action wastes time and requires significant physical efforts, as it is usually done alone. This study suggests some potential solutions, related to equipment, training, workers and work organization, to reduce the risk of injury while loading stretchers. PMID- 28802431 TI - Ankle restrictive firefighting boots alter the lumbar biomechanics during landing tasks. AB - Firefighters incur high incidences of lower back and body injuries. Firefighting boots, with specific design requirements, have been shown to reduce ankle range of motion. This reduction has been associated with impaired force dissipation and lower body kinematic alterations. Thus, the aim of this study was to determine the relationship between firefighting boots, lumbar biomechanics and load carriage during landing. Our data indicates that when wearing firefighting boots, lumbar forces increased and kinematics changed in frontal and transverse planes. These changes may be occurring due to the restrictive shaft of the firefighting boot reducing ankle range of motion. Comparisons between unloaded and loaded conditions also showed increased changes in lumbar biomechanics, independent of footwear worn. Therefore, wearing firefighting boots, in addition to operational loading, may be placing firefighters at greater risk of lumbar injuries. Future research investigating firefighting boots and additional load carriage on lower body biomechanics during landing is recommended. PMID- 28802432 TI - Thirty years of anthropometric changes relevant to the width and depth of transportation seating spaces, present and future. AB - This paper reports the results of an investigation into changes in body shape anthropometry over the past several decades and discusses the impact of those changes on seating in transport, especially airliners. Changes in some body shape dimensions were confirmed in a sample of students at TU Delft; several of the changes, e.g. hip breadth, seated, are relevant to the ongoing design of seating. No change in buttock knee length was observed. The fit between current user anthropometry and current airline seat design, especially regarding seat width, was investigated. A comparison of the average current seat breadth with global anthropometric data suggests that accommodation may be problematic, with less than optimal width for passengers' shoulder and elbow widths. PMID- 28802433 TI - A survey of the prevalence of fatigue, its precursors and individual coping mechanisms among U.S. manufacturing workers. AB - Advanced manufacturing has resulted in significant changes on the shop-floor, influencing work demands and the working environment. The corresponding safety related effects, including fatigue, have not been captured on an industry-wide scale. This paper presents results of a survey of U.S. manufacturing workers for the: prevalence of fatigue, its root causes and significant factors, and adopted individual fatigue coping methods. The responses from 451 manufacturing employees were analyzed using descriptive data analysis, bivariate analysis and Market Basket Analysis. 57.9% of respondents indicated that they were somewhat fatigued during the past week. They reported the ankles/feet, lower back and eyes were frequently affected body parts and a lack of sleep, work stress and shift schedule were top selected root causes for fatigue. In order to respond to fatigue when it is present, respondents reported coping by drinking caffeinated drinks, stretching/doing exercises and talking with coworkers. Frequent combinations of fatigue causes and individual coping methods were identified. These results may inform the design of fatigue monitoring and mitigation strategies and future research related to fatigue development. PMID- 28802434 TI - Evaluation of postural sway and impact forces during ingress and egress of scissor lifts at elevations. AB - Workers are at risk when entering (ingress) or exiting (egress) elevated scissor lifts. In this study, we recorded ground impact forces and postural sway from 22 construction workers while they performed ingress and egress between a scissor lift and an adjacent work surface with varying conditions: lift opening designs, horizontal and vertical gaps, and sloped work surfaces. We observed higher peak ground shear forces when using a bar-and-chain opening, with larger horizontal gap, with the lift surface more than 0.2 m below the work surface, and presence of a sloped (26 degrees ) work surface. Similar trends were observed for postural sway, except that the influence of vertical distance was not significant. To reduce slip/trip/fall risk and postural sway of workers while ingress or egress of an elevated scissor lift, we suggest scissor lifts be equipped with a gate type opening instead of a bar-and-chain design. We also suggest the lift surface be placed no more than 0.2 m lower than the work surface and the horizontal gap between lift and work surfaces be as small as possible. Selecting a non-sloped surface to ingress or egress a scissor lift is also preferred to reduce risk. PMID- 28802435 TI - Gait characteristics in women's safety shoes. AB - Although workers in Japan are required to wear safety footwear, there is concern about occupational accidents that occur when wearing safety shoes. This study aimed to analyze the effect of wearing hardsoled safety shoes on both spatiotemporal gait characteristics and the muscle activity in the lower extremities. Seventeen young women participated in this study. A 5-m gait trial and a surface electromyography trial were conducted while the women walked in either safety shoes or sports shoes. Paired t-tests were performed to analyze the differences in gait characteristics when walking in the two different pairs of shoes. Walking in safety shoes was associated with a significant increase in vastus lateralis, biceps femoris and tibialis anterior activity. This increased muscle activity in the lower extremities is likely compensating for the lower flexibility of the safety shoes. PMID- 28802436 TI - Quantifying the cognitive cost of laparo-endoscopic single-site surgeries: Gaze based indices. AB - BACKGROUND: Despite the growing interest concerning the laparo-endoscopic single site surgery (LESS) procedure, LESS presents multiple difficulties and challenges that are likely to increase the surgeon's cognitive cost, in terms of both cognitive load and performance. Nevertheless, there is currently no objective index capable of assessing the surgeon cognitive cost while performing LESS. We assessed if gaze-based indices might offer unique and unbiased measures to quantify LESS complexity and its cognitive cost. We expect that the assessment of surgeon's cognitive cost to improve patient safety by measuring fitness-for-duty and reducing surgeons overload. METHODS: Using a wearable eye tracker device, we measured gaze entropy and velocity of surgical trainees and attending surgeons during two surgical procedures (LESS vs. multiport laparoscopy surgery [MPS]). None of the participants had previous experience with LESS. They performed two exercises with different complexity levels (Low: Pattern Cut vs. High: Peg Transfer). We also collected performance and subjective data. RESULTS: LESS caused higher cognitive demand than MPS, as indicated by increased gaze entropy in both surgical trainees and attending surgeons (exploration pattern became more random). Furthermore, gaze velocity was higher (exploration pattern became more rapid) for the LESS procedure independently of the surgeon's expertise. Perceived task complexity and laparoscopic accuracy confirmed gaze-based results. CONCLUSION: Gaze-based indices have great potential as objective and non intrusive measures to assess surgeons' cognitive cost and fitness-for-duty. Furthermore, gaze-based indices might play a relevant role in defining future guidelines on surgeons' examinations to mark their achievements during the entire training (e.g. analyzing surgical learning curves). PMID- 28802437 TI - Effects of cursor freeze time on the performance of older adult users on mouse related tasks. AB - This study determines the optimum range of cursor freeze time (CFT) for basic target acquisition tasks. The effect of five levels of CFT was measured on double clicking, clicking, and drag-and-drop operations, along with the inconvenience perceived by users at these levels. Older adult users find these standard mouse operations challenging because of slipping and accidental cursor movement. In this study, 24 older adult participants (13 males and 11 females) performed the abovementioned tasks repeatedly across five levels of CFT (0, 200, 400, 600, and 800 ms) and rated their perceived inconvenience at each level. CFT was found to have a significant effect on the three basic target acquisition tasks as well as the inconvenience perceived by participants. Performance on the drag-and-drop task was negatively influenced when the CFT was increased from 600 to 800 ms. The analysis suggests that a CFT of 200-400 ms is the optimum range for improved performance on the tasks. PMID- 28802438 TI - Investigation of index finger triggering force using a cadaver experiment: Effects of trigger grip span, contact location, and internal tendon force. AB - A cadaver study was conducted to investigate the effects of triggering conditions (trigger grip span, contact location, and internal tendon force) on index finger triggering force and the force efficiency of involved tendons. Eight right human cadaveric hands were employed, and a motion simulator was built to secure and control the specimens. Index finger triggering forces were investigated as a function of different internal tendon forces (flexor digitorum profundus + flexor digitorum superficialis = 40, 70, and 100 N), trigger grip spans (40, 50, and 60 mm), and contact locations between the index finger and a trigger. Triggering forces significantly increased when internal tendon forces increased from 40 to 100 N. Also, trigger grip spans and contact locations had significant effects on triggering forces; maximum triggering forces were found at a 50 mm span and the most proximal contact location. The results revealed that only 10-30% of internal tendon forces were converted to their external triggering forces. PMID- 28802439 TI - Does this range suit me? Range satisfaction of battery electric vehicle users. AB - User satisfaction is a vital design criterion for sustainable systems. The present research aimed to understand factors relating to individually perceived range satisfaction of battery electric vehicle (BEV) users. Data from a large scale BEV field trial (N = 72) were analyzed. Apart from an initial drop in range satisfaction, increasing practical experience was related to increased range satisfaction. Classical indicators of users' mobility profiles (daily travel distances) were only weakly related to lower range satisfaction (not significant), after controlling for practical experience and preferred coverage of mobility needs. The regularity/predictability of users' mobility patterns, the percentage of journeys not coverable because of range issues, and users' individual comfortable range accounted for variance in range satisfaction. Finally, range satisfaction was related to key indicators of general BEV acceptance (e.g., purchase intentions). These results underline the complex dynamics involved in individual range satisfaction, as well as its central role for BEV acceptance. PMID- 28802440 TI - Debiasing visual pilots' weather-related decision making. AB - Pilots who decide to continue a flight into deteriorating weather conditions, rather than turn back or divert, are a significant cause of fatal crashes in general aviation. Earlier research has suggested that cognitive biases such as the anchoring effect and confirmation bias are implicated in many decisions to continue into worsening weather. In this study, we explored whether a simple debiasing technique, 'considering the alternative', reduced the effect of these two potentially fatal biases. Despite the study being adequately powered, our attempts to reduce the effects of biases were both unsuccessful. Negative findings such as these are particularly useful in aviation, as they can provide information on what does not work in this high stakes industry, even though such strategies may work elsewhere. PMID- 28802441 TI - Validity and reliability of the HEMPA method for patient handling assessment. AB - Specific methods currently exist to assess occupational hazards resulting from patient handling in the healthcare sector, according to ISO/TR 12296. They are all similar in nature, but with a different analysis perspective; for that reason a comparison of the most relevant methods was performed in a previous research. As a result, a basis of a new tool that integrates the complementary aspects of those methods was proposed. To verify the validity and reliability of that method, a study within a hospital setting was carried out in five medical and surgical units of a public health institution. Based on the obtained results, the analysed method (called HEMPA) proved to be valid and reliable. Also, this method reflects a positive correlation between risk and damage and correctly quantifies risks regarding patient's dependence. PMID- 28802442 TI - The duration perception of loading applications in smartphone: Effects of different loading types. AB - The loading time of a smartphone application is an important issue, which affects the satisfaction of phone users. This study evaluated the effects of black loading screen (BLS) and animation loading screen (ALS) during application loading on users' duration perception and satisfaction. A total of 43 volunteers were enrolled. They were asked to complete several tasks by clicking the icons of each application, such as camera or message. The duration of loading time for each application was manipulated. The participants were asked to estimate the duration, evaluate the loading speed and their satisfaction. The results showed that the estimated duration increased and the satisfaction for loading period declined along with the loading time increased. Compared with the BLS, the ALS prolonged the estimated duration, and lowered the evaluation of speed and satisfaction. We also discussed the tendency and key inflection points of the curves involving the estimated duration, speed evaluation and satisfaction with the loading time. PMID- 28802443 TI - Controlling robots in the home: Factors that affect the performance of novice robot operators. AB - For robots to successfully integrate into everyday life, it is important that they can be effectively controlled by laypeople. However, the task of manually controlling mobile robots can be challenging due to demanding cognitive and sensorimotor requirements. This research explores the effect that the built environment has on the manual control of domestic service robots. In this study, a virtual reality simulation of a domestic robot control scenario was developed. The performance of fifty novice users was evaluated, and their subjective experiences recorded through questionnaires. Through quantitative and qualitative analysis, it was found that untrained operators frequently perform poorly at navigation-based robot control tasks. The study found that passing through doorways accounted for the largest number of collisions, and was consistently identified as a very difficult operation to perform. These findings suggest that homes and other human-orientated settings present significant challenges to robot control. PMID- 28802444 TI - Identifying the critical physical demanding tasks of paramedic work: Towards the development of a physical employment standard. AB - Public safety related occupations including police, fire and military commonly apply physical employment standard (PES) to facilitate job matching, an approach to evaluate if candidates demonstrate acceptable physical capabilities as required to perform the job safely and effectively. In Canada, paramedics remain as one of the few public safety occupations without an evidence-based, validated PES. The purpose of this study was to document and describe the physical demands of paramedic work and to identify the most physically demanding tasks. These outcomes are essential to inform the design and development of an evidence-based PES for the paramedic sector. Physical demands of paramedic work were documented and described using a direct observation-based task analysis technique. Five paramedic's were trained to document the physical demands of their work, then applied their training to observe more than 90 calls over the course of 20 full 12-h work shifts. Physical demands data were then listed in a survey, administered service-wide, where 155 frontline paramedics identified critically demanding tasks and rank-ordered physical demands from not physically demanding to very strongly demanding. Critically important and physically demanding tasks were identified such as: transferring a patient; loading or unloading a stretcher in to or out of the ambulance; performing CPR; and, raising and lowering a stretcher. It is important that a paramedic-based PES evaluate a candidate's physical capabilities to perform the critical and physically demanding tasks identified in this study. PMID- 28802445 TI - The Dibber: Designing a standardised handheld tool for lay-up tasks. AB - We present an application of engineering and ergonomics principles in the design of a standardised tool, The Dibber, which is a tool with multiple geometric features to fit the diversity of lay-up tasks used in the composites industry. The Dibber is the result of a design process, which consists of a series of observations and prototyping to extract geometric requirements for lay-up tasks. To demonstrate that it is possible to design a standardised tool prototypes of the Dibber were distributed and 91 participants gave feedback. Our results are positive and show consistent patterns of use across industry sectors, as well as between novice and expert laminators. PMID- 28802446 TI - Toward a process-level view of distributed healthcare tasks: Medication management as a case study. AB - We aim to highlight the importance of using a process-level view in analyzing distributed healthcare tasks through a case study analysis of medication management (MM). MM during older adults' hospital-to-skilled-home-healthcare (SHHC) transitions is a healthcare process with tasks distributed across people, organizations, and time. MM has typically been studied at the task level, but a process-level is needed to fully understand and improve MM during transitions. A process-level view allows for a broader investigation of how tasks are distributed throughout the work system through an investigation of interactions and the resultant emergent properties. We studied MM during older adults' hospital-to-SHHC transitions through interviews and observations with 60 older adults, their 33 caregivers, and 79 SHHC providers at 5 sites associated with 3 SHHC agencies. Study findings identified key cross-system characteristics not observable at the task-level: (1) identification of emergent properties (e.g., role ambiguity, loosely-coupled teams performing MM) and associated barriers; and (2) examination of barrier propagation across system boundaries. Findings highlight the importance of a process-level view of healthcare delivery occurring across system boundaries. PMID- 28802447 TI - Development of a press and drag method for hyperlink selection on smartphones. AB - The present study developed a novel touch method for hyperlink selection on smartphones consisting of two sequential finger interactions: press and drag motions. The novel method requires a user to press a target hyperlink, and if a touch error occurs he/she can immediately correct the touch error by dragging the finger without releasing it in the middle. The method was compared with two existing methods in terms of completion time, error rate, and subjective rating. Forty college students participated in the experiments with different hyperlink sizes (4-pt, 6-pt, 8-pt, and 10-pt) on a touch-screen device. When hyperlink size was small (4-pt and 6-pt), the novel method (time: 826 msec; error: 0.6%) demonstrated better completion time and error rate than the current method (time: 1194 msec; error: 22%). In addition, the novel method (1.15, slightly satisfied, in 7-pt bipolar scale) had significantly higher satisfaction scores than the two existing methods (0.06, neutral). PMID- 28802448 TI - User perception and interpretation of tornado probabilistic hazard information: Comparison of four graphical designs. AB - Effective design for presenting severe weather information is important to reduce devastating consequences of severe weather. The Probabilistic Hazard Information (PHI) system for severe weather is being developed by NOAA National Severe Storms Laboratory (NSSL) to communicate probabilistic hazardous weather information. This study investigates the effects of four PHI graphical designs for tornado threat, namely, "four-color"," red-scale", "grayscale" and "contour", on users' perception, interpretation, and reaction to threat information. PHI is presented on either a map background or a radar background. Analysis showed that the accuracy was significantly higher and response time faster when PHI was displayed on map background as compared to radar background due to better contrast. When displayed on a radar background, "grayscale" design resulted in a higher accuracy of responses. Possibly due to familiarity, participants reported four-color design as their favorite design, which also resulted in the fastest recognition of probability levels on both backgrounds. Our study shows the importance of using intuitive color-coding and sufficient contrast in conveying probabilistic threat information via graphical design. We also found that users follows a rational perceiving-judging-feeling-and acting approach in processing probabilistic hazard information for tornado. PMID- 28802449 TI - Living with an autonomous spatiotemporal home heating system: Exploration of the user experiences (UX) through a longitudinal technology intervention-based mixed methods approach. AB - Rising energy demands place pressure on domestic energy consumption, but savings can be delivered through home automation and engaging users with their heating and energy behaviours. The aim of this paper is to explore user experiences (UX) of living with an automated heating system regarding experiences of control, understanding of the system, emerging thermal behaviours, and interactions with the system as this area is not sufficiently researched in the existing homes setting through extended deployment. We present a longitudinal deployment of a quasi-autonomous spatiotemporal home heating system in three homes. Users were provided with a smartphone control application linked to a self-learning heating algorithm. Rich qualitative and quantitative data presented here enabled a holistic exploration of UX. The paper's contribution focuses on highlighting key aspects of UX living with an automated heating systems including (i) adoption of the control interface into the social context, (ii) how users' vigilance in maintaining preferred conditions prevailed as a better indicator of system over ride than gross deviation from thermal comfort, (iii) limited but motivated proactivity in system-initiated communications as best strategy for soliciting user feedback when inference fails, and (iv) two main motivations for interacting with the interface - managing irregularities when absent from the house and maintaining immediate comfort, latter compromising of a checking behaviour that can transit to a system state alteration behaviour depending on mismatches. We conclude by highlighting the complex socio-technical context in which thermal decisions are made in a situated action manner, and by calling for a more holistic, UX-focused approach in the design of automated home systems involving user experiences. PMID- 28802450 TI - The effect of motor task precision on pupil diameter. AB - It is well established that an increase in cognitive task demands is associated with increased pupil diameter. However, the effect of increased motor task demands on pupil diameter is less clear. Previous research indicates that higher motor task complexity increases pupil diameter but suggests that higher motor task precision demands may decrease pupil diameter during task movement. The current study investigated the effect of increased motor task precision on pupil diameter using a Fitts' Law movement task to manipulate motor response precision. Increased precision demands were associated with reduced pupil diameter during the response preparation and response execution phases of the movement trials. This result has implications for the interpretation of pupil diameter as an index of workload during tasks which involve precise motor movements. PMID- 28802451 TI - More than the Useful Field: Considering peripheral vision in driving. AB - Applied research on driving and basic vision research have held similar views on central, fovea-based vision as the core of visual perception. In applied work, the concept of the Useful Field, as determined by the Useful Field of View (UFOV) test, divides vision between a "useful" region towards the center of the visual field, and the rest of the visual field. While compelling, this dichotomization is at odds with findings in vision science which demonstrate the capabilities of peripheral vision. In this paper, we examine driving research from this new perspective, and argue for the need for an updated understanding of how drivers acquire information about their operating environment using peripheral vision. The concept of the Useful Field and the UFOV test are not discarded; instead we discuss their strengths, limitations, and future directions. We discuss key findings from vision science on peripheral vision, and a theory that provides insights into its capabilities and limitations. This more complete basic science understanding of peripheral vision informs appropriate use of the UFOV and the Useful Field in driving research going forward. PMID- 28802452 TI - Connoted hazard and perceived importance of fluorescent, neon, and standard safety colors. AB - OBJECTIVE: The perceived hazard and rated importance of standard safety, fluorescent, and neon colors are investigated. BACKGROUND: Colors are used in warnings to enhance hazard communication. Red has consistently been rated as the highest in perceived hazard. Orange, yellow, and black are the next highest in connoted hazard; however, there is discrepancy in their ordering. Safety standards, such as ANSI Z535.1, also list colors to convey important information, but little research has examined the perceived importance of colors. In addition to standard safety colors, fluorescent colors are more commonly used in warnings. Understanding hazard and importance perceptions of standard safety and fluorescent colors is necessary to create effective warnings. METHODS: Ninety participants rated and ranked a total of 33 colors on both perceived hazard and perceived importance. RESULTS: Rated highest were the safety red colors from the American National Standard Institute (ANSI), International Organization for Standardization (ISO), and Federal Highway Administration (FHWA) together with three fluorescent colors (orange, yellow, and yellow-green) from 3 M on both dimensions. Rankings were similar to ratings except that fluorescent orange was the highest on perceived hazard, while fluorescent orange and safety red from the ANSI were ranked as the highest in perceived importance. CONCLUSION: Fluorescent colors convey hazard and importance levels as high as the standard safety red colors. APPLICATION: Implications for conveying hazard and importance in warnings through color are discussed. PMID- 28802453 TI - The effects of luminance contrast, colour combinations, font, and search time on brand icon legibility. AB - This study explored and identified the effects of luminance contrast, colour combinations, font, and search time on brand icon legibility. A total of 108 participants took part in the experiment. As designed, legibility was measured as a function of the following independent variables: four levels of luminance contrast, sixteen target/background colour combinations, two fonts, and three search times. The results showed that a luminance contrast of 18:1 provided readers with the best legibility. Yellow on black, yellow on blue, and white on blue were the three most legible colour combinations. One of this study's unique findings was that colour combinations may play an even more important role than luminance contrast in the overall legibility of brand icon design. The 12-s search time corresponded with the highest legibility. Arial font was more legible than Times New Roman. These results provide some guidance for brand icon and product advertisement design. PMID- 28802454 TI - A novel low-cost solution for driving assessment in individuals with and without disabilities. AB - Brake reaction time is a key component to studying driving performance and evaluating fitness to drive. Although commercial simulators can measure brake reaction time, their cost remains a major barrier to clinical access. Therefore, we developed open-source software written in C-sharp (C#) for measuring driving related reaction times, which includes a subject-controlled vehicle with straight line dynamics and several testing scenarios. The software measures both simple and cognitive load based reaction times and can use any human interface device compliant steering wheel and pedals. Measures from the software were validated against a commercial simulator and tested for reproducibility. Further, experiments were performed using hand controls in both able-bodied and spinal cord injured patients to determine clinical feasibility for disabled populations. The software demonstrated high validity when measuring brake reaction times, showed excellent test-retest reliability, and was sensitive enough to determine significant brake reaction time differences between able-bodied and spinal cord injured subjects. These results indicate that the proposed simulator is a simple and feasible low-cost solution to perform brake reaction time tests and evaluate fitness to drive. PMID- 28802455 TI - From control to causation: Validating a 'complex systems model' of running related injury development and prevention. AB - INTRODUCTION: There is a need for an ecological and complex systems approach for better understanding the development and prevention of running-related injury (RRI). In a previous article, we proposed a prototype model of the Australian recreational distance running system which was based on the Systems Theoretic Accident Mapping and Processes (STAMP) method. That model included the influence of political, organisational, managerial, and sociocultural determinants alongside individual-level factors in relation to RRI development. The purpose of this study was to validate that prototype model by drawing on the expertise of both systems thinking and distance running experts. MATERIALS AND METHODS: This study used a modified Delphi technique involving a series of online surveys (December 2016- March 2017). The initial survey was divided into four sections containing a total of seven questions pertaining to different features associated with the prototype model. Consensus in opinion about the validity of the prototype model was reached when the number of experts who agreed or disagreed with survey statement was >=75% of the total number of respondents. RESULTS: A total of two Delphi rounds was needed to validate the prototype model. Out of a total of 51 experts who were initially contacted, 50.9% (n = 26) completed the first round of the Delphi, and 92.3% (n = 24) of those in the first round participated in the second. Most of the 24 full participants considered themselves to be a running expert (66.7%), and approximately a third indicated their expertise as a systems thinker (33.3%). After the second round, 91.7% of the experts agreed that the prototype model was a valid description of the Australian distance running system. CONCLUSION: This is the first study to formally examine the development and prevention of RRI from an ecological and complex systems perspective. The validated model of the Australian distance running system facilitates theoretical advancement in terms of identifying practical system-wide opportunities for the implementation of sustainable RRI prevention interventions. This 'big picture' perspective represents the first step required when thinking about the range of contributory causal factors that affect other system elements, as well as runners' behaviours in relation to RRI risk. PMID- 28802456 TI - Can a smart chair improve the sitting behavior of office workers? AB - Prolonged sitting can cause health problems and musculoskeletal discomfort. There is a need for objective and non-obstructive means of measuring sitting behavior. A 'smart' office chair can monitor sitting behavior and provide tactile feedback, aiming to improve sitting behavior. This study aimed to investigate the effect of the feedback signal on sitting behavior and musculoskeletal discomfort. In a 12 week prospective cohort study (ABCB design) among office workers (n = 45) was measured sitting duration and posture, feedback signals and musculoskeletal discomfort. Between the study phases, small changes were observed in mean sitting duration, posture and discomfort. After turning off the feedback signal, a slight increase in sitting duration was observed (10 min, p = 0.04), a slight decrease in optimally supported posture (2.8%, p < 0.01), and musculoskeletal discomfort (0.8, p < 0.01) was observed. We conclude that the 'smart' chair is able to monitor the sitting behavior, the feedback signal, however, led to small or insignificant changes. PMID- 28802457 TI - Reducing the impact of speed dispersion on subway corridor flow. AB - The rapid increase in the volume of subway passengers in Beijing has necessitated higher requirements for the safety and efficiency of subway corridors. Speed dispersion is an important factor that affects safety and efficiency. This paper aims to analyze the management control methods for reducing pedestrian speed dispersion in subways. The characteristics of the speed dispersion of pedestrian flow were analyzed according to field videos. The control measurements which were conducted by placing traffic signs, yellow marking, and guardrail were proposed to alleviate speed dispersion. The results showed that the methods of placing traffic signs, yellow marking, and a guardrail improved safety and efficiency for all four volumes of pedestrian traffic flow, and the best-performing control measurement was guardrails. Furthermore, guardrails' optimal position and design measurements were explored. The research findings provide a rationale for subway managers in optimizing pedestrian traffic flow in subway corridors. PMID- 28802458 TI - Semantic distance as a critical factor in icon design for in-car infotainment systems. AB - In-car infotainment systems require icons that enable fluent cognitive information processing and safe interaction while driving. An important issue is how to find an optimised set of icons for different functions in terms of semantic distance. In an optimised icon set, every icon needs to be semantically as close as possible to the function it visually represents and semantically as far as possible from the other functions represented concurrently. In three experiments (N = 21 each), semantic distances of 19 icons to four menu functions were studied with preference rankings, verbal protocols, and the primed product comparisons method. The results show that the primed product comparisons method can be efficiently utilised for finding an optimised set of icons for time critical applications out of a larger set of icons. The findings indicate the benefits of the novel methodological perspective into the icon design for safety critical contexts in general. PMID- 28802459 TI - Head, trunk and arm posture amplitude and variation, muscle activity, sedentariness and physical activity of 3 to 5 year-old children during tablet computer use compared to television watching and toy play. AB - Young children (ages 3 to 5) are using mobile touchscreen technology, including tablet computers, yet little is known on the potential musculoskeletal and physical activity implications of its use. This within-subject laboratory study (n = 10) examined head, trunk and arm postures, upper trapezius muscle activity, and total body and upper limb physical activity during playing with tablets compared to during TV watching and playing with non-screen toys. Overall, this study found that during tablet play children had greater mean head, trunk and upper arm angles compared to both TV watching and toy play. Conversely, compared to toy play, children playing with tablets had lesser trunk, upper arm and elbow postural variation, lesser trapezius activity, more time sitting and lesser physical activity. Thus, to minimize potential musculoskeletal and sedentary risks, non-screen toy play should be encouraged and education and guidelines provided for parents and caretakers to support wise use of tablets. PMID- 28802460 TI - Are the warning icons more attentional? AB - The rapid growth of attention to visual warnings is a representation of the adaptive behavior of humans. However, the ways warning icons attract attention in the cognition context has yet to be clarified. This research aims to investigate cognitive mechanism of warning icons under various perceptual loads. The results of Experiment A, whose average attentional capture effect of the warning icons (69 ms) was significantly higher than that of the ordinary icons (35 ms), show that compared with ordinary icons, warning icons are prioritized in processing under both high and low perceptual loads. Besides, the attention capturing abilities of non-target warning icons are the same under high and low perceptual loads. To isolate the effects of salient visual features and semantics, warning icons in Experiment B are replaced with transposed icons with saliency but no semantics. The attentional capture effect of warning icons is found to be significantly smaller under high load than under low load, so the effect in Experiment A can be attributed to the semantics of warning icons. In Experiment C the icons of negative and neutral semantics without salient frames are used as interfering stimuli, and the RT to the negative icons (823 ms) was longer than both the RT to the neutral icons (780 ms) and to the no interference icons (743 ms) (P < 0.001), which show that negative icons have stronger attention capturing ability than neutral icons. This research verifies that the semantics of icons is vital, and icons with salient visual features and negative semantics can enhance attentional capture effect. PMID- 28802461 TI - Applying fractal analysis to pupil dilation for measuring complexity in a process monitoring task. AB - This laboratory experiment was designed to use fractal dimension as a new method to analyze pupil dilation to evaluate the level of complexity in a multitasking environment. By using the eye-head integrated tracking system, we collected both pupil responses and head positions while participants conducted both process monitoring task and Multi-Attribute Task Battery (MATB-II) tasks. There was a significant effect of scenario complexity on a composite index of multitasking performance (Low Complexity " High Complexity). The fractal dimension of pupil dilation was also significantly influenced by complexity. The results clearly showed that the correlation between pupil dilation and multitasking performance was stronger when the pupil data was analyzed by using the fractal dimension method. The participants showed a higher fractal dimension when they performed a low complexity multitasking scenario. The findings of this research help us to advance our understanding of how to evaluate the complexity level of real-world applications by using pupillary responses. PMID- 28802462 TI - Driver performance and attention allocation in use of logo signs on freeway exit ramps. AB - The objective of this research was to quantify the effects of driver age, ramp signage configuration, including number of panels, logo format and sign familiarity, on driver performance and attention allocation when exiting freeways. Sixty drivers participated in a simulator study and analysis of variance models were used to assess response effects of the controlled manipulations. Results revealed elderly drivers to demonstrate worse performance and conservative control strategies as compared to middle-aged and young drivers. Elderly drivers also exhibited lower off-road fixation frequency and shorter off road glance durations compared to middle-aged and young drivers. In general, drivers adopted a more conservative strategy when exposed to nine-panel signs as compared to six-panel signs and were more accurate in target detection when searching six-panels vs. nine and with familiar vs. unfamiliar logos. These findings provide an applicable guide for agency design of freeway ramp signage accounting for driver demographics. PMID- 28802463 TI - Improving long term driving comfort by taking breaks - How break activity affects effectiveness. AB - During long duration journeys, drivers are encouraged to take regular breaks. The benefits of breaks have been documented for safety; breaks may also be beneficial for comfort. The activity undertaken during a break may influence its effectiveness. Volunteers completed 3 journeys on a driving simulator. Each 130 min journey included a 10 min break after the first hour. During the break volunteers either stayed seated, left the simulator and sat in an adjacent room, or took a walk on a treadmill. The results show a reduction in driver discomfort during the break for all 3 conditions, but the effectiveness of the break was dependent on activity undertaken. Remaining seated in the vehicle provided some improvement in comfort, but more was experienced after leaving the simulator and sitting in an adjacent room. The most effective break occurred when the driver walked for 10 min on a treadmill. The benefits from taking a break continued until the end of the study (after a further hour of driving), such that comfort remained the best after taking a walk and worst for those who remained seated. It is concluded that taking a break and taking a walk is an effective method for relieving driving discomfort. PMID- 28802464 TI - Mirage events & driver haptic steering alerts in a motion-base driving simulator: A method for selecting an optimal HMI. AB - This paper describes a new method, a 'mirage scenario,' to support formative evaluation of driver alerting or warning displays for manual and automated driving. This method provides driving contexts (e.g., various Times-To-Collision (TTCs) to a lead vehicle) briefly presented and then removed. In the present study, during each mirage event, a haptic steering display was evaluated. This haptic display indicated a steering response may be initiated to drive around an obstacle ahead. A motion-base simulator was used in a 32-participant study to present vehicle motion cues similar to the actual application. Surprise was neither present nor of concern, as it would be for a summative evaluation of a forward collision warning system. Furthermore, no collision avoidance maneuvers were performed, thereby reducing the risk of simulator sickness. This paper illustrates the mirage scenario procedures, the rating methods and definitions used with the mirage scenario, and analysis of the ratings obtained, together with a multi-attribute utility theory (MAUT) approach to evaluate and select among alternative designs for future summative evaluation. PMID- 28802465 TI - Integrative Medicine for Geriatric and Palliative Care. AB - More than 80% of people in the United States who are older than 65 years have 1 or more chronic medical problems, and 50% have 2 or more. The cost of care for the elderly is at least 3 to 4 times that of younger populations and is rapidly growing, mostly because of a lack of preventive approaches and overly medicalized and fragmented care. This article summarizes the most up-to-date evidence for specific integrative modalities for common geriatric conditions, including falls, frailty, osteoporosis, and end-of-life palliative care. PMID- 28802466 TI - In Pursuit of the Fourth Aim in Health Care: The Joy of Practice. AB - In today's health care system where there are increased demands for health care provider productivity, increased pay for performance metrics, decreased reimbursements, and ever-increasing demands of electronic medical records, providers are at risk for high rates of burnout. Indeed, recent studies have indicated that more than 50% of US physicians are now experiencing burnout and that burnout is rising dramatically faster among physicians than in any other US professional field. These high rates of burnout have many downstream consequences, for both the providers and for the patients they serve. PMID- 28802467 TI - Complementary Therapies for Mental Health Disorders. AB - Approximately 18% of the US adult population has a mental illness, yet only 13% with mental illness receive any treatment. Although pharmacotherapy and psychotherapy are the mainstays of treatment, treatment discontinuation and failure are common. Skepticism toward such treatments has fueled interest in and use of complementary therapies, such as acupuncture, meditation, and natural products. Many medical providers are unaware of the use of these therapies by their patients, and knowledge of the evidence base for these therapies is often lacking. This article presents current evidence-based recommendations for complementary therapies in the treatment of depression, anxiety, and posttraumatic stress disorder. PMID- 28802468 TI - Integrative Medicine for Insomnia. AB - Difficulty initiating and/or maintaining sleep is a common issue. Patients experiencing insomnia symptoms frequently self-treat their symptoms with sleep medications. However, there remains concern regarding the short- and long-term health impacts of sleep medications. This article discusses the evidence supporting integrative approaches to insomnia treatment, including cognitive behavioral therapy and mind-body therapies (mindfulness meditation, yoga, tai chi), as well as emerging data for use of other less well supported approaches (dietary supplements, acupuncture). PMID- 28802469 TI - Complementary and Integrative Medicine for Neurologic Conditions. AB - Although many neurologic conditions are common, cures are rare and conventional treatments are often limited. Many patients, therefore, turn to complementary and alternative medicine (CAM). The use of selected, evidence-based CAM therapies for the prevention and treatment of migraine, carpal tunnel syndrome, and dementia are presented. Evidence is growing many of modalities, including nutrition, exercise, mind-body medicine, supplements, and acupuncture. PMID- 28802470 TI - Integrative Medicine for Cardiovascular Disease and Prevention. AB - Cardiovascular disease (CVD) is traditionally treated through medications and lifestyle modifications, yet adherence to these treatments is often poor. The use of complementary therapies is increasing, and it is vital for physicians to be aware of the risks and benefits of these options. This article summarizes the current evidence base on integrative therapies for the prevention and treatment of CVD, including hypertension, hyperlipidemia, coronary artery disease, heart failure, and arrhythmias. Where applicable, recommendations are included for therapies that may be used as an adjunct to traditional medical care to improve cardiovascular health and quality of life. PMID- 28802473 TI - Integrative Women's Health. AB - This article addresses the common women's health concerns of menopause-related symptoms, premenstrual syndrome, and chronic pelvic pain. Each can be effectively addressed with an integrative approach that incorporates interventions such as pharmaceuticals, nutraceuticals, mind-body approaches, acupuncture, and lifestyle modification. PMID- 28802472 TI - Complementary and Integrative Gastroenterology. AB - Complementary and integrative medicine is developing within gastroenterology, expanding options particularly for inflammatory bowel disease, irritable bowel syndrome, and reflux esophagitis. This article encompasses new developments in complementary integrative medicine with an emphasis on herbal therapies. Studies of potential therapies have been advancing with increasing sophistication. The best studied with the most promising results in ulcerative colitis is the use of curcumin both for the induction and maintenance of remission. Other polyphenols, such as resveratrol and epigallocatechin-3-gallate, also have supportive data for ulcerative colitis. Mind-body approaches have been applied in these diseases with positive data, particularly for irritable bowel syndrome. PMID- 28802474 TI - Integrative Oncology. AB - Integrative oncology helps support the health of patients with cancer and their caregivers through an evidence-informed approach to lifestyle and behavior modification and the use of complementary health therapies as part of conventional cancer care. Integrative approaches can provide patients relief from cancer and cancer treatment-related symptoms, leading to improvements in their physical and psychosocial health. An evidence-informed approach is important when recommending an integrative cancer plan. Efforts at enhancing communication between patients and health care providers, as well as between integrative practitioners and conventional health care teams, are critical to achieving optimal health and healing for patients with cancer. PMID- 28802471 TI - Integrative Medicine for Respiratory Conditions: Asthma and Chronic Obstructive Pulmonary Disease. AB - Asthma and chronic obstructive pulmonary disease are 2 common chronic respiratory disorders in primary care that cause considerable morbidity and mortality. This article reviews disease pathophysiology and outlines an integrative, multidimensional approach to the evaluation and management of these conditions, including pharmacotreatment, nutrition, supplements, self-care strategies, mind body therapies, and other integrative modalities. PMID- 28802475 TI - Integrative Pain Management. AB - Chronic pain is one of the most common conditions seen in the clinic, and it is often one of the most frustrating for both clinicians and patients. This condition stems from common comorbidities, including depression, insomnia, fatigue, and physical deconditioning, which often create barriers to recovery. In addition, chronic pain has had divergent approaches for treatment, including an overemphasis on analgesia and curative treatments while underemphasizing the biopsychosocial needs of those in pain. This article attempts to provide an initial framework for approaching those in pain and initiating patient-centered options to support improvements in pain, function, and self-care. PMID- 28802477 TI - Integrative Medicine and Health. PMID- 28802476 TI - Enhancing the Doctor-Patient Relationship. PMID- 28802478 TI - Dynamics of network fluids. AB - Network fluids are structured fluids consisting of chains and branches. They are characterized by unusual physical properties, such as, exotic bulk phase diagrams, interfacial roughening and wetting transitions, and equilibrium and nonequilibrium gels. Here, we provide an overview of a selection of their equilibrium and dynamical properties. Recent research efforts towards bridging equilibrium and non-equilibrium studies are discussed, as well as several open questions. PMID- 28802479 TI - Emulsion templated vesicles with symmetric or asymmetric membranes. AB - Emulsion droplets with well-controlled topologies are used as templates for forming vesicles with either symmetric or asymmetric membranes. This review summarizes the available technology to produce these templates, the strategies and critical parameters involved in the transformation of emulsion droplets into vesicles, and the properties of the generated vesicles, with a special focus on the composition and material distribution of the vesicle membrane. Here, we also address limitations in the field and point to future fundamental and applied research in the area. PMID- 28802480 TI - [Non-invasive mechanical ventilation after the successful weaning: where are the limits of venturi mask?] PMID- 28802481 TI - [Noninvasive ventilation after extubation]. PMID- 28802482 TI - Recent advances on CDK inhibitors: An insight by means of in silico methods. AB - The cyclin dependent kinases (CDKs) are a small family of serine/threonine protein kinases that can act as a potential therapeutic target in several proliferative diseases, including cancer. This short review is a survey on the more recent research progresses in the field achieved by using in silico methods. All the "armamentarium" available to the medicinal chemists (docking protocols and molecular dynamics, fragment-based, de novo design, virtual screening, and QSAR) has been employed to the discovery of new, potent, and selective inhibitors of cyclin dependent kinases. The results cited herein can be useful to understand the nature of the inhibitor-target interactions, and furnish an insight on the structural/molecular requirements necessary to achieve the required selectivity against cyclin dependent kinases over other types of kinases. PMID- 28802483 TI - Left Ventricular Systolic Myocardial Deformation: A Comparison of Two- and Three Dimensional Echocardiography in Children. AB - BACKGROUND: The clinical applicability and reliability of three-dimensional (3D) speckle-tracking echocardiography has not been well studied in pediatric patients. The aim of this study was to compare two-dimensional (2D) echocardiography and 3DE real-time full-volume-derived strain and rotation indices in healthy children and patients with dilated cardiomyopathy (DCM). METHODS: Children with either normal function or DCM were prospectively recruited in an outpatient setting, and deformation indices, including circumferential, radial, and longitudinal strain and torsion, were measured by 2D and 3D echocardiography. Control subjects were compared with patients using the Mann Whitney U test, correlations between 2D and 3D measurements were analyzed using Spearman correlation analysis, and reproducibility analyses are reported using intraclass correlation coefficients and coefficient of variations. RESULTS: The study cohort consisted of 15 patients (47%) with DCM and 17 control subjects (53%). The median age of the cohort was 13.4 years (range, 5.7-19.3 years). By both 2D and 3D analysis, magnitudes of global longitudinal (P = .01), circumferential (P = .007), and radial (P = .004) strain were significantly lower in patients with DCM in comparison with control subjects. Using receiver operating characteristic curves, lower values of absolute circumferential (area under the curve = 0.95, P < .0001) and longitudinal (area under the curve = 0.93, P < .0001) strain were associated with left ventricular dysfunction. No difference was noted in torsion between control subjects and patients. Three dimensional analysis was superior to 2D analysis in terms of intraobserver, interobserver, and test-retest reliability. CONCLUSIONS: Left ventricular deformation shows significant changes while torsion is preserved in outpatients with DCM compared with control subjects. Three-dimensional global strain can discriminate subtle left ventricular dysfunction and has better reproducibility in comparison with 2D echocardiography. High-resolution 3D imaging is a useful clinical assessment tool for cardiac performance and may overcome some of the limitations of 2D analysis. PMID- 28802484 TI - Electrosurgery for the Treatment of Moderate or Severe Rhinophyma. AB - Rhinophyma, a rare and progressive disfiguring condition, is thought to be the final stage of rosacea. Several surgical treatments are available, including dermabrasion, cryosurgery, scalpel excision, electrosurgery, and carbon dioxide laser. The last 2 techniques are the most effective for the management of rhinophyma. We describe a series of cases of moderate or severe rhinophyma treated with high-frequency electrosurgery in the dermatology department of Hospital Simon Bolivar and in private clinics in Bogota, Colombia, between 2012 and 2016. The cosmetic result, as assessed by both the clinicians and the patients, was satisfactory in all cases. Three patients presented hypertrophic scars that were treated with steroid injections and silicone gel sheeting. Two patients presented persistent erythema. However, there were no serious infections and none of the patients required further surgery. Electrosurgery is one of the simplest and most cost-effective techniques currently available for the treatment of rhinophyma by dermatologists. PMID- 28802485 TI - Dermoscopy Can Indicate the Grade of Actinic Keratoses. PMID- 28802486 TI - Unilateral Digital Hyperpigmentation in a Teenager. PMID- 28802487 TI - A 65-Year-Old Woman With Multiple Papules in a Unilateral Segmental Distribution. PMID- 28802489 TI - A Selfie of Mohs Micrographic Surgery in Spain. PMID- 28802488 TI - Characterization of Surgical Procedures in the Spanish Mohs Surgery Registry (REGESMOHS) for 2013-2015. AB - INTRODUCTION: The Spanish Mohs Surgery Registry is used to collect data on the use and outcomes of Mohs micrographic surgery (MMS) in Spain. The aim of this study was to describe perioperative and intraoperative data recorded for MMS procedures performed between July 2013 (when the registry started) and January 2016. MATERIAL AND METHODS: Prospective cohort study of data from 18 hospitals. The data collected included type of anesthesia, surgical technique, hospital admission, number of Mohs stages, management of preoperative risk factors, additional treatments, previous treatments, type of tumor, operating time, and complications. RESULTS: Data were available for 1796 operations. The most common tumor treated by MMS was basal cell carcinoma (85.96%), followed by squamous cell carcinoma (6.18%), lentigo maligna (2.81%), and dermatofibrosarcoma protuberans (1.97%). Primary tumors accounted for 66.9% of all tumors operated on; 19.2% of tumors were recurrent and 13.9% were persistent. The most common previous treatment was surgical. MMS was mostly performed under local anesthesia (86.7% of cases) and as an outpatient procedure (71.8%). The frozen section technique was used in 89.5% of cases. One stage was needed to achieve tumor-free margins in 56.45% of patients; 2 stages were required in 32.1% of patients, 3 in 7.1%%, 4 in 2.7%, and 5 or more in 1.8%. The defect was reconstructed by the dermatologist in 98% of patients and the most common technique was flap closure (47.2%). Intraoperative complications were recorded for just 1.62% of patients and the median (interquartile range) duration of surgery was 75 (60-100) minutes. CONCLUSION: The characteristics of the patients and tumors treated by MMS are similar to those reported for similar studies in other geographic areas. Lentigo maligna and dermatofibrosarcoma protuberans accounted for a higher proportion of cases in our series, and repair of the surgical defect by a dermatologist was also more common. Operating times in MMS are not much longer than those reported for other procedures and the rate of intraoperative complications is very low. PMID- 28802490 TI - Clinical Research in Dermatology in Spain. PMID- 28802491 TI - RF-Rituximab: Revolutionizing the Treatment of Pemphigus. PMID- 28802492 TI - Blue Nevi and Related Tumors. AB - The major entities related to blue nevus are common blue nevus, cellular blue nevus, atypical blue nevus, and malignant blue nevus. These lesions share presence of dermal pigmented dendritic melanocytes derived from embryonal precursors to melanocytes, Schwann cells, and glial cells migrating to the skin from the ventral neural crest. Genetically, blue nevi harbor mutations in G protein-coupled receptor subunits GNAQ and GNA11. Progression to malignant blue nevus is associated with additional mutations and partial gains and losses of chromosomal material. This article discusses recent advances in pathology of blue nevi with emphasis on differential diagnosis and molecular pathology. PMID- 28802493 TI - Sentinel Lymph Nodes in Cutaneous Melanoma. AB - Examination of sentinel lymph nodes (SLNs) has probably become the most popular method of early staging of patients with cutaneous melanoma. SLNs are considered to be the most likely ones to contain metastatic deposits; thus, they can be examined in a more intense manner than in standard lymphadenectomy. Most processing protocols use formalin-fixed, paraffin-embedded sections stained with hematoxylin-eosin with the addition of immunohistochemistry. Approximately 20% of patients with cutaneous melanoma show melanoma cells in the SLNs. Different methods of quantification of tumor burden in SLNs provide clinically important prognostic information. PMID- 28802494 TI - Toward a Molecular-Genetic Classification of Spitzoid Neoplasms. AB - The histopathologic spectrum of Spitzoid neoplasms includes Spitz nevi, atypical Spitz tumors, and Spitzoid melanomas. Advances in molecular genetics have evolved to the point that Spitzoid lesions can now be reasonably classified according to their distinctive molecular-genetic alterations: Spitzoid lesions with (1) 11p amplification and/or HRAS mutations; (2) isolated loss of 6q23 by fluorescence in situ hybridization (FISH); (3) homozygous deletion of 9p21 by FISH; (4) BAP1 loss and BRAFV600 E mutation; (5) translocations involving any of a number of different oncogenic kinase drivers, including ROS1, ALK, NTRK1, NTRK3, MET, BRAF, and RET; and (6) TERT promoter mutations. PMID- 28802495 TI - The Immunology of Melanoma. AB - The relatively high DNA mutational burden in melanoma allows for the creation of potentially "foreign," immune-stimulating neoantigens, and leads to its exceptional immunogenicity. Brisk tumor-infiltrating lymphocytes, a marker of immune editing, confer improved overall survival in melanoma, possibly due to reduced sentinel lymph node spread. Meanwhile, T-cell-stimulating drugs, so called T-cell checkpoint inhibitors, which reverse peripheral tolerance-dependent tumor escape, have demonstrated unparalleled clinical success in metastatic melanoma. Markers to predict response to immunotherapy are currently imperfect, and the subject of intense research, which will guide the future of ancillary pathologic testing in this setting. PMID- 28802496 TI - Molecular Melanoma Diagnosis Update: Gene Fusion, Genomic Hybridization, and Massively Parallel Short-Read Sequencing. AB - Molecular evaluation of melanocytic tumors can be diagnostically useful to confirm malignancy or benignancy. Molecular tools are ancillary and supplemental to histopathologic evaluation and do not replace conventional microscopy. Immunohistochemistry, fluorescence in situ hybridization, array comparative genomic hybridization, and massively parallel short-read sequencing, often referred to as next-generation sequencing, each provide varied (and often incomplete) additional information, and careful planning is necessary if tissue is limited. PMID- 28802497 TI - Update on Merkel Cell Carcinoma. AB - Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine malignancy. Merkel cell polyomavirus, a tumorigenic DNA virus, is present in most MCC tumors, with implications for tumor biology, diagnosis, and management. Merkel cell polyomavirus-negative tumors have a high burden of UV-signature mutations, similar to melanoma. The histopathologic diagnosis of MCC requires immunohistochemistry to exclude morphologically similar entities. Therapies for advanced disease are currently lacking. Here, the features of MCC are reviewed, including recent molecular discoveries with implications for improved therapy for advanced disease. PMID- 28802498 TI - Cutaneous Squamous Cell Carcinoma. AB - Cutaneous squamous cell carcinoma (cSCC) is a malignant neoplasm of the skin characterized by an aberrant proliferation of keratinocytes. Cutaneous SCC is the second most common malignancy globally, and usually arises in the chronically sun damaged skin of elderly white individuals. From a pathologist's perspective, it is important to differentiate cSCC from the benign and reactive squamoproliferative lesions and identify the high-risk features associated with aggressive tumor behavior. In this article, we provide an up-to-date overview of cSCC along with its precursor lesions and important histologic variants, with a particular emphasis on the histopathologic features and molecular pathogenesis. PMID- 28802500 TI - Primary Cutaneous B-cell Lymphomas. AB - B-cell lymphomas represent approximately 20% to 25% of primary cutaneous lymphomas. Within this group, most cases (>99%) are encompassed by 3 diagnostic entities: primary cutaneous marginal zone lymphoma, primary cutaneous follicle center lymphoma, and primary cutaneous diffuse large B-cell lymphoma, leg type. In this article, the authors present clinical, histopathologic, immunophenotypic, and molecular features of each of these entities and briefly discuss the rarer intravascular large B-cell lymphoma. PMID- 28802499 TI - Cutaneous T-cell Lymphoma. AB - Cutaneous T-cell lymphomas comprise a heterogeneous group of diseases characterized by monoclonal proliferations of T lymphocytes primarily involving skin, modified skin appendages, and some mucosal sites. This article addresses the basic clinical, histologic, and immunohistochemical characteristics of this group of diseases, with additional attention to evolving literature on dermoscopy, reflectance confocal microscopy, flow cytometry, and molecular data that may increasingly be applied to diagnostic and therapeutic algorithms in these diseases. Select unusual phenotypes or diagnostic examples of classic phenotypes are demonstrated, and flags for consideration while making a pathologic diagnosis of cutaneous T-cell lymphoma are suggested. PMID- 28802501 TI - Myeloid Neoplasms. AB - The classification of myeloid neoplasms has undergone major changes and currently relies heavily on genetic abnormalities. Cutaneous manifestations of myeloid neoplasms may be the presenting sign of underlying bone marrow disease. Dermal infiltration by neoplastic cells may occur in otherwise normal skin or in sites of cutaneous inflammation. Leukemia cutis occasionally precedes evidence of blood and/or bone marrow involvement (aleukemic leukemia cutis). PMID- 28802502 TI - Cutaneous Sweat Gland Carcinomas with Basaloid Differentiation: An Update with Emphasis on Differential Diagnoses. AB - This article focuses on primary cutaneous sweat gland carcinomas with basaloid differentiation, including cribriform apocrine carcinoma, endocrine mucin producing sweat gland carcinoma, mucinous carcinoma, adenoid cystic carcinoma, spiradenocarcinoma, and digital papillary adenocarcinoma. These tumors are rare and pose a significant diagnostic challenge. Their clinical presentation is nonspecific and there is significant overlap of their histologic features. Confident diagnosis is necessary because their clinical behavior ranges from indolent, nonrecurring, nonmetastasizing tumors to those with potential for disseminated disease and mortality. They should be separated from cutaneous metastases of primary visceral adenocarcinomas. Salient features of these rare entities are discussed with emphasis on distinguishing features and diagnostic clues. PMID- 28802503 TI - Fibrohistiocytic Tumors. AB - Fibrohistiocytic tumors are a diverse group of reactive and neoplastic lesions including xanthoma, fibrous histiocytoma and its variants, solitary xanthogranuloma, dermatofibrosarcoma protuberans, and atypical fibroxanthoma. This article reviews some of the more commonly encountered fibrohistiocytic tumors with an emphasis on clinical presentation, macroscopic and histologic characteristics, molecular/cytogenetic findings where applicable, and differential diagnoses. PMID- 28802505 TI - Soft Tissue Tumors of Uncertain Histogenesis: A Review for Dermatopathologists. AB - The mesenchymal tumors discussed herein represent a heterogeneous group of neoplasms with distinctive morphologic, immunophenotypic, and molecular genetic features. These uncommon tumors often arise in the dermis and subcutis and can pose a major diagnostic challenge to dermatopathologists because they closely mimic melanoma, carcinoma, fibrous histiocytoma, schwannoma, or granulomatous inflammation. This article reviews the clinical presentation, histopathology, differential diagnosis, and diagnostic pitfalls of epithelioid sarcoma, clear cell sarcoma, perivascular epithelioid cell tumor, ossifying fibromyxoid tumor, pleomorphic hyalinizing angiectatic tumor, and hemosiderotic fibrolipomatous tumor. Associated molecular genetic findings are also briefly reviewed with an emphasis on their diagnostic usefulness. PMID- 28802504 TI - Cutaneous Malignant Vascular Neoplasms. AB - Accurate diagnosis of cutaneous malignant vascular tumors, including angiosarcoma and epithelioid hemangioendothelioma, is critical for determination of appropriate clinical management and prognosis. Although there have been significant advances in understanding genetic aspects of cutaneous vascular biology, differential diagnosis of malignant vascular tumor involving skin and superficial soft tissue is a frequent source of difficulty. This brief overview highlights the clinicopathologic features of primary and secondary cutaneous angiosarcoma and epithelioid hemangioendothelioma and also provides a short summary of newer molecular data. PMID- 28802506 TI - Inflammatory Dermatopathology for General Surgical Pathologists. AB - Owing to the wide variety and complexity of inflammatory skin diseases, inflammatory dermatopathology can be a challenging topic for dermatopathologists and general surgical pathologists alike. Following a basic tissue reaction pattern approach, this article reviews the most common and important entities of each pattern, with emphasis on differential diagnosis, diagnostic pitfalls, and appropriate workup when indicated. A few dermatologic emergencies are also discussed. PMID- 28802507 TI - Preface. PMID- 28802508 TI - Prognostic Significance of Left Ventricular Fibrosis in Patients With Congenital Bicuspid Aortic Valve. AB - This study sought to evaluate the prognostic value of left ventricular (LV) fibrosis assessed by late gadolinium enhancement (LGE) of the myocardium during cardiac magnetic resonance (CMR) imaging in patients with bicuspid aortic valve (BAV), which is associated with early aortic valve fibrosis and calcification. To what degree the LV myocardial wall is affected by fibrosis and its prognostic value is currently unknown. This is a retrospective, single-center study evaluating all adult patients with BAV who had CMR and followed from March 2002 to March 2016. CMR and transthoracic echocardiogram images were reviewed. Clinical data were abstracted from the electronic medical record. A total of 29 patients were included in the study, of which 11 (38%) had CMR studies that demonstrated the presence of LGE. Patients with LGE had significantly higher aortic valve mean gradients by echocardiography when compared with LGE-negative patients (30.3 +/- 7.2 mm Hg vs 14.7 +/- 3.6 mm Hg, p = 0.049). They were also more likely to have LV hypertrophy. Patients with LGE were 10 times more likely to need aortic valve replacement within 1 year of the CMR study than did patients without LGE (55% vs 5.5%, p = 0.0028). In conclusion, evaluation of LGE by CMR as a marker of LV myocardial fibrosis can have additional prognostic value when evaluating patients with aortic stenosis secondary to BAV. PMID- 28802509 TI - Value of Strain Imaging and Maximal Oxygen Consumption in Patients With Hypertrophic Cardiomyopathy. AB - Longitudinal strain (LS) has been shown to be predictive of outcome in hypertrophic cardiomyopathy (HC). Percent predicted peak oxygen uptake (ppVO2), among other cardiopulmonary exercise testing (CPX) metrics, is a strong predictor of prognosis in HC. However, there has been limited investigation into the combination of LS and CPX metrics. This study sought to determine how LS and parameters of exercise performance contribute to prognosis in HC. One hundred and thirty-one consecutive patients with HC who underwent CPX and stress echocardiography were included. Global, septal, and lateral LS were assessed at rest and stress. Eighty matched individuals were used as controls. Patients were followed for the composite end point of death and worsening heart failure. All absolute LS components were lower in patients with HC than in controls (global 14.3 +/- 4.0% vs 18.8 +/- 2.2%, p <0.001; septal 11.9 +/- 4.9% vs 17.9 +/- 2.7%, p <0.001; lateral 16.0 +/- 4.7% vs 19.4 +/- 3.1%, p = 0.001). Global strain reserve was also reduced in patients with HC (13 +/- 5% vs 19 +/- 8%, p = 0.002). Over a median follow-up of 56 months (interquartile range 14 to 69), the composite end point occurred in 53 patients. Global LS was predictive of outcome on univariate analysis (0.55 [0.41 to 0.74], p <0.001). When combined with CPX metrics, lateral LS was the only strain variable predictive of outcome along with indexed left atrial volume (LAVI) and ppVO2. The worst outcomes were observed for patients with lateral LS <16.1%, LAVI >52 ml/m2, and ppVO2 <80%. The combination of lateral LS, LAVI, and ppVO2 presents a simple model for outcome prediction. PMID- 28802511 TI - Residual Risk After Treatment of Patients With Atherosclerotic Cardiovascular Disease With Proprotein Convertase Subtilisin-Kexin Type 9 Monoclonal Antibody Therapy (from the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk Trial). PMID- 28802510 TI - Aortic Dilatation Associated With Bicuspid Aortic Valve: Relation to Sex, Hemodynamics, and Valve Morphology (the National Heart Lung and Blood Institute Sponsored National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions). AB - This study analyzed the impact of sex, hemodynamic profile, and valve fusion pattern on aortopathy associated with bicuspid aortic valve (BAV). The National Heart Lung and Blood Institute-sponsored National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) provided comprehensive information on a large population of well-characterized patients with BAV. Of 969 enrolled patients with BAV, 551 (57%, 77% male) had already undergone valvular and/or aortic surgery. Echocardiographic imaging data were available on 339 unoperated or preoperative participants who formed the basis of this study. BAV function was normal in 45 (14%), with a predominant aortic regurgitation (AR) in 127 (41%) and a predominant aortic stenosis (AS) in 76 (22%). Moderate-severe AR was associated with larger sinus of Valsalva (SOV) diameters compared with normal function and AS (all p <0.01). Moderate-severe AS was associated with a larger ascending aortic (AscAo) diameter compared with normal function (p = 0.003) but not with AR. The SOV diameter was larger in men than in women (3.7 +/- 0.7 vs 3.3 +/- 0.6 cm, p <0.0001), whereas AscAo diameters were comparable (3.9 +/- 0.9 vs 3.7 +/- 0.9 cm, p = 0.08). Right-left commissural fusion was associated with a larger SOV diameter (3.7 +/- 0.7 vs 3.3 +/- 0.6 cm, p <0.0001) compared with a right-noncoronary fusion pattern. Predominant AR was more common in men (45% vs 27%, p = 0.004), whereas AS was more common in women (29% vs 18%, p = 0.04). In conclusion, in the GenTAC Registry, AR was associated with diffuse (annular, SOV, and AscAo) enlargement, whereas moderate-severe AS was only associated with AscAo enlargement. Male sex and right-left cusp pattern of cusp fusion were associated with larger SOV diameters and a greater likelihood of AR, whereas women had a higher prevalence of AS. PMID- 28802512 TI - Cangrelor Versus Clopidogrel on a Background of Unfractionated Heparin (from CHAMPION PHOENIX). AB - Cangrelor is approved for use during percutaneous coronary intervention (PCI) and is administered with different parenteral anticoagulants. We examined the efficacy and safety of cangrelor in the subgroup of patients who received unfractionated heparin (UFH) during PCI in the modified intention-to-treat population of the randomized CHAMPION PHOENIX trial (cangrelor vs clopidogrel; n = 10,939). The primary efficacy end point was the composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis (ST) at 48 hours. The key secondary efficacy end point was ST. UFH was used in 69.2% (7,569/10,939) of patients. In the UFH subgroup, cangrelor reduced the primary composite efficacy end point at 48 hours compared with clopidogrel (4.8% vs 5.9%; odds ratio [OR] 0.80 [0.65 to 0.98]; p = 0.03). Cangrelor consistently reduced ST at 2 hours (0.7% vs 1.3%; OR 0.56 [0.35 to 0.90]; p = 0.01) and 48 hours (0.9% vs 1.4%; OR 0.70 [0.45 to 1.07]; p = 0.10). There was no difference in GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries)-defined severe or life threatening bleeding (0.1% vs 0.1%; OR 1.24 [0.33 to 4.61]; p = 0.75) or blood transfusion requirement at 48 hours (0.4% vs 0.2%; OR 1.87 [0.83 to 4.21]; p = 0.12). In conclusion, cangrelor reduces early ischemic periprocedural complications without increasing severe bleeding compared with clopidogrel in patients undergoing PCI with UFH. PMID- 28802514 TI - Third nerve palsy after influenza vaccination in inflammatory bowel disease (IBD). PMID- 28802513 TI - Nonconvulsive Status Epilepticus After Electroconvulsive Therapy: A Review of Literature. AB - BACKGROUND: The clinical presentation and risk factors of nonconvulsive status epilepticus (NCSE) in the context of electroconvulsive therapy (ECT) are poorly understood, and guidance regarding diagnosis and management remains scarce. In this article, we identify case reports of ECT-induced NCSE from literature, and discuss the presentation, diagnosis, and management of these cases in the context of what is known about NCSE from the neurology literature. METHODS: A literature search on PubMed for case reports of NCSE after ECT. RESULTS: We identified 13 cases for this review. Diagnosis in all cases was based on clinical features and electroencephalogram (EEG) findings. Clinical presentation was altered mental status or unresponsiveness, with subtle motor phenomena in some cases. All cases had nonspecific risk factors that have been associated with prolonged seizures and convulsions, such as recent discontinuation/reduction of benzodiazepines or anticonvulsants, and concurrent use of antipsychotics and antidepressants. All patients were treated with either benzodiazepines or antiepileptic agents. Outcomes in these post-ECT NCSE cases were generally favorable. DISCUSSION: Although rare, post-ECT NCSE should be kept in mind by physicians when confusion or unresponsiveness develops and continues after ECT; multilead EEG is gold standard for diagnosis. An intravenous (IV) antiepileptic drug (AED) challenge can help clarify the diagnosis. Initial treatment is recommended with IV benzodiazepines, with a repeat dose if necessary. If seizures persist, IV AEDs are warranted. NCSE refractory to this treatment should be treated with a scheduled IV or oral AED. Serial multilead EEGs should be used to monitor resolution of symptoms. CONCLUSION: NCSE after ECT is a rare but recognizable clinical event. A high clinical suspicion and low threshold for EEG is necessary for prompt diagnosis. PMID- 28802516 TI - Cancer-related knowledge and health status among cancer survivors in Portugal. PMID- 28802515 TI - Alcohol in the city: wherever and whenever. AB - Alcohol urban environment has been associated with individual alcohol behaviors. We are constantly exposed to a wide variety of alcohol products, its marketing and promotion and signs of alcohol consumption that may influence alcohol drinking behaviors. In this photo-essay, we include photographs that visually explain the exposure to alcohol in the urban streetscape of Madrid. These photographs show the pervasiveness of alcohol products in this city, which can be found everywhere at any time. PMID- 28802517 TI - Effectiveness of a parent-training program in Spain: reducing the Southern European evaluation gap. AB - OBJECTIVE: We implemented and evaluated the Parenting Skills Program for families in Spain 1) to examine differences in parenting skills, social support, children's behaviours and parental stress pre, immediately post and six months post intervention and 2) to identify mechanisms by which the intervention is related to changes in the four outcomes examined. METHODS: Quasi-experimental study design with pre (T0), post (T1), a follow-up (T2) and no control group, complemented by a qualitative study was used. The outcome variables were social support, parenting skills, parental stress and children's behaviours. 216 parents completed pre and post questionnaire and 130 parents the follow-up questionnaire. 39 professionals and 34 parents participated in 17 interviews and 5 discussion groups. RESULTS: Compared with T0, all four outcomes improved significantly at T1. 76% of the participants improved parenting skills and 61% social support. 56% reduced children's negative behaviours and 66% parental stress. All outcomes maintained this significant improvement at T2. Parents and professionals describe different changes in parents' parenting skills, stress and social support after participation in the PSP, and in their children's behaviours. Some subcategories emerged after analysing parents' and professionals' discourses. CONCLUSIONS: This study describes positive parenting effects on participants of a parent-training program in Spain, which is a country where implementation and evaluation of these kind of interventions is an incipient issue. PMID- 28802518 TI - Effect of total dairy products, milk and calcium intake on the development of type 2 diabetes. PMID- 28802519 TI - ESPEN guidelines on nutritional support for polymorbid internal medicine patients. AB - BACKGROUND & AIMS: Polymorbidity (also known as multimorbidity) - defined as the co-occurrence of at least two chronic health conditions - is highly prevalent, particularly in the hospitalized population. Nonetheless, clinical guidelines largely address individual diseases and rarely account for polymorbidity. The aim of this project was to develop guidelines on nutritional support for polymorbid patients hospitalized in medical wards. METHODS: The methodology used for the development of the current project follows the standard operating procedures for ESPEN guidelines. It started with an initial meeting of the Working Group in January 2015, where twelve key clinical questions were developed that encompassed different aspects of nutritional support: indication, route of feeding, energy and protein requirements, micronutrient requirements, disease-specific nutrients, timing, monitoring and procedure of intervention. Systematic literature searches were conducted in three different databases (Medline, Embase and the Cochrane Library), as well as in secondary sources (e.g. published guidelines), until April 2016. Retrieved abstracts were screened to identify relevant studies that were used to develop recommendations, which were followed by submission to Delphi voting rounds. RESULTS: From a total of 4532 retrieved abstracts, 38 relevant studies were analyzed and used to generate a guideline draft that proposed 22 recommendations and four statements. The results of the first online voting showed a strong consensus (agreement of >90%) in 68% of recommendations and 75% of statements, and consensus (agreement of >75-90%) in 32% of recommendations and 25% of statements. At the final consensus conference, a consensus greater than 89% was reached for all of the recommendations. CONCLUSIONS: Despite the methodological difficulties in creating non-disease specific guidelines, the evidence behind several important aspects of nutritional support for polymorbid medical inpatients was reviewed and summarized into practical clinical recommendations. Use of these guidelines offer an evidence-based nutritional approach to the polymorbid medical inpatient and may improve their outcomes. PMID- 28802520 TI - An Analysis of Long-Term Ischemic Stroke Risk in Survivors of Septicemia. AB - INTRODUCTION: Sepsis increases the long-term incidence of ischemic stroke (IS). The chances for long-term IS in patients who are discharged after sepsis are unclear. Our aim was to demonstrate long-term risk chances of IS after septicemia discharge. We used a nomogram to identify those septicemia survivors with the higher risk of developing IS. METHODS: Inpatient data were used from the Taiwan Longitudinal Health Insurance Database, from 2001 to 2003. The event was IS rehospitalization after discharge of septicemia. We used multivariate Cox proportional regression of the risk factors for IS in septicemia survivors to create a nomogram. RESULTS: There were 642 IS incidents in this study. The risk factors for IS in survivors of septicemia were advanced age (hazard ratio [HR] 1.035 [95% confidence interval (CI) 1.029-1.042]), new-onset atrial fibrillation (HR 1.875 [95% CI 1.327-2.651]), hypertension (HR 2.042 [95% CI 1.687-2.471]), diabetes mellitus (HR 1.735 [95% CI 1.469-2.05]), coronary artery disease (HR 1.661 [95% CI 1.408-1.96]), chronic kidney disease (HR 1.264 [95% CI 1.071 1.49]), chronic obstructive pulmonary disease (HR 1.201 [95% CI 1.016-1.421]), and local hospital admission (HR 1.414 [95% CI 1.155-1.731]). The model showed good calibration and discrimination, with a bootstrap-corrected concordance index of .785. CONCLUSION: With this prognostic nomogram, we found age with the strongest factor for IS. There was increased IS incidence with more comorbid conditions in advance-aged septicemia survivors. Physicians must identify high IS risk patients and control risk factors to prevent adverse events in the clinical setting. PMID- 28802521 TI - Midterm Follow-Up of 20 Consecutive Patients with Nonaneurysmal Subarachnoid Hemorrhage of Unknown Origin in a Single-Center: Two Cases of De Novo Development of Dural Arteriovenous Fistula. AB - BACKGROUND AND PURPOSE: The mechanisms and prognosis of underlying subarachnoid hemorrhage of unknown origin remain unclear. Previous investigators have suggested a relationship between nonaneurysmal perimesencephalic subarachnoid hemorrhage and venous abnormalities like a primitive venous drainage of the basal vein of Rosenthal. We report the outcome of a midterm follow-up of 20 consecutive patients with nonaneurysmal subarachnoid hemorrhage of unknown origin, and 2 patients in whom the development of new dural arteriovenous fistulas after subarachnoid hemorrhage of unknown origin were detected during follow-up. METHODS: All patients who were admitted to our hospital for nontraumatic subarachnoid hemorrhage between April 2008 and March 2016 were retrospectively analyzed. RESULTS: Of 705 patients included in the study, 20 (2.8%) were diagnosed with nontraumatic subarachnoid hemorrhage of unknown origin. During the follow-up periods, there was no rebleeding. Although 18 patients did not show any vascular abnormalities, the other 2 patients were diagnosed with dural arteriovenous fistula. Both fistulas were successfully treated with endovascular embolization. CONCLUSIONS: Subarachnoid hemorrhage of unknown origin had a low incidence rate, and its clinical course was excellent without rebleeding. Although no vascular abnormalities were observed during the patients' initial admission, venous lesions might have been involved in both subarachnoid hemorrhages and delayed dural arteriovenous fistulas. Here, the possible pathogenesis is discussed with a review of the literature. PMID- 28802522 TI - Comprehensive Evaluation of Diagnostic and Treatment Strategies for Idiopathic Spinal Subarachnoid Hemorrhage. AB - BACKGROUND: Idiopathic spinal subarachnoid hemorrhage (IS-SAH), defined as spinal SAH without apparent cause, is extremely rare. The objective of the present study was to establish a consensus on the diagnosis and management of IS-SAH. METHODS: We enrolled 5 consecutive cases of IS-SAH at our institution, and we enrolled 19 previously published cases as a literature review. The patient presentations, diagnostic test findings, treatment strategies, and outcomes were retrospectively assessed. Possible causes of spinal SAH were basically excluded by multimodalities, including brain and spinal digital subtraction angiographies. RESULTS: IS-SAH usually developed in middle-aged people around 55 years old and typically presented with acute migrating back pain. Lumbar puncture and spinal magnetic resonance imaging demonstrated xanthochromia or an abnormal intensity area around the spine in all study patients who underwent these diagnostic tests. All of the patients from our institution were discharged with 1 patient (20%) complaining of neurologic dysfunction at discharge, and 1 patient (5.3%) in the published cases died during hospitalization and 5 (26.3%) complained of neurologic dysfunction at discharge. In addition, the surgical findings in 1 case from our institution suggested that one of the mechanisms of IS-SAH is a bleeding from a microvessel around the spine, and we newly propose spinal drainage as one of the treatment options in patients with IS-SAH based on our experience. CONCLUSIONS: We summarized our experience of 5 cases of IS-SAH with a literature review. We demonstrated that spinal drainage could be one of the treatment options in patients with IS-SAH. PMID- 28802524 TI - Characterization of chromatographic peaks using the linearly modified Gaussian model. Comparison with the bi-Gaussian and the Foley and Dorsey approaches. AB - To characterize column performance in liquid chromatography, several parameters must be obtained from experimental data. These parameters can be computed through the numerical integration of the net signal to calculate the moments after subtraction of the baseline. This requires the establishment of the peak integration limits. The whole process introduces significant uncertainty. For this reason, several alternative procedures have been proposed to measure the area, mean time and variance, based on the assumption that the chromatographic peak can be described with a mathematical function. This allows the calculation of the peak position and variance making use of the values of the experimental half-widths. In this work, the linear modified Gaussian model is used to derive several equations for the evaluation of the associated moments. Affordable equations for the calculation of the area, mean time, variance and efficiency are provided, using the half-width values at 10% peak height. The behaviour of experimental peaks obtained under a large variety of experimental conditions is examined to verify the validity of the proposed equations. The values of the peak parameters are compared with those calculated based on the bi-Gaussian model, and the exponentially modified Gaussian model using the equations developed by Foley and Dorsey. The bi-Gaussian model offered the best quantifications for the mean time. The Foley and Dorsey approach gave rather satisfactory results for the area and the best results for the variance and efficiency for tailing peaks of small asymmetry. The LMG approach gave better evaluation of the area for peaks showing small asymmetry, and satisfactory values for the mean time, variance and efficiency in the whole range of asymmetries found in liquid chromatography. PMID- 28802523 TI - Development of a split-flow system for high precision variable sample introduction in supercritical fluid chromatography. AB - In this study, we propose a novel variable sample injection system based on full loop injection, named the split-flow sample introduction system, for application in supercritical fluid chromatography (SFC). In this system, the mobile phase is split by the differential pressure between two back pressure regulators (BPRs) after full-loop injection suitable for SFC, and this differential pressure determines the introduction rate. Nine compounds with a wide range of characteristics were introduced with high reproducibility and universality, confirming that a robust variable sample injection system was achieved. We also investigated the control factors of our proposed system. Sample introduction was controlled by the ratio between the column-side pressure drops in splitless and split flow, DeltaPcolumnsideinsplitless and DeltaPcolumnsideinsplit, respectively, where DeltaPcolumnsideinsplitless is related to the mobile phase flow rate and composition and the column resistance. When all other conditions are kept constant, increasing the make-up flow induces an additional pressure drop on the column side of the system, which leads to a reduced column-side flow rate, and hence decreased the amount of sample injected, even when the net pressure drop on the column side remains the same. Thus, sample introduction could be highly controlled at low sample introduction rate, regardless of the introduction conditions. This feature is advantageous because, as a control factor, the solvent in the make-up pump is independent of the column-side pressure drop. PMID- 28802525 TI - Layered double hydroxides based ion exchange extraction for high sensitive analysis of non-steroidal anti-inflammatory drugs. AB - Layered double hydroxides (LDHs) are ideal sorbents for solid phase extraction (SPE) because of the excellent ion exchange capacity and high specific surface area. However, difficult elution of the analytes from the LDHs is a problem due to the strong ionic interaction between anions and LDHs. High concentrated NaOH solution is employed to elute the sample, but it not suitable for analyzing by HPLC. To solve this problem, a simple acid-base neutralization method was proposed after elution, and then the neutral samples were directly injected to HPLC for analysis. Nickel-aluminum layered double hydroxides (NiAl-LDHs) were synthesized by co-precipitation method and packed into a micro pipette tip for the extraction of three non-steroidal anti-inflammatory drugs (NSAIDs) including ketoprofen, naproxen and flurbiprofen from aqueous samples. After optimization of the experimental parameters such as the concentration of the NaOH, sample pH, sampling rate and sample volume, excellent extraction efficiency towards three NSAIDs was obtained with high enrichment factors of 28-32. A NiAl-LDHs based SPE HPLC method was developed for quantitative analysis of NSAIDs, and the method showed low limits of detection (0.002-0.1ng/mL), good linearity (R2>=0.9995) and good reproducibility (intraday RSD<=4.37%). The developed method was also applied to the analysis of three NSAIDs in spiked human plasma and rat plasma after oral administration, which demonstrated the practicality of the proposed method. PMID- 28802526 TI - Sodium hyaluronate-functionalized urea-formaldehyde monolithic column for hydrophilic in-tube solid-phase microextraction of melamine. AB - A novel sodium hyaluronate-functionalized urea-formaldehyde (UF) monolithic column has been developed by in-situ polycondensation of urea, formaldehyde and sodium hyaluronate (HA). HA plays both the roles of crosslinking and hydrophilic functionalization. The preparation factors including different molecular weights of HA and different amounts of HA were optimized, and then a uniform monolith with satisfactory permeability and hydrophilic binding capacity was obtained. Due to the excellent hydrophilicity of HA, HA-functionalized UF monolith showed higher hydrophilic extraction efficiency than UF monolith, and was applied for hydrophilic in-tube solid-phase microextraction (SPME) of melamine (MEL). Several factors for hydrophilic in-tube SPME, such as ACN percentage in the sampling solution, salt concentration and pH value of the sampling solution, elution volume, sampling and elution flow rate, were investigated with respect to the extraction efficiency of MEL. Under the optimized SPME conditions, the limit of detection (LOD) of MEL was found to be 0.2ng/mL in the milk formula samples, the recoveries of MEL spiked in milk formula samples ranged from 87.3% to 96.7% with relative standard deviations (RSDs) less than 5.1%. Owing to the excellent hydrophilic extraction ability, the novel HA-functionalized UF monolith could provide a promising tool for the sensitive analysis of polar analytes in complicated samples. PMID- 28802527 TI - Application of an immobilized ionic liquid for the passive sampling of perfluorinated substances in water. AB - Ionic liquids have been used to efficiently extract a wide range of polar and nonpolar organic contaminants from water. In this study, imidazole ionic liquids immobilized on silica gel were synthesized through a chemical bonding method, and the immobilized dodecylimidazolium ionic liquid was selected as the receiving phase material in a POCIS (polar organic chemical integrative sampler) like passive sampler to monitor five perfluoroalkyl substances (PFASs) in water. Twenty-one days of integrative accumulation was conducted in laboratory scale experiments, and the accumulated PFASs in the samplers were eluted and analyzed by high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). The partitioning coefficients of most PFASs between sampler sorbents and water in the immobilized ionic liquid (IIL)-sampler were higher than those in the HLB-sampler, especially for compounds with shorter alkyl chains. The effects of flow velocity, temperature, dissolved organic matter (DOM) and pH on the uptake of these analytes were also evaluated. Under the experimental conditions, the uptake of PFASs in the IIL-sampler slightly increased with the flow velocity and temperature, while different influences of DOM and pH on the uptake of PFAS homologues with short or long chains were observed. The designed IIL-samplers were applied in the influent and effluent of a wastewater treatment plant. All five PFASs could be accumulated in the samplers, with concentrations ranging from 6.5*10-3-3.6*10-1nmol/L in the influent and from 1.3*10-2-2.2*10 1nmol/L in the effluent. The calculated time-weighted average concentrations of most PFASs fit well with the detected concentrations of the active sampling, indicating the applicability of the IIL-sampler in monitoring these compounds in water. PMID- 28802528 TI - How Young Is Too Young in Breast Cancer?-Young Breast Cancer Is Not a Unique Biological Subtype. AB - BACKGROUND: There is no uniformly adopted cutoff value to define "young patients" with breast cancer. This study was designed to determine an optimal cutoff value, to investigate prognostic factors and to explore gene expression profiles of young female breast cancer. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results database was examined to identify cases of female breast cancer diagnosed between 2000 and 2007. The optimal cutoff value for young age was determined using the X-tile program (Yale University, version 3.6.1). Age specific gene expression profiles were explored using RNA sequence data from the Cancer Genome Atlas database. RESULTS: The age of 40 years was determined as the optimal cutoff value. Among 94,087 patients, 12,755 were aged 40 years or younger (younger group), and 81,332 were older (older group). The 5- and 10-year cancer specific survival rates in younger and older groups were 88.74% and 80.65%, respectively, and 93.22% and 88.43%, respectively (P < .001). Univariate and multivariate analyses indicated younger patients had worse prognosis. Subgroup analysis according to estrogen receptor (ER) showed the risk for cancer-specific death of ER-positive (ER+) younger patients increased by approximately 2 times (hazard ratio, 1.96) compared with ER+ older patients. We failed to find any age related gene in 509 patients after adjusting according to subtype (50-gene prediction analysis of a microarray) and histological type. CONCLUSION: The age of 40 years is a reasonable cutoff value for defining "young." Young patients with breast cancer, especially those in the ER+ subgroup, have worse prognosis. However, we found that young breast cancer is not a unique biological entity, and therefore, a lack of new potential targets. PMID- 28802529 TI - Breast Lesions: Diagnosis Using Diffusion Weighted Imaging at 1.5T and 3.0T Systematic Review and Meta-analysis. AB - INTRODUCTION: We compared the diagnostic performance of diffusion weighted imaging (DWI) acquired with 1.5T and 3.0T magnetic resonance (MR) units in differentiating malignant breast lesions from benign ones. MATERIALS AND METHODS: A comprehensive search of the PubMed and Embase databases was performed for studies reported from January 1, 2000 to February 19, 2016. The quality of the included studies was assessed. Statistical analysis included pooling of diagnostic sensitivity and specificity and assessing data inhomogeneity and publication bias. RESULTS: A total of 61 studies were included after a full-text review. These included 4778 patients and 5205 breast lesions. The overall sensitivity and specificity were 90% (95% confidence interval [CI], 88%-92%) and 86% (95% CI, 82%-89%), respectively. The pooled diagnostic odds ratio was 53 (95% CI, 37-74). For breast cancer versus benign lesions, the area under the curve was 0.94 (95% CI, 0.92-0.96). For the 44 studies that used a 1.5T MR unit, the pooled sensitivity and specificity were 91% (95% CI, 89%-92%) and 86% (95% CI, 81%-90%), respectively. For the 17 studies that used a 3.0T MR unit, the pooled sensitivity and specificity were 88% (95% CI, 83%-91%) and 84% (95% CI, 0.78-0.89), respectively. Publication bias and significant heterogeneity were observed; however, no threshold was found among the 61 studies. No significant difference was found in the sensitivity or specificity between the subgroups. CONCLUSION: The results of the comparison between the subgroups that had used either a 1.5T or 3.0T MR unit suggest that the diagnostic accuracy for breast cancer compared with benign lesions is not significantly different. PMID- 28802530 TI - Report of the International Society for Heart and Lung Transplantation Working Group on Primary Lung Graft Dysfunction, part II: Epidemiology, risk factors, and outcomes-A 2016 Consensus Group statement of the International Society for Heart and Lung Transplantation. PMID- 28802531 TI - Corrigendum to "Characterization of the efficiency and uncertainty of skimmed milk flocculation for the simultaneous concentration and quantification of water borne viruses, bacteria and protozoa" [J. Microbiol. Methods 134 (2017) 46-53]. PMID- 28802532 TI - Challenges and Controversies in Hypertrophic Cardiomyopathy: Clinical, Genomic and Basic Science Perspectives. PMID- 28802533 TI - Bifurcation Culprit Lesions in ST-segment Elevation Myocardial Infarction: Procedural Success and 5-year Outcome Compared With Nonbifurcation Lesions. AB - INTRODUCTION AND OBJECTIVES: We assessed short- and long-term outcomes of primary angioplasty in ST-segment elevation myocardial infarction by comparing bifurcation culprit lesions (BCL) with non-BCL. METHODS: Observational study with a propensity score matched control group. Among 2746 consecutive ST-segment elevation myocardial infarction patients, we found 274 (10%) patients with BCL. The primary outcome was a composite endpoint including all-cause death, myocardial infarction, coronary artery bypass grafting or target vessel revascularization, assessed at 30-days and 5-years. RESULTS: Baseline characteristics showed no differences after propensity matching (1:1). In the BCL group, the most frequent strategy was provisional stenting of the main branch (84%). Compared with the non-BCL group, the procedures were technically more complex in the BCL group in terms of need for balloon dilatation (71% BCL vs 59% non-BCL; P = .003), longer procedural time (70 +/- 29minutes BCL vs 62.8 +/- 28.9minutes non-BCL; P = .004) and contrast use (256.2 +/- 87.9mL BCL vs 221.1 +/ 82.3mL non-BCL; P < .001). Main branch angiographic success was similar (93.4% BCL vs 93.8% non-BCL; P = .86). Thirty-day all-cause mortality was similar between groups: 4.7% BCL vs 5.1% non-BCL; P = .84. At the 5-year follow-up, there were no differences in all-cause death (12% BCL vs 13% non-BCL; P = .95) or the combined event (22% BCL vs 21% non-BCL; P = .43). CONCLUSIONS: Primary angioplasty of a BCL was technically more complex; however, main branch angiographic success was similar, and there were no differences in long-term prognosis compared with non-BCL patients. PMID- 28802534 TI - Cheilectomy for Treatment of Symptomatic Distal Interphalangeal Joint Osteoarthritis: A Review of 78 Patients. AB - PURPOSE: To determine whether open cheilectomy and debridement of the distal interphalangeal (DIP) joint is a safe and effective alternative to joint arthrodesis for the treatment of symptomatic osteoarthritis. METHODS: Seventy eight patients with symptomatic DIP joint osteoarthritis and with a minimum follow-up of 24 months were retrospectively reviewed. Preoperative radiographs were graded. Open cheilectomy and debridement of the DIP joint was performed in all patients. The DIP joint was immobilized for 4 weeks after surgery. Patients were evaluated clinically and radiographically. Visual analog scale pain scores and range of motion were assessed. RESULTS: At a median final follow-up of 36 months (minimum, 24 months), there was a significant improvement in mean visual analog scale pain scores from 8 to 1. Distal interphalangeal joint flexion contracture was improved by a mean of 6 degrees and DIP joint range of motion was improved by a mean of 20 degrees . No postoperative infections or other complication were noted. No reoperations were required/performed during the follow-up period. CONCLUSIONS: Open DIP joint cheilectomy is a safe and effective alternative to DIP joint arthrodesis in patients with symptomatic osteoarthritis who wish to preserve joint motion. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 28802535 TI - The Effects of Autologous Platelet-Rich Fibrin on Flexor Tendon Healing in a Rabbit Model. AB - PURPOSE: Platelet-rich plasma containing large amounts of growth factors is purported to increase repaired flexor tendon strength. However, the use of bovine thrombin has the risk of antibody formation. We evaluated the effects of the newer generation autologous platelet-rich fibrin (PRF) on flexor tendon healing. METHODS: We performed surgical repair of 32 flexor tendons from the index and ring digits of the hind paws of 8 New Zealand white rabbits. In the PRF group, the PRF membrane was either wrapped around or interposed between the repair sites. At 3 weeks after surgery, the tested tendons were subjected to range of motion analysis, cross-sectional area measurement, biomechanics testing, and histological analysis. RESULTS: The results showed no significant increase in range of motion in the PRF group compared with the control group, but there was a significant increase in cross-sectional area of the tendons in the PRF group. The biomechanical testing suggested that the control had a higher load to failure and stress to failure but similar stiffness and modulus to the PRF group. CONCLUSIONS: The PRF did not have a major influence on cellular organization. It also had an undesirable effect on the biomechanical properties of repaired flexor tendons. CLINICAL RELEVANCE: The findings of this study suggest PRF may, in certain situations, hinder rather than enhance, the healing for repaired flexor tendons. PMID- 28802536 TI - Incidence of Glove Perforation During Hand Surgical Procedures. AB - PURPOSE: To determine the rate of glove perforation during hand surgery. METHODS: We prospectively examined the rate of glove perforations among 10 fellowship trained hand surgeons at our institution during a 6 week period. Gloves were tested for perforation using a water-fill technique at the conclusion of each surgical procedure. Surgeons recorded the presence of any glove perforations. RESULTS: Eleven perforations were identified in 10 gloves among 600 surgical procedures during the study period. The perforation rate per case was 1.5% (95% confidence interval, 0.78% to 2.8%). Forty percent of perforations (n = 4) occurred during fracture surgery. Other holes occurred during isolated carpal tunnel release (n = 3) or combined carpal tunnel and trigger finger release (n = 3). The perforation was noticed intraoperatively in only 2 gloves. The difference in perforation rate between single- and double-gloved procedures was not significant. There were no perforations in the inner glove of surgeons who double gloved. A total of 73% of holes (8 of 11) occurred on surgeons' index finger; 75% of these were on the dominant hand. The dominant thumb, non-dominant ring and nondominant little fingers each had a single perforation. CONCLUSIONS: The rate of glove perforation during hand surgery is low. Holes can occur even during soft tissue procedures of short duration. The dominant index finger appears to be at greatest risk for perforation. When they do occur, most often holes are not noticed by the operating surgeon. The baseline glove perforation rate is unknown. CLINICAL RELEVANCE: A high level of vigilance is required to maintain sterile technique. PMID- 28802537 TI - Psychosocial reactions to upper extremity limb salvage: A cross-sectional study. AB - STUDY DESIGN: Descriptive cross-sectional survey study. INTRODUCTION: Limb salvage spares an extremity at risk for amputation after a major traumatic injury. Psychosocial recovery for individuals with lower extremity limb salvage has been discussed in the literature. However, to date, psychosocial reactions for individuals with upper extremity (UE) limb salvage have not been examined. PURPOSE OF THE STUDY: To determine which factors may influence psychosocial adaptation to UE limb salvage. METHODS: Participants (n = 30; 28 males) were adults (mean, 30.13; range, 18-61) who sustained an UE limb salvage from a traumatic event. Adaptation was measured using a modified version of the Reactions to Impairment and Disability Inventory. RESULTS: A linear mixed-effects regression found that worse psychosocial adaptation was associated with having less than a college degree, being less than 6 months post-injury, being older than 23 years, and having more pain. Dominant hand injuries were found to influence poor adaptation on the denial Reactions to Impairment and Disability Inventory subscale only. DISCUSSION: The results of this study indicate that there is potential for nonadaptive reactions and psychological distress with certain variables in UE limb salvage. Therapists may use these results to anticipate which clients may be at risk for poor psychosocial outcomes. CONCLUSIONS: This study indicates the need for early consideration to factors that affect psychological prognosis for the UE limb salvage population. However, future research is indicated to better understand the unique psychosocial challenges and needs of these individuals. LEVEL OF EVIDENCE: 4. PMID- 28802538 TI - What is the reliability of clinical measurement tests for humeral head position? A systematic review. AB - STUDY DESIGN: Systematic review. INTRODUCTION: Physiotherapists routinely assess the position of the humeral head (HH) in patients with shoulder pain. PURPOSE OF THE STUDY: To conduct a systematic review to determine the quality and content of studies that evaluated the reliability of clinical measurement methods for assessing the HH position. METHODS: Five databases and gray literature were searched for studies fitting the eligibility criteria. After abstract and full text review, the included studies were appraised using the Quality Appraisal of Reliability Studies checklist. Articles were considered of high quality if 8 was achieved on the checklist, and the overall quality of evidence was classified using prespecified criteria. Multiple raters extracted and performed quality ratings; a consensus process was used to finalize the reliability data that were synthesized and presented in a narrative synthesis. Reliability was classified as excellent if the intracorrelation coefficients or intercorrelation coefficients (ICCs) reported exceeded 0.75. RESULTS: Fifteen studies on the reliability of ultrasound (US) and 3 studies on palpation were included. The methodologic quality was moderate in 17 of 18 studies. The intrarater reliability for all studies was excellent (ICC, 0.76-0.99) with the exception of the 90 degrees abduction in internal rotation position (ICC, 0.48) for palpation. The inter rater reliability tended to be lower (ICC, 0.48-0.68) for palpation and higher (ICC, 0.66-0.99) for US. Physiotherapists demonstrated excellent intrarater reliability across different levels of training in ultrasonography. DISCUSSION: Our study found a moderate overall level of evidence to support the use of US for assessing HH position in symptomatic or asymptomatic subjects. CONCLUSION: A moderate overall level of evidence exists for the use of US to reliably assess the HH position. Limited research supports the methods used for palpation within a clinical setting. LEVEL OF EVIDENCE: 2a. PMID- 28802539 TI - Barriers and Solutions to Fieldwork Education in Hand Therapy. AB - STUDY DESIGN: Survey. INTRODUCTION: Fieldwork education is a vital component of training the next generation of CHTs. Barriers and solutions to fieldwork rotations in hand therapy are examined, as well as proposed solutions, including recommendations for student preparation. PURPOSE OF THE STUDY: This descriptive study examined barriers for certified hand therapist clinicians to accept students for clinical rotations and clinicians' preferences for student preparation before a rotation in a hand setting. METHODS: A survey was developed, peer reviewed, and distributed using the electronic mailing list of the Hand Therapy Certification Commission via SurveyMonkey. Aggregate responses were analyzed to identify trends including barriers to student clinical rotations and recommendations for students to prepare for hand rotations. RESULTS: A total of 2080 participants responded to the survey, representing a 37% response rate. Common logistical barriers were identified for accepting students such as limited clinical time and space. Many clinicians (32% agree and 8% strongly agree) also felt that the students lack the clinical knowledge to be successful. Areas of knowledge, skill set, and experience were surveyed for development before a clinical rotation in a hand setting. Most respondents (74%) reported increased likelihood of accepting a student with the recommended preparation. Novel qualitative responses to improve clinical experiences are presented as well. DISCUSSION: Student preparation before a clinical rotation in a hand setting appears to be a significant barrier based on the survey results. Areas of recommended knowledge, skill set, and experience may serve to guide both formal and informal methods of student preparation before a hand-specific clinical rotation to facilitate knowledge translation from experienced certified hand therapists to the next generation. CONCLUSION: Although logistical barriers may be difficult to overcome, hand-specific preparation based on clinician' recommendations may facilitate student acceptance and success in hand specialty clinical rotations. LEVEL OF EVIDENCE: N/A. PMID- 28802540 TI - Corrigendum to 'The menagerie of the basal forebrain: how many (neural) species are there, what do they look like, how do they behave and who talks to whom?' [Curr Opin Neurobiol 2017, 44:159-166]. PMID- 28802541 TI - Opioid doses and acute care utilization outcomes for adults with sickle cell disease: ED versus acute care unit. AB - BACKGROUND: Acute care units (ACUs) with focused sickle cell disease (SCD) care have been shown to effectively address pain and limit hospitalizations compared to emergency departments (ED), the reason for differences in admission rates is understudied. Our aim was compare effects of usual care for adult SCD pain in ACU and ED on opioid doses and discharge pain ratings, hospital admission rates and lengths of stay. METHODS: In a retrospective, comparative cohort, single academic tertiary center study, 148 adults with sickle cell pain received care in the ED, ACU or both. From the medical records we documented opioid doses, unit discharge pain ratings, hospital admission rates, and lengths of stay. FINDINGS: Pain on admission to the ED averaged 8.7+/-1.5 and to the ACU averaged 8.0+/-1.6. The average pain on discharge from the ED was 6.4+/-3.0 and for the ACU was 4.5+/ 2.5. 70% of the 144 ED visits resulted in hospital admissions as compared to 37% of the 73 ACU visits. Admissions from the ED or ACU had similar inpatient lengths of stay. Significant differences between ED and ACU in first opioid dose and hourly opioid dose were noted. CONCLUSIONS: Applying guidelines for higher dosing of opioids for acute painful episodes in adults with SCD in ACU was associated with improved pain outcomes and decreased hospitalizations, compared to ED. Adoption of this approach for SCD pain in ED may result in improved outcomes, including a decrease in hospital admissions. PMID- 28802542 TI - The impact of IV alteplase on long-term patient survival: The Georgia Coverdell acute stroke registry's experience. AB - INTRODUCTION: Intravenous alteplase reduces disability and improves functionality among acute ischemic stroke patients. Two decades after its approval, only a small fraction of patients get the treatment, and demonstrating its impact on mortality may make a strong case for its wider use. This study assessed the impact of thrombolytic treatment by alteplase on 1-year mortality and readmission among acute ischemic stroke patients. METHOD: The 2008-2013 Georgia Coverdell Acute Stroke Registry data were linked with the 2008-2013 hospital discharge and the 2008-2014 death data in Georgia. Multiple imputation was applied; a propensity score measuring the probability of receiving intravenous alteplase was calculated and used for matching. A conditional logistic regression was applied to compare 1-year mortality and readmission among propensity score matched pairs. RESULTS: Overall, 20.3% of 9620 acute ischemic stroke patients died and 22.4% were readmitted in one year. The multivariable regression result showed that patients who did not receive IV alteplase had a 1.49 (95%CI: 1.09-2.04; p value=0.01) times higher odds of dying at one year than those who were treated with the thrombolytic agent. Among patients discharged home, no statistically significant difference was documented in the odds of being readmitted at least once within 365days post-stroke discharge. DISCUSSION AND CONCLUSION: After accounting for patient differences and missing value, intravenous alteplase is associated with reduction in long-term mortality. The results of this study suggest that patients who are identified as eligible for intravenous alteplase need to be offered the treatment. PMID- 28802543 TI - Outcomes and predictors of failure of non-invasive ventilation in patients with community acquired pneumonia in the ED. AB - OBJECTIVE: We set out to describe the use and analyze the predictors of non invasive ventilation failure in patients with community-acquired pneumonia who receive non-invasive ventilation as first line ventilatory therapy in the emergency department. METHODS: A retrospective cohort study was conducted among consecutive patients with community acquired pneumonia requiring ventilator support presenting to two tertiary care university-affiliated emergency departments. Multivariable logistic regression analysis was used to determine predictors of non-invasive ventilation failure at initiation of non-invasive ventilation and at two hours of non-invasive ventilation use; RESULT: After excluding patients with a do not resuscitate order status, 163 (74.8%) patients with community acquired pneumonia were initially treated with non-invasive ventilation on initial presentation to the emergency department. Non-invasive ventilation failure occurred in 50% of patients and was found to be associated with the absence of chronic obstructive airway disease, APACHE II score, the need for hemodynamic support and the number of CXR quadrants involved. Two-hour physiological parameters associated with non-invasive ventilation failure included higher respiratory rate, lower serum pH and the ongoing need of hemodynamic support. CONCLUSION: In conclusion, the use of non-invasive ventilation to support patients presenting to the emergency department with respiratory failure and community acquired pneumonia is common and is associated with a significant failure rate. Hemodynamic support is a strong predictor of failure. The selection of the appropriate patient and monitoring of physiological parameters while on NIV is crucial to ensure successful treatment. PMID- 28802544 TI - A role of the endothelial nitric oxide system in acute renal colic caused by ureteral stone. AB - BACKGROUND AND AIMS: Endothelial nitric oxide synthase gene polymorphisms play a role in some pathophysiological processes. In this study, the possible effects of endothelial nitric oxide synthase gene polymorphisms on ureteral stone disease in patients who were admitted to the emergency department with severe pain due to renal colic are examined. MATERIALS AND METHODS: The study groups were designed as controls and patients. The control group was formed from the healthy volunteers who applied to the blood center next to the emergency service. The patient group comprised patients who were diagnosed with ureteral stone disease with severe pain. All of the genetic studies were based on extracted peripheral blood samples using the necessary procedures from the Genome and Stem Cell Center at Erciyes University (GENKOK). The data were analyzed with SPSS (IBM, ver 20, United Sate). RESULTS: The study group comprised 62 females and 138 males, and the control group comprised 64 females and 136 males. All of the stones that caused renal colic were found to be localized in the ureters and the ureterovesical junction. The genotypes of the intron 4 polymorphism were found to be as follows: 4a/4a in 10 people, 4b/4a in 115, and 4b/4b in 275 people. The GG genotype of the eNOS-G894T polymorphism was found in 108 patients in the study group and in117 of the healthy individuals. There was no statistically significant difference between the two groups regarding these data. CONCLUSION: Although this study is the first in the literature to examine the relationship between renal colic and endothelial nitric oxide synthase gene polymorphisms, our study demonstrated that no relation was found. PMID- 28802545 TI - Brazilian Portuguese version of the Female Genital Self Image Scale (FGSIS) for women seeking abdominoplasty. PMID- 28802546 TI - Paediatric dermatofibrosarcoma protuberans (DFSP): Evaluation of a rare childhood malignancy, the Welsh experience. PMID- 28802548 TI - Optic nerve glioblastoma detected by 11C-Methionine brain PET/CT. PMID- 28802547 TI - Good Ol' Fat: Links between Lipid Signaling and Longevity. AB - Aging is the single greatest risk factor for the development of disease. Understanding the biological molecules and mechanisms that modulate aging is therefore critical for the development of health-maximizing interventions for older people. The effect of fats on longevity has traditionally been disregarded as purely detrimental. However, new studies are starting to uncover the possible beneficial effects of lipids working as signaling molecules on health and longevity. These studies highlight the complex links between aging and lipid signaling. In this review we summarize accumulating evidence that points to changes in lipid metabolism, and in particular lipid signaling, as an underlying mechanism for healthy aging. PMID- 28802549 TI - Diffuse Renal Cortical Hemorrhage in the Setting of Subcapsular Hematoma: Diagnosis and Treatment with Embolization. AB - PURPOSE: To describe radiologic findings, embolization technique, and clinical outcomes in patients with renal subcapsular hematoma and diffuse cortical hemorrhage. MATERIALS AND METHODS: Ten patients with renal subcapsular hematoma and diffuse cortical hemorrhage were reviewed. Nine of the 10 had undergone procedures (nephrostomy, n = 4; biopsy, n = 4; embolization of a cerebral aneurysm, n = 1) and 1 patient was receiving oral anticoagulation. Computed tomography (CT), angiography, and embolization of bleeding sites were performed in all patients. RESULTS: CT and angiography revealed subcapsular hematoma with diffuse cortical hemorrhage at the level of the interlobar and/or arcuate branches. Total embolization of intrarenal arterial branches was required in 3 patients. Partial embolization, which also resulted in permanent functional loss, was required in 4. The functional loss was likely caused by the embolization procedure and the underlying renal disease. In these 4 patients, renal failure was demonstrated by scintigraphy in 3 cases and based on the need to start chronic hemodialysis in 1 case. In the remaining three patients, embolization did not compromise renal function. CONCLUSIONS: Diffuse cortical hemorrhage unrelated to the site of puncture may be seen in some cases of subcapsular hematoma. The cause is likely the laceration of transcortical capsular arteries secondary to enlargement of the subcapsular hematoma. In the present case series, embolization achieved hemorrhage control, but loss of renal function was observed in patients with underlying renal disease. PMID- 28802550 TI - MR Coagulation: A Novel Minimally Invasive Approach to Aneurysm Repair. AB - PURPOSE: To demonstrate a proof of concept of magnetic resonance (MR) coagulation, in which MR imaging scanner-induced radiofrequency (RF) heating at the end of an intracatheter long wire heats and coagulates a protein solution to effect a vascular repair by embolization. MATERIALS AND METHODS: MR coagulation was simulated by finite-element modeling of electromagnetic fields and specific absorption rate (SAR) in a phantom. A glass phantom consisting of a spherical cavity joined to the side of a tube was incorporated into a flow system to simulate an aneurysm and flowing blood with velocities of 0-1.7 mL/s. A double lumen catheter containing the wire and fiberoptic temperature sensor in 1 lumen was passed through the flow system into the aneurysm, and 9 cm3 of protein solution was injected into the aneurysm through the second lumen. The distal end of the wire was laid on the patient table as an antenna to couple RF from the body coil or was connected to a separate tuned RF pickup coil. A high RF duty cycle turbo spin-echo pulse sequence excited the wire such that RF energy deposited at the tip of the wire coagulated the protein solution, embolizing the aneurysm. RESULTS: The protein coagulation temperature of 60 degrees C was reached in the aneurysm in ~12 seconds, yielding a coagulated mass that largely filled the aneurysm. The heating rate was controlled by adjusting pulse-sequence parameters. CONCLUSIONS: MR coagulation has the potential to embolize vascular defects by coagulating a protein solution delivered by catheter using MR imaging scanner-induced RF heating of an intracatheter wire. PMID- 28802551 TI - A Survey of Submassive Pulmonary Embolism Treatment Preferences among Medical and Endovascular Physicians. AB - PURPOSE: To determine treatment preferences among endovascular and medical physicians who manage acute submassive pulmonary embolism (PE). MATERIALS AND METHODS: From July through August 2016, 83 sites across the United States were surveyed, and 60 completed the survey. Endovascular and medical physicians were asked to rate their predilection for catheter-directed thrombolysis (CDT) on a 5 point scale and for systemic thrombolysis (ST) as "yes" or "no" in seven case scenarios of submassive PE. A CDT score >= 4 was considered to represent a predilection for CDT. Mean scores were used to compare CDT preferences between physicians. Percentages of physicians who preferred CDT or ST were calculated. P values < .05 were considered statistically significant. RESULTS: Across all scenarios (numbered S1-S7) combined, endovascular physicians had a significantly higher CDT score (mean, 3.52) than medical physicians (mean, 3.01; P < .0001). Scenario-by-scenario analysis revealed that the mean CDT score was significantly higher for endovascular physicians (S1, 4.25; S2, 3.72; S3, 2.82; S4, 2.68; S5, 3.45; S6, 3.67; S7, 4.02) compared with medical physicians (S1, 3.62 [P < .001]; S2, 3.18 [P < .001]; S3, 2.45 [P = .001]; S4, 2.37 [P = .011]; S5, 2.97 [P < .001]; S6, 3.20 [P < .001]; S7, 3.53 [P < .001]). Overall, a significantly higher percentage of endovascular physicians (56.7%) indicated a predilection for CDT compared with medical physicians (37.9%; P < .001). Also, a significantly higher percentage of physicians, regardless of specialty, indicated a predilection for CDT (47.2%) than did for ST (5.3%; P < .0001). CONCLUSIONS: Endovascular physicians exhibited a greater predilection for CDT to treat acute submassive PE compared with their medical colleagues. Endovascular and medical physicians seemed to more frequently choose CDT than ST. PMID- 28802552 TI - Randomized Controlled Trial Comparing Radiologic Pigtail-Retained Gastrostomy and Radiologic Mushroom-Retained Gastrostomy. AB - PURPOSE: To prospectively compare 2 different types of percutaneous fluoroscopic gastrostomy procedures (pigtail-retained gastrostomy [PG] vs mushroom-retained gastrostomy [MG]). MATERIALS AND METHODS: Between March 2014 and February 2016, 100 patients were randomly assigned to receive 14-F PG or 20-F MG. Block randomization (block size 4) was performed, and sample size was calculated to assess the difference in minor complications. One patient withdrew from the study after allocation. Baseline characteristics were not significantly different between groups (P > .05). Technical success, defined as successful placement of gastrostomy tube, and procedural complications were evaluated. Procedural complications were divided into major and minor complications according to the Society of Interventional Radiology criteria. RESULTS: Technical success rate was 100%. In the PG group, the major complication rate was 2% (1 of 50); 1 patient had a misplaced PG in the peritoneal cavity between the gastric and abdominal walls and developed peritonitis that had to be surgically treated. The minor complication rate was 34% (17 of 50) in the PG group. In the MG group, the major complication rate was 0%, and the minor complication rate was 12.2% (6 of 49). The most common minor complication was tube occlusion. Minor complication rate was significantly higher in the PG group (P = .016). Mean fluoroscopy time was significantly longer in the MG group (P = .013). CONCLUSIONS: Both PG and MG demonstrated high technical success rates in all indications. MG had lower complication rates than PG at the cost of an increase in fluoroscopy times. PMID- 28802553 TI - Effect of cold argon plasma on eggs of the blow fly, Lucilia cuprina (Diptera: Calliphoridae). AB - Non-thermal plasma has been used in many medical applications, including treatment of living cells, blood coagulation, wound healing, and sterilization. The process uses an environmentally friendly gas (e.g., argon, helium, oxygen, nitrogen, or hydrogen) to destroy bacteria cells with no serious adverse effect on humans or animals. However, information on the effect of argon plasma on blow fly eggs is lacking. In this study, we explored the ability of cold argon plasma to destroy the eggs of the Australian sheep blow fly, Lucilia cuprina (Wiedemann, 1830); its larvae are a myiasis-producing agent in both human and animals. We tested the effect of cold argon plasma exposure for 1, 2, 3 and 5min on L. cuprina eggs. Since the temperature of cold Ar plasma is around 30 degrees C, to clarify the effect of temperature on the fly eggs, hot air from an electric dryer was tested for comparison. Cold argon plasma exposure in eggs significantly reduced the survival rates of second instar larvae at all exposures tested; the effects were time dependent, with a stronger effect at longer exposure (32% survival rate after a 1-min treatment; 20%, 2min; 20%, 3min; and 6%, 5min), compared to the control (86%). No significant differences were observed in larval survival rates from eggs treated with hot air (80-84%, after 1- to 5-min treatments) versus the control (86%). These results were supported by observing the treated eggshells under a scanning electron microscope (SEM), we found noticeable aberrations only in the plasma treated groups. The emission spectrum of the argon gas discharge revealed emission lines of hydroxyl radicals at 309.1nm; these may cause the deterioration of the treated L. cuprina eggs. Our results have shown the possibility of using cold argon plasma in medical applications, in particular treating myiasis wounds. PMID- 28802554 TI - Response to "Physical exercise to manage sleep problems in pediatric patients with epilepsy and ADHD". PMID- 28802555 TI - JPS drives prosthodontics with pride and responsibility. PMID- 28802557 TI - Parents' Perspectives of Closeness and Separation With Their Preterm Infants in the NICU. AB - OBJECTIVE: To discover parents' perceptions of closeness to and separation from their preterm infants in the NICU. DESIGN: Qualitative descriptive. SETTING: Urban Level III NICU. PARTICIPANTS: Twenty parents of preterm infants in the NICU. METHODS: After ethics approval, data were collected with a smartphone application created for this study. Parents recorded their descriptions of moments of closeness and separation over a 24-hour period in the NICU. Data were transcribed verbatim and content was analyzed. RESULTS: Five themes related to parents' perceptions of closeness and separation were identified: Having a role as a parent: Feeling autonomous and making decisions; Providing for and getting to know the infant: Feeding, holding, and interacting; Support from staff; Reluctantly leaving the infant's bedside; and NICU environment. CONCLUSION: Autonomy is a key element of a parent's perception of closeness. Staff in the NICU can facilitate autonomy by involving parents in the care of their preterm infants as much as possible to reinforce the parental role. Parents described leaving their infants' bedsides as very difficult. PMID- 28802556 TI - Randomized sham-controlled trials in endoscopy: a systematic review and meta analysis of adverse events. AB - BACKGROUND AND AIMS: Sham procedures in endoscopy are used with the intention of controlling for placebo response, potentially allowing more precise evaluation of treatment effect. Nevertheless, this type of study may impose significant risk without potential benefit for those in the sham group. The aim of the current study was to systematically review and analyze the endoscopic literature to assess the safety of sham controls. METHODS: MEDLINE and Embase databases were searched for endoscopic sham procedures for all dates to July 2017. Only randomized controlled trials comparing an endoscopic therapy with a sham were included. Primary outcome was adverse events (AEs) categorized as mild, moderate, or severe. Results were combined using a random-effects model. Heterogeneity was assessed with the I2 statistic, and publication bias was assessed with the Egger test and funnel plots. RESULTS: Data were extracted from 34 publications (1987 2017; 100% full text), with a total of 2492 procedures (1355 treatment/1137 sham). Sham procedures involved upper endoscopy (31 studies) and ERCP (3 studies). Treatment arms included procedures with the following indications: weight loss (38.2%), GI bleeding (26.5%), GERD (20.6%), sphincter of Oddi dysfunction (8.8%), and dysphagia (6.2%). Overall percentage of severe adverse events (SAEs) in the sham group was 1.7% (19/1137). Of these, the most common SAEs in the sham groups were need for surgery/intensive care unit stay (35.3%), post-ERCP pancreatitis (23.5%), and perforation (11.8%). There was no significant difference in the odds of developing an SAE between the treatment group and the sham group (odds ratio, 1.3; 95% confidence interval [CI], 0.7-2.3). The pooled additional risk incurred from being initially randomized to the sham arm and then receiving a cross-over intervention was significant (RR, 1.33; 95% CI, 1.14-1.56; P < .001), compared with patients initially randomized to the study intervention. CONCLUSION: The frequency of AEs in endoscopic sham procedures is substantial, and patients are subjected to considerable morbidity. These results raise a serious ethical dilemma regarding the use of sham-controlled trials. PMID- 28802558 TI - Women, Infants, and Opioids. PMID- 28802559 TI - Absence of subchronic oral toxicity and genotoxicity of rice koji with Aspergillus terreus. AB - Koji products have been considered as an effective fermented food consumed in East Asia with many health benefits. Particularly, rice koji with Aspergillus terreus (RAT) has been reported to be able to prevent hyperlipidemia and hepatic steatosis through regulating cholesterol synthesis. Despite its biological activities, there is a lack of comprehensive information to give an assurance of its safety. Therefore, the objective of this study was to perform a series of toxicological studies (repeated dose oral toxicity and genotoxicity) according to test guidelines published by the Organization for Economic Cooperation and Development. Along with acute toxicity study using rats and beagle dogs, a 13 week toxicity study revealed no clear RAT-related toxic changes, including body weight, mortality, hematology, serum biochemistry, organ weight, and histopathology after oral administration at doses of 500, 1000, and 2000 mg/kg BW. The no-observed-adverse-effect level of RAT was considered to be more than 2000 mg/kg BW/day in rats of both genders. In addition, potential genotoxicity was evaluated using a standard battery of tests (Ames test, chromosome aberration assay, and micronucleus assay) which revealed that RAT showed no genotoxicity. Accordingly, these results suggest that RAT is a safe and non-toxic functional food for human consumption at proper dose. PMID- 28802561 TI - Recombinant human elafin promotes alveologenesis in newborn mice exposed to chronic hyperoxia. AB - BACKGROUND/AIMS: Elastase inhibitors reverse elastin degradation and abnormal alveologenesis and attenuate the lung structural abnormalities induced by mechanical ventilation with O2-rich gas. The potential of these molecules to improve endothelial function and to ameliorate severe bronchopulmonary dysplasia (BPD) during lung development is not yet understood. We sought to determine whether the intratracheal treatment of newborn mice with the elastase inhibitor elafin would prevent hyperoxia-induced lung elastin degradation and the cascade of events that cause abnormal alveologenesis. METHODS: Newborn mice were exposed to 85% O2 for 3, 7, 14 or 21days. Recombinant human elafin was administered by intratracheal instillation from the first day every two days for 20days. We next used morphometric analyses, quantitative RT-PCR, immunostaining, Western blotting, and ELISA methods to assess the key variables involved in elastogenesis disruption and the potential signaling pathways noted below in recombinant human elafin-treated mouse pups that had been exposed to 85% O2. RESULTS: We found that impaired alveolar development and aberrant elastin production were associated with elevations in whole lung elastase levels in 85% O2-exposed lungs. Elafin attenuated the structural disintegration that developed in the hyperoxia-damaged lungs. Furthermore, elafin prevented the elastin degradation, neutrophil influx, activation of TGF-beta1 and apoptosis caused by 85% O2 exposure. CONCLUSIONS: Pulmonary elastase plays an important role in disrupting elastogenesis during O2 induced damage, which is the result of a pulmonary inflammatory response. Elafin prevents these changes by inhibiting elastase and the TGF-beta1 signalling cascade and may be a new therapeutic target for preventing O2-induced lung injury in neonates. PMID- 28802560 TI - Traumatic brain injuries during development disrupt dopaminergic signaling. AB - Traumatic brain injuries (TBI) sustained during peri-adolescent development produce lasting neuro-behavioral changes that render individuals at an increased risk for developing substance abuse disorders. Experimental and clinical evidence of a prolonged period of hypodopaminergia after TBI have been well documented, but the effect of juvenile TBI on dopaminergic dysfunction and its relationship with substance abuse have not been investigated. In order to determine the effect of juvenile brain injury on dopaminergic signaling, female mice were injured at 21days of age and then beginning seven weeks later were assessed for behavioral sensitization to amphetamine, a drug that increases synaptic dopamine availability. Together with a histological analysis of tyrosine hydroxylase, dopamine transporter, and dopamine D2 receptor expression, our data are indicative of a persistent state of hypodopaminergia well into adulthood after a juvenile TBI. Further, mice that sustained a juvenile TBI exhibited a significantly reduced activation of cFos in the urocortin-positive cells of the Edinger-Westphal nucleus in response to ethanol administration. Taken together, these data provide strong evidence for the vulnerability of juveniles to the development of lasting neuro-behavioral problems following TBI, and indicate a role of injury-induced hypodopaminergia as a risk factor for substance abuse later in life. PMID- 28802562 TI - Current research development of single cell genome in urological tumor. AB - The technique of whole genome amplification is advancing rapidly and generating attention on detecting genomic lesions in individual cancer cells. Also, single cell genome could label the uniqueness of each cell, its individual mutations and structural variations especially in cancer studies. In this Review, we provide the insight into the current state of single-cell genome in urological tumor mainly including kidney cancer, bladder cancer and prostate cancer. We put more forward on the new progress of the technique used by single-cell genomes and different results of the genes transform on random tumor tissue from single cell isolated on account of tumor heterogeneity. With the advent of more complete and accurate genome information, single-cell sequencing will become a standard tool in early diagnosis and targeted therapy and prognosis judgement. PMID- 28802563 TI - Metabolic Circuit Involving Free Fatty Acids, microRNA 122, and Triglyceride Synthesis in Liver and Muscle Tissues. AB - BACKGROUND & AIMS: Effective treatments are needed for hepatic steatosis characterized by accumulation of triglycerides in hepatocytes, which leads to hepatocellular carcinoma. MicroRNA 122 (MIR122) is expressed only in the liver, where it regulates lipid metabolism. We investigated the mechanism by which free fatty acids (FFAs) regulate MIR122 expression and the effect of MIR122 on triglyceride synthesis. METHODS: We analyzed MIR122 promoter activity and validated its target mRNAs by transfection of Luciferase reporter plasmids into Huh7, BNL-1ME, and HEK293 cultured cell lines. We measured levels of microRNAs and mRNAs by quantitative real-time PCR analysis of RNA extracted from plasma, liver, muscle, and adipose tissues of C57BL/6 mice given the FFA-inducer CL316243. MIR122 was inhibited using an inhibitor of MIR122. Metabolic profiles of mice were determined using metabolic chambers and by histologic analyses of liver tissues. We performed RNA sequence analyses to identify metabolic pathways involving MIR122. RESULTS: We validated human Agpat1 and Dgat1 mRNAs, involved in triglyceride synthesis, as targets of MIR122. FFAs increased MIR122 expression in livers of mice by activating the retinoic acid-related orphan receptor alpha, and induced secretion of MIR122 from liver to blood. Circulating MIR122 entered muscle and adipose tissues of mice, reducing mRNA levels of genes involved in triglyceride synthesis. Mice injected with an inhibitor of MIR122 and then given CL316243, accumulated triglycerides in liver and muscle tissues, and had reduced rates of beta-oxidation. There was a positive correlation between level of FFAs and level of MIR122 in plasma samples from 6 healthy individuals, collected before and during fasting. CONCLUSIONS: In biochemical and histologic studies of plasma, liver, muscle, and adipose tissues from mice, we found that FFAs increase hepatic expression and secretion of MIR122, which regulates energy storage vs expenditure in liver and peripheral tissues. Strategies to reduce triglyceride levels, by increasing MIR122, might be developed for treatment of metabolic syndrome. PMID- 28802564 TI - Interactions Between Platelets and Inflammatory Monocytes Affect Sickness Behavior in Mice With Liver Inflammation. AB - BACKGROUND & AIMS: Patients with inflammatory liver disease commonly develop debilitating symptoms, called sickness behaviors, which arise via changes in brain function. Monocytes that produce tumor necrosis factor interact with cerebral endothelial cells to activate microglial cells and promote sickness behavior. Platelets regulate inflammation, and aggregates of monocytes and platelets are increased in the circulation of patients with liver disease. We investigated the role of platelets in inducing inflammatory features of circulating monocytes and promoting sickness behaviors in mice with cholestatic liver injury. METHODS: We performed bile-duct ligations or sham surgeries on C57BL/6 or toll-like receptor 4 (TLR4)-knockout mice to induce liver inflammation. Liver inflammation was also induced in a separate group of mice by administration of concanavalin A. Circulating platelets, aggregates of monocytes and platelets, and activation of microglial cells were measured by flow cytometry. To deplete platelets, mice were given anti-thrombocyte serum or normal rabbit serum (control) 4 days after surgery. Interactions between monocytes and cerebral endothelial cells were analyzed by intravital microscopy. Sickness behaviors were quantified based on time spent by adult mice engaging in social behaviors toward a juvenile mouse, compared with time spent in nonsocial behavior or remaining immobile. RESULTS: Aggregates of monocytes and platelets in circulation of mice increased significantly following bile-duct ligation. Platelet-monocyte interactions were required for activation of inflammatory monocytes and production of tumor necrosis factor. Platelet depletion greatly reduced adhesive interactions between inflammatory monocytes and adhesive interactions with cerebral endothelial cells and activation of the microglia, as well as development of sickness behavior. Furthermore, TLR4 signaling was important for aggregation of monocytes and platelets, and development of sickness behavior following bile-duct ligation. These findings were confirmed in mice with concanavalin A-induced liver injury. CONCLUSIONS: In mice with liver inflammation, we found TLR4 and aggregates of monocytes and platelets to regulate microglial activation and development of sickness behavior. These findings might lead to new therapeutic strategies for liver disease-associated symptoms. PMID- 28802565 TI - The Safety and Efficacy of an Alcohol-Free Pancreatic Cyst Ablation Protocol. AB - BACKGROUND & AIMS: Endoscopic ultrasound (EUS)-guided chemoablation with ethanol lavage followed by infusion of paclitaxel is effective for the treatment of mucinous pancreatic cysts. However, complications arise in 3%-10% of patients, presumably linked to the inflammatory effects of ethanol. We aimed to determine whether alcohol is required for effective pancreatic cyst ablation, if removing alcohol from the ablation process would improve complication rates, and whether a multi-agent chemotherapeutic cocktail could increase the rate of complete cyst resolution compared with findings reported from previous trials using alcohol followed by paclitaxel alone. METHODS: Between November 2011 and December 2016, we conducted a single-center, prospective, double-blind trial of 39 patients with mucinous-type pancreatic cysts. Patients were randomly assigned to 1 of 2 groups that underwent EUS-guided pancreatic cyst lavage with either 80% ethanol (control) or normal saline (alcohol-free group). Cysts in both groups were then infused with an admixture of paclitaxel and gemcitabine. Primary outcomes were the rates of complete ablation 12 months after the procedure, and rates of serious and minor adverse events within 30 days of the procedure. RESULTS: At 12 months, 67% of patients who underwent alcohol-free EUS-guided cyst chemoablation had complete ablation of cysts compared with 61% of patients in the control group. Serious adverse events occurred in 6% of patients in the control group vs none of the patients in the alcohol-free group. Minor adverse events occurred in 22% of patients in the control group and none of the patients in the alcohol-free group. The overall rate of complete ablation was 64%. CONCLUSIONS: In this prospective, randomized, controlled trial, we found that alcohol is not required for effective EUS-guided pancreatic cyst ablation, and when alcohol is removed from the ablation process, there is a significant reduction in associated adverse events. A multi-agent chemotherapeutic ablation admixture did not appear to significantly improve rates of complete ablation compared with the current standard of alcohol lavage followed by paclitaxel alone. ClinicalTrials.gov ID: NCT01475331. PMID- 28802566 TI - Alcohol Use and Cardiovascular Disease Risk in Patients With Nonalcoholic Fatty Liver Disease. AB - BACKGROUND & AIMS: Cardiovascular disease (CVD) is the leading cause of death among patients with nonalcoholic fatty liver disease (NAFLD). Moderate drinking (vs abstinence) is associated with lower risk of CVD in the general population. We assessed whether alcohol use is associated with CVD risk in patients with NAFLD. METHODS: We analyzed data from participants in the Coronary Artery Risk Development in Young Adults longitudinal cohort study of 5115 black and white young adults, 18-30 years old, recruited from 4 cities in the United States from 1985 through 1986. Participants self-reported alcohol use at study entry and then again after 15, 20, and 25 years. At year 25 (2010-2011), participants underwent computed tomography examination of the thorax and abdomen and tissue Doppler echocardiography with myocardial strain measured by speckle tracking. Coronary artery calcification was defined as an Agatston score above 0. NAFLD was defined as liver attenuation <51 Hounsfield Units after exclusions. Drinkers reported 1 21 (men) or 1-14 (women) standard drinks/week at years 15, 20, or 25. Nondrinkers reported no alcohol use at years 15, 20, and 25. RESULTS: Of the 570 participants with NAFLD (mean age, 50 years; 54% black; 46% female), 332 (58%) were drinkers; significantly higher proportions of drinkers were white, male, and with higher levels of education compared with nondrinkers (P < .05 for all). Higher proportions of drinkers had obesity, diabetes, and metabolic syndrome compared with nondrinkers (P < .01). There was no difference in liver attenuation between groups (P = .12). After multivariable adjustment, there was no association between alcohol use and CVD risk factors (diabetes, hypertension, hyperlipidemia) or subclinical CVD measures (coronary artery calcification, early transmitral velocity/late (atrial) transmitral velocity (E/A) ratio, global longitudinal strain). CONCLUSIONS: In a population-based sample of individuals with NAFLD in midlife, prospectively assessed alcohol use is not associated with significant differences in risk factors for CVD or markers of subclinical CVD. In contrast to general population findings, alcohol use may not reduce the risk of CVD in patients with NAFLD. PMID- 28802567 TI - Nano-sized and other improved reporters for magnetic resonance imaging of angiogenesis. AB - Magnetic Resonance Imaging (MRI) enables to provide anatomical, functional and molecular information of pathological angiogenesis when used with properly tailored imaging probes. Functional studies have been the domain of Dynamic Contrast Enhancement (DCE) -MRI protocols from which it is possible to extract quantitative estimations on key parameters such as the volumes of vascular and extracellular compartments and the rates of the bidirectional exchange of the imaging reporters across the endothelial barrier. Whereas paramagnetic Gd complexes able to reversibly bind to serum albumin act better than the clinically used small-sized, hydrophilic species, new findings suggest that an accurate assessment of the vascular volume is possible by analyzing images acquired upon the i.v. administration of Gd-labelled Red Blood Cells (RBCs). As far as it concerns molecular MRI, among the many available biomarkers, alphavbeta3 integrins are the most investigated ones. The low expression of these targets makes mandatory the use of nano-sized systems endowed with the proper signal enhancing capabilities. A number of targeted nano-particles have been investigated including micelles, liposomes, iron oxides and perfluorocarbon containing systems. Finally, a growing attention is devoted to the design and testing of "theranostic" agents based on the exploitation of MRI to monitor drug delivery processes and therapeutic outcome. PMID- 28802568 TI - The Application of Suctioning Flexible Ureteroscopy With Intelligent Pressure Control in Treating Upper Urinary Tract Calculi on Patients With a Solitary Kidney. AB - OBJECTIVE: To investigate the usage of intelligently pressure-controlled flexible ureteroscopy (URS) in managing upper urinary tract calculi in patients with a solitary kidney. METHODS: Forty patients with a solitary kidney and upper urinary tract calculus were included in this study. All the patients underwent suctioning URS with intelligent control of renal pelvic pressure by connecting pressure measuring suctioning ureteral access sheath to an irrigation and suctioning platform. Treatment outcome and perioperative data were collected. RESULTS: The mean operative time was 25.2 +/- 14.5 minutes. The mean hospital stay was 4.7 +/- 1.4 days. The stone-free rate at 4 weeks after surgery was 87.5%, and it was 92.5% at 12 weeks after surgery. Two patients (5%) experienced complications of fever postoperatively. There were no complications of elevated serum creatinine, severe bleeding, sepsis, stone street, ureteral mucosa stripping, and ureteral stenosis. CONCLUSION: It is safe and efficient to use the intelligently pressure controlled flexible URS in treating upper urinary tract calculi for patients with a solitary kidney with advantages of high lithotripsy efficacy and low complication rate. PMID- 28802569 TI - Gender and Subspecialty of Urology Faculty in Department-based Leadership Roles. AB - OBJECTIVE: To characterize the current gender and subspecialty of those holding academic departmental administrative and educational leadership roles in urology. METHODS: We conducted a cross-sectional observational study of U.S. Urology Residency Programs in 2016-2017. Inclusion criteria were participation in the Urology Residency Match Program and having a department of urology website. From June 1, 2016 to August 20, 2016, each department's website was queried. If information was missing or unclear, we reviewed faculty biographies and contacted residency program coordinators. RESULTS: We queried 124 urology residency programs. For administrative leadership roles, women comprised 3.3% of chairs, 4.5% of vice chairs, and 7.9% of division directors. For educational leadership roles, women comprised 9.4% of fellowship directors, 8.1% of residency directors, and 27.4% of medical student clerkship directors. The most common subspecialties for chairs included oncology (49.2%), endourology (16.4%), and female urology (7.4%). Among division directors, female urology had the highest representation of women (27.8%) followed by pediatric urology (9.8%), reconstruction (5%), endourology (4.3%), and andrology (4%). CONCLUSION: Overall, women are disproportionately underrepresented when it comes to educational and administrative positions of urology departmental leadership. There is also a wide yet narrowing gender gap as more women are pursuing careers in this field. Given this upward trend we may see more women in positions of leadership over time. Future efforts should be made to help promote the advancement of women to positions of leadership. PMID- 28802570 TI - Organ Preservation Is Less Frequently Performed in Women Surgically Treated for Papillary Renal Cell Carcinoma-Results of a Comprehensive Multicenter Study. AB - OBJECTIVE: To analyze the impact of gender on the clinicopathologic features and survival of patients with surgically treated papillary renal cell carcinoma (papRCC) using a comprehensive international multicenter database. MATERIALS AND METHODS: Data of 2325 patients undergoing surgery for unilateral papRCC between 1984 and 2015 in 17 European and North American centers were retrospectively collated. The impact of clinicopathologic features on the likelihood of nephron sparing surgery (NSS) was evaluated using a multivariable logistic regression model. The influence on cancer-specific mortality (CSM) and other-cause mortality was analyzed by multivariable competing-risk regression models. Finally, subgroup analyses were conducted for organ-confined (n = 2075) and non-organ-confined tumors (n = 250). The median follow-up was 47 months. RESULTS: The study cohort included 1782 (77%) male patients (male-to-female ratio 3.3:1.0). Considering age, symptoms at presentation, performance status, pathologic tumor size, stage, and grade, we observed that there were no significant gender-specific differences. In contrast, female patients underwent NSS significantly less frequently (P <.001). On multivariable analysis, the likelihood of NSS was 72% higher in male patients after adjusting for all relevant cofactors (P <.001). No significant gender-specific differences in terms of CSM and other-cause mortality were demonstrated, but CSM was 59% lower in female patients in the subgroup of organ-confined tumors (P = .001). CONCLUSION: No impact of gender on survival was found analyzing this large cohort of patients undergoing surgery for papRCC. However, CSM appears to be lower in female patients with organ-confined disease. In this context, it is interesting that the likelihood of NSS seems to be significantly higher in male patients. PMID- 28802572 TI - Effect of cadmium on uptake of iron, zinc and copper and mRNA expression of metallothioneins in HepG2 cells in vitro. AB - The intake of cadmium contaminated fish was mimicked by incubating human hepatoblastoma cells (Cell line HepG2) with a combination of different levels of cadmium (0-5MUM) plus the n-3 fatty acids docosahexaenoic acid and eicosapentaenoic acid, which are typical for fish. Uptake of cadmium, iron, copper and zinc was measured by ICP-MS. In addition mRNA expression of two metallothioneins (mt1 g and mt1 m) was evaluated by real-time PCR. The obtained data shows that the presence of cadmium increases the uptake of iron and zinc into the HepG2 cells while the uptake of copper remains unaffected. The presence of the chosen fatty acids did not affect the uptake of either cadmium or iron, zinc and copper. The presence of already 1MUM cadmium increased the mRNA expression of mt1 g and mt1 m significantly, while the fatty acids did not interfere with the effect of cadmium. PMID- 28802571 TI - Omega-3 polyunsaturated fatty acids improve endothelial function in humans at risk for atherosclerosis: A review. AB - Epidemiology studies and clinical trials show that omega-3 polyunsaturated fatty acids (n-3 PUFAs) can prevent atherosclerotic morbidity and evidence suggests this may be mediated by improving endothelial dysfunction. Endothelial dysfunction is characterized by reduced vasodilation and a pro-inflammatory, pro thrombotic state, and is an early pathological event in the development of atherosclerosis. Flow-mediated dilation (FMD), a gold standard for assessing endothelial dysfunction, is a predictor of future cardiovascular events and coronary heart disease risk. Notably, risk factors for endothelial dysfunction include classic risk factors for atherosclerosis: Elevated lipids, diabetes, hypertension, elevated BMI, cigarette smoking, and metabolic syndrome. In this paper, we review the ability of n-3 PUFAs to improve endothelial dysfunction in individuals with classic risk factors for atherosclerosis, but lacking diagnosed atherosclerotic disease, with the goal of identifying those individuals that might gain the most vasoprotection from n-3 PUFA supplements. We include trials using eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or alpha-linolenic acid (ALA) alone, or EPA+DHA; and assessing endothelial function by FMD, forearm blood flow, or peripheral arterial tonometry. We found that n-3 PUFAs improved endothelial dysfunction in 16 of 17 studies in individuals with hyperlipidemia, elevated BMI, metabolic syndrome, or that smoked cigarettes, but only in 2 of 5 studies in diabetics. Further, these trials showed that use of EPA+DHA consistently improve endothelial dysfunction; ALA-enriched diets appear promising; but use of EPA or DHA alone requires further study. We conclude that individuals with hyperlipidemia, elevated BMI, metabolic syndrome, or that smoke could derive vaosprotective benefits from EPA+DHA supplementation. PMID- 28802573 TI - Cytotoxicity and CYP1A inhibition in rainbow trout liver (RTL-W1) cell lines exposed to dispersant Corexit 9500 and its major surfactant components. AB - As part of a large study examining the toxicity of the Corexit(r) family of oil spill dispersants on aquatic vertebrates, we examined effects on the liver in an in vitro study using the rainbow trout liver cell line (RTL-W1). We exposed RTL W1 cells to the dispersant Corexit 9500 and its major surfactant components and measured their cytotoxic effects as well as modulation of activity of CYP1A, one of the major enzymes responsible for organic contaminant metabolism. The anionic surfactant DOSS was found to be the most cytotoxic with a 24h EC50 of 10mg/L, as compared to 45 to 91mg/L for the non-ionic surfactants, Tween 80 and 85 and Span 80. The EC50 for Corexit was intermediate between these compounds at 29mg/L. Corexit 9500 and the non-ionic surfactants Tween 80 and 85, but not DOSS or Span 80 knocked down CYP1A activity induced by benzo[a]pyrene, a model agonist, demonstrating the potential of these compounds to compromise the ability of exposed organisms to metabolize petroleum hydrocarbons or other CYP1A substrates. PMID- 28802574 TI - "Doing our best to keep a routine:" How low-income mothers manage child feeding with unpredictable work and family schedules. AB - Significant changes in work and family conditions over the last three decades have important implications for understanding how young children are fed. The new conditions of work and family have placed pressures on families. The aim of this study was to explore the work and family pressures shaping the ways parents feed their young children on a day-to-day basis. Twenty-two purposively recruited low income employed mothers of 3-4 year old children from a rural county Head Start program in Upstate New York reported details about the context of their children's eating episodes in a 24-h qualitative dietary recall. Participating mothers were employed and/or in school at least 20 h a week and varied in partner and household characteristics. Interview transcripts were open coded using the constant comparative method for usual ways of feeding children. A typology of three emergent child feeding routines was identified based on mothers' accounts of the recurring ways they fed their child. Mothers' feeding routines were distinguished by a combination of four recurring key strategies - planning ahead, delegating, making trade-offs, and coordinating. Work schedule predictability and other adults helped mothers maintain feeding routines. Unexpected daily events, such as working overtime or waking up late, disrupted child feeding routines and required modifications. These findings suggest that understanding how young children are fed requires recognizing the socio-ecological environments that involve working mothers' daily schedules and household conditions and the multiple ways that mothers manage food and feeding to fit environmental constraints. There is a need to look at more than just family meals to understand parents' daily strategies for feeding young children and their implications for child nutrition. PMID- 28802575 TI - Military experience can influence Women's eating habits. AB - BACKGROUND: Disordered eating, ranging from occasional binge eating or restriction to behaviors associated with eating disorder diagnoses, is common among military personnel and veterans. However, there is little information on how military service affects eating habits. OBJECTIVE: To describe possible pathways between military service and disordered eating among women veterans, a high risk group. MATERIALS AND METHODS: Twenty women veterans who reported changing eating habits in response to stress participated in audio-recorded focus groups or dyadic interviews between April 2013 and October 2014. We used thematic analysis of transcripts to identify and understand women's self-reported eating habits before, during, and after military service. RESULTS: Participants reported entering the military with varied eating habits, but little disordered eating. Participants described several ways military environments affected eating habits, for example, by promoting fast, irregular, binge-like eating and disrupting the reward value of food. Participants believed military-related stressors, which were often related to gender, also affected eating habits. Such stressors included military sexual trauma and the need to meet military weight requirements in general and after giving birth. Participants also reported that poor eating habits continued after military service, often because they remained under stress. CONCLUSIONS: For some women, military service can result in socialization to poor eating habits, which when combined with exposure to stressors can lead to disordered eating. Additional research is needed, including work to understand possible benefits associated with providing support in relation to military weight requirements and the transition out of military service. Given the unique experiences of women in the military, future work could also focus on health services surrounding pregnancy-related weight change and the stress associated with being a woman in predominantly male military environments. PMID- 28802576 TI - Atorvastatin and lovastatin, but not pravastatin, increased cellular complex formation between PCSK9 and the LDL receptor in human hepatocyte-like C3A cells. AB - Statins are the first-line treatment for hypercholesterolemic patients. Herein, the effects of three statins on complex formation between proprotein convertase subtilisin-kexin 9 (PCSK9) and the low density lipoprotein receptor (LDLR), a critical step for the PCSK9-dependent degradation of LDLR in the lysosome, were examined. Human hepatocyte-like C3A cells grown in control (containing 10% fetal bovine serum) or MITO+ (supplemented with BDTM MITO + serum extender) medium were also treated with atorvastatin (Atorv), lovastatin (Lov), or pravastatin (Prav) for 24 h. RNA and protein expression studies and determinations of PCSK9/LDLR complex formation were performed. As expected, the statins increased the expression of PCSK9 and LDLR independently of the medium employed. Interestingly, Atov and Lov caused increases in PCSK9/LDLR complex formation, whereas Prav decreased complex formation when compared to cells treated without drugs. These results may explain why Prav works better for statin intolerant patients than other statins such as Atorv and Lov. PMID- 28802577 TI - How fast fast-folding proteins fold in silico. AB - In reported microcanonical molecular dynamics simulations, fast-folding proteins CLN025 and Trp-cage autonomously folded to experimentally determined native conformations. However, the folding times of these proteins derived from the simulations were more than 4-10 times longer than their experimental values. This article reports autonomous folding of CLN025 and Trp-cage in isobaric-isothermal molecular dynamics simulations with agreements within factors of 0.69-1.75 between simulated and experimental folding times at different temperatures. These results show that CLN025 and Trp-cage can now autonomously fold in silico as fast as in experiments, and suggest that the accuracy of folding simulations for fast folding proteins begins to overlap with the accuracy of folding experiments. This opens new prospects of developing computer algorithms that can predict both ensembles of conformations and their interconversion rates for a protein from its sequence for artificial intelligence on how and when a protein acts as a receiver, switch, and relay to facilitate various subcellular-to-tissue communications. Then the genetic information that encodes proteins can be better read in the context of intricate biological functions. PMID- 28802578 TI - Purification of functional reprogramming factors in mammalian cell using FLAG Tag. AB - Induced pluripotent stem cells (iPSCs) technology is a method for generating pluripotent stem cells in vitro from fully differentiated cells such as fibroblast cells. The potential applications of iPSC technology in cell therapy and disease modeling could influence current medical practices. Despite current advances in iPSC technology, many patient-derived reprogrammed cells are not suitable for clinical trial because most protocols rely on virus-based techniques, which pose the risk of integration of the viral genome into the chromosomes. Therefore, non-viral methods such as mRNA and protein-based reprogramming are promising alternatives when generating clinically safe iPSCs. In a previous study, we generated human iPSCs using cell extracts with cell penetration peptide (CPP) for the delivery of reprogramming proteins [Kim et al. Cell Stem Cells, 2009]. In here, we show that the expression of reprogramming factors in mammalian cells and subsequent purification of these factors by FLAG Tag could reprogram fibroblasts into iPSCs. PMID- 28802579 TI - Atorvastatin prevents endothelial dysfunction in high glucose condition through Skp2-mediated degradation of FOXO1 and ICAM-1. AB - OBJECTIVE: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin has been reported to exert vasculo-protective action in diabetes. We investigated the vasculo-protective mechanism of atorvastatin by evaluating its effect on two major pathogenic molecules, FOXO1 and ICAM1, mediated by S-phase kinase-associated protein 2 (Skp2) in diabetic endothelial dysfunction. APPROACH AND RESULTS: [1] FOXO1: Hyperglycemic condition increased FOXO1 protein level in endothelial cells, which was reversed by atorvastatin. This atorvastatin effect was obliterated by treatment of protease inhibitor, suggesting that atorvastatin induces degradation of FOXO1. Immunoprecipitation showed that atorvastatin facilitated the binding of Skp2 to FOXO1, leading to ubiquitination and degradation of FOXO1. [2] ICAM-1: Increased ICAM1 in high glucose condition was reduced by atorvastatin. But this effect of atorvastatin was obliterated when Skp2 was inhibited, suggesting that atorvastatin enhances binding of Skp2 to ICAM1 leading to degradation. Actually, ubiquitination and degradation of ICAM-1 were reduced when Skp2 was inhibited. In vitro monocyte adhesion assay revealed that atorvastatin reduced monocyte adhesion on endothelial cells in high glucose condition, which was reversed by Skp2 knock-down. CONCLUSION: Atorvastatin strengthens Skp2 binding to FOXO1 or ICAM1, leading to ubiquitination and degradation. Skp2-dependent ubiquitination of major pathogenic molecules is the key mechanism for statin's protective effect on endothelial function in diabetes. PMID- 28802580 TI - Suppressive role of OGT-mediated O-GlcNAcylation of BAP1 in retinoic acid signaling. AB - BRCA1-associated protein 1 (BAP1) has been implicated in diverse biological functions, including tumor suppression. However, its regulation via glycosylation and its role in embryonic stem (ES) cells are poorly defined. BAP1 was recently reported to interact with O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT). Here, we confirmed the physical interaction and investigated its functional significance. The O-GlcNAcylation of BAP1, which requires OGT, was examined in vivo and in vitro, and was proven using alloxan, an OGT inhibitor. OGT promoted the BAP1-induced repression of retinoic acid (RA)-induced RA receptor (RAR) activation. The repressive activity of BAP1 was relieved by alloxan but exacerbated by PUGNAc, an O-GlcNAcase (OGA) inhibitor. Finally, we addressed the role of O-GlcNAcylation in the RA-induced differentiation of murine ES cells. Alkaline phosphatase staining revealed the cooperation of RA and alloxan for impairing the pluripotency of ES cells. This cooperation was also observed by measuring the size of embryonic bodies and the expression of Sox2, a pluripotency marker. Overall, our data suggest that OGT-mediated O-GlcNAcylation of BAP1 prefers the maintenance of pluripotency, whereas its inhibition facilitates RA-induced differentiation in ES cells. PMID- 28802581 TI - PKM2 aggravates palmitate-induced insulin resistance in HepG2 cells via STAT3 pathway. AB - Studies have identified that PKM2 is related to the development of glucose intolerance and insulin resistance in rodents and humans. However, the underlying mechanism remains largely unknown. In the present study, we found that PKM2 expression was significantly elevated in insulin-resistant hepatic tissues and hepatocytes, implicating an association between PKM2 expression and hepatic insulin resistance (IR). In vitro study revealed that overexpression of PKM2 impaired the insulin signaling pathway by decreasing the phosphorylation of protein kinase B (Akt) and glycogen synthase kinase-3beta (GSK3beta). Furthermore, PKM2 overexpression enhanced the effects of PA on the lipid accumulation, the expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) and hepatic glucose uptake. Intriguingly, PA induced insulin resistance was suppressed following by the ablation of PKM2 in HepG2 cells. We also found that STAT3 was significantly activated by PKM2 overexpression. Moreover, we identified that PKM2 could interact directly with STAT3. Taken together, these studies demonstrate that PKM2 may promote hepatic IR via STAT3 pathway and would provide a new insight into dissecting the molecular pathogenesis of hepatic insulin resistance. PMID- 28802582 TI - Label-free quantitative proteomic analysis of Lactobacillus fermentum NCDC 400 during bile salt exposure. AB - Lactobacillus fermentum NCDC 400 is a commonly used and a comprehensively studied probiotic organism. The distinctive capability to endure the harsh environment of the gastrointestinal tract owing to the presence of bile salts in gastric juice facilitates gut microbiota, especially the probiotic organisms to transiently inhabit the host gut. In the present study, Label-Free Quantification (LFQ) approach has been employed to analyze the expression pattern of Lactobacillus fermentum NCDC 400 strain proteins, under bile acid stress, using high-resolution mass spectrometer connected to nano-liquid chromatography (LC) system. We report the identification of a total of 538 differentially expressed (DE) proteins in response to 1.2% bile salt which is required for the growth of this bacterium. Among the DE proteins, 80 were found to be up-regulated, with greater than 1.3 fold change vis-a-vis 107 proteins which were down-regulated with <0.76 fold change (p<0.05). The functions of down-regulated proteins were largely unknown nevertheless; the putative functions of the up-regulated proteins were categorized into categories viz. stress response, DNA repair, peptidoglycan biosynthesis, amino acids metabolism, signal transduction, transcription, translation, and carbohydrate metabolism. These results suggest that the differentially expressed proteins provide the tolerance towards the various gastrointestinal challenges and involved in bile acid stress response mechanism. PMID- 28802584 TI - Molecular characterization of the pA3J1 plasmid from the psychrotolerant Antarctic bacterium Pseudomonas sp. ANT_J3. AB - The knowledge on plasmids of cold-active bacteria is highly limited. In this study, the molecular characterization of the pA3J1 plasmid of Antarctic psychrotolerant bacterium Pseudomonas sp. ANT_J3 was performed. Within this plasmid, thirteen putative open reading frames were identified. Nine of them encoded proteins involved in replication, partitioning, postsegregational elimination of plasmid-less cells (via a toxin-antitoxin system activity), multimer resolution and mobilization by conjugal transfer. These genes constitute the plasmid backbone. The functional analysis of the pA3J1 maintenance region revealed that it is a narrow host range replicon, stably maintained in the host cells by the combined activities of the partitioning and relBE-type toxin antitoxin systems. It was also suggested that the replication system of the pA3J1 plasmid may be temperature-sensitive. Comparative analyses revealed the presence of 16 Pseudomonas plasmids encoding homologous replication proteins and 5 plasmids carrying mobA genes homologous to the corresponding gene of pA3J1. The relaxase (MobA) of the pA3J1 plasmid was classified into MOBQ family, and the phylogenetic analysis suggested that this may be a representative of a novel group (or subgroup) within this family. The structural and comparative analyses revealed that the arrangement of genetic modules in the pA3J1 plasmid is unique. PMID- 28802585 TI - Genomics of the new species Kingella negevensis: diagnostic issues and identification of a locus encoding a RTX toxin. AB - Kingella kingae, producing the cytotoxic RTX protein, is a causative agent of serious infections in humans such as bacteremia, endocarditis and osteoarticular infection, especially in young children. Recently, Kingella negevensis, a related species, has been isolated from the oral cavity of healthy children. In this study, we report the isolation of K. negevensis strain eburonensis, initially misidentified as K. kingae with MALDI-TOF MS, from a vaginal specimen of a patient suffering of vaginosis. The genome sequencing and analysis of this strain together with comparative genomics of the Kingella genus revealed that K. negevensis possesses a full homolog of the rtx operon of K. kingae involved in the synthesis of the RTX toxin. We report that a K. kingae specific diagnostic PCR, based on the rtxA gene, was positive when tested on K. negevensis strain eburonensis DNA. This cross-amplification, and risk of misidentification, was confirmed by in silico analysis of the target gene sequence. To overcome this major diagnostic issue we developed a duplex real-time PCR to detect and distinguish K. kingae and K. negevensis. In addition to this, the identification of K. negevensis raises a clinical issue in term of pathogenic potential given the production of a RTX hemolysin. PMID- 28802583 TI - Cytoskeleton and nuclear lamina affection in recessive osteogenesis imperfecta: A functional proteomics perspective. AB - : Osteogenesis imperfecta (OI) is a collagen-related disorder associated to dominant, recessive or X-linked transmission, mainly caused by mutations in type I collagen genes or in genes involved in type I collagen metabolism. Among the recessive forms, OI types VII, VIII, and IX are due to mutations in CRTAP, P3H1, and PPIB genes, respectively. They code for the three components of the endoplasmic reticulum complex that catalyzes 3-hydroxylation of type I collagen alpha1Pro986. Under-hydroxylation of this residue leads to collagen structural abnormalities and results in moderate to lethal OI phenotype, despite the exact molecular mechanisms are still not completely clear. To shed light on these recessive forms, primary fibroblasts from OI patients with mutations in CRTAP (n=3), P3H1 (n=3), PPIB (n=1) genes and from controls (n=4) were investigated by a functional proteomic approach. Cytoskeleton and nucleoskeleton asset, protein fate, and metabolism were delineated as mainly affected. While western blot experiments confirmed altered expression of lamin A/C and cofilin-1, immunofluorescence analysis using antibody against lamin A/C and phalloidin showed an aberrant organization of nucleus and cytoskeleton. This is the first report describing an altered organization of intracellular structural proteins in recessive OI and pointing them as possible novel target for OI treatment. SIGNIFICANCE: OI is a prototype for skeletal dysplasias. It is a highly heterogeneous collagen-related disorder with dominant, recessive and X-linked transmission. There is no definitive cure for this disease, thus a better understanding of the molecular basis of its pathophysiology is expected to contribute in identifying potential targets to develop new treatments. Based on this concept, we performed a functional proteomic study to delineate affected molecular pathways in primary fibroblasts from recessive OI patients, carrying mutations in CRTAP (OI type VII), P3H1 (OI type VIII), and PPIB (OI type IX) genes. Our analyses demonstrated the occurrence of an altered cytoskeleton and, for the first time in OI, of nuclear lamina organization. Hence, cytoskeleton and nucleoskeleton components may be considered as novel drug targets for clinical management of the disease. Finally, according to our analyses, OI emerged to share similar deregulated pathways and molecular aberrances, as previously described, with other rare disorders caused by different genetic defects. Those aberrances may provide common pharmacological targets to support classical clinical approach in treating different diseases. PMID- 28802586 TI - Nontypeable Haemophilus influenzae (NTHi) directly interfere with the regulation of E-cadherin in lung epithelial cells. AB - Loss of epithelial barriers characterized by reduction of E-cadherin is a hallmark of chronic obstructive pulmonary disease (COPD). We investigated the effects of nontypeable Haemophilus influenzae (NTHi) infections, associated with acute exacerbations of chronic bronchitis, on the regulation of E-cadherin in host cells. NTHi infection decreased E-cadherin mRNA and protein-levels in lung epithelial cells. E-cadherin reduction was mediated by activation of the fibroblast growth factor 2 (FGF2), the mammalian target of rapamycin (mTOR) and Slug. These data indicate that epithelial integrity and barrier function is disturbed by NTHi infection. Mainly, the destruction of cell-cell contacts is a prominent feature in NTHi infection. PMID- 28802587 TI - Pre-transplant infusion of donor-derived dendritic cells maintained at the immature stage by sinomenine increases splenic Foxp3+ Tregs in recipient rats after renal allotransplantation. AB - OBJECTIVE: The immunosuppressive mechanism of sinomenine in organ allotransplantation was investigated, especially its effect of blocking dendritic cell (DC) maturation, which might influence the frequency of regulatory T cells (Tregs). METHODS: Bone marrow cells from male donor Wistar rats were induced to differentiate into DCs in vitro in the presence or absence of sinomenine, and characterized by flow cytometry. These two groups of DCs were respectively injected into male recipient Sprague-Dawley rats via the tail vein, at both high and low doses. Sprague-Dawley rats receiving saline injection were used as controls. Seven days later, renal transplantation was performed from donor Wistar rats to the recipient Sprague-Dawley rats. Seven days after transplantation, spleens were collected from the recipients. The proportions of Tregs and Foxp3+ Tregs to CD4+ T cells were determined using flow cytometry. RESULTS: With sinomenine treatment, the frequency of mature DCs was reduced, as indicated by lower expression of the surface markers CD80, CD86, and RT1B. In recipient Sprague-Dawley rats that received sinomenine-treated DCs before renal allotransplantation, the proportions of splenic Tregs and Foxp3+ Tregs were significantly higher than in control recipients receiving saline or DCs without sinomenine treatment (all p<0.05). A high dose of sinomenine-treated DCs (106 cells) had a more obvious effect in increasing Tregs than the low dose (105 cells) (p<0.05). CONCLUSION: Pre-transplant infusion of donor-derived sinomenine induced maturation arrested DCs could result in the increase of Foxp3+ Tregs in the spleens of recipients after renal allotransplantation. PMID- 28802588 TI - T cell costimulation blockade promotes transplantation tolerance in combination with sirolimus and post-transplantation cyclophosphamide for haploidentical transplantation in children with severe aplastic anemia. AB - We conducted a pilot study employing extended T cell costimulation blockade (COSBL) with Abatacept along with sirolimus and post-transplantation cyclophosphamide (PTCy) in 10 patients (median age 12) with severe aplastic anemia (SAA). Nine patients engrafted in the COSBL group, compared to all 10 patients (median 14 vs 13days) treated on PTCy protocols without abatacept (CONTROL group). The incidence of acute graft-versus-host disease (GVHD) was 10.5% in the COSBL group compared to 50% in the CONTROL group (p=0.04). Chronic GVHD (12.5% vs 56%, p=0.02) and CMV reactivation (30% vs 80%, p=0.03) were also reduced in the COSBL group. T and NK cell subset analysis revealed higher CD56brightCD16- NK cells in the CONTROL group (p=0.004), but similar CD56dimCD16+ NK cells in both groups at day+30. Tregs (CD4+CD25+CD127dim/- FoxP3+) were markedly higher in the COSBL group at day+30 (8.4% vs 1.1%) and the trend was maintained through day+90 (p<0.01). The GVHD and Disease-free survival at one year in the COSBL group was 80% vs. 30% in the CONTROL group (p=0.05). Our preliminary findings suggest that COSBL in combination with PTCy and sirolimus might augment transplantation tolerance in children with SAA, probably due to synergistic effect on early recovery of Tregs. PMID- 28802589 TI - Ventral lateral parietal cortex and episodic memory retrieval. AB - With the advent of functional neuroimaging it quickly became apparent that successful episodic memory retrieval was consistently associated with enhanced activity in ventral lateral parietal cortex (VLPC), especially the left angular gyrus. Here, we selectively review recent neuropsychological and functional neuroimaging evidence relevant to the question of the functional significance of this activity. We argue that the balance of the evidence suggests that the angular gyrus supports the representation of retrieved episodic information, and that this likely reflects a more general role for the region in representing multi-modal and multi-domain information. PMID- 28802590 TI - Blue mussels (Mytilus edulis spp.) as sentinel organisms in coastal pollution monitoring: A review. AB - The blue mussel (Mytilus spp.) is widely used as a bioindicator for monitoring of coastal water pollution (mussel watch programs). Herein we provide a review of this study field with emphasis on: the suitability of Mytilus spp. as environmental sentinels; uptake and bioaccumulation patterns of key pollutant classes; the use of Mytilus spp. in mussel watch programs; recent trends in Norwegian mussel monitoring; environmental quality standards and background concentrations of key contaminants; pollutant effect biomarkers; confounding factors; particulate contaminants (microplastics, engineered nanomaterials); climate change; harmonization of monitoring procedures; and the use of deployed mussels (transplant caging) in pollution monitoring. Lastly, the overall state of the art of blue mussel pollution monitoring is discussed and some important issues for future research and development are highlighted. PMID- 28802591 TI - Maternal Sociodemographic Characteristics and Behaviors as Correlates of Preadolescent's Breakfast Habits. AB - PURPOSE: To explore factors affecting skipping breakfast rate, and to identify its perceived reasons among preadolescent students and their mothers in Jordan. DESIGN AND METHODS: Using cluster stratified sampling, preadolescent (10-11years) students (N=1915) and their mothers (N=1299) from 26 public and private schools completed a self-reported questionnaire. Breakfast skipping and its related habits were described. Children's and mothers' perceptions of regular breakfast eating and sociodemographic factors were analyzed in relation to breakfast skipping in children. RESULTS: Although the majority of both children and mothers perceived breakfast as very important, 23% of the children and mothers reported skipping breakfast. Male students skipped breakfast more than female students. Students whose mothers had a low level of education and students with a low value of breakfast consumption had a higher likelihood of skipping breakfast. Mothers' high value of breakfast and encouragement of children to eat breakfast were directly related to an increase in children's perceived importance of breakfast consumption. Preadolescents' and mothers' perceptions of the importance of breakfast and mothers' encouragement to eat breakfast were significant predictors of breakfast consumption among students. CONCLUSION: The high prevalence of breakfast skipping among students, and knowledge about association between mothers' perceived importance of breakfast consumption and encouragement highlighted the pivotal role of mothers in preadolescent's breakfast consumption. PRACTICAL IMPLICATIONS: The findings suggest that health care providers, including school health practitioners, are recommended to assess children's and mothers' perceived value of breakfast and to include mothers in health promotion interventions on breakfast consumption. PMID- 28802592 TI - Gender Differences in Sexual Behaviors in Korean Adolescents. AB - PURPOSE: The purposes of this study were to identify whether there are gender differences in sexual behaviors among Korean adolescents and to explore the factors that influence safe sex practices across both sexes. METHODS: A secondary analysis was conducted using nationally representative data obtained from the 2014 Youth Risk Behavior Web-based Survey. Sample consisted of 3,210 adolescents who had experience of sexual intercourse. The dependent variable in this study was practicing safe sex. The independent variables included a range of individual, family, and school factors. RESULTS: Female adolescents were less likely to practice safe sex (i.e., always using a condom). Individual (smoking, no drinking before sexual intercourse), family (living with parents, higher allowance per week) and school factors (non-coeducational school students, had received school-based sex education) were significant predictors of practicing safe sex in males. In contrast, family (lower economic status) and school factors (middle school students) predicted practicing safe sex among female adolescents. CONCLUSION: We demonstrated that gender plays an important role in the sexual behavior of adolescents. The findings of this study indicate a need to design and implement gender-specific interventions. PMID- 28802593 TI - Evaluation of ultrasound-guided posterior quadratus lumborum block for postoperative analgesia after laparoscopic gynecologic surgery. AB - STUDY OBJECTIVE: This study aimed to determine the efficacy of ultrasound-guided posterior quadratus lumborum block (QLB) in treating postoperative pain following laparoscopic gynecologic surgery. DESIGN: Prospective randomized controlled study. PATIENTS: Seventy adult patients scheduled for elective laparoscopic gynaecological surgery under general anesthesia. INTERVENTION: This randomized controlled study involved two groups of adult females who were scheduled to undergo laparoscopic gynecologic surgery under general anesthesia. Patients were randomly assigned to either the QLB group or Control group. In the QLB group, patients underwent posterior QLB with 20mL of 0.375% ropivacaine on each side. Patients were blinded to treatment. MEASUREMENTS: At 0, 1, 3, and 24 hours after anesthesia recovery, evaluator recorded the severity of postoperative pain in movement and at rest using a Numeric Rating Scale (NRS). We also evaluated the severity of nausea using NRS and number of additional analgesics. MAIN RESULTS: Immediately after recovery from anesthesia, the NRS score for pain in movement did not differ significantly between groups. NRS scores for pain both in movement and at rest were significantly higher in the Control group than in the QLB group at 1, 3, and 24h after recovery from anesthesia. CONCLUSION: Our results suggest that posterior QLB significantly reduces postoperative pain in movement and at rest following laparoscopic gynecologic surgery. PMID- 28802594 TI - Intraoperative ketorolac dose of 15mg versus the standard 30mg on early postoperative pain after spine surgery: A randomized, blinded, non-inferiority trial. AB - STUDY OBJECTIVE: The primary aim of this study is to show the non-inferiority of 15mg intraoperative dose of ketorolac as compared to the standard 30mg ketorolac by looking at the visual analog scale pain (VAS) scores 4h after an adult spine surgery. DESIGN: The study design is a prospective randomized non-inferiority clinical trial looking at non-inferiority of intraoperative 15mg ketorolac from the standard 30mg dose. SETTING: Quaternary care center. PATIENTS: 50 adult (18 65years of age) undergoing lumbar decompression spine surgery. INTERVENTIONS: Group A received a single intraoperative dose of 15mg ketorolac at the end of surgery and group B received single intraoperative dose of 30mg ketorolac. MEASUREMENTS: The primary outcome was the visual analog scale (VAS) pain scores 4h after an adult spine surgery. Secondary measures were morphine usage in the first 8 and 24h postoperatively, numeric rating scores (NRS) up to 24h, sedation, nausea, vomiting, respiratory depression, pruritus and bleeding complications. MAIN RESULTS: Intention to treat analysis showed a mean increase in 4h VAS pain score of 7.9mm (95% CI: -4.5mm to 20.4mm) in patients administered 15mg ketorolac. This difference was neither statistically (P=0.207) nor clinically significant (<18mm on VAS scale). A similar increase in the 15mg group was noted through a per protocol analysis, 6.9mm (95% CI: -6.6mm to 20.5mm, P=0.307) greater in the 15mg group. Non-inferiority of 15mg was not confirmed. No significant difference was found in secondary endpoints. CONCLUSIONS: Ketorolac 30mg intravenous was not superior to 15mg intravenous for post-operative pain management after spine surgery. However, 15mg failed to meet the pre-specified criteria for non-inferiority to the 30mg dose. PMID- 28802595 TI - Variability in opioid prescribing for children undergoing ambulatory surgery in the United States. AB - STUDY OBJECTIVE: We attempted to describe the opioid prescribing patterns for ambulatory pediatric surgery in the United States from 2007 to 2014. DESIGN: Retrospective database review. SETTING: Operating room ambulatory encounters as determined by the Truven Health Marketscan Commercial Claims and Encounters database. PATIENTS: A total of 929,874 ambulatory surgical encounters were identified in patients <18years of age and, of these, 439,286 encounters generated an analgesic prescription. INTERVENTIONS: N/A MEASUREMENTS: The analgesic prescription was described in terms of the type of opioid along with the inclusion of acetaminophen and/or NSAIDs. MAIN RESULTS: The probability of receiving a post-operative analgesic prescription increased with age, ranging from 18.2% of infants to 71.7% of teens. Acetaminophen with codeine (APAP/C) was the most common drug for infants (63.8%), while acetaminophen with hydrocodone (APAP/H) was the most common analgesic prescription for teens (53.6%). APAP/C and APAP/H were the predominant drugs used for all procedure types. CONCLUSIONS: Substantial variability in analgesic prescribing at the level of the procedure performed, both in terms of the probability of receiving a prescription and in which drugs were prescribed. We observed significant age and procedure-based variability in opioid prescribing following pediatric ambulatory surgery. PMID- 28802596 TI - Effects of differential-phase remote ischemic preconditioning intervention in laparoscopic partial nephrectomy: A single blinded, randomized controlled trial in a parallel group design. AB - STUDY OBJECTIVE: There are two windows of protection for remote ischemic preconditioning (RIPC), an early (ERIPC) and a late-phase (LRIPC). While ERIPC has been well studied, works on LRIPC are relatively scarce, especially for the kidneys. We aimed to compare the effects of early-phase versus late-phase RIPC in patients with laparoscopic partial nephrectomy (LPN). DESIGN: A randomized controlled study SETTING: The Second Affiliated Hospital of Anhui Medical University, 1 May 2012 to 30 October 2013 PATIENTS: Sixty-five ASA 1 to 2 patients scheduled for LPN were located randomly to ERIPC group, LRIPC group and CON group (control). INTERVENTIONS: Three five-minute cycles of right upper limb ischaemia and reperfusion were performed after induction of anesthesia in ERIPC group. Patients in LRIPC group received similar treatment 24h before surgery, while control patients were not subjected to preconditioning. MEASUREMENTS: Serum neutrophil gelatinase-associated lipocalin (NGAL) and serum cystatin C (CysC) were evaluated before the induction of anesthesia (0h), 2h (2h) and 6h (6h) after surgery. Unilateral glomerular filtration rates (GFR) were assessed before and after surgery to evaluate overall renal function. MAIN RESULTS: Serum NGAL and CysC were significantly lower in ERIPC and LRIPC groups at 2h post-operation (P<0.001), 6h post-operation (P<0.001). Additionally, The GFR were significantly lower in ERIPC and LRIPC groups than in CON group at the 3rd month after surgery (P=0.019; P<0.001). Moreover, compared to the ERIPC group, concentration of NGAL and CysC in LRIPC group decreased to a greater extent, while GFR and the percentage of decrement was significantly less in the LRIPC group (P=0.016; P<0.001). CONCLUSIONS: Regardless of early-phase or late-phase intervention, limb remote ischemic preconditioning confers protection on renal ischemia-reperfusion injury in patients with laparoscopic partial nephrectomy, and the late-phase protection is more prominent. PMID- 28802597 TI - "High" glucose level in epidural catheter aspirate during combined spinal epidural anesthesia. PMID- 28802599 TI - Patients with central disorders of excessive hypersomnolence and their perioperative risks and anesthetic management. PMID- 28802600 TI - Selecting anesthesiology residency candidates-Beyond the numbers. PMID- 28802598 TI - Effect of parecoxib sodium pretreatment combined with dexmedetomidine on early postoperative cognitive dysfunction in elderly patients after shoulder arthroscopy: A randomized double blinded controlled trial. AB - STUDY OBJECTIVE: To evaluate effect of parecoxib sodium pretreatment combined with dexmedetomidine on early postoperative cognitive dysfunction in elderly patients after shoulder arthroscopy. DESIGN: Randomized, double-blind study. SETTING: University-affiliated teaching hospital. PATIENTS: One hundred and fifty two elderly patients scheduled for shoulder arthroscopy. INTERVENTIONS: At 15min before the induction of anesthesia, 152 patients received intravenously parecoxib sodium 40mg and dexmedetomidine at a dose of 0.5MUg/kg over 15min, followed by a continuous infusion at a rate of 0.5MUg/kg/h until the end of surgery. Then all patients who received postoperative patient-controlled intravenous analgesia were divided 2 groups: sufentanil(0.04MUg/kg/h, S group), sufentanil (0.04MUg/kg/h) plus dexmedetomidine(0.06MUg/kg/h) (SD group). MEASUREMENTS: The mini-mental status examination score in SD group was significantly higher than S group at 1, 2 and 7days after surgery. The incidence of postoperative cognitive dysfunction during 7days after surgery in S and SD groups was respectively 17.1% and 6.7%. Compared with the S group, the visual analogue scale scores at rest and upon movement were significantly lower at 6, 14, 24, 36 and 48h after surgery in SD group; analgesia pump liquid amount during 24h after surgery and number of rescue analgesia during 48h after surgery were significantly lower in SD group. Jugular venous oxygen partial pressure and jugular venous oxygen saturation values in SD group were significantly higher than S group at postoperative 24h. The occurrence of nausea and vomiting within 48h after surgery in SD group were significantly lower than S group. We found no complications including respiratory depression and sinus bradycardia within 48h after surgery in all patients. CONCLUSIONS: Parecoxib sodium pretreatment combined with dexmedetomidine could reduce the incidence of early postoperative cognitive dysfunction in elderly patients. This might be related to the improvement of postoperative analgesia effect and cerebral oxygen metabolism in patients. PMID- 28802601 TI - Perioperative risk stratification of mechanically ventilated critically ill patients: An important first step. PMID- 28802603 TI - PECS2 blocks for breast surgery: A case for multimodal anesthesia. PMID- 28802602 TI - Labor analgesia: We need to better understand and educate our obstetric patients. PMID- 28802604 TI - A novel treatment for herpes zoster pain using an electrical stimulating catheter with a steering guidewire. PMID- 28802605 TI - Laparoscopic cholecystectomy under neuraxial anesthesia compared with general anesthesia: Systematic review and meta-analyses. AB - BACKGROUND: Pneumoperitoneum during laparoscopic cholecystectomy (LC) can cause hypercapnia, hypoxemia, hemodynamic changes and shoulder pain. General anesthesia (GA) enables the control of intraoperative pain and ventilation. The need for GA has been questioned by studies suggesting that neuraxial anesthesia (NA) is adequate for LC. STUDY OBJECTIVE: To quantify the prevalence of intraoperative pain and to verify whether evidence on the maintenance of ventilation, circulation and surgical anesthesia during NA compared with GA is consistent. DESIGN: Systematic review with meta-analyses. SETTING: Anesthesia for laparoscopic cholecystectomy. PATIENTS: We searched Medline, Cochrane and EBSCO databases up to 2016 for randomized controlled trials that compared LC in the two groups under study, neuraxial (subarachnoid or epidural) and general anesthesia. MEASUREMENTS: The primary outcome was the prevalence of intraoperative pain referred to the shoulder in the NA group. Hemodynamic and respiratory outcomes and adverse effects in both groups were also collected. MAIN RESULTS: Eleven comparative studies were considered eligible. The pooled prevalence of shoulder pain was 25%. Intraoperative hypotension and bradycardia occurred more frequently in patients who received NA, with a risk ratio of 4.61 (95% confidence interval [CI] 1.70-12.48, p=0.003) and 6.67 (95% CI 2.02-21.96, p=0.002), respectively. Postoperative nausea and vomiting was more prevalent in patients who submitted to GA. The prevalence of postoperative urinary retention did not differ between the techniques. Postoperative headache was more prevalent in patients who received NA, while the postoperative pain intensity was lower in this group. Performing meta-analyses on hypertension, hypercapnia and hypoxemia was not possible. CONCLUSIONS: NA as sole anesthetic technique, although feasible for LC, was associated with intraoperative pain referred to the shoulder, required anesthetic conversion in 3.4% of the cases and did not demonstrate evidence of respiratory benefits for patients with normal pulmonary function. PMID- 28802606 TI - Comparison of LMA SupremeTM with i-gelTM and LMA ProSealTM in children for airway management during general anaesthesia: A meta-analysis of randomized controlled trials. AB - STUDY OBJECTIVE: A few randomized trials have compared LMA SupremeTM with LMA ProSealTM and i-gelTM in children but their conclusions varied widely. This systematic review and meta analysis has compared the former device with the latter two devices. DESIGN: Meta-analysis and systematic review using the Mantel Haenszel method and pooled mean difference using inverse variance method. SETTING: Meta-analysis of published prospective randomized controlled trials. PATIENTS: Paediatric patients undergoing surgery under general anaesthesia. INTERVENTION: LMA SupremeTM with LMA ProSealTM or i-gelTM as airway management device. RESULTS: Electronic database searching revealed four randomized trials where LMA SupremeTM has been compared with LMA ProSealTM and three trials where a comparison was made between LMA SupremeTM and i-gelTM in paediatric population. LMA SupremeTM provided similar oropharyngeal leak pressure when compared to LMA ProSealTM [mean difference (95% CI) 1.57 (-1.33, 4.47)cm H2O; p=0.29] and i-gelTM [mean difference (95% CI) 1.18 (-2.11, 4.47)cm H2O; p=0.48]. First insertion success rate is also similar when LMA SupremeTM is compared to LMA ProSealTM [RR (95% CI) 1.03 (0.97, 1.1); p=0.74] and i-gelTM [RR (95% CI) 0.99 (0.95, 1.03); p=0.51]. Device insertion is significantly faster with LMA SupremeTM than i-gelTM [mean difference (95% CI) 1.87 (0.93, 2.81) s; p<0.0001]. CONCLUSION: We suggest that LMA SupremeTM may be an alternative to LMA ProSealTM and i-gelTM in children for airway management during general anaesthesia. PMID- 28802607 TI - Cervical interfascial plane (CIP) block and multifidus cervicis plane (MCP) block: Similarities and tips. PMID- 28802608 TI - Application of a skin traction method to facilitate ultrasound-guided brachial plexus block in obese patient with short neck. PMID- 28802609 TI - Another quest for the holy grail of abolishing post operative nausea and vomiting. PMID- 28802610 TI - Ultrasound-guided transversus thoracic muscle plane block: Complication in 299 consecutive cases. PMID- 28802611 TI - Lumbar vertebra surgery performed with a bilateral posterior quadratus lumborum block. PMID- 28802612 TI - Biological evidence of the impact of burnout on the health of anesthesiologists. PMID- 28802613 TI - Perioperative use of 5% dextrose to decrease postoperative nausea and vomiting. PMID- 28802614 TI - Uncommon combinations of ICD10-PCS or ICD-9-CM operative procedure codes account for most inpatient surgery at half of Texas hospitals. AB - STUDY OBJECTIVE: Recently, there has been interest in activity-based cost accounting for inpatient surgical procedures to facilitate "value based" analyses. Research 10-20years ago, performed using data from 3 large teaching hospitals, found that activity-based cost accounting was practical and useful for modeling surgeons and subspecialties, but inaccurate for individual procedures. We hypothesized that these older results would apply to hundreds of hospitals, currently evaluable using administrative databases. DESIGN: Observational study. SETTING: State of Texas hospital discharge abstract data for 1st quarter of 2016, 4th quarter of 2015, 1st quarter of 2015, and 4th quarter of 2014. PATIENTS: Discharged from an acute care hospital in Texas with at least 1 major therapeutic ("operative") procedure. MEASUREMENTS: Counts of discharges for each procedure or combination of procedures, classified by ICD-10-PCS or ICD-9-CM. MAIN RESULTS: At the average hospital, most surgical discharges were for procedures performed at most once a month at the hospital (54%, 95% confidence interval [CI] 51% to 55%). At the average hospital, approximately 90% of procedures were performed at most once a month at the hospital (93%, CI 93% to 94%). The percentages were insensitive to the quarter of the year. The percentages were 3% to 6% greater with ICD-10-PCS than for the superseded ICD 9 CM. CONCLUSIONS: There are many different procedure codes, and many different combinations of codes, relative to the number of different hospital discharges. Since most procedures at most hospitals are performed no more than once a month, activity-based cost accounting with a sample size sufficient to be useful is impractical for the vast majority of procedures, in contrast to analysis by surgeon and/or subspecialty. PMID- 28802615 TI - Nebulized ketamine for successful management of difficult airway. PMID- 28802616 TI - The combination of sugammadex and desflurane may increase the risk of bronchospasm during general anesthesia. PMID- 28802617 TI - Clinical efficacy of a supraglottic airway device with a pressure gauge for robot assisted surgery. PMID- 28802618 TI - Is gabapentin effective and safe in open hysterectomy? A PRISMA compliant meta analysis of randomized controlled trials. AB - BACKGROUND: Pain management after open hysterectomy has been investigated for years. Owing to the effect of significant analgesic, gabapentin was often administrated for pre-emptive analgesia. However, the relationship between gabapentin and postoperative pain after open hysterectomy is still controversial. This meta-analysis was applied to assess the efficacy of pre-emptive use of gabapentin in open hysterectomy. METHODS: This meta-analysis of randomized controlled trials (RCTs) was performed to compare the use of gabapentin with placebo in open hysterectomy regarding (1) the mean difference (MD) of postoperative opioid requirements; (2) the changes of visual analogue scale (VAS) scores in two groups; and (3) incidence rate of adverse effects. Systematic searches of all related literatures was conducted using the following databases: MEDLINE, EMBASE, ClinicalTrials.gov and Web of Science. Only randomized controlled trials (RCTs) for open hysterectomy were included. The MD of postoperative opioid requirements and VAS scores, relative risk (RR) of incidence rate of adverse effects in the gabapentin group versus placebo group were extracted throughout the study. RESULTS: Fourteen trials were included in this meta-analysis. The total opioid consumption at 24h was a less in gabapentin group. (MD=-11.61, 95% CI: -16.71 to -6.51, P=0.00) The visual analogue scale (VAS) score at 4, 12 and 24h were less in the gabapentin group. (MD=-16.83, 95% CI: -22.88 to -10.77, P=0.00), (MD=-17.45, 95% CI: -21.83 to -13.08, P=0.00), (MD=-9.83, 95% CI: -13.31 to -6.35, P=0.00) The incidence rate of vomiting and nausea were significantly less in gabapentin groups. (RR 0.13, 95% CI 0.45 to 0.73, P=0.00), (RR 0.67, 95% CI 0.49 to 0.93, P=0.02). Compared with placebo, gabapentin achieved higher patient satisfaction. (MD=20.43, 95% CI: 12.42 to 28.44, P<0.00). CONCLUSION: This meta-analysis suggested that the employment of gabapentin was efficacious in reduction of postoperative opioid consumption, VAS score and some side effects after open hysterectomy. PMID- 28802619 TI - Sugammadex efficacy for reversal of rocuronium- and vecuronium-induced neuromuscular blockade: A pooled analysis of 26 studies. AB - STUDY OBJECTIVE: To summarize and compare efficacy of sugammadex with neostigmine or placebo for reversal of rocuronium- or vecuronium-induced neuromuscular blockade (NMB), and to demonstrate consistency of sugammadex results across various patient populations. DESIGN: Pooled analysis on data from 26 multicenter, randomized, Phase II and III studies. SETTING: Operating room. PATIENTS: 1855 adults undergoing surgery under general anesthesia and receiving rocuronium or vecuronium for NMB. INTERVENTIONS: Sugammadex (2.0mg/kg at second twitch reappearance [T2; moderate NMB], 4.0mg/kg at 1-2 post-tetanic counts [PTC; deep NMB] or 16.0mg/kg at 3min after rocuronium 1.2mg/kg), neostigmine or placebo. MEASUREMENTS: Time to recovery of the train-of-four (TOF) ratio to 0.9. MAIN RESULTS: Geometric mean (95% CI) times to recovery to TOF ratio of 0.9 were 1.9 (1.8-2.0) min following sugammadex 2.0mg/kg and 10.6 (9.8-11.6) min following neostigmine administration at T2 after rocuronium, and 2.9 (2.5-3.4) min and 17.4 (13.4-22.6) min, respectively, after vecuronium. Recovery times were 2.2 (2.1 2.3) min following sugammadex 4.0mg/kg and 19.0 (14.8-24.6) min following neostigmine administered at a target of 1-2 PTC after rocuronium, and 3.8 (3.0 5.0) min and 67.6 (56.3-81.2) min after vecuronium. Sugammadex administered 3min after rocuronium 1.2mg/kg resulted in rapid recovery (1.7 [1.5-2.0] min). Modest increases in mean recovery time were associated with vecuronium use (+1.6min [78%; (61%-98%)] versus rocuronium), mild-to-moderate renal impairment (+0.4min [20%; (9%-32%)] versus normal renal function) and geographic location (+1.0min [38%; (25%-52%)] in subjects in USA/Canada versus Europe/Japan). CONCLUSIONS: Sugammadex administered at recommended doses provides rapid and predictable reversal of rocuronium and vecuronium-induced moderate and deep NMB, and effective reversal 3min after rocuronium 1.2mg/kg. Robust recovery was seen across various patient factors, providing further confirmation of labeled dose recommendations. PMID- 28802620 TI - Modified open-access scheduling for new patient evaluations at an academic chronic pain clinic increased patient access to care, but did not materially reduce their mean cancellation rate: A retrospective, observational study. AB - STUDY OBJECTIVE: To determine if open-access scheduling would reduce the cancellation rate for new patient evaluations in a chronic pain clinic by at least 50%. DESIGN: Retrospective, observational study using electronic health records. SETTING: Chronic pain clinic of an academic anesthesia department. PATIENTS: All patients scheduled for evaluation or follow-up appointments in the chronic pain clinic between April 1, 2014, and December 31, 2015. INTERVENTIONS: Open-access scheduling was instituted in April 2015 with appointments offered on a date of the patient's choosing >=1 business day after calling, with no limit on the daily number of new patients. MEASUREMENTS: Mean cancellation rates for new patients were compared between the 12-month baseline period prior to and for 7months after the change, following an intervening 2-month washout period. The method of batch means (by month) and the 2-sided Student t-test were used; P<0.01 required for significance. MAIN RESULTS: The new patient mean cancellation rate decreased from a baseline of 35.7% by 4.2% (95% confidence interval [CI] 1.4% to 6.9%; P=0.005); however, this failed to reach the 50% reduction target of 17.8%. Appointment lag time decreased by 4.7days (95% CI 2.3 to 7.0days, P<0.001) from 14.1days to 9.4days in the new patient group. More new patients were seen within 1week compared to baseline (50.6% versus 19.1%; P<0.0001). The mean number of new patient visits per month increased from 158.5 to 225.0 (P=0.0004). The cancellation rate and appointment lag times did not decrease for established patient visits, as expected because open-access scheduling was not implemented for this group. CONCLUSIONS: Access to care for new chronic pain patients improved with modified open-access scheduling. However, their mean cancellation rate only decreased from 35.7% to 31.5%, making this a marginally effective strategy to reduce cancellations. PMID- 28802621 TI - Submental intubation - Practical alternative airway in maxillofacial surgeries. PMID- 28802622 TI - Discharges with surgical procedures performed less often than once per month per hospital account for two-thirds of hospital costs of inpatient surgery. AB - STUDY OBJECTIVE: Most surgical discharges (54%) at the average hospital are for procedures performed no more often than once per month at that hospital. We hypothesized that such uncommon procedures would be associated with an even greater percentage of the total cost of performing all surgical procedures at that hospital. DESIGN: Observational study. SETTING: State of Texas hospital discharge abstract data: 4th quarter of 2015 and 1st quarter of 2016. PATIENTS: Inpatients discharged with a major therapeutic ("operative") procedure. MEASUREMENTS: For each of N=343 hospitals, counts of discharges, sums of lengths of stay (LOS), sums of diagnosis related group (DRG) case-mix weights, and sums of charges were obtained for each procedure or combination of procedures, classified by International Classification of Diseases version 10 Procedure Coding System (ICD-10-PCS). Each discharge was classified into 2 categories, uncommon versus not, defined as a procedure performed at most once per month versus those performed more often than once per month. MAIN RESULTS: Major procedures performed at most once per month per hospital accounted for an average among hospitals of 68% of the total inpatient costs associated with all major therapeutic procedures. On average, the percentage of total costs associated with uncommon procedures was 26% greater than expected based on their share of total discharges (P<0.00001). Average percentage differences were insensitive to the endpoint, with similar results for the percentage of patient days and percentage of DRG case-mix weights. CONCLUSIONS: Approximately 2/3rd (mean 68%) of inpatient costs among surgical patients can be attributed to procedures performed at most once per month per hospital. The finding that such uncommon procedures account for a large percentage of costs is important because methods of cost accounting by procedure are generally unsuitable for them. PMID- 28802623 TI - An analytical model which determines the apparent T1 for Modified Look-Locker Inversion Recovery - Analysis of the longitudinal relaxation under the influence of discontinuous balanced (classical MOLLI) and spoiled gradient echo readouts. AB - Quantitative nuclear magnetic resonance imaging (MRI) shifts more and more into the focus of clinical research. Especially determination of relaxation times without/and with contrast agents becomes the foundation of tissue characterization, e.g. in cardiac MRI for myocardial fibrosis. Techniques which assess longitudinal relaxation times rely on repetitive application of readout modules, which are interrupted by free relaxation periods, e.g. the Modified Look Locker Inversion Recovery = MOLLI sequence. These discontinuous sequences reveal an apparent relaxation time, and, by techniques extrapolated from continuous readout sequences, a putative real T1 is determined. What is missing is a rigorous analysis of the dependence of the apparent relaxation time on its real partner, readout sequence parameters and biological parameters as heart rate. This is provided in this paper for the discontinuous balanced steady state free precession (bSSFP) and spoiled gradient echo readouts. It turns out that the apparent longitudinal relaxation rate is the time average of the relaxation rates during the readout module, and free relaxation period. Knowing the heart rate our results vice versa allow to determine the real T1 from its measured apparent partner. PMID- 28802624 TI - A portable real-time in situ gamma-ray analysis system. AB - A portable CeBr3 based gamma-ray detection system was designed and built for rapid turnaround, high throughput, real-time, and in situ sample analysis. The new technique allows automated data transmission from the field unit to a central laboratory controller to ensure laboratory quality of the data collected by field users without gamma-ray spectroscopy expertise. The method validation data indicates that the system's data quality objectives are adequate for radiological or nuclear emergency response or targeted surveillance programs where gamma-ray analysis is needed. PMID- 28802625 TI - Ionic liquids as solvents for Cerenkov counting and the effect of a wavelength shifter. AB - We study the wavelength shift of the Cerenkov light - generated in the ionic liquid (BMIMCl) - caused by the addition of the highly fluorescent ionic liquid (BMIMHPTS). 18F and 32P efficiencies increases up to 124% and 14%, respectively, compared with the values obtained with pure BMIMCl. With this improvement, ionic liquid mixtures become a good alternative - when using the TDCR-Cherenkov technique - to standardize radionuclides having electron emissions energies close to the threshold energy in water (~ 260keV). As an advantage compared with other solvents, the Ionic liquid mixture can be reused, in the case of short-lived radionuclides, by simply removing all water content in a vacuum oven. PMID- 28802626 TI - Determination of the neutron activation profile of core drill samples by gamma ray spectrometry. AB - This paper provides guidance for determining the neutron activation profile of core drill samples taken from the biological shield of nuclear reactors using gamma spectrometry measurements. Thus, it provides guidance for selecting a model of the right form to fit data and using least squares methods for model fitting. The activity profiles of two core samples taken from the biological shield of a nuclear reactor were determined. The effective activation depth and the total activity of core samples along with their uncertainties were computed by Monte Carlo simulation. PMID- 28802627 TI - Sensorless control for switched reluctance motor based on special position detection. AB - This paper proposes a new sensorless control approach for switched reluctance motor (SRM) in the single pulse control mode in high speed operation. The sensorless method uses the cross point position of transformer electromotive force (EMF) and motional back electromotive force (BEMF) to estimate the rotor position. The cross point position can be derived from the inductance model of SRM, and it is regarded as reference position. The rotor position can be calculated by detecting the special position for each electrical cycle. The proposed position estimation method is not affected by the magnetic saturation of SRM. Importantly, no additional hardware and no complicated computation or memory storage are required with the proposed method. Finally, the simulation and experimental results on a three-phase 12/8-pole SRM demonstrate the validity of the proposed sensorless scheme. PMID- 28802628 TI - Physical activity domains and cognitive function over three years in older adults with subjective memory complaints: Secondary analysis from the MAPT trial. AB - OBJECTIVES: We aimed to examine the associations of physical activity (PA) domains (i.e., PA in leisure-time (LTPA), for housework (HPA), or for gardening (GPA)) with cognitive function in older adults with subjective memory complaints (no-dementia) and to investigate if those associations were dependent on the status of apolipoprotein E allele 4 (APOE4), omega-3 levels and mild cognitive impairment (MCI). DESIGN: Observational prospective secondary analysis using longitudinal data from a randomized controlled trial. METHODS: Participants were 420 French community-dwelling people (aged 75.6+/-4.4; 66.4% women) randomized into the placebo group. They were assessed at baseline, 6-, 12-, 24- and 36-month using a battery of neuropsychological tests; a composite cognitive Z score was elaborated for all time points. Data on PA come from baseline and was obtained using a self-reported questionnaire. RESULTS: In time-adjusted analysis, LTPA significantly predicted cognitive function over three years for almost all tests and the composite Z score, with higher LTPA associated with better function; multivariate analysis showed a significant association only for verbal fluency. HPA was not associated to cognitive function, whereas GPA had mixed results. The magnitude of the PA-cognition associations was very weak, being the strongest for LTPA. Stratified analyses showed that the associations between PA and cognitive function were stronger for MCI, people with normal omega-3 index levels, and APOE4 non-carriers. CONCLUSIONS: PA domain is an important aspect to take into account when examining the associations between PA and cognitive function. Biomarkers of cognitive function may modulate the PA-cognition associations. PMID- 28802629 TI - Multiple magnets trapped at the esophagogastric junction of a child. PMID- 28802630 TI - Infantile hypophosphatasia combined with vitamin B6-responsive seizures and reticular formation lesions on magnetic resonance imaging: A case report. AB - BACKGROUND: Hypophosphatasia (HPP) is a rare genetic disorder characterized by rachitic bone manifestations and a low serum alkaline phosphatase (ALP) level. It is caused by mutations in the tissue non-specific alkaline phosphatase (TNSALP) gene, which encodes the tissue non-specific isozyme of ALP. HPP patients exhibit various presentations depending on their age at onset, such as infantile HPP combined with vitamin B6-responsive seizures. CASE PRESENTATION: A newborn with infantile HPP presented with tonic convulsions from day 5 after birth and received intravenous vitamin B6 (10mg/kg/day pyridoxal phosphate). Eleven days later, frequent apneic episodes occurred, and head magnetic resonance imaging (MRI) showed bilateral reticular formation lesions in the brain stem, including the medulla oblongata. After the pyridoxal phosphate dose was increased (to 40mg/kg/day), the patient's seizures and apnea resolved, and her MRI findings also improved. Genetic testing revealed that she was homozygous for the 1559delT mutation of TNSALP. CONCLUSIONS: High-dose pyridoxal phosphate is a useful treatment for HPP-induced seizures and might improve reticular formation lesions. PMID- 28802631 TI - The design and SAR of a novel series of 2-aminopyridine based LRRK2 inhibitors. AB - Leucine-rich repeat kinase 2 (LRRK2) has attracted considerable interest as a therapeutic target for the treatment of Parkinson's disease. Compounds derived from a 2-aminopyridine screening hit were optimised using a LRRK2 homology model based on mixed lineage kinase 1 (MLK1), such that a 2-aminopyridine-based lead molecule 45, with in vivo activity, was identified. PMID- 28802632 TI - Discovery of potent and selective CDK8 inhibitors through FBDD approach. AB - A fragment library screen was carried out to identify starting points for novel CDK8 inhibitors. Optimization of a fragment hit guided by co-crystal structures led to identification of a novel series of potent CDK8 inhibitors which are highly ligand efficient, kinase selective and cellular active. Compound 16 was progressed to a mouse pharmacokinetic study and showed good oral bioavailability. PMID- 28802634 TI - Individual Differences in Heparin Sensitivity and Their Effect on Heparin Anticoagulation During Arterial Vascular Surgery. AB - OBJECTIVES: To investigate whether a fixed heparin dose results in adequate heparinisation levels and consequent inhibition of haemostatic activation in all patients. METHODS: This prospective clinical pilot study included 24 patients undergoing arterial vascular surgery. Individual heparin responsiveness was assessed using the Heparin Dose Response (HDR) test, while the activated clotting time (ACT) and heparin concentration were measured to monitor the peri-procedural degree of anticoagulation. Finally, peri-operative haemostasis was evaluated with rotational thromboelastometry (ROTEM). RESULTS: Eight patients were identified with reduced heparin sensitivity (RS group) and 16 patients with normal heparin sensitivity (NS group). Compared with the NS group, the RS group showed less prolonged ACTs after heparinisation with heparin concentrations below the calculated target heparin concentration. ROTEM revealed shorter clot formation times in the intrinsically activated coagulation test (INTEM) 3 min (114 +/- 48 s vs. 210 +/- 128 s) and 30 min after the initial heparin bolus (103 +/- 48 s vs. 173 +/- 81 s) in the RS group compared with the NS group. In the RS group, one patient developed a major thromboembolic complication. CONCLUSIONS: This study shows that a third of the study population had reduced heparin sensitivity, which was associated with lower levels of heparinisation, and lower inhibition levels of clot initiation and clot formation. Identifying patients with reduced heparin sensitivity by monitoring the anticoagulant effect of heparin could decrease the risk of thrombotic complications after arterial vascular surgery. PMID- 28802633 TI - 1-Acetyl-5-phenyl-1H-pyrrol-3-ylacetate: An aldose reductase inhibitor for the treatment of diabetic nephropathy. AB - Diabetic nephropathy (DN) is the most common and serious complication in diabetes mellitus, but the efficacy of available strategies for preventing this disorder remains poor. The aim of this study was to investigate the possible beneficial effects of 1-acetyl-5-phenyl-1H-pyrrol-3-ylacetate (APPA), an aldose reductase inhibitor, on DN. In the present study, a model of rat glomerular mesangial cells (HBZY-1) damaged by high glucose was used to confirm the protective effects of APPA in vitro. Then, a rat model of streptozotocin-induced diabetes was used to assess the effects of APPA in vivo. APPA increased viability and reduced apoptosis in HBZY-1 cells. In vivo, APPA improved the signs of DN as determined by measurements of blood glucose, urinary microalbumin, serum total antioxidant capacity, serum catalase activity, serum glutathione levels, and serum total superoxide dismutase activity. Hematoxylin and eosin staining of kidney tissue confirmed the protective effect. Moreover, APPA reduced the levels of transforming growth factor-beta1, collagen IV, and laminin in HBZY-1cells incubated in high glucose, and in serum in DN rats. In summary, APPA can effectively prevent apoptosis and the symptoms of streptozotocin-induced diabetes by inhibiting the polyol pathway in rats. This suggests that APPA could be a potential drug in treating DN. PMID- 28802635 TI - Aorta Related and All-cause Mortality in Patients with Aortic Intramural Haematoma. AB - OBJECTIVES: The prognosis of patients with intramural haematoma (IMH) of the aorta beyond the first year after diagnosis remains largely unknown. In particular, patients that do not undergo interventions are lost to follow-up. The aim was to assess medium-term outcome in IMH patients. METHODS: Post hoc analysis of 63 consecutive patients presenting with IMH between 1999 and 2013 was performed. Patients meeting imaging criteria at the first presentation were included even if follow-up imaging showed evidence of intimal disruption or false lumen flow. RESULTS: Eighteen patients presented with type A and 45 with type B IMH (29% vs. 71%, p < .001). The mean age was 71 +/- 9.2 years, range 42-88 years. Follow-up was completed in 97% of patients by May 2017 and represents a mean follow-up of 6.3 +/- 3.6 years. Freedom from intervention in patients with type B IMH was 40%. TEVAR was performed in 47% because of development, unmasking of an entry tear (57%), progression to acute type B dissection (24%), or subsequent dilation of the affected aortic segments (19%). Open repair was performed in 13% of type B IMH patients because of dilation of the descending aorta. In type A IMH, 89% underwent open repair. Aorta related 30 day, 6 month, 1 year, and late mortality were 1.6%, 6.3%, 6.3%, and 9.5%, respectively, for all IMH patients. All-cause 30 day, 6 month, 1 year, and late mortality were 1.6%, 6.3%, 6.3%, and 47.6%, respectively, for all IMH patients. Late mortality in type B IMH did not differ whether patients underwent TEVAR, open repair, or received best medical treatment only (26% vs. 22%, p = 1.0). CONCLUSIONS: Late aorta related mortality in IMH was low whereas all-cause mortality was substantial. Aorta related mortality in IMH patients only occurs during the first year after diagnosis. Interventions after the first year are rarely necessary. PMID- 28802637 TI - Blood pressure responses to dietary sodium: Association with autonomic cardiovascular function in normotensive adults. AB - Blood pressure responses to dietary sodium vary widely person-to-person. Salt sensitive rodent models display altered autonomic function, a trait thought to contribute to poor cardiovascular health. Thus, we hypothesized that increased salt sensitivity (SS) in normotensive humans would be associated with increased muscle sympathetic nerve activity (MSNA), decreased high frequency heart rate variability (HF-HRV), and decreased baroreflex sensitivity. Healthy normotensive men and women completed 1week of high (300mmol.day-1) and 1week of low (20mmol.day-1) dietary sodium (random order) with 24h mean arterial pressure (MAP) assessed on the last day of each diet to assess SS. Participants returned to the lab under habitual sodium conditions for testing. Forty-two participants are presented in this analysis, 19 of which successful MSNA recordings were obtained (n=42: age 39+/-2yrs., BMI 24.3+/-0.5kg.(m2)-1, MAP 83+/-1mmHg, habitual urine sodium 93+/-7mmol.24h-1; n=19: MSNA burst frequency 20+/-2 bursts.min-1). The variables of interest were linearly regressed over the magnitude of SS. Higher SS was associated with increased MSNA (burst frequency: r=0.469, p=0.041), decreased HF-HRV (r=-0.349, p=0.046), and increased LF/HF-HRV (r=0.363, p=0.034). SS was not associated with sympathetic or cardiac baroreflex sensitivity (p>0.05). Multiple regression analysis accounting for age found that age, not SS, independently predicted HF-HRV (age adjusted no longer significant; p=0.369) and LF/HF-HRV (age adjusted p=0.273). These data suggest that age-related salt sensitivity of blood pressure in response to dietary sodium is associated with altered resting autonomic cardiovascular function. PMID- 28802638 TI - Spiritual perspectives of emergency medicine doctors and nurses in caring for end of-life patients: A mixed-method study. AB - BACKGROUND: End-of-life care is becoming more prevalent in the Emergency Department. Quality end-of-life care includes spiritual support. As spirituality is a relatively vague concept, understanding healthcare professionals' spiritual perspectives is important. AIMS: To explore the perspectives of Emergency Department doctors and nurses in (i) spirituality, (ii) spiritual care domain in end-of-life care and (iii) factors influencing spiritual care provision in the Emergency Department. DESIGN: A sequential explanatory mixed-method design was used. SETTING: An Emergency Department of a tertiary teaching hospital in Singapore, which treats more than 120,000 patients annually. PARTICIPANTS: This study involved Emergency Department doctors and nurses who meet the eligibility criteria. In phase one, 64 doctors and 112 nurses were recruited. In phase two, 14 doctors and 15 nurses participated. METHODS: The quantitative phase was conducted first using a socio-demographic form and validated Spiritual Care Giving Scale on all potential participants. The Spiritual Care-Giving Scale explores one's perspectives of spirituality and spiritual care. Using a six-point Likert scale, participants would indicate their degree of agreement towards the statements. The qualitative phase was then conducted using focus group discussions on a convenience sample of 14 doctors and 15 nurses. RESULTS: Overall, participants had positive attitudes and understanding of spirituality and spiritual care, as the mean total Spiritual Care-Giving Scale score was 167.87 (SD=24.35) out of 210. Some knowledge deficits were observed in the focus group discussions as several participants equated spirituality to religion and had limited understanding about spiritual care. Significant differences between the spiritual perspectives of doctors and nurses were reported in Spiritual Perspectives (p-value=0.018) and Spiritual Care Values (p-value=0.004) of the Spiritual Care-Giving Scale. Scores by nurses were higher than those of doctors. CONCLUSION: The study findings emphasized the need for education regarding spirituality and spiritual care across different cultures. This may help healthcare professionals feel more competent to broach such issues and cope with the emotional burden when providing spiritual care. PMID- 28802636 TI - Cardiac neuroanatomy - Imaging nerves to define functional control. AB - The autonomic nervous system regulates normal cardiovascular function and plays a critical role in the pathophysiology of cardiovascular disease. Further understanding of the interplay between the autonomic nervous system and cardiovascular system holds promise for the development of neuroscience-based cardiovascular therapeutics. To this end, techniques to image myocardial innervation will help provide a basis for understanding the fundamental underpinnings of cardiac neural control. In this review, we detail the evolution of gross and microscopic anatomical studies for functional mapping of cardiac neuroanatomy. PMID- 28802639 TI - Body weight perception and body weight control behaviors in adolescents. AB - OBJECTIVE: To investigate the association between the perception of body weight (as above or below the desired) and behaviors for body weight control in adolescents. METHODS: This was a cross-sectional study that included 1051 adolescents (aged 15-19 years) who were high school students attending public schools. The authors collected information on the perception of body weight (dependent variable), weight control behaviors (initiative to change the weight, physical exercise, eating less or cutting calories, fasting for 24h, taking medications, vomiting, or taking laxatives), and measured body weight and height to calculate the body mass index and then classify the weight status. Associations were tested by multinomial logistic regression analysis. RESULTS: Adolescents of both sexes who perceived their body weight as below the expected weight took more initiatives to gain weight, and those who perceived themselves as overweight made more efforts to lose weight. In adolescents who perceived themselves as overweight, the behavior of not taking medication was associated with the outcome only in boys (Odds Ratio=8.12), whereas in girls, an association was observed with the variables eating less, cutting calories, or avoiding fatty foods aiming to lose or avoid increasing body weight (Odds Ratio=3.39). Adolescents of both sexes who practiced exercises were more likely to perceive themselves as overweight (male Odds Ratio=2.00; Odds Ratio=1.93 female). CONCLUSION: The perception of the body weight as above and below one's expected weight was associated with weight control behaviors, which were more likely to result in initiatives to lose and gain weight, respectively. PMID- 28802640 TI - Nonalcoholic fatty liver disease associated with metabolic syndrome: Influence of liver fibrosis stages on characteristics of very low-density lipoproteins. AB - BACKGROUND: We evaluated possible changes in VLDLcharacteristics, and metabolic related factors, in MetS-associated NAFLD and accompanying liver fibrosis. METHODS: We studied 36 MetS patients with biopsy-proven NAFLD (MetS+NAFLD) and 24 MetS without ultrasound NAFLD evidence. Further, MetS+NAFLD was sub-divided according to fibrosis stage into, non-to-moderate (F0-F2, n=27) and severe (F3 F4, n=9) fibrosis. We measured: lipid profile, VLDL composition and size (size exclusion-HPLC), CETP and lipoprotein lipase (LPL) activities and adiponectin. Additionally, in MetS+NAFLD type IV collagen 7S domain was measured. RESULTS: MetS+NAFLD showed increased VLDL-mass, VLDL particle number, VLDL-triglyceride% and large VLDL-% (p<0.04). CETP activity tended to increase in MetS+NAFLD (p=0.058), while LPL activity was unchanged. Moreover, in MetS+NAFLD, adiponectin was decreased (p<0.001), and negatively correlated with VLDL-mass and VLDL particle number (p<0.05), independently of insulin-resistance. Within MetS+NAFLD group, despite greater insulin-resistance, patients with severe fibrosis showed lower plasma triglycerides, VLDL-mass, VLDL-triglyceride%, large VLDL-% and CETP activity (p<0.05), while type IV collagen was increased (p=0.009) and inversely correlated with large VLDL-% (p=0.045). CONCLUSIONS: In MetS, NAFLD is associated with larger and triglyceride over-enriched circulating VLDLs, of greater atherogenicity. However, when NAFLD progresses to severe fibrosis, circulating VLDL features apparently improved, probably due to early alterations in hepatic synthetic function. PMID- 28802641 TI - Enhanced effects of DNA vaccine against botulinum neurotoxin serotype A by targeting antigen to dendritic cells. AB - As dendritic cells (DCs) play a critical role in priming antigen-specific immune responses, the efficacy of DNA vaccines may be enhanced by targeting the encoded antigen proteins to DCs. In this study, we constructed a DC-targeted DNA vaccine encoding the Hc domain of botulinum neurotoxin serotype A (AHc) fused with scDEC, a single-chain Fv antibody (scFv) specific for the DC-restricted antigen-uptake receptor DEC205. Intramuscular injections of mice with the DC-targeted DNA vaccine (pVAX1-scDEC-AHc) stimulated more DCs to mature than the non-targeted DNA vaccine (pVAX1-SAHc) in the splenocytes. The DC-targeted DNA vaccine could induce more DCs maturation at the site of inoculation. The DC-targeted DNA vaccine induced stronger AHc-specific humoral immune responses, lymphocyte proliferative responses and protective potency against BoNT/A in mice than did pVAX1-SAHc. Moreover, the DC-targeting DNA vaccine provided effective protection after only two inoculations. In summary, these results showed that the DC-targeted fusion DNA vaccine could generate strong immunity, indicating that maturation of DCs induced by pVAX1-scDEC-AHc may be helpful for priming and boosting immune responses. Thus, we propose that the strategy of targeting antigen to DCs in vivo via DEC205 can enhance effectively the potency of DNA vaccines against BoNTs or other pathogens in an animal model. PMID- 28802643 TI - Update on Urinary Stones in Children: Current and Future Concepts in Surgical Treatment and Shockwave Lithotripsy. AB - CONTEXT: Miniaturized instrumentation used for endoscopic treatment of urinary stone disease in children has been readily adopted in clinical practice. However, there is a need to optimize and individualize the surgical approach according to the patient's age, body habitus, and stone characteristics. Promising novel equipment and techniques will continue to advance the surgical care of these children. OBJECTIVE: To review the literature regarding surgical and shockwave lithotripsy (SWL) treatment of urinary stone disease in children and provide an overview on future treatment innovations. EVIDENCE ACQUISITION: We conducted a nonsystematic review of the literature using the PubMed database. The search focused on the most recent two decades to provide a contemporary overview of surgical outcomes. EVIDENCE SYNTHESIS: Although SWL use has proportionally decreased over time, it remains an important treatment option for kidney stones <2cm and upper ureteral calculi, with success rates between 49% and 97%. Rigid/semirigid ureteroscopy is the first-line therapy for distal ureteral stones and has success rates comparable to SWL for upper ureteral stones. Success rates between 80% and 100% are achieved with retrograde intrarenal surgery (RIRS) for kidney stones <2cm but may require pre-stenting in smaller children. Mini percutaneous nephrolithotomy (PNL) is the most efficient technique for treating kidney stones in children. Micro-PNL and ultramini-PNL are valuable alternatives, especially for smaller renal stones. CONCLUSIONS: Modern endoscopic treatment options together with SWL allow personalized management of stone disease in the pediatric population. Future technical improvements on the horizon offer the promise of increasing the efficiency of current procedures while minimizing complications. PATIENT SUMMARY: Miniaturization of the instruments used for treatment of stone disease in children provides a variety of options for clinical practice. Rather than routinely using a single technique, personalized treatment is recommended to increase the success of each procedure. PMID- 28802642 TI - Prognostic Value of TERT Alterations, Mutational and Copy Number Alterations Burden in Urothelial Carcinoma. AB - : Point mutations in the TERT gene promoter occur at high frequency in multiple cancers, including urothelial carcinoma (UC). However, the relationship between TERT promoter mutations and UC patient outcomes is unclear due to conflicting reports in the literature. In this study, we examined the association of TERT alterations, tumor mutational burden per megabase (Mb), and copy number alteration (CNA) burden with clinical parameters and their prognostic value in a cohort of 398 urothelial tumors. The majority of TERT mutations were located at two promoter region hotspots (chromosome 5, 1 295 228 C>T and 1 295 250 C>T). TERT alterations were more frequently present in bladder tumors than in upper tract tumors (73% vs 53%; p=0.001). ARID1A, PIK3CA, RB1, ERCC2, ERBB2, TSC1, CDKN1A, CDKN2A, CDKN2B, and PTPRD alterations showed significant co-occurrence with TERT alterations (all p<0.0025). TERT alterations and the mutational burden/Mb were independently associated with overall survival (hazard ratio[HR] 2.31, 95% confidence interval [CI] 1.46-3.65; p<0.001; and HR 0.96, 95% CI 0.93 0.99; p=0.002), disease-specific survival (HR 2.23, 95% CI 1.41-3.53; p<0.001; and HR 0.96, 95% CI 0.93-0.99; p=0.002), and metastasis-free survival (HR 1.63, 95% CI 1.05-2.53; p=0.029; and HR 0.98, 95% CI 0.96-1.00; p=0.063) in multivariate models. PATIENT SUMMARY: The majority of TERT gene mutations that we detected in urothelial carcinoma are located at two promoter hotspots. Urothelial tumors with TERT alterations had worse prognosis compared to tumors without TERT alterations, whereas tumors with a higher mutational burden had more favorable outcome compared to tumors with low mutational burden. PMID- 28802644 TI - Rapid characterization of the CHO platform cell line and identification of pseudo attP sites for PhiC31 integrase. AB - The Chinese Hamster Ovary (CHO) cell lines, applicable to post-translational modifications, are preferred systems for biopharmaceutical protein production. In this study, by using the Jump-InTM TITM technology which employs PhiC31 and R4 bacteriophage recombinases, a platform CHO-K1 cell line containing a R4-attP site was generated. Here, a combination of Quantitative Fluorescent-Polymerase Chain Reaction (QF-PCR) and semi-random, two-step PCR (ST-PCR), was performed to feature the platform cell clones. Our results show that QF-PCR and ST-PCR, can be utilized for efficient and accelerated cell line characterization. By applying these approaches, we were able to accurately identify the copy number of integrated R4-attP sites and the genomic position of recombination of many clones. Three novel PhiC31 pseudo-attP sites were identified on chromosomes 1, 3 and 6, and their genomic features were analyzed. The characterized platform cell lines are stable, and because of single-copy, site-specific R4 recognition attP site, the cell lines could be retargeted for recombinant protein production and drug discovery applications. PMID- 28802645 TI - P2X7 purinergic receptors participate in the expression and extinction processes of contextual fear conditioning memory in mice. AB - The purinergic system consists of two large receptor families - P2X and P2Y. Both are activated by adenosine triphosphate (ATP), although presenting different functions. These receptors are present in several brain regions, including those involved in emotion and stress-related behaviors. Hence, they seem to participate in fear- and anxiety-related responses. However, few studies have investigated the purinergic system in threatening situations, as observed in contextual fear conditioning (CFC). Therefore, this study investigated the involvement of purinergic receptors in the expression and extinction of aversive memories. C57Bl/6 background mice were submitted to the CFC protocol. Wildtype (WT) mice received i.p. injection of either a nonselective P2 receptor (P2R) antagonist, P178 (10 or 30 mg/kg); a selective P2X7 receptor (P2X7R) antagonist, A438079 (10 mg/kg); a selective P2Y1 receptor (P2Y1R) antagonist, MRS2179 (10 mg/kg); or vehicle 10 min prior to or immediately after the extinction session. Additionally, P2X7R KO mice were tested in the CFC protocol. After P2R antagonist treatment, contextual fear recall increased, while acquisition of extinction was impaired. Similar results were observed with the selective P2X7R antagonist, but not with the selective P2Y1R antagonist. Interestingly, P2X7R KO mice showed increased contextual fear recall, associated with impaired acquisition of extinction, in accordance with pharmacologic P2X7R antagonism. Our results suggest that specific pharmacological or genetic blockade of P2X7R promotes anxiogenic-like effects, along with deficits in extinction learning. Thus, these receptors could present an alternative treatment of stress-related psychiatric disorders. PMID- 28802646 TI - Involvement of extracellular signal-regulated kinase (ERK) in the short and long lasting antidepressant-like activity of NMDA receptor antagonists (zinc and Ro 25 6981) in the forced swim test in rats. AB - Short and long acting NMDA receptor (NMDAR) antagonists exert their antidepressant-like effects by activating signaling pathways involved in the synthesis of synaptic proteins and formation of new synaptic connections in the prefrontal cortex (PFC) of rats. The blockade of the ERK pathway abolishes ketamine and Ro 25-6981 antidepressant potency. However, the role of ERK in the antidepressant-like activity of short acting NMDAR antagonists is still unclear. More puzzling is the fact that the precise role of ERK in the short and long lasting effects of long-acting NMDAR antagonists is unknown. In this study, we show that zinc, (Zn) a short-acting NMDAR antagonist evokes only transient ERK activation, which is observed 7 min after its administration in the PFC of rats. In contrast to Zn, the long acting NMDAR antagonist Ro 25-6981 produces persistent ERK activation lasting up to 24 h. Pretreatment with the MAPK/ERK inhibitor (U0126) totally abolished Zn and Ro 25-6981 antidepressant-like activities in the forced swim test in rats. However, when U0126 is administered 15 min after Zn or Ro 25-6981 both compounds maintain their short-lasting antidepressant-like activity. On the other hand, posttreatment with U0126 significantly attenuated the long lasting antidepressant-like activity of Ro 25 6981. These results indicate that the activation of ERK is crucial for the short- and long lasting antidepressant-like activity observed in the FST in rats. PMID- 28802647 TI - Pharmacological modulation of Acid-Sensing Ion Channels 1a and 3 by amiloride and 2-guanidine-4-methylquinazoline (GMQ). AB - Acid-Sensing Ion Channels (ASICs) are cation channels activated by extracellular acidification that emerge as potential pharmacological targets in pain and other neurological disorders. Here, we compare the pharmacological modulation of ASIC1a and ASIC3 channels by amiloride and 2-guanidine-4-methylquinazoline (GMQ), two compounds commonly used for their in vitro and in vivo investigation. We analyzed the effect of amiloride on the pH-dependent activation and inactivation, the relative influence of the extracellular domain and the transmembrane/cytosolic domains on the effect of amiloride and GMQ using chimeras between ASIC1a and ASIC3, and how these compounds potentiate the physiologically relevant ASIC3 sustained window current. We showed that amiloride and GMQ shift the pH-dependent activation and inactivation in the same directions, which depend on the channel, and that their effects rely on the nature of the extracellular domain but can be indirectly modulated in their amplitude by the transmembrane/cytosolic domains. The extracellular domain explains the pharmacological potentiating effect of amiloride and GMQ on the window current in ASIC3, and why these compounds failed to generate a window current in ASIC1a. Amiloride and GMQ have similar and purely additive effects suggesting that they act through a common unique binding site different from acidic pockets. Finally, a simple cycle analysis using GMQ that targets the nonproton ligand-sensor, and two peptide inhibitors of ASIC1a targeting the acidic pockets (PcTx1 and mambalgin-1), shows overlap between the mechanisms by which GMQ and PcTx1 modify inactivation and suggests shared mechanisms of regulation of the pH-dependent inactivation of ASIC1a between these two regions. PMID- 28802648 TI - Designing binding kinetic assay on the bio-layer interferometry (BLI) biosensor to characterize antibody-antigen interactions. AB - The Octet biosensors provide a high-throughput alternative to the well established surface plasmon resonance (SPR) and SPR imaging (SPRi) biosensors to characterize antibody-antigen interactions. However, the utility of the Octet biosensors for accurate and reproducible measurement of binding rate constants of monoclonal antibodies (mAbs) is limited due to challenges such as analyte rebinding, and mass transport limitation (MTL). This study focuses on addressing these challenges and provides experimental conditions to reliably measure kinetics of mAb-antigen interactions. The mAb capture density of less than 0.6 nm was found to be optimal to measure a wide range of binding affinities on Octet HTX biosensor. The titration kinetic and single cycle kinetic assays performed on Octet HTX generated reproducible binding kinetic parameters and correlated with the values measured on Biacore 4000 and MASS-1. Kinetic assays performed on 0.1 nm density mAb surfaces significantly reduced MTL and enabled characterization of picomolar affinity mAbs. Finally, kinetic analysis performed on 150 antibodies to 10 antigens with molecular weights ranging from 21kD to 105kD showed concordance between Octet HTX, Biacore 4000 and MASS-1 (R2 > 0.90). The data presented in this study suggest that under optimal experimental conditions, Octet biosensor is capable of generating kinetic values comparable to SPR/SPRi biosensors. PMID- 28802649 TI - "Chase perfection, catch excellence". PMID- 28802650 TI - Crossing the boundaries. PMID- 28802651 TI - Reoperating after endovascular therapy: A future challenge of cardiovascular surgery. PMID- 28802652 TI - An autophagic mechanism is involved in the 6-hydroxydopamine-induced neurotoxicity in vivo. AB - 6-hydroxydopamine (6-OHDA) is one of the most common agents for modeling dopaminergic neuron degeneration in Parkinson's disease (PD). So far, the role of autophagy in 6-OHDA-induced neurotoxicity remains controversial and most evidence is collected from in vitro studies. In this study, we determined the role of autophagy activation in 6-OHDA-induced neurotoxicity in a rat model of PD. Following 6-OHDA treatment, we observed a concomitant activation of autophagy and apoptosis. To further explore the interaction between autophagy and apoptosis induced by 6-OHDA, autophagy inhibitor 3-methylademine (3-MA) or cysteine protease inhibitor Z-FA-fmk was applied. We found that both 3-MA and Z-FA-fmk could not only exert immediate protection against 6-OHDA-induced neuronal apoptosis, but also prevent dopaminergic neuron loss in the long-term, which was related to reduced autophagosome formation. Furthermore, by monitoring the sequential changes of mTOR-related signaling pathways, we found that reactive oxygen species (ROS)-mediated AKT/AMPK-mTOR signaling pathway participated in but was not the initial cause of autophagy activation by 6-OHDA. Collectively, our data suggest that 6-OHDA-induced autophagy activation contributes to its neurotoxicity and targeting autophagy activation or cysteine proteases could be promising for developing neuroprotective agents for PD. PMID- 28802653 TI - In vitro interactions of malachite green and leucomalachite green with hepatic drug-metabolizing enzyme systems in the rainbow trout (Onchorhyncus mykiss). AB - Malachite green (MG) has been widely used in aquaculture to treat a number of microbial and parasitic diseases. It is currently banned in the EU because of the high cytotoxicity and carcinogenic activity, which is also shared by leucomalachite green (LMG), a reduced MG metabolite that can persist in fish tissues for months. There is scant information about the ability of either compound to interact with drug metabolizing enzymes in fish. Therefore we evaluated the in vitro effects of MG and LMG (25, 50 and 100MUM) on some DMEs and glutathione (GSH) content in rainbow trout liver subfractions. LMG did not affect any of the examined parameters. In contrast, MG proved to deplete GSH and to depress to a various extent the activities of NAD(P)H cytochrome c reductase, 7 ethoxycoumarin O-deethylase, 1-naphthol uridindiphosphoglucuronyl-transferase and maximally those of 7-ethoxyresorufin O-deethylase (EROD) and glutathione S transferase (GST) accepting 1-chloro2,4-dinitrobenzene (CDNB) as substrate. The inhibition mechanisms of EROD and GST were investigated by means of non-linear Michaelis-Menten kinetics and Lineweaver-Burk plots using 0.175-8MUM MG. The calculated IC50 for EROD was 7.1MUM, and the inhibition appeared to be competitive (Ki 2.78+/-0.24MUM). In the case of GST, the calculated IC50 was 0.53MUM. The inhibition was best described as competitive toward GSH (Ki 0.39+/ 0.02MUM) and of mixed-type toward CDNB (Ki 0.64+/-0.06MUM). Our findings indicate that, contrary to LMG, MG behaves as a relatively strong inhibitor of certain liver DMEs and can reversibly bind GSH. PMID- 28802654 TI - Income, physical activity, sedentary behavior, and the 'weekend warrior' among U.S. adults. AB - The present study examines the association between income and physical activity intensity along the entire continuum using accelerometry in a nationally representative sample of U.S. adults. Specifically, we assessed the relationship between annual household income, sedentary behavior, light, and moderate-vigorous intensity physical activity, and meeting physical activity guidelines over a brief, 2-day period ('weekend warrior'), and during the entire week. The sample consisted of 5206 National Health and Examination Survey adult participants (2003 2006) who wore accelerometers and completed pertinent survey questions. Ordinary Least Square models were computed to examine the relationship between income and the dependent variables (sedentary behavior, light, and moderate to vigorous intensity activity) adjusting for covariates. Logistic regression was employed to examine the association between income and meeting physical activity guidelines during a 2-day and 7-day time-period. Results indicate that individuals with an annual income of >=$75,000 engaged in 4.6 more daily minutes of moderate to vigorous activity (p-value<0.01), in comparison to the reference group (<$20,000 annual income). Those in the high-income strata were 1.6 and 1.9 times more likely to meet physical activity guidelines during a 2 and 7-day period (respectively) than their lower income counterparts (p<0.05 for both). Further, those in the high-income strata spent 11.8 more minutes daily being sedentary than their lower income counterparts (p-value<0.01). In conclusion, higher annual household income is related to more intense, less frequent (per week) patterns of physical activity and more daily sedentary time. PMID- 28802655 TI - Alternating trifascicular block and cardiac memory. AB - We describe a case of a 70year-old woman with effort dyspnea and alternating trifascicular conduction pattern, worsened with exercise to atrioventricular block (AV Block). The alternating conduction at rest resulted in marked T wave changes. We discuss the mechanism of T wave memory changes and the management of exercise-induced AV Block. PMID- 28802656 TI - Rethinking papillary muscle resection for refractory ventricular tachycardia in the LVAD era. A case report. AB - We report the case of a 57-year-old man with a history of ischemic cardiomyopathy who presented to the hospital with recurrent episodes of ventricular tachycardia refractory to antiarrhythmic medications. Mapping identified a deep premature ventricular contraction focus in the anterolateral papillary muscle, an area that has been previously identified as difficult to treat with radiofrequency catheter ablation. The hospital course was complicated by cardiogenic shock and VT-storm, and the patient ultimately underwent surgical resection of the anterolateral papillary muscle with left ventricular assist device placement as a successful bridge to cardiac transplantation. PMID- 28802657 TI - Occurrence of pharmaceuticals and UV-filters in riverine run-offs and waters of the German Baltic Sea. AB - The occurrence of pharmaceuticals and personal care products (PPCPs) in the marine environment is of great concern. This study was done to determine the emergence of eight pharmaceuticals and eleven ultraviolet filters (UV-Filters) in 5 rivers/streams discharging into the Baltic Sea. Furthermore, a focus was put on the influence of wastewater treatment plant as indirect source and the occurrence of the PPCPs in close beach proximity. Two pharmaceuticals (sulfamethoxazole, salicylic acid) and two UV-filters (2-phenylbenzimidazole-5-sulfonic acid, octocrylene) were detected in all analyzed water samples, with concentration ranging from 0.6ng/L to 836.3ng/L. In all rivers the PPCP concentration decreases towards the Baltic Sea. Sulfamethoxazole was detected at comparable concentration along the coast, which leads to the assumption of stable concentration in beach proximity. Along the coast UV-filters appeared in varying concentrations, leading to the conclusion that the direct input into the marine environment plays a bigger role than the indirect input. PMID- 28802658 TI - Detecting long-term temporal trends in sediment-bound metals in the western Adriatic (Mediterranean Sea). AB - Major and trace metal concentrations were determined in western Adriatic sediment cores. Based on sediment chronology, the earliest anthropogenic influence appeared as a Zn and Pb increase in the Po River prodelta starting from ~1914. The increasing contamination signal of these trace metals propagated southward as far as 450km with a growing delay, taking ~10years to reach the south Adriatic Sea. Although greater inventories of excess trace metals in the northern sector pointed to the influence of the intense human activities in the Po River drainage basin and Venice lagoon system, we observed a reduction of excess trace metals from mid-1980s, related to the implementation of stricter environmental regulations on chemical wastewaters. In contrast, an increase in trace metal accumulation in surficial sediment from the 2000s in front of the cities of Ancona and Bari suggested a recent local input of trace metals, probably due to harbor activities. PMID- 28802659 TI - Hypoxia off the Changjiang (Yangtze River) estuary and in the adjacent East China Sea: Quantitative approaches to estimating the tidal impact and nutrient regeneration. AB - Large areas of hypoxia have been reported off The Changjiang Estuary and in the East China Sea. Five cruises, covering winter, spring, and summer, were carried out from 2007 to 2013 in this region, and in August 2013 (summer), an extensive hypoxic event (11,150km2) was observed, which was characterized by an estimated bulk oxygen depletion of 5.1 million tons. A strong tidal impact was observed associated with the bottom oxygen depletion, with the periodicity of diel variations in dissolved oxygen being 12h (i.e., similar to the tidal cycle). A conservative estimate of nutrient regeneration suggested that during the hypoxic event of August 2013, the amount of regenerated nitrogen (as nitrate) and phosphorus (as dissolved inorganic phosphorus) was 27,000-30,000 tons and 1300 41,000tons, respectively. Estimates of the absolute (bulk) regenerated nutrient fluxes were much greater than the conservative estimates. PMID- 28802660 TI - Heavy metal distribution in blood, liver and kidneys of Loggerhead (Caretta caretta) and Green (Chelonia mydas) sea turtles from the Northeast Mediterranean Sea. AB - The aim of the present study was to determine the concentrations of the most investigated environmentally relevant heavy metals in two highly endangered sea turtle species (Caretta caretta and Chelonia mydas) from the important nesting area on the Northeast Mediterranean Sea. The highest mean concentration was of Fe, while Hg and Pb were lowest. All tissue concentrations of Al, As, Fe and Mn were significantly different between the species. In particular, As, Cd, Cu, Mn, Ni, Se, Zn concentrations were lower in Caretta caretta and Cd, Hg, Mn, Zn concentrations were lower in Chelonia mydas than those reported in other parts of the world. Compared to studies conductud in other parts of the Mediterranean, Cd was lower. PMID- 28802661 TI - Efficacy of isolated limb perfusion (ILP) in patients with Merkel cell carcinoma (MCC): A multicenter experience. AB - BACKGROUND: Merkel cell carcinoma (MCC) is a rare and potentially aggressive neuroendocrine tumor of the skin, with a propensity for locoregional metastases. In two expert referral centers, isolated limb perfusion (ILP) is used to obtain locoregional control in selected locoregionally advanced MCC patients. This study describes our experience. METHOD: Patients who underwent ILP for MCC were analyzed. ILP was performed with melphalan and tumor necrosis factor (TNF) combination therapy. Depending on the institution, either a normothermic or a hyperthermic temperature regimen was used. Baseline characteristics, toxicity data, locoregional progression-free survival (LPFS) and overall survival (OS) were assessed. RESULTS: Four males and 6 females with a median age of 78 years (IQR 61-84 years) were included. Four patients underwent ILP for upper extremity disease and 6 for lower extremity disease. All patients received combination therapy with Melphalan and TNF, one patient with the addition of interferon gamma. No signs of systemic toxicity were present post-ILP. Severe locoregional toxicity (compartment syndrome) occurred in 1 patient and 1 elderly patient with extensive atherosclerosis had to undergo transfemoral amputation due to critical ischemia. Eight patients could be included for response evaluation. The overall response rate (ORR) was 87.5% with a complete response (CR) rate of 62.5%. Two long-term responses of 53 months and 71 months were observed. Median LPFS was 5 months and median OS was 54 months. CONCLUSION: ILP shows a high CR rate that can be durable. Therefore, ILP should be considered an effective treatment modality for locally advanced MCC. PMID- 28802662 TI - The metastasis status and tumor burden-associated CA125 level combined with the CD4/CD8 ratio predicts the prognosis of patients with advanced pancreatic cancer: A new scoring system. AB - INTRODUCTION: Although CA125 and the tumor immune response have been reported to be associated with pancreatic cancer, their prognostic value for advanced pancreatic cancer patients undergoing chemotherapy remain uncertain. We thus studied the prognostic value of the combination of the CA125 level with the CD4/CD8 ratio. METHODS: After excluding patients who were lost to follow-up or for whom complete clinical data were missing, 369 participants were ultimately examined. Univariate and multivariate analyses were performed using the Cox hazards model, and Kaplan-Meier methods and log-rank tests were used for the comparison of survival rates. RESULTS: Univariate and multivariate analyses showed that a high CA125 level and a high CD4/CD8 ratio were independent prognostic factors (CA125 >= 35 U/ml, Hazard Ratio (HR) = 1.90, p < 0.001; CD4/CD8 >= 1.8, HR = 1.37, p = 0.004). Moreover, after combining the CA125 level and CD4/CD8 ratio to form a new scoring system, the HR was substantially elevated (CA125 >= 35 U/ml and CD4/CD8 >= 1.8, score 2, HR = 2.76, 95% confidence interval: 2.04 to 3.74, p < 0.001). CONCLUSIONS: A new scoring system based on the combination of the CA125 level with the CD4/CD8 ratio could further predict the prognosis of patients with advanced pancreatic cancer. PMID- 28802663 TI - Peripheral Gamma Delta T cells secrete inflammatory cytokines in women with idiopathic recurrent pregnancy loss. AB - BACKGROUND: Gamma delta (gammadelta) T cells are known to link innate and adaptive immunity. Decidual gammadelta T cells are known to provide immunotolerance by producing IL-10 and TGF-beta. In recurrent pregnancy loss (RPL) females, the role of peripheral gammadelta T cells remain unstudied. OBJECTIVE: To investigate the different phenotypes of gammadelta T cells in the peripheral blood of women with idiopathic RPL and their possible involvement in RPL condition. METHODS: A total of 120 women were recruited for the study. Peripheral blood lymphocytes were isolated and they were stained with appropriate antibodies to determine the phenotype of gammadelta T cells and major cytokines produced by them in the blood using flow cytometry. RESULTS: We observed a significant decrease in the proportion of CD3+CD4-CD8-gammadelta T cells (p<0.001) and increase in the percentage of IFN-gamma (p<0.05) and IL-17 (p<0.001) producing gammadelta T cells in RPL pregnant as compared to normal pregnant females. CONCLUSION: Increase in IFN-gamma and IL-17-producing CD3+ CD4 CD8- gammadelta T cells is associated with creating inflammatory cytokine milieu, thereby, may contribute towards pregnancy loss in RPL females. PMID- 28802664 TI - Cytokines and soluble HLA-G levels in bone marrow stroma and their association with the survival rate of patients exhibiting childhood T-cell acute lymphoblastic leukemia. AB - Leukemic cells can induce defective expression of soluble factors and change marrow cytokine profile, leading to aberrant cell signaling, cell fixation and cell proliferation in bone marrow. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disorder which accounts for 15% of pediatric ALL. To evaluate the contribution of immunological factors on T-ALL survival, we measured Th1, Th2, Th17 cytokines and soluble HLA-G (sHLA-G) levels in bone marrow from 32 Brazilian children at diagnosis (D0), after induction (D19) and after consolidation (D49) of the chemotherapy phase. Data were analyzed using non-parametric tests, and survival rates were evaluated by Kaplan-Meier method (log-rank test). TNF, IL-10 and IL-6 levels were increased at diagnosis compared to D19 and D49. IL-10 levels<4.57pg/mL at diagnosis were associated with increased survival rate, in presence of positive correlation between IL-2 and IL-17 levels. Increased survival rate was also associated with IFN-gamma levels<1.17pg/mL at D49, with a positive correlation observed between IL-4 and IL-2 as well IL-4 and IL-17 levels. In contrast, worse survival rate was associated with IL-2, IL-4 and IL-10 levels imbalance. In addition, increased sHLA-G levels at diagnosis were associated with increased leukocyte count, a well-known factor for poor prognosis. In conclusion, cytokines and sHLA-G play an essential role in marrow T ALL microenvironment during chemotherapy, especially the immunosuppressive cytokine IL-10 which can be used as biomarker of disease outcome, being also a potential target for novel T-ALL treatments. PMID- 28802665 TI - No evidence of association between optic neuritis and secondary LHON mtDNA mutations in patients with multiple sclerosis. AB - Leber's Hereditary Optic Neuropathy (LHON) shares features with Multiple Sclerosis (MS). Both diseases develop optic lesions. Frequent secondary LHON mutations in MS patients may explain the optic damage. Here, we tested the hypothesis that secondary LHON mutations are associated with optic neuritis (ON) in MS patients. We recruited 56 MS subjects with ON and 47 MS subjects without ON. DNA was extracted by salting out, after sampling of peripheral blood from each participant. We completed Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) analysis with appropriate primers and restriction endonucleases for seven secondary LHON mutations. Products were visualized using 3% agarose gel electrophoresis with the aid of DNA safe stain in a UV transilluminator. Accuracy of the genotyping procedure was confirmed by sequencing. Data was analyzed using chi square and Fisher exact tests and logistic regression analysis. There was no significant difference between the numbers of MS subjects with ON and without ON that carried secondary LHON mutations (T4216C [P=0.1], A4917G [P=0.2], G13708A [P=0.6], G15257A [P=1], G15812A [P=0.8], G15927A [P=1], G15928A [P=0.4]). The evidence from the present study are not consistent with the hypothesis that secondary LHON mutations are associated with ON in MS subjects. PMID- 28802666 TI - Humanin directly protects cardiac mitochondria against dysfunction initiated by oxidative stress by decreasing complex I activity. AB - Humanin (HN) is an endogenous peptide that exerts cytoprotection against oxidative stress and apoptosis. We recently reported that Humanin analogue (HNG) pretreatment can reduce reactive oxygen species production in the heart subjected to ischemia/reperfusion (I/R) injury via attenuating mitochondrial dysfunction. However, it is unclear if HNG has direct effects on mitochondrial function against oxidative stress. Thus, we sought to determine the effects of HNG on mitochondrial function under hydrogen peroxide (H2O2) induced oxidative stress in isolated cardiac mitochondria. We found that HNG has direct protective effects on cardiac mitochondrial function against H2O2 induced oxidative stress through decreasing complex I activity. PMID- 28802668 TI - Two novel lncRNAs discovered in human mitochondrial DNA using PacBio full-length transcriptome data. AB - In this study, we established a general framework to use PacBio full-length transcriptome sequencing for the investigation of mitochondrial RNAs. As a result, we produced the first full-length human mitochondrial transcriptome using public PacBio data and characterized the human mitochondrial genome with more comprehensive and accurate information. Other results included determination of the H-strand primary transcript, identification of the ND5/ND6AS/tRNAGluAS transcript, discovery of palindrome small RNAs (psRNAs) and construction of the "mitochondrial cleavage" model, etc. These results reported for the first time in this study fundamentally changed annotations of human mitochondrial genome and enriched knowledge in the field of animal mitochondrial studies. The most important finding was two novel long non-coding RNAs (lncRNAs) of MDL1 and MDL1AS exist ubiquitously in animal mitochondrial genomes. PMID- 28802669 TI - Studies on the dynamic resolution of Crizotinib intermediate. AB - Crizotinib is an anti-cancer agent approved for treatment of non-small cell lung carcinoma. Retrosynthetic analysis revels 1-(2,6-dichloro-3-fluorophenyl)ethanol as an important intermediate, which can be made available by different biocatalytic approaches. Herein we report our results on the kinetic and dynamic resolution towards the desired chiral intermediate for Crizotinib synthesis. The results obtained show that very good conversions and high selectivity could be obtained for the kinetic resolution (45% conv. and E>200) while dynamic kinetic resolution under continuous-flow conditions afforded the desired product in 57% conversion and 98% e.e. PMID- 28802667 TI - Different approaches to modeling analysis of mitochondrial swelling. AB - Mitochondria are critical players involved in both cell life and death through multiple pathways. Structural integrity, metabolism and function of mitochondria are regulated by matrix volume due to physiological changes of ion homeostasis in cellular cytoplasm and mitochondria. Ca2+ and K+ presumably play a critical role in physiological and pathological swelling of mitochondria when increased uptake (influx)/decreased release (efflux) of these ions enhances osmotic pressure accompanied by high water accumulation in the matrix. Changes in the matrix volume in the physiological range have a stimulatory effect on electron transfer chain and oxidative phosphorylation to satisfy metabolic requirements of the cell. However, excessive matrix swelling associated with the sustained opening of mitochondrial permeability transition pores (PTP) and other PTP-independent mechanisms compromises mitochondrial function and integrity leading to cell death. The mechanisms of transition from reversible (physiological) to irreversible (pathological) swelling of mitochondria remain unknown. Mitochondrial swelling is involved in the pathogenesis of many human diseases such as neurodegenerative and cardiovascular diseases. Therefore, modeling analysis of the swelling process is important for understanding the mechanisms of cell dysfunction. This review attempts to describe the role of mitochondrial swelling in cell life and death and the main mechanisms involved in the maintenance of ion homeostasis and swelling. The review also summarizes and discusses different kinetic models and approaches that can be useful for the development of new models for better simulation and prediction of in vivo mitochondrial swelling. PMID- 28802673 TI - Quasi-experimental study designs: making a case for non-experimental designs in the spectrum. PMID- 28802671 TI - The internet and nurse education. AB - Participation in a community of practice through asynchronous writing is useful for learning in higher education. We argue that such computer-mediated communication via the internet is valuable in nurse education, but that it often should take place at sites protected from search with access restricted to a limited group to make the students confident and enable learning. We further argue why we think discussion of patient stories in educational settings often should be done without computers. Reflection around patient stories is a fundamental part of the education of a clinician, but should be done either with fictional cases or as face-to-face activities to protect patient confidentiality. PMID- 28802672 TI - Congruence between patient characteristics and interventions may partly explain medication adherence intervention effectiveness: an analysis of 190 randomized controlled trials from a Cochrane systematic review. AB - OBJECTIVES: Due to the negative outcomes of medication nonadherence, interventions to improve adherence have been the focus of countless studies. The congruence between adherence-related patient characteristics and interventions may partly explain the variability of effectiveness in medication adherence studies. In their latest update of a Cochrane review reporting inconsistent effects of adherence interventions, the authors offered access to their database for subanalysis. We aimed to use this database to assess congruence between adherence-related patient characteristics and interventions and its association with intervention effects. STUDY DESIGN AND SETTING: We developed a congruence score consisting of six features related to inclusion criteria, patient characteristics at baseline, and intervention design. Two independent raters extracted and scored items from the 190 studies available in the Cochrane database. We correlated overall congruence score and individual features with intervention effects regarding adherence and clinical outcomes using Kruskal Wallis rank sum test and Fisher's exact test. RESULTS: Interrater reliability for newly extracted data was almost perfect with a Cohen's Kappa of 0.92 [95% confidence interval (CI) = 0.89-0.94; P < 0.001]. Although present in only six studies, the inclusion of nonadherent patients was the single feature significantly associated with effective adherence interventions (P = 0.003). Moreover, effective adherence interventions were significantly associated with improved clinical outcomes (odds ratio = 6.0; 95% CI = 3.1-12.0; P < 0.0001). However, neither the overall congruence score nor any other individual feature (i.e., "determinants of nonadherence as inclusion criteria," "tailoring of interventions to the inclusion criteria," "reasons for nonadherence assessed at baseline," "adjustment of intervention to individual patient needs," and "theory based interventions") was significantly associated with intervention effects. CONCLUSION: The presence of only six studies that included nonadherent patients and the interdependency of this feature with the remaining five might preclude a conclusive assessment of congruence between patient characteristics and adherence interventions. In order to obtain clinical benefits from effective adherence interventions, we encourage researchers to focus on the inclusion of nonadherent patients. PMID- 28802670 TI - Chemoselective fluorination and chemoinformatic analysis of griseofulvin: Natural vs fluorinated fungal metabolites. AB - Griseofulvin is a fungal metabolite and antifungal drug used for the treatment of dermatophytosis in both humans and animals. Recently, griseofulvin and its analogues have attracted renewed attention due to reports of their potential anticancer effects. In this study griseofulvin (1) and related analogues (2-6, with 4 being new to literature) were isolated from Xylaria cubensis. Six fluorinated analogues (7-12) were synthesized, each in a single step using the isolated natural products and Selectflour, so as to examine the effects of fluorine incorporation on the bioactivities of this structural class. The isolated and synthesized compounds were screened for activity against a panel of cancer cell lines (MDA-MB-435, MDA-MB-231, OVCAR3, and Huh7.5.1) and for antifungal activity against Microsporum gypseum. A comparison of the chemical space occupied by the natural and fluorinated analogues was carried out by using principal component analysis, documenting that the isolated and fluorinated analogues occupy complementary regions of chemical space. However, the most active compounds, including two fluorinated derivatives, were centered around the chemical space that was occupied by the parent compound, griseofulvin, suggesting that modifications must preserve certain attributes of griseofulvin to conserve its activity. PMID- 28802674 TI - The Yusuf-Peto method was not a robust method for meta-analyses of rare events data from antidepressant trials. AB - OBJECTIVES: The aim of the study was to identify the validity of effect estimates for serious rare adverse events in clinical study reports of antidepressants trials, across different meta-analysis methods. STUDY DESIGN AND SETTING: Four serious rare adverse events (all-cause mortality, suicidality, aggressive behavior, and akathisia) were meta-analyzed using different methods. The Yusuf Peto odds ratio ignores studies with no events and was compared with the alternative approaches of generalized linear mixed models (GLMMs), conditional logistic regression, a Bayesian approach using Markov Chain Monte Carlo (MCMC), and a beta-binomial regression model. RESULTS: The estimates for the four outcomes did not change substantially across the different methods; the Yusuf Peto method underestimated the treatment harm and overestimated its precision, especially when the estimated odds ratio deviated greatly from 1. For example, the odds ratio for suicidality for children and adolescents was 2.39 (95% confidence interval = 1.32-4.33), using the Yusuf-Peto method but increased to 2.64 (1.33-5.26) using conditional logistic regression, to 2.69 (1.19-6.09) using beta-binomial, to 2.73 (1.37-5.42) using the GLMM, and finally to 2.87 (1.42 5.98) using the MCMC approach. CONCLUSION: The method used for meta-analysis of rare events data influences the estimates obtained, and the exclusion of double zero event studies can give misleading results. To ensure reduction of bias and erroneous inferences, sensitivity analyses should be performed using different methods instead of the Yusuf-Peto approach, in particular the beta-binomial method, which was shown to be superior through a simulation study. PMID- 28802676 TI - Instrumental variable meta-analysis Comment on: Adjustment for compliance behavior in trials of epidural analgesia in labor using instrumental variable meta-analysis. PMID- 28802675 TI - GRADE equity guidelines 4: considering health equity in GRADE guideline development: evidence to decision process. AB - OBJECTIVES: The aim of this paper is to provide detailed guidance on how to incorporate health equity within the GRADE (Grading Recommendations Assessment and Development Evidence) evidence to decision process. STUDY DESIGN AND SETTING: We developed this guidance based on the GRADE evidence to decision framework, iteratively reviewing and modifying draft documents, in person discussion of project group members and input from other GRADE members. RESULTS: Considering the impact on health equity may be required, both in general guidelines and guidelines that focus on disadvantaged populations. We suggest two approaches to incorporate equity considerations: (1) assessing the potential impact of interventions on equity and (2) incorporating equity considerations when judging or weighing each of the evidence to decision criteria. We provide guidance and include illustrative examples. CONCLUSION: Guideline panels should consider the impact of recommendations on health equity with attention to remote and underserviced settings and disadvantaged populations. Guideline panels may wish to incorporate equity judgments across the evidence to decision framework. This is the fourth and final paper in a series about considering equity in the GRADE guideline development process. This series is coming from the GRADE equity subgroup. PMID- 28802677 TI - An overview of research in orthopaedic and trauma nursing. PMID- 28802678 TI - Gonococcal Vaccine Development: Lessons from Group B Meningococcal Vaccines. PMID- 28802679 TI - Impact of cell wall peptidoglycan O-acetylation on the pathogenesis of Staphylococcus aureus in septic arthritis. AB - Staphylococcus aureus (S. aureus) is one of the most common pathogen causing septic arthritis. To colonize the joints and establish septic arthritis this bacterium needs to resist the host innate immune responses. Lysozyme secreted by neutrophils and macrophages is an important defense protein present in the joint synovial fluids. S. aureus is known to be resistant to lysozyme due to its peptidoglycan modification by O-acetylation of N-acetyl muramic acid. In this study we have investigated the role of O-acetylated peptidoglycan in septic arthritis. Using mouse models for both local and hematogenous S. aureus arthritis we compared the onset and progress of the disease induced by O-acetyl transferase mutant and the parenteral wild type SA113 strain. The disease progression was assessed by observing the clinical parameters including body weight, arthritis, and functionality of the affected limbs. Further X-ray and histopathological examinations were performed to monitor the synovitis and bone damage. In local S. aureus arthritis model, mice inoculated with the DeltaoatA strain developed milder disease (in terms of knee swelling, motor and movement functionality) compared to mice inoculated with the wild type SA113 strain. X-ray and histopathological data revealed that DeltaoatA infected mice knee joints had significantly lesser joint destruction, which was accompanied by reduced bacterial load in knee joints. Similarly, in hematogenous S. aureus arthritis model, DeltaoatA mutant strain induced significantly less severe clinical septic arthritis compared to its parental strain, which is in accordance with radiological findings. Our data indicate that peptidoglycan O-acetylation plays an important role in S. aureus mediated septic arthritis. PMID- 28802682 TI - [Unusual presentation of myelodysplastic syndrome: Isolated vitreous hemorrhage]. PMID- 28802681 TI - Activated FGFR3 promotes bone formation via accelerating endochondral ossification in mouse model of distraction osteogenesis. AB - Achondroplasia (ACH) is one of the most common short-limbed skeletal dysplasias caused by gain-of-function mutations in the fibroblast growth factor receptors 3 (FGFR3) gene. Distraction osteogenesis (DO) is a treatment option for short stature in ACH in some countries. Although the patients with ACH usually show faster healing in DO, details of the newly formed bone have not been examined. We have developed a mouse model of DO and analyzed new bone regenerates of the transgenic mice with ACH (Fgfr3ach mice) histologically and morphologically. We established two kinds of DO protocols, the short-DO consisted of 5days of latency period followed by 5days of distraction with a rate of 0.4mm per 24h, and the long-DO consisted of the same latency period followed by 7days of distraction with a rate of 0.3mm per 12h. The callus formation was evaluated radiologically by bone fill score and quantified by micro-CT scan in both protocols. The histomorphometric analysis was performed in the short-DO protocol by various stainings, including Villanueva Goldner, Safranin-O/Fast green, tartrate resistant acid phosphatase, and type X collagen. Bone fill scores were significantly higher in Fgfr3ach mice than in wild-type mice in both protocols. The individual bone parameters, including bone volume and bone volume/tissue volume, were also significantly higher in Fgfr3ach mice than in wild-type mice in both protocols. The numbers of osteoblasts, as well as osteoclasts, around the trabecular bone were increased in Fgfr3ach mice. Cartilaginous tissues of the distraction region rapidly disappeared in Fgfr3ach mice compared to wild-type mice during the consolidation phase. Similarly, type X collagen-positive cells were markedly decreased in Fgfr3ach mice during the same period. Fgfr3ach mice exhibited accelerated bone regeneration after DO. Accelerated endochondral ossification could contribute to faster healing in Fgfr3ach mice. PMID- 28802683 TI - Orbital cellulitis due to ophthalmic herpes zoster in an immunocompetent child: A case report. PMID- 28802684 TI - [Management of post-traumatic aphakia and aniridia: Retrospective study of 17 patients undergoing scleral-sutured artificial iris intraocular lens implantation. Management of aphakia-aniridia with scleral-sutured artificial iris intraocular lenses]. AB - PURPOSE: To evaluate the long-term outcomes of artificial iris intraocular lenses sutured to the sclera for managing traumatic aphakia and aniridia. METHODS: All consecutive cases receiving a Morcher(r) combination implant from June 2008 to February 2016 in Edouard-Herriot Hospital (Lyon, France) were included in this single-center retrospective study. Visual acuity, subjective degree of glare, quality of life and surgical complications were evaluated. RESULTS: Seventeen eyes of 17 patients were included, among which 82% were male. The mean age was 42 years. The injuries consisted of 23.5% contusion and 70.5% open globe injuries, of which 41% were globe ruptures. There was one postoperative case. A penetrating keratoplasty was performed at the same time for eight eyes. The mean follow-up was 32 months. Best-corrected visual acuity improved in 41.2%, remained the same in 17.6% and decreased in 41.2% of our cases. Distance vision averaged 1+/-0.25 line better and near vision 2.2+/-0.32 lines better when visual acuity was quantifiable before surgery. Glare improved in 80% of patients and remained stable in 20%, decreasing on average from 3.3/5 [min. 3-max. 4; SD: 0.48] before surgery to 1.9/5 [min. 0-max. 4; SD: 1.197] after surgery. Regarding the esthetic results, 78% of the patients declared themselves reasonably to very satisfied; 57% reported no limitation of activities of daily living, and 43% reported mild limitation. Ocular hypertension and glaucoma, found in 40% of eyes, were the main postoperative complications. CONCLUSION: Implantation of prosthetic iris device combined with an intraocular lens appears to be safe and effective in reducing glare disability and improving visual acuity. Close, long-term monitoring is essential for the success of this surgery. PMID- 28802685 TI - Results at 7years after cross-linking procedure in keratoconic patients. AB - PURPOSE: Long-term evaluation of functional results based on visual acuity, keratometry, spherical equivalent and refractive cylinder in patients with progressive keratoconus treated with corneal collagen cross-linking (CXL). MATERIALS AND METHODS: We studied a group of 114 eyes of 91 consecutive patients treated from 2006 to 2009 by "Epi-off type" CXL. In the preoperative period, all patients had a complete ophthalmologic examination. The inclusion criteria were: patients aged 15 to 54years, with various stages of keratoconus, with a corneal thickness of at least 400MUm at the thinnest point. The exclusion criteria were: patients with a corneal thickness of less than 400MUm at the thinnest point, with Vogt's striae or herpetic keratitis, dry eye syndrome or aphakia. The patients were then followed at 1, 3 and 6months, and then every year between 1 and 7years postoperatively. RESULTS: There was a decrease in the minimum K and maximum K, respectively 1.6 and 2.0, at 7years postop. (P<0.05). The cylinder decreased from -4.45 D to -3.50 D at 7 years postop (P<0.05). The spherical equivalent decreased by 1.66 D at 7 years (P<0.05). Uncorrected visual acuity increased from an average of 0.78 to 0.679 log MAR (P<0.05) at 7 years postop. The best-corrected visual acuity increased from a mean of 0.64 to 0.52 log Mar (P<0.05) at 7 years postop. CONCLUSIONS: The results of CXL were stable at 7 years in all patients, consisting of reduction of keratometric values and refraction, and improvement in visual acuity. PMID- 28802686 TI - [Neovascular sea-fan formation after arteriolar-venular anastomosis in sickle cell retinopathy]. PMID- 28802687 TI - [OCT topographic characteristics of the optic nerve in patients clinically suspected to have large optic disc cupping in Togo]. AB - PURPOSE: To describe topographic characteristics of optic discs clinically suspected of large cupping. MATERIALS AND METHODS: This is retrospective study conducted from the January 2 to December 31 on the OCT registry and data base of a private ophthalmologic center in Lome (Togo). We included records of patients with large cupping - CDR (cup-to-disc ratio) >= 0.4 -clinically observed and having undergone OCT-optic disc analysis. RESULTS: Three hundred and thirty-five patients (619 eyes) were studied, with a mean age of 41.87 years+/-17.51 years [6 years and 80 years] and a sex-ratio of 1.01 with a slight female predominance. The mean clinical CDR was 0.51+/-0.126 [0.4 and 0.9] (95 % CI [0.503 to 0.531]). The clinical CDR was >= 0.7 in 7.75 % of cases. The mean neuroretinal rim area was 1.63+/-0.43 mm2 [0.34 and 2.85 mm2]. The mean cup area was 1.43+/-0.54 mm2 [0.13 and 4.29 mm2], and the mean cup volume 0.47+/-0.28 mm3 [0.01 and 1.72 mm3]. The mean global CDR on OCT was 0.46+/-0.13 [0.21 and 0.87], of which 30.85 % (191 cases) had CDR <0.4. The CDR on OCT was >0.7 in 40 (6.46 %) eyes vs. 48 (7.75 %) eyes on clinical examination. CONCLUSION: On the average, optics discs exhibit large size and large cup volume. Topographic evaluation of the optic disc by the means of OCT offers important data and gives way to etiological research of large cupping in the black African. PMID- 28802688 TI - [The role of the temporo-jugal rotation flap in the surgical treatment of a giant basal cell epithelioma of the lower eyelid]. PMID- 28802689 TI - [Bilateral leptospiral anterior granulomatous uveitis: Case report]. PMID- 28802691 TI - The genome analysis of Oleiphilus messinensis ME102 (DSM 13489T) reveals backgrounds of its obligate alkane-devouring marine lifestyle. AB - Marine bacterium Oleiphilus messinensis ME102 (DSM 13489T) isolated from the sediments of the harbor of Messina (Italy) is a member of the order Oceanospirillales, class Gammaproteobacteria, representing the physiological group of marine obligate hydrocarbonoclastic bacteria (OHCB) alongside the members of the genera Alcanivorax, Oleispira, Thalassolituus, Cycloclasticus and Neptunomonas. These organisms play a crucial role in the natural environmental cleanup in marine systems. Despite having the largest genome (6.379.281bp) among OHCB, O. messinensis exhibits a very narrow substrate profile. The alkane metabolism is pre-determined by three loci encoding for two P450 family monooxygenases, one of which formed a cassette with ferredoxin and alcohol dehydrogenase encoding genes and alkane monoxygenase (AlkB) gene clustered with two genes for rubredoxins and NAD+-dependent rubredoxin reductase. Its genome contains the largest numbers of genomic islands (15) and mobile genetic elements (140), as compared with more streamlined genomes of its OHCB counterparts. Among hydrocarbon-degrading Oceanospirillales, O. messinensis encodes the largest array of proteins involved in the signal transduction for sensing and responding to the environmental stimuli (345 vs 170 in Oleispira antarctica, the bacterium with the second highest number). This must be an important trait to adapt to the conditions in marine sediments with a high physico-chemical patchiness and heterogeneity as compared to those in the water column. PMID- 28802690 TI - Nanoparticle-releasing nanofiber composites for enhanced in vivo vaginal retention. AB - Current approaches for topical vaginal administration of nanoparticles result in poor retention and extensive leakage. To overcome these challenges, we developed a nanoparticle-releasing nanofiber delivery platform and evaluated its ability to improve nanoparticle retention in a murine model. We individually tailored two components of this drug delivery system for optimal interaction with mucus, designing (1) mucoadhesive fibers for better retention in the vaginal tract, and (2) PEGylated nanoparticles that diffuse quickly through mucus. We hypothesized that this novel dual-functioning (mucoadhesive/mucus-penetrating) composite material would provide enhanced retention of nanoparticles in the vaginal mucosa. Equivalent doses of fluorescent nanoparticles were vaginally administered to mice in either water (aqueous suspension) or fiber composites, and fluorescent content was quantified in cervicovaginal mucus and vaginal tissue at time points from 24 h to 7d. We also fabricated composite fibers containing etravirine-loaded nanoparticles and evaluated the pharmacokinetics over 7d. We found that our composite materials provided approximately 30-fold greater retention of nanoparticles in the reproductive tract at 24 h compared to aqueous suspensions. Compared to nanoparticles in aqueous suspension, the nanoparticles in fiber composites exhibited sustained and higher etravirine concentrations after 24 h and up to 7d, demonstrating the capabilities of this new delivery platform to sustain nanoparticle release out to 3d and drug retention out to one week after a single administration. This is the first report of nanoparticle-releasing fibers for vaginal drug delivery, as well as the first study of a single delivery system that combines two components uniquely engineered for complementary interactions with mucus. PMID- 28802692 TI - De novo transcriptome assembly and RNA-Seq expression analysis in blood from beluga whales of Bristol Bay, AK. AB - Assessing the health of marine mammal sentinel species is crucial to understanding the impacts of environmental perturbations on marine ecosystems and human health. In Arctic regions, beluga whales, Delphinapterus leucas, are upper level predators that may serve as a sentinel species, potentially forecasting impacts on human health. While gene expression profiling from blood transcriptomes has widely been used to assess health status and environmental exposures in human and veterinary medicine, its use in wildlife has been limited due to the lack of available genomes and baseline data. To this end we constructed the first beluga whale blood transcriptome de novo from samples collected during annual health assessments of the healthy Bristol Bay, AK stock during 2012-2014 to establish baseline information on the content and variation of the beluga whale blood transcriptome. The Trinity transcriptome assembly from beluga was comprised of 91,325 transcripts that represented a wide array of cellular functions and processes and was extremely similar in content to the blood transcriptome of another cetacean, the bottlenose dolphin. Expression of hemoglobin transcripts was much lower in beluga (25.6% of TPM, transcripts per million) than has been observed in many other mammals. A T12A amino acid substitution in the HBB sequence of beluga whales, but not bottlenose dolphins, was identified and may play a role in low temperature adaptation. The beluga blood transcriptome was extremely stable between sex and year, with no apparent clustering of samples by principle components analysis and <4% of genes differentially expressed (EBseq, FDR<0.05). While the impacts of season, sexual maturity, disease, and geography on the beluga blood transcriptome must be established, the presence of transcripts involved in stress, detoxification, and immune functions indicate that blood gene expression analyses may provide information on health status and exposure. This study provides a wealth of transcriptomic data on beluga whales and provides a sizeable pool of preliminary data for comparison with other studies in beluga whale. PMID- 28802693 TI - Diversity of tissue-resident NK cells. AB - Although natural killer (NK) cells were initially named for their spontaneous tumor-killing capacity, their concept has been greatly expanded with more than 40 years of extensive investigation. Currently, NK cells are known as a heterogeneous population of innate lymphoid cell (ILC) family, consisting of different subsets with unique phenotypic and functional features. Recent studies have shown that tissue-resident NK (trNK) cells, which are distinct from conventional NK (cNK) cells, preferentially distribute in non-lymphoid tissues, such as the liver, uterus, salivary gland, and adipose. In this review, we provide a comprehensive overview of the current knowledge about the phenotype, function and development of trNK cells across different tissues and describe the similarities and differences between diverse trNK cells and cNK cells, with a particular focus on the tissue-specific characteristics of different trNK cells. PMID- 28802695 TI - Scarce Resource Allocation During Disasters: A Mixed-Method Community Engagement Study. AB - BACKGROUND: During a catastrophe, health-care providers may face difficult questions regarding who will receive limited life-saving resources. The ethical principles that should guide decision-making have been considered by expert panels but have not been well explored with the public or front-line clinicians. The objective of this study was to characterize the public's values regarding how scarce mechanical ventilators should be allocated during an influenza pandemic, with the ultimate goal of informing a statewide scare resource allocation framework. METHODS: Adopting deliberative democracy practices, we conducted 15 half-day community engagement forums with the general public and health-related professionals. Small group discussions of six potential guiding ethical principles were led by trained facilitators. The forums consisted exclusively of either members of the general public or health-related or disaster response professionals and were convened in a variety of meeting places across the state of Maryland. Primary data sources were predeliberation and postdeliberation surveys and the notes from small group deliberations compiled by trained note takers. RESULTS: Three hundred twenty-four individuals participated in 15 forums. Participants indicated a preference for prioritizing short-term and long-term survival, but they indicated that these should not be the only factors driving decision-making during a crisis. Qualitative analysis identified 10 major themes that emerged. Many, but not all, themes were consistent with previously issued recommendations. The most important difference related to withholding vs withdrawing ventilator support. CONCLUSIONS: The values expressed by the public and front-line clinicians sometimes diverge from expert guidance in important ways. Awareness of these differences should inform policy making. PMID- 28802694 TI - Exposure to Ambient Particulate Matter Is Associated With Accelerated Functional Decline in Idiopathic Pulmonary Fibrosis. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF), a progressive disease with an unknown pathogenesis, may be due in part to an abnormal response to injurious stimuli by alveolar epithelial cells. Air pollution and particulate inhalation of matter evoke a wide variety of pulmonary and systemic inflammatory diseases. We therefore hypothesized that increased average ambient particulate matter (PM) concentrations would be associated with an accelerated rate of decline in FVC in IPF. METHODS: We identified a cohort of subjects seen at a single university referral center from 2007 to 2013. Average concentrations of particulate matter < 10 and < 2.5 MUg/m3 (PM10 and PM2.5, respectively) were assigned to each patient based on geocoded residential addresses. A linear multivariable mixed-effects model determined the association between the rate of decline in FVC and average PM concentration, controlling for baseline FVC at first measurement and other covariates. RESULTS: One hundred thirty-five subjects were included in the final analysis after exclusion of subjects missing repeated spirometry measurements and those for whom exposure data were not available. There was a significant association between PM10 levels and the rate of decline in FVC during the study period, with each MUg/m3 increase in PM10 corresponding with an additional 46 cc/y decline in FVC (P = .008). CONCLUSIONS: Ambient air pollution, as measured by average PM10 concentration, is associated with an increase in the rate of decline of FVC in IPF, suggesting a potential mechanistic role for air pollution in the progression of disease. PMID- 28802696 TI - Community-Acquired Pneumonia Visualized on CT Scans but Not Chest Radiographs: Pathogens, Severity, and Clinical Outcomes. AB - BACKGROUND: The clinical significance of pneumonia visualized on CT scan in the setting of a normal chest radiograph is uncertain. METHODS: In a multicenter prospective surveillance study of adults hospitalized with community-acquired pneumonia (CAP), we compared the presenting clinical features, pathogens present, and outcomes of patients with pneumonia visualized on a CT scan but not on a concurrent chest radiograph (CT-only pneumonia) and those with pneumonia visualized on a chest radiograph. All patients underwent chest radiography; the decision to obtain CT imaging was determined by the treating clinicians. Chest radiographs and CT images were interpreted by study-dedicated thoracic radiologists blinded to the clinical data. RESULTS: The study population included 2,251 adults with CAP; 2,185 patients (97%) had pneumonia visualized on chest radiography, whereas 66 patients (3%) had pneumonia visualized on CT scan but not on concurrent chest radiography. Overall, these patients with CT-only pneumonia had a clinical profile similar to those with pneumonia visualized on chest radiography, including comorbidities, vital signs, hospital length of stay, prevalence of viral (30% vs 26%) and bacterial (12% vs 14%) pathogens, ICU admission (23% vs 21%), use of mechanical ventilation (6% vs 5%), septic shock (5% vs 4%), and inhospital mortality (0 vs 2%). CONCLUSIONS: Adults hospitalized with CAP who had radiological evidence of pneumonia on CT scan but not on concurrent chest radiograph had pathogens, disease severity, and outcomes similar to patients who had signs of pneumonia on chest radiography. These findings support using the same management principles for patients with CT-only pneumonia and those with pneumonia seen on chest radiography. PMID- 28802697 TI - The insertion of Polybia-MP1 peptide into phospholipid monolayers is regulated by its anionic nature and phase state. AB - Polybia-MP1 or simply MP1 (IDWKKLLDAAKQIL-NH2) is a peptide with broad-spectrum bactericidal activity and a strong inhibitory effect against cancer cells. The aim of this work was to evaluate the effect of biophysical properties such as membrane texture and film thickness on MP1 interaction with neutral and anionic lipid membranes. For this purpose, we first explored the peptide's surface behavior. MP1 showed high surface activity, adsorbing onto bare air/aqueous interfaces up to higher surface pressures than the collapse pressure of MP1 Langmuir films. The MP1-lipid membrane interaction was studied using Langmuir phosphatidylcholine and phosphatidylserine (PS) monolayers as model membrane systems. PS was chosen since this negatively charged lipid was found predominantly on the outer leaflet of tumor cells, and it enhances MP1 activity for PS-containing membranes to a greater extent than for other negatively charged lipids. MP1 incorporated into anionic PS monolayers, which show a liquid-expanded (LE) phase or LE-liquid-condensed (LC) phase coexistence, up to lipid-packing densities higher than those of cell membranes. The mixed lipid/MP1 films were explored by Brewster angle microscopy and atomic force microscopy. MP1 partitioned preferentially into the LE phase state of PS films, and were thus excluded from the coexisting LC phase. This interaction had strong electrostatic bases: in pure water, the lipid-peptide interaction was strong enough to induce formation of reversible lipid-peptide 3D structures associated with the interface. MP1 incorporation into the LE phase was accompanied by a shift of the phase transition pressure to higher values and a thinning of the lipid film. These results showed a clear correlation between peptide penetration capacity and the presence or induction of the thin LE phase. This capacity to regulate membrane physical properties may be of relevance in the binding, incorporation and membrane selectivity of this promising antitumor peptide. PMID- 28802698 TI - In-hospital costs of diabetic foot disease treated by a multidisciplinary foot team. AB - BACKGROUND: The diabetic foot imposes significant burden on healthcare systems. Obtaining knowledge on the extent of the costs of diabetic foot ulcers (DFUs) is of value to health care researchers investigating cost-effectiveness of interventions that prevent these costly complications. OBJECTIVES: To estimate the in-hospital costs associated with the treatment of DFUs by a multidisciplinary diabetic foot team. METHODS: Persons with DFUs presenting to our team in 2013 and 2014 were followed and use of care was estimated. Exclusion criteria were a single visit only and ulcers above the ankle. Demographic data and per-person incremental clinical outcomes (e.g., healing with or without amputation and rehabilitation) were assessed. Resource use was identified, measured and multiplied by unit costs. RESULTS: Eighty-nine persons were identified with 56 persons meeting the inclusion criteria (with 69 DFU episodes). The median in-hospital care was 17weeks (inter quartile range: 7-34). Average in hospital costs were US$ 10,827 (range: 702-82,880) per DFU episode. Primary healed DFUs costs on average US$ 4830, single minor amputations on average US$ 13,580, multiple minor amputations on average US$ 31,835 and major amputations on average US$ 73,813 per episode. Costs differed significantly between groups (p<0.001). CONCLUSION: DFUs are associated with substantial immediate and long term in-hospital costs. Our study provides estimates of these costs, aiding researchers and health policy analysis. PMID- 28802699 TI - Relationship between limited joint mobility of hand and carotid atherosclerosis in patients with type 2 diabetes. AB - AIM: Limited joint mobility (LJM) of hand, which is one of a complication of diabetic hand, has a close association with diabetic microangiopathy. However, it remains to be elucidated about the relationships between LJM of hand and subclinical atherosclerosis in patients with type 2 diabetes. Therefore, we conducted a cross-sectional study to evaluate the relationships between LJM of hand and carotid intima-media thickness (IMT) and plaque score in patients with type 2 diabetes. METHODS: We evaluated the relationships between LJM of hand, and carotid IMT and plaque score, evaluated by carotid ultrasound examination, in 341 consecutive patients with type 2 diabetes. LJM of hand was diagnosed using a 'prayer sign' or 'table test'. RESULTS: LJM of hand was present in 72 patients. Carotid IMT and plaque score were higher in patients with LJM of hand than those in patients without (1.45+/-0.66vs. 1.14+/-0.68mm, P=0.013 and 8.0+/-5.3vs. 5.4+/ 4.8mm, P<0.001). Multivariate linear regression analysis revealed that LJM of hand was positively correlated with plaque score (beta=0.423, P=0.043) after adjusted for age, sex, durations of diabetes, body mass index, hemoglobin A1c, creatinine, uric acid, smoking, hypertension and dyslipidemia. CONCLUSIONS: Our results demonstrate a relation between LJM of hand and subclinical atherosclerosis, especially plaque score, in patients with type 2 diabetes. Diagnosis of diabetic hand is simple and non-invasive, and thus is a useful method for assessment of subclinical atherosclerosis in patients with type 2 diabetes. PMID- 28802700 TI - Salivary extracellular RNA biomarkers for insulin resistance detection in hispanics. AB - AIMS: Insulin resistance (IR) detection is challenging and no test is currently used in clinical practice. We developed salivary biomarkers that could be used for IR detection. METHODS: We collected saliva from 186 healthy and 276 pre diabetic participants, divided them into high and low IR groups based on a HOMA cutoff of 2.5. We profiled extracellular transcriptome by microarray in saliva supernatant from 23 high IR and 15 low IR participants, and pre-validated the top ten extracellular mRNA (exRNA) markers in a new cohort of 40 high and 40 low IR participants. A prediction panel was then built and validated in an independent cohort of 149 high and 195 low IR participants. RESULTS: Transcriptomic analyses identified 42 exRNA candidates differentially present in saliva of high and low IR participants. From the top ten candidates, six were individually validated (PRKCB, S100A12, IL1R2, CAMP, VPS4B, CAP1) (p<0.01) and yielded AUC values ranging from 0.66 to 0.76. Body mass index (BMI) was significant higher in high compared to low IR group with AUC of 0.66, and showed no correlation with any of candidate biomarkers. The combination of four exRNA markers (IL1R2, VPS4B, CAP1, LUZP6) with BMI achieved excellent results in the prediction panel building dataset (AUC=0.79, sensitivity=79%, specificity=64%). The prediction model was validated in an independent cohort (AUC=0.82, sensitivity=63%, specificity=92%). CONCLUSIONS: A panel of four salivary exRNA biomarkers (IL1R2, VPS4B, CAP1, LUZP6) and BMI was validated that can distinguish high and low IR participants, overall and in subgroups of healthy and pre-diabetic participants. PMID- 28802701 TI - Acyl modification and binding of mitochondrial ACP to multiprotein complexes. AB - The mitochondrial acyl carrier protein (ACPM/NDUFAB1) is a central element of the mitochondrial fatty acid synthesis type II machinery. Originally ACPM was detected as a subunit of respiratory complex I but the reason for the association with the large enzyme complex remained elusive. Complex I from the aerobic yeast Yarrowia lipolytica comprises two different ACPMs, ACPM1 and ACPM2. They are anchored to the protein complex by LYR (leucine-tyrosine-arginine) motif containing protein (LYRM) subunits LYRM3 (NDUFB9) and LYRM6 (NDUFA6). The ACPM1 LYRM6 and ACPM2-LYRM3 modules are essential for complex I activity and assembly/stability, respectively. We show that in addition to the complex I bound fraction, ACPM1 is present as a free matrix protein and in complex with the soluble LYRM4(ISD11)/NFS1 complex implicated in Fe-S cluster biogenesis. We show that the presence of a long acyl chain bound to the phosphopantetheine cofactor is important for docking ACPMs to protein complexes and we propose that association of ACPMs and LYRMs is universally based on a new protein-protein interaction motif. PMID- 28802702 TI - Novel method of extracting motion from natural movies. AB - BACKGROUND: The visual system in primates can be segregated into motion and shape pathways. Interaction occurs at multiple stages along these pathways. Processing of shape-from-motion and biological motion is considered to be a higher-order integration process involving motion and shape information. However, relatively limited types of stimuli have been used in previous studies on these integration processes. NEW METHOD: We propose a new algorithm to extract object motion information from natural movies and to move random dots in accordance with the information. The object motion information is extracted by estimating the dynamics of local normal vectors of the image intensity projected onto the x-y plane of the movie. RESULTS: An electrophysiological experiment on two adult common marmoset monkeys (Callithrix jacchus) showed that the natural and random dot movies generated with this new algorithm yielded comparable neural responses in the middle temporal visual area. COMPARISON WITH EXISTING METHODS: In principle, this algorithm provided random dot motion stimuli containing shape information for arbitrary natural movies. This new method is expected to expand the neurophysiological and psychophysical experimental protocols to elucidate the integration processing of motion and shape information in biological systems. CONCLUSIONS: The novel algorithm proposed here was effective in extracting object motion information from natural movies and provided new motion stimuli to investigate higher-order motion information processing. PMID- 28802703 TI - Identification and characterization of Clostridium botulinum group III field strains by matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF MS). AB - Animal botulism is primarily due to botulinum neurotoxin (BoNT) types C, D or their chimeric variants C/D or D/C, produced by Clostridium botulinum group III, which appears to include the genetically indistinguishable Clostridium haemolyticum and Clostridium novyi. In the present study, we used matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI TOF MS) to identify and characterize 81 BoNT-producing Clostridia isolated in 47 episodes of animal botulism. The instrument's default database, containing no entries for Clostridium botulinum, permitted reliable identification of 26 strains at the genus level. Although supplementation of the database with reference strains enhanced the instrument's ability to identify the neurotoxic strains at the genus level, resolution was not sufficient to recognize field strains at species level. Characterization by MALDI TOF confirmed the well-documented phenotypic and genetic differences between Clostridium botulinum strains of serotypes normally implicated in human botulism (A, B, E, F) and other Clostridium species able to produce BoNTs type C and D. The chimeric and non-chimeric field strains grouped separately. In particular, very low similarity was found between two non-chimeric type C field strains isolated in the same outbreak and the other field strains. This difference was comparable with the differences among the various Clostridia species included in the study. Characterization by MALDI TOF confirmed that BoNT producing Clostridia isolated from animals are closely related and indistinguishable at the species level from Clostridium haemolyticum and Clostridium novyi reference strains. On the contrary, there seem to be substantial differences among chimeric and some non-chimeric type C strains. PMID- 28802704 TI - Early miscarriage rate in lean polycystic ovary syndrome women after euploid embryo transfer - a matched-pair study. AB - The early miscarriage rate is reported to be higher in patients with polycystic ovary syndrome (PCOS) compared with non-PCOS patients. However, whether PCOS is an independent risk factor for early miscarriage is still controversial; to what extent embryonic aneuploidy accounts for miscarriages of PCOS is still unknown. In this 1:3 matched-pair study, 67 lean PCOS patients and 201 controls matched for age, body mass index (BMI) and embryo scores undergoing a single euploid blastocyst transfer in vitrified-warmed cycles were analysed. Clinical pregnancy, early miscarriage and live birth rates were compared. Logistic regression analysis was performed to further evaluate the factors associated with early miscarriage and live birth. Clinical pregnancy rates were 50.7% in PCOS and 55.2% in control groups. Early miscarriage rate was significantly (P = 0.029) increased in the PCOS group compared with controls; non-PCOS patients had a significantly higher live birth rate than PCOS patients, P < 0.001. Further regression analyses showed that PCOS was significantly associated with a higher risk of early miscarriage and decreased chance of live birth. In conclusion, PCOS in women undergoing pre-implantation genetic diagnosis may, independently from BMI and karyotype, increase the risk of miscarriage. PMID- 28802705 TI - rLH versus uHCG supplementation in poor ovarian responders. PMID- 28802706 TI - The impact of adenomyosis on the outcome of IVF-embryo transfer. AB - Our study examined the impact of adenomyosis on the chance of clinical pregnancy after IVF and embryo transfer (IVF-ET). This was a prospective multicentre study from April 2013 to October 2015. We included 375 women with history of infertility who attended for a 3D scan prior to IVF-ET. A total of 150/375 (40.0%, 95% confidence interval [CI] 35.2-45.0) women had clinical pregnancy. Women with any feature of adenomyosis had a lower clinical pregnancy rate (21/72 [29.2%, 95% CI 18.6-39.6] versus 129/303 [42.6%, 95% CI 37.1-48.2], P = 0.044, relative risk (RR) 0.68 [95% CI 0.47-1.00]). Logistic regression selected an adenomyosis score of 4 or higher as an independent predictor of clinical pregnancy (odds ratio [OR] 0.35 [95% CI 0.15-0.82]). Estimated probability of clinical pregnancy decreased from 42.7% (95% CI 37.1-48.3) for women with no adenomyosis features to 22.9% (95% CI 13.4-32.6) for those with four and 13.0% (95% CI 2.2-23.9) for those with all seven. Women with adenomyosis have lower clinical pregnancy rate after IVF-ET. Condition severity expressed as a number of morphological features on ultrasound scan increases the magnitude of the effect. PMID- 28802707 TI - Boosting innate immunity to sustainably control diseases in crops. AB - Viruses cause epidemics in all major crops, threatening global food security. The development of efficient and durable resistance able to withstand viral attacks represents a major challenge for agronomy, and relies greatly on the understanding of the molecular dialogue between viral pathogens and their hosts. Research over the last decades provided substantial advances in the field of plant-virus interactions. Remarkably, the advent of studies of plant innate immunity has recently offered new strategies exploitable in the field. This review summarizes the recent breakthroughs that define the mechanisms underlying antiviral innate immunity in plants, and emphasizes the importance of integrating that knowledge into crop improvement actions, particularly by exploiting the insights related to immune receptors. PMID- 28802708 TI - Robotic excision of large retroperitoneal Schwannoma (with video). PMID- 28802709 TI - Sex differences in cancer risk and survival: A Swedish cohort study. AB - AIM: The aim of this study is to firmly delineate temporal and age trends regarding sex discrepancies in cancer risk and survival as well as quantifying the potential gain achieved by eliminating this inequality. METHODS: We performed a population-based cohort study using data on all adult incident cancer cases (n = 872,397) recorded in the Swedish Cancer Register in 1970-2014. To assess the associations between sex and cancer risk and sex and survival, male-to-female incidence rate ratios (IRRs) and excess mortality ratios (EMRs) adjusted for age and year of diagnosis were estimated using Poisson regression. RESULTS: Men were at increased risk for 34 of 39 and had poorer prognosis for 27 of 39 cancers. Women were at increased risk for 5 of 39 and had significantly poorer survival for 2 of 39 cancers. IRRs among male predominant sites ranged from 1.05; 95% confidence interval (CI), 1.03--1.1 (lung adenocarcinoma) to 8.0; 95% CI, 7.5-8.5 (larynx). EMRs among sites with male survival disadvantage ranged from 1.1; 95% CI, 1.03-1.1 (colon) to 2.1; 95% CI, 1.5--2.8 (well-differentiated thyroid). CONCLUSION: Male sex is associated with increased risk and poorer survival for most cancer sites. Identifying and eliminating factors driving the observed sex differences may reduce the global cancer burden. PMID- 28802710 TI - Cardiovascular causes of maternal sudden death. Sudden Arrhythmic Death Syndrome is leading cause in UK. AB - OBJECTIVE: This study aims to determine the causes of sudden cardiac death during pregnancy and in the postpartum period and patients' characteristics. There are few studies in the literature. METHODS: Eighty cases of sudden unexpected death due to cardiac causes in relation to pregnancy and postpartum period in a database of 4678 patients were found and examined macroscopically and microscopically. RESULTS: The mean age was 30+/-7years with a range from 16 to 43 years. About 30% were 35 years old or older; 50% of deaths occurred during pregnancy and 50% during the postpartum period. About 59.18% were obese or overweight where body mass index data were available. The leading causes of death were sudden arrhythmic death syndrome (SADS) (53.75%) and cardiomyopathies (13.80%). Other causes include dissection of aorta or its branches (8.75%), congenital heart disease (2.50%) and valvular disease (3.75%). CONCLUSION: This study highlights sudden cardiac death in pregnancy or in the postpartum period, which is mainly due to SADS with underlying channelopathies and cardiomyopathy. We wish to raise awareness of these frequently under-recognised entities in maternal deaths and the need of cardiological screening of the family as a result of the diagnosis. PMID- 28802711 TI - Reply to "Letter to the Editor" by M. Saijo et al. "Glasgow prognostic score is predictive of prognosis for patients with endometrial cancer ". PMID- 28802712 TI - A STAG3 missense mutation in two sisters with primary ovarian insufficiency. PMID- 28802713 TI - Detecting exact breakpoints of deletions with diversity in hepatitis B viral genomic DNA from next-generation sequencing data. AB - Many studies have suggested that deletions of Hepatitis B Viral (HBV) are associated with the development of progressive liver diseases, even ultimately resulting in hepatocellular carcinoma (HCC). Among the methods for detecting deletions from next-generation sequencing (NGS) data, few methods considered the characteristics of virus, such as high evolution rates and high divergence among the different HBV genomes. Sequencing high divergence HBV genome sequences using the NGS technology outputs millions of reads. Thus, detecting exact breakpoints of deletions from these big and complex data incurs very high computational cost. We proposed a novel analytical method named VirDelect (Virus Deletion Detect), which uses split read alignment base to detect exact breakpoint and diversity variable to consider high divergence in single-end reads data, such that the computational cost can be reduced without losing accuracy. We use four simulated reads datasets and two real pair-end reads datasets of HBV genome sequence to verify VirDelect accuracy by score functions. The experimental results show that VirDelect outperforms the state-of-the-art method Pindel in terms of accuracy score for all simulated datasets and VirDelect had only two base errors even in real datasets. VirDelect is also shown to deliver high accuracy in analyzing the single-end read data as well as pair-end data. VirDelect can serve as an effective and efficient bioinformatics tool for physiologists with high accuracy and efficient performance and applicable to further analysis with characteristics similar to HBV on genome length and high divergence. The software program of VirDelect can be downloaded at https://sourceforge.net/projects/virdelect/. PMID- 28802715 TI - Elucidating virus entry using a tetracysteine-tagged virus. AB - Fluorescent tags constitute an invaluable tool in facilitating a deeper understanding of the mechanistic processes governing virus-host interactions. However, when selecting a fluorescent tag for in vivo imaging of cells, a number of parameters and aspects must be considered. These include whether the tag may affect and interfere with protein conformation or localization, cell toxicity, spectral overlap, photo-stability and background. Cumulatively, these constitute challenges to be overcome. Bluetongue virus (BTV), a member of the Orbivirus genus in the Reoviridae family, is a non-enveloped virus that is comprised of two architecturally complex capsids. The outer capsid, composed of two proteins, VP2 and VP5, together facilitate BTV attachment, entry and the delivery of the transcriptionally active core in the cell cytoplasm. Previously, the significance of the endocytic pathway for BTV entry was reported, although a detailed analysis of the role of each protein during virus trafficking remained elusive due to the unavailability of a tagged virus. Described here is the successful modification, and validation, of a segmented genome belonging to a complex and large capsid virus to introduce tags for fluorescence visualization. The data generated from this approach highlighted the sequential dissociation of VP2 and VP5, driven by decreasing pH during the transition from early to late endosomes, and their retention therein as the virus particles progress along the endocytic pathway. Furthermore, the described tagging technology and methodology may prove transferable and allow for the labeling of other non-enveloped complex viruses. PMID- 28802716 TI - Presence of Modic type 1 change increases risk of postoperative pyogenic discitis following decompression surgery for lumbar canal stenosis. AB - STUDY DESIGN: Multicenter retrospective study. BACKGROUND: Postoperative surgical site infection is one of the most serious complications following spine surgery. Previous studies do not appear to have investigated pyogenic discitis following lumbar laminectomy without discectomy. This study aimed to identify risk factors for postoperative pyogenic discitis following lumbar decompression surgery. METHODS: We examined data from 2721 patients undergoing lumbar laminectomy without discectomy in five hospitals from April 2007 to March 2012. Patients who developed postoperative discitis following laminectomy (Group D) and a 4:1 matched cohort (Group C) were included. Fisher's exact test was used to determine risk factors, with values of p < 0.05 considered statistically significant. RESULTS: The cumulative incidence of postoperative discitis was 0.29% (8/2721 patients). All patients in Group D were male, with a mean age of 71.6 +/- 7.2 years. Postoperative discitis was at L1/2 in 1 patient, at L3/4 in 3 patients, and at L4/5 in 4 patients. Except for 1 patient with discitis at L1/2, every patient developed discitis at the level of decompression. The associated pathogens were methicillin-resistant Staphylococcus aureus (n = 3, 37.5%), methicillin-susceptible Staphylococcus epidermidis (n = 1, 12.5%), methicillin sensitive S. aureus (n = 1, 12.5%), and unknown (n = 3, 37.5%). In the analysis of risk factors for postoperative discitis, Group D showed a significantly lower ratio of patients who underwent surgery in the winter and a significantly higher ratio of patients who had Modic type 1 in the lumbar vertebrae compared to Group C. CONCLUSIONS: Although further prospective studies, in which other preoperative modalities are used for the evaluation, is needed, our data suggest the presence of Modic type 1 as a risk factor for discitis following laminectomy. Latent pyogenic discitis should be carefully ruled out in patients with Modic type 1. If lumbar laminectomy is performed for such patients, more careful observation is necessary to prevent the development of postoperative discitis. PMID- 28802714 TI - In silico structure-based approaches to discover protein-protein interaction targeting drugs. AB - A core concept behind modern drug discovery is finding a small molecule that modulates a function of a target protein. This concept has been successfully applied since the mid-1970s. However, the efficiency of drug discovery is decreasing because the druggable target space in the human proteome is limited. Recently, protein-protein interaction (PPI) has been identified asan emerging target space for drug discovery. PPI plays a pivotal role in biological pathways including diseases. Current human interactome research suggests that the number of PPIs is between 130,000 and 650,000, and only a small number of them have been targeted as drug targets. For traditional drug targets, in silico structure-based methods have been successful in many cases. However, their performance suffers on PPI interfaces because PPI interfaces are different in five major aspects: From a geometric standpoint, they have relatively large interface regions, flat geometry, and the interface surface shape tends to fluctuate upon binding. Also, their interactions are dominated by hydrophobic atoms, which is different from traditional binding-pocket-targeted drugs. Finally, PPI targets usually lack natural molecules that bind to the target PPI interface. Here, we first summarize characteristics of PPI interfaces and their known binders. Then, we will review existing in silico structure-based approaches for discovering small molecules that bind to PPI interfaces. PMID- 28802717 TI - Chronic D609 treatment interferes with cell cycle and targets the expression of Olig2 in Glioma Stem like Cells. AB - Glioma Stem-like Cells (GSCs) isolated from patient derived tumors have high metabolic activity and survive in the absence of exogenous growth factors. We recently demonstrated that acute D609 (Tricyclodecan-9-yl-xanthogenate), a PC-PLC inhibitor with anti-oxidative property, can decrease the ATP content & GADD45beta protein in GSCs cultured without growth factors, but not in the presence of growth factors. In this study we examined the effect of chronic D609 treatment on GSCs cultured in complete medium containing growth factors. Our results show that chronic exposure of GSCs to D609 decreased the ATP content and reduced the expression of GADD45beta protein. Furthermore, cyclin D1 content and the phosphorylation of retinoblastoma protein also diminished, resulting in the arrest of cells in G1 phase of cell cycle after D609 treatment. In addition, the expression of Olig2, a protein responsible for the progression of glioblastoma was reduced by D609. Together these results indicate that chronic D609 treatment can inhibit the growth of glioma cells by arresting cells in G1 phase of cell cycle and/or reducing Olig2 expression. PMID- 28802718 TI - Curcumin ameliorates cardiac dysfunction induced by mechanical trauma. AB - Curcumin, a phytochemical component derived from turmeric (Carcuma longa), has been extensively investigated because of its anti-inflammatory and anti-oxidative properties. Inflammation and oxidative stress play critical roles in posttraumatic cardiomyocyte apoptosis, which contributes to secondary cardiac dysfunction. This research was designed to identify the protective effect of curcumin on posttraumatic cardiac dysfunction and investigate its underlying mechanism. Noble-Collip drum was used to prepare a mechanical trauma (MT) model of rats, and the hemodynamic responses of traumatized rats were observed by ventricular intubation 12h after trauma. Myocardial apoptosis was determined through terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and caspase-3 activity assay. Tumor necrosis factor-alpha (TNF-alpha) and reactive oxygen species (ROS) generated by monocytes and myocardial cells were identified through enzyme-linked immunosorbent assay (ELISA), and the intracellular alteration of Ca2+ in cardiomyocytes was examined through confocal microscopy. In vivo, curcumin effectively ameliorated MT-induced secondary cardiac dysfunction and significantly decreased the apoptotic indices of the traumatized myocardial cells. In vitro, curcumin inhibited TNF-alpha production by monocytes and reduced the circulating TNF-alpha levels. With curcumin pretreatment, ROS production and Ca2+ overload in H9c2 cells were attenuated when these cells were incubated with traumatic plasma. Therefore, curcumin can effectively ameliorate MT-induced cardiac dysfunction mainly by inhibiting systemic inflammatory responses and by weakening oxidative stress reaction and Ca2+ overload in cardiomyocytes. PMID- 28802719 TI - Tandem ureteral stents in the management of double-J stent dysfunction in gynecological malignancies. AB - PURPOSE: The goal of this study was to determine the efficacy and safety of tandem ureteral stent placement in the management of malignant ureteral obstruction (MUO) refractory to single ureteral double-J stent drainage in women with gynecological malignancies. MATERIALS AND METHODS: A retrospective study was performed on 14 women (mean age, 54.5+/-9.6 [SD] years; range: 38-70 years) who had tandem stent placement following failed single ureteral double-J stent placement from 2012 to 2017. Survival analyses were performed with Kaplan-Meier method. RESULTS: Twenty-nine successful procedures were performed on 19 ureters (19 primary stent placement and 9 exchange procedures). Technical success of primary tandem stent placement was 95% (19/20 procedures). Mean follow-up was 180.1+/-173.7 (SD) days (range: 62-616 days). Median estimated survival of the patients was 118 days (Q1: 261, Q3: 95; range: 62-616 days). Primary stent failure rate was 25% and assisted stent failure rate was 21.4%. There was no significant difference among survival of patients with and without tandem stent failure. Mean estimated primary stent patency and assisted stent patency were 171.4+/-13.8 (SD) days and 409.9+/-59.8 (SD) days, respectively. Four patients underwent 1 to 3 stent exchanges. Median exchange time was 181 days (Q1: 151, Q3: 191, range: 141-214 days) and technical success rate was 100%. Grade 2 and 3 complication rates were 25% and 3.6%, respectively. CONCLUSION: Tandem ureteral stent placement is a feasible, safe and effective procedure for the management of failed ureteral double-J stent placement in women with gynecological malignancies. PMID- 28802720 TI - Application of green fluorescent protein to measure antimicrobial efficacy and the kinetics of cell death against Escherichia coli. AB - Industrial antimicrobials have been extensively used to control unwanted microbial growth by incorporation into a variety of products such as plastics and paints, reducing biodeterioration and biofouling and extending the lifespan of the product. Industrial antimicrobials generally have broad sites of action affecting core cellular functions such as central metabolism, enzyme function, cell wall or DNA synthesis and can either be biocidal or biostatic. In addition, susceptibility can be affected by the metabolic state of the microbe, with metabolically inactive cells generally more resistant than metabolically active cells. Previously it was demonstrated that cytosolically expressed green fluorescent protein could be used as a real-time viability indicator in the yeast Aureobasidium pullulans based on the pH dependent fluorescence of GFP and the collapse of the proton gradient across the cell membrane during cell death. In this study we report on the development and validation of an equivalent GFP fluorescence viability assay in Escherichia coli and used this assay to study the effect of five antimicrobials commonly used in plastics; 4,5-dichloro-2-octyl isothiazol-3-one (DCOIT), sodium pyrithione, 1,2-benzisothiazol-3-one (BIT), 2 octyl-isothiazol-3-one (OIT) and n-butyl-1,2-benzisothiazol-3-one (BBIT). The results demonstrate broad differences amongst the antimicrobials in both relative efficacy, rate of effect and for some antimicrobials, marked differences in sensitivity toward growing and non-growing cells. PMID- 28802721 TI - Comparison of commercially-available preservatives for maintaining the integrity of bacterial DNA in human milk. AB - BACKGROUND: Inhibiting changes to bacteria in human milk between sample collection and analysis is necessary for unbiased characterization of the milk microbiome. Although cold storage is considered optimal, alternative preservation is sometimes necessary. RESEARCH AIM/QUESTION: The objective of this study was to compare the effectiveness of several commercially-available preservatives with regard to maintaining bacterial DNA in human milk for delayed microbiome analysis. Specifically, we compared Life Technologies' RNAlater(r) stabilization solution, Biomatrica's DNAgard(r) Saliva, Advanced Instruments' Broad Spectrum Microtabs IITM, and Norgen Biotek Corporation's Milk DNA Preservation and Isolation Kit. METHODS: Aliquots of 8 pools of human milk were treated with each preservative. DNA was extracted immediately and at 1, 2, 4, and 6wk, during which time milk was held at 37 degrees C. The V1-V3 region of the bacterial 16S rRNA gene was amplified and sequenced. Changes in bacterial community structure and diversity over time were evaluated. RESULTS: Comparable to other studies, the most abundant genera were Streptococcus (33.3%), Staphylococcus (14.0%), Dyella (6.3%), Pseudomonas (3.0%), Veillonella (2.5%), Hafnia (2.0%), Prevotella (1.7%), Rhodococcus (1.6%), and Granulicatella (1.4%). Overall, use of Norgen's Milk DNA Preservation and Isolation Kit best maintained the consistency of the bacterial community structure. Total DNA, diversity, and evenness metrics were also highest in samples preserved with this method. CONCLUSIONS: When collecting human milk for bacterial community analysis in field conditions where cold storage is not available, our results suggest that Norgen's Milk DNA Preservation and Isolation Kit may be a useful method, at least for a period of 2weeks. PMID- 28802722 TI - Quantification of biofilm biomass by staining: Non-toxic safranin can replace the popular crystal violet. AB - Crystal violet staining is commonly used for quantification of biofilm formation, although it is highly toxic. Here we test safranin as a non-toxic replacement. Safranin staining provided similar results as crystal violet, but with higher reproducibility. We therefore recommend safranin staining for biofilm biomass quantification. PMID- 28802723 TI - Site formation processes of the early Acheulean assemblage at EF-HR (Olduvai Gorge, Tanzania). AB - This paper investigates the formation history of the early Acheulean site of EF HR (Olduvai Gorge, Tanzania). Our study focuses on the main site (T2-Main Trench) and adjacent trenches (T12 and T9), which constitute the bulk of the archaeological assemblage recently excavated in the EF-HR area (de la Torre et al., 2018a). Site formation processes are investigated through taphonomic proxies and spatial analysis, and consider artifact features, orientation patterns, and topographic data retrieved during archaeological excavation. This enables an assessment of the impact of natural agents on the assemblage and a discussion of the relevance of water disturbance in shaping the structure of the EF-HR archaeological record. Our results indicate that fluvial action over the assemblage was significant, although it is likely that EF-HR still preserves areas marginally affected by water sorting and rearrangement. In summary, by applying a novel approach that combines a systematic analysis of artifact attributes with GIS spatial analysis of archaeological remains and topographic features, our study aims to provide a fresh look at the interaction of human and natural agents in the formation of Early Stone Age assemblages at Olduvai Gorge. PMID- 28802724 TI - Juvenile body mass estimation: A methodological evaluation. AB - Two attempts have been made to develop body mass prediction formulae specifically for immature remains: Ruff (Ruff, C.C., 2007, Body size prediction from juvenile skeletal remains. American Journal Physical Anthropology 133, 698-716) and Robbins et al. (Robbins, G., Sciulli, P.W., Blatt, S.H., 2010. Estimating body mass in subadult human skeletons. American Journal Physical Anthropology 143, 146 150). While both were developed from the same reference population, they differ in their independent variable selection: Ruff (2008) used measures of metaphyseal and articular surface size to predict body mass in immature remains, whereas Robbins et al. (2010) relied on cross-sectional properties. Both methods perform well on independent testing samples; however, differences between the two methods exist in the predicted values. This research evaluates the differences in the body mass estimates from these two methods in seven geographically diverse skeletal samples under the age of 18 (n = 461). The purpose of this analysis is not to assess which method performs with greater accuracy or precision; instead, differences between the two methods are used as a heuristic device to focus attention on the unique challenges affecting the prediction of immature body mass estimates in particular. The two methods differ by population only in some cases, which may be a reflection of activity variation or nutritional status. In addition, cross-sectional properties almost always produce higher estimates than metaphyseal surface size across all age categories. This highlights the difficulty in teasing apart information related to body mass from that relevant to loading, particularly when the original reference population is urban/industrial. PMID- 28802725 TI - Body mass estimation in hominoids: Age and locomotor effects. AB - While there are a number of methods available for estimation of body mass in adult nonhuman primates, very few are available for juveniles, despite the potential utility of such estimations in both analyses of fossils and in museum collection based research. Furthermore, because of possible scaling differences, adult based body mass estimation equations may not be appropriate for non-adults. In this study, we present new body mass estimation equations for both adult and immature nonhuman hominoids based on joint and metaphyseal dimensions. Articular breadths of the proximal and distal femur, distal humerus and tibial plateau, and metaphyseal breadths of the distal femur and humerus were collected on a reference sample of 159 wild Pan, Gorilla, Pongo, Hylobates, and Symphalangus specimens of known body mass from museum and research collections. Scaling of dimensions with body weight was assessed in both the adult and the ontogenetic sample at several taxonomic levels using reduced major axis regression, followed by regression of each dimension against body mass to generate body mass estimation equations. Joint dimensions were found to be good predictors of body mass in both adult and immature hominoids, with percent prediction errors of 10 20%. However, subtle scaling differences between taxa impacted body mass estimation, suggesting that phylogeny and locomotor effects should be considered when selecting reference samples. Unlike patterns of joint growth in humans, there was little conclusive evidence for consistently larger joints relative to body mass in the non-adult sample. Metaphyseal breadths were strong predictors of body mass and, with some exceptions, gave more precise body mass estimates for non-adults than epiphyseal breadths. PMID- 28802726 TI - Science communication in the field of fundamental biomedical research (editorial). AB - The aim of this special issue on science communication is to inspire and help scientists who are taking part or want to take part in science communication and engage with the wider public, clinicians, other scientists or policy makers. For this, some articles provide concise and accessible advice to individual scientists, science networks, or learned societies on how to communicate effectively; others share rationales, objectives and aims, experiences, implementation strategies and resources derived from existing long-term science communication initiatives. Although this issue is primarily addressing scientists working in the field of biomedical research, much of it similarly applies to scientists from other disciplines. Furthermore, we hope that this issue will also be used as a helpful resource by academic science communicators and social scientists, as a collection that highlights some of the major communication challenges that the biomedical sciences face, and which provides interesting case studies of initiatives that use a breadth of strategies to address these challenges. In this editorial, we first discuss why we should communicate our science and contemplate some of the different approaches, aspirations and definitions of science communication. We then address the specific challenges that researchers in the biomedical sciences are faced with when engaging with wider audiences. Finally, we explain the rationales and contents of the different articles in this issue and the various science communication initiatives and strategies discussed in each of them, whilst also providing some information on the wide range of further science communication activities in the biomedical sciences that could not all be covered here. PMID- 28802727 TI - Brain activation during processing of genuine facial emotion in depression: Preliminary findings. AB - OBJECTIVE: The current study aimed to examine the neural correlates of processing genuine compared with posed emotional expressions, in depressed and healthy subjects using a novel functional magnetic resonance imaging (fMRI) paradigm METHOD: During fMRI scanning, sixteen depressed patients and ten healthy controls performed an Emotion Categorisation Task, whereby participants were asked to distinguish between genuine and non-genuine (posed or neutral) facial displays of happiness and sadness. RESULTS: Compared to controls, the depressed group showed greater activation whilst processing genuine versus posed facial displays of sadness, in the left medial orbitofrontal cortex, caudate and putamen. The depressed group also showed greater activation whilst processing genuine facial displays of sadness relative to neutral displays, in the bilateral medial frontal/orbitofrontal cortex, left dorsolateral prefrontal cortex, right dorsal anterior cingulate, bilateral posterior cingulate, right superior parietal lobe, left lingual gyrus and cuneus. No differences were found between the two groups for happy facial displays. LIMITATIONS: Relatively small sample sizes and due to the exploratory nature of the study, no correction was made for multiple comparisons. CONCLUSION: The findings of this exploratory study suggest that depressed individuals may show a different pattern of brain activation in response to genuine versus posed facial displays of sadness, compared to healthy individuals. This may have important implications for future studies that wish to examine the neural correlates of facial emotion processing in depression. PMID- 28802729 TI - Predictors of pathologic upstaging in early esophageal adenocarcinoma: Results from the national cancer database. AB - BACKGROUND: Upstaging in early esophageal adenocarcinoma (EAC) patients happens at a high rate and has implications for treatment. We sought to identify risk factors predicting upstaging. STUDY DESIGN: The National Cancer Database (2010 2013) was queried for all patients with clinical T1/T2 and N0 EAC who underwent esophagectomy without neoadjuvant therapy. Logistic regression models were developed to investigate risk factors for upstaging. RESULTS: A total of 1120 patients were included. Pathologic upstaging occurred in 21.3% (n = 239). After adjustment, risk of upstaging increased with tumor size (tumor size 1-3 cm, OR 4.57,95% CI 2.58-8.10, tumor size >3 cm, OR 10.57, 95% CI 5.77-19.35, as compared to tumors <1 cm) as well as with positive margins (OR 4.13, 95% CI 2.17-7.87) and > than 10 lymph nodes examined (OR 1.85, 95% CI 1.29-2.63), while facility volume was not significant. Odds of upstaging increased linearly with number of lymph nodes examined (OR 1.02 per node). CONCLUSION: Our data underscore the importance of tumor size as a predictor for upstaging and of completing a thorough lymph node dissection for staging purposes. PMID- 28802728 TI - Mental health problems in college freshmen: Prevalence and academic functioning. AB - BACKGROUND: Mental health problems in college and their associations with academic performance are not well understood. The main aim of this study was to investigate to what extent mental health problems are associated with academic functioning. METHODS: As part of the World Mental Health Surveys International College Student project, 12-month mental health problems among freshmen (N = 4921) was assessed in an e-survey of students at KU Leuven University in Leuven, Belgium. The associations of mental health problems with academic functioning (expressed in terms of academic year percentage [or AYP] and grade point average [GPA]) were examined across academic departments. RESULTS: Approximately one in three freshman reports mental health problems in the past year, with internalizing and externalizing problems both associated with reduced academic functioning (2.9-4.7% AYP reduction, corresponding to 0.2-0.3 GPA reduction). The association of externalizing problems with individual-level academic functioning was significantly higher in academic departments with comparatively low average academic functioning. LIMITATIONS: Limited sample size precluded further investigation of interactions between department-level and student-level variables. No information was available on freshman secondary school academic performance. CONCLUSIONS: Mental health problems are common in college freshman, and clearly associated with lower academic functioning. Additional research is needed to examine the potentially causal nature of this association, and, if so, whether interventions aimed at treating mental health problems might improve academic performance. PMID- 28802730 TI - Corrigendum to "Optimization of remotely delivered intensive lifestyle treatment for obesity using the Multiphase Optimization Strategy: Opt-IN study protocol" [Contemp. Clin. Trials 38 (2014) 251-259]. PMID- 28802731 TI - En Face Optical Coherence Tomography Analysis to Assess the Spectrum of Perivenular Ischemia and Paracentral Acute Middle Maculopathy in Retinal Vein Occlusion. PMID- 28802732 TI - Osteochondroma of maxillary sinus, an unusual location. PMID- 28802733 TI - Cranio-cervical junction cerebrospinal fluid leak after microdebrider-assisted adenoidectomy - A rare case report. PMID- 28802734 TI - Adding markers of organ damage to risk score models improves cardiovascular risk assessment: Prospective analysis of a large cohort of adult outpatients. AB - INTRODUCTION: Global cardiovascular (CV) risk stratification is recommended in all outpatients. Risk score charts, however, do not include markers of organ damage (OD). AIM: To evaluate the potential added value of including different markers of subclinical OD to US Framingham, European SCORE and Italian Cuore risk score calculators. METHODS: We prospectively evaluated adult outpatients, who underwent blood pressure (BP) assessment and global CV risk stratification. The following OD markers were considered: 1) cardiac OD: electrocardiographic) or echocardiographic left ventricular (LV) hypertrophy; 2) vascular OD: carotid atherosclerotic plaque; 3) renal OD: reduced estimated glomerular filtration rate or creatinine clearance. Different risk score calculators were applied for comparisons. RESULTS: We included an overall population sample of 1979 outpatients (44.0% female, age 57.2+/-13.0years, BMI 26,6+/-4,4kg/m2, clinic systolic/diastolic BP 145.4+/-18.3/85.8+/-10.7mmHg), among whom 117 (5.9%) presented cardiac, 161 (8.1%) vascular, and 117 (5.9%) renal OD. US Framingham, European SCORE and Italian Cuore risk scores were all significantly raised in patients with than in those without OD. A trend toward increase for US Framingham CVD death, European ESC and Italian Cuore scores was observed according to degree of all markers of OD. Among these, reduced ClCr and eGFR showed high sensitivity and specificity to identify high risk individuals. CONCLUSIONS: Presence of cardiac, vascular or renal OD is associated with higher risk scores, independently by the types of calculators, age and gender classes. OD detection should be included in CV risk stratification in order to improve diagnostic, prognostic and therapeutic processes. PMID- 28802735 TI - Incidence of cardiovascular events and vascular interventions in patients with type 2 diabetes. AB - OBJECTIVE: Diabetes mellitus is associated with an increased risk for cardiovascular morbidity and mortality. The vascular burden in terms of incidence of cardiovascular events (CVE) and vascular interventions is however poorly quantified. In this study we evaluated the incidence rates of CVE and vascular interventions in patients with type 2 diabetes (T2DM) with and without cardiovascular disease (CVD) in comparison to patients without type 2 diabetes. RESEARCH DESIGN AND METHODS: In a cohort of 9.808 high-risk patients with and without cardiovascular disease and type 2 diabetes originated from the ongoing, single-center prospective SMART (Second Manifestations of ARTerial disease) cohort, the number and incidence rates of CVE and interventions were calculated. The incidence rates were adjusted for confounders using Poisson regression models. CVE were defined as vascular death, stroke and myocardial infarction (MI). Interventions were defined as percutaneous coronary intervention, coronary artery bypass grafting, percutaneous transluminal angioplasty or stenting of the peripheral arteries and amputation. RESULTS: Patients with T2DM and CVD had a 4 fold higher incidence rate of CVE and a 8-fold higher incidence rate of vascular interventions compared to high-risk patients without T2DM and CVD after adjusting for confounders. The incidence rate for the composite of non-fatal MI, non-fatal stroke and vascular death was 5.8 per 1000person-years in patients without T2DM or CVD at baseline, 15.2 per 1000person-years in patients with T2DM but without CVD at baseline, 26.0 per 1000person-years in patients without T2DM but with CVD and 40.7 per 1000person-years in patients with both T2DM and CVD at baseline. A similar increasing incidence rate was seen for all vascular interventions from patients without T2DM or CVD to patients with both T2DM and CVD. CONCLUSIONS: Patients with type 2 diabetes or CVD are subject to an increased incidence of cardiovascular events and interventions compared to high-risk patients without type 2 diabetes or vascular disease. Patients with type 2 diabetes and CVD have the highest incidence of new cardiovascular diseases and vascular interventions when compared to patients without type 2 diabetes and CVD. These results underline the need for optimal risk factor treatment as well as the need for new prevention and treatment strategies in this very high risk population. PMID- 28802736 TI - Synthesis of PEGylated polyglutamic acid peptide dendrimer and its application in dissolving thrombus. AB - Nattokinase (NK) has been used as a new generation thrombolytic drug, due to its high safety, low cost and low side effects. However, it is sensitive to external environment and may lose the enzyme activity easily. Peptide dendrimer possesses functional groups on its surface, adjustable sizes, biodegradability, biocompatibility, and low toxicity, which could be used as ideal carrier for drug protection and delivery. Demonstrated for the first time in this paper, a PEGylated dendrimer (Gn-PEG-Gn) composed of polyglutamic acid is designed and synthesized as delivery platform of NK for thrombus treatment. A panel of PEGylated dendrimers with three different generations of 2, 3, 4 was prepared to investigate the effect of dendrimer architecture on the properties and therapeutic efficacy of the resultant NK-loaded delivery systems in terms of the morphology, dimension and enzyme activity. The results demonstrated that the NK loaded G3-PEG-G3 (G3-PEG-G3/NK ratio of 6/1), of all the formulations, displayed the optimal enzyme activity for dissolving thrombus in vitro, thus offering great potential for the treatment of thrombus. PMID- 28802737 TI - Multi-biofunctional polymer graphene composite for bone tissue regeneration that elutes copper ions to impart angiogenic, osteogenic and bactericidal properties. AB - Despite several recent advances, poor vascularization in implanted scaffolds impedes complete regeneration for clinical success of bone tissue engineering. The present study aims to develop a multi-biofunctional nanocomposite for bone tissue regeneration using copper nanoparticle decorated reduced graphene oxide (RGO_Cu) hybrid particles in polycaprolactone (PCL) matrix (PCL/RGO_Cu). X-ray photoelectron spectroscopy and X-ray diffraction confirmed the presence of copper oxides (CuO and Cu2O) on RGO. Thermogravimetric analysis showed that 11.8% of copper was decorated on RGO. PCL/RGO_Cu exhibited steady release of copper ions in contrast to burst release from the composite containing copper alone (PCL/Cu). PCL/RGO_Cu exhibited highest modulus due to enhanced filler exfoliation. Endothelial cells rapidly proliferated on PCL/RGO_Cu confirming cytocompatibility. The sustained release of ions from PCL/RGO_Cu composites augmented tube formation by endothelial cells evidenced enhanced angiogenic activity. Gene expression of angiogenic markers VEGF and ANG-2 was higher on PCL/RGO_Cu compared to PCL. The osteogenic activity of PCL/RGO_Cu was confirmed by the 87% increase in mineral deposition by pre-osteoblasts compared to PCL. The bactericidal activity of PCL/RGO_Cu showed 78% reduction in viability of Escherichia coli. Thus, the multi-biofunctional PCL/RGO_Cu composite exhibits angiogenic, osteogenic and bactericidal properties, a step towards addressing some of the critical challenges in bone tissue engineering. PMID- 28802739 TI - Does vital exhaustion enhance our ability to predict type 2 diabetes? PMID- 28802738 TI - Bioaccumulation and toxicity of CdSe/ZnS quantum dots in Phanerochaete chrysosporium. AB - The growing potential of quantum dots (QDs) in biomedical applications has raised considerable concerns regarding their toxicological impact. Consequently, there has been a need to understand the underlying toxicity mechanism of QDs. In this work, we comprehensively investigated the bioaccumulation and toxicity of three CdSe/ZnS QDs (COOH CdSe/ZnS 525, NH2 CdSe/ZnS 525, and NH2 CdSe/ZnS 625) in Phanerochaete chrysosporium (P. chrysosporium) using confocal laser scanning microscopy, reactive oxygen species (ROS) measurements, and cell viability assays. Confocal laser scanning microscopy analytical results indicated that all the CdSe/ZnS QDs, with the concentration ranging from 10 to 80nM, could accumulate largely in the hyphae and induce the generation of ROS, showing a direct toxicity to P. chrysosporium. And the bioaccumulation and toxicity of CdSe/ZnS QDs presented dose-dependent and time-dependent effects on P. chrysosporium. Furthermore, the CdSe/ZnS QDs-induced cytotoxicity was also related to their physicochemical properties, including particle size and surface charges: NH2 CdSe/ZnS 525 with small size was more cytotoxic as compared to NH2 CdSe/ZnS 625 with large size, and the smaller negative charged NH2 CdSe/ZnS 525 resulted in greater cytotoxicity than the larger negative charged COOH CdSe/ZnS 525. The obtained results provide valuable information for exploring and understanding of toxicity mechanism of QDs in living cells. PMID- 28802740 TI - Alexithymia as a health risk and resilience factor: Response to Dr. Davydov. PMID- 28802741 TI - Further discussion of "cerebral aneurysm blood flow simulations are sensitive to basic solver settings". PMID- 28802742 TI - The challenges of measuring in vivo knee collateral ligament strains using ultrasound. AB - Ultrasound-based methods have shown promise in their ability to characterize non uniform deformations in large energy-storing tendons such as the Achilles and patellar tendons, yet applications to other areas of the body have been largely unexplored. The noninvasive quantification of collateral ligament strain could provide an important clinical metric of knee frontal plane stability, which is relevant in ligament injury and for measuring outcomes following total knee arthroplasty. In this pilot cadaveric experiment, we investigated the possibility of measuring collateral ligament strain with our previously validated speckle tracking approach, but encountered a number of challenges during both data acquisition and processing. Given the clinical interest in this type of tool, and the fact that this is a developing area of research, the goal of this article is to transparently describe this pilot study, both in terms of methods and results, while also identifying specific challenges to this work and areas for future study. Some challenges faced relate generally to speckle-tracking of soft tissues (e.g. the limitations of using a 2D imaging modality to characterize 3D motion), while others are specific to this application (e.g. the small size and complex anatomy of the collateral ligaments). This work illustrates a clear need for additional studies, particularly relating to the collection of ground-truth data and more thorough validation work. These steps will be critical prior to the translation of ultrasound-based measures of collateral ligament strains into the clinic. PMID- 28802743 TI - Tungsten accumulation by highly tolerant marine hydrothermal Sulfitobacter dubius strains carrying a tupBCA cluster. AB - Tungsten (W) has industrial and economic importance, and is in the European Union list of metals with a high supply risk. It is used by living organisms, which transport it into the cell, in the form of tungstate ion (WO42-), using three different ABC-type transporters from the specific W-uptake system coded by tupABC gene cluster. In this study, strains from a collection recovered from deep-sea hydrothermal sediments were selected according to their ability to tolerate metals and to possess the tup genetic determinants. Three multimetal-tolerant strains, Sulfitobacter dubius NA4, As(V)4 and Sb5, were chosen. The strains were able to grow in the presence of high tungsten concentrations and their growth was unaffected by 1mM tungsten. Moreover, strain Sb5 was able to accumulate up to 52MUg W mg-1 protein. Their tup genes were shown to be organized as tupBCA, which is not the most usual gene arrangement. All three strains had the classical TupA conserved motif TTTS, comprising a first Thr replaced by a Val, which seems to be a common feature of the genus Sulfitobacter. This study was an important first step in the exploration of new biological strategies for recovering tungsten from natural or anthropogenic W-impacted environments. PMID- 28802744 TI - Remediation of Thiothrix spp. associated bulking problems by raw wastewater feeding: A full-scale experience. AB - An industrial wastewater treatment plant (WWTP) in Australia has long suffered from bulking problems associated with the proliferation of Thiothrix spp. The WWTP consists of a covered anaerobic lagoon (CAL) followed by a sequencing batch reactor (SBR). The CAL functions as both an anaerobic digester and surge lagoon for the irregular flow of wastewater generated from the production of seasonal products. Chemical analysis of the raw influent showed it was composed of a mixture of organic acids, phenols and alcohols. The CAL effluent was characterised by high acetic acid and phenolic concentrations. An attempt was made to manipulate the SBR microbial community to improve settling by direct feeding small volumes of raw influent into the SBR. After raw feeding, the plant ceased bulking as the settled sludge volume reduced from 930 to 200mLL-1. 16S rRNA gene profiling and biovolumes of SBR samples revealed major changes in the microbial community. The Thiothrix spp. population decreased from 36.8% to 0.2%, and Zoogloea spp. dominated all samples after raw feeding. Therefore, direct feeding is proposed as a control method for industrial plants with surge/anaerobic lagoons in order to manage the bulking problems caused by Thiothrix spp. in downstream SBRs. PMID- 28802745 TI - Circumferential bone grafting around an absorbable gelatin sponge core reduced the amount of grafted bone in the induced membrane technique for critical-size defects of long bones. AB - OBJECTIVES: The objectives of the study were to introduce a circumferential bone graft around an absorbable gelatin sponge core using an induced membrane technique, to assess its ability to reduce the required amount of graft and to maintain the bone graft, and to evaluate the clinical outcomes in the management of critical-size bone defects. PATIENTS AND METHODS: Circumferential bone grafting using a staged induced membrane technique for managing critical-size bone defects was performed in 21 patients. Postoperative computed tomography scans were performed 7days after Hemovac drain removal and 3 months after bone grafting. Volumetric measurements of the defect size, gelatin sponge proportion, and amount of grafted bone were performed by two independent observers using three-dimensional (3D) software. RESULTS: The critical-size defects were located at the metadiaphyseal area of 11 tibias, eight femurs, and two humeri. The average defect size was 8.9cm in length and 65.2cm3 in volume. The absorbable gelatin sponge core replaced 21.4% (average) of the defect volume. There was no significant deterioration in the shape of the grafted bone among the serial 3D models. Eighteen patients (86%) were healed radiographically at 9.1 months (average). CONCLUSION: Our study suggests that circumferential bone grafting in association with the induced membrane technique could reduce the required amount of bone graft and adequately maintain graft position and shape, with favourable clinical outcomes. PMID- 28802746 TI - Is it who you are or where you live? Residential segregation and racial gaps in childhood asthma. AB - Higher asthma rates are one of the more obvious ways that health inequalities between African American and other children are manifested beginning in early childhood. In 2010, black asthma rates were double non-black rates. Some but not all of this difference can be explained by factors such as a higher incidence of low birth weight (LBW) among blacks; however, even conditional on LBW, blacks have a higher incidence of asthma than others. Using a unique data set based on the health records of all children born in New Jersey between 2006 and 2010, we show that when we split the data by whether or not children live in a "black" zip code, this racial difference in the incidence of asthma among LBW children entirely disappears. All LBW children in these zip codes, regardless of race, have a higher incidence of asthma. Our results point to the importance of residential segregation and neighborhoods in explaining persistent racial health disparities. PMID- 28802747 TI - The market for paid sick leave. AB - In many countries, general practitioners (GPs) are assigned the task of controlling the validity of their own patients' insurance claims. At the same time, they operate in a market where patients are customers free to choose their GP. Are these roles compatible? Can we trust that the gatekeeping decisions are untainted by private economic interests? Based on administrative registers from Norway with records on sick pay certification and GP-patient relationships, we present evidence to the contrary: GPs are more lenient gatekeepers the more competitive is the physician market, and a reputation for lenient gatekeeping increases the demand for their services. PMID- 28802748 TI - Ultrasonographic assessment of tonsillar volume in children. PMID- 28802749 TI - Enhanced fluorescence detection of proteins using ZnO nanowires integrated inside microfluidic chips. AB - Nanostructure-enhanced detection is promising for a number of applications such as early cancer diagnosis, environmental monitoring and mine safety, among which nanostructures integrated microfluidic chips offers unique advantage of ultra-low quantitative analyses. Here, dense ZnO nanowires of varied diameter and length were obtained by changing the content of polyethyleneimine (PEI) and growth time via simple hydrothermal growth in microfluidic channels for protein detection. We showed that this approach was superiorly efficient compared to the conventional hydrothermal method due to the flow-induced replenishment of nutrient and the effect of shear stress. When immobilizing FITC conjugated anti-bovine immunoglobulin G (IgG) on ZnO nanowires, the fluorescence emission was significantly amplified compared to glass substrate and ZnO seed layer. Under the different growth conditions, the most remarkable fluorescence enhancement was observed on the ZnO nanowire substrate grown for 3h with 5mM PEI in solution. It is ascribed not only to the increase of the binding surface area of proteins but also the intrinsic fluorescence enhancement of ZnO nanowires as waveguides. We further used the optimized ZnO nanowires to demonstrate multiple detection of cancer biomarkers, achieving a superior limit of detection (LOD) as low as 1pg/mL in human alpha-fetoprotein (AFP) assay and 100 fg/mL in carcinoembryonic antigen (CEA) assay with large dynamic range of 6-7 orders, which suggests that ZnO nanowire integrated microfluidic chips are promising for high-throughput fluorescence-based diagnostic assays. PMID- 28802750 TI - para-Sulfonatocalix[4]arene stabilized gold nanoparticles multilayers interfaced to electrodes through host-guest interaction for sensitive ErbB2 detection. AB - Nanoparticle (NP) structure, compositing and the nature of the NP-functionalized electrode interface have a strong influence upon electrochemical properties that are critical in applications such as sensing, photocatalysis and electrocatalysis. Existing methods to fabricate NP-functionalized electrodes do not allow or precise control over all these variables, especially the NP electrode interface, making it difficult to understand and predict how structural changes influence electrode activity and consequently limit the application. To conquer this problem, in this study, we fabricated a stepwise construction of a novel supramolecular stabilized gold nanoparticles (AuNPs) multilayer mediated by guest molecules, yielding 3D AuNPs assembly at the electrode interface. para Sulfonatocalix[4]arene (pSC4), a water soluble macrocyclic synthetic receptor, has been served as a stabilizing ligand for preparation and gaining new insights into pSC4 stabilized gold nanoparticles (pSC4-AuNPs) tethered on the electrode interface through host-guest interaction. We investigated the electrochemical properties of multilayer pSC4-AuNPs modified gold electrode using different core size of AuNPs with varying layer number. The electron transfer ability was characterized by electrochemical impedance spectroscopy (EIS). Electrochemical signals are significantly enhanced through the layer-by-layer assembly of pSC4 AuNPs due to its high conductivity and high effective area. With this innovative method, by taking the assay of a tumor marker as an example, human epidermal growth factor receptor 2 (ErbB2) was successfully measured with a detection limit of 0.5ng/mL. Taking the advantage of the pSC4-AuNPs multilayer's good biocompatibility, high effective area and high electronic transmission, 3D AuNPs multilayer produced on the electrode interface suggests a portable synthetic pathway for the application into sensitive electrochemical biosensor. PMID- 28802751 TI - Acute Management of Hemostasis in Patients With Neurological Injury. AB - Neurological injuries can be divided into those with traumatic and nontraumatic causes. The largest groups are traumatic brain injury (TBI) and nontraumatic stroke. TBI patients may present with intracranial hemorrhages (contusions, or subdural or epidural hematomas). Strokes are ischemic or hemorrhagic. In all these disorders, thrombosis and hemostasis play a major role. Treatment aims to either cease bleeding and/or restore perfusion. We reviewed hemostatic and thrombolytic therapies in patients with neurological injuries by MEDLINE and EMBASE search using various key words for neurological disorders and hemostatic therapies restricted to English language and human adults. Review of articles fulfilling inclusion criteria and relevant references revealed that, in patients with ischemic stroke, intravenous thrombolytic therapy with recombinant tissue plasminogen activator within 4.5-5 hours after onset of symptoms improves clinical outcome. In contrast, there are no hemostatic therapies that are proven to improve clinical outcome of patients with hemorrhagic stroke or TBI. In patients with hemorrhagic stroke who use vitamin K antagonist or direct oral anticoagulants, there is evidence that specific reversal therapies improve hemostatic laboratory parameters but without an effect on clinical recovery. In patients with hemorrhagic stroke or TBI who use concomitant antiplatelet therapy, there is evidence for harm of platelet transfusion. In patients with aneurysmal subarachnoid hemorrhage, tranexamic acid was shown to reduce rebleeding rate without improving clinical outcome. The effects of tranexamic acid in patients with TBI are still under investigation. We conclude that, in patients with ischemic stroke, thrombolytic therapy improves outcome when given within 4.5-5 hours. In hemorrhagic stroke and TBI, most hemostatic therapies improved or corrected laboratory parameters but not clinical outcome. Currently, in several trials, the effects of tranexamic acid are being studied of which the results are eagerly awaited. Because improving clinical outcome should be the goal of new therapies, we encourage to use clinical outcome scales as the primary outcome measure in trials that investigate effects of hemostatic therapies in patients with neurological injury. PMID- 28802752 TI - In vitro and in vivo studies of deglycosylated chimeric porcine reproductive and respiratory syndrome virus as a vaccine candidate and its realistic revenue impact at commercial pig production level. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) causes major economic losses in the swine industry worldwide. Vaccination is the most effective method to control the disease. In a previous study, a chimeric PRRSV named as K418 which had a genome composed of ORF 1 from the FL12 strain and ORF 2-7 from the Korean representative LMY strain was created. We constructed K418DM, K418 with deglycosylated glycoprotein 5 (GP5), to improve its humoral immunity. In the follow-up on in vivo and in vitro virological and serological tests, no back mutation in amino acids of GP5 associated with deglycosylation was shown after 9 passages on MARC-145 cells, whereas only one case of back mutation was detected after single passage in pig. In serological study, K418DM induced higher serum neutralization (SN) antibody and more limited viremia compared with those of K418 virus. In clinical trial and economic analysis, the K418DM elicited SN antibody titers and PRRSV-specific IgG over protection limit. From the economic viewpoint, there was statistically significant reduction in percentage of weak pigs. These results indicated that vaccination with the K418DM may provide enhanced protection for pigs in PRRS endemic situation and increase growth performance in commercial pig farms. PMID- 28802753 TI - Challenges in immunisation service delivery for refugees in Australia: A health system perspective. AB - BACKGROUND: Refugees are at risk of being under-immunised in their countries of origin, in transit and post-resettlement in Australia. Whilst studies have focused on identifying barriers to accessibility of health services among refugees, few focus on providers' perspectives on immunisation service delivery to this group. Health service providers are well placed to provide insights into the pragmatic challenges associated with refugee health service delivery, which can be useful in identifying strategies aimed at improving immunisation coverage among this group. METHODS: A qualitative study involving 30 semi-structured interviews was undertaken with key stakeholders in immunisation service delivery across all States and Territories in Australia between December 2014 and December 2015. Thematic analysis was undertaken. RESULTS: Variability in accessing program funding and vaccines, lack of a national policy for catch-up vaccination, unclear roles and responsibilities for catch-up, a lack of a central immunisation register and insufficient training among general practitioners were seen as the main challenges impacting on immunisation service delivery for refugees. CONCLUSIONS: This study provides insight into the challenges that impact on effective immunisation service delivery for refugees. Deliberate strategies such as national funding for relevant vaccines, improved data collection nationally and increased guidance for general practitioners on catch-up immunisation for refugees would help to ensure equitable access across all age groups. PMID- 28802754 TI - Cost-benefit analyses of supplementary measles immunisation in the highly immunized population of New Zealand. AB - As endemic measles is eliminated from countries through increased immunisation, the economic benefits of enhanced immunisation programs may come into question. New Zealand has suffered from outbreaks after measles introductions from abroad and we use it as a model system to understand the benefits of catch up immunisation in highly immunised populations. We provide cost-benefit analyses for measles supplementary immunisation in New Zealand. We model outbreaks based on estimates of the basic reproduction number in the vaccinated population (Rv, the number of secondary infections in a partially immunised population), based on the number of immunologically-naive people at district and national levels, considering both pre- and post-catch up vaccination scenarios. Our analyses suggest that measles Rv often includes or exceeds one (0.18-3.92) despite high levels of population immunity. We calculate the cost of the first 187 confirmed and probable measles cases in 2014 to be over NZ$1 million (~US$864,200) due to earnings lost, case management and hospitalization costs. The benefit-cost ratio analyses suggest additional vaccination beyond routine childhood immunisation is economically efficient. Supplemental vaccination-related costs are required to exceed approximately US$66 to US$1877 per person, depending on different scenarios, before supplemental vaccination is economically inefficient. Thus, our analysis suggests additional immunisation beyond childhood programs to target naive individuals is economically beneficial even when childhood immunisation rates are high. PMID- 28802755 TI - Pneumococcal conjugate vaccination response in patients after community-acquired pneumonia, differences in patients with S. pneumoniae versus other pathogens. AB - OBJECTIVES: The goal of this study is to investigate the immune response to the 13-valent pneumococcal conjugate vaccine (PCV13) in former pneumococcal CAP patients. We hypothesize that an impaired or suboptimal humoral immune response against (specific) pneumococcal serotypes might explain the vulnerability for pneumococcal disease. METHODS: Hospitalised adult CAP patients who participated in two trials (2004-2006 (n=201) and, 2007-2009 (n=304)) were screened. Patients eligible for inclusion had CAP caused by either S. pneumoniae (pneuCAP) or due to another well-defined pathogen (otherCAP). Serotype-specific pneumococcal antibody concentrations (total IgG and IgG2/IgG1) before and 3-4weeks after PCV13 administration were measured (Luminex) and compared between pneuCAP and otherCAP patients. RESULTS: We vaccinated 60 patients:i.e. 34 pneuCAP and 26 otherCAP patients. In the pneuCAP group, 74% of patients were categorized as good responders (>=9/13 serotypes with concentration>=1300ng/ml), versus 77% in the otherCAP group. Significantly fewer full responders (i.e. 13/13 serotypes with a concentration>=1300ng/mL) were identified in the pneuCAP group (15% vs 42% respectively, p=0.02). For serotype 1, total IgG and IgG2/IgG1 subset post vaccination concentrations were significantly lower among pneuCAP patients. Our additional case-series showed that of 16 pneuCAP patients who were infected by a serotype included in PCV13 three patients did not respond against the serotype originally responsible for their CAP episode, including one former bacteraemic pneumococcal CAP patient who also failed to show a response against the serotype responsible for CAP during infection. Thirteen patients did respond to the previously infecting serotype following PCV13 including three patients who had bacteraemic pneumococcal pneumonia and did not show a response during infection against the serotype responsible for CAP. CONCLUSIONS: Our results confirm the immunogenic properties of PCV13 in former pneumococcal CAP patients including patients previously regarded as potential hyporesponders. A slightly diminished overall humoral response to polysaccharides characterizes the former pneumococcal CAP patients. ClinicalTrials.gov Identifier: NCT02141009. PMID- 28802756 TI - Feasibility of using global system for mobile communication (GSM)-based tracking for vaccinators to improve oral poliomyelitis vaccine campaign coverage in rural Pakistan. AB - Despite multiple rounds of immunization campaigns, it has not been possible to achieve optimum immunization coverage for poliovirus in Pakistan. Supplementary activities to improve coverage of immunization, such as door-to-door campaigns are constrained by several factors including inaccurate hand-drawn maps and a lack of means to objectively monitor field teams in real time, resulting in suboptimal vaccine coverage during campaigns. Global System for Mobile Communications (GSM) - based tracking of mobile subscriber identity modules (SIMs) of vaccinators provides a low-cost solution to identify missed areas and ensure effective immunization coverage. We conducted a pilot study to investigate the feasibility of using GSM technology to track vaccinators through observing indicators including acceptability, ease of implementation, costs and scalability as well as the likelihood of ownership by District Health Officials. The real time location of the field teams was displayed on a GSM tracking web dashboard accessible by supervisors and managers for effective monitoring of workforce attendance including 'time in-time out', and discerning if all target areas - specifically remote and high-risk locations - had been reached. Direct access to this information by supervisors eliminated the possibility of data fudging and inaccurate reporting by workers regarding their mobility. The tracking cost per vaccinator was USD 0.26/month. Our study shows that GSM-based tracking is potentially a cost-efficient approach, results in better monitoring and accountability, is scalable and provides the potential for improved geographic coverage of health services. PMID- 28802757 TI - The Typhoid Vaccine Acceleration Consortium (TyVAC): Vaccine effectiveness study designs: Accelerating the introduction of typhoid conjugate vaccines and reducing the global burden of enteric fever. Report from a meeting held on 26-27 October 2016, Oxford, UK. AB - Typhoid fever is estimated to cause between 11.9-26.9 million infections globally each year with 129,000-216,510 deaths. Access to improved water sources have reduced disease incidence in parts of the world but the use of efficacious vaccines is seen as an important public health tool for countries with a high disease burden. A new generation of Vi typhoid conjugate vaccines (TCVs), licensed for use in young children and expected to provide longer lasting protection than previous vaccines, are now available. The WHO Strategic Advisory Group of Experts on Immunization (SAGE) has convened a working group to review the evidence on TCVs and produce an updated WHO position paper for all typhoid vaccines in 2018 that will inform Gavi, the Vaccine Alliance's future vaccine investment strategies for TCVs. The Typhoid Vaccine Acceleration Consortium (TyVAC) has been formed through a $36.9 million funding program from the Bill & Melinda Gates Foundation to accelerate the introduction of TCVs into Gavi eligible countries. In October 2016, a meeting was held to initiate planning of TCV effectiveness studies that will provide the data required by policy makers and stakeholders to support decisions on TCV use in countries with a high typhoid burden. Discussion topics included (1) the latest evidence and data gaps in typhoid epidemiology; (2) WHO and Gavi methods and data requirements; (3) data on TCV efficacy; (4) cost effectiveness analysis for TCVs from mathematical models; (5) TCV delivery and effectiveness study design. Specifically, participants were asked to comment on study design in 3 sites for which population-based typhoid surveillance is underway. The conclusion of the meeting was that country-level decision making would best be informed by the respective selected sites in Africa and Asia vaccinating children aged from 9-months to 15-years-old, employing either an individual or cluster randomized design with design influenced by population characteristics, transmission dynamics, and statistical considerations. PMID- 28802758 TI - Impact of rapid identification of Staphylococcus aureus bloodstream infection without antimicrobial stewardship intervention on antibiotic optimization and clinical outcomes. AB - Few studies have evaluated the clinical impact of polymerase chain reaction (PCR) for Staphylococcus aureus bloodstream infections in resource-limited settings that lack direct antimicrobial stewardship intervention. This retrospective cohort study compared patients with standard microbiological identification (n=343) to those with additional identification by (PCR) (n=130). Time to initiation of optimal therapy was similar between groups but substantially shorter in the PCR group for those infected with methicillin susceptible S. aureus (median 40.0h vs. 28.3h, P=0.001). After controlling for confounding factors including infectious diseases consultation, the PCR group had a shorter time to initiation of optimal therapy by 9.7h (95% CI 4.3-15.0h). Clinical outcomes were similar in the non-PCR and PCR groups. While time to initiation of optimal therapy was shorter in the PCR group, greater reductions may be realized through additional education, direct antimicrobial stewardship intervention, or additional clinician notification. PMID- 28802759 TI - Sensor assisted self-management in Parkinson's disease: A feasibility study of ambulatory posture detection and feedback to treat stooped posture. AB - INTRODUCTION: A stooped posture is one of the characteristic motor symptoms of patients with Parkinson's disease, and has been linked to impairments in daily activities and quality of life. We aimed to test the efficacy, safety, practical utility and user-friendliness of a posture correction and vibrotactile trunk angle feedback device (the UpRight) in the home setting of patients with Parkinson's disease with a stooped posture. It was hypothesized that ambulatory use of the UpRight would be safe, feasible and result in a less stooped posture, i.e. a lower trunk angle during daily activities. METHODS: 15 patients wore the UpRight during a baseline period of 1 week (no feedback), followed by an intervention period of 1 week (feedback). RESULTS: We found a significant decrease (average -5,4 degrees ) in trunk angle from baseline period to intervention period without the occurrence of adverse events. In addition, patients found the device usable and beneficial to posture. CONCLUSION: Use of the feedback and correction device has a positive effect on ambulatory trunk angles. The device appears to be both safe and useful for self-management of stooped posture in patients with Parkinson's Disease. PMID- 28802760 TI - Involvement of obliquus capitis inferior muscle in dystonic head tremor. AB - INTRODUCTION: Head tremor is a common feature in cervical dystonia (CD) and often less responsive to botulinum neurotoxin (BoNT) treatment than dystonic posturing. Ultrasound allows accurate targeting of deeper neck muscles. METHODS: In 35 CD patients with dystonic head tremor the depth and thickness of the splenius capitis (SPL), semispinalis capitis and obliquus capitis inferior muscles (OCI) were assessed using ultrasound. Ultrasound guided EMG recordings were performed from the SPL and OCI. RESULTS: Burst-like tremor activity was present in both OCI in 25 and in one in 10 patients. In 18 patients, tremor activity was present in one SPL and in 2 in both SPL. Depth and thickness of OCI, SPL and semispinalis capitis muscles were very variable. CONCLUSION: Muscular activity underlying tremulous CD is most commonly present in OCI. Due to the variability of muscle thickness, we suggest ultrasound guided BoNT injections into OCI. PMID- 28802761 TI - Ultrasound versus magnetic resonance imaging of the temporomandibular joint in juvenile idiopathic arthritis: a systematic review. AB - A systematic review of published articles on ultrasound (US) and magnetic resonance imaging (MRI) of the temporomandibular joint (TMJ) in juvenile idiopathic arthritis (JIA) was performed to answer the question "What is the sensitivity and specificity of US as compared to MRI in diagnosing acute and chronic joint changes in patients with JIA?" The most recent evidence was sought in published articles via a search of the PubMed, Ovid, and Embase databases. Article appraisal was performed by two reviewers. Nineteen articles reporting prospective or ambispective studies comparing US to MRI in TMJ imaging were found. Six of these articles were specific to JIA patients. The heterogeneity of these articles made comparison difficult. Of the acute and chronic changes assessed (disk displacement, joint effusion, bony deformity), only joint effusion was appropriately assessed by multiple authors, with US having a sensitivity of 0 72% and specificity of 70-83% as compared to MRI. There was a paucity of studies specific to JIA, with many studying adult, non-rheumatic patients. This systematic review found that dynamic imaging with high-resolution US improves sensitivity and specificity compared to static, low-resolution US. Additionally, there is evidence to suggest that US imaging following a baseline MRI can increase US sensitivity and specificity and may have a future role in disease surveillance. PMID- 28802763 TI - Cytomegalovirus-associated protein-losing enteropathy in a healthy man. PMID- 28802762 TI - Clinical application of autogenous partially demineralized dentin matrix prepared immediately after extraction for alveolar bone regeneration in implant dentistry: a pilot study. AB - The aim of this study was to examine the efficacy and safety of autogenous partially demineralized dentin matrix (APDDM) prepared onsite, for clinical application in bone regeneration procedures related to implant dentistry, including socket preservation, alveolar ridge augmentation, and maxillary sinus floor augmentation. In this study, 16 patients underwent dental implant placement using APDDM transplantation. There were no systemic or local complications (including surgical site infection) in any of the cases, and oral rehabilitation using dental implants was successful in all cases for at least 2 years after attachment of the suprastructure. This report describes the clinical application of APDDM prepared immediately after tooth extraction to bone augmentation, taking advantage of the relatively short preparation time due to partial demineralization. APDDM, as introduced in this study, is an efficient, safe, and reasonable bone substitute. Consequently, this material has the potential to become one of the options as a bone substitute in implant dentistry. PMID- 28802764 TI - Factors influencing renal graft survival: 7-Year experience of a single center. AB - BACKGROUND AND OBJECTIVE: The demand for kidney transplants exceeds the existing supply. This leads to a recently growing interest of research in the area of factors that could prolong graft long-term outcomes and survival. In Lithuania, approximately 90% of kidney transplantations are from deceased donors. Donor organs are received and shared only inside the country territory in Lithuania; therefore, donor data is accurate and precise. This study was performed to present particularities of kidney transplantation data in Lithuania and to identify the effect of donor and recipient factors and histologic findings on renal graft outcomes. The aim of this study was to identify the effect of donor and recipient factors and histologic findings on renal graft outcomes. MATERIALS AND METHODS: We analyzed the influence of deceased donor and recipient factors and histological findings on the graft function in 186 renal transplant patients. Graft survival was estimated within the first year after transplantation. RESULTS: The donors and recipients were older in worse eGFR group 1 year after transplantation. Dissimilarity of degree of glomerulosclerosis (GS), interstitial fibrosis (IF) and arteriolar hyalinosis (AH) were significant in inferior and superior renal function groups (GS >20% 11.4 vs. 0%, P=0.017; IF 9.3 vs. 0%, P=0.034; AH 69 vs. 26.2%, P<0.001). Nine independent variables were significantly associated with a worse renal transplant function 1 year posttransplantation: AH (OR=6.287, P<0.001), an episode of urinary tract infection (OR=2.769, P=0.020), acute graft rejection (OR=3.605, P=0.037), expanded criteria (OR=4.987, P=0.001), female gender donors (OR=3.00, P=0.014), cerebrovascular disease caused donor brain death (OR=5.00, P=0.001), donor's age (OR=1.07, P<0.001), and recipient's age (OR=1.047, P=0.022). Worse renal graft survival 1 year posttransplantation was associated with a delayed graft function and a higher level of glomerulosclerosis in time-zero biopsy. CONCLUSIONS: Donor factors, such as age, female gender, brain death of cerebrovascular cause and expanded criteria donor status had a significant negative impact on the renal graft function 1 year after transplantation. Recipients' age, urinary tract infection and acute graft rejection episodes after transplantation were associated with a worse kidney function 1 year after transplantation. Lower 1-year graft survival was related to a delayed graft function (DGF) and a higher degree of glomerulosclerosis. PMID- 28802765 TI - Disparities in care for elderly women with endometrial cancer adversely effects survival. AB - PURPOSE: Elderly women with endometrial cancer are at increased risk of local recurrence and cancer-specific death compared to younger women. We sought to investigate adjuvant radiotherapy (RT) practice patterns and effects on survival in elderly women with endometrial cancer. METHODS: Women from the National Cancer Data Base (NCDB) with FIGO IA grade 3 to FIGO IVA endometrial cancer diagnosed from 2004-2013 were included. Chi square analysis was used to compare the elderly (80+) and non-elderly women (18-79) and women who received RT and those that did not. Univariate and multivariate logistic regression were used to determine predictors of receipt of oncologic surgery and adjuvant RT. Univariate and multivariate Cox survival analyses were performed to examine the effect of radiotherapy on survival. Propensity score matching and shared frailty analysis were done in the elderly cohort. RESULTS: We identified 48,871 women for analysis. Rates of oncologic surgery were higher in the women 80+ compared with rates of adjuvant RT (95% versus 34%). Rates of RT receipt were higher in non elderly women (48% versus 34%, p<0.001). Age over 80 was a negative predictive factor (OR 0.62, p<0.001) for receipt of adjuvant RT and oncologic surgery (OR 0.81, p=0.03). Adjuvant RT was associated with a decreased risk of death in elderly (HR 0.79, p<0.001) and non-elderly women (HR 0.77, p<0.001). CONCLUSION: Endometrial cancer patients over age 80 have similar rates of oncologic surgery as younger women but are significantly less likely to receive adjuvant RT, and this negatively impacts their survival. PMID- 28802767 TI - Real rock-microfluidic flow cell: A test bed for real-time in situ analysis of flow, transport, and reaction in a subsurface reactive transport environment. AB - Physical, chemical, and biological interactions between groundwater and sedimentary rock directly control the fundamental subsurface properties such as porosity, permeability, and flow. This is true for a variety of subsurface scenarios, ranging from shallow groundwater aquifers to deeply buried hydrocarbon reservoirs. Microfluidic flow cells are now commonly being used to study these processes at the pore scale in simplified pore structures meant to mimic subsurface reservoirs. However, these micromodels are typically fabricated from glass, silicon, or polydimethylsiloxane (PDMS), and are therefore incapable of replicating the geochemical reactivity and complex three-dimensional pore networks present in subsurface lithologies. To address these limitations, we developed a new microfluidic experimental test bed, herein called the Real Rock Microfluidic Flow Cell (RR-MFC). A porous 500MUm-thick real rock sample of the Clair Group sandstone from a subsurface hydrocarbon reservoir of the North Sea was prepared and mounted inside a PDMS microfluidic channel, creating a dynamic flow-through experimental platform for real-time tracking of subsurface reactive transport. Transmitted and reflected microscopy, cathodoluminescence microscopy, Raman spectroscopy, and confocal laser microscopy techniques were used to (1) determine the mineralogy, geochemistry, and pore networks within the sandstone inserted in the RR-MFC, (2) analyze non-reactive tracer breakthrough in two- and (depth-limited) three-dimensions, and (3) characterize multiphase flow. The RR MFC is the first microfluidic experimental platform that allows direct visualization of flow and transport in the pore space of a real subsurface reservoir rock sample, and holds potential to advance our understandings of reactive transport and other subsurface processes relevant to pollutant transport and cleanup in groundwater, as well as energy recovery. PMID- 28802766 TI - A phase I trial of intraperitoneal GEN-1, an IL-12 plasmid formulated with PEG PEI-cholesterol lipopolymer, administered with pegylated liposomal doxorubicin in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancers: An NRG Oncology/Gynecologic Oncology Group study. AB - OBJECTIVE: The study's purpose was to assess safety and efficacy of escalating doses of weekly GEN-1 with pegylated liposomal doxorubicin (PLD) in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancers (EOC). METHODS: Patients had persistent or recurrent platinum-resistant EOC. The trial was a standard 3+3 phase I dose escalation design with patients receiving intravenous PLD 40mg/m2 (dose level 1 and 2) or 50mg/m2 (dose level 3) every 28days and intraperitoneal GEN-1 at 24mg/m2 (dose level 1) or 36mg/m2 (dose level 2 and 3) on days 1, 8, 15, and 22 of a 28day cycle. Cycles were repeated every 28days until disease progression. Patients were monitored for toxicity, clinical efficacy, and evidence of systemic and intraperitoneal immunologic effect. RESULTS: Sixteen evaluable patients received a median of 4cycles (range 1 8). No dose limiting toxicities were found. The adverse side effects were 4 grade 3 anemia, 2 grade 3 abdominal pain, 7 grade 3 neutropenia, and 2 grade 4 neutropenia. A clinical benefit of 57.1% (PR=21.4%; SD=35.7%) was found in the 14 patients with measurable disease. The highest number of partial responses (28.6%) and stable disease (57.1%) were found at dose level 3. The maximum tolerated dose was not reached. Increases in IL-12, IFN-gamma, and TNF-alpha levels were found in peritoneal fluid following GEN-1 treatment. CONCLUSIONS: GEN-1 in combination with PLD has encouraging clinical benefit and biological activity in recurrent or persistent EOC and warrants further investigation with escalating doses of GEN-1. PMID- 28802768 TI - When you can, scale up: Large-scale study shows no effect of tDCS in an ambiguous risk-taking task. AB - BACKGROUND: A wide range of neuroimaging and neuromodulation studies have shown that the dorsolateral prefrontal cortex (DLPFC) plays a pivotal role in decision making. Of particular interest is the question of its role in decision-making when conditions are uncertain and whether manipulating this neural substrate through neuromodulation changes subsequent risk-taking behaviour. Previous work using the Balloon Analogue Risk Task (BART) suggests that bilateral tDCS stimulation of the DLPFC reduces risk-taking behaviour but unilateral stimulation has no effect. However, participant numbers have been limited and may have biased the estimate of the size of the effect of the stimulation on task performance. OBJECTIVES/HYPOTHESIS: We aimed to test the robustness and generalizability of these previous findings by using a very similar methodology but with a much larger sample. METHODS: During both 20- and 30-min tDCS stimulation at 2mA, we administered the BART to about 200 participants assigned to bilateral DLPFC stimulation of either right anodal/left cathodal, left anodal/right cathodal or sham (Study 1 and Study 2); and to unilateral stimulation conditions (Study 2): right anodal, left anodal or sham with the referent electrode over the contralateral supraorbital region. RESULTS: In the first bilateral study, we found that risk-taking was greater for participants in the right anodal/left cathodal stimulation group compared to those who received left anodal/right cathodal stimulation, but not compared to sham. The results obtained in the bilateral and unilateral stimulation protocols implemented in Study 2 yielded no evidence of any effect of stimulation. Combining the data from both studies, we found no statistically significant differences between mean performances of the nine stimulation groups. Indeed, all 95% confidence intervals for the nine means overlapped, suggesting that these randomly vary around a common population mean. CONCLUSIONS: This study showed that there was no detectable effect of tDCS stimulation on risky decision-making under ambiguity, compared to sham stimulation. Hence, using a much larger sample, we did not replicate previous work reporting a reduction in risky decision-making by bilateral stimulation of the DLPFC compared to sham. When the results of our bilateral and unilateral stimulation studies were combined, it emerged that the most likely explanation for the apparent significant results in our bilateral stimulation study was random variation in performance. This outcome is a further reminder of the need for appropriately sized samples to potentially achieve reliable outcomes in brain modulation studies. PMID- 28802769 TI - Electrophysiological correlates of voice memory for young and old speakers in young and old listeners. AB - Faces of one's own-age group are easier to recognize than other-age faces. Using behavioral measures and EEG, we studied whether an own-age bias (OAB) also exists in voice memory. Young (19 - 26 years) and old (60-75 years) participants studied young (18-25 years) and old (60-77 years) unfamiliar voices from short sentences. Subsequently, they classified studied and novel voices as "old" (i.e. studied) or "new", from the same sentences. Recognition performance was higher in young compared to old participants, and for old compared to young voices, with no OAB. At the same time, we found evidence for higher distinctiveness of old compared to young voices, both in terms of acoustic measures and subjective ratings (independent of rater age). Analyses of event-related brain potentials (ERPs) indicated more negative-going deflections (400-1000ms) for old compared to young voices in young participants. In old participants, we observed a reversed OLD/NEW memory effect, with overall more positive amplitudes for novel compared to studied old (but not young) voices (400-1000ms). Time-frequency analyses revealed less beta power (16-26Hz) for young compared to old voices at left anterior sites, and also reduced beta power for correctly recognized studied (compared to novel) voices at left posterior sites (300-900ms). These findings could suggest an engagement of cortical areas during stimulus-specific recollection from about 300ms, in a task that emphasized the analysis of individual acoustic features. PMID- 28802770 TI - Efficacy of navigation may be influenced by retrosplenial cortex-mediated learning of landmark stability. AB - Human beings differ considerably in their ability to orient and navigate within the environment, but it has been difficult to determine specific causes of these individual differences. Permanent, stable landmarks are thought to be crucial for building a mental representation of an environment. Poor, compared to good, navigators have been shown to have difficulty identifying permanent landmarks, with a concomitant reduction in functional MRI (fMRI) activity in the retrosplenial cortex. However, a clear association between navigation ability and the learning of permanent landmarks has not been established. Here we tested for such a link. We had participants learn a virtual reality environment by repeatedly moving through it during fMRI scanning. The environment contained landmarks of which participants had no prior experience, some of which remained fixed in their locations while others changed position each time they were seen. After the fMRI learning phase, we divided participants into good and poor navigators based on their ability to find their way in the environment. The groups were closely matched on a range of cognitive and structural brain measures. Examination of the learning phase during scanning revealed that, while good and poor navigators learned to recognise the environment's landmarks at a similar rate, poor navigators were impaired at registering whether landmarks were stable or transient, and this was associated with reduced engagement of the retrosplenial cortex. Moreover, a mediation analysis showed that there was a significant effect of landmark permanence learning on navigation performance mediated through retrosplenial cortex activity. We conclude that a diminished ability to process landmark permanence may be a contributory factor to sub optimal navigation, and could be related to the level of retrosplenial cortex engagement. PMID- 28802771 TI - DMD and West syndrome. AB - Duchenne Muscular Dystrophy (DMD) is the most frequent muscular dystrophy in childhood, with a worldwide incidence of one in 5000 live male births. It is due to mutations in the dystrophin gene leading to absence of full-length dystrophin protein. Central nervous system involvement is well-known in Duchenne Muscular Dystrophy. The multiple dystrophin isoforms expressed in brain have important roles in cerebral development and functioning. The association of Duchenne Muscular Dystrophy with seizures has been reported, and there is a higher prevalence of epilepsy in Duchenne Muscular Dystrophy patients (between 6.3% and 12.3%) than in the general pediatric population (0.5-1%). Duchenne Muscular Dystrophy patients may present with focal seizures, generalized tonic-clonic seizures or absences. We report on two boys in whom Duchenne Muscular Dystrophy is associated with epileptic spasms and hypsarrhythmia that fulfil the criteria for West syndrome, thus extending the spectrum of seizure types described in Duchenne Muscular Dystrophy patients. PMID- 28802772 TI - Effectiveness of a combined exercise training and home-based walking programme on physical activity compared with standard medical care in moderate COPD: a randomised controlled trial. AB - OBJECTIVE: To estimate the effectiveness of a 10-week combined exercise training and home-based walking programme on daily physical activity (PA) compared with standard medical care in patients with moderate chronic obstructive pulmonary disease (COPD). DESIGN: Randomised controlled trial. SETTING: Primary care physiotherapy. PARTICIPANTS: Consecutive patients with stable COPD at Gold Stage II with a score of two or more on the Medical Research Council Dyspnoea Scale. INTERVENTION: Ten-week combined exercise training and home-based walking programme compared with standard medical care. MAIN OUTCOMES: At baseline and after 10 weeks, daily PA was evaluated by accelerometry using three levels of intensity and expressed as metabolic equivalent of task. In addition, daily activities (Physical Activity Scale for the Elderly), functional exercise capacity (6-minute Walk Test), health-related quality of life (Chronic Respiratory Questionnaire) and exercise self-efficacy (Exercise Self-Regulatory Efficacy Scale) were measured. RESULTS: Fifty-two patients {34 females; mean age 70.2 [standard deviation (SD) 9.5] years; mean forced expiratory volume in 1second 67% (SD 9.2) of predicted} were randomised. PA, adjusted for baseline differences, increased significantly in the intervention group compared with the control group, by 26.1minutes/day [95% confidence interval (CI) 7.3 to 44.9]. The increase in functional capacity between groups was clinically relevant (34.0m, 95% CI 2.3 to 65.6) in favour of the intervention group. CONCLUSIONS: A combined exercise training and home-based walking programme in primary care physiotherapy improved PA in patients with moderate COPD. Clinical trial registration number NL24766.018.08. PMID- 28802773 TI - Active physiotherapy interventions following total knee arthroplasty in the hospital and inpatient rehabilitation settings: a systematic review and meta analysis. AB - BACKGROUND: Physiotherapy is a routine component of postoperative management following total knee arthroplasty (TKA). As the demand for surgery increases it is vital that postoperative physiotherapy interventions are effective and efficient. OBJECTIVES: Determine the most beneficial active physiotherapy interventions in acute hospital and inpatient rehabilitation for improving pain, activity, range of motion and reducing length of stay for adults who have undergone TKA. DATA SOURCES: Electronic databases MEDLINE, CINAHL, PUBMED and EMBASE. STUDY ELIGIBILITY CRITERIA: Randomised controlled trials investigating the effect of active physiotherapy interventions in the acute hospital or inpatient rehabilitation setting for adults who have undergone TKA. STUDY APPRAISAL AND SYNTHESIS METHODS: Risk of bias for individual studies was assessed using the Physiotherapy Evidence Database (PEDro) scale. Standardised Mean Differences (SMD) or Mean Differences (MD) and 95% confidence intervals were calculated and combined in meta-analyses. Quality of meta-analyses was assessed using the Grades of Research, Assessment, Development and Evaluation approach. RESULTS: Accelerated physiotherapy regimens were effective for reducing acute hospital length of stay (MD -3.50 days, 95% CI -5.70 to -1.30). Technology assisted physiotherapy did not show any difference for activity (SMD -0.34, 95% CI -0.82 to 0.13). From high quality individual studies pain, activity and range of motion improved with accelerated physiotherapy regimens and activity improved with hydrotherapy. LIMITATIONS: Lack of blinding and small sample sizes across the included trials. CONCLUSION: After TKA, there is low level evidence that accelerated physiotherapy regimens can reduce acute hospital length of stay. Systematic review registration number PROSPERO (Registration number CRD42014013414) http://www.crd.york.ac.uk/PROSPERO. PMID- 28802774 TI - A rule-based, dose-finding design for use in stroke rehabilitation research: methodological development. AB - BACKGROUND: Dose-optimisation studies as precursors to clinical trials are rare in stroke rehabilitation. OBJECTIVE: To develop a rule-based, dose-finding design for stroke rehabilitation research. DESIGN: 3+3 rule-based, dose-finding study. Dose escalation/de-escalation was undertaken according to preset rules and a mathematical sequence (modified Fibonacci sequence). The target starting daily dose was 50 repetitions for the first cohort. Adherence was recorded by an electronic counter. At the end of the 2-week training period, the adherence record indicated dose tolerability (adherence to target dose) and the outcome measure indicated dose benefit (10% increase in motor function). The preset increment/decrease and checking rules were then applied to set the dose for the subsequent cohort. The process was repeated until preset stopping rules were met. PARTICIPANTS: Participants had a mean age of 68 (range 48 to 81) years, and were a mean of 70 (range 9 to 289) months post stroke with moderate upper limb paresis. MODEL TASK: A custom-built model of exercise-based training to enhance ability to open the paretic hand. OUTCOME MEASURE: Repetitions per minute of extension/flexion of paretic digits against resistance. ANALYSIS: Usability of the preset rules and whether the maximally tolerated dose was identifiable. RESULTS: Five cohorts of three participants were involved. Discernibly different doses were set for each subsequent cohort (i.e. 50, 100, 167, 251 and 209 repetitions/day). The maximally tolerated dose for the model training task was 209 repetitions/day. CONCLUSIONS: This dose-finding design is a feasible method for use in stroke rehabilitation research. PMID- 28802775 TI - Catastrophic antiphospholipid syndrome (CAPS)-induced ischemic pancreatic ducts injury mimicking intraductal papillary mucinous neoplasm (IPMN). AB - OBJECTIVES: Catastrophic antiphospholipid syndrome (CAPS) is a life-threatening disease characterized by multiple small-vessel occlusions of rapid onset. Ischemic pancreatic duct lesions secondary to CAPS have never been reported. METHODS: We describe 4 patients who presented lesions suspected to be intraductal papillary mucinous neoplasm (IPMN) of the pancreas following a CAPS. RESULTS: All patients had a history of CAPS months or years before the IPMN diagnosis. They had abdominal pain or abnormal liver test results and had undergone radiography. In a 36-year-old man, endoscopic ultrasonography and magnetic resonance cholangiopancreatography demonstrated parietal thickening, stenoses and dilatations of the main pancreatic duct, which suggested IPMN. A pancreatic resection was performed because of presumed risk of malignancy. Histology revealed pancreatitis and thrombosis of small pancreatic vessels but no IPMN. The 3 other cases had lesions consistent with IPMN disclosed on MRI. From the first case experience, regular radiography surveillance was decided for the 3 other patients. After more than 4 years of follow-up, lesions remained unchanged. CONCLUSION: Physicians must be aware that these lesions may be encountered in CAPS and may closely mimic IPMN, with subsequent risk of performing unnecessary pancreatectomy. PMID- 28802776 TI - The psychosocial burden of psoriatic arthritis. AB - OBJECTIVE: To assess the psychosocial impact of psoriatic arthritis (PsA), describe how health-related quality of life (QoL) is affected in patients with PsA, discuss measures used to evaluate the psychosocial impact of PsA, and review studies examining the effect of therapy on QoL. METHODS: A targeted review on the impact of PsA on QoL and the role of tailored psychosocial management in reducing the psychosocial burden of the disease was performed. PubMed literature searches were conducted using the terms PsA, psychosocial burden, QoL, and mood/behavioral changes. Articles were deemed relevant if they presented information regarding the psychosocial impact of PsA, methods used to evaluate these impacts, or ways to manage/improve management of PsA and its resulting comorbidities. The findings of this literature search are descriptively reviewed and the authors' expert opinion on their interpretation is provided. RESULTS: The psychosocial burden of PsA negatively affects QoL. Patients suffer from sleep disorders, fatigue, low level stress, depression and mood/behavioral changes, poor body image, and reduced work productivity. Additionally, each patient responds to pain differently, depending on a variety of psychological factors including personality structure, cognition, and attention to pain. Strategies for evaluating the burdens associated with PsA and the results of properly managing patients with PsA are described. CONCLUSIONS: PsA is associated with a considerable psychosocial burden and new assessment tools, specific to PsA, have been developed to help quantify this burden in patients. Future management algorithms of PsA should incorporate appropriate assessment and management of psychological and physical concerns of patients. Furthermore, patients with PsA should be managed by a multidisciplinary team that works in coordination with the patient and their family or caregivers. PMID- 28802777 TI - Local Infiltration Analgesia With Liposomal Bupivacaine Improves Pain Scores and Reduces Opioid Use After Total Knee Arthroplasty: Results of a Randomized Controlled Trial. AB - BACKGROUND: Local infiltration analgesia (LIA) with liposomal bupivacaine (LB) in patients undergoing total knee arthroplasty (TKA) has yielded mixed results. The PILLAR study, which was designed to minimize limitations associated with previous studies, compared the effects of LIA with or without LB on pain scores, opioid consumption, including proportion of opioid-free patients, time to first opioid rescue, and safety after primary unilateral TKA. METHODS: Patients (N = 140) were randomized to LIA with LB 266 mg/20 mL (admixed with bupivacaine HCl 0.5%, 20 mL) or LIA with bupivacaine HCl 0.5%, 20 mL. Standardized infiltration techniques and a standardized multimodal pain management protocol were used. The coprimary efficacy endpoints were area under the curve (AUC) of visual analog scale pain intensity scores 12-48 hours (AUC12-48) postsurgery and total opioid consumption 0-48 hours postsurgery. RESULTS: Mean AUC12-48 of visual analog scale pain intensity score was 180.8 with LB and 209.3 without LB (least squares [LS] mean treatment difference -26.88, P = .0381). LS mean total opioid consumption 0-48 hours postsurgery was 18.7 mg with and 84.9 mg without LB (LS ratio 0.220, P = .0048). Significant differences in favor of LB were observed for the percentage of opioid-free patients (P < .01) and time to first opioid rescue (P = .0230). Treatments were similarly well tolerated. CONCLUSION: This study provides data on LIA with LB administered using optimal techniques specific to TKA. In this setting, LIA with LB significantly improved postsurgical pain, opioid consumption, and time to first opioid rescue, with more opioid-free patients and no unexpected safety concerns. PMID- 28802778 TI - Cryotherapy Treatment After Unicompartmental and Total Knee Arthroplasty: A Review. AB - BACKGROUND: Cryotherapy is widely utilized to enhance recovery after knee surgeries. However, the outcome parameters often vary between studies. Therefore, the purpose of this review is to compare (1) no cryotherapy vs cryotherapy; (2) cold pack cryotherapy vs continuous flow device cryotherapy; (3) various protocols of application of these cryotherapy methods; and (4) cost-benefit analysis in patients who had unicompartmental knee arthroplasty (UKA) or total knee arthroplasty (TKA). METHODS: A search for "knee" and "cryotherapy" using PubMed, EBSCO Host, and SCOPUS was performed, yielding 187 initial reports. After selecting for RCTs relevant to our study, 16 studies were included. RESULTS: Of the 8 studies that compared the immediate postoperative outcomes between patients who did and did not receive cryotherapy, 5 studies favored cryotherapy (2 cold packs and 3 continuous cold flow devices). Of the 6 studies comparing the use of cold packs and continuous cold flow devices in patients who underwent UKA or TKA, 3 favor the use of continuous flow devices. There was no difference in pain, postoperative opioid consumption, or drain output between 2 different temperature settings of continuous cold flow device. CONCLUSION: The optimal device to use may be one that offers continuous circulating cold flow, as there were more studies demonstrating better outcomes. In addition, the pain relieving effects of cryotherapy may help minimize pain medication use, such as with opioids, which are associated with numerous potential side effects as well as dependence and addiction. Meta-analysis on the most recent RCTs should be performed next. PMID- 28802779 TI - Pharmacological aspects of closed loop insulin delivery for type 1 diabetes. AB - Insulin deficiency and impaired glucose homeostasis are hallmarks of type 1 diabetes. Since the discovery of insulin, pharmacological and clinical developments have endeavoured to replicate its endogenous pharmacokinetics (PK) and pharmacodynamics (PD). Closed loop insulin delivery systems operate as an artificial pancreas by making automated insulin dose adjustments based on real time continuous glucose monitoring. The increasing adoption of continuous insulin pump therapy and evolving technological advances have seen significant progress in the development of closed loop insulin delivery systems. This article reviews the current landscape of closed loop insulin delivery systems and pharmacological advances that could overcome current barriers. PMID- 28802780 TI - Herringbone-like hydrodynamic structures in microchannels: A CFD model to evaluate the enhancement of surface binding. AB - Selected adsorption efficiency of a molecule in solution in a microchannel is strongly influenced by the convective/diffusive mass transport phenomena that supply the target molecule to the adsorption surface. In a standard microchannel with a rectangular cross section, laminar flow regime limits the fluid mixing, thus suggesting that mass transport conditions can be improved by the introduction of herringbone-like structures. Tuning of these geometrical patterns increases the concentration gradient of the target molecule at the adsorption surface. A computational fluid dynamic (CFD) study was performed to evaluate the relation between the geometrical herringbone patterns and the concentration gradient improvement in a 14 mm long microchannel. The results show that the inhomogeneity of the concentration gradient can provide an improved and localized adsorption under specific geometrical features, which can be tuned in order to adapt the adsorption pattern to the specific assay requirements. PMID- 28802781 TI - Elevated lead levels from e-waste exposure are linked to decreased olfactory memory in children. AB - Lead (Pb) is a developmental neurotoxicant and can cause abnormal development of the nervous system in children. Hence, the aim of this study was to investigate the effect of Pb exposure on child olfactory memory by correlating the blood Pb levels of children in Guiyu with olfactory memory tests. We recruited 61 preschool children, 4- to 7-years of age, from Guiyu and 57 children from Haojiang. The mean blood Pb level of Guiyu children was 9.40 MUg/dL, significantly higher than the 5.04 MUg/dL mean blood Pb level of Haojiang children. In addition, approximately 23% of Guiyu children had blood Pb levels exceeding 10.00 MUg/dL. The correlation analysis showed that blood Pb levels in children highly correlated with e-waste contact (rs = 0.393). Moreover, the mean concentration of serum BDNF in Guiyu children (35.91 ng/ml) was higher than for Haojiang (28.10 ng/ml) and was positively correlated with blood Pb levels. Both item and source olfactory memory tests at 15 min, 5 h and 24 h after odor exposure showed that scores were lower in Guiyu children indicative of reduced olfactory memory in Guiyu children. Olfactory memory tests scores negatively correlated with blood Pb and serum BDNF levels, but were positively associated with parental education levels. At the same time, scores of both tests on children in the high blood Pb level group (blood Pb levels > 5.00 MUg/dL) were lower than those in the low blood Pb level group (blood Pb levels <= 5.00 MUg/dL), implying that Pb exposure decreases olfactory memory in children. Our findings suggest that Pb exposure in e-waste recycling and dismantling areas could result in an increase in serum BDNF level and a decrease in child olfactory memory, in addition, BDNF might be involved in olfactory memory impairment. PMID- 28802782 TI - A case of Galen vein thrombosis occurring after bilateral acetabular fractures in the Tibet plateau - what can we learn? AB - Hypoxia leads to increased red blood cells and blood viscosity at high altitude while moderate trauma increases coagulation in blood. Under the above-mentioned conditions, venous sinus thrombosis is more likely to occur. A patient suffering bilateral acetabular fractures together with the gradual disturbance of consciousness was admitted to our hospital. Though computed tomography arteriogram (CTA) of the brain displayed normal blood vessels; bilateral thalamus and brainstem infarction were found on head computed tomography (CT) and Galen vein thrombosis on cerebral computed tomography venography (CTV). Dehydration and tracheotomy were immediately conducted with antiplatelet, anticoagulant and neurotrophic medicine administered to the patient. After three days' treatment, the patient's consciousness gradually improved and eventually became clear enough to leave the hospital. On follow-up, no dysfunction was documented. PMID- 28802783 TI - An Emergency Medicine-Primary Care Partnership to Improve Rural Population Health: Expanding the Role of Emergency Medicine. AB - The health of rural America is failing and our traditional approaches have proved ineffective at improving health in rural communities. Rural populations are now a health disparity population, facing higher mortality rates for the 5 leading causes of death compared with their urban counterparts. We must generate novel, rural-specific approaches to solve this challenge-and there is a clear role for the field of emergency medicine. Building on emergency departments' (EDs') expanding role in health care delivery and emergency medicine's increasing involvement in population health, we propose a new health care delivery model for rural population health based on partnership between emergency medicine and primary care that embraces the important role that EDs play in rural areas. PMID- 28802784 TI - A hybrid straightwire technique. AB - An original straightwire appliance was developed in order to easily adapt force and friction to the different stages and needs of treatment. The appliance features: (1) conventional brackets with a 0.020*0.030" slot in the anterior area, passive self-ligating brackets with a 0.022*0.030" slot in the lateral area, and tubes with a 0.022*0.030" slot in the molar area; (2) archwires which adapt to the different stages of treatment and increase their section and stiffness progressively, starting with 0.014" superelastic NiTi, passing through 0.016*0.025" and 0.019*0.025" heat-activated NiTi and reaching 0.019*0.025" stainless steel working archwires; (3) use of several ligation systems which progressively increase their binding (low-friction ligatures, "O"- or "8"-shape elastomeric ligatures). Clinical cases are shown to illustrate the technique. PMID- 28802785 TI - ? PMID- 28802786 TI - Transition to Practice: A Global Surgery Approach. AB - OBJECTIVE: To determine the feasibility of a global surgery setting for a transition to practice experience. SETTING: A rural hospital in Malawi, Africa. PARTICIPANTS: A recent graduate of a U.S. general surgery residency program. RESULTS: Fellow performed 305 cases across the surgical disciplines with demonstrated improvements in operative ability. CONCLUSION: The global surgery approach to transition to practice offers a unique opportunity to complement domestic training while providing critical assistance to communities with few surgical providers. PMID- 28802787 TI - Reliability and Validity of Speech Evaluation in Adductor Spasmodic Dysphonia. AB - OBJECTIVES: The aim of this study was to evaluate speech in patients with adductor spasmodic dysphonia (ADSD) by perceptual evaluations and acoustic measures, and to examine the reliability and validity of these measures. METHODS: Twenty-four patients with ADSD and 24 healthy volunteers were included in the study. Speech materials consisted of three sentences constructed from serial voiced syllables to elicit abductor voice breaks. Three otolaryngologists rated the degree of voice symptoms using a visual analog scale (VAS). VAS sheets with five 100-mm horizontal lines were given to each rater. The ends of the lines were labeled normal vs severe, and the five lines were labeled as overall severity of each of the four speech symptoms (strangulation, interruption, tremor and strained speech). Nine words were selected for acoustic analysis, and abnormal acoustic events were classified into one of the three categories. To evaluate the intra- and inter-rater and intermeasurer reliabilities of the VAS scores or acoustic measures, Pearson r correlations were calculated. To examine the validity of perceptual evaluations and acoustic measures, the sensitivity and the specificity were calculated. RESULTS: Pearson r correlation coefficients for overall severity showed the highest intra- and inter-rater reliabilities. For acoustic events, the intrameasurer reliabilities were r = .645 (frequency shifts), r = .969 (aperiodic segments), and r = 1.0 (phonation breaks), and the intermeasurer reliability ranged from r = .102 to r = 1.0. Perceptual evaluation showed high sensitivity (91.7%) and specificity (100%), whereas acoustic analysis showed low sensitivity (70.8%) and high specificity (100%). CONCLUSION: Both perceptual evaluation and acoustic measures alone were found likely to overlook patients with true ADSD. PMID- 28802788 TI - Auditory-Perceptual Evaluation of Dysphonia: A Comparison Between Narrow and Broad Terminology Systems. AB - OBJECTIVE: In auditory-perceptual voice analysis, a multiparameter approach and a more reductionist approach may be compared with narrow and broad phonetic transcription and used interchangeably, depending on the purpose. The aim of this study was to investigate the perspectives of a translation of the terminology used in the multiparameter Danish Dysphonia Assessment (DDA) approach into the five-parameter GRBAS system. METHODS: Voice samples illustrating type and grade of the voice qualities included in DDA were rated by five speech language pathologists using the GRBAS system with the aim of estimating inter- and intrarater reliability. The same samples were then rated using the DDA terminology. RESULTS: Both inter- and intrarater reliability were found to be very high for the GRBAS parameters grade, rough, and breathy, but somewhat lower for asthenic and strained. Further, strong and clear associations were found between the DDA and GRBAS rating for grade, rough, breathy, and strained, whereas the relation between DDA ratings and asthenic was weaker and less clear. CONCLUSION: The data strongly support that the DDA system can be translated into the GRBAS system for auditory-perceptual voice analysis. The consensus discussion prior to the listening test is believed to have contributed to the high degree of inter- and intrarater reliability. We suggest for future use of the GRBAS system that rater reliability for asthenic and strained can increase, if these parameters are defined as behavioral terms and antagonists, reflecting muscular hypo- and hyperfunction. PMID- 28802789 TI - Cytochrome c in patients undergoing coronary artery bypass grafting: A post hoc analysis of a randomized trial. AB - PURPOSE: To establish whether plasma cytochrome c is detectable in patients undergoing cardiac surgery, whether cytochrome c levels are associated with lactate/inflammatory markers/cellular oxygen consumption, and whether cytochrome c levels are associated with clinical outcomes. MATERIALS AND METHODS: This was an observational sub-study of a randomized trial comparing thiamine to placebo in patients undergoing coronary artery bypass grafting. Patients had blood drawn before, after, and again 6h after surgery. Cytochrome c, inflammatory markers, and cellular oxygen consumption were measured. RESULTS: 64 patients were included. Cytochrome c was detectable in 63 (98%) patients at baseline with a median cytochrome c level of 0.18ng/mL (quartiles: 0.13, 0.55). There was no difference from baseline level to post-surgical level (0.19ng/mL [0.09, 0.51], p=0.36) or between post-surgical level and 6-hour post-surgical level (0.17ng/mL [0.10, 0.57], p=0.61). There was no difference between the thiamine and placebo groups' change in cytochrome c levels from baseline to after surgery (p=0.22). Cytochrome c levels were not associated with lactate, inflammatory markers, cellular oxygen consumption, or clinical outcomes. CONCLUSIONS: Cytochrome c levels did not increase after cardiac surgery and was not associated with the degree of inflammation or clinical outcomes. PMID- 28802790 TI - Vascular air embolism: A silent hazard to patient safety. AB - PURPOSE: To narratively review published information on prevention, detection, pathophysiology, and appropriate treatment of vascular air embolism (VAE). MATERIALS AND METHODS: MEDLINE, SCOPUS, Cochrane Central Register and Google Scholar databases were searched for data published through October 2016. The Manufacturer and User Facility Device Experience (MAUDE) database was queried for "air embolism" reports (years 2011-2016). RESULTS: VAE may be introduced through disruption in the integrity of the venous circulation that occurs during insertion, maintenance, or removal of intravenous or central venous catheters. VAE impacts pulmonary circulation, respiratory and cardiac function, systemic inflammation and coagulation, often with serious or fatal consequences. When VAE enters arterial circulation, air emboli affect cerebral blood flow and the central nervous system. New medical devices remove air from intravenous infusions. Early recognition and treatment reduce the clinical sequelae of VAE. An organized team approach to treatment including clinical simulation can facilitate preparedness for VAE. The MAUDE database included 416 injuries and 95 fatalities from VAE. Data from the American Society of Anesthesiologists Closed Claims Project showed 100% of claims for VAE resulted in a median payment of $325,000. CONCLUSIONS: VAE is an important and underappreciated complication of surgery, anesthesia and medical procedures. PMID- 28802791 TI - Difference in inspiratory flow between volume and pressure control ventilation in patients with flow dyssynchrony. AB - PURPOSE: Flow dyssynchrony is common during volume control ventilation but minimized during pressure control. Characterizing inspiratory flow during pressure control breaths can inform adjustments of the fixed flow of volume control to address flow dyssynchrony. This study compared inspiratory flow peak and pattern between volume control and adaptive pressure control breaths. MATERIAL AND METHODS: Subjects with or at risk for ARDS were ventilated with volume control decreasing ramp flow at different tidal volumes and subsequently with adaptive pressure control targeting those same tidal volumes. Inspiratory flows of volume control breaths exhibiting flow dyssynchrony, and those of pressure control breaths at the same set tidal volumes without flow dyssynchrony were analyzed, for a total of 17 subject-tidal volume conditions. Peak flow and flows at 10, 25, 50 and 75% of inspiratory time were compared between modes. RESULTS: Group peak flows were not different between modes, but at 50 and 75% of inspiratory time flows were higher during adaptive pressure control. In 8 subject tidal volume conditions VT were higher (>1ml/kg PBW) on adaptive pressure control than on volume control. CONCLUSIONS: In patients with flow dyssynchrony during volume control ventilation, adjustment of inspiratory flow pattern should be considered to minimize this dyssynchrony. PMID- 28802792 TI - Fat mass, fat-free mass, and resting metabolic rate in weight-stable sleeve gastrectomy patients compared with weight-stable nonoperated patients. AB - BACKGROUND: There is evidence that body composition and resting metabolic rate (RMR) in weight-stable patients after Roux-en-Y gastric bypass and duodenal switch is similar to that of nonoperated individuals within the same body mass index (BMI) interval. Currently, data concerning fat mass (FM), fat-free mass (FFM), and RMR on weight-stable patients after sleeve gastrectomy (SG) are lacking. OBJECTIVES: To assess FM, FFM, and RMR, in a selected and homogenous population of weight-stable SG patients (WSSG) and compare them with those obtained from healthy normal weight-stable nonoperated (WSNO) volunteers controls of similar sex, age, and BMI. SETTING: University hospital, Italy. METHODS: We assessed total weight, FM, and FFM by bioelectrical impedance assay, and RMR by indirect calorimetry, in 70 WSSG patients (47 females, 23 males) at a mean follow up of 3.2 +/- 2.1 years after SG and compared them with 70 healthy WSNO volunteers, as controls (47 females, 23 males). RESULTS: There was no significant difference between WSSG and WSNO groups concerning total weight (males, 72 +/- 2.66 versus 72.8 +/- 1.99 kg, P = .0254; females 65.1 +/- 2.53 versus 63.7 +/- 2.87 kg, P = .0139), FM (males, 17.7 +/- 1.53 versus 16.7 +/- 1.57 kg, P = .0341; females 19.6 +/- 0.50 versus 18.5 +/- 2.85 kg, P = .0104), FFM (males, 54.3 +/- 3.07 versus 56.1 +/- 3.30 kg; P = .049; females 45.5 +/- 2.29 versus 45.1 +/- 1.13 kg, P = .287), and RMR (males, 1541 +/- 121.3 versus 1463 +/- 74.4 kcal/d; P = .0118; females 1214 +/- 54.9 versus 1250 +/- 90.1 kcal/d, P = .0215). CONCLUSION: At a mean follow-up of 3.2 +/- 2.1 years after SG, WSSG patients of both sexes have a FM, FFM, and RMR comparable to that of healthy WSNO individuals within the same age and BMI interval. These findings further support bariatric surgery-induced weight loss as a physiologic process and indicate that young patients, in the setting of an adequate preoperative and postoperative specific diet and moderate physical activity, do not suffer from excessive FFM depletion after SG in the mid-term. PMID- 28802794 TI - A novel and organic solvent-free preparation of solid lipid nanoparticles using natural biopolymers as emulsifier and stabilizer. AB - In this work, a new and novel organic solvent-free and synthetic surfactant-free method was reported to fabricate stable solid lipid nanoparticles (SLNs) from stearic acid, sodium caseinate (NaCas) and pectin, as well as water. Melted stearic acid was directly emulsified into an aqueous phase containing NaCas and pectin, followed by pH adjustment and thermal treatment to induce the formation of a compact and dense polymeric coating which stabilized SLNs. The preparation procedures and formulations were comprehensively optimized. The inter- and intra molecular interactions among three ingredients were characterized by fluorescence and Fourier transform infrared spectroscopies. The stability of as-prepared SLNs was evaluated under simulated gastrointestinal conditions, and compared with traditional SLNs prepared with organic solvents. Our results revealed that the SLNs prepared from this organic solvent-free method had superior physicochemical properties over the traditional SLNs, including smaller size and better stability. Furthermore, redispersible SLNs powders were obtained by nano spray drying, but only the SLNs prepared by organic solvent-free method had sub-micron scale, uniform and spherical morphology. The organic solvent-free preparation method was proved to be a promising approach to prepare stable and uniform SLNs for potential oral delivery applications. PMID- 28802793 TI - Pickering emulsions stabilized by biodegradable block copolymer micelles for controlled topical drug delivery. AB - Surfactant-free biocompatible and biodegradable Pickering emulsions were investigated as vehicles for skin delivery of hydrophobic drugs. O/w emulsions of medium-chain triglyceride (MCT) oil droplets loaded with all-trans retinol as a model hydrophobic drug were stabilized by block copolymer nanoparticles: either poly(lactide)-block-poly(ethylene glycol) (PLA-b-PEG) or poly(caprolactone)-block poly(ethylene glycol) (PCL-b-PEG). Those innovative emulsions were prepared using two different processes allowing drug loading either inside oil droplets or inside both oil droplets and non-adsorbed block copolymer nanoparticles. Skin absorption of retinol was investigated in vitro on pig skin biopsies using the Franz cell method. Supplementary experiments by confocal fluorescence microscopy allowed the visualization of skin absorption of the Nile Red dye on histological sections. Retinol and Nile Red absorption experiments showed the large accumulation of hydrophobic drugs in the stratum corneum for the Pickering emulsions compared to the surfactant-based emulsion and an oil solution. Loading drug inside both oil droplets and block copolymer nanoparticles enhanced again skin absorption of drugs, which was ascribed to the supplementary contribution of free block copolymer nanoparticles loaded with drug. Such effect allowed tuning drug delivery to skin over a wide range by means of a suitable selection of either the formulation or the drug loading process. PMID- 28802795 TI - Atomic layer deposition-A novel method for the ultrathin coating of minitablets. AB - We introduce atomic layer deposition (ALD) as a novel method for the ultrathin coating (nanolayering) of minitablets. The effects of ALD coating on the tablet characteristics and taste masking were investigated and compared with the established coating method. Minitablets containing bitter tasting denatonium benzoate were coated by ALD using three different TiO2 nanolayer thicknesses (number of deposition cycles). The established coating of minitablets was performed in a laboratory-scale fluidized-bed apparatus using four concentration levels of aqueous Eudragit(r) E coating polymer. The coated minitablets were studied with respect to the surface morphology, taste masking capacity, in vitro disintegration and dissolution, mechanical properties, and uniformity of content. The ALD thin coating resulted in minimal increase in the dimensions and weight of minitablets in comparison to original tablet cores. Surprisingly, ALD coating with TiO2 nanolayers decreased the mechanical strength, and accelerated the in vitro disintegration of minitablets. Unlike previous studies, the studied levels of TiO2 nanolayers on tablets were also inadequate for effective taste masking. In summary, ALD permits a simple and rapid method for the ultrathin coating (nanolayering) of minitablets, and provides nanoscale-range TiO2 coatings on porous minitablets. More research, however, is needed to clarify its potential in tablet taste masking applications. PMID- 28802796 TI - Antibacterial prophylaxis for gram-positive and gram-negative infections in cranial surgery: A meta-analysis. AB - BACKGROUND: Perioperative antibiotic prophylaxis against gram positive and gram negative infections is considered standard of care in the perioperative management of patients undergoing cranial surgery. The antibiotic regimen which best reduces the risk of surgical site infections (SSIs) remains controversial. OBJECTIVES: A systematic literature review and meta-analysis were conducted to examine the effect of various prophylactic antibiotics on infection incidence among patients undergoing cranial surgeries. METHODS: A comprehensive search was conducted on Pubmed, EMBASE and Cochrane databases through October 2014 for studies that evaluated the efficacy of antibiotic prophylaxis among patients undergoing cranial surgeries. Pooled effect estimates using both fixed- and random-effect models were calculated. RESULTS: Eight articles were included in the meta-analysis, with a combined total of 1655 cranial procedures. Among these, 74 cases of SSIs were reported after patients received a single antibiotic or a combination of 2 or more antibiotics (pooled incidence of SSIs=6.00%; 95% CI=4.80%, 7.50%; fixed-effects model; I2=73.7%; P-heterogeneity<0.01). Incidence of SSI was 1.00% (95% CI=0.40%, 2.60%) for non-MRSA gram-positive bacterial infections; 2.70% (95% CI=0.90%, 8.00%) for gram-negative bacterial infections; 6.00% (95% CI=4.50%, 7.80%) for gram negative, and non-MRSA gram-positive bacterial infections; and 11.3% (95% CI=7.20%, 17.4%) for gram negative and MRSA gram-positive bacterial infections. Subgroup analysis revealed an effect modification by drug class (P=0.05) and infection type (P-interaction=0.01). More specifically, lincosamides (2.70%; n=1 group), glycopeptides (2.80%; n=1), third generation cephalosporins (5.30%; n=2), antibiotics combination (4.90%; n=4), and penicillin-family antibiotics (5.90%, n=1) offered better coverage against infections than first generation cephalosporins (22.0%; n=2). A meta-regression analysis on study length was not significant (P=0.13). Random-effect models were not materially different form fixed-effects. No evidence of publication bias was found. CONCLUSION: Lincosamides, glycopeptides, third generation cephalosporins, other combinations of prophylactic antibiotics, or penicillin-family antibiotics alone offer better coverage against SSIs than first generation cephalosporin among cranial surgery patients. PMID- 28802797 TI - Cerebral venous sinus Thrombosis: Clinical Features, Long-Term outcome and recanalization. AB - Recanalization and prognosis of cerebral venous sinus thrombosis (CVST) are generally considered to be good, and various factors have been reported to be associated with recanalization in previous studies. Fifty patients diagnosed with CVST between September 2007 and July 2016 were analyzed retrospectively. Modified Rankin scale (mRS) scores at six months and results of follow-up imaging of patients with at least six months follow-up were also reviewed for the assessment of long term outcome, recanalization rates and factors associated with recanalization. The mean age of the patients (39 female, 11 male) was 34.6+/ 11.2years (17-69). Of the 50 patients enrolled, 31 (62%) had at least six months follow-up with available data and 26 (83.9%) of these had favorable outcomes (mRS 0-1) at six months. Complete recanalization was observed in 15 patients (48.4%), partial recanalization in 14 (45.2%) and no recanalization in 2 (6.5%). Univariate analysis revealed that complete recanalization rates were higher in female patients (p=0.013) and lower in patients with multiple thrombosis in more than one dural sinus (p=0.03). The prognosis and recanalization rates of CVST were good, and complete or partial recanalization of venous sinuses was not associated with clinical outcome. PMID- 28802798 TI - Most common sites on MRI of intracranial neoplastic leptomeningeal disease. AB - Neoplastic leptomeningeal disease (LMD) represents infiltration of the leptomeninges by tumor cells. Knowledge of the frequencies of locations of LMD on MRI may assist in early detection, help elucidate the process of leptomeningeal spread of cancer and understand how LMD affects the central nervous system. Our goal was to identify intracranial sites of neoplastic LMD predilection on MRI in patients with cytologically-proven LMD. The presence of FLAIR signal hyperintensity and T1-weighted post-contrast enhancement in the sulci of the supratentorial compartment and cerebellum and enhancement of the cranial nerves (CNs), basal cisterns, pituitary stalk, and ependymal surface of the lateral ventricles, as well as the presence of parenchymal metastasis were recorded. Within each imaging sequence, sites were ordered by prevalence and compared using McNemar's test. The study included 270 patients. Positive MRI findings were present in 185/270 (68.5%) patients. FLAIR signal hyperintensity was significantly more common (p<=0.003) in the cerebellum (n=96) and occipital lobe (n=92) relative to the other lobes. Leptomeningeal enhancement was also significantly more common (p<=0.009) in the cerebellum (n=82) and occipital lobe (n=67) relative to the other lobes. Enhancement was most commonly found involving CN VII/VIII and the ependymal surface of the lateral ventricles compared to other sites. Parenchymal metastases were present in 110 (40.1%) of the patients. In conclusion, neoplastic LMD predominantly involves the cerebellum and occipital lobes, CN VII/VIII, and the ependymal lining of the lateral ventricles. Parenchymal metastases are frequently present in patients with neoplastic LMD. PMID- 28802799 TI - A comparative study of quality of life and marital satisfaction in patients with depression and their spouses. AB - Spouses of patients suffering from depression experience various forms of burden. Present study assesses and compares the marital satisfaction and quality of life (QOL) of the patients and their spouses. Further it assesses these variables in terms of illness severity, duration of untreated illness (DUI) and other demographic parameters especially gender. In this cross sectional study, 50 patients diagnosed with Depressive Disorder along with their spouses were recruited. Both groups were assessed separately for marital satisfaction and QOL along with demographic details followed by appropriate statistical analysis. A high level of marital distress found amongst both patients and their spouses whereas only patients reported poor QOL. Increasing DUI worsens both marital satisfaction and QOL in spouses with no effects on patients. Illness severity worsens QOL in both groups with no effect on marital satisfaction. Gender was not found to have any impact on either of the groups. Small sample size and cross sectional study design were main limitations. Early and faster intervention will be helpful in patient's prognosis, and also the perception and QOL of spouses. A better treatment response may be expected if focus is at improvement in QOL rather than only symptom control. Further work will be needed with a larger population and in a longitudinal study design. Future research also needs to focus upon establishment of better norms for the DUI for depressive disorder. PMID- 28802800 TI - State of the Art and Promise of Structural Neuroimaging in Postoperative Delirium and Postoperative Cognitive Decline. PMID- 28802801 TI - Nodal status and survival in anal cancer. PMID- 28802802 TI - Nodal stage migration and prognosis in anal cancer: a systematic review, meta regression, and simulation study. AB - BACKGROUND: In patients with squamous cell carcinoma of the anus (SCCA), lymph node positivity (LNP) indicates poor prognosis for survival and is central to radiotherapy planning. Over the past three decades, LNP proportion has increased, mainly reflecting enhanced detection with newer imaging modalities; a process known as nodal stage migration. If accompanied by constant T stage distributions, prognosis for both lymph node-positive and lymph node-negative groups may improve without any increase in overall survival for individual patients; a paradox termed the Will Rogers phenomenon. Here, we aim to systematically evaluate the impact of nodal stage migration on survival in SCCA and address a novel hypothesis that this phenomenon results in reduced prognostic discrimination. METHODS: We did a systematic review and meta-regression to quantify changes in LNP over time and the impact of this change on survival and prognostic discrimination. We searched MEDLINE, Embase, and the Cochrane Library to identify randomised trials and observational studies in patients with SCCA published between Jan 1, 1970, and Oct 11, 2016. Studies were eligible if patients received chemoradiotherapy or radiotherapy as the main treatment, reported LNP proportions (all studies), and reported overall survival (not necessarily present in all studies). We excluded studies with fewer than 50 patients. We extracted study level data with a standardised, piloted form. The primary outcome measure was 5 year overall survival. To investigate scenarios in which reduced prognostic discrimination might occur, we simulated varying true LNP proportions and true overall survival, and compared these with expected observed outcomes for varying levels of misclassification of true nodal state. FINDINGS: We identified 62 studies reporting LNP proportions, which included 10 569 patients. From these, we included 45 studies (6302 patients) with whole cohort 5-year overall survival, 11 studies with 5-year survival stratified by nodal status, and 20 studies with hazard ratios in our analyses of temporal changes. In 62 studies, the LNP proportions increased from a mean estimate of 15.3% (95% CI 10.5-20.1) in 1980 to 37.1% (34.0-41.3) in 2012 (p<0.0001). In 11 studies with prognostic data, increasing LNP was associated with improved overall survival in both lymph node positive and lymph node-negative categories, whereas the proportions with combined tumour stage T3 and T4 remained constant. In 20 studies, across a range of LNP proportions from 15% to 40%, the hazard ratios for overall survival of lymph node-positive versus lymph node-negative patients decreased significantly from 2.5 (95% CI 1.8-3.3) at 15% LNP to 1.3 (1.2-1.9; p=0.014) at 40% LNP. The simulated scenarios reproduced this effect if the true LNP proportions were 20% or 25%, but not if the true LNP proportions were 30% or greater. INTERPRETATION: We describe a consequence of staging misclassification in anal cancer that we have termed reduced prognostic discrimination. We used this new observation to infer that the LNP proportions of more than 30% seen in modern clinical series (11 out of 15 studies with a median year since 2007) are higher than the true LNP proportion. The introduction of new staging technologies in oncology might misclassify true disease stage, spuriously informing disease management and ultimately increasing the risk of overtreatment. FUNDING: Bowel Disease Research Foundation. PMID- 28802803 TI - Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: A systematic review and meta-analysis. AB - This systematic review investigated whether the insulin sensitiser metformin has a geroprotective effect in humans. Pubmed and Embase were searched along with databases of unpublished studies. Eligible research investigated the effect of metformin on all-cause mortality or diseases of ageing relative to non-diabetic populations or diabetics receiving other therapies with adjustment for disease control achieved. Overall, 260 full-texts were reviewed and 53 met the inclusion criteria. Diabetics taking metformin had significantly lower all-cause mortality than non-diabetics (hazard ratio (HR)=0.93, 95%CI 0.88-0.99), as did diabetics taking metformin compared to diabetics receiving non-metformin therapies (HR=0.72, 95%CI 0.65-0.80), insulin (HR=0.68, 95%CI 0.63-0.75) or sulphonylurea (HR=0.80, 95%CI 0.66-0.97). Metformin users also had reduced cancer compared to non-diabetics (rate ratio=0.94, 95%CI 0.92-0.97) and cardiovascular disease (CVD) compared to diabetics receiving non-metformin therapies (HR=0.76, 95%CI 0.66 0.87) or insulin (HR=0.78, 95%CI 0.73-0.83). Differences in baseline characteristics were observed which had the potential to bias findings, although statistical adjustments were made. The apparent reductions in all-cause mortality and diseases of ageing associated with metformin use suggest that metformin could be extending life and healthspans by acting as a geroprotective agent. PMID- 28802804 TI - Transcranial direct current stimulation in Parkinson's disease dementia: A randomised double-blind crossover trial. PMID- 28802805 TI - Facial gender and hemispheric asymmetries: A hf-tRNS study. PMID- 28802806 TI - Comparing Parietal Quantity-Processing Mechanisms between Humans and Macaques. AB - Quantity processing studies typically assume functional homology between regions within macaque and human intraparietal sulcus (IPS), where apparently similar locations respond to broadly similar tasks. However, macaque single cell neurophysiology is difficult to compare to human functional magnetic resonance imaging (fMRI); particularly in multivoxel pattern analysis and adaptation paradigms, or where different tasks are used. fMRI approaches incorporating neural tuning models allow closer comparison, revealing human numerosity selective responses only outside the IPS. Extensive functional similarities support this novel homology of physical quantity processing. Human IPS instead houses a network responding to comparisons of physical quantities, symbolic numbers, and other stimulus features. This network likely reflects interactions between physical quantity processing, spatial processing, and (in humans) linguistic processing. PMID- 28802807 TI - Acute-phase response in Babesia canis and Dirofilaria immitis co-infections in dogs. AB - Babesia canis and Dirofilaria immitis are emerging and geographically overlapping vector-borne pathogens in dogs. Infection with B. canis leads to acute-phase response (APR) that can be mild to severe and results in either non-complicated or complicated forms of the disease. The aim of this study was to determine whether acute B. canis infection is more severe in dogs with underlying asymptomatic D. immitis infection. Dogs of both sexes, different ages and breeds, with naturally occurring mono-infections with B. canis (n=13) and D. immitis (n=18) and co-infected dogs (n=7) were enrolled as well as healthy controls (n=15). Routine haematology and biochemistry, agarose gel electrophoresis (agEF) protein fraction separation and enzyme-linked immunosorbent assay (ELISA) for serum amyloid A (SAA) were performed. Based on clinical and laboratory findings, sepsis was diagnosed in the majority of dogs with acute B. canis infection with or without underlying asymptomatic D. immitis infection. Overall, haematology, biochemistry and agEF pattern changes were induced and dictated by acute B. canis infection whether or not the dogs had an asymptomatic D. immitis infection. D. immitis infection slightly influenced the level of anaemia, slightly aggravated the level of dehydration and increased the concentration of gamma-globulins in acute-phase B. canis infection. D. immitis infection prevented B. canis-induced leukopenia. SAA equally increased in dogs with acute B. canis infection with or without underlying D. immitis infection. The level of SAA was not changed in dogs with asymptomatic D. immitis when compared to the controls. In conclusion, asymptomatic D. immitis infection does not influence overall APR after acute B. canis infection. PMID- 28802808 TI - Novel Oral Anticoagulants in Direct Current Cardioversion for Atrial Fibrillation. AB - BACKGROUND: For some patients with atrial fibrillation, direct current cardioversion (DCCV) is one strategy that can be used to establish sinus rhythm but appropriate anticoagulation is mandatory to prevent thromboembolic events. Historically, patients were anticoagulated with warfarin with bridging with unfractionated or low molecular weight heparin, however, recently novel oral anticoagulants (NOACs), apixaban, dabigatran and rivaroxaban have become more popular. Despite the increase in use, real world data on safety and efficacy is limited. METHODS: We retrospectively analysed patients that underwent DCCV at Wollongong Hospital from 1 January 2014 to 30 June 2016 and compared peri procedural anticoagulation with warfarin and the three NOACs. Patients were treated with at least 24hours of anticoagulation before and at least four weeks after the procedure unless contraindication developed. All patients underwent transoesophageal echocardiography prior to cardioversion regardless of anticoagulation type or duration. Patients with left atrial or left atrial appendage thrombus did not undergo cardioversion. We analysed the utilisation rates of NOACs and compared the incidence of post procedural ischaemic strokes and major bleeding events at eight weeks follow-up. RESULTS: Over the study period, 284 patients underwent DCCV; 109 (38.4%) patients were anticoagulated with warfarin and 175 (61.6%) with one of the three NOACs; 77 (27.1%) with apixaban, 60 (21.1%) with rivaroxaban and 38 (13.4%) with dabigatran. Patients treated with warfarin were on average older (71.3+/-9.7 vs. 65.2+/-12.9; p value, 0.0005) with more cardiac risk factors including documented heart failure with reduced ejection fraction (39.4% vs. 22.9%; p value, 0.0032), medically treated hypertension (76.1% vs. 48.6%; p value, 0.0001) and peripheral vascular disease (31.2% vs. 12.1%; p value, 0.0004). The NOACs were more frequently used in patients with lower CHA2DS2-VASc scores; 179 patients had a score<=3 with 52 (29.1%) patients treated with warfarin and 127 (70.9%) treated with a NOAC (p value, 0.0001). In our cohort, the use of NOACs increased over the study period from 45.6% in 2014 to 82.8% in 2016. There was a low incidence of ischaemic stroke and bleeding events in both groups, 1.8% versus 0.6% (p value, 0.5607) and 3.6% versus 1.7% (p value, 0.4343) respectively. In the NOAC group, 95 of the 174 patients were anticoagulation-naive and anticoagulated for less than five days; in comparison to longer duration therapy there was no difference in ischaemic stroke and bleeding events. CONCLUSION: In our institution, the use of NOACs in electrical cardioversion increased significantly over the study period and in our experience, they appear to be as safe as warfarin with low rates of ischaemic stroke and major bleeding. In addition, a short duration NOAC strategy was comparable to longer duration therapy. PMID- 28802809 TI - Effect of Sutureless Prosthetic Valves. PMID- 28802810 TI - Early Invasive Versus Initially Conservative Strategy in Elderly Patients Older Than 75 Years with Non-ST-Elevation Acute Coronary Syndrome: A Meta-Analysis. AB - BACKGROUND: Fear of complications related to the procedure and unclear benefits in elderly patients are common reasons for invasive angiography being withheld. METHODS: We searched PubMed and Embase from inception until February 2016 for studies that enrolled individuals older than 75 years with non-ST-elevation acute coronary syndrome (NSTE-ACS) and allocated patients to either an invasive or conservative strategy. RESULTS: Thirteen studies (four randomised controlled trials (RCTs) and nine observational studies) enrolling 832,007 elderly NSTE-ACS patients were analysed. Compared with the conservative treatment, the early invasive approach does significantly reduce the risk of death at follow-up from 6 months to 5 years (risk ratio [RR] 0.65, 95% confidence interval [CI] 0.59-0.73, p<0.001); the definite benefit was mainly observed in observational studies (RR 0.63, 95% CI 0.57-0.70, p<0.001), and the risk of death also showed a strong trend toward reduction with invasive approach (RR 0.82, 95% CI 0.64-1.05, p=0.119) in RCTs. For the outcome of bleeding complications, there was a higher risk of any bleeding occurring in-hospital (RR 2.51, 95% CI 1.53-4.11, p<0.001) in patients treated with invasive strategy than those treated with conservative strategy. However, no difference of in-hospital major bleeding (RR 1.78, 95% CI 0.31-10.13, p=0.514) was observed between the two strategies. CONCLUSION: Elderly patients with NSTE-ACS might benefit from an early invasive strategy but with increasing risk of any bleeding complications. More RCTs are needed to assess early invasive strategies in the elderly. PMID- 28802811 TI - Effects of Respiratory Training on Heart Rate Variability and Baroreflex Sensitivity in Individuals With Chronic Spinal Cord Injury. AB - OBJECTIVE: To evaluate the effects of pressure threshold respiratory training (RT) on heart rate variability and baroreflex sensitivity in persons with chronic spinal cord injury (SCI). DESIGN: Before-after intervention case-controlled clinical study. SETTING: SCI research center and outpatient rehabilitation unit. PARTICIPANTS: Participants (N=44) consisted of persons with chronic SCI ranging from C2 to T11 who participated in RT (n=24), and untrained control subjects with chronic SCI ranging from C2 to T9 (n=20). INTERVENTIONS: A total of 21+/-2 RT sessions performed 5 days a week during a 4-week period using a combination of pressure threshold inspiratory and expiratory devices. MAIN OUTCOME MEASURES: Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and beat-to-beat arterial blood pressure and heart rate changes during the 5-second long maximum expiratory pressure maneuver (5s MEP) and the sit-up orthostatic stress test, acquired before and after the RT program. RESULTS: In contrast to the untrained controls, individuals in the RT group experienced significantly increased FVC and FEV1 (both P<.01) in association with improved quality of sleep, cough, and speech. Sympathetically (phase II) and parasympathetically (phase IV) mediated baroreflex sensitivity both significantly (P<.05) increased during the 5s MEP. During the orthostatic stress test, improved autonomic control over heart rate was associated with significantly increased sympathetic and parasympathetic modulation (low- and high-frequency change: P<.01 and P<.05, respectively). CONCLUSIONS: Inspiratory-expiratory pressure threshold RT is a promising technique to positively affect both respiratory and cardiovascular dysregulation observed in persons with chronic SCI. PMID- 28802812 TI - Noninvasive Brain Stimulation Improves Hemispatial Neglect After Stroke: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To evaluate the effectiveness of noninvasive brain stimulation (NIBS) repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS)-on hemispatial neglect and performance in activities of daily living (ADL) after stroke. DATA SOURCES: MEDLINE (PubMed), EMBASE, Cochrane CENTRAL, Scopus, SciELO, and Physiotherapy Evidence Database were searched from database inception to December 2016. DATA SELECTION: Randomized controlled trials or crossover trials focused on determining the effects of tDCS or rTMS combined or not combined with other therapies for hemispatial neglect after stroke. DATA EXTRACTION: Methodological characteristics of the studies, number of participants, comparison groups, interventions, and outcomes were extracted. DATA SYNTHESIS: Ten trials comprising 226 participants had data that were suitable for the meta-analysis. Meta-analysis showed that NIBS combined with other therapies significantly improves hemispatial neglect (standardized mean difference [SMD]=-1.91; 95% confidence interval [CI], -2.57 to -1.25; I2=71%). A sensitivity analysis showed that rTMS (SMD=-2.16; 95% CI, -3.00 to -1.33; I2=76%) and tDCS (SMD=-1.07; 95% CI, -1.76 to -0.37; I2=0%) had positive effects on hemispatial neglect. Furthermore, both excitatory (SMD=-2.34; 95% CI, -3.56 to 1.12; I2=65%) and inhibitory (SMD=-1.69; 95% CI, -2.49 to -0.88; I2=75%) stimulations were effective. CONCLUSIONS: This meta-analysis reveals moderate quality evidence for the effectiveness of NIBS protocols combined with other therapies on hemispatial neglect and performance in ADL after stroke. PMID- 28802813 TI - Evaluating Hospital Readmission Rates After Discharge From Inpatient Rehabilitation. AB - OBJECTIVE: To examine facility-level rates of all-cause, unplanned hospital readmissions for 30 days after discharge from inpatient rehabilitation facilities (IRFs). DESIGN: Observational design. SETTING: Inpatient rehabilitation facilities. PARTICIPANTS: Medicare fee-for-service beneficiaries (N=567,850 patient-stays). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The outcome is all-cause, unplanned hospital readmission rates for IRFs. We adapted previous risk-adjustment and statistical approaches used for acute care hospitals to develop a hierarchical logistic regression model that estimates a risk standardized readmission rate for each IRF. The IRF risk-adjustment model takes into account patient demographic characteristics, hospital diagnoses and procedure codes, function at IRF admission, comorbidities, and prior hospital utilization. We presented national distributions of observed and risk standardized readmission rates and estimated confidence intervals to make statistical comparisons relative to the national mean. We also analyzed the number of days from IRF discharge until hospital readmission. RESULTS: The national observed hospital readmission rate by 30 days postdischarge from IRFs was 13.1%. The mean unadjusted readmission rate for IRFs was 12.4%+/-3.5%, and the mean risk-standardized readmission rate was 13.1%+/-0.8%. The C-statistic for our risk-adjustment model was .70. Nearly three-quarters of IRFs (73.4%) had readmission rates that were significantly different from the mean. The mean number of days to readmission was 13.0+/-8.6 days and varied by rehabilitation diagnosis. CONCLUSIONS: Our results demonstrate the ability to assess 30-day, all cause hospital readmission rates postdischarge from IRFs and the ability to discriminate between IRFs with higher- and lower-than-average hospital readmission rates. PMID- 28802814 TI - Safety and efficacy of a fixed-dose combination regimen of grazoprevir, ruzasvir, and uprifosbuvir with or without ribavirin in participants with and without cirrhosis with chronic hepatitis C virus genotype 1, 2, or 3 infection (C-CREST-1 and C-CREST-2, part B): two randomised, phase 2, open-label trials. AB - BACKGROUND: There is a need for hepatitis C virus (HCV) therapies with excellent efficacy across genotypes and in diverse populations. Part A of the C-CREST-1 and C-CREST-2 trials led to the selection of a three-drug regimen of grazoprevir (MK 5172; an HCV NS3/4A protease inhibitor; 100 mg/day) plus ruzasvir (MK-8408; an NS5A inhibitor; 60 mg/day) plus uprifosbuvir (MK-3682; an HCV NS5B polymerase inhibitor; 450 mg/day). Part B of the studies tested this combination as a single formulation in different treatment durations in a broader population. METHODS: Part B of these randomised, phase 2, open-label clinical trials enrolled individuals from 15 countries who were chronically infected with HCV genotypes 1 6 (HCV RNA >=10 000 IU/mL) with or without compensated cirrhosis. Those with genotype 1, genotype 2, genotype 4, or genotype 6 were treatment-naive; those with genotype 3 could be treatment-naive or treatment-experienced with pegylated interferon and ribavirin. Randomisation occurred centrally using an interactive voice response system and integrated web response system. Participants were randomly assigned to receive treatment for 8, 12, or 16 weeks with a fixed-dose combination of grazoprevir, ruzasvir, and uprifosbuvir with or without ribavirin. The primary endpoint was the proportion of participants achieving sustained virological response 12 weeks after the end of all study therapy (SVR12), defined as HCV RNA less than the lower limit of quantification (either target detected unquantifiable or target not detected [<15 IU/mL]). The trials are registered at ClinicalTrials.gov, numbers NCT02332707 and NCT02332720. FINDINGS: 676 participants were randomly assigned between Feb 18, 2015, and Aug 16, 2016. In all 675 participants who received at least one dose of study drug (full analysis set), SVR12 for the 8-week regimen of grazoprevir, ruzasvir, and uprifosbuvir with and without ribavirin was achieved in 39 (93% [95% CI 81-99]) of 42 participants with genotype 1a, 45 (98% [88-100]) of 46 with genotype 1b, 54 (86% [75-93]) of 63 with genotype 2, 98 (95% [89-98]) of 103 with genotype 3, and seven (100% [59-100]) of seven participants with genotype 4. SVR12 for the 12 week regimen with and without ribavirin was achieved in 87 (99% [95% CI 94-100]) of 88 participants with genotype 1, 61 (98% [91-100]) of 62 with genotype 2, and four (100% [40-100]) of four with genotype 6. Among participants with cirrhosis who were infected with genotype 3, SVR12 for the 12-week regimen with and without ribavirin was achieved in 28 (97% [95% CI 82-100]) of 29 of those who were treatment-naive and 29 (100% [88-100]) of 29 who were treatment-experienced. SVR12 for the 16-week regimen with and without ribavirin was achieved in 26 (100% [95% CI 87-100]) of 26 participants with genotype 2 infection and 72 (96% [89 99]) of 75 participants with genotype 3 infection. The most common adverse events were headache (143 [22%] of 664), fatigue (129 [19%] of 664), and nausea (83 [13%] of 664). 16 (2%) of 664 participants had serious adverse events. INTERPRETATION: The combined regimen of grazoprevir (100 mg/day), ruzasvir (60 mg/day), and uprifosbuvir (450 mg/day) has the potential to provide a simplified treatment for HCV that is effective and well tolerated in most individuals infected with HCV, as well as a shorter duration of treatment in many individuals. FUNDING: Merck & Co, Inc. PMID- 28802815 TI - Shortening the duration of therapy for chronic hepatitis C infection. AB - Combination direct-acting antiviral therapy of 8-24 weeks is highly effective for the treatment of chronic hepatitis C infection. However, shortening the treatment duration to less than 8 weeks could potentially reduce overall treatment costs and improve adherence. Here we explore the arguments for and against the development of short-duration regimens and existing data on treatment for 6 weeks or less among patients with chronic hepatitis C virus genotype 1 infection. Additionally, we identify potential predictors of response to short-course combination therapies with direct-acting antiviral drugs that might be explored in future clinical trials. PMID- 28802817 TI - Shortening HCV therapy: science meets public health. PMID- 28802816 TI - Safety and efficacy of an 8-week regimen of grazoprevir plus ruzasvir plus uprifosbuvir compared with grazoprevir plus elbasvir plus uprifosbuvir in participants without cirrhosis infected with hepatitis C virus genotypes 1, 2, or 3 (C-CREST-1 and C-CREST-2, part A): two randomised, phase 2, open-label trials. AB - BACKGROUND: New hepatitis C virus (HCV) therapies with pan-genotypic efficacy are needed. The goals of part A of C-CREST-1 and C-CREST-2 were to compare the efficacies of two doses (300 mg or 450 mg once daily) of uprifosbuvir (MK-3682; NS5B inhibitor) in an 8-week regimen combined with grazoprevir (NS3/4A inhibitor; 100 mg once daily) and an NS5A inhibitor, either elbasvir (50 mg once daily) or ruzasvir (MK-8408; 60 mg once daily), and to evaluate the safety and tolerability of these combination regimens in individuals infected with genotypes 1, 2, or 3. METHODS: Part A of these phase 2, randomised, multicentre, open-label, clinical trials enrolled participants from 11 countries, aged 18 years or older, chronically infected with HCV genotypes 1, 2, or 3, with HCV RNA of at least 10 000 IU/mL, without evidence of cirrhosis, who had not received previous treatment for HCV infection. Within each HCV genotype, participants were randomly assigned (1:1:1:1) with a block size of 4, to open-label treatment to one of four treatment groups: grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (300 mg/day); grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (450 mg/day); grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (300 mg/day); or grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (450 mg/day), according to a computer-generated allocation schedule. Randomisation was centrally implemented using an interactive voice response system and integrated web response system. The primary endpoint was the proportion of participants achieving sustained virological response at 12 weeks (SVR12; HCV RNA less than the lower limit of quantitation at 12 weeks after the end of all study therapy) in the per-protocol analysis set, which included all participants who were randomised and received at least one dose of study drug. The trials are registered with ClinicalTrials.gov, numbers NCT02332707 and NCT02332720. FINDINGS: 241 participants were randomised between Feb 18, 2015, and March 16, 2015. 240 participants completed 8 weeks of treatment and reached follow-up 12 weeks after the end of treatment. Of the four regimens, grazoprevir plus ruzasvir plus uprifosbuvir 450 mg had the most consistently high SVR12 (>90%) for participants infected with genotype 1 (21 [91%] of 23), genotype 2 (15 [94%] of 16), and genotype 3 (20 [91%] of 22). In particular, among those with genotype 2 infection, the grazoprevir plus ruzasvir plus uprifosbuvir 450 mg regimen had a higher SVR12 (15 [94%] of 16) than the grazoprevir plus ruzasvir plus uprifosbuvir 300 mg regimen (ten [71%] of 14), grazoprevir plus elbasvir plus uprifosbuvir 300 mg regimen (11 [69%] of 16), or grazoprevir plus elbasvir plus uprifosbuvir 450 mg regimen (nine [60%] of 15). Overall, the most common adverse events were headache (55 [23%] of 240), fatigue (47 [20%] of 240), and nausea (32 [13%] of 240). Two (<1%) of 240 participants had serious adverse events (pharyngeal abscess and keratitis), which were not considered drug related by the respective investigators. INTERPRETATION: These results support further evaluation of the three-drug direct-acting antiviral agent regimen of grazoprevir 100 mg plus ruzasvir 60 mg plus uprifosbuvir 450 mg among a more diverse HCV infected population, including those with compensated cirrhosis, previous treatment with an interferon-containing regimen, and HCV-HIV co-infection. FUNDING: Merck & Co, Inc. PMID- 28802818 TI - Schizophrenia and psychosis: Does changing the label change the beliefs? PMID- 28802819 TI - Increased prevalence of Toxoplasma gondii seropositivity in patients with treatment-resistant schizophrenia. PMID- 28802820 TI - Attenuated psychotic symptoms in children and adolescent offspring of patients with schizophrenia. PMID- 28802821 TI - Association of sex hormones with metabolic syndrome among Egyptian males. AB - BACKGROUND: Studies have shown that testosterone and estradiol (E2) are associated with metabolic syndrome (MetS). To our knowledge, few studies, if any about the association of endogenous sex hormones with MetS have been done in Egypt. AIM: To study the relation between endogenous sex hormones and MetS among Egyptian males. SUBJECTS AND METHOD: For the study, 80 Egyptian males were enrolled: 40 males with MetS and 40 healthy age-matched males. Anthropometric measurements and blood pressure were taken for both groups. FBG, TC, HDL-C, TG, testosterone, and E2 levels were determined; LDL-C was calculated. RESULTS: Males with MetS had significantly lower testosterone levels and significantly higher E2 levels compared to those without MetS (p value 0.0001). The lowest quartile of testosterone was most prevalent among males with MetS (19/40 males, 47.5%) compared to those without MetS (0/40 males, 0%, p value 0.011). Estradiol in the third quartile was most prevalent among males with MetS (19/40 males, 47.5%) compared to those without MetS (1/40 males, 2.5%, p value 0.0001). Serum testosterone and E2 levels were independent predictors of MetS with optimum cut off value (<=2.37ng/ml) for testosterone and (>16.78pg/ml) for E2. CONCLUSION: Endogenous testosterone and estradiol are independently associated with MetS with potential utility as predictors of MetS. PMID- 28802822 TI - Stillbirth prevalence in Brazil: an exploration of regional differences. AB - OBJECTIVE: Brazil is a large, heterogeneous, and diverse country, marked by social, economic, and regional inequalities. Stillbirth is a global concern, especially in low- and middle-income countries. This study investigated the prevalence and possible determinants of stillbirth in different regions of Brazil. METHODS: This is a cross-sectional study including all women of reproductive age who had had a pregnancy in the last five years, enrolled in the most recent Brazilian Demographic and Health Survey (DHS/PNDS-2006/07). Logistic regression was used to assess the association between region and other maternal characteristics and stillbirth risk. RESULTS: The prevalence of stillbirth in Brazil was 14.82 per 1000 births, with great variation by region of the country, and a higher prevalence among the most deprived. The North and Northeast regions had the highest odds of stillbirth compared to the Center-West, which persisted after adjustment for multiple confounders - including deprivation level and ethnicity. Low maternal age and maternal obesity were also related to higher odds of stillbirth. CONCLUSION: In Brazil, the region influences stillbirth risk, with much higher risk in the North and Northeast. Variation in socioeconomic level does not explain this finding. Further research on the subject should explore other possible explanations, such as antenatal care and type of delivery, as well as the role of the private and public health systems in determining stillbirth. Preventive strategies should be directed to these historically disadvantaged regions, such as guaranteeing access and quality of care during pregnancy and around the time of birth. PMID- 28802823 TI - Access to and use of health services as factors associated with neonatal mortality in the North, Northeast, and Vale do Jequitinhonha regions, Brazil. AB - OBJECTIVE: To analyze the factors associated with neonatal mortality related to health services accessibility and use. METHODS: Case-control study of live births in 2008 in small- and medium-sized municipalities in the North, Northeast, and Vale do Jequitinhonha regions, Brazil. A probabilistic sample stratified by region, population size, and information adequacy was generated for the choice of municipalities. Of these, all municipalities with 20,000 inhabitants or less were included in the study (36 municipalities), whereas the remainder were selected according to the probability method proportional to population size, totaling 20 cities with 20,001-50,000 inhabitants and 19 municipalities with 50,001-200,000 inhabitants. All deaths of live births in these cities were included. Controls were randomly sampled, considered as four times the number of cases. The sample size comprised 412 cases and 1772 controls. Hierarchical multiple logistic regression was used for data analysis. RESULTS: The risk factors for neonatal death were socioeconomic class D and E (OR=1.28), history of child death (OR=1.74), high-risk pregnancy (OR=4.03), peregrination in antepartum (OR=1.46), lack of prenatal care (OR=2.81), absence of professional for the monitoring of labor (OR=3.34), excessive time waiting for delivery (OR=1.97), borderline preterm birth (OR=4.09) and malformation (OR=13.66). CONCLUSION: These results suggest multiple causes of neonatal mortality, as well as the need to improve access to good quality maternal-child health care services in the assessed places of study. PMID- 28802824 TI - Highly accurate prediction of protein self-interactions by incorporating the average block and PSSM information into the general PseAAC. AB - It is a challenging task for fundamental research whether proteins can interact with their partners. Protein self-interaction (SIP) is a special case of PPIs, which plays a key role in the regulation of cellular functions. Due to the limitations of experimental self-interaction identification, it is very important to develop an effective biological tool for predicting SIPs based on protein sequences. In the study, we developed a novel computational method called RVM-AB that combines the Relevance Vector Machine (RVM) model and Average Blocks (AB) for detecting SIPs from protein sequences. Firstly, Average Blocks (AB) feature extraction method is employed to represent protein sequences on a Position Specific Scoring Matrix (PSSM). Secondly, Principal Component Analysis (PCA) method is used to reduce the dimension of AB vector for reducing the influence of noise. Then, by employing the Relevance Vector Machine (RVM) algorithm, the performance of RVM-AB is assessed and compared with the state-of-the-art support vector machine (SVM) classifier and other exiting methods on yeast and human datasets respectively. Using the fivefold test experiment, RVM-AB model achieved very high accuracies of 93.01% and 97.72% on yeast and human datasets respectively, which are significantly better than the method based on SVM classifier and other previous methods. The experimental results proved that the RVM-AB prediction model is efficient and robust. It can be an automatic decision support tool for detecting SIPs. For facilitating extensive studies for future proteomics research, the RVMAB server is freely available for academic use at http://219.219.62.123:8888/SIP_AB. PMID- 28802825 TI - The role of nuclear mechanics in cell deformation under creeping flows. AB - Despite the relevant regulatory role that nuclear deformation plays in cell behaviour, a thorough understanding of how fluid flow modulates the deformation of the cell nucleus in non-confined environments is lacking. In this work, we investigated the dynamics of cell deformation under different creeping flows as a general simulation tool for predicting nuclear stresses and strains. Using this solid-fluid modelling interaction framework, we assessed the stress and strain levels that the cell nucleus experiences as a function of different microenvironmental conditions, such as physical constraints, fluid flows, cytosol properties, and nucleus properties and size. Therefore, the simulation methodology proposed here allows the design of deformability-based experiments involving fluid flow, such as real-time deformability cytometry and dynamic cell culture in bioreactors or microfluidic devices. PMID- 28802826 TI - Human leptospirosis cases in Palermo Italy. The role of rodents and climate. AB - Many regions of the world are increasingly exposed to leptospirosis due to poverty, global warming and high urban density. Here, we report a molecular survey for pathogenic Leptospira spp. in rodents and two symptomatic human cases of leptospirosis in the city of Palermo, Italy. Four rodent species were captured in six areas of the city, and a molecular analysis for pathogenic Leptospira spp. on DNA from the kidney samples showed a different prevalence of leptospirosis in all the species of rodents. In addition, two human cases that occurred in May and October of 2009 in the city were also reported. A 67-year-old woman recovered after antibiotic treatment, whereas a 71-year-old woman did not survive. The weather during both of those times was notable for a violent cloudburst that caused street flooding. For the past several years, the incidence of leptospirosis has remained steady at 9 human cases every 10 years across the entire island of Sicily, with a population of almost 5 million inhabitants. The high prevalence of leptospirosis in rodents and the simultaneous presence of known risk factors, such as a mild/wet climate, street flooding and garbage accumulation, could explain the two cases of leptospirosis within the same city in the same year. This occurrence should raise awareness of this under-estimated zoonosis among public health authorities, especially given the potential fatality among elderly and immune-compromised individuals in urban settings in developed countries. PMID- 28802827 TI - The novel heme-dependent inducible protein, SRRD regulates heme biosynthesis and circadian rhythms. AB - Heme plays a role in the regulation of the expression of genes related to circadian rhythms and heme metabolism. In order to identify new heme-regulated proteins, an RNA sequence analysis using mouse NIH3T3 cells treated without or with 5-aminolevulinic acid (ALA) was performed. Among the changes observed in the levels of various mRNAs including heme oxygenase-1 (HO-1) and ALA synthase-1 (ALAS1), a mouse homologue of the plant circadian-regulating protein SRR1, SRR1 domain containing (SRRD) was induced by the ALA treatment. The expression of SRRD was dependent on heme biosynthesis, and increased the production of heme. SRRD was expressed under circadian rhythms, and influenced the expression of clock genes including PER2, BMAL1, and CLOCK. The knockout of SRRD arrested the growth of cells, indicating that SRRD plays roles in heme-regulated circadian rhythms and cell proliferation. PMID- 28802829 TI - Embryonic zebrafish primary cell culture for transfection and live cellular and subcellular imaging. AB - Although having great potential for live cell imaging to address numerous cell biological questions with high spatial and temporal resolution, primary cell cultures of zebrafish embryos are not widely used. We present an easy-to-use protocol for preparing primary cell cultures of 2 dpf zebrafish embryos allowing for live cell imaging of fully differentiated cells such as neurons and myocytes. We demonstrate that different cell types can be identified by morphology and expression of transgenic cell type-specific fluorescent reporters and that fluorescent cells can be sorted by flow cytometry to prepare an enriched culture. To facilitate subcellular imaging in live primary cells, we successfully tested a selection of fluorescent vital dyes. Most importantly, we demonstrate that zebrafish primary cells can be transfected efficiently with expression constructs allowing for visualizing subcellular structures with fluorescent marker proteins for time lapse imaging. We propose zebrafish primary cell culture as a versatile tool to address cell biological questions in combination with a powerful in vivo model. PMID- 28802828 TI - Photolyase: Dynamics and electron-transfer mechanisms of DNA repair. AB - Photolyase, a flavoenzyme containing flavin adenine dinucleotide (FAD) molecule as a catalytic cofactor, repairs UV-induced DNA damage of cyclobutane pyrimidine dimer (CPD) and pyrimidine-pyrimidone (6-4) photoproduct using blue light. The FAD cofactor, conserved in the whole protein superfamily of photolyase/cryptochromes, adopts a unique folded configuration at the active site that plays a critical functional role in DNA repair. Here, we review our comprehensive characterization of the dynamics of flavin cofactor and its repair photocycles by different classes of photolyases on the most fundamental level. Using femtosecond spectroscopy and molecular biology, significant advances have recently been made to map out the entire dynamical evolution and determine actual timescales of all the catalytic processes in photolyases. The repair of CPD reveals seven electron-transfer (ET) reactions among ten elementary steps by a cyclic ET radical mechanism through bifurcating ET pathways, a direct tunneling route mediated by the intervening adenine and a two-step hopping path bridged by the intermediate adenine from the cofactor to damaged DNA, through the conserved folded flavin at the active site. The unified, bifurcated ET mechanism elucidates the molecular origin of various repair quantum yields of different photolyases from three life kingdoms. For 6-4 photoproduct repair, a similar cyclic ET mechanism operates and a new cyclic proton transfer with a conserved histidine residue at the active site of (6-4) photolyases is revealed. PMID- 28802830 TI - GFAP in early multiple sclerosis: A biomarker for inflammation. AB - OBJECTIVE: The role of Glial Fibrillic Acidic Protein (GFAP) as a potential biomarker for relapsing-remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS) has been controversially discussed. The aim was to characterize the added value of GFAP levels in the CSF of RRMS and CIS patients in correlation with MRI lesion load. MATERIALS & METHODS: GFAP levels in the CSF from 18 patients with RRMS, 8 patients with CIS and 35 controls were analyzed together with MRI data for acute and chronic inflammatory lesion load. RESULTS: GFAP levels of patients vs. controls were higher (p=0.005), while there was no difference between GFAP levels in RRMS and CIS. There was no correlation between the number of supra- or infratentorial gadolinium enhancing lesions and GFAP levels, while there was a correlation between GFAP levels with infratentorial chronic inflammatory lesion load (p=0.0035). Most importantly, a highly significant correlation could be observed between GFAP levels and the intensity of gadolinium-enhancement as a parameter for the acute activity of inflammatory processes (p=0.0002). CONCLUSIONS: GFAP seems to be a useful biomarker for highly active acute inflammation in patients with RRMS as well as with CIS. PMID- 28802831 TI - Validation of a Targeted RNA Sequencing Assay for Kinase Fusion Detection in Solid Tumors. AB - Kinase gene fusions are important drivers of oncogenic transformation and can be inhibited with targeted therapies. Clinical grade diagnostics using RNA sequencing to detect gene rearrangements in solid tumors are limited, and the few that are available require prior knowledge of fusion break points. To address this, we have analytically validated a targeted RNA sequencing assay (OSU SpARKFuse) for fusion detection that interrogates complete transcripts from 93 kinase and transcription factor genes. From a total of 74 positive and 36 negative control samples, OSU-SpARKFuse had 93.3% sensitivity and 100% specificity for fusion detection. Assessment of repeatability and reproducibility revealed 96.3% and 94.4% concordance between intrarun and interrun technical replicates, respectively. Application of this assay on prospective patient samples uncovered OLFM4 as a novel RET fusion partner in a small-bowel cancer and led to the discovery of a KLK2-FGFR2 fusion in a patient with prostate cancer who subsequently underwent treatment with a pan-fibroblast growth factor receptor inhibitor. Beyond fusion detection, OSU-SpARKFuse has built-in capabilities for discovery research, including gene expression analysis, detection of single nucleotide variants, and identification of alternative splicing events. PMID- 28802832 TI - Retroviral gene transfer into primary human NK cells activated by IL-2 and K562 feeder cells expressing membrane-bound IL-21. AB - Natural killer (NK) cells are capable of rapidly recognizing and efficiently killing tumor cells. This makes them a potentially promising agent for cancer immunotherapy. Additional genetic modifications of NK cells may further improve their anti-tumor efficacy. Numerous technical challenges associated with gene delivery into NK cells have significantly tempered this approach. We achieved efficient retroviral vector transduction of primary human NK cells that were stimulated by a combination of IL-2 and engineered K562 cells expressing membrane bound IL-21. The activated NK cells were in less differentiated state and expressed NK cell activation receptors NKG2D, NKp30, CD16, and were highly HLA-DR positive. This NK cell population was highly susceptible to the transduction by both GFP- and NGFR-expressing retroviral vectors, with transduction efficiency exceeding 50%. More mature CD57+ NK cell population was generally resistant to retroviral vector transduction because of poor response to the stimulation. Our findings may facilitate retroviral vector-mediated genetic engineering of human primary NK cells for future immunotherapies. PMID- 28802834 TI - Vegetable-derived bioactive nitrate and cardiovascular health. AB - Vegetable derived nitrate is now recognised as an important bioactive phytochemical with cardioprotective properties. Nitrate, through the recently described enterosalivary nitrate-nitrite-nitric oxide (NO) pathway, increases NO, a molecule pivotal for cardiovascular health. Clinical trials have observed that dietary nitrate has similar effects to NO when supplied exogenously. These effects include reduced blood pressure and improvements in other markers of vascular health such as endothelial function, arterial stiffness, ischemia reperfusion injury, blood flow, and platelet aggregation. Few observational studies, however, have examined dietary nitrate intake and long term cardiovascular health outcomes. This represents a significant gap in the literature. There is also a lingering concern about a possible carcinogenic effect of nitrate intake. Additionally, a number of potential factors that could impact nitrate to nitrite to NO reduction have been identified. This review will provide an overview of the evidence to date that nitrate, through its effects on endogenous NO and vascular health, is an important bioactive cardioprotective component of a diet rich in vegetables. PMID- 28802836 TI - Neocortical prodynorphin expression is transiently increased with learning: Implications for time- and learning-dependent neocortical kappa opioid receptor activation. AB - There are several lines of evidence that indicate a prominent role for the opioid system in the acquisition and consolidation of learned associations. Specifically, kappa opioid receptor (KOR) modulation has been demonstrated to alter various behavioral tasks including whisker trace eyeblink conditioning (WTEB). WTEB is an associative conditioning paradigm in which a neutral conditioned stimulus (CS; Whisker stimulation) is paired following a short stimulus free trace interval with a salient unconditioned stimulus that elicits a blink response (US; Eye shock). Work from our laboratory has shown that WTEB conditioning is dependent upon and induces plasticity in primary somatosensory cortex (S1), a likely site for memory storage. Our subsequent studies have shown that WTEB acquisition or consolidation are impaired when the initial or later phase of KOR activation in S1 is respectively blocked. Interestingly, this mechanism by which KOR is activated in S1 during learning remains unexplored. Dynorphin (DYN), KOR's endogenous ligand, is synthesized from the precursor prodynorphin (PD) that is synthesized from preprodynorphin (PPD). In S1, most PPD is found in inhibitory GABAergic somatostatin interneurons (SOM), suggesting that these SOM interneurons are upstream regulators of learning induced KOR activation. Using immunofluorescence to investigate the expression of PD and SOM, the current study found that PD/SOM expression was transiently increased in S1 during learning. Interestingly, these findings have direct implications towards a time- and learning-dependent role for KOR activation in neocortical mechanisms mediating learning. PMID- 28802837 TI - Development of simulation optimization methods for solving patient referral problems in the hospital-collaboration environment. AB - This research studied a patient referral problem among multiple cooperative hospitals for sharing imaging services' referrals. The proposed problem consisted of many types of patients and the uncertainty associated with the number of patients of each type, patients' arrival time, and patients' medical operation time, leading to a difficulty in finding solutions due to the uncertain environment. This research used system simulation to construct a model and develop a simulation optimization method, combining the heuristic algorithm (patient referral mechanism) with the particle swarm optimization (PSO) method, to determine a better way to refer patients from one hospital (referring hospital) to another (recipient hospital) to receive certain imaging services. After the simulated model was verified and validated, three patient referral mechanisms to dispatch referring patients to the appropriate recipient hospitals were proposed. Based on the numerical results, the findings showed that Mechanism 2, transferring patients to the hospital with the shortest waiting time, had good performance in both scenarios: allowing patient referrals among all hospitals and limiting the patients' waiting time. Finally, this study presents the conclusions and some directions for future research. PMID- 28802835 TI - Residues in the eighth transmembrane domain of the proton-coupled folate transporter (SLC46A1) play an important role in defining the aqueous translocation pathway and in folate substrate binding. AB - The proton-coupled folate transporter (PCFT-SLC46A1) is required for intestinal folate absorption and folate transport across the choroid plexus. This report addresses the structure/function of the 8th transmembrane helix. Based upon biotinylation of cysteine-substituted residues by MTSEA-biotin, 14 contiguous exofacial residues to Leu316 were accessible to the extracellular compartment of the 23 residues in this helix (Leu303-Leu325). Pemetrexed blocked biotinylation of six Cys-substituted residues deep within the helix implicating an important role for this region in folate binding. Accessibility decreased at 4 degrees C vs RT. The influx Kt, Ki and Vmax were markedly increased for the P314C mutant, similar to what was observed for Y315A and Y315P mutants. However, the Kt, alone, was increased for the P314Y mutant. To correlate these observations with PCFT structural changes during the transport cycle, homology models were built for PCFT based upon the recently reported structures of bovine and rodent GLUT5 fructose transporters in the inward-open and outward- open conformations, respectively. The models predict substantial structural alterations in the exofacial region of the eighth transmembrane helix as it cycles between its conformational states that can account for the extended and contiguous aqueous accessibility of this region of the helix. Further, a helix break in one of the two conformations can account for the critical roles Pro314 and Tyr315, located in this region, play in PCFT function. The data indicates that the 8th transmembrane helix of PCFT plays an important role in defining the aqueous channel and the folate binding pocket. PMID- 28802833 TI - New pro-resolving n-3 mediators bridge resolution of infectious inflammation to tissue regeneration. AB - While protective, the acute inflammatory response when uncontrolled can lead to further tissue damage and chronic inflammation that is now widely recognized to play important roles in many commonly occurring diseases, such as cardiovascular disease, neurodegenerative diseases, metabolic syndrome, and many other diseases of significant public health concern. The ideal response to initial challenges of the host is complete resolution of the acute inflammatory response, which is now recognized to be a biosynthetically active process governed by specialized pro resolving mediators (SPM). These chemically distinct families include lipoxins, resolvins, protectins and maresins that are biosynthesized from essential fatty acids. The biosynthesis and complete stereochemical assignments of the major SPM are established, and new profiling procedures have recently been introduced to document the activation of these pathways in vivo with isolated cells and in human tissues. The active resolution phase leads to tissue regeneration, where we've recently identified new molecules that communicate during resolution of inflammation to activate tissue regeneration in model organisms. This review presents an update on the documentation of the roles of SPMs and the biosynthesis and structural elucidation of novel mediators that stimulate tissue regeneration, coined conjugates in tissue regeneration. The identification and actions of the three families, maresin conjugates in tissue regeneration (MCTR), protectin conjugates in tissue regeneration (PCTR), and resolvin conjugates in tissue regeneration (RCTR), are reviewed here. The identification, structural elucidation and the pathways and biosynthesis of these new mediators in tissue regeneration demonstrate the host capacity to protect from collateral tissue damage, stimulate clearance of bacteria and debris, and promote tissue regeneration via endogenous pathways and molecules in the resolution metabolome. PMID- 28802838 TI - Identification of immune correlates of protection in Shigella infection by application of machine learning. AB - BACKGROUND: Immunologic correlates of protection are important in vaccine development because they give insight into mechanisms of protection, assist in the identification of promising vaccine candidates, and serve as endpoints in bridging clinical vaccine studies. Our goal is the development of a methodology to identify immunologic correlates of protection using the Shigella challenge as a model. METHODS: The proposed methodology utilizes the Random Forests (RF) machine learning algorithm as well as Classification and Regression Trees (CART) to detect immune markers that predict protection, identify interactions between variables, and define optimal cutoffs. Logistic regression modeling is applied to estimate the probability of protection and the confidence interval (CI) for such a probability is computed by bootstrapping the logistic regression models. RESULTS: The results demonstrate that the combination of Classification and Regression Trees and Random Forests complements the standard logistic regression and uncovers subtle immune interactions. Specific levels of immunoglobulin IgG antibody in blood on the day of challenge predicted protection in 75% (95% CI 67 86). Of those subjects that did not have blood IgG at or above a defined threshold, 100% were protected if they had IgA antibody secreting cells above a defined threshold. Comparison with the results obtained by applying only logistic regression modeling with standard Akaike Information Criterion for model selection shows the usefulness of the proposed method. CONCLUSION: Given the complexity of the immune system, the use of machine learning methods may enhance traditional statistical approaches. When applied together, they offer a novel way to quantify important immune correlates of protection that may help the development of vaccines. PMID- 28802839 TI - Prevalence, patterns, and predictors of massage practitioner utilization: Results of a US nationally representative survey. AB - BACKGROUND: The use of massage therapy is common, especially in patients with musculoskeletal pain. The purpose of this study was to examine the prevalence, utilization, socio-demographic and health-related predictors of massage practitioner consultations in the US population. METHODS: Cross-sectional data from the 2012 National Health Interview Survey for adults (n = 34,525). RESULTS: Prevalence of massage practitioner utilization were 12.8% (lifetime) and 6.8% (last 12 months). Compared to non-users, those who used massage in the last year were more likely: female, at least high school educated, annual income >= US$ 15,000, diagnosed with spinal pain or arthritis, report moderate physical activity level as compared to low level, and consume alcohol as compared to being abstinent. Massage was mainly used for general wellness or disease prevention (56.3%), but also for specific, typically musculoskeletal, health problems (41.9%) for which 85.2% reported massage helped to some or a great deal. Most (59.1%) did not disclose massage use to their health care provider, despite 69.4% reporting massage therapy combined with medical treatment would be helpful. CONCLUSIONS: Approximately 7% (15.4 million) of US adults used massage therapy in the past year, mainly for general disease prevention, wellness or musculoskeletal pain. The majority of respondents reported positive outcomes of massage on specific health problems and overall well-being. Massage utilization was rarely covered by health insurance. Despite the majority of massage users considered massage therapy combined with medical care helpful, most did not disclose massage therapy use to their health care provider. PMID- 28802840 TI - Clinical effectiveness of geriatric assessment for predicting the tolerability of outpatient chemotherapy in older adults with cancer. PMID- 28802841 TI - Effects of symbiotic status on cellular immunity dynamics in Sitophilus oryzae. AB - Many insects maintain intracellular symbiosis with mutualistic bacteria that improve their adaptive capabilities in nutritionally poor habitats. Adaptation of insect immune systems to such associations has been shown in several symbiotic consortia, including that of the rice weevil Sitophilus oryzae with the gammaproteobacterium Sodalis pierantonius. Although authors have mostly focused on the role of humoral immunity in host-symbiont interactions, recent studies suggest that symbiotic bacteria may also interfere with the cellular, hemocyte based, immunity. Here, we have explored hemocyte dynamics in S. oryzae in the presence or absence of S. pierantonius, and in response to bacterial challenges. We have identified five morphotypes within larval hemocytes, whose abundance and morphometry drastically change along insect development. We show that hemocytes make part of the weevil immune system by responding to pathogenic infections. In contrast with previous results on other insect species, however, our analyses did not reveal any symbiotic-dependent modulation of the hemocyte global population. PMID- 28802843 TI - Co-concentration effect of silane with natural extract on biodegradable polymeric films for food packaging. AB - Novel biodegradable films were prepared by blending guar gum, chitosan and poly (vinyl alcohol) having mint (ME) and grapefruit peel (GE) extracts and crosslinked with nontoxic tetraethoxysilane (TEOS). The co-concentration effect of TEOS with natural extracts on the films was studied. FTIR analysis confirmed the presence of incorporated components and the developed interactions among the polymer chains. The surface morphology of the films by SEM showed the hydrophilic character due to porous network structure. The films having both ME and GE with maximum amount of crosslinker (100MUL), showed maximum swelling (58g/g) and stability while the optical properties showed increased protection against UV light. This film sample showed compact network structure which enhanced the ultimate tensile strength (40.03MPa) and elongation at break (104.8%). ME/GE conferred the antioxidant properties determined by radical scavenging activity and total phenolic contents (TPC) as ME films have greater TPC compared to GE films. The soil burial test exhibited the degradation of films rapidly (6days) confirming their strong microbial activity in soil. The lower water vapour transmission rate and water vapour permeability showed better shelf life; hence, these biodegradable films are environmental friendly and have potential for food and other packaging. PMID- 28802844 TI - Structural basis for Cullins and RING component inhibition: Targeting E3 ubiquitin pathway conductors for cancer therapeutics. AB - Cullin (CUL)-RING E3 ubiquitin ligases (CRLs) are attractive therapeutic targets as they regulate diverse biological processes important for cancer cell survival by conferring substrate selectivity for ubiquitination and degradation. Given the complexity of CRL complexes, steps toward the structure-based design of small molecule inhibitors to modulate their activity have remained elusive. In this study, we explored the structural assembly and interaction details of closely related CUL scaffolds (CUL1, CUL2, CUL3, CUL4A, CUL4B, CUL5 and CUL7) with RBX1 to screen potent small molecules against CRLs. The RING-Box (RBX1 and RBX2) proteins heterodimerize with CULs and dynamically facilitate the ubiquitination process. The docked complexes of conserved CUL C-terminal domains exhibited a common RBX1 binding pattern through the incorporation of intermolecular beta sheet and alpha/beta core, stabilized by hydrophobic contacts. The comparative binding pattern analysis of CUL-RBX1 interfaces revealed a unique structural motif (VLYRLWLN) that directs the binding of RBX1 N-terminal beta-strand. Through reinvigorating the subtle structural dynamics of bound complexes and application of structure-based drug design approaches, we proposed a set of inhibitors which could be further optimized to target CRL activity. One reference compound (C64) was extensively characterized for selective binding at the RBX1-binding grooves/VLYRLWLN of CUL1-7. We speculate that mechanistic information of the individual residual contributions through structure-guided approaches could be pivotal for the rational design of more promising and active drug candidates against CRLs. PMID- 28802845 TI - Fluorescence quenching, structural and unfolding studies of a purified cysteine protease, ZCPG from Zingiber montanum rhizome. AB - A first attempt was made to study the fluorescence quenching, structure and unfolding nature of the purified Zingiber montanum (J.Koenig) Link ex A.Dietr. cysteine protease glycoprotein (ZCPG). ATR-IR spectra showed the presences of amide groups along with carbohydrate stretch indicating the glycoprotein nature. UV-vis spectra determined the presences of peptide groups and aromatic sidechains of tyrosine, tryptophan and phenylalanine. Far UV-Circular Dichroism spectrum revealed that the secondary structure consists of 47.6% alpha-helix, 14.1% beta sheet, 16.1% beta-turn, and 22.2% random coil. CD signals revealed pronounced structural stability until 70 degrees C followed by a significant variation in the secondary structure content in the transition temperature between 80-90 degrees C. ZCPG retained most of its secondary structure in the pH range of 3.0 10.0. The extrinsic study shows that at pH 2.0, ZCPG revealed characteristics of a molten globule-like state exhibiting strong ANS binding. The effect of GdnHCl on ZCPG evaluated by far-CD emission maximum and fluorescence emission revealed that the unfolding was incomplete determining the stability of the protein. The microenvironment of the tryptophan residues indicated the presence of relatively exposed single tryptophan residue (per monomer) with positively charged side chains. PMID- 28802846 TI - Effect of domestic cooking on the starch digestibility, predicted glycemic indices, polyphenol contents and alpha amylase inhibitory properties of beans (Phaseolis vulgaris) and breadfruit (Treculia africana). AB - The effect of processing on starch digestibility, predicted glycemic indices (pGI), polyphenol contents and alpha amylase inhibitory properties of beans (Phaseolis vulgaris) and breadfruit (Treculia africana) was studied. Total starch ranged from 4.3 to 68.3g/100g, digestible starch ranged from 4.3 to 59.2 to 65.7g/100g for the raw and processed legumes; Resistance starch was not detected in most of the legumes except in fried breadfruit and the starches in both the raw and processed breadfruit were more rapidly digested than those from raw and cooked beans. Raw and processed breadfruit had higher hydrolysis curves than raw and processed beans with the amylolysis level in raw breadfruit close to that of white bread. Raw beans had a low glycemic index (GI); boiled beans and breadfruit had intermediate glycemic indices respectively while raw and fried breadfruit had high glycemic indices. Aqueous extracts of the food samples had weak alpha amylase inhibition compared to acarbose. The raw and processed legumes contained considerable amounts of dietary phenols and flavonoids. The significant correlation (r=0.626) between alpha-amylase inhibitory actions of the legumes versus their total phenolic contents suggests the contribution of the phenolic compounds in these legumes to their alpha-amylase inhibitory properties. PMID- 28802847 TI - Structural, antioxidant and antibacterial activities of polysaccharides extracted from olive leaves. AB - In the present study, hot-water extraction procedure was used to recover polysaccharides from olive leaves. Primary structural characteristics were determined by nuclear magnetic resonance spectroscopy (1H NMR and 13C NMR), Fourier Transform-Infrared spectroscopy (FT-IR) and X-ray diffractometry analysis. Emulsifying capacity, Zeta (zeta) potential and differential scanning calorimetric (DSC) of olive leaf polysaccharides (OLP) were investigated. Antioxidant and antibacterial activities were then examined. Infrared spectroscopy data revealed that OLP were constituted of functional groups OH, CO and CH which were specific to polysaccharides. Results of zeta-potential showed that OLP possessed an anionic structure and exhibited donated electron capacities. OLP displayed strong DPPH-radical scavenging activity (IC 50=34.80MUg/mL). They showed also important reducing power and beta-carotene bleaching inhibition activities. Besides, OLP have attractive antibacterial activity against S.enterica and M.luteus with inhibition zones of 23.5 and 21.5mm, respectively. PMID- 28802842 TI - The role of G protein-coupled receptors in lymphoid malignancies. AB - B cell lymphoma consists of multiple individual diseases arising throughout the lifespan of B cell development. From pro-B cells in the bone marrow, through circulating mature memory B cells, each stage of B cell development is prone to oncogenic mutation and transformation, which can lead to a corresponding lymphoma. Therapies designed against individual types of lymphoma often target features that differ between malignant cells and the corresponding normal cells from which they arise. These genetic changes between tumor and normal cells can include oncogene activation, tumor suppressor gene repression and modified cell surface receptor expression. G protein-coupled receptors (GPCRs) are an important class of cell surface receptors that represent an ideal target for lymphoma therapeutics. GPCRs bind a wide range of ligands to relay extracellular signals through G protein-mediated signaling cascades. Each lymphoma subgroup expresses a unique pattern of GPCRs and efforts are underway to fully characterize these patterns at the genetic level. Aberrations such as overexpression, deletion and mutation of GPCRs have been characterized as having causative roles in lymphoma and such studies describing GPCRs in B cell lymphomas are summarized here. PMID- 28802848 TI - Structure and intracellular antioxidant activity of pectic polysaccharide from acerola (Malpighia emarginata). AB - Malpighia emarginata is a tropical fruit plant, found naturally in the Caribbean islands and South America that produces an edible fruit known as acerola or Barbados Cherry. Its polysaccharides were obtained by aqueous extraction, subjected to a freezing and thawing process and ultrafiltration. A homogeneous fraction (ACWS-01E) was analyzed by sugar composition, HPSEC, methylation and NMR spectroscopy analyses. The results showed an arabinan-rich pectic polysaccharide, with 6.1*104g/mol and formed mainly by a high methyl esterified (DM=86%) homogalacturonan and branched arabinan. This latter is anchored in type I rhamnogalacturonan regions. The main chain of arabinan consisted of (1->5)-linked alpha-Araf, branched only at O-3. The potential ACWS-01E intracellular antioxidant activity against H2O2-induced oxidative stress in murine fibroblast cell line (3T3) was determined by DCFH-DA assay. The treatment with ACWS-01E significantly reduced H2O2-induced cytotoxic effect and the levels of reactive oxygen species (ROS). These findings suggested that ACWS-01E protected and improved NIH 3T3 cell viability from H2O2-induced toxicity by decreasing intracellular levels of ROS. PMID- 28802849 TI - Silk fibroin/chitosan scaffold with tunable properties and low inflammatory response assists the differentiation of bone marrow mesenchymal stem cells. AB - The physical and chemical properties of the scaffold are known to play important roles in three-dimensional (3D) cell culture, which always determine the cellular fate or the results of implantation. To control these properties becomes necessary for meeting the requirements of a variety of tissue engineering applications. In this study, a series of silk fibroin/chitosan (SF/CS) scaffolds with tunable properties were prepared using freeze-drying method, and the rat bone marrow-derived mesenchymal stem cells (BM-MSCs) were seeded in these scaffolds to evaluate their availability of use in tissue engineering. The 3D structure, mechanical properties and degradation ability of SF/CS scaffold can be tuned by changing the total concentration of the precursor solution and the blending ratio between SF and CS. BM-MSCs cultured in the SF/CS scaffold exhibited excellent proliferation and multiple morphologies. The induction of osteogenic and adipogenic differentiation of BM-MSCs were successful in this scaffold when cultured in vitro. Subcutaneous implantation of the SF/CS scaffolds did not cause any inflammatory response within four weeks, which revealed good compatibility. Moreover, the implanted scaffold allowed host cells to invade, adhere, grow and form new blood vessels. With these excellent performance, SF/CS scaffold has great potential in preparing implants for tissue engineering applications. PMID- 28802850 TI - Thermo-sensitive chitosan copolymer-gold hybrid nanoparticles as a nanocarrier for delivery of erlotinib. AB - Here, using (poly(N-isopropylacrylamide)-co-oleic acid)-g-chitosan ((PNIPAAm-co OA)-g-CS), CS copolymer-gold hybrid nanoparticles (CGH NPs) were synthesized by autoreduction of auric cations (HAuCl4) in aqueous solution in the absence of any other reducing agent. The engineered thermo-sensitive CS copolymer with free amino groups could reduce auric cations and stabilized the resultant NPs. CGH NPs were prepared using different concentrations of CS copolymer (0.1-1% w/v) and HAuCl4 (50-500MUL, 0.2% w/v). They were characterized in terms of structure, surface Plasmon band, zeta potential, atomic absorption, stability, size and size distribution. The obtained CGH NPs showed a size range of 80-100nm and high stability at different pHs with no observable agglomeration/sedimentation for couple of months. The loading efficiency of erlotinib (ETB) in the CGH NPs was about 30%. The ETB was released from the CGH NPs in a thermo-responsive manner. FACS flow cytometry analysis confirmed high cellular uptake (85.81%) of CGH NPs by A549 cells. The cytotoxicity evaluations proved the cytocompatibility and high anti-tumor effect of the engineered CGH NPs. Based on these findings, having used thermo-sensitive CS copolymer, CGH NPs were obtained in one-pot procedure, which could be considered as stimuli-responsive delivery system with potential biomedical applications. PMID- 28802851 TI - Does hydroxyapatite coating of uncemented cups improve long-term survival? An analysis of 28,605 primary total hip arthroplasty procedures from the Nordic Arthroplasty Register Association (NARA). AB - OBJECTIVE: It is unclear whether hydroxyapatite (HA) coating of uncemented cups used in primary total hip arthroplasty (THA) improves bone ingrowth and reduces the risk of aseptic loosening. We therefore investigated survival of different uncemented cups that were available with or without HA coating. METHOD: We investigated three different cup types used with or without HA coating registered in the Nordic Arthroplasty Register Association (NARA) database that were inserted due to osteoarthritis (n = 28,605). Cumulative survival rates and adjusted hazard ratios (HRs) for the risk of revision were calculated. RESULTS: Unadjusted 13-year survival for cup revision due to aseptic loosening was 97.9% (CI: 96.5-99.4) for uncoated and 97.8% (CI: 96.3-99.4) for HA-coated cups. Adjusted HRs were 0.66 (CI 0.42-1.04) for the presence of HA coating during the first 10 years and 0.87 (CI 0.14-5.38) from year 10-13, compared with uncoated cups. When considering the endpoint cup revision for any reason, unadjusted 13 year survival was similar for uncoated (92.5% [CI: 90.1-94.9]) and HA-coated (94.7% [CI: 93.2-96.3]) cups. The risk of revision of any component due to infection was higher in THA with HA-coated cups than in THA with uncoated cups (adjusted HR 1.4 [CI 1.1-1.9]). CONCLUSIONS: HA-coated cups have a similar risk of aseptic loosening as uncoated cups, thus the use of HA coating seems to not confer any added value in terms of implant stability. The risk of infection seemed higher in THA with use of HA-coated cups, an observation that must be investigated further. PMID- 28802852 TI - Autophagy regulates accumulation and functional activity of granulocytic myeloid derived suppressor cells via STAT3 signaling in endotoxin shock. AB - Autophagy extensively participates in immune responses and inflammatory diseases. Myeloid-derived suppressor cells (MDSCs) are derived from CD11b+Gr1+ cells under pathological conditions and play an immunosuppressive role in the pathogenesis of cancer and inflammatory diseases. However, the role of autophagy in regulating the accumulation and activity of MDSCs remains unknown. In the present study, we evaluated the effects and mechanisms of autophagy on regulating accumulation and activity of MDSCs. We first found that granulocytic MDSCs (G-MDSCs), but not monocytic MDSCs (M-MDSCs), were accumulated in mice challenged by lipopolysaccharide (LPS) and showed an elevated autophagy activity. Pharmacological inhibition of autophagy significantly enhanced accumulation of G MDSCs in vivo and in vitro. Notably, inhibition of autophagy enhanced the immunosuppressive activity of G-MDSCs on M1 macrophage polarization by promoting reactive oxygen species (ROS) production. Inhibition of autophagy promotes the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in G-MDSCs, which is required for the accumulation and activity of MDSCs. In addition, in vivo pharmacological inhibition of autophagy significantly attenuated the condition of mice challenged by LPS. Thus, we conclude that inhibition of autophagy contributes to accumulation and immunosuppressive function of G-MDSCs by promoting the activation of STAT3 signaling, suggesting that autophagy may play a critical role in regulating accumulation and activity of MDSCs. Our study provides new insights into understanding the mechanisms of autophagy in regulating immune responses and pathogenesis of inflammatory diseases. PMID- 28802853 TI - Diversity not quantity in caregiver speech: Using computational modeling to isolate the effects of the quantity and the diversity of the input on vocabulary growth. AB - Children who hear large amounts of diverse speech learn language more quickly than children who do not. However, high correlations between the amount and the diversity of the input in speech samples makes it difficult to isolate the influence of each. We overcame this problem by controlling the input to a computational model so that amount of exposure to linguistic input (quantity) and the quality of that input (lexical diversity) were independently manipulated. Sublexical, lexical, and multi-word knowledge were charted across development (Study 1), showing that while input quantity may be important early in learning, lexical diversity is ultimately more crucial, a prediction confirmed against children's data (Study 2). The model trained on a lexically diverse input also performed better on nonword repetition and sentence recall tests (Study 3) and was quicker to learn new words over time (Study 4). A language input that is rich in lexical diversity outperforms equivalent richness in quantity for learned sublexical and lexical knowledge, for well-established language tests, and for acquiring words that have never been encountered before. PMID- 28802854 TI - Use of axenic media to determine antibiotic efficacy against coxiella burnetii. AB - The traditional methods of measuring minimum inhibitory concentration (MIC) of antibiotics against Coxiella burnetii are time-consuming and technically difficult. The discovery of axenic media for C. burnetii culture provided an opportunity to determine the feasibility of using both broth dilution and an antimicrobial gradient method (Etest) as a convenient method of measuring MICs. The MICs for a range of antibiotics that have proven or potential use in the treatment of Q fever, namely doxycycline, ciprofloxacin, levofloxacin, moxifloxacin and co-trimoxazole, were measured. It was possible to measure MICs using both microdilution and Etest methods. MICs obtained were comparable to those from other methods. This study demonstrates the potential use of a relatively simple test to measure MIC in an organism that is difficult to culture. PMID- 28802855 TI - Antifungal resistance in mucorales. AB - The order Mucorales, which includes the agents of mucormycosis, comprises a large number of species. These fungi are characterised by high-level resistance to most currently available antifungal drugs. Standardised antifungal susceptibility testing methods are now available, allowing a better understanding of the in vitro activity of antifungal drugs against members of Mucorales. Such tests have made apparent that antifungal susceptibility within this group may be species specific. Experimental animal models of mucormycosis have also been developed and are of great importance in bridging the gap between in vitro results and clinical trials. Amphotericin B, posaconazole and isavuconazole are currently the most active agents against Mucorales; however, their activity remains suboptimal and new therapeutic strategies are needed. Combination therapy could be a promising approach to overcome resistance, but further studies are required to confirm its benefits and safety for patients. PMID- 28802856 TI - Different mathematical processing of absorption, ratio and derivative spectra for quantification of mixtures containing minor component: An application to the analysis of the recently co-formulated antidiabetic drugs; canagliflozin and metformin. AB - In the presented work several spectrophotometric methods were performed for the quantification of canagliflozin (CGZ) and metformin hydrochloride (MTF) simultaneously in their binary mixture. Two of these methods; response correlation (RC) and advanced balance point-spectrum subtraction (ABP-SS) were developed and introduced for the first time in this work, where the latter method (ABP-SS) was performed on both the zero order and the first derivative spectra of the drugs. Besides, two recently established methods; advanced amplitude modulation (AAM) and advanced absorbance subtraction (AAS) were also accomplished. All the proposed methods were validated in accordance to the ICH guidelines, where all methods were proved to be accurate and precise. Additionally, the linearity range, limit of detection and limit of quantification were determined and the selectivity was examined through the analysis of laboratory prepared mixtures and the combined dosage form of the drugs. The proposed methods were capable of determining the two drugs in the ratio present in the pharmaceutical formulation CGZ:MTF (1:17) without the requirement of any preliminary separation, further dilution or standard spiking. The results obtained by the proposed methods were in compliance with the reported chromatographic method when compared statistically, proving the absence of any significant difference in accuracy and precision between the proposed and reported methods. PMID- 28802857 TI - Spectrophotometric methods for the determination of urea in real samples using silver nanoparticles by standard addition and 2nd order derivative methods. AB - In this work, we have developed simple, sensitive and inexpensive methods for the spectrophotometric determination of urea in urine samples using silver nanoparticles (AgNPs). The standard addition and 2nd order derivative methods were adopted for this purpose. AgNPs were prepared by chemical reduction of AgNO3 with hydrazine using 1,3-di-(1H-imidazol-1-yl)-2-propanol (DIPO) as a stabilizing agent in aqueous medium. The proposed methods were based on the complexation of AgNPs with urea. Using this concept, urea in the urine samples was successfully determined spectrophotometric methods. The results showed high percent recovery with +/-RSD. The recoveries of urea in the three urine samples by spectrophotometric standard addition were 99.2%+/-5.37, 96.3%+/-4.49, 104.88%+/ 4.99 and that of spectrophotometric 2nd order derivative method were 115.3%+/ 5.2, 103.4%+/-2.6, 105.93%+/-0.76. The results show that these methods can open doors for a potential role of AgNPs in the clinical determination of urea in urine, blood, biological, non-biological fluids. PMID- 28802858 TI - Effect of solvent on the electronic absorption spectral properties of some mixed beta-octasubstituted Zn(II)-tetraphenylporphyrins. AB - A series of mixed beta-octasubstituted Zn(II)-porphyrins, 2,3,12,13 tetra(chloro/cyano/methyl)-5,7,8,10,15,17,18,20-octaphenylporphinato zinc(II), ZnTPP(Ph)4X4 (X=CN, Cl and CH3) have been examined by electronic absorption spectroscopy in various solvents. These Zn(II)-porphyrins exhibited varying degree of red-shift of absorption bands as high as 20-30nm in 'B' band and 50 60nm in longest wavelength band, 'Q(0,0)' band in polar solvents relative to that found in nonpolar solvents. The red-shift of B and Q(0,0) bands showed an unusual trend, ZnTPP(Ph)4(CN)4>ZnTPP(Ph)4(CH3)4>ZnTPP(Ph)4Cl4 but fails to follow an anticipated anodic shift in first porphyrin ring oxidation (vs Ag/AgCl) potential: ZnTPP(Ph)4(CN)4 (1.02V)>ZnTPP(Ph)4Cl4 (0.74V)>ZnTPP(Ph)4(CH3)4 (0.38V). Such a trend suggests the combined effect of non-planarity of the macrocycle and electronic effect of the peripheral substituents. The equilibrium constants for the binding of nitrogenous bases with the Zn(II)-porphyrins showed as high as twenty fold increase for ZnTPP(Ph)4X4 (X=Br and CN) relative to ZnTPP(Ph)4(CH3)4 and follow the order: ZnTPP(Ph)4(CN)4>ZnTPP(Ph)4Br4>ZnTPP(Ph)4(CH3)4<=ZnTPP which is approximately in line with an increase in anodic shift of their first ring redox potentials (ZnTPP(Ph)4(CN)4 (1.02V)>ZnTPP(Ph)4Br4 (0.72V)>ZnTPP (0.84V)>ZnTPP(Ph)4(CH3)4) (0.38V). PMID- 28802859 TI - Special issue on meibomian glands. PMID- 28802860 TI - Upregulation of IL-9 and JAK-STAT signaling pathway in children with autism. AB - Autism spectrum disorder (ASD) gradually develops predominantly neurodevelopmental disorders, which are socially diagnosed in early childhood. Though the etiopathology of ASD is not clear, immune alteration has been suggested as autism's pathophysiological mechanism. Previous studies found that several cytokines and transcription factor activation pathways were significantly increased in ASD. IL-9 has been confirmed to play a significant role in the central nervous system (CNS). The aim of the present study was to investigate the understudied role of pro- and anti-inflammatory cytokines and the JAK-STAT signaling pathway in ASD. We examined the IL-1beta, IL-4, IFN-gamma, and IL-9 positive immunostaining in all cells, and CD4+ T cells, in ASD and normally developing control children (TD), on peripheral blood mononuclear cells (PBMCs), using flow cytometry. We explored PBMC mRNA expression levels for IL-1beta, IL-4, IFN-gamma, IL-9, JAK1, and STAT5, by using real-time PCR (RT-PCR). We also explored PBMC protein expression levels for IL-1beta, IL-4, IL-9, pJAK1, and pSTAT5 by using western blotting. We found that the children with ASD had increased IL-1beta, IL-4, IFN-gamma, and IL-9 positive immunostaining in all cells, and in CD4+ cells, relative to the TD controls. The mRNA and protein expression for IL-1beta, IL-4, IFN-gamma, IL-9, JAK1, pJAK1, STAT5, and pSTAT5 were also significantly elevated in ASD relative to TD controls. These results suggested that cytokines and JAK-STAT activation signaling have an essential role in immune dysfunction in ASD. PMID- 28802861 TI - Contrasting effects of vortioxetine and paroxetine on pineal gland biochemistry in a tryptophan-depletion model of depression in female rats. AB - We studied the effects of the multi-modal antidepressant, vortioxetine and the SSRI, paroxetine on pineal melatonin and monoamine synthesis in a sub-chronic tryptophan (TRP) depletion model of depression based on a low TRP diet. Female Sprague-Dawley rats were randomised to groups a) control, b) low TRP diet, c) low TRP diet+paroxetine and d) low TRP diet+vortioxetine. Vortioxetine was administered via the diet (0.76mg/kg of food weight) and paroxetine via drinking water (10mg/kg/day) for 14days. Both drugs resulted in SERT occupancies >90%. Vortioxetine significantly reversed TRP depletion-induced reductions of pineal melatonin and serotonin (5-HT) and significantly increased pineal noradrenaline NA. Paroxetine did none of these things. Other studies suggest pineal melatonin synthesis may involve N-methyl-d-aspartate (NMDA) receptors and glutamatergic modulation. Here observed changes may be mediated via vortioxetine's strong 5-HT reuptake blocking action together with possible additional effects on glutamate neurotransmission in the pineal via NMDA receptor-modulation and possibly with added impetus from increased NA output. PMID- 28802863 TI - Comparison of three different assays for measuring thyroglobulin and thyroglobulin antibodies in patients with chronic lymphocytic thyroiditis. AB - OBJECTIVE: To evaluate how thyroglobulin (Tg) and thyroglobulin antibody (TgAb) results compare among different chemiluminescence methods. METHODS: Serum specimens from 153 patients with thyroiditis and 127 apparently healthy individuals were collected at the Peking Union Medical College Hospital from September 2014 to December 2014. TgAb and Tg levels were analyzed by using three different platforms manufactured by Roche, Beckman, and Siemens. The chi2 test was performed to analyze the TgAb results from the different methods. Passing Bablok regression equations and Bland-Altman plots were used to estimate the relationship and bias among the Tg results obtained with the different analyses. RESULTS: The overall coincidence rates for the TgAb results were 82.9% between the Beckman and Roche methods, 78.6% between the Siemens and Roche methods, and 81.1% between the Siemens and Beckman methods. The borderline positive coincidence rate among the different TgAb methods was very poor (9.1-24.2%). Of the 280 samples, the TgAb results for 26.4% of the samples differed among the three CLIA platforms. A good linear relationship among the Tg levels was shown in TgAb-negative subjects analyzed with the different CLIA systems. However, for TgAb-positive subjects, the linear relationship of the Tg levels measured with the Siemens system, compared with the other two systems, was poor. Bland-Altman plots demonstrated significant differences among the different Tg assays. CONCLUSIONS: Current Tg and TgAb methods are highly variable and cannot be used interchangeably. PMID- 28802864 TI - beta3-Adrenergic receptor regulates hepatic apolipoprotein A-I gene expression. AB - BACKGROUND: beta3-adrenergic receptor (beta3-AR) was shown to upregulate hepatic apolipoprotein A-I (apoA-I) expression and reverse atherosclerotic plaques in vivo experiments. However, the effect of beta3-AR on apoA-I expression in vitro is unknown. The specific mechanism underlying beta3-AR prevention of atherosclerosis is unclear. OBJECTIVE: The present study was designed to investigate the molecular mechanism of beta3-AR-mediated regulation of hepatic apoA-I gene expression. METHODS: HepG2 cells were preincubated with/without a selective protein kinase A inhibitor (H-89) and then treated with a selective beta3-AR agonist (BRL37344) or antagonist (SR59230A). The hepatic apoA-I expression was detected by reverse transcription real-time quantitative polymerase chain reaction and Western blot analysis. Enzyme-linked immunosorbent assay was used to evaluate the secretion of apoA-I. A recombinant plasmid containing the apoA-I promoter was constructed and transiently transfected into HepG2 cells, and dual-luciferase reporter assays were used to examine the activity of the apoA-I promoter. A chromatin immunoprecipitation polymerase chain reaction assay was used to evaluate binding activities of hepatocyte nuclear factor-4 (HNF-4), HNF-3, and early growth response protein-1. RESULTS: beta3-AR activation significantly upregulated apoA-I expression, promoted apoA-I secretion, and enhanced the activities of the apoA-I promoter, HNF-4, and HNF-3 in hepatocytes, whereas early growth response protein-1 was not affected. Moreover, protein kinase A inhibition partially suppressed the activation of the apoA-I promoter, HNF-4, and HNF-3 and almost completely blocked the upregulation of apoA-I expression induced by beta3-AR. CONCLUSION: beta3-AR activation increased the activities of the apoA-I promoter, HNF-4, and HNF-3, which might account for the mechanism of beta3-AR-mediated upregulation of hepatic apoA-I expression. beta3-AR might exert an anti-atherosclerotic effect by upregulating hepatic apoA-I expression and promoting the cholesterol reverse transport process. PMID- 28802862 TI - MicroRNA-21: Expression in oligodendrocytes and correlation with low myelin mRNAs in depression and alcoholism. AB - MiR-21 is a microRNA implicated in cancer, development, and cardiovascular diseases and expressed in the central nervous system (CNS), especially after injury. However, the cellular expression of miR-21 in the adult CNS has not been clearly established either in mice or human subjects, while its alteration in psychiatric disorders is unknown. MiR-21 expression was characterized in reporter mice expressing beta-galactosidase (LacZ) under the endogenous miR-21 promoter (miR-21/LacZ). Brain co-localization of miR-21/LacZ with specific neural markers was examined by double immunofluorescence in reporter mice, while extent of immunostaining for myelin basic protein and PDGFRalpha was determined in miR-21 knockout and wild-type mice. Levels of miR-21, and mRNAs of selected miR-21 targets, miR-21 regulator STAT3 and myelin-related proteins were measured by qRT PCR in the white matter (WM) adjacent to the left postmortem orbitofrontal cortex (OFC) of human subjects with major depressive disorder (MDD), alcoholism, comorbid MDD plus alcoholism (MDA) and non-psychiatric control subjects. MiR 21/LacZ was highly expressed in cell bodies of WM and myelinated portions of gray matter (GM). Labeled cell bodies were identified as oligodendrocytes, while miR 21/LacZ was barely detectable in other cell types. MiR-21, as well as the mRNAs of several myelin-related proteins, were reduced in the WM of subjects with MDD and alcoholism. MiR-21 positively correlated with mRNA of myelin-related proteins and astrocytic GFAP. High expression of miR-21 in adult oligodendrocytes and the correlation of miR-21 decrease with mRNA of some myelin proteins, regulator STAT3, and oligodendrocyte-related transcription factors suggest an involvement of miR-21 in WM alterations in depression and alcoholism. PMID- 28802865 TI - Interleukin-13/interleukin-4 receptor pathway is crucial for production of Sda sialomucin in mouse small intestinal mucosa by Nippostrongylus brasiliensis infection. AB - Mucin is a major component of mucus in gastrointestinal mucosa. Increase of specific sialomucins having Sda blood group antigen, NeuAcalpha2-3(GalNAcbeta1 4)Galbeta1-4GlcNAcbeta-, is considered to be associated with expulsion of the parasitic intestinal nematode Nippostrongylus brasiliensis. In this study, we examined the relationship between interleukin (IL)-13 pathway and expression of Sda-sialomucins in small intestinal mucosa with N. brasiliensis infection. Nematode infection induced marked increases in small intestinal mucins that reacted with anti-Sda antibody in wild type (wt) mice. However, this increase due to infection was supressed in IL-4 receptor alpha deficient (IL-4Ralpha-/-) mice, which lack both IL-4 and IL-13 signaling via IL-4R, and severe combined immunodeficient (SCID) mice, which have defects in B- and T-lymphocytes. Analysis using tandem mass spectroscopy showed that Sda-glycans were not expressed in small intestinal mucins in IL-4Ralpha-/- and SCID mice after infection despite the appearance of Sda-glycans in the infected wt mice. Inoculation of recombinant IL-13 into the infected SCID mice restored expression of Sda-glycan. Our results suggest that the IL-13/IL-4R axis is important for the production of Sda sialomucins in the host intestinal mucosa with parasitic nematode infection. PMID- 28802867 TI - Novel single-cell technologies in acute myeloid leukemia research. AB - Acute myeloid leukemia (AML) is a lethal malignancy because patients who initially respond to chemotherapy eventually relapse with treatment refractory disease. Relapse is caused by leukemia stem cells (LSCs) that reestablish the disease through self-renewal. Self-renewal is the ability of a stem cell to produce copies of itself and give rise to progeny cells. Therefore, therapeutic strategies eradicating LSCs are essential to prevent relapse and achieve long term remission in AML. AML is a heterogeneous disease both at phenotypic and genotypic levels, and this heterogeneity extends to LSCs. Classical studies in AML have aimed at characterization of the bulk tumor population, thereby masking cellular heterogeneity. Single-cell approaches provide a novel opportunity to elucidate molecular mechanisms in heterogeneous diseases such as AML. In recent years, major advancements in single-cell measurement systems have revolutionized our understanding of the pathophysiology of AML and enabled the characterization of LSCs. Identifying the molecular mechanisms critical to AML LSCs will aid in the development of targeted therapeutic strategies to combat this deadly disease. PMID- 28802866 TI - Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2015-2016. AB - Four World Health Organization (WHO) Collaborating Centres for Reference and Research on Influenza and one WHO Collaborating Centre for the Surveillance, Epidemiology and Control of Influenza (WHO CCs) assessed antiviral susceptibility of 14,330 influenza A and B viruses collected by WHO-recognized National Influenza Centres (NICs) between May 2015 and May 2016. Neuraminidase (NA) inhibition assay was used to determine 50% inhibitory concentration (IC50) data for NA inhibitors (NAIs) oseltamivir, zanamivir, peramivir and laninamivir. Furthermore, NA sequences from 13,484 influenza viruses were retrieved from public sequence databases and screened for amino acid substitutions (AAS) associated with reduced inhibition (RI) or highly reduced inhibition (HRI) by NAIs. Of the viruses tested by WHO CCs 93% were from three WHO regions: Western Pacific, the Americas and Europe. Approximately 0.8% (n = 113) exhibited either RI or HRI by at least one of four NAIs. As in previous seasons, the most common NA AAS was H275Y in A(H1N1)pdm09 viruses, which confers HRI by oseltamivir and peramivir. Two A(H1N1)pdm09 viruses carried a rare NA AAS, S247R, shown in this study to confer RI/HRI by the four NAIs. The overall frequency of A(H1N1)pdm09 viruses containing NA AAS associated with RI/HRI was approximately 1.8% (125/6915), which is slightly higher than in the previous 2014-15 season (0.5%). Three B/Victoria-lineage viruses contained a new AAS, NA H134N, which conferred HRI by zanamivir and laninamivir, and borderline HRI by peramivir. A single B/Victoria-lineage virus harboured NA G104E, which was associated with HRI by all four NAIs. The overall frequency of RI/HRI phenotype among type B viruses was approximately 0.6% (43/7677), which is lower than that in the previous season. Overall, the vast majority (>99%) of the viruses tested by WHO CCs were susceptible to all four NAIs, showing normal inhibition (NI). Hence, NAIs remain the recommended antivirals for treatment of influenza virus infections. Nevertheless, our data indicate that it is prudent to continue drug susceptibility monitoring using both NAI assay and sequence analysis. PMID- 28802868 TI - Development and Implementation of an Ultrasound-Guided Peripheral Intravenous Catheter Program for Emergency Nurses. AB - PROBLEM: Emergency medical care often necessitates placement of peripheral intravenous (PIV) catheters. When traditional methods for obtaining PIV access are not successful, ultrasound guidance is a rescue technique for peripheral vascular placement that improves the quality of patient care. METHODS: The aim of this training program was to develop a process where emergency nurses would be competent to perform ultrasound guided PIV to improve the quality of patient care delivered while reducing throughput time. Administrative program development required creating a nursing practice statement, procedure guideline, operational plan, and competency validation. A training program comprising both didactic and hands-on training was developed and provided by emergency medicine physicians with formal ultrasound fellowship training. RESULTS: In determining whether the training program was adequate in preparing the student to place an ultrasound guided PIV, 92.9% of students "agreed" or "strongly agreed." In having confidence in their ability to obtain an ultrasound guided PIV catheter placement, 35.7% of respondents "agreed" and 64.3% "strongly agreed." In finding it difficult to be successful in achieving ultrasound guided PIV catheter placement, 71.4% of students "strongly disagreed" and 14.3% "disagreed." All students (100%) felt it was a feasible task to train nurses to successfully place ultrasound-guided PIV catheters and 71.4% of students strongly support continuing to provide this training program and competency validation. DISCUSSION: Establishment of an effective didactic and hands-on training program resulted in emergency department nurses becoming competent in placement of ultrasound guided PIV catheters to provide optimal patient care. PMID- 28802869 TI - Use of a Standardized Procedure to Improve Behavioral Health Patients' Care: A Quality Improvement Initiative. AB - PROBLEM: Meeting the complex needs of behavioral health (BH) patients in the emergency department is an ongoing challenge. Delays in care can have adverse consequences for patient and staff safety and delay transfer to specialized care. METHODS: A quality improvement, nurse-driven initiative using a standardized procedure (STP) was developed and implemented in our busy Southern California Emergency Department, which focused on improving time to first medication and reduction of restraints. The project used a multidisciplinary team to develop the STP scoring tool and corresponding medications. Improvement was seen in all quality metrics. Time to first medication decreased from 43 minutes to less than 5 minutes. Adopting the STP resulted in a 50% decrease in use of restraints and time in restraints. Staff injuries remained low, with less than 3.6% of staff sustaining physical injuries. DISCUSSION: The STP is an effective method to initiate immediate treatment of patients with signs of anxiety and aggression and thus reduce risk of violence. Additional benefits are reduced time to disposition and earlier initiation of specialized BH care. This process can be replicated in other emergency departments with similar clinical environments through the use of STPs or protocols based on state regulations. Contribution to Emergency Nursing Practice. PMID- 28802871 TI - Stack Locally and Act Globally: A Few Nucleotides Make All the Difference in Enterovirus 71 IRES Binding hnRNAP A1 and Infectious Phenotypes: Commentary on "HnRNP A1 Alters the Structure of a Conserved Enterovirus IRES Domain to Stimulate Viral Translation". PMID- 28802870 TI - Audio-visual synchrony and spatial attention enhance processing of dynamic visual stimulation independently and in parallel: A frequency-tagging study. AB - The neural processing of a visual stimulus can be facilitated by attending to its position or by a co-occurring auditory tone. Using frequency-tagging, we investigated whether facilitation by spatial attention and audio-visual synchrony rely on similar neural processes. Participants attended to one of two flickering Gabor patches (14.17 and 17 Hz) located in opposite lower visual fields. Gabor patches further "pulsed" (i.e. showed smooth spatial frequency variations) at distinct rates (3.14 and 3.63 Hz). Frequency-modulating an auditory stimulus at the pulse-rate of one of the visual stimuli established audio-visual synchrony. Flicker and pulsed stimulation elicited stimulus-locked rhythmic electrophysiological brain responses that allowed tracking the neural processing of simultaneously presented Gabor patches. These steady-state responses (SSRs) were quantified in the spectral domain to examine visual stimulus processing under conditions of synchronous vs. asynchronous tone presentation and when respective stimulus positions were attended vs. unattended. Strikingly, unique patterns of effects on pulse- and flicker driven SSRs indicated that spatial attention and audiovisual synchrony facilitated early visual processing in parallel and via different cortical processes. We found attention effects to resemble the classical top-down gain effect facilitating both, flicker and pulse driven SSRs. Audio-visual synchrony, in turn, only amplified synchrony-producing stimulus aspects (i.e. pulse-driven SSRs) possibly highlighting the role of temporally co-occurring sights and sounds in bottom-up multisensory integration. PMID- 28802872 TI - Smoking and binge-drinking among adolescents, Ontario, Canada: Does the school neighbourhood matter? AB - This study examines whether access to alcohol and tobacco around the school relates to higher or lower odds of cigarette smoking and binge-drinking among Ontario high school students. The 2013 Ontario Student Drug Use and Health Survey provides data on self-reported smoking and drinking, individual covariates and subjective socio-economic status for 6142 students (grades 9-12) in Ontario, Canada. Locations of schools were geocoded and 1.6km network buffers defined the school neighbourhoods. Multi-level logistic regression examines individual and school neighbourhood factors with smoking and binge drinking as the dependent variable. Higher density of retail outlets increased the odds of smoking, but not the odds of binge-drinking. Older age, lower SES and being male increased the odds of smoking; while older age and being male also increased the odds of binge drinking. Lower SES and higher population density decreased the odds of binge drinking. Proximity to tobacco and alcohol outlets was not significant. Findings showed that a greater number of outlets in the school neighbourhood is significantly associated with higher odds of smoking, but not binge-drinking. School neighbourhood access to tobacco outlets should be considered when formulating policy interventions to reduce smoking for adolescents. PMID- 28802873 TI - Gut check on diabesity: leveraging gut mechanisms for the treatment of type 2 diabetes and obesity. AB - Gut hormones have long been understood to regulate food intake and metabolism. Bariatric surgery significantly elevates circulating gut hormone levels and is proven to affect acute remission of type 2 diabetes before any weight loss is observed. Subsequent weight loss is accrued over weeks to months but is sustained into the long term. Hence, there exists great enthusiasm to recapitulate these changes in gut hormones in the form of novel combination drugs for type 2 diabetes and obesity. PMID- 28802874 TI - Targeting gastrointestinal nutrient sensing mechanisms to treat obesity. AB - Gut hormones have important roles in the regulation of appetite and glucose homeostasis. Understanding how macronutrient sensing in the gastrointestinal tract modulates gut hormone release may reveal novel pharmacological or dietary approaches to metabolic disease. In this short review we discuss the mechanisms by which the gut senses macronutrients and the products of macronutrient digestion, and their putative utility in treating obesity and related conditions. PMID- 28802875 TI - Primary sclerosing cholangitis - a comprehensive review. AB - Primary sclerosing cholangitis (PSC) is a rare disorder characterised by multi focal bile duct strictures and progressive liver disease. Inflammatory bowel disease is usually present and there is a high risk of cholangiocarcinoma and colorectal cancer. Most patients ultimately require liver transplantation, after which disease recurrence may occur. With limited therapeutic options and a lack of proven surveillance strategies, patients currently have significant unmet needs. In the present seminar, we provide a comprehensive review of the status of the field. We emphasise developments related to patient stratification and disease behaviour, and provide an overview of management options from a practical, patient-centered perspective. We survey advances made in the understanding of PSC pathogenesis and summarise the ongoing efforts to develop an effective therapy based on these insights. PMID- 28802876 TI - Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: A systematic review, meta-analyses, and meta-regression. AB - BACKGROUND & AIMS: The risk of hepatocellular carcinoma (HCC) occurrence or recurrence following direct-acting antiviral (DAA) hepatitis C virus (HCV) therapy remains unclear. The aims of this study were to compare the rate of HCC occurrence in patients with HCV-related cirrhosis, following DAA vs. interferon (IFN)-based cure, and to compare the rate of HCC recurrence in patients who received curative HCC treatment, following DAA vs. IFN-based cure. METHODS: A search was conducted for reports published between January 2000 and February 2017. Studies were included if they assessed HCC outcomes by type and response to HCV therapy. Random-effects meta-analyses were undertaken to determine a combined estimate of HCC incidence rate per 100/person-years (py) among patients with a sustained virological response (SVR). RESULTS: A total of 41 studies (n=13,875 patients), including 26 on HCC occurrence (IFN=17, DAA=9; prospective=19, retrospective=5, retrospective-prospective=2), and 17 on HCC recurrence (IFN=7, DAA=10; prospective=11, retrospective=5 and retrospective-prospective=1) were included. In studies assessing HCC occurrence, average follow-up was shorter (1.0 vs. 5.5years), and average age older (60 vs. 52years) in DAA studies. In studies assessing HCC recurrence, average follow-up was shorter (1.3 vs. 5.0years), but average age similar (64 vs. 66years) in DAA studies. HCC occurrence was 1.14/100 py (95% CI 0.86-1.52) and 2.96/100 py (95% CI 1.76-4.96) in IFN and DAA studies respectively. HCC recurrence was 9.21/100 py (95% CI 7.18-11.81) and 12.16/100 py (95% CI 5.00-29.58) in IFN and DAA studies respectively. In meta-regression adjusting for study follow-up and age, DAA therapy was not associated with higher HCC occurrence (RR 0.68; 95% CI 0.18-2.55; p=0.55) or recurrence (RR 0.62, 95% CI 0.11-3.45, p=0.56). CONCLUSION: There is no evidence for differential HCC occurrence or recurrence risk following SVR from DAA and IFN-based therapy. LAY SUMMARY: The risk of hepatocellular carcinoma (HCC) occurrence or recurrence following direct-acting antiviral (DAA) hepatitis C virus (HCV) therapy remains unclear. We conducted a meta-analysis to compare occurrence and recurrence of HCC in patients receiving either DAA or interferon (IFN) therapy. There is no evidence that HCC occurrence or recurrence is different between patients receiving DAA or IFN therapy. PMID- 28802877 TI - Declining mortality in critically ill patients with cirrhosis in Australia and New Zealand between 2000 and 2015. AB - BACKGROUND & AIMS: Few studies have described the outcomes of patients with cirrhosis receiving intensive care unit (ICU) admission at a population level. We aimed to describe trends in the mortality of such patients in Australia and New Zealand (ANZ), and to investigate the relationship with associated organ failures. METHODS: We studied patients admitted to 172 ICUs on a non-elective basis, with and without cirrhosis between January 1st 2000 and December 31st 2015, as recorded by the ANZ Intensive Care Society Centre for Outcome and Resource Evaluation Adult Patient Database. We assessed severity of illness on admission using organ failure models and acute physiology scores. The primary outcome was hospital mortality. RESULTS: Patients with cirrhosis accounted for 17,044 of 776,873 non-elective ICU admissions (2.2%). Cirrhosis hospital mortality was 32.4% compared to 16.9% in the non-cirrhotic group (p<0.0001). After adjustment for key confounders, cirrhosis had an independent effect on mortality with an odds ratio (OR) of 1.10 (1.06-1.15). There was no difference in the adjusted annual decline in mortality between patients with or without cirrhosis (OR 0.96 [0.95-0.97] vs. 0.96 [0.96-0.96], p=0.67). No difference was seen in the adjusted decline in mortality of patients with cirrhosis when stratified by mechanical ventilation (p=0.92), liver transplant centre status (p=0.27) or presence of sepsis (p=0.09). Mortality increased with number of organ failures, however, the presence of cirrhosis was not found to affect this relationship (p=0.33). CONCLUSIONS: The mortality of patients with cirrhosis admitted to ICU on a non-elective basis has declined significantly over time, comparable to patients without cirrhosis, and is predominantly governed by the number of organ failures. Outcomes are similar between non-liver transplant ICUs and liver transplant centres. LAY SUMMARY: The outcomes of patients with liver cirrhosis admitted to intensive care units (ICUs) have been previously regarded as poor. We have demonstrated that in Australia and New Zealand, annual in hospital death rates following ICU admission in this patient group are lower than previously reported, have improved over 16years to 29% and are at a rate similar to patients without cirrhosis. Our data justify recommendations that advocate better access to intensive care for patients with cirrhosis. PMID- 28802878 TI - Prehospital sodium bicarbonate use could worsen long term survival with favorable neurological recovery among patients with out-of-hospital cardiac arrest. AB - BACKGROUND: Sodium bicarbonate (SB) is widely used for resuscitation in out-of- hospital cardiac arrest (OHCA); however, its effect on long term outcomes is unclear. METHODS: From 2005-2016, we prospectively conducted a province-wide population-based observational study including adult non-traumatic OHCA patients managed by paramedics. SB was administered by paramedics based on their clinical assessments. To examine the association of SB administration and survival and favorable neurological outcome to hospital discharge, defined as modified Rankin scale of 3 or less, we performed a multivariable logistic regression analysis: (1) within propensity score matched comparison groups, and; (2) within the full cohort with missing variables addressed by multiple imputation techniques. RESULTS: Of 15 601 OHCA patients, 13,865 were included in this study with 5165 (37.3%) managed with SB. In the SB treated group, 118 (2.3%) patients survived and 62 (1.2%) had favorable neurological outcomes to hospital discharge, compared to 1699 (19.8%) and 831 (10.6%) in the non-SB treated group, respectively. In the 1:1 propensity matched cohort including 5638 OHCA patients, SB was associated with decreased probability of outcomes (adjusted OR for survival: 0.64, 95% CI 0.45-0.91, and adjusted OR for favorable neurological outcome: 0.59, 95% CI 0.39 0.88, respectively). The association remained consistent in the multiply imputed cohort (adjusted OR 0.48, 95 CI 0.36-0.64, and adjusted OR 0.54, 95% CI 0.38 0.76, respectively). CONCLUSIONS: In OHCA patients, prehospital SB administration was associated with worse survival rate and neurological outcomes to hospital discharge. PMID- 28802879 TI - Quadrulella texcalense sp. nov. from a Mexican desert: An unexpected new environment for hyalospheniid testate amoebae. AB - Quadrulella (Amoebozoa, Arcellinida, Hyalospheniidae) is a genus of testate amoebae with unmistakable morphology, which secretes characteristic square plates to reinforce the test. They are mainly known from fens and freshwater habitats and have never been documented in deserts. We describe a new species, Quadrulella texcalense, from biological soil crusts in the intertropical desert of Tehuacan (state of Puebla, Mexico). Quadrulella texcalense occurred only at altitudes between 2140 and 2221m.a.s.l., together with the bryophyte genera Pseudocrossidium, Weissia, Bryum, Didymodon, Neohyophyla and Aloina. The soil was extremely dry (moisture of 1.97-2.6%), which contrasts sharply with previous reports for the Quadrulella genus. Single cell mitochondrial cytochrome oxidase I (COI) barcoding of thirteen isolated cells showed an important morphological variability despite having all the same COI barcode sequence. Quadrulella texcalense was placed in a tree containing other Hyalsopheniidae, including a newly barcoded South African species, Q. elegans. Q. texcalense unambiguously branched within genus Quadrulella in a compact clade but with a long branch, suggesting accelerated evolution due to a transition towards a new environment and/or under-sampling. PMID- 28802880 TI - Isobutanol and 2-ketoisovalerate production by Klebsiella pneumoniae via a native pathway. AB - Isobutanol is a valuable chemical and is considered a new generation biofuel. Construction of isobutanol synthesis pathways in bacteria is a hot topic in isobutanol production. Here, we show that an isobutanol synthesis pathway exists naturally in Klebsiella pneumoniae; however, this pathway is dormant in the wild type bacterium. K. pneumoniae is a 2,3-butanediol producer, and the synthesis pathways of 2,3-butanediol, valine and isobutanol all start from condensation of two pyruvate molecules to yield alpha-acetolactate. Inactivation of alpha acetolactate decarboxylase (encoded by budA) resulted in alpha-acetolactate flowing into the valine pathway, which led to synthesis of isobutanol and 2 ketoisovalerate (a precursor of isobutanol). ldhA (lactate dehydrogenase) deletion further increased the isobutanol and 2-ketoisovalerate production. In the first step of this pathway, BudB (alpha-acetolactate synthase) was identified as responsible for most of the alpha-acetolactate synthesis. Complementation of ilvBN or ilvIH (isoenzymes of budB) both resulted in a remarkable increase in 2 ketoisovalerate production. Thus, alpha-acetolactate formation is the rate limiting step of 2-ketoisovalerate production. ilvC (acetohydroxy acid isomeroreductase) and ilvD (dihydroxy acid dehydratase) were identified responsible for 2-ketoisovalerate synthesis from alpha-acetolactate. ipdC, which encodes an indole-3-pyruvate decarboxylase, was identified responsible for most of the isobutyraldehyde formation from 2-ketoisovalerate, and isobutanol production was increased 15.7 fold in the ipdC complementation strain, with a final titer of 2.45g/L. Isobutanol dehydrogenase activity is distributed across multiple alcohol dehydrogenase enzymes expressed by K. pneumoniae. BudC, DhaT, DhaD and YqhD all had isobutanol dehydrogenase activity in vitro. YqhD uses NADPH as the coenzyme, while the other dehydrogenases use NADH. However, inactivating one or two of these dehydrogenases had no effect on isobutanol production in vivo with isobutyraldehyde as the substrate. These results reveal a novel method for biological production of isobutanol and 2-ketoisovalerate. PMID- 28802881 TI - Recent Topics of Research in the Characterization and Quality Control of Biopharmaceuticals in Japan. AB - The research and development of next-generation innovative medicines is a prominent interest of both the government and industries in Japan. On June 29, 2017, a kickoff meeting of a new research group focused on the quality issues of biopharmaceuticals was held in Tokyo with Prof. John Carpenter as an invited guest. The group's research focuses mainly on the evaluation and control of protein aggregates/subvisible particles in drug products, but the research topics also include glycan analysis, host-cell protein evaluation, bioassay validation, and analytical quality by design. The purpose of the group's activities is to resolve the critical and fundamental quality issues important to pharmaceutical companies through the collaboration of industries, academia, and regulatory agencies. In this commentary, our current plan to address these issues and the discussion at the kickoff meeting are described. PMID- 28802882 TI - Chronic Opioid Therapy Modifies QST Changes After Ketamine Infusion in Chronic Pain Patients. AB - : The long-term effects of opioids on sensitization processes are believed to be mediated through the N-methyl-D-aspartate receptor. Quantitative sensory testing (QST) changes observed after a ketamine infusion have been previously described but the effect that chronic opioids will have is not known. The results of this prospective randomized factorial trial compared the thermal QST changes observed after a .05 mg/kg ketamine infusion or a saline placebo in chronic pain subjects who were either opioid-naive or were chronically using opioids for chronic noncancer pain are presented. No baseline QST differences were noted between the 4 groups at baseline. Comparison of changes preinfusion with postinfusion QST measurements resulted in decreased average change in temporal summation response between opioid subjects who received a placebo compared with those who received a ketamine infusion (-5.22, SD = 9.96 vs 13.81, SD = 19.55; P = .004). Additionally, the average change in temporal summation was decreased among subjects who received a ketamine infusion and were not chronically using opioids compared with subjects who were using chronic opioids and received a placebo infusion (-1.91, SD = 13.25 vs 13.81, SD = 19.55; P = .007). The results indicate that low-dose ketamine infusions produce subtle changes in QST phenotypes that are modified by the chronic use of opioids. This illustrates the potential diagnostic and therapeutic value of ketamine in the setting of chronic opioid use. PERSPECTIVE: The presented data further our understanding of modulation of sensory perception in the setting of chronic opioid use and the role of the N methyl-D-aspartate receptor. The use of low-dose ketamine infusions may be useful for the treatment as well as diagnosis of opioid-related neuropathic conditions. PMID- 28802883 TI - Neoadjuvant therapy for localized and locally advanced renal cell carcinoma. AB - Neoadjuvant Targeted Molecular Therapy in the setting of localized and locally advanced renal cell carcinoma has emerged as a strategy to render primary renal tumors amenable to planned surgical resection in settings where radical resection or nephron-sparing surgery was not thought to be safe or feasible. Presurgical tumor reduction has been demonstrated in a number of studies including a recently published randomized double-blind placebo-controlled study, and an expanding body of literature suggests benefit in select patients. Nonetheless, most reports are small phase II clinical trials or retrospective reports. Thus, large randomized clinical trial data are not present to support this approach, and guidelines for use of presurgical therapy have not been promulgated. The advent of immunomodulation through checkpoint inhibition represents an exciting horizon for neoadjuvant strategies. This article reviews the current status and future prospects of neoadjuvant therapy in nonmetastatic renal cell carcinoma. PMID- 28802884 TI - Astrocytes and endoplasmic reticulum stress: A bridge between obesity and neurodegenerative diseases. AB - Endoplasmic reticulum (ER) is a subcellular organelle involved in protein folding and processing. ER stress constitutes a cellular process characterized by accumulation of misfolded proteins, impaired lipid metabolism and induction of inflammatory responses. ER stress has been suggested to be involved in several human pathologies, including neurodegenerative diseases and obesity. Different studies have shown that both neurodegenerative diseases and obesity trigger similar cellular responses to ER stress. Moreover, both diseases are assessed in astrocytes as evidences suggest these cells as key regulators of brain homeostasis. However, the exact contributions to the effects of ER stress in astrocytes in the various neurodegenerative diseases and its relation with obesity are not well known. Here, we discuss recent advances in the understanding of molecular mechanisms that regulate ER stress-related disorders in astrocytes such as obesity and neurodegeneration. Moreover, we outline the correlation between the activated proteins of the unfolded protein response (UPR) in these pathological conditions in order to identify possible therapeutic targets for ER stress in astrocytes. We show that ER stress in astrocytes shares UPR activation pathways during both obesity and neurodegenerative diseases, demonstrating that UPR related proteins like ER chaperone GRP 78/Bip, PERK pathway and other exogenous molecules ameliorate UPR response and promote neuroprotection. PMID- 28802885 TI - [Stereophotogrammetry and facial surgery: Principles, applications and prospects]. AB - The clinical examination of the face needs a reliable, objective and innocuous tool. Stereophotogrammetry for a medical use has been available for more than fifteen years but its popularity is still limited by a high cost. We hereby define the principles of stereophotogrammetry, its fields of application in facial surgery and the prospects, which might soon be offered by a wider access to this technique. PMID- 28802886 TI - [Lumbar artery perforator flap for breast reconstruction]. AB - Even though DIEP-SIEA flaps or latissimus dorsi musculocutaneous flap are the most frequently used, a wide variety of flaps have been described for autologous breast reconstruction. Concerning the choice of donor-site, the aim is to prevent and to limit the morbidity. That is why the donor-site should be carefully chosen, according to the morphology of the patient. Lumbar artery perforator flap (LAP) is an option for breast reconstruction, but it is not well known and its use is limited. This study summarizes the authors' early experience with free LAP flap for breast reconstruction. Three patients underwent immediate or delayed autologous breast reconstruction using a LAP flap. No vascular by pass was required to lengthen the pedicle. No partial or complete flap necrosis has been reported. There was no surgical donor-site complication. Mean operative time was 7hours. LAP flap can be considered as a good option for autologous breast reconstruction, especially in patients with unfavorable abdominal donor-site, and impossibility to use a DIEP flap. PMID- 28802887 TI - Clinical Outcomes of Patients With T1 Nested Variant of Urothelial Carcinoma Compared to Pure Urothelial Carcinoma of the Bladder. AB - PURPOSE: Evaluate oncologic outcomes of patients with cT1 nested variant (NV) of urothelial carcinoma (UC) and compare with cases of pure UC of the bladder. MATERIALS AND METHODS: We retrospectively identified 30 patients with NV who, between 1997 and 2012, underwent transurethral resection with T1 tumor stage, followed by restaging transurethral resection within 3 months confirming non muscle-invasive disease. Radical cystectomy within 3 months of restaging transurethral resection was considered "early" treatment. We matched 3 patients with pure UC to each nested patient. RESULTS: Median follow-up for survivors was 4.3 years from T1-staged transurethral resection. Patients with NV had no statistically significant difference in metastasis-free survival (P = .2) and cancer-specific survival (P = .2) compared with patients with pure UC. However, it is concerning that the rate of upstaging to bladder and/or lymph nodes was 54% in patients with NV who underwent early radical cystectomy, even after rigorous restaging. CONCLUSIONS: Although NV UC may be diagnosed at a higher stage, when stage matched we have not seen any statistical evidence that it is more aggressive than typical UC. Because patients with NV UC who are cT1 on restaging transurethral resection appear to have a higher propensity to develop nodal metastatic disease and a higher rate of upstaging, patients with cT1 NV UC on restaging biopsy may benefit from "early" radical cystectomy, whereas patients with = 3 years after T1, survival was poor compared with the general population (RS5 = 0.50 or lower in SEER-Medicare). Similar patterns were observed in the younger Mayo validation cohort, although prognosis was better overall among the Mayo patients, and patients with favorable fluorescence in situ hybridization retreated >= 3 years after T1 had close to normal expected survival (RS5 = 0.87). CONCLUSION: Further research is needed to quantify the degree to which targeted therapies provide meaningful improvements over CIT in long-term outcomes for older patients with relapsed CLL/SLL. PMID- 28802892 TI - The spatial dynamics of ecosystem engineers. AB - The changes on abiotic features of ecosystems have rarely been taken into account by population dynamics models, which typically focus on trophic and competitive interactions between species. However, understanding the population dynamics of organisms that must modify their habitats in order to survive, the so-called ecosystem engineers, requires the explicit incorporation of abiotic interactions in the models. Here we study a model of ecosystem engineers that is discrete both in space and time, and where the engineers and their habitats are arranged in patches fixed to the sites of regular lattices. The growth of the engineer population is modeled by Ricker equation with a density-dependent carrying capacity that is given by the number of modified habitats. A diffusive dispersal stage ensures that a fraction of the engineers move from their birth patches to neighboring patches. We find that dispersal influences the metapopulation dynamics only in the case that the local or single-patch dynamics exhibit chaotic behavior. In that case, it can suppress the chaotic behavior and avoid extinctions in the regime of large intrinsic growth rate of the population. PMID- 28802893 TI - Complex mixtures of dissolved pesticides show potential aquatic toxicity in a synoptic study of Midwestern U.S. streams. AB - Aquatic organisms in streams are exposed to pesticide mixtures that vary in composition over time in response to changes in flow conditions, pesticide inputs to the stream, and pesticide fate and degradation within the stream. To characterize mixtures of dissolved-phase pesticides and degradates in Midwestern streams, a synoptic study was conducted at 100 streams during May-August 2013. In weekly water samples, 94 pesticides and 89 degradates were detected, with a median of 25 compounds detected per sample and 54 detected per site. In a screening-level assessment using aquatic-life benchmarks and the Pesticide Toxicity Index (PTI), potential effects on fish were unlikely in most streams. For invertebrates, potential chronic toxicity was predicted in 53% of streams, punctuated in 12% of streams by acutely toxic exposures. For aquatic plants, acute but likely reversible effects on biomass were predicted in 75% of streams, with potential longer-term effects on plant communities in 9% of streams. Relatively few pesticides in water-atrazine, acetochlor, metolachlor, imidacloprid, fipronil, organophosphate insecticides, and carbendazim-were predicted to be major contributors to potential toxicity. Agricultural streams had the highest potential for effects on plants, especially in May-June, corresponding to high spring-flush herbicide concentrations. Urban streams had higher detection frequencies and concentrations of insecticides and most fungicides than in agricultural streams, and higher potential for invertebrate toxicity, which peaked during July-August. Toxicity-screening predictions for invertebrates were supported by quantile regressions showing significant associations for the Benthic Invertebrate-PTI and imidacloprid concentrations with invertebrate community metrics for MSQA streams, and by mesocosm toxicity testing with imidacloprid showing effects on invertebrate communities at environmentally relevant concentrations. This study documents the most complex pesticide mixtures yet reported in discrete water samples in the U.S. and, using multiple lines of evidence, predicts that pesticides were potentially toxic to nontarget aquatic life in about half of the sampled streams. PMID- 28802894 TI - Doomed to collapse: Why Algerian steppe rangelands are overgrazed and some lessons to help land-use transitions. AB - This work illustrates the application of a simulation model to analyse how swiftly large-scale land-use changes can drive broad territories to collapse. In this sense, the economic needs of a population should not clash with the natural environment but rather be reconciled with it. Abundant literature deals with the integration of socioeconomic drivers, ecological aspects, farming management, and climatology related to Algerian rangeland degradation. The present study seeks to compare the time course of Alfa grass biomass and the livestock raised on these distinctive rangelands under two different land-use strategies. The traditional one has nomads as the main inhabitants of these lands. For centuries, their strategy for alleviating pressure on resources was to move from one area to other. The more recent sedentary land-use leads to overgrazing supported by the massive use of cheap supplemental feed. Additionally, the model was used as a platform to launch scenarios for sustainable land-use management under a competitive market-economy. A key finding for preserving grazing resources was the increment of supplemental feed prices, which is compatible with stocking rates higher than the historical ones. PMID- 28802895 TI - Physical activity and obesity among nine-year-old children with and without chronic health problems, illness, or disabilities in Ireland. AB - BACKGROUND: Regular engagement in physical activity can help youth control their weight during childhood while decreasing one's chances of developing chronic diseases (e.g., coronary heart disease, diabetes) throughout the lifespan. While numerous studies have explored physical activity participation and weight status among typically developing children, few epidemiological studies utilizing nationally representative data has focused on children with chronic health problems, illness, or disabilities (CHID). OBJECTIVE: Thus, the primary purpose of this secondary-data analysis was to examine physical activity participation and the prevalence of overweight/obesity among nine-year-old children with CHID in Ireland. METHODS: The weighted nationally-represented data for the obesity analysis (N = 6114) and physical activity analysis (N = 6165) were derived from the Growing up in Ireland national study. Logistic regression analyses were conducted to examine associations between child weight status and likelihood of meeting physical activity guidelines. Children's primary caregiver weight status, child gender, and CHID status were correlates, while estimated household income, reported hours of weekly physical education, and locale were covariates. RESULTS: Children with CHID had significantly higher odds (1.51, 95% CI 1.19-1.91) of being classified as overweight/obese compared to peers without CHID, when controlling for locale, income, and weekly physical education hours. Conversely, having a CHID was not significantly associated with the odds of children meeting recommended physical activity guidelines. CONCLUSIONS: Children with CHID had significantly higher odds of being overweight/obese, and these odds increased if the child had a primary caregiver who was overweight/obese. Physical activity levels did not differ between children with and without CHID. PMID- 28802896 TI - Head flexion and different walking speeds do not affect gait stability in older females. AB - Head flexion is destabilizing in older individuals during quiet stance, yet the effect head flexion has on gait is not known. The study examined whether head flexion and gait parameters were altered when walking freely and fixed to a visual target, at different walking speeds. 15 young (23+/-4years) and 16 older (76+/-6years) healthy females walked at three different walking speeds (slow, comfortable, and fast) under two visual conditions (natural and fixed [focusing on a visual target set at eye level]). Head flexion was assessed using 2D video analysis, whilst gait parameters (step length, double support time, step time, and gait stability ratio) were recorded during a 9m flat walkway. A mixed design ANOVA was performed for each variable, with age as the between-subject factor and, visual condition and walking speed as within-subject factors. When walking freely, older displayed a greater need for head flexion between walking speeds (P<0.05) when compared to young. Walking under fixed condition reduced head flexion at all walking speeds in the older (P<0.05), but had no effect on the young (P>0.05). Walking at different speeds showed no difference in head flexion when walking under either visual condition and had no effect on gait stability for both groups. Despite older displaying differences in head flexion between visual conditions, there was no effect on gait parameters. Walking speed presented trivial difference in head flexion in older females, whilst overall gait stability was unaffected by different walking speeds. PMID- 28802897 TI - The different effects of lithium and tamoxifen on memory formation and the levels of neurotrophic factors in the brain of male and female rats. AB - Lithium (Li) is a mood-stabilizing drug used in the treatment of bipolar disorder (BD). Recently, preclinical studies have demonstrated the potential of tamoxifen (TMX) in the treatment of acute episodes of BD. However, the prolonged use of TMX for mood disorders treatment is controversial. In this study, we evaluated the effects of TMX or Li on cognitive behavior, as well as the levels of neurotrophic factors in the brain of male and female rats. Male and female Wistar rats received administrations of water (control group), TMX or Li via gavage for a period of 28days; the rats were then subjected to the open-field test (to evaluate spontaneous locomotion), and the novel object recognition and step-down inhibitory avoidance tests (to evaluate cognition). The levels of NGF, BDNF and GDNF were evaluated in the hippocampus and frontal cortex of the subject rats. No significant differences were observed in the open-field and inhibitory avoidance tests after drug administration in either the male or female rats. The administration of TMX, but not Li, decreased the recognition index of both the male and female rats in the object recognition test. The chronic administration of TMX decreased, whereas Li increased the levels of BDNF in the hippocampus of both the male and female rats. Tamoxifen decreased the levels of NGF in the hippocampus of female rats. In conclusion, it can be suggested that long-term treatments with TMX can lead to significant cognitive impairments by reducing the levels of neurotrophic factors in the brain of rats. PMID- 28802898 TI - Neurochemical evidence that cocaine- and amphetamine-regulated transcript (CART) 55-102 peptide modulates the dopaminergic reward system by decreasing the dopamine release in the mouse nucleus accumbens. AB - CART (Cocaine- and Amphetamine-Regulated Transcript) peptide is a neurotransmitter naturally occurring in the CNS and found mostly in nucleus accumbens, ventrotegmental area, ventral pallidum, amygdalae and striatum, brain regions associated with drug addiction. In the nucleus accumbens, known for its significant role in motivation, pleasure, reward and reinforcement learning, CART peptide inhibits cocaine and amphetamine-induced dopamine-mediated increases in locomotor activity and behavior, suggesting a CART peptide interaction with the dopaminergic system. Thus in the present study, we examined the effect of CART (55-102) peptide on the basal, electrical field stimulation-evoked (EFS-evoked) (30V, 2Hz, 120 shocks) and returning basal dopamine (DA) release and on the release of the DA metabolites 3,4-dihydroxyphenyl acetaldehyde (DOPAL), 3,4 dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3,4 dihydroxyphenylethanol (DOPET), 3-methoxytyramine (3-MT) as well as on norepinephrine (NE) and dopamine-o-quinone (Daq) in isolated mouse nucleus accumbens, in a preparation, in which any CART peptide effects on the dendrites or soma of ventral tegmental projection neurons have been excluded. We further extended our study to assess the effect of CART (55-102) peptide on basal cocaine induced release of dopamine and its metabolites DOPAL, DOPAC, HVA, DOPET and 3-MT as well as on NE and Daq. To analyze the amount of [3H]dopamine, dopamine metabolites, Daq and NE in the nucleus accumbens superfusate, a high-pressure liquid chromatography (HPLC), coupled with electrochemical, UV and radiochemical detections was used. CART (55-102) peptide, 0.1MUM, added alone, exerted: (i) a significant decrease in the basal and EFS-evoked levels of extracellular dopamine (ii) a significant increase in the EFS-evoked and returning basal levels of the dopamine metabolites DOPAC and HVA, major products of dopamine degradation and (iii) a significant decrease in the returning basal levels of DOPET. At the same concentration, 0.1MUM, CART (55-102) peptide did not have any effect on the release of noradrenaline. In the presence of CART (55-102) peptide, 0.1MUM, the effect of cocaine, 30MUM, on the basal dopamine release was inhibited and the effect on the basal DOPAC release substantially increased. To our knowledge, our findings are the first to show direct neurochemical evidence that CART (55-102) peptide plays a neuromodulatory role on the dopaminergic reward system by decreasing dopamine in the mouse nucleus accumbens and by attenuating cocaine induced effects on dopamine release. PMID- 28802899 TI - A species dependent response to the pro-epileptic drug pentylentetrazole in birds. AB - Epilepsy is common disorder that affects over 50 million people worldwide. Birds remain a promising yet largely under-explored model of epilepsy. This study reports the comparison of the response of two species of birds, Australian Parrots (APs) and Sparrows (SPs), to a pro-epileptic drug, Pentylenetetrazole (PTZ). PTZ injections caused myoclonic jerks (MCJs) and tonic clonic seizures (TCSs) in both species. The frequency of MCJs in APs was greater at the dose of 75mg/kg compared to both 50mg/kg and 25mg/kg while it was not significantly different in SPs. The comparison of APs and SPs showed that the frequency of MCJs was greater in APs compared to SPs at 25mg/kg and 75mg/kg while its latency was reduced at 25mg/kg and 50mg/kg. Interestingly SPs had a reduced latency of TCSs compared to APs at 75mg/kg. Glutamatergic and Gabaergic cell count was conducted to determine an association with the epileptic response to PTZ. The Glutamatergic cell counts for SPs was significantly greater than APs and conversely the Gabaergic cell counts in APs was higher compared to SPs. The reason for this difference in findings needs to be further investigated. This study shows that birds, and APs and SPs in particular, are a valid, interesting and under-explored model of epilepsy that should be further explored in order to understand the mysteries of epilepsy. PMID- 28802901 TI - Effect of vertical sleeve gastrectomy on alcohol consumption and preferences in dietary obese rats and mice: A plausible role for altered ghrelin signaling. AB - Vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) are the most common surgical options for the treatment of obesity and metabolic disorder. Whereas RYGB may result in greater and more durable weight loss, recent clinical and pre-clinical studies in rats have raised concerns that RYGB surgery may increase risk for alcohol use disorder (AUD). In contrast, recent clinical reports suggest a lesser risk for AUD following VSG, although no preclinical studies have been done to confirm that. Therefore, the present study sought to determine the effects of VSG on ethanol intake and preferences in rodent models using protocols similar to those previously used in animal studies for RYGB. Male Sprague Dawley rats and male C57B6 mice were made obese on a high fat diet (60%kcal from fat) and received VSG or no surgery (controls). All animals then were given access to increasing concentrations of ethanol (2%, 4%, 6%, and 8%), presented for few days each. Compared to controls, VSG rats consumed significantly less of 2, 6 and 8% ethanol and showed significantly reduced preferences to 6 and 8% ethanol over water. VSG mice also displayed reduced intake and preference for 6 and 8% ethanol solutions. After a two-week period of forced abstinence, 8% ethanol was reintroduced and the VSG rats and mice continued to exhibit reduced consumption and less preference for ethanol. Regarding the underlying mechanism, we hypothesized that the removal of the ghrelin producing part of the stomach in the VSG surgery is a possible contributor to the observed reduced ethanol preference. To test for functional changes at the ghrelin receptors, the VSG and control rats were given IP injections of acyl-ghrelin (2.5nmol and 5nmol) prior to ethanol access. Neither concentration of ghrelin resulted in a significant increase in 8% ethanol consumption of VSG or control subjects. Next, the rats were given IP injections of the ghrelin receptor antagonist, JMV (2.5mg/kg body weight). This dose induced a significant reduction in 8% ethanol consumption in the VSG group, but no effect on ethanol intake in the controls. While ghrelin injection was uninformative, increased sensitivity to subthreshold doses of the ghrelin receptor antagonist may indicate reduced ghrelin signaling following VSG. Overall, these findings suggest that bariatric patients with increased susceptibility to AUD may benefit from receiving VSG instead of RYGB surgery, and that changes in ghrelin signaling, at least in part, may play a role in the differential AUD risks between the two most commonly performed bariatric surgical procedures. PMID- 28802900 TI - Adolescent chronic variable social stress influences exploratory behavior and nicotine responses in male, but not female, BALB/cJ mice. AB - Anxiety disorders and nicotine use are significant contributors to global morbidity and mortality as independent and comorbid diseases. Early-life stress, potentially via stress-induced hypothalamic-pituitary-adrenal axis (HPA) dysregulation, can exacerbate both. However, little is known about the factors that predispose individuals to the development of both anxiety disorders and nicotine use. Here, we examined the relationship between anxiety-like behaviors and nicotine responses following adolescent stress. Adolescent male and female BALB/cJ mice were exposed to either chronic variable social stress (CVSS) or control conditions. CVSS consisted of repeated cycles of social isolation and social reorganization. In adulthood, anxiety-like behavior and social avoidance were measured using the elevated plus-maze (EPM) and social approach-avoidance test, respectively. Nicotine responses were assessed with acute effects on body temperature, corticosterone production, locomotor activity, and voluntary oral nicotine consumption. Adolescent stress had sex-dependent effects on nicotine responses and exploratory behavior, but did not affect anxiety-like behavior or social avoidance in males or females. Adult CVSS males exhibited less exploratory behavior, as indicated by reduced exploratory locomotion in the EPM and social approach-avoidance test, compared to controls. Adolescent stress did not affect nicotine-induced hypothermia in either sex, but CVSS males exhibited augmented nicotine-induced locomotion during late adolescence and voluntarily consumed less nicotine during adulthood. Stress effects on male nicotine-induced locomotion were associated with individual differences in exploratory locomotion in the EPM and social approach-avoidance test. Relative to controls, adult CVSS males and females also exhibited reduced corticosterone levels at baseline and adult male CVSS mice exhibited increased corticosterone levels following an acute nicotine injection. Results suggest that the altered nicotine responses observed in CVSS males may be associated with HPA dysregulation. Taken together, adolescent social stress influences later-life nicotine responses and exploratory behavior. However, there is little evidence of an association between nicotine responses and prototypical anxiety-like behavior or social avoidance in BALB/cJ mice. PMID- 28802902 TI - Pseudomonas aeruginosa-mannose sensitive hemagglutinin injection treated cytokine induced killer cells combined with chemotherapy in the treatment of malignancies. AB - Pseudomonas aeruginosa-mannose sensitive hemagglutinin (PA-MSHA) injection serves as immunological adjuvant in clinical treatment of cancer patients. In present study, we investigated whether PA-MSHA injection enhanced the anti-tumor efficacy of CIK cells. Twenty patients with malignancies were enrolled in this retrospective clinical trial. They were divided into two groups: 10 patients received PA-MSHA treated CIK cells transfusion combined with chemotherapy, and other patients accepted CIK cells and chemotherapy. The efficacy of PA-MSHA treated CIK cells was also observed in vitro and in vivo. With PA-MSHA treatment CIK cells exhibited enhanced proliferation but decreased expression of inhibitory cell surface markers such as Tim-3 and PD-1. Particularly in CIK cells, PA-MSHA promoted the extrusion of pro-inflammatory cytokines like IFN-gamma. Of 10 patients with PA-MSHA treated CIK cells and chemotherapy, two patients reached partial remissions, 7 patients had stable disease and the other one had progressive disease. Some of these patients experienced fever after cell infusion. 8 patients with CIK cells showed stable disease and 2 patients had progressive disease. Moreover, the side effects were small in patients with CIK treatment. Our data indicated that PA-MSHA improves the functions of CIK cells and shed new light on developing more potent therapeutic approaches for malignancies. PMID- 28802903 TI - Role of canonical transient receptor potential channel-3 in acetylcholine-induced mouse airway smooth muscle cell proliferation. AB - AIMS: Canonical transient receptor potential channel-3 (TRPC3)-encoded Ca2+ permeable nonselective cation channel (NSCC) has been proven to be an important native constitutively active channel in airway smooth muscle cell (ASMC), which plays significant roles in physiological and pathological conditions by controlling Ca2+ homeostasis in ASMC. Acetylcholine (ACh) is generally accepted as a contractile parasympathetic neurotransmitter in the airway. Recently studies have revealed the pathological role of ACh in airway remodeling, however, the mechanisms remain unclear. Here, we investigated the role of TRPC3 in ACh-induced ASMC proliferation. MATERIALS AND METHODS: Primary mouse ASMCs were cultured with or without ACh treatment, then cell viability, TRPC3 expression, NSCC currents and [Ca2+]i changes were examined by MTT assay, cell counting, Western blotting, standard whole-cell patch clamp recording and calcium imaging, respectively. Small interfering RNA (siRNA) technology was used to confirm the contribution of TRPC3 to ACh-induced ASMC proliferation. KEY FINDINGS: TRPC3 blocker Gd3+, antibody or siRNA largely inhibited ACh-induced up-regulation of TRPC3 protein, enhancement of NSCC currents, resting [Ca2+]i and KCl-induced changes in [Ca2+]i, eventually inhibiting ACh-induced ASMC proliferation. SIGNIFICANCE: Our data suggested ACh could induce ASMC proliferation, and TRPC3 may be involved in ACh induced ASMC proliferation that occurs with airway remodeling. PMID- 28802904 TI - Baicalin may alleviate inflammatory infiltration in dextran sodium sulfate induced chronic ulcerative colitis via inhibiting IL-33 expression. AB - AIMS: To investigate the therapeutic effect of baicalin treatment in chronic ulcerative colitis (UC), and explore the potential anti-inflammation mechanism(s) via IL-33 pathway. MAIN METHODS: UC model were established by giving three cycles of 5-day 2% dextran sodium sulfate (DSS) with two intervals of 14-day recovery in mice, totaling 43days. At the 13th day of the UC modeling, mice received baicalin at doses of 50, 100, or 150mg/kg, respectively. Disease activity index (DAI) assessment as well as HE and PAS staining were performed. Serum levels of TNF alpha, IL-1beta and IL-6 were determined by ELISA. Myeloperoxidase (MPO) activity and nitric oxide (NO) contents in colon were measured. The expressions of IL-33 and Ly6/G were examined by immunochemistry. And contents of IL-33 protein and NF kappaB-related proteins were tested by Western blot. KEY FINDINGS: Morphological and histological analyses revealed that baicalin administration had a significant effect on reducing the severity of DSS-induced UC in mice. Besides, baicalin treatment significantly reduced the levels of MPO and NO. Moreover, increased levels of inflammatory cytokines, such as TNF-alpha, IL-1beta, and IL-6, have been identified in damaged colon tissue, which was noticeably reduced by baicalin treatment. Our data demonstrated that protein levels of IL-33 and NF-kappaB p65 were elevated in colon tissues of chronic UC mice. Baicalin treatment significantly suppressed levels of IL-33 and NF-kappaB p65, whereas levels of IkappaB-alpha were increased. SIGNIFICANCE: Baicalin treatment effectively alleviated DSS-induced chronic UC, and the protective mechanisms may involve inhibition of IL-33 expression and subsequent NF-kappaB activation. PMID- 28802905 TI - Thoracic Oncology Clinical Trial Eligibility Criteria and Requirements Continue to Increase in Number and Complexity. AB - INTRODUCTION: Eligibility criteria and screening procedures are designed to optimize the scientific yield and maximize the safety of clinical trials. However, they may also heighten trial complexity, hinder enrollment, decrease generalizability, and increase costs. We analyzed the types and number of eligibility criteria and screening procedures among thoracic oncology clinical trials sponsored or endorsed by the Eastern Cooperative Oncology Group. METHODS: We identified trials and obtained protocols from the Eastern Cooperative Oncology Group website. Eligibility criteria were grouped and categorized as comorbidity (classified by organ system), administrative requirements, prior treatment, and measurable disease requirements. Associations between trial characteristics and eligibility criteria were analyzed by using the Kruskal-Wallis and Wilcoxon tests. RESULTS: A total of 74 lung cancer trials activated in 1986-2016 were identified. The total number of eligibility criteria was associated with trial principal therapy (a median of nine for surgical, 18 for radiation, and 20 for medical therapy [p = 0.02]), trial primary end point (a median of 20 for overall survival, 28 for progression-free survival, and 17 for other [p = 0.001]), number of therapies (p = 0.05), and year of activation (a median of 16 for 1986-1995, 19 for 1996-2005, and 27 for 2006-2016 [P < 0.001]). The increase in trial eligibility requirements over time was limited to medical therapy trials. Over time, there was also an increase in blood test screening procedures (p = 0.05) but not in imaging, cardiac assessment, or pulmonary function screening procedures. CONCLUSIONS: The number of eligibility criteria and screening procedures in medical therapy lung cancer clinical trials continues to rise. Continued efforts to simplify protocol eligibility and procedures are warranted to promote trial adherence, enrollment, completion, and generalizability. PMID- 28802906 TI - Pathways towards indolent B-cell lymphoma - Etiology and therapeutic strategies. AB - Although patients with indolent B-cell lymphomas have a relatively good survival rate, conventional chemotherapy is not curative. Disease courses are typically characterized by multiple relapses and progressively shorter response duration with subsequent lines of therapy. There has been an explosion of innovative targeted agents in the past years. This review discusses current knowledge on the etiology of indolent B-cell lymphomas with respect to the role of micro organisms, auto-immune diseases, and deregulated pathways caused by mutations. In particular, knowledge on the mutational landscape of indolent B-cell lymphomas has strongly increased in recent years and harbors great promise for more accurate decision making in the current wide range of therapeutic options. Despite this promise, only in chronic lymphocytic leukemia the detection of TP53 mutations and/or del17p currently have a direct effect on treatment decisions. Nevertheless, it is expected that in the near future the role of genetic testing will increase for prediction of response to targeted treatment as well as for more accurate prediction of prognosis in indolent B-cell lymphomas. PMID- 28802908 TI - Apoptosis signaling and BCL-2 pathways provide opportunities for novel targeted therapeutic strategies in hematologic malignances. AB - Apoptosis is an essential biological process involved in tissue homeostasis and immunity. Aberrations of the two main apoptotic pathways, extrinsic and intrinsic, have been identified in hematological malignancies; many of these aberrations are associated with pathogenesis, prognosis and resistance to standard chemotherapeutic agents. Targeting components of the apoptotic pathways, especially the chief regulatory BCL-2 family in the intrinsic pathway, has proved to be a promising therapeutic approach for patients with hematological malignances, with the expectation of enhanced efficacy and reduced adverse events. Continuous investigations regarding the biological importance of each of the BCL-2 family components and the clinical rationale to achieve optimal therapeutic outcomes, using either monotherapy or in combination with other targeted agents, have generated inspiring progress in the field. Genomic, epigenomic and biological analyses including BH3 profiling facilitate effective evaluation of treatment response, cancer recurrence and drug resistance. In this review, we summarize the biological features of each of the components in the BCL 2 apoptotic pathways, analyze the regulatory mechanisms and the pivotal roles of BCL-2 family members in the pathogenesis of major types of hematologic malignances, and evaluate the potential of apoptosis- and BCL-2-targeted strategies as effective approaches in anti-cancer therapies. PMID- 28802907 TI - The who, how and why: Allogeneic transplant for acute myeloid leukemia in patients older than 60years. AB - Acute myelogenous leukemia (AML) is primarily a disease of the elderly, and as such, our approach to treatment needs to be tailored to address an aging population. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only potentially curative treatment for intermediate and high risk AML, and until recently, its use had been limited to a younger population and dependent on availability of a donor. Advances in conditioning regimens, supportive care, and the use of alternative donor sources have greatly expanded access to this therapy. In this review, we summarize the challenges and unique biological aspects of treatment with allogeneic stem cell transplantation in this group of patients older than 60years. We also highlight areas of ongoing research including measurement of residual disease prior to and following transplant, post remission maintenance therapy, and natural killer cell immunotherapy. Finally, we propose future directions for AML treatment in an elderly and aging population. PMID- 28802909 TI - Variable prognostic value of blood pressure response to exercise. AB - AIM: The aim of this study was to evaluate the impact of patient background including exercise capacity on the relationship between the blood pressure (BP) response to exercise and prognosis in patients visiting a cardiovascular hospital. METHODS: A total of 2134 patients who were referred to our hospital underwent symptom-limited maximal cardiopulmonary exercise testing, and were followed through medical records and mail. The BP response to exercise was defined as the difference between peak and rest systolic BP. The end point was set as cardiovascular events including cardiovascular death, acute coronary syndrome, hospitalization for heart failure, and cerebral infarction. RESULTS: During a median follow-up period of 3 years, 179 (8%) patients reached the end point (2.5%/year). Multivariate analysis showed that BP response was independently and negatively associated with the occurrence of the end point. This prognostic significance of BP response was consistent regardless of left ventricular ejection fraction, renal function, presence of heart failure symptoms, the presence of organic heart disease, and hypertension. However, peak VO2 showed a significant interaction with the effects of BP response on the end point, suggesting that the prognostic value of BP response was limited in patients with preserved exercise capacity. CONCLUSIONS: The role of BP response to exercise as the predictor depends on exercise capacity of each patient. PMID- 28802910 TI - Inter-rater reliability of physical abuse determinations in young children with fractures. AB - As there is no "gold standard" in determining whether a fracture is caused by accident or abuse, agreement among medical providers is paramount. Using abstracted medical record data from 551 children <36months of age presenting to a pediatric emergency department, we examined the extent of agreement between specialists who evaluate children with fractures for suspected abuse. To simulate clinical scenarios, two pediatric orthopaedists and two child abuse pediatricians (CAPs) reviewed the full abstraction and imaging, whereas the two pediatric radiologists reviewed a brief history and imaging. Each physician independently rated each case using a 7-point ordinal scale designed to distinguish accidental from abusive injuries. For any discrepancy in independent ratings, the two specialists discussed the case and came to a joint rating. We analyzed 3 types of agreement: (1) within specialties using independent ratings, (2) between specialties using joint ratings, and (3) between clinicians (orthopaedists and CAPs) with more versus less experience. Agreement between pairs of raters was assessed using Cohen's weighted kappa. Orthopaedists (kappa=0.78) and CAPs (kappa=0.67) had substantial within-specialty agreement, while radiologists (kappa=0.53) had moderate agreement. Orthopaedists and CAPs had almost perfect between-specialty agreement (kappa=0.81), while agreement was much lower for orthopaedists and radiologists (kappa=0.37) and CAPs and radiologists (kappa=0.42). More-experienced clinicians had substantial between-specialty agreement (kappa=0.80) versus less-experienced clinicians who had moderate agreement (kappa=0.60). These findings suggest the level of clinical detail a physician receives and his/her experience in the field has an impact on the level of agreement when evaluating fractures in young children. PMID- 28802911 TI - Childhood maltreatment and high dietary fat intake behaviors in adulthood: A birth cohort study. AB - Childhood maltreatment has been associated with a wide range of chronic medical conditions including obesity, other metabolic events and eating disorders. However, little is known about the association between childhood maltreatment and high dietary fat intake. This study addresses the extent to which co-occurring and specific forms of substantiated childhood maltreatment are associated with self-reported high dietary fat intake in adulthood and whether there is a gender childhood maltreatment interaction in predicting this association. The study also examines the association between age at substantiation of maltreatment, number of childhood maltreatment substantiations and high dietary fat intake-related behaviors. The data were from a prospective Australian pre-birth mother-child dyads study, the Mater-University of Queensland Study of Pregnancy. The study followed 7223 mother-child dyads following the birth of a live, singleton baby at the Mater hospital. Recruitment was early in pregnancy, and then follow-ups at 3 5days postpartum and again when the child was 6 months, 5, 14 and 21 years of age. The data were linked to agency-substantiated cases of childhood maltreatment 0-14 years. This study extended the data linkage to 3766 (47.4% female) participants who had complete data on dietary fat intake behaviors at the 21-year follow-up. Consecutive logistic regressions were used to estimate odds ratios with respective 95% confidence intervals for high dietary fat intake for multiple and specific forms of childhood maltreatment, as well as age at and number of childhood maltreatment substantiations. Finally, a gender-childhood maltreatment interaction term was used to predict the outcome. In both unadjusted and adjusted analyses, substantiated childhood maltreatment including physical abuse were associated with high dietary fat intake-related behaviors. Similarly, substantiation of childhood maltreatment between the ages of 5 and 14 years was significantly associated with high dietary fat intake-related behaviors as were two or more substantiations of maltreatment. Inclusion of gender-childhood maltreatment interaction only had a minor impact on the size and direction of the association. Chronic and severe forms of childhood maltreatment including physical abuse are associated with a higher rate of dietary fat intake in young adulthood. Further research to replicate this association might focus on possible neuro-hormonal mechanisms that might explain this behavior. PMID- 28802912 TI - Perceptions of Brain Health and Cognition in Older African Americans and Caucasians With HIV: A Focus Group Study. AB - As people age with HIV, cognitive problems may become more prevalent and severe, but lifestyle behaviors (i.e., physical activity) have been shown to protect brain health and cognition. We examined the perceptions that older adults living with HIV have about protecting and improving brain health and cognition through lifestyle behaviors. Qualitative data were analyzed from four focus groups (N = 30) of African Americans and Caucasians living with HIV and at least 50 years of age. An open-coding scheme using conventional content analysis was employed. Two results were found. First, many older adults with HIV in our study expressed a variety of cognitive complaints that interfered with daily function. Second, these participants reported few specific ideas about how such health behaviors were important to their own brain health and cognition. Education interventions may help older adults with HIV learn to improve and protect brain health and cognition as they age. PMID- 28802913 TI - Salvage high-dose-rate brachytherapy and external beam radiotherapy for isolated vaginal recurrences of endometrial cancer with no prior adjuvant therapy. AB - PURPOSE: To evaluate clinical outcomes for isolated vaginal recurrence of endometrial cancer without adjuvant therapy treated with salvage external beam radiation therapy (EBRT) and high-dose-rate CT-based inverse-planned brachytherapy. METHODS AND MATERIALS: Thirty women were included in this retrospective study. Median time to first recurrence was 16.7 months, and median age at recurrence was 73 years. Initial grade was 1 or 2 in 19 patients (63%), and 2009 FIGO stage IA in 19 patients. All patients received pelvic EBRT in 1.8 Gy daily fractions to a total of 45 or 50.4 Gy. Interstitial brachytherapy was used in 27 patients (90%). The median total EQD2 dose was 68.3 Gy. Kaplan-Meier estimates of overall survival (OS), cause-specific survival (CSS), progression free survival (PFS), locoregional failure-free survival, and distant failure-free survival (DFFS) were calculated. RESULTS: Median follow-up was 76.4 months for vital status and 57.7 months for disease status after salvage therapy. The 5-year OS, CSS, PFS, locoregional failure-free survival, and DFFS after salvage therapy were 77%, 83%, 75%, 87%, and 86%. Initial high-grade disease was prognostic for OS, CSS, and DFFS (5-year OS 95% vs. 29%, p = 0.005). Initial stage beyond IA was prognostic for CSS, PFS, and DFFS (5-year CSS 93% vs. 74%, p = 0.025). CONCLUSIONS: Salvage EBRT and high-dose-rate brachytherapy resulted in a high rate of locoregional control. Initial high-grade and advanced stage disease were associated with greater distant failure and cancer-related mortality after salvage therapy. PMID- 28802914 TI - Forced but not free-choice nicotine during lactation alters maternal behavior and noradrenergic system of pups: Impact on social behavior of adolescent isolated male rats. AB - Adverse effects of nicotine during pregnancy have been greatly studied, while nowadays few works are focused on consequences of maternal tobacco smoking after birth. The present study investigated the behavioral and early neurochemical effects of nicotine treatment during first weeks of post-natal life in rats. We used "free choice" treatment (H2O+NIC dams could drink from two bottles, containing 10mg/L nicotine hydrogen tartrate salt, or water) versus "forced choice" (NIC+NIC mothers could drink from two bottles both containing nicotine hydrogen tartrate salt, range from 0.75mg/L to 4.09mg/L). We found that only "forced nicotine" had impact on maternal behavior, causing increased high-quality maternal care. This immediately impacted on neuro-chemical development, affecting NE levels (only males) in pup's striatum and prefrontal cortex (pFC) at PND 12. After weaning, animals were reared in normal conditions (two brother rats) or in Social Isolation. After two weeks, they were tested with Social Interaction Test (isolated rats met non-isolated opponents, siblings vs. non-siblings). As expected, isolated rats displayed an aggressive form of soliciting behavior: when facing an isolated unknown partner, the non-isolated rat tried to escape. Interestingly, if their dams were exposed to forced nicotine, both rats sooner behaved very affiliative (possibly empathic) between non-sibling partners. As expected, being exposed to post-natal nicotine could alter neuro-chemical development, but with important interactions between both maternal care and adolescent social behavior. PMID- 28802915 TI - Neurological evaluation of the selection stage of metaphor comprehension in individuals with and without autism spectrum disorder. AB - Because of their difficulties with figurative language in conversation, it is commonly thought that individuals with autism spectrum disorder (ASD) do not understand figurative meaning. However, recent research indicates that individuals with and without ASD are similar in the first two stages of metaphor comprehension, up to and including successful generation of the figurative meaning. In the current study, we used a sentence decision task to evaluate the subsequent stage of metaphor comprehension, the selection stage, which requires suppression/inhibition of the unintended meaning as part of selecting the intended meaning. fMRI activation and functional connectivity were used to compare the selection stage of metaphor comprehension between high-functioning individuals with ASD and carefully matched controls. Cortical and subcortical regions of interest were selected based on the basal-ganglia model of cognitive control. Compared to controls, individuals with ASD recruited greater activation in regions related to verbal memory (thalamus), semantic associations (medial temporal gyrus), and basic visual processing (middle occipital gyrus). Functional connectivity analysis revealed fewer overall connections and cortical-subcortical connections in the ASD group compared to controls. There was a novel finding of maintenance of subcortical-subcortical connectivity in the ASD group, specific to the selection condition, despite differences in cortically involved connections. Reduced cortical-subcortical connectivity in the ASD group compared to controls may reflect a more global impairment in cognitive control pathways, while consistent subcortical-subcortical connectivity may reflect systemic inflexibility or preserved subcortical function and dissociation between subcortical and cortical systems. Further investigation is required. PMID- 28802916 TI - Brain region- and sex-specific alterations in mitochondrial function and NF kappaB signaling in the TgCRND8 mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common late onset neurodegenerative disorder with indications that women are disproportionately affected. Mitochondrial dysfunction has been one of the most discussed hypotheses associated with the early onset and progression of AD, and it has been attributed to intraneuronal accumulation of amyloid beta (Abeta). It was suggested that one of the possible mediators for Abeta-impaired mitochondrial function is the nuclear factor kappa B (NF-kappaB) signaling pathway. NF-kappaB plays important roles in brain inflammation and antioxidant defense, as well as in the regulation of mitochondrial function, and studies have confirmed altered NF-kappaB signaling in AD brain. In this study, we looked for sex-based differences in impaired bioenergetic processes and NF-kappaB signaling in the AD-like brain using transgenic (Tg) CRND8 mice that express excessive brain Abeta, but without tau pathology. Our results show that mitochondrial dysfunction is not uniform in affected brain regions. We observed increased basal and coupled respiration in the hippocampus of TgCRND8 females only, along with a decreased Complex II dependent respiratory activity. Cortical mitochondria from TgCRND8 mice have reduced uncoupled respiration capacity, regardless of sex. The pattern of changes in NF-kappaB signaling was the same in both brain structures, but was sex specific. Whereas in females there was an increase in all three subunits of NF kappaB, in males we observed increase in p65 and p105, but no changes in p50 levels. These results demonstrate that mitochondrial function and inflammatory signaling in the AD-like brain is region- and sex-specific, which is an important consideration for therapeutic strategies. PMID- 28802917 TI - Aerobic exercise in adolescence results in an increase of neuronal and non neuronal cells and in mTOR overexpression in the cerebral cortex of rats. AB - Better cognitive performance and greater cortical and hippocampal volume have been observed in individuals who undertook aerobic exercise during childhood and adolescence. One possible explanation for these beneficial effects is that juvenile physical exercise enables better neural development and hence more cells and neuronal circuitries. It is probable that such effects occur through intracellular signaling proteins associated with cell growth, proliferation and survival. Based on this information, we evaluated the number of neuronal and non neuronal cells using isotropic fractionation and the expression and activation of intracellular proteins (ERK, CREB, Akt, mTOR and p70S6K) in the cerebral cortex and hippocampal formation of the rats submitted to a physical exercise program on a treadmill during adolescence. Results showed that physical exercise increases the number of neuronal and non-neuronal cortical cells and hippocampal neuronal cells in adolescent rats. Moreover, mTOR overexpression was found in the cortical region of exercised adolescent rats. These findings indicate a significant cellular proliferative effect of aerobic exercise on the cerebral cortex in postnatal development. PMID- 28802918 TI - Genes and Nonmotor Symptoms in Parkinson's Disease. AB - Published data on genetic risk factors of nonmotor symptoms (NMS) are relatively lacking since the first mutation responsible for Parkinson's disease (PD) being reported in 1996. This chapter provides a concise summary of genetic links to common individual NMS such as cognitive impairment, depression, psychosis, olfactory dysfunction, pain, and sleep disorders. Although some genetic variants such as apolipoprotein E and glucocerebrosidase demonstrate consistent links with certain NMS, it is difficult to draw definitive conclusions. A concerted effort involving standardized protocol in multiple centers and multiethnic groups will be useful to further investigate the association. With the help of high throughput genomic techniques, more causative genes and novel genes will be discovered in the future and this will contribute further to the understanding of genetic susceptibility of NMS in PD. PMID- 28802919 TI - Nonmotor Signs in Genetic Forms of Parkinson's Disease. AB - Although only a minority (i.e., ~5%) of Parkinson's disease (PD) cases is due to well-defined genetic causes, important clues about the common, "idiopathic" PD (iPD) can be garnered from monogenic model diseases. Nonmotor signs (NMS) are also present in monogenic PD and reviewed in this chapter for the confirmed PD genes SNCA, LRRK2, VPS35, Parkin, PINK1, DJ-1, and the risk factor gene GBA. Within the context of the MDSGene database (www.mdsgene.org), we performed a systematic literature search and extracted information on cognitive decline, depression, psychotic signs and symptoms, autonomic signs and symptoms, anxiety, sleep disorder, and olfactory impairment. Notably, relatively few studies specifically addressed NMS in genetic PD and missing data ranged from 42% to 100%. Diagnostic criteria and examination methods were variable and cases differed widely for age at onset, disease duration, ethnicity, treatment, and comorbidity. Although in comparison to IPD, SNCA duplication carriers have the most similar course of disease, even for duplication carriers the frequencies of dementia, hallucinations, and depression seem higher than in IPD. Supporting the notion that LRRK2-linked PD has a similar course to iPD but is slightly more benign, the frequency of dementia is below that of iPD. For Parkin, the frequency of cognitive decline falls within the range of the general population above the age of 65 years. GBA mutations are associated with a distinct profile of cognitive impairment and a greater prevalence of depression. Despite the current data gaps, NMS should be considered as an important and often treatable concomitant feature of genetic parkinsonism. PMID- 28802920 TI - Neuropathology of Nonmotor Symptoms of Parkinson's Disease. AB - Parkinson's disease (PD), a multiorgan neurodegenerative disorder associated with alpha-synuclein deposits throughout the nervous system and many organs, is clinically characterized by motor and nonmotor features, many of the latter antedating motor dysfunctions by 20 or more years. The causes of the nonmotor manifestations such as olfactory, autonomic, sensory, neuropsychiatric, visuospatial, sleep, and other disorders are unlikely to be related to single lesions. They are mediated by the involvement of both dopaminergic and nondopaminergic systems, and diverse structures outside the nigrostriatal system that is mainly responsible for the motor features of PD. The nonmotor alterations appear in early/prodromal stages of the disease and its further progression, suggesting a topographical and chronological spread of the lesions. This lends further support for the notion that PD is a multiorgan proteinopathy, although the exact relationship between presymptomatic and later developing nonmotor features of PD and neuropathology awaits further elucidation. PMID- 28802921 TI - Imaging the Nonmotor Symptoms in Parkinson's Disease. AB - Parkinson's disease is acknowledged to be a multisystem syndrome, manifesting as a result of multineuropeptide dysfunction, including dopaminergic, cholinergic, serotonergic, and noradrenergic deficits. This multisystem disorder ultimately leads to the presentation of a range of nonmotor symptoms, now appreciated to be an integral part of the disease-specific spectrum of symptoms, often preceding the diagnosis of motor Parkinson's disease. In this chapter, we review the dopaminergic and nondopaminergic basis of these symptoms by exploring the neuroimaging evidence based on several techniques including positron emission tomography, single-photon emission computed tomography molecular imaging, magnetic resonance imaging, functional magnetic resonance imaging, and diffusion tensor imaging. We discuss the role of these neuroimaging techniques in elucidating the underlying pathophysiology of NMS in Parkinson's disease. PMID- 28802922 TI - Biomarkers of Nonmotor Symptoms in Parkinson's Disease. AB - Biomarkers are helpful for early diagnosis, assessment of disorder severity, prognosis, and prediction of response to therapy. Given that early therapeutic intervention may be useful in forestalling or slowing neurodegenerative conditions, employing reliable biomarkers to identify asymptomatic individuals who are destined to develop clinical Parkinson's disease (PD) is critical. Two important observations have been repeatedly found in persons who eventually develop clinical PD: (1) significant neuronal loss occurs in the substantia nigra and (2) the presence of nonmotor symptoms (NMS). Each of these findings occurs prior to the development of motor signs and symptoms, often preceding the clinical diagnosis of PD by a decade or more. As such, NMS themselves, and factors associated with their development may be useful clinical biomarkers for predicting future development of motor PD. Recently, research criteria for prodromal PD, defined as presence of motor and/or NMS, but not yet fulfilling the classic PD diagnosis, have been proposed by the International Parkinson and Movement Disorder Society Task Force. Although there are a small number of biomarkers associated with NMS of PD, in this chapter, discussion follows concerning the expanding literature associated with clinical, biochemical, imaging, and genetic biomarkers of NMS in patients with PD. PMID- 28802923 TI - Measurement of Nonmotor Symptoms in Clinical Practice. AB - Nonmotor symptoms constitute a prominent part of Parkinson's disease manifestations. They are present since the first phases of the disease, increase their number and severity with disease progression, and importantly impact on patients' health and quality of life, caregivers' burden, and social resources. Research on Parkinson's disease has traditionally focused on the motor aspects of the disease, but an increasing interest in the nonmotor manifestations has risen in the past decade. The availability of assessment instruments for detecting and measuring these symptoms has allowed understanding of their importance and course over time, as well as estimation of therapeutic effects on them. In this chapter, a review of the basic characteristics of nonmotor symptom assessments used in clinical practice and research are presented. PMID- 28802924 TI - The Status of "Nonmotor" Features of the Malady in an Essay on the Shaking Palsy (1817). AB - This chapter examines the status James Parkinson accorded "nonmotor" features of the malady set out in his 1817 Essay. In reading the Essay through the lens of this recently developed dichotomy I use "nonmotor" to mean the application of a late 20th-century category to a 200 year old account, whereas nonmotor designates application of the concept to contemporary understanding. While Parkinson granted "motor" components of the malady high definitional visibility, the Essay shows he was also attentive to patients' overall well-being and noticed some "nonmotor" aspects of the malady, in particular, constipation, interrupted speech, and difficulties with saliva and swallowing. He appears to have granted these features more than incidental status, especially in assessing variant pictures of the Shaking Palsy. PMID- 28802925 TI - Objective Measurement and Monitoring of Nonmotor Symptoms in Parkinson's Disease. AB - The comprehensive evaluation of nonmotor symptoms (NMS) in Parkinson's disease (PD) starts with the awareness of physicians, patients, and caregivers on their nature, clinical presentation, and effect on patient's daily activities and quality of life. This awareness can be better achieved if the symptoms can be visualized, measured, and monitored. As NMS are largely subjective in nature, a majority of them cannot be visualized (unlike tremor, which is easily seen), making their identification and quantification difficult. While symptoms are nonmotor, it does not mean that they are not measurable, as many NMS are integral to motor symptoms of Parkinson's, yet often neglected. In this review, we attempt to provide the most up-to-date and comprehensive literature review on the objective measurement and monitoring of NMS in PD. The aim is to make it clinically relevant by approaching NMS by domains as identified in the NMS Questionnaire. A section on the assessment of nonmotor fluctuations is also included, providing prospects for future objective monitoring. With the advances of technology, it is likely that many NMS will have objective outcomes, thus making these symptoms easily measurable and hopefully lead to future clinical trials that incorporate nonmotor outcomes. Nevertheless, it still requires a physician's judgment to determine which method, scales, objective measures, or monitoring devices or a combination of these is most appropriate to the individual patient in order to answer a particular clinical question. PMID- 28802927 TI - Nonmotor Symptoms in Parkinson's Disease: Gender and Ethnic Differences. AB - Nonmotor symptoms (NMS) are recognized to profoundly affect the quality of life of patients with Parkinson's disease (PD) and of their caregivers. In order to further understand the underlying pathophysiology, clinical presentation, response to medication, and prognosis, it is important to identify and analyze possible factors, which have an impact on PD. Gender and ethnicity have been reported to possibly influence incidence, prevalence, and motor presentation in PD, as well as other neurological conditions. However, the impact of gender and ethnicity on the presentation of NMS in PD is currently unclear. In this chapter, the currently available knowledge about gender and ethnic differences in NMS in PD will be summarized and possible factors that might contribute to those observed differences will be discussed. PMID- 28802926 TI - Nonmotor Symptoms and Natural History of Parkinson's Disease: Evidence From Cognitive Dysfunction and Role of Noninvasive Interventions. AB - Parkinson's disease (PD) is a common neurodegenerative disorder, characterized by motor and nonmotor symptoms (NMS). Several subsequent studies substantiate the great functional burden related to NMS, their progression, and negative effect on quality of life in PD. Additional evidence indicates interesting relationships between striatal dopaminergic function and NMS. The basal ganglia are implicated in the modulation and integration of sensory information and pain, bladder function is under control of both inhibitory (D1) and facilitatory (D2) dopaminergic inputs, finally reduced dopaminergic activity in the mesocortical and mesolimbic pathways is involved in the development of several NMS including mood, motivational, and cognitive alterations. Some NMS fluctuate in response to dopaminergic treatment and are relieved by dopamine replacement therapy, other are insensitive to current therapeutic strategies. The relation among the overall disease complications, perhaps the most important for PD patients and family members' well-being and functionality is dementia that affects most PD patients over the course of disease. Specific pharmacological treatment is lacking, and alternative approaches have been implemented to improve everyday functionality and quality of life. The state of the art suggests that cognitive rehabilitation in PD is possible and may either increase performance or preserve cognitive level over the time. However, it is also evident that cognitive abnormalities in PD are heterogeneous and we still do not have biomarkers to detect early patients at risk for dementia. Cognitive dysfunction is one the most prevalent NMS and is a clinically and functionally important disease milestone. Given the available clinical and imaging evidence it is possible to use cognition to model NMS progression and design nonpharmacological interventions. In this chapter we will address the use of cognitive rehabilitation and noninvasive brain stimulation techniques to modulate cognitive performance and rescue connectivity in affected brain circuitry. PMID- 28802928 TI - Nonmotor Subtyping in Parkinson's Disease. AB - Nonmotor symptoms are integral to Parkinson's disease. Several subtypes dominated by specific nonmotor symptoms have emerged. In this chapter, the rationale behind nonmotor subtyping and currently proposed nonmotor subgroups within Parkinson's disease based on data-driven cluster analysis and clinical observations will be summarized. Furthermore, the concept of seven clinical nonmotor subtypes will be discussed in detail including the clinical presentation, potential biomarkers, and the clinical relevance. In future, nonmotor subtypes will possibly play a major role within the aim to achieve personalized medicine. PMID- 28802929 TI - Caregiver Burden and the Nonmotor Symptoms of Parkinson's Disease. AB - Parkinson's disease has traditionally been considered as primarily a motor disorder (Chaudhuri & Schapira, 2009). It is clear however that it is the burden of the nonmotor symptomatology which impacts significantly more highly on caregiver burden and quality of life (Benavides, Alberquerque, & Chana-Cuevas, 2013; Martinez-Martin, 2011). As Parkinson's disease advances there is an almost inevitable accrual of nonmotor symptoms alongside the motor aspects of the disease. Patients as their disease progresses require increasing support and this is not infrequently provided by an informal caregiver, most typically a spouse or family member (Martinez-Martin, Forjaz, Frades-Payo, et al., 2007). The role of the caregiver while being emotionally, physically, and psychosocially demanding is also costly and time intensive. The cost of care is typically borne by the family and one survey has estimated that the average caregiver spends an average of 22h per week fulfilling their role. The caregiver has a unique and privileged view of the patient's condition and often due to symptoms of apathy, cognitive impairment, and depression can provide a more accurate appraisal of symptoms and treatment effect. It is therefore imperative that the caregiver is involved, where possible in clinical appointments and treatment decisions. During this chapter the impact of nonmotor symptoms on the caregiver will be highlighted and the need for early and continued collaboration with the caregiver reiterated. The influence of certain key nonmotor symptoms on caregiver burden will be explored in more detail and the narrative will be punctuated with carer reflections as experienced by Jon Hiseman while caring for his wife Barbara, a world renowned saxophonist. PMID- 28802930 TI - Quality of Life and Nonmotor Symptoms in Parkinson's Disease. AB - Health-related quality of life (HRQoL) is defined as "the perception and evaluation by patients themselves of the impact caused on their lives by the disease and its consequences." HRQoL is conceptualized as a combination of physical, psychological, and social well-being in the context of a particular disease. Following earlier studies revolving on the impact of the classic motor symptoms of Parkinson's disease on HRQoL, mounting evidence have been produced that nonmotor symptoms (NMS) significantly and independently contribute to worse HRQoL. This holds particularly true for such NMS such as neuropsychiatric disturbances, cognitive impairment, and fatigue, the burden of which might well exceed the effects of the motor symptoms. Nonetheless, there is very sparse evidence on how to manage these NMS and whether targeting NMS would in fact lead to an improvement of HRQoL, which calls for the need of future trials with NMS as primary outcomes. PMID- 28802931 TI - Nonmotor Aspects of Parkinson's Disease-How Do They Help Diagnosis? AB - Not only are nonmotor aspects of Parkinson's disease important because of their impact, they also can help diagnose Parkinson's. This chapter summarizes the ways in which recognition of the nonmotor profile of Parkinson's can help in clinical diagnosis. It also emphasizes the essential role that nonmotor Parkinson's disease plays in the diagnosis of prodromal stages of disease. PMID- 28802932 TI - Anosmia and Ageusia in Parkinson's Disease. AB - Anosmia, the loss of sense of smell, is a common nonmotor feature of Parkinson's disease (PD). Ageusia, the loss of sense of taste, is additionally an underappreciated nonmotor feature of PD. The olfactory tract is involved early in PD as indicated by frequent occurrence of hyposmia or anosmia years or decades before motor symptoms and by autopsy studies showing early synuclein pathology in the olfactory tract and anterior olfactory nucleus even in the early stages of PD. Testing for olfaction consists of evaluation of olfactory thresholds, smell identification and discrimination, and olfactory memory. Testing for gustation involves evaluating thresholds and discrimination of five basic tastes (salty, sweet, bitter, sour, and umami). The presence of a specific pattern of loss in both olfaction and gustation in PD has been proposed, but this has not yet been confirmed. Within PD, olfactory loss is strongly tied with cognitive status though links to other features of PD or a particular PD phenotype is debated. Hyposmia is more often present and typically more severe in PD patients than other parkinsonian syndromes, making it a potentially useful biomarker for the disease. PMID- 28802933 TI - Cognition in Parkinson's Disease. AB - Cognitive decline is now recognized as a common nonmotor symptom of Parkinson's disease, and it has been the subject of increasing research in recent decades. Cognitive deficits in Parkinson's disease can be distinguished as dopaminergically mediated executive dysfunction seen in the milder stages vs a global dementia syndrome that can occur with disease progression. The neural basis of these deficits has been explored from the perspective of multimodal imaging techniques to measure the structural, functional, and metabolic correlates of cognitive decline in Parkinson's disease. Increasingly, changes in neurotransmitter systems beyond dopamine, including the noradrenergic, serotonergic, and cholinergic systems, are being recognized for their contribution to cognitive decline. The impact of certain genetic variations on cognitive function has also been established, including links between cognitive decline and polymorphisms affecting COMT, MAPT, APOE, and GBA genotypes. Although therapeutic options for cognitive decline are still far less established than for motor systems, both pharmacological and nonpharmacological strategies are continuing to develop. PMID- 28802934 TI - Psychosis in Parkinson's Disease. AB - Although illusions, hallucinations and delusions did not play a prominent role in James Parkinson's original clinical descriptions, the longitudinal view of disease progression he advocated has important lessons for the study of such symptoms today. A focus on longitudinal progression rather than individual symptoms led to the concept of PD psychosis-a spectrum of positive symptoms in Parkinson's disease. The publication of criteria for PD psychosis in 2007 helped unify the disparate set of symptoms, raising their profile and resulting in a rapid expansion of literature focussing on clinical aspects, mechanisms, and treatment. Here we review this literature and the evolving view of PD psychosis. Adding to previous evidence of a prospective risk for dementia and the move to supervised care, key recent developments include: recognition of prevalence increase with disease duration; a broadening of symptoms included in PD psychosis; better characterization of higher visual and cognitive dysfunction risk factors; structural, functional, and neurotransmitter imaging biomarker evidence; and approval of pimavanserin in the United States for the treatment of PD psychosis. The accumulating evidence raises novel questions and directions for future research that promise a better understanding of the clinical management of PD psychosis and its role as a biomarker for PD stage and progression. PMID- 28802935 TI - Depression and Anxiety in Parkinson's Disease. AB - Depression and anxiety are some of the most common comorbidities arising in patients with Parkinson's disease. However, their timely recognition and diagnosis are often hindered by overlap with other somatic features and a low rate of self-report. There is a need for greater awareness and for better assessment and treatment options are highly required. Currently available scales can serve as tools to monitor change over time and the effect of interventional strategies. Development of new therapeutic strategies, including nonpharmacological approaches such as transcranial magnetic stimulation and deep brain stimulation, may provide alternatives to currently available treatment approaches. In this chapter we will give an overview of the most recent advances in the diagnosis and treatment of these important nonmotor symptoms. PMID- 28802936 TI - Nonmotor Symptoms in Experimental Models of Parkinson's Disease. AB - Nonmotor symptoms of Parkinson's disease (PD) range from neuropsychiatric, cognitive to sleep and sensory disorders and can arise from the disease process as well as from drug treatment. The clinical heterogeneity of nonmotor symptoms of PD is underpinned by a wide range of neuropathological and molecular pathology, affecting almost the entire range of neurotransmitters present in brain and the periphery. Understanding the neurobiology and pathology of nonmotor symptoms is crucial to the effective treatment of PD and currently a key unmet need. This bench-to-bedside translational concept can only be successful if robust animal models of PD charting the genesis and natural history of nonmotor symptoms can be devised. Toxin-based and transgenic rodent and primate models of PD have given us important clues to the underlying basis of motor symptomatology and in addition, can provide a snapshot of some nonmotor aspects of PD, although the data are far from complete. In this chapter, we discuss some of the nonmotor aspects of the available experimental models of PD and how the development of robust animal models to understand and treat nonmotor symptoms needs to become a research priority. PMID- 28802937 TI - Apathy in Parkinson's Disease. AB - The normal maintenance of human motivation depends on the integrity of subcortical structures that link the medial and lateral prefrontal cortex with the limbic system. Apathy is highly prevalent in Parkinson's disease and causes major impact on the quality of life of patients and caregivers, comparable to depression or cognitive impairment. The clinical differentiation of apathy from the emotional symptoms of depression, and from difficulties in planning or organizing mental programs as a consequence of executive dysfunction, may guide a rationale for individualized treatment approach of apathetic symptoms, which is presently lacking. To review the different apathetic syndromes that can be diagnosed in clinical practice by appropriate scales, as well as the brain systems that subserve each syndrome, helps to explain how dopaminergic, antidepressant, or cholinergic medications may lead to individual improvements in apathy. PMID- 28802938 TI - Impulse Control and Related Disorders in Parkinson's Disease. AB - Impulse control disorders (ICDs), such as compulsive gambling, buying, sexual, and eating behaviors, are a serious and increasingly recognized complication in Parkinson's disease (PD), occurring in up to 20% of PD patients over the course of their illness. Related behaviors include punding (stereotyped, repetitive, purposeless behaviors), dopamine dysregulation syndrome (DDS) (compulsive medication overuse), and hobbyism (e.g., compulsive internet use, artistic endeavors, and writing). These disorders have a significant impact on quality of life and function, strain interpersonal relationships, and worsen caregiver burden, and are associated with significant psychiatric comorbidity. ICDs have been most closely related to the use of dopamine agonists (DAs), while DDS is primarily associated with shorter acting, higher potency dopamine replacement therapy (DRT), such as levodopa. However, in preliminary research ICDs have also been reported to occur with monoamine oxidase inhibitor-B and amantadine treatment, and after deep brain stimulation (DBS) surgery. Other risk factors for ICDs may include sex (e.g., male sex for compulsive sexual behavior, and female sex for compulsive buying behavior); younger age overall at PD onset; a pre-PD history of an ICD; personal or family history of substance abuse, bipolar disorder, or gambling problems; and impulsive personality traits. Dysregulation of the mesocorticolimbic dopamine system is thought to be the major neurobiological substrate for ICDs in PD, but there is preliminary evidence for alterations in opiate and serotonin systems too. The primary treatment of ICDs in PD is discontinuation of the offending treatment, but not all patients can tolerate this due to worsening motor symptoms or DA withdrawal syndrome. While psychiatric medications and psychosocial treatments are frequently used to treat ICDs in the general population, there is limited empirical evidence for their use in PD, so it is critical for patients to be monitored closely for ICDs from disease onset and routine throughout its course. In the future, it may be possible to use a precision medicine approach to decrease the incidence of ICDs in PD by avoiding DA use in patients determined to be at highest risk based on their clinical and neurobiological (e.g., motor presentation, behavioral measures of medication response, genetics, dopamine transporter neuroimaging) profile. Additionally, as empirically validated treatments for ICDs and similar disorders (e.g., substance use disorders) emerge, it will also be important to examine their efficacy and tolerability in individuals with comorbid PD. PMID- 28802939 TI - Sleep Dysfunction in Parkinson's Disease. AB - The spectrum of sleep problems in Parkinson's disease (PD) is broad. These symptoms are recognized as being clinically relevant by the PD patients and may seriously affect their quality of life. Some studies reveal the occurrence of sleep disorders in more than half of the PD patients. The etiology is multifactorial and it mainly involves the degeneration of the sleep-regulating structures. Sleep disorders in PD can be classified into: disturbances of sleep and disturbances of wakefulness. Generic and specific scales were designed to help the screening and evaluation of sleep dysfunction. Further assessment can be done using sleep recording techniques, like actigraphy or polysomnography. All types of sleep disturbances may be encountered in PD: insomnia, excessive daytime sleepiness, rapid eye movement sleep behavior disorders, and restless legs syndrome. This chapter will focus on reviewing the main characteristics, pathophysiology, assessment, and management of the most frequent sleep disturbances encountered in PD. PMID- 28802940 TI - Fatigue in Parkinson's Disease. AB - Fatigue is a common symptom in Parkinson's disease (PD), affecting approximately half of all patients. Fatigue is a significant contributor to reduction in quality of life and is a leading cause of disability. Despite the clear impact of fatigue on persons living with PD, research progress has been slow in this area in terms of uncovering the mechanisms of fatigue and there are currently no evidence-based treatments. Although fatigue is often viewed as a subjective and nonspecific symptom which cannot be studied rigorously, there is an emerging science of fatigue which is based on a careful and precise taxonomy of the construct of fatigue. In this chapter we will review advances in our conceptualization of fatigue, including providing definitions useful for both research and clinical care. We will then provide an overview for an approach to the assessment and management of persons with PD who complain of problematic fatigue. We will conclude by reviewing methods for clinical research, including outcome measures for clinical trials, findings from recent mechanistic studies, and suggestions for future research. PMID- 28802941 TI - The Epidemiology of Nonmotor Symptoms in Parkinson's Disease (Cohort and Other Studies). AB - Nonmotor symptoms (NMS) of Parkinson's disease (PD) were recognized by James Parkinson himself and are now considered to be an integral part of PD. While clinical assessment had focused on prevalence and severity of individual NMS such as dementia and depression, work in the last decade has concentrated on global or holistic assessment of NMS using validated tools such as the NMS questionnaire and NMS scale. These studies from cohorts of varying sizes have allowed comparison of NMS across different disease stages, duration, age, and ethnicity in PD. The data also allow exploration of the concept of the nonlinear relationship of NMS to disease duration of PD and motor stages as well as nonmotor subtypes of PD. In this chapter, these aspects of epidemiological studies of NMS in PD cohorts are described. PMID- 28802942 TI - Prefaces. PMID- 28802943 TI - Pregnancy outcomes after transvaginal sacrospinous hysteropexy. AB - AIM: To evaluate the pregnancy outcomes in women who underwent transvaginal sacrospinous hysteropexy with the review of the literature STUDY DESIGN: 54 women who underwent transvaginal sacrospinous hysteropexy due to >=grade 2 uterine prolapse during six-year period were identified from a computer based database. 8 of these who had pregnancy resulted in live birth subsequent to transvaginal sacrospinous hysteropexy were enrolled in this study. They were examined in case of pelvic organ prolapse recurrence and were questioned about their current self satisfaction status and PISQ-12 questionnaire. RESULTS: The median age of women was 36 years (range 29-43 years). All of the women were multiparous and there were no women with a previous cesarean section. All of the subsequent conceptions following operation occured spontaneously. The median time between hysteropexy and conception was 16 months (range 10-30 months). The pregnancies continued at least 37 weeks with only one preterm delivery (due to twin pregnancy). All 8 pregnancies were delivered by cesarean section. The median follow-up period after cesarean section was 45 months (range 7-60 months). Majority of women (7/8, 87.5%) were satisfied with current outcomes of sacrospinous hysteropexy and PISQ12 questionnaire scores revealed improvement in 87.5% (7/8) of women. CONCLUSION: Transvaginal sacrospinous hysteropexy is an appropriate surgical treatment method for symptomatic uterovaginal descensus in women who wish to preserve their uterine and future childbearing. And cesarean section is a reliable and satisfactory delivery route for women who underwent transvaginal sacrospinous hysteropexy. PMID- 28802944 TI - What are patient goals after an anterior colporrhaphy operation? AB - OBJECTIVES: The aim of this study was to describe patient-reported goals after an anterior colporrhaphy operation for anterior vaginal wall prolapse, the fulfilment of goals, and the correlation with subjective patient-reported outcomes. STUDY DESIGN: A prospective study involving 100 women. Preoperatively, patients completed three modified questions from the International Consultation on Incontinence Questionnaire - Vaginal Symptoms (ICIQ-VS) named ICIQ-VS short form (ICIQ-VS SF) and stated three goals for the operation. A telephone interview was performed 3 months postoperatively. RESULTS: A Visual Analogue Scale (VAS) score from one to 10 estimated the extent to which goals were achieved. Goals were divided into eight groups: 1: mechanical symptoms (bulging), 2: voiding symptoms, 3: quality of life (physical), 4: quality of life (emotional), 5: avoidance of urinary tract infection, 6: cure of incontinence, 7: sexual function and 8: others. ICIQ-VS SF preoperatively was mean 13.6 and postoperatively mean 1.7 (p<0.001). A total of 276 goals were stated, 63.4% of the goals were fulfilled with a VAS score of 10. The majority of the goals (27%) were in group 1 concerning symptoms of bulging. Mean VAS score for all goals was 8.6 (SD 2.5). Group 1 concerning mechanical symptoms of bulging had most goals fulfilled with a VAS of 10 (76%), and group 6 concerning cure of incontinence had fewest goals fulfilled with a VAS of 10 (31%). Forty patients (40%) fulfilled all their goals. CONCLUSIONS: Patient-described goal achievement was high. The majority of the fulfilled goals concerned mechanical symptoms of bulging, and goals concerning incontinence were the least fulfilled. PMID- 28802945 TI - Effect of dual compared to no or single renin-angiotensin system blockade on risk of renal replacement therapy or death in predialysis patients: PREPARE-2 study. AB - Current guidelines on hypertension treatment in chronic kidney disease (CKD) patients discourage combined angiotensin-converting enzyme inhibitor (ACEi) and angiotensin II receptor blocker (ARB) use due to the risk of an increased kidney function decline. However, dual compared to single renin-angiotensin system (RAS) blockade may have more efficacy with regard to hypertension and proteinuria. Among incident predialysis patients (CKD 4-5), we compared dual with no or single RAS blockade regarding kidney function decline and risk of renal replacement therapy (RRT) or death. In a multicenter cohort study, 495 incident predialysis patients (>18 years) were included between 2004 and 2011 and followed until RRT, death, or October 2016. At baseline, patients were divided into four categories: nonuser, single or dual user of ACEi and/or ARB. Cox models were used to estimate the hazard ratio for the combined end point RRT or death. Differences in decline of kidney function among the four drug groups were compared with a linear mixed model. A total of 119 patients were nonusers, 164 ACEi users, 133 ARB users, and 79 dual RAS users. Compared to nonusers, the multivariable adjusted hazard ratio (95% confidence interval) for the combined end point was 0.75 (0.65 to 0.86) for ACEi users, 0.87 (0.76 to 1.00) for ARB users, and 0.79 (0.67 to 0.94) for dual RAS users. The average annual decline in kidney function did not differ among the four groups. We observed in predialysis patients that compared to no RAS blockade, both dual RAS blockade and single ACEi use were associated with about 20%-25% lower risk of RRT or death, without difference in kidney function decline. PMID- 28802946 TI - Effects of experimental Angiostrongylus cantonensis infection on the reproductive biology of Biomphalaria straminea and Biomphalaria tenagophila. AB - Eosinophilic meningoencephalitis is an endemic zoonosis in Southeast Asia and the Pacific Islands, but in recent years, new cases have been reported in various countries outside these regions, including Brazil, where it is considered an emerging disease. In this study, the effect of infection by the nematode Angiostrongylus cantonensis, one of the main etiologic agent of this disease, on the reproductive biology of the planorbid snails Biomphalaria straminea and B. tenagophila was investigated during the pre-patent period. Alterations in the reproductive biology of B. straminea and B. tenagophila were analyzed in laboratory-reared specimens infected by A. cantonensis during 21days; the number of eggs, number of egg masses, number of eggs/mass, number of eggs/snail, viable eggs/snail, survival and galactogen content in the albumen gland were measured. The results indicated the occurrence of initial compensation in reproductive effort in both snail species, but at different moments in the pre-patent period. More specifically, a reduction of 46.53% in the eggs/egg mass ratio in infected B. straminea was observed, a reflection of a 50% decline in the concentration of galactogen contained in the albumen gland. Changes in this parameter were also noted in B. tenagophila, but only at the end of the study period, with a reduction of 15.49%. Histological analyses indicate that changes observed can be explained by the tissue damages caused by the migration and development of the larvae. These results shed more light on the host-parasite relationship and indicate the importance of studying reproductive aspects for efforts to control infected snails. Considering that terrestrial snails can also transmit eosinophilic meningitis (in addition to aquatic mollusks), the data obtained expand knowledge of this host-parasite relationship and provide support for programs to control this zoonosis. PMID- 28802947 TI - Canine diabetes mellitus risk factors: A matched case-control study. AB - Different subtypes of canine diabetes mellitus (CDM) have been described based on their aetiopathogenesis. Therefore, manifold risk factors may be involved in CDM development. This study aims to investigate canine diabetes mellitus risk factors. Owners of 110 diabetic dogs and 136 healthy controls matched by breed, sex, and age were interviewed concerning aspects related to diet, weight, physical activity, oral health, reproductive history, pancreatitis, and exposure to exogenous glucocorticoids. Two multivariate multivariable statistical models were created: The UMod included males and females without variables related to oestrous cycle, while the FMod included only females with all analysed variables. In the UMod, "Not exclusively commercial diet" (OR 4.86, 95%CI 2.2-10.7, P<0.001) and "Overweight" (OR 3.51, 95%CI 1.6-7.5, P=0.001) were statistically significant, while in the FMod, "Not exclusively commercial diet" (OR 4.14, 95%CI 1.3-12.7, P=0.01), "Table scraps abuse" (OR 3.62, 95%CI 1.1-12.2, P=0.03), "Overweight" (OR 3.91, 95%CI 1.2-12.6, P=0.02), and "Dioestrus" (OR 5.53, 95%CI 1.9-16.3, P=0.002) were statistically significant. The findings in this study support feeding not exclusively balanced commercial dog food, overweight, treats abuse, and diestrus, as main CDM risk factors. Moreover, those results give subside for preventive care studies against CDM development. PMID- 28802948 TI - Modelling the toxicity of a large set of metal and metal oxide nanoparticles using the OCHEM platform. AB - Inorganic nanomaterials have become one of the new areas of modern knowledge and technology and have already found an increasing number of applications. However, some nanoparticles show toxicity to living organisms, and can potentially have a negative influence on environmental ecosystems. While toxicity can be determined experimentally, such studies are time consuming and costly. Computational toxicology can provide an alternative approach and there is a need to develop methods to reliably assess Quantitative Structure-Property Relationships for nanomaterials (nano-QSPRs). Importantly, development of such models requires careful collection and curation of data. This article overviews freely available nano-QSPR models, which were developed using the Online Chemical Modeling Environment (OCHEM). Multiple data on toxicity of nanoparticles to different living organisms were collected from the literature and uploaded in the OCHEM database. The main characteristics of nanoparticles such as chemical composition of nanoparticles, average particle size, shape, surface charge and information about the biological test species were used as descriptors for developing QSPR models. QSPR methodologies used Random Forests (WEKA-RF), k-Nearest Neighbors and Associative Neural Networks. The predictive ability of the models was tested through cross-validation, giving cross-validated coefficients q2 = 0.58-0.80 for regression models and balanced accuracies of 65-88% for classification models. These results matched the predictions for the test sets used to develop the models. The proposed nano-QSPR models and uploaded data are freely available online at http://ochem.eu/article/103451 and can be used for estimation of toxicity of new and emerging nanoparticles at the early stages of nanomaterial development. PMID- 28802949 TI - An investigation into secondary transfer-The transfer of textile fibres to seats. AB - Textile fibres can be transferred directly, person to person or person to scene (primary transfer), or indirectly via an intermediate (secondary transfer). In criminal cases involving a transfer of textile fibres, it is often the case that whilst the provenance of recovered 'crime significant' fibres is accepted by the defence, it is a particular activity leading to their transfer to a surface in question which is disputed. In such circumstances, transfer and persistence studies relating to fibres on a particular substrate in particular conditions assist in evaluating whether the presence of crime relevant fibres is more likely to have occurred by one particular activity compared to another. This study investigates the effect of a time delay between the primary transfer of fibres to a garment on the numbers of subsequently secondarily transferred fibres to a seat. Two donor garments composed of polyester and cotton fibres respectively were employed in this study and secondarily transferred to seats after time intervals of 0, 0.5, 2, 6 and 24h. The number of secondarily transferred fibres were recorded according to fibre type and time interval and compared against levels recorded at the primary transfer stage. The results showed that only a relatively small percentage of the original primary transfer is likely to be secondarily transferred and that the numbers found were inversely proportional to the time interval between the primary and secondary transfer. In addition, it was found that the secondary transfer of cotton fibres was an order of magnitude higher than for polyester. PMID- 28802950 TI - Application of dye analysis in forensic fibre and textile examination: Case examples. AB - Seven cases and a quality assurance test are presented. In these cases, fibres or textiles submitted for investigation were analysed by HPLC-DAD-MS to identify the dyes present. The cases presented illustrate that it is possible to identify textile dyes in fibre traces recovered for forensic analysis. The results show that a mixture of dyes is present in all textiles investigated, except one sample that was taken from a manufacturer dye shade card. It is concluded that dye analyses improves the evidential value of forensic fibre examinations, as it becomes possible to distinguish textiles that are different in dye chemistry, but have a similar colour. In addition dye analysis makes the examination more robust, as it becomes possible to attribute colour differences between samples to identical dyes (mixed in different ratios) or to chemically different dyes. PMID- 28802951 TI - Smoke on the water-Oral fluid analysis at sea. AB - This study outlines the operational challenges and findings of an illicit drug oral fluid testing program carried out on the skippers (those in charge) of water vessels in Queensland, Australia. Between 2010 and 2016, 953 tests of skippers were conducted on water (waterside) for three proscribed illicit drugs; delta-9 tetrahydrocannabinol (THC), methylamphetamine (MA) and 3,4 methylendioxymethylamphetamine (MDMA). 126 (13%) of the skippers tested returned an on-site positive during waterside testing, 125 were confirmed positive for one or more illicit drug by subsequent laboratory analysis, whilst one skipper did not provide an oral fluid sample for confirmatory analysis. The skippers were entirely male (100%) with an average age of 39 years (range 17-59). THC was by far the most common drug detected (91%); MA was detected in 22% of skippers and a combination or THC and MA in 14% of specimens. MDMA was identified only once during the study, this being in combination with THC. As a single waterside operation can take more than a week, operational pre-planning becomes essential. Aspects of the operation such as, weather, shift times, food, testing consumables, sleeping quarters, hygiene, liaison between different agencies and multiple other factors need to be taken into account prior to commencement. A waterside operation must be mobile and, in Queensland at least, able to cover a large area of water. There is also a much lower volume of vessels likely to be encountered at sea compared to a roadside operation targeting motor vehicles. PMID- 28802952 TI - Cyst of Nuck: A Disregarded Pathology. PMID- 28802953 TI - Incompetent and Dilated Left Ovarian Vein. PMID- 28802954 TI - Creation of a Neovagina by Laparoscopic Modified Davydov Vaginoplasty in Patients with Partial Androgen Insensitivity Syndrome. AB - STUDY OBJECTIVE: To evaluate the feasibility, safety, and outcome of laparoscopic modified Davydov vaginoplasty in subjects with partial androgen insensitivity syndrome (PAIS). DESIGN: A retrospective cohort study (Canadian Task Force classification III). SETTING: A tertiary referral center. PATIENTS: Ten continuous patients operated on between October 2008 and May 2014. INTERVENTIONS: Laparoscopic modified Davydov vaginoplasty. The surgical technique was tailored on PAIS subjects who presented a male pelvic anatomy and, frequently, anomalies of the external genitalia. MEASUREMENTS AND MAIN RESULTS: Anatomic success was defined as a neovaginal width allowing the insertion of 2 fingers and a neovaginal length of at least 5 cm. Functional success was defined as the presence of regular sexual intercourse. Laparoscopic modified Davydov vaginoplasty was successfully performed in all patients without surgical complications. At hospital discharge, anatomic success was achieved in all patients. At the 12-month follow-up, anatomic success was achieved in 9 patients and functional success in 7 patients. Two patients with anatomic success did not start any sexual activity by personal choice. One patient had an anatomic failure with a neovaginal length of 2 cm. This patient had not complied with the postoperative use of vaginal dilators. CONCLUSION: This is the first study reporting the outcomes of laparoscopic modified Davydov vaginoplasty in subjects with PAIS. Postoperative long-term outcomes were comparable with those achieved in women with Rokitansky syndrome. The laparoscopic modified Davydov operation may represent the procedure of choice for the creation of a neovagina and the concomitant correction of anomalies of the external genitalia in subjects with PAIS. PMID- 28802955 TI - Hysterscopic Resection of Premalignant and Malignant Endometrial Polyps: Is it a Safe Alternative to Hysterectomy? AB - STUDY OBJECTIVE: The standard treatment of endometrial cancer (EC) and complex atypical hyperplasia (CAH) is hysterectomy with or without adnexectomy. In the last decade several centers have attempted to perform hysteroscopic resection of malignant and premalignant polyps as an alternative to hysterectomy. In the present study we evaluated the safety of this procedure in regard to residual uterine pathology. DESIGN: Retrospective chart review (Canadian Task Force classification II-2). SETTING: University hospital. PATIENTS: Women (n = 1766) who underwent hysteroscopic polypectomy during the years 1998 to 2016. INTERVENTIONS: Patients with CAH and endometrioid type EC in the removed polyps who underwent hysterectomy were included in the study. Patients with nonendometrioid pathology were excluded. The operative and pathologic reports of the hysteroscopy and hysterectomy procedures were revised. MEASUREMENTS AND MAIN RESULTS: Forty-three women (2.4%) were diagnosed with premalignant and malignant polyps: 21 with EC and 22 with CAH. Thirty-four women (79.0%) underwent hysterectomy and were included in the study group. The median age was 62 years (range, 35-83). Most women (79.4%) presented with postmenopausal bleeding or menorrhagia. In 13 patients (38.2%) more than 1 polyp was removed. The median size of the polyps was 2 cm (range, 1-4). In 27 women there were no other visible endometrial findings during the hysteroscopy except for the removed polyp. However, in 24 women (88.9%) residual CAH or EC was present in the hysterectomy specimen, mostly (55.6%) as multifocal lesions. CONCLUSION: Our results indicate that hysteroscopic evaluation of the uterine cavity and polyp resection are not enough for the eradication of premalignant and malignant endometrial lesions. This alternative should be reserved for well-selected cases such as for fertility preservation and for patient with surgical risk factors that after the hysteroscopic polypectomy will receive further medical treatment. PMID- 28802957 TI - Diagnostic dilemma: ALPS versus Evans syndrome. PMID- 28802956 TI - Magnetic Resonance Imaging Compared with Rectal Endoscopic Sonography for the Prediction of Infiltration Depth in Colorectal Endometriosis. AB - STUDY OBJECTIVE: To compare the accuracies of magnetic resonance imaging (MRI) and rectal endoscopic sonography (RES) in the prediction of the infiltration depth of colorectal endometriosis. DESIGN: A retrospective cohort study (Canadian Task Force classification II-2). SETTING: A university teaching hospital. PATIENTS: Forty patients with symptomatic deep infiltrating endometriosis (DIE) of the rectum who underwent colorectal resection were included. INTERVENTIONS: All patients underwent abdominopelvic MRI and RES preoperatively to assess the infiltration depth of colorectal endometriosis, and segmental resection of the rectosigmoid by laparoscopy was performed if RES showed bowel invasion. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive and negative likelihood ratios (LRs), and intermethod agreement were calculated for DIE muscularis and submucosal/mucosal infiltration confirmed by histopathological analysis. MEASUREMENTS AND MAIN RESULTS: For MRI detection of DIE muscularis infiltration, the sensitivity, specificity, PPV, NPV, and negative LR were 68%, 100%, 100%, 20%, and 0.32, respectively. For the MRI detection of DIE submucosal/mucosal involvement, the sensitivity, specificity, PPV, NPV, and positive and negative LRs were 47%, 81%, 69%, 63%, 2.49, and 0.65, respectively. The PPV of RES detection of DIE muscularis infiltration was 93%. For the RES detection of DIE submucosal/mucosal layers, the sensitivity, specificity, PPV, NPV, and positive and negative LRs were 79%, 48%, 58%, 71%, 1.51, and 0.44, respectively. CONCLUSION: In the current study, MRI is valuable for detecting endometriosis of the rectum but is less accurate in detecting submucosal/mucosal involvement than RES. Magnetic resonance imaging was not successful for preoperative determination of segmental resection versus a more conservative approach. When bowel involvement is detected by MRI, RES is not essential. When symptoms suggest DIE in patients without intestinal lesions detected by MRI, RES is necessary to exclude bowel invasion. PMID- 28802958 TI - Interaction of erythromycin and ketoconazole on the neurological, biochemical and behavioral responses in crucian carp. AB - The presence of pharmaceuticals in the aquatic environment has received great attention due to their potential impacts on public health. The single, as well as the combined toxicities of erythromycin (ERY) and ketoconazole (KCZ) on the bioaccumulation, biochemical and behavioral responses, were examined in crucian carp. This study focused on the uptake of contaminants, acetylcholinesterase (AChE) activity in the brain, swimming and shoaling behavior of fish. After 14days of binary exposure, the addition of KCZ at nominal concentrations of 0.2, 2 and 20MUg/L significantly increased the accumulation of ERY in the brain of the fish and the bioconcentration factor of 2.08 was 2.6-fold higher than that calculated from the ERY-alone exposure. The brain AChE activity was significantly inhibited by ERY and KCZ with a significant correlation with respect to the accumulative concentration of the contaminants. The inhibition rates of swimming activity to KCZ were increased with a corresponding increase in the exposure concentration of KCZ in the single exposure. However, this manner was altered by the combined exposure. In addition, shoaling was significantly enhanced by KCZ alone exposure, which was significantly correlated with the swimming activity. This study indicates that the mixture of the contaminants may cause endocrine disrupting effects and behavior modification especially in fish with known ecological and evolutionary consequences. PMID- 28802959 TI - A combined tract-based spatial statistics and voxel-based morphometry study of the first MRI scan after diagnosis of amyotrophic lateral sclerosis with subgroup analysis. AB - BACKGROUND AND PURPOSE: This study aims to compare the cortical and subcortical deep gray matter (GM) and white matter (WM) of ALS subjects and controls and to compare ALS subjects with (ALScog) and without (ALSnon-cog) cognitive impairment. MATERIALS AND METHODS: The study was performed in 30 ALS subjects, and 19 healthy controls. Structural T1- and diffusion-weighted MRI data were analyzed using voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS). RESULTS: All DTI measures and GM volume differed significantly between ALS subjects and controls. Compared to controls, greater DTI changes were present in ALScog than ALSnon-cog subjects. GM results showed reduction in the caudate nucleus volume in ALScog subjects compared to ALSnon-cog. and comparing all ALS with controls, there were changes on the right side and in a small region in the left middle frontal gyrus. CONCLUSION: This combined DTI and VBM study showed changes in motor and extra-motor regions. The DTI changes were more extensive in ALScog than ALSnon-cog subjects. It is likely that the inclusion of ALS subjects with cognitive impairment in previous studies resulted in extra-motor WM abnormalities being reported in ALS subjects. PMID- 28802960 TI - Post-surgery pCASL perfusion MRI of endolymphatic sac tumor. PMID- 28802961 TI - Recurrent nonhealing wound in old burn scar may be due to Heterotopic Ossification. PMID- 28802962 TI - A skeletal case of hypertrophic osteoarthropathy from the Canary Islands dating from 1000 BP. AB - A left tibia, the distal right tibia, and the proximal four fifths of the right ulna and radius, probably belonging to an adult prehispanic man (antiquity of ~1000 years BP) were found among commingled bone remains in a collective burial cave of the island of El Hierro, in the Canary Archipelago. All four bones show an intense periosteal bone formation, encrusting the preserved cortical bone of the diaphyses. Differential diagnosis include melorheostosis, syphilis, and leprosy, although the most likely diagnosis is hypertrophic osteoarthropathy, which is usually associated with lung neoplasm or non-malignant diseases leading to chronic hypoxemia. The marked bone proliferation, possibly due to a chronic condition, suggests that possibly the underlying illness was a non-malignant one. PMID- 28802963 TI - Slot-type fractures of the scapula at New Kingdom Tell El-Amarna, Egypt. AB - Amarna is the archaeological representation of Akhetaten, the short-lived Egyptian capital city of Akhenaten (reign 1352-1336BCE).Five adult males excavated from the South Tombs Cemetery (STC) (total n>400) at Amarna exhibit slot-type fracture lesions of the scapula, and two of these lesions exhibit evidence of active bone remodeling at the time of death.The lesions in question are described and a full differential diagnosis is considered.The differential diagnosis rules out atrophic perforations, scapular foramina, tumors, and occupational and accidental trauma.Given the location, morphology, and surrounding bony changes, these lesions are consistent with sharp force trauma, specifically stabbing.These lesions most likely represent the consequence of corporal punishment in the form of "strokes" accompanied by "open wounds" known from Egyptian literature for punishment of a wide range of civil and criminal activities.Alternatively, several pigs at Amarna show similar wound morphologies of the cranium and scapulae, which have been interpreted by other authors to represent ritualized punishment of the god Seth, who is often represented as a pig.The lesions described here are consistent in morphology and positioning with the swine examples, and may represent further, cross-species, evidence of ritualized punishment at the ancient capital city. PMID- 28802964 TI - A rare case of os odontoideum from an Early Intermediate period tomb at the Huacas de Moche, Peru. AB - Os odontoideum is an uncommon vertebral anomaly where there is a smoothly corticated ossicle independent from a shortened odontoid peg. An example of os odontoideum was observed in an Early Intermediate period skeleton excavated from the Huacas de Moche (Moche IV, AD 400-700), Peru. The affected individual is a middle adult male who presents additional minor developmental anomalies of the axial skeleton. This individual was interred with a middle adult female who also has developmental anomalies of the axial skeleton, including block cervical vertebra (Klippel-Feil). Os odontoideum is infrequently reported in the medical literature and there continues to be debate about whether it is acquired or congenital. Unlike clinical cases, archaeological cases present an opportunity to examine the entirety of the skeleton. In the present case, there does not appear to be macroscopic or radiographic evidence for a healed fracture, and since the individual has multiple minor axial developmental anomalies, a congenital etiology is plausible. This case is the first to be described from the archaeological context of South America and one of few paleopathological examples worldwide. PMID- 28802965 TI - Variation in large ectocranial lesions from pre-Columbian Kuelap, Peru. AB - This paper analyses a diverse collection of previously undescribed cranial lesions observed from 42 individuals from the pre-Columbian site of Kuelap, eastern montane, Peru. I describe the presence of cranial lesions, their location on the vault location, shape, and size of affected area, and evidence of remodeling. Seventeen percent of the total cranial sample demonstrates similar superficial cranial lesions including males (25/117, 21.4%) and females (14/74, 18.9%), and adolescents (3/27, 11%). Most lesions are narrow ovals or long and leaf-shaped, with depression of the external cranial vault. While some are well healed and smooth-surfaced, others are more irregular with variable degrees of remodeling. The highest frequency is on the superior and posterior aspects of the vault, usually along the sagittal plane. Differential diagnoses are considered but no single pathology is clear for all cases. There are some common features consistent with active and healing osteitis and a few are directly associated with trepanation. General patterning suggests intentional treatment, perhaps even possible cauterization of scalp injuries or healed infections. These large cranial "scars" have not been observed at coastal Peruvian sites and may reflect specific regional conditions related to highland environmental factors, local medical treatments of cranial injuries, or population specific malformations. PMID- 28802966 TI - An unusual exostotic lesion of the maxillary sinus from Roman Lincoln. AB - This report provides a differential diagnosis of an exostotic bony lesion within the left maxillary sinus of a Romano-British (3rd to 4th century AD) adult male from Newport, Lincoln. Macroscopic, radiographic, and cone beam computed tomography (CBCT) analyses suggest that the lesion is likely of odontogenic origin. The overall size of the lesion and areas of sclerosis and radiolucency, together with its hypothesised odontogenic origin, suggest that the lesion represents a chronic exostotic osteomyelitic reaction to the presence of odontogenic bacteria. While modern case studies of odontogenic maxillary sinus osteomyelitis are noteworthy, published cases of this condition are extremely rare in an archaeological context and may be underreported due to the enclosed nature of the sinuses. Such infections may have serious implications for individual and population health, and non-destructive investigation should be considered in cases where significant maxillary caries are present. PMID- 28802967 TI - A possible case of Garre's sclerosing osteomyelitis from Medieval Tuscany (11th 12th centuries). AB - Archaeological excavations carried out at the castle of Monte di Croce near Florence brought to light a small cemetery complex belonging to the castle church, dated back to the 11th-12th centuries. An elite stone tomb contained the skeletal remains of a male aged 35-45 years with obvious pathology of the right tibia. The proximal metaphysis and the upper half of the diaphysis appear massively enlarged as a result of severe chronic periostitis. A transverse section illustrates complete obliteration of the medullary cavity by new spongy bone, with some large cavitations. The primary, but completely remodeled tibial shaft is still recognizable. This finding and the strong sclerotic reaction with some central cavitations rule out any form of bone tumor and indicate a chronic inflammatory disease. The morphological and radiological picture and the tibial localization suggest a diagnosis of chronic sclerosing osteomyelitis of Garre, a rare form of chronic osteomyelitis characterized by an intense periosteal reaction with little or no suppuration. PMID- 28802968 TI - Survival after trepanation-Early cranial surgery from Late Iron Age Switzerland. AB - Trepanation is defined as the intentional perforation of the cranial vault with removal of a piece of skull bone. In Europe, trepanation is known to have been practiced at least since the Neolithic, and it can still be found today in East African native tribes. Two skulls with lesions from the Late Iron Age site Munsingen-Rain (420-240 BC) were investigated. The aim of this study was to analyse the lesions and to determine whether they were caused by surgical interventions. Both individuals were analysed by current morphologic anthropological methods and radiological examinations were performed with a multislice CT-scanner. Additionally, this work surveys trepanations reported in Switzerland and calculates survival rates. In Switzerland, 34 individuals with trepanations have been published. As a tendency, the survival rate appears to be relatively high from the Neolithic to Late Antiquity but then decreases until Pre Modern times. The 78% survival rate in Late Iron Age Switzerland indicates that the surgery was often performed successfully. Skull injuries sustained in conflicts could have been a reason for trepanation during the Iron Age. PMID- 28802969 TI - Cartilage-derived tumor in a prehispanic individual from La Gomera (Canary Islands). AB - We present the case of a left tibia with an outgrowth at its distal metaphyseal/epiphyseal end, composed of cancellous bone, surrounding a destructive process that, on radiological examination, reaches the tibiotalar joint surface. The cancellous bone of the outgrowth is well preserved and is in continuity with intramedullary cancellous bone. The tibia belonged to a prehispanic adult individual, probably male, from La Gomera, in the Canary Archipelago. The antiquity of the sample is unknown, but radiocarbon dating of other samples ranges from 1600 to1800 years BP. The lesion is suggestive of a cartilage-derived tumor, most likely a chondrosarcoma. Other etiologic possibilities are also discussed, including osteochondroma, enchondroma, chondromyxoid fibroma or chondroblastoma. PMID- 28802970 TI - A kidney's ingenious path to trimillennar preservation: Renal tuberculosis in an Egyptian mummy? AB - Irtieru is a male mummy enclosed in cartonnage, dating to the Third Intermediate Period in the Egyptian collection of the Museu Nacional de Arqueologia in Lisbon. The computed tomography scans of this mummy showed a small dense bean-shaped structure at the left lumbar region. Its anatomical location, morphologic and structural analysis support a diagnosis of end-stage renal tuberculosis. If this diagnosis is correct, this will be the oldest example of kidney tuberculosis, and the first one recorded in an intentionally mummified ancient Egyptian. PMID- 28802971 TI - Skeletal indicators of reactive arthritis: A case study comparison to other skeletal conditions, such as rheumatoid arthritis, ankylosing spondylitis, ankylosing sero-negative SpA, and DISH. AB - In this case study we report a unique modern case of severe reactive arthritis (Reiter's Syndrome) observed on an elderly Cypriot female from the St. Nicholas cemetery in Limassol, Cyprus and the successful differential diagnosis of the condition. The individual exhibited lesions specific to fusion of the thoracic and lumbar spinal column, primarily along the posterior aspect of the spine with sacroiliac fusion, fusion of the left femoral head within the acetabulum, no intervertebral fusion, and severe Launois's deformity with no corresponding fusion or arthritis mutilans of the hands. Diagnosis of reactive arthritis is much more compatible than other common HLA-B27 related seronegative spondylarthropathies such as ankylosing spondylitis, psoriatic arthropathy, or enteropathic arthropathy given the suite of conditions present. We conclude with the confirmation of reactive arthritis and stress the importance of having a broad literature base when making differential diagnoses. PMID- 28802972 TI - Gendered Differences in Accidental Trauma to Upper and Lower Limb Bones at Aquincum, Roman Hungary. AB - It was hypothesized that men and women living in the border provinces of the Roman Empire may have encountered different risks associated with their different occupations and activities. Limb bone trauma data were used to assess sex-based differences in physical hazards and evidence for fracture healing and treatment. Two hundred and ten skeletons were examined from a late 1st to early 4th century AD cemetery at Aquincum (Budapest, Hungary). Upper and lower limb bone fracture types, frequencies, distributions, and associated complications were recorded, and gendered patterns in injury risks were explored. Of the 23 fractures identified, both sexes had injuries indicative of falls; males exhibited the only injuries suggestive of higher-energy and more direct forces. Most fractures were well-healed with few complications. The extremity trauma at Aquincum suggests that people buried here experienced less hazardous physical activities than at other Roman provincial sites. The patterns of trauma indicate the occurrence of "traditional" gender roles, whereby male civilians participated in more physically dangerous activities than females. Additionally, treatment may have been equally accessible to men and women, but certain fracture types proved more challenging to reduce using the techniques available. PMID- 28802973 TI - Pre-Columbian tuberculosis in Tierra del Fuego? Discussion of the paleopathological and molecular evidence. AB - This work contributes to ongoing discussions about the nature of tuberculosis in the Western Hemisphere prior to the time of European contact. Our example, from the extreme south of South America was, at the time of our study, without firm temporal association or molecular characterization. In Tierra del Fuego, Constantinescu (1999) briefly described vertebral bone lesions compatible with TB in an undated skeleton from Myren 1 site (Chile). The remains of Myren are estimated to represent a man between 18 and 23 years old at the time of death. The objectives of this research are to extend this description, to present molecular results, to establish a radiocarbon date, and to report stable isotopic values for the remains. We provide further description of the remains, including tuberculosis-like skeletal pathology. Radiocarbon dating of 640+/-20 years BP attributes this individual to the precontact fourteenth-fifteenth centuries. Isotopic ratios for nitrogen and carbon from bone collagen suggest a mixed diet. Molecular results were positive for the rpoB quantitative PCR (qPCR) assays but negative for two independent IS6110 and IS1081 qPCR assays. Further testing using genomic methods to target any mycobacteria for specific identification are needed. PMID- 28802974 TI - Characteristics of thrombin generation in a fulminant porcine sepsis model. AB - INTRODUCTION: The activation of blood coagulation has been demonstrated in most cases of sepsis, however previous studies in humans could not detect hypercoagulability with global hemostasis assays. In a fulminant porcine sepsis model we analysed coagulation screening tests and thrombin generation to evaluate hemostatic alterations. MATERIALS AND METHODS: Live Escherichia coli bacteria were inoculated to female pigs and prothrombin time, activated partial thromboplastin time, thrombin time and fibrinogen were measured by coagulometry. Platelet counts, platelet aggregates and platelet phosphatidyl serine (PS) expression were studied, furthermore in in vitro experiments the PS-inducing ability of septic and control plasmas was investigated by flow cytometry. Thrombin generation was carried out by the Ascent Fluoroscan reader and results were evaluated by the Thrombinoscope software. RESULTS: Clotting assays showed a large variability, but no systematic changes during the 4-hour observation period. Platelet count significantly decreased and the number of platelet aggregates increased already by 2h compared to baseline values and to control animals. Although the increase in platelet PS expression was non-significant in the septic group, the septic plasma elicited PS expression on normal human red blood cells. Thrombin generation became significantly faster, but the quantity of formed thrombin demonstrated both hypo- and hypercoagulability depending on the setting of the assay. CONCLUSIONS: Enhanced thrombin generation without activators and the PS-inducing capacity of septic plasma are signs of hemostatic activation during fulminant sepsis while the decreased amount of generated thrombin upon tissue factor and phospholipid induced activation demonstrates attenuated thrombin forming ability. PMID- 28802975 TI - Impact of pneumatic tube system transport for the monitoring of heparin therapy. PMID- 28802976 TI - Prognostic factors associated with the accuracy of deformable image registration in lung cancer patients treated with stereotactic body radiotherapy. AB - We evaluated the accuracy of an in-house program in lung stereotactic body radiation therapy (SBRT) cancer patients, and explored the prognostic factors associated with the accuracy of deformable image registrations (DIRs). The accuracy of the 3 programs which implement the free-form deformation and the B spline algorithm was compared regarding the structures on 4-dimensional computed tomography (4DCT) image datasets between the peak-inhale and peak-exhale phases. The dice similarity coefficient (DSC) and normalized DSC (NDSC) were measured for the gross tumor volumes from 19 lung SBRT patients. We evaluated the accuracy of DIR using gross tumor volume, magnitude of displacement from 0% phase to 50% phase, whole lung volume in the 50% phase image, and status of tumor pleural attachment. The median NDSC values using the NiftyReg, MIM Maestro and Velocity AI programs were 1.027, 1.005, and 0.946, respectively, indicating that NiftyReg and MIM Maestro programs had similar accuracy with an uncertainty of < 1 mm. Larger uncertainty of 1 to 2 mm was observed using the Velocity AI program. The NiftyReg and the MIM programs provided higher NDSC values than the median values when the gross tumor volume was attached to the pleura (p <0.05). However, it showed a different trend in using the Velocity AI program. All software programs provided unexpected results, and there is a possibility that such results would reduce the accuracy of 4D treatment planning and adaptive radiotherapy. The unexpected results may be because the tumors are surrounded by other tissues, and there are differences regarding the region of interest for rigid and nonrigid registration. Furthermore, our results indicated that the pleural attachment status might be an important predictor of DIR accuracy for thoracic images, indicating that there is a potentially large dose distribution discrepancy concerning 4D treatment planning and adaptive radiotherapy. PMID- 28802978 TI - Gas-phase hydration of glyoxylic acid: Kinetics and atmospheric implications. AB - Oxocarboxylic acids are one of the most important organic species found in secondary organic aerosols and can be detected in diverse environments. But the hydration of oxocarboxylic acids in the atmosphere has still not been fully understood. Neglecting the hydration of oxocarboxylic acids in atmospheric models may be one of the most important reasons for the significant discrepancies between field measurements and abundance predictions of atmospheric models for oxocarboxylic acids. In the present paper, glyoxylic acid, as the most abundant oxocarboxylic acids in the atmosphere, has been selected as an example to study whether the hydration process can occur in the atmosphere and what the kinetic process of hydration is. The gas-phase hydration of glyoxylic acid to form the corresponding geminal diol and those catalyzed by atmospheric common substances (water, sulfuric acid and ammonia) have been investigated at the CCSD(T)-F12/cc pVDZ-F12//M06-2X/6-311++G(3df,3pd) level of theory. The contour map of electron density difference of transition states have been further analyzed. It is indicated that these atmospheric common substances can all catalyze on the hydration to some extent and sulfuric acid is the most effective reducing the Gibbs free energy of activation to 9.48 kcal/mol. The effective rate constants combining the overall rate constants and concentrations of the corresponding catalysts have shown that water and sulfuric acid are both important catalysts and the catalysis of sulfuric acid is the most effective for the gas-phase hydration of glyoxylic acid. This catalyzed processes are potentially effective in coastal regions and polluted regions. PMID- 28802979 TI - Navigating professional and prescribing boundaries: Implementing nurse prescribing in New Zealand. AB - Non-medical prescribing is now well established in a number of countries. Because prescribing has traditionally been viewed as a medical role, there are inevitable interprofessional boundary tensions when non-medical prescribing is introduced. In New Zealand, enabling legislation has allowed nurse practitioners to apply for prescriptive authority after undertaking appropriate educational preparation. This study explored the experiences and perspectives of one of the first cohorts of nurse prescribers and their strategies in establishing the role and negotiating the associated professional boundaries. Semi-structured interviews were undertaken with ten newly registered nurse-prescribers. Two broad categories, each comprising three themes, were identified: 'shifting professional boundaries' and 'navigating boundaries of practice'. Participants described how they were faced with the challenge of an unprepared environment as they began to prescribe and how they built trust in their prescribing practice among their colleagues and patients. They also related how they determined their personal prescribing boundaries in this new environment. They described the new professional relationship between nurse prescribers and doctors as collaborative, but with the crucial difference of it being interdependent, not dependent. The study offers insights into the challenges associated with the establishment of new professional roles such as prescribing. PMID- 28802977 TI - Adsorption and coadsorption mechanisms of Cr(VI) and organic contaminants on H3PO4 treated biochar. AB - The study of simultaneous removal of heavy metals and organic contaminants has practical applications due to the coexistence of complex pollutants in the wastewater or soil. In this work, biochar was prepared to study the removal efficiencies of Cr(VI), naphthalene (NAP) and bisphenol A (BPA) in the single or mixed systems. H3PO4-treated biochar presented a much higher adsorption capacity of the pollutants than the untreated biochar and also showed a high resistance to coexisting salts. The maximum adsorption capacities for Cr(VI) and BPA were 116.28 mg g-1 and 476.19 mg g-1, respectively. Coadsorption experiments revealed that the presence of organic pollutants caused a limited decrease (~10%) of removal efficiency of Cr(VI) and no further decrease was observed with higher concentrations of organic pollutants, while the presence of Cr(VI) had little impact on the removal of NAP. Infrared spectra and molecular simulation demonstrated that Cr(VI) was mainly adsorbed on the biochar via chemical complexation, while the organic pollutants through pi-pi interaction. Unexpectedly, the addition of Cr(VI) increased the removal efficiency of BPA, probably due to the increased H-bond interactions between BPA and the biochar through bridge bonds of oxygenic groups from CrO42-. PMID- 28802980 TI - Corrigendum to "Sealing frequency of B104 cells declines exponentially with decreasing transection distance from the axon hillock" [Exp. Neurol. 279 (2016) 149-158]. PMID- 28802981 TI - Errors in Patient Positioning for Bone Mineral Density Assessment by Dual X-Ray Absorptiometry: Effect of Technologist Retraining. AB - Improper positioning is one of the factors that can lead to incorrect bone mineral density (BMD) results. This study aimed to assess the frequencies of erroneous positioning during three periods: before retraining of the technologists (BR), after retraining (AR), and at the current timepoint 8 years after retraining (C). The BMD images of the first 150 consecutive patients who underwent DXA of the lumbar spine and hip during each of the three periods were retrospectively reviewed. Patients were excluded if they had severe scoliosis, rendering proper positioning impossible. Each BMD image was assessed by an International Society of Clinical Densitometry certified clinical densitometrist who was blinded to the date of the initial examination. For the lumbar spine in the BR group, the criteria frequently not met were inclusion of both iliac crests (33.8%), straightness (30.3%), and midline positioning (20.4%); the respective frequencies were significantly reduced to 0.8%-5.6%, 2.1%-3.0%, and 0%-2.8% in the AR and C groups (p < 0.05). For the hip in the BR group, the criteria frequently not met were straightness (52.8%) and internal rotation (21.8%); the respective frequencies were significantly reduced to 0%-4.2% and 8.3%-8.4% in the AR and C groups (p < 0.05). Overall improper positioning in the BR group was 49.3% and 57.3% at the lumbar spine and the hip, respectively; the respective frequencies were reduced to 9.3% and 12.7% in the AR group, and to 2.7% and 7.3% in the C group. The least significant change values for the lumbar spine, femoral neck, and total hip also became smaller after retraining. Retraining the technologists improved patient positioning, as evidenced by the decreased frequencies of erroneous positioning and the improved least significant change values after the retraining. PMID- 28802982 TI - Reducing of salivary alpha-amylase inhibition by using bovine serum albumin and calcium chloride for forensic saliva screening. AB - Inhibiting salivary alpha-amylase is a critical issue of forensic saliva identification using the catalytic method. This study aims to identify human alpha-amylase inhibitors in forensic saliva screening by using a blue starch amylase test and to measure the extent of enzyme inhibition. Thus, in order to demonstrate the presence of inhibitors, we prepared positively charged metal ion sources or chelators that were mixed into the saliva stains. The results of this study show that ferric chloride (FeCl3), magnesium chloride, ethylenediaminetetraacetic acid, and citric acid significantly decrease the alpha amylase activity of saliva stains. We also verified this approach using blood, a magnesium-containing liquid supplement, and two citric acid-containing soft drinks that were contaminated with saliva stains as forensic mock samples; these samples also showed a significant reduction in salivary alpha-amylase activity. To establish an inhibitor-resistant blue starch amylase test, we applied bovine serum albumin (BSA) and calcium chloride (CaCl2) to the reaction system. The results show that salivary alpha-amylase inhibition of the forensic mock samples occurred under normal test conditions (i.e., 300ng/uL BSA, 0mM CaCl2), and that inhibition was significantly relieved under the BSA+CaCl2 conditions (i.e., 1000ng/uL BSA, 5mM CaCl2). Therefore, the results of this study demonstrate that both BSA and CaCl2 can be utilized as reaction stabilizers in forensic saliva screening. PMID- 28802983 TI - Systemic and Local Management of Burn Wounds. AB - Management of severe burn injury (SBI) requires prompt, complex, and aggressive care. Despite major advances in the management of SBI-including patient-targeted resuscitation, management of inhalation injuries, specific nutritional support, enhanced wound therapy, and infection control-the consequences of SBI often result in complex, multiorgan metabolic changes. Consensus guidelines and clinical evidence regarding specific management of small animal burn patients are lacking. This article aims to review updated therapeutic consideration for the systemic and local management of SBI that are proven effective to optimize outcomes in human burn patients and may translate to small animal patients. PMID- 28802984 TI - Free Grafts and Microvascular Anastomoses. AB - Skin grafts and free skin flaps are useful options for closure of wounds in which primary closure or use of traditional skin flaps is not feasible. Grafts are classified by their morphology and host-donor relationship. Free skin flaps with microvascular anastomoses are developed from previously described axial pattern flaps and have the added advantage of reestablishing robust vascular supply to the flap, but require specialized equipment and a high degree of technical expertise. Despite intensive perioperative care and the risk of graft or flap failure, skin grafts and free skin flaps can serve as rewarding methods of closing difficult wounds. PMID- 28802985 TI - Clinical analysis of 48-h emergency department visit post outpatient extracorporeal shock wave lithotripsy for urolithiasis. AB - BACKGROUND: Patients suffering from renal or ureteral stones can undergo significant discomfort, even when timely diagnosed and treated. The aim of this study was to assess the risk factors and safety of outpatient Extracorporeal Shock Wave Lithotripsy (ESWL) in the management of patients with renal or ureteral stones. METHODS: In this study, our cohort consisted of 844 outpatients who underwent outpatient ESWL treated between February 2012 and November 2014 at Taipei Veterans General Hospital. Patients who visited the emergency room (ER) within 48 h after Outpatient ESWL were included in this article. This article analyzes the stone size, stone shape (long to short axis ratio), stone location, previous medical management, urinalysis data, complications and treatment received in the emergency department. RESULTS: Among the 844 initial consecutive patients who underwent outpatient ESWL a total of 1095 times, there were 22 (2%) patients who sought help at our emergency room within 48 h after the outpatient ESWL. Of those 22 patients, the mean age was 54.3 +/- 12.6 years, and the BMI was 25.9 +/- 3.2. The most common complication complaint was flank pain (55.2%). Other complications included hematuria (13.8%), fever (17.2%), nausea with vomiting (6.9%), acute urinary retention (3.4%) and chest tightness with cold sweating (3.4%). In 22 patients who went back to the ER, 7 patients were admitted to the ward and 1 patient again returned to the ER. All patients received medical treatment without ESWL or surgical management. The meaningful risk factor of ER visiting rate following outpatient ESWL within 48 h was stone location, and the renal stones showed statistic significant (p = 0.047) when compared to ureteral stones. CONCLUSION: Our study indicated that renal stone contributed to a significantly higher risk of ER-visiting rate to patients than did ureteral stone, following outpatient ESWL within 48 h. This study confirmed that Outpatient ESWL is a safe treatment for renal or ureteral stones, while inpatient ESWL is not absolutely necessary. PMID- 28802986 TI - Research digest: more cardiovascular outcome trials in diabetes. PMID- 28802987 TI - Glucose-lowering drugs: balancing risks and benefits. PMID- 28802988 TI - Does education play a role in language reorganization after surgery in drug refractory temporal lobe epilepsy: An fMRI based study? AB - OBJECTIVES: Patients with drug refractory epilepsy (DRE) and a high level of education may differ in their language recovery after surgery. Our aim was to determine whether there were differences in the extent of improvement and pattern of reorganization of language functions on functional magnetic resonance imaging (fMRI) after surgery to treat refractory temporal lobe epilepsy (TLE) between patients with more than 12 years of formal education versus those with a shorter period of regular schooling. METHODS: After approval by an institutional ethics committee, 60 right-handed, adult patients of left TLE and 20 right-handed, healthy controls were recruited to the study. Multiple aspects of language (Repetition, Naming, Word fluency, Visual word and Comprehension reading) were tested using the Indian Aphasia Battery (IAB) in the Hindi language; fMRI was performed using a standardized Hindi language paradigm (lexical, semantic, syntactic and comprehension components) in both cases and controls, before and after an anterior temporal lobectomy (in cases) with a 1.5T MR Scanner. An array of performance tests of intelligence and the verbal adult intelligence scale (VAIS) were used to measure the Intelligence Quotient (IQ) in Left TLE (LTLE) patients before and after surgery. Language laterality was estimated using the laterality index (LI-toolbox-spm8). Cohen's d test was performed to determine the effect sizes of the differences in the IAB scores, and Pearson's correlation was applied between regional (IFG and STG) activation in controls and TLE patients with more than 12 years of schooling [higher educational status (HES subgroup)] and those with less than 12 years of schooling [lower educational status (LES subgroup)]. RESULTS: At the baseline, clinical testing with IAB showed better scores in controls than in cases. Better scores were observed in subjects with higher levels of education than in those with lower levels of education. An improvement was observed in IQ scores in both the HES and LES groups after ATLR; significant worsening in the abstract ability subtest was noted in the LES group, whereas in the HES group there was an improvement. Blood-oxygen-level dependent (BOLD) activation during language tasks was observed in both cerebral hemispheres in the TLE cases, while it was observed in the traditional left hemispheric language areas in controls. Postoperatively, greater BOLD activation was observed in the left inferior frontal gyri (IFG, r=0.65*; p<0.05), middle frontal gyrus (MFG, r=0.77**; p<0.01) superior temporal gyri (STG, r=0.88* p<0.02) and angular gyrus (AG, r=0.73*; p<0.04) in HES compared to LES subjects. Similarly, LI showed left lateralization of the frontal (LIw=0.77 & 0.71) and temporal (LIw=0.74 & 0.5) regions in controls and the TLE group (post-surgery) compared to the pre surgery group during language tasks. CONCLUSIONS: Greater improvement in language skills and BOLD activation in the left hemisphere in TLE-patients (after epilepsy surgery) with a high level of education was similar to that of healthy controls, implying that education has an effect on the functional reorganization/recovery of language areas. PMID- 28802989 TI - Do polyethylene microplastic beads alter the intestinal uptake of Ag in rainbow trout (Oncorhynchus mykiss)? Analysis of the MP vector effect using in vitro gut sacs. AB - Microplastic (MP) vector effects have been well described in the literature but surprisingly little is in known about the impact of MPs on the intestinal uptake of contaminants. The present study aimed to determine whether the intestinal fate of Ag was affected by the presence of polyethylene MP beads. Ag (added as 110mAg) was introduced into the lumen of rainbow trout (Oncorhynchus mykiss) anterior/mid intestine gut sac preparations as Ag only, Ag and MPs (co-exposure) and Ag incubated MPs (where Ag was adsorbed to the MP). Results show that after 3 h exposure the distribution of accumulated Ag between the four intestinal compartments (mucus layer, mucosal epithelium, muscle layer and serosal saline) was not affected by either MP condition when compared to Ag alone (p > 0.05, One way ANOVA). Across all treatment groups mucus layer binding dominated (54.2 72.6%) whereas relatively little Ag was transported to the blood compartment (i.e. combined muscle layer and serosal saline compartments, 8.5-15.0%). Accompanying adsorption/desorption studies were performed in relevant media. Over 24 h, 60.6+/- 2.9% of the available Ag in artificial freshwater adhered to the surface of the PE MPs. In pH adjusted luminal fluids (pH 2.2, 4.1, 7.4 and 9.8) that span the range of conditions encountered within the rainbow trout digestive tract, there was almost complete dissociation at acidic pHs within 3 h (<2% remaining on MPs at both pH 2.2 and pH 4.1). Such pHs are typical of piscine stomach. Based on our finding we suggest that following the ingestion of MPs with adsorbed pollutants, desorption would occur prior to entering the site of uptake. The MPs themselves have no impact on the trans-epithelial transport of the contaminant, but the net result of the MP vector effect is to potentially introduce labile contaminant forms into the intestine. PMID- 28802990 TI - Spatio-temporal variations in PM leaf deposition: A meta-analysis. AB - Particulate matter (PM) pollution in urban cities is of great concern for public health due to its global and adverse effect of human health while ecosystems function and vegetation control is an effective and eco-friendly way to alleviate PM pollution. We reviewed 150 studies conducted in 15 countries that were published between 1960 and 2016 and used a meta-analysis to examine the time trends and regional differences in leaf deposited PM of urban greening plants. The results suggested that the weekly PM leaf deposition varied markedly with both plant species and space-time and the average value was 1.71 +/- 0.05 g m 2.wk-1, and the variations occurred because of vegetation factors, characteristics of the PM source and meteorological factors. Moreover, fine particulate matter accounts for the minimum proportion of the total PM mass but its number ratio is maximum, more than 90% of the total number of particles. This meta-analysis illustrated the spatio-temporal trends and variations in PM leaf deposition and the influencing factors, which provides a scientific basis for the mechanism of PM deposition on leaf surface as well as plant selection and configuration in urban greening. PMID- 28802991 TI - Volcanogenic SO2, a natural pollutant: Measurements, modeling and hazard assessment at Vulcano Island (Aeolian Archipelago, Italy). AB - Sulfur dioxide (SO2) is a major component of magmatic gas discharges. Once emitted in the atmosphere it can affect the air and land environment at different spatial and temporal scales, with harmful effects on human health and plant communities. We used a dense dataset of continuous SO2 flux and meteorological measurements collected at Vulcano over an 8-year period spanning from May 2008 to February 2016 to model air SO2 concentrations over the island. To this end, we adopted the DISGAS (DISpersion of GAS) numerical code coupled with the Diagnostic Wind Model (DWM). SO2 concentrations in air were determined for three different SO2 emission rates: a reference SO2 flux of ~18 t/d (the median of more than 800 measurements), an enhanced SO2 flux of 40 t/d (average of all measurements plus 1 sigma), and a maximum SO2 flux of 106 t/d (maximum value measured in the investigated period). Maximum SO2 concentrations in air were estimated at the crater, near the high-T fumarole field that is the source of the gas, and ranged from 2000 ppb to ~24,000 ppb for the reference flux, from 2000 ppb to 51,000 ppb for the enhanced flux and from 5000 ppb to 136,000 ppb for the maximum flux, with peak values in limited areas at the bottom of the crater. These concentrations pose a hazard for people visiting the crater, for sensitive individuals in particular. Based on estimated SO2 concentrations in air, we also consider the phytotoxic effects of SO2 on local vegetation. PMID- 28802992 TI - Effects of humic acid and heavy metals on the sorption of polar and apolar organic pollutants onto biochars. AB - The effects of humic acid (HA) and heavy metals (Cu2+ and Ag+) on the sorption of polar and apolar organic pollutants onto biochars that were produced at temperatures of 200 degrees C (BC200) and 700 degrees C (BC700) were studied. Due to the plentiful polar functional groups on BC200, cationic propranolol exhibited higher levels of sorption than naphthalene on BC200 while naphthalene and propranolol showed similar sorption capacities on BC700. HA changed the characteristics of biochars and generally inhibited the sorption of target organic pollutants on biochars; however, enhancement occurred in some cases depending on the pollutants involved and their concentrations, biochars used and the addition sequences and concentrations of HA. On BC200, HA modifications mainly influenced sorption by decreasing its polarity and increasing its aromaticity, while on BC700, the surface area and pore volume greatly decreased due to the pore-blocking effects of HA. Residue dissolved HA in solution may also contribute to sorption inhibition. Complexation between polar functional groups on BC200 and heavy metals slightly enhanced the sorption of neutral naphthalene and significantly enhanced that of anionic 4-nitro-1-naphtol, while limited the sorption of cationic propranolol. Heavy metals together with their associated water molecules decreased the sorption of target chemicals on BC700 via pore filling or pore-mouth-covering. Inhibition of heavy metals for 4-nitro-1-naphthol was found to be the weakest due to the bridge effects of heavy metals between 4 nitro-1-naphtol and BC700. The higher polarizability of Ag+ led to the increase of its sorption on biochars in the presence of organic aromatic pollutants. The results of the present study shed light on the sorption mechanisms of bi-solute systems and enable us to select suitable biochar sorbents when chemicals co exist. PMID- 28802993 TI - Microbial community structure and activity in trace element-contaminated soils phytomanaged by Gentle Remediation Options (GRO). AB - Gentle remediation options (GRO) are based on the combined use of plants, associated microorganisms and soil amendments, which can potentially restore soil functions and quality. We studied the effects of three GRO (aided phytostabilisation, in situ stabilisation and phytoexclusion, and aided phytoextraction) on the soil microbial biomass and respiration, the activities of hydrolase enzymes involved in the biogeochemical cycles of C, N, P, and S, and bacterial community structure of trace element contaminated soils (TECS) from six field trials across Europe. Community structure was studied using denaturing gradient gel electrophoresis (DGGE) fingerprinting of Bacteria, alpha- and beta Proteobacteria, Actinobacteria and Streptomycetaceae, and sequencing of DGGE bands characteristic of specific treatments. The number of copies of genes involved in ammonia oxidation and denitrification were determined by qPCR. Phytomanagement increased soil microbial biomass at three sites and respiration at the Biogeco site (France). Enzyme activities were consistently higher in treated soils compared to untreated soils at the Biogeco site. At this site, microbial biomass increased from 696 to 2352 mg ATP kg-1 soil, respiration increased from 7.4 to 40.1 mg C-CO2 kg-1 soil d-1, and enzyme activities were 2 11-fold higher in treated soils compared to untreated soil. Phytomanagement induced shifts in the bacterial community structure at both, the total community and functional group levels, and generally increased the number of copies of genes involved in the N cycle (nirK, nirS, nosZ, and amoA). The influence of the main soil physico-chemical properties and trace element availability were assessed and eventual site-specific effects elucidated. Overall, our results demonstrate that phytomanagement of TECS influences soil biological activity in the long term. PMID- 28802994 TI - Expression and purification of norovirus virus like particles in Escherichia coli and their immunogenicity in mice. AB - Norovirus (NoV) virus like particles (VLPs) produced in Spodoptera frugiperda (Sf9) cells have been tested in human volunteers as vaccine candidate and were shown to be protective against NoV induced acute gastroenteritis. In this study, prevailing Sydney-2012-like NoV major capsid protein gene with or without N terminal deletions (N26 and N38, 26 and 38 amino acids deleted from N terminus,respectively) were sub-cloned into prokaryotic expression vector, pCold III and pCold IV. Soluble and insoluble proteins were detected for both vectors after induction and higher levels of protein expression were observed for constructs pCold III-N26 and pCold III-N38. Electron microscopy observation of unpurified and purified lysates indicated in vivo assembly of VLPs with two sizes in accordance with those observed in Sf9 cells. In vitro salivary HBGA-VLP binding assay demonstrated that VLPs assembled in Escherichia coli (E. coli) exhibited the same binding pattern as that of VLPs assembled in Sf9 cells. Immunization of mice with purified VLPs derived from pCold III-N38 demonstrated higher IgG antibody titers and blocking antibody titers when compared with full length capsid protein assembled VLPs from recombinant baculovirus expression system. In conclusion, NoV VLPs produced in E. coli using pCold expression vector might be used for the development of NoV vaccine. PMID- 28802995 TI - Examining the high rate of cigarette smoking among adults with a GED. AB - OBJECTIVES: We seek to identify characteristics of GED holders that explain their very high smoking rates compared with high school (HS) graduates. METHODS: We pooled data from the 2006-2014 National Health Interview Surveys (NHIS) for adults aged 25 and older (n=235,031) to describe cigarette smoking behaviors and smoking history for adults in six education categories, with a focus on comparing GED holders to HS graduates. Logistic regression was used to predict the odds of current cigarette smoking and successful quitting, accounting for demographic, employment, family/sociocultural, mental health, and other potential confounders. RESULTS: The smoking rate among adults with a GED (44.1%) was more than five times the rate for those with a college degree (8.3%) and almost twice the rate of adults whose highest level of education was a high school diploma (23.6%). GED holders were also more likely to have started smoking before the age of 15 (32.2%) compared with HS graduates (12.2%) (p<0.001). Even after controlling for 23 socio-demographic and health characteristics, GED holders retained significantly higher odds of current smoking compared to HS graduates (OR=1.73; 95% CI: 1.56, 1.93) and significantly lower odds of successful quitting (OR=0.83, 95% CI: 0.73, 0.94). CONCLUSIONS: GED holders had greater odds of being a current cigarette smoker, regardless of other characteristics that usually explain smoking. Earlier smoking initiation among GED holders, in combination with lower odds of quitting, contributed to their higher current smoking rate. PMID- 28802996 TI - IL-33-matured dendritic cells promote Th17 cell responses via IL-1beta and IL-6. AB - IL-33 is associated with a variety of autoimmune diseases, such as sclerosis, inflammatory bowel disease, and rheumatoid arthritis. Although IL-33 is mainly involved in the induction of Th2 cells, however, the relationship between IL-33 and Th17 cells is still largely unknown. In this study, we investigated the effects of IL-33 on DC-mediated CD4+ T cell activation and Th17 cell differentiation because DCs are essential cells for presenting self-antigens to CD4+ T cells in autoimmune disease conditions. OT-II mice were injected with IL 33-treated DCs or untreated DCs that were primed by OVA323-339 peptide, and their Th17 cell responses were compared. Th17 cell population and IL-17 expression levels were significantly increased in draining lymph nodes of mice injected with IL-33-treated DCs, compared with those in mice injected with untreated DCs. IL-33 treatment maturated DCs to present self-antigens and to increase production of proinflammatory cytokines such as IL-1beta and IL-6, which have a crucial role in Th17 cell differentiation. We found that the IL-33-matured DCs enhanced the expression of an early T cell activation marker (CD69) and the Th17 master transcription factor (RORgammat), but IL-33 did not directly affect CD4+ T cell differentiation or increase Th17 polarization. Notably, neutralizing IL-1beta and/or IL-6 significantly decreased IL-17 expression levels and Th17 cell population which were increased by the coculture of CD4+ T cells with IL-33 matured DCs, indicating that IL-33 may induce Th17 cell responses via IL-1beta and IL-6 derived from IL-33-matured DCs. PMID- 28802997 TI - Prophylactic use of an intra-aortic balloon pump in a high-risk patient with peripartum cardiomyopathy requiring cesarean delivery. AB - The use of intra-aortic balloon counter-pulsation for circulatory support in pregnant women with cardiac failure is limited to several case reports. Few publications have addressed the use of intra-aortic balloon counter-pulsation during delivery. We report a case using prophylactic intra-aortic balloon counter pulsation during the management of a cesarean delivery in a patient with peripartum cardiomyopathy. A 28-year-old primigravid female at 37weeks of gestation was admitted with signs of worsening heart failure, and transthoracic echocardiography revealed a decreased left ventricular ejection fraction of 25%. A plan to proceed with cesarean delivery, using hemodynamic support with intra aortic balloon counter-pulsation, was made during a multidisciplinary meeting. Shortly after initiation of intra-aortic balloon counter-pulsation, the patient's hemodynamics improved, with a decrease in heart rate and an increase in mean arterial blood pressure. After uneventful cesarean delivery of a healthy 3.2kg infant, the patient was transferred to intensive care and was extubated three hours later. Due to hemodynamic instability, intra-aortic balloon counter pulsation support and vasopressor infusion were maintained for four postoperative days. The patient was discharged from the hospital on diuretics and beta-blocker treatment after 20days. Heart failure persisted, requiring heart transplantation 25months later. This report highlights the role of a multidisciplinary team approach in the management of delivery in an obstetric patient with peripartum cardiomyopathy. PMID- 28802998 TI - On the sulfation of O-desmethyltramadol by human cytosolic sulfotransferases. AB - BACKGROUND: Previous studies have demonstrated that sulfate conjugation is involved in the metabolism of the active metabolite of tramadol, O desmethyltramadol (O-DMT). The current study aimed to systematically identify the human cytosolic sulfotransferases (SULTs) that are capable of mediating the sulfation of O-DMT. METHODS: The sulfation of O-DMT under metabolic conditions was demonstrated using HepG2 hepatoma cells and Caco-2 human colon carcinoma cells. O-DMT-sulfating activity of thirteen known human SULTs and four human organ specimens was examined using an established sulfotransferase assay. pH Dependency and kinetic parameters were also analyzed using, respectively, buffers at different pHs and varying O-DMT concentrations in the assays. RESULTS: Of the thirteen human SULTs tested, only SULT1A3 and SULT1C4 were found to display O-DMT sulfating activity, with different pH-dependency profiles. Kinetic analysis revealed that SULT1C4 was 60 times more catalytically efficient in mediating the sulfation of O-DMT than SULT1A3 at respective optimal pH. Of the four human organ specimens tested, the cytosol prepared from the small intestine showed much higher O-DMT-sulfating activity than cytosols prepared from liver, lung, and kidney. Both cultured HepG2 and Caco-2 cells were shown to be capable of sulfating O-DMT and releasing sulfated O-DMT into cultured media. CONCLUSION: SULT1A3 and SULT1C4 were the major SULTs responsible for the sulfation of O-DMT. Collectively, the results obtained provided a molecular basis underlying the sulfation of O-DMT and contributed to a better understanding about the pharmacokinetics and pharmacodynamics of tramadol in humans. PMID- 28802999 TI - Primordial membranes: more than simple container boundaries. AB - Cellular membranes, which are self-assembled bilayer structures mainly composed of lipids, proteins and conjugated polysaccharides, are the defining feature of cell physiology. It is likely that the complexity of contemporary cells was preceded by simpler chemical systems or protocells during the various evolutionary stages that led from inanimate to living matter. It is also likely that primitive membranes played a similar role in protocell 'physiology'. The composition of such ancestral membranes has been proposed as mixtures of single hydrocarbon chain amphiphiles, which are simpler versions of modern lipids. In this review, we discuss the origins, self-assembly patterns, potential functions of these amphiphiles, and their possible roles in protocell activities, as well as their possible evolution towards modern lipids. PMID- 28803000 TI - Interaction of niobium with iron-oxide colloids and the role of humic acid. AB - In this work, we report the sorption of Nb on iron oxides and the effect of humic acid. Iron oxides viz. goethite, hematite and magnetite were chemically synthesised and characterised by X-ray diffraction, particle size, surface area and zeta potential measurement. The sorption of Nb on all the three iron oxides was low (~40%) at pH 1, increased to ~ 90% at pH 8 and decreased marginally above pH 8. The effect of humic acid on the sorption was very small. Thermodynamic parameters viz. activation energy, enthalpy, entropy, free energy and sticking probability were calculated to understand the mechanism of the sorption process. Although the enthalpy was positive, the free energy change was negative i.e. the sorption was entropy driven process. The sorption followed pseudo-second-order kinetics and sticking probability model indicated that the process was chemisorption. This study is important to understand the probable migration of 94Nb (half life 20300 y) during underground storage of radioactive waste. PMID- 28803001 TI - Continuation of comprehensive quality control of the itG 68Ge/68Ga generator and production of 68Ga-DOTATOC and 68Ga-PSMA-HBED-CC for clinical research studies. AB - : Performance of a second itG 68Ge/68Ga generator system and production of 68Ga DOTATOC and 68Ga-PSMA-HBED-CC were tested over one year as an accompaniment to a previously published study (J Nucl Med. 2016;57:1402-1405). METHODS: Performance of a 1951MBq 68Ge/68Ga generator was characterized and the eluate used for preparation of 68Ga-DOTATOC and 68Ga-PSMA-HBED-CC. Weekly elution profiles of 68Ga elution yield and 68Ge breakthrough were determined. RESULTS: 68Ga elution yields averaged 82% (61.8-98.4%) and 68Ge breakthrough averaged 0.002% (0.0007% to 0.004%). The radiochemical purities of 68Ga-DOTATOC and 68Ga-PSMA-HBED-CC were determined by HPLC analysis to be >98% and specific activity was 12.6 and 42GBq/MUmol, respectively. 68Ge contamination in the product was under the detection limit (0.00001%). Final sterile, pyrogen-free formulation of 68Ga DOTATOC and 68Ga-PSMA-HBED-CC in physiologic saline with 5%-7% ethanol was achieved. CONCLUSION: Performance of a 68Ge/68Ga generator was studied over one year with satisfactory results. The generator eluate was used to synthesize 68Ga DOTATOC and 68Ga-PSMA-HBED-CC on a routine basis in high purity. PMID- 28803002 TI - The characteristics of reports to the police of child sexual abuse and the likelihood of cases proceeding to prosecution after delays in reporting. AB - Delays in disclosing and reporting child sexual abuse to the police are common, particularly among males and those who have been abused by clergy and others in a position of trust. This study, commissioned by the Royal Commission into Institutional Responses to Child Sexual Abuse, examined the patterns of timely and delayed reporting of sexual offences against children, and the likelihood of legal action commencing. De-identified unit record data for all sexual offences against children reported to the police over 20 years were obtained from official crime statistics agencies in two Australian states. While there were similarities between the two states in terms of the influence of public inquiries on reporting numbers over this period, and in the factors associated with delayed reporting, there were substantial differences in the likelihood of legal action being taken in cases reported by a child or adult complainants. In one state, legal action was more likely with increasing delay, until the delays extended to 10-20 years, after which the likelihood of legal action decreased. In the other state, the pattern was quite different - reports of sexual assault were somewhat more likely to result in legal action with immediate reporting. The least likely to proceed were cases involving young children in more recent years; long delays into adulthood were not necessarily adverse for prosecution. PMID- 28803003 TI - Pathogenic features and characteristics of food borne pathogens biofilm: Biomass, viability and matrix. AB - Biofilm is a ubiquitous growth pattern of bacterial species survival but is notorious for its threat on public health and food contamination. Extensive studies of the biofilm structure, formation, quantification, quorum sensing system and underlying control strategies have been reported during the past decades. Insightful elucidation of the pathogenic features and characteristic of bacterial biofilm can facilitate in devising appropriate control strategies for biofilm eradication. Therefore, this review mainly summarized the pathogenic features of biofilms from food borne microorganisms, including the biomass (which could be quantified using crystal violet and fluorogenic dye Syto9 assays), viability (which could be determined by tetrazolium salts, fluorescein diacetate, resazurin staining and alamar blue assays) and matrix (which are commonly detected by dimethyl methylene blue and wheat germ agglutinin assays). In addition, three features were further compared with its particular benefits in specific application. PMID- 28803004 TI - "Just" blood donors? A study on the multi-affiliations of blood donors. AB - BACKGROUND: The present work proposes to explore a phenomenon well known in the world of blood donation, but little explored by literature: multi-affiliations. By that term, in this paper we mean blood donors' engagement in multiple associations of various natures (donation, recreation, sports, etc.) simultaneously. The first objective proposes to explore the phenomenon of multi affiliations in descriptive terms; the second is to look into the differences-in terms of motivations, family-work-volunteerism reconciliation, life satisfaction, and membership satisfaction-between those who "only" carry out blood donation activity and those who instead participate in multiple associative realities concurrently. METHOD: Participating in the research were 2674 donors from the Italian Association of Blood Donors (AVIS) (age range 18-65; 66.6% male) to which a self-report questionnaire was administered in the waiting rooms of numerous blood donation centers. RESULTS: Regarding the first objective, it emerged that only 35.9% of the participants "only" donate blood, while a good 64.1% is engaged also in other associations. Regarding the second objective, statistically significant differences emerge regarding many of the variables considered: social, values, ego-protection, and career motivation; capacity to reconcile family-volunteering and work-volunteering; life satisfaction; and membership satisfaction. CONCLUSIONS: The study offers precious information to the agencies that handle recruiting and retaining of donors. The agencies in fact can take away information on how to improve the multi-affiliations of their donors, an aspect that can facilitate their long-term retention. PMID- 28803005 TI - Safety and feasibility of therapeutic platelet depletion with Spectra Optia in a pregnant woman. AB - INTRODUCTION: Thrombocytapheresis is an alternative treatment beneficial in rare circumstances, when cytoreductive agents are contraindicated, drug therapy gave no response or the expected response would be too slow. Here we present a case of a pregnant woman who underwent 5 thrombocytaphereses using Spectra Optia device to reduce circulating platelets (PLT) count and prepare for Cesarian section. PATIENT CHARACTERISTICS AND PERFORMED TREATMENT: A 39-year-old woman with diagnosed chronic myeloid leukemia (CML) was treated with interferon because of too high PLT count. The treatment was well tolerated but the effect was not satisfactory (PLT count remained high). Because of high risk of bleeding during childbirth, the healthcare providers decided to perform thrombocytapheresis to reduce circulating PLT count below 1000*10E3/MUl, and to prepare the patient for a planned Cesarean section. The results are presented as mean+/-SD. RESULTS: Five therapeutic aphereses procedures were performed, with a Spectra Optia device (TerumoBCT). A mean of 1.3+/-0.3 total blood volume was processed and we observed a mean PLT drop of 42.3+/-17.7%. Each apheresis procedure resulted in a PLT level <=1000*10E3/MUl. PLT CE1 was high 50.6+/-2.6% and reproducible. The white blood cell (WBC) loss was low (18.5%+/-11.0%). No adverse effects were observed. CONCLUSION: Therapeutic platelet depletion using the Spectra OptiaTM Apheresis System can be effective and safe during pregnancy. Thrombocytapheresis procedures were reproducible and Spectra Optia system successfully adjusted settings to each procedure conditions. Thrombocytapheresis seems to be a viable and safe option even in pregnant women. PMID- 28803006 TI - Genetic analysis of new progesterone-based fertility traits in dairy cows measured on-farm. AB - The objectives of this study were (1) to analyze the agreement of a standard laboratory ELISA for progesterone (P4) with an automated on-farm ELISA kit operated under commercial conditions in 1,297 milk samples from 50 dairy cows; (2) to study the influence of the method of detection of luteal activity on genetic parameters of fertility traits based on P4 measured with an automated on farm ELISA once weekly from wk 3 to 9 postpartum in the milk of 1,304 cows; and (3) to study the influence of sampling frequency (once or twice weekly from wk 3 to 9) on the same traits from 296 cows. Luteal activity can be detected when there is an active corpus luteum in the ovary producing P4 and indicating the onset of reproductive cyclicity after calving. The on-farm ELISA overestimated P4 contents by a mean square error of prediction of 2.76 ng/mL and had an intermediate Spearman correlation with the laboratory kit (0.54). For the second objective, the postpartum interval to the commencement of luteal activity (C-LA), proportion of luteal activity between d 15 and 63 postpartum (P-LA), calculated as the number of samples above the threshold for high P4 values divided by the number of all samples, and delay of first ovulation (DOV1), defined as C-LA occurring later than d 45 postpartum, were derived from the P4 profiles. Both C LA and DOV1 were determined by (a) thorough qualitative visual inspection of the profile, (b) the profile's mean as threshold for the first increase in P4 postpartum, indicating commencement of luteal activity, and (c) 3 ng/mL as threshold for the first increase in P4, a value that has been used by many other studies. Similarly, P-LA was determined by using methods (b) and (c). Estimates of heritability were 0.04 to 0.13 for C-LA, 0.12 to 0.23 for P-LA, and 0.03 to 0.07 for DOV1. Genetic correlation of P-LA with C-LA and with the profile's mean P4 was -1.00. The profile's mean had a higher estimate of heritability (0.11 0.12) than C-LA or DOV1. It can be calculated as the arithmetic mean of all P4 values of a profile, whereas C-LA, P-LA, and DOV1 need a definition of a threshold for high P4 values. We therefore suggest the profile's mean as a promising candidate for further research. For the third objective, once-weekly sampling was mimicked by neglecting every second sample, and C-LA and DOV1 shifted toward a later onset of cyclicity. Thus, a common standard for sampling regimen and detection algorithm is essential to avoid incompatibility between studies. PMID- 28803007 TI - Associations between biosecurity practices and bovine digital dermatitis in Danish dairy herds. AB - The relationship between biosecurity and digital dermatitis (DD) was evaluated in 8,269 cows from a convenience sample of 39 freestall dairy herds. The hypothesis was that poor implementation of biosecurity was associated with higher within herd prevalence of DD. All lactating cows were scored as negative or positive for DD at the hind legs during milking in the milking parlor. Information about biosecurity was obtained through questionnaires addressed to farmers, on-farm observations, and information from the Danish Cattle Database (www.seges.dk). These assessment tools covered potential infection sources of DD pathogens to susceptible cows (e.g., via animals, humans, manure, vehicles, equipment, and facilities). External and internal biosecurity measures were explanatory variables in 2 separate logistic regression models, whereas within-herd DD prevalence was the outcome. Overall DD prevalence among cows and herds were 24 and 97%, respectively; the within-herd DD prevalence ranged from 0 to 56%. Poor external biosecurity measures associated with higher prevalence of DD were recent animal purchase, access to pasture, lack of boots available for visitors, farm staff working at other dairy farms as well, hoof trimming without a professional attending, and animal transporters having access to cattle area. For internal biosecurity, higher DD prevalence were associated with infrequent hoof bathing, manure scraping less than 8 times a day, manure removal direction from cows to heifers, animal pens' exit without water hoses, manure-handling vehicle used in other activities, and water troughs contaminated with manure. These findings showed that improvements on biosecurity may be beneficial for controlling DD in dairy herds. The study is relevant for farmers facing problems with DD, as well as hoof trimmers, advisors, and veterinarians, who can use the results for optimized recommendations regarding biosecurity in relation to DD. Furthermore, our results might be considered by future studies investigating DD pathogen reservoirs and transmission routes. PMID- 28803008 TI - Two-step large-volume magnetic separation combined with PCR assay for sensitive detection of Listeria monocytogenes in pasteurized milk. AB - Immunomagnetic separation (IMS) is an effective tool for the preconcentration and purification of food-borne pathogens from complex food samples because of its high capture efficiency (CE). In conventional IMS, antibodies are usually conjugated on the surface of magnetic beads (MB); the random orientation and conformation changes of antibodies on the MB surface can decrease their bioactivity. Moreover, the Brownian motion of immobilized antibodies is weakened, thereby rendering their binding efficiency with bacteria lower than that of free antibodies. Thus, abundant antibodies are commonly required to ensure high CE for IMS, particularly for large volumes. In this study, a 2-step large-volume magnetic separation (10 mL) was proposed to preconcentrate Listeria monocytogenes from pasteurized milk. First, the biotinylated anti-L. monocytogenes monoclonal antibodies (mAb) were bound with L. monocytogenes in 10 mL of diluted milk through an antigen-antibody interaction, and then streptavidin-labeled MB were used to capture biotin-mAb coated with L. monocytogenes by biotin and streptavidin interaction. Under optimal conditions, the CE of 2-step magnetic separation was >90% with L. monocytogenes concentrations ranging from 8 * 100 to 8 * 104 cfu/mL, whereas the amount of biotin-mAb was 14 fold lower than that of the conventional IMS method. Coupled with a PCR assay, the detection limit of the proposed method was 8 * 100 cfu/mL in pure culture and 8 * 101 cfu/mL in pasteurized milk without any pre-enrichment process. Moreover, the overall detection time, including sample preparation, large-volume magnetic separation, and PCR, took less than 7 h. In summary, the developed 2-step large-volume IMS combined with PCR was highly sensitive and low cost and, thus, has considerable potential for the rapid screening of food-borne pathogenic bacteria. PMID- 28803009 TI - Involvement of plasma adipokines in metabolic and reproductive parameters in Holstein dairy cows fed with diets with differing energy levels. AB - This study aimed to investigate the association between plasma adipokine concentrations and metabolic and reproductive parameters in Holstein dairy cows fed diets with different energy levels during the peripartum period. The experiment started 1 mo before first calving and was maintained for 2 lactations. Dry matter intake and energy balance in animals fed a low-energy (LE) diet were significantly lower than that of animals fed a high-energy (HE) diet in the first lactation. Body weight, milk production, back fat thickness, and plasma concentrations of fatty acids, glucose, and insulin were not affected by diet, whereas plasma leptin and adiponectin concentrations were lower and plasma resistin concentrations higher in animals fed the LE diet. Unlike concentrations of adiponectin, plasma resistin concentrations were positively correlated with back fat thickness and plasma fatty acids concentrations and negatively correlated with dry matter intake and plasma leptin concentrations. No effect of diet was found on reproductive variables; that is, pregnancy rates at 35 or 90 d after artificial insemination (AI); numbers of small (3-5 mm), medium (>5 and <=7 mm), and large (>7 mm) follicles; calving-to-AI and calving-to-calving intervals; and magnitude and duration of the LH surge. However, the commencement of luteal activity after first calving occurred sooner and the frequency of LH pulses was higher in the HE group than in the LE group. A significant positive correlation was found between the number of follicles (of any size) and the area under the curve of plasma resistin concentrations. The number of small follicles was also positively correlated with the nadir of plasma resistin concentrations. Taken together, these results suggest that dietary energy content in the range applied here can alter the resumption of ovarian activity and LH pulsatility without affecting fat mobilization. Plasma adipokine profiles (leptin, resistin, and adiponectin) were significantly altered by diet and negative energy balance but relationships with reproductive variables were limited to follicular growth characteristics and plasma resistin concentrations. PMID- 28803010 TI - Short communication: Apparent ruminal synthesis of B vitamins in lactating dairy cows fed Saccharomyces cerevisiae fermentation product. AB - Apparent ruminal synthesis and duodenal flow of thiamin, riboflavin, niacin, vitamin B6, folates, and vitamin B12 were evaluated in an experiment using 15 ruminally and duodenally cannulated lactating Holstein cows fed a basal diet, according to a crossover design, supplemented or not with 56 g/d of Saccharomyces cerevisiae fermentation product. Duration of the treatment period was 28 d. The basal ration had 28% neutral detergent fber, 30% starch and 16.5% crude protein; forages were corn silage (67% of forage dry matter) and alfalfa silage (33% of forage dry matter). Concentrations of B vitamins were analyzed in feed and duodenal digesta. Apparent ruminal synthesis of each B vitamin was calculated as the duodenal flow minus the intake. Under the present experimental conditions, a dietary supplement of Saccharomyces cerevisiae fermentation product had no effect apparent synthesis of B vitamins in the rumen or on the amounts of these vitamins reaching the duodenum and available for absorption by the dairy cow. PMID- 28803012 TI - Effect of fermented milk containing Lactobacillus rhamnosus SD11 on oral microbiota of healthy volunteers: A randomized clinical trial. AB - The aims of this study were to evaluate whether short-term consumption of fermented milk containing Lactobacillus rhamnosus SD11 affected levels of oral microbiota in vivo and whether L. rhamnosus SD11 could colonize in the human mouth. We also monitored for potential side effects of the probiotic. The applicability of using L. rhamnosus SD11 compared with Lactobacillus bulgaricus as a starter culture for fermented milk was evaluated. After informed consent, 43 healthy young adults were recruited and randomly assigned to either the probiotic or control group and received fermented milk containing L. rhamnosus SD11 or L. bulgaricus, respectively, once daily for 4 wk. The numbers of mutans streptococci, lactobacilli, and total bacteria in saliva were counted at baseline and then after 4 and 8 wk. An oral examination was performed at baseline and after 8 wk. The persistence of L. rhamnosus SD11 was investigated by DNA fingerprinting using arbitrary primer-PCR. Results demonstrated that statistically significant reductions in mutans streptococci and total bacteria were observed in the probiotic group compared with the control group, and the number of lactobacilli was significantly increased in both groups after receiving fermented milks. Lactobacillus rhamnosus SD11 could be detected (in >80% of subjects) up to 4 wk following cessation of dosing among subjects in the probiotic group. No side effects were reported. Thus, L. rhamnosus SD11 could be used as a starter culture for fermented milk. Daily consumption of L. rhamnosus SD11-containing fermented milk for 4 wk may have beneficial effects on oral health by reducing salivary levels of mutans streptococci. The probiotic was apparently able to colonize the oral cavity for a longer time than previously reported. However, the potential benefits of probiotic L. rhamnosus SD11 on oral health require further evaluation with a larger group of volunteers in a longer term study. PMID- 28803011 TI - New insights on the metabolism of ricinoleic acid in ruminants. AB - Dairy goats were fed a total mixed ration with or without the inclusion of castor oil [40 g/kg of dry matter (DM)] to study the metabolism of ricinoleic acid (12 OH,cis-9-18:1). Ten goats, at 39.7 +/- 4.0 d in milk, were individually penned and allocated at random to the 2 experimental diets. Goats were manually milked twice a day. Milk fatty acids (FA) were analyzed as methyl esters and hydroxyl groups were derivatized in trimethylsilyl ethers. Apart from ricinoleic acid, 6 FA were only detected in the milk of the castor oil group. Ricinoleic acid composed 0.3% of total FA in milk of the castor oil group, whereas the hydroxy-FA (8-OH-14:0, 10-OH-16:0, and 12-OH-18:0) and oxo-FA (8-oxo-14:0, 10-oxo-16:0, and 12-oxo-18:0) reached 7.5% of total FA in milk. We anticipate that these FA were derived from the metabolism of ricinoleic acid, although it was not clear if they were produced in the rumen or in the tissues. To confirm that, we conducted in vitro batch incubations repeated for 3 consecutive weeks with castor oil (40 g/kg of DM) and strained rumen fluid from 2 fistulated sheep. To examine the products formed over time, incubation tubes were stopped at 0, 6, 12, 24, 48, and 72 h. The results of the in vitro experiment showed that ricinoleic acid was metabolized in the rumen at a slow rate and the main products formed were 12-OH 18:0 and 12-oxo-18:0, by hydrogenation of the cis-9 double bond, followed by oxidation of the hydroxyl group, respectively. Our results suggest that the 12-OH 18:0 and 12-oxo-18:0 escape rumen and are further metabolized through partial beta-oxidation in ruminant tissues. We propose that the 10-OH-16:0 and 8-OH-14:0 found in goat milk of the castor oil group are successive products of the beta oxidation of 12-OH-18:0, and the 10-oxo-16:0 and 8-oxo-14:0 are successive products of the 12-oxo-18:0 in tissues. Overall, our results indicate that ricinoleic acid is extensively metabolized in the rumen and tissues, producing mainly oxo- and hydroxy-FA that are further excreted in milk. PMID- 28803013 TI - Short communication: Detection of stx2 and elt genes in bovine milk by using a multiplex PCR system. AB - The aim of this study was to detect 2 important toxin genes from diarrheagenic Escherichia coli (DEC) in bovine milk using a new multiplex PCR. To standardize the multiplex PCR, the stx2 and elt genes were investigated for the detection of Shiga toxin-producing Escherichia coli (STEC) and enterotoxigenic E. coli (ETEC), respectively. The DNA template was prepared with a thermal procedure (boiling) and a commercial kit. Samples consisted of UHT and pasteurized milk, both skimmed, and STEC and ETEC were tested in concentrations between 101 and 109 cfu/mL. With the thermal procedure, the multiplex PCR system detected both pathotypes of E. coli at 109 cfu/mL in UHT and pasteurized milk. When the commercial kit was used for template preparation, STEC and ETEC could be detected at concentrations as low as 104 cfu/mL in UHT and pasteurized milk. Negative controls (Listeria monocytogenes, Salmonella Typhimurium, Salmonella Enteritidis, and Escherichia coli strain APEC 13) were not amplified with the multiplex PCR. These results indicate that the multiplex PCR was a rapid (less than 6 h) and efficient method to detect STEC and ETEC in milk using different methods for DNA preparation; however, the commercial kit was more sensitive than the thermal procedure. PMID- 28803014 TI - Fertility of lactating Holstein cows submitted to a Double-Ovsynch protocol and timed artificial insemination versus artificial insemination after synchronization of estrus at a similar day in milk range. AB - Our objective was to compare the AI submission rate and pregnancies per artificial insemination (P/AI) at first service of lactating Holstein cows submitted to a Double-Ovsynch protocol and timed artificial insemination (TAI) versus artificial insemination (AI) to a detected estrus after synchronization of estrus at a similar day in milk range. Lactating Holstein cows were randomly assigned to receive their first TAI after a Double-Ovsynch protocol (DO; n = 294) or to receive their first AI after a synchronized estrus (EST; n = 284). Pregnancy status was determined 33 +/- 3 d after insemination and was reconfirmed 63 +/- 3 d after insemination. Data were analyzed by ANOVA and logistic regression using the MIXED and GLIMMIX procedures of SAS (SAS Institute Inc., Cary, NC). By design, days in milk at first insemination did not differ between treatments (76.9 +/- 0.2 vs. 76.7 +/- 0.3 for DO vs. EST cows, respectively), but more DO cows were inseminated within 7 d after the end of the voluntary waiting period than EST cows (100.0 vs. 77.5%). Overall, DO cows had more P/AI than EST cows at both 33 d (49.0 vs. 38.6%) and 63 d (44.6 vs. 36.4%) after insemination, but pregnancy loss from 33 to 63 d after insemination did not differ between treatments. Primiparous cows had more P/AI than multiparous cows 33 and 63 d after insemination, but the treatment by parity interaction was not significant. Synchronization rate to the hormonal protocols was 85.3%, which did not differ between treatments; however, synchronized DO cows had more P/AI 33 d after insemination than synchronized EST cows (54.7 vs. 44.5%). In summary, submission of lactating Holstein cows to a Double-Ovsynch protocol and TAI for first insemination increased the percentage of cows inseminated within 7 d after the end of the voluntary waiting period and increased P/AI at 33 and 63 d after first insemination resulting in 64 and 58% more pregnant cows, respectively, than submission of cows for first AI after detection of estrus at a similar day in milk range. We conclude that, because the proportion of synchronized cows did not differ between treatments, DO cows had more P/AI than EST cows because of an intrinsic increase in fertility after submission to a fertility program. PMID- 28803015 TI - Calf and replacement heifer mortality from birth until weaning in pasture-based dairy herds in New Zealand. AB - The aims of this study were to (1) estimate the perinatal (birth to 24 h) and postnatal (~24 h to the mean weaning age of 13 wk) mortality risk in pasture based dairy calves until weaning, and (2) identify associated risk factors in the 2015 calving season. A prospective survey of 32 seasonal calving dairy farms was undertaken. Farmers recorded (daily) the number and sex of the calves alive or dead in the paddocks where cows calved. All daily animal movements in and out of the calf rearing facilities, including death and euthanasia, and the identification of the animals (if applicable) were recorded, and a survey of the farm management practices was undertaken. Individual and farm-level risk factors for perinatal mortality were modeled separately using generalized logistic mixed models with a random effect fitted for herd. Postnatal mortality incidence risk was calculated using time at risk for each calf from 24 h of age, collapsed into weeks, and multiplying the incidence risk by the mean weaning age of the study population. Farm-level risk factors contributing to postnatal mortality in the first week of life were assessed using a multivariable logistic mixed regression model. The mean perinatal mortality risk was 5.7% (95% confidence interval 5.4 to 6.1%) with a range from 2.2 to 8.6% (18,437 calves, 30 farms). Perinatal calf mortality was greater for male relative to female calves (odds ratio 1.39; 95% confidence interval 1.22 to 1.59), calves born in the first week of the calving period in comparison to wk 2 to 11 (odds ratio 0.32 to 0.66), and those born on days with greater rainfall (odds ratio 1.01 per 1 mm increase; 95% confidence interval 1.00 to 1.02). At the farm level, perinatal mortality increased for every extra week of calving period length (odds ratio 1.12; 95% confidence interval 1.06 to 1.17). The mean postnatal mortality risk was 4.1% (95% confidence interval 3.6 to 4.6%) with a range of 0 to 11% between farms. Farm level risk factors contributing to mortality in the first week of life included farmer-reported disease problems in calves (odds ratio 2.2; 95% confidence interval 1.62 to 2.96), or calves hand-fed colostrum in the first 12 h of life (odds ratio 1.66; 95% confidence interval 1.26 to 2.19), which was assumed to be associated with poor colostrum quality and bacterial contamination. Regional differences were also observed in both perinatal and postnatal mortality risks, indicating that weather conditions, herd size, and management variations contribute to mortality incidence. In summary, the mortality risk of perinatal calves and postnatal calves until weaning on pasture-based farms is comparable with data published from other dairying systems despite the notable management differences. Several risk factors were identified that could be managed to reduce mortality incidence of dairy calves. PMID- 28803016 TI - Association between ambient temperature and humidity, vaginal temperature, and automatic activity monitoring on induced estrus in lactating cows. AB - The objective of this study was to determine the association between ambient temperature and humidity, vaginal temperature, and automated activity monitoring in synchronized cows. Lactating Holstein cows (n = 641; 41.5 +/- 9.4 kg of milk/d) were fitted with leg-mounted pedometers, resulting in 843 evaluated activity episodes of estrus. Vaginal temperature was monitored using thermometers attached to an intravaginal device as part of a timed artificial insemination (TAI) protocol; vaginal temperature was recorded every 10 min for 3 d. Ambient temperature and relative humidity were monitored using an external thermometer placed in the center of each pen. Milk production and body condition score (BCS) data were collected at the time of thermometer insertion. All statistical analysis was performed in R (https://www.r-project.org/) using Pearson correlation, analysis of variance, and logistic regression. Heat stress was calculated based on the percentage of time the cow spent with a vaginal temperature >=39.1 degrees C (PCT39) 9 to 11 d before TAI, and was classified as high (>=22.9%) or low (<22.9%). The mean vaginal temperature was 38.9 +/- 0.2 degrees C, and the mean maximum and minimum vaginal temperatures were 39.7 +/- 0.5 degrees C and 38.0 +/- 0.8 degrees C, respectively, with an average amplitude of 1.71 +/- 0.9 degrees C. Mean relative increase (RI) of estrus walking activity was 237.0 +/- 160%. Animals with low BCS had a lower RI compared with cows with medium BCS (260.31 +/- 17.45% vs. 296.42 +/- 6.62%). Cows in early lactation showed lower RI compared with mid- and late-lactation animals (265.40 +/- 9.90% vs. 288.36 +/- 11.58% vs. 295.75 +/- 11.29% for early, mid, and late lactation, respectively). Temperature-humidity index (THI) conditions categorized as low (THI <=65) were associated with greater RI compared with medium (>65 to <70) and high THI (>=70). We detected no significant effect of PCT39 or milk production on RI, whereas parity exhibited a tendency. Cows that displayed greater RI at estrus had greater pregnancies per artificial insemination (P/AI) than cows with low RI (27 vs. 20%) or no RI (27 vs. 12%). Primiparous cows had greater P/AI than multiparous cows (27 vs. 20%), and cows in early and mid lactation had improved P/AI than those in late lactation (26 vs. 22 vs. 16% for early, mid, and late lactation, respectively). An interaction was observed between PCT39 and THI on P/AI, where a subpopulation of cows with high PCT39 had decreased P/AI under high THI conditions, but no differences in P/AI were observed for high PCT39 cows under medium or low THI conditions (13 vs. 24 vs. 26%). Future research should aim to refine variables related to hyperthermia and to understand the effects of body temperature on estrus expression and pregnancy rates. PMID- 28803017 TI - Technical note: Use of an automated grooming brush by heifers and potential for radiofrequency identification-based measurements of this behavior. AB - Healthy cattle readily use grooming brushes but this behavior subsides when animals become ill. Tracking use of a brush may provide an opportunity for health monitoring, especially if the process could be automated. We assessed how healthy heifers groom themselves on a brush and hypothesized that radiofrequency identification (RFID) could be used to accurately and automatically record this behavior. Angus and Hereford heifers (n = 16) were fitted with 2 ultra-high frequency RFID ear tags and monitored in groups of 8 while housed in a pen with an electronic brush, video cameras, and 4 RFID antennas. Each heifer was observed for a 6-h period using continuous video recordings, and brush contact was characterized in terms of anatomic region involved (head/neck, trunk, or posterior) and when not touching the brush but within 1 body length of it. The RFID data were collected for the same period and then processed such that intervals of up to 16 s with no detections but contained between 2 recordings were also considered positive (animal in brush proximity). Brush proximity (RFID) was regressed against brush contact duration (video) and the sensitivity and specificity for each individual heifer calculated. Across heifers, the majority of brush use involved the head/neck, although a few heifers demonstrated relatively large amounts of posterior contact, which contributed to false negative readings when antennas failed to read the ear tags. Furthermore, for the majority of time that animals were near the brush, they were not in contact with it but rather standing or lying nearby, resulting in false-positive readings. It follows that the ability of the RFID system to accurately detect brush contact varied widely across individual heifers (sensitivity 0.54-1.0; specificity 0.59 0.98), with RFID generally overestimating the duration of brush proximity relative to actual time spent in brush contact. The implication is that RFID based ear tag recording of brush proximity relative to continuous video observations of contact does not yield accurate results in certain heifers and therefore, as currently configured, is not a reliable representation of this type of grooming behavior. PMID- 28803018 TI - Short communication: Molecular characteristics, antimicrobial susceptibility, and pathogenicity of clinical Nocardia cyriacigeorgica isolates from an outbreak of bovine mastitis. AB - The occurrence of nocardial mastitis, mostly in the context of outbreaks, has been reported in many countries. However, there is a paucity of reports regarding detailed characterization of Nocardia cyriacigeorgica from bovine mastitis. Thus, herein we report characteristics, antimicrobial susceptibility patterns, molecular identification, and pathogenicity of N. cyriacigeorgica isolated from an outbreak of clinical mastitis in a dairy herd in northern China. A total of 182 (80.2%) lactating cows had clinical mastitis with severe inflammation and firmness of the udder, reduced milk production, and anorexia, with no apparent clinical response to common antibiotics. Out of 22 mastitic milk samples submitted to our laboratory, 12 N. cyriacigeorgica were isolated and characterized using standard microbiological analysis, 16S rRNA gene sequencing, random amplified polymorphic DNA PCR analysis, biochemical assays, and antibiotic susceptibility testing. Additionally, in vivo experiments were done to determine pathogenicity of these clinical mastitis isolates. All isolates were resistant to ampicillin, amoxicillin-clavulanic acid, ciprofloxacin, minocycline, rifampicin, and aminoglycosides (type VI pattern). Additionally, intramammary inoculation of mice with N. cyriacigeorgica caused chronic inflammatory changes, including hyperemia, edema, and infiltration of lymphocytes and neutrophils, as well as hyperplasia of lymph nodules in mammary glands. Therefore, we concluded that N. cyriacigeorgica was involved in the current outbreak of mastitis. To our best knowledge, this is the first report to characterize N. cyriacigeorgica isolated from cases of bovine mastitis in China. PMID- 28803019 TI - Daily lying behavior of lactating Holstein cows during an estrus synchronization protocol and its associations with fertility. AB - Objectives were to quantify lying behavior (LB) during an estradiol and progesterone-based synchronization protocol, to assess risk factors for ovulation, pregnancy per AI (P/AI), and degree of behavioral change at estrus, and to investigate the associations between estrus LB and walking activity. Holstein cows (43.6 +/- 11.0 kg of milk/d) were fitted with leg-mounted accelerometers. Total lying time/d (L_time), bout frequency (bout_N), average lying bout duration, and relative increase in walking activity (ACT%) were evaluated for 1,411 timed artificial insemination events. The day with lowest L_time or bout_N among d -2, -1, and 0 (day of timed artificial insemination) determined the day of behavioral estrus. The variables L_time% and bout_N% represent relative ratios between lowest L_time and baseline (d -7), L_time, and lowest bout_N, and baseline (d -7) bout_N, respectively [e.g., (lowest L_time/baseline L_time) * 100]. Correlation coefficients between L_time% and bout_N% and ACT% were -0.38 and -0.31, respectively. Estrus LB change was considered large if <75% of baseline and small if >=75% of baseline for both L_time% and bout_N%; average lying bout duration did not change with estrus. Lowest L_time% and bout_N% corresponded to, respectively, 65 +/- 21% (mean +/- standard deviation; 447 +/- 157 min/d) and 65 +/- 24% (8.5 +/- 4.0 bouts/d) of baseline. The change in L_time% at estrus was smaller when cows had milk yield above average; the change in bout_N% was smaller among multiparous cows and for estrus occurring in the colder season. Likelihood of ovulation was greater when there was larger change in L_time% [odds ratio = 4.9; ovulation rate = 93 (large change) and 76% (small change)], as well as when a corpus luteum was present at start of protocol (odds ratio = 3.6; in the model with L_time%). Likelihood of pregnancy at d 32 was 1.6 times greater for estrus with large change in LB [L_time% or bout_N%; P/AI = 34% (large change in L_time%) and 26% (small change in L_time%)]. Among estrus events with ACT% >=300% (high intensity), classification by small or large L_time% did not influence P/AI at 32 d. The magnitude of LB change at estrus and its association with fertility suggest potential application toward improved use of activity monitors (e.g., increased estrus detection, fertility prediction). The contribution of LB to accuracy of estrus detection when physical activity is known remains to be addressed. The relationship between intensity of estrus expression and fertility requires further investigations of its physiological rationale and on-farm applications. PMID- 28803020 TI - A missense mutation in PFAS (phosphoribosylformylglycinamidine synthase) is likely causal for embryonic lethality associated with the MH1 haplotype in Montbeliarde dairy cattle. AB - A candidate mutation in the sex hormone binding globulin gene was proposed in 2013 to be responsible for the MH1 recessive embryonic lethal locus segregating in the Montbeliarde breed. In this follow-up study, we excluded this candidate variant because healthy homozygous carriers were observed in large-scale genotyping data generated in the framework of the genomic selection program. We fine mapped the MH1 locus in a 702-kb interval and analyzed genome sequence data from the 1,000 bull genomes project and 54 Montbeliarde bulls (including 14 carriers and 40 noncarriers). We report the identification of a strong candidate mutation in the gene encoding phosphoribosylformylglycinamidine synthase (PFAS), a protein involved in de novo purine synthesis. This mutation, located in a class I glutamine amidotransferase-like domain, results in the substitution of an arginine residue that is entirely conserved among eukaryotes by a cysteine (p.R1205C). No homozygote for the cysteine-encoding allele was observed in a large population of more than 25,000 individuals despite a 6.7% allelic frequency and 122 expected homozygotes under neutrality assumption. Genotyping of 18 embryos collected from heterozygous parents as well as analysis on nonreturn rates suggested that most homozygous carriers died between 7 and 35 d postinsemination. The identification of this strong candidate mutation will enable the accurate testing of the reproducers and the efficient selection against this lethal recessive embryonic defect in the Montbeliarde breed. PMID- 28803021 TI - Effect of dietary supplementation with heat-treated canola meal on ruminal nutrient metabolism in lactating dairy cows. AB - An experiment was conducted to quantify the effects of incremental levels of heat moisture-treated canola meal (TCM) fed to dairy cows on the relationship between ruminal nutrient digestion and milk production. Experimental diets were fed to 4 multiparous rumen-cannulated Nordic Red cows, averaging (mean +/- standard deviation) 681 +/- 54.8 kg of body weight, 111 +/- 16 d in milk, and 29.1 +/- 9.1 kg of milk/d at the start of the study, in a Latin square design with four 21-d periods. The 4 experimental dietary treatments consisted of a basal diet of grass silage and crimped barley, and 3 diets in which the crimped barley was replaced with TCM, giving 3 incremental levels of protein supplementation. Nutrient flow was quantified by the omasal sampling technique using 3 markers (Cr, Yb, and indigestible neutral detergent fiber). Continuous infusion of 15N was used to label bacterial crude protein. Additionally, ruminal sampling and evacuations and measurements of total-tract digestibility were conducted. The experimental diets provided 132, 148, 164, and 180 g of crude protein/kg of dry matter. The increased level of TCM linearly increased dry matter intake from 15.1 to 16.6 kg/d and energy-corrected milk yield from 21.0 to 25.6 kg/d. The increased proportion of TCM when substituting barley with TCM was associated with greater total-tract digestibility of neutral detergent fiber and potentially digestible neutral detergent fiber, which could be explained by increased digestion rate of potentially digestible neutral detergent fiber. Omasal flow of nonammonia N naturally increased with greater dietary TCM inclusion, but the increased intestinal supply of rumen-undegradable protein was partly offset by diminished microbial protein synthesis when feeding more TCM. This was also reflected in a decreased proportion of milk protein from ruminal bacterial protein when TCM supplementation increased. PMID- 28803022 TI - Short communication: Antioxidative and antibacterial activities on Staphylococcus aureus and Escherichia coli O157:H4 in milk with added ginseng marc extract fermented by Lactobacillus plantarum KCCM 11613P. AB - Ginseng marc, a by-product of the extraction of fresh ginseng, is known to have bioactive compounds, but is frequently discarded as agriculture waste. The objectives of our study were to assess the antioxidative activity of fermented ginseng marc extract using Lactobacillus plantarum KCCM 11613P and to evaluate antibacterial activity of fermented milk with added ginseng marc extract during fermentation. After 24 h of fermentation of ginseng marc extract, the viable cell number was increased to 7.7 +/- 0.1 log cfu/mL, and the pH and total titratable acidity were 4.2 +/- 0.4 and 0.6% lactic acid, respectively. The total phenolic and flavonoid contents of fermented ginseng marc extract increased by 32.4 and 23.3%, respectively. Higher antioxidative activity of fermented ginseng marc extract was obtained in the beta-carotene bleaching, ferric-reducing ability of plasma, and ferric thiocyanate assays than the 1,1-diphenyl-2-picrylhydrazy assay. However, the 1,1-diphenyl-2-picrylhydrazy scavenging effect decreased due to lowered pH. During production of fermented milk with ginseng, inhibition rate of Staphylococcus aureus and Escherichia coli were 9.7 and 2.3%, respectively. The present study shows the possibilities of Lactobacillus plantarum KCCM 11613P used as a fermentation strain and ginseng marc used as a functional supplement in milk. PMID- 28803023 TI - Consumer acceptance of dairy products with a saturated fatty acid-reduced, monounsaturated fatty acid-enriched content. AB - Agriculture-based reformulation initiatives, including oleic acid-rich lipid supplementation of the dairy cow diet, provide a novel means for reducing intake of saturated fatty acids (SFA) at a population level. In a blinded manner, this study evaluated the consumer acceptance of SFA-reduced, monounsaturated fatty acid-enriched (modified) milk, Cheddar cheese, and butter when compared with control and commercially available comparative samples. The effect of providing nutritional information about the modified cheese was also evaluated. Consumers (n = 115) rated samples for overall liking (appearance, flavor, and texture) using 9-point hedonic scales. Although no significant differences were found between the milk samples, the modified cheese was liked significantly less than a regular-fat commercial alternative for overall liking and liking of specific modalities and had a lower liking of texture score compared with the control cheese. The provision of health information significantly increased the overall liking of the modified cheese compared with tasting the same sample in a blinded manner. Significant differences were evident between the butter samples for overall liking and modalities of liking; all of the samples were significantly more liked than the commercial butter and sunflower oil spread. In conclusion, this study illustrated that consumer acceptance of SFA-reduced, monounsaturated fatty acid-enriched dairy products was dependent on product type. Future research should consider how optimization of the textural properties of fatty acid modified (and fat-reduced) cheese might enhance consumer acceptance of this product. PMID- 28803024 TI - A comparison of splicing assays to detect an intronic variant of the OCRL gene in Lowe syndrome. AB - Lowe syndrome is an X-linked inherited disorder diagnosed by congenital cataracts, intellectual impairment, and renal tubular dysfunction. It is caused by pathogenic variants of the oculocerebrorenal syndrome of Lowe gene (OCRL), of which more than 250 have been reported so far. Around 30 of these variants are intronic nucleotide changes; however, to show the pathogenicity of these variants is usually laborious. In this report, we conducted genetic testing of a patient clinically diagnosed with Lowe syndrome to detect the presence of OCRL variants. We analyzed variant transcript expression in peripheral blood leukocytes and using a minigene construct in addition to in silico analysis. We detected a 9 base pair intronic insertion between OCRL exon 10 and exon 11 derived from the alteration of the splicing acceptor site in intron 10 caused by the intronic splicing variant NM_000276.3: c.940-11G>A (p.Lys313_Val314insAsnSer*). The findings obtained from transcript analysis of peripheral blood leukocytes and the minigene construct assay were identical to those of in silico analysis. All assays detected the same transcript abnormality and were reliable in revealing the pathogenicity of the intronic variant. The in vitro assay can also be used to clarify the complicated splicing mechanisms in inherited kidney diseases. PMID- 28803025 TI - The effect of nano-TiO2 photocatalysis on the antioxidant activities of Cu, Zn SOD at physiological pH. AB - Security issues of nanoparticles on biological toxicity and potential environmental risk have attracted more and more attention with the rapid development and wide applications of nanotechnology. In this work, we explored the effect and probable mechanism of nano-TiO2 on antioxidant activity of copper, zinc superoxide dismutase (Cu, Zn-SOD) under natural light and mixed light at physiological pH. Nano-TiO2 was prepared by sol-hydrothermal method, and then characterized by X-ray Diffraction (XRD) and Transmission electron micrographs (TEM). The Cu, Zn-SOD was purified by sephadex G75 chromatography and qualitatively analyzed by sodium dodecyl sulfate polypropylene amide gel electrophoresis (SDS-PAGE). The effect and mechanism were elucidated base on Fourier Transform Infrared Spectrometer (FT-IR), Circular Dichroism (CD), zeta potential, and electron spin resonance (ESR) methods. Accompanying the results of FT-IR, CD and zeta potential, it could be concluded that nano-TiO2 had no effect on the antioxidant activity of Cu, Zn-SOD by comparing the relative activity under natural light at physiological pH. But the relative activity of Cu, Zn-SOD significantly decreased along with the increase of nano-TiO2 concentration under the mixed light. The results of ESR showed the cause of this phenomenon was the Cu(II) in the active site of Cu, Zn-SOD was reduced to Cu(I) by H2O2 and decreased the content of active Cu, Zn-SOD. The reduction can be inhibited by catalase. Excess O2.- produced by nano-TiO2 photocatalysis under mixed light accumulated a mass of H2O2 through disproportionation reaction in this experimental condition. The results show that nano-TiO2 cannot affect the antioxidant activity of Cu, Zn-SOD in daily life. The study on the effect of nano TiO2 on Cu, Zn-SOD will provide a valid theory support for biological safety and the toxicological effect mechanism of nanomaterials on enzyme. PMID- 28803027 TI - Alizarin Yellow R (AYR) as compatible stabilizer for miniemulsion polymerization. AB - HYPOTHESIS: Many solid particles have been used in Pickering stabilized (mini)emulsions. Stabilizing "particles" can be also formed in situ e.g. by aggregation of dye molecules as reported recently. Among the dyes sodium 2 hydroxy-5-[(E)-(4-nitrophenyl)diazenyl]benzoate (Alizarin Yellow R, (AYR)) is one of the best stabilizers. It is assumed to act as sole stabilizer also in heterophase polymerizations and offers a great potential for applications. EXPERIMENTS: Aqueous solutions of AYR in varying concentrations (0.3, 0.5, 1.0, 1.5, 2.0mg/mL (dye/water)) were employed as continuous phase in direct miniemulsions. The oil phase comprised ethenylbenzene (styrene) and hexadecane. The effects of AYR concentration and ultrasonication time on size and distribution of the droplets were investigated. The miniemulsions were polymerized with a water-soluble azo-initiator (2,2'-azobis[n-(2-carboxyethyl)-2 methylpropionamidine] n-hydrate, VA-057) and conversion and kinetics were determined. FINDINGS: The AYR is successfully employed as stabilizer in Pickering like miniemulsion polymerizations of styrene. The higher the AYR concentrations the more stable the miniemulsions, the smaller the droplet sizes and the narrower the distributions are, ranging from ca. 450 to 180nm and 0.38 to 0.15, respectively. The nucleation mechanism of the polymer particles could be revealed by the number ratio of droplets and particles and follows droplet nucleation. This is confirmed by polymerization kinetics, which is in accordance with classical miniemulsion polymerization, too. PMID- 28803028 TI - Novel Poly(l-lactide)/graphene oxide films with improved mechanical flexibility and antibacterial activity. AB - Poly(l-lactic acid) (PLLA) is a biocompatible polyester derived from renewable sources. It is desirable to reduce its brittleness and introduce antibacterial activity for biomedical applications by using graphene oxide (GO) as a structural and antibacterial agent. However, commonly used polymer/GO composite synthesis methods, such as physical mixing and covalent functionalization, either cause phase segregation or compromise the intrinsic properties of GO. Here, a novel approach is demonstrated to synthesize PLLA/GO films. First, perylene bisimides containing PLLA (PBI-PLLA) was synthesized via ring-opening polymerization of l lactide using a hydroxyl-derivate of perylene bisimides (PBI-OH) as the initiator. Next, PBI-PLLA was conjugated with GO via pi-pi stacking to form PLLA conjugated GO (PLLA-c-GO). Last, PLLA/GO films were fabricated by simple solution casting of commercial PLLA and PLLA-c-GO dissolved in chloroform. Detailed characterization shows that GO retains its morphology and functional groups in PLLA-c-GO, which enables unique properties in the PLLA/GO films. The starting thermal degradation temperature of PLLA/GO films in N2 increases to 313 degrees C comparing to commercial PLLA films at 293 degrees C. Their surface is more hydrophilic with the water contact angle of 53 degrees . Their elongation at break improves significantly from 3% to 30% compared to commercial PLLA films, demonstrating much better flexibility. Most importantly, the PLLA/GO films show good antibacterial activity towards Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and Bacillus subtiliscells (B. subtilis) cells with the bacterial colony number reduction by 80%. At the same time, they show low toxicity towards mammalian cells, such asL929 and macrophage cells. Overall, the novel PLLA/GO films demonstrate various beneficial characteristics for potential biomedical applications. PMID- 28803026 TI - Novel mesoporous graphitic carbon nitride modified PbBiO2Br porous microspheres with enhanced photocatalytic performance. AB - Sustainable mesoporous graphitic carbon nitride (mpg-C3N4) modified PbBiO2Br porous microsphere (mpg-C3N4/PbBiO2Br) had been successfully synthesized via solvothermal process. Multiple techniques were applied to explore the structure, morphology, optical and electronic properties of the as-prepared photocatalysts. It could be found that the mpg-C3N4 was uniformly distributed on the surface of the PbBiO2Br porous microsphere. Compared with the pure PbBiO2Br, the mpg C3N4/PbBiO2Br exhibited superior photocatalytic activity for the degradation of organic pollutants under visible light irradiation. When the mass fraction of mpg C3N4 was 3%, the mpg-C3N4/PbBiO2Br composite materials exhibited the highest photocatalytic performance. The results indicated that the introduction of mpg C3N4 could effectively enhance the electron mobility to promote the catalytic activity. The enhanced photocatalytic activity of the mpg-C3N4/PbBiO2Br materials can be attributed to the stronger optical trapping capability and the more effective separation efficiency of photogenerated electron-hole pairs. During the process of photocatalysis, the main active species of the photocatalysts were determined to be the and hole under visible light irradiation. Based on the relative band positions of mpg-C3N4 and PbBiO2Br, a possible photocatalytic mechanism of mpg-C3N4/PbBiO2Br composite catalyst was proposed. PMID- 28803029 TI - Do patient perceptions of provider communication relate to experiences of physical pain? AB - OBJECTIVES: Patient-provider communication is an important component of the medical interaction yet little research has examined the relationships between perceptions of communication and health outcomes or the mechanisms by which communication may ameliorate the pain experience. This is the first study to examine the relationships between patients' perceptions of provider communication, pain intensity and self-efficacy for managing chronic disease. METHODS: The total sample contained 1027 (85.8% male) Veteran patients. Patients responded to surveys about their experiences and outcomes of care, including measures of patient-provider communication, self-efficacy and pain outcomes including pain intensity and pain interference. RESULTS: Results showed more positive perceptions of provider communication were related to lower levels of pain intensity and pain interference and that this relationship was significantly mediated by higher levels of self-efficacy for managing chronic disease. CONCLUSION: More positive provider communication was related to higher levels of self-efficacy, which in turn was related to lower levels of pain intensity and pain interference. Findings suggest that providers may be able to elicit higher levels of self-efficacy in their patients by providing patient-centered communication, which in turn will reduce pain intensity and interference in their patient's lives. PMID- 28803030 TI - Neurofeedback, sham neurofeedback, and cognitive-behavioural group therapy in adults with attention-deficit hyperactivity disorder: a triple-blind, randomised, controlled trial. AB - BACKGROUND: Many studies suggest that electroencephalographic (EEG) neurofeedback might be beneficial in the treatment of attention-deficit hyperactivity disorder (ADHD). However, numbers of well controlled studies are low and neurofeedback techniques are regarded as highly controversial. The present trial examined the efficacy (compared with sham neurofeedback) and efficiency (compared with meta cognitive therapy) of a standard EEG neurofeedback protocol in adults with ADHD. METHODS: We did a concurrent, triple-blind, randomised, controlled trial using authorised deception in adults with ADHD from one centre (University of Tubingen) in Tubingen, Germany. Participants were eligible if they fulfilled the DSM-IV-TR criteria for ADHD, were aged between 18 years and 60 years, and had no or stable use of medication for at least 2 months with no intention to change. We excluded participants who had comorbid schizophrenia or schizoaffective disorder, bipolar disorder, borderline personality disorder, epilepsy, or traumatic brain injury; substance abuse or dependence; or current or planned other psychological treatment. Those eligible were randomly assigned to three groups: a neurofeedback group which received 30 verum theta-to-beta neurofeedback sessions over 15 weeks, a sham neurofeedback group which received 15 sham followed by 15 verum theta-to beta neurofeedback sessions over 15 weeks, or a meta-cognitive group therapy group which received 12 sessions over 12 weeks. Participants were assigned equally to one of the three interventions through a computerised minimisation randomisation procedure stratified by sex, age, and baseline symptom severity of ADHD. Participants were masked as to whether they were receiving neurofeedback or sham neurofeedback, but those receiving meta-cognitive therapy were aware of their treatment. Clinical assessors (ie, those assessing outcomes) and research staff who did the neurofeedback training were masked to participants' randomisation status only for neurofeedback and sham neurofeedback. The primary outcome was symptom score on the Conners' adult ADHD rating scale, assessed before treatment, at midtreatment (after 8 weeks), after treatment (after 16 weeks), and 6 months later. All individuals with at least one observation after randomisation were included in the analyses. This trial is registered with ClinicalTrials.gov, number NCT01883765. FINDINGS: Between Feb 1, 2013, and Dec 1, 2015, 761 people were assessed for eligibility. 656 (86%) were excluded and 118 (15%) were eligible for participation in this study. Eligible participants were randomly assigned to neurofeedback (38 [32%]), sham neurofeedback (39 [33%]), or meta-cognitive therapy (41 [35%]). 37 (97%) individuals for neurofeedback, 38 (97%) for sham neurofeedback, and 38 (93%) for meta-cognitive therapy were included in analyses. Self-reported ADHD symptoms decreased substantially for all treatment groups (B=-2.58 [95% CI -3.48 to -1.68]; p<0.0001) between pretreatment and the end of 6 month follow-up, independent of treatment condition (neurofeedback vs sham neurofeedback B=-0.89 [95% CI -2.14 to 0.37], p=0.168; neurofeedback vs meta-cognitive therapy -0.30 [-1.55 to 0.95], p=0.639). No treatment-related or trial-related serious adverse events were reported. INTERPRETATION: Our findings suggest that neurofeedback training is not superior to a sham condition or group psychotherapy. All three treatments were equivalently effective in reducing ADHD symptoms. This first randomised, sham controlled trial did not show any specific effects of neurofeedback on ADHD symptoms in adults. FUNDING: German Research Foundation. PMID- 28803031 TI - Neurofeedback in adults with attention-deficit hyperactivity disorder. PMID- 28803032 TI - Re: Critical Analysis of Early Recurrence After Laparoscopic Radical Cystectomy in a Large Cohort by the ESUT. PMID- 28803033 TI - The Risk of Tumour Recurrence in Patients Undergoing Renal Transplantation for End-stage Renal Disease after Previous Treatment for a Urological Cancer: A Systematic Review. AB - CONTEXT: Renal transplantation is the gold standard renal replacement therapy in end-stage renal disease owing to its superior survival and quality of life compared with dialysis. When the potential recipient has a history of cancer, the waiting period before renal transplantation is usually based on the Cincinnati Registry. OBJECTIVE: To systematically review all available evidence on the risk of cancer recurrence in end-stage renal disease patients with a history of urological cancer. EVIDENCE ACQUISITION: Medline, Embase, and the Cochrane Library were searched up to March 2017 for all relevant publications reporting oncologic outcomes of urological cancer in patients who subsequently received a transplantation or remained on dialysis. The primary outcome was time to tumour recurrence. Secondary outcomes included cancer-specific and overall survival. Data were narratively synthesised in light of methodological and clinical heterogeneity. The risk of bias of each included study was assessed. EVIDENCE SYNTHESIS: Thirty-two retrospective studies enrolling 2519 patients (1733 dialysed, 786 renal transplantation) were included. For renal cell carcinomas, the risks of recurrence, cancer-specific, and overall survival were similar between transplantation and dialysis. For prostate cancer, most of the tumours had favourable prognoses consistent with nomograms. Studies dealing with urothelial carcinomas (UCs) mainly included upper urinary tract UC in the context of aristolochic acid nephropathy, for which the risks of synchronous bilateral tumour and recurrence were high. Data on testicular cancer were scarce. CONCLUSIONS: Immunosuppression after renal transplantation does not affect the outcomes and natural history of low-risk renal cell carcinomas and prostate cancer. Therefore, the waiting time from successful treatment for these cancers to transplantation could be reduced. Except in the particular situation of aristolochic acid nephropathy, more studies are needed to standardise the waiting period after UC owing to the paucity of data. PATIENT SUMMARY: Renal transplantation does not appear to increase the risk of recurrence of renal carcinoma or the recurrence of low-risk prostate cancer compared with dialysis. More reliable evidence is required to recommend a standard waiting period especially for urothelial and testicular carcinomas. PMID- 28803034 TI - Variations in the Costs of Radical Cystectomy for Bladder Cancer in the USA. AB - BACKGROUND: Radical cystectomy (RC) for muscle-invasive bladder cancer (BCa) has potential for serious complications, prolonged length of stay and readmissions all of which may increase costs. Although variations in outcomes are well described, less is known about determinants driving variation in costs. OBJECTIVE: To assess surgeon- and hospital-level variations in costs and predictors of high- and low-cost RC. DESIGN, SETTING, AND PARTICIPANTS: Cohort study of 23 173 patients who underwent RC for BCa in 208 hospitals in the USA from 2003 to 2015 in the Premier Healthcare Database. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Ninety-day direct hospital costs; multilevel hierarchal linear models were constructed to evaluate contributions of each variable to costs. RESULTS AND LIMITATIONS: Mean 90-d direct hospital costs per RC was $39 651 (standard deviation $34 427), of which index hospitalization accounted for 87.8% ($34 803) and postdischarge readmission(s) accounted for 12.2% ($4847). Postoperative complications contributed most to cost variations (84.5%), followed by patient (49.8%; eg, Charlson Comorbidity Index [CCI], 40.5%), surgical (33.2%; eg, year of surgery [25.0%]), and hospital characteristics (8.0%). Patients who suffered minor complications (odds ratio [OR] 2.63, 95% confidence interval [CI]: 2.03-3.40), nonfatal major complications (OR 12.7, 95% CI: 9.63-16.8), and mortality (OR 13.5, 95% CI: 9.35-19.4, all p<0.001) were significantly associated with high costs. As for low-cost surgery, sicker patients (CCI=2: OR 0.41, 95% CI: 0.29-0.59; CCI=1: OR 0.58, 95% CI: 0.46-0.75, both p<0.001), those who underwent continent diversion (vs incontinent diversion: OR 0.29, 95% CI: 0.16 0.53, p<0.001), and earlier period of surgery were inversely associated with low costs. CONCLUSIONS: This study provides insight into the determinants of costs for RC. Postoperative morbidity, patient comorbidities, and year of surgery contributed most to observed variations in costs, while other hospital- and surgical-related characteristics such as volume, use of robot assistance, and type of urinary diversion contribute less to outlier costs. PATIENT SUMMARY: Efforts to address high surgical cost must be tailored to specific determinants of high and low costs for each operation. In contrast to robot-assisted radical prostatectomy where surgeon factors predominate, high costs in radical cystectomy were primarily determined by postoperative complication and patient comorbidities. PMID- 28803035 TI - Bone tunnel change develops within two weeks of double-bundle anterior cruciate ligament reconstruction using hamstring autograft: A comparison of different postoperative immobilization periods using computed tomography. AB - BACKGROUND: The purpose of this study was to evaluate bone tunnel changes following anterior cruciate ligament (ACL) reconstruction during the early postoperative period using computed tomography (CT), and to understand the impact of postoperative immobilization on these changes. METHODS: Twenty patients who underwent double-bundle ACL reconstruction using hamstring tendon autografts were included. We subcategorized patients into two groups: patients who underwent isolated ACL reconstruction and had three days of knee immobilization (Group A, n=10); and patients with concomitant meniscus injuries who underwent ACL reconstruction and meniscus repair simultaneously (Group B, n=10) had their knees immobilized for two weeks after surgery. Bone tunnel enlargement was evaluated using CT imaging at one to three days, two weeks, one month, three months and six months after surgery. The cross-sectional area of the femoral and tibial tunnels was measured, and enlargement rate was calculated. The tunnel center location at two weeks after surgery was also evaluated. RESULTS: The mean cross-sectional area adjacent to the joint space of the femoral and tibial tunnels significantly increased immediately after surgery, especially in the first month (P<0.01). However, after one to six months they were not increased (P>0.01). There was no significant difference in tunnel enlargement rate between group A and B. Tunnel center location changed even in the first two weeks. CONCLUSIONS: Bone tunnel enlargement following double-bundle ACL reconstruction occurred at an earlier time point after surgery than anticipated. Postoperative immobilization could not prevent bone tunnel enlargement, but might prevent tunnel migration. PMID- 28803036 TI - Relationship between atrial fibrillation and cognitive decline in individuals aged 80 and older. AB - BACKGROUND: Atrial fibrillation (AF) and dementia are largely prevalent and incident in progressively older subjects, suggesting a link between the two conditions. While in the general population there are several findings supporting a causal relationship between AF and dementia, it is unclear whether or not this association is still present in individuals aged 80 and older. RESULTS: So far, the few studies that analysed this issue did not provide enough evidence supporting the causative role of AF in increasing the risk of cognitive decline or dementia in patients aged 80 and older. Conversely, a relevant role of optimal anticoagulation control in determining a significant reduction in the risk of cognitive decline is suggested, in AF subjects aged 80years or older. CONCLUSIONS: Further data, coming from population-based studies specifically investigating very old individuals and based upon large samples and comprehensive cognitive assessments, are needed to fully elucidate the relationship between AF and dementia in very old individuals. PMID- 28803037 TI - Caveats in the work-up of iron deficiency anaemia. PMID- 28803038 TI - SRSF shape analysis for sequencing data reveal new differentiating patterns. AB - MOTIVATION: Sequencing-based methods to examine fundamental features of the genome, such as gene expression and chromatin structure, rely on inferences from the abundance and distribution of reads derived from Illumina sequencing. Drawing sound inferences from such experiments relies on appropriate mathematical methods to model the distribution of reads along the genome, which has been challenging due to the scale and nature of these data. RESULTS: We propose a new framework (SRSFseq) based on square root slope functions shape analysis to analyse Illumina sequencing data. In the new approach the basic unit of information is the density of mapped reads over region of interest located on the known reference genome. The densities are interpreted as shapes and a new shape analysis model is proposed. An equivalent of a Fisher test is used to quantify the significance of shape differences in read distribution patterns between groups of density functions in different experimental conditions. We evaluated the performance of this new framework to analyze RNA-seq data at the exon level, which enabled the detection of variation in read distributions and abundances between experimental conditions not detected by other methods. Thus, the method is a suitable supplement to the state-of-the-art count based techniques. The variety of density representations and flexibility of mathematical design allow the model to be easily adapted to other data types or problems in which the distribution of reads is to be tested. The functional interpretation and SRSF phase-amplitude separation technique give an efficient noise reduction procedure improving the sensitivity and specificity of the method. PMID- 28803039 TI - Suicidal behaviors and their relationship with psychotic-like symptoms in children and adolescents at clinical high risk for psychosis. AB - BACKGROUND: Previous research has demonstrated elevated rates of suicide attempts and ideation in individuals with psychosis. This study investigated rates and severity of suicidal behavior in youth with and at clinical high risk for psychosis, and examined the positive, negative, and disorganized symptoms associated with suicidal behaviors among the clinical high risk group. METHODS: Eighty-six youth ages 7-18 (n=21 non-clinical controls [NCC], n=40 clinical high risk [CHR], n=25 diagnosed psychotic disorder [PD]) were recruited. CHR and PD participants were identified using the Structured Interview for Prodromal Symptoms (SIPS) and Schedule for Affective Disorders and Schizophrenia for School Age Children-Present and Lifetime Version (KSADS-PL). All participants completed the Suicide Behaviors Questionnaire-Revised (SBQ-R). RESULTS: Findings indicated significantly higher levels of suicidal behavior among CHR and PD relative to NCC participants (F=7.64, p=0.001). 17.5% of CHR participants had previously attempted suicide. Dysphoric Mood and Odd Behavior or Appearance were significantly correlated with suicidal behavior severity among CHR youth. CONCLUSION: Suicidal behavior was observed with greater frequency and severity in the CHR and PD groups than in the NCC group. CHR suicidal behavior severity was correlated most strongly with Dysphoric Mood and Odd Behavior or Appearance, a relationship which warrants further investigation. PMID- 28803040 TI - Attachment and thought problems in an adolescent inpatient sample: The mediational role of theory of mind. AB - BACKGROUND: Previous research has documented increased incidence of insecure attachment and theory of mind (ToM) deficits in individuals experiencing psychotic disorders. ToM has been theorized as a possible mediator of the relation between attachment and psychosis (Korver-Nieberg et al., 2014). The current study sought to extend this area of research to adolescents for the first time by examining adolescent-parent attachment and ToM in inpatient adolescents. METHODS: Participants were 362 inpatient adolescents and their parents; participants completed the Child Attachment Interview, Movie for the Assessment of Social Cognition, Youth Self Report, and Child Behavior Checklist. RESULTS: Bivariate correlations indicated that attachment coherence (a marker of security) was significantly and positively correlated with ToM abilities, and that low attachment coherence and poor ToM performance were each associated with increased youth- and parent-reported thought problems. Mediational models indicated that ToM mediated the relation between insecure attachment and thought problems according to both parent- and self-report. CONCLUSIONS: The results of the current study provide support for a model in which impairments in ToM contribute to the frequently documented association between insecure attachment and emerging psychotic symptoms. Theoretical and clinical implications of these results are discussed, including the potential support for ToM-based interventions for early psychotic symptoms. PMID- 28803041 TI - The influence of traumatic brain injury on treatment outcomes of Concurrent Treatment for PTSD and Substance Use Disorders Using Prolonged Exposure (COPE) in veterans. AB - BACKGROUND: The co-occurrence of posttraumatic stress disorder (PTSD), substance use disorders (SUD), and traumatic brain injury (TBI) in veterans of Operations Enduring/Iraqi Freedom and New Dawn has received much attention in the literature. Although hypotheses have been presented and disseminated that TBI history will negatively influence treatment response, little data exist to support these claims. The present study investigates the influence of TBI history on response to COPE (Concurrent Treatment of PTSD and SUD Using Prolonged Exposure), a 12-session, integrated psychotherapy designed to address co occurring PTSD and SUD. METHOD: Participants were 51 veterans with current PTSD and SUD enrolled in a clinical trial examining COPE. Assessments of PTSD symptoms, substance use, and depression were collected at baseline and each treatment session. A TBI measure was used to dichotomize veterans into groups with and without a history of TBI (ns=30 and 21, respectively). RESULTS: Participants with and without TBI history demonstrated significant improvements in PTSD and depression symptoms during the course of treatment. However, participants with TBI history experienced less improvement relative to participants without TBI history. CONCLUSIONS: The present findings suggest that, although patients with a TBI history respond to treatment, their response to treatment was less so than that observed in patients without a TBI history. As such, identification, symptom monitoring, and treatment practices may require alteration and further special consideration in individuals with PTSD, SUD and TBI. PMID- 28803043 TI - Structure-based development of novel triazoles and related thiazolotriazoles as anticancer agents and Cdc25A/B phosphatase inhibitors. Synthesis, in vitro biological evaluation, molecular docking and in silico ADME-T studies. AB - Synthesis of twenty nine new 1,2,4-triazoles and some derived thiazolothiadiazoles (structurally-relevant to some reported triazoles with anticancer and/or Cdc25A/B inhibitory activities) is described in this study. The obtained NCI's in vitro antitumor data revealed that five analogs (12, 15, 18, 19 and 22) displayed considerable tumor percentage growth inhibitory activity (GI%), among which the analog 18 possessed a special antitumor potential and spectrum. Additionally, the same five analogs showed a marginal GI effect on the normal breast epithelial cell line MCF-10A indicating higher selectivity towards cancer cells. The same active analogs 12, 15, 18, 19 and 22 were further assessed for their in vitro Cdc25A/B phosphatase inhibitory activity (a possible antitumor target), where 18 and 22 displayed a distinctive inhibitory affinity towards the Cdc25B isozyme (6.7 and 8.4 MUM, respectively). Docking of 12, 15, 18, 19 and 22 with the active site of human Cdc25B phosphatase enzyme demonstrated superior binding profile by the top-scoring analog 18 relative to a reported Cdc25 phosphatase ligand. In silico calculations of molecular properties revealed that all of the active compounds comply with Lipinski's RO5 and Veber's criteria for good bioavailability suggesting good drug-likeness upon oral administration with a predicted high safety profile. PMID- 28803042 TI - Who are likely to attempt suicide again? A comparative study between the first and multiple timers. AB - BACKGROUND: Various explanations account for suicide incidents, and some patients continue to attempt afterwards and others never again. The suicide mortality rate increases with the number of serious attempts. The prevention of secondary attempt of suicide should be an important approach to reduce suicide mortality. However, the characteristics of the targeted population of repeated suicide attempters are understudied. METHODS: This was a cross-sectional data collection from hospital emergency room from patients who had either attempted suicide for the first time (n=721) or for two or more times (n=70). The subjects were between 14 and 53years old and comprised 293 males and 498 females. In-depth interview was conducted for each suicide attempter with a semi-structural protocol. Demographic and social-psychological characteristics were compared between the two groups of suicide attempters. Logistic regression was used to identify independent predictors of multiple attempts. FINDINGS: The two groups only differed in religion factor among demographic characteristics and multiple suicide attempters group have a higher percentage of subjects who reported to have a religion affiliation than first time suicide attempters. Multiple attempters were more likely to have family suicide history, physical illness, mental disorder, higher scores on Beck Hopelessness Scale (BHS) and Suicide Intent Scale (SIS) and lower scores on Duke Social Support Scale (DSSI). In the final regression model, family history of suicide, mental disorder, hopelessness and social support emerged as significant predictors of multiple suicide attempts. CONCLUSION: Suicide attempters that have mental disorder, family history of suicide, higher level of hopelessness and lower level of social support are more likely to re-attempt suicide again. Social and clinical interventions may have to also focus on this sub-group of patients with these characteristics to effectively reduce suicide mortality rate. PMID- 28803045 TI - Discovery of novel 3-(hydroxyalkoxy)-2-alkylchromen-4-one analogs as interleukin 5 inhibitors. AB - A series of novel chromen-4-one analogs 9a-d and 10a-u was designed, synthesized and evaluated for their IL-5 inhibitory activity. Most of the chromen-4-one analogs showed strong inhibitory activity in low micro molar potency. Among them, 5-(cyclohexylmethoxy)-3-(3-hydroxypropoxy)-2-isopropyl-4H-chromen-4-one (10t, 90.0% inhibition at 30 MUM, IC50 = 5.5 MUM, CLogP = 4.76887) and 2-cyclohexyl-5 (cyclohexylmethoxy)-3-(3-hydroxypropoxy)-4H-chromen-4-one (10u, 95.5% inhibition at 30 MUM, IC50 = 3.0 MUM, CLogP = 5.96187) showed the best inhibition. The structure activity relationship reveals that the hydrophobic cyclohexylmethoxy group at the position 5 of the chromen-4-one ring A is preferable than at position 6 and the dual hydrogen bonding acceptor property on the chromen-4-one ring should be important for the inhibitory activity. In addition, the optimum length of the side chain at position 3 of chromen-4-one ring is critical for the donation of hydrogen to the binding site and the 3-hydroxypropoxy group showed the best activity. Moreover, the conformational restrictor (isopropyl, cyclohexyl group) at position 2 is much more favorable for the formation of effective conformer of side chain with hydrogen bonding donor property of these chromen-4 one analogs. PMID- 28803044 TI - New racemic annulated pyrazolo[1,2-b]phthalazines as tacrine-like AChE inhibitors with potential use in Alzheimer's disease. AB - A novel series of tacrine-like compounds 7a-u possessing a fused pyrazolo[1,2 b]phthalazine structure were designed and synthesized as potent and selective inhibitors of AChE. The in-vitro biological assessments demonstrated that several compounds had high anti-AChE activity at nano-molar level. The more promising compound 7l with IC50 of 49 nM was 7-fold more potent than tacrine and unlike tacrine, it was highly selective against AChE over BuChE. The cell-based assays against hepatocytes (HepG2) and neuronal cell line (PC12) revealed that 7l had significantly lower hepatotoxicity compared to tacrine, with additional neuroprotective activity against H2O2-induced damage in PC12 cells. This compound could also inhibit AChE-induced and self-induced Abeta peptide aggregation. The advantages including synthetic accessibility, high potency and selectivity, low toxicity, adjunctive neuroprotective and Abeta aggregation inhibitory activity, make this compound as a new multifunctional lead for Alzheimer's disease drug discovery. PMID- 28803046 TI - Design, synthesis and biological evaluation of novel pyrazolochalcones as potential modulators of PI3K/Akt/mTOR pathway and inducers of apoptosis in breast cancer cells. AB - Cancer has been established as the "Emperor of all maladies". In recent years, medicinal chemistry has focused on identifying novel anti-cancer compounds; though discovery of these compounds appears to be a herculean task. In present study, we synthesized forty pyrazolochalcone conjugates and explored their cytotoxic activity against a panel of sixty cancer cell lines. Fifteen conjugates of the series showed excellent growth inhibition (13b-e, 13h-j, 14c-d, 15 a, 15 c d, 16b, 16d and 18f; GI50 for MCF-7: 0.4-20 MUM). Conjugates 13b, 13c, 13d, 16b and 14d were also evaluated for their cytotoxic activity in human breast cancer cell line (MCF-7). The promising candidates induced cell cycle arrest, mitochondrial membrane depolarization and apoptosis in MCF-7 cells at a 2 MUM concentration. Furthermore, inhibition of PI3K/Akt/mTOR pathway-regulators such as PI3K, p-PI3K, p-AKT, and mTOR were observed; as well as upregulation of p GSK3beta and tumor-suppressor protein, PTEN. Our study indicates that pyrazolochalcone conjugates could serve as potential leads in the development of tailored cancer therapeutics. PMID- 28803047 TI - Puromycin based inhibitors of aminopeptidases for the potential treatment of hematologic malignancies. AB - Substantial progress has been described in the study of puromycin and its analogs for antibiotic properties. However, the peptidase inhibitory activity of related analogs has not been explored as extensively. Specifically, inhibiting aminopeptidases for achieving antitumor effect has been sparsely investigated. Herein, we address this challenge by reporting the synthesis of a series of analogs based on the structural template of puromycin. We also present exhaustive biochemical and in vitro analyses in support of our thesis. Analyzing the structure-activity relationship revealed a steric requirement for maximum potency. Effective inhibitors of Puromycin-Sensitive Aminopeptidase (PSA) are disclosed here. These potential therapeutic agents display superior in vitro antitumor potency against two leukemic cell lines, as compared to known inhibitors of aminopeptidases. PMID- 28803048 TI - Novel unsaturated glycyrrhetic acids derivatives: Design, synthesis and anti inflammatory activity. AB - To develop novel anti-inflammatory agents, a series of unsaturated glycyrrhetic acids were designed, synthesized and evaluated for anti-inflammatory activity using RAW264.7 cells. The structure-activity relationship (SAR) of NO inhibitory activity was analyzed. alpha,beta-Unsaturated glycyrrhetic acids showed better activity, among them, compounds 6k and 6l with piperazine unit exhibited the most potent nitric oxide (NO) and interleukin-6 (IL-6) inhibitory activity (IC50 = 13.3 and 15.5 MUM respectively). Furthermore, compound 6k could also significantly suppress LPS-induced iNOS and COX-2 expression and IL-6 production through MAPKs and NF-kB signaling pathway. PMID- 28803049 TI - Modeling aging in HIV infection in nonhuman primates to address an emerging challenge of the post-ART era. AB - The advent of antiretroviral therapy (ART) has dramatically improved both quality and length of life for subjects infected with human immunodeficiency virus (HIV), delaying or preventing progression to acquired immunodeficiency syndrome (AIDS). However, the virus induces aging-related changes to the immune system which confound treatment. Additionally, the normal physiologic events that occur during aging lead to deficiencies in immunity which not only exacerbate HIV pathogenesis but also trigger a variety of comorbidities. Here, the synergistic linkage between aging and HIV infection is examined in regard to the immunological and pathological mechanisms that drive both senescence and disease progression. The use of NHPs to investigate potential therapeutic strategies to control the deleterious consequences of aging with HIV infection is also reviewed. PMID- 28803050 TI - The AREST CF experience in biobanking - More than just tissues, tubes and time. AB - Research to further improve outcomes for people with CF is dependent upon well characterised, archived and accessible clinical specimens. The recent article by Beekman et al. published in Journal of Cystic Fibrosis summarised a scientific meeting at the 13th ECFS Basic Science Conference. This meeting discussed how well-annotated, clinical biobanks for CF could be established in Europe to meet the needs of therapeutic development. The Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) has conducted biobanking of CF research and clinical specimens since the late 1990s and is custodian of the most comprehensive paediatric CF biobank in the world that focuses on the first years of life. This short communication will describe the approach undertaken by AREST CF in establishing a clinical specimen biobank. PMID- 28803051 TI - Variations in the labyrinthine segment of facial nerve canal revealed by high resolution computed tomography. AB - OBJECTIVE: To study variations in the labyrinthine segment of fallopian canal and the associated middle and inner ear malformations. METHOD: The high-resolution computed tomography (HRCT) images of the temporal bone in 24 patients with congenital variations in the labyrinthine segment of fallopian canal were analyzed retrospectively. The length of labyrinthine segment of the facial nerve and angle of the first genu of 10 normal subjects were also measured. Based on the original axial images, multi-planar reformation (MPR) and curved-planar reformation (CPR) images of bilateral ossicular chains, inner ear structure and fallopian canal were reconstructed. HRCT features of congenital variations in the labyrinthine segment of the facial nerve were analyzed, including its beginning site, dehiscence, length, angle of the first genu and the associated middle and inner ear malformations. RESULTS: Among the normal subjects, the length of labyrinthine segment of the facial nerve was 3.56+/-0.41mm, and angle of the first genu was 71.87+/-8.09 degrees . Five types of variations in the labyrinthine segment of the facial nerve were found in 45 ears of 24 cases, including dehiscence in geniculate fossa in 25 ears, anteromedial displacement at the beginning site in 27 ears (widening of Bill's bar in 7 cases), enlargement of the angle of the first genu in 30 ears with an average value of 107.2 degrees (96.0-126.0 degrees ), increase of length in 30 ears with an average length of 6.8mm (5.2-8.3mm) and bifurcation in one ear. Associated middle ear malformation in 6 ears and inner ear malformation in 36 ears were also found. CONCLUSION: A variety of congenital variations may occur in the labyrinthine segment of the facial nerve and they are often associated with middle or inner ear malformations, which can be clearly displayed by HRCT with MPR or CPR images. PMID- 28803052 TI - Difference in attenuation among Mn, As, and Fe in riverbed sediments. AB - We report, for the first time, a detailed study at river water and hyporheic zone systems through collection and analyses of shallow sediments and selected source rocks, pore water, and river water from forty-two locations at the Chianan Plain (CP), SW Taiwan. The study was focused to understand the possible changes in the river water and sediment chemistry as a consequence of high arsenic (mean+/ SD=71.28+/-16.24MUg/L, n=46) groundwater discharge to three major rivers in the plain. The study shows, except few locations, As concentration in river sediments corresponds to average As concentration in soil and upper crustal abundance and of source rock. Sequential extraction indicates that As is mostly bound to FeOOH. No enrichment of arsenic in river sediments or depletion of aqueous As and iron in pore water was observed down to the maximum sampling depth of 1.7m although manganese is enriched in sediments. Dissolved As concentrations in the river sediments are much lower compared to the hotspots in the CP aquifers. This suggests that no As attenuation processes are active or they cannot be detected in this zone. Mn precipitates at higher redox level compared to Fe and As and thus attenuates in the studied zone. PMID- 28803053 TI - Optimized transitory ectopic expression of promastigote surface antigen protein in Nicotiana benthamiana, a potential anti-leishmaniasis vaccine candidate. AB - In recent years, plants have been shown to be an efficient alternative expression system for high-value pharmaceuticals such as vaccines. However, constitutive expression of recombinant protein remains uncertain on their level of production and biological activity. To overcome these problems, transitory expression systems have been developed. Here, a series of experiments were performed to determine the most effective conditions to enhance vaccine antigen transient accumulation in Nicotiana benthamiana leaves using the promastigote surface antigen (PSA) from the parasitic protozoan Leishmania infantum. This protein has been previously identified as the major antigen of a licensed canine anti leishmaniasis vaccine. The classical prokaryote Escherichia coli biosystem failed in accumulating PSA. Consequently, the standard plant system based on N. benthamiana has been optimized for the production of putatively active PSA. First, the RNA silencing defense mechanism set up by the plant against PSA ectopic expression was abolished by using three viral suppressors acting at different steps of the RNA silencing pathway. Then, we demonstrated that the signal peptide at the N-terminal side of the PSA is required for its accumulation. The PSA ER signaling and retention with the PSA signal peptide and the KDEL motif, respectively were optimized to significantly increase its accumulation. Finally, we demonstrate that the production of recombinant PSA in N. benthamiana leaves allows the conservation of its immunogenic property. These approaches demonstrate that based on these optimizations, plant based systems can be used to effectively produce the biological active PSA protein. PMID- 28803054 TI - Decolorization of reactive azo dyes using a sequential chemical and activated sludge treatment. AB - Textile wastewater contains high concentrations of organic substances derived from diverse dyes and auxiliary chemicals, some of which are non-biodegradable and/or toxic. Therefore, it is essential that textile wastewater is treated and that these substances are removed before being discharged into the environment. A combination of advanced oxidation processes (AOPs) to obtain partial dye degradation followed by a biological treatment has been suggested as a promising method for cost-effective decolorization of wastewater. The aim of this study was to develop and evaluate a combined method of partial Fenton's oxidation and biological treatment using activated sludge for decolorization of azo dyes, which represent an important group of recalcitrant, toxic textile dyes. Using Reactive Violet 5 (RV5) as a model dye, color removal was significantly higher when the combined Fenton treatment/activated sludge method was used, as opposed to separate application of these treatments. More specifically, pretreatment with Fenton's reagent removed 52.9, 83.9 and 91.3 % of color from a 500 mg l-1 RV5 aqueous solution within 60 min when H2O2 concentrations of 1.0, 1.5, and 2.0 mM were used, respectively. Subsequent biological treatment was found to significantly enhance the chemical treatment, with microbial decolorization removing 70.2 % of the remaining RV5 concentration, on average. Molecular analysis of the microbial community within the activated sludge revealed that exposure to RV5 shifted the community composition from diverse towards a highly specialized community harboring taxa with azo dye degrading activity, including Trichosporon, Aspergillus and Clostridium species. PMID- 28803055 TI - Aristolochic acid and its derivatives as inhibitors of snake venom L-amino acid oxidase. AB - Snake venom L-amino acid oxidase (LAAO) exerts toxicity by inducing hemorrhage, pneumorrhagia, pulmonary edema, cardiac edema, liver cell necrosis etc. Being well conserved, inhibitors of the enzyme may be synthesized using the template of the substrate, substrate binding site and features of the catalytic site of the enzyme. Previous findings showed that aristolochic acid (AA), a major constituent of Aristolochia indica, inhibits Russell's viper venom LAAO enzyme activity since, AA interacts with DNA and causes genotoxicity, derivatives of this compound were synthesized by replacing the nitro group to reduce toxicity while retaining the inhibitory potency. The interactions of AA and its derivatives with LAAO were followed by inhibition kinetics and surface plasmon resonance. Similar interactions with DNA were followed by absorption spectroscopy and atomic force microscopy. LAAO-induced cytotoxicity was evaluated by generation of reactive oxygen species (ROS), cell viability assays, confocal and epifluorescence microscopy. The hydroxyl (AA-OH) and chloro (AA-Cl) derivatives acted as inhibitors of LAAO but did not interact with DNA. The derivatives significantly reduced LAAO-induced ROS generation and cytotoxicity in human embryonic kidney (HEK 293) and hepatoma (HepG2) cell lines. Confocal images indicated that AA, AA OH and AA-Cl interfered with the binding of LAAO to the cell membrane. AA-OH and AA-Cl significantly inhibited LAAO activity and reduced LAAO-induced cytotoxicity. PMID- 28803056 TI - Analysis of microcystin-LR and nodularin using triple quad liquid chromatography tandem mass spectrometry and histopathology in experimental fish. AB - Microcystins (MCs) are hepatotoxic cyanobacterial metabolites produced sporadically in aquatic environments under favorable environmental conditions. Affinity of these toxins to covalently bind with protein phosphatases poses a challenge in their detection. Lemieux oxidation to release 2-methyl-3-methoxy-4 phenylbutyric acid (MMPB), a common moiety to all MCs congeners, has been used in detection of these compounds, however a lack of sensitivity has limited the usefulness of the method. In this study, modifications of the oxidation and solid phase extraction procedures, combined with a sensitive LC/MS/MS (liquid chromatography/mass spectrometry) detection, have resulted in 25 ng/g method detection limits in both liver and plasma samples. Samples harvested from six fingerling channel catfish (Ictalurus punctatus) dosed intraperitoneally with a sublethal MC-LR dose of 250 MUg/kg were analyzed, and microcystin concentrations ranging from 370 to 670 ng/g in plasma and 566-1030 ng/g in liver were detected. Similarly, 250 MUg/kg nodularin-dosed channel catfish fish were found to contain 835-1520 ng/g in plasma and 933-1140 ng/g in liver. Detection of the toxins in serum and liver combined with the presence of histopathological lesions consistent with these hepatocellular toxin in exposed fish and no positive findings in the control fish demonstrates the usefulness of this analytical procedure for the diagnosis of suspected algal toxicity cases. PMID- 28803057 TI - Cross-reactivity and cross-immunomodulation between venoms of the snakes Bothrops asper, Crotalus simus and Lachesis stenophrys, and its effect in the production of polyspecific antivenom for Central America. AB - A mixture of the venoms of Bothrops asper, Crotalus simus and Lachesis stenophrys is used as immunogen to produce the polyspecific Central American antivenom (PoliVal-ICP). In this work, we studied the ability of each of these venoms to modulate the antibody response induced by the other two venoms included in the immunization mixture. For that, equine monospecific, bispecific and polyspecific antivenoms were prepared and compared regarding their ability to neutralize the phospholipase A2, coagulant and lethal activities of each venom, and their anti venom antibodies concentration. Results indicate that there is low cross reactivity and cross-neutralization between venoms of B. asper, C. simus and L. stenophrys, hence justifying the use of all of them as immunogens for the production of the Central American antivenom. It was also found that the venom of B. asper reduces the anti-crotalic response while the venom of C. simus does not affect the anti-bothropic response. On the other hand, the venoms of B. asper and C. simus increase the anti-lachesic response, and L. stenoprhys venom reduced both the anti-bothropic and anti-crotalic responses. On the basis of these results, the immunization strategy can be adjusted by preventing or taking advantage of cross-immunomodulation between venoms, in order to maximize the antibody response towards all venoms. Immune responses can be improved by injecting horses with several immunogen mixtures, composed by one or two of the three venoms, and administering them at different times during the immunization, eventually generating a high titer against the three venoms. Our results suggest that addressing the issue of immunomodulation by venoms might improve antivenom manufacture worldwide. PMID- 28803058 TI - Survey of ferns and clinico-pathological studies on the field cases of Enzootic bovine haematuria in Himachal Pradesh, a north-western Himalayan state of India. AB - Enzootic bovine haematuria (EBH) in cattle occurs in upland areas of the world. In India, the disease is present in isolated pockets in the Himalayas and in the Nilgiri Hills. The variation in the disease incidence has been attributed to different environmental conditions and animal rearing practices followed in the different regions. The aim of the study was to conduct field surveys in parts of EBH endemic regions of Himachal Pradesh, a north-western Himalayan state of India. Out of the total 103 plant samples collected, a total of 95 samples were identified as ferns. The major ferns identified included, Onychium japonicum (Thunb.) Kunze, Polystichum piceopaleaceum Tagawa, Dryopteris juxtaposita Christ, Pseudocyclosorus canus (Baker) Holttum and J.W. Grimes, Onychium contiguum C. Hope, Dryopteris nigropaleacea (Fraser-Jenk.), Pteridium aquilinum (L.) Kuhn, Diplazium esculentum (Retz.) Sw., Allantodia maxima (D. Don) Ching, Woodwardia unigemmata (Makino) Nakai, Pteris cretica L., Pteris vittata L., Asplenium trichomanes L., Thelypteris phegopteris (L.) Sloss. ex Rydb, Adiantum venustum D. Don and Paraceterach vestita (Hook.) R.M. Tryon. The concentration of ptaquiloside (PTA) and pterosin B (PtB) in some of the ferns collected from Kullu and Chamba regions ranged from 0 to 358.6 +/- 70.5 MUg/g and 0 to 652.4 +/- 50.0 MUg/g, respectively. In addition, field cases of the disease in cattle were also studied in the EBH endemic districts. A total of sixteen cattle urine samples and one urinary bladder of EBH affected cattle were collected. On physical, chemical (benzidine test) and microscopic examination of urine sediment, all the sixteen field samples were found to be positive for erythrocytes and the cases were diagnosed as macrohaematuria. The clinico-pathological studies on the field cases and the presence of PTA and PtB in the ferns indicated that EBH is a prevalent disease and there is an association between chronic fern ingestion and EBH in cattle. On the basis of gross pathology, histopathology and immunohistochemistry (p53 and H-ras nuclear expression in the urothelial cells) of the urinary bladder tissue, the field case was diagnosed as transitional cell adenocarcinoma with chronic lymphocytic cystitis. PMID- 28803059 TI - Consciousness operationalized, a debate realigned. AB - This paper revisits the debate about cognitive phenomenology. It elaborates, defends, and improves on our earlier proposal for resolving that debate, according to which the test for irreducible phenomenology is the presence of explanatory gaps. After showing how proposals like ours have been misunderstood or misused by others, we deploy our operationalization to argue that the correct way to align the debate over cognitive phenomenology is not between sensory and (alleged) cognitive phenomenology, but rather between non-conceptual and (alleged) conceptual or propositional phenomenology. In doing so we defend three varieties of non-sensory (amodal)1 non-conceptual phenomenology: valence, a sense of approximate number, and a sense of elapsed time. PMID- 28803060 TI - Predictions of biochar production and torrefaction performance from sugarcane bagasse using interpolation and regression analysis. AB - This study focuses on the biochar formation and torrefaction performance of sugarcane bagasse, and they are predicted using the bilinear interpolation (BLI), inverse distance weighting (IDW) interpolation, and regression analysis. It is found that the biomass torrefied at 275 degrees C for 60min or at 300 degrees C for 30min or longer is appropriate to produce biochar as alternative fuel to coal with low carbon footprint, but the energy yield from the torrefaction at 300 degrees C is too low. From the biochar yield, enhancement factor of HHV, and energy yield, the results suggest that the three methods are all feasible for predicting the performance, especially for the enhancement factor. The power parameter of unity in the IDW method provides the best predictions and the error is below 5%. The second order in regression analysis gives a more reasonable approach than the first order, and is recommended for the predictions. PMID- 28803061 TI - Carbon streaming in microalgae: extraction and analysis methods for high value compounds. AB - There is a growing recognition that carbon-neutral biofuels and microalgae are eco-friendly options because of their high CO2 sequestering capability and ability to grow in wastewater/sea water and non-arable land. Also the intrinsic properties of microalgal systems can be exploited for high value compounds such as carbohydrates, lipids, pigments and proteins. This article provides a comprehensive review of various microalgae cultivation practices utilizing organic and inorganic carbon sources. The merits and demerits of the various extraction and analytical procedures have also been discussed in detail. PMID- 28803062 TI - Purification and reuse of non-point source wastewater via Myriophyllum-based integrative biotechnology: A review. AB - In this review, the applications of Myriophyllum-based integrative biotechnology to remove common non-point source (NPS) pollutants, such as nitrogen, phosphorus, heavy metals, and organic pollutants (e.g., pesticides and antibiotics) are summarized. The removal of these pollutants via various mechanisms, including uptake by plant and microbial communities in macrophyte-based treatment systems are discussed. This review highlights the potential use of Myriophyllum biomass to produce animal feed, fertilizer, and other valuable by-products, which can yield cost-effective returns and attract more attention to the regulation and recycling of NPS pollutants. In addition, it demonstrates that utilization of Myriophyllum species is a promising and reliable strategy for wastewater treatment. The future development of sustainable Myriophyllum-based treatment systems is discussed from various perspectives. PMID- 28803063 TI - Cascading biomethane energy systems for sustainable green gas production in a circular economy. AB - Biomethane is a flexible energy vector that can be used as a renewable fuel for both the heat and transport sectors. Recent EU legislation encourages the production and use of advanced, third generation biofuels with improved sustainability for future energy systems. The integration of technologies such as anaerobic digestion, gasification, and power to gas, along with advanced feedstocks such as algae will be at the forefront in meeting future sustainability criteria and achieving a green gas supply for the gas grid. This paper explores the relevant pathways in which an integrated biomethane industry could potentially materialise and identifies and discusses the latest biotechnological advances in the production of renewable gas. Three scenarios of cascading biomethane systems are developed. PMID- 28803064 TI - High-glucose induces tau hyperphosphorylation through activation of TLR9-P38MAPK pathway. AB - Diabetic encephalopathy (DE) is one of the most common complications of diabetes. The major pathological variations include neurofibrillary tangles (NFTs), which are caused by tau hyperphosphorylation, and senile plaques (SPs) consisting of amyloid beta- protein(Abeta) deposits. In recent years, DE research studies have focused on exploring the activation of the inflammatory signaling pathway in immune cells. Toll-like receptor 9 (TLR9) is well known to regulate the inflammatory reactions in immune processes. During the tau hyperphosphorylation process, TLR9 in microglia plays bidirectional roles. However, no studies have clearly demonstrated the relationship between TLR9 and tau hyperphosphorylation in neurons. Based on our experiments, we found significant increase in TLR9 expression in neurons and an increase in tau hyperphosphorylation in high-glucose media. However, these alterations can be reversed by TLR9 inhibitor. Furthermore, we specifically inhibited the activation of P38mitogenactivated protein kinase(P38MAPK) and found an effective decrease in tau hyperphosphorylation. This effect is likely related to Unc93b1. Meanwhile, High glucose levels can induce neuronal apoptosis via the TLR9 signaling pathway. Our studies are the first to reveal that high glucose can regulate tau hyperphosphorylation and neuronal apoptosis via TLR9-P38MAPK signaling pathway. These findings provide a new method for studying the mechanism underlying DE. PMID- 28803065 TI - Flow induced adherens junction remodeling driven by cytoskeletal forces. AB - Adherens junctions (AJs) are a key structural component for tissue organization and function. Under fluid shear stress, AJs exhibit dynamic assembly/disassembly, but how shear stress couples to AJs is unclear. In MDCK cells we measured simultaneously the forces in cytoskeletal alpha-actinin and the density and length of AJs using a genetically coded optical force sensor, actinin-sstFRET, and fluorescently labeled E-cadherin (E-cad). We found that shear stress of 0.74dyn/cm2 for 3h significantly enhanced E-cad expression at cell-cell contacts and this phenomenon has two phases. The initial formation of segregated AJ plaques coincided with a decrease in cytoskeletal tension, but an increase in tension was necessary for expansion of the plaques and the formation of continuous AJs in the later phase. The changes in cytoskeletal tension and reorganization appear to be an upstream process in response to flow since it occurred in both wild type and dominant negative E-cad cells. Disruption of F actin with a Rho-ROCK inhibitor eliminated AJ growth under flow. These results delineate the shear stress transduction paths in cultured cells, which helps to understand pathology of a range of diseases that involve dysfunction of E cadherin. PMID- 28803066 TI - A novel RIPK1 inhibitor that prevents retinal degeneration in a rat glaucoma model. AB - In glaucoma, retinal ganglion cells (RGCs) are exposed to ischemic stress with elevation of the intraocular pressure and are subsequently lost. Necroptosis, a type of regulated necrosis, is known to play a pivotal role in this loss. We observed that receptor-interacting protein kinase 1 (RIPK1), the key player of necroptosis, was activated by diverse ischemic stresses, including TCZ, chemical hypoxia (CH), and oxygen glucose deprivation (OGD). In this study, we introduce a RIPK1-inhibitory compound (RIC) with a novel scaffold. RIC inhibited downstream events following RIPK1 activation, including necrosome formation and mitochondrial dysfunction in RGC5 cells. Moreover, RIC protected RGCs against ischemic injury in the rat glaucoma model, which was induced by acute high intraocular pressure. However, RIC displayed biochemical characteristics that are distinct from those of previous RIPK1 inhibitors (necrostatin-1; Nec-1 and Compound 27; Cpd27). RIC protected RGCs against OGD insult, while Nec-1 and Cpd27 did not. Conversely, Nec-1 and Cpd27 protected RGCs from TNF-stimulated death, while RIC failed to inhibit the death of RGCs. This implies that RIPK1 activates alternative pathways depending on the context of the ischemic insults. PMID- 28803067 TI - PPARGC1A is upregulated and facilitates lung cancer metastasis. AB - Lung cancer remains a leading cause of cancer-related mortality, with metastatic progression remaining the single largest cause of lung cancer mortality. Hence it is imperative to determine reliable biomarkers for lung cancer prognosis. We performed quantitative real-time PCR (qRT-PCR) analysis to explore epithelial mesenchymal transition (EMT) inducers that regulate EMT process in three patients with advanced lung cancer disease. Peroxisome proliferator-activated receptor gamma (PPARGC1A) was uniformly the topmost overexpressed gene in all three human non-small cell lung cancer (NSCLC) patient samples. Further evaluation in human normal lung and metastatic lung cancer cell lines revealed that the expression of PPARGC1A was upregulated in metastatic lung cancer cell lines. Metagenomic analysis revealed direct correlation among PPARGC1A, zinc-finger transcription factor snail homolog 1 (SNAI1), and metastatic lung disease. Upregulation of PPARGC1A transcript expression was independent of a differential upregulation of the upstream AMP-dependent protein kinase (AMPK) activation or steady state expression of the silent mating type information regulation 2 homolog 1 (SIRT1). Xenograft tail vein colonization assays proved that the high expression of PPARGC1A was a prerequisite for metastatic progression of lung cancer to brain. Our results indicate that PPARGC1A might be a potential biomarker for lung cancer prognosis. PMID- 28803068 TI - Improved therapeutic efficacy of mammalian expressed-recombinant interferon gamma against ovarian cancer cells. AB - Human interferon gamma (hIFNgamma) affects tumour cells and modulates immune responses, showing promise as an anti-cancer biotherapeutic. This study investigated the effect of glycosylation and expression system of recombinant hIFNgamma in ovarian carcinoma cell lines, PEO1 and SKOV3. The efficacy of E. coli- and mammalian-expressed hIFNgamma (hIFNgamma-CHO and HEK293, glycosylated/de-glycosylated) on cytostasis, cell death (MTT, and Guava ViaCount(r) flow-cytometry) and apoptotic signalling (Western blot of Cdk2, histone H3, procaspase-3, FADD, cleaved PARP, and caspase-3) was examined. Hydrophilic Interaction Liquid Chromatography determined the structure of N linked glycans present in HEK293-expressed hIFNgamma (hIFNgamma-HEK). PEO1 was more sensitive to hIFNgamma than SKOV3, but responses were dose-dependent and expression platform/glycosylation status-independent, whereas SKOV3 responded to mammalian-expressed hIFNgamma in a dose-independent manner, only. Complex-type oligosaccharides dominated the N-glycosylation pattern of hIFNgamma-HEK with some terminal sialylation and core fucosylation. Cleaved PARP and cleaved caspase-3 were not detected in either cell line, but FADD was expressed in SKOV3 with levels increased following treatment. In conclusion, hIFNgamma did not induce apoptosis in either cell line. Mammalian- expressed hIFNgamma increased cell death in the drug-resistant SKOV3. The presence of FADD in SKOV3, which may inhibit apoptosis through activation of NF-kappaB, could serve as a novel therapeutic target. PMID- 28803069 TI - Estimating the reproductive number, total outbreak size, and reporting rates for Zika epidemics in South and Central America. AB - As South and Central American countries prepare for increased birth defects from Zika virus outbreaks and plan for mitigation strategies to minimize ongoing and future outbreaks, understanding important characteristics of Zika outbreaks and how they vary across regions is a challenging and important problem. We developed a mathematical model for the 2015/2016 Zika virus outbreak dynamics in Colombia, El Salvador, and Suriname. We fit the model to publicly available data provided by the Pan American Health Organization, using Approximate Bayesian Computation to estimate parameter distributions and provide uncertainty quantification. The model indicated that a country-level analysis was not appropriate for Colombia. We then estimated the basic reproduction number to range between 4 and 6 for El Salvador and Suriname with a median of 4.3 and 5.3, respectively. We estimated the reporting rate to be around 16% in El Salvador and 18% in Suriname with estimated total outbreak sizes of 73,395 and 21,647 people, respectively. The uncertainty in parameter estimates highlights a need for research and data collection that will better constrain parameter ranges. PMID- 28803070 TI - Sex disparities in cancer incidence in Jiashan County, China, 1995-2014. AB - PURPOSE: To describe the sex-specific incidence rates and the male-to-female incidence-rate ratios (IRRs) of different cancer types, and to explore the corresponding sex disparities in an area of Eastern China. METHODS: We used data from the Cancer Registry in Jiashan County, and calculated the sex-specific age standardized (2010 China standard population) incidence rates and the male-to female IRRs for different cancer types during the period 1995-2014. RESULTS: The age-standardized incidence rates of all cancers for the whole period 1995-2014 were 151.48 per 100,000 person-years for males and 83.75 per 100,000 person-years for females, and the corresponding male-to-female IRR was 1.81 (95% confidence interval: 1.77-1.85). Specifically, males presented higher incidences in most types of cancer with the exceptions of cancers of connective and other soft tissues, gallbladder (including extrahepatic bile ducts), and thyroid gland. In addition, the age-specific incidences of the ten most common cancers in males were higher than those in females in most age groups. CONCLUSIONS: Our results reveal a male predominance in incidence for a majority of cancers in Jiashan County, Eastern China. Possible explanations for these sex disparities in cancer incidence may include lifestyle factors, particularly smoking. PMID- 28803072 TI - Palliative Care Development in Tajikistan. AB - Tajikistan's health system has undergone a series of complex changes associated with reforms aimed at the transition to a more sophisticated control mechanism, financing, and operation. As in many developing countries, there is an increase in morbidity and mortality from cancer and chronic diseases, including tuberculosis and HIV. Attention is needed by the state for the development of cost-effective palliative care that will be integrated into the existing public health system. A recent palliative care country needs assessment identified the following areas of work that need to be addressed for palliative care to be implemented. PMID- 28803071 TI - Responses of Szarvasi-1 energy grass to sewage sludge treatments in hydroponics. AB - Sewage sludge (SS) originating from communal wastewater is a hazardous material but have a potentially great nutritive value. Its disposal after treatment in agricultural lands can be a very economical and safe way of utilization once fast growing, high biomass, perennial plants of renewable energy production are cultivated. Szarvasi-1 energy grass (Elymus elongatus subsp. ponticus cv. Szarvasi-1), a good candidate for this application, was grown in hydroponics in order to assess its metal accumulation and tolerance under increasing SS amendments. The applied SS had a composition characteristic to SS from communal wastes and did not contain any toxic heavy metal contamination from industrial sludge in high concentration. Toxic effects was assessed in quarter strength Hoagland nutrient solution and only the two highest doses (12.5-18.75 g dm-3) caused decreases in root growth, shoot water content and length and stomatal conductance whereas shoot growth, root water content, chlorophyll concentration and the maximal quantum efficiency of photosystem II was unaffected. Shoot K, Ca, Mg, Mn, Zn and Cu content decreased but Na and Ni increased in the shoot compared to the unamended control. The nutritive effect was tested in 1/40 strength Hoagland solution and only the highest dose (12.5 g dm-3) decreased root growth and stomatal conductance significantly while lower doses (1.25-6.25 g dm-3) had a stimulative effect. Shoot K, Na, Fe and Ni increased and Ca, Mg, Mn, Zn and Cu decreased in this treatment. It was concluded that SS with low heavy metal content can be a potentially good fertilizer for high biomass non-food crops such as Szarvasi-1 energy grass. PMID- 28803073 TI - Leadership Development Initiative: Growing Global Leaders... Advancing Palliative Care. AB - The International Palliative Care Leadership Development Initiative (LDI) was a model demonstration project that aimed to expand the global network of palliative care leaders in low- and moderate-resource countries who are well positioned to apply their new leadership skills. Thirty-nine palliative medicine physicians from 25 countries successfully completed the two-year curriculum that included three thematic residential courses, mentorship, and site visits by senior global palliative care leaders and personal projects to apply their new leadership skills. The focus on self-reflection, leadership behaviors and practices, strategic planning, high-level communication, and teaching skills led to significant personal and professional transformation among the participants, mentors, and the LDI team. The resulting residential course curriculum and the personal leadership stories and biosketches of the leaders are now available open access at IPCRC.net. Already, within their first-year postgraduation, the leaders are using their new leadership skills to grow palliative care capacity through significant changes in policy, improved opioid/other medication availability, new and enhanced educational curricula and continuing education activities, and development/expansion of palliative care programs in their organizations and regions. We are not aware of another palliative care initiative that achieves the global reach and ripple effect that LDI has produced. PMID- 28803074 TI - Hospice Palliative Care Development in Hungary. AB - During the past 25 years, many developmental steps have occurred in Hungary in palliative care. Further education and service development is needed to provide a quality palliative care for all the Hungarian people. Hungary has a universal health care system with a developed infrastructure. The first Hungarian hospice team started in 1991. At that time, the concept of hospice care was unknown. Symptom control and psychosocial support for the dying patient was inadequate. The regulatory framework was based on the 1997 Health Care Act which was followed by significant palliative care legislation including documents on the legal requirements for palliative care (2004). National guidelines were developed in 2002. Home and inpatient hospice care are reimbursed by the National Insurance Fund. Patients and families pay nothing. The multidisciplinary team provides care for patients and families and hospice home care is widely available across the country. Inpatient units are still lacking in Hungary. Strong opioids are readily available in the country and can be prescribed for cancer and noncancer patients. Palliative care is taught in medical and nursing undergraduate and postgraduate education. From 2014, physicians in Hungary can take a one-year course to qualify for a license in palliative medicine. PMID- 28803075 TI - The Palliative Care Chaplain as Story Catcher. AB - The role of the professional chaplain on the palliative care team in the health care setting formalizes the concern for the emotional, spiritual, and social well being of the care recipients and their caregivers. The chaplain also has a peculiar role on the team, in that her most fundamental task is her intentional listening-and-hearing of the other person's story. One palliative chaplain introduces herself as a Story Catcher to care recipients, in an effort both to overcome the resistance some may have to her presence on the team and communicate her essential role and intent in providing spiritual care. This self-appointed sobriquet resonates with the author's embrace of the theory and practice of the late theologian, educator, and civil rights activist Nelle Morton, who coined the phrase "hearing into speech" to describe the process by which another person, through being truly heard and entering into a relationship with the hearer, claims her/his own truth, hope, and identity in the face of adversity. The chaplain as Story Catcher functions as the agent of healing and hope for those who choose to tell their stories and are heard, as they resist their illness and death rather than submit to its indignity. PMID- 28803076 TI - Palliative Care in Vietnam: Long-Term Partnerships Yield Increasing Access. AB - Palliative care began in Vietnam in 2001, but steady growth in palliative care services and education commenced several years later when partnerships for ongoing training and technical assistance by committed experts were created with the Ministry of Health, major public hospitals, and medical universities. An empirical analysis of palliative care need by the Ministry of Health in 2006 was followed by national palliative care clinical guidelines, initiation of clinical training for physicians and nurses, and revision of opioid prescribing regulations. As advanced and specialist training programs in palliative care became available, graduates of these programs began helping to establish palliative care services in their hospitals. However, community-based palliative care is not covered by government health insurance and thus is almost completely unavailable. Work is underway to test the hypothesis that insurance coverage of palliative home care not only can improve patient outcomes but also provide financial risk protection for patients' families and reduce costs for the health care system by decreasing hospital admissions near the end of life. A national palliative care policy and strategic plan are needed to maintain progress toward universally accessible cost-effective palliative care services. PMID- 28803077 TI - Empathy, Compassion, and Beyond: The Lesson Learned From a Child Patient. PMID- 28803078 TI - Safety and Effectiveness of Palliative Drug Treatment in the Last Days of Life-A Systematic Literature Review. AB - CONTEXT: Dying patients commonly experience potentially distressing symptoms. Palliative care guidelines recommend opioids, anticholinergics, antipsychotics, and benzodiazepines for symptom relief. OBJECTIVES: The objective of this study was to systematically review the effectiveness and safety of palliative drug treatment in the last days of life of adult patients, focusing on the management of pain, dyspnea, anxiety, restlessness, and death rattle. METHODS: A systematic search of the literature was published before December 2016 in PubMed/MEDLINE, Embase, CINAHL, PsycINFO, Cochrane, ClinicalTrials.gov, and SveMed+. Studies on safety or effectiveness of drug therapy in dying adults with at least one outcome on symptom control, adverse effects, or survival were included. Data for included studies were extracted. Study quality was assessed using the Effective Public Health Practice Quality assessment tool for quantitative studies. RESULTS: Of the 5940 unique titles identified, 12 studies met the inclusion criteria. Five studies assessed anticholinergics for death rattle, providing no evidence that scopolamine hydrobromide and atropine were superior to placebo. Five studies examined drugs for dyspnea, anxiety, or terminal restlessness, providing some evidence supporting the use of morphine and midazolam. Two studies examined opioids for pain, providing some support for morphine, diamorphine, and fentanyl. Eight studies included safety outcomes, revealing no important differences in adverse effects between the interventions and no evidence for midazolam shortening survival. CONCLUSION: There is a lack of evidence concerning the effectiveness and safety of palliative drug treatment in dying patients, and the reviewed evidence provides limited guidance for clinicians to assist in a distinct and significant phase of life. PMID- 28803079 TI - Development and Psychometric Properties of a Survey to Assess Barriers to Implementing Advance Care Planning in Primary Care. AB - CONTEXT: Valid and reliable measurement of barriers to advance care planning (ACP) in health care settings can inform the design of robust interventions. OBJECTIVE: This article describes the development and psychometric evaluation of an instrument to measure the presence and magnitude of perceived barriers to ACP discussion with patients from the perspective of family physicians. METHODS: A questionnaire was designed through literature review and expert input, asking family physicians to rate the importance of barriers (0 = not at all a barrier and 6 = an extreme amount) to ACP discussions with patients and administered to 117 physicians. Floor effects and missing data patterns were examined. Item-by item correlations were examined using Pearson correlation. Exploratory factor analysis was conducted (iterated principle factor analysis with oblique rotation), internal consistency (Cronbach's alpha) overall and within factors was calculated, and construct validity was evaluated by calculating three correlations with related questions that were specified a priori. RESULTS: The questionnaire included 31 questions in three domains relating to the clinician, patient/family and system or external factors. No items were removed due to missing data, floor effects, or high correlation with another item. A solution of three factors accounted for 71% of variance. One item was removed because it did not load strongly on any factor. All other items except one remained in the original domain in the questionnaire. Cronbach's alpha for the three factors ranged from 0.84 to 0.90. Two of three a priori correlations with related questions were statistically significant. CONCLUSION: This questionnaire to assess barriers to ACP discussion from the perspective of family physicians demonstrates preliminary evidence of reliability and validity. PMID- 28803080 TI - Palliative Care Development in Kyrgyzstan. AB - Palliative care began in Kyrgyzstan in 2005 as a pilot home-based care program in Osh Cancer Center and was supported by a small group of nurses and one physician from Scotland. In 2010, the Soros Foundation-Kyrgyzstan and the Open Society Foundation's International Palliative Care Initiative began supporting work on palliative care policy, legislation, essential medicine availability, education, advocacy, and implementation. A Ministry of Health working group was established to lead this initiative, and technical assistance was provided by an international palliative care consultant. Work began with a national needs assessment, which identified the existing barriers to the provision of quality palliative care, and recommendations were made to the working group to address these challenges. Today, palliative care is included in many national health care policies and laws, a national palliative care association has been established, undergraduate medical and nursing education include elements of palliative care, oral morphine and fentanyl patches are now available in parts of the country, inpatient services exist in the National Cancer Center in Osh and Bishkek, two tuberculosis hospitals with multidrug resistant/extensively drug resistant, and home care services in Osh and Bishkek. Public information campaigns and advocacy activities continue to increase public awareness about palliative care and press government action. PMID- 28803082 TI - Addressing Patient Emotional and Existential Needs During Serious Illness: Results of the Outlook Randomized Controlled Trial. AB - CONTEXT: Few interventions exist to address patients' existential needs. OBJECTIVES: Determine whether an intervention to address seriously ill patients' existential concerns improves preparation, completion (elements of quality of life [QOL] at end of life), and reduces anxiety and depression. METHODS: A randomized controlled trial comparing outlook intervention, relaxation meditation (RM), and usual care (UC). Measures included primary-a validated measure of QOL at the end of life and secondary-Functional Assessment of Cancer Therapy-General, anxiety (Profile of Mood States), depression (Center for Epidemiological Studies Depression Scale), and spiritual well-being (Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being). Qualitative interviews assessed outlook intervention acceptability. Enrolled patients were nonhospice eligible veterans with advanced cancer, congestive heart failure, chronic obstructive pulmonary disease, end-stage renal disease, or end-stage liver disease. RESULTS: Patients (n = 221) were randomly assigned 1:1:1 to outlook, RM, and UC. Patients were 96% males, 46% with cancer, 58.4% married, and 43.9% of African American origin. Compared with UC, outlook participants had higher preparation (a validated measure of QOL at the end of life) (mean difference 1.1; 95% CI 0.2, 2.0; P = 0.02) and mean completion (1.6; 95% CI 0.05, 3.1; P = 0.04) at the first but not second postassessment. Compared with RM, outlook participants did not show significant differences over time. Exploratory analyses indicated that in subgroups with cancer and low sense of peace, outlook participants had improved preparation at first and not second postassessment, as compared with UC (mean difference 1.4; 95% CI 0.03, 2.7; P = 0.04) (mean difference = 1.8; 95% CI 0.3, 3.3; P = 0.02), respectively. CONCLUSION: Outlook had an impact on social well being and preparation compared with UC. The lack of impact on anxiety and depression differs from previous results among hospice patients. Results suggest that outlook is not demonstratively effective in populations not experiencing existential or emotional distress. PMID- 28803081 TI - Building an Outpatient Kidney Palliative Care Clinical Program. AB - CONTEXT: A diagnosis of advanced chronic kidney disease or end-stage renal disease represents a significant life change for patients and families. Individuals often experience high symptom burden, decreased quality of life, increased health care utilization, and end-of-life care discordant with their preferences. Early integration of palliative care with standard nephrology practice in the outpatient setting has the potential to improve quality of life through provision of expert symptom management, emotional support, and facilitation of advance care planning that honors the individual's values and goals. OBJECTIVES: This special report describes application of participatory action research methods to develop an outpatient integrated nephrology and palliative care program. METHODS: Stakeholder concerns were thematically analyzed to inform translation of a known successful model of outpatient kidney palliative care to a practice in a large urban medical center in the U.S. RESULTS: Stakeholder needs and challenges to meeting these needs were identified. We uncovered a shared understanding of the clinical need for palliative care services in nephrology practice but apprehension toward practice change. Action steps to modify the base model were created in response to stakeholder feedback. CONCLUSION: The development of a model of care that provides a new approach to clinical practice requires attention to relevant stakeholder concerns. Participatory action research is a useful methodological approach that engages stakeholders and builds partnerships. This creation of shared ownership can facilitate innovation and practice change. We synthesized stakeholder concerns to build a conceptual model for an integrated nephrology and palliative care clinical program. PMID- 28803083 TI - The Impact of Combined Use of Opioids, Antipsychotics, and Anxiolytics on Survival in the Hospice Setting. AB - CONTEXT: Opioids and sedatives are the cornerstone of symptom management in the end-of-life patients, but undertreatment is a common problem. Although several studies explored the individual effect of opioids, anxiolytics, and antipsychotics on survival, not much is known regarding their combined use. As these drugs share similar and potentially fatal side effects, primarily respiratory depression which occurs more often during night-hours, it is crucial to explore whether their interaction poses a danger for fragile hospice patients. OBJECTIVES: To analyze the relationship of a combination of opioids, anxiolytics, and antipsychotics on survival and the change of night-time death percentage. METHODS: A retrospective study of 765 consecutive patients admitted to hospice in Croatia over the period of four years (2013-2017). The main outcome was the total length of survival of hospice patients regarding different drug combination, along with night-time death percentage. RESULTS: Different combinations of opioids, anxiolytics, and antipsychotics were associated with longer survival in hospice compared with patients using no such drugs. When we included different parameters which affected overall survival into a multivariate analysis, only the patients who had the combination of both opioids, anxiolytics, and antipsychotics in their regular therapy were associated with longer survival in hospice (11 vs. five days, hazard ratio 0.54, P < 0.001). No combination of opioids, anxiolytics, and antipsychotics significantly changed the night-time death percentage. CONCLUSION: This research supports the safety of opioids, anxiolytics, and antipsychotics in the hospice setting when used both individually as well as in combination. PMID- 28803084 TI - A Patient-Centered Approach to Research on Palliative Care for Patients With Advanced Illnesses and Their Caregivers. PMID- 28803085 TI - Palliative Care in South Africa. AB - The Hospice Palliative Care Association (HPCA) was established in 1987 by hospices in South Africa who felt the need for a national body to share best practices and to promote palliative care services in South Africa. HPCA supports member hospices in providing palliative care to people of any age with a life limiting condition. HPCA has the further aim to ensure access to palliative care in settings other than member hospices. Many projects were launched over the years to influence policy, and to educate medical practitioners, nurses, social workers, theologians, and community caregiver; and to develop services. A key initiative was the development of a mentorship program to assist organizations to develop accredited palliative care services in South Africa. This article highlights some of the HPCA projects funded over the years by the Open Society Foundations' International Palliative Care Initiative. PMID- 28803086 TI - Death With Dignity: Is There Such a Thing? PMID- 28803088 TI - Treat the Pain Program. AB - CONTEXT: Globally, low- and middle-income countries are home to 70% of cancer deaths and 99% of HIV deaths, but they consume just 7% of opioid analgesics. OBJECTIVE: The American Cancer Society's Treat the Pain program partners with governments in low- and middle-income countries to improve access to high-quality essential pain medicines. METHOD: Treat the Pain has developed the MORPHINE Framework to provide a structure to describe challenges to access to pain relief and to group and sequence interventions to address these challenges. RESULTS: Treat the Pain has used the framework to improve access to oral morphine in partner countries in Sub-Saharan Africa, including Nigeria, Ethiopia, Uganda, Kenya, and Swaziland, addressing both supply- and demand-side challenges. CONCLUSION: Treat the Pain is supporting governments in Sub-Saharan Africa to reduce needless suffering and improve access to essential pain medicines for patients in pain by supporting the expansion of locally produced, affordable oral morphine solution and expanding basic training in pain assessment and management. PMID- 28803089 TI - The International Palliative Care Initiative. AB - This journal series describes the Open Society Foundation's International Palliative Care Initiative (IPCI) and the work of its national, regional, and international foundations and grantees to advance and develop palliative care globally. It provides examples of funding initiatives of IPCI honoring both grass roots and elite strategies of IPCI to integrate palliative care into national and international health policy based on a human rights approach. PMID- 28803087 TI - Effect of Prophylactic Fentanyl Buccal Tablet on Episodic Exertional Dyspnea: A Pilot Double-Blind Randomized Controlled Trial. AB - CONTEXT: Episodic dyspnea is one of the most common, debilitating, and difficult to-treat symptoms. OBJECTIVE: We conducted a pilot study to examine the effect of prophylactic fentanyl buccal tablet (FBT) on exercise-induced dyspnea. METHODS: In this parallel, double-blind randomized placebo-controlled trial, opioid tolerant patients were asked to complete a six-minute walk test (6MWT) at baseline and then a second 6MWT 30 minutes after a single dose of FBT (equivalent to 20-50% of their total opioid dose) or matching placebo. We compared dyspnea Numeric Rating Scale (NRS, 0-10, primary outcome), walk distance, vital signs, neurocognitive function, and adverse events between the two 6MWTs. RESULTS: Among 22 patients enrolled, 20 (91%) completed the study. FBT was associated with a significant within-arm reduction in dyspnea NRS between 0 and six minutes (mean change -2.4, 95% CI -3.5, -1.3) and respiratory rate (mean change -2.6, 95% CI 4.7, -0.4). Placebo was also associated with a nonstatistically significant decrease in dyspnea (mean change -1.1). Between-arm comparison of dyspnea scores in the second 6MWT favored FBT, albeit not statistically significant (estimate 0.25, P = 0.068). Global impression revealed more patients in the FBT group than placebo group reporting their dyspnea was at least "somewhat better" in the second 6MWT (4 of 9 vs. 0 of 11, P = 0.03). The other secondary outcomes did not differ significantly between arms. CONCLUSIONS: This study supports that prophylactic FBT was associated with a reduction of exertional dyspnea and was well tolerated. Our findings support the need for larger trials to confirm the therapeutic potential of rapid-onset opioids. PMID- 28803090 TI - Palliative Care in Rwanda: Aiming for Universal Access. AB - In 2011, Rwanda's Ministry of Health set a goal of universal access to palliative care by 2020. Toward this audacious egalitarian and humanitarian goal, the Ministry of Health worked with partners to develop palliative care policies and a strategic plan, secure adequate supplies of opioid for the country, initiate palliative care training programs, and begin studying a model for integrating coordinated palliative care into the public health care system at all levels. It also initiated training of a new cadre of home-based care practitioners to provide palliative care in the home. Based on these developments, the goal appears within reach. PMID- 28803091 TI - Depression-A Major Contributor to Poor Quality of Life in Patients With Advanced Cancer. AB - CONTEXT: Quality of life (QoL) and depression are important patient-reported outcomes in cancer care. However, the relative importance of depression severity in predicting QoL remains unclear because of few methodologically sound studies. OBJECTIVES: To examine whether depression contributes to impairment of QoL irrespective of prognostic factors and symptom burden. METHODS: A total of 563 patients were included from the European Palliative Care Research Collaborative Computerized Symptom Assessment Study, an international, multi-center, cross sectional study. The relative importance of prognostic factors (systemic inflammation [modified Glasgow Prognostic Score-mGPS]), co-morbidities and physical performance (Karnofsky Performance Status), symptom burden (loss of appetite, breathlessness, nausea [Edmonton Symptom Assessment Scale], and pain [Brief Pain Inventory]), and depression severity (Patient Health Questionnaire 9) in predicting Global Health/QoL (European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire [EORTC-QLQ-C30]) were assessed using hierarchical multiple regression models. RESULTS: Fifty-five percent were women, median age was 64 years, 87% had metastatic disease, median Karnofsky Performance Status was 70, and mean global QoL was 50.5 (SD = 23.3). Worse QoL was associated with increased systemic inflammation (mGPS = 1 beta = -0.12, P = 0.003; mGPS = 2 beta = -0.09, P = 0.023), lower physical performance (beta = 0.17, P < 0.001), reduced appetite (beta = -0.15, P < 0.001), breathlessness (beta = -0.11, P = 0.004), pain (beta = -0.14, P = 0.002), and higher depression severity (beta = 0.27, P < 0.001). The full model accounted for 29% of the observed variance in QoL scores. The strongest predictor was depression severity, accounting for 5.8% of the variance. CONCLUSION: Depression severity was the strongest single predictor of poorer QoL in this sample of patients with advanced cancer, after accounting for a wide range of clinically relevant variables. Future studies should investigate the contribution of psychosocial variables on QoL. Our findings emphasize the importance of managing depression to achieve the best possible QoL for these patients. PMID- 28803092 TI - Uniform field loop-gap resonator and rectangular TEU02 for aqueous sample EPR at 94GHz. AB - In this work we present the design and implementation of two uniform-field resonators: a seven-loop-six-gap loop-gap resonator (LGR) and a rectangular TEU02 cavity resonator. Each resonator has uniform-field-producing end-sections. These resonators have been designed for electron paramagnetic resonance (EPR) of aqueous samples at 94GHz. The LGR geometry employs low-loss Rexolite end-sections to improve the field homogeneity over a 3mm sample region-of-interest from near cosine distribution to 90% uniform. The LGR was designed to accommodate large degassable Polytetrafluorethylen (PTFE) tubes (0.81mm O.D.; 0.25mm I.D.) for aqueous samples. Additionally, field modulation slots are designed for uniform 100kHz field modulation incident at the sample. Experiments using a point sample of lithium phthalocyanine (LiPC) were performed to measure both the uniformity of the microwave magnetic field and 100kHz field modulation, and confirm simulations. The rectangular TEU02 cavity resonator employs over-sized end sections with sample shielding to provide an 87% uniform field for a 0.1*2*6mm3 sample geometry. An evanescent slotted window was designed for light access to irradiate 90% of the sample volume. A novel dual-slot iris was used to minimize microwave magnetic field perturbations and maintain cross-sectional uniformity. Practical EPR experiments using the application of light irradiated rose bengal (4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein) were performed in the TEU02 cavity. The implementation of these geometries providing a practical designs for uniform field resonators that continue resonator advancements towards quantitative EPR spectroscopy. PMID- 28803093 TI - Parental reflective functioning as a moderator of child internalizing difficulties in the context of child sexual abuse. AB - The objective was to examine pathways from child sexual abuse (CSA) and maternal mentalizing to child internalizing and externalizing difficulties and to test a model of MRF as a moderator of the relationships between CSA and child difficulties. The sample was comprised of 154 mothers and children aged 2-12 where 64 children had experienced CSA. To assess parental mentalizing the Parental Development Interview was rated with the Parental Reflective Functioning Scale. Child internalizing and externalizing difficulties were assessed with the Child Behavior Checklist (CBCL). Results indicate that there were significant inverse relationships between maternal mentalizing and child internalizing and externalizing difficulties. When maternal mentalizing was considered together with CSA, only maternal mentalizing was a significant predictor of child difficulties. Furthermore, maternal mentalizing moderated the relationship between CSA and child internalizing difficulties. These findings provide evidence of the importance of the parents' mentalizing stance for psychiatric symptoms of children aged 2-12, as well as children's recovery from CSA. The clinical implications of the findings are discussed. PMID- 28803094 TI - Brief psychoeducation for bipolar disorder: Evaluation of trophic factors serum levels in young adults. AB - The aim of this study was to evaluate the impact of psychoeducation in serum levels of BDNF, NGF and GDNF in young adults presenting bipolar disorder (BD). This is a randomized clinical trial including 39 young adults (18-29 years) diagnosed with BD through the Structured Clinical Interview for DSM-IV (SCID-CV). Participants were randomized in two treatment groups: usual treatment (medication) and combined intervention (medication plus psychoeducation). Depressive symptoms were assessed using the Hamilton Depression Rating Scale (HDRS) and severity of manic and hypomanic symptoms was evaluated through the Young Mania Rating Scale (YMRS). The serum levels of trophic factors were measured with an ELISA kit. In both intervention groups, there was an improvement in depressive symptoms significantly between baseline and post-intervention. In the combined intervention, GDNF serum levels increased significantly from baseline to post-intervention. However, there were no differences in BDNF and NGF serum levels. In the usual treatment group, no changes were observed in serum levels of GDNF, BDNF, and NGF the post-intervention in individuals. Our data suggests that only combined intervention was effective in improving depressive symptoms and increasing GDNF levels in a sample of young adults with bipolar disorder. PMID- 28803095 TI - Acute effects of smoked marijuana in marijuana smokers at clinical high-risk for psychosis: A preliminary study. AB - Marijuana use is associated with psychosis, but its effects are understudied in individuals with preexisting risk for psychotic disorders. This preliminary study examined the acute psychological and physiological effects of smoked marijuana (0.0% or 5.5% Delta9-THC) in marijuana users at clinical high-risk (CHR; n = 6) to develop a psychotic disorder, and those not at risk (n = 6), under controlled laboratory conditions. CHR marijuana users exhibited temporary increases in psychotic-like states and decreases in neurocognitive performance during marijuana intoxication but control marijuana smokers did not. These findings, if replicated, may support a psychotogenic role for marijuana in CHR individuals. PMID- 28803096 TI - Upgrading of the symbiosis of Nitrosomanas and anammox bacteria in a novel single stage partial nitritation-anammox system: Nitrogen removal potential and Microbial characterization. AB - A novel single-stage partial nitritation-anammox process equipped with porous functional suspended carriers was developed at 25 degrees C in a CSTR by controlling dissolved oxygen <0.3mg/L. The nitrogen removal performance was almost unchanged over a nitrogen loading rate ranging from 0.5 to 2.5kgNH4+ N/m3/d with a high nitrogen removal efficiency of 81.1%. The specific activity of AOB and anammox bacteria was of 3.00g-N/g-MLVSS/d (the suspended sludge), 3.56g N/g-MLVSS/d (the biofilm sludge), respectively. The results of pyrosequencing revealed that Nitrosomonas (5.66%) and Candidatus_Kuenenia (4.95%) were symbiotic in carriers while Nitrosomonas (40.70%) was predominant in the suspended flocs. Besides, two specific types of heterotrophic filamentous bacteria in the suspended flocs (Haliscomenobacter) and the functional carrier biofilm (Longilinea) were shown to confer structural integrity to the aggregates. The novel single-stage partial nitritation-anammox process equipped with functional suspended carriers was shown to have good potential for the nitrogen-rich wastewater treatment. PMID- 28803097 TI - A parametric response surface study of fermentative hydrogen production from cheese whey. AB - Batch factorial experiments were performed on cheese whey+wastewater sludge mixtures to evaluate the influence of pH and the inoculum-to-substrate ratio (ISR) on fermentative H2 production and build a related predictive model. ISR and pH affected H2 potential and rate, and the fermentation pathways. The specific H2 yield varied from 61 (ISR=0, pH=7.0) to 371L H2/kg TOCwhey (ISR=1.44gVS/g TOC, pH=5.5). The process duration range was 5.3 (ISR=1.44gVS/g TOC, pH=7.5) - 183h (ISR=0, pH=5.5). The metabolic products included mainly acetate and butyrate followed by ethanol, while propionate was only observed once H2 production had significantly decreased. The multiple metabolic products suggested that the process was governed by several fermentation pathways, presumably overlapping and mutually competing, reducing the conversion yield into H2 compared to that expected with clostridial fermentation. PMID- 28803098 TI - Simultaneous removal of nitrogen and phosphorous from domestic wastewater using Bacillus cereus GS-5 strain exhibiting heterotrophic nitrification, aerobic denitrification and denitrifying phosphorous removal. AB - A newly isolated GS-5 strain exhibiting heterotrophic nitrification, aerobic denitrification and denitrifying phosphorous removal was identified as Bacillus cereus GS-5 based on its phenotypic and phylogenetic characteristics. The isolate had exhibited efficient NH4+-N, NO3--N, NO2--N and PO43--P removal from nutrient spiked real domestic wastewater with average rates of 2.62, 2.69, 1.16 and 0.42mgL-1h-1, respectively under aerobic condition. Metabolic inhibitor based mass balance analysis indicated that dinitrogen gas (41%), intracellular nitrogen (29%) and intracellular phosphorous (60%) were the major fates of the initial NH4+-N and PO43--P. The successfully expression of hydroxylamine oxidase (hao), nitrate reductase (nar), nitrite reductase (nir) and poly phosphate kinase (ppk) enzyme in the cell free extracts and PCR amplification of nar, nir and ppk genes in the isolated strain provided further evidences for the nutrient removal possibility. A possible pathway of for nitrogen removal by GS-5 is suggested. PMID- 28803099 TI - Renewable platform chemicals from directional microwave-assisted liquefaction coupling stepwise extraction of waste biomass. AB - Directional microwave-assisted liquefaction and stepwise extraction are introduced for producing platform chemicals: aromatics and monosaccharides. When sulfuric acid was used as a catalyst, a 45% monosaccharides yield and a 29% aromatics yield were obtained from bamboo with 0.3g catalyst per 18g methanol and 2g bamboo at 160 degrees C with 10min. Approximately 78-86wt% of the six biomass materials were converted into liquid products. After the stepwise extraction and precipitation process, the yields of monosaccharide derivatives and three phenolic compound fractions were 39-45% and 28-32%, respectively. Monosaccharides from holocellulose collected with a high purity of methyl glycosides were higher than 90%. Aromatic derivatives with different weight-molecular distributions were separated into three fractions with more than 80% phenolics. As their similar chemical properties within each fraction, platform chemicals have great commercial potential for producing high-quality chemicals and biofuels using mild upgrading conditions. PMID- 28803100 TI - Optimization of Aqueous Ammonia Soaking of manure fibers by Response Surface Methodology for unlocking the methane potential of swine manure. AB - Swine manure mono-digestion often results to economically non-feasible processes, due to the high dilution and ammonia concentration together with the low degradation rates it presents. The effects of different parameters of Aqueous Ammonia Soaking (AAS) as a pretreatment for improving the digestion of manure fibers when coupled to an ammonia removal step were investigated in this study. Response Surface Methodology was followed and the influence and interactions of the following AAS parameters were studied: NH3 concentration, duration and solid to-liquid ratio. The mild conditions found to be optimal (7%w/w NH3, 96h, and 0.16kg/L) in combination to a significant increase of the short term CH4 yield (244% in 17days), make this pretreatment a promising solution for improving swine manure mono-digestion. Furthermore, compositional analysis of the manure fibers revealed significant solubilization of hemicellulose, while no lignin removal or loss of cellulose occurred under optimal conditions. PMID- 28803101 TI - Persulfate oxidation assisted hydrochar production from Platanus Orientalis Leaves: Physiochemical and combustion characteristics. AB - Platanus Orientalis Leaves (POL), a widely planted tree in parks and along streets, was employed by sequential persulfate oxidation (Fe2+and persulfate) and hydrothermal treatment (HTC) to improve the thermal stability, energy yield and combustion behavior of hydrochars (HCs). Higher heating values (HHVs) of HCs derived from persulfate pretreated POL was increased by 30.5% at mild HTC temperature (i.e., 210 degrees C) as compared to char without pretreatment. Elevating Fe2+/persulfate ratio to 0.2 enables HCs with high fractions of lignin, thus promoting the energy yield going up to 64.4%. The ultimate and proximate analysis, N2 adsorption-desorption isotherms, FT-IR spectroscopy and thermogravimetric analysis were conducted to probe into chars' physiochemical and combustion characteristics. Results indicated that persulfate pretreatment on POL strengthened efficient HTC conversion from volatile matter to fixed carbon, increasing the ignition temperature of HCs from 261.5 to 404.3 degrees C as compared to the char obtained with only HTC. PMID- 28803102 TI - Kinetics of the release of elemental precursors of syngas and syngas contaminants during devolatilization of switchgrass. AB - In this study, the results from laboratory measurements of the devolatilization kinetics of switchgrass in a rapidly heated fixed bed reactor flushed with argon and operated at constant temperatures between 600 and 800 degrees C was reported. Results indicate that switchgrass decomposes in two sequential stages during pyrolysis: stage I involves the evaporation and devolatilization of water and extractives and stage II involves that of hemicellulose, cellulose, and lignin. The estimated global activation energy for stage II increased from 52.80 to 59.39kJ/mol as the reactor temperature was increased from 600 to 800 degrees C. The maximum conversion of carbon, hydrogen, oxygen, sulfur, and nitrogen ranged from 0.68 to 0.70, 0.90 to 0.95, 0.88 to 0.91, 0.70 to 0.80, and 0.55 to 0.66, respectively. The retention of alkali and alkaline earth metal (AAEM) species in the solid char after complete pyrolysis was significantly higher than in the original feed, indicating the importance of AAEM species in subsequent char processing. PMID- 28803103 TI - Engineering Halomonas bluephagenesis TD01 for non-sterile production of poly(3 hydroxybutyrate-co-4-hydroxybutyrate). AB - Poly(3-hydroxybutyrate-co-4-hydroxybutyrate), short as P(3HB-co-4HB), was successfully produced by engineered Halomonas bluephagenesis TD01 grown in glucose and gamma-butyrolactone under open non-sterile conditions. Gene orfZ encoding 4HB-CoA transferase of Clostridium kluyveri was integrated into the genome to achieve P(3HB-co-4HB) accumulation comparable to that of strains encoding orfZ on plasmids. Fed-batch cultivations conducted in 1-L and 7-L fermentors, respectively, resulted in over 70g/L cell dry weight (CDW) containing 63% P(3HB-co-12mol% 4HB) after 48h under non-sterile conditions. The processes were further scaled up in a 1000-L pilot fermentor to reach 83g/L CDW containing 61% P(3HB-co-16mol% 4HB) in 48h, with a productivity of 1.04g/L/h, again, under non-sterile conditions. The elastic P(3HB-co-16mol% 4HB) shows an elongation at break of 1022+/-43%. Results demonstrate that the engineered Halomonas bluephagenesis TD01 is a suitable industrial strain for large scale production under open non-sterile conditions. PMID- 28803105 TI - Glucose bioconversion profile in the syngas-metabolizing species Clostridium carboxidivorans. AB - Some clostridia produce alcohols (ethanol, butanol, hexanol) from gases (CO, CO2, H2) and others from carbohydrates (e.g., glucose). C. carboxidivorans can metabolize both gases as well as glucose. However, its bioconversion profile on glucose had not been reported. It was observed that C. carboxidivorans does not follow a typical solventogenic stage when grown on glucose. Indeed, at pH 6.2, it produced first a broad range of acids (acetic, butyric, hexanoic, formic, and lactic acids), several of which are generally not found, under similar conditions, during gas fermentation. Medium acidification did not allow the conversion of fatty acids into solvents. Production of some alcohols from glucose was observed in C. carboxidivorans but at high pH rather than under acidic conditions, and the total concentration of those solvents was low. At high pH, formic acid was produced first and later converted to acetic acid, but organic acids were not metabolized at low pH. PMID- 28803104 TI - Exploration of a mechanism for the production of highly unsaturated fatty acids in Scenedesmus sp. at low temperature grown on oil crop residue based medium. AB - The ability of algae to produce lipids comprising of unsaturated fatty acids varies with strains and culture conditions. This study investigates the effect of temperature on the production of unsaturated fatty acids in Scenedesmus sp. grown on oil crop residue based medium. At low temperature (10 degrees C), synthesis of lipids compromising of high contents of unsaturated fatty acids took place primarily in the early stage while protein accumulation mainly occurred in the late stage. This stepwise lipid-protein synthesis process was found to be associated with the contents of acetyl-CoA and alpha-KG in the algal cells. A mechanism was proposed and tested through simulation experiments which quantified the carbon flux allocation in algal cells at different cultivation stages. It is concluded that low culture temperature such as 10 degrees C is suitable for the production of lipids comprising of unsaturated fatty acids. PMID- 28803106 TI - Effects of fractal roughness of membrane surfaces on interfacial interactions associated with membrane fouling in a membrane bioreactor. AB - Fractal roughness is one of the most important properties of a fractal surface. In this study, it was found that, randomly rough membrane surface was a fractal surface, which could be digitally modeled by a modified two-variable Weierstrass Mandelbrot (WM) function. Fractal roughness of membrane surfaces has a typical power function relation with the statistical roughness of the modeled surface. Assessment of interfacial interactions showed that an increase in fractal roughness of membrane surfaces will strengthen and prolong the interfacial interactions between membranes and foulants, and under conditions in this study, will significantly increase the adhesion propensity of a foulant particle on membrane surface. This interesting result can be attributed to that increase in fractal roughness simultaneously improves separation distance and interaction surface area for adhesion of a foulant particle. This study gives deep insights into interfacial interactions and membrane fouling in MBRs. PMID- 28803107 TI - Conversion of lipids from wet microalgae into biodiesel using sulfonated graphene oxide catalysts. AB - Four solid acid catalysts including graphene oxide (GO), sulfonated graphene oxide (SGO), sulfonated graphene (SG), and sulfonated active carbon (SAC) were used to convert lipids in wet microalgae into biodiesel. The physiochemical properties of the catalysts were characterized with scanning electron microscope, X-ray diffraction, and thermogravimetric analysis. SGO provided the highest conversion efficiency (84.6% of sulfuric acid) of lipids to fatty acid methyl esters (FAME). Whereas SAC converted few lipids into FAME. Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and elemental analysis revealed that much higher hydrophilic hydroxyl content in SGO catalyst resulted in a considerable higher conversion efficiency of lipids to FAME than that (48.6%) catalyzed by SG, although SO3H groups (0.44mmol/g) in SGO were less than those (1.69mmol/g) in SG. Given its higher SO3H group content than GO (0.38mmol/g), SGO had higher conversion efficiency than GO (73.1%), when they had similar hydrophilic hydroxyl contents. PMID- 28803108 TI - Enhanced biobutanol production with high yield from crude glycerol by acetone uncoupled Clostridium sp. strain CT7. AB - This study reports a unique acetone uncoupled Clostridium species strain CT7, which shows efficient capability of glycerol utilization with high butanol ratio. Medium compositions, such as substrate concentration, micronutrients and pH show significant effects on butanol production from glycerol by strain CT7. To further maximize butanol production, fermentation conditions were optimized by using response surface methodology (RSM). Final butanol production of 16.6g/L with yield of 0.43g/g consumed glycerol was obtained, representing the highest butanol production and yield from glycerol in the batch fermentation mode. Furthermore, strain CT7 could directly convert crude glycerol to 11.8g/L of butanol without any pretreatment. Hence, strain CT7 shows immense potential for biofuels production using waste glycerol as cheap substrate. PMID- 28803109 TI - Second-generation ethanol from non-detoxified sugarcane hydrolysate by a rotting wood isolated yeast strain. AB - This work aims to evaluate the production of second-generation ethanol from sugarcane bagasse hydrolysate without acetic acid (inhibitor) detoxification. Three isolated yeast strains from lignocellulosic materials were evaluated, and one strain (UFFS-CE-3.1.2), identified using large subunit rDNA sequences as Wickerhamomyces sp., showed satisfactory results in terms of ethanol production without acetic acid removal. A Plackett-Burman design was used to evaluate the influence of hydrolysate composition and nutrients supplementation in the fermentation medium for the second-generation ethanol production. Two fermentation kinetics were performed, with controlled pH at 5.5, or keeping the initial pH at 4.88. The fermentation conducted without pH adjustment and supplementation of nutrients reported the best result in terms of second generation ethanol production. Wickerhamomyces sp., isolated as UFFS-CE-3.1.2, was considered promising in the production of second-generation ethanol by using crude (non-detoxified) sugarcane hydrolysate. PMID- 28803110 TI - Dynamics of microbial activities and community structures in activated sludge under aerobic starvation. AB - The knowledge of the effect of aerobic starvation on the functional bacterial activities and community structures is important for the recovery of nutrient removal in activated sludge system. Four aerobic starvation processes (3, 7, 14 and 30days) for nitrifiers and polyphosphate accumulating organisms (PAOs) were studied. The results showed that nitrifiers could utilize the released ammonium for growth during the first 7days of the aerobic starvation, and then gradually decayed. In the recovery period, the slower recovery ability of nitrite-oxidizing bacteria (NOB) than ammonium-oxidizing bacteria (AOB) contributed to the nitrite accumulation. Besides, the sequential consumption of polyhydroxyalkanoates (PHA), glycogen and the utilization of polyphosphate (poly-P) in PAOs provided the energy to maintain bacterial metabolic activity. High-throughput sequencing analysis revealed that aerobic starvation had substantial impacts on the succession of microbial community, and the majority of original dominant species within the phylum Proteobacteria and Bacteroidetes declined while Firmicutes increased. PMID- 28803111 TI - Laccase enzyme detoxifies hydrolysates and improves biogas production from hemp straw and miscanthus. AB - The impact of various phenolic compounds, vanillic acid, ferulic acid, p-coumaric acid and 4-hydroxybenzoic acid on anaerobic digestion of lignocellulosic biomass (hemp straw and miscanthus) was studied. Such phenolic compounds have been known to inhibit biogas production during anaerobic digestion. The different phenolic compounds were added in various concentrations: 0, 100, 500, 1000 and 2000mg/L. A difference in inhibition of biomethane production between the phenolic compounds was noted. Hydrolysis rate, during anaerobic digestion of miscanthus was inhibited up to 50% by vanillic acid, while vanillic acid had no influence on the initial rate of biogas production during the anaerobic digestion of hemp straw. Miscanthus has a higher lignin concentration (12-30g/100gDM) making it less accessible for degradation, and in combination with phenolic compounds released after harsh pretreatments, it can cause severe inhibition levels during the anaerobic digestion, lowering biogas production. To counter the inhibition, lignin degrading enzymes can be used to remove or degrade the inhibitory phenolic compounds. The interaction of laccase and versatile peroxidase individually with the different phenolic compounds was studied to have insight in the polymerization of inhibitory compounds or breakdown of lignocellulose. Hemp straw and miscanthus were incubated with 0, 100 and 500mg/L of the different phenolic compounds for 0, 6 and 24h and pretreated with the lignin degrading enzymes. A laccase pretreatment successfully detoxified the substrate, while versatile peroxidase however was inhibited by 100mg/L of each of the individual phenolic compounds. Finally a combination of enzymatic detoxification and subsequent biogas production showed that a decrease in phenolic compounds by laccase treatment can considerably lower the inhibition levels of the biogas production. PMID- 28803112 TI - In vivo documentation of shape and position changes of MRI-visible mesh placed in rectovaginal septum. AB - BACKGROUND AND OBJECTIVE: Large deformations in synthetic meshes used in pelvic organ prolapse surgery may lead to suboptimal support for the underlying tissue, graft-related complications as well as recurrence. Our aim was to quantify in vivo longitudinal changes in mesh shape and geometry in a large animal model. We compare two commonly used mesh shapes, armed and flat, that are differently affixed. The secondary outcomes were active and passive biomechanical properties. METHODS: A total of 18 animals were used. Six each were implanted with either an arm mesh, a flat mesh or underwent a sham surgery. PVDF meshes loaded with Fe2O3 were used to facilitate their visualization in vivo. MR images were taken at 2, 14 and 60 days after implantation and 3D models of the meshes were created at each time point. We calculate the Effective Surface Area (ESA), i.e. the support that the mesh provides to the underlying tissue using custom developed techniques. Longitudinal changes in the mesh shape were studied by comparing the respective 3D models using part comparison analyses. The root means square difference (RMSD) and the modified Hausdorff distance (MHD) were calculated to obtain an objective value for the part comparisons. Wall thickness maps were produced on 3D models. Mesh arm length and their ellipticity profiles were also evaluated. Active and passive biomechanical tests on vaginal tissue overlaying the mesh were conducted using a contractility assay and a uniaxial loading protocol. RESULTS: MR images of 5 animals in each group were used for longitudinal comparison. Compared to the initial implant size, there was an immediate drop in the ESA measurement at day 2 of almost 32.22 [7.06] % (median [IQR]) for flat meshes, and by 17.59 [6.50] % for arm meshes. After 14 days, the reduction in area was 41.84 [14.89] % and 27.18 [20.44] %, and at day 60 it was 36.61 [6.64] % and 26.43 [14.56] % for the flat and armed meshes respectively. The reduction in area in the two groups was different between the two groups only day 14 (p = 0.046). The ellipticity of the arms was 0.81 [0.08] (median [IQR]) and there was no significant change in the ellipticity profiles over time. The mesh arm length did not change significantly over time. The part comparison showed a maximum difference of 4.26 [3.29] mm in 3D models according to the MHD measure, which is clinically not relevant. Comparison of high thickness areas on the thickness maps correlated well with the areas of mesh folding in the arm mesh group observed during postmortem dissection. Thickness maps did not help us understand why the flat meshes had a reduction in support area. The comfort zone stiffness of the flat mesh and of the central part of the arm mesh were 2.4 fold and 4.5 times stiffer compared to sham groups, respectively. The arms were 36% stiffer than the central part of the mesh. The comfort zone length of the sham group was 46% longer than the flat mesh group (p = 0.027) and 59% longer than that of the central part of the arm mesh (p = 0.005). There was no significant difference in vaginal contractile forces generated in samples from the arm, flat mesh, and sham groups. CONCLUSIONS: This is a first longitudinal study observing deformations in vaginally implanted synthetic meshes in a large animal model. A novel methodology is presented to calculate the area of the vaginal tissue effectively supported by the mesh implant. Immediately post-operatively, a reduction in 32% and 17% was noted, which remained stable over the 60 following days of observation. We use thickness maps to analyze the cause of this dramatic immediate reduction. In the armed mesh we found it to be mesh folding at the interface between the arms and central part. For the flat mesh we suggest that pore aggregation during suturing. PMID- 28803113 TI - How a decreased fibrillar interconnectivity influences stiffness and swelling properties during early cartilage degeneration. AB - OBJECTIVE: The functional coupling between the fibrillar network and the high swelling proteoglycans largely determines the mechanical properties of the articular cartilage matrix. The objective of this new study was to show specifically how changes in fibrillar interconnectivity arising from early cartilage degeneration influence transverse stiffness and swelling properties at the tissue level. DESIGN: Radial zone transverse layers of cartilage matrix were obtained from intact and mildly degenerate bovine patellae. Each layer was then subdivided to assess tensile stiffness, free-swelling response, glycosaminoglycan (GAG) content, and micro- and ultra-structural features. RESULTS: The tensile modulus was significantly lower and the degree of swelling significantly higher for the degenerate matrix compared to the intact. Scanning electron microscopy revealed a homogeneous response to transverse strain in the intact cartilage, whereas large non-fibrillar spaces between fibril aggregates were visible in the degenerate matrix. Although there were no significant differences in GAG content it did correlate significantly with stiffness and swelling in the intact samples but not in the degenerate. CONCLUSIONS: The lower degree of fibril network interconnectivity in the degenerate matrix led to both a decreased transverse stiffness and reduced resistance to osmotic swelling. This network 'de structuring' also resulted in a reduced functional interaction between the fibrillar network and the proteoglycans. The study provides new insights into the role of the fibrillar network and how changes in the network arising from the degenerative cascade will influence tissue level behaviour. PMID- 28803115 TI - Immunological response to nitroglycerin-loaded shear-responsive liposomes in vitro and in vivo. AB - Liposomes formulated from the 1,3-diamidophospholipid Pad-PC-Pad are shear responsive and thus promising nano-containers to specifically release a vasodilator at stenotic arteries. The recommended preclinical safety tests for therapeutic liposomes of nanometer size include the in vitro assessment of complement activation and the evaluation of the associated risk of complement activation-related pseudo-allergy (CARPA) in vivo. For this reason, we measured complement activation by Pad-PC-Pad formulations in human and porcine sera, along with the nanopharmaceutical-mediated cardiopulmonary responses in pigs. The evaluated formulations comprised of Pad-PC-Pad liposomes, with and without polyethylene glycol on the surface of the liposomes, and nitroglycerin as a model vasodilator. The nitroglycerin incorporation efficiency ranged from 25% to 50%. In human sera, liposome formulations with 20mg/mL phospholipid gave rise to complement activation, mainly via the alternative pathway, as reflected by the rises in SC5b-9 and Bb protein complex concentrations. Formulations having a factor of ten lower phospholipid content did not result in measurable complement activation. The weak complement activation induced by Pad-PC-Pad liposomal formulations was confirmed by the results obtained by performing an in vivo study in a porcine model, where hemodynamic parameters were monitored continuously. Our study suggests that, compared to FDA-approved liposomal drugs, Pad-PC-Pad exhibits less or similar risks of CARPA. PMID- 28803114 TI - The inferomedial femoral neck is compromised by age but not disease: Fracture toughness and the multifactorial mechanisms comprising reference point microindentation. AB - The influence of ageing on the fracture mechanics of cortical bone tissue is well documented, though little is known about if and how related material properties are further affected in two of the most prominent musculoskeletal diseases, osteoporosis and osteoarthritis (OA). The femoral neck, in close proximity to the most pertinent osteoporotic fracture site and near the hip joint affected by osteoarthritis, is a site of particular interest for investigation. We have recently shown that Reference Point micro-Indentation (RPI) detects differences between cortical bone from the femoral neck of healthy, osteoporotic fractured and osteoarthritic hip replacement patients. RPI is a new technique with potential for in vivo bone quality assessment. However, interpretation of RPI results is limited because the specific changes in bone properties with pathology are not well understood and, further, because it is not conclusive what properties are being assessed by RPI. Here, we investigate whether the differences previously detected between healthy and diseased cortical bone from the femoral neck might reflect changes in fracture toughness. Together with this, we investigate which additional properties are reflected in RPI measures. RPI (using the Biodent device) and fracture toughness tests were conducted on samples from the inferomedial neck of bone resected from donors with: OA (41 samples from 15 donors), osteoporosis (48 samples from 14 donors) and non age-matched cadaveric controls (37 samples from 10 donoros) with no history of bone disease. Further, a subset of indented samples were imaged using micro-computed tomography (3 osteoporotic and 4 control samples each from different donors) as well as fluorescence microscopy in combination with serial sectioning after basic fuchsin staining (7 osteoporotic and 5 control samples from 5 osteoporotic and 5 control donors). In this study, the bulk indentation and fracture resistance properties of the inferomedial femoral neck in osteoporotic fracture, severe OA and control bone were comparable (p > 0.05 for fracture properties and <10% difference for indentation) but fracture toughness reduced with advancing age (7.0% per decade, r = -0.36, p = 0.029). Further, RPI properties (in particular, the indentation distance increase, IDI) showed partial correlation with fracture toughness (r = 0.40, p = 0.023) or derived elastic modulus (r = -0.40, p = 0.023). Multimodal indent imaging revealed evidence of toughening mechanisms (i.e. crack deflection, bridging and microcracking), elastoplastic response (in terms of the non-conical imprint shape and presence of pile-up) and correlation of RPI with damage extent (up to r = 0.79, p = 0.034) and indent size (up to r = 0.82, p < 0.001). Therefore, crack resistance, deformation resistance and, additionally, micro structure (porosity: r = 0.93, p = 0.002 as well as pore proximity: r = -0.55, p = 0.027 for correlation with IDI) are all contributory to RPI. Consequently, it becomes clear that RPI measures represent a multitude of properties, various aspects of bone quality, but are not necessarily strongly correlated to a single mechanical property. In addition, osteoporosis or osteoarthritis do not seem to further influence fracture toughness of the inferomedial femoral neck beyond natural ageing. Since bone is highly heterogeneous, whether this finding can be extended to the whole femoral neck or whether it also holds true for other femoral neck quadrants or other material properties remains to be shown. PMID- 28803116 TI - Efficient molecularly imprinted polymer as a pipette-tip solid-phase sorbent for determination of carvedilol enantiomers in human urine. AB - In this work, an efficient pipette tip based on molecularly imprinted polymers solid-phase extraction (PT-MIP-SPE) method was developed for carvedilol (CAR) analysis. This compound is available in clinical practice as a racemic mixture, in which (-)-(S)-CAR is a beta- and alpha1-adrenergic antagonist, while (+)-(R) CAR only acts as an alpha1-adrenergic antagonist. Enantioseparation of CAR presented satisfactory retention times (5.85 and 14.84min), acceptable theoretical plates (N=2048 and 2018) and good resolution (Rs=9.27). The separation was performed using a Chiralpak(r) IA column (100mm*4.6mm, 3MUm), a mixture of methanol:ethanol:water (64:15:21, v/v/v) plus 0.3% diethylamine as mobile phase, temperature of 35 degrees C and flow rate of 1.5mLmin-1. After density functional theory calculations based on prepolymerization complexes, the best protocol for the MIP synthesis was chosen. Then, some parameters that affect the PT-MIP-SPE technique were investigated. After optimization, the best conditions were 300MUL of water as washing solvent, 500MUL of acetonitrile:acetic acid (7:3, v/v) as eluting solvent, 20mg of MIP, 500MUL of urine sample (pH 12.5) and no addition of NaCl. Recoveries+/-relative standard deviation (RSD%) for (+) (R)-CAR and (-)-(S)-CAR were 101.9+/-4.8% and 104.6+/-2.1%, respectively. The method was linear over the concentration range from 20 to 1280ngmL-1 for each enantiomer, with correlation coefficients larger than 0.99 for both enantiomers. The method was applied successfully in a preliminary study of urinary excretion after administration of CAR racemate to a healthy volunteer. PMID- 28803117 TI - Phenolics from Rubus fairholmianus induces cytotoxicity and apoptosis in human breast adenocarcinoma cells. AB - Herbal medicine is an important part of health care system in most of the countries. Rubus fairholmianus is an unexplored berry in folkloric medicine. In this study, we aimed to understand the importance of R. fairholmianus in pharmaceutical industry for the development of cost-effective cancer therapeutic drugs using in vivo and in vitro analysis. Chemical characterization, antioxidant, antiproliferative and apoptosis inducing properties of R. fairholmianus root methanolic column subfraction (RFM) were investigated. The RFM displayed the presence of alpha-tocopherol, flavonol glycoside and apigenin in the chemical characterization. DPPH (2, 2-diphenyl-1-picrylhydrazyl) and ABTS (2, 2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)) radical scavenging assays exhibited an activity of 7.56 MUg/mL (IC50) and 20514.7 MUM trolox equivalents/g respectively. The solid and ascites tumors in mice were reduced significantly upon 100 mg/kg RFM treatment by reducing the tumor volume (1.86 cm3), tumor weight (69%) and increasing life span (31.74 days). The morphological features of RFM treated MCF-7 cells showed the cell damage and decreased cell numbers. The viability of treated cells decreased with 67.73% at 20 MUg/mL against 96.50% in untreated cells. The treated cells (20 MUg/mL) resulted in a substantial decrease (p < 0.001) in cellular ATP proliferation, increased the LDH cytotoxicity, increased apoptotic cells population (33.92%) and reduced the population of viable cells (Annexin V-/PI-) (45.56%). Increased caspase 3/7 activity and cytochrome c release were also observed in treated cells. This is the first evidence about in vitro and in vivo anticancer activity of R. fairholmianus phenolics. The major phenolics such as alpha-tocopherol, flavonol glycoside, and apigenin might be the reason behind the caspase-mediated apoptosis. Further work is warranted to study the individual effects of these bioactive compounds in the induction of cell death. Due to the apoptosis inducing properties, it can be considered as an effective adjuvant therapeutic agent in clinical trials. PMID- 28803118 TI - Complex interactions between the subject factors of biological sex and prior histories of binge-drinking and unpredictable stress influence behavioral sensitivity to alcohol and alcohol intake. AB - Alcohol use disorders, affective disorders and their comorbidity are sexually dimorphic in humans. However, it is difficult to disentangle the interactions between subject factors influencing alcohol sensitivity in studies of humans. Herein, we combined murine models of unpredictable, chronic, mild stress (UCMS) and voluntary binge-drinking to examine for sex differences in the interactions between prior histories of excessive ethanol-drinking and stress upon ethanol induced changes in motor behavior and subsequent drinking. In Experiment 1, female mice were insensitive to the UCMS-induced increase in ethanol-induced locomotion and ethanol intake under continuous alcohol-access. Experiment 2 revealed interactions between ethanol dose and sex (females>males), binge drinking history (water>ethanol), and UCMS history (UCMS>controls), with no additive effect of a sequential prior history of both binge drinking and UCMS observed. We also observed an interaction between UCMS history and sex for righting recovery. UCMS history potentiated subsequent binge-drinking in water controls of both sexes and in male binge-drinking mice. Conversely, a prior binge drinking history increased subsequent ethanol intake in females only, irrespective of prior UCMS history. In Experiment 3, a concurrent history of binge-drinking and UCMS did not alter ethanol intake, nor did it influence the ethanol dose-locomotor response function, but it did augment alcohol-induced sedation and reduced subsequent alcohol intake over that produced by binge drinking alone. Thus, the subject factors of biological sex, prior stressor history and prior binge-drinking history interact in complex ways in mice to impact sensitivity to alcohol's motor-stimulating, -incoordinating and intoxicating effects, as well as to influence subsequent heavy drinking. PMID- 28803119 TI - The effects of low-intensity cycling on cognitive performance following sleep deprivation. AB - This study examined the effect of 24h of sleep deprivation on cognitive performance and assessed the effect of acute exercise on cognitive performance following sleep deprivation. Young, active, healthy adults (n=24, 14 males) were randomized to control (age=24.7+/-3.7years, BMI=27.2+/-7.0) or exercise (age=25.3+/-3.3years, BMI=25.6+/-5.1) groups. Cognitive testing included a 5-min psychomotor vigilance task (PVT), three memory tasks with increasing cognitive load, and performance of the PVT a second time. On morning one, cognitive testing followed a typical night's sleep. Following 24-h of sustained wakefulness, cognitive testing was conducted again prior to and after the acute intervention. Participants in the exercise condition performed low-intensity cycling (~40%HRR) for 15-min and those in the control condition sat quietly on the bike for 15-min. t-Tests revealed sleep deprivation negatively affected performance on the PVT, but did not affect memory performance. Following the acute intervention, there were no cognitive performance differences between the exercise and rested conditions. We provide support for previous literature suggesting that during simple tasks, sleep deprivation has negative effects on cognitive performance. Importantly, in contrast to previous literature which has shown multiple bouts of exercise adding to cognitive detriment when combined with sleep deprivation, our results did not reveal any further detriments to cognitive performance from a single-bout of exercise following sleep deprivation. PMID- 28803121 TI - Corrigendum to "Serotonin Activates Bacterial Quorum Sensing and Enhances the Virulence of Pseudomonas aeruginosa in the Host" [EBioMedicine 9 (2016) 161-169]. PMID- 28803120 TI - Chlamydia trachomatis Prevents Apoptosis Via Activation of PDPK1-MYC and Enhanced Mitochondrial Binding of Hexokinase II. AB - The intracellular human bacterial pathogen Chlamydia trachomatis pursues effective strategies to protect infected cells against death-inducing stimuli. Here, we show that Chlamydia trachomatis infection evokes 3-phosphoinositide dependent protein kinase-1 (PDPK1) signaling to ensure the completion of its developmental cycle, further leading to the phosphorylation and stabilization of MYC. Using biochemical approaches and imaging we demonstrate that Chlamydia induced PDPK1-MYC signaling induces host hexokinase II (HKII), which becomes enriched and translocated to the mitochondria. Strikingly, preventing the HKII interaction with mitochondria using exogenous peptides triggers apoptosis of infected cells as does inhibiting either PDPK1 or MYC, which also disrupts intracellular development of Chlamydia trachomatis. These findings identify a previously unknown pathway activated by Chlamydia infection, which exhibits pro carcinogenic features. Targeting the PDPK1-MYC-HKII-axis may provide a strategy to overcome therapeutic resistance of infection. PMID- 28803122 TI - Comparison of Pharmacokinetics and Safety of a Fixed-dose Combination of Rosuvastatin and Ezetimibe Versus Separate Tablets in Healthy Subjects. AB - PURPOSE: Rosuvastatin and ezetimibe are concomitantly used for dyslipidemia treatment. Compared with separate tablets, fixed-dose combination (FDC) tablets of rosuvastatin/ezetimibe could increase patient compliance. The aim of this study was to compare the pharmacokinetic (PK) profiles of an FDC tablet of rosuvastatin/ezetimibe and co-administration of rosuvastatin and ezetimibe as separate tablets in healthy Korean volunteers. METHODS: This trial was a randomized, open-label, single-dose, 2-way crossover study. The healthy subjects received an FDC tablet of rosuvastatin 20 mg/ezetimibe 10 mg (test) or co administration of rosuvastatin 20 mg and ezetimibe 10 mg (reference) in each period (periods 1 and 2), with a 14-day washout period. The blood samples for PK analysis were collected predose and up to 96 hours after administration, and safety was assessed throughout the study. FINDINGS: Sixty-four healthy Korean subjects were enrolled, and 57 subjects completed the study. All subjects were men and mean age was 28.52 +/- 5.93. The geometric least squares mean ratios (test/reference) and 90% CIs of Cmax and AUC0-last were 101.54% (94.03-109.65) and 97.71% (91.86-103.93) for rosuvastatin, 108.93% (98.55-120.40) and 102.90% (96.72-109.47) for free ezetimibe, and 106.74% (98.18-116.05) and 104.24 % (99.53 109.17) for total ezetimibe. Twenty-four adverse events (AEs) were reported in 22 subjects. Three cases were related to the study drugs; 2 cases were mild, and 1 case was severe. However, all AEs were resolved without any sequelae. In addition, there were no serious AEs throughout the study. IMPLICATIONS: The FDC tablet of rosuvastatin/ezetimibe was well tolerated and resulted in comparable systemic exposure with co-administration of rosuvastatin and ezetimibe. ClinicalTrials.gov identifier: NCT02941848. PMID- 28803123 TI - Highly selective on-off fluorescence recognition of Fe3+ based on a coumarin derivative and its application in live-cell imaging. AB - A novel coumarin chemosensor, 7-hydroxy-2-oxo-N-(pyridin-2-ylmethyl)chromene-3 carboxamide (Probe 1), demonstrated significant selectivity towards Fe3+ ions. Probe 1 exhibited high fluorescence emission profile at 447nm, excellent selectivity towards Fe3+ over other biologically important metal ions (Al3+, Ba2+, Co2+, Cu2+, Zn2+, Cd2+, Hg2+, Pb2+ and Sn2+). Interestingly, there was ~30 fold decrease in fluorescence intensity upon Fe3+ binding. The limit of detection of Fe3+ was found to be 0.76MUM (~40ppb). Probe 1 also exhibited high potential as an intracellular chemosensor for Fe3+. PMID- 28803124 TI - Influence of depth of neuromuscular blockade on surgical conditions during low pressure pneumoperitoneum laparoscopic cholecystectomy: A randomized blinded study. AB - STUDY OBJECTIVE: To evaluate the influence of neuromuscular blockade (NMB) on surgical conditions during low-pressure pneumoperitoneum (8mmHg) laparoscopic cholecystectomy (LC), while comparing moderate and deep NMB. Secondary objective was to evaluate if surgical conditions during low-pressure pneumoperitoneum LC performed with deep NMB could be comparable to those provided during standard pressure pneumoperitoneum (12mmHg) LC. DESIGN: Prospective, randomized, blinded clinical trial. SETTING: Operating room. PATIENTS: Ninety ASA 1-2 patients scheduled for elective LC. INTERVENTIONS: Patients were allocated into 3 groups: Group 1: low-pressure pneumoperitoneum with moderate-NMB (1-3 TOF), Group 2: low pressure pneumoperitoneum with deep-NMB (1-5 PTC) and Group 3: standard pneumoperitoneum (12mmHg). Rocuronium was used to induce NMB and acceleromiography was used for NMB monitoring (TOF-Watch-SX). MEASUREMENTS: Three experienced surgeons evaluated surgical conditions using a four-step scale at three time-points: surgical field exposure, dissection of the gallbladder and extraction/closure. MAIN RESULTS: Low-pressure pneumoperitoneum (Group 1 vs. 2): good conditions: 96.7 vs. 96.7%, 90 vs. 80% and 89.6 vs. 92.3%, respectively for the time-points, p>0.05. No differences in optimal surgical conditions were observed between the groups. Surgery completion at 8mmHg pneumoperitoneum: 96.7 vs. 86.7%, p=0.353. Standard-pressure pneumoperitoneum vs. low-pressure pneumoperitoneum with deep NMB (Group 3 vs. 2): good conditions: 100% in Group 3 for the three time-points (p=0.024 vs. Group 2 at dissection of the gallbladder). Significantly greater percentage of optimal conditions during standard-pressure pneumoperitoneum LC at the three time points of evaluation. CONCLUSIONS: The depth of NMB was found not to be decisive neither in the improvement of surgical conditions nor in the completion of low-pressure pneumoperitoneum LC performed by experienced surgeons. Surgical conditions were considered better with a standard pressure pneumoperitoneum, regardless of the depth of NMB, than during low pressure pneumoperitoneum with deep NMB. PMID- 28803125 TI - Sildenafil related cerebral venous thrombosis following spinal anesthesia. PMID- 28803126 TI - Fed-batch production of vanillin by Bacillus aryabhattai BA03. AB - Bacillus aryabhattai BA03, a strain isolated in our laboratory, has interesting properties related to the production of natural aromas and flavors. Specifically, we have found that it was able to produce vanillin from ferulic acid (FA). Furthermore, this strain produces high amounts of 4-vinylguaiacol in only 14h, this being the only intermediate metabolite observed in the process. FA is an inexpensive feedstock for the production of natural value-added compounds when extracted from lignocellulosic wastes. In this study, we optimized the operational conditions (temperature, pH and agitation), medium composition and bioconversion technology (batch or fed-batch) to produce vanillin. In a fed-batch process conducted with just one additional supplementation after 24h, the maximal concentration of vanillin (147.1+/-0.9mg/L) was observed after 216h (QV=0.681mg/Lh; YV/fFA=0.082mg/mg) after degrading 90.3% FA. In view of our data, we postulate that Bacillus aryabhattai BA03 carries out a decarboxylation of ferulic acid as a metabolic pathway. PMID- 28803127 TI - Direct antioxidant properties of methotrexate: Inhibition of malondialdehyde acetaldehyde-protein adduct formation and superoxide scavenging. AB - Methotrexate (MTX) is an immunosuppressant commonly used for the treatment of autoimmune diseases. Recent observations have shown that patients treated with MTX also exhibit a reduced risk for the development of cardiovascular disease (CVD). Although MTX reduces systemic inflammation and tissue damage, the mechanisms by which MTX exerts these beneficial effects are not entirely known. We have previously demonstrated that protein adducts formed by the interaction of malondialdehyde (MDA) and acetaldehyde (AA), known as MAA-protein adducts, are present in diseased tissues of individuals with rheumatoid arthritis (RA) or CVD. In previously reported studies, MAA-adducts were shown to be highly immunogenic, supporting the concept that MAA-adducts not only serve as markers of oxidative stress but may have a direct role in the pathogenesis of inflammatory diseases. Because MAA-adducts are commonly detected in diseased tissues and are proposed to mitigate disease progression in both RA and CVD, we tested the hypothesis that MTX inhibits the generation of MAA-protein adducts by scavenging reactive oxygen species. Using a cell free system, we found that MTX reduces MAA-adduct formation by approximately 6-fold, and scavenges free radicals produced during MAA-adduct formation. Further investigation revealed that MTX directly scavenges superoxide, but not hydrogen peroxide. Additionally, using the Nrf2/ARE luciferase reporter cell line, which responds to intracellular redox changes, we observed that MTX inhibits the activation of Nrf2 in cells treated with MDA and AA. These studies define previously unrecognized mechanisms by which MTX can reduce inflammation and subsequent tissue damage, namely, scavenging free radicals, reducing oxidative stress, and inhibiting MAA-adduct formation. PMID- 28803129 TI - Low plasma glucose limits glucose metabolism by RBCs and heart in some species of teleosts. AB - Within teleosts there is a species range in plasma glucose levels from undetectable to 20mM. At low plasma glucose levels the gradient from the extracellular to the intracellular space is decreased. The impact of this on glucose metabolism by RBCs and heart from species with different steady state levels of plasma glucose (Atlantic cod ~5mM; Atlantic salmon ~5mM, cunner ~1mM, lumpfish <1mM; short-horned sculpin <1mM) is the subject of this review. Under normoxia, at physiological levels of extracellular glucose, RBCs and heart produce lactate although the contribution of anaerobic metabolism to ATP production is small. Sustained lactate production from extracellular glucose appears to be the primary fate of extracellular glucose. In many cases, glycogen is not mobilized and the rate of glucose metabolism=two times the rate of lactate production. As such, alternative metabolic sources are required to fuel oxidative metabolism. Under hypoxia, hearts from Atlantic cod and rainbow trout increase rates of both glucose metabolism and lactate production, partially supported by glycogen reserves. But in lumpfish and short-horned sculpin hearts there is no change in rates of glucose metabolism. The most likely explanation is that glucose uptake is compromised in lumpfish and short-horned sculpin hearts due to a low diffusion gradient. Under these conditions rates of lactate production are well below that of Atlantic cod or rainbow trout. Energy demand must be reduced under hypoxia in lumpfish and short-horned sculpin hearts in order to maintain ATP balance. PMID- 28803128 TI - Tetrahydrobiopterin in antenatal brain hypoxia-ischemia-induced motor impairments and cerebral palsy. AB - Antenatal brain hypoxia-ischemia, which occurs in cerebral palsy, is considered a significant cause of motor impairments in children. The mechanisms by which antenatal hypoxia-ischemia causes brain injury and motor deficits still need to be elucidated. Tetrahydrobiopterin is an important enzyme cofactor that is necessary to produce neurotransmitters and to maintain the redox status of the brain. A genetic deficiency of this cofactor from mutations of biosynthetic or recycling enzymes is a well-recognized factor in the development of childhood neurological disorders characterized by motor impairments, developmental delay, and encephalopathy. Experimental hypoxia-ischemia causes a decline in the availability of tetrahydrobiopterin in the immature brain. This decline coincides with the loss of brain function, suggesting this occurrence contributes to neuronal dysfunction and motor impairments. One possible mechanism linking tetrahydrobiopterin deficiency, hypoxia-ischemia, and neuronal injury is oxidative injury. Evidence of the central role of the developmental biology of tetrahydrobiopterin in response to hypoxic ischemic brain injury, especially the development of motor deficits, is discussed. PMID- 28803131 TI - Do continuum beliefs reduce schizophrenia stigma? Effects of a laboratory intervention on behavioral and self-reported stigma. AB - BACKGROUND AND OBJECTIVES: Correlational research shows that belief in a continuum of psychiatric problems predicts decreased public stigma. However, the correlational findings fail to inform the stigma reduction prospects of manipulating continuum beliefs. All extant experimental work has been executed online. This study examined effects of a laboratory-based continuum intervention on behavioral and self-report measures of psychiatric stigma. METHODS: Sixty-nine undergraduates believed that they would meet a man with schizophrenia. They then read a bogus scientific article that attested to a categorical view of schizophrenia, a continuum view, or that merely described schizophrenia. Some participants then completed a task that required reflection on their differences from (categorical group) or similarities to (continuum group) the man with schizophrenia. Participants eventually moved to an adjacent room and sat in one of several seats that varied in their proximity to a seat ostensibly occupied by the man with schizophrenia. RESULTS: The continuum intervention decreased self reported social distance and the categorical intervention increased endorsement of damaging stereotypes. Seat selection was unaffected by our manipulation, but we obtained evidence of significant links to validated stigma measures. LIMITATIONS: Our sample was small, and our behavioral stigma measure could be modified to maximize variability in participants' seat selection. CONCLUSIONS: The study offers modest support of the stigma reduction effect of continuum belief intervention. It offers new evidence of the pernicious consequences of interventions that inflate perceptions of the "otherness" of individuals with psychiatric problems. Finally, it shines new light on stigma-related behavior measurable in the laboratory. PMID- 28803130 TI - Prenatal phthalate exposures and child temperament at 12 and 24 months. AB - INTRODUCTION: Gestational phthalate exposures have been adversely associated with attention, externalizing, and internalizing behaviors in childhood. Early childhood temperament may be a marker of later behavioral patterns. We therefore sought to determine whether gestational phthalate exposures were associated with infant and toddler temperament. METHODS: The Mount Sinai Children's Environmental Health Study is a prospective cohort study of children born between May 1998 and July 2001 in New York City (N=404). Phthalate metabolites were measured in spot urine samples collected from pregnant women in their third trimester. Child temperament was assessed by parental report at 12-months using the Infant Behavior Questionnaire (IBQ) (N=204) and at 24-months using the Toddler Behavior Assessment Questionnaire (TBAQ) (N=279). We used multiple linear regression to evaluate associations between urinary phthalate metabolites and eleven temperament domains. RESULTS: Phthalate biomarker concentrations were weakly associated with lower gross motor activity levels as well as higher duration of orienting at the 12-month assessment. Mono(3-carboxypropyl) phthalate (MCPP), monobenzyl phthalate (MBzP) and the sum of metabolites of di(2-ethylhexyl) phthalate (?DEHP) were associated with lower levels of smiling and laughing at 12 months. At 24-months, social fear and lower pleasure was linked to higher concentrations of MCPP and MBzP, and higher ?DEHP was weakly associated with increased anger levels at 24-months. CONCLUSIONS: Though we observed some weak associations between biomarkers of prenatal exposure to phthalates and temperament at 12- and 24-months, overall phthalates biomarkers were not strongly associated with alterations in temperament. PMID- 28803132 TI - Quantum chemical study of mechanism and stereoselectivity of secondary alcohol dehydrogenase. AB - Secondary alcohol dehydrogenase from Thermoanaerobacter brockii (TbSADH) is a Zn- and NADP-dependent enzyme that catalyses the reversible transformation of secondary alcohols into ketones. It is of potential biocatalytic interest as it can be used in the synthesis of chiral alcohols by asymmetric reduction of ketones. In this paper, density functional theory calculations are employed to elucidate the origins of the enantioselectivity of TbSADH using a large model of the active site and considering two different substrates, 2-butanol and 3 hexanol. For these two substrates the enzyme has experimentally been shown to have the opposite enantioselectivity. The energy profiles for the reactions are calculated and the stationary points along the reaction path are characterised. The calculations first confirm that the general mechanism proposed for other alcohol dehydrogenases is energetically viable. In this mechanism, a proton is first transferred from the substrate to a histidine residue at the surface, followed by a hydride transfer to the NADP cofactor. The calculated overall energy barrier is consistent with the measured rate constant. Very importantly, the calculations are able to reproduce and rationalise the enantioselectivity of the enzyme for both substrates. The detailed characterisation of the energies and geometries of the involved transition states will be valuable in the rational engineering of TbSADH to expand its utility in biocatalysis. PMID- 28803133 TI - Predictive value of multiple cytokines and chemokines for mortality in an admixed population: 15-year follow-up of the Bambui-Epigen (Brazil) cohort study of aging. AB - Inflammation, particularly elevated IL-6 serum levels, has been associated with increased mortality risk, mostly in Caucasians. The influence of genetic ethno racial background on this association is unknown. We examined associations between baseline serum levels of Interleukin-6 (IL-6) and other cytokines (IL1-2, TNF, IL-10, and IL1beta) and chemokines (CCL2, CCL5, CXCL8, CXCL9 and CXCL10) with 15-year mortality in 1,191 admixed Brazilians aged 60years and over. Elevated IL6 level (but not other biomarkers) was associated with increased risk of deaths with fully adjusted hazard ratios of 1.51 (95% CI=1.15, 1.97), 1.54 (95% CI=1.20, 1.96) and 1.79 (95% CI=1.40, 2.29) for the 2nd, 3rd and the highest quartiles, respectively. Genomic African and Native American proportions did not modify the association (p>0.05). The discriminatory ability to predict death of a model based on IL-6 alone was similar as that of a comprehensive morbidity score (C statistics=0.59 and 0.60, respectively). The abilities of IL-6 and the morbidity score models to predict death remained stable for very long term after the baseline measurement. Our results indicate that genome-based African and Native American ancestries have no impact on the prognostic value of IL-6 for mortality. PMID- 28803134 TI - Age-related changes of physiological performance and survivorship of bank voles selected for high aerobic capacity. AB - Variation in lifespans is an intriguing phenomenon, but how metabolic rate influence this variation remains unclear. High aerobic capacity can result in health benefits, but also in increased oxidative damage and accelerated ageing. We tested these contradictory predictions using bank voles (Myodes=Clethrionomys glareolus) from lines selected for high swim-induced aerobic metabolism (A), which had about 50% higher maximum metabolic rate and a higher basal and routine metabolic rates, than those from unselected control lines (C). We measured sprint speed (VSmax), forced-running maximum metabolic rate (VO2run), maximum long distance running speed (VLmax), running speed at VO2run (VVO2), and respiratory quotient at VO2run (RQ) at three age classes (I: 3-5, II: 12-14, III: 17 19months), and analysed survivorship. We asked if ageing, understood as the age related decline of the performance traits, differs between the A and C lines. At age class I, voles from A lines had 19% higher VO2run, and 12% higher VLmax, but tended to have 19% lower VSmax, than those from C lines. RQ was nearly 1.0 for both A and C lines. The pattern of age-related changes differed between the lines mainly between age classes I and II, but not in older animals. VSmax increased by 27% in A lines and by 10% in C lines between age class I and II, but between classes II and III, it increased by 16% in both selection directions. VO2run decreased by 7% between age class I and II in A lines only, but in C lines it remained constant across all age classes. VLmax decreased by 8% and VVO2 by 12% between age classes II and III, but similarly in both selection directions. Mortality was higher in A than in C lines only between the age of 1 and 4months. The only trait for which the changes in old animals differed between the lines was RQ. In A lines, RQ increased between age classes II and III, whereas in C lines such an increase occurred between age classes I and II. Thus, we did not find obvious effects of selection on the pattern of ageing. However, the physiological performance and mortality of bank voles remained surprisingly robust to ageing, at least until the age of 17-19months, similar to the maximum lifespan under natural conditions. Therefore, it is possible that the selection could affect the pattern of ageing in even older individuals when symptoms of senility might be more profound. PMID- 28803136 TI - Anti-inflammatory activity of natural stilbenoids: A review. AB - Resveratrol and other natural stilbenoids, including piceatannol, pterostilbene, and gnetol, are well-known anti-inflammatory compounds with indisputable activity in vitro as well as in vivo. Their molecular targets include inducible nitric oxide synthase, cyclooxygenases, leukotrienes, nuclear factor kappa B, tumor necrosis factor alpha, interleukins and many more. This anti-inflammatory activity together with their antioxidant activity is believed to stand behind their other positive health effects against cancer, cardiovascular and neurodegenerative diseases or diabetes. Thus, they are nowadays commercially marketed as nutraceuticals. Naturally, they are present in wine, grapes or berries. However, there is a rigorous debate about the real effect of these compounds on human health. It is argued that the concentration of stilbenoids in food and beverages is too low to have any therapeutic potential and this concentration is further reduced by their low bioavailability and extensive metabolism. Therefore, this review focuses on in vitro, in vivo, preclinical as well as clinical data available for various natural stilbenoids and summarizes the anti-inflammatory targets on molecular level, compares the relevance of the experimental studies, discusses the metabolism of stilbenoids and the potential activity of their metabolites and relates this knowledge to human health. Moreover, the ways to augment stilbenoids efficacy are suggested with special focus on multitargeted therapy and nanocarriers. PMID- 28803135 TI - Effects of aging on basement membrane of the soleus muscle during recovery following disuse atrophy in rats. AB - Aging is known to lead to the impaired recovery of muscle after disuse as well as the increased susceptibility of the muscle to damage. Here, we show that, in the older rats, reloading after disuse atrophy, causes the damage of the muscle fibers and the basement membrane (BM) that structurally support the muscle fibers. Male Wistar rats of 3-(young) and 20-(older) months of age were subjected to hindlimb-unloading for 2weeks followed by reloading for a week. In the older rats, the soleus muscles showed necrosis and central nuclei fiber indicating the regeneration of muscle fibers. Furthermore, ectopic immunoreactivity of collagen IV, a major component of the BM, remained mostly associated with the necrotic appearance, suggesting that the older rats were impaired with the ability of repairing the damaged BM. Further, after unloading and reloading, the older rats did not show a significant alteration, although the young rats showed clear response of Col4a1 and Col4a2 genes, both coding for collagen IV. In addition, during the recovery phase, the young rats showed increase in the amount of Hsp47 and Sparc mRNA, which are protein folding-related factor genes, while the older rats did not show any significant variation. Taken together, our findings suggest that the atrophic muscle fibers of the older rats induced by unloading were vulnerable to the weight loading, and that attenuated reactivity of the BM synthesizing fibroblast to gravity contributes to the fragility of muscle fibers in the older animals. PMID- 28803137 TI - Aspiration Pneumonia in Carbon Monoxide Poisoning Patients with Loss of Consciousness: Prevalence, Outcomes, and Risk Factors. AB - BACKGROUND: Aspiration pneumonia is associated with significant morbidity and mortality; however, little is known about aspiration pneumonia in patients with carbon monoxide intoxication, which is the leading cause of poisoning-related death. This study aimed to evaluate the prevalence, clinical impacts, and risk factors for developing aspiration pneumonia in patients with carbon monoxide poisoning with loss of consciousness. METHODS: A retrospective analysis of a carbon monoxide poisoning registry was performed at our emergency department for the period January 2008 to December 2015. All adult carbon monoxide poisoning patients with loss of consciousness were included. RESULTS: Aspiration pneumonia developed in 103 (19.2%) of 537 patients. It was associated with increased ventilator use (52.4% vs 3.2%), length of hospital stay (median [interquartile range], 3.6 [2.1-5.1] vs 1.3 [0.6-2.1] days), and in-hospital mortality (5.8% vs 0.0%) (all P < .001). Altered mental status on emergency department arrival, white blood cell count, and increased exposure duration were the independent factors associated with development of aspiration pneumonia; odds ratios were 9.46 (95% confidence interval [CI] 4.92-18.19; P < .001), 1.19 (95% CI 1.13-1.26; P < .001), and 1.12 (95% CI 1.06-1.19; P < .001), respectively. For painful or unresponsive mental status and white blood cell count >12,000/mm3, the odds ratio increased up to 17.75 (95% CI 10.65-29.59; P < .001). CONCLUSIONS: The prevalence of aspiration pneumonia was 19.2% in carbon monoxide poisoning patients with loss of consciousness and was associated with poor outcomes. Additionally, altered mental status on emergency department arrival, white blood cell count, and increased exposure duration were independently associated with the development of aspiration pneumonia. PMID- 28803138 TI - Low Albumin Levels Are Associated with Mortality Risk in Hospitalized Patients. AB - BACKGROUND: The aim of this study was to investigate the association of albumin levels on admission and change in levels during hospitalization with hospitalization outcomes. METHODS: Historical prospective data of patients hospitalized between 2011 and 2013 were collected. Levels of albumin were classified as marked hypoalbuminemia (<2.5 mg/dL), mild hypoalbuminemia (2.5-3.5 mg/dL), normal albumin (3.5-4.5 mg/dL), and hyperalbuminemia (>4.5 mg/dL). Main outcomes were length of hospitalization, in-hospital mortality, and long-term mortality. RESULTS: The cohort included 30,732 patients (mean age 67 +/- 18 years, 51% male). Most patients had normal albumin levels on admission (n = 20,124, 65%), 29% of patients had hypoalbuminemia, mostly mild (n = 7,334, 24%), and 5% of patients had marked hypoalbuminemia (n = 1436). Hyperalbuminemia on admission was evident in 6% of the patients (n = 1838). Follow-up (median +/- standard deviation) was 1675 +/- 325 days. Compared with in-hospital mortality with normal albumin on admission (2%), mortality was higher with mild (12%) and marked hypoalbuminemia (34%) and lower with hyperalbuminemia (0.3%). Mortality rate at the end of follow-up was 29% with normal albumin levels, 67% and 83% with mild and marked hypoalbuminemia, respectively. Patients with hyperalbuminemia on admission and before discharge have the best short- and long-term survival. This pattern was similar when analyzed separately in different age groups. In patients with hypoalbuminemia on admission, normalization of albumin levels before discharge was associated with better short- and long-term survival, compared with patients with hypoalbuminemia before discharge. CONCLUSIONS: Low albumin levels on admission are associated with increased short- and long-term mortality. Normalization of albumin levels before discharge was associated with lower mortality risk, compared with hypoalbuminemia before discharge. PMID- 28803139 TI - Effect of Age on the Manifestations and Outcomes of Invasive Pneumococcal Disease in Adults. AB - BACKGROUND: Although a considerable amount is known about the effect of age on the manifestations and outcomes of pneumonia, the same is not true for invasive pneumococcal disease. METHODS: This was a prospective observational study of all cases (2435) of invasive pneumococcal disease in adults in Northern Alberta from 2000 to 2014. Rates of invasive pneumococcal disease per 100,000, sociodemographic variables, clinical characteristics, and invasive pneumococcal disease-related outcomes were compared for the following age groups: 17-54, 55 64, 65-74, and >=75 years. RESULTS: The rate of invasive pneumococcal disease per 100,000 increased with increasing age. Although only 27.3% of the cases were in those aged >=65 years, they accounted for 48% of the deaths. The case fatality rate increased with increasing age, from 9.6% for those aged 17-54 years to 31.7% for those aged >=75 years. The rate of meningitis decreased with increasing age, as did admission to intensive care and use of mechanical ventilation. There was a marked reduction in the rate of invasive pneumococcal disease due to protein conjugate vaccine 7 and protein conjugate vaccine 13 serotypes in those aged >=55 years but a much smaller decline in rates for those aged 17-54 years. Replacement with non-vaccine serotypes constituted approximately 50% of the cases. CONCLUSIONS: The rate of invasive pneumococcal disease is highest in the very elderly, and manifestations of invasive pneumococcal disease are influenced by age. PMID- 28803140 TI - A competent catalytic active site is necessary for substrate induced dimer assembly in triosephosphate isomerase. AB - The protozoan parasite Trichomonas vaginalis contains two nearly identical triosephosphate isomerases (TvTIMs) that dissociate into stable monomers and dimerize upon substrate binding. Herein, we compare the role of the "ball and socket" and loop 3 interactions in substrate assisted dimer assembly in both TvTIMs. We found that point mutants at the "ball" are only 39 and 29-fold less catalytically active than their corresponding wild-type counterparts, whereas Deltaloop 3 deletions are 1502 and 9400-fold less active. Point and deletion mutants dissociate into stable monomers. However, point mutants assemble as catalytic competent dimers upon binding of the transition state substrate analog PGH, whereas loop 3 deletions remain monomeric. A comparison between crystal structures of point and loop 3 deletion monomeric mutants illustrates that the catalytic residues in point mutants and wild-type TvTIMs are maintained in the same orientation, whereas the catalytic residues in deletion mutants show an increase in thermal mobility and present structural disorder that may hamper their catalytic role. The high enzymatic activity present in monomeric point mutants correlates with the formation of dimeric TvTIMs upon substrate binding. In contrast, the low activity and lack of dimer assembly in deletion mutants suggests a role of loop 3 in promoting the formation of the active site as well as dimer assembly. Our results suggest that in TvTIMs the active site is assembled during dimerization and that the integrity of loop 3 and ball and socket residues is crucial to stabilize the dimer. PMID- 28803141 TI - The poly-proline tail of SIVmac Vpx provides gain of function for resistance to a cryptic proteasome-dependent degradation pathway. AB - The lentiviral accessory protein Vpx is critical for viral infection of myeloid cells and acts by hijacking CRL4(DCAF1) E3 ubiquitin ligase to induce the degradation of the host restriction factor SAMHD1. It has been observed that the sequences from HIV-2 and SIVsmm/SIVmac Vpx contain a poly-proline tail which is distinct from other SIV Vpx proteins. However, the role of this region in Vpx function is controversial. Herein, we found proteasome-dependent degradation of a Vpx mutant lacking the poly-proline tail in the nucleus in a CRL4(DCAF1) E3 ligase-independent fashion. Unlike wild-type Vpx, the poly-proline tail mutant Vpx is partly defective in enhancing viral infection in macrophages. Our findings suggest that during Vpx evolution, Vpx of the HIV-2/SIVsm/SIVmac lineage is targeted by a CRL4(DCAF1) E3 ligase-independent ubiquitination pathway, and have gained this interesting region, allowing them to maintain nuclear accumulation as part of their adaptation to host cell regulation. PMID- 28803143 TI - Insomnia-related sleep disruptions, cognition and detailed concurrent anxiety testing during the inter-episode phase of bipolar disorder: A Herculean task or a necessity? PMID- 28803144 TI - Reply to: Insomnia-related sleep disruptions, cognition and detailed concurrent anxiety testing during the inter-episode phase of bipolar disorder: A Herculean task or a necessity? PMID- 28803142 TI - Identification and characterization of a long non-coding RNA up-regulated during HIV-1 infection. AB - Long non-coding RNAs (lncRNAs) are rapidly emerging as important regulators of a diverse array of cellular functions. Here, we describe a meta-analysis of two independent RNA-seq studies to identify lncRNAs that are differentially expressed upon HIV-1 infection. Only three lncRNA genes exhibited altered expression of >= 2-fold in HIV-1-infected cells. Of these, the uncharacterized lncRNA LINC00173 was chosen for further study. Both transcript variants of LINC00173 (lnc173 TSV1 and 2) could be detected by qPCR, localized predominantly to the nucleus and were reproducibly up-regulated during infection. Knock-out of the LINC00173 locus did not have detectable effects on HIV-1 replication. Interestingly, however, stimulation of Jurkat T cells with PMA/ionomycin resulted in a decrease of lnc173 expression, and Jurkat cells deficient for lnc173 on average expressed higher levels of specific cytokines than control cells. These data suggest that lnc173 may have a role in the regulation of cytokines in T cells. PMID- 28803145 TI - PLASMIX management: LCA of six possible scenarios. AB - Only a small percentage of the separately collected plastic is recycled. The mechanical selection process of source segregated plastic materials generates considerable amounts of residues that are commonly named as Plasmix. By means of a life cycle assessment (LCA) modelling, the environmental performances of the main Plasmix management options (thermal treatment, energy recovery, and landfilling) were compared. Six treatment scenarios, with different pre-treatment alternatives, were evaluated. Landfilling after waste washing and Plasmix substitution of coke in a blast furnace represent the most favorable options, since the performances of thermal treatment and energy recovery are worsened by specific emissions of a variety of toxic compounds and heavy metals within plastic materials as additives. PMID- 28803146 TI - Reforming sewage sludge pyrolysis volatile with Fe-embedded char: Minimization of liquid product yield. AB - Obtaining high quality syngas from sewage sludge (SS) means transferring a low grade SS into a high-grade fuel or raw materials for chemical products. In this study, Fe is added to SS in form of Fe2(SO4)3 to produce an effective and self sufficient catalyst in order to obtain more syngas and minimize liquid products from SS pyrolysis. The Fe-embedded sewage sludge chars (SSCs) were used as catalysts for volatile reforming at 600 degrees C. It has been found that the gas yield increases from 15.9 to 35.8wt% of the SS and that of liquids decreases from 31.9 to 10.2wt% after volatile reforming with Fe-embedded SSC when Fe was added equal to 7 % in the dried SS. In addition, the content of nitrogen-containing compounds in the oily products decreased. After reforming with Fe-embedded SSC, the molar fractions of syngas combustible components, including H2, CH4 and CO, increase, and the higher heating value of the syngas increased to 17.0MJ/Nm3 from the original 12.5MJ/Nm3 obtained from SS pyrolysis at 550 degrees C. Moreover, the volatile reforming seems to reduce the level of some important syngas pollutants, like H2S, HCl and HCN, even though it was also observed an increase of the contents of SO2, NH3, NO2, HCNO and N2O. PMID- 28803147 TI - Ovarian hormones, sleep and cognition across the adult female lifespan: An integrated perspective. AB - Loss of ovarian function in women is associated with sleep disturbances and cognitive decline, which suggest a key role for estrogens and/or progestins in modulating these symptoms. The effects of ovarian hormones on sleep and cognitive processes have been studied in separate research fields that seldom intersect. However, sleep has a considerable impact on cognitive function. Given the tight connections between sleep and cognition, ovarian hormones may influence selective aspects of cognition indirectly, via the modulation of sleep. In support of this hypothesis, a growing body of evidence indicates that the development of sleep disorders following menopause contributes to accelerated cognitive decline and dementia in older women. This paper draws from both the animal and human literature to present an integrated view of the effects of ovarian hormones on sleep and cognition across the adult female lifespan. PMID- 28803149 TI - Concentrations of polycyclic aromatic hydrocarbons and trace elements in Arctic soils: A case-study in Svalbard. AB - A combined assessment on the levels and distribution profiles of polycyclic aromatic hydrocarbons (PAHs) and trace elements in soils from Pyramiden (Central Spitsbergen, Svalbard Archipelago) is here reported. As previously stated, long range atmospheric transport, coal deposits and previous mining extractions, as well as the stack emissions of two operative power plants at this settlement are considered as potential sources of pollution. Eight top-layer soil samples were collected and analysed for the 16 US EPA priority PAHs and for 15 trace elements (As, Be, Cd, Co, Cr, Cu, Hg, Mn, Mo, Ni, Pb, Sn, Tl, V and Zn) during late summer of 2014. The highest levels of PAHs and trace elements were found in sampling sites located near two power plants, and at downwind from these sites. The current PAH concentrations were even higher than typical threshold values. The determination of the pyrogenic molecular diagnostic ratios (MDRs) in most samples revealed that fossil fuel burning might be heavily contributing to the PAHs levels. Two different indices, the Pollution Load Index (PLI) and the Geoaccumulation Index (Igeo), were determined for assessing soil samples with respect to trace elements pollution. Samples collected close to the power plants were found to be slightly and moderately polluted with zinc (Zn) and mercury (Hg), respectively. The Spearman correlation showed significant correlations between the concentrations of 16 PAHs and some trace elements (Pb, V, Hg, Cu, Zn, Sn, Be) with the organic matter content, indicating that soil properties play a key role for pollutant retention in the Arctic soils. Furthermore, the correlations between ?16 PAHs and some trace elements (e.g., Hg, Pb, Zn and Cu) suggest that the main source of contamination is probably pyrogenic, although the biogenic and petrogenic origin of PAHs should not be disregarded according to the local geology. PMID- 28803148 TI - Combustion-derived nanoparticles, the neuroenteric system, cervical vagus, hyperphosphorylated alpha synuclein and tau in young Mexico City residents. AB - Mexico City (MC) young residents are exposed to high levels of fine particulate matter (PM2.5), have high frontal concentrations of combustion-derived nanoparticles (CDNPs), accumulation of hyperphosphorylated aggregated alpha synuclein (alpha-Syn) and early Parkinson's disease (PD). Swallowed CDNPs have easy access to epithelium and submucosa, damaging gastrointestinal (GI) barrier integrity and accessing the enteric nervous system (ENS). This study is focused on the ENS, vagus nerves and GI barrier in young MC v clean air controls. Electron microscopy of epithelial, endothelial and neural cells and immunoreactivity of stomach and vagus to phosphorylated alpha-synuclein Ser129 and Hyperphosphorylated-Tau (Htau) were evaluated and CDNPs measured in ENS. CDNPs were abundant in erythrocytes, unmyelinated submucosal, perivascular and intramuscular nerve fibers, ganglionic neurons and vagus nerves and associated with organelle pathology. alphaSyn and Htau were present in 25/27 MC gastric,15/26 vagus and 18/27 gastric and 2/26 vagus samples respectively. We strongly suggest CDNPs are penetrating and damaging the GI barrier and reaching preganglionic parasympathetic fibers and the vagus nerve. This work highlights the potential role of CDNPs in the neuroenteric hyperphosphorylated alpha-Syn and tau pathology as seen in Parkinson and Alzheimer's diseases. Highly oxidative, ubiquitous CDNPs constitute a biologically plausible path into Parkinson's and Alzheimer's pathogenesis. PMID- 28803150 TI - Residential greenness and allergic respiratory diseases in children and adolescents - A systematic review and meta-analysis. AB - BACKGROUND: The aetiology of allergic respiratory disease in children is not yet fully understood. Environmental factors are believed to play a major part. The amount of green vegetation surrounding the home (residential greenness) has been recently identified as a potentially important exposure OBJECTIVES: Our goal was to provide a systematic review and quantitative summary of the evidence regarding the relationship between residential greenness and allergic respiratory diseases in children. METHODS: Peer-reviewed literature published prior to 1 March 2017 was systematically searched using nine electronic databases. Meta-analyses were conducted if at least three studies published risk estimates for the same outcome and exposure measures. RESULTS: We included 11 articles across broad outcomes of asthma and allergic rhinitis. Reported effects were inconsistent with varying measures to define residential greenness. Only limited meta-analysis could be conducted, with the pooled odds ratios for asthma (OR 1.01 95%CI 0.93, 1.09; I2 68.1%) and allergic rhinitis (OR 0.99 95%CI 0.87, 1.12; I2 72.9%) being significantly heterogeneous. CONCLUSIONS: Inconsistencies between the studies were too large to accurately assess the association between residential greenness and allergic respiratory disease. A standardised global measure of greenness which accounts for seasonal variation at a specific relevant buffer size is needed to create a more cohesive body of evidence and for future examination of the effect of residential greenness on allergic respiratory diseases. PMID- 28803151 TI - Sex-specific differences in effect of prenatal exposure to dioxin-like compounds on neurodevelopment in Japanese children: Sapporo cohort study. AB - BACKGROUND: Consistent reports are not available on the effects of dioxin-like polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins (PCDD)/ polychlorinated dibenzofurans (PCDF) (dioxin-like compounds [DLCs]) on child neurodevelopment. Further, the effect of background-level exposure to individual DLC isomers is not known. OBJECTIVES: We carried out the Sapporo cohort study to evaluate the effect of prenatal exposure to each DLC isomer on child neurodevelopment at 6 and 18 months of age, and assessed sex-specific differences in these effects. METHODS: The levels of all and each individual DLC isomers were estimated in maternal peripheral blood. Neurodevelopment was evaluated using the Bayley Scales of Infant Development-2nd Edition for 6-month-old infants (n = 190) and 18-month-old children (n = 121). RESULTS: In male children, levels of 10 DLC isomers were significantly negatively associated with the Psychomotor Developmental Index (PDI) at 6 months of age after adjustment for potential confounding variables. However, at 18 months of age, these associations were absent. In female children, the level of only one DLC isomer was significantly negatively associated with PDI at 6 months of age. However, in contrast to the male children, the levels of six DLC isomers in 18-month-old female children were significantly positively associated with the Mental Developmental Index. CONCLUSIONS: These findings indicate that adverse neurodevelopmental effects of prenatal background-level exposure to DLCs may be stronger in male children. PMID- 28803152 TI - Bioassessment of heavy metal toxicity and enhancement of heavy metal removal by sulfate-reducing bacteria in the presence of zero valent iron. AB - A simple and valid toxicity evaluation of Zn2+, Mn2+ and Cr6+ on sulfate-reducing bacteria (SRB) and heavy metal removal were investigated using the SRB system and SRB+Fe0 system. The heavy metal toxicity coefficient (beta) and the heavy metal concentration resulting in 50% inhibition of sulfate reduction (I) from a modeling process were proposed to evaluate the heavy metal toxicity and nonlinear regression was applied to search for evaluation indices beta and I. The heavy metal toxicity order was Cr6+ > Mn2+ > Zn2+. Compared with the SRB system, the SRB+Fe0 system exhibited a better capability for sulfate reduction and heavy metal removal. The heavy metal removal was above 99% in the SRB+Fe0 system, except for Mn2+. The energy-dispersive spectroscopy (EDS) analysis showed that the precipitates were removed primarily as sulfide for Zn2+ and hydroxide for Mn2+ and Cr6+.The method of evaluating the heavy metal toxicity on SRB was of great significance to understand the fundamentals of the heavy metal toxicity and inhibition effects on the microorganism and regulate the process of microbial sulfate reduction. PMID- 28803153 TI - Comparison of sediment and nutrient export and runoff characteristics from watersheds with centralized versus distributed stormwater management. AB - Stormwater control measures (SCMs) are used to retain stormwater and pollutants. SCMs have traditionally been installed in a centralized manner using detention to mitigate peak flows. Recently, distributed SCM networks that treat runoff near the source have been increasingly utilized. The aim of this study was to evaluate differences among watersheds that vary in SCM arrangement by assessing differences in baseflow nutrient (NOx-N and PO4-) concentrations and fluxes, stormflow export of suspended sediments and particulate phosphorus (PP), and runoff characteristics. A paired watershed approach was used to compare export between 2004 and 2016 from one forested watershed (For-MD), one suburban watershed with centralized SCMs (Cent-MD), and one suburban watershed with distributed SCMs (Dist-MD). Results indicated baseflow nitrate (NOx-N) concentrations typically exceeded 1 mg-N/L in all watersheds and were highest in Dist-MD. Over the last 10 years in Dist-MD, nitrate concentrations in both stream baseflow and in a groundwater well declined as land use shifted from agriculture to suburban. Baseflow nitrate export temporarily increased during the construction phase of SCM development in Dist-MD. This temporary pulse of nitrate may be attributed to the conversion of sediment control facilities to SCMs and increased subsurface flushing as infiltration SCMs came on line. During storm flow, Dist-MD tended to have less runoff and lower maximum specific discharge than Cent-MD for small events (<1.3 cm), but runoff responses became increasingly similar to Cent-MD with increasing precipitation (>1.3 cm). Mass export estimated during paired storm events indicated Dist-MD exported 30% less sediment and 31% more PP than Cent-MD. For large precipitation events, export of sediment and PP was similar among all three watersheds. Results suggest that distributed SCMs can reduce runoff and sediment loads during small rain events compared to centralized SCMs, but these differences become less evident for large events when peak discharge likely leads to substantial bank erosion. PMID- 28803154 TI - Prospects, recent advancements and challenges of different wastewater streams for microalgal cultivation. AB - Microalgae are recognized as one of the most powerful biotechnology platforms for many value added products including biofuels, bioactive compounds, animal and aquaculture feed etc. However, large scale production of microalgal biomass poses challenges due to the requirements of large amounts of water and nutrients for cultivation. Using wastewater for microalgal cultivation has emerged as a potential cost effective strategy for large scale microalgal biomass production. This approach also offers an efficient means to remove nutrients and metals from wastewater making wastewater treatment sustainable and energy efficient. Therefore, much research has been conducted in the recent years on utilizing various wastewater streams for microalgae cultivation. This review identifies and discusses the opportunities and challenges of different wastewater streams for microalgal cultivation. Many alternative routes for microalgal cultivation have been proposed to tackle some of the challenges that occur during microalgal cultivation in wastewater such as nutrient deficiency, substrate inhibition, toxicity etc. Scope and challenges of microalgal biomass grown on wastewater for various applications are also discussed along with the biorefinery approach. PMID- 28803155 TI - Assisted phytoremediation of a multi-contaminated soil: Investigation on arsenic and lead combined mobilization and removal. AB - The removal of contaminants from an earthy matrix by phytoremediation requires the selection of appropriate plant species and a suitable strategy to be effective. In order to set up an assisted phytoremediation intervention related to a disused industrial site affected by an arsenic and lead complex contamination, an extensive experimental investigation on micro and mesocosm scale has been conducted. Particular attention was given to the choice of plant species: using crop plants (Lupinus albus, Helianthus annuus and Brassica juncea) a series of parallel test campaigns have been realized to investigate different scenarios for the reclamation. With regard to the arsenic contamination, which is certainly the most worrying, the possibility of employing a hyper-accumulator species (Pteris vittata) has also been investigated, highlighting advantages and difficulties associated with such an approach. The application of various mobilizing agents in different concentrations was tested, in order to maximize the extraction efficiency of plants in respect of both contaminants, showing the necessity of a chemically assisted approach to promote their uptake and translocation in the shoots. Phosphate addition appears to produce the desired results, positively affecting As phyto-extraction for both hyper-accumulator and crop plants, while minimizing its toxic effects at the investigated concentrations. With regard to Pb, although tests with EDDS have been encouraging, EDTA should be preferred at present due to lower uncertainties about its effectiveness. The performed tests also improved the addition of mobilizing agents, allowing the simultaneous removal of the two metals despite their great diversity (which in general discourages such approach), with significant saving of time and an obvious improvement of the overall process. PMID- 28803156 TI - Sequential transition of the injury phenotype, temperature-dependent survival and transcriptional response in Listeria monocytogenes following lethal H2O2 exposure. AB - The food-borne pathogen Listeria monocytogenes is present persistently in food processing environments, where this bacterium is exposed to various stress factors, including oxidative stress. This study aimed to elucidate the temperature-dependent response of L. monocytogenes to H2O2 exposure and the phenotypic changes in colony formation by H2O2-treated bacteria. Survival curves indicated an increase in the resistance to H2O2 in L. monocytogenes as the temperature decreased during the stress exposure procedure. Transcriptional induction of genes with key roles in response to H2O2, including sigB and kat, was observed at 37 degrees C, but not at 20 degrees C, whereas other stress response genes were induced at both temperatures. Following H2O2 exposure, L. monocytogenes produced small colony phenotypes and the colony size decreased in a stress exposure duration-dependent manner. Resuscitated cells with no ability to form colonies in the absence of sodium pyruvate were also found. Our findings show the possibility that a sequential transition in the injury phenotype from small colony phenotype to resuscitated cells occurred during the course of exposure to H2O2. The higher H2O2 resistance at 20 degrees C than 37 degrees C suggests further investigation of the response to H2O2 exposure under the lower temperatures, including refrigeration temperature, which may contribute to elucidation of bacterial survival over extended time periods in food-processing environments. PMID- 28803157 TI - Toward comprehensive tDCS safety standards. PMID- 28803158 TI - Balasubramide derivative 3C modulates microglia activation via CaMKKbeta dependent AMPK/PGC-1alpha pathway in neuroinflammatory conditions. AB - Neuroinflammation plays a vital role in the pathological process of cerebral ischemic stroke, but currently there is no effective treatment. After ischemia, microglia-produced proinflammatory mediator expression contributes to the aggravation of neuroinflammation, while anti-inflammatory activation of microglia develops an anti-neuroinflammatory effect via secretion of anti-inflammatory factor. Promoting the anti-inflammatory activation of microglia might be an effective treatment of stroke. Previously, we discovered one derivative of the natural product (+)-balasubramide, compound 3C, that exhibits a remarkably anti neuroinflammatory effect in vitro with unknown mechanisms. Thus in this study, we aimed to clarify its molecular mechanisms and determine whether compound 3C has a neuroprotective effect after ischemia via regulation on microglial inflammation. We found that compound 3C promoted the anti-inflammatory mediator expression and reduced the proinflammatory mediator expression in LPS-stimulated BV2 cells and mouse primary microglia cells, which were reversed by AMP-activated protein kinase (AMPK) inhibition or AMPK upstream calmodulin-dependent protein kinase kinase beta (CaMKKbeta) inhibition. Compound 3C also prevented LPS-stimulated JNK activation and enhanced PGC-1alpha activation in microglia, which was attenuated by AMPK inhibition. Additionally, compound 3C ameliorated depressive behaviors in LPS-induced neuroinflammatory mice by promoting the anti-inflammatory activation of microglia. Furthermore, we found that compound 3C markedly reduced brain infarct volume, improved the neurological deficit in rats with ischemia and reduced the activated microglia/macrophage cells in the ischemic area, which concomitantly enhanced the anti-inflammatory mediator expression. A mechanistic study showed that the compound 3C-mediated activation of CaMKKbeta, AMPK and PGC 1alpha is involved in the anti-neuroinflammatory and neuroprotective effects of 3C in the brain of LPS-treated mice and ischemic rats. Taken together, our results show that compound 3C could suppress neuroinflammation in vitro and in vivo by modulating microglial activation state through the CaMKKbeta-dependent AMPK/PGC-1alpha signaling pathway, and maybe further be developed as a promising new drug candidate for the treatment of brain disorders such as stroke associated with brain inflammation. PMID- 28803159 TI - Telangiectasias: Small lesions referring to serious disorders. AB - Telangiectasias are prominent small vessels (venules, capillaries or arterioles) that are visible as small red-purple focal lesions in the skin and mucous membranes. They can serve as a cutaneous marker for a number of primary (mostly hereditary) disorders and they can be secondary to other (systemic) diseases. Patients with telangiectasias are seen by general health practitioners, pediatricians, (pediatric) neurologists, dermatologists, and ophthalmologists. In this article we give an overview of the different disorders in which telangiectasias are a prominent feature, focusing on neurocutaneous disorders in which they serve as a marker for establishing the right diagnosis. The pattern of distribution of the telangiectasias, their age of onset and associated features are helpful to distinguish between the different disorders. PMID- 28803160 TI - Differentiate low impedance media in closed steel tank using ultrasonic wave tunneling. AB - Ultrasonic wave tunneling through seriously mismatched media, such as steel and water, is possible only when the frequency matches the resonance of the steel plate. But it is nearly impossible to realize continuous wave tunneling if the low acoustic impedance media is air because the transducer frequency cannot be made so accurate. The issue might be resolved using tone-burst signals. Using finite element simulations, we found that for air media when the cycle number is 20, the -6dB bandwidth of energy transmission increased from 0.001% to 5.9% compared with that of continuous waves. We show that the tunneling waves can give us enough information to distinguish low acoustic impedance media inside a steel tank. PMID- 28803161 TI - On-line prognosis of fatigue crack propagation based on Gaussian weight-mixture proposal particle filter. AB - Accurate on-line prognosis of fatigue crack propagation is of great meaning for prognostics and health management (PHM) technologies to ensure structural integrity, which is a challenging task because of uncertainties which arise from sources such as intrinsic material properties, loading, and environmental factors. The particle filter algorithm has been proved to be a powerful tool to deal with prognostic problems those are affected by uncertainties. However, most studies adopted the basic particle filter algorithm, which uses the transition probability density function as the importance density and may suffer from serious particle degeneracy problem. This paper proposes an on-line fatigue crack propagation prognosis method based on a novel Gaussian weight-mixture proposal particle filter and the active guided wave based on-line crack monitoring. Based on the on-line crack measurement, the mixture of the measurement probability density function and the transition probability density function is proposed to be the importance density. In addition, an on-line dynamic update procedure is proposed to adjust the parameter of the state equation. The proposed method is verified on the fatigue test of attachment lugs which are a kind of important joint components in aircraft structures. PMID- 28803162 TI - [Impact of air pollution in paediatric consultations in Primary Health Care: Ecological study]. AB - OBJECTIVE: To study the correlation between the levels of environmental pollutants and the number of paediatric consultations related to respiratory disease in Primary Health Care. PATIENTS AND METHODS: An ecological study is performed, in which the dependent variable analysed was the number of paediatric consultations in an urban Primary Health Care centre in Madrid over a 3 year period (2013-2015), and specifically the consultations related to bronchiolitis, recurrent bronchospasm, and upper respiratory diseases. The independent variables analysed were the levels of environmental pollutants. Coefficients of correlation and multiple lineal regressions were calculated. An analysis has been carried out comparing the average of paediatric consultations when the levels of nitrogen dioxide (NO2) were higher and lower than 40MUg/m3. RESULTS: During the period of the study, there were a total of 52,322 paediatric consultations in the health centre, of which 6,473 (12.37%) were related to respiratory diseases. A positive correlation was found between SO2, CO, NOx and NO2 and benzene levels and paediatric consultations related to respiratory diseases, and a negative correlation with temperature. The number of consultations was significantly higher when NO2 levels exceeded 40MUg/m3. In the multiple lineal regression (P=.0001), the correlation was only positive between consultations and NO2 levels (3.630, 95% CI: 0.691-6.570), and negative with temperature (-5,957, 95% CI: 8.665 to -3.248). CONCLUSIONS: NO2 environmental pollution is related to an increase in respiratory diseases in children. Paediatricians should contribute to promote an improvement in urban air quality as a significant preventive measure. PMID- 28803163 TI - [Hirschsprung-associated enterocolitis: Observational study in a paediatric emergency care unit]. AB - INTRODUCTION: Hirschsprung-associated enterocolitis is a significant cause of morbidity and mortality in infants with Hirschsprung's disease. The fact that the symptoms are so variable and unspecific leads to a slow or incorrect diagnosis. The purpose of this study is to identify clinical factors associated with the diagnosis, as well as to evaluate the subsequent management of children with suspected Hirschsprung-associated enterocolitis in a paediatric emergency department. MATERIAL AND METHODS: A retrospective descriptive study was conducted on patients with Hirschsprung's disease who were seen in a paediatric emergency department between April 2011 and November 2015 due to clinical symptoms compatible with enterocolitis. An analytical multivariate analysis was also performed on the epidemiological and clinical variables associated to enterocolitis. RESULTS: A total of 75 consultation episodes in the Paediatric Emergency Department were studied, of which 52% (39) were finally diagnosed as enterocolitis. Overall, diarrhoea was the most frequent reason for consultation (74.7%). Lethargy, abdominal distension, and pathological findings on the X-ray showed a significant association with the diagnosis of Hirschsprung-associated enterocolitis. Hospital admission rate was 77.3%. CONCLUSION: Hirschsprung associated enterocolitis should be considered in all children with Hirschsprung's disease that consult the Emergency Department, especially those with gastrointestinal symptoms associated with lethargy, abdominal distension and pathological findings on the X-ray. The therapeutic diagnostic process should be initiated as soon as possible, either by clinical observation, if there are any doubts, or by medical treatment if there is a high clinical suspicion. PMID- 28803164 TI - Electrochemically active microorganisms from an acid mine drainage-affected site promote cathode oxidation in microbial fuel cells. AB - The limited database of acidophilic or acidotolerant electrochemically active microorganisms prevents advancements on microbial fuel cells (MFCs) operated under low pH. In this study, three MFCs were used to enrich cathodic biofilms using acid mine drainage (AMD) sediments as inoculum. Linear sweep voltammetry showed cathodic current plateaus of 5.5 (+/-0.7) mA at about -170mV vs Ag/AgCl and 8.5 (+/-0.9) mA between -500mV to -450mV vs Ag/AgCl for biofilms developed on small graphite fiber brushes. After gamma irradiation, biocathodes exhibited a decrease in current density approaching that of abiotic controls. Electrochemical impedance spectroscopy showed six-fold lower charge transfer resistance with viable biofilm. Pyrosequencing data showed that Proteobacteria and Firmicutes dominated the biofilms. Acidithiobacillus representatives were enriched in some biocathodes, supporting the potential importance of these known iron and sulfur oxidizers as cathodic biocatalysts. Other acidophilic chemolithoautotrophs identified included Sulfobacillus and Leptospirillum species. The presence of chemoautotrophs was consistent with functional capabilities predicted by PICRUSt related to carbon fixation pathways in prokaryotic microorganisms. Acidophilic or acidotolerant heterotrophs were also abundant; however, their contribution to cathodic performance is unknown. This study directs subsequent research efforts to particular groups of AMD-associated bacteria that are electrochemically active on cathodes. PMID- 28803165 TI - Exploring the determinants of confidence in the bat-and-ball problem. AB - People often fail to solve deceptively simple mathematical problems, a tendency popularly demonstrated by the bat-and-ball problem. The most prominent explanation of this finding is that, to spare cognitive effort, people substitute the difficult task with an easier one, without being aware of the substitution. Despite this latter assumption, recent studies have found decreased levels of post-decision confidence ratings when people gave the answer of an easier calculation, suggesting that people are sensitive to their errors. In the current study, we investigated a mechanism that might be responsible for such a decrease in people's confidence ratings when they make errors: their attempts to make certain that their answer is correct (verification) and the perceived level of task difficulty (verifiability). We found that these two factors predicted people's confidence, suggesting that people's self-assessment of the perceived task difficulty and of their attempt to verify their response might determine their confidence. Implication for current models of post-decision confidence on reasoning problems is discussed. PMID- 28803166 TI - Advanced age in mares affects endometrial secretion of arachidonic acid metabolites during equine subclinical endometritis. AB - Even if mares continue to breed up to an advanced age, in aging mares reproductive failure is quite common. Subclinical endometritis, which occurs more often in aging mares than in younger counterparts, may cause prolongation or shortening of the inter-estrus period or the corpus luteum lifespan. We hypothesized that during subclinical endometritis the secretion of selected arachidonic acid metabolites may differ in aging mares compared to younger females. To verify this thesis, ex vivo organ cultures of endometrium were established with subsequent measurements of concentrations of prostaglandin E2 (PGE2), 6-keto-PGF1alpha and both leukotrienes (LTs), LTB4 and LTC4 in the culture supernatants. The endometrial biopsies were obtained from 82 mares of known breeding history. This study revealed that the concentrations of the selected arachidonic acid metabolites, which act both as immunological mediators and endocrine modulators in the reproductive organs, depends on the mares' ages. Spontaneous endometrial secretion of PGE2, 6-keto-PGF1alpha and LTC4 was increased in mares aged 16-23 years that suffered from subclinical endometritis, compared with control counterparts. Moreover, secretion of these metabolites was higher in endometritis-positive mares aged 16-23 years than in younger females. We conclude that advanced age in mares further disturbs the immuno-endocrine balance in endometritis-positive mares. PMID- 28803167 TI - IgG4-Related Disease: A New Etiology Underlying Diffuse Intracranial Dilating Vasculopathy. AB - BACKGROUND: Diffuse intracranial aneurysmal vasculopathy is a rare condition, previously described in patients with human immunodeficiency virus infection. IgG4-related disease (IgG4-RD) is a recognized inflammatory disease of systemic organs, leading to fibrosis of connective tissues. It also has been linked to inflammatory dilating aortic aneurysms, coronary vascular disease, hypophysitis, orbital pseudotumor, and pachymeningitis. It has not yet been described as a cause of diffuse intracranial dilating vasculopathy. Histologically, this disease is characterized by IgG4-plasma cell infiltration, fibrosis, and phlebitis. CASE DESCRIPTION: A 40-year-old woman presented with acute heart failure, valvular insufficiency, and mycotic coronary aneurysms, concerning for endocarditis. Infectious workup was negative. Concurrent neurovascular workup revealed intracranial aneurysms, appearing mycotic in origin. Despite aggressive treatment for more than 5 years, she suffered multiple episodes of subarachnoid hemorrhage from a progressive dilating intracranial vasculopathy. Serum IgG levels and aneurysm wall pathology were consistent with IgG4-RD. CONCLUSIONS: This is the first reported case of a diffuse intracranial dilating vasculopathy secondary to IgG4-RD. Recognition of similar pathologic findings in clinical presentation and radiologic workup should prompt further rheumatologic workup and possible immunosuppressive therapies. PMID- 28803168 TI - Metastatic Cardiac Angiosarcoma to the Lung, Spine, and Brain: A Case Report and Review of the Literature. AB - BACKGROUND: Metastatic angiosarcoma to the brain is a rare entity without an established management protocol. CASE DESCRIPTION: A man with primary cardiac angiosarcoma presented with a rare brain metastasis. The patient underwent successful resection of the brain metastasis and was initiated on chemotherapy only for his systemic disease. The patient did not develop local recurrence. A review of primary and metastatic central nervous system angiosarcoma, its pathologic features, clinical disease course, treatment strategies, and genomics is also provided. CONCLUSIONS: Angiosarcomas are rare tumors that are difficult to treat. Gross total resection of a central nervous system metastasis is recommended before initiation of adjuvant chemotherapy or radiation therapy. Close follow-up is still required given the propensity for continued metastasis of these tumors. Future treatments may be developed based on the genomics of angiosarcomas. PMID- 28803169 TI - Stereotactic Radiosurgery for Dural Arteriovenous Fistulas without Cortical Venous Reflux. AB - BACKGROUND: The rationale for treatment of dural arteriovenous fistulas (dAVFs) without cortical venous reflux is symptomatic resolution. Most studies of dAVF treatment, including those for stereotactic radiosurgery, have focused on angiographic obliteration instead of clinical symptomatic outcome. METHODS: The authors evaluated their institutional experience with stereotactic radiosurgery for cerebral dAVFs without cortical venous reflux from 1991 to 2016, evaluating angiographic and clinical outcomes, focusing on the course of pulsatile tinnitus and/or ocular symptoms after treatment. They subsequently pooled their results with those from a systematic literature review. RESULTS: Pooled outcomes data from 349 low-risk dAVF (120 patients with pulsatile tinnitus and 229 patients with ocular symptoms) were analyzed. Over a mean follow-up of 2.6 years, 77% of patients presenting with pulsatile tinnitus experienced resolution and an additional 21% had improvement, with an angiographic obliteration rate of 70.9%. Among 229 patients with ocular symptoms from carotid-cavernous dAVFs, improvement or resolution of symptoms occurred in 95% of those with chemosis, 90% of those with ophthalmoparesis, and 96% of those with proptosis. The angiographic obliteration rate was 76.2%. There were six permanent complications in 349 total treated low-risk dAVF (1.7%). CONCLUSIONS: Rates of clinically significant symptomatic improvement/resolution of symptoms referable to "low-risk" dAVFs are even greater than their angiographic obliteration rate, an important factor in patient counseling and when considering the optimal treatment approach for these dAVFs. PMID- 28803170 TI - Anatomy of the Alar Ligament: Part II: Variations of Its Attachment onto the Dens. AB - OBJECTIVE: Various authors have described the morphology of the alar ligaments; however, there are no reports of a cadaveric study focusing on their attachments onto the dens. The purpose of this study was to use fresh cadaveric specimens to describe in detail different attachment patterns of the alar ligaments onto the dens. METHODS: This study used 22 sides from 11 fresh frozen cadaveric heads. Specimens were obtained from 8 men and 3 women who were 67-99 years old at death. Dissection of the exact attachment of the alar ligaments onto the dens was observed from posterior, superior, and anterior views under the surgical microscope. RESULTS: From a posterior view, 6 alar ligaments passed over the tip of the dens, and 16 alar ligaments attached onto the posterolateral part of the dens; the right and left ligaments had no continuity. From a superior view, the alar ligament was classified in 2 ways: depending on the covered area of the dens (entirely or posterior two thirds) and continuity of the alar ligament (transversely, separately, or combination). Fourteen alar ligaments covered the posterior two thirds of the dens. From an anterior view, in 1 specimen, the alar ligament extended to the anterior surface of the dens. CONCLUSIONS: Wide posterolateral anchoring to the dens coupled with the nearly horizontal trajectory explains the biomechanical advantage of the alar ligaments in undertaking a stabilizing function in limiting head rotation that would otherwise be ineffective in the case of weaker attachments or a more vertical orientation. PMID- 28803171 TI - Open Versus Minimally Invasive Surgery for Extraforaminal Lumbar Disk Herniation: A Systematic Review and Meta-Analysis. AB - INTRODUCTION: Extraforaminal disk herniation (EDH) accounts for 3%-11% of all disk herniations. Despite the heterogeneity of spinal procedures, there is a paucity of literature comparing the outcomes from different surgical approaches. METHODS: We performed a systematic review and meta-analysis of available literature on EDHs. We compared patients undergoing open surgery (OS) with those undergoing minimally invasive surgery (MIS) approaches, including tubular microscopic, percutaneous endoscopic, and microendoscopic. RESULTS: A total of 41 studies with 1813 patients (1239 OS, 574 MIS) were included our analysis. The MIS group showed no significant difference from OS group in the incidence of complications (MIS: 0.01 vs. OS: 0.01, P = 0.971) or reoperation (OS: 0.04, MIS: 0.03; P = 0.382). There was an increased incidence of poor patient satisfaction according to the Macnab criteria for the OS group compared with the MIS group, but the difference was not statistically significant (OS: 0.14 vs. MIS: 0.06; P = 0.237). The OS group had greater estimated blood loss (mean difference [MD]: 38.6 mL), slightly longer operation time (MD: 12.2 minutes), longer hospital stay (MD: 30.3 hours), and longer return to work time (MD: 3.3 weeks). Tubular microscopic procedures had a lower incidence of reoperation than both percutaneous endoscopic (0.01 vs. 0.06, P = 0.01) and microendoscopic procedures (0.01 vs. 0.05, P = 0.03). CONCLUSIONS: Minimally invasive procedures for EDHs are associated with a similar incidence of complications and reoperation but lower estimated blood loss, shorter operative time, shorter hospital stay, and faster return to work time compared to OS. Tubular microscopic have the lowest reoperation rate of MIS procedures. PMID- 28803172 TI - Influence of Obesity on Complications, Clinical Outcome, and Subsidence After Anterior Lumbar Interbody Fusion (ALIF): Prospective Observational Study. AB - BACKGROUND: The complications associated with obesity have been well described for posterior lumbar spinal surgery. However, the influence of obesity on anterior lumbar interbody fusion (ALIF) is not well established. We aimed to compare complication risks, functional outcomes, and subsidence rates in normal weight, overweight, and obese patients who underwent ALIF. METHODS: A total of 137 consecutive patients undergoing ALIF surgery from 2012 to 2014 were followed prospectively. Patients were categorized into 3 groups according to their body mass index (BMI). Patients were evaluated preoperative and postoperatively. Outcome measures included Short Form-12, Oswestry Disability Index, surgical complications, and subsidence. RESULTS: There was no significant difference between the BMI groups in terms of baseline age, proportion of men, levels operated, smoking status, diabetes status, or anterior, posterior, or average disc height. There was no difference in operative duration, blood loss, or hospital stay. At 12-month follow-up, no difference was found in terms of total complications, change in Short Form-12 mental or physical component scores, or Oswestry Disability Index scores. Average disc height was significant lower for the obese group (11.3 mm) compared with the normal-weight (14.4 mm) group. Fusion rate was also significantly lower for patients who were obese (60%) compared with normal-weight (88.2%) and overweight patients (76%) (P = 0.014). Delayed subsidence rates also were similar between normal-weight and overweight patients. CONCLUSIONS: There were no differences in functional outcomes or complications in patients with elevated BMI compared with normal-weight patients. Fusion rates were lower for patients were obese. Obesity should not be considered a contraindication to surgery in patients with appropriate indication to undergo ALIF. PMID- 28803173 TI - Ruptured Vertebral Artery Dissecting Aneurysm Concurrent with Spontaneous Cervical Internal Carotid Artery Dissection: A Report of Three Cases and Literature Review. AB - BACKGROUND: Multiple dissections rarely occur with ruptured vertebral artery dissecting aneurysms (VADAs). Here we report 3 cases of ruptured VADA concurrent with spontaneous cervical internal carotid artery (ICA) dissection. CASE DESCRIPTION: None of the 3 patients had a history of vasculopathy or trauma. All ruptured VADAs were treated with internal coil trapping in the acute stage of subarachnoid hemorrhage (SAH). Rebleeding was not observed in any patients after the treatment. In 1 patient, carotid artery stenting (CAS) was performed 3 days after VADA obliteration to improve hemodynamic compromise. In another patient, CAS was performed 3 weeks after treatment because the dissecting lesion was gradually enlarging. In the third patient, the dissecting lesion resolved with conservative management. CONCLUSIONS: The clinical management of patients with SAH and cervical ICA dissection is complicated. Given that rebleeding of VADA is fatal, achieving hemostasis is the priority. Subsequently, ICA revascularization should be considered to manage ischemic stroke or aneurysmal changes, depending on the SAH stage. In contrast to the typically benign course of sporadic cervical ICA dissection, hemodynamic changes related to SAH and internal trapping of a VADA may exacerbate the cervical ICA dissection. Careful follow-up may be required for cervical dissecting aneurysms in this specific pathological setting. PMID- 28803174 TI - Intraoperative Vascular Neuromonitoring in Patients with Subarachnoid Hemorrhage: A Pilot Study Using Combined Laser-Doppler Spectrophotometry. AB - BACKGROUND: Intraoperative monitoring of cerebral microcirculation in patients with subarachnoid hemorrhage (SAH) may predict the postoperative neurologic outcome. In this pilot study, we examined the value of a novel noninvasive real time measurement technique for detecting changes in local microcirculation. METHODS: We used the O2C (Oxygen to see) laser-Doppler spectrophotometry system in 14 patients with Hunt & Hess grade 2-5 SAH who underwent microsurgical cerebral aneurysm clipping. A subdural probe recorded capillary venous oxygenation (SO2), relative hemoglobin concentration, blood cell velocity, and blood flow at a tissue depth of 7 mm. Data were recorded immediately before dural closure. We also recorded somatosensory evoked potentials (SEPs) with median and tibial nerve stimulation. Results were compared with neurologic performance, as measured on the modified Rankin Scale, at the day of discharge from the hospital and 12 months thereafter. RESULTS: Patient functional outcomes after discharge and 12 months were correlated with pathological decreased flow and increased SO2 values. In 6 of 8 patients, microcirculatory monitoring parameters indicated ischemia during surgery, as shown by electrophysiological SEP changes and infarction detected on the postoperative computed tomography (CT) scan. Pathological SEP results correlated closely with infarct demarcation as seen on CT. CONCLUSIONS: Our results indicate the potential benefit of intraoperative combined laser-Doppler flowmetry and spectrophotometry for predicting postoperative clinical outcomes in this small patient sample. Larger-cohort testing is needed to verify our findings and show the possible merits of this novel method. PMID- 28803175 TI - Seeding of Abdomen with Primary Intracranial Hemangiopericytoma by Ventriculoperitoneal Shunt: Case Report. AB - BACKGROUND: Ventriculoperitoneal shunt (VPS) placement has been implicated in extraneural metastasis of many primary central nervous system tumors. Reported cases include, but are not limited to, medulloblastoma, germ cell tumor, astrocytoma, oligodendroglioma, lymphoma, ependymoma, melanoma, and choroid plexus tumors. However, a literature review reveals no reported cases of extraneural metastasis of solitary fibrous tumor/hemangiopericytoma (SFT/HPC). CASE DESCRIPTION: Here we report the case of a 34-year-old man with recurrent intracranial malignant SFT/HPC who had undergone surgical tumor resection and subsequent placement of a VPS for obstructive hydrocephalus in 2004. Subsequently, the patient presented in 2011 and again in 2013 with abdominal SFT/HPC metastasis likely caused by the presence of the VPS. CONCLUSION: The case raises concern regarding placement of a VPS in patients with obstructive hydrocephalus caused by SFT/HPC. To avoid spread of SFT/HPC to the abdomen, we propose that patients with intracranial SFT/HPC and obstructive hydrocephalus be treated primarily by endoscopic third ventriculostomy. PMID- 28803176 TI - Easy, Efficient, and Mobile Way to Train Microsurgical Skills During Busy Life of Neurosurgical Residency in Resource-Challenged Environment. AB - BACKGROUND: Residents' lives are hectic-it is hard to find a place and time for training basic and advanced microsurgical skills. Surgical instruments and sutures can be purchased (or loaned from another department), but the most expensive and space-occupying device is the microscope. In developing countries, microscopes are used where they are needed most, in operating rooms. Furthermore, a conventional microscope is not portable. For all of these reasons, the availability of microscopes for training microsurgery is limited. METHOD: We used a coffee cup and smartphone (CCS) as a training device instead of a microscope. The coffee cup was the base, and the smartphone functioned to magnify, illuminate, and visualize objects. We measured 2 residents' performance on end-to end artificial bypass before and after 5 days of CCS-based training. RESULTS: We were able to quickly set up the environment for practicing microsurgical skills in any surrounding. After 5 days of training with CCS we could see significant development of microsurgical performance with a conventional microscope as well. The learning curve was dependent on baseline performance. CONCLUSION: CCS is efficient, mobile, and easy to set up. Even though our smartphone-based training was in 2 dimensions, we could improve our microsurgical performance with conventional microscopes, which have 3-dimensional capability. CCS also provides an easy method to record one's microsurgical training. CCS improved both of the subjects' microsurgical performance, making it a good alternative for a traditional microscope. PMID- 28803177 TI - Clusterin, a New Cerebrospinal Fluid Biomarker in Severe Subarachnoid Hemorrhage: A Pilot Study. AB - BACKGROUND: Inflammation following subarachnoid hemorrhage (SAH) involves numerous mediators with biomarker properties. Preliminary studies indicated that clusterin, a multifunctional chaperon protein, was a potential biomarker in SAH. We aimed to clarify the status of clusterin in SAH. METHODS: From 27 patients with severe SAH, 47 cerebrospinal fluid (CSF) samples were collected 0-3, 5-7, and 10-14 days after SAH. Control CSF was collected from 25 age- and sex-matched healthy control subjects undergoing spinal anesthesia for minor surgery. Clusterin concentrations were assayed using enzyme-linked immunosorbent assay and compared with inflammatory markers, imaging findings, and treatment outcome. RESULTS: In healthy control subjects, mean CSF clusterin level (1908.5 ng/mL +/- 36.0) was significantly higher than in the patient group (P < 0.001). In the patient group, mean clusterin level was 741.1 ng/mL +/- 759.2 0-3 days, 601.6 ng/mL +/- 507.2 5-7 days, and 639.2 ng/mL +/- 446.8 10-14 days after SAH. Clusterin level failed to differentiate between good (Glasgow Outcome Scale 4-5) and poor (Glasgow Outcome Scale 1-3) outcomes 0-3 days and 10-14 days after SAH (P = 0.238 and P = 0.225), but significantly higher levels of CSF clusterin were found 5-7 days after SAH in patients with good outcome (P = 0.017). There was a significant correlation between CSF clusterin level 5-7 days after SAH and Glasgow Outcome Scale at 3 months (correlation coefficient = 0.633). The best correlation was found for World Federation of Neurological Societies scale (correlation coefficient = -0.741). CONCLUSIONS: SAH is associated with immediate decrease in CSF clusterin concentrations. Clusterin level at one point was a good predictor of outcome, and it may serve as a biomarker. PMID- 28803178 TI - Treatment of Unstable Thoracolumbar Fractures: Does Fracture-Level Fixation Accelerate the Bone Healing? AB - OBJECTIVE: To investigate the effect of fusion on short segment including fractured level (SSIFL) and long segment (LS) transpedicular fixation after acute thoracolumbar junction burst fractures. The 2-year clinical and radiologic follow up results of the 2 groups also were compared. METHODS: Seventy-four patients were randomized into one of 2 groups: SSIFL (n = 39) or LS (n = 35). The SSIFL group included one level above and one level below, including the fracture level, whereas the LS group included 2 levels above and 2 levels below, excluding the fracture level, for the transpedicular fixation. Fusion was assessed by technetium 99m-methylendiphosphonate, bone scintigraphy, and single-photon emission computed tomography. The 2-year follow-up results were compared clinically (Oswestry Disability Index and visual analog scale) and radiologically (kyphosis angle, sagittal index, anterior vertebral body height loss) at regular intervals. The clinical scores and radiologic parameters of patients with and without fusion also were compared. RESULTS: The number of patients with fusion was significantly greater in the SSIFL group compared with the LS group. There was a significant reduction of the clinical scores of patients who had fusion compared with the fusion-free group; however, there was no radiologically significant difference. Furthermore, there was no significant difference between the SSIFL and LS groups in terms of the 2-year radiologic and clinical follow-up results. CONCLUSIONS: Fusion occurred sooner and patients experienced earlier clinical recovery in the SSIFL group compared with the LS group. PMID- 28803179 TI - Bevacizumab Plus Radiosurgery for Nonsquamous Non-Small Cell Lung Cancer Patients with Brain Metastases: Safe Combination? AB - INTRODUCTION: In the context of bronchial cancers, the brain is one of the most frequent sites for metastases. Local treatments of these metastases have evolved and are often combined to obtain greater efficiency, while the main objective remains to reduce the symptoms. Radiosurgery is currently used as a primary option for patients harboring few numbers of small to middle-sized brain metastases. In nonsquamous non-small cell lung cancer (NSCLC), chemotherapy is often associated with bevacizumab. Our goal was to assess the safety of this early combination. CLINICAL PRACTICE POINTS: Six patients with advanced nonsquamous NSCLC were treated with radiosurgery for the management of their brain metastases (n = 40), followed within <4 weeks by a treatment with bevacizumab. No systemic or cerebral adverse event of grade 3 (intratumoral or parenchymal hemorrhage) or unexpected toxicity secondary to bevacizumab has been indexed. CONCLUSION: Radiosurgery may be safely combined with bevacizumab quite early on for patients with nonsquamous NSCLC with brain metastases. PMID- 28803180 TI - Anxiety Contributes to Poorer Asthma Outcomes in Inner-City Black Adolescents. AB - BACKGROUND: The factors associated with poor asthma control, exacerbations, and health care utilization in black adolescents are complex and not well understood. Although psychological comorbidities such as anxiety are common in patients with asthma, these have not been studied in this population. OBJECTIVE: This study characterized anxiety and associated asthma features in a cohort of black inner city adolescents with persistent asthma and determined the association between anxiety symptoms, persistent uncontrolled asthma, and prospective health care utilization over 1 year. METHODS: Eighty-six black adolescents were enrolled, phenotyped, and screened for anxiety symptoms with the Hospital Anxiety and Depression Scale anxiety subscale (HADS-A). Participants were telephoned every 2 months and a second study visit was completed at 1 year. Primary outcomes included persistent uncontrolled asthma, asthma exacerbations requiring systemic corticosteroids, and unscheduled health care utilization during the 1-year study period. RESULTS: A total of 31% (n = 27) of adolescents had probable anxiety (ie, HADS-A score >7) and 27% (n = 23) had possible anxiety (ie, HADS-A score 5-7) at the baseline visit. Anxiety symptoms were associated with poorer asthma control, more impaired quality of life, and more insomnia symptoms. Adolescents with probable anxiety disorders also had increased odds of persistent uncontrolled asthma and emergency department utilization, with no differences in physician visits or systemic corticosteroid receipt. CONCLUSIONS: Inner-city black adolescents with persistent asthma have a high prevalence of anxiety symptoms associated with poorer asthma control, impaired quality of life, insomnia, and increased prospective emergency department utilization for asthma. Routine screening for anxiety disorders may be useful in the clinical management of adolescents with asthma. PMID- 28803181 TI - Blue dye allergy: Pitfalls in diagnosis and how to avoid them. PMID- 28803182 TI - Subphenotypes of type 2 severe asthma in adults. PMID- 28803183 TI - Chronic Urticaria Patient Perspective (CUPP): The First Validated Tool for Assessing Quality of Life in Clinical Practice. AB - BACKGROUND: There is a need for validated tools to assess health-related quality of life (HRQoL) in routine clinical practice. OBJECTIVE: The aim of this study was to validate the Chronic Urticaria Patient Perspective (CUPP) for assessment of patients with chronic urticaria (CU) in clinical practice. METHODS: A provisional CUPP was developed from candidate items identified by following an iterative process in a retrospective analysis of 249 Chronic Urticaria Quality of Life Questionnaire questionnaires. The psychometric properties of the CUPP were then tested on a sample of patients enrolled in 13 Italian centers. RESULTS: The study population in the validation phase comprised 152 patients. The 10-item version of the CUPP showed satisfactory internal consistency (Cronbach's alpha values of 0.76 at visit 1 and 0.90 at visit 2), good criteria, and discriminative and convergent validity. Reliability was assessed in 34 patients with no changes in health (Global Rating Scale = 0 at visit 2) and was satisfactory (CCC [concordance correlation coefficient] = 0.9). Changes in CUPP scores were significantly associated with changes in Urticaria Activity Score (UAS)-Hive count (r = 0.36, P < .001), UAS-Itch severity (r = 0.48, P < .001), and UAS-Total score (r = 0.342, P < .001), all of which indicated good responsiveness. The minimal important difference was 1.5. CONCLUSIONS: CUPP is a simple 10-question tool with good psychometric properties that provides a valid, reliable, and standardized measurement of HRQoL in patients with CU. PMID- 28803185 TI - Risk of Allergic Reactions to Recurrent Intravenous Penicillin Administration in Penicillin Skin Test Negative Patients. AB - BACKGROUND: Patients with a history of penicillin allergy who are found to be skin test negative to penicillin are able to tolerate repeated oral doses of penicillin with low rates of resensitization. However, the resensitization rate after repeated doses of intravenous penicillin is less clear. OBJECTIVE: We sought to evaluate the risk of allergic reactions to repeated doses of intravenous penicillin in patients who previously reported penicillin allergy and were found to be penicillin skin test and oral challenge negative. METHODS: A retrospective review was conducted between 2010 and 2016 of adult patients who were treated at our academically affiliated hospitals. Patients included in the review had negative penicillin allergy testing and were treated with 2 or more courses of intravenous penicillins. Charts were evaluated to identify any adverse drug reactions. RESULTS: Thirty-two patients met our inclusion criteria. The index penicillin-associated reactions ranged from rash to hypotension and were, for the most part, remote as 75% had reported reactions more than 10 years previously. More than 50% of patients received 3 or more courses of intravenous penicillins. The most frequently repeated intravenous penicillin overall was piperacillin/tazobactam. Thirty-two patients received a total of 111 courses of intravenous penicillins and none developed an immediate hypersensitivity reaction. CONCLUSIONS: In patients who report penicillin allergy and have negative penicillin allergy testing, repeated administration of intravenous penicillin antibiotics appears to be safe. Larger prospective studies should be performed to confirm these observations. PMID- 28803184 TI - Association of Asthma with Rheumatoid Arthritis: A Population-Based Case-Control Study. AB - BACKGROUND: TH1 and TH2 cells have counterregulatory relationships. However, the relationship between asthma, a TH2-predominant condition, and risk of systemic inflammatory diseases such as rheumatoid arthritis (RA), a TH1 condition, is poorly understood. OBJECTIVE: We aimed to determine whether asthma was associated with increased risks of incident RA among adults. METHODS: We conducted a retrospective population-based case-control study that examined existing incident RA cases and controls matched by age, sex, and registration year from the general population in Olmsted County, Minnesota, between January 2002 and December 2007. We performed comprehensive medical record reviews to ascertain asthma status using predetermined asthma criteria. The frequency of a history of asthma before the index date was compared between cases and controls. Logistic regression models were used to adjust for confounding factors. RESULTS: We enrolled 221 RA cases and 218 controls. Of the 221 RA cases, 156 (70.6%) were females, 207 (93.7%) were white, the median age at the index date was 52.5 years, and 53 (24.0%) had a history of asthma. Controls had similar characteristics except that 35 of 218 controls (16.1%) had a history of asthma. After adjustment for sex, age, smoking, body mass index, socioeconomic status, and comorbidity, asthma was significantly associated with increased risks of RA (adjusted odds ratio, 1.74; 95% CI, 1.05-2.90; P = .03). CONCLUSIONS: Despite the counterregulatory relationship between TH1 and TH2 cells, patients with asthma had a significantly higher risk of developing RA than healthy individuals. PMID- 28803186 TI - Asthma Exacerbations and Triggers in Children in TENOR: Impact on Quality of Life. AB - BACKGROUND: Data examining associations between asthma exacerbations, triggers, and asthma-related quality of life (QOL) in children with severe/difficult-to treat asthma are unavailable. OBJECTIVE: To evaluate real-world data on relationships between asthma exacerbations, triggers, and QOL in children using data from TENOR (The Epidemiology and Natural History of Asthma Outcomes and Treatment Regimens), a 3-year observational study of patients with severe/difficult-to-treat asthma, including those aged 6 to 12 years. METHODS: QOL was examined using the Pediatric Asthma Quality of Life Questionnaire (PAQLQ) and defined exacerbations hierarchically (descending order of severity): hospitalization, emergency department visit, steroid burst, no exacerbation, using the highest value from months 6 and 12. One-way ANOVA was used to test for differences in PAQLQ domain scores at month 12 across exacerbation severity, total number of asthma exacerbations, and number of baseline asthma triggers. Mantel-Haenszel chi-square test was used to test the association between the number of triggers and exacerbation hierarchy. RESULTS: Greater severity of asthma exacerbations was associated with significantly (P < .001) lower mean PAQLQ domain scores, indicating poorer QOL. A higher number of asthma exacerbations was associated with significantly (P < .001) lower mean PAQLQ domain scores. PAQLQ scores were significantly lower with higher numbers of baseline triggers. Higher baseline number of asthma triggers was associated with greater severity (P = .05) and number of asthma exacerbations (P < .001). CONCLUSIONS: A higher number of asthma triggers at baseline was associated with greater asthma severity and number of asthma exacerbations and lower QOL in children with severe/difficult-to-treat asthma. PMID- 28803187 TI - Reinforcing carbon fixation: CO2 reduction replacing and supporting carboxylation. AB - Carbon dioxide enters the biosphere via one of two mechanisms: carboxylation, in which CO2 is attached to an existing metabolite, or reduction, in which CO2 is converted to formate or carbon monoxide before further assimilation. Here, we focus on the latter mechanism which usually receives less attention. To better understand the possible advantages of the 'reduction-first' approach, we compare the two general strategies according to the kinetics of the CO2-capturing enzymes, and the resource consumption of the subsequent pathways. We show that the best CO2 reducing enzymes can compete with the best carboxylases. We further demonstrate that pathways that fix CO2 by first reducing it to formate could have an advantage over the majority of their carboxylation-only counterparts in terms of ATP-efficiency and hence biomass yield. We discuss and elaborate on the challenges of implementing 'reduction-first' pathways, including the thermodynamic barrier of CO2 reduction. We believe that pathways based on CO2 reduction are a valuable addition to nature's arsenal for capturing inorganic carbon and could provide promising metabolic solutions that have been previously overlooked. PMID- 28803188 TI - Remediation of internal phosphorus loads with modified clays, influence of fluvial suspended particulate matter and response of the benthic macroinvertebrate community. AB - Clay-based phosphorus (P) sorbents have been increasingly used as geoengineering materials for the management sediment-derived internal P loading in eutrophic lakes. However, the long-term behavior of these sorbents has remained elusive along with their response to burial under suspended particulate matter (SPM), and their effect on macroinvertebrate communities occupying dynamic regions at the sediment-water interface of shallow and turbid lakes. In this study, field mesocosm experiments were undertaken in Lake Chaohu, China, to study the effects of the application of lanthanum-modified bentonite (LMB) and thermally-modified calcium-rich attapulgite (TCAP) on sediment internal P loading and to assess their influence on macroinvertebrate community structure. A complementary laboratory core incubation study was also undertaken to investigate the effects of SPM deposition on LMB and TCAP performance. In the field, both LMB and TCAP effectively intercepted P released from sediment for up to five months. A P fractionation analysis indicated that LMB and TCAP application results in a substantial increase in inert P fractions in sediment. Laboratory studies indicated that deposition of SPM may increase in mobile P both in the upper sediment and across the new post-SPM deposition sediment-water interface. Importantly, a comparison of sediment chemical extractions and estimated P fluxes suggests that chemically-defined forms of P in the sediment may be used as a proxy to estimate the net sediment P flux. Significantly, the surficial application of either LMB or TCAP did not cause negative effects on macroinvertebrate communities. This study indicates that to sustain a low P flux across the sediment-water interface in shallow, turbid lakes, repeat dosing of geoengineering materials, temporally aligned to the deposition of fluvial SPM, may be required. PMID- 28803189 TI - Efficacy of radiant catalytic ionization to reduce bacterial populations in air and on different surfaces. AB - Air contamination by biological agents is often observed in medical or veterinary facilities and industrial plants. Bioaerosols may sediment and pose the surface contamination. Microorganisms present on them may become a source of infections among humans and food contamination. This study determined the use of oxidative gases, including ozone and peroxide, generated by the Radiant Catalytic Ionization (RCI) cell for the inactivation of Acinetobacter baumannii, Escherichia coli, Enterococcus faecalis, Pseudomonas aeruginosa, Salmonella Enteritidis, Listeria monocytogenes, Staphylococcus aureus, Streptococcus epidermidis, Bacillus subtilis, Clostridium sporogenes, Candida albicans, Aspergillus niger and Penicillium chrysogenumon in air and on different surfaces. Results showed that oxidative gases produced by the RCI cell reduced all tested microorganisms. The full elimination of studied microorganisms from the air was obtained for E. coli and C. albicans. RCI also proved to be an effective method of eliminating microbes from the examined surfaces. Regarding of the species, strains origin and the type of surface, the reduction rate ranged from 19.0% for C. albicans to over 99% for A. baumanii. For both, air and surface, the most resistant to RCI was C. sporogenes spores, for which the percentage reduction rate ranged from -2.6% to 71.2% on the surfaces and was equal 71.7% in the air. PMID- 28803190 TI - Legacy and new halogenated persistent organic pollutants in polar bears from a contamination hotspot in the Arctic, Hudson Bay Canada. AB - A large and complex suite of 295 legacy and new halogenated persistent organic pollutants (POPs) were investigated in fat or liver tissue samples of polar bears collected in 2013-2014 from Southern (SHB) and Western (WHB) subpopulations of the Canadian Arctic contaminants hotspot of Hudson Bay. A total of 210 POPs were detected and/or quantifiable with some frequency in all fat or liver samples. POP profile and concentration differences were investigated both within (e.g. age and sex) and between the two subpopulations. Two time-point comparisons were made relative to POPs reported for Hudson Bay polar bears harvested in 2007-2008. SigmaPolychlorinated biphenyl (PCB) concentrations at both time points were the most concentrated of the POP groups, and were spatially uniform with no detectable influence of sex or age, as were concentrations of the dominant congener CB153. SigmaChlordanes (SigmaCHLs, 74-79% oxychlordane) and the Sigmaperfluoroalkyl substances (SigmaPFASs, ~60% perfluorooctane sulfonate (PFOS)) had the second greatest POP group concentrations in SHB and WHB respectively, with SigmaPFASs and SigmaCHLs being significantly influenced by age and/or sex. SigmaCHLs were spatially uniform but SigmaPFASs were greater in the SHB bears, as were e.g. some flame retardants, due to e.g. local contamination and/or changes in bear behavior and diet. Endosulfans and hexabromocyclododecane were detectable in samples from 2007-2008 but not from 2013-2014, which is consistent with their global POP regulations. SigmaPolychlorinated naphthalenes (SigmaPCNs) were consistently detected at relatively high concentrations compared to other arctic wildlife, however these concentrations were low relative to legacy POPs. SigmaShort-chain chlorinated paraffins (SigmaSCCPs) were major contributors to the overall POPs burden with concentrations comparable to other legacy POPs, though there was no significant difference between or within subpopulations for PCNs or SCCPs. Except for octachlorostyrene, POPs concentrations were generally lower in female and male bears from SHB in 2013 2014 relative to 2007-2008, however those of WHB males were greater over the same timeframe for almost all POPs. PMID- 28803191 TI - Enhancing recovery of magnesium as struvite from landfill leachate by pretreatment of calcium with simultaneous reduction of liquid volume via forward osmosis. AB - Landfill leachate contains substances that can be potentially recovered as valuable resources. In this study, magnesium in a landfill leachate was recovered as struvite with calcium pretreatment; meanwhile, the leachate volume was reduced by using a submerged forward osmosis (FO) process, thereby enabling significant reduction of further treatment footprint and cost. Without pretreatment, calcium exhibited strong competition for phosphate with magnesium. The pretreatment with a Ca2+: CO32- molar ratio of 1:1.4 achieved a relatively low loss rate of Mg2+ (24.1+/-2.0%) and high Ca2+ removal efficiency (89.5+/-1.7%). During struvite recovery, 98.6+/-0.1% of magnesium could be recovered with a significantly lower residual PO43--P concentration (<25mgL-1) under the condition of (Mg+Caresidual): P molar ratio of 1:1.5 and pH9.5. The obtained struvite had a similar crystal structure and composition (19.3% Mg and 29.8% P) to that of standard struvite. The FO process successfully recovered water from the leachate and reduced its volume by 37%. The configuration of calcium pretreatment - FO - struvite recovery was found to be the optimal arrangement in terms of FO performance. These results have demonstrated the feasibility of magnesium recovery from landfill leachate and the importance of the calcium pretreatment, and will encourage further efforts to assess the value and purity of struvite for commercial use and to develop new methods for resource recovery from leachate. PMID- 28803192 TI - Early life secondhand smoke exposure assessed by hair nicotine biomarker may reduce children's neurodevelopment at 2years of age. AB - Exposure to secondhand smoke (SHS) can affect fetal brain development as well as subsequent neurodevelopment. This study aimed to determine the association between prenatal and postnatal SHS exposure with children's neurodevelopment at 2years of age. Among 107 mother-child pairs from a Malaysia prospective cohort, prenatal and postnatal SHS exposure was determined based on maternal and child hair nicotine concentrations. Multiple linear regressions were used to determine the association between prenatal and postnatal levels of nicotine in maternal and children's' hair with children's neurodevelopment. After adjustment for confounders, prenatal nicotine concentration levels were negatively associated with communication (beta=-2.059; p=0.015) and fine motor skills (beta=-2.120; p=0.002) while postnatal nicotine concentration levels were inversely associated with fine motors (beta=-0.124; p=0.004) and problem solving skills (beta=-0.117; p=0.013). In conclusion, this study suggests that early life exposure to SHS may affect children's neurodevelopment. PMID- 28803193 TI - A detailed risk assessment of shale gas development on headwater streams in the Pennsylvania portion of the Upper Susquehanna River Basin, U.S.A. AB - The development of unconventional oil and gas (UOG) involves infrastructure development (well pads, roads and pipelines), well drilling and stimulation (hydraulic fracturing), and production; all of which have the potential to affect stream ecosystems. Here, we developed a fine-scaled (1:24,000) catchment-level disturbance intensity index (DII) that included 17 measures of UOG capturing all steps in the development process (infrastructure, water withdrawals, probabilistic spills) that could affect headwater streams (<200km2 in upstream catchment) in the Upper Susquehanna River Basin in Pennsylvania, U.S.A. The DII ranged from 0 (no UOG disturbance) to 100 (the catchment with the highest UOG disturbance in the study area) and it was most sensitive to removal of pipeline cover, road cover and well pad cover metrics. We related this DII to three measures of high quality streams: Pennsylvania State Exceptional Value (EV) streams, Class A brook trout streams and Eastern Brook Trout Joint Venture brook trout patches. Overall only 3.8% of all catchments and 2.7% of EV stream length, 1.9% of Class A streams and 1.2% of patches were classified as having medium to high level DII scores (>50). Well density, often used as a proxy for development, only correlated strongly with well pad coverage and produced materials, and therefore may miss potential effects associated with roads and pipelines, water withdrawals and spills. When analyzed with a future development scenario, 91.1% of EV stream length, 68.7% of Class A streams and 80.0% of patches were in catchments with a moderate to high probability of development. Our method incorporated the cumulative effects of UOG on streams and can be used to identify catchments and reaches at risk to existing stressors or future development. PMID- 28803194 TI - Calculation and application of Sb toxicity coefficient for potential ecological risk assessment. AB - The potential ecological risk index (RI) is a diagnostic tool for pollution control which integrate the concentration of heavy metals with ecological effect, environmental effect and toxicity. However, the lack of toxicity coefficients for specific heavy metals limits its widespread use. In this study, we calculated the toxicity coefficient (=7) for antimony (Sb) based on Hakanson's principles, thus broadening the range of potential applications of this risk assessment tool. Taking the case of Xikuangshan (XKS), the largest Sb mine in the world, we predicted the potential ecological risk factor (Eri) of Sb for sediment and soil. This was then compared with the enrichment factor (EF) and index of geoaccumulation (Igeo). Results showed that Sb shared the similar pollution categories regardless of Eri, EF or Igeo indexes was used indicating the appropriateness of the determined toxicity coefficient. Regression analysis results further demonstrated that Eri was in agreement with bioavailable concentrations (Diffusive Gradient in Thin Films and Community Bureau of Reference extraction concentrations), particularly in sediments. This means that Eri is a reliable and logical index for evaluating Sb pollution in sediments within aquatic environments and in soils within terrestrial environments. PMID- 28803195 TI - A GIS-based atmospheric dispersion model for pollutants emitted by complex source areas. AB - Gaussian dispersion models are widely used to simulate the concentrations and deposition fluxes of pollutants emitted by source areas. Very often, the calculation time limits the number of sources and receptors and the geometry of the sources must be simple and without holes. This paper presents CAREA, a new GIS-based Gaussian model for complex source areas. CAREA was coded in the Python language, and is largely based on a simplified formulation of the very popular and recognized AERMOD model. The model allows users to define in a GIS environment thousands of gridded or scattered receptors and thousands of complex sources with hundreds of vertices and holes. CAREA computes ground level, or near ground level, concentrations and dry deposition fluxes of pollutants. The input/output and the runs of the model can be completely managed in GIS environment (e.g. inside a GIS project). The paper presents the CAREA formulation and its applications to very complex test cases. The tests shows that the processing time are satisfactory and that the definition of sources and receptors and the output retrieval are quite easy in a GIS environment. CAREA and AERMOD are compared using simple and reproducible test cases. The comparison shows that CAREA satisfactorily reproduces AERMOD simulations and is considerably faster than AERMOD. PMID- 28803196 TI - Prenatal exposure to dioxin-like compounds is associated with decreased cord blood IgE and increased risk of wheezing in children aged up to 7years: The Hokkaido study. AB - INTRODUCTION: In utero exposure to dioxin-like compounds (DLCs) may cause imbalance of immune development in early infancy. However, there are few epidemiological studies into the effects of in utero exposure to DLCs on allergies and infections during childhood. This study evaluates associations between concentrations of maternal DLCs and cord blood immunoglobulin (Ig) E, as well as allergies and infections during childhood. METHOD: We recruited 514 pregnant women in a maternity hospital in Sapporo, Japan, and measured concentrations of DLCs in 426 maternal blood samples using high-resolution gas chromatography/high-resolution mass spectrometry. We examined the relationship between concentrations of maternal DLCs and cord blood IgE at birth (n=239), as well as for allergies and infections in children at 3.5 (n=327) and 7 (n=264) years, using regression analysis adjusted for confounding variables. RESULTS: We found a positive association between maternal DLC concentrations and frequency of wheezing in children aged up to 7years [odds ratio (OR); 7.81 (95% confidence interval (CI), 1.42 to 42.9)]. At 3.5years, boys showed inverse associations between maternal DLC concentrations and cord blood IgE [partial regression coefficient; -0.87 (95% CI), -1.68 to -0.06], and frequency of wheezing [OR; 0.03 (95% CI), 0.00 to 0.94] but girls did not. DISCUSSION: As one reason for the significant association observed at 7 but absent at 3.5years, we suggest that allergic symptoms are more obvious in older children due to matured immune function. CONCLUSION: The findings suggest that prenatal exposure to DLCs may modify offspring immune responses and result in increased risk of allergy among children of school age. PMID- 28803197 TI - Sources and accumulation of plutonium in a large Western Pacific marginal sea: The South China Sea. AB - In order to examine the sources of plutonium (Pu) and elaborate its scavenging and accumulation processes, 240Pu/239Pu atom ratios and 239+240Pu activities in the water column of the South China Sea (SCS) were determined and compared with our previously reported data for the sediments. Consistently high 240Pu/239Pu atom ratios that ranged from 0.184-0.250 (average=0.228+/-0.015), indicative of non-global fallout Pu sources were observed both in the surface water and at depth during 2012-2014. The spatial distribution of the 240Pu/239Pu atom ratio in the SCS showed a decreasing trend away from the Luzon Strait, which was very consistent with the introduction pathway of the Kuroshio Current. The Kuroshio had an even heavier Pu isotopic ratio ranging from 0.250-0.263 (average=0.255+/ 0.006), traceable to the non-global fallout Pu signature from the Pacific Proving Grounds (PPG). Using a simple two end-member mixing model, we further revealed that this PPG source contributed 41+/-17% of the Pu in the SCS water column. The 239+240Pu activities in the SCS surface seawater varied from 1.59 to 2.94mBqm-3, with an average of 2.34+/-0.38mBqm-3. Such an activity level was ~40% higher than that in the Kuroshio. The distribution of 239+240Pu in the surface seawater further showed a general trend of increase from the Kuroshio to the SCS basin, suggesting significant accumulation of Pu within the SCS. The 239+240Pu inventory of the water column in the SCS basin at the SEATS station with a total depth of ~3840m was estimated to be ~29Bqm-2, which was substantially higher than the sediment core estimates made for the SCS basin (3.75Bqm-2) but much lower than the sediment core estimates made for the shelf of the northern SCS (365.6Bqm-2). Such differences were determined by the lower scavenging efficiency of Pu in the SCS basin compared to the northern SCS shelf. PMID- 28803199 TI - Use of partial order in environmental pollution studies demonstrated by urban BTEX air pollution in 20 major cities worldwide. AB - Urban air pollution with benzene, toluene, ethyl benzene and xylenes (BTEX) is a common phenomenon in major cities where the pollution mainly originates from traffic as well as from residential heating. An attempt to rank cities according to their BTEX air pollution is not necessarily straight forward as we are faced with several individual pollutants simultaneously. A typical procedure is based on aggregation of data for the single compounds, a process that not only hides important information but is also subject to compensation effects. The present study applies a series of partial ordering tools to circumvent the aggregation. Based on partial ordering, most important indicators are disclosed, and an average ranking of the cities included in the study is derived. Since air pollution measurements are often subject to significant uncertainties, special attention has been given to the possible effect of uncertainty and/or data noise. Finally, the effect of introducing weight regimes is studied. In a concluding section the gross national income per person (GNI) is brought into play, demonstrating a positive correlation between BTEX air pollution and GNI. The results are discussed in terms of the ability/willingness to combat air pollution in the cities studied. The present study focuses on Almaty, the largest city in Kazakhstan and compares the data from Almaty to another 19 major cities around the world. It is found that the benzene for Almaty appears peculiar high. Overall Almaty appears ranked as the 8th most BTEX polluted city among the 20 cities included in the study. PMID- 28803198 TI - Variability of indoor fungal microbiome of green and non-green low-income homes in Cincinnati, Ohio. AB - "Green" housing is designed to use low-impact materials, increase energy efficiency and improve occupant health. However, little is known about the indoor mycobiome of green homes. The current study is a subset of a multicenter study that aims to investigate the indoor environment of green homes and the respiratory health of asthmatic children. In the current study, the mycobiome in air, bed dust and floor dust was compared between green (study site) and non green (control site), low-income homes in Cincinnati, Ohio. The samples were collected at baseline (within four months following renovation), and 12months after the baseline at the study site. Parallel sample collection was conducted in non-green control homes. Air samples were collected by PM2.5 samplers over 5 days. Bed and floor dust samples were vacuumed after the air sampling was completed. The DNA sample extracts were analyzed using ITS amplicon sequencing. Analysis indicated that there was no clear trend in the fungal communities between green and non-green homes. Instead, fungal community differences were greatest between sample types - air, bed, and floor. Microbial communities also changed substantially between sampling intervals in both green and non-green homes for all sample types, potentially indicating that there was very little stability in the mycobiomes. Research gaps remain regarding how indoor mycobiome fluctuates over time. Longer follow-up periods might elucidate the effect of green renovation on microbial load in buildings. PMID- 28803200 TI - Ecological state of a mountain river before and after a large flood: Implications for river status assessment. AB - Assessment of the ecological status of rivers is key to monitoring the achievement of the environmental goal of the EU Water Framework Directive and the success of restoration projects. In summer of 2009 and 2010, repeated assessments of physical habitat conditions and of fish and benthic invertebrate communities were performed at low-flow conditions in 10 unmanaged and 10 channelized cross sections of the Biala River, Polish Carpathians. Between the two surveys, an 80 year flood occurred, significantly affecting habitat characteristics and river communities. In unmanaged cross-sections, active channel width increased, whereas the degree of cross-sectional variation of flow velocity decreased. In channelized cross-sections, the increase in active channel width and the cross sectional variation of flow velocity was accompanied by a decrease in bed material grain size. Before the flood, the unmanaged cross-sections hosted 2.3 times more benthic invertebrate taxa than the channelized ones, whereas after the flood, the number of taxa they supported was so reduced that the taxonomic richness of benthic invertebrate assemblages in both cross-section types became similar. In comparison to pre-flood conditions, the abundance of fish juveniles (YOY) in unmanaged cross-sections was reduced nearly by half; before the flood they hosted 5 times more juvenile individuals than channelized cross-sections and only twice as many after the flood. Finally, a differing assessment of flood impact on the ecological river quality was obtained with the invertebrate-based BMWP-PL index and the European Fish Index, with the former indicating a significant reduction of the quality in unmanaged cross-sections and the latter pointing to no such change. The results indicate that assessments performed before or after a major flood may yield significantly different results for the quality of abiotic and biotic elements of the river ecosystem. Final assessment should thus be based on repeated surveys to balance the effect of extreme hydrological events. PMID- 28803201 TI - Influence of architectural style on indoor radon concentration in a radon prone area: A case study. AB - Indoor radon is a major health concern as it is a known carcinogenic. Nowadays there is a trend towards a greater energy conservation in buildings, which is reflected in an increasing number of regulations. But, can this trend increase the indoor radon concentration? In this paper, we selected a radon prone area in Spain and focused on single-family dwellings constructed in a variety of architectural styles. These styles ranged from 1729 up to 2014, with varying construction techniques (from local resources to almost universally standard building materials) and regulations in force (from none to the Spanish regulation in force). The 226Ra concentrations in soil and surface radon exhalation rates were rather similar in this area, mean values ranging 70-126Bq/kg and 49 100mBq/m2.s, respectively. Indoor radon concentration was generally greater than the contribution from soil exhalation (surface exhalation rates), especially in New dwellings (1980-2014). Its concentration in dwellings built in the Traditional style (1729-1940) was significantly lower than in the new houses. This can be consequence of the air tightness of the dwellings as a consequence of the different regulations in force. In the period covered by the Traditional style, there was no regulation in force, and dwelling had loose air tight. Whereas in recent times, there are mandatory regulations assuring a better air tightness of the buildings. Refurbishment of Traditional dwellings also seems to increase the indoor radon concentration, as they must also comply with the regulations in force. PMID- 28803202 TI - Interplay of hydrology, community ecology and pollutant attenuation in the hyporheic zone. PMID- 28803203 TI - Use of bias correction techniques to improve seasonal forecasts for reservoirs - A case-study in northwestern Mediterranean. AB - In this paper, we have compared different bias correction methodologies to assess whether they could be advantageous for improving the performance of a seasonal prediction model for volume anomalies in the Boadella reservoir (northwestern Mediterranean). The bias correction adjustments have been applied on precipitation and temperature from the European Centre for Middle-range Weather Forecasting System 4 (S4). We have used three bias correction strategies: two linear (mean bias correction, BC, and linear regression, LR) and one non-linear (Model Output Statistics analogs, MOS-analog). The results have been compared with climatology and persistence. The volume-anomaly model is a previously computed Multiple Linear Regression that ingests precipitation, temperature and in-flow anomaly data to simulate monthly volume anomalies. The potential utility for end-users has been assessed using economic value curve areas. We have studied the S4 hindcast period 1981-2010 for each month of the year and up to seven months ahead considering an ensemble of 15 members. We have shown that the MOS analog and LR bias corrections can improve the original S4. The application to volume anomalies points towards the possibility to introduce bias correction methods as a tool to improve water resource seasonal forecasts in an end-user context of climate services. Particularly, the MOS-analog approach gives generally better results than the other approaches in late autumn and early winter. PMID- 28803204 TI - Silver nanoparticles or free silver ions work? An enantioselective phytotoxicity study with a chiral tool. AB - Nowadays, silver nanoparticles (AgNP) have been widely used and there are raising concerns about their potential adverse effects on organism. As for the exact toxicity mechanism of AgNP, opinions still vary and whether the released silver ions (Ag+) or AgNP themselves are responsible for the toxicity remains debatable. In the present study, we have designed two exposure systems where Ag+ and AgNP coexisted but differed in quantification by using photo-reduced method with cysteine enantiomers, and their toxicities to freshwater microalgae Scenedesmus obliquus and model plant Arabidopsis thaliana were determined. In the results, Ag+ was in suit photo-reduced by cysteine enantiomers, and the UV-Vis and circular dichroism spectrum evidence confirmed the quantification difference between Ag-l-cysteine (Ag-l-Cys) and Ag-d-cysteine (Ag-d-Cys), where there was more AgNP and less Ag+ in Ag-l-Cys. Furthermore, the toxicity assay data revealed that Ag-d-Cys was more toxic to S. obliquus but A. thaliana was more susceptible to Ag-l-Cys. The metal element distribution in Arabidopsis leaves was also influenced in an enantioselective manner, which was related to the oxidative stress. Considering the quantification difference between Ag-l-Cys and Ag-d-Cys, it can be concluded that AgNP exhibited their toxicity to S. obliquus by the action of Ag+, but toxicity brought to A. thaliana was attributed to AgNP themselves rather than Ag+. The results of the present study help to better clarify the role of Ag+ in AgNP toxicity and offer a chiral tool and a new sight to investigate the toxicity mechanism of AgNP. PMID- 28803205 TI - Water footprint assessment for crop production based on field measurements: A case study of irrigated paddy rice in East China. AB - Water footprint (WF) is a comprehensive measure of water consumption by human activities and can be used to assess the impact on both water volume and quality. This study aims to explore the feasibility of evaluating green, blue and grey WFs of crop production based on field measurements. The irrigated paddy rice grown in three different experimental sites in different typical irrigation districts in Huai'an, East China over 2011 to 2014 was taken as study case. With fixed irrigation and fertilization, on the basis of measuring field water and fertilizer balance at daily step, we calculated WF of crop production under different test treatments. Results show that crop water requirement of rice was measured as 667.1mm and 6.2% of the total nitrogen (T-N) was washed away from farmland accompany with drainage and percolation. Average annual WF of paddy rice during 2011-2014 in Huai'an was 1.760m3/kg (33.3% green, 25.8% blue and 40.9% grey). The level of WF and blue water proportion in different locations (irrigation districts) and different years changed slightly, while the proportion of green and grey WF changed with the variance of precipitation. Green water proportion was 25.1%, 34.2 and 44.2%, while 48.0%, 40.2% and 31.0% for grey water proportion under precipitation levels of 400, 600 and 800mm, respectively. The reduced grey WF was due to increased drainage. This study not only proved the feasibility of assessing WF of crop production with field experiments, but also provided a new method for WF calculation based on field water and fertilizer migration processes. PMID- 28803206 TI - Transport of Hexabromocyclododecane (HBCD) into the soil, water and sediment from a large producer in China. AB - Hexabromocyclododecane (HBCD) is used as a flame retardant with extensive industrial applications, which is mainly produced at facilities on the coast of China. Radially distributed soil samples and equidistant paired water and sediment samples were taken around one of the biggest HBCD production enterprises to reflect its environmental behavior via air deposition and wastewater discharge of HBCD diastereoisomers (alpha-, beta- and gamma-HBCD). Worldwide high concentrations of HBCD (11,700ng/g in the soil, 5080ng/L in the water and 6740ng/g in the sediment) were detected in these environmental samples. Concentrations dropped by two orders of magnitude over several kilometers distance from the plant. The diastereoisomer pattern varied in the three environmental compartments examined, such that gamma-HBCD was the predominant diastereoisomer in the soil and sediment whilst alpha- and gamma-HBCD shared the predominance in the water. The mass inventories of HBCD in the local soil and sediment were estimated to be 5006kg and 30kg respectively, suggesting that soil was the major sink of HBCD in the production area. As for the soil, the environmental burdens in the areas with radiuses of 2, 4 and 6km were 3210, 3770 and 4590kg respectively. PMID- 28803207 TI - Phase separation of in situ forming poly (lactide-co-glycolide acid) implants investigated using a hydrogel-based subcutaneous tissue surrogate and UV-vis imaging. AB - Phase separation of in situ forming poly (lactide-co-glycolide acid) (PLGA) implants with agarose hydrogels as the provider of nonsolvent (water) mimicking subcutaneous tissue was investigated using a novel UV-vis imaging-based analytical platform. In situ forming implants of PLGA-1-methyl-2-pyrrolidinone and PLGA-triacetin representing fast and slow phase separating systems, respectively, were evaluated using this platform. Upon contact with the agarose hydrogel, the phase separation of the systems was followed by the study of changes in light transmission and absorbance as a function of time and position. For the PLGA-1-methyl-2-pyrrolidinone system, the rate of spatial phase separation was determined and found to decrease with increasing the PLGA concentration from 20% to 40% (w/w). Hydrogels with different agarose concentrations (1% and 10% (w/v)) were prepared for providing the nonsolvent, water, to the in situ forming PLGA implants simulating the injection site environment. The resulting implant morphology depended on the stiffness of hydrogel matrix, indicating that the matrix in which implants are formed is of importance. Overall, the work showed that the UV-vis imaging-based platform with an agarose hydrogel mimicking the subcutaneous tissue holds potential in providing bio-relevant and mechanistic information on the phase separation processes of in situ forming implants. PMID- 28803208 TI - N-glucuronidation catalyzed by UGT1A4 and UGT2B10 in human liver microsomes: Assay optimization and substrate identification. AB - N-glucuronidation is an important pathway for metabolism and disposition of tertiary amines in humans. This reaction is mainly catalyzed by the enzymes UGT1A4 and UGT2B10. However, the metabolic patterns of UGT1A4- and UGT2B10 mediated N-glucuronidation are not fully clear. In this study, we first optimized in vitro reaction conditions for N-glucuronidation by using specific substrates (i.e., trifluoperazine for UGT1A4, cotinine and amitriptyline for UGT2B10). Furthermore, we found that hepatic N-glucuronidation showed significant species differences. In addition, UGT1A4 and UGT2B10 were primarily responsible for N glucuronidation of many tertiary amines, including asenapine, loxapine, clozapine, chlorpromazine, dothiepin, doxepin, mirtazapine, mianserin, chlorcyclizine, cyclizine, promethazine, cyclobenzaprine, imatinib, retrorsine, strychnine and brucine. In conclusion, this study provides an in vitro assay system for evaluating N-glucuronidation of amines. Also, UGT1A4- and UGT2B10 mediated N-glucuronidation might play significant roles in metabolism and detoxification of tertiary amines in humans. PMID- 28803209 TI - 20-Hydroxyecdysone attenuates cardiac remodeling in spontaneously hypertensive rats. AB - BACKGROUND: Ecdysteroids, a group of steroid hormones found in insects and many plants, have been shown to prevent various changes in mammalian tissues after female sex hormone deprivation. PURPOSE: To examine whether an ecdysteroid, 20 hydroxyecdysone (20-HE), exhibits regulatory or protective roles in the cardiovascular system. STUDY DESIGN/METHOD: Blood pressure and cardiac function were evaluated in spontaneously hypertensive rats (SHR) during and after daily treatment with 20-HE for six weeks. RESULTS: The progressive increase in systolic blood pressure with age in SHR rats was significantly lower in animals treated with either 5 or 10mg/kg body weight of 20-HE. However, treatment with 20-HE did not diminish the increase in diastolic pressure. Echocardiography after six weeks of treatment demonstrated that the left ventricular chamber of SHR rats treated with 20-HE was smaller than that of SHR controls, while contractility was not affected by 20-HE. Histological images also demonstrated a decrease in cardiomyocyte cross-sectional area in 20-HE treated groups. Interestingly, treatment with 20-HE caused a shift in cardiac myosin heavy chain towards more beta-isoforms. SHR rats treated with 20-HE also exhibited a decrease in seminal vesicular weight and an increase in testicular weight, especially at a dose of 10mg/kg body weight. This finding suggests a possible anti-androgenic effect of 20-HE. CONCLUSION: Our finding reveal that 20-HE has a beneficial effect on reducing blood pressure and consequently preventing dilated cardiac hypertrophy in SHR rats. PMID- 28803210 TI - Investigation of pH and substituent effects on the distribution ratio of novel steroidal ring D- and A-fused arylpyrazole regioisomers and evaluation of their cell-growth inhibitory effects in vitro. AB - Novel androstanopyrazoles have been efficiently synthesized from steroidal beta ketoaldehydes with different arylhydrazine hydrochlorides both under acidic and basic conditions. Knorr-type transformations of 16-hydroxymethylene dehydroepiandrosterone containing its 1,3-dicarbonyl moiety on ring D, proved to be regioselective in pyridine at room temperature, while mixtures of regioisomers were obtained in acidic EtOH under reflux. Contrarily, the cyclocondensation reactions of 2-hydroxymethylene-dihydrotestosterone bearing its reactive functionalities on ring A, led to a mixture of pyrazole regioisomers in varying ratio depending on the applied medium. The regioisomeric distribution was found to depend on the electronic character of the substituent of the phenylhydrazine applied. After separating the related isomers by column chromatography, they were subjected to in vitro pharmacological studies to investigate their antiproliferative activities against three human breast malignant cell lines (MCF7, T47D, MDA-MB-231). Flow cytometry revealed that the most potent agents elicited a cell cycle disturbance on MDA-MB-231 and T47D cells. PMID- 28803211 TI - Melatonin protects chondrocytes from impairment induced by glucocorticoids via NAD+-dependent SIRT1. AB - Intra-articular injection of glucocorticoids is used to relieve pain and inflammation in osteoarthritis patients, which is occasionally accompanied with the serious side effects of glucocorticoids in collagen-producing tissue. Melatonin is the major hormone released from the pineal gland and its beneficial effects on cartilage has been suggested. In the present study, we investigated the protective role of melatonin on matrix degeneration in chondrocytes induced by dexamethasone (Dex). The chondrocytes isolated from mice knee joint were treated with Dex, melatonin, EX527 and siRNA targeted for SIRT6, respectively. Dex treatment induced the loss of the extracellular matrix, NAD+/NADH ratio and NADPH concentration in chondrocytes. Melatonin alone have no effect on the quantity of proteoglycans and collagen type IIa1, however, the pretreatment of melatonin reversed the negative effects induced by Dex. Meanwhile, the significant decrease in NAD+/NADH ratio and NADPH concentration in Dex group were up-regulated by pretreatment of melatonin. Furthermore, it was revealed that inhibition of SIRT1 blocked the protective effects of melatonin. The enhancement of NAD+-dependent SIRT1 activity contributes to the chondroprotecfive effects of melatonin, which has a great benefit to prevent dexamethasone-induced chondrocytes impairment. PMID- 28803212 TI - Data-driven classification of patients with primary progressive aphasia. AB - Current diagnostic criteria classify primary progressive aphasia into three variants-semantic (sv), nonfluent (nfv) and logopenic (lv) PPA-though the adequacy of this scheme is debated. This study took a data-driven approach, applying k-means clustering to data from 43 PPA patients. The algorithm grouped patients based on similarities in language, semantic and non-linguistic cognitive scores. The optimum solution consisted of three groups. One group, almost exclusively those diagnosed as svPPA, displayed a selective semantic impairment. A second cluster, with impairments to speech production, repetition and syntactic processing, contained a majority of patients with nfvPPA but also some lvPPA patients. The final group exhibited more severe deficits to speech, repetition and syntax as well as semantic and other cognitive deficits. These results suggest that, amongst cases of non-semantic PPA, differentiation mainly reflects overall degree of language/cognitive impairment. The observed patterns were scarcely affected by inclusion/exclusion of non-linguistic cognitive scores. PMID- 28803213 TI - Effect of salting and ripening on the physicochemical and sensory quality of goat and sheep cured legs. AB - Physicochemical and sensory characteristics of sheep and goat cured legs were evaluated. The pH values (5.7-5.8) and aw (0.87 and 0.83) found to be adequate to control meat deterioration, promoting safety and stability to shelf life of products with respect to microbial growth. The high protein (46.2 and 38.4%) and low fat (5.3 and 8.7%) percentages of the goat and sheep cured legs were the main evidence of the effect of salting and ripening processes. A low cholesterol content of 4.5% is particularly evident in sheep cured legs. Curing process produced a slight increase in the P/S ratio 0.23 and 0.17 for goat and sheep cured legs, respectively. TBARS values are much lower than the value of 2mg of MDA/Kg which is the upper limit of rancidity. Physico-chemical and sensory characteristics indicate that producing cured goat and sheep legs from cull animals can be an interesting way of adding value to animals with very low commercial prices. PMID- 28803214 TI - Self-defensive antibiotic-loaded layer-by-layer coatings: Imaging of localized bacterial acidification and pH-triggering of antibiotic release. AB - : Self-defensive antibiotic-loaded coatings have shown promise in inhibiting growth of pathogenic bacteria adhering to biomaterial implants and devices, but direct proof that their antibacterial release is triggered by bacterially-induced acidification of the immediate environment under buffered conditions remained elusive. Here, we demonstrate that Staphylococcus aureus and Escherichia coli adhering to such coatings generate highly localized acidification, even in buffered conditions, to activate pH-triggered, self-defensive antibiotic release. To this end, we utilized chemically crosslinked layer-by-layer hydrogel coatings of poly(methacrylic acid) with a covalently attached pH-sensitive SNARF-1 fluorescent label for imaging, and unlabeled-antibiotic (gentamicin or polymyxin B) loaded coatings for antibacterial studies. Local acidification of the coatings induced by S. aureus and E. coli adhering to the coatings was demonstrated by confocal-laser-scanning-microscopy via wavelength-resolved imaging. pH-triggered antibiotic release under static, small volume conditions yielded high bacterial killing efficiencies for S. aureus and E. coli. Gentamicin-loaded films retained their antibacterial activity against S. aureus under fluid flow in buffered conditions. Antibacterial activity increased with the number of polymer layers in the films. Altogether, pH-triggered, self-defensive antibiotic-loaded coatings become activated by highly localized acidification in the immediate environment of an adhering bacterium, offering potential for clinical application with minimized side-effects. STATEMENT OF SIGNIFICANCE: Polymeric coatings were created that are able to uptake and selectively release antibiotics upon stimulus by adhering bacteria in order to understand the fundamental mechanisms behind pH triggered antibiotic release as a potential way to prevent biomaterial-associated infections. Through fluorescent imaging studies, this work importantly shows that adhering bacteria produce highly localized pH changes even in buffer. Accordingly such coatings only demonstrate antibacterial activity by antibiotic release in the presence of adhering bacteria. This is clinically important, because ad libitum releasing antibiotic coatings usually show a burst release and have often lost their antibiotic content when bacteria adhere. PMID- 28803215 TI - Structural, tribological, and mechanical properties of the hind leg joint of a jumping insect: Using katydids to inform bioinspired lubrication systems. AB - : This study investigates the structural properties of the hind leg femur-tibia joint in adult katydids (Orthoptera: Tettigoniidae), including its tribological and mechanical properties. It is of particular interest because the orthopteran (e.g., grasshoppers, crickets, and katydids) hind leg is highly specialized for jumping. We show that the katydid hind leg femur-tibia joint had unique surfaces and textures, with a friction coefficient (MU) at its coupling surface of 0.053+/ 0.001. Importantly, the sheared surfaces at this joint showed no sign of wear or damage, even though it had undergone thousands of external shearing cycles. We attribute its resiliency to a synergistic interaction between the hierarchical surface texture/pattern on the femoral surfaces, a nanograded internal nanostructure of articulating joints, and the presence of lubricating lipids on the surface at the joint interface. The micro/nanopatterned surface of the katydid hind leg femur-tibia joint enables a reduction in the total contact area, and this significantly reduces the adhesive forces between the coupling surfaces. In our katydids, the femur and tibia joint surfaces had a maximum effective elastic modulus (Eeff) value of 2.6GPa and 3.9GPa, respectively. Presumably, the decreased adhesion through the reduction of van der Waals forces prevented adhesive wear, while the contact between the softer textured surface and harder smooth surface avoided abrasive wear. The results from our bioinspired study offer valuable insights that can inform the development of innovative coatings and lubrication systems that are both energy efficient and durable. STATEMENT OF SIGNIFICANCE: Relative to body length, insects can outjump most animals. They also accelerate their bodies at a much faster rate. Orthopterans (e.g., grasshoppers, crickets, and katydids) have hind legs that are specialized for jumping. Over an individual's lifetime, the hind leg joint endures repeated cycles of flexing and extending, including jumping, and its efficiency and durability easily surpass that of most mechanical devices. Although the efficient functioning of insect joints has long been recognized, the mechanism by which insect joints experience friction/adhesion/wear, and operate efficiently/reliably is still largely unknown. Our study on the structural, tribological, and mechanical properties of the orthopteran hind leg joints reveals the potential of katydid bioinspired research leading to more effective coatings and lubrication systems. PMID- 28803216 TI - 3D/2D Registration with superabundant vessel reconstruction for cardiac resynchronization therapy. AB - A key component of image guided interventions is the registration of preoperative and intraoperative images. Classical registration approaches rely on cross modality information; however, in modalities such as MRI and X-ray there may not be sufficient cross-modality information. This paper proposes a fundamentally different registration approach which uses adjacent anatomical structures with superabundant vessel reconstruction and dynamic outlier rejection. In the targeted clinical scenario of cardiac resynchronization therapy (CRT) delivery, preoperative, non contrast-enhanced, MRI is registered to intraoperative, contrasted X-ray fluoroscopy. The adjacent anatomical structures are the left ventricle (LV) from MRI and the coronary veins reconstructed from two contrast enhanced X-ray images. The novel concept of superabundant vessel reconstruction is introduced to bypass the standard reconstruction problem of establishing one to-one correspondences. Furthermore, a new dynamic outlier rejection method is proposed, to enable globally optimal point set registration. The proposed approach has been qualitatively and quantitatively evaluated on phantom, clinical CT angiography with ground truth and clinical CRT data. A novel evaluation method is proposed for clinical CRT data based on previously implanted artificial aortic and mitral valves. The registration accuracy in 3D was 2.94 mm for the aortic and 3.86 mm for the mitral valve. The results are below the required accuracy identified by clinical partners to be the half-segment size (16.35 mm) of a standard American Heart Association (AHA) 16 segment model of the LV. PMID- 28803218 TI - Do you hear 'feather' when listening to 'rain'? Lexical tone activation during unconscious translation: Evidence from Mandarin-English bilinguals. AB - Although lexical tone is a highly prevalent phonetic cue in human languages, its role in bilingual spoken word recognition is not well understood. The present study investigates whether and how adult bilinguals, who use pitch contours to disambiguate lexical items in one language but not the other, access a tonal L1 when exclusively processing a non-tonal L2. Using the visual world paradigm, we show that Mandarin-English listeners automatically activated Mandarin translation equivalents of English target words such as 'rain' (Mandarin 'yu3'), and consequently were distracted by competitors whose segments and tones overlapped with the translations of English target words ('feather', also 'yu3' in Mandarin). Importantly, listeners were not distracted by competitors that overlapped with the translations of target words in all segments but not tone ('fish'; Mandarin 'yu2'), nor were they distracted by competitors that overlapped with the translations of target words in rime and tone ('wheat', Mandarin 'gu3'). These novel results demonstrate implicit access to L1 lexical representations through automatic/unconscious translation, as a result of cross-language top-down and/or lateral influence, and highlight the critical role of lexical tone activation in bilingual lexical access. PMID- 28803217 TI - Accurate model-based segmentation of gynecologic brachytherapy catheter collections in MRI-images. AB - The gynecological cancer mortality rate, including cervical, ovarian, vaginal and vulvar cancers, is more than 20,000 annually in the US alone. In many countries, including the US, external-beam radiotherapy followed by high dose rate brachytherapy is the standard-of-care. The superior ability of MR to visualize soft tissue has led to an increase in its usage in planning and delivering brachytherapy treatment. A technical challenge associated with the use of MRI imaging for brachytherapy, in contrast to that of CT imaging, is the visualization of catheters that are used to place radiation sources into cancerous tissue. We describe here a precise, accurate method for achieving catheter segmentation and visualization. The algorithm, with the assistance of manually provided tip locations, performs segmentation using image-features, and is guided by a catheter-specific, estimated mechanical model. A final quality control step removes outliers or conflicting catheter trajectories. The mean Hausdorff error on a 54 patient, 760 catheter reference database was 1.49 mm; 51 of the outliers deviated more than two catheter widths (3.4 mm) from the gold standard, corresponding to catheter identification accuracy of 93% in a Syed Neblett template. In a multi-user simulation experiment for evaluating RMS precision by simulating varying manually-provided superior tip positions, 3sigma maximum errors were 2.44 mm. The average segmentation time for a single catheter was 3 s on a standard PC. The segmentation time, accuracy and precision, are promising indicators of the value of this method for clinical translation of MR guidance in gynecologic brachytherapy and other catheter-based interventional procedures. PMID- 28803219 TI - Revealing the mechanisms of human face perception using dynamic apertures. AB - Faces are notoriously hard to perceive when turned upside-down. It is often claimed that perceptual decrements reflect a qualitative switch from parallel whole-face processing, to a serial analysis of individual features. To test this view, we examined observers' ability to categorize faces presented in their entirety, or viewed through a dynamic aperture that moved incrementally across the facial image. Exposing faces region-by-region disrupts holistic processing, but permits serial analysis of local features. In line with the holistic accounts, we predicted that aperture viewing would greatly impair judgements of upright, but not inverted faces. As expected, identity, gender, age, and expression were categorized more precisely when faces were presented upright and in their entirety. Contrary to holistic accounts, however, the detrimental effects of inversion seen in the whole-face condition were no greater than in the aperture condition. Moreover, we found comparable aperture effects for upright and inverted faces; observers exhibited less decision noise when faces were viewed in their entirety, than when viewed through the aperture, irrespective of orientation. We replicate these findings in control experiments and show that the same pattern is seen irrespective of the direction of aperture transition or the nature of the fill used to replace the occluded regions of the to-be-judged image. These results challenge holistic accounts of the face inversion effect and support an alternative interpretation. First, in line with previous findings, they indicate that perceptual decrements when viewing upside-down faces result from impoverished descriptions of local regions, not the loss of whole-face processing. Second, when interpreting inverted faces, access to the wider face context appears to be far more important than currently believed. PMID- 28803220 TI - Deaths following pentavalent vaccine and the revised AEFI classification. PMID- 28803221 TI - Reflective student narratives: honing professionalism and empathy. AB - The affective domain is not explicitly targeted during medical studies and poor skills in this domain may lead to conflict when dealing with patients. Reflective narratives are said to promote humanitarianism and professional development. We aimed to examine reflective narratives written by medical students in our institution for content relating to ethical and professional Attitude and Behaviour, Communication, respect for Diversity and Disability, and Empathy (the ABCDE paradigm). We were also interested in understanding how far the students enjoyed learning through the writing of narratives and in determining their perceived learning from the exercise. Volunteer medical students were introduced to Gibbs' reflective cycle during a half-day workshop. After giving written informed consent, they submitted anonymous reflective narratives (online), based on an interaction that they witnessed between a patient and a doctor/student. The authors performed directed content analysis of the submissions, using predetermined codes pertaining to ABCDE. At the end of the study, the participants sent in their feedback through a questionnaire on the process and the learning acquired, if any. Twenty-six students volunteered and 15 narratives were submitted. The issues that had been identified were discussed with the students. Feedback was submitted by 12 students, who strongly felt that the writing of narratives enhanced learning about ethics, professionalism, communication, diversity and empathy. We conclude that reflective student narratives are a useful and enjoyable way of teaching students about issues in the affective domain that are not conventionally taught. PMID- 28803222 TI - Biobanking in the subcontinent: exploring concerns. AB - Biobanking is an important tool for biomedical research. However, it raises a variety of ethical issues, which are compounded in the developing world. This paper is based on data from three sources on the ethical issues associated with biobanking, including a mixed method pilot study conducted with students in Karachi, Pakistan, a workshop in Karachi, and another workshop held in Bengaluru, India. Findings from these sources reveal a unanimous lack of clarity about what constitutes a biobank. While informed consent was deemed necessary for storage of materials, participants were unsure of how this could be achieved for samples stored indefinitely for future research. Although study participants showed limited understanding of genetic research, concerns were raised in the Karachi workshop. A majority of survey participants found it acceptable to transfer biospecimens across borders, but possibility of misuse was highlighted in both workshops. This paper reveals ambiguities with respect to ethical challenges of biobanking, indicating the need for further discourse. PMID- 28803223 TI - Social responsibilities of a physician: reflections of Major General S L Bhatia (1891-1981). AB - This paper examines various documents written by Major General SL Bhatia CIE, MC, IMS from the 1920s to the1960s on the "Social Responsibilities of a Physician". His reflections are of historical significance, since they provide us with an insight into the challenges confronting the people who attempted to rebuild a nation plagued by poverty resulting from fractured agricultural growth, a feudalistic social structure and the regional inequalities that accompany it, and prolonged imperial rule, among other things. Bhatia's thoughts, especially on medical education and the condition of rural health and sanitation, enable us to understand India's present health concerns through the prism of the past. The writings of Bhatia, who lived during a period of transition in India, reflect an understanding of health issues from the perspectives both of an administrator and a physician struggling to meet the challenges of a nascent nation. He insisted on rooting his medical teachings in the principles of the humanities and ethics. PMID- 28803224 TI - Broadening the argument on limb lengthening. PMID- 28803225 TI - Carboxylesterase 1A2 encoding gene with increased transcription and potential rapid drug metabolism in Asian populations. AB - The carboxylesterase 1 gene (CES1) encodes a hydrolase implicated in the metabolism of commonly used drugs. CES1A2, a hybrid of CES1 and a CES1-like pseudogene, has a promoter that is weak in most individuals. However, some individuals harbor a promoter haplotype of this gene with two overlapping Sp1 sites that confer significantly increased transcription potentially leading to rapid drug metabolism. This CES1A2 haplotype has previously been reported to be common among Asians. Using polymerase chain reaction followed by sequencing, the present study examined variation in the promoter and 5' untranslated region of CES1A2 in 120 Han Chinese and 120 Japanese people enrolled in the 1000 Genomes Project. We identified 11 single nucleotide variations, two of which were novel, in 145 of the individuals who were found to carry CES1A2. Alignment analysis indicated that the CES1A2 haplotype with the overlapping Sp1 sites has been generated by incorporation of a segment of CES1. All minor allele frequencies were equal to or below 0.022 and the frequencies of the minor haplotypes were up to 40-fold lower than previously reported, including that of the haplotype with the overlapping Sp1 sites. This information is novel and suggests that the pharmacogenetic relevance of CES1A2 is limited in Asians. PMID- 28803226 TI - Nursing Students' and Faculty Members' Experiences of Comfort during Transition to Context-Based Learning. AB - There is evidence supporting student-centered learning (SCL) as an effective pedagogy to prepare professionals to work in the evolving health care system of the twenty-first century. SCL has many benefits, among them that it helps students to learn to work in teams and develop problem-solving, critical thinking and communication skills. The focus on the student means that the teacher's power is decreased. This, along with openness of the approach, can make the transition to SCL a challenge. This study used an exploratory descriptive qualitative design to explore how comfortable nursing students and faculty members were in a context based learning (CBL) program, a version of SCL. Nursing students and faculty discussed common challenges of trusting the CBL process. They also discussed the emphasis on self-directed learning and how it could mean that tutors are not as involved with students. To enhance a smooth transition, recommendations have been made, including clarifying the CBL philosophy at orientation, and mentoring and reassuring students. PMID- 28803227 TI - Perspectives from Academic Leaders of the Nursing Faculty Shortage in Canada. AB - There is a world-wide shortage of nursing faculty, which is complicated by the need for French, English, and bilingual professors in Canada. The purpose of this qualitative study was to explore the current status and effects of the nursing faculty shortage on Canadian Schools of Nursing (SON) from a leadership perspective. We conducted semi-structured interviews with 12 Deans and Directors of Canadian Schools of Nursing. The participants spoke about the faculty shortage in terms of demand, supply, and strategies employed. The participants were concerned about the ramifications of some of the decisions deemed necessary for continued viability of their programs, such as over-assigning teaching workloads. In light of mass upcoming retirements, shortening the time to completion for PhD studies and making graduate education more accessible are important priorities. PMID- 28803228 TI - Utility of routine urine CMV PCR and total serum IgM testing of small for gestational age infants: a single center review. AB - BACKGROUND: Due to the extremely low incidence of TORCH (toxoplasmosis, rubella, CMV, herpes simplex virus) infections, diagnostic testing of all small for gestational age (SGA) infants aimed at TORCH etiologies may incur unnecessary tests and cost. OBJECTIVE: To determine the frequency of urine CMV PCR and total IgM testing among infants with birth weight <10% and the rate of test positivity. To evaluate the frequency of alternative etiologies of SGA in tested infants. METHODS: Retrospective chart review of SGA infants admitted to the neonatal intensive care unit (NICU) at NYU Langone Medical Center between 2007 and 2012. Subjects were classified as being SGA with or without intrauterine growth restriction (IUGR). The IUGR subjects were then further categorized as having either symmetric or asymmetric IUGR utilizing the Fenton growth chart at birth. Initial testing for TORCH infections, which included serum total IgM, CMV PCR and head ultrasound, were reviewed and analyzed. RESULTS: Three hundred and eighty six (13%) infants from a total of 2953 NICU admissions had a birth weight <=10th percentile. Of these, 44% were IUGR; 34% being symmetric IUGR and 10% asymmetric. A total of 32% of SGA infants had urine CMV PCR and total IgM tested with no positive results. As expected, significantly higher percentage of symmetric IUGR infants were tested compared to asymmetric IUGR and non-IUGR SGA infants, (64% vs. 47% vs. 19%) P<=0.01. However, 63% of infants with a known cause for IUGR had same testing done aimed at TORCH infections. We calculated additional charges of $64,065 that were incurred by such testing. CONCLUSIONS: The majority of infants in our study who received testing for urine CMV PCR and total IgM aimed at TORCH infections had one or more other known non-infectious etiologies for IUGR. Because the overall yield of such testing is extremely low, we suggest tests for possible TORCH infections may be limited to symmetric IUGR infants without other known etiologies. Improved guidelines testing for TORCH infections can result in reducing hospital charges and unnecessary studies. PMID- 28803229 TI - Non-Motor Symptoms Assessed by Non-Motor Symptoms Questionnaire and Non-Motor Symptoms Scale in Parkinson's Disease in Selected Asian Populations. AB - BACKGROUND: Ethnic variations have been described in medical conditions, such as hypertension, diabetes, and multiple sclerosis. Whether ethnicity plays a role in Parkinson's disease (PD), particularly with regard to non-motor symptoms (NMS), remains unclear. Existing literature is diverse, controversial, and inadequately documented. This review aims to analyse and report the currently available literature on NMS, specifically in Asian PD patients. SUMMARY: We conducted a literature review using PubMed, searching for articles and currently available publications that reference and assess NMS in PD patients living in Asia using the validated NMS Questionnaire (NMS Quest) and NMS Scale (NMSS). In total, 24 articles were included: 12 using the NMS Quest and 12 using the NMSS. Symptoms of constipation, memory impairment, and nocturia were the most frequently self reported symptoms (NMS Quest) in selected Asian populations, while symptoms within the domains sleep/fatigue, attention/memory, and mood/apathy were most prevalent when applying the health-professional completed NMSS. Key Messages: NMS are generally prevalent and highly burdensome within selected Asian PD populations living in countries included in this review. Our review suggests that NMS-driven phenotypic heterogeneity is present in Asian patients, and compared to Western PD populations there might be variations in assessed NMS. PMID- 28803230 TI - Revised Reference Values for Potassium Intake. AB - BACKGROUND: The nutrition societies of Germany, Austria and Switzerland have revised the reference values for potassium intake in January 2017. METHODS: For adults, the estimated value was based on the 24-h urinary potassium excretion and on preventive considerations regarding hypertension and stroke. The estimated values for children and adolescents were extrapolated from the adult estimated value considering differences in body mass. For infants aged 0 to under 4 months, the estimated value was set based on the potassium intake via breast milk. From this reference value, the estimated value for infants aged 4 to under 12 months was also derived by extrapolation. The estimated value for lactating women takes into account the potassium loss via breast milk. RESULTS: The estimated values for potassium intake are set at 400 mg/day for breastfed infants aged 0 to under 4 months, 600 mg/day for infants aged 4 to under 12 months, 1,100-4,000 mg/day for children and adolescents, 4,000 mg/day for adults and pregnant women and 4,400 mg/day for lactating women. CONCLUSIONS: The consumption of potassium-rich foods should be generally increased. Supplemental intake beyond the estimated values has no health benefit and is therefore not recommended. PMID- 28803231 TI - In Potential Stroke Patients on Warfarin, the International Normalized Ratio Predicts Ischemia. AB - BACKGROUND: Stroke can occur in patients on warfarin despite anticoagulation. Patients with a low international normalized ratio (INR) should theoretically be at greater risk for ischemia than those who are therapeutic. Therefore, INR may be able to indicate whether new neurological deficits are more likely strokes or stroke mimics in patients on warfarin. This study evaluates the association and predictive value of INR in determining the likelihood of ischemia. METHODS: Patients were identified using the acute stroke registry at a Primary Stroke Center from January 2013 through December 2014. All adult patients undergoing evaluation for acute stroke with prior documented use of warfarin and an INR level at presentation were included. Data were collected regarding patient demographics, medical comorbidities, stroke severity, reason for anticoagulation, and laboratory studies including INR. Student t tests and chi2 analysis were used to evaluate factors associated with increased likelihood of ischemia (stroke or transient ischemic attack) versus mimic. Significant results were entered into a multivariable regression analysis. Sensitivity and specificity analyses were conducted to determine the predictive value of INR for ischemic risk. RESULTS: 116 patients were included; 46 were diagnosed with ischemia, 70 were diagnosed as mimics. 75% of patients were on warfarin for atrial fibrillation versus 25% for venous thrombosis. A statistically significant difference in mean INR for patients with ischemia (n = 46) versus mimics (n = 70) was observed (1.7 vs. 2.8; p < 0.001). In multivariable analysis, both sub-therapeutic INR (p < 0.001) and atrial fibrillation (p = 0.014) were predictors of ischemia. In patients with an INR >=2, the predictive value of having a non-ischemic etiology was 79%. No patient with an INR of >=3.6 was found to have ischemia. CONCLUSIONS: Sub therapeutic INR and atrial fibrillation are strongly associated with ischemia in patients on warfarin presenting with acute neurologic symptoms. Ischemia is far less likely in patients with an INR of >=2 and rare in those with an INR >=3.6. This study shows that the INR value of a patient on warfarin can help stratify patients' risk for acute ischemic stroke and guide further neurologic imaging and workup. PMID- 28803232 TI - Digestive System Mixed Neuroendocrine-Non-Neuroendocrine Neoplasms. AB - Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) are a heterogeneous subgroup of rare neoplasms that represent about a third of all poorly differentiated neuroendocrine carcinomas (PDNEC). MiNEN combine a neuroendocrine component, usually a PDNEC, and a non-neuroendocrine component, generally an adenocarcinoma, both accounting for at least 30% of the neoplasm. MiNEN are classified as high-, intermediate-, or low-grade malignancies depending on the metastatic potential of the tumour components. High-grade malignant component should be considered even if it represents <30% of the tumour. The prognosis of MiNEN is generally intermediate between those of the two "pure" components composing it. The aim of this comprehensive review of the literature is to suggest a standardized management of MiNEN. An increasing body of evidence suggests that PDNEC components share molecular abnormalities with their adenocarcinoma counterparts, but also display additional alterations. This advocates for a common origin, and that the presence of a PDNEC component in an adenocarcinoma could indicate a turning point in carcinogenesis. PMID- 28803233 TI - Comprehensive Analysis of the Chemical Composition and In Vitro Cytotoxic Mechanisms of Pallines Spinosa Flower and Leaf Essential Oils Against Breast Cancer Cells. AB - BACKGROUND/AIMS: In our quest for new natural anticancer agents, we studied the cytotoxicity of the essential oils extracted from flowers and leaves of Pallines spinosa. METHODS: The essential oils were extracted by hydrodistillation and solid phase microextraction (SPME) from flowers and leaves of the plant and their composition was determined by GC/GC-MS. The cytotoxicity of the oils was evaluated against MCF-7 and MDA-MB-231 breast adenocarcinomas, and the non cancerous MCF-10-2A cells, using a flow cytometry-based assay Apoptosis was evaluated by flow cytometry, nuclear staining, caspases activation, and Western blotting techniques, and cell cycle by measuring DNA contents. RESULTS: The hydrodistilled flower oil contained mainly sesquiterpenes (96.39%), while the leaf sample was dominated by oxygenated-sesquiterpenes (51.60%) and sesquiterpene hydrocarbons (34.06%). In contrast, the SPME oil contained mainly monoterpene hydrocarbons (44.09%) and sesquiterpene-hydrocarbons (34.15%) in the flower and leaf samples, respectively. The cytotoxicity of the flower oil against MCF-7 (IC50 0.25 +/- 0.03 ug/mL) and MDA-MB-231 (IC50 0.21 +/- 0.03 ug/mL) was much stronger than the leaf oil (IC50 2.4 +/- 0.5 ug/mL and 1.5 +/- 0.1 ug/mL, respectively). The toxicity of the flower oil was ~5 to 8-times less in normal MCF-10-2A (IC50 1.3 +/- 0.2 ug/mL) and blood mononuclear cells (2.80 +/- 0.45 ug/mL) as compared to breast and hematological cancer cells, respectively. Both oils induced a caspase-dependent and -independent apoptosis in MCF-7 and MDA-MB 231 cells, and altered the levels of Bcl-2 and Bax proteins. In addition, the oils arrested cell cycle in both cancer cell lines at G0/G1 phase by modulating the expression of cyclin D1, CDK4 and p21 proteins. CONCLUSION: The cytotoxicity of P. spinosa oils were mediated by apoptosis and cell cycle arrest, suggesting the potential use of their bioactive compounds as natural anticancer compounds. PMID- 28803234 TI - RNA Sequencing and Bioinformatics Analysis Implicate the Regulatory Role of a Long Noncoding RNA-mRNA Network in Hepatic Stellate Cell Activation. AB - BACKGROUND/AIMS: To analyze the long noncoding (lncRNA)-mRNA expression network and potential roles in rat hepatic stellate cells (HSCs) during activation. METHODS: LncRNA expression was analyzed in quiescent and culture-activated HSCs by RNA sequencing, and differentially expressed lncRNAs verified by quantitative reverse transcription polymerase chain reaction (qRT-PCR) were subjected to bioinformatics analysis. In vivo analyses of differential lncRNA-mRNA expression were performed on a rat model of liver fibrosis. RESULTS: We identified upregulation of 12 lncRNAs and 155 mRNAs and downregulation of 12 lncRNAs and 374 mRNAs in activated HSCs. Additionally, we identified the differential expression of upregulated lncRNAs (NONRATT012636.2, NONRATT016788.2, and NONRATT021402.2) and downregulated lncRNAs (NONRATT007863.2, NONRATT019720.2, and NONRATT024061.2) in activated HSCs relative to levels observed in quiescent HSCs, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that changes in lncRNAs associated with HSC activation revealed 11 significantly enriched pathways according to their predicted targets. Moreover, based on the predicted co-expression network, the relative dynamic levels of NONRATT013819.2 and lysyl oxidase (Lox) were compared during HSC activation both in vitro and in vivo. Our results confirmed the upregulation of lncRNA NONRATT013819.2 and Lox mRNA associated with the extracellular matrix (ECM)-related signaling pathway in HSCs and fibrotic livers. CONCLUSION: Our results detailing a dysregulated lncRNA mRNA network might provide new treatment strategies for hepatic fibrosis based on findings indicating potentially critical roles for NONRATT013819.2 and Lox in ECM remodeling during HSC activation. PMID- 28803235 TI - 18F-FDG Uptake in Well-Differentiated Neuroendocrine Tumors Correlates with Both Ki-67 and VHL Pathway Inactivation. AB - BACKGROUND: 18F-FDG-PET scan positivity correlates with poor prognosis in neuroendocrine neoplasms (NEN). Glucose transporter 1 (GLUT1) and carbonic anhydrase 9 (CA9) are markers of aggressiveness in tumors. Together with von Hippel-Lindau protein (pVHL), they are involved in tumor cell metabolism via the hypoxia-inducible factor signaling pathway. The aim of this study was to compare, in a series of well-differentiated neuroendocrine tumors (NET), the 18F-FDG uptake and expression of the proliferation markers Ki-67, GLUT1, CA9, and pVHL. PATIENTS AND METHODS: This retrospective study included 27 patients with well differentiated NET. 18F-FDG-PET images were evaluated by the maximum standardized uptake value (SUVmax). GLUT1, CA9, and pVHL were analyzed by immunohistochemistry. RESULTS: The NET were of pancreatic (n = 19), midgut (n = 4), duodenal (n = 1), esophageal (n = 1), rectal (n = 1), and pulmonary (n = 1) origin. Eight, 11, and 8 tumors were grade 1, 2, and 3, respectively. The mean/median Ki-67 index was 15/10% (1-60). The mean/median SUVmax was 6.2/5.2 (1.4-18.7). SUVmax correlated with greater tumor size (p = 0.03), higher expression of Ki-67 (p = 0.04), and lower expression of pVHL (p = 0.008). In the group of 16 NET with a low proliferative index (Ki-67 index <10%), 5/6 (83%) of the tumors with a high SUVmax had decreased pVHL expression (p = 0.0013). CONCLUSION: This study confirms that 18F-FDG-PET uptake correlates with both tumor size and proliferation in well-differentiated NET, and it highlights a subset of low-grade but 18F-FDG-PET-positive NET related to sporadic inactivation of the VHL pathway. PMID- 28803236 TI - Enhancement of Bone Healing by Local Administration of Carbon Nanotubes Functionalized with Sodium Hyaluronate in Rat Tibiae. AB - It has been reported that carbon nanotubes (CNTs) serve as nucleation sites for the deposition of bone matrix and cell proliferation. Here, we evaluated the effects of multi-walled CNTs (MWCNTs) on bone repair of rat tibiae. Furthermore, because sodium hyaluronate (HY) accelerates bone restoration, we associated CNTs with HY (HY-MWCNTs) in an attempt to boost bone repair. The bone defect was created by a 1.6-mm-diameter drill. After 7 and 14 days, tibiae were processed for histological and morphometric analyses. Immunohistochemistry was used to evaluate the expression of vascular endothelial growth factor (VEGF) in bone defects. Expression of osteocalcin (OCN), bone morphogenetic protein-2 (BMP-2), and collagen I (Col I) was assessed by real-time PCR. Histomorphometric analysis showed a similar increase in the percentage of bone trabeculae in tibia bone defects treated with HY and HY-MWCNTs, and both groups presented more organized and thicker bone trabeculae than nontreated defects. Tibiae treated with MWCNTs or HY- MWCNTs showed a higher expression of VEGF. Treatment with MWCNTs or HY MWCNTs increased the expression of molecules involved in the bone repair process, such as OCN and BMP-2. Also, HY- and MWCNT-treated tibiae had an increased expression of Col I. Thus, it is tempting to conclude that CNTs associated or not with other materials such as HY emerged as a promising biomaterial for bone tissue engineering. PMID- 28803237 TI - ATF3-Dependent Regulation of EGR1 in vitro and in vivo. AB - BACKGROUND/AIMS: Activating transcription factor 3 (ATF3) and early growth response protein 1 (EGR1) are reported to interact, but their use as prognostic factors in cancer is discussed controversially. METHODS: We measured ATF3 and EGR1 gene expression changes in human mini-organ cultures (MOCs) of healthy nasal epithelia, UM-SCC-22B, and FADUDD cells after acid reflux exposure. Next, ATF3 and EGR1 gene expression was analysed in tumour tissues and related to the median expression of autologous reference tissue samples. RESULTS: ATF3 and EGR1 mRNA expression was significantly reduced after consecutive exposure of MOCs at pH <7.0 to artificial gastric juice (refluxate). In contrast, ATF3 mRNA was upregulated significantly within the first hour of incubation. EGR1 mRNA exhibited no significant changes. The analysed cell lines exhibited a cell line specific alteration. In FADUDD cells, the upregulation of EGR1 was significant after refluxate exposure, but in HN-SCC 22B, no significant changes were detected. The analysis of the HNSCC samples confirmed the heterogeneous data of the literature. CONCLUSION: The data maintain the hypothesis that ATF3 and EGR1 are involved in the beginning of inflammatory processes. Whether these two transcription factors act as tumour suppressors or promoters is context dependent and warrants analysis in further studies. PMID- 28803238 TI - The Contribution of Anthroposophic Medicine to Self-Management: An Exploration of Concepts, Evidence, and Patient Perspectives. AB - BACKGROUND: In Western healthcare policies, promotion of self-management of patients is an important topic. Currently, there is also a worldwide interest in the integration of complementary and alternative medicine (CAM) and conventional medicine into integrative medicine. This article explores the contribution of anthroposophic medicine (AM) to the promotion of self-management of patients. MATERIAL AND METHODS: The scientific literature on concepts of, evidence on and experiences of patients with AM was explored. RESULTS: The AM approach contributes to: (1) a patient-centered, collaborative promotion of patient self management by means of application of basic values (equivalence, servitude, and presence of mind) and specific methods; (2) a better coping with health-related issues by providing a spiritual worldview that serves as a coping strategy; by treating patients in such a way that they (further) develop self-regulating functioning, both on the physiological and the psychosocial level, thus enabling the self-management of disease-related symptoms; and by treating with (non verbal) therapies that improve emotion-focused coping skills; and (3) a better self-monitoring of: one's own activity during treatment and in dealing with treatment- and health-related issues, and the physiological and/or psychological responses to these (self-reflection) activities. CONCLUSION: AM provides specific contributions to promoting self-management of patients. PMID- 28803239 TI - Therapeutic Effect of 0.1% Tacrolimus Eye Drops in the Tarsal Form of Vernal Keratoconjunctivitis. AB - OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of 0.1% tacrolimus eye drops in the tarsal form of vernal keratoconjunctivitis (VKC) and to survey the changes of dendritic cells at the palpebral conjunctiva in patients with VKC by in vivo confocal microscopy. METHODS: A total of 17 patients (34 eyes) with the tarsal form of VKC were enrolled in this prospective, nonrandomized case series. They were treated with 0.1% tacrolimus eye drops twice daily after discontinuation of all other topical medications. Subjective ocular symptoms and objective ocular signs were scored on a 4-point scale by one ophthalmologist and the characteristics of the dendritic cells in each right eye at the palpebral conjunctiva were evaluated by in vivo confocal microscopy before treatment and at the 1st, 2th, 4th, and 8th weeks after treatment. RESULTS: After 1 week of treatment with 0.1% tacrolimus eye drops, the score for each symptom in all patients showed a significant (p < 0.001) improvement, and 13 patients (76%) experienced dramatic relief of symptoms. In addition, there was a significantly (p < 0.001) decreased clinical sign score (except for giant papillae) after 4 weeks, and a significant (p < 0.001) improvement in the score of giant papillae after 8 weeks of treatment. The characteristics of dendritic cells (including cell count, total area, average size, perimeter, and diameter) showed a significant (p < 0.05) decrease after 2 weeks of treatment. During the follow-up, no other topical medications were required and no significant changes in visual acuity were documented. No cataracts or elevation of intraocular pressures were detected. Only 5 patients (29%) had a tingling or burning sensation or discomfort. CONCLUSIONS: Tacrolimus 0.1% eye drops are an effective and safe treatment for the tarsal form of VKC, and can rapidly inhibit the activity of dendritic cells, improve symptoms, reduce papillary hyperplasia, and reverse damage at the palpebral conjunctiva. The side effects could affect the compliance of some patients. PMID- 28803240 TI - Impact of Body Site, Age, and Gender on the Collagen/Elastin Index by Noninvasive in vivo Vertical Two-Photon Microscopy. AB - BACKGROUND/AIMS: Extrinsic and intrinsic skin aging is subject to constant remodeling and degradation processes, primarily in components of the extracellular matrix. While collagen fibers thin out during the aging process, the amorphous elastin fibers accumulate. These are essential formative components of the dermis. So far, these processes have been detected in vertical histological sections of invasive biopsies and recently in noninvasive horizontal scans. METHODS: In this pilot study, a modified noninvasive 2-photon microscope was applied to measure the collagen/elastin index of skin in vivo. The obtained images permit an immediate vertical survey and allow a conclusion on the dermal composition at once. The collagen/elastin index was quantified by the second harmonic to autofluorescence aging index of dermis (SAAID) depending on volunteers' age (18-66 years), gender, and body area. RESULTS: The highest SAAID was measured at the volar forearm as compared to the abdominal SAAID, which was significantly lower (p < 0.05). The gluteal region showed the significantly lowest SAAID (p < 0.05). The SAAID in female skin was higher compared to male skin and decreased with increasing age. CONCLUSION: These effects are to be considered in subsequent studies to be able to specifically detect and evaluate influences. PMID- 28803241 TI - Gender-Specific Aspects in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation: A Single-Center Experience. AB - OBJECTIVE: Limited data exist on gender-specific aspects in hematologic malignancies and have been obtained mostly in non-Hodgkin lymphomas. The objective of this study was to investigate gender-specific aspects in patients with multiple myeloma (MM) undergoing autologous stem cell transplantation (ASCT). METHODS: A retrospective data analysis of 191 patients with MM who underwent ASCT was performed. Data collected from clinical records included age, sex, stage, induction therapy, outcome of induction, kind of stem cell mobilization, response to induction therapy and ASCT, cytogenetic aberrations, progression-free survival, and overall survival. RESULTS: Eighty-one patients (42%) were female, whereas 110 patients were male (58%). No differences between female and male patients could be observed according to the international staging system (ISS) (e.g. , ISS III: 14.8 vs. 17.3%), type of paraprotein, and cytogenetic aberrations (e.g., Del(13q): 32.7 vs. 28.9%). Five-year overall survival rates, when calculated from time to ASCT until death, were 27.2 and 36.4% and, when calculated from time to diagnosis until death, were 34.6 and 44.5%, respectively, and did not differ between groups according to ISS subgroups. CONCLUSION: Prognosis and baseline characteristics were identical and no differences could be observed between female and male patients with MM undergoing ASCT. PMID- 28803242 TI - Laterality of Grooming and Tool Use in a Group of Captive Bonobos (Pan paniscus). AB - Humans exhibit population level handedness for the right hand; however, the evolution of this behavioral phenotype is poorly understood. Here, we compared the laterality of a simple task (grooming) and a complex task (tool use) to investigate whether increasing task difficulty elicited individual hand preference among a group of captive bonobos (Pan paniscus). Subjects were 17 bonobos housed at the Columbus Zoo and Aquarium. Laterality of grooming was recorded using group scans; tool use was recorded using all-occurrence sampling. Grooming was characterized as unimanual or bimanual, and both tasks were scored as right-handed or left-handed. Most individuals did not exhibit significant hand preference for unimanual or bimanual (asymmetrical hand use) grooming, although 1 individual was lateralized for each. For the 8 subjects who engaged in termite fishing enough for statistical testing, 7 individuals exhibited significant laterality and strong individual hand preference. Four subjects preferred their left hand, 3 preferred their right, and 1 had no preference. Grooming, a simple behavior, was not lateralized in this group, yet a more complex behavior revealed a strong individual hand preference, and these results are congruent with other recent findings that demonstrate complex tasks elicit hand preference in bonobos. PMID- 28803244 TI - How to Become an Agent of One's Own Healing Processes: Self-Management for Chronically Ill Patients in Integrative Health Care. PMID- 28803243 TI - Lithium Sensitivity of Store Operated Ca2+ Entry and Survival of Fibroblasts Isolated from Chorea-Acanthocytosis Patients. AB - BACKGROUND: The widely expressed protein chorein fosters activation of the phosphoinositide 3 kinase (PI3K) pathway thus supporting cell survival. Loss of function mutations of the chorein encoding gene VPS13A (vacuolar protein sorting associated protein 13A) causes chorea-acanthocytosis (ChAc), a neurodegenerative disorder paralleled by deformations of erythrocytes. In mice, genetic knockout of chorein leads to enhanced neuronal apoptosis. PI3K dependent signalling upregulates Orai1, a pore forming channel protein accomplishing store operated Ca2+ entry (SOCE). Increased Orai1 expression and SOCE have been shown to confer survival of tumor cells. SOCE could be up-regulated by lithium. The present study explored, whether SOCE and/or apoptosis are altered in ChAc fibroblasts and could be modified by lithium treatment. METHODS: Fibroblasts were isolated from ChAc patients and age-matched healthy volunteers. Cytosolic Ca2+ activity ([Ca2+]i) was estimated from Fura-2-fluorescence, SOCE from increase of [Ca2+]i following Ca2+ re-addition after Ca2+-store depletion with sarcoendoplasmatic Ca2+-ATPase (SERCA) inhibitor thapsigargin (1 uM), and apoptosis from annexin-V/propidium iodide staining quantified in flow cytometry. RESULTS: SOCE was significantly smaller in ChAc fibroblasts than in control fibroblasts. Lithium (2 mM, 24 hours) significantly increased and Orai1 blocker 2-Aminoethoxydiphenyl Borate (2-APB, 50 uM, 24 hours) significantly decreased SOCE. Annexin-V-binding and propidium iodide staining were significantly higher in ChAc fibroblasts than in control fibroblasts. In ChAc fibroblasts annexin-V-binding and propidium iodide staining were significantly decreased by lithium treatment, significantly increased by 2 APB and virtually lithium insensitive in the presence of 2-APB. CONCLUSIONS: In ChAc fibroblasts, downregulation of SOCE contributes to enhanced susceptibility to apoptosis. Both, decreased SOCE and enhanced apoptosis of ChAc fibroblasts can be reversed by lithium treatment. PMID- 28803245 TI - MiR-143-5p Deficiency Triggers EMT and Metastasis by Targeting HIF-1alpha in Gallbladder Cancer. AB - BACKGROUND/AIMS: Early metastasis plays a pivotal role in tumor-caused death in gallbladder cancer (GBC) patients. Increasing evidence suggest that miR-143-5p is an active player involved in cancer metastasis and a potential therapeutic target. However, its role in the development of GBC cells remains unclear. The aim of this study is to reveal the inhibiting effects of miR-143-5p on the proliferation and metastasis in GBC. METHODS: Quantitative real-time PCR were used to investigate miR-143-5p and its target HIF-1alpha mRNA levels. Protein expression was measured by immunohistochemistry and western blot. The function and regulation mechanism of miR-143-5p was confirmed by MTS, colony formation, wound healing, transwell, and luciferase reporter assays. RESULTS: miR-143-5p was first found significantly reduced in GBC tissues compared with corresponding noncancerous gallbladder tissues. In addition, miR-143-5p deficiency correlated well with larger tumor size, advanced TNM stage, and poorer survival rate. In vitro, miR-143-5p addition dramatically suppressed GBC cells proliferation, migration and invasion, whereas miR-143-5p antisense led the opposite effects. Further elucidating the molecular mechanism inside, we found miR-143-5p exerted its inhibitory function through downregulating the expression of HIF-1alpha, which further reduced Twist1 and impeded epithelial-mesenchymal transition (EMT). CONCLUSIONS: Altogether, our studies identified a novel regulator, miR-143-5p, implicated in GBC prognosis through targeting HIF-1alpha/EMT related signaling pathway, which could serve as a biomarker and therapeutic target for GBC. PMID- 28803246 TI - Biofunctional Ionic-Doped Calcium Phosphates: Silk Fibroin Composites for Bone Tissue Engineering Scaffolding. AB - The treatment and regeneration of bone defects caused by traumatism or diseases have not been completely addressed by current therapies. Lately, advanced tools and technologies have been successfully developed for bone tissue regeneration. Functional scaffolding materials such as biopolymers and bioresorbable fillers have gained particular attention, owing to their ability to promote cell adhesion, proliferation, and extracellular matrix production, which promote new bone growth. Here, we present novel biofunctional scaffolds for bone regeneration composed of silk fibroin (SF) and beta-tricalcium phosphate (beta-TCP) and incorporating Sr, Zn, and Mn, which were successfully developed using salt leaching followed by a freeze-drying technique. The scaffolds presented a suitable pore size, porosity, and high interconnectivity, adequate for promoting cell attachment and proliferation. The degradation behavior and compressive mechanical strengths showed that SF/ionic-doped TCP scaffolds exhibit improved characteristics for bone tissue engineering when compared with SF scaffolds alone. The in vitro bioactivity assays using a simulated body fluid showed the growth of an apatite layer. Furthermore, in vitro assays using human adipose derived stem cells presented different effects on cell proliferation/differentiation when varying the doping agents in the biofunctional scaffolds. The incorporation of Zn into the scaffolds led to improved proliferation, while the Sr- and Mn-doped scaffolds presented higher osteogenic potential as demonstrated by DNA quantification and alkaline phosphatase activity. The combination of Sr with Zn led to an influence on cell proliferation and osteogenesis when compared with single ions. Our results indicate that biofunctional ionic-doped composite scaffolds are good candidates for further in vivo studies on bone tissue regeneration. PMID- 28803247 TI - Potential Gender-Related Aging Processes Occur Earlier and Faster in the Vermis of Patients with Bipolar Disorder: An MRI Study. AB - BACKGROUND: In the last decades, there has been increasing interest in investigating the role of the vermis in bipolar disorder (BD), especially because of its involvement in cognitive processes. The main aims of this study were to explore the integrity of the vermis and elucidate the role of demographic and clinical variables on vermis volumes in BD patients, stratified according to gender. METHODS: T1-weighted images were obtained for 38 BD patients and 38 healthy controls using a 1.5-T MRI scanner. Images were analyzed with a PC workstation with BRAINS2 software on a Linux system. Anatomical regions were traced manually from a blinded operator, with respect to subject identity and other clinical variables. RESULTS: The direct comparison between the 2 groups showed no significant gray matter differences in vermis volumes. Interestingly, vermis volumes were significantly inversely associated with chronological age and age of BD onset, particularly in male subjects. CONCLUSIONS: Our study provides evidence of the impact of aging on the vermis in BD, potentially related to earlier and faster gender-related neurodegenerative phenomena occurring during the progression of the disease. PMID- 28803248 TI - A Functional Assay for Sick Sinus Syndrome Genetic Variants. AB - BACKGROUND/AIMS: Congenital Sick Sinus Syndrome (SSS) is a disorder associated with sudden cardiac death due to severe bradycardia and prolonged pauses. Mutations in HCN4, the gene encoding inward Na+/K+ current (If), have been described as a cause of congenital SSS. The objective of this study is to develop an SSS model in embryonic zebrafish, and use zebrafish as a moderate-throughput assay to functionally characterize HCN4 variants. METHODS: To determine the function of hcn4 in zebrafish, embryos were either bathed in the If -specific blocker (ZD-7288), or endogenous hcn4 expression was knocked down using splice blocking morpholinos. To assess whether the zebrafish model discriminates benign from pathogenic variants, we tested four HCN4 mutations known to cause human SSS and four variants of unknown significance (VUS). RESULTS: Pharmacological blockade and knockdown of hcn4 in zebrafish phenocopied human SSS, displaying bradycardia and cardiac pauses in intact embryos and explanted hearts. The zebrafish assay correctly identified all disease-causing variants. Of the VUS, the assay predicted 2 as benign and 2 as hypomorphic variants. CONCLUSIONS: We conclude that our embryonic zebrafish assay is a novel and effective tool to functionally characterize human HCN4 variants, which can be translated into important clinical prognostic information. PMID- 28803249 TI - A Brief Outline of the Use of New Technologies for Treating Substance Use Disorders in the European Union. AB - BACKGROUND: Clinicians in the field of drug addiction have started to exploit the growth of Technology-Based Interventions (TBIs). However, there is little information on how health personnel evaluate them. METHODS: Semi-structured interviews were conducted among 20 European experts. RESULTS: All of the interviewees recognised TBIs as a valuable tool to improve the management of substance-use disorders (SUDs). Most interviewees indicated that combining both traditional face-to-face therapist-patient clinic appointment with TBIs is probably the most effective method. Most interviewees agree that TBIs are valuable tools to overcome both physical and social barriers, and hence significantly facilitate the access to treatment. Poor infrastructure and lack of digital literacy are recognised as major barriers to the diffusion of these tools. CONCLUSIONS: The application of various forms of technology in SUD treatment is an interesting development for the European Union. Technical and non technical barriers exist and impede their full exploitation. PMID- 28803250 TI - Optical Coherence Tomography Angiography in Children with Leber-Coats Disease. AB - INTRODUCTION: The aim of this work was to describe the optical coherence tomography (OCT) angiography (OCTA) features in paediatric Leber-Coats disease. METHODS: Three children presenting with unilateral, clinically active Leber-Coats disease were evaluated using spectral domain OCT and OCTA. OCT angiograms were analysed and compared with the current literature. RESULTS: All 3 OCT angiograms showed that the vessels had lost most of their collateral branches and presented many loops. The capillaries were rarefied and anomalies in vessel size, vasodilatation, and macroaneurysms were evident. CONCLUSION: This is the first case series of OCTA performed in children with Leber-Coats disease. OCTA is a non invasive and non-contact technique, which can be considered of fundamental importance for the diagnosis, clinical management, and follow-up of the disease. PMID- 28803251 TI - Epidemiological Study of Huntington's Disease in the Province of Ferrara, Italy. AB - BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the abnormal expansion of CAG triplet repeat. We aimed to reappraise HD epidemiology in a northern Italian population, in relation to introduction of genetic testing. METHODS: Through ICD-9M code 333.4 and medical fare exemption code RF0080, HD cases were identified from administrative health data and medical records from the Units of Neurology and Genetics, Ferrara University Hospital, and from other provincial neurological structures. RESULTS: HD mean annual incidence rate in 1990-2009 was 0.3 per 100,000 (95% CI 0.2-0.5). All incident cases were found to have symptoms of the disease's classic form, and neither juvenile nor the rigid Westphal variant was detected. The mean (SD) age at onset was 50.2 (12.7 years; range 32-82 years), 54.9 (14.6) for men and 45.8 (9.4) for women. On prevalence day, December 31, 2014, HD prevalence was 4.2 per 100,000 (95% CI 2.4-7.0), with a male:female ratio of 1:2. CONCLUSIONS: The prevalence and incidence of HD in our population were lower than the prevalence and incidence reported for other European and Italian populations, but higher compared to those of Asia, Africa, and Eastern Europe. Compared to previous studies, HD incidence and prevalence did not change significantly. PMID- 28803252 TI - Two-Dimensional Echocardiography Estimates of Fetal Ventricular Mass throughout Gestation. AB - BACKGROUND: Two-dimensional (2D) ultrasound quality has improved in recent years. Quantification of cardiac dimensions is important to screen and monitor certain fetal conditions. We assessed the feasibility and reproducibility of fetal ventricular measures using 2D echocardiography, reported normal ranges in our cohort, and compared estimates to other modalities. METHODS: Mass and end diastolic volume were estimated by manual contouring in the four-chamber view using TomTec Image Arena 4.6 in end diastole. Nomograms were created from smoothed centiles of measures, constructed using fractional polynomials after log transformation. The results were compared to those of previous studies using other modalities. RESULTS: A total of 294 scans from 146 fetuses from 15+0 to 41+6 weeks of gestation were included. Seven percent of scans were unanalysable and intraobserver variability was good (intraclass correlation coefficients for left and right ventricular mass 0.97 [0.87-0.99] and 0.99 [0.95-1.0], respectively). Mass and volume increased exponentially, showing good agreement with 3D mass estimates up to 28 weeks of gestation, after which our measurements were in better agreement with neonatal cardiac magnetic resonance imaging. There was good agreement with 4D volume estimates for the left ventricle. CONCLUSION: Current state-of-the-art 2D echocardiography platforms provide accurate, feasible, and reproducible fetal ventricular measures across gestation, and in certain circumstances may be the modality of choice. PMID- 28803253 TI - Assessing Serum Levels of ADAMTS1 and ADAMTS4 as New Biomarkers for Patients with Type A Acute Aortic Dissection. AB - BACKGROUND Type A AAD, a serious cardiovascular emergency requiring urgent surgery, is the most common and serious AAD. The aim of this study was to investigate the diagnostic value of ADAMTS1 and ADAMTS4 in patients with type A acute aortic dissection (AAD). MATERIAL AND METHODS Immunohistochemistry and qRT PCR were used to evaluate the protein and mRNA expression levels of ADAMTS1 and ADAMTS4 in 14 type A acute aortic dissection (AAD) tissues and 10 control aortic tissues. Serum ADAMTS1 and ADAMTS4 expression levels in 74 patients with type A AAD, 36 patients with hypertension (HPT), and 34 healthy donors were examined by ELISA. The diagnostic value of serum ADAMTS1 and ADAMTS4 were determined by receiver operator characteristic curve (ROC). Furthermore, the dynamic change of serum ADAMTS1, ADAMTS4, D-dimer, and CRP were detected before and after surgery at different time-points in 14 patients with type A AAD. RESULTS ADAMTS1 and ADAMTS4 protein and mRNA expression levels were found to be significantly higher in 14 type A AAD tissues (p<0.0001) compared with 10 control tissues. Serum ADAMTS1 and ADAMTS4 levels were significant higher in patients with type A AAD than those in the HPT and HD group (p<0.0001 for both). The AUC value, sensitivity, and specificity of ADAMTS1 were 0.9710 (95% CI: 0.9429 to 0.9991), 87.84%, and 97.06%, respectively, and those of ADAMTS4 were 0.9893 (95% CI: 0.9765 to 1.002), 94.59%, and 97.06%, respectively. In addition, serum ADAMTS4 level was gradually decreased with the time extension after surgery, similar to D dimer change. CONCLUSIONS These data suggest that measurement of serum ADAMTS1 and ADAMTS4 levels could be potential diagnostic biomarkers for type A AAD, and ADAMTS4 might be a risk factor associated with type A AAD. PMID- 28803254 TI - Helicobacter pylori cytotoxin-associated gene A impairs the filtration barrier function of podocytes via p38 MAPK signaling pathway. AB - Helicobacter pylori (Hp) specific antigens were found deposited in the glomeruli in some kidney diseases. However, the underlying molecular mechanisms remain to be elucidated. The aim of this study was to investigate the effect of cytotoxin associated gene A protein (CagA), a key virulence factor of Hp, on mouse podocytes. Cells were cultured and treated with recombinant CagA protein. The expression of the tight junction protein ZO-1 and p38 MAPK signaling pathway activation were measured with real-time RT-PCR and western blotting. The filtration barrier function of podocytes was evaluated with albumin influx assay. CagA decreased the expression and membrane distribution of ZO-1, impaired the filtration barrier function of podocytes, while activating p38 MAPK signaling pathway in these cells. Selective p38 MAPK inhibition partly prevented CagA induced filtration barrier dysfunction of podocytes through ameliorating ZO-1 downregulation. Taken together, the results suggested that CagA, at least via p38 MAPK signaling pathway, may induce podocyte injury. Anti-Hp therapy may be beneficial for the treatment of kidney diseases related to Hp antigen deposition. PMID- 28803255 TI - Panel of serum metabolites discriminates cancer patients and healthy participants of lung cancer screening - a pilot study. AB - INTRODUCTION: Blood biomarkers may support early diagnosis of lung cancer by enabling pre-selection of candidates for computed tomography screening or discrimination between benign and malignant screening-detected nodules. We aimed to identify features of serum metabolome distinguishing individuals with early detected lung cancer from healthy participants of the lung cancer screening program. METHODS: Blood samples were collected in the course of a low-dose computed tomography screening program performed in the Gdansk district (Northern Poland). The analysis included 31 patients with screening-detected lung cancer and the pair-matched group of 92 healthy controls. The gas chromatography coupled to mass spectrometry (GC/MS) approach was used to identify and quantify small metabolites present in serum. RESULTS: There were several metabolites detected in the sera whose abundances discriminated patients with lung cancer from controls. Majority of the differentiating components were downregulated in cancer samples, including amino acids, carboxylic acids and tocopherols, whereas benzaldehyde was the only compound significantly upregulated. A classifier including nine serum metabolites allowed separation of cancer and control samples with 100% sensitivity and 95% specificity. CONCLUSIONS: Signature of serum metabolites discriminating between cancer patients and healthy participants of the early lung cancer screening program was identified using a GC/MS metabolomics approach. This signature, though not validated in an independent dataset, deserves further investigation in a larger cohort study. PMID- 28803256 TI - Surface structure changes of pathological placenta tissue observed using scanning electron microscopy - a pilot study. AB - Structural changes within the placenta are observed in the course of pathological pregnancy. The aim of the study was to perform initial assessment of morphological features of placenta. The analysis was conducted by Scanning Electron Microscopy. Samples of placenta of women who delivered neonates appropriate for gestational age were characterized by a homogenous surface texture with natural corrugation. The surface of IUGR placenta from the group of mothers with pregnancy induced hypertension was definitely heterogeneous - noticeable swelling of tissue surface was observed. Samples from LGA group also demonstrated a number of surface bulges and heterogeneities which were, nonetheless, characterized by a certain repeatability. PMID- 28803257 TI - Synthesis and biological evaluation of 4'-O-acetyl-isoxanthohumol and its analogues as antioxidant and antiproliferative agents. AB - Isoxanthohumol (2) and its 4'-O-monoacylated (3) and 7,4'-O-diacetylated (4) derivatives were synthesized and evaluated in vitro for their cytotoxic activity against several cancer cell lines of various origins: MCF-7 (breast), A549 (lung), MESSA (uterine sarcoma), LoVo (colon), drug-resistant human cancer cells (MESSA/DX and LoVo/DX), glioblastoma (U-118 MG), and also towards the non cancerous cell line MCF-10A (normal breast cells). An antiproliferative assay indicates that 7,4'-di-O-acylisoxanthohumol (4) has similar cytotoxicity to its precursor, isoxanthohumol (2), against selected cell lines (A549, MES-SA, MES SA/5DX, and U-118 MG). Compound 4 was only slightly more cytotoxic to lung, colon, breast (cancerous and normal) and uterine sarcoma (drug sensitive and drug resistant) cell lines compared to its monoacylated derivative (3). Both acylated isoxanthohumols showed preferential activity against tumor cells (MCF-7) and low cytotoxicity to normal cells (MCF-10A), which suggests selectivity of the acylated isoxanthohumols towards cancer cells. Additionally, the activity of the acylated isoxanthohumols was higher than for 2. To the best of our knowledge this is the first report on bioactivity of monoacylated isoxanthohumol (3) and its ester derivatives as antiproliferative compounds in drug resistant cell cultures. Acylation of 2 decreased the antioxidant activity determined by the DPPH method in the order isoxanthohumol (2) >4'-O-acetylisoxanthohumol (3) >7,4'-di-O acetylisoxanthohumol (4). PMID- 28803258 TI - The impact of antimicrobial prophylaxis in morbidity and infections during azacitidine treatment. AB - The clinical consequences of the infectious events in patients receiving azacitidine are poorly documented. Likewise, the role of primary antimicrobial prophylaxis is unknown. In this retrospective, single-center study, we compare the impact of prophylaxis on the incidence of infection and morbidity in all consecutive higher-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients, during the first 4 azacitidine cycles. Seventy-six patients, corresponding to 283 azacitidine cycles, were studied. There were infectious events in 43% of the patients. Development of infections led to more hospital admissions, increased red blood cells and platelet requirements, and a delay in subsequent cycles. Median overall survival was comparable between patients with or without infections. In the multivariate analysis, a neutrophil count below 0.5 * 109/L (OR 12.5 [2.6-50]) and antimicrobial prophylaxis (OR 0.1 [0.02-04]) were independent factors for the development of infection. We conclude that infectious events have a significant impact in the early clinical course of azacitidine treated patients by increasing hospital admissions and transfusion requirements. Antimicrobial prophylaxis may prevent infections, leading to a decreased need for supportive care in these patients with poor outcome. PMID- 28803259 TI - Opportunities and challenges in the immunological therapy of pediatric malignancy: a concise snapshot. AB - Over the last 50 years, collaborative clinical trials have reduced the number of children dying from pediatric cancer significantly. Unfortunately, certain tumor types have remained resistant to conventional surgical, radiotherapy and chemotherapy combinations, and relapsing and/or refractory disease remains associated with dismal outcomes. Recently, renewed attention has been given to the role for immunotherapies in pediatric oncology. In fact, these combine several attractive features, including (but possibly not limited to) the specificity for cancer cells, potentially in vivo persistence and longevity, and potency against refractory disease. In this narrative review designed for the academic pediatrician, we will concisely review the biological underpinnings behind the immunological therapy of pediatric neoplasms and illustrate the current humoral, cellular approaches, and novel drugs targeting the immune checkpoint, oncolytic viruses, and tumor vaccines. We will also comment on the future directions, challenges, and open questions faced by the field. What is Known: * Cancer immunotherapy drives immune cells and its humoral weaponry to eliminate tumor cells. * This occurs by recognizing antigens ideally expressed only on tumoral, but not normal/healthy, cells. What is New: * Clinical immunotherapy trials have shown responses in children with relapsing/refractory neoplasms. * Novel humoral/cellular immunotherapies, immune checkpoint inhibitors, oncolytic viruses, and tumor vaccines are currently being investigated in pediatric oncology. PMID- 28803260 TI - Microbial volatile compounds alter the soil microbial community. AB - Volatile organic compounds (VOCs) from soil bacteria are likely to have an important role in the interactions among soil microorganisms. However, their effects on the soil microbial community have not been extensively studied. In this study, the effect of bacterial VOCs generated by growing Bacillus amyloliquefaciens NJN-6 on modified MS medium on soil microbial community was evaluated. B. amyloliquefaciens NJN-6 was able to produce 48 volatile compounds as determined by solid-phase microextraction-GC/MS. MiSeq sequencing data showed that bacterial VOCs could alter the composition of both soil bacterial and soil fungal communities and could decrease the alpha-diversity of the soil microbial community. Taxonomic analysis revealed that bacterial VOCs significantly increased the relative abundance of Proteobacteria, Bacteroidetes, and Firmicutes. Moreover, bacterial VOCs significantly increased the relative abundance of Ascomycota. The qPCR data showed that bacterial VOCs of strain NJN-6 decreased the soil fungal biomass and increased the soil bacterial biomass. Further evaluation of the effect of bacterial VOCs on functional genes revealed that VOCs could reduce the copies of nifH, nirS, and a gene encoding nonribosomal peptide synthase, while increasing the copy number of the ammonium-oxidizing bacteria gene. The effect on gene encoding polyketide synthase was insignificant. Results from this study indicated that bacterial VOCs could influence the soil microbial community as well as functional gene abundance. PMID- 28803261 TI - Advantages in Prognosis of Adult Patients with Ewing Sarcoma: 11-years Experiences and Current Treatment Management. AB - Ewing sarcoma (ES) is an exceptionally rare tumor in adults. Data regarding outcomes of adult patients with ES and experiences with age-adapted therapeutic strategies are very limited. The aim of this study was to evaluate prognostic factors and clinical outcome in a cohort of adult patients treated according to pediatric protocols in the Czech Republic. The records of 58 adult ES patients diagnosed between 2002 and 2013 were reviewed and factors relevant to prognosis and survival were analyzed. The median age of study cohort was 29 years (range, 18-59). The most frequent location was axial (36.2%), followed by involvement of extraskeletal tissues (34.5%) and bones of the extremities (29.3%). Twenty-eight (48.3%) patients had metastatic disease. In cases with localized ES, the 5-year overall survival (OS) was 76.5%. Using the log-rank test, the presence of metastasis at diagnosis, local treatment without surgery and a failure to achieve complete remission were associated with significantly shorter survival. In a multivariate Cox proportional hazard analysis, the achievement of complete remission was an independent predictor of patients's survival time. Outcomes of adults with localized ES treated according to multimodal pediatric protocols are similar to children. The achievement of complete remission is an independent predictor of survival time in ES patients. Severe hematological toxicity is foreseeable and manageable. Prognosis of patients with metastases or progression remains dismal. PMID- 28803262 TI - Topic anaesthesia with a eutectic mixture of lidocaine/prilocaine cream after elective caesarean section: a randomised, placebo-controlled trial. AB - PURPOSE: Aim of the study was to investigate the topical application of a eutectic mixture of lidocaine/prilocaine (EMLA(r)) cream after caesarean section (CS) and its effect on postoperative pain, time to mobilisation, and time to discharge. MATERIALS AND METHODS: A total of 189 pregnant women were enrolled; full data sets were available for 139 of them, who were prospectively randomised to receive either placebo (control group) or EMLA(r) cream (study group) on the CS lesion directly as well as 24 h after surgery. Postoperative pain was assessed 24 and 48 h after surgery using the short form of the McGill Pain Questionnaire (SF-MPQ). Additional analgesic pain medication on demand was assessed in both groups. RESULTS: A total of 62 women were allocated randomly to the study and 77 patients to the control group before primary CS. There were no statistically significant differences regarding demographic and surgical parameters comparing both collectives. In addition, the postoperative total pain scores after 24 h [McGill total: 38.5 (0-102) vs. 50 (0-120) p = 0.0889] as well as after 48 h [24 (0-79) vs. 30.5 (0-92); p = 0.1455] showed no significant differences. Furthermore, time to mobilisation (hours) [9.68 (2.18-51.38) vs. 9.47 (4.18 41.77); p = 0.5919] and time to discharge (hours) [98.6 (54.08-170.15) vs. 98.2 (43.45-195.87); p = 0.5331] were comparable. CONCLUSION: The postoperative application of EMLA(r) cream after CS did not reduce postoperative pain or time to mobilisation or discharge, so that its use in this context has to be seen critically. PMID- 28803263 TI - Carotenoids from the extreme halophilic archaeon Haloterrigena turkmenica: identification and antioxidant activity. AB - Haloterrigena turkmenica was able to synthesize carotenoids when grown in halobacteria medium. These molecules have antioxidant properties and find application in food, cosmetic, and pharmaceutical fields. The carotenoids were extracted with methanol, separated by RP-HPLC, and identified by mass spectrometry and UV/Vis spectra analyses. The C50 carotenoids were the main pigments, and C30, C40, and C51 carotenoids were also detected. Seven geometric isomers were distinguished for bacterioruberin, monoanhydrobacterioruberin, and bisanhydrobacterioruberin. The assignment to a specific isomer was tentatively attempted through the analysis of the corresponding UV/Vis spectrum, the intensity of the cis peak, and its spectral fine structure. Lycopene, phytoene, and lycopersene were among the minor carotenoids further identified. The extract displayed antioxidant power higher than alpha-tocopherol, butylhydroxytoluene, and ascorbic acid used as reference compounds. Our studies identified for the first time seven geometric isomers of bacterioruberin derivatives and 30 carotenoids in a haloarchaeon. PMID- 28803264 TI - Hyaluronan in the experimental injury of the cartilage: biochemical action and protective effects. AB - INTRODUCTION: Our knowledge of extracellular matrix (ECM) structure and function has increased enormously over the last decade or so. There is evidence demonstrating that ECM provides signals affecting cell adhesion, shape, migration, proliferation, survival, and differentiation. ECM presents many domains that become active after proteolytic cleavage. These active ECM fragments are called matrikines which play different roles; in particular, they may act as potent inflammatory mediators during cartilage injury. FINDINGS: A major component of the ECM that undergoes dynamic regulation during cartilage damage and inflammation is the non-sulphated glycosaminoglycan (GAG) hyaluronan (HA). In this contest, HA is the most studied because of its different activity due to the different polymerization state. In vivo evidences have shown that low molecular weight HA exerts pro-inflammatory action, while high molecular weight HA possesses anti-inflammatory properties. Therefore, the beneficial HA effects on arthritis are not only limited to its viscosity and lubricant action on the joints, but it is especially due to a specific and effective anti-inflammatory activity. Several in vitro experimental investigations demonstrated that HA treatment may regulate different biochemical pathways involved during the cartilage damage. Emerging reports are suggesting that the ability to recognize receptors both for the HA degraded fragments, whether for the high-polymerized native HA involve interaction with integrins, toll-like receptors (TLRs), and the cluster determinant (CD44). The activation of these receptors induced by small HA fragments, via the nuclear factor kappa-light-chain enhancer of activated B cell (NF-kB) mediation, directly or other different pathways, produces the transcription of a large number of damaging intermediates that lead to cartilage erosion. CONCLUSIONS: This review briefly summarizes a number of findings of the recent studies focused on the protective effects of HA, at the different polymerization states, on experimental arthritis in vitro both in animal and human cultured chondrocytes. PMID- 28803265 TI - Measuring the end-of-life premium in cancer using individual ex ante willingness to pay. AB - For the assessment of value of new therapies in healthcare, Health Technology Assessment (HTA) agencies often review the cost per quality-adjusted life-year (QALY) gained. Some HTA agencies accept a higher cost per QALY gained when treatment is aimed at prolonging survival for patients with a short expected remaining lifetime, a so-called end-of-life (EoL) premium. The objective of this study is to elicit the existence and size of an EoL premium in cancer. Data was collected from 509 individuals in the Swedish general population 20-80 years old using a web-based questionnaire. Preferences were elicited using subjective risk estimation and the contingent valuation (CV) method. A split-sample design was applied to test for order bias. The mean value of a QALY was MSEK4.8 (?528,000), and there was an EoL premium of 4-10% at 6 months of expected remaining lifetime. Using subjective risk resulted in more robust and valid estimates of the value of a QALY. Order of scenarios did not have a significant impact on the WTP and the result showed scale sensitivity. Our result provides some support for the use of an EoL premium based on individual preferences when expected remaining lifetime is short and below 24 months. Furthermore, we find support for a value of a QALY that is above the current threshold of several HTA agencies. PMID- 28803266 TI - A Degradome-Based Polymerase Chain Reaction to Resolve the Potential of Environmental Samples for 2,4-Dichlorophenol Biodegradation. AB - A clean way to overcome environmental pollution is biodegradation. In this perspective, at the intersection of biodegradation and metagenomics, the degradome is defined as the totality of genes related to the biodegradation of a certain compound. It includes the genetic elements from both culturable and uncultured microorganisms. The possibility of assessing the biodegradation potential of an environmental samples, using a degradome-based polymerase chain reaction, was explored. 2,4-Dichlorophenol (2,4-DCP) was chosen as a model and the use of tfdB gene as a biodegradation marker was confirmed by bioinformatics study of TfdB protein. Five primer pairs were designed for the detection of different tfdB gene families. A total of 16 environmental samples were collected from Egyptian agricultural soils and wastewaters and tested for the presence of 2,4-DCP. The biodegradation capacity of 2,4-DCP was determined, for all isolated consortia, to reach up to 350 mg/l. Metagenomic DNA was extracted directly from the soil samples while successive 2,4-DCP-degrading microbial communities were enriched, with increasing concentrations of 2,4-DCP, then their DNA was extracted. The extracted DNA was tested for the distribution of the tfdB gene using a degradome-based polymerase chain reaction. tfdB-1 and tfdB-2 were detected in 5 and 9 samples, respectively. However, the co-existence of both genes was detected only in five samples. All tfdB positive samples were capable of 2,4-DCP degradation. The developed approach of assessing the potential of different environments for degrading 2,4-DCP was successfully measured in terms of accuracy (81.25%) and specificity (100%). PMID- 28803267 TI - Feasibility and response to nedaplatin monotherapy in older patients with ovarian cancer. AB - PURPOSE: Nedaplatin (NDP), a second-generation platinum analog, has been developed to reduce the toxicity of cisplatin. Although the use of NDP for older patients seems suitable because of the reduced risk of toxicity, few studies have investigated its application to older patients with ovarian cancer (OC). The objective of this study was to compare the tolerability and effectiveness of NDP between patients older and younger than 70 years of age with OC. METHODS: We enrolled 56 patients with OC who were treated with NDP monotherapy and divided them into those who were 70 years and older (n = 18) and younger than 70 years (n = 38). NDP was administered intravenously until disease progression or unacceptable toxicities occurred. RESULTS: The incidences of grade 3/4 hematological toxicities were significantly higher in the older patients than in the younger patients, including anemia (p = 0.0021), leucopenia (p = 0.029), neutropenia (p = 0.0048), and thrombocytopenia (p = 0.0024). The incidence of elevated creatinine was also significantly higher in the older patients (p = 0.0063). Older patients had significantly more frequent dose reductions (p = 0.017) and treatment interruptions from toxicity (p = 0.04). The tumor response rate for NDP did not differ significantly between younger (29%) and older (28%) patients (p = 0.47). The two age groups also did not significantly differ in progression-free survival (p = 0.27) and overall survival (p = 0.46). CONCLUSIONS: Although NDP is a useful therapeutic option for OC, careful consideration of the adverse effect should be given for patients 70 years and older. PMID- 28803268 TI - Proteomic profiling of the dystrophin complex and membrane fraction from dystrophic mdx muscle reveals decreases in the cytolinker desmoglein and increases in the extracellular matrix stabilizers biglycan and fibronectin. AB - The almost complete loss of the membrane cytoskeletal protein dystrophin and concomitant drastic reduction in dystrophin-associated glycoproteins are the underlying mechanisms of the highly progressive neuromuscular disorder Duchenne muscular dystrophy. In order to identify new potential binding partners of dystrophin or proteins in close proximity to the sarcolemmal dystrophin complex, proteomic profiling of the isolated dystrophin-glycoprotein complex was carried out. Subcellular membrane fractionation and detergent solubilisation, in combination with ion exchange, lectin chromatography and density gradient ultracentrifugation, was performed to isolate a dystrophin complex-enriched fraction. Following gradient gel electrophoresis and on-membrane digestion, the protein constituents of the dystrophin fraction were determined by peptide mass spectrometry. This proteomic strategy resulted in the novel identification of desmoglein and desmoplakin, which act as cytolinker proteins and possibly exist in close proximity to the dystrophin complex in the sarcolemma membrane. Interestingly, comparative immunoblotting showed a significant reduction in desmoglein in dystrophin-deficient mdx skeletal muscles, reminiscent of the pathobiochemical fate of the dystrophin-associated core proteins in muscular dystrophy. Comparative membrane proteomics was used to correlate this novel finding to large-scale changes in the dystrophic phenotype. A drastic increase in the extracellular stabilizers biglycan and fibronectin was shown by both mass spectrometric analysis and immunoblotting. The reduced expression of desmoglein in dystrophin-deficient skeletal muscles, and simultaneous increase in components of the extracellular matrix, suggest that muscular dystrophy is associated with plasmalemmal disintegration, loss of cellular linkage and reactive myofibrosis. PMID- 28803269 TI - The Callosal Relay Model of Interhemispheric Communication: New Evidence from Effective Connectivity Analysis. AB - Interhemispheric auditory connectivity via the corpus callosum has been demonstrated to be important for normal speech processing. According to the callosal relay model, directed information flow from the right to the left auditory cortex has been suggested, but this has not yet been proven. For this purpose, 33 healthy participants were investigated with 64-channel EEG while performing the dichotic listening task in which two different consonant-vowel syllables were presented simultaneously to the left (LE) and right ear (RE). eLORETA source estimation was used to investigate the functional (lagged phase synchronization/LPS) and effective (isolated effective coherence/ICoh) connectivity between right and left primary (PAC) and secondary auditory cortices (SAC) in the gamma-band (30-100 Hz) during right and left ear reports. The major finding was a significantly increased effective connectivity in the gamma-band from the right to the left SAC during conscious perception of LE stimuli. In addition, effective and functional connectivity was significantly enhanced during LE as compared to RE reports. These findings give novel insight into transcallosal information transfer during auditory perception by showing that LE performance requires causal interhemispheric inputs from the right to the left auditory cortices, and that this interaction is mediated by synchronized gamma band oscillations. PMID- 28803271 TI - Brain biopsies requiring Creutzfeldt-Jakob disease precautions in the Republic of Ireland 2005-2016. AB - AIMS: Creutzfeldt-Jakob disease (CJD) risk precautions are required when performing brain biopsies on patients with a dementing illness and in 'risk' groups. The impact on a diagnostic neuropathology service is considerable. We sought to determine if better case selection might reduce the necessity for application of CJD risk precautions. METHODS: We reviewed the clinical information, contributory investigations and final neuropathologic diagnosis in a cohort of patients (n = 21), referred to the National CJD Surveillance Centre between January 1, 2005, and December 31, 2016. RESULTS: Of this 21-patient cohort, five were positive for CJD, four belonged to the 'at risk of CJD' category requiring brain surgery, while the remaining 12 were referred to the National CJD Surveillance Unit with CJD as part of their differential diagnosis. CJD was confirmed in 5/21 (three sporadic [s]CJD, one variant [v]CJD and one iatrogenic [i] CJD). CJD was clinically probable in 4/5 proven CJD patients (80%). The patients (n = 4) in the 'at risk of CJD' group were diagnosed with tumour (n = 2), inflammation (n = 1) and non-specific changes (n = 1). Of the remaining 12 patients (in whom CJD was included in the differential diagnosis), the final neuropathologic diagnoses included tumour (n = 2), neurodegenerative (n = 2), inflammatory (n = 1), metabolic (n = 2), vascular (n = 2) and non-specific gliosis (n = 3). CONCLUSIONS: More often than not, the clinical suspicion of CJD was not borne out by the final neuropathological diagnosis. Failure by clinicians to adhere to the recommended CJD investigation algorithm impacts adversely on the neuropathology workload and causes unnecessary concern among operating theatre, laboratory and nursing personnel. PMID- 28803270 TI - Costs of vitamin D testing and prescribing among children in primary care. AB - : Vitamin D has attracted considerable interest in recent years, with a marked increase in diagnosis of vitamin D deficiency seen among children in clinical practice in the UK. The economic implications of this change in diagnostic behaviour have not been explored. We performed a cohort study to examine longitudinal trends in healthcare expenditure arising from vitamin D testing and prescribing for children in primary care in England, using the electronic healthcare records of 722,525 children aged 0-17 years held in The Health Improvement Network database. Combined costs of vitamin D tests and prescriptions increased from L1647 per 100,000 person-years in 2008 (95% CI, L934 to L3007) to L28,913 per 100,000 person-years in 2014 (95% CI, L26,361 to L31,739). The total cost of vitamin D prescriptions and tests for children in primary care at the national level in England in 2014 was estimated to be L4.31 million (95% CI, L2.96-L6.48 million). CONCLUSION: There has been a marked increase in healthcare expenditure on vitamin D tests and prescriptions for children in primary care over the past decade. Future research should explore the drivers for this change in diagnostic behaviour and the reasons prompting investigation of vitamin D status in clinical practice. What is Known: * Vitamin D deficiency has attracted considerable interest in recent years, with a marked increase in diagnosis seen in children. * The economic implications of this change in diagnostic behaviour have not been explored. What is New: * There has been a large increase in healthcare expenditure on vitamin D tests and prescriptions for children in primary care in England over the past decade (> 15 fold between 2008 and 2013). * Screening of vitamin D status in children without specific risk factors or clinical features of deficiency may represent avoidable healthcare expenditure. PMID- 28803272 TI - Inpatient Monitoring of Decompensated Heart Failure: What Is Needed? AB - PURPOSE OF REVIEW: Acute decompensated heart failure is a serious and common condition where close monitoring of symptoms, vital signs, haemodynamic and other markers are needed after the patient is admitted to hospital as the in-hospital outcome is poor. This review focuses on advances in the assessment and monitoring of these patients. RECENT FINDINGS: The adoption of the CHAMP acronym to identify precipitating factors and of the classification using wet-warm, wet-cold, dry warm and dry-cold categories is an improvement regarding assessment. Although the outcome of acute decompensated heart failure has remained poor with no new treatments found for a number of years, a structured approach to assessment and monitoring is now available. PMID- 28803274 TI - ? PMID- 28803275 TI - ? PMID- 28803273 TI - Transport and transformation of mercury during wet flue gas cleaning process of nonferrous metal smelting. AB - Reducing mercury emission is hot topic for international society. The first step for controlling mercury in fuel gas is to investigate mercury distribution and during the flue gas treatment process. The mercury transport and transformation in wet flue gas cleaning process of nonferrous smelting industry was studied in the paper with critical important parameters, such as the solution temperature, Hg0 concentration, SO2 concentration, and Hg2+ concentration at the laboratory scale. The mass ratio of the mercury distribution in the solution, flue gas, sludge, and acid fog from the simulated flue gas containing Hg2+ and Hg0 was 49.12~65.54, 18.34~35.42, 11.89~14.47, and 1.74~3.54%, respectively. The primary mercury species in the flue gas and acid fog were gaseous Hg0 and dissolved Hg2+. The mercury species in the cleaning solution were dissolved Hg2+ and colloidal mercury, which accounted for 56.56 and 7.34% of the total mercury, respectively. Various mercury compounds, including Hg2Cl2, HgS, HgCl2, HgSO4, and HgO, existed in the sludge. These results for mercury distribution and speciation are highly useful in understanding mercury transport and transformation during the wet flue gas cleaning process. This research is conducive for controlling mercury emissions from nonferrous smelting flue gas and by-products. PMID- 28803276 TI - ? PMID- 28803277 TI - ? PMID- 28803278 TI - ? PMID- 28803279 TI - ? PMID- 28803281 TI - ? PMID- 28803280 TI - ? PMID- 28803282 TI - ? PMID- 28803283 TI - ? PMID- 28803284 TI - ? PMID- 28803285 TI - ? PMID- 28803286 TI - ? PMID- 28803288 TI - ? PMID- 28803287 TI - ? PMID- 28803289 TI - ? PMID- 28803290 TI - ? PMID- 28803291 TI - ? PMID- 28803292 TI - ? PMID- 28803293 TI - [COPD - Smoking cessation is the most important therapy]. PMID- 28803294 TI - [Barbecue burns]. PMID- 28803295 TI - ? PMID- 28803296 TI - ? PMID- 28803297 TI - ? PMID- 28803298 TI - ? PMID- 28803299 TI - ? PMID- 28803300 TI - ? PMID- 28803301 TI - ? PMID- 28803302 TI - ? PMID- 28803303 TI - ? PMID- 28803304 TI - ? PMID- 28803305 TI - ? PMID- 28803306 TI - ? PMID- 28803307 TI - ? PMID- 28803308 TI - ? PMID- 28803310 TI - ? PMID- 28803309 TI - ? PMID- 28803311 TI - ? PMID- 28803312 TI - ? PMID- 28803313 TI - ? PMID- 28803314 TI - ? PMID- 28803315 TI - ? PMID- 28803316 TI - ? PMID- 28803317 TI - ? PMID- 28803319 TI - ? PMID- 28803320 TI - ? PMID- 28803321 TI - ? PMID- 28803322 TI - ? PMID- 28803323 TI - Effect of footshock stress on place conditioning produced by Delta9 tetrahydrocannabinol and the fatty acid amide hydrolase (FAAH) inhibitor, URB597, in Sprague-Dawley rats. AB - RATIONALE: Unlike other drugs of abuse, Delta9-tetrahydrocanabinol (THC) is generally aversive in rodent conditioned place preference models, but little is known about how stress may modify THC affective properties. OBJECTIVE: We evaluate the potential of footshock stress to enhance the rewarding effects of THC and the fatty acid amide hydrolase inhibitor, URB597, as it has been shown to enhance their anxiolytic effects. MATERIALS AND METHODS: The effect of footshock stress 24 h prior to each conditioning trial on the rewarding/aversive effects of THC (1, 0.1, 0.5 mg/kg, ip) and URB597 (0.3 mg/kg, ip) was evaluated in an unbiased place conditioning procedure in rats. Subsequently, the same stressor was given immediately prior to conditioning with THC (1 and 0.1 mg/kg). Locomotor activity was also measured during conditioning. RESULTS: A dose of 1 mg/kg THC, but not 0.1-0.5 mg/kg, produced a conditioned place aversion (CPA) that was not modified by footshock delivered 24 h prior to conditioning trials; however, footshock delivered immediately prior to conditioning trials prevented that CPA. Lower doses of THC and URB597 produced no place conditioning regardless of footshock conditions. A dose of 1 mg/kg THC produced locomotor suppression during conditioning trials that was prevented by footshock delivered 24 h before and reversed to locomotor activation by footshock delivered immediately before conditioning. CONCLUSIONS: Unlike the effect of footshock on THC- and URB597 induced anxiolytic effects, footshock does not promote THC or URB597-induced reward in a conditioned place preference paradigm. However, footshock stress reverses the sedative effects of 1 mg/kg THC. PMID- 28803324 TI - Decreased serum L-arginine and L-citrulline levels in major depression. AB - RATIONALE: It has been suggested that endothelial dysfunction caused by a decreased endothelial production of nitric oxide (NO) may contribute to the consistently observed increased risk of developing cardiovascular disease (CVD) in physically healthy patients suffering from major depression (MD). NO is a gas synthesized from Larginine (a conditionally essential amino acid) and oxygen by endothelial nitric oxide synthase (eNOS). The end products of NO production include both NO and L-citrulline. NO is rapidly reduced to the anions nitrite and nitrate, classically referred to as NO metabolites. Their measurement has been used as a surrogate measurement for endothelial NO production. We and others have shown decreased levels of NO metabolites in the serum of MD patients. The mechanism of this decreased production of NO by the endothelium has not yet been elucidated. OBJECTIVES: The purpose of this study is to assess serum levels of L arginine and L-citrulline in patients with MD. METHODS: Levels of L-arginine and L-citrulline were measured in 35 unmedicated physically healthy MD patients and 36 healthy controls (HCs). RESULTS: L-arginine and L-citrulline concentrations were significantly lower in MD patients than in healthy controls (L-arginine, 73.54 + 21.53 MUmol/L and 84.89 + 25.16, p = 0.04 MUmol/L and L-citrulline 31.58 + 6.05 MUmol/L and 35.19 + 6.85 MUmol/L, p = 0.03, respectively). CONCLUSIONS: The decrease in L-arginine levels in MD patients is a possible explanation for the decrease in NO metabolites in MD patients and therefore may contribute, through endothelial dysfunction, to the increased CV risk associated with MD. PMID- 28803325 TI - An endoplasmic reticulum-localized Coffea arabica BURP domain-containing protein affects the response of transgenic Arabidopsis plants to diverse abiotic stresses. AB - KEY MESSAGE: The Coffea arabica BURP domain-containing gene plays an important role in the response of transgenic Arabidopsis plants to abiotic stresses via regulating the level of diverse proteins. Although the functions of plant specific BURP domain-containing proteins (BDP) have been determined for a few plants, their roles in the growth, development, and stress responses of most plant species, including coffee plant (Coffea arabica), are largely unknown. In this study, the function of a C. arabica BDP, designated CaBDP1, was investigated in transgenic Arabidopsis plants. The expression of CaBDP1 was highly modulated in coffee plants subjected to drought, cold, salt, or ABA. Confocal analysis of CaBDP1-GFP fusion proteins revealed that CaBDP1 is localized in the endoplasmic reticulum. The ectopic expression of CaBDP1 in Arabidopsis resulted in delayed germination of the transgenic plants under abiotic stress and in the presence of ABA. Cotyledon greening and seedling growth of the transgenic plants were inhibited in the presence of ABA due to the upregulation of ABA signaling-related genes like ABI3, ABI4, and ABI5. Proteome analysis revealed that the levels of several proteins are modulated in CaBDP1-expressing transgenic plants. The results of this study underscore the importance of BURP domain proteins in plant responses to diverse abiotic stresses. PMID- 28803326 TI - Short-term results of endovascular surgery with tissue plasminogen activator injection for central retinal vein occlusion. AB - PURPOSE: To examine the effects of retinal endovascular surgery (REVS) with tissue plasminogen activator injection into the retinal vein in central retinal vein occlusion (CRVO) eyes. METHODS: Sixteen consecutive CRVO patients with macular edema and decreased visual acuity who were referred to Toyama University Hospital between March 2014 and February 2016 were included in this study. Changes in visual acuity (VA) and central retinal thickness (CRT) were evaluated up to 6 months after REVS. Staining and leakage of the retinal veins in fluorescein angiography (FA) was graded in nine patients. RESULTS: Ten of 16 eyes were determined to be non-ischemic while the remaining six were ischemic. The mean logarithm of the minimum angle of resolution (logMAR) of VA was significantly improved from 0.98 +/- 0.58 (mean +/- standard deviation) at baseline to 0.78 +/- 0.61 at 3 months (p = 0.002), and 0.64 +/- 0.60 at 6 months (p = 0.003) after REVS. At 6 months, VA was improved in eight eyes (50%), while the other eight (50%) showed no change; none showed worsening. In the 10 eyes with non-ischemic CRVO, the mean VA was significantly improved at 6 months (p = 0.002), whereas no improvement was found in the six eyes with ischemic CRVO, . In all eyes, the mean CRT was significantly improved from 804 +/- 343 MUm at baseline to 506 +/- 304 MUm at 2 months (p = 0.014), 332 +/- 229 MUm at 3 months (p = 0.0001), and 305 +/- 235 MUm at 6 months (p = 0.00001). The postoperative complications observed were prolonged vitreous hemorrhage in one eye and neovascular glaucoma in two eyes. For postoperative recurrence of macular edema, sub-tenon injection of triamcinolone acetonide was given to five eyes, and intravitreal injection of an anti-VEGF agent was given to five eyes. Pan-retinal photocoagulation was performed on six eyes with ischemic type CRVO. The FA score was significantly improved after REVS (p = 0.018). CONCLUSIONS: REVS using a specially made micro-needle may be a surgical treatment option for non-ischemic CRVO, but it did not seem effective for ischemic CRVO. PMID- 28803327 TI - A proclaimed accidental fall of an infant-an experimental case reconstruction study. AB - The differentiation between a non-accidental injury and injuries resulting from accidents, such as falls to the ground or onto various objects, is a challenge not only for forensic experts but also for all clinicians caring for children. The forensic-biomechanical analysis of accidents in infants aims at the assessment of the loading characteristics based on the reconstruction of the particular incident. It includes an evidence-based analytical comparison between the actual injuries presented and the injuries that should be expected as a result of the proclaimed accident. With the help of kinematical and dynamical parameters of the described actions and the resulting loading situations, the forensic-biomechanical analysis can assess the plausibility of the proclaimed course of the event and thus contribute to the differentiation between accidental and non-accidental injuries. The quality of such a forensic-biomechanical expert opinion depends on the accuracy and quantity of available data regarding biomechanical tolerance of tissues, organs, and body parts. Case-specific measurements can contribute significantly to the insight of the kinematics and dynamics of the proclaimed event, its feasibility, etc. The present article demonstrates, based on one case report, the potential as well as the limits of such an analysis of proclaimed accidental fall injuries. PMID- 28803328 TI - Traditional Chinese medicine as adjunctive therapy improves the long-term survival of lung cancer patients. AB - PURPOSE: Traditional Chinese medicine is one of the popular alternative treatments for cancer, mainly enhancing host immune response and reducing adverse effect of chemotherapy. This study first explored traditional Chinese medicine treatment effect on long-term survival of lung cancer patients. METHODS: This study evaluated whether traditional Chinese medicine combined with conventional cancer treatment improved overall survival of lung cancer patients. We had conducted a retrospective cohort study on 111,564 newly diagnosed lung cancer patients in 2000-2009 from National Health Insurance Program database. RESULTS: A total of 23,803 (21.31%) patients used traditional Chinese medicine for lung cancer care. Eligible participants were followed up until 2011 with a mean follow up period of 1.96 years (standard deviation 2.55) for non-TCM users and 3.04 years (2.85) for traditional Chinese medicine users. Patients with traditional Chinese medicine utilization were significantly more likely to have a 32% decreased risk of death [hazard ratio = 0.62; 95% confidence interval = 0.61 0.63], compared with patients without traditional Chinese medicine utilization after multivariate adjustment. We also observed a similar significant reduction risk across various subgroups of chronic lung diseases. Qing Zao Jiu Fei Tang was the most effective traditional Chinese medicine agent for mortality reduction both in the entire lung cancer (0.81; 0.72-0.91) and matched populations (0.86; 0.78-0.95). CONCLUSION: This study demonstrated adjunctive therapy with traditional Chinese medicine may improve overall survival of lung cancer patients. This study also suggested traditional Chinese medicine may be used as an adjunctive therapy for cancer treatment. These observational findings need being validated by future randomized controlled trials to rule out the possibility of effect due to holistic care. PMID- 28803329 TI - Childhood body mass index and height in relation to site-specific risks of colorectal cancers in adult life. AB - As colorectal cancers have a long latency period, their origins may lie early in life. Therefore childhood body mass index (BMI; kg/m2) and height may be associated with adult colorectal cancer. Using a cohort design, 257,623 children from The Copenhagen School Health Records Register born from 1930 to 1972 with measured heights and weights at ages 7 to 13 years were followed for adult colon and rectal adenocarcinomas by linkage to the Danish Cancer Registry. Hazard ratios (HRs) with 95% confidence intervals (CI) were estimated by Cox proportional hazard regressions. During follow-up, 2676 colon and 1681 rectal adenocarcinomas were diagnosed. No sex differences were observed in the associations between child BMI or height and adult colon or rectal cancers. Childhood BMI and height were positively associated with colon cancer; at age 13 years the HRs were 1.09 (95% CI 1.04-1.14) and 1.14 (95% CI 1.09-1.19) per z score, respectively. Children who were persistently taller or heavier than average, had increased risk of colon cancer. Similarly, growing taller or gaining more weight than average was positively associated with colon cancer. No associations were observed between BMI or height and rectal cancer. Childhood BMI and height, along with above average change during childhood are significantly and positively associated with adult colon cancers, but not with rectal cancer, suggesting different etiologies. PMID- 28803330 TI - BIME2, a novel gene required for interhomolog meiotic recombination in the protist model organism Tetrahymena. AB - Meiotic recombination is initiated by DNA double-strand breaks (DSBs). Most DSBs are converted into nonreciprocal exchanges (gene conversions) or crossovers (COs) between sister chromatids. Only a minority of DSBs are processed toward interhomolog COs, the precursors of the chiasmata that connect homologous chromosomes. Dmc1, the meiosis-specific paralog of the universal recombination protein Rad51, is required for interhomolog COs; in its absence, univalents are primarily formed. Here, we report a ciliate-specific novel meiotic gene, BIME2, which also promotes interhomolog crossing over. In the bime2Delta mutant, DSBs are formed and repaired normally, but bivalent formation is strongly reduced. Bime2 protein forms foci on chromatin during meiotic prophase, and chromatin localization of Bime2 and Dmc1 is largely interdependent. Bime2 distantly resembles budding yeast Rdh54/Tid1 and the vertebrate Rad54B helicases and may have similar functions in promoting or stabilizing Dmc1 nucleoprotein filaments. PMID- 28803331 TI - Impact of monitoring health-related quality of life in clinical practice in children with type 1 diabetes mellitus. AB - PURPOSE: To test whether the systematic monitoring of health-related quality of life (HRQOL) in clinical practice in Spanish pediatric patients with T1DM helps improve their daily life in a multicenter longitudinal study. METHODS: One hundred thirty-six patients participated, recruited from five centers in Barcelona, Spain (72 girls, mean age 13.4 years). Complete data were collected for 119 patients (85%). Pediatricians were randomly assigned to the HRQOL intervention (n = 70), or control group (n = 49). The intervention group discussed the results of HRQOL face to face with the physician, quarterly over a year. The control group received care as usual. HRQOL was assessed using KIDSCREEN-27 collected online. Standardized mean differences (effect size, ES) and generalized estimating equation (GEE) were computed to compare group differences between baseline and follow-up, taking into account sociodemographic and clinical variables. RESULTS: Statistically significant higher scores were seen in the intervention group at follow-up for the dimensions of Psychological well-being (ES = 0.56), School environment (ES = 0.56), and the KIDSCREEN-10 index (ES = 0.63). No differences were found in the control group. GEE analysis showed an improvement in HRQOL at follow-up with statistically significant association of the intervention on Psychological well-being (B = 4.32; p 0.03 for the interaction of group by follow-up) and School environment (B = 4.64; p 0.02 for the same interaction term). CONCLUSIONS: Routine assessment and face-to-face patient-physician discussion of HRQOL results improved HRQOL scores after a year of follow-up, especially in Psychological well-being and school environment. The results support the routinary use of HRQOL assessment in clinical practice. PMID- 28803332 TI - Financial development and oil resource abundance-growth relations: evidence from panel data. AB - This study investigates whether financial development dampens the negative impact of oil resource abundance on economic growth. Because of substantial cross sectional dependence in our data, which contain a core sample of 63 oil-producing countries from 1980 through 2010, we use the common correlated effect mean group (CCEMG) estimator to account for the high degree of heterogeneity and drop the outlier countries. The empirical results reveal that oil resource abundance affects the growth rate in output contingent on the degree of development in financial markets. More developed financial markets can channel the revenues from oil into more productive activities and thus offset the negative effects of oil resource abundance on economic growth. Thus, better financial development can reverse resource curse or enhance resource blessing in oil-rich economies. PMID- 28803333 TI - Low-dose tolvaptan PK/PD: comparison of patients with hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion to healthy adults. AB - PURPOSE: Tolvaptan (TLV) is indicated to treat hyponatremia due to syndrome of inappropriate diuretic hormone (SIADH) in Europe. Treatment is to be initiated at 15 mg QD but post-approval reporting indicates increasing use of 7.5 mg as the starting dose. Physicians believe 7.5 mg is effective and has a lower incidence of overly rapid correction of serum sodium. METHODS: Single TLV doses of 3.75, 7.5, and 15 mg were administered to 14 healthy adults in a crossover design and to 29 subjects >=18 years with SIADH and serum sodium between 120 and 133 mmol/L in a parallel-group design. Pharmacodynamics and TLV plasma concentrations were assessed for 24 h post-dose. RESULTS: In SIADH subjects, corrections of serum sodium (Delta of >=8 mmol/L in the first 8 h or >=12 mmol/L in the first 24 h) were observed in one, one, and two subjects in the 3.75-, 7.5-, and 15-mg dose groups. Fluid balance (FB) for 0-6 h post-dose was correlated (r 2 = 0.37) with maximum increases in serum sodium; subjects with large corrections had large (~1 L) negative FB. Compared to healthy adults, subjects with SIADH did not drink in response to their negative FB and had larger increases in serum sodium at 24 h. Median time of maximum increase in healthy adults was 6 h, with no rapid corrections, and FB was near 0 mL by 24 h. CONCLUSION: Starting titration with 7.5 mg TLV will not eliminate the risk of rapid corrections in serum sodium. Monitoring FB may indicate that a subject is at risk for over correction. PMID- 28803334 TI - Surgical approaches to adenocarcinoma of the gastroesophageal junction: the Siewert II conundrum. AB - BACKGROUND: The Siewert classification system for gastroesophageal junction adenocarcinoma has provided morphological and topographical information to help guide surgical decision-making. Evidence has shown that Siewert I and III tumors are distinct entities with differing epidemiologic and histologic characteristics and distinct patterns of disease progression, requiring different treatment. Siewert II tumors share some of the characteristics of type I and III lesions, and the surgical approach is not universally agreed upon. Appropriate surgical options include transthoracic esophagogastrectomy, transhiatal esophagectomy, and transabdominal extended total gastrectomy. PURPOSE: A review of the available evidence of the surgical management of Siewert II tumors is presented. CONCLUSIONS: Careful review of the data appear to support the fact that a satisfactory oncologic resection can be achieved via a transabdominal extended total gastrectomy with a slight advantage in terms of perioperative complications, and overall postoperative quality of life. Overall and disease free survival compares favorably to the transthoracic approach. These results can be achieved with careful selection of patients balancing more than just the Siewert type in the decision-making but considering also preoperative T and N stages, histological type (diffuse type requiring longer margins that are not always achievable via gastrectomy), and the presence of Barrett's esophagus. PMID- 28803335 TI - Intraoperative ventilation during thoracoscopic repair of neonatal congenital diaphragmatic hernia. AB - PURPOSE: To evaluate the optimal ventilation mode during thoracoscopic repair (TR) of neonatal congenital diaphragmatic hernia (CDH), we compared high frequency oscillatory ventilation (HFOV) with conventional mechanical ventilation (CMV). METHODS: Twenty-three neonatal CDH cases who underwent TR without intraoperative inhalation of nitric oxide at our institution between 2007 and 2016 were reviewed. Patients were initially ventilated with HFOV, which was converted to CMV if the HFOV settings were decreased to FiO2 <0.4, stroke volume <4 mL/kg and mean airway pressure <12 cmH2O. Arterial blood gases in the perioperative period were compared between HFOV and CMV. RESULTS: Seventeen patients were ventilated with HFOV (group I), and six patients were ventilated with CMV (group II). Preoperative PaCO2 was significantly higher and pH was significantly lower in group I compared with group II. In both groups I and II, intraoperative PaCO2 increased significantly and pH decreased significantly compared with preoperation. Although intraoperative PaCO2 and pH were not different between the groups, group II showed greater worsening of intraoperative PaCO2 and pH as compared to their respective preoperative values. CONCLUSIONS: HFOV seems to prevent deterioration of hypercapnia and acidosis to a greater extent than CMV during TR in neonatal cases of CDH, although patients can also be ventilated with CMV. PMID- 28803336 TI - Transgenic Mice Overexpressing Vitamin D Receptor (VDR) Show Anti-Inflammatory Effects in Lung Tissues. AB - Vitamin D insufficiency is increasingly recognized as a prevalent problem worldwide, especially in patients with a chronic lung disease. Chronic obstructive pulmonary disease (COPD) is a type of chronic inflammatory lung disease. Previous clinical studies have shown that COPD leads to low vitamin D levels, which further increase the severity of COPD. Vitamin D homeostasis represents one of the most important factors that potentially determine the severity of COPD. Nonetheless, the mechanisms underlying the anti-inflammatory effects of vitamin D receptor (VDR) in lung tissues are still unclear. To investigate the anti-inflammatory effects of VDR, we generated transgenic mice that show lung-specific VDR overexpression under the control of the surfactant protein C promoter (TG mice). The TG mice were used to study the expression patterns of proinflammatory cytokines using real-time polymerase chain reaction and immunohistochemistry. The TG mice had lower levels of T helper 1 (Th1) related cytokines than wild-type (WT) mice did. No significant differences in the expression of Th2 cytokines were observed between TG and WT mice. This study is the first to achieve lung-specific overexpression of VDR in TG mice: an interesting animal model useful for studying the relation between airway cell inflammation and vitamin D signaling. VDR expression is an important factor that influences anti-inflammatory responses in lung tissues. Our results show the crucial role of VDR in anti-inflammatory effects in lungs; these data are potentially useful for the treatment or prevention of COPD. PMID- 28803337 TI - Production of rhamnolipids by semi-solid-state fermentation with Pseudomonas aeruginosa RG18 for heavy metal desorption. AB - Foaming problem and cost of substrate limit the commercial application of rhamnolipids, a potential biosurfactant produced by Pseudomonas aeruginosa. We explored the production of rhamnolipids by a semi-solid-state (SSS) fermentation strategy with glycerol as carbon source and rapeseed/wheat bran as matrix, along with the capacity of the produced rhamnolipids to solubilize lead and cadmium in aqueous solution. Structural analysis by MALDI-TOF MS indicated the increased proportion of mono-rhamnolipids from SSS fermentation. E24 results showed the stronger emulsification capacity and reduced water tension of the SSS fermentation product. Rhamnolipids from SSS fermentation can desorb lead/cadmium from contaminated soil effectively and heavy metals in exchangeable and carbonate forms were easily removed. Our findings suggest that SSS fermentation is an alternative for the economical production of rhamnolipids and the product can be used to solubilize heavy metals from soils. PMID- 28803338 TI - The early history of our understanding of the functions of the spinal cord. PMID- 28803339 TI - Dual-energy computed tomography has limited diagnostic sensitivity for short-term gout. AB - The aim of this study was to discuss the diagnostic value of dual-energy computed tomography (DECT) in patients with gout during different disease phases. Two hundred twenty-one patients (136 with gout and 85 with other arthritic diseases) were recruited to the study. Arthrosis pain was evaluated in all patients by DECT scans. We calculated the sensitivity and specificity of DECT for the diagnosis of gout, including the first onset period, less than 24 months period, and more than 24 months period. We then investigated the related risk factors of urate crystals volume in the foot. The diagnostic sensitivity of DECT in the first onset, less than 24 months, and more than 24 months groups was 35.71, 61.54, and 92.86%, respectively. The overall sensitivity and specificity values were 80.88 and 88.24%, respectively. The multilinear regression analysis showed that longer disease duration (P = 0.001) and higher serum uric acid (SUA) (P = 0.001) were the two important predictive factors of the monosodium urate (MSU) crystal volume in the foot. DECT provides good diagnostic accuracy for detection of MSU crystal deposits in gout patients. However, DECT has limited diagnostic sensitivity for short-term gout patients, especially for the first onset patients. Longer disease duration and higher SUA were predictive factors of MSU crystal volume. PMID- 28803340 TI - Emission characteristics of PBDEs during flame-retardant plastics extruding process: field investigation and laboratorial simulation. AB - Though mechanical recycling of WEEE plastics is supposed to be a promising method, PBDEs release and the resulting contamination during its processing remain unclear yet. The distribution of PBDEs pollution in production lines was investigated from two flame-retardant plastic modification plants in Southern China. This was followed by laboratory simulation experiments to characterize the emission processes. PBDEs concentrations ranged from 37 to 31,305 ng/L in cooling water and from 40,043 to 216,653 ng/g dry wt in solid samples taken during the field investigation. In the laboratory simulation, concentrations ranged from 146 to 433 ng/L in cooling water and from 411,436 to 747,516 ng/Nm3 in flue gas. All samples were dominated by BDE-209 among the congeners. Temperatures and impurities in plastic substrate can significantly affect PBDEs release. Special attention should be paid to the risks of water directly discharge from the cooling system, especially for the biological sludge and sediments, as well as flue gas emissions to the environment. PMID- 28803341 TI - Gypsy moth herbivory induced volatiles and reduced parasite attachment to cranberry hosts. AB - Interactions between species can have cascading effects that shape subsequent interactions. For example, herbivory can induce plant defenses that affect subsequent interactions with herbivores, pathogens, mycorrhizae, and pollinators. Parasitic plants are present in most ecosystems, and play important roles in structuring communities. However, the effects of host herbivory on parasitic plants, and the potential mechanisms underlying such effects, are not well known. We conducted a greenhouse study to ask whether gypsy moth (Lymantria dispar) damage, host cultivar, and their interaction affected preference of the stem parasite dodder (Cuscuta spp.) on cranberry hosts (Vaccinium macrocarpum). We then assessed the mechanisms that could underlie such effects by measuring induced changes in phytohormones and secondary compounds. We found that damage by gypsy moths delayed dodder attachment by approximately 0.3 days when dodder stems were added 2 days after damage, and reduced attachment by more than 50% when dodder stems were added 1 week after host plant damage. Gypsy moth damage significantly increased jasmonic acid (JA) levels, total volatile emissions, and the flavonol, quercetin aglycone, suggesting possible mechanisms underlying variation in dodder ability to locate or attach to hosts. Dodder preference also differed between cranberry cultivars, with the highest attachment on the cultivar that had significantly lower levels of total volatile emissions and total phenolic acids, suggesting that volatile composition and phenolics may mediate dodder preference. Our results indicate that herbivory can reduce subsequent attachment by a highly damaging parasitic plant, demonstrating the potential importance of early damage for shaping subsequent species interactions. PMID- 28803342 TI - Alleviation of Arsenic-Induced Pulmonary Oxidative Damage by GSPE as Shown during In vivo and In vitro Experiments. AB - A long-term exposure to arsenic may lead to lung damage due to oxidative stress. In this context, GSPE can play a major role as a strong antioxidant. Our study attempted to reveal the connection between arsenic-induced lung injury and the antagonistic effect of GSPE. For this purpose, BEAS-2B cells and Kunming mice were exposed to different dosages of As2O3 and GSPE. Oxidative stress indicators were detected both in vivo and in vitro. Cell survival rate and morphological changes in the lung tissue (H&E staining) were evaluated as well. It was exhibited that As2O3 increased oxidative stress both in vivo and in vitro and decreased cells viability. In contrast, higher cell survival rate was revealed in the group treated with arsenic plus GSPE after 24 h as compared to that in the arsenic group. GSPE effectively reduced oxidative stress levels, along with increasing antioxidant capacity. In vivo experiments in arsenic-exposed group showed alveolar septum to be significantly thickened with considerable capillary congestion and invasion by inflammatory cells. After the intervention with GSPE, there seemed to be a dramatic reversal of morphology with thinning of the alveolar septum, decrease in capillary congestion, and number of inflammatory cells. This had shown that GSPE can effectively reduce the levels of oxidative stress, induced by arsenic in mice lung tissue. Conversely, antioxidant enzymes or products were increased. The experiment proved that GSPE can protect the lungs from oxidative damage induced by arsenic, and it may also be used as an antagonist against arsenic injuries. PMID- 28803343 TI - Sediment lipid biomarkers record phytoplankton dynamics of Lake Heihai (Yunnan Province, SW China) driven by climate warming since the 1980s. AB - Increased phosphorus (P) export from sediments to the overlying water column is a significant factor driving the variation of phytoplankton in productivity and community structure in lakes. However, the lack of long-term instrumental data often impeded analyses attempting to associate dynamics of phytoplankton with variation of internal P loading. Here, elements and lipid biomarkers were analyzed in a sediment core from Lake Heihai, a small, deep, and ultraoligotrophic alpine lake in Haba Mountain, Yunnan Province, SW China. The data document incredible enrichment of element iron (Fe) in the sediment, whose concentrations are much higher than those of other common major elements including titanium (Ti), aluminum (Al), calcium (Ca), and magnesium (Mg). This finding, together with the abundance correlation between P and Fe (n = 30, R 2 = 0.783) suggested that P was probably retained in sediments through sorption with micro-layer of FeOOH at the sediment-water interface. The P/Ti ratios, P/Fe ratios, and P/total organic carbon (TOC) ratios all declined in the sediment since 1980, perhaps indicating increased P release from sediments to the overlying water column initiated by hypolimnion anoxia and sulfidic, which is presumably triggered by regional climate warming since the 1980s. The P-rich bottom water can be injected into photic zone during wind-driven mixing and overturn of the water column, although its frequency and intensity might decline due to stronger water column stratification in warming climate. In response, diatoms exhibited a rapid increase of productivity at this time, because diatoms have a storage vacuole and thereby nutrients such as P can be concentrated and used for cell division long after they are depleted in the bulk fluid. Elevated diatom biomass produced shading of light penetration, allowing for a low productivity for dinoflagellates. This study deepens our understanding of the impact of climate warming on lake systems and highlights the element biogeochemical cycle contributing to the variation of nutrients in the lake water column. PMID- 28803345 TI - Substantial clinical benefit for Neck Disability Index revisited: establishing the goal for treatment? AB - PURPOSE: It is difficult for clinicians to inform patients about the success rate of a treatment as a cervical anterior discectomy procedure. Ideally, a proportion of good outcome as rated by patients is known. Patient-reported outcome measurements are helpful. The purpose is to relate the difference in Neck Disability Index (NDI) after a cervical anterior discectomy procedure for single level cervical degenerative disc disease with the patients' rating of their actual clinical situation after long-term follow-up to define the substantial clinical benefit (SCB). METHODS: After completion of the NDI, patients who were surgically treated for cervical single level degenerative disease were asked to complete a five-item Likert scale to rate their clinical situation. After dichotomisation of the outcome in good versus less than good, a cut-off value was defined by determining the value of the difference of NDI with the highest specificity and sensitivity. Funding was not obtained. RESULTS: SCB for NDI after surgery for cervical single level degenerative disease should be set at ten with area under the curve (AUC) of 0.71 for sensitivity as well specificity. CONCLUSIONS: The goal for each treatment is a good outcome. While comparing treatments for cervical degenerative disc disease only those with an SCB of ten will be relevant for the patient, as patients who achieved this difference in NDI rated their actual situation at long-term follow-up as good. PMID- 28803344 TI - Outcome one year after robot-assisted rectal cancer surgery: a consecutive cohort study. AB - PURPOSE: The aim of this study was to investigate outcome after robot-assisted rectal cancer surgery (RARCS). We focused on conversion rate, postoperative complications, pathological evaluation (adequacy of resection margins), and bowel function (low anterior resection syndrome (LARS)) 1 year after surgery. METHODS: An observational study of prospectively registered patients with data obtained from medical records. Data comprise the initial 208 rectal cancer patients operated with robot-assisted surgery at a single Danish university hospital from October 2011 to October 2014. RESULTS: In total, 27 procedures (13%) were converted to open surgery, and 23 of the 27(85%) conversions were in the obese and overweight patients. The anastomotic leak rate was 12 (9%), and further 5 (2%) developed a complication requiring re-operation (ileus, bleeding, wound abscess). In total, 14 (7%) patients had a circumferential resection margin (CRM) <= 1 mm (R1-resection). In regard to bowel function, 15/22 (68%) of TME patients had major LARS at 6 months follow-up but at 12 months follow-up this proportion was reduced to 18/34 (53%). CONCLUSIONS: The outcomes after RARCS at a single high-volume university center are overall comparable to outcomes reported from laparoscopic surgery. The results are satisfying because they are achieved during implementation of RARCS. Randomized trials are, however, needed and focus should especially be on long-term follow-up in regard to functional outcome. PMID- 28803346 TI - Sense of coherence, self-esteem, and health locus of control in subjects with type 1 diabetes mellitus with/without satisfactory metabolic control. AB - BACKGROUND: Despite intensive training, a few individuals with Type 1 diabetes mellitus (T1DM) fail to reach the desired metabolic targets. AIM: To evaluate the association between disease-related emotional and cognitive aspects and metabolic control in subjects with T1DM. SUBJECTS AND METHODS: Health locus of control (HLOC), sense of coherence (SOC), and self-esteem were assessed in T1DM subjects using validated questionnaires. Sixty-seven consecutive subjects who did not attain the desired HbA1c target (mean HbA1c, 8.3% [67 mmol/mol]) were compared with 30 cases in satisfactory metabolic control (HbA1c levels <7%-53 mmol/mol). RESULTS: In the overall population, SOC was negatively associated with BMI and average HbA1c, as was the association of self-esteem with HbA1c. Subjects attaining the desired metabolic target were characterized by higher SOC scores, higher Internal HLOC and prevalent Internal vs. Powerful-others HLOC. Compared to subjects in good metabolic control, subjects with unsatisfactory control had lower scores of SOC, Internal HLOC and Self-esteem, with no difference in Powerful others, or Chance HLOC. In the same group, SOC in the upper tertile was significantly associated with self-esteem (OR 1.35; 95% CI 1.08-1.69) and PHLOC (OR 1.24; 95% CI 1.03-1.49), after adjustment for age, sex, educational level, and comorbidities. CONCLUSIONS: Patients who fail to reach a satisfactory metabolic control tend to rely on significant others, trusting in the physicians' skills or on the efficiency of the health-care system. Strategies aimed at increasing self-efficacy and SOC, based on personal ability, are eagerly awaited to help patients improve diabetes care. PMID- 28803348 TI - Effect of small proportion of butanol additive on the performance, emission, and combustion of Australian native first- and second-generation biodiesel in a diesel engine. AB - This paper aims to investigate the effect of the addition of 5% alcohol (butanol) with biodiesel-diesel blends on the performance, emissions, and combustion of a naturally aspirated four stroke multi-cylinder diesel engine at different engine speeds (1200 to 2400 rpm) under full load conditions. Three types of local Australian biodiesel, namely macadamia biodiesel (MB), rice bran biodiesel (RB), and waste cooking oil biodiesel (WCB), were used for this study, and the data was compared with results for conventional diesel fuel (B0). Performance results showed that the addition of butanol with diesel-biodiesel blends slightly lowers the engine efficiency. The emission study revealed that the addition of butanol additive with diesel-biodiesel blends lowers the exhaust gas temperature (EGT), carbon monoxide (CO), nitrogen oxide (NOx), and particulate matter (PM) emissions whereas it increases hydrocarbon (HC) emissions compared to B0. The combustion results indicated that in-cylinder pressure (CP) for additive added fuel is higher (0.45-1.49%), while heat release rate (HRR) was lower (2.60-9.10%) than for B0. Also, additive added fuel lowers the ignition delay (ID) by 23-30% than for B0. Finally, it can be recommended that the addition of 5% butanol with Australian biodiesel-diesel blends can significantly lower the NOx and PM emissions. PMID- 28803349 TI - Scary symptoms? Functional magnetic resonance imaging evidence for symptom interpretation bias in pathological health anxiety. AB - Patients with pathological health anxiety (PHA) tend to automatically interpret bodily sensations as sign of a severe illness. To elucidate the neural correlates of this cognitive bias, we applied an functional magnetic resonance imaging adaption of a body-symptom implicit association test with symptom words in patients with PHA (n = 32) in comparison to patients with depression (n = 29) and healthy participants (n = 35). On the behavioral level, patients with PHA did not significantly differ from the control groups. However, on the neural-level patients with PHA in comparison to the control groups showed hyperactivation independent of condition in bilateral amygdala, right parietal lobe, and left nucleus accumbens. Moreover, patients with PHA, again in comparison to the control groups, showed hyperactivation in bilateral posterior parietal cortex and left dorsolateral prefrontal cortex during incongruent (i.e., harmless) versus congruent (i.e., dangerous) categorizations of body symptoms. Thus, body-symptom cues seem to trigger hyperactivity in salience and emotion processing brain regions in PHA. In addition, hyperactivity in brain regions involved in cognitive control and conflict resolution during incongruent categorization emphasizes enhanced neural effort to cope with negative implicit associations to body symptom-related information in PHA. These results suggest increased neural responding in key structures for the processing of both emotional and cognitive aspects of body-symptom information in PHA, reflecting potential neural correlates of a negative somatic symptom interpretation bias. PMID- 28803347 TI - Melatonin, mitochondria, and the skin. AB - The skin being a protective barrier between external and internal (body) environments has the sensory and adaptive capacity to maintain local and global body homeostasis in response to noxious factors. An important part of the skin response to stress is its ability for melatonin synthesis and subsequent metabolism through the indolic and kynuric pathways. Indeed, melatonin and its metabolites have emerged as indispensable for physiological skin functions and for effective protection of a cutaneous homeostasis from hostile environmental factors. Moreover, they attenuate the pathological processes including carcinogenesis and other hyperproliferative/inflammatory conditions. Interestingly, mitochondria appear to be a central hub of melatonin metabolism in the skin cells. Furthermore, substantial evidence has accumulated on the protective role of the melatonin against ultraviolet radiation and the attendant mitochondrial dysfunction. Melatonin and its metabolites appear to have a modulatory impact on mitochondrion redox and bioenergetic homeostasis, as well as the anti-apoptotic effects. Of note, some metabolites exhibit even greater impact than melatonin alone. Herein, we emphasize that melatonin-mitochondria axis would control integumental functions designed to protect local and perhaps global homeostasis. Given the phylogenetic origin and primordial actions of melatonin, we propose that the melatonin-related mitochondrial functions represent an evolutionary conserved mechanism involved in cellular adaptive response to skin injury and repair. PMID- 28803350 TI - Comparison of mitral competence after mitral repair with papillary muscle approximation versus papillary muscle relocation for functional mitral regurgitation. AB - The purpose of this study was to evaluate the surgical results of papillary muscle approximation (PMA) and papillary muscle relocation (PMR) for functional mitral regurgitation (FMR) and to compare the effects of both procedures on the change in mitral regurgitation (MR) and echocardiogram parameters associated with tethering. Eighteen patients with moderate-to-severe FMR (MR grade >=2) who underwent PMA or PMR were retrospectively analyzed. Underlying diseases were ischemic cardiomyopathy, idiopathic dilated cardiomyopathy, and aortic valve disease for seven, six, and five patients, respectively. Eleven patients underwent PMA and seven patients underwent PMR. Mitral annuloplasty and surgical ventricular restoration were performed concomitantly for 18 and 6 patients, respectively. None of these patients died in the hospital. Three patients died during the late period; two of these deaths were cardiac related. The rate of 3 years of freedom from cardiac-related death was 89%. After a mean follow-up of 33 months, MR grade was significantly improved compared with preoperative values (3.0 +/- 0.8 to 0.7 +/- 1.2; p < 0.01). Recurrence of MR grade >=2 occurred in three patients and the rate of 3 years of freedom from recurrence of MR grade >=2 was 87%. During follow-up, tenting height (1.1 +/- 0.2 to 0.7 +/- 0.2 cm; p < 0.01), tenting area (2.2 +/- 0.7 to 0.9 +/- 0.5 cm2; p < 0.01), and anterior leaflet tethering angle (39 degrees +/- 11 degrees to 26 degrees +/- 8 degrees ; p < 0.01) were significantly improved compared with preoperative values. Posterior leaflet tethering angle significantly deteriorated from 40 degrees +/- 7 degrees to 53 degrees +/- 15 degrees (p < 0.01); however, it did not further deteriorate compared with the early postoperative value of 55 degrees +/- 16 degrees (p = 0.7). There was no difference in echocardiogram parameters associated with tethering between PMA and PMR throughout the observation period. Both methods were associated with lasting relief of MR and reverse left ventricular remodeling. There was no difference between PMA and PMR regarding the effect on mitral valve competence. Both methods allowed durable mitral repair and good clinical outcomes. PMID- 28803351 TI - Dose and Schedule Selection of the Oral Proteasome Inhibitor Ixazomib in Relapsed/Refractory Multiple Myeloma: Clinical and Model-Based Analyses. AB - BACKGROUND: The oral proteasome inhibitor ixazomib has been approved by regulatory authorities around the world, including in the United States and the European Union, for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy, based on the pivotal phase III TOURMALINE MM1 study. OBJECTIVE: The objective of this study was to quantitatively characterize the benefit-risk profile of ixazomib in relapsed/refractory MM in support of the approved dose and schedule. METHODS: We report early-phase study data and exposure-response analyses of TOURMALINE-MM1 data that support the selection of the recommended ixazomib dose and schedule. RESULTS: Single-agent ixazomib studies showed a favorable efficacy/safety profile with weekly versus twice-weekly dosing; a phase I/II study of ixazomib in combination with lenalidomide and dexamethasone (IRd) identified a weekly ixazomib dose that offered an acceptable efficacy/safety profile. In IRd exposure-response analyses from TOURMALINE-MM1, ixazomib systemic exposure was not a significant predictor of progression-free survival or probability of response. Significant associations were observed between ixazomib exposure and the probability of grade >=3 anemia and thrombocytopenia, and grade >=2 diarrhea, fatigue, nausea, peripheral neuropathy, and rash. Additionally, higher ixazomib exposure was associated with lower lenalidomide relative dose intensity. CONCLUSIONS: These analyses support a favorable benefit-risk profile for weekly ixazomib 4.0 mg on days 1, 8, and 15 of 28-day cycles, which was selected for the phase III TOURMALINE registration program. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov NCT00932698, NCT00963820, NCT01217957, NCT01564537. PMID- 28803352 TI - Breast cancer in elderly women and altered clinico-pathological characteristics: a systematic review. AB - PURPOSE: Breast cancer is the most common malignancy in women in terms of incidence and mortality. Age is undoubtedly the biggest breast cancer risk factor. In this study we examined clinical, histological, and biological characteristics and mortality of breast cancer in elderly women along with their changes with advancing age. METHODS: We reviewed 63 original articles published between 2006 and 2016 concerning women over 70 years with breast cancer. RESULTS: Compared to patients 70-79 years, patients aged 80 and over had larger tumor size with fewer T1 (42.9% vs 57.7%, p < 0.01) and more T2 lesions (43.5% vs 33.0%, p < 0.01). Lymph nodes and distant metastases were more frequent, with more N + (49.5% vs 44.0%, p < 0.01) and more M1 (8.0% vs 5.9%, p < 0.01). Infiltrating mucinous carcinomas were more frequent (4.3% vs 3.7%, p < 0.01). Tumors had lower grades, with more grade 1 (23.2% vs 19.8%, p = 0.01) and fewer grade 3 (21.5% vs 25.5%, p < 0.01), and were more hormone-sensitive: PR was more often expressed (72.6% vs 67.3%, p < 0.01). Lympho-vascular invasion was less frequent in the 80 years and over (22.9% vs 29.7%, p = 0.01). Breast cancer-specific mortality was higher both at 5 years (25.8% vs 17.2%, p < 0.01) and 10 years (32.7% vs 26.6%, p < 0.01). CONCLUSION: Clinico-pathological characteristics, increased incidence, and mortality associated with aging can be explained on one hand by biological changes of the breast such as increased estrogen sensitivity, epithelial cell alterations, immune senescence, and tumor microenvironment modifications. However, sociologic factors such as increased life expectancy, under-treatment, late diagnosis, and insufficient individual screening, are also involved. PMID- 28803353 TI - Palliative care in ovarian carcinoma patients-a personalized approach of a team work: a review. AB - Most ovarian cancer patients are diagnosed in an advanced stage; and after the initial treatment experience disease recurrence, which eventually becomes palliative. Many questions arise in this setting including how to address patients in the palliative setting, how to discuss end-of-life issues, and how to manage symptoms. In this review, we discuss the timing and setting of end-of-life discussion in the context of end-stage ovarian cancer. We review the approach to relieving disease burden by improving and decreasing symptoms. These symptoms include recurrent ascites, bowel obstruction, pain, pulmonary effusion, and deep vein thrombosis. PMID- 28803354 TI - Facultative myiasis of domestic cats by Sarcophaga argyrostoma (Diptera: Sarcophagidae), Calliphora vicina and Lucilia sericata (Diptera: Calliphoridae) in northern Italy. AB - We describe five cases of myiasis of domestic cats, Felis silvestris catus L. (Carnivora: Felidae), reported in 2016 in northern Italy and caused by three Diptera species: Sarcophaga argyrostoma (Robineau-Desvoidy) (Sarcophagidae), Calliphora vicina Robineau-Desvoidy and Lucilia sericata (Meigen) (Calliphoridae). Three were cases of traumatic myiasis, one by S. argyrostoma and two by L. sericata, one was a case of auricular myiasis by C. vicina and one was a case of ophthalmomyiasis caused by an association of L. sericata and C. vicina. The myiasis by S. argyrostoma is the first reported case of this species in a cat, whereas the two myiases by C. vicina are the first reported cases in cats in Italy. PMID- 28803355 TI - Evaluation of developmental prognosis for esophageal atresia with tracheoesophageal fistula. AB - PURPOSE: This study investigated risk factors for developmental disorders after the repair of esophageal atresia with tracheoesophageal fistula (EA/TEF). METHODS: The clinical charts of all infants with EA/TEF (gross type C) treated at our institution between 1993 and 2013 were analyzed. Patients with chromosomal aberrations were excluded. Forty-seven patients were divided into groups according to the presence (D) or absence (N) of developmental disorders. Patients were assessed with appropriate developmental examinations at age >3 years. RESULTS: Group D comprised 13 patients. The 34 patients in the group N had received a standard education. In groups D and N, gestational age was 36.5 versus 38.5 weeks, birth weight was 1808 versus 2662 g, and congenital cardiac anomalies occurred in 76.9 versus 23.5%. These differences reached significance. Operative data did not differ significantly. Overall complications occurred in 69.2 versus 29.4%, gastroesophageal reflux (GER) requiring fundoplication in 46.1 versus 8.8%, and oral ingestion difficulty in 61.5 versus 14.7%, which were significantly different. The frequencies of anastomotic leakage, anastomotic stricture, and recurrent fistula did not differ significantly. CONCLUSION: Gestation, birth weight, and cardiac anomalies could be risk factors for developmental disorders. Moreover, overall complications, GER, and oral ingestion may affect development. PMID- 28803356 TI - The prognostic impact of malnutrition in patients with severely decompensated acute heart failure, as assessed using the Prognostic Nutritional Index (PNI) and Controlling Nutritional Status (CONUT) score. AB - Patients with heart failure (HF) are sometimes classified as malnourished, but the prognostic value of nutritional status in acute HF (AHF) remains largely unstudied. 1214 patients who were admitted to the intensive care unit between January 2000 and June 2016 were screened based on their serum albumin, lymphocyte count, and total cholesterol measures. A total of 458 HF patients were enrolled in this study. The Prognostic Nutritional Index (PNI) is calculated as 10 * serum albumin (g/dL) + 0.005 * lymphocyte count (per mm3) (lower = worse). The Controlling Nutritional Status (CONUT) score is points based, and is calculated using serum albumin, total cholesterol, and lymphocyte count (range 0-12, higher = worse). Patients were divided into three groups according to PNI: high-PNI (PNI < 35, n = 331), middle-PNI (35 <= PNI < 38, n = 50), and low-PNI (PNI >= 38, n = 77). They were also divided into four groups according to CONUT score: normal CONUT (0-1, n = 128), mild-CONUT (2-4, n = 179), moderate-CONUT (5-8, n = 127), and severe-CONUT (>=9, n = 24). The PNI, which exhibited a good balance between sensitivity and specificity for predicting in-hospital mortality [66.1 and 68.4%, respectively; area under the curve (AUC) 0.716; 95% confidence interval (CI) 0.638-0.793), was 39.7 overall, while the CONUT score was 5 overall (61.4 and 68.4%, respectively; AUC 0.697; 95% CI 0.618-0.775). A Kaplan-Meier curve indicated that the prognosis, including all-cause death, was significantly (p < 0.001) poorer in low-PNI patients than in high-PNI groups and was also significantly poorer in severe-CONUT patients than in normal-CONUT and mild-CONUT groups. A multivariate Cox regression model showed that the low-PNI and severe CONUT categories were independent predictors of 365-day mortality [hazard ratio (HR) 2.060, 95% CI 1.302-3.259 and HR 2.238, 95% CI 1.050-4.772, respectively). Malnutrition, as assessed using both the PNI and the CONUT score, has a prognostic impact in patients with severely decompensated AHF. PMID- 28803357 TI - Determinants of functional outcome in hip fracture: the role of comorbidity. AB - BACKGROUND AND AIMS: Executed studies did not clearly identify which index of comorbidity was an independent outcome determinant. The aim of this prospective observational cohort study was to address this issue. METHODS: We analyzed 200 consecutive patients with hip fracture. All patients underwent rehabilitation. At admission comorbidity was assessed through the cumulative severity, severity index, and comorbidity index of the Cumulative Illness Rating Scale. Discharge scores and effectiveness in the Functional Independence Measure motor subscale, and discharge destination were the outcome measures. Multivariate regression analyses were performed to identify determinants of outcome. RESULTS: Mini Mental State Examination and comorbidity index of the Cumulative Illness Rating Scale were important independent determinants of final (respectively, beta = 0.46 and 0.25) and effectiveness (respectively, beta = 0.47 and -0.25) in motor Functional Independence Measure scores, while hip strength and Rankin score were determinants of final motor Functional Independence Measure score (respectively, beta = 0.21 and -0.20). Comorbidity index of the Cumulative Illness Rating Scale (odds ratio 8.18 for >=3 versus < 3 comorbidity score; 95% confidence interval, 1.03-64.7) and Geriatric Depression Scale (odds ratio 4.02 for >=6 versus <=5 depression scale score; 95% confidence interval, 1.52-10.63) were risk indicators for nursing home. CONCLUSIONS: Among the indices of the Cumulative Illness Rating Scale, comorbidity index is the sole independent determinant of both motor Functional Independence Measure scores and discharge destination in hip fracture patients. This suggests to specifically evaluate this index to identify the patients who may be admitted to a rehabilitation program. PMID- 28803358 TI - Prospective head-to-head comparison of 11C-choline-PET/MR and 11C-choline-PET/CT for restaging of biochemical recurrent prostate cancer. AB - PURPOSE: Whole-body integrated 11C-choline PET/MR might provide advantages compared to 11C-choline PET/CT for restaging of prostate cancer (PC) due to the high soft-tissue contrast and the use of multiparametric MRI, especially for detection of local recurrence and bone metastases. MATERIALS AND METHODS: Ninety four patients with recurrent PC underwent a single-injection/dual-imaging protocol with contrast-enhanced PET/CT followed by fully diagnostic PET/MR. Imaging datasets were read separately by two reader teams (team 1 and 2) assessing the presence of local recurrence, lymph node and bone metastases in predefined regions using a five-point scale. Detection rates were calculated. The diagnostic performance of PET/CT vs. PET/MR was compared using ROC analysis. Inter-observer and inter-modality variability, radiation exposure, and mean imaging time were evaluated. Clinical follow-up, imaging, and/or histopathology served as standard of reference (SOR). RESULTS: Seventy-five patients qualified for the final image analysis. A total of 188 regions were regarded as positive: local recurrence in 37 patients, 87 regions with lymph node metastases, and 64 regions with bone metastases. Mean detection rate between both readers teams for PET/MR was 84.7% compared to 77.3% for PET/CT (p > 0.05). Local recurrence was identified significantly more often in PET/MR compared to PET/CT by team 1. Lymph node and bone metastases were identified significantly more often in PET/CT compared to PET/MR by both teams. However, this difference was not present in the subgroup of patients with PSA values <=2 ng/ml. Inter-modality and inter-observer agreement (K > 0.6) was moderate to substantial for nearly all categories. Mean reduction of radiation exposure for PET/MR compared to PET/CT was 79.7% (range, 72.6-86.2%). Mean imaging time for PET/CT was substantially lower (18.4 +/- 0.7 min) compared to PET/MR (50.4 +/- 7.9 min). CONCLUSIONS: 11C-choline PET/MR is a robust imaging modality for restaging biochemical recurrent PC and interpretations between different readers are consistent. It provides a higher diagnostic value for detecting local recurrence compared to PET/CT with the advantage of substantial dose reduction. Drawbacks of PET/MR are a substantially longer imaging time and a slight inferiority in detecting bone and lymph node metastases in patients with PSA values >2 ng/ml. Thus, we suggest the use of 11C choline PET/MR especially for patients with low (<=2 ng/ml) PSA values, whereas PET/CT is preferable in the subgroup with higher PSA values. PMID- 28803359 TI - Expression of cationic amino acid transporters in pig skeletal muscles during postnatal development. AB - The cationic amino acid transporter (CAT) protein family transports lysine and arginine in cellular amino acid pools. We hypothesized that CAT expression changes in pig skeletal muscles during rapid pig postnatal development. We aimed to investigate the tissue distribution and changes in the ontogenic expression of CATs in pig skeletal muscles during postnatal development. Six piglets at 1, 12, 26, 45, and 75 days old were selected from six litters, and their longissimus dorsi (LD), biceps femoris (BF), and rhomboideus (RH) muscles, and their stomach, duodenum, jejunum, ileum, colon, liver, kidney, heart, and cerebrum were collected. CAT-1 was expressed in all the 12 tissues investigated. CAT-2 (CAT-2A isoform) expression was highest in the skeletal muscle and liver and lowest in the jejunum, ileum, kidney, and heart. CAT-3 was expressed mainly in the colon and detected in the jejunum, ileum, and cerebrum. The CAT-1 expression was higher in the skeletal muscle of day 1 pigs than in that of older pigs (P < 0.05). The CAT-2 mRNA level was lowest at day 1, but increased with postnatal development (P < 0.05). There was no significant change in CAT-1 expression among the LD, BF, and RH during postnatal development (P > 0.05); however, there was a change in CAT-2 expression. The CAT-2 expression was highest in the LD of 12-, 26-, 45-, and 75-day-old pigs, followed by the BF and RH (P < 0.05). These results suggest that CAT-1 and CAT-2 play different roles in pig skeletal muscles during postnatal development. PMID- 28803360 TI - Contrasting complexity of adjacent habitats influences the strength of cascading predatory effects. AB - Although cascading effects of top predators can help structure communities, their influence may vary across habitats that differentially protect prey. Therefore, to understand how and to what degree habitat complexity can affect trophic interactions in adjacent habitats, we used a combination of a broad regional scale survey, manipulative field trials, and an outdoor mesocosm experiment to quantify predator-prey interaction strengths across four trophic levels. Within estuaries of the southeastern USA, bonnethead sharks (Sphyrna tiburo) hunt blue crabs on mudflats and adjacent oyster reefs, two habitats with vastly different aboveground structure. Using 12-h tethering trials of blue crabs we quantified habitat-dependent loss rates of 37% on reefs and 78% on mudflats. We hypothesized that the sharks' predatory effects on blue crabs would cascade down to release a lower-level mud crab predator, which subsequently would increase juvenile oyster mortality, but that the cascade strength would be habitat-dependent. We experimentally manipulated predator combinations in split-plot mesocosms containing reef and mudflat habitats, and quantified oyster mortality. Bonnetheads exerted strong consumptive and non-consumptive effects on blue crabs, which ceased eating oysters in the sharks' presence. However, mud crabs, regardless of shark and blue crab presence, continued to consume oysters, especially within the structural refuge of the reef where they kept oyster mortality high. Thus, bonnetheads indirectly boosted oyster survival, but only on the mudflat where mud crabs were less active. Our work demonstrates how structural differences in adjacent habitats can moderate trophic cascades, particularly when mesopredators exhibit differential use of structure and different sensitivities to top predators. PMID- 28803361 TI - Toxoplasma gondii and Neospora caninum induce different host cell responses at proteome-wide phosphorylation events; a step forward for uncovering the biological differences between these closely related parasites. AB - Toxoplasma gondii and Neospora caninum are closely related intracellular protozoan parasites and tissue cyst-forming Coccidia of the phylum Apicomplexa. There are remarkable similarities between the morphology, genomes and transcriptomes of both parasites. Toxoplasma is zoonotic, with a wide host range and is mainly transmitted horizontally between its definitive host, the cat, and its intermediate hosts. Neospora causes disease within a narrow host range and with reduced virulence potential to the hosts. The dog is the definitive host of Neospora and its epidemiology in cattle mainly depends on vertical transmission. What causes these biological differences is not well understood. Since these parasites secrete an array of secretory proteins, including kinases, during infection to manipulate host cell responses. Host-parasite interactions due to phosphorylation of host cell proteins by T. gondii kinases enhance virulence and maintenance of infection. In this study, proteome-wide phosphorylation events of host cell proteins were investigated in response to infection with T. gondii and N. caninum using phosphoproteomic analyses, followed by pathway analysis on host signalling pathways. A few interesting differences in host responses at both the qualitative and quantitative levels were identified between the two infections; about one third of the phosphoproteomes, approximately 21% of the phospho-motifs and several pathways such as glycolysis/gluconeogenesis and mTOR pathways of the host cell were found differentially enriched between infection with these parasites. Identifying the differences in host-parasite interactions represents a promising step forward for uncovering the biological dissimilarities between both parasites. PMID- 28803362 TI - Perceptuo-motor planning during functional reaching after stroke. AB - In healthy young adults, reaching movements are planned such that the initial grasp position on the object is modulated based on the final task goal. This perceptuo-motor coupling has been described as the end-state comfort effect. This study aimed to determine the extent to which visuo-perceptual and motor deficits, but not neglect, due to stroke impact end-state comfort measured as the grasp height effect. Thirty-four older adults (17 controls, 17 chronic stroke) performed a functional goal-directed two-sequence task with each arm, consisting of reaching and moving a cylindrical object (drain plunger) from an initial to four target platform heights, standardized to body height, in a block randomized sequence. Arm motor impairment (Fugl-Meyer Assessment) and visual-perceptual deficits (Motor-Free Visual Perception Test) were assessed in stroke subjects, and arm and trunk kinematics were assessed in all subjects. The primary outcome measure of the grasp-height effect was the relationship between the grasp heights used at the home position and the final target platform heights. Mixed model analysis was used for data analysis. The grasp-height effect was present in all participants, but decreased in stroke subjects with visuo-perceptual impairments compared to controls. In stroke subjects with sensorimotor impairments alone, indicated by altered kinematics, the grasp-height effect was comparable to controls. This first study examining the grasp-height effect in individuals with stroke provides new knowledge of the impact of visuo-perceptual deficits on movement planning and execution, which may assist clinicians in selecting more effective treatment strategies to improve perceptuo-motor skills and enhance motor recovery. PMID- 28803363 TI - Evaluation of nonablative fractional laser treatment in scar reduction. AB - Fractional lasers have been used for the improvement of scar tissue in the recent years but there has not been extensive research on their impact. The purpose of this study was to evaluate the efficacy of nonablative fractional laser (NAFL) on acne, burn, and surgery/traumatic scar. The scars were also categorized as atrophic, hypertrophic, and keloid, and treatment efficacy was investigated accordingly. This is a retrospective, single-center study. Scar tissues were treated using a nonablative fractional 1550-nm Erbium glass laser in high-energy parameters at 4-week interval for 4-8 sessions. The scar regression score (SRS) was used to determine the decrease in scar appearance. Forty-six patients with acne (n:18), burn (n:13), or surgery/traumatic (n:15) scar were included. The number of sessions was higher for burn patients while SRS in burn patients was lower than in patients with acne or a surgical/traumatic scar. Evaluation according to scar types showed that atrophic scars had a significantly better response to NAFL treatment. This study indicates that NAFL treatment with the high-energy parameters has better outcomes in atrophic acne scars, while the success rate is considerably low in post-burn and keloid scars. PMID- 28803365 TI - Energy drinks and their component modulate attention, memory, and antioxidant defences in rats. AB - PURPOSE: This study aimed to evaluate the effects of the subchronic consumption of energy drinks and their constituents (caffeine and taurine) in male Wistar rats using behavioural and oxidative measures. METHODS: Energy drinks (ED 5, 7.5, and 10 mL/kg) or their constituents, caffeine (3.2 mg/kg) and taurine (40 mg/kg), either separately or in combination, were administered orally to animals for 28 days. Attention was measured though the ox-maze apparatus and the object recognition memory test. Following behavioural analyses, markers of oxidative stress, including SOD, CAT, GPx, thiol content, and free radicals, were measured in the prefrontal cortex, hippocampus, and striatum. RESULTS: The latency time to find the first reward was lower in animals that received caffeine, taurine, or a combination of both (P = 0.003; ANOVA/Bonferroni). In addition, these animals took less time to complete the ox-maze task (P = 0.0001; ANOVA/Bonferroni), and had better short-term memory (P < 0.01, Kruskal-Wallis). The ED 10 group showed improvement in the attention task, but did not differ on other measures. In addition, there was an imbalance in enzymatic markers of oxidative stress in the prefrontal cortex, the hippocampus, and the striatum. In the group that received both caffeine and taurine, there was a significant increase in the production of free radicals in the prefrontal cortex and in the hippocampus (P < 0.0001; ANOVA/Bonferroni). CONCLUSIONS: Exposure to a combination of caffeine and taurine improved memory and attention, and led to an imbalance in the antioxidant defence system. These results differed from those of the group that was exposed to the energy drink. This might be related to other components contained in the energy drink, such as vitamins and minerals, which may have altered the ability of caffeine and taurine to modulate memory and attention. PMID- 28803364 TI - Volatile terpenoids: multiple functions, biosynthesis, modulation and manipulation by genetic engineering. AB - MAIN CONCLUSION: Terpenoids play several physiological and ecological functions in plant life through direct and indirect plant defenses and also in human society because of their enormous applications in the pharmaceutical, food and cosmetics industries. Through the aid of genetic engineering its role can by magnified to broad spectrum by improving genetic ability of crop plants, enhancing the aroma quality of fruits and flowers and the production of pharmaceutical terpenoids contents in medicinal plants. Terpenoids are structurally diverse and the most abundant plant secondary metabolites, playing an important role in plant life through direct and indirect plant defenses, by attracting pollinators and through different interactions between the plants and their environment. Terpenoids are also significant because of their enormous applications in the pharmaceutical, food and cosmetics industries. Due to their broad distribution and functional versatility, efforts are being made to decode the biosynthetic pathways and comprehend the regulatory mechanisms of terpenoids. This review summarizes the recent advances in biosynthetic pathways, including the spatiotemporal, transcriptional and post-transcriptional regulatory mechanisms. Moreover, we discuss the multiple functions of the terpene synthase genes (TPS), their interaction with the surrounding environment and the use of genetic engineering for terpenoid production in model plants. Here, we also provide an overview of the significance of terpenoid metabolic engineering in crop protection, plant reproduction and plant metabolic engineering approaches for pharmaceutical terpenoids production and future scenarios in agriculture, which call for sustainable production platforms by improving different plant traits. PMID- 28803368 TI - Political Affiliation, Spirituality, and Religiosity: Links to Emerging Adults' Life Satisfaction and Optimism. AB - The goal of this study was to extend the existing literature regarding the intersection between belief systems shaping psychological processes and subjective well-being among emerging adults. A nationwide sample of 3966 college students reported on their political affiliation, spirituality, and religiosity in relation to their subjective well-being. Multivariate analyses demonstrated that politically conservative participants were significantly more optimistic and satisfied with life than their liberal counterparts and Republican emerging adults reported significantly higher life satisfaction than Democrats. Republican emerging adults also reported significantly higher rates of religiosity and spirituality than Democratic and Independent politically affiliated emerging adults. Our findings corroborate and expand upon existing literature regarding belief systems and political identity as determinants of subjective well-being in emerging adults. PMID- 28803367 TI - The role of agonist and antagonist muscles in explaining isometric knee extension torque variation with hip joint angle. AB - PURPOSE: The biarticular rectus femoris (RF), operating on the ascending limb of the force-length curve, produces more force at longer lengths. However, experimental studies consistently report higher knee extension torque when supine (longer RF length) compared to seated (shorter RF length). Incomplete activation in the supine position has been proposed as the reason for this discrepancy, but differences in antagonistic co-activation could also be responsible due to altered hamstrings length. We examined the role of agonist and antagonist muscles in explaining the isometric knee extension torque variation with changes in hip joint angle. METHOD: Maximum voluntary isometric knee extension torque (joint MVC) was recorded in seated and supine positions from nine healthy males (30.2 +/ 7.7 years). Antagonistic torque was estimated using EMG and added to the respective joint MVC (corrected MVC). Submaximal tetanic stimulation quadriceps torque was also recorded. RESULT: Joint MVC was not different between supine (245 +/- 71.8 Nm) and seated (241 +/- 69.8 Nm) positions and neither was corrected MVC (257 +/- 77.7 and 267 +/- 87.0 Nm, respectively). Antagonistic torque was higher when seated (26 +/- 20.4 Nm) than when supine (12 +/- 7.4 Nm). Tetanic torque was higher when supine (111 +/- 31.9 Nm) than when seated (99 +/- 27.5 Nm). CONCLUSION: Antagonistic co-activation differences between hip positions do not account for the reduced MVC in the supine position. Rather, reduced voluntary knee extensor muscle activation in that position is the major reason for the lower MVC torque when RF is lengthened (hip extended). These findings can assist standardising muscle function assessment and improving musculoskeletal modelling applications. PMID- 28803366 TI - Does hypoglycaemia affect the improvement in QoL after the transition to insulin in people with type 2 diabetes? AB - PURPOSE: Quality of Life (QoL) of insulin-naive people with type 2 diabetes mellitus (T2DM) improves after transition to insulin. Little is known about the role of hypoglycaemia in this context. Secondary analyses of the Study of the Psychological Impact in Real care of Initiating insulin glargine Treatment (SPIRIT) aimed to investigate the relationship between hypoglycaemia and QoL when transitioning to insulin. METHODS: Insulin-naive Dutch people with T2DM in suboptimal glycaemic control (HbA1c >53 mmol/mol; 7.0%) on maximum dose of oral glucose-lowering medications were included from 363 primary care practices (n = 911). Participants started insulin glargine and completed QoL-questionnaires (WHO 5 Well-being Index (WHO-5; emotional well-being), Hypoglycaemia Fear Survey-worry scale (HFS-w; hypoglycaemia fear) and Diabetes Symptom Checklist-revised (DSC-r; diabetes symptom distress) at baseline, 3 and 6 months follow-up. Linear GEE analyses were used to investigate the association between symptomatic, nocturnal, severe hypoglycaemia (number of episodes during 3 months prior to visit) and QoL over time. RESULTS: 52.5% men participated, mean age 62.2 years (SD +/- 10.92), and median HbA1c 67 mmol/mol (range 61-77) (8.3%). More symptomatic hypoglycaemic episodes were associated with higher HFS-w and DSC-r scores (P < 0.01). Experiencing multiple nocturnal or severe episodes was related to higher symptom distress as well, when compared to no episodes. These associations did not change significantly over time. CONCLUSIONS: Hypoglycaemia is associated with lower QoL in terms of hypoglycaemia fear and diabetes symptom distress. The transition to insulin does not affect this relationship, suggesting hypoglycaemia in itself has a detrimental effect on diabetes-related QoL independent of treatment regimen. PMID- 28803369 TI - Volume Balance and Intradialytic Ultrafiltration Rate in the Hemodialysis Patient. AB - PURPOSE OF REVIEW: Volume management in hemodialysis patients is often challenging. Assessing volume status and deciding how much fluid to remove during hemodialysis, the so-called ultrafiltration rate (UFR), has remained a conundrum. RECENT FINDINGS: To date there is no objective assessment tool to determine the needed UFR during each hemodialysis session. Higher volume overload or higher UFR is associated with poor outcomes including worse mortality and unfavorable clinical outcomes. We suggest combined use of the following criteria to determine UFR or post-dialysis target dry weight: pre-hemodialysis blood pressure and its intradialytic changes, muscle cramps, dyspnea from pulmonary vascular congestion, peripheral edema, tachycardia or palpitation, headache or lightheadedness, perspiration, and post-dialysis fatigue. Restricting fluid and salt intake-and high-dose loop diuretic use in cases of residual kidney function-can be helpful in controlling fluid gains. More frequent and more severe hypotensive episodes are associated with poor outcomes including higher death risk. PMID- 28803371 TI - Isolation, molecular characterization and an artificial infection model for a variant porcine epidemic diarrhea virus strain from Jiangsu Province, China. AB - Porcine epidemic diarrhea virus (PEDV) is a causative agent of porcine intestinal disease, which causes vomiting, diarrhea, and dehydration in piglets. PEDV is associated with the most severe pathogenesis in one-week-old piglets, with mortality rates reaching 100%. A PEDV strain was isolated from the intestinal tract of diarrheic piglets from a pig farm in Jiangsu Province in March 2016, termed the JS201603 isolate. The isolated virus was confirmed to be PEDV via RT PCR, electron microscopy, a cytopathic effect assay and sequence analysis. The S and ORF3 genes of the JS201603 isolate were sequenced, revealing that the S gene was associated with a 15-base insertion at 167 nt, 176 - 186 nt, and 427 - 429 nt, as well as a six-base deletion in 487 - 492 nt, indicating that it was a current epidemic variant compared with the classical strain, CV777. No deletion occurred between 245 - 293 nt of the ORF3 gene in the JS201603 isolate compared with the vaccine isolates YY2013 and SQ2014. An experimental infection model indicated that the piglets in the challenge group successively developed diarrhea, exhibiting yellow-colored loose stools with a foul odor. The piglets in the JS201603 isolate challenge group displayed reduced food consumption, lost weight, and in severe cases even died. No abnormalities were observed in the control group. The JS201603 variant isolated in this study contributes to the evolutionary analysis of diarrhea virus. The experimental infection model has established a foundation for further studies on vaccine development. PMID- 28803372 TI - Oxidation of winery wastewater by sulphate radicals: catalytic and solar photocatalytic activations. AB - The treatment of winery effluents through sulphate radical-based advanced oxidation processes (SR-AOPs) driven by solar radiation is reported in this study. Photolytic and catalytic activations of peroxymonosulphate (PMS) and persulphate (KPS and SPS) at different pH values (4.5 and 7) were studied in the degradation of organic matter. Portugal is one of the largest wine producers in Europe. The wine making activities generate huge volume of effluents characterized by a variable volume and organic load, being their seasonal nature one of the most important drawbacks. Recently, SR-AOPs are gradually attracting attention as in situ chemical oxidation technologies, instead of hydroxyl radical AOPs (HR-AOPs). The studied concentrations are suitable to obtain notable values of organic matter degradation, with TOC removal around 50%. In general terms, no notable differences were observed between treatments at pH values 4.5 and 7. Photolytic activation of SPS with solar radiation treatments obtained the highest efficiency (28 and 40% of TOC removal with 1 and 50 mM, respectively, at pH 4.5) in comparison to KPS and PMS. The addition of a transition metal as catalyst, such as Fe(II) or Co(II), increased considerably the TOC removal efficiency higher than 50%, but not in all cases. For instance, the combination KPS or PMS with Co(II) at pH 4.5 did not allow to obtain better results than photolytic activation of these persulphate salts. In summary, the use of SR-AOPs could be a serious alternative as tertiary treatment for winery wastewaters. PMID- 28803373 TI - TH2A is phosphorylated at meiotic centromere by Haspin. AB - Histone phosphorylation is sometimes associated with mitosis and meiosis. We have recently identified a phosphorylation of the 127th threonine on TH2A (pTH2A), a germ cell-specific H2A variant, in condensed spermatids and mitotic early preimplantation embryos of mice. Here, we further report the existence of pTH2A at the centromeres in metaphase I spermatocytes and oocytes. Moreover, we identified Haspin, a known kinase for the 3rd threonine on H3, is responsible for pTH2A in vivo. In contrast to the severe meiotic defect in oocytes treated with a Haspin inhibitor, pTH2A-deficient mice, in which the 127th threonine was replaced by alanine, maintained the fertility and exhibited no obvious defect in both oocytes and spermatogenesis. Interestingly, pTH2A was significantly decreased in aged oocytes, suggesting that its accumulation is regulated by centromeric cohesins. Collectively, our study proposes a new set of kinase-histone pair at meiotic centromere, which is highly coordinated during meiosis. PMID- 28803374 TI - Let me be your guide: physical guidance improves spatial learning for older adults with simulated low vision. AB - Monitoring one's safety during low vision navigation demands limited attentional resources which may impair spatial learning of the environment. In studies of younger adults, we have shown that these mobility monitoring demands can be alleviated, and spatial learning subsequently improved, via the presence of a physical guide during navigation. The present study extends work with younger adults to an older adult sample with simulated low vision. We test the effect of physical guidance on improving spatial learning as well as general age-related changes in navigation ability. Participants walked with and without a physical guide on novel real-world paths in an indoor environment and pointed to remembered target locations. They completed concurrent measures of cognitive load on the trials. Results demonstrate an improvement in learning under low vision conditions with a guide compared to walking without a guide. However, our measure of cognitive load did not vary between guidance conditions. We also conducted a cross-age comparison and found support for age-related declines in spatial learning generally and greater effects of physical guidance with increasing age. PMID- 28803376 TI - Debris flow-induced topographic changes: effects of recurrent debris flow initiation. AB - Chushui Creek in Shengmu Village, Nantou County, Taiwan, was analyzed for recurrent debris flow using numerical modeling and geographic information system (GIS) spatial analysis. The two-dimensional water flood and mudflow simulation program FLO-2D were used to simulate debris flow induced by rainfall during typhoon Herb in 1996 and Mindulle in 2004. Changes in topographic characteristics after the debris flows were simulated for the initiation of hydrological characteristics, magnitude, and affected area. Changes in topographic characteristics included those in elevation, slope, aspect, stream power index (SPI), topographic wetness index (TWI), and hypsometric curve integral (HI), all of which were analyzed using GIS spatial analysis. The results show that the SPI and peak discharge in the basin increased after a recurrence of debris flow. The TWI was higher in 2003 than in 2004 and indicated higher potential of landslide initiation when the slope of the basin was steeper. The HI revealed that the basin was in its mature stage and was shifting toward the old stage. Numerical simulation demonstrated that the parameters' mean depth, maximum depth, affected area, mean flow rate, maximum flow rate, and peak flow discharge were increased after recurrent debris flow, and peak discharge occurred quickly. PMID- 28803375 TI - Lung ultrasound in internal medicine efficiently drives the management of patients with heart failure and speeds up the discharge time. AB - Lung ultrasound (LUS) is a valid tool for the assessment of heart failure (HF) through the quantification of the B-lines. This study in HF patients aims to evaluate if LUS: (1) can accelerate the discharge time; (2) can efficiently drive diuretic therapy dosage; and (3) may have better performance compared to the amino-terminal portion of B type natriuretic peptide (NT-proBNP) levels in monitoring HF recovery. A consecutive sample of 120 HF patients was admitted from the Emergency Department (ED) to the Internal Medicine Department (Verona University Hospital). The Chest X-ray (CXR) group underwent standard CXR examination on admission and discharge. The LUS group underwent LUS on admission, 24, 48 and 72 h later, and on discharge. The Inferior Cava Vein Collapsibility Index, ICVCI, and the NT-proBNP were assessed. LUS discharge time was significantly shorter if compared to CXR group (p < 0.01). During hospitalization, the LUS group underwent an increased number of diuretic dosage modulations compared to the CXR group (p < 0.001). There was a stronger association between partial pressure of oxygen in arterial blood (PaO2) and B lines compared to the association between PaO2 and NT-proBNP both on admission and on discharge (p < 0.001). The B-lines numbers were significantly higher on admission in patients with more severe HF, and the ICVCI was inversely associated with B-lines number (p < 0.001). The potential of LUS in tailoring diuretic therapy and accelerating the discharge time in HF patients is confirmed. Until the technique comes into common use in different departments, it is plausible that LUS will evolve with different facets. PMID- 28803370 TI - IP3 receptor signaling and endothelial barrier function. AB - The endothelium, a monolayer of endothelial cells lining vessel walls, maintains tissue-fluid homeostasis by restricting the passage of the plasma proteins and blood cells into the interstitium. The ion Ca2+, a ubiquitous secondary messenger, initiates signal transduction events in endothelial cells that is critical to control of vascular tone and endothelial permeability. The ion Ca2+ is stored inside the intracellular organelles and released into the cytosol in response to environmental cues. The inositol 1,4,5-trisphosphate (IP3) messenger facilitates Ca2+ release through IP3 receptors which are Ca2+-selective intracellular channels located within the membrane of the endoplasmic reticulum. Binding of IP3 to the IP3Rs initiates assembly of IP3R clusters, a key event responsible for amplification of Ca2+ signals in endothelial cells. This review discusses emerging concepts related to architecture and dynamics of IP3R clusters, and their specific role in propagation of Ca2+ signals in endothelial cells. PMID- 28803377 TI - Temporary successful results of ventral rectopexy for enterocele surgical correction, about 138 patients. AB - PURPOSE: This work aimed to analyse short- and long-term results of enterocele surgical treatment by ventral rectopexy. METHODS: All females who underwent ventral rectopexy for enterocele in our department were included. All patients underwent standardized preoperative evaluation. Data was retrospectively collected, after examination of patients or by telephone survey. Postoperative evaluation was performed by an independent observer. RESULTS: One hundred thirty eight females (median age = 63 years [21-86 years]) were included. They were postmenopausal and multiparous in 94 and 70% of cases, respectively. Pelvic pressure, vaginal prolapse, or the both were observed in 28, 16 or 56% of the patients, respectively. The most frequent associated symptoms were dyschezia (63%) and faecal incontinence (30%). On preoperative workup, enterocele was isolated in two cases. Rectocele, internal rectal prolapse and cervicocystoptosis were the most frequently associated pelvic floor disorders. Ventral rectopexy was performed through laparoscopy in 128 patients (93%). In the short term, all pelvic symptoms were significantly improved, except urinary incontinence. At the end of follow-up (56 months [7-125]), specific symptoms and dyschezia were still significantly improved. Secondary failure was reported in 31% of patients. By multivariate analysis, two predictive factors for long-term failure were found: diagnosis of rectocele on preoperative MRI (odd ratio = 15; 95% CI 1.4-163; p = 0.03) and conversion into open surgery (odd ratio = 8; 95% CI 1.4-43; p = 0.02). CONCLUSION: This study suggests that ventral rectopexy is an effective treatment of enterocele, but secondary failure can be observed. Patients should be informed of the potential risk of long-term degradation. PMID- 28803378 TI - QT interval prolongation in hospitalized patients on cardiology wards: a prospective observational study. AB - PURPOSE: Prolonged QT interval may lead to a lethal form of arrhythmia, torsades de pointes (TdP), which is associated with cardiovascular mortality. Therefore, we aimed to identify prevalence of QT interval prolongation, compare clinical characteristics of patients with normal and prolonged QT interval, and identify predictors of QT interval prolongation. METHODS: A prospective observational study was conducted in cardiology wards of two teaching hospitals in Pakistan. Bazett's correction formula was used for the calculation of QTc interval. Prevalence of QT prolongation and pro-QTc scores were calculated. Comparative analysis was performed with respect to various clinical characteristics by applying t test and chi-square test. Odds ratios were calculated using regression analysis. RESULTS: Among 417 patients, 44.6% were found having prolonged QT interval, of which, 17.3% presented with an abnormally high QTc interval (> 500 ms). Significant difference was recorded between the groups (normal vs. prolonged) with respect to age, all prescribed medications, QT drugs, number of risk factors, QT-DDIs (QT-prolonging drug-drug interactions), gender, and diuretics use. Multivariate logistic regression analysis showed significant results for various predictors such as male gender (p = 0.03), various age categories 41-50 years (p = 0.04), 51-60 years (p = 0.01), and > 60 years (p < 0.001), and diuretics (p = 0.008). CONCLUSION: A substantial number of patients in cardiology wards presented with QT prolongation. Proper considerations are needed in order to minimize the associated risk particularly in patients with abnormally high QT prolongation, old age, polypharmacy, one or more QT-prolonging drugs, and high pro-QTc scores. PMID- 28803379 TI - Effects of live Myriophyllum aquaticum and its straw on cadmium accumulation in Nasturtium officinale. AB - The purpose of this study is to determine whether the allelopathy of living Myriophyllum aquaticum and its straw has the same effects; two pot experiments were conducted to study the effects of intercropping using M. aquaticum and its straw on the growth and cadmium (Cd) accumulation of Nasturtium officinale. Different planting ratios (1:3, 2:2 and 3:1) of N. officinale and M. aquaticum led to an increase in the biomass of both plant species and increased the Cd content in roots and shoots of N. officinale, but led to a reduction in the Cd content in roots and shoots of M. aquaticum. When the intercropping ratio of N. officinale and M. aquaticum was 3:1, the Cd amount in whole plants reached the maximum of 293.96 MUg pot-1. Mulching the straw of M. aquaticum roots on the soil surface increased the biomass of N. officinale, but mulching the straw of M. aquaticum stems and leaves led to a decrease. Mulching the straw of roots, stems and leaves of M. aquaticum reduced Cd content and amounts in roots and shoots of N. officinale. Intercropping with M. aquaticum can improve the Cd uptake ability of N. officinale, but mulching M. aquaticum straw can reduce its Cd uptake ability. PMID- 28803380 TI - Aerobic interval training reduces vascular resistances during submaximal exercise in obese metabolic syndrome individuals. AB - PURPOSE: The aim of this study was to determine the effects of high-intensity aerobic interval training (AIT) on exercise hemodynamics in metabolic syndrome (MetS) volunteers. METHODS: Thirty-eight, MetS participants were randomly assigned to a training (TRAIN) or to a non-training control (CONT) group. TRAIN consisted of stationary interval cycling alternating bouts at 70-90% of maximal heart rate during 45 min day-1 for 6 months. RESULTS: CONT maintained baseline physical activity and no changes in cardiovascular function or MetS factors were detected. In contrast, TRAIN increased cardiorespiratory fitness (14% in VO2PEAK; 95% CI 9-18%) and improved metabolic syndrome (-42% in Z score; 95% CI 83-1%). After TRAIN, the workload that elicited a VO2 of 1500 ml min-1 increased 15% (95% CI 5-25%; P < 0.001). After TRAIN when subjects pedaled at an identical submaximal rate of oxygen consumption, cardiac output increased by 8% (95% CI 4 11%; P < 0.01) and stroke volume by 10% (95% CI, 6-14%; P < 0.005) being above the CONT group values at that time point. TRAIN reduced submaximal exercise heart rate (109 +/- 15-106 +/- 13 beats min-1; P < 0.05), diastolic blood pressure (83 +/- 8-75 +/- 8 mmHg; P < 0.001) and systemic vascular resistances (P < 0.01) below CONT values. Double product was reduced only after TRAIN (18.2 +/- 3.2-17.4 +/- 2.4 bt min-1 mmHg 10-3; P < 0.05). CONCLUSIONS: The data suggest that intense aerobic interval training improves hemodynamics during submaximal exercise in MetS patients. Specifically, it reduces diastolic blood pressure, systemic vascular resistances, and the double product. The reduction in double product, suggests decreased myocardial oxygen demands which could prevent the occurrence of adverse cardiovascular events during exercise in this population. CLINICALTRIALS. GOV IDENTIFIER: NCT03019796. PMID- 28803381 TI - Effect of soil pH and organic matter on the adsorption and desorption of pentachlorophenol. AB - Various properties of soil affect the partition of organic contaminants within, and conversely, the properties of the organic contaminants also directly affect their partition behavior in soil. Therefore, understanding the effects of various properties of soil on the partition of organic contaminants favors subsequent assessment and provides soil remediation methods for policymakers. This study selected pentachlorophenol (PCP), a common hydrophobic ionizable organic compound in contaminated sites worldwide, as the target contaminant. The effects of pH, organic matter, and the combination of both, on PCP adsorption/desorption behavior in soil were investigated. Phosphoric acid and potassium hydroxide were used as buffer solutions to modify the soil pH by the batch and column extraction methods. A common retail organic fertilizer and fulvic acid were selected as additives to manipulate the soil organic content. Modifying the pH of the soil samples revealed that acidic soil exhibited a greater PCP adsorption rate than alkaline soil. The amount of PCP desorption increased regardless of pH of the in situ contaminated soil. The adsorption of PCP increased with increasing amount of organic additive. However, addition of fulvic acid yielded different results compared to the addition of organic fertilizer. Specifically, the organic fertilizer could not compete with the in situ contaminated soil in PCP adsorption, whereas fulvic acids increased the PCP dissolution to facilitate adsorbing contaminant adsorption. The combined effect of pH modification and organic matter addition provides additional PCP adsorption sites; therefore, adding the organic fertilizer to decrease the soil pH elevated the PCP adsorption rates of the laterite, alluvial, and in situ contaminated soil samples. The study results revealed that both pH and organic matter content are crucial to PCP adsorption/desorption in soil. Therefore, the effects of soil pH and organic matter should be considered in facilitating PCP treatment for soil remediation. PMID- 28803384 TI - Does obesity modify the relationship between physical activity and breast cancer risk? AB - PURPOSE: With only 5-10% of breast cancer cases attributed to genetic inheritance, prevention efforts have focused on modifiable risk factors. Physical activity plays a role in reducing breast cancer risk; however, the interaction between physical activity and other modifiable risk factors, such as obesity, has received little attention. METHODS: A systematic review and meta-analysis was conducted of studies examining the relationship between physical activity and breast cancer and how it may be modified by body mass index (BMI). RESULTS: A total of 29 papers were included: 18 were cohort and 11 were case-control studies. Overall, a significant reduction in the relative risk of breast cancer was found in postmenopausal women with high versus low levels of physical activity for women with a BMI <25 kg/m2 (RR 0.85, 95% CI 0.79, 0.92) and >=25 kg/m2 (RR 0.87, 95% CI 0.81, 0.93) but not >=30 kg/m2 (RR: 0.93, 95% CI 0.76, 1.13). Physical activity was not associated with a significant reduction in risk of breast cancer in premenopausal women in any BMI group. CONCLUSION: The results of this meta-analysis suggest that physical activity is associated with a larger breast cancer risk reduction among women who are normal weight or overweight than among women who are obese. Since the included studies used diverse methods for assessment of physical activity and categories of BMI, results should be interpreted with caution and additional work is needed. PMID- 28803383 TI - Synchronous colorectal liver metastases: focus on the elderly : An Effectiveness Study from Routine Care. AB - PURPOSE: The goal of this study was to analyze the use and the effectiveness of both surgery and different chemotherapies in patients with synchronous colorectal liver metastases (CLMs) >=70 years compared to younger patients. METHODS: Survival was analyzed in 456 patients (24.3% >=70 years) treated for CLM in a single center using Kaplan-Meier estimation of overall survival (OS), calculation of relative survival as estimate for disease-specific survival, and a Cox regression model. RESULTS: Complete surgical resections were achieved more often in patients aged <70 years (39.2 vs. 28.1%, P = 0.056), and young patients more frequently received irinotecan or platin-based chemotherapies (70.3 vs. 41.6%, P < 0.001). Three-year OS and relative survival of patients >=70 years were significantly lower compared to younger patients (OS 34.3 vs. 43.5%, P = 0.0114). In a Cox regression model, complete surgical removal of liver metastases was the most effective treatment (HR 0.313, P < 0.001) followed by chemotherapy (irinotecan/platin-based: HR 0.371, 5-FU only: HR 0.673, P < 0.001). Having >5 liver metastases, the presence of extrahepatic metastases, high grading, and a nodal positive primary but not age >=70 years were associated with an increased risk of death. CONCLUSIONS: Our data support radical resection and highly effective chemotherapy in selected elderly patients with CLM. PMID- 28803382 TI - Cortical afferent inhibition abnormalities reveal cholinergic dysfunction in Parkinson's disease: a reappraisal. AB - Parkinson's disease (PD) is a multisystem neurodegenerative disorder affecting, besides the dopaminergic function, multiple neurotransmission systems, including the cholinergic system. Central cholinergic circuits of human brain can be tested non-invasively by coupling peripheral nerve stimulation with transcranial magnetic stimulation (TMS) of motor cortex; this test is named short latency afferent inhibition (SAI). SAI abnormalities have been reported in PD patients with gait disturbances and many non-motor symptoms, such as visual hallucinations (VHs), REM sleep behavior disorder (RBD), dysphagia, and olfactory impairment. The findings of these TMS studies strongly suggest that cholinergic degeneration is an important contributor to a number of clinical features of PD. TMS and neuropsychological raise the possibility that the presence of RBD, VHs and olfactory dysfunction indicate increased risk of cognitive impairment in patients with PD. Longitudinal studies of the patients are required to verify whether SAI abnormalities can predict a future severe cognitive decline. TMS can provide simple measures that may represent suitable biomarkers of cholinergic neurotransmission in PD. SAI studies enable an early recognition of PD patients with cholinergic system degeneration, and this might allow future targeted cholinergic treatment approaches, in addition to dopaminergic therapy, to ameliorate non-motor and motor clinical symptoms in PD patients. PMID- 28803385 TI - 'Real-life experience': recurrence rate at 3 years with Hexvix(r) photodynamic diagnosis-assisted TURBT compared with good quality white light TURBT in new NMIBC-a prospective controlled study. AB - PURPOSE: To compare the recurrence rate at 3 years (RR-3y) for non-muscle invasive bladder cancer (NMIBC) between good quality (GQ) PDD-TURBT and GQWL TURBT where PDD is used in routine practice for all new tumours. METHODS: All new, consecutive, NMIBC that received "good quality" criteria first TURBT across a university hospital service were prospectively recruited to this study over a 4 year period. Data were prospectively collected on all WL-TURBTs performed in 2007/8 and compared with PDD-TURBT from 2009/10. Only resection meeting strict "good quality criteria" were included from each cohort to control for resection quality, then cases were further matched 1:1 based on demographic and pathological criteria. The primary outcome was overall and risk group-specific recurrence rate at 3 years. RESULTS: Of 808 patients recruited, 345 had GQ-TURBT for NMIBC and were included. RR-3y was significantly less for GQ-PDD overall [RR 3y: GQ-PDD: 57/146 (39.0%), GQ-WL: 72/135 (53.3%) OR = 0.56 (0.35-0.90) p = 0.02] and on a 1:1 matched pair basis [RR GQ-PDD: 29/118 (24.6) vs. 59/118 (50.0) OR 0.33 (0.19-0.57) p < 0.001)]. Benefit was most marked in high-risk patients: RR 3y in high-risk patients treated with GQ-PDD was 25/48 (52.1%) vs. 28/35 (80%) for GQ-WL [OR 0.27 (0.10-0.74) p = 0.01]. CONCLUSION: When adopted for all new bladder tumour resections in routine practice, PDD appears to be associated with significantly reduced recurrence rates at 3 years in our "real life" experience, particularly in high-risk patients. PMID- 28803386 TI - Sexual intercourse as a new option in the medical expulsive therapy of distal ureteral stones in males: a prospective, randomized, controlled study. AB - PURPOSE: To investigate the effect of sexual intercourse on the spontaneous passage of distal ureteral stones 5-10 mm in size. METHODS: A total of 190 male patients with distal ureteral stones were randomly divided into three groups. Patients in group 1 were administered tamsulosin 0.4 mg/day (n = 60). Patients in group 2 were asked to have sexual intercourse at least three times a week (n = 66). Patients in group 3 received standard medical therapy alone and acted as the controls (n = 64). The expulsion rate was controlled after 2 and 4 weeks. Differences between the groups were analyzed statistically by the Chi-square and Student's t test. p < 0.05 was considered as statistically significant. RESULTS: The mean ages of the patients in groups 1, 2, and 3 were 34.4 +/- 13.5 (18-60), 38.6 +/- 14.1 (18-63), and 36.92 +/- 12.4 (18-59) years, respectively (p > 0.05). The mean stone size was 7.09 +/- 1.4 mm in group 1, 7.01 +/- 1.4 mm in group 2, and 7.1 +/- 1.3 mm in group 3 (p > 0.05). Spontaneous passage rates in groups 1, 2, and 3 were 81.6, 81.8, and 51.5%, respectively, and it was significantly higher in group 1 (p = 0.0394) and group 2 (p = 0.0350). There was no significant difference between groups 1 and 2 (p = 0.9925). The analgesic needs in groups 1, 2, and 3 were found to be 1.3 +/- 0.4, 1.2 +/- 0.6, and 1.4 +/- 0.4 times, respectively, and were significantly lower in the sexual intercourse group than in the control group (p = 0.0276). CONCLUSIONS: Tamsulosin and sexual intercourse increase the spontaneous passage of distal ureteral stones 5-10 mm in size. At least three sexual intercourses per week seem to be at least as effective as tamsulosin. Sexual intercourse also reduces the need for analgesics in ureteric colic due to ureteral stones. PMID- 28803387 TI - 1H, 15N, and 13C chemical shift assignments of the regulatory domain of human calcineurin. AB - Calcineurin (CaN) plays an important role in T-cell activation, cardiac system development and nervous system function. Previous studies have demonstrated that the regulatory domain (RD) of CaN binds calmodulin (CaM) towards the N-terminal end. Calcium-loaded CaM activates the serine/threonine phosphatase activity of CaN by binding to the RD, although the mechanistic details of this interaction remain unclear. It is thought that CaM binding at the RD displaces the auto inhibitory domain (AID) from the active site of CaN, activating phosphatase activity. In the absence of calcium-loaded CaM, the RD is disordered, and binding of CaM induces folding in the RD. In order to provide mechanistic detail about the CaM-CaN interaction, we have undertaken an NMR study of the RD of CaN. Complete 13C, 15N and 1H assignments of the RD of CaN were obtained using solution NMR spectroscopy. The backbone of RD has been assigned using a combination of 13C-detected CON-IPAP experiments as well as traditional HNCO, HNCA, HNCOCA and HNCACB-based 3D NMR spectroscopy. A 15N-resolved TOCSY experiment has been used to assign Halpha and Hbeta chemical shifts. PMID- 28803388 TI - Genetic diversity of the human head lice, Pediculus humanus capitis, among primary school girls in Saudi Arabia, with reference to their prevalence. AB - The present work aimed at investigating the genetic diversity of the head louse Pediculus humanus capitis (P. humanus capitis) among infested primary school girls at Bisha governorate, Saudi Arabia, based on the sequence of mitochondrial cytochrome b (mt cyt b) gene of 121 P. humanus capitis adults. Additionally, the prevalence of pediculosis capitis was surveyed. The results of sequencing were compared with the sequence of human head lice that are genotyped previously. Phylogenetic tree analysis showed the presence of 100% identity (n = 26) of louse specimens with clade A (prevalent worldwide) of the GenBank data base. Louse individuals (n = 50) showed 99.8% similarity with the same clade A reference having a single base pair difference. Also, a number of 22 louse individuals revealed 99.8% identity with clade B reference (prevalent in North and Central Americas, Europe, and Australia) with individual diversity in two base pairs. Moreover, 14 louse individual sequences revealed 99.4% identity with three base pair differences. It was concluded that moderate pediculosis (~13%) prevailed among the female students of the primary schools. It was age-and hair texture (straight or curly)-dependent. P. humanus capitis prevalence diversity is of clades A and B genotyping. PMID- 28803389 TI - Gastrointestinal Manifestations of STAT3-Deficient Hyper-IgE Syndrome. AB - OBJECTIVE: STAT 3 deficiency (autosomal dominant hyper immunoglobulin E syndrome (AD-HIES)) is a primary immunodeficiency disorder with multi-organ involvement caused by dominant negative signal transducer and activator of transcription gene 3 (STAT3) mutations. We sought to describe the gastrointestinal (GI) manifestations of this disease. METHODS: Seventy subjects aged five to 60 years with a molecular diagnosis of AD-HIES were evaluated at the National Institutes of Health (NIH). Data collection involved a GI symptom questionnaire and retrospective chart review. RESULTS: In our cohort of 70 subjects, we found that 60% had GI symptoms (42/70). The most common manifestations were gastroesophageal reflux disease (GERD) observed in 41%, dysphagia in 31%, and abdominal pain in 24%. The most serious complications were food impaction in 13% and colonic perforation in 6%. Diffuse esophageal wall thickening in 74%, solid stool in the right colon in 50% (12/24), and hiatal hernia in 26% were the most prevalent radiologic findings. Esophagogastroduodenoscopy (EGD) demonstrated esophageal tortuosity in 35% (8/23), esophageal ulceration in 17% (4/23), esophageal strictures requiring dilation in 9% (2/23), and gastric ulceration in 17% (4/23). Esophageal eosinophilic infiltration was an unexpected histologic finding seen in 65% (11/17). CONCLUSION: The majority of AD-HIES subjects develop GI manifestations as part of their disease. Most notable are the symptoms and radiologic findings of GI dysmotility, as well as significant eosinophilic infiltration, concerning for a secondary eosinophilic esophagitis. These findings suggest that the STAT3 pathway may be implicated in a new mechanism for the pathogenesis of several GI disorders. PMID- 28803390 TI - Cancer Clonal Theory, Immune Escape, and Their Evolving Roles in Cancer Multi Agent Therapeutics. AB - PURPOSE OF REVIEW: The knowledge base of malignant cell growth and resulting targets is rapidly increasing every day. Clonal theory is essential to understand the changes required for a cell to become malignant. These changes are then clues to therapeutic intervention strategies. Immune system optimization is a critical piece to find, recognize, and eliminate all cancer cells from the host. Only by administering (1) multiple therapies that counteract the cancer cell's mutational and externally induced survival traits and (2) by augmenting the immune system to combat immune suppression processes and by enhancing specific tumor trait recognition can cancer begin to be treated with a truly targeted focus. RECENT FINDINGS: Since the sequencing of the human genome during the 1990s, steady progress in understanding genetic alterations and gene product functions are being unraveled. In cancer, this is proceeding very fast and demonstrates that genetic mutations occur very rapidly to allow for selection of survival traits within various cancer clones. Hundreds of mutations have been identified in single individual cancers, but spread across many clones in the patient's body. Precision oncology will require accurate measurement of these cancer survival benefiting mutations to develop strategies for effective therapy. Inhibiting these cellular mechanisms is a first step, but these malignant cells need to be eliminated by the host's mechanisms, which we are learning to direct more specifically. Cancer is one of the most complicated cellular aberrations humans have encountered. Rapidly developing significant survival traits require prompt, repeated, and total body measurements of these attributes to effectively develop multi-agent treatment of the individual's malignancy. Focused drug development to inhibit these beneficial mutations is critical to slowing cancer cell growth and, perhaps, triggering apoptosis. In many cases, activation and targeting of the immune system to kill the remaining malignant cells is essential to a cure. PMID- 28803391 TI - Mutational analysis of the RB1 gene and the inheritance patterns of retinoblastoma in Jordan. AB - Retinoblastoma (RB) is a childhood cancer developing in the retina due to RB1 pathologic variant. Herein we are evaluating the oncogenic mutations in the RB1 gene and the inheritance patterns of RB in the Jordanian patients. In this prospective study, the peripheral blood of 50 retinoblastoma patients was collected, genomic DNA was extracted, mutations were identified using Quantitative multiplex PCR (QM-PCR), Allele-specific PCR, Next Generation Sequencing analysis, and Sanger sequencing. In this cohort of 50 patients, 20(40%) patients had unilateral RB and 30(60%) were males. Overall, 36(72%) patients had germline disease, 17(47%) of whom had the same RB1 pathologic variant detected in one of the parents (inherited disease). In the bilateral group, all (100%) patients had germline disease; 13(43%) of them had inherited mutation. In the unilateral group, 6(30%) had germline disease, 4(20%) of them had inherited mutation. Nonsense mutation generating a stop codon and producing a truncated non-functional protein was the most frequent detected type of mutations (n = 15/36, 42%). Only one (2%) of the patients had mosaic mutation, and of the 17 inherited cases, 16(94%) had an unaffected carrier parent. In conclusion, in addition to all bilateral RB patients in our cohort, 30% of unilateral cases showed germline mutation. Almost half (47%) of germline cases had inherited disease from affected (6%) parent or unaffected carrier (94%). Therefore molecular screening is critical for the genetic counseling regarding the risk for inherited RB in both unilateral and bilateral cases including those with no family history. PMID- 28803392 TI - Attitudes of Individuals with Gaucher Disease toward Substrate Reduction Therapies. AB - Type 1 Gaucher disease (GD) is the most common lysosomal storage disorder. Previously, treatment for GD was limited to intravenous enzyme replacement therapies (ERTs). More recently, oral substrate reduction therapies (SRTs) were approved for treatment of GD. Although both therapies alleviate disease symptoms, attitudes toward SRTs and patient perceptions of health while using SRT have not been well established. Electronic surveys were administered to adults with GD and asked about treatment history, attitudes toward SRTs, and perception of health while using SRTs as compared to ERTs, if applicable to the participant. ERT users that were offered treatment with SRTs cited potential side effects, wanting more research on SRTs, and satisfaction with their current treatment regimen as reasons for declining SRTs. SRT users expressed convenience and less invasiveness as reasons for choosing SRTs. Additionally, those using SRTs most often perceived their health to be similar to when they previously used ERT. Participant responses illustrate that attitudes toward SRTs can be variable and that one particular treatment may not be ideal for all patients with GD depending on individual perceptions of factors such as convenience, invasiveness, or side effects. Thus, individuals with GD should be counseled adequately by healthcare providers about both ERTs and SRTs for treatment of GD now that SRTs are clinically available. PMID- 28803394 TI - Generation and management of waste electric vehicle batteries in China. AB - With the increasing adoption of EVs (electric vehicles), a large number of waste EV LIBs (electric vehicle lithium-ion batteries) were generated in China. Statistics showed generation of waste EV LIBs in 2016 reached approximately 10,000 tons, and the amount of them would be growing rapidly in the future. In view of the deleterious effects of waste EV LIBs on the environment and the valuable energy storage capacity or materials that can be reused in them, China has started emphasizing the management, reuse, and recycling of them. This paper presented the generation trend of waste EV LIBs and focused on interrelated management development and experience in China. Based on the situation of waste EV LIBs management in China, existing problems were analyzed and summarized. Some recommendations were made for decision-making organs to use as valuable references to improve the management of waste EV LIBs and promote the sustainable development of EVs. PMID- 28803395 TI - Isolated severe microblepharon in a neonate: a rare case. AB - PURPOSE: To report a rare case of isolated severe microblepharon in a neonate. METHODS: A 27 days old male child was brought by parents with redness, photophobia and discharge for two weeks. Thorough ophthalmological and systemic examination was performed. RESULTS: The diagnosis of isolated severe microblepharon with infectious keratitis was made. After the appropriate management of infectious keratitis and achieving complete resolution, the child was subjected to bilateral lid reconstruction was done in the form of upper lid skin grafting and tarsorrhaphy and the patient is being followed up. CONCLUSION: A rare case of bilateral isolated severe microblepharon affecting all four eyelids is being reported. Urgent surgical intervention is recommended in such cases in order to achieve good corneal coverage which results in faster healing of infective keratitis and a good visual outcome. PMID- 28803396 TI - Early Regression of Carotid Intima-Media Thickness after Bariatric Surgery and Its Relation to Serum Leptin Reduction. AB - PURPOSE: Bariatric surgery (BS) promotes carotid intima-media thickness (C-IMT) regression as early as 6 months post-surgery. To verify whether C-IMT regression occurs even earlier, we aimed at the effect of Roux-en-Y gastric bypass (RYGBP) and biliopancreatic diversion (BPD) on C-IMT 1-2 months and 12 months post surgery. SUBJECTS/METHODS: Prospective trial. BS was performed on 109 patients either with (RYGBP = 42; BDP = 40) or without type 2 diabetes (RYGBP = 27). Healthy volunteers served as control group. FOLLOW-UP: baseline, 1-2 months, 12 months post-surgery. ENDPOINTS: changes (?) in C-IMT, weight, body mass index, fat mass, waist and neck circumferences, blood pressure, HbA1c, glucose, insulin, insulin sensitivity [HOMA-IR; OGIS, from meal tolerance test], lipids, C-reactive protein, leptin, adiponectin, MCP-1. RESULTS: All surgery subgroups had similar levels of ?-C-IMT. C-IMT in the pooled surgery group reduced from [mean (95% confidence interval)] 0.81 (0.77-0.84) mm to 0.66 (0.63-0.69) mm, p < 0.001 [ 17.1 (-20.4 to -13.8)%] at 1-2 months, and to 0.63 (0.59-0.66) mm, p < 0.001 [ 21.8 (-25.3 to -18.4)%] at 12 months post-surgery. ?-C-IMT 1-2 months and 12 months post-surgery correlated to baseline C-IMT, and with ?-leptin at 1-2 months, but not at 12 months post-surgery. In linear regression analysis, ? leptin and baseline C-IMT were predictors of ?-C-IMT 1-2 months post-surgery. CONCLUSIONS: A remarkable C-IMT regression occurred as early as 1-2 months after BS in obese patients either with or without type 2 diabetes, which was associated to the early reduction in leptin, (at least partially) independent of weight loss. Whether this is a causative or correlative association needs further investigation. PMID- 28803393 TI - Challenges and Opportunities for Occupational Epidemiology in the Twenty-first Century. AB - PURPOSE OF REVIEW: There are many opportunities and challenges for conducting occupational epidemiologic studies today. In this paper, we summarize the discussion of a symposium held at the Epidemiology in Occupational Health (EPICOH) conference, Chicago 2014, on challenges for occupational epidemiology in the twenty-first century. RECENT FINDINGS: The increasing number of publications and attendance at our conferences suggests that worldwide interest in occupational epidemiology has been growing. There are clearly abundant opportunities for new research in occupational epidemiology. Areas ripe for further work include developing improved methods for exposure assessment, statistical analysis, studying migrant workers and other vulnerable populations, the use of biomarkers, and new hazards. Several major challenges are also discussed such as the rapidly changing nature and location of work, lack of funding, and political/legal conflicts. As long as work exists there will be occupational diseases that demand our attention, and a need for epidemiologic studies designed to characterize these risks and to support the development of preventive strategies. Despite the challenges and given the important past contribution in this field, we are optimistic about the importance and continued vitality of the research field of occupational epidemiology. PMID- 28803398 TI - Brainstem angiocentric gliomas with MYB-QKI rearrangements. PMID- 28803397 TI - Is Concomitant Cholecystectomy Necessary for Asymptomatic Cholelithiasis During Laparoscopic Sleeve Gastrectomy? AB - BACKGROUND: There is not any consensus on concomitant cholecystectomy for asymptomatic gallbladder stones during laparoscopic sleeve gastrectomy (LSG). The aim of this study was to evaluate the surveillance results of the LSG patients who have asymptomatic gallbladder stones and did not undergo cholecystectomy. METHODS: Patients who underwent laparoscopic sleeve gastrectomy with preoperatively detected gallbladder stones and completed at least 6 months follow up were included in the study. Concomitant cholecystectomy was performed for symptomatic patients while it was not performed for asymptomatic subjects. At the end of the follow-up time, symptoms and signs related to gallbladder disease were recorded. Clinical and demographic characteristics were compared between symptomatic and asymptomatic patients. RESULTS: Between February 2012 and October 2016, 312 laparoscopic sleeve gastrectomies were performed. Among the patients, 24 were regarded as asymptomatic cholelithiasis, and cholecystectomy was not performed. The mean follow-up period was 27 (6-58) months. The mean preoperative BMI was 50.0 +/- 7.6 kg/m2, and at the end of the follow-up time, it decreased to 35.6 +/- 8.8 kg/m2. Five (20.8%) patients experienced biliary colic. Acute cholecystitis or obstructive jaundice was not observed in any of the patients. Characteristics of patients who developed symptomatic gallbladder disease (n = 5) were not significantly different from those of patients who remained asymptomatic (n = 19). CONCLUSIONS: The risk of becoming symptomatic for asymptomatic cholelithiasis is very close to the healthy population after sleeve gastrectomy. Although further studies with a high number of cases are needed, we suggest only observation for asymptomatic gallbladder stones in patients who will undergo sleeve gastrectomy. PMID- 28803399 TI - Blood purine measurements as a rapid real-time indicator of reversible brain ischaemia. AB - To preserve the disequilibrium between ATP and ADP necessary to drive cellular metabolism, enzymatic pathways rapidly convert ADP to adenosine and the downstream purines inosine and hypoxanthine. During ischaemia, these same pathways result in the production of purines. We performed a prospective observational study to test whether purine levels in arterial blood might correlate with brain ischaemia. We made real-time perioperative measurements, via microelectrode biosensors, of the purine levels in untreated arterial blood from 18 patients undergoing regional anaesthetic carotid endarterectomy. Pre operatively, the median purine level was 2.4 MUM (95% CI 1.3-4.0 MUM); during the cross-clamp phase, the purines rose to 6.7 MUM (95% CI 4.7-11.5 MUM) and fell back to 1.9 MUM (95% CI 1.4-2.7 MUM) in recovery. Three patients became unconscious during carotid clamping, necessitating insertion of a temporary carotid shunt to restore cerebral blood flow. In these, the pre-operative median purine level was 5.4 MUM (range 4.7-6.1 MUM), on clamping, 9.6 MUM (range 9.4 16.1 MUM); during shunting, purines fell to below the pre-operative level (1.4 MUM, range 0.4-2.9 MUM) and in recovery 1.8 MUM (range 1.8-2.6 MUM). Our results suggest that blood purines may be a sensitive real-time and rapidly produced indicator of brain ischaemia, even when there is no accompanying neurological obtundation. PMID- 28803401 TI - Immigrants from Mexico experience serious behavioral and psychiatric problems at far lower rates than US-born Americans. AB - PURPOSE: To examine the prevalence of self-reported criminal and violent behavior, substance use disorders, and mental disorders among Mexican immigrants vis-a-vis the US born. METHODS: Study findings are based on national data collected between 2012 and 2013. Binomial logistic regression was employed to examine the relationship between immigrant status and behavioral/psychiatric outcomes. RESULTS: Mexican immigrants report substantially lower levels of criminal and violent behaviors, substance use disorders, and mental disorders compared to US-born individuals. CONCLUSION: While some immigrants from Mexico have serious behavioral and psychiatric problems, Mexican immigrants in general experience such problems at far lower rates than US-born individuals. PMID- 28803400 TI - Novel Biomarkers for the Risk Stratification of Heart Failure with Preserved Ejection Fraction. AB - PURPOSE OF REVIEW: The use of biomarkers in heart failure (HF) is a rapidly changing field. The purpose of this review is to assess the current evidence of the use of biomarkers for risk stratification in patients with HF with preserved ejection fraction (HFpEF). RECENT FINDINGS: Despite differences in pathophysiology between HF with reduced ejection fraction and HFpEF, traditional HF biomarkers such as brain natriuretic peptide and troponin retain prognostic value in most HFpEF-specific populations. Biomarkers of key pathophysiologic components of HFpEF, such as myocardial fibrosis, remodeling, and systemic inflammation are also valuable prognostic markers. Further investigation into HF biomarkers may identify significant therapeutic targets for the treatment of HFpEF. PMID- 28803402 TI - Actin filaments regulate the adhesion between the plasma membrane and the cell wall of tobacco guard cells. AB - During the opening and closing of stomata, guard cells undergo rapid and reversible changes in their volume and shape, which affects the adhesion of the plasma membrane (PM) to the cell wall (CW). The dynamics of actin filaments in guard cells are involved in stomatal movement by regulating structural changes and intracellular signaling. However, it is unclear whether actin dynamics regulate the adhesion of the PM to the CW. In this study, we investigated the relationship between actin dynamics and PM-CW adhesion by the hyperosmotic induced plasmolysis of tobacco guard cells. We found that actin filaments in guard cells were depolymerized during mannitol-induced plasmolysis. The inhibition of actin dynamics by treatment with latrunculin B or jasplakinolide and the disruption of the adhesion between the PM and the CW by treatment with RGDS peptide (Arg-Gly-Asp-Ser) enhanced guard cell plasmolysis. However, treatment with latrunculin B alleviated the RGDS peptide-induced plasmolysis and endocytosis. Our results reveal that the actin depolymerization is involved in the regulation of the PW-CW adhesion during hyperosmotic-induced plasmolysis in tobacco guard cells. PMID- 28803403 TI - Endoscopic Surveillance in Long-standing Colitis. AB - OPINION STATEMENT: There is a relative increase in the risk of colon cancer in patients with inflammatory bowel disease (IBD) affecting the colon, and endoscopic surveillance is advocated to mitigate this risk. The current standard practice is to survey this high-risk patient population using colonoscopy. Chromoendoscopy with targeted biopsies has emerged as the colonoscopy modality recommended by the major societies to optimize dysplasia detection. Studies over the past year support the improved yield from targeted as compared to random biopsies and improved dysplasia detection from chromoendoscopy as compared to white light endoscopy. Ongoing efforts should focus on the implementation of chromoendoscopy as the primary modality for colorectal cancer surveillance in IBD. Our review will describe current status and provide an update on the recent literature on surveillance colonoscopy in patients with IBD. PMID- 28803405 TI - PCB dechlorination hotspots and reductive dehalogenase genes in sediments from a contaminated wastewater lagoon. AB - Polychlorinated biphenyls (PCBs) are a class of persistent organic pollutants that are distributed worldwide. Although industrial PCB production has stopped, legacy contamination can be traced to several different commercial mixtures (e.g., Aroclors in the USA). Despite their persistence, PCBs are subject to naturally occurring biodegradation processes, although the microbes and enzymes involved are poorly understood. The biodegradation potential of PCB-contaminated sediments in a wastewater lagoon located in Virginia (USA) was studied. Total PCB concentrations in sediments ranged from 6.34 to 12,700 mg/kg. PCB congener profiles in sediment sample were similar to Aroclor 1248; however, PCB congener profiles at several locations showed evidence of dechlorination. The sediment microbial community structure varied among samples but was dominated by Proteobacteria and Firmicutes. The relative abundance of putative dechlorinating Chloroflexi (including Dehalococcoides sp.) was 0.01-0.19% among the sediment samples, with Dehalococcoides sp. representing 0.6-14.8% of this group. Other possible PCB dechlorinators present included the Clostridia and the Geobacteraceae. A PCR survey for potential PCB reductive dehalogenase genes (RDases) yielded 11 sequences related to RDase genes in PCB-respiring Dehalococcoides mccartyi strain CG5 and PCB-dechlorinating D. mccartyi strain CBDB1. This is the first study to retrieve potential PCB RDase genes from unenriched PCB-contaminated sediments. PMID- 28803404 TI - Polymorphisms in XRCC1, ERCC2, and ERCC3 DNA repair genes, CYP1A1 xenobiotic metabolism gene, and tobacco are associated with bladder cancer susceptibility in Tunisian population. AB - Other than the established environmental risk factors associated with bladder cancer (BC), little is known about the genetic variations determining the individual susceptibility of this complex disease. This study aimed to investigate the relationship of BC with environmental agents and polymorphisms in XRCC1, ERCC2, and ERCC3 DNA repair genes and CYP1A1, CYP2D6, NAT1, and NAT2 xenobiotic metabolism genes through a hospital-based case-control study in Tunisia. The selection of the single nucleotide polymorphisms (SNPs) (rs25487, rs 13181, rs415407, rs446421, rs1058172, rs4921880, and rs1208) was performed using the dbSNP database. DNA genotyping was determined by PCR-RFLP after DNA extraction from whole blood. The risks of BC associated with every polymorphism as well as the studied environmental factors were estimated by multivariate adjusted logistic regression using R software. In addition, gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR) methods. Results showed that tobacco smoking and chewing parameters were significantly associated with BC risk. Single-gene variant analysis showed significant associations of the TT genotype of CYP1A1 and the rare GG genotype of ERCC2 with bladder cancer susceptibility (OR = 1.34, 95% CI 1.22-1.40, P < 0.0001). According to GMDR analysis, our findings indicated a significant association between BC and gene-gene interaction among the CYP1A1, ERCC3, and XRCC1. The present results suggest a potential role of XRCC1, ERCC2, ERCC3, and CYP1A1 besides tobacco intake in susceptibility to BC. PMID- 28803406 TI - Does Wolbachia Infection Change the Overwintering Ability of Trichogramma brassicae (Hymenoptera: Trichogrammatidae)? AB - The overwintering ability of a biological control agent helps predict potential survival and establishment in natural conditions. Here, we compared the overwintering ability in sexual and asexual Trichogramma brassicae Bezdenko, a key natural enemy of Lepidopteran pests in Iran over two consecutive winters in central Alborz Mountains. Our aim was to investigate the effect of Wolbachia infection on the overwintering rate of T. brassicae after emergence in the subsequent year. We also wanted to know whether there is any difference in the overwintering capacity of T. brassicae populations either in terms of exposure date or emergence date. Parasitized host eggs were exposed under outdoor conditions between 8 October and 27 November 2013 and between 8 October and 11 December 2014. Samples were checked weekly until adult emergence of overwintered individuals in the following spring, and proportion of adult emergence was recorded on each exposure date. Our results demonstrated that both populations were able to overwinter in natural conditions of central Alborz Mountains; however, sexual T. brassicae was more successful in overwintering than asexual one. No differences were observed in the emergence date and maximum emergence rate between two populations. Our study clearly identified a potential negative impact of Wolbachia on fitness of T. brassicae by a lower rate of emergence. PMID- 28803407 TI - Frequency of hemoglobin E/beta-thalassemia compound heterozygotes with low hemoglobin F phenotype among cases with a diagnosis of hemoglobin E homozygote, determined by high-performance liquid chromatography, in prenatal control program for beta-thalassemia. PMID- 28803408 TI - Iodine-Rich Herbs and Potassium Iodate Have Different Effects on the Oxidative Stress and Differentiation of TH17 Cells in Iodine-Deficient NOD.H-2h4 Mice. AB - Iodine-rich herbs such as seaweed, kelp, and sea tangle were widely used to treat various types of goiter with good effect and without any adverse side effects in China. When compared with potassium iodate (PI), iodine-rich herbs had a positive effect on the recovery of goiter resulting from iodine deficiency without any obvious harmful effects. In NOD.H-2h4 mice, an autoimmune thyroiditis-prone model, iodine excess can increase infiltration of lymphocytes and structural damage of the thyroid follicles, hence resulting in thyroiditis. Until now, there has been little research on the comparative effects of PI and iodine-rich herbs on thyroid in an autoimmune thyroiditis-prone model. This study was designed to compare the different effects of iodine-rich herbs and PI on the thyroid gland in iodine-deficient NOD.H-2h4 mice. Excessive intake of PI cause oxidative injury in the thyroid gland and increase the risk of autoimmune thyroiditis, while iodine rich herbs cause less oxidative injury, significantly enhancing antioxidant capacity, and inhibit the high differentiation of Th17 cells in the thyroid glands of NOD.H-2h4 mice. PMID- 28803410 TI - An Investigation of Moral Principles and Mental Training in the Pali Nikayas and Their Implications for Behaviour Modification and Mental Health. AB - This article explicates the fundamental moral principles and mental training of Buddhism that have implications for behavioural transformation and mental health promotion. These techniques are considered to be effective for transforming the unwholesome thoughts and overcoming the afflictions (asavas). It investigates some methods of mental training that can be designed to fit the behaviour of a practitioner. It also investigates the three key interdependent elements of mindfulness techniques and, in particular, how a simple practice of mindfulness (sati), full awareness (sampajanna), and proper attention (yoniso-manasikara) can help us modify our behaviour and achieve mental health. PMID- 28803409 TI - Comparative 16SrDNA Gene-Based Microbiota Profiles of the Pacific Oyster (Crassostrea gigas) and the Mediterranean Mussel (Mytilus galloprovincialis) from a Shellfish Farm (Ligurian Sea, Italy). AB - The pacific oyster Crassostrea gigas and the Mediterranean mussel Mytilus galloprovincialis are two widely farmed bivalve species which show contrasting behaviour in relation to microbial diseases, with C. gigas being more susceptible and M. galloprovincialis being generally resistant. In a recent study, we showed that different susceptibility to infection exhibited by these two bivalve species may depend on their different capability to kill invading pathogens (e.g., Vibrio spp.) through the action of haemolymph components. Specific microbial-host interactions may also impact bivalve microbiome structure and further influence susceptibility/resistance to microbial diseases. To further investigate this concept, a comparative study of haemolymph and digestive gland 16SrDNA gene-based bacterial microbiota profiles in C. gigas and M. galloprovincialis co-cultivated at the same aquaculture site was carried out using pyrosequencing. Bacterial communities associated with bivalve tissues (hemolymph and digestive gland) were significantly different from those of seawater, and were dominated by relatively few genera such as Vibrio and Pseudoalteromonas. In general, Vibrio accounted for a larger fraction of the microbiota in C. gigas (on average 1.7-fold in the haemolymph) compared to M. galloprovincialis, suggesting that C. gigas may provide better conditions for survival for these bacteria, including potential pathogenic species such as V. aestuarianus. Vibrios appeared to be important members of C. gigas and M. galloprovincialis microbiota and might play a contrasting role in health and disease of bivalve species. Accordingly, microbiome analyses performed on bivalve specimens subjected to commercial depuration highlighted the ineffectiveness of such practice in removing Vibrio species from bivalve tissues. PMID- 28803411 TI - Electro-chemical deposition of nano hydroxyapatite-zinc coating on titanium metal substrate. AB - BACKGROUND: Titanium is an inert metal that does not induce osteogenesis and has no antibacterial properties; it is proposed that hydroxyapatite coating can enhance its bioactivity, while zinc can contribute to antibacterial properties and improve osseointegration. AIMS: A nano-sized hydroxyapatite-zinc coating was deposited on commercially pure titanium using an electro-chemical process, in order to increase its surface roughness and enhance adhesion properties. METHODS: The hydroxyapatite-zinc coating was attained using an electro-chemical deposition in a solution composed of a naturally derived calcium carbonate, di-ammonium hydrogen phosphate, with a pure zinc metal as the anode and titanium as the cathode. The applied voltage was -2.5 for 2 h at a temperature of 85 degrees C. The resultant coating was characterized for its surface morphology and chemical composition using a scanning electron microscope (SEM), energy dispersive x-ray spectroscope (EDS), and Fourier transform infrared (FT-IR) spectrometer. The coated specimens were also evaluated for their surface roughness and adhesion quality. RESULTS: Hydroxyapatite-zinc coating had shown rosette-shaped, homogenous structure with nano-size distribution, as confirmed by SEM analysis. FT-IR and EDS proved that coatings are composed of hydroxyapatite (HA) and zinc. The surface roughness assessment revealed that the coating procedure had significantly increased average roughness (Ra) than the control, while the adhesive tape test demonstrated a high-quality adhesive coat with no laceration on tape removal. CONCLUSIONS: The developed in vitro electro-chemical method can be employed for the deposition of an even thickness of nano HA-Zn adhered coatings on titanium substrate and increases its surface roughness significantly. PMID- 28803413 TI - Neovascularization during leafy gall formation on Arabidopsis thaliana upon Rhodococcus fascians infection. AB - MAIN CONCLUSION: Extensive de novo vascularization of leafy galls emerging upon Rhodococcus fascians infection is achieved by fascicular/interfascicular cambium activity and transdifferentiation of parenchyma cells correlated with increased auxin signaling. A leafy gall consisting of fully developed yet growth-inhibited shoots, induced by the actinomycete Rhodococcus fascians, differs in structure compared to the callus-like galls induced by other bacteria. To get insight into the vascular development accompanying the emergence of the leafy gall, the anatomy of infected axillary regions of the inflorescence stem of wild-type Arabidopsis thaliana accession Col-0 plants and the auxin response in pDR5:GUS tagged plants were followed in time. Based on our observations, three phases can be discerned during vascularization of the symptomatic tissue. First, existing fascicular cambium becomes activated and interfascicular cambium is formed giving rise to secondary vascular elements in a basipetal direction below the infection site in the main stem and in an acropetal direction in the entire side branch. Then, parenchyma cells in the region between both stems transdifferentiate acropetally towards the surface of the developing symptomatic tissue leading to the formation of xylem and vascularize the hyperplasia as they expand. Finally, parenchyma cells in the developing gall also transdifferentiate to vascular elements without any specific direction resulting in excessive vasculature disorderly distributed in the leafy gall. Prior to any apparent anatomical changes, a strong auxin response is mounted, implying that auxin is the signal that controls the vascular differentiation induced by the infection. To conclude, we propose the "sidetracking gall hypothesis" as we discuss the mechanisms driving the formation of superfluous vasculature of the emerging leafy gall. PMID- 28803414 TI - Laparoscopic reversal of mini-gastric bypass to original anatomy for severe postoperative malnutrition. AB - PURPOSE: Malnutrition after mini-gastric bypass (MGB) is a rare and dreaded complication with few data available regarding its surgical management. We aim to report the feasibility, safety, and results of laparoscopic reversal of MGB to normal anatomy (RMGB) in case of severe and refractory malnutrition syndrome after intensive nutritional support (SRMS). METHODS: A 10-year retrospective chart review was performed on patients who underwent RMGB (video included) for SRMS following MGB. RESULTS: Twenty-six of 2934 patients underwent a RMGB at a mean delay of 20.9 +/- 13.4 months post-MGB. At presentation, mean body mass index (BMI), excess weight loss (%EWL), and albumin serum level were 22 +/- 4.4 kg/m2, 103.6 +/- 22.5%, and 25.5 +/- 3.6 gr/L, respectively. Seventeen (63.5%) patients had at least one severe malnutrition related complication including severe edema in 13 (50%), venous ulcers in 2 (7.7%), infectious complications in 7 (27%), deep venous thrombosis in 5 (19.2%), and motor deficit in 5 (19.2%) patients. At surgical exploration, 8 of 12 (66.5%) patients had a biliary limb longer than 200 cm and 9 (34.6%) had bile reflux symptoms. Overall morbidity was 30.8% but lower when resecting the entire previous gastrojejunostomy with creation of a new jejunojejunostomy (8.3 vs 50%, p = 0.03). After a mean follow up of 8 +/- 9.7 months, all patients experienced a complete clinical and biological regression of the SRMS after the RMGB despite a mean 13.9 kg weight regain in 16 (61.5%) patients. CONCLUSIONS: Post-MGB SRMS and its related comorbidities are rare but dreaded conditions. Although burdened by a significant postoperative morbidity and weight regain, RMGB remains an effective option to consider, when intensive nutritional support fails. PMID- 28803412 TI - Alpha-synuclein oligomers: a new hope. AB - Alpha-synuclein is a protein implicated in Parkinson's disease and thought to be one of the main pathological drivers in the disease, although it remains unclear how this protein elicits its neurotoxic effects. Recent findings indicate that the assembly of toxic oligomeric species of alpha-synuclein may be one of the key processes for the pathology and spread of the disease. The absence of a sensitive in situ detection method has hindered the study of these oligomeric species and the role they play in the human brain until recently. In this review, we assess the evidence for the toxicity and prion-like activity of oligomeric forms of alpha-synuclein and discuss the advances in our understanding of the role of alpha-synuclein in Parkinson's disease that may be brought about by the specific and sensitive detection of distinct oligomeric species in post-mortem patient brain. Finally, we discuss current approaches being taken to therapeutically target alpha-synuclein oligomers and their implications. PMID- 28803416 TI - Rapid screening method for male DNA by using the loop-mediated isothermal amplification assay. AB - Screening for male-derived biological material from collected samples plays an important role in criminal investigations, especially those involving sexual assaults. We have developed a loop-mediated isothermal amplification (LAMP) assay targeting multi-repeat sequences of the Y chromosome for detecting male DNA. Successful amplification occurred with 0.5 ng of male DNA under isothermal conditions of 61 to 67 degrees C, but no amplification occurred with up to 10 ng of female DNA. Under the optimized conditions, the LAMP reaction initiated amplification within 10 min and amplified for 20 min. The LAMP reaction was sensitive at levels as low as 1-pg male DNA, and a quantitative LAMP assay could be developed because of the strong correlation between the reaction time and the amount of template DNA in the range of 10 pg to 10 ng. Furthermore, to apply the LAMP assay to on-site screening for male-derived samples, we evaluated a protocol using a simple DNA extraction method and a colorimetric intercalating dye that allows detection of the LAMP reaction by evaluating the change in color of the solution. Using this protocol, samples of male-derived blood and saliva stains were processed in approximately 30 min from DNA extraction to detection. Because our protocol does not require much hands-on time or special equipment, this LAMP assay promises to become a rapid and simple screening method for male-derived samples in forensic investigations. PMID- 28803415 TI - A measles outbreak in Sindh, Pakistan caused by a genotype B3 virus. AB - Measles continues to be a major public health issue causing substantial outbreaks worldwide, mostly affecting young children. Molecular analysis of measles viruses provides important information on outbreak linkages and transmission pathways that can be helpful towards implementation of appropriate control programs. In Pakistan, the control of measles is still tenuous, and progress towards elimination has been irregular and challenging. In the 2013 measles outbreak we received 4,682 sera collected from suspected patients in 23 districts across Sindh. A total of 3,283 samples were confirmed measles positive using IgM ELISA with the highest infection rate in children aged 1-12 months. Males were more affected than females and a visible peak was observed from January to April. Among the 3,283 cases, 59.1% were unvaccinated, 29.6% had received 1 dose and 10.3% had received 2 doses of measles vaccine while 0.85% had an unknown vaccination status. For genotype detection and phylogenetic analysis, 60 throat swab samples were collected from suspected patients below 15 years of age in eight districts of Sindh province. Forty four (73%; 44/60) throat swab samples were successfully genotyped using RT-PCR. Phylogenetic analyses based on partial sequences of the nucleocapsid protein gene revealed that all Pakistani measles virus strains belonged to genotype B3 and were closely related to those isolated from neighboring countries such as Iran, Afghanistan (99.1-100%) and India with 98.6 - 99.6% nucleotide homology. This is the first report on the phylogenetic analysis of measles B3 genotype strains from Pakistan and highlights the need for strengthening the surveillance systems and improving immunization coverage across the country. PMID- 28803417 TI - Cardiac tamponade due to apixaban therapy in patient with unknown pericardial hemangioma. PMID- 28803418 TI - Clinical results after microincision biaxial cataract surgery and implantation of an Incise intraocular lens. AB - PURPOSE: To evaluate clinical outcomes after uncomplicated microincision biaxial cataract surgery and implantation of Incise intraocular lens (IOL). METHODS: This study included 47 eyes of 29 patients (mean age 62.2 +/- 8.6 years), who underwent 1.4-mm biaxial cataract surgery with implantation of the Incise IOL (Bausch and Lomb). At third month, surgically induced astigmatism (SIA) was calculated. Three, 6 and 12 months postoperatively, uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), corrected near visual acuity (CNVA) LogMAR ETDRS, spherical equivalent refraction (SER), photopic distance corrected contrast sensitivity (CS) with and without glare (85 cd/m2) (CSV-1000) were assessed. One year after surgery, late complications were assessed and subjects were questioned for subjective symptoms. RESULTS: Mean of SIA was equal 0.29 +/- 0.16 D. Three months postoperatively: mean UDVA improved from 0.83 to 0.04 (p < 0.001), CDVA from 0.58 to -0.05 (p < 0.001) and CNVA from 0.58 to -0.02 (p < 0.001) and all were stable during 1-year follow-up. Three months postoperatively, the mean SER was equal 0.07 +/- 0.61 D and was within +/ 0.5 D in 79%, and within 1 D in 88% of eyes. During follow-up period, corrected CS with and without glare for distance was found to be within normal limits. The only late complication was posterior capsule opacification (PCO). Subjective quality of vision was very high; none of patients complained about glare. CONCLUSIONS: Biaxial cataract surgery with implantation of the Incise IOL provided excellent clinical outcomes by minimizing SIA, stable refraction and low incidence of PCO. PMID- 28803419 TI - Specific periodontopathic bacterial infection affects hypertension in male cardiovascular disease patients. AB - Hypertension (HT) is a systemic disorder that results in the decline of quality of life and death. While patients with periodontitis are at a high risk of HT, little causal information has been provided to date. To clarify the relationship, periodontopathic bacterial infection in cardiovascular patients with or without HT was evaluated. The subjects were patients with (n = 412) or without (n = 199) HT who attended Tokyo Medical and Dental University hospital. Blood examinations and periodontal measurements were performed. Three periodontopathic bacteria existence and antibody titers were evaluated. We found that specific periodontopathic bacteria, Aggregatibacter actinomycetemcomitans and Prevotella intermedia, were highly detected in male subjects with HT compared to non-HT subjects, while they were comparable in the female patients. Mean probing pocket depth of elderly male patients with HT was higher compared to non-HT patients. The rates of obesity, dyslipidemia, and diabetes showed partial statistical difference between the two groups. Specific periodontopathic bacterial infection may affect HT in male cardiovascular patients. PMID- 28803420 TI - Psychosocial Needs and Facilitators of Mothers Caring for Children with Duchenne/Becker Muscular Dystrophy. AB - Care guidelines for Duchenne/Becker muscular dystrophy (DBMD) include recommendations for assessment of caregivers of patients with DBMD followed by proactive psychosocial interventions. To inform clinical assessment, this study described appraisals of psychosocial needs and caregiving facilitators of mothers of individuals with DBMD. Two hundred and five mothers completed an online survey. More than 50% endorsed unmet needs for managing uncertainty about the future and managing DBMD fears. Higher levels of unmet need were associated with less disease progression/earlier stage of DBMD (rho = -0.166 p = 0.02). Twenty one percent regularly used respite care and 57% worried about allowing others to care for their child. Highly-endorsed care facilitators included partner relationships (63%), child's approach to life (59%), and family relationships (49%). Our findings highlight the importance of psychological and social support for caregivers. Starting when children are young, clinicians should assess caregivers' unmet psychological needs, particularly uncertainty and fear. Exploring needs and facilitators may allow clinics to target and customize interventions that build upon existing strengths and supports. Our findings have implications for efforts to promote early diagnosis and newborn screening, in that increased needs in mothers of younger children should be anticipated and built into counseling. Further research can assess whether and how unmet needs change as new therapies become available. PMID- 28803421 TI - Quantitative coronary plaque analysis predicts high-risk plaque morphology on coronary computed tomography angiography: results from the ROMICAT II trial. AB - Semi-automated software can provide quantitative assessment of atherosclerotic plaques on coronary CT angiography (CTA). The relationship between established qualitative high-risk plaque features and quantitative plaque measurements has not been studied. We analyzed the association between quantitative plaque measurements and qualitative high-risk plaque features on coronary CTA. We included 260 patients with plaque who underwent coronary CTA in the Rule Out Myocardial Infarction/Ischemia Using Computer Assisted Tomography (ROMICAT) II trial. Quantitative plaque assessment and qualitative plaque characterization were performed on a per coronary segment basis. Quantitative coronary plaque measurements included plaque volume, plaque burden, remodeling index, and diameter stenosis. In qualitative analysis, high-risk plaque was present if positive remodeling, low CT attenuation plaque, napkin-ring sign or spotty calcium were detected. Univariable and multivariable logistic regression analyses were performed to assess the association between quantitative and qualitative high-risk plaque assessment. Among 888 segments with coronary plaque, high-risk plaque was present in 391 (44.0%) segments by qualitative analysis. In quantitative analysis, segments with high-risk plaque had higher total plaque volume, low CT attenuation plaque volume, plaque burden and remodeling index. Quantitatively assessed low CT attenuation plaque volume (odds ratio 1.12 per 1 mm3, 95% CI 1.04-1.21), positive remodeling (odds ratio 1.25 per 0.1, 95% CI 1.10 1.41) and plaque burden (odds ratio 1.53 per 0.1, 95% CI 1.08-2.16) were associated with high-risk plaque. Quantitative coronary plaque characteristics (low CT attenuation plaque volume, positive remodeling and plaque burden) measured by semi-automated software correlated with qualitative assessment of high-risk plaque features. PMID- 28803422 TI - Salidroside improved cerebrovascular vasodilation in streptozotocin-induced diabetic rats through restoring the function of BKCa channel in smooth muscle cells. AB - Vessel disease is a kind of severe complication in diabetic patients. However, few pharmacologic agents can directly recover diabetic vascular function. Salidroside (SAL), a major ingredient from Rhodiola rosea, has been found to have an obvious hypoglycemic effect and a beneficial protection on vascular function in diabetes. However, whether SAL is a suitable treatment for diabetes has not so far been evaluated and the underlying mechanisms remain unknown. The present work aims to (1) investigate the potential effects of SAL on cerebrovascular relaxation in streptozotocin-induced diabetic rats or when exposed to acute hyperglycemia condition and (2) examine whether function of the BKCa channel is involved in SAL treatment for diabetic vascular relaxation. Our results indicate that chronic administration of 100 mg/kg/day SAL not only improves cerebrovascular relaxation but also increases BKCa beta1-subunit expressions at both protein and mRNA levels and enhances BKCa whole-cell and single-channel activities in cerebral VSMCs of diabetic rats. Correspondingly, acute application of 100 MUM SAL induces cerebrovascular relaxation by activation of the BKCa channel. Furthermore, SAL activated the BKCa channel mainly through acting on the beta1-subunit in HEK293 cells transfected with hSloalpha+beta1 constructs. We concluded that SAL improved vasodilation in diabetic rats through restoring the function of the BKCa-beta1 subunit in cerebrovascular smooth muscle cells, which may be the underlying mechanism responsible for the vascular protection of SAL in diabetes. PMID- 28803423 TI - Oxygen mass transfer and shear stress effects on Pseudomonas putida BCRC 14365 growth to improve bioreactor design and performance. AB - In this work, the experimental evidence is presented for two basic issues including oxygen mass transfer and shear analysis on the microorganism containing medium on the most prominent sections of the bioreactor. Computational fluid dynamics (CFD) methodology reproduces shear rate values for specific impeller designs using the commercial code (Fluent 6.2). CFD calculates volumetric mass transfer coefficient based on the Higbie's penetration theory. Four types of impeller are used. The spherical probe is used to measure flow hydrodynamic parameters to obtain shear rate by electro-diffusion (ED) method. The obtained results are validated experimentally and it is shown that a fully axial pattern impeller represents more enhanced results than partially axial and radial. In this regard, experimental results for volumetric oxygen mass transfer coefficient (k l a) confirm CFD predictions by acceptable deviations of 2.65, 8.90, and 9.20 for 0.15, 0.2, and 0.3 VVM, respectively. These results collaboratively indicate that LIGHTNIN-C 200 type operates more efficiently by reflecting the flow to the bottom corner stagnation areas with the minimum tolerable shear and the most velocity distribution uniformity. Furthermore, the values of k l a improve by aeration rate. Conversely, increasing the rotational speed of impeller creates difficulties for cell growth due to the generated harsh shear condition. CFD provide a better understanding of how operational and geometrical variables may be manipulated to achieve a moderate shear rate and acceptable level of mass transfer. PMID- 28803424 TI - Nitrate pollution in the Warta River (Poland) between 1958 and 2016: trends and causes. AB - The article presents analyses of long-term water quality data from the Warta River between 1958 and 2016. A clear increasing trend in nitrate concentrations was observed from 1958 to the early 1990s. This trend was mainly related to the increasing use of fertilizers in Poland in this period. Then, after the early 1990s, a slow decreasing trend related to improvements in water and sewage management and more rational fertilizer use was observed after political and economic changes in Poland. The influence of long-term hydrological droughts on nitrate concentrations was also investigated. Sharp increases in the nitrate concentration in surface water were related to the accumulation of contaminants in the soil and aeration zone during drought periods and the subsequent transport of these contaminants to groundwater and surface water via recharge infiltration after each drought period. The presented results highlight the importance of surface water-groundwater interactions and suggest that groundwater protection in an entire catchment area is essential for surface water quality protection. PMID- 28803426 TI - Speciation of As(IotaIotaIota)/As(V) and Total Inorganic Arsenic in Biological Fluids Using New Mode of Liquid-Phase Microextraction and Electrothermal Atomic Absorption Spectrometry. AB - In this paper, a new extraction method based on countercurrent liquid-liquid microextraction (CLLME) has been developed for the extraction and preconcentration of inorganic arsenic (iAs) in plasma and urine samples prior to their analysis by electrothermal atomic absorption spectrometry (ETAAS). In this method, firstly, 5 ml of water is added to the extraction vessel. Then 30.0 MUl of the extracting solvent is added to it in order for the extracting solvent to be placed in the narrow-necked vessel. In total, 10 ml of a standard solution or a pretreated real sample is added to the sample container and it is connected to the extraction vessel via a connector. While opening the embedded valve at the bottom of the sample container and the one in the extraction vessel, the sample solution flows into the extracting solvent with the same flow rate, leading to the successful extraction of metal ligand into the extracting organic solvent. Under the optimum conditions, calibration curves are linear in the range of 0.1 50 MUg l-1, and limit of detections (LODs) are in the range of 0.03-0.05 MUg l-1. The enhancement factor and enrichment factor were in the range of 220-240 and 198 212, respectively. Repeatability (intra-day) and reproducibility (inter-day) of method based on seven replicate measurements of 5.0 MUg l-1 of arsenic were in the range of 2.3-3.5% and 4.0-5.7%, respectively. The applicability of the proposed CLLME and ETAAS methods was demonstrated by analyzing the iAs in spiked urine and plasma samples. The obtained recoveries of the arsenic in the range of 92-107% indicated the excellent capability of the developed method for speciation of arsenic from plasma and urine samples. Graphical Abstract ?. PMID- 28803425 TI - Frameshift Mutations in Repeat Sequences of ANK3, HACD4, TCP10L, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 Genes in Colon Cancers. AB - Diminished ANK3 contributes to cell survival by inhibiting detachment-induced apoptosis. TP53BP1 that interacts with p53 and MFN1 that encodes a mitochondrial membrane protein are considered to have tumor suppressor gene (TSG) functions. HACD4 involving fatty acid synthesis and TCPL10 with transcription regulation functions are considered TSGs. Many genes involved in DNA methylations such as LCMT2, RNMT, TRMT6, METTL8 and METTL16 are often perturbed in cancer. The aim of our study was to find whether these genes were mutated in colorectal cancer (CRC). In a genome database, we observed that each of these genes harbored mononucleotide repeats in the coding sequences, which could be mutated in cancers with high microsatellite instability (MSI-H). For this, we studied 124 CRCs for the frameshift mutations of these genes and their intratumoral heterogeneity (ITH). ANK3, HACD4, TCP10L, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 harbored 11 (13.9%), 3 (3.8%), 0 (0%), 5 (6.3%), 1 (1.3%), 2 (2.5%), 4 (5.1%), 3 (3.8%), 2 (2.5%) and 2 (2.5%) of 79 CRCs with MSI-H, respectively. However, we found no such mutations in microsatellite stable (MSS) cancers in the nucleotide repeats. There were ITH of the frameshift mutations of ANK3, MFN1 and TP53BP1 in 1 (6.3%), 1 (6.3%) and 1 (6.3%) cases, respectively. Our data exhibit that cancer related genes ANK3, HACD4, TP53BP1, MFN1, LCMT2, RNMT, TRMT6, METTL8 and METTL16 harbor mutational ITH as well as the frameshift mutations in CRC with MSI-H. Also, the results suggest that frameshift mutations of these genes might play a role in tumorigenesis through their inactivation in CRC. PMID- 28803427 TI - Unknown onset ischemic strokes in patients last-seen-well >4.5 h: differences between wake-up and daytime-unwitnessed strokes. AB - Patients with unknown time of stroke onset (UOS) represent around one-third of ischemic stroke patients. These are patients with wake-up stroke (WUS) or daytime unwitnessed stroke (DUS), often presenting outside the time-window for reperfusion therapy. UOS patients presenting between 4.5 and 12 h after time of last-seen-well were included. Clinical and imaging characteristics were compared between WUS and DUS patients. Good functional outcome was defined as a modified Rankin scale of <=2 at follow-up. Sixty-one UOS patients were included: 42 WUS and 19 DUS patients. Stroke severity at presentation was mild to moderate with a median National Institutes of Health Stroke Scale of 5 in WUS and 6 in DUS patients. Time between last-seen-well and presentation at the hospital was shorter in patients with DUS compared to WUS (506 vs 362 min, p < 0.01). CT imaging results were similar, with a median Alberta Stroke Program Early CT Score of 10 for both WUS and DUS patients. After correction for age and NIHSS at presentation, no difference in good functional outcome was found between WUS (52%) and DUS (22%). In patients with unknown onset ischemic strokes presenting between 4.5 and 12 h after time of last-seen-well, clinical and radiological features were in large part similar between WUS and DUS. The outcome in the overall cohort was rather poor despite a favorable neuroimaging profile at presentation. These findings underscore the need for clinical trials in patients in whom stroke onset time is unknown. PMID- 28803428 TI - Environmental hazard assessment by the Ecoscore system to discriminate PAH polluted soils. AB - A bioassay battery-integrated index was applied to different soils sampled from a former coke factory, with the aim to evaluate the discriminating capacity of the Ecoscore system (ES) to assess the environmental hazard of PAH-polluted soils. Two soils from a former coke factory, polluted with polycyclic aromatic hydrocarbons (PAHs), were evaluated for their ecotoxicity to terrestrial and aquatic organisms and their genotoxicity. These soils have been already presented in a previous paper but data have been reanalyzed for the present article in an endeavor to standardize the ES. One soil was sampled in the untreated site and the second underwent a windrow treatment. While these soils had a similar total concentrations of US-EPA 16PAHs (around 3000 mg kg-1), different ecoscores were obtained when subjected to a set of solid- and liquid-phase bioassays measuring acute, chronic, and genotoxic effects. The total PAH content of the soil is not a pertinent parameter to assess soil pollution hazards contrary to the ES. ES is a robust method to classify soils according to their toxicity level. Four levels of toxicity have been defined: no (ecoscore = 0), weak (0 < ecoscore <=33), moderate (33 < ecoscore <=67), and strong toxicity (67 < ecoscore <= 100). The combination of chemical and toxicological data highlights the relationship between three-ring PAHs and acute ecotoxicity. Conversely, chronic effects of water extracts on algal growth could be explained by high molecular weight PAHs, such as five- and six-ring PAHs. PMID- 28803429 TI - Patients with primary breast and primary female genital tract diffuse large B cell lymphoma have a high frequency of MYD88 and CD79B mutations. AB - This study is to retrospectively evaluate the prevalence of MYD88 and CD79B mutations and the clinicopathologic characteristics of patients with primary diffuse large B cell lymphoma (DLBCL) of the female genital tract and breast. The characteristics, treatments, and outcomes of 19 patients diagnosed with primary DLBCL of the female genital tract and breast, who had formalin-fixed and paraffin embedded tissues obtained from diagnostic samples diagnosed between January 2004 and June 2016, were analyzed retrospectively. Nineteen female patients (7 with primary breast and 12 with primary female genital tract DLBCL) were included in this retrospective study. Eleven patients (57.9%) carried a MYD88 mutation, including 10 with MYD8 L265P and 1 with the MYD88 L265S mutation. Seven patients (36.8%) harbored a CD79B mutation, which included two cases with CD79B Y196H, two cases with CD79B Y196N, one case with CD79B Y196D, one case with CD79B Y196F, and one case with CD79B Y196X. Four cases had both MYD88 and CD79B mutations. The clinicopathologic parameters, progression-free survival (PFS), and overall survival (OS) of the MYD88 mutation-carrying group were not significantly different from those of the MYD88 wild-type group except for higher LDH levels. Six patients received cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP), while 13 patients received rituximab plus CHOP, and 13 patients received central nervous system prophylaxis. The median OS and PFS were 73 and 56 months, respectively. Patients with primary breast and primary female genital tract DLBCL have a high frequency of MYD88 and CD79B mutations. The presence of these mutations does not affect survival but may offer additional therapeutic options. PMID- 28803430 TI - Effects of stimulated aggrecanolysis on nanoscale morphological and mechanical properties of wild-type and aggrecanase-resistant mutant mice cartilages. AB - A key event in arthritis pathogenesis is the degradation of aggrecan, the major component in articular cartilage. In this work, we investigate the effects of stimulated aggrecanolysis on the morphological and nanomechanical properties of cartilage harvested from wild-type mice and aggrecanase-resistant mutant mice named "Jaffa". The cartilages were native or were subjected to stimulated aggrecanolysis by interleukin-1[Formula: see text] (IL-1[Formula: see text]) treatment. The nanoscale morphological and mechanical properties of the sectioned cartilages were measured by using a sharp probe by atomic force microscopy (AFM). The IL-1[Formula: see text] treatment resulted in a higher nanoroughess and stiffness of the cartilage from wild-type mice. However, the same treatment did not lead to any measurable change in the nanoroughness or stiffness of the cartilage from mutant mice Jaffa. This suggests that blocking aggrecanolysis by genetic modification has created the stability in the structures and mechanical properties of the cartilage at nanoscale. The present study provides insight into the mechanism of aggrecan degradation, which can complement the examination by biochemical and histological techniques. PMID- 28803431 TI - SB2: An Infliximab Biosimilar. AB - SB2 is a biosimilar of the reference anti-TNF-alpha antibody infliximab. In May 2015, it was approved in the EU for use in all indications for which reference infliximab is approved, including rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriatic arthritis and psoriasis. It is also approved in these indications in several other countries, including Korea, the USA and Australia. Characterization of SB2 in preclinical studies showed that it is similar to reference infliximab. SB2 demonstrated pharmacokinetic biosimilarity to reference infliximab in healthy volunteers, and clinically equivalent efficacy in patients with moderate to severe rheumatoid arthritis despite methotrexate therapy. SB2 was generally well tolerated; the safety and immunogenicity profiles were similar to those of reference infliximab with no additional safety concerns identified. Switching from reference infliximab to SB2 did not impact clinical efficacy, safety or immunogenicity. The role of reference infliximab in the management of autoimmune inflammatory conditions is well established, and SB2 provides an effective biosimilar alternative for patients requiring infliximab therapy. PMID- 28803432 TI - Quality of life in home-ventilated children and their families. AB - : HMV (home mechanical ventilation) in children has increased over the last years. The aim of the study was to assess perceived quality of life (QOL) of these children and their families as well as the problems they face in their daily life.We performed a multicentric cross-sectional study using a semi structured interview about the impact of HMV on families and an evaluation questionnaire about perceived QOL by the patient and their families (pediatric quality of life questionnaire (PedsQL4.0)). We studied 41 subjects (mean age 8.2 years). Global scores in PedsQL questionnaire for subjects (median 61.4), and their parents (median 52.2) were below those of healthy children. 24.4% received medical follow-up at home and 71.8% attended school. Mothers were the main caregivers (75.6%), 48.8% of which were fully dedicated to the care of their child. 71.1% consider economic and healthcare resources insufficient. All families were satisfied with the care they provide to their children, even though it was considered emotionally overwhelming (65.9%). Marital conflict and neglect of siblings appeared in 42.1 and 36% of families, respectively. CONCLUSIONS: Perceived QOL by children with HMV and their families is lower than that of healthy children. Parents are happy to care for their children at home, even though it negatively affects family life. What is Known: * The use of home mechanical ventilation (HMV) in children has increased over the last years. * Normal family functioning is usually disrupted by HMV. What is New: * The aim of HMV is to provide a lifestyle similar to that of healthy children, but perceived quality of life by these patients and their parents is low. * Most of the families caring for children on HMV agree that support and resources provided by national health institutions is insufficient. PMID- 28803433 TI - Distribution of serum levels of persistent organic pollutants, heterocyclic aromatic amine theoretical intake and nutritional cofactors in a semi-rural island population. AB - Persistent organic pollutant (POP) exposure is strongly associated with negative health effects in humans. Heterocyclic aromatic amines (HAAs) are formed during high temperature cooking of foods (i.e. meat and fish). Human exposure to HAA is through food consumption and from similar food groups to POPs. A study of serum samples for POPs in a non-occupational exposed population (n = 149, age range 18 80 years, recruited in 2012) and comparison with estimated HAA daily intake calculations based on food diaries were undertaken. Three different age groups (group 1, 18-29 years; group 2, 30-44 years; and group 3, 45-80 years) were used to explore possible relationships between POP levels present in blood, HAA intake and nutritional cofactors. Significant differences (p < 0.05) between groups (1 and 3) for POP levels were found for p,p'-DDE, polychlorinated biphenyl (PCB) 153, PCB 138 and the sum of PCBs. A similar trend was found between groups 2 and 3 for PCB 153 and sum of PCBs. Significant differences were found between groups 1 and 3 and groups 2 and 3 for HAA intake., i.e. HAA intake was lowest in those of middle age, which may well reflect a different pathway of human exposure between HAA and POPs through the diet preferences. PMID- 28803434 TI - Special Issue of Biophysical Reviews dedicated to the 19th IUPAB Conference in Edinburgh, Scotland (July 2017) . AB - From the 16th to the 20th of July 2017, the 19th IUPAB (International Union of Pure and Applied Biophysics) world congress was held in Edinburgh, Scotland. Organized in conjunction with the 11th EBSA (European Biophysical Societies' Association) the meeting attracted over 1430 participants, had 35 scientific sessions and 10 plenary speakers. Each invited speaker was invited to contribute either a short review or a letter article that summarized the contents of their session. This special issue of Biophysical Reviews is dedicated to providing contextual background to some of the many talks presented at the meeting in Edinburgh. The reader is referred to supplementary issue 1 of volume 46 of the European Biophysics Journal for a complete listing of abstracts for all presented talks and posters. PMID- 28803435 TI - A kinetic solution for the paradoxical difference between F-Dopa and methionine. PMID- 28803436 TI - Acute regulated expression of pendrin in human urinary exosomes. AB - It is well known that pendrin, an apical Cl-/HCO3-exchanger in type B intercalated cells, is modulated by chronic acid-base disturbances and electrolyte intake. To study this adaptation further at the acute level, we analyzed urinary exosomes from individuals subjected to oral acute acid, alkali, and NaCl loading. Acute oral NH4Cl loading (n = 8) elicited systemic acidemia with a drop in urinary pH and an increase in urinary NH4 excretion. Nadir urinary pH was achieved 5 h after NH4Cl loading. Exosomal pendrin abundance was dramatically decreased at 3 h after acid loading. In contrast, after acute equimolar oral NaHCO3 loading (n = 8), urinary and venous blood pH rose rapidly with a significant attenuation of urinary NH4 excretion. Alkali loading caused rapid upregulation of exosomal pendrin abundance at 1 h and normalized within 3 h of treatment. Equimolar NaCl loading (n = 6) did not alter urinary or venous blood pH or urinary NH4 excretion. However, pendrin abundance in urinary exosomes was significantly reduced at 2 h of NaCl ingestion with lowest levels observed at 4 h after treatment. In patients with inherited distal renal tubular acidosis (dRTA), pendrin abundance in urinary exosomes was greatly reduced and did not change upon oral NH4Cl loading. In summary, pendrin can be detected and quantified in human urinary exosomes by immunoblotting. Acid, alkali, and NaCl loadings cause acute changes in pendrin abundance in urinary exosomes within a few hours. Our data suggest that exosomal pendrin is a promising urinary biomarker for acute acid-base and volume status changes in humans. PMID- 28803437 TI - Geographic variation in Chinese children' forced vital capacity and its association with long-term exposure to local PM10: a national cross-sectional study. AB - The purpose of this study was to estimate the association between Chinese children's forced vital capacity (FVC) and particulate matter with aerodynamic diameter <=10 MUm (PM10). The FVC data of 71,763 children aged 7 to 18 was collected from 2010 Chinese National Survey on Students' Construction and Health (CNSSCH). The local annual average concentration of PM10, relative humidity, ambient temperature, and other air pollutant data of 30 cities was collected from China Meteorological Administration and Ministry of Environment Protection of China. Then, we used generalized additive model (GAM) to estimate the association between children's FVC and PM10. The obvious geographic variation in FVC was found in children of 30 Chinese cities ranging from 1647 ml in Xining to 2571 ml in Beijing. The annual average concentration of PM10 was also different, ranging from 40 MUg/m3 in Haikou to 155 MUg/m3 in Lanzhou. After adjusted individual characteristics, socioeconomic conditions, ambient temperature, relative humidity, and other air pollutants (e.g., NO2 and SO2) in the generalized additive model, we found that the increase of PM10 was associated with decrease of FVC in Chinese children. A 10-MUg/m3 increase of PM10 was associated with 1.33 ml decrease in FVC (95% confidence interval: -2.18 to -0.47). We also found a larger effect estimate of PM10 on FVC in boys than that in girls. Consistent associations were found in both physically inactive and active children. The increase of PM10 was associated with decrease of children's FVC. We should develop proper public health policy to protect children's respiratory health during growth and development in polluted areas. PMID- 28803439 TI - Comparison of the ability of esCCO and Volume View to measure trends in cardiac output in patients undergoing cardiac surgery. AB - BACKGROUND: Cardiac output (CO) is a physiological variable that should be monitored during cardiac surgery. The purpose of this study was to assess the trending ability of two CO monitors, esCCO (Nihon KohdenTM, Tokyo, Japan) and Volume View (VV) (Edwards Lifesciences, Irvine, USA). METHODS: A total of 19 patients were included in the study. Before cardiopulmonary bypass (CPB), CO was measured simultaneously using both esCCO and VV devices before and after three CO modifying manoeuvres (passive leg raise [PLR], the end expiratory occlusion test [EEOT] and positive end expiratory pressure [PEEP] at 10 cm H2O). Five CO values for esCCO and three for VV were averaged and compared during a one-minute period of time before and after each manoeuvre. RESULTS: A total of 114 paired readings were collected. Median CO values were 4.3 L min-1 (IQR: 3.8; 5.2) and 3.8 L min-1 (IQR: 3.5; 4.5) for esCCO and VV, respectively. The precision error was 1.4% (95% CI:1.0-1.7) for esCCO and 2.2% (95% CI: 1.8-2.7) for VV. The bias between esCCO and VV values was normally distributed (P = 0.0596). Between esCCO and VV, the mean bias was +0.6 L min-1 with a Limit of Agreement (LOA) of -1.8 L min-1 and +3.0 L min-1. The concordance rate was 43% (95% CI: 29-58) between esCCO and VV. CONCLUSION: Both single and trended measurements of CO using esCCO and VV were not in agreement. This large discrepancy leads one to the conclusion that any outcome study conducted with one of these devices cannot be applied to the other. PMID- 28803438 TI - Inhibitor of Endocannabinoid Deactivation Protects Against In Vitro and In Vivo Neurotoxic Effects of Paraoxon. AB - The anticholinesterase paraoxon (Pxn) is related to military nerve agents that increase acetylcholine levels, trigger seizures, and cause excitotoxic damage in the brain. In rat hippocampal slice cultures, high-dose Pxn was applied resulting in a presynaptic vulnerability evidenced by a 64% reduction in synapsin IIb (syn IIb) levels, whereas the postsynaptic protein GluR1 was unchanged. Other signs of Pxn-induced cytotoxicity include the oxidative stress-related production of stable 4-hydroxynonenal (4-HNE)-protein adducts. Next, the Pxn toxicity was tested for protective effects by the fatty acid amide hydrolase (FAAH) inhibitor AM5206, a compound linked to enhanced repair signaling through the endocannabinoid pathway. The Pxn-mediated declines in syn IIb and synaptophysin were prevented by AM5206 in the slice cultures. To test if the protective results in the slice model translate to an in vivo model, AM5206 was injected i.p. into rats, followed immediately by subcutaneous Pxn administration. The toxin caused a pathogenic cascade initiated by seizure events, leading to presynaptic marker decline and oxidative changes in the hippocampus and frontal cortex. AM5206 exhibited protective effects including the reduction of seizure severity by 86%, and improving balance and coordination measured 24 h post-insult. As observed in hippocampal slices, the FAAH inhibitor also prevented the Pxn-induced loss of syn IIb in vivo. In addition, the AM5206 compound reduced the 4-HNE modifications of proteins and the beta1 integrin activation events both in vitro and in vivo. These results indicate that Pxn exposure produces oxidative and synaptic toxicity that leads to the behavioral deficits manifested by the neurotoxin. In contrast, the presence of FAAH inhibitor AM5206 offsets the pathogenic cascade elicited by the Pxn anticholinesterase. PMID- 28803440 TI - Electrical impedance tomography for diagnosis and monitoring of pulmonary function disorders in the intensive care unit - case report and review of literature. AB - The aim of this paper is to describe the possibility of using Electrical Impedance Tomography (EIT) as a treatment monitoring tool in the ICU. It was based on case report and literature review. A 19-year-old female was admitted to ICU due to severe acute respiratory distress syndrome. Despite aggressive treatment there was no improvement. We decided to use EIT in the monitoring of treatment because of difficulties in transporting the patient to the radiology department in order to perform a control CT scan. After identifying the causing factor (Pneumocyctis jiroveci), EIT monitoring was maintained to assess the effectiveness of targeted microbial treatment. In the following days, we observed an improvement of regional ventilation of the upper and middle segments of the left lung that corresponded well with laboratory test results, especially arterial blood gas analysis. The use of Electrical Impedance Tomography enables non-invasive, bedside, continuous assessment of regional lung ventilation. It is possible to use it in both mechanically ventilated and spontaneously breathing patients. It allows efficient and dynamic monitoring of the course of the therapeutic process. Interpretation of the results is relatively easy to learn and does not require specialist knowledge. Moreover, it is possible to use EIT in those cases where other methods are of high risk or contraindicated. PMID- 28803441 TI - Thermoregulation disorders of central origin - how to diagnose and treat. AB - Fever is a common symptom in the Intensive Care Unit. At least half of febrile episodes are caused by infection. Excluding infectious etiology and other non infectious causes of fever, especially in patients with central nervous system (CNS) disorders, attention should be paid to disturbances of thermoregulatory centre. In particular, subarachnoid haemorrhage, cerebral trauma, along with ischaemic or haemorrhagic stroke are strongly associated with the development of central fever. Proper, speedy diagnosis of the cause of fever makes it possible to implement preventive measures against the harmful effects of hyperthermia on the CNS and to avoid the consequences of inappropriate treatment. The aim of this review is to present the current treatment options for the management of central fever and to analyze recent recommendations for the treatment of hyperthermia, including the use of hypothermia. The recommendations of American and European associations are inconsistent, mainly due to the lack of randomized clinical trials confirming the effectiveness of such treatment. The diagnosis of central fever is still made by the exclusion of other causes. The authors of the review intended to present the characteristic features of central fever, differentiating this state from infectious fever and also analyze the presence of central fever in particular neurological diseases. It seems particularly important to establish diagnostic criteria for central fever or to find diagnostic markers. It is also necessary to conduct further randomized clinical trials evaluating the indications for treatment of hyperthermia. PMID- 28803442 TI - Neutrophils, NETs, NETosis - old or new factors in sepsis and septic shock? AB - Neutrophils are an key part of the innate immune system in the host's defences against pathogens. Circulating neutrophils are recruited at the sites of infection or sterile inflammation in response to pathogen and host-derived inflammatory mediators. In addition to phagocytosis and degranulation, neutrophils display the release of NETs in order to restrain infection. NETs are able to entrap and kill microbes, and display proinflammatory and prothrombotic properties. PMID- 28803444 TI - Atypical parkinsonian syndromes: a general neurologist's perspective. AB - The differential diagnosis of atypical parkinsonian syndromes is challenging. These severe and often rapidly progressive neurodegenerative disorders are clinically heterogeneous and show significant phenotypic overlap. Here, clinical, imaging, neuropathological and genetic features of multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration and frontotemporal lobar degeneration (FTLD) are reviewed. The terms corticobasal degeneration and FTLD refer to pathologically confirmed cases of corticobasal syndrome and frontotemporal dementia (FTD). Frontotemporal lobar degeneration clinically presents as the behavioral variant FTD, semantic variant primary progressive aphasia (PPA), non-fluent agrammatic variant PPA, logopenic variant PPA and FTD associated with motor neuron disease. While progressive supranuclear palsy and corticobasal syndrome have been called Parkinson-plus syndromes in the past, they are now classified as FTD-related disorders, reflecting that they pathologically differ from alpha-synucleinopathies like multiple system atrophy and Parkinson disease. The contribution of genetic factors to atypical parkinsonian syndromes is increasingly recognized. Genes involved in the etiology of FTLD include MAPT, GRN and C9orf72. Novel neuroimaging techniques, including tau positron emission tomography imaging, are being investigated. Multimodal magnetic resonance imaging approaches and automated magnetic resonance imaging volume segmentation techniques are being evaluated for optimized differential diagnosis. Current treatment options are symptomatic, and disease modifying therapies are under active investigation. PMID- 28803443 TI - Solasodine inhibits human colorectal cancer cells through suppression of the AKT/glycogen synthase kinase-3beta/beta-catenin pathway. AB - Solasodine is a main active component isolated from Solanum incanum L. that performs a wide range of functions containing anti-oxidant, anti-infection, and neurogenesis promotion. In this study, we explored the influence of solasodine on three types of human colorectal cancer (CRC) cell lines. The results show that solasodine prohibited CRC cell proliferation dose- and time-dependently and impeded CRC cell motility by downregulating MMPs. Solasodine was also found to fuel caspase-cascade reaction and increase the ratio between Bax and Bcl-2 so as to induce CRC cell apoptosis. When cells were pretreated with AKT activator (insulin-like growth factor-1) followed by solasodine, the solasodine-induced apoptosis was partially abrogated by insulin-like growth factor-1. Moreover, solasodine hindered tumor development and stimulated similar mechanisms in vivo. In general, our study provides the first evidence that solasodine has a suppressive effect on CRC cells and that this agent may be a novel therapeutic drug for CRC treatment. PMID- 28803445 TI - A systematic review of primary outcomes and outcome measure reporting in randomized trials evaluating treatments for pre-eclampsia. AB - BACKGROUND: An evaluation of outcome reporting is required to develop a core outcome set. OBJECTIVES: To assess primary outcomes and outcome measure reporting in pre-eclampsia trials. SEARCH STRATEGY: Five online databases were searched from inception to January 2016 using terms including "preeclampsia" and "randomized controlled trial". SELECTION CRITERIA: Randomized controlled trials evaluating treatments for pre-eclampsia published in any language were included. DATA COLLECTION AND ANALYSIS: Primary outcomes and data on outcome measure reporting were systematically extracted and categorized. MAIN RESULTS: Overall, 79 randomized trials including data from 31 615 women were included. Of those, 38 (48%) reported 35 different primary outcomes; 28 were maternal outcomes and seven were fetal/neonatal outcomes. Three randomized trials reported composite outcomes, incorporating between six and nine outcome components. The method of definition or measurement was infrequently or poorly reported. Even when outcomes were consistent across trials, different methods of definition or measurement were frequently described. CONCLUSIONS: In randomized trials evaluating interventions for pre-eclampsia, critical information related to the primary outcome, including definition and measurement, is regularly omitted. Developing a core outcome set for pre-eclampsia trials would help to inform primary outcome selection and outcome measure reporting. PMID- 28803446 TI - Urinary tract infections caused by ESBL-producing Enterobacteriaceae in renal transplant recipients: A systematic review and meta-analysis. AB - BACKGROUND: Urinary tract infections (UTIs) are the most common infectious complications among renal transplant recipients (RTR). UTIs caused by extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-PE) have been associated with inferior clinical outcomes and increased financial burden. METHODS: We performed a systematic review and meta-analysis by searching through the PubMed and EMBASE databases (to May 20, 2016) and identifying studies that reported data on the number of RTR who developed an ESBL-PE UTI. RESULTS: Our analysis included seven studies, out of 357 non-duplicate articles, that provided data on 2824 patients. Among them, 10% (95% confidence interval [CI] 4%-17%) developed an ESBL-PE UTI over their follow-up periods. The proportion of RTR affected by an ESBL-PE UTI was 2% in North America (95% CI 1%-3%), 5% in Europe (95% CI 4%-6%), 17% in South America (95% CI 10%-27%), and 33% in Asia (95% CI 27%-41%). In addition, patients affected with an ESBL-PE UTI were 2.75-times (95% CI 1.97-3.83) more likely to suffer a recurrent UTI. CONCLUSIONS: Based on a limited number of studies, one in 10 RTR will develop a UTI caused by an ESBL-PE, and these patients face an almost 3 times greater risk of recurrence. A more rigorous monitoring of RTR, both during and after resolution of their infection, should be evaluated in order to reduce the incidence and the clinical impact of these resistant infections. PMID- 28803447 TI - Registration free automatic identification of gold fiducial markers in MRI target delineation images for prostate radiotherapy. AB - PURPOSE: The superior soft tissue contrast of magnetic resonance imaging (MRI) compared to computed tomography (CT) has urged the integration of MRI and elimination of CT in radiotherapy treatment (RT) for prostate. An intraprostatic gold fiducial marker (GFM) appears hyperintense on CT. On T2-weighted (T2w) MRI target delineation images, the GFM appear as a small signal void similar to calcifications and post biopsy fibrosis. It can therefore be difficult to identify the markers without CT. Detectability of GFMs can be improved using additional MR images, which are manually registered to target delineation images. This task requires manual labor, and is associated with interoperator differences and image registration errors. The aim of this work was to develop and evaluate an automatic method for identification of GFMs directly in the target delineation images without the need for image registration. METHODS: T2w images, intended for target delineation, and multiecho gradient echo (MEGRE) images intended for GFM identification, were acquired for prostate cancer patients. Signal voids in the target delineation images were identified as GFM candidates. The GFM appeared as round, symmetric, signal void with increasing area for increasing echo time in the MEGRE images. These image features were exploited for automatic identification of GFMs in a MATLAB model using a patient training dataset (n = 20). The model was validated on an independent patient dataset (n = 40). The distances between the identified GFM in the target delineation images and the GFM in CT images were measured. A human observatory study was conducted to validate the use of MEGRE images. RESULTS: The sensitivity, specificity, and accuracy of the automatic method and the observatory study was 84%, 74%, 81% and 98%, 94%, 97%, respectively. The mean absolute difference in the GFM distances for the automatic method and observatory study was 1.28 +/- 1.25 mm and 1.14 +/- 1.06 mm, respectively. CONCLUSIONS: Multiecho gradient echo images were shown to be a feasible and reliable way to perform GFM identification. For clinical practice, visual inspection of the results from the automatic method is needed at the current stage. PMID- 28803448 TI - Microvascular and lymphovascular tumour invasion are associated with poor prognosis and metastatic spread in renal cell carcinoma: a validation study in clinical practice. AB - OBJECTIVE: To validate microvascular (MVI) and lymphovascular (LVI) invasion as prognostic factors in patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: Data of patients with RCC who underwent radical or nephron-sparing surgery were prospectively collected from three academic centres. The occurrence of MVI and LVI was determined with standard staining protocols by experienced pathologists at the time of diagnosis. The association of MVI and LVI with clinicopathological data, metastatic spread, and cancer-specific survival (CSS) were evaluated with Fisher's exact tests, binary logistic regression analyses, and univariable and multivariable Cox proportional hazard regression models. RESULTS: MVI was present in 201 of 747 patients (26.9%) and was associated with advanced Tumour-Node-Metastasis (TNM) stages, high Fuhrman grades, and sarcomatoid features (all P < 0.001). MVI was associated with a higher rate of metastatic spread. LVI was present in 32 of 573 patients (5.5%) and was associated with advanced TNM stages, high Fuhrman grade, and sarcomatoid features (all P < 0.001). Two-thirds of LVI-positive patients died (P < 0.001). Both LVI and MVI were significantly associated with CSS in all patients, clear cell RCC (ccRCC), and localised RCC in univariable analysis (all P < 0.001). On multivariable analysis, presence of MVI was identified as an independent prognostic factor (hazard ratio 2.09; P = 0.001). Moreover, MVI [odds ratio (OR) 2.7; P = 0.001] and not macrovascular invasion (P = 0.895) was an independent predictor of sychronuous metastatic spread. LVI was the strongest factor associated with sychronous metastatic spread (OR 4.73, 95% confidence interval 1.84-12.14; P = 0.001) in all patients and in the subgroup of patients with ccRCC (P = 0.001). CONCLUSIONS: The present study validated LVI and MVI as prognostic factors for poor outcome in RCC. These findings endorse an evaluation of both variables in the clinical routine setting to facilitate survival prognostication in follow-up protocols and for assignment to adjuvant treatment trials. PMID- 28803449 TI - Prospective comparison between magnetic resonance imaging and computed tomography in colorectal cancer staging. AB - BACKGROUND: Diffusion-weighted (DW) imaging is a functional magnetic resonance imaging (MRI) technique that detects lesions with high cellularity, such as malignant tumours. This prospective study was performed to compare the accuracy of DW-MRI with multidetector computed tomography (MDCT) in staging of colorectal cancer. METHODS: Thirty patients with histologically proven colorectal cancer were prospectively recruited. Each patient underwent both MDCT and DW-MRI of the abdomen-pelvis for primary staging. Images were evaluated for nodal and distant metastases. The reference standard was histopathological findings for nodal involvement and surveillance imaging for suspected hepatic metastases. RESULTS: The primary cancers were located in the rectum (n = 16, 53.3%), sigmoid colon (n = 9, 30%) and right colon (n = 5, 16.6%). For nodal metastases, the sensitivity and specificity of DW-MRI were 84.6% (95% confidence interval (CI): 54.6-98.1%) and 20.0% (95% CI: 2.5-55.6%) compared with 84.6% (95% CI: 54.6-98.1%) and 40.0% (95% CI: 12.2-73.8%) for MDCT. For liver metastases, the sensitivity and specificity for DW-MRI were 100.0% (95% CI: 63.1-100.0%) and 100% (95% CI: 84.6 100%) compared with 87.5% (95% CI: 47.4-99.7%) and 95.5% (95% CI: 77.2-99.9%) for MDCT. DW imaging altered the clinical management in three (10.0%) patients by detecting missed hepatic metastases in two patients and accurately diagnosing another patient with a hepatic cyst, mistaken for metastasis on MDCT. CONCLUSION: DW-MRI is more accurate for detecting hepatic metastases in colorectal cancer compared with MDCT. PMID- 28803450 TI - Manoeuvre to aid Endoscopic division of aryepiglottic folds (Aryepiglottoplasty). PMID- 28803451 TI - Laparoscopic hepatectomy combined with endoscopic papillary balloon dilation for complex bile duct stones. AB - BACKGROUND: We evaluated the feasibility and efficacy of laparoscopic hepatectomy (LH) combined with endoscopic papillary balloon dilation (EPBD) for removing intra- and extrahepatic bile duct stones. METHODS: A total of 26 patients with intra- and extrahepatic bile duct stones underwent LH and EPBD. Selective hemi hepatic vascular occlusion was used to complete the LH. EPBD was performed under the guidance of a guidewire, and stones were removed with a stone basket or balloon. RESULTS: A one-stage LH with EPBD lithotomy was successfully performed in 26 cases. No residual bile duct stones, intestinal or bile duct perforations were found. In addition, no severe post-operative bleeding, severe pancreatitis or mortality occurred. Post-operative hyperamylasemia was observed in five cases and bile leakage in one case. Post-operative hospital stays lasted 7-11 days. CONCLUSION: LH combined with EPBD applied to intra- and extrahepatic bile duct stones was feasible, effective and safe, resulting in rapid recovery and few post operative complications. PMID- 28803452 TI - Colonoscopic surveillance: quality, guidelines and effectiveness. AB - Colonoscopic surveillance in patients with a personal or family history of colorectal carcinoma or colonic polyps represents a significant workload for endoscopy services. Effective colonoscopic surveillance relies on quality endoscopic examination and appropriate surveillance interval. This review will discuss quality in colonoscopy and review guidelines for surveillance. PMID- 28803454 TI - Serum carbohydrate antigen 19-9 in pancreatic adenocarcinoma: a mini review for surgeons. AB - The optimal management of oncological conditions is reflected by the careful interpretation of investigations for screening, diagnosis, staging, prognostication and surveillance. Serum tumour markers are examples of commonly requested tests in conjunction with other imaging and endoscopic tests that are used to help clinicians to stratify therapeutic decisions. Serum carbohydrate antigen 19-9 (CA19-9) is a key biomarker for pancreatic cancers. Although this biomarker is considered clinically useful and informative, clinicians are often challenged by the accurate interpretation of elevated serum CA19-9 levels. Recognizing the pitfalls of normal and abnormal serum CA19-9 concentrations will facilitate its appropriate use. In this review, we appraised the biomarker, serum CA19-9, and highlighted the clinical utility and limitations of serum CA19-9 in the investigation and management of pancreatic cancers. PMID- 28803453 TI - Repeated exposure to two stressors in sequence demonstrates that corticosterone and paraventricular nucleus of the hypothalamus interleukin-1beta responses habituate independently. AB - A wide range of stress-related pathologies such as post-traumatic stress disorder are considered to arise from aberrant or maladaptive forms of stress adaptation. The hypothalamic-pituitary-adrenal (HPA) axis readily adapts to repeated stressor exposure, yet little is known about adaptation in neuroimmune responses to repeated or sequential stress challenges. In Experiment 1, rats were exposed to 10 days of restraint alone (60 minutes daily), forced swim alone (30 minutes daily) or daily sequential exposure to restraint (60 minutes) followed immediately by forced swim (30 minutes), termed sequential stress exposure. Habituation of the corticosterone (CORT) response occurred to restraint by 5 days and swim at 10 days, whereas rats exposed to sequential stress exposure failed to display habituation to the combined challenge. Experiment 2 compared 1 or 5 days of forced swim with sequential stress exposure and examined how each affected expression of several neuroimmune and cellular activation genes in the paraventricular nucleus of the hypothalamus (PVN), prefrontal cortex (PFC) and hippocampus (HPC). Sequential exposure to restraint and swim increased interleukin (IL)-1beta in the PVN, an effect that was attenuated after 5 days. Sequential stress exposure also elicited IL-6 and tumour necrosis factor-alpha responses in the HPC and PFC, respectively, which did not habituate after 5 days. Experiment 3 tested whether prior habituation to restraint (5 days) would alter the IL-1beta response evoked by swim exposure imposed immediately after the sixth day of restraint. Surprisingly, a history of repeated exposure to restraint attenuated the PVN IL-1beta response after swim in comparison to acutely-exposed subjects despite an equivalent CORT response. Overall, these findings suggest that habituation of neuroimmune responses to stress proceeds: (i) independent of HPA axis habituation; (ii) likely requires more daily sessions of stress to develop; and (iii) IL-1beta displays a greater tendency to habituate after repeated stress challenges compared to other stress-reactive cytokines. PMID- 28803455 TI - Effect of positive perioperative donor and recipient respiratory bacterial cultures on early post-transplant outcomes in lung transplant recipients. AB - BACKGROUND: It is standard practice to administer prophylactic antibiotics post lung transplantation. However, no studies have evaluated the impact of culture positivity. The purpose of this study was to evaluate early post-transplant outcomes of culture-positive and culture-negative lung transplant (LT) recipients and the appropriateness of the empiric regimens used. METHODS: Adult patients who received an LT at Emory University Hospital between January 1, 2010 and August 31, 2015 were reviewed and stratified into three groups: (i) culture-positive appropriate empiric treatment, (ii) culture-positive inappropriate empiric treatment, and (iii) culture-negative. Antibiotics were defined as appropriate if bacteria were sensitive to the empiric regimen. The primary endpoint was 30-day mortality. Secondary endpoints included hospital length of stay (LOS), intensive care unit (ICU) LOS, percent neutrophil count in a bronchoalveolar lavage (BAL) sample, presence of airway ischemia, and appropriateness of the empiric antibiotic regimen. RESULTS: Nine, zero, and four patients died within 30 days in the culture-positive appropriate (n = 113), culture-positive inappropriate (n = 5), and culture-negative groups (n = 29) (P = .564) respectively. The median hospital LOS was 19, 16, and 15 days respectively. Median ICU LOS was 6, 5, and 7 respectively. The respective percent neutrophil counts in the BAL fluid were 79, 83, and 65. The presence of airway ischemia was only documented in eight patients, all in the culture-positive appropriate group. CONCLUSION: We did not identify an association between antibiotic appropriateness and 30-day mortality, hospital LOS, or ICU LOS in post-LT recipients. PMID- 28803457 TI - Development of a proficiency-based virtual reality simulation training curriculum for laparoscopic appendicectomy. AB - BACKGROUND: Proficiency-based virtual reality (VR) training curricula improve intraoperative performance, but have not been developed for laparoscopic appendicectomy (LA). This study aimed to develop an evidence-based training curriculum for LA. METHODS: A total of 10 experienced (>50 LAs), eight intermediate (10-30 LAs) and 20 inexperienced (<10 LAs) operators performed guided and unguided LA tasks on a high-fidelity VR simulator using internationally relevant techniques. The ability to differentiate levels of experience (construct validity) was measured using simulator-derived metrics. Learning curves were analysed. Proficiency benchmarks were defined by the performance of the experienced group. Intermediate and experienced participants completed a questionnaire to evaluate the realism (face validity) and relevance (content validity). RESULTS: Of 18 surgeons, 16 (89%) considered the VR model to be visually realistic and 17 (95%) believed that it was representative of actual practice. All 'guided' modules demonstrated construct validity (P < 0.05), with learning curves that plateaued between sessions 6 and 9 (P < 0.01). When comparing inexperienced to intermediates to experienced, the 'unguided' LA module demonstrated construct validity for economy of motion (5.00 versus 7.17 versus 7.84, respectively; P < 0.01) and task time (864.5 s versus 477.2 s versus 352.1 s, respectively, P < 0.01). Construct validity was also confirmed for number of movements, path length and idle time. Validated modules were used for curriculum construction, with proficiency benchmarks used as performance goals. CONCLUSION: A VR LA model was realistic and representative of actual practice and was validated as a training and assessment tool. Consequently, the first evidence based internationally applicable training curriculum for LA was constructed, which facilitates skill acquisition to proficiency. PMID- 28803456 TI - Evaluation of prenatal corticosteroid use in spontaneous preterm labor in the Brazilian Multicenter Study on Preterm Birth (EMIP). AB - OBJECTIVE: To evaluate prenatal corticosteroid use in women experiencing spontaneous preterm labor and preterm delivery. METHODS: The present cross sectional multicenter study analyzed interview data from patients attending 20 hospitals in Brazil owing to preterm delivery between April 1, 2011 and July 30, 2012. Patients were stratified based on preterm delivery occurring before 34 weeks or at 34-36+6 weeks of pregnancy, and the frequency of prenatal corticosteroid use at admission was compared. Prenatal corticosteroid use, sociodemographic data, obstetric characteristics, and neonatal outcomes were examined. RESULTS: There were 1455 preterm deliveries included in the present study; 527 (36.2%) occurred before 34 weeks of pregnancy and prenatal corticosteroids were used in 285 (54.1%) of these pregnancies. Among neonates delivered at 32-33+6 weeks, prenatal corticosteroid use was associated with lower pneumonia (P=0.026) and mortality (P=0.029) rates. Among neonates delivered at 34-36+6 weeks, prenatal corticosteroid use was associated with longer neonatal hospital admission (P<0.001), and an increased incidence of 5-minute Apgar scores below 7 (P=0.010), endotracheal intubation (P=0.042), surfactant use (P=0.006), neonatal morbidities (P=0.048), respiratory distress (P=0.048), and intraventricular hemorrhage (P=0.023). CONCLUSION: Preterm labor and late preterm delivery were associated with worse neonatal outcomes following prenatal corticosteroids. This could reflect a sub-optimal interval between administration and delivery. PMID- 28803458 TI - Neglect and aphasia in the acute phase as predictors of functional outcome 7 years after ischemic stroke. AB - BACKGROUND AND PURPOSE: Visuospatial inattention (VSI) and language impairment (LI) are often present early after stroke and associations with an unfavorable short-term functional outcome have been reported. The purpose of this study was to investigate whether a screening of VSI and LI as indicators of cortical symptoms early after stroke could predict long-term functional outcomes. METHODS: A consecutive cohort of 375 patients with ischemic stroke was assessed for the occurrence of VSI at a median of 7 days after admission (interquartile range, 1-5 days) using the Star Cancellation Test and for LI (within the first 7 days) with the language item in the Scandinavian Stroke Scale. Seven years later, functional outcomes were assessed by the modified Rankin scale and Frenchay Activities Index in 235 survivors without recurrent stroke. Relationships between baseline predictors and functional outcome at 7 years were analyzed with bivariate correlations and multiple categorical regressions with optimal scaling. RESULTS: The regression model significantly explained variance in the modified Rankin scale (R2 = 0.435, P < 0.001) and identified VSI (P = 0.001) and neurological deficits (P < 0.001; Scandinavian Stroke Scale score without the language item) as the significant independent predictors. The model for Frenchay Activities Index was also significant (R2 = 0.269, P < 0.001) with VSI (P = 0.035) and neurological deficits (P < 0.001) as significant independent predictors. CONCLUSIONS: Visuospatial inattention at acute stroke has an independent impact on long-term functional outcomes. Early recognition may enable targeted rehabilitative interventions. PMID- 28803460 TI - [Gastrostomy tubes: indications and infectious complications in a tertiary hospital]. AB - OBJECTIVE: Gastrostomy tube is the best option for long-term enteral nutrition. Among its limitations, infections represent the most frequent minor complication. Our aim is the knowledge of the number and type of gastrostomy tubes and its main indication in our hospital. In addition, prevalence of infectious complications was studied paying attention to the main etiologic agents and their antibiotic susceptibility. METHODS: Observational retrospective study from January 2010 to July 2015 through the electronic clinical history and the clinical microbiology laboratory software. Identification and antibiotic susceptibility of clinically significant isolates from patients with suspicion of gastrostomy tube infection have been analysed. RESULTS: Percutaneous endoscopic gastrostomy was performed in 203 patients (70.5%) and surgical gastrostomy in 85 (29.5%). The main reason identified for starting enteral nutrition through gastrostomy tube was malignant neoplasy, above all, lip, oral cavity and pharynx cancer (11.8%) and that from digestive organs (8.7%). Global prevalence of gastrostomy tube infection was 16.6%. The most common bacterial pathogens isolated were Staphylococcus aureus (21.3%), Pseudomonas aeruginosa (13.1%), and Escherichia coli (9.8%). The percentage of multi resistant isolates was 3.1%. CONCLUSIONS: Gastrostomy tube indications and type, and also, prevalence and microorganisms isolated from culture in infectious complications are similar to those described previously in the literature. The study allows the adaptation of the antibiotic prophylaxis and empirical antibiotic treatment thanks to the knowledge of the etiologic agents and their antibiotic susceptibility. PMID- 28803459 TI - Prediction of esophageal stricture in patients given locoregional triamcinolone injections immediately after endoscopic submucosal dissection. AB - BACKGROUND AND AIM: Esophageal endoscopic submucosal dissection (ESD) to resect widespread lesions has increased the incidence of strictures, and some patients develop strictures despite receiving prophylactic locoregional triamcinolone injections. The present study evaluated the predictive factors for esophageal stricture formation in patients given prophylactic triamcinolone injections after ESD. METHODS: This was a retrospective observational study. Of 552 consecutive patients who underwent ESD, those who received prophylactic triamcinolone injections immediately after ESD were enrolled. Primary outcome was predictive factors for esophageal stricture formation in patients given prophylactic triamcinolone injections. RESULTS: We evaluated 101 en bloc resections involving 144 lesions in 96 patients. Strictures occurred following 17 (16.8%) resections. Wider circumferential mucosal defect (odds ratio [OR] 2.42, 95% confidence interval [CI]: 1.01-5.80; P = 0.048) was an independent predictive factor for stricture development. Cut-off value associated with stricture formation was five sixths of the circumferential mucosal defect. Propensity analysis determined that frequency of esophageal strictures increased in patients with circumferential mucosal defects of more than five-sixths compared with those less than five sixths (OR = 5.70, 95% CI: 1.61-20.18; P = 0.007). CONCLUSION: Resections involving circumferential mucosal defects of more than five-sixths increased the likelihood of stricture formation in patients given prophylactic locoregional triamcinolone injections after esophageal ESD. PMID- 28803461 TI - [Streptobacillus moniliformis: in vivo and in vitro differences]. PMID- 28803462 TI - Structural Characterization of Methylenedianiline Regioisomers by Ion Mobility Mass Spectrometry, Tandem Mass Spectrometry, and Computational Strategies. 3. MALDI Spectra of 2-Ring Isomers. AB - Characterization of methylenedianiline (MDA) 2-ring isomers (2,2'-, 2,4'-, and 4,4'-MDA) is reported using matrix assisted laser desorption/ionization-mass spectrometry (MALDI-MS), a common technique used for characterizing synthetic polymers. MDA is a precursor to methylene diphenyl diisocyanate (MDI), a hard block component in polyurethane (PUR) synthesis. This work focuses on comparing MALDI results to those of our previous electrospray ionization-mass spectrometry (ESI-MS) studies. In ESI, 2-ring MDA isomers formed single unique [M + H]+ (199 Da) parent ions, whereas in MALDI each isomer shows significant formation of three precursor ions: [M - H]+ = 197 Da, [M*]+ = 198 Da, and [M + H]+ = 199 Da. Structures and schemes are proposed for the MALDI fragment ions associated with each precursor ion. Ion mobility-mass spectrometry (IM-MS), tandem mass spectrometry (MS/MS), and computational methods were all critical in determining the structures for both precursor and fragment ions as well as the fragmentation mechanisms. The present study indicates that the [M - H]+ and [M*]+ ions are formed by the MALDI process, explaining why they were not observed with ESI. PMID- 28803463 TI - Bacterial Microcolonies in Gel Beads for High-Throughput Screening of Libraries in Synthetic Biology. AB - Synthetic biologists increasingly rely on directed evolution to optimize engineered biological systems. Applying an appropriate screening or selection method for identifying the potentially rare library members with the desired properties is a crucial step for success in these experiments. Special challenges include substantial cell-to-cell variability and the requirement to check multiple states (e.g., being ON or OFF depending on the input). Here, we present a high-throughput screening method that addresses these challenges. First, we encapsulate single bacteria into microfluidic agarose gel beads. After incubation, they harbor monoclonal bacterial microcolonies (e.g., expressing a synthetic construct) and can be sorted according their fluorescence by fluorescence activated cell sorting (FACS). We determine enrichment rates and demonstrate that we can measure the average fluorescent signals of microcolonies containing phenotypically heterogeneous cells, obviating the problem of cell-to cell variability. Finally, we apply this method to sort a pBAD promoter library at ON and OFF states. PMID- 28803464 TI - Changes in Virgin Olive Oil Volatiles Caused by in Vitro Digestion. AB - Volatile compounds are responsible for some sensory characteristics of virgin olive oil (VOO); however, they have not been studied from a nutritional point view. In this work, the effect of the simulated digestion on VOO volatile compounds responsible for green flavor was studied, analyzing their changes through the three steps of an in vitro digestion model (mouth, stomach, and small intestine). Index of recovery and bioaccessibility were determined for the main volatiles of "Picual" VOO. At end of the duodenal step, higher recoveries of ethanol, pent-1-en-3-ol, beta-ocimene, and nonanal were observed. From the 10 volatile compounds analyzed, only six compounds were bioaccessible. The compounds with the highest bioaccessibility were pent-1-en-3-ol, nonanal, beta-ocimene, and ethanol. The results showed for the first time the recovery and bioaccessibility of several volatile compounds present in VOO. PMID- 28803465 TI - Hypervalent Iodine Mediated Chemoselective Iodination of Alkynes. AB - Reported herein are practical approaches for the chemoselective mono-, di-, and tri-iodination of alkynes based on efficient oxidative iodinations catalyzed by hypervalent iodine reagents. The reaction conditions were systematically optimized by altering the iodine source and/or the hypervalent iodine reagent system. The tetrabutylammonium iodide (TBAI)/(diacetoxyiodo)benzene (PIDA) system is specific for monoiodination, while the KI/PIDA system results in di iodination. Combining the TBAI/PIDA and KI/PIDA systems in one pot provided the corresponding tri-iodination products efficiently. These reaction conditions can be applied to the synthetically important iodination of aromatic and aliphatic alkynes, which was accomplished in good yield (up to 99%) and excellent chemoselectivity. These synthetic methods can also be applied to the efficient chemoselective synthesis of iodoalkyne derivatives, intermediates, and related biologically active compounds. PMID- 28803466 TI - Deciphering the Fluorine Code-The Many Hats Fluorine Wears in a Protein Environment. AB - Deciphering the fluorine code is how we describe not only the focus of this Account, but also the systematic approach to studying the impact of fluorine's incorporation on the properties of peptides and proteins used by our groups and others. The introduction of fluorine has been shown to impart favorable, but seldom predictable, properties to peptides and proteins, but up until about two decades ago the outcomes of fluorine modification of peptides and proteins were largely left to chance. Driven by the motivation to extend the application of the unique properties of the element fluorine from medicinal and agro chemistry to peptide and protein engineering we have established extensive research programs that enable the systematic investigation of effects that accompany the introduction of fluorine into this class of biopolymers. The introduction of fluorine into amino acids offers a universe of options for modifications with regard to number and position of fluorine substituents in the amino acid side chain. Moreover, it is important to emphasize that the consequences of incorporating the C-F bond into a biopolymer can be attributed to two distinct yet related phenomena: (i) the fluorine substituent can directly engage in intermolecular interactions with its environment and/or (ii) the other functional groups present in the molecule can be influenced by the electron withdrawing nature of this element (intramolecular) and in turn interact differently with their immediate environment (intermolecular). Based on our studies, we have shown that a change in number and/or position of as subtle as one single fluorine substituent has the power to considerably modify key properties of amino acids such as hydrophobicity, polarity, and secondary structure propensity. These properties are crucial factors in peptide and protein engineering, and thus, fluorinated amino acids can be applied to fine-tune properties such as protein folding, proteolytic stability, and protein-protein interactions provided we understand and become able to predict the outcome of a fluorine substitution in this context. With this Account, we attempt to analyze information we gained from our recent projects on how the nature of the fluorine atom and C-F bond influence four key properties of peptides and proteins: peptide folding, protein-protein interactions, ribosomal translation, and protease stability. These results impressively show why the introduction of fluorine creates a new class of amino acids with a repertoire of functionalities that is unique to the world of proteins and in some cases orthogonal to the set of canonical and natural amino acids. Our concluding statements aim to offer a few conserved design principles that have emerged from systematic studies over the last two decades; in this way, we hope to advance the field of peptide and protein engineering based on the judicious introduction of fluorinated building blocks. PMID- 28803468 TI - Functional Multi-Nanolayer Coatings of Amorphous Carbon/Tungsten Carbide with Exceptional Mechanical Durability and Corrosion Resistance. AB - A novel functional multilayer coating with periodically stacked nanolayers of amorphous carbon (a:C)/tungsten carbide (WC) and an adhesion layer of chromium (Cr) was deposited on 304 stainless steel using a dual magnetron sputtering technique. Through process optimization, highly densified coatings with high elasticity and shear modulus, excellent wear resistance, and minimal susceptibility to corrosive and caustic media could be acquired. The structural and mechanical properties of the optimized coatings were studied in detail using a variety of analytical techniques. Furthermore, finite element method simulations indicated that the stress generated due to contact against a steel ball was distributed well within the coating, which allowed the stresses to be lower than the yield threshold of the coating. Thus, an ultralow wear rate of ~10 12mm3/N mm could be achieved in dry sliding conditions under relatively high Hertzian contact pressures of ~0.4-0.9 GPa. The amorphous and pinhole-free structure of the individual layers, sufficient number of pairs, and the relatively dense stacked layers resulted in significant polarization resistance (Z" = 5.5 * 106 Omega cm2) and increased the corrosion resistance of the coating by 10-fold compared to that of recently reported corrosion-resistant coatings. PMID- 28803467 TI - NOT Gate Genetic Circuits to Control Gene Expression in Cyanobacteria. AB - To downregulate gene expression in cyanobacteria, we constructed NOT gate genetic circuits using orthogonal promoters and their cognate repressors regulated translationally by synthetic riboswitches. Four NOT gates were tested and characterized in five cyanobacterial strains using fluorescent reporter-gene assays. In comparison to alternative systems used to downregulate gene expression in cyanobacteria, these NOT gates performed well, reducing YFP reporter expression by 4 to 50-fold. We further evaluated these NOT gates by controlling the expression of the ftsZ gene, which encodes a prokaryotic tubulin homologue that is required for cell division and is essential for Synechococcus elongatus PCC 7942. These NOT gates would facilitate cyanobacterial genetic engineering or the study of essential cellular processes. PMID- 28803469 TI - Chiral Ceramic Nanoparticles and Peptide Catalysis. AB - The chirality of nanoparticles (NPs) and their assemblies has been investigated predominantly for noble metals and II-VI semiconductors. However, ceramic NPs represent the majority of nanoscale materials in nature. The robustness and other innate properties of ceramics offer technological opportunities in catalysis, biomedical sciences, and optics. Here we report the preparation of chiral ceramic NPs, as represented by tungsten oxide hydrate, WO3-x.H2O, dispersed in ethanol. The chirality of the metal oxide core, with an average size of ca. 1.6 nm, is imparted by proline (Pro) and aspartic acid (Asp) ligands via bio-to-nano chirality transfer. The amino acids are attached to the NP surface through C-O-W linkages formed from dissociated carboxyl groups and through amino groups weakly coordinated to the NP surface. Surprisingly, the dominant circular dichroism bands for NPs coated by Pro and Asp are different despite the similarity in the geometry of the NPs; they are positioned at 400-700 nm and 500-1100 nm for Pro- and Asp-modified NPs, respectively. The differences in the spectral positions of the main chiroptical band for the two types of NPs are associated with the molecular binding of the two amino acids to the NP surface; Asp has one additional C-O-W linkage compared to Pro, resulting in stronger distortion of the inorganic crystal lattice and greater intensity of CD bands associated with the chirality of the inorganic core. The chirality of WO3-x.H2O atomic structure is confirmed by atomistic molecular dynamics simulations. The proximity of the amino acids to the mineral surface is associated with the catalytic abilities of WO3 x.H2O NPs. We found that NPs facilitate formation of peptide bonds, leading to Asp-Asp and Asp-Pro dipeptides. The chiroptical activity, chemical reactivity, and biocompatibility of tungsten oxide create a unique combination of properties relevant to chiral optics, chemical technologies, and biomedicine. PMID- 28803470 TI - Effect of DMSO on Protein Structure and Interactions Assessed by Collision Induced Dissociation and Unfolding. AB - Given the frequent use of DMSO in biochemical and biophysical assays, it is desirable to understand the influence of DMSO concentration on the dissociation or unfolding behavior of proteins. In this study, the effects of DMSO on the structure and interactions of avidin and Mycobacterium tuberculosis (Mtb) CYP142A1 were assessed through collision-induced dissociation (CID) and collision induced unfolding (CIU) as monitored by nanoelectrospray ionization-ion mobility mass spectrometry (nESI-IM-MS). DMSO concentrations higher than 4% (v/v) destabilize the avidin tetramer toward dissociation and unfolding, via both its effects on charge state distribution (CSD) as well as at the level of individual charge states. In contrast, DMSO both protects against heme loss and increases the stability of CYP142A1 toward unfolding even up to 40% DMSO. Tandem MS/MS experiments showed that DMSO could modify the dissociation pathway of CYP142A1, while CIU revealed the protective effect of the heme group on the structure of CYP142A1. PMID- 28803472 TI - Blue Light Switchable Bacterial Adhesion as a Key Step toward the Design of Biofilms. AB - The control of where and when bacteria adhere to a substrate is a key step toward controlling the formation and organization in biofilms. This study shows how we engineer bacteria to adhere specifically to substrates with high spatial and temporal control under blue light, but not in the dark, by using photoswitchable interaction between nMag and pMag proteins. For this, we express pMag proteins on the surface of E. coli so that the bacteria can adhere to substrates with immobilized nMag protein under blue light. These adhesions are reversible in the dark and can be repeatedly turned on and off. Further, the number of bacteria that can adhere to the substrate as well as the attachment and detachment dynamics are adjustable by using different point mutants of pMag and altering light intensity. Overall, the blue light switchable bacteria adhesions offer reversible, tunable and bioorthogonal control with exceptional spatial and temporal resolution. This enables us to pattern bacteria on substrates with great flexibility. PMID- 28803471 TI - Altering the Peptide Binding Selectivity of Polymeric Reverse Micelle Assemblies via Metal Ion Loading. AB - Supramolecular reverse micelle assemblies, formed by amphiphilic copolymers, can selectively encapsulate molecules in their interiors depending on the functional groups present in the polymers. Altering the binding selectivity of these materials typically requires the synthesis of alternate functional groups. Here, we demonstrate that the addition of Zr(IV) ions to the interiors of reverse micelles having phosphonate functional groups transforms the supramolecular materials from ones that selectively bind positively charged peptides into materials that selectively bind phosphorylated peptides. We also show that the binding selectivity of these reverse micelle assemblies can be further tuned by varying the fractions of phosphonate groups in the copolymer structure. The optimized reverse micelle materials can selectively transfer and bind phosphorylated peptides from aqueous solutions over a wide range of pH conditions and can selectively enrich phosphorylated peptides even in complicated mixtures. PMID- 28803473 TI - Inkjet Printing Based Separation of Mammalian Cells by Capillary Electrophoresis. AB - This study describes a method to investigate the separation of cells by capillary electrophoresis (CE) coupled with inkjet printing system. The results validated the feasibility of inkjet printing for mammalian cells to achieve the drop-on demand and convenient sampling into capillary then zone electrophoresis was applied to separate different cells according to their electrophoretic mobility, finally the peak signal were measured by UV detector. Linear relationship between the peak area and the droplet number was obtained within the range of 25-400 drops (R2 = 0.996) at a fixed cell concentration 106/mL, indicating that this system could be used for rapid and accurate quantification of cells. PMID- 28803474 TI - Bioinspired Indole Prenylation Reactions in Water. AB - Isoprene units derived from dimethylallyl diphosphate (DMAPP) are an important motif in many natural products including terpenoids, carotenoids, steroids, and natural rubber. Understanding the chemical characteristics of DMAPP is an important topic in natural products chemistry, organic chemistry, and biochemistry. We have developed a direct bioinspired indole prenylation reaction using DMAPP or its equivalents as the electrophile in homogeneous aqueous acidic media in the absence of enzyme to provide prenylated indole products. After establishing the bioinspired indole prenylation reaction, this was then used to achieve the synthesis of a series of natural products, namely, N-prenylcyclo-l tryptophyl-l-proline, tryprostatins, rhinocladins, and terezine D. PMID- 28803475 TI - Intuitive Label-Free SERS Detection of Bacteria Using Aptamer-Based in Situ Silver Nanoparticles Synthesis. AB - The characteristic of an ideal bacteria-detection method should have high sensitivity and specificity, be easy to operate, and not have a time-consuming culture process. In this study, we report a new bacteria-detection strategy that can recognize bacteria quickly and directly by surface-enhanced Raman scattering (SERS) with the formation of well-defined bacteria-aptamer@AgNPs. SERS signals generated by bacteria-aptamer@AgNPs exhibited a linear dependence on bacteria (R2 = 0.9671) concentration ranging from 101 to 107 cfu/mL. The detection limit is sensitive down to 1.5 cfu/mL. Meanwhile, the bacteria SERS signal was dramatically enhanced by its specifically recognized aptamer, and the bacteria could be identified directly and visually through the SERS spectrum. This strategy eliminates the puzzling data analysis of previous studies and offers significant advantages over existing approaches, getting a critical step toward the creation of SERS-based biochips for rapid in situ bacteria detection in mixture samples. PMID- 28803476 TI - Rationally Turning the Interface Activity of Mesoporous Silicas for Preparing Pickering Foam and "Dry Water". AB - We develop a novel protocol to prepare smart, gas/water interface-active, mesoporous silica particles. This protocol involves modification of highly mesoporous silicas with a mixture of hydrophobic octyl organosilane and hydrophilic triamine organosilane. Their structure and compositions are characterized by transmission electron microscopy (TEM), N2 sorption, solid state NMR, X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectra (FT-IR), thermogravimetric analysis (TGA), and elemental analysis. It is demonstrated that our protocol enables the interface activity of mesoporous silica particles to be facilely tuned, so that the stable gas-water interfaces ranging from air bubbles dispersed in water (Pickering foam) and water droplets dispersed in air ("dry water") can be achieved, depending on the molar ratio of these two organosilanes. The "dry water" is not otherwise attainable for the analogous nonporous silica particles, indicting the uniqueness of the chosen mesoporous structures. Moreover, these particle-stabilized Pickering foams and "dry waters" can be disassembled in response to pH. Interestingly, it was found that aqueous potassium carbonate droplets stabilized by these interface-active mesoporous silica particles ("dry K2CO3-containing water") could automatically capture CO2 from a simulated flue gas with enhanced adsorption rate and adsorption capacity when compared to the aqueous potassium carbonate bulk solution. This study not only supplies a novel type of efficient, smart, gas/water interface-active mesoporous silica particles but also demonstrates an innovative application of mesoporous materials in gas adsorption. PMID- 28803477 TI - Mg2+-Channel-Inspired Nanopores for Mg2+/Li+ Separation: The Effect of Coordination on the Ionic Hydration Microstructures. AB - The separation behaviors of Mg2+ and Li+ were investigated using molecular dynamics. Two functionalized graphene nanopore models (i.e., co_5 and coo_5) inspired by the characteristic structural features of Mg2+ channels were used. Both nanopores exhibited a higher preference to Mg2+ than to Li+, and the selectivity ratios were higher for coo_5 than for co_5 under all the studied transmembrane voltages. An evaluation of the effect of coordination on the ionic hydration microstructures for both nanopores showed that the positioning of the modified groups could better fit a hydrated Mg2+ than a hydrated Li+, as if Mg2+ was not dehydrated according to hydrogen bond analysis of the ionic hydration shells. This condition led to a lower resistance for Mg2+ than for Li+ when traveling through the nanopores. Moreover, a distinct increase in hydrogen bonds occurred with coo_5 compared with co_5 for hydrated Li+, which made it more difficult for Li+ to pass through coo_5. Thus, a higher Mg2+/Li+ selectivity was found in for coo_5 than for co_5. These findings provide some design principles for developing artificial Mg2+ channels, which have potential applications as Mg2+ sensors and novel devices for Mg2+/Li+ separation. PMID- 28803478 TI - Biomimetic Bone-like Hydroxyapatite by Mineralization on Supramolecular Porous Fiber Networks. AB - Hydroxyapatite (HA), the main inorganic component of bone tissue, is mineralized with collagen fibril scaffolds during bone formation. Inspired by the process, a self-assembled porous network architecture was designed and synthesized by using the 2-ureido-4[1H]-pyrimidone (UPy) modified glycerol molecule UPy-Gly, which was further utilized as a template for biomimetic mineralization. When incubated in simulated body fluid (SBF), the HA nucleus first formed in the holes of the template by the induction of hydroxyls on the surface, grew along the nanofibers, and fused with the template to fabricate hydroxyapatite composites (UPy-Gly/HA). Transmission electron microscopic observation demonstrates that the mineral clusters are accumulated by lamella-like nano hydroxyapatite and the elasticity modulus measured by atomic force microscopy is about 5.5 GPa, which is quite close to the natural cancellous bone tissue of human both in structure and in mechanical properties. The Cell Counting Kit 8 (CCK-8) assay of UPy-Gly and UPy Gly/HA shows noncytotoxicity to mouse fibroblast L-929 cells. This bioinspired composite will be a promising material for potential use in bone tissue implantation and regeneration engineering. PMID- 28803479 TI - Design of Cyclic Peptide Based Glucose Receptors and Their Application in Glucose Sensing. AB - Glucose assay is of great scientific significance in clinical diagnostics and bioprocess monitoring, and to design a new glucose receptor is necessary for the development of more sensitive, selective, and robust glucose detection techniques. Herein, a series of cyclic peptide (CP) glucose receptors were designed to mimic the binding sites of glucose binding protein (GBP), and CPs' sequence contained amino acid sites Asp, Asn, His, Asp, and Arg, which constituted the first layer interactions of GBP. The properties of these CPs used as a glucose receptor or substitute for the GBP were studied by using a quartz crystal microbalance (QCM) technique. It was found that CPs can form a self assembled monolayer at the Au quartz electrode surface, and the monolayer's properties were characterized by using cyclic voltammetry, electrochemical impedance spectroscopy, and atomic force microscopy. The CPs' binding affinity to saccharide (i.e., galactose, fructose, lactose, sucrose, and maltose) was investigated, and the CPs' sensitivity and selectivity toward glucose were found to be dependent upon the configuration,i.e., the amino acids sequence of the CPs. The cyclic unit with a cyclo[-CNDNHCRDNDC-] sequence gave the highest selectivity and sensitivity for glucose sensing. This work suggests that a synthetic peptide bearing a particular functional sequence could be applied for developing a new generation of glucose receptors and would find huge application in biological, life science, and clinical diagnostics fields. PMID- 28803480 TI - Tuning the Spin State in LaCoO3 Thin Films for Enhanced High-Temperature Oxygen Electrocatalysis. AB - The slow kinetics of oxygen surface exchange hinders the efficiency of high temperature oxygen electrocatalytic devices such as solid oxide fuel cells and oxygen separation membranes. Systematic investigations of material properties that link to catalytic activity can aid in the rational design of highly active cathode materials. Here, we explore LaCoO3 thin films as a model system for tuning catalytic activity through strain-induced changes in the Co spin state. We demonstrate that Raman spectroscopy can be used to probe the Co-O bond strength at different temperatures to determine the relative spin occupancies of LaCoO3. We find that strain can be used to reduce the spin transition temperature and promote the occupation of higher spin states that weaken the Co-O bond. The decrease in Co-O bond strength and increased spin moment of the thin films result in significant enhancements of the oxygen surface exchange kinetics by up to 2 orders of magnitude. PMID- 28803481 TI - Autonomous Collision-Free Navigation of Microvehicles in Complex and Dynamically Changing Environments. AB - Self-propelled micro- and nanoscale robots represent a rapidly emerging and fascinating robotics research area. However, designing autonomous and adaptive control systems for operating micro/nanorobotics in complex and dynamically changing environments, which is a highly demanding feature, is still an unmet challenge. Here we describe a smart microvehicle for precise autonomous navigation in complicated environments and traffic scenarios. The fully autonomous navigation system of the smart microvehicle is composed of a microscope-coupled CCD camera, an artificial intelligence planner, and a magnetic field generator. The microscope-coupled CCD camera provides real-time localization of the chemically powered Janus microsphere vehicle and environmental detection for path planning to generate optimal collision-free routes, while the moving direction of the microrobot toward a reference position is determined by the external electromagnetic torque. Real-time object detection offers adaptive path planning in response to dynamically changing environments. We demonstrate that the autonomous navigation system can guide the vehicle movement in complex patterns, in the presence of dynamically changing obstacles, and in complex biological environments. Such a navigation system for micro/nanoscale vehicles, relying on vision-based close-loop control and path planning, is highly promising for their autonomous operation in complex dynamic settings and unpredictable scenarios expected in a variety of realistic nanoscale scenarios. PMID- 28803483 TI - Sleeve Gastrectomy: Managing the Morbidity of Obesity. PMID- 28803482 TI - Corynebacterium glutamicum Chassis C1*: Building and Testing a Novel Platform Host for Synthetic Biology and Industrial Biotechnology. AB - Targeted top-down strategies for genome reduction are considered to have a high potential for providing robust basic strains for synthetic biology and industrial biotechnology. Recently, we created a library of 26 genome-reduced strains of Corynebacterium glutamicum carrying broad deletions in single gene clusters and showing wild-type-like biological fitness. Here, we proceeded with combinatorial deletions of these irrelevant gene clusters in two parallel orders, and the resulting library of 28 strains was characterized under various environmental conditions. The final chassis strain C1* carries a genome reduction of 13.4% (412 deleted genes) and shows wild-type-like growth behavior in defined medium with d glucose as carbon and energy source. Moreover, C1* proves to be robust against several stresses (including oxygen limitation) and shows long-term growth stability under defined and complex medium conditions. In addition to providing a novel prokaryotic chassis strain, our results comprise a large strain library and a revised genome annotation list, which will be valuable sources for future systemic studies of C. glutamicum. PMID- 28803484 TI - Social connectedness improves public mental health: Investigating bidirectional relationships in the New Zealand attitudes and values survey. AB - BACKGROUND: The importance of social connectedness in supporting public mental health is well established. However, the reverse causal pathway (that psychological ill-health leads to reduced social connectedness) remains a dominant perspective among mental health practitioners. Our analysis aimed to provide a rigorous test of the directionality of this relationship. METHOD: A cross-lagged panel analysis of a large longitudinal national probability sample ( N ~ 21,227), the New Zealand Attitudes and Values Survey, was used to assess the bidirectional longitudinal relationship between social connectedness and mental health, controlling for baseline levels of both variables and demographics. RESULTS: Social connectedness was found to be a stronger and more consistent predictor of mental health year-on-year than mental health was of social connectedness. CONCLUSION: These results further demonstrate how the psychological resources conferred by social connectedness can act as a 'social cure' for psychological ill-health, and provide the strongest evidence to date for the direction of this relationship in the general community. PMID- 28803485 TI - Raynaud's phenomenon and its impact on activities in daily life during one year of follow-up in early systemic sclerosis. AB - OBJECTIVE: To investigate Raynaud's phenomenon (RP) and its impact on daily life activities during 1 year of follow-up in early systemic sclerosis (SSc). METHOD: Fourteen SSc patients with a median disease duration of 2 years were enrolled in the study. Every 7 weeks the patients completed a 7 day diary documenting the frequency and duration of RP attacks, the activity causing the attack, and how they handled the attack. The patients also recorded in the diary daily self assessments of the difficulties with RP, using a 0-10 ordinal scale according to the Raynaud's Condition Score. RESULTS: Ninety-eight RP weekly diaries were analysed. The median number of RP attacks varied between six and nine per week, and the median score reflecting the difficulty associated with the attacks varied between 2.0 and 2.9. No difference was found in the number of attacks or the difficulties associated with them between winter, spring, and autumn. Fewer attacks and less difficulty were reported in August than in any of the other documented weeks (p < 0.05). In all diaries, all patients reported RP attacks associated with domestic activities. The use of heating devices varied during the follow-up. In February, all patients except one used such devices, while about half of the group used devices during the rest of the year. CONCLUSIONS: Difficulties resulting from RP are present and disabling all year round, which underscore the importance of intense vasoactive therapy and non-pharmacological strategies throughout the year. PMID- 28803486 TI - Daclizumab for the treatment of adults with relapsing forms of multiple sclerosis. AB - INTRODUCTION: The goal of the article is to review the mechanism of action and the use of daclizumab, a humanized monoclonal antibody (mAb) against the alpha subunit of the high affinity interleukin-2 (IL-2) receptor, in the treatment of Multiple Sclerosis (MS). Areas covered: PubMed was searched for the terms 'daclizumab' and 'multiple sclerosis'. The mechanisms of action, pharmacokinetics and pharmacodynamics, major studies, side effects and drug interactions of daclizumab in MS are discussed. Expert commentary: Monthly daclizumab-beta [DAC beta, formerly daclizumab high yield process (DAC HYP), approved as ZINBRYTA(r), which has a different form and structure than an earlier form of daclizumab], is an effective and convenient treatment option for patients with relapsing forms of MS who have failed other treatment, or as a first-line option in highly active MS patients. IL-2 signaling modulation by daclizumab constitutes a novel mechanism of action which may also underlie the adverse and serious adverse events and risk profile of the drug that requires appropriate patient selection, monitoring and risk-mitigation programs. PMID- 28803487 TI - A mechanism based approach to management of children with end-stage liver disease. AB - INTRODUCTION: Due to parallel advances in surgical and acute care disciplines, liver transplantation (LT) has revolutionized the outlook for children with end stage liver disease (ESLD). Contrary to advances in technical aspects of LT and the peri-operative care, pre-transplant management of ESLD remains quite a formidable challenge. Areas covered: This review provides mechanisms based management strategies to address common complications of ESLD including malnutrition, amended metabolic pathways, gastrointestinal dysfunction, and development of ascites. Clinically relevant discussion of each paradigm is followed by an account of high impact therapeutic interventions which can be used as guides for formulating management plans. A tabulated summary of the suggested interventions is also provided. Indeed, execution of a dynamic plan tailored to the evolution of pathophysiologic derangements can further enhance outcomes of pediatric LT. Expert commentary: LT has evolved as a dependable therapeutic option for a variety of fatal pediatric liver diseases. However, relative organ shortage remains a formidable challenge. Similarly, consumer expectations continue to grow for sustained improvement of graft and patient survival after LT. In this environment, the level of sophistication applied to the management ESLD before LT stands out as a major opportunity with lasting impact on the future of pediatric LT. PMID- 28803488 TI - Clinical outcome and predictive factors of postoperative myasthenic crisis in 173 thymomatous myasthenia gravis patients. AB - PURPOSE: Thymectomy is the first-line therapy for thymomatous myasthenia gravis patients. The aim of this study is to explore the clinical outcome and predictors of postoperative myasthenic crisis (POMC) in these patients. METHOD: Clinical data of 173 thymomatous myasthenia gravis patients undergoing thymectomy from January 2000 to March 2013 were, retrospectively reviewed. Variables potentially affecting the occurrence of POMC were evaluated using binary logistic regression analysis. The difference in survival was determined by the log-rank test. RESULT: Fifty-one patients experienced POMC. Univariate analysis revealed that events significantly associated with increased risk of POMC include symptom duration before operation >2.75months, preoperative bulbar symptoms, incomplete resection, operation time >=122.5 min and advanced stages (stage III or IV). Multivariate logistic regression analysis showed that preoperative bulbar symptoms (OR = 3.207 [1.413-7.278]; P = 0.005) and incomplete resection (OR = 4.182 [1.332-13.135]; P = 0.014) were independent risk factors for POMC. Twenty-eight patients (16.9%) died during the follow-up. The log-rank test revealed survival for patients with POMC was significantly worse than that for patients without POMC (P = 0.042). CONCLUSION: The important risk factors for developing POMC in thymomatous myasthenia gravis patients include the preoperative bulbar symptoms and incomplete resection of thymoma. Moreover, the patients with POMC had a worse prognosis compared with patients without POMC. Our study highlights the need of appropriate preoperative management of thymomatous myasthenia gravis patients to prevent the occurrence of POMC. PMID- 28803489 TI - Recent advances in systemic targeted therapy for cutaneous T-cell lymphoma. PMID- 28803490 TI - Parkin, PINK1 and DJ1 as possible modulators of mTOR pathway in ganglioglioma. AB - PURPOSE: Ganglioglioma (GG) is a non-malignant tumor classified as G1 by the WHO. Although we currently know that the neoplasm may result from the hyperactivity of protein kinase B (PKB or Akt) or extracellular-regulated kinase (Erk), which upregulates mammalian target of rapamycin kinase (mTOR) and leads to translation of proteins responsible for cell cycle regulation, there are still many questions to be answered. In the current paper we try to analyze the link between GG formation and activity of three proteins known to play a role in neuroprotection (parkin, PINK1 and DJ1). MATERIALS AND METHODS: In our paper, we review the current information on the involvement of these proteins in the transmission of information in the cell and triggering various cell signals, like survival or apoptosis. We also review current literature data on involvement of parkin, DJ1 and PINK1 in the regulation of mTOR, the pathway probably contributing to the development of GG. RESULTS: Parkin is an E3 ubiquitin ligase, shown to trigger proteasome-dependent degradation and autophagy, necessary for the maintenance of homeostasis in neurons. PINK1, a mitochondrial protein kinase, is required for mitochondrial maintenance and neuronal survival. DJ1 is a sensor of reactive oxygen species, and protects the cells against oxidative stress. Mutations in the genes encoding these three proteins are known to underlie autosomal recessive forms of Parkinson's disease, as well as other neurodegenerative and neuroinflammatory disorders. CONCLUSION: It appears that mutations of parkin, PINK1 and DJ1 may result in the development of both neurodegeneration and tumors. Also, these proteins might be used as markers of disease, thus allowing better diagnosis and therapy. PMID- 28803491 TI - Optimal long-term pharmacological treatment of patients with venous thromboembolism that was unprovoked or associated with weak risk factors. AB - INTRODUCTION: Unprovoked venous thromboembolism (VTE) tend to recur. Many factors, patient- or event-related, influence the individual risk of recurrence. After initial and long-term (usually for 3-6 months) anticoagulant therapy, extended anticoagulation has been recommended in patients at high risk of recurrence, provided they do not have a high risk of bleeding. Areas covered: The effect of different risk factors on the risk of recurrence is discussed, as well as risk factors for bleeding. The estimation of individual balance between these two risks is crucial to decide which can be the best treatment duration in single patients. The use of direct oral anticoagulants, with likely less risk of bleeding, may influence the balance. D-dimer assessment during and after anticoagulation is stopped is also commented for its role to help identifying the individual risk of recurrence. Expert commentary: All patients with a first VTE should be reconsidered after the initial 3-6 months of treatment. Anticoagulation can then be stopped or continued in relation to low or very high risk of recurrence, respectively. Serial D-dimer assessment during the first 2 or 3 months after anticoagulation is stopped is useful in patients with uncertain risk evaluation (especially after unprovoked events). PMID- 28803492 TI - Rifampin vs. rifapentine: what is the preferred rifamycin for tuberculosis? AB - INTRODUCTION: One-third of the world's population is infected with Mycobacterium tuberculosis (M.tb.). Latent tuberculosis infection (LTBI) can progress to tuberculosis disease, the leading cause of death by infection. Rifamycin antibiotics, like rifampin and rifapentine, have unique sterilizing activity against M.tb. What are the advantages of each for LTBI or tuberculosis treatment? Areas covered: We review studies assessing the pharmacokinetics (PK), pharmacodynamics (PD), drug interaction risk, safety, and efficacy of rifampin and rifapentine and provide basis for comparing them. Expert commentary: Rifampin has shorter half-life, higher MIC against M.tb, lower protein binding, and better distribution into cavitary contents than rifapentine. Drug interactions for the two drugs maybe similar in magnitude. For LTBI, rifapentine is effective as convenient, once-weekly, 12-week course of treatment. Rifampin is also effective for LTBI, but must be given daily for four months, therefore, drug interactions are more problematic. For drug-sensitive tuberculosis disease, rifampin remains the standard of care. Safety profile of rifampin is better-described; adverse events differ somewhat for the two drugs. The registered once-weekly rifapentine regimen is inadequate, but higher doses of either drugs may shorten the treatment duration required for effective management of TB. Results of clinical trials evaluating high-dose rifamycin regimens are eagerly awaited. PMID- 28803493 TI - Health-related quality of life of people with multimorbidity at a community based, interprofessional student-assisted clinic: Implications for assessment and intervention. AB - Objective This study examined the relationship between the number of comorbidities and health-related quality of life (HRQoL) and between select physical conditions and HRQoL. Differences in HRQoL in comparison to a normative sample were also examined. Method A cross-sectional study among people with multimorbidity ( n = 401) attending a community-based, interdisciplinary health clinic was conducted. HRQoL was measured using the eight dimensions of the SF-36. Multiple linear regression and t-tests were used to analyse the data. Results A downward trend in HRQoL continued from 2 to 14 concurrent comorbidities. Patients with a higher number of comorbidities reported greater deficits in HRQoL, when age, gender, education and perceived social support were controlled for (beta = 0.11 to -0.31). The impact of the number of comorbidities was greatest for the bodily pain dimension of the SF-36 (beta = -0.31). Deficits were greatest for people with gastrointestinal conditions and back pain or sciatica. Moderate to large deficits in HRQoL compared to a normative population were found (Cohen's d = 0.54-1.16). Discussion Understanding associations between the number and type of physical comorbidities and HRQoL may assist clinical services to design broad but targeted interventions to optimize HRQoL in this group of people. PMID- 28803494 TI - Prognostic DNA methylation markers for renal cell carcinoma: a systematic review. AB - AIM: Despite numerous published prognostic methylation markers for renal cell carcinoma (RCC), none of these have yet changed patient management. Our aim is to systematically review and evaluate the literature on prognostic DNA methylation markers for RCC. MATERIALS & METHODS: We conducted an exhaustive search of PubMed, EMBASE and MEDLINE up to April 2017 and identified 49 publications. Studies were reviewed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, assessed for their reporting quality using the Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK) criteria, and were graded to determine the level of evidence (LOE) for each biomarker. RESULTS: We identified promoter methylation of BNC1, SCUBE3, GATA5, SFRP1, GREM1, RASSF1A, PCDH8, LAD1 and NEFH as promising prognostic markers. Extensive methodological heterogeneity across the included studies was observed, which hampers comparability and reproducibility of results, providing a possible explanation why these biomarkers do not reach the clinic. CONCLUSION: Potential prognostic methylation markers for RCC have been identified, but they require further validation in prospective studies to determine their true clinical value. PMID- 28803495 TI - Molecular signature of complex regional pain syndrome (CRPS) and its analysis. AB - INTRODUCTION: Complex Regional Pain Syndrome (CRPS) is a rare, but often disabling pain disease. Biomarkers are lacking, but several inflammatory substances have been associated with the pathophysiology. This review outlines the current knowledge with respect to target biomolecules and the analytical tools available to measure them. Areas covered: Targets include cytokines, neuropeptides and resolvins; analysis strategies are thus needed for different classes of substances such as proteins, peptides, lipids and small molecules. Traditional methods like immunoassays are of importance next to state-of-the art high-resolution mass spectrometry techniques and 'omics' approaches. Expert commentary: Future biomarker studies need larger cohorts, which improve subgrouping of patients due to their presumed pathophysiology, and highly standardized workflows from sampling to analysis. PMID- 28803496 TI - Management of multidrug-resistant Pseudomonas aeruginosa in the intensive care unit: state of the art. AB - INTRODUCTION: Pseudomonas aeruginosa (PA) is one of the most important causes of healthcare-related infections among Gram-negative bacteria. The best therapeutic approach is controversial, especially for multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains as well as in the setting of most severe patients, such as in the intensive care unit (ICU). Areas covered: This article addresses several points. First, the main microbiological aspects of PA, focusing on its wide array of resistance mechanisms. Second, risk factors and the worse outcome linked to MDR-PA infection. Third, the pharmacological peculiarity of ICU patients, that makes the choice of a proper antimicrobial therapy difficult. Eventually, the current therapeutic options against MDR-PA are reviewed, taking into account the main variables that drive antimicrobial optimization in critically ill patients. Literature search was carried out using Pubmed and Web of Science. Expert commentary: Methodologically rigorous studies are urgently needed to clarify crucial aspects of the treatment against MDR-PA, namely monotherapy versus combination therapy in empiric and targeted settings. In the meanwhile, useful options are represented by newly approved drugs, such as ceftolozane/tazobactam and ceftazidime/avibactam. In critically ill patients, at least as empirical approach, a combination therapy is a prudent choice when a MDR PA strain is suspected. PMID- 28803497 TI - Exploring the potential value of improved care for secondary hyperparathyroidism with a novel calcimimetic therapy. AB - AIMS: This study explored the use of a value-based pricing approach for the new calcimimetic etelcalcetide indicated for the treatment of secondary hyperparathyroidism (SHPT) in patients receiving hemodialysis. It used the US payer perspective and applied the cost-effectiveness framework. Because etelcalcetide is an intravenous therapy that can be titrated for individual patients, and because its utilization is yet to be assessed in real world settings, a range of plausible doses were estimated for etelcalcetide to define a range of prices. These were either in relation to the existing oral calcimimetic cinacalcet or compared to no calcimimetic treatment. MATERIALS AND METHODS: The value-based price of etelcalcetide was determined via a Markov model. This model combined data from the etelcalcetide trials and previously published cost effectiveness models in SHPT, and allowed extrapolation of treatment effects on mortality, cardiovascular events, fracture, and parathyroidectomy. Several dosing scenarios were explored covering the dose ranges of 30.0-64.18 mg per day for cinacalcet and 1.07-3.11 mg per day for etelcalcetide. These included the mean dose from the etelcalcetide trials, the preliminary defined daily dose, and the expected most common dose in real world. An acceptable price range for etelcalcetide was assessed by comparing the incremental cost-effectiveness ratios obtained with the willingness-to-pay threshold range of $100,000-$300,000/quality adjusted life-years. RESULTS: Cost-effectiveness analysis supported value-based prices for etelcalcetide ranging from $21.15-$49.97/mg vs cinacalcet, and $13.79 $119.45/mg vs no calcimimetics. LIMITATIONS: There is uncertainty around what the real-world dosing will be for etelcalcetide. Another important nuance is that no studies have examined etelcalcetide effects on hard outcomes and, therefore, this modeling exercise relied on an extrapolation approach. CONCLUSIONS: This cost effectiveness analysis, including scenarios to address uncertainties, allowed estimation of a value-based price range to aid reimbursement decisions in the US. PMID- 28803498 TI - Screening circular RNA related to chemotherapeutic resistance in breast cancer. AB - AIM: We aimed to identify circular RNAs (circRNAs) associated with breast cancer chemoresistance. MATERIALS & METHODS: CircRNA microarray expression profiles were obtained from Adriamycin (ADM) resistant MCF-7 breast cancer cells (MCF-7/ADM) and parental MCF-7 cells and were validated using quantitative real-time reverse transcription PCR. The expression data were analyzed bioinformatically. RESULTS: We detected 3093 circRNAs and identified 18 circRNAs that are differentially expressed between MCF-7/ADM and MCF-7 cells; after validating by quantitative real-time reverse transcription PCR, we predicted the possible miRNAs and potential target genes of the seven upregulated circRNAs using TargetScan and miRanda. The bioinformatics analysis revealed several target genes related to cancer-related signaling pathways. Additionally, we discovered a regulatory role of the circ_0006528-miR-7-5p-Raf1 axis in ADM-resistant breast cancer. CONCLUSION: These results revealed that circRNAs may play a role in breast cancer chemoresistance and that hsa_circ_0006528 might be a promising candidate for further functional analysis. PMID- 28803501 TI - Men's weight loss stories: How personal confession, responsibility and transformation work as social control. AB - Obesity is considered a public health concern. In Australia, there are a greater number of overweight or obese men compared with women. The media is an important source of information about body weight and weight management. We undertook a qualitative study to analyse men's weight loss stories in a popular men's magazine. Between January 2009 and December 2012, we collected 47 men's weight loss stories from the Australian edition of Men's Health magazine. We undertook thematic analysis to examine the stories. Confession, personal responsibility, appearance and transformation were key themes. The stories describe the men's self-discipline and their monitoring and tracking of their behaviours as activities which supported their weight loss. In this way, the stories promote the importance of such panoptic self-surveillance and self-discipline to the readers. We consider how such stories contribute to the wider synoptic system of media messages about body weight. PMID- 28803502 TI - Immunogenicity, antibody persistence, and safety of the 60 MUg hepatitis B vaccine in hemodialysis patients: a multicenter, randomized, double-blind, parallel-controlled trial. AB - BACKGROUND: To evaluate the immunogenicity, antibody persistence, and safety of the 60 ug hepatitis B vaccine in hemodialysis patients in China. METHODS: We conducted a multicenter, randomized, double-blind, parallel-controlled trial including 352 hemodialysis patients who were centrally randomized in a ratio of 1:1 to receive a 20 ug (IM20 group) or 60 ug (IM60 group) recombinant hepatitis B vaccine at months 0, 1, and 6. RESULTS: The vaccine-elicited antibody responses peaked at month 7, and declined at month 12. At month 7, the IM60 group had stronger GMC of anti-HBs, and a higher proportion of seroconversion and high level response than the IM20 group did (P < 0.05). Better immune responses were observed in the IM60 group, especially for those aged or in the high-frequency hemodialysis population. CONCLUSION: The high dose 60 ug recombinant hepatitis B vaccines elicited stronger immune responses than the 20 ug hepatitis B vaccine did among hemodialysis patients. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT02963714. PMID- 28803503 TI - HIV Testing and awareness of HIV status among people who inject drugs in greater Kuala Lumpur, Malaysia. AB - HIV testing services are the gateway into HIV treatment and are critical for monitoring the epidemic. HIV testing is recommended at least annually in high risk populations, including people who inject drugs (PWID). In Malaysia, the HIV epidemic is concentrated among PWID, but their adherence to testing recommendations and the proportion of HIV-positive PWID who are aware of their status remain unknown. We recruited 460 PWID in Greater Kuala Lumpur using respondent-driven sampling and conducted HIV testing. We examined past testing behaviors, estimating testing frequency, correlates of testing in the past 12 months, and the proportion of those living with HIV who were aware of their status. Results showed that most PWID living with HIV (90.4%, 95% CI: 83.6% 95.9%) were aware of their status. Among those never previously diagnosed with HIV, few had accessed HIV testing in the past 12 months (14.3%, 95% CI: 11.1% 18.0%). Prison (57.0%) and compulsory drug detention centers (36.1%) were the primary locations where PWID reported ever being HIV tested, and the main correlate of recent testing in regression was recent criminal justice involvement. Although awareness of HIV status may be high among PWID living with HIV in Kuala Lumpur, testing occurs primarily in prisons and compulsory drug detention centers, where it is involuntary and linkage to care is limited. A shift in HIV testing policy is needed to align health and human rights objectives, replacing mandatory testing with voluntary testing in settings where individuals can be rapidly linked to HIV care. PMID- 28803504 TI - The pharmacological management of NAFLD in children and adolescents. AB - INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) represents a spectrum, including 'simple' steatosis, non-alcoholic steatohepatitis (NASH), and fibrosis. Increasing prevalence of NAFLD has followed the international rise in obesity and lifestyle modification is the mainstay therapy for children. To date, pharmacological trials have had varying efficacy but a large number of new agents are in early phase trials for adults. Areas covered: This review explores the effect of current and potential future paediatric NAFLD treatments in terms of histological and biochemical endpoints. The potential for the extension of adult treatments to children is discussed, as well as what limits the use of certain agents in children. Expert commentary: No drugs have yet to be licenced for NAFLD. Trial heterogeneity makes comparison of drugs between studies challenging. FXR agonists are yet to be trialled in children but may represent a safe and potentially efficacious therapy. Future treatments would likely encompass a multimodal approach that may include bariatric surgery. PMID- 28803505 TI - Extracorporeal membrane oxygenation in an HIV-positive man with severe acute respiratory distress syndrome secondary to pneumocystis and cytomegalovirus pneumonia. AB - The management of critically ill human immunodeficiency virus (HIV)-positive patients is challenging; however, intensive care unit-related mortality has declined significantly in recent years. There are 10 case reports in the literature of extracorporeal membrane oxygenation (ECMO) use in HIV-positive patients, of whom seven survived to hospital discharge. We describe a 33-year-old Brazilian man who presented with Pneumocystis jirovecii pneumonia and severe hypoxic respiratory failure. He developed refractory acute respiratory distress syndrome (ARDS) and was commenced on veno-venous ECMO. He was successfully decannulated following 21 days of ECMO and survived to hospital discharge. Despite poor evidence surrounding the use of ECMO in immunocompromised patients, it is evident that ECMO could represent an important rescue therapy in HIV positive patients with refractory ARDS. PMID- 28803506 TI - Parental stress and depressive symptoms increase the risk of separation among parents with children less than 11 years of age in Sweden. AB - AIMS: Parental separations have become more frequent in recent decades. In Western countries, about 25% of children experience parental separation. There is a need to explore the risk factors for separation to give children an optimal childhood. The objective of the present study was to examine parental stress and depressive symptoms during early parenthood and their association with parental separation. METHODS: Four hundred and seven couples completed questionnaires on depressive symptoms for 3 months and parental stress for 18 months after childbirth. Total parental stress and five sub-areas were investigated. To study the separation rate, parents' addresses were recorded 9 to 11 years after childbirth. RESULTS: Twenty-nine percent of the parents were separated 9 to 11 years after childbirth. Separation was associated with depressive symptoms at 3 months (mothers p = .002, fathers p = .025) and total parental stress at 18 months after childbirth (mothers p = .010, fathers p = .005). The sub-areas of parental stress, Spouse relationship problems (mothers p = <.001, fathers p = .001) and fathers' Social isolation ( p = .005), were associated with separation. In multivariable regression analyses of the parents' separation rate 9 to 11 years after childbirth, the only significant predictor was mothers' Spouse relationship problems ( p < .001). CONCLUSIONS: The knowledge that parental stress and depressive symptoms are risk factors for separation may simplify professional support for parents in early parenting. Courses for new and expectant parents can use this knowledge to increase parents' awareness. PMID- 28803508 TI - Commentary: Hybrid Repair for Ascending Aortic Dissections and Aneurysms. PMID- 28803507 TI - What Box: A task for assessing language lateralization in young children. AB - The assessment of active language lateralization in infants and toddlers is challenging. It requires an imaging tool that is unintimidating, quick to setup, and robust to movement, in addition to an engaging and cognitively simple language processing task. Functional Transcranial Doppler Ultrasound (fTCD) offers a suitable technique and here we report on a suitable method to elicit active language production in young children. The 34-second "What Box" trial presents an animated face "searching" for an object. The face "finds" a box that opens to reveal a to-be-labelled object. In a sample of 95 children (1 to 5 years of age), 81% completed the task-32% with >=10 trials. The task was validated (rho = 0.4) against the gold standard Word Generation task in a group of older adults (n = 65, 60-85 years of age), though was less likely to categorize lateralization as left or right, indicative of greater measurement variability. Existing methods for active language production have been used with 2-year-old children while passive listening has been conducted with sleeping 6-month-olds. This is the first active method to be successfully employed with infants through to pre schoolers, forming a useful tool for populations in which complex instructions are problematic. PMID- 28803509 TI - Analytical validation and reference intervals for freezing point depression osmometer measurements of urine osmolality in dogs. AB - Urine osmolality (UOsm) is considered the most accurate measure of urine concentration and is used to assess body fluid homeostasis and renal function. We performed analytical validation of freezing point depression measurement of canine UOsm, to establish reference intervals (RIs) and to determine the effect of age, sex, and reproductive status on UOsm in dogs. Clinically healthy dogs ( n = 1,991) were retrospectively selected and stratified in groups by age (young [0 12 mo], adults [13-84 mo], and seniors [>84 mo]), sex (females and males), and reproductive status (intact and neutered). RIs were calculated for each age group. Intra- and inter-assay coefficients of variation were <1% in all cases. Good linearity ( r2 = 1, p < 0.001) and recovery (89-98%) were observed. The limit of detection and limit of quantification were zero. Urine specific gravity and UOsm had a highly significant positive correlation ( r = 0.96, p < 0.001) but had inconsistent agreement. The 95% RI for canine UOsm was 369-2,416 mOsm/kg in young and adult dogs, and 366-2,178 mOsm/kg in seniors. Senior dogs had a significantly lower UOsm than young and adult dogs ( p < 0.000). Neutered females had a significantly lower UOsm than intact female dogs ( p < 0.002). These results indicate that the method evaluated is adequate for UOsm measurement and that RIs based on age and reproductive status should be used in dogs. PMID- 28803510 TI - Epizootic hemorrhagic disease virus serotype 6 outbreak in Israeli cattle in 2015. AB - In September 2015, a large outbreak caused by epizootic hemorrhagic disease virus (EHDV) was identified in Israeli dairy and beef farms. The main clinical signs were reduced milk production, weakness, drooling, lameness and recumbency, fever, slight erythema of nasal and oral mucosae, weight loss, and abortion. Dyspnea, cachexia, and death were observed less frequently. The clinical diagnosis was confirmed by ELISAs and EHDV-specific real-time reverse transcription PCR (RT rtPCR), followed by conventional RT-PCR of the VP2 gene and sequence analysis. According to the sequence and phylogenetic analysis of theVP2 gene, the 2015 Israeli EHD outbreak was caused by EHDV-6, which was found not only in clinically ill cattle, but also in aborted fetuses. PMID- 28803511 TI - Commentary: The First Balloon-Expandable Stent-Graft Approved for Treatment of Iliac Occlusive Disease. PMID- 28803512 TI - Heterogeneous pathological processes account for thalamic degeneration in multiple sclerosis: Insights from 7 T imaging. AB - BACKGROUND: Thalamic degeneration impacts multiple sclerosis (MS) prognosis. OBJECTIVE: To investigate heterogeneous thalamic pathology, its correlation with white matter (WM), cortical lesions and thickness, and as function of distance from cerebrospinal fluid (CSF). METHODS: In 41 MS subjects and 17 controls, using 3 and 7 T imaging, we tested for (1) differences in thalamic volume and quantitative T2* (q-T2*) (2) globally and (3) within concentric bands originating from the CSF/thalamus interface; (4) the relation between thalamic, cortical, and WM metrics; and (5) the contribution of magnetic resonance imaging (MRI) metrics to clinical scores. We also assessed MS thalamic lesion distribution as a function of distance from CSF. RESULTS: Thalamic lesions were mainly located next to the ventricles. Thalamic volume was decreased in MS versus controls ( p < 10 2); global q-T2* was longer in secondary progressive multiple sclerosis (SPMS) only ( p < 10-2), indicating myelin and/or iron loss. Thalamic atrophy and longer q-T2* correlated with WM lesion volume ( p < 0.01). In relapsing-remitting MS, q T2* thalamic abnormalities were located next to the WM ( p < 0.01 (uncorrected), p = 0.09 (corrected)), while they were homogeneously distributed in SPMS. Cortical MRI metrics were the strongest predictors of clinical outcome. CONCLUSION: Heterogeneous pathological processes affect the thalamus in MS. While focal lesions are likely mainly driven by CSF-mediated factors, overall thalamic degeneration develops in association with WM lesions. PMID- 28803513 TI - Mechanisms of unexpected death and autopsy findings in Friedreich ataxia. AB - A 36-year-old woman with a clinical history of Friedreich ataxia and hypertrophic cardiomyopathy was found unexpectedly dead at her home. The heart showed asymmetric left ventricular hypertrophy, with an interventricular septal thickness of 20-25 mm (the remainder of the left ventricular wall measured 15 mm). Histologically, both ventricles had irregular areas of marked myocyte hypertrophy with associated interstitial fibrosis and focal myofibre disarray. There was neuronal loss within the dentate nucleus of the cerebellum, with vacuolation and axonal loss in the dorsal columns and spinocerebellar tracts of the upper cervical spinal cord. Death was due to hypertrophic cardiomyopathy complicating Friedreich ataxia. Other causes of death in this condition include embolic stroke, cerebral haemorrhage, aspiration pneumonia, renal failure, diabetic ketoacidosis, myocardial infarction, generalised inanition and trauma. Sudden death due to cardiac disease, resulting in presentation for medicolegal autopsy, may be the presenting feature at all ages, including childhood. PMID- 28803514 TI - Investigation, sensitivity analysis, and multi-objective optimization of effective parameters on temperature and force in robotic drilling cortical bone. AB - The bone drilling process is very prominent in orthopedic surgeries and in the repair of bone fractures. It is also very common in dentistry and bone sampling operations. Due to the complexity of bone and the sensitivity of the process, bone drilling is one of the most important and sensitive processes in biomedical engineering. Orthopedic surgeries can be improved using robotic systems and mechatronic tools. The most crucial problem during drilling is an unwanted increase in process temperature (higher than 47 degrees C), which causes thermal osteonecrosis or cell death and local burning of the bone tissue. Moreover, imposing higher forces to the bone may lead to breaking or cracking and consequently cause serious damage. In this study, a mathematical second-order linear regression model as a function of tool drilling speed, feed rate, tool diameter, and their effective interactions is introduced to predict temperature and force during the bone drilling process. This model can determine the maximum speed of surgery that remains within an acceptable temperature range. Moreover, for the first time, using designed experiments, the bone drilling process was modeled, and the drilling speed, feed rate, and tool diameter were optimized. Then, using response surface methodology and applying a multi-objective optimization, drilling force was minimized to sustain an acceptable temperature range without damaging the bone or the surrounding tissue. In addition, for the first time, Sobol statistical sensitivity analysis is used to ascertain the effect of process input parameters on process temperature and force. The results show that among all effective input parameters, tool rotational speed, feed rate, and tool diameter have the highest influence on process temperature and force, respectively. The behavior of each output parameters with variation in each input parameter is further investigated. Finally, a multi-objective optimization has been performed considering all the aforementioned parameters. This optimization yielded a set of data that can considerably improve orthopedic osteosynthesis outcomes. PMID- 28803515 TI - Protocol-driven remote monitoring of cardiac resynchronization therapy as part of a heart failure disease management strategy. AB - BACKGROUND: Cardiac resynchronisation therapy (CRT) is an established treatment for heart failure (HF) with reduced ejection fraction. CRT devices are equipped with remote monitoring functions, which are pivotal in the detection of device problems, but may also facilitate disease management. The aim of this study was to provide a comprehensive overview of the clinical interventions taken based on remote monitoring. METHODS: This is a single centre observational study of consecutive CRT patients (n = 192) participating in protocol-driven remote follow up. Incoming technical- and disease-related alerts were analysed together with subsequently triggered interventions. RESULTS: During 34 +/- 13 months of follow up, 1372 alert-containing notifications were received (2.53 per patient-year of follow-up), comprising 1696 unique alerts (3.12 per patient-year of follow-up). In 60%, notifications resulted in a phone contact. Technical alerts constituted 8% of incoming alerts (0.23 per patient-year of follow-up). Rhythm (1.43 per patient-year of follow-up) and bioimpedance alerts (0.98 per patient-year of follow-up) were the most frequent disease-related alerts. Notifications included a rhythm alert in 39%, which triggered referral to the emergency room (4%), outpatient cardiology clinic (36%) or general practitioner (7%), or resulted in medication changes (13%). Sole bioimpedance notifications resulted in a telephone contact in 91%, which triggered outpatient evaluation in 8% versus medication changes in 10%. Clinical outcome was excellent with 97% 1-year survival. CONCLUSIONS: Remote CRT follow-up resulted in 0.23 technical- versus 2.64 disease related alerts annually. Rhythm and bioimpedance notifications constituted the majority of incoming notifications which triggered an actual intervention in 22% and 15% of cases, respectively. PMID- 28803516 TI - Well-defined protein immobilization on photo-responsive phosphorylcholine polymer surfaces. AB - In this study, we propose a new polymer substrate that is able to covalently couple intended proteins and reduce nonspecific protein fouling. Poly[2 methacryloyloxyethyl phosphorylcholine (MPC)-ran-N-methacryloyl-(L) tyrosinemethylester (MAT)] [P(MPC/MAT)] was synthesized by free-radical polymerization. The photooxidation of the MAT unit in the copolymer was observed under ultraviolet (UV) light at 254 nm. P(MPC/MAT) was spin-coated on silicon (Si) and gold substrates. Without UV irradiation of the polymer-coated surface, P(MPC/MAT) physisorbed on the substrates, and the thickness of the polymer layer was less than 10 nm, regardless of the polymer concentration in the coating solution. In contrast, when the polymer-coated surface was irradiated with UV light, the thickness of the polymer layer could be controlled by changing the polymer concentration of the coating solution. Competitive protein adsorption on P(MPC/MAT) was studied. Bovine serum albumin was first contacted with the surface and later challenged with bovine fibrinogen. On bare gold and Si substrates, a large amount of albumin was adsorbed, and the competitive adsorption of albumin and fibronectin was observed. In contrast, the non-UV-irradiated P(MPC/MAT) surface effectively reduced protein adsorption. Interestingly, on the UV irradiated P(MPC/MAT) surface, the primary protein preferably bonded, and significantly less secondary protein was adsorbed compared to primary protein. Cell adhesion was also tested on the substrate to clarify the effects of proteins existing on the substrates. On the bare Si surface, many adherent cells were observed, regardless of the protein pretreatment. On the non-UV-irradiated P(MPC/MAT) surface, cell adhesion was effectively reduced along with protein adsorption. Cell adhesion on the UV-irradiated P(MPC/MAT) surface depended strongly on the type of protein that was initially in contact with the surface. We concluded that the desired proteins could be immobilized on the photo activated P(MPC/MAT) surface while preserving their function. Moreover, competitive protein exchange and multilayer adsorption hardly occurred on the surface. PMID- 28803517 TI - Evaluation of 16 commercial antibody ELISAs for the detection of bovine viral diarrhea virus-specific antibodies in serum and milk using well-characterized sample panels. AB - We performed a thorough fit-for-purpose evaluation of commercial ELISAs for the detection of bovine viral diarrhea virus (BVDV)-specific antibodies in serum and in milk by testing 2 panels of well-characterized serum and milk samples. Sixteen ELISAs from 9 different manufacturers, available on the Belgian market at the time of our study, were assessed for their diagnostic and analytical sensitivity (DSe and ASe, respectively), diagnostic specificity (DSp), and repeatability relative to the virus neutralization (VN) test considered to be the gold standard assay. Using serum as a matrix, DSe was much lower for competitive (c)ELISAs (min. 45%, max. 65%) than for indirect (i)ELISAs (min. 85%, max. 100%), partly because of the lower detection of positive samples from vaccinated animals included in the panel. ASe was also better for iELISAs; DSp was >95% for all but 2 ELISAs. Repeatability, expressed as coefficients of variation (CV) of optical densities, was generally good, although 3 ELISAs had a mean CV >10%. With milk samples, as observed for serum, DSe was lower for cELISAs (min. 57%, max. 75%) than for iELISAs (min. 61%, max. 89%), and DSp was high for all ELISAs (min. 94%, max. 100%). Both DSe and ASe were lower when testing milk samples compared to serum samples. These results confirm that serologic monitoring of BVDV-free herds should be performed using serum samples of unvaccinated animals to avoid interference of vaccination and to maximize the chance of detecting seroconversion linked to BVDV infection. Further investigations using a larger collection of field samples are recommended. PMID- 28803519 TI - A Case Report of Benzocaine-Induced Methemoglobinemia. AB - Methemoglobinemia is a serious medical condition characterized by the disrupted binding of oxygen to iron on hemoglobin, with a consequent impaired oxygen delivery to body tissues. Various drugs including the local anesthetics such as benzocaine can cause acquired methemoglobinemia. The reported case describes methemoglobinemia that occurred in association with the use of topical benzocaine spray and lozenges in a previously healthy 51-year-old female who had undergone colon surgery to remove a bleeding polyp. Pulse oximetry revealed the patient was hypoxic and a measured methemoglobin (MetHB) serum concentration was 32.4%, well above the normal of less than 2%. Treatment with intravenous methylene blue resulted in a rapid improvement in the patient's respiratory status. The case emphasizes the need for practitioners to appreciate that topical benzocaine products can cause potentially fatal methemoglobinemia. PMID- 28803518 TI - A Feminist Intervention That Hurt Women: Biological Differences, Ergonomics, and Occupational Health: Une intervention feministe qui a nui aux femmes: differences biologiques, egalite, ergonomie et sante au travail. AB - The University of Quebec in Montreal has agreements with trade unions providing access to university resources. Researchers involved in this program worked in partnership with union women's and health and safety committees for more than twenty years. Not all studies succeeded in improving women's working conditions. One joint project involved observational studies of tasks done by health-care workers, complemented by interviews and questionnaires. We found that task assignments, movements, postures, and work-related musculoskeletal disorders varied by gender/sex and made recommendations for change. However, issues of pay equity, spending on health care, and contracting-out of "ancillary work" were salient. Researchers learned that in the absence of changes in power relationships in the workplace, women may be disadvantaged by denial as well as by exaggeration of female-male differences. Men may also be at risk when their gender is invisible. We suggest some feminist approaches to workplace solutions and some pathways for research. Resume L'Universite du Quebec a Montreal a signe avec des centrales syndicales des ententes leur donnant un acces a des ressources universitaires. Des chercheures ont travaille en partenariat avec des comites syndicaux de condition des femmes et de sante-securite au travail pendant plus de 25 ans, mais ce ne sont pas toutes les etudes qui ont abouti a des ameliorations. Un projet concernait des observations du travail d'employe.e.s du secteur de la sante, dont les taches, mouvements, et postures variaient selon le genre/sexe. Nous avons recommande des transformations, mais des enjeux d'equite salariale, de couts et de sous-traitance y ont fait obstacle. Les chercheures ont appris qu'en l'absence de transformation des rapports de pouvoir au travail, le deni des differences hommes-femmes, autant que leur exageration, peut desavantager les travailleuses (et les travailleurs). Nous suggerons des approches feministes aux solutions pour le milieu de travail, ainsi que des pistes de recherche. PMID- 28803520 TI - Probable Rivaroxaban-Induced Full Body Rash: A Case Report. AB - INTRODUCTION: Rivaroxaban is a novel oral anticoagulant with several indications, one of which is for stroke prevention in nonvalvular atrial fibrillation. We present a case of probable rivaroxaban-induced rash. CASE SUMMARY: A 79-year-old female with a medical history of atrial fibrillation experienced a stroke, after which she was prescribed rivaroxaban 20 mg. After several days, she developed a rash requiring admission to the emergency department and several days of treatment. The rash resolved and she was switched from rivaroxaban to apixaban and did not experience any adverse drug events. DISCUSSION: Onset of symptoms occurred within days of rivaroxaban initiation. The patient had no allergy history and never reported a similar reaction while on concurrent home medication regimen. The resolution of rash and toleration of apixaban suggest a rivaroxaban specific reaction. The mechanism of this rash is currently unclear. CONCLUSION: We report one of the first cases of probable rivaroxaban-induced rash, whereas the patient tolerated apixaban. Further investigation is warranted, but prescribers should be cognizant of this potential issue when choosing a factor Xa inhibitor for anticoagulation. PMID- 28803521 TI - Evaluation of Direct-Acting Oral Anticoagulant Use in Patients With Cancer. AB - PURPOSE: To evaluate the use of direct-acting oral anticoagulants in patients with cancer and venous thromboembolism (VTE) treated at Ochsner Medical Center with the intent of determining the efficacy and safety of these agents. METHODS: Patients were identified by a retrospective data extraction of patients treated at Ochsner Medical Center from January 1, 2013, through December 31, 2015. Patients were included for review if they were >=18 years of age, with a confirmed diagnosis of VTE and active or history of cancer, and if they received dabigatran, apixaban, rivaroxaban, or edoxaban for at least 6 months. The primary objectives were the rate of recurrence of VTE and the incidence of bleeding at 6 months. RESULTS: Thirty-seven patients were identified. Twelve patients were diagnosed with PE, 21 with DVT, 3 with DVT and PE, and 1 with DVT and superficial vein thrombosis (SVT). Apixaban was used most often (n = 27). No patients experienced a recurrent DVT or PE at 6 months. Two patients experienced adverse effects during treatment. CONCLUSIONS: In this single-center, retrospective, observational study in patients with cancer receiving DOAC therapy, there were no episodes of recurrent VTE and only 2 episodes of clinically significant bleeding. PMID- 28803522 TI - A case of a giant right ventricular myxoma in the multimodality imaging era. PMID- 28803523 TI - Left ventricular noncompaction or hypertrophic cardiomyopathy? Both! PMID- 28803524 TI - Endocrinopathies in paediatric-onset neuromyelitis optica spectrum disorder with aquaporin 4 (AQP4) antibody. AB - The involvement of the diencephalic regions in neuromyelitis optica spectrum disorder (NMOSD) may lead to endocrinopathies. In this study, we identified the following endocrinopathies in 60% (15/25) of young people with paediatric-onset aquaporin 4-Antibody (AQP4-Ab) NMOSD: morbid obesity ( n = 8), hyperinsulinaemia ( n = 5), hyperandrogenism ( n = 5), amenorrhoea ( n = 5), hyponatraemia ( n = 4), short stature ( n = 3) and central hypothyroidism ( n = 2) irrespective of hypothalamic lesions. Morbid obesity was seen in 88% (7/8) of children of Caribbean origin. As endocrinopathies were prevalent in the majority of paediatric-onset AQP4-Ab NMOSD, endocrine surveillance and in particular early aggressive weight management is required for patients with AQP4-Ab NMOSD. PMID- 28803525 TI - Cytologic features and staining characteristics of Gamna-Gandy bodies from seven canine fine-needle aspirate preparations. AB - Gamna-Gandy (GG) bodies are non-infectious, hyphal-like structures associated with siderotic nodules in lymphoid tissue; GG bodies are very rarely reported in veterinary cytologic samples. Cytologically, GG bodies can be misidentified as hyphae or plant material. Seven canine lymphoid tissue aspiration cases that contained GG bodies were investigated for morphologic variability and staining characteristics. Available archived cytology slides containing GG bodies were stained with reagents known to show positive results (Prussian blue, Alizarin red S, Von Kossa) and negative results (Gomori methenamine silver) in histologic samples. Calcofluor white staining was also performed. GG bodies in Wright-Giemsa stained cytology samples displayed considerable variability but were generally 2 5 um diameter, 10-35 um long, refractile, clear, pale-tan or pale-yellow, wavy or straight, tubular structures. Six cases allowed for cytochemical staining; staining properties were similar to histology samples. The bodies did not stain with calcofluor white; this stain may be helpful in distinguishing GG bodes from fungal hyphae. PMID- 28803526 TI - Familiarity and Within-Person Facial Variability: The Importance of the Internal and External Features. AB - As faces become familiar, we come to rely more on their internal features for recognition and matching tasks. Here, we assess whether this same pattern is also observed for a card sorting task. Participants sorted photos showing either the full face, only the internal features, or only the external features into multiple piles, one pile per identity. In Experiments 1 and 2, we showed the standard advantage for familiar faces-sorting was more accurate and showed very few errors in comparison with unfamiliar faces. However, for both familiar and unfamiliar faces, sorting was less accurate for external features and equivalent for internal and full faces. In Experiment 3, we asked whether external features can ever be used to make an accurate sort. Using familiar faces and instructions on the number of identities present, we nevertheless found worse performance for the external in comparison with the internal features, suggesting that less identity information was available in the former. Taken together, we show that full faces and internal features are similarly informative with regard to identity. In comparison, external features contain less identity information and produce worse card sorting performance. This research extends current thinking on the shift in focus, both in attention and importance, toward the internal features and away from the external features as familiarity with a face increases. PMID- 28803527 TI - Science's disparate responsibilities: Patterns across European countries. AB - It is a distinctive feature of European science policy that science is expected to meet economic and broader societal objectives simultaneously. Science should be governed democratically and take significant responsibilities towards the economy, the political system and civil society, but the coherency of these multiple claims is underexplored. Using metrics that emerge from both quantitative and qualitative studies, we examine the interrelatedness of different responsibilities at the level of countries. A total of 33 European Union member states and associated countries are included in the analysis. We find no trade-off between economic and broader societal contributions. Europe is, however, characterised by major divisions in terms of the location of science in society. There is a significant East-West divide, and Europe appears to be far from accomplishing an integrated European Research Area. PMID- 28803528 TI - The role of endoscopy in eosinophilic esophagitis: from diagnosis to therapy. AB - INTRODUCTION: Eosinophilic esophagitis (EoE) has arisen as a common disorder in current clinical and endoscopic gastroenterology practice. Areas covered: A comprehensive review of the literature to summarize and update different aspects related with the use of endoscopy in the diagnostic workout and treatment of pediatric and adult EoE patients is conducted. Expert commentary: Endoscopic features in EoE are frequently subtle, so were inadverted in some initial reports of the disease. Literature has described a wide number of EoE-associated features, systematized in the EREFS classification, which standardized the grade and severity of exudates, rings, edema, furrows, and strictures. The insufficient reliability of these features to predict eosinophilic inflammation still makes biopsies essential in diagnosing or monitoring EoE. EoE causes half of the food impactions requiring endoscopy; food impaction leads to EoE diagnosis in up to half of cases. Long term consequences of EoE include esophageal remodeling leading to strictures and narrowing, thus impairing symptoms and needs dilation. Recognizing the risks from dilation in EoE required carrying out a safe technique to avoid the high complication rate reported in the early literature. Endoscopic dilation should be considered in patients with esophageal narrowing and dysphagia/food impaction unresponsive to diet or drugs-based anti-inflammatory treatment. PMID- 28803529 TI - The role of the amygdala in incongruity resolution: the case of humor comprehension. AB - A dominant theory of humor comprehension suggests that people understand humor by first perceiving some incongruity in an expression and then resolving it. This is called "the incongruity-resolution theory." Experimental studies have investigated the neural basis of humor comprehension, and multiple neural substrates have been proposed; however, the specific substrate for incongruity resolution is still unknown. The reason may be that the resolution phase, despite its importance in humor comprehension, has not been successfully distinguished from the perception phase because both phases occur almost simultaneously. To reveal the substrate, we conducted a functional magnetic resonance study using 51 healthy participants. We used a humor-producing frame of "Given A, I'd say B, because C" so as to focus on the resolution phase independently by suspending humor processing just after the perception phase. This frame allowed us to separate the two phases. Based on our results, incongruity resolution evoked positive emotion and activated the left amygdala, which is known to be related to positive emotion. On the basis of these findings, we argue that the amygdala plays an important role in humor comprehension, considering its functional role in emotional evaluation, particularly the relevance detection for incoming stimuli. PMID- 28803531 TI - Editorial. PMID- 28803530 TI - Enhancing the Alignment of the Preclinical and Clinical Stroke Recovery Research Pipeline: Consensus-Based Core Recommendations From the Stroke Recovery and Rehabilitation Roundtable Translational Working Group. AB - Stroke recovery research involves distinct biological and clinical targets compared to the study of acute stroke. Guidelines are proposed for the pre clinical modeling of stroke recovery and for the alignment of pre-clinical studies to clinical trials in stroke recovery. PMID- 28803533 TI - Corrigendum. AB - Kuczynski AM, Dukelow SP, Semerau JA, Kirton A. Robotic quantification of position sense in children with perinatal stroke. Neurorehabil Neural Repair. 2016;30:762-772. doi:10.1177/1545968315624781. PMID- 28803534 TI - Moving Rehabilitation Research Forward: Developing Consensus Statements for Rehabilitation and Recovery Research. AB - Stroke recovery is the next frontier in stroke medicine. While growth in rehabilitation and recovery research is exponential, a number of barriers hamper our ability to rapidly progress the field. Standardized terminology is absent in both animal and human research, methods are poorly described, recovery biomarkers are not well defined, and we lack consistent timeframes or measures to examine outcomes. Agreed methods and conventions for developing, monitoring, evaluating and reporting interventions directed at improving recovery are lacking, and current approaches are often not underpinned by biology. We urgently need to better understand the biology of recovery and its time course in both animals and humans to translate evidence from basic science into clinical trials. A new international partnership of stroke recovery and rehabilitation experts has committed to advancing the research agenda. In May 2016, the first Stroke Recovery and Rehabilitation Roundtable will be held, with the aim of achieving an agreed approach to the development, conduct and reporting of research. A range of methods will be used to achieve consensus in four priority areas: pre-clinical recovery research; biomarkers of recovery; intervention development, monitoring and reporting; and measurement in clinical trials. We hope to foster a global network of researchers committed to advancing this exciting field. Recovery from stroke is challenging for many survivors. They deserve effective treatments underpinned by our evolving understanding of brain recovery and human behaviour. Working together, we can develop game-changing interventions to improve recovery and quality of life in those living with stroke. PMID- 28803536 TI - Bovine viral diarrhea virus 1b fetal infection with extensive hemorrhage. AB - Bovine viral diarrhea virus (BVDV) 1b was isolated from tissues of a term bovine fetus with petechial hemorrhages noted throughout the body and placenta at autopsy. Fresh lung, kidney, thymus, and liver tissues were examined by direct fluorescent antibody testing and were positive for BVDV antigen and negative for bovine herpesvirus 1 antigen. An organ pool of fresh tissues was positive for noncytopathic (NCP) BVDV-1 by virus isolation. BVDV-1b was identified by sequencing of the 5'-UTR region of the genome. Fixed brain, placenta, thymus, lymph node, lung, kidney, skeletal muscle, liver, and bone marrow were positive for BVDV antigen by immunohistochemistry. Although BVDV hemorrhage and/or thrombocytopenia has been associated historically with NCP strains of BVDV-2, this case adds to more recent reports of BVDV-1 infections and hemorrhage in cattle. This BVDV-1b isolate should be investigated for its potential to cause hemorrhage in postnatal cattle. PMID- 28803535 TI - Robotic Assistance for Training Finger Movement Using a Hebbian Model: A Randomized Controlled Trial. AB - BACKGROUND: Robots that physically assist movement are increasingly used in rehabilitation therapy after stroke, yet some studies suggest robotic assistance discourages effort and reduces motor learning. OBJECTIVE: To determine the therapeutic effects of high and low levels of robotic assistance during finger training. METHODS: We designed a protocol that varied the amount of robotic assistance while controlling the number, amplitude, and exerted effort of training movements. Participants (n = 30) with a chronic stroke and moderate hemiparesis (average Box and Blocks Test 32 +/- 18 and upper extremity Fugl-Meyer score 46 +/- 12) actively moved their index and middle fingers to targets to play a musical game similar to GuitarHero 3 h/wk for 3 weeks. The participants were randomized to receive high assistance (causing 82% success at hitting targets) or low assistance (55% success). Participants performed ~8000 movements during 9 training sessions. RESULTS: Both groups improved significantly at the 1-month follow-up on functional and impairment-based motor outcomes, on depression scores, and on self-efficacy of hand function, with no difference between groups in the primary endpoint (change in Box and Blocks). High assistance boosted motivation, as well as secondary motor outcomes (Fugl-Meyer and Lateral Pinch Strength)-particularly for individuals with more severe finger motor deficits. Individuals with impaired finger proprioception at baseline benefited less from the training. CONCLUSIONS: Robot-assisted training can promote key psychological outcomes known to modulate motor learning and retention. Furthermore, the therapeutic effectiveness of robotic assistance appears to derive at least in part from proprioceptive stimulation, consistent with a Hebbian plasticity model. PMID- 28803537 TI - Statins. PMID- 28803538 TI - Pharmacokinetics of tafamidis, a transthyretin amyloidosis drug, in rats. AB - 1. We characterized the pharmacokinetics of tafamidis, a novel drug to treat transthyretin-related amyloidosis, in rats after intravenous and oral administration at doses of 0.3-3 mg/kg. In vitro Caco-2 cell permeability and liver microsomal stability, as well as in vivo tissue distribution and plasma protein binding were also examined. 2. After intravenous injection, systemic clearance (CL), volumes of distribution at steady state (Vss) and half-life (T1/2) remained unaltered as a function of dose, with values in the ranges of 6.41-7.03 mL/h/kg, 270-354 mL/kg and 39.5-46.9 h, respectively. Following oral administration, absolute bioavailability was 99.7-104% and was independent of doses from 0.3 to 3 mg/kg. In the urine and faeces, 4.36% and 48.9% of tafamidis, respectively, were recovered. 3. Tafamidis was distributed primarily in the liver and not in the brain, kidney, testis, heart, spleen, lung, gut, muscle, or adipose tissue. Further, tafamidis was very stable in rat liver microsomes, and its plasma protein binding was 99.9%. 4. In conclusion, tafamidis showed dose independent pharmacokinetics with intravenous and oral doses of 0.3-3 mg/kg. Tafamidis undergoes minimal first-pass metabolism, distributes mostly in the liver and plasma, and appears to be eliminated primarily via biliary excretion. PMID- 28803539 TI - FIGHTING FOR THE FUTURE OF ANTIBODIES. AB - Nathan Blow looks at how efforts to create guidelines and scoring systems could change the way you buy antibodies. PMID- 28803540 TI - Preparation of highly multiplexed small RNA sequencing libraries. AB - MicroRNAs (miRNAs) are ~22-nucleotide-long small non-coding RNAs that regulate the expression of protein-coding genes by base pairing to partially complementary target sites, preferentially located in the 3' untranslated region (UTR) of target mRNAs. The expression and function of miRNAs have been extensively studied in human disease, as well as the possibility of using these molecules as biomarkers for prognostication and treatment guidance. To identify and validate miRNAs as biomarkers, their expression must be screened in large collections of patient samples. Here, we develop a scalable protocol for the rapid and economical preparation of a large number of small RNA sequencing libraries using dual indexing for multiplexing. Combined with the use of off-the-shelf reagents, more samples can be sequenced simultaneously on large-scale sequencing platforms at a considerably lower cost per sample. Sample preparation is simplified by pooling libraries prior to gel purification, which allows for the selection of a narrow size range while minimizing sample variation. A comparison with publicly available data from benchmarking of miRNA analysis platforms showed that this method captures absolute and differential expression as effectively as commercially available alternatives. PMID- 28803541 TI - Ion-exchange chromatography purification of extracellular vesicles. AB - Despite numerous studies, isolating pure preparations of extracellular vesicles (EVs) has proven challenging. Here, we compared ion-exchange chromatography (IEC) to the widely used sucrose density gradient (SDG) centrifugation method for the purification of EVs. EVs in bulk were isolated from pooled normal human amniotic fluid (AF) by differential centrifugation followed by IEC or sucrose density gradient separation. The purity of the isolated EVs was evaluated by electrophoresis and lectin blotting/immuno blotting to monitor the distribution of total proteins, different EVs markers, and selected N-glycans. Our data showed efficient separation of negatively charged EVs from other differently charged molecules, while comparative profiling of EVs using SDG centrifugation confirmed anion-exchange chromatography is advantageous for EV purification. Finally, although this IEC-based method was validated using AF, the approach should be readily applicable to isolation of EVs from other sources as well. PMID- 28803542 TI - Spin infection enables efficient gene delivery to muscle stem cells. AB - Viral vector-mediated foreign gene expression in cultured cells has been extensively used in stem cell studies to explore gene function. However, it is difficult to obtain high-quality stem cells and primary cells after viral vector infection. Here, we describe a new protocol for high-efficiency retroviral infection of primary muscle stem cell (satellite cell) cultures. We compared multiple commercially available transfection reagents to determine which was optimal for retroviral infections of primary myoblasts. Centrifugation force was also tested, and a spin infection protocol with centrifugation at 2800 * g for 90 min had the highest infection efficiency for primary myoblasts. We confirmed that infected muscle stem cells maintain cell proliferation and the capacity for in vitro and in vivo myogenic differentiation. Our new, efficient retroviral infection protocol for muscle stem cells can be applied to molecular biology experiments as well as translational studies. PMID- 28803543 TI - BODIPY-based dye for no-wash live-cell staining and imaging. AB - In nonpolar solvents, hydrophobic organic fluorophores often show bright fluorescence, whereas in polar media, they usually suffer from aggregation-caused quenching (ACQ). Here, we harnessed this solvatochromic behavior of a 1,3,5,7 tetramethyl-BODIPY derivative for cell staining and applied it to live-cell imaging and flow cytometry. As opposed to commercially available dyes, this BODIPY derivative showed excellent contrast immediately after staining and did not require any wash-off. PMID- 28803544 TI - Overcoming qRT-PCR interference by select carbon nanotubes in assessments of gene expression. AB - Nanomaterials (NMs) of various types, including carbon nanotubes (CNTs), can interfere with standard quantitative real-time PCR (qRT-PCR) assays, resulting in inaccurate gene expression measurements; however, the precise step in the qRT-PCR pipeline where this interference occurs has not been well described. Here, we investigated where in the process surface-oxidized multi-walled CNTs (oxMWNTs) inhibited qRT-PCR measurement of the expression of the housekeeping gene GAPDH and explored several strategies to minimize such inhibition. We determined that the interference occurred during the reverse transcription (RT) step and found that doubling reaction reagents or adding BSA successfully mitigated the inhibition. We observed assay interference in the presence of CNTs that were surface-oxidized, but pristine CNTs did not cause the same level of interference. These results highlight the importance of monitoring qRT-PCR assays for interference by CNTs that differ by surface chemistry, as these NMs are commonly used in gene expression assays at concentrations that we have shown to be inhibitory. PMID- 28803547 TI - Cryoablation of cardiophrenic angle lymph node metastases: a case report. AB - BACKGROUND: Cardiophrenic angle lymph node metastases are relatively rare. Surgical resection is the main treatment for cardiophrenic angle lymph node metastasis, but it is not always possible. CASE PRESENTATION: Here, we report our initial experience with cryoablation of a cardiophrenic angle lymph node metastasis from liver cancer. As the cardiophrenic angle lymph node metastasis was located close to the heart, about 200 mL of 0.9% saline was injected into the pericardium to separate the heart from the target area. The cardiophrenic angle lymph node metastasis was successfully ablated, without any complications. CONCLUSIONS: Cryoablation may be a suitable alternative treatment for cardiophrenic angle lymph node metastasis. PMID- 28803548 TI - Gestational hypertensive disorders and retinal microvasculature: the Generation R Study. AB - BACKGROUND: Changes in the microvasculature associated with pre-eclampsia and gestational hypertension have been proposed as a potential pathway in the development of cardiovascular disease. We examined whether gestational hypertensive disorders, such as pre-eclampsia and gestational hypertension, are related to the maternal retinal microvasculature status after pregnancy. METHODS: This study is part of an ongoing population-based prospective cohort study. During pregnancy and 6.2 years after the index pregnancy (90% range 5.7-7.4 years), we examined 3391 women with available information on pre-eclampsia, gestational hypertension, and retinal vascular calibers. Retinal arteriolar and venular calibers were measured in the left eye from digitized retinal photographs. RESULTS: Women with pre-eclampsia had smaller retinal arteriolar calibers 6 years after pregnancy than women with a normotensive pregnancy (adjusted difference: -0.40 standard deviation score [SDS]; 95% confidence interval [CI]: -0.62, -0.19). For women with previous gestational hypertension, similar trends were observed (-0.20 SDS; 95% CI: -0.34, -0.05). With respect to retinal venular calibers, we did not observe consistent trends for women with previous pre-eclampsia. However, in women with previous gestational hypertension, we observed larger venular calibers (0.22 SDS; 95% CI: 0.07-0.36) than in women with a previous normotensive pregnancy. The association of gestational hypertensive disorders with retinal vessel calibers was mediated through mean arterial pressure at the time of retinal imaging. CONCLUSIONS: Compared to women with a previous normotensive pregnancy, women with pre-eclampsia and gestational hypertension show an altered status of the microvasculature 6 years after the index pregnancy. This is reflected by smaller retinal arteriolar calibers and wider retinal venular calibers. These microvascular changes may possibly contribute to the development of cardiovascular disease in later life. PMID- 28803550 TI - Palliative end ileostomy and gastrojejunostomy for a metastatic distal transverse colonic malignancy complicated by a proximal duodenocolic fistula: a case report. AB - BACKGROUND: Fistulae between the colon and upper gastrointestinal tract are distressing and uncommon complications of malignancies involving this region. We report a case of a middle-aged man with a locally advanced and metastatic distal transverse colon malignancy who presented with a duodenocolic fistula proximal to the primary tumor and underwent palliative surgery. CASE PRESENTATION: A 50-year old Sri Lankan man presented to our hospital with a history of feculent vomiting of 1 week's duration preceded by worsening constipation and abdominal fullness of 2 months' duration. He also complained of anorexia and significant weight loss over the previous month. His physical examination was unremarkable except for his wasted appearance. Flexible sigmoidoscopy done at his local hospital had not revealed any abnormality in the left colon. Gastroduodenoscopy did not reveal fecal matter or any mucosal abnormalities in the stomach or duodenum. An abdominal contrast-enhanced computed tomographic scan showed a mid-to-distal transverse colonic tumor with a duodenocolic fistula proximal to the primary lesion. At laparotomy, he was found to have an unresectable, locally advanced mid transverse colon tumor with diffuse peritoneal and mesenteric deposits and mild ascites. Palliative end ileostomy and gastrojejunostomy were performed before closure. Histology from the malignant deposits revealed a well-differentiated adenocarcinoma. He made an uneventful recovery with good symptomatic relief. CONCLUSIONS: Malignant gastric or duodenocolic fistulae are uncommon complications of locally advanced colonic malignancies with direct invasion to the stomach or duodenum. Although the characteristic clinical presentation of feculent vomiting suggests the diagnosis, cross-sectional imaging is confirmative in addition to staging the disease. Management is guided by disease stage, nutritional status, and the general condition of the patient and ranges from extensive bowel resection including the fistula to palliative options. PMID- 28803551 TI - Hospitalisation for lower respiratory tract infection in children in the province of Quebec, Canada, before and during the pneumococcal conjugate vaccine era. AB - Streptococcus pneumoniae is an important cause of community-acquired pneumonia and pneumococcal conjugate vaccines (PCVs) may reduce this burden. This study's goal was to analyse trends in lower respiratory tract infections (LRTI) hospitalisations before and during a routine vaccination programme targeting all newborns with PCV was started in the province of Quebec, Canada in December 2004. The study population included hospital admissions with a main diagnosis of LRTI among 6-59 month-old Quebec residents from April 2000 to December 2014. Trends in proportions and rates were analysed using Cochran-Armitage tests and Poisson regression models. We observed a general downward trend in all LTRI hospitalisations rate: from 11.55/1000 person-years in 2000-2001 to 9.59/1000 in 2013-2014, a 17.0% reduction, which started before the introduction of PCV vaccination. Downward trends in hospitalisation rates were more pronounced for all-cause of pneumonia (minus 17.8%) than for bronchiolitis (minus 15.4%). There was also a decrease in the mean duration of hospital stay. There was little evidence that all-cause pneumonia decreased over the study period due mainly to the introduction of PCVs. Trends may be related to changes in clinical practice. This study casts doubt on the interpretation of ecological analyses of the implementation of PCV vaccination programmes. PMID- 28803549 TI - Comparative gut microbiota and resistome profiling of intensive care patients receiving selective digestive tract decontamination and healthy subjects. AB - BACKGROUND: The gut microbiota is a reservoir of opportunistic pathogens that can cause life-threatening infections in critically ill patients during their stay in an intensive care unit (ICU). To suppress gut colonization with opportunistic pathogens, a prophylactic antibiotic regimen, termed "selective decontamination of the digestive tract" (SDD), is used in some countries where it improves clinical outcome in ICU patients. Yet, the impact of ICU hospitalization and SDD on the gut microbiota remains largely unknown. Here, we characterize the composition of the gut microbiota and its antimicrobial resistance genes ("the resistome") of ICU patients during SDD and of healthy subjects. RESULTS: From ten patients that were acutely admitted to the ICU, 30 fecal samples were collected during ICU stay. Additionally, feces were collected from five of these patients after transfer to a medium-care ward and cessation of SDD. Feces from ten healthy subjects were collected twice, with a 1-year interval. Gut microbiota and resistome composition were determined using 16S rRNA gene phylogenetic profiling and nanolitre-scale quantitative PCRs. The microbiota of the ICU patients differed from the microbiota of healthy subjects and was characterized by lower microbial diversity, decreased levels of Escherichia coli and of anaerobic Gram positive, butyrate-producing bacteria of the Clostridium clusters IV and XIVa, and an increased abundance of Bacteroidetes and enterococci. Four resistance genes (aac(6')-Ii, ermC, qacA, tetQ), providing resistance to aminoglycosides, macrolides, disinfectants, and tetracyclines, respectively, were significantly more abundant among ICU patients than in healthy subjects, while a chloramphenicol resistance gene (catA) and a tetracycline resistance gene (tetW) were more abundant in healthy subjects. CONCLUSIONS: The gut microbiota of SDD treated ICU patients deviated strongly from the gut microbiota of healthy subjects. The negative effects on the resistome were limited to selection for four resistance genes. While it was not possible to disentangle the effects of SDD from confounding variables in the patient cohort, our data suggest that the risks associated with ICU hospitalization and SDD on selection for antibiotic resistance are limited. However, we found evidence indicating that recolonization of the gut by antibiotic-resistant bacteria may occur upon ICU discharge and cessation of SDD. PMID- 28803552 TI - Effect of acaricidal components isolated from lettuce (Lactuca sativa) on carmine spider mite (Tetranychus cinnabarinus Boisd.). AB - This study aimed to evaluate the acaricidal activity of lettuce (Lactuca sativa) extracts against carmine spider mites (Tetranychus cinnabarinus Boisd.) and isolate the acaricidal components. Acaricidal activities of lettuce extracts isolated from different parts (the leaf, root and seed) using various solvents (petroleum ether, acetone and methanol) were evaluated with slide-dip bioassay and relatively high median lethal concentration (LC50) values were detected. Acetone extracts of lettuce leaves harvested in July and September were fractionated and isolated with silica gel and thin-layer chromatography. Consequently, acetone extracts of lettuce leaves harvested in July exhibited higher acaricidal activity than those harvested in September, with an LC50 value of 0.268 mg ml-1 at 72 h post-treatment. A total of 27 fractions were obtained from the acetone extract of lettuce leaves harvested in July, and mite mortalities with the 11th and 12th fractions were higher than those with the other 25 fractions (LC50: 0.751 and 1.258 mg ml-1 at 48 h post-treatment, respectively). Subsequently, active acaricidal components of the 11th fraction were identified by infrared, nuclear magnetic resonance and liquid chromatography/mass spectrometry. Five components were isolated from the 11th fraction, with components 11-a and 11-b showing relatively high acaricidal activities (LC50: 0.288 and 0.114 mg ml-1 at 48 h post-treatment, respectively). Component 11-a was identified as beta-sitosterol. In conclusion, acetone extracts of lettuce leaves harvested in July might be used as a novel phytogenic acaricide to control mites. PMID- 28803553 TI - Tetanus vaccination, antibody persistence and decennial booster; Reply to 'New guidelines about tetanus vaccination schedules in Europe should be evaluated with caution' by Eldin and co-workers. PMID- 28803554 TI - WEALTH-BASED INEQUALITY IN CHILD IMMUNIZATION IN INDIA: A DECOMPOSITION APPROACH. AB - SummaryDespite years of health and medical advancement, children still suffer from infectious diseases that are vaccine preventable. India reacted in 1978 by launching the Expanded Programme on Immunization in an attempt to reduce the incidence of vaccine-preventable diseases (VPDs). Although the nation has made remarkable progress over the years, there is significant variation in immunization coverage across different socioeconomic strata. This study attempted to identify the determinants of wealth-based inequality in child immunization using a new, modified method. The present study was based on 11,001 eligible ever married women aged 15-49 and their children aged 12-23 months. Data were from the third District Level Household and Facility Survey (DLHS-3) of India, 2007-08. Using an approximation of Erreyger's decomposition technique, the study identified unequal access to antenatal care as the main factor associated with inequality in immunization coverage in India. PMID- 28803555 TI - Bedside Registered Nurse Roles in Antimicrobial Stewardship: A Survey of Acute Care Hospitals in Los Angeles County. PMID- 28803556 TI - Buffering effects of safe, supportive, and nurturing relationships among women with childhood histories of maltreatment. AB - BACKGROUND: Adults who were victims of childhood maltreatment tend to have poorer health compared with adults who did not experience abuse. However, many are in good health. We tested whether safe, supportive, and nurturing relationships buffer women with a history of childhood maltreatment from poor health outcomes in later life. METHODS: Participants included women from the Environmental Risk (E-Risk) Longitudinal Twin Study who were involved in an intimate relationship at some point by the time their twin children were 10 years old. Women were initially interviewed in 1999-2000 (mean age = 33 years) and 2, 5, and 7 years later. They reported on their physical and mental health, and their health-risk behaviours. RESULTS: Compared with women who did not experience abuse in childhood, women with histories of maltreatment were at elevated risk for mental, physical, and health-risk behaviours, including major depressive disorder, sleep, and substance use problems. Cumulatively, safe, supportive, and nurturing relationships characterized by a lack of violence, emotional intimacy, and social support buffered women with a history of maltreatment from poor health outcomes. CONCLUSIONS: Our findings emphasize that negative social determinants of health - such as a childhood history of maltreatment - confer risk for psychopathology and other physical health problems. If, however, a woman's current social circumstances are sufficiently positive, they can promote good health, particularly in the face of past adversity. PMID- 28803557 TI - Altered intrinsic functional connectivity of the cingulate cortex in children with severe temper outbursts. AB - Severe temper outbursts (STO) in children are associated with impaired school and family functioning and may contribute to negative outcomes. These outbursts can be conceptualized as excessive frustration responses reflecting reduced emotion regulation capacity. The anterior cingulate cortex (ACC) has been implicated in negative affect as well as emotional control, and exhibits disrupted function in children with elevated irritability and outbursts. This study examined the intrinsic functional connectivity (iFC) of a region of the ACC, the anterior midcingulate cortex (aMCC), in 5- to 9-year-old children with STO (n = 20), comparing them to children with attention-deficit/hyperactivity disorder (ADHD) without outbursts (ADHD; n = 18). Additional analyses compared results to a sample of healthy children (HC; n = 18) and examined specific associations with behavioral and emotional dysregulation. Compared to the ADHD group, STO children exhibited reduced iFC between the aMCC and surrounding regions of the ACC, and increased iFC between the aMCC and precuneus. These differences were also seen between the STO and HC groups; ADHD and HC groups did not differ. Specificity analyses found associations between aMCC-ACC connectivity and hyperactivity, and between aMCC-precuneus iFC and emotion dysregulation. Disruption in aMCC networks may underlie the behavioral and emotional dysregulation characteristic of children with STO. PMID- 28803558 TI - Global comparison of national individual food consumption surveys as a basis for health research and integration in national health surveillance programmes. AB - Individual food consumption surveys (IFCS) are performed to evaluate compliance with food/nutrient intake requirements or exposure to potential harmful dietary contaminants/components. In this review, we inventoried methods and designs used in national IFCS and discussed the methodologies applied across countries. Literature searches were performed using fixed sets of search terms in different online databases. We identified IFCS in thirty-nine countries from six world continents. National IFCS systems are available in most of the high-income countries, while such surveys are scarce in low- and middle-income countries (e.g. Africa, Eastern Europe and several Asian countries). Few countries (n 9) have their national IFCS incorporated into national health and nutrition surveys, allowing the investigation of dietary-related disease outcomes. Of the integrated surveys, most have the advantage of being continuous/regular, contrary to other IFCS that are mostly erratic. This review serves as the basis to define gaps and needs in IFCS worldwide and assists in defining priorities for resource allocation. In addition, it can serve as a source of inspiration for countries that do not have an IFCS system in place yet and advocate for national IFCS to be incorporated into national health and nutrition surveys in order to create: (1) research opportunities for investigating diet-disease relationships and (2) a frame to plan and evaluate the effect of diet-related policies (e.g. promotion of local nutrient-rich foods) and of nutrition recommendations, such as food-based dietary guidelines. Countries that integrate their IFCS within their national health and nutrition survey can serve as proof-of-principle for other countries. PMID- 28803559 TI - Rethinking the idea of late autism spectrum disorder onset. AB - A common theory of autism spectrum disorder (ASD) symptom onset includes toddlers who do not display symptoms until well after age 2, which are termed late-onset ASD cases. Objectives were to analyze differences in clinical phenotype between toddlers identified as ASD at initial evaluations (early diagnosed) versus those initially considered nonspectrum, then later identified as ASD (late diagnosed). Two hundred seventy-three toddlers recruited from the general population based on a failed developmental screening form or parent or physician concerns were followed longitudinally from 12 months and identified as early- and late diagnosed cases of ASD, language delayed, or typically developing. Toddlers completed common standardized assessments and experimental eye-tracking and observational measures every 9-12 months until age 3. Longitudinal performance on standardized assessments and experimental tests from initial evaluations were compared. Delay in social communication skills was seen in both ASD groups at early-age initial assessment, including increased preference for nonsocial stimuli, increased stereotypic play, reduced exploration, and use of gestures. On standardized psychometric assessments, early-diagnosed toddlers showed more impairment initially while late-diagnosed toddlers showed a slowing in language acquisition. Similar social communication impairments were present at very early ages in both early-detected ASD and so-called late-onset ASD. Data indicate ASD is present whether detected or not by current methods, and development of more sensitive tools is needed. PMID- 28803561 TI - Letter to the Editor: New guidelines about tetanus vaccination schedules in Europe should be evaluated with caution; Comment on: Tetanus vaccination, antibody persistence and decennial booster: a serosurvey of university students and at-risk workers. By Borrella-Venturini et al. PMID- 28803560 TI - Evidence of exposure of laughing doves (Spilopelia senegalensis) to West Nile and Usutu viruses in southern Tunisian oases. AB - It has previously been suggested that southern Tunisian oases may be suitable areas for the circulation of flaviviruses. In order to anticipate and prevent possible epidemiological spread of flaviviruses in humans and domestic animals, the ecology of their transmission in the oasis system needs to be better understood. Thus, the aim of this study was to assess the seroprevalence of anti flavivirus antibodies in the laughing dove (Spilopelia senegalensis), an abundant resident bird in Tunisian oases. Anti-flavivirus antibodies were detected in 17% of sampled doves. Ten per cent of the total tested doves were West Nile virus (WNV) seropositive and 4% were Usutu virus (USUV) seropositive, which provides the first evidence of USUV circulation in Tunisian birds. We also found that the occurrence probability of anti-flavivirus antibodies in dove plasma increased with decreasing distance to coast, suggesting that doves inhabiting coastal oases were more exposed to flaviviruses compared with those inhabiting inland oases. We also found significantly higher antibody occurrence probability in adult doves compared with young doves, which underlines the effect of exposure time. Overall, our results suggest that the laughing dove may be used for WNV and USUV surveillance in southern Tunisia. They also stress the need for investigations combining data on birds and mosquitoes to better understand the ecological factors governing the circulation of flaviviruses in this area. PMID- 28803562 TI - Dopamine receptor D2 (DRD2), dopamine transporter solute carrier family C6, member 4 (SLC6A3), and catechol-O-methyltransferase (COMT) genes as moderators of the relation between maternal history of maltreatment and infant emotion regulation. AB - Although infants less than 18 months old are capable of engaging in self regulatory behavior (e.g., avoidance, withdrawal, and orienting to other aspects of their environment), the use of self-regulatory strategies at this age (as opposed to relying on caregivers) is associated with elevated behavioral and physiological distress. This study investigated infant dopamine-related genotypes (dopamine receptor D2 [DRD2], dopamine transporter solute carrier family C6, member 4 [SLC6A3], and catechol-O-methyltransferase [COMT]) as they interact with maternal self-reported history of maltreatment to predict observed infant independent emotion regulation behavior. A community sample (N = 193) of mother infant dyads participated in a toy frustration challenge at infant age 15 months, and infant emotion regulation behavior was coded. Buccal cells were collected for genotyping. Maternal maltreatment history significantly interacted with infant SLC6A3 and COMT genotypes, such that infants with more 10-repeat and valine alleles of SLC6A3 and COMT, respectively, relative to infants with fewer or no 10 repeat and valine alleles, utilized more independent (i.e., maladaptive) regulatory behavior if mother reported a more extensive maltreatment history, as opposed to less. The findings indicate that child genetic factors moderate the intergenerational impact of maternal maltreatment history. The results are discussed in terms of potential mechanism of Gene * Environment interaction. PMID- 28803563 TI - Association between wetland presence and incidence of Salmonella enterica serotype Javiana infections in selected US sites, 2005-2011. AB - Salmonella causes an estimated 1.2 million illnesses annually in the USA. Salmonella enterica serotype Javiana (serotype Javiana) is the fourth most common serotype isolated from humans, with the majority of illnesses occurring in southeastern states. The percentage of wetland cover by wetland type and the average incidence rates of serotype Javiana infection in selected counties of the Foodborne Disease Active Surveillance Network (FoodNet) were examined. This analysis explored the relationship between wetland environments and incidence in order to assess whether regional differences in environmental habitats may be associated with observed variations in incidence. Findings suggest that environmental habitats may support reservoirs or contribute to the persistence of serotype Javiana, and may frequently contribute to the transmission of infection compared with other Salmonella serotypes. PMID- 28803564 TI - International Psychogeriatrics paper of the year 2016. AB - Since 2014, the year in which International Psychogeriatrics celebrated 25 years of existence, International Psychogeriatrics has featured a "paper of the month" (POM) category. Chosen by the editorial team which ranks available new International Psychogeriatrics manuscripts from the categories "original research articles" and "reviews," a POM is identified representing high scientific quality and clinical relevance. Each POM is accompanied by a short commentary highlighting its findings and relevance. For the year 2016 this resulted in twelve papers of the month of which nine were original research articles and three were systematic reviews or meta-analyses. PMID- 28803565 TI - Evidence-informed decision making for nutrition: African experiences and way forward. AB - Although substantial amount of nutrition research is conducted in Africa, the research agenda is mainly donor-driven. There is a clear need for a revised research agenda in Africa which is both driven by and responding to local priorities. The present paper summarises proceedings of a symposium on how evidence can guide decision makers towards context-appropriate priorities and decisions in nutrition. The paper focuses on lessons learnt from case studies by the Evidence Informed Decision Making in Nutrition and Health Network implemented between 2015 and 2016 in Benin, Ghana and South Africa. Activities within these countries were organised around problem-oriented evidence-informed decision making (EIDM), capacity strengthening and leadership and horizontal collaboration. Using a combination of desk-reviews, stakeholder influence mapping, semi-structured interviews and convening platforms, these country-level studies demonstrated strong interest for partnership between researchers and decision makers, and use of research evidence for prioritisation and decision making in nutrition. Identified capacity gaps were addressed through training workshops on EIDM, systematic reviews, cost-benefit evaluations and evidence contextualisation. Investing in knowledge partnerships and development of capacity and leadership are key to drive appropriate use of evidence in nutrition policy and programming in Africa. PMID- 28803566 TI - The pyogenic potential of the different Streptococcus anginosus group bacterial species: retrospective cohort study. AB - Streptococcus anginosus Group (SAG) bacteria are common causes of pyogenic infections (PIs). We examined the association between SAG species and the presence of a PI through a retrospective, observational, cohort study, between the years 2009 and 2015. All adults with clinically significant SAG infections in one hospital in Israel were assessed for association between SAG species and the presence of a PI defined as an abscess, empyema, or deep/organ space surgical site infection. Risk factors for PI were assessed using multivariate backward stepwise logistic regression analysis. We identified 263 patients with significant SAG infections, 182 (69%) of which were caused by S. anginosus, 45 (17.1%) by S treptococcus constellatus and 36 (13.7%) by S treptococcus intermedius. The mean age of the patients was 56.8 +/- 19.1 years. PIs were identified among 160 (60%) of the patients and were mostly non-bacteraemic (147/160, 91.8%), while most non-PI patients had bacteraemia (70/103, 68%). S. anginosus and S. constellatus were associated with a significantly lower incidence of PI than S. intermedius, OR 0.18 (95% CI 0.06-0.53) and 0.14 (0.04 0.48), respectively. Patients with PI were younger and, in general, had less co morbidities. S. intermedius was associated with pyogenic non-bacteraemic infections, while S. anginosus and S. constellatus were associated with bacteraemia with no abscess or empyema formation. These data may indicate differences in virulence mechanisms of these SAG bacteria. PMID- 28803567 TI - Effects of delayed mating on the reproductive biology of the vine mealybug, Planococcus ficus (Hemiptera: Pseudococcidae). AB - The effect of increasing mating delay on the reproductive performance and population growth rates of the vine mealybug, Planococcus ficus (Signoret) (Hemiptera: Pseudococcidae), was investigated under laboratory conditions. Virgin females were mated at 1, 3, 5, 7, 14, 21 and 28 days after emergence and reproductive and life table parameters were estimated. The pre-oviposition period (number of days between mating and the onset of oviposition) significantly decreased in females mated within 7 days, whereas females mated at older ages showed equivalent pre-oviposition periods (7 days, as shorter delays in mating did not reduce the population growth rates. PMID- 28803568 TI - History of child maltreatment and telomere length in immune cell subsets: Associations with stress- and attachment-related hormones. AB - Experiencing maltreatment during childhood can have long-lasting consequences for both mental and physical health. Immune cell telomere length (TL) shortening might be one link between child maltreatment (CM) experiences and adverse health outcomes later in life. While the stress hormone cortisol has been associated with TL attrition, the attachment-related hormone oxytocin may promote resilience. In 15 mothers with and 15 age- and body mass index-matched mothers without CM, we assessed TL in peripheral blood mononuclear cells and selected immune cell subsets (monocytes, naive, and memory cytotoxic T cells) by quantitative fluorescence in situ hybridization, as well as peripheral cortisol and oxytocin levels. Memory cytotoxic T cells showed significantly shorter TL in association with CM, whereas TL in monocytes and naive cytotoxic T cells did not significantly differ between the two groups. Across both groups, cortisol was negatively associated with TL, while oxytocin was positively associated with TL in memory cytotoxic T cells. These results indicate that long-lived memory cytotoxic T cells are most affected by the increased biological stress state associated with CM. Keeping in mind the correlational and preliminary nature of the results, the data suggest that cortisol may have a damaging and oxytocin a protective function on TL. PMID- 28803569 TI - Detection of Kobe-type and Otsu-type Babesia microti in wild rodents in China's Yunnan province. AB - Babesiosis is an emerging tick-transmitted zoonosis prevalent in large parts of the world. This study was designed to determine the rates of Babesia microti infection among small rodents in Yunnan province, where human cases of babesiosis have been reported. Currently, distribution of Babesia in its endemic regions is largely unknown. In this study, we cataloged 1672 small wild rodents, comprising 4 orders, from nine areas in western Yunnan province between 2009 and 2011. Babesia microti DNA was detected by polymerase chain reaction in 4.3% (72/1672) of the rodents analyzed. The most frequently infected rodent species included Apodemus chevrieri and Niviventer fulvescens. Rodents from forests and shrublands had significantly higher Babesia infection rates. Genetic comparisons revealed that Babesia was most similar to the Kobe- and Otsu-type strains identified in Japan. A variety of rodent species might be involved in the enzootic maintenance and transmission of B. microti, supporting the need for further serological investigations in humans. PMID- 28803570 TI - Decontamination of an Extracorporeal Membrane Oxygenator Contaminated With Mycobacterium chimaera. AB - Water samples taken from extracorporeal membrane oxygenator (ECMO) devices used at University Hospitals Birmingham yielded high total viable counts (TVCs) containing a variety of microorganisms, including M. chimaera. Disinfection resulted in the reduction of TVCs and eradication of Mycobacterium chimaera. Weekly disinfection and water sampling are required to manage the water quality in these devices. Infect Control Hosp Epidemiol 2017;38:1244-1246. PMID- 28803571 TI - A national register-based study of paediatric varicella hospitalizations in Denmark 2010-2016. AB - Varicella, usually a mild disease of childhood, can also cause complications and hospitalization. Universal varicella immunization is implemented in several countries worldwide, but not in Denmark. Taking advantage of unique national registers, we aimed to estimate the incidence of paediatric varicella hospitalizations and assess determinants for hospitalization. For this purpose, we designed a nationwide, retrospective register study of paediatric varicella hospitalizations and applied a case-cohort design and logistic regression analysis comparing hospitalized varicella patients to a sample of the entire paediatric population in Denmark. Varicella patients were identified in The Danish National Patient Register and referents were randomly selected from the Danish Civil Registration System. The incidence of paediatric varicella admissions was 11/100 000 children 0-18 years of age/year. Of admitted children 67.1% had complications and 30.0% had underlying disease. All categories of underlying disease significantly increased the odds of hospitalization as well as male gender and not having been born in Denmark. In conclusion, we found a considerable burden of paediatric varicella disease in Danish hospitals, of similar magnitude as in other European countries comparable to Denmark. With this study we have provided epidemiological data needed for considering implementation of varicella vaccine in Denmark. PMID- 28803572 TI - Medical Assistance in Dying (MAID) and the Neurosurgeon: Position Statement of the Canadian Neurosurgical Society (CNSS). PMID- 28803574 TI - Retrospective evaluation of the BIG score to predict mortality in pediatric blunt trauma. AB - OBJECTIVES: This study's objective was to measure the criterion validity of the BIG score (a new pediatric trauma score composed of the initial base deficit [BD], international normalized ratio [INR], and Glasgow Coma Scale [GCS]) to predict in-hospital mortality among children admitted to the emergency department with blunt trauma requiring an admission to the intensive care unit, knowing that a score <16 identifies children with a high probability of survival. METHODS: This was a retrospective cohort study performed in a single tertiary care pediatric hospital between 2008 and 2016. Participants were all children admitted to the emergency department for a blunt trauma requiring intensive care unit admission or who died in the emergency department. The primary analysis was the association between a BIG score >=16 and in-hospital mortality. RESULTS: Twenty eight children died among the 336 who met the inclusion criteria. Two hundred eighty-four children had information on the three components of the BIG score, and they were included in the primary analysis. A BIG score >=16 demonstrated a sensitivity of 0.93 (95% confidence interval [CI]: 0.76-0.98) and specificity of 0.83 (95% CI: 0.78-0.87) to identify mortality. Using receiver operating characteristic curves, the area under the curve was higher for the BIG score (0.97; 95% IC: 0.95-0.99) in comparison to the Injury Severity Score (0.78; 95% IC: 0.71-0.85). CONCLUSION: In this retrospective cohort, the BIG score was an excellent predictor of survival for children admitted to the emergency department following a blunt trauma. PMID- 28803573 TI - The school environment and sugar-sweetened beverage consumption among Guatemalan adolescents. AB - OBJECTIVE: The current study sought to examine Guatemalan adolescents' consumption of sugar-sweetened beverages (SSB), identify which individual-level characteristics are associated with SSB consumption and describe school characteristics that may influence students' SSB consumption. DESIGN: Within this observational pilot study, a questionnaire was used to assess students' consumption of three varieties of SSB (soft drinks, energy drinks, sweetened coffees/teas), as well as a variety of sociodemographic and behavioural characteristics. We collected built environment data to examine aspects of the school food environment. We developed Poisson regression models for each SSB variety and used descriptive analyses to characterize the sample. SETTING: Guatemala City, Guatemala. SUBJECTS: Guatemalan adolescents (n 1042) from four (two public, two private) secondary schools. RESULTS: Built environment data revealed that students from the two public schools lacked access to water fountains/coolers. The SSB industry had a presence in the schools through advertisements, sponsored food kiosks and products available for sale. Common correlates of SSB consumption included school type, sedentary behaviour, frequency of purchasing lunch in the cafeteria, and frequency of purchasing snacks from vending machines in school and off school property. CONCLUSIONS: Guatemalan adolescents frequently consume SSB, which may be encouraged by aspects of the school environment. Schools represent a viable setting for equitable population health interventions designed to reduce SSB consumption, including increasing access to clean drinking-water, reducing access to SSB, restricting SSB marketing and greater enforcement of existing food policies. PMID- 28803575 TI - Placental Expressions of CDKN1C and KCNQ1OT1 in Monozygotic Twins with Selective Intrauterine Growth Restriction. AB - CDKN1C and KCNQ1OT1 are imprinted genes that might be potential regulators of placental development. This study investigated placental expressions of CDKN1C and KCNQ1OT1 in monozygotic twins with and without selective intrauterine growth restriction (sIUGR). Seventeen sIUGR and fifteen normal monozygotic(MZ) twin pairs were examined. Placental mRNA expressions of CDKN1C and KCNQ1OT1 were detected by real-time fluorescent quantitative PCR. CDKN1C protein expression was detected by immunohistochemical assay and Western-blotting. In the sIUGR group, smaller fetuses had a smaller share of the placenta, and CDKN1C protein expression was significantly increased while KCNQ1OT1 mRNA expression was significantly decreased. The CDKN1C/KCNQ1OT1 mRNA ratio was lower in the larger fetus than in the smaller fetus (p < .05). In the control group, CDKN1C protein expression showed no difference between larger and smaller fetuses, while KCNQ1OT1 mRNA expression was significantly lower in the larger fetus, and the CDKN1C/KCNQ1OT1 mRNA ratio was higher in the larger fetus than in the smaller fetus (p < .05). Our findings showed that pathogenesis of sIUGR may be related to the co-effect of the up-regulated protein expression of CDKN1C and down-regulated mRNA expression of KCNQ1OT1 in the placenta. PMID- 28803576 TI - Age at castration (surgical or immunological) impacts carcass characteristics and meat quality of male pigs. AB - In order to accurately estimate body composition at slaughter and to meet specific market targets, the influence of age at time of castration (surgical or immunological) on body composition and boar taint indicators must be determined for male pigs. In all, 48 males were randomly assigned to one of four management regimens: (1) entire male pigs (EM), (2) EM surgically castrated at ~40 kg BW and 10 weeks of age (late castrates; LC), (3) conventional, early surgical castrates (within 4 days of birth; EC) and (4) EM immunized with a gonadotropin-releasing hormone (GnRH) analog (primary dose at 30 kg BW and 8 weeks of age; booster dose at 70 kg and 14 weeks of age; IM). Pigs were fed corn and soybean meal-based diets that were not limiting in essential nutrients. Back fat was sampled on days -3, 8, 18 and 42, relative to administering the booster dose of GnRH analog at day 0, to determine androstenone concentrations (n=8 or 9/group). Fat androstenone concentrations in IM were lower than EM between days 8 and 42 after administering the booster dose (173 v. 863 ng/g, respectively; P<0.01), and were not different from surgically castrated males (EC and LC) after day 18. Slaughter occurred at ~115 kg BW, 42 days (6 weeks) after administering the booster dose for IM, and 10 and 20 weeks after surgical castration for LC and EC, respectively (n=8 or 9/group). At slaughter, live BW, liver weight as a percent of live BW, dissectible bone as a percent of cold carcass side, body protein and water contents and whole-body protein deposition decreased with time after surgical castration (linear; P<0.05), whereas dressing percentage, dissectible fat, probe fat depth and body fat content increased with time after surgical castration (linear; P<0.05). The IM had intermediate dressing percentage and dissected fat to EM and EC, whereas liver weight as a percent of live BW and body protein and lipid contents were not different from EM. Whole-body lipid deposition tended to be greater in IM than in EM between 14 and 20 weeks of age (373 v. 286 g/d; P=0.051). In conclusion, castration of male pigs after 6 weeks of age has a lasting effect on physical and chemical body composition. The relationship between time after castration and body composition may be developed to predict carcass composition and can be used to determine the ideal immunization schedule aimed at specific markets in the future. PMID- 28803577 TI - Auditory brainstem response (ABR) profiling tests as diagnostic support for schizophrenia and adult attention-deficit hyperactivity disorder (ADHD). AB - OBJECTIVE: To evaluate the performances of two auditory brainstem response (ABR) profiling tests as potential biomarkers and diagnostic support for schizophrenia and adult attention-deficit hyperactivity disorder (ADHD), respectively, in an investigator-initiated blinded study design. METHOD: Male and female patients with schizophrenia (n=26) and adult ADHD (n=24) meeting Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM IV) diagnostic criteria and healthy controls (n=58) comprised the analysis set (n=108) of the total number of study participants (n=119). Coded sets of randomized ABR recordings were analysed by an independent party blinded to clinical diagnoses before a joint code-breaking session. RESULTS: The ABR profiling test for schizophrenia identified schizophrenia patients versus controls with a sensitivity of 84.6% and a specificity of 93.1%. The ADHD test identified patients with adult ADHD versus controls with a sensitivity of 87.5% and a specificity of 91.4%. CONCLUSION: The ABR profiling tests discriminated schizophrenia and ADHD versus healthy controls with high sensitivity and specificity. The methods deserve to be further explored in larger clinical studies including a broad range of psychiatric disorders to determine their utility as potential diagnostic biomarkers. PMID- 28803578 TI - Physiotherapy managers' views of musculoskeletal physiotherapy service provision in Ireland: a qualitative study. AB - : Aim Integrated multidisciplinary primary healthcare is still in a relatively early stage of development in Ireland, with significant restructuring occurring in the past decade. Musculoskeletal physiotherapy services traditionally provided in acute hospital settings have been relocated into the primary care setting where the physiotherapist works as part of the multidisciplinary team. This study aimed to explore physiotherapy managers' experiences of managing musculoskeletal physiotherapy services in primary care to gain an insight into the opportunities and challenges in service delivery, changing roles and ongoing professional development needs of staff. Participants Qualitative design using semi-structured interviews with primary care physiotherapy managers in the Republic of Ireland was employed. RESULTS: Five interviews took in a mix of rural and urban areas nationally. The relationship with the GP was an important one in musculoskeletal physiotherapy services in primary care. Physiotherapists were well skilled but opportunities for professional and career development were restricted. Methods of optimising resources in the face of staffing restrictions were identified. Whilst there were many examples of innovations in service delivery, various barriers negatively impacted on optimal service including resource constraints and national strategy. CONCLUSIONS: A number of factors that impact on musculoskeletal service delivery in primary care from the perspective of physiotherapy managers were identified in this study. Future research should explore the views of other stakeholders to provide a more thorough understanding of the relevant issues affecting musculoskeletal physiotherapy service provision in primary care in Ireland. PMID- 28803579 TI - Zika Virus and Neurological Disease: Investing in Prevention. PMID- 28803580 TI - Is Aboriginal nutrition a priority for local government? A policy analysis. AB - OBJECTIVE: The present study aimed to explore how Australian local governments prioritise the health and well-being of Aboriginal populations and the extent to which nutrition is addressed by local government health policy. DESIGN: In the state of Victoria, Australia, all seventy-nine local governments' public health policy documents were retrieved. Inclusion of Aboriginal health and nutrition in policy documents was analysed using quantitative content analysis. Representation of Aboriginal nutrition 'problems' and 'solutions' was examined using qualitative framing analysis. The socio-ecological framework was used to classify the types of Aboriginal nutrition issues and strategies within policy documents. SETTING: Victoria, Australia. SUBJECTS: Local governments' public health policy documents (n 79). RESULTS: A small proportion (14 %, n 11) of local governments addressed Aboriginal health and well-being in terms of nutrition. Where strategies aimed at nutrition existed, they mostly focused on individual factors rather than the broader macroenvironment. CONCLUSIONS: A limited number of Victorian local governments address nutrition as a health issue for their Aboriginal populations in policy documents. Nutrition needs to be addressed as a community and social responsibility rather than merely an individual 'behaviour'. Partnerships are required to ensure Aboriginal people lead government policy development. PMID- 28803581 TI - Nutrition Facts Panel use is associated with diet quality and dietary patterns among Latinos with type 2 diabetes. AB - OBJECTIVE: The study aims were to (i) identify determinants of Nutrition Facts Panel (NFP) use and (ii) describe the association between NFP use and dietary intake among Latinos with type 2 diabetes. DESIGN: Baseline cross-sectional data from a clinical trial were used to assess the association between NFP use and dietary intake. Diet was measured using two methods: (i) a diet quality score (the Healthy Eating Index-2010) derived from a single 24 h recall and (ii) dietary pattern (exploratory factor analyses) from an FFQ. Multivariable logistic and non-parametric quantile regressions were conducted, as appropriate. Settings Hartford County, Connecticut, USA. SUBJECTS: Latino adults (n 203), >=21 years of age, with diagnosed type 2 diabetes, glycosylated Hb>=7 %, and without medical conditions limiting physical activity. RESULTS: Participants' education level, diabetes-related knowledge and English speaking were positively associated with NFP use. At the higher percentiles of diet quality score, NFP use was significantly associated with higher diet quality. Similarly, NFP users were more likely to consume a 'healthy' dietary pattern (P=0.003) and less likely to consume a 'fried snack' pattern (P=0.048) compared with NFP non-users. CONCLUSIONS: The association between reported NFP use and diet quality was positive and significantly stronger among participants who reported consuming a healthier diet. While NFP use was associated with a healthier dietary pattern, not using NFP was associated with a less-healthy, fried snack pattern. Longitudinal studies are needed to understand whether improving NFP use could be an effective intervention to improve diet quality among Latinos with type 2 diabetes. PMID- 28803582 TI - Recovery of Surgical Equipment Sterile Processing During a Floodwater Boil Advisory. AB - Excessive rainfall and dam failures resulted in floodwater contaminating our public water supply. The endotoxin risk in the contaminated water created challenges in recovery of sterile processing for our surgical equipment. Recovery plans should include a potable water source and a method to connect it to the required location. We share our solution of plumbing our sterile processing equipment to tanker-transported potable water sources. (Disaster Med Public Health Preparedness. 2018; 12: 415-418). PMID- 28803583 TI - Cross-sectional Survey of Long-Term Care Facilities in the Rockaway Peninsula: Preparedness and Response During Hurricane Sandy. AB - BACKGROUND: Few studies have described the challenges experienced by long-term care facilities (LTCFs) following Hurricane Sandy. This study examined LTCF preparedness and experiences during and after the storm. METHODS: A cross sectional survey was conducted 2 years after Hurricane Sandy to assess LTCF demographics, preparation, and post-storm resources. Surveys were conducted at LTCFs located on the Rockaway Peninsula of New York City. All LTCFs located in a heavily affected area were approached. RESULTS: Of 29 facilities, 1 had closed, 5 did not respond, 9 declined to participate, and 14 participated, yielding a response rate of 50% for open facilities. Twenty-one percent of the facilities had preparations specifically for hurricanes. More than 70% of the facilities had lost electricity, heat, and telephone service, and one-half had evacuated. Twenty one percent of the facilities reported not receiving any assistance and over one half reported that relief resources did not meet their needs. CONCLUSIONS: Many LTCFs lacked plans specific to such a large-scale event. Since nearly all of the LTCFs in the region were affected, preexisting transportation and housing plans may have been inadequate. Future preparation could include hazard-specific planning and reliance on resources from a wider geographic area. Access to electricity emerged as a top priority. (Disaster Med Public Health Preparedness. 2018;12:194-200). PMID- 28803584 TI - Table Talk: development of an observational tool to assess verbal feeding communications in early care and education settings. AB - OBJECTIVE: Children's dietary intake impacts weight status and a range of short- and long-term health outcomes. Accurate measurement of factors that influence children's diet is critical to the development and evaluation of interventions designed to improve children's diets. The purpose of the current paper is to present the development of the Table Talk observational tool to measure early care and education teachers' (ECET) verbal feeding communications. DESIGN: An observational tool to assess ECET verbal communication at mealtimes was deigned based on the extant literature. Trained observers conducted observations using the tool during lunch for both lead and assistant ECET. Descriptive statistics, test-retest for a subgroup, interclass correlations for each item, and comparisons between leads and assistants were conducted. SETTING: Head Start centres, Southern USA. SUBJECTS: Seventy-five Head Start educators. RESULTS: On average, 17.2 total verbal feeding communications (sd 8.9) were observed per ECET. For lead ECET, the most prevalent Supportive Comment was Exploring Foods whereas for assistants Making Positive Comments was the most prevalent. Overall, lead ECET enacted more Supportive Comments than assistant ECET (F(2,72)=4.8, P=0.03). The most common Unsupportive Comment was Pressuring to Eat, with a mean of 3.8 (sd 4.3) and a maximum of 25. There was no difference in Unsupportive Comments between lead and assistant ECET. CONCLUSIONS: Table Talk may be a useful tool to assess verbal feeding communications of ECET, with potential applications such as informing ECET training and assessing intervention efforts. PMID- 28803585 TI - Performance and financial consequences of stillbirth in Holstein dairy cattle. AB - Stillbirth is an economically important trait on dairy farms. Knowledge of the consequences of, and the economic losses associated with stillbirth can help the producer when making management decisions. The objectives of this study were to determine the effects of stillbirth on productive and reproductive performance as well as financial losses due to stillbirth incidence in Iranian Holstein dairy farms. Economic and performance data were collected from nine Holstein dairy farms in Isfahan and Khorasan provinces of Iran from March 2008 to December 2013. The final data set included 160 410 calving records from 53 265 cows. A linear mixed model was developed to evaluate the effects of stillbirth on performance of primiparous and multiparous cows separately and overall. An economic model was used to estimate the economic losses due to stillbirth. The incidence of stillbirth cases per cow per year was 4.2% on average (3.4% to 6.8% at herd level). The least square means results showed that a case of stillbirth significantly (P0.05). Overall, a case of stillbirth reduced 305-day milk yield by 544.0+/-76.5 kg/cow per lactation. Stillbirth had no significant effects on 305-day fat and protein percentages in either primiparous or multiparous cows. Overall, cows that gave birth to stillborn calves had significantly increased days open by 14.6+/-2.6 days and the number of inseminations per conception by 0.2 compared with cows that gave birth to live calves (P<0.01). In general, the negative productive and reproductive effects associated with stillbirth were smaller and non-significant for primiparous cows compared with multiparous cows. The financial losses associated with stillbirth incidence averaged US$ 938 per case (range from $US 767 to $US 1189 in the nine investigated farms). The loss of a calf was not the only cost associated with stillbirth, as it accounted for 71.0% of the total cost. The costs of dystocia (7.6%) and culling and replacement expenses (6.3%) were the next most important costs associated with stillbirth. These results can be used to assess the potential return from management strategies to reduce the occurrence of stillbirths. PMID- 28803586 TI - Genetic evaluation and selection response for growth in meat-type quail through random regression models using B-spline functions and Legendre polynomials. AB - The objective was to estimate (co)variance functions using random regression models (RRM) with Legendre polynomials, B-spline function and multi-trait models aimed at evaluating genetic parameters of growth traits in meat-type quail. A database containing the complete pedigree information of 7000 meat-type quail was utilized. The models included the fixed effects of contemporary group and generation. Direct additive genetic and permanent environmental effects, considered as random, were modeled using B-spline functions considering quadratic and cubic polynomials for each individual segment, and Legendre polynomials for age. Residual variances were grouped in four age classes. Direct additive genetic and permanent environmental effects were modeled using 2 to 4 segments and were modeled by Legendre polynomial with orders of fit ranging from 2 to 4. The model with quadratic B-spline adjustment, using four segments for direct additive genetic and permanent environmental effects, was the most appropriate and parsimonious to describe the covariance structure of the data. The RRM using Legendre polynomials presented an underestimation of the residual variance. Lesser heritability estimates were observed for multi-trait models in comparison with RRM for the evaluated ages. In general, the genetic correlations between measures of BW from hatching to 35 days of age decreased as the range between the evaluated ages increased. Genetic trend for BW was positive and significant along the selection generations. The genetic response to selection for BW in the evaluated ages presented greater values for RRM compared with multi-trait models. In summary, RRM using B-spline functions with four residual variance classes and segments were the best fit for genetic evaluation of growth traits in meat-type quail. In conclusion, RRM should be considered in genetic evaluation of breeding programs. PMID- 28803587 TI - The rise of methicillin resistant Staphylococcus aureus: now the dominant cause of skin and soft tissue infection in Central Australia. AB - This study aimed to examine the epidemiology and treatment outcomes of community onset purulent staphylococcal skin and soft tissue infections (SSTI) in Central Australia. We performed a prospective observational study of patients hospitalised with community-onset purulent staphylococcal SSTI (n = 160). Indigenous patients accounted for 78% of cases. Patients were predominantly young adults; however, there were high rates of co-morbid disease. Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) was the dominant phenotype, accounting for 60% of cases. Hospitalisation during the preceding 6 months, and haemodialysis dependence were significant predictors of CA-MRSA infection on univariate analysis. Clinical presentation and treatment outcomes were found to be comparable for methicillin-susceptible S. aureus (MSSA) and methicillin resistant cases. All MRSA isolates were characterised as non-multi-resistant, with this term used interchangeably with CA-MRSA in this analysis. We did not find an association between receipt of an active antimicrobial agent within the first 48 h, and progression of infection; need for further surgical debridement; unplanned General Practitioner or hospital re-presentation; or need for further antibiotics. At least one adverse outcome was experienced by 39% of patients. Clindamycin resistance was common, while rates of trimethoprim-sulfamethoxazole resistance were low. This study suggested the possibility of healthcare associated transmission of CA-MRSA. This is the first Australian report of CA MRSA superseding MSSA as the cause of community onset staphylococcal SSTI. PMID- 28803588 TI - The history of paediatric cardiology on stamps. AB - Paediatric cardiology is arguably the sub-specialty in which the greatest advances have been made in both disease diagnosis and treatment over the past half a century. Paediatric cardiology emerged as a discipline in the 1930s. Since then, advances in imaging techniques such as echocardiography, angiography, CT, or magnetic resonance and extracorporeal circulation have provided excellent diagnosis and treatment of CHD. The pioneers of paediatric cardiology are more than eponyms, for each used in new and original ways the tools and concepts available in his or her era. This brief overview of the history of paediatric cardiology on stamps begins from William Harvey up to our own time, and includes the milestones in paediatric cardiology. PMID- 28803589 TI - HEALTH TECHNOLOGY ASSESSMENT IN CENTRAL, EASTERN, AND SOUTH EUROPEAN COUNTRIES: CROATIA. AB - OBJECTIVES: The aim of this study was to provide a brief, 7-year history of health technology assessment (HTA) implementation in Croatia through national and international activities. METHODS: We used retrospective descriptive analysis of key documents related to the legal framework, process of decision making, and HTA. Analysis of the Agency's plan for and experience with the implementation of a transparent HTA process in Croatia was performed by addressing seven key components of the HTA implementation scorecard framework. The main challenges and facilitating factors were also assessed. RESULTS: HTA is not yet fully implemented in Croatia. The main challenges are the insufficient legal framework, limited human and financial resources, and limited stakeholder involvement. Facilitating factors are active international collaboration and education through EUnetHTA and the International Society for Pharmacoeconomics and Outcomes Research and production of national and international HTA reports. CONCLUSIONS: The HTA process is not yet sustainable in Croatia and HTA reports are still not mandatory for reimbursement/investment or disinvestment decision processes. There are still barriers to overcome. PMID- 28803590 TI - Differential protein analysis of serum exosomes post-intravenous immunoglobulin therapy in patients with Kawasaki disease. AB - BACKGROUND: Kawasaki disease, which is characterised by systemic vasculitides accompanied by acute fever, is regularly treated by intravenous immunoglobulin to avoid lesion formation in the coronary artery; however, the mechanism of intravenous immunoglobulin therapy is unclear. Hence, we aimed to analyse the global expression profile of serum exosomal proteins before and after administering intravenous immunoglobulin. METHODS: Two-dimensional electrophoresis coupled with mass spectrometry analysis was used to identify the differentially expressed proteome of serum exosomes in patients with Kawasaki disease before and after intravenous immunoglobulin therapy. RESULTS: Our analysis revealed 69 differential protein spots in the Kawasaki disease group with changes larger than 1.5-fold and 59 differential ones in patients after intravenous immunoglobulin therapy compared with the control group. Gene ontology analysis revealed that the acute-phase response disappeared, the functions of the complement system and innate immune response were enhanced, and the antibacterial humoral response pathway of corticosteroids and cardioprotection emerged after administration of intravenous immunoglobulin. Further, we showed that complement C3 and apolipoprotein A-IV levels increased before and decreased after intravenous immunoglobulin therapy and that the insulin-like growth factor binding protein complex acid labile subunit displayed reverse alteration before and after intravenous immunoglobulin therapy. These observations might be potential indicators of intravenous immunoglobulin function. CONCLUSIONS: Our results show the differential proteomic profile of serum exosomes of patients with Kawasaki disease before and after intravenous immunoglobulin therapy, such as complement C3, apolipoprotein A-IV, and insulin-like growth factor-binding protein complex acid labile subunit. These results may be useful in the identification of markers for monitoring intravenous immunoglobulin therapy in patients with Kawasaki disease. PMID- 28803591 TI - Genetic and Environmental Influences on Correlations Between Hearing and Cognitive Functions in Middle and Older Chinese Twins. AB - The genetic and environmental impacts on correlations between hearing and cognitive functions have not been well studied. Cognitive function was evaluated by the Montreal Cognitive Assessment (MoCA). Hearing function was assessed by audiometric pure-tone hearing thresholds at different frequencies, including 0.5 kHz, 1 kHz, 2 kHz, 4 kHz, 8 kHz, and 12.5 kHz, with the lower hearing thresholds indicating better hearing function. Cognitive and hearing functions were measured on 379 complete twin pairs (240 monozygotic and 139 dizygotic pairs) with a median age of 50 years (range: 40-80 years). Bivariate twin models were fitted to quantify the genetic and environmental components of the correlations between hearing and cognitive functions. The analysis showed significantly high genetic correlation between 2 kHz of hearing and cognition (r G = -1.00, 95% CI [-1.00, 0.46]) and moderate genetic correlation between 4 kHz of hearing and cognition (r G = -0.62, 95% CI [-1.00, -0.14]). We found no significant genetic correlations between low as well as high frequencies of hearing and cognition. Low to moderate common and unique environmental correlations were shown between low frequencies of hearing and cognition (-0.13 to -0.39) and the common environmental correlation between 8 kHz, one of the high frequencies of hearing, and cognition (-0.22). The middle frequencies of hearing and cognitive functions may have a shared genetic basis. Low frequencies of hearing and cognition may share similar common and unique environmental factors. At 8 kHz, the high frequency of hearing and cognition may share similar common environment. This twin study detected a significant genetic and environmental basis in the phenotype correlation between cognition and hearing, which differed across frequencies. PMID- 28803592 TI - Brain alterations potentially associated with aggression and terrorism. AB - A large proportion of the persons who join terrorist groups as well as lone acting terrorists have a history of violent behavior or mental disorder that predated their becoming terrorists. This suggests that brain alterations found to occur in violent perpetrators may also be present in a significant percentage of terrorists. After a short delineation of phylogenetically old neuronal networks that are important for the generation of aggressive behavior in inconspicuous brains, this review summarizes structural and functional brain-imaging studies in violent offenders published over the last 10 years. Depending on the subtype of violence (impulsive or instrumental), deviations in structure or function were mainly found in the prefrontal, orbitofrontal, and insular cortex, as well as in temporolimbic structures (e.g., the amygdala, hippocampus, and parahippocampus). These brain areas are essentially responsible for the control of the archaic neuronal generators of aggression located in the hypothalamus and limbic system. This regional distribution of brain alterations also shows a remarkable overlap with those brain regions that are crucial for such prosocial traits as empathy and compassion. Feelings of superiority, dominance, and satisfaction gained by performing violent and terroristic attacks suggest that a hedonistic component via an activation of brain reward systems plays an additional role. In our current debate about the causes of terrorism, aspects of brain dysfunction should receive more attention. PMID- 28803593 TI - Predictors of obtaining follow-up care in the province of Ontario, Canada, following a new diagnosis of atrial fibrillation, heart failure, and hypertension in the emergency department. AB - OBJECTIVE: Patients with cardiovascular diseases are common in the emergency department (ED), and continuity of care following that visit is needed to ensure that they receive evidence-based diagnostic tests and therapy. We examined the frequency of follow-up care after discharge from an ED with a new diagnosis of one of three cardiovascular diseases. METHODS: We performed a retrospective cohort study of patients with a new diagnosis of heart failure, atrial fibrillation, or hypertension, who were discharged from 157 non-pediatric EDs in Ontario, Canada, between April 2007 and March 2014. We determined the frequency of follow-up care with a family physician, cardiologist, or internist within seven and 30 days, and assessed the association of patient, emergency physician, and family physician characteristics with obtaining follow-up care using cause specific hazard modeling. RESULTS: There were 41,485 qualifying ED visits. Just under half (47.0%) had follow-up care within seven days, with 78.7% seen by 30 days. Patients with serious comorbidities (renal failure, dementia, COPD, stroke, coronary artery disease, and cancer) had a lower adjusted hazard of obtaining 7 day follow-up care (HRs 0.77-0.95) and 30-day follow-up care (HR 0.76-0.95). The only emergency physician characteristic associated with follow-up care was 5-year emergency medicine specialty training (HR 1.11). Compared to those whose family physician was remunerated via a primarily fee-for-service model, patients were less likely to obtain 7-day follow-up care if their family physician was remunerated via three types of capitation models (HR 0.72, 0.81, 0.85) or via traditional fee-for-service (HR 0.91). Findings were similar for 30-day follow-up care. CONCLUSIONS: Only half of patients discharged from an ED with a new diagnosis of atrial fibrillation, heart failure, and hypertension were seen within a week of being discharged. Patients with significant comorbidities were less likely to obtain follow-up care, as were those with a family physician who was remunerated via primarily capitation methods. PMID- 28803594 TI - Does adherence to the Mediterranean dietary pattern reduce asthma symptoms in children? A systematic review of observational studies. AB - OBJECTIVE: The purpose of the present systematic review was to synthesize evidence from the literature to assess efficacy of the Mediterranean dietary pattern in childhood asthma. Design/Setting A systematic search of six databases, three clinical trial registries and hand-search of peer-reviewed articles was conducted up to 29 October 2016. Inclusion criteria included exposure to a Mediterranean dietary pattern, measurement of asthma symptoms and study population of children aged <18 years. Quality assessment was conducted. Due to significant heterogeneity, meta-analysis was not feasible. RESULTS: Of the 436 articles identified, after removal of duplicates and based on inclusion criteria, fifteen observational studies conducted in Mediterranean and non-Mediterranean countries were relevant. No randomized controlled trials were retrieved. Twelve studies reported an inverse association between adherence to a Mediterranean dietary pattern and asthma in children, two studies showed no association and one study showed an increase in asthma symptoms. In fourteen out of fifteen studies, quality assessment checks revealed good reliability and validity among study methodologies. CONCLUSIONS: The current systematic review revealed a consistent inverse relationship (protective) between a Mediterranean dietary pattern and asthma in children. Future well-designed randomized controlled trials are needed to provide solid evidence. Nevertheless, the existing level of evidence adds to the public health message relating to the beneficial effects of a Mediterranean type diet in children suffering with asthma. PMID- 28803595 TI - Vitamin D intake and risk of CVD and all-cause mortality: evidence from the Caerphilly Prospective Cohort Study. AB - OBJECTIVE: Prospective data on the associations between vitamin D intake and risk of CVD and all-cause mortality are limited and inconclusive. The aim of the present study was to investigate the associations between vitamin D intake and CVD risk and all-cause mortality in the Caerphilly Prospective Cohort Study. DESIGN: The associations of vitamin D intake with CVD risk markers were examined cross-sectionally at baseline and longitudinally at 5-year, 10-year and >20-year follow-ups. In addition, the predictive value of vitamin D intake for CVD events and all-cause mortality after >20 years of follow-up was examined. Logistic regression and general linear regression were used for data analysis. SETTING: Participants in the UK. SUBJECTS: Men (n 452) who were free from CVD and type 2 diabetes at recruitment. RESULTS: Higher vitamin D intake was associated with increased HDL cholesterol (P=0.003) and pulse pressure (P=0.04) and decreased total cholesterol:HDL cholesterol (P=0.008) cross-sectionally at baseline, but the associations were lost during follow-up. Furthermore, higher vitamin D intake was associated with decreased concentration of plasma TAG at baseline (P=0.01) and at the 5-year (P=0.01), but not the 10-year examination. After >20 years of follow-up, vitamin D was not associated with stroke (n 72), myocardial infarctions (n 142), heart failure (n 43) or all-cause mortality (n 281), but was positively associated with increased diastolic blood pressure (P=0.03). CONCLUSIONS: The study supports associations of higher vitamin D intake with lower fasting plasma TAG and higher diastolic blood pressure. PMID- 28803596 TI - Associations of Baltic Sea and Mediterranean dietary patterns with bone mineral density in elderly women. AB - OBJECTIVE: Dietary quality in relation to bone health has been analysed in relatively few studies. The current study aimed to assess the association of the Baltic Sea diet (BSD) and the Mediterranean diet (MD) with bone mineral density (BMD) among elderly women. DESIGN: Lumbar, femoral and total body BMD were measured by dual-energy X-ray absorptiometry at baseline and year 3. Dietary intake was measured by 3 d food record at baseline. BSD and MD scores were calculated from food and alcohol consumption and nutrient intake. Information on lifestyle, diseases and medications was collected by questionnaires. Longitudinal associations of BSD and MD scores with BMD were analysed using linear mixed models. SETTING: Interventional prospective Kuopio Osteoporosis Risk Factor and Fracture Prevention study including women aged 65-71 years and residing in Kuopio province, Finland. SUBJECTS: Women (n 554) with mean age of 67.9 (sd 1.9) years and mean BMI of 28.8 (sd 4.7) kg/m2. RESULTS: Higher BSD scores were associated with higher intakes of fruit and berries, vegetables, fish and low-fat dairy products, and lower intake of sausage. Higher MD scores were associated with higher consumption of fruit and berries and vegetables. BSD and MD scores were associated with higher PUFA:SFA and higher fibre intake. Femoral, lumbar or total body BMD was not significantly different among the quartiles of BSD or MD score. CONCLUSION: The lack of associations suggest that Baltic Sea and Mediterranean dietary patterns may not adequately reflect dietary factors relevant to bone health. PMID- 28803597 TI - Somali, Latino and Hmong parents' perceptions and approaches about raising healthy-weight children: a community-based participatory research study. AB - OBJECTIVE: Immigrants in the USA are confronted with health disparities, including childhood obesity and obesity-related chronic diseases. We aimed to identify perceptions of childhood body weight, approaches to raising healthy children and desires for supportive programmes of Somali, Latino and Hmong (SLM) parents in the Twin Cities, Minnesota, USA. DESIGN: Using community-based participatory research, ten focus groups (FG) were conducted with sixty-seven parents (n 28 Somali, three FG; n 19 Latino, four FG; n 20 Hmong, three FG) of 3 12-year-old children in their native language. Demographic information was collected. RESULTS: SLM parents perceived that health is not necessarily weight based; childhood obesity is caused by overeating, eating unhealthy foods and sedentary activities; traditional foods are generally healthy while American foods are generally unhealthy; and healthy children are inherently physically active. Parents identified their goals as feeding children so they would be healthy and happy, helping them be active and safe, and teaching them to cook traditional foods to be self-sufficient and maintain their cultural identity. Parents were challenged by children's unhealthy food and sedentary preferences, their own uncertainties about healthy foods and behaviours, and structural factors. Parents thought interventions could help them with these challenges, including information about healthy foods, age-appropriate portion sizes, safe places to be active and strategies tailored to their cultural norms. CONCLUSIONS: SLM parents are trying to raise healthy-weight children based on their understanding of children's health, weight, diet and physical activity, while dealing with social, economic and environmental challenges and trying to maintain cultural identity and traditions. PMID- 28803598 TI - Adapting the standardised computer- and interview-based 24 h dietary recall method (GloboDiet) for dietary monitoring in Latin America. AB - OBJECTIVE: The present study describes the procedure and approaches needed to adapt and harmonise the GloboDiet methodology, a computer- and interview-based 24 h dietary recall, for use in two Latin American pilot countries, Brazil and Mexico. DESIGN: About seventy common and country-specific databases on foods, recipes, dietary supplements, quantification methods and coefficients were customised and translated following standardised guidelines, starting from existing Spanish and Portuguese versions. SETTING: Brazil and Mexico. SUBJECTS: Not applicable. RESULTS: New subgroups were added into the existing common food classification together with new descriptors required to better classify and describe specific Brazilian and Mexican foods. Quantification methods were critically evaluated and adapted considering types and quantities of food consumed in these two countries, using data available from previous surveys. Furthermore, the photos to be used for quantification purposes were identified for compilation in country-specific but standardised picture booklets. CONCLUSIONS: The completion of the customisation of the GloboDiet Latin America versions in these two pilot countries provides new insights into the adaptability of this dietary international tool to the Latin American context. The ultimate purpose is to enable dietary intake comparisons within and between Latin American countries, support building capacities and foster regional and international collaborations. The development of the GloboDiet methodology could represent a major benefit for Latin America in terms of standardised dietary methodologies for multiple surveillance, research and prevention purposes. PMID- 28803599 TI - Invited review: resource allocation mismatch as pathway to disproportionate growth in farm animals - prerequisite for a disturbed health. AB - The availability of resources including energy, nutrients and (developmental) time has a crucial impact on productivity of farm animals. Availability of energy and nutrients depends on voluntary feed intake and intestinal digestive and absorptive capacity at optimal feeding conditions. Availability of time is provided by the management in animal production. According to the resource allocation theory, resources have to be allocated between maintenance, ontogenic growth, production and reproduction during lifetime. Priorities for these processes are mainly determined by the genetic background, the rearing system and the feeding regimen. Aim of this review was to re-discuss the impact of a proper resource allocation for a long and healthy life span in farm animals. Using the barrel model of resource allocation, resource fluxes were explained and were implemented to specific productive life conditions of different farm animal species, dairy cows, sows and poultry. Hypothetically, resource allocation mismatch neglecting maintenance is a central process, which might be associated with morphological constraints of extracellular matrix components; evidence for that was found in the literature. A potential consequence of this limitation is a phenomenon called disproportionate growth, which counteracts the genetically determined scaling rules for body and organ proportions and could have a strong impact on farm animal health and production. PMID- 28803600 TI - Development and Validation of a Stability-Indicating HPLC Method for Imidapril and Its Degradation Products Using a Design of Experiment (DoE) Approach. AB - The present work focused on the application of design of experiment (DoE) principles to the development and optimization of a stability-indicating method (SIM) for the drug imidapril hydrochloride and its degradation products (DPs). The resolution of peaks for the DPs and their drug in a SIM can be influenced by many factors. The factors studied here were pH, gradient time, organic modifier, flow rate, molar concentration of the buffer, and wavelength, with the aid of a Plackett-Burman design. Results from the Plackett-Burman study conspicuously showed influence of two factors, pH and gradient time, on the analyzed response, particularly, the resolution of the closely eluting DPs (DP-5 and DP-6) and the retention time of the last peak. Optimization of the multiresponse processes was achieved through Derringer's desirability function with the assistance of a full factorial design. Separation was achieved using a C18 Phenomenex Luna column (250 * 4.6 mm id, 5 um particle size) at a flow rate of 0.8 mL/min at 210 nm. The optimized mobile phase composition was ammonium-acetate buffer (pH 5) in pump A and acetonitrile-methanol (in equal ratio) in pump B with a run time of 40 min using a gradient method. PMID- 28803609 TI - CoMIC, the hidden dynamics of mitochondrial inner compartments. AB - Mitochondria have evolutionarily, functionally and structurally distinct outer- (OMM) and inner-membranes (IMM). Thus, mitochondrial morphology is controlled by independent but coordinated activity of fission and fusion of the OMM and IMM. Constriction and division of the OMM are mediated by endocytosis-like machineries, which include dynamin-related protein 1 with additional cytosolic vesicle scissoring machineries such as actin filament and Dynamin 2. However, structural alteration of the IMM during mitochondrial division has been poorly understood. Recently, we found that the IMM and the inner compartments undergo transient and reversible constriction prior to the OMM division, which we termed CoMIC, Constriction of Mitochondrial Inner Compartment. In this short review, we further discuss the evolutionary perspective and the regulatory mechanism of CoMIC during mitochondrial division. [BMB Reports 2017; 50(12): 597-598]. PMID- 28803608 TI - Identification of simvastatin-regulated targets associated with JNK activation in DU145 human prostate cancer cell death signaling. AB - The results of this study show that c-Jun N-terminal kinase (JNK) activation was associated with the enhancement of docetaxel-induced cytotoxicity by simvastatin in DU145 human prostate cancer cells. To better understand the basic molecular mechanisms, we investigated simvastatin-regulated targets during simvastatin induced cell death in DU145 cells using two-dimensional (2D) proteomic analysis. Thus, vimentin, Ras-related protein Rab-1B (RAB1B), cytoplasmic hydroxymethylglutaryl-CoA synthase (cHMGCS), thioredoxin domain-containing protein 5 (TXNDC5), heterogeneous nuclear ribonucleoprotein K (hnRNP K), N-myc downstream-regulated gene 1 (NDRG1), and isopentenyl-diphosphate Delta-isomerase 1 (IDI1) protein spots were identified as simvastatin-regulated targets involved in DU145 cell death signaling pathways. Moreover, the JNK inhibitor SP600125 significantly inhibited the upregulation of NDRG1 and IDI protein levels by combination treatment of docetaxel and simvastatin. These results suggest that NDRG1 and IDI could at least play an important role in DU145 cell death signaling as simvastatinregulated targets associated with JNK activation. [BMB Reports 2017; 50(9): 466-471]. PMID- 28803611 TI - A cross-sectional analysis of local government health and wellbeing plans and priorities in Victoria, Australia. AB - The aim of this study is to explore local health and wellbeing plans and priorities by Victorian local governments (LGs), specifically to: (1) analyse how LG priority areas are described in comparison to the State-level plan; (2) identify differences between regional and metropolitan health priorities; and (3) identify differences between LGs with high and low socioeconomic status. Content analysis of 79 LG health and wellbeing plans was undertaken. Differences in health and wellbeing priorities between LGs were examined using the t-test for two proportions. In total, 20% of the plans did not specify actions to address health priorities. One in three (34%) did not specify how evaluation will be done. Alcohol and other drugs, gambling and housing were prioritised more by metropolitan LGs, whereas disease prevention was prioritised more in regional LGs. There was no significant difference in health and wellbeing priorities of LGs with high and low socioeconomic status except for gambling. State-level health and wellbeing plans should be sensitive to differences in priorities of LGs. There is a need for local plans to commit to specific actions and evaluation. This analysis provides basis for more community-reflective, State level planning and calls for more emphasis on identifying actions and evaluation in local level planning. PMID- 28803610 TI - Two distinct nodes of translational inhibition in the Integrated Stress Response. AB - The Integrated Stress Response (ISR) refers to a signaling pathway initiated by stress-activated eIF2alpha kinases. Once activated, the pathway causes attenuation of global mRNA translation while also paradoxically inducing stress response gene expression. A detailed analysis of this pathway has helped us better understand how stressed cells coordinate gene expression at translational and transcriptional levels. The translational attenuation associated with this pathway has been largely attributed to the phosphorylation of the translational initiation factor eIF2alpha. However, independent studies are now pointing to a second translational regulation step involving a downstream ISR target, 4E-BP, in the inhibition of eIF4E and specifically cap-dependent translation. The activation of 4E-BP is consistent with previous reports implicating the roles of 4E-BP resistant, Internal Ribosome Entry Site (IRES) dependent translation in ISR active cells. In this review, we provide an overview of the translation inhibition mechanisms engaged by the ISR and how they impact the translation of stress response genes. [BMB Reports 2017; 50(11): 539-545]. PMID- 28803612 TI - New strategies to improve the health of Chinese people by 2030. AB - In October 2016, the leadership team of the Communist Party of China (CPC) adopted a plan aiming to build a healthy China over the next 15 years. The strategic tasks, mainly focused on promoting healthy lifestyles, optimising health services, improving health protection, building a healthy environment and developing the health industry, were proposed to deal with the health problems faced by China. According to the plan, China's health plan is likely to undergo a major change. PMID- 28803613 TI - First sonographic description of idiopathic Cutaneous Angiosarcoma of the Head and Neck. PMID- 28803614 TI - Pustular Secondary Cutaneous Aspergillosis in an Immunosuppressed Patient. PMID- 28803615 TI - Spanish Cultural Adaptation of the Questionnaire Early Arthritis for Psoriatic Patients. AB - INTRODUCTION AND OBJECTIVES: The Early Arthritis for Psoriatic patients (EARP) questionnaire is a screening tool for psoriatic arthritis. The original Italian version has good measurement properties but the EARP required translation and adaptation for use in Spain. This article describes the cultural adaptation process as a step prior to validation. MATERIAL AND METHODS: We used the principles of good practice for the cross-cultural adaptation of patient-reported outcomes measurement established by the International Society Pharmacoeconomics and Outcome Research. The steps in this process were preparation, forward translation, reconciliation, back-translation and review, harmonization, cognitive debriefing and review, and proofreading. During preparation the developers of the original questionnaire were asked for their permission to adapt the EARP for use in Spain and to act as consultants during the process. RESULTS: The original questionnaire was translated into Spanish by native Spanish translators, who made slight changes that were approved by the questionnaire's developers. The Spanish version was then back-translated into Italian; that version was reviewed to confirm equivalence with the original Italian text. The reconciled Spanish EARP was then tested for comprehensibility and interpretation in a group of 35 patients. All the patients answered all items without making additional comments. CONCLUSION: This cultural adaptation of the EARP questionnaire for Spanish populations is the first step towards its later use in routine clinical practice. The application of a cross-cultural adaptation method ensured equivalence between the original and Spanish versions of the EARP. The Spanish questionnaire will be validated in a second stage. PMID- 28803616 TI - Unfounded dumbfounding: How harm and purity undermine evidence for moral dumbfounding. AB - Two paradigm-shifting ideas have gained widespread influence in current accounts of moral cognition: (a) that moral judgments are pluralistic, extending beyond domains of harm and fairness, and (b) that people's judgments are driven primarily by intuition, such that people are "morally dumbfounded" about the reasons behind their own judgments. An ongoing debate has emerged regarding the former claim of moral pluralism, with opposing sides in disagreement about whether moral judgments are best understood as reflecting multiple moral domains vs. a single moral domain. The current analysis demonstrates that however this debate concerning pluralism is resolved, evidence of moral dumbfounding is undermined. This evidentiary basis for intuitive moral judgment is therefore not well supported, and additional evidence indicates that moral judgments are more reasoned and malleable than the dumbfounding account would allow. PMID- 28803617 TI - Is there increasing difficulty in managing patients hospitalized in medical services? PMID- 28803618 TI - Letter to the Editor. PMID- 28803619 TI - Basis and ECG measurement of global ventricular repolarization. AB - Ventricular repolarization and its manifestation in the T wave of the electrocardiogram have long been a focus of clinical and experimental electrocardiology. In this short article, we shall review the basics of cellular and organ repolarization electrophysiology, the classical and emerging methods of measuring global repolarization, and methodology that relates directly measured cardiac indices of repolarization to the body surface electrocardiogram. PMID- 28803620 TI - Language Growth in English Monolingual and Spanish-English Bilingual Children from 2.5 to 5 Years. AB - OBJECTIVE: To describe the trajectories of English and Spanish language growth in typically developing children from bilingual homes and compare those with the trajectories of English growth in children from monolingual homes, to assess effects of dual language exposure on language growth in typically developing children. STUDY DESIGN: Expressive vocabularies were assessed at 6-month intervals from age 30 to 60 months, in English for monolinguals and English and Spanish for bilinguals. Use of English and Spanish in the home was assessed via parental report. RESULTS: Multilevel modeling, including parent education as a covariate, revealed that children from bilingual homes lagged 6 months to 1 year behind monolingual children in English vocabulary growth. The size of the lag was related to the relative amount of English use in the home, but the relation was not linear. Increments in English use conferred the greatest benefit most among homes with already high levels of English use. These homes also were likely to have 1 parent who was a native English speaker. Bilingual children showed stronger growth in English than in Spanish. CONCLUSIONS: Bilingual children can lag 6 months to 1 year behind monolingual children in normal English language development. Such lags may not necessarily signify clinically relevant delay if parents report that children also have skills in the home language. Shorter lags are associated with 2 correlated factors: more English exposure and more exposure from native English speakers. Early exposure to Spanish in the home does not guarantee acquisition of Spanish. PMID- 28803621 TI - Blunt cervical spine injury in adult polytrauma: incidence, injury patterns and predictors of significant ligament injury on CT. AB - AIM: To describe the pattern of cervical spine fractures in adult major trauma and identify computed tomography (CT) parameters that can predict significant ligament injury when fractures are absent; to define the normal range for parameters used; and identify common variations due to position of cervical immobilisation in a trauma patient. MATERIALS AND METHODS: In this retrospective study all polytrauma patients imaged using multidetector CT over a period of 5 years were identified. Patients with cervical spine fracture and suspected ligament injury in the absence of fracture were collated based on the polytrauma CT report. Predictors of ligament injury were defined based on published historical data on plain radiographs and posterior paraspinal fat pad assessment at CT. These parameters were recorded for each study with comparison to subsequent magnetic resonance imaging (MRI) as the reference standard. RESULTS: Significant ligament injury on MRI was detected at the craniocervical junction, when CT showed a basion dens interval of >10 mm, widened incongruous C0/C1 facet joint space of >3 mm, and widened C1/2 facet joint space of >6 mm. In the subaxial cervical spine, facet subluxation >50% and obscured posterior paraspinal fat pad were the only reliable predictors of ligament injury, as confirmed on subsequent MRI. CONCLUSION: When fractures are absent, signs of significant ligament injury on CT at the craniocervical junction were increased basion dens interval and widened facet joints. In the subaxial cervical spine, >50% subluxation of a facet joint and obscured posterior paraspinal fat pad are indicators of significant ligament injury. PMID- 28803622 TI - Effect of hyoscine butylbromide on prostate multiparametric MRI anatomical and functional image quality. AB - AIM: To evaluate the effect of the spasmolytic agent hyoscine butylbromide (HBB) on the quality of anatomical and functional imaging of the prostate. MATERIALS AND METHODS: One hundred and seventy-three patients were included in this retrospective study. Eighty-seven patients received intravenous HBB prior to scanning (HBB group) and 86 patients did not (non-HBB group). Multiparametric (mp) 3 T magnetic resonance imaging (MRI) was performed using a 32-channel body coil. Two radiologists independently evaluated the image quality of T2-weighted imaging (WI), diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps, using a five-point Likert scale. DWI was further assessed for distortion and artefact (four-point Likert scale), and T2WI for the presence of motion artefact or blurring. Dynamic contrast-enhanced (DCE) image quality was assessed by recording the number of corrupt contrast curve data points. RESULTS: T2W image quality in the HBB group was significantly higher than in the non-HBB group (3.63+/-1.11 versus 2.84+/-0.899); p<0.001. The HBB group also showed significantly less T2W motion and T2W blur than the non-HBB group (23% and 51.7% versus 53.5% and 83.7%, respectively; p<0.001); however, there was no significant improvement in DWI or ADC image quality, or DWI degree of distortion or artefact. There was a trend towards a lower number of corrupted data points from the contrast curve (2.47+/-2.44 versus 3.68+/-2.64), but this did not reach significance (p=0.052). CONCLUSION: Administration of HBB significantly improves the image quality of T2WI images. These results provide evidence for the use of HBB in routine patient preparation prior to prostate mpMRI. PMID- 28803623 TI - Inferno-the causes of the causes. PMID- 28803624 TI - The quality of primary care provided by nurse practitioners to vulnerable Medicare beneficiaries. AB - BACKGROUND: Studies suggest nurse practitioners are heavily represented among primary care providers for vulnerable Medicare beneficiaries. PURPOSE: The purpose of this study was to compare quality indicators among three groups of vulnerable beneficiaries managed by MDs and nurse practitioners (NPs). METHODS: The methods include retrospective cohort design examining 2012 and 2013 Medicare claims for three beneficiary groups: (a) initially qualified for the program due to disability, (b) dually eligible for Medicare and Medicaid, and (c) both disabled and dually eligible. Validated quality indicators in four domains were analyzed. DISCUSSION: Gaps in outcomes suggest better performance for primary care nurse practitioners (PCNPs) in preventable hospitalizations and adverse outcomes. Outcome gaps suggesting better performance for primary care physicians in chronic disease management were diminished for beneficiaries who were both disabled and dually eligible suggesting improved performance for PCNPs within this subpopulation. CONCLUSION: These findings add new evidence indicating the quality of primary care provided to vulnerable Medicare beneficiaries by PCNPs is generally consistent with clinical guidelines and the less intensive use of costly health care services. PMID- 28803625 TI - Modified reduced order observer based linear active disturbance rejection control for TITO systems. AB - This paper proposes an observer based control approach for two input and two output (TITO) plant affected by the lumped disturbance which includes the undesirable effect of cross couplings, parametric uncertainties, and external disturbances. A modified reduced order extended state observer (ESO) based active disturbance rejection control (ADRC) is designed to estimate the lumped disturbance actively as an extended state and compensate its effect by adding it to the control. The decoupled mechanism has been used to determine the controller parameters, while the proposed control technique is applied to the TITO coupled plant without using decoupler to show its efficacy. Simulation results show that the proposed design is efficiently able to nullify the interactions within the loops in the multivariable process with better transient performance as compared to the existing proportional-integral-derivative (PID) control methods. An experimental application of two tanks multivariable level control system is investigated to present the validity of proposed scheme. PMID- 28803627 TI - Bubble-bubble interactions in a 2d foam, close to the wet limit. AB - Following the general approach of Morse and Witten for the deformation of a bubble in contact with neighbouring bubbles, we develop a model for contacting bubbles in two dimensions which can be solved analytically. The force displacement relations are derived by elementary methods; unlike the case of 3d, no logarithmic factors arise in two dimensions. We also discuss the case of a uniform compression of a symmetric foam structure; the (osmotic) compressibility depends on the number of contacts, as was shown in earlier work by Lacasse et al. Our model, which is based on first principles, without any free parameters, may be extended to simulate 2d foams. PMID- 28803628 TI - Dominique Langevin Festschrift: Four decades opening gates in Colloid and Interface Science. PMID- 28803626 TI - Putting the Piezolyte Hypothesis under Pressure. AB - A group of small molecules that stabilize proteins against high hydrostatic pressure has been classified as piezolytes, a subset of stabilizing cosolutes. This distinction would imply that piezolytes counteract the effects of high hydrostatic pressure through effects on the volumetric properties of the protein. The purpose of this study was to determine if cosolutes proposed to be piezolytes have an effect on the volumetric properties of proteins through direct experimental measurements of volume changes upon unfolding of model proteins lysozyme and ribonuclease A, in solutions containing varying cosolute concentrations. Solutions containing the proposed piezolytes glutamate, sarcosine, and betaine were used, as well as solutions containing the denaturants guanidinium hydrochloride and urea. Changes in thermostability were monitored using differential scanning calorimetry whereas changes in volume were monitored using pressure perturbation calorimetry. Our findings indicate that increasing stabilizing cosolute concentration increases the stability and transition temperature of the protein, but does not change the temperature dependence of volume changes upon unfolding. The results suggest that the pressure stability of a protein in solution is not directly affected by the presence of these proposed piezolytes, and so they cannot be granted this distinction. PMID- 28803629 TI - Reply. PMID- 28803630 TI - Evaluation of the training capacity of the Spanish Resident Book of Otolaryngology (FORMIR) as an electronic portfolio. AB - BACKGROUND: and objectives We have evaluated the training capacity of the Spanish resident training book as an electronic portfolio to achieve the learning objectives of otorhinolaryngology (ENT) residents. METHODS: A multi-method qualitative investigation with transversal characteristics, temporal and retrospective guidance was performed on Spanish ENT residents using a structured questionnaire, a semi-structured interview, and a computer application on the FORMIR website. RESULTS: A 56.5% of ENT-residents specialising in one of the 63 accredited Spanish hospitals between 2009-2012 participated in the study. The results obtained show that the ENT residents who used the e-portfolio were better able to implement self-guided study, were more aware of their learning objectives, fulfilled the training programme more efficiently, identified the causes of learning gaps more clearly, and considered FORMIR in e-portfolio format to be an ideal training tool to replace the resident training book in paper format. CONCLUSIONS: The ENT residents greatly appreciated the training benefits of FORMIR as an e-portfolio, especially its simple and intuitive interface, the ease and comfort with which they could record their activities, the automatic and numeric feedback on the acquisition of their competencies (which facilitates self guided learning), its storage capacity for evidence, and its ability to be used as UEMS logbook as well as a standard curriculum vitae. All these features make FORMIR a training and evaluation tool that outperforms similar instruments available to ENT residents. They do not hesitate to identify it as the ideal resident training book for facilitating their specialised training. PMID- 28803631 TI - Primary tuberculosis of the nasal septum: The non-ulcerated form presenting as septal thickening. PMID- 28803632 TI - Carotid canal bone erosion. Gradenigo's syndrome. PMID- 28803633 TI - Subglottis inflammatory pseudotumour in a 3-year-old child. PMID- 28803634 TI - Arteria lusoria: A rare cause of tracheal compression. PMID- 28803636 TI - On the association between human papillomavirus vaccine and sleep disorders: Evaluation based on vaccine adverse events reporting systems. PMID- 28803635 TI - Varicoceles in the pediatric and adolescent population: threat to future fertility? AB - Determining the effect of varicoceles on future fertility is challenging owing to multiple issues in children/adolescents, including: limitations in obtaining and interpreting semen analyses; potential for unequal differential testicular growth during puberty regardless of varicocele presence; and the potential for a lengthy interval between surgical intervention for varicocele in adolescence and attempts at paternity. This review presents a summary and evaluation of the available evidence relating to future fertility among children and adolescents with varicoceles. Data relating to proxy fertility measures in children/adolescents, including testicular size asymmetry and semen analysis abnormalities, demonstrate that these proxy measures are imperfect predictors of future fertility. Two large, recently published series of adolescents undergoing varicocele treatment showed conflicting paternity outcomes. Pediatric and adolescent varicocele will remain a clinical conundrum, subject to both over- and under-treatment, until more definitive prospective data are available. PMID- 28803637 TI - Building an evidence base on shaky ground: Examination of data, statistics and references of a vaccine critical paper. PMID- 28803638 TI - Impact of Obesity on Intensive Care Unit Resource Utilization After Cardiac Operations. AB - BACKGROUND: Much has been published about the effect of obesity on adverse outcomes after cardiac operations, yet little is known regarding the effect of obesity on intensive care unit (ICU) resource utilization. This study examined the effect of obesity on ICU resource utilization after cardiac operations. METHODS: All patients with a body mass index (BMI) of 18.5 kg/m2 or higher who underwent a cardiac surgical procedure between 2006 and 2013 were stratified into the following weight categories: normal (BMI 18.5 to 24.99 kg/m2), preobese (BMI 25 to 29.99 kg/m2), obese class I (BMI 30 to 34.99 kg/m2), obese class II (BMI 35 to 39.99 kg/m2), and obese class III (BMI >=40 kg/m2). Comparisons between weight categories were done, and the risk-adjusted effect of weight category on prolonged ICU stay, prolonged ventilation, and ICU readmission was determined. RESULTS: Of the 5,365 included patients, 1,948 were obese. Patients with greater obesity experienced longer ICU time, longer ventilation time, and increased ICU readmission. After adjustment, increasing obesity remained independently associated with greater likelihood of prolonged ICU stay (obese class II: odds ratio [OR], 2.4; 95% confidence interval [CI], 1.55 to 3.61; obese class III: OR, 4.1; 95% CI, 2.38 to 7.05), prolonged ventilation (obese class III: OR, 3.4; 95% CI, 1.57 to 7.22), and ICU readmission (obese class II: OR, 3.0; 95% CI, 1.70 to 5.31; obese class III: OR, 2.9; 95% CI, 1.32 to 6.36). CONCLUSIONS: Increasing obesity was associated with a significant increase in ICU resource utilization after cardiac operations. Further study is needed to determine the mechanisms underlying this association and how the adverse effects of obesity may be mitigated. PMID- 28803639 TI - Atrial fibrillation and stroke as initial manifestations of painless type A aortic dissection. AB - Aortic dissection is diagnostically challenging, especially in pain-free patients. Detection of acute ischemic stroke secondary to painless aortic dissection is a challenge for emergency physicians and neurologists. We report a previously healthy 58-years old female, admitted because of nausea, dizziness, somnolence, a left-sided hemiparesis and arterial hypotension. The electrocardiogram showed atrial fibrillation with ST-elevations and ST depressions. Perfusion CT-imaging showed a dilatation of the aortic arch and intraluminal structures indicating an intima flap of aortic dissection. Four hours after onset of symptoms the patient died on the way to the cardiac surgery. In conclusion, apart from imaging the aortic arch by computed tomography in acute stroke patients, the electrocardiogram may be indicative for aortic dissection if it shows signs for myocardial ischemia in previously healthy patients. PMID- 28803640 TI - Optic neuritis in a patient with celiac disease. PMID- 28803641 TI - The assessment of risk factors for febrile seizures in children. AB - OBJECTIVE: The aim of the paper was to assess the risk factors of febrile seizures in children. METHODS: The paper presents an analysis of a group of 176 children aged 6 months to 5 years who were admitted to A&E because of febrile seizures. RESULTS: The analysed group of 176 children comprised 61.96% boys and 38.07% girls, and the average age equalled 23 months. Family history was significant in 9.66% of patients. A statistically significant difference was noticed between insignificant family history and the incidence of febrile seizures. In all the studied groups of children the factor that determined the incidence of febrile seizures was a sudden increase in the body temperature with an infection of the upper respiratory tract of several day's duration as another cause. Febrile seizure incident was most frequently associated with a sudden increase in the body temperature in 53.40% children. A statistically significant difference was observed between persisting fever and an increase thereof during the day. Yet another factor predisposing for febrile seizures incidence was an infection of the upper respiratory system that could be observed in 32.95% patients. The mean body temperature when the seizures occurred was 38.9 degrees C. CONCLUSIONS: A sudden increase in the body temperature within the first day of pyrexia predisposes for the incidence of febrile seizures and it was proved that it depends on how long fever persists during the day. The other factor triggering the seizures was an infection of the upper respiratory tract of several days' duration. PMID- 28803642 TI - [Genomic tests in early breast cancer management: Real-life experience]. PMID- 28803644 TI - Surgical experience and the practice of pancreatoduodenectomy. AB - BACKGROUND: Experienced surgeons demonstrate improved pancreatoduodenectomy outcomes, but little is known about what distinguishes their practice. Furthermore, the concept of experience has been variably interpreted in the surgical literature. We investigated how 4 interpretations of experience influence pancreatoduodenectomy management decisions. METHODS: A survey assessing pancreatoduodenectomy practice patterns was distributed by 6 surgical societies. Regression analysis identified behaviors associated with 4 forms of experience: years in practice, surpassing the learning curve (>=50 pancreatoduodenectomies), high annual volume (>=25 pancreatoduodenectomy/year), and high career volume (>200 pancreatoduodenectomy). RESULTS: In the study, 861 surgeons responded, representing 6 continents. Senior surgeons were more likely to use pancreatogastrostomy, dunking/invagination, and external stents (all P < .05). Sixty-five percent of respondents surpassed the learning curve, and these surgeons were more likely to use a 2-layer pancreatic enteric anastomosis, stents, and the Fistula Risk Score (all P < .05). High annual volume surgeons were more likely to use the same reconstruction on every case and autologous tissue patches but less likely to use the Roux limb technique and multiple drains (all P < .05). High career volume surgeons mirrored the behaviors of those surpassing the learning curve except for using the Fistula Risk Score. CONCLUSION: Experience encompasses several components, each of which seems to influence decision making in different ways. PMID- 28803643 TI - Effect of surgeon "experience" with laparoscopy on postoperative outcomes after colorectal surgery. AB - BACKGROUND: Although the relationship between laparoscopic surgery and improved clinical outcomes has been well established across a variety of procedures, the effect of operative experience with laparoscopic surgery remains less defined. The present study sought to assess the comparative benefit of laparoscopic colorectal surgery relative to surgeon volume. METHODS: Commercially insured patients aged 18 to 64 years undergoing a colorectal resection were identified using the MarketScan Database from 2010-2014. Multivariable logistic regression analysis was used to calculate and compare postoperative mortality/morbidity by operative approach relative to surgeon volume. RESULTS: A total of 21,827 patients were identified who met inclusion criteria. The median age among patients was 53 years (interquartile range: 46-59) with a slight majority of patients being female (n = 11,248, 51.5%). Laparoscopic operations were performed in 49.2% of patients (n = 10,756), whereas 50.7% (n = 11,071) underwent an open colorectal resection. On multivariable analysis, laparoscopic surgery was associated with 64% decreased odds of developing a postoperative complication or mortality (odds ratio = 0.36, 95% confidence interval, 0.32-0.41, P < .001). Patients who underwent colectomy performed by a higher operative volume surgeon (high versus low: odds ratio = 0.68, 95% confidence interval, 0.61-0.77, P < .001) demonstrated decreased odds of developing a postoperative complication/mortality. Interestingly the potential decrease in risk-adjusted morbidity/mortality between laparoscopic and open surgery was somewhat greater among high-operative-volume surgeons (odds ratio = 0.29, 95% confidence interval, 0.25-0.34, P < .001) and intermediate-operative-volume surgeons (odds ratio = 0.30, 95% confidence interval, 0.25-0.36, P < .001) compared with low-operative volume surgeons (odds ratio = 0.36, 95% confidence interval, 0.32-0.41, P < .001). CONCLUSION: Although laparoscopic surgery was associated with improved postoperative clinical outcomes, the effect of laparoscopic surgery varied somewhat according to surgeon volume. PMID- 28803645 TI - Liquid chromatography - quadrupole Orbitrap mass spectrometry method for selected pharmaceuticals in water samples. AB - This study developed an analytical approach for sub-ppb level detection and confirmation of 13 pharmaceuticals and personal care products (PPCPs) in water samples using ultra high pressure liquid chromatography hyphenated with a quadrupole Orbitrap mass spectrometer (UHPLC- Q-Orbitrap-MS). Sample preparation was performed by using solid phase extraction (SPE) employing hydrophilic lipophilic balance cartridges, with elution of sorbed analytes using methanol. Acceptable automatic gain control (AGC) target and maximum injection time (IT) were 1*106 and 200ms, respectively, resulting in a mass accuracy <2ppm. High response signals with sufficient data points per peaks (20-30) were obtained whilst maintaining high resolution of approximately 70,000 full width at half maximum. Extracted ion chromatograms provided quantitative analysis with linearity (R2) ranging from 0.9875 to 0.9993 and method detection limits ranging from 0.01-0.61ngmL-1. Compounds were further analysed by MS/MS analysis, with the MS operated in parallel reaction monitoring (PRM) mode under precursor ion analysis intervals and collision energies chosen for the different PPCPs. The developed method was applied to analyse water samples obtained from sources in Victoria, Australia. PMID- 28803646 TI - Effect of solvent composition on the van't Hoff enthalpic curve using amylose 3,5 dichlorophenylcarbamate-based sorbent. AB - Van't Hoff plots have been widely used for investigating the thermodynamic properties of adsorption processes in various chromatography systems. By measuring the retention factor k over a certain temperature range, the plot of ln k versus 1/T often yields a straight line with a slope of -DeltaHvH0/R. Although this method provides information on adsorption enthalpy changes, its theoretical basis does not account for the effect of the solvent. In this paper, the relationship between apparent enthalpy changes determined directly from van't Hoff plots and solvent modifier concentrations is systematically investigated using three simple solutes-tetrahydrofuran, acetone, and tert-butanol-in an n hexane-methyl tert-butyl ether (MTBE) mobile phase with an amylose 3,5 dichlorophenylcarbamate-based sorbent. The apparent enthalpy changes of solutes are strongly dependent on MTBE concentration, increasing rapidly with MTBE content at low concentrations but leveling off after DeltaH0 reaches approximately -15kJ/mol. These data cannot be explained by the thermodynamic model currently used in the literature. A new three-equilibrium-constant thermodynamic model is developed herein to account for solute-sorbent, solvent sorbent, and solute-solvent interactions. The thermodynamic parameters of the model are estimated from the apparent enthalpy changes at different MTBE concentrations. The results reveal that two key dimensionless groups control the van't Hoff enthalpic curves: the fractions of solute molecules bound to modifier molecules and adsorption sites occupied by modifier molecules. As a result, the shapes of van't Hoff enthalpic curves reflect the adsorption isotherm of MTBE without complexation or information regarding solute-MTBE complexation without MTBE competitive adsorption. The new model is thus demonstrated to be more reliable than the current model for examining the thermodynamic properties of retention mechanisms. PMID- 28803647 TI - Determination of selected endogenous anabolic androgenic steroids and ratios in urine by ultra high performance liquid chromatography tandem mass spectrometry and isotope pattern deconvolution. AB - An isotope dilution mass spectrometry (IDMS) method for the determination of selected endogenous anabolic androgenic steroids (EAAS) in urine by UHPLC-MS/MS has been developed using the isotope pattern deconvolution (IPD) mathematical tool. The method has been successfully validated for testosterone, epitestosterone, androsterone and etiocholanolone, employing their respective deuterated analogs using two certified reference materials (CRM). Accuracy was evaluated as recovery of the certified values and ranged from 75% to 108%. Precision was assessed in intraday (n=5) and interday (n=4) experiments, with RSDs below 5% and 10% respectively. The method was also found suitable for real urine samples, with limits of detection (LOD) and quantification (LOQ) below the normal urinary levels. The developed method meets the requirements established by the World Anti-Doping Agency for the selected steroids for Athlete Biological Passport (ABP) measurements, except in the case of androsterone, which is currently under study. PMID- 28803648 TI - Automated multi-filtration cleanup with nitrogen-enriched activated carbon material as pesticide multi-residue analysis method in representative crop commodities. AB - An automated multi-filtration cleanup (Auto m-FC) method with nitrogen-enriched activated carbon material based on modified QuEChERS (quick, easy, cheap, effective, rugged, and safe) extracts was developed. It was applied to pesticide multi-residue analysis in six representative crop commodities. The automatic device was aimed to improve the cleanup efficiency and reduce manual operation workload in cleanup step. By controlling extracts volume, flow rate and Auto m-FC cycles, the device could finish cleanup process accurately. In this work, nitrogen-enriched activated carbon mixed with alternative sorbents and anhydrous magnesium sulfate (MgSO4) was packed in a column for Auto m-FC and followed by liquid chromatography with tandem mass spectrometric (LC-MS/MS) detection. This newly developed carbon material showed excellent cleanup performance. It was validated by analyzing 23 pesticides in six representative matrices spiked at two concentration levels of 10 and 100MUg/kg. Water addition volume, salts, sorbents, Auto m-FC procedure including the flow rate and the Auto m-FC cycles for each matrix were optimized. Then, three general Auto m-FC methods were introduced to high water content, high oil and starch content, difficult commodities. Spike recoveries were within 82 and 106% and 1-14% RSD for all analytes in the tested matrices. Matrix-matched calibrations were performed with the coefficients of determination over 0.997 between concentration levels of 10 and 1000MUg/kg. The developed method was successfully applied to the determination of pesticide residues in market samples. PMID- 28803649 TI - Root cause investigation of deviations in protein chromatography based on mechanistic models and artificial neural networks. AB - In protein chromatography, process variations, such as aging of column or process errors, can result in deviations of the product and impurity levels. Consequently, the process performance described by purity, yield, or production rate may decrease. Based on visual inspection of the UV signal, it is hard to identify the source of the error and almost unfeasible to determine the quantity of deviation. The problem becomes even more pronounced, if multiple root causes of the deviation are interconnected and lead to an observable deviation. In the presented work, a novel method based on the combination of mechanistic chromatography models and the artificial neural networks is suggested to solve this problem. In a case study using a model protein mixture, the determination of deviations in column capacity and elution gradient length was shown. Maximal errors of 1.5% and 4.90% for the prediction of deviation in column capacity and elution gradient length respectively demonstrated the capability of this method for root cause investigation. PMID- 28803650 TI - Lipid determination in bone marrow and mineralized bone tissue: From sample preparation to improved high-performance thin-layer and liquid chromatographic approaches. AB - In view of their key roles in the bone physiology (e.g., in the biomineralization process) and their potential implication in bone pathologies, an approach to study lipids in situ is needed. The aim of the present paper is to propose an original procedure to characterize lipids in both bone marrow (BM) and mineralized tissue (MT) compartments, taking into consideration sample preparation, lipid extraction and analytical issues, when using small sample size (<= 0.5g of rat femurs). The potential contamination of the MT by marrow lipids and the poor accessibility of certain lipids from the MT - two major issues in bone handling - were taking care, respectively by performing two cleaning steps after BM removal and by adding a demineralization step to the overall lipid extraction protocol. For lipid analyses, a multi-one-dimensional HP-TLC method was developed to analyze the major neutral and polar lipids at once and showed an excellent resolution (for 15 standards) and a good precision (inter-day RSD<13%). When subjected to the entire "lipid extraction-HP-TLC" protocol, spike recoveries of the standards ranged between 76 and 122%. This HP-TLC method was suitable for lipid determination in both BM and MT [e.g., the MT had 5-times lesser lipids and a lower TG/phospholipid ratio than the BM (P <0.05)], and was quite reliable in term of lipid quantification. The demineralization step allowed to extract additional phosphatidylserine and esterified cholesterol from the MT, suggesting that these two species were associated to the mineralized matrix possibly in relation to their physiological role in the bone. Moreover, a reverse phase HPLC method for fatty acid determination as naphthacyl esters was set up to study fatty acids in bone samples and was used to validate the HP-TLC data. The fatty acid profile of the MT exhibited lower linoleic acid (18:2 n-6) and linolenic acid (18:3 n-3+n-6) levels and higher arachidonic acid (20:4 n-6) and docosahexaenoic acid (22:6 n-3) levels (P<0.05, compared to BM), suggesting that the MT is more metabolically active than the BM in term of long chain fatty acid production. In sum, the present work should contribute to facilitate future studies in the bone lipid field in view to understand better their implication in the marrow fat expansion-associated bone pathologies, such as osteoporosis. PMID- 28803651 TI - Using national hip fracture registries and audit databases to develop an international perspective. AB - Hip fracture is the commonest reason for older people to need emergency anaesthesia and surgery, and leads to prolonged dependence for many of those who survive. People with this injury are usually identified very early in their hospital care, so hip fracture is an ideal marker condition with which to audit the care offered to older people by health services around the world. We have reviewed the reports of eight national audit programmes, to examine the approach used in each, and highlight differences in case mix, management and outcomes in different countries. The national audits provide a consistent picture of typical patients - an average age of 80 years, with less than a third being men, and a third of all patients having cognitive impairment - but there was surprising variation in the type of fracture, of operation and of anaesthesia and hospital length of stay in different countries. These national audits provide a unique opportunity to compare how health care systems of different countries are responding to the same clinical challenge. This review will encourage the development and reporting of a standardised dataset to support international collaboration in healthcare audit. PMID- 28803652 TI - Long-term follow-up evaluation of autologous chondrocyte implantation for symptomatic cartilage lesions of the knee: A single-centre prospective study. AB - INTRODUCTION: Autologous Chondrocyte Implantation (ACI) has been the first technique in reconstruction of a valid articular surface. The aim of this study was to evaluate clinical results of this technique at an average follow up of 162+/-27months (range 88-208) in a group of patients who underwent ACI. MATERIALS AND METHODS: 32 patients were operated between 1997 and 2007 for chondral lesions or osteochondritis dissecans of the knee. Mean size of the defect was 5.48cm2+/ 1.53 (range 2-9). Nine patients were treated with I generation technique and 23 with II generation. All patients were evaluated with Subjective IKDC and Tegner Activity Scales for clinical outcomes and with EQ-VAS for a quantitative measure of health after intervention, starting from pre-operative period and at regular follow up (minimum 88 months-maximum 208 months). RESULTS: A significant increment of all scores was noticed comparing preoperative and postoperative results. In particular medium IKDC score increased from 40.3+/-9.6 in preoperative evaluation to 74.2+/-11.6 at one year (p<0.00001) and to 83.9+/-10.4 at 5 years follow up (p<0.001). Mean IKDC values at the last follow-up were 80.3+/-14.2, showing no statistical differences with those obtained at five-year follow-up. Tegner Activity Scale values increased from 2.8+/-1.1 preoperatively to 4.1+/-1.1 (p<0.0001) after one year and to 6+/-1.1 at five years (p<0.0001). Mean Tegner Activity Scale values decreased to 4.8+/-1.4 at the last follow-up. EQ-VAS evaluation showed superposable results comparing the 5 years evaluation with the ones at a medium follow up of 162+/-27months. DISCUSSION: The most important finding is the reliability at long-term of ACI technique, which in our series gave excellent clinical results. No statistical differences were observed between first- and second-generation. Clinical outcomes were significantly better for defects in the femoral condyles, influenced by age (worse results over 30 years old). CONCLUSIONS: ACI represents a valid technique for chondral and osteochondral lesions of the knee in a population heterogeneous for age, sex and activity level with good results even at a long term follow up. PMID- 28803653 TI - Effect of Dietary Intake of Saturated Fatty Acids on the Development of Atrial Fibrillation and the Effect of Replacement of Saturated With Monounsaturated and Polyunsaturated Fatty Acids. AB - The aim of the present study was to explore substitution of intake of saturated fatty acids (FAs) with monounsaturated and polyunsaturated FAs and incident atrial fibrillation (AF) in men and women. A total of 57,053 Danish participants aged 50 to 64 years were enrolled in the Diet, Cancer and Health cohort study in 1993 to 1997 and completed a semiquantitative food frequency questionnaire at baseline. Follow-up was registry-based and data were analyzed using Cox proportional hazards regression. The statistical model was formulated in such a way that 1 g/day of saturated FAs was replaced with 1 g/day of monounsaturated or polyunsaturated FAs while keeping total fat intake, total energy intake, and energy intake from protein and carbohydrates constant. During a median follow-up of 17 years, 5,175 incident cases of AF occurred. In men, there was a higher hazard of AF when total n-3 polyunsaturated FAs replaced dietary saturated FAs hazard ratio per 1-g substitution of FAs of 1.08 (95% confidence interval 1.02 to 1.14) in a model adjusted for lifestyle factors. For other substitutions of FAs (monounsaturated, total or n-6 polyunsaturated FAs), no consistent nor statistically significant associations were found. In conclusion, we found a moderately higher risk of AF in men, but not in women, when total n-3 polyunsaturated FAs replaced dietary saturated FAs. Substitution of saturated FAs with monounsaturated, total or n-6 polyunsaturated FAs was not associated with the risk of AF. PMID- 28803654 TI - Temporal Pattern and Prognostic Significance of Hypokalemia in Patients Undergoing Targeted Temperature Management Following Cardiac Arrest. AB - Hypokalemia has been consistently reported as a common occurrence during targeted temperature management (TTM) in comatose survivors of cardiac arrest. We sought to better describe changes in serum potassium throughout the different stages of TTM and to assess for any prognostic significance. We analyzed a prospectively collected cohort of 240 patients treated with TTM following cardiac arrest at a tertiary care hospital between 2007 and 2014. The primary outcome was poor neurologic outcome at hospital discharge, defined as a Cerebral Performance Category score >2. Secondary outcomes included death and recurrent ventricular arrhythmia before hospital discharge. Multivariable logistic regression was used to assess for association of hypokalemia and hyperkalemia with the designated outcomes. During all phases of TTM, hypokalemia and hyperkalemia occurred in 207 (86%) and 77 (32%) of patients, respectively. Hypokalemia occurred in 203 (85%) patients at target temperature, and 25 (10%) patients were hyperkalemic following normothermia. In multivariable logistic regression, hypokalemia was not associated with poor neurologic outcomes or recurrent ventricular arrhythmia. Hypokalemia was associated with reduced odds of death before hospital discharge (odds ratio = 0.36, 95% confidence interval 0.13 to 0.97, p = 0.044). Hyperkalemia was not associated with poor neurologic outcomes, death, or recurrent ventricular arrhythmia. PMID- 28803655 TI - Usefulness of PA32540 in Protecting the Gastric Layer While Providing Secondary Prevention for Coronary Artery Disease. AB - Aspirin has been the mainstay for secondary prevention of coronary artery disease to decrease early recurrence and severity of recurrent cardiovascular events. However, an increase in gastrointestinal bleeding due to aspirin is preventing many patients from adhering to this daily regimen. PA32540, a combination pill with aspirin and omeprazole, is a newly emerging intervention that has the potential to reinforce patient compliance with the aspirin regimen due to fewer gastrointestinal adverse effects. This systematic review assessed three recent phase 3 clinical trials investigating the safety and efficacy of PA32540. Clinical trials were chosen based on inclusion criteria such as phase 3, randomized, open-label or blinded studies, utilization of enteric-coated aspirin 325 mg dose, and measured GI adverse effects and major adverse cardiac events (MACE) as primary outcomes. Study A, a 6-month phase-3 study by Whellan et al., used two identically designed, randomized, double-blind trials to compare the GI adverse events and MACE after the use of PA32540 to 325mg of enteric coated Aspirin (EC-ASA) in subjects at risk for aspirin-associated gastric ulcers. Results showed fewer upper GI symptoms, decreased size of ulcers, and improved heartburn symptoms in subjects receiving PA32540 compared to EC-ASA. Study B, a 12-month phase-3 study by Hatoum et al., assessed secondary cardiovascular event prevention in a study population that was treated with PA32540 in comparison to a community setting (CS) group that was started on a standard antiplatelet treatment. Results indicated a 28% reduction of CV events in subjects treated with PA32540 compared to the CS group. Study C, a phase-3 open-label study by Goldstein et al., evaluating secondary prevention of cardiovascular/cerebrovascular events with the use of PA32450 for 12 months found that none of the 12-month completers were reported to have new-onset gastric ulcers. In conclusion, PA32540 could be an effective therapy for secondary prevention of coronary artery disease as studies are showing similar efficacy in preventing MACE with reduced GI side effects. PMID- 28803656 TI - Outcomes of Transcatheter Versus Surgical Aortic Valve Implantation for Aortic Stenosis in Patients With Hepatic Cirrhosis. AB - Current risk prediction tools for transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR) do not include variables associated with clinically significant hepatic disease. Accordingly, outcome data of TAVI or SAVR in patients with liver cirrhosis are limited. We sought to assess contemporary trends and outcomes of TAVI and SAVR in patients with liver cirrhosis using a national database. The Nationwide Inpatient Sample was used to identify patients with liver cirrhosis who underwent TAVI or SAVR between 2003 and 2014. Outcomes of propensity-matched groups of patients undergoing TAVI or SAVR were assessed. The reported number of TAVI and SAVR procedures in patients with liver cirrhosis increased from 376 cases in 2003 to 1,095 cases in 2014. A total of 1,766 patients with liver cirrhosis who underwent TAVI (n = 174) or SAVR (n = 1,592) were included in the analysis. In-hospital mortality was higher in patients who underwent SAVR versus TAVI (20.2% vs 8%, p <0.001). Major adverse events were also more frequent after SAVR. Propensity matching attained 2 groups of 268 patients who underwent TAVI (n = 134) or SAVR (n = 134). Following propensity matching, in-hospital mortality remained higher in the SAVR group (18.7% vs 8.2%, p = 0.018), but major adverse events were not different between the 2 groups. Hospital length of stay was longer, and nonhome disposition rates were higher in the SAVR group. In conclusion, the number of reported TAVI and SAVR in patients with liver cirrhosis and aortic stenosis increased 3-folds between 2003 and 2014. In these patients, TAVI was associated with lower in hospital mortality when compared with SAVR. PMID- 28803657 TI - Early extubation after cardiac surgery: The evolution continues. PMID- 28803658 TI - Myriad manifestations of myxoma. PMID- 28803659 TI - Seizing Control of KCC2: A New Therapeutic Target for Epilepsy. AB - Deficits in GABAergic inhibition result in the abnormal neuronal activation and synchronization that underlies seizures. However, the molecular mechanisms responsible for transforming a normal brain into an epileptic one remain largely unknown. Hyperpolarizing inhibition mediated by type A GABA (GABAA) receptors is dependent on chloride extrusion by the neuron-specific type 2K+-Cl- cotransporter (KCC2). Loss-of-function mutations in KCC2 are a known cause of infantile epilepsy in humans and KCC2 dysfunction is present in patients with both idiopathic and acquired epilepsy. Here we discuss the growing evidence that KCC2 dysfunction has a central role in the development and severity of the epilepsies. PMID- 28803660 TI - Multiple sclerosis: Skin-induced antigen-specific immune tolerance. AB - Multiple sclerosis (MS) is a highly prevalent demyelinating disorder, presumed to be driven by an autoimmune response toward the central nervous system (CNS) components. All currently available treatments modulate the immune system globally and besides the reduction of disease activity, they may also impose considerable disturbances on the immune protective mechanisms. Thus, induction of antigen-specific immune tolerance remains the ultimate goal of MS therapy. Such approach carries promising therapeutic perspectives and, above all, a desirable safety profile. Several studies have been performed to evaluate highly selective, antigen-induced, therapies for experimental autoimmune encephalomyelitis (EAE) and MS. These trials have also indicated the importance of the antigen administration route. The continued efforts to develop efficient and safe MS therapy gave rise to the idea of incorporating the skin immune system in order to modulate autoimmunity in MS. Skin is the largest immunological organ of human body, and thus provides ample opportunities to modify immune responses. Skin dendritic cells have a significant ability to modulate the immune reactions, promoting either immunity or tolerance. Their capacity to induce tolerance has already been described in several experimental models of MS. In a one-year, double-blinded, placebo-controlled study assessing the effectiveness of transdermal myelin peptides patches, significant changes in the morphology of Langerhans cells (LCs) and shifts in the dendritic cell (DC) populations in the draining lymph nodes have been observed. In addition, patients treated with myelin patches showed a decreased brain inflammatory activity on MRI and a reduced relapse rate. In this review, we further discuss the potential to use skin-induced immune tolerance for MS treatment, with a particular focus on dermal DCs. PMID- 28803661 TI - Daily bathing strategies and cross-transmission of multidrug-resistant organisms: Impact of chlorhexidine-impregnated wipes in a multidrug-resistant gram-negative bacteria endemic intensive care unit. AB - BACKGROUND: Health-care associated infections are a major cause of morbidity and mortality in critical care units. The aim of this study is to evaluate the effectiveness of chlorhexidine gluconate (CHG)-impregnated wipes in the daily bathing of patients in an intensive care unit (ICU) to prevent cross-transmission and colonization by multidrug-resistant organisms (MDROs) METHODS: Prospective cohort study with an intervention of 11 months. The intervention consisted of using CHG-impregnated wipes for the daily bathing of patients on mechanical ventilation or colonized by MDROs. Monthly trends in the number of patients colonized by MDROs and the incidence of nosocomial infections were evaluated. RESULTS: A total of 1,675 patients were admitted to the unit during the intervention period, and 430 (25.7%) were bathed with chlorhexidine wipes. A significant decrease was observed in the incidence of colonization by MDROs over the months (beta = -0.209; r2 = 0.549; P = .027), and in the number of patients colonized compared with the equivalent period of the previous year (22.0% vs 18.4%; P = .01). No significant decrease was observed in the incidence of nosocomial infection between the two periods (4.11% vs 4.57%; P = .355). No dermatologic problems were observed in the treated patients. CONCLUSIONS: The use of CHG-impregnated wipes reduces cross-transmission and colonization by MDROs in the ICUs in an endemic situation because of multidrug-resistant Enterobacteriaceae. PMID- 28803662 TI - Acrylic stent to aid placement of footplate of palatal distractor during surgically-assisted rapid palatal expansion. PMID- 28803663 TI - Simple method of covering maxillectomy defects with lyophilised amniotic membrane. PMID- 28803664 TI - Should patients take vitamin D before mandibular operations? AB - Vitamin D deficiency is endemic in the United Kingdom (UK), particularly in high risk groups. We report the outcomes of patients with low concentrations of the vitamin who had complications after reduction of mandibular fractures or osteotomy, and those who were screened preoperatively. A deficiency can be diagnosed with a simple and inexpensive blood test, and in the UK the cost of a vitamin D tablet is about L0.04/tablet/day. Patients at risk of a deficiency should be screened before mandibular operations, and those listed for orthognathic surgery or replacement of the temporomandibular joint should be asked to take a supplement before operation. PMID- 28803665 TI - [Teledermatology between two French hospitals: Two years of experience]. AB - BACKGROUND: Teledermatology is currently booming. Due to the shortage of dermatologists in hospitals access to dermatological consultations is very limited in some hospitals. We present our experience of collaboration between an expert center, the dermatology department of the Victor-Dupouy Hospital Centre in Argenteuil, and all medical structures under the Andre-Mignot Hospital in Versailles (CHV), including 2 prison medical centers (UCSA), traditional departments and emergency department. PATIENTS AND METHODS: Teledermatology, developed in the form of tele-expertise, began at the UCSA in November 2013. This expertise was then extended in June 2014 to the Internal Medicine department of CHV, and in December 2014 to all departments, including the emergency department. The rules and ethics of teledermatology were strictly adhered to. While UCSA could file all expertise dossiers, only urgent or difficult cases could be filed by other CHV departments. RESULTS: In 26 months, 347 expertise requests were filed: 231 by prisons and 116 by the other departments of the CHV. No patients refused teledermatology. The quality of information and photographs was considered good or excellent in over 95% of cases. A response was given within 3hours in more than 50% of cases and in all cases within 24hours (on working days). Analysis of diseases diagnosed illustrates the wide variety of conditions encountered in dermatology, with different structures having their own specific features. CONCLUSION: Our example illustrates the possibility of developing such an inter-hospital platform. However, it does not yet cater for requests made by patients to dermatologists, by dermatologists to dermatologists, or by dermatologists to the hospital teledermatology department. Acceptability was considered excellent by patients (with no refusals), physicians at the CHV, and the expert center. PMID- 28803666 TI - [Inefficacy of aflibercept in the treatment of idiopathic macular telangiectasia type 2 without neovascularization]. AB - Idiopathic macular telangectasia type 2 is a rare disease consisting primarily of bilateral macular capillary telangiectasia, alterations of the ellipsoid zone and intraretinal cysts that may appear as cystoid macular edema in the absence of neovascularization. Our goal was to study the efficacy of aflibercept in the treatment of these cysts. Thus, we performed a series of three intravitreal injections of aflibercept in the right eye of a woman with a typical presentation of macular telangectasia type 2 complicated by cystoid macular edema without neovascularization. These injections did not significantly improve the anatomical or functional results. Other studies investigating the efficacy of other anti VEGF in this disease led mainly to a decrease in macular thickness on OCT after injection, without any functional improvement. The anti-VEGFs therefore appear to be of little value in treating MacTel 2 intraretinal cysts without neovascularization. PMID- 28803667 TI - Future prospect of faecal microbiota transplantation as a potential therapy in asthma. AB - There is convincing evidence from both human and animal studies suggesting that the gut microbiota plays an important role in regulating immune responses associated with the development of asthma. Certain intestinal microbial strains have been demonstrated to suppress or impair immune responsiveness in asthma experimental models, suggesting that specific species among gut commensal microbiota may play either a morbific or phylactic role in the progression of asthma. Evidence to date suggests that the intestinal microbiota represent fertile targets for prevention or management of asthma. The faecal microbiota transplantation (FMT) is a rather straightforward therapy that manipulates the human gastrointestinal (GI) microbiota, by which a healthy donor microbiota is transferred into an existing but disturbed microbial ecosystem. The FMT may therefore represent a therapeutic approach for asthma treatment in the foreseeable future. At present, FMT therapy for asthma is very limited and should be actively studied. Considerable efforts are needed to increase our knowledge in the field of FMT therapy for asthma. In this review, we aimed to provide several insights into the development of FMT therapy for asthma. PMID- 28803669 TI - Editorial comment. PMID- 28803668 TI - When does atopic dermatitis warrant systemic therapy? Recommendations from an expert panel of the International Eczema Council. AB - BACKGROUND: Although most patients with atopic dermatitis (AD) are effectively managed with topical medication, a significant minority require systemic therapy. Guidelines for decision making about advancement to systemic therapy are lacking. OBJECTIVE: To guide those considering use of systemic therapy in AD and provide a framework for evaluation before making this therapeutic decision with the patient. METHODS: A subgroup of the International Eczema Council determined aspects to consider before prescribing systemic therapy. Topics were assigned to expert reviewers who performed a topic-specific literature review, referred to guidelines when available, and provided interpretation and expert opinion. RESULTS: We recommend a systematic and holistic approach to assess patients with severe signs and symptoms of AD and impact on quality of life before systemic therapy. Steps taken before commencing systemic therapy include considering alternate or concomitant diagnoses, avoiding trigger factors, optimizing topical therapy, ensuring adequate patient/caregiver education, treating coexistent infection, assessing the impact on quality of life, and considering phototherapy. LIMITATIONS: Our work is a consensus statement, not a systematic review. CONCLUSION: The decision to start systemic medication should include assessment of severity and quality of life while considering the individual's general health status, psychologic needs, and personal attitudes toward systemic therapies. PMID- 28803670 TI - Future Benefits from Contemporary Evosystem Services: A Response to Rudman et al. PMID- 28803671 TI - Contemporary Evosystem Services: A Reply to Faith et al. PMID- 28803672 TI - International endorsement of the ESCEO algorithm for management of knee osteoarthritis in clinical practice. PMID- 28803674 TI - Healing of Apical Periodontitis after Nonsurgical Treatment in Patients with Type 2 Diabetes. AB - INTRODUCTION: The purpose of this prospective study was to compare the success of primary root canal treatment between type 2 diabetic and nondiabetic patients and to investigate the effect of periapical healing on glycated hemoglobin (HbA1c) in type 2 diabetic patients with apical periodontitis. METHODS: Sixty mandibular molars with necrotic pulps and apical radiolucency (size >= 2 mm * 2 mm) were included in the study. Based on the HbA1c levels, patients were divided into 2 groups: type 2 diabetic (HbA1c >=6.5%) and nondiabetic (HbA1c <6.5%). Forty-six teeth were evaluated at the 12-month follow-up time period. The primary outcome measure was the change in apical bone density as determined by the periapical index. RESULTS: Both the diabetic and nondiabetic group depicted a significant reduction in the periapical score after endodontic treatment at the 12-month follow-up (P < .05). Significantly less periapical healing was observed in the diabetic group (43%) compared with the nondiabetic group (80%) at the 12-month follow-up (P < .05). HbA1c levels in the diabetic group increased at each follow up after endodontic treatment. CONCLUSIONS: Diabetes mellitus may have a negative impact on the outcome of endodontic treatment in terms of periapical healing. Nonsurgical endodontic treatment did not improve HbA1c levels in patients with type 2 diabetes. PMID- 28803673 TI - Tubulointerstitial damage predicts end stage renal disease in lupus nephritis with preserved to moderately impaired renal function: A retrospective cohort study. AB - OBJECTIVES: The presence of tubulointerstitial damage (TID) on renal biopsy is considered to be a late sequela of lupus nephritis (LN). The objective of this study was to determine if TID predicts progression to end stage renal disease (ESRD) in LN patients without advanced kidney disease. METHODS: All SLE patients with an index biopsy consistent with LN between January 2005 and July 2015, and eGFR >= 30mL/min/1.73m2 were included. Moderate-to-severe TID was defined as the presence of moderate-to-severe tubular atrophy and/or interstitial fibrosis. Time to ESRD was defined as time from the index biopsy date to incident ESRD date; non ESRD patients were censored at the time of death or the last visit before December 2015. Time-dependent analyses were conducted to evaluate whether moderate-to-severe TID was predictive of ESRD progression. RESULTS: Of the 131 LN patients with eGFR >= 30mL/min/1.73m2, 17 (13%) patients progressed to ESRD. Moderate-to-severe TID was present in 13% of biopsies with eGFR >= 60mL/min/1.73m2 and in 33% of biopsies with eGFR between 30 and 60mL/min/1.73m2. Moderate-to-severe TID was associated with a higher risk of ESRD progression: adjusted hazard ratio (HR) = 4.1, 95% CI: 1.4-12.1, p = 0.01 for eGFR >= 30mL/min/1.73m2; HR = 6.2, 95% CI: 1.7-23.2, p = 0.008 for eGFR >= 60mL/min/1.73m2. There was no association between tubulointerstitial inflammation (TII) and ESRD progression. CONCLUSIONS: Moderate-to-severe TID, but not TII, was a strong predictor of ESRD progression independent of eGFR or glomerular findings, therefore, providing an important window for potential early interventions. PMID- 28803676 TI - Ranavirus phylogenomics: Signatures of recombination and inversions among bullfrog ranaculture isolates. AB - Ranaviruses are emerging pathogens of fish, amphibians, and reptiles that threaten aquatic animal industries and wildlife worldwide. Our objective was to genetically characterize ranaviruses isolated during separate bullfrog Lithobates catesbeianus die-offs that occurred eight years apart on the same North American farm. The earlier outbreak was due to a highly pathogenic strain of common midwife toad virus (CMTV) previously known only from Europe and China. The later outbreak was due to a chimeric ranavirus that displayed a novel genome arrangement and a DNA backbone typical for Frog virus 3 (FV3) strains except for interspersed fragments acquired through recombination with the CMTV isolated earlier. Both bullfrog ranaviruses are more pathogenic than wild-type FV3 suggesting recombination may have resulted in the increased pathogenicity observed in the ranavirus isolated in the later outbreak. Our study underscores the role international trade in farmed bullfrogs may have played in the global dissemination of highly pathogenic ranaviruses. PMID- 28803675 TI - The Yale Fitness Intervention Trial in female cancer survivors: Cardiovascular and physiological outcomes. AB - BACKGROUND: Induced premature menopause and cardio-toxic therapy increase cardiovascular disease risk in female cancer survivors. OBJECTIVE: To compare the effects of a 12 month aerobic-resistance fitness center intervention to home based physical activity on cardiovascular function and metabolic risk factors. METHODS: Subjects (N = 154) who had completed primary and/or adjuvant chemotherapy (past 3 years) were randomized to a fitness center intervention or a home based group. The fitness center intervention was a structured thrice weekly aerobic (30 min brisk walking treadmill in target heart range) combined with resistance (30 min of lower body strength training) exercise program, supervised for the first 6 months. The home based group received national guidelines for 30 min moderate intensity exercise most days of the week. Fasting serum samples were collected at baseline, 6 and 12 months for insulin, glucose, lipids and hemoglobin A-1C. A graded exercise stress test was also performed at baseline and 6 months. RESULTS: The majority of subjects were white (85.7%), had breast cancer (83.1%) and the average age was 51.9 years. Subjects in the fitness center intervention had significantly improved time on treadmill (p = .039), improved heart rate recovery at 1 min (p = .028), greater MET minutes/week (p <= .0001), a trend for improved insulin resistance (p = .067) and stable insulin levels (p = .045) compared to the home based physical activity group. CONCLUSIONS: Exercise represents a potential cardiac risk reduction intervention for cancer survivors. CLINICAL TRIALS.GOV: NCT01102985. PMID- 28803677 TI - Indole-fused azepines and analogues as anticancer lead molecules: Privileged findings and future directions. AB - The search for new lead compounds of simple structure, displaying highest quality anti-tumor potency with new mechanisms of action and least adverse effects is the major intention of cancer drug discovery now a days. For the time being, indole fused azepines emerged as a simple class of compounds prolifically designed with strong pharmacological significances in particular of cancer protecting ability. In the recent years from the efforts of our research group, indole-fused heteroazepines, a simple structural class achieved by fusion of indole with oxygen, sulphur and nitrogen containing heteroazepine rings, have known for its superior outcomes in cancer treatment. Surprisingly, the chemistry and biology of these unique families with an amazing role in cancer drug discovery has remained broadly unexplored. This short review is consequently an endeavor to highlight the preliminary ideas over this structural class and to draw the medical attention towards future development of indole-fused azepines and analogues for their promising function in cancer drug discovery. PMID- 28803678 TI - Laparoscopic partial nephrectomy with prior superselective embolisation as treatment for giant renal angiomyolipoma. AB - OBJECTIVE: Cases of giant renal angiomyolipoma (>9cm) are a therapeutic challenge due to their low frequency and large size. The treatment objective for patients with renal angiomyolipoma should be complete tumour extirpation, with a nephron sparing surgical technique, without complications and using a minimally invasive approach. MATERIAL AND METHODS: We present 3 cases of giant angiomyolipoma (10 12 and 14cm) treated with a combined approach: superselective embolisation and subsequent laparoscopic partial nephrectomy, in 3 separate hospitals. RESULTS: None of the cases required conversion to open surgery. One of the 3 patients underwent arterial clamping, and none of the patients had complications. CONCLUSIONS: The combined approach provides a procedure with the criteria of minimal invasiveness, nephron sparing, little bleeding and reduced warm ischaemia time. PMID- 28803679 TI - Systematic review of kidney transplantation functional predictors. AB - CONTEXT: Kidney transplantation from donors with expanded criteria has increased the pool of kidneys at the cost of a higher risk of short and long-term graft dysfunction. The main issue lies in determining which kidneys will offer acceptable function and survival compared with the risk represented by surgery and subsequent immunosuppression. OBJECTIVE: The objective of our article is to review the current evidence on the tools for predicting the functionality of kidney transplantation from cadaveric donors with expanded criteria and determining the validity for their use in standard practice. ACQUISITION OF EVIDENCE: We conducted a systematic literature review according to the PRISM criteria, through Medline (http://www.ncbi.nlm.nih.gov) and using the keywords (in isolation or in conjunction) "cadaveric renal transplantation; kidney graft function appraisal, graft function predictors". We selected prospective and retrospective series and review articles. A total of 375 articles were analysed, 39 of which were ultimately selected for review. SUMMARY OF THE EVIDENCE: The predictors of functionality include the following: The donor risk indices; the calculation of the renal functional weight or the assessment of the nephronic mass; the measurement of vascular resistances during perfusion in hypothermia; the measurement of the donor's biomarkers in urine and in the perfusion liquid; the measurement of functional and reperfusion parameters in normothermia; and the measurement of morphological parameters (microscopic and macroscopic) of the target organ. In this article, we present an explanatory summary of each of these parameters, as well as their most recent evidence on this issue. DISCUSSION: None of the reviewed parameters in isolation could reliably predict renal function and graft survival. There is a significant void in terms of the macroscopic assessment of kidney transplantation. CONCLUSIONS: We need to continue developing predictors of renal functionality to accurately define the distribution of each currently available donor kidney. PMID- 28803680 TI - Corrigendum to "Analysis of association between common SNPs in ErbB4 and bipolar affective disorder, major depressive disorder and schizophrenia in the Han Chinese population" [Prog. Neuro-Psychopharmacol. Biol. Psychiatry, 36 (2012) 17 21]. PMID- 28803681 TI - A survey on stimuli for visual cortical function assessment in infants. AB - Visual processing, as a significant and complex functionality of the human brain, changes during the life span with the most developmental changes in the infancy. Different types of visual stimuli are needed for evaluating different functionalities of the infants' visual system. Selecting appropriate visual stimuli is an important issue in evaluating visual cortical functions in infants. Properties of stimulation influence responses of visual system and must be adjusted according to the age and specific function which is going to be investigated. In this review, the most commonly used stimuli to elicit visual evoked potentials (VEPs) are evaluated and characteristics of VEPs extracted by these stimulations are studied. Furthermore, various studies investigating different functionalities such as selectivity for orientation and directional motion are presented. Valuable results regarding emerging and maturation times of different functions and normative data for clinical diagnosis are provided by these studies. PMID- 28803682 TI - Volumetric absorptive microsampling: Current advances and applications. AB - Recently, volumetric absorptive microsampling (VAMS) has been introduced for the sampling of biological fluids, and more particularly whole blood, on a porous hydrophilic tip. VAMS enables the collection of small, accurate and precise blood volumes (10 or 20MUL) regardless of the hematocrit. After drying, the samples can be stored or directly analyzed. The stability of various compounds in dried samples supported on VAMS tips varies from one day to a few months at room temperature, and increases at lower temperatures. The complete tip is used during a simple and straightforward sample preparation. Compounds can be extracted with a variety of solvents, and thereafter directly analyzed. A design of experiments is recommended to determine the optimal extraction conditions for a reproducible recovery. The recovery of compounds might be influenced by the hematocrit. In the last two years, various pharmacokinetic and therapeutic drug monitoring studies have been conducted with VAMS. This review covers the general aspects related with the use of VAMS and its applicability is demonstrated through examples. PMID- 28803683 TI - ? AB - Takayasu arteritis (TAK) is a vasculitis of the large arteries. The arterial wall, target of the immune reaction, is composed of vascular dendritic cells, endothelial cells, vascular smooth muscle cells and fibroblasts, which engage in an interaction with T cells and macrophages to, ultimately, cause luminal stenosis or aneurysmal wall damage of the vessel. A multitude of cytokines have been identified to increase in case of TAK and to be linked to disease activity. A better understanding of the physiopathological pathways and mechanisms involved, might enable a more tailored therapeutic approach in TAK. PMID- 28803684 TI - Role of Two-Dimensional Speckle-Tracking Echocardiography Strain in the Assessment of Right Ventricular Systolic Function and Comparison with Conventional Parameters. AB - Despite the already well-known role the right side of the heart plays in many diseases, right ventricular (RV) function has only recently been carefully considered. Echocardiography is the first-line diagnostic technique for the assessment of the right ventricle and right atrium, whereas cardiac magnetic resonance is considered the gold standard but is limited by cost and availability. According to the current guidelines, systolic RV function should be assessed by several conventional measurements, but the efficacy of these parameters as diagnostic and prognostic tools has been questioned by many authors. The development in recent years of myocardial deformation imaging techniques and their application to the right heart chambers has allowed deeper evaluation of the importance of RV function in the pathophysiology of a large number of cardiovascular conditions, but the real value of this new tool has not been completely clarified. The aim of this review is to provide a wide and careful analysis of findings available in the literature about the assessment of RV systolic function by strain measurements, comparing them with conventional parameters and evaluating their role in several clinical settings. PMID- 28803685 TI - Quantification of Pulmonary Regurgitation by Vector Flow Mapping in Congenital Heart Patients after Repair of Right Ventricular Outflow Obstruction: A Preliminary Study. AB - BACKGROUND: Vector flow mapping (VFM) enables direct visualization of flow pattern and estimation of flow volume. The aim of this study was to determine its accuracy in the quantification of pulmonary regurgitation (PR) in congenital heart patients after repair of right ventricular (RV) outflow obstruction. METHODS: This study comprised two parts: (1) validation of VFM in the quantification of PR in patients with repaired tetralogy of Fallot by cardiac magnetic resonance and (2) clinical application of VFM to determine PR in patients after biventricular repair of pulmonary atresia and stenosis with intact ventricular septum. PR was quantified by calculation of VFM-derived pulmonary regurgitant ratio (PRVFM), defined as ratio of backward to forward flow volume. RESULTS: Coefficients of variations for intra- and interobserver variability in the measurements of PRVFM were 7.0% and 10.4%, respectively. Fourteen patients with repaired tetralogy of Fallot aged 31.3 +/- 7.3 years were studied. Their PRVFM correlated strongly with cardiac magnetic resonance-derived PR fraction (r = 0.95, P < .001) and RV end-diastolic volume (r = 0.84, P < .001). In the second part, 14 patients with pulmonary atresia with intact ventricular septum aged 25.6 +/- 6.0 years, 14 patients with pulmonary stenosis aged 24.2 +/- 7.0 years, and 14 healthy control subjects were studied. PRVFM was found to increase across groups of subjects with absent (4.6 +/- 3.3%), mild (11.1 +/- 7.1%), moderate (29.6 +/- 7.8%), and severe (50.1 +/- 8.2%) PR as defined semiquantitatively by color flow mapping. Furthermore, PRVFM correlated strongly with the ratio of PR color jet to width of RV outflow (r = 0.92, P < .001). CONCLUSIONS: VFM is a reproducible technique for accurate quantification of PR in congenital heart patients after repair of RV outflow obstruction. PMID- 28803686 TI - Are Cyclin-dependent Kinase 4/6 Inhibitors Needed for all Oestrogen Receptor positive Metastatic Breast Cancers? PMID- 28803687 TI - Predictors of Asymptomatic Radiation-induced Abdominal Atherosclerosis. AB - AIMS: To identify predictors of asymptomatic radiation-induced abdominal atherosclerosis in patients treated with radiotherapy and evaluated by abdominal vascular ultrasonography. MATERIALS AND METHODS: Forty-two testicular classic seminoma patients (median age 34 years, range 16-56) undergoing radical inguinal orchiectomy were analysed. Twenty-six patients underwent post-surgery radiotherapy (median total dose 25 Gy, range 25-43), two of them also received chemotherapy (CHT) and 16 patients were treated with surgery alone or by surgery followed by CHT (control group). The presence of stenosis in an abdominal vessel and renal resistive index (RRI), evaluated by echo-colour Doppler (ECD), were considered as indicators of late vascular damage. Chi-square and Mann-Whitney tests were used to compare groups. For the radiotherapy group, near maximum (D2%) and mean dose (Dmean) metrics of critical structures (abdominal arteries and renal hila) were extracted from retrievable dose maps (18 of 26 radiotherapy patients). To evaluate clinical and dosimetric factors associated with vascular damage, univariate and multivariate analyses were carried out. The impact of dose to arteries, evaluated as separate subvolumes, was analysed comparing the stenotic arteries with normal ones by logistic regression. The area under the receiver operator characteristic curve (AUC) was used to evaluate the test accuracy. RESULTS: In the radiotherapy group there was a significantly different incidence of stenosis (31% versus 0%, P = 0.016) and a higher median average RRI (0.63 versus 0.60, P = 0.032) compared with the control group. The median time intervals between treatment and ECD were 64 months (range 12-120) and 48 months (range 12-168) in the radiotherapy and control groups (P = 0.399), respectively. A younger age at radiotherapy was the only clinical risk factor for stenosis (P = 0.006). Artery Dmean was significantly associated with stenosis (P = 0.008), with an odds ratio of 1.13 (95% confidence interval 1.01-1.26) and an AUC of 0.85 (95% confidence interval 0.77-0.91). Renal hilum D2% was correlated with RRI (Rs = 0.406, P = 0.02). CONCLUSIONS: Late vascular damage represents a potential effect of abdominal radiotherapy, even at a moderate dose. Younger age at irradiation, artery and renal hila dose metrics are associated with increased risk. Ultrasound based follow-up may allow for non-invasive early detection of asymptomatic radiation-induced damage, helping to prevent severe vascular events. PMID- 28803688 TI - Demand/withdraw communication in the context of intimate partner violence: Implications for psychological outcomes. AB - Intimate partner violence (IPV) is associated with symptoms of posttraumatic stress disorder (PTSD) and generalized anxiety disorder (GAD). To clarify the influence of a dyadic conflict pattern that has previously been shown to accompany violence in romantic relationships (partner demand/self withdraw) on these mental health outcomes, we examined the associations between three forms of IPV (physical, emotional-verbal, dominance-isolation), partner demand/self withdraw, and PTSD and GAD symptoms, in a sample of 284 IPV-exposed women. Using structural equation modeling, we found significant associations between dominance isolation IPV, partner demand/self withdraw, and clinician-assessed GAD symptoms. Associations between emotional-verbal IPV and partner demand/self withdraw were also significant. Associations for physical IPV, partner demand/self withdraw, and clinician-assessed PTSD symptoms were not statistically significant. These results underscore the need for research on the mental health outcomes associated with specific forms of IPV and the long-term psychological consequences of the conflict patterns that uniquely characterize violent relationships. PMID- 28803690 TI - New insights into non-conventional epitopes as T cell targets: The missing link for breaking immune tolerance in autoimmune disease? AB - The mechanism by which immune tolerance is breached in autoimmune disease is poorly understood. One possibility is that post-translational modification of self-antigens leads to peripheral recognition of neo-epitopes against which central and peripheral tolerance is inadequate. Accumulating evidence points to multiple mechanisms through which non-germline encoded sequences can give rise to these non-conventional epitopes which in turn engage the immune system as T cell targets. In particular, where these modifications alter the rules of epitope engagement with MHC molecules, such non-conventional epitopes offer a persuasive explanation for associations between specific HLA alleles and autoimmune diseases. In this review article, we discuss current understanding of mechanisms through which non-conventional epitopes may be generated, focusing on several recently described pathways that can transpose germline-encoded sequences. We contextualise these discoveries around type 1 diabetes, the prototypic organ specific autoimmune disease in which specific HLA-DQ molecules confer high risk. Non-conventional epitopes have the potential to act as tolerance breakers or disease drivers in type 1 diabetes, prompting a timely re-evaluation of models of a etiopathogenesis. Future studies are required to elucidate the disease relevance of a range of potential non-germline epitopes and their relationship to the natural peptide repertoire. PMID- 28803689 TI - Sun exposure influences the prognostic power of components of mineral metabolism in patients with coronary artery disease. AB - BACKGROUND AND AIM: Calcidiol (vitamin D metabolite) plasma levels vary with sun exposure (SE). However, it is not known if SE influences its prognostic ability. We have studied the effect of SE on plasma levels of the components of mineral metabolism (calcidiol, fibroblast growth factor-23 [FGF-23], parathormone [PTH], and phosphate [P]) and on their prognostic value in patients with coronary artery disease (CAD). METHODS AND RESULTS: We studied prospectively 704 patients with stable CAD. Clinical variables and baseline calcidiol, FGF-23, PTH, and P plasma levels were assessed. We divided the population in two subgroups, according to the period of plasma extraction: High SE (HSE) (April-September) and low SE (LSE) (October-March). The outcome was the development of acute ischemic events (acute coronary syndrome, stroke, or transient ischemic attack), heart failure, or death. Mean follow-up was 2.15 +/- 0.99 years. Calcidiol and P levels were higher in HSE group. In the whole population, calcidiol (HR = 0.84 for each 5 ng/ml increase, 95% CI = 0.71-0.99; p = 0.038) and FGF-23 (HR = 1.14 for each 100 RU/ml increase, 95% CI = 1.05-1.23; p = 0.009) were predictors of the outcome, along with age, hypertension, body-mass index, peripheral artery disease, and P levels. In the LSE subgroup, calcidiol (HR = 0.75; 95% CI = 0.57-0.99; p = 0.034) and FGF 23 (HR = 1.34; 95% CI = 1.13-1.58; p = 0.003) remained as predictors of the outcome. In the HSE group calcidiol and FGF-23 had not independent prognostic value. CONCLUSIONS: In patients with stable CAD, low calcidiol and high FGF-23 plasma levels predict an adverse prognosis only when the sample is obtained during the months with LSE. SE should be taken into account in the clinical practice. PMID- 28803691 TI - Effectiveness of Lavendula stoechas essential oil in treatment of mild to moderate carpal tunnel syndrome: A randomized controlled trial. AB - STUDY DESIGN: Randomized controlled trial. INTRODUCTION: Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy of the upper extremity. To date, no previous study has evaluated the efficacy of topical Lavendula stoechas (Lavender) oil in CTS patients. PURPOSE OF THE STUDY: To investigate the effectiveness of topical Lavender essential oil in pain intensity, isometric pinch strength, electrophysiological features, and functional status of patients with mild to moderate CTS. METHODS: Forty eight patients with mild to moderate CTS were enrolled in this randomized placebo-controlled trial. Group A was treated with night wrist orthotic and topical lavender oil ointment. Group B was treated with night wrist orthotic and a placebo ointment. Patients were evaluated at baseline, and after 40 days of intervention with Boston CTS questionnaire (BCTQ), visual analog scale (VAS) for pain, pinch grip strength, power grip, median compound motor action potential latency, and median sensory nerve action potential latency. RESULTS: At the end of the study period, both groups improved significantly in terms of BCTQ, VAS, isometric pinch powers, and electrodiagnosis study parameters. However, group A showed significantly greater improvements in BCTQ (mean difference, 0.39 +/- 0.31 vs 0.6 +/- 0.35; P = .03), VAS (3.37 +/- 1.86 vs 1.33 +/- 2.07; P = .001), and pinch grip strength (0.73 +/- 0.63 vs 0.27 +/- 0.54; P = .01) than group B. No significant differences in power grip, median compound motor action potential latency, and median sensory nerve action potential latency were seen between the 2 groups. CONCLUSION: This study was the first trial of topical lavender oil used in patients with CTS. Wrist orthotic combined with topical lavender oil was more effective than orthotic and placebo in treatment of mild to moderate CTS. LEVEL OF EVIDENCE: 1b. PMID- 28803693 TI - Editorial overview: Cell dynamics: Dynamic cell decision making. PMID- 28803692 TI - A Janus-Faced IM30 Ring Involved in Thylakoid Membrane Fusion Is Assembled from IM30 Tetramers. AB - Biogenesis and dynamics of thylakoid membranes likely involves membrane fusion events. Membrane attachment of the inner membrane-associated protein of 30 kDa (IM30) affects the structure of the lipid bilayer, finally resulting in membrane fusion. Yet, how IM30 triggers membrane fusion is largely unclear. IM30 monomers pre-assemble into stable tetrameric building blocks, which further align to form oligomeric ring structures, and differently sized IM30 rings bind to membranes. Based on a 3D reconstruction of IM30 rings, we locate the IM30 loop 2 region at the bottom of the ring and show intact membrane binding but missing fusogenic activity of loop 2 mutants. However, helix 7, which has recently been shown to mediate membrane binding, was located at the oppossite, top side of IM30 rings. We propose that a two-sided IM30 ring complex connects two opposing membranes, finally resulting in membrane fusion. Thus, IM30-mediated membrane fusion requires a Janus-faced IM30 ring. PMID- 28803694 TI - Shaping an Optimal Soil by Root-Soil Interaction. AB - Crop production depends on the availability of water and mineral nutrients, and increased yields might be facilitated by a greater focus on roots-soil interactions. Soil properties affecting plant growth include drought, compaction, nutrient deficiency, mineral toxicity, salinity, and submergence. Plant roots respond to the soil environment both spatially and temporally by avoiding stressful soil environments and proliferating in more favorable environments. We observe that crops can be bred for specific root architectural and biochemical traits that facilitate soil exploration and resource acquisition, enabling greater crop yields. These root traits affect soil physical and chemical properties and might be utilized to improve the soil for subsequent crops. We argue that optimizing root-soil interactions is a prerequisite for future food security. PMID- 28803695 TI - STAT3: Down the R(h)oAd. PMID- 28803696 TI - Differential modulation of glial cell mediated neuroinflammation in Plasmodium berghei ANKA infection by TGF beta and IL 6. AB - Modulation of pro-inflammatory and anti-inflammatory axis and orientation of glial cell function towards neuroinflammation, were hallmark signs of cerebral malaria (CM). CM pathogenesis was concerned with the circulating levels of Interleukin 6 (IL 6) and Transforming growth factor beta (TGF beta). Definite roles of these two cytokines in brain related pathology remained largely unexplored. To study the effect of these two cytokines, we have examined changes in morphology and in activation profile of the glial cells after TGF beta and IL 6 neutralization during CM in cortex and cerebellum of the Plasmodium berghei ANKA (PbA) infected male swiss albino mice. PbA infection caused severe inflammation by inducing changes in morphological features as well as in activation profile of the astrocytes and microglia. Similar inflammatory signs were evident in Anti TGF beta treated set. Interestingly in the Anti IL 6 treated set, reduced level of activation of these glial cells corresponds to the reduced level of inflammatory profile. Microglial activation was found to be synchronous with TLR4 engagement. Neuronal death was triggered by neuroinflammatory milieu seen in PbA and PbA+Anti TGF beta treated set. In conclusion, it can be said that IL 6 and TGF beta perform essential role in CM pathogenesis by modulating the level of glial cell induced neuroinflammation. PMID- 28803697 TI - Tumor necrosis factor alpha gene polymorphisms and haplotypes in Egyptian children with nephrotic syndrome. AB - BACKGROUND: Nephrotic syndrome (NS) characterized by complex pathogenesis and clinical course with relapses; and needs novel breakthroughs for decades. Polymorphisms of cytokines genes including tumor necrosis factor alpha (TNF alpha)may influence susceptibility to NS as well as different patients' steroid responses. In the current study, we demonstrated the potential roles of TNF-alpha promoter gene polymorphisms [-238, -308, -863] and haplotypes in susceptibility to childhood NS. Also, elucidating their possible influence on patients' steroid response and serum TNF-alpha level. METHODS: This case-control study included 150 children suffering from NS and 150 healthy children. Polymerase chain reaction- restriction-fragment length polymorphism (PCR-RFLP) was performed to evaluate different TNF-alpha gene polymorphism. TNF-alpha serum levels were assessed by ELISA. RESULTS: Serum TNF-alpha levels were significantly higher in NS patients than in controls and in steroid resistant NS (SRNS) than in steroid sensitive NS (SSNS) (P<0.001 for each). The risk of NS in patients carrying TNF-alpha-238GA genotype, and TNF-alpha-308GA or AA genotypes and allele A was significantly increased compared to healthy children. While no significant association was detected between TNF-alpha-863 and NS. The risk of resistance to steroid therapy was significantly high in NS carrying TNF-alpha-238GA genotype and A allele, TNF alpha-308, AA genotypes and A allele, and TNF-alpha-863CA, AA genotypes and A allele. The TNF-alpha GCG (-308/-863/-238) haplotype has protective roles against NS and steroid resistance. However, the risk of NS was significantly high in TNF alpha AAG and AAA haplotype's carriers compared to healthy children. Additionally the risk of steroid resistance was significantly high in TNF-alpha AAA haplotype's NS carrier (OR (95%CI): 2.2 (1.19-4.36), P=0.01). Moreover, we found significant higher serum TNF-alpha levels NS patients including SSNS and SRNS carrying mutant allele TNF-alpha-238GA genotype, -308GA and AA and -863CA and AA wild genotype's carriers than in those GG, GG and CC respectively. Interstingely, TNF-alpha levels were significantly higher in healthy children carrying TNF alpha(-308/-863/-238) [AAG and AAA haplotypes], NS cases carrying [ACA, AAG, AAA haplotypes], and in SSNS carrying [ACA and AAA haplotypes] than in those carrying GCG, haplotype of wild alleles. CONCLUSION: This study reported, for the first time, that TNF-alpha promoter gene polymorphisms and/or haplotypes are risk factors of NS and resistance to steroid among Egyptian children. PMID- 28803699 TI - Crowdsourcing Samples in Cognitive Science. AB - Crowdsourcing data collection from research participants recruited from online labor markets is now common in cognitive science. We review who is in the crowd and who can be reached by the average laboratory. We discuss reproducibility and review some recent methodological innovations for online experiments. We consider the design of research studies and arising ethical issues. We review how to code experiments for the web, what is known about video and audio presentation, and the measurement of reaction times. We close with comments about the high levels of experience of many participants and an emerging tragedy of the commons. PMID- 28803698 TI - Genomics and Ecology of Novel N2O-Reducing Microorganisms. AB - Microorganisms with the capacity to reduce the greenhouse gas nitrous oxide (N2O) to harmless dinitrogen gas are receiving increased attention due to increasing N2O emissions (and our need to mitigate climate change) and to recent discoveries of novel N2O-reducing bacteria and archaea. The diversity of denitrifying and nondenitrifying microorganisms with capacity for N2O reduction was recently shown to be greater than previously expected. A formerly overlooked group (clade II) in the environment include a large fraction of nondenitrifying N2O reducers, which could be N2O sinks without major contribution to N2O formation. We review the recent advances about fundamental understanding of the genomics, physiology, and ecology of N2O reducers and the importance of these findings for curbing N2O emissions. PMID- 28803700 TI - Association of androgen deprivation therapy and depression in the treatment of prostate cancer: A systematic review and meta-analysis. AB - BACKGROUND: There is increasing evidence that androgen deprivation therapy (ADT) may be associated with depression. Existing studies have shown conflicting results. METHODS: PubMed, Web of Science, Embase, and PsycINFO were queried on April 5, 2017. Eligible studies were in English and reported depression among individuals with prostate cancer exposed to a course of ADT vs. a lesser-exposed group (e.g., any-ADT vs. no ADT and continuous ADT vs. intermittent ADT). We used the MOOSE statement guidelines and the Cochrane Review Group's data extraction template. Study quality was evaluated by Newcastle-Ottawa Scale criteria. We conducted a random-effects meta-analysis to calculate summary statistic risk ratios (RRs) and 95% CIs. Heterogeneity was quantified using the I2 statistic and prespecified subgroup analysis. Small study effects were evaluated using Begg and Egger statistics. RESULTS: A total of 1,128 studies were initially identified and evaluated. A meta-analysis of 18 studies among 168,756 individuals found that ADT use conferred a 41% increased risk of depression (RR = 1.41; 95% CI: 1.18-1.70; P<0.001). We found a consistent strong statistically significant association when limiting our analysis to studies in localized disease (RR = 1.85; 95% CI: 1.20 2.85; P = 0.005) and those using a clinical diagnosis of depression (RR = 1.19; 95% CI: 1.08-1.32; P = 0.001). We did not find an association for continuous ADT with depression risk compared to intermittent ADT (RR = 1.00; 95% CI: 0.50-1.99; P = 0.992). There was no statistically significant evidence of small study effects. Statistically significant heterogeneity in the full analysis (I2 = 80%; 95% CI: 69-87; P<0.001) resolved when examining studies using a clinical diagnosis of depression (I2 = 16%; 95% CI: 0-60; P = 0.310). CONCLUSION: The currently available evidence suggests that ADT in the treatment of prostate cancer is associated with an increased risk of depression. PMID- 28803701 TI - Contemporary practice patterns and survival outcomes for locally advanced urethral malignancies: A National Cancer Database Analysis. AB - PURPOSE: Primary urethral carcinoma (PUC) has an aggressive natural history; however, controversy exists regarding the role of multimodal therapy for its treatment. Our objective was to examine practice patterns and survival outcomes for locally advanced urethral cancers. METHODS: The National Cancer Database was queried for patients with T2-4 or N1-2M0 PUC with urothelial, squamous, or adenocarcinoma histology from 2004 to 2013. Temporal trends for receipt of local or definitive surgery, radiotherapy (XRT), and systemic therapy were assessed. Adjusting for clinicopathologic characteristics, we evaluated the effect of tumor stage and histology on receipt of definitive multimodal therapy (cystectomy + chemotherapy +/- XRT) and effects of treatment on overall survival. RESULTS: A total of 1,749 patients met inclusion criteria (22.2% adenocarcinoma, 29.3% squamous, and 48.5% urothelial). Only 29.6% underwent cystectomy +/- XRT, and 15.6% underwent definitive multimodal therapy. Following adjustment, older patients (age 50-75: odds ratio [OR] = 0.42 [95% CI: 0.28-0.63]; age 75+: OR = 0.06 [95% CI: 0.03-0.13]) and those with squamous histology (OR = 0.46 [95% CI: 0.3-0.7]) were less likely to receive definitive multimodal therapy. More advanced stage (T3: OR = 1.66 [95% CI: 1.15-2.41]; T4: OR = 3.57 [95% CI: 2.47 5.16]); and N2 status (OR = 1.88 [95% CI: 1.27-2.78]) were more likely to receive definitive multimodal therapy. On adjusted analysis, an overall survival benefit was only observed with definitive multimodal therapy for PUC of urothelial origin (hazard ratio = 0.61 [95% CI: 0.45-0.83]). CONCLUSIONS: Despite a survival benefit, most patients with locally advanced PUC do not undergo definitive multimodal therapy. We advocate for a multidisciplinary-based treatment approach for these patients. Future prospective trials of multimodal therapy are crucial. PMID- 28803702 TI - Patient- and Physician-reported Satisfaction With Systemic Lupus Erythematosus Treatment in US Clinical Practice. AB - PURPOSE: This two-part study comprised two descriptive, cross-sectional surveys to evaluate treatment satisfaction among patients with systemic lupus erythematosus (SLE) and their physicians from US clinical practices. The Lupus Plus Project (LPP; part one) involved belimumab-containing regimens; the Disease Specific Program (DSP; part two) included all treatments and was designed to build on the body of evidence from part one. METHODS: The LPP recruited patients receiving belimumab, and comprised 2 paper questionnaires: a patient self completion questionnaire (PSC) and a patient record form (PRF) completed by the physician. The DSP enrolled patients with SLE receiving any treatment and comprised four parts: a PSC, a PRF completed by the physician after patient consultation, face-to-face physician interviews, and a workload form completed by the physicians to indicate their total SLE patient workload. The key objective of this study was to assess physician and patient satisfaction with current treatment. FINDINGS: From the PSCs, data regarding patient-reported satisfaction with current treatment were available for 263 patients who were receiving belimumab combination therapy (LPP) and 250 patients who were receiving non belimumab treatment (DSP). The majority of patients (belimumab, 86.3% [227/263]; non-belimumab, 78.4% [196/250]) responded positively (at least "somewhat satisfied") when asked about current treatment satisfaction, as did physicians (belimumab, 82.9% [311/375]; non-belimumab, 74.3% [326/439]). In multivariate analysis, factors most strongly associated with patient-reported satisfaction for patients receiving belimumab were patient-reported improvements in leisure activities since taking belimumab (odds ratio [OR] = 4.66), physician-reported improvements in fatigue (OR = 3.72), patient-reported improvements in general symptoms (OR = 3.02), and pain/achiness (OR = 2.71). Physician satisfaction was associated with clinical outcome such as improvements in pain/achiness (OR = 6.16), fatigue (OR = 3.76), and patient-reported satisfaction with treatment frequency (OR = 3.91). In patients receiving other SLE treatments, dosing frequency of current treatment (OR = 3.64) and a reduction in fatigue severity (OR = 3.61) were most strongly associated with patient-reported satisfaction; physician satisfaction was most strongly associated with a reduction in fatigue (OR = 6.22) and current remission status (OR = 6.05). IMPLICATIONS: When considering SLE treatment satisfaction patients tend to consider impact on daily functioning, whereas physicians take into account a wider range of clinical outcomes; however, both strongly consider improvements in fatigue. These surveys provide insights into treatment satisfaction among prescribers and patients with SLE. GSK-ClinicalStudyRegister.com identifiers: GSK study 202146 [HO 15-15509] and 205086 [HO 15-16709]. PMID- 28803703 TI - Viral Hijacking of Formins in Neurodevelopmental Pathologies. AB - The 2015 Zika virus (ZIKV) outbreak caused global concern when it was determined to cause microcephaly, hearing loss, and other neurodevelopmental manifestations upon fetal exposure. Significant progress has been made in our understanding of the interactions between ZIKV and the pregnant host, but there is still a critical need to understand how ZIKV and other neurotropic viruses affect fetal neurodevelopment. Diaphanous-related formins (Diaphs) have recently been identified as microcephaly-associated proteins in humans and mice. Mutations in Diaphs affect the function of neural progenitor cells, much like prenatal viral infection. We present a novel hypothesis that viruses 'hijack' Diaphs in neural progenitor cells, causing autonomous differentiation and apoptosis of neural progenitor cells, which could potentially contribute to virus-associated neurological pathologies. PMID- 28803705 TI - Collagen fibril organization in chicken and porcine skeletal muscle perimysium under applied tension and compression. AB - The tension/compression asymmetry observed in the stress-stretch response of skeletal muscle is not well understood. The collagen network in the extracellular matrix (ECM) almost certainly plays a major role, but the details are unknown. This paper reports qualitatively and quantitatively on skeletal muscle ECM reorganization during applied deformation using confocal imaging of collagen through use of a fluorescently-tagged specific collagen binding protein (CNA35 EGFP) of porcine and chicken muscle samples under tensile and compressive deformation in both the fibre and cross-fibre directions. This reveals the overall three-dimensional structure of collagen in perimysium in planes perpendicular and parallel to the muscle fibres in both species. Furthermore, there is clear evidence of the reorganization of these structures under compression and tension applied in both the muscle fibre and cross-fibre directions. These observations improve our understanding of perimysium structure and response to three-dimensional deformations and are an important basis for constitutive models of passive skeletal muscle. Although overall behaviour was similar, some differences in perimysium structure were observed between chicken and porcine muscle tissue. Further work is required to better understand which structures are responsible for the tension and compression stress-strain asymmetry previously observed in the mechanical response of passive skeletal muscle. PMID- 28803704 TI - Effectiveness of graded activity versus physiotherapy in patients with chronic nonspecific low back pain: midterm follow up results of a randomized controlled trial. AB - BACKGROUND: Low back pain (LBP) is a major health and economic problem worldwide. Graded activity and physiotherapy are commonly used interventions for nonspecific low back pain. However, there is currently little evidence to support the use of one intervention over the other in the medium-term. OBJECTIVE: To compare the effectiveness of graded activity exercises to physiotherapy-based exercises at mid-term (three and six months' post intervention) in patients with chronic nonspecific LBP. METHODS: Sixty-six patients were randomly allocated to two groups: graded activity group (n=33) and physiotherapy group (n=33). These patients received individual sessions twice a week for six weeks. Follow-up measurements were taken at three and six months. The main outcome measurements were intensity pain (Pain Numerical Rating Scale) and disability (Rolland Morris Disability Questionnaire). RESULTS: No significant differences between groups after three and six month-follow ups were observed. Both groups showed similar outcomes for pain intensity at three months [between group differences: -0.1 (95% confidence interval [CI]=-1.5 to 1.2)] and six months [0.1 (95% CI=-1.1 to 1.5)], disability at three months was [-0.6 (95% CI=-3.4 to 2.2)] and six months [0.0 (95% CI=-2.9 to 3.0)]. CONCLUSION: The results of this study suggest that graded activity and physiotherapy have similar effects in the medium-term for patients with chronic nonspecific low back pain. PMID- 28803706 TI - Health policy in times of austerity-A conceptual framework for evaluating effects of policy on efficiency and equity illustrated with examples from Europe since 2008. AB - The objective of this paper is to provide a framework for evaluation of changes in health policy against overarching health system goals. We propose a categorisation of policies into seven distinct health system domains. We then develop existing analytical concepts of insurance coverage and cost-effectiveness further to evaluate the effects of policies in each domain on equity and efficiency. The framework is illustrated with likely effects of policy changes implemented in a sample of European countries since 2008. Our illustrative analysis suggests that cost containment has been the main focus and that countries have implemented a mix of measures that are efficient or efficiency neutral. Similarly, policies are likely to have mixed effects on equity. Additional user charges were a common theme but these were frequently accompanied by additional exemptions, making their likely effects on equity difficult to evaluate. We provide a framework for future, and more detailed, evaluations of changes in health policy. PMID- 28803707 TI - Patients' reasons for and against undergoing Roux-en-Y gastric bypass, adjustable gastric banding, and vertical sleeve gastrectomy. AB - BACKGROUND: The most common bariatric procedures, Roux-en-Y gastric bypass (RYGB), adjustable gastric banding (LAGB), and sleeve gastrectomy (SG), generally induce significant weight loss and health improvements. However, little is known about how patients decide which procedure to undergo. OBJECTIVE: Investigate patients' reasons for and against undergoing RYGB, LAGB, and SG. SETTING: Online questionnaire. METHODS: Data were analyzed from 236 Australian adults with current RYGB (15.7%), LAGB (22.0%), or SG (62.3%) who completed a questionnaire including an open-ended question about why they underwent their procedure. Data were coded for content and analyzed. RESULTS: Patients most often underwent RYGB because of its evidence base and success rate and the patient's characteristics, whereas the most common reason for SG was a medical practitioner's recommendation, preference, or choice, followed by the patients' evaluation of information gathered from their own research and observations of others' success. The most common reasons for undergoing LAGB related to characteristics of the procedure, including its reversibility and a perception of LAGB as less invasive. The most common reason against undergoing both RYGB and SG was a desire to avoid postsurgical complications and risks such as leaks or malabsorption, whereas the most common reason against LAGB was information and evidence from other people's unsuccessful experiences and failure rates. CONCLUSIONS: Patients' reasons for and against procedures differed by procedure. In addition to the surgeon's influence, patients demonstrated clear procedure preferences based on their own research, knowledge, and experiences. Preferences should be understood to assist patients to select the most appropriate procedure for their circumstances. PMID- 28803708 TI - Anti-phospholipid syndrome: Current opinion on mechanisms involved, laboratory characterization and diagnostic aspects. AB - Anti-phospholipid syndrome is a complex and severe clinical situation, associated with symptoms such as recurrent thrombosis, arterial or venous, at any site, pregnancy loss, and other related syndromes. These clinical burdens, are highly variable from patient to patient, and are associated with biological abnormalities, such as the presence of the Lupus Anticoagulant or phospholipid dependent antibodies, confirmed on two occasions at least 12 weeks apart. From the diagnosis standpoint, both, functional (clotting) or immunological assays, are difficult to standardize and to optimize, due to the absence of reference material, or a characteristic clinical group, and international reference preparations. Large cohort studies are necessary for defining the usefulness of each assay, in terms of specificity, sensitivity, accuracy and for following-up the disease evolution. Clotting assays are based on Activated Partial Thromboplastin Time (APTT) and diluted Russell Viper Venom Time (dRVVT), performed at low and high phospholipid concentration, or on 1:1 mixtures of tested sample and a normal plasma pool. They allow evaluation of the paradoxal effects of LAs, which are pro-thrombotic in vivo, and anticoagulant in vivo. Use of synthetic phospholipids improves assay specificities and sensitivities, especially in patients treated with anticoagulants. Immunoassays can also be used for testing phospholipid dependent antibodies, first identified and measured as anti-cardiolipin antibodies, but now characterized as targeted to phospholipid cofactor proteins: mainly beta2GP1 (which exposes cryptic epitopes upon binding to phospholipids), and in some cases prothrombin, and more rarely Protein S, Factor XIII, Protein Z or Annexin V. Use of optimized assays designed with well characterized anionic phospholipids, then complexed with highly purified phospholipid cofactor protein (mainly beta2GP1), offers a better link between reactivity and clinical associations, than the former assays which were empirically designed with cardiolipin. Standardization also remains complicated due to the absence of international standards and harmonized quantitation units. Validation on large cohorts of negative and positive patients remains the key approach for defining assay performance and clinical usefulness. Laboratory practice for all these methods is now greatly facilitated thanks to the use of automated instruments and dedicated software. Along with clinical criteria, laboratory assays are of great usefulness for identification and confirmation of the anti-phospholipid syndrome and they allow disease follow-up when appropriate patient management is in place. PMID- 28803709 TI - Low back pain: Identifying sub-groups, clinical prediction rules and measuring results. PMID- 28803711 TI - A hopeful therapy for Niemann-Pick C diseases. PMID- 28803710 TI - Intrathecal 2-hydroxypropyl-beta-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1-2 trial. AB - BACKGROUND: Niemann-Pick disease, type C1 (NPC1) is a lysosomal storage disorder characterised by progressive neurodegeneration. In preclinical testing, 2 hydroxypropyl-beta-cyclodextrins (HPbetaCD) significantly delayed cerebellar Purkinje cell loss, slowed progression of neurological manifestations, and increased lifespan in mouse and cat models of NPC1. The aim of this study was to assess the safety and efficacy of lumbar intrathecal HPbetaCD. METHODS: In this open-label, dose-escalation phase 1-2a study, we gave monthly intrathecal HPbetaCD to participants with NPC1 with neurological manifestation at the National Institutes of Health (NIH), Bethesda, MD, USA. To explore the potential effect of 2-week dosing, three additional participants were enrolled in a parallel study at Rush University Medical Center (RUMC), Chicago, IL, USA. Participants from the NIH were non-randomly, sequentially assigned in cohorts of three to receive monthly initial intrathecal HPbetaCD at doses of 50, 200, 300, or 400 mg per month. A fifth cohort of two participants received initial doses of 900 mg. Participants from RUMC initially received 200 or 400 mg every 2 weeks. The dose was escalated based on tolerance or safety data from higher dose cohorts. Serum and CSF 24(S)-hydroxycholesterol (24[S]-HC), which serves as a biomarker of target engagement, and CSF protein biomarkers were evaluated. NPC Neurological Severity Scores (NNSS) were used to compare disease progression in HPbetaCD-treated participants relative to a historical comparison cohort of 21 NPC1 participants of similar age range. FINDINGS: Between Sept 21, 2013, and Jan 19, 2015, 32 participants with NPC1 were assessed for eligibility at the National Institutes of Health. 18 patients were excluded due to inclusion criteria not met (six patients), declined to participate (three patients), pursued independent expanded access and obtained the drug outside of the study (three patients), enrolled in the RUMC cohort (one patient), or too late for the trial enrolment (five patients). 14 patients were enrolled and sequentially assigned to receive intrathecal HPbetaCD at a starting dose of 50 mg per month (three patients), 200 mg per month (three patients), 300 mg per month (three patients), 400 mg per month (three patients), or 900 mg per month (two patients). During the first year, two patients had treatment interrupted for one dose, based on grade 1 ototoxicity. All 14 patients were assessed at 12 months. Between 12 and 18 months, one participant had treatment interrupted at 17 months due to hepatocellular carcinoma, one patient had dose interruption for 2 doses based on caregiver hardship and one patient had treatment interrupted for 1 dose for mastoiditis. 11 patients were assessed at 18 months. Between Dec 11, 2013, and June 25, 2014, three participants were assessed for eligibility and enrolled at RUMC, and were assigned to receive intrathecal HPbetaCD at a starting dose of 200 mg every 2 weeks (two patients), or 400 mg every two weeks (one patient). There were no dropouts in this group and all 3 patients were assessed at 18 months. Biomarker studies were consistent with improved neuronal cholesterol homoeostasis and decreased neuronal pathology. Post-drug plasma 24(S)-HC area under the curve (AUC8-72) values, an indicator of neuronal cholesterol homoeostasis, were significantly higher than post-saline plasma 24(S)-HC AUC8-72 after doses of 900 mg (p=0.0063) and 1200 mg (p=0.0037). CSF 24(S)-HC concentrations in three participants given either 600 or 900 mg of HPbetaCD were increased about two fold (p=0.0032) after drug administration. No drug-related serious adverse events were observed. Mid-frequency to high-frequency hearing loss, an expected adverse event, was documented in all participants. When managed with hearing aids, this did not have an appreciable effect on daily communication. The NNSS for the 14 participants treated monthly increased at a rate of 1.22, SEM 0.34 points per year compared with 2.92, SEM 0.27 points per year (p=0.0002) for the 21 patient comparison group. Decreased progression was observed for NNSS domains of ambulation (p=0.0622), cognition (p=0.0040) and speech (p=0.0423). INTERPRETATION: Patients with NPC1 treated with intrathecal HPbetaCD had slowed disease progression with an acceptable safety profile. These data support the initiation of a multinational, randomised, controlled trial of intrathecal HPbetaCD. FUNDING: National Institutes of Health, Dana's Angels Research Trust, Ara Parseghian Medical Research Foundation, Hope for Haley, Samantha's Search for the Cure Foundation, National Niemann-Pick Disease Foundation, Support of Accelerated Research for NPC Disease, Vtesse, Janssen Research and Development, a Johnson & Johnson company, and Johnson & Johnson. PMID- 28803712 TI - Oral cholera vaccine coverage in hard-to-reach fishermen communities after two mass Campaigns, Malawi, 2016. AB - CONTEXT: From December 2015 to August 2016, a large epidemic of cholera affected the fishermen of Lake Chilwa in Malawi. A first reactive Oral Cholera Vaccines (OCV) campaign was organized, in February, in a 2km radius of the lake followed by a preemptive one, conducted in November, in a 25km radius. We present the vaccine coverage reached in hard-to-reach population using simplified delivery strategies. METHOD: We conducted two-stage random-sampling cross-sectional surveys among individuals living in a 2km and 25km radius of Lake Chilwa (islands and floating homes included). Individuals aged 12months and older from Machinga and Zomba districts were sampled: 43 clusters of 14 households were surveyed. Simplified strategies were used for those living in islands and floating homes: self- delivery and community-supervised delivery of the second dose. Vaccine coverage (VC) for at-least-two-doses was estimated taking into account sampling weights and design effects. RESULTS: A total of 1176 households were surveyed (2.7% of non-response). Among the 2833 individuals living in the 2km radius of Lake and the 2915 in the 25km radius: 457 (16.1%) and 239 (8.2%) lived in floating homes or on islands at some point in the year, respectively. For the overall population, VC was 75.6% and 54.2%, respectively. In the 2km radius, VC was 92.2% for those living on the lake at some point of the year: 271 (64.8%) used the simplified strategies. The main reasons for non-vaccination were absence during the campaign and vaccine shortage. Few adverse events occurring in the 24h following vaccination was reported. CONCLUSIONS: We reached a high two-dose coverage of the most at-risk population using simplified delivery strategies. Because of the high fishermen mobility, regular catch-up campaigns or another strategy specifically targeting fishermen need to be assessed for more efficient vaccines use. PMID- 28803713 TI - A review of the key factors to improve adult immunization coverage rates: What can the clinician do? AB - Adult immunization coverage rates remain low in the United States and internationally, despite obvious benefits to vaccinating and maintaining a well vaccinated adult population. Broad policy changes are required to identify and address gaps in financing, in immunization infrastructure, and patient and provider awareness and knowledge to improve the protection of our adult and aging population from vaccine-preventable diseases. There is good evidence that efforts are now underway both within the United States and across the world to advance these policy changes. There are successful interventions that have been demonstrated to improve rates in the pediatric population that must be translated into the adult patient population to meet the critical gaps that remain at the interface of the delivery of vaccinations to adults. Improvements in overall policy will only increase adult immunization coverage rates if interventions are adapted and implemented for adult patients. Often, these same interventions will be applicable to adolescent patients as well. These interventions have been reviewed by the United States Preventive Services Task Force and recommended interventions fall into three categories: (1) Enhancing Patient Access to Vaccination; (2) Improving community/patient demand; and (3) Provider- and healthcare system-directed interventions. Specific interventions that have been demonstrated successful for the adult population include interventions such as reducing patient out-of-pocket costs for vaccinations, patient or family incentive rewards, and implementation of quality measures and quality improvement interventions. Addressing the poor performance in adult immunizations requires approaches predicated on not repeating previous efforts and will require innovative thinking to integrate multiple interventions that have been successful separately, into a holistic approach to support and automate immunization assessment, recommendation, and administration. This can then lead to increased valuation of adult and adolescent immunizations within the priorities of a healthcare system, and improvements in clinic efficiency within a practice. PMID- 28803714 TI - Building capacity for active surveillance of vaccine adverse events in the Americas: A hospital-based multi-country network. AB - New vaccines designed to prevent diseases endemic in low and middle-income countries are being introduced without prior utilization in countries with robust vaccine pharmacovigilance systems. Our aim was to build capacity for active surveillance of vaccine adverse events in the Americas. We describe the implementation of a proof-of-concept study for the feasibility of an international collaborative hospital-based active surveillance system for vaccine safety. The study was developed and implemented in 15 sentinel sites located in seven countries of the region of the Americas, under the umbrella of the World Health Organization (WHO) Global Vaccine Safety Initiative. The study evaluated the associations between measles-mumps-rubella vaccines and two well-recognized adverse events: Immune thrombocytopenic purpura (ITP) and aseptic meningitis. The regional network contributed 63 confirmed ITP and 16 confirmed aseptic meningitis eligible cases to the global study, representing, respectively, 33% and 19% of the total cases. To ensure long-term sustainability and usefulness to investigate adverse events following new vaccine introductions in low and middle-income countries, the network needs to be strengthened with additional sites and integrated into national health systems. PMID- 28803716 TI - Prolongation of terminal latency of the phrenic nerve in amyotrophic lateral sclerosis - Is it clinically useful, and what are the mechanisms? PMID- 28803715 TI - A phase 1 randomized open-label clinical study to evaluate the safety and tolerability of a novel recombinant hepatitis E vaccine. AB - BACKGROUND: This study aimed to evaluate the safety and tolerability for variable dosages of a novel hepatitis E vaccine p179. METHODS: The randomized open-label parallel control phase 1 clinical trial enrolled 120 eligible participants aged 16-65years in Jiangsu Province, China. The experimental groups were randomized to receive different dosages of 20MUg, 30MUg, and 40MUg Hepatitis E Virus (HEV) p179 vaccines, with the 30MUgHEV vaccine p239 Hecolin as control, and vaccinated at 0, 1 and 6month intervals. Participants were observed for solicited local and systemic adverse reactions (ARs) occurring within 7days after each vaccination, and any serious adverse events (SAEs) occurring within 6months post-vaccination. Blood samples were collected from participants 3days before and after each injection, to determine the blood routine and serum biochemical indexes. RESULTS: The solicited local ARs incidence in experimental groups were significantly lower than that of the control group (P=0.027). The difference between solicited total and systemic ARs incidence of experimental groups and the control group were not significant (P>0.05). Similar patterns were observed when the analyses were performed on the group having ARs of varying grades and symptoms. All changes in blood biochemical indexes and routine blood tests before and after different vaccinations were mild (grade 1) or moderate (grade 2), and the difference in experimental groups and the control group were not statistically significant. No vaccine related SAEs occurred in any of the subjects during the study. CONCLUSION: Three different dosages of HEV p179 vaccine were deemed safe and well tolerated. No vaccine-associated SAEs were identified, and the 30MUg dosage formulation was selected for further investigation for efficacy. Clinical trials registration number: 2012L01657. PMID- 28803717 TI - Noninvasive stroke volume variation using electrical velocimetry for predicting fluid responsiveness in dogs undergoing cardiac surgery. AB - OBJECTIVE: To evaluate the ability of a noninvasive cardiac output monitoring system with electrical velocimetry (EV) for predicting fluid responsiveness in dogs undergoing cardiac surgery. STUDY DESIGN: Prospective experimental trial. ANIMALS: A total of 30 adult Beagle dogs. METHODS: Stroke volume (SV), stroke volume variation (SVV) and cardiac index were measured using the EV device in sevoflurane-anaesthetized, mechanically ventilated dogs undergoing thoracotomies for experimental creation of right ventricular failure. The dogs were considered fluid responsive if stroke volume (SVI; indexed to body weight), measured using pulmonary artery thermodilution, increased by 10% or more after volume loading (10 mL kg-1). Relationships of SVV, central venous pressure (CVP) and pulmonary artery occlusion pressure (PAOP) with SVI were analysed to estimate fluid responsiveness. RESULTS: Better prediction of fluid responsiveness, with a significant area under the receiver operating characteristic curve, was observed for SVV (0.85+/-0.07; p=0.0016) in comparison with CVP (0.65+/-0.11; p=0.17) or PAOP (0.60+/-0.12; p=0.35), with a cut-off value of 13.5% (84% specificity and 73% sensitivity). CONCLUSIONS AND CLINICAL RELEVANCE: SVV derived from EV is useful for identification of dogs that are likely to respond to fluids, providing valuable information on volume status under cardiothoracic anaesthesia. PMID- 28803718 TI - Total Neoadjuvant Therapy: A Shifting Paradigm in Locally Advanced Rectal Cancer Management. AB - Colorectal carcinoma is the second leading cause of cancer-related deaths in the United States, with rectal cancer accounting for approximately one-third of newly diagnosed cases, thus representing a major socioeconomic health burden. Although minimally invasive procedures (ie, transanal excision) may be appropriate for a subset of patients with small, superficially invasive tumors, a more comprehensive trimodality approach with neoadjuvant chemoradiotherapy, total mesorectal excision, and systemic chemotherapy is recommended for medically operable patients with nonmetastatic, locally advanced rectal cancer (LARC). Although such multimodality therapy has markedly reduced local recurrence rates, there remains an estimated 5-year distant relapse rate of 35%, representing the leading cause of death in this population. This review critically assesses the literature regarding neoadjuvant therapy for LARC, as well as the available evidence to support selective exclusion of individual modalities from the contemporary therapeutic paradigm, including controversies of nonoperative management, selective radiation sparing, and neoadjuvant systemic therapy. Through the review of existing data and the anticipated results of ongoing clinical trials, we outline the pragmatic opportunities for future investigation into questions of efficacy, safety, and ultimate improvements to the current status quo. PMID- 28803719 TI - Assessment of aortic valve calcium load by multidetector computed tomography. Anatomical validation, impact of scanner settings and incremental diagnostic value. AB - OBJECTIVES: To validate aortic valve calcium (AVC) load measurements by multidetector row computed tomography (MDCT), to evaluate the impact of tube potential and slice thickness on AVC scores, to examine the accuracy of AVC load in distinguishing severe from nonsevere aortic stenosis (AS) and to investigate its effectiveness as an alternative diagnosis method when echocardiography remains inconclusive. METHODS: We prospectively studied 266 consecutive patients with moderate to severe AS who underwent MDCT to measure AVC load and a comprehensive echocardiographic examination to assess AS severity. AVC load was validated against valve weight in 57 patients undergoing aortic valve replacement. The dependence of AVC scores on tube potential and slice thickness was also tested, as well as the relationship between AVC load and echocardiographic criteria of AS severity. RESULTS: MDCT Agatston score correlated well with valve weight (r = 0.82, p < 0.001) and hemodynamic indices of AS severity (all p < 0.001). Ex-vivo Agatston scores decreased significantly with increasing tube potential and slice thickness (repeated measures ANOVA p < 0.001). Multivariate analysis identified mean gradient, the indexed effective orifice area, male gender and left ventricular outflow tract cross-sectional area as independent correlates of the in-vivo AVC load. CONCLUSIONS: MDCT-derived AVC load correlated well with valve weight and hemodynamic indices of AS severity. It also depends on tube potential and slice thickness, thus suggesting that these parameters should be standardized to optimize reproducibility and accuracy. PMID- 28803720 TI - Impact of the self-care education program on quality of life in patients with type II diabetes. AB - INTRODUCTION: Diabetes is an irreversible disease requiring lifetime self-care and rehabilitation. Patient education to improve their ability in administering self-care is also effective, lowering the risks of developing complications and promoting the quality of life. This study was conducted to assess the effect of self-care educational programs in promoting the quality of life of diabetic patients. METHODS: In this pre-test/post-test intervention study design, 30 diabetes patients were included on the basis of a non-randomized sampling, using each subject as her/his own control. The self-care educational program was introduced to participants by researcher through two 55-min sessions. Quality of life by using Iranian Short Form Health Survey was assessed before and after the educational sessions. The paired t-test was used to compare the total and subscale mean scores of the Quality of life before and after the training. RESULTS: Finding showed that there was a significant increase in General health (P=0.027), Physical role (P<0.001), Physical functioning (P=0.027), Social functioning (P=0.029) and Body pain (P=0.020). CONCLUSION: The results from the present study demonstrate that structured patient education improves patients 'well-being' after the teaching program. Diabetes educational program should be a basis for the management of diabetes. PMID- 28803722 TI - Advantages of analyzing postmortem brain samples in routine forensic drug screening-Case series of three non-natural deaths tested positive for lysergic acid diethylamide (LSD). AB - Three case reports are presented, including autopsy findings and toxicological screening results, which were tested positive for the potent hallucinogenic drug lysergic acid diethylamide (LSD). LSD and its main metabolites were quantified in brain tissue and femoral blood, and furthermore hematoma and urine when available. LSD, its main metabolite 2-oxo-3-hydroxy-LSD (oxo-HO-LSD), and iso-LSD were quantified in biological samples according to a previously published procedure involving liquid-liquid extraction and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). LSD was measured in the brain tissue of all presented cases at a concentration level from 0.34 10.8MUg/kg. The concentration level in the target organ was higher than in peripheral blood. Additional psychoactive compounds were quantified in blood and brain tissue, though all below toxic concentration levels. The cause of death in case 1 was collision-induced brain injury, while it was drowning in case 2 and 3 and thus not drug intoxication. However, the toxicological findings could help explain the decedent's inability to cope with brain injury or drowning incidents. The presented findings could help establish reference concentrations in brain samples and assist in interpretation of results from forensic drug screening in brain tissue. This is to the author's knowledge the first report of LSD, iso-LSD, and oxo-HO-LSD measured in brain tissue samples. PMID- 28803721 TI - Conditioning neoadjuvant therapies for improved immunotherapy of cancer. AB - Recent advances in the treatment of melanoma and non-small cell lung cancer (NSCLC) by combining conventional therapies with anti-PD1/PD-L1 immunotherapies, have renewed interests in immunotherapy of cancer. The emerging concept of conventional cancer therapies combined with immunotherapy differs from the classical concept in that it is not simply taking advantage of their additive anti-tumor effects, but it is to use certain therapeutic regimens to condition the tumor microenvironment for optimal response to immunotherapy. To this end, low dose immunogenic chemotherapies, epigenetic modulators and inhibitors of cell cycle progression are potential candidates for rendering tumors highly responsive to immunotherapy. Next generation immunotherapeutics are therefore predicted to be highly effective against cancer, when they are used following appropriate immune modulatory compounds or targeted delivery of tumor cell cycle inhibitors using nanotechnology. PMID- 28803723 TI - Perceived social support among patients with burn injuries: A perspective from the developing world. AB - BACKGROUND: Social support is among the most well-established predictors of post burn psychopathology after burn. Despite a disproportionately large burden of burns in the developing world, the nature of social support among burn patients in this context remains elusive. We, therefore, seek to investigate social support and its biopsychosocial determinants among patients with burn injuries in Pakistan. METHODS: A cross-sectional study of 343 patients presenting with burn injuries at four teaching hospitals in the Punjab province of Pakistan was conducted. Patient evaluation consisted of a multi-part survey of demographic status, clinical features, and social support as measured by the validated Urdu translation of the Multidimensional Scale of Perceived Social Support (MSPSS). Multiple regression analysis was performed to evaluate associations between patient characteristics and MSPSS score. RESULTS: Mean overall MSPSS score was 57.64 (std dev 13.57). Notable positive predictors of social support include male gender, Punjabi ethnicity, burn surface area, and ego resiliency. CONCLUSION: Our study reveals a troubling pattern of inadequate social support among certain subgroups of Pakistani burn patients. Addressing these inequities in the provision of social support must be prioritized as part of the global burn care agenda. PMID- 28803724 TI - Implementation and outcomes of an evidence-based precepting program for burn nurses. AB - INTRODUCTION: There is significant nationwide interest in transitioning new and new-to-specialty nurses into practice, especially in burn care. Lack of a structured transition program in our Burn Center was recognized as a contributing factor for nursing dissatisfaction and increased turnover compared to other hospital units. Employee evaluations exposed a need for more didactic instruction, hands-on learning, and preceptor support. The goal of this project was to implement an evidence-based transition to practice program specific to the burn specialty. MATERIAL AND METHODS: The Iowa Model of Evidence-based Practice served as the model for this project. A working group was formed consisting of nurse scientists, clinical nurse leaders, clinical nurse specialists, lead preceptors, staff nurse preceptors and wound care coordinators. A systematic review of the literature was conducted focusing on nurse transition; preceptor development and transitioning nurse training programs with competency assessment, ongoing multifaceted evaluation and retention strategies were created. The evidence-based Vermont Nurses in Partnership (VNIP) Clinical Transition Framework was selected and subsequent education was provided to all Burn Center leaders and staff. Benchmarks for basic knowledge assessment (BKAT) and burn wound care were established among current staff by work site and education level to help evaluate transitioning nurses. Policies were modified to count each preceptor/transitioning nurse dyad as half an employee on the schedule. Multiple high-fidelity simulation scenarios were created to expand hands-on opportunities. RESULTS: From September 2012-December 2013, 110 (57% acute care nursing) Burn Center staff attended the VNIP Clinical Coaching Course, to include 34 interdisciplinary staff (rehabilitation, education, respiratory therapy, and outpatient clinic staff) and 100% of identified preceptors (n=33). A total of 30 new nurses participated in the transition program: 26 (87%) completed, 3 (10%) did not complete, and 1 (3%) received exception (no patient care). Transitioning nurses achieved passing BKAT scores (n=22; 76%) and WC scores (n=24; 93%); individual remediation was provided for those failing to achieve unit benchmarks and transition training was modified to improve areas of weakness. Transitioning nurses' weekly competency progression average initial ratings on a 10 point scale (10 most competent) were 5+/-2; final ratings averaged 9+/-1 (n=25) (p<0.0001). CONCLUSIONS: An evidence-based team practice approach toward preceptorship created a standardized, comprehensive and flexible precepting program to assist and support transition to specialty burn practice for experienced nurses. Use of objective metrics enabled ongoing assessment and made training adaptable, individualized, and cost effective. Application of this standardized approach across our organization may improve consistency for all transitions in practice specialty. PMID- 28803725 TI - Schistosomiasis: Drugs used and treatment strategies. AB - Neglected tropical diseases (NTDs) affect millions of people in different geographic regions, especially the poorest and most vulnerable. Currently NTDs are prevalent in 149 countries, seventeen of these neglected tropical parasitic diseases are classified as endemic. One of the most important of these diseases is schistosomiasis, also known as bilharzia, a disease caused by the genus Schistosoma. It presents several species, such as Schistosoma haematobium, Schistosoma japonicum and Schistosoma mansoni, the latter being responsible for parasitosis in Brazil. Contamination occurs through exposure to contaminated water in the endemic region. This parasitosis is characterized by being initially asymptomatic, but it is able to evolve into more severe clinical forms, potentially causing death. Globally, more than 200 million people are infected with one of three Schistosome species, including an estimated 40 million women of reproductive age. In Brazil, about 12 million children require preventive chemotherapy with anthelmintic. However, according to the World Health Organization (WHO), only about 15% of the at-risk children receive regular treatment. The lack of investment by the pharmaceutical industry for the development and/or improvement of new pharmaceutical forms, mainly aimed at the pediatric public, is a great challenge. Currently, the main forms of treatment used for schistosomiasis are praziquantel (PZQ) and oxaminiquine (OXA). PZQ is the drug of choice because it presents as a high-spectrum anthelmintic, used in the treatment of all known species of schistosomiasis and some species of cestodes and trematodes. OXA, however, is not active against the three Schistosome species. This work presents a literature review regarding schistosomiasis. It addresses points such as available treatments, the role of the pharmaceutical industry against neglected diseases, and perspectives for treatment. PMID- 28803726 TI - Golgi-Resident Galphao Promotes Protrusive Membrane Dynamics. AB - To form protrusions like neurites, cells must coordinate their induction and growth. The first requires cytoskeletal rearrangements at the plasma membrane (PM), the second requires directed material delivery from cell's insides. We find that the Galphao-subunit of heterotrimeric G proteins localizes dually to PM and Golgi across phyla and cell types. The PM pool of Galphao induces, and the Golgi pool feeds, the growing protrusions by stimulated trafficking. Golgi-residing KDELR binds and activates monomeric Galphao, atypically for G protein-coupled receptors that normally act on heterotrimeric G proteins. Through multidimensional screenings identifying > 250 Galphao interactors, we pinpoint several basic cellular activities, including vesicular trafficking, as being regulated by Galphao. We further find small Golgi-residing GTPases Rab1 and Rab3 as direct effectors of Galphao. This KDELR -> Galphao -> Rab1/3 signaling axis is conserved from insects to mammals and controls material delivery from Golgi to PM in various cells and tissues. PMID- 28803727 TI - Elimination of Toxic Microsatellite Repeat Expansion RNA by RNA-Targeting Cas9. AB - Microsatellite repeat expansions in DNA produce pathogenic RNA species that cause dominantly inherited diseases such as myotonic dystrophy type 1 and 2 (DM1/2), Huntington's disease, and C9orf72-linked amyotrophic lateral sclerosis (C9-ALS). Means to target these repetitive RNAs are required for diagnostic and therapeutic purposes. Here, we describe the development of a programmable CRISPR system capable of specifically visualizing and eliminating these toxic RNAs. We observe specific targeting and efficient elimination of microsatellite repeat expansion RNAs both when exogenously expressed and in patient cells. Importantly, RNA targeting Cas9 (RCas9) reverses hallmark features of disease including elimination of RNA foci among all conditions studied (DM1, DM2, C9-ALS, polyglutamine diseases), reduction of polyglutamine protein products, relocalization of repeat-bound proteins to resemble healthy controls, and efficient reversal of DM1-associated splicing abnormalities in patient myotubes. Finally, we report a truncated RCas9 system compatible with adeno-associated viral packaging. This effort highlights the potential of RCas9 for human therapeutics. PMID- 28803728 TI - Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade. AB - Immune-checkpoint blockade is able to achieve durable responses in a subset of patients; however, we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4- and anti-PD-1-induced tumor rejection. To address these issues, we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor-infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor-infiltrating T cell populations. Anti-PD-1 predominantly induces the expansion of specific tumor infiltrating exhausted-like CD8 T cell subsets. In contrast, anti-CTLA-4 induces the expansion of an ICOS+ Th1-like CD4 effector population in addition to engaging specific subsets of exhausted-like CD8 T cells. Thus, our findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint-blockade-induced immune responses are driven by distinct cellular mechanisms. PMID- 28803729 TI - The Ground State and Evolution of Promoter Region Directionality. AB - Eukaryotic promoter regions are frequently divergently transcribed in vivo, but it is unknown whether the resultant antisense RNAs are a mechanistic by-product of RNA polymerase II (Pol II) transcription or biologically meaningful. Here, we use a functional evolutionary approach that involves nascent transcript mapping in S. cerevisiae strains containing foreign yeast DNA. Promoter regions in foreign environments lose the directionality they have in their native species. Strikingly, fortuitous promoter regions arising in foreign DNA produce equal transcription in both directions, indicating that divergent transcription is a mechanistic feature that does not imply a function for these transcripts. Fortuitous promoter regions arising during evolution promote bidirectional transcription and over time are purged through mutation or retained to enable new functionality. Similarly, human transcription is more bidirectional at newly evolved enhancers and promoter regions. Thus, promoter regions are intrinsically bidirectional and are shaped by evolution to bias transcription toward coding versus non-coding RNAs. PMID- 28803730 TI - Renal Sodium Gradient Orchestrates a Dynamic Antibacterial Defense Zone. AB - Lower urinary tract infections are among the most common human bacterial infections, but extension to the kidneys is rare. This has been attributed to mechanical forces, such as urine flow, that prevent the ascent of bladder microbes. Here, we show that the regional hypersalinity, required for the kidney's urine-concentrating function, instructs epithelial cells to produce chemokines that localize monocyte-derived mononuclear phagocytes (MNPs) to the medulla. This hypersaline environment also increases the intrinsic bactericidal and neutrophil chemotactic activities of MNPs to generate a zone of defense. Because MNP positioning and function are dynamically regulated by the renal salt gradient, we find that patients with urinary concentrating defects are susceptible to kidney infection. Our work reveals a critical accessory role for the homeostatic function of a vital organ in optimizing tissue defense. PMID- 28803731 TI - Purification and characterization of the colicin A immunity protein in detergent micelles. AB - The immunity proteins against pore-forming colicins represent a family of integral membrane proteins that reside in the inner membrane of producing cells. Cai, the colicin A immunity protein, was characterized here in detergent micelles by circular dichroism (CD), size exclusion chromatography, chemical cross linking, nuclear magnetic resonance (NMR) spectroscopy, cysteine accessibility, and colicin A binding in detergent micelles. Bile-salt derivatives induced extensive protein polymerization that precluded further investigation. The physical characterization of detergent-solubilized protein indicates that phosphate-containing detergents are more efficient in extracting, solubilizing and maintaining Cai in a monomeric state. Yet, their capacity to ensure protein activity, reconstitution, helix packing, and high-quality NMR spectra was inferior to that of milder detergents. Solvent ionic strength and composition greatly modified the solubilizing capacity of milder detergents. Most importantly, binding to the colicin A pore-forming domain (pf-ColA) occurred almost exclusively in sugar-derived detergents. The relative performance of the different detergents in each experiment depends on their impact not only on Cai structure, solubility and oligomerization state, but also on other reaction components and technical aspects. Thus, proteoliposomes were best obtained from protein in LDAO micelles, possibly also due to indirect effects on the lipidic bilayer. The compatibility of a detergent with Cai/pf-ColA complex formation is influenced by its effect on the conformational landscape of each protein, where detergent-mediated pf-ColA denaturation could also lead to negative results. The NMR spectra were greatly affected by the solubility, monodispersity, fold and dynamics of the protein-detergent complexes, and none of those tested here provided NMR spectra of sufficient quality to allow for peak assignment. Cai function could be proven in alkyl glycosides and not in those detergents that afforded the best solubility, reconstitution efficiency or spectral quality indicating that these criteria cannot be taken as unambiguous proof of nativeness without the support of direct activity measurements. PMID- 28803733 TI - Corrigendum to "Characteristics of Cervical Spine Trauma in Patients with Ankylosing Spondylitis and Ossification of the Posterior Longitudinal Ligament" [World Neurosurgery 96 (2016) 202-208]. PMID- 28803734 TI - Erratum to "Mortality-Associated Characteristics of Patients with Traumatic Brain Injury at the University Teaching Hospital of Kigali, Rwanda" [World Neurosurgery 102 (2017) 571-582]. PMID- 28803732 TI - Reck and Gpr124 Are Essential Receptor Cofactors for Wnt7a/Wnt7b-Specific Signaling in Mammalian CNS Angiogenesis and Blood-Brain Barrier Regulation. AB - Reck, a GPI-anchored membrane protein, and Gpr124, an orphan GPCR, have been implicated in Wnt7a/Wnt7b signaling in the CNS vasculature. We show here that vascular endothelial cell (EC)-specific reduction in Reck impairs CNS angiogenesis and that EC-specific postnatal loss of Reck, combined with loss of Norrin, impairs blood-brain barrier (BBB) maintenance. The most N-terminal domain of Reck binds to the leucine-rich repeat (LRR) and immunoglobulin (Ig) domains of Gpr124, and weakening this interaction by targeted mutagenesis reduces Reck/Gpr124 stimulation of Wnt7a signaling in cell culture and impairs CNS angiogenesis. Finally, a soluble Gpr124(LRR-Ig) probe binds to cells expressing Frizzled, Wnt7a or Wnt7b, and Reck, and a soluble Reck(CC1-5) probe binds to cells expressing Frizzled, Wnt7a or Wnt7b, and Gpr124. These experiments indicate that Reck and Gpr124 are part of the cell surface protein complex that transduces Wnt7a- and Wnt7b-specific signals in mammalian CNS ECs to promote angiogenesis and regulate the BBB. PMID- 28803735 TI - Previously successful dental implants can fail when patients commence anti resorptive therapy-a case series. AB - This article reports a type of localized osteonecrosis that can occur in patients who have had successful osseointegrated implants for many years and then commence anti-resorptive therapy. Eleven female patients were identified who had successful implant insertion, but who were placed on anti-resorptive therapy (bisphosphonates or denosumab) several years later and developed osteonecrosis around the implants. In each case, the osteonecrosis occurred only around the implants and not around the patient's remaining teeth. The implants of eight patients were removed with a sequestrum of bone tightly adherent to the implant. This is different from the normal pattern of implant failure. Implant failure can occur when patients with successfully integrated implants are later placed on anti-resorptive therapy, and the osteonecrosis takes a particular form where a sequestrum forms that remains adherent to the implant. Why the adjacent remaining teeth are not affected is unclear. PMID- 28803736 TI - An aggressive and fatal craniofacial group A Streptococcus infection resulting from a minimally displaced orbital floor fracture. AB - While sharp, penetrating trauma is often associated with group A Streptococcus (GAS) infections and subsequent necrotizing fasciitis (NF) and streptococcal toxic shock syndrome (STSS), there are scant reports in the oral and maxillofacial surgery literature regarding blunt, non-penetrating trauma in association with these conditions. With a clinical course that initially appears relatively benign following blunt trauma, NF can progress swiftly through the fascial planes and may quickly become life-threatening if the oral and maxillofacial surgeon fails to recognize some of the critical pathognomonic signs. The case of a 64-year-old female who suffered a ground-level mechanical fall with a minimally displaced lateral orbital wall fracture is reported here. This seemingly benign, non-penetrating injury subsequently developed into rapidly progressive, fatal NF and STSS. This case is used to highlight the necessity for early detection of NF and STSS prior to rapid clinical decline, as these scenarios, particularly bilateral peri-orbital NF with resulting mortality, have been reported infrequently following blunt, craniofacial trauma in the literature related to this specialty. PMID- 28803737 TI - Cone beam computed tomography-based cephalometric norms for Brazilian adults. AB - This study established cone beam computed tomography (CBCT)-based cephalometric norms for Brazilian adults, including the assessment of sexual dimorphism. An observer performed McNamara's cephalometric analysis twice on 60 CBCT datasets acquired from patients with a normal dental occlusion, divided equally into two groups by sex. Welch's t-test was applied to assess differences between the sexes in hard tissue cephalometric measurements, and Dahlberg's formula was used to calculate measurement error introduced by the observer. The cephalometric measurements of effective mandibular length, effective midfacial length, maxillomandibular differential, and lower anterior facial height presented sexual dimorphism. Linear measurements had error <=0.78mm, and angular measurements had error <=1.24 degrees . The results show that (1) the CBCT-based cephalometric norms established in this study are reliable for use by researchers and clinicians, and (2) Brazilian adult males and females have similar craniofacial morphology, with males possessing larger jaws than females. PMID- 28803738 TI - Vertical platysma myocutaneous flap reconstruction for oral defects using three different incision designs: experience with 68 cases. AB - This study evaluated the effects of three different incision designs for the vertical platysma myocutaneous flap (VPMF): apron, MacFee, and T-shaped. This flap was used for the reconstruction of intraoral defects following cancer ablation in selected patients. Sixty-eight cases of VPMF reconstruction were assessed: the apron incision was used in 28, MacFee incision in 22, and T-shaped incision in 18. With regard to postoperative outcomes, there were 26 cases of flap survival and two of partial necrosis with the apron incision; 20 of survival and two of partial necrosis with the MacFee incision; 15 of survival and three of partial necrosis with the T-shaped incision. Success rates were 92.9%, 90.9% and 83.3%, respectively, for VPMF with the apron, MacFee, and T-shaped incisions. A wound healing disturbance in the neck was seen in three cases of VPMF with the apron incision and one case with the MacFee incision. The MacFee incision had the best aesthetic effect, and the postoperative neck scar was more obvious for the T shaped incision. It is recommended that VPMF with the MacFee or apron incision be used for the reconstruction of larger buccal mucosa and floor of the mouth defects, while VPMF with the T-shaped incision should be used for smaller intraoral defects, especially tongue defects of the lateral surface. PMID- 28803739 TI - Two-stage reconstruction of the severely deficient alveolar ridge: bone graft followed by alveolar distraction osteogenesis. AB - Distraction osteogenesis for the augmentation of severe alveolar bone deficiency has gained popularity during the past two decades. In cases where the vertical bone height is not sufficient to create a stable transport segment, performing alveolar distraction osteogenesis (ADO) is not possible. In these severe cases, a two-stage treatment protocol is suggested: onlay bone grafting followed by ADO. An iliac crest onlay bone graft followed by ADO was performed in 13 patients: seven in the mandible and six in the maxilla. Following ADO, endosseous implants and prosthetic restorations were placed. In all cases, the onlay bone graft resulted in inadequate height for implant placement, but allowed ADO to be performed. ADO was performed to a mean total vertical augmentation of 13.7mm. Fifty-two endosseous implants were placed. During a mean follow-up of 4.85 years, two implants failed, both during the first 6 months; the survival rate was 96.15%. In severe cases lacking the required bone for ADO, using an onlay bone graft as a first stage treatment increases the bone height thus allowing ADO to be performed. This article describes a safe and stable two-stage treatment modality for severely atrophic cases, resulting in sufficient bone for implant placement and correction of the inter-maxillary vertical relationship. PMID- 28803741 TI - The cardiovascular toxicity of triadimefon in early life stage of zebrafish and potential implications to human health. AB - The health risk of triadimefon (TF) to cardiovascular system of human is still unclear, especially to pesticide suicides population, occupational population (farmers, retailers and pharmaceutical workers), and special population (young children and infants, pregnant women, older people, and those with compromised immune systems) who are at a greater risk. Therefore, firstly we explored the toxic effects and possible mechanism of cardiovascular toxicity induced by TF using zebrafish model. Zebrafish at stage of 48 h post fertilization (hpf) exposed to TF for 24 h exhibited morphological malformations which were further confirmed by histopathologic examination, including pericardial edema, circulation abnormalities, serious venous thrombosis and increased distance between the sinus venosus (SV) and bulbus arteriosus (BA) regions of the heart. In addition to morphological changes, TF induced functional deficits in the heart of zebrafish, including bradycardia and a significant reduced cardiac output that became more serious at higher concentrations. To better understand the possible molecular mechanisms underlying cardiovascular toxicity in zebrafish, we investigated the transcriptional level of genes related to calcium signaling pathway and cardiac muscle contraction. Q-PCR (quantitative real-time polymerase chain reaction) results demonstrated that the expression level of genes related to ATPase (atp2a1l, atp1b2b, atp1a3b), calcium channel (cacna1ab, cacna1da) and cardiac troponin C (tnnc1a) were significantly decreased after TF exposure. For the first time, the present study revealed that TF exposure had observable morphological and functional negative impacts on cardiovascular system of zebrafish. Mechanistically, this toxicity might result from the pressure of down regulation of genes associated with calcium signaling pathway and cardiac muscle contraction following TF exposure. These findings generated here can provide information for better pesticide poisoning treatments, occupational disease prevention, and providing theoretical foundation for risk management measures. PMID- 28803740 TI - Vorinostat Renders the Replication-Competent Latent Reservoir of Human Immunodeficiency Virus (HIV) Vulnerable to Clearance by CD8 T Cells. AB - : Latently human immunodeficiency virus (HIV)-infected cells are transcriptionally quiescent and invisible to clearance by the immune system. To demonstrate that the latency reversing agent vorinostat (VOR) induces a window of vulnerability in the latent HIV reservoir, defined as the triggering of viral antigen production sufficient in quantity and duration to allow for recognition and clearance of persisting infection, we developed a latency clearance assay (LCA). The LCA is a quantitative viral outgrowth assay (QVOA) that includes the addition of immune effectors capable of clearing cells expressing viral antigen. Here we show a reduction in the recovery of replication-competent virus from VOR exposed resting CD4 T cells following addition of immune effectors for a discrete period. TAKE HOME MESSAGE: VOR exposure leads to sufficient production of viral protein on the cell surface, creating a window of vulnerability within this latent reservoir in antiretroviral therapy (ART)-suppressed HIV-infected individuals that allows the clearance of latently infected cells by an array of effector mechanisms. PMID- 28803742 TI - Gastric cardia lesion with abnormal volumetric laser endomicroscopy imaging result. PMID- 28803743 TI - Gastric antral vascular ectasia presenting as a polypoid mass in a patient with cirrhosis. PMID- 28803744 TI - Novel 1 L polyethylene glycol-based bowel preparation NER1006 for overall and right-sided colon cleansing: a randomized controlled phase 3 trial versus trisulfate. AB - BACKGROUND AND AIMS: NER1006 is the first 32 fluid ounce (1 L) polyethylene glycol-based bowel preparation. This randomized, multicenter, colonoscopist/central reader-blinded phase 3 non-inferiority trial assessed the efficacy, safety, and tolerability of NER1006 versus trisulfate for bowel cleansing. METHODS: Patients undergoing colonoscopy were randomized (1:1) to receive NER1006 or trisulfate, using evening/morning split-dosing administration. Blinded central readers used the validated Harefield Cleansing Scale to evaluate 2 alternative primary endpoints: overall bowel-cleansing success and high-quality cleansing of the ascending colon/cecum. Secondary endpoints included lesion detection, Boston Bowel Preparation Scale (BBPS) assessment, and adherence. The non-inferiority margin was 10% and the significance threshold was P < .025. RESULTS: Of 621 patients randomized (NER1006, n=310; trisulfate, n=311), 556 were evaluated for efficacy (NER1006, n=276; trisulfate, n=280). NER1006 achieved non inferiority versus trisulfate for both primary endpoints of overall bowel cleansing success (85.1% vs 85.0%; difference, 0.14%; one-sided 97.5% lower confidence limit [LCL], -8.15%; P = .528) and high-quality cleansing of the ascending colon/cecum (35.9% versus 29.3%; difference, 6.58%; LCL, -1.69%; P = .059). BBPS assessments supported overall bowel-cleansing success rates. Lesion detection rates were similar between the groups. The percentage of patients with treatment-related adverse events was 14.9% with NER1006 and 9.4% with trisulfate. Both bowel preparations showed similar overall tolerability and safety profiles. Adherence was very high in both arms. CONCLUSIONS: With evening/morning split dosing, NER1006 was as effective as trisulfate for overall bowel and right-sided colon cleansing. Adverse event rates were slightly higher with NER1006 than trisulfate, but did not compromise tolerability, adherence, or efficacy. (Clinical trial registration number: NCT02254486.). PMID- 28803745 TI - Further development of the MRONJ minipig large animal model. AB - Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious and potentially severe side effect of antiresorptive therapy with bisphosphonates or denosumab. Recently, a large animal minipig MRONJ model was introduced which led to early necrotic lesions in the majority of extraction sites after bisphosphonate administration. The aim of this project was to modify the preoperative cumulative bisphosphonate dose (zoledronate) and hereby firstly to demonstrate the reliability and reproducibility of the established model. Secondly, the MRONJ lesions should be carefully investigated using clinical and MUCT as well as detailed histological analyses. Twelve 1.5-year-old Gottingen minipigs were divided into three groups. In group 1 (n = 3) minipigs received weekly doses of zoledronate intravenously (0.05 mg/kg bodyweight) for 20 weeks. No interventions were performed. In group 2 (n = 6) animals received the identical zoledronate dosage as animals in group 1 and tooth extractions of two premolars (PM 2 and 4) in each jaw (maxilla and mandible) were performed after 12 weeks. Group 3 (n = 3) served as tooth extraction only control (no zoledronate administrations). The jaw-bones were subjected to detailed macroscopic, radiological and histological investigations. All extraction sites (24/24) in animals of group 2 showed clinical, radiological and histological signs of MRONJ (mainly stage II), whereas no bone necrosis was found in group 3. Animals of group 1 and group 2 showed further MRONJ lesions in areas where infections (periodontitis) were present. This is the first large animal model to show a 100% incidence of MRONJ at all extraction sites in bisphosphonate pretreated animals (group 2). In addition, in this preclinical model for MRONJ it is shown that tooth extractions are not mandatory for a MRONJ manifestation. MRONJ also developed in areas of gingival or periodontal infections. PMID- 28803746 TI - Air bubbles and hemolysis of blood samples during transport by pneumatic tube systems. AB - BACKGROUND: Transport of blood samples through pneumatic tube systems (PTSs) generates air bubbles in transported blood samples and, with increasing duration of transport, the appearance of hemolysis. We investigated the role of air-bubble formation in PTS-induced hemolysis. METHODS: Air was introduced into blood samples for 0, 1, 3 or 5min to form air bubbles. Hemolysis in the blood was assessed by (H)-index, lactate dehydrogenase (LD) and potassium in plasma. In an effort to prevent PTS-induced hemolysis, blood sample tubes were completely filled, to prevent air bubble formation, and compared with partially filled samples after PTS transport. We also compared hemolysis in anticoagulated vs clotted blood subjected to PTS transport. RESULTS: As with transport through PTSs, the duration of air bubble formation in blood by a gentle stream of air predicted the extent of hemolysis as measured by H-index (p<0.01), LD (p<0.01), and potassium (p<0.02) in plasma. Removing air space in a blood sample prevented bubble formation and fully protected the blood from PTS-induced hemolysis (p<0.02 vs conventionally filled collection tube). Clotted blood developed less foaming during PTS transport and was partially protected from hemolysis vs anticoagulated blood as indicated by lower LD (p<0.03) in serum than in plasma after PTS sample transport. CONCLUSIONS: Prevention of air bubble formation in blood samples during PTS transport protects samples from hemolysis. PMID- 28803747 TI - Novel heterozygous mutations of the INSR gene in a familial case of Donohue syndrome. AB - Donohue syndrome (DS), a rare autosomal recessive disease which represents severe insulin resistance, pre- and postnatal growth retardation, hypertrichosis, and dysmorphic features, is caused by mutations in the insulin receptor (INSR) gene. Here, we have reported the clinical, molecular, and biochemical characterizations of a patient with DS. In this article, we have also reported a case with 2 novel INSR mutations and the DS phenotype. Using next-generation sequencing (NGS), we screened 27 known genes involved in inherited maturity-onset diabetes of the young (MODY) and identified compound heterozygous mutations in the INSR gene in the patient with DS, c.62T>G (p.L21R) and c.2563G>T (p.V855F). The positive correlation of these mutations with DS was further validated by Sanger DNA sequencing of his lineal consanguinity, indicating that these pathogenic mutations were inherited maternally and paternally, respectively. Therefore, our finding expanded the number of reported cases of this rare disease and the mutation spectrum of INSR mutation, suggesting that NGS is an accurate, rapid, and cost-effective method for the genetic diagnosis of this rare disease. PMID- 28803748 TI - Management and prognosis of ovarian yolk sac tumors; an analysis of the National Cancer Data Base. AB - OBJECTIVE: To evaluate the clinico-pathological characteristics, management and prognosis of women diagnosed with ovarian yolk sac tumors (OYSTs). METHODS: The U.S National Cancer Data Base was queried for women diagnosed with OYST between 2004 and 2014. Overall survival (OS) was calculated following generation of Kaplan-Meir curves. Univariate analysis was performed with the log-rank test. A Cox model was constructed to determine independent predictors of mortality. RESULTS: A total of 561 women were identified with a median age of 23years. The majority (58.5%) had early stage (I-II), while 29.6% and 11.9% had stage III and IV disease respectively. Five-year OS for women with stage I, II, III and IV disease were 94.8%, 97.1%, 70.9% and 51.6% respectively, p<0.001. Better 5-yr OS was observed for adolescents (94.4%) and young adults (89.3%) compared to older premenopausal (67.6%) and postmenopausal women (30.6%), p<0.001. Omentectomy, hysterectomy and lymph node sampling/dissection (LND) were not associated with better OS. Women who received adjuvant chemotherapy had superior OS compared to those who did not, p=0.016. Early disease stage, younger age and receipt of adjuvant chemotherapy, but not LND were independently associated with better mortality. CONCLUSIONS: Women with OYST commonly present with early stage disease. Administration of adjuvant chemotherapy, early stage and younger age are associated with superior outcomes. PMID- 28803749 TI - The effects of 17beta-estradiol on blood brain barrier integrity in the absence of the estrogen receptor alpha; an in-vitro model. AB - The blood-brain barrier (BBB), which saves the brain from toxic substances, is formed by endothelial cells. It is mainly composed of tight junction (TJ) proteins existing between endothelial cells. Estrogen is an important regulatory hormone of BBB permeability. It protects the BBB before menopause, but may increase BBB permeability with aging. In addition, nitric oxide modulates BBB permeability. Alcohol impairs the integrity of the BBB with oxidants and inflammatory mediators such as iNOS. We investigated the effects of estrogen on BBB integrity in an in vitro BBB model created with ERalpha-free HUVEC (human umbilical vein endothelial-like cells) to mimics the menopausal period. In vitro BBB model is created with HUVEC/C6 (rat glioma cells) co-culture. The effect of 17beta-estradiol on ethanol-induced BBB disruption and change/or increase of iNOS activity, which modulate BBB integrity, were evaluated. Inducibility and functionality of BBB were investigated using transendothelial electrical resistance (TEER) and the expression of proteins TJ proteins (occludin and claudin-1) and iNOS activity by immunostaining. Our results revealed that 17beta estradiol treatment before and after ethanol decrease expression of occludin and claudin-1 and value of TEER which are BBB disrupt indicators. In addition, ethanol and 17beta-estradiol separately and pre- and post-ethanol 17beta estradiol treatment increased iNOS expression. Thus our study suggests caution in the use of 17beta-estradiol after menopause because 17beta-estradiol at this time may both increase the inflammatory process as well as damage the BBB. We think that beneficial effects of 17beta-estradiol may be through ERalpha but it needs further studies. PMID- 28803750 TI - Motor cortex and spinal cord neuromodulation promote corticospinal tract axonal outgrowth and motor recovery after cervical contusion spinal cord injury. AB - Cervical injuries are the most common form of SCI. In this study, we used a neuromodulatory approach to promote skilled movement recovery and repair of the corticospinal tract (CST) after a moderately severe C4 midline contusion in adult rats. We used bilateral epidural intermittent theta burst (iTBS) electrical stimulation of motor cortex to promote CST axonal sprouting and cathodal trans spinal direct current stimulation (tsDCS) to enhance spinal cord activation to motor cortex stimulation after injury. We used Finite Element Method (FEM) modeling to direct tsDCS to the cervical enlargement. Combined iTBS-tsDCS was delivered for 30min daily for 10days. We compared the effect of stimulation on performance in the horizontal ladder and the Irvine Beattie and Bresnahan forepaw manipulation tasks and CST axonal sprouting in injury-only and injury+stimulation animals. The contusion eliminated the dorsal CST in all animals. tsDCS significantly enhanced motor cortex evoked responses after C4 injury. Using this combined spinal-M1 neuromodulatory approach, we found significant recovery of skilled locomotion and forepaw manipulation skills compared with injury-only controls. The spared CST axons caudal to the lesion in both animal groups derived mostly from lateral CST axons that populated the contralateral intermediate zone. Stimulation enhanced injury-dependent CST axonal outgrowth below and above the level of the injury. This dual neuromodulatory approach produced partial recovery of skilled motor behaviors that normally require integration of posture, upper limb sensory information, and intent for performance. We propose that the motor systems use these new CST projections to control movements better after injury. PMID- 28803752 TI - Optimal Dose, Timing and Ratio of Blood Products in Massive Transfusion: Results from a Systematic Review. AB - Optimal dose, timing and ratio to red blood cells (RBC) of blood component therapy (fresh frozen plasma [FFP], platelets, cryoprecipitate or fibrinogen concentrate) to reduce morbidity and mortality in critically bleeding patients requiring massive transfusion is unknown. We performed a systematic review for randomized controlled trials (RCT) in MEDLINE, The Cochrane Library, Embase, CINAHL, PubMed the Transfusion Evidence Library and using multiple clinical trials registries to 21 February 2017. Sixteen RCTs were identified: six completed (five in adult trauma patients, one pediatric burn patients) and ten ongoing trials. Of the completed trials: three were feasibility trials, comparing a FFP, platelets and RBC ratio of 1:1:1 to laboratory-guided transfusion practice [n=69], early cryoprecipitate compared to standard practice [n=41], and early fibrinogen concentrate compared to placebo [n=45]; one trial compared the effect of FFP, platelets and RBC ratio of 1:1:1 with 1:1:2 on 24-hour and 30-day mortality [n=680]; one compared whole blood to blood component therapy on 24-hour blood use [n=107]; one compared a FFP to RBC ratio of 1:1 with 1:4 [n=16]. Data from two trials were pooled in a meta-analysis for 28-day mortality because the transfusion ratios achieved were similar. Results from these two trials suggest higher transfusion ratios were associated with transfusion of more FFP and platelets without evidence of significant difference with respect to mortality or morbidity. On the limited evidence available, there is insufficient basis to recommend a 1:1:1 over a 1:1:2 ratio or standard care for adult patients with critical bleeding requiring massive transfusion. PMID- 28803753 TI - Recent progresses in biomedical applications of aptamer-functionalized systems. AB - Aptamers, known as "chemical antibodies" are screened via a combinational technology of systematic evolution of ligands by exponential enrichment (SELEX). Due to their specific targeting ability, high binding affinity, low immunogenicity and easy modification, aptamer-functionalized systems have been extensively applied in various fields and exhibit favorable results. However, there is still a long way for them to be commercialized, and few aptamer functionalized systems have yet successfully entered clinical and industrial use. Thus, it is necessary to overview the recent research progresses of aptamer functionalized systems for the researchers to improve or design novel and better aptamer-functionalized systems. In this review, we first introduce the recent progresses of aptamer-functionalized systems' applications in biosensing, targeted drug delivery, gene therapy and cancer cell imaging, followed by a discussion of the challenges faced with extensive applications of aptamer functionalized systems and speculation of the future prospects of them. PMID- 28803751 TI - Insulin prevents aberrant mitochondrial phenotype in sensory neurons of type 1 diabetic rats. AB - Diabetic neuropathy affects approximately 50% of diabetic patients. Down regulation of mitochondrial gene expression and function has been reported in both human tissues and in dorsal root ganglia (DRG) from animal models of type 1 and type 2 diabetes. We hypothesized that loss of direct insulin signaling in diabetes contributes to loss of mitochondrial function in DRG neurons and to development of neuropathy. Sensory neurons obtained from age-matched adult control or streptozotocin (STZ)-induced type 1 diabetic rats were cultured with or without insulin before determining mitochondrial respiration and expression of mitochondrial respiratory chain and insulin signaling-linked proteins. For in vivo studies age-matched control rats and diabetic rats with or without trace insulin supplementation were maintained for 5months before DRG were analyzed for respiratory chain gene expression and cytochrome c oxidase activity. Insulin (10nM) significantly (P<0.05) increased phosphorylation of Akt and P70S6K by 4 fold and neurite outgrowth by 2-fold in DRG cultures derived from adult control rats. Insulin also augmented the levels of selective mitochondrial respiratory chain proteins and mitochondrial bioenergetics parameters in DRG cultures from control and diabetic rats, with spare respiratory capacity increased by up to 3 fold (P<0.05). Insulin-treated diabetic animals exhibited improved thermal sensitivity in the hind paw and had increased dermal nerve density compared to untreated diabetic rats, despite no effect on blood glucose levels. In DRG of diabetic rats there was suppressed expression of mitochondrial respiratory chain proteins and cytochrome c oxidase activity that was corrected by insulin therapy. Insulin elevates mitochondrial respiratory chain protein expression and function in sensory neurons and this is associated with enhanced neurite outgrowth and protection against indices of neuropathy. PMID- 28803754 TI - Corrigendum to "eHealth literacy in chronic disease patients: An item response theory analysis of the eHealth literacy scale (eHEALS)" [Patient Educ. Counseling 100 (2) (February 2017) 320-326]. PMID- 28803755 TI - Communicating complex genomic information: A counselling approach derived from research experience with Autism Spectrum Disorder. AB - Individuals with Autism Spectrum Disorder (ASD) share characteristics (impairments in socialization and communication, and repetitive interests and behaviour), but differ in their developmental course, pattern of symptoms, and cognitive and language abilities. The development of standardized phenotyping has revealed ASD to clinically be vastly heterogeneous, ranging from milder presentations to more severe forms associated with profound intellectual disability. Some 100 genes have now been implicated in the etiology of ASD, and advances in genome-wide testing continue to yield new data at an unprecedented rate. As the translation of this data is incorporated into clinical care, genetic professionals/counsellors, as well as other health care providers, will benefit from guidelines and tools to effectively communicate such genomic information. Here, we present a model to facilitate communication regarding the complexities of ASD, where clinical and genetic heterogeneity, as well as overlapping neurological conditions are inherent. We outline an approach for counselling families about their genomic results grounded in our direct experience from counselling families participating in an ASD research study, and supported by rationale from the literature. PMID- 28803757 TI - NOGG and NICE: New guidelines and quality standards for osteoporosis. PMID- 28803756 TI - Speciation, range contraction and extinction in the endemic New Zealand King Shag complex. AB - New Zealand's endemic King Shag (Leucocarbo carunculatus) has occupied only a narrow portion of the northeastern South Island for at least the past 240years. However, pre-human Holocene fossil and archaeological remains have suggested a far more widespread distribution of the three Leucocarbo species (King, Otago, Foveaux) on mainland New Zealand at the time of Polynesian settlement in the late 13th Century CE. We use modern and ancient DNA, and morphometric and osteological analyses, of modern King Shags and Holocene fossil Leucocarbo remains to assess the pre-human distribution and taxonomic status of the King Shag on mainland New Zealand, and the resultant conservation implications. Our analyses show that the King Shag was formerly widespread around southern coasts of the North Island and the northern parts of the South Island but experienced population and lineage extinctions, and range contraction, probably after Polynesian arrival. This history parallels range contractions of other New Zealand seabirds. Conservation management of the King Shag should take into account this species narrow distribution and probable reduced genetic diversity. Moreover, combined genetic, morphometric and osteological analyses of prehistoric material from mainland New Zealand suggest that the now extinct northern New Zealand Leucocarbo populations comprised a unique lineage. Although these distinctive populations were previously assigned to the King Shag (based on morphological similarities and geographic proximity to modern Leucocarbo populations), we herein describe them as a new species, the Kohatu Shag (Leucocarbo septentrionalis). The extinction of this species further highlights the dramatic impacts Polynesians and introduced predators had on New Zealand's coastal and marine biodiversity. The prehistoric presence of at least four species of Leucocarbo shag on mainland NZ further highlights its status as a biodiversity hotspot for Phalacrocoracidae. PMID- 28803758 TI - Association between body weight and proximal tibial bone mineral density after bilateral total knee arthroplasty. AB - BACKGROUND: Proximal tibial bone mineral density (BMD) has been studied for its potential impact on subsidence and loosening of the tibial component after total knee arthroplasty (TKA). However, no known studies of proximal tibial BMD after TKA have evaluated the effect of major impact factors such as body weight (BW), muscle strength, and level of activity. We aim to determine whether factors such as level of activity, quadriceps strength, BW, gender, age, and prosthetic design affect proximal tibial BMD over the mid- to long-term following TKA. METHODS: We evaluated 36 patients (72 knees) who were undergoing bilateral TKA performed by a single surgeon. Median follow up time was 115months (range, 60-211months) for a minimum of five years. We measured BMD in the proximal tibia and used a hand-held dynamometer to measure quadriceps isometric strength, recording the maximum value of three measurements for each patient. RESULTS: Univariate analyses using Spearman's correlation coefficient for continuous variables revealed a weak negative correlation between age and BMD (r=-0.316, P=0.007) and a moderate positive correlation between BW and BMD (r=0.430, P<0.001). However, no significant correlations were found between the other factors above and BMD for continuous and discrete variables. Based on multivariate analyses, only BW had a significant effect on BMD (beta=0.342, P=0.003). CONCLUSIONS: BW is the most impact factor on the proximal tibial BMD after mid- to long-term follow up TKA. Therefore, the management of BW may contribute to prevention of decline of tibial BMD for TKA patients owing to aging. PMID- 28803759 TI - Role of tear location on outcomes of open primary repair of the anterior cruciate ligament: A systematic review of historical studies. AB - BACKGROUND: The general opinion is that outcomes of open primary repair of the anterior cruciate ligament (ACL) in the historical literature were disappointing. Since good outcomes of primary repair of proximal tears have recently been reported, we aimed to assess the role of tear location on open primary repair outcomes in the historical literature. METHODS: All studies reporting outcomes of open primary ACL repair published between the inception of PubMed, Embase and Cochrane and 2000 were identified. Studies were included if tear location was reported. Outcome scores, return to sports, stability examinations, failures and patient satisfaction were collected and reviewed in the total study cohort and in a subgroup of studies treating only proximal tears. Spearman correlation analysis was performed between the percentage of proximal tears in the studies and all outcomes. RESULTS: Twenty-nine studies were included reporting outcomes of open primary in 1457 patients of which 72% had proximal and 23% midsubstance tears. Mean age was 30years, 65% were males, and mean follow-up was 3.6years. Good outcomes were noted in the total cohort, and excellent outcomes were noted following repair of proximal tears. Positive correlation was found between the percentage proximal tears in the studies and percentage satisfied patients (p=0.010). CONCLUSION: Tear location seems to have played a role on the outcomes of open primary ACL repair. Outcomes of open primary repair in patients with proximal tears were excellent, which confirms there may be a potential role for primary repair as treatment for proximal ACL tears. PMID- 28803761 TI - An in silico perspective on the toxicodynamic of tetrodotoxin and analogues - A tool for supporting the hazard identification. AB - Tetrodotoxin (TTX) is a potent neurotoxin naturally found in terrestrial and marine animals targeting the voltage-gated sodium channels. Historically, TTX has raised food safety concerns mainly in the Asian countries due to the consumption of the typical pufferfish-derived delicacy fugu. However, the diffusion of TTX is getting wider today, reasonably threating in a close future a broader number of consumers than before. The understanding of TTX group toxicity is still incomplete as most of the analogues and metabolites found together with TTX are largely understudied. This prevents the establishment of a solid background for risk assessment and additional data have been claimed to timely foster the assessment of TTX toward a group-based approach. However, the high costs in sourcing TTX analogues make practically unfeasible the wide-scale assessment using experimental trials. The toxicological assessment in silico may succeed in extending data on compounds poorly affordable, hierarchizing compound to focus experiments and supporting the hazard identification. Therefore, the present work investigated the toxicodynamic of TTX, analogues and metabolites by using a molecular modeling approach. In the framework of the hazard identification, the model analyzed TTX analogues never tested before assessing qualitatively their potential toxicity in comparison to TTX. While the analogues from TTX bearing species appeared to be less toxic than TTX, some human metabolites showed a better interaction with the toxin binding site. Such results suggest that human metabolism may partially fail in preventing the interaction with the biological target. Therefore, the identification and assessment of human metabolites should be done to support the decision making process from a more informed perspective. PMID- 28803760 TI - Mechanism of action of botulinum neurotoxin: Unexpected consequences. AB - Botulinum neurotoxin (BoNT) is a widely used therapeutic in part because its mechanism of action is much wider than initially expected. Since BoNT is taken up more avidly in active presynaptic terminals, there is some selectivity for weakening muscles involved in frequent involuntary movements. BoNT blocks gamma motoneurons as well as alpha motoneurons, hence reducing afferent spindle activity which appears to have a favorable effect. Some BoNT is retrogradely transported in the motor axons, leading at least to reduction in recurrent inhibition mediated by the Renshaw cell. There are also central nervous system changes after BoNT injections and these may be due to brain plasticity. PMID- 28803762 TI - Apigenin protects against alcohol-induced liver injury in mice by regulating hepatic CYP2E1-mediated oxidative stress and PPARalpha-mediated lipogenic gene expression. AB - Alcohol is a major cause of liver injury, and there are currently no ideal pharmacological reagents that can prevent or reverse this disease. Apigenin is one of the most common flavonoids present in numerous plants and has many beneficial effects. But whether or not apigenin may protect against alcohol induced liver injury remains unknown. Our aim was to examine the effect and potential mechanisms. The experimental mice were given 56% erguotou wine or simultaneously given apigenin 150-300 mg/kg by gavage for 30 days. The results showed that in the apigenin-treated mice, the expression of hepatic cytochrome P450 2E1 (CYP2E1) and nuclear factor kappa B proteins as well as contents of hepatic malondialdehyde and tumor necrosis factor-alpha were reduced, while the levels of hepatic reduced glutathione, glutathione reductase, glutathione peroxidase, and glutathione S-transferase were increased, especially in the 300 mg/kg group. A significant change in hepatic steatosis was also observed in the apigenin 300 mg/kg group. Apigenin pretreatment could increase the expression of hepatic peroxisome proliferator-activated receptor alpha (PPARalpha) and carnitine palmitoyltransferase-1 proteins, and decrease the expression of hepatic sterol regulatory element binding protein-1c, fatty acid synthase, and diacylglycerol acyltransferase proteins. These findings demonstrated that apigenin might exert a protective effect on alcohol-induced liver injury, and its mechanisms might be related to the regulations of hepatic CYP2E1-mediated oxidative stress and PPARalpha-mediated lipogenic gene expression. PMID- 28803763 TI - Laboratory simulations of the mixed solvent extraction recovery of dominate polymers in electronic waste. AB - The recovery of four dominant plastics from electronic waste (e-waste) using mixed solvent extraction was studied. The target plastics included polycarbonate (PC), polystyrene (PS), acrylonitrile butadiene styrene (ABS), and styrene acrylonitrile (SAN). The extraction procedure for multi-polymers at room temperature yielded PC, PS, ABS, and SAN in acceptable recovery rates (64%, 86%, 127%, and 143%, respectively, where recovery rate is defined as the mass ratio of the recovered plastic to the added standard polymer). Fourier transform infrared spectroscopy (FTIR) was used to verify the recovered plastics' purity using a similarity analysis. The similarities ranged from 0.98 to 0.99. Another similar process, which was denoted as an alternative method for plastic recovery, was examined as well. Nonetheless, the FTIR results showed degradation may occur over time. Additionally, the recovery cost estimation model of our method was established. The recovery cost estimation indicated that a certain range of proportion of plastics in e-waste, especially with a higher proportion of PC and PS, can achieve a lower cost than virgin polymer product. It also reduced 99.6%, 30.7% and 75.8% of energy consumptions and CO2 emissions during the recovery of PC, PS and ABS, and reduced the amount of plastic waste disposal via landfill or incineration and associated environmental impacts. PMID- 28803764 TI - Effect of a food waste disposer policy on solid waste and wastewater management with economic implications of environmental externalities. AB - In this study, the carbon footprint of introducing a food waste disposer (FWD) policy was examined in the context of its implications on solid waste and wastewater management with economic assessment of environmental externalities emphasizing potential carbon credit and increased sludge generation. For this purpose, a model adopting a life cycle inventory approach was developed to integrate solid waste and wastewater management processes under a single framework and test scenarios for a waste with high organic food content typical of developing economies. For such a waste composition, the results show that a FWD policy can reduce emissions by nearly ~42% depending on market penetration, fraction of food waste ground, as well as solid waste and wastewater management schemes, including potential energy recovery. In comparison to baseline, equivalent economic gains can reach ~28% when environmental externalities including sludge management and emissions variations are considered. The sensitivity analyses on processes with a wide range in costs showed an equivalent economic impact thus emphasizing the viability of a FWD policy although the variation in the cost of sludge management exhibited a significant impact on savings. PMID- 28803765 TI - Response of methanotrophic activity to extracellular polymeric substance production and its influencing factors. AB - The accumulation of extracellular polymeric substance (EPS) is speculated to be related with the decrease of CH4 oxidation rate after a peak in long-term laboratory landfill covers and biofilters. However, few data have been reported about EPS production of methanotrophs and its feedback effects on methanotrophic activity. In this study, Methylosinus sporium was used asa model methanotroph to investigate EPS production and its influencing factors during CH4 oxidation. The results showed that methanotrophs could secret EPS into the habits during CH4 oxidation and had a negative feedback effect on CH4 oxidation. The EPS amount fitted well with the CH4 oxidation activity with the exponential model. The environmental factors such as pH, temperature, CH4, O2, NO3--N and NH4+-N could affect the EPS production of methanotrophs. When pH, temperature, CH4, O2 and N concentrations (including NO3--N and NH4+-N) were 6.5-7.5, 30-40 degrees C, 10 15%, 10% and 20-140mgL-1, respectively, the high cell growth rate and CH4 oxidation activity of Methylosinus sporium occurred in the media with the low EPS production, which was beneficial to sustainable and efficient CH4 oxidation. In practice, O2-limited condition such as the O2 concentration of 10% might be a good way to control EPS production and enhance CH4 oxidation to mitigate CH4 emission from landfills. PMID- 28803766 TI - Different neural routes to autobiographical memory recall in healthy people and individuals with left medial temporal lobe epilepsy. AB - Individuals with medial temporal lobe epilepsy (mTLE) are poor at recalling vivid details from autobiographical memories (AM), instead retrieving gist-like schematic memories. Recent research has suggested that this impoverished recall in comparison to controls may reflect (1) differential engagement of anterior vs posterior regions of the hippocampus (HC) and/or (2) differences between the engagement of the HC vs the ventromedial prefrontal cortex (vmPFC). Here we examined these hypotheses by comparing connectivity amongst hippocampal regions and between vmPFC and other brain regions during construction (retrieval of a particular event) vs elaboration (retrieval of perceptual detail) phases of AM recall in 12 individuals with left mTLE and 12 matched controls. Whereas functional connectivity amongst hippocampal regions changed from AM construction to elaboration in controls, the pattern of intra-hippocampal connectivity was unvarying in patients. Furthermore, patterns of connectivity from the vmPFC differed between phases in distinct ways in the two groups of participants. In patients, vmPFC activation was correlated with other prefrontal and lateral temporal cortices during construction and with visual-perceptual cortices during elaboration. While controls did not show a difference in whole-brain connectivity, they did uniquely show a dynamic shift from vmPFC connectivity to anterior HC during construction and to posterior HC during elaboration. Together, these findings suggest that impoverished AM recall in mTLE is a consequence of reduced activation and flexibility of bilateral hippocampal networks and greater reliance on neocortical contributions to memory retrieval. PMID- 28803768 TI - Assessment of Preoperative Anxiety in Cardiac Surgery Patients Lacking a History of Anxiety: Contributing Factors and Postoperative Morbidity. AB - OBJECTIVES: The aim of this study was to measure the level of preoperative anxiety in patients scheduled for cardiac surgery, identify any influencing clinical factors, and assess the relationship between anxiety and postoperative morbidity. DESIGN: A prospective and consecutive study. SETTING: A single university hospital. PARTICIPANTS: The study comprised 200 patients scheduled for cardiac surgery. INTERVENTIONS: Each patient was asked to grade his or her preoperative anxiety level using the Visual Analogue Scale for Anxiety, Amsterdam Preoperative Anxiety and Information Scale, and set of specific anxiety-related questions. Demographic data (age, sex, body mass index) and anesthetic and surgical data (American Society of Anesthesiologists physical status, EuroSCORE surgical risk, preoperative length of stay, and previous anesthetic experience) were registered. Also, postoperative morbidity was assessed. MEASUREMENTS AND MAIN RESULTS: Twenty-eight percent of the patients developed high preoperative anxiety. The mean Amsterdam Preoperative Anxiety and Information Scale score was 11.4 +/- 4.3, and the mean Visual Analogue Scale for Anxiety score was 48 +/- 21. Patients scheduled for coronary artery bypass surgery, who had no previous anesthetic experience, and who were hospitalized before surgery, had higher anxiety scores. Coronary bypass surgery (odds ratio 3.026; 1.509-6.067; p = 0.002) was associated independently with preoperative high-level anxiety. Anxiety most commonly was caused by waiting for surgery, not knowing what is happening, fearing not being able to awaken from anesthesia, and being at the mercy of staff. Anxiety did not modify the postoperative course. CONCLUSIONS: In patients waiting to undergo cardiac surgery, both fear of the unknown and lack of information, especially related to the surgery, are crucial factors in high levels of preoperative anxiety in cardiac surgery. Coronary bypass surgery is a determining factor for preoperative anxiety. The anxiety level did not modify the postoperative course in these patients. PMID- 28803767 TI - Semantic control deficits impair understanding of thematic relationships more than object identity. AB - Recent work has suggested a potential link between the neurocognitive mechanisms supporting the retrieval of events and thematic associations (i.e., knowledge about how concepts relate in a meaningful context) and semantic control processes that support the capacity to shape retrieval to suit the circumstances. Thematic associations and events are inherently flexible: the meaning of an item changes depending on the context (for example, lamp goes with reading, bicycle and police). Control processes might stabilise weak yet currently-relevant interpretations during event understanding. In contrast, semantic retrieval for objects (to understand what items are, and the categories they belong to) is potentially constrained by sensory-motor features (e.g., bright light) that change less across contexts. Semantic control and event understanding produce overlapping patterns of activation in healthy participants in left prefrontal and temporoparietal regions, but the potential causal link between these aspects of semantic cognition has not been examined. We predict that event understanding relies on semantic control, due to associations being necessarily context dependent and variable. We tested this hypothesis in two ways: (i) by examining thematic associations and object identity in patients with semantic aphasia, who have well-documented deficits of semantic control following left frontoparietal stroke and (ii) using the same tasks in healthy controls under dual-task conditions that depleted the capacity for cognitive control. The patients were impaired on both identity and thematic matching tasks, and they showed particular difficulty on non-dominant thematic associations which required greater control over semantic retrieval. Healthy participants showed the same pattern under conditions of divided attention. These findings support the view that semantic control is necessary for organising and constraining the retrieval of thematic associations. PMID- 28803770 TI - Using Ultrasound Wisely: A Tool to Enhance Good Clinical Practice. PMID- 28803769 TI - Urine Biomarkers of Tubular Renal Cell Damage for the Prediction of Acute Kidney Injury After Cardiac Surgery-A Pilot Study. AB - OBJECTIVE: To evaluate the perioperative course of urine levels of the renal damage biomarkers tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin like growth factor-binding protein 7 (IGFBP7) and to evaluate the predictive value of elevated TIMP-2 * IGFBP7 concentrations to predict acute kidney injury (AKI) early after cardiac on-pump surgery. DESIGN: Prospective, observational cohort study. SETTING: University hospital. PARTICIPANTS: The study comprised 110 consecutive patients undergoing elective cardiac surgery with cardiopulmonary bypass (CPB) between January and March 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Urinary TIMP-2 * IGFBP7 levels were quantified using a commercially available kit at the following measurement points: before surgery, 1 hour after starting CPB, 4 hours after weaning from CPB, and 24 hours after weaning from CPB (time points 1-4). Postoperative AKI was defined according to Kidney Disease Improving Global Outcomes criteria. AKI after cardiac surgery was diagnosed in 9 patients (8%). The perioperative course of TIMP-2 * IGFBP7 was significantly different in patients with and without postoperative AKI (p < 0.001). TIMP-2 * IGFBP7 levels were significantly higher in patients with AKI 1 hour after CPB start and 24 hours after weaning from CPB (p < 0.05). TIMP-2 * IGFBP7 levels >0.40 (ng/mL)2/1,000 measured at 1 hour after starting CPB were found to be the optimal cut-off, with a sensitivity of 0.778 and a specificity of 0.641. The negative predictive value was 0.972. CONCLUSIONS: Urine levels of TIMP 2 * IGFBP7 are predictive for AKI at an early time point (1 hour after starting CPB). Renal damage biomarkers such as TIMP-2 and IGFBP7 might be recommended as a supplement to traditionally used criteria of AKI prediction. PMID- 28803771 TI - Perioperative Management of Patients With End-Stage Renal Disease. AB - End-stage renal disease (ESRD) is associated with significant alterations in cardiovascular function; homeostasis of body fluid, electrolytes, and acid-base equilibrium; bone metabolism, erythropoiesis; and blood coagulation. The prevalence of ESRD is increasing rapidly worldwide, as is the number of patients requiring surgery under general anesthesia. Patients with ESRD have significantly higher risks of perioperative morbidity and mortality due to multiple comorbidities. The perioperative management of patients with ESRD under general anesthesia therefore requires special considerations and a careful multidisciplinary approach. In this review, the authors summarize the available literature to address common issues related to patients with ESRD and discuss the best perioperative approach for this patient subgroup. PMID- 28803772 TI - Perioperative Statins Do Not Prevent Acute Kidney Injury After Cardiac Surgery: A Meta-analysis of Randomized Controlled Trials. AB - OBJECTIVES: To evaluate whether perioperative statins reduce the risk of acute kidney injury (AKI) after cardiac surgery. DESIGN: Systematic review and meta analysis of randomized trials. SETTING: Perioperative management in hospitals that perform cardiac surgery. PARTICIPANTS: Adult patients undergoing cardiac surgery. INTERVENTIONS: PubMed, EMBASE, and the Cochrane Library databases were searched for randomized trials. Random-effects meta-analyses were performed to compare the effects of statins versus placebo/control. Trial sequential analysis was conducted to confirm the results. MEASUREMENTS AND MAIN RESULTS: The primary outcome was incidence of postoperative AKI. Eight trials enrolling 3,204 patients were included. The statin arms and the control arms were comparable in incidence of postoperative AKI (risk ratio [RR] = 1.02, 95% confidence interval [CI] = 0.82 1.28), need for renal replacement therapy (RR = 1.09, 95% CI = 0.45-2.66), mechanical ventilation duration (mean difference [MD] = 24.84 min, 95% CI = 55.53-105.20), intensive care unit length of stay (MD = 0.04 days, 95% CI = -3.13 3.20), hospital length of stay (MD = -0.08 days, 95% CI = -0.31-0.15), and in hospital mortality (RR = 3.76, 95% CI = 0.93-15.14). Trial sequential analysis confirmed that it is unlikely that perioperative statin therapy could achieve a 20% or more relative risk reduction in AKI incidence. CONCLUSIONS: Among patients undergoing cardiac surgery, perioperative statin treatment did not reduce the risk of AKI. Statin therapy should not be initiated to prevent AKI following cardiac surgery. PMID- 28803773 TI - Low-Dose Versus High-Dose Tranexamic Acid Reduces the Risk of Nonischemic Seizures After Cardiac Surgery With Cardiopulmonary Bypass. AB - OBJECTIVE: The incidence of postoperative nonischemic seizures associated with the use of tranexamic acid (TXA) and the possibility of prevention with a low dose regimen of TXA were evaluated. DESIGN: Retrospective study. SETTING: Tertiary care university hospital. PARTICIPANTS: A total of 12,195 patients who underwent cardiac surgical procedures under cardiopulmonary bypass (CPB) were evaluated. INTERVENTIONS: The files of every clinical seizure case diagnosed in the surgical intensive care unit between April 2006 and April 2014 were reviewed. Patients who experienced a postoperative seizure underwent a cerebral computed tomography scan to exclude an ischemic lesion. Dosage and type of antifibrinolytic used and surgery characteristics were retrieved from perfusion files. Low-dose TXA was defined as 1,000-mg bolus, 400-mg/h infusion, and 500 mg in CPB priming. High-dose TXA was defined as 30-mg/kg bolus, 15 mg/kg/h, and 2 mg/kg in CPB priming. RESULTS: No seizure was observed in the 886 patients who did not receive antifibrinolytics. A total of 98 clinical seizures (0.8%) were recorded in the intensive care unit, and ischemic cause was excluded in the majority of them after computed tomography scan results were reviewed (91 patients [93%]). Low-dose TXA was associated with fewer seizures than was high dose TXA (46 of 7,452 cases [0.70%] v 34 of 2,190 cases [1.55%], respectively; p < 0.0001). Open-chamber cardiac surgery also was linked to a higher incidence of seizures compared with revascularization (80 of 6,662 [1.20%] and 11 of 5,533 [0.20%], respectively; p < 0.0001). CONCLUSIONS: Lower doses of TXA were associated with a lower incidence of nonischemic seizures compared with higher doses of the drug. PMID- 28803774 TI - Do Low Tidal Volumes Decrease Lung Injury During One-Lung Ventilation? PMID- 28803775 TI - Pulmonary function in patients with eosinophilic chronic rhinosinusitis. AB - OBJECTIVE: There is a close relationship between upper and lower respiratory tract diseases. Chronic rhinosinusitis patients frequently have lung diseases including asthma and chronic obstructive pulmonary disease. Eosinophilic chronic rhinosinusitis is considered a refractory and intractable subtype of chronic rhinosinusitis. However, there has been no report on pulmonary function in patients with eosinophilic chronic rhinosinusitis. The purpose of this study is to examine the pulmonary function in eosinophilic chronic rhinosinusitis patients and non-eosinophilic chronic rhinosinusitis patients, and evaluate clinical factors associated with the pulmonary function of these patients. METHODS: Pulmonary function was measured in 53 patients with eosinophilic chronic rhinosinusitis with asthma, 58 patients with eosinophilic chronic rhinosinusitis without asthma, and 30 patients with non-eosinophilic chronic rhinosinusitis. The diagnosis of chronic rhinosinusitis was based on the definition in the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) 2012. Eosinophilic chronic rhinosinusitis was diagnosed based on the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) scoring system. The relationship between pulmonary function and clinical parameters was assessed. These parameters included radiographic severity of chronic rhinosinusitis, peripheral blood eosinophil percentage, serum total immunoglobulin E level, and eosinophilic infiltration in nasal polyps. RESULTS: The pulmonary function of the patients with eosinophilic chronic rhinosinusitis was significantly affected. The eosinophilic chronic rhinosinusitis patients had more peripheral airway obstruction as compared to the patients with non-eosinophilic chronic rhinosinusitis. CONCLUSION: Our findings indicated latent obstructive lung function changes in the eosinophilic chronic rhinosinusitis patients. The patients with eosinophilic chronic rhinosinusitis should be carefully monitored in order to detect lung diseases. PMID- 28803776 TI - Mechanism of Enzyme Repair by the AAA+ Chaperone Rubisco Activase. AB - How AAA+ chaperones conformationally remodel specific target proteins in an ATP dependent manner is not well understood. Here, we investigated the mechanism of the AAA+ protein Rubisco activase (Rca) in metabolic repair of the photosynthetic enzyme Rubisco, a complex of eight large (RbcL) and eight small (RbcS) subunits containing eight catalytic sites. Rubisco is prone to inhibition by tight-binding sugar phosphates, whose removal is catalyzed by Rca. We engineered a stable Rca hexamer ring and analyzed its functional interaction with Rubisco. Hydrogen/deuterium exchange and chemical crosslinking showed that Rca structurally destabilizes elements of the Rubisco active site with remarkable selectivity. Cryo-electron microscopy revealed that Rca docks onto Rubisco over one active site at a time, positioning the C-terminal strand of RbcL, which stabilizes the catalytic center, for access to the Rca hexamer pore. The pulling force of Rca is fine-tuned to avoid global destabilization and allow for precise enzyme repair. PMID- 28803778 TI - An Unstable Singularity Underlies Stochastic Phasing of the Circadian Clock in Individual Cyanobacterial Cells. AB - The endogenous circadian clock synchronizes with environmental time by appropriately resetting its phase in response to external cues. Of note, some resetting stimuli induce attenuated oscillations of clock output, which has been observed at the population-level in several organisms and in studies of individual humans. To investigate what is happening in individual cellular clocks, we studied the unicellular cyanobacterium S. elongatus. By measuring its phase-resetting responses to temperature changes, we found that population-level arrhythmicity occurs when certain perturbations cause stochastic phases of oscillations in individual cells. Combining modeling with experiments, we related stochastic phasing to the dynamical structure of the cyanobacterial clock as an oscillator and explored the physiological relevance of the oscillator structure for accurately timed rhythmicity in changing environmental conditions. Our findings and approach can be applied to other biological oscillators. PMID- 28803777 TI - Paraoxonase 2 Facilitates Pancreatic Cancer Growth and Metastasis by Stimulating GLUT1-Mediated Glucose Transport. AB - Metabolic deregulation is a hallmark of human cancers, and the glycolytic and glutamine metabolism pathways were shown to be deregulated in pancreatic ductal adenocarcinoma (PDAC). To identify new metabolic regulators of PDAC tumor growth and metastasis, we systematically knocked down metabolic genes that were overexpressed in human PDAC tumor samples using short hairpin RNAs. We found that p53 transcriptionally represses paraoxonase 2 (PON2), which regulates GLUT1 mediated glucose transport via stomatin. The loss of PON2 initiates the cellular starvation response and activates AMP-activated protein kinase (AMPK). In turn, AMPK activates FOXO3A and its transcriptional target, PUMA, which induces anoikis to suppress PDAC tumor growth and metastasis. Pharmacological or genetic activation of AMPK, similar to PON2 inhibition, blocks PDAC tumor growth. Collectively, our results identify PON2 as a new modulator of glucose transport that regulates a pharmacologically tractable pathway necessary for PDAC tumor growth and metastasis. PMID- 28803779 TI - Chromodomain Protein CDYL Acts as a Crotonyl-CoA Hydratase to Regulate Histone Crotonylation and Spermatogenesis. AB - Lysine crotonylation (Kcr) is a newly identified histone modification that is associated with active transcription in mammalian cells. Here we report that the chromodomain Y-like transcription corepressor CDYL negatively regulates histone Kcr by acting as a crotonyl-CoA hydratase to convert crotonyl-CoA to beta hydroxybutyryl-CoA. We showed that the negative regulation of histone Kcr by CDYL is intrinsically linked to its transcription repression activity and functionally implemented in the reactivation of sex chromosome-linked genes in round spermatids and genome-wide histone replacement in elongating spermatids. Significantly, Cdyl transgenic mice manifest dysregulation of histone Kcr and reduction of male fertility with a decreased epididymal sperm count and sperm cell motility. Our study uncovers a biochemical pathway in the regulation of histone Kcr and implicates CDYL-regulated histone Kcr in spermatogenesis, adding to the understanding of the physiology of male reproduction and the mechanism of the spermatogenic failure in AZFc (Azoospermia Factor c)-deleted infertile men. PMID- 28803780 TI - Methylation of DNA Ligase 1 by G9a/GLP Recruits UHRF1 to Replicating DNA and Regulates DNA Methylation. AB - DNA methylation is an essential epigenetic mark in mammals that has to be re established after each round of DNA replication. The protein UHRF1 is essential for this process; it has been proposed that the protein targets newly replicated DNA by cooperatively binding hemi-methylated DNA and H3K9me2/3, but this model leaves a number of questions unanswered. Here, we present evidence for a direct recruitment of UHRF1 by the replication machinery via DNA ligase 1 (LIG1). A histone H3K9-like mimic within LIG1 is methylated by G9a and GLP and, compared with H3K9me2/3, more avidly binds UHRF1. Interaction with methylated LIG1 promotes the recruitment of UHRF1 to DNA replication sites and is required for DNA methylation maintenance. These results further elucidate the function of UHRF1, identify a non-histone target of G9a and GLP, and provide an example of a histone mimic that coordinates DNA replication and DNA methylation maintenance. PMID- 28803782 TI - Emotion regulation in adolescents: An ERP study. AB - AIMS: The use of emotion regulation strategies can reduce the intensity of negative emotional experiences. Event related potentials (ERPs), specifically the late positive potential (LPP), are known to be sensitive to this modulation in adults. This is the first study to explore the neural correlates of expressive suppression in adolescents. We sought to replicate previous findings from emotion regulation studies with adult populations, show that the LPP can be modulated by expressive suppression in healthy adolescents, and examine the influence of age on LPP changes. METHOD: ERPs of 53 healthy adolescents (12-17 years old) performing an emotion regulation task (expressive suppression) were recorded. RESULTS: Expressive suppression altered the LPP in adolescents with both increases and decreases noted depending on time window and recording site. The LPP during expressive suppression was decreased with increasing age. CONCLUSIONS: The findings suggest that 1) the LPP is an effective tool to study processes associated with emotion regulation in adolescents, and 2) expressive suppression, in terms of its neural indicators, seems to become more effective with age. The nature and utility of expressive suppression as a specific form of emotion regulation in adolescents are discussed. PMID- 28803783 TI - Impact of mutations within the [Fe-S] cluster or the lipoic acid biosynthesis pathways on mitochondrial protein expression profiles in fibroblasts from patients. AB - Lipoic acid (LA) is the cofactor of the E2 subunit of mitochondrial ketoacid dehydrogenases and plays a major role in oxidative decarboxylation. De novo LA biosynthesis is dependent on LIAS activity together with LIPT1 and LIPT2. LIAS is an iron-sulfur (Fe-S) cluster-containing mitochondrial protein, like mitochondrial aconitase (mt-aco) and some subunits of respiratory chain (RC) complexes I, II and III. All of them harbor at least one [Fe-S] cluster and their activity is dependent on the mitochondrial [Fe-S] cluster (ISC) assembly machinery. Disorders in the ISC machinery affect numerous Fe-S proteins and lead to a heterogeneous group of diseases with a wide variety of clinical symptoms and combined enzymatic defects. Here, we present the biochemical profiles of several key mitochondrial [Fe-S]-containing proteins in fibroblasts from 13 patients carrying mutations in genes encoding proteins involved in either the lipoic acid (LIPT1 and LIPT2) or mitochondrial ISC biogenesis (FDX1L, ISCA2, IBA57, NFU1, BOLA3) pathway. Ten of them are new patients described for the first time. We confirm that the fibroblast is a good cellular model to study these deficiencies, except for patients presenting mutations in FDX1L and a muscular clinical phenotype. We find that oxidative phosphorylation can be affected by LA defects in LIPT1 and LIPT2 patients due to excessive oxidative stress or to another mechanism connecting LA and respiratory chain activity. We confirm that NFU1, BOLA3, ISCA2 and IBA57 operate in the maturation of [4Fe-4S] clusters and not in [2Fe-2S] protein maturation. Our work suggests a functional difference between IBA57 and other proteins involved in maturation of [Fe-S] proteins. IBA57 seems to require BOLA3, NFU1 and ISCA2 for its stability and NFU1 requires BOLA3. Finally, our study establishes different biochemical profiles for patients according to their mutated protein. PMID- 28803781 TI - Myc Regulates Chromatin Decompaction and Nuclear Architecture during B Cell Activation. AB - 50 years ago, Vincent Allfrey and colleagues discovered that lymphocyte activation triggers massive acetylation of chromatin. However, the molecular mechanisms driving epigenetic accessibility are still unknown. We here show that stimulated lymphocytes decondense chromatin by three differentially regulated steps. First, chromatin is repositioned away from the nuclear periphery in response to global acetylation. Second, histone nanodomain clusters decompact into mononucleosome fibers through a mechanism that requires Myc and continual energy input. Single-molecule imaging shows that this step lowers transcription factor residence time and non-specific collisions during sampling for DNA targets. Third, chromatin interactions shift from long range to predominantly short range, and CTCF-mediated loops and contact domains double in numbers. This architectural change facilitates cognate promoter-enhancer contacts and also requires Myc and continual ATP production. Our results thus define the nature and transcriptional impact of chromatin decondensation and reveal an unexpected role for Myc in the establishment of nuclear topology in mammalian cells. PMID- 28803784 TI - Race-Ethnic Disparities in Cardiometabolic Risk Profiles among Stroke Survivors with Undiagnosed Diabetes and Prediabetes in the United States. AB - BACKGROUND AND PURPOSE: Up to 25% of the U.S. population has undiagnosed diabetes. Diabetes and stroke both disproportionately afflict race/ethnic minorities. We assessed race/ethnic differences in the prevalence of undiagnosed diabetes, prediabetes, and cardiometabolic risk profiles among stroke survivors in the United States. METHODS: The prevalence of diabetes and prediabetes among adults (>=20 years) with a self-reported history of stroke was assessed using the National Health and Nutrition Examination Surveys (NHANES) from 1999 to 2010. Cardiometabolic risk factors across race/ethnic groups were compared using linear and logistic regression before and after adjusting for covariates. RESULTS: From 1999 to 2010, 1070 individuals who participated in NHANES had a self-reported history of stroke. Among stroke survivors without a formal diagnosis of diabetes and prediabetes, 233 (32%) had undiagnosed prediabetes and 27 (3.7%) had undiagnosed diabetes. The prevalence of undiagnosed diabetes and prediabetes was the highest among non-Hispanic (NH) blacks (8% and 38%) compared with Mexican Americans (4% and 26%) and NH whites (3% and 32%). Compared with NH whites, NH blacks were significantly younger, more likely to take antihypertensive medications, more likely to smoke, and have poorly controlled diabetes. NH blacks were twice as likely as NH whites to have poorly controlled blood pressure, after adjustment for sociodemographic and vascular risk factors. CONCLUSION: In the United States, NH black stroke survivors have the highest rates of undiagnosed diabetes and prediabetes, and have poorer cardiometabolic risk factor control than their NH white counterparts. PMID- 28803785 TI - Vascular endothelial growth factor (VEGF) gene polymorphisms (rs699947, rs833061, and rs2010963) and psoriatic risk in South Indian Tamils. AB - BACKGROUND: Psoriasis is a chronic inflammatory disease of the skin. Vascular endothelial growth factor (VEGF), a pro-angiogenic factor, is involved in the pathogenesis of psoriasis. Being highly polymorphic, several SNPs of VEGF have been reported to be associated with increased risk of psoriasis. OBJECTIVES: We determined the association of VEGF gene polymorphisms with risk of psoriasis in South Indian Tamils. METHODS: 300 cases of psoriasis and 300 controls were recruited in this case-control study. Genotyping of SNPs of VEGF gene was done using Taqman 5' allele discrimination assay. Estimation of VEGF levels in plasma was done by ELISA. RESULTS: VEGF (rs2010963) polymorphism and the CTC haplotype were found to confer an increased risk of psoriasis. However, two other VEGF SNPs, rs833061, and rs699947, showed no association with psoriasis susceptibility. VEGF levels were higher in patients with psoriasis, as compared with controls and significantly correlated with disease severity. CONCLUSIONS: Our results indicate that VEGF (rs2010963) polymorphism and CTC haplotype of the VEGF SNPs (rs699947, rs833061, and rs2010963) confer an increased risk of psoriasis in the South Indian Tamil population. Plasma VEGF levels are higher in patients with psoriasis, as compared with controls and are significantly correlated with disease severity. PMID- 28803786 TI - Distribution of HLA-A, -B and -DRB1 antigenic groups and haplotypes from the Brazilian bone marrow donor registry (REDOME). AB - To improve assistance for patients awaiting a bone marrow transplant from an unrelated donor, it is important to genetically characterize the Brazilian volunteer bone marrow donors registry (REDOME). Our objective was to describe the antigenic groups and haplotype frequencies of HLA-A, HLA-B and HLA-DRB1 in the five regions of Brazil and by self-reported ethnicity groups using the REDOME data. Our study included 3,038,286 individuals. HLA antigenic groups and haplotype frequencies were estimated using an Expectation-Maximization (EM) algorithm. All described HLA-A*, HLA-B* and HLA-DRB1* groups were identified in this study. A*02 (25.9%), B*35 (11.8%) and DRB1*13 (13.4%) are the most frequent antigenic groups in REDOME, and the A*01-B*08-DRB1*03 haplotype is the most frequent in the registry. The antigenic group and haplotype frequency data obtained in this study could be helpful for national donor recruitment strategies across the country. PMID- 28803787 TI - Expression analyses of Phactr1 (phosphatase and actin regulator 1) during mouse brain development. AB - Phactr1 (Phosphatase and actin regulator 1) is abundantly expressed in the central nervous system and considered to regulate various neuronal processes through the regulation of protein phosphorylation and actin cytoskeletal organization. In this study, we prepared a specific antibody against Phactr1, anti-Phactr1, and carried out biochemical and morphological analyses of Phactr1 with mouse brain tissues. Western blotting analyses revealed that Phactr1 was expressed in a tissue-dependent profile in the young adult mouse and in a developmental stage-dependent manner in the mouse brain. In primary cultured hippocampal neurons, while Phactr1 was diffusely distributed in the nucleus and cytoplasm, it was visualized in axon and dendrites with partial colocalization with synapses. Phactr1 was also detected in the synaptosomal and postsynaptic density fractions in biochemical fractionation. Immunohistochemical analyses clarified that Phactr1 was differentially expressed in cortical neurons during corticogenesis; the protein was frequently accumulated in the nucleus at the embryonic stage while it came to diffusely distribute in the cell body at the prepubertal stage. The obtained results suggest that Phactr1 takes part in neuronal functions regulated in a spatiotemporal manner. PMID- 28803788 TI - Central nervous system development-related microRNAs levels increase in the serum of gestational diabetic women during the first trimester of pregnancy. AB - MicroRNAs are heterochronic molecules important during brain development, which could be altered by gestational diabetes mellitus (GDM). To explore these molecules in maternal serum, we performed an RT-qPCR analysis. Our results revealed the heterochronic character of some neural development-related microRNA in serum samples of pregnant women. In relation to the first trimester, higher levels of miR-183-5p, -200b-3p, and -125-5p in the second trimester, and higher levels of miR-137 in the third trimester, were found. Furthermore, an insult such as GDM led to higher levels of miR-183-5p, -200b-3p, -125-5p, and -1290 relative to the control in the first trimester, which might be related to changes in neurogenesis and cell proliferation. An in silico analysis suggested that increased microRNAs in the second trimester in the control contributed to cell proliferation and neuron differentiation and that the rise in miR-137 in the third trimester led to neuron maturation. In the diabetic, higher levels of the microRNAs in the first trimester suggested alterations in cell proliferation and neuron differentiation. In conclusion, we showed that fetal-related microRNAs can be detected in the serum of pregnant woman and exhibit temporary regulation during pregnancy and that microRNAs involved in cell proliferation and neuron differentiation are upregulated under GDM. PMID- 28803789 TI - The anti-bacterial effect of an electrochemical anti-fouling method intended for the protection of miniaturised oceanographic sensors. AB - An electrochemical anti-fouling method, based upon the generation of chlorine from seawater, was applied to a proprietary design of Lab on a Chip conductivity, temperature and dissolved oxygen sensor. The method was evaluated using PCR after a six-week field trial in which it significantly reduced the burden of bacterial biofouling. PMID- 28803790 TI - Utility of the cytochrome c oxidase subunit I gene for the diagnosis of toxoplasmosis using PCR. AB - Toxoplasmosis is caused by the protozoan parasite Toxoplasma gondii, which belongs to the phylum Apicomplexa. Since this parasite causes severe clinical symptoms in immunocompromised patients, early diagnosis of toxoplasmosis is essential. PCR is currently used for early diagnosis, but there is no consensus regarding the most effective method for amplifying Toxoplasma DNA. In this study, we considered the utility of the cytochrome c subunit I (cox1) gene, which is encoded in the mitochondrial DNA of this parasite, as a novel target of PCR for the diagnosis of toxoplasmosis. To do this, we compared its copy number per haploid nuclear genome and the detection sensitivity of cox1-PCR with the previously reported target genes B1 and 18S rRNA and the AF146527 repeat element. We found that the copy number of cox1 was high and that the PCR using cox1 primers was more efficient at amplifying Toxoplasma DNA than the other PCR targets examined. In addition, PCR using clinical samples indicated that the cox1 gene would be useful for the diagnosis of toxoplasmosis. These findings suggest that use of cox1-PCR would facilitate the diagnosis of toxoplasmosis in clinical laboratories. PMID- 28803791 TI - Squamous Differentiation Predicts Poor Response to Cisplatin-Based Chemotherapy and Unfavorable Prognosis in Urothelial Carcinoma of the Urinary Bladder. AB - OBJECTIVE: The efficacy of chemotherapy on UCSD is not known. This study was conducted to investigate the efficacy of cisplatin-based chemotherapy and prognosis of patients with UC with or without SD of the bladder. METHODS: Patients with invasive bladder cancer (clinical T3-4aN0M0) who were treated between March 2003 and March 2015 with 2 or 3 cycles of neoadjuvant chemotherapy followed by radical cystectomy were retrospectively evaluated. Treatment outcomes were compared for each pathologic type in UCSD and pure UC. The primary end point was pathologic response in the cystectomy specimens. Disease-free survival and overall survival were secondary end points. RESULTS: We evaluated 9 patients with UCSD and 29 patients with pure UC. In the cystectomy specimens, pathologic complete response without residual tumors was not seen in any patients with UCSD, but evident in 10 patients (34.5%) with pure UC. The proportion of pathologic downstaging was significantly lower in patients with UCSD than in those with pure UC (11.1% vs. 51.7%; P = .031). Patients with UCSD had poorer disease-free survival (P < .001) and overall survival (P = .001) than those with pure UC. On multivariate Cox regression analysis, SD in UC was an independent predictor of recurrence (hazard ratio, 4.43; 95% confidence interval, 1.44-13.6, P = .009) and mortality (hazard ratio, 3.51; 95% confidence interval, 1.11-11.1, P = .032). CONCLUSIONS: UCSD of the bladder is less sensitive to cisplatin-based chemotherapy and has poor prognosis. PMID- 28803792 TI - Rapid and visual detection of Leptospira in urine by LigB-LAMP assay with pre addition of dye. AB - Leptospirosis is considered to be the most widespread zoonotic disease caused by pathogenic species of Leptospira. The present study reports a novel set of primers targeting LigB gene for visual detection of pathogenic Leptospira in urine samples through Loop-mediated isothermal amplification (LAMP). The results were recorded by using Hydroxyl napthol blue (HNB), SYBR GREEN I and calcein. Analytical sensitivity of LAMP was as few as 10 leptospiral organisms in spiked urine samples from cattle and dog. LigB gene based LAMP, termed as LigB-LAMP, was found 10 times more sensitive than conventional PCR. The diagnostic specificity of LAMP was 100% when compared to SYBR green qPCR for detection of Leptospira in urine samples. Though qPCR was found more sensitive, the rapidity and simplicity in setting LAMP test followed by visual detection of Leptospira infection in clinical samples makes LigB-LAMP an alternative and favourable diagnostic tool in resource poor setting. PMID- 28803793 TI - Schistosomiasis from a Snail's Perspective: Advances in Snail Immunity. AB - The snail's immune response is an important determinant of schistosome infection success, acting in concert with host, parasite, and environmental factors. Coordinated by haemocytes and humoral factors, it possesses immunological hallmarks such as pattern recognition receptors, and predicted gastropod-unique factors like the immunoglobulin superfamily domain-containing fibrinogen-related proteins. Investigations into mechanisms that underpin snail-schistosome compatibility have advanced quickly, contributing functional insight to many observational studies. While the snail's immune response is important to continue studying from the perspective of evolutionary immunology, as the foundational determinants of snail-schistosome compatibility continue to be discovered, the possibility of exploiting the snail for schistosomiasis control moves closer into reach. Here, we review the current understanding of immune mechanisms that influence compatibility between Schistosoma mansoni and Biomphalaria glabrata. PMID- 28803794 TI - Arsenic trioxide consolidation in APL. PMID- 28803795 TI - Integrative sequencing of metastatic cancer. PMID- 28803796 TI - Shoulder muscle activation patterns and levels differ between open and closed chain abduction. AB - OBJECTIVES: Open and closed-chain abduction of the shoulder are commonly used in rehabilitation and exercise programs to assess and/or improve shoulder muscle function. However, it is not known if shoulder muscle activation patterns differ between these two exercises. Therefore the purpose of this study was to compare muscle activation patterns during closed-chain shoulder abduction performed using a shoulder press machine with open-chain abduction using free weights. DESIGN: Experimental study. METHODS: Open and closed-chain abduction were performed by 15 and 14 subjects respectively at low (25%), medium (50%) and high (75%) load. Surface and indwelling electrodes were used to record the activation pattern of seven shoulder muscles during the concentric phase of each exercise. Data were normalised to maximum voluntary contractions (MVC), time normalised and compared over the common range of motion (40 degrees -140 degrees abduction). RESULTS: Only the activation pattern of middle deltoid had a strong positive correlation between exercises (r>=0.65, p<0.05) with similar activation levels at all loads (35%, 50% and 60% MVC, p=1.0). All other muscles tested had inconsistent, low or negative correlations between exercises. Significantly lower average activation levels were recorded during closed-chain abduction for subscapularis at all loads, upper trapezius at medium and high loads and infraspinatus and lower trapezius at high load (p <0.05). CONCLUSIONS: Open-chain abduction is required to facilitate the stabilising role of the rotator cuff and axioscapular muscles, in response to middle deltoid activity. Closed-chain exercises may enable full range shoulder abduction earlier in rehabilitation programs, with an inherent stability and less demand on the rotator cuff. PMID- 28803797 TI - M-wave normalization of EMG signal to investigate heat stress and fatigue. AB - OBJECTIVES: We examined the extent to which peripheral changes affect EMG signal adjustments during repeated sprinting in temperate and hot conditions. DESIGN: Randomised, crossover study. METHODS: Ten males performed 10*6-s 'all-out' cycling sprints (recovery=30s) in either a temperate (24 degrees C/30%rH) or a hot (35 degrees C/40%rH) environment with concomitant surface EMG recordings of the vastus lateralis (VL) and rectus femoris (RF). In addition, peak-to-peak M wave amplitudes were obtained for each muscle after each sprint (i.e., 15s into recovery). RESULTS: For both the VL and RF muscles RMS decreased across sprint repetitions (P<0.01), while significantly lower values for the VL (P=0.012), but not the RF (P=0.096), occurred in hot vs. temperate conditions. M-wave-normalised RMS for VL muscle decreased across sprint repetitions (P=0.030), with no condition or interaction effects (both P>0.621). M-wave-normalised RMS for the RF muscle was lower in the heat (P<0.034), with no significant sprint or interaction effects (both P>0.240). CONCLUSIONS: Controlling for changes in maximal M-wave amplitude of the quadriceps muscles after each bout of a repeated cycling exercise in hot and temperate conditions allows researchers to account for fatigue- and/or heat-induced neural and peripheral adjustments. PMID- 28803798 TI - Radiosynthesis and preclinical PET evaluation of 89Zr-nivolumab (BMS-936558) in healthy non-human primates. AB - Cancer immunotherapy, unlike traditional cytotoxic chemotherapeutic treatments, engages the immune system to identify cancer cells and stimulate immune responses. The Programmed Death-1 (PD-1) protein is an immunoinhibitory receptor expressed by activated cytotoxic T-lymphocytes (CTL) that seek out and destroy cancer cells. Multiple cancer types express and upregulate the Programmed Death Ligand 1 (PD-L1) and 2 (PD-L2) which bind to PD-1 as an immune escape mechanism. Nivolumab is a fully human IgG4 anti-PD-1 monoclonal antibody (mAb) approved for treatment of multiple cancer types. This study reports the preparation and in vivo evaluation of 89Zr labeled nivolumab in healthy non-human primates (NHP) as a preliminary study of biodistribution and clearance. The radiochemical and in vivo stabilities of the 89Zr complex were shown to be acceptable for imaging. Three naive NHPs were intravenously injected with tracer only or tracer co injected with nivolumab followed by co-registered by positron emission tomography (PET) and magnetic resonance imaging (MRI), acquired for eight days following injection. Image-derived standardized uptake values (SUV) were quantified by region of interest (ROI) analysis. Radioactivity in the spleen was significantly reduced by addition of excess nivolumab compared to the tracer only study at all imaging time points. Liver uptake of the radiotracer was consistent as a clearance organ with minimal signal from other tissues: lung, muscle, brain, heart, and kidney. The results indicate specific biodistribution to the spleen, which can be blocked by co-administration of excess nivolumab. Distribution to other organs is consistent with elimination pathways of antibodies, with primary clearance through the liver. PMID- 28803799 TI - Constructing novel dihydrofuran and dihydroisoxazole analogues of isocombretastatin-4 as tubulin polymerization inhibitors through [3+2] reactions. AB - [3+2] reactions play a key role in constructing various pharmaceutical moleculars. In this study, using Mn(OAc)3 mediated and 1,3-dipolar [3+2] cyclization reactions, 38 novel dihydrofuran and dihydroisoxazole analogues of isoCA-4 were synthesized as inhibitors of tubulin polymerization. Among them, compound 6g was found to be the most potent cytotoxic agents against PC-3 cells with IC50 value of 0.47MUM, and compound 5p exhibted highest activity on HeLa cells with IC50 vaule of 2.32uM. Tubulin polymerization assay revealed that 6g was a dose-dependent and effective inhibitor of tubulin assembly. Immunohistochemistry studies and cell cycle distribution analysis indicated that 6g severely disrupted microtubule network and significantly arrested most cells in the G2/M phase of the cell cycle in PC-3 cells. In addition, molecular docking studies showed that two chiral isomers of 6g can bind efficiently and similarly at colchicine binding site of tubulin. PMID- 28803800 TI - "Ping-pong" technique for treating a balloon uncrossable chronic total occlusion. AB - Balloon uncrossable lesions are a well-known challenge during chronic total occlusion (CTO) interventions. The technique of using two different catheters into the same coronary artery, the so-called "ping-pong" technique, is a technique described for treating complications during percutaneous coronary intervention (PCI), like perforations or rotational atherectomy burr entrapment. We describe a case where the "ping-pong" technique was successfully used to facilitate treatment of a balloon uncrossable CTO lesion. PMID- 28803801 TI - ST elevation myocardial infarction in patients with anomalous left main coronary artery: Case series and review of the literature. AB - Anomalous left main coronary artery is rare. We present four cases where anomalous left main coronary artery was diagnosed during emergent cardiac catheterization for ST elevation myocardial infarction. Procedural characteristics, technical challenges, and relevant literature are discussed. PMID- 28803802 TI - ? PMID- 28803803 TI - ? PMID- 28803804 TI - Effect of esthetic coating on surface roughness of orthodontic archwires. AB - BACKGROUND AND AIM: Esthetic wires are commonly used in orthodontic treatments. Surface roughness is an important factor in the friction and bacterial adhesion in these wires. Surface roughness of esthetic wires has not been assessed, except in a few recent (mostly qualitative esthetics) studies. The aim of this study was to quantitatively compare the surface roughness of 4 coated esthetic wires with that of a conventional orthodontic wire. MATERIALS AND METHODS: In this in vitro trial, 25 coated and uncoated orthodontic archwires were studied, including: NiTi Memory wire (American Orthodontics, USA) as a control group; Orthocosmetic Elastinol (Ortho Organizers, USA); Perfect (Hubit, Korea); Imagination (Gestenco, Sweden); EverWhite (American Orthodontics, USA). All were .016*.022" rectangular maxillary wires. Fifteen millimeters of wire was cut off at the posterior end and a surface area of 2000*2000nm was probed using a Scanning Probe Microscope (DS95 50E/DME, Denmark) to determine the surface roughness values. The roughness parameters of Sa, Sdq, Sv and Sy were measured and statistically compared by Kruskal-Wallis and Mann-Whitney U tests. RESULTS: The average range of the 4 parameters was the highest for the uncoated Ni-Ti Memory wire (control group) while the Perfect coated wire showed the lowest values. The differences were significant for parameters Sa and Sy (P<0.02 and P<0.023) and non-significant for Sv and Sdq. Significant differences existed between uncoated and coated wires regarding Sa and Sy values (P<0.01), being higher for the uncoated wires. CONCLUSION: Taking into account the study limitations, the surface roughness values of NiTi uncoated archwires were significantly higher than those of the coated wires. PMID- 28803805 TI - Three-dimensional evaluation of molar buccolingual inclinations after orthodontic treatment using edgewise mechanics. AB - OBJECTIVES: The purpose of this study was to measure changes in buccolingual inclination and in thickness of maxillary and mandibular buccal and lingual bone of maxillary and mandibular molars following orthodontic treatment using edgewise mechanics. MATERIALS AND METHODS: Cone-beam computed tomography scans of 48 patients taken before and after completion of comprehensive orthodontic treatment were collected for this retrospective study. Buccolingual molar inclinations were reported as angular measurements using the long axis of the teeth and inferior border of the nasal floor and inferior border of the mandible, respectively. Distances between the buccal and lingual cusps of maxillary and mandibular molars, respectively, were measured to the occlusal plane to assess the change in buccolingual inclination after orthodontic treatment. The amount of buccal and lingual bone at the level of the root apex of each molar was also evaluated before and after orthodontic treatment. RESULTS AND CONCLUSION: Orthodontic edgewise mechanics caused significant increases in mandibular first molars' inclination angle, lingual bone, and mandibular second molars' buccal bone and inclination angle. Significant decreases were noted in mandibular first molars' buccal bone, inclination distance and mandibular second molars' lingual bone and inclination distance. Maxillary teeth had fewer significant changes than the mandibular teeth. Significant decreases were found for maxillary first molars' buccal bone, inclination distance, and maxillary second molar buccal bone. PMID- 28803806 TI - The use of computer-assisted corticotomy to enhance surgical procedures. AB - In recent years, several surgical techniques have been proposed with the main goal of reducing the length of orthodontic treatment. Some of these techniques use a piezoelectric surgical instrument to perform alveolar bone cuts and promote localized bone turnover. One of the main limitations of these surgical techniques is that corticotomies may damage dental roots since traditional radiographic examinations do not allow the surgeon to precisely determine the length and three dimensional position of the roots. In this case report, the authors aim to describe a method in which, starting from the patient's CBCT dicom files, they were able to plan the location and depth of the bone cuts and to build a surgical guide to be used during piezoelectric bone surgery. In addition, the technique and final results are described, as well as a two-year follow-up showing stable results. PMID- 28803807 TI - ? PMID- 28803808 TI - Two novel mutations (p.(Ser160Pro) and p.(Arg472Cys)) causing glucose-6-phosphate isomerase deficiency are associated with erythroid dysplasia and inappropriately suppressed hepcidin. AB - Glucose-6-phosphate isomerase (GPI) deficiency, a genetic disorder responsible for chronic nonspherocytic hemolytic anemia, is the second most common red blood cell glycolytic enzymopathy. We report three patients from two unrelated families of Czech and Slovak origin with macrocytic hemolytic anemia due to GPI deficiency. The first patient had 15% of residual GPI activity resulting from two new heterozygous missense mutations c.478T>C and c.1414C>T leading to substitutions p.(Ser160Pro) and p.(Arg472Cys). Two other patients (siblings) inherited the same c.1414C>T p.(Arg472Cys) mutation in a homozygous constitution and lost approximately 89% of their GPI activity. Erythroid hyperplasia with dysplastic features was observed in the bone marrow of all three patients. Low hepcidin/ferritin ratio and elevated soluble transferrin receptor detected in our GPI-deficient patients suggest disturbed balance between erythropoiesis and iron metabolism contributing to iron overload. PMID- 28803809 TI - Improved androgen specificity of AR-EcoScreen by CRISPR based glucocorticoid receptor knockout. AB - The AR-EcoScreen is a widely used reporter assay for the detection of androgens and anti-androgens. Endogenous expression of glucocorticoid receptors and their affinity for the androgen responsive element that drives reporter expression, however, makes the reporter cells sensitive to interference by glucocorticoids and less specific for (anti-)androgens. To create a glucocorticoid insensitive derivative of the AR-EcoScreen, CRISPR/Cas9 genome editing was used to develop glucocorticoid receptor knockout mutants by targeting various sites in the glucocorticoid gene. Two mutant cell lines were further characterized and validated against the unmodified AR-EcoScreen with a set of 19 environmentally relevant chemicals and a series of environmental passive sampler extracts with (anti-)androgenic activity. Sequencing of the targeted sites revealed premature stop codons following frame-shift mutations, leading to an absence of functional glucocorticoid receptor expression. The introduced mutations rendered cell lines insensitive to glucocorticoid activation and caused no significant difference in the responsiveness towards (anti-)androgens, compared to the unmodified AR EcoScreen cells, allowing the selective, GR-independent, determination of (anti )androgenicity in environmental passive sampler extracts. The increase in selectivity for (anti-)androgens improves reliability of the AR-EcoScreen and will provide higher accuracy in determining (anti-)androgenic potential when applied in toxicity screening and environmental monitoring of both single compounds and mixtures. PMID- 28803810 TI - Autophagy plays a positive role in zinc-induced apoptosis in intestinal porcine epithelial cells. AB - A high-zinc (Zn) diet has been found to promote growth performance in pigs, but causes cell apoptosis in the intestinal epithelium. To investigate the mechanism underlying the high dietary Zn-induced apoptosis in porcine small intestinal epithelium, IPEC-J2 cells (intestinal porcine epithelial cells) were used to determine the effect of Zn on cell inhibitory, apoptosis, and mitochondrial membrane potential and autophagy in vitro. Results showed that Zn inhibited IPEC J2 cell proliferation and induced apoptosis and autophagy. High concentrations of Zn induced DNA fragmentation and nuclear morphological changes, and increased intracellular Zn concentration. It also increased the protein expression level of cleaved caspase-3, caspase-8, beclin 1 and microtubule-associated protein 1 light chain 3 (LC3)-II, and the translocation of cytochrome c (Cyto C) into cytosol from mitochondria, and decreased the protein expression level of P62/SQSTM1. While 3-MA (3-methyladenine, as an autophagy inhibitor) suppressed the Zn-induced changes in the protein expression level of cleaved caspase-3 (CASP3), caspase-8 (CASP8), Cyto C, beclin 1, LC3-II and P62/SQSTM1. 3-MA decreased the Zn-induced mitochondrial apoptosis. High concentration of Zn up-regulated the relative mRNA expression level of BAX, CYCS, CASP3, CASP8, LC3-II and P62/SQSTM1 genes (p<0.05), which were also ameliorated by 3-MA supplementation. In conclusion, autophagy inhibition significantly reduced the Zn-induced loss of mitochondrial membrane potential and attenuated the elevation of apoptosis in IPEC-J2. Autophagy and apoptosis act as partners in the Zn-induced cellular death in IPEC J2. PMID- 28803811 TI - Office Operative Hysteroscopy: An Update. AB - Hysteroscopy is considered the gold standard for the evaluation of intracavitary pathology in both premenopausal and postmenopausal patients associated with abnormal uterine bleeding, as well as for the evaluation of infertile patients with suspected cavity abnormalities. Office-based operative hysteroscopy allows patients to resume activities immediately and successfully integrates clinical practice into a "see and treat" modality, avoiding the added risks of anesthesia and the inconvenience of the operating room. For 2017, the Centers for Medicare and Medicaid Services has provided a substantial increase in reimbursement for a select number of office-based hysteroscopic procedures. This review provides an update on the indications, equipment, and procedures for office hysteroscopy, as well as the management of complications that may arise within an office-based practice. PMID- 28803812 TI - Thermal Bladder Injury at Laparoscopic Hysterectomy. PMID- 28803813 TI - The challenges of cholera at the 2017 Hajj pilgrimage. PMID- 28803814 TI - Revision Total Hip Arthroplasty With a Monoblock Splined Tapered Grit-Blasted Titanium Stem. AB - BACKGROUND: In revision total hip arthroplasty (THA), proximal femoral bone loss creates a challenge of achieving adequate stem fixation. The purpose of this study was to examine the outcomes of a monoblock, splined, tapered femoral stem in revision THA. METHODS: Outcomes of revision THA using a nonmodular, splined, tapered femoral stem from a single surgeon were reviewed. With a minimum of 2 year follow-up, there were 68 cases (67 patients). Paprosky classification was 3A or greater in 85% of the cases. Preoperative and postoperative Harris Hip Scores (HHS), radiographic subsidence and osseointegration, limb length discrepancy, complications, and reoperations were analyzed. RESULTS: The Harris Hip Score improved from 37.4 +/- SD 19.4 preoperatively to 64.6 +/- SD 21.8 at final follow up (P < .001). There were 16 revision procedures-8 for septic indications and 8 for aseptic indications. Subsidence occurred at a rate of 3.0% and dislocation at 7.4%. Limb length discrepancy of more than 1 cm after revision was noted in 13.6% of patients. Bone ingrowth was observed in all but 4 patients (94.1%). At 4-year follow-up, Kaplan-Meier estimated survival was 72.9% (95% confidence interval [CI] 57.0-83.8) for all causes of revision, 86.6% (95% CI 72.0-93.9) for all aseptic revision, and 95.5% (95% CI 86.8-98.5) for aseptic femoral revision. CONCLUSION: Although complications were significant, revision for femoral aseptic loosening occurred in only 3 patients. Given the ability of this monoblock splined tapered stem to adequately provide fixation during complex revision THA, it remains a viable option in the setting of substantial femoral bone defects. PMID- 28803815 TI - Patient-Specific Contact Stress Does Not Predict Polyethylene Wear Rate in a Specific Pressfit Cup. AB - BACKGROUND: The most common reason for revision total hip arthroplasty remains polyethylene wear. Development dysplasia of the hip and revision situations requires a conscious compromise of implant position. The surgeon should know about the consequence on wear via a possible change in hip contact force. The objective of this study is to investigate whether annual wear is dependent on hip contact force. METHODS: Forty-five inserts (DuraLoc, DePuy) that were explanted in our department were included. Three-dimensional gravimetric determination of the wear was performed by fluid displacement. Then, the hip contact force was determined using radiographs according to the Blumentritt model. RESULTS: No correlation was found between patient-specific factors and the annual wear. The hip contact force estimated by the Blumentritt model also showed no correlation between hip contact force and annual wear. Two single model parameters correlated significantly with wear: VRECAB as a ratio of the lever length of the spinocrural and the pelvitrochanteric muscles and the angle Alpha as a measure of the position of the center of rotation in relation to the greater trochanter. The greater the ratio spinocrural/pelvitrochanteric lever arm (R = 0.408, P = .005) and the greater the Alpha angle (more valgus the femoral neck) (R = 0.377, P = .011) were, the greater was the wear. CONCLUSION: These results lead to the conclusion that neither patient-specific factors nor the estimated hip contact force have a major influence on annual wear in the case of DuraLoc cups. Only a coxa valga and a small femoral offset contribute in a limited amount to an increase in wear. PMID- 28803816 TI - Midterm-Adjusted Survival Comparing the Best Performing Unicompartmental and Total Knee Arthroplasties in a Registry. AB - BACKGROUND: Recent literature suggests that the difference in revision risk between unicompartmental knee arthroplasty (UKA) and total knee arthroplasty (TKA) can be influenced by surgeon volume and other confounders. We hypothesized that implant selection might decrease the relative risk of revision in an adjusted model. METHODS: We selected the best performing (BP) primary UKAs and TKAs performed for osteoarthritis between January 2001 and December 2012 collected through a joint replacement registry. We compared aseptic and all-cause risk of revision using a surgeon-stratified Cox regression model with propensity score adjustment. RESULTS: One thousand fifty-four UKAs were compared with 74,185 TKAs. The rate for all-cause revision was lower for UKAs (2.1%) than for TKAs (2.4%), whereas the rate for aseptic revision was higher for UKAs (2.0%) than TKAs (1.4%). The adjusted risk of aseptic revision was not significantly higher for UKA than TKA (hazard ratio = 2.02 [0.68, 5.96], P = .203) or all-cause revision (hazard ratio = 1.24 [0.52, 2.98], P = .603). CONCLUSION: When comparing the survivorship of the BP UKAs to the BP TKAs in our registry, the adjusted risk of revision remained higher for UKAs than for TKAs, although the difference did not reach statistical significance. PMID- 28803817 TI - 6MWT can identify type 3 SMA patients with neuromuscular junction dysfunction. AB - The aim of the study was to establish if the decrease in gait velocity on the 6 minute walk test relates to signs of neuromuscular junction dysfunction in spinal muscular atrophy type 3 patients. 6 minute walk test and low-rate repetitive nerve stimulation test were performed in fifteen ambulant patients with spinal muscular atrophy type 3 of age between 9 and 66 years. The 6 minute walk distance ranged between 66 and 575 m. The difference between the first and the 6th minute ranged between 0 and -69%. The low-rate repetitive nerve stimulation test measured in % of loss ranged between -31.7% to +4.2% to the axillary nerve. The correlation between 6 minute walk test changes and low-rate repetitive nerve stimulation test changes was 0.86. Our data suggest that the 6 minute walk test can identify fatigue in the ambulant type 3 patients who have a concurrent neuromuscular junction dysfunction. The identification of fatigue with a simple clinical test may help to target patients who may benefit from drugs that facilitate neuromuscular transmission. PMID- 28803818 TI - A homozygous DPM3 mutation in a patient with alpha-dystroglycan-related limb girdle muscular dystrophy. AB - Defects of O-linked glycosylation of alpha-dystroglycan cause a wide spectrum of muscular dystrophies ranging from severe congenital muscular dystrophy associated with abnormal brain and eye development to mild limb girdle muscular dystrophy. We report a female patient who developed isolated pelvic girdle muscle weakness and wasting, which became symptomatic at age 42. Exome sequencing uncovered a homozygous c.131T > G (p.Leu44Pro) substitution in DPM3, encoding dolichol-P mannose (DPM) synthase subunit 3, leading to a 50% reduction of enzymatic activity. Decreased availability of DPM as an essential donor substrate for protein O-mannosyltransferase (POMT) 1 and 2 explains defective skeletal muscle alpha-dystroglycan O-glycosylation. Our findings show that DPM3 mutations may lead to an isolated and mild limb girdle muscular dystrophy phenotype without cardiomyopathy. PMID- 28803819 TI - Therapeutic nanomaterials for cancer therapy and tissue regeneration. PMID- 28803820 TI - TITRATION: A Randomized Study to Assess 2 Treatment Algorithms with New Insulin Glargine 300 units/mL. AB - OBJECTIVE: It was uncertain whether an algorithm that involves increasing insulin dosages by 1 unit/day may cause more hypoglycemia with the longer-acting insulin glargine 300 units/mL (GLA-300). The objective of this study was to compare safety and efficacy of 2 titration algorithms, INSIGHT and EDITION, for GLA-300 in people with uncontrolled type 2 diabetes mellitus, mainly in a primary care setting. METHODS: This was a 12-week, open-label, randomized, multicentre pilot study. Participants were randomly assigned to 1 of 2 algorithms: they either increased their dosage by 1 unit/day (INSIGHT, n=108) or the dose was adjusted by the investigator at least once weekly, but no more often than every 3 days (EDITION, n=104). The target fasting self-monitored blood glucose was in the range of 4.4 to 5.6 mmol/L. RESULTS: The percentages of participants reaching the primary endpoint of fasting self-monitored blood glucose <=5.6 mmol/L without nocturnal hypoglycemia were 19.4% (INSIGHT) and 18.3% (EDITION). At week 12, 26.9% (INSIGHT) and 28.8% (EDITION) of participants achieved a glycated hemoglobin value of <=7%. No differences in the incidence of hypoglycemia of any category were noted between algorithms. Participants in both arms of the study were much more satisfied with their new treatment as assessed by the Diabetes Treatment Satisfaction Questionnaire. Most health-care professionals (86%) preferred the INSIGHT over the EDITION algorithm. The frequency of adverse events was similar between algorithms. CONCLUSIONS: A patient-driven titration algorithm of 1 unit/day with GLA-300 is effective and comparable to the previously tested EDITION algorithm and is preferred by health-care professionals. PMID- 28803821 TI - Regarding Insulin Initiation in Type 2 Diabetes Mellitus and the Risk for Hypoglycemia. PMID- 28803822 TI - Egg Consumption and Cardiovascular Risk. PMID- 28803823 TI - ? PMID- 28803824 TI - The Clinical Spectrum of Hepatic Manifestations in Chronic Lymphocytic Leukemia. AB - Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world, characterized by the presence of long-lived circulating leukemic cells in the peripheral blood that may infiltrate all organs, particularly those of the reticulo-endothelial system. Liver enlargement and elevation of liver enzymes related to specific involvement by the underlying disease are well-recognized features in these patients. In CLL, the differential diagnosis of liver disorders is broad and includes liver infiltration by leukemic cells, immunologic manifestations associated with CLL, primary and secondary hepatic malignancies, drug-induced hepatotoxicity, infections, and Richter transformation. The above conditions can cause serious and even fatal complications such as acute liver failure. The aim of this study was to summarize all available published literature on hepatic manifestations encountered in CLL. This review contains sections on liver enlargement because of leukemic infiltration, autoimmune induced hepatic dysfunction, acute liver failure, drug-induced liver toxicity, and associated malignancies. A high index of clinical suspicion and appropriate diagnostic evaluation, including liver biopsy in special circumstances, are important for both accurate diagnosis and deciding on the most appropriate treatment to prevent the development of fatal complications of acute liver failure. PMID- 28803826 TI - Hospital Leadership Recognizes Need to Create Partnerships to Treat Consequences of Poverty. AB - In this paper, two senior administrative leaders at a tertiary care children's hospital explain why they decided to partner with a community organization in order to better fulfill the hospital mission. PMID- 28803825 TI - Cardiovascular Events After Exposure to Nilotinib in Chronic Myeloid Leukemia: Long-term Follow-up. AB - INTRODUCTION: Nilotinib is a highly effective tyrosine kinase inhibitor in the treatment of chronic myeloid leukemia (CML). However, reports of cardiovascular toxicities caused by nilotinib have recently raised critical concerns. The aim of the present study was to evaluate the incidence of cardiovascular events (CVEs) and frequency of asymptomatic peripheral arterial disease (PAD) after long-term exposure to nilotinib. PATIENTS AND METHODS: In the present retrospective cohort, we evaluated the incidence of CVEs in 63 CML patients treated with nilotinib. The results of Doppler ultrasound examination of the carotid and vertebral and lower extremity arteries with ankle-brachial index measurements were collected in asymptomatic patients. The clinical outcome was a composite endpoint of PAD, acute coronary events, stroke, heart failure, and cardiovascular death. RESULTS: Sixty-three patients with a median age of 60 years were followed up for a median duration of 63 months. After a median nilotinib exposure of 49.30 months (range, 7.00-117.95 months), for a total exposure of 178.7 patient-years, 6 patients (9%) had experienced the clinical outcome. Four patients (8%) had abnormal arterial leg Doppler ultrasound findings. No significant lesions were reported in carotid/vertebral artery ultrasound examinations. Together, hypertension and low density lipoprotein cholesterol > 2 mmol/L significantly increased the risk of CVEs or abnormal ultrasound findings (odds ratio, 37.65; 95% confidence interval, 4.06-348.9). CONCLUSION: The incidence of CVEs and the frequency of asymptomatic PAD in this population was low, and CVEs were associated with cardiovascular risk factors. Aggressive risk factor modification and applying standard definitions for measuring cardiovascular outcomes might have contributed to the findings. Further prospective and adequately powered studies are needed to explore the effect of the cardiovascular risk profile on CVEs in CML patients taking nilotinib. PMID- 28803827 TI - Caring for the Caregiver: Supporting Families of Youth With Special Health Care Needs. AB - Caregivers of youth with special health care needs (YSHCN) are a critical part of the health care team. It is important for pediatric providers to be cognizant of the burden and strain caregiving can create. This article will discuss the health, psychological, social, and financial effects of caregiving, as well as strategies to screen for caregiver strain among families of YSHCN. Caregivers of YSHCN, for example, are more likely to report poor health status and demonstrate higher rates of depression and anxiety. Numerous validated screens for caregiver strain have been developed to address the multi-faceted effects of caregiving. Finally, we will discuss strategies to alleviate caregiver strain among this vulnerable population. We will describe services pediatric providers can encourage caregivers to utilize, including financial support through Supplemental Security Income (SSI), benefits available through the Family Medical Leave Act (FMLA), and options for respite care. Addressing caregiver strain is an important aspect of maintaining a family centered approach to the care of YSHCN. PMID- 28803828 TI - Preparing for Transition of Youth with Special Health Care Needs. PMID- 28803830 TI - The effect of perceptual load on tactile spatial attention: Evidence from event related potentials. AB - To investigate whether tactile spatial attention is modulated by perceptual load, behavioural and electrophysiological measures were recorded during two spatial cuing tasks in which the difficulty of the target/non-target discrimination was varied (High and Low load tasks). Moreover, to study whether attentional modulations by load are sensitive to the availability of visual information, the High and Low load tasks were carried out under both illuminated and darkness conditions. ERPs to cued and uncued non-targets were compared as a function of task (High vs. Low load) and illumination condition (Light vs. Darkness). Results revealed that the locus of tactile spatial attention was determined by a complex interaction between perceptual load and illumination conditions during sensory specific stages of processing. In the Darkness, earlier effects of attention were present in the High load than in the Low load task, while no difference between tasks emerged in the Light. By contrast, increased load was associated with stronger attention effects during later post-perceptual processing stages regardless of illumination conditions. These findings demonstrate that ERP correlates of tactile spatial attention are strongly affected by the perceptual load of the target/non-target discrimination. However, differences between illumination conditions show that the impact of load on tactile attention depends on the presence of visual information. Perceptual load is one of the many factors that contribute to determine the effects of spatial selectivity in touch. PMID- 28803829 TI - The Vascular Niche Regulates Hematopoietic Stem and Progenitor Cell Lodgment and Expansion via klf6a-ccl25b. AB - In mammals, hematopoietic stem and progenitor cells (HSPCs) rapidly expand in the fetal liver (FL), but the underlying mechanism remains unclear. Here, we characterize zebrafish caudal hematopoietic tissue (CHT) and identify an important cellular and molecular mechanism of HSPC expansion. Time-lapse imaging showed that HSPCs localize adjacent to vascular endothelial cells (ECs), and their migration and expansion display caudal vein-specific orientation in the CHT. RNA sequencing and functional analysis identified that an EC-expressed transcription factor, Kruppel-like factor 6a (Klf6a), is essential for the CHT niche. We further demonstrated that Klf6a directly regulates the expression of the chemokine (C-C motif) ligand 25b to modulate HSPC lodgment and proliferation. Ex vivo culture results support the conserved role of Ccl21/Ccr7 signaling in promoting HSPC expansion in mammals. Together, we identify the Klf6a-Ccl25b/Ccr7 axis in controlling the complex HSPC-CHT niche interaction, which may be applicable to in vitro expansion or engraftment of HSPCs after transplantation. PMID- 28803831 TI - Localization of connexin 43 gap junctions and hemichannels in tanycytes of adult mice. AB - Tanycytes are specialized glial cells lining the lateral walls and the floor of the third ventricle behind the optic chiasm. In addition to functioning as barrier cells, they also have an important role in the regulation of neuroendocrine axes and energy homeostasis. To determine whether tanycytes communicate with each other via Connexin 43 (Cx43) gap junctions, individual tanycytes were loaded with Lucifer yellow (LY) through a patch pipette. In all cases, LY filled a larger group of tanycytes as well as blood vessels adjacent to tanycyte processes. The Cx43-blocker, carbenoxolone, inhibited spreading of LY. The greatest density of Cx43-immunoreactive spots was observed in the cell membrane of alpha-tanycyte cell bodies. Cx43-immunoreactivity was also present in the membrane of beta-tanycyte cell bodies, but in lower density. Processes of both types of tanycytes also contained Cx43-immunoreactivity. At the ultrastructural level, Cx43-immunoreactivity was present in the cell membrane of all types of tanycytes including their ventricular surface, but gap junctions were more frequent among alpha-tanycytes. Cx43-immunoreactivity was also observed in the cell membrane between contacting tanycyte endfeet processes, and between tanycyte endfeet process and axon varicosities in the external zone of the median eminence and capillaries in the arcuate nucleus and median eminence. These results suggest that gap junctions are present not only among tanycytes, but also between tanycytes and the axons of hypophysiotropic neurons. Cx43 hemichannels may also facilitate the transport between tanycytes and extracellular fluids, including the cerebrospinal fluid, extracellular space of the median eminence and bloodstream. PMID- 28803832 TI - Congenital absence of ribs: A case report and review of the literature. PMID- 28803833 TI - Letter to the editor: Automated night-time deep brain stimulation battery checks can induce symptoms: Identification and management of a new hardware complication. PMID- 28803834 TI - Transcutaneous auricular vagal nerve stimulation (taVNS) might be a mechanism behind the analgesic effects of auricular acupuncture. AB - BACKGROUND: Randomized clinical trials (RCT) demonstrated that auricular acupuncture (AA) is effective in treatment of acute and chronic pain, although the mechanisms behind AA are not elucidated. METHODS: The data concerning the localization of AA points, which are commonly used to treat pain, were extracted from the meta-analysis of 17 RCTs and evaluated using the anatomical map of auricular afferent nerve supply. RESULTS: Fifteen out of 20 specific AA points, used in the treatment of pain, are situated in areas innervated mostly by the auricular branch of the vagal nerve (ABVN), whereas sham stimulation was applied at the helix of the auricle, innervated by cervical nerves. CONCLUSION: Considering the clinical data relating to the anatomy of neural pathways and experimental findings of the mechanisms of transcutaneous auricular vagal nerve stimulation, the analgesic effects of AA may be explained by stimulation of ABVN. PMID- 28803835 TI - Receptor distribution studies. AB - Receptor distribution studies have played a key role in the characterization of receptor systems (e.g. GABAB, NMDA (GluNRs), and Neurokinin 1) and in generating hypotheses to exploit these systems as potential therapeutic targets. Distribution studies can provide important information on the potential role of candidate receptors in normal physiology/disease and alert for possible adverse effects of targeting the receptors. Moreover, they can provide valuable information relating to quantitative target engagement (e.g. % receptor occupancy) to drive mechanistic pharmacokinetic/pharmacodynamic (PK/PD) hypotheses for compounds in the Drug Discovery process. Finally, receptor distribution and quantitative target engagement studies can be used to validate truly translational technologies such as PET ligands and pharmacoEEG paradigms to facilitate bridging of the preclinical/clinical interface and thus increase probability of success. PMID- 28803836 TI - Methionine sulfoxide reductase A protects against lipopolysaccharide-induced septic shock via negative regulation of the proinflammatory responses. AB - Methionine sulfoxide reductase A (MsrA) is a major antioxidant enzyme that specifically catalyzes the reduction of methionine S-sulfoxide. In this study, we used MsrA gene-knockout (MsrA-/-) mice and bone marrow-derived macrophages (BMDMs) to investigate the role of MsrA in the regulation of inflammatory responses induced by lipopolysaccharide (LPS). MsrA-/- mice were more susceptible to LPS-induced lethal shock than wild-type (MsrA+/+) mice. Serum levels of the proinflammatory cytokines IL-6 and TNF-alpha induced by LPS were higher in MsrA-/ than in MsrA+/+ mice. MsrA deficiency in the BMDMs also increased the LPS induced cytotoxicity as well as TNF-alpha level. Basal and LPS-induced reactive oxygen species (ROS) levels were higher in MsrA-/- than in MsrA+/+ BMDMs. Phosphorylation levels of p38, JNK, and ERK were higher in MsrA-/- than in MsrA+/+ BMDMs in response to LPS, suggesting that MsrA deficiency increases MAPK activation. Furthermore, MsrA deficiency increased the expression and nuclear translocation of NF-kappaB and the expression of inducible nitric oxide synthase, a target gene of NF-kappaB, in response to LPS. Taken together, our results suggest that MsrA protects against LPS-induced septic shock, and negatively regulates proinflammatory responses via inhibition of the ROS-MAPK-NF-kappaB signaling pathways. PMID- 28803837 TI - Silencing of Glut1 induces chemoresistance via modulation of Akt/GSK-3beta/beta catenin/survivin signaling pathway in breast cancer cells. AB - Cancer cells require increased aerobic glycolysis to support rapid cell proliferation. For their increased energy demands, cancer cells express glucose transporter (Glut) proteins at a high level. Glut1 is associated with basal-like breast cancer and is considered a potential therapeutic target. To investigate the possibility of Glut1 as a therapeutic target in breast cancer cells, we downregulated Glut1 in triple-negative breast cancer (TNBC) cell lines using a short hairpin system. We determined whether Glut1 silencing might enhance anti proliferative effect of chemotherapeutic agents. Contrary to our hypothesis, ablation of Glut1 attenuated apoptosis and increased drug resistance via upregulation of p-Akt/p-GSK-3beta (Ser9)/beta-catenin/survivin. These results indicated that the potential of Glut1 as a therapeutic target should be carefully reevaluated. PMID- 28803838 TI - Current epidemiology of resistance among Gram-negative bacilli in paediatric patients in Turkey. AB - OBJECTIVES: The increasing incidence of infections caused by drug-resistant Gram negative organisms has led to a re-emergence worldwide. This study attempted to investigate the changes in resistance of Gram-negative bacteria to different classes of antibiotics and the treatment options for invasive infections. METHODS: A retrospective study was performed between January 2012 and January 2017 in a Turkish tertiary care university hospital. A total of 302 patients with Gram-negative bacteraemia (n=274; 90.7%) or meningitis (n=28; 9.3%) were identified and their demographic, clinical and microbiological features were evaluated. RESULTS: A total of 302 patients with Gram-negative bacterial infection (bacteraemia or meningitis) were investigated. Klebsiella spp. was the most frequent causative agent (n=119; 39.4%), followed by Escherichia coli (n=67; 22.2%), Acinetobacter spp. (n=42; 13.9%), Pseudomonas spp. (n=41; 13.6%) and Enterobacter spp. (n=33; 10.9%). In total, 115 isolates (38.1%) were multidrug resistant (MDR), 63 (20.9%) were extensively drug-resistant (XDR) and 6 (2.0%) were pandrug-resistant (PDR). Over the years, peak antibiotic resistance occurred in 2013, with an increase in the following years. CONCLUSIONS: These data indicate that the resistance pattern of Gram-negative bacteria may change over the years in hospital settings. Therefore, active surveillance of the resistance patterns of micro-organisms is necessary for better management of infections caused by highly resistant bacteria. PMID- 28803839 TI - New risk equations for complications of type 2 diabetes are welcome, but a broader perspective is needed. PMID- 28803841 TI - Coronary Artery Embolism From a Blood Cyst of the Mitral Valve. AB - Blood cysts are benign, congenital tumours of the heart endothelium, found most commonly on heart valves. Adult cases are rare, since most spontaneously regress with age. However, reports of symptomatic cases with embolic phenomena and valve dysfunction have been described. We present a case of a previously healthy 44 year-old woman with no cardiovascular risk factors who developed acute myocardial infarction caused by coronary artery embolism from a blood cyst of the anterior mitral valve leaflet. PMID- 28803840 TI - Development and validation of Risk Equations for Complications Of type 2 Diabetes (RECODe) using individual participant data from randomised trials. AB - BACKGROUND: In view of substantial mis-estimation of risks of diabetes complications using existing equations, we sought to develop updated Risk Equations for Complications Of type 2 Diabetes (RECODe). METHODS: To develop and validate these risk equations, we used data from the Action to Control Cardiovascular Risk in Diabetes study (ACCORD, n=9635; 2001-09) and validated the equations for microvascular events using data from the Diabetes Prevention Program Outcomes Study (DPPOS, n=1018; 1996-2001), and for cardiovascular events using data from the Action for Health in Diabetes (Look AHEAD, n=4760; 2001-12). Microvascular outcomes were nephropathy, retinopathy, and neuropathy. Cardiovascular outcomes were myocardial infarction, stroke, congestive heart failure, and cardiovascular mortality. We also included all-cause mortality as an outcome. We used a cross-validating machine learning method to select predictor variables from demographic characteristics, clinical variables, comorbidities, medications, and biomarkers into Cox proportional hazards models for each outcome. The new equations were compared to older risk equations by assessing model discrimination, calibration, and the net reclassification index. FINDINGS: All equations had moderate internal and external discrimination (C-statistics 0.55-0.84 internally, 0.57-0.79 externally) and high internal and external calibration (slopes 0.71-1.31 between observed and estimated risk). Our equations had better discrimination and calibration than the UK Prospective Diabetes Study Outcomes Model 2 (for microvascular and cardiovascular outcomes, C-statistics 0.54-0.62, slopes 0.06-1.12) and the American College of Cardiology/American Heart Association Pooled Cohort Equations (for fatal or non-fatal myocardial infarction or stroke, C-statistics 0.61-0.66, slopes 0.30-0.39). INTERPRETATION: RECODe might improve estimation of risk of complications for patients with type 2 diabetes. FUNDING: National Institute for Diabetes and Digestive and Kidney Disease, National Heart, Lung and Blood Institute, and National Institute on Minority Health and Health Disparities, National Institutes of Health, and US Department of Veterans Affairs. PMID- 28803842 TI - Experimental evidence for hybridization of closely related lineages in Plasmodium relictum. AB - Over 50 avian Plasmodium species have been described. However, PCR-based information shows much broader diversity of genetic lineages in these parasites. This discrepancy indicates insufficient knowledge about taxonomic diversity and boundaries of a single species in avian Plasmodium species. In recent taxonomy, most of genetically closely related lineages that share the same morphology and development patterns are attributed to the same biological species, but there is no information if these lineages are able to cross. This information is crucial to understand if these lineages form single or multiple evolutionary units. Due to presence of sexual process and sporogonic development of Plasmodium parasites in mosquitoes, self and cross-fertilization can occur and be identified during the oocyst stage. We initiated in vivo hybridization experiments of two widespread Plasmodium relictum lineages (pSGS1 and pGRW11) in experimentally infected Culex pipiens pipiens form molestus mosquitoes. To study putative hybrid oocysts, we used a laser microdissection technique together with PCR-based analyses of mitochondrial and nuclear genes. We demonstrate that both pSGS1 and pGRW11 lineages develop in infected mosquitoes in parallel, but also form hybrid oocysts of these two lineages. Our results are in accord to a recent global phylogeographic study of P. relictum that suggested that cross-fertilization between pSGS1 and pGRW11 might occur. This information helps to understand population structure, gene flow and the evolutionary process of haemosporidian parasites. PMID- 28803843 TI - High-throughput screening of hybridoma supernatants using multiplexed fluorescent cell barcoding on live cells. AB - With current available assay formats using either immobilized protein (ELISA, enzyme-linked immunosorbent assay) or immunostaining of fixed cells for primary monoclonal antibody (mAb) screening, researchers often fail to identify and characterize antibodies that recognize the native conformation of cell-surface antigens. Therefore, screening using live cells has become an integral and important step contributing to the successful identification of therapeutic antibody candidates. Thus the need for developing high-throughput screening (HTS) technologies using live cells has become a major priority for therapeutic mAb discovery and development. We have developed a novel technique called Multiplexed Fluorescent Cell Barcoding (MFCB), a flow cytometry-based method based upon the Fluorescent Cell Barcoding (FCB) technique and the Luminex fluorescent bead array system, but is applicable to high-through mAb screens on live cells. Using this technique in our system, we can simultaneously identify or characterize the antibody-antigen binding of up to nine unique fluorescent labeled cell populations in the time that it would normally take to process a single population. This has significantly reduced the amount of time needed for the identification of potential lead candidates. This new technology enables investigators to conduct large-scale primary hybridoma screens using flow cytometry. This in turn has allowed us to screen antibodies more efficiently than before and streamline identification and characterization of lead molecules. PMID- 28803844 TI - The ATF6alpha arm of the Unfolded Protein Response mediates replicative senescence in human fibroblasts through a COX2/prostaglandin E2 intracrine pathway. AB - Senescence is recognized as a cellular state acquired in response to various stresses. It occurs in correlation with the activation of the Unfolded Protein Response (UPR) pathway. However, the UPR targets which might relay the establishment of the senescent phenotype are not known. Herein, we investigated whether the up-regulation of the COX2 (PTGS2) limiting enzyme in the prostaglandin biosynthesis pathway, known to mediate cellular senescence in normal human fibroblasts, could be controlled by the UPR sensors ATF6alpha, IRE1alpha and PERK. We found that UPR inducers cause premature senescence through an increase in COX2 expression, and an overproduction of prostaglandin E2 (PGE2) in wild type fibroblasts but not in ATF6alpha invalidated ones. In replicative senescent fibroblasts, ATF6alpha and IRE1alpha silencing abrogated COX2 up regulation and PGE2 production. The expanded ER and the large cell size characteristics of senescent fibroblasts were both reduced upon the invalidation of COX2 as well as ATF6alpha. These effects of the ATF6alpha invalidation were prevented by favoring the import of PGE2, but not just by supplying extracellular PGE2. Taken together, our results support a critical role of ATF6alpha in the establishment and maintenance of cellular senescence in normal human fibroblasts via the up-regulation of a COX2/PGE2 intracrine pathway. PMID- 28803845 TI - Improvement of post-thaw sperm survivals using liquid nitrogen vapor in a spermcasting oyster Ostrea angasi. AB - Low survival of cryopreserved sperm impedes the application of cryopreservation technique in spermcasting oyster species. This study developed a simple method of liquid nitrogen vapor freezing to improve post-thaw sperm survival in the spermcasting oyster Ostrea angasi. The results indicate that the permeable cryoprotectants, dimethyl sulfoxide (DMSO), ethylene glycol (EG) and propylene glycol (PG) were non-toxic to sperm up to 20% concentration and 90 min exposure whereas methanol at 10% or higher was toxic to sperm for any exposure over 30 min. Among the treatments with permeable cryoprotectants, 15% EG produced the highest post-thaw sperm motility. Sperm motility was further improved by the addition of non-permeable cryoprotectants (trehalose and glucose), with 15% EG + 0.2 M trehalose resulting in the highest post-thaw sperm motility among all the combinations evaluated. The durations of 20, 30 and 60 min equilibrations produced a higher post-thaw sperm motility and plasma membrane integrity (PMI) than 10 min. Higher post-thaw motility and PMI were achieved by freezing sperm at the 8 cm height from the liquid nitrogen surface than at the 2, 4, 6, 10 or 12 cm height. Holding sperm for 10 min in liquid nitrogen vapor produced higher post thaw motility and PMI than for 2, 5 or 20 min. The cryopreservation protocol developed in this study improved both post-thaw motility and PMI of O. angasi sperm at least 15% higher than those cryopreserved using programmable freezing method. Liquid nitrogen vapor freezing might have greater applicability in improving post-thaw sperm quality of spermcasting oyster species. PMID- 28803846 TI - Embryo survival and birth rate after minimum volume vitrification or slow freezing of in vivo and in vitro produced ovine embryos. AB - The objective was to evaluate pregnancy outcomes and birth rate of in vivo derived vs. in vitro produced ovine embryos submitted to different cryopreservation methods. A total of 197 in vivo and 240 in vitro produced embryos were cryopreserved either by conventional freezing, or by vitrification with Cryotop or Spatula MVD methods on Day 6 after insemination/fertilization. After thawing/warming and transfer, embryo survival rate on Day 30 of gestation was affected by the source of the embryos (in vivo 53.3%, in vitro 20.8%; P < 0.05) and by the method of cryopreservation (conventional freezing 26.5%, Cryotop 52.0%, Spatula MVD 22.2%; P < 0.05). For in vivo derived embryos, survival rate after embryo transfer was 45.6% for conventional freezing, 67.1% for Cryotop, and 40.4% for Spatula MVD. For in vitro produced embryos, survival rate was 7.3% for conventional freezing, 38.7% for Cryotop, and 11.4% for Spatula MVD. Fetal loss from Day 30 to birth showed a tendency to be greater for in vitro (15.0%) rather than for in vivo produced embryos (5.7%), and was not affected by the cryopreservation method. Gestation length, weight at birth and lamb survival rate after birth were not affected by the source of the embryo, the cryopreservation method or stage of development (average: 150.5 +/- 1.8 days; 4232.8 +/- 102.8 g; 85.4%; respectively). This study demonstrates that embryo survival and birth rate of both in vivo and in vitro produced ovine embryos are improved by vitrification with the minimum volume Cryotop method. PMID- 28803847 TI - Psychotic symptoms influence the development of anterior cingulate BOLD variability in 22q11.2 deletion syndrome. AB - Chromosome 22q11.2 deletion syndrome (22q11DS) is a neurodevelopmental disorder associated with a broad phenotype of clinical, cognitive and psychiatric features. Due to the very high prevalence of schizophrenia (30-40%), the investigation of psychotic symptoms in the syndrome is promising to reveal biomarkers for the development of psychosis, also in the general population. Since schizophrenia is seen as a disorder of the dynamic interactions between brain networks, we here investigated brain dynamics, assessed by the variability of blood oxygenation level dependent (BOLD) signals, in patients with psychotic symptoms. We included 28 patients with 22q11DS presenting higher positive psychotic symptoms, 29 patients with lower positive psychotic symptoms and 69 healthy controls between 10 and 30years old. To overcome limitations of mass univariate approaches, we employed multivariate analysis, namely partial least squares correlation, combined with proper statistical testing, to analyze resting state BOLD signal variability and its age-relationship in patients with positive psychotic symptoms. Our results revealed a missing positive age-relationship in the dorsal anterior cingulate cortex (dACC) in patients with higher positive psychotic symptoms, leading to globally lower variability in the dACC in those patients. Patients without positive psychotic symptoms and healthy controls had the same developmental trajectory in this region. Alterations of brain structure and function in the ACC have been previously reported in 22q11DS and linked to psychotic symptoms. The present results support the implication of this region in the development of psychotic symptoms and suggest aberrant BOLD signal variability development as a potential biomarker for psychosis. PMID- 28803848 TI - Disengagement in immigrant groups receiving services for a first episode of psychosis. AB - OBJECTIVE: Although early intervention (EI) programs for psychosis invest in clients remaining engaged in treatment, disengagement remains a concern. It is not entirely clear whether immigrants are likelier to disengage. The rates and predictors of disengagement for immigrant vis-a-vis non-immigrant clients in a Canadian EI setting were analyzed. METHOD: 297 clients were included in a time-to event analysis with Cox Proportional Hazards regression models. Immigrant status (first- or second-generation immigrant or non-immigrant), age, gender, education, substance abuse, family contact, social and material deprivation and medication non-adherence were tested as predictors of service disengagement. RESULTS: 24.2% (n=72) of the clients disengaged from services before completing two years. Disengagement rates did not differ between first-generation immigrants (23.3%), second-generation immigrants (22.7%) and non-immigrants (25.3%). For all clients, only medication non-adherence predicted disengagement (HR=3.81, 95% CI 2.37 6.14). For first-generation immigrants, age (HR=1.17, 95% CI 1.02-1.34) and medication non-adherence (HR=2.92, 95% CI 1.09-7.85) were significant predictors. For second-generation immigrants, material deprivation (HR=1.03, 95% CI 1.00 1.05) and medication non-adherence (HR=11.07, 95% CI 3.20-38.22) were significant. CONCLUSION: Disengagement rates may be similar between immigrants and non-immigrants, but their reasons for disengagement may differ. Medication adherence was an important predictor for all, but the role of various sociodemographic factors differed by group. Sustaining all clients' engagement in EI programs may therefore require multi-pronged approaches. PMID- 28803849 TI - Characteristics of ethanol-induced behavioral sensitization in rats: Molecular mediators and cross-sensitization between ethanol and cocaine. AB - Repeated exposure to drugs of abuse can induce a progressive increase in locomotor activity, known as behavioral sensitization. However, little is known about behavioral sensitization to ethanol. We examined whether ethanol could induce behavioral sensitization and investigated several molecular changes accompanying sensitization. We also assessed whether "cross-sensitization" occurred between ethanol and cocaine, another abused drug. Ethanol-induced sensitization was examined in rats after ethanol treatment (0.5 or 2g/kg) for 15days. The biochemical effects of low- or high-dose ethanol were examined in terms of N-methyl-d-aspartate (NMDA) receptor subunit phosphorylation or expression. Neuronal activity after ethanol treatment was assessed by measuring the level of early growth response (Egr-1) expression. Ethanol-induced behavioral sensitization was observed at the low dose (0.5g/kg) but not the high dose (2g/kg). Although acute treatment with the sensitizing dose of ethanol robustly increased Egr-1 protein and mRNA levels, the expression and phosphorylation of NMDA receptor subunits were not affected. The biochemical responses to ethanol seemed to be enhanced in ethanol-sensitized animals. Cross-sensitization between ethanol and cocaine was observed, which supports the hypothesis that there are commonalities among substances in the pathophysiology of substance dependence. PMID- 28803851 TI - Manganese and neurobehavioral impairment. A preliminary risk assessment. AB - Similar patterns of cognitive and motor deficits have been widely reported from manganese exposures in welding, metallurgical and chemical industry workers. A risk assessment was performed based on studies reported in the literature, extending some earlier work, and deriving new estimates of exposure response and excess risk. Many investigations of manganese neurological effects in humans have insufficient information to derive an exposure response; however, findings from a chemical manufacturer, two smelter and two welder populations permitted application of the benchmark dose procedure for continuous end-points. Small particles and aggregates of condensation fume (condensing vaporized metal, <0.1MUm in diameter) appear to have a higher potency per unit mass than larger particles from dusts (>1.0MUm). Consideration was given to long-term effects of continuous low exposures that instead of producing increasing toxicity attain a steady-state condition. Impairment was defined as excursions beyond the 5th percentile in a normal population and the concentrations of manganese predicted to result in 1% excess prevalence of impairment over different time periods were calculated. Over five years, exposures resulting in 1% excess prevalence of impairment (for purposes of discussion) were in the vicinity of 10MUg/m3 for manganese fume and 25MUg/m3 for larger particle dusts. These levels are below current recommendations for occupational limits on manganese exposure in the United States. PMID- 28803850 TI - Association of exposure to manganese and iron with striatal and thalamic GABA and other neurometabolites - Neuroimaging results from the WELDOX II study. AB - OBJECTIVE: Magnetic resonance spectroscopy (MRS) is a non-invasive method to quantify neurometabolite concentrations in the brain. Within the framework of the WELDOX II study, we investigated the association of exposure to manganese (Mn) and iron (Fe) with gamma-aminobutyric acid (GABA) and other neurometabolites in the striatum and thalamus of 154 men. MATERIAL AND METHODS: GABA-edited and short echo-time MRS at 3T was used to assess brain levels of GABA, glutamate, total creatine (tCr) and other neurometabolites. Volumes of interest (VOIs) were placed into the striatum and thalamus of both hemispheres of 47 active welders, 20 former welders, 36 men with Parkinson's disease (PD), 12 men with hemochromatosis (HC), and 39 male controls. Linear mixed models were used to estimate the influence of Mn and Fe exposure on neurometabolites while simultaneously adjusting for cerebrospinal fluid (CSF) content, age and other factors. Exposure to Mn and Fe was assessed by study group, blood concentrations, relaxation rates R1 and R2* in the globus pallidus (GP), and airborne exposure (active welders only). RESULTS: The median shift exposure to respirable Mn and Fe in active welders was 23MUg/m3 and 110MUg/m3, respectively. Airborne exposure was not associated with any other neurometabolite concentration. Mn in blood and serum ferritin were highest in active and former welders. GABA concentrations were not associated with any measure of exposure to Mn or Fe. In comparison to controls, tCr in these VOIs was lower in welders and patients with PD or HC. Serum concentrations of ferritin and Fe were associated with N-acetylaspartate, but in opposed directions. Higher R1 values in the GP correlated with lower neurometabolite concentrations, in particular tCr (exp(beta)=0.87, p<0.01) and choline (exp(beta)=0.84, p=0.04). R2* was positively associated with glutamate glutamine and negatively with myo-inositol. CONCLUSIONS: Our results do not provide evidence that striatal and thalamic GABA differ between Mn-exposed workers, PD or HC patients, and controls. This may be due to the low exposure levels of the Mn-exposed workers and the challenges to detect small changes in GABA. Whereas Mn in blood was not associated with any neurometabolite content in these VOIs, a higher metal accumulation in the GP assessed with R1 correlated with generally lower neurometabolite concentrations. PMID- 28803852 TI - Dynamic feet distance: A new functional assessment during treadmill locomotion in normal and thoracic spinal cord injured rats. AB - Of all the detrimental effects of spinal cord injury (SCI), one of the most devastating is the disruption of the ability to perform functional movement. Very little is known on the recovery of hindlimb joint kinematics after clinically relevant contusive thoracic lesion in experimental animal models. A new functional assessment instrument, the dynamic feet distance (DFD) was used to describe the distance between the two feet throughout the gait cycle in normal and affected rodents. The purpose of this investigation was the evaluation and characterization of the DFD during treadmill locomotion in normal and T9 contusion injured rats, using three-dimensional (3D) instrumented gait analysis. Despite that normal and injured rats showed a similar pattern in the fifth metatarsal head joints distance excursion, we found a significantly wider distance between the feet during the entire gait cycle following spinal injury. This is the first study to quantify the distance between the two feet, throughout the gait cycle, and the biomechanical adjustments made between limbs in laboratory rodents after nervous system injury. PMID- 28803854 TI - Dissociation between the neural correlates of recollection and familiarity in the striatum and hippocampus: Across-study convergence. AB - In tests of recognition memory, neural activity in the striatum has consistently been reported to differ according to the study status of the test item. A full understanding of the functional significance of striatal 'retrieval success' effects is impeded by a paucity of evidence concerning whether the effects differ according to the nature of the memory signal supporting the recognition judgment (recollection vs. familiarity). Here, we address this issue through an analysis of retrieval-related striatal activity in three independent fMRI studies (total N = 88). Recollection and familiarity were operationalized in a different way in each study, allowing the identification of test-independent, generic recollection and familiarity-related effects. While activity in a bilateral dorsal striatal region, mainly encompassing the caudate nucleus, was enhanced equally by recollected and 'familiar only' test items, activity in bilateral ventral striatum and adjacent subgenual frontal cortex was enhanced only in response to items that elicited successful recollection. By contrast, relative to familiar items, activity in anterior hippocampus was enhanced for both recollected and novel test items. Thus, recollection- and familiarity-driven recognition memory judgments are associated with anatomically distinct patterns of retrieval-related striatal activity, and these patterns are at least partially independent of recollection and novelty effects in the hippocampus. PMID- 28803853 TI - Developmental suppression of forebrain trkA receptors and attentional capacities in aging rats: A longitudinal study. AB - Basal forebrain (BF) cholinergic neurons innervating the cortex regulate cognitive, specifically attentional, processes. Cholinergic atrophy and cognitive decline occur at an accelerated pace in age-related neurodegenerative disorders such as Alzheimer's disease; however, the mechanism responsible for this phenomenon remains unknown. Here we hypothesized that developmental suppression of nerve growth factor signaling, mediated via tropomyosin-related kinase A (trkA) receptors, would escalate age-related attentional vulnerability. An adeno associated viral vector expressing trkA shRNA (AAV-trkA) was utilized to knockdown trkA receptors in postnatal rats at an ontogenetic time point when cortical cholinergic inputs mature, and the impact of this manipulation on performance was assessed in animals maintained on an operant attention task throughout adulthood and until old (24 months) age. A within-subject comparison across different time points illustrated a gradual age-related decline in attentional capacities. However, the performance under baseline and distracted conditions did not differ between the AAV-trkA-infused and animals infused with a vector expressing shRNA against the control protein luciferase at any time point. Additional analysis of cholinergic measures conducted at 24 months showed that the capacity of cholinergic terminals to release acetylcholine following a depolarizing stimulus, cortical cholinergic fiber density and BF cholinergic cell size remained comparable between the two groups. Contrary to our predictions, these data indicate that developmental BF trkA disruption does not impact age related changes in attentional functions. It is possible that life-long engagement in cognitive activity might have potentially rescued the developmental insults on the cholinergic system, thus preserving attentional capacities in advanced age. PMID- 28803855 TI - Elucidating the functions of brain GSK3alpha: Possible synergy with GSK3beta upregulation and reversal by antidepressant treatment in a mouse model of depressive-like behaviour. AB - Glycogen synthase kinase 3 (GSK3) has been linked to the mechanisms of stress, mood regulation, and the effects of antidepressants. The functions of the GSK3beta isoform have been extensively investigated, but little is known about the alpha-isoform, although they may functionally related. In a recently established modified swim test with a third delayed swim exposure, brain GSK3beta mRNA expression positively correlated with floating behaviour on the third test. A two-week-long pretreatment regime with imipramine (7.5mg/kg/day) or thiamine (200mg/kg/day), which is known to have antidepressant properties, reduced the GSK3beta over-expression and decreased floating behaviour on Day 5. GSK3alpha mRNA levels were measured in the hippocampus and prefrontal cortex on Days 1, 2 and 5. GSK3alpha expression was decreased in the prefrontal cortex on Day 2 and increased on Day 5. In this model, GSK3alpha mRNA changes were prevented by imipramine or thiamine treatment. There was a significant correlation between the expression of the two isoforms in the prefrontal cortex on Day 2 in untreated group. These results provide the first evidence for the potential involvement of GSK3alpha in depressive-like behaviours and as a target of anti-depressant therapy. Furthermore, the correlations suggest some cross-talk may exist between the two GSK3 isoforms. PMID- 28803856 TI - Bioenergetic costs and state influence distance perception. AB - Bioenergetic resources and states have been found to influence visual perception, with greater expected energy expenditure being associated with perceptions of greater distances and steeper slopes. Here we tested whether resting metabolic rate (RMR), which can serve as a proxy for the bioenergetic costs of completing physical activity, is positively correlated with perceived distance. We also tested whether temporarily depleting bioenergetic resources through exercise would result in greater perceived distance. Eighty-two members of the public were recruited at a beach in Weston-super-Mare, UK. Half completed moderate exercise and half acted as controls. They then estimated distance to a set point. Results showed that RMR (computed using a recognized equation) was positively correlated with distance perception, meaning that participants requiring greater energy to traverse a set distance perceived the set point as farther away. In addition, those participants who had their bioenergetic resources temporarily depleted through exercise perceived the set distance as greater, compared to controls. There was no interaction effect between RMR and exercise. To our knowledge, these results are the first to show a relationship between metabolic rate and distance perception, and they contribute to the literature on embodied perception. PMID- 28803857 TI - Mapping of quantitative trait loci for temporal growth and age at maturity in coho salmon: Evidence for genotype-by-sex interactions. AB - Phenotypic differences between males and females are ubiquitous throughout the animal kingdom. Therefore, investigating the extent to which sex-dependent genetic effects contribute to phenotypic variation is important in understanding the evolutionary response of each sex to natural and artificial selection. Sex specific differences in growth patterns and age at sexual maturity have been observed in a number of anadromous salmonid fishes. In these species, faster growing individuals in a given cohort often mature earlier than conspecifics, and earlier maturing individuals are often males. The aim of this study was to determine whether sex-dependent genetic effects contribute to phenotypic variation in age at sexual maturity and growth in coho salmon reared through juvenile stages to first maturity. To achieve this aim, quantitative trait loci (QTL) underlying growth-related traits and age at first maturity were mapped across four families, and interactions between offspring sex and trait were examined by investigating the significance of genotype-by-sex (QTL*sex) interactions. Several temporally expressed growth-related QTL mapped to the same position, suggesting that these regions affected growth across many months. QTL*sex interactions were widespread, indicating that the effect of QTL on age at sexual maturity and growth over the course of development in coho salmon may be under sex-specific genetic control. We also found evidence for epistatic interactions between some growth traits. Our results provide insights into the genetic architecture underlying growth-related traits in coho salmon, and have implications for understanding the genetic and evolutionary basis of important fitness-related traits. PMID- 28803858 TI - In-silico investigations of the functional impact of KCNA5 mutations on atrial mechanical dynamics. AB - A recent study has identified six novel genetic variations (D322H, E48G, A305T, D469E, Y155C, P488S) in KCNA5 (encoding Kv1.5 which carries the atrial-specific ultra-rapid delayed rectifier current, IKur) in patients with early onset of lone atrial fibrillation. These mutations are distinctive, resulting in either gain-of function (D322H, E48G, A305T) or loss-of-function (D469E, Y155C, P488S) of IKur channels. Though affecting potassium channels, they may modulate the cellular active force and therefore atrial mechanical functions, which remains to be elucidated. The present study aimed to assess the inotropic effects of the identified six KCNA5 mutations on the human atria. Multiscale electromechanical models of the human atria were used to investigate the impact of the six KCNA5 mutations on atrial contractile functions. It was shown that the gain-of-function mutations reduced active contractile force primarily through decreasing the calcium transient (CaT) via a reduction in the L-type calcium current (ICaL) as a secondary effect of modulated action potential, whereas the loss-of-function mutations mediated positive inotropic effects by increased CaT via enhancing the reverse mode of the Na+/Ca2+ exchanger. The 3D atrial electromechanical coupled model predicted different functional impacts of the KCN5A mutation variants on atrial mechanical contraction by either reducing or increasing atrial output, which is associated with the gain-of-function mutations or loss-of-function mutations in KCNA5, respectively. This study adds insights to the functional impact of KCNA5 mutations in modulating atrial contractile functions. PMID- 28803859 TI - Interventions for walled off necrosis using an algorithm based endoscopic step-up approach: Outcomes in a large cohort of patients. AB - OBJECTIVES: The minimally invasive step-up approach for treatment of walled off necrosis (WON) involves drainage followed by later necrosectomy as needed, and is superior to primary surgical necrosectomy. Reported series of endoscopic transluminal necrosectomy include highly selected patients. We report outcomes of a large series of patients with WON managed by an algorithm based on an endoscopically centered step-up approach. METHODS: Consecutive patients with necrotizing pancreatitis from 2009 to 2014, with intervention only for infected or persistently symptomatic WON. The primary approach involved endoscopic transluminal drainage plus minus necrosectomy whenever feasible, with percutaneous catheter drainage (PCD) plus minus sinus tract endoscopy if not feasible or sufficient. Surgery was reserved for failures of the step up approach. RESULTS: Of 109 consecutive patients with necrotizing pancreatitis, intervention was required in 83, including endoscopic transluminal drainage in 73 (88%) (alone in 49 and combined with PCD in 24), and PCD alone in 10 (12%). 64 (77%) of the 83 patients required endoscopic transluminal and/or sinus tract necrosectomy. Adverse events occurred in 11 (13%). Three patients (4%) failed step up approach and required open surgical necrosectomy. All-cause mortality occurred in 6 (7%) of 83 patients after intervention, including 2 of 3 requiring surgery. CONCLUSIONS: An algorithm based step-up approach for interventions in necrotizing pancreatitis using primarily endoscopic techniques with adjunctive percutaneous approaches as needed resulted in favorable outcomes with small numbers proceeding to open surgery, and with acceptable rates of major complications and mortality. A purely endoscopic transluminal approach was feasible in approximately 60% of patients requiring intervention in this series. PMID- 28803860 TI - Intestinal permeability changes, systemic endotoxemia, inflammatory serum markers and sepsis after Whipple's operation for carcinoma of the pancreas head. AB - POURPOSE: The aim was to evaluate the relationship between failure of gut barrier function, inflammatory markers and septic complications after pancreatoduodenectomy for pancreatic adenocarcinoma. METHODOLOGY: 44 patients were enrolled in this prospective observational clinical study and underwent curative open pancreatoduodenectomy for adenocarcinoma of the head of the pancreas. All patients underwent assessment of intestinal permeability using the lactulose/manitol excretions ratios (L/M ratio), endotoxemia, IL-1beta, IL-6, CRP, and elastase levels before surgery and on postoperative days 1, 3 and 7. Septic complication was defined as a specific clinical condition related to infection by bacterium, virus, or fungus in a specific organ/compartment with positive culture. RESULTS: Septic complications developed in 25% of patients. There were no significant differences in preoperative L/M ratio, endotoxine, CRP, IL-1beta, IL-6, and elastase levels between sepsis-positive and sepsis-negative groups. All patients showed a significant increase in intestinal permeability, endotoxemia, IL-1, IL-6, CRP and elastase on the first postoperative day. At postoperative day 7, the sepsis-positive group continued to demonstrate an increase in intestinal permeability, endotoxemia and elastase; a significant difference was observed between the two groups (P = 0.02), whereas there was no significant difference in IL-1, IL-6, and CRP levels. CONCLUSION: The pattern of change of intestinal permeability, systemic endotoxemia, and elastase concentration in the postoperative period is significantly higher in patients in whom sepsis develops, while the concentration of IL-1beta, IL-6 and CRP do not permit to distinguish infection from inflammation. PMID- 28803861 TI - Long-Duration Complete Remissions of Diffuse Large B Cell Lymphoma after Anti CD19 Chimeric Antigen Receptor T Cell Therapy. AB - T cells expressing anti-CD19 chimeric antigen receptors (CARs) can induce complete remissions (CRs) of diffuse large B cell lymphoma (DLBCL). The long-term durability of these remissions is unknown. We administered anti-CD19 CAR T cells preceded by cyclophosphamide and fludarabine conditioning chemotherapy to patients with relapsed DLBCL. Five of the seven evaluable patients obtained CRs. Four of the five CRs had long-term durability with durations of remission of 56, 51, 44, and 38 months; to date, none of these four cases of lymphomas have relapsed. Importantly, CRs continued after recovery of non-malignant polyclonal B cells in three of four patients with long-term complete remissions. In these three patients, recovery of CD19+ polyclonal B cells took place 28, 38, and 28 months prior to the last follow-up, and each of these three patients remained in CR at the last follow-up. Non-malignant CD19+ B cell recovery with continuing CRs demonstrated that remissions of DLBCL can continue after the disappearance of functionally effective anti-CD19 CAR T cell populations. Patients had a low incidence of severe infections despite long periods of B cell depletion and hypogammaglobulinemia. Only one hospitalization for an infection occurred among the four patients with long-term CRs. Anti-CD19 CAR T cells caused long-term remissions of chemotherapy-refractory DLBCL without substantial chronic toxicities. PMID- 28803862 TI - Recombinant LCMV Vectors Induce Protective Immunity following Homologous and Heterologous Vaccinations. AB - Successful vaccination against cancer and infectious diseases relies on the induction of adaptive immune responses that induce high-titer antibodies or potent cytoxic T cell responses. In contrast to humoral vaccines, the amplification of cellular immune responses is often hampered by anti-vector immunity that either pre-exists or develops after repeated homologous vaccination. Replication-defective lymphocytic choriomeningitis virus (LCMV) vectors represent a novel generation of vaccination vectors that induce potent immune responses while escaping recognition by neutralizing antibodies. Here, we characterize the CD8 T cell immune response induced by replication-defective recombinant LCMV (rLCMV) vectors with regard to expansion kinetics, trafficking, phenotype, and function and we perform head-to-head comparisons of the novel rLCMV vectors with established vectors derived from adenovirus, vaccinia virus, or Listeria monocytogenes. Our results demonstrate that replication-deficient rLCMV vectors are safe and ideally suited for both homologous and heterologous vaccination regimens to achieve optimal amplification of CD8 T cell immune responses in vivo. PMID- 28803865 TI - Ureaplasma urealyticum necrotizing soft tissue infection. AB - Ureaplasma urealyticum is a urogenital commensal and often associated with localised infection. With the advent of monoclonal immunosuppressive therapy and improved diagnostic methods, reports of non-urogenital infections are accumulating. We report a rare case of U. urealyticum necrotizing soft tissue infection and left hip septic arthritis in a hypogammaglobulinaemic patient. Consideration of this organism as an etiological agent, and potential early use of nucleic-acid diagnostic investigation with empiric therapy including activity against Ureaplasma in this patient population may be warranted. PMID- 28803863 TI - Epidermal E-Cadherin Dependent beta-Catenin Pathway Is Phytochemical Inducible and Accelerates Anagen Hair Cycling. AB - Unlike the epidermis, which regenerates continually, hair follicles anchored in the subcutis periodically regenerate by spontaneous repetitive cycles of growth (anagen), degeneration (catagen), and rest (telogen). The loss of hair follicles in response to injuries or pathologies such as alopecia endangers certain inherent functions of the skin. Thus, it is of interest to understand mechanisms underlying follicular regeneration in adults. In this work, a phytochemical rich in the natural vitamin E tocotrienol (TRF) served as a productive tool to unveil a novel epidermal pathway of hair follicular regeneration. Topical TRF application markedly induced epidermal hair follicle development akin to that during fetal skin development. This was observed in the skin of healthy as well as diabetic mice, which are known to be resistant to anagen hair cycling. TRF suppressed epidermal E-cadherin followed by 4-fold induction of beta-catenin and its nuclear translocation. Nuclear beta-catenin interacted with Tcf3. Such sequestration of Tcf3 from its otherwise known function to repress pluripotent factors induced the plasticity factors Oct4, Sox9, Klf4, c-Myc, and Nanog. Pharmacological inhibition of beta-catenin arrested anagen hair cycling by TRF. This work reports epidermal E-cadherin/beta-catenin as a novel pathway capable of inducing developmental folliculogenesis in the adult skin. PMID- 28803864 TI - The detection of microorganisms related to urethritis from the oral cavity of male patients with urethritis. AB - OBJECTIVES: To investigate the presence of microorganisms related to urethritis in the oral cavity of male patients with urethritis and the efficacies of antimicrobials for urethritis on microorganisms in the oral cavity. METHODS: Ninety-two male patients with urethritis and 17 male controls participated to this study at 12 urology clinics in Japan between March 2014 and March 2015. The first voided urine (FVU) and oral wash fluid (OWF) specimens were collected from the participants. The microorganisms in both FVU and OWF specimens were detected by nucleic acid amplification tests at the first and follow-up visit. The efficacies of antimicrobials were evaluated after 1-4 weeks treatment completion. RESULTS: In a total of 92 male patients with urethritis, Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma hominis, Mycoplasma genitalium, Ureaplasma urealyticum, Ureaplasma parvum, Trichomonas vaginalis and Gardnerella vaginalis were detected from OWF specimens of 12%, 3%, 9%, 0%, 12%, 3%, 3% and 15% patients, respectively. From control males, no microorganism was detected from OWF specimens. Among 46 patients who could be evaluated for antimicrobial efficacies at the follow-up visit, 5 in FVU specimens failed by azithromycin (AZM), and 10 failed in OWF specimens (7 by AZM, 2 by tetracycline, 1 by spectinomycin; p = 0.002). Especially, a high prevalence of G. vaginalis remained positive after treatment for urethritis in the oral cavity. CONCLUSION: Microorganisms related to urethritis were detected in the oral cavity of male patients with urethritis. Antimicrobials that focused on urethritis, especially AZM regimen seem to be less effective for microorganisms in the oral cavity. PMID- 28803866 TI - Pericarditis caused by Campylobacter fetus subspecies fetus associated with ingestion of raw beef liver. AB - Campylobacter fetus is an organism residing primarily in the gastrointestinal tracts of cattle and sheep and transmitting to humans through ingestion of contaminated food products or surface water. The organism has caused various extraintestinal infections but, to date, purulent pericarditis due to the organism has rarely been described. We report a case of purulent pericarditis due to C. fetus subsp. fetus, occurring in a patient having several predisposing conditions, including receiving hemodialysis therapy, recent surgery for cecal cancer, and administration of esomeprazole. The patient mentioned having eaten homemade raw beef liver two weeks before the onset, suggesting that the ingested food product was contaminated with C. fetus and the organism transmitted to the pericardium through the bloodstream although blood culture was negative. The causative organism, recovered from the pericardial effusion, was unidentifiable with commercial systems but determinable with molecular methods at the subspecies level. The patient fully improved with pericardiocentesis and subsequent administration of ciprofloxacin, to which the organism was considered susceptible, for a total of four weeks. This is the first case of C. fetus pericarditis in which a history of ingesting a raw food product was clearly mentioned. PMID- 28803867 TI - Dynamics of EEG functional connectivity during statistical learning. AB - Statistical learning is a fundamental mechanism of the brain, which extracts and represents regularities of our environment. Statistical learning is crucial in predictive processing, and in the acquisition of perceptual, motor, cognitive, and social skills. Although previous studies have revealed competitive neurocognitive processes underlying statistical learning, the neural communication of the related brain regions (functional connectivity, FC) has not yet been investigated. The present study aimed to fill this gap by investigating FC networks that promote statistical learning in humans. Young adults (N=28) performed a statistical learning task while 128-channels EEG was acquired. The task involved probabilistic sequences, which enabled to measure incidental/implicit learning of conditional probabilities. Phase synchronization in seven frequency bands was used to quantify FC between cortical regions during the first, second, and third periods of the learning task, respectively. Here we show that statistical learning is negatively correlated with FC of the anterior brain regions in slow (theta) and fast (beta) oscillations. These negative correlations increased as the learning progressed. Our findings provide evidence that dynamic antagonist brain networks serve a hallmark of statistical learning. PMID- 28803869 TI - Metabolic Flexibility Underpins Growth Capabilities of the Fastest Growing Alga. AB - The factors rate-limiting growth of photosynthetic organisms under optimal conditions are controversial [1-8]. Adaptation to extreme environments is usually accompanied by reduced performance under optimal conditions [9, 10]. However, the green alga Chlorella ohadii, isolated from a harsh desert biological soil crust [11-17], does not obey this rule. In addition to resistance to photodamage [17, 18], it performs the fastest growth ever reported for photosynthetic eukaryotes. A multiphasic growth pattern (very fast growth [phase I], followed by growth retardation [phase II] and additional fast growth [phase III]) observed under constant illumination and temperature indicates synchronization of the algal population. Large physiological changes at transitions between growth phases suggest metabolic shifts. Indeed, metabolome analyses at points along the growth phases revealed large changes in the levels of many metabolites during growth with an overall rise during phase I and decline in phase II. Multivariate analysis of the metabolome data highlighted growth phase as the main factor contributing to observed metabolite variance. The analyses identified putrescine as the strongest predictive metabolite for growth phase and a putative growth regulator. Indeed, extracellular additions of polyamines strongly affected the growth rate in phase I and the growth arrest in phase II, with a marked effect on O2 exchange. Our data implicate polyamines as the signals harmonizing metabolic shifts and suggest that metabolic flexibility enables the immense growth capabilities of C. ohadii. The data provide a new dimension to current models focusing on growth-limiting processes in photosynthetic organisms where the anabolic and catabolic metabolisms must be strictly regulated. PMID- 28803870 TI - Industrial Melanism in the Seasnake Emydocephalus annulatus. AB - Although classically associated with urban environments in invertebrates, melanism in terrestrial snakes is more often linked to occupancy of cool climates [1-3]. Thermal advantages to melanism do not apply in aquatic snakes [4], but although turtle-headed seasnakes (Emydocephalus annulatus) are banded or blotched across a wide geographic range [5], most individuals are melanic in polluted inshore bays of the Pacific island of New Caledonia [4]. Why has melanism evolved in these urban sites? Because trace elements bind to melanin, darker feathers enhance a bird's ability to shed pollutants [6]. Reptiles in polluted habitats also accumulate trace elements, which are expelled when the skin is sloughed [7 11]. Might melanism enable snakes to rid themselves of harmful pollutants? We measured trace elements in sloughed skins of seasnakes from urban-industrial versus other areas and in dark versus light skin. For the latter comparison, we used data from laticaudine seasnakes (sea kraits Laticauda spp.), in which each individual is dark and light banded, facilitating comparisons between dark and light skin. As predicted, concentrations of trace elements were higher in snakes from urban-industrial areas and higher in darker than paler skin (even within the same slough). The rate of excretion of trace elements is further enhanced by higher frequencies of sloughing in melanic than banded individuals, even within the same population, because of higher rates of algal settlement on darker skin. Thus, melanism of seasnakes in polluted sites may facilitate excretion of trace elements via sloughing. VIDEO ABSTRACT. PMID- 28803868 TI - Integration of Sweet Taste and Metabolism Determines Carbohydrate Reward. AB - Post-ingestive signals related to nutrient metabolism are thought to be the primary drivers of reinforcement potency of energy sources. Here, in a series of neuroimaging and indirect calorimetry human studies, we examine the relative roles of caloric load and perceived sweetness in driving metabolic, perceptual, and brain responses to sugared beverages. Whereas caloric load was manipulated using the tasteless carbohydrate maltodextrin, sweetness levels were manipulated using the non-nutritive sweetener sucralose. By formulating beverages that contain different amounts of maltodextrin+sucralose, we demonstrate a non-linear association between caloric load, metabolic response, and reinforcement potency, which is driven in part by the extent to which sweetness is proportional to caloric load. In particular, we show that (1) lower-calorie beverages can produce greater metabolic response and condition greater brain response and liking than higher-calorie beverages and (2) when sweetness is proportional to caloric load, greater metabolic responses are observed. These results demonstrate a non-linear association between caloric load and reward and describe an unanticipated role for sweet taste in regulating carbohydrate metabolism, revealing a novel mechanism by which sugar-sweetened beverages influence physiological responses to carbohydrate ingestion. PMID- 28803871 TI - An RNAi Screen in a Novel Model of Oriented Divisions Identifies the Actin Capping Protein Z beta as an Essential Regulator of Spindle Orientation. AB - Oriented cell divisions are controlled by a conserved molecular cascade involving Galphai, LGN, and NuMA. We developed a new cellular model of oriented cell divisions combining micropatterning and localized recruitment of Galphai and performed an RNAi screen for regulators acting downstream of Galphai. Remarkably, this screen revealed a unique subset of dynein regulators as being essential for spindle orientation, shedding light on a core regulatory aspect of oriented divisions. We further analyze the involvement of one novel regulator, the actin capping protein CAPZB. Mechanistically, we show that CAPZB controls spindle orientation independently of its classical role in the actin cytoskeleton by regulating the assembly, stability, and motor activity of the dynein/dynactin complex at the cell cortex, as well as the dynamics of mitotic microtubules. Finally, we show that CAPZB controls planar divisions in vivo in the developing neuroepithelium. This demonstrates the power of this in cellulo model of oriented cell divisions to uncover new genes required in spindle orientation in vertebrates. PMID- 28803872 TI - Parallel Trajectories of Genetic and Linguistic Admixture in a Genetically Admixed Creole Population. AB - Joint analyses of genes and languages, both of which are transmitted in populations by descent with modification-genes vertically by Mendel's laws, language via combinations of vertical, oblique, and horizontal processes [1-4] provide an informative approach for human evolutionary studies [5-10]. Although gene-language analyses have employed extensive data on individual genetic variation [11-23], their linguistic data have not considered corresponding long recognized [24] variability in individual speech patterns, or idiolects. Genetically admixed populations that speak creole languages show high genetic and idiolectal variation-genetic variation owing to heterogeneity in ancestry within admixed groups [25, 26] and idiolectal variation owing to recent language formation from differentiated sources [27-31]. To examine cotransmission of genetic and linguistic variation within populations, we collected genetic markers and speech recordings in the admixed creole-speaking population of Cape Verde, whose Kriolu language traces to West African languages and Portuguese [29, 32-35] and whose genetic ancestry has individual variation in European and continental African contributions [36-39]. In parallel with the combined Portuguese and West African origin of Kriolu, we find that genetic admixture in Cape Verde varies on an axis separating Iberian and Senegambian populations. We observe, analogously to vertical genetic transmission, transmission of idiolect from parents to offspring, as idiolect is predicted by parental birthplace, even after controlling for shared parent-child birthplaces. Further, African genetic admixture correlates with an index tabulating idiolectal features with likely African origins. These results suggest that Cape Verdean genetic and linguistic admixture have followed parallel evolutionary trajectories, with cotransmission of genetic and linguistic variation. PMID- 28803873 TI - Neural Circuitry that Evokes Escape Behavior upon Activation of Nociceptive Sensory Neurons in Drosophila Larvae. AB - Noxious stimuli trigger a stereotyped escape response in animals. In Drosophila larvae, class IV dendrite arborization (C4 da) sensory neurons in the peripheral nervous system are responsible for perception of multiple nociceptive modalities, including noxious heat and harsh mechanical stimulation, through distinct receptors [1-9]. Silencing or ablation of C4 da neurons largely eliminates larval responses to noxious stimuli [10-12], whereas optogenetic activation of C4 da neurons is sufficient to provoke corkscrew-like rolling behavior similar to what is observed when larvae receive noxious stimuli, such as high temperature or harsh mechanical stimulation [10-12]. The receptors and the regulatory mechanisms for C4 da activation in response to a variety of noxious stimuli have been well studied [13-23], yet how C4 da activation triggers the escape behavior in the circuit level is still incompletely understood. Here we identify segmentally arrayed local interneurons (medial clusters of C4 da second-order interneurons [mCSIs]) in the ventral nerve cord that are necessary and sufficient to trigger rolling behavior. GFP reconstitution across synaptic partners (GRASP) analysis indicates that C4 da axons form synapses with mCSI dendrites. Optogenetic activation of mCSIs induces the rolling behavior, whereas silencing mCSIs reduces the probability of rolling behavior upon C4 da activation. Further anatomical and functional studies suggest that the C4 da-mCSI nociceptive circuit evokes rolling behavior at least in part through segmental nerve a (SNa) motor neurons. Our findings thus uncover a local circuit that promotes escape behavior upon noxious stimuli in Drosophila larvae and provide mechanistic insights into how noxious stimuli are transduced into the stereotyped escape behavior in the circuit level. PMID- 28803874 TI - Range Expansion Compromises Adaptive Evolution in an Outcrossing Plant. AB - Neutral genetic diversity gradients have long been used to infer the colonization history of species [1, 2], but range expansion may also influence the efficacy of natural selection and patterns of non-synonymous polymorphism in different parts of a species' range [3]. Recent theory predicts both an accumulation of deleterious mutations and a reduction in the efficacy of positive selection as a result of range expansion [4-8]. These signatures have been sought in a number of studies of the human range expansion out of Africa, but with contradictory results [9-14]. We analyzed the polymorphism patterns of 578,125 SNPs (17,648 genes) in the European diploid plant Mercurialis annua, which expanded its range from an eastern Mediterranean refugium into western habitats with contrasted climates [15]. Our results confirmed strong signatures of bottlenecks and revealed the accumulation of mildly to strongly deleterious mutations in range front populations. A significantly higher number of these mutations were homozygous in individuals in range-front populations, pointing to increased genetic load and reduced fitness under a model of recessive deleterious effects. We also inferred a reduction in the number of selective sweeps in range-front versus core populations. These signatures have persisted even in a dioecious herb subject to substantial interpopulation gene flow [15]. Our results extend support from humans to plants for theory on the dynamics of mutations under selection during range expansion, showing that colonization bottlenecks can compromise adaptive potential. PMID- 28803875 TI - A Novel Plasma Membrane-Anchored Protein Regulates Xylem Cell-Wall Deposition through Microtubule-Dependent Lateral Inhibition of Rho GTPase Domains. AB - Spatial control of cell-wall deposition is essential for determining plant cell shape [1]. Rho-type GTPases, together with the cortical cytoskeleton, play central roles in regulating cell-wall patterning [2]. In metaxylem vessel cells, which are the major components of xylem tissues, active ROP11 Rho GTPases form oval plasma membrane domains that locally disrupt cortical microtubules, thereby directing the formation of oval pits in secondary cell walls [3-5]. However, the regulatory mechanism that determines the planar shape of active Rho of Plants (ROP) domains is still unknown. Here we show that IQD13 associates with cortical microtubules and the plasma membrane to laterally restrict the localization of ROP GTPase domains, thereby directing the formation of oval secondary cell-wall pits. Loss and overexpression of IQD13 led to the formation of abnormally round and narrow secondary cell-wall pits, respectively. Ectopically expressed IQD13 increased the presence of parallel cortical microtubules by promoting microtubule rescue. A reconstructive approach revealed that IQD13 confines the area of active ROP domains within the lattice of the cortical microtubules, causing narrow ROP domains to form. This activity required the interaction of IQD13 with the plasma membrane. These findings suggest that IQD13 positively regulates microtubule dynamics as well as their linkage to the plasma membrane, which synergistically confines the area of active ROP domains, leading to the formation of oval secondary cell-wall pits. This finding sheds light on the role of microtubule plasma membrane linkage as a lateral fence that determines the planar shape of Rho GTPase domains. PMID- 28803876 TI - Distasteful Nectar Deters Floral Robbery. AB - Toxic nectar is an ecological paradox [1, 2]. Plants divert substantial resources to produce nectar that attracts pollinators [3], but toxins in this reward could disrupt the mutualism and reduce plant fitness [4]. Alternatively, such compounds could protect nectar from robbers [2], provided that they do not significantly alter pollinator visitation to the detriment of plant fitness [1, 5-8]. Indeed, very few studies have investigated the role of plant toxins in nectar for defense against nectar robbers [4, 9, 10]. Here, we compared two Aconitum species (A. napellus and A. lycoctonum) that have flowers specialized for long-tongued bumblebee pollinators (Bombus hortorum) but are occasionally robbed by short tongued bumblebees (B. terrestris) [6, 11-13]. Pollinator visits to flowers were much more frequent than by robbers, but visits correlated negatively with nectar alkaloid concentration and declined sharply between 200 and 380 ppm. However, alkaloid concentrations of >20 ppm were deterrent to B. terrestris, suggesting that robbers were less tolerant of nectar alkaloids. Nectar of both plant species contained similar concentrations of carbohydrates and toxic alkaloids, but A. lycoctonum was more likely to secrete nectar in each flower and was also visited more frequently by pollinators and robbers. We conclude that alkaloids in Aconitum spp. nectar affect rates of both pollinator visitation and robbery but may have co-evolved with nectar availability to maintain the fitness benefits of specialized plant-pollinator relationships. Chemical defense of nectar is, however, ultimately constrained by pollinator gustatory sensitivity. PMID- 28803878 TI - Comments on "Effects of high intensity resistance aquatic training on body composition and walking speed in women with mild knee osteoarthritis: a 4-month RCT with 12-month follow-up". PMID- 28803877 TI - Face Pareidolia in the Rhesus Monkey. AB - Face perception in humans and nonhuman primates is rapid and accurate [1-4]. In the human brain, a network of visual-processing regions is specialized for faces [5-7]. Although face processing is a priority of the primate visual system, face detection is not infallible. Face pareidolia is the compelling illusion of perceiving facial features on inanimate objects, such as the illusory face on the surface of the moon. Although face pareidolia is commonly experienced by humans, its presence in other species is unknown. Here we provide evidence for face pareidolia in a species known to possess a complex face-processing system [8-10]: the rhesus monkey (Macaca mulatta). In a visual preference task [11, 12], monkeys looked longer at photographs of objects that elicited face pareidolia in human observers than at photographs of similar objects that did not elicit illusory faces. Examination of eye movements revealed that monkeys fixated the illusory internal facial features in a pattern consistent with how they view photographs of faces [13]. Although the specialized response to faces observed in humans [1, 3, 5-7, 14] is often argued to be continuous across primates [4, 15], it was previously unclear whether face pareidolia arose from a uniquely human capacity. For example, pareidolia could be a product of the human aptitude for perceptual abstraction or result from frequent exposure to cartoons and illustrations that anthropomorphize inanimate objects. Instead, our results indicate that the perception of illusory facial features on inanimate objects is driven by a broadly tuned face-detection mechanism that we share with other species. PMID- 28803879 TI - Pathway profiles based on gene-set enrichment analysis in the honey bee Apis mellifera under brood rearing-suppressed conditions. AB - Perturbation of normal behaviors in honey bee colonies by any external factor can immediately reduce the colony's capacity for brood rearing, which can eventually lead to colony collapse. To investigate the effects of brood-rearing suppression on the biology of honey bee workers, gene-set enrichment analysis of the transcriptomes of worker bees with or without suppressed brood rearing was performed. When brood rearing was suppressed, pathways associated with both protein degradation and synthesis were simultaneously over-represented in both nurses and foragers, and their overall pathway representation profiles resembled those of normal foragers and nurses, respectively. Thus, obstruction of normal labor induced over-representation in pathways related with reshaping of worker bee physiology, suggesting that transition of labor is physiologically reversible. In addition, some genes associated with the regulation of neuronal excitability, cellular and nutritional stress and aggressiveness were over expressed under brood rearing suppression perhaps to manage in-hive stress under unfavorable conditions. PMID- 28803880 TI - Vitamin D and symptoms of depression in overweight or obese adults: A cross sectional study and randomized placebo-controlled trial. AB - Recent evidence suggests that vitamin D deficiency may contribute to increased risk of depression. However, previous studies are limited by variability in participant characteristics including vitamin D deficiency status and presence of existing diseases, use of low doses of vitamin D supplementation for short durations, and use of co-interventions or psychotropic drugs. We examined whether 25-hydroxyvitamin D (25(OH)D) concentrations were associated with symptoms of depression, as well as whether vitamin D supplementation reduced symptoms of depression in overweight or obese and vitamin D-deficient, but otherwise healthy adults. Cross-sectional analyses were performed on baseline data from 63 (39M/24F) overweight or obese (body mass index (BMI) >=25kg/m2) and vitamin D deficient (25(OH)D <=50 nmol/l) adults (mean age=31.3+/-8.5), without clinical depression. Participants were randomized to either a bolus oral dose of 100,000 IU followed by 4000 IU daily of cholecalciferol, or matching placebo for 16 weeks. Interventional analyses were performed on data from 48 participants (30M/18F) who completed the trial. We measured serum 25(OH)D concentrations; anthropometry: BMI, waist-to-hip ratio (WHR), % body fat (dual X-ray absorptiometry); and depressive symptoms using the Beck Depression Inventory (BDI) before and after intervention. Data on dietary vitamin D intake (3-day food record), physical activity (international physical activity questionnaire), and sun exposure habits were collected using questionnaires. At baseline, mean 25(OH)D concentration was 32.9+/-11.3 nmol/l and total BDI score was 6.6+/-6.3 (range=0-33). There were no associations between 25(OH)D concentrations and total BDI scores or BDI subscales (all p>0.1). After the 16-week intervention, 25(OH)D concentrations increased in the vitamin D group compared to placebo (56.0+/-20.8 versus 2.7+/-13.9 nmol/L, respectively; p <0.0001). Change in total BDI scores did not differ between vitamin D and placebo groups (-2.0+/-4.5 versus -1.5+/ 2.9, respectively; p=0.7). There were no differences in BDI subscales between groups (both p>0.1). Results remained non-significant after adjusting for multiple covariates including sun exposure, physical activity, and dietary vitamin D intake (all p>0.1). Our findings suggest that vitamin D deficiency may not be related to increased risk of depression in individuals without clinically significant depression and that the use of vitamin D supplementation may not be warranted for reducing depressive symptoms in this population. Further large scale studies are needed to establish whether vitamin D supplementation may be beneficial for improving depressive symptoms in other population groups, including in those with existing depressive or psychiatric disorders. PMID- 28803881 TI - Cell-specific and dose-dependent effects of PAHs on proliferation, cell cycle, and apoptosis protein expression and hormone secretion by placental cell lines. AB - In the preset study we measured the concentrations of 16 priority PAHs in maternal blood and placental tissue by using the GC-MS/MS system, and investigated the effects of selected PAHs (naphthalene, anthracene, phenanthrene, pyrene) and mixtures on BeWo and JEG-3 human placental cell line proliferation (Alamar Blue), cytotoxicity (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (XTT), lactate dehydrogenase (LDH), acid phosphatase (AP), endocrine activity (progesterone and estradiol secretion) and apoptosis (cyclin A1, cyclin D2, cdk 2, cdk 4, Bcl-xl, Bax, and caspase-3 protein expression). The concentrations of 16 PAHs in maternal blood were higher than in placental tissue. In JEG-3 cells except for naphthalene, all PAHs studied and their mixtures at maternal doses, and only naphthalene at placental doses, increased XTT, while in BeWo cells, placental doses increased XTT and AP activity. A cell-type dependent action: a proapoptotic effect (increased Bax and caspase-3) in BeWo cells and an antiapoptotic effect (decreased Bax and increased cdk2 and cyclin D1) in JEG-3 cells was observed. Naphthalene, pyrene, and phenanthrene exhibited an endocrine disrupting effect in JEG3 cells but not in BeWo cells. Our results provide evidence of cell specific effects of selected low molecular weight PAHs on proliferation, the cell cycle, proapoptotic protein expression, and hormone secretion. PMID- 28803882 TI - Changes in coumarin kinetics and subcellular localization of CYP2E1 contribute to bile duct damage and reduce hepatocellular damage after repeated administration of coumarin in rats. AB - Coumarin exhibits different hepatotoxicity in rats depending on the administration frequency. To investigate the underlying mechanisms for the differences, we administered coumarin to rats as a single dose or repeatedly for 4 weeks. We found large increases in blood levels of liver enzymes and noticeable centrilobular hepatic necrosis after a single dose of coumarin. After repeated administration, enzyme levels mildly increased, while those of gamma-GTP and total bilirubin significantly increased, suggesting bile duct damage. In the control group, cytochrome P450 2E1 (CYP2E1) showed a diffuse subcellular distribution but accumulated within the hepatocyte endoplasmic reticulum after repeated coumarin administration. The maximum blood concentrations of coumarin and its metabolites were significantly lower upon repeated administration. The results suggest that changes in coumarin pharmacokinetics and CYP2E1 subcellular distribution contribute to resistance to coumarin-induced hepatic necrosis, while cytotoxicity of metabolic conjugates shown in vitro may contribute to bile duct damage upon repeated coumarin administration. PMID- 28803883 TI - The provision of emergency contraception in Kinshasa's private sector pharmacies: experiences of mystery clients. AB - OBJECTIVES: Recent programmatic and research efforts on addressing gaps in health systems of low-income countries increasingly see task shifting, i.e. the provision of healthcare by non-medically trained personnel, as a possible solution to increase the availability of specific services and commodities. In Kinshasa, private-sector pharmacies are the primary and preferred provider of family planning (FP) methods, and thus constitute a potential resource for expanding access to specific contraceptives. The objective of this study is to explore selected pharmacies' readiness to serve women seeking emergency contraception (EC). STUDY DESIGN: This study used a mystery client (MC) methodology to visit 73 pharmacies in Kinshasa, Democratic Republic of Congo (DRC). Trained interviewers posed as novice EC users and asked specific questions to evaluate the pharmacy staff's technical knowledge of EC and their attitudes towards EC clients. The results of the MC visit were recorded immediately after the MC left the pharmacy. RESULTS: Findings indicate that more than two-thirds of EC providers were knowledgeable about EC dosage, timeframe, and side effects, and 90% were deemed helpful towards novice EC users. Rare but glaring misconceptions about EC timeframe (20% of providers) and long-term side effects (4% of providers), as well as frequent stock-out (22%) and cost issues highlight priorities for programmatic improvements. CONCLUSIONS: As new service delivery strategies are explored to complement the uneven network of health structures in DRC, this study suggests that, given proper training and integration in FP programming, private-sector pharmacies have the potential to meet specific contraceptive needs for women living in Kinshasa. IMPLICATION STATEMENT: Private pharmacies included in study sample in Kinshasa (DRC) have adequate family planning (FP) service skills to provide clients with emergency contraceptive pills. These higher-end outlets constitute an opportunity for expanding access to FP, although, under total market approaches, a more diverse range of drugs shops should be investigated. PMID- 28803885 TI - Minimalizing bleeding and tearing at vaginal birth: One practitioner's experience. PMID- 28803884 TI - Challenging the colonisation of birth: Koori women's birthing knowledge and practice. AB - BACKGROUND: The 2007 United Nations Declaration on the Rights of Indigenous Peoples states that Indigenous peoples have the right to self-determination for social and cultural development. This fundamental right has been impeded worldwide through colonisation where many Indigenous peoples have had to adapt to ensure continuation of cultural knowledge and practice. In South East Australia colonisation was particularly brutal interrupting a 65,000 year-old oral culture and archives have increasing importance for cultural revival. AIM: The aim of this research was to collate archival material on South East Australian Aboriginal women's birthing knowledge and practice. METHODS: Archivist research methods were employed involving a search for artefacts and compiling materials from these into a new collection. This process involved understanding the context of the artefact creation. Collaborative yarning methods were used to reflect on materials and their meaning. FINDINGS: Artefacts found included materials written by non-Aboriginal men and women, materials written by Aboriginal women, oral histories, media reports and culturally significant sites. Material described practices that connected birth to country and the community of the women and their babies. Practices included active labour techniques, pain management, labour supports, songs for labour, ceremony and the role of Aboriginal midwives. Case studies of continuing cultural practice and revival were identified. CONCLUSION: Inclusion of Aboriginal women's birthing practices and knowledge is crucial for reconciliation and self-determination. Challenging the colonisation of birthing, through the inclusion of Aboriginal knowledge and practice is imperative, as health practices inclusive of cultural knowledge are known to be more effective. PMID- 28803886 TI - A method for extracting and characterizing RNA from urine: For downstream PCR and RNAseq analysis. AB - Readily accessible samples such as urine or blood are seemingly ideal for differentiating and stratifying patients; however, it has proven a daunting task to identify reliable biomarkers in such samples. Noncoding RNA holds great promise as a source of biomarkers distinguishing physiologic wellbeing or illness. Current methods to isolate and characterize RNA molecules in urine are limited. In this proof of concept study, we present a method to extract and identify small noncoding RNAs in urine. Initially, quantitative reverse transcription PCR was applied to confirm the presence of microRNAs in total RNA extracted from urine. Once the presence of micro RNA in urine was confirmed, we developed a method to scale up RNA extraction to provide adequate amounts of RNA for next generation sequence analysis. The method described in this study is applicable to detecting a broad range of small noncoding RNAs in urine; thus, they have wide applicability for health and disease analyses. PMID- 28803887 TI - A miniaturized peptidyl-prolyl isomerase enzyme assay. AB - Prolyl-peptidyl isomerases (PPIases) are enzymes that are found in all living organisms. They form an essential part of the cellular protein folding homeostasis machinery. PPIases are associated with many important human diseases, e.g. cardiovascular disease, cancer and Alzheimer's. The development of novel PPIase inhibitors has been limited by the lack of a rapid, laboratory-based assay for these enzymes, as their substrates and products are challenging to distinguish. A well described continuous assay, coupled with the hydrolysis of a peptide by chymotrypsin is highly effective, but comparatively slow. To address this, we developed an improved version of the traditional assay using a temperature controlled plate reader. This assay allows semi-automated medium throughput assays in an academic laboratory for 84 samples per day. The assay shows lower errors, with an average Z' of 0.72. We further developed the assay using a fluorogenic peptide-based FRET probe. This provides an extremely sensitive PPIase assay using substrate at 200 nM, which approaches single turnover conditions. The fluorescent probe achieves an excellent quenching efficiency of 98.6%, and initial experiments showed acceptable Z' of 0.31 and 0.30 for cyclophilin A and hFKBP12 respectively. The assays provide an improved toolset for the quantitative, biochemical analysis of PPIases. PMID- 28803889 TI - Cancer risk in people living with HIV. PMID- 28803888 TI - Cancer risk in HIV-infected people in the USA from 1996 to 2012: a population based, registry-linkage study. AB - BACKGROUND: Monitoring cancer risk among HIV-infected people in the modern antiretroviral therapy (ART) era is essential given their elevated risk for many cancers and prolonged survival with immunosuppression, ART exposure, and ageing. We aimed to examine cancer risk in HIV-infected people in the USA as compared with that in the general population. METHODS: We did a registry-linkage study with data from population-based HIV and cancer registries in the USA (the HIV/AIDS Cancer Match Study). We assessed a cohort of HIV-infected people identified in HIV registries in Colorado, Connecticut, Georgia, Maryland, Michigan, New Jersey, New York, Puerto Rico, and Texas from 1996 to 2012. Follow up started 3 months after either the latest of the beginning of systematic name based state HIV registration, HIV report date (or AIDS diagnosis, if this was earlier), start of cancer registration, or Jan 1, 1996, and ended at the earliest of either death, end of cancer-registry coverage, or Dec 31, 2012. We identified diagnoses of cancer in this population through linkage with corresponding cancer registries and calculated standardised incidence ratios (SIRs) to measure cancer risk in people with HIV compared with the USA general population, by dividing the observed number of cases in people with HIV by the expected number (estimated by applying general population cancer-incidence rates to person-time in the HIV population based on sex, age, race or ethnic group, calendar year, and registry). We tested SIR differences by AIDS status and over time using Poisson regression. FINDINGS: Among 448 258 people with HIV (who contributed 3 093 033 person-years), 21 294 incident cancers were diagnosed during 1996-2012. In these people, compared with the general population, risk was elevated (p<0.0001 for all) for cancer overall (SIR 1.69, 95% CI 1.67-1.72), AIDS-defining cancers (Kaposi's sarcoma [498.11, 477.82-519.03], non-Hodgkin lymphoma [11.51, 11.14-11.89], and cervix [3.24, 2.94-3.56]), most other virus-related cancers (eg, anus [19.06, 18.13-20.03], liver [3.21, 3.02-3.41], and Hodgkin's lymphoma [7.70, 7.20-8.23]), and some virus-unrelated cancers (eg, lung [1.97, 1.89-2.05]), but not for other common cancers. Risk for several cancers was higher after AIDS onset and declined across calendar periods. After multivariable adjustment, SIRs decreased significantly across 1996-2012 for Kaposi's sarcoma, two subtypes of non-Hodgkin lymphoma, and cancer of the anus, liver, and lung, but remained elevated. SIRs did not increase over time for any cancer. INTERPRETATION: For several virus related cancers and lung cancer, declining risks over time in HIV-infected people probably reflect the expansion of ART since 1996. Additional efforts aimed at cancer prevention and screening in people with HIV are warranted. FUNDING: National Cancer Institute. PMID- 28803890 TI - Hybrid whole body 18F-FDG PET/MR in evaluation of plexiform neurofibromatosis type 1. PMID- 28803891 TI - Cholecystectomy decreased the recurrent cholangitis after clearance of bile duct stones by ERCP in patients with gallstone-related cholangitis. AB - BACKGROUND: This study assessed whether cholecystectomy can decrease recurrent cholangitis and all-cause mortality in patients who received endoscopic retrograde cholangiopancreatography (ERCP) with sphincterotomy and successful clearance of bile duct (BD) stones after gallstone-related cholangitis. METHODS: We analyzed data from the National Health Insurance research database of Taiwan. Patients who had gallstone-related cholangitis and underwent successful endoscopic clearance of BD stones were eligible for enrollment. This population based, propensity score (PS)-matched cohort study involved 2 cohorts; (1) patients who underwent cholecystectomy after ERCP with BD stone clearance as the study group; and (2) those who had no cholecystectomy after ERCP with BD stone clearance as the control group. The primary endpoint was recurrent cholangitis, and the secondary endpoint was all-cause mortality. RESULTS: During a mean 5.7 year follow-up, the incidence rates of recurrent cholangitis were 20.47 per 1000 person-years in the cholecystectomy cohort, and 34.60 per 1000 person-years in the PS-matched control cohort. The risk of recurrent cholangitis was significantly lower in the cholecystectomy cohort than in the control cohort (HR, 0.62; 95% confidence interval [CI], 0.45-0.87; P = 0.006). The HR for all cause mortality among the cholecystectomy cohort was 0.70 (95% CI, 0.54-0.90; P = 0.006) compared with the control cohort. CONCLUSION: Cholecystectomy decreased the recurrent cholangitis and all-cause mortality in patients with endoscopic sphincterotomy and successful clearance of BD stones after gallstone-related cholangitis. PMID- 28803892 TI - Acoustic radiation force imaging (ARFI): A new powerful tool of ultrasound. PMID- 28803893 TI - The companion dog as a unique translational model for aging. AB - The dog is a unique species due to its wide variation among breeds in terms of size, morphology, behaviour and lifespan, coupled with a genetic structure that facilitates the dissection of the genetic architecture that controls these traits. Dogs and humans co-evolved and share recent evolutionary selection processes, such as adaptation to digest starch-rich diets. Many diseases of the dog have a human counterpart, and notably Alzheimer's disease, which is otherwise difficult to model in other organisms. Unlike laboratory animals, companion dogs share the human environment and lifestyle, are exposed to the same pollutants, and are faced with pathogens and infections. Dogs represented a very useful model to understand the relationship between size, insulin-like growth factor-1 genetic variation and lifespan, and have been used to test the effects of dietary restriction and immunotherapy for Alzheimer's disease. Very recently, rapamycin was tested in companion dogs outside the laboratory, and this approach where citizens are involved in research aimed at the benefit of dog welfare might become a game changer in geroscience. PMID- 28803894 TI - Exosomes in cancer: Use them or target them? AB - Exosomes are small extracellular vesicles with a significant role in most processes associated with cancer. On one hand, exosomes role in the different hallmarks of cancer has been widely described, highlighting the urge to understand the potential to target communication mediated by exosomes as a novel therapeutic approach in cancer. On the other hand, exosomes stability in circulation and tumor-targeting capacity shows their applicability in the delivery of anti-cancer molecules. This review will discuss the dual applicability of exosomes in cancer focusing on their usage for therapy improvement, or their targeting to block their supportive role in tumor progression and response to therapy. We highlight the current developments and the strategies used to enhance the potential of exosomes to become clinical partners in the treatment of cancer. PMID- 28803895 TI - Periderm: Life-cycle and function during orofacial and epidermal development. AB - Development of the secondary palate involves a complex series of embryonic events which, if disrupted, result in the common congenital anomaly cleft palate. The secondary palate forms from paired palatal shelves which grow initially vertically before elevating to a horizontal position above the tongue and fusing together in the midline via the medial edge epithelia. As the epithelia of the vertical palatal shelves are in contact with the mandibular and lingual epithelia, pathological fusions between the palate and the mandible and/or the tongue must be prevented. This function is mediated by the single cell layered periderm which forms in a distinct and reproducible pattern early in embryogenesis, exhibits highly polarised expression of adhesion complexes, and is shed from the outer surface as the epidermis acquires its barrier function. Disruption of periderm formation and/or function underlies a series of birth defects that exhibit multiple inter-epithelial adhesions including the autosomal dominant popliteal pterygium syndrome and the autosomal recessive cocoon syndrome and Bartsocas Papas syndrome. Genetic analyses of these conditions have shown that IRF6, IKKA, SFN, RIPK4 and GRHL3, all of which are under the transcriptional control of p63, play a key role in periderm formation. Despite these observations, the medial edge epithelia must rapidly acquire the capability to fuse if the palatal shelves are not to remain cleft. This process is driven by TGFbeta3-mediated, down-regulation of p63 in the medial edge epithelia which allows periderm migration out of the midline epithelial seam and reduces the proliferative potential of the midline epithelial seam thereby preventing cleft palate. Together, these findings indicate that periderm plays a transient but fundamental role during embryogenesis in preventing pathological adhesion between intimately apposed, adhesion-competent epithelia. PMID- 28803896 TI - The thalamo-habenula projection revisited. AB - The thalamus is one of the most highly connected hubs of the vertebrate brain, with roles in perception, arousal, navigation, memory and consciousness. One connection that is missing from contemporary maps is a link to the habenula. This link was reported in the early part of the last century, but appears to have slipped into obscurity. Here, I review the evidence for the existence of this innervation and consider the potential roles it could play. In particular, the possibility that this pathway is involved in non-visual responses to ambient illumination, including emotional responses, is examined. PMID- 28803897 TI - Quantum cell expansion system: Safe and rapid expansion. PMID- 28803898 TI - Electrospun fibrous membranes featuring sustained release of ibuprofen reduce adhesion and improve neurological function following lumbar laminectomy. AB - Electrospun fibrous membranes provide suitable physical anti-adhesion barriers for reducing tissue anti-adhesion following surgery. However, often during the biodegradation process, these barriers trigger inflammation and cause a foreign body reaction with subsequent decrease in anti-adhesion efficacy. Here, a facile strategy comprising the incorporation of ibuprofen (IBU) into implantable membranes and its sustained release was proposed in order to improve anti adhesion effects and neurological outcomes, namely to prevent failed back surgery syndrome (FBSS). The combination of free IBU and a newly synthetized polymeric prodrug of IBU, namely poly(hydroxyethyl methacrylate) with ester-linked IBU, was successfully used in order to reduce initial burst drug release and provide sustained drug release from fibrous membranes throughout several weeks. Such release profile was shown useful in preventing both acute and chronic inflammation in rats following laminectomy and membrane implantation. Moreover, histological analysis provided evidence of an excellent anti-adhesion effect, while associated neurological deficits were effectively reduced. Furthermore, the assessment of macrophage density, neovascularization, and related gene expression at the lesion site revealed that a sustained anti-inflammatory effect was achieved with the IBU-loaded proposed fibrous membranes. Results suggested that the COX2 pathway plays an important role in the development epidural fibrosis and arachnoiditis. Overall, this study provided evidence that precisely engineered IBU-loaded electrospun fibrous membranes may be useful in preventing FBSS and able to potentially impact the outcome of patients undergoing spine surgery. PMID- 28803899 TI - Revolutionize Genetic Studies and Crop Improvement with High-Throughput and Genome-Scale CRISPR/Cas9 Gene Editing Technology. PMID- 28803900 TI - Dissecting the Genetic Basis of Grain Shape and Chalkiness Traits in Hybrid Rice Using Multiple Collaborative Populations. PMID- 28803901 TI - The cubital tunnel syndrome caused by the intraneural or extraneural ganglion cysts: Case report and review of the literature. AB - Cubital tunnel syndrome is the second most common nerve compression syndrome in peripheral nerve compression disease. Although potential ulnar nerve entrapment can occur at multiple points along its course, such as the arcade of struthers, the medial intermuscular septum, the medial epicondyle, the cubital tunnel, and the deep flexor pronator aponeurosis, the most common site of entrapment is the cubital tunnel. However, cubital tunnel syndrome could also be caused by the occupying masses along the course of ulnar nerve, such as intraneural or extraneural ganglia. The cubital tunnel syndrome caused by intraneural or extraneural ganglion cysts has been rarely reported. In our hospital, there were 184 patients with cubital tunnel syndrome who underwent surgical treatment from January 2010 to January 2014. Of these patients, 16 had extraneural cysts and 3 had intraneural ganglion cysts. The incidence rate of cysts in the cubital tunnel was 10.33%. Electromyography was used as routine examination. Ultrasound was used only in some patients in whom elbow mass was suspected. In the surgery of the cubital tunnel syndrome combined with cyst, if any other cysts were found, we should be remove completely the cyts and decompress the ulnar nerve thoroughly with the ulnar nerve being anterior transposition. These cysts were confirmed by histopathological examination. Finally, we compared the clinical features of patients who had a medial elbow ganglion with those of patients who had only cubital tunnel syndrome. B ultrasound can significantly improve the diagnosis. All patients were followed up for 4 months to 2 years, and the curative effect was good. PMID- 28803902 TI - Association Between Irritable Bowel Syndrome and Overactive Bladder: A Research Survey. AB - OBJECTIVE: To investigate the relationship between irritable bowel syndrome (IBS) and overactive bladder (OAB) in men and women using questionnaires. MATERIALS AND METHODS: This research survey was based on multicenter data (men and women older than 20 years). The Korean version of the Rome III criteria was used for the diagnosis of IBS, Overactive Bladder Symptom Score (OABSS) was used for screening OAB, Self-Rating Depression Scale was used for depressive symptoms, and International Prostate Symptom Score and Quality of Life were used to determine the degrees of lower urinary tract symptoms. RESULTS: A total of 609 (men: 257, women: 352) people answered the questionnaire. The prevalence of IBS and OAB was 31.9% (men vs women: 27.3% vs 39.2%) and 19.2% (men vs women: 25.3% vs 18.5%), respectively. The OABSS values of patients with IBS and non-IBS patients were 1.70 +/- 2.48 and 2.48 +/- 2.79 (P <.001). On the Self-Rating Depression Scale, individuals with IBS had a higher score than non-IBS individuals (n = 201) (44.92 +/- 13.71 vs 39.19 +/- 10.39, P <.001). In men, non-IBS (n = 56) had higher OABSS and OABSS question number 3 responses than patients with IBS (OABSS: 2.56 +/- 2.69 vs 1.57 +/- 2.43, P = .01, OABSS Q3: 0.92 +/- 1.26 vs 0.66 +/- 1.13, P = .17). Also, in women, non-IBS (n = 214) had higher OABSS and OABSS question number 3 responses than patients with IBS (n = 138) (OABSS: 2.40 +/- 2.87 vs 1.76 +/- 2.52, P = .03, OABSS Q3: 0.83 +/- 1.25 vs 0.70 +/- 1.18, P = .32). CONCLUSION: IBS in adults had no relationship with OAB in our study. These data suggest that more studies are needed to determine the relationship between IBS and OAB. PMID- 28803903 TI - Structured illumination microscopy reveals actin I localization in discreet foci in Plasmodium berghei gametocytes. AB - Actin has important roles in Plasmodium parasites but its exact function in different life stages is not yet fully elucidated. Here we report the localization of ubiquitous actin I in gametocytes of the rodent model parasite P. berghei. Using an antibody specifically recognizing F-actin and deconvolution microscopy we detected actin I in a punctate pattern in gametocytes. 3D Structured Illumination Microscopy which allows sub-diffraction limit imaging resolved the signal into structures of less than 130 nm length. A portion of actin I was soluble, but the protein was also found complexed in a stabilized form which could only be completely solubilized by treatment with SDS. An additional population of actin was pelleted at 100 000 * g, consistent with F actin. Our results suggest that actin in this non-motile form of the parasite is present in short filaments cross-linked to other structures in a cytoskeleton. PMID- 28803904 TI - Complete mitochondrial genomes of Triodontophorus serratus and Triodontophorus nipponicus, and their comparison with Triodontophorus brevicauda. AB - Triodontophorus serratus and Triodontophorus nipponicus are two of the most common nematodes inhabiting in the large intestine of horse. In the present study, the complete mitochondrial (mt) genome sequences of T. serratus and T. nipponicus have been determined. The mt genomes of T. serratus and T. nipponicus are circular molecules with 13,794 bp and 13,701 bp in size, respectively. These circular mt genomes encode 36 genes, including 12 protein-coding genes, two rRNA genes and 22 tRNA genes. All of these genes are transcribed in the same direction and gene arrangements are consistent with that of gene arrangement 3 (GA3-type). T. serratus and T. nipponicus had two non-coding regions, but T. brevicauda had three. Phylogenetic relationships were reconstructed using concatenated amino acid sequences of the 12 protein-coding genes with three methods, indicating that three species of Triodontophorus clustered together with strong statistical support. However, the genera of Strongylus and Triodontophorus belonged to Strongylinae do not cluster together, and Triodontophorus is more closely related to Cylicocyclus insigne, Cylicocyclus nassatus, Cylicostephanus goldi (Cyathostominae) than to Strongylus. The findings from the present study provide useful genetic markers for studying the molecular ecology, systematics, and population genetics of Triodontophorus in equine. PMID- 28803905 TI - Azithromycin treatment is able to control the infection by two genotypes of Toxoplasma gondii in human trophoblast BeWo cells. AB - Trophoblast infection by Toxoplasma gondii plays a pivotal role in the vertical transmission of toxoplasmosis. Here, we investigate whether the antibiotic therapy with azithromycin, spiramycin and sulfadiazine/pyrimethamine are effective to control trophoblast infection by two Brazilian T. gondii genotypes, TgChBrUD1 or TgChBrUD2. Two antibiotic protocols were evaluated, as follow: i) pre-treatment of T. gondii-tachyzoites with selected antibiotics prior trophoblast infection and ii) post-treatment of infected trophoblasts. The infection index/replication and the impact of the antibiotic therapy on the cytokine milieu were characterized. It was observed that TgChBrUD2 infection induced lower infection index/replication as compared to TgChBrUD1. Regardless the therapeutic protocol, azithromycin was more effective to control the trophoblast infection with both genotypes when compared to conventional antibiotics. Azithromycin induced higher IL-12 production in TgChBrUD1-infected cells that may synergize the anti-parasitic effect. In contrast, the effectiveness of azithromycin to control the TgChBrUD2-infection was not associated with the IL-12 production. BeWo-trophoblasts display distinct susceptibility to T. gondii genotypes and the azithromycin treatment showed to be more effective than conventional antibiotics to control the T. gondii infection/replication regardless the parasite genotype. PMID- 28803906 TI - Viscosupplementation for Hip Osteoarthritis: A Systematic Review and Meta Analysis of the Efficacy on Pain and Disability, and the Occurrence of Adverse Events. AB - OBJECTIVE: To assess the efficacy of viscosupplementation (hyaluronic acid [HA]) on the pain and disability caused by hip osteoarthritis, and to determine the occurrence of adverse events. DATA SOURCES: PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov database, and specific journals up to March 2017. STUDY SELECTION: Randomized controlled trials (RCTs) comparing HA with any other intra articular injection. DATA EXTRACTION: Performed according to Cochrane/Grades of Recommendation, Assessment, Development, and Evaluation criteria. Two authors extracted data and assessed the risk of bias and quality of evidence. A random effects meta-analysis was conducted. DATA SYNTHESIS: Eight RCTs were retrieved (n=807): 4 comparing HA to placebo; 3 to platelet-rich plasma (PRP); 3 to methylprednisolone; and 1 to mepivacaine. Some RCTs had 3 arms. There is very low evidence that HA is not superior to placebo for pain at 3 months (standardized mean difference [SMD]=-.06; 95% CI, -.38 to .25; P=.69), and high evidence that it is not superior in adverse events (risk ratio [RR]=1.21; 95% CI, .79-1.86; P=.38). There is low evidence that HA is not superior to PRP for pain at 1 month. There is very low evidence that HA is not superior to PRP for pain at 6 and 12 months (mean difference in visual analog scale [in cm]: -.05 [95% CI, -.81 to .71], 1.0 [95% CI, -1.5 to 3.50], and .81 [95% CI, -1.11 to 2.73], respectively). There is high evidence that HA is no different from methylprednisolone for pain at 1 month (SMD=.02; 95% CI, -.18 to .22; P=.85). There is low evidence that HA is no different from methylprednisolone for Outcome Measures in Rheumatoid Arthritis Clinical Trials-Osteoarthritis Research Society International Responders Index at 1 month (RR=.44; 95% CI, .10-1.95; P=.28). There is high evidence that HA is no different from methylprednisolone for adverse events (RR=1.21; 95% CI, .79-1.87; P=.38). CONCLUSIONS: We do not recommend viscosupplementation for hip osteoarthritis. Compared with placebo, data show scarce evidence of its efficacy up to 3 months, and suggest no difference at 6 months. However, future RCTs could present HA as an alternative to methylprednisolone for short-term symptom relief. PMID- 28803907 TI - Cu-sensing transcription factor Mac1 coordinates with the Ctr transporter family to regulate Cu acquisition and virulence in Aspergillus fumigatus. AB - Copper (Cu) is an essential trace element and is regarded as an important virulence factor in fungal pathogens. Previous studies suggest that a putative Cu sensing transcription factor Mac1 and the Cu transporter Ctr family play important roles during fungal development and virulence. However, how Cu importers of the Ctr family are involved in the Cu acquisition and what is the functional relationship between them have not been fully investigated yet. Here, we demonstrate that the yeast Mac1 homolog in the opportunistic human pathogen Aspergillus fumigatus is required during colony development under low Cu conditions. Transcriptional profiling combined with LacZ reporter analyses indicate that Cu transporters ctrA2 and ctrC are expressed in an Afmac1-dependent manner upon Cu starvation, and over-expression of ctrA2 or ctrC transporters almost completely rescue the Afmac1-deletion defects, suggesting a redundancy of both transporters in Afmac1-mediated Cu uptake. Genetic analysis showed that ctrC may play a dominant role against Cu starvation relative to ctrA2 and elevated expression of ctrA2 can compensate for ctrC deletion under Cu starvation. Interestingly, both ctrA2 and ctrC deletions can suppress ctrB deletion colony defects. Our findings suggest that Ctr family proteins might coordinately regulate their functions to adapt to different Cu environments. Compared to yeast homologs, Cu family proteins in A. fumigatus may have their own working styles. Most importantly, the Afmac1 deletion strain shows a significantly attenuated pathogenicity in the neutropenic immunocompromised (a combination of cyclophosphamide and hydrocortisone) mice model, demonstrating that Afmac1 is required for pathogenesis in vivo. PMID- 28803908 TI - Comparative analysis of basidiomycete transcriptomes reveals a core set of expressed genes encoding plant biomass degrading enzymes. AB - Basidiomycete fungi can degrade a wide range of plant biomass, including living and dead trees, forest litter, crops, and plant matter in soils. Understanding the process of plant biomass decay by basidiomycetes could facilitate their application in various industrial sectors such as food & feed, detergents and biofuels, and also provide new insights into their essential biological role in the global carbon cycle. The fast expansion of basidiomycete genomic and functional genomics data (e.g. transcriptomics, proteomics) has facilitated exploration of key genes and regulatory mechanisms of plant biomass degradation. In this study, we comparatively analyzed 22 transcriptome datasets from basidiomycetes related to plant biomass degradation, and identified 328 commonly induced genes and 318 repressed genes, and defined a core set of carbohydrate active enzymes (CAZymes), which was shared by most of the basidiomycete species. High conservation of these CAZymes in genomes and similar regulation pattern in transcriptomics data from lignocellulosic substrates indicate their key role in plant biomass degradation and need for their further biochemical investigation. PMID- 28803909 TI - Depletion of the mitotic kinase Cdc5p in Candida albicans results in the formation of elongated buds that switch to the hyphal fate over time in a Ume6p and Hgc1p-dependent manner. AB - The fungal pathogen Candida albicans differentiates between yeast, hyphae and pseudohyphae in order to enhance survival in the human host. Environmental cues induce hyphal development and expression of hyphal-specific genes. Filaments also result from yeast cell cycle arrest, but the nature of these cells and their mechanisms of formation are less clear. We previously demonstrated that depletion of the mitotic polo-like kinase Cdc5p resulted in the production of filaments under yeast growth conditions that were distinct from hyphae with respect to several criteria, yet expressed hyphal-specific genes at later stages of development. In order to clarify the identity of these growth forms and their relationship to true hyphae, we conducted time course-based investigations of aspects of the polar growth machinery, which can distinguish cell types. During later stages of Cdc5p depletion, the myosin light chain Mlc1p demonstrated a Spitzenkorper-like localization in the tips of some filaments, and the Cdc42p GAP Rga2p became hyper-phosphorylated, as in true hyphae. Hyphal-specific genes HWP1, UME6 and HGC1 were strongly expressed at approximately the same time. HWP1 expression was dependent on Ume6p, and absence of Ume6p or Hgc1p influenced late stage filament morphology and integrity. Finally, polarized growth and UME6 expression in Cdc5p-depleted cells were independent of the transcription factor Hms1p. Thus, depleting Cdc5p generates elongated buds that switch to a hyphal fate over time through a mechanism that involves UME6 and HGC1 induction, possibly in response to maintenance of polarized growth. The results expand on the multiple strategies with which C. albicans can modulate growth mode and expression of virulence determinants. PMID- 28803910 TI - A measure to quantify the degree of cooperativity in overall titration curves. AB - In the framework of the grand canonical ensemble, different definitions of cooperativity commonly used in the context of ligand binding are not equivalent. A unifying definition is the existence of non-real roots of the binding polynomial. Using this qualitative criterion, an open question is how to quantify the degree of cooperativity. In this work, we introduce a theoretical measure to quantify the degree of cooperativity of a titriation curve. Its definition is based on a minimal energy approach mapping a given binding polynomial to the minimal interaction energy which is required to generate it. We show that the degree of cooperativity can be calculated easily, if the molecule under consideration is assumed to consist of energetically identical binding sites. Moreover, the property of sub-multiplicativity allows us to determine upper bounds for the degree of cooperativity in asymmetric systems. The approach is consistent with the qualitative definition of cooperativity based on the existence of non-real roots of the binding polynomial, and thus helps to put the concept of cooperativity on a solid theoretical ground. It connects macro- and microstates, but takes here also into account that an infinite number of different molecules can cause the same macroscopic ligand binding behavior, which means that the underlying microsystem cannot be uniquely identified based on the titration curve only. PMID- 28803912 TI - Outstanding increase in immediate citations of Annals articles. PMID- 28803911 TI - Functional heterogeneity of Fo.F1H+-ATPase/synthase in coupled Paracoccus denitrificans plasma membranes. AB - Fo.F1H+-ATPase/synthase in coupled plasma membrane vesicles of Paracoccus denitrificans catalyzes ATP hydrolysis and/or ATP synthesis with comparable enzyme turnover. Significant difference in pH-profile of these alternative activities is seen: decreasing pH from 8.0 to 7.0 results in reversible inhibition of hydrolytic activity, whereas ATP synthesis activity is not changed. The inhibition of ATPase activity upon acidification results from neither change in ADP(Mg2+)-induced deactivation nor the energy-dependent enzyme activation. Vmax, not apparent KmATP is affected by lowering the pH. Venturicidin noncompetitively inhibits ATP synthesis and coupled ATP hydrolysis, showing significant difference in the affinity to its inhibitory site depending on the direction of the catalysis. This difference cannot be attributed to variations of the substrate-enzyme intermediates for steady-state forward and back reactions or to possible equilibrium between ATP hydrolase and ATP synthase Fo.F1 modes of the opposite directions of catalysis. The data are interpreted as to suggest that distinct non-equilibrated molecular isoforms of Fo.F1 ATP synthase and ATP hydrolase exist in coupled energy-transducing membranes. PMID- 28803913 TI - Synthetic rescue couples NADPH generation to metabolite overproduction in Saccharomyces cerevisiae. AB - Engineering the redox cofactor metabolism is known to be a key challenge in developing a platform strain for biosynthesis of valuable products. Hence, general strategies for manipulation of co-factor metabolism in industrially relevant hosts are of significance. Here, we demonstrate an improvement in alpha ketoglutarate (AKG) production in S. cerevisiae using a novel approach based on synthetic rescue. Here, we first perturb the cytosolic NADPH metabolism via deletion of glucose-6-phosphate dehydrogenase (ZWF1). In parallel, we used a strain design algorithm to identify strategies for further improvement in AKG production. Implementation of the identified genetic targets, including disruption of succinyl-CoA Ligase (LSC2) and constitutive expression of NADP+ specific isocitrate dehydrogenases (IDP1 and IDP2) resulted in more than 3 fold improvement in AKG production as compared to the wild type. Our results demonstrate this improvement is due to a synthetic rescue mechanism in which the metabolic flux was redirected towards AKG production through the manipulation of redox cofactors. Disrupting lsc2 in zwf1 mutant improved specific growth rate more than 15% as compared to the zwf1 mutant. In addition, our result suggests that cytosolic isocitrate dehydrogenase (IDP2) may be regulated by isocitrate pools. Together, these results suggest the ability to improve metabolite production via a model guided synthetic rescue mechanism in S. cerevisiae and the potential for using IDP2 expression as a generalized strategy to effectively meet NADPH requirements in engineered strains. PMID- 28803914 TI - Targeted Disruption of TCF12 Reveals HEB as Essential in Human Mesodermal Specification and Hematopoiesis. AB - Hematopoietic stem cells arise from mesoderm-derived hemogenic endothelium (HE) during embryogenesis in a process termed endothelial-hematopoietic transition (EHT). To better understand the gene networks that control this process, we investigated the role of the transcription factor HEB (TCF12) by disrupting the TCF12 gene locus in human embryonic stem cells (hESCs) and inducing them to differentiate toward hematopoietic outcomes. HEB-deficient hESCs retained key features of pluripotency, including expression of SOX2 and SSEA-4 and teratoma formation, while NANOG expression was reduced. Differentiation of HEB-/- hESCs toward hematopoietic fates revealed a severe defect in mesodermal development accompanied by decreased expression of regulators of mesoendodermal fate choices. We also identified independent defects in HE formation at the molecular and cellular levels, as well as a failure of T cell development. All defects were largely rescued by re-expression of HEB. Taken together, our results identify HEB as a critical regulator of human mesodermal and hematopoietic specification. PMID- 28803915 TI - Neural Crest Cell Implantation Restores Enteric Nervous System Function and Alters the Gastrointestinal Transcriptome in Human Tissue-Engineered Small Intestine. AB - Acquired or congenital disruption in enteric nervous system (ENS) development or function can lead to significant mechanical dysmotility. ENS restoration through cellular transplantation may provide a cure for enteric neuropathies. We have previously generated human pluripotent stem cell (hPSC)-derived tissue-engineered small intestine (TESI) from human intestinal organoids (HIOs). However, HIO-TESI fails to develop an ENS. The purpose of our study is to restore ENS components derived exclusively from hPSCs in HIO-TESI. hPSC-derived enteric neural crest cell (ENCC) supplementation of HIO-TESI establishes submucosal and myenteric ganglia, repopulates various subclasses of neurons, and restores neuroepithelial connections and neuron-dependent contractility and relaxation in ENCC-HIO-TESI. RNA sequencing identified differentially expressed genes involved in neurogenesis, gliogenesis, gastrointestinal tract development, and differentiated epithelial cell types when ENS elements are restored during in vivo development of HIO-TESI. Our findings validate an effective approach to restoring hPSC derived ENS components in HIO-TESI and may implicate their potential for the treatment of enteric neuropathies. PMID- 28803917 TI - SCA1+ Cells from the Heart Possess a Molecular Circadian Clock and Display Circadian Oscillations in Cellular Functions. AB - Stem cell antigen 1-positive (SCA1+) cells (SPCs) have been investigated in cell based cardiac repair and pharmacological research, although improved cardiac function after injection has been variable and the mode of action remains unclear. Circadian (24-hr) rhythms are biorhythms regulated by molecular clocks that play an important role in (patho)physiology. Here, we describe (1) the presence of a molecular circadian clock in SPCs and (2) circadian rhythmicity in SPC function. We isolated SPCs from human fetal heart and found that these cells possess a molecular clock based on typical oscillations in core clock components BMAL1 and CRY1. Functional analyses revealed that circadian rhythmicity also governs SPC proliferation, stress tolerance, and growth factor release, with large differences between peaks and troughs. We conclude that SPCs contain a circadian molecular clock that controls crucial cellular functions. Taking circadian rhythms into account may improve reproducibility and outcome of research and therapies using SPCs. PMID- 28803916 TI - Mitigating Ischemic Injury of Stem Cell-Derived Insulin-Producing Cells after Transplant. AB - The advent of large-scale in vitro differentiation of human stem cell-derived insulin-producing cells (SCIPC) has brought us closer to treating diabetes using stem cell technology. However, decades of experiences from islet transplantation show that ischemia-induced islet cell death after transplant severely limits the efficacy of the therapy. It is unclear to what extent human SCIPC are susceptible to ischemia. In this study, we show that more than half of SCIPC die shortly after transplantation. Nutrient deprivation and hypoxia acted synergistically to kill SCIPC in vitro. Amino acid supplementation rescued SCIPC from nutrient deprivation, likely by providing cellular energy. Generating SCIPC under physiological oxygen tension of 5% conferred hypoxia resistance without affecting their differentiation or function. A two-pronged strategy of physiological oxygen acclimatization during differentiation and amino acid supplementation during transplantation significantly improved SCIPC survival after transplant. PMID- 28803918 TI - Modeling of TREX1-Dependent Autoimmune Disease using Human Stem Cells Highlights L1 Accumulation as a Source of Neuroinflammation. AB - Three-prime repair exonuclease 1 (TREX1) is an anti-viral enzyme that cleaves nucleic acids in the cytosol, preventing accumulation and a subsequent type I interferon-associated inflammatory response. Autoimmune diseases, including Aicardi-Goutieres syndrome (AGS) and systemic lupus erythematosus, can arise when TREX1 function is compromised. AGS is a neuroinflammatory disorder with severe and persistent intellectual and physical problems. Here we generated a human AGS model that recapitulates disease-relevant phenotypes using pluripotent stem cells lacking TREX1. We observed abundant extrachromosomal DNA in TREX1-deficient neural cells, of which endogenous Long Interspersed Element-1 retrotransposons were a major source. TREX1-deficient neurons also exhibited increased apoptosis and formed three-dimensional cortical organoids of reduced size. TREX1-deficient astrocytes further contributed to the observed neurotoxicity through increased type I interferon secretion. In this model, reverse-transcriptase inhibitors rescued the neurotoxicity of AGS neurons and organoids, highlighting their potential utility in therapeutic regimens for AGS and related disorders. PMID- 28803919 TI - Therapy-Related Clonal Hematopoiesis in Patients with Non-hematologic Cancers Is Common and Associated with Adverse Clinical Outcomes. AB - Clonal hematopoiesis (CH), as evidenced by recurrent somatic mutations in leukemia-associated genes, commonly occurs among aging human hematopoietic stem cells. We analyzed deep-coverage, targeted, next-generation sequencing (NGS) data of paired tumor and blood samples from 8,810 individuals to assess the frequency and clinical relevance of CH in patients with non-hematologic malignancies. We identified CH in 25% of cancer patients, with 4.5% harboring presumptive leukemia driver mutations (CH-PD). CH was associated with increased age, prior radiation therapy, and tobacco use. PPM1D and TP53 mutations were associated with prior exposure to chemotherapy. CH and CH-PD led to an increased incidence of subsequent hematologic cancers, and CH-PD was associated with shorter patient survival. These data suggest that CH occurs in an age-dependent manner and that specific perturbations can enhance fitness of clonal hematopoietic stem cells, which can impact outcome through progression to hematologic malignancies and through cell-non-autonomous effects on solid tumor biology. PMID- 28803921 TI - Molecular Evidence of Apatococcus, including A. fuscideae sp. nov., as Photobiont in the Genus Fuscidea. AB - The knowledge of the taxonomy and classification of algae (including lichenized) has recently increased rapidly, but there are still many gaps. We aimed to 1) identify the Fuscidea photobionts by locating their taxonomic positions in the green algal classification, and 2) to resolve their interspecific relationships. The lichenized algae were examined based on morphological observations of axenic isolates as well as molecular studies of 18S and ITS nrDNA sequences. Analysis of the secondary structure of the ITS2 operon complemented these investigations. We found that the Fuscidea photobionts were placed within the Trebouxiophyceae, related to Apatococcus lobatus (Chodat) J.B.Petersen. Phylogenetic analyses revealed one clade nesting free-living and lichenized Apatococcus F.Brand which comprised six different lineages in the ITS phylogeny. The lichenized alga associated with the investigated Fuscidea species, except for F. lightfootii (Sm.) Coppins & James, represents a hitherto unknown lineage within Apatococcus. Fuscidea lightfootii was lichenized with a separate lineage within Apatococcus, together with free-living members, which were already known from Genbank sequences. All retrieved groups within Apatococcus were rather different in their ITS sequences, thus most likely corresponding to different species. The most common photobiont of Fuscidea species, Apatococcus fuscideae A.Beck & Zahradn., was described as new to science. PMID- 28803920 TI - Open Chromatin Profiling in hiPSC-Derived Neurons Prioritizes Functional Noncoding Psychiatric Risk Variants and Highlights Neurodevelopmental Loci. AB - Most disease variants lie within noncoding genomic regions, making their functional interpretation challenging. Because chromatin openness strongly influences transcriptional activity, we hypothesized that cell-type-specific open chromatin regions (OCRs) might highlight disease-relevant noncoding sequences. To investigate, we mapped global OCRs in neurons differentiating from hiPSCs, a cellular model for studying neurodevelopmental disorders such as schizophrenia (SZ). We found that the OCRs are highly dynamic and can stratify GWAS-implicated SZ risk variants. Of the more than 3,500 SZ-associated variants analyzed, we prioritized ~100 putatively functional ones located in neuronal OCRs, including rs1198588, at a leading risk locus flanking MIR137. Excitatory neurons derived from hiPSCs with CRISPR/Cas9-edited rs1198588 or a rare proximally located SZ risk variant showed altered MIR137 expression, dendrite arborization, and synapse maturation. Our study shows that noncoding disease variants in OCRs can affect neurodevelopment, and that analysis of open chromatin regions can help prioritize functionally relevant noncoding variants identified by GWAS. PMID- 28803922 TI - Studying furosemide solubilization using an in vitro model simulating gastrointestinal digestion and drug solubilization in neonates and young infants. AB - OBJECTIVE: The aim of the present study was to study the oral performance of furosemide in neonates and young infants using a newly developed in vitro model simulating digestion and drug solubilization in the gastrointestinal (GI) tract of the human neonate and young infant population (age 0-2months). METHODS: The utilized in vitro model was designed to mimic the digestion and drug solubilization processes occurring in the stomach, and the small intestine of the neonate and young infant population, using physiologically relevant media, volumes and digestive enzymes. Overall the experimental model setup was based on the dynamic in vitro lipolysis model previously described by Fernandez et al. (2009). The amount of furosemide solubilized in the aqueous phase during a digestion study was used as an estimate for the amount of drug available for absorption in vivo. By varying different factors in the model setup, e.g. presence of food (food-effect), effect of digestion (tested with and without addition of digestive enzymes), and properties of the dosage form, it was possible to estimate the importance of these factors in vivo. KEY FINDINGS AND CONCLUSIONS: The present in vitro data suggest that the oral performance of furosemide in neonates and young infants will be increased by the presence of food (frequent feedings) due to increased drug solubilization, however, not influenced by the GI digestion of this food. The properties of the dosage form (immediate release tablets) did not affect the drug solubilization as compared to administration of the pure drug powder. PMID- 28803924 TI - Differential regulation of the TLR4 signalling pathway in post-mortem prefrontal cortex and cerebellum in chronic schizophrenia: Relationship with SP transcription factors. AB - Alterations in innate immunity may underlie the pathophysiology of schizophrenia (SZ). Toll-like receptor-4 (TLR4) is a master element of innate immunity. The specificity proteins (SPs), transcription factors recently implicated in SZ, are putative regulatory agents of this. This work was aimed at describing alterations in the TLR4 signalling pathway in postmortem brain prefrontal cortex (PFC) and cerebellum (CB) of 16 chronic SZ patients and 14 controls. The possible association of TLR4 pathway with SP1 and SP4 and SZ negative symptomatology is explored. In PFC, TLR4/myeloid differentiation factor 88 (MyD88)/inhibitory subunit of nuclear factor kappa B alpha (IkappaBalpha) protein levels were lower in SZ patients, while nuclear transcription factor-kappaB (NFkappaB) activity, cyclooxygenase-2 (COX-2) expression and the lipid peroxidation index malondialdehyde (MDA) appeared increased. The pattern of changes in CB is opposite, except for COX-2 expression that remained augmented and MDA levels unaltered. Network interaction analysis showed that TLR4/MyD88/IkappaBalpha/NFkappaB/COX-2 pathway was coupled in PFC and uncoupled in CB. SP4 co-expressed with TLR4 and NFkappaB in PFC and both SP1 and SP4 co expressed with NFkappaB in CB. In PFC, correlation analysis found an inverse relationship between NFkappaB and negative symptoms. In summary, we found brain region-specific alterations in the TLR4 signalling pathway in chronic SZ, in which SP transcription factors could participate at different levels. Further studies are required to elucidate the regulatory mechanisms of innate immunity in SZ and its relationship with symptoms. PMID- 28803925 TI - Impact of Prostatic-specific Antigen Threshold and Screening Interval in Prostate Cancer Screening Outcomes: Comparing the Swedish and Finnish European Randomised Study of Screening for Prostate Cancer Centres. AB - BACKGROUND: The European Randomised Study of Screening for Prostate Cancer trial has shown a 21% reduction in prostate cancer (PC) mortality with prostate specific antigen (PSA)-based screening. Sweden used a 2-yr screening interval and showed a larger mortality reduction than Finland with a 4-yr interval and higher PSA cut-off. OBJECTIVE: To evaluate the impact of screening interval and PSA cut off on PC detection and mortality. DESIGN, SETTING, AND PARTICIPANTS: We analysed the core age groups (55-69 yr at entry) of the Finnish (N=31 866) and Swedish (N=5901) screening arms at 13 yr and 16 yr of follow-up. Sweden used a screening interval of 2 yr and a PSA cut-off of 3.0ng/ml, while in Finland the screening interval was 4 yr and the PSA cut-off 4.0ng/ml (or PSA 3.0-3.9ng/ml with free PSA<16%). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We compared PC detection rate and PC mortality between the Finnish and Swedish centres and estimated the impact of different screening protocols. RESULTS AND LIMITATIONS: If the Swedish screening protocol had been followed in Finland, 122 additional PC cases would have been diagnosed at screening, 84% of which would have been low-risk cancers, and four leading to PC death. In contrast, if a lower PSA threshold had been applied in Finland, at least 127 additional PC would have been found, with 19 PC deaths. CONCLUSIONS: The small number of deaths among cases that would have been potentially detectable in Finland with the Swedish protocol (or those that would have been missed in Sweden with the Finnish approach) is unlikely to explain the differences in mortality in this long of a follow-up. PATIENT SUMMARY: A prostate specific antigen threshold of 3ng/ml versus 4ng/ml or a screening interval of 2 yr instead of 4 yr is unlikely to explain the larger mortality reduction achieved in Sweden compared with Finland. PMID- 28803927 TI - Limited Relationship of Voltage Criteria for Electrocardiogram Left Ventricular Hypertrophy to Cardiovascular Mortality. AB - BACKGROUND: Numerous methods have been proposed for diagnosing left ventricular hypertrophy using the electrocardiogram. They have limited sensitivity for recognizing pathological hypertrophy, at least in part due to their inability to distinguish pathological from physiological hypertrophy. Our objective is to compare the major electrocardiogram-left ventricular hypertrophy criteria using cardiovascular mortality as a surrogate for pathological hypertrophy. METHODS: This study was a retrospective analysis of 16,253 veterans < 56 years of age seen at a large Veterans Affairs Medical Center from 1987 to 1999 and followed a median of 17.8 years for cardiovascular mortality. Receiver operating characteristics and Cox hazard survival techniques were applied. RESULTS: Of the 16,253 veterans included in our target population, the mean age was 43 years, 8.6% were female, 33.5% met criteria for electrocardiogram-left ventricular hypertrophy, and there were 744 cardiovascular deaths (annual cardiovascular mortality 0.25%). Receiver operating characteristic analysis demonstrated that the greatest area under the curve (AUC) for classification of cardiovascular death was obtained using the Romhilt-Estes score (0.63; 95% confidence interval, 0.61-0.65). Most of the voltage-only criteria had nondiagnostic area under the curves, with the Cornell being the best at 0.59 (95% confidence interval, 0.57 0.62). When the components of the Romhilt-Estes score were examined using step wise Wald analysis, the voltage criteria dropped from the model. The Romhilt Estes score >= 4, the Cornell, and the Peguero had the highest association with cardiovascular mortality (adjusted hazard ratios 2.2, 2.0, and 2.1, consecutively). CONCLUSION: None of the electrocardiogram leads with voltage criteria exhibited sufficient classification power for clinical use. PMID- 28803926 TI - Differences in Associations of Antidepressants and Hospitalization Due to Hyponatremia. AB - BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) and other antidepressants are important as a cause of hyponatremia. However, most studies have focused on the effect on sodium levels regardless of clinical symptoms, or have been too small to be able to discriminate between the effects of specific antidepressant drugs. The objective of the present study was to investigate the association between different groups of antidepressants and the risk of hospitalization due to hyponatremia. METHODS: In this register-based case-control study of patients in the general Swedish population, we identified 14,359 individuals with a main diagnosis of hyponatremia. For every case, 4 matched controls were included (n = 57,382). To investigate the temporal aspects of drug induced hyponatremia, antidepressant exposure was divided into patients with newly initiated and ongoing treatment. Univariable and multivariable logistic regression was used to analyze the association of antidepressant use and hospitalization. RESULTS: For newly initiated antidepressants, adjusted odds ratios (95% confidence interval) for a main diagnosis of hyponatremia compared with controls were: citalopram 5.50 (4.71-6.44); sertraline 4.96 (3.81-6.48); venlafaxine 5.28 (3.20-8.83); tricyclic antidepressants 1.59 (1.13-2.24); and mirtazapine 2.54 (2.04-3.16). Adjusted odds ratio (confidence interval) for individuals with ongoing treatment ranged from 0.57 (0.52-0.63) for citalopram to 1.08 (0.85-1.36) for other SSRIs. CONCLUSIONS: There was a strong association between newly initiated treatment with SSRIs or venlafaxine and hospitalization due to hyponatremia. The association for tricyclic antidepressants and mirtazapine was small to moderate. In contrast, there was no evidence that ongoing treatment with antidepressants increases the risk for hospitalization due to hyponatremia. PMID- 28803928 TI - Cerebral Air Embolism Following Central Venous Catheter Removal. PMID- 28803929 TI - An Uncommon Cause of Low Back Pain. PMID- 28803923 TI - Stress induced neural reorganization: A conceptual framework linking depression and Alzheimer's disease. AB - Chronic stress is a risk factor for a number of physiological disorders including cardiovascular disease, obesity and gastrointestinal disorders, as well as psychiatric and neurodegenerative disorders. There are a number of underlying molecular and cellular mechanisms altered in the course of chronic stress, which may increase the vulnerability of individuals to develop psychiatric disorders such as depression, and neurodegenerative disorders such as Alzheimer's Disease (AD). This is evident in the influence of stress on large-scale brain networks, including the resting state Default Mode Network (DMN), the effects of stress on neuronal circuitry and architecture, and the cellular and molecular adaptations to stress, which may render individuals with stress related psychiatric disorders more vulnerable to neurodegenerative disease later in life. These alterations include decreased negative feedback inhibition of the hypothalamic pituitary axis (HPA) axis, decreased dendritic arborization and spine density in the prefrontal cortex (PFC) and hippocampus, and the release of proinflammatory cytokines, which may suppress neurogenesis and promote neuronal cell death. Each of these factors are thought to play a role in stress-related psychiatric disease as well as AD, and have been observed in clinical and post-mortem studies of individuals with depression and AD. The goal of the current review is to summarize clinical and preclinical evidence supporting a role for chronic stress as a putative link between neuropsychiatric and neurodegenerative disease. Moreover, we provide a rationale for the importance of taking a medical history of stress-related psychiatric diseases into consideration during clinical trial design, as they may play an important role in the etiology of AD in stratified patient populations. PMID- 28803930 TI - Identification of neuroglobin as a novel player in anti-bacterial responses in amphioxus. AB - Theoretical considerations support various functions of neuroglobin (Ngb), but further studies are required for full characterization of these functions. In this study, we identified the presence of a single Ngb gene, BjNgb, in the amphioxus Branchiostoma japonicum. BjNgb was expressed in various tissues including the notochord, gonads (ovary and testis) and gill, and up-regulated significantly in response to the challenge with LPS and LTA, suggesting involvement in immune response of amphioxus against bacterial infection. In accord, we demonstrated for the first time that recombinant BjNgb (rBjNgb) not only interacted with the Gram-positive and negative bacteria as well as their conserved surface components LPS and LTA, but also enhanced the phagocytosis of bacteria by macrophages. Collectively, these data suggest that BjNgb is a novel player in amphioxus, via functioning as a pattern recognition molecule and an opsonin. PMID- 28803931 TI - Explicit definitions of potentially inappropriate prescriptions of antibiotics in older patients: a compilation derived from a systematic review. AB - Potentially inappropriate prescriptions (PIPs) of antibiotics (antibiotic-PIPs) are generally detected by applying implicit definitions based on expert opinion. Explicit definitions are less frequently used, even though this approach would enable the automated detection of antibiotic-PIPs in electronic health records. Here, explicit definitions of antibiotic-PIPs used in studies of older adults were systematically reviewed. The MEDLINE(r), Scopus(r) and Web of ScienceTM core collection databases were searched with a combination of three terms and their synonyms: 'potentially inappropriate prescription' AND 'antibiotic treatment' AND 'older patients'. Following standardised selection of publications, explicit definitions of antibiotic-PIPs were extracted and were classified into infectious diseases domains and subdomains. A total of 600 search queries identified 4270 records, 93 of which were selected for review. A total of 160 mentions of antibiotic-PIPs were found, corresponding to 62 distinct definitions in 19 infectious diseases domains. Nearly one-half of the definitions were related to upper respiratory tract infections (n = 11 definitions; 17.7%), lower respiratory tract infections (n = 8; 12.9%) and drug-drug interactions (n = 11; 17.7%). Almost 75% of definitions (n = 46) were mentioned in a single study only. Only three definitions concerned critically important antibiotics such as third generation cephalosporins and fluoroquinolones. This systematic review identified 62 explicit definitions of antibiotic-PIPs. Most of the definitions were not found in more than one study and they varied in the degree of precision. We advocate the implementation of an expert consensus on explicit definitions of antibiotic-PIPs that correspond to today's challenges in public health. PMID- 28803932 TI - The thiopurine nucleoside analogue 6-methylmercaptopurine riboside (6MMPr) effectively blocks Zika virus replication. AB - Since the emergence of Zika virus (ZIKV) in Brazil in 2015, 48 countries and territories in the Americas have confirmed autochthonous cases of disease caused by the virus. ZIKV-associated neurological manifestations and congenital defects make the development of safe and effective antivirals against ZIKV of utmost importance. Here we evaluated the antiviral activity of 6-methylmercaptopurine riboside (6MMPr), a thiopurine nucleoside analogue derived from the prodrug azathioprine, against the epidemic ZIKV strain circulating in Brazil. In all of the assays, an epithelial (Vero) and a human neuronal (SH-SY5Y) cell line were used to evaluate the cytotoxicity and effective concentrations of 6MMPr against ZIKV. Levels of ZIKV-RNA, viral infectious titre and the percentage of infected cells in the presence or absence of 6MMPr were used to determine antiviral efficacy. 6MMPr decreased ZIKV production by >99% in both cell lines in a dose- and time-dependent manner. Interestingly, 6MMPr was 1.6 times less toxic to SH SY5Y cells compared with Vero cells, presenting a 50% cytotoxic concentrations (CC50) of 460.3 uM and 291 uM, respectively. The selectivity index of 6MMPr for Vero and SH-SY5Y cells was 11.9 and 22.7, respectively, highlighting the safety profile of the drug to neuronal cells. Taken together, these results identify, for the first time, the thiopurine nucleoside analogue 6MMPr as a promising antiviral candidate against ZIKV that warrants further in vivo evaluation. PMID- 28803933 TI - Phages in urban wastewater have the potential to disseminate antibiotic resistance. AB - A total of 29 Escherichia coli phages were isolated from wastewater samples collected from an urban wastewater treatment plant and were characterised by host range determination, transmission electron microscopy, antibiotic resistance gene identification and phage transduction. beta-Lactam resistance genes (blaCMY, blaTEM, blaSHV, blaCTX-M and blaOXA) were amplified on phage DNA by PCR. Of nine host range patterns observed, six were able to multiply in three or more indicator strains, including Shiga toxin-producing E. coli (STEC). Twelve E. coli phages were able to grow in all four E. coli O157 strains tested. The blaTEM gene was detected in 15 phages, of which 6 were able to transduce blaTEM into E. coli ATCC 13706. These data suggest that phages with broad host range are prevalent in the urban environment and can serve as a natural reservoir of antibiotic resistance genes. These phages can also transfer antibiotic resistance genes via phage transduction and may contribute to the dissemination of antibiotic resistance in the environment. PMID- 28803935 TI - TNF-alpha upregulates HIF-1alpha expression in pterygium fibroblasts and enhances their susceptibility to VEGF independent of hypoxia. AB - The clinical manifestations of pterygium are characterized by rapid growth and postoperative recurrences. We had previously proposed that hypoxia-inducible factor (HIF)-1alpha recruits progenitor cells during the development and progression of pterygia. Recently, it was reported that various stimuli, including inflammation, could activate HIF-1alpha even under normoxic conditions. The ocular surface directly faces external environments, and is thus frequently exposed to inflammatory insults. First, we examined the gene expression of HIF 1alpha, its downstream molecule, vascular endothelial growth factor (VEGF)-A, and VEGF receptor (VEGFR)-2 in corneal and conjunctival cells compared with cultured human umbilical vein endothelial cells. Corneal fibroblasts had high expression of VEGFR-2 in the presence of TNF-alpha, and HIF-1alpha was activated by TNF alpha in diverse ocular surface cells. The HIF-1alpha/VEGF/VEGFR signaling pathway in response to TNF-alpha was evaluated in cultured human pterygium fibroblasts (HPFs) at the gene and protein levels and was compared to treatment with cobalt chloride (CoCl2), a hypoxic mimetic, to exclude the effect of hypoxia. Although VEGF-A expression was not changed by TNF-alpha, expression of HIF-1alpha and VEGFR-2 was enhanced in HPFs treated with TNF-alpha, independent of hypoxia conditioning. In addition, VEGF-C gene expression was activated solely by TNF-alpha in HPF, but VEGF-B levels were not significantly affected. These results may provide mechanistic explanations for the uniquely vigorous proliferation of pterygium fibrovascular tissue during TNF-alpha-induced ocular surface inflammation. PMID- 28803934 TI - Dose, duration, and animal sex predict vancomycin-associated acute kidney injury in preclinical studies. AB - BACKGROUND: Although the exposure-dependent efficacy thresholds of vancomycin have been probed, less is known about acute kidney injury (AKI) thresholds for this drug. Sensitive urinary biomarkers, such as kidney injury molecule 1 (KIM 1), have shown high sensitivity and specificity for vancomycin-associated AKI. The aims of the study were to determine if there were dose-response curves with urinary KIM-1, and to evaluate the impact of therapy duration and sex on observed relationships. METHODS: A systematic review was conducted via PubMed/MEDLINE. Data were compiled from preclinical studies that reported individual subject data for urinary KIM-1 concentrations, vancomycin dose (mg/kg), duration of treatment, and sex. Sigmoidal Hill-type models were fit to the individual dose-response data. RESULTS: A total of 15 studies were identified, 6 of which reported vancomycin dose and KIM-1 data. Of these, three included individual animal-level data suitable for analysis. For all pooled rats, increasing total daily vancomycin doses displayed a dose-response curve with urinary KIM-1 concentrations (50% maximal toxic response=130.4 mg/kg/day). Dose-response curves were shifted left for females vs. males (P = 0.05) and for long (i.e. >=7 days) vs. short (i.e. <4 days) duration of vancomycin therapy (P=0.02). CONCLUSIONS: The collective findings demonstrate a clear dose-response relationship between vancomycin dose and AKI. As these analyses focused exclusively on dose-response relationships, additional preclinical data are needed to more clearly define vancomycin exposures that predict the onset of AKI. PMID- 28803937 TI - Annual variation in the reproductive hormone and behavior rhythm in a population of the Asian short-toed lark: Can spring temperature influence activation of the HPG axis of wild birds? AB - Although a number of studies have demonstrated a correlation between ambient temperature and the timing of reproductive behavior in many bird species, the relationships between temperature, activation of the hypothalamus-pituitary-gonad (HPG) axis, laying, and hatching in free-living birds, remain unclear. We investigated the relationships between spring temperature, reproductive hormones, and behavior, in a population of the Asian short-toed lark (Calandrella cheleensis) on the Inner Mongolian Grasslands in 2014, 2015 and 2016. LH and T levels peaked earliest in the year with the highest April temperature (2014) and latest in the year with the lowest April temperature (2016), and rose faster in 2014 than in 2015 or 2016. Laying and hatching occurred earliest in 2014 and latest in 2016. E2 also peaked earlier in 2014 than in the other two years but there was no significant difference in peak E2 levels among the three years. The peak of hatching only coincided with the peak in grasshopper nymph (the main food of nestlings) abundance in 2015 and the nestling fledging rate in 2015 was significantly higher than that in 2014 and 2016. We also conducted a controlled experiment on the effect of temperature on plasma LH, T and E2 levels in wild caught larks, which shows that mean plasma LH, T and E2 levels in the 16 degrees C group all peaked 4days earlier than in the 13 degrees C group. All these results suggest that activation of HPG endocrine axis in the Asia short-toed lark population is closely related to ambient temperature, and that this subsequently influences the timing of laying and hatching. The HPG axis' endocrine function is a physiological factor that mediates effects of ambient temperature on the timing of breeding. Temperature induced annual variation in the timing of hatching was, however, insufficient to synchronize the nestling period with the annual peak in grasshopper nymph abundance. Unusually warm, or cold, spring temperatures advanced, or delayed, grasshopper nymph development to an extent that exceeded the Asian short-toed lark's capacity to advance or delay the onset of breeding and reproductive success was lower in the two years of the study in which the nestling period was asynchronous with the peak of grasshopper nymph abundance. Long-term research on the relationship between the timing of reproduction and population demographics of the Asian short-toed lark is required to understand the effects of climate change on this species and on temperate birds in general. PMID- 28803936 TI - Inhibition of HUVEC tube formation via suppression of NFkappaB suggests an anti angiogenic role for SLURP1 in the transparent cornea. AB - Previously, we have reported that the Secreted Ly6/uPAR related protein-1 (SLURP1) serves an important immunomodulatory function in the ocular surface. Here, we examine the involvement of SLURP1 in regulating corneal angiogenic privilege. Slurp1 expression detected by QPCR, immunoblots and immunofluorescent stain, was significantly decreased in mouse corneas subjected to alkali burn induced corneal neovascularization (CNV). Addition of exogenous SLURP1 (6XHis tagged, E. coli expressed and partially purified using Ni-ion columns) significantly suppressed the tumor necrosis factor-alpha (TNF-alpha)-stimulated human umbilical cord vascular endothelial cell (HUVEC) tube formation. SLURP1 suppressed the HUVEC tube length, tube area and number of branch points, without affecting their viability and/or proliferation. Exogenous SLURP1 in HUVEC also suppressed the TNF-alpha-induced (i) interleukin-8 (IL-8) and TNF-alpha production, (ii) adhesion to different components of the extracellular matrix, (iii) migration, and (iv) nuclear localization of NFkappaB. Together, these results demonstrate that SLURP1 suppresses HUVEC tube formation by blocking nuclear translocation of NFkappaB, and suggest a potential role for SLURP1 in promoting corneal angiogenic privilege. PMID- 28803938 TI - Organoids as preclinical models to improve intraperitoneal chemotherapy effectiveness for colorectal cancer patients with peritoneal metastases: Preclinical models to improve HIPEC. AB - BACKGROUND: Peritoneal metastases (PM), corresponding to tumor implants into the peritoneal cavity, are associated with impaired prognosis and low responsiveness to systemic chemotherapy. A new therapeutic approach has dramatically changed the prognosis of patients with PM from colorectal cancer (CRC), consisting in the association of a complete cytoreductive surgery followed by intraperitoneal chemotherapy associated to hyperthermia (HIPEC). Many drugs have been administered intraperitoneally, but no clear consensus has been approved. Therefore, relevant preclinical models are essentials for the efficient translation of treatments option into affected patients. METHOD: Organoids, the last generation of preclinical models, were used to rationalize and improve intraperitoneal chemotherapy. We tested several cytotoxics, combination, effect of hyperthermia, exposure duration and frequency. RESULTS: Organoids were a representative model of response to chemotherapies used for the treatment of PM from CRC; 460mg/m2 of oxaliplatin being the most efficient cytotoxic treatment. Repeated incubations with oxaliplatin; mimicking cycles of intraperitoneal treatment, resulted in an increased efficacy. CONCLUSION & DISCUSSION: Organoids are relevant models to study the chemosensitivity of peritoneal metastases from CRCs. These models could be used for large scale drug screening strategies or personalized medicine, for colorectal carcinoma but also for PM from other origins. PMID- 28803939 TI - Bubble-generating nano-lipid carriers for ultrasound/CT imaging-guided efficient tumor therapy. AB - Ideal therapeutic effectiveness of chemotherapy is obtained only when tumor cells are exposed to a maximal drug concentration, which is often hindered by dose limiting toxicity. We designed a bubble-generating liposomal delivery system by introducing ammonium bicarbonate and gold nanorods into folic acid-conjugated liposomes to allow both multimodal imaging and the local release of drug (doxorubicin) with hyperthermia. The key component, ammonium bicarbonate, allows a controlled, rapid release of doxorubicin to provide an effective drug concentration in the tumor microenvironment. An in vitro temperature-triggered drug release study showed that cumulative release improved more than two-fold. In addition, in vitro and in vivo studies indicated that local heat treatment or ultrasonic cavitation enhanced the therapeutic efficiency greatly. The delivery system could also serve as an excellent contrast agent to allow ultrasonic imaging and computerized tomography imaging simultaneously to further achieve the aim of accurate diagnostics. Results of this study showed that this versatile bubble-generating liposome is a promising system to provide optimal therapeutic effects that are guided by multimodal imaging. PMID- 28803941 TI - Fast imaging for mapping dynamic networks. AB - The development of highly accelerated fMRI acquisition techniques has led to novel possibilities to monitor cerebral activity non-invasively and with unprecedented temporal resolutions. With the emergence of dynamic connectivity and its ability to provide a much richer characterization of brain function compared to static measures, fast fMRI may yet play a crucial role in tracking dynamically varying networks. In spite of the dominance of slow hemodynamic contributions to the BOLD signal, high temporal sampling rates nevertheless improve the measurement of physiological noise, yielding an exceptional sensitivity for the detection of periods of transient connectivity at time scales of a few tens of seconds. There is also evidence that relevant BOLD fluctuations are detectable at high frequencies, implying that the benefits of fast fMRI extend beyond the ability to sample nuisance confounds. Here we review the latest technological advancements that have established fast fMRI as an effective acquisition technique, as well as its current and future implications on the analysis of dynamic networks. PMID- 28803940 TI - Real-time motion analytics during brain MRI improve data quality and reduce costs. AB - Head motion systematically distorts clinical and research MRI data. Motion artifacts have biased findings from many structural and functional brain MRI studies. An effective way to remove motion artifacts is to exclude MRI data frames affected by head motion. However, such post-hoc frame censoring can lead to data loss rates of 50% or more in our pediatric patient cohorts. Hence, many scanner operators collect additional 'buffer data', an expensive practice that, by itself, does not guarantee sufficient high-quality MRI data for a given participant. Therefore, we developed an easy-to-setup, easy-to-use Framewise Integrated Real-time MRI Monitoring (FIRMM) software suite that provides scanner operators with head motion analytics in real-time, allowing them to scan each subject until the desired amount of low-movement data has been collected. Our analyses show that using FIRMM to identify the ideal scan time for each person can reduce total brain MRI scan times and associated costs by 50% or more. PMID- 28803943 TI - An Uncommon Cause of Feverish Swelling in a Patient With Crohn's Disease. PMID- 28803944 TI - A Peculiar Cause of Rectal Prolapse. PMID- 28803942 TI - An adaptive, individualized fMRI delay discounting procedure to increase flexibility and optimize scanner time. AB - Research on the rate at which people discount the value of future rewards has become increasingly prevalent as discount rate has been shown to be associated with many unhealthy patterns of behavior such as drug abuse, gambling, and overeating. fMRI research points to a fronto-parietal-limbic pathway that is active during decisions between smaller amounts of money now and larger amounts available after a delay. Researchers in this area have used different variants of delay discounting tasks and reported various contrasts between choice trials of different types from these tasks. For instance, researchers have compared 1) choices of delayed monetary amounts to choices of the immediate monetary amounts, 2) 'hard' choices made near one's point of indifference to 'easy' choices that require little thought, and 3) trials where an immediate choice is available versus trials where one is unavailable, regardless of actual eventual choice. These differences in procedure and analysis make comparison of results across studies difficult. In the present experiment, we designed a delay discounting task with the intended capability of being able to construct contrasts of all three comparisons listed above while optimizing scanning time to reduce costs and avoid participant fatigue. This was accomplished with an algorithm that customized the choice trials presented to each participant with the goal of equalizing choice trials of each type. We compared this task, which we refer to here as the individualized discounting task (IDT), to two other delay discounting tasks previously reported in the literature (McClure et al., 2004; Amlung et al., 2014) in 18 participants. Results show that the IDT can examine each of the three contrasts mentioned above, while yielding a similar degree of activation as the reference tasks. This suggests that this new task could be used in delay discounting fMRI studies to allow researchers to more easily compare their results to a majority of previous research while minimizing scanning duration. PMID- 28803945 TI - An Unusual Cause of Upper Gastrointestinal Bleeding. PMID- 28803946 TI - A Refractory Disease With Recurrent Profuse Watery Diarrhea. PMID- 28803947 TI - Monitoring stress with a wrist device using context. AB - Being able to detect stress as it occurs can greatly contribute to dealing with its negative health and economic consequences. However, detecting stress in real life with an unobtrusive wrist device is a challenging task. The objective of this study is to develop a method for stress detection that can accurately, continuously and unobtrusively monitor psychological stress in real life. First, we explore the problem of stress detection using machine learning and signal processing techniques in laboratory conditions, and then we apply the extracted laboratory knowledge to real-life data. We propose a novel context-based stress detection method. The method consists of three machine-learning components: a laboratory stress detector that is trained on laboratory data and detects short term stress every 2min; an activity recognizer that continuously recognizes the user's activity and thus provides context information; and a context-based stress detector that uses the outputs of the laboratory stress detector, activity recognizer and other contexts, in order to provide the final decision on 20-min intervals. Experiments on 55days of real-life data showed that the method detects (recalls) 70% of the stress events with a precision of 95%. PMID- 28803948 TI - Effectiveness of postprescription antibiotic stewardship to reduce carbapenem consumption: a quantitative study. PMID- 28803950 TI - Interferon-free therapy of hepatitis C during wait list and post-transplant risk of hepatocellular carcinoma recurrence. PMID- 28803949 TI - Measuring temporal summation in visual detection with a single-photon source. AB - Temporal summation is an important feature of the visual system which combines visual signals that arrive at different times. Previous research estimated complete summation to last for 100ms for stimuli judged "just detectable." We measured the full range of temporal summation for much weaker stimuli using a new paradigm and a novel light source, developed in the field of quantum optics for generating small numbers of photons with precise timing characteristics and reduced variance in photon number. Dark-adapted participants judged whether a light was presented to the left or right of their fixation in each trial. In Experiment 1, stimuli contained a stream of photons delivered at a constant rate while the duration was systematically varied. Accuracy should increase with duration as long as the later photons can be integrated with the proceeding ones into a single signal. The temporal integration window was estimated as the point that performance no longer improved, and was found to be 650ms on average. In Experiment 2, the duration of the visual stimuli was kept short (100ms or <30ms) while the number of photons was varied to explore the efficiency of summation over the integration window compared to Experiment 1. There was some indication that temporal summation remains efficient over the integration window, although there is variation between individuals. The relatively long integration window measured in this study may be relevant to studies of the absolute visual threshold, i.e., tests of single-photon vision, where "single" photons should be separated by greater than the integration window to avoid summation. PMID- 28803951 TI - Monocytes inhibit hepatitis C virus-induced TRAIL expression on CD56bright NK cells. AB - BACKGROUND & AIMS: Natural killer (NK) cells play an important role in the pathogenesis of hepatitis C virus (HCV) infection. We have previously shown that culture-derived HCV (HCVcc) enhance tumor necrosis-factor-related apoptosis inducing ligand (TRAIL) expression on healthy NK cells, but not on those from patients infected with HCV, which was likely dependent on accessory cells. Here we sought to elucidate the mechanisms involved in altered TRAIL upregulation in this setting. METHODS: Peripheral blood mononuclear cells (PBMC) from controls and patients infected with HCV were exposed to HCVcc. Cell depletions were performed to identify cells responsible for NK cell activation. Flow cytometry and ELISA were used to identify the cytokines involved in the NK activation process. RESULTS: In patients infected with HCV, soluble factors secreted by control PBMC restored the ability of NK cells to express TRAIL. Of note, CD14+ cell depletion had identical effects upon virus exposure and promoted increased degranulation. Moreover, increased concentrations of interleukin (IL)-18 binding protein a (IL-18BPa) and IL-36 receptor antagonist (IL-36RA) were observed after PBMC exposure to HCVcc in patients with HCV. HCVcc-induced NK cell TRAIL expression was inhibited by IL-18BPa and IL-36RA in control subjects. There were statistically significant correlations between IL-18BPa and indices of liver inflammation and fibrosis, supporting a role for this protein in the pathogenesis of chronic HCV infection. CONCLUSIONS: During chronic HCV infection, monocytes play a key role in negative regulation of NK cell activation, predominantly via secretion of inhibitors of IL-18 and IL-36. LAY SUMMARY: Coordination and collaboration between immune cells are essential to fight pathogens. Herein we show that during HCV infection monocytes secrete IL-18 and IL-36 inhibitory proteins, reducing NK cell activation, and consequently inhibiting their ability to express TRAIL and kill target cells. PMID- 28803952 TI - Reply to: "Performance status in patients with HCC: New kid on the block". PMID- 28803953 TI - Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. AB - BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is very common in the general population, but identifying patients with increased risk of mortality and liver-specific morbidity remains a challenge. Non-alcoholic steatohepatitis (NASH) is thought to enhance this risk; therefore, resolution of NASH is a major endpoint in current pharmacologic studies. Herein, we aim to investigate the long term prognosis of a large cohort of NAFLD patients, and to study the specific effect of NASH and fibrosis stage on prognosis. METHODS: We conducted a retrospective cohort study of 646 biopsy-proven NAFLD patients. Each case was matched for age, sex and municipality to ten controls. Outcomes on mortality and severe liver disease, defined as cirrhosis, liver decompensation/failure or hepatocellular carcinoma, were evaluated using population-based registers. Cox regression models adjusted for age, sex and type 2 diabetes were used to examine the long-term risk according to fibrosis stage. Likelihood ratio tests were used to assess whether adding NASH to these models increased the predictive capacity. Laplace regression was used to estimate the time to severe liver disease according to stage of fibrosis. RESULTS: During a follow-up of mean 20years (range 0-40) equivalent to 139,163 person-years, 12% of NAFLD patients and 2.2% of controls developed severe liver disease (p<0.001). Compared to controls, the risk of severe liver disease increased per stage of fibrosis (hazard ratio ranging from 1.9 in F0 to 104.9 in F4). Accounting for the presence of NASH did not change these estimates significantly (likelihood ratio test >0.05 for all stages of fibrosis). Similar results were seen for overall mortality. The lower end of the 95% confidence interval for the 10th percentile of time to development of severe liver disease was 22-26years in F0-1, 9.3years in F2, 2.3years in F3, and 0.9years to liver decompensation in F4. CONCLUSIONS: In this, the largest ever study of biopsy-proven NAFLD, the presence of NASH did not increase the risk of liver-specific morbidity or overall mortality. Knowledge of time to development of severe liver disease according to fibrosis stage can be used in individual patient counselling and for public health decisions. LAY SUMMARY: Non alcoholic fatty liver disease (NAFLD) is very common in the general population, but reaching an accurate prognosis remains challenging. We investigate the long term prognosis of a large cohort of NAFLD patients. In this, the largest ever study of biopsy-proven NAFLD, the presence of NASH did not increase the risk of liver-specific morbidity or overall mortality. Knowledge of time to development of severe liver disease according to fibrosis stage can be used in individual patient counselling and for public health decisions. PMID- 28803954 TI - Performance status in patients with HCC: New kid on the block. PMID- 28803955 TI - Valproic acid exposure decreases the mRNA stability of Bcl-2 via up-regulating miR-34a in the cerebellum of rat. AB - Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction, limited verbal communication and repetitive behaviors. Previous studies have shown that the level of Bcl-2 in the brain tissues of ASD patients is significantly decreased. However, the mechanisms underlie the down-regulation of Bcl-2 in ASD is still unknown. In this study, we investigated the alteration of Bcl-2 level and associated mechanisms in valproic acid (VPA) exposed ASD rats. VPA exposure resulted in ASD-like behaviors in rats, such as repetitive behavior and social interaction impairment. VPA exposure also down-regulated the expression of Bcl-2 both at mRNA and protein levels, either in cerebellar cortex or primary cerebellar cortical neuronal cells. Furthermore, VPA treatment decreased the mRNA stability of Bcl-2 instead of down-regulating its transcriptional activity. Meanwhile, VPA exposure up-regulated the expression of miR-34a in cerebellar cortex and primary cerebellar cortical neuronal cells. The mimics of miR-34a directly inhibited the expression of Bcl-2 and its antagonist blocked the down-regulation effect of VPA on Bcl-2 in primary cerebellar cortical neuronal cells. Our study implies that VPA may influence ASD through sequential up-regulating miR-34a and therefore down-regulating Bcl-2 in the brain tissues of rats. PMID- 28803956 TI - Selective cholinergic depletion of pedunculopontine tegmental nucleus aggravates freezing of gait in parkinsonian rats. AB - Many patients of advanced Parkinson's disease (PD) suffer from intractable axial symptoms (severe gait and postural impairments), which were recently speculated to be more relevant to cholinergic degeneration in the brainstem than dopaminergic degeneration in the substantia nigra compacta (SNc). To investigate the role of the cholinergic cells of the pedunculopontine tegmental nucleus (PPTg) on motor deficits, especially the axial motor impairments, we measured and analyzed the gait performance of sham lesion rats, SNc dopaminergic lesion rats, PPTg cholinergic lesion rats, and combined lesion rats by using the CatWalk system. Motor performance of PPTg cholinergic lesion rats was also tested on the rotarod. Independent loss of cholinergic neurons in the PPTg did not induce gait disturbance in CatWalk, but PPTg lesion rats showed motor impairments on the rotarod when the demands of the motor task increased. Both SNc lesion rats and combined lesion rats displayed significant changes in many gait parameters, but the terminal dual stance increased much higher in combined lesion group than SNc lesion group. Furthermore, combined lesion rats showed more severe freezing of gait (FOG) than SNc lesion rats during behavioral re-evaluations after lesion. These results suggest that the PPTg cholinergic neurons play a vital role in the occurrence of FOG in PD. PMID- 28803957 TI - A standardization of the Novelty-Suppressed Feeding Test protocol in rats. AB - Tests based on hyponeophagia phenomena are the most widely used to check the efficacy and efficiency of new-generation chronic antidepressant treatments. Even so, these tests lack strict consensus about their methodology, which reduces their validity, reproducibility and makes translatability difficult. Therefore, after an extensive literature review on this subject, we propose a methodological protocol for the Novelty-Suppressed Feeding Test to normalize this situation. Animals were induced to a reserpine-induced depression model and were then chronically treated with duloxetine, desvenlafaxine or vehicle. After a 14-day treatment, a standardized Novelty-Suppressed Feeding Test was performed. Standardization included three-phase deprivation and the introduction of standard highly palatable food. The duloxetine-treated and desvenlafaxine-treated animals exhibited behavioral improvement of depressive-like symptoms. They took less time to eat from the center of the open-field, and approached food more times per minute than the vehicle-treated animals. This normalization proposal proves effective in measuring the antidepressant effect on chronic treatment. Thus introducing this normalization proposal would reduce inter-laboratory variability and increase the validity and robustness of this behavioral test. PMID- 28803958 TI - Identification and characterization of lymph organ microRNAs in red swamp crayfish, Procambarus clarkii infected with white spot syndrome virus. AB - MicroRNAs (miRNAs) were important post-transcriptional regulators and played vital roles in innate immunity system of invertebrates, especially in the aspect of antivirus. In this study, using high-throughput small RNAs Illumina sequencing system, differentially expressed miRNAs (DEMs) from lymph organs in red swamp crayfish, Procambarus clarkii, infected with white spot syndrome virus, were identified. As a result, 32 known miRNAs and 7 novel miRNAs were identified in crayfish lymph organ small RNAs library of NG and WG. Among them, 7 differentially expressed miRNAs (DEMs) were predicted to be involved in the lymph organ antiviral innate immunity of P. clarkii. Besides, the results showed that putative target genes of these DEMs were related with tight junction, RNA transport, regulation of actin cytoskeleton, focal adhesion, vascular smooth muscle contraction, mRNA surveillance pathway, NOD-like receptor signaling pathway, leukocyte transendothelial migration, and protein processing in endoplasmic reticulum. These results might provide the guiding theoretical foundation for future studies about crustaceans' antiviral innate immunity. PMID- 28803959 TI - Thymosin beta4 is involved in the antimicrobial immune response of Golden pompano, Trachinotus ovatus. AB - Thymosin beta belongs to the thymosin family, which consists of a series of highly conserved peptides involved in various biological processes. In teleosts, understanding of the immunological functions of thymosin beta is limited, particularly in vivo, which is essentially unknown. In the current study, we cloned and identified thymosin beta 4 from the teleost fish Golden pompano (Trachinotus ovatus), which we have named TroTbeta4. We investigated the expression patterns and functions of TroTbeta4 in both in vivo and in vitro assays. TroTbeta4 is composed of 44 amino acids and shares high sequence identities with known thymosin beta4 species in other teleosts, which contains a highly conserved actin-binding motif (LKKTET). The expression of TroTbeta4 was most abundant in immune organs, and was significantly up-regulated in response to infection bacterial with one of a number of bacteria (including Edwardsiella tarda, Vibrio harveyi, and Streptococcus agalactiae). Purified recombinant TroTbeta4 (rTroTbeta4) inhibited the growth of bacteria, as measured using an automatic growth curve analyzer, indicating that TroTbeta4 has antimicrobial functions. When administered in vivo, overexpression of TroTbeta4 in T. ovatus, bacterial colonization of tissues was significantly reduced. In contrast, when a DNA vector-based siRNA technology was used to knock down TroTbeta4 expression, bacterial dissemination and colonization of tissues increased significantly. Taken together, these results provide the first in vivo evidence to indicate that teleost thymosin beta 4 plays a significant role in innate antibacterial immune responses in addition to in vitro bacteriostatic activity. This provides valuable information regarding the biological functions of teleost thymosin beta. PMID- 28803960 TI - Evaluating impacts of different longitudinal driver assistance systems on reducing multi-vehicle rear-end crashes during small-scale inclement weather. AB - Multi-vehicle rear-end (MVRE) crashes during small-scale inclement (SSI) weather cause high fatality rates on freeways, which cannot be solved by traditional speed limit strategies. This study aimed to reduce MVRE crash risks during SSI weather using different longitudinal driver assistance systems (LDAS). The impact factors on MVRE crashes during SSI weather were firstly analyzed. Then, four LDAS, including Forward collision warning (FCW), Autonomous emergency braking (AEB), Adaptive cruise control (ACC) and Cooperative ACC (CACC), were modeled based on a unified platform, the Intelligent Driver Model (IDM). Simulation experiments were designed and a large number of simulations were then conducted to evaluate safety effects of different LDAS. Results indicate that the FCW and ACC system have poor performance on reducing MVRE crashes during SSI weather. The slight improvement of sight distance of FCW and the limitation of perception reaction time of ACC lead the failure of avoiding MVRE crashes in most scenarios. The AEB system has the better effect due to automatic perception and reaction, as well as performing the full brake when encountering SSI weather. The CACC system has the best performance because wireless communication provides a larger sight distance and a shorter time delay at the sub-second level. Sensitivity analyses also indicated that the larger number of vehicles and speed changes after encountering SSI weather have negative impacts on safety performances. Results of this study provide useful information for accident prevention during SSI weather. PMID- 28803961 TI - The 99th percentile and imprecision of point-of-care cardiac troponin I in comparison to central laboratory tests in a large reference population. AB - OBJECTIVES: Determination of cardiac troponin (cTn) is central in the emergency department (ED) for the diagnosis of myocardial infarction. In view of adverse effects of long waiting time on patient outcome, implementation of point-of-care testing (POCT) is suggested if the turn-around-time is longer than 60min. The present study aimed to determine the 99th percentile and imprecision of two POCT in a healthy population measuring cTnI and cTnT and compare these analytical characteristics against three central laboratory test (CLT) for cTnI. DESIGN & METHODS: CTnI and cTnT were determined in parallel by means of the AQT90 FLEX analyzer in about 2250 plasma samples from individuals with known health status. Results were compared to previously determined performance data of three CLT. RESULTS: The 99th percentile of cTnI in the POCT was determined at 19ng/L, the lowest concentration with an imprecision of 10% was reached at 22ng/L while an imprecision of 20% was reached at 13ng/L. Age, sex, or physical activity did not affect the 99th percentile of cTnI. Compared to CLT the AQT90 cTnI POCT the analytical performance was equivalent. The cTnT POCT could not be assessed due a considerable number of high values and an inadequate imprecision profile. CONCLUSION: While the cTnI POCT showed analytical performance comparable to CLT, the results of the cTnT assay on the same device did not suffice to determine a reliable 99th percentile. The present evaluation supports the usage of the cTnI POCT, but application of the cTnT POCT needs further evaluation. PMID- 28803962 TI - Post-analytical stability of 23 common chemistry and immunochemistry analytes in incurred samples. AB - BACKGROUND: Storage of blood samples after centrifugation, decapping and initial sampling allows ordering of additional blood tests. The pre-analytic stability of biochemistry and immunochemistry analytes has been studied in detail, but little is known about the post-analytical stability in incurred samples. METHODS: We examined the stability of 23 routine analytes on the Dimension Vista(r) (Siemens Healthineers, Denmark): 42-60 routine samples in lithium-heparin gel tubes (Vacutainer, BD, USA) were centrifuged at 3000*g for 10min. Immediately after centrifugation, initial concentration of analytes were measured in duplicate (t=0). The tubes were stored decapped at room temperature and re-analyzed after 2, 4, 6, 8 and 10h in singletons. The concentration from reanalysis were normalized to initial concentration (t=0). Internal acceptance criteria for bias and total error were used to determine stability of each analyte. Additionally, evaporation from the decapped blood collection tubes and the residual platelet count in the plasma after centrifugation were quantified. RESULTS AND CONCLUSION: We report a post-analytical stability of most routine analytes of >=8h and do therefore - with few exceptions - suggest a standard 8hour-time limit for reordering and reanalysis of analytes in incurred samples. PMID- 28803963 TI - Model analysis of bidirectional interference in two-stage labeled-ligand immunoassays. AB - OBJECTIVES: Immunoassays involving sample incubation followed by a wash step prior to introduction of labeled analyte are potentially subject to both positive and negative interference (bidirectional interference) by a competing ligand. We examine this phenomenon from a theoretical standpoint using a mathematical model for sequential-step immunoassays in the presence of interferent. DESIGN & METHODS: Competitive binding to antibody between analyte and interferent was modeled for sequential-step immunoassays. A primary assumption was that the ratio of affinity constants between the intended analyte and the interferent reflected the ratio of dissociation rate constants, with the higher dissociation rate constant for the lesser affinity ligand. RESULTS: Relationships of parameters (relative affinity constants, relative concentrations) for analyte and interferent were determined for conditions in which bidirectional interference can occur, for both steady-state and non-steady-state sample incubation conditions. Non-steady state sample incubation conditions can enhance the effects of an interferent. Homogeneous assay formats utilizing labeled ligand without a wash step can also demonstrate bidirectional interference, but positive interference is favored under such formats. CONCLUSIONS: Model calculations demonstrate the theoretical basis for bidirectional interference in two-stage immunoassays. Results delineate constraints on conditions in which bidirectional interference can occur. PMID- 28803964 TI - TGFbeta/SMAD signalling modulates MLL and MLL-AF4 mediated 5-lipoxygenase promoter activation. AB - 5-Lipoxygenase (5-LO) catalyzes the initial two steps of the conversion of arachidonic acid to leukotrienes which represent a group of pro-inflammatory lipid mediators involved in immune defense reactions as well as inflammation, allergy and cancer. Transforming growth factor-beta (TGFbeta) and calcitriol strongly upregulate 5-LO expression during myeloid cell differentiation and MLL AF4 has been shown to strongly activate the 5-LO promoter. Here, we investigated the role of TGFbeta/SMAD signalling in 5-LO promoter activation. We identified two functional SMAD binding elements in the proximal part of the 5-LO promoter which significantly induce 5-LO promoter activity via TGFbeta and SMAD3/4. Since aberrant 5-LO gene expression has been linked with mixed lineage leukemia (MLL) which is characterized by the presence of MLL fusion proteins (e.g. MLL-AF4), we also investigated the influence of TGFbeta/SMADs on MLL- and MLL-AF4-mediated 5 LO promoter activation. Our data show that induction of 5-LO promoter activity by SMAD3/4 is MLL-dependent and that knockdown of the MLL complex component MEN1 attenuates the SMAD effect. Our data suggest that induction of 5-LO gene expression by TGFbeta is at least in part due to stimulation of transcript initiation. PMID- 28803968 TI - Acute spinal cord injury: A review of pathophysiology and potential of non steroidal anti-inflammatory drugs for pharmacological intervention. AB - Acute spinal cord injury (SCI) is one of the serious central nervous system injuries, which can lead to significant neurological impairments and a reduction in quality of life with loss in sensory and motor functions. Although recent advancements contribute to the understanding of the underlying pathophysiological processes developed after SCI, currently, there is limited innovative and effective treatment options besides conventional rehabilitation and management of SCI to alleviate the condition. Improvements in neurological functions of the individuals with SCI depend mainly on the mechanical damage occurring in the primary injury and on pathophysiological alterations associated with secondary damage. Since in the treatment of SCI, there are no therapeutic strategies for neurological alterations caused by primary injury, all innovative treatments utilize treatment strategies targeting to the secondary damage. Non-steroidal anti-inflammatory drugs (NSAIDs) have become the focus of various experimental SCI models as these may be expected to reduce inflammation in secondary damage due to their potent anti-inflammatory effects. Experimentally, they exhibit neuro protective and apoptotic effects by suppressing axonal re-growth, thus inhibiting the RhoA pathway, which leads to apoptotic cell death, in addition to the recovery of motor functions along with histological improvement. However, histological improvement is not significantly associated with improvement of motor function. The main target of SCI research should not only focus on histological improvement of lesion, but also on its potential for contribution to effective clinical therapies targeting improvements in sensory and motor functions. In the present review, we have summarized the current knowledge about pathophysiologic mechanisms working after SCI and discussed the potential of NSAIDs as promising agents in the management of SCI. PMID- 28803965 TI - The great divide: Separation between in vitro and in vivo effects of PSNCBAM based CB1 receptor allosteric modulators. AB - While allosteric modulators of the cannabinoid type-1 receptor (CB1) continue to be developed and characterized, the gap between the in vitro and in vivo data is widening, raising questions regarding translatability of their effects and biological relevance. Among the CB1 allosteric modulators, PSNCBAM-1 has received little attention regarding its effects in vivo. Recently, pregnenolone was reported to act as an allosteric modulator of CB1, blocking THC's effects in vitro and in vivo, highlighting the potential of CB1 allosteric modulators for treatment of cannabis intoxication. We investigated the pharmacological effects of PSNCBAM-1 and two structural analogs, RTICBM-15 and -28, as well as pregnenolone, in both signaling and behavioral assays including [35S]GTPgammaS binding, the cannabinoid tetrad and drug discrimination. While the CB1 allosteric modulator PSNCBAM-1 attenuated THC-induced anti-nociception and its structural analog RTICBM-28 reduced THC's potency in drug discrimination, most cannabinoid effects in mice were unaffected. In contrast to the mouse studies, PSNCBAM-1 and analogs insurmountably antagonized CP55,940- and THC-stimulated [35S]GTPgammaS binding and exhibited negative binding cooperativity with [3H]SR141716 with similar apparent affinities. Notably, RTICBM-28, which contains a cyano substitution at the 4-chlorophenyl position of PSNCBAM-1, exhibited enhanced binding cooperativity with CP55,940. In contrast to previous findings, pregnenolone did not block THC's effects in drug discrimination or [35S]GTPgammaS. These data further highlight the difficulty in translating pharmacological effects of CB1 allosteric modulators in vivo but confirm the established pharmacology of PSNCBAM-1 and analogs in molecular assays of CB1 receptor function. PMID- 28803967 TI - IGDB-2, an Ig/FNIII protein, binds the ion channel LGC-34 and controls sensory compartment morphogenesis in C. elegans. AB - Sensory organ glia surround neuronal receptive endings (NREs), forming a specialized compartment important for neuronal activity, and reminiscent of glia ensheathed synapses in the central nervous system. We previously showed that DAF 6, a Patched-related protein, is required in glia of the C. elegans amphid sensory organ to restrict sensory compartment size. LIT-1, a Nemo-like kinase, and SNX-1, a retromer component, antagonize DAF-6 and promote compartment expansion. To further explore the machinery underlying compartment size control, we sought genes whose inactivation restores normal compartment size to daf-6 mutants. We found that mutations in igdb-2, encoding a single-pass transmembrane protein containing Ig-like and fibronectin type III domains, suppress daf-6 mutant defects. IGDB-2 acts in glia, where it localizes to glial membranes surrounding NREs, and, together with LIT-1 and SNX-1, regulates compartment morphogenesis. Immunoprecipitation followed by mass spectrometry demonstrates that IGDB-2 binds to LGC-34, a predicted ligand-gated ion channel, and lgc-34 mutations inhibit igdb-2 suppression of daf-6. Our findings reveal a novel membrane protein complex and suggest possible mechanisms for how sensory compartment size is controlled. PMID- 28803969 TI - Molecular detection and characterization of Influenza 'C' viruses from western India. AB - Since 2003, India has had a well-established influenza surveillance network, though Influenza C virus was not the focus of study. We therefore retrospectively analyzed clinical samples from Pune, western India collected during January 2009 to August 2015, by real-time RT-PCR. Three of 2530 samples of patients with influenza-like illness (ILI) or severe acute respiratory illness (SARI) showed positivity for Influenza C virus infection, while 105 and 31 samples were positive for Influenza A and B viruses respectively. Influenza C viruses were successfully isolated using the embryonated egg system and whole genomes were sequenced and analyzed phylogenetically. HE gene-based phylogeny showed that two viruses C/India/P119564/2011 and C/India P121719/2012 clustered with the C/Sao Paulo/378/82 (SP82) lineage, whereas C/India/P135047/2013 clustered with the C/Kanagawa/1/76 (KA76) lineage. The internal gene of these viruses grouped in two lineages. The PB1, PB2, M and NS genes of the study viruses grouped with C/Yamagata/26/81 (YA81), while the P3 (PA) and NP genes grouped with C/Mississippi/80 (MS80). Bayesian clock studies conclude that the Indian strains may have emerged through multiple reassortment events. PMID- 28803966 TI - A chimeric prokaryotic-eukaryotic pentameric ligand gated ion channel reveals interactions between the extracellular and transmembrane domains shape neurosteroid modulation. AB - Pentameric ligand-gated ion channels (pLGICs) are the targets of several clinical and endogenous allosteric modulators including anesthetics and neurosteroids. Molecular mechanisms underlying allosteric drug modulation are poorly understood. Here, we constructed a chimeric pLGIC by fusing the extracellular domain (ECD) of the proton-activated, cation-selective bacterial channel GLIC to the transmembrane domain (TMD) of the human rho1 chloride-selective GABAAR, and tested the hypothesis that drug actions are regulated locally in the domain that houses its binding site. The chimeric channels were proton-gated and chloride selective demonstrating the GLIC ECD was functionally coupled to the GABArho TMD. Channels were blocked by picrotoxin and inhibited by pentobarbital, etomidate and propofol. The point mutation, rho TMD W328M, conferred positive modulation and direct gating by pentobarbital. The data suggest that the structural machinery mediating general anesthetic modulation resides in the TMD. Proton-activation and neurosteroid modulation of the GLIC-rho chimeric channels, however, did not simply mimic their respective actions on GLIC and GABArho revealing that across domain interactions between the ECD and TMD play important roles in determining their actions. Proton-induced current responses were biphasic suggesting that the chimeric channels contain an additional proton sensor. Neurosteroid modulation of the GLIC-rho chimeric channels by the stereoisomers, 5alpha-THDOC and 5beta THDOC, were swapped compared to their actions on GABArho indicating that positive versus negative neurosteroid modulation is not encoded solely in the TMD nor by neurosteroid isomer structure but is dependent on specific interdomain connections between the ECD and TMD. Our data reveal a new mechanism for shaping neurosteroid modulation. PMID- 28803970 TI - Hidden Markov phylogenetic models offer an interesting perspective to identify "high risk lineages" of environmental pathogens. PMID- 28803971 TI - OTP: An automatized system for managing and processing NGS data. AB - The One Touch Pipeline (OTP) is an automation platform managing Next-Generation Sequencing (NGS) data and calling bioinformatic pipelines for processing these data. OTP handles the complete digital process from import of raw sequence data via alignment of sequencing reads to identify genomic events in an automated and scalable way. Three major goals are pursued: firstly, reduction of human resources required for data management by introducing automated processes. Secondly, reduction of time until the sequences can be analyzed by bioinformatic experts, by executing all operations more reliably and quickly. Thirdly, storing all information in one system with secure web access and search capabilities. From software architecture perspective, OTP is both information center and workflow management system. As a workflow management system, OTP call several NGS pipelines that can easily be adapted and extended according to new requirements. As an information center, it comprises a database for metadata information as well as a structured file system. Based on complete and consistent information, data management and bioinformatic pipelines within OTP are executed automatically with all steps book-kept in a database. PMID- 28803972 TI - Self-aggregation behavior of hydrophobic sodium alginate derivatives in aqueous solution and their application in the nanoencapsulation of acetamiprid. AB - In this study, cholesteryl-grafted sodium alginate derivatives (CSAD) with different molecular weights were synthesized by esterification. The structure of CSAD was confirmed by FT-IR and 1H NMR spectrometers. The effects of pH and CSAD polymer concentration on the self-assembled behavior and particle size of CSAD were investigated by fluorescence measurement (FM) and dynamic light scattering (DLS). In the presence of Ca2+, the cholesteryl-grafted sodium alginate derivative was used for fabricating self-assembled nanoparticles that can effectively encapsulate the drug acetamiprid. The drug-loaded nanoparticles were characterized by transmission electron microscopy (TEM). The encapsulation efficiency (EE) and acetamiprid drug release behavior from the nanoparticles were also studied. The results reveal that CSAD self-assembled nanoparticles had a diameter of 100nm and were nonaggregated in aqueous media; Moreover, the encapsulation efficiency and the release behavior of nanoparticles were influenced by the MW of CSAD. The mechanism of acetamiprid release was found to vary from non-Fickian (anomalous) to Fickian transport with a decrease in the molecular weight of CSAD. PMID- 28803973 TI - Improved biotransformation of arsenic by arsenite oxidase - Chitosan nanoparticle conjugates. AB - Recent developments in the potential use of nanoparticles as carriers of enzyme have attracted great attention. In the present study, arsenite oxidase (AOase) enzyme capable of transforming the more toxic arsenite [As(III)] to the less toxic arsenate [As(V)] was extracted from an arsenic resistant bacterium (Exiguobacterium sp. As-9) and partially purified. Chitosan nanoparticles were prepared on the basis of ionic gelation of chitosan with tripolyphosphate (TPP) anions. The purified AOase was immobilized efficiently by physical adsorption on to chitosan nanoparticles and were characterized for particle size, morphology, zeta potential, AOase loading efficiency and in vitro transformation assay. The chitosan nanoparticles were spherical in shape with the average diameter of 100nm which increased to 294nm upon successful loading of AOase. Under optimized conditions, the loading capacity of the chitosan nanoparticle was determined to be 71% for AOase. Further, immobilization also increased the stability of AOase at varying temperature (4-37 degrees C) and pH (5-10) for a period of 30days with the increased enzymatic activity (159.57Uml-1). It also facilitated increased biotransformation (89%) of As(III) to As(V). A conceptual understanding of biological responses to AOase loaded chitosan nanoparticles is needed for the development of novel methods of drug delivery. PMID- 28803974 TI - Influence of amylose content and oxidation level of potato starch on acetylation, granule structure and radicals' formation. AB - This study was aimed at determining the effect of the amylose content of starch and oxidation level of potato starch on the structure of starch granules, and susceptibility to chemical modification (acetylation) and subsequent generation of radicals. Potato starch and waxy potato starch were oxidised with sodium hypochlorite applied in doses corresponding to 10, 20, and 30gCl/kg starch, and then acetylated with acetic acid anhydride. The carboxyl, carbonyl, acetyl groups were determined in modified starches. Structural properties of starch granules were evaluated based on gelatinisation, crystallinity, specific surface, intrinsic viscosity, and microphotographs by SEM microscope. The electron paramagnetic resonance (EPR) measurements were carried out to establish starch susceptibility to radical creation upon chemical modification and UV radiation. The amount of formed radicals was treated as a measure of the starch structure stability. The higher amount of amylose and the highest level of oxidation led to strong starch structure destruction and consequently facilitated radical generation. Study results showed also that amylose content as well as the degree of starch oxidation modified consecutive acetylation process. The different effectiveness of the acetylation processes influenced the morphology and structure of starch granules. PMID- 28803975 TI - Effects of acid hydrolysis intensity on the properties of starch/xanthan mixtures. AB - The effects of acid hydrolysis intensity on the physicochemical properties of starch/xanthan gum (XG) system were studied. Waxy corn starch (WCS) was subjected to different concentrations of hydrochloric acid, and crystallization and relative molecular weight analysis were performed. The results revealed that the starch granules became smaller during acid hydrolysis. X-ray diffraction pattern analysis showed that the crystal structure did not change with acid hydrolysis. Evaluation of the properties and digestibility of different acid-thinned starch/XG systems indicated that the viscosity of acid-thinned starch/XG decreased with increased acid hydrolysis intensity. Rheological property measurements indicated that the compound systems were a pseudo-plastic fluid, which is a typical weak gel structure. Finally, we show that the WCS1.0M/XG has the highest stability of the tested mixtures. We conclude that adjusting the conditions of acid hydrolysis improves the stability and food quality-enhancing properties of starch. PMID- 28803976 TI - Canavalia bonariensis lectin: Molecular bases of glycoconjugates interaction and antiglioma potential. AB - CaBo is a mannose/glucose-specific lectin purified from seeds of Canavalia bonariensis. In the present work, we report the CaBo crystal structure determined to atomic resolution in the presence of X-man, a specific ligand. Similar to the structural characteristics of other legume lectins, CaBo presented the jellyroll motif, a metal binding site occupied by calcium and manganese ions close to the carbohydrate-recognition domain (CRD). In vitro test of CaBo cytotoxicity against glioma cells demonstrated its ability to decrease the cellular viability and migration by induction of autophagy and cell death. Molecular docking simulations corroborate previous data indicating that the lectin's biological activities occur mostly through interactions with glycoproteins since the lectin interacted favorably with several N-glycans, especially those of the high-mannose type. Together, these results suggest that CaBo interacts with glycosylated cell targets and elicits a remarkable antiglioma activity. PMID- 28803977 TI - A comparison of Canthaxanthine Pickering emulsions, stabilized with cellulose nanocrystals of different origins. AB - Cellulosic nanocrystals from different origins were made to stabilize the canthaxanthin (CTX) in pickering emulsion. Nanocrystals were obtained by hydrochloric acid hydrolysis. Dynamic light scattering (DLS) demonstrated that the length of solid particles were in the range of 112nm-4000nm. AFM indicated the needle-like shape of the cotton cellulose nanocrystals (CCNs) and bacterial cellulose nanocrystals (BCNs) and also illustrated the thickness of the particles to be 6 and 7nm respectively. The crystallinity of both BCNs and CCNs was higher than the cellulose source they were isolated (CL: 75.4%, CCNs: 86.6; BC: 79.2%, BCNs: 88.5%). Effects of different factors such as temperature, pH and ionic concentration on stability were investigated. The results revealed that an increase in both temperature and pH was accompanied by an improvement in emulsion stability in all tested samples. However, increase in ionic concentration resulted in emulsions with less stability. In all the samples, CCN emulsions had better stability than the BCN emulsions, which was associated to smaller particle size and more coverage ability. Test of stability to light showed that CCN emulsions can preserve CTX better than BCN against the light. PMID- 28803978 TI - Intraperitoneal injection of d-serine inhibits high-fat diet intake and preference in male mice. AB - d-serine is a co-agonist of the N-methyl d-aspartate (NMDA) receptor, an important modulator of glutamatergic excitatory synaptic transmission. We previously reported that oral d-serine ingestion inhibited the intake of highly preferred food and promoted the intake of less preferred food in mice. Here, we analyzed the effects of intraperitoneal (IP) d-serine injections on feeding behavior in mice. We assessed the effects of d-serine during both the acquisition and maintenance of a preference for high-fat diets (HFDs). Aversiveness of IP d serine was analyzed in the conditioned taste aversion paradigm. The effects on food intake were assessed by providing liquid meals with different fat contents. Finally, we measured brain d-serine and l-serine levels after d-serine administration. We found that IP-injected d-serine effectively inhibited the acquisition of a HFD preference, but failed to prevent expression of a previously learned HFD preference. IP-injected d-serine was not sufficient to condition taste aversion. The effect on HFD preference acquisition was associated with increases in d-serine levels in the cerebral cortex, hypothalamus, and cerebellum. IP-injected d-serine most effectively inhibited the intake of liquid meals with high fat content. This effect was dose-dependent, but the responses varied significantly among male C57BL/6J mice. The differential responses to d serine were consistent among multiple trials in each mouse. In summary, IP injected d-serine inhibited HFD intake and the acquisition of an HFD preference. Individual mice with the same genetic background showed different sensitivities to d-serine; thus, d-serine sensitivity may be associated with unidentified traits. PMID- 28803979 TI - The first entomophthoralean killing millipedes, Arthrophaga myriapodina n. gen. n. sp., causes climbing before host death. AB - A new species and genus of entomophthoralean fungus, Arthrophaga myriapodina kills polydesmid millipedes. This species was first seen over a century ago but never described. It is the first millipede pathogen known from the order Entomophthorales, species of which are best known as pathogens of a wide diversity of insects. The fungus induces pre-death climbing behavior in its hosts, enabling the fungus to broadcast its forcibly-discharged conidia from a high vantage, which presumably increases the fitness of the fungus. Study of herbarium specimens and photographic discoveries on the internet suggest the fungus occurs widely in eastern North America. PMID- 28803980 TI - Humoral immune response of Galleria mellonella after repeated infection with Bacillus thuringiensis. AB - The insect immune system relies on innate mechanisms only. However, there is an increasing number of data reporting that previous immune challenge with microbial elicitors or a low number of microorganisms can modulate susceptibility after subsequent lethal infection with the same or different pathogen. This phenomenon is called immune priming. Its biochemical and molecular mechanisms remain unravelled. Here we present that Galleria mellonella larvae that survived infection induced by intrahemocelic injection of a low dose of Bacillus thuringiensis were more resistant to re-injection of a lethal dose of the same bacteria but not other bacteria and fungi tested. This correlated with enhanced activity detected in full hemolymph as well as in separated hemolymph polypeptides. In addition, we observed differences in the hemolymph protein pattern between primed and non-primed larvae after infection with the lethal dose of B. thuringiensis. Expression of genes encoding inducible defence molecules was not enhanced in the primed larvae after the infection with the lethal dose of B. thuringiensis. It is likely that priming affects the turnover of immune related hemolymph proteins; hence, upon repeated contact, the immune response may be more ergonomic. PMID- 28803981 TI - First report of Coelomomyces santabrancae sp. nov. (Blastocladiomycetes: Blastocladiales) infecting mosquito larvae (Diptera: Culicidae) in central Brazil. AB - A project from 2013 to 2017 sought to discover pathogenic fungi and oomycetes from dipteran species that are vectors of major diseases of humans and animals in central Brazil and to begin evaluating the potential of these pathogens as potential biological control agents concentrated on mosquito larvae. Some collecting sites proved to be especially productive for pathogens of naturally occurring mosquito species and for placements of healthy sentinel larvae of Aedes aegypti in various sorts of containers in a gallery forest in the Santa Branca Ecoturismo Private Reserve of Natural Patrimony (RPPN) near Terezopolis de Goias (GO). Collections during May-April of 2016 and February 2017 yielded a few dead mosquito larvae of an undetermined Onirion sp. (Culicidae: Sabethini) whose hemocoels contained many ovoid, thick-walled, yellow-golden to golden-brown, ovoid thick-walled resistant sporangia, 38.3+/-4*22.8+/-2.3um, decorated by numerous, closely and randomly spaced punctations of variable size and shape. These were the first indisputable collections from Brazil of any Coelomomyces species. Comparisons of the morphology of these sporangia with those of other species of Coelomomyces, confirmed that this Brazilian fungus represented a new species that is described here as Coelomomyces santabrancae. PMID- 28803982 TI - Specific inhibition of Xenorhabdus hominickii, an entomopathogenic bacterium, against different types of host insect phospholipase A2. AB - Phospholipase A2 (PLA2) hydrolyzes ester bond of phospholipids at the sn-2 position to release free fatty acid and lysophospholipids. Some PLA2s preferentially release arachidonic acid which is subsequently oxygenated into eicosanoids to mediate immune responses in insects. Xenorhabdus hominickii is an entomopathogenic bacterium that can suppress insect immunity by inhibiting PLA2 activity. However, little is known about target PLA2 types inhibited by X. hominickii. Therefore, the objective of this study was to determine PLA2 types in the host insect, Spodoptera exigua using specific inhibitors. All developmental stages of S. exigua possessed significant PLA2 activities, with late larval stages showing relatively higher PLA2 activities. In different larval tissues, hemocytes had higher PLA2 activities than fat body, gut, or epidermis. Various developmental and tissue extracts exhibited differential susceptibilities to three different PLA2 inhibitors. Late larva-to-adult stages were highly susceptible to all three different types of PLA2 inhibitors. In contrast, extracts from egg and young larval stages were not susceptible to secretory PLA2 (sPLA2) or calcium-independent cellular PLA2 (iPLA2) inhibitors, although they were susceptible to a calcium-dependent cellular PLA2 (cPLA2) inhibitor in a dose dependent manner. Different tissues of fifth instars exhibited variation in susceptibility to inhibitors, with epidermal tissue being sensitive to cPLA2 inhibitor only while other tissues were sensitive to all three types of inhibitors. Bacterial challenge with heat-killed X. hominickii significantly increased PLA2 activity. However, live bacteria suppressed the induction of PLA2 activity. An organic extract of X. hominickii-culture broth inhibited the susceptibility of S. exigua to sPLA2- and iPLA2- specific inhibitors, but not to cPLA2-specific inhibitor. Oxindole, a component of the organic extract, exhibited an inhibitory pattern similar to the organic extract. Taken together, our results indicate that S. exigua possesses different PLA2 types and that X. hominickii can inhibit PLA2s susceptible to sPLA2- and iPLA2- specific inhibitors. PMID- 28803983 TI - Molecular structure of a prostaglandin D synthase requiring glutathione from the brown planthopper, Nilaparvata lugens. AB - Prostaglandins are involved in many physiological processes, and prostaglandin synthases facilitate the detoxification of xenobiotics as well as endogenous compounds, such as through glutathione conjugation. Specifically, prostaglandin D synthase (PGDS) catalyzes the isomerization of PGH2 to PGD2. Here we report the identification and structural analysis of PGDS from the brown planthopper rice pest Nilaparvata lugens (nlPGDS), which belongs to the sigma-class glutathione transferases. The structure of nlPGDS in complex with glutathione was determined at a resolution of 2.0 A by X-ray crystallography. Bound glutathione was localized to the glutathione-binding site (G-site). Enzyme activity measurements following site-directed mutagenesis of nlPGDS indicated that amino acid residues Tyr8, Leu14, Trp39, Lys43, Gln50, Val51, Gln63, and Ser64 in the G-site contribute to its catalytic activity. To our knowledge, this represents the first report of a PGDS in insects. Our findings provide insights into the mechanism of nlPGDS activity and potentially that of other insects and therefore may facilitate the development of more effective and safe insecticides. PMID- 28803984 TI - Canagliflozin potentiates GLP-1 secretion and lowers the peak of GIP secretion in rats fed a high-fat high-sucrose diet. AB - The glucose-induced secretion of incretins, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), is dependent on luminal glucose levels and transport of glucose via the sodium-glucose transporter 1 (SGLT1) in the small intestine. Because GLP-1 and GIP function in decreasing and increasing the body weight, respectively, we aimed to analyze the effect of transient inhibition of SGLT1 by canagliflozin on incretin secretion in an obese rat model. Male Sprague-Dawley rats were maintained on a high-fat high sucrose diet for 6-7 weeks, and plasma GLP-1 and GIP levels were measured during an oral glucose tolerance test (OGTT). In addition, GLP-1 secretion was examined in a murine GLP-1 producing enteroendocrine cell line, GLUTag. Concomitant administration of 10 mg/kg canagliflozin with glucose loading suppressed glucose excursion, increased total GLP-1 levels, and reduced total GIP levels in systemic circulation, as revealed in the OGTT. Total and active GLP-1 levels were increased in portal blood, whereas total and active GIP levels tended to be decreased 15 min after the administration of canagliflozin with glucose. Canagliflozin (at 0.1-30 MUM) did not directly affect release of GLP-1 in vitro. These results suggest that the oral administration of canagliflozin suppresses GIP secretion via the inhibition of SGLT1 in the upper part of the intestine and enhances GLP-1 secretion by increasing the glucose delivery to the lower part of the small intestine in an obese rodent model. PMID- 28803985 TI - miR-199a-3p affects adipocytes differentiation and fatty acid composition through targeting SCD. AB - Body fat mass is closely associated to diseases related to obesity. MicroRNAs (miRNAs, miR) are important regulatory molecules that function as post transcriptional gene regulators of adipocyte development. In the current study, we revealed that reduced expression of miR-199a-3p in adipose tissue resulting from high fat diet (HFD)-induced obesity in mice. Overexpression of miR-199a-3p promoted adipocyte proliferation by regulating the expression of regulating factors of the cell cycle. Furthermore, miR-199a-3p blunted lipid accumulation in 3T3-L1 adipocytes. This was accompanied by a marked decrease in the expression of adipocyte-specific genes involved in lipogenic transcription, fatty acid synthesis, and fatty acid transportation. Furthermore, the fatty acid oxidation process was enhanced. Luciferase activity assays confirmed that miR-199a-3p regulates adipocyte differentiation by directly targeting the 3'-untranslated region (3'-UTR) of stearoyl-CoA desaturase (SCD). Moreover, miR-199a-3p regulates fatty acid composition by decreasing the ratio of unsaturated fatty acids (UFAs) in adipocytes transfected with miR-199a-3p mimics. These results suggest that miR 199a-3p may promote adipocyte proliferation, while also repressing adipocyte differentiation by down-regulating SCD and changing fatty acid composition during adipogenesis. PMID- 28803986 TI - Ubiquitin C-Terminal Hydrolase L1 regulates myoblast proliferation and differentiation. AB - Skeletal muscles are dynamic tissues that possess regenerative abilities, which require multiple processes and regulatory factors. Ubiquitin C-Terminal Hydrolase L1 (UCHL1), which is primarily expressed in neuronal tissues, was upregulated in skeletal muscles in disease conditions but its functional role in skeletal muscles is unknown. Using mouse myoblast cells C2C12 as an in vitro model, this study reported that UCHL1 elicits different regulation in myoblast cell proliferation and differentiation. We first observed that UCHL1 protein level was continuously declined during cell differentiation. Gene knockdown of UCHL1 by siRNA resulted in a significant decrease in cell proliferation but marked acceleration of cell differentiation and myotube formation. Meanwhile, UCHL1 gene knockdown upregulated myogenic factors myoD and Myogenin (MyoG). In mice, UCHL1 was significantly upregulated in denervated skeletal muscle. Overall, these novel data suggest that UCHL1 may play a role in myogenesis by promoting myoblast proliferation and inhibiting differentiation. PMID- 28803987 TI - Paradoxical low-flow low-gradient severe aortic stenosis in a woman with apical hypertrophy. PMID- 28803988 TI - Repeated transapical TAVI for the treatment of a degenerated bioprosthetic valve. PMID- 28803989 TI - Mdr65 decreases toxicity of multiple insecticides in Drosophila melanogaster. AB - ABC transporters are ubiquitous membrane-bound proteins, present in both prokaryotes and eukaryotes. The major function of eukaryotic ABC transporters is to mediate the efflux of a variety of substrates (including xenobiotics) out of cells. ABC transporters have been widely investigated in humans, particularly for their involvement in multidrug resistance (MDR). Considerably less is known about their roles in transport and/or excretion in insects. ABC transporters are only known to function as exporters in insects. Drosophila melanogaster has 56 ABC transporter genes, including eight which are phylogenetically most similar to the human Mdr genes (ABCB1 clade). We investigated the role of ABC transporters in the ABCB1 clade in modulating the susceptibility to insecticides. We took advantage of the GAL4/UAS system in D. melanogaster to knockdown the expression levels of Mdr65, Mdr50, Mdr49 and ABCB6 using transgenic UAS-RNAi lines and conditional driver lines. The most notable effects were increased sensitivities to nine different insecticides by silencing of Mdr65. Furthermore, a null mutation of Mdr65 decreased the malathion, malaoxon and fipronil LC50 values by a factor of 1.9, 2.1 and 3.9, respectively. Altogether, this data demonstrates the critical role of ABC transporters, particularly Mdr65, in altering the toxicity of specific, structurally diverse, insecticides in D. melanogaster. PMID- 28803990 TI - High doses of baicalin induces kidney injury and fibrosis through regulating TGF beta/Smad signaling pathway. AB - Baicalin is a major flavonoid compound purified from Scutellariae radix, which has been described as an herb in the Chinese Pharmacopoeia. Previous studies have suggested baicalin possessed extensive anti-inflammatory, anti-cancer, anti-viral properties. However, up to known, there have been no reports of safety and toxicity in the rats following oral administration of baicalin. In this present study, we showed the first evidence that treatment of baicalin (400, 800 and 1600mg/kg/day) induced significantly kidney injury and fibrosis. The collagen synthesis and fibrosis-related protein expression were increased in the kidney of Sprague-Dawley (SD) rats after treatment with high doses of baicalin. We further investigated the potential molecular mechanism of baicalin-mediated renal fibrosis and revealed that baicalin activated the transforming growth factor-beta (TGF-beta)/Smad signaling pathway in a dose-dependent manner. Moreover, we also observed that baicalin induced Smad3 interaction with transcriptional coactivator p300 accompanying with increment of Smad3 acetylation. Our results may contribute to better understanding of the future pharmacological and toxicological studies of Scutellaria baicalensis Georgi and its active compounds on the human disease. PMID- 28803991 TI - DHEA increases epithelial markers and decreases mesenchymal proteins in breast cancer cells and reduces xenograft growth. AB - Breast cancer is one of the most common neoplasias and the leading cause of cancer death in women worldwide. Its high mortality rate is linked to a great metastatic capacity associated with the epithelial-mesenchymal transition (EMT). During this process, a decrease in epithelial proteins expression and an increase of mesenchymal proteins are observed. On the other hand, it has been shown that dehydroepiandrosterone (DHEA), the most abundant steroid in human plasma, inhibits migration of breast cancer cells; however, the underlying mechanisms have not been elucidated. In this study, the in vitro effect of DHEA on the expression pattern of some EMT-related proteins, such as E-cadherin (epithelial), N-cadherin, vimentin and Snail (mesenchymal) was measured by Western blot and immunofluorescence in MDA-MB-231 breast cancer cells with invasive, metastatic and mesenchymal phenotype. Also, the in vivo effect of DHEA on xenograft tumor growth in nude mice (nu-/nu-) and on expression of the same epithelial and mesenchymal proteins in generated tumors was evaluated. We found that DHEA increased expression of E-cadherin and decreased N-cadherin, vimentin and Snail expression both in MD-MB-231 cells and in the formed tumors, possibly by DHEA induced reversion of mesenchymal phenotype. These results were correlated with a tumor size reduction in mouse xenografts following DHEA administration either a week earlier or concurrent with breast cancer cells inoculation. In conclusion, DHEA could be useful in the treatment of breast cancer with mesenchymal phenotype. PMID- 28803992 TI - P-REX1 amplification promotes progression of cutaneous melanoma via the PAK1/P38/MMP-2 pathway. AB - P-REX1 (PIP3-dependent Rac exchange factor-1) is a guanine nucleotide exchange factor that activates Rac by catalyzing exchange of GDP for GTP bound to Rac. Aberrant up-regulation of P-REX1 expression has a role in metastasis however, copy number (CN) and function of P-REX1 in cutaneous melanoma are unclear. To explore the role of P-REX1 in melanoma, SNP 6.0 and Exon 1.0 ST microarrays were assessed. There was a higher CN (2.82-fold change) of P-REX1 in melanoma cells than in melanocytes, and P-REX1 expression was significantly correlated with P REX1 CN. When P-REX1 was knocked down in cells by P-REX1 shRNA, proliferation, colony formation, 3D matrigel growth, and migration/invasiveness were inhibited. Loss of P-REX1 inhibited cell proliferation by inhibiting cyclin D1, blocking cell cycle, and increased cell apoptosis by reducing expression of the protein survivin. Knockdown of P-REX1 expression inhibited cell migration/invasiveness by disrupting P-REX1/RAC1/PAK1/p38/MMP-2 pathway. Assessment of patient tumors and disease outcome demonstrated lower distant metastasis-free survival among AJCC stage I/II/III patients with high P-REX1 expression compared to patients with low P-REX1 expression. These results suggest P-REX1 plays an important role in tumor progression and a potential theranostic target. PMID- 28803994 TI - Lepistatins A-C, chlorinated sesquiterpenes from the cultured basidiomycete Lepista sordida. AB - Three new chlorinated sesquiterpenes, named lepistatins A-C, were isolated from the culture broth of Basidiomycete Lepista sordida. The structures were determined by the analysis of spectroscopic data including HREIMS and 1D and 2D NMR. The absolute configuration of lepistatin B was determined by comparing the specific rotation and circular dichroism spectrum with those of known structurally related compounds bearing the same chiral carbon. The structures of lepistatins A-C feature the indanone core structure, but differ from other indanone-containing sesquiterpenes of fungal origin by the alkyl substitution pattern. This indicates that lepistatins A-C probably possess a new sesquiterpene scaffold derived from the common precursor, trans-humulyl cation, by an alternative cyclization. PMID- 28803993 TI - Nanoemulsion formulation of a novel taxoid DHA-SBT-1214 inhibits prostate cancer stem cell-induced tumor growth. AB - The main aim of this study was to evaluate the therapeutic efficacy of an oil-in water nanoemulsion formulation encapsulating DHA-SBT-1214, a novel omega-3 fatty acid conjugated taxoid prodrug, against prostate cancer stem cells. Nanoemulsions of DHA-SBT-1214 (NE-DHA-SBT-1214) were prepared and characterized. In vitro delivery efficiency and cytotoxicity of NE-DHA-SBT-1214 was compared with solution formulation in PPT2 cells. In vivo studies included analysis of comparative efficacy of NE-DHA-SBT-1214 with Abraxane(r) and placebo nanoemulsions as well as post-treatment alternations in clonogenic and sphere forming capabilities of the tumor cells. Qualitative intracellular uptake studies of dye encapsulated NEs by confocal imaging showed uptake by both monolayer and spheroid cultured PPT2 cells. Treatment of PPT2 cells with NE DHA-SBT-1214 (1nM 1MUM for monolayer culture of cells grown on collagen-coated dishes for 48 h) induced complete cell death, showing higher efficacy as compared to the drug solution. This nanoemulsion (10nM-10MUM) also showed toxicity in 3D culture of floating spheroids. Weekly intravenous administration of the NE-DHA-SBT-1214 to NOD/SCID mice bearing subcutaneous PPT2 tumor xenografts led to dramatic suppression of tumor growth compared to Abraxane(r) and placebo nanoemulsion formulation. Viable cells that survived from this in vivo treatment regimen were no longer able to induce floating spheroids and holoclones, whereas control and Abraxane(r) treated tumor cells induced a large number of both. The results show that NE-DHA-SBT-1214 possesses significant activity against prostate CD133high/CD44+/high tumor-initiating cells both in vitro and in vivo. PMID- 28803995 TI - Depsidones and an alpha-pyrone derivative from Simplicillium sp. PSU-H41, an endophytic fungus from Hevea brasiliensis leaf [corrected]. AB - Nine previously undescribed depsidones (simplicildones A-I) and one previously undescribed alpha-pyrone (simplicilopyrone) were isolated from the endophytic fungus Simplicillium sp. PSU-H41 along with 11 known compounds. Their structures were established by extensive spectroscopic analysis. Simplicildone A and known botryorhodine C displayed weak antibacterial against Staphylococcus aureus with equal MIC values of 32 MUg/mL. Additionally, botryorhodine C was active against methicillin-resistant S. aureus with the same MIC value. Simplicildone C exhibited weak antifungal activity against Cryptococcus neoformans with an MIC value of 32 MUg/mL. In addition, simplicildones A and C and botryorhodine C were noncytotoxic against noncancerous Vero cells. PMID- 28803996 TI - Perioperative hemodynamics and outcomes of patients on metyrosine undergoing resection of pheochromocytoma or paraganglioma. AB - INTRODUCTION: To describe outcomes of patients with metyrosine (MET) pretreatment for abdominal surgical resection of pheochromocytoma or paraganglioma (PCC/PGL) compared with patients who had phenoxybenzamine (PBZ) pretreatment. METHODS: Retrospective review of perioperative outcomes for PCC/PGL patients treated with MET and propensity-matched comparison of MET and PBZ (MET + PBZ) with PBZ alone. RESULTS: MET preparation was given in 63 cases (26 laparoscopic and 37 open, of which 55 also received PBZ). All patients had wide perioperative hemodynamic oscillations. Patients with open procedures required more intravenous fluids and blood transfusions; 35% required postoperative vasopressor infusions for hypotension and 38% developed acute kidney injury. One laparoscopic procedure required postoperative vasopressor infusion, and 12% of patients developed acute kidney injury. Forty-five MET + PBZ patients were propensity-matched with PBZ only patients. Intraoperatively, MET + PBZ patients had lower minimum systolic and diastolic blood pressures than PBZ-only patients (median systolic, 74 vs 80 mm Hg, P = 0.01; median diastolic, 42 vs 46 mm Hg, P = 0.005) and larger intraoperative blood pressure oscillations (median systolic range, 112 vs 93 mm Hg, P = 0.06; median diastolic range, 58 vs 51 mm Hg, P = 0.02). Postoperative vasopressor infusion use was similar between MET + PBZ and PBZ only (16% vs 11%, P = 0.76). Major outcomes were not different between regimens. CONCLUSION: Large hemodynamic oscillations were present in our PCC/PGL patients treated with MET + PBZ. These patients had a wider range of intraoperative blood pressure variations than PBZ-only patients. No differences in postoperative comorbid outcomes were found between MET + PBZ and PBZ-only groups. PMID- 28803997 TI - The impact of distance from transplant unit on outcomes following kidney transplantation. AB - BACKGROUND: Following transplantation, many patients travel long distances for follow-up care. Many studies have examined the influence of distance from transplant centre on access to transplantation, but few have examined post transplant outcomes. MATERIALS AND METHODS: Distance from transplant centre was calculated for all kidney transplant recipients transplanted over a 5-year period. Outcomes measured were rates of acute rejection, graft and patient survival. RESULTS: Complete follow up data was available for 571 of the 585 kidney transplants performed over the study period. Distance from home to transplant centre ranged from 1.3 to 257.4 km (median 33.7 km). Patients were divided into quartiles according to their distance from the transplant centre. Distance from the transplant centre did not influence rates of acute rejection (p = 0.102). One-year graft survival for 'nearest' and 'farthest' quartiles was 99% and 97% respectively and five-year graft survival was 78% and 89% respectively (log rank p-value of 0.212). There were no differences in patient survival at 1 and 5 years between the 'nearest' and 'farthest' groups. CONCLUSION: Distance from transplant centre does not affect early outcomes following kidney transplantation. The centralized practice which involves a low threshold for rapid assessment and readmission of patients post-transplantation appears to provide good outcomes for kidney transplant recipients. PMID- 28803998 TI - High serum lactate as an adjunct in the early prediction of anastomotic leak following oesophagectomy. AB - BACKGROUND: Anastomotic leak (AL) following oesophagectomy carries a high mortality and morbidity. Early detection and intervention is required for a successful outcome. We have examined the role of a high postoperative serum lactate in predicting which patients are at risk of developing an anastomotic leak(AL). MATERIALS AND METHODS: All patients who underwent transthoracic oesophagectomy over a 3-year period were identified from a prospectively collected database. Medical records were reviewed to identify the highest serum lactate recorded from blood gas analysis over each 24hr post-operative period. Patients who underwent transhiatal and left thoraco-abdominal oesophagectomies were excluded. Patients who developed a chyle leak were excluded. RESULTS: Of a total of 136 oesophagectomies included for analysis, 18 developed an AL (13.2%). Of these patients, 10 underwent thoracoscopic oesophageal mobilization with cervical anastomosis and the rest an Ivor Lewis procedure. Predictive factors for AL included neoadjuvant chemotherapy (15/18 83.3% vs 55/118 46.6% p = 0.0046) and number of positive lymph nodes (mean 4.2 vs control mean 2.3 p = 0.045). Overall net fluid balance was comparable between the 2 groups, although AL patients received slightly more fluid on Day 3. High lactate levels on days 1-3 were associated with an AL. Using a Day 2 lactate of 1.7 mmol/L, the sensitivity of predicting AL was 72% and specificity 88%. The mean lag time using existing diagnostic modalities was 7.9 days. CONCLUSION: A serum lactate of >1.7 mmol/l on day 2 should raise the possibility of a potential AL. Such patients should be selected for more intensive monitoring, optimization and selective gastroscopy. PMID- 28804000 TI - The mechanics of DNA loops bridged by proteins unveiled by single-molecule experiments. AB - Protein-induced DNA bridging and looping is a common mechanism for various and essential processes in bacterial chromosomes. This mechanism is preserved despite the very different bacterial conditions and their expected influence on the thermodynamic and kinetic characteristics of the bridge formation and stability. Over the last two decades, single-molecule techniques carried out on in vitro DNA systems have yielded valuable results which, in combination with theoretical works, have clarified the effects of different parameters of nucleoprotein complexes on the protein-induced DNA bridging and looping process. In this review, I will outline the features that can be measured for such processes with various single-molecule techniques in use in the field. I will then describe both the experimental results and the theoretical models that illuminate the contribution of the DNA molecule itself as well as that of the bridging proteins in the DNA looping mechanism at play in the nucleoid of E. coli. PMID- 28803999 TI - Growth arrest and morphological changes triggered by emodin on Trypanosoma cruzi epimastigotes cultivated in axenic medium. AB - Emodin is an anthraquinone obtained from Rheum palmatum rootstocks. Here we tested the cytotoxic effects of emodin on Trypanosoma cruzi epimastigotes, as well as the morphological changes that were induced by this compound in the parasite. Emodin was permeable and blocked in vitro cell division of T. cruzi epimastigotes in axenic medium, causing growth arrest in a dose-dependent but reversible manner. Emodin-exposed epimastigotes underwent duplication of organelles, such as the nucleus, kinetoplast and flagellum, but were incapable of completing cytokinesis. Neither elongation of the parasite body nor appearance of the regular longitudinal cleavage furrow was displayed, suggesting that emodin is most likely affecting components of the parasite cytoskeleton. Moreover, drug treated parasites acquired alterations such as protuberances, folds and indentations on their membrane surface. Since emodin has been shown to be a potent protein kinase CK2 inhibitor, and we have previously described an association between tubulin and CK2 in T. cruzi epimastigotes (De Lima et al. Parasitology132, 511-523, 2006), we also measured the indirect effect of the drug on tubulin. Incubation of epimastigotes with axenic medium containing emodin hindered the endogenous phosphorylation of tubulin in whole-cell parasite extracts. All our results suggested that the parasite CK2 may be important for the maintenance of the morphology and for the regulation of mitosis-cytokinesis transition in T. cruzi epimastigotes. PMID- 28804001 TI - Production of trans and conjugated fatty acids in dairy ruminants and their putative effects on human health: A review. AB - Consumption of milk and dairy products is important in Western industrialised countries. Fat content is an important constituent contributing to the nutritional quality of milk and dairy products. In order to improve the health of consumers, there is high interest in improving their fatty acid (FA) composition, which depends principally on rumen and mammary metabolism. This paper reviews the lipid metabolism in ruminants, with a particular focus on the production of trans and conjugated linoleic acids (CLA) and conjugated linolenic acids (CLnA) in the rumen. After the lipolysis of dietary lipids, an extensive biohydrogenation of unsaturated FA occurs by rumen bacteria, leading to numerous cis and trans isomers of 18:1, non-conjugated of 18:2, CLA and CLnA. The paper examines the different putative pathways of ruminal biohydrogenation of cis9-18:1, 18:2n-6, 18:3n-3 and long-chain FA and the bacteria implicated. Then mechanisms relative to the de novo mammary synthesis are presented. Ruminant diet is the main factor regulating the content and the composition of milk fat. Effects of nature of forage and lipid supplementation are analysed in cows and small ruminants species. Finally, the paper briefly presents the effects of these FA on animal models and human cell lines. We describe the properties of ruminant trans 18:1, when compared to industrial trans 18:1, CLA and CLnA on human health from meta analyses of intervention studies and then explore the underlying mechanisms. PMID- 28804002 TI - A novel glycoside hydrolase family 97 enzyme: Bifunctional beta-l arabinopyranosidase/alpha-galactosidase from Bacteroides thetaiotaomicron. AB - Glycoside hydrolase family 97 (GH97) is one of the most interesting glycosidase families, which contains inverting and retaining glycosidases. Currently, only two enzyme types, alpha-glucoside hydrolase and alpha-galactosidase, are registered in the carbohydrate active enzyme database as GH97 function-known proteins. To explore new specificities, BT3661 and BT3664, which have distinct amino acid sequences when compared with that of GH97 alpha-glucoside hydrolase and alpha-galactosidase, were characterized in this study. BT3664 was identified to be an alpha-galactosidase, whereas BT3661 exhibits hydrolytic activity toward both beta-l-arabinopyranoside and alpha-d-galactopyranoside, and thus we designate BT3661 as a beta-l-arabinopyranosidase/alpha-d-galactosidase. Since this is the first dual substrate specificity enzyme in GH97, we investigated the substrate recognition mechanism of BT3661 by determining its three-dimensional structure and based on this structural data generated a number of mutants to probe the enzymatic mechanism. Structural comparison shows that the active-site pocket of BT3661 is similar to GH97 alpha-galactosidase BT1871, but the environment around the hydroxymethyl group of the galactopyranoside is different. While BT1871 bears Glu361 to stabilize the hydroxy group of C6 through a hydrogen bond with its carboxy group, BT3661 has Asn338 at the equivalent position. Amino acid mutation analysis indicates that the length of the side chain at Asn338 is important for defining specificity of BT3661. The kcat/Km value for the hydrolysis of p-nitrophenyl alpha-galactoside decreases when Asn338 is substituted with Glu, whereas an increase is observed when the mutation is Ala. Interestingly, mutation of Asn338 to Ala reduces the kcat/Km value for hydrolysis of p-nitrophenyl beta-l-arabinopyranoside. PMID- 28804003 TI - Effect and proposed mechanism of vitamin C modulating amino acid regulation of autophagic proteolysis. AB - Autophagy is an intracellular bulk degradation process, induced under nutrient starvation. Failure of autophagy has been recognized as a contributor to aging and multiple age related neurodegenerative diseases. Improving autophagy is a beneficial anti-aging strategy, however very few physiological regulators have been identified. Here, we demonstrate that vitamin C is a nutritional stimulator of autophagy. Supplementation of fresh hepatocytes with vitamin C increased autophagic proteolysis significantly in the presence of amino acids in a dose- and time-dependent manner, although no effect was observed in the absence of amino acids. In addition, inhibitor studies with 3-methyladenine, chloroquine, leupeptin and beta-lactone confirmed that vitamin C is active through the lysosomal autophagy and not the proteasome pathway. Furthermore, the autophagy marker LC3 protein was significantly increased by vitamin C, suggesting its possible site of action is at the formation step. Both the reduced (ascorbic acid, AsA) and oxidized form (dehydroascorbic acid, DHA) of vitamin C exhibited equal enhancing effect, indicating that the effect does not depend on the anti oxidation functionality of vitamin C. To understand the mechanism, we established that the effective dose (50 MUM) was 15* lower than the intracellular content suggesting these would be only a minor influx from the extracellular pool. Moreover, transporter inhibitor studies in an AsA deficient ODS model rat revealed more accurately that the enhancing effect on autophagic proteolysis still existed, even though the intracellular influx of AsA was blocked. Taken together, these results provide evidence that vitamin C can potentially act through extracellular signaling. PMID- 28804004 TI - Charge density, not current density, is a more comprehensive safety measure of transcranial direct current stimulation. PMID- 28804005 TI - Performance assessment of the SAPS II and SOFA scoring systems in Hanta virus Hemorrhagic Fever with Renal Syndrome. AB - BACKGROUND: Hemorrhagic Fever with Renal Syndrome (HFRS), caused by the hantavirus, is a natural infectious disease characterized by fever, hemorrhage and renal damage. China is the most severely endemic area for HFRS in the world. In recent years, critical scoring systems based on quantitative classification have become an important clinical tool for predicting and evaluating the prognosis of critical illness, and provide guidelines for clinical practice. METHODS: The sample comprised 384 patients with HFRS treated in the Taizhou Hospital from January 2006 to February 2017. The patients were divided into the severe group and the mild group according to their clinical characteristics. By comparing the differences in clinical symptoms, signs and laboratory data between the two groups, the clinically relevant indicators of severe HFRS were explored. According to the previous studies, we incorporated the positive fecal occult blood test (FOBT) into the sepsis-related organ failure assessment (SOFA) tool and formulated a new scoring system specifically for HFRS, named H-SOFA. By comparing the simplified acute physiology score II (SAPS II), SOFA and H-SOFA scores of the two groups, their predictive values for the progression of HFRS were assessed. RESULTS: Compared to the mild group, patients in the severe group had longer hospital stays; higher frequencies of nausea, vomiting, abdomen pain, signs of congestion and hemorrhage; and more pronounced impairment of liver and renal function. The levels of PLT, PCT, TB, and FOBT were positively correlated with the progression of HFRS (P<0.001). Patients with HFRS in the severe group got significantly higher scores on the SAPS II, SOFA, and H-SOFA scoring systems (P<0.001). The values of SAPS II, SOFA and H-SOFA, were significantly correlated with the severity of HFRS, and the AUC values were 0.90, 0.96, and 0.98, respectively. CONCLUSION: PLT, PCT, TB, and FOBT were independent predictors of severe HFRS; SAPS II, SOFA, and H-SOFA had high predictive value for the progression of severe HFRS, with H-SOFA being the highest. PMID- 28804006 TI - Vitamin D deficiency is a risk factor for infections in patients affected by HCV related liver cirrhosis. AB - OBJECTIVES: To evaluate the prevalence of vitamin D deficiency and its impact on infections in HCV-related liver cirrhosis. METHODS: We enrolled 291 patients affected by HCV-related liver cirrhosis. Serum vitamin D levels were dosed at enrolment. The presence of infection was assessed at baseline and during follow up based on physical examination and laboratory analyses. RESULTS: Vitamin D deficiency (<20ng/mL) was diagnosed in 68.3% of patients, and a total of 102 infections were detected. Urinary tract infections were the most common infections diagnosed (41.2%). Vitamin D deficiency rates were higher in patients with decompensated cirrhosis (Child-Pugh B vs A p=0.008, and Child-Pugh C vs A p=0.024). Infection was significantly associated with vitamin D deficiency (p<0.001), MELD score >15 (p=0.003), Child-Pugh class B/C vs A (p<0.001), and active hepatocellular carcinoma (HCC) (p<0.001). At multivariate analysis, vitamin D deficiency (p<0.01), HCC (p<0.05), hospitalization (p<0.001) and exposure to immunosuppressant agents (p<0.05) were independent risk factors for infection at baseline. CONCLUSIONS: Vitamin D may play a role in the development of infections in patients affected by liver cirrhosis, and preventive strategies with vitamin D supplementation are to be evaluated in randomized controlled trials. PMID- 28804007 TI - Antibiotic therapy duration for prosthetic joint infections treated by Debridement and Implant Retention (DAIR): Similar long-term remission for 6 weeks as compared to 12 weeks. AB - BACKGROUND: The required duration of antibiotic treatment for prosthetic joint infections (PJI) with debridement and retention of the implant (DAIR procedure) is unknown. METHODS: Multicenter retrospective study emphasizing the duration of antibiotic therapy in patients treated with by DAIR. RESULTS: We included 87 hip or knee PJI episodes in 87 patients from three university hospitals in France and Switzerland. All debridements were performed within 3 weeks of symptom onset. After a mean follow-up of 52.1 months, 60 patients with PJI (69%) remained in remission, with no significant difference between hip and knee cases (73.3% vs. 59.3%, 95% confidence interval (CI), 0.20-1.38), or between patients receiving 6 compared with 12 weeks of antibiotic treatment (70.5% vs.67.4%, 95%CI 0.27-2.10, p=0.60). Methicillin-resistant Staphylococcus aureus was isolated from 13.8% of infections and this was the only variable associated with a poorer outcome (remission in 41.7% vs. 73.3% for those with other pathogens, 95%CI 0.05-0.77, p=0.02). CONCLUSIONS: In patients undergoing DAIR for hip or knee PJI, the likelihood of long-term remission was not significantly different for those receiving 6 versus 12 weeks of antibiotic therapy. Prospective randomized trials are required to confirm this observation. PMID- 28804008 TI - PERK as a hub of multiple pathogenic pathways leading to memory deficits and neurodegeneration in Alzheimer's disease. AB - Cell signaling in response to an array of diverse stress stimuli converges on the phosphorylation of eukaryotic initiation factor-2alpha (eIF2alpha). In the brain, eIF2alpha is a hub for controlling learning and memory function and for maintaining neuronal integrity in health and disease. Among four eIF2alpha kinases, PERK is emerging as a key regulator for memory impairments and neurodegeneration in Alzheimer's disease (AD). Genetic and pharmacological manipulations of PERK-eIF2alpha signaling have revealed that the overactivation of this pathway is not a mere consequence of the neurodegenerative process but play critical roles in AD pathogenesis and the occurrence of memory deficits. This review provides an overview of recent progress in animal model studies, which demonstrate that dysregulated PERK accounts for memory deficits and neurodegeneration not only as a detrimental mediator downstream of beta amyloidosis and tauopathy but also as an important determinant upstream of both pathogenic mechanisms in AD. A therapeutic perspective is also discussed, in which interventions targeting the PERK-eIF2alpha pathway are expected to provide multiple beneficial outcomes in AD, including enhanced mnemonic function, neuroprotection and disease modification. PMID- 28804009 TI - Effects of Timing of Whey Protein Intake on Appetite and Energy Intake in Healthy Older Men. AB - BACKGROUND: Protein-rich supplements are used widely to prevent and manage malnutrition in older adults. We previously showed that 30 g whey protein ingestion, 3 hours before a buffet meal, suppressed energy intake in young, but not in older men. Information about the impact of the timing of ingestion of protein drinks on the suppression of energy intake in older adults is lacking. OBJECTIVE: The aim of the study was to determine the effect of the timing of whey protein ingestion on appetite and subsequent ad libitum energy intake in healthy older men. DESIGN: In a single blind, randomized design, 16 older men were studied on 5 occasions, on which they consumed a whey protein drink (30 g/120 kcal, 140 mL) 3, 2, 1 hour(s), or immediately before a buffet meal, from which ad libitum energy intake was quantified, and isopalatable noncaloric drinks (~1 kcal) at the remaining time points. On the control day, noncaloric drinks were ingested at all time points. Perceptions of appetite and gastrointestinal symptoms were determined, by visual analog scales, throughout the study days. RESULTS: There was no effect of the timing of protein ingestion on perceptions of appetite and gastrointestinal symptoms (P > .05) or energy intake at the buffet meal (3 hours: 888 +/- 49 kcal, 2 hours: 879 +/- 56 kcal, 1 hours: 909 +/- 47 kcal, 0 hour: 892 +/- 51 kcal, control: 930 +/- 49 kcal, P = .94). Total energy intake (ie, preload + test meal) was higher on the protein days compared with control (82 +/- 24 kcal increase, P = .003). CONCLUSIONS: In older men, ingestion of 30 g protein increased total energy intake, irrespective of the time of intake in relation to the meal. These observations support the use of "pure" whey protein drinks to increase overall protein and energy intake in older adults at risk of undernutrition. PMID- 28804010 TI - Frailty and Malnutrition: Related and Distinct Syndrome Prevalence and Association among Community-Dwelling Older Adults: Singapore Longitudinal Ageing Studies. AB - OBJECTIVE: The association between frailty and malnutrition is widely noted, but the common and distinct aspects of this relationship are not well understood. We investigated the prevalence of prefrailty/frailty and malnutrition/nutritional risk; their overlapping prevalence; compared their sociodemographic, physical, and mental health risk factors; and assessed their association, independently of other risk factors. METHODS: Cross-sectional study of population-based cohort (Singapore Longitudinal Ageing Study [SLAS]-1 [enrolled 2003-2005] and SLAS-2 [enrolled 2010-2013]) of community-dwelling older Singaporeans aged >=55 (n = 6045). MEASUREMENTS: Mini Nutritional Assessment (MNA)-Short Form (SF), Nutritional Screening Initiative (NSI) Determine Checklist, Fried physical frailty phenotype. RESULTS: The overall prevalence of MNA malnutrition was 2.8%, and at risk of malnutrition was 27.6%; the prevalence of frailty and prefrailty were 4.5%, and 46.0% respectively. Only 26.5% of participants who were malnourished were frail, but 64.2% were prefrail (totally 90.7% prefrail or frail). The prevalence of malnutrition among frail participants was 16.1%, higher than in other studies (10%); nearly one-third of the whole population sample had normal nutrition while being prefrail (27.7%) or frail (1.5%). The prevalence of risk factors for prefrailty/frailty and malnutrition/nutritional risk were remarkably similar. MNA at risk of malnutrition and malnutrition were highly significantly associated with prefrailty (odds ratio [OR] 2.11 and 6.71) and frailty (OR 2.72 and 17.4), after adjusting for many other risk factors. The OR estimates were substantially lower with NSI moderate and high nutritional risk for prefrailty (OR 1.39 and 1.74) and frailty (OR 1.27 and 1.93), but remain significantly elevated. CONCLUSION: Frailty and malnutrition are related but distinct conditions in community-dwelling older adults. The contribution of poor nutrition to frailty in this population is notably greater. Both frail/prefrail elderly and those who are malnourished/at nutritional risk should be identified early and offered suitable interventions. PMID- 28804011 TI - Functional Outcomes, Subsequent Healthcare Utilization, and Mortality of Stroke Postacute Care Patients in Taiwan: A Nationwide Propensity Score-matched Study. AB - OBJECTIVE: To evaluate the benefits of the national stroke postacute care (PAC) program on clinical outcomes and subsequent healthcare utilization. DESIGN: Propensity score-matched case-control study using the National Health Insurance data. PARTICIPANTS: A total of 1480 stroke cases receiving PAC services and 3159 matched controls with similar stroke severity but without PAC services. MEASUREMENTS: Demographic characteristics, functional outcomes (modified Rankin Scale, Barthel Index, Lawton-Brody Instrumental Activities of Daily Living, Functional Oral Intake Scale, Mini-Nutritional Assessment, Berg Balance Test, Usual Gait Speed Test, 6-Minute Walk Test, Fugl-Meyer Assessment (modified sensation and motor), Mini-Mental State Examination, Motor Activity Log, and the Concise Chinese Aphasia Test), subsequent healthcare utilization (90-day stroke re-admission and emergency department visits), and 90-day mortality. RESULTS: After propensity score matching, baseline characteristics, stroke severity, and status of healthcare utilization before index stroke admission were similar between cases and controls. After PAC services, the case group obtained significant improvement in all functional domains and may have reduced subsequent disability. Among all functional assessments, balance was the most significantly improved domain and was suggestive for the reduction of subsequent falls risk and related injuries. Compared with controls, patients receiving PAC services had significantly lower 90-day hospital re-admissions [11.1% vs 21.0%, adjusted odds ratio (aOR) 0.47 with 95% confidence interval (CI) 0.34-0.64], stroke-related re admissions (2.1% vs 8.8%, aOR 0.22, 95% CI 0.12-0.41), and emergency department visits (13.5% vs 24.0%, aOR 0.49, 95% CI 0.37-0.65), but the 90-day mortality rate remained similar between groups (1.4% case group vs 2.0% control group, aOR 0.68, 95% CI 0.29-1.62). CONCLUSIONS: PAC significantly improved the recovery of stroke patients in all functional domains through the program, with universal interorganizational staff training, periodic functional assessment, and high intensity rehabilitation. Further longitudinal research is needed to evaluate the long-term survival benefits and healthcare utilization. PMID- 28804013 TI - Fidelity of translation in the presence of mammalian mitochondrial initiation factor 3. AB - Initiation factor 3 (IF3) is a conserved translation factor. Mutations in mitochondrial IF3 (IF3mt) have been implicated in disease pathology. Escherichia coli infCDelta55, compromised for IF3 activity, has provided an excellent heterologous system for IF3mt structure-function analysis. IF3mt allowed promiscuous initiation from AUA, AUU and ACG codons but avoided initiation with initiator tRNAs lacking the conserved 3GC pairs in their anticodon stems. Expression of IF3mt N-terminal domain, or IF3mt devoid of its typical N-, and C terminal extensions improved fidelity of initiation in E. coli. The observations suggest that the IF3mt terminal extensions relax the fidelity of translational initiation in mitochondria. PMID- 28804012 TI - Incidence of Second Malignancy after Successful Treatment of Limited-Stage Small Cell Lung Cancer and Its Effects on Survival. AB - INTRODUCTION: Extended survival outcomes from improved treatments for patients with cancer come with an increased risk for development of a metachronous second malignancy (MSM). We evaluated the incidence of MSM after successful treatment of SCLC and compared survival between patients with SCLC in whom MSM developed and those in whom it did not. METHODS: Selection criteria were a diagnosis of limited stage SCLC and receipt of at least 45 Gy of radiotherapy and chemotherapy at a single institution in 1985-2012. MSM was defined as a tumor of a different histologic type than the primary that appeared more than 2 years after the diagnosis of SCLC. RESULTS: Of 704 patients identified, 32 were excluded for lack of follow-up, 48 for having SCLC as MSM after treatment of another type of cancer, 37 for nonmelanoma skin cancer as MSM, and 46 for MSM within 2 years after SCLC diagnosis. Of the remaining 541 patients, 346 had recurrent SCLC, 180 had no second malignancy and no recurrence, and 15 (2.8%) had MSM (13 in a lung [eight adenocarcinomas and five squamous cell carcinomas], one sarcoma, and one acute myeloid leukemia). All 15 patients with MSM achieved complete response to the SCLC treatment. Overall survival was longer for patients with MSM than for patients with no other malignancies and no recurrence, with 10-year rates of 61.9% (95% confidence interval: 30.0%-82.6%) and 29.9% (95% confidence interval: 21.5%-38.6%), respectively (p = 0.03). CONCLUSIONS: Long-term survivors after treatment for SCLC should be made aware of the risk for MSM and the necessity of follow-up. PMID- 28804014 TI - Foundations, facts, photos and Facebook. PMID- 28804015 TI - A debate about the merits of debate in nurse education. AB - In this 'Issues for Debate' paper, the issue is debate. Today's nurses must be able to advocate, lead, and grow 'big ideas', as well as knowing their way around a patient's body and mind. This paper reports, partly, on a research study into the use of debate to develop clinical reasoning and thinking skills in nursing students. The study was conducted with first and third-year nursing students enrolled at an Australian regional university. Students were asked to comment on the effectiveness of debate as an educational strategy. We combine the results of this research study with literature and discussion into the educational uses of debate to put the argument that using debate in nursing education can be an effective way to foster the type of creative, intelligent, thoughtful and forward thinking nurses needed in the modern healthcare system. PMID- 28804016 TI - Dynamic thiol-disulphide homeostasis in low-grade gliomas: Preliminary results in serum. AB - OBJECTIVE: Maintaining of precise balance between oxidation and anti-oxidation is important in both physiological and pathological states. Knowledge about this balance may give an idea about the process of the disease. The aim of this study was to investigate dynamic thiol-disulfide homeostasis in patients with low-grade gliomas. PATIENTS AND METHODS: Serial serum samples were collected in 13 patients operated on low-grade gliomas before and after surgery. Control serum samples were obtained from venous cord blood from 13 healthy women during cesarean section. Total thiol, native thiol, and disulfide bond formation were measured and compared with the controls. RESULTS: Total thiols, native thiols, and disulfide bond formation were significantly elevated in patients before the surgery compared to the controls (p<0.05). Even after the surgery, these three parameters were still high in patients, and the differences were significant (p<0.05). Although no significant difference was found between patients and controls regarding the ratios of disulfide/total thiol, disulfide/native thiol, and native thiol/total thiol (p>0.05), the balance seemed to shift to oxidative side. CONCLUSIONS: Thiol-disulfide homeostasis was disrupted in patients with low grade gliomas, and oxidation may play a role in the process of this disease. Supplementation with antioxidants before and after surgery may be taken into consideration. PMID- 28804017 TI - Involvement of xanthine oxidase activity with oxidative and inflammatory renal damage in silver catfish experimentally infected with Streptococcus agalactiae: Interplay with reactive oxygen species and nitric oxide. AB - Xanthine oxidase (XO) is a final enzyme of purine metabolism linked with initiation and progression of infectious diseases, since is considered an important source of reactive oxygen species (ROS) and nitric oxide (NO), developing a pro-oxidant and pro-inflammatory profile in some infectious diseases. Thus, the aim of this study was to evaluate the involvement of XO activity in the renal oxidative and inflammatory damage, as well as the interplay with ROS and metabolites of nitric oxide (NOx) levels in silver catfish experimentally infected with Streptococcus agalactiae. Xanthine oxidase activity, and uric acid, ROS and NOx levels increased in renal tissue of infected animals compared to uninfected animals. Moreover, the histopathological analyses revealed the presence of necrosis, generalized edema and nuclear degeneration of renal tubules. Based on these evidences, the upregulation on renal XO activity exerts a pro-oxidant and pro-inflammatory profile in kidney of fish infected with S. agalactiae. The excessive uric acid levels induced the release of oxidative and inflammatory mediators, such as ROS and NOx, that directly contribute to renal oxidative and inflammatory damage. In summary, the upregulation on XO activity may be considered a pathway involved in the renal injury during S. agalactiae infection. PMID- 28804019 TI - Pseudomonas aeruginosa auto inducer3-oxo-C12-HSL exerts bacteriostatic effect and inhibits Staphylococcus epidermidis biofilm. AB - Pseudomonas aeruginosa has evolved the 3-oxo-C12-HSL and C4-HSL based quorum sensing system which is responsible for the regulation of various virulence factors and helps to dominates over other bacterial species. Staphylococcus epidermidis has frequently been reported with P. aeruginosa while the role of C4 HSL and 3-oxo-C12-HSL on the S. epidermidis had widely been unexplored, and as per our knowledge, this is the first report on the impact of C4-HSL and 3-oxo-C12 HSL overS. epidermidis growth and biofilm. We found that among the two AHL molecules; only 3-oxo-C12-HSL was able to exert a significant effect in all the experiments including growth and biofilm of S. epidermidis. 3-oxo-C12-HSL at 100 MUM and 200 MUM concentrations were able to initiate the apparent transient type of planktonic growth inhibition in S. epidermidis. Microscopic analysis and biofilm quantification assay showed the inhibitory effect of 3-oxo-C12-HSL against S. epidermidis biofilm, initial attachment, and EPS production. The study concludes that P. aeruginosa associated 3-oxo-C12-HSL exerts the inhibitory effect on S. epidermidis growth and biofilms and thus it may also help Pseudomonasto dominate under the co-infection conditions. PMID- 28804018 TI - Anti-biofilm activity of A22 ((S-3,4-dichlorobenzyl) isothiourea hydrochloride) against Pseudomonas aeruginosa: Influence on biofilm formation, motility and bioadhesion. AB - Bacterial biofilms are involved in various medical infections and for this reason it is of great importance understanding adhesion mechanisms of involved microorganisms is essential to develop new strategies of prevention and control. Different approaches have been used for preventing biofilm related infections in health care settings, such as use of surface coatings agents in medical implants. In this context, is necessary to explore new compounds with anti-biofilm activity. Thus, this study evaluated for the first time the action of A22 against biofilms of Pseudomonas aeruginosa PAO1 strain and multi-resistant clinical isolates on biotic and abiotic surfaces. A22 acts as inhibitor of the MreB protein of the bacterial cell wall, causing the rods to change shape to the coccoid form. In this work, A22 at subinhibitory concentrations was able to prevent biofilm formation, and atomic force microscopy images showed that A22 was highly effective in inhibiting adhesion on polyethylene surfaces. Pseudomonas aeruginosa PAO1 exhibited a strong ability to adhere to HeLa cells, and A22 inhibited the aggregation after 4 h of exposure. Swarming and twitching motilities were significantly altered by A22 at subinhibitory concentrations. Thus, by changing the shape of the bacterial cell, many properties can be affected, such as motility, surface adhesion and biofilm formation. This work presents A22 as a promising novel antibacterial or surface coating agent of medical materials. PMID- 28804020 TI - Porcine 2', 5'-oligoadenylate synthetase 2 inhibits porcine reproductive and respiratory syndrome virus replication in vitro. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is acknowledged a fulminating infectious pathogen affecting the pig farming industry, and current vaccines and drugs could hardly inhibit this virus. The 2', 5'-oligoadenylate synthetase (OASs) have antiviral activities, but the role(s) played by porcine OAS2 in protection against PRRSV infection are unknown. Here we found that endogenous expression of the porcine OAS2 gene could be promoted by interferon (IFN)-beta or PRRSV infection in porcine alveolar macrophages. Knockdown of porcine OAS2 led to increases in PRRSV replication, and OAS2 expression suppressed replication of PRRSV in a retinoic acid inducible gene I (RIG-I) dependent manner, anti-PRRSV activity of porcine OAS2 would be lost if RNase L and OAS2 were both silenced. This discovery illustrates a pathway that porcine OAS2 responses to host anti-PRRSV function. PMID- 28804021 TI - Intervention to maximise the probability of epidemic fade-out. AB - The emergence of a new strain of a disease, or the introduction of an existing strain to a naive population, can give rise to an epidemic. We consider how to maximise the probability of epidemic fade-out - that is, disease elimination in the trough between the first and second waves of infection - in the Markovian SIR with-demography epidemic model. We assume we have an intervention at our disposal that results in a lowering of the transmission rate parameter, beta, and that an epidemic has commenced. We determine the optimal stage during the epidemic in which to implement this intervention. This may be determined using Markov decision theory, but this is not always practical, in particular if the population size is large. Hence, we also derive a formula that gives an almost optimal solution, based upon the approximate deterministic behaviour of the model. This formula is explicit, simple, and, perhaps surprisingly, independent of beta and the effectiveness of the intervention. We demonstrate that this policy can give a substantial increase in the probability of epidemic fade-out, and we also show that it is relatively robust to a less than ideal implementation. PMID- 28804022 TI - Anti-obesity and anti-diabetic effects of nitrate and nitrite. AB - Prevalence of obesity is increasing worldwide and type 2 diabetes to date is the most devastating complication of obesity. Decreased nitric oxide bioavailability is a feature of obesity and diabetes that links these two pathologies. Nitric oxide is synthesized both by nitric oxide synthase enzymes from l-arginine and nitric oxide synthase-independent from nitrate/nitrite. Nitric oxide production from nitrate/nitrite could potentially be used for nutrition-based therapy in obesity and diabetes. Nitric oxide deficiency also contributes to pathogeneses of cardiovascular disease and hypertension, which are associated with obesity and diabetes. This review summarizes pathways for nitric oxide production and focuses on the anti-diabetic and anti-obesity effects of the nitrate-nitrite-nitric oxide pathway. In addition to increasing nitric oxide production, nitrate and nitrite reduce oxidative stress, increase adipose tissue browning, have favorable effects on nitric oxide synthase expression, and increase insulin secretion, all effects that are potentially promising for management of obesity and diabetes. Based on current data, it could be suggested that amplifying the nitrate-nitrite-nitric oxide pathway is a diet-based strategy for increasing nitric oxide bioavailability and the management of these two interlinked conditions. Adding nitrate/nitrite to drugs that are currently used for managing diabetes (e.g. metformin) and possibly anti-obesity drugs may also enhance their efficacy. PMID- 28804023 TI - Association of serum autoantibodies with pregnancy outcome of patients undergoing first IVF/ICSI treatment: A prospective cohort study. AB - The relevance of antiphospholipid (aPL), antinuclear (ANA) or antithyroid (ATA) antibodies in women undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) are controversial. The present study aims to investigate which autoantibodies are associated with the pregnancy outcome of patients undergoing first IVF/ICSI treatment. A total of 3763 IVF/ICSI patients were recruited from January to December 2015. Forty-five patients positive for aPL presenting adverse outcomes in their first cycle received low-dose aspirin treatment before the second transfer. Logistic regression analyses were performed to assess any association between autoantibodies and IVF/ICSI outcomes. The aCL IgG was significantly associated with live birth rate (OR 0.58, 95% CI 0.36-0.96, p<0.05) and miscarriage rate (OR 2.04, 95% CI 1.23-3.40, p<0.01). The aCL-IgM was associated with miscarriage rate (OR 2.14, 95% CI 1.29-3.54, p<0.01). The abeta2GPI-IgG was associated with implantation rate and clinical pregnancy rate (OR 0.61, 95% CI 0.24-0.96, p<0.05; OR 0.40, 95% CI 0.13-0.87, p<0.05, respectively). After the low-dose aspirin treatment, the live birth rate (37.0% vs. 19.1%, p<0.05) increased significantly in patients with positive for aPL. In contrary, the abeta2GPI-IgM, ANA, anti-thyroglobulin (aTG) and anti thyroperoxidase (aTPO) antibodies had no association with IVF/ICSI outcome. It is suggested that the presence of aCL-IgG, aCL-IgM and abeta2GPI-IgG might exert a detrimental effect on IVF/ICSI outcomes. Low-dose aspirin treatment could be useful for patients positive for these antibodies. Therefore, it is suggested that these antibodies should be assessed prior to IVF/ICSI treatment. PMID- 28804024 TI - Staff working in hospital units with greater social capital experience less work home conflict: Secondary analysis of a cross-sectional study. AB - BACKGROUND: When the interplay between work and private life does not function correctly (work-home conflict), this constitutes a well-known risk factor for poorer health, increased absenteeism and lower work performance. Information about influencing factors of work-home conflict is therefore indispensable in order to avoid it. In this study, we analyse whether a good working atmosphere that fosters mutual trust, support and a 'sense of unity' (organizational social capital) can reduce an employee's conflict between work and private life. OBJECTIVE: This study investigates the link between organizational social capital and work-home conflict in health professionals. DESIGN: This issue was investigated using a cross-sectional study conducted in 2013. PARTICIPANTS AND SETTING: Data from questionnaires completed by physicians and nurses (n=1733) were linked with structural data from 66 neonatal intensive care units in Germany. METHODS: Using multi-level analyses, we investigated associations between organizational social capital at the ward level and work-home conflict at the level of individual employees, taking into account additional structural and individual characteristics. RESULTS: Employees on wards with greater social capital reported significantly less work-home conflict. Our results support the hypothesis that organizational social capital is an important collective resource. CONCLUSION: As such, more attention should be given to establishing a good working atmosphere that fosters mutual trust, support and a 'sense of unity', and this should be encouraged in a targeted fashion. PMID- 28804025 TI - Early seasonal influenza vaccination and delayed influenza peaks - A possible cause of end-of-season outbreaks. PMID- 28804026 TI - Usefulness of serum lactate dehydrogenase/pleural fluid adenosine deaminase ratio for differentiating Mycoplasma pneumoniae parapneumonic effusion and tuberculous pleural effusion. PMID- 28804027 TI - The potential of a portable, point-of-care electronic nose to diagnose tuberculosis. AB - INTRODUCTION: Tuberculosis (TB) is the leading cause of death due to an infectious disease worldwide. Especially in low-income countries, new diagnostic techniques that are accessible, inexpensive and easy-to-use, are needed to shorten transmission time and initiate treatment earlier. OBJECTIVE: We conducted a study with a handheld, point-of-care electronic nose (eNose) device to diagnose TB through exhaled breath. SETTING: This study includes a total of 110 patients and visitors of an expert centre of respiratory diseases in Asuncion, Paraguay. TB diagnosis was established by culture of Mycobacterium tuberculosis complex and compared with the eNose results in two phases. RESULTS: The calibration phase, including only culture confirmed TB cases versus healthy people, demonstrated a sensitivity and specificity of 91% and 93% respectively. The confirmation phase, including all participants, showed a sensitivity of 88% and a specificity of 92%. The eNose showed high acceptance rate among participants, and was easy to operate. CONCLUSION: The eNose resulted in a powerful technique to differentiate between healthy people and TB patients. Its comfort, speed and usability promise great potential in vulnerable groups, in remote areas and hospital settings to triage patients with suspicion of TB. PMID- 28804029 TI - Widefield Endoscopic Mucosal Resection for Treatment of Proximal Esophageal Leukoplakia. PMID- 28804028 TI - Prevalence and treatment outcome of extensively drug-resistant tuberculosis plus additional drug resistance from the National Clinical Center for Tuberculosis in China: A five-year review. AB - OBJECTIVES: The objective of this study was to explore the prevalence and primary clinical outcomes of extensively drug-resistant tuberculosis plus addition resistance to all drug tested (XDR-TB-Plus) between 2011 and 2015 in Beijing Chest Hospital. METHODS: We retrospectively reviewed the drug susceptibility testing (DST) results of clinical Mycobacterium tuberculosis (MTB) strains from TB patients seeking health care in the National Clinical Center for Tuberculosis, between 2011 and 2015. The medical records of patients classified as XDR-TB-Plus were reviewed, including demographic characteristics, treatment regimen, and treatment outcome. RESULTS: Of 9544 MTB isolates, there were 3376 (35.4%), 842 (8.8%) and 61 (0.64%) isolates identified as multidrug resistant tuberculosis (MDR-TB), extensively drug resistant tuberculosis (XDR-TB) and XDR-TB-Plus, respectively. The proportion of XDR-TB showed significant increase from 6.3% in 2011 to 9.1% in 2015 (Chi-square trend 5.94, P = 0.015). Similarly, the proportion of XDR-TB-Plus seemed to increase from 0.46% in 2011 to 0.74% in 2015, while the increasing trend was not significant (Chi-square trend 1.50, P = 0.221). The most frequently prescribed anti-TB drug was moxifloxacin (18/29, 62.1%), followed by protionamide (16/29, 55.2%), clofazimine (15/29, 51.7%), and pyrazinamide (15/29, 51.7%). Patients receiving regimens containing linezolid (LZD) were almost 27 times more likely to have favorable treatment outcome compared with those receiving regimens without LZD [odds ratios = 27.00; 95% CI = 2.50-291.19; P = 0.003]. CONCLUSIONS: In conclusion, our data have demonstrated that the proportion of XDR-TB has significantly increased over the past five years in Beijing Chest Hospital. In addition, the XDR-TB-Plus patients were more likely to reach favorable clinical outcome under the treatment of regimen containing LZD. PMID- 28804030 TI - Development and Validation of Trigger Algorithms to Identify Delays in Diagnostic Evaluation of Gastroenterological Cancer. AB - BACKGROUND & AIMS: Colorectal cancer (CRC) and hepatocellular cancer (HCC) are common causes of death and morbidity, and patients benefit from early detection. However, delays in follow-up of suspicious findings are common, and methods to efficiently detect such delays are needed. We developed, refined, and tested trigger algorithms that identify patients with delayed follow-up evaluation of findings suspicious of CRC or HCC. METHODS: We developed and validated two trigger algorithms that detect delays in diagnostic evaluation of CRC and HCC using laboratory, diagnosis, procedure, and referral codes from the Department of Veteran Affairs National Corporate Data Warehouse. The algorithm initially identified patients with positive test results for iron deficiency anemia or fecal immunochemical test (for CRC) and elevated alpha-fetoprotein results (for HCC). Our algorithm then excluded patients for whom follow-up evaluation was unnecessary, such as patients with a terminal illness or those who had already completed a follow-up evaluation within 60 days. Clinicians reviewed samples of both delayed and nondelayed records, and review data were used to calculate trigger performance. RESULTS: We applied the algorithm for CRC to 245,158 patients seen from January 1, 2013, through December 31, 2013 and identified 1073 patients with delayed follow up. In a review of 400 randomly selected records, we found that our algorithm identified patients with delayed follow-up with a positive predictive value of 56.0% (95% CI, 51.0%-61.0%). We applied the algorithm for HCC to 333,828 patients seen from January 1, 2011 through December 31, 2014, and identified 130 patients with delayed follow-up. During manual review of all 130 records, we found that our algorithm identified patients with delayed follow-up with a positive predictive value of 82.3% (95% CI, 74.4% 88.2%). When we extrapolated the findings to all patients with abnormal results, the algorithm identified patients with delayed follow-up evaluation for CRC with 68.6% sensitivity (95% CI, 65.4%-71.6%) and 81.1% specificity (95% CI, 79.5% 82.6%); it identified patients with delayed follow-up evaluation for HCC with 89.1% sensitivity (95% CI, 81.8%-93.8%) and 96.5% specificity (95% CI, 94.8% 97.7%). Compared to nonselective methods, use of the algorithm reduced the number of records required for review to identify a delay by more than 99%. CONCLUSIONS: Using data from the Veterans Affairs electronic health record database, we developed an algorithm that greatly reduces the number of record reviews necessary to identify delays in follow-up evaluations for patients with suspected CRC or HCC. This approach offers a more efficient method to identify delayed diagnostic evaluation of gastroenterological cancers. PMID- 28804031 TI - Effects of a Brief Educational Program on Optimization of Fluoroscopy to Minimize Radiation Exposure During Endoscopic Retrograde Cholangiopancreatography. AB - BACKGROUND & AIMS: Fluoroscopy during endoscopic retrograde cholangiopancreatography (ERCP) is increasingly performed by therapeutic endoscopists, many of whom have not received formal training in modulating fluoroscopy use to minimize radiation exposure. Exposure to ionizing radiation has significant health consequences for patients and endoscopists. We aimed to evaluate whether a 20-minute educational intervention for endoscopists would improve use of fluoroscopy and decrease ERCP-associated exposure to radiation for patients. METHODS: We collected data from 583 ERCPs, performed in California from June 2010 through November 2012; 331 were performed at baseline and 252 following endoscopist education. The educational intervention comprised a 20-minute video explaining best practices for fluoroscopy, coupled with implementation of a formal fluoroscopy time-out protocol before the ERCP was performed. Our primary outcome was the effect of the educational intervention on direct and surrogate markers of patient radiation exposure associated with ERCPs performed by high volume endoscopists (HVEs) (200 or more ERCPs/year) vs low-volume endoscopists (LVEs) (fewer than 200 ERCPs/year). RESULTS: At baseline, total radiation dose and dose area product were significantly higher for LVEs, but there was no significant difference between HVEs and LVEs following education. Education was associated with significant reductions in median fluoroscopy time (48% reduction for HVEs vs 30% reduction for LVEs), total radiation dose (28% reduction for HVEs vs 52% for LVEs) and dose area product (35% reduction for HVEs vs 48% reduction for LVEs). All endoscopists significantly increased their use of low magnification and collimation following education. CONCLUSIONS: A 20-minute educational program with emphasis on ideal use of modifiable fluoroscopy machine settings results in an immediate and significant reduction in ERCP-associated patient radiation exposure for low-volume and high-volume endoscopists. Training programs should consider radiation education for advanced endoscopy fellows. PMID- 28804032 TI - Risk of Pancreatitis Following Treatment of Irritable Bowel Syndrome With Eluxadoline. AB - BACKGROUND & AIMS: The Food and Drug Administration approved eluxadoline for the treatment of diarrhea-predominant irritable bowel syndrome despite cases of pancreatitis in early stage trials. We investigated the frequency of pancreatitis attributed to eluxadoline in postmarketing surveillance. METHODS: We extracted reports on eluxadoline submitted to the Federal Adverse Event Reporting System from January through September 2016. We collected data on patient age and sex, event date, reporting entity (consumer, physician, pharmacist, legal worker, or other), medications, dosages, presumed role in the event (coinciding, primary, or secondary suspect), treatment indication, and outcome (death, life threatening, hospitalization, disability, or other).We compared data for eluxadoline with data from antidiarrheals, oxycodone, and rifaximin using the kappa2 test, Kruskal Wallis rank test, and analysis of variance; findings with P < .05 were considered statistically significant. RESULTS: Pancreatitis accounted for 16.4% of the 597 reports of adverse events linked to eluxadoline; 53 cases required hospitalization. Pancreatitis was listed as treatment complication of other agents in significantly lower proportions of cases (loperamide, 0.3%; diphenoxylate, 0.4%; oxycodone, 0.2%; rifaximin, 0.5%), with 75% of these submissions not considering the agent as causal. CONCLUSIONS: In an analysis of reports on eluxadoline submitted to the Federal Adverse Event Reporting System, we confirmed a previously reported risk of pancreatitis associated with eluxadoline. The need for hospitalization in at least half of these instances and a recent report of 2 fatalities should prompt reassessments of the agent's risk benefit ratio. PMID- 28804033 TI - A Case of a Giant Fecaloma. PMID- 28804034 TI - Silymarin for Treatment of Nonalcoholic Steatohepatitis-A New Kid on the Block? PMID- 28804035 TI - High Rate of Mortality More Than 30 Days After Upper Gastrointestinal Bleeding. PMID- 28804036 TI - Evolutionary analysis of Chironius snakes unveils cryptic diversity and provides clues to diversification in the Neotropics. AB - Recent hypotheses to explain tropical diversity involves the Neogene and Quaternary geoclimatic dynamics, but the absence of unambiguous data permitting the choice between alternative hypotheses makes a general theory for the origin of tropical biodiversity far to be achieved. The occurrence of Chironius snakes in well-defined biogeographical regions led us to adopt Chironius as a model to unveil patterns of vertebrate diversification in the Neotropics. Here, we used molecular markers and records on geographic distribution to investigate Chironius evolution and, subsequently, providing hints on diversification in the Neotropics. To avoid analyzing nominal species that do not constitute exclusive evolutionary lineages, we firstly conducted a species delimitation study prior to carrying out the species distribution modeling analysis. We generated 161 sequences of 12S, 16S, c-mos and rag2 for 15 species and 50 specimens, and included additional data from GenBank yielding a matrix of 137 terminals, and performed the following evolutionary analyses: inference of a concatenated gene tree, estimation of gene divergence times, inference of the coalescent-based phylogeny of Chironius, estimation of effective population sizes and modeling potential distribution of species across the last millennia. We tested for species boundaries within Chironius by implementing a coalescent-based Bayesian species delimitation approach. Our analyses supported the monophyly of Chironius, although our findings underscored cryptic candidate species in C. flavolineatus and C. exoletus. The inferred timetree suggested that Chironius snakes have evolved in the early Miocene (ca. 20.2Mya) and began to diversify from the late Miocene to the early Pliocene, values that are much older than previously reported. Following genetic divergence of virtually all extant Chironius species investigated, the effective sizes of the populations have expanded when compared to their MRCAs. The evolutionary and SDM data from C. brazili and C. diamantina provided additional evidence of the origin of species in the Neotropics. We argue that temperature, instead of altitude, has been the major driving factor in the evolution of both species, and thus we present a case for the consequences of global warming. PMID- 28804037 TI - The longitudinal effects of early developmental cadmium exposure on conditioned place preference and cardiovascular physiology in zebrafish. AB - Cadmium (Cd) is a naturally occurring trace metal that is widely considered to be highly toxic to aquatic organisms and a significant health hazard to humans (Amzal et al., 2009; Bernhoft 2013; Burger, 2008; Satarug et al., 2009). The zebrafish (Danio rerio) has been used as a model organism for toxicological studies with Cd (Banni et al., 2011; Blechinger et al., 2007; Chow et al., 2009; Chow et al., 2008; Favorito et al., 2011; Kusch et al., 2007; Matz et al., 2007; Wang and Gallagher, 2013). We asked what the lasting longitudinal effects would be from short early developmental Cd exposure (between 24 and 96h post fertilization) in a range that larvae might experience living atop typical Cd containing surface sediments (0, 0.01, 0.1, 1.0 and 10MUM CdCl2: 1.124, 11.24, 112.4 and 1124MUg Cd/L). The goal of this exposure window was to specifically target secondary neurogenesis, monoaminergic differentiation and cardiovascular development, without affecting earlier patterning processes. Developmental abnormalities in body size and CNS morphology increased with concentration, but were statistically significant only at the highest concentration used (10MUM). Heart rate for Cd-treated larvae increased with concentration, and was significant even at the lowest concentration used (0.01MUM). Longitudinal survival was significantly lower for fish developmentally exposed to the highest concentration. Except for brain weight, overall morphology was not affected by developmental Cd exposure. However, developmental exposure to lower concentrations of Cd (0.01, 0.1, and 1.0MUM) progressively lowered cocaine induced conditioned place preference (CPP), used to measure function of the reward pathways in the brain. Baseline heart rate was significantly lower in longitudinal fish developmentally exposed to 1.0MUM Cd. Cardiovascular response to isoproterenol, a potent beta-adrenergic agonist, in longitudinal adults was also significantly affected by developmental exposure to Cd at low doses (0.01, 0.1 and 1.0MUM). Surviving longitudinal adult fish exposed to the highest concentration of Cd showed normal CPP and cardiovascular physiology. The data imply that even lower exposure concentrations can potentially result in fitness affecting parameters without affecting survival in a laboratory setting. PMID- 28804038 TI - Subependymomas Are Low-Grade Heterogeneous Glial Neoplasms Defined by Subventricular Zone Lineage Markers. AB - OBJECTIVE: Subependymomas are infrequent, low-grade gliomas associated with the ventricular system and the spinal cord. Little is known about the origin and natural history of these slow-growing lesions. METHODS: We identified all patients with pathologically proven subependymomas presenting to our institution between 1998 and 2016. We retrospectively reviewed clinical, radiographic, histologic, and surgical outcomes data in all patients who underwent surgical resection. Immunohistochemical analyses for cell lineage markers were performed. RESULTS: A total of 31 patients with pathologically proven subependymomas were identified. Of these, 7 asymptomatic lesions were discovered at autopsy and 24 symptomatic cases were treated surgically. There were 15 (48%) lateral ventricle tumors, 11 (35%) fourth ventricular tumors, and 5 (17%) spinal tumors. Symptomatic intracranial lesions most commonly presented with headaches and balance and gait abnormalities. Subependymomas had no distinguishing radiographic features that provided definitive preoperative diagnosis. At last follow-up, no patient treated surgically experienced recurrence. Immunohistochemical analyses demonstrated a diffusely GFAP-positive glial neoplasm with mixed populations of cells that were variably positive for Olig2, NHERF1, Sox2, and CD44. The Ki67 proliferation index was generally low (<1% in many of the tumors). CONCLUSIONS: Subependymomas demonstrate mixed populations of cells expressing glial lineage markers as well as putative stem cell markers, suggesting these tumors may arise from multipotent glial progenitors that reside in the subventricular zone. Definitive diagnosis requires surgical sampling. Although the clinical course of subependymomas appears benign, the inability to radiographically diagnose these lesions, and the possibility of an alternative malignant lesion support a low threshold for early and safe maximal resection. PMID- 28804039 TI - Surgical Decompression for Chiari Malformation Type I: An Age-Based Outcomes Study Based on the Chicago Chiari Outcome Scale. AB - BACKGROUND: There is currently inadequate evidence on the efficacy of surgical decompression for Chiari malformation type I (CM1) in different age groups of patients. In this study, we compared postoperative outcomes across 3 different age groups using the Chicago Chiari Outcome Scale (CCOS). METHODS: A total of 144 patients who underwent Chiari decompression at our institution between 2008 and 2014 were divided into 3 groups: group A, children age 0-18 years; group B, younger adults age 19-40 years; and group C, older adults, age 41+ years. Patient outcomes were assigned a numerical value based on the CCOS and subjected to statistical analysis. Direct comparisons were made across the 3 age groups. RESULTS: The mean overall score was 14.0 over a mean follow-up of 27.2 months. All 3 groups demonstrated clinical improvement following Chiari decompression; however, group A demonstrated significantly better postoperative improvements than groups B and C in total CCOS scores (7.8% and 12.2%, respectively; P < 0.001) and all the component scores except complications. Group B was not significantly different from group C in total score or any of the component scores. There was a logarithmic relationship between age and outcome (R2 = 0.64), in which the outcome scores experienced an initial decline with increasing age but leveled off by early adulthood. CONCLUSIONS: A direct comparison among the age groups revealed a negative age effect on surgical decompression outcomes in CM1 patients. Children performed significantly better than younger and older adults. This finding supports early surgical intervention for symptomatic pediatric patients to achieve long-term surgical benefit. PMID- 28804040 TI - Significance of the Tentorial Alignment in Protecting the Occipital Lobe with the Poppen Approach for Tentorial or Pineal Area Meningiomas. AB - OBJECTIVE: We aimed to identify the factors that can predict the risk of occipital lobe damage preoperatively when resecting tumors located at the tentorial or pineal regions with the occipital-transtentorial approach (Poppen approach). METHODS: In 27 consecutive patients who underwent tumor resection with the Poppen approach for tentorial or pineal region meningiomas, the following morphologic parameters were assessed on a preoperative magnetic resonance imaging: (1) tentorial angle, (2) tentorial length, and (3) the shortest distance from the confluence of the sinus to the tumor. These parameters, together with tumor size, texture, and resection extent, were correlated with occipital lobe damage by using the one-way analysis of variance, chi2, or Fisher's exact tests. RESULTS: The mean value was 55.3 degrees +/- 5.6 degrees (range, 45 degrees -66 degrees ) for the tentorial angle, which was significantly associated with the occipital lobe damage grades (P = 0.008), but this was not the case for the tentorial length (P = 0.802) and the shortest distance from the confluence of the sinus to the tumor (P = 0.695). Interestingly, age was also strongly associated with occipital lobe damage risk (P = 0.020). The patients in the subgroup with no occipital damage (grade 4) were the youngest (aged 47.3 years), compared with other grades, with age of 58.0 years for grade 1, 54.3 years for grade 2, and 58.6 years for grade 3. These 2 parameters were also significant after multivariate analysis. No correlation was observed between either tumor nature or the extent of resection and damage grades. CONCLUSIONS: The risk of occipital lobe damage increases in the presence of a steep tentorial angle during the Poppen approach for tentorial or pineal area tumors. Awareness of such anatomic features preoperatively is important for minimizing operative complications. PMID- 28804041 TI - Cell Therapy as a New Approach to the Treatment of Posttraumatic Syringomyelia. AB - BACKGROUND: Cell transplantation with autologous bone marrow-derived mesenchymal stromal cells (MSCs) seems to be a therapeutic promise for patients with established spinal cord injury, achieving improvement in their quality of life, but there is no experience with the application of this type of cell therapy in patients suffering posttraumatic syringomyelia. OBJECTIVE: To study the possible utility of cell therapy with autologous MSCs in posttraumatic syringomyelia. METHODS: A 40-year-old man with complete paraplegia since 1991 as a consequence of a Th4 vertebral fracture showed a great posttraumatic syringomyelia that extended up to C2 vertebral level, without signs of recent worsening. Autologous MSCs (150 * 106) were injected into the syrinx, without drainage or aspiration. RESULTS: One year after cell therapy, syrinx was reduced without collapse of cervical spinal cord. During the course of follow-up, clear clinical improvement was observed, mainly in sphincter dysfunction. CONCLUSIONS: Injection of MSCs in the syrinx of posttraumatic syringomyelia is safe and is associated with clinical and neuroimaging improvement. The possibility of cell therapy as a new approach to posttraumatic syringomyelia, or even for idiopathic syringomyelia, is an open door that requires further study. PMID- 28804042 TI - Four-Hand Suction-Irrigation Technique Leads to Gross Total Resection and Long Term Progression-Free Survival in Fourth Ventricular Ependymoma. AB - BACKGROUND: Gross total resection is often avoided in posterior fossa ependymoma surgery because of the fear of permanent neurologic deficits after operation. However, the extent of resection is a major prognostic factor for progression free and overall survival. This study evaluates the outcome of posterior fossa ependymoma gross total resection in adult patients using a 4-hand suction irrigation technique at the floor of the fourth ventricle. METHODS: All surgical procedures for posterior fossa ependymomas performed since 2001 in the Department of Neurosurgery, University Medicine Greifswald were analyzed. RESULTS: Eight patients (2 women and 6 men; mean age, 41.9 years; range, 29-56 years) underwent surgery for posterior fossa ependymoma. All tumors were World Health Organization grade II. Tumor adherence was found to be in the caudal rhomboid fossa (between the obex and striae medullare, but below the facial colliculus) in all patients. The 4-hand suction-irrigation technique led to gross total resection in all patients (100%), without significant permanent neurologic deficits after surgery. None of the patients got further treatment (chemotherapy, radiation therapy, or second surgery). In none of these patients, tumor recurrence was seen on magnetic resonance imaging after a mean follow-up of 102 months (range, 14-181 months). CONCLUSIONS: Long-term progression-free survival in adult patients suffering from posterior fossa ependymoma is possible by gross total resection without adjuvant radio- or chemotherapy. By careful bimanual microsurgical dissection using the 4 hand suction-irrigation technique and avoidance of bipolar coagulation on the floor of the fourth ventricle, the risk for permanent neurologic deficits is low. PMID- 28804043 TI - The Top-100 Most-Cited Articles on Meningioma. AB - BACKGROUND: There is an abundance of articles published on meningioma. OBJECTIVE: To identify the 100 most-cited articles on meningioma and to perform a bibliometric analysis. METHODS: In November 2016, we performed a title-specific search of the Scopus database using "meningioma" as our search query term without publication date restrictions. The top 100 most cited articles were obtained and reviewed. RESULTS: The top 100 most cited articles received a mean 198 citations per paper. Publication dates ranged from 1953 to 2013; most articles were published between 1994 and 2003, with 50 articles published during that period. NEUROSURGERY published the greatest number of top cited articles (22 of 100). The most frequent study categories were laboratorial studies (31 of 100) and natural history studies (28 of 100). Nonoperative management studies were twice as common as operative management studies in the top-cited articles. Neurosurgery as a specialty contributed to 50% of the top 100 list. The most contributing institute was the Mayo Clinic (11%); the majority of the top cited articles originated in the United States (53%). CONCLUSIONS: We identified the top 100 most-cited articles on meningioma that may be considered significant and impactful works, as well as the most noteworthy. In addition, we recognized the historical development and advances in meningioma research and the important contributions of various authors, specialty fields, and countries. A large proportion of the most cited articles were written by authors other than neurosurgeons, and many of these articles were published in non-neurosurgery journals. PMID- 28804044 TI - Real-Time Ultrasound Doppler Enhances Precision in Image-Guided Approaches to the Cerebellopontine Angle. AB - OBJECTIVE: To evaluate efficacy and reliability of intraoperative Doppler sonography in localizing the transverse and sigmoid sinuses during lateral suboccipital craniotomy. METHODS: A 16-Mhz intraoperative micro-Doppler ultrasound (16Mhz, Multi-Dop pro, Compumedics, Singen, Germany) was applied to detect the medial border of the sigmoid sinus and the inferior border of the transverse sinus in 25 patients. Micro-Doppler measurements were compared with magnetic resonance- and computed tomography-based image guidance (Kolibri, Brainlab, Munich, Germany). Visual detectability of the sinuses with the operating microscope was also documented. RESULTS: Inadvertent incision of the transverse or sigmoid sinuses did not occur in any patient when the 2 localizing methods have been used in combination. The mean mismatch of image-guided system and micro-Doppler was 2.64 mm (range, 0-6 mm; standard deviation, 1.55 mm). With the microscope the transverse sinus was invisible in 7 patients, the sigmoid sinus was visually undetectable in 1 case. The micro-Doppler indicated blood flow outside the visible borders of the sinuses in 5 patients. CONCLUSIONS: A combination of image-guidance and micro-Doppler enhances the accuracy in localizing the margins of the transverse and sigmoid sinuses using the retrosigmoid approach, thus preventing inadvertent injury. The method could potentially be applied during other craniotomies involving the exposure of a venous sinus. PMID- 28804045 TI - Unusual Magnetic Resonance Imaging Findings of a Glioblastoma Arising During Treatment with Lenvatinib for Thyroid Cancer. AB - BACKGROUND: Glioblastoma (GBM) is a lesion radiologically characterized by magnetic resonance imaging findings, such as ring enhancement with extensive perifocal edema and a butterfly appearance extending into the bilateral lobes. However, these characteristic findings could be changed by antiangiogenic therapy, with decreased contrast enhancement and improved perifocal edema. Herein, we report a case of GBM that arose during treatment with a tyrosine kinase inhibitor for another cancer. CASE DESCRIPTION: A 57-year-old man presented with seizures. Until the seizure onset, he had been treated with the multireceptor tyrosine kinase inhibitor lenvatinib for 4 years for thyroid cancer and its metastasis to the thoracic vertebral body. Magnetic resonance imaging revealed a slightly high intensity lesion in the left frontal base area on T2 weighted or fluid-attenuated inversion recovery images, and the lesion showed only faint enhancement on T1-weighted images after gadolinium administration. Total resection was performed and the histopathologic diagnosis was GBM. However, grade IV histology was observed in only a limited area, and most of the specimen showed lower grade histology with moderate vascularization that lacked microvascular proliferation. CONCLUSIONS: Lenvatinib, which is antiangiogenic, might have affected the radiologic characteristics, as well as the pathology of the tumor. Brain tumors arising during treatment with receptor tyrosine kinases for other cancers could show atypical imaging findings. PMID- 28804046 TI - Power training using pneumatic machines vs. plate-loaded machines to improve muscle power in older adults. AB - OBJECTIVES: Power training has been shown to be more effective than conventional resistance training for improving physical function in older adults; however, most trials have used pneumatic machines during training. Considering that the general public typically has access to plate-loaded machines, the effectiveness and safety of power training using plate-loaded machines compared to pneumatic machines is an important consideration. The purpose of this investigation was to compare the effects of high-velocity training using pneumatic machines (Pn) versus standard plate-loaded machines (PL). METHODS: Independently-living older adults, 60years or older were randomized into two groups: pneumatic machine (Pn, n=19) and plate-loaded machine (PL, n=17). After 12weeks of high-velocity training twice per week, groups were analyzed using an intention-to-treat approach. Primary outcomes were lower body power measured using a linear transducer and upper body power using medicine ball throw. Secondary outcomes included lower and upper body muscle muscle strength, the Physical Performance Battery (PPB), gallon jug test, the timed up-and-go test, and self-reported function using the Patient Reported Outcomes Measurement Information System (PROMIS) and an online video questionnaire. Outcome assessors were blinded to group membership. RESULTS: Lower body power significantly improved in both groups (Pn: 19%, PL: 31%), with no significant difference between the groups (Cohen's d=0.4, 95% CI (-1.1, 0.3)). Upper body power significantly improved only in the PL group, but showed no significant difference between the groups (Pn: 3%, PL: 6%). For balance, there was a significant difference between the groups favoring the Pn group (d=0.7, 95% CI (0.1, 1.4)); however, there were no statistically significant differences between groups for PPB, gallon jug transfer, muscle muscle strength, timed up-and-go or self-reported function. No serious adverse events were reported in either of the groups. CONCLUSIONS: Pneumatic and plate loaded machines were effective in improving lower body power and physical function in older adults. The results suggest that power training can be safely and effectively performed by older adults using either pneumatic or plate-loaded machines. PMID- 28804047 TI - Effect of resistance training volume on walking speed performance in postmenopausal women: A randomized controlled trial. AB - : Low muscle strength and high abdominal fatness play an important role in fast and usual walking speeds decrement in postmenopausal women (PW). Low-volume resistance training (RT) improves muscle strength. However, high-volume RT has shown to improve muscle strength and abdominal fatness in PW. Thus, high-volume RT would elicit greater improvement in fast and usual walking speeds than low volume RT. OBJECTIVE: To confirm whether the high-volume RT is better than the low-volume RT, we performed a randomized controlled trial (clinical trial registration: RBR-8SBBVP) study to investigated the effects of two different RT volumes (three sets vs. six sets) on fast and usual walking speed performances (fast: one-mile walk test and usual: four-meter walk), muscle strength (1RM test), and abdominal fatness (WC - waist circumference; WC/W waist circumference to-weight ratio; WHtR - waist-to-height ratio; ABSI - A body shape index; BRI - body roundness index; CI - conicity index) in PW. METHODS: Thirty-three PW were randomized (simple randomization) in three groups: control group (CT - no exercise), low-volume RT (LV) and high-volume RT (HV). The RT consisted of eight total body exercises at 70% of one repetition maximum for 16weeks performed three times a week. RESULTS: The fast walking speed (6.1% [CI 95% 2.3-9.9]), WC (-4.1% [CI 95% -6.9 to -1.4]), WHtR (-4.2% [CI 95% -7.0 to -1.4]) and BRI (-10.3% [CI 95% -17.3 to -3.4]) improved in the HV when compared to the LV and CT. The WC/W ( 3.7% [CI 95% -6.5 to -0.93]), ABSI (-3.8% [CI 95% -6.5 to -1.2]) and CI (-3.9% [CI 95% -6.6 to -1.3]) improved in the HV when compared to the CT. Muscle strength improved similarly in trained groups (LV: 49.1% [CI 95% 42.5-55.6] and HV: 43.7% [CI 95% 33.0-54.5]) when compared with the CT. No differences were observed in usual walking speed. CONCLUSION: Our results suggest that high-volume RT (six sets) at 70% of 1RM is necessary to promote an improved fast walking speed performance and abdominal fatness in PW. PMID- 28804048 TI - Effects of concurrent and aerobic exercises on postexercise hypotension in elderly hypertensive men. AB - : Despite the fact that simultaneous performance of resistance and aerobic exercises (i.e., concurrent exercise) has become a standard exercise prescription for the elderly, no information is available on its effects on post-exercise hypotension (PEH) in elderly men with hypertension. PURPOSE: To compare the effects of different types of exercise on PEH in elderly men with hypertension. METHODS: Twenty elderly men with essential hypertension participated in three crossover interventions, in random order, and on separate days: a non-exercise control session at seated rest, aerobic exercise performed for 45min, and 45min of concurrent resistance and aerobic exercise consisted of 4 sets of 8 repetitions at 70% 1RM of resistance exercise followed by aerobic exercise on treadmill. After each session, blood pressure (BP) was measured continuously for 1h in the laboratory and for 24h under ambulatory conditions. RESULTS: During the first hour in laboratory, diastolic BP was lower after aerobic (-5mmHg) and concurrent exercise (-6mmHg) in comparison with Control. Day-time diastolic BP was significantly lower after aerobic exercise (-7mmHg) when compared to the control. No significant differences were found among the three experimental sessions for night-time and 24-hour diastolic BP, as well as day-time, night-time and 24-hour systolic BP. CONCLUSION: Concurrent exercise produced acute PEH similar to aerobic exercise but such effect did not last as long as aerobic exercise in elderly patients with essential hypertension. PMID- 28804049 TI - A new method of SC image processing for confluence estimation. AB - Stem cells images are a strong instrument in the estimation of confluency during their culturing for therapeutic processes. Various laboratory conditions, such as lighting, cell container support and image acquisition equipment, effect on the image quality, subsequently on the estimation efficiency. This paper describes an efficient image processing method for cell pattern recognition and morphological analysis of images that were affected by uneven background. The proposed algorithm for enhancing the image is based on coupling a novel image denoising method through BM3D filter with an adaptive thresholding technique for improving the uneven background. This algorithm works well to provide a faster, easier, and more reliable method than manual measurement for the confluency assessment of stem cell cultures. The present scheme proves to be valid for the prediction of the confluency and growth of stem cells at early stages for tissue engineering in reparatory clinical surgery. The method used in this paper is capable of processing the image of the cells, which have already contained various defects due to either personnel mishandling or microscope limitations. Therefore, it provides proper information even out of the worst original images available. PMID- 28804050 TI - Diagnostic Errors in Primary Care Pediatrics: Project RedDE. AB - OBJECTIVE: Diagnostic errors (DEs), which encompass failures of accuracy, timeliness, or patient communication, cause appreciable morbidity but are understudied in pediatrics. Pediatricians have expressed interest in reducing high-frequency/subacute DEs, but their epidemiology remains unknown. The objective of this study was to investigate the frequency of two high frequency/subacute DEs and one missed opportunity for diagnosis (MOD) in primary care pediatrics. METHODS: As part of a national quality improvement collaborative, 25 primary care pediatric practices were randomized to collect 5 months of retrospective data on one DE or MOD: elevated blood pressure (BP) and abnormal laboratory values (DEs), or adolescent depression evaluation (MOD). Relationships between DE or MOD proportions and patient age, gender, and insurance status were explored with mixed-effects logistic regression models. RESULTS: DE or MOD rates in pediatric primary care were found to be 54% for patients with elevated BP (n = 389), 11% for patients with abnormal laboratory values (n = 381), and 62% for adolescents with an opportunity to evaluate for depression (n = 400). When examining the number of times a pediatrician may have recognized an abnormal condition but either knowingly or unknowingly did not act according to recommended guidelines, providers did not document recognition of an elevated BP in 51% of patients with elevated BP, and they did not document recognition of an abnormal laboratory value without a delay in 9% of patients with abnormal laboratory values. CONCLUSIONS: DEs and MODs occur at an appreciable frequency in pediatric primary care. These errors may contribute to care delays and patient harm. PMID- 28804051 TI - Development and validation of a novel scale for measuring interpersonal factors underlying injection drug using behaviours among injecting partnerships. AB - BACKGROUND: People who inject drugs with sexual partners or close friends have high rates of syringe/ancillary equipment sharing and HIV and hepatitis C virus (HCV) infection. Although evidence suggests that interpersonal factors underlie these higher risk profiles, there is no quantitative measure of how interpersonal factors operate within injecting relationships. We aimed to develop and validate a quantitative scale to assess levels of injecting drug-related interpersonal factors associated with risky injecting behaviours within injecting partnerships. METHODS: We conducted qualitative interviews with 45 people who inject drugs (PWID) who reported having injecting partners to inform item development, and tested these items in a quantitative study of 140 PWID from San Francisco, USA, to assess internal reliability (Cronbach's alpha) and validity (convergent, and discriminant validity). RESULTS: With results from the qualitative interview data, we developed the Interpersonal Dynamics in Injecting Partnerships (IDIP) scale with 54 final items for 5 subscales of injecting-related interpersonal factors. Exploratory factor analysis revealed 5 factors ("trust", "power", "risk perception", "intimacy", and "cooperation") with eigenvalues of 14.32, 6.18, 3.55, 2.46, and 2.14, explaining 57% of the variance, and indicating good internal reliability (alpha: 0.92-0.68). Strong convergent validity was observed in bivariate logistic regression models where higher levels of trust, intimacy, and cooperation within partnerships were positively associated with partners sharing needles and injecting equipment, whereas higher levels of power and risk perception were negatively associated with partners sharing needles and injecting equipment. CONCLUSIONS: These findings offer strong evidence that the IDIP scale provides a psychometrically sound measure of injecting drug-related interpersonal dynamics. This measurement tool has the potential to facilitate additional investigations into the individual and collective impact of trust, intimacy, power, cooperation, and risk perception on injection drug using behaviours and engagement in HIV and HCV testing and treatment among PWID in a variety of settings. PMID- 28804054 TI - ELMSTREET (Esophageal Lesions during MitraClip uSing TRansEsophageal Echocardiography Trial). AB - AIMS: We aimed to evaluate possible detrimental effects of transoesophageal echocardiography (TEE) on the oesophageal tissue during percutaneous mitral valve repair (PMVR). METHODS AND RESULTS: From March 2014 to July 2015, 186 patients were treated for severe mitral regurgitation with PMVR using the MitraClip system. In 40 patients, oesophago-gastro-duodenoscopy was performed due to symptoms related to the gastrointestinal tract. Based on the procedure duration, patients were classified into group 1 (>60 minutes, n=23) or into group 2 (<60 minutes, n=17), respectively. Oesophageal lesions (OL) were found in 19 patients (group 1: n=17 vs. group 2: n=2, p<0.0001). We observed a change in leucocyte count after the procedure (group 1: +2.00 Gpt/L [SEM+/-0.48] vs. group 2: +0.54 Gpt/L [SEM+/-0.36], p=0.028). This change was more apparent when comparing patients with OL vs. those without (lesions: +2.65 Gpt/L [SEM+/-0.56] vs. no lesions: +0.23 Gpt/L [SEM+/-0.12], p<0.0001). CONCLUSIONS: Prolonged use of TEE during PMVR with a procedure time of longer than 60 minutes increases the risk of oesophageal damage. An exceptional rise of leucocyte count after PMVR may raise suspicion of new oesophageal damage. PMID- 28804053 TI - Leptospirosis on captive wild animals in Latin America. AB - Leptospirosis is a worldwide bacterial infection, being more prevalent in tropical regions. Human beings, domestic animals and wildlife species are susceptible to a wide variety of serovars. Zoos have a great importance in keeping endangered species, increasing populations and accumulating knowledge on these species. Although some studies describe the occurrence of leptospirosis in captivity animals, a systematic review regarding the infection in these animals in tropical areas has never been conducted. Thus, the objective of this study was to systematically gather and analyze data regarding leptospirosis among captive wild animals in Latin America. A total of 141 species were studied, 93 genus, 44 families and 15 orders from three classes. Median seroprevalence ranged from 0 to 52% and predominant serogroups were Canicola and Icterohaemorrhagiae for mammalian, and Sejroe for reptiles. One important outcome is that, when kept on zoos, wildlife is more frequently infected by incidental strains instead of adapted strains. Preventive measures should consider periodic serosurvey of all animal species in captivity, as well as the use of commercial vaccines to reduce leptospiral infection and its hazards. PMID- 28804055 TI - Extensive revascularisation by balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension beyond haemodynamic normalisation. AB - AIMS: Balloon pulmonary angioplasty (BPA) improves hemodynamics and exercise capacity in patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, even after BPA many patients still suffered from exertional dyspnea. Our purpose is to clarify the clinical validity of extensive revascularization by BPA (ERBPA) beyond hemodynamic normalization. METHODS AND RESULTS: 35 CTEPH patients with normalized or borderline mean pulmonary arterial pressure (mPAP) after BPA were retrospectively analyzed. We evaluated the clinical efficacy of ERBPA strategy in 15 patients (ERBPA group) by comparing with the natural course of 20 patients who could be followed without additional BPA (conventional BPA group). ERBPA reduced the number of pulmonary arterial segments with residual stenoses from 11.7+/-0.4 to 5.3+/-0.5 segments. Symptoms, six-minute walking distance, and VE/VCO2 slope were significantly improved in the ERBPA group but not the conventional BPA group, which indicated that this improvement was due to ERBPA and not merely a natural progression after hemodynamic normalization. Complications accompanied with ERBPA were fewer than that of the initial BPA therapy. CONCLUSION: ERBPA targeting residual stenoses can safely ameliorate symptoms and exercise capacity by additional improvement of hemodynamics. The results encourage us to optimize the current BPA goal to be more aggressive. PMID- 28804052 TI - Understanding interactions of formerly incarcerated HIV-positive men and transgender women with substance use treatment, medical, and criminal justice systems. AB - BACKGROUND: Low levels of medical care engagement have been noted for HIV positive people leaving systems of incarceration in the United States. Substance misuse frequently co-occurs with criminal justice involvement in individuals who are living with HIV. METHODS: We analyzed data from in-depth interviews with 19 HIV-positive individuals who were currently or formerly incarcerated in order to elucidate challenges faced in accessing care and maintaining HIV treatment regimens when cycling out of (and often back into) custody. Our thematic analysis used an ecosocial framework to describe participants' shifts between substance use treatment, medical care, and criminal justice systems. RESULTS: Dominant themes included the dramatic increase in HIV-treatment-related autonomy required following release from jail because of differences in care delivery between custody-based and community-based care systems; the important, but temporary stabilization provided by residential substance use treatment programmes; and the inconsistency of substance use treatment approaches with chronic care models of disease management. CONCLUSION: Enhanced integration of criminal justice, medical care, and substance use treatment institutions in planning for reentry of HIV populations may ease the impact of the dramatic shifts in context that often dissuade linkage and retention. This integration should include coordination with custody release processes, periodic assessments for active substance misuse in HIV treatment settings, support for (re)establishing health-promoting social networks, and options for long-term, residential substance use treatment programmes. PMID- 28804056 TI - Transfemoral TAVI using the self-expanding ACURATE neo prosthesis: one-year outcomes of the multicentre "CE-approval cohort". AB - AIMS: The aim of this study was to assess the safety and performance of the ACURATE neo transcatheter heart valve and its transfemoral delivery system. METHODS AND RESULTS: The prospective, multicentre "CE-approval cohort" consists of a prospective series of the first 89 patients implanted with the ACURATE neo prosthesis. The primary endpoint was all-cause mortality at 30 days. Mean patient age was 83.7+/-4.4 years and logistic EuroSCORE I was 26.5+/-7.7%. Procedural success was obtained in 84 patients (94.4%). At 30 days, three patients had died, and two major strokes and one reintervention for a ventricular septal defect occurred, leading to a major adverse cardiac and cerebrovascular event (MACCE) rate of 6.7%. Eight patients (10.3%) received a permanent pacemaker. At one year, 20 patients (22.5%) had died and the MACCE rate was 27%. Effective orifice area was 1.76+/-0.34 cm2, and mean gradient 7.5+/-2.8 mmHg. Only three patients (4.5%) had moderate paravalvular regurgitation. NYHA Class III/IV was present in 94.4% of patients at baseline, in 9.9% at 30 days and in 4.5% at one year post procedure. CONCLUSIONS: This first-in-human experience with a novel self expanding heart valve showed low rates of procedural mortality, major stroke and pacemaker implantation, and good performance outcomes. PMID- 28804057 TI - Pressure wire versus microcatheter for FFR measurement: a head-to-head comparison. AB - AIMS: Recently developed microcatheters can be used instead of a pressure wire for fractional flow reserve (FFR) measurement. We sought to assess the haemodynamic and clinical impact of using a larger profile device to measure FFR. METHODS AND RESULTS: Our prospective registry included 77 consecutive patients who underwent invasive FFR measurement of intermediate coronary stenoses between June 2015 and July 2016. FFR values were obtained first using a pressure wire only (FFRw), second using a Navvus microcatheter (FFRMC), and finally using the wire with the microcatheter still in the stenosis (FFRw-MC) during intravenous adenosine infusion. Eighty-eight stenoses were suitable for a thorough head-to head comparison. Mean FFRw (0.83+/-0.08) was significantly higher than mean FFRMC (0.80+/-0.10) and FFRw-MC (0.80+/-0.10). Mean FFRMC and FFRw-MC did not differ significantly. Bland-Altman analysis showed a bias of -0.03+/-0.05 for lower FFRMC values compared to FFRw values. Using a threshold of 0.80 for FFR, the indication for revascularisation would have differed when based on FFRMC versus FFRw in 20/88 (23%) of the lesions and 18/77 (23%) of the patients. CONCLUSIONS: FFR measured using a microcatheter overestimates stenosis severity, leading to erroneous indication for revascularisation in a sizeable proportion of cases. PMID- 28804058 TI - Intravenous enoxaparin anticoagulation in percutaneous left atrial cardiac procedures. AB - AIMS: Percutaneous transcatheter device closure of left atrial appendage (LAA), patent foramen ovale (PFO) and atrial septal defect (ASD) are usually performed with unfractionated heparin anticoagulation. We report a first experience using intravenous (IV) enoxaparin without anticoagulation monitoring in transcatheter structural heart interventions performed in the left atrium (LA). METHODS AND RESULTS: This retrospective, non-controlled study included all consecutive and unselected patients who underwent percutaneous LAA, PFO or ASD closure at a tertiary care centre using IV enoxaparin anticoagulation. The primary composite endpoint was the occurrence of in-hospital death, embolic complications (stroke, transient ischaemic attack, and peripheral arterial embolism) and bleedings defined as type 3a or more according to the BARC definitions. We enrolled 198 patients (mean age 60+/-18 years, 55% male) with an indication for LAA (40.4%), PFO (34.3%) or ASD closure (25.3%). The majority of patients (n=163, 82%) received a single IV enoxaparin dose of 0.5 mg/kg. The composite endpoint occurred in six (3%) patients including four (2%) type 3a bleedings, one (0.5%) transient ischaemic attack and one (0.5%) death from sepsis. CONCLUSIONS: IV enoxaparin without monitoring appears to be a potentially safe and easy-to-use anticoagulation regimen in percutaneous LA cardiac interventions. Further investigations with larger cohorts of patients are warranted. PMID- 28804060 TI - Erratum. PMID- 28804061 TI - Vulnerability. PMID- 28804059 TI - Auxin-Induced Modulation of ETTIN Activity Orchestrates Gene Expression in Arabidopsis. AB - The phytohormone auxin governs crucial developmental decisions throughout the plant life cycle. Auxin signaling is effectuated by auxin response factors (ARFs) whose activity is repressed by Aux/IAA proteins under low auxin levels, but relieved from repression when cellular auxin concentrations increase. ARF3/ETTIN (ETT) is a conserved noncanonical Arabidopsis thaliana ARF that adopts an alternative auxin-sensing mode of translating auxin levels into multiple transcriptional outcomes. However, a mechanistic model for how this auxin dependent modulation of ETT activity regulates gene expression has not yet been elucidated. Here, we take a genome-wide approach to show how ETT controls developmental processes in the Arabidopsis shoot through its auxin-sensing property. Moreover, analysis of direct ETT targets suggests that ETT functions as a central node in coordinating auxin dynamics and plant development and reveals tight feedback regulation at both the transcriptional and protein-interaction levels. Finally, we present an example to demonstrate how auxin sensitivity of ETT-protein interactions can shape the composition of downstream transcriptomes to ensure specific developmental outcomes. These results show that direct effects of auxin on protein factors, such as ETT-TF complexes, comprise an important part of auxin biology and likely contribute to the vast number of biological processes affected by this simple molecule. PMID- 28804062 TI - New York State Medicaid Reforms: Opportunities and Challenges to Improve the Health of Those with Serious Mental Illness. AB - Individuals with serious mental illness face multiple barriers to accessing care and experience disproportionately poor health outcomes. Starting in 2011, New York State undertook a series of major reforms of its Medicaid system designed to address these concerns. In this commentary we review three reforms that aim to change the way New York Medicaid is delivered and experienced, especially for underserved individuals with SMI: Health Homes, Behavioral Health Managed Care, and the Delivery System Reform Incentive Payment Program. We describe the history of these reforms' and their core themes: coordination and collaboration, cross sector collaborations to address social determinants of health, prevention and early intervention, and financial reform. We describe the challenges and opportunities these reforms present for improving the health and health care of Medicaid members with SMI, both in New York and as models for change elsewhere. PMID- 28804063 TI - Separate or United: The Safety Net in the Era of Health Care Integration. AB - Rapid and significant transformation is occurring within the private sector of the health care system with consolidation, integration and the formation of new organizational structures such as Accountable Care Organizations. However, the safety-net systems upon which many patients rely, have remained largely in silos. To focus a spotlight on this issue at a community level we have compared the safety net in Alameda County, California and Denver, Colorado, the former with a safety net largely in silos and the latter an integrated safety net. We have discussed the policy implications and have delineated some of the levers that could be utilized to facilitate greater safety-net integration. PMID- 28804064 TI - Reconciling America's Research Response to Binge Drinking among American Indians and Alaskan Natives. AB - Binge drinking among American Indians and Alaskan Natives is an acute health issue in the United States. The Radcliffe Institute for Advanced Study at Harvard University convened a one-day meeting with North American experts to identify key elements for developing research methodologies to measure treatment outcomes founded in Indigenous cultural ways of knowing. Three were identified: recognize culture as treatment, overcome Western interpretations of research, and apply culturally appropriate research methodologies. Common across the elements is respectful relationship development, which mirrors the efforts of the Canadian Truth and Reconciliation Commission that was established to address the destructive legacy of residential schools among First Nations. Reconciling America's research response to binge drinking among American Indians and Alaskan Natives requires a similar commitment. PMID- 28804065 TI - The Importance of Recognizing Social Vulnerability in Patients during Clinical Practice. AB - Enrolled patients at the free clinic in Dunedin, New Zealand were not just financially poor, but also vulnerable. Large social inequalities are present in the United States and New Zealand. The literature on vulnerability originates predominantly from sociology and public health. This commentary discusses the concept of vulnerability within clinical practice, and makes a case for the improved recognition of patient vulnerability. Vulnerability arises from an individual's susceptibility to harm and their exposure to risks and negative events. Biographical factors commonly regarded as social vulnerability characteristics such as homelessness, teenage parenthood, and childhood abuse do not necessarily lead to negative health and other outcomes because of a direct, causal effect, but because they are indicative of more upstream adversities. Health professionals should address vulnerability not just during clinical encounters, but also at an institutional and policy level. PMID- 28804066 TI - Like Pulling Teeth: Expanding the Oral Health Workforce by Training Physicians in Dental Extractions. AB - In the United States, vulnerable populations at highest risk for poor oral health are more likely to visit a physician than a dentist. Patients in acute dental pain often present to hospital emergency departments or primary care offices where only palliative care is available. While numerous measures to improve oral health access in the United States are necessary, the authors propose that physician training incorporate techniques in dental diagnosis and primary dental care, including extraction where indicated, to allow providers to deliver definitive dental measures to patients unable to access the dental health care system. These skills will allow primary care providers to improve oral health, and ultimately strengthen ties to oral health providers that will improve patient care. PMID- 28804068 TI - Universal Design for Underserved Populations: Person-Centered, Recovery-Oriented and Trauma Informed. AB - Person-centered care has yet to be widely implemented in health care settings, a circumstance that disproportionately affects individuals with behavioral health disorders and those with trauma histories. A need exists for a universal approach to care that encompasses compassionate, collaborative relationships between providers and service users. Person-centered care, enhanced by recovery-oriented care and trauma-informed care, forms the basis for a universal approach to health care. For this paper, we adopted a modified Delphi method to establish consensus on a set of basic principles and practices for developing a universal design based on these three frameworks. We used a two-stage process to arrive at guidelines for use in health and human service settings by: 1) convening an expert panel to draft guidelines; and 2) conducting an online survey of multidisciplinary experts to refine the guidelines. We conclude with recommendations for implementation. PMID- 28804067 TI - Patient Navigation Program for Colorectal Cancer Screening in Chinese Americans at an Urban Community Health Center: Lessons Learned. AB - Colorectal cancer is a major cause of cancer-related deaths in Asian Americans, yet Asian Americans have the lowest colorectal cancer screening rates in New York City. The Charles B. Wang Community Health Center implemented a patient navigation program to increase colorectal cancer screening. This report describes the lessons learned from the program. PMID- 28804069 TI - Health Insurance Coverage among Puerto Rican Adults in Same-Sex Relationships. AB - OBJECTIVE: The primary objectives of this study were to measure and compare health insurance coverage between nonelderly Puerto Rican adults in cohabiting same-sex relationships and their counterparts in cohabiting different-sex relationships. METHODS: This study used data from the 2008-2014 Puerto Rican Community Survey on nonelderly adults (18-64 years) in cohabiting same-sex (n=274) and different-sex (n=58,128) relationships. Multinomial logistic regression models estimated differences in primary source of health insurance while controlling for key demographic and socioeconomic characteristics. RESULTS: Compared with men in different-sex relationships, men in same-sex relationships were less likely to have employer-sponsored insurance (ESI). Women in same-sex relationships were less likely than others to have ESI, insurance purchased directly from an insurer, and public health insurance after controlling for socio demographic factors. CONCLUSIONS: Employment-based discrimination and policy barriers may have prevented same-sex couples from enjoying the full benefits associated with marriage and cohabitation in Puerto Rico, including employer sponsored health insurance. PMID- 28804070 TI - Evaluation Activities and Influences at the Intersection of Medical and Social Services. AB - Despite a growing national interest in health care-based strategies focused on patients' social determinants of health (SDH), little has been compiled about the impacts of SDH interventions undertaken in clinical settings. To understand better what is known in this area and incentives and barriers to related research, we conducted 30 semi-structured interviews with leaders and researchers in for-and non-profit organizations developing interventions to bridge health and social service delivery. Key informants described evaluation activities primarily concentrated on program design and implementation, and less commonly on impact evaluations and dissemination research. A diversity of outcome variables being used in intervention research limits the ability to draw conclusions about comparative effectiveness. Major barriers to advancing effective research on these topics relate to confusion around ownership of the SDH space within the health care sector. PMID- 28804071 TI - Iatrogenic Injury among the Aboriginal and Total Populations of British Columbia, Canada, 1991-2010: Inequities Associated with Ethnicity and Socioeconomic Status. AB - PURPOSE: Measure population health impact, and socioeconomic, geographic, and ethnic predictors of iatrogenic injury. METHODS: Within three groups (total population, Aboriginal off-reserve, and Aboriginal on-reserve) in each of 16 Health Service Delivery Areas (HSDAs) of British Columbia, Canada we calculated crude incidence and Standardized Relative Risk (SRR) of hospitalization for iatrogenic injury. We tested hypothesized associations between HSDA census characteristics and SRR, by multivariable regression. RESULTS: Among hospitalizations due to any injury, 22.2% were iatrogenic. Crude rate of iatrogenic injury hospitalization was 20.4 per 10,000 person-years. Aboriginal rate was 24.4 per 10,000 and SRR was 1.57 (1.76 among females, 1.38 among males). Non-metropolitan HSDAs had higher SRRs. The best-fitting regression model was an excellent fit (R=0.836, p<.001) and included education, income, house needs major repairs, population per room, and Aboriginal ethnicity. CONCLUSIONS: Iatrogenic injury has significant population health impact. Aboriginal people, especially females, have higher risk. Ethnicity and socioeconomic factors explain regional disparities. PMID- 28804072 TI - Assessing Culture and Climate of Federally Qualified Health Centers: A Plan for Implementing Behavioral Health Interventions. AB - OBJECTIVE: This study examines organizational factors relating to climate and culture that might facilitate or impede the implementation of evidence-based practices (EBP) targeting behavioral health in federally qualified health centers (FQHCs). METHODS: Employees at six FQHCs participating in an evidence-based quality improvement (EBQI) initiative for mood disorders and alcohol abuse were interviewed (N=32) or surveyed using the Organizational Context Survey (OCS) assessing culture and climate (N=64). RESULTS: The FQHCs scored relatively well on proficiency, a previously established predictor of successful EBP implementation, but also logged high scores on scales assessing rigidity and resistance, which may hinder implementation. Qualitative data contextualized scores on FQHC culture and climate dimensions. CONCLUSIONS: Results suggest that the unique culture of FQHCs may influence implementation of evidence-based behavioral health interventions. PMID- 28804073 TI - Child and Adolescent Mental Disorders and Health Care Disparities: Results from the National Survey of Children's Health, 2011-2012. AB - Parents of children ages 2-17 (N = 85,637) were asked questions related to mental disorders in the 2011-2012 National Survey of Children's Health. Pearson's chi2 test and logistic regression were used to examine sociodemographic differences in the prevalence of mental disorders, mental health service needs, and service use. The lifetime and current prevalence of mental disorders was 21% and 14.8%, respectively. Overall, 7,819 children needed mental health care, representing 9.5% of the total sample; only 61% of them received treatment or counseling. Compared with Hispanics and Blacks, children ages two to five, and children without insurance, Whites, children ages five-11 and 12-17, and children having public insurance had higher odds of service use. Sustained policy initiatives and intervention efforts are needed. PMID- 28804074 TI - Health Quality Measures Addressing Disparities in Culturally and Linguistically Appropriate Services: What are Current Gaps? AB - PURPOSE: Disparities in health care persist among many at-risk groups. This study examines the current state of health quality measures addressing disparities and culturally and linguistically appropriate services (CLAS), and identifies important gaps in existing measures and their implementation. METHODS: We searched key quality reporting databases and websites to identify measures and structural program requirements addressing disparities or CLAS. We also conducted a dozen semi-structured interviews to obtain expert perspectives. RESULTS: Twenty four measures and eight private or public-sector programs with relevant structural requirements were identified. Half the measures focused on language needs. Few measures were used in national reporting programs and adoption of requirements has been limited. Barriers to implementation included lack of data among health plans, lack of health workforce training, and challenges in defining cultural competence. CONCLUSIONS: Future efforts should seek to enhance implementation of existing quality measures addressing disparities and CLAS, and address barriers to their adoption. PMID- 28804076 TI - Head Trauma in Jail and Implications for Chronic Traumatic Encephalopathy in the United States: Case Report and Results of Injury Surveillance in NYC Jails. AB - Because there is no standard reporting of injuries in jails and prisons, the national burden of head trauma during incarceration is unclear. We report on a case of repeated head trauma in the New York City (NYC) jail system, data on the incidence of head trauma and mild traumatic brain injury (mTBI), and compare those findings with national estimates. The case report revealed 64 injurious events over two years, 44% resulting in a head injury and 25% resulting in emergency hospitalization. During the 42 months of this analysis, 10,286 incidents of head trauma occurred in the NYC jail system. Mild TBI occurred in 1,507 of these instances. The rate of head trauma and mTBI was 269.0 and 39.4 per 1,000 person-years, respectively. The lack of reporting head trauma in correctional settings means that national prevalence estimates of these critical health outcomes miss the vulnerable cohort of incarcerated individuals. PMID- 28804075 TI - Do Medical Homes Offer Improved Diabetes Care for Medicaid Enrollees with Co occurring Schizophrenia? AB - PURPOSE: To determine whether Medicaid recipients with co-occurring diabetes and schizophrenia that are medical-home-enrolled are more likely to receive guideline concordant diabetes care than those who are not medical-home-enrolled, controlling for confounders. METHODS: We used administrative data on adult, non dually eligible North Carolina Medicaid beneficiaries with diagnoses of both diabetes and schizophrenia (N= 3,897) for fiscal years 2008-2010. We evaluated the relationship between medical-home-enrollment and receipt of recommended diabetes care reimbursed by Medicaid (lipid profiles, HbA1c tests, medical attention for nephropathy, and eye exams for those over 30), using fixed-effects regression models on person-month level data. RESULTS: There was a statisti-cally significant, positive effect of medical home enrollment on receipt of Medicaid funded eye exams, HbA1c tests, and medical attention for nephropathy, but not receipt of lipid profiles. CONCLUSIONS: For Medicaid enrollees with diabetes and schizophrenia, medical home enrollment is generally associated with greater likelihood of receiving guideline-concordant diabetes care. PMID- 28804077 TI - Vision Screening in Underserved and Vulnerable Populations in Kenya, Africa. AB - Eye and vision disorders are seen as serious health concerns in HIV-positive children. The vision screening project was developed, planned, and implemented as a first-step pilot project to address a dire need for vision care in the high risk HIV-positive child. This field report describes the Eye Camp where 1,349 people were screened as a collaborative endeavor with a non-profit program for HIV/AIDS infected children located in Kenya. PMID- 28804078 TI - Improving Skilled Birth Attendance in Ghana: An Evidence-Based Policy Brief. AB - This commentary has the objective of improving skilled birth attendance in Ghana to reduce maternal and neonatal mortality and morbidity. We have provided evidence of causes of low-skilled birth attendance in Ghana. Physical accessibility of health care, sociocultural factors, economic factors and health care system delivery problems were found as the main underlying causes of low levels of skilled birth attendance in Ghana. The paper provides potential strategies in addressing maternal and child health issues in Ghana. PMID- 28804079 TI - Improving Human Resources for Health means Retaining Health-Workers: Application of the WHO-Recommendations for the Retention of Health-Workers in Rural Northern Nigeria. AB - INTRODUCTION: Nigeria is one of 57 countries with critical shortage of health workers (HWs). Strategies to increase and equitably distribute HWs are critical to the achievement of Health Millennium/Sustainable Development Goals. We describe how three Northern Nigeria states adapted World Health Organisation (WHO)-recommended incentives to attract, recruit, and retain midwives. METHODS: Secondary analysis of data from two surveys assessing midwife motivation, retention, and attrition in Northern Nigeria; and expert consultations. RESULTS: Midwives highlighted financial and non-financial incentives as key factors in their decisions to renew their contracts. Their perspectives informed the consensus positions of health managers, policymakers and heads of institutions, and led to the adaptation of the WHO recommendations into appropriate state specific incentive packages. CONCLUSIONS: The feedback from midwives combined with an expert consultation approach allowed stakeholders to consider and use available evidence to select appropriate incentive packages that offer the greatest potential for helping to address inadequate numbers of rural midwives. PMID- 28804080 TI - Differences in, and Frames of Reference of, Indigenous Australians' Self-rated General and Oral Health. AB - OBJECTIVE: To compare general and oral health perceptions between Indigenous and non-Indigenous Australians and to quantify Indigenous Australian health-related frames of reference. METHODS: A mixed-methods approach was used. The quantitative component comprised data from four convenience studies of Indigenous oral health and one national oral health survey stratified by Indigenous status. Qualitative data with questions pertaining to frames of reference were collected from 19 Indigenous Australian interviews. RESULTS: Among the Indigenous studies, deficits in perceptions of excellent, very good, or good general health and excellent, very good, or good oral health ranged from 10.5% to 43.8%. Among the non Indigenous population, the deficit was 5%. Frames of reference appeared to underpin a biomedical conceptual outlook. CONCLUSION: The deficit in perceived oral health compared with general health was far greater among Indigenous Australians. The frame of reference underpinning Indigenous Australian's perceptions of health reflect those of the general Australian population. PMID- 28804081 TI - Attitudes and Perceptions Towards Access and Use of the Formal Healthcare Sector in Northern Malawi. AB - We evaluated community attitudes, perceptions, and experiences regarding access and use of health care systems in Northern Malawi. Through a qualitative descriptive approach, 12 focus group discussions were conducted in 2014 with community members (n=71) in Mzimba North, Malawi. Data were transcribed and analyzed for major themes. Both formal health care systems and traditional medicine were widely used as complementary. Health care-seeking behavior was governed by previous treatment history and by whether a disease was believed to be biological or spiritual in nature, the latter being best treated with traditional medicine. Barriers to using formal health care included cost, hospital resources/environment, socio-cultural beliefs, and transportation. Transportation was a significant barrier, often linked to increased mortality. Support of local strategies to address transportation, structural approaches to improve hospital capabilities and environment, and community education reconciling traditional beliefs and modern medicine may mitigate access issues and improve use of the health care system. PMID- 28804082 TI - Socioeconomic Disparities in Health Outcomes and Access to Health Care across Three Islands in Comoros. AB - The purpose of this paper is two-fold. First, to give an overview of the size and measure trends in health inequalities in the Comoros islands (Comoros) since 1996. Second, to assess the wide differences in health and health care across rural/urban areas and islands in Comoros, by using available and comparable leading indicators, in order to promote regular monitoring of policy goals. This assessment is aimed at reducing health inequalities and providing adequate or equal access to health care between islands. Data from the Demographic and Health Survey, Multiple Indicators Cluster Surveys from 1996, 2000 and 2012, the World Health Organization, the World Bank, the African Development Bank data sources, were analyzed for a population health-oriented approach characterized by measuring health differences from the population average, taking account of the population size of the social groups on both relative and absolute scales. The results showed that there exist geographic disparities in health in Comoros, mainly in maternal and child health. PMID- 28804083 TI - Vaginal Infections in Haitian Immigrant Women Living in Miami, Florida. AB - OBJECTIVE: To characterize vulvovaginal candidiasis (VC), trichomonas vaginalis (TV), and bacterial vaginosis (BV) among Haitian women living in Miami to identify contributing factors to cervical cancer disparity in this population. METHODS: Using a CBPR framework, 246 Haitian women (ages 21-65) were recruited. Self-collected cervical cytology specimens were analyzed for VC, TV, and BV. RESULTS: The proportion of participants with VC, TV, and BV, were 7.3%, 9.3%, and 19.9%, respectively. CONCLUSION: Haitian women may have a higher prevalence of TV than the general U.S. population, which may increase susceptibility to HPV, the primary cause of cervical cancer. PMID- 28804084 TI - Comparison of Patient Experience between a Practice for Homeless Patients and Other Practices Engaged in a Patient-Centered Medical Home Initiative. AB - Despite its increasing popularity, little is known about the patient-centered medical home (PCMH) model in primary care settings serving homeless populations. Our objective was to understand how patient experience differs between a PCMH demonstration practice designed for homeless people in Massachusetts and other practices participating in the same statewide initiative. The study population included 194 homeless patients and 1,868 patients from comparison practices. Patient experience was compared on key measures of patient-centeredness, while applying case-mix adjustment to control for sociodemographic and clinical factors. The practice for homeless patients scored higher than the comparison group on self-management support and behavioral health integration, while being equivalent on three other measures. Potential areas for improvement include measures related to communication, front desk staff, and timely appointments. We discuss possible explanations for the observed pattern of results in the context of the unique challenges faced by a practice designed to serve individuals experiencing homelessness. PMID- 28804085 TI - D/deaf Breast Cancer Survivors: Their Experiences and Knowledge. AB - D/deaf cancer patients and survivors, including D/deaf women diagnosed with breast cancer, have been largely overlooked in the research literature. To gain preliminary information we included 29 D/deaf breast cancer survivors in a larger program of community-academic research aimed at evaluating and addressing the breast cancer educational needs of D/deaf women. Seven D/deaf breast cancer survivors completed in-depth signed (American Sign Language) interviews and another 22 survivors completed a written/signed survey. Both studies revealed significant gaps in breast cancer knowledge among these women despite their having multiple contacts with medical providers, communication challenges in clinical settings, and inadequate access to support and advocacy services during diagnosis, treatment, and recovery. Research is needed to develop tailored cancer control programs for this population and to identify strategies for disseminating to health care providers and organizations information about the challenges D/deaf people face in obtaining needed services. PMID- 28804086 TI - Youth Descriptions of Mental Health Needs and Experiences with School-based Services: Identifying Ways to Meet the Needs of Underserved Adolescents. AB - While schools serve as a common entry point into mental health services for underserved youth, engagement of students in need of care remains a problem. Little is known about the ways schools can best address students' mental health needs, especially from the perspective of youth who struggle to attend school, a vulnerable group with a high burden of mental health problems. A qualitative descriptive approach was used to analyze data from in-depth interviews with a sample of 18 youth with a history of school truancy and mental health problems. Analyses explored how youth expressed mental health symptoms, and their trajectories through, and perceptions of, school-based mental health services. Results suggest that participants experienced multiple, overlapping symptoms; only a portion had their needs addressed. The quality of relationships with school staff and the perceived efficacy of treatment affected service trajectories. Promising school-based approaches to address students' mental health needs are discussed. PMID- 28804087 TI - Disparities in Accuracy of Maternal Perceptions of Obesity among Hispanic Children. AB - Maternal perceptions of their children's weight status may limit their readiness to foster healthy habits to prevent childhood obesity. We compared maternal perceptions as measured by verbal and visual scales of their children's weight status (CWS) with measured BMI/weight-for-age percentile among 75 Hispanic mothers with at least one child aged <=10 years. Mothers were significantly more likely to underestimate their CWS compared to measured BMI, particularly during verbal appraisals. Although maternal perceptions (verbal and visual scales) were significantly associated with measured CWS, the strength of the association was moderate (Verbal r=0.45 (95%CI:0.30, 0.57); Visual r=0.34 (95%CI:0.18, 0.48)). In no case, did parents in this study identify their children as "obese." These results underscore the need for more precise understandings about parental perceptions in order to develop better modes of communication regarding health risks of obesity and ways to modify and control unhealthy behaviors related to body weight. PMID- 28804088 TI - Program Evaluation of the Inner South Community Health Oral Health Program for Priority Populations. AB - BACKGROUND: This study evaluated an Oral Health Program for Priority Populations (OHPPP) in the Inner South of Melbourne, Victoria. METHODS: Social Ecological Theory and the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework informed the study. It involved administering satisfaction questionnaires to 29 clients and conducting eight in-depth interviews and four focus group discussions with either clients, health care workers or partner agencies. RESULTS: Most (92%) clients surveyed felt more positive about their health as a result of the OHPPP. Three themes emerged from the qualitative analyses: 1) good oral health is central to improving general health; 2) the OHPPP is valuable; and 3) there are difficulties in implementing the OHPPP. CONCLUSIONS: Clients and service providers view the OHPPP as accessible and rewarding. Our findings point to the need for policies that recognise the greater treatment needs of disadvantaged populations and that streamline the provision of their dental care. PMID- 28804090 TI - Repeated phlebotomies decrease body iron storage in adult dogs. AB - The aim of the present study was to determine changes in body iron storage in adult dogs following phlebotomy. We performed repeated phlebotomies by removing 1% body weight (approximately 10% of the total blood volume) weekly for a total of 12 times using adult beagle dogs without an iron-restricted diet. After treatment, stored iron was decreased, as demonstrated by gradual reductions in serum ferritin levels and hepatic iron contents. Anemia and abnormalities in blood chemistry analysis were not observed; therefore, this method was considered safe and useful for control of stored iron levels in adult dogs. PMID- 28804091 TI - Hodgkin's-like lymphoma in a ferret (Mustela putorius furo). AB - A 7-year-old castrated male ferret developed unilateral cervical lymphadenomegaly over a 1-month period. Histological examination revealed proliferation of tumor cells in a diffuse and partially nodular pattern. The tumor cells were predominantly Hodgkin cells and binucleated Reed-Sternberg cells, characterized by abundant, clear, vacuolated cytoplasm, pleomorphic, ovoid nuclei with thick nuclear membranes and distinct nucleoli. Multinucleated cells, resembling lymphocytic and histiocytic (L&H) cells, were also observed. Immunohistochemically, the tumor cells expressed Pax-5, BLA-36 and vimentin. A small population of the tumor cells expressed CD20. This case showed proliferation of Hodgkin/Reed-Sternberg cells in conjunction with L&H cells that were histologically analogous to feline Hodgkin's-like lymphoma. However, Pax-5 and BLA-36 expression along with rare CD20 expression were consistent with classical Hodgkin's lymphoma in humans. PMID- 28804093 TI - Chinese Journal of Nuclear Medicine and Molecular Imaging Volume 36, Number 6, December 25, 2016. PMID- 28804092 TI - Diurnal behavior and activity budget of the golden-crowned flying fox (Acerodon jubatus) in the Subic bay forest reserve area, the Philippines. AB - Acerodon jubatus (the Golden-Crowned flying fox) is an endemic species in the Philippines, which was suspected to be a host of the Reston strain of the Ebola virus. As nocturnal animals, the flying foxes spend daytime at the roosting site, which they use for self-maintenance and reproduction. To understand the variation in diurnal behavior and time allocation for various activities in the Golden Crowned flying fox, we investigated their daytime behavior and activity budget using instantaneous scan sampling and all occurrence focal sampling. Data collection was performed from 07:00 to 18:00 hr during January 8-17, 2017. The most frequent activity was sleeping (76.3%). The remaining activities were wing flapping (5.0%), self-grooming (4.2%), hanging relaxation (3.4%), wing spread (2.9%), movement (2.4%), mating/courtship (2.4%), aggression (1.9%), hanging alert (1.2%), excretion (0.1%) and scent marks (0.05%). The frequency of sleeping, wing flapping, self-grooming, hanging relaxation, aggression, mating/courtship and movement behaviors changed with the time of the day. Females allocated more time for resting than males, while males spent more time on the activities that helped enhance their mating opportunities, for example, movement, sexual activity and territorial behavior. PMID- 28804095 TI - The 38th Report on Survey of the Adverse Reaction to Radiopharmaceuticals (The 41st Survey in 2015). AB - This survey was performed to investigate the incidence of adverse reactions to radiopharmaceuticals in FY2015 in Japan. It was based on the responses to questionnaires sent to nuclear medicine institutions. The reply was obtained from 981 institutions among 1,274 to which the questionnaire had been sent. Fifteen cases of adverse reactions were reported. A total of 1,056,828 radiopharmaceutical administrations were reported. The incidence of adverse reactions per 100,000 cases was 1.4. No case of deficient products was reported. PMID- 28804096 TI - Application of Universal Thermal Climate Index (UTCI) for assessment of occupational heat stress in open-pit mines. AB - The purpose of this article is to examine the applicability of Universal Thermal Climate Index (UTCI) index as an innovative index for evaluating of occupational heat stress in outdoor environments. 175 workers of 12 open-pit mines in Tehran, Iran were selected for this research study. First, the environmental variables such as air temperature, wet-bulb temperature, globe temperature, relative humidity and air flow rate were measured; then UTCI, wet-bulb globe temperature (WBGT) and heat stress index (HSI) indices were calculated. Simultaneously, physiological parameters including heart rate, oral temperature, tympanic temperature and skin temperature of workers were measured. UTCI and WBGT are positively significantly correlated with all environmental parameters (p<0.03), except for air velocity (r<-0.39; p>0.05). Moreover, a strong significant relationship was found between UTCI and WBGT (r=0.95; p<0.001). The significant positive correlations exist between physiological parameters including oral temperature, tympanic and skin temperatures and heart rate and both the UTCI and WBGT indices (p<0.029). The highest correlation coefficient has been found between the UTCI and physiological parameters. Due to the low humidity and air velocity (~<1 m/s) in understudied mines, UTCI index appears to be appropriate to assess the occupational heat stress in these outdoor workplaces. PMID- 28804094 TI - Lipid Lowering Therapy and Circulating PCSK9 Concentration. AB - Hypercholesterolemia, particularly an increase in low-density lipoprotein cholesterol (LDL-C) levels, contributes substantially to the development of coronary artery disease and the risk for cardiovascular events. As the first-line pharmacotherapy, statins have been shown to reduce both LDL-C levels and cardiovascular events. However, despite intensive statin therapy, a sizable proportion of statin-treated patients are unable to achieve the recommended target LDL-C levels, and not all patients can avoid future cardiovascular events. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis by enhancing the degradation of hepatic low-density lipoprotein receptor (LDLR). Owing to its importance in lipid metabolism, PCSK9 has emerged as a novel pharmacological target for lowering LDL-C levels. In this review, the potential role of circulating PCSK9 as a new biomarker of lipid metabolism is described. Next, previous studies evaluating the effects of lipid modifying pharmacological agents, particularly statins, on circulating PCSK9 concentrations are summarized. Statins decrease hepatic intracellular cholesterol, resulting in increased LDLRs as well as increased PCSK9 protein. There is a clear dose-response effect of statin treatment on PCSK9 level, as increasing doses of statins also increase the level of circulating PCSK9. Finally, the available therapeutic strategies to inhibit PCSK9 are present. Monoclonal antibodies against PCSK9, in combination with statins, are one of the most promising and novel approaches to achieve further reduction of LDL-C levels and reduce the risk of cardiovascular events. PMID- 28804098 TI - Chinese Journal of Nuclear Medicine and Molecular Imaging Volume 37, Number 5, May 25, 2017. PMID- 28804097 TI - Teacher's sleep quality: linked to social job characteristics? AB - Besides dealing with high workload, being a teacher is challenging with respect to the social context. There is increasing evidence that adverse social job characteristics challenge sleep quality. The current study tests whether restraint sleep quality (defined as worse sleep quality before than during vacation) is related to time-related job stressors, job resources, and social job characteristics. Forty-eight elementary school teachers (42% women) participated both during the last week before and the first week after vacation. Before vacation, teachers were asked for demographics and working conditions with reference to the last 30 d, and sleep quality with reference to the last 7 d. After vacation sleep quality during vacation was assessed and used as reference for working time sleep quality. Results showed mean levels of sleep quality increased during vacation. In teachers with restrained working time sleep quality (38%), experiences of failure at work, social exclusion, and emotional dissonance were more frequent than in teachers with unrestrained working time sleep quality (Ps<0.05). Groups did not differ in time-related stressors, time control and social support from supervisors. Emotion work, social exclusion and individual experience of failure seem to challenge sleep quality in teachers. PMID- 28804099 TI - Atrial septal defect in a Korean wild raccoon dog. AB - An approximately two-year-old, male 6.1 kg body weight, Korean wild raccoon dog (Nyctereutes procyonoides koreensis) was captured by the wildlife medical rescue center of Kangwon National University. Upon physical examination, the heart rate was 87 beats per min and there were no clinical signs. The hematological, and blood biochemical profiles revealed no remarkable findings; however, thoracic radiographs showed cardiac enlargement, especially in the right atrium. On electrocardiogram, sinus node dysfunction and bradyarrhythmia were revealed. Echocardiography showed a left-to-right shunting atrial septal defect. Based on these findings, this Korean wild raccoon dog was diagnosed with atrial septal defect. This is the rare case report of atrial septal defect in wildlife. PMID- 28804100 TI - Chinese Journal of Nuclear Medicine and Molecular Imaging Volume 37, Number 4, April 25, 2017. PMID- 28804101 TI - Chinese Journal of Nuclear Medicine and Molecular Imaging Volume 37, Number 6, June 25, 2017. PMID- 28804102 TI - Chinese Journal of Nuclear Medicine and Molecular Imaging Volume 37, Number 1, January 25, 2017. PMID- 28804103 TI - Chinese Journal of Nuclear Medicine and Molecular Imaging Volume 37, Number 2, February 25, 2017. PMID- 28804104 TI - alpha-Cyperone Inhibits PMA-Induced EPCR Shedding through PKC Pathway. AB - alpha-Cyperone, a sesquiterpene compound represents 25.23% of the total oil and is the most abundant compound in Cyperus rotundus oil. Endothelial cell protein C receptor (EPCR) is a main member in protein C (PC) anti-coagulation system. EPCR could be shed from cell surface, and is mediated by tumor necrosis factor-alpha converting enzyme (TACE). Nothing that EPCR is a marker of vascular barrier integrity in vascular inflammatory disease and takes part in systemic inflammatory disease. In this study, we investigated whether alpha-cyperone could inhibit EPCR shedding. To observe the effect, we investigated this issue by detection the effect of alpha-cyperone on phorbol-12-myristate 13-acetate (PMA) induced EPCR shedding in human umbilical vein endothelial cells (HUVECs). The cells were pretreated with alpha-cyperone for 12 h, and then stimulated by PMA for 1 h. The solute EPCR (sEPCR) and expression of membrane EPCR (mEPCR) were measured by enzyme-linked immunosorbent assay (ELISA) and Western blot. The mRNA, protein level and activity of TACE were tested by quantitative (q)RT-PCR, Western blot and InnoZyme TACE activity assay kit. Furthermore, we measured the protein level of mitogen-activated protein kinase (MAPK) signaling and protein kinase C (PKC) pathway under this condition by Western blot. The results showed that alpha cyperone could suppress PMA-induced EPCR shedding through inhibiting the expression and activity of TACE. In addition, alpha-cyperone could inhibit PKC translocation, but not have an effect on phosphorylation of c-Jun N-terminal kinase (JNK), p38 and extracellular regulated protein kinases (ERK) 1/2. Given these results, alpha-cyperone inhibits PMA-induced EPCR shedding through PKC pathway, which will provide an experimental basis for further research on alpha cyperone. PMID- 28804105 TI - Clinical Utility of Fractional Flow Reserve on Computed Tomography in Left Main Trunk Disease. PMID- 28804106 TI - Adult Case of Parachute-Like Asymmetrical Mitral Valve Complicated by Mitral Stenosis and Thrombus Formation. PMID- 28804107 TI - Association of the Clinical and Genetic Factors With Superior Vena Cava Arrhythmogenicity in Atrial Fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) can be initiated from arrhythmogenic foci within the muscular sleeves that extend not only into the pulmonary veins but also into both vena cavae. The superior vena cava (SVC) is a key target site for catheter ablation. Patients with SVC-derived AF often lack the clinical risk factors of AF.Methods and Results:We conducted a meta-analysis of the clinical and genetic factors of 2,170 AF patients with and without SVC arrhythmogenicity. In agreement with previous reports, the left atrial diameter was smaller in AF patients with SVC arrhythmogenicity. Among 6 variants identified in a previous genome-wide association study in Japanese patients, rs2634073 and rs6584555 were associated with SVC arrhythmogenicity. This finding was confirmed in our meta analysis using independent cohorts. We also found that SVC arrhythmogenicity was conditionally dependent on age, body mass index, and left ventricular ejection fraction. CONCLUSIONS: Both clinical and genetic factors are associated with SVC arrhythmogenicity. PMID- 28804109 TI - Effects of Different Containers on Radioactivity Measurements using a Dose Calibrator with Special Reference to 111In and 123I. AB - Low-energy characteristic x-rays emitted by 111In and 123I sources are easily absorbed by the containers of the sources, affecting radioactivity measurements using a dose calibrator. We examined the effects of different containers on the estimated activities. The radioactivities of 111In, 123I, 201Tl, and 99mTc were measured in containers frequently employed in clinical practice in Japan. The 111In measurements were performed in the vials A and B of the 111In-pentetreotide preparation kit and in the plastic syringe. The activities of 123I metaiodobenzylguanidine and 201Tl chloride were measured in the prefilled glass syringes and plastic syringes. The milking vial, vial A, vial B, and plastic syringe were used to assay 99mTc. For 111In and 123I, measurements were performed with and without a copper filter. The filter was inserted into the well of the dose calibrator to absorb low-energy x-rays. The relative estimate was defined as the ratio of the activity estimated with the dose calibrator to the standard activity. The estimated activities varied greatly depending on the container when 111In and 123I sources were assayed without the copper filter. The relative estimates of 111In were 0.908, 1.072, and 1.373 in the vial A, vial B, and plastic syringe, respectively. The relative estimates of 123I were 1.052 and 1.352 in the glass syringe and plastic syringe, respectively. Use of the copper filter eliminated the container-dependence in 111In and 123I measurements. Container-dependence was demonstrated in neither 201Tl nor 99mTc measurements. The activities of 111In and 123I estimated with a dose calibrator differ greatly among the containers. Accurate estimation may be attained using the container specific correction factor or using the copper filter. PMID- 28804108 TI - Effects of vitrification and a Rho-associated coiled-coil containing protein kinase 1 inhibitor on the meiotic and developmental competence of feline oocytes. AB - Oocyte cryopreservation is the technique of choice for the long-term storage of female gametes. However, it induces an irreversible loss of oocyte viability and function. We examined the effects of vitrification and a Rho-associated coiled coil containing protein kinase 1 (ROCK1) inhibitor (ROCKi) on the meiotic and developmental competence of feline oocytes. We examined the expression of LIM kinase (LIMK) 1 and 2, with and without ROCKi treatment. Cumulus oocyte complexes (COCs) were matured in vitro with 0, 10, 20, and 40 uM ROCKi. The oocytes were subsequently assessed for maturation rate and embryo development following in vitro fertilization. We repeated the COC experiment, but vitrified and warmed the COCs prior to culture. We detected LIMK1 and LIMK2 expression in feline oocytes, which could be downregulated by ROCKi treatment. The ROCKi at 10 uM affected neither meiotic nor developmental competence (P > 0.05, versus control). However, high concentrations of ROCKi during maturation induced meiotic arrest at metaphase I. Appropriate concentrations of ROCKi significantly improved the normal fertilization rate of vitrified warmed oocytes (49.4 +/- 3.4%) compared with that of the control (42.8 +/- 8.6%, P < 0.05). The ROCKi also significantly improved the embryo cleavage rate (36.1 +/- 3.8%) as compared with the non treated control (27.4 +/- 2.5%, P < 0.05). Thus, this study revealed that the main mediators of the ROCK cascade (LIM kinases) are expressed in feline oocytes. The ROCKi (10 uM) did not compromise the meiotic or developmental competence of feline oocytes. In addition, 10 uM ROCKi improved the cytoplasmic maturation of vitrified-warmed oocytes as indicated by their fertilization competence. PMID- 28804110 TI - Current and future prospects of nuclear medicine in dementia. AB - In clinical diagnostic imaging of Alzheimer's disease (AD), MRI and nuclear medicine studies such as cerebral blood flow SPECT are positioned as biomarkers expressing pathological conditions. With understanding its usefulness and limitations, it is important to conduct appropriate application and to utilize the correct evaluation of the result in clinical practice. Although FDG-PET and amyloid PET are still not covered for dementia by health insurance, they are extremely useful for differential diagnosis as well as early diagnosis of AD. As image biomarkers, they may have complementary implications. In addition, tau PET under development not only realizes more accurate evaluation of AD but also is expected to be applied in dementia other than AD. In the future, image biomarkers are indispensable for patient selection (early diagnosis) in mild cognitive impairment (MCI) or earlier stages and for judging the therapeutic effect of interventions in cases when early intervention for AD. PMID- 28804111 TI - An adult case of group A streptococcus meningitis associated with steroid responsive meningoencephalitis. AB - A previously healthy 80-year-old woman presented to our service in a comatose state. On examination the patient had fever and neck stiffness. Laboratory investigation showed polymorphonuclear pleocytosis in cerebro-spinal fluid (CSF). These findings prompted us to a diagnosis of bacterial or viral meningitis and combination therapy consisting of ceftriaxone, vancomycin and acyclovir was started immediately. Two days later, culture of blood yielded Streptococcus pyogenes (group A streptococcus; GAS). The antibiotic therapy was converted to intravenous ampicillin for 14 days. Fever resolved quickly, however, somnolence persisted. Fluid attenuated inversion recovery image of the brain, taken on the day 29, showed focal hyperintense lesions on the right subcortical area in the temporal and parietal lobes. Three times repeated intravenous steroid pulse therapy (methylprednisolone 1,000 mg/day, 3 days) resulted in complete improvement of her consciousness disturbance. We considered the present case to be a steroid-responsive meningoencephalitis caused by GAS infection. PMID- 28804112 TI - Low signal intensity lesions on brain susceptibility-weighted MRI in a patient with intravascular large B-cell lymphoma. AB - A 71-year-old man was admitted to our hospital because of abnormal behavior and generalized convulsion. Brain MRI revealed no abnormalities upon admission. Levels of serum lactate dehydrogenase and soluble interleukin-2 receptors were significantly elevated, whereas the initial bone marrow puncture and random skin biopsy findings were non-malignant. On the tenth day of admission, brain MRI revealed dot and strip-shaped low signal intensity lesions on susceptibility weighted images (SWI) disseminated mainly within the cerebral cortex. Administration of high dose methyl-prednisolone improved neither his condition nor these MRI findings. Ground-glass opacities within the bilateral lungs later emerged on the chest CT. The results of a transbronchial lung biopsy and second bone marrow puncture were consistent with a diagnosis of intravascular large B cell lymphoma (IVLBCL). Despite the lack of histopathological confirmation, the low signal intensities on brain SWI in this case were also considered IVLBCL lesions, reflective of micro-hemorrhagic changes. PMID- 28804113 TI - Case report of a 28-year-old male with the rapid progression of steroid-resistant central nervous system vasculitis diagnosed by a brain biopsy. AB - A 28-year-old Japanese male without a significant past medical history presented with new-onset generalized clonic seizure and headache. A brain MRI revealed multiple enhanced lesions on both cerebral hemispheres. Laboratory exams showed no evidence of systemic inflammation or auto-immune antibodies such as ANCAs. Despite four courses of high-dose methylprednisolone pulse therapy and five treatments with plasmapheresis, his symptoms worsened and the MRI lesions progressed rapidly. During these treatments, we performed a targeted brain biopsy, that revealed histological findings consistent with a predominant angiitis of parenchymal and subdural small vessels. He was provided with diagnosis of central nervous system vasculitis (CNSV). Subsequent cyclophosphamide pulse therapy enabled a progressive successful improvement of his symptoms. While diagnostic methods for CNSV remain controversial, histological findings are thought to be more useful in obtaining a more definitive diagnosis than findings in image studies, such as MRI and angiography. We suggest that a brain biopsy should be considered during the early period of cases with suspected CNSV and rapid clinical deterioration. We also detected human herpesvirus 7 (HHV-7) using PCR technology in brain biopsy specimens, however the relationship between CNSV and HHV-7 infection is unknow. PMID- 28804114 TI - Clinical, epidemiological and etiological studies of adult aseptic meningitis: Report of 11 cases with varicella zoster virus meningitis. AB - We treated 11 cases (52.7 +/- 14.9 years, all male) with varicella zoster virus (VZV) meningitis and 437 cases with adult aseptic meningitis from 2004 to 2016. The incidence rate of adult VZV meningitis in the cases with aseptic meningitis was 2.5%. Herpes zoster infections are reported to have occurred frequently in summer and autumn. VZV meningitis also occurred frequently in the similar seasons, in our patients. The diagnoses were confirmed in 9 cases with positive VZV-DNA in the cerebrospinal fluid and in 2 cases with high VZV-IgG indexes (> 2.0). For diagnosis confirmation, the former test was useful for cases within a week of disease onset, and the latter index was useful for cases after a week of disease onset. Zoster preceded the meningitis in 8 cases, while the meningitis preceded zoster in 1 case, and 2 cases did not have zoster (zoster sine herpete). Two patients were carriers of the hepatitis B virus, 1 patient was administered an influenza vaccine 4 days before the onset of meningitis, and 1 patient was orally administered prednisolone for 2 years, for treatment. Their immunological activities might have been suppressed. The neurological complications included trigeminal neuralgia, facial palsy (Ramsay Hunt syndrome), glossopharyngeal neuralgia, and Elsberg syndrome. Because the diseases in some patients can become severe, they require careful treatment. PMID- 28804116 TI - Chinese Journal of Nuclear Medicine and Molecular Imaging Volume 37, Number 3, March 25, 2017. PMID- 28804115 TI - Relevance of serum concentrations of non-esterified fatty acids and very low density lipoproteins in nulli/primiparous and multiparous cows in the close-up period. AB - Serum concentrations of non-esterified fatty acids (NEFA) and very low-density lipoprotein (VLDL) in close-up dairy cattle were compared in relation to parity. Data were obtained from 37 nulli/primiparous (NP) and 24 multiparous (MU, parity: 2-7) cows between 14 days and 1 day prepartum. A positive correlation (r=0.684, P<0.01) was found between serum NEFA and VLDL concentrations in NP cows. Among the VLDL constituents, the NEFA concentration was particularly correlated with the triglyceride (TG) concentration (r=0.658, P<0.01). However, no significant correlation was found between the concentrations of NEFA and VLDL or VLDL-TG in MU cows (r=-0.028 and 0.307). These results suggest the presence of higher hepatic secretion of NEFA-derived VLDL in NP cows. PMID- 28804117 TI - A Report on Health Resource Use in Internal Radiation Therapy with Radium Chloride (223Ra) (2nd Survey). AB - Internal radiation therapy using radium (223Ra) chloride injection (223Ra injection) is already being applied in actual clinical practice, however the NHI medical technical fee for the use of 223Ra injection has not yet been set. The Japanese Society of Nuclear Medicine surveyed health resource use for internal radiation therapy using 223Ra via questionnaires sent to medical institutions that have used 223Ra injection. Results showed that the necessary cost per patient is 1,005,567 JPY, based on the Draft Proposal for Medical Examination Value (Ver. 7.1) of the Japanese Health Insurance Federation for Surgery. 223Ra injection is supposed to be administered 6 times to each patient at 4-week intervals, and the fee per treatment was calculated to be 167,595 JPY. The appropriate NHI medical technical fee is thus considered to be 16,759 points per patient per treatment, which can be claimed 6 times per patient. PMID- 28804118 TI - Isolated Testicular Metastasis from Prostate Cancer. AB - BACKGROUND Prostatic adenocarcinoma is the most frequently diagnosed carcinoma in the male population; the most common sites of secondary lesions are nodes, bones, and lungs. We report the clinical case of a 58-year-old man presenting with a single metastasis in the left testis after a radical prostatectomy/lymphadenectomy for prostate cancer. CASE REPORT This clinical report focuses on a 58-year-old man with prostate cancer who developed an uncommon single metastasis in the left testis after radical surgery and adjuvant pelvic radiation therapy. CONCLUSIONS Prostate-specific antigen (PSA) levels are important in the follow-up of prostate cancer. At the same time, physical examination of all possible sites of metastasis and proper evaluation of all signs/symptoms are indispensable in the process of identifying recurrence and for the selection of patients undergoing adjuvant therapy. PMID- 28804119 TI - Artificial Intelligence, DNA Mimicry, and Human Health. AB - The molecular evolution of genomic DNA across diverse plant and animal phyla involved dynamic registrations of sequence modifications to maintain existential homeostasis to increasingly complex patterns of environmental stressors. As an essential corollary, driver effects of positive evolutionary pressure are hypothesized to effect concerted modifications of genomic DNA sequences to meet expanded platforms of regulatory controls for successful implementation of advanced physiological requirements. It is also clearly apparent that preservation of updated registries of advantageous modifications of genomic DNA sequences requires coordinate expansion of convergent cellular proofreading/error correction mechanisms that are encoded by reciprocally modified genomic DNA. Computational expansion of operationally defined DNA memory extends to coordinate modification of coding and previously under-emphasized noncoding regions that now appear to represent essential reservoirs of untapped genetic information amenable to evolutionary driven recruitment into the realm of biologically active domains. Additionally, expansion of DNA memory potential via chemical modification and activation of noncoding sequences is targeted to vertical augmentation and integration of an expanded cadre of transcriptional and epigenetic regulatory factors affecting linear coding of protein amino acid sequences within open reading frames. PMID- 28804121 TI - Lamin B1 regulates somatic mutations and progression of B-cell malignancies. AB - Somatic hypermutation (SHM) is a pivotal process in adaptive immunity that occurs in the germinal centre and allows B cells to change their primary DNA sequence and diversify their antigen receptors. Here, we report that genome binding of Lamin B1, a component of the nuclear envelope involved in epigenetic chromatin regulation, is reduced during B-cell activation and formation of lymphoid germinal centres. Chromatin immunoprecipitation-Seq analysis showed that kappa and heavy variable immunoglobulin domains were released from the Lamin B1 suppressive environment when SHM was induced in B cells. RNA interference mediated reduction of Lamin B1 resulted in spontaneous SHM as well as kappa-light chain aberrant surface expression. Finally, Lamin B1 expression level correlated with progression-free and overall survival in chronic lymphocytic leukaemia, and was strongly involved in the transformation of follicular lymphoma. In summary, here we report that Lamin B1 is a negative epigenetic regulator of SHM in normal B-cells and a 'mutational gatekeeper', suppressing the aberrant mutations that drive lymphoid malignancy. PMID- 28804120 TI - Mitochondrial energetics in the kidney. AB - The kidney requires a large number of mitochondria to remove waste from the blood and regulate fluid and electrolyte balance. Mitochondria provide the energy to drive these important functions and can adapt to different metabolic conditions through a number of signalling pathways (for example, mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) pathways) that activate the transcriptional co-activator peroxisome proliferator-activated receptor-gamma co-activator 1alpha (PGC1alpha), and by balancing mitochondrial dynamics and energetics to maintain mitochondrial homeostasis. Mitochondrial dysfunction leads to a decrease in ATP production, alterations in cellular functions and structure, and the loss of renal function. Persistent mitochondrial dysfunction has a role in the early stages and progression of renal diseases, such as acute kidney injury (AKI) and diabetic nephropathy, as it disrupts mitochondrial homeostasis and thus normal kidney function. Improving mitochondrial homeostasis and function has the potential to restore renal function, and administering compounds that stimulate mitochondrial biogenesis can restore mitochondrial and renal function in mouse models of AKI and diabetes mellitus. Furthermore, inhibiting the fission protein dynamin 1-like protein (DRP1) might ameliorate ischaemic renal injury by blocking mitochondrial fission. PMID- 28804122 TI - SHP2 is required for BCR-ABL1-induced hematologic neoplasia. AB - BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) have revolutionized treatment of Philadelphia chromosome-positive (Ph+) hematologic neoplasms. Nevertheless, acquired TKI resistance remains a major problem in chronic myeloid leukemia (CML), and TKIs are less effective against Ph+ B-cell acute lymphoblastic leukemia (B-ALL). GAB2, a scaffolding adaptor that binds and activates SHP2, is essential for leukemogenesis by BCR-ABL1, and a GAB2 mutant lacking SHP2 binding cannot mediate leukemogenesis. Using a genetic loss-of function approach and bone marrow transplantation models for CML and BCR-ABL1+ B ALL, we show that SHP2 is required for BCR-ABL1-evoked myeloid and lymphoid neoplasia. Ptpn11 deletion impairs initiation and maintenance of CML-like myeloproliferative neoplasm, and compromises induction of BCR-ABL1+ B-ALL. SHP2, and specifically, its SH2 domains, PTP activity and C-terminal tyrosines, are essential for BCR-ABL1+, but not WT, pre-B-cell proliferation. The mitogen activated protein kinase kinase (MEK) / extracellular signal-regulated kinase (ERK) pathway is regulated by SHP2 in WT and BCR-ABL1+ pre-B cells, but is only required for the proliferation of BCR-ABL1+ cells. SHP2 is required for SRC family kinase (SFK) activation only in BCR-ABL1+ pre-B cells. RNAseq reveals distinct SHP2-dependent transcriptional programs in BCR-ABL1+ and WT pre-B cells. Our results suggest that SHP2, via SFKs and ERK, represses MXD3/4 to facilitate a MYC-dependent proliferation program in BCR-ABL1-transformed pre-B cells. PMID- 28804123 TI - Integrating genomic alterations in diffuse large B-cell lymphoma identifies new relevant pathways and potential therapeutic targets. AB - Genome studies of diffuse large B-cell lymphoma (DLBCL) have revealed a large number of somatic mutations and structural alterations. However, the clinical significance of these alterations is still not well defined. In this study, we have integrated the analysis of targeted next-generation sequencing of 106 genes and genomic copy number alterations (CNA) in 150 DLBCL. The clinically significant findings were validated in an independent cohort of 111 patients. Germinal center B-cell and activated B-cell DLBCL had a differential profile of mutations, altered pathogenic pathways and CNA. Mutations in genes of the NOTCH pathway and tumor suppressor genes (TP53/CDKN2A), but not individual genes, conferred an unfavorable prognosis, confirmed in the independent validation cohort. A gene expression profiling analysis showed that tumors with NOTCH pathway mutations had a significant modulation of downstream target genes, emphasizing the relevance of this pathway in DLBCL. An in silico drug discovery analysis recognized 69 (46%) cases carrying at least one genomic alteration considered a potential target of drug response according to early clinical trials or preclinical assays in DLBCL or other lymphomas. In conclusion, this study identifies relevant pathways and mutated genes in DLBCL and recognizes potential targets for new intervention strategies. PMID- 28804125 TI - The expression of P2Y14, a purinergic G-protein coupled receptor, defines functionally distinct subpopulations in placenta-derived hematopoietic stem progenitor cells. PMID- 28804126 TI - Early, risk-adapted treatment with fludarabine in Binet stage A chronic lymphocytic leukemia patients: results of the CLL1 trial of the German CLL study group. PMID- 28804124 TI - Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10 year survival results of the randomized CML study IV and impact of non-CML determinants. AB - Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400 mg/day (n=400) could be optimized by doubling the dose (n=420), adding interferon (IFN) (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival was 80% and 10-year relative survival was 92%. Survival between IM400 mg and any experimental arm was not different. In a multivariate analysis, risk group, major route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs other) influenced survival significantly, but not any form of treatment optimization. Patients reaching the molecular response milestones at 3, 6 and 12 months had a significant survival advantage. For responders, monotherapy with IM400 mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients' and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease, more life-time can currently be gained by carefully addressing non-CML determinants of survival. PMID- 28804129 TI - Immunometabolism: NK cell subset expands with your waistline. PMID- 28804127 TI - Discovery of novel drug sensitivities in T-PLL by high-throughput ex vivo drug testing and mutation profiling. AB - T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells with an urgent need for rationally designed therapies to address its notoriously chemo-refractory behavior. The median survival of T-PLL patients is <2 years and clinical trials are difficult to execute. Here we systematically explored the diversity of drug responses in T-PLL patient samples using an ex vivo drug sensitivity and resistance testing platform and correlated the findings with somatic mutations and gene expression profiles. Intriguingly, all T-PLL samples were sensitive to the cyclin-dependent kinase inhibitor SNS-032, which overcame stromal-cell-mediated protection and elicited robust p53-activation and apoptosis. Across all patients, the most effective classes of compounds were histone deacetylase, phosphoinositide-3 kinase/AKT/mammalian target of rapamycin, heat-shock protein 90 and BH3-family protein inhibitors as well as p53 activators, indicating previously unexplored, novel targeted approaches for treating T-PLL. Although Janus-activated kinase-signal transducer and activator of transcription factor (JAK-STAT) pathway mutations were common in T-PLL (71% of patients), JAK-STAT inhibitor responses were not directly linked to those or other T-PLL-specific lesions. Overall, we found that genetic markers do not readily translate into novel effective therapeutic vulnerabilities. In conclusion, novel classes of compounds with high efficacy in T-PLL were discovered with the comprehensive ex vivo drug screening platform warranting further studies of synergisms and clinical testing. PMID- 28804131 TI - Innate immunity: A new way out for lysozyme. PMID- 28804128 TI - Sizing up the bacterial cell cycle. AB - It is remarkable how robustly a bacterial species can maintain its preferred size. This capacity is intimately related to control of the cell cycle: cell size and growth rate determine the duration of the cell cycle, which must accommodate the initiation and completion of DNA replication, and the assembly of the division apparatus during steady growth. Although we still lack an integrated view of the interconnections among events in the cell cycle, cell growth and cell size, the development of high-throughput imaging and image-processing protocols has stimulated a renaissance in the field. In this Review, we summarize recent findings, present simple classic models for cell size control, introduce high throughput data-collection techniques, and explore the mechanisms that coordinate cell size with essential growth and cell cycle processes. PMID- 28804132 TI - Antibodies: Herd immunity. PMID- 28804134 TI - Epidemiology: Anthrax threatens wildlife. PMID- 28804133 TI - Bacterial pathogenesis: Vibrio enters 'sleep mode' to survive. PMID- 28804130 TI - Innate lymphoid cells: major players in inflammatory diseases. AB - Recent years have seen a marked increase in our understanding of innate lymphoid cells (ILCs). ILCs can be classified into different groups based on their similarity to T cell subsets in terms of their expression of key transcription factors and cytokine production. Various immunological functions of ILCs have been described, and increasing numbers of studies have implicated these cells in inflammatory disorders. Here, we detail the roles of ILCs in inflammatory diseases; we cover type 2 inflammatory diseases (such as asthma, chronic rhinosinusitis and atopic dermatitis), as well as inflammatory bowel diseases, psoriasis and other systemic or organ-specific inflammatory and autoimmune diseases. Future directions in the field are discussed, together with potential avenues of treatment. PMID- 28804135 TI - Bacterial genetics: Splitting is never easy. PMID- 28804136 TI - Microbiota: Tell me who you are and I'll tell you what you eat. PMID- 28804137 TI - Pathogen genetics: Evolutionary dynamics driving drug resistance. PMID- 28804138 TI - Settling the score: variant prioritization and Mendelian disease. AB - When investigating Mendelian disease using exome or genome sequencing, distinguishing disease-causing genetic variants from the multitude of candidate variants is a complex, multidimensional task. Many prioritization tools and online interpretation resources exist, and professional organizations have offered clinical guidelines for review and return of prioritization results. In this Review, we describe the strengths and weaknesses of widely used computational approaches, explain their roles in the diagnostic and discovery process and discuss how they can inform (and misinform) expert reviewers. We place variant prioritization in the wider context of gene prioritization, burden testing and genotype-phenotype association, and we discuss opportunities and challenges introduced by whole-genome sequencing. PMID- 28804141 TI - A capacitive ultrasonic transducer based on parametric resonance. AB - A capacitive ultrasonic transducer based on a parametric resonator structure is described and experimentally demonstrated. The transducer structure, which we call capacitive parametric ultrasonic transducer (CPUT), uses a parallel plate capacitor with a movable membrane as part of a degenerate parametric series RLC resonator circuit with a resonance frequency of fo. When the capacitor plate is driven with an incident harmonic ultrasonic wave at the pump frequency of 2fo with sufficient amplitude, the RLC circuit becomes unstable and ultrasonic energy can be efficiently converted to an electrical signal at fo frequency in the RLC circuit. An important characteristic of the CPUT is that unlike other electrostatic transducers, it does not require DC bias or permanent charging to be used as a receiver. We describe the operation of the CPUT using an analytical model and numerical simulations, which shows drive amplitude dependent operation regimes including parametric resonance when a certain threshold is exceeded. We verify these predictions by experiments with a micromachined membrane based capacitor structure in immersion where ultrasonic waves incident at 4.28 MHz parametrically drive a signal with significant amplitude in the 2.14 MHz RLC circuit. With its unique features, the CPUT can be particularly advantageous for applications such as wireless power transfer for biomedical implants and acoustic sensing. PMID- 28804142 TI - An adaptive two-sample test for high-dimensional means. AB - Several two-sample tests for high-dimensional data have been proposed recently, but they are powerful only against certain limited alternative hypotheses. In practice, since the true alternative hypothesis is unknown, it is unclear how to choose a powerful test. We propose an adaptive test that maintains high power across a wide range of situations, and study its asymptotic properties. Its finite sample performance is compared with existing tests. We apply it and other tests to detect possible associations between bipolar disease and a large number of single nucleotide polymorphisms on each chromosome based on a genome-wide association study dataset. Numerical studies demonstrate the superior performance and high power of the proposed test across a wide spectrum of applications. PMID- 28804143 TI - Using Longitudinal Data on Career Outcomes to Promote Improvements and Diversity in Graduate Education. PMID- 28804140 TI - Vertebrate sex determination: evolutionary plasticity of a fundamental switch. AB - The discovery of the Sry gene in 1990 triggered a revolution in our understanding of sex determination. More recently, advances in non-model organisms have been fuelled by the rapid evolution of affordable genome and transcriptome technologies. This Review considers the unusual plasticity in the bipotential system of sex determination and some of the diverse mechanisms that have evolved to control this critical developmental decision, including strong genetic pathways, environmental influences and epigenetic regulation. Ideas emerging from model and non-model organisms that suggest that sex determination operates as an antagonistic network with the emergent property of bistability are discussed. PMID- 28804144 TI - For Sale: FDA Priority Review Vouchers. PMID- 28804145 TI - Approvals, Submission, and Important Labeling Changes for US Marketed Pharmaceuticals. AB - This monthly feature will help readers keep current on new drug, new indications, dosage forms and safety-related changes in labeling or use. Efforts have been made to assure the accuracy of this information; however, if there are any questions, please let us know at jgeneral@ku.edu. PMID- 28804139 TI - The interplay of epigenetic marks during stem cell differentiation and development. AB - Chromatin, the template for epigenetic regulation, is a highly dynamic entity that is constantly reshaped during early development and differentiation. Epigenetic modification of chromatin provides the necessary plasticity for cells to respond to environmental and positional cues, and enables the maintenance of acquired information without changing the DNA sequence. The mechanisms involve, among others, chemical modifications of chromatin, changes in chromatin constituents and reconfiguration of chromatin interactions and 3D structure. New advances in genome-wide technologies have paved the way towards an integrative view of epigenome dynamics during cell state transitions, and recent findings in embryonic stem cells highlight how the interplay between different epigenetic layers reshapes the transcriptional landscape. PMID- 28804146 TI - Summaries of Safety Labeling Changes Approved by the FDA: Boxed Warnings Highlights January - March 2017. PMID- 28804147 TI - ISMP Adverse Drug Reactions: Levofloxacin-Induced Neuroexcitation and Hallucinations; Statin-Induced Muscle Rupture; Mefloquine-Induced Rhabdomyolysis; Methimazole-Induced Cholestatic Hepatitis; Decitabine-Induced Hand and Foot Syndrome. AB - The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration's (FDA) MedWatch program (800-FDA-1088). If you have reported an interesting, preventable ADR to MedWatch, please consider sharing the account with our readers. Write to Dr. Mancano at ISMP, 200 Lakeside Drive, Suite 200, Horsham, PA 19044 (phone: 215-707-4936; e-mail: mmancano@temple.edu). Your report will be published anonymously unless otherwise requested. This feature is provided by the Institute for Safe Medication Practices (ISMP) in cooperation with the FDA's MedWatch program and Temple University School of Pharmacy. ISMP is an FDA MedWatch partner. PMID- 28804148 TI - Critical Care Pharmacist Market Perceptions: Comparison of Critical Care Program Directors and Directors of Pharmacy. AB - Background: While hospital beds continue to decline as patients previously treated as inpatients are stabilized in ambulatory settings, the number of critical care beds available in the United States continues to rise. Growth in pharmacy student graduation, postgraduate year 2 critical care (PGY2 CC) residency programs, and positions has also increased. There is a perception that the critical care trained pharmacist market is saturated, yet this has not been evaluated since the rise in pharmacy graduates and residency programs. Purpose: To describe the current perception of critical care residency program directors (CC RPDs) and directors of pharmacy (DOPs) on the critical care pharmacist job market and to evaluate critical care postresidency placement and anticipated changes in PGY2 CC programs. Methods: Two electronic surveys were distributed from October 2015 to November 2015 through Vizient/University HealthSystem Consortium, American Society of Health-System Pharmacists (ASHP), Society of Critical Care Medicine, and American College of Clinical Pharmacy listservs to target 2 groups of respondents: CC RPDs and DOPs. Questions were based on the ASHP Pharmacy Forecast and the Pharmacy Workforce Center's Aggregate Demand Index and were intended to identify perceptions of the critical care market of the 2 groups. Results: Of 116 CC RPDs, there were 66 respondents (56.9% response rate). Respondents have observed an increase in applicants; however, they do not anticipate increasing the number of positions in the next 5 years. The overall perception is that there is a balance in supply and demand in the critical care trained pharmacist market. A total of 82 DOPs responded to the survey. Turnover of critical care pharmacists within respondent organizations is expected to be low. Although a majority of DOPs plan to expand residency training positions, only 9% expect to increase positions in critical care PGY2 training. Overall, DOP respondents indicated a balance of supply and demand in the critical care trained pharmacist market. In comparing RPD and DOP perceptions of the demand for critical care pharmacists, DOPs perceived demand to be higher than RPDs (mean, 3.2 vs 2.8; P = .032). Conclusion: Although there is a perception of the oversupply of critical care trained pharmacists, a survey of DOPs and CC RPDs found a market with positions available, rapid hiring, stable salaries, and plans for expanded hiring of critical care trained pharmacists. PMID- 28804149 TI - Capecitabine, Oxaliplatin, and Bevacizumab (BCapOx) Regimen for Metastatic Colorectal Cancer. AB - The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc, 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: waddfour@charter.net. The information presented in this review is based on published data and clinical expertise and includes information not included in the product labeling. Incorporation of such published data provides a more robust assessment of the drugs and assists pharmacists in evaluation of orders for off-label use of these agents. PMID- 28804150 TI - Clinical Pharmacy Discharge Counseling Service and the Impact on Readmission Rates in High-Risk Patients. AB - Background: A number of patient safety and transition of care initiatives have highlighted the benefits of incorporating a clinical pharmacist in the discharge medication process. Numerous studies have identified the prominent and consequential role of medication therapy errors occurring at hospital discharge. Objective: The objective of this study was to evaluate the effects of a discharge medication counseling service on readmission rates, emergency department (ED) visits, and days to first readmission or ED visit in patients deemed high risk for hospital readmission. Methods: A retrospective chart review was conducted from October 2014 to December 2014 in adult patients admitted to a general medicine unit and identified as being at high risk for readmission. Endpoints were compared between patients who received discharge counseling (study group) and those who did not (control group). Results: Eighty-nine high-risk patient charts were reviewed. Forty-four patients were in the study group and 45 patients were in the control group. There were no differences between the baseline characteristics of both groups. There were no differences between the study and control groups in 30-day readmission rates (18.2% vs 26.7%; P = .45) and in 30 day ED visits (4.6% vs 11.1%; P = .43). The number of days to first readmission or ED visit between the study and control groups was 22 versus 12 (P = .26). Conclusion: Although no statistical difference was found between groups in this study, integration of a clinical pharmacist as part of an interdisciplinary approach in the discharge medication process resulted in numerical improvements in outcomes. Additional investigation is warranted to further highlight the potential benefits of this service. PMID- 28804151 TI - Mannitol Prescribing Practices With Cisplatin Before and After an Educational Newsletter Intervention. AB - Background: Mannitol has been used in the past for the prevention of cisplatin induced nephrotoxicity. Studies on its efficacy have conflicting results. An educational newsletter was designed for local oncologists on the conflicting data of mannitol use in preventing cisplatin-induced nephrotoxicity. Purpose: The purpose of this study was to determine whether a pharmacist-created newsletter intervention led to changes in the mannitol prescribing practices of local oncologists. Methods: A newsletter describing the paucity of evidence to support mannitol use to prevent cisplatin-induced nephrotoxicity was distributed via e mail to local oncologists in October 2010. Mannitol prescribing rates were retrospectively evaluated before and after newsletter distribution. The Mann Whitney U test was used to compare nonparametric continuous data. The chi-square test was used for nominal data. Descriptive statistics were performed for baseline demographics, and odds ratios were calculated for possible risk factors for acute kidney injury (AKI). The primary endpoint was a change in mean mannitol dose before and after the newsletter intervention. The secondary endpoint was the difference in the rate of AKI before and after the intervention. Data were collected for 67 patients with various malignancies. Results: There was a difference in the average mannitol dose before and after newsletter intervention (P = .02). The rates of AKI before and after newsletter were similar. Conclusion: A pharmacist-led newsletter intervention was associated with significantly decreased rates of mannitol usage after intervention. PMID- 28804152 TI - Pharmacists' Knowledge of the Cost of Laboratory Testing. AB - Purpose: The objective of this study was to ascertain baseline knowledge of pharmacists and pharmacy residents concerning the cost of laboratory tests for monitoring medications, and to determine whether an educational session delivered to pharmacy residents improves their knowledge of these costs. Methods: An online survey was provided to pharmacists and pharmacy residents, testing their knowledge of 15 common laboratory tests used to monitor the safety and efficacy of medications. One of the researchers presented a lecture to all pharmacy residents that detailed individual laboratory costs; after that, the researchers delivered a follow-up survey to assess the effectiveness of the educational session. Results: Baseline knowledge of pharmacists showed that greater than 64% of the responses were more than 30% away from the actual cost of the laboratory test for all 15 tests. Baseline knowledge of pharmacy residents showed that greater than 58% of the responses were more than 30% away from the actual cost of the laboratory test for each individual test. Although there was no statistically significant improvement in individual cost prediction after the educational session, 2 laboratory values showed improvement in margins of error post intervention: alanine aminotransferase/aspartate aminotransferase and lipids (P = .008 and .014, respectively). Conclusions: Pharmacists and pharmacy residents poorly predicted the costs of common laboratory tests. A brief lecture discussing the cost of laboratory tests demonstrated minor improvement in pharmacy residents' knowledge of the costs reviewed. Pharmacists need to be educated on the cost of laboratory tests to better understand the profession's contribution to health care expenditures. PMID- 28804153 TI - Adverse Drug Reaction Reporting Practices Among United Arab Emirates Pharmacists and Prescribers. AB - Background: Underreporting of adverse drug reactions (ADRs) has placed a heavy financial burden on health care resources worldwide. Realizing the importance of proper ADR reporting is paramount for implementing better patient care. Objective: This study was designed to assess knowledge, attitude, and practice (KAP) of ADR reporting among United Arab Emirates (UAE) health care professionals to clarify their present strategies and identify steps to avoid underreporting. Methods: A self-administered cross-sectional questionnaire was designed and randomly distributed to different health care personnel (n = 150). All participants were briefly informed about the aim of the study and given sufficient time to respond. The responses were collected over 6 months. The data were statistically analyzed for each reporter category (community pharmacist, hospital pharmacist, and doctors) using the chi-square test. Results: We found that 81%, 83%, and 83.3% of doctors, community pharmacists, and hospital pharmacists, respectively, were not aware of the existence of a reporting center and 56%, 60%, and 72% were not aware of a reporting procedure. Poor ADR reporting practices were shown by responders; only 19%, 14%, and 12.1% of doctors, community pharmacists, and hospital pharmacists reported ADRs. Conclusion: This study showed poor KAP results among health care professionals. Proper educational intervention strategies should be established in different health care settings for better patient care. With proper guidance, objectives in all health care settings should be targeted to positively change the concept of health care to consider ADR reporting as a common accepted daily routine practice. PMID- 28804154 TI - Postoperative Pain Management With Liposomal Bupivacaine in Patients Undergoing Orthopedic Knee and Hip Arthroplasty at a Community Hospital. AB - Objective: The objective of this study was to assess the association between liposomal bupivacaine use in patients undergoing knee or hip arthroplasty and concurrent pain control, length of hospitalization, and physical therapy milestones. Methods: This was a retrospective chart review. Patients receiving liposomal bupivacaine during a 1-year period (study group) were compared with patients seen by the same surgeon in the previous year who did not receive liposomal bupivacaine (control group). Clinical outcomes included concurrent opioid use, average pain scores, length of stay, ambulation, and range of motion. Results: A total of 357 patients were included in the study. Knee study group patients received lower amounts of opioid (209 vs 248 mg; P = .02) and had a delayed time to first rescue medication (6.3 +/- 4.7 vs 5.0 +/- 4.4 hours; P = .02). Hip study group patients had a delay in time to first rescue medication (7.1 +/- 6.3 vs 4.9 +/- 4.0 hours; P = .046). Both knee and hip study group patients had higher average pain score during the 72-hour postoperative period (6.38 vs 6.06; P = .01, and 6.32 vs 5.80; P = .02, respectively) but decreased median length of stay (2.0 vs 3.0 days; P < .0001, and 2.0 vs 3.0 days; P = .04, respectively). Conclusions: Use of liposomal bupivacaine produced a modest decrease in opioid use among knee patients and a decreased length of stay in both knee and hip patients; however, this was accompanied by a non-clinically significant increase in pain scores for knee and hip patients suggesting limited utility for orthopedic procedures. PMID- 28804155 TI - Insulin Degludec/Liraglutide. AB - Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, contact Wolters Kluwer customer service at 866-397-3433. The May 2017 monograph topics are brodalumab, etelcalcetide, guselkumab, ribociclib, and sirukumab. The MUE is on ribociclib. PMID- 28804156 TI - Inclusion of Radiation Environment Variability in Total Dose Hardness Assurance Methodology. AB - Variability of the space radiation environment is investigated with regard to parts categorization for total dose hardness assurance methods. It is shown that it can have a significant impact. A modified approach is developed that uses current environment models more consistently and replaces the radiation design margin concept with one of failure probability during a mission. PMID- 28804157 TI - Electron microscopic observations of Rb particles and pitting in 129Xe spin exchange optical pumping cells. AB - High-volume production of hyperpolarized 129Xe by spin-exchange optical pumping (SEOP) has historically fallen short of theoretical predictions. Recently, this shortfall was proposed to be caused by the formation of alkali metal clusters during optical pumping. However, this hypothesis has yet to be verified experimentally. Here, we seek to detect the presence of alkali particles using a combination of both transmission (TEM) and scanning (SEM) electron microscopy. From TEM studies, we observe the presence of particles exhibiting sizes ranging from approximately 0.2 to 1 MUm and present at densities of order 10 s of particles per 100 square microns. Particle formation was more closely associated with extensive cell usage history than short-term ([Formula: see text]1 h) SEOP exposure. From the SEM studies, we observe pits on the cell surface. These pits are remarkably smooth, were frequently found adjacent to Rb particles, and located predominantly on the front face of the cells; they range in size from 1 to 5 MUm. Together, these findings suggest that Rb particles do form during the SEOP process and at times can impart sufficient energy to locally alter the Pyrex surface. PMID- 28804158 TI - Productive procrastination: academic procrastination style predicts academic and alcohol outcomes. AB - Productive procrastination replaces one adaptive behavior with another adaptive albeit less important-behavior (e.g., organizing notes instead of studying for an exam). We identified adaptive and maladaptive procrastination styles associated with academic and alcohol outcomes in 1106 college undergraduates. Cluster analysis identified five academic procrastination styles-non-procrastinators, academic productive procrastinators, non-academic productive procrastinators, non academic procrastinators, and classic procrastinators. Procrastination style differentially predicted alcohol-related problems, cravings, risk of alcohol use disorders, and GPA (all ps < .01). Non-procrastination and academic productive procrastination were most adaptive overall; non-academic productive procrastination, non-academic procrastination, and classic procrastination were least adaptive. Productive procrastination differed from other procrastination strategies, and maladaptive procrastination styles may be a useful risk indicator for preventative and intervention efforts. PMID- 28804159 TI - Geodesic curvature driven surface microdomain formation. AB - Lipid bilayer membranes are not uniform and clusters of lipids in a more ordered state exist within the generally disorder lipid milieu of the membrane. These clusters of ordered lipids microdomains are now referred to as lipid rafts. Recent reports attribute the formation of these microdomains to the geometrical and molecular mechanical mismatch of lipids of different species on the boundary. Here we introduce the geodesic curvature to characterize the geometry of the domain boundary, and develop a geodesic curvature energy model to describe the formation of these microdomains as a result of energy minimization. Our model accepts the intrinsic geodesic curvature of any binary lipid mixture as an input, and will produce microdomains of the given geodesic curvature as demonstrated by three sets of numerical simulations. Our results are in contrast to the surface phase separation predicted by the classical surface Cahn-Hilliard equation, which tends to generate large domains as a result of the minimizing line tension. Our model provides a direct and quantified description of the structure inhomogeneity of lipid bilayer membrane, and can be coupled to the investigations of biological processes on membranes for which such inhomogeneity plays essential roles. PMID- 28804160 TI - Smart Nanoscale Drug Delivery Platforms from Stimuli-Responsive Polymers and Liposomes. AB - Since the 1960's, stimuli-responsive polymers have been utilized as functional soft materials for biological applications such as the triggered-release delivery of biologically active cargos. Over the same period, liposomes have been explored as an alternative drug delivery system with potentials to decrease the toxic side effects often associated with conventional small-molecule drugs. However, the lack of drug-release triggers and the instability of bare liposomes often limit their practical applications, causing short circulation time and low therapeutic efficacy. This perspective article highlights recent work in integrating these two materials together to achieve a targetable, triggerable nanoscale platform that fulfills all the characteristics of a near-ideal drug delivery system. Through a drop-in, post-synthesis modification strategy, a network of stimuli responsive polymers can be integrated onto the surface of liposomes to form polymer-caged nanobins, a multifunctional nanoscale delivery platform that allows for multi-drug loading, targeted delivery, triggered drug-release, and theranostic capabilities. PMID- 28804162 TI - The third global patient safety challenge: tackling medication-related harm. PMID- 28804164 TI - Public health round-up. PMID- 28804163 TI - Critical gaps in laboratory leadership to meet global health security goals. PMID- 28804165 TI - Addressing Asia's fast growing diabetes epidemic. AB - Hampered by shortages of resources, specialized services and skilled health workers, India and other countries in south-east Asia are scrambling to respond to type 2 diabetes epidemics. Sophie Cousins reports. PMID- 28804166 TI - Making evidence-based approaches to autism accessible. AB - One of the greatest challenges for the public health response to autism is providing access to evidence-based care. Sally J Rogers tells Andreia Azevedo Soares how parents can help their children mitigate the disabilities associated with autism. PMID- 28804167 TI - The impact of the roll-out of rapid molecular diagnostic testing for tuberculosis on empirical treatment in Cape Town, South Africa. AB - OBJECTIVE: To investigate the impact of introducing a rapid test as the first line diagnostic test for drug-sensitive tuberculosis in Cape Town, South Africa. METHODS: Xpert(r) MTB/RIF (Xpert(r)), an automated polymerase-chain-reaction based assay, was rolled out between 2011 and 2013. Data were available on 102 007 adults treated for pulmonary tuberculosis between 2010 and 2014. Tuberculosis notification rates per 100 000 population were calculated for each calendar year and for each year relative to the test roll-out locally, overall and by bacteriological confirmation. Empirical treatment was defined as treatment given without bacteriological confirmation by Xpert(r), sputum smear microscopy or sputum culture. FINDINGS: Between 2010 and 2014, the proportion of human immunodeficiency virus (HIV)-negative patients treated empirically for tuberculosis declined from 23% (2445/10 643) to 11% (1149/10 089); in HIV positive patients, it declined from 42% (4229/9985) to 27% (2364/8823). The overall tuberculosis notification rate decreased by 12% and 19% among HIV negative and HIV-positive patients, respectively; the rate of bacteriologically confirmed cases increased by 1% and 3%, respectively; and the rate of empirical treatment decreased by 56% and 49%, respectively. These changes occurred gradually following the test's introduction and stabilized after 3 years. CONCLUSION: Roll-out of the rapid test in a setting with a high prevalence of pulmonary tuberculosis and HIV infection was associated with a halving of empirical treatment that occurred gradually after the test's introduction, possibly reflecting the time needed for full implementation. More than a quarter of HIV-positive patients with tuberculosis were still treated empirically, highlighting the diagnostic challenge in these patients. PMID- 28804168 TI - Malaria in China, 2011-2015: an observational study. AB - OBJECTIVE: To ascertain the trends and burden of malaria in China and the costs of interventions for 2011-2015. METHODS: We analysed the spatiotemporal and demographic features of locally transmitted and imported malaria cases using disaggregated surveillance data on malaria from 2011 to 2015, covering the range of dominant malaria vectors in China. The total and mean costs for malaria elimination were calculated by funding sources, interventions and population at risk. FINDINGS: A total of 17 745 malaria cases, including 123 deaths (0.7%), were reported in mainland China, with 15 840 (89%) being imported cases, mainly from Africa and south-east Asia. Almost all counties of China (2855/2858) had achieved their elimination goals by 2015, and locally transmitted cases dropped from 1469 cases in 2011 to 43 cases in 2015, mainly occurring in the regions bordering Myanmar where Anopheles minimus and An. dirus are the dominant vector species. A total of United States dollars (US$) 134.6 million was spent in efforts to eliminate malaria during 2011-2015, with US$ 57.2 million (43%) from the Global Fund to Fight AIDS, Tuberculosis and Malaria and US$ 77.3 million (57%) from the Chinese central government. The mean annual investment (US$ 27 million) per person at risk (574 million) was US$ 0.05 (standard deviation: 0.03). CONCLUSION: The locally transmitted malaria burden in China has decreased. The key challenge is to address the remaining local transmission, as well as to reduce imported cases from Africa and south-east Asia. Continued efforts and appropriate levels of investment are needed in the 2016-2020 period to achieve elimination. PMID- 28804169 TI - A cohort study of low birth weight and health outcomes in the first year of life, Ghana. AB - OBJECTIVE: To investigate the effect of birth weight on infant mortality, illness and care seeking in rural Ghana. METHODS: Using randomized controlled trial data, we compared infants weighing 2.00-2.49, 1.50-1.99 and < 1.50 kg with non-low birth-weight infants. We generated adjusted mortality hazard ratios (aHR), adjusted illness rate ratios (aRR) and adjusted odds ratios (aOR) for health facility admissions and absence of care seeking for four time periods: infancy, the neonatal period, early infancy and late infancy - represented by ages of 0 364, 0-27, 28-182 and 183-364 days, respectively. FINDINGS: Among 22 906 infants, compared with non-low-birth-weight infants: (i) infants weighing 2.00-2.49, 1.50 1.99 and < 1.50 kg were about two (aHR: 2.13; 95% confidence interval, CI: 1.76 2.59), eight (aHR: 8.21; 95% CI: 6.26-10.76) and 25 (aHR: 25.38; 95% CI: 18.36 35.10) times more likely to die in infancy, respectively; (ii) those born weighing < 1.50 kg were about 48 (aHR: 48.45; 95% CI: 32.81-71.55) and eight (aHR: 8.42; 95% CI: 3.09-22.92) times more likely to die in the neonatal period and late infancy, respectively; (iii) those born weighing 1.50-1.99 kg (aRR: 1.57; 95% CI: 1.27-1.95) or < 1.50 kg (aRR: 1.58; 95% CI: 1.13-2.21) had higher neonatal illness rates; and (iv) for those born weighing 1.50-1.99 kg, care was less likely to be sought in the neonatal period (aOR: 3.30; 95% CI: 1.98-5.48) and early infancy (aOR : 1.74; 95% CI: 1.26-2.39). CONCLUSION: For low-birth weight infants in Ghana, strategies to minimize mortality and improve care seeking are needed. PMID- 28804170 TI - Decentralized care for multidrug-resistant tuberculosis: a systematic review and meta-analysis. AB - OBJECTIVE: To assess the effectiveness of decentralized treatment and care for patients with multidrug-resistant (MDR) tuberculosis, in comparison with centralized approaches. METHODS: We searched ClinicalTrials.gov, the Cochrane library, Embase(r), Google Scholar, LILACS, PubMed(r), Web of Science and the World Health Organization's portal of clinical trials for studies reporting treatment outcomes for decentralized and centralized care of MDR tuberculosis. The primary outcome was treatment success. When possible, we also evaluated, death, loss to follow-up, treatment adherence and health-system costs. To obtain pooled relative risk (RR) estimates, we performed random-effects meta-analyses. FINDINGS: Eight studies met the eligibility criteria for review inclusion. Six cohort studies, with 4026 participants in total, reported on treatment outcomes. The pooled RR estimate for decentralized versus centralized care for treatment success was 1.13 (95% CI: 1.01-1.27). The corresponding estimate for loss to follow-up was RR: 0.66 (95% CI: 0.38-1.13), for death RR: 1.01 (95% CI: 0.67 1.52) and for treatment failure was RR: 1.07 (95% CI: 0.48-2.40). Two of three studies evaluating health-care costs reported lower costs for the decentralized models of care than for the centralized models. CONCLUSION: Treatment success was more likely among patients with MDR tuberculosis treated using a decentralized approach. Further studies are required to explore the effectiveness of decentralized MDR tuberculosis care in a range of different settings. PMID- 28804171 TI - Threats posed by stockpiles of expired pharmaceuticals in low- and middle-income countries: a Ugandan perspective. AB - In some low- and middle-income countries, the national stores and public-sector health facilities contain large stocks of pharmaceuticals that are past their expiry dates. In low-income countries like Uganda, many such stockpiles are the result of donations. If not adequately monitored or regulated, expired pharmaceuticals may be repackaged and sold as counterfeits or be dumped without any thought of the potential environmental damage. The rates of pharmaceutical expiry in the supply chain need to be reduced and the disposal of expired pharmaceuticals needs to be made both timely and safe. Many low- and middle income countries need to: (i) strengthen public systems for medicines' management, to improve inventory control and the reliability of procurement forecasts; (ii) reduce stress on central medical stores, through liberalization and reimbursement schemes; (iii) strengthen the regulation of drug donations; (iv) explore the salvage of officially expired pharmaceuticals, through re analysis and possible shelf-life extension; (v) strengthen the enforcement of regulations on safe drug disposal; (vi) invest in an infrastructure for such disposal, perhaps based on ultra-high-temperature incinerators; and (vii) include user accountability for expired pharmaceuticals within the routine accountability regimes followed by the public health sector. PMID- 28804172 TI - Antimicrobial resistance: from global agenda to national strategic plan, Thailand. AB - PROBLEM: In Thailand, antimicrobial resistance has formed a small component of national drug policies and strategies on emerging infectious diseases. However, poor coordination and a lack of national goals and monitoring and evaluation platforms have reduced the effectiveness of the corresponding national actions. APPROACH: On the basis of local evidence and with the strong participation of relevant stakeholders, the first national strategic plan on antimicrobial resistance has been developed in Thailand. LOCAL SETTING: Before the development of the plan, ineffective coordination meant that antimicrobial resistance profiles produced at sentinel hospitals were not used effectively for clinical decision-making. There was no integrated system for the surveillance of antimicrobial resistance, no system for monitoring consumption of antimicrobial drugs by humans, livestock and pets and little public awareness of antimicrobial resistance. RELEVANT CHANGES: In August 2016, the Thai government endorsed a national strategic plan on antimicrobial resistance that comprised six strategic actions and five targets. A national steering committee guides the plan's implementation and a module to assess the prevalence of household antibiotic use and antimicrobial resistance awareness has been embedded into the biennial national health survey. A national system for the surveillance of antimicrobial consumption has also been initiated. LESSONS LEARNT: Strong political commitment, national ownership and adequate multisectoral institutional capacities will be essential for the effective implementation of the national plan. A robust monitoring and evaluation platform now contributes to evidence-based interventions. An integrated system for the surveillance of antimicrobial resistance still needs to be established. PMID- 28804173 TI - Environmental health policies for women's, children's and adolescents' health. PMID- 28804174 TI - Improving the built environment in urban areas to control Aedes aegypti-borne diseases. PMID- 28804175 TI - Corrigendum. AB - [This corrects the article DOI: 10.2471/BLT.16.187476.]. PMID- 28804177 TI - Tracking the emergence of synthetic biology. AB - Synthetic biology is an emerging domain that combines biological and engineering concepts and which has seen rapid growth in research, innovation, and policy interest in recent years. This paper contributes to efforts to delineate this emerging domain by presenting a newly constructed bibliometric definition of synthetic biology. Our approach is dimensioned from a core set of papers in synthetic biology, using procedures to obtain benchmark synthetic biology publication records, extract keywords from these benchmark records, and refine the keywords, supplemented with articles published in dedicated synthetic biology journals. We compare our search strategy with other recent bibliometric approaches to define synthetic biology, using a common source of publication data for the period from 2000 to 2015. The paper details the rapid growth and international spread of research in synthetic biology in recent years, demonstrates that diverse research disciplines are contributing to the multidisciplinary development of synthetic biology research, and visualizes this by profiling synthetic biology research on the map of science. We further show the roles of a relatively concentrated set of research sponsors in funding the growth and trajectories of synthetic biology. In addition to discussing these analyses, the paper notes limitations and suggests lines for further work. PMID- 28804179 TI - Mapping patent classifications: portfolio and statistical analysis, and the comparison of strengths and weaknesses. AB - The Cooperative Patent Classifications (CPC) recently developed cooperatively by the European and US Patent Offices provide a new basis for mapping patents and portfolio analysis. CPC replaces International Patent Classifications (IPC) of the World Intellectual Property Organization. In this study, we update our routines previously based on IPC for CPC and use the occasion for rethinking various parameter choices. The new maps are significantly different from the previous ones, although this may not always be obvious on visual inspection. We provide nested maps online and a routine for generating portfolio overlays on the maps; a new tool is provided for "difference maps" between patent portfolios of organizations or firms. This is illustrated by comparing the portfolios of patents granted to two competing firms-Novartis and MSD-in 2016. Furthermore, the data is organized for the purpose of statistical analysis. PMID- 28804178 TI - Online distribution channel increases article usage on Mendeley: a randomized controlled trial. AB - Prior research shows that article reader counts (i.e. saves) on the online reference manager, Mendeley, correlate to future citations. There are currently no evidenced-based distribution strategies that have been shown to increase article saves on Mendeley. We conducted a 4-week randomized controlled trial to examine how promotion of article links in a novel online cross-publisher distribution channel (TrendMD) affect article saves on Mendeley. Four hundred articles published in the Journal of Medical Internet Research were randomized to either the TrendMD arm (n = 200) or the control arm (n = 200) of the study. Our primary outcome compares the 4-week mean Mendeley saves of articles randomized to TrendMD versus control. Articles randomized to TrendMD showed a 77% increase in article saves on Mendeley relative to control. The difference in mean Mendeley saves for TrendMD articles versus control was 2.7, 95% CI (2.63, 2.77), and statistically significant (p < 0.01). There was a positive correlation between pageviews driven by TrendMD and article saves on Mendeley (Spearman's rho r = 0.60). This is the first randomized controlled trial to show how an online cross publisher distribution channel (TrendMD) enhances article saves on Mendeley. While replication and further study are needed, these data suggest that cross publisher article recommendations via TrendMD may enhance citations of scholarly articles. PMID- 28804180 TI - How do NIHR peer review panels use bibliometric information to support their decisions? AB - Bibliometrics is widely used as an evaluation tool to assist prospective R&D decision-making. In the UK, for example, the National Institute for Health Research (NIHR) has employed bibliometric analysis alongside wider information in several awarding panels for major funding schemes. In this paper, we examine various aspects of the use of bibliometric information by members of these award selection panels, based on interviews with ten panel members from three NIHR panels, alongside analysis of the information provided to those panels. The aim of the work is to determine what influence bibliometrics has on their decision making, to see which types of bibliometric measures they find more and less useful, and to identify the challenges they have when using these data. We find that panel members broadly support the use of bibliometrics in panel decision making, and that the data are primarily used in the initial individual assessment of candidates, playing a smaller role in the selection panel meeting. Panel members felt that the most useful measures of performance are normalised citation scores and the number or proportion of papers in the most highly cited X% (e.g. 5, 10%) for the field. Panel members expressed concerns around the comparability of bibliometrics between fields, but the discussion suggested this largely represents a lack of understanding of bibliometric techniques, confirming that effective background information is important. Based on the evidence around panel behaviour and concerns, we set out guidance around providing bibliometrics to research funding panels. PMID- 28804181 TI - Investigating the Practical Consequences of Model Misfit in Unidimensional IRT Models. AB - In this article, the practical consequences of violations of unidimensionality on selection decisions in the framework of unidimensional item response theory (IRT) models are investigated based on simulated data. The factors manipulated include the severity of violations, the proportion of misfitting items, and test length. The outcomes that were considered are the precision and accuracy of the estimated model parameters, the correlations of estimated ability ([Formula: see text]) and number-correct ([Formula: see text]) scores with the true ability ([Formula: see text]), the ranks of the examinees and the overlap between sets of examinees selected based on either [Formula: see text], [Formula: see text], or [Formula: see text] scores, and the bias in criterion-related validity estimates. Results show that the [Formula: see text] values were unbiased by violations of unidimensionality, but their precision decreased as multidimensionality and the proportion of misfitting items increased; the estimated item parameters were robust to violations of unidimensionality. The correlations between [Formula: see text], [Formula: see text], and [Formula: see text] scores, the agreement between the three selection criteria, and the accuracy of criterion-related validity estimates are all negatively affected, to some extent, by increasing levels of multidimensionality and the proportion of misfitting items. However, removing the misfitting items only improved the results in the case of severe multidimensionality and large proportion of misfitting items, and deteriorated them otherwise. PMID- 28804182 TI - Change-Plane Analysis for Subgroup Detection and Sample Size Calculation. AB - We propose a systematic method for testing and identifying a subgroup with an enhanced treatment effect. We adopts a change-plane technique to first test the existence of a subgroup, and then identify the subgroup if the null hypothesis on non-existence of such a subgroup is rejected. A semiparametric model is considered for the response with an unspecified baseline function and an interaction between a subgroup indicator and treatment. A doubly-robust test statistic is constructed based on this model, and asymptotic distributions of the test statistic under both null and local alternative hypotheses are derived. Moreover, a sample size calculation method for subgroup detection is developed based on the proposed statistic. The finite sample performance of the proposed test is evaluated via simulations. Finally, the proposed methods for subgroup identification and sample size calculation are applied to a data from an AIDS study. PMID- 28804183 TI - Women's Agency and Fertility: Recent Evidence from Egypt. AB - Fertility reached a two decade high of 3.5 births per woman in Egypt in 2014. Lower status of women is associated with higher fertility. Majority of the studies on women's agency and fertility rely on individual level cross-sectional data from South Asia, which limits the understanding of variation among communities and the direction of the relationship between women's agency and fertility in other global contexts. This study examines the relationship between women's agency and fertility longitudinally and among communities in the most populous country in the Middle East - Egypt. For 3,795 ever married women 15 to 49 years old in the 2006 and 2012 Egyptian Labor Market Panel Survey, multilevel models are estimated for having given birth and number of births between 2006 and 2012. Contrary to expectation, women with more agency with greater participation in household decision-making and mobility are, in fact, more likely to have had a birth and have a greater total number of births. Only women with more egalitarian attitudes are associated with fewer births. Community membership explains 5% of the variation in fertility. Since social norms in Egypt favor a higher number of births and labor market participation among women is low, women with agency could be fulfilling social expectations of having children and choosing to have more children. PMID- 28804184 TI - A Comparison of Three Online Recruitment Strategies for Engaging Parents. AB - Family scientists can face the challenge of effectively and efficiently recruiting normative samples of parents and families. Utilizing the Internet to recruit parents is a strategic way to find participants where they already are, enabling researchers to overcome many of the barriers to in-person recruitment. The present study was designed to compare three online recruitment strategies for recruiting parents: e-mail Listservs, Facebook, and Amazon Mechanical Turk (MTurk). Analyses revealed differences in the effectiveness and efficiency of data collection. In particular, MTurk resulted in the most demographically diverse sample, in a short period of time, with little cost. Listservs reached a large number of participants and resulted in a comparatively homogeneous sample. Facebook was not successful in recruiting a general sample of parents. Findings provide information that can help family researchers and practitioners be intentional about recruitment strategies and study design. PMID- 28804187 TI - A DFT study of uranyl hydroxyl complexes: structure and stability of trimers and tetramers. AB - A DFT study of U(VI) hydroxy complexes was performed with special attention paid to the [(UO2)3(OH)5(H2O)4-7]+ and [(UO2)4(OH)7(H2O)5-8]+ species. It was established that the ionicity of the U=O bond increased when moving from [(UO2)(H2O)5]2+, [(UO2)2(OH)(H2O)8]3+, [(UO2)2(OH)2(H2O)6]2+, [(UO2)3(OH)5(H2O)4 6]+ to [(UO2)4(OH)7(H2O)5-8]+ species. In both [(UO2)3(OH)5(H2O)4-6]+ and [(UO2)4(OH)7(H2O)5-8]+ complexes, the U=O bond was observed to have a range of different lengths which depended on the composition of the first coordination sphere of UO22+. The cyclic structures of trimeric complexes were somewhat more stable than their linear structures, which was probably due to the steric effect. PMID- 28804188 TI - About the Cover. PMID- 28804189 TI - About the Cover. PMID- 28804186 TI - 47Sc production development by cyclotron irradiation of 48Ca. AB - The therapeutic radionuclide 47Sc was produced through the 48Ca(p,2n) channel on a proton beam accelerator. The obtained results show that the optimum proton energies are in the range of 24-17 MeV, giving the possibility to produce 47Sc radionuclide containing 7.4% of 48Sc. After activation, the powdery CaCO3 target material was dissolved in HCl and scandium isotopes were isolated from the targets. The performed separation experiments indicate that, due to the simplicity of the operations and the chemical purity of the obtained 47Sc the best separation process is when scandium radioisotopes are separated on the 0.2 um filter. PMID- 28804185 TI - Somatostatin analogues labeled with copper radioisotopes: current status. AB - Peptide receptor radionuclide therapy (PRRT) is a promising way to treat patients with inoperable tumors or metastatic neuroendocrine tumors. This therapeutic strategy is using radiolabeled peptides, which are capable of selective biding to receptors overexpressed in the cancer cells. One of the group of receptor-avid peptide used in the PRRT are the analogues of somatostatin (SST) connected to the complexes of radionuclides (e.g. 90Y, 177Lu or 111In). Many studies have shown that radiopharmaceuticals based on Cu radioisotopes are promising for the diagnosis and treatment of various cancers. This mini-review focuses on recent developments and summarises the results of multiple studies addressing SST agonists and antagonists radiolabeled to Cu radioisotopes. PMID- 28804190 TI - About the Cover. PMID- 28804191 TI - About the Cover. PMID- 28804193 TI - About the Cover. PMID- 28804192 TI - About the Cover. PMID- 28804195 TI - About the Cover. PMID- 28804194 TI - About the Cover. PMID- 28804196 TI - About the Cover. PMID- 28804197 TI - About the Cover. PMID- 28804198 TI - Association between Cullin-3 Single-Nucleotide Polymorphism rs17479770 and Essential Hypertension in the Male Chinese Han Population. AB - BACKGROUND: Hypertension, including essential and secondary hypertension, is a multifactorial disease, affecting more than one billion people worldwide. Secondary hypertension can result from mutations of cullin-3 (CUL3); however, whether polymorphisms of CUL3 are associated with essential hypertension (EH) has not been reported. Here, we investigated the association between CUL3 SNPs rs17479770 and rs3738952 and EH in the Chinese Han population. METHODS: This case control study investigated 520 representatives, including 259 patients with EH and 261 normotensive controls matched for age, gender, BMI, TG, TC, and HbA1c for the distribution of functional rs17479770 and rs3738952 within the CUL3 gene by using PCR and RFLP. RESULTS: Our results showed that there was no significant difference in allele and genotype distribution of rs3738952 and haplotype distribution of rs17479770 and rs3738952 between the EH group and normotensive group, whereas the rs17479770 TT genotype in male and the full data set were significantly associated with the decreased risk of EH (P = 0.050, P = 0.042), and rs17479770 allele T in male was shown to have the correlation tendency of the decreased risk of EH (P = 0.064). CONCLUSION: Our data suggest that the CUL3 rs17479770 variant could be a protective factor in the pathogenesis of EH. PMID- 28804200 TI - Making Aircraft Vortices Visible to Radar by Spraying Water into the Wake. AB - Aircraft trailing vortices pose a danger to following aircraft during take-off and landing. This necessitates spacing rules, based on aircraft type, to be enforced during approach in IFR (Instrument Flight Regulations) conditions; this can limit airport capacity. To help choose aircraft spacing based on the actual location and strength of the wake, it is proposed that wake vortices can be detected using conventional precipitation and cloud radars. This is enabled by spraying a small quantity water into the wake from near the wing. The vortex strength is revealed by the doppler velocity of the droplets. In the present work, droplet size distributions produced by nozzles used for aerial spraying are considered. Droplet trajectory and evaporation in the flow-field is numerically calculated for a heavy aircraft, followed by an evaluation of radar reflectivity at 6 nautical miles behind the aircraft. Small droplets evaporate away while larger droplets fall out of the wake. In the humid conditions that typically prevail during IFR, a sufficient number of droplets remain in the wake and give good signal-to-noise ratios (SNR). For conditions of average humidity, higher frequency radars combined with spectral processing gives good SNR. PMID- 28804201 TI - Spectral dependence of the seawater-air radiance transmission coefficient. AB - The transmission coefficient, TL, commonly used to propagate the upwelling nadir radiance, just below the ocean surface, to above the surface has been assumed to be a constant value of 0.543 in seawater. Because the index of refraction of seawater varies with wavelength, salinity, and temperature, the variation of TL with these parameters should be taken into account, especially if low uncertainty is required for the quantities derived using TL. In particular the wavelength dependence of this factor is important. For example at a salinity of 35 g/kg and a temperature of 26 degrees C, TL will be 1.3% lower at 380 nm and 1.1 % higher at 700 nm than the constant value (0.543) and should be taken into account when calculating the water leaving radiance and normalized water leaving radiance from in-water measurements. PMID- 28804199 TI - High Sensitivity Troponins Discriminate Different Morphologies of Coronary Artery Plaques Being Assessed by Coronary Computed Tomography Angiography. AB - BACKGROUND: This study evaluates the association between high sensitivity troponin I (hsTnI) and T (hsTnT) and the morphology of coronary artery plaques detected by coronary computed tomography angiography (CCTA) in patients with suspected coronary artery disease (CAD). METHODS: Patients undergoing CCTA were prospectively enrolled. CCTA was indicated by a low to intermediate pretest probability for CAD during routine clinical care. Within 24 hours of CCTA examination, peripheral blood samples were taken to measure hsTnI, hsTnT, and N terminal probrain natriuretic peptide (NT-proBNP). RESULTS: A total of 99 patients were enrolled with 43% without CAD, 9% with noncalcified plaques, 28% with calcified plaques, and 19% with mixed type plaque lesions. Both hsTnI and hsTnT levels were able to discriminate significantly between the groups, especially in the presence of mixed coronary plaques (AUC range: 0.741-0.752; p = 0.0001). In multivariate logistic regression models, hsTnT, but not hsTnI, was still significantly associated with mixed coronary plaque morphology (odds ratio = 8.968; 95% CI 1.999-40.241; p = 0.004). CONCLUSIONS: Both hsTnI and hsTnT are able to discriminate between different coronary artery plaques morphologies, whereas hsTnT was significantly associated with mixed coronary plaques in patients with suspected CAD. This trial is registered with NCT03074253. PMID- 28804202 TI - A method to extrapolate the diffuse upwelling radiance attenuation coefficient to the surface as applied to the Marine Optical Buoy (MOBY). AB - The upwelling radiance attenuation coefficient (KLu) in the upper 10 m of the water column can be significantly influenced by inelastic scattering processes, and thus will vary even with homogeneous water properties. The Marine Optical BuoY (MOBY), the primary vicarious calibration site for many ocean color sensors, makes measurements of the upwelling radiance (Lu) at 1 m, 5 m, and 9 m and uses these values to determine KLu and propagate the upwelling radiance directed toward the zenith, Lu, at 1 m to and through the surface. Inelastic scattering causes the KLu derived from the arm measurements to be an underestimate of the true KLu from 1 m to the surface at wavelengths greater than 575 nm, thus the derived water leaving radiance is underestimated at wavelengths longer than 575 nm. A method to correct this KLu, based on a model of the upwelling radiance including Raman scattering and chlorophyll fluorescence has been developed which corrects this bias. The model has been experimentally validated, and this technique can be applied to the MOBY data set to provide new, more accurate products at these wavelengths. When applied to a 4 month MOBY deployment, the corrected water leaving radiance, Lw, can increase by 5 % (600 nm), 10 % (650 nm) and 50 % (700 nm). This method will be used to provide additional more accurate products in the MOBY data set. PMID- 28804203 TI - Clinical features and molecular basis of pseudohypoaldosteronism type 1. AB - Pseudohypoaldosteronism (PHA) type 1 is a disease showing mineralocorticoid resistance in the kidney and/or other mineralocorticoid target tissues. Patients with PHA1 present very high plasma aldosterone and renin levels, but they develop excessive salt wasting. There are three types of PHA1. The systemic form of PHA1 is inherited in an autosomal recessive manner and causes severe life-long salt loss in multiple target tissues, such as sweat glands, salivary glands, the colonic epithelium, and the lung. In the systemic form of PHA1, life-long salt supplementation is necessary. The second type is the renal form, where aldosterone resistance is shown only in the kidney, and its inheritance is autosomal dominant. In the renal form of PHA1, salt supplementation generally becomes unnecessary by 1-3 yr of age. The third type is the secondary PHA1, which is strongly associated with urinary tract infections and/or urinary tract malformations. This review summarizes the clinical features and molecular basis of PHA1. Understanding of its pathogenesis can be helpful for the early diagnosis and clinical care of affected children with PHA1. PMID- 28804204 TI - ACAN mutations as a cause of familial short stature. AB - Aggrecan, encoded by ACAN, is a major proteoglycan component of the extracellular matrix in the growth plate and articular cartilage. Aggrecan provides the hydrated gel structure important for the load-bearing properties of joints and plays a key role in cartilage and bone morphogenesis. At least 25 pathological ACAN mutations have been identified in patients with highly variable phenotypes of syndromic or non-syndromic short stature. This review provides an overview of the current understanding of ACAN and the clinical and genetic findings concerning aggrecan-associated diseases. PMID- 28804206 TI - Validation of auxological reference values for Japanese children with Noonan syndrome and comparison with growth in children with Turner syndrome. AB - We recently published growth references for Japanese individuals with Noonan syndrome (NS). However, it is uncertain whether these references can be used to evaluate the longitudinal growth of children with NS. In addition, these charts did not include detailed values suitable for clinical practice, and they did not include weight-for-height (WFH) charts. In the present study, we validated the references and established new WFH charts for children with NS. In addition, we investigated the growth patterns of these children by comparing them with those of children with Turner syndrome (TS), as well as with those of the normal population. To validate our reference values, we enrolled 32 subjects from our previous study with data available at both a younger (<= 5 yr) and an older age (>= 15 yr). We then investigated longitudinal changes in NS-specific standard deviation scores (SDSs) for height in these subjects. There was no significant difference between the initial and later SDSs (mean difference: -0.12, 95% confidence interval: -0.26-0.023, P = 0.10), suggesting that the references could be applied in clinical practice. We also confirmed that the growth patterns of children with NS in each index are significantly different from those of children with TS. In conclusion, we confirmed auxological reference values for Japanese children with NS. PMID- 28804207 TI - Sulfonylurea treatment in an infant with transient neonatal diabetes mellitus caused by an adenosine triphosphate binding cassette subfamily C member 8 gene mutation. AB - Neonatal diabetes mellitus (NDM) is an insulin-requiring monogenic form of diabetes that generally presents before six months of age. The following two types of NDM are known: transient NDM (TNDM) and permanent NDM (PNDM). Here we report on an infant with TNDM caused by a mutation (p.Gly832Cys) of the gene for the ATP binding cassette subfamily C member 8 (ABCC8). The patient exhibited hyperglycemia (600 mg/dL) at five weeks of age and insulin treatment was initiated. As genetic analysis identified a missense mutation within ABCC8, the insulin was replaced by glibenclamide at five months of age. Thereafter, the insulin was successfully withdrawn and his glycemic condition was well controlled at a dose of 0.0375 mg/kg/d. Since the patient's blood glucose was under control and serum C-peptide levels were measurable, glibenclamide was stopped at 1 yr, 10 mo of age. The lack of DM relapsed to date confirms the TNDM diagnosis. In conclusion, when insulin is replaced with a sulfonylurea-class medication (SU) in NDM patients, serum C-peptide levels should be closely monitored and fine adjustment of SU dose is recommended. PMID- 28804205 TI - Clinical practice guidelines for congenital hyperinsulinism. AB - Congenital hyperinsulinism is a rare condition, and following recent advances in diagnosis and treatment, it was considered necessary to formulate evidence-based clinical practice guidelines reflecting the most recent progress, to guide the practice of neonatologists, pediatric endocrinologists, general pediatricians, and pediatric surgeons. These guidelines cover a range of aspects, including general features of congenital hyperinsulinism, diagnostic criteria and tools for diagnosis, first- and second-line medical treatment, criteria for and details of surgical treatment, and future perspectives. These guidelines were generated as a collaborative effort between The Japanese Society for Pediatric Endocrinology and The Japanese Society of Pediatric Surgeons, and followed the official procedures of guideline generation to identify important clinical questions, perform a systematic literature review (April 2016), assess the evidence level of each paper, formulate the guidelines, and obtain public comments. PMID- 28804208 TI - Benign course after acute high dose levothyroxine intoxication in a 3-year-old boy. AB - Acute ingestion of thyroid hormone preparations is a common intoxication, with 181 cases in children <12 yr in 2009 in the Netherlands, but generally has a mild course. However, some reports show that even low dosages may cause serious events such as seizures, thyroid storm and coma. We report a 3 yr old boy case with an acute intoxication with high dose levothyroxine (0.5 mg/kg). We describe the proper management of levothyroxine intoxication in children. A 3-year-old boy with no notable medical history ingested sixty tablets of levothyroxine 150 ug. His vital-signs were normal and the only symptom during admission was a tachycardia the following day. Laboratory data showed elevated T3, fT3 and fT4 levels; and decrease TSH levels. He was treated prophylactically and therapeutically with activated charcoal and propranolol. Despite very high levels, his clinical symptoms were relatively mild. After clinical follow-up for 3 d he was discharged. We propose that children with thyroid hormone intoxication with either a levothyroxine dose >0.1 g/kg, a short interval since ingestion, symptomatic presentation, and/or a fT4 >100 pmol/l should be monitored in the hospital during at least 48-72 h post-ingestion and on an outpatient basis for 14 d. PMID- 28804209 TI - Endocrinological and phenotype evaluation in a patient with acrodysostosis. AB - Acrodysostosis is characterized by distinctive facial features and severe brachydactyly. Mutations in PRKAR1A or PDE4D are known to be responsible for this disease. Cases of hormonal resistance have been reported, particularly in patients with PRKAR1A mutations. The physical characteristics and endocrine function of pseudohypoparathyroidism type Ia is known to resemble acrodysostosis. We report the case of a 4-yr-old patient with a PRKAR1A mutation. He had characteristic facies with an upturned nose and cone-shaped epiphyses of most phalanges. These findings have not been reported as extensive for cases of pseudohypoparathyroidism type Ia. He also had TSH resistance from birth. We performed endocrinological stimulation tests to further evaluate his endocrine status. These examinations revealed resistance to TSH and PTH, but there was normal secretion of ACTH, GH, and cortisol. An Ellsworth-Howard test resulted in normal urinary cAMP excretion. This response differs from that of pseudohypoparathyroidism type Ia. In summary, the constellation of an upturned nose, cone-shaped epiphyses of most if not all phalanges, and PTH resistance with a normal urinary cAMP response may satisfactorily enable clinical diagnosis of acrodysostosis. PMID- 28804210 TI - Efficacy and safety of alogliptin in a pediatric patient with maturity-onset diabetes of the young type 1. AB - The first-line pharmacological treatment for patients with maturity-onset diabetes of the young type 1 (MODY1) and maturity-onset diabetes of the young type 3 (MODY3) are sulfonylureas (SUs) or insulin. However, several reports have suggested the possibility of using incretin-associated drugs, including dipeptidyl-peptidase-4 (DPP-4) inhibitors, for the treatment of patients with these types of MODY. Here we report a case of a pediatric patient with MODY1 who was successfully treated with a DPP-4 inhibitor, alogliptin. A 13-yr-old Japanese girl with diabetes was initially treated with insulin for 5 mo. After diagnosis of MODY1, confirmed via a genetic analysis, treatment was changed from insulin to alogliptin. SUs were prescribed temporarily, but monotherapy with alogliptin finally resulted in good glycemic control. After changing to alogliptin, the patient maintained optimal glycemic control with glycated hemoglobin levels of 6.3-7.0% while maintaining substantial beta-cell function. No adverse events associated with alogliptin were observed. These results suggest that DPP-4 inhibitors may be a potential treatment for patients with MODY1 at the early stage of the disease when residual insulin secretion is still being sustained. PMID- 28804211 TI - Apparent cyclic vaginal bleeding in a child: factitious disorder. AB - A 20-mo-old girl was brought to our department by her mother because of breast enlargement. She was diagnosed with premature thelarche. One month later, she returned to our hospital with a complaint of vaginal bleeding. During the subsequent 6 mo, her vaginal bleeding recurred every month while her breast development disappeared. We performed laboratory tests and imaging. At the end of 6 mo, we realized that her mother's menstrual bleeding and the patient's blood staining were concurrent. The mother confessed applying her vaginal flow to her daughter's underwear. Factitious disorder should be included in the differential diagnosis of unexplained vaginal bleeding in childhood. PMID- 28804212 TI - Premature pubarche in an infant: nonclassical congenital adrenal hyperplasia or mini-puberty variant? PMID- 28804213 TI - Word decoding development in incremental phonics instruction in a transparent orthography. AB - The present longitudinal study aimed to investigate the development of word decoding skills during incremental phonics instruction in Dutch as a transparent orthography. A representative sample of 973 Dutch children in the first grade (Mage = 6;1, SD = 0;5) was exposed to incremental subsets of Dutch grapheme phoneme correspondences during 6 consecutive blocks of 3 weeks of phonics instruction. Children's accuracy and efficiency of curriculum embedded word decoding were assessed after each incremental block, followed by a standardized word decoding measurement. Precursor measures of rapid naming, short-term memory, vocabulary, phonological awareness, and letter knowledge were assessed by the end of kindergarten and subsequently related to the word decoding efficiency in the first grade. The results showed that from the very beginning, children attained ceiling levels of decoding accuracy, whereas their efficiency scores increased despite the incremental character of the consecutive decoding assessments embedded in the curriculum. Structural equation modelling demonstrated high stability of the individual differences assessed by word decoding efficiency during phonics instruction during the first 5 months of the first grade. Curriculum embedded word decoding was highly related to standardized word decoding after phonics instruction was completed. Finally, early literacy and lexical retrieval, and to a lesser extent verbal and visual short term memory, predicted the first fundamental processes of mastering word decoding skills. PMID- 28804214 TI - Sonofragmentation of Ultrathin 1D Nanomaterials. AB - A simple strategy for making nanoparticles by sonofragmentation of high-aspect ratio 1D substrates is introduced. With common laboratory equipment, ultra-thin nanowires are fragmented into nanoparticles of size determined by the nanowire width, resulting within hours in monodisperse, crystalline nanoparticles of < 10 nm. This strategy is applicable to a diversity of semiconductor, oxide and metal nanowires. PMID- 28804215 TI - Seasonal changes in the preen wax composition of the Herring gull Larus argentatus. AB - The preen gland produces oily secretion, which smeared onto a bird's plumage improves its maintenance. The main components of the secretion are waxes, and its composition often changes during the year. The aim of this study was to determine the differences in the chemical composition of preen waxes in adult herring gulls Larus argentatus, captured in Poland in winter and in the breeding season. Preen gland secretions of herring gulls consist of monoester waxes, composed of about 29 saturated C7-C16 fatty acids and about 51 saturated C11-C20 alcohols. Unbranched-octanoic acid and n-hexadecanol dominated fatty acid and alcohol fractions, respectively, but 2-methyl-branched compounds were numerous in all individuals. The chemical compositions of fatty acids and alcohols differ between winter and the breeding season. In breeding gulls, 2-monomethyl-branched fatty acids were lower in content or could not be found, contrary to herring gulls in winter, where 2-monomethyl-substituted fatty acids were the second most abundant among all the fatty acids. Breeding gulls had also a higher content of n-octanoic acid and n-hexadecanol and a lower content of 2,6- and 2,8-dimethyl-substituted fatty acids than individuals caught during the winter. Differences in fatty acid composition were greater in breeding males, which incubate more often at night than breeding females. Hence, chemical changes in the preen wax composition in males may have evolved as additional nocturnal protection against mammalian predators which use olfaction to detect their prey and which are more active at night; however, this needs to be tested. Olfactory-based mate recognition in the colony also cannot be excluded at this stage of experimentation. PMID- 28804216 TI - Methyl N-methylanthranilate: major compound in the defensive secretion of Typhloiulus orpheus (Diplopoda, Julida). AB - The defensive secretion of the julid diplopod Typhloiulus orpheus contains methyl N-methylanthranilate (MNMA), an ester of N-methylanthranilic acid that comprises more than 99% of secretion of this species. MNMA is accompanied by small amounts of methyl anthranilate and two benzoquinones (2-methyl-1,4-benzoquinone and 2 ethyl-1,4-benzoquinone, respectively). MNMA is a known intermediate in the biosynthesis of both benzoquinones (as present in defensive secretions of juliformians) and glomerin-like quinazolines (chemical defense in Glomerida). The compound may have evolved independently in the pathway to glomeridan chemistry, or may even represent a pivotal branching point in the pathway to different chemical classes of diplopod defensive chemistry. PMID- 28804217 TI - The role of conviction and narrative in decision-making under radical uncertainty. AB - We propose conviction narrative theory (CNT) to broaden decision-making theory in order to better understand and analyse how subjectively means-end rational actors cope in contexts in which the traditional assumptions in decision-making models fail to hold. Conviction narratives enable actors to draw on their beliefs, causal models, and rules of thumb to identify opportunities worth acting on, to simulate the future outcome of their actions, and to feel sufficiently convinced to act. The framework focuses on how narrative and emotion combine to allow actors to deliberate and to select actions that they think will produce the outcomes they desire. It specifies connections between particular emotions and deliberative thought, hypothesising that approach and avoidance emotions evoked during narrative simulation play a crucial role. Two mental states, Divided and Integrated, in which narratives can be formed or updated, are introduced and used to explain some familiar problems that traditional models cannot. PMID- 28804218 TI - Emotion socialization in the context of risk and psychopathology: Mother and father socialization of anger and sadness in adolescents with depressive disorder. AB - This study examined parental emotion socialization processes associated with adolescent unipolar depressive disorder. Adolescent participants (N=107; 42 boys) were selected either to meet criteria for current unipolar depressive disorder or to be psychologically healthy as defined by no lifetime history of psychopathology or mental health treatment and low levels of current depressive symptomatology. A multisource/method measurement strategy was used to assess mothers' and fathers' responses to adolescent sad and angry emotion. Each parent and the adolescents completed questionnaire measures of parental emotion socialization behavior, and participated in meta-emotion interviews and parent adolescent interactions. As hypothesized, parents of adolescents with depressive disorder engaged in fewer supportive responses and more unsupportive responses overall relative to parents of nondepressed adolescents. Between group differences were more pronounced for families of boys, and for fathers relative to mothers. The findings indicate that parent emotion socialization is associated with adolescent depression and highlight the importance of including fathers in studies of emotion socialization, especially as it relates to depression. PMID- 28804219 TI - DAMPs Synergize with Cytokines or Fibronectin Fragment on Inducing Chondrolysis but Lose Effect When Acting Alone. AB - OBJECTIVE AND DESIGN: To investigate whether endogenous damage-associated molecular patterns (DAMPs) or alarmins originated from mitochondria or nucleus stimulates inflammatory response in articular chondrocytes to cause chondrolysis which leads to cartilage degradation featured in posttraumatic osteoarthritis (PTOA). MATERIALS: Primary cultures of bovine or human chondrocytes isolated from cartilage of weight-bearing joints. TREATMENT: Chondrocytes were subjected to mitochondrial DAMPs (MTDs) or HMGB1, a nuclear DAMP (NuD), with or without the presence of an N-terminal 29 kDa fibronectin fragment (Fn-f) or proinflammatory cytokines (IL-1beta and TNF-alpha). Injured cartilage-conditioned culturing medium containing a mixture of DAMPs was employed as a control. After 24 hrs, the protein expression of cartilage degrading metalloproteinases and iNOS in culture medium or cell lysates was examined with Western blotting, respectively. RESULTS: HMGB1 was synergized with IL-1beta in upregulating expression of MMP-3, MMP-13, ADAMTS-5, ADAM-8, and iNOS. Moreover, a moderate synergistic effect was detected between HMGB1 and Fn-f or between MTDs and TNF-alpha on MMP-3 expression. However, when acting alone, MTDs or HMGB1 did not upregulate cartilage degrading enzymes or iNOS. CONCLUSION: MTDs or HMGB1 could only stimulate inflammatory response in chondrocytes with the presence of cytokines or Fn-f. PMID- 28804220 TI - Antitumor Macrophage Response to Bacillus pumilus Ribonuclease (Binase). AB - Extracellular bacterial ribonucleases such as binase from Bacillus pumilus possess cytotoxic activity against tumor cells with a potential for clinical application. Moreover, they may induce activation of tumor-derived macrophages either into the M1-phenotype with well-documented functions in the regulation of the antitumor immune response or into M2-macrophages that may stimulate tumor growth, metastasis, and angiogenesis. In this study, binase or endogenous RNase1 (but not RNA or short oligonucleotides) stimulated the expression of activated NF kappaB p65 subunit in macrophages. Since no changes in MyD88 and TRIF adaptor protein expression were observed, toll-like receptors may not be involved in RNase-related NF-kappaB pathway activation. In addition, short exposure (0.5 hr) to binase induced the release of cytokines such as IL-6, MSR-1, or TNF-alpha (but not IL-4 and IL-10), indicative for the polarization into antitumor M1 macrophages. Thus, we revealed increased expression of activated NF-kappaB p65 subunit in macrophages upon stimulation by binase and RNase1, but not RNA or short oligonucleotides. PMID- 28804222 TI - Chemical Chaperone of Endoplasmic Reticulum Stress Inhibits Epithelial Mesenchymal Transition Induced by TGF-beta1 in Airway Epithelium via the c-Src Pathway. AB - Epithelial-mesenchymal transition (EMT) is a biological process that allows epithelial cells to assume a mesenchymal cell phenotype. EMT is considered as a therapeutic target for several persistent inflammatory airway diseases related to tissue remodeling. Herein, we investigated the role of endoplasmic reticulum (ER) stress and c-Src in TGF-beta1-induced EMT. A549 cells, primary nasal epithelial cells (PNECs), and inferior nasal turbinate organ cultures were exposed to 4 phenylbutylic acid (4PBA) or PP2 and then stimulated with TGF-beta1. We found that E-cadherin, vimentin, fibronectin, and alpha-SMA expression was increased in nasal polyps compared to inferior turbinates. TGF-beta1 increased the expression of EMT markers such as E-cadherin, fibronectin, vimentin, and alpha-SMA and ER stress markers (XBP-1s and GRP78), an effect that was blocked by PBA or PP2 treatment. 4-PBA and PP2 also blocked the effect of TGF-beta1 on migration of A549 cells and suppressed TGF-beta1-induced expression of EMT markers in PNECs and organ cultures of inferior turbinate. In conclusion, we demonstrated that 4PBA inhibits TGF-beta1-induced EMT via the c-Src pathway in A549 cells, PNECs, and inferior turbinate organ cultures. These results suggest an important role for ER stress and a diverse role for TGF-beta1 in upper airway chronic inflammatory disease such as CRS. PMID- 28804224 TI - PTSD and Alcohol Associations Among Trauma-Exposed Women: Critical Questions for the Field. PMID- 28804223 TI - The Effect of Transcutaneous Electrical Acupoint Stimulation on Inflammatory Response in Patients Undergoing Limb Ischemia-Reperfusion. AB - Reperfusion after tourniquet use can induce inflammation and cause remote organ injury. We evaluated the therapeutic effect of transcutaneous electrical acupoint stimulation (TEAS) on inflammatory mediators and lung function in patients receiving lower limb tourniquets. Forty patients undergoing unilateral lower extremity surgery with tourniquet were randomly assigned to two groups: the TEAS group and ischemia-reperfusion (I/R) group. The C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine ligand 8 (CXCL8), interleukin-1 (IL-1), interleukin 6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha), and arterial blood gas analysis were measured preoperatively and 6 h after tourniquet removal. The levels of CXCL8, IL-1, IL-6, TNF-alpha, and CCL2 were significantly increased compared to baseline values in both groups, but the increase was significantly smaller in the TEAS group. In the TEAS group, the partial pressure of oxygen and arterial-alveolar oxygen tension ratio were significantly decreased, and the alveolar-arterial oxygen tension difference and respiratory index were significantly increased, compared to those in the I/R group at 6 h after reperfusion. In conclusion, TEAS diminished the upregulation of proinflammatory factors in response to lower limb ischemia-reperfusion and improved pulmonary gas exchange. PMID- 28804221 TI - S1P Provokes Tumor Lymphangiogenesis via Macrophage-Derived Mediators Such as IL 1beta or Lipocalin-2. AB - A pleiotropic signaling lipid, sphingosine-1-phosphate (S1P), has been implicated in various pathophysiological processes supporting tumor growth and metastasis. However, there are only a few descriptive studies suggesting a role of S1P in tumor lymphangiogenesis, which is critical for tumor growth and dissemination. Corroborating own data, the literature suggests that apoptotic tumor cell-derived S1P alters the phenotype of tumor-associated macrophages (TAMs) to gain protumor functions. However, mechanistically, the role of TAM-induced lymphangiogenesis has only been poorly described, mostly linked to the production of lymphangiogenic factors such as vascular endothelial growth factor C (VEGF-C) and VEGF-D, or transdifferentiation into lymphatic endothelial cells. Recent findings highlight a rather underappreciated role of S1P in tumor lymphangiogenesis, referring to the production of interleukin-1beta (IL-1beta) and lipocalin-2 (LCN2) by a tumor-promoting macrophage phenotype. In this review, we aim to provide to the readers with the current understanding of the molecular mechanism how apoptotic cell-derived S1P triggers TAMs to promote lymphangiogenesis. PMID- 28804226 TI - [Macroeconomic consequences of population ageing]. PMID- 28804225 TI - Efficient processing of fluorescence images using directional multiscale representations. AB - Recent advances in high-resolution fluorescence microscopy have enabled the systematic study of morphological changes in large populations of cells induced by chemical and genetic perturbations, facilitating the discovery of signaling pathways underlying diseases and the development of new pharmacological treatments. In these studies, though, due to the complexity of the data, quantification and analysis of morphological features are for the vast majority handled manually, slowing significantly data processing and limiting often the information gained to a descriptive level. Thus, there is an urgent need for developing highly efficient automated analysis and processing tools for fluorescent images. In this paper, we present the application of a method based on the shearlet representation for confocal image analysis of neurons. The shearlet representation is a newly emerged method designed to combine multiscale data analysis with superior directional sensitivity, making this approach particularly effective for the representation of objects defined over a wide range of scales and with highly anisotropic features. Here, we apply the shearlet representation to problems of soma detection of neurons in culture and extraction of geometrical features of neuronal processes in brain tissue, and propose it as a new framework for large-scale fluorescent image analysis of biomedical data. PMID- 28804227 TI - Oscillations in deviating difference equations using an iterative technique. AB - The paper deals with the oscillation of the first-order linear difference equation with deviating argument and nonnegative coefficients. New sufficient oscillation conditions, involving limsup, are given, which essentially improve all known results, based on an iterative technique. We illustrate the results and the improvement over other known oscillation criteria by examples, numerically solved in Matlab. PMID- 28804228 TI - Immersion Coefficient for the Marine Optical Buoy (MOBY) Radiance Collectors. AB - The immersion coefficient accounts for the difference in responsivity for a radiometer placed in the air versus water or another medium. In this study, the immersion coefficients for the radiance collectors on the Marine Optical Buoy (MOBY) were modeled and measured. The experiment showed that the immersion coefficient for the MOBY radiance collectors agreed with a simple model using only the index of refraction for water and fused silica. With the results of this experiment, we estimate that the uncertainty in the current value of the immersion coefficient used in the MOBY project is 0.05 % (k = 1). PMID- 28804229 TI - Fabrication of X-ray Microcalorimeter Focal Planes Composed of Two Distinct Pixel Types. AB - We are developing superconducting transition-edge sensor (TES) microcalorimeter focal planes for versatility in meeting specifications of X-ray imaging spectrometers including high count-rate, high energy resolution, and large field of-view. In particular, a focal plane composed of two sub-arrays: one of fine pitch, high count-rate devices and the other of slower, larger pixels with similar energy resolution, offers promise for the next generation of astrophysics instruments, such as the X-ray Integral Field Unit (X-IFU) instrument on the European Space Agency's Athena mission. We have based the sub-arrays of our current design on successful pixel designs that have been demonstrated separately. Pixels with an all gold X-ray absorber on 50 and 75 micron scales where the Mo/Au TES sits atop a thick metal heatsinking layer have shown high resolution and can accommodate high count-rates. The demonstrated larger pixels use a silicon nitride membrane for thermal isolation, thinner Au and an added bismuth layer in a 250 micron square absorber. To tune the parameters of each sub array requires merging the fabrication processes of the two detector types. We present the fabrication process for dual production of different X-ray absorbers on the same substrate, thick Au on the small pixels and thinner Au with a Bi capping layer on the larger pixels to tune their heat capacities. The process requires multiple electroplating and etching steps, but the absorbers are defined in a single ion milling step. We demonstrate methods for integrating heatsinking of the two types of pixel into the same focal plane consistent with the requirements for each sub-array, including the limiting of thermal crosstalk. We also discuss fabrication process modifications for tuning the intrinsic transition temperature (Tc) of the bilayers for the different device types through variation of the bilayer thicknesses. The latest results on these "hybrid" arrays will be presented. PMID- 28804230 TI - The Effect of Blood Transfusion on Outcomes in Aortic Surgery. AB - The use of blood transfusion in cardiac surgery varies widely. The beneficial effects of blood products are offset by an increase in morbidity and mortality. Despite multiple studies showing an association between blood product exposure and adverse short- and long-term events, it is difficult to determine causality. Nevertheless, the implication is sufficient to warrant the search for alternative strategies to reduce the use of blood products while providing a standard of care that optimizes postoperative outcomes. Aortic surgery, in particular, is associated with an increased risk of bleeding requiring a blood transfusion. There is a paucity of evidence within aortic surgery regarding the deleterious effects of blood products. Here, we review the current evidence regarding patient outcomes after blood transfusion in cardiac surgery, with special emphasis on aortic surgery. PMID- 28804231 TI - Preliminary Report on the Safety and Efficacy of Staged versus Complete Revascularization in Patients with Multivessel Disease at the Time of Primary Percutaneous Coronary Intervention. AB - This study aims to determine the safety and efficacy of complete versus staged percutaneous coronary intervention (PCI) of nonculprit lesions at the time of primary PCI in patients with multivessel disease. Recent trials had suggested that revascularization of nonculprit lesions at the time of primary PCI is associated with better outcomes, however; the optimum timing and overall safety of this approach is not well known. An observational prospective study was conducted, including 50 patients who presented with ST-segment elevation myocardial infarction and found to have at least an additional nonculprit significant (> 70%) type A or B lesion. According to the operator's discretion, patients either underwent complete revascularization of nonculprit significant lesions during primary PCI procedure or within 60 days of primary PCI (staged PCI). Safety outcomes evaluated were contrast-induced nephropathy (CIN), the amount of contrast used, and fluoroscopy time. Efficacy outcome assessed was major adverse events (MACE) at 1 year. The fluoroscopy time and amount of contrast used were increased in complete revascularization group (35.3 +/- 9.6 vs. 26.3 +/- 6.7 minutes, p < 0.001, and 219.5 +/- 35.1 vs. 187.5 +/- 45.5 mL, p = 0.01, respectively); while incidence of CIN remained similar ( p = 0.73). The incidence of MACE at 1 year was similar in both groups (23% in the complete revascularization group vs. 25% in the staged-PCI group, p = 0.43). Complete revascularization and staged-PCI of nonculprit type A or B lesions at the time of primary PCI were associated with similar long-term outcomes and safety profile. Larger studies are needed to further validate these results. PMID- 28804232 TI - Acute Beneficial Effects of Muscular Counterpulsation in Patients with Coronary Heart Diseases. AB - This prospective pilot study was designed to investigate the acute hemodynamic effects and clinical applicability of muscular counterpulsation (MCP), a one-shot procedure for biomechanical circulatory support. The study included 17 consecutive patients with coronary artery disease (CAD) and impaired ejection fraction (EF <=45%) who underwent elective coronary artery bypass grafting (CABG). Patients were divided into control ( n = 7) and treatment ( n = 10) groups. MCP was applied through adhesive skin electrodes to the thighs and calves with a battery-powered, portable, ECG-triggered device for 15 minutes prior to general anesthesia. Standard ECG and invasive hemodynamic data were obtained from all patients. MCP was well tolerated in all patients, with no complications. Patients receiving MCP exhibited better cardiac function as indicated by reduced systemic vascular resistance and an augmented cardiac stroke index (+10%), which was maintained over time. After inducing general anesthesia via endotracheal intubation, the treatment group exhibited a reduced after-load (systemic vascular resistance index -28% and mean arterial pressure -10%) with increased left ventricular efficiency (stroke index/left ventricular stroke work index, +22%). Our findings indicate that MCP method was safe and easy to use in this patient population. In conclusion, a one-shot application of MCP prior to anesthesia was associated with an improvement in cardiac pump function and myocardial contractility. PMID- 28804233 TI - Effects of Physical Activity and Ginkgo Biloba on Cognitive Function and Oxidative Stress Modulation in Ischemic Rats. AB - Either exercise or Ginkgo biloba is reported to improve cognitive functioning. The aim of this study is to compare the protective effects of forced exercise and Ginkgo biloba on oxidative stress as well as memory impairments induced by transient cerebral ischemia. Adult male Wistar rats were treated with treadmill running or Ginkgo biloba extract for 2 weeks before cerebral ischemia. Memory was assessed using a Morris water maze (MWM) task. At the end of the behavioral testing, oxidative stress biomarkers were evaluated in the hippocampus tissue. As expected, the cerebral ischemia induced memory impairment in the MWM task, and oxidative stress in the hippocampus. These effects were significantly prevented by treadmill running. Indeed, it ameliorated oxidative stress and memory deficits induced by ischemia. In contrast, Ginkgo biloba was not as effective as exercise in preventing ischemia-induced memory impairments. The results confirmed the neuroprotective effects of treadmill running on hippocampus-dependent memory. PMID- 28804234 TI - Nitric Oxide: Link between Inflammation and Endothelial Dysfunction in Rheumatoid Arthritis. AB - Nitric oxide (NO) plays an important role in inflammatory joint disease and endothelial function. Endothelial dysfunction has been attributed to a reduction in NO bioactivity in rheumatoid arthritis (RA). However, the relationship of NO with inflammation and endothelial dysfunction in RA has not yet been investigated. To investigate the relationship of nitrite with inflammation and endothelial dysfunction in RA. Total 28 patients satisfying 2010 Rheumatoid Arthritis Classification Criteria were recruited for the study. Serum nitrite estimation was performed by Griess reaction. Flow-mediated dilation (FMD) assessed using AngioDefender. Inflammatory disease activity measures included disease activity score of 28 joints (DAS28), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Proinflammatory cytokines (TNF-alpha, IL-6, and IL-1) measured using standard ELISA kits. Twenty-five healthy controls matched for age and sex were included for comparison. The serum nitrite level in patients with RA was markedly elevated as compared with controls ( p < 0.05). FMD was significantly impaired in RA patients than controls ( p < 0.05). DAS28 was significantly higher in RA patients ( p < 0.05). Levels of ESR, CRP, TNF alpha, IL-1, and IL-6 were significantly higher in RA patients than controls ( p < 0.05). Significant positive correlation was observed between nitrite and CRP ( r = 0.46, p < 0.05), TNF-alpha ( r = 0.53, p < 0.05), and inverse correlation with FMD ( r =0.62, p < 0.05). Inflammatory disease activity and endothelial dysfunction in RA are associated with increased concentration of proinflammatory cytokines and NO. Inflammatory triggered release of cytokines induced NO production that mediates endothelial dysfunction. These findings suggest a role for NO in inflammation-induced endothelial dysfunction in RA. PMID- 28804236 TI - Discrepancies in Prevalence of Peripheral Arterial Disease between Lower Extremities at Rest and Postexercise. AB - Background Lower extremity peripheral arterial disease (PAD) is a common medical condition causing substantial morbidity. Limited data exist on whether discrepancies in PAD prevalence exist between the lower extremities using resting ankle-brachial indices (ABIs) and postexercise pressures. Objective We predicted the prevalence of PAD between the lower extremities. Methods and Results Consecutive patients who had undergone a noninvasive arterial lower extremity study at Mayo Clinic, Rochester, MN, between January 1996 and December 2012 with suspected PAD were retrospectively reviewed. We identified 12,312 consecutive patients who underwent an arterial lower extremity and an exercise treadmill study. Prevalence of PAD was assessed at rest and after exercise using two criteria: a resting ABI <= 0.90 and a postexercise pressure decrease of > 30 mm Hg. Mean age was 67 +/- 12 years and there were 4,780 (39%) women studied. At rest, we found a higher prevalence of PAD on the left extremity (27.4%) compared with the right (24.6%) ( p < 0.0001). After exercise, we found a higher prevalence of PAD on the right extremity (25.1%) compared with the left (19.0%) ( p < 0.0001). These discrepancies between the prevalence of PAD at rest and after exercise were present in women and men. Conclusion Using validated criteria of a resting ABI of <= 0.90 and postexercise ankle pressure decrease > 30 mm Hg, our results suggest that there is a significantly higher prevalence of PAD in the left lower extremity at rest, in contrast to a greater prevalence of abnormal postexercise testing in the right lower extremity. The reason(s) of these discrepancies remain to be studied. PMID- 28804235 TI - Management of Varicose Veins and Chronic Venous Insufficiency in a Comparative Registry with Nine Venoactive Products in Comparison with Stockings. AB - The aim of this registry study was to compare products used to control symptoms of CVI. Endpoints of the study were microcirculation, effects on volume changes, and symptoms (analogue scale). Pycnogenol, venoruton, troxerutin, the complex diosmin-hesperidin, Antistax, Mirtoselect (bilberry), escin, and the combination Venoruton-Pycnogenol (VE-PY) were compared with compressions. No safety or tolerability problems were observed. At inclusion, measurements in the groups were comparable: 1,051 patients completed the registry. Best performers : Venoruton, Pycnogenol, and the combination VE-PY produced the best effects on skin flux. These products and the combination VE-PY better improved PO 2 and PCO 2 . The edema score was decreased more effectively with the combination and with Pycnogenol. Venoruton; Antistax also had good results. Considering volumetry, the best performers were the combination PY-VE and the two single products Venoruton and Pycnogenol. Antistax results for edema were also good. The best improvement in symptoms score were obtained with Pycnogenol and compression. A larger decrease in oxidative stress was observed with Pycnogenol, Venoruton, and with the VE-PY combination. Good effects of Antistax were also observed. Parestesias were lower with Pycnogenol and with Antistax. Considering the need for interventions, the best performers were Pycnogenol, VE-PY, and compression. The efficacy of Pycnogenol and the combination are competitive with stockings that do not have the same tolerability in warmer climates. A larger and more prolonged evaluation is suggested to evaluate cost-efficacy (and non-interference with drugs) of these products in the management of CVI. The registry is in progress; other products are in evaluation. PMID- 28804237 TI - Aneurysmal Degeneration of the Brachial Artery after Vascular Access Creation: Surgical Treatment Results. AB - True peripheral artery aneurysms proximal to a longstanding arteriovenous fistula is a well-recognized complication. Late aneurysmal degeneration is rare. This study analyzed the characteristics, therapeutic options, and outcomes of true donor brachial artery aneurysms (DBAA) after arteriovenous fistula (AVF) for hemodialysis. We retrospectively collected the data of patients with DBAA after AVF creation, surgically repaired between January 2001 and September 2015. We excluded patients with pseudoaneurysms, anastomotic aneurysms, and infected aneurysms. We recorded patient's demographics, type of access, aneurysm characteristics, symptoms, treatment, and follow-up. Ten patients were treated for aneurysmal degeneration of the brachial artery. Average aneurysm diameter was 37.5 mm. All cases had, at least, one previous distal AVF, ligated or thrombosed, at the time of diagnosis. The first access was created in mean 137 months before the diagnosis of DBAA. Nine patients had previous medical history of renal transplant and were under immunosuppressive therapy. All patients were symptomatic at the time of diagnosis. In all cases, the treatment was aneurysmectomy followed by interposition bypass. One patient developed a postoperative hematoma with the need of surgical drainage. At 50 months of follow up, one patient was submitted to percutaneous angioplasty due to an anastomotic stenosis. No other complications occurred during the entire follow-up period (mean: 69 months). The pathogenesis underlying DBAA remains unclear. Increased blood flow after AVF creation, immunosuppressive therapy, and ligation/thrombosis of the AVF may contribute to aneurysm formation. Surgical treatment by aneurysmectomy and bypass, with autogenous conducts, is a safe and effective option. PMID- 28804238 TI - Percutaneous Closure of the Aorto-Ostial Origin of a Coronary Artery Saphenous Bypass Graft with a Large Pseudoaneurysm Using the AMPLATZER Muscular Ventricular Septal Defect Occluder. AB - We report the case of a 76-year-old male patient with a history of coronary artery bypass graft surgery presented with a large pseudoaneurysm emerging from a previously occluded saphenous bypass graft (SVG). A largely contained hematoma is seen in the mediastinum on computed tomography angiography (CTA) of the chest. Flow was seen from the ascending aorta into the pseudoaneurysm through the aorto ostial opening of the bypass graft. Closure of the aorto-ostial origin of the graft was performed using the AMPLATZER muscular ventricular septal defect (VSD) occluder (St Jude's Medical, St. Paul, MN) with immediate interruption of flow into the graft and the pseudoaneurysm. A repeat CTA of the ascending aorta at 6 months postprocedure continued to confirm an optimal positioning of the occluder with no flow into the pseudoaneurysm. This case offers an endovascular alternative to close the aorto-ostial opening of a saphenous bypass graft in the setting of a rare but potentially life-threatening SVG pseudoaneurysm. PMID- 28804239 TI - Iatrogenic Great Cardiac Vein Anastomosis during Coronary Artery Bypass Surgery. AB - Inadvertent anastomosis of the left internal mammary artery (LIMA) or a saphenous vein graft (SVG) to the great cardiac vein (GCV) is a rare complication of coronary artery bypass grafting (CABG). We present two cases with a LIMA to GCV and a SVG to GCV anastomosis, respectively, resulting in angina and dyspnea in the postoperative state. As an alternative to repeat CABG, both patients underwent percutaneous coronary intervention with percutaneous coil embolization or implantation of an Amplatzer vascular plug within the bypass graft to GCV conduit. This report highlights that percutaneous options exist for the relief of ischemic symptoms in this rare clinical setting. PMID- 28804241 TI - Tunably Rugged Landscapes With Known Maximum and Minimum. AB - We propose NM landscapes as a new class of tunably rugged benchmark problems. NM landscapes are well defined on alphabets of any arity, including both discrete and real-valued alphabets, include epistasis in a natural and transparent manner, are proven to have known value and location of the global maximum and, with some additional constraints, are proven to also have a known global minimum. Empirical studies are used to illustrate that, when coefficients are selected from a recommended distribution, the ruggedness of NM landscapes is smoothly tunable and correlates with several measures of search difficulty. We discuss why these properties make NM landscapes preferable to both NK landscapes and Walsh polynomials as benchmark landscape models with tunable epistasis. PMID- 28804240 TI - Dual Method Use among Postpartum HIV-Infected and HIV-Uninfected Malawian Women: A Prospective Cohort Study. AB - Dual method use, use of condoms plus another effective contraceptive method, is important in settings with high rates of unintended pregnancy and HIV infection. We evaluated the association of HIV status with dual method use in a cohort of postpartum women. Women completed baseline surveys in the postpartum ward and telephone surveys about contraceptive use 3, 6, and 12 months later. Nonpregnant women who completed at least one follow-up survey were eligible for this secondary analysis. Prevalence ratios were calculated using generalized estimating equations. Of the 511 sexually active women who completed a follow-up survey, condom use increased from 17.6% to 27.7% and nonbarrier contraceptive use increased from 73.8% to 87.6% from 3 to 12 months after delivery. Dual method use increased from 1.0% to 18.9% at 3 to 12 months after delivery. Dual method use was negligible and comparable between HIV-infected and HIV-uninfected women at 3 months but significantly higher among HIV-infected women at 6 months (APR = 3.9, 95% CI 2.2, 7.1) and 12 months (APR = 2.7, 95% CI 1.7, 4.3). Dual method use was low but largely driven by condom use among HIV-infected women at 6 and 12 months after delivery. PMID- 28804242 TI - Immuno-Oncology Integrative Networks: Elucidating the Influences of Osteosarcoma Phenotypes. AB - In vivo and in vitro functional phenotyping characterization was recently obtained with reference to an experimental pan-cancer study of 22 osteosarcoma (OS) cell lines. Here, differentially expressed gene (DEG) profiles were recomputed from the publicly available data to conduct network inference on the immune system regulatory activity across the characterized OS phenotypes. Based on such DEG profiles, and for each phenotype that was analyzed, we obtained coexpression networks and bio-annotations for them. Then, we described the immune modulated influences in phenotype-specific networks' integrating pathway, transcription factor, and microRNA regulations. Overall, this approach seems suitable for representing heterogeneity in OS tumorigenesis. PMID- 28804243 TI - A Quantitative Systems Pharmacology Platform to Investigate the Impact of Alirocumab and Cholesterol-Lowering Therapies on Lipid Profiles and Plaque Characteristics. AB - Reduction in low-density lipoprotein cholesterol (LDL-C) is associated with decreased risk for cardiovascular disease. Alirocumab, an antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduces LDL-C. Here, we report development of a quantitative systems pharmacology (QSP) model integrating peripheral and liver cholesterol metabolism, as well as PCSK9 function, to examine the mechanisms of action of alirocumab and other lipid-lowering therapies, including statins. The model predicts changes in LDL-C and other lipids that are consistent with effects observed in clinical trials of single or combined treatments of alirocumab and other treatments. An exploratory model to examine the effects of lipid levels on plaque dynamics was also developed. The QSP platform, on further development and qualification, may support dose optimization and clinical trial design for PCSK9 inhibitors and lipid-modulating drugs. It may also improve our understanding of factors affecting therapeutic responses in different phenotypes of dyslipidemia and cardiovascular disease. PMID- 28804244 TI - Development of New Contrast Agents for Imaging Function and Metabolism by Magnetic Resonance Imaging. AB - Liposomes are interesting nanosystems with a wide range of medical application. One particular application is their ability to enhance contrast in magnetic resonance images; when properly loaded with magnetic/superparamagnetic nanoparticles, this means to act as contrast agents. The design of liposomes loaded with magnetic particles, magnetoliposomes, presents a large number of possibilities depending on the application from image function to metabolism. More interesting is its double function application as theranostics (diagnostics and therapy). The synthesis, characterization, and possible medical applications of two types of magnetoliposomes are reviewed. Their performance will be compared, in particular, their efficiency as contrast agents for magnetic resonance imaging, measured by their relaxivities r1 and r2 relating to their particular composition. One of the magnetoliposomes had 1,2-diacyl-sn-glycero-3 phosphocholine (soy) as the main phospholipid component, with and without cholesterol, varying its phospholipid to cholesterol molar ratios. The other formulation is a long-circulating liposome composed of 1,2-diacyl-sn-glycero-3 phosphocholine (egg), cholesterol, and 1,2-distearoyl-sn-glycerol-3 phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]. Both nanosystems were loaded with superparamagnetic iron oxide nanoparticles with different sizes and coatings. PMID- 28804245 TI - DNA Microarray Analysis of Estrogen Responsive Genes in Ishikawa Cells by Glabridin. AB - Based on a previous study, glabridin displayed a dose-dependent increase in estrogenic activity and cell proliferative activity in Ishikawa cells. However, when treated in combination with 17beta-E2, synergistic estrogenic effect was observed but without the same synergistic increase in cell proliferative effect. This study aimed to identify the estrogen and nonestrogen-regulated activities induced by glabridin and in combination with 17beta-E2 in comparison with 17beta E2. The results showed that 10 uM glabridin and the combination treatment of 100 nM glabridin with 1 nM 17beta-E2 regulated both the genomic and nongenomic estrogen pathways to possibly provide benefits of estrogens in cardiovascular, circulatory, and vasculature systems. Meanwhile, the combination of 100 nM glabridin with 1 nM 17beta-E2 seems to be more suitable to be used as an estrogen replacement. Finally, the results of this study have added on to the present knowledge of glabridin's function as a phytoestrogen and suggested new ideas for the usage of glabridin. PMID- 28804247 TI - Ophthalmology in North America: Early Stories (1491-1801). AB - New World plants, such as tobacco, tomato, and chili, were held to have beneficial effects on the eyes. Indigenous healers rubbed or scraped the eyes or eyelids to treat inflammation, corneal opacities, and even eye irritation from smoke. European settlers used harsh treatments, such as bleeding and blistering, when the eyes were inflamed or had loss of vision with a normal appearance (gutta serena). In New Spain, surgery for corneal opacity was performed in 1601 and cataract couching in 1611. North American physicians knew of contralateral loss of vision after trauma or surgery (sympathetic ophthalmia), which they called "sympathy." To date, the earliest identified cataract couching by a surgeon trained in the New World was performed in 1769 by John Bartlett of Rhode Island. The American Revolution negatively affected ophthalmology, as loyalist surgeons were expelled and others were consumed with wartime activities. After the war, cataract extraction was imported to America in earnest and academic development resumed. Charles F Bartlett, the son of John, performed cataract extraction but was also a "rapacious privateer." In 1801, a doctor in the frontier territory of Kentucky observed anticholinergic poisoning by Datura stramonium (Jimsonweed) and suggested that this agent be applied topically to dilate the pupil before cataract extraction. John Warren at Harvard preferred couching in the 1790s, but, after his son returned from European training, recommended treating angle closure glaucoma by lens extraction. Other eye procedures described or advertised in America before the 19th century included enucleation, resection of conjunctival lesions or periocular tumors, treatment of lacrimal fistula, and fitting of prosthetic eyes. PMID- 28804246 TI - The role of functional, social, and mobility dynamics in facilitating older African Americans participation in clinical research. AB - PURPOSE: Older African Americans experience disproportionately higher incidence of morbidity and mortality related to chronic and infectious diseases, yet are significantly underrepresented in clinical research compared to other racial and ethnic groups. This study aimed to understand the extent to which social support, transportation access, and physical impediments function as barriers or facilitators to clinical trial recruitment of older African Americans. METHODS: Participants (N=221) were recruited from six African American churches in Atlanta and surveyed on various influences on clinical trial participation. RESULTS: Logistic regression models demonstrated that greater transportation mobility (odds ratio [OR]=2.10; p=0.007) and social ability (OR=1.77; p=0.02) were associated with increased intentions of joining a clinical trial, as was greater basic daily living ability (OR=3.25; p=0.03), though only among single participants. Among adults age >=65 years, those with lower levels of support during personal crises were more likely to join clinical trials (OR=0.57; p=0.04). CONCLUSION: To facilitate clinical trial entry, recruitment efforts need to consider the physical limitations of their potential participants, particularly basic physical abilities and disabilities. Crisis support measures may be acting as a proxy for personal health issues among those aged >65 years, who would then be more likely to seek clinical trials for the personal health benefits. Outreach to assisted living homes, hospitals, and other communities is a promising avenue for improved clinical trial recruitment of older African Americans. PMID- 28804248 TI - Effect of Chronic Hepatitis C Virus Treatment by Combination Therapy on Cardiovascular System. AB - BACKGROUND: The prevalence of hepatitis C virus (HCV) in Egypt is quite high, and the combined oral direct-acting antiviral agents (DAAs) may have impressive results. OBJECTIVE: To assess the cardiovascular effects of DAAs in patients with HCV. METHODS: A total of 170 patients with HCV were divided into 2 groups: first group (100 patients) received triple combination therapy (pegylated interferon alfa, sofosbuvir, and ribavirin, whereas the second group (70 patients) received dual combination therapy (sofosbuvir and simeprevir). Group 1 patients were followed up for 1 year more than 3 visits, whereas group 2 patients were followed up for 6 months more than 2 visits; and the end point of the study was the development of a major cardiovascular event (eg, congestive heart failure, echocardiographic evidence of left ventricular dysfunction, occurrence of significant arrhythmias, or acute coronary syndrome). The following parameters were accomplished: medical history and clinical examination, electrocardiogram, echo-Doppler study, and laboratory investigations. RESULTS: No significant differences were found between the 2 study groups regarding demographic criteria. None of the both group patients had developed any major cardiac event. No significant changes were observed regarding ST-T wave abnormalities, arrhythmias, or QT interval. None of the both group patients developed echocardiographic regional wall motion abnormalities at baseline or at study end. Systolic function parameters showed minute nonsignificant changes over study visits. Diastolic function parameters showed nonsignificant changes between baseline and 6-month and 12-month visits. CONCLUSIONS: The DAAs used in combination regimen with interferon or used orally in combination do not significantly affect the cardio vascular system. PMID- 28804249 TI - Pacing Spikes All Over. AB - Ventricular safety pacing (VSP) is used to avoid cross talk by delivering ventricular stimulus shortly after an atrial-paced event if ventricular-sensed event occurs. Although VSP is a protective feature that exists for decades in different pacing devices, there are some reports of unfavorable outcomes of this algorithm. More so, health care providers sometimes face difficulties in interpreting and dealing with VSP strips. This case report discusses an important pacemaker algorithm and encourages further attention to possible pitfalls and hence avoids unnecessary interventions. PMID- 28804250 TI - Modern Contraceptive Choice Among Patients Seen at the "Cameroon National Planning Association for Family Welfare" Clinic Yaounde. AB - BACKGROUND: To understand the low modern contraceptive prevalence in Cameroon, we reviewed the methods chosen and determined their side effects among patients in an urban setting. METHODS: We conducted a cross-sectional study at the "Cameroon National Planning Association for Family Welfare (CAMNAFAW) Clinic" in Yaounde. Data were processed by SPSS software version 20.0 for Windows, and all tests were considered statistically significant at P < .05. RESULTS: Of the 1180 women sampled, the most chosen methods were as follows: depot medroxy progesterone acetate: 72.1% (787 of 1091), followed by oral combined contraceptives: 21.3% (232 of 1091), subcutaneous implants: 3.2% (35 of 1091), and intrauterine contraceptive devices: 1.9% (21 of 1091). A hundred and forty two (14.5%) of the 977 women received at least once (revisits) at the Center, reported at least one side effect. Irregular vaginal bleeding was the most frequent side effect: 44.6% (84 of 188 total documented side effects). Side effects were most common among users of subcutaneous implants: 28% (7 of the 25 implant users). CONCLUSIONS: Prescription of contraceptives should reflect not only the desire of couples but also the side effects associated with each method. This would optimize observance and adherence, consequently decreasing the failure rate. PMID- 28804251 TI - [Reliability and validity of Turkish translation of the pediatric sleep questionnaire]. AB - OBJECTIVE: Aim of this study was to investigate the validity and reliability of the Turkish translation of Pediatric Sleep Questionnaire (PSQ)-the extended version. The Pediatric Sleep Questionnaire (PSQ) has two versions: a shorter one, which has been validated for sleep-related breathing disorders, and an extended version, which deals with a wider range of sleep disturbances. METHOD: After translation and back-translation of the PSQ, it was filled in by the parents of 99 patients with Attention Deficit Hyperactivity Disorder (ADHD), 34 patients with Upper Airway Resistance and Snoring (UARS), and 42 healthy controls. Cronbach alpha was computed as a measure of internal consistency along with test retest reliability and item-total score correlations. We used principal components analysis and varimax rotation to investigate the factor structure. The Receiver Operator Characteristic (ROC) curves were used to determine cut-off points, sensitivity, specificity, and negative and positive predictive values. RESULTS: Cronbach alpha coefficient was 0.77 for the whole questionnaire. Similar to the original PSQ study, we found four factors, namely "Snoring," "Behavioral Problems," "Breathing Problems," and "Other Problems.". However, different items loaded to these factors. While the first three factors were reliable and valid, this was not the case for the last factor. ADHD patients had higher "Breathing Problems" score than the controls, while all sleep related problems were higher in the UARS group than the other two groups. Cut-off points obtained from the ROC curves indicated that when a PSQ total score of 6 points was used as a cut-off, UARS group and the controls could be discriminated easily. In order to discriminate the ADHD and UARS groups, using the "Total Sleep Problems Score", which did not include the "Behavioral Problems" factor, resulted in greater specificty and sensitivity. DISCUSSION: These results indicated that the Turkish version of the PSQ was a valid and reliable measure, that the PSQ total score could discriminate patients with primary sleep disorder from healthy controls, and that the "Total Sleep Problems Score", which was obtained by omitting the Behavioral Problems factor score, could be used to discriminate primary sleep problems from secondary sleep problems associated with ADHD. PMID- 28804252 TI - Effect of Ferritin on Short-Term Treatment Response in Attention Deficit Hyperactivity Disorder. AB - OBJECTIVES: Several studies have shown that iron deficiency and ferritin levels are associated with parent and teacher Attention Deficit Hyperactivity Disorder (ADHD) ratings. Although there are conflicting results, it has also been reported that iron supplementation may help to decrease ADHD symptoms. When all these previous studies are taken into account, it is clear that a large study investigating the effects of iron deficiency and ferritin levels on routine pharmacological treatment of ADHD with stimulants would be helpful to elucidate this treatment from a clinical point of view. METHODS: A total of 345 subjects with combined or predominantly hyperactive-impulsive (PHI) subtypes of ADHD were included. All diagnoses were based on the DSM-IV criteria and ascertained by direct interviews conducted by the authors, who are experienced child psychiatrists certified in the use of the Schedule for Affective Disorders and Schizophrenia for School-Age Children - Present and Lifetime Version (K-SADS-PL) semi-structured interview. The two treatment response criteria were: 1) 25% or more decrease in pre-treatment Conners Parent Rating Scale (CPRS) and Conners Teacher Rating Scale (CTRS) Hyperactivity (HA) and Total Problems scores; 2) CPRS and CTRS HA scores lower than the cut-off point ("very improved"). RESULTS: A total of 255 (73.9%) patients were on OROS-methylphenidate (OROS-MPH) and 90 (26.1%) were on immediate release methylphenidate (IR-MPH). The mean+/-sd of OROS MPH and IR-MPH doses were 28.8+/-8.1 and 20.9+/-7.1 mg, respectively. More than half (52.5%) of the subjects were previously drug-naive at treatment inception. Two hundred and seventy eight (80.6%) subjects had combined subtype ADHD and the remainder had predominantly hyperactive-impulsive subtype. Only 60 (17.4%) of the subjects had no comorbid disorders, while 38.3% had one comorbid disorder, 32.8% had two comorbid disorders, and 11.6% had three or more comorbid disorders. The most frequent comorbidity was Oppositional Defiant Disorder/Conduct Disorder (ODD/CD, 51.6%), followed by Learning Disabilities (LD, 35.4%) and Anxiety Disorders (AD, 15.9%). Logistic regression analysis showed that subjects with comorbid ODD/CD and LD were less likely to respond to treatment. Ferritin levels and iron deficiency were not associated significantly with outcomes. CONCLUSIONS: In a large sample of subjects with combined or predominantly hyperactive impulsive subtypes of ADHD, after controlling for several factors, we found that neither iron deficiency (ferritin <12 ng/ml) nor ferritin levels were associated with less favorable short-term treatment outcomes with stimulants. Subjects with comorbid ODD/CD and LD were less likely to have a 25% or more decrease in CTRS Total score. The presence of ODD/CD was also a negative predictor of treatment response in terms of CPRS Total and HA scores. The lack of a negative treatment response in ADHD subjects with iron deficiency and lack of a negative association with ferritin levels suggest that the relationship between iron metabolism and ADHD, a highly heterogeneous disorder, may be more complicated than previously believed. PMID- 28804253 TI - Effect of microbial activity on penetrometer resistance and elastic modulus of soil at different temperatures. AB - : We explore the effect of microbial activity stimulated by root exudates on the penetrometer resistance of soil and its elastic modulus. This is important because it is a measure of the mechanical strength of soil and it correlates closely with the rate of elongation of roots. A sandy soil was incubated with a synthetic root exudate at different temperatures, for different lengths of time and with selective suppression of either fungi or bacteria. The shape of the temperature response of penetrometer resistance in soil incubated with synthetic exudate was typical of a poikilothermic temperature response. Both penetrometer resistance and small strain shear modulus had maximum values between 25 and 30 degrees C. At temperatures of 20 degrees C and less, there was little effect of incubation with synthetic root exudate on the small strain shear modulus, although penetrometer resistance did increase with temperature over this range (4 20 degrees C). This suggests that in this temperature range the increase in penetrometer resistance was related to a greater resistance to plastic deformation. At higher temperatures (> 25 degrees C) penetrometer resistance decreased. Analysis of the DNA sequence data showed that at 25 degrees C the number of Streptomyces (Gram-positive bacteria) increased, but selective suppression of either fungi or bacteria suggested that fungi have the greater role with respect to penetrometer resistance. HIGHLIGHTS: Effect of microbial activity stimulated by synthetic root exudates on the mechanical properties.We compared penetrometer measurements and estimates of elastic modulus with microbial community.Penetrometer resistance of soil showed a poikilothermic temperature response.Penetrometer resistance might be affected more by fungi than bacteria. PMID- 28804254 TI - Developing scientists in Hispanic substance use and health disparities research through the creation of a national mentoring network. AB - Hispanics are disproportionately affected by substance use and related health harms yet remain underrepresented across scientific disciplines focused on researching and addressing these issues. An interdisciplinary network of scientists committed to fostering the development of social and biomedical researchers focused on Hispanic substance use and health disparities developed innovative mentoring and career development activities. We conducted a formative evaluation study using anonymous membership and conference feedback data to describe specific mentoring and career development activities developed within the national network. Successful mentoring initiatives and career development activities were infused with cultural and community values supportive of professional integration and persistence. Mentoring initially occurred within an annual national conference and was then sustained throughout the year through formal training programs and informal mentoring networks. Although rigorous evaluation is needed to determine the success of these strategies in fostering long-term career development among scientists conducting Hispanic health and substance use research, this innovative model may hold promise for other groups committed to promoting career development and professional integration and persistence for minority (and non-minority) scientists committed to addressing health disparities. PMID- 28804255 TI - A phase-plane analysis of localized frictional waves. AB - Sliding frictional interfaces at a range of length scales are observed to generate travelling waves; these are considered relevant, for example, to both earthquake ground surface movements and the performance of mechanical brakes and dampers. We propose an explanation of the origins of these waves through the study of an idealized mechanical model: a thin elastic plate subject to uniform shear stress held in frictional contact with a rigid flat surface. We construct a nonlinear wave equation for the deformation of the plate, and couple it to a spinodal rate-and-state friction law which leads to a mathematically well-posed problem that is capable of capturing many effects not accessible in a Coulomb friction model. Our model sustains a rich variety of solutions, including periodic stick-slip wave trains, isolated slip and stick pulses, and detachment and attachment fronts. Analytical and numerical bifurcation analysis is used to show how these states are organized in a two-parameter state diagram. We discuss briefly the possible physical interpretation of each of these states, and remark also that our spinodal friction law, though more complicated than other classical rate-and-state laws, is required in order to capture the full richness of wave types. PMID- 28804256 TI - Direct linearizing transform for three-dimensional discrete integrable systems: the lattice AKP, BKP and CKP equations. AB - A unified framework is presented for the solution structure of three-dimensional discrete integrable systems, including the lattice AKP, BKP and CKP equations. This is done through the so-called direct linearizing transform, which establishes a general class of integral transforms between solutions. As a particular application, novel soliton-type solutions for the lattice CKP equation are obtained. PMID- 28804257 TI - Gyro-elastic beams for the vibration reduction of long flexural systems. AB - The paper presents a model of a chiral multi-structure incorporating gyro-elastic beams. Floquet-Bloch waves in periodic chiral systems are investigated in detail, with the emphasis on localization and the formation of standing waves. It is found that gyricity leads to low-frequency standing modes and generation of stop bands. A design of an earthquake protection system is offered here, as an interesting application of vibration isolation. Theoretical results are accompanied by numerical simulations in the time-harmonic regime. PMID- 28804258 TI - Modulational instability in the full-dispersion Camassa-Holm equation. AB - We determine the stability and instability of a sufficiently small and periodic travelling wave to long-wavelength perturbations, for a nonlinear dispersive equation which extends a Camassa-Holm equation to include all the dispersion of water waves and the Whitham equation to include nonlinearities of medium amplitude waves. In the absence of the effects of surface tension, the result qualitatively agrees with the Benjamin-Feir instability of a Stokes wave. In the presence of the effects of surface tension, it qualitatively agrees with those from formal asymptotic expansions of the physical problem and improves upon that for the Whitham equation, predicting the critical wave number at the strong surface tension limit. We discuss the modulational stability and instability in the Camassa-Holm equation and other related models. PMID- 28804259 TI - Multi-fractal characterization of bacterial swimming dynamics: a case study on real and simulated Serratia marcescens. AB - To add to the current state of knowledge about bacterial swimming dynamics, in this paper, we study the fractal swimming dynamics of populations of Serratia marcescens bacteria both in vitro and in silico, while accounting for realistic conditions like volume exclusion, chemical interactions, obstacles and distribution of chemoattractant in the environment. While previous research has shown that bacterial motion is non-ergodic, we demonstrate that, besides the non ergodicity, the bacterial swimming dynamics is multi-fractal in nature. Finally, we demonstrate that the multi-fractal characteristic of bacterial dynamics is strongly affected by bacterial density and chemoattractant concentration. PMID- 28804260 TI - Modelling the fear of crime. AB - How secure people feel in a particular region is obviously linked to the actual crime suffered in that region but the exact relationship between crime and its fear is quite subtle. Two regions may have the same crime rate but their local perception of security may differ. Equally, two places may have the same perception of security even though one may have a significantly lower crime rate. Furthermore, a negative perception might persist for many years, even when crime rates drop. Here, we develop a model for the dynamics of the perception of security of a region based on the distribution of crime suffered by the population using concepts similar to those used for opinion dynamics. Simulations under a variety of conditions illustrate different scenarios and help us determine the impact of suffering more, or less, crime. The inhomogeneous concentration of crime together with a memory loss process is incorporated into the model for the perception of security, and results explain why people are often more fearful than actually victimized; why a region is perceived as being insecure despite a low crime rate; and why a decrease in the crime rate might not significantly improve the perception of security. PMID- 28804261 TI - The role of molybdenum in suppressing cold dwell fatigue in titanium alloys. AB - We test a hypothesis to explain why Ti-6242 is susceptible to cold dwell fatigue (CDF), whereas Ti-6246 is not. The hypothesis is that, in Ti-6246, substitutional Mo-atoms in alpha-Ti grains trap vacancies, thereby limiting creep relaxation. In Ti-6242, this creep relaxation enhances the loading of grains unfavourably oriented for slip and they subsequently fracture. Using density functional theory to calculate formation and binding energies between Mo-atoms and vacancies, we find no support for the hypothesis. In the light of this result, and experimental observations of the microstructures in these alloys, we agree with the recent suggestion (Qiu et al. 2014 Metall. Mater. Trans. A45, 6075-6087. (doi:10.1007/s11661-014-2541-5)) that Ti-6246 has a much smaller susceptibility to CDF because it has a smaller grain size and a more homogeneous distribution of grain orientations. We propose that the reduction of the susceptibility to CDF of Ti-6242 at temperatures above about 200 degrees C is due to the activation of slip in 'hard' grains, which reduces the loading of grain boundaries. PMID- 28804262 TI - Effects of boundary conditions on bistable behaviour in axisymmetrical shallow shells. AB - Multistable shells are thin-walled structures that have more than one stable state of self-stress. We consider isotropic axisymmetrical shallow shells of arbitrary polynomial shapes using a Foppl-von Karman analytical model. By employing a Rayleigh-Ritz approach, we identify stable shapes from local minima in the strain energy formulation, and we formally characterize the level of influence of the boundary conditions on the critical geometry for achieving bistable inversion-an effect not directly answered in the literature. Systematic insight is afforded by connecting the boundary to ground through sets of extensional and rotational linear springs. For typical cap-like shells, it is shown that bistability is generally enhanced when the extensional spring stiffness increases and when the rotational spring stiffness decreases, i.e. when boundary movements in-plane are resisted but when their rotations are not; however, for certain other shapes and large in-plane stiffness values, bistability can be enhanced by resisting but not entirely preventing edge rotations. Our predictions are furnished as detailed regime maps of the critical geometry, which are accurately correlated against finite-element analysis. Furthermore, the suitabilities of single degree-of-freedom models, for which solutions are achieved in closed form, are evaluated and compared to our more accurate predictions. PMID- 28804263 TI - Trigonal curves and algebro-geometric solutions to soliton hierarchies I. AB - This is the first part of a study, consisting of two parts, on Riemann theta function representations of algebro-geometric solutions to soliton hierarchies. In this part, using linear combinations of Lax matrices of soliton hierarchies, we introduce trigonal curves by their characteristic equations, explore general properties of meromorphic functions defined as ratios of the Baker-Akhiezer functions, and determine zeros and poles of the Baker-Akhiezer functions and their Dubrovin-type equations. We analyse the four-component AKNS soliton hierarchy in such a way that it leads to a general theory of trigonal curves applicable to construction of algebro-geometric solutions of an arbitrary soliton hierarchy. PMID- 28804264 TI - Trigonal curves and algebro-geometric solutions to soliton hierarchies II. AB - This is a continuation of a study on Riemann theta function representations of algebro-geometric solutions to soliton hierarchies. In this part, we straighten out all flows in soliton hierarchies under the Abel-Jacobi coordinates associated with Lax pairs, upon determining the Riemann theta function representations of the Baker-Akhiezer functions, and generate algebro-geometric solutions to soliton hierarchies in terms of the Riemann theta functions, through observing asymptotic behaviours of the Baker-Akhiezer functions. We emphasize that we analyse the four component AKNS soliton hierarchy in such a way that it leads to a general theory of trigonal curves applicable to construction of algebro-geometric solutions of an arbitrary soliton hierarchy. PMID- 28804265 TI - Piecewise affine stress-free martensitic inclusions in planar nonlinear elasticity. AB - We consider a partial differential inclusion problem which models stress-free martensitic inclusions in an austenitic matrix, based on the standard geometrically nonlinear elasticity theory. We show that for specific parameter choices there exist piecewise affine continuous solutions for the square-to oblique and the hexagonal-to-oblique phase transitions. This suggests that for specific crystallographic parameters the hysteresis of the phase transformation will be particularly small. PMID- 28804266 TI - Modulational instability, beak-shaped rogue waves, multi-dark-dark solitons and dynamics in pair-transition-coupled nonlinear Schrodinger equations. AB - The integrable coupled nonlinear Schrodinger equations with four-wave mixing are investigated. We first explore the conditions for modulational instability of continuous waves of this system. Secondly, based on the generalized N-fold Darboux transformation (DT), beak-shaped higher-order rogue waves (RWs) and beak shaped higher-order rogue wave pairs are derived for the coupled model with attractive interaction in terms of simple determinants. Moreover, we derive the simple multi-dark-dark and kink-shaped multi-dark-dark solitons for the coupled model with repulsive interaction through the generalizing DT. We explore their dynamics and classifications by different kinds of spatial-temporal distribution structures including triangular, pentagonal, 'claw-like' and heptagonal patterns. Finally, we perform the numerical simulations to predict that some dark solitons and RWs are stable enough to develop within a short time. The results would enrich our understanding on nonlinear excitations in many coupled nonlinear wave systems with transition coupling effects. PMID- 28804268 TI - Error bounds for the asymptotic expansion of the Hurwitz zeta function. AB - In this paper, we reconsider the large-a asymptotic expansion of the Hurwitz zeta function zeta(s,a). New representations for the remainder term of the asymptotic expansion are found and used to obtain sharp and realistic error bounds. Applications to the asymptotic expansions of the polygamma functions, the gamma function, the Barnes G-function and the s-derivative of the Hurwitz zeta function zeta(s,a) are provided. A detailed discussion on the sharpness of our error bounds is also given. PMID- 28804267 TI - Mathematical and computational modelling of skin biophysics: a review. AB - The objective of this paper is to provide a review on some aspects of the mathematical and computational modelling of skin biophysics, with special focus on constitutive theories based on nonlinear continuum mechanics from elasticity, through anelasticity, including growth, to thermoelasticity. Microstructural and phenomenological approaches combining imaging techniques are also discussed. Finally, recent research applications on skin wrinkles will be presented to highlight the potential of physics-based modelling of skin in tackling global challenges such as ageing of the population and the associated skin degradation, diseases and traumas. PMID- 28804269 TI - Psycholinguistic, cognitive, and neural implications of bimodal bilingualism. AB - Bimodal bilinguals, fluent in a signed and a spoken language, exhibit a unique form of bilingualism because their two languages access distinct sensory-motor systems for comprehension and production. Differences between unimodal and bimodal bilinguals have implications for how the brain is organized to control, process, and represent two languages. Evidence from code-blending (simultaneous production of a word and a sign) indicates that the production system can access two lexical representations without cost, and the comprehension system must be able to simultaneously integrate lexical information from two languages. Further, evidence of cross-language activation in bimodal bilinguals indicates the necessity of links between languages at the lexical or semantic level. Finally, the bimodal bilingual brain differs from the unimodal bilingual brain with respect to the degree and extent of neural overlap for the two languages, with less overlap for bimodal bilinguals. PMID- 28804271 TI - Healthy Migrants in an Unhealthy City? The Effects of Time on the Health of Migrants Living in Deprived Areas of Glasgow. AB - This paper examines the healthy immigrant effect in Glasgow, a post-industrial city where the migrant population has more than doubled in the last decade. Using data from a community survey in 15 communities across the city, the paper compares four health outcomes for the following three groups: British-born, social and economic migrants and asylum seekers and refugees. Migrants were found to be healthier than the indigenous population on all four measures, particularly in the case of adult households in both migrant groups and for older asylum seeker and refugee households. Health declines for social and economic migrants with time spent in the UK, but there is no clear pattern for asylum seekers and refugees. Health declined for refugees according to time spent awaiting a decision, whilst their health improved after a leave-to-remain decision. Indigenous and social and economic migrant health declines with time spent living in a deprived area; this was true for three health indicators for the former and two indicators for the latter. Asylum seekers and refugees who had lived in a deprived area for more than a year had slightly better self-rated health and well being than recent arrivals. The study's findings highlight the role of destination city and neighbourhood in the health immigrant effect, raise concerns about the restrictions placed upon asylum seekers and the uncertainty afforded to refugees and suggest that spatial concentration may have advantages for asylum seekers and refugees. PMID- 28804272 TI - Fitting Position Latent Cluster Models for Social Networks with latentnet. AB - latentnet is a package to fit and evaluate statistical latent position and cluster models for networks. Hoff, Raftery, and Handcock (2002) suggested an approach to modeling networks based on positing the existence of an latent space of characteristics of the actors. Relationships form as a function of distances between these characteristics as well as functions of observed dyadic level covariates. In latentnet social distances are represented in a Euclidean space. It also includes a variant of the extension of the latent position model to allow for clustering of the positions developed in Handcock, Raftery, and Tantrum (2007). The package implements Bayesian inference for the models based on an Markov chain Monte Carlo algorithm. It can also compute maximum likelihood estimates for the latent position model and a two-stage maximum likelihood method for the latent position cluster model. For latent position cluster models, the package provides a Bayesian way of assessing how many groups there are, and thus whether or not there is any clustering (since if the preferred number of groups is 1, there is little evidence for clustering). It also estimates which cluster each actor belongs to. These estimates are probabilistic, and provide the probability of each actor belonging to each cluster. It computes four types of point estimates for the coefficients and positions: maximum likelihood estimate, posterior mean, posterior mode and the estimator which minimizes Kullback-Leibler divergence from the posterior. You can assess the goodness-of-fit of the model via posterior predictive checks. It has a function to simulate networks from a latent position or latent position cluster model. PMID- 28804270 TI - Knockdown of miR-155 protects microglia against LPS-induced inflammatory injury via targeting RACK1: a novel research for intracranial infection. AB - BACKGROUND: Intracranial infection, one of the complications of traumatic brain injury, is usually associated with inflammation. Several microRNAs (miRNAs), including miR-155, have been reported to be critical modulators in peripheral and central nervous system inflammation. In this study, we investigated the role of miR-155 in lipopolysaccharide (LPS)-induced inflammatory injury in mouse microglia BV2 cells. RESULTS: The expression level of miR-155 was significantly up-regulated after LPS stimulation in BV2 cells. LPS administration decreased BV2 cell viability, promoted apoptosis and increased the release of pro-inflammatory cytokines; while miR-155 knockdown rescued BV2 cell from LPS-induced injury. RACK1 was a directly target of miR-155. Interestingly, miR-155 knockdown did not attenuate LPS-induced inflammatory injury when RACK1 was knocked down. The mechanistic study indicated that miR-155 knockdown deactivated MAPK/NF-kappaB and mTOR signaling pathways under LPS-treated conditions. CONCLUSIONS: Knockdown of miR-155 protected mouse microglia BV2 cells from LPS-induced inflammatory injury via targeting RACK1 and deactivating MAPK/NF-kappaB and mTOR signaling pathways. PMID- 28804273 TI - Influence of the Number of Axial Bexarotene Ligands on the Cytotoxicity of Pt(IV) Analogs of Oxaliplatin. AB - We present the synthesis and cytotoxic potencies of new Pt(IV) complexes with bexarotene, an anticancer drug that induces cell differentiation and apoptosis via selective activation of retinoid X receptors. In these complexes bexarotene is positioned as an axial ligand. The complex of one bexarotene ligand attached to Pt(IV) oxaliplatin moiety was potent whereas its counterpart carrying two bexarotene ligands was inactive. PMID- 28804274 TI - Non-invasive urinary metabolomic profiling discriminates prostate cancer from benign prostatic hyperplasia. AB - INTRODUCTION: Prostate cancer (PCa) is one of the most common malignancies in men worldwide. Serum prostate specific antigen (PSA) level has been extensively used as a biomarker to detect PCa. However, PSA is not cancer-specific and various non malignant conditions, including benign prostatic hyperplasia (BPH), can cause a rise in PSA blood levels, thus leading to many false positive results. OBJECTIVES: In this study, we evaluated the potential of urinary metabolomic profiling for discriminating PCa from BPH. METHODS: Urine samples from 64 PCa patients and 51 individuals diagnosed with BPH were analysed using 1H nuclear magnetic resonance (1H-NMR). Comparative analysis of urinary metabolomic profiles was carried out using multivariate and univariate statistical approaches. RESULTS: The urine metabolomic profile of PCa patients is characterised by increased concentrations of branched-chain amino acids (BCAA), glutamate and pseudouridine, and decreased concentrations of glycine, dimethylglycine, fumarate and 4-imidazole-acetate compared with individuals diagnosed with BPH. CONCLUSION: PCa patients have a specific urinary metabolomic profile. The results of our study underscore the clinical potential of metabolomic profiling to uncover metabolic changes that could be useful to discriminate PCa from BPH in a clinical context. PMID- 28804275 TI - Metabolomics based markers predict type 2 diabetes in a 14-year follow-up study. AB - BACKGROUND: The growing field of metabolomics has opened up new opportunities for prediction of type 2 diabetes (T2D) going beyond the classical biochemistry assays. OBJECTIVES: We aimed to identify markers from different pathways which represent early metabolic changes and test their predictive performance for T2D, as compared to the performance of traditional risk factors (TRF). METHODS: We analyzed 2776 participants from the Erasmus Rucphen Family study from which 1571 disease free individuals were followed up to 14-years. The targeted metabolomics measurements at baseline were performed by three different platforms using either nuclear magnetic resonance spectroscopy or mass spectrometry. We selected 24 T2D markers by using Least Absolute Shrinkage and Selection operator (LASSO) regression and tested their association to incidence of disease during follow-up. RESULTS: The 24 markers i.e. high-density, low-density and very low-density lipoprotein sub-fractions, certain triglycerides, amino acids, and small intermediate compounds predicted future T2D with an area under the curve (AUC) of 0.81. The performance of the metabolic markers compared to glucose was significantly higher among the young (age < 50 years) (0.86 vs. 0.77, p-value <0.0001), the female (0.88 vs. 0.84, p-value =0.009), and the lean (BMI < 25 kg/m2) (0.85 vs. 0.80, p-value =0.003). The full model with fasting glucose, TRFs, and metabolic markers yielded the best prediction model (AUC = 0.89). CONCLUSIONS: Our novel prediction model increases the long-term prediction performance in combination with classical measurements, brings a higher resolution over the complexity of the lipoprotein component, increasing the specificity for individuals in the low risk group. PMID- 28804276 TI - Qualitative causal analyses of biosimulation models. AB - We describe an approach for performing qualitative, systems-level causal analyses on biosimulation models that leverages semantics-based modeling formats, formal ontology, and automated inference. The approach allows users to quickly investigate how a qualitative perturbation to an element within a model's network (an increment or decrement) propagates throughout the modeled system. To support such analyses, we must interpret and annotate the semantics of the models, including both the physical properties modeled and the dependencies that relate them. We build from prior work understanding the semantics of biological properties, but here, we focus on the semantics for dependencies, which provide the critical knowledge necessary for causal analysis of biosimulation models. We describe augmentations to the Ontology of Physics for Biology, via OWL axioms and SWRL rules, and demonstrate that a reasoner can then infer how an annotated model's physical properties influence each other in a qualitative sense. Our goal is to provide researchers with a tool that helps bring the systems-level network dynamics of biosimulation models into perspective, thus facilitating model development, testing, and application. PMID- 28804277 TI - Celebrating volume 10 of the European journal of ageing. PMID- 28804278 TI - Gender and active ageing in Europe. AB - Increasing longevity in Europe should be a cause for celebration. However, demographic ageing creates challenges. Over the last 10 years the leading policy response to these challenges has been "active ageing". Despite much positive political rhetoric, it is evident that there is considerable uncertainty about what this means in practice. Also it often serves as a convenient term for a range of policies which affect men and women differently. This article argues that an active ageing strategy can provide a basis for countries to respond to the challenges presented by an ageing population. However, this strategy must reflect the need for a partnership between citizens and society and be comprehensive, noncoercive, and inclusive in its approach. In particular, it needs to acknowledge the gendered nature of ageing and previous life course events and emphasise well-being rather than just the production of resources and services. Finally, it contends that the designation of 2012 as the European year of active ageing provided the context for a renewed focus on active ageing policy in the European Union, an opportunity which should be embraced urgently. PMID- 28804279 TI - Values and adult age: findings from two cohorts of the European Social Survey. AB - Human values are assessed biannually in a multinational sample as part of the European Social Survey (ESS). Based on theories of adaptive ageing, it was predicted that ten lower order values and four higher order values would show age differences that would be invariant across (a) two sample cohorts (2002 and 2008), (b) gender and (c) 12 industrialised nations. The value categories measured by the ESS are the following: conservative values (tradition, conformity and security), openness to change values (self-direction, hedonism and stimulation), self-transcendent values (universalism, benevolence) and self enhancement values (power, achievement). Of the ten lower order values, tradition shows the strongest positive relation with adult age, while the value of stimulation shows the strongest negative relation with age. With regards to the four higher order value categories, conservative values increased across age groups, while openness to change values decreased. Neither of these value types showed cohort or gender differences. Self-transcendence values were greater in midlife and older adults compared with young adults, were higher in women than in men, and higher in the 2008 compared with the 2002 cohort. Self-enhancement values showed a negative relation with age, with men of all age groups scoring higher in this value type than women. Age effects on the four higher order value types were replicated across all 12 countries in the sample, with the single exception of self-enhancement values in Spain, which show no relation with age. PMID- 28804280 TI - Leaving the labour market: the impact of exit routes from employment to retirement on health and wellbeing in old age. AB - The study analyses whether and to what degree specific routes into retirement affect older people, i.e. the relationship between heterogeneous exit patterns and post-retirement health and wellbeing. We used longitudinal data from two points in time; data related to t0 were collected in 1993, 1994, 1995 and 1996 and data related to t1 were collected in 2002 and 2003 (N = 589). We focused on older people (55+ at t1) who were employed at t0 and retired at t1. We used confirmative factor analysis to identify identical measures of health and wellbeing at both t0 and t1. Hence, we were able to control for pre-retirement health and wellbeing when evaluating the effects of different exit routes. These routes were defined as dependence on incomes from sickness benefit, disability pension, part-time pension, unemployment insurance and active labour market programmes. Our initial structural equation model showed a clear relation between exit routes and post-retirement wellbeing. People who prior to retirement were pushed into social benefit programmes related to health and unemployment were significantly worse off as retirees, especially those with health-related benefits. However, these relationships disappeared once pre-retirement wellbeing was added to the model. Our main conclusion is that post-retirement wellbeing first and foremost is a consequence of accumulation of advantages and disadvantages during the life course. Both labour market exit routes and post retirement wellbeing can be seen as outcomes of this process. There are no independent effects of the retirement process. Judging from our findings, there is no reason to believe that involvement in social security programmes allowing early retirement on health grounds has any additional negative consequences for health and wellbeing. PMID- 28804281 TI - Depressive symptoms as predictor of dementia versus continuous cognitive decline: a 3-year prospective study. AB - Previous research including meta-analytic efforts supports the assumption that depression is able to predict dementia. The mechanisms of this association still remain to be revealed. Some possible explanations as, for example, the glucocorticoid cascade hypothesis assumes that there are underlying changes at the cortical level that drive the association. Therefore, gradual levels of depressive symptoms may also predict gradual change (decline) in cognitive performance. However, testing both of these predictions (depressive symptoms lead to dementia, and depressive symptoms lead to cognitive decline, respectively) with the same data has to our knowledge not been done in the previous literature. A sample of 562 participants aged 65 or older was examined four times over a period of 3 years. Study participants completed established measures of depression and cognitive functioning. Results based on Cox regression analysis showed that depressive symptoms were not able to predict the conversion to dementia during the following 3 years. Additionally, structural equation models as well as latent change score models did not support the assumption that depressive symptoms predict cognitive decline, measured as a continuous variable. We discuss several possibilities to explain these findings including the potential and possible limits of the glucocorticoid cascade hypothesis. PMID- 28804282 TI - Development of a home visitation programme for the early detection of health problems in potentially frail community-dwelling older people by general practices. AB - The integration within existing health care systems of preventive initiatives to maintain independent living among older people is increasingly emphasized. This article describes the development and refinement of the [G]OLD home visitation programme: an eight-step programme, including a comprehensive geriatric assessment, for the early detection of health and well-being problems among older people (>=75 years) by general practices. A single group post-test study using a mixed model design is performed to evaluate (a) the feasibility of the home visitation programme in general practice, (b) the practical usefulness of the geriatric assessment instrument, and (c) programme implementation with respect to reinventions introduced by general practitioners (GPs) and practice nurses (PNs). Within 3 months time, 22 PNs of 18 participating general practices visited 240 community-dwelling older people (mean age = 82.0 years; SD 4.2) who had not been in contact with their general practice for more than 6 months. Mean time investment of the programme per older person was 118.1 min (SD 27.0) for GPs and PNs combined. Evaluation meetings revealed that GPs and PNs considered the home visitation programme to be feasible in daily practice. They judged the geriatric assessment to be useful, although minor adjustments are needed (e.g., lay-out, substitution of tests). PNs often failed to register follow-up actions for detected problems in a care and treatment plan. Future training for PNs should address this issue. No reinventions were introduced that threatened fidelity of implementation. The findings are used to improve the home visitation programme before its evaluation in a large-scale controlled trial. PMID- 28804283 TI - Sense of threat and coping strategies of Israeli older adults during a military operation. AB - To examine what levels of sense of threat functionally disabled older people experience during war and the coping strategies they use to protect themselves; to examine factors that explain their sense of threat and coping strategies. A convenience sample that included 138 respondents who were functionally disabled older adults and received homecare services. Face-to-face interviews were conducted using a structured questionnaire. The majority of respondents stayed in their homes during the military operation and used a shelter during part or all the times when there was rocket shelling. The findings showed that a variety of factors were significantly correlated with sense of threat and coping strategies; gender and education were significant in explaining sense of threat, and living arrangement was significant in explaining use of shelter; while number of children was significant in explaining frequency of staying at home during the military operation. However, Holocaust survivor status, formal and informal support, and functional status were insignificant in explaining any of the dependent variables. Holocaust survivors feel no more threat compared to those who did not experience the Holocaust. Communities should be prepared to provide emergency services to ease the sense of threat of functionally disabled older adults during wartime and to assure their use of shelter, in particular those who live alone. PMID- 28804284 TI - Erratum to: Unexpected retirement from full time work after age 62: consequences for life satisfaction in older Americans. AB - [This corrects the article DOI: 10.1007/s10433-012-0229-5.]. PMID- 28804285 TI - Conceptualisation of self-management intervention for people with early stage dementia. AB - Dementia is a major challenge for health and social care services. People living with dementia in the earlier stages experience a "care-gap". Although they may address this gap in care, self-management interventions have not been provided to people with dementia. It is unclear how to conceptualise self-management for this group and few published papers address intervention design. Initial focusing work used a logic mapping approach, interviews with key stakeholders, including people with dementia and their family members. An initial set of self-management targets were identified for potential intervention. Self-management for people living with dementia was conceptualised as covering five targets: (1) relationship with family, (2) maintaining an active lifestyle, (3) psychological wellbeing, (4) techniques to cope with memory changes, and (5) information about dementia. These targets were used to focus literature reviewing to explore an evidence base for the conceptualisation. We discuss the utility of the Corbin and Strauss (Unending work and care: managing chronic illness at home. Jossey-Bass, Oxford, 1988) model of self-management, specifically that self-management for people living with dementia should be conceptualised as emphasising the importance of "everyday life work" (targets 1 and 2) and "biographical work" (target 3), with inclusion of but less emphasis on specific "illness work" (targets 4, 5). We argue that self management is possible for people with dementia, with a strengths focus and emphasis on quality of life, which can be achieved despite cognitive impairments. Further development and testing of such interventions is required to provide much needed support for people in early stages of dementia. PMID- 28804286 TI - Examining the process of driving cessation in later life. AB - Driving cessation for many older people is associated with a poorer quality of life and can lead to health problems such as depression. This paper aims to reveal the process of giving-up driving, examining in particular triggers for giving-up driving, how information on alternative modes of transport is sought and how new transport and travel behaviour is integrated into older people's lives. It examines the challenges faced and how these are overcome and what impact the process has on self-reported quality of life, as articulated by the participants themselves. To this end, twenty-one individuals from three locations in the United Kingdom (UK) were followed over a period of 10 months, through five waves of data collection. Each participant took part in three interviews, a focus group and completed a diary of travel behaviour. Findings suggest that although a similar pattern was found between the trigger and life post-car, not all older people go through the stages of giving-up driving in the same way. Instead, a range of responses are seen, from contemplation of gradually reducing driving, through to stopping abruptly, with the route taken having consequences for the eventual outcome for any individual. Triggers for contemplating driving cessation could be varied and often involved health and social factors. Importantly, people who engaged in pre-planning reported a relatively higher quality of life beyond the car, whilst for those who were more reactive and engaged in little or no pre planning a poorer quality of life resulted. In addition (and in conjunction with planning), other factors, such as flexibility in travel destinations, the role of family and friends, and wider support networks are also seen as important. With such evidence of the importance of pre-planning it is suggested that more could be done to support giving-up driving and encouraging contemplation at a younger age to mitigate the negative effects experienced by some. PMID- 28804287 TI - Migrants' motivations to work in the care sector: experiences from England within the context of EU enlargement. AB - Migrant workers are considered an economic utility, especially for secondary labour markets such as that of long-term care. The dynamics of migrant workers across the globe are governed by interacting macro, state level, and micro, personal level, factors. On the macro level immigration policies, historical and current political and economic links between countries play a crucial part in such dynamics. On an individual level, choices, actions and motivations to migrate and work in certain labour sectors are entangled with and governed by macro level policies. Since 2003, the enlargement of the European Economic Area (EEA) has enabled employers in the UK to freely recruit staff from EEA countries. This article investigates reported individual motivations and the decision making process while accounting for macro factors, specifically ease of labour mobility within the EEA versus a more elaborate process when migrating to work in social care in the UK from outside the EEA. Face to face interviews were conducted with 96 migrant social care and social work staff in six diverse areas of England (2007-2009). The analysis indicates differences in stated motivations to migrate to the UK and to work in the care sector among different groups of migrants, particularly among those from Commonwealth countries, from the EEA, and migrants from other parts of the globe. The findings highlight the importance of taking into account the role of immigration policies and consequently immigration status when investigating the policy framework and delivery of care services for older people. PMID- 28804288 TI - Fear of crime in old age: precautious behaviour and its relation to situational fear. AB - This study aimed to provide further insight into the question of why older adults show a higher precautionary behaviour regarding crime (behavioural fear), although they do not estimate their victimisation risk as higher than young adults and they do not experience fear more often. In two cross-sectional studies, the hypothesis was tested that the age-related increase in precautionary behaviour is an expression of higher dispositional fear with age. The vignette technique was employed to induce situational fear of crime across various situations as a proxy for dispositional fear. In contrast to the hypothesis, in Study 1 (young: 18-30 years, N = 179 vs. middle-aged: 50-64 years, N = 106), only younger adults reported higher situational fear in two vignettes. In Study 2 (young: 18-30 years, N = 129 vs. young-old: 65-84 years, N = 114), younger adults indicated higher situational fear again; however, young-old adults reported higher situational fear in other vignettes. The findings suggest that there is no general increase in the intensity of situational fear of crime with age and thus no age-related change in dispositional fear. Moreover, situational fear did not serve as mediator in the relationship between age and precautionary behaviour. Alternative accounts for the increase in behavioural fear of crime are discussed as well as emotion regulation mechanisms in response to the induction method. PMID- 28804289 TI - Validity and reliability of the SF-36 in Chilean older adults: the ALEXANDROS study. AB - To validate short-form-36 health survey (SF-36) with specific scoring algorithm obtained in a large sample of Chilean older people and to associate quality of life in this sample with social and health related factors. A cross-sectional study on 2,143 community-living subjects aged 60-92 years (33 % men and 67 % women) conducted in Santiago, Chile. Scores in 8 scales of SF-36-physical function (PF), role physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role emotional (RE) and mental health (MH)-, were calculated. Factor analysis was used to extract two principal factors and logistic regression model was applied to estimate its association with socio demographic and health variables. The internal consistency of scales was high (Cronbach's alpha 0.86-0.87). Factor analysis retained two factors: mental (MCS) and physical (PCS) components accounting for 65.3 % of total variance (55.3 and 10.0 % respectively). High correlations (0.61-0.94) between MCS and MH, V, RE and SF were obtained. PCS correlated highest (0.72-0.86) with RP, PF and BP. Self perceived symptoms of depression (GDS-15 >=5) was the main variable explaining low scores in both MCS and PCS (adjusted OR = 26.9; 95 % CI: 15.3-47.2; OR = 3.4; 95 % CI: 2.1-5.5, respectively). We have demonstrated the reliability and validity of SF-36 questionnaire to evaluate health related quality of life, reporting Chilean-Specific factor score coefficients for MCS and PCS based in national Chilean means and standard deviations for older people. After adjusting by age and gender, the main predictors of low health related QoL in Chilean older people were self-perceived symptoms of depression, the presence of two or more chronic diseases and illiteracy. Important gender inequalities were observed in all of these results, being consistently less favorable in women than in men. PMID- 28804290 TI - Learning in later life: participation in formal, non-formal and informal activities in a nationally representative Spanish sample. AB - This article examines the participation of Spanish older people in formal, non formal and informal learning activities and presents a profile of participants in each kind of learning activity. We used data from a nationally representative sample of Spanish people between 60 and 75 years old (n = 4,703). The data were extracted from the 2007 Encuesta sobre la Participacion de la Poblacion Adulta en Actividades de Aprendizaje (EADA, Survey on Adult Population Involvement in Learning Activities). Overall, only 22.8 % of the sample participated in a learning activity. However, there was wide variation in the participation rates for the different types of activity. Informal activities were far more common than formal ones. Multivariate logistic regression indicated that education level and involvement in social and cultural activities were associated with likelihood of participating, regardless of the type of learning activity. When these variables were taken into account, age did not predict decreasing participation, at least in non-formal and informal activities. Implications for further research, future trends and policies to promote older adult education are discussed. PMID- 28804291 TI - Social network and mobility improvement among older Europeans: the ambiguous role of family ties. AB - This study examined the social network correlates of improvement in lower extremity mobility among respondents aged 65 and older from the longitudinal sample of the Survey of Health, Ageing and Retirement in Europe. The study focused on those who self-reported having difficulties with four lower extremity functions: (1) walking 100 m; (2) rising from a seated position; (3) climbing flights of steps; and (4) stooping, kneeling, or crouching. Multivariate logistic regression analyses revealed that social networks were variously associated with improvement in lower extremity function at the two-year follow-up. The findings suggest that under certain circumstances, a lack of social support in late life may actually promote mobility improvement. The research also shows that family networks are not always facilitative of mobility improvement. This is in contrast to previously published social network research positing that supportive relationships help foster health and buffer stressors in late life. Family caregivers and social services should keep this in mind when devising treatment plans upon discharge from the hospital and implementing care management plans for frail older persons in the community. PMID- 28804292 TI - Family, state, class and solidarity: re-conceptualising intergenerational solidarity through the grounded theory approach. AB - The relationship between class and intergenerational solidarities in the public and private spheres calls for further conceptual and theoretical development. This article discusses the findings from the first wave of a qualitative longitudinal study entitled Changing Generations, conducted in Ireland in 2011 2012, comprising 100 in-depth interviews with men and women across the age and socioeconomic spectrums. Constructivist grounded theory analysis of the data gives rise to the following postulates: (1) intergenerational solidarity at the family level is strongly contoured by socioeconomic status (SES); (2) intergenerational solidarity evolves as family generations observe each others' practices and adjust their expectations accordingly; (3) intergenerational solidarity within families is also shaped by the public sphere (the welfare state) that generates varying expectations and levels of solidarity regarding State supports for different age groups, again largely dependent on SES; (4) the liberal welfare state context, especially at a time of economic crisis, enhances the significance of intergenerational solidarity within families. We conclude by calling for research that is attuned to age/generation, gender and class, and how these operate across the family and societal levels. PMID- 28804293 TI - "You're saying something by giving things to them:" communication and family inheritance. AB - The study purpose was to contribute to a more complete understanding of the experience and meaning of family inheritance. The aim of this article is to describe and discuss the meaning of communication in inheritance experiences among Canadian families. A constructivist/interpretive methodological approach guided this research. Participants were recruited through purposive, convenience sampling from two cities and one town in southern and southwestern Ontario, Canada. Fifty face-to-face, semi-structured, audio-taped, in-depth interviews were conducted between June 2006 and April 2007. NVivo software was used to organize and analyze the data. A content analysis method guided data analysis. Participants interpreted the meaning of family structure, relationships, feelings, and past inheritance experiences to construct their family inheritance communication. Analysis of the findings revealed four themes regarding the role of communication in family inheritance including: (a) avoiding conflict and preserving biological ties, (b) resisting conversations about possessions, (c) achieving confidence withpossession communication, and (d) lasting effects. Participants from non-blended and blended families experienced similar inheritance communication challenges related to past experience with their parents' wills and distribution of their own possessions. Participants with past positive inheritance experiences with parents adopted similar strategies when communicating their own inheritance wishes. Negative messages conveyed to participants by their parent's wills inspired participants to communicate in opposite ways in their own inheritance planning. The study findings are useful for gerontologists, lawyers, family counselors, and estate planners. PMID- 28804294 TI - Older family carers in rural areas: experiences from using caregiver support services based on Information and Communication Technology (ICT). AB - The aim of this intervention study was to illuminate the meaning of ICT-based caregiver support as experienced by older family carers living in vast rural areas, caring for a spouse at home. In order to access, the support service participants were provided with a computer and high speed Internet in their homes. Semi structured webcam-interviews were carried out with 31 family carers. A strategy for webcam interviewing was developed to ensure quality and create a comfortable interview situation for the family carers. Interviews were analysed using content analyses, resulting in the themes: Adopting new technology with help from others and Regaining social inclusion. The results indicate that ICT based support can be valuable for older family carers in rural areas as it contributes to improve quality in daily life in a number of ways. In order to fully experience the benefits, family carers need to be frequent users of the provided support. Adequate training and encouragement from others were essential in motivating family carers to use the support service. Access to Internet and webcamera contributed to reducing loneliness and isolation, strengthening relationships with relatives living far away and enabled access to services no longer available in the area. Use of the ICT-service had a positive influence on the relationship between the older carer and adult grandchildren. It also contributed to carer competence and promote feelings of regaining independence and a societal role. PMID- 28804295 TI - Need fulfillment in the nursing home: resident and observer perspectives in relation to resident well-being. AB - Self-reports in nursing homes generally show highly satisfied residents, whereas observational studies provide more nuanced results. In this study, which is based on self-determination theory, the perspective of nursing home residents (self reports) is compared to the perspective of trained "neutral" observers (video observations). The experiences of physically frail older residents are measured with regard to the fulfillment of their needs for relatedness, autonomy, and competence. Self-reports of need fulfillment in general, in the caring relationship, and during a caregiving episode recorded on videotape of 36 residents (64 % female, mean age 80 years) were compared with observer ratings of resident need fulfillment during the latter caregiving episode. Furthermore, it was investigated which measure relates best to residents' self-reported well being. The results show that residents rate their need fulfillment higher than observers. There is weak to moderate agreement between resident and observer ratings. Furthermore, only residents' self-reported need fulfillment in general is related with self-reported well-being. Different explanations are provided, including the "barrier of happiness," the use of cognitive strategies, a change in identity and existing power relations. There seems to be a paradox in caregiving: Residents and their needs should be central, but because residents might adapt their needs and wishes it is hard to assess these. Suggestions for practical applications are given. PMID- 28804296 TI - Prospective memory tasks related to goals and concerns are rated as more important by both young and older adults. AB - There has been little research on variables that affect importance ratings for real prospective memory tasks (e.g., remembering to take medications). Our primary purpose was to test a claim in the motivational-cognitive model of prospective memory, namely that prospective memory tasks highly related to a person's goals and concerns will be rated as more important. We also tested whether this relationship held in both young and older adults. A secondary purpose was to investigate age-related differences in the perceived importance of prospective memory tasks. Older adults and two younger adult groups completed a questionnaire that assessed current prospective memory tasks, their importance, and whether the tasks were related to participants' goals and concerns. As predicted, participants provided higher importance ratings for prospective memory tasks that were highly relevant to their personal goals or concerns, and this was true for both young and older adults. Task importance ratings did not differ for older adults and young college students; however, young nonstudents rated their prospective memory tasks as less important than the other two groups. In all three groups, females gave higher prospective memory task importance ratings than males. In conclusion, our findings suggest that the importance of a prospective memory task is partly determined by its goal-relatedness. This newly demonstrated link suggests important avenues for future research, including research on the mechanisms through which goals improve prospective memory performance. PMID- 28804297 TI - Rumination and reminiscence in older adults: implications for clinical practice. AB - Reminiscence is proposed as an important activity for well-being in late life but recent reviews highlight the differential outcomes of this behavior. If older adults engage in reminiscing as a natural process, but do so with a ruminative style of thinking, it may actually be detrimental to successful development and well-being. This project explored the relationship between rumination, reminiscence, mood, and psychosocial development. One hundred and fifty community dwelling older adults completed measures assessing these variables. As expected, increased rumination was related to increased depressed mood. Fifty-four of the participants completed a follow-up measure of depressed mood. Rumination also accounted for follow-up depressed mood beyond that explained by time-1 mood. The interaction between rumination and reminiscing significantly predicted future depressed mood after controlling for main effects and baseline mood. Further, this interaction significantly predicted overall psychosocial development. Implications for clinical practice are discussed. PMID- 28804298 TI - Religious activity, life expectancy, and disability-free life expectancy in Taiwan. AB - Research has implicated religious activity as a health determinant, but questions remain, including whether associations persist in places where Judeo-Christian religions are not the majority; whether public versus private religious expressions have equivalent impacts, and the precise advantage expressed as years of life. This article addresses these issues in Taiwan. 3,739 Taiwanese aged 53+ were surveyed in 1999, 2003, and 2007. Mortality and disability were recorded. Religious activities in public and private settings were measured at baseline. Multistate life-tables produced estimates of total life expectancy and activity of daily living (ADL) disability-free life expectancy across levels of public and private religious activity. There is a consistent positive gradient between religious activity and expectancy with greater activity related to longer life and more years without disability. Life and ADL disability-free life expectancies for those with no religious affiliation fit in between the lowest and highest religious activity groups. Results corroborate evidence in the West. Mechanisms that intervene may be similar in Eastern religions despite differences in the ways in which popular religions are practiced. Results for those with no affiliation suggest benefits of religion can be accrued in alternate ways. PMID- 28804299 TI - Sampling and non-response bias on health-outcomes in surveys of the oldest old. AB - Surveys of the oldest old population are associated with several design issues. Place of residence and possible physical or cognitive impairments make it difficult to maintain a representative study population. Based on a Swedish nationally representative survey among individuals 77+, the present study analyze the potential bias of not using proxy interviews and excluding the institutionalized part of the population in surveys of the oldest old. The results show that compared to directly interviewed people living at home, institutionalized and proxy interviewed individuals were older, less educated and more likely to be female. They had more problems with health, mobility and ADL, and a significantly increased mortality risk. If the study had excluded the institutionalized part of the population and/or failed to use proxy interviews, the result would have been severely biased and resulted in underestimated prevalence rates for ADL, physical mobility and psychologic problems. This could not be compensated for weighting the data by age and sex. The results from this study imply that accurate population estimates require a representative study population, in which all individuals are included regardless of their living conditions, health status, and cognitive ability. PMID- 28804300 TI - Inter-rater agreement of a modified and extended Swedish version of the Frenchay Activities Index (FAI). AB - The point of departure for this study was the need for an instrument capturing social activities updated to the living circumstances of the 21st century. Starting out from the Frenchay Activities Index (FAI), the objective was to investigate the inter-rater agreement of the scoring of a modified and extended Swedish version, capturing activity performance and participation. Thirty-one older people, living in the community post stroke, were interviewed in their homes by two raters using the Swedish FAI version, extended with items on use of mode of transport and use of telephone, and modified with additional scales. Besides the original frequency scale, the new scales captured changes in frequency, reasons for change, and performance satisfaction; inter-rater agreement was analyzed with kappa statistics. Overall, the inter-rater agreement was high or very high, with weighted [Formula: see text] = 0.924 for the frequency scale and [Formula: see text]= 0.784-0.940 for the new scales. As a conclusion, while further validity and reliability testing is necessary, when out of-home activities are of interest the scoring of the modified and extended Swedish FAI version can be administered with high inter-rater agreement. PMID- 28804301 TI - Pilot study into impaired judgement, self-toileting behaviour in fallers and non fallers. AB - Falls are a significant cause of morbidity and mortality in older people. There is an increased frequency of falls in older adults with cognitive impairment and dementia which may be due to impaired judgement of self capability to mobilise safely. This case control study assessed 53 Aged Care subjects aged 75+ years that were hospitalised post fall, from January 2008-December 2009, and compared these subjects' responses to those of 26 non-fallers to a standard question: 'While you are in the hospital, what would you do if you need to go to the toilet later?' This hypothetical scenario question was designed to assess judgement based on self-toileting behaviour and mobility. The study group and control group were similar in age (83.9 +/- 4.7 vs. 82.0 +/- 4.6 years respectively, p = 0.081) but the study group had statistically lower MMSE results when compared to controls (median 23 vs. 26.5 respectively, p = 0.031). Impaired judgement, defined as an unsafe/inappropriate response to the scenario question, was significantly more prevalent in the study group (fallers) compared to the control group (non-fallers) (41.5 vs. 15.4 %, p = 0.020). Impaired judgement was also more common with lower MMSE scores with 80.9 % of unsafe/inappropriate responses given by participants with MMSE of <=20. The authors suggest there may be an association between impaired judgement, evidenced by responses to a standardised question, and falls history in older subjects, particularly in those with cognitive impairment or dementia. Ultimately, this may lead to identification of people at increased risk of falls and possibly effective falls prevention strategies in this population. PMID- 28804302 TI - European ageing research in the social, behavioural and health areas: a multidimensional account. AB - At the 10th anniversary of the European Journal of Ageing in 2013, this article makes an attempt towards a comprehensive overview of European ageing research (EAR) from the three perspectives of this Journal: the social, behavioural and health related domains. First, we provide some general observations on the state of EAR, noting the difficulties of defining this field. Second, we provide a description of EAR and its current trends and characteristics in terms of research themes and theoretical directions. Towards this end, we use the 10 volumes of the European Journal of Ageing as well as other available information. Third, we address the infrastructure of EAR as reflected in major studies, looking at data availability, language, education and training. Given this background, we derive a set of six recommendations to further consolidate and expand EAR. PMID- 28804303 TI - Asset accumulation and transfer for old age: a study on Peruvian and Moroccan migration to Spain. AB - Population ageing constitutes a major determinant of contemporary international migration, acting both as a push and pull factor in countries of origin and reception. From a micro-perspective, longevity, economic instability and migration are also affecting personal life as well as family organisation and solidarity. The aim of this paper is to focus on the strategies, in individual and family spheres, that migrants and their loved ones develop to accumulate and transfer assets, in order to respond to the demands of the elderly and counteract the uncertainties of advancing age. To capture this reality we conducted in-depth interviews and focus groups with Peruvian and Moroccan migrants in Spain, and with returnees and relatives in the two countries of origin between 2006 and 2010. Both cases demonstrate that country contexts, together with personal experiences and family relationships, determine where to stay, and with whom or with what to support oneself as one grows older. More recently, the economic crisis in Spain that is negatively influencing social and migration policies, reducing migrants' economic gains, and placing new burdens on people's shoulders, is affecting these asset accumulation and transfer activities for old age. PMID- 28804304 TI - Differences in late-life loneliness: a comparison between Turkish and native-born older adults in Germany. AB - The aim of this study was (1) to examine whether Turkish older migrants are indeed-as is often claimed without solid scientific evidence-lonelier than their peers with no migration background and (2) to determine the factors that account for the differences in loneliness between them. We analysed data of adults aged 50-79 from the first wave of the German Generations and Gender Survey and a supplementary survey of Turkish nationals in Germany (N = 3,248 born in Germany and N = 494 born in Turkey). Differences in degree of loneliness between Turkish and native-born older adults were determined by the six-item Loneliness Scale of de Jong Gierveld. To identify the specific factors contributing to these loneliness differences, a series of multivariate regression analyses were conducted, examining the impact of two groups of risk factors (poor health and low socioeconomic status) and two groups of protective factors (social embeddedness in the family and informal support exchanges) on loneliness. Results showed that feelings of loneliness are indeed more prevalent among older adults of Turkish origin than their German counterparts, which is entirely attributable to their lower socioeconomic status and poorer health. Living with a partner or children, frequent contacts with non-coresident children, emotional support exchange and looking after grandchildren-though important factors to prevent loneliness at the individual level-did not specifically protect Turkish older adults from loneliness, or did so rarely. These findings not only indicate new and challenging directions for further research but also raise questions about the effectiveness of the most common loneliness interventions, which focus on improving number and quality of social relationships. PMID- 28804305 TI - Positive and negative evaluation of caregiving among three different types of informal care relationships. AB - Based on the caregiver stress model, we examined how care demands, caregiver motivation, coping style and external support are associated with positive evaluation and caregiver burden among spousal, adult child and other types of care relations. Data from a sample of Dutch informal caregivers of 1,685 older persons (55 and older) were analyzed employing multivariate linear regression analyses for each of the care relationship types. Spouses (N = 206) report high positive evaluation and high burden, adult children (N = 1,093) report low positive evaluation, and other caregivers (N = 386) report high positive evaluation and a low burden. Multivariate linear regression analyses showed that motives and external support were important for positive evaluation but the impact varied among types of caregivers, whereas care demands and not asking for help were associated with burden for all types. Only among 'other' caregiver relationships, positive evaluation was negatively associated with burden. It is concluded that results confirm the dual nature of caregiving among spouses and children. The care context and motivation of the different types of caregivers explain their differences in care evaluation. Various interventions for types of caregivers are discussed. PMID- 28804306 TI - Being, belonging and bestowing: differing degrees of community involvement amongst rural elders in England and Wales. AB - Government exhortations for full community involvement in their locales in England and Wales have particular significance for rural elders as the literature suggests that they are amongst the most active in this sphere. But different people have different propensities to 'join in'. A taxonomy of different degrees of involvement in community is derived: antagonising, absenting, being, belonging, bestowing and communing. Being, belonging and bestowing are explored empirically, because they are the elements of principal concern to policy, making use of surveys of rural elders in six locations in England and Wales. A minority of respondents undertook bestowing activity (actively assisting others or taking part in voluntary activity) but most felt there were benefits from being (just living in a place) or belonging (having an identity with place) to a community. Of those who did not join in, most claimed that this was because they did not want to. Education and qualifications had the strongest association with 'joining in', although income and wealth per se had little impact. Two lessons for government community policy are important. First, many older people do not wish to 'join in', and second, the variables that tended to be associated with participation may not be that easy to influence through community policy. PMID- 28804307 TI - Multiple standards of aging: gender-specific age stereotypes in different life domains. AB - Whereas it is often stated that aging might have more negative consequences for the evaluation of women compared to men, evidence for this assumption is mixed. We took a differentiated look at age stereotypes of men and women, assuming that the life domain in which older persons are rated moderates gender differences in age stereotypes. A sample of 298 participants aged 20-92 rated 65-year-old men and women on evaluative statements in eight different life domains. Furthermore, perceptions of gender- and domain-specific age-related changes were assessed by comparing the older targets to 45-year-old men and women, respectively. The results speak in favor of the domain specificity of evaluative asymmetries in age stereotypes for men and women, and imply that an understanding of gendered perceptions of aging requires taking into account the complexities of domain specific views on aging. PMID- 28804309 TI - The European Journal of Ageing and the debate on consequences of population ageing. PMID- 28804308 TI - The effect of population aging on health expenditure growth: a critical review. AB - Although the consequences of population aging for growth in health expenditures have been widely investigated, research on this topic is rather fragmented. Therefore, these consequences are not fully understood. This paper reviews the consequences of population aging for health expenditure growth in Western countries by combining insights from epidemiological and health economics research. Based on a conceptual model of health care use, we first review evidence on the relationship between age and health expenditures to provide insight into the direct effect of aging on health expenditure growth. Second, we discuss the interaction between aging and the main societal drivers of health expenditures. Aging most likely influences growth in health expenditures indirectly, through its influence on these societal factors. The literature shows that the direct effect of aging depends strongly on underlying health and disability. Commonly used approximations of health, like age or mortality, insufficiently capture complex dynamics in health. Population aging moderately increases expenditures on acute care and strongly increases expenditures on long term care. The evidence further shows that the most important driver of health expenditure growth, medical technology, interacts strongly with age and health, i.e., population aging reinforces the influence of medical technology on health expenditure growth and vice versa. We therefore conclude that population aging will remain in the centre of policy debate. Further research should focus on the changes in health that explain the effect of longevity gains on health expenditures, and on the interactions between aging and other societal factors driving expenditure growth. PMID- 28804310 TI - Macro- and micro-level predictors of age categorization: results from the European Social Survey. AB - This study evaluated macro- and micro-level variables associated with individuals' perception of the ending of youth, the beginning of old age, and the length of the middle age period. The European Social Survey is a biennial multi country, cross-sectional survey. Our analysis is based on the fourth wave, which included a rotating module on ageism. The source sample consisted of 28 countries and a total of 54,988 respondents. Whereas macro-level variability accounted for 14 % of the variance associated with the perception of the ending of youth, only 5.7 % of the variance associated with the perception of the beginning of old age was accounted for by macro-level variability. Almost 10 % of the variance associated with the perception of the middle age period was associated with macro level variability. Different patterns of macro- and micro-level correlates emerged for the ending of youth, beginning of old age, and the period of middle age. Overall, results demonstrate that individual differences in the perception of the ending of youth, the beginning of old age, and the length of the middle age period are more pronounced than contextual differences. Results also suggest that individuals' mental maps regarding the timing of these events are not necessarily concordant. PMID- 28804311 TI - Long-term exposure to income inequality: implications for physical functioning at older ages. AB - The 'inequality hypothesis' proposes that higher levels of societal income inequality have a direct negative causal effect on health. Support for this hypothesis has been mixed; particularly among older people. However, most previous studies have not accounted for people's exposure to inequality over the long-term. We aimed to address this problem by examining the implications of long term inequality exposure for older people's physical health. Data on individual health and covariates were drawn from three large, comparable surveys of older people, covering 16 countries: the English Longitudinal Study of Ageing, the Survey of Health and Retirement in Europe and the U.S. Health and Retirement Study. Historical inequality information was derived from the Standardised World Income Inequality Database. We used multilevel regression methods to model the association between long-term average inequality and three measures of physical functioning: grip strength, lung function and self-reported activity limitation. Exposure to higher average long-term levels of inequality was significantly negatively related to objectively measured grip strength and lung function, but unrelated to self-reported limitations (although increasing inequality over time was positively related to self-reported limitations). The grip strength and lung function associations were partially explained by between-country differences in height, and in the latter case this factor may fully account for the apparent effect of inequality. We discuss implications of these results for the inequality hypothesis. PMID- 28804312 TI - Why are women more likely than men to extend paid work? The impact of work-family life history. AB - Extending working life beyond the state pension age is a key European Union policy. In the UK, women are more likely to extend paid work than men, indicating that factors other than the state pension age play a role in working longer. Women are less able to build pension income due to their role as carer within the family. It, therefore, follows that gender inequalities over the life course continue into older age to influence need, capacity and desire to undertake paid work after state pension age. This paper explores how work, marital and fertility history impact upon the likelihood of extending employment. It uses the British Household Panel Survey's retrospective data from the first 14 waves to summarise work-family histories, and logistic regression to understand the impact of work and family histories on extending paid work. Findings show that, on the one hand, women are extending paid work for financial reasons to make up for 'opportunity costs' as a result of their caring role within the family, with short breaks due to caring, lengthy marriages, divorcing and remaining single with children all being important. Yet, there is also evidence of 'status maintenance' from working life, with the women most likely to extend paid work, also those with the highest work orientation, prior to state pension age. But lengthy dis-attachment (due to caring) from the labour market makes extending working life more difficult. This has implications for policy strategies to entice women into paid work to make up for low independent financial resources. PMID- 28804313 TI - Older immigrants' use of public home care and residential care. AB - The purpose of this paper is to analyse the extent to which length of residence in the country and country of origin are of importance to older immigrants' use of long-term care services compared to native older people. The analyses were conducted on a population of over 65s living in the Municipality of Copenhagen on 1st Jan 2007. Information was drawn from the administrative registers of the Municipality of Copenhagen on the population's use in 2007 of home care and of residential care in a nursing home. These data were combined by Statistics Denmark with demographic data, socio-economic data and data on the use of health services. It was found that older immigrants are less likely than ethnic Danes to use municipal long-term care services when other predisposing, enabling and need factors are controlled for. The difference is greatest between ethnic Danes and immigrants from non-western countries who have only lived in Denmark for a few years. The difference decreases the longer the immigrant has lived in the country. The findings may be explained, at least in part, by poorer language skills and poorer knowledge of the Danish welfare system among older immigrants and the fact that they are more likely to be cared for by relatives than ethnic Danes are. However, in the course of time language skills improve and knowledge of the system increases and life style with respect to care may approach that of older Danes. PMID- 28804314 TI - Relocation to ordinary or special housing in very old age: aspects of housing and health. AB - Relocation in very old age is considered to be a major life event and a move could be triggered by many different economic, social, health-related, or environmental reasons. Based on the notion of person-environment (P-E) fit as expressed in the Ecological Theory of Ageing, the aim of this prospective study over 4 years was to explore which aspects of housing and health predict relocation to ordinary or special housing among very old people. At baseline, the participants (80-89 years old) lived alone in ordinary housing in Sweden (N = 384). Data collection at home visits included assessments and observations on aspects of objective and perceived housing as well as on aspects of health. After 4 years, 18 % (n = 70) of the participants had moved, either to ordinary housing (n = 24) or to special housing (n = 46). Cox regression models showed dependence in cleaning, perceived functional independence, and living in a one-family house to predict moves to ordinary housing. Dependence in cooking, cognitive deficits, and accessibility problems predicted moves to special housing. In conclusion, aspects of housing and health are related to relocation in very old age, but in different patterns for relocation to ordinary housing and special housing, respectively. This kind of knowledge has practical implications for relocation counselling and societal planning targeting very old people. PMID- 28804315 TI - Environmental facilitators for outdoor walking and development of walking difficulty in community-dwelling older adults. AB - Older adults who report environmental barriers in their neighborhood have a higher risk for walking difficulty. However, environmental facilitators that protect against walking difficulty are not well known. The objective of this study was to identify the effect of environmental facilitators for outdoor walking on development of walking difficulty in community-dwelling older people. This was a prospective study with a 3.5-year follow-up time on 261 community dwelling people aged 75-81 years, who at baseline were able to walk 0.5 km without difficulty. Environmental facilitators for outdoor walking were self reported with standardized questionnaires, including having features in one's home which make it easy to access the outdoors, having a park or other green area within a walking distance from home, having outdoor recreational facilities within a walking distance from home, having features in the nearby environment, which are attractive for outdoor activities, and perceiving the surrounding environment or facilities nearby as motivating factors for physical activity. Self-reported difficulty in walking 0.5 km was assessed every 6 months. Of the participants, 46 % developed walking difficulty during the follow-up. Having a park or other green area within a walking distance from home was the most frequently reported facilitator. Environmental facilitators decreased the risk for development of walking difficulty, hazard ratio per item 0.86, (95 % confidence interval 0.73-1.02). The results indicate that the mobility of older community-dwelling people may be promoted with outdoor recreational facilities that are easy to access and located within a walking distance from home. PMID- 28804316 TI - Association of perceived health and depression with older adults' subjective memory complaints: contrasting a specific questionnaire with general complaints questions. AB - The objectives of this paper were to evaluate the association of subjective memory complaints (SMC) with perceived state of health, mood and episodic memory (associative and everyday memory). We studied these areas using two different complaint assessment methods (three general questions and a validated scale). The study included 269 older adults (aged 65-87) with age-related memory changes, but without cognitive impairment. They were evaluated with Mini-cognitive Exam, Rivermead Behavioural Memory Test (a test of everyday memory), Paired Associates Learning Test, Memory Failures of Everyday Questionnaire, three memory complaints questions, Nottingham Health Profile and Geriatric Depression Scale. The results indicated that memory for everyday performance, mood and perceived health were independent predictors of SMC, with mood and perceived health being stronger predictors than actual memory performance. Age was not associated with subjective memory and, with regard to level of education, only the illiterate level was associated with SMC. A specific questionnaire on subjective memory was found to be preferable to an aggregate of complaints questions on self-reported memory; only health profile was found to predict the outcomes on memory complaints questions. Our conclusion is that a group of underlying factors other than everyday memory were playing a role in SMC; these SMC of subjects with age related memory changes were mainly associated with subjective evaluations of their health. PMID- 28804317 TI - Fluid mechanics moderate the effect of implementation intentions on a health prospective memory task in older adults. AB - The aim of the present study was to test if a cognitive strategy improves older adults' prospective memory performance in a naturalistic health task. Moreover, it was tested if a possible strategy effect is moderated by individual differences. Therefore, a group of older adults was asked to perform a task taken from the medication adherence literature (i.e., blood pressure monitoring). Half of them were asked to form implementation intentions. Additionally, crystallized pragmatics and fluid mechanics, conscientiousness, self-efficacy, and lifestyle factors were assessed as possible moderators. Results showed a strong positive strategy effect on prospective memory. Moreover, the effect was qualified by a significant interaction and only emerged for participants with low levels in fluid mechanics. No other moderator showed an effect. In conclusion, an enhancing effect of implementation intentions on prospective memory seems to be dependent on individual differences in cognitive capacity and less related to key motivational or personality variables. PMID- 28804318 TI - Revisiting the age-prospective memory-paradox: the role of planning and task experience. AB - The present study aimed at investigating age-related differences in prospective memory performance using a paradigm with high ecological validity and experimental control. Thirty old and 30 young adults completed the Dresden Breakfast task; a meal preparation task in the lab that comprises several subtasks including event- and time-based prospective memory tasks. Participants were required to plan how to perform the task. Results showed that young adults outperformed old adults: they completed more subtasks, showed better event- and time-based prospective memory performance and planning quality. In contrast, old adults adhered to their plans more closely than young adults. Further exploratory gender-specific analyses indicated that old women did not differ from young men in time-based prospective memory performance, general task performance and time monitoring in contrast to old men. Possibly, differences in experience in breakfast preparation might account for these differential findings. PMID- 28804319 TI - Self-esteem across adulthood: the role of resources. AB - It is still not well understood how and why developmental trajectories of self esteem change, particularly in late life. We investigated the role of resources for self-esteem change across adulthood. In detail, we explored between-person differences in self-esteem levels and change in relation to resources with participants who ranged in age from 17 to 100 years. Study 1 consisted of a cross sectional representative German sample of 12,609 participants, where we observed few age differences in mean levels of self-esteem across adulthood. Being married or in a relationship and positive subjective health were associated with higher levels of self-esteem. In addition, relations of resources of subjective health as well as neuroticism with self-esteem appeared to be smaller in late compared to young adulthood. Longitudinal studies including young (N = 338) and older adults (N = 325) indicated both reasonably high stability regarding rank-order and mean levels of self-esteem across 4 and 8 years. Again, age-differential resources appeared to be important for higher levels of self-esteem with education being related to self-esteem in young adults and subjective health in late life. However, no resource was associated with changes in self-esteem in either young or late adulthood. Overall, findings suggest that self-esteem levels are reflective of age-specific constraints and risks. PMID- 28804320 TI - Do mobility, cognitive functioning, and depressive symptoms mediate the association between social activity and mortality risk among older men and women? AB - Social activity and health correlate in old age, but less is known about what explains this association. The aim of this study was to investigate whether mobility, cognitive functioning, and depressive symptoms mediate the association between social activity and mortality risk, or whether they alternatively should be considered as prerequisites for social activity in older Finnish men and women. In 1988, 406 men and 775 women aged 65-84 years took part in face-to-face interviews about their health, socioeconomic status, and social activities. Confirmatory factor analyses were used to form latent variables describing collective and productive social activity. Latent variable models were used to investigate the possible pathways among social activity, mobility, cognitive functioning, depressive symptoms, and mortality risk. In the 21-year follow-up, 89 % of men and 81 % of women had died. Collective and productive social activity correlated with a lower risk for mortality among men and women. Part of the association between social activity and mortality was mediated by mobility. Cognitive functioning and depressive symptoms were not mediators in the association. Instead, good cognitive functioning and having less depressive symptoms were prerequisites for participating in collective social activity among men and women. Among men, good cognitive functioning, and among women, good cognitive functioning and having less depressive symptoms were prerequisites for productive social activity. The health-enhancing influences of social activity may be partly explained by better mobility among persons who are socially active. Moreover, social activity may maintain mobility and thus decreases mortality risk, as many social activities also include physical activity. Better cognitive functioning and having less depressive symptoms should be considered as prerequisites for participating in social activities. PMID- 28804321 TI - Suicide among older people in relation to their subjective and objective well being in different European regions. AB - The aim of this study was to establish how different types of welfare states shape the context of the everyday life of older people by influencing their subjective well-being, which in turn might manifest itself in suicide rates. Twenty-two European countries studied were divided into Continental, Nordic, Island, Southern, and post-socialist countries, which were subdivided into Baltic, Slavic, and Central-Eastern groups based on their socio-political and welfare organization. Suicide rates, subjective well-being data, and objective well-being data were used as parameters of different welfare states and obtained from the World Health Organization European Mortality Database, European Social Survey, and Eurostat Database. This study revealed that the suicide rates of older people were the highest in the Baltic countries, while in the Island group, the suicide rate was the lowest. The suicide rate ratios between the age groups 65+ and 0-64 were above 1 (from 1.2 to 2.5), except for the group of the Island countries with a suicide rate ratio of 0.8. Among subjective well-being indicators, relatively high levels of life satisfaction and happiness were revealed in Continental, Nordic, and Island countries. Objective well-being indicators like old age pension, expenditure on old age, and social protection benefits in GDP were the highest in the Continental countries. The expected inverse relationship between subjective well-being indicators and suicide rates among older people was found across the 22 countries. We conclude that welfare states shape the context and exert influence on subjective well-being, and thus may lead to variations in risk of suicide at the individual level. PMID- 28804322 TI - A multidimensional view of out-of-home behaviors in cognitively unimpaired older adults: examining differential effects of socio-demographic, cognitive, and health-related predictors. AB - Previous studies on predictors of out-of-home behavior (OOHB) have often neglected the multidimensional nature of this construct. The present study distinguished between two levels of analyzing OOHB: out-of-home mobility seen as single behavioral units (e.g., number of places visited, action range, and walking) versus OOHBs seen as engagement in integrated, larger activity units (e.g., cognitively and physically demanding activities). We examined whether a differential relationship between these levels of OOHBs with established predictors of OOHBs, i.e., socio-demographic variables, cognitive abilities, physical functioning, and depression, exists. A sample of 100 cognitively healthy, community-dwelling adults with a mean age of 70.8 years underwent a multi-method OOHB assessment using GPS- (out-of-home mobility) and questionnaire based (out-of-home activity engagement) measures. Predictors were assessed based on internationally implemented procedures. Regression analyses showed that walking-based mobility and engagement in physical activities could be predicted by physical functioning, whereas most effects of socio-demographic variables, such as age and gender, and of depression on OOHBs were negligible. At the bivariate level, episodic memory was related to action range, global mobility, and to cognitively demanding activity engagement, but not to walking, whereas executive function was related with physically demanding activity engagement only. However, some of these connections became weaker in the full predictor model. Findings support the notion that it is necessary to assess OOHB as a multiple-indicator construct. PMID- 28804324 TI - Structured ambivalence in grandchild care and the quality of life among European grandparents. AB - This study employs the concept of structured ambivalence to analyse the effect of grandchild care on quality of life (QoL) in different cultural contexts. We define structured ambivalence as the contradiction between behaviour and cultural norms. The analysis is based on the Survey of Health, Ageing and Retirement in Europe with 14 countries in the sample. We focus on grandparents aged 50 and over with at least one grandchild 12 years old or younger (n = 12,740). In countries with high grandparent obligations, grandparents who did not look after their grandchildren reported a lower quality of life. Compliance with such grandparental obligations (e.g. providing grandchild care in a country with high grandparent obligations) was found to increase the QoL of grandparents. Family policy should consider family practices that better match the realities of current grandparents' lives in order to reduce structured ambivalence and increase the QoL of grandparents. PMID- 28804323 TI - Dual sensory loss and social participation in older Europeans. AB - The purpose of the study was to describe the prevalence of hearing difficulties, vision difficulties and dual sensory difficulties in 11 European countries, and to study whether sensory difficulties are associated with social inactivity in older Europeans. This cross-sectional study is based on the 2004 data collection of the Survey of Health, Ageing and Retirement in Europe comprising 27,536 men and women aged 50 years and older. Hearing and vision difficulties, as well as participation in seven different social activities were assessed using a structured computer-assisted personal interview. Logistic regression models were used for analyses. Altogether, 5.9 % of the participants reported both hearing and vision difficulties (dual sensory loss), 10.2 % vision difficulties only, and 13.5 % hearing difficulties only. More than two-thirds (68.6 %) of the participants with dual sensory loss were socially inactive compared to half of those who reported no sensory difficulties. The participants who reported dual sensory loss had 2.18 (95 % CI 1.83-2.59) times higher odds for social inactivity compared to persons without hearing or vision difficulties. In a model adjusted for age, gender, mobility, depressive symptoms, cognition, education and wealth the corresponding odds ratio was 1.21 (95 % CI 1.00-1.47). According to our results, sensory difficulties were associated with social inactivity, but the higher likelihood for social inactivity among persons with sensory difficulties was attenuated by other health and socio-economic indicators. Our results suggest that various preventive and rehabilitative actions targeting older persons' sensory functions may enhance their social activity. PMID- 28804325 TI - Individual differences in criterion-based dropout learning in old age: the role of processing speed and verbal knowledge. AB - In the present study, individual differences in criterion-based dropout learning in old age were investigated. The predictive role of processing speed and verbal knowledge for individual differences in this type of learning was analyzed. Learning trajectories were modeled using a multilevel approach based on N = 47 older participants (Mage = 69.3, SD = 6.4). Participants learned five lists of eight cue-target word pairs across six study-test cycles maximally possible. Results indicate that there were reliable individual differences in the initial level, speed of learning, and quadratic growth of learning. After adjusting for age-related effects, both higher verbal knowledge and higher processing speed had a positive effect on speed of learning. Additionally, verbal knowledge had a negative effect on quadratic growth of learning. Speed of learning and quadratic growth had a positive effect on a delayed recall test after adjusting for effects of processing speed and verbal knowledge. These results emphasize the role of cognitive abilities for individual differences in criterion-based dropout learning in old age. PMID- 28804326 TI - Changes in physical functioning over 6 years in older women: effects of sitting time and physical activity. AB - The combined effects of physical activity (PA) and sitting time (ST) on physical functioning (PF) may be stronger than for each factor separately. This study examined associations between ST, PA, and PF over 6 years in older women. Data were from 6,611 participants in the Australian Longitudinal Study on Women's Health (mean age 78 +/- 1.5 years). Activity pattern at baseline (2002) was categorized as one of 12 combinations of ST (<4, 4-7, or >=8 h/day) and PA (<40, 40-450, 450-900, or >=900 MET min/week). PF was measured using the SF-36 (range 0 100) in 2002, 2005, and 2008. General estimating equations for linear regression were used with adjustment for confounders. Baseline PF ranged from 40 to 74 in the least to the most active groups. PF was 6.3 (95 % confidence interval [CI] 7.6 to -5.0) points lower in participants sitting >=8 h/day than in participants sitting <4 h/day, and 16.9 (CI 15.7-18.0) points higher in participants reporting >=900 MET min/week than in participants reporting <40 MET min/week PA. Compared with the least active pattern, those in the most active pattern scored 24.5 (CI 22.5-26.4) points higher. The decline over 6 years was greater in the more active categories: 5 and 16 points in the least and most active categories. In conclusion, in women, both high physical activity and low sitting time are important for establishing a certain level of PF prior to age 76-81, but do not protect against decline in PF over time later in life. The combined effect of ST and PA did not differ from their individual effects on PF. PMID- 28804327 TI - Are physically frail older persons more at risk of adverse outcomes if they also suffer from cognitive, social, and psychological frailty? AB - Frailty is considered a predictor for negative outcomes such as disability, decreased quality of life, and hospital admission. Frailty measures have been developed that include different dimensions. We examined whether people who are physically frail are more at risk for negative outcomes of frailty if they also suffer from psychological, cognitive, or social frailty. Frailty was measured at baseline by means of the Groningen Frailty Indicator (GFI), which comprises a physical, cognitive, social, and psychological dimension. Only frail persons were included in the study (GFI >= 5) that, in addition, had to be frail in the physical dimension (i.e., >=1 on this dimension). IADL disability and quality of life were measured at baseline and at 12 months. Hospital admission was assessed during this period. In this, physically frail sample effects of the other three frailty dimensions were studied in regression models. The sample (n = 334, mean age 78.1, and range 70-92) included 40.1 % frail men and 59.9 % frail women. Overall, no additional effects for the cognitive, social, or psychosocial dimensions were found: other frailty dimensions did not have an additional impact on disability, quality of life, or hospital admission in people who already suffered from physical frailty. Higher scores of physical frailty were significantly related to IADL disability (p < 0.05) and hospital admission (p < 0.05). Additional analysis showed that the physical frailty score predicted IADL disability and hospital admission better than the GFI overall score. Results of this study suggest that persons, who are physically frail, according to the GFI, are not more at risk for negative outcomes of frailty (i.e., IADL disability, decreased quality of life, and hospital admission) if they in addition suffer from cognitive, social, or psychological frailty. In addition, for the prediction of IADL disability or hospital admission, the focus for screening should be on the physical frailty score instead of the GFI overall score including different dimensions. PMID- 28804328 TI - Age-related differences in proprioceptive and visuo-proprioceptive function in relation to fine motor behaviour. AB - Leversen et al. (PLoS One 7(6):e38830, 2012) emphasise the importance of understanding the principles of life-long development. In their study of motor control, they found a common tendency towards improved motor performance from childhood to adulthood and a subsequent deterioration. The aim of our study was to examine this issue further by investigating fine motor behaviour (tracing a model line) in 196 participants (age range 12-95 years old) in two sensory conditions-proprioceptive + visual (PV) and proprioceptive only-in both hands and in two types of movement, frontal and transversal. Regression analyses of line length and task performance speed in relation to age were conducted for the different test conditions. The best performance was found in middle age, and a quadratic function provided the best fit for most of the test conditions. The corresponding inflection points (the age at which graphical analysis showed a change in performance as a peak of maturation before decline due to ageing) showed earlier ages in the proprioceptive condition. For most types of movement analysed, performance speed was slower under the PV condition. Paired correlation analysis showed that the symmetry of precision performance between hands became stronger with age. The results provide information on age-dependent differences in proprioception based on fine motor performance. They may be of use in the design of preventive strategies for preserving proprioceptive function by reducing the risk of falls and accidents or diseases such as Parkinson's. PMID- 28804329 TI - The influence of ageing on bra preferences and self-perception of breasts among mature women. AB - The ageing process has both psychological and physiological effects on women, and tactical choices are often made regarding beauty interventions to mask the outward signs of increasing age. The bra is believed to counteract the negative effects of ageing on the breast and alter the perceptions of one's body. Due to the profound anatomical changes to the breast with increasing age, this paper aimed to examine the influence of ageing on women's perceptions of their breasts and their bra preferences. 208 women aged 45-65 years were surveyed about their breasts, their bras and how they felt ageing may have influenced these. The findings showed 80 % of women surveyed had noticed a significant change in their breasts with ageing, just 7 % of the women surveyed were still proud of their breasts and 84 % of women dressed to look younger. Further, over 50 % of respondents would now not wear the bra they had worn in their twenties, indicating a change in bra preferences with age. The bra variables of primary importance to participants were: comfort, the bra's ability to stay in place, optimal fit, appearance under clothing, support, discreetness, shoulder strap design, silhouette, breast shape, fabric and breast lift. These variables are perceived as being influential in the appropriateness of the bra and its social role for mature women; therefore, it is these bra variables that should be the focus of subsequent research regarding the optimisation of bras for women aged 45 65 years. PMID- 28804330 TI - Evidence for an own-age bias in age estimation from voices in older persons. AB - Previous studies have investigated the effect of ageing on age estimation from faces as well as the occurrence of an own-age bias in such age estimation from faces. To the best of our knowledge, the occurrence of an own age effect on age estimation from voices has never been examined earlier using an experimental design in which the age of participants (young vs. old) and the age of voice stimuli (young vs. old) were crossed. Results revealed an own-age bias in older adults only. In comparison with younger adults, older participants showed age estimation abilities that are preserved for voices from their own age group and impaired for younger voices. This own age bias was absent in younger participants. PMID- 28804331 TI - The balance of intergenerational family transfers: a life-cycle perspective. AB - The aim of this study is to determine the likelihood and net amount of parent child transfers over the adult life cycle across European welfare regimes. The study introduces an economic life-cycle model of family transfers to describe the evolution of family exchanges across generations over time, which reveals a nonlinear relationship of age and net family transfers. Furthermore, it refines the method of estimating parent-child net transfers. Data come from the Survey of Health, Ageing, and Retirement in Europe, and include 36,095 parent-child dyads from 11 European countries representing social democratic, conservative, and traditional welfare-state regimes. The findings reveal net value of family intergenerational support follows a nonlinear pattern across the adult life cycle, with positive transfers from parents to adult children decreasing modestly until advanced old age when the decrease intensifies. Net family support benefits individuals and generations with larger relative need. The transition in the net family support pattern starts later and is less pronounced across social democratic welfare-regime countries while the opposite is true in traditional welfare-regime countries. These findings might be interpreted as being linked to differences in the public policies guaranteeing different levels of provision for dependent populations across different welfare regimes. They are consistent with a comparatively smaller role of family support in the intergenerational redistribution of resources in societies with larger public intergenerational support to dependent populations. PMID- 28804332 TI - Who opts for self-employment after retirement? A longitudinal study in the Netherlands. AB - Self-employment among older age groups is rising. A better understanding of the role of self-employment in extending the working lives of individuals is, therefore, relevant from a policy perspective. By bridging the gap in the literature on work/retirement decision-making and entrepreneurship, the present study examines the factors associated with entry into self-employment post retirement, after a worker has left a regular salaried position. This decision is modelled as a choice between full retirement and prolonged labour force participation, in the form of either a typical wage-providing job or self employment. Data were derived from the Netherlands Interdisciplinary Demographic Institute Work and Retirement Panel, an ongoing longitudinal survey of older workers (50 years and over) employed by three private sector organisations and employed as civil servants in the Netherlands. These data were then analysed using multinomial logistic regression analysis. The results of this study show that the decision to pursue self-employment is primarily taken by retirees with relatively high levels of financial and human capital (wealth and educational attainment), those possessing entrepreneurial attitudes (high self-efficacy scores) and those who perceive their retirements to be completely involuntary. The results lend support to self-employment being selected as a postretirement path through opportunity rather than out of necessity. The fact that the retirements of the studied population were generally quite early, while not considered involuntary also suggests that the timing of the decision to retire may be driven by the emergence of new (business) opportunities. PMID- 28804333 TI - Life-course occupational social class and health in later life: the importance of frequency and timing of measures. AB - Research investigating associations between social class over the life-course and later health relies primarily on secondary analysis of existing data, limiting the number and timing of available measurements. This paper aims to examine the impact of these constraints on the measurement of life-course occupational social class and subsequent explanatory analyses predicting health in later life. Participants of the UK Boyd Orr Lifegrid Subsample (n = 294), aged an average of 68 years, provided retrospective information on their life-course occupational social class, coded at 6-month intervals. This was used to simulate two types of life-course data: (1) Theoretical: Life stage (four data-points at key life stages); (2) A-theoretical: Panel data (data-points at regular intervals of varying length). The percentage of life time in disadvantage and the predictive value for limiting longstanding illness (LLI) in later life using the full life course and simulated data was compared. The presence of 'critical periods' of exposure and the role of trajectories of social class were also investigated. Compared with the full data, the life stage approach estimated a higher percentage of life time in disadvantage and emphasised 'transient' periods in disadvantage (e.g. labour market entry). With varying intervals using the a theoretical approach, there was no clear pattern. Percentage of life time in manual class was a significant predictor of LLI only when using the four-point life stage approach. Occupational social class at labour market entry was a predictor of LLI in later life, suggesting a 'critical period'. Comparison of trajectories of social class further emphasised the importance of the sequence and timing of exposures to disadvantage in determining later health. We conclude that producing a valid summary of life-course occupational social class does not necessarily require a large number of data-points, particularly if guided by relevant theory, and that such measures can reveal important associations with later health. PMID- 28804334 TI - Ageing and poverty: how older Portuguese adults became less poor in the noughties. AB - The poverty rate amongst older Portuguese adults has decreased significantly in recent years as their incomes have increased and their levels of inequality and material deprivation have converged to the national average. This paper investigates whether this improved situation is homogeneous across this population group, but concludes that poverty pockets subsist. In particular, those aged 75+ and living alone record a poverty rate above 30 % in 2010, showing that this group is still subject to great economic and social vulnerability. An important feature of this income heterogeneity is the higher average income of the 65-74 age group versus the 75+ group. The evolution of both contributive and means-tested pensions has been a key element in the reduction of poverty amongst older people in Portugal and in improving their living standards. However, the austerity policies implemented post-2010 have made a strong impact on pensions and may reverse these positive developments. PMID- 28804335 TI - Informal support in Portugal by individuals aged 50. AB - In Portugal, individuals aged 50+ have an important role in the provision of co residential care. This study aimed to rank Portugal relative to 15 European countries with regard to the prevalence of co-residential care (daily or almost daily personal care), and extra-residential help/care (household help and/or personal care) provided by individuals aged 50+, and determine the factors associated with the provision of these types of support in the Portuguese context. The study used data from the SHARE wave 4 project (2010-2011) and was based on an analysis of variance and logistic regression models. Portugal differs from other European countries, as it has the highest rate of co-residential care (12.4 %) and the lowest rate of provision of extra-residential help/care (10.8 %). It is concluded that the quality of life (QoL) of Portuguese co-residential carers is lower than the QoL of non-carers, but extra-residential help/care provided once a month or less has a positive impact on the QoL of the providers. Co-residential care and the provision of frequent extra-residential help/care (daily or weekly) were associated with a higher number of depressive symptoms. The results further showed that, in Portugal, co-residential carers and extra residential helpers/carers have different socio-demographic, economic and health characteristics. This study demonstrates that it is important for scientific research to differentiate the type and frequency of informal support, since this can help us design policies to meet the specific needs of the various types of informal carers aged 50+. PMID- 28804336 TI - Intergenerational private transfers: Portugal in the European context. AB - Intergenerational private transfers should be made important as a common occurrence in familialistic societies when establishing the identity of Southern European welfare state regimes. They function as a safety net and as a way of reinforcing the bonds amongst elements in a family. Although Portugal is undoubtedly a Southern European country, it is frequently ignored in comparative studies, and is assumed to share the characteristics of Spain and Italy. But do these countries really belong to a common, distinctive model? Portugal was included in the fourth wave of the survey of health, ageing and retirement in Europe, which provides a large sample for the study of intergenerational private transfers in this country. It also enables comparison with what happens elsewhere in Europe. We examine the upward and downward flows between generations and identify several important determinants of each type of transfers. Additionally, we show that the different types and directions of transfers are positively correlated, pointing to a self-reinforcement of transfer behaviour in families. We find that Portugal has an especially low probability of private transfers of time and money. After taking into consideration the household-level characteristics, none of the countries included in this study has a significantly lower probability of occurrence of any type of transfer than that of Portugal. A Southern European specific pattern of family transfers is only partially confirmed, yet Portugal and Spain do share the same model. PMID- 28804337 TI - Psychometric analysis of the short-form UCLA Loneliness Scale (ULS-6) in older adults. AB - The aim of this investigation was to present new empirical evidence regarding the psychometric properties of the short-form UCLA Loneliness Scale (ULS-6) among Portuguese older people. The study included 1,154 persons (60 % women and 40 % men), aged 60-90 (M = 71.26; SD = 6.66). The psychometric properties of the ULS-6 were analysed by means of confirmatory factor analysis, internal consistency, and criterion-related validity methods. Confirmatory factor analysis supported a unidimensional structure of the measure with adequate values of various fit indices. The ULS-6 presented satisfactory psychometric properties, with a high level of internal consistency. Furthermore, the ULS-6 showed a negative relationship with self-esteem, satisfaction with life, and positive affect; and a positive one with negative affect. The results confirm that the ULS-6 provides a brief, psychometrically sound measure of loneliness that is appropriate for use among older adults. PMID- 28804339 TI - Care utilisation in the last years of life in Sweden: the effects of gender and marital status differ by type of care. AB - The effects of gender and marital status on care utilisation in the last years of life are highly correlated. This study analysed whether gender differences in use of eldercare (home help services or institutional care) or hospital care in the last 5 years of life, and the place of death, could be attributed to differences in marital status and thereby to potential access to informal care. A longitudinal Swedish study provided register data on 567 participants (aged 83 +) who died between 1995 and 2004. A higher proportion of unmarried than married people used home help services; this was true of both men and women. The likelihood of receiving home help was lower for those living with their spouse (OR = 0.38) and for those with children (OR = 0.60). In the 2 years preceding death, the proportion receiving home help services decreased and the proportion in institutional care increased. Women were significantly more likely to die in institutional care (OR = 1.88) than men. Although men were less likely to live in institutional care than women and more likely to be inpatients in the 3 months preceding death, after controlling for residence in institutional care, neither gender nor marital status was statistically significant when included in the same model. In summary, the determining factor for home help utilisation seemed to be access to informal care, whereas gender differences in health status could explain women's higher probability of dying in institutional care. PMID- 28804338 TI - Depressive symptoms in later life: differential impact of social support and motivational processes on depression in individuals with and without cognitive impairment. AB - This study investigates the role of a motivational process based on a composite of four subcomponents (self-efficacy, decision regulation, activation regulation and motivation regulation), as a mediator of the relationship between social support and depression assessed with the Geriatric Depression Scale in cognitively impaired and unimpaired individuals. Participants were 229 adults with a mean age of 74 years (range: 52-94 years). The sample comprised 64 participants diagnosed with mild cognitive impairment (MCI), 47 participants diagnosed with early-stage Alzheimer's disease (AD), and a group of 118 participants without any cognitive impairment. In this cross-sectional study, bivariate correlations and linear regression models were used to assess the association between the predictor variables and depression. Linear regression models were controlled for age, gender, education, cognitive status, cognitive impairment and activities. In the total sample, social support (beta = -0.15, p < 0.05) and motivational processes (beta = -0.41, p < 0.001) were significantly associated with depression; the impact of social support was mediated by motivational processes. While motivational processes were associated with depression in all three groups (no impairment: beta = -0.61, p < 0.001; MCI: beta = -0.28, p < 0.05; early AD: beta = -0.30, p < 0.06), social support lost significance (no impairment: beta = -0.36, p < 0.001; MCI: beta = 0.07, p = 0.59; early AD: beta = -0.08, p = 0.62). Based on these findings, it can be argued that the impact of social support on depressive symptoms is attenuated by cerebral deterioration in cognitively impaired individuals, while motivational processes remain relevant. PMID- 28804340 TI - The European Journal of Ageing continues to expand in scope and impact. PMID- 28804341 TI - Training and wages of older workers in Europe. AB - The financial deficits of many social security systems caused by ageing populations and stagnating economies are forcing workers to retire later from the labour market. An extended working life, combined with rapid technological progress in many sectors, is likely making older workers' skills obtained in school obsolete. In this context, lifelong investment in training is widely recognised among the international research and policy community as a key element to increase or at least limit the decline in productivity of older workers. This paper investigates the relationship between training undertaken by European older workers and their wages, relying on the Survey of Health, Ageing and Retirement in Europe. There is no evidence of training wage premium for older workers residing in many European countries including Denmark, Sweden, Belgium, the Netherlands, and Switzerland. Very high premiums are instead found for Austria, Germany, Greece and Italy. It is, however, likely that these high premiums are overestimated due to training endogeneity and sample selection bias. PMID- 28804342 TI - "I want to break free". The role of working conditions on retirement expectations and decisions. AB - We investigate the role of working conditions on the desire to retire as soon as possible and on the probability of transition from employment to either full or partial retirement, using different measures of work quality. We find that low work quality strongly correlates with the desire to retire as soon as possible of "young-old" workers. This might be explained by the deterioration of employer employee match with age due to reduced incentives for firms to invest in training and work practises that enhance workability of their senior workers. When we move from intentions to decisions, the role of work quality is less clear-cut and it mainly plays a role in the transitions from employment to full retirement. PMID- 28804343 TI - Firms' contribution to the internal and external employability of older employees: evidence from Germany. AB - In the examination of older employees' employability, one can distinguish between internal and external employability. Internal employability can be measured by individual employment stability, and external employability occurs when employees replace one employment relationship with another. Most studies focus on the personal skills and characteristics that are necessary to maintain employability. However, external factors also contribute to individual employability. Therefore, this study examines which organisational attributes of firms contribute to older employees' employability in Germany. Taking firm and individual characteristics into account, the results of discrete-time survival models show that in specific organisational structures, older employees have higher internal employability. Accordingly, older employees are more likely to maintain employment in the service sector and in recruiting organisations facing (skilled) labour shortages. However, the results also indicate that financially investing organisations facilitate early labour market exits. With regard to older employees' external employability, the results show only little evidence indicating an association between organisational attributes of firms and the likelihood of job change. PMID- 28804344 TI - Transitions between states of labor-force participation among older Israelis. AB - The study examines the labor-force behavior of Israelis at older ages, focusing on the determinants of the transitions between states of labor-force participation between 2005 and 2010. The study uses panel data from the first two waves of the SHARE-Israel longitudinal survey. A multinomial logit model is used to examine the impact of sociodemographic characteristics, health state, and economic resources on labor-force transitions of people aged 50-67. The results emphasize the role of age and poor health in "pushing" older people out of the labor force or "keeping" them there. Spouse's participation is found to encourage individuals to leave the labor force or to refrain from joining it. However, living with a participating spouse is negatively associated with staying out of the labor force, consistent with the dominance of the complementarity of leisure effect found in the literature. Wealth as an economic resource available to individuals for retirement is also found to encourage individuals to leave the labor force or to refrain from joining it. PMID- 28804345 TI - Feeling the squeeze? The effects of combining work and informal caregiving on psychological well-being. AB - Does employment provide respite or add stress to caregivers? As a result of population aging and increasing female employment rates, growing numbers are facing the competing demands of paid work and caregiving. This study explores the effect of providing regular personal care by employment status on six dimensions of psychological well-being. We concentrate on partner and parent care recipients and differentiate between in-household and out-of-household caregiving. We use cross-sectional data from the Norwegian Life Course, Ageing and Generation study (n = 11,047, age 25-64). Results indicate that out-of-household caregiving has no significant relationship with men or women's well-being, irrespective of employment status. In-household caregiving, however, relates to lower psychological well-being, but only among women who do not work full-time. The advantages of full-time employment to caregivers may be due to greater opportunity to achieve the full benefits that this role has to offer. There is little to suggest that combining work and caregiving harms well-being. In fact, a "double burden" seems to be experienced by women who combine extensive caregiving with limited employment. PMID- 28804346 TI - Are we living longer but less healthy? Trends in mortality and morbidity in Catalonia (Spain), 1994-2011. AB - Evidence on trends in prevalence of disease and disability can clarify whether countries are experiencing a compression or expansion of morbidity. An expansion of morbidity, as indicated by disease, has appeared in Europe and other developed regions. It is likely that better treatment, preventive measures, and increases in education levels have contributed to the declines in mortality and increments in life expectancy. This paper examines whether there has been an expansion of morbidity in Catalonia (Spain). It uses trends in mortality and morbidity and links these with survival to provide estimates of life expectancy with and without diseases and mobility limitations. We use a repeated cross-sectional health survey carried out in 1994 and 2011 for measures of morbidity, and information from the Spanish National Statistics Institute for mortality. Our findings show that at age 65 the percentage of life with disease increased from 52 to 70 % for men, and from 56 to 72 % for women; the expectation of life with mobility limitations increased from 24 to 30 % for men and from 40 to 47 % for women between 1994 and 2011. These changes were attributable to increases in the prevalence of diseases and moderate mobility limitation. Overall, we find an expansion of morbidity along the period. Increasing survival among people with diseases can lead to a higher prevalence of diseases in the older population. Higher prevalence of health problems can lead to greater pressure on the health care system and a growing burden of disease for individuals. PMID- 28804347 TI - The relationship between health and partnership history in adulthood: insights through retrospective information from Europeans aged 50 and over. AB - The association between health and partnership status is a growing concern within the social sciences. Some partnership situations exhibit positive effects on health, while partnership breakdowns display negative impacts. However, case studies show that these associations may change with age, due to potential sources of heterogeneity within a population. The current analysis explored this association over the adult life course (ages 30-64) of Europeans aged 50 years and older based on retrospective information on health and partnership from SHARELIFE (N = 23,535 after data screening). The data allowed us to control for socio-demographic covariates as well as for individual infirmity, measured by childhood health. We also considered contextual survival selection effects by comparing 13 European countries for which pre-adult mortality levels largely differed among the cohorts involved (1907-1958). Discrete-time hazard analyses examined the risk of suffering from a major episode of poor health (self reported) in adulthood as a function of partnership history, using two approaches: a pooled model and country-specific models. The results revealed no differences between those who lived with a partner (first union) and single individuals in terms of the retrospective hazards of poor health. We hypothesize that this result stems from the cumulative effect of survival selection on individuals in advanced ages according to partnership status. The results also partially point to the plausibility of a contextual survival selection, which should be confirmed by further research based on additional health indicators. PMID- 28804348 TI - Prevalence and correlates of successful ageing: a comparative study between China and South Korea. AB - Successful ageing is often defined as a later life with less disease and disease related disability, high level of cognitive and physical functions, and an active life style. Few studies have compared successful ageing across different societies in a non-Western social context. This study aims to compare prevalence and correlates of successful ageing between China and South Korea. The data come from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) and the Korean Longitudinal Study of Ageing (KLoSA). A total of 19,346 community-dwelling elders over 65 years were included, 15,191 from China and 4,155 from Korea. A multidimensional construct of successful ageing was used, with the criteria of no major comorbidity, being free of disability, good mental health, engaging in social or productive activity, and satisfaction on life. Correlates of successful ageing included demographics (gender, age, and rural/urban residence), socioeconomic features (financial status, education, and spouse accompany), and health behaviours (smoking, alcohol-drinking, and exercising). The results showed that 18.6 % of the older adults in China was successful agers, which was less than 25.2 % in Korea. When gender and age were adjusted, older adults were 51 % less likely to be successful agers in China than Korea (p < 0.001). The association patterns between successful ageing and its correlates are similar between China and Korea. However, before the socioeconomic variables are under control, rural residence was negatively related to successful ageing in China, whereas this is not the case in Korea. And the gender gap of successful ageing was mostly explained by socioeconomic features and health behaviours in Korea, but not in China. In both countries, good financial condition was highly associated with successful ageing. The study suggests that advancement of public health system could better control progression of non-communicable diseases among old people and thus promote successful ageing. PMID- 28804349 TI - Models of long-term care use among older people with disabilities in Taiwan: institutional care, community care, live-in migrant care and family care. AB - The four main models of long-term care (LTC) for older people in Taiwan are institutional care, community and home-based care, live-in migrant care and family care. This study aims to examine the factors associated with the four above-mentioned LTC models, using the Andersen model as its framework for analysis. Data were from the 2005 National Taiwanese Health Interview Survey (n = 30,680), and in this study, 592 over 65-year-old persons who require personal care in daily life were included. The findings showed that the majority of older people with care needs lived with family and were cared only by their family. The second largest group was those older people who were cared by migrant care workers, and the third group used institutional care. Only a very small proportion used community/home-based care services. If older people had intensive care needs, they either hired migrant care workers or used institutional care, depending on social and economic backgrounds. Multinomial logistic regression results showed that the way how disabled older people use different LTC models was affected by three components of the Andersen model: their needs (level of ADL and IADL), predisposing factors (age, education) and enabling factors (family networks). Results suggest that there is a need for LTC policies in Taiwan to provide more available and accessible community/home-based care services, particularly for older people with intensive care needs, in order to support their 'ageing in place' and to decrease the use of migrant care workers. PMID- 28804350 TI - Training in the functional movement circle to promote strength and mobility related activities in older adults: a randomized controlled trial. AB - Movements of everyday life (e.g., climbing stairs, rising from a chair, walking) are essential for older adults to stay functional and independent. Due to the aging process, muscle mass decreases and balance abilities are reduced. One major criticism of former interventions is that implemented resistance and balance exercises were not associated with movements needed in older adults' everyday life. The Functional Movement Circle for older adults (FuMoC) includes the combination of three aspects: resistance, balance, and movements of everyday life. The aim of this study was to compare the effects of training in the FuMoC with those of other training programs. A randomized controlled trial (RCT) with three intervention groups (IG1: FuMoC; IG2: resistance and balance training; IG3: coordination training) with a training period of 6 months and one inactive control group (CG) was conducted. At baseline (T1), after three (T2) and six (T3) months, parameters of strength (isometric strength measurement and One-Repetition Maximum test in leg and chest press) and mobility-related activities (gait analysis, Multisurface Obstacle Test for Older Adults (MSOT), Chair Rise Test (CRT), Timed Up & Go Test (TUG), Maximum Step Length Test (MSLT)) were assessed as primary outcomes. Data of 78 (43 males, 35 females) older adults were analyzed (mean age: 68.4 years). Significant (p < 0.05) interactions between time and group were observed in most of the primary outcomes. IG1 showed the highest improvement rates in MSOT (+16 %), CRT (+28 %), TUG (+14 %), and MSLT (+15 %); demonstrating advantages of training in the FuMoC compared to other training programs. PMID- 28804351 TI - The role of cognitive resources for subjective work ability and health in nursing. AB - Cognitive resources can be considered to be key variables in the context of work ability and health, particularly in the aging workforce. However, research on this issue is sparse, lacking a comprehensive examination of specific cognitive functions. Therefore, the aim of the present study was to examine the association of cognitive resources with subjective work ability and health in more detail. In 166 geriatric care workers (mean age 42.1 years, SD = 11.5, range 20-62), subjective work ability and health were assessed. Additionally, a comprehensive battery of cognitive tests measuring crystallized intelligence, cognitive speed, short-term memory, working memory, and inhibition was administered in a standardized procedure. Controlling for individual differences in age, education, depressive symptoms, self-regulation strategies (in terms of selective optimization with compensation), and cognitive resources (particularly better performance in short-term memory, working memory, and inhibition) were related to better subjective work ability and health. The present results demonstrate the relation of a variety of specific cognitive functions with subjective work ability and health over and above individual differences in age, education, depressive symptoms, and self-regulation strategies. Implications to explicitly consider a set of cognitive resources in models of work and organizational psychology, particularly with respect to the aging workforce, are discussed. PMID- 28804352 TI - Problem-focused and emotion-focused coping options and loneliness: how are they related? AB - We examine the extent to which coping options endorsed by older adults help alleviate loneliness, and experiences with loneliness influence the coping options. Two ways of coping are distinguished: problem-focused, i.e., improving one's relationships, and emotion-focused, i.e., lowering one's expectations about relationships. Loneliness is assessed using three observations over 6 years among 1,033 61- to 99-year-old respondents in the Longitudinal Aging Study Amsterdam. Combining the first two observations yielded four loneliness types: not lonely at T0 and T1, recently lonely, persistently lonely, and recovered from loneliness. Between the second and third observations, respondents were asked to evaluate which coping options lonely peers described in various vignettes had. From this, individual coping scores were calculated. The option to improve relationships did not affect the likelihood of one's own loneliness, and the option to lower expectations even increased it. Compared to non-lonely respondents, recently lonely ones endorsed both ways of coping equally frequently, persistently lonely ones endorsed improving relationships less frequently and lowering expectations more frequently and recovered respondents endorsed improving relationships equally frequently and lowering expectations more frequently. We conclude that considering various ways of coping does not help alleviate loneliness and that persistently lonely and recovered respondents are at risk of a circular process with loneliness experiences resulting in considering lowering expectations more frequently, which results in a greater likelihood of loneliness, thus contributing to sustaining or re-establishing loneliness. PMID- 28804353 TI - Parental disability, parent care, and offspring mental health outcomes. AB - Decades of research supports a widely held view that providing parent care is stressful, and that these stresses are associated with adverse mental health outcomes. However, some recent studies suggest an additional possibility, namely that "noncaregiver stress"-a consequence of having a parent with major care needs, but not being an active caregiver-may be a serious problem as well. This finding emerges in data which permit separate controls for parental needs for care and offspring provision of parent care. We extend these results using Generations and Gender Programme data from five countries-Bulgaria, France, Georgia, Romania, and Russia-for which the necessary variables can be comparably measured. Our outcome variable is a depression score based on a 7-item scale. In country-specific regressions, we find two instances of statistically significant associations of depression with the regular provision of personal care to a parent with care needs, i.e., the usual "caregiver stress" result. However, we also find two instances of statistically significant differences in respondents' depressive symptoms that are associated with having a parent with care needs, i.e., instances of "noncaregiver stress." We find limited evidence of gender specific responses to both forms of stress. Our evidence supports both the typical caregiver stress response and the less-studied noncaregiver stress response, which suggests the need for additional research. PMID- 28804355 TI - An abbreviated German version of the Sense of Competence Questionnaire among informal caregivers of relatives who had a stroke: development and validation. AB - Caregiver burden is a main outcome domain in caregiver intervention research. A recommended instrument for measuring burden is the Sense of Competence Questionnaire (SCQ). In this study, we evaluated the psychometric properties of the German version of the SCQ with informal caregivers of stroke patients. Baseline data of a randomized controlled trial (n = 122) and survey data (n = 76) of caregivers of stroke patients were used. Data were collected at the caregiver's or the care receiver's home or over the telephone. We evaluated the homogeneity, the construct validity, and the clinical validity of the German version and the homogeneity of a new abbreviated version. The homogeneity of the SCQ indicates good reliability (Cronbach's alpha: 0.89). The three-factor structure of the SCQ was mostly confirmed through principal components analyses using oblimin rotation. Clinical validity was supported through correlations between sense of competence and burden (r = -0.51), depression (r = -0.52), and care recipient's cognitive function (r = 0.36). Sixteen items with consistent factor loadings were extracted and proposed as a new abbreviated version of the SCQ (Cronbach's alpha: 0.84). The abbreviated German rendition of the SCQ version that was validated in this study offers a consistent version that can be applied across different languages and among caregivers of stroke survivors or people with dementia. PMID- 28804354 TI - Living conditions as predictor of elderly residential satisfaction. A cross European view by poverty status. AB - Although there is an extensive body of literature on the use of residential satisfaction to measure the impact of housing conditions on well-being in later life, less is known about differences and similarities between sub-populations and national contexts. By means of a cross-European analysis (EU15), this study aims to examine how objective and subjective factors of living conditions shape the perceptions of older Europeans about the adequacy of their residential environment. Two patterns of housing quality are explored: (1) international heterogeneity of the EU15 countries, and (2) intra-national heterogeneity, where we distinguish between households at risk of poverty and those not at risk in the elderly population of these countries. Data were drawn from the 2007 wave of the European Union Statistics on Income and Living Conditions survey, providing a sample of more than 58,000 individuals aged 65 years and older. The housing characteristics surveyed were reduced using tetrachoric correlations in a principal component analysis. The resulting predictors, as well as control variables (including gender, age, health status and tenure), are assessed using multiple linear regression analysis to explore their association with a high or low level of residential satisfaction. Despite a generally positive assessment by older Europeans of their living space, major geographic and household income differences existed in the factors that explained residential satisfaction. Identifying factors associated with residential satisfaction in different household income groups and national contexts may facilitate the development of EU policies that attempt to make 'ageing in place' a viable and suitable option for older Europeans. PMID- 28804356 TI - "The closer you get ...": age, attitudes and self-serving evaluations about older drivers. AB - The present study investigates the attitudes of older drivers and road safety measures with a particular focus on self-serving evaluations. Driving capacity is considered here as an indicator of awareness of age-related changes that may lead to a higher risk of self-stereotyping, motivating self-serving evaluations with advancing age. In order to test this notion, we used the perceived distance between one's chronological age and the age assigned to the social categories of "older driver" and "old person" as an indicator of age-group dissociation or identification, respectively. Self-serving evaluations were expected depending on the distance between chronological and subjective age estimates. In addition to this, we tested gender and age effects on the specific evaluations. A sample of 350 participants aged 19-88 completed an online questionnaire on negative and positive stereotypes about older drivers and road safety measures. Results indicated in general a more positive than negative view of older drivers; approval with measures to increase road safety by regulating older drivers was comparatively low. Female participants tended to agree more with negative stereotypes and regulative measures than male participants. Regression analyses revealed as well that increasing chronological age was associated with less agreement with negative stereotypes and measures for road safety. Differences between chronological age and subjective age estimates of when a person is old or an old driver were differentially related with the criteria. The closer the chronological age and subjective age estimates were the lower was the agreement with negative stereotypes and measures to regulate road safety. Findings underline in general that road safety enhancing efforts should avoid highlighting chronological age as the sole driving risk factor to circumvent negative stereotyping with ageing and unjustified driving cessation. PMID- 28804357 TI - Factors associated with Spanish older people's membership in political organizations: the role of active aging activities. AB - This study explores older people's membership in political organizations by using data from the Survey on older people 2010, carried out by Spain's National Institute for older people and social services. The objectives were to describe the extent of this kind of participation among Spaniards aged 65 and over, and to analyze the factors that are associated with it. Results show that only slightly less than 7 % of the sample belonged to a political organization. To analyze the factors related to this membership, a set of models of multivariate analyses were run, including socioeconomic resources and participation in other types of active aging activity (participation in leisure, learning, and productive activities). Educational level, leisure activities, learning activities, and only volunteering in the case of productive activities were found to be associated with membership in political organizations. Results provide partial support for the socioeconomic resources model and suggest that engagement in leisure activities, learning activities, and volunteering might have an enhancing effect on membership in political organizations. PMID- 28804358 TI - Improving walking conditions for older adults. A three-step method investigation. AB - The benefits of walking are widely recognized. In this regard, the Norwegian government has urged local authorities to develop walking strategies. The aim of such strategies is to influence a local walking culture and framework conditions for pedestrians. Older citizens are an important focus group because what is an accessible environment for them can be attractive for all groups. The primary aim of this study is to improve our understanding of how physical, social and individual factors affect whether older groups perceive that they need, can and want to walk. Second, we show how a mixed-method approach for collecting data gives an important input when planning a walking strategy. Combining quantitative and qualitative data gave deeper insights into how elders perceived their walking environment. The three steps (survey, participatory observation and workshop) made it possible to involve elders and practitioners from the municipality and the Norwegian Public Roads Administration directly in the study. This gave first hand experience about how to facilitate the environment for older pedestrians. The findings suggest that the need, can and want dimensions of walking interact and reinforce each other. We find that measures affecting more than one such dimension seem to provide the best response for walking activity. This can be important for practitioners to take into consideration when developing good walking areas in the city. PMID- 28804359 TI - Effects of interventions on physical activity in nursing home residents. AB - The aim of this review was to evaluate current evidence regarding the effects of interventions on physical activity in the subgroup of nursing home residents as well as to critically review the assessment methods used in this regard. Published studies through January 2015 were searched in The Cochrane Library, PubMed, CINAHL, Web of Knowledge, PsycInfo, Psyndex, Psycarticles, CC Med, and DissOnline; and by manual search. For randomized controlled trials (RCTs) to be included, an intervention had to be conducted with nursing home residents aged 65 years and above and physical activity had to be assessed using standardized, quantitative methods. Study quality was evaluated using an established Cochrane rating tool for RCTs. Eight studies met the inclusion criteria. Only one intervention study with main focus on a modification of physical activity behavior could be identified. Physical activity assessments used in the studies were partly limited regarding objectivity or psychometric quality. Hence, the documentation of effects of interventions is restricted. Six studies reported significant increases of physical activity in nursing home residents and thus positive intervention effects, which points at the feasibility and high potential of intervention programs to promote physical activity in this setting. Enhanced individual contact as well as physical exercise combined with behavioral interventions and the inclusion of nursing staff seems to be most effective in this regard. As only one study involved post-intervention follow-up assessments, sustainability of effects remained unclear. PMID- 28804360 TI - Neighborhood and healthy aging in a German city: distances to green space and senior service centers and their associations with physical constitution, disability, and health-related quality of life. AB - The composition of the residential environment may have an independent influence on health, especially in older adults. In this cross-sectional study, we examined the associations between proximity to two features of the residential environment (green space and senior service centers) and three aspects of healthy aging (self rated physical constitution, disability, and health-related quality of life). We included 1711 inhabitants from the city of Augsburg, Germany, aged 65 years or older, who participated in the KORA-Age study conducted in 2008/2009. We calculated the Euclidian distances between each participant's residential address and the nearest green space or senior service center, using a geographic information system. Multilevel logistic regression models were fitted to analyze the associations, controlling for demographic and socioeconomic factors. Contrary to expectations, we did not find clear associations between the distances to the nearest green space or senior service center and any of the examined aspects of healthy aging. The importance of living close to green space may largely depend on the study location. The city of Augsburg is relatively small (about 267,000 inhabitants) and has a high proportion of greenness. Thus, proximity to green space may not be as important as in a densely populated metropolitan area. Moreover, an objectively defined measure of access such as Euclidian distance may not reflect the actual use. Future studies should try to assess the importance of resources of the residential environment not only objectively, but also from the resident's perspective. PMID- 28804361 TI - Complex health problems among the oldest old in Sweden: increased prevalence rates between 1992 and 2002 and stable rates thereafter. AB - Studies of health trends in older populations usually focus on single health indicators. We include multiple medical and functional indicators, which together indicate the broader impact of health problems experienced by individuals and the need for integrated care from several providers of medical and long-term care. The study identified severe problems in three health domains (diseases/symptoms, mobility, and cognition/communication) in three nationally representative samples of the Swedish population aged 77+ in 1992, 2002, and 2011 (n ~ 1900; response rate >85 %). Institutionalized people and proxy interviews were included. People with severe problems in two or three domains were considered to have complex health problems. Results showed a significant increase of older adults with complex health problems from 19 % in 1992 to 26 % in 2002 and no change thereafter. Changes over time remained when controlling for age and sex. When stratified by education, complex health problems increased significantly for people with lower education between 1992 and 2002 and did not change significantly between 2002 and 2011. For higher-educated people, there was no significant change over time. Among the people with severe problems in the symptoms/disease domain, about half had no severe problems in the other domains. People with severe mobility problems, on the other hand, were more likely to also have severe problems in other domains. Even stable rates may imply an increasing number of very old people with complex health problems, resulting in a need for improved coordination between providers of medical care and social services. PMID- 28804362 TI - Social networks and mental health among older Europeans: are there age effects? AB - This study examined different components of personal social networks-structure, interaction, and quality-and the extent to which each is related to mental health among a 65+ sample (n = 26,784) taken from the fourth wave of the Survey of Health, Ageing, and Retirement in Europe. The first aim of the study was to determine which network components had the strongest associations with the number of depressive symptoms, measured on the EURO-D scale. Secondly, the study considered if and how age impacted the associations between social network and depression, using interaction terms that paired age category (age 65-79; age 80+) with the score on each network component. Hierarchical OLS regressions revealed that social network quality and network structure were both negatively related to the number of depressive symptoms. The association between network size (structure) and depression was even greater among those 80+. Age differences were also found for network interaction. More frequent contact with the network was related to a greater extent of depressive symptoms, but only among respondents aged 80 and older. Closer geographic proximity was related to having fewer depressive symptoms, but only among respondents aged 65-79. The findings imply that the association between meaningful personal relationships and depression in late life is nuanced by both network characteristics and by age. PMID- 28804363 TI - Social engagement across the retirement transition among "young-old" adults in the French GAZEL cohort. AB - The objective of this study was to test predictors of change in social engagement across the retirement transition in a cohort of 10,692 French utility workers retiring between 1992 and 2004, aged 51-65 in 2004. Three measures of social engagement (organizational activity participation, number of close family members, and number of close friends) were collected in 1991 and 2004; 1991 scores were subtracted from 2004 scores to determine change. We used ordered logistic regression to model predictors of change. Compared with those retiring just before the follow-up measure, those retiring 2-5 years earlier had greater positive change in organizational activity participation (OR 1.22, 95 % CI 1.07, 1.39) and greater positive change in number of close friends (OR 1.19, 95 % CI 1.04, 1.37) after retirement compared with before, but no difference in family contact, and no clear linear trend by retirement timing relative to the follow-up measure. Women were less likely than men to increase organizational activities and contact with close family ties. Poor self-rated health at follow-up consistently predicted decreased engagement. For specific activities, those retired longest had not only the greatest odds of increased political/religious organizational involvement and sports/hobby/leisure involvement but also the greatest odds of decreased volunteering. Those of low midlife socioeconomic status (SES) were more likely to decrease levels of formal engagement from before retirement to after, compared to those of higher SES. Overall, certain changes in social engagement emerged with increasing time in retirement. However, retirement timing was a weaker predictor of change in engagement than factors such as low midlife SES or poor health. Findings suggest that disparities in social engagement may emerge during retirement. PMID- 28804364 TI - Full-time versus part-time employment: Does it influence frequency of grandparental childcare? AB - The impact of grandparents' employment on grandparental childcare has been examined repeatedly, but the findings have so far been inconsistent. We contend that these inconsistencies may have resulted from variations in model specification and crude measurement of employment status. Furthermore, we assert that earlier research overlooked gender differences in the ability to combine paid employment and caregiving as well as variations between maternal and paternal grandparents. We also question the causal interpretation of earlier findings that were based on cross-sectional data. We revisit the issue of the impact of the intensity of employment and analyze SHARE data from 19 countries. We find a significant positive association between part-time employment (as compared to full-time employment) and the frequency of grandparental childcare in a cross-sectional sample, but only among paternal grandmothers. Capitalizing on the panel component of SHARE, we use a within-person estimator to show that this association is unlikely to reflect a causal effect of the intensity of labor market attachment on the frequency of the care of grandchildren, but more probably results from omitted variable bias. We argue that grandparents most likely to provide (intensive) childcare are also most likely to adjust their employment in anticipation of caregiving. The paper documents the usefulness of role strain theory among grandparents and highlights that part-time jobs may reduce role conflict and may thus make grandparenting a more easily manageable experience. PMID- 28804365 TI - Societies' tightness moderates age differences in perceived justifiability of morally debatable behaviors. AB - Research on age differences in moral judgment tends to focus on children and adolescents. The current study examined age differences in perceived justifiability of morally debatable behaviors across adulthood cross-culturally. A large cross-cultural dataset consisting of 25,142 individuals of varying ages (15-95 years old) from 20 societies was drawn from the World Values Survey. Hierarchical linear modeling was used to test age differences in perceived justifiability of morally debatable behaviors on issues pertaining to honesty and fairness as well as the moderating effect of societies' tightness. Across societies, older adults judged moral transgression less leniently than did younger adults. However, this pattern was moderated by the societies' tightness, such that age was a stronger predictor of perceived justifiability of morally debatable behaviors in loose societies relative to tight societies. The current study highlights the importance of examining moral development from the lifespan development perspective. The findings may illuminate potential mechanisms for inter-generational misunderstanding about moral issues. PMID- 28804366 TI - Long-term and short-term predictors of worries about getting Alzheimer's disease. AB - Cumulative stresses associated with concerns about cognitive functioning and worries about developing Alzheimer's disease (AD) have been shown to be related to poorer health and lower psychological well-being. Among older persons, AD also generates higher levels of fear than any other disease. But much remains to be learned about predictors of worries and fears, especially from a temporal perspective. Thus, the principal objective of the current research is to examine long-term effects of self-perceptions of cognitive functioning on worries about developing AD. Data for the study are drawn from the University of Michigan's Health and Retirement Study. We use up to ten measurements of self-perceived cognitive functioning collected from 1992 to 2010 for respondents 50 years of age and older at the time of their entrance into the study. Demographics (marital status, age, education, and gender); beliefs about the role of genetics, personal knowledge of someone with AD, and their interaction; and depression and health are other variables included in the model. The data are analyzed using the full information maximum likelihood procedure and latent growth curve modeling to account for the long-term effects. The analysis shows evidence of both short-term effects of depression, age, beliefs, and the interaction of beliefs and personal familiarity and long-term effects of cognitive self-assessment on worries about getting AD. Further analyses of these relationships and inclusion of these items in other studies are recommended. PMID- 28804367 TI - Successful ageing as a persistent priority in ageing research. PMID- 28804368 TI - Physical activity, self-efficacy, and quality of life in older Czech adults. AB - Despite efforts to expand global physical activity (PA) surveillance data to include both low- and high-income countries worldwide, our understanding of the relationship between PA and quality of life (QOL) in older adults from culturally diverse backgrounds is limited. We tested McAuley's social-cognitive model of the PA-QOL relationship in the cultural context of the Czech Republic, a post communist central European country. A total of 546 older Czech adults (mean age 68 years) completed a battery of questionnaires assessing indicators of PA, self efficacy, health status, and global QOL. A structural equation model was used to test the relationship between PA and QOL. The model hypothesized an indirect relationship between PA and QOL: PA predicted self-efficacy, which in turn predicted global QOL through mental and physical health status. The analyses indicated an acceptable fit of the proposed model, albeit with different emphases than those of studies from Western countries. Above all, we observed a stronger effect of PA on self-efficacy and a weaker mediating effect of health status on the PA-QOL relationship. Our findings supported the validity of McAuley's PA-QOL social-cognitive model for a non-Western cultural context. However, it seems that self-efficacy and health status may influence the PA-QOL relationship in this population in a manner different from that proposed in McAuley's model. PMID- 28804369 TI - Health and function assessments in two adjacent Danish birth cohorts of centenarians: Impact of design and methodology. AB - Using the results from measures of functional ability, cognitive and physical performance from two adjacent birth cohorts of 100-year-old adults, we aimed to elucidate the possible impact of difference in participation rates, design, and interviewer mode. Participants were birth cohort members born in 1910 (DK-1910) and 1911-12 (DK-1911). Both surveys used the same assessment instruments, but the design was different, and data collection was carried out by trained survey agency interviewers in DK-1910 and trained nurses in DK-1911. Participation rate in DK-1911 (49.8 % (251/504)) was lower than in DK-1910 (66.9 % (273/408)) (p < 0.001). The proportion of interviews with the participant answering alone or mainly alone was significantly higher in DK-1911 (77 %) than in DK-1910 (56 %), and the proportion living in nursing home was significantly lower (44 vs. 54 %, respectively). Higher proportions of DK-1911 independently performed all activities of daily living (ADL) compared to DK-1910, but only significantly for toileting, bathing, and feeding (all p < 0.01). Mini-mental state examination (MMSE) score was higher in DK-1911 than in DK-1910 (23.5 vs. 21.0; p < 0.001). Handgrip strength, gait speed, and chair stand were almost similar. DK-1911 participants had significantly better one-year survival than DK-1911 non participants and DK-1910 participants and non-participants (p = 0.001). These results suggest that lower participation rate entails selection towards healthier participants in terms of ADL and cognitive functioning. Caution is warranted when comparing studies of centenarians with different participation rates, design, and interviewer mode, and further studies of these methodological issues are required. PMID- 28804370 TI - How voluntary is the active ageing life? A life-course study on the determinants of extending careers. AB - In Switzerland, as in many other European states, there is an increasing emphasis in public policy on promoting later retirement from the labour market. But this accelerating drive in Swiss policy-making to extend occupational activity does not mean that every worker is currently likely to retire late, nor does it imply that all those who do retire late do so voluntarily. This article uses a life course approach, first to study the determinants of late retirement, and secondly to analyse whether the decision to postpone retirement is made voluntarily or involuntarily. Both objectives are addressed on the basis of data from the Swiss survey Vivre/Leben/Vivere. The results of logistic regression modelling indicate that, whereas self-employed and more highly educated individuals are more likely to retire late, people with access to private pension funds and workers who have benefited from periods of economic growth have a lower tendency to retire late. Regarding voluntariness, those who are more likely to opt for voluntary late retirement tend to be Swiss citizens, more highly educated, and also benefited from periods of economic expansion, while the self-employed, men and widowed individuals leaving the labour market late tend to do so involuntarily. In conclusion, the article discusses the absence of a social inequality debate in the design of active ageing policies. PMID- 28804372 TI - European Journal on Ageing: Reviewers 2015. PMID- 28804371 TI - Costs of informal care in a sample of German geriatric stroke survivors. AB - Stroke is a leading cause of long-term disability. A large proportion of geriatric stroke survivors receive informal care. The assessment and monetary valuation of informal care should therefore constitute an essential part of any health economic analysis, but it is hardly measured in stroke caregiver studies. The aim of the current research was to estimate the amount of informal care provided by caregivers of stroke survivors aged 60 years and older and to calculate its economic value. Information about caregiving time in activities of daily living (ADL), instrumental activities of daily living (IADL), and supervision during the last 3 months was obtained from 122 caregivers by means of structured interviews. The proxy good method was applied for the monetary valuation of time. About 63 % of the stroke survivors in our sample were moderately cognitively impaired. The results showed that the majority of the main caregivers assisted in ADL and IADL. Supervision was delivered by 45.9 %. The median amount of help in ADL was 13.9, in IADL 22.2, and in supervision 13.9 h/week. The median overall amount of care was 42.8 h/week. Fifty percent were supported by additional persons (2.7 h/week). The mean overall costs of informal care were calculated at 2252 ?/month. Our results reveal the high social and economic costs of informal care. The main burden of caregiving appears to be carried by the primary caregiver. Consequently, support and counseling of this group is important. Furthermore, caregiver interventions should be aimed at the mobilization of informal resources. PMID- 28804373 TI - Increasing social participation of older people: are there different barriers for those in poor health? Introduction to the special section. PMID- 28804374 TI - Do predictors of volunteering in older age differ by health status? AB - It has been widely recognised that poor health is one of the main barriers to participation in volunteer activities in older age. Therefore, it is crucial to examine the participation of older people in volunteering, especially those in poor health. Based on the resource theory of volunteering, the aim of this study is to better understand the correlates of volunteering among older people with different health statuses, namely those without health problems (neither multimorbidity nor disability), those with mild health problems (multimorbidity or disability), and those with severe health problems (multimorbidity and disability). Data were drawn from the fourth wave (2011-2012, release 1.1.1) of the Survey of Health, Ageing and Retirement in Europe, which includes European people aged 50 years or older. The results showed that variables linked to volunteering were generally similar regardless of health status, but some differences were nevertheless identified. For older people with mild or severe health problems, for instance, depressive symptoms were negatively associated with their involvement in volunteer activities. We found a positive association of being widowed (rather than married) with volunteering in older people with particularly poor health, whereas high income was associated with volunteering in the case of mild health problems only. These results demonstrate that variables associated with volunteer participation partially differ between older people depending on their health status. These differences should be considered by policy makers in their attempts to promote volunteering in older people, as a means of preventing their social exclusion. PMID- 28804375 TI - Fit for caring: factors associated with informal care provision by older caregivers with and without multimorbidity. AB - Due to an increased prevalence of chronic diseases, older individuals may experience a deterioration of their health condition in older ages, limiting their capacity for social engagement and in turn their well-being in later life. Focusing on care provision to grandchildren and (older) relatives ('informal care') as forms of engagement, this paper aims to identify which individual characteristics may compensate for health deficits and enable individuals with multimorbidity to provide informal care. We use data from the SHARE survey (2004 2012) for individuals aged 60 years and above in 10 European countries. Logistic regression estimates for the impact of different sets of characteristics on the decision to provide care are presented separately for people with and without multimorbidity. Adapting Arber and Ginn's resource theory, we expected that older caregivers' resources (e.g., income or having a spouse) would facilitate informal care provision to a greater extent for people with multimorbidity compared to those without multimorbidity, but this result was not confirmed. While care provision rates are lower among individuals suffering from chronic conditions, the factors associated with caregiving for the most part do not differ significantly between the two groups. Results, however, hint at reciprocal intergenerational support patterns within families, as the very old with multimorbidity are more likely to provide care than those without multimorbidity. Also, traditional gender roles for women are likely to be weakened in the presence of health problems, as highlighted by a lack of gender differences in care provision among people with multimorbidity. PMID- 28804376 TI - Uncovering the care setting-turnover intention relationship of geriatric nurses. AB - In times of global demographic changes, strategies are needed for improving nursing staff retention. We examined the association of care setting (nursing homes and home care) with geriatric nurses' intention to leave their job and their profession. Thus far, it is unclear why nurses' turnover intention and behaviour do not differ between care settings, although working conditions tend to be better in home care. We used the Job Demands-Resources model to explain indirect and buffering effects by job demands (time pressure, social conflicts) and resources (task identity, supervisor support, and co-worker support) via nurses' perceived health and job satisfaction on nurses' leaving intentions. The present cross-sectional questionnaire study was conducted with a sample of N = 278 registered nurses and nursing aides in German geriatric care. As expected, there was no direct relationship between care setting and leaving attitudes. Demands and resources predicted the intention to leave with job satisfaction as mediator. We found more demands in nursing homes but no differences in resources. Serial mediation effects of care setting on intentions to leave via demands/resources and health/job satisfaction as mediators were found only for time pressure and social conflicts. Unexpectedly, there were no clear differences between intention to leave the job and the profession. As hypotheses were only partly confirmed, other buffering and detrimental effects on leaving intentions are discussed. The present data suggest that detailed concepts for personnel and career planning in geriatric care are needed. PMID- 28804377 TI - How aging affects self-reports. AB - A lot of information used in aging research relies on self-reports. Surveys or questionnaires are used to assess quality of life, attitudes toward aging, experiences of aging, subjective well-being, symptomatology, health behaviors, financial information, medication adherence, etc. Growing evidence suggests that older and younger respondents are differentially affected by questionnaire features and the cognitive tasks that question answering pose. This research has shown that age-related changes in cognitive and communicative functioning can lead to age-related differences in self-reports that are erroneously interpreted as real age differences in attitudes and behaviors. The current review highlights how the processes underlying respondents' self-report change as a function of respondents' age; it updates our previous reviews of this literature. PMID- 28804378 TI - Life resources and personal goals in old age. AB - It has been theorized that life resources influence goal engagement. The aim of the present study was to examine whether personal characteristics, and socio economic, social and health resources are associated with personal goal content in old age. The participants were 824 community-dwelling people aged 75-90 from the Life-Space Mobility in Old Age project. Personal goals were elicited using a revised version of the Personal Project Analysis in a structured interview. Cross sectional bi- and multivariate analyses using logistic regression modelling were conducted. The results showed that the most commonly reported goals were health maintenance related. People with better health resources were more likely to report goals related to leisure-time, social and physical activities and less likely to report goals related to recovery of health. Those with poor social resources were at risk for having no personal goals in their lives. The results are in line with theorizing on the influence of life resources on goal setting in old age. Further longitudinal studies are needed on whether resource loss precedes goal modification, and how goal setting strategies influence both mental and physical well-being in old age. PMID- 28804379 TI - Identifying important factors for older adults' physical activity participation across individual/group, structured/unstructured contexts. AB - Most Canadian older adults do not meet physical activity recommendations. Researchers have investigated participation barriers and facilitators, with little consideration given to how specific factors influence activity participation for older adults. The purpose of this study was to identify unique factors that influence older adults' activity selection and to determine in which type of setting they are preferred. Using a two-phase methodology, identification of 25 factors affecting participation was followed by 45 older adults ranking the factors within four categories of activities: individual unstructured, group unstructured, individual structured, and group structured. Phase 1 analysis ranked each factor within each category. Further analysis found that there was a statistical difference between categories, indicating that older adults found different factors important, depending on the category of physical activity in question. This led to phase 2 analyses which identified three levels of factor groupings including the following factors: level A: fun, satisfaction, commitment, and energize; level B: safety, learning, awareness, internal motivation, and productive; and level C: meaningful contribution, intensity, and motivation. Additionally, some factors which were not identified in all categories were identified as unique to certain categories. These included creativity, hobbies, meaningful contribution, spiritual, competence, interaction casual, regularly scheduled, competition, self-efficacy physical, and team. This information can be used by individuals as well as program providers to nurture these factors within physical activity programs, which may lead to increased participation in this age cohort. PMID- 28804380 TI - Gender difference in the prevalence and socio-demographic correlates of mobility disability among older adults in Nigeria. AB - The aim of the current study is to examine gender differences in mobility disability among older people in Nigeria, and to explore factors associated with gender differences in mobility disability in later life. Data were used from the first (2010-2011) wave of the Nigeria General Household Survey-Panel, which included 3586 respondents aged 50 years and above. Mobility disability was assessed as self-reported difficulty in walking 100 m, walking 1 km, walking uphill, running, bending or stooping, and climbing stairs. Regression analyses were used to estimate the extent to which socio-demographic conditions contribute to gender differences in mobility disability. We observed a higher prevalence of mobility disability among women compared to men (20.1 vs. 12.5 %, P < 0.001). The prevalence ratios (PR) of mobility disability for women versus men was 1.61 (95 % CI 1.38-1.88, P < 0.001); after adjusting for age, marital status, place of residence, self-reported health status and cognitive difficulties, the PR was 1.55 (95 % CI 1.30-1.85, P < 0.001). In the fully adjusted model, mobility disability still remained significantly higher among women (PR 1.60, 95 % CI 1.32 1.93, P < 0.001). The marginal effects of socio-demographic and health factors were stronger for women than for men. Socio-demographic and health variables considered in this study explained between 19.3 % (men) and 22.3 % (women) of variance in mobility disability suggesting that additional factors beyond those considered in this study warrant further investigation, so that differences in mobility disability between older men and women in Nigeria can be fully understood. PMID- 28804381 TI - The distribution and the functions of autobiographical memories: Why do older adults remember autobiographical memories from their youth? AB - In the present study, the distribution of autobiographical memories was examined from a functional perspective: we examined whether the extent to which long-term autobiographical memories were rated as having a self-, a directive, or a social function affects the location (mean age) and scale (standard deviation) of the memory distribution. Analyses were based on a total of 5598 autobiographical memories generated by 149 adults aged between 50 and 81 years in response to 51 cue-words. Participants provided their age at the time when the recalled events had happened and rated how frequently they recall these events for self-, directive, and social purposes. While more frequently using autobiographical memories for self-functions was associated with an earlier mean age, memories frequently shared with others showed a narrower distribution around a later mean age. The directive function, by contrast, did not affect the memory distribution. The results strengthen the assumption that experiences from an individual's late adolescence serve to maintain a sense of self-continuity throughout the lifespan. Experiences that are frequently shared with others, in contrast, stem from a narrow age range located in young adulthood. PMID- 28804382 TI - Positive messages enhance older adults' motivation and recognition memory for physical activity programmes. AB - Although physical activity is an effective way to cope with ageing-related impairments, few older people are motivated to turn their sedentary lifestyle into an active one. Recent evidence suggests that walking can be more effectively promoted in older adults with positive messages about the benefits of walking than with negative messages about the risks of inactivity. This study examined motivation and memory as the supposed mechanisms underlying the greater effectiveness of positively framed compared to negatively framed messages for promoting activity. Older adults (N = 53, age 60-87 years) were introduced to six physical activity programmes that were randomly paired with either positively framed or negatively framed messages. Participants indicated how motivated they were to participate in each programme by providing ratings on attractiveness, suitability, capability and intention. They also completed surprise free recall and recognition tests. Respondents felt more motivated to participate in physical activity programmes paired with positively framed messages than in those with negatively framed ones. They also had better recognition memory for positively framed than negatively framed messages, and misremembered negatively framed messages to be positively framed. Findings support the notion that socioemotional selectivity theory-a theory of age-related changes in motivation-is a useful basis for health intervention design. PMID- 28804383 TI - Antecedents of late life outcomes: the case of Israel. PMID- 28804384 TI - Migration and changes in loneliness over a 4-year period: the case of older former Soviet Union immigrants in Israel. AB - Both older adult and immigrant populations are at a high risk of loneliness. The current research compares older veteran Israelis to older immigrants who arrived in Israel from the former Soviet Union (FSU) after 1989. Early studies have found high levels of loneliness among older FSU immigrants; however, little is known regarding changes in loneliness among this group over time. The present study examines change in loneliness among older FSU immigrants and older veteran Jewish Israelis and its potential predictors. A prospective association between immigrant's status and loneliness over time was examined using the second (2009/2010) and third (2013) waves of SHARE-Israel. The sample consisted of 208 FSU immigrants and 1080 veteran Jewish Israelis. Bivariate analyses indicated that in 2009/2010, older FSU immigrants were significantly lonelier than older veteran Jews, and more disadvantaged on all social and health variables measured. Yet, no significant differences emerged between the two groups with regard to loneliness in 2013. In the adjusted model, older immigrants presented positive change in loneliness (less loneliness over time) compared with veteran Jewish Israelis. Depressive symptoms explained a large part of the variance in change in loneliness. Potential explanations suggest that the long-term psychological adjustment process and the characteristics of the FSU immigrants in Israel as a large and relatively strong immigrant group have served as protective factors with regard to changes in loneliness over time. PMID- 28804385 TI - Depression statuses and related predictors in later life: A 10-year follow-up study in Israel. AB - The aim of the current study was to investigate the factors associated with depression statuses in a 10-year follow-up of community-dwelling older adults in Israel. Longitudinal data were used from the Israeli sample of the Survey of Health, Aging and Retirement in Europe, assessing the depressive symptoms in 1042 respondents, aged 50 or above, at three time points: 2004/2005 (Wave I); 2009/2010 (Wave II); and 2014/2015 (Wave III). Multinomial logistic regression was used to determine the relationships among explanatory variables and depression statuses (no-depression, intermittent depression, or persistent depression). Some 46.5 % of the participants suffered from intermittent or persistent depression. Five factors were associated with increasing the probability of both intermittent and persistent depression: being female, unemployed, less educated, physically disabled, and in poor health. Five other explanatory variables were associated only with a higher risk for persistent depression: low family income, widowhood, physical inactivity, more than two chronic diseases, and cognitive dysfunction. According to these findings, depression is common among older people in Israel. Low socio-economic status and poor subjective and physical health are significant determinants of depression statuses over time, underlining the importance of taking measures to improve these conditions in order to reduce the risk of depression in old age. PMID- 28804386 TI - Which category of lifetime adversity accelerates physical impairment among Israeli older adults? AB - Preliminary evidence suggests that exposure to lifetime cumulative adversity is related to faster increase in physical impairment with time, especially when depressive symptoms are present. Nevertheless, it is still unclear whether different adversity categories accelerate impairment. The current study capitalized on the unique accounts of adversity available in the Israeli component of the Survey of Health, Ageing and Retirement in Europe (SHARE-Israel) by focusing on different categories of adversity, while accounting for their interaction with depressive symptoms in predicting trajectories of physical impairment (i.e., chronic medical conditions and disability). Data of 1665 participants (mean age = 63.08, SD = 10.04 at Wave 1) were drawn from the first three waves of SHARE-Israel. Respondents reported exposure to bereavement (e.g., experiencing the death of a spouse), war and terrorism (e.g., being wounded in terrorist attack), and victimization (e.g., being a victim of abuse or assault). Other measures assessed depressive symptoms, chronic medical conditions, and disability. Growth-curve models showed that bereavement and exposure to war and terrorism were related to specific measures of physical impairment. Moreover, three-way interactions showed that clinical level of depressive symptoms coupled with exposure to either bereavement or war and terrorism predicted a faster increase in chronic medical conditions and disability. The findings offer a differentiated outlook on the effect of adversity on age-related increase in physical impairment. Practitioners should consider that older adults previously exposed to bereavement, war and terrorism are at risk for a hastened physical decline, especially when they suffer from depressive symptoms. PMID- 28804387 TI - Age differences in the understanding of wealth and power: the mediating role of future time perspective. AB - Individuals' understanding of wealth and power largely determines their use of resources. Moreover, the age range of wealth and power holders is increasing in modern societies. Thus, the current study examines how people of different ages understand wealth and power. As varying future time perspective is related to changes in prioritised life goals, it was tested as a potential mediator of the age differences. A total of 133 participants aged 18-78 years were asked 8 open ended questions regarding their understanding of the possible use and desired use of wealth and power, after which they reported their future time perspective. Compared with possible use, the participants mentioned relatively more prosocial elements when they talked about their desired use of the resources, especially power. The older adults expressed more prosocial understanding in regard to the desired use of wealth and the possible use of power compared to their younger counterparts. The age differences were fully mediated by future time perspective. The results suggest that age is a critical factor that influences individuals' conceptualisation of wealth and power. Life-span developmental stage and future time perspective are important factors to consider for explaining individual differences in the exercise of wealth and power and for promoting their prosocial usage. PMID- 28804388 TI - Patterns of productive activity engagement among older adults in urban China. AB - This study aims to identify patterns of productive activity engagement among older adults in urban China. Once patterns are identified, we further explore how a set of individual characteristics is associated with these patterns. Using data from the 2011 baseline survey of the China Health and Retirement Longitudinal Study (CHARLS), we performed a latent class analysis (LCA) on a national representative sample of adults aged 60 years and over (N = 3019). A specified range of productive activity indicators that fit the context of urban China was used for performing LCA (including working, grandchildren's care, parental care, spousal care, informal helping, and formal volunteering). A multinomial logistic regression was used to assess whether individual characteristics are associated with the identified patterns. The results indicated that a four-class model fit the data well, with the interpretable set of classes: spouse carer (51.2 %), working grandparents (21.7 %), multifaceted contributor (16.6 %), and light engaged volunteer (10.5 %). Age, gender, education, number of children, proximity with the nearest child, household composition and functional status contributed to differentiating these classes. This study captured the reality of productive engagement among older adults by drawing attention to how multiple productive activities intersect in later-life stages. Our findings have implications for policy-makers, health care practitioners, and community advocates to develop programs that facilitate this aging population in assuming meaningful productive activities. PMID- 28804389 TI - Taking a closer look at ageism: self- and other-directed ageist attitudes and discrimination. PMID- 28804390 TI - Relations between views on ageing and perceived age discrimination: a domain specific perspective. AB - This study investigates the relation between age stereotypes and perceived age discrimination. Existing evidence for such a relation is notoriously ambiguous with regard to its direction-age stereotypes can predict (perceived) discrimination, but experiencing discrimination may also change views on ageing which is why we used a dataset with two waves to disentangle the direction of the associations. Considering research on the multi-dimensionality of views on ageing and perceived age discrimination, we addressed this question from a domain- and age group-specific perspective. Drawing on data from two measurement points of the German Ageing Survey (DEAS; t1: 2008, t2: 2011; age range at t1: 40-93 years, n = 6092 participants at t1), we examined reciprocal relations between views on ageing and perceived age discrimination. Cross-lagged models revealed that domain specific views on ageing predict subsequent changes in perceived discrimination in corresponding domains: Negative views on ageing regarding personal competence, physical decline, and social interactions were associated with increases in perceived discrimination in the domains of work, medical care, and social life, respectively. However, we did not find evidence for a reciprocal effect of perceived age discrimination on views on ageing. In sum, results indicate that negative views on ageing act as self-fulfilling prophecies by predisposing people to categorize other people's behaviour as age discrimination or to act themselves in a way that might elicit ageist behaviour in others. PMID- 28804391 TI - Accelerated increase and relative decrease in subjective age and changes in attitudes toward own aging over a 4-year period: results from the Health and Retirement Study. AB - The passage of time may force people to adjust their subjective age in response to changes in their attitudes toward own aging (ATOA). Although positive associations have been found between well-being and both positive ATOA and younger subjective age, the relationships between changes in these measures have not been examined yet. We expected (1) a decrease in positive ATOA to be associated with an accelerated increase in subjective age and (2) an increase in positive ATOA to be associated with a relative decrease in subjective age. Participants were individuals and their spouses, aged 50 and over, recruited by the Health and Retirement Study, who provided responses to a question concerning one's subjective age in 2008 and 2012 (n = 4174). A change in subjective age over the two waves was regarded as (1) an accelerated increase if it was greater than 5 years (36.2 % of the sample); (2) a relative decrease (39.1 %), if it was less than the 3 years; (3) no change if it did not comply with criteria 1 or 2 (24.7 %). A decrease in positive ATOA over the two waves resulted in an accelerated increase in subjective age, and an increase resulted in a relative decrease in subjective age. Older age and more physical impairments and depressive symptoms in 2012 compared with 2008 were associated with an accelerated increase in subjective age. Our findings emphasize the consequences ATOA might have on subjective age experiences, and the need to improve them. PMID- 28804392 TI - The impact of aging stereotypes on dementia worry. AB - Dementia worry, an anxiety-related response to the possibility of developing dementia, represents an important yet underexplored health concern for an aging population. Such a construct is likely impacted by stereotypes concerning aging, including biased associations of aging with inevitable cognitive decline. The present article explores the impact of mixed positive and negative aging stereotype messages on levels of dementia worry. The Fear of Alzheimer's Disease Scale (FADS) was used to measure impact of priming with different proportions of positive and negative aging stereotype words. The priming intervention was modeled after Levy (J Pers Soc Psychol 71:1092-1107, 1996, doi:10.1037/0022 3514.71.6.1092). Eighty older adult participants (Mage = 71.65, SD = 6.57) were exposed to mostly positive aging stereotype words, half positive/half negative words, mostly negative words, all negative words, or non-stereotype words. Mean FADS item response was significantly impacted by priming such that those in the all negative condition had highest levels of dementia worry, F(4, 75) = 2.48, p = .05, [Formula: see text]. This effect was strengthened when relevance of aging stereotypes was controlled for, p < .01. Results suggested that brief exposure to negative aging stereotype content increased levels of dementia worry, particularly when stereotypes were self-relevant. These findings indicate addressing aging stereotypes may be one way of impacting dementia worry. PMID- 28804393 TI - Ageism among physicians, nurses, and social workers: findings from a qualitative study. AB - This study investigated ageism among healthcare professionals in various therapeutic settings in Israel. Using a qualitative approach, the current study aimed to examine similarities and differences across healthcare disciplines. Three focus groups were conducted with physicians, nurses, and social workers. Data from each focus group were analyzed separately, and then commonalities and differences across the groups were evaluated. Three main themes relating to older adults emerged from the data. The first theme pertains to perceived difficulties that healthcare professionals experience in working with older adults and their family members; the second focuses on invisibility and discriminatory communication patterns; and the third theme relates to provision of inappropriate care to older adults. Similarities and differences across the three disciplines were found. The differences related mainly to the examples provided for manifestations of ageism in the healthcare system. Provision of inadequate treatment to older adults due to their age appeared to be the most complex theme, and is discussed at length in the Discussion. Briefly, the complexity stems from the fact that although some behaviors can be clearly described as inappropriate and undesirable, other behaviors such as avoidance of invasive medical procedures for older patients raise ethical dilemmas. Potentially, avoidance of invasive medical treatment can be perceived as compassionate care rather than as undertreatment due to ageist perceptions. A related dilemma, i.e., longevity versus quality-of-life, is also discussed in light of the finding that the balance of these two aspects changes as patients grow old. PMID- 28804394 TI - Hard and soft age discrimination: the dual nature of workplace discrimination. AB - The paper concentrates on the problem of age discrimination in the labour market and the way it can be conceptualised and measured in a multi-disciplinary way. The approach proposed here combines two understandings of age discrimination-a sociological and legal one, what allows for a fuller and expanded understanding of ageism in the workplace. At the heart of the study is a survey carried out in Poland with a sample of 1000 men and women aged 45-65 years. The study takes a deeper and innovative look into the issue of age discrimination in employment. Confirmatory factor analysis with WLSMV estimation and logistic regressions were used to test the hypotheses. The study shows that age discrimination in labour market can take on different forms: hard and soft, where the hard type of age discrimination mirrors the legally prohibited types of behaviours and those which relate to the actual decisions of employers which can impact on the employee's career development. The soft discrimination corresponds with those occurrences, which are not inscribed in the legal system per se, are occurring predominantly in the interpersonal sphere, but can nevertheless have negative consequences. Soft discrimination was experienced more often (28.6% of respondents) than hard discrimination (15.7%) with higher occurrences among women, persons in precarious job situation or residents of urban areas. The role of education was not confirmed to influence the levels of perceived age discrimination. PMID- 28804396 TI - European Journal of Ageing: Reviewers 2016. PMID- 28804395 TI - Social exclusion of older persons: a scoping review and conceptual framework. AB - As a concept, social exclusion has considerable potential to explain and respond to disadvantage in later life. However, in the context of ageing populations, the construct remains ambiguous. A disjointed evidence-base, spread across disparate disciplines, compounds the challenge of developing a coherent understanding of exclusion in older age. This article addresses this research deficit by presenting the findings of a two-stage scoping review encompassing seven separate reviews of the international literature pertaining to old-age social exclusion. Stage one involved a review of conceptual frameworks on old-age exclusion, identifying conceptual understandings and key domains of later-life exclusion. Stage two involved scoping reviews on each domain (six in all). Stage one identified six conceptual frameworks on old-age exclusion and six common domains across these frameworks: neighbourhood and community; services, amenities and mobility; social relations; material and financial resources; socio-cultural aspects; and civic participation. International literature concentrated on the first four domains, but indicated a general lack of research knowledge and of theoretical development. Drawing on all seven scoping reviews and a knowledge synthesis, the article presents a new definition and conceptual framework relating to old-age exclusion. PMID- 28804397 TI - Impact of depression and anxiety disorders on adherence to oral hypoglycemics in older adults with diabetes mellitus in Canada. AB - The prevalence of diabetes mellitus is increasing in Canada, and nonadherence to oral hypoglycemics is a common problem among older adults. This study aims to document the impact of depression and anxiety disorders on adherence to oral hypoglycemics in older adults with diabetes mellitus. Data used in this study came from the longitudinal Quebec survey on senior's health (Enquete sur la Sante des Aines), using a representative sample of 2811 older adults aged 65 and over. The final sample for analysis consisted of 301 patients who received oral hypoglycemic pharmacotherapy. Medication adherence was measured with the medication possession ratio. An adapted version of Andersen's behavioral model was used to explain adherence to oral hypoglycemic medication while considering the following predisposing factors: age, gender, and level of education: enabling factors: marital status and income level: and need factors: physical and mental health status. Our explanatory model of oral hypoglycemic medication adherence was tested using a latent growth curve model. The results of the multiple-group analysis did not show any significant difference in oral hypoglycemic medication adherence (p > 0.05). Furthermore, individuals with higher levels of education were less adherent to oral hypoglycemics than those with lower levels of education (p < 0.05). Medication adherence to oral hypoglycemics did not show any significant difference between participants with and without depression and anxiety disorders. Future studies with larger samples are needed to fully explore the association between mental disorders and oral hypoglycemic medication adherence in the older adult populations. PMID- 28804398 TI - The transfer of skills from cognitive and physical training to activities of daily living: a randomised controlled study. AB - Ageing is associated with the deterioration of all cognitive functions, including attention, memory and psychomotor speed. It has not yet been clearly confirmed whether the effects of cognitive and physical interventions can improve activities of daily living (ADL). This study compared the effectiveness of cognitive and physical training on cognitive functions and the transfer to ADL. Eighty older people with mild cognitive impairment (mean age 67.07 +/- 4.3 years) were randomly divided into an experimental group (n = 40) and a control group (n = 40). Data were collected in an outpatient psychiatric clinic in a randomised controlled trial. Primary outcome measures included the following: cognitive functions were evaluated using the mini mental state examination, the AVLT Auditory verbal learning test, the Stroop test, the TMT-trail making test, the DRT-disjunctive reaction time and the NHPT-nine hole peg test. Secondary outcome measure was the Bristol activities of daily living scale. The experimental group underwent a CogniPlus and physical training; consisting of 20 training sessions over 10 weeks. Both groups went through 30 min of daily physical training for 10 weeks. After the training, significant differences in favour of the experimental group were found in almost all the tests. In memory (AVLT) (p <= 0.0001, effect size (ES) eta2 = 0.218. In reduction of the response time on attention tasks (Stroop tasks) (p <= 0.006, ES = 0.092-0.115). In lower error rates in all tests: Stroop tasks, DRT, TMT, NHPT (p <= 0.02-0.001, ES = 0.062-0.176). In ADL (p <= 0.0001, ES = 0.176). The combined cognitive and physical training had better efficacy for most cognitive functions and for ADL when compared with the physical training only. PMID- 28804399 TI - Care service use in 2 years preceding suicide among older adults: comparison with those who died a natural death and those who lived longer. AB - The aim of the study is (1) to describe and analyse health and social service use and medicine purchases in the last 2 years of life among older adults who died by suicide and (2) to compare use and purchases between three groups: those who died by suicide, died a natural death or who lived longer. Nation-wide Finnish register data were used. The data consist of 316,639 decedents who died at the age of 70 years or older in 1998-2008 and 222,967 people who lived longer. Use of hospital, long-term care and home care, and the purchase of prescribed psychotropic medications were studied for the 2-year period. Binary logistic regression analyses were applied. 1118 older adults died by suicide (0.4 % of all deaths). A majority of older adults who died by suicide had multiple somatic diseases and mental disorders, especially depression, and had contact with health and social services in the last 2 years of life. At the same level of morbidity, use of hospital and long-term care was less common among those who died by suicide than among those who died of natural causes, but more common than among those who lived longer. Those who died by suicide received less home care than those who lived longer. A high proportion of suicides occurred in the first month following hospital discharge. Health and social services should improve support for older adults with chronic diseases and depression. PMID- 28804401 TI - Being slower, feeling older? Experimentally induced cognitive aging experiences have limited impact on subjective age. AB - Initial experimental research has shown that subjective age may change in response to induced aging experiences, but replication and extension are needed. The present study investigates if age-related cognitive gain or loss experiences evoke decreases/increases in subjective age. A multidimensional subjective age measure was used to explore domain-specific internalization effects. 78 individuals aged 59-70 years were randomly assigned to two experimental conditions and a control group. Participants took a cognitive attention test and received gain-oriented feedback on their accuracy or loss-oriented feedback on their processing speed. A mixed factors analysis of covariance was used to examine changes in feel age, look age, do age, and interest age. After being primed with age-related losses, participants reported older do ages as compared to before the experimental priming. Priming age-related gains had only a marginally significant effect on do age. All other subjective age dimensions remained unaffected by the experimental priming. Although previous research has shown that subjective age can be manipulated experimentally, findings from the present study underscore that a comprehensive and cross-domain improvement of subjective age may require personally relevant and repeated experiences of age related gains. PMID- 28804400 TI - Differential age-related changes in localizing a target among distractors across an extended visual field. AB - Age differences in the spatial distribution of attention over a wide field of view have only been described in terms of the spatial extent, leaving the topographical aspect unexplored. This study examined age differences between younger and older adults in good general health in an important topographical characteristic, the asymmetry between the upper and lower visual fields. In Experiment 1, we found age differences across the entire attentional visual field. In addition, age differences were greater in the upper compared to the lower field. In Experiment 2, we examined whether the finding of a greater age difference in the ability to localize a target among distractors in the upper visual field in Experiment 1 was a result of possible differential age differences between the upper and lower visual fields in the ability to localize a target even when there was no distractor competing for attention. Our results suggested that the age differences we observed were linked to age differences in the ability to filter out distractors that compete with the target for attention rather than the ability to process only the target over a wide field of view. While younger adults demonstrated an upper visual field advantage in the ability to localize a target among distractors, there was no such field advantage in older adults. We discuss this finding of diminished upper visual field advantage in older adults in light of an account of pervasive loss of neural specialization with age. We postulate that one possible explanation of age differences in the asymmetry between the upper and lower visual fields may be an adaptation to age related physical decline. We also discuss important implications of our findings in risks of falls and vehicle crashes. PMID- 28804402 TI - Comparative contexts of health and care: findings from the Survey of Health, Ageing and Retirement in Europe. PMID- 28804403 TI - Later life health in Europe: how important are country level influences? AB - In this article, we examine the extent and pattern of country level differences in later life health in Europe and compare five competing explanations for this variation. We used data from 14 European countries, drawn from Northern (Denmark and Sweden), Western (Austria, France, Ireland, Germany Belgium, the Netherlands and Switzerland), Mediterranean (Spain, Italy and Greece) and Eastern (Poland and Czechia) regions of Europe, N = 33,528. Our results suggest that about a quarter (24%) of the overall variation in later life health in Europe appears to be due to country level differences. The Scandinavian countries along with Germany, the Netherlands and Switzerland appear to have the best health, whereas Spain, Italy and Poland had the lowest health score. Country level influences on health were largely associated with differences in the level of egalitarianism of each country as measured by the Gini coefficient, with more inequality being associated with poorer health. Differences in health-related lifestyle, as approximated by the prevalence of obesity in each country, also had a substantial macrolevel influence on later life health, with a lower national prevalence of obesity being associated with better health. Our results indicate the presence of systematic macrolevel health variation in Europe and suggest that policies to reduce income inequality as well as population interventions to promote healthier lifestyles and decrease the prevalence of obesity have the potential to improve population health and potentially offset some of the challenges posed by population ageing in Europe. PMID- 28804404 TI - Variations in preventive care utilisation in Europe. AB - Prevention has been identified as an effective strategy to lead healthy, active and independent lives in old age. Developing effective prevention programs requires understanding the influence of both individual and health system level factors on utilisation of specific services. This study examines the variations in utilisation of preventive services by the population aged 50 and over in 14 European countries, pooling data from the two waves of Survey of Health Ageing and Retirement in Europe and the British Household Panel Survey. The models used allow for the impact of individual level demand-side characteristics and supply side health systems features to be separately identified. The analysis shows significant variations in preventive care utilisation both within and across European countries. In all countries, controlling for individual health status and country-level systemic differences, higher educated and higher income groups use more preventive services. At the health system level, high public health expenditures and high GP density is associated with a high level of preventive care use, but specialist density does not appear to have any effect. Moreover, payment schemes for GPs and specialists appear to significantly affect the incentives to provide preventive health care. In systems where doctors are paid by fee-for-service the utilisation of all health services, including cancer screening, are higher. PMID- 28804405 TI - Transitions in formal and informal care utilisation amongst older Europeans: the impact of national contexts. AB - The objective of this study was to explore how long-term care systems, and in particular the incorporation of needs-based entitlements to care services or benefits, influence formal and informal care utilisation dynamics. We used the Survey of Health, Ageing and Retirement in Europe (SHARE) wave 1 and 2 data, restricting the sample to persons 65+ from 9 European countries (N = 6,293). The effects of changes in health and household composition on formal and informal care transitions were estimated using logistic regression, allowing these effects to vary across countries. The results indicated that, in all countries, formal and informal care were more often complements than substitutes. The likelihood of becoming a formal or informal care user varied significantly between countries. In the Scandinavian countries and in several continental European countries with needs-based entitlements, the transition to formal care was strongly related to informal support being or becoming unavailable. We found little evidence of country differences in the effect of health variables on the transition to formal care. The analysis suggested that, whilst rates of formal care utilisation continue to differ considerably between European countries, formal care allocation practices are not very dissimilar across Northern and continental European welfare states, as we found evidence for all countries of targeting of older persons living alone and of the most care-dependent older people. PMID- 28804407 TI - Identifying effects of health and long-term care policies through cross-national analysis. PMID- 28804406 TI - Gendered support to older parents: do welfare states matter? AB - The aim of this study is to examine the association of welfare state policies and the gendered organisation of intergenerational support (instrumental help and personal care) to older parents. The study distinguishes between support to older parents provided at least weekly, i.e. time-intensive and often burdening support, and supplemental sporadic support. Three policy instruments were expected to be associated with daughters' and sons' support or gender inequality in intergenerational support respectively: (1) professional social services, (2) cash-for-care payments and (3) legal obligations to provide or co-finance care for parents. The analyses based on the Survey of Health, Ageing and Retirement in Europe showed that daughters provided somewhat more sporadic and much more intensive support than sons throughout Europe. While about half of all children who sporadically supported a parent were men, this applied to only one out of four children who provided intensive support. Logistic multilevel models revealed that legal obligations were positively associated with daughters' likelihood of giving intensive support to parents but did not affect the likelihood of sons doing so. Legal obligations thus stimulate support in a gender-specific way. Both legal obligations and cash-for-care schemes were also accompanied by a more unequal distribution of involvement in intensive support at the expense of women. Social services, in contrast, were linked to a lower involvement of daughters in intensive support. In sum, the results suggest that welfare states can both preserve or reduce gender inequality in intergenerational support depending on specific arrangements. PMID- 28804408 TI - Population ageing in Central and Eastern Europe and its demographic and social context. AB - The article focuses on several demographic and socio-economic idiosyncrasies in Central and Eastern Europe, which impact the process of population ageing and intergenerational relations. These include the adverse mortality trends and especially the excess male mortality in certain countries, which exacerbated sex differences in life expectancy beyond anything ever recorded in peace-time population history, the combination of natural population decrease and net emigration, the disordered cohort flows and the shorter generational length. The rapid demographic change in these countries coincided with political, economic and social transformations. The shock of the fall of communism affected differently younger people, who could relatively easily reorganize their life cycles so as to adapt to the changed circumstances, and older persons for whom such reorganization was more difficult, or even impossible. This created the possibility for the opening of an intergenerational rift, as older generations felt being the losers of the transition. The article explores the implications of these idiosyncrasies and social context for living arrangements, kin networks, individual wellbeing and inter-generational relations, and identifies areas where particular challenges are likely to be faced when it comes to policies and programs aimed at older persons. PMID- 28804409 TI - Learning you are "at risk": seniors' experiences of nutrition risk screening. AB - Nutrition risk screening can help identify community-dwelling older adults who may benefit from nutrition education and interventions to improve food intake. Research has shown, however, that older adults who are found "at risk" through nutrition screening commonly do not see themselves at risk, and many do not follow through with accessing recommended nutrition services. Thus, the purpose of this qualitative study was to examine older adults' experiences of learning they were at risk through nutrition screening and to identify what influenced their perspectives and responses to their screening results. Face-to-face interviews were conducted with 22 older adults who had screened at risk (SCREEN II(c) scores < 54) through a nutrition screening process conducted by mail. Participants received their screening results in a personalized letter before the interview, along with some recommendations to help improve food intake and decrease their nutrition risk. Interviews were transcribed and analyzed for themes. When participants reflected about receiving their screening results, some described feeling surprised or even upset by the message that they were at increased risk, whereas others felt unconcerned or reacted with heightened attentiveness to their nutrition. They also began to rationalize their screening score and found ways to explain away their risk. The message that they were at increased risk was poorly understood and not well received because it contradicted their perspective: they felt they were doing the right things, they saw room for improvement rather than seeing themselves at risk, and they tended to make comparisons that helped support the view that they were not truly at risk. Further, even though participants saw room for improvement, they described barriers to change and commonly felt that the recommendations were more applicable for others than themselves. Strategies to improve communication of nutrition screening results and recommendations are discussed to help seniors better understand their risk and take steps to improve their nutrition. PMID- 28804410 TI - Guest editorial: Shifting boundaries of elder care: changing roles and responsibilities. PMID- 28804411 TI - Changing policies, changing patterns of care: Danish and Swedish home care at the crossroads. AB - Despite pursuing the policy of ageing in place, the two Nordic countries of Denmark and Sweden have taken diverse roads in regard to the provision of formal, public tax-financed home care for older people. Whilst Sweden has cut down home care and targeted services for the most needy, Denmark has continued the generous provision of home care. This article focuses on the implication of such diverse policies for the provision and combination of formal and informal care resources for older people. Using data from Level of Living surveys (based on interviews with a total of 1,158 individuals aged 67-87 in need of practical help), the article investigates the consequences of the two policy approaches for older people of different needs and socio-economic backgrounds and evaluates how the development corresponds with ideals of universalism in the Nordic welfare model. Our findings show that in both countries tax-funded home care is used across social groups but targeting of resources at the most needy in Sweden creates other inequalities: Older people with shorter education are left with no one to resort to but the family, whilst those with higher education purchase help from market providers. Not only does this leave some older people more at risk, it also questions the degree of de-familialisation which is otherwise often proclaimed to be a main characteristic of the Nordic welfare model. PMID- 28804412 TI - Changing social organizations of care: a comparison of European policy reforms encouraging paid domestic work. AB - In many European countries different types of policy reforms intending to encourage growth in the domestic service sector have been introduced. The methods and reforms differ but mainly the reforms intend to stimulate growth of a 'new' legal labour market sector within private households. This potential growth sector in combination with insufficient or declining welfare states, inclining female labour market participation and ageing populations could be viewed as explanatory factors to the increased demand for domestic services. A growing amount of those performing paid domestic work in European homes are migrant women with or without papers. The aim of this article is to create a model that enables comparisons of these reforms, with a special focus on changing social organizations of care for elders, children and other dependent persons. Included in the analysis are European countries that have introduced wide domestic service policy reforms as measurement to encourage growth in the domestic service sector, i.e. Austria, Belgium, Denmark, Finland, France, Germany and Sweden. PMID- 28804413 TI - Care work in changing welfare states: Nordic care workers' experiences. AB - This article focuses on Nordic eldercare workers and their experiences of working conditions in times of change and reorganisation. In recent years New Public Management-inspired ideas have been introduced to increase efficiency and productivity in welfare services. These reforms have also had an impact on day-to day care work, which has become increasingly standardized and set out in detailed contracts, leading to time-pressure and an undermining of care workers' professional discretion and autonomy. The empirical data comes from a survey of unionised eldercare workers in home care and residential care in Denmark, Finland, Norway and Sweden (N = 2583) and was analysed by bi- and multi-variate methods. The care workers reported that they found their working conditions physically and mentally arduous. They had to a great extent experienced changes for the worse in terms of working conditions and in their opportunity to provide good quality care. In addition, the majority felt they did not receive support from their managers. An alarming finding was that one out of three care workers declared that they had seriously considered quitting their jobs. Care workers with multiple problems at work were much more likely to consider quitting, and the likelihood was increasing with the number of problems reported. Furthermore, care workers lacking support from their managers had double odds of wanting to quit. The Nordic welfare states with growing older populations are facing challenges in retaining care staff in the eldercare services and ensuring they have good working conditions and support in their demanding work. PMID- 28804414 TI - Negotiating care in the context of Finnish and Italian elder care policies. AB - Negotiation is an integral part of all elder care, which by definition involves a relation between at least two people. In this article, we analyse negotiations concerning elder care in the context of Finnish and Italian elder care policies. At the macro level negotiations on elder care are shaped by elder care policies and at the micro level by individual skills and resources. Our focus is on the negotiations on eligibility that take place when elders attempt to access care. The data consist of qualitative interviews with Finnish and Italian elders in need of care. The analysis of individual experiences of care negotiations reflects the practical consequences of elder care policies to older people. The results indicate that the most negotiated eligibility criteria when seeking access to elder care are need, money and social relations. These criteria are negotiated when seeking eligibility to different sources of care: informal care, grey market, market-based, non-profit and public services. In Italy, negotiation is particularly crucial when accessing grey market care. Cash as the main Italian elder care policy tool tends to enhance the role of and need for negotiation. In Finland, a greater part of elder care is provided by the public sector and therefore the process of negotiation is more standardized than in Italy. PMID- 28804415 TI - Diversification of care policy measures supporting older people: towards greater flexibility for carers? AB - Originally part of the private domain of families, care of the older people is now the concern of public policy. Yet, in the European context of cost containment, it is not easy to make a case for increasing public support and the caring function of families remains prominent in social policy. In this paper, the authors question public policies around care of the older people in relation to both the needs of old people, but also those of adult children, mainly women, who work and provide care for their old parents. We investigate the interactions between public support in long-term care and the caring function of families. The paper presents some results of a comparative research study based on the identification of the policy measures which have been implemented in different European countries in the sector of care of the older people, and on the detailed analysis of care arrangements set up by a sample of 86 family carers in these various national contexts. We argue that in a context of cost containment, whatever the usual patterns of care and the role given to the family and public authorities, the policy measures which have been introduced since the 90s aim to support family carers in various ways with the common objective of giving them the flexibility they need in the organisation of care arrangements, combining various resources (formal professional care, unpaid informal care, semi-formal care). Different patterns of flexibility can be identified according to the regulation of the policy measures. PMID- 28804416 TI - Analyses of welfare-state reform policies towards long-term senior care in a cross-European perspective. AB - The aim of this article is to introduce a systematic, structured conceptual framework for the comparative analysis of welfare-state reform policies towards long-term senior care and the care structures in a cross-European perspective. A welfare state's policies on the long-term care of senior citizens frame the different aspects of their care: the care options of the older people, the employment situation of the different types of caregivers and the care quality. The actual structure of senior care is mainly based on the specific care provision mix in a welfare state and on the main types of care employment. It is should not, however, be treated as a direct outcome of care policies in analyses of welfare-state policies, since the care recipients and care givers all act within the broader framework of the complex and often contradictory cultural, institutional, social and economic context-the specific 'care arrangement' of a country. PMID- 28804417 TI - ICT activity in later life: Internet use and leisure activities amongst senior citizens in Finland. AB - The article examines the relationship between the Internet use and leisure activities amongst Finnish seniors. Traditionally, the young have been the most active users of the Internet and other information and communication technologies (ICTs). In recent years, however, older age groups have increasingly become more interested in ICT, yet a significant proportion of Finnish seniors rarely log on. Using data from a nationally representative survey (N = 542) conducted in the summer of 2010, we explored the connection between the frequent Internet use and general leisure activity. The basic socio-demographic variables were controlled in the analysis. The findings indicate that the active Internet use in old age has a strong positive correlation with the number of different leisure activities amongst Finnish seniors. As most European societies continue to age, it is clear that future research should focus on the implications and the role the Internet and other new ICTs will play in the everyday life amongst the ageing citizens. PMID- 28804418 TI - Sex differences in depression among older adults: are older women more vulnerable than men in social risk factors? The case of open care centers for older people in Greece. AB - This study examined depression, which, research has indicated, is the most common mental health problem affecting older people, especially women. Our objective was to estimate the prevalence of depression among older people in an urban Greek population and to investigate the covariates of depression symptoms prevalence by gender. The sample consisted of 360 individuals, 218 women and 142 men, aged 60 years or older, members of four open care centers for older people in Greece. A questionnaire for socio-demographic and medical data was used. Depression was probed by use of the geriatric depression scale short form. One-hundred and nine persons (30.3%), 32 men (22.53%) and 77 women (35.12%) were found to have depressive symptoms. The results indicated that women have more depression symptoms than men. Being currently unmarried and suffering from multimorbidity were associated with depression symptoms in both gender groups. Meetings with friends were found to be protective factors for both sexes; care of grandchildren and participating in outings and excursions seemed to be protective factors for women only. Unfavorable economic situations, and being childless, were associated with prevalence of depression symptoms among women only. This study confirmed the relationship between depression symptoms and gender and the importance of social and medical factors in the prevalence of depression symptoms, in both gender groups. It also indicated the greater vulnerability of women to some social factors. PMID- 28804420 TI - Can personality predict retirement behaviour? A longitudinal analysis combining survey and register data from Norway. AB - This study investigates how far personality can predict the timing and routes of people's retirement. It uses a large comprehensive Norwegian survey, with larger sample size than earlier related studies, providing estimates of personality based on the five-factor model. The survey data are matched with administrative data, allowing observations of retirement over the 2002-2007 period. The analysis distinguishes between the disability and the non-disability retirements. Retirement is investigated using discrete time, competing risk, logistic regression models amongst individuals aged 50-69. Results indicate that personality predicts disability retirement but not non-disability retirement. Neuroticism increases the risk of disability retirement in women. Agreeableness and extraversion may prevent disability retirement, whereas openness may increase the risk of disability in men. Personality effects are generally consistent across models controlling, or not controlling, for well-known predictors of retirement behaviour including education, income and occupational group. The main exception is that poor health explains the effect of neuroticism on women's disability retirement. PMID- 28804419 TI - Early retirement in the day-care sector: the role of working conditions and health. AB - This article studies the role of working conditions and health for elderly female day-care teachers' decision to enter early retirement. Entry into retirement is analysed in a duration framework that allows for unobserved heterogeneity in the baseline hazard. Data are from a Danish longitudinal data set based on administrative register records for 1997-2006. Working conditions are measured by four indicators. First, work pressure is measured by the child-to-teacher ratio, which varies across municipalities and over time. Second, working conditions are measured by the proportion of children with a problematic social background. Third, the share of trained teachers is considered an indicator of working conditions. And fourth, the size of the institution is assessed as an indicator of working conditions. Regressions in a duration model framework show that there is no significant relationship between the child-to-teacher ratio or the size of the institution and early retirement. However, working conditions measured by the social background of the children and the share of trained day-care teachers have a significant effect on the probability of early retirement. Finally, a poor health condition is associated with a higher propensity to enter early retirement. PMID- 28804421 TI - Health and retirement: a complex relationship. AB - Health and retirement are bi-directionally linked. Health is central to the timing of retirement, and retirement may have varying effects on health. Three studies of the special section of this issue add to the evidence about factors determining early retirement from three different perspectives. Blekesaune and Skirbekk investigated how personality factors were associated with non-disability and disability pension in Norway; Gortz studied working conditions, health and early retirement in the day-care sector in Denmark; and Clarke et al. modelled trajectories of expectations not to retire early but to work full time after age 62 in a sample of older Americans as well as implications for health when such expectations were unmet. All studies incorporated health measures in the analyses. Nevertheless, health can have several roles in the retirement process. The complexity of the relationship of health and retirement is discussed in this commentary, several methodological issues are addressed and implications for future studies are identified. PMID- 28804422 TI - Understanding retirement: the promise of life-span developmental frameworks. AB - The impending retirement of large population cohorts creates a pressing need for practical interventions to optimize outcomes at the individual and societal level. This necessitates comprehensive theoretical models that acknowledge the multi-layered nature of the retirement process and shed light on the dynamic mechanisms that drive longitudinal patterns of adjustment. The present commentary highlights ways in which contemporary life-span developmental frameworks can inform retirement research, drawing on the specific examples of Bronfenbrenner's Ecological Model, Baltes and Baltes Selective Optimization with Compensation Framework, Schulz and Heckhausen's Motivational Theory of Life-Span Development, and Carstensen's Socioemotional Selectivity Theory. Ultimately, a life-span developmental perspective on retirement offers not only new interpretations of known phenomena but may also help to identify novel directions for future research as well as promising pathways for interventions. PMID- 28804423 TI - Individual risk factors of feelings of unsafety in later life. AB - The aim of this contribution is twofold: on one hand to examine the individual risk factors regarding feelings of unsafety among older people and on the other hand to investigate whether they differ between third-age adults (aged 60-79) and fourth-age adults (aged 80+). This study seeks to identify the relationship between demographic variables, lack of economic resources, well-being and perceived ageism on the one side and feelings of unsafety on the other. On the basis of data from the Belgian Ageing Studies (N = 26,116), it was found that fourth-age adults experienced higher levels of feelings of unsafety than third age adults. Furthermore, hierarchical regression models indicated that gender, number of children and perceived ageism were significantly related to feelings of unsafety across the third and fourth ages. However, several individual characteristics were found to be specific to the different age groups. Conclusively, practical implications and research issues are critically discussed by emphasising the importance of tackling structural inequalities among older persons to reduce their feelings of unsafety. PMID- 28804424 TI - Age identity, self-rated health, and life satisfaction among older adults in Dakar, Senegal. AB - The objectives of this quantitative study were to (1) ascertain to what extent older adults aged 50 and above feel and desire to be younger than their age, and classify themselves as young versus old; (2) compare these patterns with those found among other cross-cultural populations; and (3) assess the extent to which self-rated health and life satisfaction predict age identities. This study was carried out on a sample of 500 dwellers of the Senegalese capital aged 50 and older. This sample was constructed using the quota method to strive for representativeness. Most of the respondents wanted to be younger than their chronological age (51.8 %), but only 27.8 % felt younger than they were. Moreover, 80 % of the sample claimed to be old. Self-rated health predicted felt age and the feeling of being old. Furthermore, the less-satisfied Dakar residents were with their life, the younger they wanted to be. We first discuss our results in a comparative perspective focused on how orientations toward individualism and collectivism could be related to age identity, and on demographic characteristics of the Senegalese population-where life expectancy is 59.3 years old. We then analyze the relevance of age identity dimensions as indicators of successful aging in Dakar. PMID- 28804425 TI - Components and determinants of quality of life in community-dwelling older adults. AB - The objectives of this study are to detect the main components of global quality of life (QoL) of community-dwelling older adults from their own perspective and to identify determinants of health-related and global QoL in the same population. This is a cross-sectional study covering a representative sample of 1,106 community-dwelling adults aged 60 years and older residing in Spain. The survey collected information on QoL through a face-to-face interview asking for QoL components in free-format, as well as the completion of two QoL measures, the EQ 5D and the Personal Wellbeing Index. The most important QoL dimensions, according to the participants of this study, were health, family, and finances. Depression was the main determinant of both QoL indices, while functional independence and social support specifically influenced health-related and global QoL, respectively. Based on the perspective of the older adults as well as on statistical analysis, this work emphasizes the importance of health, family, and social support as areas of special interest in aging. There was a discrepancy when comparing findings related to the importance of financial status. Results also support that global and health-related QoL share some common determinants, but with different weights for functional independence and social support. PMID- 28804426 TI - Using the Folstein Mini Mental State Exam (MMSE) to explore methodological issues in cognitive aging research. AB - Cognitive scales are used frequently in geriatric research and practice. These instruments are constructed with underlying assumptions that are a part of their validation process. A common measurement scale used in older adults is the Folstein Mini Mental State Exam (MMSE). The MMSE was designed to screen for cognitive impairment and is used often in geriatric research. This paper has three aims. Aim one was to explore four potential threats to validity in the use of the MMSE: (1) administering the exam without meeting the underlying assumptions, (2) not reporting that the underlying assumptions were assessed prior to test administration, (3) use of variable and inconsistent cut-off scores for the determination of presence of cognitive impairment, and (4) failure to adjust the scores based on the demographic characteristics of the tested subject. Aim two was to conduct a literature search to determine if the assumptions of (1) education level assessment, (2) sensory assessment, and (3) language fluency were being met and clearly reported in published research using the MMSE. Aim three was to provide recommendations to minimalize threats to validity in research studies that use cognitive scales, such as the MMSE. We found inconsistencies in published work in reporting whether or not subjects meet the assumptions that underlie a reliable and valid MMSE score. These inconsistencies can pose threats to the reliability of exam results. Fourteen of the 50 studies reviewed reported inclusion of all three of these assumptions. Inconsistencies in reporting the inclusion of the underlying assumptions for a reliable score could mean that subjects were not appropriate to be tested by use of the MMSE or that an appropriate test administration of the MMSE was not clearly reported. Thus, the research literature could have threats to both validity and reliability based on misuse of or improper reported use of the MMSE. Six recommendations are provided to minimalize these threats in future research. PMID- 28804427 TI - Dementia worry: a psychological examination of an unexplored phenomenon. AB - According to recent surveys, dementia worry (DW) is a widespread phenomenon in mid-life and old age, at least in Western populations. DW has been shown to be only loosely related to sociodemographic factors. Unfortunately, the concept of DW has found only very little conceptual and empirical attention in previous research. In this conceptual review, we take (mostly) a psychological approach to DW. First, we define DW as an emotional response to the perceived threat of developing dementia. We then conceptualise DW as a hybrid, combining elements of ageing anxiety and health anxiety. On the population level, we argue that the high prevalence of DW may be reflective of the increasing awareness of dementia in times of increasing ''dementia encounters', widespread misperceptions of risks and consequences of dementia and a perceived lack of coping resources. Finally, we propose that DW may affect a range of important behaviours, such as how people interpret evidence of their own or others' age-related cognitive changes, how they interact with people with dementia, how they anticipate and plan for their future, how they engage in screening and prevention behaviours and how they exploit healthcare resources. We conclude with suggestions for future research, including a further in-depth investigation of psychological and micro /macrosocial factors associated with DW. PMID- 28804428 TI - Loneliness in old age in Eastern and Western European societies: theoretical perspectives. AB - Data from European countries participating in the Generations and Gender Surveys showed that mean loneliness scores of older adults are higher in Eastern than in Western European countries. Although co-residence is considered as one of the fundamental types of social integration, and although co-residence is more common in Eastern Europe, the mean loneliness scores of older co-resident adults in Eastern Europe are still very high. This article investigates mechanisms behind the puzzling between-country differences in social integration and loneliness. Firstly, the theoretical framework of loneliness is discussed starting from the individual's perspective using the deficit and the cognitive discrepancy approach and taking into account older adults' deprived living conditions. Secondly, mechanisms at the societal level are investigated: cultural norms, the demographical composition and differences in societal wealth and welfare. It is argued that an integrated theoretical model, as developed in this article, combining individual and societal level elements, is most relevant for understanding the puzzling reality around social integration and loneliness in country-comparative research. An illustration of the interplay of individual and societal factors in the emergence of loneliness is presented. PMID- 28804429 TI - 'Who is going to explain it to me so that I understand?' Health care needs and experiences of older patients with advanced heart failure. AB - Heart failure is a leading cause of death and can result in significant palliative care needs. The aim of this study was to explore the needs of older patients with advanced heart failure, and their experiences with health care delivery in Germany. Qualitative interviews were carried out with 12 patients (6 men, 6 women; age 73-94 years; heart failure in an advanced stage according to the New York Heart Association Functional Classification) recruited in two geriatric hospitals. The interviews were analyzed by a qualitative descriptive approach. The main categories derived from the patient interviews were: understanding of illness and prognosis, health care services and social life. The patients expressed the need for better information and communication regarding illness and prognosis, and the desire for more respectful treatment by health care providers. Heart failure was not recognized as a potentially life-limiting disease, and the patients had no experience with palliative care services. The study emphasizes the need for improving communication with patients with advanced heart failure. To achieve this, strengthening the palliative care approach in all relevant services that deliver care for these patients and introducing advanced care planning appear to be promising strategies. PMID- 28804430 TI - Determinants of change in self-rated health among older adults in Europe: a longitudinal perspective based on SHARE data. AB - The present study aims at detecting factors which may predict a decline or an improvement in self-rated health (SRH) of older adults (persons aged 50 or higher) among socio-demographic characteristics, physical and mental health indicators and risky health behaviours. In the analysis, multinomial logistic regression models are applied to data from waves 1 and 2 of the Survey of Health Ageing and Retirement in Europe (carried out about 3 years apart); persons who report a decline or an improvement in SRH at wave 2 are compared to those who report no change while controlling for SRH at baseline and country of residence. The analysis was carried out for the whole sample and two subgroups, persons aged 50-64 and 65 or higher. The results indicate that female sex and higher educational attainment have a strong protective effect against decline in SRH. Worse health at baseline is an important predictor of subsequent decline but changes occurring between the waves have a more pronounced effect, implying that SRH is influenced more by recent developments. The findings also indicate that improvement in SRH is a more complex concept than decline and is strongly affected by factors other than health. Among behavioural risk factors, low levels of physical activity and a decrease in the levels of activity between the waves are significantly related to decline while frequent drinking seems associated with improvement. Differentiations by age are modest and probably suggest that advancing age is related to a milder view of one's health. PMID- 28804431 TI - The moderating role of age in the relationship between volunteering motives and well-being. AB - Driven by socioemotional selectivity theory, this study examined whether age moderated the associations of volunteering motives with physical and psychological well-being in a sample of Hong Kong Chinese volunteers. Volunteering motives were measured by the volunteer functions inventory. Findings revealed that even after controlling for demographic characteristics and volunteering experience, age was related to higher social and value motives but lower career motives, and moderated the associations of social and protective motives with well-being. The associations of social motives with physical well being were positive among older volunteers, but were negative among younger- and middle-aged volunteers. While protective motives were positively related to psychological well-being among all the volunteers, such effects were stronger among younger- and middle-aged volunteers than among older volunteers. Findings highlight the role of age in determining the relationship between volunteering motives and well-being. PMID- 28804432 TI - Adolescent grandchildren's perceptions of grandparents' involvement in UK: an interpretation from life course and evolutionary theory perspective. AB - In this article, we study grandparental involvement from the viewpoint of evolutionary theory and sociological life course perception. We have used 'the Involved Grandparenting and Child Well-Being 2007' survey, which is the first nationally representative sample of British and Welsh adolescents aged 11-16 (n = 1,488). First, we explore with the descriptive statistics the amount of grandparental involvement reported by adolescents. The result follows the predicted pattern: maternal grandparent is reported to involve in a grandchild's life the most, second maternal grandfather, third paternal grandmother and the last paternal grandfather. Second, we focus more closely on separate grandparents and show with four linear regression models which factors are connected to each grandparent's involvement. Grandchild's age, grandparent's health, grandparent's labour force participation and distance between a grandparent and a grandchild were factors that have similar effects in relation to all grandparents. Marital status mattered only for grandfathers, whereas family structure of a grandchild has opposite effects in relation to maternal and paternal grandparents. Grandchild's sex, grandparent's age, the number of grandchildren and the number of living grandparents all mattered, but only with respect to some grandparents. The study shows that it is advantageous to merge sociological and evolutionary viewpoints when studying a grandparental involvement in a modern society. PMID- 28804433 TI - Meaning in life and mastery mediate the relationship of negative reminiscence with psychological distress among older adults with mild to moderate depressive symptoms. AB - To understand the adaptive value of reminiscence, a mediational model of reminiscence was tested in a sample of older adults with mild to moderate depressive symptoms. Using structural equation modeling, we investigated if psychological resources (mastery and meaning in life) mediate the relation between reminiscence (positive: identity construction and problem solving; and negative: bitterness revival and boredom reduction) and psychological distress (depressive symptoms and anxiety symptoms). A total of 202 older Dutch adults living in the community participated in this study. The present study consisted of baseline measurements of a randomized controlled trial that evaluated the effectiveness of a life-review therapy intervention on depression. Results showed that psychological resources fully mediated the relation between negative reminiscence and psychological distress. Specifically, negative reminiscing is related to decreased psychological distress through meaning in life and sense of mastery. The study contributes to current knowledge on the relation between reminiscence and mental health, both empirically and clinically. It helps to increase understanding of how reminiscence is related to psychological distress, especially in depressed older adults, and the relative importance of psychological resources, i.e., mastery and meaning in life. From a clinical perspective, these findings suggest the usefulness of focusing on strengthening psychological resources in therapeutic reminiscence-based strategies for older adults with depressive symptoms. PMID- 28804434 TI - Associations between received social support and positive and negative affect: evidence for age differences from a daily-diary study. AB - Recent evidence suggests negative associations between received social support and emotional well-being. So far, these studies mainly focused on younger adults. Quantity and quality of social support changes with age; therefore, this study investigated whether there are age differences regarding the association between received social support and positive affect (PA) and negative affect (NA). Moreover, it was tested whether these age effects might be due to a differential effectiveness of different sources of support for younger and older individuals. Forty-two individuals (21 younger adults, aged 21-40 and 21 older adults, aged 61 73) completed 30-daily diaries on their received social support, PA/NA and the sources of support provision. Data were analyzed using multilevel modeling. Results indicated age-related differential effects: for younger individuals, received social support was negatively associated with indicators of emotional well-being, whereas these associations were positive for older respondents. Regarding NA, these effects held when testing lagged predictions and controlling for previous-day affect. No age differences emerged regarding the associations between different sources of support and indicators of affect. Conceptual implications of these age-differential findings are discussed. PMID- 28804435 TI - Color, anthocyanin, and antioxidant characteristics of young wines produced from spine grapes (Vitis davidii Foex) in China. AB - Background: Spine grape has gained attention in the field of wine science due to its good growth characteristics. Spine grape wine has been made by local residents for a long time. However, the scientific evaluation of spine wine has not been systemically documented compared to Vitis vinifera grape wines Methods: We compared 11 spine wines from south China (W1-W11) with 7 high-quality international wines (W12-W18). The total phenolic content, the total anothcyanin content and the antioxidant activity of these wines were analyzed and compared. Meanwhile, anthocyanin profiles of these wines were also documented. Results: Compared with other wines most of the spine wines had a strong red intensity with a blue hue. Malvidin-3,5-O-diglucoside and malvidin-3-O-(6-O-coumaroyl)-glucoside 5-glucoside appeared to be the major anthocyanins in these wines. The scavenging capacity analyses of these wines using ABTS, DPPH, and CUPRAC assays indicated that spine wines possessed high antioxidant properties, especially spine wine W3, W4, W6 and W8. Their high antioxidant properties were mainly related to the high levels of the total phenolic content and anthocyanins. Conclusion: These results suggested that spine wine might be considered a good wine source for the Chinese wine industry and provided useful information on the knowledge of spine grape. PMID- 28804436 TI - Intake of different types of red meat, poultry, and fish and incident colorectal cancer in women and men: results from the Malmo Diet and Cancer Study. AB - Background : Colorectal cancer (CRC) is considered one of the most common forms of cancer in the Western world. High intake of red and processed meat is considered to increase CRC development. Objective : This study examined associations between intake of red meats, poultry, and fish and incident CRC, and if weight status modifies the associations. Design : In the Malmo Diet and Cancer Study, dietary data was collected through a modified diet history method. Via the Swedish Cancer Registry, 728 cases of CRC were identified during 428 924 person years of follow-up of 16 944 women and 10 987 men. Results : Beef intake was inversely associated with colon cancer. However, in men high intake of beef was associated with increased risk of rectal cancer. High intake of pork was associated with increased incidence of CRC, and colon cancer. Processed meat was associated with increased risk of CRC in men. Fish intake was inversely associated with risk of rectal cancer. No significant interactions were found between different types of meat and weight status. Conclusions : Findings suggest that associations between meat intake and CRC differ depending on meat type, sex, and tumor location in the bowel. Weight status did not modify observed associations. PMID- 28804437 TI - Essential and toxic metals in animal bone broths. AB - Background: This investigation examines the extraction of metals from animal bones into broth, and assesses whether bone broths are good sources of essential metals and the risks associated with the consumption of toxic metals. Method:Three sets of controlled experiments were performed to study the factors (cooking time, acidity, bone type and animal species) that influence metal extractions. Three types of animal bone broth-based foods were also tested. Results: Reducing the broth pH from 8.38 to 5.32 significantly (p < 0.05) increased Ca and Mg extraction by factors of 17.4 and 15.3, respectively. A long cooking time, > 8 h, yielded significantly higher (p < 0.05) Ca and Mg extraction than shorter cooking times. The extraction characteristics of metals, particularly Ca, Mg, Cu and Al, from the leg and rib bones differed. The between species variations in extraction were larger than those of within-species. Conclusions:The Ca and Mg levels in home-made or commercial broth/soup were found not to exceed low tenths of milligram per serving, or <5% of the daily recommended levels. The risks that are associated with the ingestion of heavy metals such as Pb and Cd in broth are minimal because the levels were in the ranges of a few MUg per serving. PMID- 28804439 TI - Association between the number of fungiform papillae on the tip of the tongue and sensory taste perception in children. AB - Background: To measure sensory taste perception in children with an accurate and reproducible method is challenging and objective measurement methods are scarce. Objective: Aim was to characterize sensory taste perception, by measuring the number of fungiform papillae (FP) and to investigate whether the number of FP is associated with sensitivity for bitter taste and with taste preferences for sweet, salty, fatty or umami in children between 8 and 11 years of age. Design: Number of FP was measured with a digital camera in 83 children in a German subsample of the IDEFICS study. Among those 56 children performed a taste threshold test for bitter and taste preference tests for sweet, salty, fatty and umami. The association between the number of FP and sensory taste perception was analysed. Results: There is a tendency towards a lower number of FP in children with a higher fat preference (30 vs. 25 papillae, p=0.06). Results show no association between the number of FP and neither the bitter taste thresholds nor taste preferences for sweet, salty and umami. Conclusion: Bitter taste threshold might be independent of the number of FP, while the perception of fat was associated with the number of FP. PMID- 28804438 TI - Green tea extract induces genes related to browning of white adipose tissue and limits weight-gain in high energy diet-fed rat. AB - Background: A wealth of research has reported on the anti-obesity effects of green tea extract (GTE). Although browning of white adipose tissue (WAT) has been reported to attenuate obesity, no study has disclosed the effects of GTE on browning in Sprague Dawley rats. Objectives: The aims of the study were to investigate the effects of GTE on anti-obesity and browning, and their underlying mechanisms. Methods: Four groups of rats (n=10/group) were used including a normal diet with vehicle treatment, and a high-energy diet (HED) with vehicle or GTE by oral gavage at 77.5 or 155 mg/kg/day for 8 weeks. Body weight, fat accumulation, and serum biochemical parameters were used to evaluate obesity. The gene expressions were analyzed using RT-qPCR and western blotting. Results: GTE modulated HED-induced body weight, fat accumulation, and serum levels of triacylglycerol, total cholesterol, low-density lipoprotein, free fatty acids, aspartate aminotransferase, and alanine aminotransferase. Moreover, GTE enhanced the serum high-density lipoprotein. Most importantly, the biomarkers of beige adipose tissue were up-regulated in WAT in GTE-given groups. GTE induced genes involved in different pathways of browning, and reduced transducin-like enhancer protein-3 in WAT. Conclusion: Our results suggest that GTE may improve obesity through inducing browning in HED-fed rats. Abbreviations: ALT: Alanine transaminase; AST: Aspartate transaminase; BAT: Brown adipose tissue; BMP-7: Bone morphogenetic protein-7; BW: Body weight; CIDEA: Cell death activator; CPT-1: Carnitine palmitoyltransferase-1; EFP: Epididymal fat pad; FFA: Free fatty acid; FGF-21: Fibroblast growth factor-21; GTE: Green tea extract; HDL: High-density lipoprotein; HED: high-energy diet; LDL: Low-density lipoprotein; MFP: Mesenteric fat pad; PGC-1alpha: Activates PPAR-gamma coactivator-1; PPAR-gamma: Peroxisome proliferator-activated receptor-gamma; PRDM-16: PR domain containing 16; RFP: Renal fat pad; SD: Sprague Dawley; TC: Total cholesterol; TG: Triacylglycerol; TLE-3: Transducin-like enhancer protein-3: UCP-1: Uncoupling protein-1; WAT: White adipose tissue. PMID- 28804440 TI - Effect of dietary interventions during weaning period on parental practice and lipoproteins and vitamin D status in two-year-old children. AB - Objective: Evaluate if a two-day course for parents on nutrition and applied baby food preparation had an effect on child's intake of home-made foods, lipid concentration, and vitamin D status. Design: Randomized controlled trial at age 6 months and follow-up at ages 15 and 24 months. Setting: Four health care clinics in Kristiansand, Norway. Subjects: Thirty-nine pairs of 6-month-old children and their parents in the intervention group and 20 pairs in the control group. Results: At age 15 months, the intervention group had lower intakes of ready-made porridge (2.0 vs. 5.8 servings per week (p < 0.05)), lower intake of canned baby food (2.9 vs. 6.3 servings per week (p < 0.05)) and higher intakes of home-made porridge (4.8 servings vs. 0.9 servings per week (p < 0.001)) compared with the control group. The intervention group had higher HDL cholesterol concentrations at 2 years than the control group, 1.08 mol/l compared to 0.89 mol/l (p < 0.05). Conclusions: This is the first study to show that providing dietary information and applied baby food preparation to parents during the weaning period may have impact on the children's diet at 15 and 24 months and improve their lipid profile. Our results call for studies with more power and longer follow-up. PMID- 28804441 TI - Comparison study on antioxidant, DNA damage protective and antibacterial activities of eugenol and isoeugenol against several foodborne pathogens. AB - Eugenol and its isomer isoeugenol are both used as flavouring agents or food additives in food products, and have both some similar biological properties. However, the difference in biological activities between eugenol and isoeugenol is rarely studied. In this study, the profiles of antioxidant, DNA-protective effects and antibacterial activities of eugenol and isoeugenol against several common foodborne pathogens were investigated and compared under various experiment conditions. Results showed that eugenol and isoeugenol had strong antioxidant activity, the protective effect against DNA damage and antibacterial activity. In addition, it was found that isoeugenol exhibited the higher biological activities mentioned above than eugenol, which was because isoeugenol had a carbon-carbon double bond closer to the benzene ring compared with eugenol. However, the specific reason needs to be further studied. PMID- 28804442 TI - Mesozeaxanthin protects the liver and reduces cardio-metabolic risk factors in an insulin resistant rodent model. AB - Background: Mesozeaxanthin (MZ) is a macular carotenoid which has been reported to have a number of pharmacological properties, including the antioxidant, and anticarcinogenic property, and has been stated to decrease the hepatocyte lipid content. Objective: In this study, we investigated the effect of MZ on cardio metabolic health risk (CMHR) and its probable mechanisms of action in rats fed a high-fat diet (HFD). Design: Rats were randomly divided into four groups consisting of (i) Control, (ii) MZ, (iii) HFD, and (iv) HFD+MZ. Results: MZ treatment increased the antioxidant enzyme activities and helped improve the liver function. The treatment alleviated CMHR and decreased the level of nuclear factor kappa B (NF-kappaB p65) and tumor necrosis factor-alpha (TNF-alpha). The levels of hepatic peroxisome proliferator-activated receptor gamma (PPAR-gamma), phosphorylated insulin receptor substrate 1 (p-IRS-1), beta,beta-carotene 9',10' oxygenase 2 (BCO2) and nuclear factor erythroid 2-related factor 2 (Nrf2), which decrease in HFD rats, were found to be significantly higher in MZ supplemented animals. Conclusion: MZ has antioxidant and anti-inflammatory properties and can is reported in this study toprotect against fatty liver and cardio-metabolic syndrome, possibly through regulation of PPAR-gamma, IRS-1, Nrf2 and NF-kappaB proteins, in an insulin-resistant rodent model. PMID- 28804443 TI - Technology-Based Rehabilitation to Improve Communication after Acquired Brain Injury. AB - The utilization of technology has allowed for several advances in aphasia rehabilitation for individuals with acquired brain injury. Thirty-one previous studies that provide technology-based language or language and cognitive rehabilitation are examined in terms of the domains addressed, the types of treatments that were provided, details about the methods and the results, including which types of outcomes are reported. From this, we address questions about how different aspects of the delivery of treatment can influence rehabilitation outcomes, such as whether the treatment was standardized or tailored, whether the participants were prescribed homework or not, and whether intensity was varied. Results differed by these aspects of treatment delivery but ultimately the studies demonstrated consistent improvement on various outcome measures. With these aspects of technology-based treatment in mind, the ultimate goal of personalized rehabilitation is discussed. PMID- 28804445 TI - Commentary: Interaction between facial expression and color. PMID- 28804444 TI - Intrinsic and Antipsychotic Drug-Induced Metabolic Dysfunction in Schizophrenia. AB - For decades, there have been observations demonstrating significant metabolic disturbances in people with schizophrenia including clinically relevant weight gain, hypertension, and disturbances in glucose and lipid homeostasis. Many of these findings pre-date the use of antipsychotic drugs (APDs) which on their own are also strongly associated with metabolic side effects. The combination of APD induced metabolic changes and common adverse environmental factors associated with schizophrenia have made it difficult to determine the specific contributions of each to the overall metabolic picture. Data from drug-naive patients, both from the pre-APD era and more recently, suggest that there may be an intrinsic metabolic risk associated with schizophrenia. Nevertheless, these findings remain controversial due to significant clinical variability in both psychiatric and metabolic symptoms throughout patients' disease courses. Here, we provide an extensive review of classic and more recent literature describing the metabolic phenotype associated with schizophrenia. We also suggest potential mechanistic links between signaling pathways associated with schizophrenia and metabolic dysfunction. We propose that, beyond its symptomatology in the central nervous system, schizophrenia is also characterized by pathophysiology in other organ systems directly related to metabolic control. PMID- 28804446 TI - Induction of miR-155 after Brain Injury Promotes Type 1 Interferon and has a Neuroprotective Effect. AB - Traumatic brain injury (TBI) produces profound and lasting neuroinflammation that has both beneficial and detrimental effects. Recent evidence has implicated microRNAs (miRNAs) in the regulation of inflammation both in the periphery and the CNS. We examined the expression of inflammation associated miRNAs in the context of TBI using a mouse controlled cortical impact (CCI) model and found increased levels of miR-21, miR-223 and miR-155 in the hippocampus after CCI. The expression of miR-155 was elevated 9-fold after CCI, an increase confirmed by in situ hybridization (ISH). Interestingly, expression of miR-155 was largely found in neuronal nuclei as evidenced by co-localization with DAPI in MAP2 positive neurons. In miR-155 knock out (KO) mice expression of type I interferons IFNalpha and IFNbeta, as well as IFN regulatory factor 1 and IFN-induced chemokine CXCL10 was decreased after TBI relative to wild type (WT) mice. Unexpectedly, miR-155 KO mice had increased levels of microglial marker Iba1 and increased neuronal degeneration as measured by fluoro-jade C (FJC) staining, suggesting a neuroprotective role for miR-155 in the context of TBI. This work demonstrates a role for miR-155 in regulation of the IFN response and neurodegeneration in the aftermath of TBI. While the presence of neuronal nuclear miRNAs has been described previously, their importance in disease states is relatively unknown. Here, we show evidence of dynamic regulation and pathological function of a nuclear miRNA in TBI. PMID- 28804447 TI - Activity-Dependent Arc Expression and Homeostatic Synaptic Plasticity Are Altered in Neurons from a Mouse Model of Angelman Syndrome. AB - Angelman syndrome (AS) is a neurodevelopmental disorder that results from deletions or mutations in chromosome 15, which usually includes the UBE3A gene. Ube3A protein is an E3 ubiquitin ligase that ubiquitinates proteins and targets them for degradation. The immediate-early gene Arc, a master regulator of synaptic plasticity, was identified as a putative substrate of Ube3A, but there have been conflicting reports on whether Arc is a bona fide E3 ligase substrate. Using multiple approaches, we found no evidence for a physical interaction between Arc and Ube3A in vivo. Nonetheless, activity-induced subcellular distribution of Arc is altered in brains from Ube3am-/p+ mice, with abnormal concentration of Arc at synapses. Furthermore, although activation of Arc transcription is normal, the stability of Arc protein is enhanced in dendrites of hippocampal neurons cultured from Ube3am-/p+ mice. Finally, homeostatic synaptic scaling of surface AMPA receptors does not occur in Ube3am-/p+ hippocampal neurons, reminiscent of neurons that lack Arc protein. Although Ube3A does not seem to bind Arc in a canonical E3 ligase-substrate interaction, Arc-dependent synaptic plasticity is still altered in Ube3am-/p+ mice, which may underlie the cognitive deficits observed in AS. PMID- 28804448 TI - Erythropoietin Protects Against Lipopolysaccharide-Induced Microgliosis and Abnormal Granule Cell Development in the Ovine Fetal Cerebellum. AB - Erythropoietin (EPO) ameliorates inflammation-induced injury in cerebral white matter (WM). However, effects of inflammation on the cerebellum and neuroprotective effects of EPO are unknown. Our aims were to determine: (i) whether lipopolysaccharide (LPS)-induced intrauterine inflammation causes injury to, and/or impairs development of the cerebellum; and (ii) whether recombinant human EPO (rhEPO) mitigates these changes. At 107 +/- 1 days gestational age (DGA; ~0.7 of term), fetal sheep received LPS (~0.9 MUg/kg; i.v.) or an equivalent volume of saline, followed 1 h later with 5000 IU/kg rhEPO (i.v.) or an equivalent volume of saline (i.v.). This generated the following experimental groups: control (saline + saline; n = 6), LPS (LPS + saline, n = 8) and LPS + rhEPO (n = 8). At necropsy (116 +/- 1 DGA; ~0.8 of term) the brain was perfusion fixed and stained histologically (H&E) and immunostained to identify granule cells (Neuronal Nuclei, NeuN), granule cell proliferation (Ki67), Bergmann glia (glial fibrillary acidic protein, GFAP), astrogliosis (GFAP) and microgliosis (Iba-1). In comparison to controls, LPS fetuses had an increased density of Iba-1 positive microglia (p < 0.005) in the lobular WM; rhEPO prevented this increase (p < 0.05). The thickness of both the proliferative (Ki67-positive) and post mitotic zones (Ki67-negative) of the EGL were increased in LPS-exposed fetuses compared to controls (p < 0.05), but were not different between controls and LPS + rhEPO fetuses. LPS also increased (p < 0.001) the density of granule cells (NeuN-positive) in the internal granule layer (IGL); rhEPO prevented the increase (p < 0.01). There was no difference between groups in the areas of the vermis (total cross-section), molecular layer (ML), IGL or WM, the density of NeuN positive granule cells in the ML, the linear density of Bergmann glial fibers, the areal density or somal area of the Purkinje cells, the areal coverage of GFAP positive astrocytes in the lobular and deep WM, the density of Iba-1-positive microglia in the deep WM or the density of apopotic cells in the cerebellum. LPS induced intrauterine inflammation caused microgliosis and abnormal development of granule cells. rhEPO ameliorated these changes, suggesting that it is neuroprotective against LPS-induced inflammatory effects in the cerebellum. PMID- 28804449 TI - Loss of Leptin-Induced Modulation of Hippocampal Synaptic Trasmission and Signal Transduction in High-Fat Diet-Fed Mice. AB - Hippocampal plasticity is triggered by a variety of stimuli including sensory inputs, neurotrophins and inflammation. Leptin, whose primary function is to regulate food intake and energy expenditure, has been recently shown to affect hippocampal neurogenesis and plasticity. Interestingly, mice fed a high-fat diet (HFD) exhibit impaired hippocampal function, but the underlying mechanisms are poorly understood. To address this issue, we compared leptin responsiveness of hippocampal neurons in control and HFD-fed mice by combining single-cell electrophysiology and biochemical assays. We found that leptin modulated spontaneous and evoked synaptic transmission in control, but not HFD, mice. This functional impairment was paralleled by blunted activation of STAT-3, one of the key signal transduction pathways controlled by the fully functional isoform of the leptin receptor, ObRb. In addition, SOCS-3 expression was non-responsive to leptin, indicating that modulation of negative feedback impinging on ObRb was also altered. Our results advance the understanding of leptin action on hippocampal plasticity and, more importantly, suggest that leptin resistance is a key determinant of hippocampal dysfunction associated with hypercaloric diet. PMID- 28804450 TI - Whole-Brain Mapping of the Inputs and Outputs of the Medial Part of the Olfactory Tubercle. AB - The medial part of the olfactory tubercle (OT) is a brain structure located at the interface of the reward and olfactory system. It is closely related to pheromone-rewards, natural reinforcement, addiction and many other behaviors. However, the structure of the anatomic circuitry of the medial part of the OT is still unclear. In the present study, the medial part of the OT was found to be highly connected with a wide range of brain areas with the help of the pseudorabies virus tracing tool. In order to further investigate the detailed connections for specific neurons, another tracing tool - rabies virus was utilized for D1R-cre and D2R-cre mice. The D1R and D2R neurons in the medial part of the OT were both preferentially innervated by the olfactory areas, especially the piriform cortex, and both had similar direct input patterns. With the help of the adeno-associated virus labeling, it was found that the two subpopulations of neurons primarily innervate with the reward related brain regions, with slightly less axons projecting to the olfactory areas. Thus, the whole-brain input and output circuitry structures for specific types of neurons in the medial part of the OT were systematically investigated, and the results revealed many unique connecting features. This work could provide new insights for further study into the physiological functions of the medial part of the OT. PMID- 28804452 TI - Supervised and Unsupervised Learning Technology in the Study of Rodent Behavior. AB - Quantifying behavior is a challenge for scientists studying neuroscience, ethology, psychology, pathology, etc. Until now, behavior was mostly considered as qualitative descriptions of postures or labor intensive counting of bouts of individual movements. Many prominent behavioral scientists conducted studies describing postures of mice and rats, depicting step by step eating, grooming, courting, and other behaviors. Automated video assessment technologies permit scientists to quantify daily behavioral patterns/routines, social interactions, and postural changes in an unbiased manner. Here, we extensively reviewed published research on the topic of the structural blocks of behavior and proposed a structure of behavior based on the latest publications. We discuss the importance of defining a clear structure of behavior to allow professionals to write viable algorithms. We presented a discussion of technologies that are used in automated video assessment of behavior in mice and rats. We considered advantages and limitations of supervised and unsupervised learning. We presented the latest scientific discoveries that were made using automated video assessment. In conclusion, we proposed that the automated quantitative approach to evaluating animal behavior is the future of understanding the effect of brain signaling, pathologies, genetic content, and environment on behavior. PMID- 28804451 TI - Behavioral Changes Over Time Following Ayahuasca Exposure in Zebrafish. AB - The combined infusion of Banisteriopsis caapi stem and Psychotria viridis leaves, known as ayahuasca, has been used for centuries by indigenous tribes. The infusion is rich in N, N-dimethyltryptamine (DMT) and monoamine oxidase inhibitors, with properties similar to those of serotonin. Despite substantial progress in the development of new drugs to treat anxiety and depression, current treatments have several limitations. Alternative drugs, such as ayahuasca, may shed light on these disorders. Here, we present time-course behavioral changes induced by ayahuasca in zebrafish, as first step toward establishing an ideal concentration for pre-clinical evaluations. We exposed adult zebrafish to five concentrations of the ayahuasca infusion: 0 (control), 0.1, 0.5, 1, and 3 ml/L (n = 14 each group), and behavior was recorded for 60 min. We evaluated swimming speed, distance traveled, freezing and bottom dwelling every min for 60 min. Swimming speed and distance traveled decreased with an increase in ayahuasca concentration while freezing increased with 1 and 3 ml/L. Bottom dwelling increased with 1 and 3 ml/L, but declined with 0.1 ml/L. Our data suggest that small amounts of ayahuasca do not affect locomotion and reduce anxiety-like behavior in zebrafish, while increased doses of the drug lead to crescent anxiogenic effects. We conclude that the temporal analysis of zebrafish behavior is a sensitive method for the study of ayahuasca-induced functional changes in the vertebrate brain. PMID- 28804453 TI - Delta Power Is Higher and More Symmetrical in Ischemic Stroke Patients with Cortical Involvement. AB - A brain injury resulting from unilateral stroke critically alters brain functionality and the complex balance within the cortical activity. Such modifications may critically depend on lesion location and cortical involvement. Indeed, recent findings pointed out the necessity of applying a stratification based on lesion location when investigating inter-hemispheric balance in stroke. Here, we tested whether cortical involvement could imply differences in band specific activity and brain symmetry in post stroke patients with cortico subcortical and subcortical strokes. We explored brain activity related to lesion location through EEG power analysis and quantitative Electroencephalography (qEEG) measures. Thirty stroke patients in the subacute phase and 10 neurologically intact age-matched right-handed subjects were enrolled. Stroke patients were equally subdivided in two groups based on lesion location: cortico subcortical (CS, mean age +/- SD: 72.21 +/- 10.97 years; time since stroke +/- SD: 31.14 +/- 11.73 days) and subcortical (S, mean age +/- SD: 68.92 +/- 10.001 years; time since stroke +/- SD: 26.93 +/- 13.08 days) group. We assessed patients' neurological status by means of National Institutes of Health Stroke Scale (NIHSS). High density EEG at rest was recorded and power spectral analysis in Delta (1-4 Hz) and Alpha (8-14 Hz) bands was performed. qEEG metrics as pairwise derived Brain Symmetry Index (pdBSI) and Delta/Alpha Ratio (DAR) were computed and correlated with NIHSS score. S showed a lower Delta power in the Unaffected Hemisphere (UH) compared to Affected Hemisphere (AH; z = -1.98, p < 0.05) and a higher Alpha power compared to CS (z = -2.18, p < 0.05). pdBSI was negatively correlated with NIHSS (R = -0.59, p < 0.05). CS showed a higher value and symmetrical distribution of Delta band activity (z = -2.37, p < 0.05), confirmed also by a higher DAR value compared to S (z = -2.48, p < 0.05). Patients with cortico-subcortical and subcortical lesions show different brain symmetry in the subacute phase. Interestingly, in subcortical stroke patient brain activity is related with the clinical function. qEEG measures can be explicative of brain activity related to lesion location and they could allow precise definition of diagnostic-therapeutic algorithms in stroke patients. PMID- 28804454 TI - An Evaluation of the Design and Usability of a Novel Robotic Bilateral Arm Rehabilitation Device for Patients with Stroke. AB - STUDY DESIGN: Case series. EVIDENCE LEVEL: IV (case series). INTRODUCTION: Robot assisted therapy for upper limb rehabilitation is an emerging research topic and its design process must integrate engineering, neurological pathophysiology, and clinical needs. PURPOSE OF THE STUDY: This study developed/evaluated the usefulness of a novel rehabilitation device, the MirrorPath, designed for the upper limb rehabilitation of patients with hemiplegic stroke. METHODS: The process follows Tseng's methodology for innovative product design and development, namely two stages, device development and usability assessment. During the development process, the design was guided by patients' rehabilitation needs as defined by patients and their therapists. The design applied synchronic movement of the bilateral upper limbs, an approach that is compatible with the bilateral movement therapy and proprioceptive neuromuscular facilitation theories. MirrorPath consists of a robotic device that guides upper limb movement linked to a control module containing software controlling the robotic movement. RESULTS: Five healthy subjects were recruited in the pretest, and 4 patients, 4 caregivers, and 4 therapists were recruited in the formal test for usability. All recruited subjects were allocated to the test group, completed the evaluation, and their data were all analyzed. The total system usability scale score obtained from the patients, caregivers, and therapists was 71.8 +/- 11.9, indicating a high level of usability and product acceptance. DISCUSSION AND CONCLUSION: Following a standard development process, we could yield a design that meets clinical needs. This low-cost device provides a feasible platform for carrying out robot-assisted bilateral movement therapy of patients with hemiplegic stroke. CLINICAL TRIAL REGISTRATION: identifier NCT02698605. PMID- 28804455 TI - Comparison of the Long-Term Effect of Positioning the Cathode in tDCS in Tinnitus Patients. AB - Objective: Transcranial direct current stimulation (tDCS) is one of the methods described in the literature to decrease the perceived loudness and distress caused by tinnitus. However, the main effect is not clear and the number of responders to the treatment is variable. The objective of the present study was to investigate the effect of the placement of the cathode on the outcome measurements. Methods: Patients considered for the trial were chronic non pulsatile tinnitus patients with complaints for more than 3 months and a Tinnitus Functional Index (TFI) score that exceeded 25. The anode was placed on the right dorsolateral prefrontal cortex (DLPFC). In the first group-"bifrontal"-the cathode was placed on the left DLPFC, while in the second group-"shoulder"-the cathode was placed on the shoulder. Each patient received two sessions of tDCS weekly and eight sessions in total. Evaluations took place on the first visit for an ENT consultation, at the start of therapy, after eight sessions of tDCS and at the follow-up visit, which took place 84 days after the start of the therapy. Subjective outcome measures such as TFI, Visual Analog Scales (VAS) for loudness and percentage of consciousness of tinnitus were administered in every patient. Results: There was no difference in the results for tinnitus loudness and the distress experienced between the placement of the cathode on the left DLPFC or on the shoulder. In addition, no statistically significant overall effect was found between the four test points. However, up to 39.1% of the patients experienced a decrease in loudness, measured by the VAS for loudness. Moreover, 72% of those in the bifrontal group, but only 46.2% of those in the shoulder group reported some improvement in distress. Conclusion: While some improvement was noted, this was not statistically significant. Both electrode placements stimulated the right side of the hippocampus, which could be responsible for the effect found in both groups. Further research should rule out the placebo effect and investigate alternative electrode positions. PMID- 28804457 TI - Association between Hypometabolism in the Supplementary Motor Area and Fear of Falling in Older Adults. AB - Background: A better understanding of the neural mechanisms that underlie the development of fear of falling (FoF) in seniors may help to detect potential treatable factors and reduce future falls. We therefore investigate the neural correlates of FoF in older adults using 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET). Methods: This cohort study included 117 community-dwelling older adults. At baseline, participants were assessed for FoF, psychiatric symptoms, walking speed, global cognition and cerebral glucose metabolism with FDG-PET. The incidence of FoF in the participants who did not report FoF (N-FoF) at baseline was again ascertained 2 years later. FDG uptake was compared between the FoF and non-FoF groups. Logistic regression analyses to examine the predictors of newly developed FoF (D-FoF) using normalized regional FDG uptake were then performed. Results: At baseline, 50.4% (n = 59) of participants had FoF. The FoF group had significantly decreased glucose metabolism in the left superior frontal gyrus (supplementary motor area, SMA; BA6) compared to the non FoF group. After 2 years, 19 out of the 58 participants in the non-FoF group developed FoF. Logistic regression analysis revealed that decreased cerebral glucose metabolism in the left SMA at the baseline was a significant predictor of the future development of FoF, independently of psychiatric symptoms and walking speed. Conclusion: In healthy older adults, hypometabolism in the left SMA, which is involved in motor planning and motor coordination, contributes to the development of FoF. Our result might help elucidate underlying mechanism of the association between deficits in motor control and FoF. PMID- 28804456 TI - Lessons Learned about Neurodegeneration from Microglia and Monocyte Depletion Studies. AB - While bone marrow-derived Ly6Chi monocytes can infiltrate the central nervous system (CNS) they are developmentally and functionally distinct from resident microglia. Our understanding of the relative importance of these two populations in the distinct processes of pathogenesis and resolution of inflammation during neurodegenerative disorders was limited by a lack of tools to specifically manipulate each cell type. During recent years, the development of experimental cell-specific depletion models has enabled this issue to be addressed. Herein we compare and contrast the different depletion approaches that have been used, focusing on the respective functionalities of microglia and monocyte-derived macrophages in a range of neurodegenerative disease states, and discuss their prospects for immunotherapy. PMID- 28804458 TI - Induced Pluripotent Stem Cells-Derived Mesenchymal Stem Cells Attenuate Cigarette Smoke-Induced Cardiac Remodeling and Dysfunction. AB - The strong relationship between cigarette smoking and cardiovascular disease (CVD) has been well-documented, but the mechanisms by which smoking increases CVD risk appear to be multifactorial and incompletely understood. Mesenchymal stem cells (MSCs) are regarded as an important candidate for cell-based therapy in CVD. We hypothesized that MSCs derived from induced pluripotent stem cell (iPSC MSCs) or bone marrow (BM-MSCs) might alleviate cigarette smoke (CS)-induced cardiac injury. This study aimed to investigate the effects of BM-MSCs or iPSC MSCs on CS-induced changes in serum and cardiac lipid profiles, oxidative stress and inflammation as well as cardiac function in a rat model of passive smoking. Male Sprague-Dawley rats were randomly selected for exposure to either sham air (SA) as control or 4% CS for 1 h per day for 56 days. On day 29 and 43, human adult BM-MSCs, iPSC-MSCs or PBS were administered intravenously to CS-exposed rats. Results from echocardiography, serum and cardiac lipid profiles, cardiac antioxidant capacity, cardiac pro- and anti-inflammatory cytokines and cardiac morphological changes were evaluated at the end of treatment. iPSC-MSC-treated group showed a greater effect in the improvement of CS-induced cardiac dysfunction over BM-MSCs-treated group as shown by increased percentage left ventricular ejection fraction and percentage fractional shortening, in line with the greater reversal of cardiac lipid abnormality. In addition, iPSC-MSCs administration attenuated CS-induced elevation of cardiac pro-inflammatory cytokines as well as restoration of anti-inflammatory cytokines and anti oxidative markers, leading to ameliorate cardiac morphological abnormalities. These data suggest that iPSC-MSCs on one hand may restore CS-induced cardiac lipid abnormality and on the other hand may attenuate cardiac oxidative stress and inflammation via inhibition of CS-induced NF-kappaB activation, leading to improvement of cardiac remodeling and dysfunction. Thus, iPSC-MSCs may be a promising candidate in cell-based therapy to prevent cardiac complications in smokers. PMID- 28804459 TI - Metabolic Variability of a Multispecies Probiotic Preparation Impacts on the Anti inflammatory Activity. AB - Background: In addition to strain taxonomy, the ability of probiotics to confer beneficial effects on the host rely on a number of additional factors including epigenetic modulation of bacterial genes leading to metabolic variability and might impact on probiotic functionality. Aims: To investigate metabolism and functionality of two different batches of a probiotic blend commercialized under the same name in Europe in models of intestinal inflammation. Methods: Boxes of VSL#3, a probiotic mixture used in the treatment of pouchitis, were obtained from pharmacies in UK subjected to metabolomic analysis and their functionality tested in mice rendered colitis by treatment with DSS or TNBS. Results: VSL#3-A (lot DM538), but not VSL#3-B (lot 507132), attenuated "clinical" signs of colitis in the DSS and TNBS models. In both models, VSL#3-A, but not VSL#3-B, reduced macroscopic scores, intestinal permeability, and expression of TNFalpha, IL 1beta, and IL-6 mRNAs, while increased the expression of TGFbeta and IL-10, occludin, and zonula occludens-1 (ZO-1) mRNAs and shifted colonic macrophages from a M1 to M2 phenotype (P < 0.05 vs. TNBS). In contrast, VSL#3-B failed to reduce inflammation, and worsened intestinal permeability in the DSS model (P < 0.001 vs. VSL#3-A). A metabolomic analysis of the two formulations allowed the identification of two specific patterns, with at least three-folds enrichment in the concentrations of four metabolites, including 1-3 dihydroxyacetone (DHA), an intermediate in the fructose metabolism, in VSL#3-B supernatants. Feeding mice with DHA, increased intestinal permeability. Conclusions: Two batches of a commercially available probiotic show divergent metabolic activities. DHA, a product of probiotic metabolism, increases intestinal permeability, highlighting the complex interactions between food, microbiota, probiotics, and intestinal inflammation. PMID- 28804460 TI - Editorial: Systems Biology and the Challenge of Deciphering the Metabolic Mechanisms Underlying Cancer. PMID- 28804461 TI - The Effect of Resistance Exercise on Inflammatory and Myogenic Markers in Patients with Chronic Kidney Disease. AB - Background: Muscle wasting is a common complication of Chronic Kidney Disease (CKD) and is clinically important given its strong association with morbidity and mortality in many other chronic conditions. Exercise provides physiological benefits for CKD patients, however the molecular response to exercise remains to be fully determined. We investigated the inflammatory and molecular response to resistance exercise before and after training in these patients. Methods: This is a secondary analysis of a randomized trial that investigated the effect of 8 week progressive resistance training on muscle mass and strength compared to non exercising controls. A sub-set of the cohort consented to vastus lateralis skeletal muscle biopsies (n = 10 exercise, n = 7 control) in which the inflammatory response (IL-6, IL-15, MCP-1 TNF-alpha), myogenic (MyoD, myogenin, myostatin), anabolic (P-Akt, P-eEf2) and catabolic events (MuRF-1, MAFbx, 14 kDa, ubiquitin conjugates) and overall levels of oxidative stress have been studied. Results: A large inflammatory response to unaccustomed exercise was seen with IL 6, MCP-1, and TNF-alpha all significantly elevated from baseline by 53-fold (P < 0.001), 25-fold (P < 0.001), and 4-fold (P < 0.001), respectively. This response was reduced following training with IL-6, MCP-1, and TNF-alpha elevated non significantly by 2-fold (P = 0.46), 2.4-fold (P = 0.19), and 2.5-fold (P = 0.06), respectively. In the untrained condition, an acute bout of resistance exercise did not result in increased phosphorylation of Akt (P = 0.84), but this was restored following training (P = 0.01). Neither unaccustomed nor accustomed exercise resulted in a change in myogenin or MyoD mRNA expression (P = 0.88, P = 0.90, respectively). There was no evidence that resistance exercise training created a prolonged oxidative stress response within the muscle, or increased catabolism. Conclusions: Unaccustomed exercise creates a large inflammatory response within the muscle, which is no longer present following a period of training. This indicates that resistance exercise does not provoke a detrimental on-going inflammatory response within the muscle. PMID- 28804462 TI - Heat Acclimation-Mediated Cross-Tolerance: Origins in within-Life Epigenetics? AB - The primary outcome of heat acclimation is increased thermotolerance, which stems from enhancement of innate cytoprotective pathways. These pathways produce "ON CALL" molecules that can combat stressors to which the body has never been exposed, via cross-tolerance mechanisms (heat acclimation-mediated cross tolerance-HACT). The foundation of HACT lies in the sharing of generic stress signaling, combined with tissue/organ- specific protective responses. HACT becomes apparent when acclimatory homeostasis is achieved, lasts for several weeks, and has a memory. HACT differs from other forms of temporal protective mechanisms activated by exposure to lower "doses" of the stressor, which induce adaptation to higher "doses" of the same/different stressor; e.g., preconditioning, hormesis. These terms have been adopted by biochemists, toxicologists, and physiologists to describe the rapid cellular strategies ensuring homeostasis. HACT employs two major protective avenues: constitutive injury attenuation and abrupt post-insult release of help signals enhanced by acclimation. To date, the injury-attenuating features seen in all organs studied include fast-responding, enlarged cytoprotective reserves with HSPs, anti oxidative, anti-apoptotic molecules, and HIF-1alpha nuclear and mitochondrial target gene products. Using cardiac ischemia and brain hypoxia models as a guide to the broader framework of phenotypic plasticity, HACT is enabled by a metabolic shift induced by HIF-1alpha and there are less injuries caused by Ca+2 overload, via channel or complex-protein remodeling, or decreased channel abundance. Epigenetic markers such as post-translational histone modification and altered levels of chromatin modifiers during acclimation and its decline suggest that dynamic epigenetic mechanisms controlling gene expression induce HACT and acclimation memory, to enable the rapid return of the protected phenotype. In this review the link between in vivo physiological evidence and the associated cellular and molecular mechanisms leading to HACT and its difference from short acting cross-tolerance strategies will be discussed. PMID- 28804463 TI - Effect of Oral Docosahexaenoic Acid (DHA) Supplementation on DHA Levels and Omega 3 Index in Red Blood Cell Membranes of Breast Cancer Patients. AB - Rationale: Docosahexaenoic acid (DHA) in cell membrane may influence breast cancer (BC) patients' prognosis, affecting tumor cells sensitivity to chemo- and radio-therapy and likely modulating inflammation. The possibility of identifying BC patients presenting with low DHA levels and/or low ability of DHA incorporation into cell membrane might help to treat this condition. Methods: We enrolled BC patients and healthy controls, recording their seafood dietary intake. DHA in form of algal oil was administered for 10 consecutive days (2 g/day). Blood samples were collected at baseline (T0) and after 10 days of supplementation (T1) to assess DHA, omega-3 index, as the sum of DHA + eicosapentaenoic acid (EPA), in red blood cells (RBC) membranes and plasma tumor necrosis factor-alpha and interleukin-6 levels. Pre- and post-treatment fatty acid profiles were obtained by gas-chromatography. Parametric and non-parametric tests were performed, as appropriate, and P-value < 0.05 was considered statistically significant. Results: Forty-three women were studied, divided into 4 groups: 11 patients with BRCA1/2 gene mutation (M group), 12 patients with familiar positive history for BC (F group), 10 patients with sporadic BC (S group), and 10 healthy controls (C group). DHA and omega-3 index increased from T0 to T1 in the 3 groups of BC patients and in controls (P < 0.001). No difference was found in DHA incorporation between each group of BC patients and between patients and controls, except for M group, which incorporated higher DHA levels with respect to controls (beta = 0.42; P = 0.03). No association was documented between cytokines levels and DHA and omega-3 index at baseline and after DHA supplementation. Independent of the presence of BC, women considered as "good seafood consumers" showed at baseline DHA and omega-3 index higher with respect to "low seafood consumers" (P = 0.04; P = 0.007, respectively). After supplementation, the increase in DHA levels was greater in "low seafood consumers" with respect to "good seafood consumers" (P < 0.0001). Conclusion: DHA supplementation was associated with increased DHA levels and omega-3 index in RBC membranes of BC cancer patients, independent of the type of BC presentation, and in controls. BRCA1/2 mutation, as well as low seafood consuming habits in both BC patients and healthy controls, seem to be associated with greater ability of DHA incorporation. Larger samples of BC patients are necessary to confirm our observation. PMID- 28804464 TI - Retinal Vascular Autoregulation during Phase IV of the Valsalva Maneuver: An Optical Coherence Tomography Angiography Study in Healthy Chinese Adults. AB - The impairment of retinal vascular autoregulation can be an early manifestation of many systemic and ocular diseases. Therefore, quantifying retinal vascular autoregulation in a non-invasive manner is very important. This study evaluated the effects of a Valsalva maneuver (VM)-induced blood pressure increases on retinal vascular autoregulation. Parafoveal and peripapillary retinal vessel density were measured with optical coherence tomography angiography before (baseline) and 5 s after each subject completed a VM (Phase IV [VM-IV]). Hemodynamic parameters and intraocular pressure (IOP) were examined. Blood pressure (systolic, diastolic, and mean arterial) and ocular perfusion pressure significantly increased during VM-IV, but IOP and heart rate (HR) did not change. The VM-induced blood pressure overshoot significantly decreased parafoveal (8.43%) and peripapillary (1.57%) perfused retinal vessel density (both P < 0.001). The response in the parafoveal region was greater than that in the peripapillary region (P < 0.001), and was age-dependent (r = 0.201, P < 0.05). Foveal avascular zone area detectable with OCTA significantly increased from baseline by 6.63% during VM-IV (P < 0.05). Autoregulatory responses to a VM did not show gender-related differences in either retinal region. The autoregulation of retinal vessels may vary in different regions of the fundus. Optical coherence tomography angiography could be a useful method for evaluating the autoregulation of the retinal vascular system. PMID- 28804465 TI - Personality Traits Related to Binge Drinking: A Systematic Review. AB - The pattern of alcohol consumption in the form of binge drinking (BD) or heavy episodic drinking has increased notably worldwide in recent years, especially among adolescent and young people, being currently recognized as a global health problem. Although only a minority of binge drinkers will develop a substance use disorder, BD may have negative personal and social consequences in the short and medium term. The objective of this article is to review the findings on personality traits related to binge drinkers and to emphasize the aspects that should be examined in order to make progress in this area. The main characteristics of personality related to the practice of BD, regardless of the theoretical model used, are high Impulsivity and high Sensation seeking, as well as Anxiety sensitivity, Neuroticism (Hopelessness), Extraversion and low Conscientiousness. The data obtained may have theoretical implications to elucidate the endophenotype of BD, but they are especially useful for their preventive applications. Integration into prevention programs of emotional self control skills, decision-making, social skills, and strategies to manage negative emotions will minimize the risk factors or consequences of BD associated with personality and will improve their effectiveness. In the future, it is necessary to harmonize a common measurement instrument for the assessment of personality, develop longitudinal studies with large samples that also integrate biological and neurocognitive measurements, and determine the reciprocal relationship between personality and BD together with its modulating variables, as well as the possible cultural differences. PMID- 28804466 TI - Interpersonal Movement Synchrony Responds to High- and Low-Level Conversational Constraints. AB - Much work on communication and joint action conceptualizes interaction as a dynamical system. Under this view, dynamic properties of interaction should be shaped by the context in which the interaction is taking place. Here we explore interpersonal movement coordination or synchrony-the degree to which individuals move in similar ways over time-as one such context-sensitive property. Studies of coordination have typically investigated how these dynamics are influenced by either high-level constraints (i.e., slow-changing factors) or low-level constraints (i.e., fast-changing factors like movement). Focusing on nonverbal communication behaviors during naturalistic conversation, we analyzed how interacting participants' head movement dynamics were shaped simultaneously by high-level constraints (i.e., conversation type; friendly conversations vs. arguments) and low-level constraints (i.e., perceptual stimuli; non-informative visual stimuli vs. informative visual stimuli). We found that high- and low-level constraints interacted non-additively to affect interpersonal movement dynamics, highlighting the context sensitivity of interaction and supporting the view of joint action as a complex adaptive system. PMID- 28804467 TI - Learning about Expectation Violation from Prediction Error Paradigms - A Meta Analysis on Brain Processes Following a Prediction Error. AB - Modifying patients' expectations by exposing them to expectation violation situations (thus maximizing the difference between the expected and the actual situational outcome) is proposed to be a crucial mechanism for therapeutic success for a variety of different mental disorders. However, clinical observations suggest that patients often maintain their expectations regardless of experiences contradicting their expectations. It remains unclear which information processing mechanisms lead to modification or persistence of patients' expectations. Insight in the processing could be provided by Neuroimaging studies investigating prediction error (PE, i.e., neuronal reactions to non-expected stimuli). Two methods are often used to investigate the PE: (1) paradigms, in which participants passively observe PEs ("passive" paradigms) and (2) paradigms, which encourage a behavioral adaptation following a PE ("active" paradigms). These paradigms are similar to the methods used to induce expectation violations in clinical settings: (1) the confrontation with an expectation violation situation and (2) an enhanced confrontation in which the patient actively challenges his expectation. We used this similarity to gain insight in the different neuronal processing of the two PE paradigms. We performed a meta analysis contrasting neuronal activity of PE paradigms encouraging a behavioral adaptation following a PE and paradigms enforcing passiveness following a PE. We found more neuronal activity in the striatum, the insula and the fusiform gyrus in studies encouraging behavioral adaptation following a PE. Due to the involvement of reward assessment and avoidance learning associated with the striatum and the insula we propose that the deliberate execution of action alternatives following a PE is associated with the integration of new information into previously existing expectations, therefore leading to an expectation change. While further research is needed to directly assess expectations of participants, this study provides new insights into the information processing mechanisms following an expectation violation. PMID- 28804468 TI - Individual Difference Factors in the Learning and Transfer of Patterning Discriminations. AB - In an associative patterning task, some people seem to focus more on learning an overarching rule, whereas others seem to focus on acquiring specific relations between the stimuli and outcomes involved. Building on earlier work, we further investigated which cognitive factors are involved in feature- vs. rule-based learning and generalization. To this end, we measured participants' tendency to generalize according to the rule of opposites after training on negative and positive patterning problems (i.e., A+/B+/AB- and C-/D-/CD+), their tendency to attend to global aspects or local details of stimuli, their systemizing disposition and their score on the Raven intelligence test. Our results suggest that while intelligence might have some influence on patterning learning and generalization, visual processing style and systemizing disposition do not. We discuss our findings in the light of previous observations on patterning. PMID- 28804469 TI - Longitudinal Relationships between Social Support and Posttraumatic Growth among Adolescent Survivors of the Wenchuan Earthquake. AB - This study aimed to explore the longitudinal relationships between social support and posttraumatic growth (PTG) among adolescent survivors of the Wenchuan earthquake. Follow-up assessments were conducted with 452 participants at 12, 18, and 24 months after the earthquake. The results showed that the level of social support at 12 and 18 months following the earthquake predicted subsequent PTG, but not vice versa. In addition, multi-group analyses of gender showed no gender differences between social support and PTG in the cross-lagged model. Thus, psychological interventions and care for survivors should focus on improving adolescent perceptions of social support when responding to stressful experiences. PMID- 28804470 TI - Evaluating Fit Indices for Multivariate t-Based Structural Equation Modeling with Data Contamination. AB - In conventional structural equation modeling (SEM), with the presence of even a tiny amount of data contamination due to outliers or influential observations, normal-theory maximum likelihood (ML-Normal) is not efficient and can be severely biased. The multivariate-t-based SEM, which recently got implemented in Mplus as an approach for mixture modeling, represents a robust estimation alternative to downweigh the impact of outliers and influential observations. To our knowledge, the use of maximum likelihood estimation with a multivariate-t model (ML-t) to handle outliers has not been shown in SEM literature. In this paper we demonstrate the use of ML-t using the classic Holzinger and Swineford (1939) data set with a few observations modified as outliers or influential observations. A simulation study is then conducted to examine the performance of fit indices and information criteria under ML-Normal and ML-t in the presence of outliers. Results showed that whereas all fit indices got worse for ML-Normal with increasing amount of outliers and influential observations, their values were relatively stable with ML-t, and the use of information criteria was effective in selecting ML-normal without data contamination and selecting ML-t with data contamination, especially when the sample size was at least 200. PMID- 28804471 TI - CAHOST: An Excel Workbook for Facilitating the Johnson-Neyman Technique for Two Way Interactions in Multiple Regression. AB - When using multiple regression, researchers frequently wish to explore how the relationship between two variables is moderated by another variable; this is termed an interaction. Historically, two approaches have been used to probe interactions: the pick-a-point approach and the Johnson-Neyman (JN) technique. The pick-a-point approach has limitations that can be avoided using the JN technique. Currently, the software available for implementing the JN technique and creating corresponding figures lacks several desirable features-most notably, ease of use and figure quality. To fill this gap in the literature, we offer a free Microsoft Excel 2013 workbook, CAHOST (a concatenation of the first two letters of the authors' last names), that allows the user to seamlessly create publication-ready figures of the results of the JN technique. PMID- 28804472 TI - Editorial: Impression Management and Faking in Job Interviews. PMID- 28804473 TI - Confirmatory Factor Analysis of the French Version of the Anticipatory and Consummatory Interpersonal Pleasure Scale. AB - The Anticipatory and Consummatory Interpersonal Pleasure Scale (ACIPS), a measure specifically designed to assess hedonic capacity for social and interpersonal pleasure, was used to evaluate the presence of social anhedonia in patients as well as the general population. The first goal of this study was to validate the structure of the French version of the ACIPS. The second objective was to verify whether a one, two or three factor solution is most appropriate for the ACIPS scale. The French version of the ACIPS was tested on 263 French-speaking pre graduate students or professional volunteers. For the confirmatory factor analysis, data were treated as categorical ordinal and all the models were estimated using a robust weighted least squares estimator with adjustments for the mean and variance. Three models were estimated. A one-factor model representing a general undifferentiated "pleasure" latent construct was first tested on the 17 ACIPS items. A two-factor model distinguishing anticipatory pleasure and consummatory-pleasure was tested next. Finally, a three-factor model including subdomains of intimate social interactions, group social interactions, and social bonding was tested. The one and two-factor models showed a somewhat poor fit to the data. However, the goodness of fit of the three factor model was adequate. These results suggest that individuals who enjoyed interaction in one of these three subdomains were more likely to enjoy doing so in the two other domains. However, on the basis of the comparison between the one and three factor models, these three types of interactions may not be considered as indistinguishable. Rather, they represent distinct and theoretically meaningful dimensions. These results show the French version of the ACIPS is a useful and valid scale to measure the capacity of savoring different kinds of social relationships. PMID- 28804474 TI - A Longitudinal Electromyography Study of Complex Movements in Poststroke Therapy. 1: Heterogeneous Changes Despite Consistent Improvements in Clinical Assessments. AB - Poststroke weakness on the more-affected side may arise from reduced corticospinal drive, disuse muscle atrophy, spasticity, and abnormal coordination. This study investigated changes in muscle activation patterns to understand therapy-induced improvements in motor-function in chronic stroke compared to clinical assessments and to identify the effect of motor-function level on muscle activation changes. Electromyography (EMG) was recorded from five upper limb muscles on the more-affected side of 24 patients during early and late therapy sessions of an intensive 14-day program of Wii-based Movement Therapy (WMT) and for a subset of 13 patients at 6-month follow-up. Patients were classified according to residual voluntary motor capacity with low, moderate, or high motor-function levels. The area under the curve was calculated from EMG amplitude and movement duration. Clinical assessments of upper limb motor function pre- and post-therapy included the Wolf Motor Function Test, Fugl-Meyer Assessment and Motor Activity Log Quality of Movement scale. Clinical assessments improved over time (p < 0.01) with an effect of motor-function level (p < 0.001). The pattern of EMG change by late therapy was complex and variable, with differences between patients with low compared to moderate or high motor-function levels. The area under the curve (p = 0.028) and peak amplitude (p = 0.043) during Wii-tennis backhand increased for patients with low motor-function, whereas EMG decreased for patients with moderate and high motor-function levels. The reductions included movement duration during Wii-golf (p = 0.048, moderate; p = 0.026, high) and Wii-tennis backhand (p = 0.046, moderate; p = 0.023, high) and forehand (p = 0.009, high) and the area under the curve during Wii-golf (p = 0.018, moderate) and Wii-baseball (p = 0.036, moderate). For the pooled data over time, there was an effect of motor-function (p = 0.016) and an interaction between time and motor-function (p = 0.009) for Wii-golf movement duration. Wii baseball movement duration decreased as a function of time (p = 0.022). There was an effect on Wii-tennis forehand duration for time (p = 0.002), an interaction of time and motor-function (p = 0.005) and an effect of motor-function level on the area under the curve (p = 0.034) for Wii-golf. This study demonstrated different patterns of EMG changes according to residual voluntary motor-function levels, despite heterogeneity within each level that was not evident following clinical assessments alone. Thus, rehabilitation efficacy might be underestimated by analyses of pooled data. PMID- 28804475 TI - Midterm Blood Pressure Variability Is Associated with Poststroke Cognitive Impairment: A Prospective Cohort Study. AB - OBJECTIVE: The aim of this study was to investigate the relationship between blood pressure variability (BPV) and poststroke cognitive impairment (PSCI). METHODS: Seven-hundred ninety-six patients with acute ischemic stroke were included in this study. Midterm BPV was evaluated by calculating the SD and coefficient of variation (CV, 100 * SD/mean) of systolic blood pressure (SBP) and diastolic blood pressure during the 7 days after stroke onset. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) at admission and at all follow-up visits. Patients with MoCA scores <26 were considered to have PSCI. RESULTS: The incidence of PSCI reached its peak (72%) 3 months after stroke onset and decreased to 30.3% at 12 months poststroke. After adjusting for covariables, the increase in the prevalence of PSCI at 3 months was independently associated with increases in the CV of blood pressure during the 7 days after stroke [odds ratios and 95% CI for patients in the second to fifth quintiles of SBP CV were 2.28 (1.18, 4.39), 2.33 (1.18, 4.62), 2.69 (1.31, 5.53), and 4.76 (1.95, 11.67), respectively]. Sub-analysis of the MoCA scores revealed that the patients had impairments in visuoperceptual abilities and executive functions, as well as in naming and delayed recall (p < 0.05). CONCLUSION: Midterm BPV during the early phase of acute ischemic stroke is independently associated with PSCI, especially in the visuoperceptual, executive, and delayed recall domains. CLINICAL TRIAL REGISTRATION: http://www.chictr.org.cn, identifier ChiCTR-TRC-14004804. PMID- 28804476 TI - Wood Ash Induced pH Changes Strongly Affect Soil Bacterial Numbers and Community Composition. AB - Recirculation of wood ash from energy production to forest soil improves the sustainability of this energy production form as recycled wood ash contains nutrients that otherwise would be lost at harvest. In addition, wood-ash is beneficial to many soils due to its inherent acid-neutralizing capabilities. However, wood ash has several ecosystem-perturbing effects like increased soil pH and pore water electrical conductivity both known to strongly impact soil bacterial numbers and community composition. Studies investigating soil bacterial community responses to wood ash application remain sparse and the available results are ambiguous and remain at a general taxonomic level. Here we investigate the response of bacterial communities in a spruce forest soil to wood ash addition corresponding to 0, 5, 22, and 167 t wood ash ha-1. We used culture based enumerations of general bacteria, Pseudomonas and sporeforming bacteria combined with 16S rRNA gene amplicon sequencing to valuate soil bacterial responses to wood ash application. Results showed that wood ash addition strongly increased soil pH and electrical conductivity. Soil pH increased from acidic through neutral at 22 t ha-1 to alkaline at 167 t ha-1. Bacterial numbers significantly increased up to a wood ash dose of 22 t ha-1 followed by significant decrease at 167 t ha-1 wood ash. The soil bacterial community composition changed after wood ash application with copiotrophic bacteria responding positively up to a wood ash dose of 22 t ha-1 while the adverse effect was seen for oligotrophic bacteria. Marked changes in bacterial community composition occurred at a wood ash dose of 167 t ha-1 with a single alkaliphilic genus dominating. Additionally, spore-formers became abundant at an ash dose of 167 t ha-1 whereas this was not the case at lower ash doses. Lastly, bacterial richness and diversity strongly decreased with increasing amount of wood ash applied. All of the observed bacterial responses can be directly explained by the wood ash induced changes in pH, electrical conductivity and the addition of wood ash inherent nutrients. PMID- 28804477 TI - Glaciers and Ice Sheets As Analog Environments of Potentially Habitable Icy Worlds. AB - Icy worlds in the solar system and beyond have attracted a remarkable attention as possible habitats for life. The current consideration about whether life exists beyond Earth is based on our knowledge of life in terrestrial cold environments. On Earth, glaciers and ice sheets have been considered uninhabited for a long time as they seemed too hostile to harbor life. However, these environments are unique biomes dominated by microbial communities which maintain active biochemical routes. Thanks to techniques such as microscopy and more recently DNA sequencing methods, a great biodiversity of prokaryote and eukaryote microorganisms have been discovered. These microorganisms are adapted to a harsh environment, in which the most extreme features are the lack of liquid water, extremely cold temperatures, high solar radiation and nutrient shortage. Here we compare the environmental characteristics of icy worlds, and the environmental characteristics of terrestrial glaciers and ice sheets in order to address some interesting questions: (i) which are the characteristics of habitability known for the frozen worlds, and which could be compatible with life, (ii) what are the environmental characteristics of terrestrial glaciers and ice sheets that can be life-limiting, (iii) What are the microbial communities of prokaryotic and eukaryotic microorganisms that can live in them, and (iv) taking into account these observations, could any of these planets or satellites meet the conditions of habitability? In this review, the icy worlds are considered from the point of view of astrobiological exploration. With the aim of determining whether icy worlds could be potentially habitable, they have been compared with the environmental features of glaciers and ice sheets on Earth. We also reviewed some field and laboratory investigations about microorganisms that live in analog environments of icy worlds, where they are not only viable but also metabolically active. PMID- 28804478 TI - The Entomopathogenic Fungi Isaria fumosorosea Plays a Vital Role in Suppressing the Immune System of Plutella xylostella: RNA-Seq and DGE Analysis of Immunity Related Genes. AB - Most, if not all, entomopathogenic fungi have been used as alternative control agents to decrease the insect resistance and harmful effects of the insecticides on the environment. Among them, Isaria fumosorosea has also shown great potential to control different insect pests. In the present study, we explored the immune response of P. xylostella to the infection of I. fumosorosea at different time points by using RNA-Sequencing and differential gene expression technology at the genomic level. To gain insight into the host-pathogen interaction at the genomic level, five libraries of P. xylostella larvae at 12, 18, 24, and 36 h post infection and a control were constructed. In total, 161 immunity-related genes were identified and grouped into four categories; immune recognition families, toll and Imd pathway, melanization, and antimicrobial peptides (AMPs). The results of differentially expressed immunity-related genes depicted that 15, 13, 53, and 14 up-regulated and 38, 51, 56, and 49 were down-regulated in P. xylostella at 12, 18, 24, and 36 h post-treatment, respectively. RNA-Seq results of immunity-related genes revealed that the expression of AMPs was reduced after treatment with I. fumosorosea. To validate RNA-Seq results by RT-qPCR, 22 immunity-related genes were randomly selected. In conclusion, our results demonstrate that I. fumosorosea has the potential to suppress the immune response of P. xylostella and can become a potential biopesticide for controlling P. xylostella. PMID- 28804479 TI - Molecular Characterization of Arbuscular Mycorrhizal Fungi in an Agroforestry System Reveals the Predominance of Funneliformis spp. Associated with Colocasia esculenta and Pterocarpus officinalis Adult Trees and Seedlings. AB - Pterocarpus officinalis (Jacq.) is a leguminous forestry tree species endemic to Caribbean swamp forests. In Guadeloupe, smallholder farmers traditionally cultivate flooded taro (Colocasia esculenta) cultures under the canopy of P. officinalis stands. The role of arbuscular mycorrhizal (AM) fungi in the sustainability of this traditional agroforestry system has been suggested but the composition and distribution of AM fungi colonizing the leguminous tree and/or taro are poorly characterized. An in-depth characterization of root-associated AM fungal communities from P. officinalis adult trees and seedlings and taro cultures, sampled in two localities of Guadeloupe, was performed by pyrosequencing (GS FLX+) of partial 18S rRNA gene. The AM fungal community was composed of 215 operational taxonomic units (OTUs), belonging to eight fungal families dominated by Glomeraceae, Acaulosporaceae, and Gigasporaceae. Results revealed a low AM fungal community membership between P. officinalis and C. esculenta. However, certain AM fungal community taxa (10% of total community) overlapped between P. officinalis and C. esculenta, notably predominant Funneliformis OTUs. These findings provide new perspectives in deciphering the significance of Funneliformis in nutrient exchange between P. officinalis and C. esculenta by forming a potential mycorrhizal network. PMID- 28804480 TI - Microbial Community Structure and the Persistence of Cyanobacterial Populations in Salt Crusts of the Hyperarid Atacama Desert from Genome-Resolved Metagenomics. AB - Although once thought to be devoid of biology, recent studies have identified salt deposits as oases for life in the hyperarid Atacama Desert. To examine spatial patterns of microbial species and key nutrient sources, we genomically characterized 26 salt crusts from three sites along a fog gradient. The communities are dominated by a large variety of Halobacteriales and Bacteroidetes, plus a few algal and Cyanobacterial species. CRISPR locus analysis suggests the distribution of a single Cyanobacterial population among all sites. This is in stark contrast to the extremely high sample specificity of most other community members. Only present at the highest moisture site is a genomically characterized Thermoplasmatales archaeon (Marine Group II) and six Nanohaloarchaea, one of which is represented by a complete genome. Parcubacteria (OD1) and Saccharibacteria (TM7), not previously reported from hypersaline environments, were found at low abundances. We found no indication of a N2 fixation pathway in the communities, suggesting acquisition of bioavailable nitrogen from atmospherically derived nitrate. Samples cluster by site based on bacterial and archaeal abundance patterns and photosynthetic capacity decreases with increasing distance from the ocean. We conclude that moisture level, controlled by coastal fog intensity, is the strongest driver of community membership. PMID- 28804481 TI - The Type VI Secretion System: A Dynamic System for Bacterial Communication? AB - Numerous studies in Gram-negative bacteria have focused on the Type VI Secretion Systems (T6SSs), Quorum Sensing (QS), and social behavior, such as in biofilms. These interconnected mechanisms are important for bacterial survival; T6SSs allow bacteria to battle other cells, QS is devoted to the perception of bacterial cell density, and biofilm formation is essentially controlled by QS. Here, we review data concerning T6SS dynamics and T6SS-QS cross-talk that suggest the existence of inter-bacterial communication via T6SSs. PMID- 28804482 TI - Risk Factors for Intensive Care Unit Admission in Patients with Autoimmune Encephalitis. AB - BACKGROUND: Prevention and early recognition of critical illness in patients with autoimmune encephalitis (AE) is essential to achieve better outcome. AIM OF THE STUDY: To evaluate risk factors for intensive care unit (ICU) admission and its prognostic impact in patients with AE. PATIENTS AND METHODS: A reclassification of patients hospitalized between 2011 and 2016 revealed 17 "definite" and 15 "probable" AE cases. Thirteen patients (41%) developed critical illness and required ICU admission. The underlying conditions were intractable seizures or status epilepticus (54%), altered mental state (39%), and respiratory failure (8%). RESULTS: ICU admission was associated with longer time from first symptoms to hospitalization (p = 0.046). Regression analysis revealed that anemia on hospital admission and definite diagnosis of AE was associated with a higher risk of acquiring critical illness. At last follow-up after a median of 31 months (range 2.5-52.4), seven patients had died (23%) and 63% had a good outcome [modified Rankin Scale (mRS) 0-3]. Anemia was associated with poor prognosis (p = 0.021), whereas development of critical illness did not impact mortality and functional outcome. CONCLUSION: We confirmed the need for ICU care in a subgroup of patients and the prevailing objective is improved seizure control, and definite diagnosis of AE and anemia were identified as risk factors for development of critical illness. However, prognosis was not affected by ICU admission. PMID- 28804484 TI - Neutrophil Extracellular Traps Open the Pandora's Box in Severe Malaria. PMID- 28804485 TI - Transcriptional Profiling of Midguts Prepared from Trypanosoma/T. congolense Positive Glossina palpalis palpalis Collected from Two Distinct Cameroonian Foci: Coordinated Signatures of the Midguts' Remodeling As T. congolense-Supportive Niches. AB - Our previous transcriptomic analysis of Glossina palpalis gambiensis experimentally infected or not with Trypanosoma brucei gambiense aimed to detect differentially expressed genes (DEGs) associated with infection. Specifically, we selected candidate genes governing tsetse fly vector competence that could be used in the context of an anti-vector strategy, to control human and/or animal trypanosomiasis. The present study aimed to verify whether gene expression in field tsetse flies (G. p. palpalis) is modified in response to natural infection by trypanosomes (T. congolense), as reported when insectary-raised flies (G. p. gambiensis) are experimentally infected with T. b. gambiense. This was achieved using the RNA-seq approach, which identified 524 DEGs in infected vs. non infected tsetse flies, including 285 downregulated genes and 239 upregulated genes (identified using DESeq2). Several of these genes were highly differentially expressed, with log2 fold change values in the vicinity of either +40 or -40. Downregulated genes were primarily involved in transcription/translation processes, whereas encoded upregulated genes governed amino acid and nucleotide biosynthesis pathways. The BioCyc metabolic pathways associated with infection also revealed that downregulated genes were mainly involved in fly immunity processes. Importantly, our study demonstrates that data on the molecular cross-talk between the host and the parasite (as well as the always present fly microbiome) recorded from an experimental biological model has a counterpart in field flies, which in turn validates the use of experimental host/parasite couples. PMID- 28804486 TI - First Association of Interleukin 12 Receptor Beta 1 Deficiency with Sjogren's Syndrome. AB - INTRODUCTION: Interleukin 12 receptor beta 1 (IL12Rbeta1) deficiency is a primary immunodeficiency resulting mainly in susceptibility to opportunistic infection by non-tuberculous, environmental mycobacteria and severe infection caused by Salmonella spp. Till now, less than 300 patients with IL12Rbeta1 deficiency have been reported. Among them, only three have been described to develop autoimmunity. CASE PRESENTATION: We present the case of a 50-year-old male with IL12Rbeta1 deficiency due to compound heterozygosity [c. 1623_1624delGCinsTT (pGln542Stop) and c.1791 + 2T > C (donor splice site)], who-18 months after diagnosis of disseminated BCGitis-presented with recurrent fever and sicca syndrome. No indication of an infectious origin of these symptoms could be found at that point. The diagnosis of a Sjogren's syndrome (SS) was made on the basis of fulfilled American-European consensus classification criteria, including a positive minor salivary gland biopsy. CONCLUSION: Apart from persistent antigenic stimulation, which may drive autoimmune inflammation in primary immunodeficiency, evidence on the involvement of interleukin 12 in pathogenesis of SS suggests that the same immunological mechanism may underlie both defense against infection and the maintenance of tolerance. To our knowledge, this is the first report of a case of autoimmunity in the form of SS in a patient with a primary immunodeficiency and one of the rare cases of IL12Rbeta1 deficiency with manifested autoimmunity. PMID- 28804487 TI - The Response of Phagocytes to Indoor Air Toxicity. AB - This perspective presents a viewpoint on potential methods assessing toxicity of indoor air. Until recently, the major techniques to document moldy environment have been microbial isolation using conventional culture techniques for fungi and bacteria as well as in some instances polymerase chain reaction to detect microbial genetic components. However, it has become increasingly evident that bacterial and fungal toxins, their metabolic products, and volatile organic substances emitted from corrupted constructions are the major health risks. Here, we illustrate how phagocytes, especially neutrophils can be used as a toxicological probe. Neutrophils can be used either in vitro as probe cells, directly exposed to the toxic agent studied, or they can act as in vivo indicators of the whole biological system exposed to the agent. There are two convenient methods assessing the responses, one is to measure chemiluminescence emission from activated phagocytes and the other is to measure quantitatively by flow cytometry the expression of complement and immunoglobulin receptors on the phagocyte surface. PMID- 28804488 TI - Anti-Adhesion Therapies in Inflammatory Bowel Disease-Molecular and Clinical Aspects. AB - The number of biologicals for the therapy of immunologically mediated diseases is constantly growing. In contrast to other agents that were previously introduced in rheumatologic or dermatologic diseases and only later adopted for the treatment of inflammatory bowel diseases (IBDs), the field of IBD was ground breaking for the concept of anti-adhesion blockade. Anti-adhesion antibodies selectively target integrins controlling cell homing to the intestine, which leads to reduction of inflammatory infiltration to the gut in chronic intestinal inflammation. Currently, the anti-alpha4beta7-antibody vedolizumab is successfully used for both Crohn's disease and ulcerative colitis worldwide. In this mini-review, we will summarize the fundamental basis of intestinal T cell homing and explain the molecular groundwork underlying current and potential future anti-adhesion therapies. Finally, we will comment on noteworthy clinical aspects of anti-adhesion therapy and give an outlook to the future of anti integrin antibodies and inhibitors. PMID- 28804483 TI - The Impact of Western Diet and Nutrients on the Microbiota and Immune Response at Mucosal Interfaces. AB - Recent findings point toward diet having a major impact on human health. Diets can either affect the gut microbiota resulting in alterations in the host's physiological responses or by directly targeting the host response. The microbial community in the mammalian gut is a complex and dynamic system crucial for the development and maturation of both systemic and mucosal immune responses. Therefore, the complex interaction between available nutrients, the microbiota, and the immune system are central regulators in maintaining homeostasis and fighting against invading pathogens at mucosal sites. Westernized diet, defined as high dietary intake of saturated fats and sucrose and low intake of fiber, represent a growing health risk contributing to the increased occurrence of metabolic diseases, e.g., diabetes and obesity in countries adapting a westernized lifestyle. Inflammatory bowel diseases (IBD) and asthma are chronic mucosal inflammatory conditions of unknown etiology with increasing prevalence worldwide. These conditions have a multifactorial etiology including genetic factors, environmental factors, and dysregulated immune responses. Their increased prevalence cannot solely be attributed to genetic considerations implying that other factors such as diet can be a major contributor. Recent reports indicate that the gut microbiota and modifications thereof, due to a consumption of a diet high in saturated fats and low in fibers, can trigger factors regulating the development and/or progression of both conditions. While asthma is a disease of the airways, increasing evidence indicates a link between the gut and airways in disease development. Herein, we provide a comprehensive review on the impact of westernized diet and associated nutrients on immune cell responses and the microbiota and how these can influence the pathology of IBD and asthma. PMID- 28804489 TI - Normalized Synergy Predicts That CD8 Co-Receptor Contribution to T Cell Receptor (TCR) and pMHC Binding Decreases As TCR Affinity Increases in Human Viral Specific T Cells. AB - The discovery of naturally occurring T cell receptors (TCRs) that confer specific, high-affinity recognition of pathogen and cancer-associated antigens remains a major goal in cellular immunotherapies. The contribution of the CD8 co receptor to the interaction between the TCR and peptide-bound major histocompatibility complex (pMHC) has previously been correlated with the activation and responsiveness of CD8+ T cells. However, these studies have been limited to model systems of genetically engineered hybridoma TCRs or transgenic mouse TCRs against either a single epitope or an array of altered peptide ligands. CD8 contribution in a native human antigen-specific T cell response remains elusive. Here, using Hepatitis C Virus-specific precursor CTLs spanning a large range of TCR affinities, we discovered that the functional responsiveness of any given TCR correlated with the contribution of CD8 to TCR/pMHC binding. Furthermore, we found that CD8 contribution to TCR/pMHC binding in the two dimensional (2D) system was more accurately reflected by normalized synergy (CD8 cooperation normalized by total TCR/pMHC bonds) rather than synergy (total CD8 cooperation) alone. While synergy showed an increasing trend with TCR affinity, normalized synergy was demonstrated to decrease with the increase of TCR affinity. Critically, normalized synergy was shown to correlate with CTL functionality and peptide sensitivity, corroborating three-dimensional (3D) analysis of CD8 contribution with respect to TCR affinity. In addition, we identified TCRs that were independent of CD8 for TCR/pMHC binding. Our results resolve the current discrepancy between 2D and 3D analysis on CD8 contribution to TCR/pMHC binding, and demonstrate that naturally occurring high-affinity TCRs are more capable of CD8-independent interactions that yield greater functional responsiveness even with CD8 blocking. Taken together, our data suggest that addition of the normalized synergy parameter to our previously established TCR discovery platform using 2D TCR affinity and sequence test would allow for selection of TCRs specific to any given antigen with the desirable attributes of high TCR affinity, CD8 co-receptor independence and functional superiority. Utilizing TCRs with less CD8 contribution could be beneficial for adoptive cell transfer immunotherapies using naturally occurring or genetically engineered T cells against viral or cancer-associated antigens. PMID- 28804490 TI - A Vision for Incorporating Environmental Effects into Nitrogen Management Decision Support Tools for U.S. Maize Production. AB - Meeting crop nitrogen (N) demand while minimizing N losses to the environment has proven difficult despite significant field research and modeling efforts. To improve N management, several real-time N management tools have been developed with a primary focus on enhancing crop production. However, no coordinated effort exists to simultaneously address sustainability concerns related to N losses at field- and regional-scales. In this perspective, we highlight the opportunity for incorporating environmental effects into N management decision support tools for United States maize production systems by integrating publicly available crop models with grower-entered management information and gridded soil and climate data in a geospatial framework specifically designed to quantify environmental and crop production tradeoffs. To facilitate advances in this area, we assess the capability of existing crop models to provide in-season N recommendations while estimating N leaching and nitrous oxide emissions, discuss several considerations for initial framework development, and highlight important challenges related to improving the accuracy of crop model predictions. Such a framework would benefit the development of regional sustainable intensification strategies by enabling the identification of N loss hotspots which could be used to implement spatially explicit mitigation efforts in relation to current environmental quality goals and real-time weather conditions. Nevertheless, we argue that this long-term vision can only be realized by leveraging a variety of existing research efforts to overcome challenges related to improving model structure, accessing field data to enhance model performance, and addressing the numerous social difficulties in delivery and adoption of such tool by stakeholders. PMID- 28804492 TI - Population Genetic Differentiation and Taxonomy of Three Closely Related Species of Saxifraga (Saxifragaceae) from Southern Tibet and the Hengduan Mountains. AB - The effects of rapid, recent uplift of the Hengduan Mountains on evolution and diversification of young floristic lineages still remain unclear. Here, we investigate diversification of three closely related Saxifraga species with a distribution restricted to the Hengduan Mountains (HM) and southern Tibet, and comment on their taxonomy based on molecular evidence. Three chloroplast DNA fragments (rbcL, trnL-F, trnS-G) and the nuclear ribosomal DNA internal transcribed spacer (ITS) were employed to study genetic structure across 104 individuals from 12 populations of Saxifraga umbellulata, S. pasumensis, and S. banmaensis. Chloroplast DNA (cpDNA) phylogenies revealed two well supported clades, corresponding to S. umbellulata and S. pasumensis plus S. banmaensis. Topology of the ITS phylogeny was largely congruent with that generated from cpDNA haplotypes, but with minor conflicts which might be caused by incomplete lineage sorting. Analyses of molecular variance of both cpDNA and ITS datasets revealed that most variation was held between S. pasumensis s.l. (with S. banmaensis) and S. umbellulata (92.31% for cpDNA; 69.78% for ITS), suggesting a high degree of genetic divergence between them. Molecular clock analysis based on ITS dataset suggested that the divergence between S. pasumensis s.l. and S. umbellulata can be dated to 8.50 Ma, probably a result of vicariant allopatric diversification associated with the uplift events of the HM. Vicariance associated with HM uplifts may also have been responsible for infraspecific differentiation in S. pasumensis. In contrast, infraspecific differentiation in S. umbellulata was most likely triggered by Quaternary glaciations. The much lower levels of gene diversity within populations of S. pasumensis compared with S. umbellulata could have resulted from both range contractions and human collection on account of its putative medicinal properties. Combining evidence from morphology, geographical distributions and molecular phylogenetic data, we recommend that S. banmaensis should be treated as a synonym of S. pasumensis which in turn, and based on the same sources of evidence, should be treated as a separate species rather than as a variety of S. umbellulata. PMID- 28804493 TI - A Comprehensive Biophysical Model of Ion and Water Transport in Plant Roots. I. Clarifying the Roles of Endodermal Barriers in the Salt Stress Response. AB - In this paper, we present a detailed and comprehensive mathematical model of active and passive ion and water transport in plant roots. Two key features are the explicit consideration of the separate, but interconnected, apoplastic, and symplastic transport pathways for ions and water, and the inclusion of both active and passive ion transport mechanisms. The model is used to investigate the respective roles of the endodermal Casparian strip and suberin lamellae in the salt stress response of plant roots. While it is thought that these barriers influence different transport pathways, it has proven difficult to distinguish their separate functions experimentally. In particular, the specific role of the suberin lamellae has been unclear. A key finding based on our simulations was that the Casparian strip is essential in preventing excessive uptake of Na+ into the plant via apoplastic bypass, with a barrier efficiency that is reflected by a sharp gradient in the steady-state radial distribution of apoplastic Na+ across the barrier. Even more significantly, this function cannot be replaced by the action of membrane transporters. The simulations also demonstrated that the positive effect of the Casparian strip of controlling Na+ uptake, was somewhat offset by its contribution to the osmotic stress component: a more effective barrier increased the detrimental osmotic stress effect. In contrast, the suberin lamellae were found to play a relatively minor, even non-essential, role in the overall response to salt stress, with the presence of the suberin lamellae resulting in only a slight reduction in Na+ uptake. However, perhaps more significantly, the simulations identified a possible role of suberin lamellae in reducing plant energy requirements by acting as a physical barrier to preventing the passive leakage of Na+ into endodermal cells. The model results suggest that more and particular experimental attention should be paid to the properties of the Casparian strip when assessing the salt tolerance of different plant varieties and species. Indeed, the Casparian strip appears to be a more promising target for plant breeding and plant genetic engineering efforts than the suberin lamellae for the goal of improving salt tolerance. PMID- 28804494 TI - Editorial: Population Genetics of Worldwide Jewish People. PMID- 28804495 TI - Snakebite envenomation turns again into a neglected tropical disease! AB - On June 9th, 2017 WHO categorized snakebite envenomation into the Category A of the Neglected Tropical Diseases. This new situation will allow access to new funding, paving the way for wider and deeper researches. It should also expand the accessibility of antivenoms. Let us hope that it also leads to cooperation among stakeholders, aiming at improving the management of snakebites in developing countries. PMID- 28804496 TI - Shape Completion Using Deep Boltzmann Machine. AB - Shape completion is an important task in the field of image processing. An alternative method is to capture the shape information and finish the completion by a generative model, such as Deep Boltzmann Machine. With its powerful ability to deal with the distribution of the shapes, it is quite easy to acquire the result by sampling from the model. In this paper, we make use of the hidden activation of the DBM and incorporate it with the convolutional shape features to fit a regression model. We compare the output of the regression model with the incomplete shape feature in order to set a proper and compact mask for sampling from the DBM. The experiment shows that our method can obtain realistic results without any prior information about the incomplete object shape. PMID- 28804491 TI - Phylloremediation of Air Pollutants: Exploiting the Potential of Plant Leaves and Leaf-Associated Microbes. AB - Air pollution is air contaminated by anthropogenic or naturally occurring substances in high concentrations for a prolonged time, resulting in adverse effects on human comfort and health as well as on ecosystems. Major air pollutants include particulate matters (PMs), ground-level ozone (O3), sulfur dioxide (SO2), nitrogen dioxides (NO2), and volatile organic compounds (VOCs). During the last three decades, air has become increasingly polluted in countries like China and India due to rapid economic growth accompanied by increased energy consumption. Various policies, regulations, and technologies have been brought together for remediation of air pollution, but the air still remains polluted. In this review, we direct attention to bioremediation of air pollutants by exploiting the potentials of plant leaves and leaf-associated microbes. The aerial surfaces of plants, particularly leaves, are estimated to sum up to 4 * 108 km2 on the earth and are also home for up to 1026 bacterial cells. Plant leaves are able to adsorb or absorb air pollutants, and habituated microbes on leaf surface and in leaves (endophytes) are reported to be able to biodegrade or transform pollutants into less or nontoxic molecules, but their potentials for air remediation has been largely unexplored. With advances in omics technologies, molecular mechanisms underlying plant leaves and leaf associated microbes in reduction of air pollutants will be deeply examined, which will provide theoretical bases for developing leaf-based remediation technologies or phylloremediation for mitigating pollutants in the air. PMID- 28804497 TI - Subjective Global Assessment and Handgrip Strength as Predictive Factors in Patients with Liver Cirrhosis. AB - BACKGROUND AND AIMS: Malnutrition is common in patients with chronic liver disease. We aimed to evaluate malnutrition assessment tools in predicting severity and survival of patients with liver cirrhosis. MATERIAL AND METHODS: We examined patients with liver cirrhosis. Nutritional evaluation was performed on admission, using subjective global assessment (SGA), handgrip strength (HGS), and anthropometry. Patients were followed up for 6 months. RESULTS: We included 100 patients, 72 men, with mean age of 59.2 years. According to disease severity, patients were 23% Child-Pugh A, 46% Child-Pugh B, and 31% Child-Pugh C. SGA and HGS significantly correlated with Child-Pugh, MELD, and MELD-Na scores on admission. At 6 months follow-up, 80.4% (78 of 97) of patients survived, while 3 patients were lost from observation. Survival was predicted by SGA (1 death in 32 patients SGA A, 8 deaths in 46 patients SGA B, and 9 deaths in 19 patients SGA C, p = 0.001) and HGS (25.1 +/- 8.5 in deceased versus 30.6 +/- 10.9 in survivors, p = 0.046). The mean BMI and MAMC values did not significantly differ between patients who survived or were deceased at 6 months. CONCLUSION: HGS and SGA may predict severity and short-term survival in cirrhotic patients. PMID- 28804498 TI - Feasibility of Cervical Epidural Anesthesia for Breast Cancer Surgery. AB - BACKGROUND: Effects of perioperative cervical level neuraxial blocks on the dissemination of cancer metastases have become a matter of substantial interest. However, experience with these catheters has been limited and data on feasibility and efficacy is sparse. METHODS: Data from 39 patients scheduled to undergo breast cancer surgery while awake with a cervical epidural alone was retrospectively analyzed. RESULTS: In 26 patients (66,7%, 95% CI 51,7-81,7) the cervical epidural catheter was sufficient for surgery. In one patient (2.6%, 95% CI 0-7.6) identification of the epidural space was not possible. Four patients (10.3%, 95% CI 0,7-19,9) had an insufficient sensory block. Seven patients (17.9%, 95% CI 5,7-30,1) had a partially insufficient sensory block. Rates of failed epidural blocks were not significantly different between different insertion levels. 21 patients (80.8%, 95% CI 65,4-96,1) developed hypotension and required an intravenous vasopressor. One patient developed nausea. In one patient the dura was accidentally punctured. No neurological damage was observed. No other major complications were observed. DISCUSSION: Epidural punctures in the cervical region are feasible but do bear potential for major complications. Anesthesiologists should familiarize themselves with high epidural block techniques. PMID- 28804499 TI - Empirical Comparison of Visualization Tools for Larger-Scale Network Analysis. AB - Gene expression, signal transduction, protein/chemical interactions, biomedical literature cooccurrences, and other concepts are often captured in biological network representations where nodes represent a certain bioentity and edges the connections between them. While many tools to manipulate, visualize, and interactively explore such networks already exist, only few of them can scale up and follow today's indisputable information growth. In this review, we shortly list a catalog of available network visualization tools and, from a user experience point of view, we identify four candidate tools suitable for larger scale network analysis, visualization, and exploration. We comment on their strengths and their weaknesses and empirically discuss their scalability, user friendliness, and postvisualization capabilities. PMID- 28804502 TI - Purification, Preliminary Characterization, and Immunological Activity of Polysaccharides from Crude Drugs of Sijunzi Formula. AB - Sijunzi Decoction (SJZD) is a conventional prescription for curing spleen deficiency in Traditional Chinese Medicine and polysaccharide is its main ingredient. In order to explore the effective ingredients contributing to the immunological activity of SJZD, we isolated and purified seven homogeneous polysaccharides from Radix Ginseng (RS-3-1 and RS-3-2), Rhizoma Atractylodis Macrocephalae (BZ-3-1, BZ-3-2, and BZ-3-3), Poria (FL-3-1), and Radix Glycyrrhizae (GC-3-1) decoctions, respectively. The molecular weight of seven homogeneous polysaccharides ranged from 5.42 * 104 to 5.65 * 104 Da. Monosaccharide composition determined by GC-MS analysis showed that these polysaccharides were primarily composed of Rha, Ara, Xyl, Man, Glc, and Gal with various ratios. Immunological activity assay revealed that polysaccharides from four crude drug components of SJZD displayed inhibitory effects on the complement system. RS-3-1, BZ-3-1, FL-3-1, and GC-3-1 could significantly enhance the phagocytosis and increase the NO production and tumor necrosis factor (TNF-alpha) level in RAW 264.7 cells (p < 0.05). These results demonstrated the immunological activities of these polysaccharides from the four crude drugs. This study supports the therapeutic effect of SJZD in clinical use and is essential for further identification the immunopolysaccharide from SJZD decoction. PMID- 28804501 TI - Regulatory Role of Redox Balance in Determination of Neural Precursor Cell Fate. AB - In 1990s, reports of discovery of a small group of cells capable of proliferation and contribution to formation of new neurons in the central nervous system (CNS) reversed a century-old concept on lack of neurogenesis in the adult mammalian brain. These cells are found in all stages of human life and contribute to normal cellular turnover of the CNS. Therefore, the identity of regulating factors that affect their proliferation and differentiation is a highly noteworthy issue for basic scientists and their clinician counterparts for therapeutic purposes. The cues for such control are embedded in developmental and environmental signaling through a highly regulated tempo-spatial expression of specific transcription factors. Novel findings indicate the importance of reactive oxygen species (ROS) in the regulation of this signaling system. The elusive nature of ROS signaling in many vital processes from cell proliferation to cell death creates a complex literature in this field. Here, we discuss the emerging thoughts on the importance of redox regulation of proliferation and maintenance in mammalian neural stem and progenitor cells under physiological and pathological conditions. The current knowledge on ROS-mediated changes in redox-sensitive proteins that govern the molecular mechanisms in proliferation and differentiation of these cells is reviewed. PMID- 28804500 TI - Pluripotent Stem Cell Metabolism and Mitochondria: Beyond ATP. AB - Metabolism is central to embryonic stem cell (ESC) pluripotency and differentiation, with distinct profiles apparent under different nutrient milieu, and conditions that maintain alternate cell states. The significance of altered nutrient availability, particularly oxygen, and metabolic pathway activity has been highlighted by extensive studies of their impact on preimplantation embryo development, physiology, and viability. ESC similarly modulate their metabolism in response to altered metabolite levels, with changes in nutrient availability shown to have a lasting impact on derived cell identity through the regulation of the epigenetic landscape. Further, the preferential use of glucose and anaplerotic glutamine metabolism serves to not only support cell growth and proliferation but also minimise reactive oxygen species production. However, the perinuclear localisation of spherical, electron-poor mitochondria in ESC is proposed to sustain ESC nuclear-mitochondrial crosstalk and a mitochondrial-H2O2 presence, to facilitate signalling to support self-renewal through the stabilisation of HIFalpha, a process that may be favoured under physiological oxygen. The environment in which a cell is grown is therefore a critical regulator and determinant of cell fate, with metabolism, and particularly mitochondria, acting as an interface between the environment and the epigenome. PMID- 28804503 TI - Effects of Angelica Extract on Schwann Cell Proliferation and Expressions of Related Proteins. AB - The present study investigated the effects of Angelica extract (AE) on Schwann cell proliferation and expressions of related proteins, including brain derived neurotrophic factor (BDNF), neural cell adhesion molecule (NCAM), and proliferating cell nuclear antigen (PCNA). Proliferation activity and cell cycles of SCs were evaluated by MTT assay and flow cytometry methods, respectively, after 12 h treatment of AE at different concentrations (62.5, 125, 250, 1000, 2000, 4000, and 8000 mg/L). SCs were treated by 500, 1000, and 2000 mg/L AE for 24 h or 48 h; the related genes mRNA and proteins expressions in SCs were detected by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) kit. At the concentration range of 125-2000 mg/L, the SC proliferation was induced by AE in a dose-dependent manner, especially 1000 and 2000 mg/L; cells in drug-treated groups showed the most increase. Cells counts were ascended significantly in (G2/M + S) phase compared to control group. BDNF, NCAM, and PCNA protein expressions significantly increased at drug-treated groups. Relative genes mRNA expressions levels were also significantly higher compared to control group. The results indicated that AE facilitated SC proliferation and related genes and proteins expressions, which provided a basic guideline for nerve injury repair in clinic. PMID- 28804504 TI - Efficacy of Auricular Acupressure for Chronic Low Back Pain: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVES: To identify the efficacy of auricular acupressure on pain and disability for chronic LBP by systematic review. METHODS: A search of randomized controlled trials was conducted in four English medical electronic databases and three Chinese databases. Two reviewers independently retrieved related studies, assessed the methodological quality, and extracted data with a standardized data form. Meta-analyses were performed using all time-points meta-analysis. RESULTS: A total of 7 trials met the inclusion criteria, of which 4 had the low risk of bias. The findings of this study showed that, for the immediate effect, auricular acupressure had large, significant effects in improving pain within 12 weeks. As for the follow-up effect, the pooled estimates also showed promising effect at 4 week follow-up after 4-week intervention (standardized mean difference = -1.13, 95% CI (-1.70, -0.56), P < 0.001). But, for the disability level, the therapeutic effect was not significant (mean difference = -1.99, 95% CI (-4.93, 0.95), P = 0.18). No serious adverse effects were recorded. CONCLUSIONS: The encouraging evidence of this study indicates that it is recommended to provide auricular acupressure to patients with chronic low back pain. However, a more accurate estimate of the effect will require further rigorously designed large-scale RCTs on chronic LBP for improving pain and disability. PMID- 28804505 TI - An etiologic prediction model incorporating biomarkers to predict the bladder cancer risk associated with occupational exposure to aromatic amines: a pilot study. AB - BACKGROUND: No etiological prediction model incorporating biomarkers is available to predict bladder cancer risk associated with occupational exposure to aromatic amines. METHODS: Cases were 199 bladder cancer patients. Clinical, laboratory and genetic data were predictors in logistic regression models (full and short) in which the dependent variable was 1 for 15 patients with aromatic amines related bladder cancer and 0 otherwise. The receiver operating characteristics approach was adopted; the area under the curve was used to evaluate discriminatory ability of models. RESULTS: Area under the curve was 0.93 for the full model (including age, smoking and coffee habits, DNA adducts, 12 genotypes) and 0.86 for the short model (including smoking, DNA adducts, 3 genotypes). Using the "best cut-off" of predicted probability of a positive outcome, percentage of cases correctly classified was 92% (full model) against 75% (short model). Cancers classified as "positive outcome" are those to be referred for evaluation by an occupational physician for etiological diagnosis; these patients were 28 (full model) or 60 (short model). Using 3 genotypes instead of 12 can double the number of patients with suspect of aromatic amine related cancer, thus increasing costs of etiologic appraisal. CONCLUSIONS: Integrating clinical, laboratory and genetic factors, we developed the first etiologic prediction model for aromatic amine related bladder cancer. Discriminatory ability was excellent, particularly for the full model, allowing individualized predictions. Validation of our model in external populations is essential for practical use in the clinical setting. PMID- 28804506 TI - Improved k-t PCA Algorithm Using Artificial Sparsity in Dynamic MRI. AB - The k-t principal component analysis (k-t PCA) is an effective approach for high spatiotemporal resolution dynamic magnetic resonance (MR) imaging. However, it suffers from larger residual aliasing artifacts and noise amplification when the reduction factor goes higher. To further enhance the performance of this technique, we propose a new method called sparse k-t PCA that combines the k-t PCA algorithm with an artificial sparsity constraint. It is a self-calibrated procedure that is based on the traditional k-t PCA method by further eliminating the reconstruction error derived from complex subtraction of the sampled k-t space from the original reconstructed k-t space. The proposed method is tested through both simulations and in vivo datasets with different reduction factors. Compared to the standard k-t PCA algorithm, the sparse k-t PCA can improve the normalized root-mean-square error performance and the accuracy of temporal resolution. It is thus useful for rapid dynamic MR imaging. PMID- 28804510 TI - The Nonverbal Communication of Positive Emotions: An Emotion Family Approach. AB - This review provides an overview of the research on nonverbal expressions of positive emotions, organised into emotion families, that is, clusters sharing common characteristics. Epistemological positive emotions (amusement, relief, awe, and interest) are found to have distinct, recognisable displays via vocal or facial cues, while the agency-approach positive emotions (elation and pride) appear to be associated with recognisable visual, but not auditory, cues. Evidence is less strong for the prosocial emotions (love, compassion, gratitude, and admiration) in any modality other than touch, and there is little support for distinct recognisable signals of the savouring positive emotions (contentment, sensory pleasure, and desire). In closing, some limitations of extant work are noted and some proposals for future research are outlined. PMID- 28804509 TI - Lifetime Stress Exposure and Health: A Review of Contemporary Assessment Methods and Biological Mechanisms. AB - Life stress is a central construct in health research because it is associated with increased risk for a variety of serious mental and physical health problems, including anxiety disorders, depression, cardiovascular disease, autoimmune disorders, Alzheimer's disease, certain cancers, and other diseases of aging. In this review, we examine how lifetime stress exposure contributes to elevated disease risk, and explore ongoing measurement and scientific issues related to this topic. To accomplish these goals, we first review existing instruments that have been developed for assessing perceived stress, self-reported life events, interviewer-assessed life stressors, and lifetime stress exposure. Next, we describe laboratory-based tasks that have been used for characterizing individual differences in psychological and biological stress reactivity. These methods have yielded an enormous amount of data showing how life stress influences the activity of the hypothalamic-pituitary-adrenal axis, hypothalamic-pituitary gonadal axis, sympathetic-adrenal-medullary axis, and immune system, and how such processes can in turn cause allostatic load and biological embedding of the stress effect at the level of the human brain and genome. At the same time, many critical measurement and scientific issues remain unresolved, and we discuss these topics last while describing some pressing issues and opportunities for future research on stress and health. PMID- 28804508 TI - A psychology of the human brain-gut-microbiome axis. AB - In recent years, we have seen increasing research within neuroscience and biopsychology on the interactions between the brain, the gastrointestinal tract, the bacteria within the gastrointestinal tract, and the bidirectional relationship between these systems: the brain-gut-microbiome axis. Although research has demonstrated that the gut microbiota can impact upon cognition and a variety of stress-related behaviours, including those relevant to anxiety and depression, we still do not know how this occurs. A deeper understanding of how psychological development as well as social and cultural factors impact upon the brain-gut-microbiome axis will contextualise the role of the axis in humans and inform psychological interventions that improve health within the brain-gut microbiome axis. Interventions ostensibly aimed at ameliorating disorders in one part of the brain-gut-microbiome axis (e.g., psychotherapy for depression) may nonetheless impact upon other parts of the axis (e.g., microbiome composition and function), and functional gastrointestinal disorders such as irritable bowel syndrome represent a disorder of the axis, rather than an isolated problem either of psychology or of gastrointestinal function. The discipline of psychology needs to be cognisant of these interactions and can help to inform the future research agenda in this emerging field of research. In this review, we outline the role psychology has to play in understanding the brain-gut-microbiome axis, with a focus on human psychology and the use of research in laboratory animals to model human psychology. PMID- 28804511 TI - Comment: Respecifying Emotional Influence. AB - To what extent does the level of overlap between social appraisal and social referencing depend upon the particular definitions adopted when following different research agendas? I argue that processes of both kinds fall under the more inclusive heading of relation alignment. Relation alignment also covers emotional influence that is not mediated by the communication of appraisal. Similarities, interdependences, and distinctions between these various relation alignment processes warrant further investigation. PMID- 28804507 TI - 2017 update of the WSES guidelines for emergency repair of complicated abdominal wall hernias. AB - Emergency repair of complicated abdominal wall hernias may be associated with worsen outcome and a significant rate of postoperative complications. There is no consensus on management of complicated abdominal hernias. The main matter of debate is about the use of mesh in case of intestinal resection and the type of mesh to be used. Wound infection is the most common complication encountered and represents an immense burden especially in the presence of a mesh. The recurrence rate is an important topic that influences the final outcome. A World Society of Emergency Surgery (WSES) Consensus Conference was held in Bergamo in July 2013 with the aim to define recommendations for emergency repair of abdominal wall hernias in adults. This document represents the executive summary of the consensus conference approved by a WSES expert panel. In 2016, the guidelines have been revised and updated according to the most recent available literature. PMID- 28804513 TI - Noncirrhotic hepatocellular carcinoma: etiology and occult hepatitis B virus infection in a hepatitis B virus-endemic area. AB - BACKGROUND: Although hepatocellular carcinoma (HCC) usually develops in cirrhotic livers, a minority of cases occur in noncirrhotic livers (NCLs). We investigated etiology, clinicopathological features, and occult hepatitis B virus (HBV) infection (OBI) in patients with NCL HCC in an HBV-endemic area. METHODS: A total of 710 patients who underwent resection or transplantation for HCC at the National Cancer Center (NCC), Korea, were enrolled. HCC and fibrosis stage were diagnosed pathologically. RESULTS: A total of 178 patients (25%) did not have cirrhosis (NCL group). The main cause of HCC was HBV infection (77.2%), followed by cryptogenic disease (11.0%). The prevalence of NCL was 19.2%, 32.5%, 50.0%, and 48.7% among patients with HBV, hepatitis C virus (HCV), alcoholic, and cryptogenic disease, respectively (p < 0.05); corresponding nonfibrosis rates were 8.1%, 0%, 19.0%, and 24.3%, respectively. The NCL group was significantly older, with a larger tumor size, smaller tumor number, lower tumor stage, and more frequent non-HBV etiology. Among non-HBV HCC cases, 130 (80.2%) had antibodies against HBV core (HBc) and 55 (38.5%) had OBI. OBI-positive rates of 0%, 31.8%, and 52.6% were detected among HCV, alcoholic, and cryptogenic HCC cases, respectively. OBI did not correlate with advanced fibrosis. The NCL and liver cirrhosis (LC) groups did not differ in median overall survival. CONCLUSION: Regardless of etiology, a significant number of HCC patients, including half of nonviral cases, did not have LC. Half of cryptogenic HCC cases had OBI. This study promotes an understanding of fibrosis and OBI among patients with HCC in an HBV-endemic area. PMID- 28804512 TI - Engineering Shewanella oneidensis enables xylose-fed microbial fuel cell. AB - BACKGROUND: The microbial fuel cell (MFC) is a green and sustainable technology for electricity energy harvest from biomass, in which exoelectrogens use metabolism and extracellular electron transfer pathways for the conversion of chemical energy into electricity. However, Shewanella oneidensis MR-1, one of the most well-known exoelectrogens, could not use xylose (a key pentose derived from hydrolysis of lignocellulosic biomass) for cell growth and power generation, which limited greatly its practical applications. RESULTS: Herein, to enable S. oneidensis to directly utilize xylose as the sole carbon source for bioelectricity production in MFCs, we used synthetic biology strategies to successfully construct four genetically engineered S. oneidensis (namely XE, GE, XS, and GS) by assembling one of the xylose transporters (from Candida intermedia and Clostridium acetobutylicum) with one of intracellular xylose metabolic pathways (the isomerase pathway from Escherichia coli and the oxidoreductase pathway from Scheffersomyces stipites), respectively. We found that among these engineered S. oneidensis strains, the strain GS (i.e. harbouring Gxf1 gene encoding the xylose facilitator from C. intermedi, and XYL1, XYL2, and XKS1 genes encoding the xylose oxidoreductase pathway from S. stipites) was able to generate the highest power density, enabling a maximum electricity power density of 2.1 +/ 0.1 mW/m2. CONCLUSION: To the best of our knowledge, this was the first report on the rationally designed Shewanella that could use xylose as the sole carbon source and electron donor to produce electricity. The synthetic biology strategies developed in this study could be further extended to rationally engineer other exoelectrogens for lignocellulosic biomass utilization to generate electricity power. PMID- 28804514 TI - Is EUS-guided drainage a suitable alternative technique in case of proximal biliary obstruction? AB - BACKGROUND: Results of endoscopic ultrasound-guided biliary drainage (EUBD) are unknown in case of proximal stricture. The aim is to assess clinical outcomes of EUBD in patients with malignant hilar obstruction. METHODS: Patients undergoing EUBD with hilar strictures were prospectively included. Primary outcome was clinical success at 7 and 30 days (defined by 50% bilirubin decrease). Secondary outcomes were technical success, procedure-related complications, length of hospital stay, reintervention rate, survival and chemotherapy administration. RESULTS: Eighteen patients with a mean age of 68.8 years were included. On 15 classable stenosis, 7 (47%) were noted Bismuth I-II, 7 (47%) Bismuth III, and 1 (6.7%) Bismuth IV. Reasons for EUBD were surgically modified anatomy in 10 patients (55.6%), impassable stricture at ERCP in 7 (38.9%) and duodenal obstruction in 1 (5.6%). Only hepaticogastrostomy was performed. Clinical success was at day 7 and 30 respectively 72.2% and 68.8%. Technical success was 94%. Complications occurred in 3 (16.7%) patients. Median (range) length of hospital stay was 10 (6-35) days. Reintervention rate was 16.7%. Median (range) survival was 79 (5-390) days. Chemotherapy was possible in 10 (55.6%) patients. CONCLUSIONS: EUBD is feasible for hilar obstruction for surgically altered anatomy or after ERCP failure. Clinical outcome is satisfactory when considering underlying advanced disease, allowing chemotherapy. PMID- 28804515 TI - MMX(r) technology and its applications in gastrointestinal diseases. AB - The Multimatrix(r) (MMX(r)) preparation MMX(r) is a recently obtained drug formulation developed to facilitate release of high concentrations of active drugs into the colon, with a homogeneous distribution along all colonic segments, particularly the most distal ones; the distal colonic tracts, indeed, are the most difficult to reach in significant amounts when a drug is given orally. The MMX(r) formulation is characterized by a lipophilic matrix dispersed in a hydrophilic structure. Indeed, in the last few years, MMX(r) technology has been widely used in the development of various drugs for the treatment of inflammatory and infectious gastrointestinal diseases localized in the colon. In particular, MMX(r) mesalamine, budesonide and parnaparin formulations have been investigated in patients with ulcerative colitis, and the first two have reached worldwide registration for the treatment of this disease. Moreover, MMX(r)-rifamycin is being positively tested in the treatment of colonic bacterial infections, including traveler's diarrhea. MMX(r) technology is, thus, proving to be a very effective formulation for the treatment of various colonic diseases. This effectiveness has been related not only to specific colonic delivery, but also to its ability to act in a once-daily dosage, thus favouring patients' adherence to prescribed schedules of treatment. The effective delivery of the active molecule to the site of need in the colon is also associated with very low systemic absorption and very low rates of adverse events (AEs). In this paper, we have reviewed all clinical trials performed with an MMX(r)-bound drug and all possible real-life reports, in order to give an overall evaluation of MMX(r). PMID- 28804516 TI - The role of sebelipase alfa in the treatment of lysosomal acid lipase deficiency. AB - Lysosomal acid lipase deficiency (LALD) is a lysosomal storage disorder (LSD) characterized either by infantile onset with fulminant clinical course and very poor prognosis or childhood/adult-onset disease with an attenuated phenotype. The disorder is often misdiagnosed or remains undiagnosed in children and adults due to a rather unspecific clinical presentation with dyslipidemia and steatohepatitis. Until recently, no good treatment options were available for LALD. Despite supportive and symptomatic therapies, death occurred before 1 year of age in patients with infantile-onset disease and patients with childhood/adult onset LALD suffered from significant complications, such as liver cirrhosis, requiring liver transplantation and early-onset cardiovascular disease. With the recent approval of sebelipase alfa for clinical use in infantile- as well as childhood/adult-onset LALD, a new treatment era for this disorder has begun. Sebelipase alfa is a recombinant human lysosomal acid lipase (LAL), which is administered via the intravenous route. Clinical trials have shown significant improvement of disease parameters such as liver transaminases, hepatomegaly, and dyslipidemia in childhood/adult-onset LALD patients. Treatment of infants with the severe infantile-onset form of the disease has led to improved survival beyond the age of 1 year, and also showed improvement of hepatic and gastrointestinal symptoms, as well as growth. Overall, sebelipase alfa has a favorable safety profile and promises to be a good long-term treatment option for patients with LALD, with significant reduction of disease burden and increased life expectancy. PMID- 28804517 TI - Update on the role of nanoliposomal irinotecan in the treatment of metastatic pancreatic cancer. AB - Median survival for patients with metastatic pancreatic cancer (MPC) treated with combination chemotherapeutic agents such as gemcitabine-based regimens and FOLFIRINOX is currently less than 12 months. This highlights the need for more efficacious first-line, as well as second-line therapies. Nanoliposomal irinotecan, in combination with 5-fluorouracil (5-FU)/folinic acid has recently been assessed as second-line therapy after initial gemcitabine-based therapy. It is the first, second-line treatment approved by the US Food and Drug Administration to treat patients with MPC based on results of the NAnoliPOsomaL Irinotecan (NAPOLI-1) study, which showed that this regimen significantly prolonged progression-free survival (3.1 months versus 1.5 months) and overall survival (6.2 months versus 4.1 months) compared with 5-FU/folinic acid alone. In addition, this study also represented an important step forward in improving the efficacy of previously used chemotherapeutic agents by using nanoformulation to extend pharmacokinetic advantages such as slow clearance, low steady-state volume of distribution, and longer half-life. However, certain adverse effects that are seen more frequently with nanoliposomal irinotecan and 5-FU/folinic acid, compared with 5-FU/folinic acid alone, include neutropenia, fatigue, diarrhea, and nausea/vomiting. This merits close monitoring of patients who are on this combination, since these adverse events may necessitate dose reductions and growth factor support. It is imperative to check UGT1A1 gene status in all patients being considered for treatment with nanoliposomal irinotecan. Patients found to be homozygous for the UGT1A1*28 gene need to be started on a lower initial dose. As we gain more data with clinical use, we anticipate further characterization of the aforementioned toxicities in patients with UGT1A1 gene polymorphisms and other genetic variants. PMID- 28804518 TI - Comparative frequency of four different types of pregnancy-associated thyrotoxicosis in a single thyroid centre. AB - BACKGROUND: Pregnancy and delivery markedly influence thyroid function. However, the comparative prevalence of gestational thyrotoxicosis (GT), new onset of Graves' disease during pregnancy (GD during pregnancy), postpartum destructive thyrotoxicosis (PPT), and postpartum Graves' thyrotoxicosis (PPGD) has not yet been determined. METHODS: We prospectively registered and performed a review of 4127 consecutive non treated female patients with thyrotoxicosis, seen between August 2008 and December 2013 in our outpatient clinic of Kuma Hospital. 187 out of the 4127 women had new diagnosis of thyrotoxicosis during pregnancy or in the postpartum period. We investigated the prevalence of new diagnosis of GT, GD during pregnancy, PPT and PPGD and compared the characteristics of these types of thyrotoxicosis. The postpartum period is defined as twelve months after delivery. RESULTS: Out of 187 pregnant or postpartum women, we identified 30 (16.0%) with GT, 13 (7.0%) with GD during pregnancy, 42 (22.5%) with PPT, and 102 (54.5%) with PPGD. The onset time of thyrotoxicosis during pregnancy, i.e., both GT and GD during pregnancy, was delayed by a couple of weeks when hCG peaked at 10 gestational weeks. Seventy-six percent of patients with PPT developed thyrotoxicosis between delivery and 4 months postpartum; on the other hand, 83.3% of patients with PPGD developed thyrotoxicosis at 6 months postpartum or later. CONCLUSIONS: We named gestational thyrotoxicosis, new onset of Graves' disease during pregnancy, postpartum destructive thyrotoxicosis, and postpartum Graves' thyrotoxicosis as pregnancy-associated thyrotoxicosis. A clinically significant number of women developed Graves' disease in the postpartum period in a single thyroid centre. PMID- 28804519 TI - Dealing with the death of a long term patient; what is the impact and how do podiatrists cope? AB - BACKGROUND: It is common for podiatrists and patients to develop long term professional relationships. Patient's decline in health or death may impact a practitioner's mental wellbeing. This research aimed to understand the impact of long term patient death on podiatrists and identify coping strategies. METHOD: Australian podiatrists were eligible to participate if they had been practicing longer than 5 years and experienced the death of a long term patient in the previous 12 months. Individual semi-structured interviews were conducted with podiatrists and were audio-recorded, transcribed verbatim and individually analysed to identify key themes. Interpretative phenomenological analysis was used to explore the perceptions of podiatrists on the personal and professional impact following the death of a long term patient. RESULTS: Fifteen podiatrists (11 female) with a median of 15 (range 8-50) years' experience participated. Three major themes emerged: acknowledging connections, willing to share and listen, and creating support through starting the conversation. Participants indicated importance in recognition of the emotional influence of professional patient relationships. They also discussed the importance of debriefing about death with the right person, which was most commonly colleagues. Participants talked about the emotional impact of death, suggesting the need for supporting discussion and resources, especially for new graduates. CONCLUSION: Death and dying can be an emotive topic and one which podiatrists may not be prepared for, yet likely to have to deal with throughout their career. These findings enable a better understanding of the impact of patient death and provide possible future directions for the profession to better support podiatrists in this area. PMID- 28804520 TI - Fast Simulation of Lipid Vesicle Deformation Using Spherical Harmonic Approximation. AB - Lipid vesicles appear ubiquitously in biological systems. Understanding how the mechanical and intermolecular interactions deform vesicle membranes is a fundamental question in biophysics. In this article we develop a fast algorithm to compute the surface configurations of lipid vesicles by introducing surface harmonic functions to approximate the membrane surface. This parameterization allows an analytical computation of the membrane curvature energy and its gradient for the efficient minimization of the curvature energy using a nonlinear conjugate gradient method. Our approach drastically reduces the degrees of freedom for approximating the membrane surfaces compared to the previously developed finite element and finite difference methods. Vesicle deformations with a reduced volume larger than 0.65 can be well approximated by using as small as 49 surface harmonic functions. The method thus has a great potential to reduce the computational expense of tracking multiple vesicles which deform for their interaction with external fields. PMID- 28804521 TI - Home advantage in the Winter Paralympic Games 1976-2014. AB - PURPOSE: There is a limited amount of home advantage research concerned with winter sports. There is also a distinct lack of studies that investigate home advantage in the context of para sport events. This paper addresses this gap in the knowledge by examining home advantage in the Winter Paralympic Games. METHODS: Using a standardised measure of success, we compared the performances of host nations at home with their own performances away from home between 1976 and 2014. Both country level and individual sport level analysis is conducted for this time period. Comparisons are also drawn with the Winter Olympic Games since 1992, the point from which both the Winter Olympic Games and the Winter Paralympic Games have been hosted by the same nations and in the same years. RESULTS: Clear evidence of a home advantage effect in the Winter Paralympic Games was found at country level. When examining individual sports, only alpine skiing and cross country skiing returned a significant home advantage effect. When comparing home advantage in the Winter Paralympic Games with the Winter Olympic Games for the last seven host nations (1992-2014), we found that home advantage was generally more pronounced (although not a statistically significant difference) in the case of the former. CONCLUSION: The causes of home advantage in the Winter Paralympic Games are unclear and should be investigated further. PMID- 28804524 TI - Mechanism of secondary recrystallization of Goss grains in grain-oriented electrical steel. AB - Since its invention by Goss in 1934, grain-oriented (GO) electrical steel has been widely used as a core material in transformers. GO exhibits a grain size of over several millimeters attained by secondary recrystallization during high temperature final batch annealing. In addition to the unusually large grain size, the crystal direction in the rolling direction is aligned with <001>, which is the easy magnetization axis of alpha-iron. Secondary recrystallization is the phenomenon in which a certain very small number of {110}<001> (Goss) grains grow selectively (about one in 106 primary grains) at the expense of many other primary recrystallized grains. The question of why the Goss orientation is exclusively selected during secondary recrystallization has long been a main research subject in this field. The general criterion for secondary recrystallization is a small and uniform primary grain size, which is achieved through the inhibition of normal grain growth by fine precipitates called inhibitors. This paper describes several conceivable mechanisms of secondary recrystallization of Goss grains mainly based on the selective growth model. PMID- 28804522 TI - Nanomaterials for the Capture and Therapeutic Targeting of Circulating Tumor Cells. AB - Circulating tumor cells are a hallmark of cancer metastasis which accounts for approximately 90% of all cancer-related deaths. Their detection and characterization have significant implications in cancer biology and clinical practice. However, CTCs are rare cells and consist of heterogeneous subpopulations, requiring highly sensitive and specific techniques to identify and isolate them with high efficiency. Nanomaterials, with unique structural and functional properties, have shown strong promise to meet the challenging demands. In this review, we discuss CTC capture and therapeutic targeting, emphasizing the significance of the nanomaterials being used for this purpose. The next generation of therapy for metastatic cancer may well involve capturing and even directly neutralizing CTCs using nanomaterials. PMID- 28804523 TI - Tri-methylation of H3K79 is decreased in TGF-beta1-induced epithelial-to mesenchymal transition in lung cancer. AB - BACKGROUND: The epithelial-to-mesenchymal transition (EMT) enables epithelial cancer cells to acquire mesenchymal features and contributes to metastasis and resistance to treatment. This process involves epigenetic reprogramming for gene expression. We explored global histone modifications during TGF-beta1-induced EMT in two non-small cell lung cancer (NSCLC) cell lines and tested different epigenetic treatment to modulate or partially reverse EMT. RESULTS: Loss of classical epithelial markers and gain of mesenchymal markers were verified in A549 and H358 cell lines during TGF-beta1-induced EMT. In addition, we noticed increased expression of the axonal guidance protein semaphorin 3C (SEMA3C) and PD L1 (programmed death-ligand 1) involved in the inhibition of the immune system, suggesting that both SEMA3C and PD-L1 could be the new markers of TGF-beta1 induced EMT. H3K79me3 and H2BK120me1 were decreased in A549 and H358 cell lines after a 48-h TGF-beta1 treatment, as well as H2BK120ac in A549 cells. However, decreased H3K79me3 was not associated with expression of the histone methyltransferase DOT1L. Furthermore, H3K79me3 was decreased in tumors compared in normal tissues and not associated with cell proliferation. Associations of histone deacetylase inhibitor (SAHA) with DOT1L inhibitors (EPZ5676 or SGC0946) or BET bromodomain inhibitor (PFI-1) were efficient to partially reverse TGF beta1 effects by decreasing expression of PD-L1, SEMA3C, and its receptor neuropilin-2 (NRP2) and by increasing epithelial markers such as E-cadherin. CONCLUSION: Histone methylation was modified during EMT, and combination of epigenetic compounds with conventional or targeted chemotherapy might contribute to reduce metastasis and to enhance clinical responses. PMID- 28804525 TI - MDTS: automatic complex materials design using Monte Carlo tree search. AB - Complex materials design is often represented as a black-box combinatorial optimization problem. In this paper, we present a novel python library called MDTS (Materials Design using Tree Search). Our algorithm employs a Monte Carlo tree search approach, which has shown exceptional performance in computer Go game. Unlike evolutionary algorithms that require user intervention to set parameters appropriately, MDTS has no tuning parameters and works autonomously in various problems. In comparison to a Bayesian optimization package, our algorithm showed competitive search efficiency and superior scalability. We succeeded in designing large Silicon-Germanium (Si-Ge) alloy structures that Bayesian optimization could not deal with due to excessive computational cost. MDTS is available at https://github.com/tsudalab/MDTS. PMID- 28804526 TI - Solid state ionics: a Japan perspective. AB - The 70-year history of scientific endeavor of solid state ionics research in Japan is reviewed to show the contribution of Japanese scientists to the basic science of solid state ionics and its applications. The term 'solid state ionics' was defined by Takehiko Takahashi of Nagoya University, Japan: it refers to ions in solids, especially solids that exhibit high ionic conductivity at a fairly low temperature below their melting points. During the last few decades of exploration, many ion conducting solids have been discovered in Japan such as the copper-ion conductor Rb4Cu16I7Cl13, proton conductor SrCe1-x Y x O3, oxide-ion conductor La0.9Sr0.9Ga0.9Mg0.1O3, and lithium-ion conductor Li10GeP2S12. Rb4Cu16I7Cl13 has a conductivity of 0.33 S cm-1 at 25 degrees C, which is the highest of all room temperature ion conductive solid electrolytes reported to date, and Li10GeP2S12 has a conductivity of 0.012 S cm-1 at 25 degrees C, which is the highest among lithium-ion conductors reported to date. Research on high temperature proton conducting ceramics began in Japan. The history, the discovery of novel ionic conductors and the story behind them are summarized along with basic science and technology. PMID- 28804527 TI - Synthesis and characterisation of cross-linked chitosan composites functionalised with silver and gold nanoparticles for antimicrobial applications. AB - We present a study of a range of cross-linked chitosan composites with potential antimicrobial applications. They were formed by cross-linking chitosan and siloxane networks and by introducing silver and gold nanoparticles (NPs). The aim was to investigate whether adding the metal NPs to the chitosan-siloxane composite would lead to a material with enhanced antimicrobial ability as compared to chitosan itself. The composites were synthesised in hydrogel form with the metal NPs embedded in the cross-linked chitosan network. Spectroscopic and microscopic techniques were employed to investigate the structural properties of the composite and the tensile strength of the structures was measured. It was found that the addition of metal NPs did not influence the mechanical strength of the composite. A crystal violet attachment assay results displayed a significant reduction in the attachment of E. coli to the cross-linked chitosan surfaces. Release profile tests suggest that the metal NPs do not contribute to the overall antimicrobial activity under neutral conditions. The contribution to the mechanical and antimicrobial properties from cross-linking with siloxane is significant, giving rise to a versatile, durable, antimicrobial material suitable for thin film formation, wound dressings or the coating of various surfaces where robustness and antimicrobial control are required. PMID- 28804528 TI - Individual Characteristics, Family Factors, and Classroom Experiences as Predictors of Low-Income Kindergarteners' Social Skills. AB - There has been increasing awareness of the need for research and theory to take into account the intersection of individual characteristics and environmental contexts when examining predictors of child outcomes. The present longitudinal, multi-informant study examined the cumulative and interacting contributions of child characteristics (language skills, inattention/hyperactivity, and aggression) and preschool and family contextual factors in predicting kindergarten social skills in 389 low-income preschool children. Child characteristics and classroom factors, but not family factors, predicted teacher rated kindergarten social skills, while child characteristics alone predicted change in teacher-rated social skills from preschool to kindergarten. Child characteristics and family factors, but not classroom factors, predicted parent rated kindergarten social skills. Family factors alone predicted change in parent rated social skills from preschool to kindergarten. Individual child characteristics did not interact with family or classroom factors in predicting parent- or teacher-rated social skills, and support was therefore found for an incremental, rather than an interactive, predictive model of social skills. The findings underscore the importance of assessing outcomes in more than one context, and of considering the impact of both individual and environmental contextual factors on children's developing social skills when designing targeted intervention programs to prepare children for kindergarten. PMID- 28804529 TI - REJOINDER: "FIBER DIRECTION ESTIMATION, SMOOTHING AND TRACKING IN DIFFUSION MRI". PMID- 28804530 TI - Evolution of Reduced Graphene Oxide-SnS2 Hybrid Nanoparticle Electrodes in Li-Ion Batteries. AB - Hybrid nanomaterials where active battery nanoparticles are synthesized directly onto conductive additives such as graphene hold the promise of improving the cyclability and energy density of conversion and alloying type Li-ion battery electrodes. Here we investigate the evolution of hybrid reduced graphene oxide tin sulfide (rGO-SnS2) electrodes during battery cycling. These hybrid nanoparticles are synthesized by a one-step solvothermal microwave reaction which allows for simultaneous synthesis of the SnS2 nanocrystals and reduction of GO. Despite the hybrid architecture of these electrodes, electrochemical impedance spectroscopy shows that the impedance doubles in about 25 cycles and subsequently gradually increases, which may be caused by an irreversible surface passivation of rGO by sulfur enriched conversion products. This surface passivation is further confirmed by post-mortem Raman spectroscopy of the electrodes, which no longer detects rGO peaks after 100 cycles. Moreover, galvanostatic intermittent titration analysis during the 1st and 100th cycles shows a drop in Li-ion diffusion coefficient of over an order of magnitude. Despite reports of excellent cycling performance of hybrid nanomaterials, our work indicates that in certain electrode systems, it is still critical to further address passivation and charge transport issues between the active phase and the conductive additive in order to retain high energy density and cycling performance. PMID- 28804531 TI - Communicating Results of a Dietary Exposure Study Following Consumption of Traditionally Smoked Salmon. AB - One expectation of community-based participatory research (CBPR) is participant access to study results. However, reporting experimental data produced by studies involving biological measurements in the absence of clinical relevance can be challenging to scientists and participants. We applied best practices in data sharing to report the results of a study designed to explore polycyclic aromatic hydrocarbons absorption, metabolism, and excretion following consumption of traditionally smoked salmon by members of the Confederated Tribes of the Umatilla Indian Reservation (CTUIR). A dietary exposure study was developed, in which nine Tribal members consumed 50 g of traditionally smoked salmon and provided repeated urine samples over 24 hours. During recruitment, participants requested access to their data following analysis. Disclosing data is an important element of CBPR and must be treated with the same rigor as that given to the data analysis. The field of data disclosure is relatively new, but when handled correctly can improve education within the community, reduce distrust, and enhance environmental health literacy. Using the results from this study, we suggest mechanisms for sharing data with a Tribal community. PMID- 28804532 TI - Associations between Specific Redox Biomarkers and Age in a Large European Cohort: The MARK-AGE Project. AB - Oxidative stress and antioxidants play a role in age-related diseases and in the aging process. We here present data on protein carbonyls, 3-nitrotyrosine, malondialdehyde, and cellular and plasma antioxidants (glutathione, cysteine, ascorbic acid, uric acid, alpha-tocopherol, and lycopene) and their relation with age in the European multicenter study MARK-AGE. To avoid confounding, only data from countries which recruited subjects from all three study groups (five of eight centers) and only participants aged >=55 years were selected resulting in data from 1559 participants. These included subjects from (1) the general population, (2) members from long-living families, and (3) their spouses. In addition, 683 middle-aged reference participants (35-54 years) served as a control. After adjustment for age, BMI, smoking status, gender, and country, there were differences in protein carbonyls, malondialdehyde, 3-nitrotyrosine, alpha-tocopherol, cysteine, and glutathione between the 3 study groups. Protein carbonyls and 3-nitrotyrosine as well as cysteine, uric acid, and lycopene were identified as independent biomarkers with the highest correlation with age. Interestingly, from all antioxidants measured, only lycopene was lower in all aged groups and from the oxidative stress biomarkers, only 3-nitrotyrosine was increased in the descendants from long-living families compared to the middle aged control group. We conclude that both lifestyle and genetics may be important contributors to redox biomarkers in an aging population. PMID- 28804533 TI - In Vivo Radioprotective Activity of Cell-Permeable Bifunctional Antioxidant Enzyme GST-TAT-SOD against Whole-Body Ionizing Irradiation in Mice. AB - GST-TAT-SOD was the fusion of superoxide dismutase (SOD), cell-permeable peptide TAT, and glutathione-S-transferase (GST). It was proved to be a potential selective radioprotector in vitro in our previous work. This study evaluated the in vivo radioprotective activity of GST-TAT-SOD against whole-body irradiation. We demonstrated that intraperitoneal injection of 0.5 ml GST-TAT-SOD (2 kU/ml) 2 h before the 6 Gy whole-body irradiation in mice almost completely prevented the splenic damage. It could significantly enhance the splenic antioxidant activity which kept the number of splenic white pulp and consequently resisted the shrinkage of the spleen. Moreover, the thymus index, hepatic antioxidant activity, and white blood cell (WBC) count of peripheral blood in irradiated mice pretreated with GST-TAT-SOD also remarkably increased. Although the treated and untreated irradiated mice showed no significant difference in the growth rate of animal body weight at 7 days postirradiation, the highest growth rate of body weight was observed in the GST-TAT-SOD-pretreated group. Furthermore, GST-TAT-SOD pretreatment increased resistance against 8 Gy whole-body irradiation and enhanced 30 d survival. The overall effect of GST-TAT-SOD seemed to be a bit more powerful than that of amifostine. In conclusion, GST-TAT-SOD would be a safe and potentially promising radioprotector. PMID- 28804534 TI - mTOR Inhibition Rejuvenates the Aging Gingival Fibroblasts through Alleviating Oxidative Stress. AB - The aging periodontium may be vulnerable to periodontal pathogens and poor response to inflammation and susceptible to tumorigenesis. Human gingival fibroblasts (hGFs) through continuously replicative culture served as an in vitro surrogate for aging. To investigate the effects of the mechanistic target of rapamycin (mTOR) inhibition on the aging gingiva, we stimulated the high-passage hGFs with rapamycin (20 nmol/L) for 3 days and 30 days. The cellular and biological changes were examined by immunofluorescence, real-time PCR, ELISA, Western blotting, and flow cytometry. The data demonstrated that the inhibition of mTOR signaling led to fewer senescence-associated beta-galactosidase- (SA-beta Gal-) positive cells, delayed the onset of senescence, preserved the capability of proliferation, and lowered the expression levels of relevant senescence associated markers, such as p16INK4a, p21CIP1a, interleukin-6 (IL-6), and IL-8. In addition, when infected by prominent periodontal pathogens, Porphyromonas gingivalis (ATCC 33277), rapamycin-pretreated groups decreased the expression of inflammatory cytokines (IL-6 and IL-8) compared with the control group. mTOR inhibition upregulated the gene expression of antioxidant components (Cat, Sod2, and Prdx3; P < 0.05) and consequently neutralized the excessive reactive oxygen species (ROS). In conclusion, our results indicated that mTOR inhibition might rejuvenate the aging gingiva to some extent and relieve inflammation through eliminating oxidative stress. PMID- 28804535 TI - Hongjingtian Injection Attenuates Myocardial Oxidative Damage via Promoting Autophagy and Inhibiting Apoptosis. AB - Natural products with antioxidative activities are widely applied to prevent and treat various oxidative stress related diseases, including ischemic heart disease. However, the cellular and molecular mechanisms of those therapies are still needed to be illustrated. In this study, we characterized the cardioprotective effects of Hongjingtian Injection (HJT), an extensively used botanical drug for treating coronary heart disease. The H/R-induced profound elevation of oxidative stress was suppressed by HJT. HJT also attenuates oxidative injury by promoting cell viability, intracellular ATP contents, and mitochondrial oxygen consumption. Validation experiments indicated that HJT inhibited H/R-induced apoptosis and regulated the expression of apoptosis associated proteins Bcl-2 and cleaved caspase3. Interestingly, HJT significantly regulated the expression of autophagy-related proteins LC3, Beclin, and mTOR as well as ERK and AKT. We provide evidence that the mechanism involves activation of AKT/Beclin-1, AKT, and ERK/mTOR pathway in cardiomyocyte autophagy. Histological and physiological evaluation revealed that HJT significantly decreased the infarct area of the heart, improved cardiac function, and increased the expression of LC3B in a rat model of coronary occlusion. From the obtained data, we proposed that HJT diminished myocardial oxidative damage through regulating the balance of autophagy and apoptosis and reducing oxidative stress. PMID- 28804536 TI - Combined Respiratory Chain Deficiency and UQCC2 Mutations in Neonatal Encephalomyopathy: Defective Supercomplex Assembly in Complex III Deficiencies. AB - Vertebrate respiratory chain complex III consists of eleven subunits. Mutations in five subunits either mitochondrial (MT-CYB) or nuclear (CYC1, UQCRC2, UQCRB, and UQCRQ) encoded have been reported. Defects in five further factors for assembly (TTC19, UQCC2, and UQCC3) or iron-sulphur cluster loading (BCS1L and LYRM7) cause complex III deficiency. Here, we report a second patient with UQCC2 deficiency. This girl was born prematurely; pregnancy was complicated by intrauterine growth retardation and oligohydramnios. She presented with respiratory distress syndrome, developed epileptic seizures progressing to status epilepticus, and died at day 33. She had profound lactic acidosis and elevated urinary pyruvate. Exome sequencing revealed two homozygous missense variants in UQCC2, leading to a severe reduction of UQCC2 protein. Deficiency of complexes I and III was found enzymatically and on the protein level. A review of the literature on genetically distinct complex III defects revealed that, except TTC19 deficiency, the biochemical pattern was very often a combined respiratory chain deficiency. Besides complex III, typically, complex I was decreased, in some cases complex IV. In accordance with previous observations, the presence of assembled complex III is required for the stability or assembly of complexes I and IV, which might be related to respirasome/supercomplex formation. PMID- 28804538 TI - Exendin-4-assisted adipose derived mesenchymal stem cell therapy protects renal function against co-existing acute kidney ischemia-reperfusion injury and severe sepsis syndrome in rat. AB - This study tested the hypothesis that combined therapy with exendin-4 (Ex4) and autologous adipose-derived mesenchymal stem cells (ADMSCs) was superior to either alone for protecting renal function against acute kidney ischemia-reperfusion (IR; 40-min ischemia/27-h reperfusion) injury when complicated by sepsis syndrome (SS; by cecal-ligation-puncture). Adult-male Sprague-Dawley rats (n=40) were equally divided into group 1 (sham-control), group 2 (IR-SS), group 3 (IR-SS + Ex4, 10 MUg/kg subcutaneously 30 min after reperfusion and daily for 3 days), group 4 [IR-SS + ADMSC (1.2 * 106)], and group 5 (IR-SS + Ex4 + ADMSC). The circulating levels of BUN and creatinine and the ratio of urine protein to creatinine were highest in group 2, lowest in group 1, significantly higher in groups 3 and 4 than group 5, and significantly higher in group 3 than in group 4 (all P<0.0001). Microscopic findings of kidney injury score, inflammatory cells (CD14+, F4/80+), and expressions of glomerular-damage indicators (FSP-1+/WT-1+) and renal tubular-damage indicators (KIM-1+/snail+) showed an identical pattern, whereas expressions of indices of glomerular-integrity (ZO-1+/p cadherin+/podocin+/synaptopodin+) and angiogenesis (CD31+/vWF+/number of small vessels) biomarkers demonstrated an opposite pattern, to that of creatinine level (all P<0.001). Protein expressions of inflammatory (MMP-9/IL-1beta/TNF-alpha/TLR 2/TLR-4), apoptotic (cleaved caspase-3/PARP/mitochondrial Bax), and oxidative stress (NOX-1/NOX-2/oxidized protein) biomarkers exhibited an identical pattern, whereas anti-inflammatory (IL-10/IL-4) biomarkers displayed an opposite pattern, to that of creatinine level (all P<0.001). In conclusion, combined Ex4 and ADMSC therapy significantly protected kidney from acute IR-SS injury. PMID- 28804539 TI - miR-371, miR-138, miR-544, miR-145, and miR-214 could modulate Th1/Th2 balance in asthma through the combinatorial regulation of Runx3. AB - Asthma is tightly related to the imbalance of Th1/Th2 cells, and Runx3 plays a pivotal role in the differentiation of T helper cells. The present study aimed to investigate dysregulated microRNAs that may target Runx3 in CD4+ T cells from asthmatic patients and reveal Runx3 function in Th1/Th2 balance regulation. We detected the levels of Th1- and Th2-related cytokines by ELISA and analyzed the differentiation marker gene of T helper cells by qRT-PCR. Results indicated that an imbalance of Th1/Th2 cells was present in our asthmatic subject. Runx3 expression was reduced in the CD4+ T cells from asthmatic patients. Overexpression of Runx3 could restore the Th1/Th2 balance. After performing microRNA microarray assay, we found a series of microRNAs that were considerably altered in the CD4+ T cells from asthmatic patients. Among these upregulated microRNAs, eight microRNAs that may target Runx3 were selected by bioinformatics prediction. Five microRNAs, namely miR-371, miR-138, miR-544, miR-145, and miR 214, were confirmed by qRT-PCR and selected as candidate microRNAs. Luciferase reporter assay showed that these five microRNAs could directly target the 3'-UTR of Runx3. However, only simultaneous inhibition of these five microRNAs could alter the expression of Runx3. Most importantly, only simultaneous inhibition could improve the Th1/Th2 balance. Thus, we suggest that miR-371, miR-138, miR 544, miR-145, and miR-214 can modulate the Th1/Th2 balance in asthma by regulating Runx3 in a combinatorial manner. PMID- 28804537 TI - An integrated approach to coronary heart disease diagnosis and clinical management. AB - The major issue in coronary heart disease (CHD) diagnosis and management is that symptoms onset in an advanced state of disease. Despite the availability of several clinical risk scores, the prediction of cardiovascular events is lacking, and many patients at risk are not well stratified according to the canonical risk factors alone. Therefore, adequate risk assessment remains the most challenging issue. Recently, the integration of imaging data with biochemical markers in a radiogenomic framework has been proposed in many fields of medicine as well as in cardiology. Multimodal imaging and advanced processing techniques can provide both direct (e.g., remodeling index, calcium score, total plaque volume, plaque burden) and indirect (e.g., myocardial perfusion index, coronary flow reserve) imaging features of CHD. Furthermore, the identification of novel non-invasive biochemical markers, mainly focused on plasma and/or serum samples, has increased the specificity of findings, reflecting several pathophysiological pathways of atherosclerosis, the principal actor in CHD. In this context, a multifaced approach, derived from the strengths of all these modalities, appears promising for finer risk stratification and treatment strategies, facilitating the decision making and clinical management of patients. This review underlines the role of different imaging modalities in the quantification of coronary atherosclerosis and describes novel blood-based markers that could improve diagnosis and have a better predictive value in CHD. PMID- 28804540 TI - Restoration of bone defects using modified heterogeneous deproteinized bone seeded with bone marrow mesenchymal stem cells. AB - The aim of the present study was to investigate the effect of modified heterogeneous deproteinized bone combined with bone marrow mesenchymal stem cells (BMSCs) in the restoration of a validated bone defect model. BMSCs were identified by flow cytometry and multilineage differentiation assay. The structural features of the modified heterogeneous deproteinized bone scaffold and biocompatibility between BMSCs and the scaffold were confirmed by scanning electron microscope (SEM) detection. The cytotoxicity of the modified heterogeneous deproteinized bone scaffolds were detected by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenytetrazolium bromide (MTT) assay. SEM detection proved that modified heterogeneous deproteinized bone scaffold had no negative impact on the proliferation of BMSCs. MTT assay results demonstrated that the scaffold had no apparent cytotoxicity. Biomechanical detection showed that the stiffness and ultimate loading of tibias in the scaffold + BMSCs group were significantly higher than those of the scaffold alone group (P < 0.05) and the control group (P < 0.01). Histological analyses confirmed that the greatest quantity of new bone was generated in the scaffold + BMSCs group, when compared with all other groups, at 8 weeks' post-operation. The bone mineral density (BMD) in the scaffold + BMSC group was significantly higher than that of the scaffold alone group (P < 0.05) and the control group (P < 0.01). Fluorometric analyses confirmed the presence of BMSCs at high concentration within the bone defect areas in the scaffold + BMSCs group at 4 weeks after transplantation. These findings suggest that the modified heterogeneous deproteinized bone scaffold seeded with BMSCs can effectively enhance the restoration of bone defects. PMID- 28804541 TI - A potential role for the Hippo pathway protein, YAP, in controlling proliferation, cell cycle progression, and autophagy in BCPAP and KI thyroid papillary carcinoma cells. AB - PURPOSE: The aims were two-fold: first, to examine the expression of Yes activated protein (YAP), a key Hippo pathway regulator, in clinical thyroid papillary carcinoma samples and to correlate this with clinicopathological parameters; second, to explore the role of YAP in regulating cell growth and division in vitro. METHODS AND RESULTS: YAP expression was determined by immunohistochemistry of clinical thyroid papillary carcinoma tissue microarrays and expression was correlated with clinicopathological parameters. YAP expression positively correlated with TNM stage and lymph node metastasis. The effect of YAP gene silencing by siRNA on BCPAP and KI cell migration, invasion, apoptosis, cell cycle progression (including expression of the cell cycle regulators, p21, p27, c Myc, and Foxo3a1), and the expression of autophagy markers (Belcin1, LC3-I, LC3 II, Atg12, Atg16L1, and Atg5) were examined. YAP gene silencing decreased cell proliferation, migration, and invasion. In contrast, there was no effect on cell apoptosis, but cells arrested at G0/G1, and this was accompanied by down regulation of c-Myc and Foxo3a and up-regulation of the cell cycle proteins, p21 and p27. The autophagy marker LC3-I was expressed at slightly higher levels than LC3-II; YAP silencing decreased both LC3-1 and LC3-II protein expression, resulting in an increase in the LC3-II/LC3-I ratio, this process was accompanied by decreases in Beclin1 and Atg5-Atg12-Atg16 complex expression. CONCLUSIONS: In papillary thyroid cancer YAP protein expression is positively correlated with the extent of TNM stage and positive lymph node metastasis. In thyroid cancer cell lines YAP appears to be important in stimulating cell proliferation while inhibiting autophagy. PMID- 28804542 TI - Significant association of TREM-1 with HMGB1, TLRs and RAGE in the pathogenesis of insulin resistance in obese diabetic populations. AB - Activated cell surface and intracellular receptors lead to insulin resistance in obesity. Among these receptors, triggering receptors expressed on myeloid cells (TREM)-1, toll like receptors (TLRs), and receptors for advanced glycation end products (RAGE) play a significant role in the induction of inflammatory response in innate immunity. TREM-1 potentially amplifies TLRs and RAGE synergistically with DNA-binding high-mobility group box 1 (HMGB-1). The objective of the study was to analyze the association between TREM-1/DAP12 and HMGB-1, RAGE and TLRs in obesity-induced insulin resistance. We examined the mRNA expression by RT-PCR and protein expression by Western blotting and immunofluorescence for TREM-1, TREM-2, DAP-12, HMGB-1, RAGE, TLR-4 and TLR-2 in omentum, subcutaneous and liver biopsy tissues of obese diabetic (n=22) and non-diabetic subjects (n=24) and compared with the non-obese non-diabetic controls (n=5). There was a significantly increased expression of TREM-1, DAP-12, HMGB-1, RAGE, TLR-4 and TLR-2 and decreased expression of TREM-2 in the omentum, subcutaneous and liver biopsy of obese diabetic subjects compared to obese non-diabetics and the non-obese population. Overall, obese diabetic subjects had high expression of TREM-1 in association with HMGB1 (100% vs 58.3%, P=0.003), RAGE (77.3% vs 41.7%, P=0.045), TLR4 (100% vs 58.3%, P=0.003), and TLR2 (100% vs 50%, P=0.003) in liver biopsy samples in comparison to obese non-diabetic subjects. Obese diabetics have significantly increased TREM-1, HMGB1, RAGE, and TLRs compared to obese non diabetics. Our findings suggest a potential pathophysiological role of TREM-1 in conjunction with HMGB1 and inflammatory cell receptors (RAGE, TLR-4 and TLR-2) in obesity-induced insulin resistance. PMID- 28804543 TI - Light of DNA-alkylating agents in castration-resistant prostate cancer cells: a novel mixed EGFR/DNA targeting combi-molecule. AB - OBJECTIVE: The mechanism underlying the therapeutic effects of combi-molecule JDF12 on prostate cancer (PCa) DU145 cells remains still unclear. This study aimed to investigate the proteomic profile after JDF12 treatment in DU145 cells by comparing with that in Iressa treated cells and untreated cells. METHODS: MTT was used to evaluate drug cytotoxicity, DAPI staining was done to assess apoptosis of cells, and flow cytometry was used to analyze cell cycle. iTRAQ and qPCR were employed to obtain the proteomic profiles of JDF12 treated, Iressa treated, and untreated DU145 cells, and validate the expression of selected differentially expressed proteins, respectively. RESULTS: JDF12 could significantly inhibit the proliferation and increase the apoptosis of DU145 cells when compared with Iressa or blank group. In total, 5071 proteins were obtained, out of which, 42, including 21 up-regulated and 21 down-regulated proteins, were differentially expressed in JDF12 group when compared with Iressa and blank groups. The up-regulated proteins were mainly involved in DNA damage/repair and energy metabolism; while the down-regulated proteins were mainly associated with cell apoptosis. qPCR confirmed the expression of several biologically important proteins in DU145 cells after JDF12 treatment. CONCLUSION: The molecular mechanisms of DNA alkylating agents on PCa therapy that with the assistant of EGFR-blocker were revealed on proteomic level, which may increase the possible applications of DNA alkylating agents and JDF12 on PCa therapy. PMID- 28804544 TI - SIRT3 attenuates AngII-induced cardiac fibrosis by inhibiting myofibroblasts transdifferentiation via STAT3-NFATc2 pathway. AB - Cardiac fibrosis is a maladaptive response to various stresses, characterized by increased interstitial collagen deposition and progressive cardiac dysfunction. The transdifferentiation of fibroblasts into myofibroblasts is an essential process in the pathogenesis of cardiac fibrosis. SIRT3, as a mitochondrial NAD+ dependent histone deacetylase, has been demonstrated beneficial in many cardiovascular diseases. However, the specific mechanism of its protective role in cardiac fibrosis needs to be elucidated further. Here, we determined the role of SIRT3 in cardiac fibrosis by subjecting Sirt3-knockout mice to chronic AngII infusion for four weeks in vivo. In this study, the Sirt3-knockout mice developed more serious cardiac fibrosis compared to wild-type controls. In vitro, primary cardiac fibroblasts from Sirt3-knockout mice transdifferentiated into myofibroblasts spontaneously and this phenotype conversion exaggerated after AngII stimulation. The SIRT3-KO myofibroblasts secret more fibrotic mediators including TGF-beta to promote cardiac fibrosis. In addition, the overexpression of SIRT3 by lentivirus transfection attenuated myofibroblasts transdifferentiation. We further demonstrated that SIRT3 directly binds to and deacetylates STAT3 to inhibit its activity. Sequentially the downstream factor, known as NFATc2, showed a reduced expression. Taken together, these results revealed that SIRT3 can protect against cardiac fibrosis by inhibiting myofibroblasts transdifferentiation via the STAT3-NFATc2 signaling pathway. PMID- 28804545 TI - Hydrogen sulfide prevents diaphragm weakness in cecal ligation puncture-induced sepsis by preservation of mitochondrial function. AB - Mitochondrial dysfunction plays an important role in the pathogenesis of diaphragm weakness during sepsis. Recently, hydrogen sulfide (H2S), a gaseous transmitter endogenously generated by cystathionine-beta-synthase (CBS), cystathionine-gamma-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST), is found to improve mitochondrial function. The present study aimed to examine whether H2S synthases are expressed in the diaphragm, and investigated the effect of H2S donor in sepsis-induced diaphragm weakness and its relationship with mitochondrial function. Immunohistochemical staining of the rat diaphragm revealed that positive immunoreactivity for CBS, CSE as well as 3-MST was predominately localized to muscle cells. Using a cecal ligation and puncture (CLP)-induced sepsis model, it was found that CBS and CSE, but not 3-MST, was significantly down-regulated in the diaphragm at 24 h post-CLP compared with sham group. To determine the effect of H2S on sepsis-induced diaphragm weakness, H2S donor NaHS was intraperitoneally administered 30 min after CLP operation. NaHS at a dose of 50 MUmol/kg significantly decreased the mortality in septic rats. CLP markedly reduced diaphragm-specific force generation (force/cross-sectional area and maximal titanic force), which was improved by NaHS treatment. In addition, CLP caused mitochondrial damage in the diaphragm tissues as evidenced by increased mitochondrial superoxide production, decreased mitochondrial membrane potential and ATP production, as well as mitochondrial ultrastructural abnormalities, which was also attenuated by NaHS treatment. These findings indicate that H2S donor may prevent sepsis-induced diaphragm weakness by preservation of mitochondrial function, suggesting that modulation of H2S levels may be considered as a potential therapeutic approach for diaphragm dysfunction during sepsis. PMID- 28804546 TI - CCR7 enhances the angiogenic capacity of esophageal squamous carcinoma cells in vitro via activation of the NF-kappaB/VEGF signaling pathway. AB - High levels of angiogenesis are associated with poor prognosis and a highly invasive phenotype in esophageal squamous carcinoma. C-C chemokine receptor type 7 (CCR7) is overexpressed in multiple tumor types and has been suggested to act as an oncogene and pro-angiogenic factor. This study aimed to elucidate the effect of CCR7 on the angiogenic capacity of esophageal squamous carcinoma cells in vitro. Expression of CCR7 in esophageal squamous carcinoma cell lines and normal human esophageal epithelial cell line was examined by western blotting and quantitative real-time PCR. CCR7 was stably overexpressed or transiently knocked down in esophageal squamous carcinoma cell lines. Overexpressing CCR7 enhanced the capacity of esophageal squamous carcinoma cell conditioned media to induce human umbilical vein endothelial cells (HUVEC) proliferation and migration and neovascularization in the chicken chorioallantoic membrane (CAM) assay. While silencing CCR7 caused an opposite outcome. Moreover, we demonstrated that CCR7 activated nuclear factor kappa-light-chain-enhancer of activated B cells (NF kappaB) signaling and regulated its targets, including vascular endothelial growth factor A (VEGF-A), VEGF-C, tumor necrosis factor-alpha (TNFalpha), interleukin (IL)-6, IL-8 and transforming growth factor-beta (TGF-beta) expression. Additionally, CCR7 down-regulation reduced tumor volume and weight in xenograft mouse model, and significantly decreased NF-kappaB signaling pathway. This study suggests that CCR7 plays an important pro-angiogenic role in esophageal squamous carcinoma via a mechanism linked to activation of the NF kappaB pathway; CCR7 may represent a potential target for anti-angiogenic therapy in esophageal squamous carcinoma. PMID- 28804547 TI - EphA2 targeted intratumoral therapy for non-small cell lung cancer using albumin mesospheres. AB - Lung cancer, primarily non-small cell lung cancer (NSCLC), is the leading cause of cancer mortality and the prognosis of patients with advanced or metastatic NSCLC is poor. Despite significant advances in diagnosis and treatment, little improvement has been seen in NSCLC mortality. Recently, Intratumoral Chemotherapy, a direct local delivery of chemotherapeutic drugs, has shown promise in clinical studies. However, toxicity and high dosage of chemotherapeutic agents used for treatment are a limitation. Moreover, these drugs damage indiscriminately, cancerous as well as normal tissues. Thus, a novel therapeutic strategy that targets only malignant tissue sparing normal tissue becomes an urgent issue. Ephrin receptor-A2 (EphA2), a new biomarker, is over expressed in NSCLC, but not on normal epithelial cells. Receptor EphA2 is a cell surface protein, which upon binding to its ligand EphrinA1 undergo phosphorylation and degradation which attenuates NSCLC growth. Targeting the tumor, sparing the normal tissue and enhancing the therapeutic effects of ligand proteins are the goal of this project. Thus a novel method, intratumoral EphA2 targeted therapy, has been developed to target the oncogenic receptors on tumor tissue by using albumin mesosphere (AMS) conjugated ephrinA1 in mice bearing NSCLC tumors. PMID- 28804548 TI - Overexpression of PTEN suppresses non-small-cell lung carcinoma metastasis through inhibition of integrin alphaVbeta6 signaling. AB - Studies have demonstrated that the abnormal expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is associated with multiple malignancies, but its functional role in non-small-cell lung carcinoma (NSCLC) metastasis remains to be elucidated. In the present study, we investigated the role of PTEN in regulating proliferation, migration, and invasion of NSCLC cells by establishing NSCLC cell strains with constitutively silenced or elevated PTEN expression. We demonstrated that ectopic expression of PTEN inhibits migration and invasion of NSCLC cells in vitro through wound healing and Transwell invasion assays. Furthermore, PTEN overexpression in NSCLC cells greatly inhibits cell viability and colony formation, which was confirmed by MTT and colony formation assays. Conversely, further analysis indicated that suppression of PTEN expression via shRNA promotes metastasis and growth of NSCLC cells. Finally, our findings demonstrate that PTEN promotes invasion and migration of NSCLC cells through the integrin alphaVbeta6 signaling pathway. Overall, this study provides novel insights into the role of PTEN as a crucial regulator of NSCLC cell metastasis, and suggests that targeted treatment of PTEN-expressing tumors serves as a new therapeutic target for NSCLC. PMID- 28804549 TI - Treatment effect of low intensity pulsed ultrasound on leukopenia induced by cyclophosphamide in rabbits. AB - OBJECTIVE: This study aims to examine the effects of low intensity pulsed ultrasound (LIPUS) on leukopenia induced by cyclophosphamide in a rabbit model. METHODS: The leukopenia model in New Zealand rabbit was established by injecting cyclophosphamide into the ear vein. Forty leukopenia model rabbits were randomly allocated to control group (n = 20) and LIPUS group (n = 20). LIPUS group underwent 20 minutes of daily ultrasound treatment at femoral metaphysis for 7 days while control group received sham treatment. Diarrhea rate, mortality and blood cell count were calculated. IgA, IgG and IgM levels were measured by ELISA. Flow cytometry was used to detect CD44, CD49d, and PU.1. HE staining was performed to analyze bone marrow hyperplasia and changes of skin and muscle. RESULTS: LIPUS treatment significantly promoted the proliferation of bone marrow nucleated cells, increased the number of WBC, IgA, IgG and IgM in the peripheral blood, and reduced the diarrhea rate and mortality. The irradiated skin and muscle tissues showed no obvious damages. LIPUS treatment promoted the migration of hematopoietic cells to peripheral blood by decreasing the expression of CD49d and CD44 on the surface of CD34 positive cells. It also promoted the differentiation of hematopoietic stem cells into granulocytes and lymphocytes by decreasing the expression of PU.1. CONCLUSION: LIPUS can be used as a safe and effective clinical treatment for cyclophosphamide induced leukopenia. PMID- 28804550 TI - Long noncoding RNA MEG3 suppressed endothelial cell proliferation and migration through regulating miR-21. AB - Long non-coding RNAs (lncRNAs) act critical roles in many biological processes, including cell proliferation, apoptosis, development, invasion and migration. LncRNA maternally expressed gene 3 (MEG3) is found to be downregulated in several tumors; however, its role in the atherosclerosis is still unknown. In the present study, we demonstrated that MEG3 expression level was downregulated in the coronary artery disease (CAD) tissues compared to in the control tissues. We also showed that TNF-alpha enhanced EC cell proliferation. In addition, the expression of MEG3 was increased in EC after treated with TNF-alpha. Overexpression of MEG3 suppressed EC cell proliferation and inhibited the expression of cyclin D1, ki-67 and PCNA. Elevated expression of MEG3 suppressed the type I collagen, type V collagen and proteoglycan expression. In addition, we showed that elevated expression of MEG3 suppressed the miR-21 expression in the EC and promoted the expression of RhoB and PTEN, which were the direct target genes of miR-21. We demonstrated that miR-21 expression level was upregulated in the CAD tissues compared to in the control tissues. Moreover, miR-21 expression was reversely correlated with MEG3 expression in the CAD tissues. Overexpression of MEG3 suppressed EC cell proliferation and type I collagen, type V collagen and proteoglycan expression through inhibiting miR-21 expression. These results suggested that MEG3 played a critical role in regulating EC proliferation and type I collagen, type V collagen and proteoglycan expression partly through suppressing miR-21 expression. PMID- 28804551 TI - A tumor-suppressive microRNA, miRNA-485-5p, inhibits glioma cell proliferation and invasion by down-regulating TPD52L2. AB - Glioblastoma multiforme is the most deadly primary brain tumor and has no effective treatment. Therefore, it is important to identify novel and effective therapies that impede glioma tumorigenesis. MicroRNAs (miRNAs) are helpful analytical biomarkers and may be useful targets for treating multiple human cancers. Previous reports suggest that miRNA-485-5p is dysregulated and contributes to tumorigenesis in some cancer types. Nevertheless, the biological role of miRNA-485-5p in glioma is not well understood. In this study, we demonstrated that miRNA-485-5p expression was reduced in gliomat issues and cell lines. In addition, miRNA-485-5p overexpression inhibited cell proliferation, migration, and invasion in glioma cell lines. Additionally, we identified Tumor Protein D52 Like 2 (TPD52L2) as a direct target of miRNA-485-5p. Moreover, we showed that miRNA-485-5p regulated glioma tumorigenesis by down-regulating TPD52L2 expression in vitro and in vivo. Our results suggest that miRNA-485-5p is a suppressor of glioma tumorigenesis and could serve as a novel candidate for therapeutic applications in glioma treatment. PMID- 28804553 TI - Sirt3 attenuates doxorubicin-induced cardiac hypertrophy and mitochondrial dysfunction via suppression of Bnip3. AB - Doxorubicin (Dox) is an anthracycline antibiotic widely used in cancer treatment. Although its antitumor efficacy appears to be dose dependent, its clinical use is greatly restricted by development of cardiotoxicity. Sirtuin-3 (Sirt3) is the major deacetylase within the mitochondrial matrix that plays an important role in regulation of cardiac function. This study was performed to identify the regulatory role of Sirt3 on Dox-induced cardiac hypertrophy and mitochondrial dysfunction in rats in vivo and in vitro. We found that adenovirus-mediated overexpression of Sirt3 resulted in marked inhibition of Dox-induced cardiac hypertrophy, particularly mitochondrial dysfunction including opening of the mitochondrial permeability transition pore (mPTP), loss of mitochondrial membrane potential (DeltaPsim), respiration dysfunction, and mitochondrial reactive oxygen species (ROS) production. Further study revealed that Bcl-2-like 19 kDa interacting protein 3 (Bnip3) mRNA and protein expression levels were altered in cardiomyocytes in vivo and in vitro after Dox treatment, and these increases were significantly inhibited by Sirt3 overexpression. Interestingly, the Dox-disrupted mitochondrial Cox1-Ucp3 complexes were preserved by Sirt3 overexpression. Finally, recombinant adeno-associated virus-mediated overexpression of Bnip3 (AAV Bnip3) in rat hearts and cardiomyocytes completely impaired the protective effects of Sirt3 on Dox-induced cardiac toxicity and mitochondrial dysfunction. These findings reveal a new molecular mechanism in which Sirt3 restores mitochondrial respiratory chain defects, and cell viability of Dox-damaged cardiomyocytes is mutually dependent on and obligatorily linked to suppression of Bnip3 gene expression. Interventions that antagonize Bnip3 may contribute to the beneficial effect of Sirt3 regarding prevention of mitochondrial injury and heart failure in cancer patients undergoing chemotherapy. PMID- 28804552 TI - In vivo opening of the mitochondrial permeability transition pore in a rat model of ventricular fibrillation and closed-chest resuscitation. AB - Opening of the mitochondrial permeability transition pore (mPTP) is considered central to reperfusion injury. Yet, most of our knowledge comes from observations in isolated mitochondria, cells, and organs. We used a rat model of ventricular fibrillation (VF) and closed-chest resuscitation to examine whether the mPTP opens in vivo and whether cyclosporine A (CsA) attenuates the associated myocardial injury. Two series of 26 and 18 rats each underwent 10 minutes of untreated VF before attempting resuscitation. In series-1, rats received 50 uCi of tritium-labeled 2-deoxyglucose ([3H]DOG) harvesting their hearts at baseline (n=5), during VF (n=5), during resuscitation (n=6), and at post-resuscitation 60 minutes (n=5) and 240 minutes (n=5). mPTP opening was estimated measuring the ratio of mitochondria to left ventricular intracellular [3H]. In series-2, rats received 10 mg/kg of CsA or vehicle before resuscitation, measuring mitochondrial NAD+ content to indirectly assess mPTP opening. In Series-1, the mPTP opening ratio vs baseline (10.4 +/- 1.9) increased during VF (16.8 +/- 2.4, NS), closed chest resuscitation (20.8 +/- 6.3, P<0.05), and at post-resuscitation 60 minutes (20.9 +/- 4.7, P<0.05) and 240 minutes (25.7 +/- 11.0, P<0.01). In series 2, CsA failed to attenuate reductions in mitochondrial NAD+ and did not affect plasma cytochrome c, plasma cardiac troponin I, myocardial function, and survival. We report for the first time in an intact rat model of VF that mPTP opens during closed-chest resuscitation consistent with previous observations in mitochondria, cells, and organs of mPTP opening upon reperfusion. CsA, at the dose of 10 mg/kg neither prevented mPTP opening nor attenuated post-resuscitation myocardial injury. PMID- 28804554 TI - Effect of omiganan on colonic anastomosis healing in a rat model of peritonitis. AB - BACKGROUND: This study investigates the effects of the antimicrobial cationic peptide omiganan-alone and combined with the antibiotic imipenem-on colonic anastomosis healing in presence of intraperitoneal sepsis induced in a rodent model of cecal ligation and puncture (CLP). METHODS: Forty male Wistar rats were divided into 5 groups of 8 animals. Group 1 (control group) underwent laparotomy and cecal mobilization and the next day received left colon anastomosis. In group 2 (CLP without treatment), group 3 (CLP + imipenem), group 4 (CLP + omiganan), and group 5 (CLP + omiganan + imipenem), the left colon anastomosis was performed the day after CLP. Imipenem and omiganan were administered by intraperitoneal injection immediately before anastomosis construction and subsequently at 24 h intervals until the 7th postoperative day, when rats were sacrificed. Anastomotic bursting pressure was measured in situ. Tissue samples were collected for determination of hydroxyproline content and histological characteristics. RESULTS: Only rats receiving omiganan + imipenem displayed re-epithelialization, reduced neovascularization of granulation tissue, and a bursting pressure that was similar to that of controls. Omiganan-alone and combined with imipenem-was associated with a better control of inflammatory parameters than imipenem alone. In addition omiganan, like imipenem, counteracted the collagen depletion typical of sepsis. CONCLUSIONS: This experimental study demonstrates the efficacy of the new antimicrobial agent omiganan, alone and in combination with imipenem, in delaying the effects of intraperitoneal sepsis on colonic anastomosis healing and provides evidence of the value of omiganan as a therapeutic agent. PMID- 28804555 TI - IMP3 is upregulated in primary ovarian mucinous carcinoma and promotes tumor progression. AB - OBJECTIVE: Primary ovarian mucinous tumors progress from benign adenoma to borderline tumors to invasive mucinous carcinoma. A proper differential diagnosis is crucial to discriminate malignancies at the early stages of disease. However, few biomarkers are clinically available. We designed this study to analyze the clinical application of the oncogene IMP3 in monitoring early malignancies in ovarian primary mucinous tumors. METHODS: We collected 250 samples of ovarian primary mucinous tumors along with the corresponding clinicopathological information between 2009 and 2015 at the Gynecology and Obstetrics Hospital of Fudan University and performed immunochemical assays. Statistical analysis of the correlation between expression of IMP3 and clinic-pathological parameters as well as the survivals of these patients was carried out. Finally, wound-healing and transwell assays were performed in SKOV3 and CAOV3 cells. RESULTS: The expression rate and intensity of IMP3 were much higher in invasive carcinoma than those in benign adenoma and classic borderline adenoma (P<0.05). The expression rate and intensity of IMP3 were also higher in cases with mucinous intraepithelial carcinoma than those in cases with classic borderline tumors (P<0.05). Among the malignant cases, the expression rate and intensity of IMP3 increased with advancing FIGO staging (P<0.05). The expression rate and intensity of IMP3 were much higher in cases with involved fallopian tubes, uterine and omentum than those in cases without the involvement of these tissues (P<0.05). The expression rate and intensity of IMP3 were much higher in cases with lymph node metastasis than those in cases without lymph node metastasis (P<0.05). Elevated expression of IMP3 significantly deteriorated the disease-free survival (DFS) and overall survival (OS) of mucinous carcinoma (P<0.05). IMP3 was an independent risk factor of DFS but not OS. Further in vitro experiments indicated that IMP3 promoted the proliferation, motility and invasive potential of ovarian tumor cells. CONCLUSIONS: IMP3 is highly expressed in ovarian mucinous tumors and is positively correlated with malignancy. IMP3 could be used in the differential diagnosis of ovarian mucinous tumors and might be applicable in monitoring tumor initiation and progression. PMID- 28804556 TI - Anti-tumor efficacy evaluation of a novel monoclonal antibody targeting neutral amino acid transporter ASCT2 using patient-derived xenograft mouse models of gastric cancer. AB - ASC amino acid transporter 2 (ASCT2), also known as solute linked carrier family 1 member A5 (SLC1A5) is a Na+-dependent glutamine/neutral amino acid transporter. ASCT2 acts as a high-affinity transporter of L-glutamine (Gln) and has been reported to be up-regulated in a variety of cancerous tissues including stomach, liver, and kidney. In this study, we evaluated anti-tumor efficacy of a novel anti-ASCT2 humanized monoclonal antibody, KM8094, which has a neutralizing activity against glutamine uptake, as a therapeutic antibody against gastric cancer and explored clinical predictive biomarker candidates by utilizing patient derived xenograft (PDX) mouse models. Anti-tumor efficacy studies revealed that some of the PDX models used were responsive to KM8094 and the others were not. Interestingly, we observed a correlation between anti-tumor efficacy and low antigen expression as well as low basal levels of glutamine uptake, suggesting ASCT2 expression level could be a potential predictive biomarker for KM8094. We then further explored predictive biomarker candidates by multi-omics analysis on gastric cancer PDX mouse models. As a result, a few potential candidates such as TFF2, MUC13, and ANG were selected by gene expression and DNA methylation array analyses. In addition, metabolomics analysis revealed clear differences in intracellular energy status and redox status between responsive and non responsive PDX models. PMID- 28804557 TI - Motor neuron degeneration following glycine-mediated excitotoxicity induces spastic paralysis after spinal cord ischemia/reperfusion injury in rabbit. AB - Spinal cord ischemia and reperfusion (SCIR) injury is the major cause of a wide range of complications, including neural degeneration and devastating paraplegia. Decrease of inhibitory neurotransmitters and increase of excitory neurotransmitters are the major cause for the excitotoxicity of neurons. However, no study has reported the temporal loss of motor neuron in the ventral horn of spinal cord area following SCIR-induced spastic paralysis, not even the mechanism under it. In the present study, we found that the rabbits were mainly spastic paralyzed after spinal cord ischemia-reperfusion injury. And the ischemia 60 min group is the optimal treating condition, because of the higher rate of spastic paralysis and lower mortality. Motor neurons in the ventral horn of spinal cord were significant degeneration at 3 h following spastic paralysis and only 12.5% motor neurons were observed at 72 h post-operation, compared with control group. ELISA results indicated that Glycine and GABA were both downregulated following spastic paralysis. But Glycine immediately decreased at 10 min post-operation and lasted for the whole process (at least 72 h). Meanwhile GABA only significantly decreased at 72 h. Furthermore, Glutamic expression was significant upregulation at 3 hours post-operation, and the upregulation back to the base level at 72 h post-operation. Glutamic receptor-(NR1) and Glycine alpha1 receptor upregulated accordingly, whereas GABBR2 didn't upregulate significantly until at 72 h post operation. Abundant extracellular Ca2+ influxed into cytoplasm in neurons following spastic paralysis. The type of paraplegia is mainly spastic paraplegia after SCIR (ischemia 60 min treatment). Following spastic paraplegia, motor neuron in the ventral horn of spinal cord area was significant degeneration at early stage and last for the whole process. It may contribute to the decrease of Glycine at early stage and followed exitotoxicity, which caused intracellular calcium overload to make neurons dead. It would lay the foundation for better understanding the motor neuron degeneration and mechanism following spastic paralysis. And it would supply a novel and effective target for spastic paralysis prevention and therapy. PMID- 28804558 TI - NADPH oxidase 2 inhibitor diphenyleneiodonium enhances ROS-independent bacterial phagocytosis in murine macrophages via activation of the calcium-mediated p38 MAPK signaling pathway. AB - Activation of NADPH oxidase 2 (NOX2) triggers reactive oxygen species (ROS) generation, both of which are essential for robust microbial clearance by phagocytes. However, it is unknown whether inhibition of NOX2 activation or ROS generation affects cellular phagocytosis. Here, we found that the classic NOX2 inhibitor diphenyleneiodonium (DPI) induced uptake of E. coli by murine peritoneal macrophages through enhancing phagocytosis, and this effect was temperature-sensitive and attenuated by cytochalasin D as well as chemical inhibition of Syk and PLCgamma, two downstream kinases involved in actin polymerization during phagocytosis. DPI also decreased the production of TNF alpha and IL-6 resulting from E. coli stimulation. The DPI-induced enhancement of phagocytosis was independent of NOX2 inhibition or ROS generation but depended on increased intracellular calcium and activation of the p38 MAPK signaling pathway. Furthermore, DPI enhanced bacterial elimination and ameliorated inflammation in E. coli-infected mice, leading to improved survival. Our results demonstrate that DPI facilitates ROS-independent bacterial phagocytosis by macrophages through activation of calcium and p38 MAPK signaling pathways. PMID- 28804559 TI - MicroRNA-1907 enhances atherosclerosis-associated endothelial cell apoptosis by suppressing Bcl-2. AB - Injury and endothelial cell apoptosis are hall marks of atherosclerosis (AS). However, the mechanisms underlying its pathogenesis remain ill-defined. Recent evidence of a role for microRNAs in AS-associated endothelial cell apoptosis encouraged us to address this question. Here, AS was developed in ApoE (-/-) mice supplied with a high-fat diet (HFD), compared to ApoE (-/-) mice supplied with a normal diet (ND). Mouse endothelial cells were isolated from the aortic arch using flow cytometry based on their expression of CD31. Human aortic endothelial cells (HAECs) were treated with oxidized low-density lipoprotein (ox-LDL) as an in vitro model for AS. Gene expression was quantified by RT-qPCR and protein levels were analyzed by Western blotting. Apoptosis was evaluated by FITC Annexin V Apoptosis assay and by TUNEL staining. Predicting binding patterns between miRNAs and the 3'-UTR of mRNA from the target gene was performed by bioinformatics analyses and confirmed by a dual luciferase reporter assay. We found that HFD mice, but not ND mice, developed AS in 12 weeks. A significant reduction in endothelial cells and a significant increase in mesenchymal cells were detected in the aortic arch of the HFD mice, compared to those of ND mice. Endothelial cell apoptosis was significantly higher in HFD mice, seemingly due to functional suppression of protein translation of anti-apoptotic Bcl-2 protein through upregulation of miR-1907, confirmed by in vitro analysis. Moreover, inhibition of miR-1907 abolished the effects of ox-LDL-induced apoptotic cell death on HAECs. Thus, AS-associated endothelial cell apoptosis may partially result from downregulation of Bcl-2, via upregulation of miR-1907 which binds and suppresses the translation of Bcl-2 mRNA. PMID- 28804560 TI - Mechanisms of miR-145 regulating invasion and metastasis of ovarian carcinoma. AB - MicroRNA-145 (miR-145) can regulate tumor cell invasion, metastasis, apoptosis, proliferation and stem cell differentiation. However, the molecular mechanisms of miR-145 used to regulate ovarian invasion and metastasis remain to be determined. In this study, Transwell cell migration and wound healing assays were used to detect the effects of miR-145 upregulation on ovarian carcinoma cell invasion and metastasis, respectively. The MUC1 expression vector, together with quantitative real-time PCR and Western blotting, was used to investigate the effects of miR 145 on E-cadherin (E-cad)-induced cell invasion and the related molecular mechanisms. The results showed that miR-145 mimics could inhibit SKOV3 cell invasion and metastasis. MiR-145 inhibited mucin 1 (MUC1) post-transcriptional expression by binding to its 3'-untranslated region. The epithelial mesenchymal transition marker E-cad, which is a downstream molecule of MUC1, was promoted by miR-145 overexpression. Furthermore, the E-cad protein level was inversely correlated with MUC1 expression in SKOV3 cells. These observations indicated that promotion of E-cad signaling induced by miR-145 was restrained by MUC1 inhibition. Thus, miR-145 may serve as a tumor suppressor which can downregulate E-cad expression by targeting MUC1, leading to the inhibition of tumor invasion and metastasis. Using miR-145 mimics may be a rational approach for therapeutic applications in ovarian carcinoma in the future. PMID- 28804561 TI - Upregulation of miR-130b protects against cerebral ischemic injury by targeting water channel protein aquaporin 4 (AQP4). AB - Altered microRNA regulation has been implicated in the pathogenesis of various disorders, including cerebral ischemia/reperfusion injury (I/RI). However, the regulatory mechanism of miR-130b in cerebral ischemia injury has not been reported. In this study, we explored the role of miR-130b in cerebral ischemia injury and investigated its potential mechanism. Levels of miR-130b were quantified by real-time PCR, and the protein level of AQP4 was detected by Western blotting. Cell apoptosis was detected by flow cytometry. In vitro, miR 130b levels in astrocytes were found significantly downregulated after OGD. Overexpression of miR-130b by miR-130b mimic decreased LDH release and apoptosis, but promoted cell health of astrocytes with OGD, thus playing a protective role in astrocyte I/RI. The level of miR-130b was also downregulated in ischemic tissues in MCAO model compared with the sham group, and the expression of miR 130b was gradually downregulated over time after reperfusion. AQP4 was upregulated both in two models, and as the reperfusion went on, AQP4 expression gradually upregulated. Our results indicated knockdown of AQP4 could ameliorate astrocyte injury induced by OGD. Finally, we found that miR-130b regulated astrocyte expression of AQP4, and rescue experiments further proved the protective role of miR-130b was mediated by AQP4 downregulation. Our study demonstrated that miR-130b might exert a neuroprotective effect following cerebral I/RI by regulating AQP4 expression at the post-transcriptional level. Therefore, miR-130b may be a potential therapeutic target for stroke treatment. PMID- 28804562 TI - Premature exhaustion of mesenchymal stromal cells from myelodysplastic syndrome patients. AB - Myelodysplastic syndrome (MDS) predominantly occurs in aging people. Over the past decades, the cellular and molecular pathologies of MDS cells have been intensively investigated. However, how the bone marrow stromal niches are altered during MDS development remains elusive. In this study, we attempted to isolate and characterize mesenchymal stromal cells (MSCs) from 30 MDS patients. We observed that only 9/30 bone marrow aspirations from MDS patients successfully formed a monolayer in vitro, while 17/17 bone marrow aspirations from normal donors (median age 45 years, range: 22-73 years) succeeded in this process. Compared to normal MSCs, the MDS MSCs showed premature exhaustion, including reduced osteogenic differentiation ability, slower passage rate, and extremely limited passage times. These functional defects were associated with downregulation of Osterix and Runx2 genes and increased cell cycle arrest and apoptosis. However, the premature exhaustion of MDS MSCs did not correlate with patients' ages, indicating that natural aging is not the cause of dysfunction in MDS MSCs. Our result provides a strong rational to target prematurely exhausting MSCs in future MDS treatment. PMID- 28804563 TI - Count-based size-correction analysis of maternal plasma DNA for improved noninvasive prenatal detection of fetal trisomies 13, 18, and 21. AB - PURPOSE: Our goal was to derive more sensitive and accurate Z-scores based on combined DNA count- and size-based algorithms to advance molecular diagnostics for noninvasive prenatal testing of fetal trisomies. METHODS: We included 180 cases at high risk for fetal aneuploidy who underwent amniotic fluid cytogenetic analysis. We calculated their traditional count-based Z-scores, as well as their 100-, 130- and 150-, and 166-bp size-corrected Z-scores, and determined each Z score's reliability based on its comparison to the cases' cytogenetic results. RESULTS: We detected for trisomies 13, 18, or 21 among the 180 cases in our study by amniotic testing and DNA sequence analysis. None trisomies 13 was detected, while 1 case of trisomies 18 and 3 cases of trisomies 21 were found. The sensitivity, specificity, and accuracy of traditional count-based Z-scores were 75%, 98.86%, and 98.33%, respectively, while these rates increased to 80%, 99.43%, and 99.44% with a count-based 100- and 166-bp size correction. Moreover, the sensitivity, specificity, and accuracy of count-based Z-scores with 130- and 150-bp size corrections were 100%, and neither of these algorithms yielded false positive trisomies, unlike other evaluated size correction Z-scores. CONCLUSIONS: Count-based Z-scores with 130- and 150-bp size corrections more robustly predict fetal trisomies than count-based methods alone or those combined with other size correction cutoffs, such as 166 bp. These testing parameters may enhance the utility of DNA sequence-based methods for noninvasive prenatal detection of fetal trisomies. PMID- 28804564 TI - IncRNA H19 promotes tongue squamous cell carcinoma progression through beta catenin/GSK3beta/EMT signaling via association with EZH2. AB - H19 is involved in tumor metastasis and associated with tumor progression. Enhancer of zest homolog 2 (EZH2) is overexpressed in multiple cancer types and correlates with tumor proliferation, epithelial-mesenchymal transition, and poor prognosis. However, the interaction between H19 and EZH2 to promote tongue squamous cell carcinoma (TSCC) progression remains largely uncharacterized. Insitu hybridization and quantitative reverse-transcription PCR (qRT-PCR) were performed to measure H19 expression in primary TSCC and adjacent normal tissues and cell lines. EZH2 expression was determined by immunohistochemistry in matched primary TSCC and adjacent normal tissues. The correlation between H19 and EZH2 expression and clinicopathological characteristics were analyzed. The roles of H19 in cell proliferation, apoptosis, and invasion were analyzed using a H19 targeted lentivirus. Western blot and qRT-PCR were carried out to detect downstream signal pathway changes. Expression levels of downstream signaling proteins in primary TSCC tissues and adjacent normal tissues were analyzed by immunohistochemistry. H19 and EZH2 were upregulated in TSCC tissues compared to matched normal tissues, and significantly correlated with WHO grade, lymph node metastasis, and poor prognosis. H19 silencing attenuated cell proliferation, apoptosis, and invasion in vitro. H19 knockdown inhibited the activation of beta catenin/GSK-3beta/cyclin D1/c-myc, upregulated E-cadherin and zonula occludens-1 (ZO-1), and inhibited N-cadherin, vimentin, Snail1, Twist1, and ZEB1. Silencing H19 expression also inhibited tumor progression and lung metastasis in an animal model. Our findings indicate that H19 promotes TSCC progression through association with EZH2, and affects downstream beta-Catenin/GSK3beta/EMT signaling, suggesting that H19 inhibition might be a potential target for the treatment of TSCC. PMID- 28804565 TI - Thrombospondin-1 inhibits ossification of tissue engineered cartilage constructed by ADSCs. AB - Cartilage tissue engineering provides a new method in the treatment of cartilage defects, and adipose derived stem cells seem to be an ideal seed cell in cartilage tissue engineering because of its characteristics. However, ossification after in vivo implantation of tissue engineered cartilage remains a challenge. Thrombospondin-1 which has been reported to have an inhibitory effect on angiogenesis, may play an important role in inhibiting the ossification of tissue engineered cartilage constructed by adipose derived stem cells. Therefore, the effect of thrombospondin-1 in inhibiting the ossification of tissue engineered cartilage was evaluated in this study. Lentivirus vectors carrying thrombospondin-1 cDNA were transfected into adipose derived stem cells, and the transfected cells were used in the experiments. The expression of thrombospondin 1 was evaluated by quantitative reverse transcriptase-polymerase chain reaction and western blot, and the effects of thrombospondin-1 over-expression on angiogenesis were analyzed by angiogenesis assays. The quality of tissue engineered cartilage and the degree of ossification were assessed by biomechanical and molecular biology methods. The results showed that thrombospondin-1 infected cells have a high expression of thrombospondin-1 in mRNA and protein level, which inhibited the tube formation of endothelial cells, indicating the anti-angiogenic effects. Gene expression analyses in vitro showed that thrombospondin-1 inhibits the osteogenic differentiation of adipose derived stem cells significantly, and the results of in vivo study revealed that thrombospondin-1 significantly inhibits the expression of osteogenic genes. Compared to that in the control group, tissue engineered cartilage constructed by thrombospondin-1 transfected adipose derived stem cells in vivo showed a higher GAG content and lower compressive modulus, which indicating lower level of ossification. In conclusion, the current study indicated that the anti-angiogenic factor thrombospondin-1 suppresses the osteogenic differentiation of adipose derived stem cells in vitro, and inhibits ossification of tissue engineered cartilage constructed by adipose derived stem cells in vivo. PMID- 28804566 TI - MicroRNA-93 inhibits apoptosis and promotes proliferation, invasion and migration of renal cell carcinoma ACHN cells via the TGF-beta/Smad signaling pathway by targeting RUNX3. AB - We investigated the ability of microRNA-93 (miR-93) to influence proliferation, invasion, migration, and apoptosisofrenal cell carcinoma (RCC) cells via transforming growth factor-beta/solvated metal atom dispersed (TGF-beta/Smad) signaling by targeting runt-related transcription factor 3 (RUNX3). RCC tissues with corresponding adjacent normal tissues were collected from 249 RCC patients. And normal renal tissues were collected from patients without RCC who received nephrectomy. The RCC cell line ACHN was treated with miR-93 mimic, mimic-negative control (NC), miR-93 inhibitor, inhibitor-NC, and miR-93 inhibitor + small interfering RNA (siRNA) against RUNX3 (si-RUNX3). Expression of miR-93, RUNX3, TGF-beta, and Smad4 were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Cell proliferation was assessed by the Metallothioneins (MTS) assay, cell invasion by the wound-healing assay, cell migration by the Transwell assay, and cell cycle and apoptosis by flow cytometry. Compared with normal renal tissues, the expression of miR-93 and TGF-beta were higher while that of RUNX3 and Smad4 were low in RCC and adjacent normal tissues (all P<0.05). RUNX3 was confirmed as a target of miR-93 by the dual luciferase reporter gene assay. Compared with mimic-NC group, cell proliferation, invasion, migration and cells from G0/G1 to S phase enhanced but the apoptosis decreased in the miR-93 mimic group (all P<0.05). Compared with inhibitor-NC group, proliferation, invasion, and migration reduced, while apoptosis increased, and cells at G0/G1 phase arrested in the miR-93 inhibitor group (all P<0.05). Compared with miR-93 inhibitor group, cell proliferation, invasion, and migration increased with increasing cells from G1 to S phase while the apoptosis decreased, in miR-93 inhibitor + si-RUNX3 group (all P<0.05). In conclusion, miR-93 inhibits apoptosis and promotes proliferation, invasion, and migration of RCC cells via TGF-beta/Smad signaling by inhibiting RUNX3. PMID- 28804567 TI - The characteristics of astrocyte on Abeta clearance altered in Alzheimer's disease were reversed by anti-inflammatory agent (+)-2-(1-hydroxyl-4 oxocyclohexyl) ethyl caffeate. PMID- 28804568 TI - Preventive effects of kudzu root on bone loss and cartilage degradation in ovariectomized rat. AB - The clinical utility of Traditional Chinese Medicine (TCM) herbs/roots extracts in osteoporosis (OP) and osteoarthritis (OA) has been described in multiple reports, but there have been few studies of TCM for preventing bone loss and cartilage degradation simultaneously. Six-month-old female Sprague-Dawley rats each were subjected to ovariectomized (OVX) or sham surgery and treated orally once daily with herbal extracts or vehicle. Body weight was recorded weekly, and blood samples were collected from fasting animals at different time points. Biochemical markers of bone resorption and cartilage degradation were analyzed. Changes in bone mineral density and calcium content were determined in the femoral center and femoral telocentric end of rats. Out of 56 TCM herbs/roots extracts, only kudzu root demonstrated consistent joint protective effects. OVX resulted in a marked increase in bone resorption and cartilage degradation, which could be significantly reversed by kudzu after three weeks of treatment. Compared to vehicle, kudzu induced a significant increase in bone mineral density in the femoral center and femoral telocentric end, and calcium content. The results show that kudzu exerts direct effects on articular cartilage in the OVX rat and can effectively prevent the acceleration of cartilage degradation induced by ovariectomy. Moreover, kudzu has demonstrated positive effects on metabolic health (cause a weight reduction) and may represent a possible treatment for OP and OA with high body mass index. Further studies are needed to investigate the potential effects of kudzu root in postmenopausal women. PMID- 28804569 TI - DYNAMIC REGISTRATION FOR GIGAPIXEL SERIAL WHOLE SLIDE IMAGES. AB - High-throughput serial histology imaging provides a new avenue for the routine study of micro-anatomical structures in a 3D space. However, the emergence of serial whole slide imaging poses a new registration challenge, as the gigapixel image size precludes the direct application of conventional registration techniques. In this paper, we develop a three-stage registration with multi resolution mapping and propagation method to dynamically produce registered subvolumes from serial whole slide images. We validate our algorithm with gigapixel images of serial brain tumor sections and synthetic image volumes. The qualitative and quantitative assessment results demonstrate the efficacy of our approach and suggest its promise for 3D histology reconstruction analysis. PMID- 28804570 TI - Value of quality of life analysis in liver cancer: A clinician's perspective. AB - Health related quality of life (HRQOL) is increasingly recognized as an important clinical parameter and research endpoint in patients with hepatocellular carcinoma (HCC). HRQOL in HCC patients is multifaceted and affected by medical factor which encompasses HCC and its complications, oncological and palliative treatment for HCC, underlying liver disease, as well as the psychological, social or spiritual reaction to the disease. Many patients presented late with advanced disease and limited survival, plagued with multiple symptoms, rendering QOL a very important aspect in their general well being. Various instruments have been developed and validated to measure and report HRQOL in HCC patients, these included general HRQOL instruments, e.g., Short form (SF)-36, SF-12, EuroQoL-5D, World Health Organization Quality of Life Assessment 100 (WHOQOL-100), World Health Organization Quality of Life Assessment abbreviated version; general cancer HRQOL instruments, e.g., the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, Functional Assessment of Cancer Therapy (FACT)-General, Spitzer Quality of Life Index; and liver-cancer specific HRQOL instruments, e.g., EORTC QLQ-HCC18, FACT-Hepatobiliary (FACT-Hep), FACT-Hep Symptom Index, Trial Outcome Index. Important utilization of HRQOL in HCC patients included description of symptomatology and HRQOL of patients, treatment endpoint in clinical trial, prognostication of survival, benchmarking of palliative care service and health care valuation. In this review, difficulties regarding the use of HRQOL data in research and clinical practice, including choosing a suitable instrument, problems of missing data, data interpretation, analysis and presentation are examined. Potential solutions are also discussed. PMID- 28804572 TI - Bacterial infections post-living-donor liver transplantation in Egyptian hepatitis C virus-cirrhotic patients: A single-center study. AB - AIM: To determine risk factors, causative organisms and antimicrobial resistance of bacterial infections following living-donor liver transplantation (LDLT) in cirrhotic patients. METHODS: This prospective study included 45 patients with hepatitis C virus-related end-stage liver disease who underwent LDLT at Ain Shams Center for Organ Transplant, Cairo, Egypt from January 2014 to November 2015. Patients were followed-up for the first 3 mo after LDLT for detection of bacterial infections. All patients were examined for the possible risk factors suggestive of acquiring infection pre-, intra- and post-operatively. Positive cultures based on clinical suspicion and patterns of antimicrobial resistance were identified. RESULTS: Thirty-three patients (73.3%) suffered from bacterial infections; 21 of them had a single infection episode, and 12 had repeated infection episodes. Bile was the most common site for both single and repeated episodes of infection (28.6% and 27.8%, respectively). The most common isolated organisms were gram-negative bacteria. Acinetobacter baumannii was the most common organism isolated from both single and repeated infection episodes (19% and 33.3%, respectively), followed by Escherichia coli for repeated infections (11.1%), and Pseudomonas aeruginosa for single infections (19%). Levofloxacin showed high sensitivity against repeated infection episodes (P = 0.03). Klebsiella, Acinetobacter and Pseudomonas were multi-drug resistant (MDR). Pre transplant hepatocellular carcinoma (HCC) and duration of drain insertion (in days) were independent risk factors for the occurrence of repeated infection episodes (P = 0.024). CONCLUSION: MDR gram-negative bacterial infections are common post-LDLT. Pre-transplant HCC and duration of drain insertion were independent risk factors for the occurrence of repeated infection episodes. PMID- 28804573 TI - Changing landscape of hepatitis C virus-positive donors. AB - With the introduction of the new highly effective antiviral therapies, there has been a dramatic increase in the use of the hepatitis C virus (HCV)-positive livers in HCV-positive recipients. In the majority of studies, HCV positivity was defined as a donor testing HCV Ab positive. In 2015, all Organ Procurement Organizations were mandated to perform and report HCV Nucleic Acid Amplification Testing (NAT) results on all deceased and living donors. Studies are not yet available on how organs are being utilized based on NAT status and whether NAT status affects recipient outcomes. Further studies are needed to maximize the use of these organs. PMID- 28804571 TI - Impact of comorbidity on waiting list and post-transplant outcomes in patients undergoing liver retransplantation. AB - AIM: To determine the impact of Charlson comorbidity index (CCI) on waiting list (WL) and post liver retransplantation (LRT) survival. METHODS: Comparative study of all adult patients assessed for primary liver transplant (PLT) (n = 1090) and patients assessed for LRT (n = 150), 2000-2007 at our centre. Demographic, clinical and laboratory variables were recorded. RESULTS: Median age for all patients was 53 years and 66% were men. Median model for end stage liver disease (MELD) score was 15. Median follow-up was 7-years. For retransplant patients, 84 (56%) had >= 1 comorbidity. The most common comorbidity was renal impairment in 66 (44.3%). WL mortality was higher in patients with >= 1 comorbidity (76% vs 53%, P = 0.044). CCI (OR = 2.688, 95%CI: 1.222-5.912, P = 0.014) was independently associated with WL mortality. Patients with MELD score >= 18 had inferior WL survival (Log-Rank 6.469, P = 0.011). On multivariate analysis, CCI (OR = 2.823, 95%CI: 1.563-5101, P = 0.001), MELD score >= 18 (OR 2.506, 95%CI: 1.044-6.018, P = 0.04), and requirement for organ support prior to LRT (P < 0.05) were associated with reduced post-LRT survival. Donor/graft parameters were not associated with survival (P = NS). Post-LRT mortality progressively increased according to the number of transplanted grafts (Log-Rank 18.455, P < 0.001). Post LRT patient survival at 1-, 3- and 5-years were significantly inferior to those of PLT at 88% vs 73%, P < 0.001, 81% vs 71%, P = 0.018 and 69% vs 55%, P = 0.006, respectively. CONCLUSION: Comorbidity increases WL and post-LRT mortality. Patients with MELD >= 18 have increased WL mortality. Patients with comorbidity or MELD >= 18 may benefit from earlier LRT. LRT for >= 3 grafts may not represent appropriate use of donated grafts. PMID- 28804574 TI - Anti-platelet and Anti-thrombotic Effects of a Poly-ingredient formulation: In vitro and in vivo experimental evidences. AB - OBJECTIVE: The present study was conducted to evaluate the efficacy of Abana(r) (a poly-ingredient formulation with natural constituents) on in vitro platelet aggregation and occlusion-induced deep venous thrombosis in rats. METHODS: Anti platelet property of Abana(r) was evaluated using ADP (Adenosin 5-diphosphate) and adrenaline-induced platelet aggregation models, and anti-thrombotic activity was evaluated against occlusion-induced deep venous thrombosis model in wistar rats. RESULTS: Under the in vitro conditions, Abana(r) (250, 500 and 1000 ug/ml) alleviated ADP and adrenaline-induced platelet aggregation in a dose-dependent manner. Abana(r) (1000 ug/ml) inhibited ADP and adrenaline-induced platelet aggregation by as much as 50.69% and 64.83% respectively. Furthermore, 6 days pre treatment with Abana(r) (250 and 500 mg/kg, p.o.) in an in vivo study showed significant and dose-dependent protection against occlusion-induced deep venous thrombosis in rats. CONCLUSION: These findings suggest that Abana(r), a polyherbal formulation possesses anti-platelet and anti-thrombotic activities in the experimental models of in vitro platelet aggregation and in vivo deep venous thrombosis in rats. PMID- 28804575 TI - Fibromatosis Colli: A Case Report. AB - Fibromatosis colli or sternocleidomastoid tumor of infancy is a condition of benign proliferation of fibrous tissue within the sternocleidomastoid muscle leading to focal or diffuse enlargement of the sternocleidomastoid muscle and is often clinically associated with torticollis. Radiological imaging especially ultrasound, if performed by an expert radiologist plays an important role in differentiating this benign condition from other causes of neck masses in this age group, thereby preventing unnecessary investigations in a neonate and decreasing parent's anxiety. We hereby, present a case report of a sternomastoid tumor in a two week old neonate diagnosed using high frequency ultrasound, signifying that every physician should be aware of this clinical entity in a neonate and refer them immediately for ultrasound. PMID- 28804576 TI - Prepubertal Hypertransfusion in Thalassemia Intermedia: A Case Report of Sustained Positive Effects on Growth, Splenic Function and Endocrine Parameters. AB - We report a known case of thalassemia intermedia (Hb Dhofar) who in spite of mild thalassemic facies, attained his normal genetic height, pubertal maturity and improved self-image with minimal splenomegaly through a hypertransfusion/chelation regimen that was started just before puberty and maintained for 5 years. As there are no clear guidelines in the management of patients with thalassemia intermedia, the option of hypertransfusion/chelation during the pubertal growth spurt may alleviate some of the complications associated with thalassemia intermedia. PMID- 28804577 TI - Antibiotics Resistance: When the Armamentarium Gets to the Verge of Being Empty. PMID- 28804578 TI - Using Nanoparticles in Medicine for Liver Cancer Imaging. AB - One of the most important types of liver cancer is hepatocellular carcinoma (HCC). HCC is the fifth most common cancer, and its correct diagnosis is very important. For the quick diagnosis of HCC, the use of nanoparticles is helpful. The major applications of nanoparticles are in medicine for organ imaging. Two methods of liver imaging are X-ray computed tomography (CT) and magnetic resonance imaging (MRI). In this review, we attempt to summarize some of the contrast agents used in imaging such as superparamagnetic iron oxide nanoparticles (SPIONs) and iron oxide nanoparticles (IONPs), various types of enhanced MRI for the liver, and nanoparticles like gold (AuNPs), which is used to develop novel CT imaging agents. PMID- 28804579 TI - Validity of Prostate Health Index and Percentage of [-2] Pro-Prostate-Specific Antigen as Novel Biomarkers in the Diagnosis of Prostate Cancer: Omani Tertiary Hospitals Experience. AB - OBJECTIVES: Prostate cancer is the leading cancer in older men. The Ministry of Health Oman Cancer Incidence Registry 2013 lists cancer of the prostate as the first most common cancer in males. Therefore, early detection is important and prostate-specific antigen (PSA) is widely used as an established laboratory test. However, despite its wide use, its value in screening, particularly in asymptomatic males, is controversial when considering the risks and benefits of early detection. METHODS: This prospective, observational study included 136 males (67.0+/-8.9 years; range 45-90) who were scheduled for a prostate biopsy in two different tertiary care teaching hospitals in Oman: the Royal Hospital and Sultan Qaboos University Hospital. Blood specimens from these patients were collected at the same setting before obtaining a prostatic biopsy. Three PSA markers (total PSA (tPSA), free PSA (fPSA), and [-2]proPSA (p2PSA)) were measured and the Prostate Health Index (phi) calculated. The histopathological report of the prostatic biopsy for each patient was obtained from the histopathology laboratory of the concerned hospital along with clinical and laboratory data through the hospital information system. RESULTS: Phi has the highest validity markers compared with other prostate markers, with a sensitivity of 82.1%, specificity of 80.6%, and area under the curve (AUC) value of 0.81 at a cutoff of 41.9. The other prostatic markers showed sensitivities and specificities of 78.6% and 25.9% for tPSA; 35.7% and 92.6% for %fPSA; and 64.3% and 82.4% for %p2PSA, respectively. The AUCs at the best cutoff values were 0.67 at 10.1 ug/L for tPSA; 0.70 at 11.6% for %fPSA; and 0.55 at 1.4% for %p2PSA. An association between phi values and aggressiveness of prostate malignancy was noted. Of the 28 patients with prostate cancer, 22 patients had tPSA > 4 ug/L. However, no patient had phi in the low-risk category, and five, six, and 17 patients had phi in the moderate , high-, and very high-risk categories, respectively. CONCLUSIONS: Phi outperforms tPSA and fPSA when used alone or in combination, and appears to be more accurate than both markers in excluding prostate cancer before biopsy. Use of this biomarker helps clinicians to avoid unnecessary biopsies, particularly in patients with gray-zone tPSA level. Phi is the strongest marker that correlates proportionally with Gleason Score; therefore, it is also useful in predicting the aggressiveness of the disease. This is the first reported experience for the use of p2PSA and phi in Oman, the Middle East, and North Africa. PMID- 28804580 TI - Growth Pattern in Children with Systemic Lupus Erythematosus. AB - OBJECTIVES: Children with childhood-onset systemic lupus erythematosus (cSLE) enter adulthood with considerable morbidity. Of the recognized morbidities, growth failure is unique to cSLE. The aim of this study was to evaluate the growth pattern in children with cSLE longitudinally and identify possible risk factors. METHODS: Serial anthropometric measurements of cSLE patients were obtained over two years and expressed as z-scores. Parental heights were obtained to calculate target height. Parent-adjusted height z-score was calculated as the difference between height z-score and target height. Growth failure was defined as parent-adjusted height z-score < -1.50. Risk factors that might have contributed to growth failure were evaluated including the presence of growth failure at baseline, disease activity, disease duration, and cumulative steroid doses. RESULTS: Twenty-five patients were included in the study. Growth failure was observed in eight patients with an overall incidence of 32.0% (95% confidence interval (CI): 14-50%). When comparing the cohort with and without growth failure, the factors that determined growth failure was the pre-existence of growth failure at the time of diagnosis (z-score < -1.95 vs. 0.35; p < 0.001); higher cumulative steroid dose (15.8 vs. 9.1 g ; p = 0.061); and tendency for longer disease duration (5.4 vs. 3.7 years; p = 0.240). However, the severity of disease activity at the time of diagnosis was not a significant contributing factor (12 vs. 14; p = 0.529). CONCLUSIONS: Children with cSLE are at risk of having a negative effect on height including patients with pre-existing growth failure, high cumulative steroid dose, and longer disease duration. However, longitudinal prospective studies are needed to examine damage over time to improve health-related quality of life. PMID- 28804581 TI - Influence of Eysenckian Personality Traits in Choice of Specialization by Young Omani Doctors. AB - OBJECTIVES: The role of personality in occupational specialty choices has been explored in many parts of the world. To our knowledge, there is a dearth of such studies in the Arab/Islamic population and Oman is no exception. This study aimed to explore the relationship between personality traits and specialty choice among residents of Oman Medical Specialty Board (OMSB). METHODS: A cross-sectional study was carried out among Omani resident physicians working under OMSB. The Eysenck Personality Questionnaire-Revised was employed to quantify personality subtypes (e.g., psychoticism, extraversion, and neuroticism). Specialties were categorized as surgical, medical, and diagnostics as per standard of North American medical specialties. A total of 255 residents in 17 medical specialties participated in the study (m = 40.4%; f = 59.6%) of 300 eligible subjects giving a response rate of 85.0%. RESULTS: Respondents who had chosen surgical specialties scored significantly higher on the psychoticism subscale than those who had opted for medical and diagnostic specialties. As for individual specialties, orthopedic respondents had statistically significant higher mean scores on psychoticism and neuroticism compared to radiologists and psychiatrists who scored the lowest in the two personality traits, respectively. CONCLUSIONS: This study found statistically significant associations between personality traits and choices of specialty by young Omani doctors. We recommend more detailed studies that examine further psychological and cultural variables that are likely to affect the choices of specializations by young Omani professionals in both medical and non-medical fields. PMID- 28804582 TI - How Do Patients Perceive and Expect Quality of Surgery, Diagnostics, and Emergency Services in Tertiary Care Hospitals? An Evidence of Gap Analysis From Pakistan. AB - OBJECTIVES: Service quality is one of the important gears to appraise services and determine the gray areas that need improvement. In countries with a resource poor health system, the first step of measuring quality is yet to be taken. This study seeks to inform policy makers in developing contextual service quality models by identifying service quality gaps in tertiary care teaching hospitals using patients' perspective. METHODS: A cross-sectional study was performed using multistage cluster sampling, and a modified version of the SERVQUAL (SERV service, QUAL-quality) instrument was administered to determine patient's expectations and perceptions. A total of 817 completed questionnaires were obtained from patients and/or their attendants using convenience sampling. RESULTS: Data analysis revealed statistically significant negative quality gaps between expectations and perceptions of tangibility, reliability, empathy, assurance, responsiveness, and communication. The difference in mean expectation and perception for responsiveness across the sexes was significant (p < 0.003; p < 0.037, respectively) as well as in perception of communication (p < 0.026). Other dimensions and overall hospital expected and perceived quality were independent of sex. Educational status showed significant difference in expectation and perception in responsiveness (p < 0.005), but the perception of each dimension was significantly different in different educational categories (assurance: p < 0.001; empathy: p < 0.001; reliability: p < 0.001; tangibility: p < 0.001; responsiveness: p < 0.001; communication: p < 0.001; and for overall service quality: p < 0.001). Age and service departments showed no relationship with any of the perceived or expected dimension of service quality of hospitals. CONCLUSIONS: Tertiary care hospitals failed to meet patients' expectations in all major areas of service quality, posing a question of how hospitals implement and evaluate their quality assurance policy. PMID- 28804583 TI - A Communicative Model of Mothers' Lifestyles During Pregnancy with Low Birth Weight Based on Social Determinants of Health: A Path Analysis. AB - OBJECTIVES: Low birth weight (LBW) is one of the major health problems worldwide. It is important to identify the factors that play a role in the incidence of this adverse pregnancy outcome. This study aimed to develop a tool to measure mothers' lifestyles during pregnancy with a view to the effects of social determinants on health and develop a correlation model of mothers' lifestyles with LBW. METHODS: This study was conducted using methodological and case-control designs in four stages by selecting 750 mothers with infants weighing less than 4000 g using multistage sampling. The questionnaire contained 160 items. Face, content, criterion, and construct validity were used to study the psychometrics of the instrument. RESULTS: After psychometrics, 132 items were approved in six domains. Test results indicated the utility and the high fitness of the model and reasonable relationships adjusted for variables based on conceptual models. Based on the correlation model of lifestyle, occupation (-0.263) and social relationships (0.248) had the greatest overall effect on birth weight. CONCLUSIONS: The review of lifestyle dimensions showed that all of the dimensions directly, indirectly, or both affected birth weight. Thus, given the importance and the role of lifestyle as a determinant affecting birth weight, attention, and training interventions are important to promote healthy lifestyles. PMID- 28804584 TI - The Expression of Activating Receptor Gene of Natural Killer Cells (KLRC3) in Patients with ?Type 1 Diabetes Mellitus (T1DM). AB - OBJECTIVES: To identify the possible role of natural killer (NK) cells in the pathogenesis of type 1 diabetes mellitus (T1DM) through studying the expression of the KLRC3 gene, which encodes the NK cell activating receptor (NKG2E). METHODS: This study was conducted at Alexandria University Children's Hospital from April to October 2015. The study was conducted with 30 newly diagnosed T1DM patients (15 males and 15 females), aged 7-13 years (10.6+/-1.8 years) and 20 non diabetic subjects served as age- and sex-matched controls. The patients were further sub-divided into two groups; group I included patients who first presented with classical symptoms of DM (polyuria, polydipsia, and polyphagia) without diabetes ketoacidosis (DKA) and group II included patients who first presented with DKA. The expression of the KLRC3 gene was measured in each group using the real-time polymerase chain reaction. RESULTS: KLRC3 gene expression was significantly downregulated in T1DM cases compared to healthy controls (p = 0.001). Expression was more downregulated in group I patients (p = 0.008). Moreover, there was higher mean value of glycated heamoglobin and lower C-peptide levels in group I than group II. Serum pancreatic amylase showed no significant difference between the two groups. CONCLUSIONS: KLRC3 gene expression was downregulated in patients with T1DM compared to healthy controls. Downregulation of expression was greater in DKA patients compared to those who presented with classical symptoms. Expression of KLRC3 in T1DM might play a role in the pathogenesis of T1DM and could be a predictor of its severity. PMID- 28804585 TI - Detection of CTX-M-15 Among Uropathogenic Escherichia coli Isolated from Five Major Hospitals in Tripoli, Libya. AB - OBJECTIVES: Multidrug resistance (MDR) and emergence of extended-spectrum beta lactamases (ESBLs) among uropathogenic Escherichia coli have been reported worldwide, but there was no information on the detection of blaCTX-M-15 in major teaching hospitals in Libya. The aim of the study was to investigate the occurrence of CTX-M-15 beta-lactamases producers isolated from five teaching hospitals in Tripoli, Libya. METHODS: A total of 346 urine samples were collected from hospitalized patients in five teaching hospitals with a diagnosis of urinary tract infection (UTI). Phenotypic confirmation of ESBLs was confirmed by E-test strip; all ESBL-producing E. coli isolates were screened for the blaCTX-M-15 gene. RESULTS: The distribution of ESBL-producing E. coli varied among the five hospitals. The highest proportion was identified in Tripoli Medical Centre (67.6%). There were extremely high proportions of isolates resistant to ceftriaxone, cefepime, and ceftazidime (93.0-100.0%) among ESBL producers compared to non-ESBL producers (2.2-4.7%). MDR was detected in 22.2% of isolates. The majority of isolates (85.9%) in which blaCTX-M-15 was identified were ESBL producers. There was a correlation (p < 0.001) between expression of CTX-M-15 and resistance to ceftazidime. CONCLUSIONS: The isolation of MDR ESBL-producing uropathogens expressing the CTX-M-15 gene will limit the choices clinicians have to treat their patients with UTIs. Continued surveillance and implementation of efficient infection control measures are required. PMID- 28804586 TI - Health-related Quality of Life and Associated Factors Among Undergraduate University Students. AB - OBJECTIVES: The aims of this study were to explore factors associated with health related quality of life (HRQOL) among students of Cumhuriyet University, Turkey. METHODS: This cross-sectional study involved 1751 undergraduate students. HRQOL was measured using the Turkish version of 36-Item Short Form Health Survey questionnaire. We looked at the effect of sociodemographic characteristics (e.g., gender, age, drinking, and smoking) on the individual HRQOL domains. RESULTS: Place of residency (odds ratio (OR) = 3.947 for role emotion dimension), smoking status (OR = -2.756 for role physical dimension), received amount of pocket money (OR = 2.463 for mental health dimension), and body mass index (OR = 1.463 for mental health dimension) were the factors significantly associated with the HRQOL. CONCLUSIONS: Young students' HRQOL is affected by socioeconomic, demographic, and behavioral factors. To improve student's HRQOL, any health promoting strategies should focus on modifiable risk factors and socioeconomic supports for students. PMID- 28804587 TI - Primary Hepatic Lymphoma Mimicking Cholangiocarcinoma. AB - Primary hepatic lymphoma (PHL) presenting with obstructive jaundice is rare and can mimic a preoperative diagnosis of cholangiocarcinoma. We should consider PHL in patients with radiological hepatic disease with normal serum alpha-fetoprotein and carcinoembryonic antigen levels, and elevated lactate dehydrogenase. We present the case of a 67-year-old male with no significant medical history presented with abdominal pain, jaundice, fever, and abnormal liver function tests. Abdominal sonography and computed tomography scan suggested a diagnosis of obstructive jaundice and cholangitis due to cholangiocarcinoma (Klatskin tumor). A subsequent liver biopsy diagnosed PHL, and the patient was treated with combination chemotherapy, including rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). PHL should be considered in patients presenting with biliary obstruction. PMID- 28804588 TI - First Reported Case of Arrhythmogenic Right Ventricular Cardiomyopathy in Oman. AB - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetic disorder characterized by fatty degeneration of the right ventricular myocardium with variable involvement of the left ventricle. The condition is associated with exercise-mediated ventricular tachycardia and is one of the recognized causes of sudden cardiac death in the young and in athletes. Here, we report the first confirmed case of ARVC in Oman and present its electrocardiographic, echocardiographic features, and radiological findings on gated, contrast-enhanced cardiac computed tomography. Our patient was a 22-year-old male who had presented to our hospital for evaluation and investigation of syncope and symptomatic palpitations. PMID- 28804589 TI - Spontaneous Coronary Artery Dissection: An Under-recognized Cause of Acute Coronary Syndromes. AB - Spontaneous coronary artery dissection (SCAD) is a rare condition that is often underdiagnosed given limitations of conventional cineangiography. In addition to the diagnostic challenge, the condition poses a major therapeutic dilemma given paucity of literature to guide management. We report the case of a 55-year-old woman, who presented with acute coronary syndrome. Coronary angiography at the time of the index hospitalization revealed type 2 SCAD. She was managed conservatively. Repeat coronary angiography three months later showed complete resolution of the previously noted dissection. Because of the high association between SCAD and fibromuscular dysplasia (FMD), a cross-sectional imaging was performed in this case, which ruled out underlying FMD. The patient has been followed longitudinally since her index event and has had no reported recurrences. PMID- 28804590 TI - Feminizing Adrenocortical Carcinoma Without Gynecomastia. AB - Malignant feminizing adrenocortical tumors are exceedingly rare. Their main presentation is gynecomastia. In these estrogen secreting tumors (with or without other adrenocortical hormones) lack of gynecomastia is exceptional as in our case. A 44-year-old man presented with abdominal pain. Radiological assessment revealed a tumor measuring 120 * 95 mm in the retroperitoneal area with numerous metastases. Pathological examination pleaded for an adrenal origin with a Weiss's score of 5. Six months later, the tumor relapsed, and he had a second surgery and was sent for hormone assessment. Clinical examination showed a skinny man with severe fatigue. He had no Cushingoid features. Gynecomastia and galactorrhea were absent. Penile length, testicular volume, and body hair growth were normal. Several cutaneous nodules were present. Biological assessment showed high morning plasma cortisol, which failed to be suppressed by treatment with 2 mg dexamethasone. Plasma estradiol and 17OH progesterone levels were high, but his testosterone levels were low. Radiological exploration showed numerous metastases: pleural, pulmonary, retroperitoneal, and abdominal. He was treated with classical chemotherapy, but he died four months after diagnosis. PMID- 28804591 TI - 70-Year-Old Woman with Impaired Consciousness. PMID- 28804592 TI - Diabetic Foot Disease in Oman: A Call for ?More Research. PMID- 28804593 TI - An innovative sealed shoe to off-load and heal diabetic forefoot ulcers - a feasibility study. AB - Background: Non-removable knee-high devices are the gold standard to treat diabetic foot ulcers located on the plantar forefoot, but they immobilize the ankle, which restricts daily life activities and has negative effects on joint functioning. Objective: To investigate the feasibility of sealing a therapeutic shoe to off-load and heal diabetic forefoot ulcers. Design: A case series of seven men with type 2 diabetes and a metatarsal head ulcer were prescribed therapeutic shoes and custom-made insoles. The shoe was sealed with a plastic band. Off-loading was assessed with the F-scan pressure measurement system. Adherence to wearing the shoe was assessed with a temperature sensor and by documenting the status of the seal. Results: The off-loading was effective and all ulcers healed. Median time to healing was 56 days (range 8-160). Complications were secondary ulcer (n = 1) and plantar hematoma (n = 1). Five of seven participants did not disturb the seal. Conclusions: Sealing a therapeutic shoe is a feasible way to off-load and heal forefoot ulcers. A controlled trial is needed to compare the effectiveness and safety of a sealed shoe to other non removable devices. PMID- 28804594 TI - Does trauma event type matter in the assessment of traumatic load? AB - Background: The likelihood of developing Posttraumatic Stress Disorder (PTSD) depends on the interaction of individual risk factors and cumulative traumatic experiences. Hence, the identification of individual susceptibility factors warrants precise quantification of trauma exposure. Previous research indicated that some traumatic events may have more severe influences on mental health than others; thus, the assessment of traumatic load may be improved by weighting event list items rather than calculating the simple sum score. Objective: We compared two statistical methods, Random Forests using Conditional Interference (RF-CI) and Least Absolute Shrinkage and Selection Operator (LASSO), based on their ability to rank traumatic experiences according to their importance for predicting lifetime PTSD. Methods: Statistical models were initially fitted in a sample of N1 = 441 survivors of the Northern Ugandan rebel war. The ability to correctly predict lifetime PTSD was then tested in an independent sample of N2 = 211, and subsequently compared with predictions by the simple sum score of different traumatic event types experienced. Results: Results indicate that RF-CI and LASSO allow for a ranking of traumatic events according to their predictive importance for lifetime PTSD. Moreover, RF-CI showed slightly better prediction accuracy than the simple sum score, followed by LASSO when comparing prediction results in the validation sample. Conclusion: Given the expense in time and calculation effort by RF-CI and LASSO, and the relatively low increase in prediction accuracy by RF-CI, we recommend using the simple sum score to measure the environmental factor traumatic load, e.g., in analyses of gene * environment interactions. PMID- 28804595 TI - Natural exposure of bats in Grenada to rabies virus. AB - Introduction: Grenada is a rabies endemic country, where terrestrial rabies is maintained in the small Indian mongoose (Herpestes auropunctatus). The role of bats in the epidemiology of rabies in Grenada is unknown. A 1974 report described one rabies virus positive Jamaican fruit bat (Artibeus jamaicensis), and a high seroprevalence in this species. In the current study, the natural exposure to rabies virus in Grenadian bats was re-evaluated. It is postulated that bats serve as a natural rabies reservoir, probably circulating a bat-specific rabies virus variant. Material and methods: Bats were trapped in 2015 in all six parishes of Grenada using mist- and hand nets. For the detection of rabies virus in brain tissue, the direct fluorescent antibody test (dFAT) and the reverse transcription polymerase chain reaction (RT-PCR) were used. Serum neutralizing antibodies were determined using the fluorescent antibody virus neutralization test (FAVN). Results and discussion: Brain tissue and sera from 111 insectivorous and frugivorous bats belonging to four species were tested (52 Artibeus jamaicensis, two Artibeus lituratus, 33 Glossophaga longirostris, 24 Molossus molossus). Rabies virus antigen and genomic RNA were not detected in brain tissues. Rabies virus neutralizing antibodies were detected in the sera of eight A. jamaicensis in four of the six parishes. Bats in Grenada continue to show natural exposure to rabies virus. As rabies virus was not isolated in this study, serology alone is not sufficient to determine the strain of rabies virus circulating in A. jamaicensis bats in Grenada. Conclusion: Artibeus jamaicensis appears to play a role as a reservoir bat species, which is of public health concern in Grenada. Dispersion of bats to neighboring islands is possible and serological bat surveys should be initiated in these neighboring states, especially in those areas that are free of rabies in terrestrial mammals. PMID- 28804596 TI - Characterisation of tumour-derived microvesicles in cancer patients' blood and correlation with clinical outcome. AB - To evaluate whether tumour-derived microvesicles (T-MV), originating from the plasma membrane, represent suitable cancer biomarkers, we isolated MV from peripheral blood samples of cancer patients with locally advanced and/or metastatic solid tumours (n = 330, including 79 head & neck cancers, 74 lung cancers, 41 breast cancers, 28 colorectal cancers and 108 with other cancer forms) and controls (n = 103). Whole MV preparations were characterised using flow cytometry. While MV carrying the tumour-associated proteins MUC1, EGFR and EpCAM were found to be enhanced in a tumour-subtype-specific way in patients' blood, expression of the matrix metalloproteinase inducer EMMPRIN was increased independent of tumour type. Higher levels of EMMPRIN+-MV correlated significantly with poor overall survival, whereas the other markers were prognostic only in specific tumour subgroups. By combining all four tumour-associated antigens, cancer patients were separated from healthy controls with an AUC of up to 0.85. Ex vivo, whole MV preparations from cancer patients, in contrast to those of controls, induced a tumour-supporting phenotype in macrophages and increased tumour cell invasion, which was dependent on the highly glycosylated isoform of EMMPRIN. In conclusion, the detection of T-MV in whole blood, even in minor amounts, is feasible with standard techniques, proves functionally relevant and correlates with clinical outcome. PMID- 28804597 TI - Size and concentration analyses of extracellular vesicles by nanoparticle tracking analysis: a variation study. AB - Current methods for characterisation of extracellular vesicles (EVs) need further standardisation in order to obtain an acceptable level of data comparability. Size and concentration of EVs can be determined by nanoparticle tracking analysis (NTA). However, both the heterogeneity of EVs and the choice of instrument settings may cause an appreciable analytical variation. Intra-assay (within-day, n = 6) and inter-assay (day-to-day, n = 6) variations (coefficient of variation, % CV) of different preparations of EVs and artificial vesicles or beads were determined using two NanoSight NS500 instruments, located at different laboratories. All analyses were performed by the same operator. The effect of applying identical software settings or instrument-optimised settings for each sample type and instrument was also evaluated. Finally, the impact of different operators and the use of two different software versions were investigated. The intra-assay CVs were 1-12% for both EVs and artificial samples, measured on the same instrument. The overall day-to-day variation was similar for both instruments, ranging from 2% to 25%. However, significantly different results were observed between the two instruments using identical software settings. The effect of applying instrument-optimised settings reduced the mismatch between the instruments, resulting in little to no significant divergences. The impact of using different operators and software versions when analysing silica microspheres and microvesicles from monocytes using instrument-optimised settings on the same instrument did not contribute to significant variation compared to the overall day-to-day variation of one operator. Performance differences between two similar NTA instruments may display significant divergences in size and concentration measurements when analysing EVs, depending on applied instrument settings and technical conditions. The importance of developing a streamlined and standardised execution of analysis, as well as monitoring longitudinal variation parameters on both biological and synthetic samples, should be highlighted. PMID- 28804598 TI - A rigorous method to enrich for exosomes from brain tissue. AB - Extracellular vesicles, including exosomes, are released by all cells, including those of the nervous system. Capable of delivering lipid, protein and nucleic acids to both nearby and distal cells, exosomes have been hypothesized to play a role in progression of many diseases of the nervous system. To date, most analyses on the role of these vesicles in the healthy and diseased state have relied on studying vesicles from in vitro sources, such as conditioned cell culture media, or body fluids. Here we have taken a critical approach to the enrichment and characterization of exosomes from human frontal cortex. This method maintains the integrity of the vesicles and their cargo, and comprehensive proteomic and genomic characterization confirms the legitimacy of the resulting extracellular vesicles as endosome-derived exosomes. This method will enable neuroscientists to acquire more detailed information about exosomes in the brain and explore the role(s) this form of intercellular communication and unique source of lipid, protein and RNA has in healthy brain function and pathogenic conditions. Furthermore, this method may have important utility in the isolation of exosomes from other tissues. PMID- 28804599 TI - Circulating exosome microRNA associated with heart failure secondary to myxomatous mitral valve disease in a naturally occurring canine model. AB - Myxomatous mitral valve disease (MMVD) is functionally and histologically identical to mitral valve prolapse (MVP) in humans. Currently, there are no medical treatments that can delay the progression of this valvular disease or associated cardiac remodelling. Therefore, there is a need to understand the molecular pathology associated with MMVD and MVP better, and thus identify potential therapeutic targets. Circulating exosomes contain small RNA, including miRNA, which reflect cell physiology and pathology. This study explored the association between circulating exosomal miRNA (ex-miRNA) content and MMVD, heart failure due to MMVD (MMVD-CHF) and ageing, which is strongly associated with MMVD. Ex-miRNA was isolated from old normal/healthy dogs (n = 6), young normal dogs (n = 7), dogs with MMVD (n = 7) and dogs with MMVD-CHF (n = 7). Separately, total plasma miRNA was isolated from normal dogs (n = 8), dogs with MMVD (n = 8) and dogs with MMVD-CHF (n = 11). Using reverse transcription quantitative polymerase chain reaction, exosomal miR-181c (p = 0.003) and miR-495 (p = 0.0001) significantly increased in dogs with MMVD-CHF compared to the other three groups. Exosomal miR-9 (p = 0.002) increased in dogs with MMVD and MMVD-CHF compared to age-matched (old) normal dogs. Exosomal miR-599 (p = 0.002) decreased in dogs with MMVD compared to old normal dogs. In total plasma, 58 miRNA were deemed significantly different (p < 0.04) between normal dogs, dogs with MMVD and dogs with MMVD-CHF. However, in contrast to ex-miRNA, none of the miRNA in total plasma remained statistically significant if the false discovery rate was <15%. Changes in ex-miRNA are observed in dogs as they age (miR-9, miR-495 and miR 599), develop MMVD (miR-9 and miR-599) and progress from MMVD to CHF (miR-181c and miR-495). Ex-miRNA expression-level changes appear to be more specific to disease states than total plasma miRNA. RESPONSIBLE EDITOR Elena Aikawa, Harvard Medical School, USA. PMID- 28804600 TI - Analysis of health economics assessment reports for pharmaceuticals in France - understanding the underlying philosophy of CEESP assessment. AB - Background: Despite the guidelines for Economic and Public Health Assessment Committee (CEESP) submission having been available for nearly six years, the dossiers submitted continue to deviate from them, potentially impacting product prices. Objective: to review the reports published by CEESP, analyse deviations from the guidelines, and discuss their implications for the pricing and reimbursement process. Study design: CEESP reports published until January 2017 were reviewed, and deviations from the guidelines were extracted. The frequency of deviations was described by type of methodological concern (minor, important or major). Results: In 19 reports, we identified 243 methodological concerns, most often concerning modelling, measurement and valuation of health states and results presentation and sensitivity analyses; nearly 63% were minor, 33% were important and 4.5% were major. All reports included minor methodological concerns, and 17 (89%) included at least one important and/or major methodological concern. Global major methodological concerns completely invalidated the analysis in seven dossiers (37%). Conclusion: The CEESP submission dossiers fail to adhere to the guidelines, potentially invalidating the health economics analysis and resulting in pricing negotiations. As these negotiations tend to be unfavourable for the manufacturer, the industry should strive to improve the quality of the analyses submitted to CEESP. PMID- 28804601 TI - Policy implementation for methicillin-resistant Staphylococcus aureus in seven European countries: a comparative analysis from 1999 to 2015. AB - Background: Policies to reduce methicillin-resistant Staphylococcus aureus (MRSA) infections, both healthcare-acquired (HA-MRSA) and livestock-associated (LA-MRSA) are implemented Europe-wide, but evaluations are difficult for countries yet to implement such policies. A descriptive study was conducted, describing multinational MRSA rates and policy implementation, focusing on MRSA mandatory surveillance. We also investigated antibiotic use and MRSA rates and the use of veterinary antibiotics. Methods: This study used Europe-wide surveillance data on infectious diseases (EARS-Net), antibiotic consumption (ESAC-Net), and veterinary medicine (ESVAC). We visualized LA- and HA-MRSA related policies and MRSA rates from 1999 to 2015 in seven European countries. Changes in MRSA rates after implementation of an MRSA mandatory surveillance policy were investigated by setting each country as rate of 1.0 and compared countries with and without such policy. Correlations between antibiotic use and MRSA rates from 1999 to 2012 were investigated using defined daily dose. Sales data were used to investigate veterinary antibiotic use. Results: MRSA rates were 1-45.4% across the seven countries between 1999 and 2015. MRSA rates changed between 0.61 and 0.24 after the implementation of mandatory surveillance policies within a 6-12 year span. The rate of decrease rate in implemented and non-implemented countries ranged from 10% in Spain to 76% in the UK. The correlation between MRSA rate and cephalosporin consumption was r = 0.419, and for fluoroquinolones r = 0.305. Mean annual sales of veterinary cephalosporin and quinolone antibiotics were lowest in the UK (0.8 mg/PCU) and highest in Spain (9.7 mg/PCU) between 2009 and 2014. Conclusions: There were similar but different health policy implications in the seven countries regarding LA- and HA-MRSA. Although causation could not be defined, some policies such as mandatory surveillance may be helpful for countries that have yet to implement an MRSA policy. Further investigations are needed to evaluate each policies. PMID- 28804602 TI - Balanced assessment systems revisited. AB - In 2014, balanced assessment systems (BAS) were proposed as a resource-conscious, 'fit-for-purpose' form of health technology assessment for middle-income countries which lack resources and competences necessary for resource-intensive health technology assessment models. BAS has undergone extensive policy debate in the period since its publication but it has not been critically assessed in a structured form yet. This article aims to describe both the contributions and the weak spots of the original framework and to reflect on them with the intention of further developing the model. PMID- 28804603 TI - Towards a more transparent HTA process in Poland: new Polish HTA methodological guidelines. AB - Introduction: Health technology assessment (HTA) in Poland supports reimbursement decisions via the Polish HTA Agency (AOTMiT), whose guidelines were updated in 2016. Methods: We identified key changes introduced by the update and, before guideline publication, analysed discrepancies between AOTMiT assessments and the submitting marketing authorisation holders (MAHs) to elucidate the context of the update. We compared the clarity and detail of the new guidelines versus those of the UK's National Institute for Health and Care Excellence (NICE). Results: The update specified more precise requirements for items such as indirect comparison or input data for economic modelling. Agency-MAH discrepancies relating to the subjects of the HTA update were found in 14.6% of published documents. The new Polish HTA guidelines were as clear and detailed as NICE's on topics such as assessing quality of evidence and economic modelling, but were less informative when describing (for example) pairwise meta-analysis. Conclusions: The Polish HTA guidelines update demonstrates lessons learned from internal and external experiences. The new guidelines adhere more closely to UK HTA standards, being clearer and more informative. While the update is expected to reduce Agency-MAH discrepancies, there remain areas for development, such as providing templates to aid HTA submissions. PMID- 28804605 TI - Up-regulation of miR-21 decreases chemotherapeutic effect of dendrosomal curcumin in breast cancer cells. AB - OBJECTIVES: Despite the good results of anticancer activities by curcumin, there are some hurdles that limit the use of curcumin as an anticancer agent. Many methods were examined to overcome this defect like the use of the dendrosomal curcumin (DNC). There is increasing evidence that miRNAs play important roles in biological processes. In this study, we focus on the roles of microRNA-21 in the anti-cancer effects of DNC in breast cancer. MATERIALS AND METHODS: Also, we have used different methods such as MTT, apoptosis, cell cycle analysis, transwell migration assay and RT-PCR to find out more. RESULTS: We observed that miR-21 decreased apoptotic cells in both cells (from 6.35% to 0.34 % and from 7.72% to 1.32% orderly) and DNC increased it. As well as, our findings indicated that cell migration capacity was increased by miR-21 over expression and was decreased by DNC. The combination of miR-21 vector transfection and DNC treatment showed lower percentage of apoptotic cells or a higher level of penetration through the membrane compared with DNC treatment alone. Furthermore, DNC induced a marked increase in the number of cells in sub G1/G1 phase and a decrease in G2/M phase of the cell cycle in both; but, we observed reverse results compared it, after transfection with miR-21 vector. CONCLUSION: We observed that miR-21 suppress many aspects of anti-cancer effects of DNC in breast cancer cells, it seems that co-treatment with DNC and mir-21 down-regulation may provide a clinically useful tool for drug-resistance breast cancer cells. PMID- 28804604 TI - Why whey? Camel whey protein as a new dietary approach to the management of free radicals and for the treatment of different health disorders. AB - The balance between free radicals and antioxidants is an important factor for maintaining health and slowing disease progression. The use of antioxidants, particularly natural antioxidants, has become an important strategy for dealing with this cause of widespread diseases. Natural antioxidants have been used as therapeutic tools against many diseases because they are safe, effective, and inexpensive and are among the most commonly used adjuvants in the treatment of several diseases. Camel whey protein (CWP) is considered a strong natural antioxidant because it decreases oxidative stress, enhances immune system function, and increases glutathione levels. The structure of CWP is very similar to that of other types of whey protein from different types of milk. CWP contains many components, such as lactoferrin (LF), lactalbumin, lactoglobulins, lactoperoxidase, and lysozyme, and is rich in immunoglobulins. However, in contrast to other WPs, CWP lacks beta-lactoglobulin, the main cause of milk allergies in children. The components of CWP have many beneficial effects, including stimulation of both innate and adaptive immunity and anti-inflammatory, anticancer, antibacterial, and antiviral activities. Recently, it has been shown that CWP and its unique components can facilitate the treatment of impaired diabetic wound healing. However, the molecular mechanisms underlying the protective effects of CWP in human and other animal disorders are not fully understood. Therefore, the current review presents a concise summary of the scientific evidence of the beneficial effects of CWP to support its therapeutic use in disease treatment and nutritional intervention. PMID- 28804606 TI - A multiple-antigen detection assay for tuberculosis diagnosis based on broadly reactive polyclonal antibodies. AB - OBJECTIVES: Detection of circulating Mycobacterium tuberculosis (M. tuberculosis) antigens is promising in Tuberculosis (TB) diagnosis. However, not a single antigen marker has been found to be widely expressed in all TB patients. This study is aimed to prepare broadly reactive polyclonal antibodies targeting multiple antigen markers (multi-target antibodies) and evaluate their efficacies in TB diagnosis. MATERIALS AND METHODS: A fusion gene consisting of 38kD, ESAT6, and CFP10 was constructed and overexpressed. The fusion polyprotein was used as an immunogen to elicit production of multi-target antibodies. Their reactivities were tested. Then, the multi-target antibodies and three corresponding antibodies elicited by each single antigen (mono-target antibodies) were evaluated with sandwich ELISA for detecting M. tuberculosis antigens. Their diagnostic efficacies for TB were also compared. RESULTS: The polyprotein successfully elicited production of multi-target antibodies targeting 38kD, ESAT6, and CFP10 as analyzed by Western blotting. When used as coating antibodies, the multi target antibodies were more efficient in capturing the three antigens than the corresponding mono-target antibodies. By testing clinical serum, the multi-target antibodies demonstrated significantly higher sensitivity for clinical TB diagnosis than all three mono-target antibodies. CONCLUSION: The multi-target antibodies allowed detecting multiple antigens simultaneously and significantly enhanced TB detection compared to routine mono-target antibodies. Our study may provide a promising strategy for TB diagnosis. PMID- 28804608 TI - Remyelination improvement after neurotrophic factors secreting cells transplantation in rat spinal cord injury. AB - OBJECTIVES: Neurotrophic factors secreting cells (NTS-SCs) may be a superior cell source for cell-based therapy in neurodegenerative diseases. NTS-SCs are able to secrete some neurotrophic Such as nerve growth factor and glia-derived neurotrophic factor. Our primary aim was to assess transplantation of neurotrophic factor secreting cells derived from human adipose-derived stem cells (hADSCs) into the damaged spinal cord rats and determine the potential of these cells in remyelination. MATERIALS AND METHODS: To this end, 40 adult male Wistar rats were categorized into four groups including; control, lysolecithin (Lysophosphatidylcholines or LPC), vehicle, and NTS-SCs transplan-tation. Local demyelination was induced using LPC injection into the lateral column of spinal cord. Seven days after the lysolecithin lesion, the cells transplantation was performed. The ultrastructure of myelinated fibers was examined with a transmission electron microscope to determine the extent of myelin destruction and remyelinization 4 weeks post cell transplantation. Moreover, the presence of oligodendrocyte in the lesion of spinal cord was assessed by immunohistochemistry procedure. RESULTS: The results of current study indicated that in NTF-SCs transplantation group, the remyelination process and the mean of myelin sheath thickness as well as axonal diameters were significantly higher than other groups (P<0.001). Furthermore, immunohistochemistry analysis revealed that in NTF-SCs transplantation group more than 10 percent of transplanted cells were positive for specific markers of oligodendrocyte cells. CONCLUSION: NTF-SCs transplantation represents a valuable option for cell-based therapy in the nervous tissue damages. PMID- 28804607 TI - Effects of buprenorphine in the adrenal, thyroid, and cytokine intra-operative responses in a rat model (Rattus norvegicus): a preliminary study. AB - OBJECTIVES: Buprenorphine is a common analgesic in experimental research, due to effectiveness and having few side-effects, including a limited influence in the immune and endocrine systems. However, how buprenorphine affects cytokine levels and the adrenal and thyroid response during general anesthesia and surgery is incompletely understood. This study aimed to assess whether buprenorphine modulated significantly those responses in rats submitted to general anesthesia, mechanical ventilation, and surgical insertion of intravascular catheters. MATERIALS AND METHODS: Animals were anesthetized with isoflurane, mechanically ventilated, and surgically instrumented for carotid artery and the femoral vein catheter placement. The test group (n=16), received buprenorphine subcutaneously before surgery, whereas the control group (n=16) received normal saline. Blood sampling to determine plasma levels of adrenocorticotropic hormone (ACTH), corticosterone (CS), total thyroxine (TT4), total triiodothyronine (TT3), thyroid stimulating hormone (TSH), TNF-alpha, IL6, IL10, TNF-alpha, IL6, and IL10 mRNA was performed at 10 min after completion of all surgical procedures and at 90, 150, 240, and 300 min thereafter, with the animals still anesthetized and with mechanical ventilation. RESULTS: Buprenorphine-treated animals had higher levels of ACTH, CS, and TT4 at several time points (P<0.05) and TSH and TT3 at all-time points (P<0.05). They also had increased IL10, TNF-alpha, and IL10 mRNA levels. CONCLUSION: In this model, buprenorphine significantly modulated the intra operative cytokine and endocrine response to anesthesia, mechanical ventilation, and surgical placement of intravascular catheters. The mechanism and significance of these findings remain undetermined. Researchers should be aware of these effects when considering the use of buprenorphine for analgesic purposes. PMID- 28804609 TI - Therapeutic effects of ellagic acid on memory, hippocampus electrophysiology deficits, and elevated TNF-alpha level in brain due to experimental traumatic brain injury. AB - OBJECTIVES: Cognitive defects such as learning and memory impairment are amongst the most repetitious sequelae after sever and moderate traumatic brain injury (TBI). It was suggested that ellagic acid (EA), an innate phenol product, display neuroprotective properties against oxidative and inflammatory damages after brain injury. The object of the current study was therapeutic properties of EA on blood brain barrier (BBB) interruption and elevated content of TNF-alpha in brain tissue followed by neurologic aftereffects, cognitive and brain electrophysiology deficits as outcomes of diffuse TBI in rat. MATERIALS AND METHODS: TBI was induced by a 200 g weight falling by a 2-m height through a free-falling tube onto the head of anesthetized rat. TBI rats treated immediately after trauma with EA (100 mg/kg, IP) once every 8 hr until 48 hr later. Neurologic outcomes, passive avoidance task (PAT), hippocampal long-term potentiation (LTP), BBB permeability and content of TNF-alpha in brain tissue were evaluated. RESULTS: TBI induced significant impairments in neurological score, BBB function, PAT and hippocampal LTP in TBI+Veh group in compare with Sham+Veh (P<0.001). EA treatment decreased neurologic severity score (NSS), restored increased BBB permeability, cognitive and hippocampal LTP abnormalities, and elevated brain content of TNF alpha due to TBI significantly (P<0.001). CONCLUSION: Our findings propose that EA can restore NSS, cognitive and LTP deficits and prevent brain inflammation may by restore BBB permeability as well as lowering brain content of TNF-alpha following TBI. PMID- 28804611 TI - Antimalarial evaluation of selected medicinal plant extracts used in Iranian traditional medicine. AB - OBJECTIVES: In an attempt to discover new natural active extracts against malaria parasites, the present study evaluated the antiplasmodial properties of selected plants based on Iranian traditional medicine. MATERIALS AND METHODS: Ten plant species found in Iran were selected and collected based on the available literature about the Iranian traditional medicine. The methanolic extracts of these plants were investigated for in vitro antimalarial properties against chloroquine-sensitive (3D7) and multi-drug resistant (K1) strains of Plasmodium falciparum. Their in vivo activity against Plasmodium berghei infection in mice was also determined. Cytotoxicity tests were carried out using the Raji cells line using the MTT assay. The extracts were phytochemically screened for their active constituents. RESULTS: According to the IC50 and selectivity index (SI) values, of the 10 selected plant species, Citrullus colocynthis, Physalis alkekengi, and Solanum nigrum displayed potent in vitro antimalarial activity against both 3D7 and K1 strains with no toxicity (IC50= 2.01-18.67 ug/ml and SI=3.55 to 19.25). Comparisons between treated and untreated control mice showed that the mentioned plant species reduced parasitemia by 65.08%, 57.97%, and 60.68%, respectively. The existence of antiplasmodial compounds was detected in these plant extracts. CONCLUSION: This was the first study to highlight the in vitro and in vivo antiplasmodial effects of C. colocynthis, P. alkekengi, and S. nigrum in Iran. Future studies can use these findings to design further biological tests to identify the active constituents of the mentioned plant species and clarify their mechanism of action. PMID- 28804610 TI - Naringin enhances osteogenic differentiation through the activation of ERK signaling in human bone marrow mesenchymal stem cells. AB - OBJECTIVES: Naringin has been reported to regulate bone metabolism. However, its effect on osteogenesis remains unclear. The aim was to investigate the effect of naringin on osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) through the activation of the ERK signaling pathway in osteogenic differentiation. MATERIALS AND METHODS: Annexin V-FITC assay and MTT assay were used to measure the effect of naringin on cytotoxicity and proliferation of hBMSCs, respectively. Alkaline phosphatase activity analysis, Alizarin Red S staining, Western blotting, and real-time PCR assay were used to evaluate both the potential effect of naringin on osteogenic differentiation and the role of ERK signaling pathway in osteogenic differentiation. RESULTS: Our results showed that naringin had no obvious toxicity on hBMSCs, and could significantly promote the proliferation of hBMSCs. Naringin also enhanced the osteogenic differentiation of hBMSCs and increased the protein and mRNA expression levels of osteogenic markers such as Runx-2, OXS, OCN, and Col1 in a dose-dependent manner. In addition, we found that the enhancing effect of naringin on osteogenic differentiation was related to the activation of phosphor-ERK, with an increase in duration of activity from 30 min to 120 min. More importantly, both the enhancing effect of naringin on osteogenic differentiation and the activity effect of naringin on ERK signaling pathway were reversed by U0126 addition. CONCLUSION: Our findings demonstrated that naringin promoted proliferation and osteogenesis of hBMSCs by activating the ERK signaling pathway and it might be a potential therapeutic agent for treating or preventing osteoporosis. PMID- 28804612 TI - Effect of genistein on expression of pancreatic SIRT1, inflammatory cytokines and histological changes in ovariectomized diabetic rat. AB - OBJECTIVES: Genistein is reported to have anti-diabetic and anti-inflammatory functions, in particular, direct effects on beta-cell proliferation and insulin secretion. In this study, we investigated the anti-inflammatory effect of genistein on the pancreatic beta-cells in ovariectomized diabetic rat. MATERIALS AND METHODS: Forty female rats were divided into four groups: sham, bilateral ovariectomy (OVX), OVX.D (OVX+diabetes) and OVX.D.G (OVX.D+genistein). After bilateral ovariectomy, rats in the diabetic groups were fed high-fat diet (HFD), ad libitum for 4 weeks, and then a low dose of streptozotocin (STZ) (30 mg/kg) injected intraperitoneally. Genistein (1 mg/kg/day; SC) was administrated for 8 weeks. At the end of 8 weeks, pancreas tissue was removed and used for western blotting and Hematoxylin-Eosin staining. RESULTS: Treatment with genistein declined inflammation and tissue injury, and this decline was correlated with the expression of SIRT1. OVX and OVX.D significantly increased Nf-kappaB and IL-1beta expression and decreased SIRT1 levels compared to sham group (P<0.05). Significant reduction of Nf-kappaB and IL-1beta, and increasing of SIRT1 were observed during genistein treatment (P<0.05). CONCLUSION: Estrogen deficiency alone or with HFD increased pancreatic inflammation. However, subcutaneous administration of gtenistein prevented from these inflammatory changes in the pancreas of a surgery animal model of ovariectomy with or without diabetes. Our results support the potential preventing effect of genistein from pancreatic injury. PMID- 28804613 TI - Novel derivatives of phthalimide with potent anticonvulsant activity in PTZ and MES seizure models. AB - OBJECTIVES: Phthalimide-based derivatives have anticonvulsant activity like as phenytoin by inhibition of sodium channel. In our previously research we mentioned about some phthalimide derivatives as potent anticonvulsant agents. MATERIALS AND METHODS: Fourteen analogs of 2-substituted phthalimide pharmacophore were synthesized and then were evaluated for the anticonvulsant activities in pentylenetetrazole-induced seizures (PTZ) and maximal electroshock seizure (MES) models. RESULTS: The in vivo screening results showed that all the analogs have the ability to protect against the maximal electroshock and PTZ. The compounds 3 and 9 elevated clonic seizure thresholds at 30 min which were more active than the standard medicine phenytoin. Compounds 3, 6, 7, 11, 13 and 14 with 100% protection were the most potent ones in tonic seizure. The most potent compound in the both PTZ and MES models was compound 3. Using a model of the open pore of sodium channel, all of the compounds were docked. Results of docking showed that the ligands interacted mainly with residues II-S6 of NaV1.2 by making hydrogen bonds and have additional hydrophobic interactions with other domains in the channel's inner pore. CONCLUSION: Some of these compounds are more potent than phenytoin simultaneously in the clonic and tonic seizures. PMID- 28804614 TI - Protective effect of bioactive compounds from Echinophora cinerea against cisplatin-induced oxidative stress and apoptosis in the PC12 cell line. AB - OBJECTIVES: The present study aims to evaluate the protective effect of the compounds isolated from Echinophora cinerea (E. cinerea) against oxidative stress and apoptosis induced by cisplatin (CIS) in PC12 cells. MATERIALS AND METHODS: Six compounds were isolated as quercetrin-3-O-beta-D-glucopyranoside (QUE), osthol (OST), verbenone-5-O-beta-D-glycopyranoside (VER), Isoimperatorin (ISO), kaempferol-3-O-beta-D-glucopyranoside (KAM), and echinophorin B (ECH). For this study, we used MTT reduction assay for detection of protective effects of isolated compounds on CIS-induced cytotoxicity in PC12 cells. The effects of isolated compounds against apoptosis induced by CIS were investigated through the measurement of mitochondrial membrane potential (MMP), Bax and Bcl2 mRNA expression, and caspase-3 activation. We also assessed oxidative stress by measuring reactive oxygen species (ROS) generation with 2', 7' dichlorofluorescein diacetate (DCFH-DA). RESULTS: Treatment of cells with QUE and OST before exposure to the CIS increased cell viability, i.e., these compounds protected the cells against CIS -induced cytotoxicity. In addition, pre-treatment with QUE and OST decreased CIS-induced apoptosis through up-regulation of Bcl-2, inhibition of caspase-3 activity, and mitochondrial membrane potential (MMP) increase. OST decreased ROS generation induced by CIS, as well. CONCLUSION: Our in vitro experiment showed that QUE and OST are apoptotic inhibitors that effectively block CIS-induced neurotoxicity predicting their therapeutic potential in the prevention of chemotherapy-induced neurotoxicity. PMID- 28804615 TI - Pharmacological effects of a synthetic quinoline, a hybrid of tomoxiprole and naproxen, against acute pain and inflammation in mice: a behavioral and docking study. AB - OBJECTIVES: In the present study, we investigated the potential anti-nociceptive activity and acute anti-inflammatory effect of a synthetic quinoline compound (2 (4-Methoxyphenyl)benzo[h]quinoline-4-carboxylic acid, QC), possessing structural elements of both naproxen and tomoxiprole drugs. MATERIALS AND METHODS: The anti nociceptive activity of QC was evaluated using chemical- and thermal-induced nociception models and its acute anti-inflammatory effect was evaluated by xylene induced ear edema test in mice. RESULTS: QC displayed a dose dependent effect in both acute anti-nociceptive tests (writhing and hot plate). This compound at dose of 6.562 mg/kg showed a high anti-nociceptive effect near equal to diclofenac 5 mg/kg. It also showed high anti-inflammatory effects (less than 6.562 mg/kg) comparable to those of reference drugs diclofenac (5 mg/kg) and celecoxib (100 mg/kg). Docking study showed that this quinoline derivative could inhibit COX-2 enzyme strongly. CONCLUSION: QC showed high anti-nociceptive and anti inflammatory effects comparable to reference drugs and can exert its anti nociceptive and anti-inflammatory activities through COX-2 inhibition. PMID- 28804616 TI - Zinc oxide nanoparticle reduced biofilm formation and antigen 43 expressions in uropathogenic Escherichiacoli. AB - OBJECTIVES: This study aimed to investigate the effect of zinc oxide nanoparticles (ZnO-np) on biofilm formation and expression of the flu gene in uropathogenic Escherichia coli (UPEC) strains. MATERIALS AND METHODS: Minimum inhibitory concentration (MIC) of ZnO-np was determined by agar dilution method. The effect of MIC and sub-MIC concentrations of ZnO-np on biofilm formation were determined by microtiter plate assay. The expression level of the flu gene was assessed by Real-Time PCR assay. RESULTS: MIC and sub-MIC ZnO-np concentrations reduced biofilm formation by 50% and 33.4%, respectively. Sub-MIC ZnO-np concentration significantly reduced the flu gene expression in the UPEC isolates (P<0.0001). CONCLUSION: The sub-MIC concentration of ZnO-np reduces biofilm formation and flu gene expression in UPEC isolates. It is suggested to use nanoparticles for coating medical devices to prevent bacterial colonization. PMID- 28804617 TI - "Typical" chiropractic patients- can they be described in terms of recovery patterns? AB - BACKGROUND: Chiropractors expect the typical patient to recover fully or to improve quickly with treatment if relapses occur. However, a mismatch between expectations and outcome would have a negative effect on both the chiropractors' professional self-esteem and patients' satisfaction with care. The prevalence of three types of recovery patterns among patients with non-specific low back pain (LBP) was calculated: 1: A full sustained recovery. 2: Initial recovery, but with one or several relapses followed by a period of recovery. 3: No initial recovery, but at least one period of recovery during the six month course of the study. Also, the number of patients classified as recovered at the end of the study was calculated. METHOD: In this Swedish clinical observational study from 2008 to 2009, an automated text message system (SMS-Track(r)) was used to ask chiropractic patients weekly for 6 months about the number of days their LBP had bothered them during the past week. Data were analyzed blindly by two researchers by viewing individual graphs and was performed twice. RESULTS: In all 176 of 262 patients with non-specific LBP were included in the analysis. 1) Twenty percent of patients (CI: 15.3-26.9) made a full sustained recovery. 2) A further 20% (CI: 14.8-26.2) recovered initially but experienced a relapse, followed by at least one new period of full recovery. 3) Twenty-three percent (CI: 17.3-29.3) of patients failed to recovery initially but experienced recovery some time during the study. 4) Thirty-seven percent (CI: 30.3-44.1) had no periods of recovery, and were therefore classified as having a non-favorable course. At the end of the study, 41% (CI: 34.1-48.1) were classified as recovered. CONCLUSIONS: The results from this study can be used to introduce a realistic approach to chiropractic care in LBP, which should reduce disappointments among both chiropractors and patients. There was no "typical" recovery pattern. Trajectories were, in fact, spread over several subgroups with somewhat more than half reporting a favorable course but only one fifth enjoyed early and sustained recovery. Further, from a research perspective, the end-of -study status does not well depict the outcome experienced by patients. PMID- 28794858 TI - Monitoring respiration and oxygen saturation in patients during the first night after elective bariatric surgery: A cohort study. AB - Background: Obstructive sleep apnoea and obese hypoventilation is not uncommon in patients with obesity. Residuals effect from surgery/anaesthesia and opioid analgesics may worsen respiration during the first nights after bariatric surgery. The aim of this observational study was to monitor respiration on the first postoperative night following elective bariatric surgery. Methods: This observational study aimed to determine the incidence and severity of hypo/apnoea in low risk obsess patients undergoing elective bariatric surgery in general anesthaesia. Patients with known or suspected sleep respiratory disturbances was not included. ESS was scored prior to surgery. Oxygen desaturation was analyzed by continuous respiratory monitoring. Mean oxygen saturation (SpO2), nadir SPo2, apnoea/hypopnea index and oxygen desaturation index was assess by standard tools. Results: 45 patients were monitored with portable polygraphy equipment (Embletta, ResMed) during the first postoperative night at the general ward following elective laparoscopic bariatric surgery. The prop ESS was 0-5 in 22, 6-10 in 14 and 11-16 in 6 of the patients studied (missing data 3). Mean SpO2 was 93%; 10 patients had a mean SpO2 of less than 92% and 4 of less than 90%. The lowest mean SpO2 was 87%. There were 16 patients with a nadir SpO2 of less than 85%, lowest nadir SpO2 being 63%. An Apnoea Hypo/apnoea Index (AHI) > 5 was found in 2 patients only (AHI 10 and 6), and an Oxygen Desaturation index (ODI) > 5 was found in 3 patients (24, 10 and 6, respectively). 3 patients had more prolonged (> 30 seconds) apnoea with nadir SpO2 81%, 83% and 86%. ESS score and type of surgery did not impact on respiration/oxygenation during the observation period. Conclusions: A low mean SpO2 and episodes of desaturation were not uncommon during the first postoperative night following elective bariatric surgery in patients without history of night time breathing disturbance. AHI and/or ODI of more than 5 were only rarely seen. Night-time respiration monitoring provided seemingly sparse additional information. Further studies are need to assess risk factors and potential impact of the desaturation episodes that occurs during sleep. PMID- 28804619 TI - Knowledge sharing in infection prevention in routine and outbreak situations: a survey of the Society for Healthcare Epidemiology of America Research Network. AB - In this cross-sectional Society for Healthcare Epidemiology of America Research Network survey on knowledge sharing in infection prevention we identified a rudimentary understanding of how to communicate and share knowledge within healthcare institutions. Our data support the need of further research in this important field. PMID- 28804620 TI - Stress and immunological response of heifers divergently ranked for residual feed intake following an adrenocorticotropic hormone challenge. AB - BACKGROUND: When an animal is exposed to a stressor, metabolic rate, energy consumption and utilisation increase primarily through activation of the hypothalamic-pituitary-adrenal (HPA) axis. Changes to partitioning of energy by an animal are likely to influence the efficiency with which it is utilised. Therefore, this study aimed to determine the physiological stress response to an exogenous adrenocorticotropic hormone (ACTH) challenge in beef heifers divergently ranked on phenotypic residual feed intake (RFI). RESULTS: Data were collected on 34 Simmental weaning beef heifers the progeny of a well characterized and divergently bred RFI suckler beef herd. Residual feed intake was determined on each animal during the post-weaning stage over a 91-day feed intake measurement period during which they were individually offered adlibitum grass silage and 2 kg of concentrate per head once daily. The 12 highest [0.34 kg DM/d] and 12 lowest [-0.48 kg DM/d] ranking animals on RFI were selected for use in this study. For the physiological stress challenge heifers (mean age 605 +/- 13 d; mean BW 518 +/- 31.4 kg) were fitted aseptically with indwelling jugular catheters to facilitate intensive blood collection. The response of the adrenal cortex to a standardised dose of ACTH (1.98 IU/kg metabolic BW0.75) was examined. Serial blood samples were analysed for plasma cortisol, ACTH and haematology variables. Heifers differing in RFI did not differ (P = 0.59) in ACTH concentrations. Concentration of ACTH peaked (P < 0.001) in both RFI groups at 20 min post-ACTH administration, following which concentration declined to baseline levels by 150 min. Similarly, cortisol systemic profile peaked at 60 min and concentrations remained continuously elevated for 150 min. A RFI * time interaction was detected for cortisol concentrations (P = 0.06) with high RFI heifers had a greater cortisol response than Low RFI from 40 min to 150 min relative to ACTH administration. Cortisol response was positively associated with RFI status (r = 0.32; P < 0.01). No effect of RFI was evident for neutrophil, lymphocytes, monocyte, eosinophils and basophil count. Plasma red blood cell number (6.07 vs. 6.23; P = 0.02) and hematocrit percentage (23.2 vs. 24.5; P = 0.02) were greater for low than high RFI animals. CONCLUSIONS: Evidence is provided that feed efficiency is associated with HPA axis function and susceptibility to stress, and responsiveness of the HPA axis is likely to contribute to appreciable variation in the efficiency feed utilisation of cattle. PMID- 28804621 TI - Development of gene polymorphisms in meditators of nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, the morbidity of which closely correlates with diversity of ethnicity, minority, family and location. Its histology spans from simple steatosis, to nonalcoholic steatohepatitis, which ultimately results in fibrosis, cirrhosis and hepatocellular carcinoma. The accelerating prevalence of NAFLD is due to an incremental incidence of metabolic syndrome that is distinguished by dyslipidemia, glucose impairment, obesity, excessive oxidative stress and adipocytokine impairment. Additionally, the pathogenesis of NAFLD is thought to be a multifactorial and complicated disease associated with lifestyle habits, nutritional factors and genetics. However, the pathogenesis and underlying mechanism in the development of NAFLD caused by genetics remains unclear. People have been increasingly emphasizing on the relationship between NAFLD and gene polymorphisms in recent years, with the aim of having a comprehensive elucidation of associated gene polymorphisms influencing the pathogenesis of the disease. In the current article, the authors attempted to critically summarize the most recently identified gene polymorphisms from the facets of glucose metabolism, fatty acid metabolism, oxidative stress and related cytokines in NAFLD that contribute to promoting the progression of the disease. PMID- 28804622 TI - Human placental growth hormone in normal and abnormal fetal growth. AB - Human placental growth hormone (PGH), encoded by the growth hormone (GH) variant gene on chromosome 17, is expressed in the syncytiotrophoblast and extravillous cytotrophoblast layers of the human placenta. Its maternal serum levels increase throughout pregnancy, and gradually replaces the pulsatile secreted pituitary GH. PGH is also detectable in cord blood and in the amniotic fluid. This placental origin hormone stimulates glyconeogenesis, lipolysis and anabolism in maternal organs, and influences fetal growth, placental development and maternal adaptation to pregnancy. The majority of these actions are performed indirectly by regulating maternal insulin-like growth factor-I levels, while the extravillous trophoblast involvement indicates a direct effect on placental development, as it stimulates trophoblast invasiveness and function via a potential combination of autocrine and paracrine mechanisms. The current review focuses on the role of PGH in fetal growth. In addition, the association of PGH alterations in maternal circulation and placental expression in pregnancy complications associated with abnormal fetal growth is briefly reviewed. PMID- 28804623 TI - Recent advances in the molecular mechanisms of Mayer-Rokitansky-Kuster-Hauser syndrome. AB - Mayer-Rokitansky-Kuster-Hauser syndrome (MRKHS) is a disease caused by congenital absence of the uterus and two-thirds of the upper vagina. The pathogenic mechanism of MRKHS may involve gene abnormalities, and there are various case reports associating MRKHS with the Wnt family member 4 (Wnt4) mutation. Analysis of genes mapped to regions in which deletion and duplication are frequently detected in patients with MRKHS has shown involvement of LIM homeobox 1 (LHX1), HNF1 homeobox B (HNF1B) and T-box 6 (TBX6). In addition, there are case reports of MRKHS caused by chromosomal translocation and epigenetic function may be involved in MRKHS onset. Overexpression of HOXA and overexposure to estrogen may contribute to the onset and regulation of expression by methylation as a pathogenic mechanism. Determination of the molecular basis of MRKHS is in progress, but current treatment only includes vaginal enlargement and vaginoplasty for improved quality of life. Clinical application of uterine transplantation to allow childbearing by MRKHS patients is under investigation and clinical trials are underway around the world. PMID- 28804624 TI - Carotid endarterectomy for in-stent restenosis: a case report and literature review. AB - It is relatively difficult to treat restenosis when restenosis occurs following carotid artery stenting. Endarterectomy with simultaneous stent removal is an effective approach when restenosis occurs. The treatment method is still not well known. The present paper reports a case of restenosis after stenting that was treated with endarterectomy with a satisfactory treatment outcome. The patient, a 74-year-old male, underwent stenting 10 months before he was re-hospitalized. He seemed to recover well after stenting until one month before he was re hospitalized, when he presented symptoms of cerebral ischemia. Imaging examination revealed that in-stent stenosis had reoccurred, with the stenosis degree ranging from 70-99%. He was given endarterectomy treatment, and intra operative findings showed that the stent grew into a carotid artery plaque and protruded below the adventitia and that the stent lumen was not covered by carotid artery intima. The surgery completely and successfully removed the plaque and the stent, while the adventitia was completely preserved. Follow-up indicated that there was no stenosis in the carotid artery, and the prognosis was good. Relevant literature was also reviewed in this paper, and the authors suggested that carotid artery plaque and stent endarterectomy is beneficial. However, surgical treatment for in-stent stenosis remains a challenging option. PMID- 28804625 TI - The relationship between tumor necrosis factor-alpha polymorphisms and gastric cancer risk: An updated meta-analysis. AB - The aim of the present study was to evaluate the relationship between tumor necrosis factor-alpha (TNF-alpha) and the development of gastric cancer, and to investigate whether it can be used as a biological marker for gastric cancer. In the current study, a new meta-analysis was performed to assess the association between TNF-alpha gene polymorphisms and gastric cancer susceptibility. Subgroup analyses based on ethnicity, control population source and non-cardia cancers were also conducted. Summary odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a random-effects model. TNF-alpha 308 polymorphisms indicated a significant relationship with gastric cancer risk among a normal population [GA/AA vs. GG; 1.17 (1.10-1.23)]. In analysis stratified by ethnicity, TNF-alpha 238 displayed an association with gastric cancer risk in eastern populations [GA/AA vs. GG: 1.24 (1.02-1.50)], but not in western populations [GA/AA vs. GG: 0.96 (0.79-1.18)]. The overall ORs (95% CIs) for TNF-alpha 857, TNF-alpha 1031 and TNF-alpha 863 were 1.13 (1.04-1.24), 0.94 (0.85-1.05) and 0.89 (0.78-1.02), respectively, under dominant genetic model comparison. Among the above three SNPs, only TNF-alpha 857 was robustly associated with gastric cancer inclination, and this association remained consistently robust when limited to non-cardia gastric cancers [GA/AA vs. GG: 1.16 (1.03-1.31)]. TNF-alpha 308 and TNF-alpha 857 genotypes were potential risk factors of statistical significance in gastric cancer, and TNF-alpha 238 indicated to be significantly associated with gastric cancer risk only in eastern populations. TNF-alpha 1031 and TNF alpha 863 were not significantly associated with gastric cancer risk. PMID- 28804626 TI - Efficacy and safety of biosimilar filgrastim in primary and secondary prevention of febrile neutropenia. AB - Neutropenia and febrile neutropenia (FN) are among the most common side effects/complications of chemotherapy. The aim of the present study was to evaluate the practice of the use of biosimilar filgrastim in the primary and secondary prevention of FN, and assess its efficacy and safety. A multi-center, non-interventional epidemiological study of 170 cancer patients aged 23-82 years was conducted. Data were collected via a questionnaire completed based on medical documentation and patient examination over five chemotherapy visits. The risk of FN related to the chemotherapy protocol used was in the range of 10-20% in >50% of the patients (53.5%) and a majority (74.7%) had additional FN risk factors. 60% of the patients received filgrastim as primary prevention of FN, and 40% received it as secondary prevention. In 40.6% of cases, six cycles of chemotherapy were used. More than 90% of patients continued chemotherapy according to the initial recommended dose. In majority of patients, no FN was observed following the final cycle of chemotherapy. Median neutrophil count at visit 1 was 2.2*103/ul and did not fall below that level. Majority of patients (>70%) performed self-injections of filgrastim, and 86.3% of patients were continuing therapy with this drug at the last visit. No treatment-related side effects were recorded. The use of biosimilar filgrastim in the primary and secondary prevention of FN allows to maintain initial chemotherapy dosage. Furthermore, the use of biosimilar filgrastim is safe and tolerable, and has a high acceptance by patients. PMID- 28804627 TI - Effect of rapamycin on early stage apoptosis of neutrophils in Sprague-Dawley rats with acute lung injury. AB - Transfusion-related acute lung injury (TRALI) is a serious complication characterized by the acute onset of non-cardiogenic pulmonary edema following transfusion of blood products. It is not known whether rapamycin has an effect on TRALI that is caused by blood transfusion. The aim of the present study was to determine the effect of rapamycin on early stage apoptosis of neutrophils in Sprague-Dawley rats with acute lung injury. Animal models of TRALI and acute pancreatitis-associated lung injury (APALI) were prepared using Sprague-Dawley rats and histopathological examination of lung tissues was used to validate acute lung injury models. Peripheral blood neutrophils were isolated and early stage apoptosis of neutrophils was detected by flow cytometry. The animal models of TRALI and APALI were constructed successfully. Early stage apoptosis of neutrophils increased in the TRALI group and decreased in the APALI group (P<0.05), while the apoptosis rates in rapamycin intervention TRALI and APALI groups were not significantly different compared to the rate in the control group (P>0.05). In conclusion, early stage apoptosis of neutrophils in TRALI was different from that in APALI, and rapamycin had a limited protective effect on TRALI and APALI in Sprague-Dawley rats. PMID- 28804628 TI - From Saccharomyces cerevisiae to human: The important gene co-expression modules. AB - Network-based systems biology has become an important method for analyzing high throughput gene expression data and gene function mining. Yeast has long been a popular model organism for biomedical research. In the current study, a weighted gene co-expression network analysis algorithm was applied to construct a gene co expression network in Saccharomyces cerevisiae. Seventeen stable gene co expression modules were detected from 2,814 S. cerevisiae microarray data. Further characterization of these modules with the Database for Annotation, Visualization and Integrated Discovery tool indicated that these modules were associated with certain biological processes, such as heat response, cell cycle, translational regulation, mitochondrion oxidative phosphorylation, amino acid metabolism and autophagy. Hub genes were also screened by intra-modular connectivity. Finally, the module conservation was evaluated in a human disease microarray dataset. Functional modules were identified in budding yeast, some of which are associated with patient survival. The current study provided a paradigm for single cell microorganisms and potentially other organisms. PMID- 28804629 TI - Clinical presentation and treatment of gastric metastasis from other malignancies of solid organs. AB - The aim of the present study was to analyze the clinicopathologic features and treatment outcomes of gastric metastasis from other malignancies of solid organs. A review was conducted of patients with metastatic tumors in the stomach from other malignancies of solid organs detected endoscopically at the Department of Surgery, Kochi Medical School, from January 1991 to December 2015. Seven patients (four men and three women), with a median age of 64 years (range, 42-71 years), had metastatic gastric tumors. Median tumor size was 7.3 cm (range, 2.5-12.0 cm). The primary malignancy leading to metastatic tumors in the stomach was esophageal cancer in three patients, breast cancer in two patients, renal cell carcinoma in one patient, and ovarian cancer in one patient. Gastric metastasis presented as solitary lesions in six patients and as multiple lesions in one patient. Four patients had solitary gastric metastasis, whereas three had multiple metastases in other organs. The median tumor size was significantly smaller in patients with solitary rather than multiple metastases (4.6 vs. 12.0 cm, respectively; P=0.038). Three patients received systemic therapy and four underwent surgical resection of the metastatic tumor, and of these, only one was alive 58 months after surgery. Clinicians should be aware of the possible existence of metastatic gastric cancer, especially in breast carcinoma and esophageal cancer. Surgical resection may considerably improve patients' quality of life, and could be of benefit when there is a risk of bleeding and/or a solitary metastasis. PMID- 28804630 TI - Protected cytoskeletal-related proteins: Towards a resolution of contradictions regarding the role of the cytoskeleton in cancer. AB - Initial reports of the role of the cytoskeleton in cancer indicated that tumor cells with a more disorganized cytoskeleton were more tumorigenic. These reports were based on stains for the F-actin cytoskeleton, for example, using phalloidin or anti-F-actin antibody reagents, and gave a basic impression of F-actin-based cytoskeletal integrity. Later developments emphasized the significance of the cytoskeletal elements in cell migration, presumably associated with either basement membrane invasion or metastasis, or both, with several specific proteins implicated in the formation of cell invadopodia. With the advent of genomics approaches, it has become clear that cytoskeletal related proteins are indeed common targets of mutagenesis in cancer and commonly rank among the most mutated proteins in cancers, presumably due to large coding region sizes and the significant stochastic component to human mutagenesis. This cytoskeletal genomics result is consistent with the loss of cytoskeleton integrity as a hallmark of tumor development, but raises the question of whether such mutational sensitivity relates to the migration and invadopodia aspects of tumor progression. In the present study, the authors report that it is possible to identify a set of cytoskeletal related proteins protected from mutation, in comparison to the commonly mutated cytoskeleton related proteins in certain, but not all cancer, datasets. PMID- 28804631 TI - The influence of D-chiro-inositol and D-myo-inositol in pregnant women with glucose intolerance. AB - The aim of the present study was to demonstrate that the use of inositol and folic acid from the first trimester of pregnancy, counteracts the onset of gestational diabetes mellitus (GDM) in women at risk, preserving the infants from macrosomia, hypoglycemia and preterm delivery. The authors collected data from the pregnant women at the laboratory (Unit of Cytogenic and Molecular Genetics), from January 2014 to April 2016, all with first trimester fasting plasma glucose (FPG) >92 mg/dl. A total of 40 women were treated with 250 mg/day D-chiro inositol, 1.75 g/day D-myo-inositol, 12.5 mg/day zinc, 10 mg/day methylsulfonylmethane, 400 ug/day 5-methyltetrahydrofolic acid. The other 43 women (control group) were treated with only 400 ug/day folic acid. The primary outcome measure was the incidence of maternal GDM. The secondary outcome measures were the incidence of fetal macrosomia, preterm delivery and neonatal hypoglycemia. At the 24th week of pregnancy, the incidence of maternal GDM was recorded in 18 women in the control group and in 5 women in the treated group [relative risk (RR)=3.35; 95% confidence interval (CI)=1.37-8.17; P=0.0028). A significant difference was observed between treated and control groups in terms of risk of macrosomia. A total of seven infants in the control group, and two in the treated group, weighed >4,000 g (RR=5,12; 95% CI=1.21-21.68; P=0.0099). No significant difference was identified between two groups, regarding the other two secondary outcomes, neonatal hypoglycemia (RR=4.650; 95% CI=0.57-38.11; P=0.1086) and preterm delivery (RR=1.74; 95% CI=0.83-3.66; P=0.1301). The current study demonstrated the potential benefit of supplementation with the association of D chiro-inositol and D-myo-inositol in pregnant 'at risk' women, with first trimester FPG >92 mg/dl, in preventing the onset of maternal GDM and macrosomia in newborns. PMID- 28804632 TI - The pattern of IL-24/mda-7 and its cognate receptors expression following activation of human hepatic stellate cells. AB - Activation of hepatic stellate cells (HSCs) is the pivotal event during liver fibrosis. Interleukin (IL)-24/melanoma differentiation-associated gene-7 (mda-7) has attracted attention in the pathophysiology of some diseases, while its role in activation/suppression of human HSCs is still unclear. It is important to elucidate whether the expression levels of the IL-24/mda-7 protein and its receptors in HSC cells are changed following activation. LX-2 cells, a human hepatic stellate cell line were activated by a combination of leptin and serum starvation. The activation state was evaluated through measuring the mRNA expression of profibrotic molecules, collagen-I, TIMP metalloproteinase inhibitor 1 and transforming growth factor-beta. The expression of IL-24/mda-7 was assessed in mRNA and protein levels by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and ELISA methods, respectively. Hence, the amount of IL-22R1 and IL-20R2 subunit expression was also compared in activated and normal LX-2 cells by RT-qPCR. The expression level of IL-24/mda-7 and its cognate receptors was detectable both in the normal and activated LX-2 cell line. Furthermore, in activated LX-2, a significant increase of IL24 expression either on IL-22R1 and IL-20R2 subunits was also noticeable in comparison to normal cells. The activation state of LX-2 cells caused significant changes of IL-24/mda-7 and its receptors expression. In addition, the elevation in IL-24/mda-7 during LX-2 cell activation, suggested that IL-24/mda-7 and its cognate receptors serve a possible role in the development of the fibrosis process. Therefore, IL-24/mda-7 and relevant signaling pathways may be employed as a target for fibrosis treatment. PMID- 28804633 TI - Fractalkine (C-X3-C motif chemokine ligand 1) as a potential biomarker for depression and anxiety in colorectal cancer patients. AB - Fractalkine, a unique chemokine of the CX3C subfamily, is involved in the pathogenesis of different types of cancer and also in non-immune mechanisms associated with psychiatric disorders. The aim of the present study was to investigate whether there is a correlation between anxiety, depression and fractalkine serum levels in colorectal cancer (CRC) patients in different stages of antitumor therapy. Four groups of patients undergoing treatment (n=20 per group) were evaluated: Patients with CRC who did not undergo surgical resection of the tumor; patients who underwent resection and who did not start adjuvant therapy; patients undergoing chemotherapy for ~3 months; and patients who had completed adjuvant chemotherapy regimen for ~6 months. The control group was composed of 20 healthy volunteers free of any psychiatric or immune system disease. Depression and anxiety were evaluated using the Hospital Anxiety and Depression Scale (HADS) and serum levels of fractalkine were measured by cytometric bead array. Clinically relevant levels of anxiety and/or depression were observed in all of the CRC patients at the different stages of antitumor therapy. Elevated serum levels of fractalkine were identified in the CRC patients in the pre-surgery (P<0.001) and pre-chemotherapy (P<0.001) groups, but reduced upon chemotherapy (P<0.05). Furthermore, a positive correlation was observed between fractalkine levels and the HADS scores in the CRC patients at different stages of antitumor therapy. These results demonstrate a link between fractalkine, depression and anxiety in CRC patients indicating that this chemokine is involved in the pathophysiology of these comorbidities. An improved understanding of the molecular mechanisms involved in these psychological disorders will allow the design of novel therapeutic strategies to assist in alleviating such symptoms in cancer patients. Therefore, fractalkine may present as a relevant biomarker for depression and anxiety in CRC patients. PMID- 28804634 TI - Muscle MRI findings in a one-year-old girl with merosin-deficient congenital muscular dystrophy type 1A due to LAMA2 mutation: A case report. AB - The objective of the present study was to characterize the muscle magnetic resonance imaging (MRI) features of a 1-year-old girl with merosin-deficient congenital muscular dystrophy type 1A (MDC1A). Beginning as an infant, this patient exhibited severe hypotonia and proximal weakness, as well as delays in developmental milestones. Her serum creatine kinase levels at 3 months, 8 months and 1 year were 2,959, 1,621 and 1,659 U/l, respectively. Brain MRI indicated symmetric, mild T1WI low, mild T2WI and FLAIR high radial patterns in the white matter of the Cornu posterius of the ventricular lateral. Gene sequencing demonstrated a heterozygous frame-shift mutation in the LAMA2 gene, consisting of an AG deletion at nucleotides 2049-2050 (LAMA2 c.2049_2050delAG). Lower limb muscle MRI presented obvious fatty infiltration of the muscles and muscle atrophy during the early stage of the disease. The gluteus maximus, erector spinae, vastus intermedius, vastus lateralis, adductor magnus, soleus and gastrocnemius muscles were involved, whereas the piriformis, obturator internus, pectineus, adductor longus, adductor brevis and sartorius muscles presented mild or no involvement. Fatty infiltration of the erector spinae was observed during the early stage of the disease. As an additional tool in the differential diagnosis of muscle disorders, muscle MRI can delay the need for muscle biopsy. PMID- 28804635 TI - Analyzing cardiovascular treatment guidelines application to women and minority populations. AB - Despite nearly 30 years of treatment guidelines for cardiovascular diseases and risk factors and a parallel growth in the understanding of cardiovascular disease disparities by sex and race/ethnicity, such disparities persist. The goals of this review are to consider the possible role of three factors: the one-size-fits all approach of most treatment guidelines, adoption of guideline-recommended treatments in clinical practice, and patient adherence to recommended practice, especially the relationship between adherence and patient perceptions. Guideline authors repeatedly call for more inclusion of women and minorities in the clinical trials that make guidelines possible, but despite challenges, guidelines are largely effective when implemented, as shown by a wealth of post hoc analyses. However, the data also suggest that one-size-fits-all treatment guidelines are not sufficiently generalizable and there is evidence of a distinct lag time between definitive clinical evidence and its widespread implementation. Patient perspectives may also play both a direct and indirect role in adherence to treatments. What emerges from the literature is an important continuing need for increased inclusion of women and minority subgroups in clinical trials to allow analyses that can provide evidence for differential treatments when needed. Increased effort is needed to implement definitive clinical improvements more rapidly. Patient input and feedback may also help inform clinical practice and clinical research with a better understanding of how to enhance patient adherence, but evidence for this is lacking for the groups most affected by disparities. PMID- 28804636 TI - Do pediatric gastroenterology doctors address pediatric obesity? AB - OBJECTIVES: To assess how often obesity is acknowledged at pediatric gastroenterology outpatient visits. METHODS: A retrospective chart review was performed to identify obese children seen at a gastroenterology subspecialty clinic over a 1-year period of time; 132 children were identified. Demographics, obesity comorbidities, reasons for referral, diagnosis of obesity, and a plan to address obesity were abstracted. Chi-square or Fisher's exact tests were used to examine statistical associations. RESULTS: Only 49% of children were given a diagnosis of obesity. In total, 52% of children were given a body mass index reduction plan. Those diagnosed with obesity were more likely to receive a body mass index reduction plan (p < 0.0001). Younger children and males were more likely to receive an obesity diagnosis (p = 0.002 and p = 0.02, respectively). Diagnosis of obesity was more likely in patients with obesity-related comorbidities (p = 0.0004) and those referred for obesity or related comorbidities (p = 0.01). CONCLUSION: Obesity is diagnosed less than 50% of the time in pediatric gastroenterology outpatient clinics. To increase opportunities for addressing childhood obesity in the pediatric gastroenterology outpatient setting, further investigation of barriers and optimal provider education is urgently required. PMID- 28804637 TI - Heterotypic Supramolecular Hydrogels. AB - Supramolecular hydrogels, formed via intermolecular interactions in water, are emerging as a new type of versatile soft materials to be applied in many areas, such as biomedical applications, catalysis, food additives, and cosmetics. While most of the supramolecular hydrogels are homotypic (i.e., one type of building blocks), heterotypic supramolecular hydrogels are less explored, but may offer unique advantages. This review discribes supramolecular hydrogels that consist of more than one type building blocks (i.e., heterotypic) to illustrate the promises and challenges of heterotypic supramolecular hydrogels as soft biomaterials. First, we discuss the driving force for producing heterotypic supramolecular hydrogels. Second, we introduce the general methods for triggering heterotypic supramolecular hydrogels. Third, we summarize the examples of heterotypic supramolecular hydrogels made of hydrogelators with or without containing amino acid residues. Fourth, we describe the applications of heterotypic supramolecular hydrogels up-to-date. Finally, we give the outlook and propose a few future directions that likely worth to be explored. PMID- 28804638 TI - Tumor-associated macrophages, potential targets for cancer treatment. AB - The fact that various immune cells, including macrophages, can be found in tumor tissues has long been known. With the introduction of concept that macrophages differentiate into a classically or alternatively activated phenotype, the role of tumor-associated macrophages (TAMs) is now beginning to be elucidated. TAMs act as "protumoral macrophages", contributing to disease progression. As the relationship between TAMs and malignant tumors becomes clearer, TAMs are beginning to be seen as potential therapeutic targets in these cases. In this review, we will discuss how TAMs can be used as therapeutic targets of cancer in clinics. PMID- 28804639 TI - Tuberculosis joint infections in four domestic cats. AB - CASE SERIES SUMMARY: This paper describes the clinical presentation, diagnostic imaging findings and outcome in four cats with confirmed joint-associated tuberculosis. The cats were 2-6 years of age, and immune competent. Three cases had tuberculosis affecting only one joint, whereas one case had at least three joints affected. Two cases were caused by Mycobacterium bovis, and the other two were caused by Mycobacterium microti. Radiological findings included osteolysis, periosteal reaction and associated soft tissue swelling. Two cases were euthanased and two cases responded well to amputation and follow-on antibiotic therapy. RELEVANCE AND NOVEL INFORMATION: To our knowledge, this is the first publication of a series of cats with joint-associated tuberculosis. Although tuberculosis is not common, a high degree of suspicion is needed to avoid delayed diagnosis. This case series highlights the importance of considering mycobacterial disease as a differential for joint disease in cats. PMID- 28804640 TI - Performance of objective functions and optimisation procedures for parameter estimation in system biology models. AB - Mathematical modelling of signalling pathways aids experimental investigation in system and synthetic biology. Ever increasing data availability prompts the development of large dynamic models with numerous parameters. In this paper, we investigate how the number of unknown parameters affects the convergence of three frequently used optimisation algorithms and four objective functions. We compare objective functions that use data-driven normalisation of the simulations with those that use scaling factors. The data-driven normalisation of the simulation approach implies that simulations are normalised in the same way as the data, making both directly comparable. The scaling factor approach, which is commonly used for parameter estimation in dynamic systems, introduces scaling factors that multiply the simulations to convert them to the scale of the data. Here we show that the scaling factor approach increases, compared to data-driven normalisation of the simulations, the degree of practical non-identifiability, defined as the number of directions in the parameter space, along which parameters are not identifiable. Further, the results indicate that data-driven normalisation of the simulations greatly improve the speed of convergence of all tested algorithms when the overall number of unknown parameters is relatively large (74 parameters in our test problems). Data-driven normalisation of the simulations also markedly improve the performance of the non-gradient-based algorithm tested even when the number of unknown parameters is relatively small (10 parameters in our test problems). As the models and the unknown parameters increase in size, the data driven normalisation of the simulation approach can be the preferred option, because it does not aggravate non-identifiability and allows for obtaining parameter estimates in a reasonable amount of time. PMID- 28804641 TI - Breast cancer detected as an incidental finding on 99mTc-MIBI scintigraphy. AB - We report a case of breast cancer detected as an incidental finding on 99mTc-MIBI scintigraphy. 99mTc-MIBI scintigraphy is usually used to evaluate cardiac perfusion or to detect ectopic parathyroid adenomas; however, it is also known to sensitively detect breast cancer. Accordingly, a few reports have described the incidental detection of breast cancer by 99mTc-MIBI scintigraphy performed to detect parathyroid adenoma. Our present case underscores the importance of attending to any incidental findings when searching for parathyroid adenomas using 99mTc-MIBI scintigraphy. PMID- 28804642 TI - E-learning for medical imaging specialists: introducing blended learning in a nuclear medicine specialist course. AB - BACKGROUND: While e-learning has become an important tool in teaching medical students, the training of specialists in medical imaging is still dominated by lecture-based courses. PURPOSE: To assess the potential of e-learning in specialist education in medical imaging. MATERIAL AND METHODS: An existing lecture-based five-day course in Clinical Nuclear Medicine (NM) was enhanced by e learning resources and activities, including practical exercises. An anonymized survey was conducted after participants had completed and passed the multiple choice electronic course examination. RESULTS: Twelve out of 15 course participants (80%) responded. Overall satisfaction with the new course format was high, but 25% of the respondents wanted more interactive elements such as discussions and practical exercises. The importance of lecture handouts and supplementary online material such as selected original articles and professional guidelines was affirmed by all the respondents (92% fully, 8% partially), while 75% fully and 25% partially agreed that the lectures had been interesting and relevant. CONCLUSION: E-learning represents a hitherto unrealized potential in the education of medical specialists. It may expedite training of medical specialists while at the same time containing costs. PMID- 28804643 TI - Local staging of sigmoid colon cancer using MRI. AB - BACKGROUND: An accurate radiological staging of colon cancer is crucial to select patients who may benefit from neoadjuvant chemotherapy. PURPOSE: To evaluate the diagnostic accuracy of preoperative magnetic resonance imaging (MRI) in identifying locally advanced sigmoid colon cancer, poor prognostic factors, and the inter-observer variation of the tumor apparent diffusion coefficient (ADC) values of diffusion-weighted imaging (DWI). MATERIAL AND METHODS: Using 1.5 T MRI with high resolution T2-weighted (T2W) imaging, DWI, and no contrast enhancement, 35 patients with sigmoid colon cancer were assessed. T-stage, N-stage, extramural vascular invasion (EMVI), and ADC values of the tumors were assessed and blindly compared by two observers using postoperative histopathological examination as the gold standard. Early tumors were defined as T1 to T3ab, and advanced tumors as T3cd or T4. RESULTS: The accuracy of the two radiologists in staging early versus advanced tumors, N-stage, and identification of EMVI was 94%/89%, 60%/66%, and 77%/60% with an inter-observer agreement of k = 0.86 (95% confidence interval [CI] = 0.67-1.00), k = 0.64 (95% CI = 0.39-0.90), and k = 0.52 (95% CI = 0.23 0.80). All the measured mean ADC values were below 1.0 * 10-3 mm2/s with an intra class correlation coefficient in T3cd-T4 tumors of 0.85. CONCLUSION: Preoperative MRI can identify locally advanced sigmoid colon cancer and has potential as the imaging of choice to select patients for neoadjuvant chemotherapy. Initial experience with ADC measurement was achieved with an excellent inter-observer agreement in advanced tumors. PMID- 28804645 TI - Risk Factors Affecting the Severity of Full-Term Neonatal Retinal Hemorrhage. AB - OBJECTIVE: The purpose of this study was to explore the underlying clinical factors associated with the degree of retinal hemorrhage (RH) in full-term newborns. METHODS: A total of 3054 full-term infants were included in this study. Eye examinations were performed with RetCamIII within one week of birth for all infants. Maternal, obstetric, and neonatal parameters were compared between newborns with RH and controls. The RH group was divided into three sections (I, II, and III) based on the degree of RH. RESULTS: RH was observed in 1202 of 3054 infants (39.36%) in this study. The quantity and proportion of newborns in groups I, II, and III were 408 (13.36%), 610 (19.97%), and 184 (6.03%), respectively. Spontaneous vaginal delivery (SVD), prolonged duration of second stage of labor, advanced maternal age, and neonatal intracranial hemorrhage positively correlated with aggravation of the degree of RH in newborns. Conversely, cesarean section was protective against the incidence of RH. CONCLUSIONS: SVD, prolonged duration of second stage of labor, advanced maternal age, and neonatal intracranial hemorrhage were potential risk factors for aggravation of the degree of RH in full-term infants. Accordingly, infants with these risk factors may require greater attention with respect to RH development. PMID- 28804644 TI - A malaria vaccine protects Aotus monkeys against virulent Plasmodium falciparum infection. AB - The Plasmodium falciparum protein, apical membrane antigen 1 forms a complex with another parasite protein, rhoptry neck protein 2, to initiate junction formation with the erythrocyte and is essential for merozoite invasion during the blood stage of infection. Consequently, apical membrane antigen 1 has been a target of vaccine development but vaccination with apical membrane antigen 1 alone in controlled human malaria infections failed to protect and showed limited efficacy in field trials. Here we show that vaccination with AMA1-RON2L complex in Freund's adjuvant protects Aotus monkeys against a virulent Plasmodium falciparum infection. Vaccination with AMA1 alone gave only partial protection, delaying infection in one of eight animals. However, the AMA1-RON2L complex vaccine completely protected four of eight monkeys and substantially delayed infection (>25 days) in three of the other four animals. Interestingly, antibodies from monkeys vaccinated with the AMA1-RON2L complex had significantly higher neutralizing activity than antibodies from monkeys vaccinated with AMA1 alone. Importantly, we show that antibodies from animals vaccinated with the complex have significantly higher neutralization activity against non-vaccine type parasites. We suggest that vaccination with the AMA1-RON2L complex induces functional antibodies that better recognize AMA1 as it appears complexed with RON2 during merozoite invasion. These data justify progression of this next generation AMA1 vaccine towards human trials. PMID- 28804646 TI - Glaucoma Quality of Life. PMID- 28804647 TI - Y-Split Recession of the Medial Rectus Muscle as a Secondary and/or Unilateral Procedure in the Treatment of Esotropia with Distance/Near Disparity. AB - INTRODUCTION: In esotropia with larger angles > near than at distance, splitting of the medial rectus muscle has been suggested as a treatment option. Previous reports of bilateral medial rectus Y-splitting as a first intervention showed a reduction of the distance/near disparity with fewer side effects compared to posterior fixation surgery. We address whether a medial rectus Y-splitting as a secondary and/or a unilateral procedure also reduce distance/near disparity. MATERIALS AND METHODS: We retrospectively reviewed the charts of four patients undergoing Y-split recession as a second and/or unilateral surgery. Main outcomes were distance/near disparity and squint angles. RESULTS AND DISCUSSION: Three of the four patients had undergone unilateral Y-splitting of the medial rectus as a secondary surgery, three as a unilateral procedure. Mean distance/near disparity was reduced from 17 PD preoperatively to zero at the final follow-up (FU). Preoperative angles ranged from 45 PD to 66 PD at near and from 25 PD to 55 PD at distance. At the final FU, these angles ranged from 0 PD to 20 PD at near and at distance. Mean FU was 42 months (range: 12-60 months). CONCLUSION: Y-split recession as a secondary and/or unilateral surgery for distance/near esotropia can reduce distance/near disparity with good long-term results. Residual esotropia can be corrected by adding resection of the lateral rectus muscle. PMID- 28804648 TI - Inhibition of Rho Kinase Induces Antioxidative Molecules and Suppresses Reactive Oxidative Species in Trabecular Meshwork Cells. AB - PURPOSE: To investigate the effect of rho kinase inhibitors on oxidative stress in trabecular meshwork (TM) cells. METHODS: TM cells were isolated from the eyes of cynomolgus monkeys. Y-27632 and menadione were used to inhibit rho kinase and induce production of reactive oxygen species (ROS), respectively. The cynomolgus monkey array and 12,613 probes were used in DNA microarray analysis, and the affected genes were categorized using gene ontology analysis. The mRNA levels of the target genes were confirmed by real-time RT-PCR. Intracellular oxidative stress was detected using a fluorescent reagent sensitive to ROS. Cell viability was assessed by the WST-8 assay. RESULTS: Gene ontology analysis revealed upregulation of genes involved in antioxidant activity, and upregulation of catalase was confirmed by real-time RT-PCR after 30 min treatment with Y-27632. Production of ROS was increased by menadione, and the effect was partly suppressed by pretreatment with Y-27632. At a lower dose of menadione, Y-27632 stimulated TM cells and significantly increased their viability following menadione treatment compared to control cells. CONCLUSION: Using microarray analysis, Y-27632 was shown to upregulate antioxidative genes including catalase and partially reduce ROS production and cell death by oxidative stress caused by menadione. PMID- 28804649 TI - Trends and Disparities in the Prevalence of Childhood Obesity in South Texas between 2009 and 2015. AB - BACKGROUND: Recent reports have highlighted possible decreases over time in obesity, particularly among children aged 2-5 years. Hispanic children experience significantly higher obesity rates, and less is known about trends for Hispanic children. METHODS: A large healthcare system-based dataset from south Texas was used to analyze body mass index (BMI) values obtained clinically from 2009 through 2015. Age and race/ethnicity specific prevalence of overweight and obesity were calculated using CDC standards and trends were examined over time using regression analyses, and mapping software was used to identify geographic variation. RESULTS: Hispanic children in south Texas experience levels of obesity (25.3%, 95% CI: 25.1-25.6) significantly higher than their white (16.6%, 95% CI: 16.0-17.2) or black (18.2%, 95% CI: 17.3-19.1) peers. Obesity in Hispanic children aged 2-5 years decreased from 18.5%, 95% CI: 16.6-20.5, in 2009 to 15.1%, 95% CI: 14.3-15.9, in 2015. Obesity in Hispanic adolescents was stable at 30.4%, 95% CI: 28.5-32.4, in 2009 and 31.3, 95% CI: 30.3-32.2, in 2015. CONCLUSIONS: While obesity decreased in the youngest age group of Hispanic children, south Texas continues to experience high levels of obesity that exceed national averages with significant disparities. PMID- 28804650 TI - The 2D : 4D Digit Ratio as a Biomarker for Autism Spectrum Disorder. AB - It has been suggested that the second (2D, index finger) to fourth (4D, ring finger) digit ratio, 2D : 4D, may be a biomarker for the risk of developing autism. The aim of the current study was to determine the usefulness of the 2D : 4D digit ratio as biomarker for autistic traits. N = 401 healthy young volunteers participated in the study. For both hands, digit lengths were measured using digital Vernier calipers. In addition to demographics, the Autism Spectrum Quotient (AQ) questionnaire was completed, comprised of five subscales, assessing "social insights and behavior," "attention switching," "communication," "imagination," and "attention to detail." Overall, no significant correlations were observed between the AQ total score, its subscales, and the 2D : 4D digit ratio. For women, the left hand 2D : 4D digit ratio correlated significantly with the subscale score "communication" (r = -0.142; p = 0.036). For men, a significant positive correlation was found between the left 2D : 4D digit ratio and the total AQ score (r = 0.157; p = 0.042) and AQ subscale "attention switching" (r = 0.182; p = 0.017). In conclusion, gender specific associations between the 2D : 4D digit ratio and specific autism traits were observed, which were stronger in men than in women. Future studies should be conducted in patients that are formally diagnosed with autism. PMID- 28804651 TI - Pharmacogenetic Biomarkers to Predict Treatment Response in Multiple Sclerosis: Current and Future Perspectives. AB - Disease-modifying therapies (DMTs) have significantly advanced the treatment of relapsing multiple sclerosis (MS), decreasing the frequency of relapses, disability, and magnetic resonance imaging lesion formation. However, patients' responses to and tolerability of DMTs vary considerably, creating an unmet need for biomarkers to identify likely responders and/or those who may have treatment limiting adverse reactions. Most studies in MS have focused on the identification of pharmacogenetic markers, using either the candidate-gene approach, which requires prior knowledge of the genetic marker and its role in the target disease, or genome-wide association, which examines multiple genetic variants, typically single nucleotide polymorphisms (SNPs). Both approaches have implicated numerous alleles and SNPs in response to selected MS DMTs. None have been validated for use in clinical practice. This review covers pharmacogenetic markers in clinical practice in other diseases and then reviews the current status of MS DMT markers (interferon beta, glatiramer acetate, and mitoxantrone). For a complex disease such as MS, multiple biomarkers may need to be evaluated simultaneously to identify potential responders. Efforts to identify relevant biomarkers are underway and will need to be expanded to all MS DMTs. These will require extensive validation in large patient groups before they can be used in clinical practice. PMID- 28804652 TI - Use of Over-the-Counter Medication among Pregnant Women in Sharjah, United Arab Emirates. AB - BACKGROUND: Over-the-counter medications are widely available in pharmacies Their safety profile, however, does not extend to pregnant women. Accordingly, there should be educational programs developed for pregnant women to protect them from the harms of the side effects. AIM: This study was planned and designed with the aim of exploring the awareness and assessing the usage of OTC medications among pregnant women in Sharjah, UAE. METHOD: A cross-sectional survey using a self administered questionnaire. RESULTS: More than three-quarters (75.7%) reported that they are familiar with the term "over-the-counter drugs." Interestingly, 40% of the respondents reported that they took OTC drugs during pregnancy, and the majority (94.2%) agreed with the survey statement "not all OTC medications are safe to be taken during pregnancy." Constipation was the most frequent side effect that most of the participants reported during the study period. Folic acid (36%), calcium (28.6%), and iron (35.1%) were the most common supplements used by the pregnant women responding. CONCLUSION: The reported 40% usage of OTC medications among pregnant women in this study is worrisome and calls for the need to educate, counsel, and increase awareness among pregnant women regarding the dangers of OTC drugs usage while pregnant in Sharjah, UAE. PMID- 28804653 TI - College Students' Perceptions of Worry and Parent Beliefs: Associations with Behaviors to Prevent Sun Exposure. AB - More research is needed to understand how attitudes impact behaviors that afford sun protection. The current study examined the impact of students' perceptions of parental beliefs about sun exposure and its influence on their practiced sun protection behaviors and worry about sun exposure. Participants were college students (N = 462) at a large Midwestern university. They completed a survey to examine their perceptions of risks and messages about sun exposure and sun exposure behaviors. Results indicated that gender and students' perceptions of parental beliefs about sun exposure were related to sun protection behaviors and their own worry over sun exposure. Specifically, males showed lower levels of sun protection behaviors, with the exception of wearing a hat with a brim, and lower levels of worry about sun exposure compared to females. Roughly a third of our sample had a family history of skin cancer, and this variable was related to worry about sun exposure and parental beliefs. Prevention messages and interventions to reduce sun risk for college students should address risks of sun exposure as well as educating young adults about the importance of wearing sunscreen, protective clothing, and hats to improve sun protection. PMID- 28804654 TI - Histoplasmosis by Histoplasma capsulatum var. duboisii Observed at the Laboratory of Pathological Anatomy of Lome in Togo. AB - Our study aimed to describe the epidemiological, clinical, and diagnostic aspects of African histoplasmosis in Togo through a descriptive and cross-sectional study on histological diagnosed African histoplasmosis in Pathology Department of Lome from 2002 to 2016 (15 years). A total of 17 cases of African histoplasmosis were diagnosed. The sex ratio (M/F) was 1.8. The annual incidence was 1.1 cases. The mean age of the patients was 27.2 +/- 0.4 years. All our patients were of social categories with a low socioeconomic level. HIV infection was known in 3 patients and one patient contracted tuberculosis. The clinical manifestations were cutaneous in 7 cases, cutaneous and mucous in 3 cases, cutaneous and lymph node in 3 cases, cutaneous and bone in 2 cases, and disseminated in 2 cases. The samples examined consisted of 14 cutaneous biopsies measuring 2-3 cm and 3 ganglionic biopsies each measuring 4 cm of major axis. Histologically, all cases were of chronic form made of granulomatous reaction with ovoid yeasts measuring between 1 and 2 microns. Despite the low frequency of this disease in our country, it should be kept constantly in mind before any granulomatous lesions, especially in the context of the HIV pandemic. PMID- 28804655 TI - A new phase for Egyptian Journal of Forensic Sciences, the official journal of The International Association of Law and Forensic Sciences (IALFS). PMID- 28804656 TI - Pneumomediastinum and Mediastinal Hematoma Secondary to Right Brachiocephalic Vein Thrombectomy Mimicking STEMI. AB - A 50-year-old male with a history of hemodialysis dependent chronic kidney disease presented to our emergency department with acute midsternal crushing chest pain. Patient was diagnosed with acute anterolateral wall Myocardial Infraction due to the presence of corresponding ST segment elevations in EKG and underwent emergent cardiac catheterization which revealed normal patent coronaries without any disease. He continued to have chest pain for which CT of the chest was done which revealed pneumomediastinum with mediastinal hematoma, due to the recent attempted thrombectomy for thrombus in his right brachiocephalic vein. PMID- 28804657 TI - A Recurrent Episode of Dermatomyositis Associated with Papillary Thyroid Cancer. AB - OBJECTIVE: It is uncommon for dermatomyositis to be associated with papillary thyroid cancer. We report an unusual case of papillary thyroid cancer presenting with dermatomyositis. METHODS: The case history, imaging and laboratory data is reviewed. RESULTS: We report the case of a 62-year-old female with a prior history of dermatomyositis and breast cancer who presented with a recurrent episode of dermatomyositis. Extensive evaluation of the cause of the dermatomyositis recurrence revealed no recurrence of the breast cancer but a thyroid nodule was identified. The nodule was biopsied and the patient was noted to have papillary thyroid cancer. The patient subsequently underwent total thyroidectomy and had gradual improvement in her dermatomyositis. CONCLUSION: It is very uncommon for dermatomyositis to be associated with papillary thyroid cancer. PMID- 28804658 TI - Extensive Causative Esophagitis Caused by Thermal Injury: A Case Report and Review of the Literature. AB - Esophagus thermal injury is a rare case that can be easily overlooked by practitioners. We herein present a case of thermally induced diffuse corrosive esophagitis with complaints of dysphagia and retrosternal chest pain after having steamed pork. A thorough disease course was demonstrated by serials of endoscopy images and video. A comprehensive review of articles and a concise overview of esophageal thermal injury clinical manifestation, disease process, typical endoscopy features, pharmacomanagement option, and outcomes will be conducted in this article. PMID- 28804659 TI - Fatal Systemic Vasoconstriction in a Case of Metastatic Small-Intestinal NET. AB - An increased release of serotonin secreted by ileal NETs is thought to be the major factor causing the carcinoid syndrome. However, in acutely arising carcinoid crisis also other vasoactive factors may lead to hazardous fluctuations in blood pressure and bronchial constriction. In rare cases, systemic vasoconstriction can be observed, probably caused by catecholamines or similar acting substances. Here, we report a fatal case of fulminant systemic vasoconstriction possibly caused by catecholamines in a patient with metastasized ileal NET. The vasospasm was detected by CT-angiography, and hemodynamic monitoring revealed a high systemic vascular resistance. Epinephrine, norepinephrine, and chromogranin A levels in plasma were elevated as was the urinary 5-hydroxyindoleacetic acid (5-HIAA). The cause of death was heart failure due to severe circulatory insufficiency. The progression of the tumor disease was confirmed by autopsy. PMID- 28804660 TI - Large Granular Lymphocytic Leukemia: A Report of Response to Rituximab. AB - Large granular lymphocytic (LGL) leukemia is a rare form of low grade leukemia characterized by large cytotoxic T cells or natural killer cells on morphological examination. Immunosuppressive therapy is employed as first-line therapy. Treatment options in refractory cases include the anti-CD52 antibody alemtuzumab and purine analogues. We report a rare case that responded to the anti-CD20 monoclonal antibody rituximab. A 77-year-old female presented with complaints of fatigue, fever, and chills of 3 months' duration. A CBC showed that pancytopenia with an absolute neutrophil count (ANC) was 0. Peripheral blood flow cytometry detected increased number of T cell large granular lymphocytes and T cell receptor rearrangement study detected a clonal T cell population. Bone marrow biopsy showed peripheral T cell lymphoma, most consistent with T-large granulocytic leukemia. The patient was treated with prednisone and oral cyclophosphamide for four months with no response. Thereafter, she received four weekly infusions of rituximab with improvement in her blood counts. A response to rituximab in refractory cases such as ours has been reported and may guide us towards exploring other immune-based therapeutics in this rare disease. PMID- 28804661 TI - Imported Asymptomatic Bancroftian Filariasis Discovered from a Plasmodium vivax Infected Patient: A Case Report from Singapore. AB - Human lymphatic filariasis is a vector-borne disease mainly caused by the parasitic nematode Wuchereria bancrofti and transmitted worldwide within the tropical and subtropical regions. Singapore was once endemic for bancroftian filariasis but recent reports are scarce and the disease is nearly forgotten. The case report presented here reports the incidental hospital laboratory finding of an asymptomatic microfilaremia in a relapsing Plasmodium vivax imported case during a malaria treatment follow-up appointment. The parasite was identified by microscopy as W. bancrofti and retrospective investigation of the sample collected during malaria onset was found to be also positive. Additional confirmation was obtained by DNA amplification, sequencing, and phylogenetic analysis of the mitochondrial cox1 gene that further related the parasite to W. bancrofti strains from the Indian region. Considering the large proportion of asymptomatic filariasis with microfilaremia, the high number of migrants and travellers arriving from the surrounding endemic countries, and the common presence of local competent mosquito vectors, Singapore remains vulnerable to the introduction, reemergence, and the spread of lymphatic filariasis. This report brings out from the shadow the potential risk of lymphatic filariasis in Singapore and could help to maintain awareness about this parasitic disease and its public health importance. PMID- 28804662 TI - Fungal Bezoar: A Rare Cause of Ureteral Obstruction. AB - A 52-year-old male, with diabetes mellitus and alcoholic liver disease, presented to the Emergency Room for right flank pain of 3 days' duration, associated with dysuria. Physical examination revealed right flank tenderness with fever and hypotension; laboratory findings showed acute kidney injury and large blood and leucocytes in the urine. A CT abdomen and pelvis showed hydronephrosis of the right collecting system of a horseshoe kidney with air and hyperdense debris in the renal pelvis. Patient was treated for multisensitive Proteus mirabilis emphysematous pyelonephritis, and a right nephrostomy tube was inserted. Symptoms recurred in 4 weeks, and repeated urine culture grew Candida albicans and CT scan showed same high density material within the right moiety of the horseshoe kidney. Patient underwent ureteroscopy, and a white fluffy material was aspirated from the right renal pelvis. Pathology of the aspirate confirmed the presence of fungal balls. Patient was given 2 weeks of oral fluconazole. Fungal pyelonephritis is unusual and difficult to treat. Candida species is responsible for the clear majority of the cases. A fungus ball should be managed with surgical and medical therapy. This patient had an endoscopic procedure to remove the fungus ball and received fluconazole. His symptoms resolved and urine culture was done before termination of the treatment was negative. PMID- 28804663 TI - Misdiagnosis of a Giant Uterine Leiomyosarcoma: Clinic and Image Challenges. AB - A 41-year-old woman (G3P2L2Ab1) was referred to gynecology clinic with chief complaints of abdominal distension and localized abdominal wall pruritus for three months. She was misdiagnosed with gastrointestinal disorder and ultimately had undergone imaging. Ultrasonography and computed tomography (CT) scan disclosed a huge solid-cystic mass originating from the ovary. On clinical examination the patient had no pain or tenderness and no gynecologic complaints. Laboratory tests showed normal tumor markers and hemoglobin at 8 g/dl. Laparotomy was carried out as diagnosis of ovarian serous cyst adenoma, but a huge tumor with attachment to uterus and ovaries and extension to pelvic floor, peripheral tissues of ureter, and upper abdomen was found. Hysterectomy with bilateral salpingooophorectomy was done. Pathology report demonstrated uterine leiomyosarcoma measuring 40 centimeters and weighing 10 kilograms. In conclusion, as pelvic masses even in a large size may present unspecific symptoms misdiagnosis may occur which lead to overgrowth, local invasion, or other complications. So, it is rather to suggest ultrasonography in patients with persistent abdominal or pelvic symptoms and if needed, more exact diagnostic modalities like magnetic resonance imaging (MRI) could be offered to avoid misdiagnosis and mismanagement. PMID- 28804664 TI - Successful Outcome of Low-Dose S-1 Used to Treat Buccal Squamous Cell Carcinoma. AB - This case report describes an 86-year-old woman with dormant right buccal squamous cell carcinoma who was able to maintain a reasonable quality of life after being treated with oral low-dose S-1 (80 mg/day). The treatment regimen started in April 2014 and consisted of two weeks of S-1 followed by a one-week interval. The patient remains on this regimen while maintaining her quality of life and she has been under follow-up as an outpatient for 36 months. The outcomes for this patient indicated that low-dose S-1 is a valid anticancer therapy that may help maintain quality of life for some patients with incurable or dormant cancers. PMID- 28804665 TI - Management of Traumatic Cataract with Posterior Capsular Rupture: A Case Report and In Vitro Model Study. AB - PURPOSE: To investigate the optimal strategy for surgical management of traumatic cataract with posterior capsular rupture. METHODS: We describe four cases of traumatic cataract with posterior capsular rupture and an in vitro model built to evaluate the optimal infusion pressure during surgery. RESULTS: All patients underwent cataract surgery. By using an anterior chamber maintainer to elevate infusion pressure, we safely performed cataract extraction without phacoemulsification. At 3 days after surgery, visual acuity was greater than 20/25 in all patients, without any complications. Phacoemulsification would also be feasible under anterior chamber maintainer infusion in a similar case of traumatic cataract with posterior capsular rupture during intravitreal injection. In addition, an in vitro model that we established using pig's eyes revealed that the anterior chamber remained stable when the height of infusion bottle was 50-90 mmHg, whereas shallowing of the anterior chamber occurred when the height of infusion bottle was reduced to 40 mmHg, and corneal edema occurred when the height of infusion bottle was raised to 100 mmHg. CONCLUSIONS: During management of traumatic cataract with posterior capsular rupture, using an anterior chamber maintainer to maintain optimal infusion pressure may reduce the risk of anterior hyaloid membrane breakup and vitreous loss. PMID- 28804666 TI - Primary Small Cell Carcinoma of the Hypopharynx: A Report of Two Cases and Review of Nine Additional Cases. AB - OBJECTIVE: Two patients with primary small cell carcinoma (SmCC) of the hypopharynx, an extremely rare site for the occurrence of SmCC, are reported and nine additional well-documented cases are reviewed. METHODS: Case report and review of the literature concerning primary SmCC of the hypopharynx. RESULTS: On the final analysis, we reviewed eleven cases of primary SmCC of the hypopharynx. The tumors contained mixed elements of SmCC and squamous cell carcinoma (SCC) in six (55%) of eleven patients. Out of eleven patients, two patients had distant metastasis at the initial presentation. Even though nine patients presented with locoregional disease, development of distant metastasis after treatment was seen in five patients (56%), whereas there was no report of treatment failure on the primary site. To achieve more than two-year survival, patients should have received more than 4 cycles of chemotherapy. CONCLUSION: We report two cases of primary SmCC of the hypopharynx with a review of the literature. In more than half of the cases, combined carcinomas with SCC are seen. Because this tumor has a strong propensity for distant metastasis even in patients with clinically localized tumor, new powerful systemic agents should be explored. PMID- 28804667 TI - Skin-Limited Graft-versus-Host Disease after Pancreatic Transplantation. AB - INTRODUCTION: The phenomenon of graft-versus-host disease, a solid organ transplant recipient, is a rare development with a very poor prognosis. CASE PRESENTATION: A 40-year-old woman with type 1 diabetes developed cutaneous graft versus-host disease following second pancreas transplantation. CONCLUSION: The development of a nonspecific rash in the early posttransplant period following a pancreas transplant warrants suspicion for graft-versus-host disease. PMID- 28804668 TI - Impaired mRNA Expression of the Migration Related Chemokine Receptor CXCR4 in Mesenchymal Stem Cells of COPD Patients. AB - Defective tissue repair and remodeling are main aspects of Chronic Obstructive Pulmonary Disease (COPD) pathophysiology. Bone marrow mesenchymal stem cells (BM MSCs) have been implicated in this direction, as their functional impairment and recruitment could possibly contribute to disease development and progression. The present study characterizes for the first time the expression of migration related chemokine receptors and their ligands in BM-MSCs from COPD patients. CXCR4/SDF1a and CCR7/CCL19-CCL21 mRNA levels were evaluated in BM-MSCs obtained from twelve COPD patients and seven healthy donors. SDF1a protein levels in sera and BM-MSCs' conditioned media were also evaluated. CXCR4, SDF1a, CCL19, and CCL21 mRNA levels were significantly reduced in COPD BM-MSCs while CCR7 levels were undetectable. Notably, SDF1a protein levels were marginally elevated in both patient sera and BM-MSCs' conditioned media while the increase in SDF1a serum levels significantly correlated with disease severity in COPD. Our findings show posttranscriptional regulation of SDF1a levels in BM-MSCs of COPD patients and significant downregulation of SDF1a and CXCR4 mRNA indicating an involvement of the SDF1a signaling pathway in the disease pathophysiology. PMID- 28804669 TI - Research on the Characteristics and Mechanism of the Cumulative Release of Antimony from an Antimony Smelting Slag Stacking Area under Rainfall Leaching. AB - We aimed to study the characteristics and the mechanism of the cumulative release of antimony at an antimony smelting slag stacking area in southern China. A series of dynamic and static leaching experiments to simulate the effects of rainfall were carried out. The results showed that the release of antimony from smelting slag increased with a decrease in the solid-liquid ratio, and the maximum accumulated release was found to be 42.13 mg Sb/kg waste and 34.26 mg Sb/kg waste with a solid/liquid ratio of 1 : 20; the maximum amount of antimony was released within 149-420 MUm size fraction with 7.09 mg/L of the cumulative leaching. Also, the antimony release was the greatest and most rapid at pH 7.0 with the minimum release found at pH 4.0. With an increase in rainfall duration, the antimony release increased. The influence of variation in rainfall intensity on the release of antimony from smelting slag was small. PMID- 28804670 TI - Synthesis and Characterization of Mixed Iron-Manganese Oxide Nanoparticles and Their Application for Efficient Nickel Ion Removal from Aqueous Samples. AB - Mixed iron-manganese oxide nanoparticles, synthesized by a simple procedure, were used to remove nickel ion from aqueous solutions. Nanostructures, prepared by using different weight percents of manganese, were characterized by transmission electron microscopy, selected area diffraction, X-ray diffraction, Raman spectroscopy, and vibrating sample magnetometry. Adsorption/desorption isotherm curves demonstrated that manganese inclusions enhance the specific surface area three times and the pores volume ten times. This feature was crucial to decontaminate both aqueous samples and food extracts from nickel ion. Efficient removal of Ni2+ was highlighted by the well-known dimethylglyoxime test and by ICP-MS analysis and the possibility of regenerating the nanostructure was obtained by a washing treatment in disodium ethylenediaminetetraacetate solution. PMID- 28804671 TI - Honesty is the best policy: A brief overview of retraction notices. PMID- 28804672 TI - Necessity of oral health intervention in schizophrenic patients - A review. AB - Individuals with mental illness often cannot perform day to day activities due to a psychiatric or emotional disorder. Schizophrenia is one such psychiatric disorder characterized by worsening self-care ability with progressing mental illness. This disease may potentially deteriorate oral health by affecting the subject's ability to perform oral hygiene measures. Literature on oral disease manifestations in schizophrenia is limited. Lack of desire for oral health care as well as generally poor awareness of oral health issues in these patients, compounded further by side effects of medications, may complicate dental management in schizophrenic patients. The present review explores clinical features and possible factors associated with oral health status among those with Schizophrenia. PMID- 28804673 TI - Changing Trends in oral cancer - a global scenario. AB - Oral cancer is one of the highly prevalent cancers worldwide and a leading cause of mortality in certain regions like South-Central Asia. It is a major public health problem. Late diagnosis, high mortality rates and morbidity are characteristics of the disease worldwide. For control of oral cancer an idea of the coverage of the same in the various regions is necessary. The estimated incidence, mortality and 5-year survival due to lip, oral cavity cancer in world is 3, 00, 373(2.1%), 1, 45, 328(1.8%) and 7, 02, 149(2.2%) respectively according to data of GLOBOCAN 2012. A changing trend in incidence and prevalence of oral cancer has been observed with more women and youngsters being affected by oral cancer. PMID- 28804674 TI - Systematic Differences in HIV, Syphilis and Risk Behaviors among Street Based and Establishment Based Female Sex Workers in Kathmandu Valley of Nepal. AB - BACKGROUND: Female Sex Workers (FSWs) are main drivers of the HIV epidemic in Nepal. The work environment of sex work in Nepal is differentiated into establishment based (e.g. massage parlors, dance restaurants, hotels and lodges) and street based (e.g. streets, parks and markets). The study compares HIV, syphilis and risk behaviours among establishment-based FSWs and street-based FSWs in Kathmandu Valley of Nepal. MATERIALS AND METHODS: Cross-sectional bio behavioral surveys in 2006, 2008, 2011 and 2015 aimed to sample 2093 FSWs using two stage cluster sampling in the Kathmandu valley. Statistical analysis used chi squared tests and logistic regression models to assess differences of HIV, syphilis and risk behaviors among street-based FSWs and establishment-based FSWs. RESULTS: The study included 39.7% street-based FSWs and 60.3% establishment-based FSWs. The street-based FSWs had lower education levels, older age groups, separated, longer duration of sex work and inconsistent condom used with clients than establishment-based FSWs (p<0.05). Establishment-based FSWs were lower exposure to HIV intervention programs and pervasive alcohol consumption and use of drugs (p<0.05). The multivariate analysis showed that street-based FSWs were more likely of HIV test (aOR=1.25, 95%CI=1.04, 1.49), HIV (aOR=4.72, 95%CI=2.19, 10.15) and syphilis (aOR=7.96, 95%CI=3.49, 18.15) than establishment-based FSWs. CONCLUSION: Street-based FSWs possessed higher risk behaviour and have higher HIV and syphilis prevalence. HIV prevention interventions targeting FSWs should consider risks and vulnerability of street-based FSWs. . PMID- 28804675 TI - Transition in Dental Treatment Utilization in Jammu And Kashmir, India - A 10 Year Retrospective Study. AB - BACKGROUND: Utilization of health services is the actual attendance by the members of the public at health care facilities to receive care. Utilization, serves as an important tool for oral health policy decision-making. The aim of the present study was to retrospectively gauge and assess the utilization pattern of the dental treatments which was given in hospital for last 10 years. MATERIALS AND METHODS: This retrospective infirmary based study was carried out at Sheri Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, India. The yearly outpatient department (OPD) records for the utilization of specific dental treatment of a total of 103963 patients were assessed retrospectively from 2014 to 2003. Trend analysis was used to assess the trend of utilization of each speciality with best fitted linear trend lines. RESULTS: The pattern of new patients has also shown a constant rise during the study period except for 2008 and 2009. The utilization of oral surgery speciality has shown a tremendous fall from 2003 to 2014 whereas the number of patients coming to periodontics and conservative dentistry has shown an increasing pattern. CONCLUSION: Utilization of oral health care has long been used as an indicator of oral health related behaviour of a population. In the present study it can be conclude that the outlook of the population under study has changed from blood and vulcanite dentistry outlook and is moving towards restorative dentistry. . PMID- 28804676 TI - Guide to the design and application of online questionnaire surveys. AB - Collecting research data through traditional approaches (face-to-face, postal or telephone survey) can be costly and time consuming. The emerging data collection approach based on internet/e-based technologies (e.g. online platforms and email), is a relatively cost effective survey alternative. These novel data collection strategies can collect large amounts of data from participants in a short time frame. Similarly, they also seem to be feasible and effective in collecting data on sensitive issues or with samples they are generally hard to reach, for example, men who have sex with men (MSM) or migrants. As a significant proportion of the population currently in the world are digitally connected, the shift from postal (paper-pencil) or telephone towards online survey use in research is in the interests of researchers in academia as well as in the commercial world. However, compared to designing and executing paper version of the questionnaire, there is limited literature to help a starting researcher with the design and a use of online questionnaires. This short paper highlights issues around: a) methodological aspect of online questionnaire survey; b) online survey planning and management; and c) ethical concerns that may arise while using this option. We believe that this paper will be useful for researchers who want to gain knowledge or apply this approach in their research. PMID- 28804677 TI - Haloselective Cross-Coupling via Ni/Photoredox Dual Catalysis. AB - The chemoselective functionalization of polyfunctional aryl linchpins is crucial for rapid diversification. Although well-explored for Csp2 and Csp nucleophiles, the chemoselective introduction of Csp3 groups remains notoriously difficult and is virtually undocumented using Ni catalysts. To fill this methodological gap, a "haloselective" cross-coupling process of arenes bearing two halogens, I and Br, using ammonium alkylbis(catecholato)silicates, has been developed. Utilizing Ni/photoredox dual catalysis, Csp3 -Csp2 bonds can be forged selectively at the iodine-bearing carbon of bromo(iodo)arenes. The described high-yielding, base free strategy accommodates various protic functional groups. Selective electrophile activation enables installation of a second Csp3 center and can be done without the need for purification of the intermediate monoalkylated product. PMID- 28804678 TI - Capacitively Coupled Arrays of Multiplexed Flexible Silicon Transistors for Long Term Cardiac Electrophysiology. AB - Advanced capabilities in electrical recording are essential for the treatment of heart-rhythm diseases. The most advanced technologies use flexible integrated electronics; however, the penetration of biological fluids into the underlying electronics and any ensuing electrochemical reactions pose significant safety risks. Here, we show that an ultrathin, leakage-free, biocompatible dielectric layer can completely seal an underlying layer of flexible electronics while allowing for electrophysiological measurements through capacitive coupling between tissue and the electronics, and thus without the need for direct metal contact. The resulting current-leakage levels and operational lifetimes are, respectively, four orders of magnitude smaller and between two and three orders of magnitude longer than those of any other flexible-electronics technology. Systematic electrophysiological studies with normal, paced and arrhythmic conditions in Langendorff hearts highlight the capabilities of the capacitive coupling approach. Our technology provides a realistic pathway towards the broad applicability of biocompatible, flexible electronic implants. PMID- 28804679 TI - Time to Neurological Deterioration in Ischemic Stroke. AB - BACKGROUND: Neurological deterioration (ND) is common, with nearly one-half of ND patients deteriorating within the first 24 to 48 hours of stroke. The timing of ND with respect to ND etiology and reversibility has not been investigated. METHODS: At our center, we define ND as an increase of 2 or more points in the National Institutes of Health Stroke Scale (NIHSS) score within 24 hours and categorize etiologies of ND according to clinical reversibility. ND etiologies were considered non-reversible if such causes may have produced or extended any areas of ischemic neurologic injury due to temporary or permanent impairment in cerebral perfusion. RESULTS: Seventy-one of 350 ischemic stroke patients experienced ND. Over half (54.9%) of the patients who experienced ND did so within the 48 hours of last seen normal. The median time to ND for non-reversible causes was 1.5 days (IQR 0.9, 2.4 days) versus 2.6 days for reversible causes (IQR 1.4, 5.5 days, p=0.011). After adjusting for NIHSS and hematocrit on admission, the log-normal survival model demonstrated that for each 1-year increase in a patient's age, we expect a 3.9% shorter time to ND (p=0.0257). In addition, adjusting for age and hematocrit on admission, we found that that for each 1-point increase in the admission NIHSS, we expect a 3.1% shorter time to ND (p=0.0034). CONCLUSIONS: We found that despite having similar stroke severity and age, patients with nonreversible causes of ND had significantly shorter median time to ND when compared to patients with reversible causes of ND. PMID- 28804680 TI - Treatment of older patients with acute myeloid leukemia (AML): revised Canadian consensus guidelines. AB - The treatment of acute myeloid leukemia (AML) in older patients is undergoing rapid changes, with a number of important publications in the past five years. Because of this, a group of Canadian leukemia experts has produced an update to the Canadian Consensus Guidelines that were published in 2013, with several new agents recommended, subject to availability. Recent studies have supported the survival benefit of induction chemotherapy for patients under age 80, except those with major co-morbidities or those with adverse risk cytogenetics who are not candidates for allogeneic hematopoietic stem cell transplantation (HSCT). Midostaurin should be added to induction therapy for patients up to age 70 with a FLT3 mutation, and gemtuzumab ozogamicin for de novo AML up to age 70 with favorable or intermediate risk cytogenetics. Daunorubicin 60 mg/m2 is the recommended dose for 3+7 induction therapy. Acute promyelocytic leukemia should be treated with arsenic trioxide plus all-trans retinoic acid, regardless of age, with cytotoxic therapy added upfront only for those with initial white blood count > 10. HSCT may be considered for selected suitable patients up to age 70 75. Haploidentical donor transplants may be considered for older patients. For non-induction candidates, azacitidine is recommended for those with adverse risk cytogenetics, while either a hypomethylating agent (HMA) or low-dose cytarabine can be used for others. HMA may also be used for relapsed/refractory disease after chemotherapy. For patients with secondary AML, CPX-351 is recommended for fit patients age 60-75. PMID- 28804681 TI - Luminol-amplified chemiluminescence detects mainly superoxide anion produced by human neutrophils. AB - Reactive oxygen species (ROS) are produced by numerous biological systems and by several phagocytes such as neutrophils and macrophages. ROS include mostly superoxide anion, hydrogen peroxide, singlet oxygen and hydroxyl radical, which are involved in a variety of biological processes such as immunity, inflammation, apoptosis and cell signaling. Thus, there is a need for a sensitive and reliable method to measure ROS. The luminol-amplified chemiluminescence technique is widely used to measure ROS production by neutrophils; however, it is unclear which ROS species are detected by this technique. In this study, we show that Xanthine/Xanthine oxidase (XXO), a known superoxide-producing system, stimulated a luminol-amplified chemiluminescence in the absence of horseradish peroxidase (HRPO), while the presence of HRPO enhanced the response. Both reactions were inhibited by superoxide dismutase (SOD), but not by catalase, confirming that superoxide anion, and not hydrogen peroxide, is the species oxidizing luminol to produce chemiluminescence. Glucose/Glucose oxidase (GGO), a known hydrogen peroxide-producing system, did not induce luminol-amplified chemiluminescence in the absence of HRPO; however, addition of HRPO resulted in a chemiluminescence response, which was inhibited by catalase, but not by SOD. Myeloperoxidase (MPO), isolated from human neutrophils, was also able to enhance the superoxide- and hydrogen peroxide-dependent luminol-amplified chemiluminescence. The production of ROS by stimulated human neutrophils was detected by luminol-amplified chemiluminescence, which was only partially inhibited by SOD and catalase. Interestingly, adding HRPO to stimulated neutrophils increased the luminol amplified chemiluminescence, which was strongly inhibited by SOD, but not by catalase. These results show that (a) luminol-amplified chemiluminescence is able to detect superoxide anion in the absence of peroxidases, but not hydrogen peroxide; (b) in the presence of peroxidases, luminol-amplified chemiluminescence is able to detect both superoxide anion and hydrogen peroxide; and PMID- 28804682 TI - Effects of intensive pitavastatin therapy on glucose control in patients with non ST elevation acute coronary syndrome. AB - Objective: This study aimed to investigate the effects of intensive pitavastatin therapy on glucose control in patients with non-ST elevation acute coronary syndrome (ACS). Methods: Patients who had ACS with significant stenosis on initial coronary angiography and received successful percutaneous coronary intervention (PCI) in the Second Hospital of Hebei Medical University, Shijiazhuang, China from August 2015 to January 2016 were enrolled in this study. The patients were randomized to receive pitavastatin (4 mg daily) or atorvastatin (20 mg daily). PCI was performed within 72 hours after admission according to the current clinical practice at the physician's discretion. The examinations of blood lipid levels and blood markers of glucose metabolism were performed at baseline and after 6-month follow-up using standard techniques. The inflammatory markers, including white blood cell, high-sensitivity C-reactive protein (hs-CRP) and fibrinogen, were also assessed before PCI and 24 hours after PCI. An independent adverse event assessment committee evaluated major adverse cardiovascular events (MACE) and any other adverse events. Results: A total of 132 patients were enrolled and randomly divided into the pitavastatin group (n = 65) or the atorvastatin group (n = 67), which had similar baseline characteristics and PCI procedural characteristics. For the inflammatory biomarkers at 24 hours after PCI, the fibrinogen level was significantly increased in the atorvastatin group; the hs-CRP levels were significantly increased in both groups, however, the hs-CRP level in the pitavastatin group was lower than that in the atorvastatin group. In addition, the blood lipid parameters (e.g., TC, LDL-C, TG, non-HDL-C and Apo B) were significantly decreased in both groups after 6-month follow-up (P < 0.01), but these parameters between the two groups had no significant difference. After 6-month follow-up, the FPG, IRI, HOMA-IR and HbA1c levels were significantly decreased in the pitavastatin group (P < 0.05) but slightly increased in the atorvastatin group, indicating that the glucose homeostasis was improved in patients in the pitavastatin group but not in the atorvastatin group. Furthermore, the incidence of MACE was not significantly different between the two groups (P > 0.05). After 6-month antiplatelet treatment, the PAR value was significantly decreased in both groups (P < 0.01), but the PAR value in the pitavastatin group was lower than that in the atorvastatin group. Conclusion: Pitavastatin therapy may improve the glucose homeostasis for patients with ACS undergoing PCI and has more favorable outcomes than atorvastatin therapy. PMID- 28804683 TI - Erratum: Leucine-nicotinic acid synergy stimulates AMPK/Sirt1 signaling and regulates lipid metabolism and lifespan in Caenorhabditis elegans, and hyperlipidemia and atherosclerosis in mice. AB - [This corrects the article on p. 33 in vol. 7, PMID: 28533928.]. PMID- 28804684 TI - Bioresorbable scaffold as a dermal substitute. AB - INTRODUCTION: Bioresorbable polymers are often used in medical procedures. Since they are biocompatible, this class of materials is a viable alternative for cases in which tissue regeneration is strongly compromised. Bioresorbable synthetic polymers may be used as membranes to support and guide cell growth through the process of tissue repair. OBJECTIVE: To assess the efficiency of a porous bioresorbable membrane Poly (L-co-DL lactic acid)-co-trimethylene carbonate, PL co-DLA-co-TMC, as a dermal substitute associated with partial skin graft in rats. METHODS: A 1.5*1.5 cm defect was created on the backs of 40 Wistar rats. The rats were divided into a control group, in which the defects were filled with partial skin graft, and a treated group, in which a membrane associated with the graft was implemented. The animals were sacrificed 7 days or 60 days after the procedure and the results were evaluated by macroscopic and microscopic analysis. RESULTS: The polymer was biocompatible and allowed better regeneration of the dermis with less shrinkage, unlike what occurs in second intention healing. Compared to the control group, the treated group showed a thicker and wider dermis with the presence of skin appendages, suggesting partial graft integration and better healing. The skin graft acted as a biological protection of the wound. CONCLUSION: The study material was shown to act as a biocompatible dermal substitute and promoted less scarring of the dermis. Further studies should be conducted to improve the methodology of the surgical procedure. PMID- 28804685 TI - Percutaneous dilatational tracheostomy through paramedian technique and lateral approach in a patient with cervical esophagostomy-a case report. AB - BACKGROUND: Percutaneous dilatational tracheostomy (PDT) is a common surgical procedure and established as first choice for securing the airway in critically ill patients needing prolonged mechanical ventilation. There are case reports of open tracheostomy through paramedian approach without complications. This case report presents a case of PDT through paramedian approach. CASE REPORT: An 18 year old female, case of firearm injury underwent cervical esophagostomy on the left side of neck approaching midline. So we perform PDT through paramedian technique and lateral approach safely with use of real time ultrasound and fiberoptic bronchoscope. DISCUSSION: PDT can be done through paramedian technique and lateral approach to trachea safely with help of ultrasound and fiberoptic bronchoscope in the conditions where midline approach is not feasible and unsafe. PMID- 28804686 TI - A comparative study of tissue expansion and free parascapular flaps in extensive facial burn scar reconstruction. AB - BACKGROUND: Large post burn scars are a very difficult problem to treat. Available methods include skin grafts and tissue expansion. The reconstructive method used should be tailored according to individual patient rather than following a textbook approach in each. PATIENTS AND METHODS: A retrospective analysis was done of cases with extensive facial burn scars in whom secondary reconstruction was done with either free parascapular flap cover or tissue expansion and flap advancement following facial burn scar excision by a single surgeon (GSK) in Department of Burns, Plastic and reconstructive surgery. RESULTS: A total of 15 patients with free parascapular flap and 15 patients with tissue expansion followed by flap advancement were analyzed in the group. There were no free flap failures, but 2 patients required skin graft at donor site. In patients undergoing tissue expansion, minor complication was noted in 1 patient. CONCLUSION: Tissue expansion is a useful technique in reconstruction of post burn scars, but has its limitations, especially in patients with extensive burns in head and neck region with limited local tissue availability. Parascapular free flap may provide a good alternative option for reconstruction in such cases. PMID- 28804687 TI - Zika Virus (ZIKV): a review of proposed mechanisms of transmission and associated congenital abnormalities. AB - Zika virus (ZIKV) has been of major international public health concern following large outbreaks in the Americas occurring in 2015-2016. Most notably, ZIKV has been seen to pose dangers in pregnancy due to its association with congenital abnormalities such as microcephaly. Numerous experimental approaches have been taken to address how the virus can cross the placenta, alter normal fetal development, and disrupt specific cellular functions. Many areas concerning the mechanisms of transmission, especially from mother to fetus, are largely unknown but demand further research. Several promising new studies are presented that provide insight into possible mechanisms of transmission, different cell types affected, and immune responses towards the virus. By aiming to better understand the processes behind altered fetal neuronal development due to ZIKV infection, the hope is to find ways to increase protection of the fetus and prevent congenital abnormalities such as microcephaly. As ZIKV infection is spreading to increasingly more areas and bringing harmful outcomes and birth defects with it, it is imperative to identify the mechanisms of transmitting this infectious agent, consider different genetic backgrounds of hosts and strain types, and navigate methods to protect those affected from the detrimental effects of this newly emerging virus. PMID- 28804688 TI - Pivotal regulators of tissue homeostasis and cancer: macrophages. AB - Macrophages are an essential component of innate immunity and play a vital role in inflammation and host defense. Based on immunological responses, the macrophages are classified into "activated" macrophage (M1 macrophages) participating in the responses of type I helper T (Th1) cells to pathogens and "alternatively activated" macrophages (M2 macrophages) in response to interleukin (IL)-4 and IL-13. In this review, we discuss the origin, classification and function of macrophages. We also discuss the mechanisms underlying polarization of different macrophage subtypes, including transcriptional, epigenetic and post transcriptional regulation. PMID- 28804690 TI - Towards Program Optimization through Automated Analysis of Numerical Precision. AB - Reducing the arithmetic precision of a computation has real performance implications, including increased speed, decreased power consumption, and a smaller memory footprint. For some architectures, e.g., GPUs, there can be such a large performance difference that using reduced precision is effectively a requirement. The tradeoff is that the accuracy of the computation will be compromised. In this paper we describe a proof assistant and associated static analysis techniques for efficiently bounding numerical and precision-related errors. The programmer/compiler can use these bounds to numerically verify and optimize an application for different input and machine configurations. We present several case study applications that demonstrate the effectiveness of these techniques and the performance benefits that can be achieved with rigorous precision analysis. PMID- 28804689 TI - The Role of the Skin and Gut Microbiome in Psoriatic Disease. AB - PURPOSE: To understand the changes in the microbiome in psoriatic disease, we conducted a systematic review of studies comparing the skin and gut microbiota in psoriatic individuals and healthy controls. FINDINGS: Our review of studies pertaining to the cutaneous microbiome showed a trend towards an increased relative abundance of Streptococcus and a decreased level of Propionibacterium in psoriasis patients compared to controls. In the gut microbiome, the ratio of Firmicutes and Bacteroidetes was perturbed in psoriatic individuals compared to healthy controls. Actinobacteria was also relatively underrepresented in psoriasis patients relative to healthy individuals. SUMMARY: Although the field of the psoriatic microbiome is relatively new, these first studies reveal interesting differences in microbiome composition that may be associated with the development of psoriatic comorbidities and serve as novel therapeutic targets. PMID- 28804692 TI - One case with dexmedetomidine-induced stuporous state in epileptic patient undergoing abdominal surgery. AB - A 56-year-old epileptic patient underwent right hemicolectomy and cholecystectomy surgery under general endotracheal anesthesia. Anesthesia was maintained with sevoflurane, and sufentanil, rocuronium, and dexmedetomidine infusions. After the operation and confirmation of neuromuscular recovery, the patient woke from anesthesia within 15 min and successfully extubated. After the vital signs of patient were stable, the patient was transported to post anesthesia care unit (PACU). 6 h after the surgery, he fell into a stuporous state for lasting 14 h and EEG showed no epileptiform discharges. Stupor did re-occur in 2 days after operation. 36 hours after operation, all signs of the stuporous state resolved spontaneously. Apparent dexmedetomidine-induced stuporous state has not been reported in the human literature. PMID- 28804691 TI - Combination of celecoxib (Celebrex(r)) and CD19 CAR-redirected CTL immunotherapy for the treatment of B-cell non-Hodgkin's lymphomas. AB - The nonsteroidal anti-inflammatory drug (NSAID) Celecoxib (Celebrex(r)) received Food and Drug Administration (FDA) approval in 1998 for treatment of osteoarthritis and rheumatoid arthritis, and in recent years, its use has been extended to various types of malignancies, such as breast, colon, and urinary cancers. To maintain the survival of malignant B cells, non-Hodgkin's Lymphoma (NHL) is highly dependent on inflammatory microenvironment, and is inhibited by celecoxib. Celecoxib hinders tumor growth interacting with various apoptotic genes, such as cyclooxygenase-2 (Cox-2), B-cell lymphoma 2 (Bcl-2) family, phosphor-inositide-3 kinase/serine-threonine-specific protein kinase (PI3K/Akt), and inhibitors of apoptosis proteins (IAP) family. CD19-redirected chimeric antigen-receptor (CD19 CAR) T cell therapy has shown promise in the treatment of B cell malignancies. Considering its regulatory effect on apoptotic gene products in various tumor types, Celecoxib is a promising drug to be used in combination with CD19 CAR T cell therapy to optimize immunotherapy of NHL. PMID- 28804693 TI - The ability of Reciproc instruments to reach full working length without glide path preparation: a clinical retrospective study. AB - BACKGROUND: Reciproc instruments are the only contemporary root canal instruments where glide path preparation is no longer strictly demanded by the manufacturer. As the complete preparation of root canals is associated with success in endodontic treatment we wanted to assess the ability and find predictors for Reciproc instruments to reach full working length (RFWL) in root canals of maxillary molars in primary root canal treatment (1 degrees RCTx) and retreatment (2 degrees RCTx) cases. METHODS: This retrospective study evaluated 255 endodontic treatment cases of maxillary molars. 180 were 1 degrees RCTx and 75 2 degrees RCTx. All root canals were prepared with Reciproc instruments. The groups were compared and in a binary logistic regression model predictors for RFWL were evaluated. RESULTS: A total of 926 root canals were treated with Reciproc without glide path preparation. This was possible in 885 canals (95.6%). In 1 degrees RCTx cases 625 of 649 (96.3%) canals were RFWL and in 2 degrees RCTx cases 260 of 277 (93.9%). In second and third mesiobuccal canals (MB2/3) 90 out of 101 (89.1%) were RFWL with Reciproc in 1 degrees RCTx and in the 2 degrees RCTx treatment group 49 out of 51 cases (96.1%). In mesio-buccal (MB1) canals "2 degrees RCTx" was identified as negative predictor for RFWL (OR 0.24 (CI [0.08-0.77])). In MB2/3 canals full working length was reached less often (OR 0.04 (CI [0.01 0.31])) if the tooth was constricted and more often if MB2/3 and MB1 canals were convergent (OR 4.60 (CI [1.07-19.61])). DISCUSSION: Using Reciproc instruments, the vast majority of root canals in primary treatment and retreatment cases can be prepared without glide path preparation. PMID- 28804694 TI - A new species of Scutellaria (Scutellarioideae, Lamiaceae) from Sichuan Province in southwest China. AB - Scutellaria wuana, a new species discovered from a xeric valley in Muli County of Sichuan Province in southwest China, is described and illustrated. Morphologically, the new species shares similarities with S. mairei, but can be readily distinguished by a suite of morphological characters including a white pubescent erect stem, conspicuous leaf petioles, and a yellow corolla with a trapeziform lower-middle lip lobe. The habitat and distribution of S. wuana are also distinctive. The position of the new species within Scutellaria is examined in a phylogenetic context using the nuclear ribosomal internal and external transcribed spacers. Additionally, we examine leaf epidermal and pollen grain micromorphology of the new species and putative relatives. PMID- 28804695 TI - Social Support, Simpatia, and Hypertension Prevalence in Hispanics/Latinos: Findings from the HCHS/SOL Sociocultural Ancillary Study. AB - There is a significant burden of hypertension in the United States, which extends to the large and growing Hispanic/Latino population. Previous literature suggests that psychosocial factors are related to hypertension in Hispanics/Latinos. However, cultural factors unique to this population have been largely understudied in this context. The purpose of the current investigation was to examine the association of hypertension prevalence with social support and simpatia, a Hispanic/Latino cultural value emphasizing social harmony. Cross sectional data from 5,313 adult Hispanics/Latinos, age 18 to 75 years, representing multiple heritage groups were collected as part of the Hispanic Community Health Study/Study of Latinos Sociocultural Ancillary Study. Contrary to predictions, higher social support was related to higher odds of hypertension prevalence across models (OR = 1.11, 95% CI: 1.02, 1.22). In the final main effects logistic regression model, higher simpatia was related to lower odds of hypertension (OR = .83, 95% CI: .77, .90). Sex modified the link between simpatia and hypertension, with significant effects for men but not women. A 1 SD increase in simpatia was associated with 36% lower odds of hypertension in Hispanic/Latino men. The findings suggest that social support was inversely related with hypertension prevalence and that simpatia may be a protective cultural characteristic in relation to hypertension in the Hispanic/Latino population, but only in men. These results contribute to a growing discourse about the role of Hispanic/Latino cultural values in cardiovascular health. PMID- 28804696 TI - Neonatal Safety Information Reported to the FDA During Drug Development Studies. AB - BACKGROUND: Relatively few neonatal drug development studies have been conducted, but an increase is expected with the enactment of the Food and Drug Administration Safety and Innovation Act (FDASIA). Understanding the safety of drugs studied in neonates is complicated by the unique nature of the population and the level of illness. The objective of this study was to examine neonatal safety data submitted to the FDA in studies pursuant to the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) between 1998 and 2015. METHODS: FDA databases were searched for BPCA and/or PREA studies that enrolled neonates. Studies that enrolled a minimum of 3 neonates were analyzed for the presence and content of neonatal safety data. RESULTS: The analysis identified 40 drugs that were studied in 3 or more neonates. Of the 40 drugs, 36 drugs received a pediatric labeling change as a result of studies between 1998 and 2015, that included information from studies including neonates. Fourteen drugs were approved for use in neonates. Clinical trials for 20 of the drugs reported serious adverse events (SAEs) in neonates. The SAEs primarily involved cardiovascular events such as bradycardia and/or hypotension or laboratory abnormalities such as anemia, neutropenia, and electrolyte disturbances. Deaths were reported during studies of 9 drugs. CONCLUSIONS: Our analysis revealed that SAEs were reported in studies involving 20 of the 40 drugs evaluated in neonates, with deaths identified in 9 of those studies. Patients enrolled in studies were often critically ill, which complicated determination of whether an adverse event was drug-related. We conclude that the traditional means for collecting safety information in drug development trials needs to be adjusted for neonates and will require the collaboration of regulators, industry, and the clinical and research communities to establish appropriate definitions and reporting strategies for the neonatal population. PMID- 28804697 TI - Evaluation of satellite and reanalysis-based global net surface energy flux and uncertainty estimates. AB - The net surface energy flux is central to the climate system yet observational limitations lead to substantial uncertainty. A combination of satellite-derived radiative fluxes at the top of atmosphere adjusted using the latest estimation of the net heat uptake of the Earth system, and the atmospheric energy tendencies and transports from the ERA-Interim reanalysis are used to estimate surface energy flux globally. To consider snowmelt and improve regional realism, land surface fluxes are adjusted through a simple energy balance approach at each grid point. This energy adjustment is redistributed over the oceans to ensure energy conservation and maintain realistic global ocean heat uptake, using a weighting function to avoid meridional discontinuities. Calculated surface energy fluxes are evaluated through comparison to ocean reanalyses. Derived turbulent energy flux variability is compared with the Objectively Analyzed air-sea Fluxes (OAFLUX) product, and inferred meridional energy transports in the global ocean and the Atlantic are also evaluated using observations. Uncertainties in surface fluxes are investigated using a variety of approaches including comparison with a range of atmospheric reanalysis products. Decadal changes in the global mean and the interhemispheric energy imbalances are quantified, and present day cross equator heat transports are reevaluated at 0.22 +/- 0.15 PW (petawatts) southward by the atmosphere and 0.32 +/- 0.16 PW northward by the ocean considering the observed ocean heat sinks. PMID- 28804698 TI - A Novel Technique of Posterolateral Suturing in Thoracoscopic Diaphragmatic Hernia Repair. AB - Background Closure of the posterolateral defect in some cases of congenital diaphragmatic hernia (CDH) can be difficult. Percutaneous transcostal suturing is often helpful to create a complete, watertight closure of the diaphragm. A challenge with the technique is passing the needle out the same tract that it entered so that no skin is caught when the knots are laid down into the subcutaneous tissue. This report describes a novel technique using a Tuohy needle to percutaneously suture the posterolateral defect during thoracoscopic repair of CDH. Case We report a case of a 6-week-old infant who presented with a CDH and ipsilateral intrathoracic kidney that was repaired using thoracoscopic approach. The posterolateral part of the defect was repaired by percutaneous transcostal suturing and extracorporeal knot tying. To assure correct placement of the sutures and knots, a Tuohy needle was used to guide the suture around the rib and out through the same subcutaneous tract. The total operative time was 145 minutes and there were no perioperative complications. The patient was followed up for 3 months, during which there was no recurrence. Conclusion Our percutaneous Tuohy technique for closure of the posterolateral part of CDH enables a secure, rapid, and tensionless repair. PMID- 28804699 TI - All-inorganic inverse perovskite solar cells using zinc oxide nanocolloids on spin coated perovskite layer. AB - We confirmed the influence of ZnO nanoparticle size and residual water on performance of all inorganic perovskite solar cells. By decreasing the size of the ZnO nanoparticles, the short-circuit current density (Jsc) and open circuit photovoltage (Voc) values are increased and the conversion efficiency is improved. Although the Voc value is not affected by the influence of residual water in the solution for preparing the ZnO layer, the Jsc value drops greatly. As a result, it was found that it is important to use the oxide nanoparticles with a small particle diameter and to reduce the water content in the oxide forming material in order to manufacture a highly efficient all inorganic perovskite solar cells. PMID- 28804701 TI - Application of methanol and sweet potato vine hydrolysate as enhancers of citric acid production by Aspergillus niger. AB - BACKGROUND: Agricultural waste is as an alternative low-cost carbon source or beneficial additives which catch most people's eyes. In addition, methanol and sweet potato vine hydrolysate (SVH) have been reported as the efficient enhancers of fermentation according to some reports. The objective of the present study was to confirm SVH as an efficient additive in CA production and explore the synergistic effects of methanol and SVH in fermentation reactions. RESULTS: The optimal fermentation conditions resulted in a maximum citric acid concentration of 3.729 g/L. The final citric acid concentration under the optimized conditions was increased by 3.6-fold over the original conditions, 0.49-fold over the optimized conditions without methanol, and 1.8-fold over the optimized conditions in the absence of SVH. Kinetic analysis showed that Qp, Yp/s, and Yx/s in the optimized systems were significantly improved compared with those obtained in the absence of methanol or SVH. Further, scanning electron microscopy (SEM) revealed that methanol stress promoted the formation of conidiophores, while SVH could neutralize the effect and prolong Aspergillus niger vegetative growth. Cell viability analysis also showed that SVH might eliminate the harmful effects of methanol and enhance cell membrane integrity. CONCLUSIONS: SVH was a superior additive for organic acid fermentation, and the combination of methanol and SVH displayed a significant synergistic effect. The research provides a preliminary theoretical basis for SVH practical application in the fermentation industry. PMID- 28804702 TI - Testing socio-cultural valuation methods of ecosystem services to explain land use preferences. AB - Socio-cultural valuation still emerges as a methodological field in ecosystem service (ES) research and until now lacks consistent formalisation and balanced application in ES assessments. In this study, we examine the explanatory value of ES values for land use preferences. We use 563 responses to a survey about the Pentland Hills regional park in Scotland. Specifically, we aim to (1) identify clusters of land use preferences by using a novel visualisation tool, (2) test if socio-cultural values of ESs or (3) user characteristics are linked with land use preferences, and (4) determine whether both socio-cultural values of ESs and user characteristics can predict land use preferences. Our results suggest that there are five groups of people with different land use preferences, ranging from forest and nature enthusiasts to traditionalists, multi-functionalists and recreation seekers. Rating and weighting of ESs and user characteristics were associated with different clusters. Neither socio-cultural values nor user characteristics were suitable predictors for land use preferences. While several studies have explored land use preferences by identifying socio-cultural values in the past, our findings imply that in this case study ES values inform about general perceptions but do not replace the assessment of land use preferences. PMID- 28804700 TI - Abridged version of the AWMF guideline for the medical clinical diagnostics of indoor mould exposure: S2K Guideline of the German Society of Hygiene, Environmental Medicine and Preventive Medicine (GHUP) in collaboration with the German Association of Allergists (AeDA), the German Society of Dermatology (DDG), the German Society for Allergology and Clinical Immunology (DGAKI), the German Society for Occupational and Environmental Medicine (DGAUM), the German Society for Hospital Hygiene (DGKH), the German Society for Pneumology and Respiratory Medicine (DGP), the German Mycological Society (DMykG), the Society for Pediatric Allergology and Environmental Medicine (GPA), the German Federal Association of Pediatric Pneumology (BAPP), and the Austrian Society for Medical Mycology (OGMM). AB - This article is an abridged version of the AWMF mould guideline "Medical clinical diagnostics of indoor mould exposure" presented in April 2016 by the German Society of Hygiene, Environmental Medicine and Preventive Medicine (Gesellschaft fur Hygiene, Umweltmedizin und Praventivmedizin, GHUP), in collaboration with the above-mentioned scientific medical societies, German and Austrian societies, medical associations and experts. Indoor mould growth is a potential health risk, even if a quantitative and/or causal relationship between the occurrence of individual mould species and health problems has yet to be established. Apart from allergic bronchopulmonary aspergillosis (ABPA) and mould-caused mycoses, only sufficient evidence for an association between moisture/mould damage and the following health effects has been established: allergic respiratory disease, asthma (manifestation, progression and exacerbation), allergic rhinitis, hypersensitivity pneumonitis (extrinsic allergic alveolitis), and increased likelihood of respiratory infections/bronchitis. In this context the sensitizing potential of moulds is obviously low compared to other environmental allergens. Recent studies show a comparatively low sensitizing prevalence of 3-10% in the general population across Europe. Limited or suspected evidence for an association exist with respect to mucous membrane irritation and atopic eczema (manifestation, progression and exacerbation). Inadequate or insufficient evidence for an association exist for chronic obstructive pulmonary disease, acute idiopathic pulmonary hemorrhage in children, rheumatism/arthritis, sarcoidosis and cancer. The risk of infection posed by moulds regularly occurring indoors is low for healthy persons; most species are in risk group 1 and a few in risk group 2 (Aspergillus fumigatus, A. flavus) of the German Biological Agents Act (Biostoffverordnung). Only moulds that are potentially able to form toxins can be triggers of toxic reactions. Whether or not toxin formation occurs in individual cases is determined by environmental and growth conditions, above all the substrate. In the case of indoor moisture/mould damage, everyone can be affected by odour effects and/or mood disorders. However, this is not a health hazard. Predisposing factors for odour effects can include genetic and hormonal influences, imprinting, context and adaptation effects. Predisposing factors for mood disorders may include environmental concerns, anxiety, condition, and attribution, as well as various diseases. Risk groups to be protected particularly with regard to an infection risk are persons on immunosuppression according to the classification of the German Commission for Hospital Hygiene and Infection Prevention (Kommission fur Krankenhaushygiene und Infektionspravention, KRINKO) at the Robert Koch- Institute (RKI) and persons with cystic fibrosis (mucoviscidosis); with regard to an allergic risk, persons with cystic fibrosis (mucoviscidosis) and patients with bronchial asthma should be protected. The rational diagnostics include the medical history, physical examination, and conventional allergy diagnostics including provocation tests if necessary; sometimes cellular test systems are indicated. In the case of mould infections the reader is referred to the AWMF guideline "Diagnosis and Therapy of Invasive Aspergillus Infections". With regard to mycotoxins, there are currently no useful and validated test procedures for clinical diagnostics. From a preventive medicine standpoint it is important that indoor mould infestation in relevant dimension cannot be tolerated for precautionary reasons. With regard to evaluating the extent of damage and selecting a remedial procedure, the reader is referred to the revised version of the mould guideline issued by the German Federal Environment Agency (Umweltbundesamt, UBA). PMID- 28804703 TI - Hybrid intraoperative imaging techniques in radioguided surgery: present clinical applications and future outlook. AB - PURPOSE: This review aims to summarise the hybrid modality radioguidance techniques currently in clinical use and development, and to discuss possible future avenues of research. Due to the novelty of these approaches, evidence of their clinical relevance does not yet exist. The purpose of this review is to inform nuclear medicine practitioners of current cutting edge research in radioguided surgery which may enter standard clinical practice within the next 5 10 years. Hybrid imaging is of growing importance to nuclear medicine diagnostics, but it is only with recent advances in technology that hybrid modalities are being investigated for use during radioguided surgery. These modalities aim to overcome some of the difficulties of surgical imaging while maintaining many benefits, or providing entirely new information unavailable to surgeons with traditional radioguidance. METHODS: A literature review was carried out using online reference databases (Scopus, PubMed). Review articles obtained using this technique were citation mined to obtain further references. RESULTS: In total, 2367 papers were returned, with 425 suitable for further assessment. 60 papers directly related to hybrid intraoperative imaging in radioguided surgery are reported on. Of these papers, 25 described the clinical use of hybrid imaging, 22 described the development of new hybrid probes and tracers, and 13 described the development of hybrid technologies for future clinical use. Hybrid gamma-NIR fluorescence was found to be the most common clinical technique, with 35 papers associated with these modalities. Other hybrid combinations include gamma-bright field imaging, gamma-ultrasound imaging, gamma-beta imaging and beta OCT imaging. The combination of preoperative and intraoperative images is also discussed. CONCLUSION: Hybrid imaging offers new possibilities for assisting clinicians and surgeons in localising the site of uptake in procedures such as in sentinel node detection. PMID- 28804706 TI - A Call to the Senses: The Community Approach. PMID- 28804705 TI - Possible Involvement of Liver Resident Macrophages (Kupffer Cells) in the Pathogenesis of Both Intrahepatic and Extrahepatic Inflammation. AB - Liver resident macrophages designated Kupffer cells (KCs) form the largest subpopulation of tissue macrophages. KCs are involved in the pathogenesis of liver inflammation. However, the role of KCs in the systemic inflammation is still elusive. In this study, we examined whether KCs are involved in not only intrahepatic inflammation but also extrahepatic systemic inflammation. Administration of clodronate liposomes resulted in the KC deletion and in the suppression of liver injury in T cell-mediated hepatitis by ConA as a local acute inflammation model, while the treatment did not influence dextran sulfate sodium- (DSS-) induced colitis featured by weight loss, intestinal shrink, and pathological observation as an ectopic local acute inflammation model. In contrast, KC deletion inhibited collagen-induced arthritis as a model of extrahepatic, systemic chronical inflammation. KC deleted mice showed weaker arthritic scores, less joint swelling, and more joint space compared to arthritis induced control mice. These results strongly suggest that KCs are involved in not only intrahepatic inflammatory response but also systemic (especially) chronic inflammation. PMID- 28804704 TI - Hypoxia in cervical cancer: from biology to imaging. AB - PURPOSE: Hypoxia imaging may improve identification of cervical cancer patients at risk of treatment failure and be utilized in treatment planning and monitoring, but its clinical potential is far from fully realized. Here, we briefly describe the biology of hypoxia in cervix tumors of relevance for imaging, and evaluate positron emission tomography (PET) and magnetic resonance imaging (MRI) techniques that have shown promise for assessing hypoxia in a clinical setting. We further discuss emerging imaging approaches, and how imaging can play a role in future treatment strategies to target hypoxia. METHODS: We performed a PubMed literature search, using keywords related to imaging and hypoxia in cervical cancer, with a particular emphasis on studies correlating imaging with other hypoxia measures and treatment outcome. RESULTS: Only a few and rather small studies have utilized PET with tracers specific for hypoxia, and no firm conclusions regarding preferred tracer or clinical potential can be drawn so far. Most studies address indirect hypoxia imaging with dynamic contrast enhanced techniques. Strong evidences for a role of these techniques in hypoxia imaging have been presented. Pre-treatment images have shown significant association to outcome in several studies, and images acquired during fractionated radiotherapy may further improve risk stratification. Multiparametric MRI and multimodality PET/MRI enable combined imaging of factors of relevance for tumor hypoxia and warrant further investigation. CONCLUSIONS: Several imaging approaches have shown promise for hypoxia imaging in cervical cancer. Evaluation in large clinical trials is required to decide upon the optimal modality and approach. PMID- 28804707 TI - Framework to Define Structure and Boundaries of Complex Health Intervention Systems: The ALERT Project. AB - Health intervention systems are complex and subject to multiple variables in different phases of implementation. This constitutes a concrete challenge for the application of translational science in real life. Complex systems as health oriented interventions call for interdisciplinary approaches with carefully defined system boundaries. Exploring individual components of such systems from different viewpoints gives a wide overview and helps to understand the elements and the relationships that drive actions and consequences within the system. In this study, we present an application and assessment of a framework with focus on systems and system boundaries of interdisciplinary projects. As an example on how to apply our framework, we analyzed ALERT [an integrated sensors and biosensors' system (BEST) aimed at monitoring the quality, health, and traceability of the chain of the bovine milk], a multidisciplinary and interdisciplinary project based on the application of measurable biomarkers at strategic points of the milk chain for improved food security (including safety), human, and ecosystem health (1). In fact, the European food safety framework calls for science-based support to the primary producers' mandate for legal, scientific, and ethical responsibility in food supply. Because of its multidisciplinary and interdisciplinary approach involving human, animal, and ecosystem health, ALERT can be considered as a One Health project. Within the ALERT context, we identified the need to take into account the main actors, interactions, and relationships of stakeholders to depict a simplified skeleton of the system. The framework can provide elements to highlight how and where to improve the project development when project evaluations are required. PMID- 28804708 TI - Pediatric Palliative Care Initiative in Cambodia. AB - Cancer care with curative intent remains difficult to manage in many resource limited settings such as Cambodia. Cambodia has a small workforce with limited financial and health-care resources resulting in delayed diagnoses and availability of limited therapeutic tools. Thus, palliative care becomes the primary form of care in most cases. Although palliative care is becoming an integral part of medical care in developed countries, this concept remains poorly understood and utilized in developing countries. Angkor Hospital for Children serves a relatively large pediatric population in northern Cambodia. According to the modern definition of palliative care, approximately two-thirds of the patients admitted to the hospital were deemed candidates to receive palliative care. In an effort to develop a pediatric palliative care team utilizing existing resources and intensive training, our focus group recruited already existing teams with different health-care expertise and other motivated members of the hospital. During this process, we have also formed a palliative care training team of local experts to maintain ongoing palliative care education. Feedback from patients and health-care providers confirmed the effectiveness of these efforts. In conclusion, palliative and sustainable care was offered effectively in a resource-limited setting with adequately trained and motivated local providers. In this article, the steps and systems used to overcome challenges in Cambodia are summarized in the hope that our experience urges governmental and non-governmental agencies to support similar initiatives. PMID- 28804710 TI - Application of Survival Analysis and Multistate Modeling to Understand Animal Behavior: Examples from Guide Dogs. AB - Epidemiology is the study of patterns of health-related states or events in populations. Statistical models developed for epidemiology could be usefully applied to behavioral states or events. The aim of this study is to present the application of epidemiological statistics to understand animal behavior where discrete outcomes are of interest, using data from guide dogs to illustrate. Specifically, survival analysis and multistate modeling are applied to data on guide dogs comparing dogs that completed training and qualified as a guide dog, to those that were withdrawn from the training program. Survival analysis allows the time to (or between) a binary event(s) and the probability of the event occurring at or beyond a specified time point. Survival analysis, using a Cox proportional hazards model, was used to examine the time taken to withdraw a dog from training. Sex, breed, and other factors affected time to withdrawal. Bitches were withdrawn faster than dogs, Labradors were withdrawn faster, and Labrador * Golden Retrievers slower, than Golden Retriever * Labradors; and dogs not bred by Guide Dogs were withdrawn faster than those bred by Guide Dogs. Multistate modeling (MSM) can be used as an extension of survival analysis to incorporate more than two discrete events or states. Multistate models were used to investigate transitions between states of training to qualification as a guide dog or behavioral withdrawal, and from qualification as a guide dog to behavioral withdrawal. Sex, breed (with purebred Labradors and Golden retrievers differing from F1 crosses), and bred by Guide Dogs or not, effected movements between states. We postulate that survival analysis and MSM could be applied to a wide range of behavioral data and key examples are provided. PMID- 28804709 TI - Exploring Animal Models That Resemble Idiopathic Pulmonary Fibrosis. AB - Large multicenter clinical trials have led to two recently approved drugs for patients with idiopathic pulmonary fibrosis (IPF); yet, both of these therapies only slow disease progression and do not provide a definitive cure. Traditionally, preclinical trials have utilized mouse models of bleomycin (BLM) induced pulmonary fibrosis-though several limitations prevent direct translation to human IPF. Spontaneous pulmonary fibrosis occurs in other animal species, including dogs, horses, donkeys, and cats. While the fibrotic lungs of these animals share many characteristics with lungs of patients with IPF, current veterinary classifications of fibrotic lung disease are not entirely equivalent. Additional studies that profile these examples of spontaneous fibroses in animals for similarities to human IPF should prove useful for both human and animal investigators. In the meantime, studies of BLM-induced fibrosis in aged male mice remain the most clinically relevant model for preclinical study for human IPF. Addressing issues such as time course of treatment, animal size and characteristics, clinically irrelevant treatment endpoints, and reproducibility of therapeutic outcomes will improve the current status of preclinical studies. Elucidating the mechanisms responsible for the development of fibrosis and disrepair associated with aging through a collaborative approach between researchers will promote the development of models that more accurately represent the realm of interstitial lung diseases in humans. PMID- 28804712 TI - Virtual and Actual Humanoid Robot Control with Four-Class Motor-Imagery-Based Optical Brain-Computer Interface. AB - Motor-imagery tasks are a popular input method for controlling brain-computer interfaces (BCIs), partially due to their similarities to naturally produced motor signals. The use of functional near-infrared spectroscopy (fNIRS) in BCIs is still emerging and has shown potential as a supplement or replacement for electroencephalography. However, studies often use only two or three motor imagery tasks, limiting the number of available commands. In this work, we present the results of the first four-class motor-imagery-based online fNIRS-BCI for robot control. Thirteen participants utilized upper- and lower-limb motor imagery tasks (left hand, right hand, left foot, and right foot) that were mapped to four high-level commands (turn left, turn right, move forward, and move backward) to control the navigation of a simulated or real robot. A significant improvement in classification accuracy was found between the virtual-robot-based BCI (control of a virtual robot) and the physical-robot BCI (control of the DARwIn-OP humanoid robot). Differences were also found in the oxygenated hemoglobin activation patterns of the four tasks between the first and second BCI. These results corroborate previous findings that motor imagery can be improved with feedback and imply that a four-class motor-imagery-based fNIRS-BCI could be feasible with sufficient subject training. PMID- 28804711 TI - Annotation of the Nuclear Receptors in an Estuarine Fish species, Fundulus heteroclitus. AB - The nuclear receptors (NRs) are ligand-dependent transcription factors that respond to various internal as well as external cues such as nutrients, pheromones, and steroid hormones that play crucial roles in regulation and maintenance of homeostasis and orchestrating the physiological and stress responses of an organism. We annotated the Fundulus heteroclitus (mummichog; Atlantic killifish) nuclear receptors. Mummichog are a non-migratory, estuarine fish with a limited home range often used in environmental research as a field model for studying ecological and evolutionary responses to variable environmental conditions such as salinity, oxygen, temperature, pH, and toxic compounds because of their hardiness. F. heteroclitus have at least 74 NRs spanning all seven gene subfamilies. F. heteroclitus is unique in that no RXRalpha member was found within the genome. Interestingly, some of the NRs are highly conserved between species, while others show a higher degree of divergence such as PXR, SF1, and ARalpha. Fundulus like other fish species show expansion of the RAR (NR1B), Rev-erb (NR1D), ROR (NR1F), COUPTF (NR2F), ERR (NR3B), RXR (NR2B), and to a lesser extent the NGF (NR4A), and NR3C steroid receptors (GR/AR). Of particular interest is the co-expansion of opposing NRs, Reverb-ROR, and RAR/RXR-COUPTF. PMID- 28804713 TI - Comment on "Are Patients with Polycystic Ovarian Syndrome Ideal Candidates for Oocyte Donation?" PMID- 28804714 TI - Reduction of Mosquito Survival in Mice Vaccinated with Anopheles stephensi Glucose Transporter. AB - Despite the fact that recent efforts to control/eradicate malaria have contributed to a significant decrease in the number of cases and deaths, the disease remains a global health challenge. Vaccines based on mosquito salivary gland antigens are a potential approach for reducing vector populations and malaria parasites. The Anopheles AGAP007752 gene encodes for a glucose transporter that is upregulated during Plasmodium infection, and its knockdown decreases the number of sporozoites in mosquito salivary glands. These results together with the fact that glucose is a vital source of energy suggested that a glucose transporter is a candidate protective antigen for the control of mosquito infestations and Plasmodium infection. To address this hypothesis, herein we investigate the effect of mice vaccination with an immunogenic peptide from mosquito glucose transporter on Anopheles stephensi fitness and Plasmodium berghei infection. We showed that vaccination with a peptide of glucose transporter reduced mosquito survival by 5% when compared to controls. However, the reduction in Plasmodium infection was not significant in mosquitoes fed on vaccinated mice. The effect of the peptide vaccination on mosquito survival is important to reduce infestation by malaria vectors. These results support further research on developing glucose transporter-based vaccines to reduce mosquito fitness. PMID- 28804715 TI - Former Very Preterm Infants Show Alterations in Thyroid Function at a Preschool Age. AB - Preterm birth is frequently associated with altered thyroid hormone levels in the newborn period. Recent data suggest a role of prematurity independent of birth size also in childhood thyroid dysfunction. Whether the high-risk population of former very preterm infants (VPI) is particularly susceptible to thyroid hormone alterations is currently unknown. The aim of the present study was to assess whether former VPI display changes in thyroid hormone status in comparison to term-born controls at a preschool age. Free triiodothyronine (fT3), free thyroxine (fT4), and thyroid stimulating hormone (TSH) concentrations were determined in former VPI and same-aged children born at term at five to seven years of age. 31 former term infants and 82 former VPI were included in the study. In comparison to children born at term, former VPI had lower fT4 (16.1 +/- 1.8 versus 17.0 +/- 2.1 pmol/l), higher fT3 (6.8 +/- 0.7 versus 6.5 pmol/l), and higher TSH levels (3.0 +/- 1.4 versus 2.3 +/- 1.0 MUU/l), independent of major neonatal morbidities. As subclinical changes in thyroid hormone status are potentially associated with adverse health profiles, close follow-up of these children is warranted. PMID- 28804716 TI - Open Wedge High Tibial Osteotomy with Distal Tubercle Osteotomy Lessens Change in Patellar Position. AB - The purpose of this study was to investigate the change in patellar position after open wedge high tibial osteotomy (OWHTO) with distal tubercle osteotomy (DTO), comparing outcomes of conventional OWHTO in young adults with proximal tibia varus deformity but no arthritic manifestations. Thirty-three patients (mean age, 31.8 years) subjected to OWHTO/DTO were matched with 30 patients (mean age, 33.5 years) undergoing conventional OWHTO. Patellar position, as measured in pre- and postoperative standing lateral radiographs, was compared. Patellar height was assessed via Insall-Salvati ratio, modified Insall-Salvati ratio, Blackburne-Peel (BP) index, Caton-Deschamps (CD) index, and modified Miura Kawamura index. Computed tomography was used to measure lateral patellar tilt and shift. In the OWHTO group, all patellar height indices decreased significantly following surgery. Although mean values of BP and CD indices decreased significantly in the OWHTO/DTO group, other determinants of patellar height showed no significant postoperative differences. Significant postoperative declines in average lateral patellar tilt were also evident in both groups, but pre- and postoperative lateral patellar shift did not differ significantly. OWHTO/DTO can be performed without significant changes in patellar height. The results obtained support that OWHTO/DTO is suitable for relatively young patients with proximal tibia vara but no arthritic change. PMID- 28804717 TI - Angiogenesis Dysregulation in Psoriatic Arthritis: Molecular Mechanisms. AB - There is evidence that psoriatic arthritis is closely linked to angiogenesis. Morphological changes described in blood vessels of psoriatic arthritis joints suggest the presence of a dysregulated angiogenesis resulting in the formation of immature vessels. Even if the reason of this inefficient angiogenesis is still unclear, an imbalance between angiogenic and antiangiogenic factors is probably responsible for inducing a dysregulated angiogenesis in psoriatic arthritis, which seems to be involved in its pathogenesis and clinical features. Nevertheless, among chronic arthritides, while angiogenesis in rheumatoid arthritis has been largely studied with a great amount of literature data, limited data on angiogenesis role in psoriatic arthritis are available. This review article is focused on current knowledge on the mechanisms responsible for dysregulated angiogenesis in psoriatic arthritis. PMID- 28804718 TI - CD36 Gene Polymorphisms Are Associated with Intracerebral Hemorrhage Susceptibility in a Han Chinese Population. AB - The CD36 gene encodes a membrane glycoprotein (type B scavenger receptor, SR-B2) that plays a crucial role in lipid sensing, innate immunity, atherogenesis, and glycolipid metabolism. In this study, we aimed to investigate the association between CD36 gene polymorphisms and intracerebral hemorrhage (ICH) in a Han Chinese population. We performed genotype and allele analyses for eleven single nucleotide polymorphisms (SNPs) of CD36 in a case-controlled study involving 292 ICH patients and 298 control participants. Eleven SNPs were genotyped by the Improved Multiple Ligase Detection Reaction (iMLDR) method. The results indicated that the SNP rs1194182 values were significantly different between ICH group and control group in a dominant model after adjusting for confounding factors. The subgroup analysis conducted for rs1194182 showed that the allele G frequencies were significantly different between ICH patients and controls in hypertension group via a dominant model. We then analyzed the rs1194182 genotype distributions among different groups of the serum lipid groups, including BMI, TC, TG, HDL, and LDL. However, no significant differences were found in the analysis of other subgroups. Taken together, these findings indicate that rs1194182 polymorphism in the CD36 gene was associated with ICH, and genotype GG could be an independent predictor. PMID- 28804719 TI - Effect of 2 Bleaching Agents with a Content of High Concentrated Hydrogen Peroxide on Stained 2 CAD/CAM Blocks and a Nanohybrid Composite Resin: An AFM Evaluation. AB - The aim of this study was to evaluate color stability of 3 restorative materials, discoloration ability of different solutions, efficacy of 2 office bleaching agents, and surface roughness and topography. Sixty specimens for Clearfil Majesty Esthetic (CME), Lava Ultimate (LU), and Vita Enamic (VE) were prepared. They were immersed into 3 staining solutions for 2 weeks and then they were bleached. According to the measured L*, a*, and b* parameters described by CIELAB system, color changes (DeltaE00), translucency parameters (TP), whiteness index values (W*), and changes in closeness to pure white (DeltaW*) were calculated. Then 3 specimens from each group were scanned with an atomic force microscope for surface analysis. After staining, CME groups and control groups of LU and VE showed clinically acceptable color changes (DeltaE00 < 1,8). After bleaching, while a reverse effect on color was observed, VE showed the furthest color values to pure white. There was no statistically significant difference between whiteness index values of LU and CME. LU was the most translucent material during the study and TP values of materials showed minimal differences. Most of the VE groups and a control group of LU showed surface roughness (Ra ) values higher than critical value for biofilm accumulation (0,2 MUm). PMID- 28804720 TI - Integron-Mediated Antibiotic Resistance in Acinetobacter baumannii Isolated from Intensive Care Unit Patients, Babol, North of Iran. AB - BACKGROUND: We investigated the integron types and their relation with antibiotic resistance among A. baumannii isolates collected from intensive care unit patients, Babol, north of Iran. METHODS: In this cross-sectional study, a total of 73 bronchoalveolar lavage samples were obtained from patients in ICU. Susceptibility testing was performed by disk diffusion method. Types of integrons were identified by an integrase gene PCR. RESULTS: In total, 47.9% A. baumannii isolates were recovered from the BAL samples. All isolates were resistant to ceftazidime. 91.4% and 58.3% of isolates were MDR and XDR, respectively. The rate of colistin resistance with the E-test was 5.7%. Molecular analysis of class I, II, and III integrons showed that 25.7%, 88.6%, and 28.6% of the isolates carried the intI, intII, and intIII genes, respectively. DISCUSSION: Our results show that different classes of integrons are commonly spread among A. baumannii strains and these genomic segments can play an important role in the acquisition of MDR and XDR phenotypes. So monitoring drug resistance in A. baumannii isolates with the use of int gene PCR is very important to plan specific infection control measures to prevent the spread of MDR-AB and XDR-AB in Iran's hospitals. PMID- 28804721 TI - Corrigendum to "Comparative Study of Exome Copy Number Variation Estimation Tools Using Array Comparative Genomic Hybridization as Control". AB - [This corrects the article DOI: 10.1155/2013/915636.]. PMID- 28804722 TI - Comment on "Application of PK/PD Modeling in Veterinary Field: Dose Optimization and Drug Resistance Prediction". PMID- 28804723 TI - Ethosomes of Phenylethyl Resorcinol as Vesicular Delivery System for Skin Lightening Applications. AB - Ethosome formulations containing phenylethyl resorcinol (PR) were developed. The formulation was produced from 0.5% w/v PR, 0.5% w/v cholesterol from lanolin, 3% w/v L-alpha-phosphatidylcholine from soybean, 30% v/v absolute ethanol, and water up to 100% v/v. It was characterized by a vesicular size of 389 nm, low polydispersity index of 0.266, zeta potential of -34.19 +/- 0.44 mV, high PR entrapment efficiency of 71%, and good stability on storage at 4 and 30 degrees C at 75% RH for 4 months. In vitro studies using pig skin revealed that permeation coefficient of PR from ethosomes was significantly higher than that from liposomes. In vitro retention profiles showed that PR accumulation in pig skin following application of ethosome formulations was 7.4-, 3.3-, and 1.8-fold higher than that achieved using liposomes, 20% propylene glycol solution, and 30% hydroethanolic solution, respectively. An inhibition value of around 80% was measured for antityrosinase activity of PR in pig skin. Consistently, ethosomes exhibited higher tyrosinase inhibition activity and melanin content reduction when compared to other formulations in B16 melanoma cells. Ethosomes did not cause acute dermal irritation in albino rabbits. These findings demonstrate that ethosomes are capable of delivering PR into the skin efficiently and hold promise for topical application of skin lightening products. PMID- 28804726 TI - Low Dose of Lipopolysaccharide Pretreatment Preventing Subsequent Endotoxin Induced Uveitis Is Associated with PI3K/AKT Pathway. AB - PURPOSE: To explore the effects of LPS pretreatment on endotoxin-induced uveitis and PI3K/AKT pathway. METHODS: Endotoxin-induced uveitis was induced by a single subcutaneous injection of 200 MUg LPS. For the endotoxin tolerance group, induction of EIU was preceded by daily subcutaneous injection of 0.1 mg/kg LPS for five days. Clinical scores were graded at 24 h after EIU under a slit lamp microscope. HE stain was performed to observe the histopathology. Aqueous humor TNF-alpha concentration was quantified with enzyme-linked immunosorbent assay. The expressions of PI3K and AKT were detected through Western blot analyses, and the activation of AKT was detected through immunofluorescence study. RESULTS: Endotoxin tolerance produced suppressive effects by significantly reducing the inflammatory reaction of anterior segment of the rats as measured by slit lamp and histopathology. Low dose of LPS pretreatment significantly reduced TNF-alpha concentrations and the expressions of PI3K and AKT. Furthermore, the activation of AKT was also inhibited. CONCLUSIONS: LPS pretreatment can ameliorate endotoxin induced uveitis in rats. This protection of endotoxin tolerance against EIU is associated with PI3K/AKT pathway by reducing level of TNF-alpha in the aqueous humor. PMID- 28804725 TI - Meprin Metalloprotease Deficiency Associated with Higher Mortality Rates and More Severe Diabetic Kidney Injury in Mice with STZ-Induced Type 1 Diabetes. AB - Meprins are membrane-bound and secreted metalloproteinases consisting of alpha and/or beta subunits that are highly expressed in kidney epithelial cells and are differentially expressed in podocytes and leukocytes (macrophages and monocytes). Several studies have implicated meprins in the progression of diabetic nephropathy (DN) and fibrosis-associated kidney disease. However, the mechanisms by which meprins modulate DN are not understood. To delineate the role of meprins in DN, we subjected meprin alphabeta knockout (alphabetaKO) mice and their wild type (WT) counterparts to streptozotocin-induced type 1 diabetes. The 18-week survival rates were significantly lower for diabetic meprin alphabetaKO mice when compared to those for their WT counterparts. There were significant decreases in mRNA and protein levels for both meprin alpha and beta in diabetic WT kidneys. Furthermore, the blood urea nitrogen levels and urine albumin/creatinine ratios increased in diabetic meprin alphabetaKO but not in diabetic WT mice, indicating that meprins may be protective against diabetic kidney injury. The brush border membrane levels of villin, a meprin target, significantly decreased in diabetic WT but not in diabetic meprin alphabetaKO kidneys. In contrast, isoform-specific increases in cytosolic levels of the catalytic subunit of PKA, another meprin target, were demonstrated for both WT and meprin alphabetaKO kidneys. PMID- 28804724 TI - MicroRNA Regulation of Glycolytic Metabolism in Glioblastoma. AB - Glioblastoma (GBM) is the most aggressive and common malignant brain tumour in adults. A well-known hallmark of GMB and many other tumours is aerobic glycolysis. MicroRNAs (miRNAs) are a class of short nonprotein coding sequences that exert posttranscriptional controls on gene expression and represent critical regulators of aerobic glycolysis in GBM. In GBM, miRNAs regulate the expression of glycolytic genes directly and via the regulation of metabolism-associated tumour suppressors and oncogenic signalling pathways. This review aims to establish links between miRNAs expression levels, the expression of GBM glycolytic regulatory genes, and the malignant progression and prognosis of GBM. In this review, the involvement of 25 miRNAs in the regulation of glycolytic metabolism of GBM is discussed. Seven of these miRNAs have been shown to regulate glycolytic metabolism in other tumour types. Further eight miRNAs, which are differentially expressed in GBM, have also been reported to regulate glycolytic metabolism in other cancer types. Thus, these miRNAs could serve as potential glycolytic regulators in GBM but will require functional validation. As such, the characterisation of these molecular and metabolic signatures in GBM can facilitate a better understanding of the molecular pathogenesis of this disease. PMID- 28804727 TI - Development of a Prediction Model for Stress Fracture During an Intensive Physical Training Program: The Royal Marines Commandos. AB - BACKGROUND: Stress fractures (SFs) are one of the more severe overuse injuries in military training, and therefore, knowledge of potential risk factors is needed to assist in developing mitigating strategies. PURPOSE: To develop a prediction model for risk of SF in Royal Marines (RM) recruits during an arduous military training program. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: RM recruits (N = 1082; age range, 16-33 years) who enrolled between September 2009 and July 2010 were prospectively followed through the 32-week RM training program. SF diagnosis was confirmed from a positive radiograph or magnetic resonance imaging scan. Potential risk factors assessed at week 1 included recruit characteristics, anthropometric assessment, dietary supplement use, lifestyle habits, fitness assessment, blood samples, 25(OH)D, bone strength as measured by heel broadband ultrasound attention, history of physical activity, and previous and current food intake. A logistic least absolute shrinkage and selection operator (LASSO) regression with 10-fold cross-validation was used to select potential predictors among 47 candidate variables. Model performance was assessed using measures of discrimination (c-index) and calibration. Bootstrapping was used for internal validation of the developed model and to quantify optimism. RESULTS: A total of 86 (8%) volunteer recruits presented at least 1 SF during training. Twelve variables were identified as the most important risk factors of SF. Variables strongly associated with SF were age, body weight, pretraining weightbearing exercise, pretraining cycling, and childhood intake of milk and milk products. The c-index for the prediction model, which represents the model performance in future volunteers, was 0.73 (optimism corrected c-index, 0.68). Although 25(OH)D and VO2max had only a borderline statistically significant association with SF, the inclusion of these factors improved the performance of the model. CONCLUSION: These findings will assist in identifying recruits at greater risk of SF during training and will support interventions to mitigate this injury risk. However, external validation of the model is still required. PMID- 28804728 TI - Relationships of Muscle Function and Subjective Knee Function in Patients After ACL Reconstruction. AB - BACKGROUND: After anterior cruciate ligament reconstruction (ACLR), relationships between objective measures of muscle function and patient-reported outcomes may change over time. Examining these measures at different time frames after surgery may help develop individualized approaches to improve post-ALCR analysis. PURPOSE: To examine the associations between subjective knee function and lower extremity muscle function in individual patients at various time points after ACLR. STUDY DESIGN: Descriptive laboratory study. METHODS: Fifty-one participants who underwent primary, unilateral ACLR (15 males, 36 females; mean age, 22.9 +/- 4.5 years; mean height, 172.4 +/- 10.1 cm; mean weight, 68.7 +/- 13.1 kg) were separated into 3 groups depending on time since surgery (early, <2 years; middle, 2-5 years; late, >5 years). Subjective knee function was quantified using the International Knee Documentation Committee (IKDC) subjective knee form and the Knee injury and Osteoarthritis Outcome Score (KOOS). Isometric knee extension and flexion strength were collected at 90 deg/s. Single-leg hop performance was measured using the single hop, triple hop, cross-over hop, and 6-m timed hop. Coefficient correlations were calculated between subjective knee function and objective measures of muscle function for each group. RESULTS: The early group demonstrated moderate correlations between the KOOS and unilateral measures of flexion peak torque (r = 0.514, P = .035) and flexion power (r = 0.54, P = .027). The middle group demonstrated the strongest correlations between the KOOS and symmetry measures of the single hop (r = 0.69, P = .002) and extension work (r = 0.71, P = .002) as well as unilateral measures of the triple hop (r = 0.52, P = .034) and extension work (r = 0.66, P = .004). The late group demonstrated strong correlations between the 6-m timed hop symmetry and the IKDC (r = 0.716, P = .001) and KOOS (r = 0.71, P = .001). CONCLUSION: Patients with a post-ACLR status of less than 2 years exhibited stronger relationships with unilateral strength measures to subjective function; graft type was found to change these relationships. Patients at 2 to 5 years postsurgery demonstrated relationships with both unilateral and symmetry measures of muscle function to subjective function. Patients who were more than 5 years after ACLR exhibited strong associations between hopping symmetry and subjective function. CLINICAL RELEVANCE: Future clinical guidelines for patients after ACLR may need to consider time since surgery as a potential factor. PMID- 28804729 TI - Organ dose variability and trends in tomosynthesis and radiography. AB - The purpose of this study was to investigate relationships between patient attributes and organ dose for a population of computational phantoms for 20 tomosynthesis and radiography protocols. Organ dose was estimated from 54 adult computational phantoms (age: 18 to 78 years, weight 52 to 117 kg) using a validated Monte-Carlo simulation (PENELOPE) of a system capable of performing tomosynthesis and radiography. The geometry and field of view for each exam were modeled to match clinical protocols. For each protocol, the energy deposited in each organ was estimated by the simulations, converted to dose units, and then normalized by exposure in air. Dose to radiosensitive organs was studied as a function of average patient thickness in the region of interest and as a function of body mass index. For tomosynthesis, organ doses were also studied as a function of x-ray tube position. This work developed comprehensive information for organ dose dependencies across a range of tomosynthesis and radiography protocols. The results showed a protocol-dependent exponential decrease with an increasing patient size. There was a variability in organ dose across the patient population, which should be incorporated in the metrology of organ dose. The results can be used to prospectively and retrospectively estimate organ dose for tomosynthesis and radiography. PMID- 28804730 TI - Breast dose reduction with organ-based, wide-angle tube current modulated CT. AB - This study aimed to estimate the organ dose reduction potential for organ-dose based tube current modulated (ODM) thoracic computed tomography (CT) with a wide dose reduction arc. Twenty-one computational anthropomorphic phantoms (XCAT) were used to create a virtual patient population with clinical anatomic variations. The phantoms were created based on patient images with normal anatomy (age range: 27 to 66 years, weight range: 52.0 to 105.8 kg). For each phantom, two breast tissue compositions were simulated: [Formula: see text] and [Formula: see text] (glandular-to-adipose ratio). A validated Monte Carlo program (PENELOPE, Universitat de Barcelona, Spain) was used to estimate the organ dose for standard tube current modulation (TCM) (SmartmA, GE Healthcare) and ODM (GE Healthcare) for a commercial CT scanner (Revolution, GE Healthcare) using a typical clinical thoracic CT protocol. Both organ dose and [Formula: see text]-to-organ dose conversion coefficients ([Formula: see text] factors) were compared between TCM and ODM. ODM significantly reduced all radiosensitive organ doses ([Formula: see text]). The breast dose was reduced by [Formula: see text]. For [Formula: see text] factors, organs in the anterior region (e.g., thyroid and stomach) exhibited substantial decreases, and the medial, distributed, and posterior region saw either an increase of less than 5% or no significant change. ODM significantly reduced organ doses especially for radiosensitive superficial anterior organs such as the breasts. PMID- 28804731 TI - Eye tracking in catheter-based cardiovascular interventions: early results. AB - Visual x-ray image processing (XRIP) represents a fundamental component of catheter-based cardiovascular interventions (CBCVIs). To date, no data are available to define XRIP in this setting. To characterize CBCVI XRIP, we developed a computer-based method allowing continuous temporal-spatial analysis of data recorded by a head-mounted eye-tracking device. Quantitative analysis of gaze duration of an expert operator (EO) revealed that the average time in minutes spent viewing the images on the display screen was [Formula: see text] and [Formula: see text] of the total recorded time in coronary angiography (CA) and in CA followed by CBCVI, respectively. Qualitative analysis of gaze data of the EO revealed consistent focus on the center point of the screen. Only if suspicious findings were detected did gaze move toward the target. In contrast, a novice operator (NO) observing a subset of cases viewed coronary artery segments separately and sequentially. The developed methodology allows continuous registration and analysis of gaze data for analysis of XRIP strategies of EOs in live-cases scenarios and may assist in the transfer of experts' reading skills to novices. PMID- 28804732 TI - Do Irregularly Shaped School Attendance Zones Contribute to Racial Segregation or Integration? AB - This research investigates if and how much the shapes of school attendance zones contribute to racial segregation in schools. We find that the typical school attendance zone is relatively compact and resembles a square-like shape. Compact zones typically draw children from local residential areas, and since local areas are often racially homogeneous, this suggests that high levels of racial segregation in the largest school districts are largely structured by existing residential segregation. Still, this study finds that the United States contains some attendance zones with highly irregular shapes-some of which are as irregular as the most irregular Congressional District. Although relatively rare, attendance zones that are highly irregular in shape almost always contain racially diverse student populations. This racial diversity contributes to racial integration within school districts. These findings contradict recent theoretical and empirical scholarship arguing that irregularly shaped zones contribute to racial segregation in schools. Our findings suggest that most racial segregation in school attendance zones is driven by large-scale segregation across residential areas rather than a widespread practice among school districts to exacerbate racial segregation by delineating irregularly shaped attendance zones. PMID- 28804733 TI - 3D-Printed Tissue-Mimicking Phantoms for Medical Imaging and Computational Validation Applications. AB - Abdominal aortic aneurysm (AAA) is a permanent, irreversible dilation of the distal region of the aorta. Recent efforts have focused on improved AAA screening and biomechanics-based failure prediction. Idealized and patient-specific AAA phantoms are often employed to validate numerical models and imaging modalities. To produce such phantoms, the investment casting process is frequently used, reconstructing the 3D vessel geometry from computed tomography patient scans. In this study the alternative use of 3D printing to produce phantoms is investigated. The mechanical properties of flexible 3D-printed materials are benchmarked against proven elastomers. We demonstrate the utility of this process with particular application to the emerging imaging modality of ultrasound-based pulse wave imaging, a noninvasive diagnostic methodology being developed to obtain regional vascular wall stiffness properties, differentiating normal and pathologic tissue in vivo. Phantom wall displacements under pulsatile loading conditions were observed, showing good correlation to fluid-structure interaction simulations and regions of peak wall stress predicted by finite element analysis. 3D-printed phantoms show a strong potential to improve medical imaging and computational analysis, potentially helping bridge the gap between experimental and clinical diagnostic tools. PMID- 28804734 TI - 3D Printing of Personalized Artificial Bone Scaffolds. AB - Additive manufacturing technologies, including three-dimensional printing (3DP), have unlocked new possibilities for bone tissue engineering. Long-term regeneration of normal anatomic structure, shape, and function is clinically important subsequent to bone trauma, tumor, infection, nonunion after fracture, or congenital abnormality. Due to the great complexity in structure and properties of bone across the population, along with variation in the type of injury or defect, currently available treatments for larger bone defects that support load often fail in replicating the anatomic shape and structure of the lost bone tissue. 3DP could provide the ability to print bone substitute materials with a controlled chemistry, shape, porosity, and topography, thus allowing printing of personalized bone grafts customized to the patient and the specific clinical condition. 3DP and related fabrication approaches of bone grafts may one day revolutionize the way clinicians currently treat bone defects. This article gives a brief overview of the current advances in 3DP and existing materials with an emphasis on ceramics used for 3DP of bone scaffolds. Furthermore, it addresses some of the current limitations of this technique and discusses potential future directions and strategies for improving fabrication of personalized artificial bone constructs. PMID- 28804735 TI - Enhanced Osteoblast Response to Porosity and Resolution of Additively Manufactured Ti-6Al-4V Constructs with Trabeculae-Inspired Porosity. AB - The addition of porosity to the traditionally used solid titanium metal implants has been suggested to more closely mimic the natural mechanical properties of bone and increase osseointegration in dental and orthopedic implants. The objective of this study was to evaluate cellular response to three-dimensional (3D) porous Ti-6Al-4V constructs fabricated by additive manufacturing using laser sintering with low porosity (LP), medium porosity (MP), and high porosity (HP) with low resolution (LR) and high resolution (HR) based on a computed tomography scan of human trabecular bone. After surface processing, construct porosity ranged from 41.0% to 76.1%, but all possessed micro-/nanoscale surface roughness and similar surface chemistry containing mostly Ti, O, and C. Biological responses (osteoblast differentiation, maturation, and local factor production) by MG63 osteoblast-like cells and normal human osteoblasts favored 3D than two dimensional (2D) solid constructs. First, MG63 cells were used to assess differences in cell response to 2D compared to LR and HR porous 3D constructs. MG63 cells were sensitive to porosity resolution and exhibited increased osteocalcin (OCN), vascular endothelial growth factor (VEGF), osteoprotegerin (OPG), and bone morphogenetic protein 2 (BMP2) on HR 3D constructs than on 2D and LR 3D constructs. MG63 cells also exhibited porosity-dependent responses on HR constructs, with up to a 6.9-fold increase in factor production on LP-HR and MP HR constructs than on HP-HR constructs. NHOsts were then used to validate biological response on HR constructs. NHOsts exhibited decreased DNA content and alkaline phosphatase activity and up to a 2.9-fold increase in OCN, OPG, VEGF, BMP2, and BMP4 on 3D HR constructs than on 2D controls. These results indicate that osteoblasts prefer a 3D architecture than a 2D surface and that osteoblasts are sensitive to the resolution of trabecular detail and porosity parameters of laser-sintered 3D Ti-6Al-4V constructs. PMID- 28804736 TI - Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) promote neurorepair in the ischemic brain. AB - Despite the fact that ischemic stroke has been considered a leading cause of mortality in the world, recent advances in our understanding of the pathophysiological mechanisms underlying the ischemic injury and the treatment of acute ischemic stroke patients have led to a sharp decrease in the number of stroke deaths. However, this decrease in stroke mortality has also led to an increase in the number of patients that survive the acute ischemic injury with different degrees of disability. Unfortunately, to this date we do not have an effective therapeutic strategy to promote neurological recovery in these growing population of stroke survivors. Cerebral ischemia not only causes the destruction of a large number of axons and synapses but also activates endogenous mechanisms that promote the recovery of those neurons that survive its harmful effects. Here we review experimental evidence indicating that one of these mechanisms of repair is the binding of the serine proteinase urokinase-type plasminogen activator (uPA) to its receptor (uPAR) in the growth cones of injured axons. Indeed, the binding of uPA to uPAR in the periphery of growth cones of injured axons induces the recruitment of beta1-integrin to the plasma membrane, beta1-integrin-mediated activation of the small Rho GTPase Rac1, and Rac1-induced axonal regeneration. Furthermore, we found that this process is modulated by the low density lipoprotein receptor-related protein (LRP1). The data reviewed here indicate that the uPA-uPAR-LRP1 system is a potential target for the development of therapeutic strategies to promote neurological recovery in acute ischemic stroke patients. PMID- 28804737 TI - Studies on the mechanisms of bile acid initiated hepatic inflammation in cholestatic liver injury. AB - The mechanism of bile acid induced cholestatic liver injury remains controversial, thus hindering the development of new therapies for these diseases. In this research highlight, we briefly review the evolution of our understanding of the pathogenesis of bile acid induced liver injury, and summarize our recent findings on this topic. Our data suggests that under pathophysiological conditions bile acid induced liver injury is mediated by inflammatory responses that are initiated from stressed hepatocytes. We conclude by mentioning potential new therapeutic approaches for treating cholestatic liver injury based on these pathophysiologic concepts. PMID- 28804738 TI - Social Observation Task in a Linear Maze for Rats. AB - Animals often learn through observing their conspecifics. However, the mechanisms of them obtaining useful knowledge during observation are beginning to be understood. This protocol describes a novel social observation task to test the 'local enhancement theory', which proposes that presence of social subjects in an environment facilitates one's understanding of the environments. By combining behavior test and in vivo electrophysiological recording, we found that social observation can facilitate the observer's spatial representation of an unexplored environment. The task protocol was published in Mou and Ji, 2016. PMID- 28804739 TI - Selection of Genetically Modified Bacteriophages Using the CRISPR-Cas System. AB - We present a CRISPR-Cas based technique for deleting genes from the T7 bacteriophage genome. A DNA fragment encoding homologous arms to the target gene to be deleted is first cloned into a plasmid. The T7 phage is then propagated in Escherichia coli harboring this plasmid. During this propagation, some phage genomes undergo homologous recombination with the plasmid, thus deleting the targeted gene. To select for these genomes, the CRISPR-Cas system is used to cleave non-edited genomes, enabling isolation of the desired recombinant phages. This protocol allows seamless deletion of desired genes in a T7 phage, and can be expanded to other phages and other types of genetic manipulations as well. PMID- 28804740 TI - Avascular necrosis of the humeral head following bilateral upper extremity vascular composite allotransplantation: a case report. AB - Vascularised composite allotransplantation (VCA) represents an exciting and emerging field in plastic and reconstructive surgery. Despite the generally good functional and psychosocial outcomes, multiple complications can be associated with the procedure. The authors describe a case of avascular necrosis of the humeral head following successful upper extremity VCA. PMID- 28804741 TI - A case of dorsal oblique fingertip amputation. AB - This study reports successful finger replantation in a patient with a dorsal oblique fingertip amputation. When repairing this unique type of injury, an evaluation of the remaining vessels is more useful for successful replantation than the anatomical zone classification. We propose that Kasai's classification is appropriate for guiding treatment. PMID- 28804742 TI - Immunological reaction after facial hyaluronic acid injection. AB - We report two rare cases of inflammatory reactions with multiple subcutaneous facial painful collections after Hyaluronic acid injections, expose their management and discuss aetiologic hypothesis. Due to unfavourable evolution despite antibiotic treatment, surgical drainage was performed. Immune-mediated delayed hypersensitivity reactions were the most probable cause. PMID- 28804743 TI - Reversed palmaris longus muscle: a report of two cases. AB - The palmaris longus muscle is the most superficial muscle of the volar forearm which demonstrates significant anatomical variance. A reversed palmaris longus muscle is one such variant. Here we discuss two cases in which reversed palmaris longus was postulated as a cause of wrist discomfort. PMID- 28804744 TI - Reduced rich-club connectivity is related to disability in primary progressive MS. AB - OBJECTIVE: To investigate whether the structural connectivity of the brain's rich club organization is altered in patients with primary progressive MS and whether such changes to this fundamental network feature are associated with disability measures. METHODS: We recruited 37 patients with primary progressive MS and 21 healthy controls for an observational cohort study. Structural connectomes were reconstructed based on diffusion-weighted imaging data using probabilistic tractography and analyzed with graph theory. RESULTS: We observed the same topological organization of brain networks in patients and controls. Consistent with the originally defined rich-club regions, we identified superior frontal, precuneus, superior parietal, and insular cortex in both hemispheres as rich-club nodes. Connectivity within the rich club was significantly reduced in patients with MS (p = 0.039). The extent of reduced rich-club connectivity correlated with clinical measurements of mobility (Kendall rank correlation coefficient tau = 0.20, p = 0.047), hand function (tau = -0.26, p = 0.014), and information processing speed (tau = -0.20, p = 0.049). CONCLUSIONS: In patients with primary progressive MS, the fundamental organization of the structural connectome in rich club and peripheral nodes was preserved and did not differ from healthy controls. The proportion of rich-club connections was altered and correlated with disability measures. Thus, the rich-club organization of the brain may be a promising network phenotype for understanding the patterns and mechanisms of neurodegeneration in MS. PMID- 28804745 TI - Dramatic rebounds of MS during pregnancy following fingolimod withdrawal. PMID- 28804746 TI - Black Women's Recommendations for Developing Effective Type 2 Diabetes Programming. AB - The purpose of this study was to learn from 29 Black women how to develop effective Type 2 diabetes programming. Three focus groups were held in Des Moines, Iowa, during fall 2012. Results highlighted themes related to diabetes knowledge, diabetes management and prevention, physical activity, diet, and diabetes management programming. Opinions were shared as to whether family members should be included in programs for supporting those diagnosed with diabetes. These results provided guidance and ideas to scholars and health care professionals aiming to improve effectiveness of diabetes programs for Black women and families. PMID- 28804747 TI - Care Experiences of Adults With a Dual Diagnosis and Their Family Caregivers. AB - Individuals diagnosed with developmental disability and mental illness (a "dual diagnosis") contend with multiple challenges and system-related barriers. Using an interpretive description approach, separate qualitative interviews were conducted with adults with a dual diagnosis (n = 7) and their caregiving parents (n = 8) to examine care-related experiences. Results indicate that individuals with a dual diagnosis and their families experience misunderstanding and stigma. Families provide informal complex care amid insufficient and uncoordinated services but are often excluded from formal care planning. A lack of available funding and services further impedes care. While negative care experiences are reported as prevalent, participants also describe instances of beneficial care. Overall, findings indicate a lack of sufficiently targeted resources, leaving families to absorb system-related care gaps. Recommendations include person- and family-centered care, navigation support, and capacity building. Prevention and emergency and crisis care services, along with housing, vocation, and other supports, are needed. Practice and research development regarding life span needs are recommended. PMID- 28804748 TI - Health of Children Living Near Coal Ash. AB - Coal ash, generated from coal combustion, is composed of small particles containing metals and other elements, such as metalloids. Coal ash is stored in open-air impoundments, frequently near communities. The objective of this study was to evaluate the prevalence of health and sleep problems in children living near coal ash and compare these prevalences to children not living near coal ash. In 2013 to 2014, we conducted a cross-sectional survey in a community adjacent to coal ash storage sites and a community not exposed to coal ash. Overall, 111 children who lived near coal ash were in the study; 55.9% (62) were males, 44.1% (49) were females, and the mean age was 10.3 years (SD = 3.9). Descriptive statistics and logistic regression were used to compare the prevalence of health and sleep problems. Attention-deficit hyperactivity disorder (P = .02), gastrointestinal problems (P = .01), difficulty falling asleep (P = .007), frequent night awakenings (P < .001), teeth grinding (P = .03), and complaint of leg cramps (P < .001) were significantly greater in the children living near coal ash. When adjusting for covariates, the odds of allergies excluding asthma, attention-deficit hyperactivity disorder, gastrointestinal problems, difficulty falling asleep, frequent night awakenings, sleep talking, and complaint of leg cramps were greater in children living near coal ash compared to children not living near coal ash (nonexposed). Several components of coal ash, such as heavy metals like lead, mercury, and arsenic, may be associated with health and sleep problems in children. More research is needed to investigate this relationship. PMID- 28804749 TI - Morphine Versus Methadone Treatment for Neonatal Withdrawal and Impact on Early Infant Development. AB - Objective. Compare developmental outcomes in infants treated with morphine versus methadone. Method. Retrospective chart review of newborns identified through use of ICD-9 code for neonatal abstinence syndrome (NAS). Thirty-six infants were evaluated-17 treated with methadone and 19 treated with morphine. Assessment was completed following treatment using the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III). Scores in Cognitive, Language, and Motor domains were compared. Results. Comparison of scores between morphine- and methadone-treated groups revealed differences in mean Cognitive Composite (91.3 vs 83.0; P = .03410) and mean Total Motor Composite Scores (96.3 vs 89.6; P = .0149). Conclusion. Newborns with NAS treated with morphine had significantly higher scores in Cognitive and Gross Motor domains compared to infants treated with methadone. Development screening should be pursued to determine if this difference persists throughout early childhood. Results may influence accepted treatment protocols for NAS. PMID- 28804750 TI - A Case of Kawasaki Disease With Concomitant Leptospirosis. PMID- 28804751 TI - Ultrasound imaging and segmentation of bone surfaces: A review. AB - Due to its real-time, non-radiation based three-dimensional (3D) imaging capabilities, ultrasound (US) has been incorporated into various orthopedic procedures. However, imaging artifacts, low signal-to-noise ratio (SNR) and bone boundaries appearing several mm in thickness make the analysis of US data difficult. This paper provides a review about the state-of-the-art bone segmentation and enhancement methods developed for two-dimensional (2D) and 3D US data. First, an overview for the appearance of bone surface response in B-mode data is presented. Then, classification of the proposed techniques in terms of the image information being used is provided. Specifically, the focus is given on segmentation and enhancement of B-mode US data. The review is concluded by discussing future directions of research and additional challenges which need to be overcome in order to make this imaging modality more successful in orthopedics. PMID- 28804752 TI - Understanding Mixed Emotions: Paradigms and Measures. AB - In this review, we examine the paradigms and measures available for experimentally studying mixed emotions in the laboratory. For eliciting mixed emotions, we describe a mixed emotions film library that allows for the repeated elicitation of a specific homogeneous mixed emotional state and appropriately matched pure positive, pure negative, and neutral emotional states. For assessing mixed emotions, we consider subjective and objective measures that fall into univariate, bivariate, and multivariate measurement categories. As paradigms and measures for objectively studying mixed emotions are still in their early stages, we conclude by outlining future directions that focus on the reliability, temporal dynamics, and response coherence of mixed emotions paradigms and measures. This research will build a strong foundation for future studies and significantly advance our understanding of mixed emotions. PMID- 28804753 TI - Concussion Incidence and Recurrence in Professional Australian Football Match Play: A 14-Year Analysis. AB - BACKGROUND: Concussion incidence rates in professional Australian football may be underreported due to the injury classification definition. A myriad of factors contribute to concussion risk; however, there is limited long-term surveillance in Australian football. This study analysed concussion in one Australian football team over an extended period. METHOD: Match-play concussion injuries in one team (n = 116 participants) were diagnosed and treated by the team physician over 14 years. Analysis of factors related to concussion including matches played, time of day and season, and return to play provided an insight into occurrence and recurrence rates. RESULTS: 140 concussions were recorded (17.6 per 1000 player match hours). A strong relationship was evident between matches played and concussion incidence (r = 0.70) and match conditions did not negatively affect the concussion rate. Whether an athlete returned to play in the same match or suffered a loss-of-consciousness concussion (p = 0.84), their ensuing rate of concussion was not affected. CONCLUSION: Concussion in professional Australian football was related to the number of matches played. Further, neither previous incidence nor loss of consciousness affected future concussion risk. This study provides ecologically valid evidence of the concussion incidence rate in professional Australian football and has implications for the management of athletes sustaining concussion injuries. PMID- 28804754 TI - Use of the full-thickness resection device (FTRD) to prevent bleeding after colonic polypectomy in a patient with a left ventricular assist device. AB - Background and study aims Treatment of colorectal polyps in patients undergoing permanent anticoagulation is associated with a significantly increased risk of peri-interventional bleeding. This specifically applies to polyps > 1 cm where endoscopic full-thickness resection (EFTR) with the full-thickness-resection device (FTRD) can be taken into consideration as an alternative approach to classical snare polypectomy. For these indications, EFTR appears to be superior to conventional techniques especially in terms of sufficient hemostasis due to the mechanical tissue compression achieved by the FTRD's integrated Over-The Scope Clip (OTSC). This is demonstrated in the following case report of a 59-year old male with a left ventricular assist device (LVAD) implanted due to congestive heart failure. He presented with intermittent hemorrhage from a large polyp in the ascending colon that was successfully treated via EFTR with the FTRD. A video is included. PMID- 28804755 TI - Editorial: Code Case - Investigating Transparency and Reproducibility. PMID- 28804756 TI - Assembly of Layered Monetite-Chitosan Nanocomposite and Its Transition to Organized Hydroxyapatite. AB - Bioinspired synthesis of hierarchically structured calcium phosphate (CaP) material is a highly promising strategy for developing improved bone substitute materials. However, synthesis of CaP materials with outstanding mechanical properties still remains an ongoing challenge. Inspired by the formation of lamellar structure in nacre, we designed an organic matrix composed of chitosan and cis-butenediolic acid (maleic acid, MAc) that could assemble into a layered complex and further guide the mineralization of monetite crystals, resulting in the formation of organized and parallel arrays of monetite platelets with a brick and-mortar structure. Using the layered monetite-chitosan composite as a precursor, we were able to synthesize hydroxyapatite (HAp) with multiscale hierarchically ordered structure via a topotactic phase transformation process. On the nanoscale, needlelike HAp crystallites assembled into organized bundles that aligned to form highly oriented plates on the microscale. On the large-scale level, these plates with different crystal orientations were stacked together to form a layered structure. The organized structures and composite feature yielded CaP materials with improved mechanical properties close to those of bone. Our study introduces a biomimetic approach that may be practical for the design of advanced, mechanically robust materials for biomedical applications. PMID- 28804757 TI - One aptamer, two functions: the full-length aptamer inhibits AMPA receptors, while the short one inhibits both AMPA and kainate receptors. AB - AMPA and kainate receptors, along with NMDA receptors, are distinct subtypes of glutamate ion channels. Excessive activity of AMPA and kainate receptors has been implicated in neurological diseases, such as epilepsy and neuropathic pain. Antagonists that block their activities are therefore potential drug candidates. In a recent article in the Journal of Biological Chemistry by Jaremko et al. 2017, we have reported on the discovery and molecular characterization of an RNA aptamer of a dual functionality: the full-length RNA (101 nucleotide) inhibits AMPA receptors while the truncated or the short (55 nucleotide) RNA inhibits both the AMPA and kainate receptors. The full-length RNA aptamer was isolated through a specially designed, systematic evolution of ligands by exponential enrichment (SELEX) using only a single type of AMPA receptors expressed in HEK-293 cells. The design feature and the results of our recent article are highlighted here, as they demonstrate the utility of the SELEX approach and the potential of using a single AMPA receptor type to develop potent, novel RNA aptamers targeting multiple subunits and AMPA/kainate receptor subtypes with length-dependent functionalities. PMID- 28804759 TI - Updated nomenclature for human and mouse neurofibromatosis type 1 genes. PMID- 28804758 TI - Brain calcifications and PCDH12 variants. AB - OBJECTIVE: To assess the potential connection between PCDH12 and brain calcifications in a patient carrying a homozygous nonsense variant in PCDH12 and in adult patients with brain calcifications. METHODS: We performed a CT scan in 1 child with a homozygous PCDH12 nonsense variant. We screened DNA samples from 53 patients with primary familial brain calcification (PFBC) and 26 patients with brain calcification of unknown cause (BCUC). RESULTS: We identified brain calcifications in subcortical and perithalamic regions in the patient with a homozygous PCDH12 nonsense variant. The calcification pattern was different from what has been observed in PFBC and more similar to what is described in in utero infections. In patients with PFBC or BCUC, we found no protein-truncating variant and 3 rare (minor allele frequency <0.001) PCDH12 predicted damaging missense heterozygous variants in 3 unrelated patients, albeit with no segregation data available. CONCLUSIONS: Brain calcifications should be added to the phenotypic spectrum associated with PCDH12 biallelic loss of function, in the context of severe cerebral developmental abnormalities. A putative role for PCDH12 variants remains to be determined in PFBC. PMID- 28804760 TI - Autopsy case of the C12orf65 mutation in a patient with signs of mitochondrial dysfunction. AB - OBJECTIVE: To describe the autopsy case of a patient with a homozygous 2-base deletion, c171_172delGA (p.N58fs), in the C12orf65 gene. METHODS: We described the clinical history, neuroimaging data, neuropathology, and genetic analysis of the patients with C12orf65 mutations. RESULTS: The patient was a Japanese woman with a history of delayed psychomotor development, primary amenorrhea, and gait disturbance in her 20s. She was hospitalized because of respiratory failure at the age of 60. Pectus excavatum, long fingers and toes, and pes cavus were revealed by physical examination. Her IQ score was 44. Neurologic examination revealed ophthalmoplegia, optic atrophy, dysphagia, distal dominant muscle weakness and atrophy, hyperreflexia at patellar tendon reflex, hyporeflexia at Achilles tendon reflex, and extensor plantar reflexes. At age 60, she died of pneumonia. Lactate levels were elevated in the patient's serum and CSF. T2 weighted brain MRI showed symmetrical hyperintense brainstem lesions. At autopsy, axial sections exposed symmetrical cyst formation with brownish lesions in the upper spinal cord, ventral medulla, pons, dorsal midbrain, and medial hypothalamus. Microscopic analysis of these areas demonstrated mild gliosis with rarefaction. Cell bodies in the choroid plexuses were eosinophilic and swollen. Electron microscopic examination revealed that these cells contained numerous abnormal mitochondria. Whole-exome sequencing revealed the 2-base deletion in C12orf65. CONCLUSIONS: We report an autopsy case of the C12orf65 mutation, and findings suggest that mitochondrial dysfunction may underlie the unique clinical presentations. PMID- 28804761 TI - Unfolding of core nucleosomes by PARP-1 revealed by spFRET microscopy. AB - DNA accessibility to various protein complexes is essential for various processes in the cell and is affected by nucleosome structure and dynamics. Protein factor PARP-1 (poly(ADP-ribose)polymerase 1) increases the accessibility of DNA in chromatin to repair proteins and transcriptional machinery, but the mechanism and extent of this chromatin reorganization are unknown. Here we report on the effects of PARP-1 on single nucleosomes revealed by spFRET (single-particle Forster Resonance Energy Transfer) microscopy. PARP-1 binding to a double-strand break in the vicinity of a nucleosome results in a significant increase of the distance between the adjacent gyres of nucleosomal DNA. This partial uncoiling of the entire nucleosomal DNA occurs without apparent loss of histones and is reversed after poly(ADP)-ribosylation of PARP-1. Thus PARP-1-nucleosome interactions result in reversible, partial uncoiling of the entire nucleosomal DNA. PMID- 28804762 TI - "Super Bowl Babies": Do Counties with Super Bowl Winning Teams Experience Increases in Births Nine Months Later? AB - Following the claim of a highly publicized National Football League (NFL) commercial, we test whether the Super Bowl provides a positive exogenous shock to fertility in counties of winning teams. Using stadium locations to identify teams' counties, we analyze the number of births in counties of both winning and losing teams for ten recent Super Bowls. We also test for state effects and general effects of the NFL playoffs. Overall, our results show no clear pattern of increases in the number of births in winning counties nine months after the Super Bowl. We also do not find that births are affected at the state level or that counties competing in the playoffs are affected. Altogether, these results cast doubt on the NFL's claim that winning cities experience increases in births nine months after the Super Bowl. PMID- 28804764 TI - Building Bridges for Collective Wisdom. PMID- 28804763 TI - Effects of Chest Physical Therapy in Patients with Non-Tuberculous Mycobacteria. AB - Antibiotic therapy against non-tuberculous mycobacteria (NTM) is prolonged and can be associated with toxicity. We sought to evaluate whether chest physical therapy (PT) was associated with clinical improvement in patients with NTM not receiving anti-mycobacterial pharmacotherapy. A retrospective review of 77 subjects that were followed from June 2006 to September 2014 was performed. Baseline time point was defined as the first positive sputum culture for NTM; symptoms, pulmonary function, and radiology reports were studied. Subjects were followed for up to 24 months and results analyzed at specified time points. Half of the subjects received chest PT at baseline. Cough improved at 12 (p = 0.001) and 24 months (p = 0.003) in the overall cohort when compared with baseline, despite lack of NTM antibiotic treatment. Cough decreased at 6 (p = 0.01), 9 (p = 0.02), 12 (p = 0.02) and 24 months (p = 0.002) in subjects that received chest PT. Sputum production also improved at 24 months in the overall cohort (p = 0.01). There was an increase in the percent change of total lung capacity in subjects that received chest PT (p = 0.005). Select patients with NTM may have clinical improvement with chest PT, without being subjected to prolonged antibiotic therapy. Future studies are warranted to prospectively evaluate outcomes in the setting of non-pharmacologic treatment and aid with the decision of antibiotic initiation. PMID- 28804765 TI - Providing Pathology Support in Low-Income Countries. PMID- 28804766 TI - Launching an Interactive Cancer Projects Map: A Collaborative Approach to Global Cancer Research and Program Development. PMID- 28804767 TI - Concurrent Chemoradiation for Cancer of the Cervix: Results of a Multi Institutional Study From the Setting of a Developing Country (India). AB - PURPOSE: The primary output of hospital-based cancer registries is data on cancer stage and treatment-based survival that can be used to evaluate patient care, but because there are many challenges in obtaining follow-up details, a separate study on patterns of care and patterns of survival for patients at selected sites was initiated under the National Cancer Registry Programme of India. This article presents the results for cervical cancer. PATIENTS AND METHODS: A standardized patient information form was used to record patient information, and data were entered into a central repository-the National Centre for Disease Informatics and Research. The study patients were from 12 institutions and were diagnosed between January 1, 2006, and December 31, 2008. Patterns of treatment were assessed for 7,336 patients, and patterns of survival were determined for 2,669 patients from six institutions, at least 70% of whom had data regarding follow-up as of December 31, 2012. RESULTS: Of 7,336 patients, 55.5% received optimal radiotherapy (RT). In all, 80.9% of patients had locally advanced cancers (stage IIB to IVA), 51.1% received RT alone, and 44.4% received concurrent chemoradiation (RTCT). In 1,753 patients with locally advanced cancers, significantly better survival was observed with RTCT than with RT alone (5-year cumulative survival, 70.2% v 47.3%; hazard ratio, 0.48; 95% CI, 0.41 to 0.56). CONCLUSION: A conservative estimate indicates that, on an annual basis, 38,771 patients with cervical cancers in India alone do not get the benefit of RTCT and thus they have poorer survival. There is a need to reiterate the National Cancer Institute's alert that advised supplementing chemotherapy to radiation for locally advanced cancer of the cervix in the context of the developing world, where 84.3% of cancers of the cervix occur. PMID- 28804768 TI - Integration of Palliative Care Into Comprehensive Cancer Treatment at Moi Teaching and Referral Hospital in Western Kenya. AB - PURPOSE: The prognosis for the majority of patients with cancer in Kenya is poor, with most patients presenting with advanced disease. In addition, many patients are unable to afford the optimal therapies required. Therefore, palliative care is an essential part of comprehensive cancer care. This study reviews the implementation of a palliative care service based at the Moi Teaching and Referral Hospital in Eldoret, Kenya, and describes the current scope and challenges of providing palliative care services in an East African tertiary public referral hospital. METHODS: This is a review of the palliative care clinical services at the only tertiary public referral hospital in western Kenya from January 2012 through September 2014. Palliative care team members documented each patient's encounter on standardized palliative care assessment forms; data were then entered into the Academic Model Providing Access to Health Care (AMPATH)-Oncology database. Interviews were also conducted to identify current challenges and opportunities for program improvement. RESULTS: This study documents the implementation of a palliative care service line in Eldoret, Kenya. Barriers to providing optimal palliative cancer care include distance to pharmacies that stock opioids, limited selection of opioid preparations, education of health care workers in palliative care, access to palliative chemoradiation, and limited availability of outpatient and inpatient hospice services. CONCLUSION: Palliative care services in Eldoret, Kenya, have become a key component of its comprehensive cancer treatment program. PMID- 28804769 TI - Cancer Care in Africa: An Overview of Resources. AB - PURPOSE: According to predictions from the International Agency for Research on Cancer, over the next 5 years, the annual number of new cases of cancer in Africa will grow to more than one million. Together with the immense loss in human life, there is a considerable economic setback attached to this number. However, most African nations are far from adequately scaling up their capacity to control cancer. METHODS: This study reviews the published data on the existing cancer control resources in Africa. It is, to our knowledge, the first combined effort looking at all resources available on the continent regarding cancer care. RESULTS: The total number of 102 cancer treatment centers, including general oncology centers, gynecologic oncology or other single-organ malignancy units, and pediatric oncology and palliative care establishments, is not sufficient to cover the increasing needs of the African population affected by cancer. In addition, the continental average total health expenditure per capita amounts to only US$82. CONCLUSION: This review could serve as a starting point for devising realistic solutions meant to improve the prevention and management of malignant disease on the African continent. PMID- 28804770 TI - Novel Humanitarian Aid Program: The Glivec International Patient Assistance Program-Lessons Learned From Providing Access to Breakthrough Targeted Oncology Treatment in Low- and Middle-Income Countries. AB - Imatinib was the first targeted therapy approved for the treatment of cancer. With its approval, it was immediately clear to Novartis that this breakthrough therapy would require an innovative approach to worldwide access, with special consideration of low- and middle-income countries. Lack of government reimbursement, universal health care, or health insurance coverage, few trained specialty physicians or diagnostic services, and poor health care infrastructure were, and continue to be, contributing barriers to access to treatment in low- and middle-income countries. The Glivec International Patient Assistance Program (GIPAP) is an international drug donation program established by Novartis Pharma AG and implemented in partnership with The Max Foundation, a nonprofit, nongovernmental organization. GIPAP was established in 2001, essentially in parallel with the first approval of imatinib for chronic myeloid leukemia. Since 2001, GIPAP has made imatinib accessible to all medically and financially eligible patients within 80 countries on an ongoing basis as long as their physicians prescribe it and no other means of access exists. To date, more than 49,000 patients have benefited from GIPAP, and 2.3 million monthly doses of imatinib have been approved through the program. GIPAP represents an innovative drug donation model that has set the standard for access programs for other targeted or innovative therapies. The purpose of this article is to describe the structure of GIPAP, as well as important lessons that have contributed to the success of the program. This article may assist other companies with the development of successful and far-reaching patient assistance programs in the future. PMID- 28804771 TI - Connecting the Global Cancer Community. PMID- 28804772 TI - Could African and Low- and Middle-Income Countries Contribute Scientifically to Global Cancer Care? PMID- 28804773 TI - Toward a Latin American Cancer Observatory. PMID- 28804774 TI - Global Practice and Efficiency of Multidisciplinary Tumor Boards: Results of an American Society of Clinical Oncology International Survey. AB - PURPOSE: Multidisciplinary tumor boards (MDTBs) are universally recommended, but recent literature has challenged their efficiency. METHODS: The American Society of Clinical Oncology (ASCO) conducted a survey of a randomly selected cohort of international ASCO members. The survey was built on SurveyMonkey and was sent via e-mail to a sample of 5,357 members. RESULTS: In all, 501 ASCO members practicing outside the United States responded, and 86% of them participated in MDTBs at their own institutions. Those who attended represented a variety of disciplines in 70% to 86% of all MDTBs. The majority of MDTBs held weekly specialty and/or general meetings. Eighty-nine percent of 409 respondents attended for advice on treatment decisions. Survey respondents reported changes of 1% to 25% in treatment plans for 44% to 49% of patients with breast cancer and in 47% to 50% of patients with colorectal cancer. They reported 25% to 50% changes in surgery type and/or treatment plans for 14% to 21% of patients with breast cancer and 12% to 18% of patients with colorectal cancer. Of the 430 respondents 96% said overall benefit to patients was worth the time and effort spent at MDTBs, and 96% said that MDTBs have teaching value. Mini tumor boards held with whatever types of specialists were available were considered valid. In all, 94.8% (425 of 448) said that MDTBs should be required in institutions in which patients with cancer are treated. CONCLUSION: MDTBs are commonplace worldwide. A majority of respondents attend them to obtain recommendations, and they report changes in patient management. Change occurred more frequently with nonmedical oncologists and with physicians who had less than 15 years in practice. MDTBs helped practitioners make management decisions. Mini tumor boards may improve time efficiency and are favored when the full team is not available. Suggestions for improving MDTBs included making them more efficient, better selection and preparation of cases, choosing an effective team leader, and improving how time is used, but more research is needed on ways to improve the efficiency of MDTBs. PMID- 28804775 TI - Compliance With Neoadjuvant Chemotherapy in T4 Oral Cancers: Place, Person, Socioeconomic Status, or Assistance. AB - PURPOSE: Approximately 15% to 20% of our patients with head and neck cancer receiving neoadjuvant chemotherapy (NACT) discontinue therapy because of various nonmedical reasons. We sought to analyze the factors associated with treatment default and noncompliance among these patients. PATIENTS AND METHODS: We performed a retrospective analysis of patients with T4 oral cancer treated with NACT between January 2011 and December 2012. We included patients who discontinued treatment for nonmedical reasons before the second cycle of NACT. The factors analyzed were income, education, socioeconomic status, age, sex, place of residence, habits, and payment pattern (government supported or personal capacity). Pearson chi2 test was used to identify significant factors associated with noncompliance. RESULTS: Of 486 patients, 91 patients (18.7%) were noncompliant. Percentages of noncompliant patients in the age groups < 30, between 30 and 60, and > 60 years were 25.0%, 17.4%, and 25.5%, respectively (P = .27). Percentages of noncompliance in patients residing within the city, same state, or different state were 20.7%, 20.9%, and 17.1%, respectively (P = .44). Noncompliance rates were 20.3%, 15.7%, 18.1%, and 22.5% in upper middle, lower middle, upper lower, and lower economic strata, respectively (P = .60). Similarly, there was no significant difference in noncompliance according to occupation, education level, payment pattern, sex, or habits. CONCLUSION: Our analysis failed to identify any specific significant factor associated with noncompliance with NACT among our patients with T4 oral cancers. PMID- 28804776 TI - Risk of Selected Cardiovascular Toxicities in Patients With Cancer Treated With MEK Inhibitors: A Comparative Systematic Review and Meta-Analysis. AB - PURPOSE: We conducted a literature-based meta-analysis of the risk of cardiovascular toxicities associated with MEK inhibitors. METHODS: Eligible trials included randomized phase II and III trials of patients with cancer who were given a mitogen activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor (trametinib, selumetinib, or cobimetinib) and that described events of hypertension and decreased ejection fraction. RESULTS: Our search strategy yielded 300 potentially relevant citations from PubMed/MEDLINE, Google Scholar, and Cochrane Central Register of Controlled Trials. After ineligible studies were excluded, a total of 10 clinical trials were considered eligible for the meta-analysis. The relative risk for all grades of hypertension was 1.54 (95% CI, 1.02 to 2.32; P = .05), 1.85 (95% CI, 1.01 to 3.40; P = .05) for high-grade hypertension, and 4.92 (95% CI, 2.93 to 8.25; P < .001) for decreased ejection fraction. Subgroup analysis revealed no difference between trametinib and selumetinib for risk of hypertension. CONCLUSION: Our meta analysis demonstrated that MEK inhibitor-based treatment is associated with an increased risk of all-grade and high-grade hypertension and asymptomatic decrease in ejection fraction. Clinicians should be aware of this risk and perform regular assessment. PMID- 28804777 TI - International Framework for Cancer Patient Advocacy: Empowering Organizations and Patients to Create a National Call to Action on Cancer. AB - PURPOSE: With the rate of cancer and other noncommunicable diseases (NCDs) growing globally, cancer prevention and control efforts are critical internationally. Moreover, since the 2011 United Nations High-Level Meeting on NCDs, the international health and development community has shifted its awareness to include NCDs as a global health priority, especially in developing countries where mortality rates are disproportionately high. Simultaneously, with the dissemination of the World Cancer Declaration and the evolution of cancer control policies, the international cancer community has recognized the value of engaging patients in reducing the global cancer burden. Cancer advocacy programs that involve patients, survivors, and nongovernmental organizations (NGOs) have increasing opportunities for global impact. METHODS: We developed a framework over 4 years through implementation of two pilot projects. We created a series of trainings and tools to build the capacity of local NGOs and patients to plan and implement a forum for patients with cancer and to create and disseminate a national call to action. The framework was piloted in South Africa from 2009 to 2011 and Japan from 2012 to 2014, and results were measured through postproject surveys completed by members of the collaborative working group and interviews with the in-country partner. RESULTS: The framework is globally relevant and could be adapted and implemented in low- and middle-income countries to amplify patient voices in the policymaking process, increase grassroots mobilization, and improve health systems and infrastructure through addressing patient needs. CONCLUSION: With the dominant paradigm of global health in developing countries which has previously focused on HIV/AIDS, maternal and child health, tuberculosis, and malaria-shifting to adapt to the burgeoning NCD burden, effective patient-centered advocacy frameworks are critical to the success of NCD control. PMID- 28804778 TI - Maggot Debridement Therapy of a Leg Wound From Kaposi's Sarcoma: A Case Report. PMID- 28804780 TI - Show Me My Health Plans: Using a Decision Aid to Improve Decisions in the Federal Health Insurance Marketplace. AB - INTRODUCTION: Since the Affordable Care Act was passed, more than 12 million individuals have enrolled in the health insurance marketplace. Without support, many struggle to make an informed plan choice that meets their health and financial needs. METHODS: We designed and evaluated a decision aid, Show Me My Health Plans (SMHP), that provides education, preference assessment, and an annual out-of-pocket cost calculator with plan recommendations produced by a tailored, risk-adjusted algorithm incorporating age, gender, and health status. We evaluated whether SMHP compared to HealthCare.gov improved health insurance decision quality and the match between plan choice, needs, and preferences among 328 Missourians enrolling in the marketplace. RESULTS: Participants who used SMHP had higher health insurance knowledge (LS-Mean = 78 vs. 62; P < 0.001), decision self-efficacy (LS-Mean = 83 vs. 75; P < 0.002), confidence in their choice (LS Mean = 3.5 vs. 2.9; P < 0.001), and improved health insurance literacy (odds ratio = 2.52, P <0.001) compared to participants using HealthCare.gov. Those using SMHP were 10.3 times more likely to select a silver- or gold-tier plan (P < 0.0001). DISCUSSION: SMHP can improve health insurance decision quality and the odds that consumers select an insurance plan with coverage likely needed to meet their health needs. This study represents a unique context through which to apply principles of decision support to improve health insurance choices. PMID- 28804779 TI - Language Mapping Using T2-Prepared BOLD Functional MRI in the Presence of Large Susceptibility Artifacts-Initial Results in Patients With Brain Tumor and Epilepsy. AB - At present, presurgical functional mapping is the most prevalent clinical application of functional magnetic resonance imaging (fMRI). Signal dropouts and distortions caused by susceptibility effects in the current standard echo planar imaging (EPI)-based fMRI images are well-known problems and pose a major hurdle for the application of fMRI in several brain regions, many of which are related to language mapping in presurgical planning. Such artifacts are particularly problematic in patients with previous surgical resection cavities, craniotomy hardware, hemorrhage, and vascular malformation. A recently developed T2-prepared (T2prep) fMRI approach showed negligible distortion and dropouts in the entire brain even in the presence of large susceptibility effects. Here, we present initial results comparing T2prep- and multiband EPI-fMRI scans for presurgical language mapping using a sentence completion task in patients with brain tumor and epilepsy. In all patients scanned, T2prep-fMRI showed minimal image artifacts (distortion and dropout) and greater functional sensitivity than EPI-fMRI around the lesions containing blood products and in air-filled cavities. This enhanced sensitivity in T2prep-fMRI was also evidenced by the fact that functional activation during the sentence completion task was detected with T2prep-fMRI but not with EPI-fMRI in the affected areas with the same statistical threshold, whereas cerebrovascular reactivity during a breath-hold task was preserved in these same regions, implying intact neurovascular coupling in these patients. Although further investigations are required to validate these findings with invasive methods such as direct cortical stimulation mapping as the gold standard, this approach provides an alternative method for performing fMRI in brain regions with large susceptibility effects. PMID- 28804781 TI - Form and function: Optional complementizers reduce causal inferences. AB - Many factors are known to influence the inference of the discourse coherence relationship between two sentences. Here, we examine the relationship between two conjoined embedded clauses in sentences like The professor noted that the student teacher did not look confident and (that) the students were poorly behaved. In two studies, we find that the presence of that before the second embedded clause in such sentences reduces the possibility of a forward causal relationship between the clauses, i.e., the inference that the student teacher's confidence was what affected student behavior. Three further studies tested the possibility of a backward causal relationship between clauses in the same structure, and found that the complementizer's presence aids that relationship, especially in a forced-choice paradigm. The empirical finding that a complementizer, a linguistic element associated primarily with structure rather than event-level semantics, can affect discourse coherence is novel and illustrates an interdependence between syntactic parsing and discourse parsing. PMID- 28804782 TI - Dopaminergic Medication Increases Reliance on Current Information in Parkinson's Disease. AB - The neurotransmitter dopamine is crucial for decision-making under uncertainty but its computational role is still a subject of intense debate. To test potential roles, we had patients with Parkinson's disease (PD), who have less internally-generated dopamine, participate in a visual decision-making task in which uncertainty in both prior and current sensory information was varied and where behavior is often predicted by Bayesian statistics. We found that many aspects of uncertainty processing were conserved in PD: they could learn the prior uncertainty and utilize both priors and current sensory information. As predicted by prominent theories, we found that dopaminergic medication influenced the weight given to sensory information. However, as PD patients learn, this bias disappeared. In addition, throughout the experiment the patients exhibited lower sensitivity to current sensory uncertainty. Our results provide empirical evidence for the idea that dopamine levels, which are affected by PD and the drugs used for its treatment, influence the reliance on new information. PMID- 28804783 TI - Functional corticostriatal connection topographies predict goal directed behaviour in humans. AB - Anatomical tracing studies in non-human primates have suggested that corticostriatal connectivity is topographically organized: nearby locations in striatum are connected with nearby locations in cortex. The topographic organization of corticostriatal connectivity is thought to underpin many goal directed behaviours, but these topographies have not been completely characterised in humans and their relationship to uniquely human behaviours remains to be fully determined. Instead, the dominant approach employs parcellations that cannot model the continuous nature of the topography, nor accommodate overlapping cortical projections in the striatum. Here, we employ a different approach to studying human corticostriatal circuitry: we estimate smoothly-varying and spatially overlapping 'connection topographies' from resting state fMRI. These correspond exceptionally well with and extend the topographies predicted from primate tracing studies. We show that striatal topography is preserved in regions not previously known to have topographic connections with the striatum and that many goal-directed behaviours can be mapped precisely onto individual variations in the spatial layout of striatal connectivity. PMID- 28804784 TI - Birinapant sensitizes platinum-resistant carcinomas with high levels of cIAP to carboplatin therapy. AB - Platinum drugs are the frontline therapy in many carcinomas, including high-grade serous ovarian cancers. Clinically, high-grade serous carcinomas have an apparent complete response to carboplatin, but tumors invariably recur and response to platinum drugs diminishes over time. Standard of care prohibits re-administration of platinum drugs to these patients who are labeled as having platinum-resistant disease. In this stage patients are treated with non-platinum agents and outcomes are often poor. In vivo and in vitro data presented here demonstrate that this clinical dogma should be challenged. Platinum drugs can be an effective therapy even for platinum-resistant carcinomas as long as they are combined with an agent that specifically targets mechanisms of platinum resistance exploited by the therapy-resistant tumor subpopulations. High levels of cellular inhibitor of apoptosis proteins cIAP1 and 2 (cIAP) were detected in up to 50% of high-grade serous and non-high-grade serous platinum-resistant carcinomas. cIAP proteins can induce platinum resistance and they are effectively degraded with the drug birinapant. In platinum-resistant tumors with >=22.4 ng of cIAP per 20 MUg of tumor lysate, the combination of birinapant with carboplatin was effective in eliminating the cancer. Our findings provide a new personalized therapeutic option for patients with platinum-resistant carcinomas. The efficacy of birinapant in combination with carboplatin should be tested in high-grade serous carcinoma patients in a clinical trial. PMID- 28804785 TI - Periprocedural Antibiotic Prophylaxis for Cardiac Implantable Electrical Device Procedures: Results From a Heart Rhythm Society Survey. PMID- 28804786 TI - Health impact assessment of the UK soft drinks industry levy: a comparative risk assessment modelling study. AB - BACKGROUND: In March, 2016, the UK Government proposed a tiered levy on sugar sweetened beverages (SSBs; high tax for drinks with >8 g of sugar per 100 mL, moderate tax for 5-8 g, and no tax for <5 g). We estimate the effect of possible industry responses to the levy on obesity, diabetes, and dental caries. METHODS: We modelled three possible industry responses: reformulation to reduce sugar concentration, an increase of product price, and a change of the market share of high-sugar, mid-sugar, and low-sugar drinks. For each response, we defined a better-case and worse-case health scenario. We developed a comparative risk assessment model to estimate the UK health impact of each scenario on prevalence of obesity and incidence of dental caries and type 2 diabetes. The model combined data for sales and consumption of SSBs, disease incidence and prevalence, price elasticity estimates, and estimates of the association between SSB consumption and disease outcomes. We drew the disease association parameters from a meta analysis of experimental studies (SSBs and weight change), a meta-analysis of prospective cohort studies (type 2 diabetes), and a prospective cohort study (dental caries). FINDINGS: The best modelled scenario for health is SSB reformulation, resulting in a reduction of 144 383 (95% uncertainty interval 5102 306 743; 0.9%) of 15 470 813 adults and children with obesity in the UK, 19 094 (6920-32 678; incidence reduction of 31.1 per 100 000 person-years) fewer incident cases of type 2 diabetes per year, and 269 375 (82 211-470 928; incidence reduction of 4.4 per 1000 person-years) fewer decayed, missing, or filled teeth annually. An increase in the price of SSBs in the better-case scenario would result in 81 594 (3588-182 669; 0.5%) fewer adults and children with obesity, 10 861 (3899-18 964; 17.7) fewer incident cases of diabetes per year, and 149 378 (45 231-262 013; 2.4) fewer decayed, missing, or filled teeth annually. Changes to market share to increase the proportion of low-sugar drinks sold in the better-case scenario would result in 91 042 (4289-204 903; 0.6%) fewer adults and children with diabetes, 1528 (4414-21 785; 19.7) fewer incident cases of diabetes per year, and 172 718 (47 919-294 499; 2.8) fewer decayed, missing, or filled teeth annually. The greatest benefit for obesity and oral health would be among individuals aged younger than 18 years, with people aged older than 65 years having the largest absolute decreases in diabetes incidence. INTERPRETATION: The health impact of the soft drinks levy is dependent on its implementation by industry. Uncertainty exists as to how industry will react and about estimation of health outcomes. Health gains could be maximised by substantial product reformulation, with additional benefits possible if the levy is passed on to purchasers through raising of the price of high-sugar and mid sugar drinks and activities to increase the market share of low-sugar products. FUNDING: None. PMID- 28804787 TI - Burden of paediatric respiratory syncytial virus disease and potential effect of different immunisation strategies: a modelling and cost-effectiveness analysis for England. AB - BACKGROUND: Vaccines and prophylactic antibodies against respiratory syncytial virus (RSV) are in development and likely to be available in the next 5-10 years. The most efficient way to use these products when they become available is an important consideration for public health decision makers. METHODS: We performed a multivariate regression analysis to estimate the burden of RSV in children younger than 5 years in England (UK), a representative high-income temperate country, and used these results to assess the potential effect of different RSV immunisation strategies (targeting vaccination for infants, or pregnant women, or prophylactic antibodies for neonates). We did a cost-effectiveness analysis for these strategies, implemented either separately or concurrently, and assessed the effect of restricting vaccination to certain months of the year. FINDINGS: We estimated that RSV is responsible for 12 primary care consultations (95% CI 11.9 12.1) and 0.9 admissions to hospital annually per 100 children younger than 5 years (95% CI 0.89-0.90), with the major burden occurring in infants younger than 6 months. The most cost-effective strategy was to selectively immunise all children born before the start of the RSV season (maximum price of L220 [95% uncertainty interval (UI) 208-232] per vaccine, for an incremental cost effectiveness ratio of L20 000 per quality-adjusted life-year). The maximum price per fully protected person that should be paid for the infant, newborn, and maternal strategies without seasonal restrictions was L192 (95% UI 168-219), L81 (76-86), and L54 (51-57), respectively. INTERPRETATION: Nearly double the number of primary care consultations, and nearly five times the number of admissions to hospital occurred with RSV compared with influenza. RSV vaccine and antibody strategies are likely to be cost-effective if they can be priced below around L200 per fully protected person. A seasonal vaccination strategy is likely to provide the most direct benefits. Herd effects might render a year-round infant vaccination strategy more appealing, although it is currently unclear whether such a programme would induce herd effects. FUNDING: UK National Institute for Health Research. PMID- 28804788 TI - Pro-Dopamine Regulator - (KB220) to Balance Brain Reward Circuitry in Reward Deficiency Syndrome (RDS). AB - We are faced with a worldwide opiate/opioid epidemic that is devastating. According to the Centers for Disease Control and Prevention (CDC), at least 127 people, young and old, are dying every day in America due to narcotic overdose. The Food and Drug Administration (FDA) has approved Medication-Assisted Treatments (MATs) for opiate/opioids as well as alcohol and nicotine. The mechanism of action of most MATS favors either blocking of dopaminergic function or a form of Opiate Substitution Therapy (OST). These treatment options are adequate for short-term treatment of the symptoms of addiction and harm reduction but fail long-term to deal with the cause or lead to recovery. There is a need to continue to seek better treatment options. This mini-review is the history of the development of one such treatment; a glutaminergic-dopaminergic optimization complex called KB220. Growing evidence indicates that brain reward circuitry controls drug addiction, in conjunction with "anti-reward systems" as the "anti reward systems" can be affected by both glutaminergic and dopaminergic transmission. KB220 may likely alter the function of these regions and provide for the possible eventual balancing the brain reward system and the induction of "dopamine homeostasis." Many of these concepts have been reported elsewhere and have become an integral part of the addiction science literature. However, the concise review may encourage readership to reconsider these facts and stimulate further research focused on the impact that the induction of "dopamine homeostasis" may have on recovery and relapse prevention. PMID- 28804789 TI - Obesity and Breast Cancer: Do Age, Race and Subtype Matter? AB - Obesity rates within the United States are on the rise. Obesity is a known risk factor for various diseases, including cancer. Numerous studies have linked obesity to the incidence and treatment outcomes of breast cancer. However, the risk of obesity may vary between breast cancer subtypes and different racial or age groups. In this article, we review the literature regarding the impact of obesity on incidence and response for different subtypes of breast cancer within different population groups. PMID- 28804791 TI - Intelligent Mortality Reporting with FHIR. AB - One pressing need in the area of public health is timely, accurate, and complete reporting of deaths and the conditions leading up to them. Fast Healthcare Interoperability Resources (FHIR) is a new HL7 interoperability standard for electronic health record (EHR), while Sustainable Medical Applications and Reusable Technologies (SMART)-on-FHIR enables third-party app development that can work "out of the box". This research demonstrates the feasibility of developing SMART-on-FHIR applications to enable medical professionals to perform timely and accurate death reporting within multiple different jurisdictions of US. We explored how the information on a standard certificate of death can be mapped to resources defined in the FHIR standard (DSTU2). We also demonstrated analytics for potentially improving the accuracy and completeness of mortality reporting data. PMID- 28804790 TI - "It just seems outside my health": How Patients with Chronic Conditions Perceive Communication Boundaries with Providers. AB - To improve care for the growing number of older adults with multiple chronic conditions, physicians and other healthcare providers need to better understand what is most important in the lives of these patients. In a qualitative study of home visits with patients and family caregivers, we found that patients withhold information from providers when communicating about what they deem important to their health and well-being. We examine the various motivations and factors that explain communication boundaries between patients and their healthcare providers. Patients' disclosures reflected perceptions of what was pertinent to share, assumptions about the consequences of sharing, and the influence of interpersonal relationships with providers. Our findings revealed limitations of existing approaches to support patient-provider communication and identified challenges for the design of systems that honor patient needs and preferences. PMID- 28804792 TI - Translational Research Training at Various Levels of Professional Experience to Address Health Disparities. AB - Translational research addressing health disparities brings interventions and medical discoveries into clinical practice to improve health outcomes. However, academic researchers' and clinicians' lack of understanding of methodologies limits the application of basic science to clinical settings. To solve the problem, a multidisciplinary collaboration from two academic institutions offered a workshop building on translational research methodologies to clarify the measures and interventions needed to address health disparities from a research perspective. Three two-day workshops targeted underrepresented minority participants whose research experience and professional development varied. The evaluation surveys administered after the three workshops indicated that workshop 1 which focused on translational and educational research increased participants' knowledge, and made all participants think critically about the subject. Training opportunities focused on translational research can enhance researchers and clinicians' confidence and capabilities to address health disparities. PMID- 28804793 TI - Role of MEK1 in TLR4 Mediated Signaling. PMID- 28804794 TI - Understanding Design Tradeoffs for Health Technologies: A Mixed-Methods Approach. AB - We introduce a mixed-methods approach for determining how people weigh tradeoffs in values related to health and technologies for health self-management. Our approach combines interviews with Q-methodology, a method from psychology uniquely suited to quantifying opinions. We derive the framework for structured data collection and analysis for the Q-methodology from theories of self management of chronic illness and technology adoption. To illustrate the power of this new approach, we used it in a field study of nine older adults with type 2 diabetes, and nine mothers of children with asthma. Our mixed-methods approach provides three key advantages for health design science in HCI: (1) it provides a structured health sciences theoretical framework to guide data collection and analysis; (2) it enhances the coding of unstructured data with statistical patterns of polarizing and consensus views; and (3) it empowers participants to actively weigh competing values that are most personally significant to them. PMID- 28804795 TI - Examining Unlock Journaling with Diaries and Reminders for In Situ Self-Report in Health and Wellness. AB - In situ self-report is widely used in human-computer interaction, ubiquitous computing, and for assessment and intervention in health and wellness. Unfortunately, it remains limited by high burdens. We examine unlock journaling as an alternative. Specifically, we build upon recent work to introduce single slide unlock journaling gestures appropriate for health and wellness measures. We then present the first field study comparing unlock journaling with traditional diaries and notification-based reminders in self-report of health and wellness measures. We find unlock journaling is less intrusive than reminders, dramatically improves frequency of journaling, and can provide equal or better timeliness. Where appropriate to broader design needs, unlock journaling is thus an overall promising method for in situ self-report. PMID- 28804796 TI - Impact of Norepinephrine Shortage on Outcomes in Patients with Septic Shock. AB - PURPOSE: With the previous norepinephrine shortage, alternative agents were required to treat patients with septic shock. This retrospective study evaluated whether the shortage of norepinephrine had an adverse effect on patients admitted to the intensive care unit with a diagnosis of severe sepsis or septic shock. METHODS: This was a retrospective chart review, which compared patients who received norepinephrine versus those who did not. Eligible patients were those >= 18 years old who were admitted to an intensive care unit with a diagnosis of sepsis and were initiated on a vasopressor to maintain hemodynamic stability. The specific primary endpoint was whether using norepinephrine versus other vasopressors had an effect on ICU length of stay. Secondary outcomes included mortality, blood pressure, mean arterial pressure, development of renal insufficiency, and vasopressor requirements. RESULTS: There were 288 patients screened and 214 patients who met the inclusion criteria (norepinephrine group=106 and nonnorepinephrine group=108). After accounting for potential differences in disease severity (APACHE II score), age, weight and gender, there was no difference in ICU length of stay (p=0.4); however, the odds of survival were 5.9 (95% CI: 3.1 to 11.1) times higher for those in the non-norepinephrine group (p<0.0001). CONCLUSION: Based on this retrospective analysis, patients that did not receive norepinephrine had a similar ICU LOS but had a higher rate of survival. The norepinephrine shortage did not have an adverse effect on patient outcomes. PMID- 28804797 TI - Bioactivities of alternative protein sources and their potential health benefits. AB - Increasing the utilisation of plant proteins is needed to support the production of protein-rich foods that could replace animal proteins in the human diet so as to reduce the strain that intensive animal husbandry poses to the environment. Lupins, quinoa and hempseed are significant sources of energy, high quality proteins, fibre, vitamins and minerals. In addition, they contain compounds such as polyphenols and bioactive peptides that can increase the nutritional value of these plants. From the nutritional standpoint, the right combination of plant proteins can supply sufficient amounts of essential amino acids for human requirements. This review aims at providing an overview of the current knowledge of the nutritional properties, beneficial and non-nutritive compounds, storage proteins, and potential health benefits of lupins, quinoa and hempseed. PMID- 28804798 TI - Probing biological redox chemistry with large amplitude Fourier transformed ac voltammetry. AB - Biological electron-exchange reactions are fundamental to life on earth. Redox reactions underpin respiration, photosynthesis, molecular biosynthesis, cell signalling and protein folding. Chemical, biomedical and future energy technology developments are also inspired by these natural electron transfer processes. Further developments in techniques and data analysis are required to gain a deeper understanding of the redox biochemistry processes that power Nature. This review outlines the new insights gained from developing Fourier transformed ac voltammetry as a tool for protein film electrochemistry. PMID- 28804799 TI - Ti2Au2C and Ti3Au2C2 formed by solid state reaction of gold with Ti2AlC and Ti3AlC2. AB - Incorporation of layers of noble metals in non-van der Waals layered materials may be used to form novel layered compounds. Recently, we demonstrated a high temperature-induced exchange process of Au with Si in the layered phase Ti3SiC2, resulting in the formation of Ti3AuC2 and Ti3Au2C2. Here, we generalize this technique showing that Au/Ti2AlC and Au/Ti3AlC2 undergo an exchange reaction at 650 degrees C to form Ti2Au2C and Ti3Au2C2 and determine their structures by electron microscopy, X-ray diffraction, and ab initio calculations. These results imply that noble-metal-containing layered phases should be possible to synthesize in many systems. The metal to be introduced should be inert to the transition metal carbide layers, and exhibit negative heat of mixing with the initial A element in a liquid phase or two-phase liquid/solid region at the annealing temperature. PMID- 28804800 TI - Interfacial rheological properties of self-assembling biopolymer microcapsules. AB - Tuning the mechanical properties of microcapsules through a cost-efficient route of fabrication is still a challenge. The traditional method of layer-by-layer assembly of microcapsules allows building a tailored composite multi-layer membrane but is technically complex as it requires numerous steps. The objective of this article is to characterize the interfacial rheological properties of self assembling biopolymer microcapsules that were obtained in one single facile step. This thorough study provides new insights into the mechanics of these weakly cohesive membranes. Firstly, suspensions of water-in-oil microcapsules were formed in microfluidic junctions by self-assembly of two oppositely charged polyelectrolytes, namely chitosan (water soluble) and phosphatidic fatty acid (oil soluble). In this way, composite membranes of tunable thickness (between 40 and 900 nm measured by AFM) were formed at water/oil interfaces in a single step by changing the composition. Secondly, microcapsules were mechanically characterized by stretching them up to break-up in an extensional flow chamber which extends the relevance and convenience of the hydrodynamic method to weakly cohesive membranes. Finally, we show that the design of microcapsules can be 'engineered' in an extensive way since they present a wealth of interfacial rheological properties in terms of elasticity, plasticity and yield stress whose magnitudes can be controlled by the composition. These behaviors are explained by the variation of the membrane thickness with the physico-chemical parameters of the process. PMID- 28804801 TI - Pancreatic enzyme supplementation after gastrectomy for gastric cancer: a randomized controlled trial. AB - BACKGROUND: Gastrectomy for gastric cancer is a significant cause of secondary exocrine pancreatic insufficiency. Pancreatic enzyme replacement therapy may influence nutritional status and quality of life after gastrectomy, but the pertinent clinical research to date remains controversial. A randomized controlled trial to test this hypothesis was carried out. METHODS: After gastrectomy, 43 patients with gastric cancer were randomly assigned to a normal diet (Normal-d; n = 21) or to a pancreatic enzyme supplementation diet (PES-d; n = 22) and were followed up during a 12-month period, assessing nutritional status and quality of life through body mass index (BMI), instant nutritional assessment (INA) class status, serum pre-albumin (SPA) values, and GastroiIntestinal Quality of Life Index (GIQLI). RESULTS: BMI was not significantly influenced by the type of diet; INA class status was significantly improved in the PES-d arm, particularly during the first 3 months after gastrectomy; SPA levels increased in both arms at 6 months after gastrectomy, reaching significantly higher values in the PES-d arm at 12 months. GIQLI was not significantly influenced by the type of diet throughout the follow-up period; however, this index significantly improved in the PES-d arm between the first and third month after gastrectomy. CONCLUSIONS: PES-d improves nutritional status and quality of life after gastrectomy for gastric cancer, particularly within 3 months from the operation. A larger, multicenter trial is necessary to address the potential influence of several confounding variables such as disease stage and adjuvant treatments. PMID- 28804802 TI - Improvement of glycerol catabolism in Bacillus licheniformis for production of poly-gamma-glutamic acid. AB - Bacillus licheniformis WX-02 is a well-studied strain to produce poly-gamma glutamic acid (gamma-PGA) with numerous applications. This study is to improve WX 02 strain's capability of assimilating glycerol, a major byproduct of biofuels industries, through metabolic manipulation. Through gene knockout, the GlpK pathway was identified as the sole functional glycerol catabolism pathway, while the DhaK pathway was inactive for this strain under either aerobic or anaerobic conditions. The enhancement of glycerol utilization was attempted by substituting the native glpFK promoter with the constitutive promoter (P43), ytzE promoter (PytzE), and bacABC operon promoter (PbacA), respectively. The glycerol consumptions of the corresponding mutant strains WX02-P43glpFK, WX02-PytzEglpFK, and WX02-PbacAglpFK were 30.9, 26.42, and 18.8% higher than that of the WX-02 strain, respectively. The gamma-PGA concentrations produced by the three mutant strains were 33.71, 23.39, and 30.05% higher than that of WX-02 strain, respectively. When biodiesel-derived crude glycerol was used as the carbon source, the mutant WX02-P43glpFK produced 16.63 g L-1 of gamma-PGA, with a productivity of 0.35 g L-1 h-1. Collectively, this study demonstrated that glycerol can be used as an effective substrate for producing gamma-PGA by metabolic engineering B. licheniformis strains. PMID- 28804803 TI - Comparison of sample preparation procedures on metal(loid) fractionation patterns in lichens. AB - The effects of different sample preparation strategies and storage on metal(loid) fractionation trends in plant material is largely underresearched. In this study, a bulk sample of lichen Parmotrema austrosinense (Zahlbr.) Hale was analysed for its total extractable metal(loid) content by ICP-MS, and was determined to be adequately homogenous (<5% RSD) for most elements. Several subsets of this sample were prepared utilising a range of sample preservation techniques and subjected to a modified sequential extraction procedure or to total metal extraction. Both experiments were repeated after 1-month storage at 4 degrees C. Cryogenic freezing gave the best reproducibility for total extractable elemental concentrations between months, indicating this to be the most suitable method of sample preparation in such studies. The combined extraction efficiencies were >82% for As, Cu, Mn, Pb, Sr and Zn but poor for other elements, where sample preparation strategies 'no sample preparation' and 'dried in a desiccator' had the best extraction recoveries. Cryogenic freezing procedures had a significantly (p < 0.05) negative effect on metal extractability, and is therefore inappropriate for sequential extraction procedures in lichens. Biotransformation over a period of a month is suspected for most elements, with the exception of Sr and Zn, where changes in the fractionation patterns were statistically significant (p < 0.05), indicating the need for minimal delay in sample cleaning and preservation when species fractionation patterns are of interest. This study also shows that the assumption that species stability can be ensured through cryopreservation and freeze drying techniques needs to be revisited. PMID- 28804804 TI - Life cycle environmental impacts of bioethanol production from sugarcane molasses in Iran. AB - In recent years, bioethanol from sugarcane molasses has been produced on an industrial scale in Iran. The aim of this study was to evaluate molasses-based bioethanol production from an environmental point of view. Data were collected from Debel Khazai agro-industry situated in southern region of Iran by using face to-face interviews and annual statistics of 2010 to 2016 (6-year life cycle of sugarcane cultivation). Ten impact categories including abiotic depletion (AD), acidification (AC), eutrophication (EP), global warming potential (GWP), ozone layer depletion (OLD), human toxicity (HT), freshwater aquatic ecotoxicity (FE), marine aquatic ecotoxicity (ME), terrestrial ecotoxicity (TE), and photochemical oxidation (PO) were selected based on CML methodology. Inventory data for production of the inputs were taken from Ecoinvent, BUWAL 250, and IDMAT 2001 databases. The results revealed that in sugarcane cultivation process, electricity and trash burning were the most important contributors to all impact categories except OLD and TE. In industrial phase, natural gas had the highest contribution to the most impact categories. Greenhouse gas (GHG) emission for production of 1000 L molasses-based bioethanol was 1322.78 kg CO2 eq. By comparing total GHG emissions from 1000 L bioethanol to gasoline, the net avoided GHG emissions came out at 503.17 kg CO2 eq. According to results, it is clear that with increasing irrigation efficiency and improving performance of heating systems in industrial phase, environmental burdens would be significantly reduced. PMID- 28804805 TI - Acid activation of upper Eocene Ca-bentonite for soybean oil clarification. AB - In central Tunisia, many upper Eocene outcrops supply smectitic claystone which are characterized by several analytical techniques (calcimetry, XRD, SediGraph, chemical analysis, surface area, etc.). Beidellite is the main mineral detected by the XRD method. Representative raw samples M1, taken from Henchir Souar (Zaghouan, Tunisia), were acid activated in order to improve their physicochemical properties. This study consists in optimizing the activation conditions with HCl 3 N by varying the following parameters: time (2, 4, and 6 h) and temperature (25, 50, 75, and 90 degrees C). The characterization by XRD and chemical analysis was carried out on the samples (M1, activated for 2 and 6 h at 75 degrees C), showing a structural modification of the clay by reduction of intensity reflection 001 order of smectite and dissolution of metal ions (Al3+, Fe3+, and Mg2+) from clay structure. Optimum condition for soybean oil clarification is obtained using a variety of amount raw clays (0.5, 0.75, and 1%). Thus, the best clarification yield is given at 0.75% of clay, showing a capacity of about 55%. Various forms of activated materials were used with a 75% proportion to leach soybean oil. Results were compared with commercial bentonite (Tonsil) having surface area (378 m2/g). The activated sample M1 during 4 h at 75 degrees C possesses a decolorizing capacity of about 85% greater than the oil treated by Tonsil in laboratory (58%). PMID- 28804806 TI - How biological background assumptions influence scientific risk evaluation of stacked genetically modified plants: an analysis of research hypotheses and argumentations. AB - Scientific risk evaluations are constructed by specific evidence, value judgements and biological background assumptions. The latter are the framework setting suppositions we apply in order to understand some new phenomenon. That background assumptions co-determine choice of methodology, data interpretation, and choice of relevant evidence is an uncontroversial claim in modern basic science. Furthermore, it is commonly accepted that, unless explicated, disagreements in background assumptions can lead to misunderstanding as well as miscommunication. Here, we extend the discussion on background assumptions from basic science to the debate over genetically modified (GM) plants risk assessment. In this realm, while the different political, social and economic values are often mentioned, the identity and role of background assumptions at play are rarely examined. We use an example from the debate over risk assessment of stacked genetically modified plants (GM stacks), obtained by applying conventional breeding techniques to GM plants. There are two main regulatory practices of GM stacks: (i) regulate as conventional hybrids and (ii) regulate as new GM plants. We analyzed eight papers representative of these positions and found that, in all cases, additional premises are needed to reach the stated conclusions. We suggest that these premises play the role of biological background assumptions and argue that the most effective way toward a unified framework for risk analysis and regulation of GM stacks is by explicating and examining the biological background assumptions of each position. Once explicated, it is possible to either evaluate which background assumptions best reflect contemporary biological knowledge, or to apply Douglas' 'inductive risk' argument. PMID- 28804807 TI - Plasma cortisol response cannot be classically conditioned in a taste-endocrine paradigm in humans. AB - RATIONALE: Peripheral immune responses can be modified by associative learning procedures. Less is known, however, whether and to what extent neuroendocrine parameters can be classically conditioned. OBJECTIVES: In this randomized double blind study, we modified an established paradigm to behaviorally condition endocrine responses in humans. METHODS: Thirty-one healthy male participants received a distinctively flavored green drink as the conditioned stimulus (CS) and intravenous injections of corticotropin-releasing hormone (CRH) (CRH group, N = 17) or NaCl (placebo group, N = 14) as the unconditioned stimulus (US) during two subsequent acquisition trials. Plasma levels of cortisol and noradrenaline, heart rate, and psychological parameters were analyzed before and 15, 30, 60, 120, and 180 min after injection. The two acquisition trials were followed by two evocation trials, during which participants underwent the same procedure but now receiving NaCl injections. RESULTS: CRH administration induced pronounced increases in cortisol and noradrenaline plasma concentrations, heart rate, and anxiety levels. However, re-exposure to the CS during evocations trials did not provoke conditioned increases in neuroendocrine parameters. Median split of the CRH group based on the cortisol baseline level into "cort-high" and "cort-low" subgroups showed that the "cort-high" subgroup displayed a significantly increased cortisol production on evocation days compared to the "cort-low" subgroup and the placebo group. CONCLUSION: This taste-endocrine paradigm employing CRH injection as the US in healthy male volunteers failed to induce a behaviorally conditioned cortisol release as a learned endocrine response. Future studies should clarify a possible role of higher baseline cortisol levels in perhaps facilitating a conditioned cortisol response. PMID- 28804808 TI - Enhanced phosphorus removal in intermittently aerated constructed wetlands filled with various construction wastes. AB - Phosphorus (P) loss by various pathways in constructed wetlands (CWs) is often variable. The effects of intermittent aeration and different construction waste substrates (gravel, red brick, fly-ash brick) on P processing using six batch operated vertical flow constructed wetlands (VFCWs) were studied for decentralized domestic wastewater treatment. Average removal of total phosphorus (TP) in three aerated CWs was markedly higher (21.06, 24.83, and 27.02 mg m-2 day 1, respectively) than non-aerated CWs (10.64, 18.16, and 25.09 mg m-2 day-1, respectively). Fly-ash brick offered superior TP removal efficiency in both aerated and non-aerated batch-operated VFCWs, suggesting its promising application for P removal in CWs. Aeration greatly promoted plant growth and thusly increased plant uptake of P by 0.57-1.45 times. Substance storage was still the main P sink accounting for 23.92-59.47% of TP removal. Other process including microbial uptake was revealed to be a very important P removal pathway (accounting for 14.86-34.84%). The contribution of microbial uptake was also indicated by microbial analysis. Long-term results suggested that the contribution of microbial P uptake could be always ignored and underestimated in most CWs. A combination of intermittent aeration and suitable substrates is effective to intensify P transformation in CWs. PMID- 28804809 TI - Therapeutic Patient Education in Cancer Pain Management: from Practice to Research: Proposals and Strategy of the French EFFADOL Program. AB - In the field of cancer pain, therapeutic patient education (TPE) allows patients to develop skills to better manage their pain. In the Lower Normandy region of France, the management of pain is based on networking, thus allowing proximity and accessibility for all concerned. We have thus designed and initiated a broad five-stage research program that includes the following: (1) training for caregivers in TPE; (2) identifying the educational expectations of patients and their relatives with regard to cancer pain; (3) the design of a TPE program; (4) the evaluation of its quality; and (5) the evaluation of its effectiveness by comparative randomization. This article presents this approach and more particularly the research phases (stages 2, 4, 5) for which the objectives, the methodology, and the expected results are justified. Among the key points, particular attention is paid to the evaluation of the educational dimension that provides patients with self-efficacy to participate actively in the management of their pain, their perception of changes in relation to it and its impact. The choice of a specific assessment criterion (subscale 9 of the Brief Pain Inventory) and of the step-wedge design are thus argued. This approach, which is based on a partnership between health care professionals and researchers, aims to demonstrate the benefits provided by TPE to patients in order to enable them to better manage their pain on a daily basis. PMID- 28804810 TI - Assessing the phytoavailability of arsenic and phosphorus to corn plant after the addition of an acrylic copolymer to polluted soils. AB - Soil pollution by arsenic increases the potential risk of arsenic entrance into the food chain. The usefulness of maleic anhydride- styrene- acrylic acid copolymer on the mobility and phytoavailability of arsenic was evaluated. Treatments were the concentrations of acrylic copolymer (0, 0.05, 0.10, and 0.20% w/w) and the concentrations of soil total arsenic (0, 6, 12, 24, 48, and 96 mg kg 1). Sodium arsenate was added in appropriate amounts to subsamples of an uncontaminated soil to give contaminated soils with different levels of arsenic. The contaminated soils were subjected to a greenhouse experiment using corn as the test crop. The results showed that contamination of soil by arsenic increased the concentrations of soil available arsenic, root and aerial parts arsenic. By the use of acrylic copolymer, the concentration of available arsenic in the soil and the accumulation of arsenic in the root and aerial parts of the corn plant decreased but the dry weights of the root and aerial parts increased significantly. When the concentration of soil total arsenic was 96 mg kg-1, the application of copolymer at the concentration of 0.20% w/w reduced the concentrations of arsenic in soil, root, and aerial parts by 62.53, 43.65, and 37.00% respectively, indicating that application of acrylic copolymer immobilized arsenic in soils. PMID- 28804811 TI - Serum Diamine Oxidase in Pseudoallergy in the Pediatric Population. AB - Histamine intolerance (pseudoallergy) is a poorly investigated type of food hypersensitivity. The main enzyme responsible for histamine degradation in the extracellular matrix is diamine oxidase (DAO). Disturbances in the concentration or activity of DAO may lead to the development of clinical signs of allergy. The aim of the present work was to assess the DAO concentration, peripheral blood morphology, lymphocytes phenotyping (CD3+, CD4+, CD8+, CD19+, NK cells, NKT cells, and activated T-cells), and natural regulatory Treg (nTregs) cell population (CD4+, CD25+, CD127low, and FoxP3) in 34 pediatric patients with histamine-dependent syndromes. Patients were divided into two groups: classical allergy and pseudoallergy on the basis of IgE concentration. The investigation was based on the analysis of peripheral blood samples. A significantly lower serum DAO, both total and specific IgE, concentration was found in the pseudoallergy group compared with the allergy group. There were no significant differences in blood morphology or lymphocyte populations. A similar level of nTreg lymphocytes was also found in both groups, although it was lower than that present in healthy individuals. The findings suggest that the serum DAO is responsible for the symptoms of histamine intolerance. Moreover, a general decrease in nTreg cells in comparison with healthy individuals may lead to symptom aggravation. PMID- 28804812 TI - Predominance of Comorbidities in the Detriment of Daily Activity in Sarcoidosis Patients. AB - Sarcoidosis may affect lung function, working ability, overall mobility, and daily activity. In the present study we performed an analysis of clinical settings in patients with sarcoidosis to disentangle its influence on daily physical activity (PA). PA assessment (number of steps per day, daily energy expenditure) was performed by accelerometry during consecutive 7 days after discharge from hospital. Thirty patients with sarcoidosis, aged 46.4 +/- 10.5, were enrolled in the study. Clinical data (age, gender, steroid consumption, weight, and comorbidities), lung function tests (forced expiratory volume in one second - FEV1, forced vital capacity - FVC, and lung diffusion for carbon monoxide - DLCO), mobility (6-minute walk test - 6 MWT) and physical performance (oxygen consumption at anaerobic threshold - VO2/AT) were estimated. The mean daily PA (5214 +/- 2699 steps/day) and VO2max (22.3 +/- 7.0 ml/kg/min) were lower when referenced to the age-group predicted values. A significant greater daily PA was observed in sarcoidosis patients without comorbidities compared with those having more than two comorbidities (p = 0.046). No association was found between steroid use, lung function, and 6MWT. Daily PA was associated with patients aerobic efficacy and VO2max (r = 0.38, p < 0.04). The findings demonstrate a significant influence of comorbidities on sarcoidosis patients' exercise tolerance and daily PA. Special treatment considerations, including the potential impact of comorbidities, may help optimize exercise regimes, link physical activity with health, and prevent sarcoidosis complications. PMID- 28804813 TI - A systematic review of the clinical applications and complications of bone marrow aspirate concentrate in management of bone defects and nonunions. AB - PURPOSE: Fracture healing encompasses a succession of dynamic multifactorial metabolic events, which ultimately re-establishes the integrity of the biomechanical properties of the bone. Up to 10% of the fractures occurring annually will need additional surgical procedures because of impaired healing. The aim of this article is to review the current literature regarding the use of bone marrow aspirate concentrate (BMAC) and its effectiveness in the management of bone defects. METHODS: We have included all published clinical literature investigating the development, techniques and applications of BMAC. Language, design and risk of bias did not deter the initial inclusion of any study. Our search was exclusively limited to studies involving human subjects. A PRISMA compliant search was carried out as published in 2009. This included the online databases: PubMed, EMBASE, clinical trial.gov and the Cochrane library from 1960 to the end of May 2015. MeSH terms used included: "Bone" AND "Marrow" AND "Aspirate" AND "Concentrate" AND "Bone Defects" AND "NONUNION". Eligible studies were independently appraised by two authors using the Critical Appraisal Skills Program checklist. For the purpose of narrative review, relevant studies were included irrespective of methodology or level of evidence. RESULTS: Thirty-four of the 103 (48 PubMed and 55 EMBASE) results yielded by the preliminary search were included. Exclusions included three duplicate records, six letters, 17 non orthopaedics related studies and four records irrelevant to our search topic. The CASP appraisal confirmed a satisfactory standard of 31 studies. They all had clearly defined objectives, were well designed and conducted appropriately to meet them. The published studies reported the use of BMAC in non-union and fracture healing (15 studies), bone defects (nine studies), spine fusion (two studies), distraction osteogensis (two studies) and complications related to the use of BMAC (seven studies). CONCLUSIONS: Stem cells found in BMAC have the potential to self-renew, undertake clonal expansion and differentiate into different musculoskeletal tissues. The commercial processing of BMAC needs to be optimized in order to achieve a consistent end product, which will provide predicable and translatable results. The future potential of cell characterization in order to determine the optimum cell for repair/regeneration of bone also needs to be explored. LEVEL OF EVIDENCE: Systematic Review of minimum level IV studies. PMID- 28804815 TI - Overview of Hemostasis and Thrombosis and Contribution of Laboratory Testing to Diagnosis and Management of Hemostasis and Thrombosis Disorders. AB - Hemostasis is a complex and tightly regulated process whereby the body attempts to maintain a homeostatic balance to permit normal blood flow, without bleeding or thrombosis. When this balance is disrupted, due to trauma or underlying congenital bleeding or thrombotic disorders, clinical intervention may be required. To assist clinicians in diagnosing and managing affected patients, hemostasis laboratories offer an arsenal of tests, both routine (screening) and more specialized (diagnostic). In general, screening assays are used to screen for hemostasis-related disease or to monitor or measure the effect of anticoagulant therapy, which may be applied to treat patients with recent thrombosis or at risk of thrombosis. Diagnostic assays are used to diagnose or exclude specific hemostasis-related diseases, and in some cases, to monitor or measure the effect of anticoagulant therapy, or alternatively procoagulant therapy that may be applied to those at risk of bleeding. This chapter provides an overview of hemostasis and thrombosis with respect to laboratory tests that may be applied to affected patients. PMID- 28804816 TI - Preanalytical Issues in Hemostasis and Thrombosis Testing. AB - Hemostasis testing is critical to many hemorrhagic and thrombotic disorders, wherein laboratory diagnostics can provide critical information for diagnosis, prognostication, and therapeutic monitoring. Due to this crucial role in modern medicine, hemostasis tests should be carried out at their highest degree of quality, thus encompassing standardization and monitoring of all phases of the testing process. It is now clearly established that the preanalytical phase is the most critical and vulnerable part of the total testing process, since up to 70% of diagnostic errors are due to highly manual activities encompassing patient preparation and collection of biological samples, as well as handling, transportation, preparation and storage of blood specimens. Due to the peculiar sample matrix required for hemostasis testing (i.e., plasma anticoagulated with buffered sodium citrate), additional critical issues may impair the reliability of these tests. Therefore, this article aims to provide an updated overview of the most important preanalytical variables that may ultimately impair the quality of hemostasis and thrombosis testing. PMID- 28804814 TI - Factors associated with cardiovascular target organ damage in children after renal transplantation. AB - BACKGROUND: Cardiovascular disease is the second-most common cause of death in pediatric renal transplant recipients. The aim of this study was to evaluate subclinical cardiovascular target organ damage defined as the presence of arterio and atherosclerotic lesions and cardiac remodeling and to analyze contributing risk factors in a large cohort of children after renal transplantation (RT). METHODS: A total of 109 children aged 13.1 +/- 3.3 years who had undergone RT at one of three German transplant centers were enrolled in this study. Patients had been transplanted a mean of 5.5 (+/-4.0) years prior to being enrolled in the study. Anthropometric data, laboratory values and office- and 24-h ambulatory blood pressure monitoring (ABPM) were evaluated. Cardiovascular target organ damage was determined through non-invasive measurements of aortic pulse wave velocity (PWV), carotid intima-media thickness (IMT) and left ventricular mass (LVM). RESULTS: Elevated PWV or IMT values were detected in 22 and 58% of patients, respectively. Left ventricular hypertrophy was found in as many as 43% of patients. The prevalence of uncontrolled or untreated hypertension was 41%, of which 16% of cases were only detected by ABPM measurements. In the multivariable analysis, higher diastolic blood pressure, everolimus intake and lower estimated glomerular filtration rate were independently associated with high PWV. Higher systolic blood pressure and body mass index were associated with elevated LVM. CONCLUSIONS: Our results showed an alarming burden of cardiovascular subclinical organ damage in children after RT. Hypertension, obesity, immunosuppressive regimen and renal function emerged as independent risk factors of organ damage. Whereas the latter is not modifiable, the results of our study strongly indicate that the management of children after RT should focus on the control of blood pressure and weight. PMID- 28804817 TI - The Interface between Immunotransfusion and Hemostasis and Thrombosis Testing. AB - Increasing evidence supports the existence of a close relationship between immunotransfusion, hemostasis, and thrombosis. The best example of such linkage is given by the influence of the ABO blood group antigens on von Willebrand factor (VWF) plasma levels and activity. It is well known, for instance, that individuals with non-O blood type (i.e., A, B, and AB) have higher VWF and factor VIII plasma levels than O blood type subjects and are consequently exposed to an increased thrombotic risk. There is also a close relationship between immunotransfusion, hemostasis, and thrombosis testing. The first part of this narrative review is dedicated to the issue of the relationship between immunotransfusion, hemostasis, and thrombosis, while the second part is focused on the relationship between immunotransfusion and hemostasis and thrombosis testing, as well as the effects on hemostasis of the transfusion of blood components (i.e., red blood cells, platelet concentrates, and fresh frozen plasma) and plasma-derived products. PMID- 28804818 TI - Optimizing the Verification of Mean Normal Prothrombin Time (MNPT) and International Sensitivity Index (ISI) for Accurate Conversion of Prothrombin Time (PT) to International Normalized Ratio (INR). AB - The Prothrombin Time (PT) assay is the most common test performed in hemostasis laboratories, most commonly as converted to an international normalized ratio (INR) to monitor anticoagulant therapy using vitamin K antagonists (VKAs) such as warfarin. Although the INR is meant to standardize PT values by taking into consideration reagent and instrument variability, substantial inter-laboratory variation in INRs still exists and suggests that this can be further improved. This paper describes the PT test, its conversion to an INR value, and methods to improve the accuracy of INRs by improving the determination of critical components to the INR, namely the mean normal prothrombin time (MNPT) and the international sensitive index (ISI). PMID- 28804819 TI - Performance of Activated Partial Thromboplastin Time (APTT): Determining Reagent Sensitivity to Factor Deficiencies, Heparin, and Lupus Anticoagulants. AB - The activated partial thromboplastin time (APTT) is a useful global assay for the assessment of the contact factor pathway of hemostasis and its inhibitors. The test is usually performed on fully automated analyzers using commercially prepared reagents. The three main clinical areas of interest are detection of factor deficiencies, detection of lupus anticoagulants and in the monitoring of therapy with unfractionated heparin. Methods are described here for assessing APTT reagents for their sensitivity to clotting time prolongation in each of these areas of interest. PMID- 28804820 TI - Performance and Interpretation of Mixing Tests in Coagulation. AB - Mixing tests in coagulation studies allow the laboratory to correctly differentiate factor deficiency from inhibitors as the cause of a prolonged clotting time. This is important in terms of subsequent laboratory follow-up and clinical patient management. In this chapter, a suggested method of performing mixing tests is given, with procedures applying two different formulas for interpretation, the percent correction and the index of circulating anticoagulant. PMID- 28804821 TI - D-Dimer Testing: Laboratory Aspects and Current Issues. AB - D-dimer has become one of the commonly requested coagulation tests, especially in the venous thromboembolism rule out setting. Appropriate D-dimer testing has significantly decreased the number of radiological investigations in this clinical scenario. D-dimer testing also plays an important role in the diagnostic process of the systemic coagulation disorders, especially disseminated intravascular coagulation in conjunction with other coagulation tests. However, widespread D-dimer testing without good understanding of the technical issues related to the test has recently caused some concerns. This review aims to address the basic physiology of D-dimer formation, the different methods available for its routine assessment, the current problems that both clinicians and laboratory scientists face with this test, and the important need for harmonization of commercial immunoassays. PMID- 28804822 TI - Determination of Fibrinogen and Thrombin Time (TT). AB - Fibrinogen is measured in plasma most commonly using the Clauss method, based on the comparison of thrombin clotting times of dilutions of plasma against a plasma standard. Thrombin time (TT) is a coagulation assay, which reflects the conversion of fibrinogen to fibrin after addition of thrombin reagent. Measurement of clottable fibrinogen and TT allows detecting inborn (congenital) and acquired qualitative and quantitative disorders of fibrinogen that can lead to thrombotic or bleeding events. PMID- 28804823 TI - An Overview of Thrombophilia and Associated Laboratory Testing. AB - Venous thromboembolism, usually entailing deep vein thrombosis, pulmonary embolism, or both, is a complex and multifactorial disorder, in which a number of putative conditions interplay and finally contribute to propel the individual risk over a certain degree, so ultimately culminating in the development of venous occlusive disorders. Thrombophilia is commonly defined as a propensity to develop venous thromboembolism on the basis of an underlying hypercoagulable state attributable to inherited or acquired disorders of blood coagulation or fibrinolysis. The thrombophilic conditions are conventionally classified as inherited (or genetically determined) and acquired. The former include deficiencies of natural anticoagulants such as antithrombin, protein C, protein S, increased values of clotting factors (especially factor VIII), as well as prothrombotic polymorphisms in genes encoding for factor V (i.e., factor V Leiden) and prothrombin. The latter conditions mainly entail antiphospholipid antibody syndrome, malignancy, acquired elevations of coagulation factors or acquired reduction of natural inhibitors, or hyperhomocysteinemia. Deepened knowledge of all potential risk factors, as well as the clear understanding of their role in the pathophysiology of venous thrombosis, are both essential to help achieve a faster and more efficient diagnosis of this condition as well as a more effective prophylaxis of patients at higher risk and treatment of those with manifest disease. PMID- 28804824 TI - Laboratory Testing for Activated Protein C Resistance (APCR). AB - Activated protein C resistance (APCR) describes a hemostatic disorder characterized by a poor anticoagulant response to activated protein C (APC). This results in an increased risk of venous thrombosis, including deep vein thrombosis and pulmonary embolism. Protein C is a natural anticoagulant that is synthesized in the liver and is activated to APC via proteolysis. APC then degrades Factors Va and VIIIa. APCR describes the reduced inability of APC to cleave Factors Va and VIIIa, which therefore promotes increased thrombin generation and potentially leads to a prothrombotic state. APCR may be hereditary or acquired. The most common hereditary defect is due to mutations in Factor V, predominantly the Factor V Leiden [FVL] mutation-a G1691A missense mutation at Arginine 506 that results in its replacement by a glutamine [R506Q] and the abolition of an APC inactivation cleavage site in Factor Va. Laboratory testing for APCR may be undertaken by a variety of methods, but this chapter describes an automated procedure using a commercial Russell Viper Venom-based clotting assay, and using CS-5100 and STA-R analyzers. PMID- 28804825 TI - Assessment of Hereditary Thrombophilia: Performance of Protein C (PC) Testing. AB - Protein C (PC) is a plasma Vitamin K-dependent pro-enzyme protein that is synthesized in the liver. Upon activation, PC regulates the coagulation process by neutralizing the procoagulant activities of factors V and VIII in the presence of the cofactor Protein S. PC is a major regulator of the coagulation process. The clotting based Protein C assay, the protocol described in this chapter, quantitates the amount of functional PC present in the specimen in a proportional fashion based on the prolongation of the Activated Partial Thromboplastin Time (APTT). Other methods for assessing PC are also available, including chromogenic and antigenic assays, but protocols for these assays are not provided. PMID- 28804826 TI - Assessment of Hereditary Thrombophilia: Performance of Protein S (PS) Testing. AB - Protein S (PS) is a Vitamin K-dependent protein that functions as a cofactor for the regulation of the coagulation system. PS works in conjunction with Activated Protein C to inactivate factors V and VIII. PS circulates in plasma either complexed to the complement protein, C4b Binding Protein or unbound. The unbound (or free) component is the functional form for the regulation of the coagulation system. PS can be measured in plasma by functional activity, the free (or unbound form) or both free and bound fractions (Total PS). The test most widely used for clinical evaluations is the Free PS Antigen assay (which is the surrogate of PS anticoagulant activity) and represents the protocol described in this chapter. The Free PS Antigen assay is an immunologic assay which specifically measures the unbound fraction of PS in test plasma. Other methods for assessing PS are also available, including PS activity and total PS Antigen assays, but protocols for these assays are not provided. PMID- 28804827 TI - Assessment of Hereditary Thrombophilia: Performance of Antithrombin (AT) Testing. AB - Antithrombin (AT) is a naturally occurring plasma inhibitor of coagulation, which is a synthesized in the liver. AT inhibits coagulation serine proteases (the enzymatically activated forms of the clotting factors), mainly thrombin (factor IIa) and factor Xa, but also to a lesser extent factors IXa, XIa, and XIIa. Acting alone, AT inhibits coagulation factors, but does this very slowly; however, when coupled with heparin as a cofactor, the speed of inhibition is increased many fold. The AT/Heparin complex is the most powerful naturally occurring anticoagulant in blood. AT levels of <70% of normal can cause significant thrombosis. Low levels of AT are caused by inherited genetic defects or acquired causes from other disease states. Plasma AT levels can be determined using a chromogenic assay with either bovine thrombin or human factor Xa as the enzyme. The generated color generated in the assay is inversely proportional to the concentration of AT in the plasma. PMID- 28804828 TI - Lupus Anticoagulant Testing: Diluted Russell Viper Venom Time (dRVVT). AB - Diluted Russell Viper Venom Time (dRVVT) has become the most popular test to detect Lupus Anticoagulant (LA). dRVVT is more sensitive than other global tests employed to detect LA and is not affected by inhibitors of factor VIII or IX. The test is most successfully implemented if you observe three steps in its execution: screening, mixing, and confirmatory studies. Interference due to the presence of heparin in tested plasma must be excluded by means of thrombin time (TT). The prior use of Vitamin K Antagonists (VKAs) or Non-vitamin K Oral Anticoagulants (NOACs) must also be evaluated by means of International Normalized Ratio, or specific tests, respectively. PMID- 28804829 TI - Lupus Anticoagulant Testing: Activated Partial Thromboplastin Time (APTT) and Silica Clotting Time (SCT). AB - Actvated partial thromboplastin time and its congener test Silica clotting time are used for the laboratory detection of lupus anticoagulants. Their performance consists of mixing test plasma with activators of the contact coagulation factors, phospholipids and calcium chloride, and recording the clotting time. Here we describe the principle, performance and extensive practical details of the two methods, the problems that may be encountered and how they can be identified and overcome. PMID- 28804830 TI - Solid Phase Immunoassay for the Detection of Anticardiolipin Antibodies. AB - The anticardiolipin (aCL) test was first developed in the 1980s and proved to be a valuable addition to the lupus anticoagulant assay for identifying patients with a disorder that came to be later known as the antiphospholipid syndrome (APS). Although the test has relatively poor specificity for APS diagnosis, particularly at low positive levels, it has continued to play a major role in the identification and management of these patients because of its high sensitivity and ability to be measured in both serum and plasma, and despite concomitant presence of anticoagulants normally given to APS patients. In this chapter we outline the procedure for producing essential assay components and for performing the aCL ELISA, which can be used to determine the presence of IgG, IgM and IgA aCL antibodies in human samples. We also provide general guidelines that will facilitate optimal performance of the aCL ELISA assay. PMID- 28804831 TI - Solid Phase Immunoassay for the Detection of Anti-beta2 Glycoprotein I Antibodies. AB - The discovery in the 1990s that the protein beta-2-glycoprotein I (beta2GPI) was an antigen of central importance in the antiphospholipid syndrome (APS) was soon followed by the development of ELISA assays capable of identifying anti-beta2GPI antibodies recognizing this antigen. The determination of these antibodies has continued to play a major role in the management of APS patients because of their extremely high specificity for diagnosing the disease, despite their relatively poor sensitivity compared to anticardiolipin antibodies. Additionally, there is abundant evidence of the pathogenic capacity of these antibodies. In this chapter we outline the procedure for producing essential assay components and for performing the anti-beta2GPI ELISA, which can be used to determine the presence of IgG, IgM and IgA anti-beta2GPI antibodies in human samples. We also provide general guidelines that will facilitate optimal performance of the anti-beta2GPI ELISA assay. PMID- 28804832 TI - Measuring Direct Oral Anticoagulants. AB - Direct oral anticoagulants (DOACs) can be quantified using methods that can be performed in any clinical or research laboratory using manual or automated instrument platforms. Dabigatran etexilate, the oral direct thrombin inhibitor, can be quantified by drug-calibrated clot or chromogenic-based assays using either thrombin or ecarin as substrates. Oral direct anti-Xa inhibitors, such as rivaroxaban, apixaban, and edoxaban, can be quantified with drug-calibrated anti Xa kits or reagents as typically used for measuring heparins (unfractionated, low molecular weight, or pentasaccharides). PMID- 28804833 TI - Laboratory Testing Protocols for Heparin-Induced Thrombocytopenia (HIT) Testing. AB - Heparin-induced thrombocytopenia (HIT) represents a significant high morbidity complication of heparin therapy. The clinicopathological diagnosis of HIT remains challenging for many reasons; thus, laboratory testing represents an important component of an accurate diagnosis. Although there are many assays available to assess HIT, these essentially fall into two categories-(a) immunological assays, and (b) functional assays. The current chapter presents protocols for several HIT assays, being those that are most commonly performed in laboratory practice and have the widest geographic distribution. These comprise a manual lateral flow based system (STiC), a fully automated latex immunoturbidimetric assay, a fully automated chemiluminescent assay (CLIA), light transmission aggregation (LTA), and whole blood aggregation (Multiplate). PMID- 28804834 TI - One-Stage Factor VIII Assays. AB - Coagulation factor assays using one-stage methodology are widely used to measure factor levels for the purpose of detecting a deficiency, or to monitor replacement therapy. In this chapter, we focus on a method to measure Factor VIII coagulant activity (FVIII:C) by the one-stage assay (FVIII:C-1), with extra information provided to also allow this method to apply to Factor IX (FIX), Factor XI (FXI), and Factor XII (FXII). From the perspective of laboratory testing, these factors are components of the "intrinsic" coagulation pathway and are all measured in test systems based on the correction of the Activated Partial Thromboplastin Time (APTT). Factor activity is assessed by measuring the ability of an unknown sample to correct the prolonged APTT of factor-deficient plasma (deficient in the factor of interest), relative to the effect of a known calibrator. These assays are used for the diagnosis of the many causes of reduced factor levels, including those causing a prolonged APTT. It is important for laboratory staff to understand the impact of method variations, limitations, and result interpretation and these aspects are also discussed. PMID- 28804835 TI - Chromogenic Factor VIII Assays for Improved Diagnosis of Hemophilia A. AB - Hemophilia A is an inherited bleeding disorder caused by a reduced level of factor VIII coagulant activity (FVIII:C) in blood. Bleeding episodes may occur spontaneously in the severe form of hemophilia or after trauma in the milder forms. It is important that patients are diagnosed correctly, which includes placing them into the correct severity category of the disorder so that appropriate treatment can be given. Diagnosis is made by determination of the amount of FVIII:C in the blood, usually using a one-stage factor VIII:C assay. However, approximately one third of patients with mild or moderate hemophilia will have much lower results by the chromogenic assay, with some of them having normal results by the one-stage assay. The chromogenic factor VIII assay is used in some specialized hemophilia reference centers and is recommended for the diagnosis of mild hemophilia A, as this assay is considered to better reflect the severity status of hemophilia patients than the one-stage assay. PMID- 28804836 TI - Assessment of Factor XIII. AB - Blood coagulation factor XIII (FXIII) is essential for maintaining hemostasis. The absence of FXIII results in severe bleeding diathesis, which without prophylaxis frequently leads to fatal bleeding. As the usual hemostasis screening tests remain normal, the diagnosis of FXIII deficiency needs specific tests. Here, we describe FXIII activity determination by the ammonia release assay, which is the first-line test in the diagnostic algorithm for FXIII deficiency. The method for another activity test, the undeservedly rarely used fibrin cross linking assay, is also presented. Further tests used for the classification of FXIII deficiencies, measurement of FXIII activity in platelets, ELISAs for the measurement of complex plasma FXIII (FXIII-A2B2) antigen and for FXIII-A2 in plasma and platelets are also included. Detailed description of the methods for the detection and measurement of neutralizing auto- and alloantibodies is also provided. PMID- 28804837 TI - Detection and Measurement of Factor Inhibitors. AB - Specific coagulation factor inhibitors, most notably to coagulation factor VIII, can develop in patients with hemophilia after exposure to replacement factor or as an acquired (autoimmune) event. Such inhibitors can be detected by a combination of prolonged coagulation screening tests, such as the activated partial thromboplastin time, plus a non-correcting mixing test. Non-correction may only be evident, or else may be extenuated, with incubation at 37 degrees C. The Bethesda assay for quantitation of inhibitor strength is based on a combination of mixing tests followed by specific factor assays. PMID- 28804838 TI - Platelet Function Tests: Preanalytical Variables, Clinical Utility, Advantages, and Disadvantages. AB - Platelet function tests are mainly used in the diagnostic work-up of platelet disorders. During the last decade, the additional use of platelet function tests to evaluate the effect of antiplatelet therapy has also emerged in an attempt to identify patients with an increased risk of arterial thrombosis. Furthermore, platelet function tests are increasingly used to measure residual effect of antiplatelet therapy prior to surgery with the aim of reducing the risk of bleeding. To a limited extend, platelet function tests are also used to evaluate hyperaggregability as a potential marker of a prothrombotic state outside the setting of antiplatelet therapy. This multifaceted use of platelet function tests and the development of simpler point-of-care tests with narrower application have increased the use of platelet function testing and also facilitated the use of platelet function tests outside the highly specialized laboratories. The present chapter describes the preanalytical variables, which should be taken into account when planning platelet function testing. Also, the most widely used platelet function tests are introduced, and their clinical utility and their relative advantages and disadvantages are discussed. PMID- 28804839 TI - Platelet Function Analyzed by Light Transmission Aggregometry. AB - Analysis of platelet function is widely used for diagnostic work-up in patients with increased bleeding tendency. During the last decades, platelet function testing has also been introduced for evaluation of antiplatelet therapy, but this is still recommended for research purposes only. Platelet function can also be assessed for hyper-aggregability, but this is less often evaluated. Light transmission aggregometry (LTA) was introduced in the early 1960s and has since been considered the gold standard. This optical detection system is based on changes in turbidity measured as a change in light transmission, which is proportional to the extent of platelet aggregation induced by addition of an agonist. LTA is a flexible method, as different agonists can be used in varying concentrations, but performance of the test requires large blood volumes and experienced laboratory technicians as well as specialized personal to interpret results. In the present chapter, a protocol for LTA is described including all steps from pre-analytical preparation to interpretation of results. PMID- 28804840 TI - Whole Blood Platelet Aggregometry. AB - Light transmittance aggregometry is the historical reference method for platelet function testing and continues to be used extensively. Whole blood impedance lumiaggregometry represents an updated methodology that provides for simplified specimen management, an assay milieu that replicates in vivo platelet activation conditions, improved reproducibility, and near-patient testing. While the impedance-based whole blood aggregometer with luminescence channel is becoming the standard for platelet function testing using this methodology, at least three near-patient whole blood instruments are available, each employing its unique technology. We provide descriptions of whole blood lumiaggregometry and three near-patient systems. We include the principle of operation, materials, and stepwise example protocols and speculate on the importance of concordance among the platforms. PMID- 28804841 TI - Assessment of Platelet Function in Whole Blood by Flow Cytometry. AB - Evaluation of platelet function is important for understanding the physiology of hemostasis and thrombosis and is utilized in clinical practice to diagnose inherited and acquired platelet bleeding disorders. Flow cytometry is a powerful tool for rapid evaluation of multiple functional properties of large number of platelets in whole blood and offers many advantages over other traditional methods. Attention to pre-analytical factors is required to ensure biologically valid and robust results. PMID- 28804842 TI - Flow Cytometry Protocols for Assessment of Platelet Function in Whole Blood. AB - Flow cytometry is a powerful tool for rapid evaluation of multiple functional properties of large numbers of platelets in whole blood. In the following chapter, we provide a number of flow cytometry-based protocols broadly aimed at (1) assessment of constitutively expressed platelet membrane receptors to diagnose inherited platelet bleeding disorders and (2) investigation of basal and agonist-induced platelet functional responses including generation of platelet leukocyte aggregates, alpha and dense granule release, calcium flux, and phosphatidylserine exposure. PMID- 28804843 TI - Diagnosis or Exclusion of von Willebrand Disease Using Laboratory Testing. AB - von Willebrand disease (VWD) is a common bleeding disorder diagnosed based on clinical features and following laboratory testing. VWD is due to deficiencies or defects in the plasma protein von Willebrand factor (VWF), a large adhesive protein with multiple activities. Laboratory testing therefore centers on assessment of VWF protein level using VWF antigen (VWF:Ag), as well as assays that measure VWF activity, most notably platelet glycoprotein (GP) Ib and collagen binding (VWF:CB) activities. Decreases in VWF:Ag and VWF activities, as well as the pattern of such changes, help define VWD and its type. Classically, the most often used assay for measuring GPIb binding activity was the ristocetin cofactor assay (VWF:RCo), which historically measured agglutination of fixed human platelets by VWF in the presence of ristocetin. This assay is now often replaced or supplemented with other assays based on binding of VWF to recombinant GPIb, generally without the use of platelets, and with or without ristocetin. This chapter briefly reviews laboratory tests for VWD, as well as recommended approaches to use of such assays to help diagnose or exclude VWD in patients showing clinical features. PMID- 28804844 TI - Laboratory Testing for von Willebrand Factor Antigen (VWF:Ag). AB - von Willebrand disease (VWD) is reportedly the most common inherited bleeding disorder and can also arise as an acquired syndrome (AVWS). These disorders arise due to defects and/or deficiency of the plasma protein von Willebrand factor (VWF). Laboratory testing for the VWF-related disorders requires assessment of both VWF level and VWF activity, the latter requiring multiple assays because of the many functions carried out by VWF to help prevent bleeding. The current paper describes protocols for assessment of VWF level by means of VWF antigen (VWF:Ag). These assays identify VWF levels by quantitative assessment of VWF protein by means of immunological assays. The most commonly performed assays for VWF:Ag comprise enzyme-linked immunosorbent assays (ELISA) and latex-enhanced immunoassays (LIA), as described in this chapter. PMID- 28804845 TI - Laboratory Testing for von Willebrand Factor Collagen Binding (VWF:CB). AB - Von Willebrand disease (VWD) is reportedly the most common inherited bleeding disorder and can also arise as an acquired syndrome (AVWS). These disorders develop due to defects and/or deficiency of the plasma protein von Willebrand factor (VWF). Laboratory testing for the VWF-related disorders requires assessment of both VWF level and VWF activity, the latter requiring multiple assays because of the many functions carried out by VWF to help prevent bleeding. This chapter describes several protocols for assessment of VWF activity by means of VWF collagen binding (VWF:CB). These assays identify VWF activity by quantitative assessment of VWF protein adhesion to collagen or collagen peptides and subsequent immunological detection of the adhered VWF. The most commonly performed assays for VWF:CB comprise enzyme-linked immunosorbent assays (ELISA) and chemiluminescent assay (CLIA), as described in this chapter. PMID- 28804846 TI - Laboratory Testing for von Willebrand Factor Ristocetin Cofactor (VWF:RCo). AB - von Willebrand disease (VWD) is reportedly the most common inherited bleeding disorder and can also arise as an acquired syndrome (AVWS). These disorders develop due to defects and/or deficiency of the plasma protein von Willebrand factor (VWF). Laboratory testing for these VWF-related disorders requires assessment of both VWF level and VWF activity, the latter requiring multiple assays because of the many functions carried out by VWF to help prevent bleeding. The current paper describes several protocols for assessment of VWF activity by means of VWF ristocetin cofactor (VWF:RCo). These assays identify VWF activity by quantitative assessment of VWF protein adhesion to platelets or other particles and subsequent detection of the adhered VWF as facilitated by inclusion of ristocetin. The most commonly performed assays for VWF:RCo comprise platelet agglutination assays, latex agglutination assays, and chemiluminescent assay (CLIA), with three of these described in this chapter. PMID- 28804847 TI - Laboratory Testing for von Willebrand Factor Activity by Glycoprotein Ib Binding Assays (VWF:GPIb). AB - In addition to assessment of von Willebrand factor (VWF) antigen (VWF:Ag), the first-line laboratory investigation of possible von Willebrand disease (VWD) often includes an assay to measure GPIb (glycoprotein Ib) binding activity of VWF. A decreased GPIb binding activity is characteristic for most of the VWD types. For many years, the most frequently used assay for measuring GPIb binding activity was the ristocetin cofactor assay (VWF:RCo), which measures the agglutination of fixed human platelets by VWF in the presence of ristocetin. Because of performance issues, including high assay variability and a lack of VWF sensitivity, this assay is currently being replaced or supplemented by assays based on the binding of VWF to recombinant GPIb. One published method (now abbreviated VWF:GPIbR) uses wild-type GPIb for triggering the binding reaction in the presence of ristocetin. Another more widely used method (now abbreviated VWF:GPIbM) uses gain-of-function GPIb without ristocetin; this permits spontaneous binding of VWF to GPIb and avoids problems associated with the nonphysiological substance ristocetin. The binding of VWF to GPIb can be quantified by using different principles, e.g., ELISA, particle agglutination, or chemiluminescence. The following chapter describes a ristocetin-free method based on particle agglutination in more detail. PMID- 28804848 TI - Laboratory Testing for von Willebrand Factor: Factor VIII Binding (for 2N VWD). AB - Von Willebrand disease (VWD) is reportedly the most common inherited bleeding disorder and can also arise as an acquired syndrome (AVWS). These disorders develop due to defects and/or deficiency of the plasma protein von Willebrand factor (VWF). Laboratory testing for the VWF-related disorders requires assessment of both VWF level and VWF activity, the latter requiring multiple assays because of the many functions carried out by VWF to help prevent bleeding. The current paper describes a protocol for assessment of VWF activity by means of VWF: factor VIII binding (VWF:FVIIIB). Such assays identify VWF activity by quantitative assessment of VWF protein adhesion to FVIII, which is the activity lost in type 2N VWD. This assay is therefore a critical assay for identification or exclusion of 2N VWD. The most commonly performed assays for VWF:FVIIIB comprise enzyme-linked immunosorbent assays (ELISA), and such an assay is described in this chapter. PMID- 28804849 TI - Ristocetin-Induced Platelet Aggregation (RIPA) and RIPA Mixing Studies. AB - Ristocetin-induced platelet aggregation (RIPA) is used as an in vitro test to determine the presence and integrity of the platelet glycoprotein (GP) Ibalpha-V IX complex and von Willebrand factor (VWF) interaction and is usually performed using platelet-rich plasma (PRP). Impairment in the response of VWF/GPIbalpha-V IX is measured with reference to several established concentrations of ristocetin and may indicate defects in VWF or in GPIbalpha-V-IX function. RIPA-based mixing studies comprise an additional approach to testing this interaction to help define whether defects identified by RIPA lie in VWF or in GPIbalpha-V-IX. For example, the correction of an abnormal RIPA trace after mixing PRP with normal plasma and rechallenging with ristocetin at 1.0 mg/mL suggests VWF function/quantity defect. RIPA mixing studies at lower doses of ristocetin (0.5 mg/mL) are recommended for discrimination of von Willebrand disease type 2B (VWD2B) from the rarer platelet-type (PT) VWD and for the phenotypic laboratory diagnosis of VWD2B. The demonstration of a plasma factor capable of inducing platelet aggregation at such low doses of ristocetin represents the hallmark for the phenotypic laboratory diagnosis of VWD2B. Moreover, since both VWD2B and PT VWD may present with thrombocytopenia, RIPA-based mixing studies are also useful in thrombocytopenic patients in whom RIPA testing is difficult to assess. PMID- 28804850 TI - Laboratory Testing for Von Willebrand Factor Multimers. AB - Von Willebrand disease (VWD) is reportedly the most common inherited bleeding disorder and can also arise as an acquired syndrome (AVWS). These disorders develop due to defects and/or deficiency of the plasma protein von Willebrand factor (VWF). Laboratory testing for the VWF-related disorders requires assessment of both VWF level and VWF activity, the latter requiring multiple assays because of the many functions carried out by VWF to help prevent bleeding. As an additional step, an evaluation of VWF structural features by multimer analysis is useful in selective investigations. The current paper therefore describes a protocol for assessment of VWF multimers by gel electrophoresis, thus enabling identification of protein bands that represent differently sized multimers. The sample protocol described in this chapter is the methodology developed by Sebia. PMID- 28804851 TI - Thrombin Generation Assays (TGAs). AB - In recent years, there has been a revival of interest in a time-honored tool of the clotting trade: the thrombin generation curve or thrombin generation (TG) assay (TGA) as we now call it. Thrombin generation is a key coagulation process that determines the extent of a hemostatic plug or a thrombotic process. The recent development of newer tests based on the continuous registration of TG under in vitro conditions that mimic more closely what occurs in vivo prompted us to reinvestigate the balance between procoagulants and anticoagulants in patients. Measurement of TG is accepted as a research tool, but the variety of sources and concentrations of reagents, as well as technical constraints, limit its potential for proper clinical use. The newer TGAs not only provide an overall assessment of hemostasis but also provide promising laboratory tools for investigating hemorrhagic coagulopathies and monitoring replacement therapy in several clinical conditions. PMID- 28804852 TI - The Overall Hemostatic Potential (OHP) Assay. AB - The principle of the overall hemostatic potential (OHP) assay is the generation of a fibrin time curve by optical density readings, which represent the balance between fibrin generation, triggered by thrombin or tissue factor, and fibrinolysis, triggered by tissue plasminogen activator (tPA). OHP measures the integrated effect of procoagulant, anticoagulant, and fibrinolytic factors, and OHP assay parameters provide a means of quantifying both the coagulation and fibrinolytic potential of platelet poor plasma. In particular, the OHP assay can be used to evaluate hypercoagulable states and abnormalities of fibrinolysis which are not well defined by assays which are routinely available in the coagulation laboratory. OHP is a technically simple assay, with potential for application in the routine laboratory at minimal cost. PMID- 28804853 TI - Thromboelastography (TEG). AB - Thromboelastography (TEG) has been used for decades to guide transfusion therapy during cardiac and hepatic surgeries. Renewed interest and improved technology have led to wider applications of TEG in other areas of hemostasis. To correctly interpret the data generated and to validate outcomes, it is important to improve the understanding of the differences in the currently available assay procedures, the issues related to sample activation, and the importance of the use of appropriate controls. Current TEG assays use a variety of samples and can vary slightly in the procedures. In this chapter, we very briefly review TEG applications and discuss interpretations, normal ranges, and reference controls, and we explain the method of TEG run using standard citrated native blood samples. We provide detailed technical steps and tips. We discuss precautions and issues related to the assay, which we hope can guide toward better application and data interpretation. PMID- 28804854 TI - Post-analytical Issues in Hemostasis and Thrombosis Testing. AB - Analytical concerns within hemostasis and thrombosis testing are continuously decreasing. This is essentially attributable to modern instrumentation, improvements in test performance and reliability, as well as the application of appropriate internal quality control and external quality assurance measures. Pre analytical issues are also being dealt with in some newer instrumentation, which are able to detect hemolysis, icteria and lipemia, and, in some cases, other issues related to sample collection such as tube under-filling. Post-analytical issues are generally related to appropriate reporting and interpretation of test results, and these are the focus of the current overview, which provides a brief description of these events, as well as guidance for their prevention or minimization. In particular, we propose several strategies for improved post analytical reporting of hemostasis assays and advise that this may provide the final opportunity to prevent serious clinical errors in diagnosis. PMID- 28804855 TI - Human heart failure with preserved ejection versus feline cardiomyopathy: what can we learn from both veterinary and human medicine? AB - Cardiovascular affections are a growing health burden in human populations. Recent advances in cardiology have improved treatments and outcomes for myocardial infarction and arrhythmias, but other conditions still remain poorly understood. To date, the classical approach to study cardiovascular diseases involves rodent models, despite their strong differences with human cardiac physiology. In this context, this review will focus on the common traits between human and feline cardiac diseases, namely heart failure with preserved ejection fraction and feline cardiomyopathies, respectively. These two affections share similar pathological patterns and epidemiological characteristics. An improved knowledge would be of interest for both human and feline patients and could lead to the establishment of a more accurate treatment and therapeutic strategy for medical doctors and veterinary practitioners. PMID- 28804856 TI - Toxic effects of copper on liver and cholinesterase of Clarias gariepinus. AB - The release of pollutants, especially heavy metals, into the aquatic environment is known to have detrimental effects on such an environment and on living organisms including humans when those pollutants are allowed to enter the food chain. The aim of this study is to analyse the damage to Clarias gariepinus' liver caused by exposure to different concentrations of copper. In the present study, samples of C. gariepinus were exposed to sub-lethal copper sulphate (CuSO4) concentrations (from 0.2 to 20.0 mg/L) for 96 h. Physiological and behavioural alterations were observed with respect to their swimming pattern, mucus secretion and skin colour. Mortality was also observed at high concentrations of copper. Histopathological alterations of the liver were analysed under light, transmission and scanning electron microscopies. The liver of the untreated group showed normal tissue structures, while histopathological abnormalities were observed in the treated fish under light and electron microscopes with increased copper concentrations. Histopathological abnormalities include necrosis, melanomacrophage, hepatic fibrosis and congested blood vessels. In addition, the enzyme activity of liver cholinesterase (ChE) was also found to be affected by copper sulphate, as 100% of cholinesterase activity was inhibited at 20.0 mg/L. Thus, liver enzyme activity and histopathological changes are proven to be alternative sources for biomarkers of metal toxicity. PMID- 28804857 TI - Nobel Prize nominees hundred years ago: Abraham Jacobi (1830-1919) and Otto Heubner (1843-1926). AB - : Pediatrics directly and indirectly played an important role in the history of the Nobel Prize in physiology or medicine. However, the history of the Nobel Prize and pediatrics goes beyond the actual laureates. Based on original files in the archive of the Nobel committee of physiology or medicine at the Karolinska Institute in Sweden, this overview aims to shed new light on why the international pioneers of pediatrics Abraham Jacobi (1830-1919) and Otto Heubner (1843-1926) were nominated but never received the prize in 1918. Moreover, Clemens von Pirquet (1874-1929), one of the founders of this journal in 1910 (previously known as Zeitschrift fur Kinderheilkunde), also appears in the Nobel records during the first decades of the twentieth century, nominated by Heubner and others. CONCLUSION: We argue that studies of Nobel nominations give new opportunities to study not only the selection process for Nobel laureates, but also to explore which pioneers were seen as the most outstanding at a particular point in time and why. What is known? * Recent historical research suggests that Nobel Prize nominations can help to reconstruct trends in medicine over time. What is new? * This paper takes a new approach on the history of pediatrics and shows why the internationally famous pediatricians Abraham Jacobi, New York, and Otto Heubner, Berlin, were runners-up for the Nobel Prize hundred years ago. PMID- 28804858 TI - Effect of feed restriction on intake of Moringa oleifera and Leucaena leucocephala and growth performance of rabbits. AB - Two experiments were conducted to evaluate the effect of feed restriction on intake of Moringa oleifera (MO) or Leucaena leucocephala (LL) and growth of rabbits. In experiment one, 45 rabbits (male and female) weighing 1.18 +/- 0.15 kg were used. They were randomly distributed to three feed restriction treatments (20, 30, and 40%) with 15 rabbits each (9 females and 6 males) and they were offered M. oleifera (MO) ad libitum. In experiment two, 45 growing male rabbits weighing 0.63 +/- 0.113 kg were used. They were randomly assigned to 0, 20, and 30% feed restriction diets, and they have free access to L. leucocephala (LL). Intake of MO increased (P < 0.05) conforming feed restriction increased (40.6, 52.9, and 55.2 g/day of MO for 20, 30, and 40%, respectively). Daily liveweight gain and feed conversion did not differ (P > 0.05), and economic efficiency was similar among treatments. Consumption of LL increased (P < 0.05) in rabbits under the 30% restriction treatment in comparison to that of rabbits restricted 20% (46.0 and 44.4 g/day, respectively). Total feed intake (LL + feed) was highest in 20% restricted rabbits (108.0, 100.8, and 93.2 g/day for 20, 30, and 0%, respectively). Daily liveweight gain and feed conversion were not affected by feed restriction (P > 0.05). Economic efficiency improved twice in feed restricted rabbits (2.0 and 2.3 for 20 and 30%, respectively) in contrast to that of the control 0% group (1.1). The results suggest that rabbits restricted up to 30% and supplemented with either MO or LL did not affect growth performance and reduced feed cost. PMID- 28804859 TI - Fertility Life Table of Tetranychus palmarum Flechtmann & Noronha (Acari: Tetranychidae) in Oil Palm. AB - Some species of spider mites belonging to the Tetranychidae family are known to associate with oil palm (Elaeis guineensis Jacq. - Arecaceae). The occurrence of Tetranychus palmarum Flechtmann & Noronha (Acari, Tetranychidae) was verified on oil palm seedlings under greenhouse conditions in the State of Para in Northern Brazil. Plants with colonies of T. palmarum presented yellowish spots on leaflets and leaves with chlorosis. The objective of this study was to access the biology and fertility life table of T. palmarum in E. guineensis leaves. The experiment was conducted under four constant temperatures, 22, 25, 28, and 31 degrees C, at 70 +/- 10% RH under a 12:12 LD photoperiod. The duration of the egg-to-adult period was 18.4 and 9.8 days, at 22 and 31 degrees C, respectively. The parameters of the fertility life table showed that 28 degrees C is most suitable for the development and reproduction of T. palmarum, with higher values for reproductive parameters (R o , r m , and lambda) and lower values for duplicating the population (TD). Therefore, it is apparent that the best temperature conditions for the development of T. palmarum are found in the warmer regions of Brazil, such as those observed in northern Brazil. PMID- 28804861 TI - Trends and socioeconomic inequalities in amenable mortality in Switzerland with international comparisons. AB - BACKGROUND: Amenable mortality is a composite measure of deaths from conditions that might be avoided by timely and effective healthcare. It was developed as an indicator to study health care quality. METHODS: We calculated mortality rates for the population aged 0-74 years for the time-period 1996-2010 and the following groups of causes of death: amenable conditions, ischaemic heart diseases (IHD, defined as partly amenable) and remaining conditions. We compared the Swiss results with those published for 16 other high-income countries. To examine the association between amenable mortality and socioeconomic position, we calculated hazard ratios (HRs) by using Cox regression. RESULTS: Amenable mortality fell from 49.5 (95% confidence interval [CI] 48.2-51.0) to 35.7 (34.6 36.9) in males and from 55.0 (53.6-56.4) to 43.4 (42.2-44.6) per 100 000 person years in females, when 1996-1998 was compared with 2008-2010. IHD mortality declined from 64.7 (95% CI 63.1-66.3) to 33.8 (32.8-34.8) in males and from 18.0 (17.2-18.7) to 8.5 (8.0-9.0) in females. However, between 1996-1998 and 2008-2010 the proportion of all-cause mortality attributed to amenable causes remained stable in both sexes (around 12% in males and 26% in females). Compared with 16 other high-income countries, Switzerland had the lowest rates of amenable mortality and ranked among the top five with the lowest ischaemic heart disease mortality. HRs of amenable causes in the lowest socioeconomic position quintile were 1.77 (95% CI 1.66-1.90) for males and 1.78 (1.47-2.16) for females compared with 1.62 (1.58-1.66) and 1.38 (1.33-1.43) for unamenable mortality. For ischaemic heart disease, HRs in the lowest socioeconomic position quintile were 1.76 (95% CI 1.66-1.87) for males and 2.33 (2.07-2.62) for females. CONCLUSIONS: Amenable mortality declined substantially in Switzerland with comparably low death rates for amenable causes. Similar to previous international studies, these Swiss results showed substantial socioeconomic inequalities in amenable mortality. Proportions of amenable mortality remained constant over time and patterns of inequalities observed for amenable causes in men did not substantially differ from those observed for non-amenable causes of death. Additional amenable mortality research is needed to better understand the factors contributing to mortality changes and social inequalities including information on disease characteristics and health care supply measures. PMID- 28804860 TI - Temperature drop and the risk of asthma: a systematic review and meta-analysis. AB - The relationship between asthma and temperature changes remains controversial. The aim of this study was to investigate the association between temperature changes and the risk of asthma. A total of 26 studies (combined total number of subjects N > 26 million), covering 13 countries and Costa Rica, were identified by using a series of keywords in different combinations and searching the papers in PubMed, EMBSEA, Web of Science, MEDLINE, AIM, LILACS, and WPRIM before February 2016. Most of the papers were published in English. Random-effects meta analyses were performed to evaluate the effect of temperature drop on risk of asthma. Several secondary analyses were also calculated based on stratification for different age, season, latitude, and region on risk of asthma. The odds ratio (OR) estimate between temperature drop and asthma was 1.05 (95% CI 1.02, 1.08) in the meta-analysis. For children, the overall OR was 1.09 (95% CI 1.03, 1.15). Dose-effect analyses showed stronger associations in asthma risk for each 1 degrees 1 degrees C decrement in short-term temperature (OR 1.055, 95% CI 1.00, 1.11). Further stratifications showed that winter (OR 1.03, 95% CI 1.01, 105) and low latitude (OR 1.72, 95% CI 1.23, 2.41) have a statistically significant association with the increased risk of asthma. Exposure of people to short-term temperature drop (per 1 degrees C decrement) was significantly associated with the risk of lower respiratory tract infections (LRTI) with asthma (OR 1.02, 95% CI 1.00, 1.04). Results suggest an adverse effect of temperature drop on asthma risk, especially in children and low-latitude areas. It may be opportune to consider the preventive actions against temperature drop, including simple face masks, to decrease the risk of asthma. PMID- 28804862 TI - Oncological patients in the intensive care unit: prognosis, decision-making, therapies and end-of-life care. AB - The effectiveness of intensive care unit (ICU) care for cancer patients remains controversial. Advances in antitumour and supportive care led to major improvements in outcomes of oncological patients in the ICU. Improved cancer therapies and supportive management of organ dysfunctions have contributed to improved survival rates. As a consequence, the number of cancer patients requiring ICU admission is rising. Frequently, cancer patients have a poor performance status and are vulnerable. It is a heterogeneous population, where the nature and curability of the neoplasm and the severity of critical illness cause a plethora of issues about ICU admissions. Therefore, oncological patients are often considered inappropriate for ICU admission. So far, no specific severity-of-illness scoring system can reliably predict the outcome of critically ill oncological patients and scoring systems or survival predictors are lacking. The major determinants of mortality and prognosis are the number of organ failures, need of mechanical ventilation (especially for acute respiratory distress syndrome), vasopressor support (>4 hours) and therapies that have preceded ICU admission. The underlying neoplasm seems to have a little impact on the outcome. The most frequent reasons leading a cancer patient to ICU are postoperative recovery, respiratory failure, infection and sepsis. To date, scientific reports suggest that acute organ dysfunction should be managed at its onset, preferably within 2 hours after the admission, whereas further aggressive ICU management should be reappraised after a few days of full support. Prognosis should be reassessed at frequent intervals with particular attention to the development of multiple organ dysfunctions. Discussing the code status is a sensitive matter and should be balanced between the patient's wish and objective medical outcome assessment. The latter can only be achieved in a multidisciplinary team of intensivists, oncologists/haematologists and potentially palliative care experts, preferably by consensus. Transition from restorative to palliative care should be made when there is no benefit from further intensive treatment, there is no trend to recovery in the first days of intensive care and where symptom palliation would improve the quality of life. Patients' autonomy and dignity should remain paramount in any decision-making. Current data do not support any absolute criteria for triaging. Establishment of clear goals and approach to admit and treatment for oncological patients in the ICU are however urgently needed. This requires further prospective studies for independent validation in different medical settings and identifying prognostic tools that can aid with decision-making and patient selection for ICU. Cancer should not be seen as an exclusion criterion and priority should be given to assure the quality of life of oncological patients. PMID- 28804863 TI - Personalised immunomodulating treatments for Graves' disease: fact or fiction? AB - Although Graves' disease has been recognised for more than 100 years, its physiopathological mechanisms are incompletely understood. Treatment strategies today mainly focus on suppression of thyroid hormone production by use of antithyroid drugs or radio-iodine, but neglect the underlying immunological mechanisms. Although Graves' disease is often seen as a prototype for an autoimmune mechanism, it is more likely to be a heterogeneous syndrome showing characteristics of both autoimmunity and immunodeficiency. The interplay of these two mechanisms may well characterise the physiopathology of this disease and its complications. Immunodeficiency may be either genetically determined or secondarily acquired. Various triggering events lead to autoimmunity with stimulation of the thyroid gland resulting in the clinical syndrome of hyperthyroidism. Also, relapse risk differs from patient to patient and can be estimated from clinical parameters incorporated into the Graves' Recurrent Events After Therapy (GREAT) score. Accurate risk stratification may help to distinguish high-risk patients for whom a more definitive treatment approach should be used from others where there is a high probability that the disease will recover with medical treatment alone. Several smaller trials having found positive effects of immunosuppressive drugs on recurrence risk in Graves' disease; therefoore, there is great potential in the use of novel immunomodulating drugs in addition to the currently used antithyroid drugs for the successful treatment of this condition. Further in-depth exploration of susceptibility, triggering factors and immunological mechanisms has the potential to improve treatment of Graves' disease, with more personalised, risk-adapted treatment strategies based on the different physiopathological concepts of this heterogeneous condition. PMID- 28804864 TI - Prescription and indication for oral nutritional supplements in a Swiss university hospital: a prospective survey. AB - AIMS OF THE STUDY: Patients with an acute or chronically negative nutritional balance are at nutritional risk. Oral nutritional supplements (ONS) are simple and effective medical treatments of nutritional risk. In the ambulatory setting, in Switzerland, ONS are reimbursed by public insurance under conditions defined by Swiss Society for Clinical Nutrition. The reimbursement requires a medical prescription for ONS and their delivery at the patient's home by a homecare service. The indication for the ONS, defined as a Nutritional Risk Screening-2002 (NRS-2002) score >=3, must also be present. This survey aimed to document: (i) the existence of a medical prescription for ONS during hospitalisation and discharge for home, (ii) the adequacy of the indication for ONS during hospitalisation and at discharge for home, and (iii) the continuation or not of ONS treatment 1 month after discharge for home. METHODS: This prospective survey included adult patients hospitalised in the departments of surgery, medicine or rehabilitation and who were about to receive ONS for the first time. Patients already on ONS, with major consciousness disorders, who refused to take ONS or to participate to the survey were excluded. The existence of a medical prescription for ONS and the adequacy of the indication (Nutritional Risk Screening-2002 [NRS 2002] score >=3) were evaluated at first ONS delivery and at hospital discharge. At home, the continuation of ONS consumption was evaluated by the homecare service 1 month after discharge. Results are presented as mean +/- standard deviation or frequencies and percentages, and comparisons between patients with and without ONS at discharge for home. RESULTS: A total of 416 patients (age 71.7 +/- 14.1 yr, 52.6% male, body mass index 23.6 +/- 5.2 kg/m2) were included. At the first delivery of ONS, 44.5% (n = 185) of patients had no medical prescription for the supplements, and 82.7% (n = 344) had an NRS-2002 score >=3. Out of 207 patients discharged for home, only 24.2% (n = 50) had an adequate homecare ONS prescription and 68% (n = 141) had a NRS-2002 score >=3. One month after discharge for home, 76% (n = 29) were still taking ONS. CONCLUSIONS: In our survey, only few patients receiving ONS during the hospital stay had a medical prescription for ONS during the hospitalisation and at discharge for home. For most patients receiving ONS during hospitalisation and at discharge for home, an NRS-2002 score of >=3 was present. If a medical prescription was provided, ONS were generally continued one month after discharge for home. CLINICAL TRIAL REGISTRATION NUMBER: NCT02476110. PMID- 28804865 TI - Value of the Pitt Bacteraemia Score to predict short-term mortality in Staphylococcus aureus bloodstream infection: a validation study. AB - BACKGROUND AND AIMS: The widely used Pitt Bacteraemia Score (PBS) has repeatedly been described as a risk factor for short-term mortality in Staphylococcus aureus bloodstream infection (BSI), but little is known about its overall predictive performance. We therefore aimed to externally validate the PBS in S. aureus BSIs. METHODS: We performed a retrospective validation study at the University Hospital Basel. Adult patients with a first episode of methicillin-susceptible S. aureus BSI between January 2008 and December 2013 were eligible for the study. We measured the overall discriminative power of the PBS at day of BSI onset in predicting 30-day all-cause mortality by receiver-operating characteristics analysis. For each PBS cut-off, we calculated the corresponding sensitivity, specificity and predictive values for prediction of 30-day all-cause mortality. RESULTS: A total of 329 patients were included in the final analysis: The median PBS at BSI onset was 0 (interquartile range, 0-2) with patients suffering from various comorbidities (Charlson Comorbidity Index median 3, interquartile range 1 5). Thirteen percent of patients (43/329) died within 30 days from any cause. At BSI onset, 52% (170/329) of patients had a PBS of zero; the concomitant specificity and positive predictive value for prediction of 30-day all-cause mortality were 0% and 13%, respectively. The overall performance of the PBS in predicting the 30-day all-cause mortality was lower than published, with an area under the curve of 0.711 (95% confidence interval 0.614-0.807; p <0.001). CONCLUSIONS: For short-term mortality, the PBS had a low predictive value in a patient population with methicillin-susceptible S. aureus BSI. There is a need to improve simple clinical scores to better predict mortality, in particular for S. aureus. PMID- 28804866 TI - Virally vectored vaccine delivery: medical needs, mechanisms, advantages and challenges. AB - Vaccines represent one of the most successful chapters in the history of medicine. Over the past decades, the advent of recombinant cDNA technology has enabled the biomedical community to genetically engineer viruses for vaccine delivery purposes. As a starting point, this review evaluates the unmet medical needs, which drive scientists and industry to exploit such fundamentally new technology for human vaccination. The author discusses the molecular functioning, production and safety profile of replication-competent and -deficient viral vector systems, representing two fundamentally distinct classes of "genetic vaccines". Building upon this knowledge, he dissects the immunological mechanisms rendering immune responses to viral vectors qualitatively and quantitatively distinct from those elicited by non-live vaccination approaches. These mechanisms comprise (1) the vectors' innate immune recognition by the host cell, (2) potent priming of CD8+ cytotoxic T cells as a result of dendritic cell targeting and endogenous protein synthesis, (3) conformational antigen display for protective antibody induction as well as (4) prolonged availability of substantial quantities of antigen. Deduced from these features, preferential indications for virally vectored vaccines are discussed, taking into consideration specific medical needs as well as risk-benefit assessments of replicating vector systems. The limitations and challenges in virally vectored vaccination must also be given careful consideration. Pre-existing and vaccination-induced anti-vector immunity can interfere with vaccine immunogenicity and prime-boost vaccination, respectively. Additionally, the requirement for eukaryotic production systems imposes technological as well as regulatory hurdles. Existing strategies to overcome these challenges are outlined. With the recent licensure of the first virally vectored vaccine this review seems timely to herald the introduction of virally vectored vaccines into daily medical practice. PMID- 28804867 TI - Sources of distress for physicians and nurses working in Swiss neonatal intensive care units. AB - BACKGROUND: Medical personnel working in intensive care often face difficult ethical dilemmas. These may represent important sources of distress and may lead to a diminished self-perceived quality of care and eventually to burnout. AIMS OF THE STUDY: The aim of this study was to identify work-related sources of distress and to assess symptoms of burnout among physicians and nurses working in Swiss neonatal intensive care units (NICUs). METHODS: In summer 2015, we conducted an anonymous online survey comprising 140 questions about difficult ethical decisions concerning extremely preterm infants. Of these 140 questions, 12 questions related to sources of distress and 10 to burnout. All physicians and nurses (n = 552) working in the nine NICUs in Switzerland were invited to participate. RESULTS: The response rate was 72% (398). The aspects of work most commonly identified as sources of distress were: lack of regular staff meetings, lack of time for routine discussion of difficult cases, lack of psychological support for the NICU staff and families, and missing transmission of important information within the caregiver team. Differences between physicians' and nurses' perceptions became apparent: for example, nurses were more dissatisfied with the quality of the decision-making process. Different perceptions were also noted between staff in the German- and French- speaking parts of Switzerland: for example, respondents from the French part rated lack of regular staff meetings as being more problematic. On the other hand, personnel in the French part were more satisfied with their accomplishments in the job. On average, low levels of burnout symptoms were revealed, and only 6% of respondents answered that the work related burden often affected their private life. CONCLUSIONS: Perceived sources of distress in Swiss NICUs were similar to those in ICU studies. Despite rare symptoms of burnout, communication measures such as regular staff meetings and psychological support to prevent distress were clearly requested. PMID- 28804868 TI - Chronic obstructive pulmonary disease - importance of active case finding and consideration of comorbidities. PMID- 28804869 TI - Myelodysplastic Syndrome and Giant Cell Arteritis: A Nonfortuitous Association that Geriatricians Should Know About. PMID- 28804871 TI - First evaluation of the Behavioral Addiction Indoor Tanning Screener (BAITS) in a nationwide representative sample. AB - BACKGROUND: Evidence suggests that indoor tanning may have addictive properties. However, many instruments for measuring indoor tanning addiction show poor validity and reliability. Recently, a new instrument, the Behavioral Addiction Indoor Tanning Screener (BAITS), has been developed. OBJECTIVES: To test the validity and reliability of the BAITS by using a multimethod approach. METHODS: We used data from the first wave of the National Cancer Aid Monitoring on Sunbed Use, which included a cognitive pretest (August 2015) and a Germany-wide representative survey (October to December 2015). In the cognitive pretest 10 users of tanning beds were interviewed and 3000 individuals aged 14-45 years were included in the representative survey. Potential symptoms of indoor tanning addiction were measured using the BAITS, a brief screening survey with seven items (answer categories: yes vs. no). Criterion validity was assessed by comparing the results of BAITS with usage parameters. Additionally, we tested internal consistency and construct validity. RESULTS: A total of 19.7% of current and 1.8% of former indoor tanning users were screened positive for symptoms of a potential indoor tanning addiction. We found significant associations between usage parameters and the BAITS (criterion validity). Internal consistency (reliability) was good (Kuder-Richardson-20, 0.854). The BAITS was shown to be a homogeneous construct (construct validity). CONCLUSIONS: Compared with other short instruments measuring symptoms of a potential indoor tanning addiction, the BAITS seems to be a valid and reliable tool. With its short length and the binary items the BAITS is easy to use in large surveys. PMID- 28804870 TI - Effect of the Tool to Reduce Inappropriate Medications on Medication Communication and Deprescribing. AB - OBJECTIVES: To examine the effect of the Tool to Reduce Inappropriate Medications (TRIM), a web tool linking an electronic health record (EHR) to a clinical decision support system, on medication communication and prescribing. DESIGN: Randomized clinical trial. SETTING: Primary care clinics at a Veterans Affairs Medical Center. PARTICIPANTS: Veterans aged 65 and older prescribed seven or more medications randomized to receipt of TRIM or usual care (N = 128). INTERVENTION: TRIM extracts information on medications and chronic conditions from the EHR and contains data entry screens for information obtained from brief chart review and telephonic patient assessment. These data serve as input for automated algorithms identifying medication reconciliation discrepancies, potentially inappropriate medications (PIMs), and potentially inappropriate regimens. Clinician feedback reports summarize discrepancies and provide recommendations for deprescribing. Patient feedback reports summarize discrepancies and self-reported medication problems. MEASUREMENTS: Primary: subscales of the Patient Assessment of Care for Chronic Conditions (PACIC) related to shared decision-making; clinician and patient communication. Secondary: changes in medications. RESULTS: 29.7% of TRIM participants and 15.6% of control participants provided the highest PACIC ratings; this difference was not significant. Adjusting for covariates and clustering of patients within clinicians, TRIM was associated with significantly more-active patient communication and facilitative clinician communication and with more medication-related communication among patients and clinicians. TRIM was significantly associated with correction of medication discrepancies but had no effect on number of medications or reduction in PIMs. CONCLUSION: TRIM improved communication about medications and accuracy of documentation. Although there was no association with prescribing, the small sample size provided limited power to examine medication-related outcomes. PMID- 28804872 TI - Lacosamide in the treatment of patients with epilepsy and intellectual disabilities: A long-term study of 136 patients. AB - OBJECTIVE: This study aimed to analyze the retention rate of lacosamide (LCM) in patients with epilepsy and intellectual disabilities (IDs), to identify factors influencing retention rate, and to investigate the LCM retention rate with and without concomitant sodium channel blocker (SCB). We hypothesized that the retention rate of LCM with concomitant SCB would be lower than without SCB. METHODS: Using the Kaplan-Meier estimator, we conducted a monocentric, retrospective, observational, open-label study to evaluate LCM retention rates in patients with IDs and drug-resistant epilepsy. In addition, the impact of therapy related variables on the long-term retention of LCM was evaluated. RESULTS: One hundred thirty-six subjects with IDs and drug-resistant epilepsy were included (age 2-66 years); most patients had focal epilepsy. Long-term retention rates were 62.0% at 1 year, 43.7% at 2 years, and 29.1% at 3 and 4 years. Reasons for LCM discontinuation included insufficient therapeutic benefits (69%), adverse events (11%), or a combination of both factors (8%). The LCM retention rate was influenced by the number of background antiepileptic drugs (AEDs). An additional and independent influence of concomitant therapy with SCB on retention rate could not be confirmed. SIGNIFICANCE: One of the major challenges in medically caring for patients with epilepsy and IDs is the high rate of drug resistance. However, there is a lack of evidence-based information about the efficacy and tolerability of AEDs in this population. It has been shown that concomitant SCB use is a key factor in increasing the risk of LCM failure in children with epilepsy. This finding has not been replicated in our predominantly adult sample of patients with IDs. PMID- 28804873 TI - Re: Frontal Fibrosing Alopecia Severity Index (FFASI): a call for a more inclusive and globally relevant severity index for frontal fibrosing alopecia: reply from the authors. PMID- 28804874 TI - High frequency jet ventilation for motion management during ablation procedures, a narrative review. AB - BACKGROUND: High frequency jet ventilation (HFJV) is a method of ventilation that has gained renewed interest over the recent years as it can reduce organ movement to near static conditions, thus enhancing surgical precision in minimal invasive procedures, for example, ablation procedures for atrial fibrillation and solid organ tumours. The aim of this review was to create a summary of the current evidence concerning the clinical use of HFJV for ablative procedures. METHOD: PubMed was searched for the key words high frequency ventilation and ablation January 1990-December 2016. RESULT: The search initially identified 34 papers, 14 met the inclusion criteria. Articles in other languages than English (n = 1), comments regarding other articles (n = 4) and articles that did not include HFJV or ablative procedures (n = 15) were excluded. Two articles were added from references in papers included from the primary search. Sixteen studies were finally included in the review; four updates/reviews and 12 papers with results from studies of HFJV on humans, with a total of 889 patients; 498 patients ventilated with HFJV and 391 controls. There were no randomised studies. The overall scientific quality of the studies was low. CONCLUSION: There is a lack of well-designed studies evaluating HFJV during ablation procedures. The available information, while sparse, supports the effect of less tissue movement, resulting in better surgical precision and outcome; such as shorter procedural time, fewer shock waves (ESWL) and less recurrence of atrial fibrillation. Randomised controlled studies are needed in this promising area of research to prove its superiority to standard ventilation. PMID- 28804875 TI - Prehospital pathways of occipital stroke patients with mainly visual symptoms. AB - OBJECTIVES: Occipital ischemic strokes typically cause homonymous visual field defects, for which means of rehabilitation are limited. Intravenous thrombolysis is increasingly and successfully used for their acute treatment. However, recognition of strokes presenting with mainly visual field defects is challenging for both patients and healthcare professionals. We studied prehospital pathways of occipital stroke patients with mainly visual symptoms to define obstacles in their early recognition. MATERIALS & METHODS: This observational, retrospective, registry-based study comprises occipital stroke patients with isolated visual symptoms treated at the neurological emergency department of Helsinki University Central Hospital in 2010-2015. We analyzed their prehospital pathways, including time from symptom onset to admission at the neurological emergency department (ODT), the number of points of care, the percentage of patients with ODT<=4.5 hours, and factors associated with delay. RESULTS: Among 245 patients, only 20.8% arrived within 4.5 hours and 6.5% received IV thrombolysis. Delayed arrival was most often due to patients' late contact to health care. Of the patients, 27.3% arrived through at least two points of care, and differential diagnostics to ophthalmologic disorders proved particularly challenging. ODT<=4.5 hours was associated with EMS utilization, direct arrival, and atrial fibrillation; a visit at an ophthalmologist and initial misdiagnosis were associated with ODT>4.5 hours. After multivariable analysis, only direct arrival predicted ODT<=4.5 hours. CONCLUSIONS: Occipital stroke patients with visual symptoms contact health care late, are inadequately recognized, and present with complex prehospital pathways. Consequently, they are often ineligible for IV thrombolysis. This presents a missed opportunity for preventing permanent visual field defects. PMID- 28804876 TI - Insulin resistance in pregnant women with and without polycystic ovary syndrome, and measures of body composition in offspring at birth and three years of age. AB - INTRODUCTION: Polycystic ovary syndrome is associated with obesity and insulin resistance in the non-pregnant state, but little is known about insulin sensitivity in the pregnant state. Our objective was to compare insulin resistance in pregnant women with and without polycystic ovary syndrome and explore the impact of polycystic ovary syndrome on body composition in offspring at birth and at three years of age. MATERIAL AND METHODS: A prospective cohort study including 2548 live-born singleton mother-child pairs residing in Odense municipality, Denmark, during 2010-2013. Of the 2548 women, 241 (9.4%) had polycystic ovary syndrome. RESULTS: Homeostatic model assessment for insulin resistance assessments were comparable in women with and without polycystic ovary syndrome. However, the subgroup of overweight women with polycystic ovary syndrome had significantly higher levels of homeostatic model assessment for insulin resistance than overweight women without polycystic ovary syndrome (mean +/- 2 SD): 4.4 (3.1) vs. 3.6 (3.4), p = 0.004. Maternal polycystic ovary syndrome did not affect offspring birthweight after accounting for age. However, polycystic ovary syndrome, adjusted for maternal body mass index, was associated with increased body mass index at three years of age (mean +/- 2 SD): 16.0 (2.2) vs. 15.7 (2.1) kg/m2 , p = 0.04. CONCLUSION: In our cohort, maternal polycystic ovary syndrome was not associated with insulin resistance after correcting for body mass index and was not an independent predictor of offspring birthweight. However, both polycystic ovary syndrome and high maternal body mass index may increase risk of childhood obesity at three years of age. PMID- 28804877 TI - Validation of a Geriatric Trauma Prognosis Calculator: A P.A.L.Li.A.T.E. Consortium Study. AB - BACKGROUND/OBJECTIVES: The P.A.L.Li.A.T.E. (prognostic assessment of life and limitations after trauma in the elderly) consortium has previously created a prognosis calculator for mortality after geriatric injury based on age, injury severity, and transfusion requirement called the geriatric trauma outcome score (GTOS). Here, we sought to create and validate a prognosis calculator called the geriatric trauma outcome score ii (GTOS II) estimating probability of unfavorable discharge. DESIGN: Retrospective cohort. SETTING: Four geographically diverse Level 1 trauma centers. PARTICIPANTS: Trauma admissions aged 65 to 102 years surviving to discharge from 2000 to 2013. INTERVENTION: None. MEASUREMENTS: Age, injury severity score (ISS), transfusion at 24 hours post-admission, discharge dichotomized as favorable (home/rehabilitation) or unfavorable (skilled nursing/long term acute care/hospice). Training and testing samples were created using the holdout method. A multiple logistic mixed model (GTOS II) was created to estimate the odds of unfavorable disposition then re-specified using the GTOS II as the sole predictor in a logistic mixed model using the testing sample. RESULTS: The final dataset was 16,114 subjects (unfavorable discharge status = 15.4%). Training (n = 8,057) and testing (n = 8,057) samples had similar demographics. The formula based on the training sample was (GTOS II = Age + [0.71 * ISS] + 8.79 [if transfused by 24 hours]). Misclassification rate and AUC were 15.63% and 0.67 for the training sample, respectively, and 15.85% and 0.67 for the testing sample. CONCLUSION: GTOS II estimates the probability of unfavorable discharge in injured elders with moderate accuracy. With the GTOS mortality calculator, it can help in goal setting conversations after geriatric injury. PMID- 28804878 TI - On the standardization of fitness and traits in comparative studies of phenotypic selection. AB - Comparisons of the strength and form of phenotypic selection among groups provide a powerful approach for testing adaptive hypotheses. A central and largely unaddressed issue is how fitness and phenotypes are standardized in such studies; standardization across or within groups can qualitatively change conclusions whenever mean fitness differs between groups. We briefly reviewed recent relevant literature, and found that selection studies vary widely in their scale of standardization, but few investigators motivated their rationale for chosen standardization approaches. Here, we propose that the scale at which fitness should be relativized should reflect whether selection is likely to be hard or soft; that is, the scale at which populations (or hypothetical populations in the case of a contrived experiment) are regulated. We argue that many comparative studies of selection are implicitly or explicitly focused on soft selection (i.e., frequency and density-dependent selection). In such studies, relative fitness should preferably be calculated using within-group means, although this approach is taken only occasionally. Related difficulties arise for the standardization of phenotypes. The appropriate scale at which standardization should take place depends on whether groups are considered to be fixed or random. We emphasize that the scale of standardization is a critical decision in empirical studies of selection that should always warrant explicit justification. PMID- 28804879 TI - Faulty ephedrine prefilled polypropylene syringe - manufacturer's reply. PMID- 28804881 TI - Category-1 caesarean section, airways and Julius Caesar. PMID- 28804880 TI - Optimising triggers for patient-assisted remifentanil analgesia during labour. PMID- 28804882 TI - A quality improvement program involving protocolised reversal from neuromuscular block. PMID- 28804883 TI - Current practice for awake fibreoptic intubation - asking the right questions. PMID- 28804884 TI - Optimising triggers for patient-assisted remifentanil analgesia during labour - a reply. PMID- 28804885 TI - Lidocaine-filled tracheal tube cuffs and sore throat - a reply. PMID- 28804886 TI - Electronic tags and anaesthetic practice. PMID- 28804887 TI - Stop Before You Block stickers. PMID- 28804888 TI - THRIVE, rapid sequence induction and aspiration risk. PMID- 28804889 TI - A randomised trial comparing real-time double-lumen endobronchial tube placement with the Disposcope(r) with conventional blind placement. AB - Double-lumen endobronchial tube placement is challenging. This study compared double-lumen tube placement with the Disposcope(r) , a wireless videostylet allowing real-time visualisation, with conventional blind placement. Patients undergoing elective thoracic surgery with normal airways requiring one-lung ventilation were randomly allocated into two groups (27 patients in each group). The Disposcope was used to assist left-sided double-lumen tube placement in one group, and conventional blind placement was performed in the control group. Placement in both groups was checked with fibreoptic bronchoscopy. The Disposcope assisted group had a shorter total mean (SD) placement time (18.6 (2.5) s vs. 21.4 (2.9) s, p < 0.001), laryngoscopy to end of auscultation time (83.4 (3.0) s vs. 93.9 (5.7) s, p < 0.001) and total operation time (130.7 (6.1) s vs. 154.5 (6.3) s, p < 0.001). In the Disposcope-assisted group, the double-lumen tube was inserted in the correct side in all patients (100.0%), whereas in the conventional group, the double-lumen tube was placed in the correct side in 25 (92.6%) patients and in the wrong side in 2 (7.4%) patients; the difference was not significant (p = 0.150). In the Disposcope-assisted group, the double-lumen tube was inserted to the optimal depth in 24 (88.9%) patients, whereas in the conventional group it was inserted to the optimal depth in one (4.0%) patient. The Disposcope increased the success rate of double-lumen tube placement, and shortened the total operation time when compared with standard placement with confirmation using fibreoptic bronchoscopy, and may replace the conventional method. PMID- 28804890 TI - Category-1 caesarean section, airways and Julius Caesar. A reply. PMID- 28804891 TI - Continued utility of awake fibreoptic intubation. PMID- 28804892 TI - Faulty ephedrine prefilled polypropylene syringe. PMID- 28804893 TI - Two further episodes of a defective Optima CLX laryngoscope blade - manufacturer's reply. PMID- 28804894 TI - Lidocaine-filled tracheal tube cuffs and sore throat. PMID- 28804895 TI - Merkel cell carcinoma: Do Australians have a more aggressive variant and a worse outcome? PMID- 28804896 TI - Load-dependence of myocardial deformation variables - a clinical strain echocardiographic study. AB - BACKGROUND: The effects of left ventricular (LV) loading on myocardial deformation variables are not well-studied in the clinical setting. In the present study, we evaluated the effects of isolated changes in preload, afterload and heart rate on LV longitudinal strain, systolic (SR-S) and early diastolic strain rate (SR-E) in post-cardiac surgery patients. METHODS: Twenty-one patients were studied early after cardiac surgery. Longitudinal myocardial strain and SR were analysed off-line using 2-D speckle echocardiography. The experimental protocol consisted of three consecutive interventions: (1) preload was increased by passive leg elevation, (2) afterload was increased by an infusion of phenylephrine to increase arterial blood pressure by 10-15% and (3) heart rate was increased 10% and 20% by atrial pacing. During both the preload and afterload challenges heart rate was kept constant by atrial pacing. Central venous pressure was kept constant during pacing by infusion of hetastarch/albumin. RESULTS: The increase in preload increased LV strain, SR-S and SR-E by 20%, 11% and 17%, respectively. The phenylephrine-induced increase in afterload, did not affect LV strain, SR-S or SR-E. LV strain was not affected while SR-S and SR-E increased by pacing-induced heart rate increase. CONCLUSION: After cardiac surgery, systolic and early diastolic strain rate are dependent on both preload and heart rate, while neither of these variables was afterload-dependent. LV strain was preload dependent but not affected by atrial pacing. When evaluating the direct effects of various pharmacological or other interventions on myocardial contractility and relaxation, preload and heart rate must be controlled. PMID- 28804897 TI - Keeping in time: Issues affecting the sustainability of obstetric emergency simulation training in outer metropolitan, rural and remote centres in Western Australia. AB - BACKGROUND: Obstetric emergency simulation training is an evidence-based intervention for the reduction of perinatal and maternal morbidity. In Western Australia, obstetric emergency training has been run using the In Time course since 2006. AIMS: The study aimed to determine if the provision of In Time train the trainer courses to outer metro, rural and remote units in Western Australia had led to sustained ongoing training in those units. Ten years following the introduction of the course, we performed a survey to examine which units are continuing to run In Time, what are the perceived benefits in units still utilising In Time, and what were the barriers to training in units that had discontinued. MATERIALS AND METHODS: A link to an online survey was sent to the units where In Time training had occurred. Telephone enquiries were additionally used to ensure a good response rate. RESULTS: The survey response rate was 100%. Six of the 11 units where training had been provided continue to run In Time. Units where training had discontinued had done so in order to take up alternatives, or as a result of trainers leaving. Of the units who had discontinued training, one wished to recommence In Time. CONCLUSIONS: Local in situ training in obstetric emergencies as exemplified by the In Time course remains a popular and valued training intervention across Western Australia. This training may be of particular benefit to small and remote units, but these are the areas in which training is hardest to sustain. PMID- 28804898 TI - Epilepsy surgery of "low grade epilepsy associated neuroepithelial tumors": A retrospective nationwide Italian study. AB - OBJECTIVE: To analyze the attitude and results of Italian epilepsy surgery centers in the surgical management of "low grade epilepsy associated neuroepithelial tumors" (LEATs). METHODS: We conducted a retrospective study enrolling 339 consecutive patients with LEATs who underwent surgery between January 2009 and June 2015 at eight Italian epilepsy surgery centers. We compared demographic, clinical, pathologic, and surgical features of patients with favorable (Engel class I) and unfavorable (Engel class II, III, and IV) seizure outcome. In addition, we compared patients with tumor-associated focal cortical dysplasia (FCD) and patients with solitary tumors to identify factors correlated with FCD diagnosis. RESULTS: Fifty-five (98.2%) of 56 patients with medically controlled epilepsy were seizure-free after surgery, compared to 249 (88.0%) of 283 patients with refractory epilepsy. At multivariate analysis, three variables independently predict unfavorable seizure outcome in the drug-resistant group. Age at surgery is largely the most significant (p = 0.001), with an odds ratio (OR) of 1.04. This means that the probability of seizure recurrence grows by 4% for every waited year. The resection site is also significant (p = 0.039), with a relative risk (RR) of 1.99 for extratemporal tumors. Finally, the completeness of tumor resection has a trend toward significance (p = 0.092), with an RR of 1.82 for incomplete resection. Among pediatric patients, a longer duration of epilepsy was significantly associated with preoperative neuropsychological deficits (p < 0.001). A statistically significant association was observed between FCD diagnosis and the following variables: tailored surgery (p < 0.001), temporal resection (p = 0.001), and surgical center (p = 0.012). SIGNIFICANCE: Our nationwide LEATs study gives important insights on factors predicting seizure outcome in refractory epilepsy and determining variability in FCD detection. Timely surgery, regardless of pharmacoresistance and oriented to optimize epileptologic, neuropsychological, and oncologic outcomes should be warranted. PMID- 28804899 TI - Coronary artery disease and risk of adverse cardiac events and stroke. AB - BACKGROUND: Patients with acute myocardial infarction are at increased risk of ischaemic stroke. Previous myocardial infarction is an important part of risk assessment for ischaemic stroke. However, there is a lack of information regarding the association between the severity and extent of coronary artery disease and long-term risk of ischaemic stroke. MATERIALS AND METHODS: A cohort study of coronary angiographies performed in western Denmark from 1 January 2003 to 31 December 2012. Patients were stratified according to the number of vessels affected by obstructive coronary artery disease (lumen narrowing >=50%) at the time of angiography: zero-, one-, two- or three-vessel disease and diffuse vessel disease. We followed patients for a maximum of 7 years. Endpoints were all-cause death, cardiac death, myocardial infarction and ischaemic stroke. Cumulative risks and crude and adjusted rate ratios were estimated. RESULTS: The study population included 78 195 patients. Of these, 32 061 (41.0%) had zero-vessel disease, 6205 (7.9%) had diffuse vessel disease, 20 202 (25.8%) had one-vessel disease, 10 675 (13.7%) had two-vessel disease, and 9038 (11.6%) had three-vessel disease. Median follow-up was 3.6 years (interquartile range 1.7-6.0 years). Increasing severity of obstructive coronary artery disease was associated with an increasing risk of all-cause death, cardiac death, myocardial infarction (MI) and ischaemic stroke during follow-up. CONCLUSIONS: The presence and extent of coronary artery disease was associated with an incremental risk of not only death, cardiac death, myocardial infarction, but also ischaemic stroke over a 7 year period. PMID- 28804902 TI - The Geriatrician Circa 2030. PMID- 28804900 TI - Phylogenetic evidence from freshwater crayfishes that cave adaptation is not an evolutionary dead-end. AB - Caves are perceived as isolated, extreme habitats with a uniquely specialized biota, which long ago led to the idea that caves are "evolutionary dead-ends." This implies that cave-adapted taxa may be doomed for extinction before they can diversify or transition to a more stable state. However, this hypothesis has not been explicitly tested in a phylogenetic framework with multiple independently evolved cave-dwelling groups. Here, we use the freshwater crayfish, a group with dozens of cave-dwelling species in multiple lineages, as a system to test this hypothesis. We consider historical patterns of lineage diversification and habitat transition as well as current patterns of geographic range size. We find that while cave-dwelling lineages have small relative range sizes and rarely transition back to the surface, they exhibit remarkably similar diversification patterns to those of other habitat types and appear to be able to maintain a diversity of lineages through time. This suggests that cave adaptation is not a "dead-end" for freshwater crayfish, which has positive implications for our understanding of biodiversity and conservation in cave habitats. PMID- 28804904 TI - Early Impact on Outpatients of Mandatory Adoption of the Diagnosis-Related Group Based Reimbursement System in Korea on Use of Outpatient Care: Differences in Medical Utilization and Presurgery Examination. AB - OBJECTIVE: To explore the impact of mandatory adoption of diagnosis-related groups (DRGs) on the use of outpatient care in Korea. DATA SOURCES: National Health Claim data from 2,022 hospitals and 1,029,101 admission cases during 2011 2014: tonsillectomy/adenoidectomy, inguinal/femoral hernia operation, and hemorrhoidectomy. STUDY DESIGN: Outcome variables included probability of outpatient visit, number of outpatient visits, and outpatient medical expenditures within 30 days. Presurgery examination before hospitalization for surgery, including basic and other examination, was conducted to evaluate a possible shift in health care service. A difference-in-difference research design was used to evaluate the impact of the DRG system on the use of outpatient care. PRINCIPAL FINDINGS: Before the introduction of the DRG system, 384,609 (91.1 percent) participants used an outpatient clinic either before or after hospitalization. In our study, the number of outpatient visits and outpatient medical expenditures within 30 days increased after mandatory adoption of the DRG system. After adoption of the DRG system, volume and costs for presurgery examinations increased before hospitalization. CONCLUSION: We observed a spillover effect after mandatory adoption of the DRG system. A future payment system should be designed for spillover effects, and the introduction of a new payment system that expands the DRG-based reimbursement system should be considered. PMID- 28804905 TI - The evolution of paroxysmal nocturnal haemoglobinuria depends on intensity of immunosuppressive therapy. PMID- 28804903 TI - Targeting of tolerogenic dendritic cells towards heat-shock proteins: a novel therapeutic strategy for autoimmune diseases? AB - Tolerogenic dendritic cells (tolDCs) are a promising therapeutic tool to restore immune tolerance in autoimmune diseases. The rationale of using tolDCs is that they can specifically target the pathogenic T-cell response while leaving other, protective, T-cell responses intact. Several ways of generating therapeutic tolDCs have been described, but whether these tolDCs should be loaded with autoantigen(s), and if so, with which autoantigen(s), remains unclear. Autoimmune diseases, such as rheumatoid arthritis, are not commonly defined by a single, universal, autoantigen. A possible solution is to use surrogate autoantigens for loading of tolDCs. We propose that heat-shock proteins may be a relevant surrogate antigen, as they are evolutionarily conserved between species, ubiquitously expressed in inflamed tissues and have been shown to induce regulatory T cells, ameliorating disease in various arthritis mouse models. In this review, we provide an overview on how immune tolerance may be restored by tolDCs, the problem of selecting relevant autoantigens for loading of tolDCs, and why heat-shock proteins could be used as surrogate autoantigens. PMID- 28804906 TI - Efficacy of a mephentermine-based product as a vasopressor and a cardiac performance enhancer when given intramuscularly to cattle. AB - The goal of this study was to confirm the vasopressor and cardiac effects of POTENAY(r) INJETAVEL (POT), a mephentermine-based product, given to cattle with induced vascular/cardiac depression. Ten healthy Holstein cattle (206 +/- 13 kg) followed a randomized-complete-block design (RCBD) utilizing crossover study design. Each animal randomly received (1 ml/25 kg, IM) of either POT (n = 10) or volume-matched placebo control (0.9%NaCl, CP, n = 10). A subset of animals (n = 5) received POT first (day 0) while the remaining (n = 5) received CP; after a six-day washout period, cattle received the opposite compound. Animals were anesthetized and catheterized for systemic/left ventricular hemodynamic monitoring. Myocardial dysfunction/hypotension was induced by increasing the end tidal isoflurane concentration until arterial blood pressure was 20% lower than at baseline and remained stable. Once the animal was determined to be hypotensive and hemodynamically stable, steady-state hypotensive baseline data (BL2) were acquired, and treatment with either POT or CP was given. Data were acquired post treatment at every 15 min for 90 min. POT improved cardiac output (+68 L/min, +/ 14%, p < 0.05), MAP (+14 mmHg, +/-4%, p < 0.05), HR (+22 bpm, +/-8%, p < 0.05), and peak rates of ventricular pressure change during both systole (dP/dtmax : +37 mmHg/s +/-13%, p < 0.05) and diastole (dP/dtmin : +31 mmHg/s, +/-7%, p < 0.05). No improvements were noted following placebo-control administration. Results indicate that POT improves cardiac performance and systemic hemodynamics in cattle with induced cardiovascular depression when given as single intramuscular injection. PMID- 28804907 TI - Allergic contact dermatitis caused by isobornyl acrylate in Freestyle(r) Libre, a newly introduced glucose sensor. AB - BACKGROUND: Glucose sensors, such as FreeStyle(r) Libre, are innovative medical devices developed for diabetes patients as a replacement for classic glucose meters, ensuring continuous glucose monitoring without the disadvantage of regular skin finger pricks. OBJECTIVES: To report several cases of allergic contact dermatitis caused by FreeStyle(r) Libre, and to report on isobornyl acrylate as a culprit allergen. PATIENTS AND METHODS: Fifteen patients presented with allergic contact dermatitis caused by FreeStyle(r) Libre. All but 1 were patch tested with a baseline series, and with pieces and/or ultrasonic bath extracts of (the adhesive part of) the glucose sensor. Isobornyl acrylate was patch tested, in various concentrations and vehicles, in 13 patients. Gas chromatography-mass spectrometry (GC-MS) of the sensors was performed. RESULTS: All patients reacted to the adhesive part of the sensor, and 12 patients were shown to be sensitized to isobornyl acrylate. Simultaneous reactions to other allergens were rarely observed. GC-MS showed the presence of isobornyl acrylate in the sensors. CONCLUSIONS: Cases of allergic contact dermatitis caused by FreeStyle(r) Libre are increasingly being observed, and isobornyl acrylate is a relevant culprit allergen. Cross-reactivity to other acrylates was infrequently observed, but other, hitherto unidentified, contact allergens may still be present in the device. PMID- 28804909 TI - Evaluation of clinical, laboratory, imaging findings and outcome in 99 dogs with leptospirosis. AB - OBJECTIVE: To report clinical, laboratory and diagnostic imaging features and prognostic factors in dogs with leptospirosis from North-East Germany. MATERIALS AND METHODS: Medical records of dogs diagnosed with leptospirosis from 2006 to 2013 were evaluated retrospectively. RESULTS: The study included 99 dogs. At initial presentation, the most common clinical signs were lethargy (96%), anorexia (88%), vomiting (85%), painful abdomen (39%), diarrhoea (38%), oliguria (27%) and tachypnoea (26%). Abnormal laboratory findings included anaemia (63%), thrombocytopenia (63%), leucocytosis (57%), increase of plasma urea (84%) and creatinine concentrations (81%), increased liver enzyme activities (80%), hyperbilirubinaemia (69%), hyperphosphataemia (67%), hyponatraemia (64%), hypoalbuminaemia (55%) and hypokalaemia (29%). Radiological pulmonary changes were detected in 57% of the dogs initially or during the course of disease. Severe dyspnoea, oliguria, azotaemia, hyperbilirubinaemia and severe radiological pulmonary changes were more often found in dogs that did not survive. There was renal, hepatic and pulmonary involvement in 95, 92 and 58% of the dogs, respectively, and multi-organ lesions in 98 dogs (98%); 32 dogs died or were euthanased. CONCLUSION: Several clinical and laboratory abnormalities were associated with a negative outcome; severe lung involvement was specifically associated with high mortality. PMID- 28804908 TI - Influence of abiraterone acetate on neuroendocrine differentiation in chemotherapy-naive metastatic castration-resistant prostate cancer. AB - BACKGROUND: To determine the influence of abiraterone Acetate (AA) on neuroendocrine differentiation (NED) in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). METHODS: We conducted an analysis in 115 chemotherapy-naive mCRPC patients who would be treated with chemotherapy. The serum levels of chromogranin A (CgA), neurone-specific enolase (NSE) were measured in 67 mCRPC patients without AA treatment and 48 patients after the failure of AA treatment, in which these markers were also measured in 34 patients before and after 6 months of AA treatment. Comparative t-test was used to evaluate the serial changes of serum NED markers during AA treatment and univariate and multivariate analyses were performed to test the influence of AA treatment on NED. RESULTS: Serum CgA were NSE were evaluated to be above the upper limit of normal (ULN) in 56 (48.7%) and 29 (25.2%) patients before chemotherapy. In 34 patients with serial evaluation, serum CgA level of 14 patients and NSE of 14 patients increased after the failure of AA treatment. There was no significant difference of NED markers (CgA or NSE variation (P = 0.243) between at baseline and after the failure of AA treatment. Compared with the CgA elevation group in the first 6 months of AA treatment and baseline supranormal CgA group, the CgA decline group, and baseline normal CgA group has a much longer median PSA PFS (14.34 vs 10.00 months, P < 0.001, and 14.23 vs 10.30 months, P = 0.02) and rPFS, respectively (18.33 vs 11.37 months, P < 0.001, and 17.10 vs 12.07 months, P = 0.03). In logistic univariate analysis, AA treatment and its duration were not independent factors influencing NED. CONCLUSIONS: We hypothesized that AA might not significantly lead to progression of NED of mCRPC in general. Furthermore, we found there was heterogeneity in changes of NED markers in different mCRPC patients during AA treatment. Serial CgA and NSE evaluation might help clinicians guide clinical treatment of mCRPC patients. PMID- 28804910 TI - T cell protein tyrosine phosphatase prevents STAT1 induction of claudin-2 expression in intestinal epithelial cells. AB - T cell protein tyrosine phosphatase (TCPTP) dephosphorylates a number of substrates, including JAK-STAT (signal transducer and activator of transcription) signaling proteins, which are activated by interferon (IFN)-gamma, a major proinflammatory cytokine involved in conditions such as inflammatory bowel disease. A critical function of the intestinal epithelium is formation of a selective barrier to luminal contents. The structural units of the epithelium that regulate barrier function are the tight junctions (TJs), and the protein composition of the TJ determines the tightness of the barrier. Claudin-2 is a TJ protein that increases permeability to cations and reduces transepithelial electrical resistance (TER). We previously showed that transient knockdown (KD) of TCPTP permits increased expression of claudin-2 by IFN-gamma. Here, we demonstrate that the decreased TER in TCPTP-deficient epithelial cells is alleviated by STAT1 KD. Moreover, increased claudin-2 in TCPTP-deficient cells requires enhanced STAT1 activation and STAT1 binding to the CLDN2 promoter. We also show that mutation of this STAT-binding site prevents elevated CLDN2 promoter activity in TCPTP-deficient epithelial cells. In summary, we demonstrate that TCPTP protects the intestinal epithelial barrier by restricting STAT-induced claudin-2 expression. This is a potential mechanism by which loss-of-function mutations in the gene encoding TCPTP may contribute to barrier defects in chronic intestinal inflammatory disease. PMID- 28804912 TI - Presence of the telescope fish Mendosoma lineatum in Patagonian waters, a new species in the ichthyological fauna from the south-west Atlantic Ocean. AB - The presence of the telescope fish Mendosoma lineatum in Patagonian waters of Argentina is reported. Mendosoma lineatum is the second species of the Latridae recorded in the south-west Atlantic Ocean and its presence in Patagonia is an addition to both the ichthyological fauna of the Argentinean Sea and the south west Atlantic Ocean. PMID- 28804911 TI - Chronic Ethanol Metabolism Inhibits Hepatic Mitochondrial Superoxide Dismutase via Lysine Acetylation. AB - BACKGROUND: Chronic ethanol (EtOH) consumption is a major cause of liver disease worldwide. Oxidative stress is a known consequence of EtOH metabolism and is thought to contribute significantly to alcoholic liver disease (ALD). Therefore, elucidating pathways leading to sustained oxidative stress and downstream redox imbalances may reveal how EtOH consumption leads to ALD. Recent studies suggest that EtOH metabolism impacts mitochondrial antioxidant processes through a number of proteomic alterations, including hyperacetylation of key antioxidant proteins. METHODS: To elucidate mechanisms of EtOH-induced hepatic oxidative stress, we investigate a role for protein hyperacetylation in modulating mitochondrial superoxide dismutase (SOD2) structure and function in a 6-week Lieber-DeCarli murine model of EtOH consumption. Our experimental approach includes immunoblotting immunohistochemistry (IHC), activity assays, mass spectrometry, and in silico modeling. RESULTS: We found that EtOH metabolism significantly increased the acetylation of SOD2 at 2 functionally relevant lysine sites, K68 and K122, resulting in a 40% decrease in enzyme activity while overall SOD2 abundance was unchanged. In vitro studies also reveal which lysine residues are more susceptible to acetylation. IHC analysis demonstrates that SOD2 hyperacetylation occurs near zone 3 within the liver, which is the main EtOH metabolizing region of the liver. CONCLUSIONS: Overall, the findings presented in this study support a role for EtOH-induced lysine acetylation as an adverse posttranslational modification within the mitochondria that directly impacts SOD2 charge state and activity. Last, the data presented here indicate that protein hyperacetylation may be a major factor contributing to an imbalance in hepatic redox homeostasis due to chronic EtOH metabolism. PMID- 28804914 TI - Interactions between Manta birostris and Sotalia guianensis in a World Heritage listed Brazilian estuary. AB - During 1442 h of visual observations over 7 years throughout the World Heritage listed Paranagua estuarine complex, Brazil, seven occurrences of interactions were observed at a single location involving breaching Manta birostris displacing schools of teleosts, which were subsequently preyed upon by Sotalia guianensis. Although the interactions were not definitively categorized as being amensal, commensal or mutual, their restriction to isolated space (adjacent to a protected area) and time (summer) supports previous assertions the area is important to regional productivity and the continuation of protected-area status. PMID- 28804913 TI - On BH3 Mimetics and Ca2+ Signaling. AB - Preclinical Research BH3 mimetics are anticancer agents that reproduce the spatial arrangement of the BH3 domain of Bcl-2 family proteins. Just like the BH3 only proteins, these compounds bind to the hydrophobic cleft of the pro-survival Bcl-2 members such as Bcl-2 or Bcl-xL, and disrupt their heterodimerization with pro-apoptotic Bax or Bak, sensitizing cells to chemotherapy. In recent years, it has become clear that Bcl-2 family proteins are engaged in regulation of intracellular Ca2+ homeostasis, including Ca2+ release from the intracellular stores as well as Ca2+ fluxes across the plasma membrane. Given that BH3 mimetics shift the balance between the prosurvival and proapoptotic Bcl-2 members, they might indirectly exert effects on intracellular Ca2+ signals. Indeed, it has been reported that some BH3 mimetics release Ca2+ from the intracellular stores causing Ca2+ overload in the cytosol. Therefore, the effects of any new BH3 mimetics on cellular Ca2+ homeostasis should be tested before these compounds progress to clinical trials. Drug Dev Res 78 : 313-318, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28804915 TI - Psychotherapy for bulimia nervosa on symptoms of depression: A meta-analysis of randomized controlled trials. AB - OBJECTIVE: Depressive symptoms are an important risk factor and consequence of binge eating and purging behavior in bulimia nervosa (BN). Although psychotherapy is effective in reducing symptoms of BN in the short- and long-term, it is unclear whether psychotherapy for BN is also effective in reducing depressive symptoms. This meta-analysis examined the efficacy of psychotherapy for BN on depressive symptoms in the short- and long-term. METHOD: Randomized controlled trials (RCTs) on BN that assessed depressive symptoms as an outcome were identified. Twenty-six RCTs were included. RESULTS: Psychotherapy was more efficacious at reducing symptoms of depression at post-treatment (g = 0.47) than wait-lists. This effect was strongest when studies delivered therapist-led, rather than guided self-help, treatment. No significant differences were observed between psychotherapy and antidepressants. There was no significant post treatment difference between CBT and other active psychological comparisons at reducing symptoms of depression. However, when only therapist-led CBT was analyzed, therapist-led CBT was significantly more efficacious (g = 0.25) than active comparisons at reducing depressive symptoms. The magnitude of the improvement in depressive symptoms was predicted by the magnitude of the improvement in BN symptoms. DISCUSSION: These findings suggest that psychotherapy is effective for reducing depressive symptoms in BN in the short-term. Whether these effects are sustained in the long-term is yet to be determined, as too few studies conducted follow-up assessments. Moreover, findings demonstrate that, in addition to being the front-running treatment for BN symptoms, CBT might also be the most effective psychotherapy for improving the symptoms of depression that commonly co-occur in BN. PMID- 28804916 TI - Lane's Disease (Erythema Palmare Hereditarium): A Report of Five Cases and a Review of the Literature. AB - BACKGROUND: Erythema palmare hereditarium (EPH), also known as Lane's disease, is a rare, benign condition presenting as persistent erythema involving the palms. EPH can appear at birth or later in life and usually in at least two members of the same family, although a sporadic case has been reported. METHODS: We report five cases of EPH and offer a review of the current literature. The first and second cases are twin boys presenting with erythema mainly on the thenar and hypothenar eminences and on the phalanges that appeared 8 months after birth. The third case is a girl with congenital palmar erythema and two other capillary malformations. The fourth case is a 58-year-old woman with palmar erythema that appeared after pregnancy. Her 32-year-old daughter had presented with the same palm redness since birth. RESULTS: A review of the literature shows that women are affected almost three times more than men. Dermoscopic evaluation showed red structureless areas with arborizing vessels, mainly running parallel along follicular openings. CONCLUSION: EPH should be considered in all patients presenting with palmar erythema, especially in familial long-lasting forms. It can be congenital or acquired, but the pathogenetic mechanism is unclear. To the best of our knowledge, this is the first dermatoscopic study of EPH and the largest case series reported in the literature, involving two families and one sporadic case. PMID- 28804917 TI - Person-city personality fit and entrepreneurial success: An explorative study in China. AB - While the study of personality differences is a traditional psychological approach in entrepreneurship research, economic research directs attention towards the entrepreneurial ecosystems in which entrepreneurial activity are embedded. We combine both approaches and quantify the interplay between the individual personality make-up of entrepreneurs and the local personality composition of ecosystems, with a special focus on person-city personality fit. Specifically, we analyse personality data from N = 26,405 Chinese residents across 42 major Chinese cities, including N = 1091 Chinese entrepreneurs. Multi level polynomial regression and response surface plots revealed that: (a) individual-level conscientiousness had a positive effect and individual-level agreeableness and neuroticism had a negative effect on entrepreneurial success, (b) city-level conscientiousness had a positive, and city-level neuroticism had a negative effect on entrepreneurial success, and (c) additional person-city personality fit effects existed for agreeableness, conscientiousness and neuroticism. For example, entrepreneurs who are high in agreeableness and conduct their business in a city with a low agreeableness level show the lowest entrepreneurial success. In contrast, entrepreneurs who are low in agreeableness and conduct their business in a city with a high agreeableness level show relatively high entrepreneurial success. Implications for research and practice are discussed. PMID- 28804918 TI - Low rank approximation methods for MR fingerprinting with large scale dictionaries. AB - PURPOSE: This work proposes new low rank approximation approaches with significant memory savings for large scale MR fingerprinting (MRF) problems. THEORY AND METHODS: We introduce a compressed MRF with randomized singular value decomposition method to significantly reduce the memory requirement for calculating a low rank approximation of large sized MRF dictionaries. We further relax this requirement by exploiting the structures of MRF dictionaries in the randomized singular value decomposition space and fitting them to low-degree polynomials to generate high resolution MRF parameter maps. In vivo 1.5T and 3T brain scan data are used to validate the approaches. RESULTS: T1 , T2 , and off resonance maps are in good agreement with that of the standard MRF approach. Moreover, the memory savings is up to 1000 times for the MRF-fast imaging with steady-state precession sequence and more than 15 times for the MRF-balanced, steady-state free precession sequence. CONCLUSION: The proposed compressed MRF with randomized singular value decomposition and dictionary fitting methods are memory efficient low rank approximation methods, which can benefit the usage of MRF in clinical settings. They also have great potentials in large scale MRF problems, such as problems considering multi-component MRF parameters or high resolution in the parameter space. Magn Reson Med 79:2392-2400, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28804920 TI - Thiopurines prevented surgical recurrence in patients with Crohn's disease after intestinal resection: Strategy based on risk stratification. AB - BACKGROUND AND AIM: Thiopurines (TPs) are effective in reducing clinical and endoscopic recurrence in postoperative patients with Crohn's disease (CD). However, whether TPs could prevent surgical recurrence (SR) remains unknown. We aimed to explore whether TPs could prevent SR and identify risk factors associated with SR. METHODS: This was a retrospective cohort study of 246 postoperative patients with CD. Cox proportional hazard model was used to identify risk factors for SR. Patients were stratified according to the presence of risk factors. RESULTS: A total of 50 (20.3%) patients suffered SR after a mean follow up of 54.3+/-46.4 months. Multivariable analysis showed independent risk factors for SR were penetrating disease behavior (HR 8.628; 95% CI 1.573-47.341; P = 0.01), ileocolonic disease location (HR 2.597; 95% CI 1.047-6.445; P = 0.04) and isolated upper gastrointestinal disease (UGID) location (HR 5.082; 95% CI 1.496-17.267; P = 0.009). However, use of TPs after surgery significantly reduced the risk of SR (HR 0.120; 95% CI 0.063-0.231; P < 0.001). When stratifying patients according to risk factors, there was no statistical difference of SR between patients treated or not by TPs (P = 0.08) in low-risk group (n = 46). However, in high risk group (n = 200), patients with TPs use had a lower risk of SR than those without TPs (HR 0.093; 95% CI 0.048-0.178; P < 0.001). CONCLUSIONS: Penetrating disease behavior and ileocolonic/isolated (UGID) location were associated with SR in CD patients. TPs use was beneficial in decreasing risk for SR in CD patients at high risk. PMID- 28804919 TI - Clinical Outcome and Prognosis of Young Patients with Mycosis Fungoides. AB - BACKGROUND/OBJECTIVES: Mycosis fungoides (MF) in young patients is rare and may have atypical presentations. There are limited data in these patients. The objective was to determine the clinical outcome and prognosis of young patients with MF. METHODS: A search of our institutional cancer registry database was conducted for patients diagnosed with MF at younger than 30 years of age. RESULTS: Our study included 74 patients (median age at diagnosis 25.5 yrs). Sixty five (88%) presented with early stage disease and variants of MF (n = 44 [59%]), leading to a median delay in diagnosis of 2.5 years. Hypopigmented MF (n = 27 [36.5%]) was the most common variant, affecting predominantly African American (44.4% vs 19%; p = 0.02) and younger (20 vs 26 yrs; p < 0.001) patients. All patients with hypopigmented MF presented with early stage disease and were less likely to develop progressive disease (PD) than those with other variants (11% vs 34%; p = 0.03). Nineteen patients (26%) developed PD during a median follow-up of 3.5 years, which was associated with advanced-stage disease (89% vs 17%; p < 0.001), older age (>20 yrs) (31% vs 13%; p = 0.08), African American race (52.6% vs 20%; p = 0.009), and poikilodermatous presentation (p < 0.01). Overall survival was good (97.2% at 5 yrs, 95.9% at 10 yrs) despite the delay in diagnosis and atypical presentation. CONCLUSIONS: Progressive disease is associated with older age, African American race, the poikilodermatous variant, and advanced-stage disease. The hypopigmented variant is a common presentation in young patients and has an indolent disease course. Our study confirms an overall favorable prognosis in young patients with MF. PMID- 28804921 TI - Serum Thymidine Kinase 1, Canine-C-Reactive Protein, Haptoglobin, and Vitamin D Concentrations in Dogs with Immune-Mediated Hemolytic Anemia, Thrombocytopenia, and Polyarthropathy. AB - BACKGROUND: Relapses of immune-mediated hemolytic anemia (IMHA), thrombocytopenia (ITP), or polyarthropathy (IMPA) occur despite normal hematologic and cytologic parameters. Thymidine kinase 1 (TK1), canine C-reactive protein (c-CRP), haptoglobin (HPT), and 25-Hydroxyvitamin-D (25(OH)D) might be adjunct to current monitoring strategies. HYPOTHESIS/OBJECTIVES: Compare serum concentrations of TK1, c-CRP, HPT, and 25(OH)D in dogs with well- and poorly controlled primary IMHA, ITP, or IMPA. ANIMALS: Thirty-eight client-owned dogs. METHODS: Prospective descriptive study. Dogs diagnosed with IMHA, ITP, or IMPA had serum biomarker concentrations measured commercially. Disease control was assessed by hematocrit/PCV and reticulocyte count, platelet count, and synovial fluid cytology for IMHA, ITP, and IMPA, respectively. Statistical analysis performed by Mann-Whitney rank-sum tests and receiver operating characteristic curves. RESULTS: TK1 and c-CRP, but not HPT significantly decreased with well- versus poorly controlled IMHA (P = 0.047, P = 0.028, P = 0.37). C-CRP, but not TK or HPT was significantly lower with well- versus poorly controlled IMPA (P = 0.05, P = 0.28, P = 0.84). Sensitivity and specificity of TK and c-CRP (simultaneously) for detecting dogs with poorly controlled IMHA were 88 and 100%, respectively. Sensitivity and specificity of c-CRP for detecting poorly controlled dogs with IMPA were 13 and 100%, respectively. 92% of dogs were vitamin D insufficient (<100 ng/mL) regardless of disease control. CONCLUSIONS AND CLINICAL IMPORTANCE: Combining TK1 and c-CRP might act markers of disease control in dogs with IMHA. Canine-CRP cannot be recommended as an independent marker of disease control in IMPA. 25(OH)D insufficiency in immune-mediated disorders might benefit from further study to determine if supplementation could improve therapeutic response or reduce disease risk. PMID- 28804922 TI - Study of Cognitive Function in Children Treated with Propranolol for Infantile Hemangioma. AB - BACKGROUND: Oral propranolol is considered the first choice for the treatment of infantile hemangiomas (IHs). There is a concern that administering propranolol in newborns and infants could induce adverse effects in learning and memory processes in the long term. The purpose of this study was to assess cognitive and memory functions in children who had been treated with propranolol for IH during their infancy. METHODS: A total of 23 children between 5 and 7.5 years of age who had been treated with oral propranolol for IH during infancy were tested for cognitive functions with the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) test and for memory functions with the Test of Memory and Learning (TOMAL). RESULTS: Comparison of our sample with a normal distribution by a Shapiro-Wilk W test showed no significant difference for any of the composite scores in the WPPSI-IV and TOMAL tests except for positive asymmetry and concentration of scores around average (p = 0.01) in the WPPSI-IV composite score (mean intelligence), due to one atypically high score. CONCLUSIONS: The distribution of scores for intelligence and memory scales in our study population was similar to that in the reference general population. These results fail to support any significant disturbance in intelligence and memory development in children treated during infancy with propranolol for IH. PMID- 28804923 TI - Hypopigmented Mycosis Fungoides with Large Cell Transformation in a Child. AB - Hypopigmented mycosis fungoides (HMF) is the most common variant of mycosis fungoides (MF) in children. Large-cell transformation in HMF has never been reported. Herein we report a case of HMF in an 8-year-old boy who presented with a 6-year history of hypopigmented patches on the bilateral arms, lower back, buttocks, posterior thighs, and lower legs. Biopsy revealed an abnormal CD8+ epidermotropic T-cell infiltrate consistent with the diagnosis of MF. The T-cell clonality study was positive. The patient was started on narrowband ultraviolet B (NBUVB) phototherapy and topical steroids. He had a 50% reduction in his patches after 10 months of treatment, after which he developed a single annular plaque on his left thigh. The biopsy specimen demonstrated large cells that were diffusely CD8+ and CD30- . Clobetasol propionate ointment was prescribed, which led to complete resolution of the plaque within 2 weeks. NBUVB phototherapy was continued and the patient had a complete response within the following 5 months. The case is an example of exceptionally rare large-cell transformation in pediatric MF and stresses the importance of regular follow-up of these patients. PMID- 28804924 TI - Flagellate Dermatitis in a Child Most Likely Secondary to Doxorubicin. AB - Flagellate dermatitis, a cutaneous eruption in which the patient appears to have been whipped, has been described with antineoplastic agents and shiitake mushroom ingestion. A 15-year-old girl with metastatic Ewing sarcoma developed pruritic erythematous linear lesions on her trunk that became hyperpigmented over time during her first cycle of chemotherapy with doxorubicin, vincristine, cyclophosphamide, and ganitumab. Flagellate dermatitis was diagnosed based on clinical and histologic findings. Flagellate dermatitis (FD) is a rare cutaneous eruption named for its appearance, in which the patient appears to have been whipped. It has been associated with chemotherapeutic agents such as bleomycin . We report FD in a child that occurred during chemotherapy treatment that included doxorubicin. PMID- 28804925 TI - Relationship between Total Homocysteine, Folic Acid, and Thyroid Hormones in Hypothyroid Dogs. AB - BACKGROUND: Both elevated homocysteine and decreased folic acid concentrations are observed in human patients with hypothyroidism and can influence the development of numerous secondary disorders. OBJECTIVES: The aim of the study was to assess total homocysteine concentration in serum and to examine its relationship with the concentration of folic acid and thyroid hormones (tT4 and fT4). ANIMALS: Ten healthy and 19 hypothyroid client-owned dogs. METHODS: Dogs with clinical signs of hypothyroidism had the diagnosis confirmed by additional tests. Total homocysteine, folic acid, total thyroxine, and free thyroxine concentrations in serum were evaluated. RESULTS: Hypothyroid dogs were diagnosed with increased homocysteine (median 22.20 MUmol/L; range, 16.50-37.75) and decreased folic acid (median 20.62 nmol/L; range, 10.54-26.35) concentrations, as compared to healthy dogs (11.52 MUmol/L; range, 10.00-16.65 and 30.68 nmol/L; range, 22.84-38.52, respectively). In sick dogs, total homocysteine was inversely correlated with folic acid (rho = -0.47, P < 0.001), total thyroxine (rho = 0.69, P = 0.0092), and free thyroxine (rho = -0.56, P = 0.0302). CONCLUSIONS: Hypothyroidism in dogs causes hyperhomocysteinemia. Concomitant mild folic acid decrease in hypothyroid dogs might be as a result of hyperhomocysteinemia. PMID- 28804926 TI - Van der Waals Epitaxial Growth of 2D Metallic Vanadium Diselenide Single Crystals and their Extra-High Electrical Conductivity. AB - 2D metallic transition-metal dichalcogenides (MTMDs) have recently emerged as a new class of materials for the engineering of novel electronic phases, 2D superconductors, magnets, as well as novel electronic applications. However, the mechanical exfoliation route is predominantly used to obtain such metallic 2D flakes, but the batch production remains challenging. Herein, the van der Waals epitaxial growth of monocrystalline, 1T-phase, few-layer metallic VSe2 nanosheets on an atomically flat mica substrate via a "one-step" chemical vapor deposition method is reported. The thickness of the VSe2 nanosheets is precisely tuned from several nanometers to several tenths of nanometers. More significantly, the 2D VSe2 single crystals are found to present an excellent metallic feature, as evidenced by the extra-high electrical conductivity of up to 106 S m-1 , 1-4 orders of magnitude higher than that of various conductive 2D materials. The thickness-dependent charge-density-wave phase transitions are also examined through low-temperature transport measurements, which reveal that the synthesized 2D metallic 1T-VSe2 nanosheets should serve as good research platforms for the detecting novel many-body states. These results open a new path for the synthesis and property investigations of nanoscale-thickness 2D MTMDs crystals. PMID- 28804927 TI - Hedgehog-Like Upconversion Crystals: Controlled Growth and Molecular Sensing at Single-Particle Level. AB - Topological control of nanostructures plays a crucial role in understanding the crystal growth process at the nanometer length scale. Here, the scalable synthesis of upconversion materials with distinct hedgehog-like morphologies by a seed-mediated synthetic procedure is reported. It is demonstrated that a close match in the crystal lattice between the core and shell components is essential for synthesizing such hierarchical nanostructures. These optical nanomaterials also enable the development of a single-particle-based platform for high sensitivity molecular sensing. PMID- 28804928 TI - The Comet assay for detection of DNA damage in canine sperm. AB - Sperm DNA integrity is a fundamental prerequisite in fertilization and embryo development. Among DNA integrity tests, the Comet assay is an accurate and sensitive test for the detection of sperm oxidative damage. The aim of this work was to evaluate sperm oxidative damage using the Comet assay and to study the correlation between Comet and routine assays for the evaluation of semen quality. Dogs were divided in two groups: group A (n = 6), comprising dogs with abnormal spermiogram, that is astheno-, terato- or oligoasthenoteratozoospermic (OAT); and group B (n = 8), comprising normospermic dogs. The distribution of sperm oxidative damage was significantly different between the two groups (p = .001): group A-median: 31.55%, interquartile range (IQR): 30.18-38.01; group B-median: 0.90%, IQR: 0.65-1.96. The correlation between oxidative damage and abnormal morphology was high (r = .846; p < .001). There was a negative correlation between progressive motility and oxidative damage (r = -.792; p = .001). Basal and oxidative DNA damage of spermatozoa are increased in dogs with non normospermic semen. In conclusion, and considering the elevated correlation with classical tests of sperm quality, the Comet assay has ample potential for clinical and research purposes in dogs. PMID- 28804929 TI - Factors moderating the relative effectiveness of varenicline and nicotine replacement therapy in clients using smoking cessation services. AB - AIMS: To assess how far the greater effectiveness of varenicline over nicotine replacement therapy (NRT) is moderated by characteristics of the smokers or setting in clinical practice. DESIGN: We used observational data from 22 472 treatment episodes between 2013 and 2016 from smoking cessation services in England to assess whether differences between varenicline and NRT were moderated by a set of smoker and setting characteristics: these included level of social deprivation, age, gender, ethnic group, nicotine dependence and treatment context. From the above, 15 640 episodes were analysed in relation to 4-week quit and 14 273 episodes at 12 weeks. All two-way interactions involving pharmacotherapy were fitted in addition to the main effects and a parsimonious model identified using a backwards stepwise selection procedure. SETTING: England PARTICIPANTS: Clients of smoking cessation service (number of individuals in 4 week quit analysis = 15 640). MEASUREMENTS: Four-week carbon monoxide-validated (primary outcome) and 12-week self-reported (secondary outcome) quit success/failure. FINDINGS: At both follow-up points, varenicline was associated with higher success rates overall [P < 0.001 at both 4 and 12 weeks; adjusted odds ratio (OR) varenicline versus NRT = 1.82 (95% confidence interval (CI) = 1.61, 2.06) and 2.58 (95% CI = 2.26, 2.94) at 4 and 12 weeks, respectively]. At 12 weeks, the relative benefits of varenicline were found to be influenced by the setting in which advice was provided [P < 0.001 for interaction pharmacotherapy * setting; adjusted odds ratio for varenicline * pharmacy setting = 0.53 (95% CI = 0.42, 0.69) and for varenicline * general practice (GP) setting = 0.79 (95% CI = 0.64, 0.98) against a baseline of 1 for varenicline * community setting]. The same trends were evident at 4 weeks, but this did not translate to statistical significance. There was inconclusive evidence for moderating effects of other variables. CONCLUSIONS: Varenicline use was associated with higher smoking cessation rates than nicotine replacement therapy in routine clinical practice, irrespective of a wide range of smoker characteristics, but the difference was less in certain intervention settings, most notably pharmacy but also GP practice, compared with community setting. PMID- 28804930 TI - Gaussian covariance graph models accounting for correlated marker effects in genome-wide prediction. AB - Several statistical models used in genome-wide prediction assume uncorrelated marker allele substitution effects, but it is known that these effects may be correlated. In statistics, graphical models have been identified as a useful tool for covariance estimation in high-dimensional problems and it is an area that has recently experienced a great expansion. In Gaussian covariance graph models (GCovGM), the joint distribution of a set of random variables is assumed to be Gaussian and the pattern of zeros of the covariance matrix is encoded in terms of an undirected graph G. In this study, methods adapting the theory of GCovGM to genome-wide prediction were developed (Bayes GCov, Bayes GCov-KR and Bayes GCov H). In simulated data sets, improvements in correlation between phenotypes and predicted breeding values and accuracies of predicted breeding values were found. Our models account for correlation of marker effects and permit to accommodate general structures as opposed to models proposed in previous studies, which consider spatial correlation only. In addition, they allow incorporation of biological information in the prediction process through its use when constructing graph G, and their extension to the multi-allelic loci case is straightforward. PMID- 28804931 TI - Amorphous Bimetallic Oxide-Graphene Hybrids as Bifunctional Oxygen Electrocatalysts for Rechargeable Zn-Air Batteries. AB - Metal oxides of earth-abundant elements are promising electrocatalysts to overcome the sluggish oxygen evolution and oxygen reduction reaction (OER/ORR) in many electrochemical energy-conversion devices. However, it is difficult to control their catalytic activity precisely. Here, a general three-stage synthesis strategy is described to produce a family of hybrid materials comprising amorphous bimetallic oxide nanoparticles anchored on N-doped reduced graphene oxide with simultaneous control of nanoparticle elemental composition, size, and crystallinity. Amorphous Fe0.5 Co0.5 Ox is obtained from Prussian blue analog nanocrystals, showing excellent OER activity with a Tafel slope of 30.1 mV dec-1 and an overpotential of 257 mV for 10 mA cm-2 and superior ORR activity with a large limiting current density of -5.25 mA cm-2 at 0.6 V. A fabricated Zn-air battery delivers a specific capacity of 756 mA h gZn-1 (corresponding to an energy density of 904 W h kgZn-1 ), a peak power density of 86 mW cm-2 and can be cycled over 120 h at 10 mA cm-2 . Other two amorphous bimetallic, Ni0.4 Fe0.6 Ox and Ni0.33 Co0.67 Ox , are also produced to demonstrate the general applicability of this method for synthesizing binary metal oxides with controllable structures as electrocatalysts for energy conversion. PMID- 28804932 TI - Kisspeptin regulates ovarian steroidogenesis during delayed embryonic development in the fruit bat, Cynopterus sphinx. AB - Cynopterus sphinx, a fruit bat, undergoes delayed embryonic development during the winter months, a period that corresponds to low levels of progesterone and estradiol synthesis by the ovary. Kisspeptins (KPs) are a group of neuropeptide hormones that act via G-protein coupled receptor 54 (GPR54) to stimulate hypothalamic secretion of Gonadotropin-releasing hormone, thereby regulating ovarian steroidogenesis, folliculogenesis, and ovulation. GPR54 is also expressed in the ovary, suggesting a direct role for KPs in ovarian steroidogenesis. The aim of present study was to determine if a low serum level of KP is responsible for reduced progesterone and estradiol levels during the period of delayed embryonic development in C. sphinx. Indeed, low serum KP abundance corresponded to reduced expression of GPR54 in ovarian luteal cells during the period of delayed development compared to normal development. In vitro and in vivo treatment with KP increased GPR54 abundance, via Extracellular signal regulated kinase and its downstream mediators, leading to increased progesterone synthesis in the ovary during delayed embryonic development. KP treatment also increased cholesterol uptake and elevated expression of Luteinizing hormone receptor and Steroid acute regulatory protein in the ovary, suggesting that elevation in circulating KP during delayed embryonic development may reactivate luteal activity. KPs may also enhance cell survival (BCL-2, reduced Caspase 3 activity) and angiogenesis (Vascular endothelium growth factor) during this period. The findings of this study thus demonstrate a regulatory role for KPs in the maintenance of luteal steroidogenesis during pregnancy in C. sphinx. PMID- 28804933 TI - Chemical Functionalization of Polysaccharides-Towards Biocompatible Hydrogels for Biomedical Applications. AB - Hydrogels have emerged as a highly interdisciplinary topic as they play a significant role for a vast number of applications. They have been studied extensively as materials for contact lenses, wound dressing and as filler material in soft-tissue augmentation, in which classical polymer backbones such as hydroxyethylmethacrylate (HEMA) are typically employed. More recently, polysaccharides have received attention, particularly in the fields of regenerative medicine and tissue engineering, as ideal candidate materials for artificial extracellular matrices (ECM). The polysaccharides of choice are dextran, alginate, chitosan, hyaluronic acid and pullulan and in order to obtain suitable hydrogels from these polysaccharides, controlled chemical functionalization is of critical importance. This short review summarizes recent developments in the chemical derivatization of polysaccharides to pave the way for crosslinking and to decorate individual polysaccharide chains with bioactive ligands. The report covers convergent and divergent protocols for crosslinking, as well strategies for bisfunctionalization of polysaccharides. Additionally, information on biological properties and biomedical applications are covered. PMID- 28804934 TI - Complicated untreated apical periodontitis causing paraesthesia: A case report. AB - The purpose of this article was to report a case of untreated apical periodontitis resulting in severe late complications. A patient with an asymptomatic crowned root canal-treated mandibular molar revealing a radiographic substandard endodontic treatment and a slight periapical radiolucency was made aware of the treatment options and opted for no treatment. The lesion slightly increased in size after 6 years, but the tooth remained asymptomatic and endodontic retreatment was again refused. After 4 more years, the patient presented with an abscess and severe pain, complicated by paraesthesia of the left chin and lip. Radiographic examination revealed that the lesion had increased considerably to involve the mandibular canal. The treatment protocol included long-term intracanal medication with calcium hydroxide and follow-ups revealed complete resolution of the periapical radiolucency and the paraesthesia had completely subsided. PMID- 28804935 TI - Confirming the mechanisms behind cognitive-behavioural therapy effectiveness in chronic pain using structural equation modeling in a sample of patients with temporomandibular disorders. AB - OBJECTIVE: To evaluate whether therapeutic mechanisms assumed to explain the effect of cognitive behavioural therapy (CBT) concerning temporomandibular symptoms are confirmed by structural equation modelling. METHOD: Patients were randomly assigned to either an experimental group receiving CBT (N = 41) or a standard therapy control group (N = 31). Subjects were assessed before and after intervention using mediator variables hypothesized according to the CBT model, as well as outcome variables and other socio-demographic and clinical measures. RESULTS: The results confirm that the effect of treatment on pain intensity was partially mediated by distress, catastrophizing, perceived control, distraction, and mental self-control. The self-medication frequency was partially mediated by distraction. Pain interference was partially mediated by distress, distraction, and mental self-control. Reduction in the number of painful points on palpation was partially explained by distress, although in this case, there was a significant direct effect of treatment not mediated by other variables. CONCLUSIONS: The results could set the principles for the development of more efficient and effective cognitive behavioural interventions for chronic pain. PMID- 28804936 TI - Subtle lower esophageal sphincter relaxation abnormalities in patients with unexplained esophageal dysphagia. AB - BACKGROUND: Esophageal dysphagia is a relatively common symptom. We aimed to evaluate whether subtle, presently not acknowledged forms of dysfunction of the lower esophageal sphincter (LES) could explain dysphagia in a subset of patients with normal findings at high-resolution manometry (HRM) according to the Chicago classification v3.0. METHODS: We used HRM to compare LES relaxation characteristics in 97 patients with unexplained dysphagia with those in 44 healthy subjects. In addition, normative values for time to LES relaxation and completeness of LES relaxation were calculated. Patients with delayed or incomplete LES relaxation were compared with patients with normal relaxation. KEY RESULTS: Dysphagia patients had a higher nadir LES pressure (P=.001) and a longer time to LES relaxation (P=.012) than healthy subjects. Based on the findings in healthy subjects, normal values of LES relaxation were defined as: >=50% of swallows with normal LES relaxation time (<5 seconds) and <=20% of swallows with incomplete LES relaxation (not reaching a value below 10 mm Hg). Dysphagia patients had significantly more often >50% swallows with delayed and/or incomplete LES relaxation than healthy controls (25% vs 4.5%; P=.004). Dysphagia patients with >50% delayed and/or incomplete LES relaxation had a significantly higher LES resting pressure (P<.001) and a significantly higher intrabolus pressure (P<.001) than dysphagia patients who did not fulfill the criteria. CONCLUSIONS AND INFERENCES: Subtle LES relaxation abnormalities, such as a delayed relaxation of the LES and/or incomplete LES relaxation, could be a cause of dysphagia in approximately one quarter of the patients with otherwise unexplained esophageal dysphagia. PMID- 28804937 TI - Breast Tumor Classification Based on a Computerized Breast Imaging Reporting and Data System Feature System. AB - OBJECTIVES: This work focused on extracting novel and validated digital high throughput features to present a detailed and comprehensive description of the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) with the goal of improving the accuracy of ultrasound breast cancer diagnosis. METHODS: First, the phase congruency approach was used to segment the tumors automatically. Second, high-throughput features were designed and extracted on the basis of each BI-RADS category. Then features were selected based on the basis of a Student t test and genetic algorithm. Finally, the AdaBoost classifier was used to differentiate benign tumors from malignant ones. RESULTS: Experiments were conducted on a database of 138 pathologically proven breast tumors. The system was compared with 6 state-of-art BI-RADS feature extraction methods. By using leave-one-out cross-validation, our system achieved a highest overall accuracy of 93.48%, a sensitivity of 94.20%, a specificity of 92.75%, and an area under the receiver operating characteristic curve of 95.67%, respectively, which were superior to those of other methods. CONCLUSIONS: The experiments demonstrated that our computerized BI-RADS feature system was capable of helping radiologists detect breast cancers more accurately and provided more guidance for final decisions. PMID- 28804938 TI - Abstract Supplement for NeuroGASTRO 2017 Congress, 24-26 August 2017, Cork, Ireland. PMID- 28804939 TI - Assessing the application of knowledge in clinical problem-solving: The structured professional reasoning exercise. AB - INTRODUCTION: Clinical reasoning is a fundamental and core clinical competence of healthcare professionals. The study aimed to investigate the utility of the Structured Professional Reasoning Exercise (SPRE), a new competence assessment method designed to measure dental students' clinical reasoning in simulated scenarios, covering the clinical areas of Oral Disease, Primary Dental Care and Restorative Dentistry, Child Dental Health and Dental Practice and Clinical Governance. MATERIALS AND METHODS: A total of 313 year-5 students sat for the assessment. Students spent 45 minutes assimilating the scenarios, before rotating through four pairs of 39 trained examiners who each independently assessed a single scenario over a ten-minute period, using a structured marking sheet. After the assessment, all students and examiners were invited to complete an anonymous perception questionnaire of the exercise. These questionnaires and the examination scores were statistically analysed. RESULTS AND DISCUSSION: Oral Disease showed the lowest scores; Dental Practice and Governance the highest. The overall Intraclass Correlation Coefficient (ICC) was 0.770, whilst examiner training helped to increase the ICC from 0.716 in 2013 to 0.835 in 2014. Exploratory factor analysis revealed one major factor with an eigenvalue of 2.75 (68.8% of total variance). The Generalizability coefficient was consistent at 0.806. A total of 295 students and 32 examiners completed the perception questionnaire. Students' lowest examination perceptions were an "Unpleasant" and "Unenjoyable" experience, whilst the highest were "Interesting", "Valuable" and "Important". The majority of students and examiners reported the assessment as acceptable, fair and valid. CONCLUSION: The SPRE offers a reliable, valid and acceptable assessment method, provided it comprises at least four scenarios with two independently marking and trained assessors. 3. PMID- 28804940 TI - Effects of polymyxin-B on TNF-alpha production in equine whole blood stimulated with three different bacterial toxins. AB - Polymyxin-B is used to treat equine systemic inflammation. Bacterial toxins other than lipopolysaccharide (LPS) contribute to systemic inflammation but the effects of polymyxin-B on these are poorly defined. Whole blood aliquots from six healthy horses diluted 1:1 with RPMI were incubated for 21 hr with 1 MUg/ml of LPS, lipoteichoic acid (LTA) or peptidoglycan (PGN) in the presence of increasing concentrations of polymyxin-B (10-3000 MUg/ml). A murine L929 fibroblast bioassay was used to measure TNF-alpha activity. Polymyxin-B significantly inhibited the effects of all three bacterial toxins. Analysis of variance showed the IC50 value for polymyxin-B for TNF-alpha inhibition caused by LTA (11.19 +/- 2.89 MUg/ml polymyxin-B) was significantly lower (p = .009) than the values for LPS (46.48 +/ 9.93 MUg/ml) and PGN (54.44 +/- 8.97 MUg/ml). There was no significant difference in IC50 values between LPS and PGN (p > .05). Maximum inhibition of TNF-alpha was 77.4%, 73.0% and 82.7% for LPS, PGN and LTA, respectively and was not significantly different between toxins. At the two highest concentrations of polymyxin-B, TNF-alpha began to increase. These data suggest that polymyxin-B may inhibit the effects of bacterial toxins other than LPS and might be a more potent inhibitor of LTA than LPS or PGN. PMID- 28804941 TI - Proteomic analysis to unravel the effect of heat stress on gene expression and milk synthesis in bovine mammary epithelial cells. AB - Heat stress can play a negative effect on milk yield and composition of dairy cattle, leading to immeasurable economic loss. The basic components of the mammary gland are the alveoli; these alveolar mammary epithelial cells reflect the milk producing ability of dairy cows. In this study, we exposed bovine mammary epithelial cells to heat stress and compared them to a control group using isobaric tags for relative and absolute quantitation combined with liquid chromatography coupled with tandem mass spectrometry. Compared with a control group, 104 differentially elevated proteins (>1.3-fold) and 167 decreased proteins (<0.77-fold) were identified in the heat treatment group. Gene Ontology analysis identified a majority of the differentially expressed proteins are associated in cell-substrate junction assembly, catabolic processes and metabolic processes. Some of these significantly regulated proteins were related to the synthesis and secretion of milk, such as milk protein and fat. This finding was further supported by the results obtained from the reduced beta-casein expression through the system of plasminogen activator - plasminogen - plasmin and decreased fatty acid synthase could partly explain why milk fat synthesis ability of dairy cows decreased under heat stress. Our results highlight the effects of heat stress on synthesis of milk protein and fat, thus providing additional clues for further studies of heat stress on dairy milk production. PMID- 28804942 TI - Metagenomic alkaline protease from mangrove sediment. AB - Functional screening of metagenomic libraries is an important tool for the discovery of new molecules. The metabolic diversity of microorganisms enables survival in harsh environments and is related to the production of enzymes. In this study, we identified a protease-producing clone from a metagenomic library derived from mangrove sediment. The protease was purified by ammonium sulphate precipitation and gel filtration chromatography, with a yield of 77.27% and a specific activity of 8.57 U MUg-1 . It had a molecular weight of approximately 70 kDa. MS/MS in ESI-Q-TOF revealed nine peptides similar to a peptidase of Bacillus safensis. The aligned partial sequence showed 47.48% identity and 82.74% similarity to the conserved domains of a glutamyl aminopeptidase from the human gut metagenome and 32.12% total coverage. The protease had an optimal pH of 8.5 and optimal activity at 60 degrees C. At pH 9-12, its activity was greater than 80%. It had moderate thermotolerance and thermostability at temperatures of 40 and 50 degrees C. The KM and Vmax values were estimated to be 0.92 mg ml-1 , and 13.15 mmol min-1 for azocasein. Substrate specificity analysis showed that PR4A3 was active on gelatin, blood, egg yolk, and milk. These results support the potential use of PR4A3 in biotechnological applications. PMID- 28804943 TI - Do we have to redefine lameness in the era of quantitative gait analysis? PMID- 28804944 TI - Progress in broodmare practice as based on recent papers in Equine Veterinary Journal. PMID- 28804945 TI - Nanoscale Metal-Organic Layers for Deeply Penetrating X-ray-Induced Photodynamic Therapy. AB - We report the rational design of metal-organic layers (MOLs) that are built from [Hf6 O4 (OH)4 (HCO2 )6 ] secondary building units (SBUs) and Ir[bpy(ppy)2 ]+ - or [Ru(bpy)3 ]2+ -derived tricarboxylate ligands (Hf-BPY-Ir or Hf-BPY-Ru; bpy=2,2' bipyridine, ppy=2-phenylpyridine) and their applications in X-ray-induced photodynamic therapy (X-PDT) of colon cancer. Heavy Hf atoms in the SBUs efficiently absorb X-rays and transfer energy to Ir[bpy(ppy)2 ]+ or [Ru(bpy)3 ]2+ moieties to induce PDT by generating reactive oxygen species (ROS). The ability of X-rays to penetrate deeply into tissue and efficient ROS diffusion through ultrathin 2D MOLs (ca. 1.2 nm) enable highly effective X-PDT to afford superb anticancer efficacy. PMID- 28804946 TI - Coefficient of Variance as Quality Criterion for Evaluation of Advanced Hepatic Fibrosis Using 2D Shear-Wave Elastography. AB - OBJECTIVES: To compare the diagnostic performance for advanced hepatic fibrosis measured by 2D shear-wave elastography (SWE), using either the coefficient of variance (CV) or the interquartile range divided by the median value (IQR/M) as quality criteria. METHODS: In this retrospective study, from January 2011 to December 2013, 96 patients, who underwent both liver stiffness measurement by 2D SWE and liver biopsy for hepatic fibrosis grading, were enrolled. The diagnostic performances of the CV and the IQR/M were analyzed using receiver operating characteristic curves with areas under the curves (AUCs) and were compared by Fisher's Z test, based on matching the cutoff points in an interactive dot diagram. All P values less than 0.05 were considered significant. RESULTS: When using the cutoff value IQR/M of 0.21, the matched cutoff point of CV was 20%. When a cutoff value of CV of 20% was used, the diagnostic performance for advanced hepatic fibrosis ( >= F3 grade) with CV of less than 20% was better than that in the group with CV greater than or equal to 20% (AUC 0.967 versus 0.786, z statistic = 2.23, P = .025), whereas when the matched cutoff value IQR/M of 0.21 showed no difference (AUC 0.918 versus 0.927, z statistic = -0.178, P = .859). CONCLUSIONS: The validity of liver stiffness measurements made by 2D SWE for assessing advanced hepatic fibrosis may be judged using CVs, and when the CV is less than 20% it can be considered "more reliable" than using IQR/M of less than 0.21. PMID- 28804947 TI - Periodontitis and Non-alcoholic Fatty Liver Disease, a population-based cohort investigation in the Study of Health in Pomerania. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) affects 20%-30% of adults with risk factors like obesity and insulin resistance putatively acting through chronic low-grade inflammation. Because periodontitis elicits low-grade inflammation, we hypothesized that it could contribute to NAFLD occurrence. OBJECTIVE: To investigate epidemiologic associations between periodontitis and the incidence of NAFLD among 2,623 participants of the Study of Health in Pomerania. METHODS: Periodontitis at baseline was defined as the percentage of sites (0%, <30%, >=30%) with (i) clinical attachment level (CAL) >=3 mm; (ii) probing pocket depth (PD) >=4 mm. Incident NAFLD was defined as a significant increase in liver echogenicity on ultrasound relative to the kidneys, with the diaphragm indistinct or the echogenic walls of the portal veins invisible. RESULTS: After a median 7.7 years of follow-up, 605 incident NAFLD cases occurred at a rate of 32.5 cases per 1,000 person-years. Relative to participants without CAL >=3 mm, NAFLD incidence was elevated slightly in participants with <30% of sites affected and moderately in participants with >=30% of sites affected (multivariable-adjusted incidence rate ratio = 1.28, 95% CI, 0.84, 1.95 and 1.60, 95% CI, 1.05-2.43), respectively. A similar dose-response relationship was not observed for PD. CONCLUSION: History of periodontitis may be a risk factor for NAFLD. PMID- 28804948 TI - Nelumbo nucifera leaf extract treatment attenuated preneoplastic lesions and oxidative stress in the livers of diethylnitrosamine-treated rats. AB - Lotus (Nelumbo nucifera Gaertn) possesses antioxidant, hepatoprotective, and anticancer potential. This study determined the protective role of aqueous extract from Nelumbo nucifera leaves (NLE) against N-diethylnitrosamine (DEN) induced oxidative stress and hepatocellular carcinogenesis in a sample of Sprague Dawley rats. NLE was fed orally to rats in which hepatic carcinoma was induced with DEN for 12 weeks. Five groups of 12 rats each were used for the study: Group I (control group) rats received distilled water; Group II rats were induced with DEN; Group III rats were induced with DEN and cotreated with 0.5% NLE; Group IV rats were induced with DEN and cotreated with 1.0% NLE; and Group V rats were induced with DEN and cotreated with 2.0% NLE. Clinical chemistry, organ weight, inflammatory marker, protein expression, enzyme, and antioxidant analyses were conducted. NLE administration to rats resulted in significantly decreased levels of serum alanine aminotransferase, aspartate aminotransferase, and albumin, which is indicative of hepatocellular damage, compared with the control group. DEN induced oxidative stress was inhibited by NLE and this inhibition was paralleled by decreased lipid peroxides and increased glutathione transferase, superoxide dismutase, catalase, and glutathione peroxidase activity in liver tissues. The status of nonenzymatic antioxidants, such as reduced glutathione, was also found to be increased in NLE-administered rats. Furthermore, NLE decreased tumor size, hepatic Rac1, PKCalpha, and GSTpi expressions compared with the DEN-only group. Thus, supplementation of NLE reduced the adverse changes that occur because of liver cancer. These results prove that NLE protects against liver carcinogenesis induced because of treatment with DEN through blocking lipid peroxidation, hepatic cell damage, and enhancing the antioxidant defense system. PMID- 28804949 TI - Portal Vein/Aorta Ratio in Dogs with Acquired Portosystemic Collaterals. AB - BACKGROUND: The portal vein (PV) diameter increases in humans with portal hypertension (PH). However, there is no evidence of PV enlargement in dogs with PH. OBJECTIVES: To measure the PV-to-aorta (PV/Ao) ratio in dogs with PH (chronic hepatitis [CH], primary hypoplasia of the PV [PHPV]), in dogs with extrahepatic congenital portosystemic shunt (EH-CPSS), and in healthy dogs, and to evaluate the relationship between PV/Ao ratio and splenic pulp pressure (SPP). ANIMALS: Twenty-five dogs with acquired portosystemic collaterals (APSCs; 15 with CH, 10 with PHPV), 32 dogs with EH-CPSS, and 20 healthy dogs. METHODS: Retrospective study. The PV/Ao ratio was calculated with images obtained by computed tomography. SPP was measured at the time of liver biopsy in 45 dogs. RESULTS: Median PV/Ao ratio was similar between dogs with CH (1.35, range 1.05-2.01) and healthy dogs (0.95, 0.80-1.15), but differed significantly between the CH group and both the PHPV (0.40, 0.24-0.67) and EH-CPSS groups (0.30, 0.11-0.64) (P < .001). The PV/Ao ratio was significantly lower in the PHPV group than in healthy dogs (P < .05). It also correlated positively with SPP (rs = 0.71; P < .001). However, there was no intragroup correlation between SPP and the PV/Ao ratio in any group. CONCLUSIONS AND CLINICAL IMPORTANCE: The PV/Ao ratio can be evaluated in dogs with APSCs on computed tomography. Further studies are needed to examine the relationship between SPP and the PV/Ao ratio in larger groups of dogs with PH and to determine its clinical relevance. PMID- 28804950 TI - Non-invasive assessment of adrenocortical function as a measure of stress in the endangered golden langur. AB - The golden langur (Trachypithecus geei) is an endangered primate endemic to northern India and Bhutan. The main stressors to the species are habitat degradation and fragmentation. Non-invasive fecal glucocorticoid metabolite (fGCM) analysis is a powerful tool for assessing stress associated with environmental disturbances in wildlife. However, interspecific differences in glucocorticoid metabolism require careful selection of the antibody used in their quantification. The goals of this study were to: 1) validate an enzyme immunoassay (EIA) to determine fecal GC metabolite (fGCM) concentrations in the golden langur and 2) compare fGCM concentrations between golden langurs living under different environmental conditions. We compared five enzyme immunoassays for determining stress related physiological responses in golden langurs by performing an adrenocorticotropic stimulation test in both sexes. Our validations identified an 11-oxoaetiocholanolone EIA detecting 11, 17 dioxoandrostanes as the most suitable assay for monitoring adrenocortical activity in the species. FGCM concentrations from semi-captive temple langurs were significantly higher than respective stress steroid concentrations in free-ranging or pet/zoo langurs. This study presents a validated practical method for non-invasive monitoring of adrenocortical function in this rare and declining species. PMID- 28804951 TI - Allometric scaling of flow-mediated dilation: is it always helpful? AB - Flow-mediated dilation (FMD) is calculated as the greatest percent change in arterial diameter following an ischaemic challenge. This Traditional %FMD calculation is thought to have statistical bias towards baseline diameter (Dbase ), which is reduced by allometric scaling. This study examined whether allometric scaling FMD influenced the difference between a group of healthy young and older adults compared to the Traditional %FMD, and to determine whether a New (allometric) scaling %FMD improved the ability to obtain individually scaled FMD. Popliteal artery FMD was assessed in 18 young (26 +/- 3 years) and 17 older adults (77 +/- 5 years). 'Corrected' mean FMD was generated from a log-linked ANCOVA model. Individual %FMD was evaluated using three calculations: (1) Traditional %FMD calculation; (2) Atkinson (allometric) scaling %FMD (peak diameter (Dpeak)/(Dbasescalingexponent)); and (3) New scaling %FMD ((Dpeak Dbase)/(Dbasescalingexponent)). Traditional %FMD was significantly larger in young (5.82 +/- 2.58%) versus old (3.72 +/- 1.26%). 'Corrected' FMD means (Y: 5.97 +/- 2.12%; O: 3.98 +/- 2.06%) were similar to Traditional %FMD; however, the logarithmic transformation prevents statistical interpretation of group differences. Individually scaled %FMD using the Atkinson scaling resulted in values that were corrected for variations in Dbase but that were twofold to threefold larger than those of the Traditional calculation. New scaling %FMD resulted in values that were similar to values expected (Y: 6.21 +/- 2.75%; O: 3.98 +/- 1.36%); however, it did not effectively correct for variation in Dbase . Recommendations regarding the advantages of allometrically scaling %FMD should be made with caution until research clearly establishes the benefits of this approach. PMID- 28804952 TI - Evaluation of cytotoxicity of propofol and its related mechanism in glioblastoma cells and astrocytes. AB - Propofol (2,6-diisopropylphenol), one of the extensively and commonly used anesthetic agents, has been shown to affect the biological behavior of various models. Previous researches have shown that propofol-induced cytotoxicity might cause anticancer effect in different cells. However, the mechanisms underlying the effect of propofol on cytotoxicity is still elusive in human glioblastoma cells. The aims of this study were to evaluate effects of propofol on cytotoxicity, cell cycle distribution and ROS production, and establish the relationship between oxidative stress and cytotoxicity in GBM 8401 human glioblastoma cells and DI TNC1 rat astrocytes. Propofol (20-30 MUM) concentration dependently induced cytotoxicity, cell cycle arrest, and increased ROS production in GBM 8401 cells but not in DI TNC1 cells. In GBM 8401 cells, propofol induced G2/M phase cell arrest, which affected the CDK1, cyclin B1, p53, and p21 protein expression levels. Furthermore, propofol induced oxygen stresses by increasing O2 and H2 O2 levels but treatment with the antioxidant N-acetylcysteine (NAC) partially reversed propofol-regulated antioxidative enzyme levels (superoxide dismutase, catalase, and glutathione peroxidase). Most significantly, propofol induced apoptotic effects by decreasing Bcl-2 but increasing Bax, cleaved caspase 9/caspase-3 levels, which were partially reversed by NAC. Moreover, the pancaspase inhibitor Z-VAD-FMK also partially prevented propofol-induced apoptosis. Together, in GBM 8401 cells but not in DI TNC1 cells, propofol activated ROS-associated apoptosis that involved cell cycle arrest and caspase activation. These findings indicate that propofol not only can be an anesthetic agent which reduces pain but also has the potential to be used for the treatment of human glioblastoma. PMID- 28804953 TI - Basic helix-loop-helix transcription factors in evolution: Roles in development of mesoderm and neural tissues. AB - Basic helix-loop-helix (bHLH) transcription factors have attracted the attention of developmental and evolutionary biologists for decades because of their conserved functions in mesodermal and neural tissue formation in both vertebrates and fruit flies. Their evolutionary history is of special interest because it will likely provide insights into developmental processes and refinement of metazoan-specific traits. This review briefly considers advances in developmental biological studies on bHLHs/HLHs. I also discuss recent genome-wide surveys and molecular phylogenetic analyses of these factors in a wide range of metazoans. I hypothesize that interactions between metazoan-specific Group A, D, and E bHLH/HLH factors enabled a sophisticated transition system from cell proliferation to differentiation in multicellular development. This control mechanism probably emerged initially to organize a multicellular animal body and was subsequently recruited to form evolutionarily novel tissues, which differentiated during a later ontogenetic phase. PMID- 28804955 TI - 3M-052 as an adjuvant for a PLGA microparticle-based Leishmania donovani recombinant protein vaccine. AB - It is believed that an effective vaccine against leishmaniasis will require a T helper type 1 (TH 1) immune response. In this study, we investigated the adjuvanticity of the Toll-like receptor (TLR) 7/8 agonist 3M-052 in combination with the Leishmania donovani 36-kDa nucleoside hydrolase recombinant protein antigen (NH36). NH36 and 3M-052 were encapsulated in separate batches of poly(lactic-co-glycolic acid) (PLGA) microparticles (MPs). The loading efficiency for NH36 was 83% and for 3M-052 was above 95%. In vitro stimulation of bone marrow-derived dendritic cells, measured by IL-12 secretion, demonstrated that 3M 052 (free or MP-formulated) had a concentration-dependent immunostimulatory effect with an optimum concentration of 2 ug/mL. In immunogenicity studies in BALB/c mice, MP-formulated NH36 and 3M-052 elicited the highest serum titers of TH 1-associated IgG2a and IgG2b antibodies and the highest frequency of IFNgamma producing splenocytes. No dose dependency was observed among MP/NH36/3M-052 groups over a dose range of 4-60 ug 3M-052 per injection. The ability of MP formulated NH36 and 3M-052 to elicit a TH 1-biased immune response indicates the potential for PLGA MP-formulated 3M-052 to be used as an adjuvant for leishmaniasis vaccines. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1587-1594, 2018. PMID- 28804956 TI - Spontaneous Regression of a Nail Matrix Melanocytic Nevus in a Child. AB - A 14-year-old Hispanic boy presented with a 0.25-mm wide, sharply demarcated, dark brown band of longitudinal melanonychia of the left thumbnail. A clinical diagnosis of nail matrix nevus was made and the boy was scheduled for follow-up. The band showed proximal fading after 6 months and had completely faded after 11 months, with the proximal nail fold showing small dark brown dots on dermoscopy. We documented the spontaneous regression of melanonychia over 11 months. PMID- 28804957 TI - Pre- and Post-Transfusion Alloimmunization in Dogs Characterized by 2 Antiglobulin-Enhanced Cross-match Tests. AB - BACKGROUND: When dogs are transfused, blood compatibility testing varies widely but may include dog erythrocyte antigen (DEA) 1 typing and rarely cross-matching. OBJECTIVES: Prospective study to examine naturally occurring alloantibodies against red blood cells (RBCs) and alloimmunization by transfusion using 2 antiglobulin-enhanced cross-match tests. ANIMALS: Eighty client-owned anemic, 72 donor, and 7 control dogs. METHODS: All dogs were typed for DEA 1 and some also for DEA 4 and DEA 7. Major cross-match tests with canine antiglobulin-enhanced immunochromatographic strip and gel columns were performed 26-129 days post transfusion (median, 39 days); some dogs had an additional early evaluation 11-22 days post-transfusion (median, 16 days). Plasma from alloimmunized recipients was cross-matched against RBCs from 34 donor and control dogs. RESULTS: The 2 cross match methods gave entirely concordant results. All 126 pretransfusion cross match results for the 80 anemic recipients were compatible, but 54 dogs died or were lost to follow up. Among the 26 recipients with follow-up, 1 dog accidently received DEA 1-mismatched blood and became cross-match-incompatible post transfusion. Eleven of the 25 DEA 1-matched recipients (44%) became incompatible against other RBC antigens. No naturally occurring anti-DEA 7 alloantibodies were detected in DEA 7- dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: The antiglobulin enhanced immunochromatographic strip cross-match and laboratory gel column techniques identified no naturally occurring alloantibodies against RBC antigens, but a high degree of post-transfusion alloimmunization in dogs. Cross-matching is warranted in any dog that has been previously transfused independent of initial DEA 1 typing and cross-matching results before the first transfusion event. PMID- 28804958 TI - Prevalence of hepatitis B and human T-lymphotropic virus infection among blood donors at a hospital in the south-central highlands of Peru. PMID- 28804959 TI - Head-to-head comparison of prasugrel versus ticagrelor in patients undergoing percutaneous coronary intervention: A meta-analysis of randomized controlled trials. AB - OBJECTIVES: We sought to compare the efficacy and safety of prasugrel and ticagrelor in patients with coronary artery disease undergoing percutaneous coronary intervention (PCI). BACKGROUND: Evidence from randomized head-to-head comparison between prasugrel and ticagrelor is rare regarding clinical endpoints. METHODS: PubMed, the Cochrane Library, and Web of Science were queried with the terms "prasugrel," "ticagrelor," and "randomized." Relevant randomized controlled trials (RCTs) or the same terms were also surveyed using clinicaltrials.gov, escardio.org, pcronline.org, and tctmd.com. The clinical endpoints were death, myocardial infarction (MI), stroke, and stent thrombosis (ST) for efficacy, and any bleeding for safety. RESULTS: A total number of 2068 patients in 12 RCTs, whose longest follow-up period was 6 months, was included in this study. The risks of death (odds ratio [OR]: 0.86, 95% confidence interval [CI]: 0.46-1.62, P = 0.647), MI (OR: 1.61, 95%CI: 0.71-3.62, P = 0.252), stroke (OR: 1.45, 95%CI: 0.25-8.36, P = 0.680), and ST (OR: 0.76, 95%CI: 0.20-2.81, P = 0.677) were similar between prasugrel and ticagrelor, respectively. While the incidence of bleeding according to the Bleeding Academic Research Consortium definitions was also comparable (OR: 0.83, 95%CI: 0.45-1.52, P = 0.539), that according to the Thrombolysis in Myocardial Infarction criteria was lower in prasugrel than ticagrelor (OR: 0.49, 95%CI: 0.24-0.97, P = 0.042). CONCLUSIONS: Although the efficacy was similar between prasugrel and ticagrelor, prasugrel may be associated with a lower risk of bleeding compared with ticagrelor during short- to mid-term follow-up period after PCI. Further studies are warranted in a larger patient population during longer-term follow up to validate these findings. PMID- 28804960 TI - Handle with Care: Rethinking the Rights versus Culture Dichotomy in Cancer Disclosure in India. AB - Medical practitioners, bioethicists, psychologists, and anthropologists have debated whether it is ethical to disclose or withhold information from patients about cancer diagnoses. This debate is framed as pitting universal individual human rights against cultural pluralism. The rights-based argument asserts that people have a right to information about their own health to make the best decisions about their treatment. The cultural variation argument suggests that in some cultural contexts there is a perception that information about one's cancer diagnosis may cause more harm than good due to the psychological trauma this may cause. Based on ethnographic research with cancer patients in India, I argue that both sides of this debate overemphasize the importance of the content of the information that may be disclosed or withheld and underestimate the central ways in which the act of disclosing or withholding information is evaluated as a symbol of care of paramount concern to patients. PMID- 28804961 TI - Gaseous Nanocarving-Mediated Carbon Framework with Spontaneous Metal Assembly for Structure-Tunable Metal/Carbon Nanofibers. AB - Vapor phase carbon (C)-reduction-based syntheses of C nanotubes and graphene, which are highly functional solid C nanomaterials, have received extensive attention in the field of materials science. This study suggests a revolutionary method for precisely controlling the C structures by oxidizing solid C nanomaterials into gaseous products in the opposite manner of the conventional approach. This gaseous nanocarving enables the modulation of inherent metal assembly in metal/C hybrid nanomaterials because of the promoted C oxidation at the metal/C interface, which produces inner pores inside C nanomaterials. This phenomenon is revealed by investigating the aspects of structure formation with selective C oxidation in the metal/C nanofibers, and density functional theory calculation. Interestingly, the tendency of C oxidation and calculated oxygen binding energy at the metal surface plane is coincident with the order Co > Ni > Cu > Pt. The customizable control of the structural factors of metal/C nanomaterials through thermodynamic-calculation-derived processing parameters is reported for the first time in this work. This approach can open a new class of gas-solid reaction-based synthetic routes that dramatically broaden the structure design range of metal/C hybrid nanomaterials. It represents an advancement toward overcoming the limitations of intrinsic activities in various applications. PMID- 28804962 TI - Biochemical analysis of uterine fluid for identification of indicators for subclinical endometritis in the water buffalo (Bubalus bubalis). AB - Alterations in biochemical constituents of uterine fluid have been suggested for diagnosis of subclinical uterine infection in the bovine. This study was undertaken to investigate whether uterine fluid biomolecules could act as tool for diagnosis of subclinical endometritis in the buffalo. Uterine fluid samples from normal (n = 22) and subclinical endometritis (n = 18; diagnosed based on uterine cytology)-affected buffaloes were subjected to biochemical analysis. Among the different biochemical constituents estimated, urea, urea N, cholesterol, total bilirubin and alkaline phosphatase (ALP) concentrations were significantly (p < 0.05) higher in uterine fluid obtained from subclinical endometritis-affected buffaloes. The extent of difference between normal and subclinical endometritis-affected buffaloes was highest in ALP (69%) followed by cholesterol (55%), bilirubin (48%), urea (30%) and urea N (30%) concentrations. Receiver operating characteristic (ROC) analysis indicated that the likelihood ratio (LR) was 3.63 for urea, indicating that buffaloes having less than the threshold concentration (47.5 mg/dl) of urea in their uterine fluid were at 3.6 times more risk to be affected with SE. The LRs for urea N, cholesterol, ALP and bilirubin were 2.33, 2.54, 2.12 and 1.65, respectively. It was concluded that ALP, urea, urea N and cholesterol concentrations in uterine fluid may serve as an aid for diagnosing subclinical endometritis in the buffalo. PMID- 28804963 TI - Effect of housing system on reproductive behaviour and on some endocrinological and seminal parameters of donkey stallions. AB - Reproductive management of male donkeys employed for artificial breeding has been poorly studied. The aim of this study was to evaluate the effect of housing system, with the animals grouped together in a paddock or kept in individual boxes, on sexual behaviour, cortisol and testosterone concentration and seminal characteristics of adult male donkeys. The study included four Amiata donkey jacks (stallions) from which ejaculates, saliva and blood were collected during two distinct 3 weeks periods, one in the group and one in the box housing system. Time needed for semen collection was shorter when donkeys were kept in paddocks compared to when they were kept in single boxes (14:57 +/- 07:27 and 20:52 +/- 09:31 min, p < .05). Native semen characteristics were not influenced by housing system, while cooled preservation in an Equitainer(r) showed that sperm motility parameters were significantly higher during the paddock period compared to the box period. Salivary cortisol was influenced by housing system, both before and 60 min after ejaculation, being statistically higher when donkeys were housed in paddocks. On the contrary, overall and basal testosterone concentrations were significantly higher when animals were kept in boxes. In conclusion, in the present study, good quality semen could be successfully collected from donkeys irrespective of the housing system despite some differences in hormone concentrations. PMID- 28804964 TI - Birth Outcome of Children Fathered by Men Treated with Systemic Corticosteroids during the Conception Period - A Cohort Study based on Nationwide Data. AB - Information on the safety of paternal use of medications prior to the time of conception is limited, and there is little available evidence regarding possible adverse effects of paternal use of systemic corticosteroids (SCS). In this cohort study, based on nationwide data, we examined the association between paternal use of SCS prior to conception and adverse birth outcome. The study includes data from all singletons born in Denmark from 1 January 1997 through 2013 (N = 1,013,994). Children fathered by men who redeemed a prescription of SCS within 3 months before conception (N = 2380) constituted the exposed groups. The outcome was congenital abnormalities (CAs), pre-term birth and small-for-gestational age (SGA). We adjusted for co-variates in multi-level logistic regression analyses. The adjusted odds ratios for pre-term birth and SGA were 0.81 (95% CI: 0.55-1.21) and 1.06 (95% CI: 0.68-1.64), respectively. The adjusted odds ratios for CAs were 1.08 (95% CI: 0.87-1.40) in children fathered by men who redeemed one prescription within 3 months before conception and 1.33 (95% CI: 0.99-1.79) in children fathered by men who redeemed two or more prescriptions. This study is the largest to date examining the effect of paternal use of SCS prior to conception on birth outcome. We found no significantly increased risk of pre-term birth or SGA. In children of fathers who redeemed at least two prescriptions of SCS within 3 months before conception, we found an increased risk of CAs, though not statistically significant. The types of CAs did not show a distinct pattern. PMID- 28804965 TI - Synthetic Manipulation of Hybrid Perovskite Systems in Search of New and Enhanced Functionalities. AB - Over the past few years the organic-inorganic hybrid perovskite systems have emerged as a promising class of materials for photovoltaic and electroluminescent thin-film device applications, in view of their unique set of tunable optoelectronic properties. Importantly, these materials can be easily solution processed at low temperatures and as such are amenable to facile molecular engineering. Thus, a variety of low-dimensional forms and quantum structures of these materials can be obtained through strategic synthetic manipulations through small molecule incorporation or molecular ion doping. In this Minireview, we specifically focus on these approaches and outline the possibilities of utilizing these for enhanced functionalities and newer application domains. PMID- 28804967 TI - Comparative proteomic analysis of different developmental stages of swamp buffalo testicular seminiferous tubules. AB - With ageing, many protein components change markedly during mammalian spermatogenesis. Most of these proteins have yet to be characterized and verified. Here, we have employed two-dimensional electrophoresis coupled to tandem mass spectrometry to explore the different proteins from pre-pubertal, pubertal and post-pubertal swamp buffalo testicular seminiferous tubules. The results showed that 25 protein spots were differentially expressed among developmental stages, and 13 of them were successfully identified by mass spectrometry. Of which four proteins were up-regulated and three proteins were down-regulated with age, and the remaining six proteins were fluctuated among developmental stages. Bioinformatics analysis indicates that these proteins were probably related to cellular developmental process (53.8%), cell differentiation (53.8%), spermatogenesis (15.4%), apoptotic process and cell death (30.8%). Expression profiles of calumenin (CALU) and galectin-1 (LGALS1) were further verified via Western blotting. In summary, the results help to develop an understanding of molecular mechanisms associated with buffalo spermatogenesis. PMID- 28804966 TI - Associations of parental alcohol use disorders and parental separation with offspring initiation of alcohol, cigarette and cannabis use and sexual debut in high-risk families. AB - BACKGROUND AND AIMS: Parental alcohol use disorders (AUDs) and parental separation are associated with increased risk for early use of alcohol in offspring, but whether they increase risks for early use of other substances and for early sexual debut is under-studied. We focused on associations of parental AUDs and parental separation with substance initiation and sexual debut to (1) test the strength of the associations of parental AUDs and parental separation with time to initiation (age in years) of alcohol, tobacco and cannabis use and sexual debut and (2) compare the strength of association of parental AUD and parental separation with initiation. DESIGN: Prospective adolescent and young adult cohort of a high-risk family study, the Collaborative Study on the Genetics of Alcoholism (COGA). SETTING: Six sites in the United States. PARTICIPANTS: A total of 3257 offspring (aged 14-33 years) first assessed in 2004 and sought for interview approximately every 2 years thereafter; 1945 (59.7%) offspring had a parent with an AUD. MEASUREMENTS: Diagnostic interview data on offspring substance use and sexual debut were based on first report of these experiences. Parental life-time AUD was based on their own self-report when parents were interviewed (1991-2005) for most parents, or on offspring and other family member reports for parents who were not interviewed. Parental separation was based on offspring reports of not living with both biological parents most of the time between ages 12 and 17 years. FINDINGS: Parental AUDs were associated with increased hazards for all outcomes, with cumulative hazards ranging from 1.19 to 2.71. Parental separation was also an independent and consistent predictor of early substance use and sexual debut, with hazards ranging from 1.19 to 2.34. The strength of association of parental separation with substance initiation was equal to that of having two AUD-affected parents, and its association with sexual debut was stronger than the association of parental AUD in one or both parents. CONCLUSIONS: Parental alcohol use disorders (AUDs) and parental separation are independent and consistent predictors of increased risk for early alcohol, tobacco and cannabis use and sexual debut in offspring from families with a high risk of parental AUDs. PMID- 28804968 TI - Continuous Production of Biorenewable, Polymer-Grade Lactone Monomers through Sn beta-Catalyzed Baeyer-Villiger Oxidation with H2 O2. AB - The Baeyer-Villiger oxidation is a key transformation for sustainable chemical synthesis, especially when H2 O2 and solid materials are employed as oxidant and catalyst, respectively. 4-substituted cycloketones, which are readily available from renewables, present excellent platforms for Baeyer-Villiger upgrading. Such substrates exhibit substantially higher levels of activity and produce lactones at higher levels of lactone selectivity at all values of substrate conversion, relative to non-substituted cyclohexanone. For 4-isopropyl cyclohexanone, which is readily available from beta-pinene, continuous upgrading was evaluated in a plug-flow reactor. Excellent selectivity (85 % at 65 % conversion), stability, and productivity were observed over 56 h, with over 1000 turnovers (mol product per mol Sn) being achieved with no loss of activity. A maximum space-time yield that was almost twice that for non-substituted cyclohexanone was also obtained for this substrate [1173 vs. 607 g(product) kg(catalyst)-1 cm-3 h-1 ]. The lactone produced is also shown to be of suitable quality for ring opening polymerization. In addition to demonstrating the viability of the Sn-beta/H2 O2 system to produce renewable lactone monomers suitable for polymer applications, the substituted alkyl cyclohexanones studied also help to elucidate steric, electronic, and thermodynamic elements of this transformation in greater detail than previously achieved. PMID- 28804969 TI - On-Chip Andreev Devices: Hard Superconducting Gap and Quantum Transport in Ballistic Nb-In0.75 Ga0.25 As-Quantum-Well-Nb Josephson Junctions. AB - A superconducting hard gap in hybrid superconductor-semiconductor devices has been found to be necessary to access topological superconductivity that hosts Majorana modes (non-Abelian excitation). This requires the formation of homogeneous and barrier-free interfaces between the superconductor and semiconductor. Here, a new platform is reported for topological superconductivity based on hybrid Nb-In0.75 Ga0.25 As-quantum-well-Nb that results in hard superconducting gap detection in symmetric, planar, and ballistic Josephson junctions. It is shown that with careful etching, sputtered Nb films can make high-quality and transparent contacts to the In0.75 Ga0.25 As quantum well, and the differential resistance and critical current measurements of these devices are discussed as a function of temperature and magnetic field. It is demonstrated that proximity-induced superconductivity in the In0.75 Ga0.25 As-quantum-well 2D electron gas results in the detection of a hard gap in four out of seven junctions on a chip with critical current values of up to 0.2 uA and transmission probabilities of >0.96. The results, together with the large g-factor and Rashba spin-orbit coupling in In0.75 Ga0.25 As quantum wells, which indeed can be tuned by the indium composition, suggest that the Nb-In0.75 Ga0.25 As-Nb system can be an excellent candidate to achieve topological phase and to realize hybrid topological superconducting devices. PMID- 28804970 TI - Arrhythmogenic gene remodelling in elderly patients with type 2 diabetes with aortic stenosis and normal left ventricular ejection fraction. AB - NEW FINDINGS: What is the central question of this study? Type 2 diabetes is associated with a higher rate of ventricular arrhythmias compared with the non diabetic population, but the associated myocardial gene expression changes are unknown; furthermore, it is also unknown whether any changes are attributable to chronic hyperglycaemia or are a consequence of structural changes. What is the main finding and its importance? We found downregulation of left ventricular ERG gene expression and increased NCX1 gene expression in humans with type 2 diabetes compared with control patients with comparable left ventricular hypertrophy and possible myocardial fibrosis. This was associated with QT interval prolongation. Diabetes and associated chronic hyperglycaemia may therefore promote ventricular arrhythmogenesis independently of structural changes. Type 2 diabetes is associated with a higher rate of ventricular arrhythmias, and this is hypothesized to be independent of coronary artery disease or hypertension. To investigate further, we compared changes in left ventricular myocardial gene expression in type 2 diabetes patients with patients in a control group with left ventricular hypertrophy. Nine control patients and seven patients with type 2 diabetes with aortic stenosis undergoing aortic valve replacement had standard ECGs, signal-averaged ECGs and echocardiograms before surgery. During surgery, a left ventricular biopsy was taken, and mRNA expressions for genes relevant to the cardiac action potential were estimated by RT-PCR. Mathematical modelling of the action potential and calcium transient was undertaken using the O'Hara-Rudy model using scaled changes in gene expression. Echocardiography revealed similar values for left ventricular size, filling pressures and ejection fraction between groups. No difference was seen in positive signal-averaged ECGs between groups, but the standard ECG demonstrated a prolonged QT interval in the diabetes group. Gene expression of KCNH2 and KCNJ3 were lower in the diabetes group, whereas KCNJ2, KCNJ5 and SLC8A1 expression were higher. Modelling suggested that these changes would lead to prolongation of the action potential duration with generation of early after-depolarizations secondary to a reduction in density of the rapid delayed rectifier K+ current and increased Na+ -Ca2+ exchange current. These data suggest that diabetes leads to pro-arrythmogenic changes in myocardial gene expression independently of left ventricular hypertrophy or fibrosis in an elderly population. PMID- 28804971 TI - Abortion in goats by Caprine alphaherpesvirus 1 in Spain. AB - An abortion outbreak occurred in a goat herd of Murciano-Granadina breed in Almeria Region in Spain where 80 pregnant females aborted. All bacteriological and parasitological examinations resulted negative, whereas virological investigations and real-time PCR assay showed the presence of Caprine alphaherpesvirus 1 DNA in the pathological specimens from aborted foetuses. Nucleotide sequence analysis revealed that the DNA was highly close related to the Swiss strain E-CH (99.7%) and a little less extent to the Italian BA.1 strain (99.4%). Histopathological examination revealed multifocal, well-circumscribed, 50- to 200-MUm-diameter foci of coagulative necrosis in the liver, lungs and kidneys of three foetuses. In the periphery of the necrosis, there were frequently epithelial cells with the chromatin emarginated by large, round, amphophilic intranuclear viral inclusion bodies. The source of the infection in the herd could not clearly find out even some hypothesis were formulated. This seems to be the first report of an abortion outbreak due to Caprine alphaherpesvirus 1 in a goat herd in Spain. PMID- 28804973 TI - A Useful Method for Preparing Mixed Brush Polymer Grafted Nanoparticles by Polymerizing Block Copolymers from Surfaces with Reversed Monomer Addition Sequence. AB - The preparation of well-defined block copolymers using controlled radical polymerization depends on the proper order of monomer addition. The reversed order of monomer addition results in a mixture of block copolymer and homopolymer and thus has typically been avoided. In this paper, the low blocking efficiency of reversed monomer addition order is utilized in combination with surface initiated reversible addition-fragmentation chain-transfer polymerization to establish a facile procedure toward mixed polymer brush grafted nanoparticles SiO2 -g-(PS (polystyrene), PS-b-PMAA (polymethacrylic acid)). The SiO2 -g-(PS, PS b-PMAA) nanoparticles are analyzed by gel permeation chromatography deconvolution, and the fraction of each polymer component is calculated. Additionally, the SiO2 -g-(PS, PS-b-PMAA) are amphiphilic in nature and show unique self-assembly behavior in water. PMID- 28804972 TI - Mendelian randomisation analysis provides no evidence for a relationship between adult height and testicular cancer risk. AB - Observational studies have suggested anthropometric traits, particularly increased height are associated with an elevated risk of testicular cancer (testicular germ cell tumour). However, there is an inconsistency between study findings, suggesting the possibility of the influence of confounding factors. To examine the association between anthropometric traits and testicular germ cell tumour using an unbiased approach, we performed a Mendelian randomisation study. We used genotype data from genome wide association studies of testicular germ cell tumour totalling 5518 cases and 19,055 controls. Externally weighted polygenic risk scores were created and used to evaluate associations with testicular germ cell tumour risk per one standard deviation (s.d) increase in genetically-defined adult height, adult BMI, adult waist hip ratio adjusted for BMI (WHRadjBMI), adult hip circumference adjusted for BMI (HIPadjBMI), adult waist circumference adjusted for BMI (WCadjBMI), birth weight (BW) and childhood obesity. Mendelian randomisation analysis did not demonstrate an association between any anthropometric trait and testicular germ cell tumour risk. In particular, despite good power, there was no global evidence for association between height and testicular germ cell tumour. However, three SNPs for adult height individually showed association with testicular germ cell tumour (rs4624820: OR = 1.47, 95% CI: 1.41-1.55, p = 2.7 * 10-57 ; rs12228415: OR = 1.17, 95% CI: 1.11-1.22, p = 3.1 * 10-10 ; rs7568069: OR = 1.13, 95% CI: 1.07 1.18, p = 1.1 * 10-6 ). This Mendelian randomisation analysis, based on the largest testicular germ cell tumour genome wide association dataset to date, does not support a causal etiological association between anthropometric traits and testicular germ cell tumour aetiology. Our findings are more compatible with confounding by shared environmental factors, possibly related to prenatal growth with exposure to these risk factors occurring in utero. PMID- 28804974 TI - Rome III vs Rome IV criteria for irritable bowel syndrome: A comparison of clinical characteristics in a large cohort study. AB - BACKGROUND: The Rome criteria for irritable bowel syndrome (IBS) have been revised and are expected to apply only to the subset of Rome III IBS subjects with abdominal pain as predominant symptom, occurring at least once a week. The aim of this study was to determine the percentage of Rome III IBS subjects that fulfills Rome IV criteria and to evaluate differences between Rome IV-positive and Rome IV-negative subjects. METHODS: Four hundred and four Rome III IBS subjects completed a 14-day end-of-day symptom diary, the Gastrointestinal Symptom Rating Scale (GSRS), Hospital Anxiety and Depression Scale, and RAND 36 item Short-Form Health Survey (SF-36). Diary-based surrogate Rome IV criteria were defined as occurrence of abdominal pain at least 1 day each week with a severity of >=2 (mild; definition 1) or >=3 (considerable; definition 2). KEY RESULTS: Using surrogate Rome IV criteria, 353 (87.4%, definition 1) and 249 (61.6%, definition 2) subjects were defined as Rome IV positive. These patients were more often female, younger, and recruited from secondary/tertiary care compared with Rome IV-negative subjects. They also presented with higher abdominal pain scores and gastrointestinal (GI) symptom severity on both end-of day diary and GSRS, higher psychological symptom scores, and lower quality of life compared with Rome IV-negative subjects. CONCLUSIONS AND INFERENCES: The Rome IV IBS population likely reflects a subgroup of Rome III IBS patients with more severe GI symptomatology, psychological comorbidities, and lower quality of life. This implies that results from Rome III IBS studies may not be directly comparable to those from Rome IV IBS populations. PMID- 28804976 TI - Demyelinating neuropathy in a 6-year-old girl with autism spectrum disorder. AB - Herein we report the case of a 6-year-old girl with autism spectrum disorder (ASD) and weakness in the distal portion of the right upper limb. Although difficult to perform, nerve conduction studies indicated demyelinating neuropathy. Magnetic resonance imaging (MRI) showed swelling a nd high-intensity signals in the right brachial plexus and cervical spinal roots. The symptoms recovered after a single course of i.v. immunoglobulin. Electrophysiological indices and MRI findings also improved after treatment. This case demonstrates the utility of neuroimaging in addition to electrophysiological assessments for the diagnosis of demyelinating neuropathy, particularly in young patients with ASD. PMID- 28804977 TI - Epstein-Barr virus hepatitis: Importance of PCR assay/serology and significance of gamma-GTP. PMID- 28804978 TI - Birthweight and serum uric acid in American adolescents. AB - Elevated serum uric acid is associated with hypertension and chronic kidney disease. We evaluated the relationship between birthweight and uric acid in a nationally representative sample of 5390 US adolescents aged 12-15 in the National Health and Nutrition Examination Survey from 1999 to 2012. There was an inverse association between birthweight and uric acid after adjustment for sex, age, race, obesity, and dietary sodium intake. Each 1 kg increase in birthweight was associated with decreased uric acid by 0.11 mg/dL (95% CI: -0.16 to -0.06; model R2 = 0.32). This relationship was stronger in adolescents with elevated blood pressure (beta = -0.25; 95% CI: -0.44 to -0.06; R2 = 0.50) but persisted in adolescents with normal blood pressure (beta = -0.10; 95% CI: -0.15 to -0.05; R2 = 0.31). In conclusion, lower birthweight is associated with higher uric acid in US adolescents. These findings may support the hypothesis that reduced nephron number is associated with elevated uric acid. PMID- 28804979 TI - Kleine-Levin syndrome elicited by encephalopathy with reversible splenial lesion. AB - Kleine-Levin syndrome is a rare sleep disorder of unknown etiology characterized by repetitive episodes of hypersomnia between asymptomatic periods. We report the case of a 13-year-old girl who presented with drowsiness triggered by influenza A as the first episode. Magnetic resonance imaging (MRI) on day 6 showed transient reduction of diffusion in the corpus callosum splenium. The patient was diagnosed with encephalopathy with a reversible splenial lesion. The symptoms resolved after 10 days, but additional episodes of hypersomnia lasting 5-10 days occurred 1, 5, 6, 11, 13, and 25 months after the first episode. MRI during hypersomnia indicated no lesions, and sleep duration and cognition were normal between episodes. The patient was diagnosed with Kleine-Levin syndrome. Electroencephalographic and clinical findings during the first episode were similar to those during the other episodes. Encephalopathy with a splenial lesion and Kleine-Levin syndrome may have similar pathological mechanisms causing a disturbance in consciousness. PMID- 28804980 TI - Using Bayes factors to evaluate evidence for no effect: examples from the SIPS project. AB - AIMS: To illustrate how Bayes factors are important for determining the effectiveness of interventions. METHOD: We consider a case where inappropriate conclusions were drawn publicly based on significance testing, namely the SIPS project (Screening and Intervention Programme for Sensible drinking), a pragmatic, cluster-randomized controlled trial in each of two health-care settings and in the criminal justice system. We show how Bayes factors can disambiguate the non-significant findings from the SIPS project and thus determine whether the findings represent evidence of absence or absence of evidence. We show how to model the sort of effects that could be expected, and how to check the robustness of the Bayes factors. RESULTS: The findings from the three SIPS trials taken individually are largely uninformative but, when data from these trials are combined, there is moderate evidence for a null hypothesis (H0) and thus for a lack of effect of brief intervention compared with simple clinical feedback and an alcohol information leaflet (B = 0.24, P = 0.43). CONCLUSION: Scientists who find non-significant results should suspend judgement unless they calculate a Bayes factor to indicate either that there is evidence for a null hypothesis (H0) over a (well-justified) alternative hypothesis (H1), or that more data are needed. PMID- 28804981 TI - Lipopolysaccharide inhibits hepatic gluconeogenesis in rats: The role of immune cells. AB - AIMS/INTRODUCTION: Bacterial septicemia has diverse clinical symptoms including severe hypoglycemia. However, sepsis-induced hypoglycemia has not yet been examined in detail. The aim of the present study was to investigate the mechanisms underlying hypoglycemia in sepsis. MATERIALS AND METHODS: We induced endotoxin shock in rats using lipopolysaccharide (LPS). After an intraperitoneal injection of LPS, we measured gluconeogenesis using the pyruvate tolerance test. The effects of LPS on glucose metabolism were investigated in perfused livers and isolated hepatocytes. Furthermore, its effects on the production of inflammatory cytokines were examined in isolated splenocytes. The interaction between splenocytes and hepatocytes in response to LPS was investigated in vitro using a co-culture of splenocytes and hepatocytes. RESULTS: In the pyruvate tolerance test, the pretreatment with LPS decreased gluconeogenesis. The in vivo pretreatment of rats with LPS did not inhibit glucose production in perfused livers. The in vitro treatment of isolated hepatocytes with LPS did not decrease hepatic gluconeogenesis. Although LPS increased the production of inflammatory cytokines (tumor necrosis factor-alpha, interferon-gamma, interleukin-1beta, interleukin-6 and interleukin-10) and nitric oxide in isolated splenocytes, only nitric oxide significantly inhibited gluconeogenesis in isolated hepatocytes. When splenocytes and hepatocytes were co-cultured in medium containing LPS, the messenger ribonucleic acid expression of glucose-6-phosphatase in hepatocytes was suppressed. CONCLUSIONS: LPS reduced hepatic gluconeogenesis, at least in part, by stimulating the production of nitric oxide in splenocytes. This effect could contribute to the mechanisms responsible for septicemia-induced hypoglycemia. PMID- 28804982 TI - Epidemiological investigation of outbreaks of fowl adenovirus infections in commercial chickens in China. AB - One hundred and five fowl adenovirus (FAdV) strains were isolated in China from 2015 to 2016 from poultry with inclusion body hepatitis (IBH) and hydropericardium syndrome (HPS). Polymerase chain reactions determined that 68 were FAdV species C, five were FAdV species D, two were FAdV species E, and 30 contained two or more different FAdV strains. A phylogenetic analysis showed that the isolated FAdV strains clustered into three major groups: FAdV-C, FAdV-D and FAdV-E. Based on a hexon gene sequencing analysis, these viruses were genetically related to FAdV-4, FAdV-7, FAdV-8b and FAdV-11, of which FAdV-4 was dominant (93% of the strains). An epidemiological analysis showed that FAdVs had been circulating in broilers, domestic chickens, and layers, and co-infections with other immunosuppressive pathogens, such as chicken infectious anaemia virus, Marek's disease virus and reticuloendotheliosis virus, were identified. To control FAdVs, strict biosecurity protection measures are necessary, and a continued surveillance of FAdVs is needed to increase our understanding of the epidemiology of the viruses that are associated with IBH and HPS. PMID- 28804983 TI - A longitudinal study of the profiles of psychological thriving, resilience, and loss in people with inflammatory bowel disease. AB - OBJECTIVES: Despite the toll of inflammatory bowel disease (IBD) on adjustment, many patients are resilient to the challenges associated with living with IBD, and successfully cope with their illness and thrive. Yet there is little research on why some individuals with IBD enter a trajectory of growth, while others may struggle to adapt. The aim of this study was to investigate the adjustment related factors that distinguished thriving, resilience, and loss in people with IBD across personal growth, life satisfaction, and relationship quality domains. DESIGN: Prospective cohort design with two data collection points, 6 months apart. METHODS: From a sample of 420 people with active IBD who completed an online survey, 152 participants completed the follow-up survey and were included in the analyses. Participants completed measures of thriving, and cognitive, affective, social, and disease-related variables known to predict adjustment. RESULTS: Time 1 ANCOVAs and pairwise comparisons controlling for demographics distinguished loss from resilience and thriving on the four outcomes - coping efficacy, illness acceptance, depressive symptoms, and perceived social support - for all three domains. Time 2 ANCOVAs and pairwise comparisons controlling for baseline outcomes revealed that the Time thriving categories predicted differences in Time 2 adjustment, mainly for the life satisfaction domain, with those experiencing loss reporting poorer adjustment than those experiencing resilience and thriving. CONCLUSIONS: Findings highlight the distinctions among profiles of thriving, resilience, and loss in adjustment to IBD, and suggest that strategies that enhance coping and address depressive symptoms may optimize thriving in the context of IBD. Statement of contribution What is already known on this subject? Inflammatory bowel disease (IBD) is associated with depression, poor coping, and stressful symptoms. Previous research has focused mainly on poor adjustment to IBD rather than on positive growth. There is little research on why some patients with IBD thrive or are resilient, while others struggle to adapt. What does this study add? This study is the first to longitudinally examine the profiles of thriving, resilience, and loss in individuals with IBD. The thriving profiles differed in coping efficacy, illness acceptance, depressive symptoms, and social support outcomes at Time 1, and predicted adjustment at T2 mainly for the life satisfaction domain. Strategies that enhance coping and social support may optimize thriving in the context of IBD. PMID- 28804984 TI - 3D Bioprinting for Cartilage and Osteochondral Tissue Engineering. AB - Significant progress has been made in the field of cartilage and bone tissue engineering over the last two decades. As a result, there is real promise that strategies to regenerate rather than replace damaged or diseased bones and joints will one day reach the clinic however, a number of major challenges must still be addressed before this becomes a reality. These include vascularization in the context of large bone defect repair, engineering complex gradients for bone-soft tissue interface regeneration and recapitulating the stratified zonal architecture present in many adult tissues such as articular cartilage. Tissue engineered constructs typically lack such spatial complexity in cell types and tissue organization, which may explain their relatively limited success to date. This has led to increased interest in bioprinting technologies in the field of musculoskeletal tissue engineering. The additive, layer by layer nature of such biofabrication strategies makes it possible to generate zonal distributions of cells, matrix and bioactive cues in 3D. The adoption of biofabrication technology in musculoskeletal tissue engineering may therefore make it possible to produce the next generation of biological implants capable of treating a range of conditions. Here, advances in bioprinting for cartilage and osteochondral tissue engineering are reviewed. PMID- 28804986 TI - Effects of (-)-hydroxycitric acid on lipid droplet accumulation in chicken embryos. AB - This study was conducted to determine the impact of (-)-hydroxycitric acid ((-) HCA) on biochemical indices and lipid metabolism parameters in chicken embryos. Two hundred and forty fertilized eggs were divided into six groups and injected with (-)-HCA at concentrations of 0, 0.1, 0.5, 1.0, 10.0 and 50 mg/kg (n = 40). After 19 days of incubation, serum and liver were collected for analysis of biochemical indices and lipid metabolism parameters. Results showed no significant differences on serum biochemical indices: 1-50 mg/kg (-)-HCA significantly increased serum glucose and hepatic glycogen contents (P < 0.05). Oil Red O staining analysis showed total area, counts of lipid droplets and hepatic triglyceride content were significantly decreased (P < 0.01), meanwhile hepatic lipase and lipoprotein lipase activity were significantly increased (P < 0.05). ACLY, ME1, SREBP-1c messenger RNA (mRNA) levels in 0.5-10 mg/kg groups and FAS mRNA level in 1-10 mg/kg groups were significantly decreased (P < 0.05), while PPARalpha mRNA level, serum adiponectin content and AdipoR1 mRNA level were significantly increased in 0.5-50 mg/kg groups (P < 0.05). These results indicated (-)-HCA treatment inhibited triglyceride synthesis via decreasing lipogenesis-related factors, mRNA expression level and accelerated lipolysis by enhancing lipoprotein lipase and hepatic lipase activity, which finally reduced lipid droplet accumulation, and this action may be associated with activating the adiponectin signaling pathway. PMID- 28804985 TI - A Randomised Controlled Comparison of Second-Level Treatment Approaches for Treatment-Resistant Adults with Bulimia Nervosa and Binge Eating Disorder: Assessing the Benefits of Virtual Reality Cue Exposure Therapy. AB - A question that arises from the literature on therapy is whether second-level treatment is effective for patients with recurrent binge eating who fail first level treatment. It has been shown that subjects who do not stop binge eating after an initial structured cognitive-behavioural treatment (CBT) programme benefit from additional CBT (A-CBT) sessions; however, it has been suggested that these resistant patients would benefit even more from cue exposure therapy (CET) targeting features associated with poor response (e.g. urge to binge in response to a cue and anxiety experienced in the presence of binge-related cues). We assessed the effectiveness of virtual reality-CET as a second-level treatment strategy for 64 patients with bulimia nervosa and binge eating disorder who had been treated with limited results after using a structured CBT programme, in comparison with A-CBT. The significant differences observed between the two groups at post-treatment in dimensional (behavioural and attitudinal features, anxiety, food craving) and categorical (abstinence rates) outcomes highlighted the superiority of virtual reality-CET over A-CBT. Copyright (c) 2017 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 28804987 TI - Divergent Asymmetric Total Synthesis of Mulinane Diterpenoids. AB - A concise, divergent, asymmetric total syntheses of mulinane diterpenoids has been achieved. Specifically, a new strategy was developed featuring a key intramolecular Friedel-Crafts reaction to construct the chiral fused 5-6-6 tricyclic motif, followed by sequential Birch reduction, conjugate methylation, and homologation/ring-expansion reactions to furnish the desired 5-6-7 tricyclic skeleton bearing five contiguous stereocenters. With this efficient strategy, seven mulinane diterpenoids and two analogues were synthesized via late-stage functional modification or functionalization in 8.6-20 % overall yields and 11-15 steps. PMID- 28804989 TI - Improving predictions of tropical forest response to climate change through integration of field studies and ecosystem modeling. AB - Tropical forests play a critical role in carbon and water cycles at a global scale. Rapid climate change is anticipated in tropical regions over the coming decades and, under a warmer and drier climate, tropical forests are likely to be net sources of carbon rather than sinks. However, our understanding of tropical forest response and feedback to climate change is very limited. Efforts to model climate change impacts on carbon fluxes in tropical forests have not reached a consensus. Here, we use the Ecosystem Demography model (ED2) to predict carbon fluxes of a Puerto Rican tropical forest under realistic climate change scenarios. We parameterized ED2 with species-specific tree physiological data using the Predictive Ecosystem Analyzer workflow and projected the fate of this ecosystem under five future climate scenarios. The model successfully captured interannual variability in the dynamics of this tropical forest. Model predictions closely followed observed values across a wide range of metrics including aboveground biomass, tree diameter growth, tree size class distributions, and leaf area index. Under a future warming and drying climate scenario, the model predicted reductions in carbon storage and tree growth, together with large shifts in forest community composition and structure. Such rapid changes in climate led the forest to transition from a sink to a source of carbon. Growth respiration and root allocation parameters were responsible for the highest fraction of predictive uncertainty in modeled biomass, highlighting the need to target these processes in future data collection. Our study is the first effort to rely on Bayesian model calibration and synthesis to elucidate the key physiological parameters that drive uncertainty in tropical forests responses to climatic change. We propose a new path forward for model-data synthesis that can substantially reduce uncertainty in our ability to model tropical forest responses to future climate. PMID- 28804988 TI - Patterns of Systemic Treatment for Psoriatic Arthritis in the US: 2004-2015. AB - OBJECTIVE: To examine trends in the use of systemic disease-modifying antirheumatic drugs (DMARDs) among patients with psoriatic arthritis (PsA) in the US. METHODS: Using claims data (2004-2015) from a large US commercial health plan, we identified patients with PsA who initiated DMARD therapy. We examined baseline patient characteristics and initial treatment patterns. We then assessed changes in the DMARD regimen over the 12-month period after the first DMARD initiation date. Using Poisson regression, we estimated age- and sex-adjusted incidence rates of treatment changes in each calendar year. RESULTS: We identified 9,222 PsA patients who initiated DMARD therapy (42.8% biologic DMARDs [bDMARDs] and 57.2% conventional synthetic DMARDs [csDMARDs]). Initiators of bDMARDs were younger than those initiating csDMARDs (mean +/- SD age 48 +/- 13 versus 52 +/- 14 years) and generally had fewer comorbidities, but a higher proportion of bDMARD initiators received nonsystemic treatments for psoriasis at baseline. Methotrexate was the most frequently used DMARD, constituting 80.6% of csDMARD initiations. Etanercept (49.1%) was the most commonly prescribed bDMARD, followed by adalimumab (34.4%). During the 12-month followup after the first DMARD initiation, 20.1% of bDMARD initiators and 31.1% of csDMARD initiators had their initial DMARD regimen modified, with an increasing trend in treatment modifications over the 11-year study period (P = 0.03). Overall, 5.3% of patients discontinued treatment, but the rates of discontinuation decreased over time (P < 0.001). CONCLUSION: In this large cohort of PsA patients with DMARD initiation, more than 40% were treated with a bDMARD. We found an increasing trend in treatment modification after use of the initial DMARD and a decreasing trend in complete DMARD discontinuation over the past decade. PMID- 28804990 TI - Characterizing the experience of auditory verbal hallucinations and accompanying delusions in individuals with a diagnosis of bipolar disorder: A systematic review. AB - OBJECTIVES: The aim of the current study was to inform ongoing attempts to identify clinically meaningful subcategories of auditory verbal hallucination (AVH), and to evaluate evidence that might pertain to the suitability of current psychological interventions for people with bipolar disorder (BD) who experience psychotic symptoms. METHODS: A comprehensive synthesis of findings on the phenomenology of AVH and delusions in BD is included, alongside a critical review of clinical and cognitive correlates. Studies published in the previous 20 years, until December 2016, were retrieved from the following databases: Embase, CINAHL, MEDLINE, PsycINFO and Web of Science. Thirty-two articles were reviewed after applying a set of predetermined inclusion criteria. RESULTS: Psychotic symptoms were common in both manic and depressive phases, although higher frequencies were indicated in mania. Few detailed characterizations of AVH phenomenology were identified. Delusions with persecutory, grandiose and referential themes were the most common in BD. AVHs were associated with delusions and there was evidence to suggest that delusion subtype may vary according to mood state and type of AVH. Data on clinical correlates of AVH in BD were sparse. However, the results indicated that cognitive appraisals or interpretations of voices might be different in BD from those established to be predictive of clinical outcomes in schizophrenia spectrum disorders. CONCLUSIONS: Clear gaps exist in our current understanding of the first-person experience of AVH in BD and the potential relationship to co-occurring symptoms, including delusions. Further research into cognitive interpretations of AVH in BD might inform adapted psychological interventions for psychotic symptoms in this population. PMID- 28804991 TI - NF-kappaB2 Controls the Migratory Activity of Memory T Cells by Regulating Expression of CXCR4 in a Mouse Model of Sjogren's Syndrome. AB - OBJECTIVE: Dysregulated chemokine signaling contributes to autoimmune diseases by facilitating aberrant T cell infiltration into target tissues, but the specific chemokines, receptors, and T cell populations remain largely unidentified. The aim of this study was to examine the role of the potent chemokine CXCL12 and its receptor CXCR4 in the T cell autoimmune response, using alymphoplasia (aly)/aly mice, a model of Sjogren's syndrome (SS). METHODS: T cell phenotypes in the salivary gland of aly/aly mice were evaluated using immunologic analysis. An in vitro migration assay was used to assess T cell migratory activity toward several chemokines. Gene expression of chemokine receptors and transforming growth factor beta receptors (TGFbetaRs) was measured by quantitative reverse transcription polymerase chain reaction. The CXCR4 antagonist AMD3100 was administered to the aly/aly mice in order to evaluate its suppressive effect on autoimmune lesions. RESULTS: Effector memory T (TEM) cells derived from aly/aly mice demonstrated higher in vitro migratory activity toward CXCL12 than did TEM cells from aly/+ mice. CXCL12 expression was specifically up-regulated in the SS target cells of aly/aly mice. TEM cells from RelB-/- mice, but not Nfkb1-/- mice, also showed high migratory activity toward CXCL12, implicating a role of the nonclassical RelB/NF-kappaB2 pathway in the regulation of TEM cell migration. TEM cells from aly/aly mice also overexpressed TGFbetaR type I (TGFbetaRI) and TGFbetaRII. The CXCR4 antagonist AMD3100 suppressed autoimmune lesions in aly/aly mice by reducing TEM cell infiltration. CONCLUSION: Our results suggest that the RelB/NF kappaB2 pathway regulates T cell migration to autoimmune targets through TGFbeta/TGFbetaR-dependent regulation of CXCL12/CXCR4 signaling. This suggests that these signaling pathways are potential therapeutic targets for the treatment of autoimmune diseases. PMID- 28804992 TI - Gold-Catalyzed [4+2] Annulation/Cyclization Cascades of Benzisoxazoles with Propiolate Derivatives to Access Highly Oxygenated Tetrahydroquinolines. AB - This work describes gold-catalyzed annulations of electron-deficient alkynes with benzisoxazoles to yield quinoline oxides chemoselectively. Chemical functionalizations of these resulting azacyclic compounds afforded various oxygenated tetrahydroquinolines which are present as the cores of many bioactive molecules. With the same reactants, a new relay catalysis using gold and zinc(II) catalysts affords highly oxygenated tetrahydroquinoline derivatives stereoselectively. PMID- 28804993 TI - Influence of surgical gloves on haptic perception thresholds. AB - BACKGROUND: Impairment of haptic perception by surgical gloves could reduce requirements on haptic systems for surgery. While grip forces and manipulation capabilities were not impaired in previous studies, no data is available for perception thresholds. METHODS: Absolute and differential thresholds (20 dB above threshold) of 24 subjects were measured for frequencies of 25 and 250 Hz with a Psi-method. Effects of wearing a surgical glove, moisture on the contact surface and subject's experience with gloves were incorporated in a full-factorial experimental design. RESULTS: Absolute thresholds of 12.8 dB and -29.6 dB (means for 25 and 250 Hz, respectively) and differential thresholds of -12.6 dB and -9.5 dB agree with previous studies. A relevant effect of the frequency on absolute thresholds was found. Comparisons of glove- and no-glove-conditions did not reveal a significant mean difference. CONCLUSIONS: Wearing a single surgical glove does not affect absolute and differential haptic perception thresholds. PMID- 28804994 TI - Neutron-activatable needles for radionuclide therapy of solid tumors. AB - Various approaches have been undertaken to enhance the delivery of therapeutic agents, including tissue-killing radionuclides, into solid tumors. Here, we describe the preparation of conical needles composed of Ti and Mo coated by pulsed laser deposition or chemical vapor deposition with elements (Ho and Re) that can readily yield radioactive isotopes following irradiation in a neutron flux. The radioactive needles, whose design were based on solid microneedle arrays used in transdermal drug delivery, can be produced with minimal handling of radioactivity and subsequently inserted into tumors as a means of internal radiation therapy. Ho and Re were specifically chosen because of their large neutron capture cross-sections as well as the desirable radiotherapeutic properties of the resultant radionuclides. Neutron-absorbing shields were also developed to prevent the production of unwanted radionuclides after neutron irradiation of the needle base materials. Neutron activation calculations showed that therapeutically significant amounts of radionuclides can be produced for treating solid tumors. Stability studies demonstrated that Re did not leach off the Mo needles. These coated neutron-activatable needles offer a new approach to internal radiation therapy of tumors that allows precise tailoring of the absorbed radiation dose delivered to the tumor by controlling the coating thickness and the irradiation time. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3273-3280, 2017. PMID- 28804995 TI - Assessing the need for arthritis training among paid carers in UK residential care homes: A focus group and interview study. AB - OBJECTIVE: The aim of the study was to perform an educational and training needs assessment for arthritis care in residential homes. METHODS: Qualitative data were collected from three purposively selected residential homes: one independent, one in a regional chain and one in a national chain. Three researcher-led focus groups were conducted with paid carers (N = 22) using vignette exercises; interviews were undertaken with 12 residents with joint pain (N = 12), five managerial staff and two general practitioners (GPs). Data were compared and analysed thematically around care practices, communication and training. RESULTS: There is a lack of arthritis awareness among paid carers, although they regularly identify and manage arthritic symptoms. Residents rely on paid carers to recognize when pain and mobility problems are treatable. Senior staff and GPs rely on carers to identify arthritic problems. However, paid carers themselves undervalued the health significance of their activities and lacked the confidence to communicate important information to healthcare professionals. Few of the paid carers had received training in arthritis and many expressed a strong desire to learn about it, to improve their ability to provide better care. CONCLUSIONS: Education for paid carers regarding arthritis is lacking and lags behind education about conditions such as dementia and diabetes. To meet the expectations of their care roles fully, paid carers require an awareness of what arthritis is and how to recognize symptoms. We suggest that training should be aimed at improving confidence in communicating with colleagues, residents and health professionals, with senior care staff receiving more in-depth training. PMID- 28804996 TI - In vitro evaluation of 3D bioprinted tri-polymer network scaffolds for bone tissue regeneration. AB - In vitro evaluations provide vital information on the ability of tissue engineered scaffolds to support cell life and promote natural physiological behaviors in culture. Such assessments are necessary to conduct before implementation of the scaffolds for tissue healing in vivo. The scaffold extracellular matrix must provide the biochemical and mechanical cues necessary to promote cellular attachment, migration and proliferation before differentiation and new tissue deposition can occur. In this study, an in vitro evaluation was conducted to assess the ability of scaffolds three-dimensional (3D) printed with a previously developed alginate-polyvinyl alcohol hydroxyapatite formulation to promote proliferation of encapsulated MC3T3 cells. A systematic investigation was conducted to increase cell proliferation, and it was determined that the concentration and duration of the calcium bath have a less effect on proliferation than the composition of the formulation itself. Collagen gel was incorporated into the formulation to provide cells with adhesion sites necessary to sufficiently attach to the matrix. Enhanced proliferation was achieved within scaffolds of increased collagen content and sufficient crosslinking. This highlighted the importance of the synergistic effect created as a result of sufficient ligand density coupled with appropriate scaffold mechanical rigidity to provide a suitable environment for proliferation. Thus, these 3D printed tri-polymer scaffolds have the ability to support cell proliferation and have potential to promote cell differentiation and new bone tissue deposition. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3262-3272, 2017. PMID- 28804997 TI - Does dental hygienist professional education meet the needs of working life? Educators' views. AB - OBJECTIVE: The aim of this study was to describe the compatibility of dental hygienist education with working life from the perspective of their educators. METHODS: We conducted a qualitative study among principal educators of dental hygienists in Finland in 2012-2013. The participants were leading educators of dental hygienists (n = 13) from the four Finnish education units. We used semi structured interviews based on previous Nordic studies to collect the data and analysed them using inductive content analysis. RESULTS: According to the educators, dental hygienists' skills at work are neither fully nor effectively utilized, even though their education meets the needs of working life quite well. The educators felt that hygienists' professional competence would prove more useful in health promotion and orthodontic measures and that the division of labour should be clearer. Clarifying this distinction in periodontal therapy could be improved. CONCLUSION: Fully utilizing dental hygienists' competence in clinical work would benefit from further development. The content of dental hygienists' clinical work should be reassessed so as to utilize their skills more fully. The compatibility of dental hygienist education corresponds largely to the needs of future working life. PMID- 28804998 TI - Peripheral nerve growth within a hydrogel microchannel scaffold supported by a kink-resistant conduit. AB - Nerve repair in several mm-long nerve gaps often requires an interventional technology. Microchannel scaffolds have proven effective for bridging nerve gaps and guiding axons in the peripheral nervous system (PNS). Nonetheless, fabricating microchannel scaffolds at this length scale remains a challenge and/or is time consuming and cumbersome. In this work, a simple computer-aided microdrilling technique was used to fabricate 10 mm-long agarose scaffolds consisting of 300 um-microchannels and 85 um-thick walls in less than an hour. The agarose scaffolds alone, however, did not exhibit adequate stiffness and integrity to withstand the mechanical stresses during implantation and suturing. To provide mechanical support and enable suturing, poly caprolactone (PCL) conduits were fabricated and agarose scaffolds were placed inside. A modified salt-leaching technique was developed to introduce interconnected porosity in PCL conduits to allow for tuning of the mechanical properties such as elastic modulus and strain to failure. It was shown that the PCL conduits were effective in stabilizing the agarose scaffolds in 10 mm-long sciatic nerve gaps of rats for at least 8 weeks. Robust axon ingress and Schwann cell penetration were observed within the microchannel scaffolds without using growth factors. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3392-3399, 2017. PMID- 28804999 TI - Diversity of astroglial responses across human neurodegenerative disorders and brain aging. AB - Astrogliopathy refers to alterations of astrocytes occurring in diseases of the nervous system, and it implies the involvement of astrocytes as key elements in the pathogenesis and pathology of diseases and injuries of the central nervous system. Reactive astrocytosis refers to the response of astrocytes to different insults to the nervous system, whereas astrocytopathy indicates hypertrophy, atrophy/degeneration and loss of function and pathological remodeling occurring as a primary cause of a disease or as a factor contributing to the development and progression of a particular disease. Reactive astrocytosis secondary to neuron loss and astrocytopathy due to intrinsic alterations of astrocytes occur in neurodegenerative diseases, overlap each other, and, together with astrocyte senescence, contribute to disease-specific astrogliopathy in aging and neurodegenerative diseases with abnormal protein aggregates in old age. In addition to the well-known increase in glial fibrillary acidic protein and other proteins in reactive astrocytes, astrocytopathy is evidenced by deposition of abnormal proteins such as beta-amyloid, hyper-phosphorylated tau, abnormal alpha synuclein, mutated huntingtin, phosphorylated TDP-43 and mutated SOD1, and PrPres , in Alzheimer's disease, tauopathies, Lewy body diseases, Huntington's disease, amyotrophic lateral sclerosis and Creutzfeldt-Jakob disease, respectively. Astrocytopathy in these diseases can also be manifested by impaired glutamate transport; abnormal metabolism and release of neurotransmitters; altered potassium, calcium and water channels resulting in abnormal ion and water homeostasis; abnormal glucose metabolism; abnormal lipid and, particularly, cholesterol metabolism; increased oxidative damage and altered oxidative stress responses; increased production of cytokines and mediators of the inflammatory response; altered expression of connexins with deterioration of cell-to-cell networks and transfer of gliotransmitters; and worsening function of the blood brain barrier, among others. Increased knowledge of these aspects will permit a better understanding of brain aging and neurodegenerative diseases in old age as complex disorders in which neurons are not the only players. PMID- 28805000 TI - A 54-Year-Old Male with Multiple Intracranial and Extracranial Masses. PMID- 28805001 TI - Introduction. PMID- 28805005 TI - A 42-Year-Old Man with AIDS and Multiple Incomplete Ring Enhancing Lesions. PMID- 28805006 TI - An 57-Year-Old Female with Sudden onset of Transient Right Homonymous Hemianopsia. PMID- 28805007 TI - A 42-Year-Old Male with Diabetes Insipidus. PMID- 28805008 TI - Erratum. PMID- 28805003 TI - Protein astrogliopathies in human neurodegenerative diseases and aging. AB - Neurodegenerative diseases are characterized by progressive dysfunction and loss of neurons associated with depositions of pathologically altered proteins showing hierarchical involvement of brain regions. The role of astrocytes in the pathogenesis of neurodegenerative diseases is explored as contributors to neuronal degeneration or neuroprotection pathways, and also as potential mediators of the transcellular spreading of disease-associated proteins. Protein astrogliopathy (PAG), including deposition of amyloid-beta, prion protein, tau, alpha-synuclein, and very rarely transactive response DNA-binding protein 43 (TDP 43) is not unprecedented or unusual in neurodegenerative diseases. Morphological characterization of PAG is considered, however, only for the neuropathological diagnosis and classification of tauopathies. Astrocytic tau pathology is seen in primary frontotemporal lobar degeneration (FTLD) associated with tau pathologies (FTLD-Tau), and also in the form of aging-related tau astrogliopathy (ARTAG). Importantly, ARTAG shares common features with primary FTLD-Tau as well as with the astroglial tau pathologies that are thought to be hallmarks of a brain injury related tauopathy known as chronic traumatic encephalopathy (CTE). Supported by experimental observations, the morphological variability of PAG might reflect distinct pathogenic involvement of different astrocytic populations. PAG might indicate astrocytic contribution to spreading or clearance of disease-associated proteins, however, this might lead to astrocytic dysfunction and eventually contribute to the degeneration of neurons. Here, we review recent advances in understanding ARTAG and other related forms of PAG. PMID- 28805009 TI - Using endoscopy to locate the round window membrane during cochlear implantation: Our experience with 25 patients. PMID- 28805002 TI - Stratification of astrocytes in healthy and diseased brain. AB - Astrocytes, a subtype of glial cells, come in variety of forms and functions. However, overarching role of these cell is in the homeostasis of the brain, be that regulation of ions, neurotransmitters, metabolism or neuronal synaptic networks. Loss of homeostasis represents the underlying cause of all brain disorders. Thus, astrocytes are likely involved in most if not all of the brain pathologies. We tabulate astroglial homeostatic functions along with pathological condition that arise from dysfunction of these glial cells. Classification of astrocytes is presented with the emphasis on evolutionary trails, morphological appearance and numerical preponderance. We note that, even though astrocytes from a variety of mammalian species share some common features, human astrocytes appear to be the largest and most complex of all astrocytes studied thus far. It is then an imperative to develop humanized models to study the role of astrocytes in brain pathologies, which is perhaps most abundantly clear in the case of glioblastoma multiforme. PMID- 28805010 TI - Characterization of Hydrogels Made of a Novel Spider Silk Protein eMaSp1s and Evaluation for 3D Printing. AB - Recombinantly produced spider silk proteins have high potential for bioengineering and various biomedical applications because of their biocompatibility, biodegradability, and low immunogenicity. Here, the recently described small spider silk protein eMaSp1s is assembled into hydrogels, which can be 3D printed into scaffolds. Further, blending with a recombinantly produced MaSp2 derivative eADF4(C16) alters the mechanical properties of the resulting hydrogels. Different spider silk hydrogels also show a distinct recovery after a high shear stress deformation, exhibiting the tunability of their features for selected applications. PMID- 28805012 TI - Increasing the accuracy and precision of relative telomere length estimates by RT qPCR. AB - As attrition of telomeres, DNA caps that protect chromosome integrity, is accelerated by various forms of stress, telomere length (TL) has been proposed as an indicator of lifetime accumulated stress. In ecological studies, it has been used to provide insights into ageing, life history trade-offs, the costs of reproduction and disease. qPCR is a high-throughput and cost-effective tool to measure relative TL (rTL) that can be applied to newly collected and archived ecological samples. However, qPCR is susceptible to error both from the method itself and pre-analytical steps. Here, repeatability was assessed overall and separately across multiple levels (intra-assay, inter-assay and inter-extraction) to elucidate the causes of measurement error, as a step towards improving precision. We also tested how accuracy, defined as the correlation between the "gold standard" for TL estimation (telomere restriction fragment length analysis with in-gel hybridization), could be improved. We find qPCR repeatability (intra- and inter-assay levels) to be at similar levels across three common storage media (ethanol, Longmire's and Queen's). However, inter-extraction repeatability was 50% lower for samples stored in Queen's lysis buffer, indicating storage medium can influence precision. Precision as well as accuracy could be increased by estimating rTL from multiple qPCR reactions and from multiple extractions. Repetition increased statistical power equivalent to a 25% (single extraction analysed twice) and 17% (two extractions) increase in sample size. Overall, this study identifies novel sources of variability in high-throughput telomere quantification and provides guidance on sampling strategy design and how to increase rTL precision and accuracy. PMID- 28805011 TI - Bicuspid and unicuspid aortic valves: Different phenotypes of the same disease? Insight from the GenTAC Registry. AB - BACKGROUND: Unicuspid aortic valve (UAV) is a rare disorder, often difficult to distinguish from bicuspid aortic valve (BAV). BAV and UAV share valve pathology such as the presence of a raphe, leaflet fusion, aortic stenosis, aortic regurgitation, and/or ascending aortic dilatation, but a comprehensive echocardiographic comparison of patients with UAV and BAV has not been previously performed. METHODS: We investigated UAV and BAV patients at an early stage of disease included in GenTAC, a national registry of genetically related aortic aneurysms and associated cardiac conditions. Clinical and echocardiographic data from the GenTAC Registry were compared between 17 patients with UAV and 17 matched-controls with BAV. RESULTS: Baseline characteristics including demographics, clinical findings including family history of BAV and aortic aneurysm/coarctation, and echocardiographic variables were similar between BAV and UAV patients; aortic stenosis was more common and more severe in patients with UAV. This was evidenced by higher mean and peak gradient, smaller aortic valve area, and more advanced valvular degeneration (all P < .05). There were no significant differences in aortic dimensions, with a similar pattern of enlargement of the ascending aorta. CONCLUSIONS: The similar baseline characteristics with more accelerated aortic valve degeneration and stenosis suggest that UAV represents an extreme in the spectrum of BAV syndromes. Therefore, it is reasonable to consider application of recommendations for the management of patients with BAV to those with the rarer UAV. PMID- 28805013 TI - Drug-Free Macromolecular Therapeutics Induce Apoptosis via Calcium Influx and Mitochondrial Signaling Pathway. AB - Recently, an innovative paradigm has been proposed in macromolecular therapeutics for treatment of B-cell lymphomas that can specifically kill cancer cells without a drug. The design rationale of this drug-free macromolecular therapeutic (DFMT) system is crosslinking the cell surface receptor to initiate apoptosis. However, how the apoptosis signal is triggered after receptor hyper-crosslinking remains to be elucidated. Here, two pathways, calcium influx dependent pathway and mitochondrial signal pathway, are identified to play major roles in triggering the programmed cell death. With the first step pretargeting and second step multiple binding, receptor hyper-crosslinking is achieved in a highly specific, time-dependent manner and largely mediated by multivalence. As a consequence, extracellular calcium influx is triggered, which subsequently decreases the mitochondrial membrane potential and induces apoptosis. The mitochondrial depolarization also stems from the Bcl-2 inhibition mediated by DFMT, followed by the cytochrome c release that activates caspase signaling. With the participation of the two-pronged mechanism, a programmed apoptosis is induced in response to DFMT treatment. The current findings can offer important implications to optimize the anti-CD20 strategies to treat B-cell non-Hodgkin lymphomas. PMID- 28805014 TI - Time-Temperature Indicator Based on Enzymatic Degradation of Dye-Loaded Polyhydroxybutyrate. AB - An enzyme activated time-temperature indicator (TTI) which produces a direct colour change concomitant to variations in integrated time and temperature conditions is described. This direct colour change is realised by degrading a dye loaded polyhydroxybutyrate (PHB) film by a depolymerase enzyme. The degradation of the PHB film by the enzyme causes the release of the dye in solution, which in turn undergoes an optical transition from clear to coloured with elapsing time. Macroscopic and microscopic optical observations confirms the uniform distribution of the dye in the PHB film. The dye release kinetics, mediated by the enzymatic reaction, are tested at different temperatures ranging from 4 to 37 degrees C, and are used to determine the suitability of a dye-loaded PHB as a time-temperature indicator for fresh food products based on kinetic parameters previously reported. The kinetic analysis shows that the activation energy of the dye release process is 74 kJ mol-1 , and that, at 37 degrees C, the dye would be totally released within 6 h. However, when incubated at 4 degrees C, the TTI requires in the range of 168 h (7 days) to release all the dye. These kinetics values highlight the potential of the TTI for monitoring fresh food products that have optimum shelf life around 4 degrees C. PMID- 28805016 TI - Assessment of Microvascular Abnormalities by Nailfold Capillaroscopy in Juvenile Dermatomyositis After Medium- to Long-Term Followup. AB - OBJECTIVE: In juvenile dermatomyositis (DM), microvascular abnormalities, measured by nailfold capillaroscopy (NFC), are common early in the disease course. We aimed to compare the presence of NFC abnormalities in patients with medium- to long-term juvenile DM with that of controls, and to explore associations between NFC abnormalities and disease activity and other disease characteristics. METHODS: Fifty-eight juvenile DM patients with a median disease duration of 16.8 (range 2-38) years were clinically examined and compared with matched controls. By NFC, we assessed nailfold capillary density (NCD), giant capillaries, scleroderma, and neovascular pattern (defined as scleroderma active or late pattern). NFC was analyzed with researchers blinded to patient/control identity and disease characteristics. We measured disease activity and damage by validated tools, and patients were categorized as having active or inactive disease according to the Paediatric Rheumatology International Trials Organisation criteria. RESULTS: Compared to controls, patients had decreased NCD (mean +/- SD 6.4 +/- 2.1/mm versus 7.6 +/- 0.8/mm; P = 0.001) and showed more abnormality in all other NFC parameters; 36% of patients versus 4% of controls had NCD <6/mm (P < 0.001). Giant capillaries, scleroderma, and neovascular pattern were found in 9%, 84%, and 41% of patients, respectively. Patients with active disease (n = 30) presented more frequently with neovascular pattern than patients with inactive disease (n = 28) (P = 0.041). Decreased NCD and neovascular pattern were associated with higher levels of disease activity and impaired muscle function. CONCLUSION: After medium- to long-term followup, juvenile DM patients had decreased NCD and, often, neovascular pattern; both were associated with higher levels of disease activity and impaired muscle function. This suggests that NFC can be a biomarker for disease activity in longstanding juvenile DM too. PMID- 28805015 TI - Role of Stromelysin 2 (Matrix Metalloproteinase 10) as a Novel Mediator of Vascular Remodeling Underlying Pulmonary Hypertension Associated With Systemic Sclerosis. AB - OBJECTIVE: To elucidate the role of gene candidates involved in pulmonary hypertension (PH) associated with systemic sclerosis (SSc). METHODS: Gene candidates were identified through microarray experiments performed on Affymetrix GeneChip Human Exon 1.0 ST arrays in endothelial progenitor cell (EPC)-derived endothelial cells (ECs) obtained from patients with SSc-associated PH, patients with SSc without PH, and healthy control subjects. Expression of identified gene candidates was assessed by quantitative sandwich enzyme-linked immunosorbent assay in the serum, and by immunohistochemistry in lesional lung tissue. The functional importance of the identified gene candidates was then evaluated in fos related antigen 2-transgenic (Fra-2-Tg) mice that spontaneously develop SSc-like features associated with an intense pulmonary vascular remodeling. RESULTS: Microarray experiments revealed that the matrix metalloproteinase 10 (MMP-10) gene was the top up-regulated gene in SSc-associated PH EPC-derived ECs. Circulating serum proMMP10 concentrations were markedly increased in patients with SSc-associated PH compared to SSc patients without PH and healthy controls. Consistent with these observations, a strong MMP10 staining of the thickened wall of distal pulmonary arteries was found both in the lungs of patients with SSc associated PH and in the lungs of Fra-2-Tg mice. Daily treatment of Fra-2-Tg mice with neutralizing anti-MMP10 antibodies did not significantly affect the development and severity of pulmonary fibrosis, but did reverse established PH and markedly reduced pulmonary vascular remodeling by reducing cell proliferation, cell survival, and the platelet-derived growth factor signaling axis. CONCLUSION: Gene expression profiling of EPC-derived ECs identified MMP10 as a novel candidate gene in SSc-associated PH. MMP10 is overexpressed in the serum and pulmonary arteries of patients with SSc-associated PH, and its blockade alleviates PH in the Fra-2-Tg mouse model. MMP10 appears to be a prospective treatment target for this devastating disorder. PMID- 28805017 TI - Estimating the between-farm transmission rates for highly pathogenic avian influenza subtype H5N1 epidemics in Bangladesh between 2007 and 2013. AB - Highly Pathogenic Avian Influenza (HPAI) is classified by the World Organization for Animal Health as one of the notifiable diseases. Its occurrence is associated with severe socio-economic impacts and is also zoonotic. Bangladesh HPAI epidemic data for the period between 2007 and 2013 were obtained and split into epidemic waves based on the time lag between outbreaks. By assuming the number of newly infected farms to be binomially distributed, we fit a Generalized Linear Model to the data to estimate between-farm transmission rates (beta). These parameters are then used together with the calculated infectious periods to estimate the respective basic reproduction numbers (R0 ). The change in beta and R0 with time during the course of each epidemic wave was explored. Finally, sensitivity analyses of the effects of reducing the delay in detecting infection on a farm as well as extended infectiousness of a farm beyond the day of culling were assessed. The point estimates obtained for beta ranged from 0.08 (95% CI: 0.06 0.10) to 0.11 (95% CI: 0.08-0.20) per infectious farm per day while R0 ranged from 0.85 (95% CI: 0.77-1.02) to 0.96 (95% CI: 0.72-1.20). Sensitivity analyses reveal that the estimates are quite robust to changes in the assumptions about the day in reporting infection and extended infectiousness. In the analysis allowing for time-varying transmission parameters, the rising and declining phases observed in the epidemic data were synchronized with the moments when R0 was greater and less than one, respectively. From an epidemiological perspective, the consistency of these estimates and their magnitude (R0 ~ 1) indicate that the effectiveness of the deployed control measures was largely invariant between epidemic waves and the trend of the time-varying R0 supports the hypothesis of sustained farm-to-farm transmission that is possibly initiated by a few unique introductions. PMID- 28805018 TI - Pain Catastrophizing, Subjective Outcomes, and Inflammatory Assessments Including Ultrasound: Results From a Longitudinal Study of Rheumatoid Arthritis Patients. AB - OBJECTIVE: Pain catastrophizing is conceptualized as a negative cognitive affective response to anticipated or actual pain and has been associated with important pain-related outcomes. The objective of this prospective study of established rheumatoid arthritis (RA) patients was to explore how pain catastrophizing was related to patient-reported outcomes (PROs), composite scores, and assessments of inflammatory activity. METHODS: RA patients starting biologic disease-modifying antirheumatic drugs were examined at baseline and after 1, 2, 3, 6, and 12 months with PROs (joint pain/patient's global visual analog scale [VAS], modified Health Assessment Questionnaire, Rheumatoid Arthritis Impact of Disease score), clinical and laboratory assessments (tender/swollen joint count, assessor's global VAS, erythrocyte sedimentation rate/C-reactive protein [CRP] level), ultrasound (US) (gray scale [GS]/power Doppler [PD] of 36 joints and 4 tendons), and pain catastrophizing. The composite scores for Disease Activity Score in 28 joints, Clinical Disease Activity Index, and Simplified Disease Activity Index were calculated. Statistical calculations included independent samples t-test, paired samples t-test, one-way analysis of variance, Pearson's correlations, and linear and logistic regression. RESULTS: Of 209 patients included, 152 (72.7%) completed 12-month followup. Pain catastrophizing, PROs, and clinical and inflammatory assessments decreased significantly (P < 0.001). Pain catastrophizing was strongly correlated with the PROs and composite scores (P < 0.001) but not with the inflammatory parameters (swollen joint count, CRP level, and GS/PD US). Patients with higher levels of pain catastrophizing had higher PROs and composite scores during the study (P < 0.001) but not inflammatory assessments. Baseline pain catastrophizing was negatively associated with achievement of remission at 6 and 12 months (P < 0.05). CONCLUSION: Pain catastrophizing was strongly associated with PROs and composite measures, but not with markers of inflammation. High levels of pain catastrophizing reduced the likelihood of achieving composite score remission and should be a factor to consider in a treat-to-target strategy. PMID- 28805019 TI - CD11b+Gr-1dim Tolerogenic Dendritic Cell-Like Cells Are Expanded in Interstitial Lung Disease in SKG Mice. AB - OBJECTIVE: SKG mice develop interstitial lung disease (ILD) resembling rheumatoid arthritis-associated ILD in humans. The aim of this study was to clarify the mechanism underlying the lung pathology by analyzing lung-infiltrating cells in SKG mice with ILD. METHODS: We assessed the severity of zymosan A (ZyA)-induced ILD in SKG mice histologically, and we examined lung-infiltrating cells by flow cytometry. Total lung cells and isolated monocytic myeloid-derived suppressor cells (MDSCs) were cultured in vitro with granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-4. The proliferation of 5,6 carboxyfluorescein diacetate N-succinimidyl ester-labeled naive T cells cocultured with isolated CD11b+Gr-1dim cells and MDSCs was evaluated by flow cytometry. CD11b+Gr-1dim cells were adoptively transferred to ZyA-treated SKG mice. RESULTS: MDSCs, Th17 cells, and group 1 and 3 innate lymphoid cells (ILC1s and ILC3s) were increased in the lungs; the proportion of these cells varied with ILD severity. In this process, we found that a unique cell population, CD11b+Gr 1dim cells, was expanded in the severely inflamed lungs. Approximately half of the CD11b+Gr-1dim cells expressed CD11c. CD11b+Gr-1dim cells were induced from monocytic MDSCs with GM-CSF in vitro and were considered tolerogenic because they suppressed T cell proliferation. These CD11b+Gr-1dim cells have never been described previously, and we termed them CD11b+Gr-1dim tolerogenic dendritic cell (DC)-like cells. Th17 cells, ILC1s, and ILC3s in the inflamed lung produced GM CSF, which may have expanded CD11b+Gr-1dim tolerogenic DC-like cells in vivo. Furthermore, adoptive transfer of CD11b+Gr-1dim tolerogenic DC-like cells significantly suppressed progression of ILD in SKG mice. CONCLUSION: We identified unique suppressive myeloid cells that were differentiated from monocytic MDSCs in SKG mice with ILD, and we termed them CD11b+Gr-1dim tolerogenic DC-like cells. PMID- 28805020 TI - Evaluation of bovine viral diarrhoea virus control strategies in dairy herds in Hokkaido, Japan, using stochastic modelling. AB - Bovine viral diarrhoea virus (BVDV) infection in cattle can result in growth retardation, reduced milk production, reproductive disorders and death. Persistently infected animals are the primary source of infection. In Hokkaido, Japan, all cattle entering shared pastures in summer are vaccinated before movement for disease control. Additionally, these cattle may be tested for BVDV and culled if positive. However, the effectiveness of this control strategy aiming to reduce the number of BVDV-infected animals has not been assessed. The aim of this study was to evaluate the effectiveness of various test-and-cull and/or vaccination strategies on BVDV control in dairy farms in two districts of Hokkaido, Nemuro and Hiyama. A stochastic model was developed to compare the different control strategies over a 10-year period. The model was individual based and simulated disease dynamics both within and between herds. Parameters included in the model were obtained from the literature, the Hokkaido government and the Japanese Ministry of Agriculture, Forestry and Fisheries. Nine different scenarios were compared as follows: no control, test-and-cull strategies based on antigen testing of either calves or only cattle entering common pastures, vaccination of all adult cattle or only cattle entering shared pastures and combinations thereof. The results indicate that current strategies for BVDV control in Hokkaido slightly reduced the number of BVDV-infected animals; however, alternative strategies such as testing all calves and culling any positives or vaccinating all susceptible adult animals dramatically reduced those. To our knowledge, this is the first report regarding the comparison of the effectiveness between the current strategies in Hokkaido and the alternative strategies for BVDV control measures. PMID- 28805021 TI - Toward Establishing a Standardized Magnetic Resonance Imaging Scoring System for Temporomandibular Joints in Juvenile Idiopathic Arthritis. AB - OBJECTIVE: The temporomandibular joints (TMJs) are frequently affected in children with juvenile idiopathic arthritis (JIA). Early detection is challenging, as major variation is present in scoring TMJ pathology on magnetic resonance imaging (MRI). Consensus-driven development and validation of an MRI scoring system for TMJs has important clinical utility in timely improvement of diagnosis and serving as an outcome measure. We report on a multi-institutional collaboration toward developing a TMJ MRI scoring system for JIA. METHODS: Seven readers independently assessed MRI scans from 21 patients (42 TMJs, from patients ages 6-16 years) using 3 existing MRI scoring systems from American, German, and Swiss institutions. Reliability scores, scoring system definitions, and items were discussed among 10 JIA experts through 2 rounds of Delphi surveys, nominal group voting, and subsequent consensus meetings to create a novel TMJ MRI scoring system. RESULTS: Average-measure absolute agreement intraclass correlation coefficients (avICCs) for the total scores of all 3 scoring systems were highly reliable at 0.96 each. Osteochondral items showed higher reliability than inflammatory items. An additive system was deemed preferable for assessing minor joint changes over time. Eight items were considered sufficiently reliable and/or important for integration into the consensus scoring system: bone marrow edema and enhancement (avICC 0.57-0.61, smallest detectable difference [SDD] +/- 45-63% prior to redefining), condylar flattening (avICC 0.95-0.96, SDD +/- 23-28%), effusions (avICC 0.85-0.88, SDD +/- 25-26%), erosions (avICC 0.94, SDD +/- 20%), synovial enhancement and thickening (previously combined, avICC 0.90-0.91, SDD +/ 33%), and disk abnormalities (avICC 0.90, SDD +/- 19%). CONCLUSION: A novel TMJ MRI scoring system was developed by consensus. Further iterative refinements and reliability testing are warranted in upcoming studies. PMID- 28805022 TI - Hesperidin Supplementation Alleviates Oxidative DNA Damage and Lipid Peroxidation in Type 2 Diabetes: A Randomized Double-Blind Placebo-Controlled Clinical Trial. AB - This study aimed to examine the effects of hesperidin supplement on the glycemic parameters, oxidative DNA damage, and lipid peroxidation in patients with type 2 diabetes. Sixty-four patients were randomly allocated to receive 500 mg/day hesperidin or placebo capsules for 6 weeks. Data on glycemic parameters, total antioxidant capacity (TAC), 8-hydroxydeoxyguanosine (8-OHDG), and malondialdehyde (MDA) were collected at the baseline and at the end of the study. In hesperidin group, TAC increased (0.74 +/- 0.16 vs. 0.82 +/- 0.18), while serum froctoseamin (5.79 +/- 5.86 vs. 5.01 +/- 4.95; p = 0.001), 8-OHDG (14.32 +/- 6.4 vs. 11.00 +/- 7.0; p = 0.000), and MDA (5.78 +/- 1.76 vs. 4.60 +/- 0.75; p = 0.000) decreased in comparison with the baseline values. There was a significant difference in percent change of TAC (13.35 +/- 19.21 vs. 3.13 +/- 10.02; p = 0.043), froctoseamin (-10.10 +/- 16.84 vs. 4.27 +/- 34.646), 8-OHDG (-25.11 +/- 28.23 vs. 8.69 +/- 35.41; p = 0.000), and MDA (-16.46 +/- 18.04 vs. -1.82 +/- 22.63; p = 0.007) between hesperidin and control groups following intervention in adjusted models. These results suggest that hesperidin may improve TAC and alleviate serum froctoseamin, 8-OHDG, and MDA levels in type 2 diabetes. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28805023 TI - Onion (Allium cepa L.) peel extract (OPE) regulates human sperm motility via protein kinase C-mediated activation of the human voltage-gated proton channel. AB - Onion (Allium cepa L.) and quercetin protect against oxidative damage and have positive effects on multiple functional parameters of spermatozoa, including viability and motility. However, the associated underlying mechanisms of action have not yet been identified. The aim of this study was to investigate the effect of onion peel extract (OPE) on voltage-gated proton (Hv1) channels, which play a critical role in rapid proton extrusion. This process underlies a wide range of physiological processes, particularly male fertility. The whole-cell patch-clamp technique was used to record the changes in Hv1 currents in HEK293 cells transiently transfected with human Hv1 (HVCN1). The effects of OPE on human sperm motility were also analyzed. OPE significantly activated the outward-rectifying proton currents in a concentration-dependent manner, with an EC50 value of 30 MUg/mL. This effect was largely reversible upon washout. Moreover, OPE induced an increase in the proton current amplitude and decreased the time constant of activation at 0 mV from 4.9 +/- 1.7 to 0.6 +/- 0.1 sec (n = 6). In the presence of OPE, the half-activation voltage (V1/2 ) shifted in the negative direction, from 20.1 +/- 5.8 to 5.2 +/- 8.7 mV (n = 6), but the slope was not significantly altered. The OPE-induced current was profoundly inhibited by 10 MUm Zn2+ , the most potent Hv1 channel inhibitor, and was also inhibited by treatment with GF109203X, a specific protein kinase C (PKC) inhibitor. Furthermore, sperm motility was significantly increased in the OPE-treated groups. OPE exhibits protective effects on sperm motility, at least partially via regulation of the proton channel. Moreover, similar effects were exerted by quercetin, the major flavonoid in OPE. These results suggest OPE, which is rich in the potent Hv1 channel activator quercetin, as a possible new candidate treatment for human infertility. PMID- 28805024 TI - Sign language in dental education-A new nexus. AB - FOCUS: The introduction of the landmark mandatory teaching of sign language to undergraduate dental students at the University of the West Indies (UWI), Mona Campus in Kingston, Jamaica, to bridge the communication gap between dentists and their patients is reviewed. LITERATURE REVIEW: A review of over 90 Doctor of Dental Surgery and Doctor of Dental Medicine curricula in North America, the United Kingdom, parts of Europe and Australia showed no inclusion of sign language in those curricula as a mandatory component. HISTORY OF SIGN LANGUAGE IN DENTAL EDUCATION: In Jamaica, the government's training school for dental auxiliaries served as the forerunner to the UWI's introduction of formal training of sign language in 2012. Outside of the UWI, a couple of dental schools have sign language courses, but none have a mandatory programme as the one at the UWI. PROGRAMME RATIONALE: Dentists the world over have had to rely on interpreters to sign with their deaf patients. The deaf in Jamaica have not appreciated the fact that dentists cannot sign and they have felt insulted and only go to the dentist in emergency situations. The mandatory inclusion of sign language in the Undergraduate Dental Programme curriculum at The University of the West Indies, Mona Campus, sought to establish a direct communication channel to formally bridge this gap. PROGRAMME DEVELOPMENT: The programme of two sign language courses and a direct clinical competency requirement was developed during the second year of the first cohort of the newly introduced undergraduate dental programme through a collaborating partnership between two faculties on the Mona Campus. IMPLEMENTATION: The programme was introduced in 2012 in the third year of the 5-year undergraduate dental programme. PROGRAMME REVIEW & OUTCOMES: To date, two cohorts have completed the programme, and the preliminary findings from an ongoing clinical study have shown a positive impact on dental care access and dental treatment for deaf patients at the UWI Mona Dental Polyclinic. IMPLICATIONS: The development of a direct communication channel between dental students and the deaf that has led to increased dental access and treatment for the deaf can be extended to dentists and to other dental students globally. The vision is that similar courses will be introduced in other health training programmes at the UWI, and conceivably, in other institutions. LIMITATIONS: The small sample size allows for informative, but not definitive, conclusions to be drawn. CONCLUSION: The mandatory inclusion of sign language and Deaf culture in the dental curricula has not just removed a communication barrier, but has assisted in the empathetic and ethical development of the dental student. PMID- 28805025 TI - The giants Gargantua and Pantagruel - 16th century lifestyle habits. PMID- 28805026 TI - Correlation of 6-min walk test with left ventricular function and quality of life in heart failure due to Chagas disease. AB - OBJECTIVES: To evaluate the correlation of the total distance walked during the six-minute walk test (6MWT) with left ventricular function and quality of life in patients with Chagas Disease (ChD) complicated by heart failure. METHODS: This is a cross-sectional study of adult patients with ChD and heart failure diagnosed based on Framingham criteria. 6MWT was performed following international guidelines. New York Heart Association functional class, brain natriuretic peptide (BNP) serum levels, echocardiographic parameters and quality of life (SF 36 and MLHFQ questionnaires) were determined and their correlation with the distance covered at the 6MWT was tested. RESULTS: Forty adult patients (19 male; 60 +/- 12 years old) with ChD and heart failure were included in this study. The mean left ventricular ejection fraction was 35 +/- 12%. Only two patients (5%) ceased walking before 6 min had elapsed. There were no cardiac events during the test. The average distance covered was 337 +/- 105 metres. The distance covered presented a negative correlation with BNP (r = -0.37; P = 0.02), MLHFQ quality-of life score (r = -0.54; P = 0.002), pulmonary artery systolic pressure (r = -0.42; P = 0.02) and the degree of diastolic dysfunction (r = -0.36; P = 0.03) and mitral regurgitation (r = -0.53; P = 0.0006) and positive correlation with several domains of the SF-36 questionnaire. CONCLUSIONS: The distance walked during the 6MWT correlates with BNP, quality of life and parameters of left ventricular diastolic function in ChD patients with heart failure. We propose this test to be adopted in endemic areas with limited resources to aid in the identification of patients who need referral for tertiary centres for further evaluation and treatment. PMID- 28805028 TI - Slow and Steady May Win This Race. AB - This retrospective cohort study compares two strategies of stent delivery balloon inflation: inflation for 30 sec and longer as needed to stabilize the balloon pressure for 30 sec at the desired pressure, versus conventional fast inflation/fast deflation of the stent balloon The experimental technique decreased target vessel revascularization by about 50% as assessed by logistic regression and propensity analyses The investigators' recommendation to routinely use their prolonged inflation protocol is supported by six other studies over the past decade demonstrating that long stent balloon inflation produces better outcomes than does short inflation. PMID- 28805027 TI - Acute and midterm results following perventricular device closure of muscular ventricular septal defects: A multicenter PICES investigation. AB - OBJECTIVES: To describe acute and mid-term results of hybrid perventricular device closure of muscular ventricular septal defects (mVSDs). BACKGROUND: Perventricular device closure of mVSDs can mitigate technical limitations of percutaneous closure and need for cardiopulmonary bypass or ventriculotomy with a surgical approach. METHODS: This is a multicenter retrospective cohort study of patients undergoing hybrid perventricular mVSD device closure from 1/2004 to 1/2014. Procedural details, adverse events, outcomes, and follow-up data were collected. Patients were divided into two groups: (1) simple (mVSD closure alone) and (2) complex (mVSD closure with concomitant cardiac surgery). RESULTS: Forty seven patients (60% female) underwent perventricular mVSD device closure at a median age of 5.2 months (IQR 1.8-8.9) and weight of 5.1 kg (IQR 4.0-6.9). Procedural success was 91% [100% (n = 22) simple and 84% (n = 21/25) complex]. Adverse events occurred in 19% (9/47) [9% (2/22) simple and 28% (7/25) complex]. Hospital length of stay (LOS) was shorter in the simple vs. complex group (4 vs. 14 days, P < 0.01). At mid-term follow-up of 19.2 months (IQR 2.3-43) 90% of pts had complete mVSD closure; none developed late heart block, increased atrioventricular (AV) valve insufficiency or ventricular dysfunction. CONCLUSIONS: Perventricular device closure of simple mVSD was associated with a high rate of procedural success, few adverse events, and short hospital LOS. Procedural adverse events were associated with the presence of concomitant complex surgery. Residual mVSD, AV valve insufficiency, or ventricular dysfunction were uncommon at mid-term follow-up. (c) 2017 Wiley Periodicals, Inc. PMID- 28805029 TI - Fabulous at 40. PMID- 28805030 TI - A hybrid technique for ventricular septal defect closure in young infants. AB - Perventricular device closure is a hybrid surgical and transcatheter technique. Perventricular device closure is a safe and effective technique to close muscular VSDs even in infants. TEE guidance is the principal tool for intra-procedural guidance. PMID- 28805031 TI - "ICE or not to ICE during LAAO?" What are the benefits and disadvantages of ICE during LAAO? AB - For left atrial appendage occlusion (LAAO), intracardiac echocardiography (ICE) could be a safe alternative to transesophageal echocardiography (TEE). ICE obviates the need for general anesthesia and can be readily implemented in practice. Randomized controlled trials are needed to assess the noninferiority of ICE to TEE for LAAO. PMID- 28805032 TI - Improving outcomes after CABG and PCI. AB - Within 1 year of coronary artery bypass surgery , 64% of percutaneous coronary interventions were performed for graft failure and 36% for native vessel disease. Predictors of graft failure were small diameter of the graft and native vessel, poor distal run-off, and disease distal to the graft. In the near future, cardiac computed tomography angiography (CCTA) and fractional flow reserve by CT (FFRct) will incorporate accurate determination of coronary anatomy and the presence and extent of myocardial ischemia. PMID- 28805033 TI - Balloon aortic valvuloplasty in the TAVR era: Not so new but definitely improved. AB - BAV in the TAVR era is not well studied BAV resulted in improvements in aortic valve area and transvalvular pressure gradient, and in patients with impaired left ventricle function, ejection fraction improved. These improvements diminished over time, but at one year were still improved compared to baseline. BAV resulted in changes of planned therapy more than half of the patients treated as bridge for TAVR did not ultimately undergo TAVR twice as many planned as bridge for surgical valve replacement actually had surgical valve replacement. BAV techniques remain unstandardized and can be improved. PMID- 28805034 TI - Direct stenting versus balloon predilation: Jury is still out. AB - Compared to balloon predilation, direct stenting (DS) shortens procedural time and reduces radiation and contrast exposure. A meta-analysis that included 7 studies comparing these 2 strategies revealed lower adverse event rate with DS. Studies included in the present meta-analysis were mostly observational and utilized first generation drug-eluting stent. Patient and lesion selection may explain these positive results. PMID- 28805035 TI - One catheter or two? Tomayto or Tomahto? AB - This retrospective study compares the performance of transradial diagnostic procedures using the single versus Judkins catheter approach. The Judkins approach had a 15% lower patient radiation exposure than single catheter approach while fluoroscopy time was comparable. Future studies of comparing such techniques may always be limited by operator preference, experience, and comfort. PMID- 28805036 TI - Classification of mechanisms of strut malapposition after angiographically optimized stent implantation: An optical coherence tomography study. AB - AIMS: To elucidate causes and extent of strut malapposition in angiographically optimized stenting. METHODS AND RESULTS: Using a new classification system for strut malapposition, the mechanisms of stent strut malapposition were classified as localized lumen enlargement, vessel asymmetry, stent undersizing, strut underexpansion and stent deployment issue. Stent implantations (n = 110) in 100 consecutive patients undergoing optical coherence tomography (OCT) after the operator considered the stent as optimally deployed angiographically were reviewed to determine if strut apposition was complete. 127,894 stent struts in 110 stents were analyzed. There were 6,644 struts malapposed (5.2% +/-7.3%), with strut malapposition found in 82 of 110 stents (74.5%). Localized lumen enlargement was the most common cause of malapposition (74.4% of malapposition clusters). Stent undersizing was the second most common cause (46.3%) followed by strut under-expansion in 29.3%, stent deployment issue in 18.2%, and vessel asymmetry in 9.7%. CONCLUSION: Malapposition of any degree is common after angiographic stent optimization, occurring in up to three-quarters of stents. The most frequent mechanism was localized lumen enlargement. The second most common cause of strut malapposition was stent undersizing, which was angiographically invisible. Whether performing OCT after angiographic optimization improves short- and long-term outcomes requires further study. (c) 2017 Wiley Periodicals, Inc. PMID- 28805038 TI - Novel approaches to direct atrial access after extracardiac fontan palliation. AB - Catheter access to the "native" atria is limited after extra-cardiac Fontan palliation of univentricular cardiac defects Catheter access to the atria is necessary to percutaneously treat acquired abnormalities after extra-cardiac Fontan palliation Direct trans-thoracic atrial access and extra-cardiac conduit puncture is technically straightforward and allows for novel catheter interventions. PMID- 28805039 TI - Unnatural milieu: Thrombus after transcatheter mitral valve replacement. AB - What the article teaches Transcatheter heart valve thrombosis in the mitral position causes increased valve gradients, valve dysfunction, and symptoms, and may be associated with lack of therapeutic anticoagulation. How it will impact practice Anticoagulation with a vitamin K antagonist should be considered in all patients undergoing transcatheter mitral valve replacement. What new research/study would help answer the question posed Efficacy, optimal duration, and safety of anticoagulation therapy, balancing reduced thrombosis against increased bleeding risk, needs to be assessed in larger cohort studies and prospective trials. PMID- 28805040 TI - HPMA Copolymer-Drug Conjugates with Controlled Tumor-Specific Drug Release. AB - Over the past few decades, numerous polymer drug carrier systems are designed and synthesized, and their properties are evaluated. Many of these systems are based on water-soluble polymer carriers of low-molecular-weight drugs and compounds, e.g., cytostatic agents, anti-inflammatory drugs, or multidrug resistance inhibitors, all covalently bound to a carrier by a biodegradable spacer that enables controlled release of the active molecule to achieve the desired pharmacological effect. Among others, the synthetic polymer carriers based on N (2-hydroxypropyl) methacrylamide (HPMA) copolymers are some of the most promising carriers for this purpose. This review focuses on advances in the development of HPMA copolymer carriers and their conjugates with anticancer drugs, with triggered drug activation in tumor tissue and especially in tumor cells. Specifically, this review highlights the improvements in polymer drug carrier design with respect to the structure of a spacer to influence controlled drug release and activation, and its impact on the drug pharmacokinetics, enhanced tumor uptake, cellular trafficking, and in vivo antitumor activity. PMID- 28805041 TI - Direct Microrolling Processing on a Silicon Wafer. AB - Although, varieties of micro- to nanoscale fabrication technologies have been invented and refined for silicon (Si) processing because Si is the basic material of integrated circuits, the layouts are based on layer-by-layer approaches, making it difficult to realize three-dimensional (3D) structures with complicated shapes normal to the planar surface (along the out-of-plane direction) of the wafers used. Here, a novel and direct Si-processing technology that enables to bend thin layers of Si surfaces into various 3D curved structures at the micrometer scale is introduced. This bending is achieved by porosifying a Si wafer surface using anodic oxidation and then performing conventional photolithography patterning and wet etching. The porosity gradient in the depth direction gives rise to a stress-internalized layer in which self-rolling action is induced via subsequent patterning and wet etching. A subsequent oxidation process further enhances the curvature deformation, leading to the formation of tubes, for example. The rolling directions can be controlled by 2D patterning of the porous Si layer, which is explained well from a structural dynamics perspective. This technology has a wide range of capabilities for realizing 3D structures on Si substrates, enabling new design possibilities for Si-based on chip devices. PMID- 28805042 TI - Fabrication and characterization of electrospun laminin-functionalized silk fibroin/poly(ethylene oxide) nanofibrous scaffolds for peripheral nerve regeneration. AB - The peripheral nerve regeneration is still one of the major clinical problems, which has received a great deal of attention. In this study, the electrospun silk fibroin (SF)/poly(ethylene oxide) (PEO) nanofibrous scaffolds were fabricated and functionalized their surfaces with laminin (LN) without chemical linkers for potential use in the peripheral nerve tissue engineering. The morphology, surface chemistry, thermal behavior and wettability of the scaffolds were examined to evaluate their performance by means of scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC) and water contact angle (WCA) measurements, respectively. The proliferation and viability of Schwann cells onto the surfaces of SF/PEO nanofibrous scaffolds were investigated using SEM and thiazolyl blue (MTT) assay. The results showed an improvement of SF conformation and surface hydrophilicity of SF/PEO nanofibers after methanol and O2 plasma treatments. The immunostaining observation indicated a continuous coating of LN on the scaffolds. Improving the surface hydrophilicity and LN functionalization significantly increased the cell proliferation and this was more prominent after 5 days of culture time. In conclusion, the obtained results revealed that the electrospun LN-functionalized SF/PEO nanofibrous scaffold could be a promising candidate for peripheral nerve tissue regeneration. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1595-1604, 2018. PMID- 28805043 TI - Fatal peste des petits ruminants disease in Chowsingha. AB - This communication reports fatal Peste des petits ruminants (PPR) disease in Chowsingha (Tetracerus quadricornis), a member of the subfamily Bovinae and family Bovidae captured in a Zoological Park. The animals showed clinical signs of acute respiratory disease with frothy nasal discharge (1-2 days) and mortality of twenty animals (80%) within 48 hr. Necropsy of dead Chowsingha showed haemorrhagic patches in trachea and severe congestion of lungs and ocular mucosa. There was no characteristic lesion in the intestine. Swabs from trachea and nasal tract along with tissue samples of spleen and lung from dead animals were found positive for PPR virus based on reverse transcription-polymerase chain reaction using H gene and partial N gene-specific primers. Sequence analysis of complete H gene and partial N gene confirmed the aetiological agent as PPR virus lineage IV. The identity of the Chowsingha tissues used for PPRV isolation was confirmed by the 12S ribosomal RNA gene sequencing, and the amplified gene was analysed identically to the Chowsingha mitochondrial 12S ribosomal RNA gene. The present information of PPR in Chowsingha is the first report of PPRV lineage IV causing cross-species fatal disease in subfamily bovinae and family Bovidae. The acute manifestation of the disease indicates high susceptibility of this vulnerable wild bovid species to PPR lineage IV. This report extends host range and demands enhanced surveillance among subfamily bovinae to strengthen PPR eradication programme. PMID- 28805044 TI - NMpi-improved re-implementation of NM+, a software for estimating gene dispersal and mating patterns. AB - This study introduces the NMpi computer program designed for estimation of plant mating system and seed and pollen dispersal kernels. NMpi is a re-implementation of the NM+ program and provides new features such as support for multicore processors, explicit treatment of dioecy, the possibility of incorporating uniparentally cytoplasmic markers, the possibility of assessing assortative mating due to phenotypic similarity and inference about offspring genealogies. The probability model of parentage (the neighbourhood model) accounts for missing data and genotyping errors, which can be estimated along with regular parameters of the mating system. The program has virtually no restrictions with respect to a number of individuals, markers or phenotypic characters. A console version of NMpi can be run under a wide variety of operating systems, including Windows, Linux or Mac OS. For Windows users, a graphical user interface is provided to facilitate operating the software. The program, user manual and example data are available on http://www.ukw.edu.pl/pracownicy/plik/igor_chybicki/3694/. PMID- 28805046 TI - Electroenhanced Antimicrobial Coating Based on Conjugated Polymers with Covalently Coupled Silver Nanoparticles Prevents Staphylococcus aureus Biofilm Formation. AB - The incidence of hospital-acquired infections is to a large extent due to device associated infections. Bacterial attachment and biofilm formation on surfaces of medical devices often act as seeding points of infection. To prevent such infections, coatings based on silver nanoparticles (AgNPs) are often applied, however with varying clinical success. Here, the traditional AgNP-based antibacterial technology is reimagined, now forming the base for an electroenhanced antimicrobial coating. To integrate AgNPs in an electrically conducting polymer layer, a simple, yet effective chemical strategy based on poly(hydroxymethyl 3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT MeOH:PSS) and (3-aminopropyl)triethoxysilane is designed. The resultant PEDOT MeOH:PSS-AgNP composite presents a consistent coating of covalently linked AgNPs, as shown by scanning electron microscopy and surface plasmon resonance analysis. The efficacy of the coatings, with and without electrical addressing, is then tested against Staphylococcus aureus, a major colonizer of medical implants. Using custom-designed culturing devices, a nearly complete prevention of biofilm growth is obtained in AgNP composite devices addressed with a square wave voltage input. It is concluded that this electroenhancement of the bactericidal effect of the coupled AgNPs offers a novel, efficient solution against biofilm colonization of medical implants. PMID- 28805045 TI - Safety and Efficacy of Intravenous Golimumab in Patients With Active Psoriatic Arthritis: Results Through Week Twenty-Four of the GO-VIBRANT Study. AB - OBJECTIVE: To evaluate the safety and efficacy of intravenous (IV) golimumab treatment in psoriatic arthritis (PsA). METHODS: In this phase III, randomized, double-blind, placebo-controlled trial, patients were randomly assigned to receive IV placebo (n = 239) or golimumab at 2 mg/kg (n = 241) at weeks 0, 4, 12, and 20. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 14. Controlled secondary end points included change from baseline in Health Assessment Questionnaire disability index (HAQ DI) score at week 14, proportions of patients with ACR50 and ACR70 responses and >=75% improvement on the Psoriasis Area and Severity Index (a PASI75 response) at week 14, and change from baseline at week 24 in the total modified Sharp/van der Heijde score (SHS) with modifications for patients with PsA. RESULTS: At week 14, an ACR20 response was achieved by 75.1% of patients in the golimumab group compared with 21.8% of patients in the placebo group (P < 0.001). Greater proportions of golimumab treated patients had an ACR50 response (43.6% versus 6.3%), an ACR70 response (24.5% versus 2.1%), and a PASI75 response (59.2% versus 13.6%) at week 14 (P < 0.001 for all). Patients in the golimumab group had greater mean changes at week 14 in HAQ DI score (-0.60 versus -0.12; P < 0.001). At week 24, the mean change in total PsA-modified SHS was -0.4 in the golimumab group and 2.0 in the placebo group (P < 0.001). Through week 24, 40.6% of patients in the placebo group and 46.3% of patients in the golimumab group had >=1 adverse event (AE); infections were the most common type. CONCLUSION: Patients receiving IV golimumab at 2 mg/kg had significantly greater improvements in the signs and symptoms of PsA and less radiographic progression through week 24. AEs were consistent with those seen with other anti-tumor necrosis factor agents. PMID- 28805047 TI - Outcomes of post-prostatectomy radiotherapy at a Regional Cancer Centre. AB - INTRODUCTION: To investigate the efficacy and toxicity of radiation therapy (RT) after radical prostatectomy (RP) for prostate cancer at Radiation Oncology Centres, Toowoomba. METHODS: The electronic medical records of 130 consecutive patients with histologically proven prostate adenocarcinoma who underwent post prostatectomy RT between January 2008 and December 2014 were analysed. Primary endpoint was Biochemical Recurrence (BCR) after RT. BCR was defined by PSA > 0.2 ng/mL and BCR endpoints were analysed using Kaplan-Meier methods. The impact of RT technique and the rates of acute and late toxicities are also reported. Toxicities were graded according to Radiation Therapy Oncology Group (RTOG) criteria. RESULTS: Median follow-up time after RT (regardless of technique) was 28 months. BCR occurred in 32 of the 126 patients (25%) whose prostate specific antigen (PSA) levels have been monitored post-RT. At 24 and 36 months, 85% and 75% of patients were BCR-free, respectively. Patients with a pre-RT PSA above 0.2 ng/mL had a higher probability of recurrence than patients with values below 0.2 ng/mL (P = 0.03). RT technique, pelvic nodal irradiation, androgen deprivation therapy, T staging or surgical margin did not significantly impact BCR results. No patient experienced acute toxicities greater than grade 2. Grade 1 or 2 late gastrointestinal (GI) toxicity occurred in 11% and 1 patient experienced a grade 3 event. 12% of patients developed grade 1 or 2 late genitourinary (GU) toxicity, with evidence of grade 3 severity in only 1 patient. Evidence of a trend in reduction in late GI toxicity with the use of intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) was apparent but not with late GU toxicity. CONCLUSION: At our regional centre, early RT (PSA < 0.2 ng/mL) was associated with significant improvement in BCR-free survival. Rates of toxicity mirror those of landmark trials which suggest no detriment for our regional prostate cancer patients. The use of IMRT/VMAT techniques was associated with a trend towards reduced rates of GI toxicity. PMID- 28805048 TI - Recommendations for Vaccination Against Seasonal Influenza in Adult High Risk Groups: South Asian Recommendations. AB - Influenza is a global public health problem and concern especially in high risk people. Prevention plays a key role in avoiding complications of influenza related illnesses. Despite the existing prevalence of influenza, and documented importance of vaccination, the uptake of influenza vaccine is very poor. This document provide recommendations for influenza vaccination in high-risk individuals and help implement best practices in the South Asian region and improve coverage of influenza vaccination to achieve better outcomes in this population. PMID- 28805049 TI - Safety-Reinforced Succinonitrile-Based Electrolyte with Interfacial Stability for High-Performance Lithium Batteries. AB - Different contents of fluoroethylene carbonate (FEC) as cosolvent is added into succinonitrile (SN) solution to form a novel electrolyte for lithium batteries. The SN-based electrolyte with 20 wt % FEC exhibits the most favorable properties involving the good thermal stability, wide electrochemical window and high ionic conductivity. Comparing with the commercial electrolyte, the 20% FEC-SN electrolyte demonstrates the advantage of high safety and excellent interfacial compatibility with lithium due to the form of compact and smooth solid electrolyte interphase layer on the anode. LiCoO2/Li cells using the SN-based electrolyte behave a high reversible discharge capacity of 122.4 mAh g-1 and keep an outstanding capacity retention of 91% (122.1 mAh g-1) at 0.5 C after 100 cycles at 25 degrees C, 50 degrees C, respectively. More importantly, the soft package cells with the SN-based electrolyte can withstand harsh surroundings at 120 degrees C for 30 min without gas emitted, and can still keep the capacity retention of 77% compared to that before heat treatment, significantly higher than traditional commercial electrolyte (0%). All above results indicate the novel SN-based electrolyte can be an excellent alternative electrolyte in a practical lithium battery. PMID- 28805050 TI - Variability in Spatially and Temporally Resolved Emissions and Hydrocarbon Source Fingerprints for Oil and Gas Sources in Shale Gas Production Regions. AB - A gridded inventory for emissions of methane, ethane, propane, and butanes from oil and gas sources in the Barnett Shale production region has been developed. This inventory extends previous spatially resolved inventories of emissions by characterizing the overall variability in emission magnitudes and the composition of emissions at an hourly time resolution. The inventory is divided into continuous and intermittent emission sources. Sources are defined as continuous if hourly averaged emissions are greater than zero in every hour; otherwise, they are classified as intermittent. In the Barnett Shale, intermittent sources accounted for 14-30% of the mean emissions for methane and 10-34% for ethane, leading to spatial and temporal variability in the location of hourly emissions. The combined variability due to intermittent sources and variability in emission factors can lead to wide confidence intervals in the magnitude and composition of time and location-specific emission inventories; therefore, including temporal and spatial variability in emission inventories is important when reconciling inventories and observations. Comparisons of individual aircraft measurement flights conducted in the Barnett Shale region versus the estimated emission rates for each flight from the emission inventory indicate agreement within the expected variability of the emission inventory for all flights for methane and for all but one flight for ethane. PMID- 28805051 TI - Proposed Empirical Entropy and Gibbs Energy Based on Observations of Scale Invariance in Open Nonequilibrium Systems. AB - There is no widely agreed definition of entropy, and consequently Gibbs energy, in open systems far from equilibrium. One recent approach has sought to formulate an entropy and Gibbs energy based on observed scale invariances in geophysical variables, particularly in atmospheric quantities, including the molecules constituting stratospheric chemistry. The Hamiltonian flux dynamics of energy in macroscopic open nonequilibrium systems maps to energy in equilibrium statistical thermodynamics, and corresponding equivalences of scale invariant variables with other relevant statistical mechanical variables such as entropy, Gibbs energy, and 1/(kBoltzmannT), are not just formally analogous but are also mappings. Three proof-of-concept representative examples from available adequate stratospheric chemistry observations-temperature, wind speed and ozone-are calculated, with the aim of applying these mappings and equivalences. Potential applications of the approach to scale invariant observations from the literature, involving scales from molecular through laboratory to astronomical, are considered. Theoretical support for the approach from the literature is discussed. PMID- 28805052 TI - In Situ TEM Investigation of the Electrochemical Behavior in CNTs/MnO2-Based Energy Storage Devices. AB - Transition metal oxides have attracted much interest owing to their ability to provide high power density in lithium batteries; therefore, it is important to understand the electrochemical behavior and mechanism of lithiation-delithiation processes. In this study, we successfully and directly observed the structural evolution of CNTs/MnO2 during the lithiation process using transmission electron microscopy (TEM). CNTs/MnO2 were selected due to their high surface area and capacitance effect, and the lithiation mechanism of the CNT wall expansion was systematically analyzed. Interestingly, the wall spacings of CNTs/MnO2 and CNTs were obviously expanded by 10.92% and 2.59%, respectively. The MnO2 layer caused structural defects on the CNTs surface that could allow penetration of Li+ and Mn4+ through the tube wall and hence improve the ionic transportation speed. This study provided direct evidence for understanding the role of CNTs/MnO2 in the lithiation process used in lithium ion batteries and also offers potential benefits for applications and development of supercapacitors. PMID- 28805053 TI - Heterogeneous Photochemistry of Agrochemicals at the Leaf Surface: A Case Study of Plant Activator Acibenzolar-S-methyl. AB - The photoreactivity of plant activator benzo(1,2,3)thiadiazole-7-carbothioic acid S-methyl ester (BTH), commonly named acibenzolar-S-methyl, was studied on the surfaces of glass, paraffinic wax films, and apple leaves. Experiments were carried out in a solar simulator using pure and formulated BTH (BION). Surface photoproducts were identified using liquid chromatography coupled with electrospray ionization and high-resolution Orbitrap mass spectrometry, while volatile photoproducts were characterized using an online thermal desorption system coupled to a gas chromatography-mass spectrometry (GC-MS) system. Pure BTH degraded quickly on wax surfaces with a half-life of 5.0 +/- 0.5 h, whereas photolysis of formulated BTH was 7 times slower (t1/2 = 36 +/- 14 h). On the other hand, formulated BTH was found to photolyze quickly on detached apple leaves with a half-life of 2.8 h +/- 0.4 h. This drastic difference in photoreactivity was attributed to the nature and spreading of the BTH deposit, as influenced by the surfactant and surface characteristics. Abiotic stress of irradiated apple leaf was also shown to produce OH radicals which might contribute to the enhanced photodegradability. Eight surface photoproducts were identified, whereas GC-MS analyses revealed the formation of gaseous dimethyl disulfide and methanethiol. The yield of dimethyl disulfide ranged between 1.5% and 12%, and a significant fraction of dimethyl disulfide produced was found to be absorbed by the leaf. This is the first study to report on the formation of volatile chemicals and OH radicals during agrochemical photolysis on plant surfaces. The developed experimental approach can provide valuable insights into the heterogeneous photoreactivity of sprayed agrochemicals and could help improve dissipation models. PMID- 28805055 TI - pH-Induced Switchable Superwettability of Efficient Antibacterial Fabrics for Durable Selective Oil/Water Separation. AB - The superhydrophobic antibacterial fabrics with intelligent switchable wettability were fabricated by the cross-link reaction among pH-responsive antibacterial copolymer tethered hydroxyl groups, methylol-contained poly(ureaformaldehyde) nanoparticles (PUF NPs), and hexamethylene diisocyanate. It was found that the surface concentration of N+ were heavily influenced by acid solutions, resulting in the rapid wettability conversion from superhydrophobicity/superoleophilicity to superhydrophilicity/underwater superoleophobicity in a remarkably short time. The above responsiveness feature of coated cotton fabric contributes a prominent selective oil/water separation property, and the separation efficiency invariably remained at greater than 95% even after 20 reuse cycles, which exhibited brilliant durability. More importantly, the coated cotton fabric possessed excellent self-cleaning performance after contamination by oil and held high bactericidal rate (more than 80%) regardless of pH treatment, and thus could abate the surface biological pollution caused by bacteria proliferation. The attractive properties of the prepared smart superwetting materials shows great promise for potential application in oil/water separation from an environmental-protection perspective. PMID- 28805054 TI - A Scalable Field Study Protocol and Rationale for Passive Ambient Air Sampling: A Spatial Phytosampling for Leaf Data Collection. AB - Stable, bioreactive, radicals known as environmentally persistent free radicals (EPFRs) have been found to exist on the surface of airborne PM2.5. These EPFRs have been found to form during many combustion processes, are present in vehicular exhaust, and persist in the environment for weeks and biological systems for up to 12 h. To measure EPFRs in PM samples, high volume samplers are required and measurements are less representative of community exposure; therefore, we developed a novel spatial phytosampling methodology to study the spatial patterns of EPFR concentrations using plants. Leaf samples for laboratory PM analysis were collected from 188 randomly drawn sampling sites within a 500-m buffer zone of pollution sources across a sampling grid measuring 32.9 * 28.4 km in Memphis, Tennessee. PM was isolated from the intact leaves and size fractionated, and EPFRs on PM quantified by electron paramagnetic resonance spectroscopy. The radical concentration was found to positively correlate with the EPFR g-value, thus indicating cumulative content of oxygen centered radicals in PM with higher EPFR load. Our spatial phytosampling approach reveals spatial variations and potential "hotspots" risk due to EPFR exposure across Memphis and provides valuable insights for identifying exposure and demographic differences for health studies. PMID- 28805056 TI - Polymer Dehalogenation-Enabled Fast Fabrication of N,S-Codoped Carbon Materials for Superior Supercapacitor and Deionization Applications. AB - Doped carbon materials (DCM) with multiple heteroatoms hold broad interest in electrochemical catalysis and energy storage but require several steps to fabricate, which greatly hinder their practical applications. In this study, a facile strategy is developed to enable the fast fabrication of multiply doped carbon materials via room-temperature dehalogenation of polyvinyl dichloride (PVDC) promoted by KOH with the presence of different organic dopants. A N,S codoped carbon material (NS-DCM) is demonstratively synthesized using two dopants (dimethylformamide for N doping and dimethyl sulfoxide for S doping). Afterward, the precursive room-temperature NS-DCM with intentionally overdosed KOH is submitted to inert annealing to obtain large specific surface area and high conductivity. Remarkably, NS-DCM annealed at 600 degrees C (named as 600-NS DCM), with 3.0 atom % N and 2.4 atom % S, exhibits a very high specific capacitance of 427 F g-1 at 1.0 A g-1 in acidic electrolyte and also keeps ~60% of capacitance at ultrahigh current density of 100.0 A g-1. Furthermore, capacitive deionization (CDI) measurements reveal that 600-NS-DCM possesses a large desalination capacity of 32.3 mg g-1 (40.0 mg L-1 NaCl) and very good cycling stability. Our strategy of fabricating multiply doped carbon materials can be potentially extended to the synthesis of carbon materials with various combinations of heteroatom doping for broad electrochemical applications. PMID- 28805057 TI - Light-Driven Wettability Tailoring of Azopolymer Surfaces with Reconfigured Three Dimensional Posts. AB - The directional light-induced mass migration phenomenon arising in the photoresponsive azobenzene-containing materials has become an increasingly used approach for the fabrication of controlled tridimensional superficial textures. In the present work we demonstrate the tailoring of the superficial wettability of an azopolymer by means of the light-driven reconfiguration of an array of imprinted micropillars. Few simple illumination parameters are controlled to induce nontrivial wetting effects. Wetting anisotropy with controlled directionality, unidirectional spreading, and even polarization-intensity driven two-dimensional paths for wetting anisotropy are obtained starting from a single pristine pillar geometry. The obtained results prove that the versatility of the light-reconfiguration process, together with the possibility of reversible reshaping at reduced costs, represents a valid approach for both applications and fundamental studies in the field of geometry-based wettability of solid surfaces. PMID- 28805058 TI - Energy-Level Alignment of a Hole-Transport Organic Layer and ITO: Toward Applications for Organic Electronic Devices. AB - 2,2',6,6'-Tetraphenyl-4,4'-dipyranylidene (DIPO-Ph4) was grown by vacuum deposition on an indium tin oxide (ITO) substrate. The films were characterized by atomic force microscopy as well as synchrotron radiation UV and X-ray photoelectron spectroscopy to gain an insight into the material growth and to better understand the electronic properties of the ITO/DIPO-Ph4 interface. To interpret our spectroscopic data, we consider the formation of cationic DIPO-Ph4 at the ITO interface owing to a charge transfer from the organic layer to the substrate. Ionization energy DFT calculations of the neutral and cationic species substantiate this hypothesis. Finally, we present the energetic diagram of the ITO/DIPO-Ph4 system, and we discuss the application of this interface in various technologically relevant systems, as a hole-injector in OLEDs or as a hole collector interfacial layer adjacent to the prototypical OPV layer P3HT:PCBM. PMID- 28805059 TI - Probing Membrane Receptor-Ligand Specificity with Surface- and Tip- Enhanced Raman Scattering. AB - The specific interaction between a ligand and a protein is a key component in minimizing off-target effects in drug discovery. Investigating these interactions with membrane protein receptors can be quite challenging. In this report, we show how spectral variance observed in surface-enhanced Raman scattering (SERS) and tip-enhanced Raman scattering (TERS) can be correlated with ligand specificity in affinity-based assays. Variations in the enhanced Raman spectra of three peptide ligands (i.e., cyclic-RGDFC, cyclic-isoDGRFC, and CisoDGRC), which have different binding affinity to alphavbeta3 integrin, are reported from isolated proteins and from receptors in intact cancer cell membranes. The SERS signal from the purified proteins provides basis spectra to analyze the signals in cells. Differences in the spectral variance within the SERS and TERS data for each ligand indicate larger variance for nonspecific ligand-receptor interactions. The SERS and TERS results are correlated with single particle tracking experiments of the ligand functionalized nanoparticles with purified receptors on glass surfaces and living cells. These results demonstrate the ability to elucidate protein-ligand recognition using the observed vibrational spectra and provide perspective on binding specificity for small-molecule ligands in intact cell membranes, demonstrating a new approach for investigating drug specificity. PMID- 28805061 TI - Triple-Helix Molecular Switch Electrochemical Ratiometric Biosensor for Ultrasensitive Detection of Nucleic Acids. AB - Biomolecular receptors such as nucleic acids that switch between two or more conformations upon binding to a specific target can be used to build specific and sensitive biosensors. In this work, based on the electrochemical dual-signaling ratiometric strategy and triple-helix molecular switch, we developed a selective, reusable, and simple electrochemical DNA (E-DNA) biosensor for target DNA (T-DNA) detection. A hairpin DNA capture probe labeled with methylene blue (MB-DNA) self assembles on the surface of a gold electrode (GE) through Au-S bond, and then a single-strand DNA modified with two ferrocenes (Fc-DNA) on each end to enhance the oxidation signal hybridizes with the MB-DNA to form a triple-helix conformation. When T-DNA exists, the Fc-DNA hybridizes with T-DNA disassembling the triple-helix stem and allowing the MB-DNA to revert to its hairpin structure. Hence, the Fc tags diffuse away from the GE surface while the MB tags remain affixed close to it, resulting in a decrease in the peak current of Fc (IFc) and an increase in that of MB (IMB). The linear relationship between the value of IMB/IFc and the T-DNA concentration is observed from 0.5 to 80 pM, and the limit of detection is as low as 0.12 pM. The developed E-DNA biosensor may have great potential in the electrochemical detection of a wide range of analytes and be a biosensing platform for early clinical diagnosis and biomedical research. PMID- 28805060 TI - Substrate-Induced Facilitated Dissociation of the Competitive Inhibitor from the Active Site of O-Acetyl Serine Sulfhydrylase Reveals a Competitive-Allostery Mechanism. AB - By classical competitive antagonism, a substrate and competitive inhibitor must bind mutually exclusively to the active site. The competitive inhibition of O acetyl serine sulfhydrylase (OASS) by the C-terminus of serine acetyltransferase (SAT) presents a paradox, because the C-terminus of SAT binds to the active site of OASS with an affinity that is 4-6 log-fold (104-106) greater than that of the substrate. Therefore, we employed multiple approaches to understand how the substrate gains access to the OASS active site under physiological conditions. Single-molecule and ensemble approaches showed that the active site-bound high affinity competitive inhibitor is actively dissociated by the substrate, which is not consistent with classical views of competitive antagonism. We employed fast flow kinetic approaches to demonstrate that substrate-mediated dissociation of full length SAT-OASS (cysteine regulatory complex) follows a noncanonical "facilitated dissociation" mechanism. To understand the mechanism by which the substrate induces inhibitor dissociation, we resolved the crystal structures of enzyme.inhibitor.substrate ternary complexes. Crystal structures reveal a competitive allosteric binding mechanism in which the substrate intrudes into the inhibitor-bound active site and disengages the inhibitor before occupying the site vacated by the inhibitor. In summary, here we reveal a new type of competitive allosteric binding mechanism by which one of the competitive antagonists facilitates the dissociation of the other. Together, our results indicate that "competitive allostery" is the general feature of noncanonical "facilitated/accelerated dissociation" mechanisms. Further understanding of the mechanistic framework of "competitive allosteric" mechanism may allow us to design a new family of "competitive allosteric drugs/small molecules" that will have improved selectivity and specificity as compared to their competitive and allosteric counterparts. PMID- 28805062 TI - Ultrafast Electron Dynamics in Solar Energy Conversion. AB - Electrons are the workhorses of solar energy conversion. Conversion of the energy of light to electricity in photovoltaics, or to energy-rich molecules (solar fuel) through photocatalytic processes, invariably starts with photoinduced generation of energy-rich electrons. The harvesting of these electrons in practical devices rests on a series of electron transfer processes whose dynamics and efficiencies determine the function of materials and devices. To capture the energy of a photogenerated electron-hole pair in a solar cell material, charges of opposite sign have to be separated against electrostatic attractions, prevented from recombining and being transported through the active material to electrodes where they can be extracted. In photocatalytic solar fuel production, these electron processes are coupled to chemical reactions leading to storage of the energy of light in chemical bonds. With the focus on the ultrafast time scale, we here discuss the light-induced electron processes underlying the function of several molecular and hybrid materials currently under development for solar energy applications in dye or quantum dot-sensitized solar cells, polymer-fullerene polymer solar cells, organometal halide perovskite solar cells, and finally some photocatalytic systems. PMID- 28805063 TI - Hierarchical Porous Co9S8/Nitrogen-Doped Carbon@MoS2 Polyhedrons as pH Universal Electrocatalysts for Highly Efficient Hydrogen Evolution Reaction. AB - The development of highly active and stable earth-abundant electrocatalysts to reduce or eliminate the reliance on noble-metal based ones for hydrogen evolution reaction (HER) over a broad pH range remains a great challenge. Herein, hierarchical porous Co9S8/N-doped carbon@MoS2 (Co9S8/NC@MoS2) polyhedrons have been synthesized by a facile hydrothermal approach using highly conductive Co/NC polyhedrons composed of cobalt nanoparticles embedded in N-doped carbon matrices as both the structural support and cobalt source. The Co/NC polyhedrons were prepared by direct carbonization of Co-based zeolitic imidazolate framework (ZIF 67) in Ar atmosphere. Benefiting from the prominent synergistic effect of N-doped carbon enhancing the conductivity of the hybrid, MoS2 and Co9S8 providing abundant catalytically active sites as well as the well-defined polyhedral structure promoting mechanical stability, the as-synthesized Co9S8/NC@MoS2 shows excellent HER activity and good stability over a broad pH range, with onset overpotentials of 4, 38, and 45 mV, Tafel slopes of 60.3, 68.8, and 126.1 mV dec 1, and overpotentials of 67, 117, and 261 mV at 10 mA cm-2 in 1.0 M KOH, 0.5 M H2SO4, and 1.0 M phosphate buffer solution (PBS), respectively. This work provides a general and promising approach for the design and synthesis of inexpensive and efficient pH-universal HER electrocatalysts. PMID- 28805064 TI - Double Crystalline Multiblock Copolymers with Controlling Microstructure for High Shape Memory Fixity and Recovery. AB - The shape memory performance of double crystalline poly(butylene succinate)-co poly(epsilon-caprolactone) (PBS-co-PCL) multiblock copolymers with controlling microstructure was studied, and the corresponding microstructure origin was further quantitatively analyzed by wide and small-angle X-ray scattering (WAXS and SAXS) experiments. It was found that the multiblock copolymer with higher PCL content, proper deformation strain, and inhibited crystallization of PBS (lower crystallinity and smaller crystal size, which could be realized by quenching from the melt) would exhibit better shape memory fixity and recovery performance. WAXS and SAXS results revealed that the shape fixity ratio (Rf) was closely related with the relative crystallinity of the PCL component, while the shape recovery ratio (Rr) strongly relied on the deformation and recovery behavior of the PBS and PCL components that changed along with compositions and deformation strains. For the copolymer with higher PCL content (BS30CL70), at the lower deformation strain (0% ~ 90%), both the PBS and PCL components after recovery had no orientation (labeled as stage I), resulting in almost complete recovery; with the deformation strain increasing (90% ~ 200%), it was the irreversible deformation of the PCL component that largely took responsibility for the decreased Rr (stage II). On the contrary, when the PCL content decreased to 50 wt % (BS50CL50), stage I (0% ~ 50%) and stage II (50% ~ 100%) appeared in much lower strains; with the deformation strain increasing (100% ~ 200%), the irreversible deformation of both PBS and PCL components was mainly responsible for the further reduction of Rr (stage III). It could exhibit excellent shape memory performance for biodegradable double crystalline multiblock copolymers by controlling the composition, deformation strain, and crystallization, which might have wide application prospects in biomedical areas. PMID- 28805065 TI - Neurohormonal modulation for treatment of cardiac involvement in dystrophinopathies and mitochondrial disease. AB - Mutations in either the nuclear or the mitochondrial genome can lead to structural and functional changes within the skeletal muscles. These genetic skeletal myopathies are rare, although not infrequent when their cumulative incidence is considered. Dystrophinopathies (Duchenne and Becker muscular dystrophies) and mitochondrial disease are some of the most frequent clinical entities, and those developing heart failure more frequently. Neurohormonal antagonism represents the cornerstone of heart failure management, even though its role in the prevention and treatment of heart failure in patients with dystrophinopathies or mitochondrial disorders remains undefined. In the present paper we will summarise current available evidence on this topic. Particular attention will be devoted to Duchenne muscular dystrophy, and to the approaches modulating neurohormonal function by targeting the skeletal muscle. PMID- 28805066 TI - Active controlled motion in early rehabilitation improves outcome after ankle fractures: a randomized controlled trial. AB - OBJECTIVE: To evaluate the use of active controlled motion (ACM) after unstable ankle fractures needing initial partial weight-bearing. DESIGN: Prospective randomized controlled trial. SETTING: Inpatient and outpatient clinic. SUBJECTS: A total of 50 patients with unstable ankle fractures and the need for partial weight-bearing for six weeks. INTERVENTIONS: Randomization in two groups: physiotherapy alone or physiotherapy with an additional ACM device. MAIN MEASURES: Follow-up after 6 and 12 weeks. Range of motion, visual analogue scale for foot and ankle (VAS FA), Philip score, Mazur score, American Orthopaedic Foot & Ankle Society (AOFAS) score and dynamic pedobarography. RESULTS: Range of motion was better in the ACM group at six weeks (mean 49 degrees +/- 11.1 degrees vs. 41.3 degrees +/- 8.1 degrees ). Questionnaires revealed better outcome after six weeks in the VAS FA (56 +/- 13.7 vs. 40.6 +/- 10.5), Mazur score (64.4 +/- 12.3 vs. 56.7 +/- 11) and AOFAS score (71.2 +/- 12 vs. 63.6 +/- 8.7) ( P > 0.02 for all). Better outcome after 12 weeks in all questionnaires (VAS FA, 77.7 +/- 13.8 vs. 61.4 +/- 16.3; Philip score, 79.1 +/- 10.9 vs. 60.1 +/ 21.7; Mazur score, 83.9 +/- 10.7 vs. 73.1 +/- 14.1; AOFAS score, 87.5 +/- 7.9 vs. 75.2 +/- 11.7) ( P < 0.01 for all). Pressure balance was better under the midfoot region after 12 weeks in the ACM group (Delta P 4.4 N vs. 34.0 N; P = 0.01). The ACM group had an earlier return to work after 10.5 (range, 3-17) versus 14.7 (range, 9-26) weeks ( P = 0.02). CONCLUSION: The use of ACM for patients needing initial partial weight-bearing after operatively treated unstable ankle fractures in the first six postoperative weeks leads to better clinical and functional results and an earlier return to work. PMID- 28805067 TI - The lncRNA, Nespas, Is Associated with Osteoarthritis Progression and Serves as a Potential New Prognostic Biomarker. AB - INTRODUCTION: In this article, we explored the hypothesis that the long noncoding RNA, Nespas, promotes osteoarthritis (OA) by supporting abnormal lipid metabolism in human chondrocytes. MATERIALS AND METHODS: Human articular chondrocytes from osteoarthritis patients were used and expression level of Nespas were determined by real-time polymerase chain reaction. Introduction of Nespas and Nespas associated genes/miRNAs were performed by using a lentiviral system. The effect of Nespas on mitochondrial function was determined by staining mitochondria and analyzing mitopotential and mitochondrial genes. Moreover, to identify the responsible molecules in Nespas-induced pathogenesis, profiling of peroxisomal genes and miRNAs were applied and interactome analysis was performed. RESULTS: Highly elevated levels of Nespas and Acyl-CoA synthetase 6 (ACSL6) were observed in OA patients. Both Nespas overexpression and ACSL6 upregulation into human chondrocytes induced typical OA characteristics, such as downregulation of type II collagen; upregulation of type I collagen, metalloproteinase 13, and caspase-1 and -3; and dysfunction of mitochondria and peroxisome. Co-expression of Nespas and ACSL6 siRNA reduced caspase-1 and -3 levels. Moreover, Nespas overexpression significantly suppressed levels of miR-291a-3p, -196a-5p, -23a-3p, -24-3p, and let-7a-5p, and these miRs are known to potentially target ACSL6 according to ingenuity pathway analysis. We also confirmed that these miRs were significantly suppressed in human OA chondrocytes. Overexpression of miR-291a-3p, -196a-5p, 23a-3p, -24-3p, or let-7a-5p in the presence of Nespas suppressed levels of ACSL6, caspase-1 and -3. DISCUSSION: Overall, we suggest that elevated Nespas level in OA are associated with OA pathogenesis by suppressing miRs targeting ACSL6 and subsequent ACSL6 upregulation. PMID- 28805068 TI - Medication Errors and Trainees: Advice for Learners and Organizations. AB - Limited information exists regarding medication errors and trainees (students or residents). Yet during the experiential education component of their training, learners are expected to assume significant responsibilities in the medication use process. This commentary addresses both trainees and organization leaders on medication safety practices and the incorporation of learners into the organization's medication safety culture. PMID- 28805069 TI - Assessing the quality of life in patients with multiple sclerosis in Kuwait: a cross sectional study. AB - The main objective of this paper was to assess the level and the determinants of quality of life (QOL) amongst patients with multiple sclerosis (MS). A cross sectional study was conducted among a convenience sample of 200 adult MS patients. Inclusion criteria were: MS diagnosis for at least one year, and aged 21+ years. However, exclusion criteria were: having other neurological diseases, serious cardiovascular, orthopedic or other disability precluding participation. Self-administered questionnaire employed MSQOL-54 with two outcomes: Physical Health Composite (PHC) and mental health composite (MHC). Satisfaction with Daily Occupation scale was adopted through face to face interviews. The median of PHC and MHC scores were 48.9/100, and 53.4/100 respectively. Multivariate analysis revealed that unemployment was a determinant of poor PHC, while low monthly income was a predictor of poor MHC. Additionally, low endurance and sensory problems were associated with poor PHC, and MHC, while motor problems were allied with only poor PHC. Patient's satisfaction level with performing activities of daily living was positively associated with PHC and MHC. Assessment of QOL is suggested to be comprised in medical settings. PMID- 28805071 TI - A systematic review of quality of life of adults on the autism spectrum. AB - Autism spectrum disorder is associated with co-existing conditions that may adversely affect an individual's quality of life. No systematic review of quality of life of adults on the autism spectrum has been conducted. Our objectives were as follows: (1) review the evidence about quality of life for adults on the autism spectrum; (2) critically appraise current practice in assessing quality of life of adults on the autism spectrum. We searched bibliographic databases and other literature to identify studies using a direct measure of quality of life of adults on the autism spectrum. Hand searching of reference lists, citation searching and personal communication with field experts were also undertaken. In total, 827 studies were identified; 14 were included. Only one quality of life measure designed for use with the general autism spectrum population was identified. Quality of life of adults on the autism spectrum is lower than that of typically developing adults, when measured with tools designed for the general population. There are no comprehensive autism spectrum disorder-specific quality of life measurement tools validated for use with representative samples of adults on the autism spectrum. There is a pressing need to develop robust measures of quality of life of autistic adults. PMID- 28805070 TI - Multivariate Analysis of Mixed Lipid Aggregate Phase Transitions Monitored Using Raman Spectroscopy. AB - The phase behavior of aqueous 1,2-dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC)/1,2-dihexanoyl-sn-glycero-3-phosphocholine (DHPC) mixtures between 8.0 C and 41.0 C were monitored using Raman spectroscopy. Temperature-dependent Raman matrices were assembled from series of spectra and subjected to multivariate analysis. The consensus of pseudo-rank estimation results is that seven to eight components account for the temperature-dependent changes observed in the spectra. The spectra and temperature response profiles of the mixture components were resolved by applying a variant of the non-negative matrix factorization (NMF) algorithm described by Lee and Seung (1999). The rotational ambiguity of the data matrix was reduced by augmenting the original temperature-dependent spectral matrix with its cumulative counterpart, i.e., the matrix formed by successive integration of the spectra across the temperature index (columns). Successive rounds of constrained NMF were used to isolate component spectra from a significant fluorescence background. Five major components exhibiting varying degrees of gel and liquid crystalline lipid character were resolved. Hydrogen bonded water networks exhibiting varying degrees of organization are associated with the lipid components. Spectral parameters were computed to compare the chain conformation, packing, and hydration indicated by the resolved spectra. Based on spectral features and relative amounts of the components observed, four components reflect long chain lipid response. The fifth component could reflect the response of the short chain lipid, DHPC, but there were no definitive spectral features confirming this assignment. A minor component of uncertain assignment that exhibits a striking response to the DMPC pre-transition and chain melting transition also was recovered. While none of the spectra resolved exhibit features unequivocally attributable to a specific aggregate morphology or step in the gelation process, the results are consistent with the evolution of mixed phase bicelles (nanodisks) and small amounts of worm-like DMPC/DHPC aggregates, and perhaps DHPC micelles, at low temperature to suspensions of branched and entangled worm-like aggregates above the DMPC gel phase transition and perforated multi-lamellar aggregates at high temperature. PMID- 28805072 TI - Chronic Nonbacterial Osteomyelitis of the Mandible: Recognition, Etiology, and Management. PMID- 28805073 TI - Do You Know What Your Kids Are Drinking? Evaluation of a Media Campaign to Reduce Consumption of Sugar-Sweetened Beverages. AB - OBJECTIVE: This study evaluates a citywide media campaign that targeted reducing sugar-sweetened beverage (SSB) consumption as a strategy for addressing obesity. DESIGN: Rolling cross-sectional survey data, collected before and during the media campaign, with 1367 parents to assess exposure to and effect of a televised public service advertisement (TV PSA) developed using a reasoned action approach. SETTING: Televised public service advertisement campaign created by the Philadelphia Department of Public Health and disseminated on cable television channels within the Philadelphia market. PARTICIPANTS: Philadelphia parents/primary caregivers with a child between the ages of 3 and 16. RESULTS: Linear regression analysis shows that exposure to the TV PSA was significantly associated with intention to substitute nonsugary drinks for SSBs for the parent ( P = .04) and the child ( P = .02). The effect of exposure on intention to reduce child's SSB consumption increased the longer the campaign was in the field. Exposure was also significantly associated with the belief that reducing SSB consumption decreases the risk of diabetes ( P = .04) and was significantly negatively related to the belief that reducing SSB consumption would make mealtimes less enjoyable ( P = .04). CONCLUSION: These findings suggest that a theory-based mass media campaign can achieve positive changes in intention related to SSB consumption by changing relevant and salient underlying beliefs. PMID- 28805074 TI - Comparing the New York State Smokers' Quitline Reach, Services Offered, and Quit Outcomes to 44 Other State Quitlines, 2010 to 2015. AB - PURPOSE: To summarize the reach, services offered, and cessation outcomes of the New York Quitline and compare with other state quitlines. DESIGN: Descriptive study. SETTING: Forty-five US states. PARTICIPANTS: State-sponsored tobacco cessation quitlines in 45 US states that provided complete data to the Centers for Disease Control and Prevention's National Quitline Data Warehouse (NQDW) for 24 quarters over 6 years (2010-Q1 through 2015-Q4). INTERVENTION: Telephone quitlines that offer tobacco use cessation services, including counseling, self help materials, and nicotine replacement therapy (NRT), to smokers at no cost to them. MEASURES: Percentage of adult tobacco users in the state who received counseling and/or free NRT from state quitlines (reach), services offered by state quitlines, and cessation outcomes among quitline clients 7 months after using quitline services. ANALYSIS: Reach, services offered, and cessation outcomes for the New York Quitline were compared with similar measures for the other 44 state quitlines with complete NQDW data for all quarters from 2010 through 2015. RESULTS: New York's average annual quitline reach from 2010 through 2015 was 3.0% per year compared to 1.1% per year for the other 44 states examined. CONCLUSION: Although the New York Quitline was open fewer hours per week and offered fewer counseling sessions and a smaller amount of free NRT than most of the other 44 state quitlines, the New York Quitline had similar quit rates to most of those state quitlines. PMID- 28805075 TI - Validity and reliability of accelerometry in identification of lying, sitting, standing or purposeful activity in adult hospital inpatients recovering from acute or critical illness: a systematic review. AB - OBJECTIVE: To investigate the validity and reliability of accelerometers to detect lying, sitting and standing postures or purposeful activity in hospitalized adults recovering from acute or critical illness. DATA SOURCES: CINAHL, MEDLINE, EMBASE, AMED, Cochrane Library, PEDro, PsycINFO and SPORTDiscuss were searched from inception to June 2017. Professional networks and reference lists of relevant articles were also searched. The main selection criteria were hospitalized adults with acute or critical illness and studies investigating the validity or reliability of accelerometers to identify body position or purposeful activity. REVIEW METHODS: Two authors individually assessed study eligibility and independently undertook methodological quality assessment and data extraction from selected articles. A narrative synthesis of the data was undertaken. RESULTS: Fifteen studies, collectively enrolling 385 hospitalized participants, were identified. Populations included stroke, the elderly, acute exacerbation of chronic respiratory disease, abdominal surgery and those recovering from critical illness. Correlations of r = 0.36 to 0.98 and levels of agreement of kappa = 0.28 to 0.98 were reported for identification of lying, sitting or standing postures. Correlations of r = 0.4 to 0.8 with general activity were found, with r = 0.94 and 0.96 reported for step count. The reliability of accelerometry measurement was investigated in one study evaluating step count quantification (intraclass correlation coefficient (ICC) = 0.99, 95% confidence interval (CI) = 0.99-1.00). CONCLUSION: The validity of accelerometers to determine lying, sitting and standing postures or quantify purposeful activity within hospitalized acute or critically ill populations is variable. The reliability of accelerometry measurement within this setting remains largely unexplored. PMID- 28805076 TI - Assessing serum metabolite profiles as predictors for feed efficiency in broiler chickens reared at geographically distant locations. AB - 1. The objective of this study was to investigate differences in growth performance, serum intermediary metabolites, acute-phase proteins and white blood cells in low, medium and high-residual feed intake (RFI) chickens. It was also assessed if the environment affects the feed efficiency (FE) and FE-related performance and serum profiles of chickens. 2. Individual body weight (BW) and feed intake (FI) were recorded from d 7 of life. At 5 weeks of age, female and male broiler chickens (Cobb 500) were selected according to their RFI (L1: Austria; L2: UK; n = 9/RFI group, sex and locatity -45on) and blood samples were collected. 3. Chickens at L1 had similar FI but a 15% higher BW gain compared to chickens at L2. The RFI values of female chickens were -231, 8 and 215 g and those of male chickens -197, 0 and 267 g for low, medium and high RFI, respectively. 4. Location affected serum glucose, urea, cholesterol, non esterified fatty acids (NEFA) and ovotransferrin in females, and serum glucose and triglycerides in male chickens. Serum uric acid and NEFA linearly increased from low to high RFI in females, whereas in males, cholesterol showed the same linear response from low to high RFI. Serum alpha-1-acid glycoprotein and blood heterophil-to-lymphocyte ratio linearly increased by 35% and 68%, respectively, from low to high RFI but only in male chickens at L1. 5. Regression analysis showed significant positive relationships between RFI and serum uric acid (R2 = 0.49) and cholesterol (R2 = 0.13). 6. It was concluded that RFI-related variation in serum metabolites of chickens was largely similar for the two environments and that serum metabolite patterns could be used to predict RFI in chickens. PMID- 28805077 TI - Relevance of age at slaughter on meat quality of turkeys stunned with CO2. AB - 1. The objective of this work was to determine the effect of slaughter age and stunning method on the quality of turkey meat from poultry processing plants. 2. One hundred B.U.T. Premium turkeys were divided into 4 groups of 25 animals according to slaughter age (15 or 17 weeks) and CO2 stunning procedure (G1 stepwise: step1: 30% CO2, 15 s; step 2: 55% CO2, 40 s; step 3: 70% CO2, 45 s; G2: progressive increase of the CO2 concentration at a rate of 0.8% per s for 100 s). The quality of the breast meat was determined in fillets taken at different post mortem times. 3. There were differences between the stunning groups for several variables (pH: 6.01 +/- 0.01 and 5.95 +/- 0.02; a*: -1.84 +/- 0.05 and -2.21 +/- 0.04; b*: 4.99 +/- 0.15 and 4.68 +/- 0.16; drip loss: 0.85 +/- 0.02 and 0.71 +/- 0.02 for G1 and G2, respectively), while no significant differences were found for L*, cooking loss and texture analysed with a Warner Bratzler Shear Force cell (WBSF). 4. Slaughter age had a significant effect on all the parameters studied (pH: 6.01 +/- 0.01 and 5.95 +/- 0.01; a*: -2.21 +/- 0.05 and -1.88 +/- 0.05, b*: 5.50 +/- 0.17 and 4.42 +/- 0.15; drip loss: 0.71 +/- 0.02 and 0.86 +/- 0.02, cooking loss: 12.56 +/- 0.22 and 14.69 +/- 0.16 for turkeys slaughtered at 15 and 17 w, respectively) except on L* and WBSF. 5. The ageing of the meat affected pH, colour values, drip loss and WBSF, with differing degrees of evolution: mean values of L* (39.36 +/- 0.35. 45.77 +/- 0.20 and 46.30 +/- 0.24, for 20 min, 24 h and 7 d post mortem, respectively) and drip loss (0.75 +/- 0.03 and 0.84 +/- 0.02 for 24 h and 7 d post mortem, respectively) increased, those of a* (-1.77 +/- 0.08, -1.94 +/- 0.07 and -2.22 +/- 0.05 for 20 min, 24 h and 7 d post mortem, respectively) and WBSF decreased (3.73 +/- 0.06 and 2.63 +/- 0.04 for 24 h and 7 d post mortem, respectively), those of pH decreased in the first 24 h and remained stable for the next 6 d (6.19 +/- 0.02, 5.87 +/- 0.01 and 5.88 +/- 0.01), and those of b* increased in the first 24 h post-mortem and remained stable for the next 6 d (3.26 +/- 0.31, 5.86 +/- 0.16 and 5.47 +/- 0.08). 6. The results revealed no critical differences between stunning methods, and suggest that animals slaughtered at 15 weeks present higher quality meat than those slaughtered at 17 weeks. PMID- 28805078 TI - Occurrence and predictive factors of heterotopic ossification in severe acquired brain injured patients during rehabilitation stay: cross-sectional survey. AB - OBJECTIVES: To report occurrence and identify patient's features and risk factors of heterotopic ossifications in patients with severe acquired brain injury in intensive rehabilitation centres. DESIGN: Multicentre cross-sectional survey. SETTING: A total of 48 severe acquired brain injury rehabilitation institutes. PARTICIPANTS: Traumatic and non-traumatic severe brain-injured patients ( N = 689) in rehabilitation centres on 28 May 2016. MAIN OUTCOME MEASURE: Occurrence of heterotopic ossifications diagnosed by standard radiological and/or sonographic evaluation on the basis of clinical suspicion. RESULTS: Heterotopic ossification occurred around one or more joints in 94/689 patients (13.6%) with a significantly higher prevalence in young males. Occurrence did not significantly differ in relation to aetiology (16.3% traumatic, 19.2% anoxic, 11.7% vascular and 11.5% other). Prevalence was significantly higher in patients with diffuse (23.3%) rather than focal brain lesions (12.4%) or unspecified lesions (11.2%; chi-square = 7.81, df = 2, P = 0.020); longer duration of coma ( P = 0.0016) and ventilation support ( P = 0.0145); paroxysmal sympathetic hyperactivity (22.6% versus 11.6%; chi-square = 10.81, df = 1, P = 0.001); and spasticity (22.7% versus 10.1%; chi-square = 18.63, df = 1, P < 0.0001). A longer interval between acute brain injury and admission to rehabilitation centre was significantly associated with higher frequency of heterotopic ossifications. CONCLUSION: Occurrence of heterotopic ossifications is frequent in patients with severe traumatic and non-traumatic brain-injury in rehabilitation centres. Our study confirms male gender, young age, paroxysmal sympathetic hyperactivity, spasticity, longer duration of coma and ventilation and longer interval between brain injury onset and admission to rehabilitation centre as possible risk factors. Further studies are necessary to investigate the role of early appropriate rehabilitation pathways to reduce occurrence of heterotopic ossifications. PMID- 28805079 TI - Nonlinear Recurrent Dynamics and Long-Term Nonstationarities in EEG Alpha Cortical Activity: Implications for Choosing Adequate Segment Length in Nonlinear EEG Analyses. AB - Nonlinear analysis of EEG recordings allows detection of characteristics that would probably be neglected by linear methods. This study aimed to determine a suitable epoch length for nonlinear analysis of EEG data based on its recurrence rate in EEG alpha activity (electrodes Fz, Oz, and Pz) from 28 healthy and 64 major depressive disorder subjects. Two nonlinear metrics, Lempel-Ziv complexity and scaling index, were applied in sliding windows of 20 seconds shifted every 1 second and in nonoverlapping windows of 1 minute. In addition, linear spectral analysis was carried out for comparison with the nonlinear results. The analysis with sliding windows showed that the cortical dynamics underlying alpha activity had a recurrence period of around 40 seconds in both groups. In the analysis with nonoverlapping windows, long-term nonstationarities entailed changes over time in the nonlinear dynamics that became significantly different between epochs across time, which was not detected with the linear spectral analysis. Findings suggest that epoch lengths shorter than 40 seconds neglect information in EEG nonlinear studies. In turn, linear analysis did not detect characteristics from long-term nonstationarities in EEG alpha waves of control subjects and patients with major depressive disorder patients. We recommend that application of nonlinear metrics in EEG time series, particularly of alpha activity, should be carried out with epochs around 60 seconds. In addition, this study aimed to demonstrate that long term nonlinearities are inherent to the cortical brain dynamics regardless of the presence or absence of a mental disorder. PMID- 28805080 TI - Evaluation of the amount of nanoparticles emitted in welding fume from stainless steel using different shielding gases. AB - The primary objective of this study was to correlate the emission of macro and nanoparticles released during the process of metal inert gas/metal active gas (MIG/MAG) of stainless steel with different gas mixtures. Using different gas mixtures with different heat inputs, it was possible to determine fume formation rates and surface areas of nanoparticles with alveolar lung deposition capacity. It was found, how the various transfer modes and the type of gas protection, in particular, the percentage of active elements in the chemical composition of the gas, affect the amount of fumes generated and also the generation of nanoparticles with a high capacity of deposition. The spray transfer mode always shows higher values of nanoparticles surface area, unlike the fume formation rates. Among the tested mixtures 82%Ar + 18%CO2 generates higher emissions of nanoparticles as well as fume formation rates. PMID- 28805081 TI - Bezlotoxumab for the prevention of Clostridium difficile recurrence. AB - INTRODUCTION: Clostridium difficile infection is a major economic and clinical burden, due to its high frequency of recurrence. Currently recommended treatments are not efficient for prevention and may contribute to the risk of recurrent infection. In recent years, research has focused on strategies to lessen this risk. Bezlotoxumab is a monoclonal antibody that prevents recurrences of C. difficile infection through the antagonism of toxin B. Areas covered: In this review, the authors discuss the burden of C. difficile infection and its recurrences, the mechanisms underlying the recurrences, and current C. difficile treatments. They subsequently analyze the strategic therapeutic rationale for bezlotoxumab use, as well as the supporting clinical evidence. Expert opinion: Bezlotoxumab is an attractive solution for reducing the unacceptable level of recurrence that occurs with the currently recommended C. difficile treatments and other alternative therapies under consideration. Even though bezlotoxumab has not been tested in large-scale trials exclusively in cases of already established recurrent C.difficile infection (rCDI), it has an advantage over current treatments in that it does not interfere with the patient's gut flora while directly neutralizing the key virulence factor. Although cost remains an important factor against its widespread use, simpler administration, fewer side effects, and better social acceptability justify its consideration for treating rCDI. PMID- 28805082 TI - Veterans transitioning from isolation to integration: a look at veteran/service dog partnerships. AB - BACKGROUND: This study explored the dynamics of veteran/service dog partnerships by gathering the perspectives of veterans with a history of post-traumatic stress disorder and/or traumatic brain injury. METHODS: Exploratory qualitative methods (focus groups and individual interviews) were used to investigate veteran/service dog relationships related to community involvement, family and friend relationships, self-care, work, and leisure. Nine male veterans, Paws, and Stripes program graduates participated. Data were audio recorded and transcribed by two research team members who used qualitative analytic software to manage and code the data. The full research team discussed themes and reached consensus on the themes that emerged from analysis. RESULTS: Five themes emerged about the perceived benefit of veteran/service dog relationship: Secluded but Seeking Society (moving from isolation to reconnection); Opening Opportunities (navigating daily life); Bridging the Gap (facilitating social opportunities); and Reclaiming Life (transforming sense of worth and purpose). An overarching theme, Calming Catalyst, connected the other four themes. CONCLUSIONS: Veterans in this study reported that their goal was to reclaim and develop key aspects of their lives and they perceived service dogs as a support in their transition from isolation to reintegration. This study found that service dogs supported the veterans to meet their goal. Implications for rehabilitation There are a significant number of veterans with post-traumatic stress disorder and/or traumatic brain injury who are facing life challenges including self-care, securing work, participating in leisure activities, and integrating into the community. Service dogs are an emerging intervention used to assist veterans with reintegration into civilian life. There is a need for professionals to be aware of potential benefits of service dog/veteran partnerships. Based on our findings, veterans could benefit from being paired with a service dog to facilitate their successful return to community life. PMID- 28805083 TI - The relationship between health related quality of life and sensory deficits among patients with diabetes mellitus. AB - PURPOSE: (1) To profile sensory deficits examined in the ability to process sensory information from daily environment and discriminate between tactile stimuli among patients with controlled and un-controlled diabetes mellitus. (2) Examine the relationship between the sensory deficits and patients' health related quality of life. METHODS: This study included 115 participants aged 33-55 with uncontrolled (n = 22) or controlled (n = 24) glycemic levels together with healthy subjects (n = 69). All participants completed the brief World Health Organization Quality of Life Questionnaire, the Adolescent/Adult Sensory Profile and performed the tactile discrimination test. RESULTS: Sensory deficits were more emphasized among patients with uncontrolled glycemic levels as expressed in difficulties to register sensory input, lower sensation seeking in daily environments and difficulties to discriminate between tactile stimuli. They also reported the lowest physical and social quality of life as compared to the other two groups. Better sensory seeking and registration predicted better quality of life. Disease control and duration contributed to these predictions. CONCLUSIONS: Difficulties in processing sensory information from their daily environments are particularly prevalent among patients with uncontrolled glycemic levels, and significantly impacted their quality of life. Clinicians should screen for sensory processing difficulties among patients with diabetes mellitus and understand their impacts on patients' quality of life. Implications for Rehabilitation Patients with diabetes mellitus, and particularly those with uncontrolled glycemic levels, may have difficulties in processing sensory information from daily environment. A multidisciplinary intervention approach is recommended: clinicians should screen for sensory processing deficits among patients with diabetes mellitus and understand their impacts on patients' daily life. By providing the patients with environmental adaptations and coping strategies, clinicians may assist in optimizing sensory experiences in real life context and elevate patients' quality of life. Relating to quality of life and emphasizing a multidisciplinary approach is of major importance in broadening our understanding of health conditions and providing holistic treatment for patients. PMID- 28805084 TI - Covalent immobilisation of transglutaminase: stability and applications in protein PEGylation. AB - Microbial transglutaminase enzyme (mTGase) is an extremely useful enzyme that is increasingly employed in the food and pharmaceutical industries and as a tool for protein modification and tagging. The current study describes how we immobilised mTGase (iTGase) on a solid support to improve its stability during the PEGylation process by which polyethylene glycol chains are attached to protein and peptide drugs. When the enzyme was immobilised at the N-terminal sequence on agarose beads, it retained more than 53% of its starting activity. Kinetic studies on the immobilised and free mTGase disclosed a 1.7 and 1.5 fold decrease of Km and Vmax, respectively. Protein PEGylation was carried out using alpha-lactalbumin (alpha LA) and granulocyte colony stimulating factor (G-CSF). In the former case, the iTGase showed a selective conjugation towards only one Gln residue of alpha-LA, avoiding formation of a mono- and bi-conjugate mixture that is achieved using the free enzyme. In the latter case, the immobilised enzyme still remained selective towards only one Gln, but avoided the undesired formation of deamidated G-CSF that took place when free mTGase was used. Overall, the results of the current study highlight the suitability of iTGase in preparing site-selective protein polymer conjugates. PMID- 28805085 TI - Strategies to release doxorubicin from doxorubicin delivery vehicles. AB - Doxorubicin (DOX) is one of the most effective cytotoxic anticancer drugs and has been successfully applied in clinics to treat haematological malignancies and a broad range of solid tumours. However, the clinical applications of DOX have long been limited due to severe dose-dependent toxicities. Recent advances in the development of DOX delivery vehicles have addressed some of the non-specific toxicity challenges associated with DOX. These DOX-loaded vehicles are designed to release DOX in cancer cells effectively by cutting off linkers between DOX and carriers response to stimuli. This article focuses on various strategies that serve as potential tools to release DOX from DOX-loaded vehicles efficiently to achieve a higher DOX concentration in tumour tissue and a lower concentration in normal tissue. With a deeper understanding of the differences between normal and tumour tissues, it might be possible to design ever more promising prodrug systems for DOX delivery and cancer therapy in the near future. PMID- 28805086 TI - Brentuximab vedotin therapy for CD30-positive cutaneous T-cell lymphoma: a targeted approach to management. AB - CD30-positive primary cutaneous T-cell lymphoma (CTCL) includes mycosis fungoides, anaplastic large-cell lymphoma and lymphomatoid papulosis type A. Brentuximab vedotin (BV) consists of an antibody targeting CD30 with a protease cleavable linker to vedotin. CD30 binding allows internalization of BV inducing cell-cycle arrest and apoptosis. Response rates >75% with manageable adverse effects in refractory Hodgkin lymphoma and systemic anaplastic large-cell lymphoma led to accelerated approval for both. Phase II studies in CD30 expressing CTCL followed and showed similar efficacy, which was ratified in a Phase III trial of BV versus physician's choice (methotrexate or bexarotene) showing significant improved responses without increase in severe adverse effects although peripheral neuropathy is frequent. BV provides an effective targeted therapy for CD30-expressing cutaneous lymphomas and welcome addition to our anti CTCL armory. PMID- 28805087 TI - Preliminary investigation of the reliability and validity of the BIRT Independent Living Scale. AB - PURPOSE: Neurorehabilitation aims to increase independence and participation in ordinary life. It is argued that the fundamental indices of this are independent living and engagement in occupational or productive activity. The Brain Injury Rehabilitation Trust Independent Living Scale was designed to capture change in levels of participation and independence following neurorehabilitation. With greater use of outcome measures in health care, it becomes necessary to develop tools which are simple to use and that capture the holistic impact of rehabilitation. This study examines the inter-rater reliability and validity of the Brain Injury Rehabilitation Trust Independent Living Scale, which comprises two single item, multiple-choice sub-scales. METHOD: Inter-rater reliability was assessed by comparing the ratings on the Brain Injury Rehabilitation Trust Independent Living Scale, by five pairs of graduate psychologists, of 37 individuals who had undergone neurorehabilitation. Retrospective data collected by other members of the clinical team for the Mayo-Portland Adaptability Inventory-4, Supervision Rating Scale and Care And Needs Scale were correlated with the Brain Injury Rehabilitation Trust Independent Living Scale to establish concurrent validity. RESULTS: Weighted kappa coefficients revealed moderate (occupation) to strong (accommodation) inter-rater reliability for the two sub scales. All correlations between the Brain Injury Rehabilitation Trust Independent Living Scale and the Mayo-Portland Adaptability Inventory-4, Supervision Rating Scale and the Care And Needs Scale were high, demonstrating good concurrent validity. CONCLUSIONS: This study highlights some of the psychometric properties of the Brain Injury Rehabilitation Trust Independent Living Scale and demonstrates its utility in assessing independent living ability and level of social participation after neurorehabilitation. Implications for rehabilitation The BIRT Independent Living Scale is a validated method for ranking accommodation and occupation status as an indicator of independent living ability and occupational activity. The two freely available single-item scales emerging from this study provide a brief method for measuring independent living ability and participation following rehabilitation in research and clinical practice. The BIRT Independent Living Scale's simplicity means it does not require specific training to administer, facilitating its use by a wide range of multidisciplinary staff members and researchers. PMID- 28805088 TI - The current therapeutic options for Crohn's disease: from medical therapy to intestinal transplantation. AB - INTRODUCTION: Crohn's disease (CD) has an annual incidence per 100.000 person year of 20.2 in North America and 12.7 in Europe, and the purpose of this review is to evaluate its medical management, from diagnosis to transplant. Pharmacologic manipulation with nutritional care aims to achieve and maintain remission, but more than half of patients will undergo an intestinal resection, very often repeated over time. They could experience short bowel syndrome (SBS) requiring total parenteral nutrition (TPN). Intestinal transplantation (ITx) represents an alternative in case of irreversible intestinal failure (IF) with life-threatening TPN complications. Patient survival after ITx is 79%, 53% and 43% at 1, 3 and 5 years respectively, with no differences among ITx for other disorders. Areas covered: The research discussed medical therapy with nutritional support, evaluating the role of endoscopy, surgery and transplant in CD. A systematic literature review was conducted using the PubMed search engine up to May 31th, 2017 without restriction of the language. The decision on paper's eligibility was reached by consensus between the 3 screening authors. Expert commentary: CD treatment is mainly medical, leaving endoscopy and surgery for a complex course. ITx represents a therapeutic option if TPN complications with IF arise. PMID- 28805089 TI - Dialogue and conflict resolution: potential and limits. PMID- 28805090 TI - Examining young children's social competence using functional ability profiles. AB - PURPOSE: To explore the use of International Classification of Functioning, Disability, and Health for Children and Youth (ICF-CY) based profiles of children's functional abilities in relation to their social competence. Subgroups based on shared profiles of functional ability were investigated as an alternative or complement to subgroups defined by disability categories. METHODS: Secondary analysis of a nationally representative data set of young children identified for special education services in the United States was used for the present study. Using five subgroups of children with shared profiles of functional ability, derived from latent class analysis in previous work, regression analyses were used to examine the relationships between social competence and functional abilities profile subgroup membership. Differences among the subgroups were examined using standardized effect sizes. R2 values were used to examine explained variance in social competence in relation to subgroup membership, disability category, and these variables in combination. RESULTS: Functional ability profile subgroup membership was moderately related to children's social competence outcomes: social skills and problem behaviors. Effect sizes showed significant differences between subgroups. Subgroup membership accounted for more variance in social competence outcomes than disability category. CONCLUSIONS: The results provide empirical support for the importance of functional ability profiles when examining social competence within a population of young children with disabilities. Implications for Rehabilitation The extent to which children with disabilities experience difficulty with social competence varies by their functional characteristics. Functional ability profiles can provide practitioners and researchers working young children with disabilities important tools to examine social competence and to inform interventions. PMID- 28805091 TI - A comparison of two low-calorie sweeteners and sugar in dark chocolate on sensory attributes and emotional conceptualisations. AB - Reducing sugar consumption is an important aspect in the prevention of and fight against obesity. A broader understanding of consumers' perceptions of low-calorie sweeteners is needed. This study examined two low-calorie sweeteners, tagatose and stevia, in comparison to sugar in dark chocolate. A total of 219 consumers participated in this study and rated overall liking and sensory attributes. Participants also listed their emotional conceptualisations upon consumption and were assessed on emotional eating behaviour and health and taste attitudes. The chocolate with tagatose was perceived as more similar to the chocolate with sugar than with stevia on overall liking, texture, bitterness, duration of aftertaste and intensity of aftertaste. Furthermore, chocolate with sugar and chocolate with tagatose both elicited positive emotional conceptualisations whereas chocolate with stevia elicited negative emotional conceptualisations. In conclusion, dark chocolate with tagatose did not significantly differ from sugar in overall liking, most sensory attributes and emotional conceptualisation. PMID- 28805092 TI - A review of BF-200 ALA for the photodynamic treatment of mild-to-moderate actinic keratosis. AB - BF-200 ALA is a combination of a nanoscale-lipid vesicle formulation and the prodrug 5-aminolevulinic acid (5-ALA). The nanoemulsion stabilizes the prodrug and enhances its penetration through the stratum corneum. It has shown excellent therapeutic results in both lesion and field-directed photodynamic therapy of actinic keratosis (AK). AK is an early form of epidermal neoplasia and a precursor of invasive cutaneous squamous cell carcinoma. It is characterized by the combination of visible neoplastic lesions and surrounding tissue also harboring tumorigenic UV-induced mutations: a concept called field cancerization. A selective, field-directed treatment is ideal to meet the requirements of field change. Here, we review the clinical data on BF-200 ALA for AK along with a summary of molecular mechanisms and future perspectives. PMID- 28805093 TI - Monitoring disease progression in spinocerebellar ataxias: implications for treatment and clinical research. AB - INTRODUCTION: Spinocerebellar ataxias (SCAs) are autosomal dominant diseases characterized by progressive gait and limb incoordination, disequilibrium, dysarthria, and eye movement disturbances. Approximately 40 genetic subtypes of SCAs are known and classified according to the causative disease gene/locus. With the possibility of the specific genetic diagnosis in patients and at-risk family members, several clinical scales and functional tests have been validated and used in ataxic patients with the purposes of measuring the entity of disease progression in natural history studies and the possible slowing of neurological impairment in therapeutic trials. Areas covered: This paper reviews the most widely used clinical scales and quantitative tests that contributed in monitoring disease progression of the most common forms of SCAs. Expert commentary: The currently available and validated clinical scales and quantitative performance scores are adequate to measure disease severity, but may require a considerable number of subjects and a long period of treatment to allow the recognition of beneficial effect of interventional therapies. Advanced MRI techniques are a consistent biomarker and maybe useful to track disease progression from the preclinical to the manifest ataxic phase in association with appropriate clinical or paraclinical investigations. PMID- 28805095 TI - Letter to the editor on the paper: "The majority of natalizumab-treated MS patients have high natalizumab concentrations at time of re-dosing". PMID- 28805094 TI - How balance task-specific training contributes to improving physical function in older subjects undergoing rehabilitation following hip fracture: a randomized controlled trial. AB - OBJECTIVE: To evaluate the efficacy of a rehabilitation programme including balance task-specific training in improving physical function, pain, activities of daily living (ADL), balance and quality of life in subjects after a hip fracture. DESIGN: Randomized controlled trial. SUBJECTS: A total of 52 older subjects selected for internal fixation due to extra-capsular hip fracture were randomized to be included in an experimental ( n = 26) and control group ( n = 26). INTERVENTIONS: The experimental group underwent a rehabilitation programme based on balance task-specific training. The control group underwent general physiotherapy, including open kinetic chain exercises and walking training. Both groups individually followed programmes of 90-minute sessions five times/week for three weeks. OUTCOME MEASURES: The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), a Pain Numerical Rating Scale, the Berg Balance Scale, the Functional Independence Measure and the 36-item Short-Form Health Survey. The participants were evaluated before and after training, and after 12 months. RESULTS: Significant effects of time, group and time * group were found for all outcome measures in favour of the experimental group. A clinically important between-group difference of 25 points was achieved after training and at follow-up in terms of the primary outcome (WOMAC function before treatment, after treatment and at follow-up was 84.8 (3.7), 39.8 (4.9) and 35.7 (6.2) for the experimental group and 80.9 (5.7), 65.2 (7.1) and 61.0 (11.1) for the control group). CONCLUSION: An inpatient rehabilitation programme based on balance task specific training is useful in improving physical function, pain, ADL and quality of life in older patients after hip fracture. PMID- 28805096 TI - Perioperative nursing of tracheal silicon stent implantation in infants: report on four cases. AB - AIMS: To report experience of perioperative nursing of tracheal silicon stent implantation in infants. METHODS: Retrospective analysis on the cases of tracheal silicon stent implantation in infants in our hospital. RESULTS AND CONCLUSIONS: Since middle of 2014, totally four tracheal silicon stent implantation were performed in our center. Of them, one case was recurrent tracheoesophageal fistula and the other three cases were traheomalacia. Parent's psychological support, infants' nutrition support and airway care were key responsibility for a nurse before implantation. During the procedure of stent implantation, it was responsible for a nurse to closely monitor the infants and to support operator. After the implantation, airway care and prevention of intra-airway bacterial colonization were important to avoid complications. PMID- 28805097 TI - Comparison of Methods to Assess Consumption of Micronutrient Powders Among Young Children in Nepal. AB - BACKGROUND: Assessing micronutrient powder (MNP) consumption is the key for monitoring program performance; no gold standard exists for assessing consumption in nutrition programs. OBJECTIVE: To compare estimates of MNP consumption assessed by maternal report versus observed unopened MNP sachets in the household. METHODS: Cross-sectional household surveys of children aged 6 to 23 months were conducted to assess an MNP project in Nepal; eligible children received 60 sachets per distribution. Mothers reported the number of sachets consumed and showed unused sachets. Directly observed difference (DOD) of MNP consumption was calculated by subtracting the number of observed unopened sachets from 60. Spearman correlation coefficient, categories of MNP consumption, and end digit preference were assessed. RESULTS: A total of 205 mothers did not show remaining unopened sachets despite reporting that all were not consumed. For the remaining 605 children, median consumption was 60.0 sachets by DOD and maternal report; the correlation coefficient was 0.91. With consumption grouped into categories of 0 to 14, 15 to 29, 30 to 44, and 45 to 60 sachets, the percent categorized into the same groupings by DOD and maternal report was 100%, 80.6%, 80.7%, and 91.2%, respectively. Excluding those who consumed 60 sachets, 16.9% and 8.0% by report and 14.2% and 6.1% DOD, ended with 0 and 5, respectively. CONCLUSION: Had the observation of unused sachets been used alone to assess MNP consumption, 205 children would not have been assessed. Estimates of MNP consumption by DOD and maternal report were similar in this population with high intake adherence. PMID- 28805098 TI - Assessment of the permeability and toxicity of polymeric nanocapsules using the zebrafish model. AB - AIM: To assess the capacity of a new drug delivery nanocapsule (NC) with a double shell of hyaluronic acid and protamine to overcome biological barriers using the zebrafish model. MATERIALS & METHODS: NCs were prepared by the solvent displacement method, tagged with fluorescent makers and physicochemically characterized. Toxicity was evaluated according to the Fish Embryo Acute Toxicity test, and permeability was tested by exposing zebrafish, with and without chorion, to the fluorescent NCs. RESULTS: Toxicity of NCs was very low as compared with that of a control nanoemulsion. Double-shell NCs were able to cross chorion and skin. CONCLUSION: Beyond the potential value of hyaluronic acid:protamine NCs for overcoming epithelial barriers, this works highlights the utility of zebrafish for fast screening of nanocarriers. PMID- 28805099 TI - Short-term daily teriparatide in patients with rheumatoid arthritis. AB - OBJECTIVE: The aim of this study was to compare the efficacy of six-month teriparatide treatment followed by six-month bisphosphonate therapy with 12-month bisphosphonate monotherapy in Japanese rheumatoid arthritis (RA) patients who had not been previously treated for osteoporosis. METHODS: A total of 34 RA patients with osteoporosis were enrolled. Thirteen patients received six-month teriparatide prior to six-month minodronate therapy (PTH group), and 21 patients received 12-month minodronate therapy (BP group). Bone mineral density (BMD), and bone turnover markers were measured prior to and 6 and 12 months after the initiation of treatment. RESULTS: Bone mineral density of the spine was significantly increased after 12 months of treatment in both groups. In the PTH group, the mean percent change of BMD of the spine was significantly higher at 12 months after the initiation of treatment, as compared to the BP group (PTH group: 9.9 +/- 1.5%, BP group: 5.5 +/- 0.7%). Femoral neck BMD was significantly increased only in the PTH group after 12 months. CONCLUSION: Therapy involving six-month teriparatide followed by six-month minodronate therapy increased spine BMD to a greater degree than 12-month minodronate monotherapy. The strategy of short-term administration of teriparatide for RA patients with osteoporosis might be useful when additional bisphosphonate therapy is considered. PMID- 28805100 TI - Older Adults With a Combination of Vision and Hearing Impairment Experience Higher Rates of Cognitive Impairment, Functional Dependence, and Worse Outcomes Across a Set of Quality Indicators. AB - OBJECTIVES: Hearing and vision impairment were examined across several health related outcomes and across a set of quality indicators (QIs) in home care clients with both vision and hearing loss (or dual sensory impairment [DSI]). METHOD: Data collected using the Resident Assessment Instrument for Home Care (RAI-HC) were analyzed in a sample of older home care clients. The QIs represent the proportion of clients experiencing negative outcomes (e.g., falls, social isolation). RESULTS: The average age of clients was 82.8 years ( SD = 7.9), 20.5% had DSI and 8.5% had a diagnosis of Alzheimer's disease (AD). Clients with DSI were more likely to have a diagnosis of dementia (not AD), have functional impairments, report loneliness, and have higher rates across 20 of the 22 QIs, including communication difficulty and cognitive decline. Clients with highly impaired hearing, and any visual impairment, had the highest QI rates. DISCUSSION: Individuals with DSI experience higher rates of adverse events across many health-related outcomes and QIs. Understanding the unique contribution of hearing and vision in this group can promote optimal quality of care. PMID- 28805101 TI - Effect of size and shape on toxicity of zinc oxide (ZnO) nanomaterials in human peripheral blood lymphocytes. AB - The multi-industrial applications of zinc oxide nanomaterials (ZnO NMs) lead to increasing exposure to humans. Though the ZnO nanoparticles (NPs) toxicity had been evaluated previously, toxicity of other forms of ZnO nanomaterials has not been evaluated. In this study, cytotoxicity and genotoxicity of four different types of ZnO NMs were evaluated using human peripheral blood lymphocytes (HPBL). In addition, the effect of anti-oxidants on ZnO NMs induced toxicity was also evaluated. Our results suggest that, size and shape of the nanomaterials have profound effects on their toxicity. The NPs and nanorods (NRs) possessed higher level of oxidative potential and ROS generation capacity than microparticles (MPs) and microrods (MRs). In contrast, MPs and MRs possessed higher level of lipid peroxidation capacity. The smaller NPs are more genotoxic while larger MPs and MRs were more cytotoxic in nature. Treatment with vitamin C or Quercetin significantly reduces the genotoxicity associated with ZnO NMs. The influence of size and shape in mediating NMs toxicity should be taken into account and the possible supplementation of anti-oxidants might mitigate the toxicity. PMID- 28805102 TI - Favourable long-term outcome after coronary artery bypass grafting in a nationwide cohort. AB - OBJECTIVES: In a nationwide cohort, we analyzed long-term outcome following coronary artery bypass grafting, using the combined strategy of left internal mammary artery to the left anterior descending artery and saphenous vein as secondary graft to other coronary targets. METHODS: 1,507 consecutive patients that underwent myocardial revascularization during 2001-2012 in Iceland. Mean follow-up was 6.8 years. Major adverse cardiac and cerebrovascular events were depicted using the Kaplan-Meier method. Cox-regression was used to define risk factors. Relative survival was estimated by comparing overall survival to the survival of Icelanders of the same age and gender. RESULTS: Mean age was 66 years, 83% were males, mean EuroSCOREst was 4.5, and 23% of the procedures were performed off-pump. At 5 years, 19.7% had suffered a major adverse cardiac or cerebrovascular event, 4.5% a stroke, 2.2% myocardial infarction, and 6.2% needed repeat revascularization. Overall 5-year survival was 89.9%, with a relative survival of 0.990. Independent predictors of major adverse cardiac and cerebrovascular events were left ventricular ejection fraction <=30%, a previous history of percutaneous coronary intervention, chronic obstructive lung disease, chronic kidney disease, diabetes, and old age. The same variables and an earlier year of operation were predictors of long-term mortality. CONCLUSIONS: The long term outcome following myocardial revascularization, using the left internal mammary artery and the great saphenous vein as conduits, is favourable and improving. This is reflected by the 5-year survival of 89.9%, deviating minimally from the survival rate of the general Icelandic population, together with a freedom from major adverse cardiac and cerebrovascular events of 80.3%. PMID- 28805103 TI - Dentoalveolar oral surgery in children and adolescents: organization and surgical treatment in a large, Danish municipal dental service. AB - OBJECTIVE: To describe a population-based organization of dentoalveolar surgical service for 0 to 18-year old subjects in a Danish municipal dental service, and analyze the type of dentoalveolar surgical interventions needed. MATERIAL AND METHODS: The study was conducted in the Municipality of Aarhus, Denmark during five consecutive school-years. An internal referral system was established within the municipality where patients could be referred to colleagues with a higher level of competencies and more experiences with paediatric dentoalveolar surgery. The analysis includes a total of 1812 children and a total of 2854 surgical interventions. RESULTS: Almost 80% of the patients, representing more than 80% of the dentoalveolar surgical interventions needed, were referred internally. Denudations were the most frequent treatment type (40.3%) carried out, followed by removal of third molars (18.0%). Furthermore, 22 odontomas and 100 supernumerary teeth were removed. CONCLUSIONS: The need of dentoalveolar surgery in children and adolescents is relatively low, but includes a wide range of interventions. An organizational system, where dentists can refer to colleagues who have developed special competencies in this field, results in most of these surgical patients being referred and treated internally. PMID- 28805104 TI - Present and future selves in Parkinson's disease. AB - The study of the self in neuropsychological patients raises not only theoretical questions on the relationships between the self, autobiographical memory (AM), and episodic future thinking but also clinical issues for patients' daily life and care. We addressed this issue in Parkinson's disease patients for whom AM and future thinking impairments have been documented. All patients and controls generated and dated up past and future self-images and provided associated past and future events. Our findings suggest a subtle pattern of preservation/impairment of different dimensions (quantitative and qualitative) of self-images, which rely partially on the episodic quality of past and future events. PMID- 28805105 TI - Economic burden of multiple myeloma among patients in successive lines of therapy in the United States. AB - This study characterized the costs of multiple myeloma (MM) during first-line (1L), second-line (2L) and third-line (3L) treatment from the US payer perspective. Patients with >=2 outpatient or >=1 inpatient claims with a primary MM diagnosis and 12 months continuous enrollment post index were identified in a retrospective claims database between 1 July 2006 and 30 June 2013. A cost per patient per-month (PPPM) metric was used to calculate total all-cause and anti-MM pharmacy costs in 1L, 2L, and 3L treatment. Of 5704 patients included, 3626 initiated 1L treatment, 1797 initiated 2L and 817 initiated 3L. Average total all cause PPPM costs were $22,527 in 1L, $35,266 in 2L and $47,417 in 3L. Anti-MM pharmacy costs represented 22%, 29% and 29% of total all-cause costs PPPM in 1L, 2L and 3L, respectively. Study results suggest that delaying 2L and/or 3L treatment initiation may result in lower treatment costs for patients with MM. PMID- 28805106 TI - Measuring fetal brain and lung transcripts in amniotic fluid supernatant: a comparison of digital PCR and RT-qPCR methods. AB - PURPOSE: Amniotic fluid (AF) cell-free RNA is a promising source of information regarding fetal physiology. Digital PCR (dPCR) is a direct approach to nucleic acid detection that reports absolute transcript copy number. The aim of this study was to compare quantification of cell-free fetal brain and lung RNA transcripts in AF by reverse transcription-qPCR (RT-qPCR) and dPCR. MATERIAL AND METHODS: Prospective hospital-based study was performed in 2016-2017. Pulmonary genes were quantified in term AF samples collected at elective cesarean birth; neurodevelopmental genes were measured in preterm samples (<34 weeks) obtained from women undergoing clinically-indicated amniocentesis. RESULTS: All 11 women in the term cohort had three lung transcripts and a reference gene successfully amplified from their AF supernatant using RT-qPCR and dPCR. SFTPC was the most abundant lung transcript, present in higher concentrations than the reference gene in seven of the eleven samples. Neurodevelopmental gene transcripts in 12 preterm pregnancies were less reliably detected by both methods and were present in low copy numbers (<10 copies/MUl). We observed significant positive correlations between transcript quantification by RT-qPCR and dPCR. CONCLUSION: This study confirms the presence of several potential mRNA markers of lung and brain development with dPCR and RT-qPCR, and a high correlation between the two methods. Transcripts of presumed fetal brain origin are present in very low copy numbers, which presents challenges to their feasibility as biomarkers of neurodevelopment. PMID- 28805107 TI - Effects of high-frequency repetitive transcranial magnetic stimulation on reducing hemiplegic shoulder pain in patients with chronic stoke: a randomized controlled trial. AB - OBJECTIVE: To examine whether high-frequency (10 Hz) repetitive transcranial magnetic stimulation (rTMS), applied over the primary motor cortex of the affected hemisphere, could be used to manage hemiplegic shoulder pain (HSP). METHODS: Twenty-four chronic stroke patients with chronic HSP, randomly assigned into the rTMS group (10 sessions of high-frequency stimulation) or the sham group (sham stimulation), were performed. The Numeric Rating Scale (NRS) was used to evaluate the intensity of pain at pretreatment, and at 1 day, and 1, 2 and 4 weeks after treatment. Changes in upper-limb motor function were evaluated using the Motricity Index (MI-UL) and modified Brunnstrom Classification (MBC). RESULTS: When compared to pretreatment, the rTMS group showed a significant decrease in the NRS score at 1 day, and 1, 2 and 4 weeks after finishing rTMS sessions, with no significant change in the sham group. The NRS score after the rTMS sessions reduced by 30.1% at 1 day, 29.3% at 1 week, 28.0% at 2 weeks and 25.3% at 4 weeks. Passive shoulder range of motion, MI-UL, and MBC, however, did not significantly change in either group. CONCLUSIONS: High-frequency rTMS could be used as a safe, beneficial therapeutic tool to manage HSP. We think it can be used as an adjuvant therapeutic modality to enhance the therapeutic outcome of HSP. PMID- 28805108 TI - A Clinicopathological Study of Small Lung Adenocarcinoma 1 cm or Less in Size: Emphasis on Histological Subtypes Associated With Lymph Node Metastasis and Recurrence. AB - BACKGROUND: The aim of this study was to assess the prognostic significance of the newly proposed 2015 World Health Organization (WHO) lung adenocarcinoma classification for patients undergoing resection for small (<=1 cm) lung adenocarcinoma. We also investigated whether lobectomy offers prognostic advantage over limited resection for this category of tumors. METHODS: A retrospective study of resected pulmonary adenocarcinomas (n = 83) in sizes 1 cm or less was carried out in which comprehensive histologic subtyping was assessed according to the 2015 WHO classification on all consecutive patients who underwent lobectomy or limited resection between 1998 and 2012. Correlation between clinicopathologic parameters and the difference in recurrence between lobectomy and limited resection group was evaluated. RESULTS: Our data show that the proposed 2015 WHO classification identifies histological subsets of small lung adenocarcinomas with significant differences in prognosis. No recurrence was noted for patients with adenocarcinoma in situ and minimally invasive adenocarcinoma. Invasive adenocarcinomas displayed high heterogeneity and the presence of micropapillary component of 5% or greater in adenocarcinomas was significantly related to lymph node involvement and recurrence ( P < .001). Stage IA patients who underwent limited resection had a higher risk of recurrence than did those treated by lobectomy ( P < .05). CONCLUSIONS: Application of the 2015 WHO classification identifies patients with adenocarcinoma in situ and minimally invasive adenocarcinoma had excellent prognosis. Micropapillary pattern was associated with high risk of lymph node metastasis and recurrence. PMID- 28805109 TI - Glucose regulation and face recognition deficits in older adults: the role of attention. AB - The present study investigated the perceptual, attentional, and memory processes underlying face recognition deficits observed in older adults with impaired glucoregulation. Participants were categorized as good glucoregulators or poor glucoregulators on the basis of an oral glucose tolerance test. Using event related potential (ERP) methodology, 23 participants (62-88 years) performed a 2 stimulus oddball task. Participants were asked to rate and memorize 10 "target" faces, which were then presented amongst 120 unfamiliar foils. Behavioral results indicated that good glucoregulators were significantly more accurate at recognizing target faces. ERP markers of early visual perception (P1 and N170 components) and memory formation (P3 component) were unaffected by glucoregulatory efficiency. The P2 component, an index of attentional processing, was larger and delayed in the poor glucoregulators. To the best of our knowledge, this study is the first to suggest that face recognition deficits in poor glucoregulators may be due to impairments in attentional processing. PMID- 28805110 TI - Lack of interaction of lopinavir solid drug nanoparticles with cells of the immune system. AB - AIM: We previously demonstrated that solid drug nanoparticles (SDNs) lopinavir (LPV) dispersed into aqueous media display favorable pharmacokinetics. METHODS: The impact of LPV SDNs on the function and phenotype of primary human T cells and macrophages (primary sites of HIV replication) was investigated. RESULTS: LPV significantly increased IL-1beta (ninefold higher than untreated cells; p = 0.045) and TNF-alpha (sixfold higher than untreated cells; p = 0.018) secretion from monocyte-derived macrophages, whereas LPV SDNs did not elicit these responses at comparable drug concentrations. LPV SDNs were demonstrated to be immunologically inert to human T cells and monocyte-derived macrophages. CONCLUSION: The LPV SDN was demonstrated to exhibit comparable, or favorable behavior compared with an LPV aqueous solution in the employed biocompatibility assessments. PMID- 28805111 TI - Chemoresistance in cancer cells: exosomes as potential regulators of therapeutic tumor heterogeneity. AB - Drug resistance in cancer cells remains a fundamental challenge. Be it nontargeted or targeted drugs, the presence of intrinsic or acquired cancer cell resistance remains a great obstacle in chemotherapy. Conventionally, a spectrum of cellular mechanisms defines drug resistance including overexpression of antiapoptotic proteins and drug efflux pumps, mutations in target and synergistic activation of prosurvival pathways in tumor cells. In addition to these well studied routes, exosome-induced chemoresistance is emerging as a novel mechanism. Mechanistically, exosomes impart resistance by direct drug export, transport of drug efflux pumps and miRNAs exchange among cells. Moreover, exosome signaling creates 'therapeutic tumor heterogeneity' and favorably condition tumor microenvironment. Here, we discuss exosomes' role in chemoresistance and possibilities of developing novel therapeutic strategies. PMID- 28805112 TI - Casting doubt on the value of assessing the cardiac index in pregnancy. AB - OBJECTIVES: The objective of this study is to assess the reliability of the cardiac index (CI) in healthy pregnant women at term by investigating the correlation between the cardiac output (CO) and the body surface area (BSA) using a novel non-invasive cardiography technique (NICaSTM). METHODS: Sixty-one healthy, normotensive women with a singleton pregnancy at term (>=37 gestational weeks) participated in this prospective observational study between 1/2015 and 6/2015 L. Each woman was assessed for CO by the NICaSTM, an impedance device that non-invasively measures the CO and its derivatives. The NICaSTM demonstrated a very good correlation with the gold standard Swan-Ganz catheter. BSA was determined by the Dubois nomogram. RESULTS: The mean +/- standard deviation maternal age was 34.2 +/- 5.3 years, mean height 166 +/- 6 cm, and mean body mass index 23.9 +/- 4.9 kg/m2. The mean gestational age was 38.8 +/- 0.7 weeks. The correlation between the CO and the BSA was poor (Pearson r = 0.254, p < .005). CONCLUSIONS: The current study demonstrated poor correlation between the CO and the BSA in pregnant women, therefore, making the CI a non-reliable variable for assessing CO in pregnant women. We, therefore, suggest that the CO rather than the CI is the preferred parameter for hemodynamic measurements in this population. PMID- 28805113 TI - Hospitalized adolescents' perception of dignity: A qualitative study. AB - BACKGROUND: Adolescents can be vulnerable to diminished dignity in the hospital because young people have significantly different healthcare needs than children and adults. They like to cooperate with caregivers only when they get respectful and dignified care. Care without considering dignity can adversely influence the adolescents' recovery. However, many studies have been conducted on exploring the concept of the patients' dignity from the adult patients and fewer studies still have explored the dignity of young people. OBJECTIVE: This study explores the hospitalized adolescents' perception about dignity. RESEARCH DESIGN: A conventional qualitative content analysis method was used to explore the meaning of hospitalized adolescents' dignity. Participants and research context: Hospitalized adolescents in general medical and surgical pediatric units were eligible to participate. Data were obtained through unstructured interviews. Purposive sampling was used and adolescents were recruited until data saturation was reached (n = 13). Ethical considerations: Ethical approval for the study was granted by the Ethics Committee of Shiraz University of Medical Sciences. Participants were provided with information about the purpose, reasons for recording interviews, voluntary participation, and confidentiality of data and interviewees. FINDINGS: Dignity was reflected in four themes: (1) protection of personal privacy, (2) protection of autonomy, (3) respect for identity, and (4) intimate communication. DISCUSSION AND CONCLUSION: Hospitalized adolescents stated that healthcare services should protect their personal privacy and autonomy. Also, they should respect the adolescent's identity and communicate intimately with them to provide the dignity. Adolescence is a discrete developmental stage, with specific healthcare needs which must be addressed effectively by healthcare providers especially nurses. PMID- 28805114 TI - Lack of compassion or poor discretion? Ways of addressing malpractice. AB - In this article, our point of departure is the 'compassion crisis' in the National Health Service in the UK and the initiatives introduced in the aftermath of scandals that were intended to strengthen healthcare professionals' ability to show compassion. We look at the two main strategies, which we term the 'recruitment and staff development strategy' and the 'amelioration of the quality systems strategy' and the debate that has arisen related to them. Based on this analysis, we question whether compassion really is a helpful concept to understand the crisis and hence to underpin relevant strategies. We introduce the concept of discretion as an alternative and better concept to comprehend the situation. One of the benefits of the concept of discretion is that it clarifies how problems can be addressed, both as structural problems and as epistemic problems and how these aspects are intertwined. It also helps us to see how solving these problems is complicated and demands comprehensive, in-depth approaches, involving formative aspects related to healthcare education, as well as development of new healthcare policies. PMID- 28805115 TI - Hindrances to achieve professional confidence: The nurse's participation in ethical decision-making. AB - BACKGROUND: Research suggests that nurses generally do not participate in ethical decision-making in accordance with ethical guidelines for nurses. In addition to completing their training, nurses need to reflect on and use ethically grounded arguments and defined ethical values such as patient's dignity in their clinical work. OBJECTIVES: The purpose of this article is to gain a deeper understanding of how nurses deal with ethical decision-making in daily practice. The chosen research question is "How do nurses participate in ethical decision-making for the patient?" DESIGN AND METHOD: We use Gadamer's philosophical hermeneutics as well as Kvale and Brinkmann's three levels of understanding in interpreting the data material. Nine registered nurses were interviewed. Ethical considerations: The Ombudsman of Norwegian Social Science Data and the head of the hospital approved the investigation. The participants received both oral and written information about the study and they gave their consent. We informed the participants that the participation was voluntary and that they were free to withdraw at any point in the course of the study. The requirement of anonymity and proper data storage was in accordance with the World Medical Association Declaration of Helsinki (1964). The participants were assured that privacy, and confidentiality would be duly protected. RESULTS: Four key themes emerged: (1) confusion in relation to professional and operational expectations of role, (2) ideal somnolence, (3) inadequate argumentation skills, and (4) compound pressure. CONCLUSION: Ethical ideals appear to be latent in the mindset of the participants; however, the main finding of this investigation is that nurses need to activate the ideals and apply them into practice. Furthermore, management needs to initiate professional reasoning and interdisciplinary discussions leading to common goals for patients. PMID- 28805116 TI - Bisphenol A and adverse pregnancy outcomes: a systematic review of the literature. AB - PURPOSE: Bisphenol A is a chemical compound related to adverse maternal and neonatal outcomes. The purpose of the present systematic review is to summarize the current knowledge in the field. MATERIALS AND METHODS: We systematically searched the Medline (1966-2017), Scopus (2004-2017), Clinicaltrials.gov (2008 2017), Cochrane Central Register of Controlled Trials CENTRAL (1999-2017) databases. RESULTS: Thirty-five studies were included in the present systematic review. According to our findings, BPA has a direct negative impact on maternal, fetal, and neonatal outcomes, including birthweight, rates of preterm birth, developmental defects, and recurrent miscarriage. Data in the field of preeclampsia and gestational diabetes mellitus remain inconclusive because current research is very limited. CONCLUSIONS: BPA exposure during pregnancy can result in significant antenatal pathology; hence, occupational exposure should be at least discouraged during this period. However, cross-sectional studies in the field that would assess the levels of exposure at timely intervals are still lacking, therefore, the actual impact of BPA remains unclear. PMID- 28805117 TI - Fungal fatal attraction: a mechanistic review on targeting liposomal amphotericin B (AmBisome(r)) to the fungal membrane. AB - Liposomal amphotericin B (AmBisome(r)) is a lipid-based nanotherapeutic that is used successfully worldwide to treat a broad range of life-threatening invasive fungal infections. In subtropical regions, AmBisome is emerging as the treatment of choice for human parasitic protozoan pathogens such as those from the genus Leishmania. The key to the remarkable efficacy of AmBisome is attributed to its liposome based formulation to deliver a potent drug at high dosage with significantly reduced toxicity in patients with immunocompromised systems. In spite of the rising frequency of AmBisome usage globally, the mechanisms underlying its ability to target to the sites of infection remain largely unknown. This review provides an overview of the current mechanistic understanding of AmBisome, discusses potential challenges and opportunities for the development of clinically effective, refractory resistant antifungal agents. PMID- 28805118 TI - Big Data analysis to improve care for people living with serious illness: The potential to use new emerging technology in palliative care. PMID- 28805119 TI - A retrospective audit on usage of Diatrizoate Meglumine (Gastrografin(r)) for intestinal obstruction or constipation in patients with advanced neoplasms. AB - BACKGROUND: Intestinal obstruction and constipation are common conditions in patients with advanced neoplasms. Diatrizoate Meglumine has been used in the management of both these conditions without good quality evidence of its effectiveness and safety. AIM: This audit aimed to assess the usage, effectiveness and adverse effects of Diatrizoate Meglumine for intestinal obstruction and constipation in patients with advanced neoplasms. DESIGN: A retrospective chart review was undertaken. Descriptive statistics were utilised. SETTING/PARTICIPANTS: All patients with known advanced neoplasms admitted to Mater Health Services and St Vincent's Private Hospital Brisbane between January 2013 and October 2015; who were administered Diatrizoate Meglumine were included. RESULTS: Seventy-one patients received Diatrizoate Meglumine. The most common diagnoses were ovarian or primary peritoneal neoplasms (33.8%). Diatrizoate Meglumine was most commonly used for intestinal obstruction (59.2%). The median dose used per patient episode was 50 mL (range: 15-500 mL). Thirty-two patients (45%) had imaging 4-24 h post-dose with Diatrizoate Meglumine being present in the large intestine in 75% of these images. Intestinal obstruction or constipation resolved in 90% of patients post-dose. CONCLUSION: Most clinicians used 50 mL of Diatrizoate Meglumine as a single dose and repeated imaging after 4 24 h. Diatrizoate Meglumine was well tolerated and may be effective in resolving intestinal obstruction and constipation in patients with advanced neoplasms. Quality controlled studies are needed to further guide the use of Diatrizoate Meglumine in intestinal obstruction and constipation in patients with advanced neoplasms. PMID- 28805120 TI - The police, social services, and psychiatry (PSP) cooperation as a platform for dealing with concerns of radicalization. AB - The police, social services, and psychiatry (PSP) is a structured cooperation between the police, social services, and the psychiatric system in Denmark. The aim of PSP is to ensure that relevant information is shared and supportive measures enhanced concerning citizens at risk, and it involves PSP representatives from each sector meeting frequently. PSP is implemented nationwide by law. In recent years, dealing with radicalization and the threat of terrorism have become key issues in society. The PSP cooperation already facilitates the identification of citizens at many kinds of risk (e.g. suicide, substance abuse, social decline, mental illness), and coordinates relevant intervention and treatment. The existing PSP cooperation is, therefore, an obvious forum for identifying and handling concerns of radicalization and extremism. The new working model includes an upgrade of all local PSP groups and an implementation of a nationwide evaluation of the initiative. This is a presentation of the working model and the experiences in practice. PMID- 28805121 TI - Canaries in the coal mine: Interpersonal violence, gang violence, and violent extremism through a public health prevention lens. AB - This paper asks what programmes and policies for preventing violent extremism (also called 'countering violent extremism', or CVE) can learn from the public health violence prevention field. The general answer is that addressing violent extremism within the wider domain of public health violence prevention connects the effort to a relevant field of research, evidence-based policy and programming, and a broader population reach. This answer is reached by examining conceptual alignments between the two fields at both the case-level and the theoretical level. To address extremist violence within the wider reach of violence prevention, having a shared model is seen as a first step. The World Health Organization uses the social-ecological framework for assessing the risk and protective factors for violence and developing effective public-health based programmes. This study illustrates how this model has been used for gang violence prevention and explores overlaps between gang violence prevention and preventing violent extremism. Finally, it provides policy and programme recommendations to align CVE with public health violence prevention. PMID- 28805122 TI - The iNEAR programme: an existential positive psychology intervention for resilience and emotional wellbeing. AB - The aim of this study was to evaluate the effectiveness of a new psychological intervention, the iNEAR, which is a resilience and wellbeing programme consisting of a classroom based set of activities designed to facilitate the formation of positive identities through the acquisition of skills for growth and personal flourishing. Three hundred and fifty-four young people aged 11 and 12, matched for age and gender, were randomly allocated to the intervention (84 girls; 80 boys) and control conditions (93 girls; 96 boys). Following the intervention, boys, compared to girls, showed higher levels of wellbeing and environmental mastery, and higher levels of tolerance to uncertainty. The intervention was effective in increasing appreciation of positive relationships with others, for girls, and, although not statistically significant, it generated change in the desired direction for boys. In contrast to boys, girls' scores on openness to diversity also increased between baseline and post-intervention. Ways in which positive psychology interventions can resource individuals to better respond to adversity, coercion, and personal uncertainty, and so contribute to safeguarding against the adoption of extreme belief systems are also discussed. PMID- 28805123 TI - Violent radicalization. PMID- 28805124 TI - Migration, violence, and the role of psychiatry in Italy. AB - Immigration to Italy has been increasing exponentially in the last decades due to the international political changes and conflicts in the Middle East. The relationship between immigration and crimes is a debated issue, and violent radicalization of second or third generations of migrants is under increased scrutiny. Consequently, many politicians and political parties use nationalist and xenophobic language. Inevitably, this will have an impact on reactions of the larger population, as well as that of migrants. Psychiatry can have a major role in dealing with immigrants' health needs, and also assessing risk and preventing violent behaviours due to mental disorders. It is possible to prevent some radicalization by employing strategies of education, leading to better integration of immigrants in the community (based on education, housing, work, etc.). However, often specialist services for migrants are lacking, and mental healthcare professionals may remain poorly trained. Italy is one of the major countries in Southern Europe with a large number of illegal and legal migrants; thereby, creating a major pressure on the resources. It is important to understand the links between globalization, migration, and violence in Italy, in order to prevent future radicalization. It is also useful for psychiatrists to act as advocates for migrants to help reduce xenophobia and discrimination supported by some national cultural and political movements. Ethno-psychiatric facilities should be promoted, as well as policies of support, integration, and prevention should be employed to promote legal migration through the European countries. PMID- 28805125 TI - Utilizing mental health professionals to help prevent the next attacks. AB - Recent high-profile cases and scientific research on lone actor terrorist attackers have indicated that there may be an association with mental illness. Simultaneously, countering violent extremism (CVE) initiatives have recently been placing more emphasis on building intervention (aka secondary prevention) programmes to address this matter, with mental health professionals possibly playing important roles in preventing lone actor terrorist attacks. Mental health professionals can contribute to intervention programmes, as practitioners and as leaders, but more so by drawing upon the threat assessment model, than because of a possible association with mental illness. A public-private partnership in Los Angeles, based on a well-regarded, community-based service for addressing targeted school violence, is attempting to further develop such services. A tabletop exercise was used as a strategy for jumpstarting interventions, so as to engage mental health and other community partners, build trust between stakeholders, and identify capacities and gaps that need to be addressed to ensure successful implementation. Further progress and future success will depend upon equitable, ethical, evidence-based, and community collaborative practices. PMID- 28805126 TI - Using culture and psychology to counter the Taliban's violent narratives. AB - Scholars, politicians, and policy-makers have increasingly pointed to the role of narratives in recruiting militants and justifying violence, highlighting the need for counter-narratives that promote peace. However, few have offered concrete guidelines on how to construct counter-narratives. This exploratory study uses prototype theory from social psychology to analyse Taliban narratives written in Arabic on the historical figure Mahmud of Ghazni (971-1030), who is portrayed as a figure worthy of emulation. Key themes emerge from the Taliban's narratives: potential ingroup members are defined as Sunni Muslims who are committed to jihad; deviant Muslims must become Sunnis; non-Muslims must be converted and humiliated; and Taliban leaders should emulate Mahmud of Ghazni's attributes. Contrasting the Taliban's narratives of Mahmud of Ghazni with the historical record reveals themes that are culled empirically around which counter-narratives could be constructed. PMID- 28805127 TI - The role of heroic doubling in ideologically motivated state and terrorist violence. AB - The psychiatrist Robert Lifton developed his model of 'doubling' to account for the capacity of some human beings to commit atrocities in one compartment of their lives, while continuing to maintain normal social relations in their domestic sphere, a phenomenon which he encountered both in interviews with former Nazi doctors working in concentration camps, and with terrorists belonging to the Japanese Aum Shinrikyo cult. By supplementing this model with a theory of heroization based on existential anthropology and Jung's concept of the Shadow, a composite heuristic explanatory paradigm is formed, 'heroic doubling', which may contribute to the empathetic understanding of acts of extreme violence being carried out by individuals who do not present symptoms of psychiatric disorder and maintain normal existences, yet are prepared to kill and be killed for a cause that confers on their lives a sense of transcendent purpose and sacrality. PMID- 28805128 TI - The reception of broadcast terrorism: recruitment and radicalisation. AB - The declaration of a caliphate by Islamic State in June 2014 witnessed the recruitment of increasing numbers of foreign terrorist fighters drawn from a diverse range of nations across the globe. This paper seeks to explore the appeal of extreme groups and how recruiters persuade young people to risk either their lives or lengthy terms of imprisonment. The processes of radicalization and recruitment are differentiated and compared with conventional means of encouraging individuals to enlist in state-sanctioned armed forces. The reasons why people join terrorist organizations are influenced by their education, formative experiences, and social or familial connections, whilst these variables, in turn, have an impact on the roles that they then undertake. Whether personality traits explain an over-representation of engineers and doctors amongst leaders of particular extremist groups remains a moot question. The increasing use of the internet and social media as instruments to propagate extremist philosophies may, in part, be responsible for the recent rise in sole actors. The need to involve respected and influential Muslim leaders and organizations is crucial in providing a counter-balance to the message of righteous adventure and belonging promoted by Islamic State. PMID- 28805129 TI - Personality, identity, risk and radicalisation. PMID- 28805130 TI - Melan A Antibody Cross-Reactivity in Molluscum Contagiosum Bodies. PMID- 28805131 TI - Brain positron emission tomography with 2-18F-2-deoxi-D-glucose of patients with dystonia and essential tremor detects differences between these disorders. AB - We studied patients with dystonia (D) and essential tremor (ET) using positron emission tomography (PET) equipped with Cortex ID software. This allowed PET brain visualisation to be compared to scans of a control group by means of the z score. The study revealed hypo-metabolism in both D and ET groups, and additionally revealed a difference between these two groups of patients in certain areas of the brain. These two nosological forms overlap in clinical features and are difficult to differentiate. The PET picture may help to provide a differential diagnosis in addition to the biochemical difference in dopamine exchange previously revealed by us in this group of patients. PMID- 28805133 TI - The shape of things to come in speech production: Visual form interference during lexical access. AB - Naming a picture is slower in categorically related compared with unrelated contexts, an effect termed semantic interference. This effect has informed the development of all contemporary models of lexical access in speech production. However, category members typically share visual features, so semantic interference might in part reflect this confound. Surprisingly, little work has addressed this issue, and the relative absence of evidence for visual form interference has been proposed to be problematic for production models implementing competitive lexical selection mechanisms. In a series of five experiments using two different naming paradigms, we demonstrate a reliable visual form interference effect in the absence of a category relation and show the effect is more likely to originate during lexical or later response selection than during perceptual/conceptual processing. We conclude visual form interference in naming is a significant complicating factor for studies of semantic interference effects and discuss the implications for current accounts of lexical access in spoken word production. PMID- 28805132 TI - Evaluation of the Decisional Fatigue Scale Among Surrogate Decision Makers of the Critically Ill. AB - Intense emotional distress and impaired information processing have been implicated in reducing a surrogate decision maker's ability to formulate informed health care decisions for a critically ill patient. The heightened intensity of negative emotions, mental effort, and impaired judgment is consistent with the manifestation of decision fatigue. The aim of this article is to describe the validity and reliability of the Decision Fatigue Scale (DFS) among surrogate decision makers of the critically ill. A convenience sample of 101 surrogate decision makers were administered the DFS and a battery of psychosocial instruments at two time points. The DFS was specified as a unidimensional measure with adequate internal consistency (Cronbach's alphas = .87, .90) and stability reliability. Discriminant validity was established with measures of emotion regulation, anxiety, and depressive symptoms. The DFS is the first subjective measure of decision fatigue for surrogate decision makers of the critically ill that demonstrates satisfactory psychometric properties. PMID- 28805135 TI - Intermittent Dosing of Dabrafenib and Trametinib in Metastatic BRAFV600E Mutated Papillary Thyroid Cancer: Two Case Reports. AB - BACKGROUND: A multi-institutional, randomized phase II trial of continuous dosing of dabrafenib with or without trametinib is ongoing in metastatic thyroid cancer. Preclinical evidence and emerging clinical experience in other cancers support evaluating intermittent dosing of these two agents to achieve more durable response, while being better tolerated and more cost effective. PATIENTS: Two consecutive patients with symptomatic, metastatic radioactive iodine-resistant BRAFV600E mutated papillary thyroid cancer and poor performance status were treated initially with dabrafenib 150 mg twice daily plus trametinib 2 mg once daily, first in continuous daily dosing, then in a five-week-on and three-week off schedule. RESULTS: Both patients showed rapid clinical improvement upon starting the regimen. They also noted improved tolerance of treatment upon transitioning to the intermittent dosing schedule. They continue to show evidence of antitumor activity 27 and 18 months respectively from the start of treatment and 15 and 13 months respectively from the start of the first break using intermittent dosing. CONCLUSIONS: Achieving durable palliation in these consecutive patients supports evaluating the intermittent dosing schedule of dabrafenib and trametinib in BRAFV600E mutated papillary thyroid cancer. Results of the ongoing phase 3 trial of continuous daily dosing and a subsequent trial of intermittent dosing, as is being tested in other cancers, will be needed to confirm that an intermittent dosing strategy in thyroid cancer can forestall resistant disease, improve tolerability, and decrease the cost of care. PMID- 28805138 TI - Corrigendum. PMID- 28805137 TI - Differential influences of Fc gamma receptor blocking on the effects of certolizumab pegol and infliximab on human monocytes. AB - OBJECTIVES: To compare the effects of certolizumab pegol (CZP) and infliximab (IFX) on human monocytes. METHODS: Highly purified monocytes from healthy donors were cultured with CZP, IFX, control IgG1, or polyethylene glycol (PEG) at pharmacological attainable concentrations in culture medium with 10% autologous normal human serum (NHS) or with fetal bovine serum (FBS) for 24 h, after which the supernatants were replaced by fresh culture medium containing LPS. After additional 24 h of incubation, the supernatants were assayed for TNF-alpha and IL 6. In some experiments, the cells were harvested after 1 h of stimulation with LPS for analysis of mRNA for TNF-alpha by quantitative PCR. RESULTS: Pre incubation of monocytes with CZP or IFX reduced the production of TNF-alpha in subsequent cultures stimulated by LPS in a dose-dependent manner. The suppressive effects of IFX on the TNF-alpha production were significantly diminished, but those of CZP were rather enhanced, in cultures with autologous NHS compared with in cultures with FBS. Addition of IgG, but not IgG F(ab')2 fragments, significantly inhibited the suppressive effects of IFX on the production of TNF alpha and IL-6, whereas either IgG or IgG F(ab')2 fragments had no significant influences on the suppressive effects of CZP. Furthermore, pre-incubation with CZP or IFX significantly inhibited the expression of mRNA for TNF-alpha and IL-6 in monocytes compared with PEG or IgG. CONCLUSION: These results indicate that the mechanism of action of CZP is different from that of IFX. Thus, CZP suppresses the production of proinflammatory cytokines independently of Fc receptors, whereas the suppressive effects of IFX on human monocytes are almost totally dependent on the interaction with Fc receptors. PMID- 28805136 TI - * The Ovine Model for Meniscus Tissue Engineering: Considerations of Anatomy, Function, Implantation, and Evaluation. AB - Meniscus injuries represent one of the most-common intra-articular knee injuries. The current treatment options include meniscectomy and allograft transplantation, both with poor long-term outcomes. Therefore, there is a need for regenerative techniques to restore meniscal function. To preclinically test scaffolds for meniscus replacement, large animal models need to be established and standardized. This review establishes the anatomical and compositional similarities between human and sheep menisci and provides guidance for implantation and evaluation of such devices. The ovine meniscus represents a scaled-down version of the human meniscus, with only slight structural differences that can be addressed during device fabrication. Implantation protocols in sheep remain a challenge, as the meniscus cannot be visualized with the arthroscopic-assisted procedures commonly performed in human patients. Thus, we recommend the appropriate implantation protocols for meniscus visualization, ligamentous restoration, and surgical fixation of both total and partial meniscus replacement devices. Last, due to the lack of standardization in evaluation techniques, we recommend a comprehensive battery of tests to evaluate the efficacy of meniscus replacement implants. We recommend other investigators utilize these surgical and testing techniques to establish the ovine model as the gold standard for preclinical evaluation of meniscus replacement devices. PMID- 28805139 TI - Mental representation of fractions: It all depends on whether they are common or uncommon. AB - This study examined whether common and uncommon fractions are mentally represented differently and whether common ones are used in accessing the magnitudes of uncommon ones. In Experiments 1 and 2, college education majors, most of whom were female, Caucasian, and in their early 20s, made comparisons involving common and uncommon fractions. In Experiment 3, participants were presented with comparison tasks involving uncommon fractions and asked to describe the strategies which they used in making such comparisons. Analysis of reaction times and error rates support the hypothesis that for common fractions, it is their holistic real value, rather than their individual components, that gets represented. For uncommon fractions, the access of their magnitudes is a process of retrieving and using a known common one having a similar value. Such results suggest that the development of the cognisance of the magnitudes of fractions may be principally a matter of common ones only and that learners' handling of uncommon fractions may be greatly facilitated through instructions on matching them with common ones having a similar value. PMID- 28805140 TI - * A Rat Model for the In Vivo Assessment of Biological and Tissue-Engineered Valvular and Vascular Grafts. AB - The demand for an improvement of the biocompatibility and durability of vascular and valvular implants requires translational animal models to study the in vivo fate of cardiovascular grafts. In the present article, a review on the development and application of a microsurgical rat model of infrarenal implantation of aortic grafts and aortic valved conduits is provided. By refinement of surgical techniques and inclusion of hemodynamic considerations, a functional model has been created, which provides a modular platform for the in vivo assessment of biological and tissue-engineered grafts. Through optional addition of procalcific diets, disease-inducing agents, and genetic modifications, complex multimorbidity scenarios mimicking the clinical reality in cardiovascular patients can be simulated. Applying this model, crucial aspects of the biocompatibility, biofunctionality and degeneration of vascular and valvular implants in dependency on graft preparation, and modification as well as systemic antidegenerative treatment of the recipient have been and will be addressed. PMID- 28805141 TI - Inhibited attachment disordered behavior in institutionalized preschool children: links with early and current relational experiences. AB - Inhibited attachment disordered behavior (IADB) is characterized by difficulty in establishing an attachment relationship with a primary caregiver; is associated with persistent social and emotional problems; and is observed most frequently in contexts of pathological care such as institutional rearing. Here, we seek to enhance understanding of the conditions that give rise to IADB among institutionalized children by examining prior family experiences of neglect and deprivation and concurrent relational experiences at the institution. The sample is comprised of 146 children, between 36 and 78 months. IADB was assessed using a semi-structured interview administered to the child's primary caregiver. Results revealed that both pre-institutionalization experiences (e.g. parental abandonment) and current relational ones (e.g. low quality of child-caregiver relationship) predicted IADB. Findings are discussed in light of the need to promote conditions which foster the establishment and maintenance of the child's selective attachment to a caregiving figure. PMID- 28805142 TI - Intravenous immunoglobulins modify relapsing membranous glomerulonephritis after kidney transplantation: a case report. AB - OBJECTIVES: Recurrence of membranous glomerulonephritis after transplant is common and is an important cause of loss of renal graft. This case supports the effect of immunoglobulins in the treatment of this disease after transplantation. It is the first report in the literature with a follow-up of more than 10 years and because of the sustained effect of the immunoglobulins, it strengthens the idea that this can alter long-term outcome. METHODS: Single case study and search of the literature. RESULTS: A female transplant recipient, who had an early histologically proven relapse of an idiopathic membranous glomerulonephritis and who was, before transplantation, refractory to various immunosuppressive agents. This relapsing disease has now been stable for over 10 years of intravenous immunoglobulins treatment in conjunction with belatacept and low doses of corticosteroids after gradual withdrawal of mycophenolate mofetil. This report supports the finding that immunoglobulins could influence the course of a relapse of membranous glomerulonephritis after transplantation. CONCLUSION: This case illustrates that immunoglobulins had long-lasting effects on the renal transplant although the glomerulonephritis had been resistant to other lines of therapy before transplant. We advocate that the use of immunoglobulins as a rescue therapy in refractory idiopathic membranous glomerulonephritis should be further investigated. Presently, existing evidence only comes from retrospective data and non-randomized trials. PMID- 28805143 TI - A pre-term infant of 32 weeks gestation with congenital tuberculosis treated successfully with antituberculosis chemotherapy. AB - An infant of 32 weeks gestation was separated from her mother at birth for treatment of hyaline membrane disease and, on recovery, was cared for by adoptive parents. At 25 days, she was treated for pneumonia with immunoglobulins and multiple antibiotics and appeared to respond. Her symptoms recurred at 8 weeks and tuberculosis was confirmed by detection in an acid-fast bacilli smear of gastric aspirate. Her mother presented with disseminated tuberculosis with meningitis 1 month after delivery. Criteria for the diagnosis of congenital tuberculosis in the infant were confirmed. PMID- 28805144 TI - A QM protein-ligand investigation of antipsychotic drugs with the dopamine D2 Receptor (D2R). AB - The dopamine D2 Receptor (D2R) is a member of the G-Protein-Coupled Receptor family and plays a critical role in neurotransmission activities in the human brain. Dysfunction in dopamine receptor signaling may lead to mental health illnesses such as schizophrenia and Parkinson's disease. D2R is the target protein of the commonly used antipsychotic drugs such as risperidone, clozapine, aripiprazole, olanzapine, ziprasidone, and quetiapine. Due to their significant side effects and non-selective profiles, the discovery of novel drugs has become a challenge for researchers working in this field. Recently, our group has focused on the interactions of these drug molecules in the active site of the D2R using different in silico approaches. We here compare the performances of different approaches in estimating the drug binding affinities using quantum chemical approaches. Conformations of drug molecules (ligands) at the binding site of the D2R taken from the preliminary docking studies and molecular dynamics simulations were used to generate protein-ligand interaction models. In a first approach, the BSSE-corrected interaction energies of the ligands with the most critical amino acid Asp114 and with the other amino acids closest to ligands in the binding cavity were calculated separately by density functional theory method in implicit water environment at the M06-2X/6-31 g(d,p) level of the theory. In a second approach, ligand binding affinities were calculated by taking into consideration not only the interaction energies but also deformation and desolvation energies of ligands with surrounding amino acid residues, in a radius of 5 A of the protein-bound ligand. The quantum mechanically obtained results were compared with the experimentally obtained binding affinity values. We concluded that although H-bond interactions of ligands with Asp114 are the most dominant interaction in the binding site, if van der Waals and steric interactions of ligands which have cumulative effect on the ligand binding are not included in the calculations, the interaction energies are overestimated. PMID- 28805145 TI - PDGF/VEGF-Related Receptor Affects Transglutaminase Activity to Control Cell Migration During Crustacean Hematopoiesis. AB - The platelet-derived growth factor (PDGF) receptor, a tyrosine kinase (TK) receptor whose ligand is PDGF, is crucial in the transduction of extracellular signals into cells and mediates numerous processes, such as cell proliferation, differentiation, survival, and migration. We demonstrate the important roles of a receptor TK related to the PDGF/VEGF family protein (PVR) in controlling hematopoietic progenitor cell migration by affecting extracellular transglutaminase (TGase) activity. Pl_PVR1, GenBank accession No. KY444650, is highly expressed in hemocytes and the hematopoietic tissue (HPT). Sunitinib malate was used to block the PVF/PVR downstream pathway in HPT cell culture. The addition of Sunitinib also caused the HPT cells to increase in size and begin spreading. An increase in extracellular TGase activity on the HPT cell membrane was observed in a dose-dependent manner after treatment with Sunitinib malate. The presence of crude Ast1 provided a combinatorial beneficial effect that enhanced the number of spreading cells after inhibition of the Pl_PVR downstream signaling cascade. In addition, an increased immunoreactivity for beta-tubulin and elongation of beta-tubulin filaments were found in Pl_PVR signaling-inhibited cells. The potential roles of PVF/PVR signaling in controlling progenitor cell activity during hematopoiesis in crayfish were investigated and discussed. PMID- 28805146 TI - Deafness and hearing aids in low- and middle-income countries. PMID- 28805147 TI - A comparison of transdermal over-the-counter lidocaine 3.6% menthol 1.25%, Rx lidocaine 5% and placebo for back pain and arthritis. AB - AIM: Transdermal lidocaine therapy has become a gold standard as part of a treatment regimen for patients who suffer from localized pain. We compared transdermal patches: over-the-counter (OTC) lidocaine 3.6% combined with menthol 1.25%, prescription lidocaine 5% (Rx) and placebo. METHODS: In a double-blind, placebo-controlled trial, 87 patients were randomized to: OTC, Rx or placebo. RESULTS: OTC met primary end points of noninferiority compared with Rx for efficacy, side effects and quality of life. Versus placebo, OTC proved superiority for efficacy, general activity and normal work. Side effects were similar. CONCLUSION: It is theorized that menthol's ability to increase skin permeability facilitated more efficient drug delivery to the site of pain causing higher than expected efficacy. Decreased cost and resource utilization could benefit patients and payers. PMID- 28805148 TI - The effects of stimulus distribution form during trace conditioning. AB - Three experiments examined the effect of distribution form of the trace interval on trace conditioning. In Experiments 1 and 2, two groups of rats were conditioned to a fixed-duration conditioned stimulus (CS) in a trace interval procedure; rats in Group Fix received a fixed-duration trace interval, whereas for rats in Group Var the trace interval was of variable duration. Responding during the CS was higher in Group Var than in Group Fix, whereas during the trace interval this difference in responding reversed-Group Fix showed higher response rates than Group Var. Experiment 3 examined whether the greater response rate observed during the CS in Group Var was due to a performance effect or the acquisition of greater associative strength by the CS. Following trace conditioning, the rats from Experiment 1 underwent a second phase of delay conditioning with the same CS; a 5-s auditory stimulus was presented in compound with the last 5 s of the 15-s CS, and the unconditioned stimulus (US) was delivered at the offset of the CSs. On test with the auditory stimulus alone, subjects in Group Var showed lower response rates during the auditory stimulus than subjects in Group Fix. We interpreted these findings as evidence that the superior responding in Group Var during the CS was a result of it acquiring greater associative strength than in Group Fix. PMID- 28805149 TI - Contestation, instrumental resistance and strategic conformation within the diagnostic process of gender dysphoria in Portugal. AB - This article aims to provide insights into the ways in which trans people (i.e. those whose gender identity or expression do not align with their assigned sex at birth) in Portugal make sense of the diagnosis of gender dysphoria. Drawing upon in-depth interviews with 10 trans men and 9 trans women carried out by the TRANSRIGHTS team, we identified three major themes: (a) contestation of gender dysphoria as a (mental) illness, (b) instrumental resistance to complete demedicalisation of gender dysphoria and (c) strategic conformation to gender essentialism within the diagnostic process of gender dysphoria. We found that the need to access medical treatments leads some trans people to approach the diagnosis strategically. While almost all trans people were in favour of the depathologisation of gender dysphoria and at the same time were against its demedicalisation, mainly for instrumental reasons, a few demonstrated contrasting positions whether by agreeing with the idea of gender dysphoria as a pathology or by rejecting medicalisation. The study offers a more nuanced perspective on gender dysphoria than that described in previous sociological and transgender literature. PMID- 28805150 TI - Diffracting addicting binaries: An analysis of personal accounts of alcohol and other drug 'addiction'. AB - Associated with social and individual harm, loss of control and destructive behaviour, addiction is widely considered to be a major social problem. Most models of addiction, including the influential disease model, rely on the volition/compulsion binary, conceptualising addiction as a disorder of compulsion. In order to interrogate this prevailing view, this article draws on qualitative data from interviews with people who describe themselves as having an alcohol or other drug 'addiction', 'dependence' or 'habit'. Applying the concept of 'diffraction' elaborated by science studies scholar Karen Barad, we examine the process of 'addicting', or the various ways in which addiction is constituted, in accounts of daily life with regular alcohol and other drug use. Our analysis suggests not only that personal accounts of addiction exceed the absolute opposition of volition/compulsion but also that the polarising assumptions of existing addicting discourses produce many of the negative effects typically attributed to the 'disease of addiction'. PMID- 28805151 TI - Recognizing and Responding to the "Toxic" Work Environment: Worker Safety, Patient Safety, and Abuse/Neglect in Nursing Homes. AB - This grounded theory study examined how the certified nursing assistant (CNA) understands and responds to bullying in the workplace. Constant comparative analysis was used to analyze data from in-depth telephone interviews with CNAs ( N = 22) who experienced bullying while employed in a nursing home. The result of the analysis is a multistep model describing CNA perceptions of how, over time, they recognized and responded to the "toxic" work environment. The strategies used in responding to the "toxic" environment affected their care provision and were attributed to the development of several resident and worker safety outcomes. The data suggest that the etiology of abuse and neglect in nursing homes may be better explained by institutional cultures rather than individual traits of CNAs. Findings highlight the relationship between worker and patient safety, and suggest worker safety outcomes may be an indicator of quality in nursing homes. PMID- 28805152 TI - Comparing the prevalence and the risk profile for antenatal depressive symptoms across cultures. AB - BACKGROUND AND AIMS: Although several studies have analyzed the risk factors of antenatal and post-partum depression, evidence on the prevalence and the risk profile for antenatal depressive symptoms (ADS) between native-born and different groups of non-native born women living in the same country is scant. The aim of this article is to compare the prevalence and the risk profile for ADS across geographical areas in women recruited from two large hospitals of North-western Italy. METHOD: The presence of ADS was defined as an Edinburgh Post-natal Depression Scale (EPDS) score >=12 or a Beck Depression Inventory, Short Form (BDI-SF) score >=9 or the presence of suicidal ideation/behavior. Crude and adjusted odds ratios (ORs) of ADS were calculated using logistic regression models. RESULTS: The prevalence of ADS was 12.4% among Italian women and ranged from 11.4% in other European to 44.7% in North-African women. Crude ORs of ADS were OR = 3.3 (95% confidence interval (CI), 1.2-8.8) for Asian, 3.3 (95% CI, 1.9 5.6) for South-American and 5.7 (95% CI, 3.4-9.6) for North-African women. Marital problems, at-risk pregnancy, past psychiatric history, pharmacological treatment, psychological treatment, financial problems, change in residence and number of children were significantly associated with ADS in multivariate analyses, regardless of women's origin. After adjusting for these variables, the OR of ADS remained significant for South-American and North-African women. CONCLUSION: Our results demonstrate that the risk of ADS varies across geographical areas of origin and is highest among North-African women. The risk factors identified should be assessed in routine obstetric care to inform decisions about interventions to prevent post-partum depression and its consequences on the mothers and the newborns. PMID- 28805153 TI - Investigating the susceptibility of mice to a bacterial challenge after intravenous exposure to durable nanoparticles. AB - AIM: The goal of this study was to determine whether bacterial clearance in a rodent model would be impaired upon exposure to gold, silver or silica nanoparticles (NPs). MATERIALS & METHODS: Mice received weekly injections of NPs followed by a challenge of Listeria monocytogenes (LM). On days 3 and 10 after LM injections, the animals were sacrificed and their tissues were collected for elemental analysis, electron microscopy and LM count determination. RESULTS: The untreated and NP-treated animals cleared LM at the same rate suggesting that bioaccumulation of NPs did not increase the animals' susceptibility to bacterial infection. CONCLUSION: The data from this study indicate that the bioaccumulation of NPs does not significantly affect the ability to react to a bacterial challenge. PMID- 28805154 TI - Mental health literacy, stigma and perception of causation of mental illness among Chinese people in Taiwan. AB - BACKGROUND: Few studies have been performed to explore mental health literacy and stigmatising attitudes towards mental illness and their relationships with causal beliefs about mental illness among Chinese people in Taiwan. AIMS: Using a comparative approach, this study attempted to compare the mental health literacy and stigmatising attitudes of Taiwanese Chinese with those found among Australian and Japanese participants in other studies and to explore how mental health literacy and stigmatising attitudes relate to different perceptions of causes of mental illness. METHODS: A convenience sample of 287 participants completed a battery of standardised questionnaires. RESULTS: A much lower percentage of Taiwanese people than Australians could correctly identify depression and schizophrenia. The Taiwanese respondents rated psychiatrists and clinical psychologists as more helpful than social workers and general practitioners (GPs) and expressed more uncertainty about the usefulness of certain medications when compared to the Australian and Japanese samples. Interestingly, Taiwanese Chinese hold similarly high levels of stigma towards schizophrenia, but lower levels of stigma towards depression when compared to the Japanese respondents. Taiwanese respondents who have higher levels of mental health literacy about schizophrenia were less willing to interact with people with schizophrenia than those with lower levels of mental health literacy. CONCLUSION: This study underlines the need for public education programmes to improve knowledge of various mental illnesses and to reduce stigmatising attitudes among Taiwanese Chinese. The aforementioned socially and culturally driven beliefs must be taken into consideration so that culturally relevant education programmes can be developed. PMID- 28805155 TI - Violence, victimization and mental health. AB - INTRODUCTION: Violence and victimization are often viewed in black and white terms by mental health professionals, an approach which is belied by more nuanced perspectives from outside psychiatry. METHODS: Given increasing empirical evidence of the pervasive burden of victimization in people with mental illness, authors focused on the available theories and evidences from the literature. RESULTS: Authors summarize the theories of victimizations, the possible measures of this phenomenon and underlie the role of research to clarify the link between psychiatry, violence and victimization. CONCLUSION: Violence and victimization need more space in the psychiatric research. This could have important implications for the lives of patients, but also for public understanding. PMID- 28805156 TI - Socioeconomic crisis and aggressive behaviour of Greek adolescents. AB - BACKGROUND: Aggressive behaviours are common during adolescence. In Greece, adolescents and their families experience a severe and enduring recession with potentially adverse impact on mental health. AIM: This study aimed to examine the correlation between adolescents' aggressive behaviour and economic factors. METHODS: The Buss-Perry Aggression Questionnaire (AQ) was used to measure aggression. Reduction in pocket money and three items of the Household Food Insecurity Access Scale were used to measure material deprivation as a result of the economic crisis. The questionnaires were administrated to a sample of 2,159 adolescent students of the Greater Athens Metropolitan Area. RESULTS: Students who during the previous 4 weeks had experienced household food insecurity (anxiety/uncertainty about food, insufficient food quality or insufficient food intake) or had their pocket money decreased within the last 6 months scored on average significantly higher in the AQ compared to their counterparts who did not. CONCLUSION: The shortage in basic goods due to the actual Greek economic crisis seems to be related to aggressive behaviours during adolescence and we should take this into account in clinical practice. PMID- 28805157 TI - Randomization failure in palliative care RCTs. PMID- 28805158 TI - PP2A Regulatory Subunit B55gamma is a Gatekeeper of Osteoblast Maturation and Lineage Maintenance. AB - Bone marrow mesenchymal stem cells (BM-MSCs) mediate skeletal remodeling by differentiating into osteoblasts. However, this remodeling is impaired with aging as well as following long-term glucocorticoid treatment, resulting in osteoporosis. In this study, we report a novel factor of osteoblast differentiation-PP2A regulatory subunit B55gamma. We show that B55gamma is induced by glucocorticoid receptor (GR) in human primary BM-MSCs during differentiation to osteoblast, but not to adipocytes, and is required for osteoblast morphogenesis and mineralization. Moreover, B55gamma knockdown under osteogenic conditions leads to the accumulation of lipid droplets in a subset of BM-MSCs. Treatment of BM-MSCs with only GR ligand dexamethasone induces B55gamma transcript, but not protein, and causes widespread generation of lipid droplets. These data indicate that B55gamma is an essential factor of osteoblast lineage, acting as a gatekeeper downstream of master regulators. This opens a new direction of research for understanding mechanisms of glucocorticoid-induced osteoporosis and bone marrow adiposity. PMID- 28805159 TI - Factors associated with vocal fry among college students. AB - PURPOSE: Vocal fry is increasingly used in everyday speech. The purpose of this study was to identify associated factors of vocal fry among young US college-age students. METHODS: Forty college students participated in a cross-sectional study. Participants produced speech under nine different room acoustic conditions (simulated). The recorded speech was perceptually evaluated by three speech language pathologists. Multivariate logistic regression analysis was used to identify variables (individual, environmental) associated with the perceptual assessment of vocal fry. RESULTS: A high occurrence of perceptually identified vocal fry was identified among college students. Two factors were significantly associated with lower occurrence of perceptually identified vocal fry: one individual (sporadic consumption of caffeinated beverages) and one environmental factor (speaking in an environment with background noise). CONCLUSIONS: Similar to modal phonation, fry-like phonation seems to be influenced by individual and environmental factors. Therefore, clinicians interested in including this technique as part of their intervention programs may take into account the caffeine consumption and the background noise conditions of the room where the therapy will take place in order to facilitate the production of fry-like phonation. PMID- 28805160 TI - Clinical Implications of Immunoglobulin G4 to Graves' Ophthalmopathy. AB - BACKGROUND: This study aimed to explore the relation of immunoglobulin G4 (IgG4) to clinical and laboratory characteristics of patients newly diagnosed with Graves' disease (GD) without or with Graves' ophthalmopathy (GO) and to analyze association of IgG4 with development and grade of GO in GD patients. METHODS: Sixty-four GD patients and 64 sex- and age-matched euthyroid subjects were enrolled. Serum levels of thyroid hormones, thyroid autoantibodies, immunoglobulin G (IgG), and IgG4 were measured, and ophthalmological and ultrasonographical evaluation was performed. RESULTS: In GD patients compared with euthyroid subjects, levels of thyroid hormones, thyroid autoantibodies and IgG4 as well as the IgG4/IgG ratio were elevated. GD patients having GO in comparison to not having GO were characterized by a female predominance; a high incidence of smoking history; high levels of T3, free T4, TSH receptor autoantibody (TRAb) and IgG4; and a high IgG4/IgG ratio after adjusting for sex. In GD patients, the IgG4 level was the independent factor associated with GO development on multivariate analysis. When severity and activity of GO were classified using the European Group on Graves' Orbitopathy criteria in GD patients with GO, IgG4 levels and IgG4/IgG ratio were elevated in the moderate-to severe group compared with the mild group and in the active group compared with the inactive group. IgG4 levels and IgG4/IgG ratio became elevated as clinical activity score increased. IgG4 levels were positively correlated with TRAb levels. The high IgG4 group in comparison to the normal IgG4 group had a high incidence of family history of autoimmune thyroid disease, high levels of free T4, TRAb and IgG4, a high IgG4/IgG ratio and extensive hypoechogenicity. CONCLUSIONS: These results suggest that IgG4 levels are elevated in newly diagnosed GD patients compared with euthyroid subjects and in the presence of GO compared with the absence of GO. Moreover, our findings suggest that IgG4 levels are associated with the development and grade of GO in GD patients. PMID- 28805161 TI - Eco-friendly and biocompatible cross-linked carboxymethylcellulose hydrogels as adsorbents for the removal of organic dye pollutants for environmental applications. AB - In this study, new eco-friendly hydrogel adsorbents were synthesized based on carboxymethylcellulose (CMC, degree of substitution [DS] = 0.7) chemically cross linked with citric acid (CA) using a green process in aqueous solution and applied for the adsorption of methylene blue (MB). Spectroscopic analyses demonstrated the mechanism of cross-linking through the reaction of hydroxyl functional groups from CMC with CA. These CMC hydrogels showed very distinct morphological features dependent on the extension of cross-linking and their nanomechanical properties were drastically increased by approximately 300% after cross-linking with 20% CA (e.g. elastic moduli from 80 +/- 15 to 270 +/- 50 MPa). Moreover, they were biocompatible using an in vitro cell viability assay in contact with human osteosarcoma-derived cells (SAOS) for 24 h. These CMC-based hydrogels exhibited adsorption efficiency above 90% (24 h) and maximum removal capacity of MB from 5 to 25 mg g-1 depending on the dye concentration (from 100 to 500 mg L-1), which was used as the model cationic organic pollutant. The adsorption of process of MB was well-fit to the pseudo-second-order kinetics model. The desorption of MB by immersion in KCl solution (3 mol L-1, 24 h) showed a typical recovery efficiency of over 60% with conceivable reuse of these CMC based hydrogels. Conversely, CMC hydrogels repelled methyl orange dye used as model anionic pollutant, proving the mechanism of adsorption by the formation of charged polyelectrolyte/dye complexes. PMID- 28805162 TI - Automated telecommunication interventions to promote adherence to cardio metabolic medications: meta-analysis of effectiveness and meta-regression of behaviour change techniques. AB - Automated telecommunication interventions, including short message service and interactive voice response, are increasingly being used to promote adherence to medications prescribed for cardio-metabolic conditions. This systematic review aimed to comprehensively assess the effectiveness of such interventions to support medication adherence, and to identify the behaviour change techniques (BCTs) and other intervention characteristics that are positively associated with greater intervention effectiveness. Meta-analysis of 17 randomised controlled trials showed a small but statistically significant effect on medication adherence, OR = 1.89, 95% CI [1.51, 2.36], I2 = 89%, N = 25,101. Multivariable meta-regression analysis including eight BCTs explained 88% of the observed variance in effect size (ES). The BCTs 'tailored' and 'information about health consequences' were positively and significantly associated with ES. Future studies could explore whether the inclusion of these and/or additional techniques (e.g., 'implementation intentions') would increase the effect of automated telecommunication interventions, using rigorous designs and objective outcome measures. PMID- 28805163 TI - Cryptosporidium in fish: alternative sequencing approaches and analyses at multiple loci to resolve mixed infections. AB - Currently, the systematics, biology and epidemiology of piscine Cryptosporidium species are poorly understood. Here, we compared Sanger - and next-generation - sequencing (NGS), of piscine Cryptosporidium, at the 18S rRNA and actin genes. The hosts comprised 11 ornamental fish species, spanning four orders and eight families. The objectives were: to (i) confirm the rich genetic diversity of the parasite and the high frequency of mixed infections; and (ii) explore the potential of NGS in the presence of complex genetic mixtures. By Sanger sequencing, four main genotypes were obtained at the actin locus, while for the 18S locus, seven genotypes were identified. At both loci, NGS revealed frequent mixed infections, consisting of one highly dominant variant plus substantially rarer genotypes. Both sequencing methods detected novel Cryptosporidium genotypes at both loci, including a novel and highly abundant actin genotype that was identified by both Sanger sequencing and NGS. Importantly, this genotype accounted for 68.9% of all NGS reads from all samples (249 585/362 372). The present study confirms that aquarium fish can harbour a large and unexplored Cryptosporidium genetic diversity. Although commonly used in molecular parasitology studies, nested PCR prevents quantitative comparisons and thwarts the advantages of NGS, when this latter approach is used to investigate multiple infections. PMID- 28805164 TI - Modelling the spatial distribution of Fasciola hepatica in bovines using decision tree, logistic regression and GIS query approaches for Brazil. AB - Fascioliasis is a condition caused by the trematode Fasciola hepatica. In this paper, the spatial distribution of F. hepatica in bovines in Brazil was modelled using a decision tree approach and a logistic regression, combined with a geographic information system (GIS) query. In the decision tree and the logistic model, isothermality had the strongest influence on disease prevalence. Also, the 50-year average precipitation in the warmest quarter of the year was included as a risk factor, having a negative influence on the parasite prevalence. The risk maps developed using both techniques, showed a predicted higher prevalence mainly in the South of Brazil. The prediction performance seemed to be high, but both techniques failed to reach a high accuracy in predicting the medium and high prevalence classes to the entire country. The GIS query map, based on the range of isothermality, minimum temperature of coldest month, precipitation of warmest quarter of the year, altitude and the average dailyland surface temperature, showed a possibility of presence of F. hepatica in a very large area. The risk maps produced using these methods can be used to focus activities of animal and public health programmes, even on non-evaluated F. hepatica areas. PMID- 28805166 TI - The influence of organic matter content and media compaction on the dispersal of entomopathogenic nematodes with different foraging strategies. AB - In laboratory experiments, we investigated how media with varying ratio of peat:sand and two levels of compaction influence dispersal success of entomopathogenic nematode (EPN) species with different foraging strategies: Steinernema carpocapsae (ambusher), Heterorhabditis downesi (cruiser) and Steinernema feltiae (intermediate). Success was measured by the numbers of nematodes moving through a 4 cm column and invading a wax moth larva. We found that both compaction and increasing peat content generally decreased EPN infective juvenile (IJ) success for all three species. Of the three species, H. downesi was the least affected by peat content, and S. carpocapsae was the most adversely influenced by compaction. In addition, sex ratios of the invading IJs of the two Steinernema species were differentially influenced by peat content, and in the case of S. feltiae, sex ratio was also affected by compaction. This indicates that dispersal of male and female IJs is differentially affected by soil parameters and that this differentiation is species-specific. In conclusion, our study shows that organic matter: sand ratio and soil compaction have a marked influence on EPN foraging behaviour with implications for harnessing them as biological pest control agents. PMID- 28805167 TI - The in vitro anthelmintic activity of the ethanol leaf extracts of Terminalia catappa L. on Fasciola gigantica. AB - At present, there are no medicinal plant extracts currently available for treatment and control of fasciolosis. The present work could provide, for the first study, conclusions on the in vitro fasciolicidal properties of the ethanol extract of Terminalia catappa L. (TcCE) leaves against adult Fasciola gigantica after incubation with RPMI-1640 medium containing the TcCE at various concentrations and times when compared with triclabendazole (TCZ). The relative motility and survival index values of the TcCE-treated flukes decreased at a more rapid rate than the TCZ-treated flukes. The death of the parasites was observed after exposed to TcCE at 3 h incubation with 400, 800 and 1000 ug mL-1, and at 6 h incubation in 100 and 200 ug mL-1. Vacuolization, blebbings and partial disruption on the parasites' tegument were observed by light microscopy. When examined by scanning electron microscopy, TcCE caused similar tegumental alterations in the parasites as those observed in TCZ treatment but with larger damage at comparative incubation periods, consisting of swelling, blebbing, disrupted blebs, loss of spines, leading to the erosion, lesion and eventual disruption of the total tegument. Therefore, the TcCE may exert its fasciolicidal effect against F. gigantica by initially causing the tegumental alteration. PMID- 28805165 TI - Repurposing as a strategy for the discovery of new anti-leishmanials: the-state of-the-art. AB - Leishmaniasis is a vector-borne neglected tropical disease caused by protozoan parasites of the genus Leishmania for which there is a paucity of effective viable non-toxic drugs. There are 1.3 million new cases each year causing considerable socio-economic hardship, best measured in 2.4 million disability adjusted life years, with greatest impact on the poorest communities, which means that desperately needed new antileishmanial treatments have to be both affordable and accessible. Established medicines with cheaper and faster development times may hold the cure for this neglected tropical disease. This concept of using old drugs for new diseases may not be novel but, with the ambitious target of controlling or eradicating tropical diseases by 2020, this strategy is still an important one. In this review, we will explore the current state-of-the-art of drug repurposing strategies in the search for new treatments for leishmaniasis. PMID- 28805169 TI - The prevalence of suicidal thoughts and behaviours among college students: a meta analysis. AB - BACKGROUND: Adolescence and young adulthood carry risk for suicidal thoughts and behaviours (STB). An increasing subpopulation of young people consists of college students. STB prevalence estimates among college students vary widely, precluding a validated point of reference. In addition, little is known on predictors for between-study heterogeneity in STB prevalence. METHODS: A systematic literature search identified 36 college student samples that were assessed for STB outcomes, representing a total of 634 662 students [median sample size = 2082 (IQR 353 5200); median response rate = 74% (IQR 37-89%)]. We used random-effects meta analyses to obtain pooled STB prevalence estimates, and multivariate meta regression models to identify predictors of between-study heterogeneity. RESULTS: Pooled prevalence estimates of lifetime suicidal ideation, plans, and attempts were 22.3% [95% confidence interval (CI) 19.5-25.3%], 6.1% (95% CI 4.8-7.7%), and 3.2% (95% CI 2.2-4.5%), respectively. For 12-month prevalence, this was 10.6% (95% CI 9.1-12.3%), 3.0% (95% CI 2.1-4.0%), and 1.2% (95% CI 0.8-1.6%), respectively. Measures of heterogeneity were high for all outcomes (I 2 = 93.2 99.9%), indicating substantial between-study heterogeneity not due to sampling error. Pooled estimates were generally higher for females, as compared with males (risk ratios in the range 1.12-1.67). Higher STB estimates were also found in samples with lower response rates, when using broad definitions of suicidality, and in samples from Asia. CONCLUSIONS: Based on the currently available evidence, STB seem to be common among college students. Future studies should: (1) incorporate refusal conversion strategies to obtain adequate response rates, and (2) use more fine-grained measures to assess suicidal ideation. PMID- 28805168 TI - 9/11-related PTSD among highly exposed populations: a systematic review 15 years after the attack. AB - BACKGROUND: The 11 September 2001 (9/11) attacks were unprecedented in magnitude and mental health impact. While a large body of research has emerged since the attacks, published reviews are few, and are limited by an emphasis on cross sectional research, short time frame, and exclusion of treatment studies. Additionally, to date, there has been no systematic review of available longitudinal information as a unique data set. Consequently, knowledge regarding long-term trajectories of 9/11-related post-traumatic stress disorder (PTSD) among highly exposed populations, and whether available treatment approaches effectively address PTSD within the context of mass, man-made disaster, remains limited. METHODS: The present review aimed to address these gaps using a systematic review of peer-reviewed reports from October 2001 to May 2016. Eligible reports were of longitudinal studies of PTSD among highly exposed populations. We identified 20 reports of 9/11-related PTSD, including 13 longitudinal prevalence studies and seven treatment studies. RESULTS: Findings suggest a substantial burden of 9/11-related PTSD among those highly exposed to the attack, associated with a range of sociodemographic and back-ground factors, and characteristics of peri-event exposure. While most longitudinal studies show declining rates of prevalence of PTSD, studies of rescue/recovery workers have documented an increase over time. Treatment studies were few, and generally limited by methodological shortcomings, but support exposure-based therapies. CONCLUSION: Future directions for research, treatment, and healthcare policy are discussed. PMID- 28805170 TI - Perspectives of patients, close relatives, nurses, and physicians on end-of-life medication management. AB - : ABSTRACTObjective:Our aim was to gain insight into the perspectives of patients, close relatives, nurses, and physicians on medication management for patients with a life expectancy of less than 3 months. METHOD: We conducted an empirical multicenter study with a qualitative approach, including in-depth interviews with patients, relatives, nurses, specialists, and general practitioners (GPs). We used the constant comparative method and ATLAS.ti (v. 7.1) software for our analysis. RESULTS: Saturation occurred after 18 patient cases (76 interviews). Some 5 themes covering 18 categories were identified: (1) priorities in end-of-life care, such as symptom management and maintaining hope; (2) appropriate medication use, with attention to unnecessary medication and deprescription barriers; (3) roles in decision making, including physicians in the lead, relatives' advocacy, and pharmacists as suppliers; (4) organization and communication (e.g., transparency of tasks and end-of-life conversations); and (5) prerequisites about professional competence, accessibility and quality of medical records, and financial awareness. Patients, relatives, nurses, specialists, and GPs varied in their opinions about these themes. SIGNIFICANCE OF RESULTS: This study adds to our in-depth understanding of the complex practice of end-of-life medication management. It provides knowledge about the diversity of the perspectives of patients, close relatives, nurses, and physicians regarding beliefs, attitudes, knowledge, skills, behavior, work setting, the health system, and cultural factors related to the matter. Our results might help to draw an interdisciplinary end-of-life medication management guide aimed at stimulating a multidisciplinary and patient-centered pharmacotherapeutic care approach. PMID- 28805171 TI - Prevalence and risk factors for colonization of Clostridium difficile among adults living near livestock farms in the Netherlands. AB - A cross-sectional study was performed among 2494 adults not living or working on a farm to assess prevalence of Clostridium difficile (CD) colonization and risk factors in a livestock dense area. CD prevalence was 1.2%. Twenty-one persons were colonized with a toxigenic strain and nine with a non-toxigenic strain. CD positive persons did not live closer to livestock farms than individuals negative for CD. Antibiotic exposure in the preceding 3 months was a risk factor for CD colonization (odds ratio 3.70; 95% confidence interval 1.25-10.95). PMID- 28805172 TI - The Developmental Origins of Health and Disease and Sustainable Development Goals: mapping the way forward. AB - In this paper, meant to stimulate debate, we argue that there is considerable benefit in approaching together the implementation of two seemingly separate recent developments. First, on the global development agenda, we have the United Nations General Assembly's 2015 finalized list of 17 Sustainable Development Goals (SDGs). Several of the SDGs are related to health. Second, the field of Developmental Origins of Health and Disease (DOHaD) has garnered enough compelling evidence demonstrating that early exposures in life affect not only future health, but that the effects of that exposure can be transmitted across generations - necessitating that we begin to focus on prevention. We argue that implementing the SDGs and DOHaD together will be beneficial in several ways; and will require attending to multiple, complex and multidisciplinary approaches as we reach the point of translating science to policy to impact. Here, we begin by providing the context for our work and making the case for a mutually reinforcing, synergistic approach to implementing SDGs and DOHaD, particularly in Africa. To do this, we initiate discussion via an early mapping of some of the overlapping considerations between SDGs and DOHaD. PMID- 28805174 TI - Socioeconomic position and depression in South African adults with long-term health conditions: a longitudinal study of causal pathways. AB - AIMS: There is convincing evidence that lower socioeconomic position is associated with increased risk of mental disorders. However, the mechanisms involved are not well understood. This study aims to elucidate the causal pathways between socioeconomic position and depression symptoms in South African adults. Two possible causal theories are examined: social causation, which suggests that poor socioeconomic conditions cause mental ill health; and social drift, which suggests that those with poor mental health are more likely to drift into poor socioeconomic circumstances. METHODS: The study used longitudinal and cross-sectional observational data on 3904 adults, from a randomised trial carried out in 38 primary health care clinics between 2011 and 2012. Structural equation models and counterfactual mediation analyses were used to examine causal pathways in two directions. First, we examined social causation pathways, with language (a proxy for racial or ethnic category) being treated as an exposure, while education, unemployment, income and depression were treated as sequential mediators and outcomes. Second, social drift was explored with depression treated as a potential influence on health-related quality of life, job loss and, finally, income. RESULTS: The results suggest that the effects of language on depression at baseline, and on changes in depression during follow-up, were mediated through education and income but not through unemployment. Adverse effects of unemployment and job loss on depression appeared to be mostly mediated through income. The effect of depression on decreasing income appeared to be mediated by job loss. CONCLUSIONS: These results suggest that both social causation and social selection processes operate concurrently. This raises the possibility that people could get trapped in a vicious cycle in which poor socioeconomic conditions lead to depression, which, in turn, can cause further damage to their economic prospects. This study also suggests that modifiable factors such as income, employment and treatable depression are suitable targets for intervention in the short to medium term, while in the longer term reducing inequalities in education will be necessary to address the deeply entrenched inequalities in South Africa. PMID- 28805173 TI - Latent traits of impulsivity and compulsivity: toward dimensional psychiatry. AB - BACKGROUND: The concepts of impulsivity and compulsivity are commonly used in psychiatry. Little is known about whether different manifest measures of impulsivity and compulsivity (behavior, personality, and cognition) map onto underlying latent traits; and if so, their inter-relationship. METHODS: A total of 576 adults were recruited using media advertisements. Psychopathological, personality, and cognitive measures of impulsivity and compulsivity were completed. Confirmatory factor analysis was used to identify the optimal model. RESULTS: The data were best explained by a two-factor model, corresponding to latent traits of impulsivity and compulsivity, respectively, which were positively correlated with each other. This model was statistically superior to the alternative models of their being one underlying factor ('disinhibition') or two anticorrelated factors. Higher scores on the impulsive and compulsive latent factors were each significantly associated with worse quality of life (both p < 0.0001). CONCLUSIONS: This study supports the existence of latent functionally impairing dimensional forms of impulsivity and compulsivity, which are positively correlated. Future work should examine the neurobiological and neurochemical underpinnings of these latent traits; and explore whether they can be used as candidate treatment targets. The findings have implications for diagnostic classification systems, suggesting that combining categorical and dimensional approaches may be valuable and clinically relevant. PMID- 28805175 TI - Outcomes of a psycho-education and monitoring programme to prevent compulsory admission to psychiatric inpatient care: a randomised controlled trial. AB - BACKGROUND: There is a need for interventions that effectively reduce compulsory admission to psychiatry. We conducted a randomised controlled trial to investigate whether an innovative intervention programme prevents compulsory re admission in people with serious mental illness. METHODS: The programme addresses primarily patients' self-management skills. It consists of individualised psychoeducation focusing on behaviours prior to and during illness-related crises, crisis cards and, after discharge from the psychiatric hospital, a 24 month preventive monitoring. A total of 238 inpatients with compulsory admission(s) in the past were randomised to the intervention group or to treatment as usual (TAU). RESULTS: Fewer participants who completed the 24-month programme were compulsorily readmitted to psychiatry (28%), compared with those receiving TAU (43%). Likewise, the number of compulsory readmissions per patient was significantly lower (0.6 v. 1.0) and involuntary episodes were shorter (15 v. 31 days), compared with TAU. A negative binomial regression model showed a significant intervention effect (RR 0.6; 95% confidence interval 0.3-0.9); further factors linked to the risk of compulsory readmission were the number of compulsory admissions in the patient's history (RR 2.8), the diagnosis of a personality disorder (RR 2.8), or a psychotic disorder (RR 1.9). Dropouts (37% intervention group; 22% TAU) were characterised by a high number of compulsory admissions prior to the trial, younger age and foreign nationality. CONCLUSIONS: This study suggests that this intervention is a feasible and valuable option to prevent compulsory re-hospitalisation in a high-risk group of people with severe mental health problems, social disabilities, and a history of hospitalisations. PMID- 28805176 TI - Estimating the risk of invasive group A Streptococcus infection in care home residents in England, 2009-2010. AB - Invasive group A streptococcal (iGAS) infections cause severe disease and death, especially in residents of long-term care facilities (LTCFs). In order to inform iGAS prevention, we compared the risk of iGAS in LTCF residents and community residents. We identified LTCF residents among cases of iGAS from national surveillance (2009-2010) using postcode matching, and cases of hospital-acquired infections via hospital admission records. We used Poisson regression to calculate incidence rate ratios (IRR) and logistic regression to explore factors associated with case fatality rate (CFR). A total of 2741 laboratory-confirmed iGAS cases were matched to a hospital admission: 156 (6%) were defined as hospital-acquired. Out of the total cases, 96 (3.5%) were LTCF residents. Compared with community residents, LTCF residents over 75 years of age had a higher risk of iGAS infection (IRR = 1.7; 95% CI 1.3-2.1) and CFR (OR = 2.3; 95% CI 1.3-3.8). Amongst community-acquired cases, the risk of iGAS in LTCF residents between 75 and 84 years of age doubled (IRR = 2.7; 95% CI 1.8-3.9) compared with their community counterparts. The CFR among community-acquired cases was higher in LTCF residents than community residents (21% vs. 11%). Age remained associated with death in our final model. Our study showed that, even controlling for age, LTCF residents have a higher risk of acquiring and dying from iGAS. Whilst existing co-morbidities may explain this, it is reasonable to assume that the institutional setting may facilitate transmission. Therefore, cases in LTCF require prompt investigation together with a better understanding of factors contributing to the acquisition of infection. PMID- 28805177 TI - Evaluation of the efficacy, safety and acceptability of a fish protein isolate in the nutrition of children under 36 months of age. AB - OBJECTIVE: To determine the effect of a fish protein isolate (FPi), administered over 6 months, on the growth of children aged 6-36 months, measured by Z-scores of height-for-age (HAZ) and weight-for-height (WHZ), compared with the standard meal without FPi; and to determine the safety and acceptability of FPi daily consumption. DESIGN: Cluster-randomized community-based controlled trial. For 6 months, the centres received either FPi replacing 50 % of total proteins in the diet or standard protein. HAZ and WHZ were used to determine the effect on growth. Acceptability was determined by daily consumption, measured by weighing the servings before and after consumption. SETTING: Day care centres and community nutritional centres in northern Lima, Peru. SUBJECTS: Children (n 441) aged 6-36 months. RESULTS: Four centres were randomized to the intervention with FPi, five centres were randomized to the standard control diet. More than 36 900 meals were prepared and administered in a supervised manner. Both groups received the same amounts of energy and proteins daily (proteins about 12-15 % of total energy). Growth of children who received the FPi diet was similar to that of children with the standard diet. Consumption was similar in the FPi and control groups (70 v. 80 % of amount offered, respectively). The protein was safe and well tolerated. No adverse events were reported. However, the cost of the intervention with FPi was 20-40 % lower v. the standard diet with animal protein derived from beef, chicken, eggs or liver. CONCLUSIONS: The FPi was well accepted and there was no significant difference in growth between both groups. FPi is a potential source of animal protein at lower cost. PMID- 28805178 TI - Socioeconomic inequalities in duration of untreated psychosis: evidence from administrative data in England. AB - BACKGROUND: Duration of untreated psychosis (DUP) is an important measure of access to care as it predicts prognosis and treatment outcomes. Little is known about potential socioeconomic inequalities in DUP. The aim of this study was to investigate inequalities in DUP associated with socioeconomic deprivation in a national cohort in England. METHOD: We analysed a cohort of 887 patients with a first-episode in psychosis using the administrative Mental Health Services Dataset in England for 2012/13-2014/15. We used a Generalised Linear Model to account for non-linearity in DUP and looked at inequalities across the whole distribution of DUP using quantile regression. RESULTS: The median DUP was 22 days (mean = 74 days) with considerable variations between and within the 31 hospital providers. We found evidence of significant inequalities regarding the level of socioeconomic deprivation. Patients living in the second, third and fourth deprived neighbourhood quintiles faced a 36, 24 and 31 day longer DUP than patients from the least deprived neighbourhoods. Inequalities were more prevalent in higher quantiles of the DUP distribution. Unemployment prolonged DUP by 40 days. Having been in contact with mental health care services prior to the psychosis start significantly reduced the DUP by up to 53 days. CONCLUSIONS: Socioeconomic deprivation is an important factor in explaining inequalities in DUP. Policies to improve equitable access to care should particularly focus on preventing very long delays in treatment and target unemployed patients as well as people that have not been in contact with any mental health professional in the past. PMID- 28805179 TI - Psychosis as a risk factor for suicidal thoughts and behaviors: a meta-analysis of longitudinal studies. AB - BACKGROUND: Research has long noted higher prevalence rates of suicidal thoughts and behaviors among individuals with psychotic symptoms. Major theories have proposed several explanations to account for this association. Given the differences in the literature regarding the operationalization of psychosis and sample characteristics, a quantitative review is needed to determine to what extent and how psychosis confers risk for suicidality. METHODS: We searched PsycInfo, PubMed, and GoogleScholar for studies published before 1 January 2016. To be included in the analysis, studies must have used at least one psychosis related factor to longitudinally predict suicide ideation, attempt, or death. The initial search yielded 2541 studies. Fifty studies were retained for analysis, yielding 128 statistical tests. RESULTS: Suicide death was the most commonly studied outcome (43.0%), followed by attempt (39.1%) and ideation (18.0%). The median follow-up length was 7.5 years. Overall, psychosis significantly conferred risk across three outcomes, with weighted mean ORs of 1.70 (1.39-2.08) for ideation, 1.36 (1.25-1.48) for attempt, and 1.40 (1.14-1.72) for death. Detailed analyses indicated that positive symptoms consistently conferred risk across outcomes; negative symptoms were not significantly associated with ideation, and were protective against death. Some small moderator effects were detected for sample characteristics. CONCLUSIONS: Psychosis is a significant risk factor for suicide ideation, attempt, and death. The finding that positive symptoms increased suicide risk and negative symptoms seemed to decrease risk sheds light on the potential mechanisms for the association between psychosis and suicidality. We note several limitations of the literature and offer suggestions for future directions. PMID- 28805180 TI - Diabetes and pregnancy in Wistar rats: renal effects for mothers in the postpartum period. AB - In this study, diabetes mellitus (DM) was induced in Wistar rats during pregnancy and maintained in the postpartum period (PP) and we evaluated systolic blood pressure (SBP), glomerular filtration rate (GFR) and renal immunohistochemical and morphometric studies from different groups: G1 (non-pregnant control rats), G2 (non-pregnant diabetic rats), G3 (control mothers) and G4 (diabetic mothers). We found that there were no differences in relation to SBP, but there was a tendency for reduction in GFR from G4 compared with the other groups (G). There was increased total kidney weight/body weight ratio of G4 compared with other G. There were increase in glomerular tuft area in G3 and G4 compared with G1 and G2. G2 and G4 showed even higher percentage of cortical collagen. G3 showed increased glomerular proliferating cells compared with G1 and G2, while in G4 this number was smaller than G3. Cell proliferation was higher in the tubulointerstitial (TBI) compartment from G4. Glomerular and TBI alpha-smooth muscle actin expression was increased in G4 compared with other G. The glomerular p-p38 expression showed a pattern similar to proliferation cell nuclear antigen, with a reduction of p-p38 in G4 relative to other G. The immunoreactivity of p-JNK was higher in both the glomeruli and TBI compartment in G4 compared with G1, G2 and G3. The DM induced during pregnancy and maintained in the PP resulted in renal structural and functional changes to mothers. In addition, altered mitogen activated protein kinase expression in association with these changes may play an important role in renal damage observed in the present investigation. PMID- 28805181 TI - Larval development of Angiostrongylus chabaudi, the causative agent of feline angiostrongylosis, in the snail Cornu aspersum. AB - Nematodes of the Angiostrongylidae family, such as Angiostrongylus vasorum and Angiostrongylus cantonensis, may cause potentially life-threatening diseases in several mammal species. Alongside these well-known species, Angiostrongylus chabaudi has been recently found affecting the cardiopulmonary system of domestic and wild cats from Italy, Germany, Greece, Romania and Bulgaria. Nonetheless, significant gaps in the understanding of A. chabaudi epidemiology include the lack of information of species acting as intermediate host and of the morphological description of larval stages. Cornu aspersum (n = 30) land snails were infected with 100 first-stage larvae of A. chabaudi collected from a naturally infected wildcat in Romania. Larvae at different developmental stages were found in 29 out of 30 (96.7%) infected snails and a total of 282 (mean 9.8 +/- 3.02 larvae per each specimen) were collected from the gastropods. Here we demonstrate that A. chabaudi develops in snails and report C. aspersum as potential intermediate host for this parasitic nematode. Findings of this study are central to understand the ecological features of feline angiostrongylosis and its epidemiology within paratenic and intermediate hosts. PMID- 28805183 TI - Letter to the Editor: Association between smoking and psychosis may be mediated by maternal smoking during pregnancy. PMID- 28805182 TI - Human induced pluripotent stem cells as a research tool in Alzheimer's disease. AB - Human-induced pluripotent stem cells (iPSCs) offer a novel, timely approach for investigating the aetiology of neuropsychiatric disorders. Although we are starting to gain more insight into the specific mechanisms that cause Alzheimer's disease and other forms of dementia, this has not resulted in therapies to slow the pathological processes. Animal models have been paramount in studying the neurobiological processes underlying psychiatric disorders. Nonetheless, these human conditions cannot be entirely recapitulated in rodents. Human cell models derived from patients' cells now offer new hope for improving our understanding of the early molecular stages of these diseases, through to validating therapeutics. The impact of dementia is increasing, and a new model to investigate the early stages of this disease is heralded as an essential, new platform for translational research. In this paper, we review current literature using iPSCs to study Alzheimer's disease, describe drug discovery efforts using this platform, and discuss the future potential for this technology in psychiatry research. PMID- 28805185 TI - 'Unmet need' and 'met un-need' in mental health services: artefacts of a categorical view of mental health problems. PMID- 28805184 TI - Recruiting young people with a visible difference to the YP Face IT feasibility trial: a qualitative exploration of primary care staff experiences. AB - BACKGROUND: Qualitative research methods embedded within feasibility trials are of significant value as they can provide important information for a definitive trial, often unable to be fulfilled by quantitative methods alone. In addition, such information can aid researchers running other trials or evaluating interventions on a similar topic. Aim This study aimed to explore GP and nurses' experiences of recruiting to a trial exploring the feasibility of evaluating YP Face IT, a novel online psychosocial intervention to support young people with appearance-altering conditions. METHODS: During the recruitment period, a focus group with participating GPs and nurses explored recruitment challenges. In addition, at the end of the recruitment period, telephone interviews were conducted with eight GPs and nurses involved in recruiting to the study, in order to inform a definitive trial of YP Face IT. Transcripts were subjected to thematic analysis. Findings Despite reporting that the study was valuable and interesting, interviewees struggled to recruit in-consultation. They appeared to lack confidence in raising the sensitive issue of a visible difference and adopted strategies to avoid mentioning the topic. Participants felt the nature of the target population, as well as pressures of the primary care environment presented challenges to recruitment, but welcomed YP Face IT as an intervention that could address unmet support needs. Primary care staff may benefit from training to help them raise the subject of a visible difference with young people in order to identify those that require additional support. PMID- 28805186 TI - Improving the social health of community-dwelling older people living with dementia through a reablement program. AB - ABSTRACTPsychological, neurological, and social impairments caused by dementia may limit the person's everyday living and experiences, but their capacity to enjoy a meaningful life is still retained. Increasingly, evidence has been shown the importance of reablement approaches to care in maximizing the older person's independence, health, and well-being through increased engagement in their daily, physical, social, and community activities. However, there is a major knowledge gap in providing reablement for people living with dementia. We describe one case of a client with moderate dementia and her daughter carer who participated as a dyad in a person centered, interdisciplinary, and reablement program called I HARP (Interdisciplinary home-based reablement program). I-HARP is designed to improve functional capacity of those community dwelling, older people living with dementia, and other health conditions. In this paper, we discussed key contributions that such a reablement approach to care can make to optimizing the social health of people living with dementia. PMID- 28805187 TI - Changes in patient characteristics following cardiac transplantation: the Montreal Heart Institute experience. AB - BACKGROUND: Heart transplantation is no longer considered an experimental operation, but rather a standard treatment; nevertheless the context has changed substantially in recent years owing to donor shortage. The aim of this study was to review the heart transplant experience focusing on very long-term survival (>= 20 years) and to compare the initial results with the current era. METHODS: From April 1983 through April 1995, 156 consecutive patients underwent heart transplantation. Patients who survived 20 years or longer (group 1) were compared with patients who died within 20 years after surgery (group 2). To compare patient characteristics with the current era, we evaluated our recent 5-year experience (group 3; patients who underwent transplantation between 2010 and 2015), focusing on differences in terms of donor and recipient characteristics. RESULTS: Group 1 (n = 46, 30%) included younger patients (38 +/- 11 v. 48 +/- 8 yr, p = 0.001), a higher proportion of female recipients (28% v. 8%, p = 0.001) and a lower prevalence of ischemic heart disease (42% v. 65%, p = 0.001) than group 2 (n = 110, 70%). Patients in group 3 (n = 54) were older (52 +/- 12 v. 38 +/- 11 yr, p = 0.001), sicker (rate of hospital admission at transplantation 48% v. 20%, p = 0.001) and transplanted with organs from older donors (42 +/- 15 v. 29 +/- 11 yr, p = 0.001) than those in group 1. CONCLUSION: Very long-term survival ( >= 20 yr) was observed in 30% of patients transplanted during the first decade of our experience. This outcome will be difficult to duplicate in the current era considering our present population of older and sicker patients transplanted with organs from older donors. PMID- 28805189 TI - Dielectric environment and/or random disorder effects on free, charged and localized excitonic states in monolayer WS2. AB - Excitonic effects play an important role on the optoelectronic behavior of atomically thin two-dimensional (2D) crystals of the WS2 transition metal dichalcogenide. In this paper, neutral and charged exciton behaviors in monolayer WS2 are handled within effective-mass approximation for which the critical parameters are ensured from our ab initio calculations. Firstly, we reveal an exciton series with a novel energy dependence on the orbital angular momentum. Considerable control of the dielectric environment on neutral and charged excitons binding energies is elucidated. We demonstrate that for accepted values of effective masses, the negative and positive trion binding energies should be identical. Secondly, localization of neutral exciton center of mass motion by random potential arising from monolayer defects is also studied. The results obtained are in agreement with available experimental work. PMID- 28805188 TI - Managing Faecal INcontinence in people with advanced dementia resident in Care Homes (FINCH) study: a realist synthesis of the evidence. AB - BACKGROUND: Eighty per cent of care home residents in the UK are living with dementia. The prevalence of faecal incontinence (FI) in care homes is estimated to range from 30% to 50%. There is limited evidence of what is effective in the reduction and management of FI in care homes. OBJECTIVE: To provide a theory driven explanation of the effectiveness of programmes that aim to improve FI in people with advanced dementia in care homes. DESIGN: A realist synthesis. This was an iterative approach that involved scoping of the literature and consultation with five stakeholder groups, a systematic search and analysis of published and unpublished evidence, and a validation of programme theories with relevant stakeholders. DATA SOURCES: The databases searched included PubMed, Cumulative Index to Nursing and Allied Health Literature, The Cochrane Library, Scopus, SocAbs, Applied Social Sciences Index and Abstracts, BiblioMap, Sirius, OpenGrey, Social Care Online and the National Research Register. RESULTS: The scoping identified six programme theories with related context-mechanism-outcome configurations for testing. These addressed (1) clinician-led support, assessment and review, (2) the contribution of teaching and support for care home staff on how to reduce and manage FI, (3) the causes and prevention of constipation, (4) how the cognitive and physical capacity of the resident affect outcomes, (5) how the potential for recovery, reduction and management of FI is understood by those involved and (6) how the care of people living with dementia and FI is integral to the work patterns of the care home and its staff. Data extraction was completed on 62 core papers with iterative searches of linked literature. Dementia was a known risk factor for FI, but its affect on the uptake of different interventions and the dementia-specific continence and toileting skills staff required was not addressed. Most care home residents with FI will be doubly incontinent and, therefore, there is limited value in focusing solely on FI or on single causes of FI such as constipation. Clinical assessment, knowledge of the causes of FI and strategies that recognise the individuals' preferences are necessary contextual factors. Valuing the intimate and personal care work that care home staff provide to people living with dementia and addressing the dementia-related challenges when providing continence care within the daily work routines are key to helping to reduce and manage FI in this population. LIMITATIONS: The synthesis was constrained by limited evidence specific to FI and people with dementia in care homes and by the lack of dementia-specific evidence on continence aids. CONCLUSIONS: This realist synthesis provides a theory-driven understanding of the conditions under which improvement in care for care home residents living with dementia and FI is likely to be successful. FUTURE WORK: Future multicomponent interventions need to take account of how the presence of dementia affects the behaviours and choices of those delivering and receiving continence care within a care home environment. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014009902. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 28805190 TI - Driving force of the orbital-relevant electronic nematicity in Fe-based superconductors. AB - The electronic nematic responses in Fe-based superconductors have been observed ubiquitously in various experimental probes. One novel nematic character is the d wave bond orbital-relevant nematic charge order which was firstly proposed by symmetry analysis and then conformed by angle-resolved photoemission spectroscopy. In this paper, we present a mechanism that the driving force of the orbital-relevant nematic charge order is the reduction of the large Hubbard energy in the particle-hole charge channel by virtual hopping processes. This is one scenario from strong-coupling consideration. The same virtual hopping processes can lead to a super-exchange interaction for the spin magnetic order in the particle-hole spin channel and a pairing interaction for the superconducting order in the particle-particle channel. Thus the electronic nematic order, the spin magnetic order and the pairing superconducting order are intrinsically entangled and they can all stem from the same microscopic virtual hopping processes in reduction of the Hubbard energy. The electronic nematicity, the spin magnetism and the pairing superconductivity in unconventional superconductors are proposed to be unified within this mechanism. PMID- 28805191 TI - Presenting a new kinetic model for methanol to light olefins reactions over a hierarchical SAPO-34 catalyst using the Langmuir-Hinshelwood-Hougen-Watson mechanism. AB - In this study, a new kinetic model for methanol to light olefins (MTO) reactions over a hierarchical SAPO-34 catalyst using the Langmuir-Hinshelwood-Hougen-Watson (LHHW) mechanism was presented and the kinetic parameters was obtained using a genetic algorithm (GA) and genetic programming (GP). Several kinetic models for the MTO reactions have been presented. However, due to the complexity of the reactions, most reactions are considered lumped and elementary, which cannot be deemed a completely accurate kinetic model of the process. Therefore, in this study, the LHHW mechanism is presented as kinetic models of MTO reactions. Because of the non-linearity of the kinetic models and existence of many local optimal points, evolutionary algorithms (GA and GP) are used in this study to estimate the kinetic parameters in the rate equations. Via the simultaneous connection of the code related to modelling the reactor and the GA and GP codes in the MATLAB R2013a software, optimization of the kinetic models parameters was performed such that the least difference between the results from the kinetic models and experiential results was obtained and the best kinetic parameters of MTO process reactions were achieved. A comparison of the results from the model with experiential results showed that the present model possesses good accuracy. PMID- 28805192 TI - Temperature dependent magnetic Compton profiles and first-principles strategies of quaternary half-Heusler alloy Co1-x Cu x MnSb(0 ? x ? 0.8). AB - Temperature dependent experimental Compton profiles of quaternary alloys Co1-x Cu x MnSb (x = 0.0, 0.2, 0.6 and 0.8) when decomposed into constituent profiles show that the sp-electron spin polarization is antiferromagnetically coupled to Mn-3d moments. The orbital magnetic moments derived from combination of magnetic Compton profiles (MCPs) and magnetization measurements are found to be small. Moreover, the first-principles full potential-linearized augmented plane wave (FP LAPW) calculations have been performed to validate the experimental investigations of spin moments and half-Heusler properties. Present experimental and theoretical work show major role of Mn atoms in building-up the absolute spin moments. Our MCP data and spin-projected density of states derived from FP-LAPW computations show an increase in sp-d interaction in conduction region on increasing the Cu concentration. Further, Ruderman-Kittel-Kasuya-Yosida-type hybridization and antiferromagnetic superexchange interactions are witnessed in the reported alloys. PMID- 28805193 TI - Optics of exciton-plasmon nanomaterials. AB - This review provides a brief introduction to the physics of coupled exciton plasmon systems, the theoretical description and experimental manifestation of such phenomena, followed by an account of the state-of-the-art methodology for the numerical simulations of such phenomena and supplemented by a number of FORTRAN codes, by which the interested reader can introduce himself/herself to the practice of such simulations. Applications to CW light scattering as well as transient response and relaxation are described. Particular attention is given to so-called strong coupling limit, where the hybrid exciton-plasmon nature of the system response is strongly expressed. While traditional descriptions of such phenomena usually rely on analysis of the electromagnetic response of inhomogeneous dielectric environments that individually support plasmon and exciton excitations, here we explore also the consequences of a more detailed description of the molecular environment in terms of its quantum density matrix (applied in a mean field approximation level). Such a description makes it possible to account for characteristics that cannot be described by the dielectric response model: the effects of dephasing on the molecular response on one hand, and nonlinear response on the other. It also highlights the still missing important ingredients in the numerical approach, in particular its limitation to a classical description of the radiation field and its reliance on a mean field description of the many-body molecular system. We end our review with an outlook to the near future, where these limitations will be addressed and new novel applications of the numerical approach will be pursued. PMID- 28805194 TI - [Lung cancer and COPD - growing clinical problem]. AB - A spread of the addiction of tobacco smoking is valued on near 1 billion of people in the world, that involves growing number of morbidity and mortality by the reason of smoke related diseases. Lung cancer and chronic obstructive pulmonary disease (COPD) are the most serious and incurable diseases which are leading to a permanent disability as well as to premature death. There are factors that naturally increase the vulnerability of an individual on the coincidence of above disorders, such as pathophysiological conditions, systemic inflammation, bronchitis, emphysema, respiratory obstructive disease and precise genetic predispositions for COPD and lung cancer. The harmful substances of the tobacco smoke are the causes of the development of diseases outside the group of respiratory disorders which affects the greater scope of comorbidity among this patient group in comparison to the normal population. The similarity of the clinical picture of lung cancer and COPD may cause numerous problems for a proper and prompt diagnosis and the implementation of the appropriate treatment. On the other hand, it is evident that the patients with COPD are carefully examined and often diagnosed with cancer while those who already suffer from cancer and undertake additional function testing are in 40-50% diagnosed with COPD. The coexistance of these two diseases influences the therapeutic procedure: COPD limits the possibilities of a radical lung cancer treatment which is determined by the general health condition and the respiratory system insufficiency as far as COPD patients are concerned. The knowledge of common pathogenesis both of cancer and COPD and the mutual relations between them shall positively affect the diagnostic and therapeutic process in the high-risk patient groups. PMID- 28805195 TI - [The plasma levels and diagnostic utility of matrix metalloproteinase-9 and CA 125 in cervical cancer patients]. AB - : Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes, involved in the degradation of extracellular matrix components. The physiological function of MMP-9 is associated with regulation of immune processes, embryogenesis, reproduction and wound healing. MMP-9 also plays a critical role in tumor invasion, degrading the basement membrane, what is observed in different types of cancers: breast, gastrointestinal, and gynecological. AIM: The aim of this study was to investigate the plasma levels and diagnostic utility of MMP-9 and CA 125 in cervical cancer patients. MATERIALS AND METHODS: The study included 72 patients with cervical cancer and 24 healthy women. Plasma levels of the MMP- 9 was determined by enzyme-linked immunosorbent assay (ELISA) and CA 15-3 - by chemiluminescent microparticle immunoassay (CMIA). RESULTS: This studies have shown increase levels of MMP-9 and CA 125 in cervical cancer patients compared to health control group. In addition, the MMP-9 concentration increased with the clinical stage of tumor. The sensitivity and specificity of MMP-9, positive and negative predictive value, were higher or equal than CA 125, but this parameter can not be used as a single marker. Our studies of MMP-9 have shown a high utility to the exclusion of cancer, similarly to CA 125. The combined analysis of MMP-9 and CA 125 significantly increased the ability to diagnose a cervical cancer and the possibility exclusion of cancer. CONCLUSIONS: MMP-9 has shown the usefulness in the diagnosis of cervical cancer, but only in the combined analysis with CA 125, as a new diagnostic panel. PMID- 28805196 TI - [The evaluation of color vision and its diagnostic value in predicting the risk of diabetic retinopathy in patients with glucose metabolism disorders]. AB - AIM: The aim of the study was to evaluate color vision and its diagnostic value in predicting the risk of diabetic retinopathy in patients with glucose metabolism disorders. MATERIALS AND METHODS: The study involved 197 people, 92 women and 105 men aged 63.21 +/- 8.74 years. In order to assess glucose metabolism disorders, patients were divided into three groups. The first group (DM) consisted of 60 people (16 women and 44 men aged 61.92 +/- 8.46 years). These were people with type 2 diabetes. Second group (IFG IGT) consisted of 67 people (35 women and 32 men aged 65 +/- 8.5 years). These were people who were diagnosed with impaired fasting glucose or impaired glucose tolerance. The third group, the control one (K) consisted of 70 people (41 women and 29 men aged 62.6 +/- 9.06 years). They were healthy individuals. In order to assess diabetic retinopathy study population was divided into two groups. The first group (BZ) consisted of 177 patients (84 women and 93 men aged 62.9 +/- 8.78 years) without diabetic retinopathy. The second group (NPDR) consisted of 20 patients (8 women and 12 men aged 65.95 +/- 8.17 years) with diabetic retinopathy. Glucose metabolism disorders were diagnosed with glucose tolerance test (OGTT). Evaluation of retinopathy was based on eye examination. All patients underwent binocular Farnsworth-Munsell 100 Hue color vision test (test result is a Total Error Score - TES). RESULTS: In the healthy control group (K) there were less patients with diabetic retinopathy (p = 0,0101), and less patients with abnormal color vision test (p = 0,0001) than in other groups. Majority of patients in K group had generalized abnormalities of color vision while other groups demonstrated tritanomalia (p = 0,0018). It was discovered that sTES value adequately distinguishes group K from group IFG, IGT, DM (AUC = 0,673), group K from group DM (AUC = 0,701), and group K from group IFG IGT (AUC = 0,648) sTES does not differentiate groups IGT, IFG and DM (AUC = 0,563). It was shown that in IGT, IFG group sTES was an independent risk factor that increased the risk of prediabetes almost six times (OR 5,924, 95% CI [1,169- 30,036], p = 0,032). In DM group sTES was an independent risk factor, which increased the risk of diabetes more than thirteen times (OR 13,408, 95% CI [2,324-77,345], p = 0,004). Higher values of sTES occurred in patients with retinopathy (NPDR) (p <0,001) and multivariate analyzes demonstrated that sTES >=1.04 was an independent risk factor that increased the risk of retinopathy over twenty times (OR 21,380, 95% CI [1,101 -89,241], p <0,001). CONCLUSIONS: sTES is an independent risk factor for glucose metabolism disorders that increases the risk of prediabetes almost six times and the risk of diabetes more than thirteen times. sTES >=1,04 is an independent risk factor for diabetic retinopathy. sTES >=1,04 increases the risk of diabetic retinopathy over twenty times. The color vision 100 Hue test can be useful in detecting glucose metabolism disorders even before the ophthalmoscopic manifestation of retinopathy. Early detection rises the possibility to prevent or delay the development of diabetes through lifestyle changes and implementation of healthy behaviors. PMID- 28805197 TI - Family of a person suffering from schizophrenia in the context of a qualitative approach to understanding the family as a system. AB - : Qualitative analysis of the family system including a person suffering from schizophrenia is an underestimated research paradigm in modern psychiatry, clinical psychology and psychotherapy. This method is important both from the cognitive point of view and for evaluation of the effectiveness of therapy. AIM: The aim of the study was a qualitative analysis of the therapeutic process in a family whose member is suffering from schizophrenic psychosis. MATERIALS AND METHODS: The study of the process using qualitative research methodology in the paradigm of systemic thinking pointing to the mutual interactions in the family system inducing relapses in the identified patient, with identification of triangulation processes, transgenerational myths inheritance and coalitions formed by the family members. RESULTS: The course of a therapeutic process of the family consisting of a parental couple and an adult daughter who was a patient with schizophrenia was investigated. Relapses of the daughter's disease occurred at the time of over-controlling attitude of the mother. Excessive control was associated with the daughter's immediate cut off from the family, discontinuation of medication, and a relapse. The relapse meant a repeated attempt of the mother to take control over the daughter's medication. CONCLUSIONS: The analyzed family is genetically predisposed to the development of schizophrenic psychosis. Schizophrenia in the daughter is likely to have a neurodevelopmental background - it has developed as a result of the interaction of biological factors (genetic predisposition) and factors that interfered with the intrauterine development of the fetus. The burden of mental disorder is inherited transgenerationally in the analyzed family. Excessive anxiety of the mother, exaggerated emotional expression, and attempts to control the treatment lead to relapses of the daughter's disease. Recurrences are a circular process induced by the mother's attitude. PMID- 28805198 TI - Severe reversible hypocalcemic cardiomyopathy diagnosed 36 years after subtotal thyroidectomy - a case report. AB - : Chronic hypocalcemia, irrespectively of its etiology, can lead to severe impairment of the left ventricular (LV) contractility manifesting as dilated cardiomyopathy, usually defined as hypocalcemic cardiomyopathy (hypocaCM). This rarely diagnosed type of heart failure (HF), can be completely reversible, when treated properly with calcium and vitamin D supplementation or, in some subjects, with human recombinant parathormone. A CASE REPORT: The authors present a case of a 60-year-old male admitted with advanced pulmonary congestion, recurrent pulmonary edema and pleural effusion. He was refractory to standard HF therapy. One year earlier, the patient was diagnosed with primary dilated cardiomyopathy with ejection fraction decreased to 25% and after coronary angiography, which revealed normal coronary arteries, he received implantable cardioverter defibrillator (ICD). However, 36 years before, the patient underwent subtotal thyroidectomy, and at the moment presented with multiplicitous symptoms suggestive of profound hypocalcemia. Laboratory investigations confirmed hypocalcemia due to iatrogenic hypoparathyroidism. Improvement of LV function during supplementation with calcium and vitamin D was monitored by echocardiography using two-dimensional longitudinal strain. One should always consider reversible causes of HF, including hypocalcemia, especially when obvious consequences of chronic hypocalcemia as myopathy, depression or cataract are seen. Correct therapy can restore LV function and prevent unnecessary implantation of ICD. PMID- 28805199 TI - [The case of an adult man with savant syndrome in the course of autism spectrum disorder]. AB - The paper reports on a case of 57-year man with autism spectrum disorder and epilepsy with an unusual feature of calendar calculation. Namely, this is the case of savant syndrome, which appears rarely in the course of various neuropsychiatric disorders. Commorbidity of epilepsy and autism particularly predispose to the aforementioned syndrome. In the presented case, apart from the calendar calculation, the man has high language abilities. As previous studies suggest, the extraordinary abilities among persons with savant syndrome works similarly to the language module in healthy persons. Savant syndrome may appear in any patient with neuropsychiatric disorders, particularly in those suffering from autism spectrum disorder with comorbid epilepsy. PMID- 28805200 TI - [Functional gastrointestinal disorders in neonate and toddler. The Rome IV criteria]. AB - Functional disorders of the gastrointestinal tract in infants and children are very frequent. To the most common belong: infant colic, regurgitation and functional constipation. In the year 2016 modified IV Rome criteria of functional gastrointestinal disorders were published. In the current work the authors discuss diagnostic criteria and therapy in regurgitation, rumination syndrome in infants, cyclic vomiting syndrome, infant colic, infant dyschezia and functional constipation in children younger than four years. PMID- 28805201 TI - [Osteoporosis and vascular calcification in rheumatoid arthritis - the role of osteoprotegerin and sclerostin]. AB - Disorders of bone tissue metabolism and increased frequency of cardiovascular diseases are among the well-known, extra-articular complications of rheumatoid arthritis (ra). The mechanisms leading to local and generalized loss of bone tissue as well as those promoting calcification of vessels are similar. Recently, a great interest has aroused among the studies related to the meaning of the RANKL/RANK/OPG system and the Wnt/beta-catenin signaling pathway, as biological links between the bone and vascular systems. In the course of ra, lowering of the mineral density of bones and intensification of vascular calcification seem to be associated with the increase of plasma concentration of osteoprotegerin (OPG) and sclerostin - the regulatory proteins of the RANKL/RANK/OPG system and the Wnt/beta-catenin pathway. Molecular mechanisms associated with the osteoblasts' activation and repression of bone resorption in the future can become the target of a precise, combination therapy in osteoporosis and calcification changes. The article presents the role of the RANKL/RANK/ OPG system and the Wnt/beta-catenin pathway in the pathogenesis of disorders of bone tissue metabolism and calcification of vessels in ra, with particular emphasis on the role of OPG and sclerostin. PMID- 28805202 TI - Erratum: High-throughput quantitation of inorganic nanoparticle biodistribution at the single-cell level using mass cytometry. AB - This corrects the article DOI: 10.1038/ncomms14069. PMID- 28805203 TI - Corrigendum: Photothermally triggered actuation of hybrid materials as a new platform for in vitro cell manipulation. AB - This corrects the article DOI: 10.1038/ncomms14700. PMID- 28805204 TI - Corrigendum: Stereocilia-staircase spacing is influenced by myosin III motors and their cargos espin-1 and espin-like. AB - This corrects the article DOI: 10.1038/ncomms10833. PMID- 28805205 TI - Erratum: Molecular preservation of 1.88 Ga Gunflint organic microfossils as a function of temperature and mineralogy. AB - This corrects the article DOI: 10.1038/ncomms11977. PMID- 28805206 TI - Corrigendum: Protective effects of ginsenoside Rg1 on intestinal ischemia/reperfusion injury-induced oxidative stress and apoptosis via activation of the Wnt/beta-catenin pathway. PMID- 28805207 TI - Periodontal diseases. AB - Periodontal diseases comprise a wide range of inflammatory conditions that affect the supporting structures of the teeth (the gingiva, bone and periodontal ligament), which could lead to tooth loss and contribute to systemic inflammation. Chronic periodontitis predominantly affects adults, but aggressive periodontitis may occasionally occur in children. Periodontal disease initiation and propagation is through a dysbiosis of the commensal oral microbiota (dental plaque), which then interacts with the immune defences of the host, leading to inflammation and disease. This pathophysiological situation persists through bouts of activity and quiescence, until the affected tooth is extracted or the microbial biofilm is therapeutically removed and the inflammation subsides. The severity of the periodontal disease depends on environmental and host risk factors, both modifiable (for example, smoking) and non-modifiable (for example, genetic susceptibility). Prevention is achieved with daily self-performed oral hygiene and professional removal of the microbial biofilm on a quarterly or bi annual basis. New treatment modalities that are actively explored include antimicrobial therapy, host modulation therapy, laser therapy and tissue engineering for tissue repair and regeneration. PMID- 28805209 TI - Neuropeptide S Induces Acute Anxiolysis by Phospholipase C-Dependent Signaling within the Medial Amygdala. AB - Neuropeptide S (NPS) is an important anxiolytic substance of the brain. However, the signaling pathways downstream of NPS receptor (NPSR) activation, underlying the behavioral effect of NPS, remain largely unknown. Here, we show that bilateral microinfusion of NPS (0.2 nmol/0.5 MUl) into the medial amygdala (MeA) of male adult Wistar rats reduced anxiety-related behavior on both the elevated plus-maze and the open field. Moreover, as shown in amygdala tissue micropunches intracerebroventricular infusion of NPS (1 nmol/5 MUl) (1) evoked phosphorylation and synthesis of CaMKIIalpha in relation to reference protein beta-tubulin representing Ca2+ influx, and (2) induced phosphorylation of mitogen-activated protein kinase ERK1/2. The NPS-induced anxiolysis was prevented by local inhibition of phospholipase C signaling using U73122 (0.5 nmol/0.5 MUl) in the MeA, indicating the behavioral relevance of this pathway. Conversely, local pharmacological blockade of adenylyl cyclase signaling using 2',5' dideoxyadenosine (12.5 nmol/0.5 MUl) failed to inhibit the anxiolytic effect of NPS infused into the MeA. Hence, NPS promotes acute anxiolysis within the MeA dependent on NPSR-mediated phospholipase C signaling. Taken together, our study extends the knowledge about the intracellular signaling mechanisms underlying the potent anxiolytic profile of NPS. PMID- 28805210 TI - Corrigendum: Contribution of classical end-joining to PTEN inactivation in p53 mediated glioblastoma formation and drug-resistant survival. AB - This corrects the article DOI: 10.1038/ncomms14013. PMID- 28805212 TI - Heterogeneous interface adsorption of colloidal particles. AB - The heterogeneous adsorption behaviors of charged colloidal particles to oil water interfaces were quantitatively and statistically investigated. Using optical laser tweezers, the particles in a sessile water drop formed in an oil phase were laterally translated toward the slope of the oil-water interface and their attachment to the interface was attempted. The adsorption probability was found to logarithmically decrease as the ionic strength decreased and to depend on the holding time during which an optically trapped particle was held at the position closest to the interface. Non-unity of the adsorption probability at particular salt concentrations and the holding time dependence offer an important clue that the particle adsorption to the interface is not deterministic but stochastic. The stochastic adsorption process can be attributed to the surface heterogeneity of colloidal particles that consequently leads to changes in the electrostatic interactions between the particles and the interface. We also demonstrated that the salt dependence on the adsorption properties of the particles, as measured by optical laser tweezers, was consistent with their bulk behaviors with regard to the stability of particle-stabilized emulsions. Furthermore, we revealed the gravity-induced spontaneous adsorption of the particles to the interface under conditions of sufficiently strong ionic strength. PMID- 28805213 TI - Oxalate-assisted formation of uniform carbon-confined SnO2 nanotubes with enhanced lithium storage. AB - SnO2 nanotubes are synthesized via an oxalate-assisted "redox etching and precipitating" route between MnOOH nanowires and Sn2+ ions. The addition of oxalate is found to be crucial to guide the formation of uniform SnO2 nanotubes. To further improve the conductivity and stability, the as-obtained SnO2 nanotubes are coated with a thin carbon layer. The resulting carbon-confined SnO2 nanotubes possess superior rate performance as an anode material for lithium-ion batteries. PMID- 28805211 TI - All-atom MD indicates ion-dependent behavior of therapeutic DNA polymer. AB - Understanding the efficacy of and creating delivery mechanisms for therapeutic nucleic acids requires understanding structural and kinetic properties which allow these polymers to promote the death of cancerous cells. One molecule of interest is a 10 mer of FdUMP (5-fluoro-2'-deoxyuridine-5'-O-monophosphate) - also called F10. Here we investigate the structural and kinetic behavior of F10 in intracellular and extracellular solvent conditions along with non-biological conditions that may be efficacious in in vitro preparations of F10 delivery systems. From our all-atom molecular dynamics simulations totaling 80 microseconds, we predict that F10's phosphate groups form close-range interactions with calcium and zinc ions, with calcium having the highest affinity of the five ions investigated. We also predict that F10's interactions with magnesium, potassium and sodium are almost exclusively long-range interactions. In terms of intramolecular interactions, we find that F10 is least structured (in terms of hydrogen bonds among bases) in the 150 mM NaCl (extracellular-like solvent conditions) and most structured in 150 mM ZnCl2. Kinetically, we see that F10 is unstable in the presence of magnesium, sodium or potassium, finding stable kinetic traps in the presence of calcium or zinc. PMID- 28805214 TI - The low populated folding intermediate of a mutant of the Fyn SH3 domain identified by a simple model. AB - Experimental studies indicate that the A39V/N53P/V55L Fyn SH3 domain folds from the unfolded state to the native state via a low-populated on-pathway intermediate, whereas the folding of the wildtype is two-state-like. To get insights into the biophysical basis of their different folding mechanisms, we used native-centric models with and without additional transferrable, sequence dependent nonnative hydrophobic interactions to study the folding behaviors of the Fyn SH3 domain and its mutant. The pure native-centric model predicts that both the wildtype and the mutant fold in a two-state manner, without any detectable intermediate. However, in the simulated trajectories based on the model with sequence-dependent nonnative hydrophobic interactions, a low populated on-pathway intermediate was identified for the mutant, but not for the wild type, although it is not sufficient to induce chevron rollover. In the modelling intermediate, the topology of strands beta1 to beta4 followed by the helix turn is native-like, while strand beta5 is mostly unstructured, which is in good agreement with experiments. Meanwhile, the nonnative contacts in the intermediate overlapped largely with those identified experimentally. Further investigation implies that different folding mechanisms between the wildtype and the mutant might arise from the distinction of the nonnative contact patterns at the transition states. In addition, we predicted that nonnative interactions led to deceleration or acceleration of the folding largely depending on whether they could destabilize or stabilize the transition state relative to the unfolded state. This study implies that the simple native-centric model augmented by sequence-dependent nonnative hydrophobic interactions should be useful in general to predict the folding of proteins with a low-populated intermediate. PMID- 28805215 TI - The influence of a thermoresponsive polymer on the microdynamic phase transition mechanisms of distinctly structured thermoresponsive ionic liquids. AB - The study of a ternary solution involving a thermoresponsive polymer, a thermoresponsive ionic liquid (IL), and a solvent will not only help with interpreting their distinct phase transition behavior, but also promote the development of novel thermoresponsive systems. In this paper, we investigate the influence of a conventional thermoresponsive polymer, poly(2-isopropyl-2 oxazoline) (PIPOZ), on the phase transition behavior of two thermoresponsive ILs ([P4,4,4,6][MC3S], [P4,4,4,4][SS]) with different structures. Although the addition of PIPOZ reduces the transition temperatures of both ILs, our analyses demonstrate that there exists a large difference in the microdynamic phase transition mechanisms between [P4,4,4,6][MC3S]/PIPOZ and [P4,4,4,4][SS]/PIPOZ aqueous solutions. Both PIPOZ and [P4,4,4,6][MC3S] experience unexpectedly an unusual over-hydration process before a two-step phase transition of the mixture solution, which can be explained by the presence of a new kind of intermolecular bridging hydrogen bond (IL-water-polymer), whereas only PIPOZ undergoes dehydration around the transition temperature of the [P4,4,4,4][SS]/PIPOZ aqueous solution. Further spectral analyses reveal that both [P4,4,4,6][MC3S] and PIPOZ engage in the phase separation of the ternary solution jointly, whereas PIPOZ takes part in the phase transition of [P4,4,4,4][SS]/PIPOZ solution more independently. PMID- 28805216 TI - Anthracene-arylamine hole transporting materials for perovskite solar cells. AB - Two arylamine-based hole transporting materials with an anthracene pi-linker have been synthesized and tested for perovskite solar cells. Improved power conversion efficiency and stability were achieved by employing A102 compared with that of spiro-OMeTAD. PMID- 28805217 TI - Mixed emulsion of liquid crystal microresonators: towards white laser systems. AB - Microdroplet systems have attracted great interest because of their wide range of applications, easiness in processing and handling, feasibility in developing miniaturized devices with high performances and large flexibility. In this study, a stable emulsion based on different dye-doped chiral liquid crystal droplets has been engineered in order to achieve simultaneous omnidirectional lasing at different wavelengths. To obtain the mixed emulsion of dye doped Bragg onion-type microresonators the twofold action, as a surfactant and a droplet stabilizer, of the polyvinyl alcohol dissolved in water has been exploited. Multiple wavelengths lasing in all directions around the mixed emulsion is demonstrated. By water evaporation, a plastic sheet including different types of chiral droplets is also obtained, retaining all the emission characteristic of the precursor emulsion. A relevant feature is the large flexibility of the preparation method that enables an easy and full control of the lasing spectrum addressing white laser systems. However, the simplicity of the procedure based on a single-step process as well as the high stability of the mixed emulsion is a relevant result, envisaging strong potentiality for developing easy and friendly technologies useful in the field of identification, sensing, imaging, coating and lab-on-a-chip architectures. PMID- 28805218 TI - Electrochemical (de)lithiation of silver ferrite and composites: mechanistic insights from ex situ, in situ, and operando X-ray techniques. AB - The structure of pristine AgFeO2 and phase makeup of Ag0.2FeO1.6 (a one-pot composite comprised of nanocrystalline stoichiometric AgFeO2 and amorphous gamma Fe2O3 phases) was investigated using synchrotron X-ray diffraction. A new stacking-fault model was proposed for AgFeO2 powder synthesized using the co precipitation method. The lithiation/de-lithiation mechanisms of silver ferrite, AgFeO2 and Ag0.2FeO1.6 were investigated using ex situ, in situ, and operando characterization techniques. An amorphous gamma-Fe2O3 component in the Ag0.2FeO1.6 sample is quantified. Operando XRD of electrochemically reduced AgFeO2 and Ag0.2FeO1.6 composites demonstrated differences in the structural evolution of the nanocrystalline AgFeO2 component. As complimentary techniques to XRD, ex situ X-ray Absorption Spectroscopy (XAS) provided insight into the short range structure of the (de)lithiated nanocrystalline electrodes, and a novel in situ high energy X-ray fluorescence nanoprobe (HXN) mapping measurement was applied to spatially resolve the progression of discharge. Based on the results, a redox mechanism is proposed where the full reduction of Ag+ to Ag0 and partial reduction of Fe3+ to Fe2+ occur on reduction to 1.0 V, resulting in a Li1+yFeIIIFeIIyO2 phase. The Li1+yFeIIIFeIIyO2 phase can then reversibly cycle between Fe3+ and Fe2+ oxidation states, permitting good capacity retention over 50 cycles. In the Ag0.2FeO1.6 composite, a substantial amorphous gamma-Fe2O3 component is observed which discharges to rock salt LiFe2O3 and Fe0 metal phase in the 3.5-1.0 V voltage range (in parallel with the AgFeO2 mechanism), and reversibly reoxidizes to a nanocrystalline iron oxide phase. PMID- 28805219 TI - Facile synthesis of sponge-like Ni3N/NC for electrocatalytic water oxidation. AB - Sponge-like Ni3N/NC was prepared through a facile approach and was examined as a catalyst for the oxygen evolution reaction (OER). This material can efficiently catalyze water oxidation to reach a current density of 10 mA cm-2 with a small overpotential of 310 mV in 1.0 M KOH aqueous solution. The high efficiency can be attributed to the good electronic conductivity, large specific surface area and fast mass diffusion ability of Ni3N/NC. PMID- 28805220 TI - Revival of the nearly extinct fluorescence of coumarin 6 in water and complete transfer of energy to rhodamine 123. AB - The nearly extinct fluorescence of coumarin 6 in water due to microcrystal formation is revived by micelles. Practically complete transfer of energy from coumarin 6 to rhodamine 123 through resonance energy transfer could be achieved. PMID- 28805221 TI - A simplified ab initio treatment of diradicaloid structures produced from stretching and breaking chemical bonds. AB - The present investigation reports on the prospect of using state specific multireference perturbation theory (SSMRPT) with an improved virtual orbital complete active space configuration interaction (IVO-CASCI) reference function (IVO-SSMRPT) to generate potential energy surfaces (PESs) for molecular systems [such as CH4, C2H6, C2H4, H2O2, LiH, and KN] by stretching and breaking of suitable bonds with modest basis sets. We have also revisited the dissociation energy profile of triplet ketene which exhibits a step-like structure in the observed rate. The application of the method has also been made to the ionization energies of H2O. Although the perturbative corrections are obtained by the diagonalization of the effective Hamiltonian, in IVO-SSMRPT, only one physically relevant solution is achievable. It is parameter free and does not require any threshold to avoid the intruder problem. It is strictly size-extensive and size consistent provided that local orbitals are used. The PESs obtained with our approach are smooth all along the reaction path. Our estimates are in close agreement with the available reference data indicating that IVO-SSMRPT is a robust paradigm for the accurate computation of ground, excited and ionized states as it captures the mutual inter-play of different flavors of correlation effects in a balanced and accurate way. PMID- 28805222 TI - Heme isomers substantially affect heme's electronic structure and function. AB - Inspection of heme protein structures in the protein data bank reveals four isomers of heme characterized by different relative orientations of the vinyl side chains; remarkably, all these have been reported in multiple protein structures. Density functional theory computations explain this as due to similar energy of the isomers but with a sizable (25 kJ mol-1) barrier to interconversion arising from restricted rotation around the conjugated bonds. The four isomers, EE, EZ, ZE, and ZZ, were then investigated as 4-coordinate hemes, as 5-coordinate deoxyhemes, in 6-coordinate O2-adducts of globins and as compound I intermediates typical of heme peroxidases. Substantial differences were observed in electronic properties relevant to heme function: notably, the spin state energy gap of O2 heme adducts, important for fast reversible binding of O2, depends on the isomer state, and O2-binding enthalpies change by up to 16 kJ mol-1; redox potentials change by up to 0.2 V depending on the isomer, and the doublet-quartet energy splitting of compound I, central to "two-state" reactivity, is affected by up to ~15 kJ mol-1. These effects are consistently seen with three distinct density functionals, i.e. the effects are not method-dependent. Thus, the nature of the isomer state is an important but overlooked feature of heme chemistry and function, and previous and future studies of hemes may be reconsidered in this new context. PMID- 28805223 TI - The effect of defects on the catalytic activity of single Au atom supported carbon nanotubes and reaction mechanism for CO oxidation. AB - The mechanism of CO oxidation by O2 on a single Au atom supported on pristine, mono atom vacancy (m), di atom vacancy (di) and the Stone Wales defect (SW) on single walled carbon nanotube (SWCNT) surface is systematically investigated theoretically using density functional theory. We determine that single Au atoms can be trapped effectively by the defects on SWCNTs. The defects on SWCNTs can enhance both the binding strength and catalytic activity of the supported single Au atom. Fundamental aspects such as adsorption energy and charge transfer are elucidated to analyze the adsorption properties of CO and O2 and co-adsorption of CO and O2 molecules. It is found that CO binds stronger than O2 on Au supported SWCNT. We clearly demonstrate that the defected SWCNT surface promotes electron transfer from the supported single Au atom to O2 molecules. On the other hand, this effect is weaker for pristine SWCNTs. It is observed that the high density of spin-polarized states are localized in the region of the Fermi level due to the strong interactions between Au (5d orbital) and the adjacent carbon (2p orbital) atoms, which influence the catalytic performance. In addition, we elucidate both the Langmuir-Hinshelwood (LH) and Eley-Rideal (ER) mechanisms of CO oxidation by O2. For the LH pathway, the barriers of the rate-limiting step are calculated to be 0.02 eV and 0.05 eV for Au/m-SWCNT and Au/di-SWCNT, respectively. To regenerate the active sites, an ER-like reaction occurs to form a second CO2 molecule. The ER pathway is observed on Au/m-SWCNT, Au/SW-SWCNT and Au/SWCNT in which the Au/m-SWCNT has a smaller barrier. The comparison with a previous study (Lu et al., J. Phys. Chem. C, 2009, 113, 20156-20160.) indicates that the curvature effect of SWCNTs is important for the catalytic property of the supported single Au. Overall, Au/m-SWCNT is identified as the most active catalyst for CO oxidation compared to pristine SWCNT, SW-SWCNT and di-SWCNT. Our findings give a clear description on the relationship between the defects in the support and the catalytic properties of Au and open a new avenue to develop carbon nanomaterial-based single atom catalysts for application in environmental and energy related fields. PMID- 28805224 TI - Molecular dynamics-based strength estimates of beta solenoid proteins. AB - The use of beta solenoid proteins as functionalizable, nanoscale, self-assembling molecular building blocks may have many applications, including templating the growth of wires or higher-dimensional structures. By understanding their mechanical strengths, we can efficiently design the proteins for specific functions. We present a study of the mechanical properties of seven beta solenoid proteins using GROMACS molecular dynamics software to produce force/torque displacement data, implement umbrella sampling of bending/twisting trajectories, produce Potentials of Mean Force (PMFs), extract effective spring constants, and calculate rigidities for two bending and two twisting directions for each protein. We examine the differences between computing the strength values from force/torque-displacement data alone and PMF data, and show how higher precision estimates can be obtained from the former. In addition to the analysis of the methods, we report estimates for the bend/twist persistence lengths for each protein, which range from 0.5-3.4 MUm. We note that beta solenoid proteins with internal disulfide bridges do not enjoy enhanced bending or twisting strength, and that the strongest correlate with bend/twist rigidity is the number of hydrogen bonds per turn. In addition, we compute estimates of the Young's modulus (Y) for each protein, which range from Y = 3.5 to 7.2 GPa. PMID- 28805225 TI - Cooperative, ion-sensitive co-assembly of tripeptide hydrogels. AB - Peptide co-assembly is of interest for the development of functional supramolecular biomaterials. Herein, computational simulations were combined with experimental validation to aid the design and understanding of cooperative co assembly of a structure-forming tripeptide (FFD) and a functional copper-binding tripeptide (GHK) leading to hydrogel formation in response to complexation with copper ions. PMID- 28805226 TI - The reaction of Criegee intermediate CH2OO with water dimer: primary products and atmospheric impact. AB - The rapid reaction of the smallest Criegee intermediate, CH2OO, with water dimers is the dominant removal mechanism for CH2OO in the Earth's atmosphere, but its products are not well understood. This reaction was recently suggested as a significant source of the most abundant tropospheric organic acid, formic acid (HCOOH), which is consistently underpredicted by atmospheric models. However, using time-resolved measurements of reaction kinetics by UV absorption and product analysis by photoionization mass spectrometry, we show that the primary products of this reaction are formaldehyde and hydroxymethyl hydroperoxide (HMHP), with direct HCOOH yields of less than 10%. Incorporating our results into a global chemistry-transport model further reduces HCOOH levels by 10-90%, relative to previous modeling assumptions, which indicates that the reaction CH2OO + water dimer by itself cannot resolve the discrepancy between the measured and predicted HCOOH levels. PMID- 28805227 TI - Landscape of the structure-O-H bond dissociation energy relationship of oximes and hydroxylamines. AB - The relationship between the homolytic O-H bond dissociation enthalpies (BDEs) and the structures of N-oxyl radical precursors (i.e. hydroxylamines and oximes) is important to predict their reactivity. Yet several crucial facts remain hidden to complete the picture such as the substituent electronic effects on the BDEs of oximes. In this work, the O-H BDEs of 120 hydroxylamines and 120 oximes have been calculated. It was found that the majority of the iminoxyl radicals are sigma radicals, except for some pi radicals. The resonance effect dominates the electronic effects on the BDEs of oximes, and electron-donating conjugation increases the BDE. However, both the resonance and the inductive effects are important in the BDEs of hydroxylamines; meanwhile, the BDEs increase with the increase of the electron-withdrawing ability of the substituents. Besides, the DeltaBDEs of oximes and hydroxylamines with two substituents almost equal the algebraic sum of the DeltaBDEs of single substituents. In addition, dipole-dipole repulsion is responsible for the difference in the BDEs of open chain and cyclic acyl hydroxylamines. Although the ring strain affects the N-O bonding property of nitroxide radicals, it has negligible effect on the BDEs of oximes. These new rules provide a complete and precise understanding of the structure-bond energy relationship of N-oxyl radical precursors. PMID- 28805228 TI - Highly-dispersed TiO2 nanoparticles with abundant active sites induced by surfactants as a prominent substrate for SERS: charge transfer contribution. AB - In this study, highly-dispersed TiO2 nanoparticles (NPs) with abundant active sites were synthesized by a simple sol-hydrothermal method with the assistance of surfactant polyethylene glycol (PEG) which served as an effective SERS-active substrate for the first time. The observed considerable SERS enhancement of 4 mercaptobenzoic acid (4-MBA) probe molecules on TiO2 NPs is attributed to the contribution of the charge transfer mechanism from the substrate to the probe molecule. It is suggested that PEG can act as a protective agent in the reductive calcination of the surfactant-coated nanocrystallite and consequently brings about abundant surface oxygen vacancies for TiO2 NPs, which provide more effective sites for the adsorption of probe molecules and promote the charge transfer effect and its consequent SERS enhancement. Moreover, the prepared TiO2 NPs can serve as an effective substrate for highly sensitive detection of p aminobenzoic acid (PABA). The detection limit of PABA is as low as 1 * 10-8 M, which is the highest sensitivity among the reported determination methods. And, it proves that the prepared TiO2 substrate with abundant active sites is characterized by high stability, which offers a unique long service lifetime for SERS detection without losing its activity. PMID- 28805229 TI - A ground state potential energy surface for HONO based on a neural network with exponential fitting functions. AB - The minimum energy structures, i.e., trans-HONO, cis-HONO, HNO2, and OH + NO, as well as the corresponding transition states, i.e., TStrans<->cis, TS1,2H-shift, and TS1,3H-shift, on the ground state potential energy surface (PES) of HONO have been characterized at the CCSD(T)-F12/cc-pVTZ-F12 level of theory. Using the same level of theory, a six-dimensional (6D) PES, encompassing the trans- and cis isomers as well as the associated transition state, is fit in a sum-of-products form using neural network exponential fitting functions. A second PES is developed based on ab initio data from CCSD(T) computations extrapolated to the complete basis set (CBS) limit. The PES fits, based on 90 neurons, are accurate (RMSEs ~ 10 cm-1) up to 10 000 cm-1 above the energy minimum. The PESs are validated by computing vibrational energies using block improved relaxation with the multi configuration time dependent Hartree (MCTDH) approach. The vibrational frequencies obtained on the PESs are compared to available experimental measurements, previous theoretical computations based on a CCSD(T)/cc-pVQZ(-g functions) PES, and anharmonic frequencies at the MP2/aug-cc-pVTZ and CCSD(T)/aug cc-pVTZ levels of theory obtained using second-order vibrational perturbation theory. The results suggest that these are the best available PESs for HONO, and thus, should be suitable for a variety of dynamics studies, including quantum dynamics with MCTDH where the sum-of-products form can be exploited for computational efficiency. PMID- 28805230 TI - The influence of topological phase transition on the superfluid density of overdoped copper oxides. AB - We show that a quantum phase transition, generating flat bands and altering Fermi surface topology, is a primary reason for the exotic behavior of the overdoped high-temperature superconductors represented by La2-xSrxCuO4, whose superconductivity features differ from what is predicted by the classical Bardeen Cooper-Schrieffer theory. This observation can open avenues for chemical preparation of high-Tc materials. We demonstrate that (1) at temperature T = 0, the superfluid density ns turns out to be considerably smaller than the total electron density; (2) the critical temperature Tc is controlled by ns rather than by doping, and is a linear function of the ns; (3) at T > Tc the resistivity rho(T) varies linearly with temperature, rho(T) ? alphaT, where alpha diminishes with Tc -> 0, whereas in the normal (non superconducting) region induced by overdoping, Tc = 0, and rho(T) ? T2. Our results are in good agreement with recent experimental observations. PMID- 28805231 TI - The Histone Methyltransferase Mixed Lineage Leukemia (MLL) 3 May Play a Potential Role on Clinical Dilated Cardiomyopathy. AB - Histone modifications play a critical role in the pathological processes of dilated cardiomyopathy (DCM). While the role and expression pattern of histone methyltransferases (HMTs), especially mixed lineage leukemia (MLL) families on DCM are unclear. To this end, twelve normal and fifteen DCM heart samples were included in the present study. A murine cardiac remodelling model was induced by transverse aortic constriction (TAC). Real-time PCR was performed to detect the expression levels of MLL families in the mouse and human left ventricles. The mRNA level of MLL3 was significantly increased in the mouse hearts treated by TAC surgery. Compared with normal hearts, higher mRNA and protein level of MLL3 was detected in the DCM hearts, and its expression level was closely associated with left ventricular end systolic diameter (LVEDD) and left ventricular ejection fraction (LVEF). However, the expression level of other MLL families (MLL, MLL2, MLL4, MLL5, SETD1A, and SETD1B) had no obvious change between control and DCM hearts or remodeled mouse hearts. Furthermore, the di-methylated histone H3 lysine 4 (H3K4me2) but not H3K4me3 was significantly increased in the DCM hearts. The protein levels of Smad3, GATA4, EGR1, which might regulate by MLL3, were remarkably elevated in the DCM hearts. Our hitherto unrecognized findings indicate that MLL3 has a potential role on pathological processes of DCM via regulating H3K4me2 and the expression of Smad3, GATA4, and EGR1. PMID- 28805232 TI - The Protective Effect of Heme Oxygenase-1 against Intestinal Barrier Dysfunction in Cholestatic Liver Injury Is Associated with NF-kappaB Inhibition. AB - Heme oxygenase-1 (HO-1) is reported to protect against liver injury, but little is known about its effect on the intestinal barrier in cholestatic liver injury. In this study, we investigated the effects of HO-1 and its enzymatic by-product on intestinal barrier dysfunction in bile duct ligation (BDL) rats and explored the possible mechanism. The HO-1 inducer cobalt protoporphyrin (CoPP) and carbon monoxide-releasing molecule-2 (CORM-2) were used; the expression levels of tight junction (TJ) proteins, intestinal inflammation and NF-kappaB p65 were measured. For an in vitro experiment, stable Caco-2 cell lines were constructed, one overexpressed the HO-1 gene and another with that gene knocked down, and the specific NF-kappaB inhibitor JSH-23 was used. CoPP and CORM-2 treatment alleviated liver and intestinal mucosa injury in BDL rats; improved ZO-1, claudin 1 and PCNA expression; and reduced cell apoptosis and intestinal interleukin-6 (IL-6) expression. In vitro studies confirmed that HO-1, ZO-1 and occludin were overexpressed in HO-1-transfected Caco-2 cells, while decreased in the sh-HO-1 group. JSH-23 significantly increased occludin expression in both the HO-1 overexpression and sh-HO-1 groups, compared with their respective controls. HO-1 overexpression also inhibited the nuclear translocation of NF-kappaB p65 after lipopolysaccharide (LPS) treatment. Additionally, phospho-p65 expression in sh-HO 1 cells was significantly increased compared with that of the HO-1 overexpression group. In conclusion, HO-1 and CORM-2 improved intestinal epithelial barrier function in BDL-induced cholestatic liver injury mainly by restoring TJ, reducing cell apoptosis and intestinal inflammation. HO-1 exerts a protective effect, which is partially correlated with the regulation of NF-kappaB. PMID- 28805233 TI - Analytic and Dynamic Secretory Profile of Patient-Derived Cytokine-Induced Killer Cells. AB - Adoptive immunotherapy with Cytokine Induced Killer (CIK) cells has shown antitumor activity against several kinds of cancers in preclinical models and clinical trials. CIK cells are a subset of ex vivo expanded T lymphocytes with T NK phenotype and MHC-unrestricted antitumor activity. Literature provides scanty information on cytokines, chemokines and growth factors secreted by CIK cells. Therefore, we investigated the secretory profile of CIK cells generated from tumor patients. The secretome analysis was performed at specific time points (day 1, day 14 and day 21) of CIK cells expansion. Mature CIK cells (day 21) produce a great variety of interleukins and secreted proteins that can be divided into 3 groups based on their secretion quantity: high (IL-13, RANTES, MIP-1alpha and 1beta), medium (IL-1Ra, IL-5, IL-8, IL-10, IL-17, IP-10, INF-gamma, VEGF and GMCSF) and low (IL-1beta, IL-4, IL-6, IL-7, IL-9, IL-12, IL-15, Eotaxin, PDGF-bb, FGF basic, G-CSF and MCP-1) secreted. Moreover, comparing PBMC (day 1) and mature CIK cells (day 14 and 21) secretome, we observed that IL-5, IL-10, IL-13, GM-CSF, VEGF resulted greatly up-regulated, while IL-1beta, IL-6, IL-8, IL-15, IL-17, eotaxin, MCP-1, and RANTES were down-regulated. We also performed a gene expression profile analysis of patient-derived CIK cells showing that mRNA for the different cytokines and secreted proteins were modulated during PBMC to CIK differentiation. We highlighted previously unknown secretory properties and provided for the first time a comprehensive molecular characterization of CIK cells. Our findings provide rationale to explore the functional implications and possible therapeutic modulation of CIK secretome. PMID- 28805235 TI - How do Singapore patients view post-anaesthesia adverse outcomes? A single-centre willingness-to-pay study. AB - INTRODUCTION: Knowing how patients value the quality of anaesthesia helps anaesthesiologists to customise their service. However, generalising findings from Western population-based willingness-to-pay studies across different cultures and societies might result in the oversight of some contextualised perspectives of the anaesthesia experience. This study aimed to capture the Singapore perspective of undesired post-anaesthesia outcomes. METHODS: 132 patients recruited in a pre-anaesthetic evaluation clinic were given questionnaires describing ten possible post-anaesthetic outcomes. Outcomes were ranked for undesirability and assigned relative value through the hypothetical proportioning of SGD 100 to avoid their occurrence. Data was analysed with reference to patients' background and anaesthetic history. RESULTS: A response rate of 69.1% (n = 132/191) was achieved. Outcomes from the most to least undesirable were pain; vomiting; nausea; shivering; orodental trauma; sore throat; abrasions; somnolence; and thirst. Relative values allocated, in descending order, were pain; vomiting; nausea; orodental trauma; abrasions; sore throat; shivering; somnolence; and thirst. CONCLUSION: Similar to previous studies in Western populations, pain, vomiting and nausea were the top three adverse outcomes that Singapore patients wished to avoid. However, discrepancies with Western patients were seen in spending attitudes, possibly accounted for by differences in healthcare socioeconomics. This study provided a better understanding of Singapore patients' perspectives on post-anaesthesia adverse outcomes and could help to improve treatment strategy and resource management. PMID- 28805234 TI - Prognostic factors for mortality due to pneumonia among adults from different age groups in Singapore and mortality predictions based on PSI and CURB-65. AB - INTRODUCTION: Pneumonia is associated with considerable mortality. However, there is limited information on age-specific prognostic factors for death from pneumonia. METHODS: Patients hospitalised with a diagnosis of pneumonia through the emergency department were stratified into three age groups: 18-64 years, 65 84 years and >= 85 years. Multivariate logistic regression and receiver operating characteristic curve analyses were conducted to evaluate prognostic factors for mortality and the performance of pneumonia severity scoring tools for mortality prediction. RESULTS: A total of 1,902 patients were enrolled (18-64 years: 614 [32.3%]; 65-84 years: 944 [49.6%]; >= 85 years: 344 [18.1%]). Mortality rates increased with age (18-64 years: 7.3%; 65-84 years: 16.1%; >= 85 years: 29.7%; p < 0.001). Malignancy and tachycardia were prognostic of mortality among patients aged 18-64 years. Male gender, malignancy, congestive heart failure and eight other parameters reflecting acute disease severity were associated with mortality among patients aged 65-84 years. For patients aged >= 85 years, altered mental status, tachycardia, blood urea nitrogen, hypoxaemia, arterial pH and pleural effusion were significantly predictive of mortality. The Pneumonia Severity Index (PSI) was more sensitive than CURB-65 (confusion, uraemia, respiratory rate >= 30 per minute, low blood pressure, age >= 65 years) for mortality prediction across all age groups. CONCLUSION: The predictive effect of prognostic factors for mortality varied among patients with pneumonia from the different age groups. PSI performed significantly better than CURB-65 for mortality prediction, but its discriminative power decreased with advancing age. PMID- 28805237 TI - Adult Spasticity International Registry Study: methodology and baseline patient, healthcare provider, and caregiver characteristics. AB - OBJECTIVE: The main aim of this study was to determine the utilization patterns and effectiveness of onabotulinumtoxinA (Botox(r)) for treatment of spasticity in clinical practice. DESIGN: An international, multicentre, prospective, observational study at selected sites in North America, Europe, and Asia. PATIENTS: Adult patients with newly diagnosed or established focal spasticity, including those who had previously received treatment with onabotulinum-toxin A. METHODS: Patients were treated with onabotulinumtoxinA, approximately every 12 weeks, according to their physician's usual clinical practice over a period of up to 96 weeks, with a final follow-up interview at 108 weeks. Patient, physician and caregiver data were collected. RESULTS: Baseline characteristics are reported. Of the 745 patients enrolled by 75 healthcare providers from 54 sites, 474 patients had previously received onabotulinumtoxinA treatment for spasticity. Lower limb spasticity was more common than upper limb spasticity, with stroke the most common underlying aetiology. The Short-Form 12 (SF-12) health survey scores showed that patients' spasticity had a greater perceived impact on physical rather than mental aspects. CONCLUSION: The data collected in this study will guide the development of administration strategies to optimize the effectiveness of onabotulinumtoxinA in the management of spasticity of various underlying aetiologies. PMID- 28805236 TI - Comparison of intrathecal morphine and surgical-site infusion of ropivacaine as adjuncts to intravenous patient-controlled analgesia in living-donor kidney transplant recipients. AB - INTRODUCTION: This prospective observational study compared the postoperative analgesic effectiveness of intrathecal morphine (ITM) and surgical-site infusion (SSI) of ropivacaine as adjuncts to intravenous (IV) patient-controlled analgesia (PCA) (fentanyl) in living-donor kidney transplant recipients. METHODS: Patients undergoing living-donor kidney transplantation who received ITM or SSI in addition to IV PCA were included. Rescue analgesia was achieved with IV meperidine as required. The primary outcome, measured using the Numeric Pain Rating Scale (NRS), was pain at rest and when coughing. Patients were assessed for 48 hours after surgery. RESULTS: A total of 53 patients (32 ITM, 21 SSI) were included in the study. The ITM group showed significantly lower NRS scores, at rest and when coughing, for up to 12 and eight hours. NRS scores were comparable between the groups at other times. The ITM group had significantly less postoperative systemic opioid requirement in the first 24 hours, but there was no significant difference between the systemic opioid consumption of the groups on postoperative Day 2. In the ITM group, 3 (9.4%) patients presented with bradypnoea and 1 (3.1%) with excessive sedation in the first 12 postoperative hours. More patients in the ITM group developed pruritus requiring treatment during the first 24 hours. There were no differences between the groups in other outcomes (e.g. nausea/vomiting, change in pulmonary or kidney functions). CONCLUSION: Compared with SSI, ITM reduced immediate postoperative pain and IV opioid consumption on postoperative Day 1 after living-donor kidney transplantation, but at the cost of increased pruritus and respiratory depression. PMID- 28805238 TI - Ultrasound assessment of gastric contents in children undergoing elective ear, nose and throat surgery: a prospective cohort study. AB - Ultrasound examination of the gastric antrum allows reliable assessment of gastric contents and volume. Postoperative assessment of gastric contents before recovery from anaesthesia could help the physician to choose the most appropriate extubation technique after surgery in children. In this prospective observational study, we assessed whether significant changes occurred in gastric contents during the intra-operative period in children undergoing elective ear, nose and throat (ENT) surgery. Children aged between six months and 16 years were recruited consecutively. Ultrasound examination of the antrum was performed before induction of anaesthesia and at the end of surgery before tracheal extubation, and included quantitative and qualitative assessment of gastric contents. The mean (SD) gastric volume was 0.28 (0.30) ml.kg-1 before surgery and 0.27 (0.30) ml.kg-1 after surgery, p = 0.82. No solid contents were identified in the antrum, and the gastric volume was < 1.5 ml.kg-1 in all patients during both ultrasound examinations. Our results suggest that, after elective ENT surgery, children are not at risk of a full stomach before tracheal extubation, and that pulmonary aspiration of blood that may occur after elective ENT surgery is probably not related to regurgitation of ingested blood from the stomach. PMID- 28805239 TI - A comparison of gastric emptying of soluble solid meals and clear fluids matched for volume and energy content: a pilot crossover study. AB - We previously demonstrated that the gastric emptying time of different liquids with the same volume mainly depended on their energy content, regardless of differences in composition. In this crossover study, we investigated whether the same applies when soluble solid foods are ingested with water. Ten healthy volunteers ingested one of five test diets consisting of two test meals (Calorie Mate(r) 100 and 200 kcal) and three test solutions (water and glucose solutions of 100 and 200 kcal), each given in a volume of 400 ml, and then underwent ultrasonography to measure the gastric antral cross-sectional area every 10 min for 120 min. The gastric emptying time was defined as the time for the antral cross-sectional area to revert to its initial value. When test diets with the same energy content were ingested, the gastric emptying curves were nearly identical, regardless of whether the original form was solid or liquid. The median (IQR[range]) gastric emptying times of Calorie Mate(r) of 100 kcal with water vs. isocaloric glucose solution were 65 (60-78 [50-80]) vs. 65 (60-70 [50 80]) min (p = 0.58), and for Calorie Mate(r) of 200 kcal with water vs. isocaloric glucose solution they were 100 (93-108 [90-120]) vs. 105 (90-110 [90 120]) min (p = 0.54). The median (IQR [range]) for water was 40 (30-40 [30-50]) min. Energy content may be a critical determinant of the gastric emptying time when ingesting soluble solid diets with water. PMID- 28805241 TI - Treatment of notalgia paraesthetica with manipulative physiotherapy. PMID- 28805242 TI - Size matters. PMID- 28805240 TI - The Role of Social, Familial, and Individual-Level Factors on Multiple Alcohol Use Outcomes During the First Year of University. AB - BACKGROUND: The first year of university attendance represents a critical time frame for the development of alcohol use and misuse given changes in autonomy and increased access to alcohol. Prior studies have demonstrated that the establishment of drinking patterns during this period is impacted by an array of demographic, environmental, and familial factors. It is critical to consider such factors jointly, and to understand potentially differential effects on stages of alcohol use/misuse, in order to identify robust predictors that may be targeted in prevention and intervention programming. METHODS: As part of a longitudinal study, students at a large, public U.S. university were invited to complete online surveys that included questions related to alcohol use, emotional and behavioral health, environmental factors, sociodemographic factors, and familial environment. This study uses data from surveys administered in the fall and spring of the first year of university. We used univariate (maximum N = 7,291) and multivariate (maximum N = 4,788) logistic and linear regressions to evaluate the associations between potential risk and protective factors with 4 alcohol use outcomes: initiation, consumption, problems, and addiction resistance. RESULTS: In multivariate models, we observed associations between demographic, social/environmental, and personal-level predictors with all 4 alcohol outcomes, several of which were consistent across each stage of alcohol use. A deviant high school peer group was one of the strongest predictors of risk across outcomes. The influence of drinking motives and alcohol expectancies varied by alcohol use outcome. Externalizing characteristics were associated with increased risk across outcomes, while internalizing symptoms were associated with more problems and lower addiction resistance. CONCLUSIONS: These findings underscore the complex network of factors influencing stages of alcohol use during the first year of university. Importantly, these findings demonstrate that the impact of predictors changes across stages of alcohol use/misuse, which presents opportunities for targeted prevention efforts. PMID- 28805243 TI - Factors associated with acceptance of pandemic flu vaccine by healthcare professionals in Spain, 2009-2010. AB - The A(H1N1)pdm09 influenza virus reached pandemic level in Spain in 2009, prompting a national vaccination campaign. To avoid transmission to patients, healthcare professionals' vaccination against pandemic influenza is crucial. The main objective of this study was to analyze factors associated with the failure by healthcare professionals to accept the pandemic vaccination in 2009. A cross sectional survey was conducted of healthcare professionals in seven of Spain's autonomous regions. A questionnaire was used to collect information about personal and professional details, the respondents' flu vaccination status in the 2008-2009 and 2009-2010 seasons (seasonal and pandemic vaccines), and their knowledge and attitudes. A total of 1,661 professionals completed the survey. In the 2009-2010 season, 38.2% had both the seasonal and the pandemic vaccine, 22.1% had had only the seasonal, and 4.7% only the pandemic vaccine. The strongest predictor of not receiving the pandemic vaccine was not having had seasonal vaccinations in that year or the previous year. Those who had not received the pandemic vaccine were more often female; nurses; under 45; denied contact with at risk groups; and had negative beliefs about the vaccine effectiveness and little concern for getting the disease, being infected at work, or passing it on to patients. It would be prudent to direct preventive campaigns not only at individuals at risk of catching flu but also at health professionals with a negative view of flu vaccine, with a particular focus on nurses, who have a key role in recommending flu vaccine. PMID- 28805244 TI - Epigenetic barrier against the propagation of fluctuating gene expression in embryonic stem cells. AB - The expression of pluripotency genes fluctuates in a population of embryonic stem (ES) cells and the fluctuations in the expression of some pluripotency genes correlate. However, no correlation in the fluctuation of Pou5f1, Zfp42, and Nanog expression was observed in ES cells. Correlation between Pou5f1 and Zfp42 fluctuations was demonstrated in ES cells containing a knockout in the NuRD component Mbd3. ES cells containing a triple knockout in the DNA methyltransferases Dnmt1, Dnmt3a, and Dnmt3b showed correlation between the fluctuation of Pou5f1, Zfp42, and Nanog gene expression. We suggest that an epigenetic barrier is key to preventing the propagation of fluctuating pluripotency gene expression in ES cells. PMID- 28805245 TI - Tropical rainforest carbon sink declines during El Nino as a result of reduced photosynthesis and increased respiration rates. AB - Changes in tropical forest carbon sink strength during El Nino Southern Oscillation (ENSO) events can indicate future behavior under climate change. Previous studies revealed ~6 Mg C ha-1 yr-1 lower net ecosystem production (NEP) during ENSO year 1998 compared with non-ENSO year 2000 in a Costa Rican tropical rainforest. We explored environmental drivers of this change and examined the contributions of ecosystem respiration (RE) and gross primary production (GPP) to this weakened carbon sink. For 1998-2000, we estimated RE using chamber-based respiration measurements, and we estimated GPP in two ways: using (1) the canopy process model MAESTRA, and (2) combined eddy covariance and chamber respiration data. MAESTRA-estimated GPP did not statistically differ from GPP estimated using approach 2, but was ~ 28% greater than published GPP estimates for the same site and years using eddy covariance data only. A 7% increase in RE (primarily increased soil respiration) and a 10% reduction in GPP contributed equally to the difference in NEP between ENSO year 1998 and non-ENSO year 2000. A warming and drying climate for tropical forests may yield a weakened carbon sink from both decreased GPP and increased RE. Understanding physiological acclimation will be critical for the large carbon stores in these ecosystems. PMID- 28805246 TI - Associations between belief inflexibility and dimensions of delusions: A meta analytic review of two approaches to assessing belief flexibility. AB - OBJECTIVES: Belief inflexibility has been suggested to maintain delusions. Different measures of assessing belief inflexibility have been developed, and it remains unclear whether patients with delusions display belief inflexibility similarly across measures. As delusions consist of multiple dimensions, the aim of this meta-analytic review was to examine how belief inflexibility is related to different aspects of delusions (conviction, distress, and preoccupation) and to compare these associations between interview-based and task-based measures of belief inflexibility. METHODS: We conducted a systematic database search (PsycINFO, PsycARTICLES, PubMed, and MEDLINE) and identified relevant articles using the following search items: belief*, delusion*, or overvalued idea*; psychosis or schizo*; flexib*, inflexib*, change, revision, or update. Meta analyses were conducted for each dimension of delusions and were reported according to the PRISMA guidelines. RESULTS: A total of 16 studies, with a total sample of 1,065, were included in the analysis. Belief inflexibility was associated with global severity of delusions (Hedges' g = 0.452, p < .001). Specifically, all dimensions of delusions were significantly associated with belief inflexibility (conviction: Hedges' g = 0.678, p < .001; preoccupation: Hedges' g = 0.274, p = .002; distress: Hedges' g = 0.200, p = .025). There was no significant heterogeneity across studies for each dimension. Preliminary subgroup analysis did not find any significant between-measure differences in the relationship between belief inflexibility and overall severity of delusions. CONCLUSIONS: Belief inflexibility, across measures, was robustly associated with delusions, with a particularly strong association for delusional conviction. Our results carried implications for process-based interventions for delusions. PRACTITIONER POINTS: Positive clinical implications Belief inflexibility is consistently associated with the maintenance of delusions. Assessing belief inflexibility in routine clinical practice will inform psychological interventions for patients with persistent delusions. Interview- and task-based measures of belief inflexibility may be used complementarily to facilitate our understanding of this reasoning bias. Aetiological factors may be more closely associated with some aspects of delusions than the others. In line with a multidimensional view of delusions, interventions targeting different dimensions of delusions may have different therapeutic emphases. Limitations The current review focused on three core dimensions of delusions only (conviction, preoccupation, distress). Other ways of dissecting delusions are possible. Comparisons between the two measures of belief inflexibility may benefit from further research. PMID- 28805247 TI - Beauty in the blink of an eye: The time course of aesthetic experiences. AB - Under normal circumstances, perception runs very fast and seemingly automatic. In just a few ms, we go from sensory features to perceiving objects. This fast time course does not only apply to general perceptual aspects but also to what we call higher-level judgements. Inspired by the study on 'very first impressions' by Bar, Neta, and Linz (2006, Emotion, 6, 269) the current research examined the speed and time course of three aspects of the aesthetic experience, namely beauty, specialness, and impressiveness. Participants were presented with 54 reproductions of paintings that covered a wide variety of artistic styles and contents. Presentation times were 10, 50, 100 and 500 ms in Experiment 1 and 20, 30 and 40 ms in Experiment 2. Our results not only show that consistent aesthetic judgements can be formed based on very brief glances of information, but that this speed of aesthetic impression formation also differs between different aesthetic judgements. Apparently, impressiveness judgements require longer exposure times than impressions of beauty or specialness. The results provide important evidence for our understanding of the time course of aesthetic experiences. PMID- 28805248 TI - Epigenetics and DNA methylomic profiling in Alzheimer's disease and other neurodegenerative diseases. AB - Recent studies have suggested a role for epigenetic mechanisms in the complex etiology of various neurodegenerative diseases. In this review, we discuss advances that have been made toward understanding the role of epigenetic processes in neurodegenerative disorders, with a particular focus on Alzheimer's disease, where the most extensive studies have been undertaken to date. We provide a brief overview of DNA modifications, followed by a summarization of studies of DNA modifications in Alzheimer's disease and other neurodegenerative diseases. PMID- 28805250 TI - Peer Review - the future is here. PMID- 28805249 TI - A non-DNA-binding activity for the ATHB4 transcription factor in the control of vegetation proximity. AB - In plants, perception of vegetation proximity by phytochrome photoreceptors activates a transcriptional network that implements a set of responses to adapt to plant competition, including elongation of stems or hypocotyls. In Arabidopsis thaliana, the homeodomain-leucine zipper (HD-Zip) transcription factor ARABIDOPSIS THALIANA HOMEOBOX 4 (ATHB4) regulates this and other responses, such as leaf polarity. To better understand the shade regulatory transcriptional network, we have carried out structure-function analyses of ATHB4 by overexpressing a series of truncated and mutated forms and analyzing three different responses: hypocotyl response to shade, transcriptional activity and leaf polarity. Our results indicated that ATHB4 has two physically separated molecular activities: that performed by HD-Zip, which is involved in binding to DNA-regulatory elements, and that performed by the ETHYLENE-RESPONSIVE ELEMENT BINDING FACTOR-associated amphiphilic repression (EAR)-containing N-terminal region, which is involved in protein-protein interaction. Whereas both activities are required to regulate leaf polarity, DNA-binding activity is not required for the regulation of the seedling responses to plant proximity, which indicates that ATHB4 works as a transcriptional cofactor in the regulation of this response. These findings suggest that transcription factors might employ alternative mechanisms of action to regulate different developmental processes. PMID- 28805251 TI - Wiskott-Aldrich syndrome protein: Emerging mechanisms in immunity. AB - The Wiskott-Aldrich syndrome protein (WASP) participates in innate and adaptive immunity through regulation of actin cytoskeleton-dependent cellular processes, including immune synapse formation, cell signaling, migration and cytokine release. There is also emerging evidence for a direct role in nuclear transcription programmes uncoupled from actin polymerization. A deeper understanding of some of the more complex features of Wiskott Aldrich syndrome (WAS) itself, such as the associated autoimmunity and inflammation, has come from identification of defects in the number and function of anti-inflammatory myeloid cells and regulatory T and B cells, as well as defects in positive and negative B cell selection. In this review we outline the cellular defects that have been characterized in both human WAS patients and murine models of the disease. We will emphasize in particular recent discoveries that provide a mechanistic insight into disease pathology, including lymphoid and myeloid cell homeostasis, immune synapse assembly and immune cell signaling. PMID- 28805252 TI - Childhood Maltreatment and Early Developmental Vulnerabilities at Age 5 Years. AB - This study examined associations between maltreatment and early developmental vulnerabilities in a population sample of 68,459 children (Mage = 5.62 years, SD = .37) drawn from the Australian state of New South Wales, using linked administrative data for the children and their parents (collected 2001-2009). Associations were estimated between (a) any maltreatment, (b) the number of maltreatment types, and (c) the timing of first reported maltreatment and vulnerability and risk status on multiple developmental domains (i.e., physical, social, emotional, cognitive, and communication). Pervasive associations were revealed between maltreatment and all developmental domains; children exposed to two or more maltreatment types, and with first maltreatment reported after 3 years of age, showed greater likelihood of vulnerability on multiple domains, relative to nonmaltreated children. PMID- 28805253 TI - Temporal association of implementation of the Arizona Health Care Cost Containment System (AHCCCS) with changes in dental-related emergency department visits in Maricopa County from 2006 to 2012. AB - OBJECTIVE: To evaluate changes in emergency department (ED) dental-related visits in Maricopa County before and after the elimination of dental benefits for adult Medicaid-insured patients as of October 2010. METHODS: Hospital visits extracted from a hospital discharge dataset were used to calculate a yearly rate ratio of dental-related versus non-dental-related ED visits (as a comparison group) for adults, children, and payer types. Changes in ED visits over time were evaluated from 2006 to 2012. RESULTS: Overall, 1.3 percent of all ED visits (8,030,767) were for dental-related purposes. Medicaid-insured patients accounted for 41.9 percent and 44.3 percent of all dental-related ED visits in 2006 and 2012, respectively. The rate ratio for the percentage of dental-related versus non dental-related ED visits in each age category and payer type showed little fluctuation over time indicating no evidence of change in the dental-related ED visits as a proportion of the overall number of visits due to the cuts in the dental benefits for adult Medicaid-insured patients. CONCLUSION: We found no evidence that cuts in dental benefits for adult Medicaid-insured patients resulted in increased dental-related ED visits in Maricopa County during the study period. Rather, we found evidence of a shift in payer type after the 2010 policy change where dental-related ED visits by self-paid patients increased as dental-related ED visits by Medicaid-insured patients decreased. Such payer shifts will result in high uncompensated care burdens for providers and, ultimately, governmental payers. PMID- 28805254 TI - Does fathers' and mothers' rumination predict emotional symptoms in their children? AB - OBJECTIVES: Although rumination can have a negative influence on the family environment and the quality of parent-child interactions, there is little research on the role of parental rumination in predicting adverse child outcomes over time. This longitudinal study examined whether mothers' and fathers' brooding rumination would each uniquely predict emotional symptoms in preschool children. METHODS: The initial sample consisted of 160 families (including 50 mothers with past depression, 33 fathers with past depression, and 7 fathers with current depression according to the Structural Clinical Interview for DSM-IV). Families were seen at two times separated by 16 months. Children's mean age at the entry into the study was 3.9 years (SD = 0.8). Each parent independently completed the Ruminative Response Scale, the Child Behavior Checklist, the Patient Health Questionnaire, and the Dyadic Adjustment Scale. RESULTS: Fathers' brooding rumination significantly predicted children's emotional symptoms over 16 months when controlling for child emotional symptoms, couple adjustment, parents' depressive symptoms, mothers' brooding and reflective rumination, and fathers' reflective rumination at baseline. Unexpectedly, mothers' brooding rumination did not significantly predict child emotional symptoms over time. Correlational analyses showed significant associations between parents' rumination and lower levels of couple adjustment. CONCLUSIONS: Findings suggest that fathers' brooding rumination may play a unique role in their children's emotional outcomes. If these findings are replicated, studies should examine the processes by which these links occur and their implications for clinical interventions. PRACTITIONER POINTS: Rumination is prevalent among individuals with depression, but to date no studies have examined the possible role of mothers' and fathers' brooding rumination in predicting children's emotional symptoms. Fathers' brooding rumination was positively associated with children's emotional symptoms over time when controlling for mothers' rumination and other important characteristics. Parental rumination might be a promising target for both prevention and intervention strategies for parents with depression and their children. The findings of this study could inform parenting interventions (e.g., educate parents about the possible effects of rumination on family interactions and children's outcomes, help parents notice when they ruminate, teach them to replace rumination with more adaptive strategies). The findings should be interpreted with caution. The study relied on self-reports, and therefore, the data are subject to shared method variance which may have artificially inflated associations between parent and child outcomes. The sample consisted of well educated parents, and therefore, the findings should be generalized to other populations with caution. PMID- 28805255 TI - Mandibular complete denture versus single-implant overdenture: a systematic review of patient-reported outcomes. AB - The single-implant mandibular overdenture (SIMO) has been proposed as an alternative for edentulous patients who are poorly adapted to their dentures due to low retention and stability of the conventional mandibular complete denture (CD). However, there is a lack of evidence regarding the effectiveness of SIMO, which can be measured by examining patient perception of treatment effects. The aim of this systematic review was to assess the comparative results of CD and SIMO treatments using patient-reported outcome measures. A literature search was carried out in PubMed, Scopus and Cochrane Central databases. The search included studies published up to July 2017. The focus question was: 'Do single-implant mandibular overdentures improve patient-reported outcomes compared to conventional complete dentures in edentulous patients?' Eligible studies were randomised clinical trials (RCT) and prospective studies. After initial screening for eligibility and full-text analysis, 11 studies were included for data extraction and quality assessment (five parallel-group RCTs, two crossover RCTs and four prospective studies). All studies reported marked improvement in satisfaction with the dentures and quality of life measures after SIMO treatment, irrespective of variations in implant treatment protocols and retention systems. Methodological considerations revealed a lack of evidence from RCTs on the comparative effectiveness of the two treatment strategies. Hence, although available evidence suggests considerable improvement in patient-reported outcomes following the insertion of a single implant to retain a mandibular denture, further well-designed comparative studies between SIMO and CD are required to improve the level of evidence and to support the indication of SIMO treatment in routine practice. PMID- 28805256 TI - Effects of euthanasia methods on stable carbon (delta13 C value) and nitrogen (delta15 N value) isotopic compositions of fry and juvenile rainbow trout Oncorhynchus mykiss. AB - RATIONALE: Carbon and nitrogen stable isotope analyses of fish tissues are now commonly used in ecological studies but mostly require the sacrifice of the animal. Ethical considerations recommend the use of anesthetics for tissue sampling. This study examines how anesthetics affect stable isotope ratios of fish compared with other euthanasia methods. METHODS: Rainbow trout fry and juveniles were sacrificed using ice-freezing (as this common method used to kill fish does not affect natural isotopic ratios), electronarcosis or an overdose of chemical anesthetics (2-phenoxyethanol, benzocaine and clove oil). For fry, we sampled the whole animal whereas, for juveniles, white dorsal muscle, liver, red blood cells, plasma, external tegument and pectoral fin were sampled. Isotopic ratios and the elemental compositions of carbon and nitrogen were then measured. RESULTS: The delta15 N values, and the C and N contents of all considered tissues as well as delta13 C values of muscle, liver, red blood cells and plasma, were not affected by the use of chemical anesthetics. Clove oil and to a lesser extent 2-phenoxyethanol and benzocaine decreased delta13 C values of whole fry and juvenile external tegument and pectoral fin. The use of electronarcosis drastically affects the delta13 C and delta15 N values of all fish tissues. CONCLUSIONS: Anesthetics should be avoided for delta13 C analysis when tissues are in contact with the water containing the anesthetic. Ice-immersion has to be preferred when approved by guidelines. If not, benzocaine and 2-phenoxyethanol should be preferred over clove oil. Electronarcosis should not be used to kill fish until further investigations are performed. PMID- 28805257 TI - Three representative inter and intra-subspecific crosses reveal the genetic architecture of reproductive isolation in rice. AB - Systematic characterization of genetic and molecular mechanisms in the formation of hybrid sterility is of fundamental importance in understanding reproductive isolation and speciation. Using ultra-high-density genetic maps, 43 single-locus quantitative trait loci (QTLs) and 223 digenic interactions for embryo-sac, pollen, and spikelet fertility are depicted from three crosses between representative varieties of japonica and two varietal groups of indica, which provide an extensive archive for investigating the genetic basis of reproductive isolation in rice. Ten newly detected single-locus QTLs for inter- and intra subspecific fertility are identified. Three loci for embryo-sac fertility are detected in both Nip * ZS97 and Nip * MH63 crosses, whereas QTLs for pollen fertility are not in common between the two crosses thus leading to fertility variation. Five loci responsible for fertility and segregation distortion are observed in the ZS97 * MH63 cross. The importance of two-locus interactions on fertility are quantified in the whole genome, which identify that three types of interaction contribute to fertility reduction in the hybrid. These results construct the genetic architecture with respect to various forms of reproductive barriers in rice, which have significant implications in utilization of inter subspecific heterosis along with improvement in the fertility of indica-indica hybrids at single- and multi-locus level. PMID- 28805259 TI - AL amyloidosis, hypothyroidism and reduced tissue availability of thyroid hormones by thyroid hormone-binding immunoglobulin: a new possible perspective. PMID- 28805258 TI - Impact of beta-blockers on cardiopulmonary exercise testing in patients with advanced liver disease. AB - BACKGROUND: Patients with advanced liver disease may develop portal hypertension that can result in variceal haemorrhage. Beta-blockers reduce portal pressure and minimise haemorrhage risk. These medications may attenuate measures of cardiopulmonary performance, such as the ventilatory threshold and peak oxygen uptake measured via cardiopulmonary exercise testing. AIM: To determine the effect of beta-blockers on cardiopulmonary exercise testing variables in patients with advanced liver disease. METHODS: This was a cross-sectional analysis of 72 participants who completed a cardiopulmonary exercise test before liver transplantation. All participants remained on their usual beta-blocker dose and timing prior to the test. Variables measured during cardiopulmonary exercise testing included the ventilatory threshold, peak oxygen uptake, heart rate, oxygen pulse, the oxygen uptake efficiency slope and the ventilatory equivalents for carbon dioxide slope. RESULTS: Participants taking beta-blockers (n = 28) had a lower ventilatory threshold (P <.01) and peak oxygen uptake (P = .02), compared to participants not taking beta-blockers. After adjusting for age, the model of end-stage liver-disease score, liver-disease aetiology, presence of refractory ascites and ventilatory threshold remained significantly lower in the beta blocker group (P = .04). The oxygen uptake efficiency slope was not impacted by beta-blocker use. CONCLUSIONS: Ventilatory threshold is reduced in patients with advanced liver disease taking beta-blockers compared to those not taking the medication. This may incorrectly risk stratify patients on beta-blockers and has implications for patient management before and after liver transplantation. The oxygen uptake efficiency slope was not influenced by beta-blockers and may therefore be a better measure of cardiopulmonary performance in this patient population. PMID- 28805260 TI - Determination of carbon isotope enrichment factors of cis-dichloroethene after precursor amendment. AB - RATIONALE: Bacterial reductive dechlorination of the groundwater contaminant tetrachloroethene (PCE) involves the formation of lower chlorinated metabolites. Metabolites can be instantaneously formed and consumed in this sequential process; quantification and validation of their isotopic effects conventionally rely on separate laboratory microcosm studies. Here, we present an evaluation method enabling the determination of the carbon isotope enrichment factor (epsilon) for the intermediate cis-dichloroethene (cis-DCE) by a single laboratory microcosm study initially amending the precursor PCE only. METHODS: Environmental samples harboring organohalide-respiring bacteria were incubated under anaerobic conditions and then successively and repeatedly amended with PCE and cis-DCE in two separate laboratory microcosm studies. Reductive dechlorination was monitored by analyzing liquid samples using Purge-and-Trap gas chromatography isotope ratio mass spectrometry GC/MS-C/IRMS. The prerequisites of the presented evaluation method are mass and delta-value balancing. The evaluation method was validated by agglomerative hierarchical classification of Rayleigh plot data points. RESULTS: The sample-sensitive range of epsiloncis-DCE extended from -10.6 +/- 0.20/00 to -26.8 +/- 0.60/00 (R2 >=98%). The maximum standard deviations of epsiloncis-DCE were +/-1.80/00 for single microcosms, +/ 1.80/00 for replicates and +/-1.00/00 for the compiled replicate data of PCE and cis-DCE amendments. A linear regression of the epsiloncis-DCE for replicates obtained by each amendment study showed a slope of 95% (5 of the 7 data points are within a 95% confidence interval), demonstrating factor congruency and the practicability of the evaluation method. CONCLUSIONS: We found metabolite degradation and formation to be sequential but also stepwise during bacterial reductive dechlorination. The stepwise phases of the degradation of the intermediate eliminate the impact of instantaneous precursor degradation. These stepwise sections were used to determine epsiloncis-DCE -values. Our results showed the validity of epsiloncis-DCE -values over a wide range at initial precursor degradation (PCE). The presented evaluation method could substantially decrease lab costs for microcosm studies designed for epsiloncis-DCE determinations. Moreover, the results indicated that the evaluation method can be applied to other PCE-metabolites. PMID- 28805261 TI - Pregnancy outcomes and impact of pregnancy on graft function in women after kidney transplantation. AB - BACKGROUND: Kidney transplantation facilitates pregnancy in women with end-stage kidney disease; however, the impact of pregnancy on short and longer-term graft function is uncertain. METHODS: Obstetric, fetal, and graft outcomes for pregnancies from a large Australian transplant unit (1976-2015) were reviewed. RESULTS: There were 56 pregnancies in 35 women with mean age at conception 30.4 +/- 0.6 years and mean transplant-pregnancy interval 5.5 +/- 0.5 years. The live birth rate was 78.9%. Preterm birth (<37 weeks) occurred in 56.5%. Hypertensive disorders affected 76% of women (pre-eclampsia in 30%). Median prepregnancy serum creatinine (SCr) was 100 MUmol/L (interquartile range (IQR), 80, 114 MUmol/L). One-third had deterioration in graft dysfunction during pregnancy; of these, 63.2% did not return to baseline. At 2 years post-partum, median SCr was 96.4 MUmol/L (IQR, 81.5-124.3). Women with prepregnancy SCr > 110 MUmol/L had increased risk of pre-eclampsia (OR 4.4; 95% CI 1.2-16.8; P = .03), but not preterm birth (OR 5.4; 95% CI 0.5-53; P = .04) or low birth-weight babies (OR 1.2; 95% CI 0.5-2.9; P = .04). Women with SCr > 140 MUmol/L preconception had worst SCr trajectory, including higher rates of graft loss. CONCLUSIONS: Kidney transplantation pregnancies remain at high risk of obstetric complications, particularly pre-eclampsia. Prepregnancy graft function can be used to predict risk of adverse pregnancy outcomes and deterioration in graft function during and after delivery. PMID- 28805262 TI - Mesenchymal stem cells attenuate liver fibrosis by suppressing Th17 cells - an experimental study. AB - This study investigates molecular and cellular mechanisms involved in mesenchymal stem cell (MSC)-mediated modulation of IL-17 signaling during liver fibrosis. Mice received CCl4 (1 MUl/g intraperitoneally) twice/week for 1 month. MSCs (1 * 106 ), or MSC-conditioned medium (MSC-CM), were intravenously injected 24 h after CCl4 and on every 7th day. Liver fibrosis was determined by macroscopic examination, histological analysis, Sirius red staining, and RT-PCR. Serum levels of cytokines, indoleamine 2,3-dioxygenase (IDO), and kynurenine were determined by ELISA. Flow cytometry was performed to identify liver-infiltrated cells. In vitro, CD4+ T cells were stimulated and cultured with MSCs. 1-methyltryptophan was used for inhibition of IDO. MSCs significantly attenuated CCl4 -induced liver fibrosis by decreasing serum levels of inflammatory IL-17, increasing immunosuppressive IL-10, IDO, and kynurenine, reducing number of IL-17 producing Th17 cells, and increasing percentage of CD4+ IL-10+ T cells. Injection of MSC-CM resulted with attenuated fibrosis accompanied with the reduced number of Th17 cells in the liver and decreased serum levels of IL-17. MSC-CM promoted expansion of CD4+ FoxP3+ IL-10+ T regulatory cells and suppressed proliferation of Th17 cells. This phenomenon was completely abrogated in the presence of IDO inhibitor. MSCs, in IDO-dependent manner, suppress liver Th17 cells which lead to the attenuation of liver fibrosis. PMID- 28805263 TI - Optical Limiting Properties of 3,5-Dithienylenevinylene BODIPY Dyes at 532 nm. AB - The optical limiting properties of a series of near infrared absorbing 3,5 dithienylenevinylene BODIPY (boron-dipyrromethene) dyes (1-3) that contain donor and acceptor moieties in their pi-conjugation systems were studied by using the z scan technique at 532 nm in the nanosecond pulse range. A strong reverse saturable absorption response was observed when the compounds are embedded into poly(bisphenol carbonate A) polymer thin films, which demonstrates that BODIPY dyes with this type of structure are suitable for use in optical limiting applications. PMID- 28805264 TI - Large nested variant of urothelial carcinoma: a clinicopathological study of 36 cases. AB - AIMS: The large nested variant of urothelial carcinoma (LNUC) has been added to the World Health Organization (WHO) 2016 classification. Scant data exist, and little is known about its clinical behaviour. MATERIAL AND RESULTS: Cases fulfilling the morphological criteria of LNUC were collected. Pure and mixed cases (i.e. with other patterns of invasive UC) were studied. Immunohistochemical staining with cytokeratin (CK)7, p63, GATA-3, CK20, p53 and Ki-67 was performed. Included were 26 cystectomies (RC) and 10 resections (TURB) belonging to 36 patients with an average age of 66.7 years. Fourteen (39%) were pure LNUCs, and 22 (61%) displayed mixed features. Seventy per cent of the TURBs had pT2 tumours, while 58% of RCs had extravesical disease (>=pT3 and/or >=pN1), with the rate of advanced disease being higher in mixed (69%) in comparison to pure cases (40%). Similarly, 38% of mixed cases had nodal metastases in comparison to 20% of pure cases. Overall, eight patients (24%) died of disease at a mean interval time of 21.7 months and seven patients (21%) showed recurrence or metastases. Disease progression was significantly higher in mixed cases (55 and 31% in mixed and pure cases, respectively). Positive staining was: CK7 = 87.5%, CK20 = 72%, GATA-3 = 91%, P63 = 100%, p53 = 56% and Ki-67 = mean of 16%. CONCLUSION: Despite the bland cytological appearance and deceptive pattern of invasion of the LNUC, our study validates its fully malignant potential with metastatic spread and tumour-related deaths. Distinguishing mixed from pure LNUCs seems to be of value. LNUCs show comparable immunophenotype to both conventional urothelial carcinoma and the nested variant of urothelial carcinoma. PMID- 28805265 TI - Use of a saliva-based diagnostic test to identify tapeworm infection in horses in the UK. AB - BACKGROUND: Anthelmintic resistance combined with limited chemotherapeutic options has prompted a change in approaches to control of equine helminth infections. Targeted selective treatment strategies use diagnostics to reduce anthelmintic use by treating individuals with worm burdens or egg shedding levels above a set threshold. While faecal egg count analysis has limitations for informing tapeworm treatment, a commercially available saliva-based diagnostic test accurately diagnoses horses with tapeworm infection. OBJECTIVES: Evaluation of a saliva-based diagnostic test to identify horses naturally infected with tapeworm and assess the impact of using the test to inform anthelmintic administration. STUDY DESIGN: Retrospective longitudinal study. METHODS: Saliva was collected from horses (n = 237) at a UK welfare charity from autumn 2015 to autumn 2016. Horses diagnosed as positive for tapeworm infection using the EquiSal(r) Tapeworm test were anthelmintic treated according to weight. The number of horses that received anthelmintic treatment based on the test result was compared with an all-group treatment approach and the reduction in anthelmintic usage calculated. Incoming horses were also tested (n = 143) and the information was used to inform quarantine treatments. RESULTS: In autumn 2015, 85% of 237 horses tested received no anthelmintic and the majority (71%) of these remained below the treatment threshold throughout the study. Of the 69 horses that received treatment, seven required treatment following three subsequent tests, while >50% of horses administered with anthelmintic fell below the treatment threshold at the following test. No increase in tapeworm prevalence within the 237 horses was observed during the study despite a substantial reduction in the application of antitapeworm treatments. A total of 41% of incoming horses required anticestode treatment. MAIN LIMITATIONS: Other management practices were not included in the analysis. CONCLUSIONS: Compared with an all-group treatment strategy, the diagnostic-led approach used here considerably reduced application of anticestode anthelmintics. This could reduce selection pressure for anthelmintic resistance. PMID- 28805266 TI - Hypothermic pulsatile preservation of kidneys from uncontrolled deceased donors after cardiac arrest - a retrospective study. AB - Kidneys from uncontrolled donors after cardiac arrest (uDCD) suffer from a period of warm ischemia between cardiac arrest and cold flushing. Aim of the study was to evaluate renal outcomes of uDCD kidneys selected on the basis of renal Resistance Index (RI) and its influence on graft function and survival. The study included 44 kidneys procured from 26 uDCD starting 1.1.2006 until 12.31.2013. The donors (Maastricht category II) underwent cardiopulmonary resuscitation by assisted ventilation and chest compression; the organs were preserved with in situ cold perfusion or a normothermic regional perfusion. All kidneys were perfused on hypothermic (1-4 degrees C) pulsatile perfusion machine (RM3; Waters Medical System) and discarded when RI >=0.5 mmHg/ml/min after 6 h of perfusion. There was one (2.2%) primary non function, while 37 recipients (84.1%) experienced delayed graft function. Graft survival was 97.6% at 1 and 3 post transplantation years. Linear regression models showed that lower values of RI at the end of perfusion were associated with higher values of Modification of Diet in Renal Disease at 3 (P = 0.049) and 6 months after transplantation (P = 0.010) and with higher values of inulin clearance at 1 year (P = 0.030). RI showed to be a useful tool to select uDCD kidneys allowing to achieve good clinical results. PMID- 28805267 TI - Practices in the evaluation of potential kidney transplant recipients who are elderly: A survey of U.S. transplant centers. AB - Limited data exist regarding the evaluation and selection of older candidates for transplantation. To help guide the development of program protocols and help define research questions in this area, we surveyed U.S. transplant centers regarding their current practices in the evaluation of older kidney transplant candidates. We emailed a 28-question survey to the medical and surgical directors of 190 adult kidney transplant programs in the USA. We received usable responses from 59 programs, a 31.1% response rate. Most (76.3%) programs do not have absolute age cutoffs for listing patients, but for the 22.0% of programs that do have cutoffs, the mean age was 79, range 70-90. Nearly one-third (29.2%) of programs require a minimum life expectancy to list for transplant, reporting a mean of 4.5 years life expectancy, (range 2-10). Programs vary significantly in evaluating candidates living in a nursing home or with cognitive impairments. Practices regarding the evaluation of older transplant candidates vary widely between U.S. programs. Further studies are needed on the impact of age and other comorbidities on transplant outcomes, to help guide decisions on which older patients are most appropriate for transplant listing. PMID- 28805268 TI - Organo-Photoredox Catalyzed Oxidative Dehydrogenation of N-Heterocycles. AB - We report here for the first time the catalytic oxidative dehydrogenation of N heterocycles by a visible-light organo-photoredox catalyst with low catalyst loading (0.1-1 mol %). The reaction proceeds efficiently under base- and additive free conditions with ambient air at room temperature. The utility of this benign approach is demonstrated by the synthesis of various pharmaceutically relevant N heteroarenes such as quinoline, quinoxaline, quinazoline, acridine, and indole. PMID- 28805269 TI - Cloning and bacterial expression systems for recombinant human heparanase production: Substrate specificity investigation by docking of a putative heparanase substrate. AB - Human heparanase (HPSE) is an enzyme that degrades the extracellular matrix. It is implicated in a multiplicity of physiological and pathological processes encouraging angiogenesis and tumor metastasis. The protein is a heterodimer composed of a subunit of 8 kDa and another of 50 kDa. The two protein subunits are noncovalently associated. The cloning and expression of the two protein subunits in Escherichia coli and their subsequent purification to homogeneity under native conditions result in the production of an active HPSE enzyme. The substrate specificity of the HPSE was studied by docking of a putative substrate that is a designed oligosaccharide with the minimum recognition backbone, with the additional 2-N-sulfate and 6-O-sulfate groups at the nonreducing GlcN and a fluorogenic tag at the reducing extremity GlcN. To develop a quantitative fluorescence assay with this substrate would be extremely useful in studies on HPSE, as the HPSE cleavage of fluorogenic tag would result in a measurable response. PMID- 28805270 TI - Histoplasmosis in transplant recipients. AB - Histoplasma capsulatum is a dimorphic fungus that most often causes asymptomatic infection in the immunocompetent population. In immunocompromised patients, including solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients, however, it is likely to cause severe life-threatening infection. Post-transplant histoplasmosis (PTH) in SOT is uncommon with an incidence of <=1% and is even rarer in HCT patients. The majority of PTH in SOT is diagnosed in the first 2 years following transplantation. Histoplasmosis may result from endogenous reactivation of latent infection, de novo post-transplant acquisition, and donor-derived infection. Disseminated infection is common. Fever is the most common symptom and clinical features are often nonspecific, but patients with disseminated infection may present with a septic picture. Other features, including pancytopenia and hepatosplenomegaly, may not be prominent early in the course of illness. Contemporary histoplasma antigen assays are the most sensitive tests but cross-reactivity with antigens of other fungi, including with Aspergillus galactomannan, is not uncommon. Treatment should be continued for at least a year. Histoplasma antigen levels have prognostic value and can be used to monitor the response to therapy. The attributable mortality is approximately 10%. Routine screening of donors and recipients is not currently recommended. PMID- 28805271 TI - Efficacy of extensive intervention models for substance use disorders: A systematic review. AB - ISSUES: Despite a growing trend towards considering addiction as a chronic disease, the development of intervention models addressing the chronicity of substance use disorder is relatively new, and no literature review on this topic is available. The aim of this systematic review is to evaluate the efficacy of intervention models designed within the perspective of addiction as a chronic disease and those tailored to persons with substance use disorder who revolve in and out of treatment. APPROACH: Electronic databases were searched to identify articles published between 2000 and 2015 reporting an empirical study of an intervention model with data on its effectiveness. Study selection, data extraction and quality appraisal were performed independently by two reviewers. KEY FINDINGS: The selection process yielded 16 studies meeting all the inclusion criteria. The intervention models were classified into four groups according to the duration, frequency and components of the interventions. In general, the models showed potential therapeutic effects. The outcomes tended to be positive immediately after the end of the treatment. However, months after, the benefits obtained during treatment did not persist. IMPLICATIONS AND CONCLUSION: The review highlights that models designed specifically for persons with multiple treatment re-entries are scarce, but promising. Further research is needed to determine the best match between the clinical profile of persons with substance use disorder and a model's components, intensity and duration. [Simoneau H, Kamgang E, Tremblay J, Bertrand K, Brochu S, FleuryM-J. Efficacy of extensive interventionmodels for substance use disorders: A systematic review. Drug Alcohol Rev 2017;00:000-000]. PMID- 28805272 TI - Clinical phenotype of South-East Asian temporomandibular disorder patients with upper airway resistance syndrome. AB - Clinical and radiographic characteristics of a subset of South East Asian temporomandibular disorder (TMD) patients with comorbid upper airway resistance syndrome (UARS) were documented in a multi-center prospective series of 86 patients (26 men and 60 women / mean age 35.7 years). All had excessive daytime sleepiness, high arousal index and Apnoea-Hypopnoea Index (AHI) <5. The mean body mass index was 20.1, mean arousal index 16.2, mean respiratory disturbance index 19.6, mean AHI 3.9 while the mean Epworth Sleepiness Scale was 14.8. Many had functional somatic complaints; 66.3% headaches, 41.9% neck aches, 53.5% masticatory muscle myalgia, 68.6% temporomandibular joint (TMJ) arthralgia while 90.7% reported sleep bruxism (SB). Unlike patients with obstructive sleep apnoea (OSA), hypertension was uncommon (4.7%) while depression was prevalent at 68.6% with short REM latency of <90 min and an increased REM composition >25% documented in 79.6% and 57.6% of these depressed patients, respectively. 65.1% displayed a posteriorly displaced condyle at maximum intercuspation with or without TMJ clicking. Most exhibited a forward head posture (FHP) characterised by loss of normal cervical lordosis (80.2%), C0-C1 narrowing (38.4%) or an elevated hyoid position (50%), and 91.9% had nasal congestion. We postulate the TMD-UARS phenotype may have originally developed as an adaptive response to 'awake' disordered breathing during growth. Patients with persistent TMD and/or reporting SB should be screened for UARS and chronic nasal obstruction, especially when they also present with FHP. The lateral cephalogram is a useful tool in the differentiation of UARS from other OSA phenotypes. PMID- 28805273 TI - Neurotoxicosis in horses associated with consumption of Trema micrantha. AB - BACKGROUND: Trema micrantha is a tree widely distributed throughout the Americas. The tree produces highly palatable leaves that have been associated with natural poisoning in goats, sheep and horses, in which hepatic necrosis and hepatic encephalopathy have been observed. OBJECTIVES: This study describes malacia and haemorrhage in the central nervous system (CNS) due to T. micrantha consumption, with minimal to absent hepatic lesions. STUDY DESIGN: Retrospective case series. METHODS: A total of 14 horses with a history of neurological signs and spontaneous consumption of T. micrantha leaves were submitted to necropsy and multiple samples were collected for histopathology. Details of clinical history and signs of the horses were obtained through inquiries to the owners and attending veterinarians. RESULTS: All the 14 horses had neurological signs of ataxia, severe sialorrhoea, involuntary running movements, sternal and lateral recumbency, and death after a clinical course that lasted from 24 h to 9 days. For a few days prior to onset of clinical signs, all horses had spontaneously consumed, potentially toxic doses of T. micrantha leaves. All 14 brains had diffuse yellowish discoloration affecting the rhombencephalon, mesencephalon, diencephalon, telencephalon and corpus striatum. In all cases, the most severe lesions were observed in the pons. Spinal cord lesions were observed affecting the lumbar intumescence, which was swollen with darken and depressed areas at the dorsal and ventral horns, and at the sacral level, which on cut surface displayed a friable and yellowish grey matter. The lesions observed grossly in brain and spinal cord consisted microscopically of severe vasculitis and liquefactive necrosis of white and grey matter of the brainstem, cerebellum and spinal cord. MAIN LIMITATIONS: This is a small retrospective series relying on clinical observations reported by owners and attending veterinarians. The mechanism of action of the plant toxin in the CNS is still unidentified. CONCLUSION: T. micrantha poisoning in horses causes predominantly a neurological disease, with minimal to absent hepatic lesions. PMID- 28805274 TI - Quantitative characterization of galectin-3-C affinity mass spectrometry measurements: Comprehensive data analysis, obstacles, shortcuts and robustness. AB - RATIONALE: Affinity mass spectrometry (AMS) is an emerging tool in the field of the study of protein*carbohydrate complexes. However, experimental obstacles and data analysis are preventing faster integration of AMS methods into the glycoscience field. Here we show how analysis of direct electrospray ionization mass spectrometry (ESI-MS) AMS data can be simplified for screening purposes, even for complex AMS spectra. METHODS: A direct ESI-MS assay was tested in this study and binding data for the galectin-3C*lactose complex were analyzed using a comprehensive and simplified data analysis approach. In the comprehensive data analysis approach, noise, all protein charge states, alkali ion adducts and signal overlap were taken into account. In a simplified approach, only the intensities of the fully protonated free protein and the protein*carbohydrate complex for the main protein charge state were taken into account. RESULTS: In our study, for high intensity signals, noise was negligible, sodiated protein and sodiated complex signals cancelled each other out when calculating the Kd value, and signal overlap influenced the Kd value only to a minor extent. Influence of these parameters on low intensity signals was much higher. However, low intensity protein charge states should be avoided in quantitative AMS analyses due to poor ion statistics. CONCLUSIONS: The results indicate that noise, alkali ion adducts, signal overlap, as well as low intensity protein charge states, can be neglected for preliminary experiments, as well as in screening assays. One comprehensive data analysis performed as a control should be sufficient to validate this hypothesis for other binding systems as well. PMID- 28805275 TI - Participation of extracellular signal-regulated kinases 1/2 in osteoblast and adipocyte differentiation of mesenchymal stem cells grown on titanium surfaces. AB - Osteoblasts and adipocytes coexist in the implantation site and affect the process of titanium (Ti) osseointegration. As extracellular signal-regulated kinases 1/2 (ERK1/2) are involved in osteogenesis and adipogenesis, the aim of our study was to investigate if the effects of Ti surface topography on osteoblast and adipocyte differentiation are modulated by ERK1/2. The experiments were conducted based on the effect of the ERK1/2 inhibitor, PD98059, on mesenchymal stem cells (MSCs) grown under osteogenic and adipogenic conditions on Ti with nanotopography (Ti-Nano) or on machined Ti (Ti-Machined). The results showed that, in general, ERK1/2 inhibition favored osteoblast and adipocyte differentiation of MSCs grown on Ti-Machined. In MSCs grown on Ti-Nano, ERK1/2 inhibition upregulated the expression of alkaline phosphatase and osteocalcin and reduced extracellular matrix mineralization. In terms of adipocyte differentiation, ERK1/2 inhibition elicited similar MSC responses to Ti-Nano and Ti-Machined, upregulating gene expression of adipocyte markers without affecting lipid accumulation. Our results indicate that, under osteogenic and adipogenic conditions, the responses of MSCs to Ti surface topography in terms of osteogenesis and adipogenesis are dependent on ERK1/2. Thus, a precise modulation of ERK1/2 expression and activity induced by surface topography could be a good strategy to drive the process of implant osseointegration. PMID- 28805276 TI - Visible-Light-Mediated Selective Arylation of Cysteine in Batch and Flow. AB - A mild visible-light-mediated strategy for cysteine arylation is presented. The method relies on the use of eosin Y as a metal-free photocatalyst and aryldiazonium salts as arylating agents. The reaction can be significantly accelerated in a microflow reactor, whilst allowing the in situ formation of the required diazonium salts. The batch and flow protocol described herein can be applied to obtain a broad series of arylated cysteine derivatives and arylated cysteine-containing dipeptides. Moreover, the method was applied to the chemoselective arylation of a model peptide in biocompatible reaction conditions (room temperature, phosphate-buffered saline (PBS) buffer) within a short reaction time. PMID- 28805277 TI - Existence of Two-Dimensional Physical Gels even at Zero Surface Pressure at the Air/Water Interface: Rheology of Self-Assembled Domains of Small Molecules. AB - Films of mesoscopic domains self-assembled from fluorocarbon/hydrocarbon diblock copolymers (FnHm) at the air/water interface were found to display highly elastic behavior. We determined the interfacial viscoelasticity of domain-patterned FnHm Langmuir monolayers by applying periodic shear stresses. Remarkably, we found the formation of two-dimensional gels even at zero surface pressure. These monolayers are predominantly elastic, which is unprecedented for surfactants, exhibiting gelation only at high surface pressures. Systematic variation of the hydrocarbon (n=8; m=14, 16, 18, 20) and fluorocarbon (n=8, 10, 12; m=16) block lengths demonstrated that subtle changes in the block length ratio significantly alter the mechanics of two-dimensional gels across one order of magnitude. These findings open perspectives for the fabrication of two-dimensional gels with tuneable viscoelasticity via self-assembly of mesoscale, low-molecular-weight materials. PMID- 28805278 TI - PALE CRESS binds to plastid RNAs and facilitates the biogenesis of the 50S ribosomal subunit. AB - The plant-specific PALE CRESS (PAC) protein has previously been shown to be essential for photoautotrophic growth. Here we further investigated the molecular function of the PAC protein. PAC localizes to plastid nucleoids and forms large proteinaceous and RNA-containing megadalton complexes. It co-immunoprecipitates with a specific subset of chloroplast RNAs including psbK-psbI, ndhF, ndhD, and 23S ribosomal RNA (rRNA), as demonstrated by RNA immunoprecipitation in combination with high throughput RNA sequencing (RIP-seq) analyses. Furthermore, it co-migrates with premature 50S ribosomal particles and specifically binds to 23S rRNA in vitro. This coincides with severely reduced levels of 23S rRNA in pac leading to translational deficiencies and related alterations of plastid transcript patterns and abundance similar to plants treated with the translation inhibitor lincomycin. Thus, we conclude that deficiency in plastid ribosomes accounts for the pac phenotype. Moreover, the absence or reduction of PAC levels in the corresponding mutants induces structural changes of the 23S rRNA, as demonstrated by in vivo RNA structure probing. Our results indicate that PAC binds to the 23S rRNA to promote the biogenesis of the 50S subunit. PMID- 28805280 TI - Nickel-Catalyzed Asymmetric Reductive Heck Cyclization of Aryl Halides to Afford Indolines. AB - A nickel-catalyzed asymmetric reductive Heck reaction of aryl chlorides has been developed that affords substituted indolines with high enantioselectivity. Manganese powder is used as the terminal reductant with water as a proton source. Mechanistically, it is distinct from the palladium-catalyzed process in that the nickel-carbon bond is converted into a C-H bond to release the product through protonation instead of hydride donation followed by C-H reductive elimination on Pd. PMID- 28805279 TI - Extreme weather-year sequences have nonadditive effects on environmental nitrogen losses. AB - The frequency and intensity of extreme weather years, characterized by abnormal precipitation and temperature, are increasing. In isolation, these years have disproportionately large effects on environmental N losses. However, the sequence of extreme weather years (e.g., wet-dry vs. dry-wet) may affect cumulative N losses. We calibrated and validated the DAYCENT ecosystem process model with a comprehensive set of biogeophysical measurements from a corn-soybean rotation managed at three N fertilizer inputs with and without a winter cover crop in Iowa, USA. Our objectives were to determine: (i) how 2-year sequences of extreme weather affect 2-year cumulative N losses across the crop rotation, and (ii) if N fertilizer management and the inclusion of a winter cover crop between corn and soybean mitigate the effect of extreme weather on N losses. Using historical weather (1951-2013), we created nine 2-year scenarios with all possible combinations of the driest ("dry"), wettest ("wet"), and average ("normal") weather years. We analyzed the effects of these scenarios following several consecutive years of relatively normal weather. Compared with the normal-normal 2 year weather scenario, 2-year extreme weather scenarios affected 2-year cumulative NO3- leaching (range: -93 to +290%) more than N2 O emissions (range: 49 to +18%). The 2-year weather scenarios had nonadditive effects on N losses: compared with the normal-normal scenario, the dry-wet sequence decreased 2-year cumulative N2 O emissions while the wet-dry sequence increased 2-year cumulative N2 O emissions. Although dry weather decreased NO3- leaching and N2 O emissions in isolation, 2-year cumulative N losses from the wet-dry scenario were greater than the dry-wet scenario. Cover crops reduced the effects of extreme weather on NO3- leaching but had a lesser effect on N2 O emissions. As the frequency of extreme weather is expected to increase, these data suggest that the sequence of interannual weather patterns can be used to develop short-term mitigation strategies that manipulate N fertilizer and crop rotation to maximize crop N uptake while reducing environmental N losses. PMID- 28805282 TI - Autologous breast reconstruction in sickle cell trait: A fine line between success & failure. AB - Autologous breast reconstructions are increasingly being performed. While increased risks for flap loss after free tissue transfer (FTT) in sickle cell patients are known to most plastic surgeons, risks for patients with sickle cell trait (SCT) are less known. Unfortunately, recommendations to prevent complications after FTT in SCT are still scarce. We present additional and novel surgical measures that we took aiming to enhance probabilities for successful FTT in a SCT patient undergoing autologous breast reconstruction. This is only the second case report describing a successful FTT without flap necrosis/loss in a patient with SCT, and the first successful report involving FTT in the breast. PMID- 28805281 TI - Efficacy and safety of a fixed-dose combination of ibuprofen and caffeine in the management of moderate to severe dental pain after third molar extraction. AB - BACKGROUND: Ibuprofen is an effective analgesic treatment with a ceiling effect at doses above 400 mg. This study compared the combination of ibuprofen 400 mg and caffeine 100 mg with ibuprofen 400 mg monotherapy, caffeine and placebo in the analgesic treatment of moderate to severe acute dental pain following third molar extraction. METHODS: Phase III, active-/placebo-controlled, double-blind, single-centre, two-stage, parallel-group study in adult patients with at least moderate baseline pain intensity. Primary endpoint was defined as the time weighted sum of pain relief and pain intensity difference over 8 h (SPRID0-8 h), secondary endpoints included duration of pain relief, time to meaningful pain relief and more. RESULTS: N = 748 patients were enrolled and N = 562 treated. Mean baseline pain intensity was 7.7 on a 0-10 numerical rating scale. Analysis of SPRID0-8 h demonstrated superior analgesic effects for a single dose of ibuprofen/caffeine versus ibuprofen, caffeine and placebo over 8 h, rescue medication in this stage was requested by more patients on ibuprofen (32.5%) than on ibuprofen/caffeine (16.0%). Median time to meaningful pain relief was shorter for ibuprofen/caffeine (1.13 h) compared with ibuprofen (1.78 h; p = 0.0001). More patients on ibuprofen/caffeine than on ibuprofen reported meaningful pain relief. Adverse events were infrequent and mostly mild or moderate across treatment groups. Tolerability was rated as 'very good' or 'excellent' by most patients in both treatment groups. CONCLUSION: This study demonstrated clinically relevant superiority of ibuprofen/caffeine over monotherapy with ibuprofen in patients with acute dental pain. All treatments were well tolerated. SIGNIFICANCE: This trial showed superior efficacy of 400/100 mg ibuprofen/caffeine, compared to 400 mg ibuprofen alone, for treating acute pain, reflecting that caffeine is an effective analgesic adjuvant. Data on efficacy of 400 mg ibuprofen combined with caffeine for the treatment of acute pain were not available yet. PMID- 28805283 TI - Closing the gap: Avian lineage splits at a young, narrow seaway imply a protracted history of mixed population response. AB - The evolutionary significance of spatial habitat gaps has been well recognized since Alfred Russel Wallace compared the faunas of Bali and Lombok. Gaps between islands influence population structuring of some species, and flightless birds are expected to show strong partitioning even where habitat gaps are narrow. We examined the population structure of the most numerous living flightless land bird in New Zealand, Weka (Gallirallus australis). We surveyed Weka and their feather lice in native and introduced populations using genetic data gathered from DNA sequences of mitochondrial genes and nuclear beta-fibrinogen and five microsatellite loci. We found low genetic diversity among extant Weka population samples. Two genetic clusters were evident in the mtDNA from Weka and their lice, but partitioning at nuclear loci was less abrupt. Many formerly recognized subspecies/species were not supported; instead, we infer one subspecies for each of the two main New Zealand islands. Although currently range restricted, North Island Weka have higher mtDNA diversity than the more wide-ranging southern Weka. Mismatch and neutrality statistics indicate North Island Weka experienced rapid and recent population reduction, while South Island Weka display the signature of recent expansion. Similar haplotype data from a widespread flying relative of Weka and other New Zealand birds revealed instances of North Island-South Island partitioning associated with a narrow habitat gap (Cook Strait). However, contrasting patterns indicate priority effects and other ecological factors have a strong influence on spatial exchange at this scale. PMID- 28805284 TI - Interaction of the N-Terminal Tandem Domains of hnRNP LL with the BCL2 Promoter i Motif DNA Sequence. AB - The human genome contains GC-rich sequences able to form tetraplex secondary structures known as the G-quadruplex and i-motif. Such sequences are notably present in the promoter region of oncogenes and are proposed to function as regulatory elements of gene expression. The P1 promoter of BCL2 contains a 39-mer C-rich sequence (Py39wt) that can fold into a hairpin or an i-motif in a pH dependent manner in vitro. The protein hnRNP LL was identified to recognise the i motif over the hairpin conformation and act as an activating transcription factor. Thus, the Py39wt sequence would act as an ON/OFF switch, according to the secondary structure adopted. Herein, a structural study of the interaction between hnRNP LL and Py39wt is reported. Both N-terminal RNA recognition motifs (RRM12) cooperatively recognise one Py39wt DNA sequence and engage their beta sheet to form a large binding platform. In contrast, the C-terminal RRMs show no binding capacity. It is observed that RRM12 binds to Py39wt regardless of the DNA conformation. We propose that RRM12 recognises a single-stranded CTCCC element present in loop 1 of the i-motif and in the apical loop of the hairpin conformation. PMID- 28805285 TI - Unusual case of tuberculous meningitis with discordant ventricular and lumbar cerebrospinal fluid; lessons in the era of world-wide migration. PMID- 28805286 TI - A survey on monopolar radiofrequency treatment. AB - This questionnaire-based study was aimed to measure the level of appreciation, awareness of the special tips, and practice patterns of monopolar radiofrequency among Korean dermatologists practicing a specific monopolar radiofrequency device (Thermage(r) Inc., Hayward, CA). A total of 82 surveys were analyzed to show that the majority of participants (78.8%) were highly satisfied with the outcomes of monopolar radiofrequency treatment. All respondents were aware of the Eye Tip 0.25 cm2 , and the majority knew the difference between the Face tip (blue) and the Total tip (orange). Most (86.3%) agreed to the statement that 900 shots were appropriate for facial tightening in those between the ages of 35 and 65 years. 66.2% of participants reported to have perform monopolar radiofrequency to extra facial sites within the past year. As for the tips, the Total tip was most popular for all body sties and the Big tip was favored for the abdomen, thighs and buttock. We hope our data allow dermatologists to better utilize monopolar radiofrequency. PMID- 28805287 TI - Nongenetically modified Lactococcus lactis-adjuvanted vaccination enhanced innate immunity against Helicobacter pylori. AB - BACKGROUND: Gram-positive enhancer matrix particles (GEM) produced by Lactococcus lactis can enhance vaccine-induced immune response. However, the mechanism under which this adjuvant mounts the efficacy of orally administered vaccines remains unexplored. MATERIALS AND METHODS: We used a prophylactic mice model to investigate the mechanism of GEM-adjuvanted vaccination. Helicobacter pylori urease-specific antibody response was monitored and detected in murine serum by ELISA. Urease-specific splenic cytokine profile was examined. Gastric inflammatory responses were measured on day 43 or 71 by quantitative real-time PCR, flow cytometry and histology. RESULTS: We found that GEM enhanced the efficiency of oral H. pylori vaccine by promoting innate immunity. The vaccine CUE-GEM composed of GEM particles and recombinant antigen CTB-UE provided protection of immunized mice against H. pylori insult. The protective response was associated with induction of postimmunization gastritis and local Th1/Th17 cell-medicated immune response. We showed that innate inflammatory responses including neutrophil chemokines CXCL1-2, neutrophils, and antimicrobial proteins S100A8 and MUC1 were significantly elevated. Within all infected mice, S100A8 and MUC1 levels were negatively correlated with H. pylori burden. Strikingly, mice receiving GEM also show reduction of colonization, possibly through natural host response pathways to recruit CD4+ T cells and promote S100A8 expression. CONCLUSIONS: These findings suggest that GEM-based vaccine may impact Th1/Th17 immunity to orchestrate innate immune response against H. pylori infection. PMID- 28805288 TI - Conditioned pain modulation is affected by occlusion cuff conditioning stimulus intensity, but not duration. AB - BACKGROUND: Various conditioned pain modulation (CPM) methodologies have been used to investigate diffuse noxious inhibitory control pain mechanisms in healthy and clinical populations. Occlusion cuff parameters have been poorly studied. We aimed to investigate whether occlusion cuff intensity and/or duration influenced CPM magnitudes. We also investigated the role of physical activity levels on CPM magnitude. METHODS: Two studies were performed to investigate the role of intensity and duration of occlusion cuff conditioning stimulus on test stimulus (tibialis anterior pressure pain thresholds). In Study 1, conditioning stimulus intensity of 2/10 or 5/10 (duration <20 s) was evaluated using a paired-samples t test. In Study 2, duration of 2/10 conditioning stimulus was 3 min. One-way repeated-measures ANOVA was used to investigate the effect of time (0, 1, 2 and 3 min) on CPM magnitude. RESULTS: In Study 1, 27 healthy volunteers (mean +/- SD: 24.9 years (+/-4.5); eight female) demonstrated that an occlusion cuff applied to the upper arm eliciting 5/10 local pain resulted in a significant (mean +/- SD: 17% +/- 46%) increase in CPM magnitude, when compared to 2/10 intensity (-3% +/- 38%, p = 0.026), whereas in Study 2, 25 healthy volunteers (22.5 years (+/-2.7); 13 female) demonstrated that 3 min of 2/10 CS intensity did not result in a significant change in CPM (p = 0.21). There was no significant relationship between physical activity levels and CPM in either study (p > 0.22). CONCLUSIONS: This study demonstrated that an occlusion cuff of 5/10 conditioning stimulus intensity, when compared to 2/10, significantly increased CPM magnitude. Maintaining 2/10 conditioning stimulus for 3 min did not increase CPM magnitude. SIGNIFICANCE: Dysfunctional conditioned pain modulation (CPM) has been associated with poor health outcomes. Various factors can influence CPM outcomes. The role of occlusion cuff conditioning stimulus intensity and duration has not been previously investigated. Intensity (5/10), but not duration of lower intensity (2/10) conditioning stimulus, affects CPM magnitude. PMID- 28805290 TI - Bilateral plasmacytoma of the breast. PMID- 28805289 TI - Identifying and assessing strategies for evaluating the impact of mobile eye health units on health outcomes. AB - OBJECTIVE: To identify and assess strategies for evaluating the impact of mobile eye health units on health outcomes. DESIGN: Systematic literature review. SETTING: Worldwide. PARTICIPANTS: Peer-reviewed journal articles that included the use of a mobile eye health unit. MAIN OUTCOME MEASURE(S): Journal articles were included if outcome measures reflected an assessment of the impact of a mobile eye health unit on health outcomes. RESULTS: Six studies were identified with mobile services offering diabetic retinopathy screening (three studies), optometric services (two studies) and orthoptic services (one study). CONCLUSION: This review identified and assessed strategies in existing literature used to evaluate the impact of mobile eye health units on health outcomes. Studies included in this review used patient outcomes (i.e. disease detection, vision impairment, treatment compliance) and/or service delivery outcomes (i.e. cost per attendance, hospital transport use, inappropriate referrals, time from diabetic retinopathy photography to treatment) to evaluate the impact of mobile eye health units. Limitations include difficulty proving causation of specific outcome measures and the overall shortage of impact evaluation studies. Variation in geographical location, service population and nature of eye care providers limits broad application. PMID- 28805291 TI - Harms of unsuccessful donation after circulatory death: An exploratory study. AB - While donation after circulatory death (DCD) has expanded options for organ donation, many who wish to donate are still unable to do so. We conducted face-to face interviews with family members (N = 15) who had direct experience with unsuccessful DCD and 5 focus groups with professionals involved in the donation process. We used qualitative content analysis to characterize the harms of nondonation as perceived by participants. Participants reported a broad spectrum of harms affecting organ recipients, donors, and donor families. Harms included waste of precious life-giving organs and hospital resources, inability to honor the donor's memory and character, and impaired ability for families to make sense of tragedy and cope with loss. Donor families empathized with the initial hope and ultimate despair of potential recipients who must continue their wait on the transplant list. Focus group members reinforced these findings and highlighted the struggle of families to navigate the uncertainty regarding the timing of death during the donation process. While families reported significant harm, many appreciated the donation attempt. These findings highlight the importance of organ donation to donor families and the difficult experiences associated with current processes that could inform development of alternative donation strategies. PMID- 28805292 TI - Incidence and outcomes of primary central nervous system lymphoma in solid organ transplant recipients. AB - Primary central nervous system lymphoma (PCNSL) risk is greatly increased in immunosuppressed human immunodeficiency virus-infected people. Using data from the US transplant registry linked with 17 cancer registries (1987-2014), we studied PCNSL and systemic non-Hodgkin lymphoma (NHL) in 288 029 solid organ transplant recipients. Transplant recipients had elevated incidence for PCNSL compared with the general population (standardized incidence ratio = 65.1; N = 168), and this elevation was stronger than for systemic NHL (standardized incidence ratio=11.5; N = 2043). Compared to kidney recipients, PCNSL incidence was lower in liver recipients (adjusted incidence rate ratio [aIRR] = 0.52), similar in heart and/or lung recipients, and higher in other/multiple organ recipients (aIRR = 2.45). PCNSL incidence was higher in Asians/Pacific Islanders than non-Hispanic whites (aIRR = 2.09); after induction immunosuppression with alemtuzumab (aIRR = 3.12), monoclonal antibodies (aIRR = 1.83), or polyclonal antibodies (aIRR = 2.03); in recipients who were Epstein-Barr virus-seronegative at the time of transplant and at risk of primary infection (aIRR = 1.95); and within the first 1.5 years after transplant. Compared to other recipients, those with PCNSL had increased risk of death (adjusted hazard ratio [aHR] = 11.79) or graft failure/retransplantation (aHR = 3.24). Recipients with PCNSL also had higher mortality than those with systemic NHL (aHR = 1.48). In conclusion, PCNSL risk is highly elevated among transplant recipients, and it carries a poor prognosis. PMID- 28805293 TI - Utility of protocol kidney biopsies for de novo donor-specific antibodies. AB - There is limited information about the role of protocol kidney biopsies for de novo donor-specific antibodies (dnDSA) in kidney transplant recipients, especially in those with stable graft function. We initiated a routine posttransplant DSA monitoring and surveillance biopsy program for dnDSA since 2014. We identified 45 kidney transplant recipients with dnDSA detected between January 2014 and February 2017 who underwent kidney biopsy within 60 days of detection of dnDSA. Twenty-nine (64%) had stable graft function and 16 (36%) had impaired graft function at the time of dnDSA detection. Even in the group with stable graft function, we found a high rate of rejection (53%) on biopsy. Eighty eight percent of patients with impaired graft function had rejection. Those patients with impaired graft function had significantly lower estimated glomerular filtration rate at 12 months postbiopsy and at last follow-up. Those with impaired graft function had more graft failures; however, this result was not statistically significant. The high rate of asymptomatic rejection, and the fact that outcomes in asymptomatic patients are poor, is in support of the utility of surveillance biopsies in patients with dnDSA. PMID- 28805294 TI - Microplastics alter composition of fungal communities in aquatic ecosystems. AB - Despite increasing concerns about microplastic (MP) pollution in aquatic ecosystems, there is insufficient knowledge on how MP affect fungal communities. In this study, we explored the diversity and community composition of fungi attached to polyethylene (PE) and polystyrene (PS) particles incubated in different aquatic systems in north-east Germany: the Baltic Sea, the River Warnow and a wastewater treatment plant. Based on next generation 18S rRNA gene sequencing, 347 different operational taxonomic units assigned to 81 fungal taxa were identified on PE and PS. The MP-associated communities were distinct from fungal communities in the surrounding water and on the natural substrate wood. They also differed significantly among sampling locations, pointing towards a substrate and location specific fungal colonization. Members of Chytridiomycota, Cryptomycota and Ascomycota dominated the fungal assemblages, suggesting that both parasitic and saprophytic fungi thrive in MP biofilms. Thus, considering the worldwide increasing accumulation of plastic particles as well as the substantial vector potential of MP, especially these fungal taxa might benefit from MP pollution in the aquatic environment with yet unknown impacts on their worldwide distribution, as well as biodiversity and food web dynamics at large. PMID- 28805295 TI - Multiparametric magnetic resonance imaging identifies significant apical prostate cancers. AB - OBJECTIVE: To determine if multiparametric (mp) magnetic resonance imaging (MRI) can identify significant apical disease, thereby informing decisions regarding preservation of the membranous urethra. MATERIALS AND METHODS: Men undergoing radical prostatectomy (RP) between January 2012 and June 2016, who underwent a 12 core transrectal ultrasonography-guided systematic biopsy (SB), preoperative 3 Tesla MRI, and sectioning of the prostate specimen with tumour foci mapping, were extracted from a single surgeon's prospective longitudinal outcomes database. Apical SB and mpMRI lesion results were compared with regard to their ability to predict aggressive tumours in the prostatic apex (PA), defined as prostate cancer grade group >1. RESULTS: Of the 100 men who met the eligibility criteria, 43 (43%) exhibited aggressive prostate cancer in the distal 5 mm of the apex. A Likert score >2 in the apical one-third of the prostate was found to be more reliable than any cancer found on apical SB at detecting aggressive cancer in the apex. On multivariate regression analysis, which included Likert score in the apex, age, prostate-specific antigen (PSA) level, prostate size and presence of any cancer on apical biopsy, only Likert score (P = 0.005) and PSA level (P = 0.025) were significant and independent predictors of aggressive cancer in the distal apex. CONCLUSION: The results of the study showed that MRI was superior to SB at identifying aggressive prostate cancer within the distal PA and may be useful for planning the extent of apical preservation during RP. PMID- 28805296 TI - Basidiomycete-specific PsCaMKL1 encoding a CaMK-like protein kinase is required for full virulence of Puccinia striiformis f. sp. tritici. AB - Calcium/calmodulin-dependent kinases (CaMKs) are Ser/Thr protein kinases (PKs) that respond to changes in cytosolic free Ca2+ and play diverse roles in eukaryotes. In fungi, CAMKs are generally classified into four families CAMK1, CAMKL, RAD53 and CAMK-Unique. Among these, CAMKL constitutes the largest family. In some fungal plant pathogens, members of the CaMKL family have been shown to be responsible for pathogenesis. However, little is known about their role(s) in rust fungi. In this study, we functionally characterized a novel PK gene, PsCaMKL1, from Puccinia striiformis f. sp. tritici (Pst). PsCaMKL1 belongs to a group of PKs that is evolutionarily specific to basidiomyceteous fungi. PsCaMKL1 shows little intra-species polymorphism between Pst isolates. PsCaMKL1 transcripts are highly elevated at early infection stages, whereas gene expression is downregulated in barely germinated urediospores under KN93 treatment. Overexpression of PsCaMKL1 in fission yeast increased resistance to environmental stresses. Knock down of PsCaMKL1 using host-induced gene silencing (HIGS) reduced the virulence of Pst accompanied by reactive oxygen species (ROS) accumulation and a hypersensitive response. These results suggest that PsCaMKL1 is a novel pathogenicity factor that exerts it virulence function by regulating ROS production in wheat. PMID- 28805297 TI - Mesenchymal stem cells deliver exogenous miR-21 via exosomes to inhibit nucleus pulposus cell apoptosis and reduce intervertebral disc degeneration. AB - Although mesenchymal stem cells (MSCs) transplantation into the IVD (intervertebral disc) may be beneficial in inhibiting apoptosis of nucleus pulposus cells (NPCs) and alleviating IVD degeneration, the underlying mechanism of this therapeutic process has not been fully explained. The purpose of this study was to explore the protective effect of MSC-derived exosomes (MSC-exosomes) on NPC apoptosis and IVD degeneration and investigate the regulatory effect of miRNAs in MSC-exosomes and associated mechanisms for NPC apoptosis. MSC-exosomes were isolated from MSC medium, and its anti-apoptotic effect was assessed in a cell and rat model. The down-regulated miRNAs in apoptotic NPCs were identified, and their contents in MSC-exosomes were detected. The target genes of eligible miRNAs and possible downstream pathway were investigated. Purified MSC-exosomes were taken up by NPCs and suppressed NPC apoptosis. The levels of miR-21 were down-regulated in apoptotic NPCs while MSC-exosomes were enriched in miR-21. The exosomal miR-21 could be transferred into NPCs and alleviated TNF-alpha induced NPC apoptosis by targeting phosphatase and tensin homolog (PTEN) through phosphatidylinositol 3-kinase (PI3K)-Akt pathway. Intradiscal injection of MSC exosomes alleviated the NPC apoptosis and IVD degeneration in the rat model. In conclusion, MSC-derived exosomes prevent NPCs from apoptotic process and alleviate IVD degeneration, at least partly, via miR-21 contained in exosomes. Exosomal miR-21 restrains PTEN and thus activates PI3K/Akt pathway in apoptotic NPCs. Our work confers a promising therapeutic strategy for IVD degeneration. PMID- 28805298 TI - Female urethral injuries associated with pelvic fracture: a systematic review of the literature. AB - To review systematically the literature on female urethral injuries associated with pelvic fracture and to determine the optimum management of this rare injury. Using Meta-analysis of Observational Studies in Epidemiology criteria, we searched the Cochrane, Pubmed and OVID databases for all articles available before 30 June 2016 using the terms 'female pelvic fracture urethroplasty', 'female urethral distraction', 'female pelvic fracture urethral injury' and 'female pelvic fracture urethra girls.' Two authors of this paper independently reviewed the titles, abstracts, and articles in duplicate. We identified 162 individual articles from the databases. Fifty-one articles met our criteria for full review, including 158 female patients with urethral trauma. Of these injuries, 83 (53%) were managed with immediate repair; 17/83 (20%) via primary alignment and 66/83 (80%) via anastomotic repair. The remaining 75/158 (47%) were managed with delayed repair. Rates of urethral stenosis and fistula were highest after primary alignment. Urethral integrity appears to be similar after both primary anastomosis and delayed repair; however, patients experienced significantly more incontinence and vaginal stenosis after delayed repair. Patients who underwent delayed urethral repair were more likely to undergo more extensive reconstructive surgery than those who underwent primary repair. The optimum management of female urethral distraction defects is based on very-low quality literature. Based on our review of the available literature, primary anastomotic repair of a female urethral distraction defect via a vaginal approach as soon as the patient is haemodynamically stable appears to be optimal. PMID- 28805299 TI - Dissociation between the pharmacokinetics and pharmacodynamics of once-daily rivaroxaban and twice-daily apixaban: a randomized crossover study. AB - : Essentials In this crossover study the anticoagulant effects of rivaroxaban and apixaban were compared. Healthy volunteers received rivaroxaban 20 mg once daily or apixaban 5 mg twice daily. Rivaroxaban was associated with more prolonged inhibition of thrombin generation than apixaban. Rivaroxaban induced a clear prolongation of prothrombin time and activated partial thromboplastin time. SUMMARY: Background The anticoagulant actions of the oral direct activated factor Xa inhibitors, rivaroxaban and apixaban, have not previously been directly compared. Objectives To compare directly the steady-state pharmacokinetics and anticoagulant effects of rivaroxaban and apixaban at doses approved for stroke prevention in patients with non-valvular atrial fibrillation. Methods Twenty-four healthy Caucasian male volunteers were included in this open-label, two-period crossover, phase 1 study (EudraCT number: 2015-002612-32). Volunteers were randomized to receive rivaroxaban 20 mg once daily or apixaban 5 mg twice daily for 7 days, followed by a washout period of at least 7 days before they received the other treatment. Plasma concentrations and anticoagulant effects were measured at steady state and after drug discontinuation. Results Overall exposure was similar for both drugs: the geometric mean area under the plasma concentration-time curve for the 0-24-h interval was 1830 MUg h L-1 for rivaroxaban and 1860 MUg h L-1 for apixaban. Rivaroxaban was associated with greater inhibition of endogenous thrombin potential (geometric mean area under the curve relative to baseline during the 0-24-h interval: 15.5 h versus 17.5 h) and a more pronounced maximal prolongation relative to baseline of prothrombin time (PT) (1.66-fold versus 1.14-fold) and activated partial thromboplastin time (APTT) (1.43-fold versus 1.16-fold) at steady state than apixaban. Conclusions Despite similar exposure to both drugs, rivaroxaban 20 mg once daily was associated with greater and more sustained inhibition of thrombin generation than apixaban 5 mg twice daily. Sensitive PT and APTT assays can be used to estimate the anticoagulant effects of rivaroxaban. PMID- 28805300 TI - The kidney allocation system does not appropriately stratify risk of pediatric donor kidneys: Implications for pediatric recipients. AB - Kidney Allocation System (KAS) was enacted in 2014 to improve graft utility, while facilitating transplantation of highly-sensitized patients and preserving pediatric access to high-quality kidneys. Central to this system is the Kidney Donor Profile Index (KDPI), a metric intended to predict transplant outcomes based on donor characteristics but derived using only adult donors. We posited that KAS had inadvertently altered the profile and quantity of kidneys made available to pediatric recipients. This question arose from our observation that most pediatric donors carry a KDPI over 35 and have therefore been rendered relatively inaccessible to pediatric recipients under KAS. Here we explore early trends in pediatric transplantation following KAS, including: (i) use of pediatric donors, (ii) use of Public Health System (PHS) high infectious risk donors, (iii) wait time, and (iv) living donor transplantation. We note some concerning preliminary changes following KAS implementation, including the allocation of fewer deceased donor pediatric kidneys to children and stagnation in pediatric wait times. Moreover, the poor predictive power of the KDPI for adult donors appears to be even worse when applied to pediatric donors. These early trends warrant further observation and consideration of changes in pediatric kidney allocation if they persist. PMID- 28805301 TI - The Lymphocytes Stimulation Induced DNA Release, a Phenomenon Similar to NETosis. AB - The release of DNA into the extracellular milieu by neutrophil during a process called NETosis has been postulated as an additional source of autoantigens; a process believed to be important in the pathogenesis of some autoimmune disease, such as systemic lupus erythematosus (SLE). However, it is not established if the B and T cells undergo the release of DNA to the extracellular milleu, in response to different stimuli. In this study, it was observed that the treatment of B and T cells with PMA, ionomycin and the serum from patients with SLE induced the extracellular DNA presence in B and T cells. These findings suggest that the phenomenon were similar to those observed in neutrophil's Etosis; B and T cells also released their DNA into the extracellular milieu. The findings express that serum from patients with SLE and SLEDAI <= 8 triggers the release of extracellular DNA in neutrophils, B and T cells, that suggested the presence of soluble factors in the serum that favoured this phenomenon. PMID- 28805303 TI - Controlled release of insulin-like growth factor 1 enhances urethral sphincter function and histological structure in the treatment of female stress urinary incontinence in a rat model. AB - OBJECTIVES: To determine the effects of controlled release of insulin-like growth factor 1 (IGF-1) from alginate-poly-L-ornithine-gelatine (A-PLO-G) microbeads on external urethral sphincter (EUS) tissue regeneration in a rat model of stress urinary incontinence (SUI), as SUI diminishes the quality of life of millions, particularly women who have delivered vaginally, which can injure the urethral sphincter. Despite several well-established treatments for SUI, growth factor therapy might provide an alternative to promote urethral sphincter repair. MATERIALS AND METHODS: In all, 44 female Sprague-Dawley rats were randomised into four groups: vaginal distension (VD) followed by periurethral injection of IGF-1 A-PLO-G microbeads (VD + IGF-1 microbeads; 1 * 104 microbeads/1 mL normal saline); VD + empty microbeads; VD + saline; or sham-VD + saline (sham). RESULTS: Urethral function (leak-point pressure, LPP) was significantly lesser 1 week after VD + saline [mean (sem) 23.9 (1.3) cmH2 O] or VD + empty microbeads [mean (sem) 21.7 (0.8) cmH2 O) compared to the sham group [mean (sem) 44.4 (3.4) cmH2 O; P < 0.05), indicating that the microbeads themselves do not create a bulking or obstructive effect in the urethra. The LPP was significantly higher 1 week after VD + IGF-1 microbeads [mean (sem) 28.4 (1.2) cmH2 O] compared to VD + empty microbeads (P < 0.05), and was not significantly different from the LPP in sham rats, demonstrating an initiation of a reparative effect even at 1 week after VD. Histological analysis showed well-organised skeletal muscle fibres and vascular development in the EUS at 1 week after VD + IGF-1 microbeads, compared to substantial muscle fibre attenuation and disorganisation, and less vascular formation at 1 week after VD + saline or VD + empty microbeads. CONCLUSION: Periurethral administration of IGF-1-A-PLO-G microbeads facilitates recovery from SUI by promoting skeletal myogenesis and revascularisation. This therapy is promising, but detailed and longer term studies in animal models and humans are needed. PMID- 28805302 TI - Torix group Rickettsia are widespread in Culicoides biting midges (Diptera: Ceratopogonidae), reach high frequency and carry unique genomic features. AB - There is increasing interest in the heritable bacteria of invertebrate vectors of disease as they present novel targets for control initiatives. Previous studies on biting midges (Culicoides spp.), known to transmit several RNA viruses of veterinary importance, have revealed infections with the endosymbiotic bacteria, Wolbachia and Cardinium. However, rickettsial symbionts in these vectors are underexplored. Here, we present the genome of a previously uncharacterized Rickettsia endosymbiont from Culicoides newsteadi (RiCNE). This genome presents unique features potentially associated with host invasion and adaptation, including genes for the complete non-oxidative phase of the pentose phosphate pathway, and others predicted to mediate lipopolysaccharides and cell wall modification. Screening of 414 Culicoides individuals from 29 Palearctic or Afrotropical species revealed that Rickettsia represent a widespread but previously overlooked association, reaching high frequencies in midge populations and present in 38% of the species tested. Sequence typing clusters the Rickettsia within the Torix group of the genus, a group known to infect several aquatic and hematophagous taxa. FISH analysis indicated the presence of Rickettsia bacteria in ovary tissue, indicating their maternal inheritance. Given the importance of biting midges as vectors, a key area of future research is to establish the impact of this endosymbiont on vector competence. PMID- 28805304 TI - A systematic review and meta-analysis of mental health service use in people who report psychotic experiences. AB - BACKGROUND: Self-reported psychotic experiences (PEs) are associated with psychopathology of all kinds, not just psychoses. However, systematic reviews on the relevance of this for health services are unavailable. Furthermore, whether association with service use is confounded by other psychopathology is unknown, and is relevant to prevention and treatment. OBJECTIVES: Literature examining associations between PEs and service use was systematically reviewed. Study quality and the direction and extent of any associations were assessed, and meta analysis conducted. METHODS: Systematic review and meta-analysis was carried out as per PRISMA guidelines. A search of electronic databases was performed based on free-text and structured terms. Included studies were evaluated by two raters using a structured tool and estimates extracted for reporting. RESULTS: Thirteen studies were returned. We found two prospective studies, and a minority of studies accounted for concurrent psychopathology, limiting our ability to test our main hypotheses. Five studies reported associations by different types of service use. Almost all studies assessed service use by self-report. Meta analysis suggested that people who reported PEs were around twice as likely to report service use compared to those who did not (pooled OR for all included studies: 2.20,95% confidence intervals (95%CI): 1.66,2.91). CONCLUSIONS: There was consistent evidence of association between PEs and mental health service use at the general population level. However, evidence for causation was poor due to a limited number of studies. Whether increased service use in this group is solely attributable to PEs, and therefore whether interventions aimed at limiting/preventing PEs might be effective, requires studies focusing on the relationships between PEs, psychopathology and service use. PMID- 28805305 TI - Systematic review of provider involvement in heart failure self-care interventions. AB - BACKGROUND AND PURPOSE: Heart failure is a global concern impacting patient outcomes. Self-care interventions improve self-care behaviors in heart failure patients. The impact of direct provider involvement on patient self-care outcomes is unknown in research. The purpose is to review self-care interventions for adults with heart failure and describe direct provider involvement versus no direct provider involvement on patient self-care behaviors. METHODS: Review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines. Studies were independently selected, grounded in the population, intervention, comparison, and outcome (PICO) question, and predetermined inclusion/exclusion criteria, including self-care interventions, adult heart failure patients, self-care behavior measurement, and 10-year publication. Quality assessment of studies was conducted. CONCLUSION: There was a lack of data and quality studies to answer the PICO question. Comparison of variables that impact self-care behaviors is problematic because the interventions are heterogeneous, which limits interpretation of results. There were minimal studies with direct provider involvement. None of the studies conceptually addressed direct provider involvement. IMPLICATIONS FOR PRACTICE: The involvement of providers, health systems, and patients in pragmatic research can impact the integration of research, policy, and practice. Strategies to decrease threats to internal validity need to be addressed as research is translated into practice. PMID- 28805306 TI - Bioprocess scale-up/down as integrative enabling technology: from fluid mechanics to systems biology and beyond. AB - Efficient optimization of microbial processes is a critical issue for achieving a number of sustainable development goals, considering the impact of microbial biotechnology in agrofood, environment, biopharmaceutical and chemical industries. Many of these applications require scale-up after proof of concept. However, the behaviour of microbial systems remains unpredictable (at least partially) when shifting from laboratory-scale to industrial conditions. The need for robust microbial systems is thus highly needed in this context, as well as a better understanding of the interactions between fluid mechanics and cell physiology. For that purpose, a full scale-up/down computational framework is already available. This framework links computational fluid dynamics (CFD), metabolic flux analysis and agent-based modelling (ABM) for a better understanding of the cell lifelines in a heterogeneous environment. Ultimately, this framework can be used for the design of scale-down simulators and/or metabolically engineered cells able to cope with environmental fluctuations typically found in large-scale bioreactors. However, this framework still needs some refinements, such as a better integration of gas-liquid flows in CFD, and taking into account intrinsic biological noise in ABM. PMID- 28805307 TI - Early Graft Loss in Two Recipients of Mate Kidneys From the Same Donor With Diabetic Nephropathy. PMID- 28805308 TI - Lymphocyte profile and cytokine mRNA expression in peripheral blood mononuclear cells of patients with recurrent respiratory papillomatosis suggest dysregulated cytokine mRNA response and impaired cytotoxic capacity. AB - OBJECTIVES: Recurrent respiratory papillomatosis (RRP) is a relatively rare, chronic disease caused by Human Papilloma Virus (HPV) 6 and 11, and characterized by wart-like lesions in the airway affecting voice and respiratory function. The majority of HPV infections are asymptomatic and resolve spontaneously, however, some individuals are afflicted with persistent HPV infections. Failure to eliminate HPV 6 and 11 due to a defect immune responsiveness to these specific genotypes is proposed to play a major role in the development of RRP. METHODS: We performed a phenotypic characterization of peripheral blood mononuclear cells (PBMC) collected from 16 RRP patients and 12 age-matched healthy controls, using immunoflow cytometry, and monoclonal antibodies against differentiation and activation markers. The cytokine mRNA profile of monocytes, T helper-, T cytotoxic-, and NK cells was assessed using RT-qPCR cytokine analysis, differentiating between Th1-, Th2-, Th3/regulatory-, and inflammatory immune responses. RESULTS: We found a dominance of cytotoxic T cells, activated NK cells, and high numbers of stressed MIC A/B expressing lymphocytes. There was an overall suppression of cytokine mRNA production and an aberrant cytokine mRNA profile in the activated NK cells. CONCLUSION: These findings demonstrate an immune dysregulation with inverted CD4+ /CD8+ ratio and aberrant cytokine mRNA production in RRP patients, compared to healthy controls. PMID- 28805309 TI - Safety of herpes zoster vaccination among inflammatory bowel disease patients being treated with anti-TNF medications. AB - BACKGROUND: The risk of herpes zoster (HZ) is elevated in inflammatory bowel disease (IBD) patients treated with anti-TNF medications. While it is optimal to give herpes zoster vaccine prior to initiation of therapy clinical circumstances may not always allow this. AIM: To determine the safety of giving herpes zoster vaccine while patients are on anti-TNF therapy. METHODS: We conducted a retrospective cohort study involving IBD patients who were followed in the Veterans Affairs (VA) healthcare system between 2001 and 2016. Patients who received herpes zoster vaccine while on anti-TNF medication were identified through vaccination codes and confirmed through individual chart review. Our outcome of interest was development of HZ between 0 and 42 days after herpes zoster vaccine administration. RESULTS: Fifty-six thousand four hundred and seventeen patients with IBD were followed in the VA healthcare system. A total of 59 individuals were on anti-TNF medication when they were given herpes zoster vaccine, and amongst them, 12 (20%) were also taking a thiopurine. Median age at the time of herpes zoster vaccine was 64.9 years and 95% of patients had a Charlson Comorbidity Index of >=2. Median number of encounters within 42 days after receiving herpes zoster vaccine was two. No case of HZ was found within 0 42 days of HZV administration. CONCLUSION: Our data suggest that co-administering the herpes zoster vaccine to patients who are taking anti-TNF medications is relatively safe. This study significantly expands the evidence supporting the use of herpes zoster vaccine in this population, having included an elderly group of patients with a high Charlson Comorbidity Index who are likely at a much higher risk of developing HZ. PMID- 28805310 TI - Use of direct oral anticoagulants for stroke prevention in elderly patients with nonvalvular atrial fibrillation. AB - BACKGROUND AND PURPOSE: Four direct oral anticoagulants (DOACs) are available for the prevention of stroke in nonvalvular atrial fibrillation (NVAF): dabigatran (a direct thrombin inhibitor); and rivaroxaban, apixaban, and edoxaban (factor Xa inhibitors). This article summarizes the safety and efficacy of DOACs for the prevention of stroke in elderly NVAF patients. METHODS: PubMed was searched to identify published results of randomized, controlled trials evaluating DOACs for stroke prevention in elderly NVAF patients. Pharmacologic and dose recommendations were obtained from the package inserts. CONCLUSIONS: DOACs are at least as effective as warfarin for stroke prevention in elderly patients with NVAF. Compared with warfarin, DOACs were associated with reduced risk of intracranial hemorrhage, while some DOACs demonstrated an increase in other bleeding events (e.g., gastrointestinal). The faster onset and offset of action and fewer food and drug interactions of DOACs may be an advantage over warfarin for some patients. IMPLICATIONS FOR PRACTICE: DOACs are an alternative to warfarin with overall equivalent safety and efficacy in elderly patients with NVAF, and may be preferable for some. Stroke risk must always be balanced against potential bleeding risk when determining an optimal anticoagulation treatment plan. Patients' needs and preferences will also impact this decision. PMID- 28805311 TI - Mechanistic Model for Blood Pressure and Heart Rate Changes Produced by Telmisartan in Human Beings. AB - Telmisartan, an angiotensin receptor blocker (ARB), is indicated for the treatment of essential hypertension. This study aimed to develop a mechanistic model of telmisartan drug effect in human beings using non-invasive markers. Data were acquired from a previous study where telmisartan 80 mg was given once daily for 6 days. Systolic (SBP) and diastolic blood pressure (DBP) and heart rate (HR) were measured before dosing for days 1-5 and serially after the last dose. Mean arterial pressure (MAP) and pulse pressure (PP) were calculated from SBP and DBP. Relationships between MAP, PP, HR and total peripheral resistance (TPR) were developed. Circadian variation was incorporated into PP and HR, and TPR was assumed to adjust itself in response to changes in PP and HR based on baroreflex mechanism. Drug effects were then described as lowering the set point of MAP through TPR with a physiological feedback effect stimulating HR and PP. Drug concentrations were described by a two-compartment disposition model with first order absorption and lag time, and first-order elimination. Circadian variation was described by cosine functions, having periods of 12 and 24 hr. A log-linear model was used to describe drug effect, with estimated drug effect parameter of 0.051/hr. Estimated fractional turnover rate of PP, HR and TPR was 11.2 hr. The model successfully described the time courses of these cardiovascular variables. This work demonstrated the feasibility of using non-invasive cardiovascular measurements to derive a mechanistic model for telmisartan in human beings. The model may be suitable for other ARBs. PMID- 28805312 TI - The dock-and-coalesce mechanism for the association of a WASP disordered region with the Cdc42 GTPase. AB - Intrinsically disordered proteins (IDPs) play key roles in signaling and regulation. Many IDPs undergo folding upon binding to their targets. We have proposed that coupled folding and binding of IDPs generally follow a dock-and coalesce mechanism, whereby a segment of the IDP, through diffusion, docks to its cognate subsite and, subsequently, the remaining segments coalesce around their subsites. Here, by a combination of experiment and computation, we determined the precise form of dock-and-coalesce operating in the association between the intrinsically disordered GTPase-binding domain (GBD) of the Wiskott-Aldrich Syndrome protein and the Cdc42 GTPase. The association rate constants (ka ) were measured by stopped-flow fluorescence under various solvent conditions. ka reached 107 m-1 .s-1 at physiological ionic strength and had a strong salt dependence, suggesting that an electrostatically enhanced, diffusion-controlled docking step may be rate limiting. Our computation, based on the transient complex theory, identified the N-terminal basic region of the GBD as the docking segment. However, several other changes in solvent conditions provided strong evidence that the coalescing step also contributed to determining the magnitude of ka . Addition of glucose and trifluoroethanol and an increase in temperature all produced experimental ka values much higher than expected from the effects on the docking rate alone. Conversely, addition of urea led to ka values much lower than expected if only the docking rate was affected. These results all pointed to ka being approximately two-thirds of the docking rate constant under physiological solvent conditions. PMID- 28805313 TI - About how to capture and exploit the CO2 surplus that nature, per se, is not capable of fixing. AB - Human activity has been altering many ecological cycles for decades, disturbing the natural mechanisms which are responsible for re-establishing the normal environmental balances. Probably, the most disrupted of these cycles is the cycle of carbon. In this context, many technologies have been developed for an efficient CO2 removal from the atmosphere. Once captured, it could be stored in large geological formations and other reservoirs like oceans. This strategy could present some environmental and economic problems. Alternately, CO2 can be transformed into carbonates or different added-value products, such as biofuels and bioplastics, recycling CO2 from fossil fuel. Currently different methods are being studied in this field. We classified them into biological, inorganic and hybrid systems for CO2 transformation. To be environmentally compatible, they should be powered by renewable energy sources. Although hybrid systems are still incipient technologies, they have made great advances in the recent years. In this scenario, biotechnology is the spearhead of ambitious strategies to capture CO2 and reduce global warming. PMID- 28805314 TI - Evolved alpha-factor prepro-leaders for directed laccase evolution in Saccharomyces cerevisiae. AB - Although the functional expression of fungal laccases in Saccharomyces cerevisiae has proven to be complicated, the replacement of signal peptides appears to be a suitable approach to enhance secretion in directed evolution experiments. In this study, twelve constructs were prepared by fusing native and evolved alpha-factor prepro-leaders from S. cerevisiae to four different laccases with low-, medium- and high-redox potential (PM1L from basidiomycete PM1; PcL from Pycnoporus cinnabarinus; TspC30L from Trametes sp. strain C30; and MtL from Myceliophthora thermophila). Microcultures of the prepro-leader:laccase fusions were grown in selective expression medium that used galactose as both the sole carbon source and as the inducer of expression so that the secretion and activity were assessed with low- and high-redox potential mediators in a high-throughput screening context. With total activity improvements as high as sevenfold over those obtained with the native alpha-factor prepro-leader, the evolved prepro-leader from PcL (alphaPcL ) most strongly enhanced secretion of the high- and medium redox potential laccases PcL, PM1L and TspC30L in the microtiter format with an expression pattern driven by prepro-leaders in the order alphaPcL > alphaPM1L ~ alphanative . By contrast, the pattern of the low-redox potential MtL was alphanative > alphaPcL > alphaPM1L . When produced in flask with rich medium, the evolved prepro-leaders outperformed the alphanative signal peptide irrespective of the laccase attached, enhancing secretion over 50-fold. Together, these results highlight the importance of using evolved alpha-factor prepro leaders for functional expression of fungal laccases in directed evolution campaigns. PMID- 28805315 TI - A Comparison of Clinical and Immunologic Phenotypes in Familial and Sporadic Forms of Common Variable Immunodeficiency. AB - Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency disease, and its prevalence varies significantly among different population. Minority of CVID patients present a familial aggregation suggesting a higher probability of heritable genetic defects. A total of 235 registered CVID patients were evaluated in this cohort study. Familial and sporadic patients were stratified, and demographic information, clinical records, laboratory and molecular data were compared among these two groups of patients. Multiple cases were identified in 12 families (30 patients) and sporadic presentation in 120 cases. The rate of parental consanguinity (83.3%) and clinical presentation of lymphoid malignancy (20.7%) were predominant in familial CVID patients, whereas significantly increased recurrent upper respiratory infections were recorded in sporadic patients (0.3 infections per year). Probands of familial group were presented with a higher severity score resulting in a profound mortality rate (41.7% after 30-year follow-up) comparing to the non-proband CVID patients in the same families with a lowered diagnostic delay. Familial CVID patients had a specific signature in clinical presentation and immunologic profile, and a high consanguinity in this group of patients suggests a Mendelian trait with an autosomal recessive inheritance pattern. Diagnosis of an index patient within a multiple case families significantly improves the diagnostic process and outcomes of the yet asymptomatic patients. PMID- 28805316 TI - Promoting empathy using video-based teaching. AB - BACKGROUND: Empathy is fundamental to patient-centred care. It has been shown to improve patient satisfaction and therapeutic outcomes. The success of educational interventions in enhancing students' empathy has been mixed, however, and a consensus on the most effective approach is lacking. METHODS: Patients were videoed discussing their hospital experiences and interactions with clinicians. These videos were shown to groups of medical students, who then took part in a facilitated discussion around themes of health care communication and patient experience. The session was delivered to 48 students over seven sessions and evaluated by way of serial attitude questionnaires (the Patient-Practitioner Orientation Scale, PPOS) and written feedback. RESULTS: There was an improvement in PPOS scores amongst participants, with pre- and post-intervention means of 78.8 and 82.0, respectively, indicating an improvement in patient-centred attitudes. Written feedback highlighted the emotional impact of hearing patients' stories, and that the discussion explored issues not covered in previous teaching. Students reported changes in their approach to patients, including introducing themselves more often, and taking measures to make patients feel more at ease on ward rounds. Empathy is fundamentalto patient-centred care DISCUSSION: This study describes the use of patient video interviews to promote empathy in medical students, by stimulating reflective discussion on themes of health care communication and patient experience. Future use of these methods are recommended, although further research would benefit from larger student numbers and the use of objective clinical examination scores to assess behaviour change. PMID- 28805317 TI - The future of biologically inspired next-generation factories for chemicals. PMID- 28805318 TI - BioZorb tissue marker as seen on multiple imaging modalities. PMID- 28805319 TI - Letter: the definition of budesonide dependence in microscopic colitis. PMID- 28805320 TI - Letter: inconsistency in reporting of hypophosphatemia after intravenous iron. PMID- 28805321 TI - Editorial: faecal microbiota transplantation for ulcerative colitis-not quite there yet? Authors' reply. PMID- 28805322 TI - Editorial: faecal microbiota transplantation for ulcerative colitis-not quite there yet? PMID- 28805323 TI - Letter: the definition of budesonide dependence in microscopic colitis-authors' reply. PMID- 28805324 TI - Editorial: probiotics in inflammatory bowel disease-wrong organisms, wrong disease, or flawed concepts? PMID- 28805325 TI - Letter: complex interplay between obesity and Clostridium difficile infection authors' reply. PMID- 28805326 TI - Editorial: good news to patients with thalassaemia-HCV clearance made easy with direct acting antivirals. Authors' reply. PMID- 28805327 TI - Letter: Helicobacter pylori in lean and obese patients with non-alcoholic fatty liver disease. PMID- 28805328 TI - Editorial: probiotics in inflammatory bowel disease-wrong organisms, wrong disease, or flawed concepts? Authors' reply. PMID- 28805329 TI - Editorial: good news to patients with thalassaemia-HCV clearance made easy with direct-acting antivirals. PMID- 28805330 TI - Letter: the treatment of coronary artery disease in cirrhotics needs more thinking-author's reply. PMID- 28805331 TI - Letter: inconsistency in reporting of hypophosphataemia after intravenous iron authors' reply. PMID- 28805332 TI - Letter: the treatment of coronary artery disease in cirrhotics needs more thinking. PMID- 28805333 TI - Letter: complex interplay between obesity and Clostridium difficile infection. PMID- 28805334 TI - 2016 European Conference on Donor Health and Management. PMID- 28805335 TI - Chipping away at the body politic one study at a time: the case for more 'unprofessional' online content. PMID- 28805336 TI - Matrix stimulation in cancer pain: Methodology, safety and effectiveness. AB - BACKGROUND: This feasibility study addresses the applicability of matrix electrodes for the reduction of ongoing pain in cancer patients via low-frequency electrical stimulation (LFS). METHODS: Low-frequency matrix stimulation (4 Hz) was applied to the skin within the 'Head's zones' referring to the tumour localization of cancer pain patients. Pain at baseline was compared to a 3-day treatment interval consisting of 5 min of matrix stimulation in the morning and evening followed by a 3-day follow-up period without therapy. Main outcome parameters included numeric rating scale values (rating scale 0-100), painDETECT, HADS, and German pain questionnaire, as well as the opioid intake, calculated as the oral morphine equivalent (OME). RESULTS: Twenty patients with cancer pain (aged 64.4 +/- 10.3; 9 women) were examined. In the majority of patients, the pain was classified as nociceptive. The mean pain reduction achieved by matrix therapy was 30%, under stable daily controlled-release opioid doses between 177 and 184 mg/day (OME). Seventeen patients (85%) were responders, defined by a pain reduction of at least 30%, while four responders experienced a pain reduction of over 50%. The only side effect was short-term erythema. CONCLUSION: Findings are consistent with the concept of synaptic long-term depression in cancer pain induced after conditioning LFS. Despite the short, but well-tolerated, treatment duration of 2 * 5 min/day, effects persisted throughout the 3-day follow-up. SIGNIFICANCE: Cutaneous neuromodulation using LFS via a matrix electrode has been shown to be a safe intervention for effectively reducing cancer pain in palliative care patients. PMID- 28805337 TI - Genetic favouring of pheomelanin-based pigmentation limits physiological benefits of coloniality in lesser kestrels Falco naumanni. AB - Pheomelanin contributes to the pigmentation phenotype of animals by producing orange and light brown colours in the integument. However, pheomelanin synthesis in melanocytes requires consumption of glutathione (GSH), the most important intracellular antioxidant. Therefore, a genetic control favouring the production of large amounts of pheomelanin for pigmentation may lead to physiological costs under environmental conditions that promote oxidative stress. We investigated this possibility in the context of breeding coloniality, a reproductive strategy that may affect oxidative stress. We found in lesser kestrel Falco naumanni nestlings that the GSH:GSSG ratio, which decreases with systemic oxidative stress, increased with the size of the colony where they were reared, but the expression in feather melanocytes of five genes involved in pheomelanin synthesis (Slc7a11, Slc45a2, CTNS, MC1R and AGRP) did not vary with colony size. The antioxidant capacity (TEAC) of lesser kestrel nestlings also increased with colony size, but in a manner that depended on Slc7a11 expression and not on the expression of the other genes. Thus, antioxidant capacity increased with colony size only in nestlings least expressing Slc7a11, a gene with a known role in mediating cysteine (a constituent amino acid of GSH) consumption for pheomelanin production. The main predictor of the intensity of pheomelanin-based feather colour was Slc45a2 expression followed in importance by Slc7a11 expression, hence suggesting that the genetic regulation of the pigmentation phenotype mediated by Slc7a11 and a lack of epigenetic lability in this gene limits birds from benefiting from the physiological benefits of coloniality. PMID- 28805338 TI - Direct and indirect effects of episodic frost on plant growth and reproduction in subalpine wildflowers. AB - Frost is an important episodic event that damages plant tissues through the formation of ice crystals at or below freezing temperatures. In montane regions, where climate change is expected to cause earlier snow melt but may not change the last frost-free day of the year, plants that bud earlier might be directly impacted by frost through damage to flower buds and reproductive structures. However, the indirect effects of frost mediated through changes in plant pollinator interactions have rarely been explored. We examined the direct and pollinator-mediated indirect effects of frost on three wildflower species in southwestern Colorado, USA, Delphinium barbeyi (Ranunculaceae), Erigeron speciosus (Asteraceae), and Polemonium foliosissimum (Polemoniaceae), by simulating moderate (-1 to -5 degrees C) frost events in early spring in plants in situ. Subsequently, we measured plant growth, and upon flowering measured flower morphology and phenology. Throughout the flowering season, we monitored pollinator visitation and collected seeds to measure plant reproduction. We found that frost had species-specific direct and indirect effects. Frost had direct effects on two of the three species. Frost significantly reduced flower size, total flowers produced, and seed production of Erigeron. Furthermore, frost reduced aboveground plant survival and seed production for Polemonium. However, we found no direct effects of frost on Delphinium. When we considered the indirect impacts of frost mediated through changes in pollinator visitation, one species, Erigeron, incurred indirect, negative effects of frost on plant reproduction through changes in floral traits and pollinator visitation, along with direct effects. Overall, we found that flowering plants exhibited species specific direct and pollinator-mediated indirect responses to frost, thus suggesting that frost may play an important role in affecting plant communities under climate change. PMID- 28805339 TI - What happens in the pith stays in the pith: tissue-localized defense responses facilitate chemical niche differentiation between two spatially separated herbivores. AB - Herbivore attack is known to elicit systemic defense responses that spread throughout the host plant and influence the performance of other herbivores. While these plant-mediated indirect competitive interactions are well described, and the co-existence of herbivores from different feeding guilds is common, the mechanisms of co-existence are poorly understood. In both field and glasshouse experiments with a native tobacco, Nicotiana attenuata, we found no evidence of negative interactions when plants were simultaneously attacked by two spatially separated herbivores: a leaf chewer Manduca sexta and a stem borer Trichobaris mucorea. T. mucorea attack elicited jasmonic acid (JA) and jasmonoyl-l-isoleucine bursts in the pith of attacked stems similar to those that occur in leaves when M. sexta attacks N. attenuata leaves. Pith chlorogenic acid (CGA) levels increased 1000-fold to levels 6-fold higher than leaf levels after T. mucorea attack; these increases in pith CGA levels, which did not occur in M. sexta attacked leaves, required JA signaling. With plants silenced in CGA biosynthesis (irHQT plants), CGA, as well as other caffeic acid conjugates, was demonstrated in both glasshouse and field experiments to function as a direct defense protecting piths against T. mucorea attack, but not against leaf chewers or sucking insects. T. mucorea attack does not systemically activate JA signaling in leaves, while M. sexta leaf-attack transiently induces detectable but minor pith JA levels that are dwarfed by local responses. We conclude that tissue-localized defense responses allow tissue-specialized herbivores to share the same host and occupy different chemical defense niches in the same hostplant. PMID- 28805340 TI - Scalable Dry Production Process of a Superior 3D Net-Like Carbon-Based Iron Oxide Anode Material for Lithium-Ion Batteries. AB - Carbon-based transition-metal oxides are considered as an appropriate anode material candidate for lithium-ion batteries. Herein, a simple and scalable dry production process is developed to produce carbon-encapsulated 3D net-like FeOx /C materials. The process is simply associated with the pyrolysis of a solid carbon source, such as filter paper, adsorbed with ferrite nitrate. The carbon derived from filter paper induces a carbothermal reduction to form metallic Fe, the addition of carbon and iron increase the conductivity of this material. As expected, this 3D net-like FeOx /C composite delivers an excellent charge capacity of 851.3 mAh g-1 after 50 cycles at 0.2 A g-1 as well as high stability and rate performance of 714.7 mAh g-1 after 300 cycles at 1 A g-1 . Superior performance, harmlessness, low costs, and high yield may greatly stimulate the practical application of the products as anode materials in lithium-ion batteries. PMID- 28805341 TI - Treatment options for severe pulmonary embolism during pregnancy and the postpartum period: a systematic review. AB - : Essentials The evidence on how to manage life-threatening pregnancy-related pulmonary embolism (PE) is scarce. We systematically reviewed all available cases of (sub)massive PE until December 2016. Thrombolysis in such severe PE was associated with a high maternal survival (94%). The major bleeding risk was much greater in the postpartum (58%) than antepartum period (18%). SUMMARY: Background Massive pulmonary embolism (PE) during pregnancy or the postpartum period is a rare but dramatic event. Our aim was to systematically review the evidence to guide its management. Methods We searched Pubmed, Embase, conference proceedings and the RIETE registry for published cases of severe (submassive/massive) PE treated with thrombolysis, percutaneous or surgical thrombectomy and/or extracorporeal membrane oxygenation (ECMO), occurring during pregnancy or within 6 weeks of delivery. Main outcomes were maternal survival and major bleeding, premature delivery, and fetal survival and bleeding. Results We found 127 cases of severe PE (at least 83% massive; 23% with cardiac arrest) treated with at least one modality. Among 83 women with thrombolysis, survival was 94% (95% CI, 86-98). The risk of major bleeding was 17.5% during pregnancy and 58.3% in the postpartum period, mainly because of severe postpartum hemorrhages. Fetal deaths possibly related to PE or its treatment occurred in 12.0% of cases treated during pregnancy. Among 36 women with surgical thrombectomy, maternal survival and risk of major bleeding were 86.1% (95% CI, 71-95) and 20.0%, with fetal deaths possibly related to surgery in 20.0%. About half of severe postpartum PEs occurred within 24 h of delivery. Conclusions Published cases of thrombolysis for massive PE during pregnancy and the postpartum period suggest a high maternal and fetal survival (94% and 88%). In the postpartum period, given the high risk of major bleeding with thrombolysis, other therapeutic options (catheter [or surgical] thrombectomy, ECMO) may be considered if available. PMID- 28805343 TI - Rest and exercise hemodynamic and metabolic findings in active duty soldiers referred for cardiac catheterization to exclude heart disease: Insights from past invasive cardiopulmonary exercise testing using multisensor high fidelity catheters. AB - OBJECTIVE: This study describes results of iCPET from the past, which used submaximal stress and multisensor high-fidelity catheters to exclude heart disease in a unique population of young adults. BACKGROUND: There has been resurgence in comprehensive hemodynamic evaluation of complex cardiovascular patients. Although dynamic assessments during cardiac catheterization have become commonplace, there remains limited information regarding left and right heart hemodynamic changes during supine exercise in young adults. METHODS: The study population was derived from a retrospective review of catheterization records at Brooke Army Medical Center for active duty patients (ages: 19-40 years) in whom hemodynamic waveforms were obtained with multisensor high-fidelity catheters and supine exercise testing (53.1 +/- 12.6 watts) and angiography performed to exclude heart disease. We report findings from 41 males and 1 female (ages: 19-40 years) found free of heart disease. RESULTS: Submaximal exercise was associated with ~ fourfold (P < 0.001) increase in minute ventilation (VE), O2 consumption (VO2 ) and carbon dioxide production (VCO2 ). VE/VCO2 ratio decreased (-16.8 +/- 13.9%, P < 0.001) and VE/VCO2 slope was 22.6 +/- 0.6 (+/-SE). Cardiac index (CI) increased with VO2 (DeltaCI/DeltaVO2 slope = 7.6 +/- 2.2). Heart rate increased nearly 10 bpm per 100 mL O2 /min/M2 , whereas, changes in stroke volume were more variable. Pulmonary artery (PA) saturations fell from 77 to 55% (P < 0.001). No change was noted in mean right atrial pressures; PA pressures increased ~10 mm Hg (P < 0.001). Pulmonary capillary wedge and left ventricular end-diastolic pressures increased ~2 mm Hg (P < 0.001) but variability noted between individuals. CONCLUSION: This study provides insight into past practices of invasive cardiopulmonary testing and furthers the understanding of metabolic and hemodynamic changes in a young population during supine submaximal exercise. (c) 2017 Wiley Periodicals, Inc. PMID- 28805342 TI - Deletion of the activating NK cell receptor NKG2D accelerates rejection of cardiac allografts. AB - It has already been shown that neutralization of the activating NK cell receptor NKG2D in combination with co-stimulation blockade prolongs graft survival of vascularized transplants. In order to clarify the underlying cellular mechanisms, we transplanted complete MHC-disparate BALB/c-derived cardiac grafts into C57BL/6 wildtypes or mice deficient for NKG2D (Klrk1-/- ). Although median survival was 8 days for both recipient groups, we detected already at day 5 posttransplantation significantly greater intragraft frequencies of NKp46+ NK cells in Klrk1-/- recipients than in wildtypes. This was followed by a significantly greater infiltration of CD4+ , but a lesser infiltration of CD8+ T cell frequencies. Contrary to published observations, co-stimulation blockade with CTLA4-Ig resulted in a significant acceleration of cardiac rejection by Klrk1-/- recipients, and this result was confirmed by applying a neutralizing antibody against NKG2D to wildtypes. In both experimental setups, grafts derived from Klrk1-/- recipients were characterized by significantly higher levels of interferon-gamma mRNA, and both CD4+ and CD8+ T cells displayed a greater capacity for degranulation and interferon-gamma production. In summary, our results clearly illustrate that NKG2D expression in the recipient is important for cardiac allograft survival, thus supporting the hypothesis that impairment of NK cells prevents the establishment of graft acceptance. PMID- 28805344 TI - High potential for temperate viruses to drive carbon cycling in chemoautotrophy dominated shallow-water hydrothermal vents. AB - Viruses are the most abundant life forms in the world's oceans and they are key drivers of biogeochemical cycles, but their impact on the microbial assemblages inhabiting hydrothermal vent ecosystems is still largely unknown. Here, we analysed the viral life strategies and virus-host interactions in the sediments of a newly discovered shallow-water hydrothermal field of the Mediterranean Sea. Our study reveals that temperate viruses, once experimentally induced to replicate, can cause large mortality of vent microbes, significantly reducing the chemoautotrophic carbon production, while enhancing the metabolism of microbial heterotrophs and the re-cycling of the organic matter. These results provide new insights on the factors controlling primary and secondary production processes in hydrothermal vents, suggesting that the inducible provirus-host interactions occurring in these systems can profoundly influence the functioning of the microbial food web and the efficiency in the energy transfer to the higher trophic levels. PMID- 28805345 TI - Laparoscopic sleeve gastrectomy improves renal transplant candidacy and posttransplant outcomes in morbidly obese patients. AB - Morbid obesity is a barrier to kidney transplantation due to inferior outcomes, including higher rates of new-onset diabetes after transplantation (NODAT), delayed graft function (DGF), and graft failure. Laparoscopic sleeve gastrectomy (LSG) increases transplant eligibility by reducing BMI in kidney transplant candidates, but the effect of surgical weight loss on posttransplantation outcomes is unknown. Reviewing single-center medical records, we identified all patients who underwent LSG before kidney transplantation from 2011-2016 (n = 20). Post-LSG kidney recipients were compared with similar-BMI recipients who did not undergo LSG, using 2:1 direct matching for patient factors. McNemar's test and signed-rank test were used to compare groups. Among post-LSG patients, mean BMI +/- standard deviation (SD) was 41.5 +/- 4.4 kg/m2 at initial encounter, which decreased to 32.3 +/- 2.9 kg/m2 prior to transplantation (P < .01). No complications, readmissions, or mortality occurred following LSG. After transplantation, one patient (5%) experienced DGF, and no patients experienced NODAT. Allograft and patient survival at 1-year posttransplantation was 100%. Compared with non-LSG patients, post-LSG recipients had lower rates of DGF (5% vs 20%) and renal dysfunction-related readmissions (10% vs 27.5%) (P < .05 each). Perioperative complications, allograft survival, and patient survival were similar between groups. These data suggest that morbidly obese patients with end stage renal disease who undergo LSG to improve transplant candidacy, achieve excellent posttransplantation outcomes. PMID- 28805346 TI - Melanin quantification by in vitro and in vivo analysis of near-infrared fluorescence. AB - Objective measurements of melanin can provide important information for differentiating melanoma from benign pigmented lesions and in assessing pigmentary diseases. Herein, we evaluate near-infrared (NIR) fluorescence as a possible tool to quantify melanin. Various concentrations of in vitro Sepia melanin in tissue phantoms were measured with NIR fluorescence and diffuse reflectance spectroscopy. Similar optic measurements were conducted in vivo on 161 normal human skin sites. Diffuse reflectance spectroscopy was used to quantify the melanin content via Stamatas-Kollias algorithm. At physiologic concentrations, increasing in vitro melanin concentrations demonstrated higher fluorescence that was linearly correlated (R2 = 0.99, p < .001). At higher concentrations, the fluorescence signal plateaued. A linear relationship was also observed with melanin content in human skin (R2 = 0.59, p < .001). Comparing the fluorescence and reflectance signals with in vitro and in vivo samples, the estimated melanin concentration in human skin ranged between 0 and 1.25 mg/ml, consistent with previous quantitative studies involving invasive methods. PMID- 28805347 TI - Bioelectricity (electromicrobiology) and sustainability. AB - Electromicrobiology is the domain of those prokaryotes able to interact with charged electrodes, using them as electron donors and/or electron acceptors. This is performed via a process called extracellular electron transport, in which outer membrane cytochromes are used to oxidize and/or reduce otherwise unavailable insoluble electron acceptors. EET-capable bacteria can thus be used for a variety of purposes, ranging from small power sources, water reclamation, to pollution remediation and electrosynthesis. Because the study of EET-capable bacteria is in its nascent phase, the applications are mostly in developmental stages, but the potential for significant contributions to environmental quality is high and moving forward. PMID- 28805348 TI - Levocarnitine Decreases Intradialytic Hypotension Episodes: A Randomized Controlled Trial. AB - Intradialytic hypotension is common complication in stage 5 chronic kidney disease patients on hemodialysis. Incidence ranges from 15 to 30%. These patients have levocarnitine deficiency. A randomized, placebo-controlled quadruple-blinded trial was designed to demonstrate the levocarnitine efficiency on intradialytic hypotension prevention. Patients were randomized into four groups, to receive levocarnitine or placebo. During the intervention period, levocarnitine and placebo was administered 0 and 30 min before each hemodialysis session, respectively. During the trial, 33 patients received 1188 hemodialysis sessions. We identified 239 (21.3%) intradialytic hypotension episodes. The intradialytic hypotension episodes were less frequent in the levocarnitine group (9.3%, 60 IH events) (P < 0.001). Hemodialysis is frequently perplexed by intradialytic hypotension episodes. Levocarnitine supplementation before each hemodialysis session efficiently diminishes the intradialytic hypotension episodes. This is a new application method that must be considered and explored. PMID- 28805349 TI - CRISPR-assisted receptor deletion reveals distinct roles for ERBB2 and ERBB3 in skin keratinocytes. AB - While the epidermal growth factor receptor (EGFR) is an established regulator of skin development and homeostasis, the functions of the related tyrosine kinase receptors ERBB2 and ERBB3 in this tissue have only recently been examined. Previously reported, skin-specific deletion of each of these receptors in mice resulted in similar defects in keratinocyte proliferation and migration, resulting in impaired wound healing and tumorigenesis. Because both ERBB2 and ERBB3 are targets for treating an array of cancer types, it is important to examine the consequences of receptor inhibition in human keratinocytes. Here, we employed the CRISPR/Cas9 technology to generate HaCaT cells (an established human keratinocyte cell line) lacking ERBB2 or ERBB3. HaCaT clones lacking ERBB2 or ERBB3 showed comparable reductions in cell proliferation as assessed by BrdU staining. Apoptosis, in contrast, was reduced in ERBB3-deficient HaCaT cells only. Assessment of cell migration using a wound healing (scratch) assay showed that the closure of the wound gaps was completed by 48 h in mock and in ERBB3 knockout clones. In contrast, this process was considerably delayed in ERBB2 knockout clones, and a complete closure of the gap in the latter cells did not occur before 72 h. In conclusion, both ERBB2 and ERBB3 are essential for normal proliferation of skin keratinocytes, but in contrast to ERBB3, ERBB2 is essential for migration of human keratinocytes. These observations might bear significance to patient adverse effects of therapeutic agents targeting ERBB2 and ERBB3. PMID- 28805350 TI - Predicting student success in nurse practitioner programs. AB - BACKGROUND AND PURPOSE: Criteria for admission to nurse practitioner (NP) and other professional programs provide a snapshot of students' potential for success in those programs. Critical examination of admission criteria is a vital component of ensuring timely matriculation and completion of NP programs. The purpose of the current study was to examine the relationship between admission criteria and student progression and completion of NP programs. METHODS: A retrospective review of 150 randomly selected student records from a total of 232 available records was conducted. A predictive correlational design was used to examine factors that influence success in NP programs. CONCLUSIONS: Statistically significant relationships existed among type of admission status, change in program concentration, age, Graduate Record Examination (GRE) verbal score, GRE quantitative score, total GRE scores, and program progression and completion. IMPLICATIONS FOR PRACTICE: Data collection from this and related research is paramount in developing information infrastructures that support consistent evaluation and revision of admission criteria and program curricula. Leaders in academia can use these data to achieve instructional excellence, improve education systems, and ensure timely matriculation through NP programs. This facilitates workforce planning and supports efforts to meet the expanding need for primary care providers. PMID- 28805351 TI - Microbial melanins for radioprotection and bioremediation. AB - Microbial melanins provide a biocompatible and scalable approach for bioremediation and radioprotection technologies due to their physicochemical properties. PMID- 28805352 TI - Vagus nerve schwannoma in the right upper mediastinum. AB - A 35-year-old woman was admitted to our hospital with an abnormal shadow on her chest roentgenogram. Computed tomography showed that a tumor was located in the right upper mediastinum. Resection of the tumor by video-assisted thoracoscopic surgery was performed. Operative findings determined that the tumor originated from the right vagus nerve and was diagnosed as schwannoma by pathological examination. PMID- 28805353 TI - The role of Melatonin receptor MTNR1A in the action of Melatonin on bovine granulosa cells. AB - Granulosa cells (GCs) play an important role in ovarian follicle growth, development, and follicular atresia. In the present study, we investigated the effects of Melatonin on bovine GCs, and asked if MTNR1A was involved in their response to this indole hormone. Our results indicated that Melatonin inhibited GC apoptosis by up-regulating the expression of BCL2, BCL-XL, GPX4, and SOD1, and down-regulating the expression of BAX, CASP3, and TP53. Moreover, Melatonin modulated bovine GC function by decreasing the expression of INHA, INHBB, FSHR, and TGFBR3, and the abundance of Inhibin beta and Activin B, while increasing the expression of LHR, INHBA, and secretion of progesterone by GCs. In contrast, knockdown of MTNR1A significantly increased the expression of BAX, CASP3, TP53, INHA, FSHR, and TGFBR3, as well as Inhibin beta abundance, while decreasing the expression of BCL2, GPX4, SOD1, and LHR, and production of progesterone and estradiol; no effect was observed on the expression of BCL-XL, INHBA, or INHBB. These results suggest that Melatonin and MTNR1A play an important role in modulating bovine GC function by regulating cellular progression, apoptosis, hormones secretion, and reproduction-related genes. Furthermore, altered expression of MTNR1A could affect how bovine GCs respond to Melatonin. PMID- 28805354 TI - Microbial ecology-based engineering of Microbial Electrochemical Technologies. AB - Microbial ecology is devoted to the understanding of dynamics, activity and interaction of microorganisms in natural and technical ecosystems. Bioelectrochemical systems represent important technical ecosystems, where microbial ecology is of highest importance for their function. However, whereas aspects of, for example, materials and reactor engineering are commonly perceived as highly relevant, the study and engineering of microbial ecology are significantly underrepresented in bioelectrochemical systems. This shortfall may be assigned to a deficit on knowledge and power of these methods as well as the prerequisites for their thorough application. This article discusses not only the importance of microbial ecology for microbial electrochemical technologies but also shows which information can be derived for a knowledge-driven engineering. Instead of providing a comprehensive list of techniques from which it is hard to judge the applicability and value of information for a respective one, this review illustrates the suitability of selected techniques on a case study. Thereby, best practice for different research questions is provided and a set of key questions for experimental design, data acquisition and analysis is suggested. PMID- 28805355 TI - Sensing Mg2+ contributes to the resistance of Pseudomonas aeruginosa to complement-mediated opsonophagocytosis. AB - Pseudomonas aeruginosa adaptation to survive in the host hinges on its ability to probe the environment and respond appropriately. Rapid adaptation is often mediated by two-component regulatory systems, such as the PhoP/PhoQ system that responds to Mg2+ ion concentration. However, there is limited information about the role of PhoQ in P. aeruginosa bloodstream infections. We used a murine model of systemic infection to test the virulence of a PhoQ-deficient mutant. Mutation of PhoQ impaired the virulence and the ability to cause bacteremia of P. aeruginosa. In the presence of blood concentrations of Mg2+ , a PhoQ mutant bound more C3 and was more susceptible to complement-mediated opsonophagocytosis than the parent strain, suggesting a direct effect of the Mg2+ on the modulation of expression of a bacterial component controlled by the PhoP/PhoQ system. Ligand blot analysis, C3 binding experiments and opsonophagocytosis assays identified this component as the outer membrane protein OprH, expression of which impaired the virulence of P. aeruginosa in a murine model of systemic infection. We demonstrate that expression of PhoQ is essential to detect Mg2+ and reduce the expression of OprH, a previously unrecognized C3 binding molecule that promotes the opsonophagocytosis of P. aeruginosa. PMID- 28805356 TI - Immersion medicine programme for secondary students. AB - BACKGROUND: Although the proportion of ethnicities representing under-represented minorities in medicine (URM) in the general population has significantly increased, URM enrolment in medical schools within the USA has remained stagnant in recent years. METHODS: This study sought to examine the effect of an immersion in community medicine (ICM) programme on secondary school students' desire to enter the field of medicine and serve their communities. The authors asked all 69 ICM alumni to complete a 14-question survey consisting of six demographic, four programme and four career questions, rated on a Likert scale of 1 (completely disagree) to 5 (completely agree), coupled with optional free-text questions. Data were analysed using GraphPad prism and nvivo software. RESULTS: A total of 61 students responded, representing a response rate of 88.4 per cent, with a majority of respondents (73.7%) from URM backgrounds. An overwhelming majority of students agreed (with a Likert rating of 4 or 5) that the ICM programme increased their interest in becoming a physician (n = 56, 91.8%). Students reported shadowing patient-student-physician interactions to be the most useful (n = 60, 98.4%), and indicated that they felt that they would be more likely to lead to serving the local community as part of their future careers (n = 52, 85.3%). Of the students that were eligible to apply to medical school (n = 13), a majority (n = 11, 84.6%) have applied to medical school. URM enrolment in medical schools within the USA has remained stagnant in recent years DISCUSSION: Use of a community medicine immersion programme may help encourage secondary students from URM backgrounds to gain the confidence to pursue a career in medicine and serve their communities. Further examination of these programmes may yield novel insights into recruiting URM students to medicine. PMID- 28805357 TI - Schedule for Rating Disabilities; Dental and Oral Conditions. Final rule. AB - This document amends the Department of Veterans Affairs (VA) Schedule for Rating Disabilities by revising the portion of the schedule that addresses dental and oral conditions. The effect of this action is to ensure that the rating schedule uses current medical terminology and to provide detailed and updated criteria for evaluation of dental and oral conditions for disability rating purposes. PMID- 28805358 TI - Medicare Program; Inpatient Rehabilitation Facility Prospective Payment System for Federal Fiscal Year 2018. Final rule. AB - This final rule updates the prospective payment rates for inpatient rehabilitation facilities (IRFs) for federal fiscal year (FY) 2018 as required by the statute. As required by section 1886(j)(5) of the Social Security Act (the Act), this rule includes the classification and weighting factors for the IRF prospective payment system's (IRF PPS) case-mix groups and a description of the methodologies and data used in computing the prospective payment rates for FY 2018. This final rule also revises the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) diagnosis codes that are used to determine presumptive compliance under the "60 percent rule," removes the 25 percent payment penalty for inpatient rehabilitation facility patient assessment instrument (IRF-PAI) late transmissions, removes the voluntary swallowing status item (Item 27) from the IRF-PAI, summarizes comments regarding the criteria used to classify facilities for payment under the IRF PPS, provides for a subregulatory process for certain annual updates to the presumptive methodology diagnosis code lists, adopts the use of height/weight items on the IRF-PAI to determine patient body mass index (BMI) greater than 50 for cases of single-joint replacement under the presumptive methodology, and revises and updates measures and reporting requirements under the IRF quality reporting program (QRP). PMID- 28805359 TI - Medicare Program; Prospective Payment System and Consolidated Billing for Skilled Nursing Facilities for FY 2018, SNF Value-Based Purchasing Program, SNF Quality Reporting Program, Survey Team Composition, and Correction of the Performance Period for the NHSN HCP Influenza Vaccination Immunization ReportingMeasure in the ESRD QIP for PY 2020. Final rule. AB - This final rule updates the payment rates used under the prospective payment system (PPS) for skilled nursing facilities (SNFs) for fiscal year (FY) 2018. It also revises and rebases the market basket index by updating the base year from 2010 to 2014, and by adding a new cost category for Installation, Maintenance, and Repair Services. The rule also finalizes revisions to the SNF Quality Reporting Program (QRP), including measure and standardized resident assessment data policies and policies related to public display. In addition, it finalizes policies for the Skilled Nursing Facility Value-Based Purchasing Program that will affect Medicare payment to SNFs beginning in FY 2019. The final rule also clarifies the regulatory requirements for team composition for surveys conducted for investigating a complaint and aligns regulatory provisions for investigation of complaints with the statutory requirements. The final rule also finalizes the performance period for the National Healthcare Safety Network (NHSN) Healthcare Personnel (HCP) Influenza Vaccination Reporting Measure included in the End-Stage Renal Disease (ESRD) Quality Incentive Program (QIP) for Payment Year 2020. PMID- 28805360 TI - Medicare Program; FY 2018 Hospice Wage Index and Payment Rate Update and Hospice Quality Reporting Requirements. Final rule. AB - This final rule will update the hospice wage index, payment rates, and cap amount for fiscal year (FY) 2018. Additionally, this rule includes new quality measures and provides an update on the hospice quality reporting program. PMID- 28805361 TI - Medicare Program; Hospital Inpatient Prospective Payment Systems for Acute Care Hospitals and the Long-Term Care Hospital Prospective Payment System and Policy Changes and Fiscal Year 2018 Rates; Quality Reporting Requirements for Specific Providers; Medicare and Medicaid Electronic Health Record (EHR)Incentive Program Requirements for Eligible Hospitals, Critical Access Hospitals, and Eligible Professionals; Provider-Based Status of Indian Health Service and Tribal Facilities and Organizations; Costs Reporting and Provider Requirements; Agreement Termination Notices. Final rule. AB - We are revising the Medicare hospital inpatient prospective payment systems (IPPS) for operating and capital-related costs of acute care hospitals to implement changes arising from our continuing experience with these systems for FY 2018. Some of these changes implement certain statutory provisions contained in the Pathway for Sustainable Growth Rate (SGR) Reform Act of 2013, the Improving Medicare Post-Acute Care Transformation Act of 2014, the Medicare Access and CHIP Reauthorization Act of 2015, the 21st Century Cures Act, and other legislation. We also are making changes relating to the provider-based status of Indian Health Service (IHS) and Tribal facilities and organizations and to the low-volume hospital payment adjustment for hospitals operated by the IHS or a Tribe. In addition, we are providing the market basket update that will apply to the rate-of-increase limits for certain hospitals excluded from the IPPS that are paid on a reasonable cost basis subject to these limits for FY 2018. We are updating the payment policies and the annual payment rates for the Medicare prospective payment system (PPS) for inpatient hospital services provided by long term care hospitals (LTCHs) for FY 2018. In addition, we are establishing new requirements or revising existing requirements for quality reporting by specific Medicare providers (acute care hospitals, PPS-exempt cancer hospitals, LTCHs, and inpatient psychiatric facilities). We also are establishing new requirements or revising existing requirements for eligible professionals (EPs), eligible hospitals, and critical access hospitals (CAHs) participating in the Medicare and Medicaid Electronic Health Record (EHR) Incentive Programs. We are updating policies relating to the Hospital Value-Based Purchasing (VBP) Program, the Hospital Readmissions Reduction Program, and the Hospital-Acquired Condition (HAC) Reduction Program. We also are making changes relating to transparency of accrediting organization survey reports and plans of correction of providers and suppliers; electronic signature and electronic submission of the Certification and Settlement Summary page of the Medicare cost reports; and clarification of provider disposal of assets. PMID- 28805362 TI - How the Affordable Care Act Has Helped Women Gain Insurance and Improved Their Ability to Get Health Care: Findings from the Commonwealth Fund Biennial Health Insurance Survey, 2016. AB - ISSUE: Prior to the Affordable Care Act (ACA), one-third of women who tried to buy a health plan on their own were either turned down, charged a higher premium because of their health, or had specific health problems excluded from their plans. Beginning in 2010, ACA consumer protections, particularly coverage for preventive care screenings with no cost-sharing and a ban on plan benefit limits, improved the quality of health insurance for women. In 2014, the law's major insurance reforms helped millions of women who did not have employer insurance to gain coverage through the ACA's marketplaces or through Medicaid. GOALS: To examine the effects of ACA health reforms on women's coverage and access to care. METHOD: Analysis of the Commonwealth Fund Biennial Health Insurance Surveys, 2001 2016. FINDINGS AND CONCLUSIONS: Women ages 19 to 64 who shopped for new coverage on their own found it significantly easier to find affordable plans in 2016 compared to 2010. The percentage of women who reported delaying or skipping needed care because of costs fell to an all-time low. Insured women were more likely than uninsured women to receive preventive screenings, including Pap tests and mammograms. PMID- 28805364 TI - Laser Direct Writing of Tree-Shaped Hierarchical Cones on a Superhydrophobic Film for High-Efficiency Water Collection. AB - Directional water collection has stimulated a great deal of interest because of its potential applications in the field of microfluidics, liquid transportation, fog harvesting, and so forth. There have been some bio or bioinspired structures for directional water collection, from one-dimensional spider silk to two dimensional star-like patterns to three-dimensional Nepenthes alata. Here we present a simple way for the accurate design and highly controllable driving of tiny droplets: by laser direct writing of hierarchical patterns with modified wettability and desired geometry on a superhydrophobic film, the patterned film can precisely and directionally drive tiny water droplets and dramatically improve the efficiency of water collection with a factor of ~36 compared with the original superhydrophobic film. Such a patterned film might be an ideal platform for water collection from humid air and for planar microfluidics without tunnels. PMID- 28805363 TI - Selective Chemical Response of Transition Metal Dichalcogenides and Metal Dichalcogenides in Ambient Conditions. AB - To fabricate practical devices based on semiconducting two-dimensional (2D) materials, the source, channel, and drain materials are exposed to ambient air. However, the response of layered 2D materials to air has not been fully elucidated at the molecular level. In the present report, the effects of air exposure on transition metal dichalcogenides (TMD) and metal dichalcogenides (MD) are studied using ultrahigh-vacuum scanning tunneling microscopy (STM). The effects of a 1-day ambient air exposure on MBE-grown WSe2, chemical vapor deposition (CVD)-grown MoS2, and MBE SnSe2 are compared. Both MBE-grown WSe2 and CVD-grown MoS2 display a selective air exposure response at the step edges, consistent with oxidation on WSe2 and adsorption of hydrocarbon on MoS2, while the terraces and domain/grain boundaries of both TMDs are nearly inert to ambient air. Conversely, MBE-grown SnSe2, an MD, is not stable in ambient air. After exposure in ambient air for 1 day, the entire surface of SnSe2 is decomposed to SnOx and SeOx, as seen with X-ray photoelectron spectroscopy. Since the oxidation enthalpy of all three materials is similar, the data is consistent with greater oxidation of SnSe2 being driven by the weak bonding of SnSe2. PMID- 28805365 TI - Removal of Cells from Body Fluids by Magnetic Separation in Batch and Continuous Mode: Influence of Bead Size, Concentration, and Contact Time. AB - The magnetic separation of pathogenic compounds from body fluids is an appealing therapeutic concept. Recently, removal of a diverse array of pathogens has been demonstrated using extracorporeal dialysis-type devices. The contact time between the fluid and the magnetic beads in such devices is limited to a few minutes. This poses challenges, particularly if large compounds such as bacteria or cells need to be removed. Here, we report on the feasibility to remove cells from body fluids in a continuous dialysis type of setting. We assessed tumor cell removal efficiencies from physiological fluids with or without white blood cells using a range of different magnetic bead sizes (50-4000 nm), concentrations, and contact times. We show that tumor cells can be quantitatively removed from body fluids within acceptable times (1-2 min) and bead concentrations (0.2 mg per mL). We further present a mathematical model to describe the minimal bead number concentration needed to remove a certain number of cells, in the presence of competing nonspecific uptake. The present study paves the way for investigational studies to assess the therapeutic potential of cell removal by magnetic blood purification in a dialysis-like setting. PMID- 28805366 TI - Simultaneous Top and Bottom Perovskite Interface Engineering by Fullerene Surface Modification of Titanium Dioxide as Electron Transport Layer. AB - Optimization of the interface between the electron transport layer (ETL) and the hybrid perovskite is crucial to achieve high-performance perovskite solar cell (PSC) devices. Fullerene-based compounds have attracted attention as modifiers on the surface properties of TiO2, the archetypal ETL in regular n-i-p PSCs. However, the partial solubility of fullerenes in the aprotic solvents used for perovskite deposition hinders its application to low-temperature solution processed PSCs. In this work, we introduce a new method for fullerene modification of TiO2 layers derived from nanoparticles (NPs) inks. Atomic force microscopy characterization reveals that the resulting ETL is a network of TiO2 NPs interconnected by fullerenes. Interestingly, this surface modification enhances the bottom interface of the perovskite by improving the charge transfer as well as the top perovskite interface by reducing surface trap states enhancing the contact with the p-type buffer layer. As a result, rigid PSCs reached a 17.2% power conversion efficiency (PCE), while flexible PSCs exhibited a remarkable stabilized PCE of 12.2% demonstrating the potential application of this approach for further scale-up of PSC devices. PMID- 28805367 TI - Tailoring Membrane Surface Properties and Ultrafiltration Performances via the Self-Assembly of Polyethylene Glycol-block-Polysulfone-block-Polyethylene Glycol Block Copolymer upon Thermal and Solvent Annealing. AB - Recently, ultrafiltration (UF) membranes have faced great challenges including the fine control of membrane surfaces for high filtration performances and antifouling properties in treating complex solution systems. Here, a particular type of amphiphilic block copolymer polyethylene glycol-block-polysulfone-block polyethylene glycol (PEG-b-PSf-b-PEG) was synthesized through one-pot step-growth polymerization with mPEG [monomethylpoly(ethylene glycol)] as two ends to achieve the mobility of hydrophilic polymer chains. Without any other polymers or additives involved, the PEG-b-PSf-b-PEG triblock copolymer UF membrane was fabricated through the non-solvent-induced phase separation (NIPS) method. The surface properties and filtration performances of UF membranes were tailored through the self-assembly of PEG-b-PSf-b-PEG triblock copolymers combining the thermal and solvent annealing treatments in water at 90 degrees C for 16 h. The annealed PEG-b-PSf-b-PEG triblock copolymer membrane significantly enhanced its water flux resulting from the increased mean pore size with the improved porosity, as well as the decreased skin layer thickness, upon annealing. More importantly, the PEG-b-PSf-b-PEG triblock copolymer membrane surface turned from hydrophobic to hydrophilic upon annealing with the PEG enrichment on the surface, and exhibited improved protein antifouling performances. Our research opens a new avenue to tailor the membrane structure and surface properties by self-assembly of amphiphilic block copolymers upon thermal and solvent annealing treatments. PMID- 28805368 TI - Pyrophosphate Recognition and Sensing in Water Using Bis[zinc(II)dipicolylamino] Functionalized Peptides. AB - Phosphate oxoanions and phosphorylated biomolecules (such as nucleotides, lipids, and proteins) play key roles in a wide range of biological processes. The ability to selectively detect these ions in the presence of each other has numerous applications in biochemistry and biomedicine. However, receptors and sensors that can discriminate between polyphosphate species with high selectivity and in biologically relevant conditions are rare. In this Account, we show how peptides (both cyclic and linear) can be used to position two zinc(II)dipicolylamine [Zn(II)DPA] binding sites in an appropriate arrangement to provide selective binding of pyrophosphate (PPi) in the presence of other polyphosphate species, including ATP, and in complex media such as cell growth buffer. The use of peptide scaffolds to position the Zn(II)DPA anion binding sites allowed the synthesis of small receptor libraries in which the arrangement of the two binding sites could be subtly altered to evaluate the factors affecting both binding selectivity and affinity for PPi. We altered a number of structural elements including peptide length, cyclic peptide ring size, amino acid composition, the positioning of the binding sites with respect to one another, and the relative stereochemistry of the peptides. Backbone modified cyclic peptides based on the Lissoclinum class of natural products were initially employed to provide an added degree of preorganization to the receptors, although it was subsequently found that short, flexible bis[Zn(II)DPA]-functionalized linear peptides are also effective scaffolds for selective pyrophosphate recognition. The peptidic receptors were successfully employed for the detection of PPi in aqueous media by indicator displacement assays using both colorimetric and fluorescent indicators, with the best compounds able to bind to PPi selectively in both cell growth media and artificial urine and also allow the accurate determination of PPi concentrations in physiologically relevant ranges (micromolar concentrations) in these complex media. Improved pyrophosphate selectivity was observed upon increasing the complexity of the media from HEPES buffer to cell growth media (Krebs saline). Pyrophosphate sensors in which a fluorescent indicator was covalently attached to either a linear or cyclic peptide scaffold through a flexible linker were then constructed. When the Zn(II)DPA binding sites and the indicator were suitably placed with respect to one another on the peptide scaffold, these 'intramolecular indicator displacement assays' showed improved selectivity for PPi over other polyphosphate anions, such as ATP, when compared to the intermolecular indicator displacement assays. This observation provides the basis for the design and application of future PPi sensors in biochemistry and biomedicine. PMID- 28805369 TI - Solid State Sensor for Simultaneous Measurement of Total Alkalinity and pH of Seawater. AB - A novel design is demonstrated for a solid state, reagent-less sensor capable of rapid and simultaneous measurement of pH and Total Alkalinity (AT) using ion sensitive field effect transistor (ISFET) technology to provide a simplified means of characterization of the aqueous carbon dioxide system through measurement of two "master variables": pH and AT. ISFET-based pH sensors that achieve 0.001 precision are widely used in various oceanographic applications. A modified ISFET is demonstrated to perform a nanoliter-scale acid-base titration of AT in under 40 s. This method of measuring AT, a Coulometric Diffusion Titration, involves electrolytic generation of titrant, H+, through the electrolysis of water on the surface of the chip via a microfabricated electrode eliminating the requirement of external reagents. Characterization has been performed in seawater as well as titrating individual components (i.e., OH-, HCO3 , CO32-, B(OH)4-, PO43-) of seawater AT. The seawater measurements are consistent with the design in reaching the benchmark goal of 0.5% precision in AT over the range of seawater AT of ~2200-2500 MUmol kg-1 which demonstrates great potential for autonomous sensing. PMID- 28805370 TI - Chirality Transfer from Chiral Monoamines to an m-Phthalic Diamide-Linked Zinc Bisporphyrinate with a Benzylamide Substituent. AB - An m-phthalic diamide-linked bisporphyrin with a benzylamide substituent has been designed and synthesized. It has two types of carbonyl groups. In the solution of this zinc bisporphyrinate, these carbonyl groups are involved in the formation of two different Zn-O coordination interactions: one is formed between neighboring zinc bisporphyrinates; another is formed within zinc bisporphyrinate. The chirality sensing abilities of this zinc porphyrinate to a number of chiral monoamines have been examined. When zinc bisporphyrinate was mixed with a series of chiral monoamines, the signs of the circular dichroism spectra for the chiral monoamines of the same handedness with an aryl group as the substituent are just opposite to those with an alkyl group as the substituent. NMR studies reveal that stepwise coordinations lead to 1:1 and 1:2 host-guest complexes. The structure of the 1:1 host-guest complex was confirmed by crystallography, it is the first time that a 1:1 host-guest complex formed between zinc bisporphyrinate and a chiral monoamine has been crystallographically characterized. The structure reveals that there is an intramolecular hydrogen bond between the amide oxygen and the coordinated NH2. We further investigated the chirality transfer mechanism by density functional theory calculations. Our studies suggest that the interactions between the linker and guests in this bisporphyrin system are crucial in the chirality transfer process, and the nature of the bulkiest substituent of chiral monoamines makes a difference. For R-type guests, with an alkyl group, the steric repulsion makes the conformer A more energetically favorable, which leads to the anticlockwise twist and negative Cotton effect. However, with an aryl group, the pi-pi interaction makes the conformer B more energetically favorable, which leads to the clockwise twist and positive Cotton effect. PMID- 28805371 TI - Wavelength-Resolved Photon Fluxes of Indoor Light Sources: Implications for HOx Production. AB - Photochemistry is a largely unconsidered potential source of reactive species such as hydroxyl and peroxy radicals (OH and HO2, "HOx") indoors. We present measured wavelength-resolved photon fluxes and distance dependences of indoor light sources including halogen, incandescent, and compact fluorescent lights (CFL) commonly used in residential buildings; fluorescent tubes common in industrial and commercial settings; and sunlight entering buildings through windows. We use these measurements to predict indoor HOx production rates from the photolysis of nitrous acid (HONO), hydrogen peroxide (H2O2), ozone (O3), formaldehyde (HCHO), and acetaldehyde (CH3CHO). Our results suggest that while most lamps can photolyze these molecules, only sunlight and fluorescent tubes will be important to room-averaged indoor HOx levels due to the strong distance dependence of the fluxes from compact bulbs. Under ambient conditions, we predict that sunlight and fluorescent lights will photolyze HONO to form OH at rates of 106-107 molecules cm-3 s-1, and that fluorescent lights will photolyze HCHO to form HO2 at rates of ~106 molecules cm-3 s-1; rates could be 2 orders of magnitude higher under high precursor concentrations. Ozone and H2O2 will not be important photochemical OH sources under most conditions, and CH3CHO will generally increase HO2 production rates only slightly. We also calculated photolysis rate constants for nitrogen dioxide (NO2) and nitrate radicals (NO3) in the presence of the different light sources. Photolysis is not likely an important fate for NO3 indoors, but NO2 photolysis could be an important source of indoor O3. PMID- 28805372 TI - Cobalt Nanoparticles Encapsulated in Porous Carbons Derived from Core-Shell ZIF67@ZIF8 as Efficient Electrocatalysts for Oxygen Evolution Reaction. AB - The synthesis of electrocatalysts consisting of selectively functionalized parts is an effective strategy to prepare nonprecious electrocatalysts with excellent performance for oxygen evolution reaction (OER). Herein, we synthesized core shell structured ZIF67@ZIF8 and converted it into Co decorated porous carbons (CS Co/Cs) consisting of the ZIF67 derived uniformly dispersed Co nanoparticles encapsulated in graphitic carbon as cores and the ZIF8 derived porous carbon as shells. Compared to individual ZIF67 derived samples (Co/Cs), the unique structure of CS-Co/Cs leads to the larger surface area and more hydrophilic surface, both of which facilitate the mass transfer, contributing to the enhanced OER performance. The optimized CS-Co/C sample presents the low overpotential of 290 mV to deliver 10 mA cm-2 toward OER in 1 M KOH, which is among the best of the reported nonprecious OER electrocatalysts. The CS-Co/C exhibits no obvious current attenuation at 1.53 V for 30 000 s, demonstrating its robust stability. PMID- 28805374 TI - Construction of MoO2 Quantum Dot-Graphene and MoS2 Nanoparticle-Graphene Nanoarchitectures toward Ultrahigh Lithium Storage Capability. AB - Herein, MoO2 quantum dots (QDs; <5 nm) are synthesized through a one-step solvothermal process. MoO2 QD-bonded graphene sheets (MoO2-QDs@RGO) are facilely produced and can be further converted through sulfidation into MoS2 nanoparticle bonded graphene sheets (MoS2-NPs@RGO). The novel MoO2-QDs@RGO electrodes demonstrate exceptionally attractive lithium storage capability (e.g., 1257 mA h g-1 at 100 mA g-1, being close to the highest values ever reported for a MoO2 based lithium ion battery electrode), rate capability, and cycle stability. Moreover, the MoS2-NPs@RGO delivered a superior capacity (1497 mA h g-1 at 100 mA g-1) with outstanding rate retention and cycling stability. The superior lithium storage capabilities are ascribed to the synergetic effects of the high-surface area graphene sheets, the well-dispersed MoS2 nanoparticles, and their strong bonding with each other, which effectively prevents aggregation of MoS2 while the composite architecture allows fast transport of electrons and ions. PMID- 28805373 TI - Inefficient Ribosomal Skipping Enables Simultaneous Secretion and Display of Proteins in Saccharomyces cerevisiae. AB - The need for recombinant expression of soluble protein slows the validation of engineered proteins isolated from combinatorial libraries and limits the number of protein variants evaluated. To overcome this bottleneck, we describe a system for simultaneous cell surface display and soluble secretion of proteins in Saccharomyces cerevisiae based on inefficient ribosomal skipping. Ribosomal skipping mediated by "self-cleaving" 2A peptides produces two proteins from a single open reading frame. Incorporation of the F2A peptide sequence-with ~50% efficiency of ribosomal skipping-between the protein of interest and the yeast cell wall protein Aga2 results in simultaneous expression of both the solubly secreted protein and the protein-Aga2 fusion that is tethered to the yeast cell surface. We show that binding proteins derived from the Sso7d scaffold and the homodimeric enzyme glucose oxidase can be simultaneously secreted solubly and expressed as yeast cell surface fusions using the F2A-based system. Furthermore, a combinatorial library of Sso7d mutants can be screened to isolate binders with higher affinity for a model target (lysozyme), and the pool of higher affinity binders can be characterized in soluble form. Significantly, we show that both N- and C-terminal fusions to Aga2 can be simultaneously secreted solubly and displayed on the cell surface; this is particularly advantageous because protein functionality can be affected by the specific position of Aga2 in the protein fusion. We expect that the F2A-based yeast surface display and secretion system will be a useful tool for protein engineering and enable efficient characterization of individual clones isolated from combinatorial libraries. PMID- 28805375 TI - Effect of Sn on Isobutane Dehydrogenation Performance of Ni/SiO2 Catalyst: Adsorption Modes and Adsorption Energies of Isobutane and Isobutene. AB - The reaction of isobutane over Ni/SiO2 catalyst changes from hydrogenolysis to dehydrogenation when Sn is introduced. The adsorption modes and energies of isobutane and isobutene over the Ni/SiO2 catalyst with and without Sn addition were determined by in situ FTIR and a novel transient response adsorption approach. In the absence of Sn, isobutane is adsorbed in a double-site mode with H atoms in two methyl groups of isobutane, facilitating hydrogenolysis of isobutane. After the addition of Sn, a single-site adsorption mode with the H atom in the methylidyne group is speculated instead, which is beneficial to the rupture of the C-H bond rather than the C-C bond. Moreover, the double-site adsorption mode of isobutene with the C?C bond and the H atom in a methyl group is turned into single-site mode with the C?C bond after the introduction of Sn. As for the adsorption energy of isobutene, the introduction of Sn leads to an obvious decrease from 74 to 50 kJ mol-1 and facilitates the prompt desorption of isobutene, resulting in a high selectivity of 81.9 wt %. PMID- 28805376 TI - Discovery and Biosensing Applications of Diverse RNA-Cleaving DNAzymes. AB - DNA-based enzymes, or DNAzymes, are not known to exist in Nature but can be isolated from random-sequence DNA pools using test tube selection techniques. Since the report of the first DNAzyme in 1994, many catalytic DNA molecules for catalyzing wide-ranging chemical transformations have been isolated and studied. Our laboratory has a keen interest in searching for diverse DNAzymes capable of cleaving RNA-containing substrates, determining their sequence requirements and structural properties, and examining their potential as biosensors. This Account begins with the description of an accidental discovery on the sequence adaptability of a small DNAzyme known as "8-17", when we performed 16 parallel selections to search for DNAzymes that targeted each and every possible dinucleotide junction of RNA for cleavage. DNAzyme 8-17 dominated all the selection pools targeting purine-containing junctions. In-depth sequence analysis revealed that 8-17 could manifest itself in many sequence options defined by the requirement of four absolutely conserved nucleotides. This study also exposed the fact that 8-17 had poor activity toward pyrimidine-pyrimidine junctions. With this information in hand, we proceeded to the discovery of diverse non-8-17 DNAzymes that exhibited robust catalytic activity under physiological conditions. These DNAzymes were found to universally interact with their substrates through two Watson-Crick binding arms and have a catalytic core of varying length and secondary-structure complexity. RNA-cleaving DNAzymes were also isolated to function at acidic conditions (pH 3-5), and these molecules exhibited intriguing pH profiles, with the highest activity precisely matching the pH used for their selection. Interestingly, these DNAzymes appear to use non-Watson-Crick interactions in defining their structures. More recently, we have embarked on the development of ligand-responsive RNA-cleaving fluorogenic DNAzymes that can recognize specific bacterial pathogens, such as Escherichia coli and Clostridium difficile, using a method that does not require a priori identification of a specific biomarker. Instead, the crude extracellular mixture as a whole is used as the target to drive the DNAzyme isolation. High recognition specificity can be achieved with a double-selection approach in which a DNA library is negatively selected against the cellular mixture prepared from unintended bacteria, followed by positive selection against the same mixture derived from a specific species or strain of bacterial pathogen. Finally, we have shown that DNAzymes' compatibility with DNA replication can benefit the design of amplification mechanisms that uniquely link the action of RNA-cleaving DNAzymes to rolling circle amplification, an isothermal DNA amplification technique. These methods are well suited for translating the target-binding and cleavage activity of an analyte activated RNA-cleaving DNAzyme into the production of massive amounts of DNA amplicons to achieve ultrahigh detection sensitivity. Given the high chemical stability of DNA, our ability to discover catalytic DNA sequences by simultaneously evaluating as many as 1016 different DNA sequences, the accessibility to diverse RNA-cleaving DNAzymes in a single DNA pool, and the availability of methods for designing simple biosensors that incorporate RNA cleaving DNAzymes, we believe we are moving closer to employing RNA-cleaving DNAzymes for exciting applications, such as point of care diagnostics or field detection of environmental toxins. PMID- 28805377 TI - Intrinsic Dynamics of the Binding Rail and Its Allosteric Effect in the Class I Histone Deacetylases. AB - The development of novel isoform/class-selective inhibitors is still of great biological and medical significance to conquer the continuously reported side effects for the histone deacetylase (HDAC) drugs. The first potent HDAC allosteric inhibitor was discovered last year, and this allosteric inhibitor design is thought to be a promising strategy to overcome the current challenges in HDAC inhibitor design. However, the detailed allosteric mechanism and its remote regulatory effects on the catalytic/inhibitor activity of HDAC are still unclear. In this work, on the basis of microsecond-time-scale all-atom molecular dynamics (MD) simulations and picosecond-time-scale density functional theory/molecular mechanics MD simulations on HDAC8, we propose that the allostery is achieved by the intrinsic conformational flexibility of the binding rail (constituted by a highly conserved X-D residue dyad), which steers the loop-loop motion and creates the diverse shapes of the allosteric sites in different HDAC isoforms. Additionally, the rotatability of the binding rail is an inherent structural feature that regulates the hydrophobicity of the linker binding channel and thus further affects the HDAC enzyme inhibitory/catalytic activity by utilizing the promiscuity of X-D dyad. Since the plastic X residue is different among class I HDACs, these new findings provide a deeper understanding of the allostery, which is guidable for the design of new allosteric inhibitors toward the allosteric site and structure modifications on the conventional inhibitors binding into the active pocket by exploiting the intrinsic dynamic features of the conserved X-D dyad. PMID- 28805378 TI - In Vitro Modulation of Renin-Angiotensin System Enzymes by Amaranth (Amaranthus hypochondriacus) Protein-Derived Peptides: Alternative Mechanisms Different from ACE Inhibition. AB - Among the factors affecting the development of cardiovascular diseases, hypertension is one of the most important. Research done on amaranth proteins has demonstrated their hypotensive capacity in vivo and in vitro; nevertheless, the mechanism underlying this effect remains unclear. The aim of this study was to analyze in vitro the inhibition of peptides derived from an amaranth hydrolysate (AHH) on other RAS enzymes other than ACE. The chymase and renin activities were studied. AHH was not able to inhibit chymase activity, although a dose-response effect was found on renin activity (IC50 0.6 mg/mL). To provide an approach to the renin inhibition mechanism, we analyzed AHH renin inhibition kinetics and performed a structural characterization of the peptides involved in the effect in terms of molecular size and hydrophobicity. Results suggest that amaranth peptides exhibit renin competitive inhibition behavior. Renin inhibition potency was directly related to peptide hydrophobicity. RP-HPLC separation of AHH and subsequent analysis of the peptide sequences showed 6 peptides belonging to 11S globulin (that can be grouped into 3 families) that would be responsible for renin inhibition. These results demonstrate that Amaranthus hypochondriacus seeds are an adequate source of peptides with renin inhibitory properties that could be used in functional food formulations. PMID- 28805379 TI - Cellular Transport of Esculin and Its Acylated Derivatives in Caco-2 Cell Monolayers and Their Antioxidant Properties in Vitro. AB - Esculin has many pharmacological effects, but these are difficult to observe after oral administration owing to poor lipid solubility. In our previous study, five acylated derivatives with different acyl chain lengths (EA, EP, EO, EL, and EM) were synthesized to improve the lipophilicity of esculin. In this study, the bioavailability and antioxidant activity of the five derivatives were investigated. The logP of esculin, EA, EP, EO, EL, and EM were -1.1 +/- 0.1, -0.3 +/- 0.14, 0.1 +/- 0.17, 1.6 +/- 0.09, 2.4 +/- 0.11, and 2.8 +/- 0.18, and their Papp were 0.71 +/- 0.02, 1.24 +/- 0.18, 1.74 +/- 0.11, 11.6 +/- 3.6, 4.11 +/- 1.03, and 2.64 +/- 0.97 * 10-6 cm/s, respectively. Besides, the bioavailability of EO, EL, and EM were seriously affected by carboxylesterase. The results of ABTS, ORAC, and DPPH assays indicated that the antiradical ability of the five derivatives did not exceed that of esculin. However, EA, EP, and EO showed more effective inhibition of AAPH-induced oxidative hemolysis than esculin did (p < 0.05), and EL and EM were less effective than esculin (p < 0.05). The mechanism was related to the distribution and localization of the derivatives in "oil-water interface" between the cytomembrane and the aqueous phase. PMID- 28805381 TI - Compressibility Anisotropy and Electronic Properties of Oxyanionic Hydrates. AB - The structural and electronic properties of oxyanionic crystalline hydrates, LiNO3.3H2O, LiClO4.3H2O, and NaClO4.H2O, have been studied using density functional theory including van der Waals interactions. It is established that the linear compressibility of lithium perchlorate trihydrate is anisotropic (a < c) and positive, while lithium nitrate trihydrate and sodium perchlorate monohydrate demonstrate negative linear compressibility along the b and c axes, respectively. Deformation of Ow-H...O hydrogen bonding motifs is correlated with the negative linear compressibility. The band gaps of lithium nitrate and lithium perchlorate trihydrates decrease with pressure, whereas the band gap of sodium perchlorate monohydrate increases. PMID- 28805380 TI - Evaluating the Antibacterial Properties of Polyacetylene and Glucosinolate Compounds with Further Identification of Their Presence within Various Carrot (Daucus carota) and Broccoli (Brassica oleracea) Cultivars Using High-Performance Liquid Chromatography with a Diode Array Detector and Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry Analyses. AB - Ongoing consumer concerns over using synthetic additives in foods has strongly influenced efforts worldwide to source suitable natural alternatives. In this study, the antibacterial efficacy of polyacetylene and glucosinolate compounds was evaluated against both Gram positive and Gram negative bacterial strains. Falcarinol [minimum inhibitory concentration (MIC) = 18.8-37.6 MUg/mL] demonstrated the best overall antibacterial activity, while sinigrin (MIC = 46.9 62.5 MUg/mL) was the most active glucosinolate compound. High-performance liquid chromatography with a diode array detector analysis showed falcarinol [85.13 244.85 MUg/g of dry weight (DW)] to be the most abundant polyacetylene within six of the eight carrot (Daucus carota) cultivars investigated. Meanwhile, sinigrin (100.2-244.3 MUg/g of DW) was the most abundant glucosinolate present within the majority of broccoli (Brassica oleracea) cultivars investigated using ultra performance liquid chromatography-tandem mass spectrometry analysis. The high abundance of both falcarinol and sinigrin within these respective species suggests that they could serve as potential sources of natural antibacterial agents for use as such in food products. PMID- 28805382 TI - Tuning Cycloparaphenylene Host Properties by Chemical Modification. AB - [8]Cycloparaphenylene derivative 1 has been synthesized and its recognition abilities toward pyridinium guests have been investigated and compared with the [8]CPP macrocycle. The results showed a fine-tuning of the binding properties of [8]CPP 1 toward pyridinium cations due to the presence of the 1,4-DMB ring. DFT calculations indicate that the close steric fitting between the rigid cavity of 1 and the pyridinium guest is the crucial factor for the stabilization of their supramolecular complex through C-H...pi and N+...pi1,4DMB interactions. PMID- 28805383 TI - Cu(II)-Catalyzed ortho-Selective Aminomethylation of Phenols. AB - A Cu(II)-catalyzed ortho-selective functionalization of free phenols with trifluoroborates to afford Csp2-Csp3 coupling products under mild conditions has been developed. A variety of functional groups on the phenol and the potassium aminomethyltrifluoroborate substrates were found compatible, furnishing the corresponding products in moderate to excellent yields. A single-electron transfer radical coupling mechanism involving a six-membered transition state is proposed to rationalize the high levels of ortho-selectivity in the reaction. This protocol provides straightforward access to ortho-aminomethyl-substituted phenols, unnatural amino acids and other bioactive small molecules. PMID- 28805384 TI - Lipidomics Insights in Health and Nutritional Intervention Studies. AB - Lipids are among the major components of food and constitute the principal structural biomolecules of human body together with proteins and carbohydrates. Lipidomics encompasses the investigation of the lipidome, defined as the entire spectrum of lipids in a biological system at a given time. Among metabolomics technologies, lipidomics has evolved due to the relevance of lipids in nutrition and their well-recognized roles in health. Mass spectrometry advances have greatly facilitated lipidomics, but owing to the complexity and diversity of the lipids, lipidome purification and analysis are still challenging. This review focuses on lipidomics strategies, applications, and achievements of studies related to nutrition and health research. PMID- 28805385 TI - Synthesis of a Series of Heavy Lanthanide(III) Monoporphyrinato Complexes with Tetragonal Symmetry. AB - A series of heavy lanthanide(III) and yttrium(III) monoporphyrinato complexes formulated in [Ln(TPP)(cyclen)]Cl (Ln = Tb, Dy, Ho, Er, Tm, Yb, and Y; TPP = 5,10,15,20-tetraphenylporphyrinato), with cyclen, 1,4,7,10-tetraazacyclododecane, as a capping ligand, have been prepared in mild conditions and studied using single-crystal X-ray diffraction crystallography. The complexes exhibit an electronic absorption band (B(0,0)) in the range of 421-423 nm, showing a bathochromic shift associated with the increase of the ionic radii of the lanthanide, as well as two peaks of Q(1,0) and Q(0,0) bands between 548-586 nm. All of the complexes are isostructural, where both TPP and cyclen are coordinated to a lanthanide(III) or yttrium(III) ion giving an eight-coordinate square antiprismatic (SAP) geometry (average skew angles are in the range of 43.01 degrees -43.67 degrees ). The mean plane of the four nitrogen atoms of TPP (N4t) and that of the cyclen (N4c) are virtually parallel with a dihedral angle of less than 1 degrees . The lanthanide(III) or yttrium(III) ions lie between N4t and N4c. The position of the metal ion is closer to the N4t plane, which is presumably caused by the different charges of the ligands, the size of the N4 square ligands, and the steric factor. The average Ln-N and interplanar distances (dN) decrease with decreasing lanthanide(III) ionic radii, showing the effect of lanthanide contraction. The skew angles, opening angles, and N-N distances are nearly unchanged, keeping the rigid square antiprismatic geometry throughout the series. PMID- 28805386 TI - Solvation Effect on Complexation of Alkali Metal Cations by a Calix[4]arene Ketone Derivative. AB - The medium effect on the complexation of alkali metal cations with a calix[4]arene ketone derivative (L) was systematically examined in methanol, ethanol, N-methylformamide, N,N-dimethylformamide, dimethyl sulfoxide, and acetonitrile. In all solvents the binding of Na+ cation by L was rather efficient, whereas the complexation of other alkali metal cations was observed only in methanol and acetonitrile. Complexation reactions were enthalpically controlled, while ligand dissolution was endothermic in all cases. A notable influence of the solvent on NaL+ complex stability could be mainly attributed to the differences in complexation entropies. The higher NaL+ stability in comparison to complexes with other alkali metal cations in acetonitrile was predominantly due to a more favorable complexation enthalpy. The 1H NMR investigations revealed a relatively low affinity of the calixarene sodium complex for inclusion of the solvent molecule in the calixarene hydrophobic cavity, with the exception of acetonitrile. Differences in complex stabilities in the explored solvents, apart from N,N-dimethylformamide and acetonitrile, could be mostly explained by taking into account solely the cation and complex solvation. A considerable solvent effect on the complexation equilibria was proven to be due to an interesting interplay between the transfer enthalpies and entropies of the reactants and the complexes formed. PMID- 28805387 TI - Polymyxin Binding to the Bacterial Outer Membrane Reveals Cation Displacement and Increasing Membrane Curvature in Susceptible but Not in Resistant Lipopolysaccharide Chemotypes. AB - Lipid-A is the causative agent of Gram-negative sepsis and is responsible for an increasingly high mortality rate among hospitalized patients. Compounds that bind Lipid-A can limit this inflammatory process. The cationic antimicrobial peptide polymyxin B (Pmx-B) is one of the simplest molecules capable of selectively binding to Lipid-A and may serve as a model for further development of Lipid-A binding agents. Gram-negative bacteria resistance to Pmx-B relies on the upregulation of a number of regulatory systems, which promote chemical modifications of the lipopolysaccharide (LPS) structure and leads to major changes in the physical-chemical properties of the outer membrane. A detailed understanding of how the chemical structure of the LPS modulates macroscopic properties of the outer membrane is paramount for the design and optimization of novel drugs targeting clinically relevant strains. We have performed a systematic investigation of Pmx-B binding to outer membrane models composed of distinct LPS chemotypes experimentally shown to be either resistant or susceptible to the peptide. Molecular dynamics simulations were carried out for Pmx-B bound to the penta- and hexa-acylated forms of Lipid-A (more susceptible) and Lipid-A modified with 4-amino-4-deoxy-l-arabinose (resistant) as well as the penta-acylated form of LPS Re (less susceptible). The present simulations show that upon binding to the bacterial outer membrane surface, Pmx-B promotes cation displacement and structural changes in membrane curvature and integrity as a function of the LPS chemotype susceptibility or resistance to the antimicrobial peptide. PMID- 28805388 TI - Transition Metal-Free trans-Selective Alkynylboration of Alkynes. AB - We report the first transition metal-free and trans-selective alkynylboration reaction of alkynes. This unprecedented carboboration reaction is enabled by pseudo-intramolecular activation of alkynylboronates using propargylic alcohols. The carboboration affords 4-alkynyl-1,2-oxaborol-2(5H)-ols, which are not only versatile building blocks but also exhibit strong violet-blue fluorescence emission. PMID- 28805389 TI - Overcoming Reductant Interference in Peroxidase-Based Assays for Hydrogen Peroxide Quantification. AB - A problem commonly encountered when using peroxidase-based methods for hydrogen peroxide quantification in biobased matrixes is interference due to the presence of endogenous reductants. Such assays are typically based on the generation of an oxidized reporter molecule in direct proportion to the amount of hydrogen peroxide reduced in the peroxidase-catalyzed reaction. Endogenous reductants confound such assays by reducing the oxidized reporter molecule, thus resulting in underestimates of hydrogen peroxide content. In the present work, we demonstrate how this problem can be circumvented by selectively oxidizing offending compounds by treatment with the oxidized reporter molecule prior to initiating the peroxidase reaction for hydrogen peroxide quantification. The approach is demonstrated using horseradish peroxidase, 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulfonic acid), as the reporter molecule and a representative garlic paste as the hydrogen peroxide-containing biobased matrix. The approach is expected to be generally applicable to a wide range of peroxidase based assays when applied to complex biobased systems. PMID- 28805390 TI - Sampling Long- versus Short-Range Interactions Defines the Ability of Force Fields To Reproduce the Dynamics of Intrinsically Disordered Proteins. AB - Molecular dynamics (MD) simulations have valuably complemented experiments describing the dynamics of intrinsically disordered proteins (IDPs), particularly since the proposal of models to solve the artificial collapse of IDPs in silico. Such models suggest redefining nonbonded interactions, by either increasing water dispersion forces or adopting the Kirkwood-Buff force field. These approaches yield extended conformers that better comply with experiments, but it is unclear if they all sample the same intrachain dynamics of IDPs. We have tested this by employing MD simulations and single-molecule Forster resonance energy transfer spectroscopy to sample the dimensions of systems with different sequence compositions, namely strong and weak polyelectrolytes. For strong polyelectrolytes in which charge effects dominate, all the proposed solutions equally reproduce the expected ensemble's dimensions. For weak polyelectrolytes, at lower cutoffs, force fields abnormally alter intrachain dynamics, overestimating excluded volume over chain flexibility or reporting no difference between the dynamics of different chains. The TIP4PD water model alone can reproduce experimentally observed changes in extensions (dimensions), but not quantitatively and with only weak statistical significance. Force field limitations are reversed with increased interaction cutoffs, showing that chain dynamics are critically defined by the presence of long-range interactions. Force field analysis aside, our study provides the first insights into how long-range interactions critically define IDP dimensions and raises the question of which length range is crucial to correctly sample the overall dimensions and internal dynamics of the large group of weakly charged yet highly polar IDPs. PMID- 28805391 TI - Chemical Transformations of the Fungal Meroterpenoid Dhilirolide A Reveal Skeletal Degradation and Rearrangement Reactions with Biosynthetic Implications. AB - Treatment of the fungal meroterpenoid dhilirolide A (1) with either sodium azide or perchloric acid results in conversion of the dhilirane carbon skeleton of 1 to the 14,15-dinordhilirane carbon skeleton of the products 5-7, with and without concomitant transfer of an acetyl residue to form a C-9 acetate ester. The discovery of these transformations, which are vinylogous retro-Claisen-type condensations, suggests an efficient biogenetic route to 14,15-dinordhiliranes such as dhilirolide K (3). PMID- 28805392 TI - Photoinduced Ultrafast Charge Transfer and Charge Migration in Small Gold Clusters Passivated by a Chromophoric Ligand. AB - Because the development of attopulses, charge migration induced by short optical pulses has been extensively investigated. We report a computational purely electronic dynamical study of ultrafast few femtoseconds (fs) charge transfer and charge migration in realistic passivated stoichiometric Au11 and Au20 gold nanoclusters functionalized by a bipyridine ligand. We show that a net significant amount of electronic charge (0.1 to 0.4 |e| where |e| is the electron charge) is permanently transferred from the bipyridine chromophore to the gold cluster during the short 5-6 fs UV-vis strong pulse. This electron transfer to the metallic core is induced by the optical excitation of electronic states with a partial charge transfer character involving the chromophore before the onset of nuclei motion. In addition, the photoexcitation by the strong fs pulse builds a nonequilibrium electronic density that beats between the chromophore and the metallic core around the average of the transferred value. Modular systems made of a donor chromophore that can be photoexcited in the UV-vis range coupled to an efficient acceptor that could trap the charge are of interest for applications to nanodevices. Our study provides understanding on the very early, purely electronic dynamics built by the fs optical excitation and the initial charge separation step. PMID- 28805393 TI - Disappearance of the Superionic Phase Transition in Sub-5 nm Silver Iodide Nanoparticles. AB - Bulk silver iodide (AgI) is known to show a phase transition from the poorly conducting beta/gamma-phases into the superionic conducting alpha-phase at 147 degrees C. Its transition temperature decreases with decreasing the size of AgI, and the alpha-phase exists stably at 37 degrees C in AgI nanoparticles with a diameter of 6.3 nm. In this Letter, we investigated the atomic configuration, the phase transition behavior, and the ionic conductivity of AgI nanoparticles with a diameter of 3.0 nm. The combination of pair distribution function (PDF) analysis and reverse Monte Carlo (RMC) modeling based on high-energy X-ray diffraction (XRD) revealed for the first time that they formed the beta/gamma-phases with atomic disorder. The results of extended X-ray absorption fine structure (EXAFS) analysis, differential scanning calorimetry (DSC), and AC impedance spectroscopy demonstrated that they did not exhibit the superionic phase transition and their ionic conductivity was lower than that of crystalline AgI. The disappearance of the superionic phase transition and low ionic conductivity in the very small AgI nanoparticles originates from their small size and disordered structure. PMID- 28805394 TI - Highly Efficiently Delaminated Single-Layered MXene Nanosheets with Large Lateral Size. AB - Single layered Ti3C2(OH)2 nanosheets have been successfully fabricated by etching its Ti3AlC2 precursor with KOH in the presence of a small amount of water. The OH group replaced the Al layer within the Ti3AlC2 structure during etching, and Ti3C2(OH)2 nanosheets could be easily and efficiently achieved through a simple washing process. The delaminated single-layered nanosheets are clearly revealed by atomic force microscopy to be several micrometers in lateral size. Interestingly, the exfoliated Ti3C2(OH)2 nanosheets could be restacked to form a new layer-structured material after drying. When redispersing this restacked Ti3C2(OH)2 materials in water again, it could be re-delaminated easily only after shaking for several hours. The easy delamination and restacking properties, coupled with intrinsic metallic conductivity and hydrophilicity, make it an ideal two-dimensional building block for fabricating a wide variety of functional materials. PMID- 28805395 TI - Strategy for the Co-Assembly of Co-Axial Nanotube-Polymer Hybrids. AB - Nanostructured materials having multiple, discrete domains of sorted components are particularly important to create efficient optoelectronics. The construction of multicomponent nanostructures from self-assembled components is exceptionally challenging due to the propensity of noncovalent materials to undergo structural reorganization in the presence of excipient polymers. This work demonstrates that polymer-nanotube composites comprised of a self-assembled nanotube wrapped with two conjugated polymers could be assembled using a layer-by-layer approach. The polymer-nanotube nanostructures arrange polymer layers coaxially on the nanotube surface. Femtosecond transient absorption (TA) studies indicated that the polymer nanotube composites undergo photoinduced charge separation upon excitation of the NDI chromophore within the nanotube. PMID- 28805396 TI - Transport Properties of a Two-Dimensional PbSe Square Superstructure in an Electrolyte-Gated Transistor. AB - Self-assembled nanocrystal solids show promise as a versatile platform for novel optoelectronic materials. Superlattices composed of a single layer of lead chalcogenide and cadmium-chalcogenide nanocrystals with epitaxial connections between the nanocrystals, present outstanding questions to the community regarding their predicted band structure and electronic transport properties. However, the as-prepared materials are intrinsic semiconductors; to occupy the bands in a controlled way, chemical doping or external gating is required. Here, we show that square superlattices of PbSe nanocrystals can be incorporated as a nanocrystal monolayer in a transistor setup with an electrolyte gate. The electron (and hole) density can be controlled by the gate potential, up to 8 electrons per nanocrystal site. The electron mobility at room temperature is 18 cm2/(V s). Our work forms a first step in the investigation of the band structure and electronic transport properties of two-dimensional nanocrystal superlattices with controlled geometry, chemical composition, and carrier density. PMID- 28805397 TI - Efficiency of Launching Highly Confined Polaritons by Infrared Light Incident on a Hyperbolic Material. AB - We investigated phonon-polaritons in hexagonal boron nitride-a naturally hyperbolic van der Waals material-by means of the scattering-type scanning near field optical microscopy. Real-space nanoimages we have obtained detail how the polaritons are launched when the light incident on a thin hexagonal boron nitride slab is scattered by various intrinsic and extrinsic inhomogeneities, including sample edges, metallic nanodisks deposited on its top surface, random defects, and surface impurities. The scanned tip of the near-field microscope is itself a polariton launcher whose efficiency proves to be superior to all the other types of polariton launchers we studied. Our work may inform future development of polaritonic nanodevices as well as fundamental studies of collective modes in van der Waals materials. PMID- 28805398 TI - Dearomatization Strategy for the Synthesis of Arylated 2H-Pyrroles and 2,3,5 Trisubstituted 1H-Pyrroles. AB - The first high-yielding route to arylated 2H-pyrroles was developed. The methodology utilizes 2,5-disubstituted pyrroles that are metalated, and the aryl substituents are introduced by a palladium-catalyzed cross-coupling reaction. The prepared pyrroles can be rearranged to 2,3,5-trisubstituted pyrroles under acidic conditions. Attempts to convert the 2,3,5-trisubstituted pyrroles to 2,3,4,5 tetrasubstituted pyrroles by the dearomatization rearrangement strategy were unsuccessful. PMID- 28805399 TI - Mind matters: A meta-analysis on parental mentalization and sensitivity as predictors of infant-parent attachment. AB - Major developments in attachment research over the past 2 decades have introduced parental mentalization as a predictor of infant-parent attachment security. Parental mentalization is the degree to which parents show frequent, coherent, or appropriate appreciation of their infants' internal states. The present study examined the triangular relations between parental mentalization, parental sensitivity, and attachment security. A total of 20 effect sizes (N = 974) on the relation between parental mentalization and attachment, 82 effect sizes (N = 6,664) on the relation between sensitivity and attachment, and 24 effect sizes (N = 2,029) on the relation between mentalization and sensitivity were subjected to multilevel meta-analyses. The results showed a pooled correlation of r = .30 between parental mentalization and infant attachment security, and rs of .25 for the correlations between sensitivity and attachment security, and between parental mentalization and sensitivity. A meta-analytic structural equation model was performed to examine the combined effects of mentalization and sensitivity as predictors of infant attachment. Together, the predictors explained 12% of the variance in attachment security. After controlling for the effect of sensitivity, the relation between parental mentalization and attachment remained, r = .24; the relation between sensitivity and attachment remained after controlling for parental mentalization, r = .19. Sensitivity also mediated the relation between parental mentalization and attachment security, r = .07, suggesting that mentalization exerts both direct and indirect influences on attachment security. The results imply that parental mentalization should be incorporated into existing models that map the predictors of infant-parent attachment. (PsycINFO Database Record PMID- 28805400 TI - Anxiety and depression as bidirectional risk factors for one another: A meta analysis of longitudinal studies. AB - Not only do anxiety and depression diagnoses tend to co-occur, but their symptoms are highly correlated. Although a plethora of research has examined longitudinal associations between anxiety and depression, these data have not yet been effectively synthesized. To address this need, the current study undertook a systematic review and meta-analysis of 66 studies involving 88,336 persons examining the prospective relationship between anxiety and depression at both symptom and disorder levels. Using mixed-effect models, results suggested that all types of anxiety symptoms predicted later depressive symptoms (r = .34), and all types of depressive symptoms predicted later anxiety symptoms (r = .31). Although anxiety symptoms more strongly predicted depressive symptoms than vice versa, the difference in effect size for this analysis was very small and likely not clinically meaningful. Additionally, all types of diagnosed anxiety disorders predicted all types of later depressive disorders (OR = 2.77), and all depressive disorders predicted later anxiety disorders (OR = 2.73). Most anxiety and depressive disorders predicted each other with similar degrees of strength, but depressive disorders more strongly predicted social anxiety disorder (OR = 6.05) and specific phobia (OR = 2.93) than vice versa. Contrary to conclusions of prior reviews, our findings suggest that depressive disorders may be prodromes for social and specific phobia, whereas other anxiety and depressive disorders are bidirectional risk factors for one another. (PsycINFO Database Record PMID- 28805401 TI - The common sense model of self-regulation: Meta-analysis and test of a process model. AB - According to the common-sense model of self-regulation, individuals form lay representations of illnesses that guide coping procedures to manage illness threat. We meta-analyzed studies adopting the model to (a) examine the intercorrelations among illness representation dimensions, coping strategies, and illness outcomes; (b) test the sufficiency of a process model in which relations between illness representations and outcomes were mediated by coping strategies; and (c) test effects of moderators on model relations. Studies adopting the common-sense model in chronic illness (k = 254) were subjected to random-effects meta-analysis. The pattern of zero-order corrected correlations among illness representation dimensions (identity, consequences, timeline, perceived control, illness coherence, emotional representations), coping strategies (avoidance, cognitive reappraisal, emotion venting, problem-focused generic, problem-focused specific, seeking social support), and illness outcomes (disease state, distress, well-being, physical, role, and social functioning) was consistent with previous analyses. Meta-analytic path analyses supported a process model that included direct effects of illness representations on outcomes and indirect effects mediated by coping. Emotional representations and perceived control were consistently related to illness-related and functional outcomes via, respectively, lower and greater employment of coping strategies to deal with symptoms or manage treatment. Representations signaling threat (consequences, identity) had specific positive and negative indirect effects on outcomes through problem- and emotion-focused coping strategies. There was little evidence of moderation of model effects by study design, illness type and context, and study quality. A revised process model is proposed to guide future research which includes effects of moderators, individual differences, and beliefs about coping and treatment. (PsycINFO Database Record PMID- 28805402 TI - Middle ground approach to paradox: Within- and between-culture examination of the creative benefits of paradoxical frames. AB - Thriving in increasingly complex and ambiguous environments requires creativity and the capability to reconcile conflicting demands. Recent evidence with Western samples has suggested that paradoxical frames, or mental templates that encourage individuals to recognize and embrace contradictions, could produce creative benefits. We extended the timely, but understudied, topic by studying the nuances of for whom and why creative advantages of paradoxical frames emerge. We suggest that people endorsing a middle ground approach are less likely to scrutinize conflict and reconcile with integrative solutions, thus receiving less creative benefits of paradoxical frames. Five studies that examined individual and cultural differences in middle ground endorsement support our theory. Study 1 found that paradoxical frames increased creativity, but failed to replicate that experienced conflict mediated the relationship in a Taiwanese sample. In both within- and between-culture analysis, we showed that the creative advantages of thinking paradoxically and experiencing conflict emerged among individuals who endorse lower (vs. higher) levels of middle ground (Study 2) and among Israelis whose culture predominantly endorses middle ground strategy less, but not among Singaporeans whose culture predominantly endorses middle ground more (Study 3). Study 4 further demonstrated the causal role of middle ground in the paradox conflict-creativity link. To answer "why," Study 5 situationally induced integrative complex thinking that sets distinctions and forms syntheses among contradictory elements, and found that low endorsers of middle ground performed more creatively when they engaged integrative complex thinking to cope with paradoxes. This program of studies offers important insights on harnessing paradoxical experiences to catalyze creativity. (PsycINFO Database Record PMID- 28805403 TI - Where's the LGBT in integrated care research? A systematic review. AB - INTRODUCTION: Lesbian, gay, bisexual, and transgender (LGBT) individuals experience more negative health outcomes compared with their heterosexual peers. The health disparities are often related to family and social rejection of the LGBT individuals. Integrated care, and Medical Family Therapy in particular, may aid in addressing the systemic nature of the negative health outcomes. METHOD: To better understand the current state of the integrated care literature on addressing the health needs of LGBT individuals, a systematic review of the research literature was conducted from January 2000 to January 2016 for articles including integrated health care interventions for LGBT populations. Independent reviewers coded identified articles. RESULTS: Only 8 research articles met criteria for inclusion out of the 2,553 initially identified articles in the search. Results indicated a lack of integrated care research on health care and health needs of LGBT individuals, and none of the articles addressed the use of family or systemic-level interventions. DISCUSSION: Implications for future research and the need for better education training are discussed. (PsycINFO Database Record PMID- 28805404 TI - Mixed methods evaluation of a collaborative care implementation using RE-AIM. AB - INTRODUCTION: Application of the reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework using mixed methods to evaluate a collaborative care practice implementation can inform the literature on real world collaborative care experiences. METHOD: Two primary care practices serving Niagara Falls, NY, implemented collaborative care. Adults age 18 and over were screened at least annually for depression, anxiety, and alcohol use using the 9 item Patient Health Questionnaire (PHQ-9), the 7-item Generalized Anxiety Disorder questionnaire (GAD-7), and the AUDIT alcohol consumption questionnaire (AUDIT-C). Primary care clinicians referred patients screening positive to the on site behavioral health care manager (BHCM) with warm handoffs; the BHCM used a mixed therapeutic approach, initiated consultations with a psychiatrist and a community resource liaison as needed, in collaboration with the clinician. External evaluators used mixed methods to assess collaborative care services' RE AIM. RESULTS: Nearly 40% of patients screened positive for at least one behavioral healthcare (BH) concern or were referred to BH services upon clinician judgment. Of these patients, 43% were referred to integrated BH services, of whom 86% accepted and 54% actually participated in services. There were no differences in changes in symptoms between those who did and did not participate in services. Patients reported the services were valuable and helped build skills for coping with complex health conditions and psychosocial issues. DISCUSSION: Evaluation of collaborative care using the RE-AIM framework may help others systematically evaluate programs, identify local improvement opportunities, and contribute to the broad literature on integrated care dissemination and implementation. (PsycINFO Database Record PMID- 28805405 TI - Understanding integrated mental health care in "real-world" primary care settings: What matters to health care providers and clients for evaluation and improvement? AB - PURPOSE: The integration of mental health specialists into primary care has been widely advocated to deliver evidence-based mental health care to a defined population while improving access, clinical outcomes, and cost efficiency. Integrated care has been infrequently and inconsistently translated into real world settings; as a result, the key individual components of effective integrated care remain unclear. METHOD: This article reports findings from a qualitative study that explored provider and client experiences of integrated care. We conducted in-depth interviews with integrated care providers (n = 13) and clients (n = 9) to understand their perspectives and experiences of integrated care including recommended areas for quality measurement and improvement. The authors used qualitative content and reflexive thematic analytic approaches to synthesize the interview data. RESULTS: Clients and integrated care providers agreed regarding the overarching concepts of the what, how, and why of integrated care including co-location of care; continuity of care; team composition and functioning; client centeredness; and comprehensive care for individuals and populations. Providers and clients proposed a number of dimensions that could be the focus for quality measurement and evaluation, illuminating what is needed for successful context-sensitive spreading and scaling of integrated care interventions. CONCLUSION: With a mounting gap between the empirical support for integrated care approaches and the implementation of these models, there is a need to clarify the aims of integrated care and the key ingredients required for widespread implementation outside of research settings. This study has important implications for future integrated care research, and health care provider and client engagement in the quality movement. (PsycINFO Database Record PMID- 28805406 TI - Does change in self-perceived problem drinker identity relate to change in alcohol use? An examination of nontreatment seeking hazardous drinkers. AB - Identity change is related to reductions in alcohol use among treatment seekers, but it is unclear the extent to which identity change is associated with reductions in alcohol use among nontreatment seeking hazardous drinkers. The goal of the current study was to examine whether change in problem drinker identity (i.e., self-reported identification as a problem or nonproblem drinker) was associated with reductions in heavy drinking among nontreatment seeking hazardous drinkers. Participants (n = 149) completed measures to assess alcohol use and were asked if they identified as a problem drinker at baseline and at 6-, 12-, 18 , and 24-month follow-ups. Two groups were compared: (a) those who identified as a problem drinker at baseline but identified as a nonproblem drinker at 12 months and (b) those who did not make the same transition. Latent mixture modeling was conducted to examine whether change in problem drinker identity was predictive of heavy drinking latent class growth trajectories. The results indicated that a self-reported transition from identification as a problem drinker to identification as a nonproblem drinker was associated with greater reductions in heavy drinking over the assessment period and a 7 times greater likelihood of being in a rapidly decreasing heavy drinking latent trajectory class compared with participants who did not make the same transition. Self-reported transitions in identity appear to be a good predictor of heavy drinking trajectories among nontreatment seekers. A better understanding of what predicts transitions in drinking identity among non-treatment and treatment seekers is needed. (PsycINFO Database Record PMID- 28805407 TI - Stressor-related drinking and future alcohol problems among university students. AB - Research using daily designs has shown that daily stressors (i.e., conflict, school/work demands) are associated with alcohol use, and that the strength of within-person links between stressors and alcohol use differs from person to person. However, to our knowledge no research has tested whether individual differences in stressor-related drinking-characterized by within-person associations between daily stressors and drinking-predict risk for future alcohol problems, a relationship suggested by theoretical models. The current study used an Internet-based daily diary design among 744 university students to (a) examine the day-level relationship between stressors and alcohol use during the first 3 years of college, and (b) test whether individual differences in the stressor drinking relationship, captured by person-specific slopes generated from multilevel models, predicted alcohol problems as measured by the Alcohol Use Disorders Identification Test (AUDIT) in the fourth year of college. Results showed that students were more likely to drink on days with many versus fewer stressors, and on drinking days, students consumed more drinks with each additional stressor they experienced. Next, using individual multilevel modeling slopes as predictors, we found that students whose odds of drinking alcohol increased more sharply on high- versus low-stressor days (steeper slopes) had more severe AUDIT alcohol problems in the fourth year than students whose drinking odds increased less sharply (flatter slopes). Findings highlight the role of daily stressors in college student drinking and suggest stressor-related drinking as a risk factor for future alcohol problems. (PsycINFO Database Record PMID- 28805408 TI - Age of initiation and substance use progression: A multivariate latent growth analysis. AB - An individual's age at first substance use may be associated with their risk for progression toward heavier substance involvement. To our knowledge, however, no studies within nationally representative samples have examined the relation between the timing of initiation and progression in use of multiple substances. The present study employed a sample of 9,421 participants from the National Longitudinal Study of Adolescent to Adult Health who reported on their ages of tobacco, alcohol, and cannabis initiation; frequency of tobacco, alcohol, and cannabis use; and quantity of tobacco and alcohol use across 4 waves. We fit latent growth models to examine (a) associations between the age of initiation and initial status and rate of change in substance involvement, and (b) the degree to which the timing of first substance use accounted for differences in trajectories. There were significant relations between all ages of initiation and rates of change in tobacco (betas = -0.21 to -0.31, ps < .01) and alcohol use frequency (betas = 0.14 to 0.31, ps < .001), age of cannabis initiation and rate of change in tobacco use quantity (beta = 0.23, p < .01), and age of tobacco initiation and rate of change in cannabis use frequency (beta = -0.14, p < .01). After adjusting for age of initiation, significant associations were observed between trajectories for tobacco and alcohol (r = .43, p < .0001) and alcohol and cannabis (r = .20, p < .05). Results highlight differences in within- and cross substance relations between the age of initiation and rate of change in use across substances. They suggest that differences in substance use trajectories are partly accounted for by age at first use. (PsycINFO Database Record PMID- 28805409 TI - Adolescents' responses to marital conflict: The role of cooperative marital conflict. AB - Not all youth exposed to hostile marital interactions develop negative responses to marital conflict. Cooperative marital conflict has long been considered as an important way of managing conflict and may serve as an important context in which hostility might convey during marital interactions. In light of little prior attention placed on the positive side of conflict processes, the main and moderating effects of cooperative marital conflict on youth responses to marital conflict were examined in a sample of 416 2-parent families using a multimethod, 2-year prospective design. Cooperative marital conflict was associated with decreases in youth emotional dysregulation, perceived threat, and behavioral dysregulation, and increases in constructive family representations and coping efficacy. As a specific dimension of cooperation, effective conflict resolution was associated uniquely with elevated youth coping efficacy, and decreased emotional and behavioral dysregulation; marital warmth was associated uniquely with increased constructive family representations. Significant interactions between marital hostility and marital cooperation also were found. These findings highlight the importance of examining cooperation above and beyond hostility in studies of marital conflict in order to better understand youth development during early adolescence. (PsycINFO Database Record PMID- 28805410 TI - American Akicita: Indigenous American warriors and military service. AB - Indigenous Americans (i.e., Native/American Indians, AK natives, Pacific Islanders) have consistently volunteered for military service at greater rates than any other ethnic group, including the majority culture, since the early days of the country. This article is an introduction to the special section which includes a number of outstanding papers that provide an innovative and compelling effort to overcome the challenges of casualties from war and render effective and culturally informed care. These manuscripts describe culturally appropriate considerations of suicide (O'Keefe), family involvement and access to care (Whealin), and telehealth for treatment of rural Native veterans (Goss). Challenging and complex treatment needs call for equally mindful and competent approaches. These authors and providers present compelling examples of addressing these needs in working with our Wounded Warriors. (PsycINFO Database Record PMID- 28805411 TI - Rural American Indian and Alaska Native veterans' telemental health: A model of culturally centered care. AB - American Indian and Alaska Native (AI/AN) veterans living in rural areas have unique health care needs and face numerous barriers to accessing health care services. Among these needs is a disproportionate prevalence of posttraumatic stress disorder and other mental illnesses. Since 2001, 14 rural communities have partnered with the U.S. Department of Veterans Affairs and the Centers for American Indian and Alaska Native Health at the University of Colorado Anschutz Medical Campus to extend telemental health clinics to American Indian veterans. Administrative and, to some extent, clinical considerations of these clinics have been reviewed previously. This paper describes a model of care, evolved over a 14 year period, that weaves together evidence-based Western treatment, traditional Native healing, and rural Native communities into 4 main components: mental health care, technology, care coordination, and cultural facilitation. We delineate improvements to care made by addressing barriers such as system transference, provider-patient trust, and videoconferencing. Similarly, the discussion notes ways that the care model leverages strengths within Native communities, such as social cohesion and spirituality. Future steps include selection of appropriate performance indicators for systematic evaluation. The identification of key constructs of this care model will facilitate comparisons with other models of care in underserved populations with chronic and complex health conditions, and eventually advance the state of care for our warriors. (PsycINFO Database Record PMID- 28805412 TI - Factors impacting rural Pacific Island veterans' access to care: A qualitative examination. AB - Pacific Island veterans suffer from greater severity of posttraumatic stress disorder (PTSD) compared with Caucasian veterans but face substantial barriers to mental health care. However, the factors that may dissuade or facilitate veterans in the Pacific Islands from seeking mental health care are not known. The main aim of this study was to identify how internal and external factors interact to impact wounded warriors' access to and use of mental health services. Veterans residing in 5 rural Pacific Island locations were mailed recruitment materials. Other veterans were made aware of the project by key stakeholders in their communities. Thirty-seven male veterans (across 5 focus groups) and 1 female veteran (via individual interview) participated. The study utilized an analytic design in which taped focus group discussions were transcribed verbatim and coded for major themes. Results indicated that most veterans identified Veterans Affairs (VA) as a positive source for health care. However, common concerns acknowledged were as follows: (a) difficulty navigating the VA system, (b) time associated with receiving care, (c) family stigma, (d) community stigma, (e) cultural differences, and (f) a lack of knowledge about VA services and benefits. Facilitators of care included the following: (a) individual knowledge and self efficacy, (b) networking with other veterans, (c) family support, and (d) rural community support. All factor levels interacted in subtle ways to ultimately impact access to care. Next steps are described, including projects designed to better meet the needs of rural Pacific Island veterans. (PsycINFO Database Record PMID- 28805413 TI - Suicide among American Indian/Alaska Native military service members and veterans. AB - Many American Indian/Alaska Native (AI/AN) communities experience high suicide rates. However, there is little discussion in epidemiological and empirical literature about suicide-related outcomes among AI/AN military service members or veterans. This article briefly reviews the literature on AI/AN suicide and discusses what is known about Native military service member and veteran suicide mortality and self-directed violence. Recent studies suggest high suicide death rates among AI/AN military service members and veterans. Discussion includes the potential for unique cultural protective and risk factors that could inform prevention efforts and some of the novel existing efforts to support AI/AN veterans are reviewed. Given concerning suicide rates among military service members and veterans, it is important for future research to clarify the risk to AI/AN military service members and veterans and how to best develop and implement effective suicide prevention/interventions. (PsycINFO Database Record PMID- 28805415 TI - Actualizing culture change: The Promoting Excellent Alternatives in Kansas Nursing Homes (PEAK 2.0) program. AB - Nursing homes have been challenged in their attempts to achieve deep, organizational change (i.e., culture change) aimed at providing quality of care and quality of life for nursing home residents through person-centered care. To attain deep change, 2 well-defined components must be in place: a shared understanding of (a) the what, or content goals, and (b) the how, or process of change. However, there are few examples of this at a macro or micro level in long term care. In an effort to enact true culture change in nursing homes statewide, the Kansas Department for Aging and Disability Services implemented the Promoting Excellent Alternatives in Kansas Nursing Homes program. This program is a Medicaid, pay-for-performance program that formalizes the content and process of achieving culture change through person-centered care principles. This article aims to detail the content (what) and process (how) of a model macro-level program of culture change throughout the State of Kansas. Applications to the micro level (individual homes) are presented, and implications for psychologists' roles in facilitating culture change are discussed. (PsycINFO Database Record PMID- 28805414 TI - A culturally adapted family intervention for rural Pacific Island veterans with PTSD. AB - : The Veterans Affairs mission to provide equitable, accessible, and patient centered care necessitates that culturally appropriate interventions are available when cultural differences may jeopardize engagement in care. However, within the VA, wounded warriors residing in rural areas in the Pacific Islands have been offered interventions that were developed and tested using largely urban mainland populations. The objectives of this article were to (a) document the cultural adaptation of a cognitive-behavioral clinical intervention for use by rural Pacific Island veterans, and (b) report feasibility data for the intervention. The 5-stage Map of the Adaptation Process (assessment, selection, preparation, piloting, and refinement) was used to structure the work. The resultant intervention, called "Koa," is a multisession family psychoeducational program that integrates selected Pacific Islander values, beliefs, and healing traditions with an empirically based mainstream U.S. INTERVENTION: To pilot Koa, rural Pacific Island dyads (28 veterans and 28 family members) participated via video teleconference and completed pre- and post- intervention measures. Outcome data indicated that participants perceived the intervention to be highly acceptable, useful, and relevant. Relationship quality scores substantially improved postintervention as measured by the Dyadic Relationship Scale (95% CI [ 10.97, -1.84], t(22) = -2.9, p = .008, d = -0.53 for veterans; 95% CI [-11.06, 2.47], t(21) = -3.28, p = .004, d = -0.68 for family members). Family caregiving burden also improved significantly. The positive results of this investigation support the development of culturally adapted mental health interventions for culturally distinct subgroups of veterans and their families. (PsycINFO Database Record PMID- 28805416 TI - Identifying barriers to culture change: A qualitative analysis of the obstacles to delivering resident-centered care. AB - A growing number of healthcare organizations have moved from traditional, institutional nursing home models to ones that emphasize culture change, or resident-centered care (RCC). In 2006, the Department of Veterans Affairs (VA) began implementing a number of changes to VA nursing homes, now called Community Living Centers (CLCs), to provide veterans with a more resident-centered and homelike environment. This study aimed to understand the barriers CLC staff face when delivering RCC. Ten CLCs were included on the basis of their performance levels on RCC and quality of care. Semistructured interviews that focused on facility efforts in RCC and quality were conducted with all levels of staff. Interviews were systematically content coded. We found similarities and differences in barriers reported at high- and low-performing sites. Staff across all performance levels cited 5 main categories of barriers to delivering RCC: staffing, resources, acuity of residents, RCC and quality of care conflicts, and regulations. Staff in high-performing sites reported fewer barriers to RCC, although 1 barrier cited was difficulty coordinating RCC across departments. Staff in low-performing sites reported additional categories of barriers related to administrator turnover/lack of guidance, CLC culture/staff morale, and difficulty working with residents and families. As RCC continues to spread, it is important to anticipate the barriers to implementing these practices. Particular focus on regulatory, leadership, organizational, workforce, and process factors may help organizations avoid or reduce barriers to RCC. Given their training and skill set, mental health providers may be uniquely situated to assist staff in overcoming these barriers. (PsycINFO Database Record PMID- 28805417 TI - Implementing a cornerstone of culture change: Consistent staff assignment in VHA community living centers. AB - In 2011, the Veterans Health Administration (VHA) began implementing consistent staff assignment in its nursing homes (called Community Living Centers or CLCs). Consistent assignment, a cornerstone of culture change, minimizes the number of staff who provide a resident's care. The present research assessed the level and stability of consistent assignment in units within VHA CLCs and identified unit characteristics related to implementation of this staff assignment model. Schedulers in 185 of 335 organizational units that make up VHA CLCs completed a Staffing Practices Survey. For the month prior to the survey, 53% of CLC units had full implementation of consistent assignment. Tracked back over time, 37% of CLC units had stable high consistent assignment, 29% had stable low consistent assignment, and 34% were variable. Units with stable high consistent assignment were most likely to use care teams with stable membership and to obtain staff input for care assignments. Schedulers in these units reported more positive experiences with consistent staff assignment and better unit functioning in terms of staff absences, complaints about workload fairness, and resolution of scheduling problems. Units with stable low and variable consistent assignment were similar in most of these respects; however, units with variable consistent assignment made greater use of stable care teams and were less likely to change assignments at a staff member's request. Overall, consistent assignment implementation was not related to unit size, nursing hours per resident day, or specialty focus. Findings can help guide consistent staff assignment implementation in VHA and community nursing homes. (PsycINFO Database Record PMID- 28805418 TI - Adaptation of a nursing home culture change research instrument for frontline staff quality improvement use. AB - Enhanced interpersonal relationships and meaningful resident engagement in daily life are central to nursing home cultural transformation, yet these critical components of person-centered care may be difficult for frontline staff to measure using traditional research instruments. To address the need for easy-to use instruments to help nursing home staff members evaluate and improve person centered care, the psychometric method of cognitive-based interviewing was used to adapt a structured observation instrument originally developed for researchers and nursing home surveyors. Twenty-eight staff members from 2 Veterans Health Administration (VHA) nursing homes participated in 1 of 3 rounds of cognitive based interviews, using the instrument in real-life situations. Modifications to the original instrument were guided by a cognitive processing model of instrument refinement. Following 2 rounds of cognitive interviews, pretesting of the revised instrument, and another round of cognitive interviews, the resulting set of 3 short instruments mirrored the concepts of the original longer instrument but were significantly easier for frontline staff to understand and use. Final results indicated frontline staff found the revised instruments feasible to use and clinically relevant in measuring and improving the lived experience of a changing culture. This article provides a framework for developing or adapting other measurement tools for frontline culture change efforts in nursing homes, in addition to reporting on a practical set of instruments to measure aspects of person-centered care. (PsycINFO Database Record PMID- 28805419 TI - Creating space for relationships. AB - Sexuality is a key component of personality and behavior, encompassing basic human needs for touch, intimacy, love, affection, and sexual behavior. The design of long-term care facilities makes it almost impossible for a resident to be sexually intimate, to share romantic moments, or to have a meal in a private setting. This case study describes the rationale and process used to establish a private guestroom called the Family Room at Patriots Place, the specialized dementia unit in the Veterans Affairs (VA) Maine Healthcare System Community Living Center (CLC). As part of an overall commitment to culture change at VA Maine, the Family Room addresses needs for privacy and sexual intimacy as expressed by residents and their partners. Supporting the dignity and independence of individuals with dementia provided the basis for the policies established to support this project. Despite potential challenges, (e.g., staff acceptance, nursing coverage, facility space needs) residents, partners, and health care staff at VA Maine have expressed positive support for the Family Room. This resource is a way to accommodate the ongoing needs for privacy, intimacy, relational continuity, and sexual expression of long-term care residents with dementia and to support their autonomy and dignity. (PsycINFO Database Record PMID- 28805420 TI - Expanding our reach: Increasing the role of psychologists in public and community mental health. AB - Psychologists are currently underrepresented in community and public mental health settings, despite the advanced training and competencies that are salient for service in various unique and important functions in the public sector. This article will explore those functions including: transformation to recovery oriented care, delivery of positive behavioral support, implementation and evaluation of evidence-based interventions, application of scholarly guided practice, emphasis on context, therapeutic relationship, and history in therapeutic interventions, provision of training, education, program development and evaluation, and development of leadership and leadership training in systems of care. To illustrate these, the authors share specific clinical applications that provide a picture of psychologists serving in these roles, with the aim of providing examples for other organizations to increase the representation of psychologists in the public sector. Finally, the potential opportunities through initiatives such as loan forgiveness and other economic incentives are briefly explored as possible mechanisms to achieve this aim. (PsycINFO Database Record PMID- 28805421 TI - Collaborating with community-based services to promote evidence-based practice: Process description of a national initiative to improve services for youth with mental health and substance use problems. AB - Many youth with significant mental health (MH) and/or substance use (SU) difficulties do not receive specialized services. Collaboration between service providers, researchers, and other stakeholders is essential to improve youth service system capacity to provide evidence-based services to meet the complex array of needs of youth. Facilitators and barriers of implementing evidence-based practice have been identified, but few studies provide examples of the processes of collaboration and implementation for youth MH services. This study explicates the design features and implementation processes of a project to improve screening activities in youth services. These processes supported the building of 16 collaborative networks of service providers from diverse youth-serving sectors (e.g., MH, youth justice, child welfare) in urban, rural, suburban, and remote Canadian communities. These cross-sectoral networks implemented an evidence-based practice (screening youth aged 12-24 years for MH and SU problems using the Global Assessment of Individual Needs-Short Screener [GAIN-SS]) across their services. Materials and resources were provided by a centralized research team. Core project components were standardized and adherence to these components was monitored. Over 800 service providers participated in cross-sectoral networks, capacity-building events, joint data analysis, or interpretation and recommendation sessions. Across the 89 participating agencies, service providers for 84% of participating youth implemented the evidence-based practice accurately in accordance with project protocols, with 98% of positive screens reviewed and addressed according to organizational protocols. Service provider feedback is reported. Facilitators, barriers, and implications of promoting implementation of evidence-based practices across sites and sectors are discussed. (PsycINFO Database Record PMID- 28805423 TI - Patterns of psychiatric emergency department utilization among community-dwelling Medicare beneficiaries under 65. AB - This study estimated patterns and trends in all-cause (any reason, including psychiatry related) and psychiatric emergency department (ED) utilization among Medicare beneficiaries under 65 who were residing in community settings (i.e., noninstitutionalized or in their own homes). Medicare beneficiaries under the age of 65 enrolled in Medicare for Social Security Disability Insurance (SSDI) due to permanent physical or mental disabilities are a population with poor health conditions and high utilization of health services; however, this vulnerable population has received limited attention from researchers and policymakers compared to the Medicare beneficiaries 65 years and older. Data from the 2002 2009 Medicare Current Beneficiary Survey (MCBS) with linked Medicare administrative claims data were used to select a total of 4,864 Medicare beneficiaries under the age of 65 with a total of 10,384 person-years (weighted n = 30,086,846 person-years). We found that trends in all-cause and psychiatric ED utilization among the young and disabled Medicare beneficiaries remained stable, but trends in the proportion of all-cause ED visits that were psychiatric related increased, and trends in the proportion of psychiatric ED visits resulting in a psychiatric inpatient stay decreased over time. Factors associated with a higher likelihood of psychiatric ED utilization included younger age, residence in the Northeast region, lower education level, Medicare-Medicaid dual eligibility, use of psychotropic medication, and greater number of chronic and psychiatric conditions. These findings highlight the need for policies, programs, and system interventions designed to reduce future psychiatric ED events and improve the access and quality of community mental health services for the community dwelling, young, and disabled Medicare population. (PsycINFO Database Record PMID- 28805422 TI - Stakeholder perspectives on a toolkit to enhance caregiver participation in community-based child mental health services. AB - Client engagement in services is a critical element of effective community-based child and family mental health service delivery. Caregiver engagement is particularly important, as caregivers often serve as gatekeepers to child mental health care and typically must consent for services, facilitate service attendance, and are often the target of intervention themselves. Unfortunately, caregiver engagement has been identified as a significant challenge in community based child mental health services. To address this gap, the Parent And Caregiver Active Participation Toolkit (PACT), which includes therapist training and participation tools for caregivers and therapists, was developed. Stakeholders' perspectives regarding the delivery of interventions designed to improve the quality and effectiveness of community-based care are essential to understanding the implementation of such interventions in routine service settings. As such, this mixed methods study examined the perspectives of 12 therapists, 8 caregivers, and 6 program managers who participated in a community-based randomized pilot study of PACT. Therapists, caregivers, and program managers agreed that PACT was acceptable, appropriate, and feasible to use in community settings and that both changes in therapist practices and caregiver participation resulted from implementing PACT. Some variable perceptions in the utility of the therapist training components were identified, as well as barriers and facilitators of PACT implementation. Results expand the parent pilot study's findings as well as complement and expand the literature on training community providers in evidence-based practices. (PsycINFO Database Record PMID- 28805424 TI - The dark side of subjective value in sequential negotiations: The mediating role of pride and anger. AB - Scholars who study negotiation increasingly recognize the importance of social context, seeing negotiations not merely as 1-shot interactions but as influenced by what came before. Under this longitudinal conceptualization of negotiation, a number of recent studies demonstrate that social psychological outcomes from prior negotiations are positively related to economic performance in subsequent negotiations when negotiating repeatedly with the same counterpart. In this report, we investigate a counterexample in the context of "sequential negotiations," which we define as multiple negotiation sessions that occur within a short time frame but facing different counterparts in each session. We theorize, in sequential negotiations, that subjective value from 1 negotiation should be negatively related to objective outcomes in a subsequent negotiation because of spillover effects of incidental anger and pride. We test this model in 2 studies: a multiround lab study with a student sample and a longitudinal field study with employees negotiating as part of their jobs. Results from both studies support the hypothesized negative relationship between subjective value from an initial negotiation and the objective outcome from a subsequent negotiation with a different counterpart. The mediating role of pride is supported partially in Study 1 and fully in Study 2, whereas the mediating role of anger is not supported in either study. We discuss implications for negotiation theory and practice. (PsycINFO Database Record PMID- 28805425 TI - Cheating under pressure: A self-protection model of workplace cheating behavior. AB - [Correction Notice: An Erratum for this article was reported in Vol 103(1) of Journal of Applied Psychology (see record 2017-44052-001). In the article, the fit statistics in Study 3 were reported in error. The fit of the measurement model is: Chi2(362) = 563.66, p = .001; CFI = .94; SRMR = .05; RMSEA = .04. The fit of the SEM model is: Chi2(362) = 563.66, p = .001; CFI = .94; SRMR = .05; RMSEA = .04.] Workplace cheating behavior is unethical behavior that seeks to create an unfair advantage and enhance benefits for the actor. Although cheating is clearly unwanted behavior within organizations, organizations may unknowingly increase cheating as a byproduct of their pursuit of high performance. We theorize that as organizations place a strong emphasis on high levels of performance, they may also enhance employees' self-interested motives and need for self-protection. We suggest that demands for high performance may elicit performance pressure-the subjective experience that employees must raise their performance efforts or face significant consequences. Employees' perception of the need to raise performance paired with the potential for negative consequences is threatening and heightens self-protection needs. Driven by self-protection, employees experience anger and heightened self-serving cognitions, which motivate cheating behavior. A multistudy approach was used to test our predictions. Study 1 developed and provided validity evidence for a measure of cheating behavior. Studies 2 and 3 tested our predictions in time-separated field studies. Results from Study 2 demonstrated that anger mediates the effects of performance pressure on cheating behavior. Study 3 replicated the Study 2 findings, and extended them to show that self-serving cognitions also mediate the effects of performance pressure on cheating behavior. Implications of our findings for theory and practice are provided. (PsycINFO Database Record PMID- 28805426 TI - Detecting and differentiating the direction of change and intervention effects in randomized trials. AB - Calls continue for randomized interventions in organizational settings. In many cases, however, practical constraints require researchers to use 2-wave randomized pretest-posttest control group designs. We discuss the importance of randomized trials for theory development with a focus on analytic options for 2 wave designs. Our discussion has implications for both designing studies and interpreting results. We review 23 published work and organizational health psychology intervention studies and find that a majority of studies featured a statistical model known to have low statistical power relative to other options. Furthermore, a majority of studies invoked terminology implying the direction of change without providing explicit statistical tests. To improve research practice, we detail statistical power differences in 3 commonly used statistical models and emphasize the distinction between (a) intervention effects and (b) the size and direction of change over time. We encourage researchers to provide inferential evidence for both types of information and show that only 1 of the 3 reviewed models provides information on the direction of change over time, but at a potential expense for statistical power to detect intervention effects. A reanalysis of data from a published work-family workplace intervention illustrates these nuances and supports recommendations for research practice. We conclude by providing recommendations. (PsycINFO Database Record PMID- 28805427 TI - On the relative importance of individual-level characteristics and dyadic interaction effects in negotiations: Variance partitioning evidence from a twins study. AB - Negotiations are inherently dyadic. Negotiators' individual-level characteristics may not only make them perform better or worse in general, but also may make them particularly well- or poorly-suited to negotiate with a particular counterpart. The present research estimates the extent to which performance in a distributive negotiation is affected by (a) the negotiators' individual-level characteristics and (b) dyadic interaction effects that are defined by the unique pairings between the negotiators and their counterparts. Because negotiators cannot interact multiple times without carryover effects, we estimated the relative importance of these factors with a new methodology that used twin siblings as stand-ins for each other. Participants engaged in a series of 1-on-1 negotiations with counterparts while, elsewhere, their cotwins engaged in the same series of 1 on-1 negotiations with the cotwins of those counterparts. In these data, dyadic interaction effects explained more variation in negotiation economic outcomes than did individual differences, whereas individual differences explain more than twice as much of the variation in subjective negotiation outcomes than did dyadic interaction effects. These results suggest dyadic interaction effects represent an understudied area for future research, particularly with regard to the economic outcomes of negotiations. (PsycINFO Database Record PMID- 28805428 TI - Ventral striatum lesions do not affect reinforcement learning with deterministic outcomes on slow time scales. AB - A large body of work has implicated the ventral striatum (VS) in aspects of reinforcement learning (RL). However, less work has directly examined the effects of lesions in the VS, or other forms of inactivation, on 2-armed bandit RL tasks. We have recently found that lesions in the VS in macaque monkeys affect learning with stochastic schedules but have minimal effects with deterministic schedules. The reasons for this are not currently clear. Because our previous work used short intertrial intervals, one possibility is that the animals were using working memory to bridge stimulus-reward associations from 1 trial to the next. In the present study, we examined learning of 60 pairs of objects, in which the animals received only 1 trial per day with each pair. The large number of object pairs and the long interval (approximately 24 hr) between trials with a given pair minimized the chances that the animals could use working memory to bridge trials. We found that monkeys with VS lesions were unimpaired relative to controls, which suggests that animals with VS lesions can still learn to select rewarded objects even when they cannot make use of working memory. (PsycINFO Database Record PMID- 28805429 TI - The effect of scopolamine on matching behavior and the estimation of relative reward magnitude. AB - We investigated the behavioral effects of scopolamine on rats that bar pressed for trains of electrically stimulating pulses under concurrent variable interval schedules of reward. For the first half of the session (30 min) a 1:4 ratio in the programmed number of stimulation trains delivered at each option was in effect. At the start of the second half of the session, an unsignaled reversal in the relative train number (4:1) occurred. We tracked the relative magnitude of reward estimated for each contiguous pair of reinforced visits to competing options. Scopolamine hydrobromide led to a reduction in the relative magnitude of reward. A similar result was obtained in a follow-up test in which relative magnitude was manipulated by varying the pulse frequency of stimulation, while equating the train number at each option. The effect of scopolamine hydrobromide could not be attributed to undermatching, side bias, nor to an effect of scopolamine on the reward integration process. When the same rats were treated with scopolamine methylbromide, no effects on matching behavior were observed. Our results suggest a cholinergic basis for the computation of choice variables related to matching behavior. (PsycINFO Database Record PMID- 28805430 TI - Context-specific habituation of the freezing response in newborn chicks. AB - Previous studies have found that in mature animals habituation is context specific in some species but not in others. Given the mixed evidence present in the literature, we decided to explore whether habituation is context-specific in newborn chicks. The results showed that 3 days after hatching, chicks were capable of using global contextual information to rapidly habituate their freezing response to a series of sudden acoustic stimuli. Our study is the 1st to show context-specific habituation in this avian species, a result in agreement with those of previous findings in adult male zebra finches (Taeniopygia guttata). Furthermore, although our study does not intend to provide a systematic investigation of the ontogeny of habituation in this species, our findings show that a few days after hatching, juvenile chicks are capable of a sophisticated associative learning process that takes into account complex environmental information. (PsycINFO Database Record PMID- 28805431 TI - Disentangling the effects of serotonin on risk perception: S-carriers of 5-HTTLPR are primarily concerned with the magnitude of the outcomes, not the uncertainty. AB - Serotonin signaling is vital for reward processing, and hence, also for decision making. The serotonin transporter gene linked polymorphic region (5-HTTLPR) has been connected to decision making, suggesting that short-allele carriers (s) are more risk averse than long-allele homozygotes (ll). However, previous research has not identified if this occurs because s-carriers (i) are more sensitive to the uncertainty of the outcomes or (ii) are more sensitive to the magnitude of the outcomes. This issue was disentangled using a willingness-to-pay task, where the participants evaluated prospects involving certain gains, uncertain gains, and ambiguous gains. The results clearly favored the hypothesis that s-carriers react more to the magnitude of the outcomes. Self-reported measures of everyday risk-taking behavior also favored this hypothesis. We discuss how these results are in line with recent research on the serotonergic impact on reward processing. (PsycINFO Database Record PMID- 28805432 TI - Strain-dependent sex differences in a long-term forced swim paradigm. AB - Women are twice as likely as men to suffer from trauma- and stressor-related disorders. The development of improved therapeutic interventions is contingent upon a more complete grasp of both the neural and behavioral dynamics of the stress response in females. The rodent forced swim test (FST) is a valuable animal model for exploring the neurobiological mechanisms responsible for selection of active and passive responses to inescapable stressors, but it is often neglected in 2-day FST studies is the dissociation of innate (Day 1) versus learned (Day 2) coping responses. Here, we used a modified, long-term (4-week) FST paradigm and immunohistological analysis to study the interactions of sex, strain, and housing arrangement on selection of active and passive coping strategies in Sprague Dawley (SD) and Long Evans (LE) rats. We observed significant strain * sex interactions in both forced swim sessions with respect to both passive (immobility) and active (climbing and headshakes) responses. In immobility measures, we observed stable sex differences in SD rats and a stable lack of sex differences in LE rats across tests. In addition, both SD and LE females displayed significantly more headshakes than males during Test 1 and more climbing in Test 2. Most notably, males, but not females, exhibited a cross-test increase in immobility, suggesting that males and females may engage different learning processes in a 2-day FST. These sex differences corresponded to c-fos expression in the medial prefrontal cortex (mPFC), indicating that the mPFC may contribute to sexually dimorphic behavior in the FST. (PsycINFO Database Record PMID- 28805433 TI - Overriding actions in Parkinson's disease: Impaired stopping and changing of motor responses. AB - We administered a stop-change paradigm, an extended version of the stop task that requires (a) stopping an ongoing motor response and (b) changing to an alternative (change) response. Performance of a group of patients diagnosed with Parkinson's disease (PD) and taking dopaminergic medication was compared with that of matched healthy control (HC) participants. Behavioral results indicated that response latencies to the initial go signal did not distinguish between the 2 groups, but that stopping latencies were prolonged in PD patients. In addition, the change response was delayed in the clinical group, indicating difficulties in flexibly changing to alternative motor actions upon external cues. The change deficit in PD related to the inhibition deficit. This dependence points to a serial processing architecture in PD according to which the stopping process has to finish before the change process can be initiated. In contrast, the HC group showed parallel stop and change processing. Analyses of sequential trial effects suggest that both HC and PD patients are susceptible to aftereffects of action override, due to the consequences of the automatic retrieval of recent associations between action and goal representations. Interestingly, postchange performance of the clinical group was hampered disproportionately, suggesting that PD is associated with an impairment in overriding previously formed action goal associations. These findings support the notion that both higher-order cognitive control processes, such as inhibiting and changing actions, as well as lower-order feature binding mechanisms rely on basal ganglia functioning and are compromised by the basal ganglia dysfunction caused by PD. (PsycINFO Database Record PMID- 28805434 TI - The differential influences of parenting and child narrative coherence on the development of emotion recognition. AB - The ability to recognize and label emotions serves as a building block by which children make sense of the world and learn how to interact with social partners. However, the timing and salience of influences on emotion recognition development are not fully understood. Path analyses evaluated the contributions of parenting and child narrative coherence to the development of emotion recognition across ages 4 through 8 in a diverse (50% female; 46% Hispanic, 18.4% Black, 11.2% White, .4% Asian, 24.0% multiracial) longitudinally followed sample of 250 caregiver-child dyads. Parenting behaviors during interactions (i.e., support, instructional quality, intrusiveness, and hostility) and children's narrative coherence during the MacArthur Story Stem Battery were observed at ages 4 and 6. Emotion recognition increased from age 4 to 8. Parents' supportive presence at age 4 and instructional quality at age 6 predicted increased emotion recognition at 8, beyond initial levels of emotion recognition and child cognitive ability. There were no significant effects of negative parenting (i.e., intrusiveness or hostility) at 4 or 6 on emotion recognition. Child narrative coherence at ages 4 and 6 predicted increased emotion recognition at 8. Emotion recognition at age 4 predicted increased parent instructional quality and decreased intrusiveness at 6. These findings clarify whether and when familial and child factors influence emotion recognition development. Influences on emotion recognition development emerged as differentially salient across time periods, such that there is a need to develop and implement targeted interventions to promote positive parenting skills and children's narrative coherence at specific ages. (PsycINFO Database Record PMID- 28805435 TI - The development of marital tension: Implications for divorce among married couples. AB - Marriages are often characterized by their positive and negative features in terms of whether they elicit feelings of satisfaction and happiness or conflict and negativity. Although research has examined the development of marital happiness, less is known about the development of negativity among married couples. We examined how marital tension (i.e., feelings of tension, resentment, irritation) develops within couples over time and whether marital tension has unique implications for divorce. Specifically, we examined marital tension among husbands and wives within the same couples from the first to the sixteenth year of marriage, as well as links between marital tension and divorce. Participants included 355 couples assessed in years 1, 2, 3, 4, 7, and 16 of marriage. Multilevel models revealed that wives reported greater marital tension than husbands. Marital tension increased over time among both husbands and wives, with a greater increase among husbands. Couples were more likely to divorce when wives reported higher marital tension, a greater increase in marital tension, and greater cumulative marital tension. Findings are consistent with the emergent distress model of marriage, but indicate that despite the greater increases in marital tension among husbands, wives' increased marital tension over the course of marriage is more consistently associated with divorce. (PsycINFO Database Record PMID- 28805436 TI - Event-related potentials discriminate familiar and unusual goal outcomes in 5 month-olds and adults. AB - Previous event-related potential (ERP) work has indicated that the neural processing of action sequences develops with age. Although adults and 9-month olds use a semantic processing system, perceiving actions activates attentional processes in 7-month-olds. However, presenting a sequence of action context, action execution and action conclusion could challenge infants' developing working memory capacities. A shortened stimulus presentation of a highly familiar action, presenting only the action conclusion of an eating action, may therefore enable semantic processing in even younger infants. The present study examined neural correlates of the processing of expected and unexpected action conclusions in adults and infants at 5 months of age. We analyzed ERP components reflecting semantic processing (N400), attentional processes (negative central in infants; P1, N2 in adults) and the infant positive slow wave (PSW), a marker of familiarity. In infants, the PSW was enhanced on left frontal channels in response to unexpected as compared to the expected outcomes. We did not find differences between conditions in ERP waves reflecting semantic processing or overt attentional mechanisms. In adults, in addition to differences in attentional processes on the P1 and the N2, an N400 occurred only in response to the unexpected action outcome, suggesting semantic processing taking place even without a complete action sequence being present. Results indicate that infants are already sensitive to differences in action outcomes, although the underlying mechanism which is based on familiarity is relatively rudimentary when contrasted with adults. This finding points toward different cognitive mechanisms being involved in action processing during development. (PsycINFO Database Record PMID- 28805437 TI - The link between perceived maternal and paternal autonomy support and adolescent well-being across three major educational transitions. AB - To what extent does maternal and paternal autonomy support enhance well-being across the major transitions of high school? We tested the degree to which perceived autonomy supportive parenting facilitated positive changes in self esteem and life satisfaction and buffered against negative changes in depressive symptoms and school related burnout in 3 Finnish longitudinal studies, each with a measurement point before and after a major transition (middle school, N1 = 760, 55.7% girls; high school, N2 = 214, 51.9% girls; post high school, N3 = 858, 47.8% girls). Results showed that perceived parental autonomy support was negatively related to depressive symptoms and positively related to self-esteem. The findings for the effects on depressive symptoms were replicated across all 3 transitions, while effects on self-esteem were only found for the high school and post high school transitions. Moreover, evidence of coregulation was found for depressive symptoms. Depressive symptoms before the transition were found to decrease autonomy support after the transition for both the high school and post high school transitions. Maternal and paternal autonomy support was of equal importance. Importantly, the effects on depressive symptoms increased as children developed, suggesting the continual importance of parents throughout high school and into emerging adulthood. (PsycINFO Database Record PMID- 28805438 TI - Situational and structural variation in youth perceptions of maternal guilt induction. AB - Parental induction of empathy-related guilt plays an important role in children's moral development. However, guilt induction can also be psychologically controlling and detrimental for youth adjustment. This study provided a more nuanced view of parental guilt induction by examining how the nature of a child's misdeed and the structure and content of the parental guilt inductive statement impact children's perceptions of it. Using hypothetical vignettes, this study experimentally examined the impact of the type (domain) of child behavior, highlighted victim, and focus of parental criticism on 156 children's and early and middle adolescents' (age: Ms = 8.82, 12.11, and 15.84 years) perceptions of maternal guilt induction. Attributions of guilt and shame increased most for younger children, when mothers focused on indirect harm to themselves about personal issues, and when mothers criticized their child as a person (shame only). Youth evaluated guilt induction least positively for personal issues and when mothers criticized the child's personality while focusing on indirect harm to themselves. With age, youth were less accepting of maternal guilt induction and more likely to endorse negative and parent-centered intentions, especially for personal issues. Older youth also drew less distinction between guilt induction over multifaceted and personal issues. Guilt induction over moral issues was generally perceived most positively. Additional interactions also emerged. These findings suggest that the meaning and effects of guilt induction on children's development may depend on the way in which it is enacted. (PsycINFO Database Record PMID- 28805439 TI - Ratios and effect size. AB - Responding to a related pair of measurements is often expressed as a single discrimination ratio. Authors have used various discrimination ratios; yet, little information exists to guide their choice. A second use of ratios is to correct for the influence of a nuisance variable on the measurement of interest. I examine 4 discrimination ratios using simulated data sets. Three ratios, of the form a/(a + b), b/(a + b), and (a - b)/(a + b), introduced distortions to their raw data. The fourth ratio, (b - a)/b largely avoided such distortions and was the most sensitive at detecting statistical differences. Effect size statistics were also often improved with a correction ratio. Gustatory sensory preconditioning experiments involved measurement of rats' sucrose and saline consumption; these flavors served as either a target flavor or a control flavor and were counterbalanced across rats. However, sensory preconditioning was often masked by a bias for sucrose over saline. Sucrose and saline consumption scores were multiplied by the ratio of the overall consumption to the consumption of that flavor alone, which corrected the bias. The general utility of discrimination and correction ratios for data treatment is discussed. (PsycINFO Database Record PMID- 28805440 TI - Do rewards reinforce the growth mindset?: Joint effects of the growth mindset and incentive schemes in a field intervention. AB - The current study draws on the motivational model of achievement which has been guiding research on the growth mindset intervention (Dweck & Leggett, 1988) and examines how this intervention interacts with incentive systems to differentially influence performance for high- and low-achieving students in Indian schools that serve low-SES communities. Although, as expected, the growth mindset intervention did interact with incentive systems and prior achievement to influence subsequent academic performance, the existing growth mindset framework cannot fully account for the observed effects. Specifically, we found that the growth mindset intervention did facilitate performance through persistence, but only when the incentive system imparted individuals with a sense of autonomy. Such a facilitation effect was only found among those students who had high prior achievement, but not among those who had underperformed. When the incentive did not impart a sense of autonomy, the growth mindset intervention undermined the performance of those who had high initial achievement. To reconcile these discrepancies and to advance understanding of the impacts of psychological interventions on achievement outcomes, we discuss how the existing theory can be extended and integrated with an identity-based motivation framework (Oyserman & Destin, 2010). We also discuss the implications of our work for future research and practice. (PsycINFO Database Record PMID- 28805441 TI - Examining overlap in behavioral and neural representations of morals, facts, and preferences. AB - Metaethical judgments refer to judgments about the information expressed by moral claims. Moral objectivists generally believe that moral claims are akin to facts, whereas moral subjectivists generally believe that moral claims are more akin to preferences. Evidence from developmental and social psychology has generally favored an objectivist view; however, this work has typically relied on few examples, and analyses have disallowed statistical generalizations beyond these few stimuli. The present work addresses whether morals are represented as fact like or preference-like, using behavioral and neuroimaging methods, in combination with statistical techniques that can (a) generalize beyond our sample stimuli, and (b) test whether particular item features are associated with neural activity. Behaviorally, and contrary to prior work, morals were perceived as more preference-like than fact-like. Neurally, morals and preferences elicited common magnitudes and spatial patterns of activity, particularly within the dorsal medial prefrontal cortex (DMPFC), a critical region for social cognition. This common DMPFC activity for morals and preferences was present across whole-brain conjunctions, and in individually localized functional regions of interest (targeting the theory of mind network). By contrast, morals and facts did not elicit any neural activity in common. Follow-up item analyses suggested that the activity elicited in common by morals and preferences was explained by their shared tendency to evoke representations of mental states. We conclude that morals are represented as far more subjective than prior work has suggested. This conclusion is consistent with recent theoretical research, which has argued that morality is fundamentally about regulating social relationships. (PsycINFO Database Record PMID- 28805442 TI - The secret to happiness: Feeling good or feeling right? AB - Which emotional experiences should people pursue to optimize happiness? According to traditional subjective well-being research, the more pleasant emotions we experience, the happier we are. According to Aristotle, the more we experience the emotions we want to experience, the happier we are. We tested both predictions in a cross-cultural sample of 2,324 participants from 8 countries around the world. We assessed experienced emotions, desired emotions, and indices of well-being and depressive symptoms. Across cultures, happier people were those who more often experienced emotions they wanted to experience, whether these were pleasant (e.g., love) or unpleasant (e.g., hatred). This pattern applied even to people who wanted to feel less pleasant or more unpleasant emotions than they actually felt. Controlling for differences in experienced and desired emotions left the pattern unchanged. These findings suggest that happiness involves experiencing emotions that feel right, whether they feel good or not. (PsycINFO Database Record PMID- 28805443 TI - The effect of the proportion of mismatching trials and task orientation on the confidence-accuracy relationship in unfamiliar face matching. AB - Unfamiliar, one-to-one face matching has been shown to be error-prone. However, it is unknown whether there is a strong relationship between confidence and accuracy in this task. If there is, then confidence could be used as an indicator of accuracy in real-world face matching settings such as border security, where the objectively correct decision is typically unknown. Two experiments examined the overall confidence-accuracy relationship, as well as the relationship for positive (match) and negative (mismatch) decisions. Furthermore, they tested whether these relationships were affected by factors relevant to applied face matching settings: the proportion of mismatching trials (PMT), and the task orientation of the decision-maker (look for matches, or look for mismatches). Both calibration analyses and signal detection methods were applied to assess performance. The results showed that confidence can have a high correspondence with accuracy overall, regardless of task orientation but with small effects of PMT. Thus, confidence is promising as an indicator of accuracy in face matching. However, PMT systematically produces large detrimental effects on the confidence accuracy relationships for positive and negative decisions, when considered separately. Signal detection measures help with understanding these effects and proposing future research directions for improving the relationships. (PsycINFO Database Record PMID- 28805444 TI - Contrast effect in spatial context: Robustness and practical significance. AB - Contrary to lay conceptions, unattractive locations can under certain circumstances increase the perceived value of neighboring areas. This phenomenon is akin to a contrast effect. However, extant research on this type of contrast suffers from two limitations. First, the use of repeated measures may inflate the likelihood of observing a contrast effect. Second, there is a lack of meaningful comparisons for gauging the size of the effect. We designed three experiments to address these issues. In each, we assessed how much participants valued places located increasingly far from an unsafe housing block. Participants either rated several target locations or just a single one at a time. We also assessed whether the positiveness of the contrast effect due to the unsafe housing block would be able to compete with the positive effect of a nearby park. The results replicate past findings of a contrast effect in spatial context; they show that the effect generalizes to a different design; and they demonstrate that a contrast effect due to an unattractive location can indeed be as "beneficial" for some neighboring areas as the effect of a genuinely attractive location. (PsycINFO Database Record PMID- 28805445 TI - Prevalence and Predictors of Learning and Psychological Diagnoses Following Pediatric Arterial Ischemic Stroke. AB - This study examined the prevalence of learning and psychological diagnoses and associated neurological and personal-environmental risk factors following perinatal and childhood arterial ischemic stroke. In our sample of 126 children and youth, 52.4% received a diagnosis following their assessment. Specifically, 32% had a single diagnosis and 21% had two or more diagnoses. Learning disability, attention deficit-hyperactivity disorder, and intellectual disability were the most prevalent diagnoses. Associated risk factors varied by diagnosis with lower intellectual functioning being the common risk factor across categories. Seizure status was associated with intellectual disability whereas family history was related to ADHD and comorbid diagnoses. PMID- 28805446 TI - Epigallocatechin Gallate as an anti-obesity therapeutic compound: an in silico approach for structure-based drug designing. AB - Epigallocatechin gallate is a polyphenol of tea plants. Other than tea its trace amounts are found in apple skin, onions and plums. It has anti-adipogenic and anti-oxidant potential. It was investigated that epigallocatechin gallate stopped the adipogenic differentiation of mice mesenchymal stem cells but its underlying mechanism is not well understood. Different proteins and transcription factors responsible for differentiation of adipocytes could be its targets. This study was designed to determine the potential target of epigallocatechin gallate in human. Human Peroxisome Proliferator-Activated Receptors (PPAR) gamma protein was selected as the potential target as it is a key transcription factor for differentiation of adipose cells. Docking analysis of PPAR gamma and epigallocatechin gallate demonstrated that epigallocatechin gallate binds with PPAR gamma at its active site and blocks its activity. This study helps in understanding the mode of action of epigallocatechin gallate that would help for anti-obesity drug development. PMID- 28805448 TI - Stakeholders' views on data sharing in multicenter studies. AB - AIM: To understand stakeholders' views on data sharing in multicenter comparative effectiveness research studies and the value of privacy-protecting methods. MATERIALS & METHODS: Semistructured interviews with five US stakeholder groups. RESULTS: We completed 11 interviews, involving patients (n = 15), researchers (n = 10), Institutional Review Board and regulatory staff (n = 3), multicenter research governance experts (n = 2) and healthcare system leaders (n = 4). Perceptions of the benefits and value of research were the strongest influences toward data sharing; cost and security risks were primary influences against sharing. Privacy-protecting methods that share summary-level data were acknowledged as being appealing, but there were concerns about increased cost and potential loss of research validity. CONCLUSION: Stakeholders were open to data sharing in multicenter studies that offer value and minimize security risks. PMID- 28805447 TI - Performance on naturalistic virtual reality tasks depends on global cognitive functioning as assessed via traditional neurocognitive tests. AB - This investigation sought to understand whether performance in naturalistic virtual reality tasks for cognitive assessment relates to the cognitive domains that are supposed to be measured. The Shoe Closet Test (SCT) was developed based on a simple visual search task involving attention skills, in which participants have to match each pair of shoes with the colors of the compartments in a virtual shoe closet. The interaction within the virtual environment was made using the Microsoft Kinect. The measures consisted of concurrent paper-and-pencil neurocognitive tests for global cognitive functioning, executive functions, attention, psychomotor ability, and the outcomes of the SCT. The results showed that the SCT correlated with global cognitive performance as measured with the Montreal Cognitive Assessment (MoCA). The SCT explained one third of the total variance of this test and revealed good sensitivity and specificity in discriminating scores below one standard deviation in this screening tool. These findings suggest that performance of such functional tasks involves a broad range of cognitive processes that are associated with global cognitive functioning and that may be difficult to isolate through paper-and-pencil neurocognitive tests. PMID- 28805449 TI - Stallion Sperm Cryopreservation Using Various Permeating Agents: Interplay Between Concentration and Cooling Rate. AB - In this study, modeling and experimental approaches were used to investigate the interplay between cooling rate and protectant concentration for cryopreservation of stallion sperm. Glycerol (GLY), ethylene glycol (EG), dimethylformamide (DMF), propylene glycol (PG), and dimethyl sulfoxide (DMSO) were tested as cryoprotective agents (CPAs), using concentrations up to 1500 mM and cooling rates ranging from 5 degrees C to 55 degrees C min-1. Modeling of the extent of sperm dehydration during freezing was done using previously determined values of the sperm membrane permeability to water to predict optimal cooling rates for cryopreservation. Sperm cryosurvival was experimentally determined through flow cytometric assessments on membrane intactness and using computer-assisted analysis of motility. Sperm could withstand exposure to 1500 mM concentrations prefreeze for all CPAs tested. The overall highest cryosurvival rates were obtained with DMF, followed by GLY and EG, whereas the use of PG and DMSO resulted in poor cryosurvival rates. Cryosurvival with DMF increased with increasing concentration, reaching a plateau at 500 mM, whereas for GLY and EG, an optimum concentration between 250 and 500 mM resulted in maximal survival. An optimal cooling rate was only observed at low CPA concentrations, whereas at higher concentrations, cryosurvival rates were not affected by the cooling rate. In the case of DMF, survival remained relatively high in the investigated range of concentrations and cooling rates, whereas with GLY and EG, a much narrower combination of CPA concentration and cooling rate resulted in optimal cryosurvival. Sperm cryopreserved with DMF showed altered motility characteristics indicating hyperactivation, which was not observed with GLY and EG. Optimal cooling rates that were predicted from calculated dehydration curves did not match experimentally determined optimal cooling rates. PMID- 28805450 TI - Commentary: Health Concerns of Brazil Nut Consumption. AB - Brazil nuts are the fruit of the enormous tropical tree Bertholletia excelsa that are produced in and exported from the territory of the Amazon. As a natural rich source of selenium (Se), the consumption of Brazil nuts is often suggested as therapeutic among patients with autoimmune thyroid diseases. In this review, the current knowledge regarding the main health concerns of Brazil nut consumption, such as Se toxicity, Se-induced type 2 diabetes mellitus, weight gain, radioactivity, aflatoxins, and allergic reactions, is presented and discussed. PMID- 28805451 TI - Genetic characterisation and analysis of infectious bronchitis virus isolated from Brazilian flocks between 2010 and 2015. AB - 1. Infectious bronchitis virus (IBV) variants in Brazil were isolated during 2010 2015 for epidemiological and molecular analysis to characterise the different variants and perform a bioinformatic analysis to compare with sequences of variants collected over the previous 40 years. 2. Of the 453 samples examined, 61.4% were positive for IBV and 75.9% of these were considered to have the BR-I genotype and were detected in birds of all ages distributed in all five Brazilian regions. 3. The ratio of non-synonymous substitutions per non-synonymous site (dN) to synonymous substitutions per synonymous site (dS), i.e. dN/dS, revealed a predominance of codons with non-synonymous substitutions in the first third of the S1 gene and a dN/dS ratio of 0.67. Additionally, prediction of N glycosylation sites showed that most of the BR-I variants (from 2003 to early 2014) had an extra site at amino acid position 20, whereas the newest variants lacked this extra site. 4. These results suggest that Brazilian IBV variants probably underwent drastic mutations at various points between 1983 and 2003 and that the selection processes became silent after achieving a sufficiently effective antigenic structure for invasion and replication in their hosts. Brazilian IBV genotype BR-I is currently the predominant genotype circulating in Brazil and South America. PMID- 28805452 TI - Birt-Hogg-Dube Syndrome with a Novel Mutation in the FLCN Gene. AB - BACKGROUND: Birt-Hogg-Dube syndrome (BHDS) is an autosomal dominant disease characterized by hair follicle hamartomas, kidney tumors, and spontaneous pneumothorax; its cause is a heterozygous mutation in the FLCN gene. Colorectal polyps and carcinoma have also been reported in BHDS. FLCN mutations can be detected in patients with isolated primary spontaneous pneumothorax (PSP), so PSP may present as part of BHDS. The aim of this report is to enhance awareness that patients presenting with spontaneous PSP should be evaluated for FLCN mutations. MATERIALS AND METHODS: A 44-year-old woman with PSP and her parents were analyzed for FLCN mutations. One of the patient's paternal aunts had a PSP and two of her paternal aunts had colon cancer diagnosed at early ages. RESULTS: A novel in frame deletion in the FLCN gene, c.932_933delCT (P311Rfs*78), was detected in the proband and in her unaffected father. CONCLUSIONS: We recommend that molecular analysis of the FLCN gene be performed in patients with PSP and their families, and that mutation carriers be examined for kidney and colon tumors. PMID- 28805453 TI - Colletotrichine A, a new sesquiterpenoid from Colletotrichum gloeosporioides GT 7, a fungal endophyte of Uncaria rhynchophylla. AB - One new compound, Colletotrichine A (1), was produced by the fungal Colletotrichum gloeosporioides GT-7. The structure was established by 1D and 2D NMR spectra. Monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitory activity of 1 was also evaluated. Compound 1 showed AChE-inhibiting activity with IC50 value of 28 MUg/mL. PMID- 28805454 TI - Breastfeeding and Infant Mortality in Indiana: Changing the Culture and Saving Lives: A Model for Other States. PMID- 28805455 TI - The effect of a peer support intervention on early recovery outcomes in men recovering from coronary bypass surgery: A randomized controlled trial. AB - BACKGROUND AND AIM: Examine the effect of a professionally-guided telephone peer support intervention on recovery outcomes including depression, perceived social support, and health services utilization after coronary artery bypass graft surgery (CABG). METHODS: A randomized controlled trial was conducted with post coronary artery bypass graft surgery men ( N=185) who were randomized before hospital discharge. The intervention arm received telephone-based peer support through weekly telephone calls from a peer volunteer over six weeks, initiated within 3-4 days of discharge. RESULTS: Although a significant difference was detected in pre-intervention depression scores at discharge, there were no differences between groups in changes in depression scores at six weeks ( p=0.08), 12 weeks (0.49) or over time ( p=0.51); and no significant differences in perceived social support scores over time ( p=0.94). At 12 weeks, the intervention group had significantly lower incidence of health services utilization (family physician ( p=0.02) and emergency room ( p=0.04)). CONCLUSIONS: Healthcare providers need to continue to investigate novel interventions to enhance social support and reduce depression in cardiac patients. PMID- 28805456 TI - A Systematic Review of the Use of Social Media for Food Safety Risk Communication. AB - This article covers the current published literature related to the use of social media in food safety and infectious disease communication. The aim was to analyze literature recommendations and draw conclusions about how best to utilize social media for food safety risk communication going forward. A systematic literature review was conducted, and 24 articles were included for analysis. The inclusion criteria were (i) original peer-reviewed articles and (ii) primary focus on communication through social media about food safety and/or infectious diseases. Studies were coded for themes about social media applications, benefits, limitations, and best practices. Trust and personal beliefs were important drivers of social media use. The wide reach, immediacy, and information gathering capacities of social media were frequently cited benefits. Suggestions for social media best practices were inconsistent among studies, and study designs were highly variable. More evidence-based suggestions are needed to better establish guidelines for social media use in food safety and infectious disease risk communication. The information gleaned from this review can be used to create effective messages for shaping food safety behaviors. PMID- 28805457 TI - Selection of Surrogate Bacteria for Use in Food Safety Challenge Studies: A Review. AB - Nonpathogenic surrogate bacteria are prevalently used in a variety of food challenge studies in place of foodborne pathogens such as Listeria monocytogenes, Salmonella, Escherichia coli O157:H7, and Clostridium botulinum because of safety and sanitary concerns. Surrogate bacteria should have growth characteristics and/or inactivation kinetics similar to those of target pathogens under given conditions in challenge studies. It is of great importance to carefully select and validate potential surrogate bacteria when verifying microbial inactivation processes. A validated surrogate responds similar to the targeted pathogen when tested for inactivation kinetics, growth parameters, or survivability under given conditions in agreement with appropriate statistical analyses. However, a considerable number of food studies involving putative surrogate bacteria lack convincing validation sources or adequate validation processes. Most of the validation information for surrogates in these studies is anecdotal and has been collected from previous publications but may not be sufficient for given conditions in the study at hand. This review is limited to an overview of select studies and discussion of the general criteria and approaches for selecting potential surrogate bacteria under given conditions. The review also includes a list of documented bacterial pathogen surrogates and their corresponding food products and treatments to provide guidance for future studies. PMID- 28805458 TI - Thermal Inactivation of Listeria monocytogenes and Salmonella during Water and Steam Blanching of Vegetables. AB - Thermal inactivation of Listeria monocytogenes and Salmonella was evaluated on peas, spinach, broccoli, potatoes, and carrots that were treated with hot water and steam. One gram-positive bacterium, L. monocytogenes, and one gram-negative bacterium, Salmonella, were selected as pertinent human pathogens for evaluation. Samples were inoculated with a composite of five strains each of L. monocytogenes and Salmonella to achieve approximately 108 to 109 CFU/g. Inoculated samples were treated with hot water at 85 and 87.8 degrees C and with steam at 85 and 96.7 degrees C for up to 3.5 min. A greater than 5-log reduction of L. monocytogenes and Salmonella was achieved on all products within 0.5 min by hot water blanching at 85 and 87.8 degrees C. Steam blanching at 85 degrees C reduced Salmonella populations by greater than 5 log on spinach and peas within 2 min and on carrots and broccoli within 3.5 min. Populations of Salmonella were reduced by more than 5 log within 1 min on carrot, spinach, and broccoli and within 2 min on peas by steam blanching at 96.7 degrees C. Steam blanching at 85 degrees C reduced L. monocytogenes populations by more than 5 log on carrots and spinach within 2 min and on broccoli and peas within 3.5 min. L. monocytogenes populations were reduced more than 5 log within 1 min on carrot, spinach, peas and broccoli by steam blanching at 96.7 degrees C. Longer treatment times and higher temperatures were required for steam-blanched samples than for samples blanched with hot water. Results suggest that hot water and steam blanching practices commonly used by the frozen vegetable industry will achieve the desired 5-log lethality of L. monocytogenes and Salmonella and will enhance microbiological safety prior to freezing. PMID- 28805459 TI - Opuntia ficus-indica (L.) Miller as a source of bioactivity compounds for health and nutrition. AB - Plants with beneficial properties are known in traditional medicine. Nowadays, in spite of widespread availability of synthetic compounds, the search goes towards natural compounds to lower cost and few side effects. The increasing interest in preventive medicine encourages use of nutraceuticals, bioactive compounds of vegetable origin with important nutritional values. Among the medicinal plants, Opuntia ficus-indica (L.) Miller (Family Cactaceae, subfamily Opuntiodeae, Genus Opuntia, subgenus Platyopuntia, species Opuntia ficus-indica (L.) Miller) is widely known for its beneficial properties. The aim of the present review is to stress the major classes of Opuntia components and their medical interest through emphasis on some of their biological effects, particularly those having the most promising expected health benefits and therapeutic impacts on fish and mammals. PMID- 28805460 TI - Case Study of Homeopathic Bowel Nosode Remedies for Dysbiotic Japanese Patients. AB - BACKGROUND: The composition of intestinal microbiota is very important in human health. Gastrointestinal disturbances are among the symptoms commonly reported by individuals diagnosed with chronic diseases, such as inflammatory bowel disease, autism, and chronic fatigue syndrome. The effects of probiotics and prebiotics for dysbiosis have been reported in many studies. Bowel nosodes are homeopathic remedies made from human gut microbiota. OBJECTIVE: Bowel nosodes made from the intestinal bacteria of European patients from the 1900s were administered to Japanese patients suffering from gastrointestinal disturbances, such as constipation and diarrhea, to determine their therapeutic efficacy. METHODS: Twenty-eight outpatients from Yoko Clinic (11 males, 17 females; age range, 4-72 years) were enrolled in this study. One nosode remedy was selected for each case. Patients took six pills for 2 days. After a month, the effect of each treatment was evaluated using the Glasgow Homeopathic Hospital Outcome Scale (grade +4 to 4). RESULTS: Patient number of each grade was +4 (N = 2), +3 (N = 4), +2 (N = 7), +1 (N = 3), 0 (N = 7), with no negative grades. Of the 23 patients analyzed, 69.6% showed some type of improvement, and no harmful effects from taking bowel nosodes were observed; 26% of patients showed major improvement or were "cured." CONCLUSION: It is difficult to find correct constitutional remedies as they often require high-level techniques and time. Since there are only 11 main bowel nosode remedies, they are easier to choose from and cheaper to use and develop than classical constitutional remedies. Herein, 69.6% of dysbiotic patients taking bowel nosodes showed improvements, and no harmful effects were reported by any patient. These results suggest that the homeopathic bowel nosodes are a useful method for controlling gastrointestinal disturbances. PMID- 28805461 TI - A new caffeic acid tetramer from the Dracocephalum moldavica L. AB - A new caffeic acid tetramer compound, named (+) methyl rabdosiin (4), together with seven known caffeic acid multimers (1-3, 5-8) and one caffeic acid monomer (9), were isolated from the aerial parts of Dracocephalum moldavica L. The structures of these compounds were assigned on the basis of 1D and 2D NMR spectroscopic and mass spectrometry analyses. The protective effects of compounds 2-4 against hydrogen peroxide (H2O2)-induced apoptosis were evaluated in primary cardiomyocytes of SD neonatal rats in vitro by the MTT method. Three compounds exhibited potent protective activities at 12.5 MUg/mL. PMID- 28805463 TI - Oxygen uptake at aerobic threshold is inversely associated with fatal cardiovascular and all-cause mortality events. AB - PURPOSE: We aimed to assess the associations of oxygen uptake at aerobic threshold (VO2 at AT) with cardiovascular and all-cause mortality. DESIGN: VO2 at AT was assessed in 1663 middle-aged men in a cohort study. Hazard ratios (HRs) were calculated for sudden cardiac death (SCD), fatal coronary heart disease (CHD) and cardiovascular disease (CVD) and all-cause mortality. RESULTS: During a median follow-up of 25.6 years, 138 SCDs, 209 fatal CHDs, 333 fatal CVDs and 719 all-cause mortality events occurred. On adjustment for established risk factors, the HRs (95% CIs) for SCD, fatal CHD, fatal CVD and all-cause mortality were 0.48 (0.28-0.82), 0.48 (0.31-0.74), 0.57 (0.41-0.79) and 0.66 (0.53-0.82), respectively comparing extreme quartiles of VO2 at AT. On further adjustment for peak VO2, the HRs were 0.87 (0.48-1.56), 0.83 (0.52-1.34), 0.91 (0.63-1.30) and 0.88 (0.69-1.12), respectively. Addition of VO2 at AT to a standard CVD mortality risk prediction model was associated with a C-index change of 0.0085 (95% CI: 0.0002-0.0172; p = .05) at 25 years. CONCLUSIONS: VO2 at AT is inversely associated with cardiovascular and all-cause mortality events, but the associations are partly dependent on peak VO2. VO2 at AT may improve the prediction of the long-term risk for CVD mortality. KEY MESSAGES Oxygen uptake at aerobic threshold (VO2 at AT), a cardiopulmonary exercise testing parameter, may be a useful prognostic tool for adverse clinical outcomes in the general population. In a population-based prospective cohort study of men, VO2 at AT was inversely associated with cardiovascular and all-cause mortality events and improved the prediction of cardiovascular mortality. In populations who cannot achieve maximal VO2, VO2 at AT may serve as a useful prognostic tool; however, further studies are warranted. PMID- 28805464 TI - Advancing Preparedness for Highly Hazardous Contagious Diseases: Admitting 10 Simulated Patients with MERS-CoV. AB - The Ebola outbreak of 2014-2016 highlighted the need for the development of a more robust healthcare infrastructure in the United States to provide isolation care for patients infected with a highly hazardous contagious disease. Routine exercises and skills practice are required to effectively and safely prepare care teams to confidently treat this special population of patients. The Nebraska Biocontainment Unit (NBU) at Nebraska Medicine in Omaha has been conducting exercises since 2005 when the unit was opened. Previous activities and exercises conducted by the Nebraska Biocontainment Unit have focused on transporting and caring for up to 3 patients with Ebola virus disease or other special pathogens. Changes in regional and national mandates, as well as the increased potential for receiving multiple patients at once, at a single location, have resulted in a greater demand to exercise protocols for the treatment of multiple patients. This article discusses in detail the planning, execution, and outcomes of a full-scale exercise involving 10 simulated patients with a highly infectious pathogen transmitted by the airborne route. PMID- 28805466 TI - The Critical Need for Rapid Influenza Serology Testing for Avian Influenza Pandemic Preparedness. PMID- 28805465 TI - What We Are Watching-Top Global Infectious Disease Threats, 2013-2016: An Update from CDC's Global Disease Detection Operations Center. AB - To better track public health events in areas where the public health system is unable or unwilling to report the event to appropriate public health authorities, agencies can conduct event-based surveillance, which is defined as the organized collection, monitoring, assessment, and interpretation of unstructured information regarding public health events that may represent an acute risk to public health. The US Centers for Disease Control and Prevention's (CDC's) Global Disease Detection Operations Center (GDDOC) was created in 2007 to serve as CDC's platform dedicated to conducting worldwide event-based surveillance, which is now highlighted as part of the "detect" element of the Global Health Security Agenda (GHSA). The GHSA works toward making the world more safe and secure from disease threats through building capacity to better "Prevent, Detect, and Respond" to those threats. The GDDOC monitors approximately 30 to 40 public health events each day. In this article, we describe the top threats to public health monitored during 2012 to 2016: avian influenza, cholera, Ebola virus disease, and the vector-borne diseases yellow fever, chikungunya virus, and Zika virus, with updates to the previously described threats from Middle East respiratory syndrome coronavirus (MERS-CoV) and poliomyelitis. PMID- 28805467 TI - Protective microencapsulation of beta-lapachone using porous glass membrane technique based on experimental optimisation. AB - Even though beta-lapachone is a novel drug with pharmacological activity, it has limitations including instability under light conditions. The main purpose of the study was to enhance the stability of beta-lapachone using the microencapsulation method. The Shirasu porous glass membrane was used to achieve uniform-sized microcapsules. The prepared microcapsules were evaluated to investigate how process parameters affect the encapsulation efficiency, photostability and particle size distribution. The experimental design was conducted to obtain optimal formulations. In addition, an operating space was drawn to identify the safer range of control factors. All control factors showed significant effects on the encapsulation efficiency and photostability. For example, when a large amount of polymers was used, encapsulation efficiency and photostability were improved. However, as the amount of polymers increased, large and polydisperse microcapsules were produced. The robust design method provided information to characterise significant factors, thereby allowing effective control of photostability and size of microcapsules. PMID- 28805468 TI - Long-term persistence with single-pill, fixed-dose combination therapy versus two pills of amlodipine and perindopril for hypertension: Australian experience. AB - OBJECTIVE: To study treatment persistence and mortality using a single-pill, fixed-dose combination tablet compared with a two-pill combination for hypertension. RESEARCH DESIGN AND METHODS: We analyzed Australian Pharmaceutical Benefit Scheme records 2011-2014 in a 10% random sample of concessional patients prescribed concomitant amlodipine and perindopril - either as a single-pill, fixed-dose combination tablet (n = 9340) or as two-pill combination therapy (n = 3093). Main outcome measures were: (a) proportions failing to continue amlodipine + perindopril over time, (b) proportions failing to continue any subsequent calcium channel and angiotensin inhibition therapy over time and (c) proportions dying. RESULTS: After 12 months, 34% of single-pill and 57% of two-pill users discontinued amlodipine + perindopril, median persistence time 42 months versus 7 months; 28% and 47% respectively discontinued any calcium channel-angiotensin inhibition therapy. After 48 months, 8% of single-pill and 18% of two-pill users had died. In a multivariate model adjusted for age, gender, duration and intensity of prior hypertension therapy, initial dose of amlodipine and perindopril, diabetes, hyperlipidemia, and complexity of care, the hazard ratio for risk of discontinuation over 42 months in the two-pill versus single-pill amlodipine + perindopril group was 1.94 (95% CI 1.83-2.06). The hazard ratio for discontinuation in two-pill versus single-pill users of any calcium channel angiotensin inhibition therapy was 1.86 (1.74-1.99). The adjusted hazard ratio for risk of death over 48 months was 1.83 (1.55-2.16), but the mortality outcome may be an overestimate due to residual confounding. CONCLUSIONS: Use of a single pill, fixed-dose combination in hypertension is associated with superior persistence and reduced mortality compared with use of two pills, suggesting a higher priority for the use of fixed-dose combinations. PMID- 28805469 TI - Long-chain triglycerides-based self-nanoemulsifying oily formulations (SNEOFs) of darunavir with improved lymphatic targeting potential. AB - The current studies entail systematic development of SNEOFs containing long-chain triglycerides for improving lymphatic targeting of darunavir for complete inhibition of HIV progression. As per QbD-oriented approach for formulation development, the QTPP was defined and CQAs were earmarked. Preformulation equilibrium solubility and phase diagram studies, and risk assessment through FMEA studies identified Lauroglycol 90, Tween 80 and Transcutol HP as the lipid, emulgent and cosolvent, respectively, for formulating SNEOFs of darunavir. Systematic optimisation of SNEOFs was conducted using IV-optimal mixture design, and the optimised formulation was chosen through numerical desirability function. Characterisation of optimised SNEOFs exhibited globule size of 50 nm, >85% drug release within 15 min and >75% permeation within 45 min. In vivo lymph cannulation and in situ intestinal perfusion studies indicated significant improvement in the drug absorption parameters from SNEOFs via intestinal lymphatic pathways, owing primarily to the presence of long-chain triglycerides. Also, in vivo pharmacokinetic studies in rat corroborated significant improvement in rate and extent of drug absorption into plasma vis-a-vis pure drug. In a nutshell, these studies indicate significant improvement in the biopharmaceutical attributes of a robust and stable SNEOFs formulation of darunavir for holistic management of viral loads in lymph and blood. PMID- 28805470 TI - Quality and readability of English-language internet information for aphasia. AB - PURPOSE: Little is known about the quality and readability of treatment information in specific neurogenic disorders, such as aphasia. The purpose of this study was to assess quality and readability of English-language Internet information available for aphasia treatment. METHOD: Forty-three aphasia treatment websites were aggregated using five different country-specific search engines. Websites were then analysed using quality and readability assessments. Statistical calculations were employed to examine website ratings, differences between website origin and quality and readability scores, and correlations between readability instruments. RESULT: Websites exhibited low quality with few websites obtaining Health On the Net (HON) certification or clear, thorough information as measured by the DISCERN. Regardless of website origin, readability scores were also poor. Approximate educational levels required to comprehend information on aphasia treatment websites ranged from 13 to 16 years of education. Significant differences were found between website origin and readability measures with higher levels of education required to understand information on websites of non-profit organisations. CONCLUSION: Current aphasia treatment websites were found to exhibit low levels of quality and readability, creating potential accessibility problems for people with aphasia and significant others. Websites including treatment information for aphasia must be improved in order to increase greater information accessibility. PMID- 28805471 TI - Prolonged release oxycodone and naloxone treatment counteracts opioid-induced constipation in patients with severe pain compared to previous analgesic treatment. AB - OBJECTIVE: Treatment with prolonged-release oxycodone/naloxone (PR OXN) has been shown to improve opioid induced constipation (OIC) in constipated patients. This publication reports on a real-life observational study investigating the efficacy of PR OXN with regard to bowel function in patients switching to PR OXN from WHO step 1, step 2 and step 3 opioids. METHODS: Patients with chronic pain experiencing insufficient pain relief and/or unacceptable side effects were switched to PR OXN and monitored in this observational study with respect to efficacy regarding bowel function and efficacy regarding pain relief in comparison with previous analgesic therapy. A patient was considered a responder with respect to efficacy if this assessment was "slightly better", "better" or "much better" compared with previous therapy. Bowel function index, pain intensity, quality of life, laxative medication use, and safety analgesic were also evaluated. RESULTS: A total of 1338 patients (mean [SD] age 64.3 [14.9], 63% female) were observed for 43 [3-166] days (median [range]) during treatment with PR OXN. Overall response rate regarding bowel function efficacy was 82.5%. Patients with symptoms of constipation at study entry obtained a clinically relevant improvement of the bowel function index (BFI) within the first 2 weeks of PR OXN treatment. Non-constipated patients at study entry maintained normal bowel function despite switching to treatment with the opioid PR OXN. CONCLUSION: In conclusion, treatment with PR OXN results in a significant and clinically relevant improvement of bowel function. During the observation of the treatment with PR OXN patients reported an improvement of quality of life (QoL). More interestingly, non-constipated patients maintained a normal bowel function, showing prevention of constipation despite the use of an opioid. PMID- 28805472 TI - Network Experiences from a Cross-Sector Biosafety Level-3 Laboratory Collaboration: A Swedish Forum for Biopreparedness Diagnostics. AB - The Swedish Forum for Biopreparedness Diagnostics (FBD) is a network that fosters collaboration among the 4 agencies with responsibility for the laboratory diagnostics of high-consequence pathogens, covering animal health and feed safety, food safety, public health and biodefense, and security. The aim of the network is to strengthen capabilities and capacities for diagnostics at the national biosafety level-3 (BSL-3) laboratories to improve Sweden's biopreparedness, in line with recommendations from the EU and WHO. Since forming in 2007, the FBD network has contributed to the harmonization of diagnostic methods, equipment, quality assurance protocols, and biosafety practices among the national BSL-3 laboratories. Lessons learned from the network include: (1) conducting joint projects with activities such as method development and validation, ring trials, exercises, and audits has helped to build trust and improve communication among participating agencies; (2) rotating the presidency of the network steering committee has fostered trust and commitment from all agencies involved; and (3) planning for the implementation of project outcomes is important to maintain gained competencies in the agencies over time. Contacts have now been established with national agencies of the other Nordic countries, with an aim to expanding the collaboration, broadening the network, finding synergies in new areas, strengthening the ability to share resources, and consolidating long-term financing in the context of harmonized European biopreparedness. PMID- 28805473 TI - The impact of persistence with mirabegron usage vs switching to onabotulinumtoxinA on healthcare costs and resource utilization in patients with overactive bladder in the United States. AB - AIMS: To compare healthcare costs and resource utilization in patients with overactive bladder (OAB) in the US who switch from mirabegron to onabotulinumtoxinA (onabotA) with those who persist on mirabegron. MATERIALS AND METHODS: A retrospective observational claims analysis of the OptumHealth Administrative Claims database conducted between April 1, 2012 and September 30, 2015 used medical and pharmacy claims to identify patients with at least one OAB diagnosis who switched from mirabegron to onabotA (onabotA group) or persisted on mirabegron for at least 180 days (mirabegron persisters). Propensity score weighting was used to balance baseline characteristics that were associated with increased healthcare expenditures across treatment groups. Multivariate analyses assessed the impact of switching and persistence on all-cause and OAB-related healthcare costs and resource utilization in the year following each patient's index date. RESULTS: In total, 449 patients were included in this study: 54 patients were included in the onabotA group, and 395 patients were included in the mirabegron persister group. Compared with the mirabegron persister patients, the onabotA patients observed significantly higher OAB-related total costs ($5,504 vs $1,772, p < .001), OAB-related medical costs ($5,033 vs $351, p < .001), sacral neuromodulation costs ($865 vs $60, p = .017), and outpatient costs ($17,385 vs $9,035, p = .009), and more OAB-related medical visits (6.0 vs 1.9, p < .001). OnabotA patients had lower OAB-related prescription costs ($470 vs $1,421, p < .001) and fewer OAB-related pharmacy claims (1.6 vs 5.0, p <.001). There were no significant differences in all-cause total medical or prescription costs. LIMITATIONS: This study was a retrospective analysis using claims data that only included patients with commercial health coverage or Medicare supplemental coverage. Accuracy of the diagnosis codes and the generalizability of the results to other OAB populations are limited. The study was not designed to determine the impact of OAB treatments on the economic outcomes examined. CONCLUSIONS: OAB patients who persisted on mirabegron treatment for at least 180 days had lower OAB-related healthcare costs and resource utilization compared with those who switched to onabotA. PMID- 28805474 TI - Dalbavancin as a cost effective antibiotic. PMID- 28805475 TI - Menopausal hormone therapy for primary prevention: why the USPSTF is wrong. AB - The US Preventive Services Task Force (USPSTF) Draft Recommendation statement on Menopausal Hormone Therapy: Primary Prevention for Chronic Diseases, released in May 2017, perpetuates a major disconnect between the primary population affected, women within roughly 10 years of menopause, and the data cited. Furthermore, major elements of the evidence relied upon have been misinterpreted or misstated, particularly in regard to coronary heart disease and breast cancer, for which there is no statistically significant evidence of harm. As currently drafted, the recommendations reiterate the USPSTF statements of 2012, 2005 and 2002, and will perpetuate egregious harm to the public health. In an attempt to avoid that outcome and to facilitate a return to rational discourse regarding menopausal hormone therapy, an ad hoc group of experts in menopausal health submitted this comprehensive response to the USPSTF. PMID- 28805476 TI - Microencapsulate Aspergillus niger peptidases from agroindustrial waste wheat bran: spray process evaluation and stability. AB - The aim of this work was to obtain microencapsulated stable Aspergillus niger peptidases by post fermentation spray drying. The enzymatic extract was evaluated before and after spray drying microencapsulation to verify the effects of five different process parameters on the extract enzymatic activity, i.e. air flow, extract feed rate, drying temperature, homogenising time and weight ratio of extract to encapsulation material. The optimal conditions were determined by desirability functions and experimentally confirmed. Additionally, the stability of the microparticles was assessed during 60 days at 4 degrees C, 25 degrees C and 40 degrees C. The results revealed that the microparticles stored at 4 degrees C retained approximately 100% of their proteolytic activity at nine days of storage. Considering the industrial adaptation of the bioprocess and the prospect of commercial application of the proteases, the evaluation of different parameters for drying enzymes is required as a valuable alternative to obtain biotechnological products with high added value. PMID- 28805477 TI - Estimated exposures to perfluorinated compounds in infancy predict attenuated vaccine antibody concentrations at age 5-years. AB - Perfluorinated alkylate substances (PFASs) are highly persistent and may cause immunotoxic effects. PFAS-associated attenuated antibody responses to childhood vaccines may be affected by PFAS exposures during infancy, where breastfeeding adds to PFAS exposures. Of 490 members of a Faroese birth cohort, 275 and 349 participated in clinical examinations and provided blood samples at ages 18 months and 5 years. PFAS concentrations were measured at birth and at the clinical examinations. Using information on duration of breastfeeding, serum-PFAS concentration profiles during infancy were estimated. As outcomes, serum concentrations of antibodies against tetanus and diphtheria vaccines were determined at age 5. Data from a previous cohort born eight years earlier were available for pooled analyses. Pre-natal exposure showed inverse associations with the antibody concentrations five years later, with decreases by up to about 20% for each two-fold higher exposure, while associations for serum concentrations at ages 18 months and 5 years were weaker. Modeling of serum-PFAS concentration showed levels for age 18 months that were similar to those measured. Concentrations estimated for ages 3 and 6 months showed the strongest inverse associations with antibody concentrations at age 5 years, particularly for tetanus. Joint analyses showed statistically significant decreases in tetanus antibody concentrations by 19-29% at age 5 for each doubling of the PFAS exposure in early infancy. These findings support the notion that the developing adaptive immune system is particularly vulnerable to immunotoxicity during infancy. This vulnerability appears to be the greatest during the first 6 months after birth, where PFAS exposures are affected by breast-feeding. PMID- 28805478 TI - Production of platelet-rich plasma gel from elderly patients under antithrombotic drugs: Perspectives in chronic wounds care. AB - Platelet-Rich Plasma (PRP) is an autologous biological therapy obtained by centrifuging the patient's own blood to concentrate platelets. The addition of autologous thrombin and calcium chloride to PRP allows the production of a semi solid form called PRP gel. PRP gel is increasingly used in a variety of tissue defects and predominantly in the management of non-healing chronic wounds. The topical application of PRP gel seems promising due to the capability of platelets to store and secrete growth factors (GF), fibrin and cytokines, which are essentials for wound healing. Most patients who suffered from chronic wounds are elderly patients with co-morbidities and polypharmacy including antithrombotic drugs such as antiplatelet agents (AP) or anticoagulants (AC), which could hamper the feasibility of this autologous platelet-derived therapy. To date, no study has investigated PRP gel formation in patients with AP or AC. The aim of this study was to evaluate the influence of AP or AC drugs on the production of PRP gel formation from elderly patients. Different biological characteristics were determined to qualify the production of PRP gel from such patients (Interquartile range (IQR) = 75-92 years) compared to healthy volunteers (IQR = 23-37 years). No significant difference was observed in the volume, composition (quantity of platelets, leukocytes and red blood cells) and functionality of platelets from PRP except a higher ADP-induced P-selectin expression in healthy donors compared with elderly patients. Autologous thrombin characteristics were similar in the two groups. Gel time formation (IQR: 120-195 seconds for controls and 135-210 seconds for elderly patients) and final composition of PRP gel were not significantly modified. Concentrations of theoretical thrombin generated in the serum and in the gel were inversely correlated with the time of formation of PRP gel (r2 = 0.57, p = 0.012). Altogether these data indicate that PRP gel preparation is not impacted by the use of antithrombotic drugs. Such results support the feasibility of using this innovative autologous biotherapy in the management of elderly patients with non-healing chronic wounds. PMID- 28805480 TI - Current evidence on the use of anti-RAAS agents in congenital or acquired solitary kidney. AB - RATIONAL: The inhibition of renin-angiotensin-aldosterone system (RAAS) is a major strategy for slowing the progression of chronic kidney disease (CKD). The utility of anti-RAAS agents in patients with congenital or acquired solitary kidney is still controversial. OBJECTIVE: A systematic literature review was conducted. MAIN FINDINGS: The conclusions of the few available studies on the topic are homogeneously in agreement with a long-term reno-protective activity of anti-RAAS drugs in patients with solitary kidney, especially if patients are hypertensive or proteinuric. However, angiotensin 2 (ANG2) levels permit a functional adaptation to a reduced renal mass in adults and is crucial for sustaining complete kidney development and maturation in children. A hormonal interference on ANG2 levels has been supposed in women. Consequently, at least in children and women, the use of ARBs appears more appropriate. Principle conclusions: Available data on this topic are limited; however, by their overall assessment, it would appear that anti-RAAS drugs might also be reno-protective in patients with solitary kidney. The use of ARBs, especially in children and in women, seems to be more appropriate. However, more experimental data would be strictly necessary to confirm this hypothesis. PMID- 28805479 TI - On variants and disease-causing mutations: Case studies of a SEMA4A variant identified in inherited blindness. AB - The p.R713Q variant of the semaphorin-4a-encoding gene, SEMA4a, has been reported to cause autosomal dominant retinitis pigmentosa. Here we show three families with retinal degeneration in which unaffected family members are either homozygous or heterozygous for the variant. The p.R713Q variant in SEMA4A is insufficient to cause either autosomal recessive or autosomal dominant retinitis pigmentosa and is unlikely to be pathogenic. PMID- 28805481 TI - A comparison of quality of sleep between patients with chronic kidney disease not on hemodialysis and end-stage renal disease on hemodialysis in a developing country. AB - Few studies have compared quality of sleep between pre-dialysis chronic kidney disease (pre-dialysis CKD) patients and end-stage renal disease patients on dialysis (ESRD) and have found inconsistent results. Objective of this study is to compare quality of sleep between patients with pre-dialysis CKD and ESRD in a developing country. This study was conducted in an out-patient department and hemodialysis unit of a tertiary care facility. Patients included had either pre dialysis CKD or ESRD. Assessment of quality of sleep was done using Pittsburgh sleep quality index (PSQI). A total of 152 patients were included in the study. Out of these patients, 79 (52%) had ESRD and 73 (48%) had pre-dialysis CKD. Median PSQI score was 6 (IQR 3-8.8). Poor sleep quality (PSQI >=5) was present in 100 (65.8%) patients. Only hemoglobin (beta = -0.39, p < .01), depression (beta = 0.56, p < .01) and history of cardiovascular disease (beta = 0.22, p < .01) were associated with PSQI global score in a multiple linear regression analysis. There was no significant association between ESRD vs. pre-dialysis CKD and PSQI global scores and no significant co-relation between eGFR and global PSQI score (r = 0.34, p value .80) in pre-dialysis CKD patients. Poor sleep quality is common in patients with CKD including hemodialysis patients in a developing country, which is independent of kidney function in non-dialysis patients. There is no difference in quality of sleep between pre-dialysis CKD and ESRD patients. PMID- 28805482 TI - Cyclophilin 20-3 is positioned as a regulatory hub between light-dependent redox and 12-oxo-phytodienoic acid signaling. AB - The jasmonate family of phytohormones plays central roles in plant development and stress acclimation. However, the regulatory modes of their signaling circuitry remain largely unknown. Here we describe that cyclophilin 20-3 (CYP20 3), a binding protein of (+)-12-oxo-phytodienoic acid (OPDA), crisscrosses stress responses with light-dependent redox reactions, which fine-tunes the activity of key enzymes in the plastid photosynthetic carbon assimilation and sulfur assimilation pathways. Under stressed states, OPDA - accumulated in the chloroplasts - binds and promotes CYP20-3 to transfer electron (e-) from thioredoxins (i.e., type-f2 and -x) to 2-Cys peroxiredoxin B (2-CysPrxB) or serine acetyltransferase 1 (SAT1). Reduction (activation) of 2-CysPrxB then optimizes peroxide detoxification and carbon metabolisms in the photosynthesis, whereas the activation of SAT1 stimulates sulfur assimilation which in turn coordinates redox-resolved nucleus gene expressions in defense responses against biotic and abiotic stresses. Thus, we conclude that CYP20-3 is positioned as a unique metabolic hub in the interface between photosynthesis (light) and OPDA signaling, where controls resource (e-) allocations between plant growth and defense responses. PMID- 28805484 TI - Disparate phospho-Smad2 levels in advanced type 2 diabetes patients with diabetic nephropathy and early experimental db/db mouse model. AB - Uncontrolled activation of transforming growth factor beta (TGF-beta) family members is hypothesized to participate in type 2 diabetes (T2D) dependent diabetic nephropathy (DN). We evaluated and compared downstream activation of the Smad2-signaling pathway in kidney samples from T2D patients to kidneys from the T2D model of leptin receptor deficient db/db mouse. Furthermore, expression of TGF-beta family members was evaluated to elucidate molecular mechanisms in the mouse model. Kidney samples from patients with advanced stages of DN showed elevated pSmad2 staining whereas db/db mouse kidneys surprisingly showed a decrease in pSmad2 in the tubular compartment. Structurally, kidney tissue showed dilated tubules and expanded glomeruli, but no clear fibrotic pattern was found in the diabetic mice. Selective TGF-beta family members were up-regulated at the mRNA level. Antagonists of bone morphogenetic protein (BMP) ligands, such as Gremlin1, USAG1 and Sclerostin, were strongly up-regulated suggesting a dampening effect on BMP pathways. Together, these results indicate a lack of translation from T2D patient kidneys to the db/db model with regards to Smad signaling pathway. It is plausible that a strong up-regulation of BMP antagonizing factors account for the lack of Smad1/5/8 activation, in spite of increased expression of several BMP members. PMID- 28805483 TI - Tet1-mediated DNA demethylation involves in neuron damage induced by bilirubin in vitro. AB - The aim of this study is to identify the role of Tet1-mediated DNA demethylation in the neurotoxicity caused by unconjugated bilirubin (UCB) in vitro. Primary neuronal cells after cultured for 72 h were exposed to UCB (0-100 MUmol/L) for 24 h. Following exposure to UCB cytotoxicity was determined with the methyl tetrazolium (MTT) assay, reactive oxygen species (ROS) and caspase-3 activity in neuron cells were measured with the corresponding assay kits. The expression of Tet1 and Klotho was determined with RT-PCR at mRNA level and western blot at protein level. Our results showed that UCB can cause time-dependent and dose dependent reduction of cell viability of neuronal cells, induce oxidative stress through increasing the production of ROS and increase caspase-3 activity. Quantitative real-time PCR and western blot analysis showed that UCB can inhibit Tet1 and Klotho expression in cultured neuronal cells at both the mRNA and protein level, respectively. These results are first to suggest UCB may, in part, exert its neurotoxicity through alteration of the neuronal antioxidant status and inhibition of Klotho and Tet1 gene expression. The elevation of DNA methylation in global genome through inhibition of Tet1 gene expression may, in part, play an important role in the neurotoxicity caused by UCB in vitro. PMID- 28805485 TI - Transcriptional activity of transposable elements may contribute to gene expression changes in the syncytium formed by cyst nematode in arabidopsis roots. AB - Transposable elements (TEs) are mobile genetic materials that constitute a large fraction of plant genomes. Recent experimental evidences indicate that TEs can play key regulatory roles in controlling the expression of adjacent genes during plant development and stress responses. Nevertheless, information about the transcriptional activity of TEs and their impact on proximal genes during plant nematode interaction remains largely unknown. Here, we identify of differentially expressed TEs and report their possible influence on the expression of nearby genes during the susceptible interaction between the beet cyst nematode Heterodera schachtii and Arabidopsis thaliana. Analysis of our RNA-seq data of H. schachtii-infected roots, and the corresponding non-infected controls, resulted in the identification of 99 and 93 differentially expressed TEs at 5 and 10 d post infection, respectively. More than 2-thirds of these TEs were activated, suggesting that H. schachtii infection induces TE activation to a much greater degree than repression. Remarkably, the majority of these TEs were located within 2 kb of protein-coding genes, many of these genes were previously found to change expression in the H. schachtii-induced feeding sites. Taken together, our analysis provides novel insight into a possible role of actively transcribed TEs in the regulation of gene transcription in the nematode feeding sites during H. schachtii parasitism of Arabidopsis. PMID- 28805486 TI - COP1 integrates light signals to ROP2 for cell cycle activation. AB - The exquisite regulation of cell division at the shoot apex according to the external environmental cues enables plants to adapt the ever-changing environment. We have recently shown that light direct signaling and carbohydrate (sugar) energy signaling are both essential for the activation of cell division at the shoot apex. Light is converted to auxin signal to activate small GTPase 2 (ROP2). Subsequently, the activated ROP2 directly interacts with Target of Rapamycin (TOR) protein kinase, a pivotal regulator of cell division, to promote its kinase activity. However, neither light nor auxin alone can activate TOR kinase without the presence of sugar. In this addendum, we showed that Constitutive Photomorphogenesis 1 (COP1) acts as an upstream factor of ROP2. COP1 regulates ROP2 and TOR activity in an auxin dependent manner. The development of true leaves in the cop1-6 mutant under darkness is compromised by auxin biosynthesis inhibitor yucasin and TOR chemical inhibitor torin2. Together, our results suggested that COP1 regulates auxin-ROP2-TOR signaling in response to light. PMID- 28805488 TI - The Underworld. PMID- 28805487 TI - State-of-the-art nanopathological diagnostics. AB - The nanopathological diagnostics (ND) is an ultra-specialized branch of pathological anatomy aimed to identify the nanoparticles of metallic, semimetallic, or nonmetallic elements in the inorganic particulate matter present inside pathological tissues, even on the nanometer scale. ND exploits an environmental scanning electron microscope, connected to an X-ray microprobe mounted on an energy-dispersive spectrometer. The searching of nanoparticles can be performed on paraffin-embedded material, omitting emissions of black overlay and plating procedures. The technique is highly sensitive and specific, reproducible and rapid, covering an entire operating cycle in few hours. Nowadays, ND finds many applications: (I) intratumor detection of heavy metals and endocrine metal disruptors; (II) identification of pathogenic nanoparticles in medical or veterinary drugs and devices, cosmetics, household products, and foodstuffs; (III) differential diagnosis of sarcoid-type granulomas (berylliosis, baritosis) and foreign body granulomas (prosthetic, iatrogenic); (IV) attestation of occupational disease correlating the datum with the occupational risk (anthracosis, asbestosis, bauxite fibrosis, byssinosis, chalicosis, siderosis, silicosis, stannosis, talcosis); and (V) forensic investigations to ascertain a causal link between disease and environmental, military, or work exposure. In addition to filling a knowledge gap, ND offers to the pathologist a current research field, with particular reference to the impact of occupational and environmental pollution on the human health and cancer. PMID- 28805489 TI - Atorvastatin attenuates experimental contrast-induced acute kidney injury: a role for TLR4/MyD88 signaling pathway. AB - OBJECTIVES: To investigate the protective effect of different atorvastatin doses on contrast-induced acute kidney injury and the related mechanism. METHODS: Healthy male Sprague-Dawley (SD) rats were randomly divided into the blank control group, experimental control group and different-dose atorvastatin groups. A rat model of contrast-induced acute kidney injury was established. We detected changes in serum creatinine (Scr) and blood urea nitrogen (BUN) before and after model establishment, observed and scored renal tubular injury, analyzed rat renal cell apoptosis, and measure the expression of signal pathway proteins and downstream inflammatory factors. RESULTS: After contrast agent injection, the Scr and BUN levels of the experimental control group were significantly increased, the different doses applied in the atorvastatin group significantly reduced the Scr and BUN levels (p < .05) and ameliorated the contrast-induced acute kidney injury (p < .05) and significantly reduced Toll-like receptor 4 (TLR4), Myeloid differentiation factor 88 (Myd88), and Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) protein expression and relative mRNA expression levels (p < .05) and significantly decreased expression levels of downstream inflammatory factors (p < .05). CONCLUSION: Different atorvastatin doses have protective effects on contrast-induced acute renal tubular injury in rats, possibly by targeting TLR4, suppressing TLR4 expression, regulating the TLR4/Myd88 signaling pathway, and inhibiting the expression of downstream inflammatory factors. PMID- 28805490 TI - Low employment and low willingness of being reemployed in Chinese working-age maintained hemodialysis patients. AB - AIM: Returning to society plays an important role in improving the quality of life in maintenance hemodialysis (MHD) patients, and retention of employment is one of the core enablers. The study is to assess the employment status and to determine the variables for unemployment in Chinese MHD patients. METHODS: Prevalent MHD patients from four dialysis centers in Shanghai China were enrolled. We assessed patients' employment status, current social functioning, hemodialysis modality, annual income and general health condition. Among current unemployed working-age patients, the reasons of quitting jobs and willingness of being reemployed were evaluated. RESULTS: A total of 231 patients were studied, among which 114 patients were unemployed 1 year before hemodialysis. Among 117 employed patients, 16 patients quitted jobs before dialysis inception, while 49 patients quitted jobs at the initiation of HD, and 26 patients followed after a few months' HD. The main reasons for ceasing employment were physical insufficiency, conflict between dialysis and work schedules, lack of support from employers and resistance from family members. Among the 166 patients who were in their working age, 26 patients were employed. The unemployed patients had the characters of elder age, lower education level, higher annual family income, higher female ratio, lower blood flow, lower physical functioning, and social functioning and lower frequency of weekend hemodialysis and HDF/HF. Among the 140 unemployed patients, only 47 patients had the willingness of being reemployed. Their unemployment status was positively associated with elder age ((OR) 3.13, 95% CI, 1.08-9.1), lower education level ((OR) 1.97, 95% CI, 1.05-5.92), and higher family income ((OR) 7.75, 95% CI, 2.49-24.14). CONCLUSION: Ratio of employment and willingness of being reemployed was low in MHD working-age patients. Lack of social and family's support also hampered patient's returning to society except for the HD treatment quality. PMID- 28805491 TI - Intermedin inhibits unilateral ureteral obstruction-induced oxidative stress via NADPH oxidase Nox4 and cAMP-dependent mechanisms. AB - NADPH oxidase Nox4-derived reactive oxygen species (ROS) play important roles in renal fibrosis. Our previous study demonstrated that intermedin (IMD) alleviated unilateral ureteral obstruction (UUO)-induced renal fibrosis by inhibition of ROS. However, the precise mechanisms remain unclear. Herein, we investigated the effect of IMD on Nox4 expression and NADPH oxidase activity in rat UUO model, and explored if these effect were achieved through cAMP-PKA pathway, the important post-receptor signal transduction pathway of IMD, in TGF-beta1-stimulated rat proximal tubular cell (NRK-52E). Renal fibrosis was induced by UUO. NRK-52E was exposed to rhTGF-beta1 to establish an in vitro model of fibrosis. IMD was overexpressed in the kidney and in NRK-52E by IMD gene transfer. We studied UUO induced ROS by measuring dihydroethidium levels and lipid peroxidation end product 4-hydroxynonenal expression. Nox4 expression in the obstructed kidney of UUO rat or in TGF-beta1-stimulated NRK-52E was measured by quantitative RT-PCR and Western blotting. We analyzed NADPH oxidase activity using a lucigenin enhanced chemiluminescence system. We showed that UUO-stimulated ROS production was remarkably attenuated by IMD gene transfer. IMD overexpression inhibited UUO induced up-regulation of Nox4 and activation of NADPH oxidase. Consistent with in vivo results, TGF-beta1-stimulated increase in Nox4 expression and NADPH oxidase activity was blocked by IMD. In NRK-52E, these beneficial effects of IMD were abolished by pretreatment with N-[2-(p-bromocinnamylamino)ethyl]-5 isoquinolinesulfonamide hydrochloride (H-89), a PKA inhibitor, and mimicked by a cell-permeable cAMP analog dibutyl-cAMP. Our results indicate that IMD exerts anti-oxidant effects by inhibition of Nox4, and the effect can be mediated by cAMP-PKA pathway. PMID- 28805492 TI - Roles of rice PHYTOCHROME-INTERACTING FACTOR-LIKE1 (OsPIL1) in leaf senescence. AB - Rice (Oryza sativa) Phytochrome-Interacting Factor-Like1 (OsPIL1), a basic helix loop-helix transcription factor, plays an important role in the elongation of internode cells. Recently, we found that OsPIL1 participates in chlorophyll biosynthesis by directly upregulating several genes encoding components of the photosystem apparatus. Here, we show that OsPIL1 negatively regulates leaf senescence in rice. During dark-induced senescence (DIS), ospil1 mutants senesced earlier than wild type; this is opposite to mutants of Arabidopsis PIF4 and PIF5, the closest homologs of OsPIL1. Microarray analysis revealed that during DIS, several senescence-associated genes were upregulated and OsGLKs, negative regulators of leaf senescence, were strongly repressed in ospil1 mutants. Transgenic Arabidopsis plants overexpressing OsPIL1 showed an early senescing phenotype during DIS. In addition, OsPIL1 expressed in Arabidopsis upregulates the transcription of ORESARA1, a major senescence-inducing NAC transcription factor and one of the downstream genes of Arabidopsis PIF4, by directly binding the promoter region. These results indicate that OsPIL1 and Arabidopsis PIF4 have similar functions, but their downstream regulatory cascades have opposite effects. PMID- 28805494 TI - Advancing Advance Care Planning. PMID- 28805493 TI - Pathways for external alkalinization in intact and in microwounded Chara cells are differentially sensitive to wortmannin. AB - Proton flows across the plant cell membranes play a major role in electrogenesis and regulation of photosynthesis and ion balance. The profiles of external pH along the illuminated internodal cells of characean algae consist of alternating high- and low-pH zones that are spatially coordinated with the distribution of photosynthetic activity of chloroplasts underlying these zones. The results based on confocal laser scanning fluorescence microscopy, pH microsensors, and pulse amplitude-modulated chlorophyll microfluorometry revealed that the coordination of H+ transport and photosynthesis is disrupted by the 2 different environmental cues (low light and wounding) and by a chemical, wortmannin interfering with the inositol phospholipid metabolism. On the one hand, the transition from moderate to low irradiance diminished the peaks in the profiles of photosystem II (PSII) quantum efficiency but did not remove the pH bands. On the other hand, the microwounding of the internode with a glass micropipette, impacting primarily the cell wall, resulted in a rapid local alkalinization of the external medium (by 2 2.5 pH units) near the cell surface, thus mimicking the appearance of natural pH bands. Despite their seeming similarity, the alkaline bands of intact cells were eliminated by wortmannin, whereas the wound-induced alkalinization was insensitive to this drug. Furthermore, the attenuation of natural pH bands in wortmannin-treated cells was accompanied by the enhancement in spatial heterogeneity of PSII efficiency and electron transport rates, which indicates the complexity of chloroplast-plasma membrane interactions. The results suggest that the light- and wound-induced alkaline areas on the cell surface are associated with different ion-transport systems. PMID- 28805495 TI - Shushing histone turnover: It's FUN protecting epigenome-genome. PMID- 28805496 TI - Natural antisense transcripts drive a regulatory cascade controlling c-MYC transcription. AB - Cis-natural antisense transcripts (cis-NATs) are long noncoding RNAs transcribed from the opposite strand and overlapping coding and noncoding genes on the sense strand. cis-NATs are widely present in the human genome and can be involved in multiple mechanisms of gene regulation. Here, we describe the presence of cis NATs in the 3' distal region of the c-MYC locus and investigate their impact on transcriptional regulation of this key oncogene in human cancers. We found that cis-NATs are produced as consequence of the activation of cryptic transcription initiation sites in the 3' distal region downstream of the c-MYC 3'UTR. The process is tightly regulated and leads to the formation of two main transcripts, NAT6531 and NAT6558, which differ in their ability to fold into stem-loop secondary structures. NAT6531 acts as a substrate for DICER and as a source of small RNAs capable of modulating c-MYC transcription. This complex system, based on the interplay between cis-NATs and NAT-derived small RNAs, may represent an important layer of epigenetic regulation of the expression of c-MYC and other genes in human cells. PMID- 28805497 TI - Putative role of glutamine in the activation of CBL/CIPK signalling pathways during salt stress in sorghum. AB - The salt overly sensitive (SOS) pathway is the only mechanism known for Na+ extrusion in plant cells. SOS pathway activation involves Ca2+-sensing proteins, such as calcineurin B-like (CBL) proteins, and CBL-interacting protein kinases (CIPKs). In this signalling mechanism, a transit increase in cytosolic Ca2+ concentration triggered by Na+ accumulation is perceived by CBL (also known as SOS3). Afterward, SOS3 physically interacts with a CIPK (also known as SOS2), forming the SOS2/SOS3 complex, which can regulate the number downstream targets, controlling ionic homeostasis. For instance, the SOS2/SOS3 complex phosphorylates and activates the SOS1 plasmalemma protein, which is a Na+/H+ antiporter that extrudes Na+ out of the cell. The CBL-CIPK networking system displays specificity, complexity and diversity, constituting a critical response against salt stress and other abiotic stresses. In a study reported in the journal Plant and Cell Physiology, we showed that NH4+ induces the robust activation of transporters for Na+ homeostasis in root cells, especially the SOS1 antiporter and plasma membrane H+-ATPase, differently than does NO3-. Despite some studies having shown that external NH4+ ameliorates salt-induced effects on ionic homeostasis, there is no evidence that NH4+ per se or some product of its assimilation is responsible for these responses. Here, we speculate about the signalling role behind glutamine in CBL-CIPK modulation, which could effectively activate the SOS pathway in NH4+-fed stressed plants. PMID- 28805499 TI - Review of Superforecasting: The Art and Science of Prediction, by P.E. Tetlock and D. Gardner. PMID- 28805498 TI - GingisKHANTM protease cleavage allows a high-throughput antibody to Fab conversion enabling direct functional assessment during lead identification of human monoclonal and bispecific IgG1 antibodies. AB - The determination of the binding strength of immunoglobulins (IgGs) to targets can be influenced by avidity when the targets are soluble di- or multimeric proteins, or associated to cell surfaces, including surfaces introduced from heterogeneous assays. However, for the understanding of the contribution of a second drug-to-target binding site in molecular design, or for ranking of monovalent binders during lead identification, affinity-based assessment of the binding strength is required. Typically, monovalent binders like antigen-binding fragments (Fabs) are generated by proteolytic cleavage with papain, which often results in a combination of under- and over-digestion, and requires specific optimization and chromatographic purification of the desired Fabs. Alternatively, the Fabs are produced by recombinant approaches. Here, we report a lean approach for the functional assessment of human IgG1s during lead identification based on an in-solution digestion with the GingisKHANTM protease, generating a homogenous pool of intact Fabs and Fcs and enabling direct assaying of the Fab in the digestion mixture. The digest with GingisKHANTM is highly specific and quantitative, does not require much optimization, and the protease does not interfere with methods typically applied for lead identification, such as surface plasmon resonance or cell-based assays. GingisKHANTM is highly suited to differentiate between affinity and avidity driven binding of human IgG1 monoclonal and bispecific antibodies during lead identification. PMID- 28805501 TI - ? PMID- 28805500 TI - Chitin receptor-mediated activation of MAP kinases and ROS production in rice and Arabidopsis. AB - Rapid induction of plant immune responses is essential to inhibit colonization and invasion by pathogens. Plants can recognize pathogen-associated molecular patterns (PAMPs) including fungal chitin and bacterial flagellin using pattern recognition receptors (PRRs), which trigger the intracellular activation of mitogen-activated protein kinase (MAPK) cascades and the production of reactive oxygen species (ROS). MAPK activation and ROS production play pivotal roles in the induction of robust immune responses. Recent investigation of chitin- and flagellin-induced immune signaling revealed that receptor-like cytoplasmic kinases (RLCKs) connect PRR-mediated pathogen recognition to MAPK activation and ROS production. In addition, although the MAPK cascade is mediated by 3 sequentially activated protein kinases, MAPK kinase kinase (MAPKKK), MAPK kinase (MAPKK), and MAPK, how MAPKKKs are activated downstream of PRRs in plants has not been identified until recently. In this review, we summarize recent findings of RLCK-mediated MAPK activation and ROS production in rice and Arabidopsis. PMID- 28805502 TI - The fundamentals of cross-sector collaboration for social change to promote population health. AB - Cross-sector collaboration is increasingly relied upon to tackle society's pressing and intractable problems. Chief among societal problems are unfavorable structural and social determinants of health. The ability to positively change these health determinants rests on the collaborative processes and structures of governance across diverse sectors in society. The purpose of this article is to present a conceptual framework that sheds light on the basic requirements of cross-sector collaboration for social change to promote the health of populations. A search for theoretical articles on cross-sector collaboration in the fields of public administration and public health was conducted within the journal databases ABI/INFORM Complete and MEDLINE. This search strategy was supplemented by an internet search of the grey literature for high-profile models of cross-sector collaboration. The conceptual framework builds on previous scholarly work by placing emphasis on five essential conditions for collective impact, and on the pivotal role of collective learning. Collective learning, at the basis of planning and taking action, is at the core of effective cross-sector initiatives, specifically because of its critical role in constantly adapting strategies to changing circumstances and unanticipated situations within complex socio-ecological systems. PMID- 28805503 TI - The effect of hydrolysis on combustion characteristics of sewage sludge and leaching behavior of heavy metals. AB - The aim of this paper is to present the effect of hydrolysis treatment on the thermal reaction characteristics of sludge and the leaching test of heavy metals contained in the sludge. Raw and hydrolysis-treated sludge (at temperature of 200 degrees C and pressure 0.4 MPa) samples were collected from local municipal sewage sludge treatment plant. Thermogravimetric analysis was carried out between 25 degrees C and 900 degrees C at the heating rate of 10 degrees C/min and 20 degrees C/min under incineration and pyrolysis atmospheres. The leaching behavior of toxic heavy metals in the sludge was studied along with ash composition. The heating rate significantly changed the thermogravimetric and differential thermogravimetric curve profiles for studied fuels under different atmospheres. After hydrolysis treatment, the heavy metals of hydrolysis-treated sludge becomes more stable. The leaching concentration of Cr, Mn, Cu and Pb in hydrolysis treated sludge were greatly reduced, when compared to raw sludge; however, no significant change was observed in Cd concentration. The X-ray diffraction pattern of bottom ash of hydrolysis-treated sludge was significantly reduced than raw sludge. This decrease is due to possible reduction in grain growth, which degrades the crystallinity of hydrolyzed sludge, implying that the hydrolysis treatment of sewage sludge could be a promising and beneficially safe disposal technology. PMID- 28805504 TI - Neural basis of altered earlier attention and higher order biological motion processing in schizophrenia. AB - Schizophrenia patients have impairments of biological motion (BM) perception, which provides critical information about social cognition. Because social cognition is underpinned by attention, the impairments of BM perception in schizophrenia could be partially attributable to altered attention. To elucidate the impairments in attention and social perception in schizophrenia, we investigated the neural basis of impaired BM processing using MRI in respect to attention deficits by eye tracker. Voxel-based morphometry was performed to evaluate the relationship between BM perception and gray matter (GM) volume. The temporo-parietal junction (TPJ) and anterior superior temporal sulcus (aSTS) were related to task accuracy. However, when the effect of attention (i.e., eye movement) was controlled, the relationship in TPJ became non-significant, while aSTS showed a significant relationship with BM perception. Alteration in TPJ might be associated with inefficient attentional strategy, whereas dysfunctional aSTS might be correlated with deficit in higher order BM processing per se. Several cognitive levels as well as corresponding brain areas are possibly involved in the manifestation of social cognitive deficits in schizophrenia. PMID- 28805505 TI - Group based learning among caregivers: assessing mothers' knowledge before and after an early childhood intervention in rural Guatemala. AB - BACKGROUND: The first three years of a child's life are a critical period for brain growth and development. Caregiver interventions during this period that improve early childhood health and development have the potential to enhance a child's physical, mental, and social well-being. METHODS: This was a pretest/posttest quasi experimental program evaluation. Early childhood education materials were adapted to create two separate interventions consisting of 30-page interactive flipchart talks to educate mothers on health and development topics relevant to 0-6 and 6-12 month old children. Three community health workers performed the talks with groups of 5-8 mothers. Short learning assessments were given individually to each mother pre-intervention (pretest), immediately post intervention (posttest 1), and two weeks post-intervention (posttest 2). Demographic surveys and focus group discussions were conducted with all participants. RESULTS: Mothers ( n = 77) had an average age of 33.6 years and had an average of 3.6 living children. Most of the mothers (71%) had received some primary education, but 23% had received no formal schooling. For the 0-6 months flipchart learning assessment ( n = 38), the mean pretest score was 77% correct. The mean posttest 1 score improved to 87% ( p < 0.0001), and the mean posttest 2 score improved further from the mean posttest 1 score to 90% ( p = 0.01). For the 6-12 months flipchart learning assessment ( n = 39), the mean pretest score was 78%. The mean posttest 1 score improved to 89% ( p < 0.0001), and the mean posttest 2 score improved further from the mean posttest 1 score to 92% ( p = 0.03). CONCLUSIONS: Mothers in an impoverished region of southwestern Guatemala significantly increased their knowledge about child health topics following a short interactive group talk. Mothers further increased their knowledge two weeks after the intervention, without specific re-exposure to the intervention materials, suggesting assimilation and informal reinforcement through group based learning with other mothers in their community. PMID- 28805506 TI - Kinematic and neuromuscular relationships between lower extremity clinical movement assessments. AB - Lower extremity injuries have immediate and long-term consequences. Lower extremity movement assessments can assist with identifying individuals at greater injury risk and guide injury prevention interventions. Movement assessments identify similar movement characteristics and evidence suggests large magnitude kinematic relationships exist between movement patterns observed across assessments; however, the magnitude of the relationships for electromyographic (EMG) measures across movement assessments remains largely unknown. This study examined relationships between lower extremity kinematic and EMG measures during jump landings and single leg squats. Lower extremity three-dimensional kinematic and EMG data were sampled from healthy adults (males = 20, females = 20) during the movement assessments. Pearson correlations examined the relationships of the kinematic and EMG measures and paired samples t-tests compared mean kinematic and EMG measures between the assessments. Overall, significant moderate correlations were observed for lower extremity kinematic (ravg = 0.41, rrange = 0.10-0.61) and EMG (ravg = 0.47, rrange = 0.32-0.80) measures across assessments. Kinematic and EMG measures were greater during the jump landings. Jump landings and single leg squats place different demands on the body and necessitate different kinematic and EMG patterns, such that these measures are not highly correlated between assessments. Clinicians should, therefore, use multiple assessments to identify aberrant movement and neuromuscular control patterns so that comprehensive interventions can be implemented. PMID- 28805507 TI - The Medical Home Model and Pediatric Asthma Symptom Severity: Evidence from a National Health Survey. AB - The objective was to investigate the association between receiving care under the medical home model and parental assessment of the severity of asthma symptoms. It was hypothesized that parents of children who received care under the medical home model reported less severe asthma symptoms compared with their counterparts, whose care did not meet the medical home criteria. Secondary analyses were conducted using cross-sectional data from the 2011-2012 National Survey of Children's Health. Children with asthma aged 0-17 years were included and classified as receiving care from the medical home if their care contained 5 components: a personal doctor, a usual source of sick care, family-centered care, no problems getting referrals, and effective care coordination. Ordinal logistic regression was used to examine the relationship between parent-rated severity of asthma symptoms (mild, moderate, and severe symptoms) and the medical home. Approximately 52% of 8229 children who reported having asthma received care from the medical home. Only 30.8% of children with severe asthma symptoms received care that met the medical home criteria, compared to 55.7% of children with mild symptoms. After accounting for confounding factors, obtaining care under the medical home model decreased the odds of parent-reported severe asthma symptoms by 31% (adjusted odds ratio 0.69; 95% CI, 0.56-0.85). Study results suggest that the medical home model can reduce parent-rated severity of asthma symptoms. The findings highlight the importance of providing medical home care to children with asthma to improve the outcomes that matter most to children and their families. PMID- 28805508 TI - Corrigendum to: "Effectiveness of a multidimensional web-based intervention program to change Brazilian health practitioners' attitudes toward the lesbian, gay, bisexual and transgender population". AB - Corrigendum to: J Health Psychol DOI 10.1177/1359105316628748 Unfortunately, the online published article has an error in one of the analyses. On page 365, fifth paragraph, the corrected statistical report is (Delta 1.66, 95% CI [3.32, .01], t (305) = -1.98, p<.05), not (Delta 1.66, 95% CI [3.32, .01], t (305) = -1.66, p <.05). In spite of this correction, there is no change in the direction of the test and therefore in the interpretation of this result. PMID- 28805509 TI - Enhanced cell killing and apoptosis of oral squamous cell carcinoma cells with ultrasound in combination with cetuximab coated albumin microbubbles. AB - Targeted microbubbles have the potential to be used for ultrasound (US) therapy and diagnosis of various cancers. In the present study, US was irradiated to oral squamous cell carcinoma cells (HSC-2) in the presence of cetuximab-coated albumin microbubbles (CCAM). Cell killing rate with US treatment at 0.9 W/cm2 and 1.0 W/cm2 in the presence of CCAM was greater compared to non-targeted albumin microbubbles (p < .05). On the other hand, selective cell killing was not observed in human myelomonocytic lymphoma cell line (U937) that had no affinity to cetuximab. Furthermore, US irradiation in the presence of CCAM showed a fivefold increase of cell apoptotic rate for HSC-2 cells (21.0 +/- 3.8%) as compared to U937 cells (4.0 +/- 0.8%). Time-signal intensity curve in a tissue phantom demonstrated clear visualisation of CCAM with conventional US imaging device. Our experiment verifies the hypothesis that CCAM was selective to HSC-2 cells and may be applied as a novel therapeutic/diagnostic microbubble for oral squamous cell carcinoma. PMID- 28805510 TI - Review of Market vs Medicine: America's Epic Fight for Better, Affordable Healthcare, by D.W. Johnson. PMID- 28805511 TI - Special issue on the PACE Trial. AB - We are proud that this issue marks a special contribution by the Journal of Health Psychology to the literature concerning interventions to manage adaptation to chronic health problems. The PACE Trial debate reveals deeply embedded differences between critics and investigators. It reveals an unwillingness of the co-principal investigators of the PACE trial to engage in authentic discussion and debate. It leads one to question the wisdom of such a large investment from the public purse (L5million) on what is a textbook example of a poorly done trial. PMID- 28805512 TI - Chronic fatigue syndrome patients have no reason to accept the PACE trial results: Response to Keith J Petrie and John Weinman. AB - Petrie and Weinman urge chronic fatigue syndrome patients to move on from their beliefs about their illness and accept the findings of thePACE trial. This is unreasonable in view of the failure of PACE to achieve evidence of recovery through cognitive behaviour therapy and graded exercise therapy in either self reports or the objective measure of the 6-minute walking test. Contrary to their suggestion, the Institute of Medicine describes chronic fatigue syndrome not as psychological but as a serious, chronic, systemic disease, with post-exertional malaise as its main feature which inhibits exercise. Linking debate about PACE with intimidation of researchers is unjustifiable and damaging to patients. PMID- 28805513 TI - Distress signals: Does cognitive behavioural therapy reduce or increase distress in chronic fatigue syndrome/myalgic encephalomyelitis? AB - Reducing the psychological distress associated with chronic fatigue syndrome/myalgic encephalomyelitis is seen as a key aim of cognitive behavioural therapy. Although cognitive behavioural therapy is promoted precisely in this manner by the National Institute of Clinical Excellence, the evidence base on distress reduction from randomised controlled trials is limited, equivocal and poor quality. Crucially, data derived from multiple patient surveys point to worsening and increase distress; however, despite being invited, such data have been dismissed as second class by National Institute of Clinical Excellence. Crucially, the claim by National Institute of Clinical Excellence that cognitive behavioural therapy reduces distress in chronic fatigue syndrome/myalgic encephalomyelitis is not only at odds with what patients repeatedly report in surveys, but with their own gold-standard randomised controlled trial and meta analytic data. PMID- 28805514 TI - Investigator bias and the PACE trial. AB - The PACE investigators reject Geraghty's suggestion that the cognitive behavior therapy/graded exercise therapy trial could have been better left to researchers with no stake in the theories under study. The potential sources and standards for determining researcher bias are considered, concluding that the PACE investigators "impartiality might reasonably be questioned." PMID- 28805515 TI - Defense of the PACE trial is based on argumentation fallacies. AB - In defense of the PACE trial, Petrie and Weinman employ a series of misleading or fallacious argumentation techniques, including circularity, blaming the victim, bait and switch, non-sequitur, setting up a straw person, guilt by association, red herring, and the parade of horribles. These are described and explained. PMID- 28805516 TI - Do graded activity therapies cause harm in chronic fatigue syndrome? AB - Reporting of harms was much better in the PACE (Pacing, graded Activity, and Cognitive behavioural therapy: a randomised Evaluation) trial than earlier chronic fatigue syndrome trials of graded exercise therapy and cognitive behavioural therapy. However, some issues remain. The trial's poor results on objective measures of fitness suggest a lack of adherence to the activity component of these therapies. Therefore, the safety findings may not apply in other clinical contexts. Outside of clinical trials, many patients report deterioration with cognitive behavioural therapy and particularly graded exercise therapy. Also, exercise physiology studies reveal abnormalities in chronic fatigue syndrome patients' responses to exertion. Given these considerations, one cannot conclude that these interventions are safe and risk-free. PMID- 28805517 TI - Further commentary on the PACE trial: Biased methods and unreliable outcomes. AB - Geraghty in the year 2016, outlines a range of controversies surrounding publication of results from the PACE trial and discusses a freedom of information case brought by a patient refused access to data from the trial. The PACE authors offer a response, writing 'Dr Geraghty's views are based on misunderstandings and misrepresentations of the PACE trial'. This article draws on expert commentaries to further detail the critical methodological failures and biases identified in the PACE trial, which undermine the reliability and credibility of the major findings to emerge from this trial. PMID- 28805518 TI - The PACE trial missteps on pacing and patient selection. AB - As others have pointed out a variety of complicating factors with the PACE trial (e.g. changing outcome criteria), I will limit my remarks to issues that involve the composition of adaptive pacing therapy and issues involving patient selection. My key points are that the PACE trial investigators were not successful in designing and implementing a valid pacing intervention and patient selection ambiguity further compromised the study's outcomes. PMID- 28805519 TI - PACE trial authors continue to ignore their own null effect. AB - Protocols and outcomes for the PACE trial were changed after the start of the trial. These changes made substantial differences, leading to exaggerated claims for the efficacy of cognitive behavior therapy and graded exercise therapy in myalgic encephalomyelitis/chronic fatigue syndrome. The small, self-reported improvements in subjective measures cannot be used to say the interventions are effective, particularly in light of the absence of objective improvement. Geraghty's criticism of the trial was reasonable and supported by the evidence. PMID- 28805520 TI - PACE team response shows a disregard for the principles of science. AB - The PACE trial of cognitive behavioural therapy and graded exercise therapy for chronic fatigue syndrome/myalgic encephalomyelitis has raised serious questions about research methodology. An editorial article by Geraghty gives a fair account of the problems involved, if anything understating the case. The response by White et al. fails to address the key design flaw, of an unblinded study with subjective outcome measures, apparently demonstrating a lack of understanding of basic trial design requirements. The failure of the academic community to recognise the weakness of trials of this type suggests that a major overhaul of quality control is needed. PMID- 28805521 TI - Once again, the PACE authors respond to concerns with empty answers. AB - In their response to Geraghty, the PACE investigators state that they have "repeatedly addressed" the various methodological concerns raised about the trial. While this is true, these responses have repeatedly failed to provide satisfactory explanations for the trial's very serious flaws. This commentary examines how the current response once again demonstrates the ways in which the investigators avoid acknowledging the obvious problems with PACE and offer non answers instead-arguments that fall apart quickly under scrutiny. PMID- 28805522 TI - PACE trial claims for recovery in myalgic encephalomyelitis/chronic fatigue syndrome - true or false? It's time for an independent review of the methodology and results. AB - The PACE trial set out to discover whether cognitive behaviour therapy and graded exercise therapy are safe and effective forms of treatment for myalgic encephalomyelitis/chronic fatigue syndrome. It concluded that these interventions could even result in recovery. However, patient evidence has repeatedly found that cognitive behaviour therapy is ineffective and graded exercise therapy can make the condition worse. The PACE trial methodology has been heavily criticised by clinicians, academics and patients. A re-analysis of the data has cast serious doubts on the recovery rates being claimed. The trust of patients has been lost. The medical profession must start listening to people with myalgic encephalomyelitis/chronic fatigue syndrome if trust is going to be restored. PMID- 28805523 TI - The PACE trial: It's time to broaden perceptions and move on. AB - The continued critiques of the PACE trial highlight how differing beliefs about the causes of chronic fatigue syndrome still influence how scientific studies in this area are accepted and evaluated. Causal beliefs about chronic fatigue syndrome and a modern version of Cartesian dualism are important in understanding the reaction to the PACE trial. The continued debate on the PACE trial seems to miss the fact that science is incremental. An unfortunate outcome of the PACE controversy and intimidation of researchers may be less research in the area. It is time to move on from criticism and collect more data on effective treatments. PMID- 28805525 TI - PACE-GATE: An alternative view on a study with a poor trial protocol. AB - The controversies surrounding the effectiveness of cognitive behavioural therapy and graded exercise therapy for chronic fatigue syndrome are explained using Cohen's d effect sizes rather than arbitrary thresholds for 'success'. This article shows that the treatment effects vanish when switching to objective outcomes. The preference for subjective outcomes by the PACE trial team leads to false hope. This article provides a more realistic view, which will help patients and their doctors to evaluate the pros and cons. PMID- 28805524 TI - Response to the editorial by Dr Geraghty. AB - This article is written in response to the linked editorial by Dr Geraghty about the adaptive Pacing, graded Activity and Cognitive behaviour therapy; a randomised Evaluation (PACE) trial, which we led, implemented and published. The PACE trial compared four treatments for people diagnosed with chronic fatigue syndrome. All participants in the trial received specialist medical care. The trial found that adding cognitive behaviour therapy or graded exercise therapy to specialist medical care was as safe as, and more effective than, adding adaptive pacing therapy or specialist medical care alone. Dr Geraghty has challenged these findings. In this article, we suggest that Dr Geraghty's views are based on misunderstandings and misrepresentations of the PACE trial; these are corrected. PMID- 28805526 TI - The problem of bias in behavioural intervention studies: Lessons from the PACE trial. AB - Geraghty's recent editorial on the PACE trial for chronic fatigue syndrome has stimulated a lively discussion. Here, I consider whether the published claims are justified by the data. I also discuss wider issues concerning trial procedures, researcher allegiance and participant reporting bias. Cognitive behavioural therapy and graded exercise therapy had modest, time-limited effects on self report measures, but little effect on more objective measures such as fitness and employment status. Given that the trial was non-blinded, and the favoured treatments were promoted to participants as 'highly effective', these effects may reflect participant response bias. In non-blinded trials, the issue of reporting biases deserves greater attention in future. PMID- 28805527 TI - Bias, misleading information and lack of respect for alternative views have distorted perceptions of myalgic encephalomyelitis/chronic fatigue syndrome and its treatment. AB - The PACE trial is one of the most recent studies evaluating cognitive behavioural therapy and graded exercise therapy for myalgic encephalomyelitis/chronic fatigue syndrome. These interventions are based on a model which assumes that symptoms are perpetuated by factors such as misguided beliefs and a lack of activity. Our analysis indicates that the researchers have shown significant bias in their accounts of the literature and may also have overstated the effectiveness of the above treatments. We submit that their approach to criticisms undermines the scientific process and is inconsistent with best practice. PMID- 28805528 TI - PACE investigators' response is misleading regarding patient survey results. AB - The PACE investigators' citation of a patient survey might mislead readers into thinking that the experience of people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) supports PACE findings. In fact, patient survey evidence directly contradicts the results of the PACE trial. A review of survey data published between 2001 and 2015 reveals that for most patients, graded exercise therapy leads to worsening of symptoms, cognitive behavioural therapy leads to no change in symptoms, and pacing leads to improvement. The experience of people with ME/CFS as reflected in surveys is a rich source of information, made more compelling by the consistency of results. Consequently, patient survey evidence can be used to inform practice, research and guidelines. Misrepresentation of patient experience must be vigorously challenged, to ensure that patients and health professionals make decisions about therapies based on accurate information. PMID- 28805529 TI - Cognitive behaviour therapy and objective assessments in chronic fatigue syndrome. AB - Most evaluations of cognitive behavioural therapy to treat people with chronic fatigue syndrome/myalgic encephalomyelitis rely exclusively on subjective self report outcomes to evaluate whether treatment is effective. Few studies have used measures appropriate to assessing whether cognitive behavioural therapy changes in more objective measures. A review of studies incorporating objective measures suggests that there is a lack of evidence that cognitive behavioural therapy produces any improvement in a patient's physical capabilities or other objective measures such as return to work. Future studies of chronic fatigue syndrome/myalgic encephalomyelitis should include some objective assessments as primary outcomes. If this is to include activity monitors, we first need a sound baseline dataset. PMID- 28805530 TI - Health-related quality of life in alcohol dependence: Similar cross-cultural impact beyond specific drinking habits. AB - This study explores sociocultural differences in alcohol-related impact on quality of life between France and United Kingdom. We included 38 alcohol dependent patients in France and United Kingdom in 10 focus groups. We used a text-mining approach. Three classes of each corpus regarded identical themes across the countries: (a) core impact on quality of life, (b) drinking habits, (c) sources of help. Core impact was similar between the two countries. Main differences were in drinking habits and referral to sources of help. Despite differences in drinking habits, the domains of life impacted by alcohol were non country specific. PMID- 28805531 TI - Fabrication and characterization of the porous duck's feet collagen sponge for wound healing applications. AB - There are several artificial dermis commonly use to cover the wound and promote healing. The major goal of wound management is fast and scarless healing. However, there is no ideal skin substitute, that is effective to accelerate wound healing without scar formation. Artificial dermis substitute also has some drawbacks, such as high cost, insufficient available period and donor pathogen infection. To overcome these problems, we developed duck's feet collagen (DFC) sponge as artificial dermal substitutes for the treatment of full-thickness skin defects. We measured these DFC sponge's comparative characteristics and performances with an artificial dermis Colladerm by carried out SEM-EDX analyze, water-binding abilities and porosity test. Biocompatibility test was also performed using CCK-8 cytotoxicity assay. We also evaluated its wound healing effects for a full-thickness skin wound and compared with Colladerm in a rat model. Histological studies were carried via hematoxylin and eosin and Masson's Trichrome staining. Although the wound healing effect of the DFC sponge was almost similar to that of Colladerm, the DFC sponge did not induce scar formation and wound contracture like Colladerm. We suggest that DFC sponge can be used as an ideal dermal substitute to the treatment of full-thickness skin wound. PMID- 28805532 TI - Etiology-based dental and craniofacial diagnostics. PMID- 28805533 TI - Women veterans and menopause: Knowledge and preferences. AB - The increasing number and older age of women Veterans receiving care at Veterans Health Administration (VHA) requires health-care providers to adjust to their changing patient population. We explored women Veterans' self-reported knowledge of menopause, current/preferred sources of menopausal health information, and perceptions/barriers regarding treatment of menopausal symptoms. Three focus groups were conducted at two South Florida VHA facilities in 2014, which included 30 women Veterans (aged 45-60 years) who visited VHA primary care clinics at least once in the past year. Participants reported using various sources to obtain general and menopausal health information, particularly family, friends, and the internet. Some women also had discussions with their health-care providers, but believed not all VHA providers were knowledgeable about menopause. Most preferred older female providers, thinking they were better informed about menopausal issues. Women favored complementary/alternative therapies and were against using hormone therapy (HT) for symptom relief, although they felt they were insufficiently informed about HT. Menopausal-age women are the fastest growing group at VHA. To provide better care and enhance their experiences, the VHA must educate all primary care providers about menopausal care and strive to address women Veterans' menopausal concerns and preferences. PMID- 28805534 TI - Health behaviors related to endocrine-disrupting chemicals and the associated factors of adolescent Korean girls. AB - In this cross-sectional study, we examined the relationships among knowledge about endocrine-disrupting chemicals (EDCs), recognition of EDCs-related female reproductive illnesses, concern for the environment, perceived susceptibility to EDCs-related diseases, self- appraisal of exposure to EDCs, and health behaviors related to EDCs in adolescent Korean girls. A convenience sample of 218 girls was recruited during July and August 2015 from middle and high schools located in a city in Korea. The self-administered questionnaire incorporated four characteristics of the participants, five related factors, and a dependent variable of health behaviors. Four of the factors explained 20.4 percent of variance in health behaviors, and after controlling covariates, concern for the environment and self-appraisal of exposure to EDCs were still significant factors explaining 29.0 percent of the variance in health behaviors. However, for one factor, knowledge about EDCs, no independent contribution to health behaviors was observed. The findings indicated that education for young women should focus on enhancing their interests in the environment and awareness of environmental hazards. Further, clear and reliable guidelines to protect young women from the exposure to EDCs should be provided to adolescent girls. PMID- 28805535 TI - If, when, and how to discuss available abortion services in the primary care setting. AB - Many women prefer to receive abortion care with their primary care provider; yet, prior studies have suggested that women do not know or assume that their provider does not offer abortion care. Our objective was to explore if, when, and how women wish to be informed of available abortion services at their primary care clinics. We conducted interviews with 21 women at their primary care site during June-July 2014. Vignettes were used to identify clinic visit types in which information regarding abortion services would be welcome and appropriate and inappropriate ways for providers to inform patients of these services. All participants were open to provider-initiated discussion of available abortion services, particularly during women's wellness exams or contraception visits. Themes associated with appropriate communication of abortion services included: 1) using sensitive language, 2) respect for and assessment of patient beliefs, and 3) contextualizing abortion services within reproductive health. Advantages to discussing available abortion services included strengthening the patient provider relationship and improved awareness of the spectrum of services offered. Routine inclusion of abortion services counseling may help educate patients about available services, strengthen the patient-provider relationship, and reduce the stigma surrounding abortion care. PMID- 28805536 TI - A Quadrupole Dalton-based multi-attribute method for product characterization, process development, and quality control of therapeutic proteins. AB - During manufacturing and storage process, therapeutic proteins are subject to various post-translational modifications (PTMs), such as isomerization, deamidation, oxidation, disulfide bond modifications and glycosylation. Certain PTMs may affect bioactivity, stability or pharmacokinetics and pharmacodynamics profile and are therefore classified as potential critical quality attributes (pCQAs). Identifying, monitoring and controlling these PTMs are usually key elements of the Quality by Design (QbD) approach. Traditionally, multiple analytical methods are utilized for these purposes, which is time consuming and costly. In recent years, multi-attribute monitoring methods have been developed in the biopharmaceutical industry. However, these methods combine high-end mass spectrometry with complicated data analysis software, which could pose difficulty when implementing in a quality control (QC) environment. Here we report a multi attribute method (MAM) using a Quadrupole Dalton (QDa) mass detector to selectively monitor and quantitate PTMs in a therapeutic monoclonal antibody. The result output from the QDa-based MAM is straightforward and automatic. Evaluation results indicate this method provides comparable results to the traditional assays. To ensure future application in the QC environment, this method was qualified according to the International Conference on Harmonization (ICH) guideline and applied in the characterization of drug substance and stability samples. The QDa-based MAM is shown to be an extremely useful tool for product and process characterization studies that facilitates facile understanding of process impact on multiple quality attributes, while being QC friendly and cost effective. PMID- 28805537 TI - High Prevalence of Extended-Spectrum beta-Lactamase-Producing Enterobacteriaceae in Wild Fish from the Mediterranean Sea in Algeria. AB - AIM: We investigated the prevalence of extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae among wild fish from the coast of Bejaia (Algeria) in the Mediterranean Sea. RESULTS: From March 2012 to August 2013, gut and gill samples of wild fish were screened for the presence of ESBL-producing Enterobacteriaceae. Strains were characterized with regard to antibiotic resistance, beta-lactamase content, plasmid-mediated quinolone resistance, aminoglycoside resistance genes, and clonality (repetitive sequence-based polymerase chain reaction profiles and multilocus sequence typing). Virulence traits were performed for Escherichia coli and Klebsiella pneumoniae isolates. Of the 300 fish studied, 64 (21.3%) isolates were screened as positive for ESBL producing by the double-disc method. The isolates corresponded to E. coli, K. pneumoniae, Enterobacter cloacae, Morganella morganii, Citrobacter freundii, and Proteus vulgaris. A predominance of blaCTX-M gene was observed with a prevalence of 60.5% (n = 46). Furthermore, our study describes the association of important coresistance and virulence factors in E. coli and K. pneumoniae. Twelve of the ESBL producers carried genes of the qnr family and oqxAB gene and six carried the aac(6')-Ib-cr gene. CONCLUSIONS: Our results highlight for the first time the diffusion of multidrug-resistant Enterobacteriaceae isolates carrying resistance and virulence genes in fish from the Mediterranean Sea in Algeria. PMID- 28805538 TI - Effects of far infrared therapy on arteriovenous fistulas in hemodialysis patients: a meta-analysis. AB - BACKGROUND: Far infrared (FIR) therapy may have a beneficial effect on maturity and function of arteriovenous fistulas (AVFs) in hemodialysis (HD) patients. Therefore, we performed this pooled analysis to assess the protective effects of FIR therapy in HD patients. METHODS: The randomized controlled trials (RCTs) and quasi-RCTs of FIR therapy for HD patients were searched from multiple databases. Relevant studies were screened according to the predefined inclusion criteria. The meta-analyses were performed using RevMan 5.2 software (The Cochrane Collaboration, Oxford, UK). RESULTS: Meta-analysis showed that FIR therapy could significantly increase the vascular access blood flow level (MD, 81.69 ml/min; 95% CI, 46.17-117.21; p < .001), AVFs diameter level (MD, 0.36 mm; 95% CI, 0.22 0.51; p < .001), and the primary AVFs patency (pooled risk ratio = 1.24; 95% CI, 1.12-1.37, p < .001). In addition, therapy with FIR ray radiation could decrease AVFs occlusion rates (pooled risk ratio = 0.20; 95% CI, 0.08-0.46; p < .001) and the level of needling pain (pooled risk ratio = 0.08; 95% CI, 0.06-0.10, p < .001). CONCLUSIONS: FIR therapy can reduce AVFs occlusion rates and needling pain level, while significantly improve the level of vascular access blood flow, AVFs diameter and the primary AVFs patency. PMID- 28805539 TI - Protective effect of regular physical activity on major depressive episodes in patients with early stages of chronic kidney disease. AB - Previous studies have demonstrated an association between physical activity (PA) and depression in diverse population. The purpose of our study is to examine if PA within the recommended level over time is associated with major depressive episode (MDE) in patients with early stages of chronic kidney disease (CKD) in Mainland China. Patients with stages 2-5 CKD not receiving dialysis were enrolled from a nephrology outpatient clinic between May 2014 and February 2016. Based on the patterns of PA over time, all patients were divided into four groups: persistently active, from inactive to active, from active to inactive, and persistently inactive. An MDE was diagnosed by using the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition)-based the Mini International Neuropsychiatric Interview. Among 150 patients, 34 had a current MDE (22.7%) and 116 did not (77.3%). After multivariable adjustment, patients being persistently active had significantly lower odds of having an MDE (odds ratio 0.102, 95% confidence interval, 0.022-0.467, p = .003) compared with those who were persistently inactive. Additionally, patients with diabetes mellitus had significantly higher odds of having an MDE (odds ratio 4.287, 95% confidence interval, 1.473-12.483, p = .008) compared with those without diabetes mellitus. Our results suggest a protective effect of regular PA on MDE in patients with early stages of CKD in Mainland China. PMID- 28805540 TI - Novel approach for structural identification of protein family: glyoxalase I. AB - Glyoxalase is one of two enzymes of the glyoxalase detoxification system against methylglyoxal and other aldehydes, the metabolites derived from glycolysis. The glyoxalase system is found almost in all living organisms: bacteria, protozoa, plants, and animals, including humans, and is related to the class of 'life essential proteins'. The enzyme belongs to the expanded Glyoxalase/Bleomycin resistance protein/Dioxygenase superfamily. At present the GenBank contains about 700 of amino acid sequences of this enzyme type, and the Protein Data Bank includes dozens of spatial structures. We have offered a novel approach for structural identification of glyoxalase I protein family, which is based on the selecting of basic representative proteins with known structures. On this basis, six new subfamilies of these enzymes have been derived. Most populated subfamilies A1 and A2 were based on representative human Homo sapiens and bacterial Escherichia coli enzymes. We have found that the principle feature, which defines the subfamilies' structural differences, is conditioned by arrangement of N- and C-domains inside the protein monomer. Finely, we have deduced the structural classification for the glyoxalase I and assigned about 460 protein sequences distributed among six new subfamilies. Structural similarities and specific differences of all the subfamilies have been presented. This approach can be used for structural identification of thousands of the so-called hypothetical proteins with the known PDB structures allowing to identify many of already existing atomic coordinate entrees. PMID- 28805541 TI - Lack of FOXE3 coding mutation in a case of congenital aphakia. AB - PURPOSE: To report the findings in a patient with congenital primary aphakia, a rare disease known to be caused by mutations in the FOXE3 gene. METHODS: The clinical appearances and visual functions of the patient were determined from the medical records. Genetic analyses were performed to search for mutations in the FOXE3 gene by Sanger sequencing and whole exome sequencing. RESULTS: The 2-month old male patient first presented with bilateral congenital aphakia associated with microphthalmia, corneal opacity, and dysplasia of the anterior segment. At the age of 2-years, his visual acuity in the left eye was 20/1000 at 30 cm, he was able to discriminate red, blue, and yellow light stimuli, and a b-wave was recorded by scotopic combined rod-cone electroretinograms. The right eye became blind during the follow-up period. No mutation in the FOXE3 gene was detected. CONCLUSION: Although congenital aphakia is known to be caused by mutations in the FOXE3 gene, the results of lack of coding mutation in this patient suggests a possible genetic heterogeneity of the disease. PMID- 28805542 TI - Plasma protein adsorption and biological identity of systemically administered nanoparticles. AB - Although a variety of nanoparticles (NPs) have been used for drug delivery applications, their surfaces are immediately covered by plasma protein corona upon systemic administration. As a result, the adsorbed proteins create a unique biological identity of the NPs that lead to unpredictable performance. The protein corona on NPs could also impede active targeting, induce off-target effects, trigger particle clearance and even provoke toxicity. This article reviews the fundamentals of NP-plasma protein interaction, the consequences of the interactions, and provides insights into the correlations of protein corona with biodistribution and cellular delivery. We hope that this review will trigger additional questions and possible solutions that lead to more favorable developments in NP-based targeted delivery systems. PMID- 28805543 TI - Exploring the relationship of phase and peak-frequency EEG alpha-band and beta band activity to temporal judgments of stimulus duration. AB - Pre-stimulus phase has been shown to influence temporal judgments concerning order, causality and simultaneity. One hypothesis is that phase cycles frame discrete perceptual snapshots over time. Yet, existing studies have explored the effect of pre-stimulus phase on fine-grained temporal judgments whereas no study has shown whether pre-stimulus phase influences sub-second temporal judgments lasting several phase cycles. If effects of phase on fine-grained temporal judgments reflect perceptual framing, then the perception of longer intervals might show some dependency on the frequency of phase cycles. Higher frequencies should promote increased temporal resolution and discrimination. We tested the relationship between the phase and frequency of oscillations and temporal judgments for longer durations. Participants judged the relative duration of two successive intervals lasting several phase cycles each. Pre-stimulus alpha-band and beta-band phase was associated with subsequent temporal judgments, although not sensitivity, therein providing evidence that pre-stimulus phase is related to temporal judgments that span a longer time-scale than has been previously demonstrated. Although we report evidence that peak-frequency of the alpha-band is related to one measure of task performance, this study does not provide evidence that higher peak frequencies of alpha- or beta-band activity are related to improved duration discrimination of longer intervals. PMID- 28805545 TI - Rural Family Physicians Are Twice as Likely to Use Telehealth as Urban Family Physicians. AB - BACKGROUND: Telehealth has the potential to reduce health inequities and improve health outcomes among rural populations through increased access to physicians, specialists, and reduced travel time for patients. INTRODUCTION: Although rural telehealth services have expanded in several specialized areas, little is known about the attitudes, beliefs, and uptake of telehealth use in rural American primary care. This study characterizes the differences between rural and urban family physicians (FPs), their perceptions of telehealth use, and barriers to further adoption. MATERIALS AND METHODS: Nationally representative randomly sampled survey of 5,000 FPs. RESULTS: Among the 31.3% of survey recipients who completed the survey, 83% practiced in urban areas and 17% in rural locations. Rural FPs were twice as likely to use telehealth as urban FPs (22% vs. 10%). Logistic regressions showed rural FPs had greater odds of reporting telehealth use to connect their patients to specialists and to care for their patients. Rural FPs were less likely to identify liability concerns as a barrier to using telehealth. DISCUSSION: Telemedicine allows rural patients to see specialists without leaving their communities and permits rural FPs to take advantage of specialist expertise, expand their scope of practice, and reduce the feeling of isolation experienced by rural physicians. CONCLUSION: Efforts to raise awareness of current payment policies for telehealth services, addressing the limitations of current reimbursement policies and state regulations, and creating new avenues for telehealth reimbursement and technological investments are critical to increasing primary care physician use of telehealth services. PMID- 28805544 TI - RNA silencing in plant symbiotic bacteria: Insights from a protein-centric view. AB - Extensive work in model enterobacteria has evidenced that the RNA chaperone Hfq and several endoribonucleases, such as RNase E or RNase III, serve pivotal roles in small RNA-mediated post-transcriptional silencing of gene expression. Characterization of these protein hubs commonly provide global functional and mechanistic insights into complex sRNA regulatory networks. The legume endosymbiont Sinorhizobium meliloti is a non-classical model bacterium with a very complex lifestyle in which riboregulation is expected to play important adaptive functions. Here, we discuss current knowledge about RNA silencing in S. meliloti from the perspective of the activity of Hfq and a recently discovered endoribonuclease (YbeY) exhibiting unprecedented catalytic versatility for the cleavage of single- and double-stranded RNA molecules. PMID- 28805546 TI - Air pollution is associated to the multiple sclerosis inflammatory activity as measured by brain MRI. AB - BACKGROUND: Some environmental factors have been already associated to increased risk of multiple sclerosis (MS), but it is plausible that additional factors might play a role. OBJECTIVE: To investigate in MS patients the relationship between inflammatory activity, detected by brain magnetic resonance imaging (MRI) with gadolinium (Gd), and air pollution, namely, particulate matters with diameter less than 10 MUm (PM10). METHODS: We analyzed from 52 remitting MS patients 226 brain MRIs, 34% with (Gd+MRI) and 66% without (Gd-MRI) T1-Gd enhancing lesions. Daily recording of PM10 in the 30 days before MRI examination was obtained by monitors depending on the residence of subjects. RESULTS: PM10 levels in the 5, 10, 15, 20, and 25 days before brain MRIs were higher (plus 16%, 21%, 24%, 25%, and 21%, respectively) with reference to Gd+MRI versus Gd-MRI. There was a significant association between Gd+MRI and PM10 levels ( p = 0.013), independent of immune therapies, smoker status, and season. In patients who had two repeated MRIs with opposite outcomes (Gd-MRI and Gd+MRI), PM10 levels were strongly higher in concurrence with Gd+MRI ( p < 0.0001). CONCLUSION: Our findings suggest that air pollution may be a risk factor for MS favoring inflammatory exacerbations. PMID- 28805547 TI - The association between methylation levels of targeted genes and albuminuria in patients with early diabetic kidney disease. AB - OBJECTIVE: The incidence of diabetes and its complications are greatly increasing world-wide. Diabeticnephropathy (DN) is the main cause of end-stage renal disease and is associated with high morbidity and mortality. It is important to predict patients with high risk for DN in the early stage. We selected the genes which have an important role on diabetic kidney disease. We aimed to investigate the association between DNA methylation levels of targeted genes and albuminuria in patients with early DN. METHODS: We collected the clinical data of patients with type 2 diabetes mellitus. We measured spot urine albumin creatinine ratio to calculate albuminuria level. We divided patients into two groups based on albumin excretion as patients with (n = 69) and without DN (n = 27). We performed methylation profiling after bisulfite conversion by pyrosequencing method. The mean value of percent methylation level of each gene was calculated. RESULTS: We compared targeted genes (TIMP-2, AKR1B1, MMP-2, MMP-9, MYL9, SCL2A4, SCL2A1, SCL4A3) methylation levels and albuminuria. We found significant negative correlation between TIMP-2 and AKR1B1 gene methylation levels and albuminuria levels. CONCLUSIONS: The present study provided evidence that hypomethylation of TIMP-2 and AKR1B1 genes can be associated with albuminuria in patients with early DN. We may speculate that the hypomethylation of TIMP-2 and AKR1B1 genes may be an early surrogate marker of DN. PMID- 28805548 TI - When is a lie acceptable? Work and private life lying acceptance depends on its beneficiary. AB - In this article we show that when analyzing attitude towards lying in a cross cultural setting, both the beneficiary of the lie (self vs other) and the context (private life vs. professional domain) should be considered. In a study conducted in Estonia, Ireland, Mexico, The Netherlands, Poland, Spain, and Sweden (N = 1345), in which participants evaluated stories presenting various types of lies, we found usefulness of relying on the dimensions. Results showed that in the joint sample the most acceptable were other-oriented lies concerning private life, then other-oriented lies in the professional domain, followed by egoistic lies in the professional domain; and the least acceptance was shown for egoistic lies regarding one's private life. We found a negative correlation between acceptance of a behavior and the evaluation of its deceitfulness. PMID- 28805549 TI - Misuse of Child Sexual Abuse Images: Treatment Course of a Self-Identified Pedophilic Pastor. AB - The recurrent use of child sexual abuse images (CSAI) for sexual arousal is considered a valid indicator for the existence of a pedophilic preference, which in turn represents a significant risk factor for committing contact offenses against children. Treatment programs for (potentially) sexually delinquent men endeavor to reduce the risk to offend by addressing relevant risk factors and emphasizing functional and socially acceptable alternative behaviors. Users of CSAI are a particular target group for prevention services and it has been suggested that the primary treatment focus should be on sexual self-regulation deficits. PMID- 28805550 TI - Moving Toward a Universal Digital Era in Mass Casualty Incidents and Disasters: Emergency Personnel's Perspective in Romania. AB - BACKGROUND: Despite a recognized need for improved communications and logistics in high acuity situations, the integration of telemedicine services into the mainstream health services has been difficult. This study reports on the opinions of Romanian professional responders to mass casualty incidents and disasters regarding the use and requirements of specific electronic medical documentation solutions. MATERIALS AND METHODS: Doctors, nurses, paramedics, and fire department officers participated in a customized online structured questionnaire. To assess factors associated with the current use of information technology and the willingness to adopt an exclusive optimized electronic system, a multivariate analysis was performed. Logistic regression was used for free input key elements regarding the most useful technical and operative improvements and medical documentation solutions for large-scale events. RESULTS: A total of 536 respondents provided answers between the second half of the year 2014 and the first half of the year 2015. Doctors and nurses were the most frequent users of documentation techniques, especially if they were employed at a high-level emergency care center. Professionals' duties were perceived as increasingly impaired by the use of current electronic systems as those duties became more complex. All respondents favored an optimized large-scale event electronic solution, emphasizing the need for enhanced communications, technical equipment, cooperation, and workflow mainly by integrating mobile devices, dedicated software, remote databases, and interlink capabilities. CONCLUSIONS: Professionals support the implementation of an integrated electronic system for large-scale events if outlined requirements are met to maximize user acceptance. PMID- 28805551 TI - Bone-targeted cabazitaxel nanoparticles for metastatic prostate cancer skeletal lesions and pain. AB - AIM: The aim of this study was to develop a novel cabazitaxel bone targeted nanoparticle (NP) system for improved drug delivery to the bone microenvironment. MATERIALS & METHODS: Nanoparticles were developed using poly(D,L-lactic-co glycolic acid) and cabazitaxel as the core with amino-bisphosphonate surface conjugation. Optimization of nanoparticle physiochemical properties, in vitro evaluation in prostate cancer cell lines and in vivo testing in an intraosseous model of metastatic prostate cancer was performed. RESULTS: This bone targeted cabazitaxel nanocarrier system showed significant reduction in tumor burden, while at the same time maintaining bone structure integrity and reducing pain in the mouse tumor limb. CONCLUSION: This bone microenvironment targeted nanoparticle system and clinically relevant approach of evaluation represents a promising advancement for treating bone metastatic cancer. PMID- 28805552 TI - Cyclic Perimenstrual Pain and Discomfort and Australian Women's Associated Use of Complementary and Alternative Medicine: A Longitudinal Study. AB - OBJECTIVE: To examine the longitudinal change in Australian women's prevalence of cyclic perimenstrual pain and discomfort and the association between their symptoms and use of complementary and alternative medicine (CAM). METHOD: Data on endometriosis, premenstrual syndrome (PMS), irregular periods, heavy periods, and severe period pain were collected over a 7-year period from the Australian Longitudinal Study on Women's Health, for women aged 28 to 33 years in 2006, and at 3-year follow-ups. Changes in symptoms and patterns of CAM practitioner and therapy/product use associated with these symptoms were analyzed using longitudinal regression modeling. RESULTS: Over the 7-year period, prevalence rates of PMS and heavy periods increased, while prevalence rates of endometriosis, irregular periods, and severe period pain remained stable. The most common use of CAM longitudinally associated with the perimenstrual symptoms was use of vitamins/minerals, yoga/meditation, massage therapy, herbal medicine, and aromatherapy. Excluding consultation with a naturopath/herbalist, over the 7 year survey women's use of all other CAM practitioners increased as did their use of vitamin/minerals, yoga/meditation, and Chinese medicines, while aromatherapy use declined. CONCLUSION: Only the prevalence of PMS and heavy periods increased with aging in this sample of women. While overall use of CAM practitioner and self-prescribed products/therapies increased over time, CAM was chosen by women mainly to treat endometriosis and PMS. The extent to which this use reflects treatment efficacy is uncertain. PMID- 28805553 TI - Top 10 Research Questions Related to Preventing Sudden Death in Sport and Physical Activity. AB - Participation in organized sport and recreational activities presents an innate risk for serious morbidity and mortality. Although death during sport or physical activity has many causes, advancements in sports medicine and evidence-based standards of care have allowed clinicians to prevent, recognize, and treat potentially fatal injuries more effectively. With the continual progress of research and technology, current standards of care are evolving to enhance patient outcomes. In this article, we provided 10 key questions related to the leading causes and treatment of sudden death in sport and physical activity, where future research will support safer participation for athletes and recreational enthusiasts. The current evidence indicates that most deaths can be avoided when proper strategies are in place to prevent occurrence or provide optimal care. PMID- 28805554 TI - Apitherapeutics and phage-loaded nanofibers as wound dressings with enhanced wound healing and antibacterial activity. AB - AIM: Develop green wound dressings which exhibit enhanced wound-healing ability and potent antibacterial effects. METHODS: Honey, polyvinyl alcohol, chitosan nanofibers were electrospun and loaded with bee venom, propolis and/or bacteriophage against the multidrug-resistant Pseudomonas aeruginosa and examined for their antibacterial, wound-healing ability and cytotoxicity. RESULTS: Among different formulations of nanofibers, honey, polyvinyl alcohol, chitosan-bee venom/bacteriophage exhibited the most potent antibacterial activity against all tested bacterial strains (Gram-positive and -negative strains) and achieved nearly complete killing of multidrug-resistant P. aeruginosa. In vivo testing revealed enhanced wound-healing results and cytotoxicity testing proved improved biocompatibility. CONCLUSION: The developed biocompatible nanofibers represent competitive wound-healing dressings with potent antibacterial and wound-healing activity. PMID- 28805555 TI - Gender Differences in Suicidal Behaviors: Mediation Role of Psychological Distress Between Alcohol Abuse/Dependence and Suicidal Behaviors. AB - : Suicide is the second leading cause of death among emerging adults ages 18 to 25. AIMS: To examine gender differences on the mediation effect of psychological distress between alcohol abuse or dependence (AAD) and suicidal behaviors (ideation, plan, and attempt). METHOD: The current study used the 2014 NSDUH public use data. Young adults aged 18 to 25 years (M = 21.02) old were selected as study participants. The three outcome variables were suicide ideation, plan, and attempt. AAD was an independent variable. As a mediation variable, psychological distress was used to test the research questions. The mediation effect was tested by using bootstrapping methods with the SPSS version of the macro (PROCESS version 2.16) developed by Preacher and Hayes. RESULTS: Six separate mediation analyses (three for a male and three for a female group) were conducted for different types of suicidal behaviors including ideation, plan, and attempt. Overall, psychological distress mediated the association between AAD and suicidal behaviors, except the relationship between AAD and suicide attempts among the male young adults group. CONCLUSIONS: The findings of the current study provide specific directions for practitioners to reduce suicide rates among young adults who are at risk for suicidal behavior. PMID- 28805556 TI - Correction: At-a-glance - The 2017 Canadian Chronic Disease Indicators. AB - [This corrects the article https://www.canada.ca/en/public health/services/reports-publications/health-promotion-chronic-disease-prevention canada-research-policy-practice/vol-37-no-8-2017/at-a-glance-2017-canadian chronic-disease-indicators.html]. PMID- 28805557 TI - Microglia: Physiological Functions Revealed through Morphological Profiles. AB - Microglia play key immunological roles in the central nervous system. Upon activation, resident microglial cells transform from a ramified form to an amoeboid form and acquire the ability to phagocytose and release pro-inflammatory cytokines. Here, we review microglial phenotypes that contribute to their functional roles in the central nervous system with the emphasis on their molecular profiles. Deeper understanding of the functions performed by microglia in physiological and pathological conditions can promote investigation of microglia activities in brain injury or disease and facilitate development of new treatment approaches. PMID- 28805558 TI - Oxytocin Modulates Expression of Neuron and Glial Markers in the Rat Hippocampus. AB - Neuropeptides including oxytocin belong to the group of factors that may play a role in the control of neuronal cell survival, proliferation and differentiation. The aim of the present study was to investigate potential contribution of oxytocin to neuronal differentiation by measuring gene and protein expression of specific neuron and glial markers in the brain. Neonatal and adult oxytocin administration was used to reveal developmental and/or acute effects of oxytocin in Wistar rats. Gene and protein expression of neuron-specific enolase (NSE) in the hippocampus was increased in 21-day and 2-month old rats in response to neonatal oxytocin administration. Neonatal oxytocin treatment induced a significant increase of gene and protein expression of the marker of astrocytes - glial fibrillary acid protein (GFAP). Oxytocin treatment resulted in a decrease of oligodendrocyte marker mRNA - 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) - in 21-day and 2-month old rats, while no change of CD68 mRNA, marker of microglia, was observed. Central oxytocin administration in adult rats induced a significant increase of gene expression of NSE and CNPase. The present study provides the first data revealing the effect of oxytocin on the expression of neuron and glial markers in the brain. It may be suggested that the oxytocin system is involved in the regulation of development of neuronal precursor cells in the brain. PMID- 28805559 TI - Effect of Stress on the Expression of Galanin Receptors in Rat Heart. AB - Neuropeptide galanin, galanin-like peptide and galanin receptors 1, 2 and 3 are a crucial part of the so-called galaninergic system. Our previous studies have shown the possible role of this system in mood modulation, especially regarding stress. So far, the galanin receptors have been found in different tissues including brain and heart. Our study deals with changes in expression of galanin receptor subtypes in the heart of Wistar rats exposed to three different types of stress. Galanin receptor subtypes were determined in fluorescently labelled samples using specific primary antibodies, and all sections were analysed in an immunofluorescent microscope and microphotographs. Image analyses were subsequently performed by software ImageJ, using the threshold method with calculation of the DAPI/galanin receptor signal ratio. We found all three types of receptors in the right and left atria and left and right ventricles. Changes in the density of galanin receptors after application of the stressor depended on the observed heart compartment. We found a significant decrease of galanin receptor 1 in all compartments after all types of stress. For GalR2 and GalR3, the increase/decrease of density was dependent on the tested compartment. These results show that galanin receptors could be involved in the function of heart during the cardiac cycle. PMID- 28805560 TI - Glycation of Matrix Proteins in the Artery Inhibits Migration of Smooth Muscle Cells from the Media to the Intima. AB - Formation and growth of atherosclerotic plaques have serious clinical consequences. One mechanism that occurs during atherogenesis is migration of smooth muscle cells from the middle layer of the artery to the intima, where they proliferate and are transformed into foam cells. This degenerative process is accompanied by glycation, by which proteins are modified and change the biomechanical and biochemical properties. The aim of the study was to determine whether glycation of collagen and elastin building the walls of blood vessels alters the adhesion and rate of myocyte migration. In vitro experiments included migration assays and immunocytochemical staining with anti alpha-actin, beta catenin anti-collagen type IV antibodies. It turns out that there is a tendency to decrease the number of cells that had migrated through the barrier consisting of glycated proteins as compared to the control. Adversely, the morphology of the cells cultured in the presence of glycated substrates is changed. The lower intensity of beta-catenin staining indicates lower adhesiveness of such cells. It is proposed that glycation inhibits migration of smooth muscle cells from the media to the intima, which represents part of the anti-atherogenic mechanism. PMID- 28805561 TI - KCNJ11 and KCNQ1 Gene Polymorphisms Are Not Associated with Post-Transplant Diabetes Mellitus in Kidney Allograft Recipients Treated with Tacrolimus. AB - Post-transplant diabetes mellitus (PTDM) is a metabolic disorder occurring after solid organ transplantation during the therapy with calcineurin inhibitors. ATP sensitive potassium channels KCNJ11 and KCNQ1 play an important role in the regulation of insulin secretion by beta cells and development of diabetes mellitus. Numerous studies have confirmed the association between KCNJ11 and KCNQ1 gene polymorphisms and type 2 diabetes. The aim of this study was to examine the association between KCNJ11 and KCNQ1 gene polymorphisms and posttransplant diabetes mellitus in kidney allograft recipients treated with tacrolimus. The study included 201 patients who received kidney transplants. The patients were subdivided into two subgroups: patients with PTDM (N = 35) and patients without PTDM (N = 166). The association between KCNJ11 and KCNQ1 gene polymorphisms and post-transplant diabetes was studied in three models of univariate Cox regression analysis, i.e., additive, dominant and recessive. In these three models there were no statistically significant associations between KCNJ11 and KCNQ1 gene polymorphisms and PTDM. The results of this study suggest lack of association between KCNJ11 and KCNQ1 gene polymorphisms and post transplant diabetes mellitus in kidney allograft recipients treated with tacrolimus in the Polish population. PMID- 28805563 TI - Infusional Therapies, Continuous Dopaminergic Stimulation, and Nonmotor Symptoms. AB - Pump-based Parkinson (PD) therapies, including subcutaneous apomorphine infusion (CSA) and levodopa-carbidopa intestinal gel (LCIG), presently constitute the most effective pharmacological treatments available for advanced PD. These therapies are based on a more constant delivery of the dopaminergic drug resulting in a more continuous dopaminergic stimulation and a more stable treatment effect. This can be detected as reduction of time in off, reduction of dyskinesia frequency and severity, as well as increase of time in on without troublesome dyskinesias. A number of open-label studies now suggest that also the nonmotor PD symptomatology can improve under CSA and LCIG therapy. The most consistent improvements are seen concerning sleep, mood, and apathy, gastrointestinal symptoms, and urological symptoms. But also cardiovascular symptoms, perception, attention, and sexual function might show beneficial effects when moving from conventional therapies to pump treatment. Further there might be negative influences on some parts of the nonmotor symptomatology through side effects of CSA and LCIG therapy. In this chapter, we review the present knowledge about these aspects of the pump-based therapies. This information might be valuable when deciding on advanced therapy for individual patients. PMID- 28805564 TI - Deep Brain Stimulation and Nonmotor Symptoms. AB - Deep brain stimulation (DBS) is currently the treatment of choice for advanced Parkinson's disease (PD). Several brain targets, including the subthalamic nucleus and the globus pallidus internus, have been successfully employed, with excellent motor outcomes. Despite less established knowledge, DBS may be a powerful tool for managing a wide variety of nonmotor symptoms (NMS) in PD patients, either directly or indirectly due to motor benefit or reduction of dopaminergic drug load. After an assessment of global nonmotor outcomes of DBS, as measured by currently available clinical scales and questionnaires, this chapter will address DBS effects on four main NMS categories: neurobehavioral, including cognitive and neuropsychiatric symptoms, autonomic dysfunction, including orthostatic hypotension, constipation, and urinary dysfunction, sleep disturbances, including insomnia, REM sleep behavior disorder, and restless leg syndrome, to conclude with sensory symptoms, mainly focusing on pain. An overall positive impact of DBS on most NMS emerges from the reviewed studies. However, current opinion on the effect of DBS on NMS in PD needs to be tempered by the relatively low number of cases and the lack of large, controlled, specifically designed studies for most NMS categories. PMID- 28805565 TI - Noninvasive Brain Stimulation and Implications for Nonmotor Symptoms in Parkinson's Disease. AB - Transcranial noninvasive brain stimulation includes both repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). TMS uses a rapidly changing magnetic field to induce currents and action potentials in underlying brain tissue, whereas tDCS involves the application of weak electrical currents to modulate neuronal membrane potential. In this chapter, we provide a literature review with a focus on the therapeutic potential of both techniques in the treatment of nonmotor symptoms of Parkinson's disease (PD). On the whole, the results of studies are rather preliminary but promising as they show some positive effects of rTMS and tDCS particularly on depressive symptoms and cognitive dysfunctions in PD. More carefully controlled trials with standardized methodology, adequately sized and well-characterized samples, and the inclusion of multimodal approaches are warranted in the future. PMID- 28805566 TI - Botulinum Toxin Therapy for Nonmotor Aspects of Parkinson's Disease. AB - The medical treatment of Parkinson's disease (PD) is symptomatic both in terms of motor and nonmotor aspects. The nonmotor symptoms therapy should be taken into account as many of them negatively influence the quality of life and are treatable. Botulinum neurotoxin (BoNT) offers effective treatment for drooling and bladder dysfunctions and alternative treatment for constipation and pain related to parkinsonism. BoNT for drooling is probably the best-documented therapy for nonmotor symptoms by clinical trials. Ultrasound-guided injections into parotid and submandibular glands can be recommended as the first line treatment, especially when anticholinergic oral medications are not indicated due to the risk of confusion, cognitive decline, or psychosis. BoNT therapy of constipation and neurogenic bladder is not so well evidenced and the latter indication is based on positive effects in clinical trials in multiple sclerosis and posttraumatic spine injuries. BoNT injections into the salivary glands or bladder are effective and safe with relatively low risk of complications. Authors reviewed the literature on the use of BoNT for all nonmotor aspects of PD, showed their position in guidelines and systematic reviews and gave the practical remarks on injection techniques and dosing. PMID- 28805567 TI - Nutrition and Nonmotor Symptoms of Parkinson's Disease. AB - To date, no guidelines exist for the screening, evaluation, and management of nutritional status in PD. Dozens of studies demonstrate an association between diet in adulthood with subsequent risk of developing PD. Individuals with PD are at increased risk of malnutrition due to the increased metabolic demands and disease pathophysiology. Risk of malnutrition is further complicated by anosmia, swallowing difficulties, constipation, and drug-nutrient interactions. An emerging body of evidence suggests that the intestinal tract is affected early in the disease, creating therapeutic opportunities for early intervention. Dietary modification and nutritional supplementation may improve symptoms of constipation, depression, insomnia, dystonia, and help prevent cognitive dysfunction. This review summarizes the state of the science related to nutrition and nonmotor symptoms of PD. PMID- 28805568 TI - Complementary and Alternative Medicine and Exercise in Nonmotor Symptoms of Parkinson's Disease. AB - The use of complementary and alternative medicine (CAM) therapy in nonmotor symptoms (NMS) for Parkinson disease (PD) is growing worldwide. Well-performed, systematic evidence-based research is largely lacking in this area and many studies include various forms of CAM with small patient numbers and a lack of standardization of the approaches studied. Taichi, Qigong, dance, yoga, mindfulness, acupuncture, and other CAM therapies are reviewed and there is some evidence for the following: Taichi in sleep and PDQ39; dance in cognition, apathy, and a mild trend to improved fatigue; yoga in PDQ39; and acupuncture in depression, PDQ39, and sleep. Exercise including occupational therapy (OT) and physical therapy (PT) has been studied in motor symptoms of PD and balance but only with small studies with a mounting evidence base for use of exercise in NMS of PD including PDQ39, sleep, fatigue, depression, and some subsets of cognition. Studies of OT and PT largely show some benefit to depression, apathy, and anxiety. Sustainability of an improvement has not been shown given short duration of follow up. Finding optimal control groups and blind for these interventions is also an issue. This is a very important area of study since patients want to be self-empowered and they want guidance on which form of exercise is the best. Additionally, evidence for PT and OT in NMS would give added weight to get these interventions covered through medical insurance. PMID- 28805569 TI - Speech, Voice, and Communication. AB - Communication changes are an important feature of Parkinson's and include both motor and nonmotor features. This chapter will cover briefly the motor features affecting speech production and voice function before focusing on the nonmotor aspects. A description of the difficulties experienced by people with Parkinson's when trying to communicate effectively is presented along with some of the assessment tools and therapists' treatment options. The idea of clinical heterogeneity of PD and subtyping patients with different communication problems is explored and suggestions are made on how this may influence clinicians' treatment methods and choices so as to provide personalized therapy programmes. The importance of encouraging and supporting people to maintain social networks, employment, and leisure activities is stated as the key to achieving sustainability. Finally looking into the future, the emergence of new technologies is seen as providing further possibilities to support therapists in the goal of helping people with Parkinson's to maintain good communication skills throughout the course of the disease. PMID- 28805570 TI - Swallowing Dysfunctions in Parkinson's Disease. AB - Dysphagia is a very frequent and highly relevant symptom in Parkinson's disease (PD) for quality of life, morbidity, and remaining lifetime, which is unfortunately widely underdiagnosed and underestimated regarding patients' centered care. Especially in early stages, the causal association between disease and swallowing disabilities remains unnoticed, which may be accounted for by the inability of caregivers and physicians to detect subtle swallowing problems and by the low self-awareness among PD patients. In order to prevent patients from serious negative consequences for health issues (e.g., aspiration pneumonia or malnutrition) as well as for negative impact on their quality of life, it is on the highest importance of managing dysphagia timely and working closely together in a multidisciplinary team, who all are involved in the patients' care system. This chapter includes background information on epidemiology, pathophysiology, and symptomatology of swallowing disorders in PD. This is followed by a summary of the clinical course and health treats, adequate diagnostic procedures for early identification of dysphagia as well as effective treatment strategies. The conclusion provides recommendations for clinical practice routine. PMID- 28805571 TI - Palliative Care and Nonmotor Symptoms in Parkinson's Disease and Parkinsonism. AB - The term palliative care (PC) is defined as a collection of interventions and strategies that helps to improve and sustain the quality of life of patients and caregivers in situations and scenarios associated with life-threatening illness. This is usually implemented by means of early identification and treatment of relevant motor and nonmotor issues such as pain, sleep, and autonomic dysfunction, dementia, and depression. In addition, a holistic PC program also includes delivery of physical, psychosocial, and spiritual support. PC as a specific discipline, as well as a treatment strategy for long-term neurological conditions such as Parkinson's disease (PD), is relatively new, but very important as neurodegenerative disorders in the United Kingdom alone affects approximately 10 million people and there are over 130,000 people with PD. With longer life expectancy, the burden of long duration and late stage PD is even more evident, bringing in focus the need for PC. However, the concept of PC in PD is still poorly defined and although there are pockets of excellence, the strategy is poorly implemented into routine clinical practice. The variable progressive nature of the disease, the heterogeneity of clinical subtypes, and also the burden of nonmotor symptoms create challenges for effective PC delivery in PD, but recent clinical trials have started addressing PC in PD and are to be welcomed. PMID- 28805572 TI - Personalized Medicine and Nonmotor Symptoms in Parkinson's Disease. AB - Parkinson's disease (PD) is a multineurotransmitter dysfunction related disorder resulting in a range of motor and nonmotor symptoms. Phenotypic heterogeneity is pronounced in PD and nonmotor symptoms dominant subtypes have been described. These endophenotypes may be underpinned by considerable nondopaminergic dysfunction; however, conventional treatment of PD continues to be mostly reliant on dopamine replacement strategy or manipulation of brain dopaminergic pathways. Consequently, treatment of many nondopaminergic nonmotor and some motor symptoms remains a key unmet need. It is also recognized that treatment strategies for PD are influenced by a number of nondrug-related issues. These include factors such as age, personality, and preferences for treatment, cultural beliefs, lifestyle, pharmacoeconomics, pharmacogenetics as well as comorbidity. Therefore, the success of clinical therapy will rest on how much these factors are considered to develop a truly holistic treatment plan. Personalized medicine is the modern way of delivering this holistic strategy for treatment of PD. Personalized medicine thus encompasses several strands of treatment. From the pharmaceutical point of view, it should involve dopaminergic and nondopaminergic strategies. In addition, there are substrategies involving precision and tailored medicine to suit the needs and requirements of individual patients. Precision medicine would be relevant for patients who may be at risk of developing the clinical syndrome of Parkinson's as identified by specific gene mutations. Precision medicine in this scenario will attempt to be preventive. Tailored medicine would address the "single multifactorial" complex nature of PD and address symptoms as well subtype specific strategies. Personalized medicine is now practiced for other conditions such as oncology as well as diabetes. In this chapter, we discuss the rationale and the need to develop strategies for personalized medicine for PD. PMID- 28805573 TI - Nonmotor Features in Atypical Parkinsonism. AB - Atypical parkinsonism (AP) comprises mainly multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), which are distinct pathological entities, presenting with a wide phenotypic spectrum. The classic syndromes are now called MSA-parkinsonism (MSA-P), MSA-cerebellar type (MSA-C), Richardson's syndrome, and corticobasal syndrome. Nonmotor features in AP have been recognized almost since the initial description of these disorders; however, research has been limited. Autonomic dysfunction is the most prominent nonmotor feature of MSA, but also gastrointestinal symptoms, sleep dysfunction, and pain, can be a feature. In PSP and CBD, the most prominent nonmotor symptoms comprise those deriving from the cognitive/neuropsychiatric domain. Apart from assisting the clinician in the differential diagnosis with Parkinson's disease, nonmotor features in AP have a big impact on quality of life and prognosis of AP and their treatment poses a major challenge for clinicians. PMID- 28805574 TI - Nonmotor Symptoms in Vascular and Other Secondary Parkinsonism. AB - Vascular parkinsonism (VP) is a relatively frequent variant of secondary parkinsonism caused by ischemic or hemorrhagic lesions of basal ganglia, midbrain, or their links with frontal cortex. According to different investigations, various forms of cerebrovascular disease cause 1%-15% of parkinsonism cases. Nonmotor symptoms are frequently found in VP and may negatively influence on quality of life. However, nonmotor symptoms such as hallucinations, orthostatic hypotension, REM-sleep behavior disorder, and anosmia are rarely revealed in VP, which may be noted to another diagnosis or mixed pathology. Clinical value of nonmotor symptoms in normal pressure hydrocephalus, toxic, and drug-induced parkinsonism is also discussed. PMID- 28805575 TI - Nonmotor Symptoms in Dystonia. AB - With the emergence of quality of life measures as an indicator for the impact of medical and surgical interventions in dystonia, focus has shifted toward unraveling the pathophysiology and neuroanatomical basis of the "nonmotor symptoms" (NMS). To date, the NMS are now recognized as the greater determinant of quality of life in dystonia, going above and beyond the motor symptomatology. This chapter highlights what is currently known in available literature on the NMS among patients with early-onset dystonia, adult-onset focal dystonia, and dystonia-plus syndromes with particular focus on the NMS involving cognition, mood, behavior (even suicide), sleep, and pain. PMID- 28805576 TI - Nonmotor Symptoms in Essential Tremor and Other Tremor Disorders. AB - Tremor, like dystonia, is a term used at the phenomenological, syndromic, and aetiopathological level. Parkinsonian, essential, and dystonic tremor are the three most common tremor diagnoses encountered in clinical practice. Investigation of nonmotor symptoms in essential tremor and dystonic tremor syndromes is significantly hampered by the lack of clear clinical diagnostic criteria for these groups at a syndromic level, and the absence of biomarkers which allow definitive diagnosis at an aetiopathological level. Much work is needed in clarifying the motor features of these disorders in order to allow delineation of the nonmotor features of the most common tremor syndromes. With this limitation in mind, this chapter reviews what is known about nonmotor symptoms in these two tremor types. The final sections deal with nonmotor symptoms observed in patients with lesional tremor, thankfully a much more clearly defined albeit less common group of patients. PMID- 28805577 TI - Nonmotor Symptoms in Huntington Disease. AB - Huntington disease (HD) is characterized by the triad of motor abnormalities, cognitive dysfunction, and behavioral changes. The aim of this chapter is to describe the frequency, clinical features, and management of behavioral and cognitive dysfunction in HD. Depression, suicidal ideation, apathy, irritability, aggressiveness, obsessions, and compulsions are the most common behavioral abnormalities in HD. All HD patients develop cognitive decline. Recent data suggest that these nonmotor changes are found in premanifest HD gene carriers. Finally, we review the therapeutic options available for behavioral and cognitive abnormalities in HD. The management of these conditions is based on experts' agreement since there is a lack of empirical data. PMID- 28805578 TI - Nonmotor Symptoms in Amyotrophic Lateral Sclerosis: A Systematic Review. AB - BACKGROUND: ALS is a progressive neurodegenerative disease with no curative treatment. Nonmotor symptoms presenting in ALS may cause significant distress, worsen prognosis, and affect survival. OBJECTIVE: To systematically review evidence for the prevalence of nonmotor ALS symptoms, and treatment options. METHODS: Multiple medical literature databases were searched and studies screened using predefined inclusion criteria. Of 4580 studies, 44 were eligible for inclusion with 25 relating to treatment and 19 to the prevalence of nonmotor symptoms in ALS. RESULTS: Nonmotor symptoms involve neuropsychiatric, autonomic, gastrointestinal, and vascular systems, and affect between 5% and 80% of people with ALS. Screening tools for individual nonmotor symptoms are useful in classifying symptom severity and to compare between treatment options. Several methods to relieve nonmotor symptoms have been trialed with varying success rates. CONCLUSIONS: Many of the current studies of nonmotor symptoms in ALS have small sample sizes, requiring more evidence to increase precision in prevalence estimates. Further research is needed to assess the efficacy of current treatments and to find new therapies. Symptom relief or treatment of these nonmotor symptoms should therefore be considered during the clinical management of ALS. PMID- 28805579 TI - Nonmotor Manifestations of Wilson's Disease. AB - Wilson disease (WD) is an autosomal genetic disorder characterized by excessive copper deposition initially in liver (hepatic variant) followed by brain (neuropsychiatric variant) and other organs such as cornea and kidney due to defect in biliary copper excretion. Predominant presentations of neuropsychiatric variant are extrapyramidal motor dysfunctions such as dystonias, Parkinsonism, choreoathetosis, tremor, and ataxias. Nonmotor symptoms (NMS) can appear before clinical disease expression and during ongoing disease process. NMS may cause confusion and delay in clinical diagnosis. In the early stage, presence of asymptomatic or symptomatic evidence of acute or chronic liver disease with or without KF ring in young subjects against the background of family history of liver disease may be indicative of underlying WD. In WD, common NMS are personality disorders, mood changes, psychosis, cognitive abnormalities, sleep disorders, and autonomic disturbances besides few systemic dysfunctions. Cognitive changes can be diagnosed by neuropsychological assessment, MRI, and SPECT study of brain. Nonmotor manifestations can be managed by metal chelator, antipsychotic agents, mood stabilizers, rarely electroconvulsive therapy, and occasional hepatic transplantation. PMID- 28805580 TI - Tourette Syndrome and Chronic Tic Disorders: The Clinical Spectrum Beyond Tics. AB - The clinical surveillance and active management of Tourette syndrome (TS) and other primary chronic tic disorders cannot be limited to tics, as these patients manifest a spectrum of sensory-, behavioral-, cognitive-, and sleep-related problems that have a major impact on their functioning and quality of life, influencing enormously clinical decision making on a routine basis. The sensory phenomena of primary tic disorders consist of premonitory urges and heightened sensitivity to external somatosensory and interoceptive stimuli. Recent evidence suggests that raised interoceptive awareness may be related to the classical premonitory urges associated with tics. The burden of behavioral comorbidities is very important in determining the degree of disability of patients with primary tic disorders. Only 10%-15% of these patients presents exclusively with a tic disorder. Obsessive-compulsive disorder (OCD) are common in TS, and the clinical distinction between compulsions and complex tics may be difficult in some cases. "Tic-related OCD" represents a phenomenologically characteristic subtype of OCD, also associated with "just right" phenomena. Probably the presence of comorbid attention deficit/hyperactivity disorder is the main determinant of cognitive dysfunction in TS patients and influences heavily also the risk of developing disruptive behaviors. Mood and anxiety disorders, impulse control disorders, rage attacks, "impulsive" tic-like behaviors (e.g., nonobscene socially inappropriate behaviors, and self-injurious behaviors), and autism spectrum disorders complete the wide psychopathological spectrum of primary chronic tic disorders. Moreover, specific sleep abnormalities have been reported in TS patients, although more research is needed on this specific clinical problem. As in other areas of clinical neuroscience, a comprehensive approach to both motor and nonmotor aspects of this group of disorders will help personalizing treatment interventions and, ultimately, improve quality of care. PMID- 28805581 TI - Nonmotor Parkinson's and Future Directions. AB - Nonmotor symptoms (NMS) of Parkinson's disease (PD) are integral to the condition largely regarded as a motor syndrome. A range of NMS underpin the prodromal stage of Parkinson's and are present with variable frequency, range, and nature across the whole journey of a patient with Parkinson's from the onset of the motor disease to palliative stage. These symptoms also are key determinants of quality of life of the patient as well as the carer. Despite this, recognition management and focused treatment of NMS of PD remain poor. Future would, therefore, need to focus on better definition and management of NMS of PD. This would include development of robust animal models of specific NMS such as cognitive, sleep, and autonomic dysfunctions as well as pain to understand the mechanistic pathways of these symptoms. In turn this will lead to better drug development using a bench to bedside model. Nonmotor clinical subtypes of PD have also been described and, in future, proper biomarkers will consolidate these findings in addition to defining the natural history of the subtypes. Revised versions of established scales and questionnaires will enable the adoption of good clinical practice with recognition of these subtypes in clinic. This will enhance the delivery of true subtype-specific therapies. Drug development should also include nondopaminergic and cell replacement restorative therapies with a nonmotor focus. An additional key area of future research would be the formalizing of true personalized medicine for PD. Personalized medicine pathways should concentrate on the role of exercise, complementary medicine as well as age, body weight, ethnicity on various NMS of PD. Genetics and pharmacogenetic developments in PD will add to the precision of the individualized approach. PMID- 28805582 TI - Autonomic Dysfunction in Parkinson's Disease: Cardiovascular Symptoms, Thermoregulation, and Urogenital Symptoms. AB - Parkinson's disease is characterized by motor, autonomic, and neuropsychiatric symptoms. These occur in varying degrees in all stages of the disease. Among the autonomic disorders, cardiovascular, urogenital, gastrointestinal, and thermoregulatory disorders are particularly relevant. Because of the significant impact on the quality of life, appropriate diagnostics and therapy should be carried out at all stages of the disease. Within cardiovascular disorders drop of blood pressure after orthostasis and nondipper behavior are very important, but also the influence of cardiovascular medication. Nocturnal sweating is the most common problem of thermoregulation disturbances, for which there is no satisfactory therapy. Urgency, nocturia, and incontinence are of particular note within the urological problems. PMID- 28805583 TI - The Gut and Nonmotor Symptoms in Parkinson's Disease. AB - Gastrointestinal (GI) symptoms are one of the most common nonmotor symptoms (NMS) in patients with Parkinson's disease (PD) involving the whole GI tract (GIT) and being evident throughout the whole course of the disease. Furthermore, constipation serves as a risk factor for PD as well as an early prodromal NMS of PD. The gut as gateway to the environment with its enteric nervous system (ENS) plays a crucial role in the neurodegenerative process that leads to PD. Alpha synucleinopathy as the pathological hallmark of PD could be found within the whole GIT in a rostrocaudal gradient interacting with the ENS, the gut microbiome, and enteric glial cells. Bidirectional interactions between the ENS and the central nervous system (CNS) via a brain-gut-enteric microbiota axis have been reported. As well as there is evidence out of animal, autopsy, and epidemiological studies that alpha-synuclein spreads via rostrocranial transmission by transsynaptic cell-to-cell transfer via the sympathetic and parasympathetic nervous system to the CNS causing the typical neuropathological changes of PD. Recognition of GI NMS as prodromal markers of PD as well as a better understanding of the brain-gut connection offers new insights in the pathophysiology of PD and might provide the opportunity of PD diagnosis before CNS involvement. Hereby the opportunity for development of neuroprotective and disease-modifying therapeutics, respectively, seem to be promising. This chapter covers the variety of GI NMS and its consequences in PD as well as the important role of the gut as part of the pathological process in PD. PMID- 28805584 TI - Constipation in Parkinson's Disease. AB - Constipation is one of the main and disabling nonmotor symptoms in Parkinson's disease (PD), with a prevalence ranging from 24.6% to 63% according to the different diagnostic criteria used to define chronic constipation. Constipation is currently recognized as a risk factor of PD in relation to the number of evacuation per week and its severity. Moreover, several studies have demonstrated that constipation may precede the occurrence of motor symptoms underlying an earlier involvement of the enteric nervous system and the dorsal motor nucleus of the vagus in the alpha-synuclein pathology. In PD, constipation is mainly due to slower colonic transit or puborectalis dyssynergia, but the concomitant use of antiparkinsonian, pain, and antidepressant medications may worsen it. An accurate diagnosis and an adequate treatment of constipation it is pivotal to prevent complications such as intestinal occlusion and to ensure an optimal clinical response to levodopa. PMID- 28805585 TI - Understanding and Treating Pain Syndromes in Parkinson's Disease. AB - Pain affects many people with Parkinson's disease (PD) and diminishes their quality of life. Different types of pain have been described, but their related pathophysiological mechanisms remain unclear. The aim of this chapter is to provide movement disorders specialists an update about the pathophysiology of pain and a practical guide for the management of pain syndromes in clinical practice. This chapter reviews current knowledge on the pathophysiological mechanisms of sensory changes and pain in PD, as well as assessment and treatment procedures to manage these symptoms. In summary, changes in peripheral and central pain processing have been demonstrated in PD patients. A decrease in pain threshold and tolerance to several stimuli, a reduced nociceptive withdrawal reflex, a reduced pain threshold, and abnormal pain-induced activation in cortical pain-related areas have been reported. There is no direct association between improvement of motor symptoms and sensory/pain changes, suggesting that motor and nonmotor symptoms do not inevitably share the same mechanisms. Special care in pain assessment in PD is warranted by the specific pathophysiological aspects and the complexity of motor and nonmotor symptoms associated with pain symptoms. Rehabilitation may represent a valid option to manage pain syndromes in PD. However, further research in this field is needed. An integrated approach to pain involving a multidisciplinary team of medical specialists and rehabilitation experts should allow a comprehensive approach to pain in PD. PMID- 28805586 TI - Sexual Dysfunctions in Parkinson's Disease: An Underrated Problem in a Much Discussed Disorder. AB - Sexual dysfunctions (SDs) are one of the most neglected nonmotor symptoms in Parkinson's disease (PD). A number of reasons including social and cultural factors might explain, at least partially, why SD is still one of the most underrecognized aspects of the condition after 200 years since the very first description by James Parkinson. SD has not been extensively investigated, however, a number of studies have shown a high prevalence of decreased libido, orgasmic dysfunction in both men and women with PD, and erectile dysfunction in male subjects. Moreover, SD in PD also comprises the increasingly recognized hypersexuality that is often associated with PD treatment. Taken together, SD in PD includes a remarkable range of symptoms and conditions that often require a multidisciplinary approach regarding assessment, investigation, and treatment. PMID- 28805587 TI - Osteoporosis: A Hidden Nonmotor Face of Parkinson's Disease. AB - Osteoporosis is a "hidden nonmotor face" of Parkinson's disease and a cause of considerable morbidity in the older general population and in Parkinson's disease patients. Some regard this as a "hidden epidemic." Women are overrepresented and have considerable problems related to osteoporosis. In general osteoporosis leads to reduced mobility aggravating the motor syndrome of PD. The nonmotor aspects and impact of osteoporosis in PD have remained unexplored. Possible nonmotor consequences include a range of pain syndromes related to local pain, fractures, falls, and injuries as well as pathological fractures and radiculopathy. In addition depression, sleep dysfunction, dementia, as well as fear of falling also complicate the clinical picture. Quality of life deteriorates both for the patient and career. Pathways of care do not always include assessments for osteoporosis and needs to become obligatory particularly in older female PD patients. Active management strategies then need to be undertaken for osteoporosis in PD. Related motor and nonmotor consequences also highlight the importance of multidisciplinary treatment in PD particularly when dealing with osteoporosis. PMID- 28805588 TI - Weight in Parkinson's Disease: Phenotypical Significance. AB - Body weight in Parkinson's disease (PD) is a significant nonmotor feature. Weight homeostasis is a complex physiological process and gets deranged in PD patients leading to changes in weight. While both the low and high body weight have been reported as risk factors for PD, the majority of PD patients have a lower weight and a subset of patients lose weight during the course of the disease, while a small proportion gain weight. A number of clinical parameters such as older age, impaired cognition, severity of disease, and an imbalance of food intake determined by satiety and hunger hormones have been reported to be associated with but not the cause of weight change. Low body weight and weight loss have a negative impact on disease severity, dyskinesia quality of life, and mortality indicative of disease progression. An early assessment of olfactory impairment seems to identify patients at risk of weight loss, the patients with more severe olfactory loss-anosmic group, lose weight as compared to the patients with some preservation of olfaction, the hyposmic group. Higher levodopa dose per kilogram body weight increases the risk of dyskinesia, higher body weight seems to be protective against this complication. The identification of PD patients according to the nonmotor phenotype of "Park-olfaction-weight-phenotype" and the "olfaction weight-dyskinesia" triad should help to develop strategies to prevent weight reduction and improve general health and complications of PD patients. The phenotype seems to reflect a differential prodromal pathology and influence clinical disease. Higher body weight patients would benefit from life style changes to achieve a healthy profile. Weight monitoring and weight orientated approach to management of PD patients should help to improve their outcome. Body weight change might be a surrogate to disease progression and may be used to investigate neuroprotection strategies. PMID- 28805589 TI - Visual Dysfunction in Parkinson's Disease. AB - This chapter describes the visual problems likely to be encountered in Parkinson's disease (PD) and whether such signs are useful in differentiating the parkinsonian syndromes. Visual dysfunction in PD may involve visual acuity, contrast sensitivity, color discrimination, pupil reactivity, saccadic and pursuit eye movements, motion perception, visual fields, and visual processing speeds. In addition, disturbance of visuospatial orientation, facial recognition problems, rapid eye movement (REM) sleep behavior disorder, and chronic visual hallucinations may be present. Problems affecting pupil reactivity, stereopsis, pursuit eye movement, and visuomotor adaptation, when accompanied by REM sleep behavior disorder, could be early features of PD. Dementia associated with PD is associated with enhanced eye movement problems, visuospatial deficits, and visual hallucinations. Visual dysfunction may be a useful diagnostic feature in differentiating PD from other parkinsonian symptoms, visual hallucinations, visuospatial dysfunction, and variation in saccadic eye movement problems being particularly useful discriminating features. PMID- 28805590 TI - Nonmotor Fluctuations in Parkinson's Disease. AB - The advanced stage of Parkinson's disease (PD) is characterized by motor complications such as motor fluctuations and dyskinesias induced by long-term levodopa treatment. Recent clinical research provides growing evidence that various nonmotor symptoms such as neuropsychiatric, autonomic, and sensory symptoms (particularly pain) also show fluctuations in patients with motor fluctuations (called nonmotor fluctuations or NMF). However, NMF have not yet been adequately considered in routine care of advanced PD patients and only few therapeutic studies are available. Since the pathophysiology of NMF remains largely unknown, innovative therapeutic concepts are largely missing. The close connection of NMF and motor fluctuations, however, strongly suggests that the strategies used to treat motor complications-namely continuous dopaminergic stimulation-also apply for the therapy of NMF. Future controlled clinical trials specifically addressing NMF are urgently warranted. PMID- 28805591 TI - Acute Presentation of Nonmotor Symptoms in Parkinson's Disease. AB - There are a few syndromes involving the nonmotor symptoms of Parkinson's disease and other movement disorders that can quickly lead to severe morbidity and mortality, and, as such, need rapid identification and management. Among these are neuroleptic malignant syndrome, serotonin syndrome, dopamine agonist withdrawal syndrome, and dystonic storm. It is important to maintain a high index of suspicion for these disorders as lack of identification can lead to death. Many of these acutely occurring nonmotor syndromes are primarily the result of imbalances in dopaminergic and serotonergic systems due to changes in pharmacologic management of psychiatric disorders or Parkinson's disease. We discuss these acutely occurring nonmotor symptoms in order to raise awareness and also to highlight how these extremes in symptoms may uniquely shed light on the pathophysiology of Parkinson's disease. PMID- 28805592 TI - Nonmotor Effects of Conventional and Transdermal Dopaminergic Therapies in Parkinson's Disease. AB - Nonmotor symptoms (NMS) are an integral component of Parkinson's disease (PD). Because the burden and range of NMS are key determinants of quality of life for patients and caregivers, their management is a crucial issue in clinical practice. Although a range of NMS have a dopaminergic pathophysiological basis, this fact is underrecognized, and thus, they are often regarded as dopamine unresponsive symptoms. However, substantial evidence indicates that many NMS respond to oral and transdermal dopaminergic therapies. In contrast, certain NMS are exacerbated or even precipitated by dopaminergic drugs and these unwanted effects may be seriously dangerous. Therefore, a dopaminergic strategy for NMS should be based on a consideration of the benefits vs the risks in individual patients with PD. PMID- 28805593 TI - Prefaces. PMID- 28805595 TI - Prenatal diagnosis of congenital lobar fluid overload. AB - Prenatal congenital lobar fluid overload (CLFO), which was first described by Ramsay and Byron, is identical to postnatal congenital lobar overinflation. It is characterized by progressive lobar overexpansion that compresses the other adjacent lung lobes. The underlying cause can be an intrinsic cartilaginous abnormality or an extrinsic airway compression. It may be associated with cardiovascular anomalies in 12%-14% of cases and affects males more frequently than females. Most cases are diagnosed postnatally, but early antenatal diagnosis and sequential follow-up are attempted for early treatment, if clinically indicated. This article provided a thorough review of CLFO, including prenatal diagnosis and differential diagnoses, as well as comprehensive illustrations of the perinatal imaging findings of CLFO. Prenatal diagnosis of fetal lung lesions should include CLFO in the differential diagnosis and prompt investigation for associated anomalies. PMID- 28805596 TI - Dyspnea in pregnancy. AB - Dyspnea in pregnancy is common. It can result from adaption to body changes in pregnancy and also from complications therein. Understanding the mechanisms of change in the respiratory system during pregnancy helps with the differential diagnosis of dyspnea in normal pregnancy as opposed to pathological dyspnea. PMID- 28805597 TI - The climate impact on female acute pyelonephritis in Taiwan: A population-based study. AB - OBJECTIVE: Urinary tract infection (UTI) is the main reason of community-acquired infection which causes large losses in social economy. The individual as well as climate factors make changes on the incidence. Acute pyelonephritis (APN) is one of the most serious UTI in female. The object of our study is to analyze whether climate factors will have effect on the incidence of female APN in Taiwan. MATERIALS AND METHODS: This study consisted of 14,568 female patients with APN from 2001 to 2013 in Taiwan and patients with repeated APN were excluded. The monthly climate data was collected from the Central Weather Bureau. The available monthly climate data included highest, lowest, and average level of temperatures, humidity, rainfall, total rain days, and sunshine hours. RESULTS: The total incidence of female APN was 23.44 each 10,000 populations. The incidence of APN was positively correlated with temperature (r = 0.66), sunshine hours (r = 0.45), rainfall (r = 0.42), rain days (r = 0.29), and humidity (r = 0.23) per month. There is the strongest correlation between the average monthly temperature and the incidence of APN (beta = 0.54). The correlation with the incidence of APN was also followed by rain days (beta = 0.28) and humidity (beta = 0.27). CONCLUSION: There is a significant expression on the incidence of female APN affected by seasonality and climate parameters. The monthly average temperature has the strongest correlation with female APN. The results of this research may facilitate the potential preventive strategies on female APN. PMID- 28805598 TI - Screening frequency and histologic type influence the efficacy of cervical cancer screening: A nationwide cohort study. AB - OBJECTIVE: To evaluate the influence of age, screening interval, and histologic type on the effect of Pap smears in cervical cancer screening. MATERIALS AND METHODS: Data were retrieved from the Taiwan National Cancer Registry and Cervical Cancer Screening Registration System for the period from 2002 to 2010. Age, Pap smear interval, FIGO stage, and histology were further analyzed. RESULTS: A total of 12,294 women with cervical cancer were enrolled, including 10,040 with squamous cell carcinoma (SCC), 1720 with adenocarcinoma (ADC), 401 with adenosquamous carcinoma (ASC), and 133 with small cell neuroendocrine carcinoma (SMC). Women who had a Pap smear at an interval of <3 years had a significantly higher proportion of stage I disease than women who had never undergone cervical cancer screening (p < 0.0001). Greater than 40% of women with SCCs in each age group had never had a Pap smear; however, women with ADCs were predominantly in the younger age and greater than 40% of women with ADCs had Pap smear at intervals < 3 years. CONCLUSIONS: Pap smear is more effective in screening for cervical SCCs compared to cervical ADCs. Improving adherence to screening recommendations is important for the prevention of cervical SCC, especially in elderly women. PMID- 28805599 TI - Nationwide trends and in-hospital complications of trachelectomy for surgically resectable cervical cancer in Taiwanese women: A population-based study, 1998 2013. AB - OBJECTIVE: To describe the nationwide trends in the utilization of trachelectomy among Taiwanese women with surgically resectable cervical cancer over the past decade, and to compare associated demographic characteristics, in-hospital complications and related outcomes using a population-based dataset from 1998 to 2013. MATERIALS AND METHODS: We conducted a population-based, cohort study using inpatient admission claims data of Taiwan's National Health Insurance program. Women who underwent trachelectomy for cervical cancers were compared by age at surgery (younger than 40 years, 40-59 years, and 60 years or older). RESULTS: Our study cohort consisted of 156 women. The overall utilization increased considerably during the study period, particularly in younger women aged 30-39 years. Compared with older women who had trachelectomy, women younger than 40 years were diagnosed more frequently in the later years of study (2007-2013, 69.9% vs 37.3%), were treated more frequently at medical centers (89.0% vs 60.2%) by physicians aged 55 years or older (50.7% vs 22.9%) with high case volume (50.7% vs 26.5%), were less likely to undergo concomitant surgeries for bilateral oophorectomy (1.4% vs 21.7%) and lysis of peritoneal adhesion (2.7% vs 24.1%), and were more likely to undergo lymph node excision (74.0% vs 47.0%) (P < 0.05 for all). During a median of follow-up of 5.4 (2.4-9.5) years, 5.1% received future hysterectomy after trachelectomy (n = 8) with a median time-to-future hysterectomy of 0.6 (0.2-5.0) years. The estimated risks of disease recurrence for cervical cancer and readmission within 30-days (n = 35) were 3.8% and 22.4%, respectively. Women's age at trachelectomy had no apparent association with the length of hospital stay (P = 0.11), in-hospital mortality, readmission within 30 days (P = 0.33), future hysterectomy (P = 0.14), and in-hospital complications (P = 0.47). CONCLUSION: Substantial increase in the trend of delayed childbearing may have influenced the decision-making of Taiwanese women with cervical cancer in favor of trachelectomy over hysterectomy over the past 16-years from 1998 to 2013. When considering the uterine preservation for future fertility, women should be counseled about the risk of disease recurrence for cervical cancer before making surgical decision for trachelectomy over hysterectomy. PMID- 28805600 TI - The effect of oxytocin and Kisspeptin-10 in ovary and uterus of ischemia reperfusion injured rats. AB - OBJECTIVE: Ischemia/reperfusion (I/R) injuries result in damage to endothelial and parenchymal cells. Oxytocin (OXY) stimulates uterine contraction during parturition and myoepithelial cells during suckling. OXY has been used as a protective antioxidant. Kisspeptin plays a key role in the central control of reproductive functions and onset of puberty. Recent studies show that these reproductive hormones have protective potential as antioxidant. The aim of this study is to investigate the potential protective effects of Kisspeptin and OXY as antioxidants on I/R injured ovary and uterus of female rats. MATERIALS AND METHODS: Rats were separated into five groups. Group 1, is control group; Group 2, rats were subjected to ischemia followed by reperfusion. Group 3, OXY administration 30 min prior to I/R applied rats; Group 4, Kisspeptin administration 30 min prior to I/R applied rats; Group 5, OXY and Kisspeptin administration 30 min prior to I/R. Ovary and uterus were removed for histopathological and biochemical observations. Malondialdehyde, glutathione levels, and superoxide dismutase activities were analyzed in order to observe antioxidant potential of OXY and Kisspeptin. Hematoxylin and Eosin staining was applied for histopathologic scoring. RESULTS: Stromal and granulosa cells in ovary, endometrial cells in uterus were damaged in I/R group. The cellular damage of ovary and uterus were reduced in OXY and Kisspeptin administered I/R group when compared to only Kisspeptin injected I/R group and I/R group. There is no significant difference between OXY and OXY + Kisspeptin injected I/R groups. MDA levels were decreased in Kisspeptin and/or Oxytocin applied I/R group compared to I/R group. SOD activity and GSH levels were increased in Kisspeptin and/or OXY applied I/R group compared to I/R group. CONCLUSIONS: The present results suggest that exogenous application of oxytocin and kisspeptin can have antioxidant effects on the uterus and ovary. PMID- 28805601 TI - Effect of oral contraceptives on balance in women: A randomized controlled trial. AB - OBJECTIVE: To detect the effect of combined oral contraceptive pills (COC) on dynamic postural balance in healthy middle aged women. MATERIALS AND METHODS: A prospective randomized controlled study included 200 patients classified into two groups. Group I received COC containing 30 MUg of EE and 3 mg of drospirenone for 12 consecutive cycles and Group II received no treatment. Overall, medio-lateral and antero-posterior stability were measured using Biodex system after 12 months. RESULTS: There was a highly statistically significant difference between the 2 study groups regarding estradiol level (12.84 +/- 1.96 vs. 38.86 +/- 3.99, P value < 0.001) and progesterone level (0.52 +/- 0.25 vs. 11.64 +/- 4.53, P value < 0.001). There was a highly statistically significant difference between the 2 study groups regarding mediolateral stability (1.84 +/- 0.23 vs. 2.40 +/- 0.56, P value < 0.001), antereoposterior stability (1.91 +/- 0.29 vs. 2.33 +/- 0.61, P value < 0.001) or overall stability (2.42 +/- 0.29 vs. 2.95 +/- 0.53, P value < 0.001). CONCLUSION: COC are effective method of contraception to improve postural balance and decrease risk of injury in normal and athletic women. NCT02855294. PMID- 28805602 TI - Laparoendoscopic single-site myomectomy using conventional laparoscopic instruments and glove port technique: Four years experience in 109 cases. AB - OBJECTIVE: To report a single surgeon's experience with 109 laparoendoscopic single-site myomectomy (LESS-M) using conventional laparoscopic instruments and a homemade glove port system. MATERIALS AND METHODS: A total of 109 consecutive women who underwent LESS-M between March 2011 and April 2015 were reviewed. RESULTS: The mean age and body mass index were 38.3 +/- 6.5 years and 22.1 +/- 3.0 kg/m2. The mean diameter of the largest myoma and the mean number of myomas were 8.1 +/- 2.4 cm and 1.6 +/- 0.7. The mean weight of the myomas was 223.2 +/- 159.7 g. The most common type of myoma was intramural (61%), followed by subserosal (23%), submucosal (9%), and intraligamental (7%). The most common site of the myomas was anterior (39%), followed by posterior (38%), lateral (15%), and fundal (9%). The mean operative time and estimated blood loss were 138.5 +/- 43.8 min and 104.9 +/- 270.1 mL. Two patients (1.8%) required intraoperative transfusion. The mean hospital stay was 2.5 +/- 0.6days. There were no conversions to laparotomy, but three patients(2.8%) were converted to two-port laparoscopic myomectomy. No patient experienced any major complication, including bowel, ureter, bladder injuries, or incisional hernia. Six women became pregnant after the operation, and five of these patients delivered their babies at full term by cesarean section. One patient delivered her baby at a gestational age at 32 weeks due to idiopathic polyhydramnios by cesarean section. One patient had the second pregnancy and delivery after LESS-M. Fourteen patients (12.8%) had small recurrent myomas that did not require treatment. CONCLUSION: LESS-M is a feasible alternative for patients with symptomatic myomas, and this technique can provide cosmetic advantages compared to conventional laparoscopic surgery. PMID- 28805603 TI - Modern human sperm freezing: Effect on DNA, chromatin and acrosome integrity. AB - OBJECTIVE: Presence of vitrification method in sperm freezing and the introduction of solid surface vitrification beside rapid freezing in vapour, opens an easy and safe way to help infertility centres. While the effects of cryopreservation on motility, morphology and viability of sperm are documented, the question of the probable alteration of sperm DNA, chromatin and acrosome integrity after freezing and thawing procedures in different methods is still controversial. MATERIALS AND METHODS: Normal sample were collected according to WHO strict criteria. Sperm suspensions were mixed 1:1 with 0.5 M sucrose and divided into four equal aliquots for freezing: fresh, nitrogen direct immersion vitrification (Vit), solid surface vitrification (SSV) and in vapour (Vapour). Sperm suspensions were transferred into a 0.25 ml sterile plastic. Then straw was inserted inside the 0.5 ml straw. For thawing, the straws were immersed in a 42 degrees C water bath. Beside the sperm parameters, we assessed the acrosome reaction by double staining, chromatin integrity by toluidine blue (Tb) and chromomycin A3 (CMA3) and DNA integrity by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) respectively. RESULTS: In progressive motility, the highest rate occurred in Vit (39.9 +/- 13.3). Moreover, the lowest rate of immotile sperm was in Vit (32.7 +/- 16.3). In normal morphology, the group Vit was similar to the fresh, while SSV and Vapour were significantly different from the fresh. The percentage of acrosome-reacted sperms was more in Vit (81.3 +/- 10.2) than the fresh group. TUNEL+ results showed that DNA fragmentation was significantly increased in Vit (p-value = 0.025). While in SSV and Vapour results were comparable to fresh. There was a significant correlation between TUNEL+ and normal morphology, TB, CMA3 and presence of intact acrosome. CONCLUSION: Sperm in Vapour was healthier in terms of DNA, chromatin and acrosome integrity. In contrast of higher motility and normal morphology; DNA, chromatin and acrosome integrity were decreased in Vit. However, these findings were more acceptable in SSV or Vapour. PMID- 28805604 TI - Evaluation of sclerotherapy for the treatment of infected postoperative lymphocele. AB - OBJECTIVE: To evaluate the efficacy and safety of sclerotherapy as the treatment of infected postoperative lymphocele in gynecologic malignancy patients. MATERIALS AND METHODS: Percutaneous catheter drainage (PCD) with or without sclerotherapy was performed for postoperative lymphocele in 75 patients from 2002 to 2014. Eighty-eight lymphoceles (43 non-infected as group A, 45 infected as group B) in 75 patients (mean age +/- SD; 50.3 +/- 11.3) were included. Sclerotherapy was performed in 17 (39.5%, group A-S) lymphoceles in group A and 14 (31.1%, group B-S) in group B. Absolute ethanol was the most frequently used sclerosant (28 of total 36 sessions). Mean follow-up period was 37 months (range: 1-154). RESULTS: Sclerotherapy was clinically successful in 13 lymphoceles in both group A-S (76.5%) and group B-S (92.9%) without statistical significance. Compared to the pre-sclerotherapy period, group B-S demonstrated significantly decreased drainage volume after sclerotherapy (662.7 ml vs. 100.6 ml, p = 0.019). Group A-S failed to demonstrate significant decrease in drainage volume after sclerotherapy. Recurrence occurred in 4 patients in group A-S and 1 in group B-S, without statistical significance. No major complication was noted. CONCLUSION: Sclerotherapy significantly reduces the drainage volume, and might help shorten catheter placement time in infected lymphoceles. PMID- 28805605 TI - Relationship between alcohol consumption and age at menopause: The Korea National Health and Nutrition Examination Survey. AB - OBJECTIVE: We used data from the 2011-2014 Korean National Health and Nutrition Examination Surveys (KNHANES) to investigate whether the age at menopause is related to alcohol consumption in South Korean women. MATERIALS AND METHODS: This was a cross-sectional study of the data for 940 women who became menopausal within the 3 years preceding the KNHANES. RESULTS: The numbers of nondrinkers, mild to moderate drinkers, and heavy drinkers in this group were 345 (34.7%), 573 (62.2%), and 22 (3%). Body mass index (BMI), smoking, and exercise were adjusted in model 1 and age was additionally adjusted in model 2. The mean ages at menopause were 51.6 +/- 0.2, 50.8 +/- 0.1, and 50.4 +/- 0.5 years (p = 0.0025) in model 1 and 51.7 +/- 0.2, 51.1 +/- 0.1, and 50.1 +/- 0.5 years (p = 0.0018) in model 2 for nondrinkers, mild to moderate drinkers, and heavy drinkers, respectively. BMI, smoking, exercise, educational level, income, duration of menopause, age at menarche, age at first delivery, and gravidity were adjusted in model 3, and the respective mean ages at menopause were 51.3 +/- 0.2, 50.7 +/- 0.2, and 50.1 +/- 0.8 years (p = 0.0402). The population was classified into groups using the Alcohol Use Disorders Identification Test (AUDIT) scores of <5 (n = 778), <10 (n = 108), and >=10 score (n = 54). The mean ages at menopause according to AUDIT score were 51.3 +/- 0.1, 50.5 +/- 0.3, and 50.4 +/- 0.4 years (p = 0.0222, model 1), 51.4 +/- 0.1, 50.8 +/- 0.3, and 50.8 +/- 0.3 years (p = 0.0261, model 2), and 51.1 +/- 0.1, 50.6 +/- 0.4, and 49.5 +/- 0.6 years (p = 0.0241, model 3) respectively. CONCLUSION: In Korean women, alcohol consumption was associated with younger age at menopause. A higher AUDIT score was also related to younger age at menopause. PMID- 28805606 TI - Detection of SEA-type alpha-thalassemia in embryo biopsies by digital PCR. AB - OBJECTIVE: Accurate and efficient pre-implantation genetic diagnosis (PGD) based on the analysis of single or oligo-cells is needed for timely identification of embryos that are affected by deleterious genetic traits in in vitro fertilization (IVF) clinics. Polymerase chain reaction (PCR) is the backbone of modern genetic diagnoses, and a spectrum of PCR-based techniques have been used to detect various thalassemia mutations in prenatal diagnosis (PND) and PGD. Among thalassemias, SEA-type alpha-thalassemia is the most common variety found in Asia, and can lead to Bart's hydrops fetalis and serious maternal complications. MATERIALS AND METHODS: To formulate an efficient digital PCR for clinical diagnosis of SEA-type alpha-thalassemia in cultured embryos, we conducted a pilot study to detect the alpha-globin and SEA-type deletion alleles in blastomere biopsies with a highly sensitive microfluidics-based digital PCR method. Genomic DNA from embryo biopsy samples were extracted, and crude DNA extracts were first amplified by a conventional PCR procedure followed by a nested PCR reaction with primers and probes that are designed for digital PCR amplification. RESULTS: Analysis of microfluidics-based PCR reactions showed that robust signals for normal alpha-globin and SEA-type deletion alleles, together with an internal control gene, can be routinely generated using crude embryo biopsies after a 106 fold dilution of primary PCR products. CONCLUSION: The SEA-type deletion in cultured embryos can be sensitively diagnosed with the digital PCR procedure in clinics. The adoption of this robust PGD method could prevent the implantation of IVF embryos that are destined to develop Bart's hydrops fetalis in a timely manner. The results also help inform future development of a standard digital PCR procedure for cost-effective PGD of alpha-thalassemia in a standard IVF clinic. PMID- 28805607 TI - The characterization of trachelectomy for benign and precancerous indications in Taiwan: A population-based study, 1998-2013. AB - OBJECTIVE: The study aimed to update the utilization trend and characterize the trachelectomy for benign and precancerous indications in Taiwanese women by comparing associated women, surgeon, and hospital-related characteristics. MATERIALS AND METHODS: We conducted a population-based trend study using inpatient admission claims data from Taiwan's National Health Insurance program from 1998 to 2013. After excluding those who had prior subtotal hysterectomy, women who underwent trachelectomy for benign and precancerous indications were compared by age at surgery (younger than 40 years, n = 130; 40 and 59 years, n = 429; and 60 years or older, n = 439). Trend analysis by age groups and indication was performed for the utilization of trachelectomy. A separate descriptive analysis was also performed to evaluate the surgeon's total trachelectomy case volume during the study period. RESULTS: A total of 998 women who underwent trachelectomy for benign and precancerous indications were included in the study cohort. The overall utilization increased considerably by 100% over the study period. The most common indications for trachelectomy were genital prolapse (75.2%) and precancerous cervical lesion (21.0%). The majority of trachelectomies were performed with concomitant colporrhaphy for genital prolapse among older women without comorbid illness or any prior catastrophic illness. Most women (62.9%) were operated by a relatively small number of surgeons with high case volume (12.6%) during the study period. Compared to women older than 40 years, younger women had less comorbidities, more likely to be treated at private medical institution by surgeons of high case volume, and were less likely to undergo concomitant anterior and posterior colporrhaphy. CONCLUSIONS: The overall utilization of trachelectomy for benign and precancerous indications has increased over the past 16-years from 1998 to 2013, particularly among older Taiwanese women without comorbid illness or any prior catastrophic illness. PMID- 28805608 TI - The utility and effectiveness of an internal iliac artery balloon occlusion catheter in surgery for large cervical uterine fibroids. AB - OBJECTIVE: Surgery for uterine cervical fibroids is difficult because of restricted surgical access and risks such as intraoperative bleeding or injury to other organs. The internal iliac artery balloon occlusion catheter (IIABOC) provides effective hemostasis for placenta previa and atonic hemorrhage, and is increasingly used in surgery for uterine fibroids for controlling intraoperative hemorrhage. We investigated the efficacy and safety of the IIABOC for controlling intraoperative bleeding in total abdominal hysterectomies (TAH) and abdominal myomectomies (AM) for large cervical fibroids. MATERIAL AND METHODS: From 2007 to 2014, the IIABOC was used in 22 cases (12 for TAH and 10 for AM) in which cervical fibroids fully occupied the pelvic cavity. Intraoperative blood loss, operating time, sample weight, use of blood transfusion, and injury to other organs were assessed. RESULT: Mean blood loss, operative time, and sample weight in the IIABOC cases were 510 mL, 178 min, and 2550 g for TAH; and 727.5 mL, 157.5 min, and 1850 g for AM. Blood loss divided by sample weight in IIABOC cases was significantly lower than that in non-IIABOC cases during the same time period, for both TAH and AM. Allogeneic blood transfusion was not necessary, and complications of injury to other organs did not occur in any of the 22 cases. CONCLUSIONS: For large cervical fibroids with limited operating space, surgery was performed under bleeding control by occlusion of the internal iliac artery with an IIABOC. This technique enables control of hemorrhage and safe operative management in gynecological surgery. PMID- 28805609 TI - Efficacy of PET/CT to exclude leiomyoma in patients with lesions suspicious for uterine sarcoma on MRI. AB - OBJECTIVE: To analyze the efficacy of positron emission tomography/computed tomography (PET/CT) for the diagnosis of uterine sarcoma. MATERIALS AND METHODS: Thirty-four patients evaluated between January 2010 and March 2015 were retrospectively enrolled. All patients in whom uterine sarcoma was suspected based on contrast-enhanced magnetic resonance imaging (MRI) findings (heterogeneous, high signal intensity on T2-weighted images and/or high intensity on T1-weighted images) underwent PET/CT for further assessment. Patients were divided into 2 groups based on postoperative pathological findings: uterine sarcoma (n = 15) and leiomyoma (n = 19). The maximum standardized uptake value (SUVmax) of all lesions was measured using PET/CT; we calculated the optimal cutoff value for diagnosing sarcoma. RESULTS: The median SUVmax for uterine sarcoma and leiomyoma was 12 and 4.1, respectively; these values were significantly different. An SUVmax of greater than 7.5 was able to exclude leiomyoma with 80.8% sensitivity and 100% specificity (area under the curve, 95.3%). A cutoff SUVmax of 7.5 yields 100% specificity, and a cutoff SUVmax of 4.4 yields a 100% negative predictive value (NPV). The combination of PET/CT and lactate dehydrogenase (LDH) levels had a sensitivity of 86.6%, specificity of 100%, positive predictive value of 100%, and an NPV of 90.4%. No relation between histopathology or International Federation of Gynecology and Obstetrics (FIGO) stage and 18-fluoro-2-deoxy-d-glucose uptake value on PET/CT was seen. The surgical outcome trended toward a correlation with the SUVmax, although this was not statistically significant. CONCLUSIONS: In patients with MRI findings consistent with either uterine sarcoma or leiomyoma, PET/CT can decrease the false-positive rate by setting an optimal cutoff SUVmax of 7.5. Using this cutoff can avoid unnecessary surgery. PMID- 28805610 TI - Validation of a high-throughput and robust technique: BACs-on-beads assay (KaryoLite BoBs) for pre-implantation aneuploidy screening. AB - OBJECTIVE: This study aims to validate the BACs-on-Beads (BoB) technology as a robust and high throughput method for pre-implantation genetic screening (PGS) for aneuploidy. MATERIAL AND METHODS: The performances with respect to the sensitivity, specificity, success rate and detection rate of this technique from new BoBs technology and traditional array chromosomal genomic hybridization (aCGH) were compared. And the use of BoBs as a screening tool for euploid embryos in PGS was evaluated. RESULT: In the first part of validation study, there were total 75 embryos completed PGS by both BoBs and aCGH. The success rate of PGS was 97.4%, and the results showed 100% concordance between BoBs and aCGH for aneuploidy. In the second part, a total 219 embryos were involved. The success rate of PGS by BoBs was 100%. BoBs identified 28% (62/219) euploidy which were further confirmed to be euploidy by aCGH. CONCLUSION: This new strategic approach using BoBs as a first tier PGS screening tool and aCGH as a confirmatory tool can increase the throughput of PGS with a reduced cost and time to meet the demand in high volume units. PMID- 28805611 TI - Propofol in combination with remifentanil for cesarean section: Placental transfer and effect on mothers and newborns at different induction to delivery intervals. AB - OBJECTIVE: This study aims to describe the administration of propofol in combination with remifentanil for the induction of general anesthesia during cesarean section (CS). Our aim was to evaluate its impact on the drug concentrations of the maternal and neonatal blood at different induction of anesthesia to delivery (I-D) intervals as well as its effect on newborns. MATERIALS AND METHODS: In this double-blind randomized controlled study, patients undergoing elective CS were administered anesthesia at short (n = 20) or long (n = 20) I-D intervals. Anesthesia was induced with 1 mg/kg propofol and 1 MUg/kg remifentanil and maintained by continuous infusion of 3 mg/kg/h propofol and 7 MUg/kg/h remifentanil. RESULTS: The mean plasma propofol concentrations at delivery in the maternal arterial (MA) blood and the fetal umbilical arterial (UA) and venous (UV) blood in the short I-D interval group were 1.91, 1.17, and 0.51 MUg/mL, respectively, while those in the long I-D interval group were 1.57, 1.07, and 0.61 MUg/mL, respectively. The mean plasma remifentanil concentrations at delivery in the MA, UA, and UV in the short I-D interval group were 2.25, 1.43, and 0.65 ng/mL, respectively, and those in the long I-D interval group were 1.96, 1.25, and 0.75 ng/mL, respectively. There were no statistically significant differences in the neonatal Apgar scores and neurological adaptive capacity scores between the two groups. CONCLUSIONS: It is safe to administer propofol in combination with remifentanil by continuous infusion after the bolus dose for the induction of anesthesia during cesarean section. Prolonging the I-D interval within a certain limit will not have any significant influence on the fetus. PMID- 28805612 TI - Detection of paternal uniparental disomy 9 in a neonate with prenatally detected mosaicism for a small supernumerary marker chromosome 9 and a supernumerary ring chromosome 9. AB - OBJECTIVE: We present the association of paternal uniparental disomy (UPD) 9 with mosaicism for a small supernumerary marker chromosome 9 [sSMC(9)] and a supernumerary ring chromosome 9 [r(9)]. MATERIALS AND METHODS: A 38-year-old woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 47,XY,+mar [25]/48,XY,+mar,+r(9) [4]/47,XY,+r(9) [1]/46,XY [6]. The parental karyotypes were normal. Array comparative genomic hybridization (aCGH) of cultured amniocytes revealed a result of de novo 9p13.1q21.11 (38,792,472-71,026,063) * 2.64. The marker chromosome was determined to be an sSMC(9) by spectral karyotyping and aCGH. A phenotypically normal baby was delivered at 38 weeks of gestation. During pediatric follow-ups at age two years, the neonate manifested normal psychomotor and growth development. Cytogenetic analysis, metaphase fluorescence in situ hybridization (FISH), single nucleotide polymorphism (SNP) aCGH and polymorphic DNA marker analysis were performed on the peripheral blood of the neonate. RESULTS: The neonate's blood had the following results. Metaphase FISH confirmed coexistence of the sSMC(9) and the supernumerary r(9). The karyotype was 47,XY,+sSMC(9) [14]/48,XY, +sSMC(9),+r(9) [10]/47,XY,+r(9) [6]/46,XY [10]. SNP aCGH revealed arr 9p22.3q21.11 (14,234,165-71,035,608) * 2-3, arr 9p24.3p22.3 (216,123-14,629,321)hmz, arr 9p21.3p13.2 (24,769,722-36,732,597)hmz and arr 9q21.11q34.3 (71,013,799-141,011,581)hmz. Polymorphic DNA marker analysis showed paternal isodisomy 9. CONCLUSION: Individuals with mosaicism for sSMC(9) and supernumerary r(9) may be associated with paternal UPD 9. PMID- 28805613 TI - A complicated urethrovaginal fistula following an inappropriate urethral diverticulum management. AB - OBJECTIVE: Urethral diverticulum is uncommon, therefore appropriate evaluation, preoperative planning and counseling must be done in order to make correct diagnosis and prevent complications. MATERIALS AND METHODS: A case of anterior vaginal wall mass was treated elsewhere by a gynecologist as periurethral cyst abscess; incision and drainage were done but a symptom of pus discharge was observed after 2 weeks. Therefore, exploration, cyst wall excision and primary closure were done though histopathological examination surprisingly confirmed the presence of urethral tissue suggestive of diverticulum. RESULTS: Subsequently, she developed persistent urinary leakage along with urethrovaginal fistula for which they again performed pervaginal multilayer closure. Patient was later referred to us with recurrent urethrovaginal fistula. We performed posterior urethral fistulectomy with anterior vaginal wall flap and multilayer closure. Three years follow up reveals complete recovery. CONCLUSION: Even urethral diverticulum is a rare condition, should be kept in mind as early diagnosis and management. PMID- 28805614 TI - Pregnancy with asymptomatic uterine complete rupture after uterine artery embolization for postpartum hemorrhage. AB - OBJECTIVE: Uterine artery embolization has become an effective treatment for postpartum hemorrhage. The safety of pregnancy after uterine artery embolization for postpartum hemorrhage has been established. CASE REPORT: We present the case of a pregnant woman with asymptomatic uterine complete rupture who underwent uterine artery embolization for a previous placenta previa. She had not been diagnosed with uterine rupture until cesarean section was performed, and fortunately, we obtained the best maternal and neonatal outcomes. CONCLUSION: Many studies have been reported that uterine artery embolization for postpartum hemorrhage did not affect subsequent pregnancy outcomes. However, we report that this procedure contains a potential risk for asymptomatic uterine rupture in a subsequent pregnancy. Although it is difficult to diagnose uterine rupture without symptoms, the obstetrician should be aware of the possibility of uterine rupture. PMID- 28805615 TI - Prenatal diagnosis of holoprosencephaly associated with Smith-Lemli-Opitz syndrome (SLOS) in a 46,XX fetus. AB - OBJECTIVE: To show the importance of measuring cholesterol precursor levels in amniotic fluid in all pregnancies with ultrasound features (such as holoprosencephaly) suggestive of Smith-Lemli-Opitz syndrome (SLOS), after exclusion of chromosomal anomalies. CASE REPORT: A 28-year-old woman, gravida 1 para 0, performed chorionic villus sampling for fetal karyotyping at 13 weeks of gestation due to positive combined first trimester screening in a fetus with increased nuchal translucency and suspected holoprosencephaly. The result was normal - 46,XX. The diagnosis of alobar holoprosencephaly was confirmed at 15 weeks of gestation, and cardiac and limb defects were also identified. Thus, a syndromic cause was considered, specifically a chromosomal microdeletion syndrome or a monogenic entity such as SLOS. The latter was confirmed by measuring 7 dehydrocholesterol (7DHC) and 8-dehydrocholesterol (8DHC) in amniotic fluid. Molecular analysis of DHCR7 gene identified a homozygous mutation in intron 8, c.964-1G>C, providing molecular confirmation for this diagnosis. CONCLUSION: The differential diagnosis of holoprosencephaly is broad. Identification of the cause of holoprosencephaly aids in establishing the prognosis and is essential to ascertain the mode of inheritance for adequate genetic counseling. PMID- 28805616 TI - Prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome derived from chromosome 16. AB - OBJECTIVE: We present prenatal diagnosis and molecular cytogenetic characterization of a small supernumerary marker chromosome (sSMC) derived from chromosome 16. CASE REPORT: A 28-year-old woman underwent amniocentesis at 17 weeks of gestation because of abnormal maternal serum screening for Down syndrome. Amniocentesis revealed a karyotype of 47,XY,+mar[5]/46,XY[9]. Parental karyotypes were normal. Prenatal ultrasound findings were unremarkable. Array comparative genomic hybridization (aCGH) analysis of cultured amniocytes revealed a de novo 16% gene dosage increase of 16q11.2-q22.1. Repeat amniocentesis at 21 weeks of gestation revealed a karyotype of 47,XY,+mar[10]/46,XY[31]. aCGH analysis of uncultured amniocytes revealed a result of arr 16q11.2q22.1 (46,492,626-68,867,969) * 2.20 with a log2 ratio of 0.15 encompassing RPGRIP1L, FTO, SLC6A2, BBS2 and CDH1. Interphase fluorescence in situ hybridization (FISH) analysis on uncultured amniocytes detected partial trisomy 16q in 36/137 (26.3%) of uncultured amniocytes. Polymorphic DNA marker analysis on amniocytes and parental bloods excluded uniparental disomy 16. Premature labor occurred at 25 weeks of gestation, and a 585-g male baby without craniofacial dysmorphism was delivered and survived. At age 11/2 years, pediatric follow-ups revealed normal psychomotor development, normal body weight, short stature, congenital hypothyroidism, hearing impairment and hypospadias in the neonate, and the peripheral blood had a karyotype of 46,XY in 40 cultured lymphocytes. CONCLUSION: aCGH, interphase FISH and polymorphic DNA marker analyses of uncultured amniocytes are useful for confirmation of prenatally detected mosaic sSMCs at amniocentesis. PMID- 28805617 TI - Molecular cytogenetic characterization of a duplication of 15q24.2-q26.2 associated with anencephaly and neural tube defect. AB - OBJECTIVE: We present molecular cytogenetic characterization of a duplication of 15q24.2-q26.2 associated with anencephaly and neural tube defect (NTD). CASE REPORT: A 35-year-old pregnant woman was found to have a fetus with anencephaly by prenatal ultrasound at 12 weeks of gestation. The pregnancy was subsequently terminated, and a malformed fetus was delivered with anencephaly. Cytogenetic analysis of the cultured placental tissues revealed a karyotype of 46,XX,dup(15) (q24.2q26.2). Parental karyotypes were normal. Array comparative genomic hybridization analysis of the placental tissues revealed a 20.36-Mb duplication of 15q24.2-q26.2 encompassing 100 Online Mendelian Inheritance of in Man (OMIM) genes including LINGO1, MTHFS, KIF7 and CHD2. Metaphase fluorescence in situ hybridization analysis using 15q25.1-specidic probe confirmed a duplication of 15q25.1. Polymorphic DNA marker analysis showed a maternal origin of the duplication. CONCLUSION: A duplication of chromosome 15q24.2-q26.2 can be associated with NTD. PMID- 28805619 TI - Intrauterine fetal death caused by seatbelt injury. AB - OBJECTIVE: Severe motor vehicle accidents involving pregnant women can result in fetal and neonatal death. We describe a case in which fetal death occurred due to relatively mild seatbelt injuries and present the characteristic magnetic resonance imaging (MRI) findings of the placenta. CASE REPORT: A 26-year-old primigravid woman at 20 weeks gestation was involved in an automobile accident. Although she suffered only a seatbelt injury, fetal death subsequently occurred. Contrast-enhanced MRI showed the region compressed by the seatbelt as a low intensity band without enhancement, and serum alpha-fetoprotein and hemoglobin F levels were elevated. CONCLUSION: Careful monitoring, including blood and abdominal examinations, should be performed when pregnant women suffer seatbelt injuries. PMID- 28805618 TI - Prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome derived from chromosome 21q11.2-q21.1 and a literature review. AB - OBJECTIVE: We present prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome (sSMC) derived from chromosome 21q11.2-q21.1, and we review the literature of an sSMC(21) with a duplication of 21q11.2-q21.1. CASE REPORT: A 40-year-old woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 47,XX,+mar [18]/46,XX [4]. The parental karyotypes were normal. Prenatal ultrasound findings were unremarkable. aCGH analysis of cultured amniocytes revealed a 2.855-Mb duplication of 21q11.2 q21.1 encompassing the genes of LIPI, ABCC13 and NRIP1. Metaphase fluorescence in situ hybridization analysis on cultured amniocytes revealed a result of 47,XX,+mar .ish der(13/21) (D13/21Z1+) [10]. Spectral karyotyping analysis determined the origin of chromosome 21 in the sSMC. A female fetus was delivered with no phenotypic features of Down syndrome and no structural abnormalities. We discuss the genotype-phenotype correlation of LIPI, ABCC13 and NRIP1, and review the literature of an sSMC(21) associated with dup(21)(q11.2q21.1). CONCLUSION: aCGH is useful for identification of the nature and genetic component of a prenatally detected sSMC. PMID- 28805620 TI - Ex utero intrapartum treatment for extremely low birth-weight neonates requiring resuscitation at birth. AB - OBJECTIVE: Difficulties often encountered during intubation in extremely low birth-weight (ELBW) neonates requiring resuscitation at birth because of the smaller airway and the pressure from the limited number of attempts before hemodynamic instability occurs. CASE REPORT: We evaluated two pregnant women at 26 weeks of gestation with premature rupture of membranes and evidence of chorioamnionitis and applied the concept of ex utero intrapartum treatment, which involved delaying cord clamping (DCC) after establishing a secured airway with adequate ventilation during cesarean delivery. The resuscitative procedure was smooth and all three neonates had favorable outcomes at one month of age. CONCLUSION: When cesarean delivery is indicated in ELBW infants and intubation after birth is anticipated, DCC after establishing a secured airway may help maintain neonatal cardiovascular stability and allow physicians to resolve the technical difficulties of intubation. PMID- 28805622 TI - Prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome derived from chromosome 21. PMID- 28805621 TI - Benign metastasizing leiomyomas thought to be nodal metastases in a case of ovarian cancer. PMID- 28805623 TI - Prenatal diagnosis of mosaicism for trisomy 2 in a single colony at amniocentesis in a pregnancy with a favorable outcome. PMID- 28805624 TI - Prenatal diagnosis of a sporadic Apert syndrome by 3-D ultrasound and 3-D helical computerized tomography. PMID- 28805625 TI - Congenital sick sinus syndrome: Prenatal diagnosis and postnatal follow-up. PMID- 28805626 TI - Reply to "Need for an up to date and comprehensive risk factor analysis to determine the lifetime risk of uterine corpus cancer in Taiwan women". PMID- 28805627 TI - The rules of computerized cardiotocography and middle cerebral artery for diagnosis of fetomaternal hemorrhage. PMID- 28805628 TI - Aortic balloon occlusion: Justifiable for placenta previa without accreta? PMID- 28805629 TI - Need for an up to date and comprehensive risk factor analysis to determine the lifetime risk of uterine corpus cancer in Taiwan women. PMID- 28805630 TI - Implications of autophagy on arbovirus infection of mosquitoes. AB - Arthropod-borne (arbo-) viruses, like all viruses, are obligate intracellular parasites that have evolved mechanisms to subvert cellular processes and evade anti-viral defenses to replicate and persist. An increasing body of research is beginning to recognize the intimate relationship between arboviruses and the cellular autophagy pathway. As a result, new therapeutic approaches that modify the autophagic response to viral infection have shown great promise. The preponderance of work thus far, however, has originated from vertebrate systems. Efforts to elucidate the role of autophagy during arbovirus infection of invertebrates have emerged, providing new insights into arbovirus-vector interactions; interactions that could be exploited for novel control strategies. PMID- 28805631 TI - Bumble bee ecophysiology: integrating the changing environment and the organism. AB - Bumble bees are among the most ecologically and economically important pollinators worldwide, yet many of their populations are being threatened by a suite of interrelated, human-mediated environmental changes. Here, I discuss recent progress in our understanding of bumble bee ecophysiology, including advances related to thermal biology in light of global warming; nutritional biology in the context of declining food resources; and the capacity for bumble bees to exhibit physiological plasticity or adaptations to novel or extreme environments, with reference to their evolutionary history and current biogeography. PMID- 28805632 TI - Juvenile hormone and hemimetabolan eusociality: a comparison of cockroaches with termites. AB - Termites are social Dictyoptera that evolved eusociality independently from social Hymenoptera. They are characterized by unique developmental plasticity that is the basis of caste differentiation and social organization. As developmental plasticity is a result of endocrine regulation, in order to understand the evolution of termite sociality it is helpful to compare the endocrine underpinning of development between termites and cockroaches. Nijhout and Wheeler (1982) proposed that varying JH titers determine caste differentiation in termites. Based on current results, we extend this model by adding the importance of social interactions. High JH titers in the presence of soldiers lead to regressive development (decrease in body size, apparent regression in development), while an absence of soldiers induces (pre-)soldier differentiation. On the opposite side, low JH titers in colonies headed by reproductives result in progressive molts toward adults, while an absence of reproductives induces development of replacement reproductives. In cockroaches, transcription factors involved in JH signaling, including the adult specifier E93 (the co-called MEKRE93 pathway) regulate the morphogenetic transition between the nymph and the adult. In termites, we speculate that castes might be determined by social effects playing a modulatory action of JH in the MEKRE93 pathway. PMID- 28805633 TI - Of phlebotomines (sandflies) and viruses: a comprehensive perspective on a complex situation. AB - Old World sandfly-borne phleboviruses are classified into three serological complexes: Sandfly fever Sicilian, Sandfly fever Naples and Salehabad. Human pathogens (febrile illness ['sandfly fever'], neuroinvasive infections) belong to the two first complexes. The increasing number of newly discovered sandfly-borne phleboviruses raises concerns about their medical and veterinary importance. They occupy a wide geographic area from Mediterranean basin to North Africa and the Middle East to the central Asia. At least nine species of sandflies can transmit these viruses. Recent results suggest that sandfly vectors are not as specific for viruses as initially believed. Recent seroprevalence studies demonstrate that humans and domestic animals are heavily exposed. Specific molecular diagnostic methods must be developed and implemented in clinical microbiology laboratories. PMID- 28805634 TI - Honey bee gut dysbiosis: a novel context of disease ecology. AB - The honey bee microbiota has become a hot-spot of recent research. Highly co evolved with its host, the hindgut microbiota of a worker honey bee consists of six bacterial species shown to occur reliably in particular proportions. Altered microbiota structure is associated with host deficiencies, and a variety of bacteria found throughout the hive environment can dominate the worker gut suppressing or displacing microbiota function. The synthesis presented here suggests environmental insults alter gut bacterial balance, leading to decreased host function and disease progression. Specific functional groups of native bacteria represent a model system to investigate dysbiosis and the evolution of host tolerance/resistance traits in honey bee-microbe interactions. PMID- 28805635 TI - Mosquito-specific and mosquito-borne viruses: evolution, infection, and host defense. AB - Recent virus discovery programs have identified an extensive reservoir of viruses in arthropods. It is thought that arthropod viruses, including mosquito-specific viruses, are ancestral to vertebrate-pathogenic arboviruses. Mosquito-specific viruses are restricted in vertebrate cells at multiple levels, including entry, RNA replication, assembly, and by the inability to replicate at high temperatures. Moreover, it is likely that the vertebrate immune system suppresses replication of these viruses. The evolution from single to dual-host tropism may also require changes in the course of infection in the mosquito host. In this review we explore the adaptive changes required for a switch from a mosquito specific to a mosquito-borne transmission cycle. PMID- 28805636 TI - West Nile virus and its vectors. AB - West Nile virus (WNV Flaviviridae; Flavivrus) is the most geographically widespread arbovirus in the world and the leading cause of arboviral encephalitis globally. Worldwide, WNV is maintained in an enzootic cycle between primarily Culex spp. mosquitoes and birds, with human infection and disease resulting from enzootic spillover. Dynamic and complex intrinsic and extrinsic factors contribute to the temporal and spatial variability in WNV transmission. The most current information on the relative contribution of each of these factors is reviewed and a case to incorporate detailed and localized environmental and genetic data into predictive models is presented. PMID- 28805637 TI - Wolbachia-mediated virus blocking in the mosquito vector Aedes aegypti. AB - Viruses transmitted by mosquitoes such as dengue, Zika and West Nile cause a threat to global health due to increased geographical range and frequency of outbreaks. The bacterium Wolbachia pipientis may be the solution reducing disease transmission. Though commonly missing in vector species, the bacterium was artificially and stably introduced into Aedes aegypti to assess its potential for biocontrol. When infected with Wolbachia, mosquitoes become refractory to infection by a range of pathogens, including the aforementioned viruses. How the bacterium is conferring this phenotype remains unknown. Here we discuss current hypotheses in the field for the mechanistic basis of pathogen blocking and evaluate the evidence from mosquitoes and related insects. PMID- 28805638 TI - Nonretroviral integrated RNA viruses in arthropod vectors: an occasional event or something more? AB - With few exceptions, all arthropod-borne viruses (arboviruses) are nonretroviral RNA viruses (NRVs). Despite NRVs do not encode reverse transcriptases and integrases, NRVs-DNA fragments are detected in mosquito cells and mosquitoes at early stages of infection as episomal DNA forms. Additionally, next generation sequencing and bioinformatics analyses have convincingly shown NRVs-vDNA integrated in vector genomes. We hypothesize vDNA role may be linked to host immunity and viral persistence. Key questions remain about nonretroviral integrated RNA virus sequences (NIRVS) in mosquitoes such as what is driving vDNA synthesis from NRVs, how does integration occur and what is their biological function. Here we review current knowledge about NIRVS highlighting connections with host immunity and virus-vector co-evolution and we suggest directions for future research. PMID- 28805639 TI - Development and evolution of brain allometry in wasps (Vespidae): size, ecology and sociality. AB - We review research on brain development and brain evolution in the wasp family Vespidae. Basic vespid neuroanatomy and some aspects of functional neural circuitry are well-characterized, and genomic tools for exploring brain plasticity are being developed. Although relatively modest in terms of species richness, the Vespidae include species spanning much of the known range of animal social complexity, from solitary nesters to highly eusocial species with some of the largest known colonies and multiple reproductives. Eusocial species differ in behavior and ecology including variation in queen/worker caste differentiation and in diurnal/nocturnal activity. Species differences in overall brain size are strongly associated with brain allometry; relative sizes of visual processing tissues increase at faster rates than antennal processing tissues. The lower relative size of the central-processing mushroom bodies (MB) in eusocial species compared to solitary relatives suggests sociality may relax demands on individual cognitive abilities. However, queens have greater relative MB volumes than their workers, and MB development is positively associated with social dominance status in some species. Fruitful areas for future investigations of adaptive brain investment in the clade include sampling of key overlooked taxa with diverse social structures, and the analysis of neural correlations with ecological divergence in foraging resources and diel activity patterns. PMID- 28805640 TI - Nutritional, endocrine, and social influences on reproductive physiology at the origins of social behavior. AB - Understanding the evolutionary origins of social behavior in insects requires understanding the physiological basis for reproductive plasticity. Solitary bees and wasps or those living in small, flexible societies will be key to understanding how conserved pathways have evolved to give rise to reproductive castes. Nutrient-sensing and endocrine pathways are decoupled from reproduction in some life stages of social insects. Heterochrony, particularly as it is related to diapause physiology, may be an important mechanism by which this decoupling occurs. Additional research is needed to understand how these pathways became sensitive to cues from the social environment. Future research targeting species with a diversity of social behaviors and diapause strategies will be key to understanding the physiological basis of social evolution. PMID- 28805641 TI - Culicoides-virus interactions: infection barriers and possible factors underlying vector competence. AB - In the United States, Culicoides midges vector arboviruses of economic importance such as Bluetongue Virus and Epizootic Hemorrhagic Disease Virus. A limited number of studies have demonstrated the complexities of midge-virus interactions, including dynamic changes in virus titer and prevalence over the infection time course. These dynamics are, in part, dictated by mesenteron infection and escape barriers. This review summarizes the overarching trends in viral titer and prevalence throughout the course of infection. Essential barriers to infection and dissemination in the midge are highlighted, along with heritable and extrinsic factors that likely contribute to these barriers. Next generation molecular tools and techniques, now available for Culicoides midges, give researchers the opportunity to test how these factors contribute to vector competence. PMID- 28805643 TI - The evolution of cuticular fertility signals in eusocial insects. AB - A reproductive division of labor is a definitive characteristic of eusocial insect societies and it requires a means through which colony members can assess the presence and productivity of reproductive individuals. Cuticular hydrocarbons are the primary means of doing so across eusocial hymenopterans. However, recent experimental work presents conflicting views on how these chemical signals function, are interpreted by workers, and evolve. These recent advances include demonstrations of hydrocarbons as evolutionarily conserved 'queen pheromones' and as species-divergent 'fertility signals' used by both queens and workers. In this review, we synthesize conflicting studies into an evolutionary framework suggesting a transition of reproductive communication from cue-like signature mixtures, to learned fertility signals, to innate queen pheromones that evolved across eusocial insects. PMID- 28805642 TI - Hytrosaviruses: current status and perspective. AB - Salivary gland hytrosaviruses (SGHVs) are entomopathogenic dsDNA, enveloped viruses that replicate in the salivary glands (SGs) of the adult dipterans, Glossina spp (GpSGHV) and Musca domestica (MdSGHV). Although belonging to the same virus family (Hytrosaviridae), SGHVs have distinct morphologies and pathobiologies. Two GpSGHV strains potentially account for the differential pathologies in lab-bred tsetse. New data suggest incorporation of host-derived cellular proteins and lipids into mature SGHVs. In addition to within the SGs, MdSGHV undergoes limited replication in the corpora allata, potentially disrupting hormone biosynthesis, and GpSGHV replicates in the milk glands providing a transmission conduit to progeny tsetse. Whereas MdSGHV is a potential biocontrol agent, the vertically transmitted GpSGHV is unsuitable for tsetse vector control but does jeopardize tsetse mass rearing. PMID- 28805644 TI - Weak links: how colonies counter the social costs of individual variation in thermal physiology. AB - Social insect nestmates often differ in thermal tolerance (the range of temperatures at which an individual functions). Worker thermal physiology can covary with body size, development, genetics and gene expression. Because colonies rely on the integration of diverse colony members, individual thermal tolerance differences can affect group performance. The weak link hypothesis states that if workers differ in thermal sensitivity, then in variable thermal environments colonies can incur performance costs due to thermal stress effects on the most thermally sensitive worker types. We discuss possible adaptive colony responses that ameliorate the costs of thermal weak links. Individual differences in thermal tolerance have profound implications for the effects of temperature variation and climate change on animal societies. Social implications of worker weak links potentially drive macroecological patterns in caste ergonomics. PMID- 28805646 TI - Editorial overview: Vectors and medical and veterinary entomology: Becoming vectors or victims, the intriguing interplay between insects and viruses. PMID- 28805645 TI - Evolutionary feedbacks between insect sociality and microbial management. AB - Fitness-determining interactions with microbes-in particular fungi-have often been considered a by-product of social evolution in insects. Here, we take the view that both beneficial and harmful microbial consortia are major drivers of social behaviours in many insect systems-ranging from aggregation to eusociality. We propose evolutionary feedbacks between the insect sociality and microbial communities that strengthen mutualistic interactions with beneficial (dietary or defensive) microbes and simultaneously increase the capacity to defend against pathogens (i.e. social immunity). We identified variation in habitat stability-as determined by breeding site predictability and ephemerality-as a main ecological factor that constrains these feedbacks. To test this hypothesis we suggest following the evolution of insect social traits upon experimental manipulation of habitat stability and microbial consortia. PMID- 28805647 TI - Editorial overview: Social insects: Integrative approaches to understanding insect sociality: why physiology is still highly relevant. PMID- 28805648 TI - Fabrication of highly luminescent and concentrated quantum dot/poly(methyl methacrylate) nanocomposites by matrix-free methods. AB - We present matrix-free methods for fabricating highly luminescent and transparent CdSe/ZnS quantum dot (QD)/polymer nanocomposites utilizing poly(methyl methacrylate) (PMMA)-grafted QDs with various molecular weights. We found that the QD-PMMA nanocomposites prepared by these matrix-free methods were superior to those prepared by a simple blending method in relation to their optical property, QD dispersion, and quantum efficiency (QE). In particular, a matrix-free nanocomposite containing PMMA with a molecular weight of 2000 had the highest QE (52.8%) and transmittance of all the samples studied even at a very high QD concentration (49 wt%). This finding was attributed to the enhanced passivation of the QD surface due to the higher grafting density of the PMMA ligands and reduced energy transfer due to more uniform dispersion of QDs. Finally, we applied the nanocomposites to LED devices, and found that the matrix-free nanocomposite exhibited a higher color conversion efficiency and smaller redshift in the peak emission wavelength than that prepared using a simple blending method. PMID- 28805649 TI - Aging-resistant nanofluids containing covalent functionalized boron nitride nanosheets. AB - Developing a thermally stable nanofluid that can maintain good thermo-conductive and flow performance at moderate or elevated temperatures for prolonged periods of time is a great challenge in heat transfer applications. Here, the thermal conductivity and rheological properties as well as their thermal stability characteristics of a nanofluid containing two-dimensional (2D) hexagonal boron nitride nanosheets (h-BNNSs) in ethylene glycol (EG) are presented, in comparison with those for a graphene oxide (GO) nanofluid as a counterpart. In place of a surfactant, hydroxyl functional groups covalently bound to the BNNS surface provided excellent compatibility and stable dispersion of the particles within EG at temperatures up to 90 degrees C. Owing to the percolation effect of the 2D sheets, the thermal conductivity of the EG base fluid was significantly enhanced by 80% at 5 vol% of BNNS, superior to that of the GO fluid. Moreover, the BNNS fluids exhibited excellent long-term stability at 90 degrees C for 5 d without loss of their high thermal conductivity, low viscosity and electrical insulating property, whereas the GO fluids underwent thermal degradation with irreversible particle aggregation and increasing viscosity due to the selective chemical reduction of the surface functional groups (i.e., C-O groups) of the GO. PMID- 28805650 TI - The status of varying constants: a review of the physics, searches and implications. AB - The observational evidence for the recent acceleration of the universe demonstrates that canonical theories of cosmology and particle physics are incomplete-if not incorrect-and that new physics is out there, waiting to be discovered. A key task for the next generation of laboratory and astrophysical facilities is to search for, identify and ultimately characterize this new physics. Here we highlight recent developments in tests of the stability of nature's fundamental couplings, which provide a direct handle on new physics: a detection of variations will be revolutionary, but even improved null results provide competitive constraints on a range of cosmological and particle physics paradigms. A joint analysis of all currently available data shows a preference for variations of alpha and MU at about the two-sigma level, but inconsistencies between different sub-sets (likely due to hidden systematics) suggest that these statistical preferences need to be taken with caution. On the other hand, these measurements strongly constrain Weak Equivalence Principle violations. Plans and forecasts for forthcoming studies with facilities such as ALMA, ESPRESSO and the ELT, which should clarify these issues, are also discussed, and synergies with other probes are briefly highlighted. The goal is to show how a new generation of precision consistency tests of the standard paradigm will soon become possible. PMID- 28805651 TI - Electrodeposition of vertically standing Ag nanoplates and nanowires on transparent conductive electrode using porous anodic aluminum oxide template. AB - We report fabricating vertically standing Ag nanoplates and nanowires on a transparent conductive substrate of indium tin oxides (ITO) with the assistance of a porous anodic aluminum oxide (AAO) template. Two-dimensional Ag nanoplates can be electrodeposited onto an AAO covered ITO surface without using an adhesion layer. Ag nanoplates obtained using AAO templates have 3 * {222} superlattice fringes, different from the 3 * {422} superlattice fringes reported in the previous study. Ag nanowires can be electrodeposited onto ITO which is initially covered with an AAO template through a conductive polymer poly (3,4 ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS). The coverage, diameter, and thickness of Ag nanoplates are strongly dependent on the electrodeposition time. These Ag nanoplates and nanowires are used for surface enhanced Raman spectroscopy (SERS) and the influence of their shape, size, and coverage on SERS enhancement is studied. PMID- 28805652 TI - Alloy multilayers and ternary nanostructures by direct-write approach. AB - The fabrication of nanopatterned multilayers, as used in optical and magnetic applications, is usually achieved by two independent steps, which consist in the preparation of multilayer films and in the successive patterning by means of lithography and etching processes. Here we show that multilayer nanostructures can be fabricated by using focused electron beam induced deposition (FEBID), which allows the direct writing of nanostructures of any desired shape with nanoscale resolution. In particular, [Formula: see text] multilayers are prepared by the alternating deposition from the metal carbonyl precursors, [Formula: see text] and [Formula: see text], and neopentasilane, [Formula: see text]. The ability to fabricate nanopatterned multilayers by FEBID is of interest for the realization of hyperbolic metamaterials and related nanodevices. In a second experiment, we treated the multilayers by low-energy electron irradiation in order to induce atomic species intermixing with the purpose to obtain ternary nanostructured compounds. Transmission electron microscopy and electrical transport measurements indicate that in thick multilayers, (n = 12), the intermixing is only partial, taking place mainly in the upper part of the structures. However, for thin multilayers, (n = 2), the intermixing is such that a transformation into the L21 phase of the Co2FeSi Heusler compound takes place over the whole sample volume. PMID- 28805653 TI - Magneto-optical properties of topological insulator thin films with broken inversion symmetry. AB - We determine the optical response of ultrathin film topological insulators in the presence of a quantizing external magnetic field taking into account both hybridization between surface states, broken inversion symmetry and explicit time reversal symmetry breaking by the magnetic field. We find that breaking of inversion symmetry in the system, which can be due to interaction with a substrate or electrical gating, results in Landau level crossings and opening of additional optical transition channels that were previously forbidden. We show that by tuning the hybridization and symmetry breaking parameters, a transition from the normal to a topological insulator phase occurs with measureable signatures in both static (dc) and dynamic (optical) conductivity. Moreover, we find that these signatures in the optical Hall conductivity remain robust against a significant range of disorder strength. PMID- 28805654 TI - Electronic and magnetic properties of multiferroic ScFeO3 available from diffraction experiments. AB - Abstract Electronic and magnetic properties of ferric ions (3d5) in multiferroic ScFeO3 are puzzling, in part because they are different from the only other multiferroic known to possess the same polar chemical structure, BiFeO3. Open questions about ScFeO3 can be addressed by confronting observations with results for G-type antiferromagnetism allowed by the lithium niobate (LiNbO3)-like parent R3c structure. Calculated structure factors for resonant x ray diffraction include all charge-like quadrupoles allowed by symmetry, and if experimental results for ScFeO3 subsequently imply they are different from zero then ferric ions cannot be in the high-spin 6S state. The same type of experiment can reveal the moment direction in the G-type antiferromagnetism, according to our calculations, and thereby contribute to understanding magnetic anisotropy. Furthermore, structure factors for magnetic neutron diffraction by ScFeO3 include Dirac multipoles that are time-odd and parity-odd, e.g., dipoles that are often called anapoles or toroidal moments. Apart from Dirac multipoles, the conventional approach to the interpretation of neutron Bragg diffraction data will be inadequate if ferric ions (Fe3?) are not in the high-spin 6S state, because the scattering amplitude includes more than simple dipole moments in the general case. . . PMID- 28805655 TI - Transfer of CVD-grown graphene for room temperature gas sensors. AB - An easy transfer procedure to obtain graphene-based gas sensing devices operating at room temperature (RT) is presented. Starting from chemical vapor deposition grown graphene on copper foil, we obtained single layer graphene which could be transferred onto arbitrary substrates. In particular, we placed single layer graphene on top of a SiO2/Si substrate with pre-patterned Pt electrodes to realize a chemiresistor gas sensor able to operate at RT. The responses to ammonia (10, 20, 30 ppm) and nitrogen dioxide (1, 2, 3 ppm) are shown at different values of relative humidity, in dark and under 254 nm UV light. In order to check the sensor selectivity, gas response has also been tested towards hydrogen, ethanol, acetone and carbon oxide. Finally, a model based on linear dispersion relation characteristic of graphene, which take into account humidity and UV light effects, has been proposed. PMID- 28805656 TI - Magnetically tuned photoelectric response observed in nanoscale Co-SiO2-Si structures. AB - We report a large magnetically tuned lateral photovoltaic effect (LPE) observed in nanoscale Co-SiO2-Si structures. This tunable effect strongly depends on the location of two electrodes. The change ratio of lateral photovoltage (LPV) can reach a considerable value of 94.15% under an external magnetic field of 1.77 Teslas. This phenomenon is mainly ascribed to the asymmetric Lorentz force acting on the photo-current in the region of the edge area of the nanostructure. It adds a new functionality to traditional LPE-based devices, and provides a potential prospect for the development of multifunctional high-sensitive photoelectric devices or sensors. PMID- 28805657 TI - Noble-metal-free tungsten oxide/carbon (WOx/C) hybrid manowires for highly efficient hydrogen evolution. AB - Developing active, stable, and low-cost electrocatalysts to generate hydrogen is a great challenge in the fields of chemistry and energy. Nonprecious metal catalysts comprised of inexpensive and earth-abundant transition metals are regarded as a promising substitute for noble metal catalysts used in hydrogen evolution reaction (HER), but are still practically unfeasible mainly due to unsatisfactory activity and durability. Here we report a facile two-step preparation method for WOx nanowires with high concentration of oxygen vacancies (OVs) via calcination of W-polydopamine compound precursors. The resulting hybrid material possesses a uniform and ultralong 1D nanowires structure and a rough and raised surface, which can effectively improve the specific surface area. The products exhibit excellent performance for H2 generation: the required overpotentials for 1 and 10 mA cm-2 are 18 and 108 mV, the Tafel slope is 46 mV/decade, and the electrochemically active surface area is estimated to be ~77.0 m2 g-1. After 1000 cycles, the catalyst works well without significant current density drop. Our experimental results verified metallic transition metal oxides as superior non-Pt electrocatalysts for practical hydrogen evolution reactions. PMID- 28805658 TI - Nanofibrous photocatalysts from electrospun nanocapsules. AB - We present the design of multicompartment metal oxide/silica nanofibrous photocatalysts by colloid-electrospinning and subsequent calcination. During the calcination process, silica nanomaterials are cemented to form the fibrous framework and metal oxide precursors are crystallized inside and onto the fibers. This multicompartment nanofibrous structure, constructed with nanoparticles and core-shell nanocapsules, is therefore beneficial for the separation of the materials and the light utilization due to the multiple reflections and scattering of incident light in the cavities. The photocatalytic activity of the fibers was verified by the successful degradation of a model dye rhodamine B. This synthetic methodology is a universal approach for the fabrication of nanomaterials with hierarchical hollow structures, which are emerging in energy and environmental related applications. PMID- 28805659 TI - The atypical antipsychotic olanzapine causes weight gain by targeting serotonin receptor 2C. AB - Atypical antipsychotics such as olanzapine often induce excessive weight gain and type 2 diabetes. However, the mechanisms underlying these drug-induced metabolic perturbations remain poorly understood. Here, we used an experimental model that reproduces olanzapine-induced hyperphagia and obesity in female C57BL/6 mice. We found that olanzapine treatment acutely increased food intake, impaired glucose tolerance, and altered physical activity and energy expenditure in mice. Furthermore, olanzapine-induced hyperphagia and weight gain were blunted in mice lacking the serotonin 2C receptor (HTR2C). Finally, we showed that treatment with the HTR2C-specific agonist lorcaserin suppressed olanzapine-induced hyperphagia and weight gain. Lorcaserin treatment also improved glucose tolerance in olanzapine-fed mice. Collectively, our studies suggest that olanzapine exerts some of its untoward metabolic effects via antagonism of HTR2C. PMID- 28805660 TI - Prolyl hydroxylase 2 inactivation enhances glycogen storage and promotes excessive neutrophilic responses. AB - Fully activated innate immune cells are required for effective responses to infection, but their prompt deactivation and removal are essential for limiting tissue damage. Here, we have identified a critical role for the prolyl hydroxylase enzyme Phd2 in maintaining the balance between appropriate, predominantly neutrophil-mediated pathogen clearance and resolution of the innate immune response. We demonstrate that myeloid-specific loss of Phd2 resulted in an exaggerated inflammatory response to Streptococcus pneumonia, with increases in neutrophil motility, functional capacity, and survival. These enhanced neutrophil responses were dependent upon increases in glycolytic flux and glycogen stores. Systemic administration of a HIF-prolyl hydroxylase inhibitor replicated the Phd2 deficient phenotype of delayed inflammation resolution. Together, these data identify Phd2 as the dominant HIF-hydroxylase in neutrophils under normoxic conditions and link intrinsic regulation of glycolysis and glycogen stores to the resolution of neutrophil-mediated inflammatory responses. These results demonstrate the therapeutic potential of targeting metabolic pathways in the treatment of inflammatory disease. PMID- 28805661 TI - The FOXN3-NEAT1-SIN3A repressor complex promotes progression of hormonally responsive breast cancer. AB - The pathophysiological function of the forkhead transcription factor FOXN3 remains to be explored. Here we report that FOXN3 is a transcriptional repressor that is physically associated with the SIN3A repressor complex in estrogen receptor-positive (ER+) cells. RNA immunoprecipitation-coupled high-throughput sequencing identified that NEAT1, an estrogen-inducible long noncoding RNA, is required for FOXN3 interactions with the SIN3A complex. ChIP-Seq and deep sequencing of RNA genomic targets revealed that the FOXN3-NEAT1-SIN3A complex represses genes including GATA3 that are critically involved in epithelial-to mesenchymal transition (EMT). We demonstrated that the FOXN3-NEAT1-SIN3A complex promotes EMT and invasion of breast cancer cells in vitro as well as dissemination and metastasis of breast cancer in vivo. Interestingly, the FOXN3 NEAT1-SIN3A complex transrepresses ER itself, forming a negative-feedback loop in transcription regulation. Elevation of both FOXN3 and NEAT1 expression during breast cancer progression corresponded to diminished GATA3 expression, and high levels of FOXN3 and NEAT1 strongly correlated with higher histological grades and poor prognosis. Our experiments uncovered that NEAT1 is a facultative component of the SIN3A complex, shedding light on the mechanistic actions of NEAT1 and the SIN3A complex. Further, our study identified the ERalpha-NEAT1-FOXN3/NEAT1/SIN3A GATA3 axis that is implicated in breast cancer metastasis, providing a mechanistic insight into the pathophysiological function of FOXN3. PMID- 28805662 TI - Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes. AB - BACKGROUND: Targeting CD30 with monoclonal antibodies in Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) has had profound clinical success. However, adverse events, mainly mediated by the toxin component of the conjugated antibodies, cause treatment discontinuation in many patients. Targeting CD30 with T cells expressing a CD30-specific chimeric antigen receptor (CAR) may reduce the side effects and augment antitumor activity. METHODS: We conducted a phase I dose escalation study in which 9 patients with relapsed/refractory HL or ALCL were infused with autologous T cells that were gene-modified with a retroviral vector to express the CD30-specific CAR (CD30.CAR-Ts) encoding the CD28 costimulatory endodomain. Three dose levels, from 0.2 * 108 to 2 * 108 CD30.CAR-Ts/m2, were infused without a conditioning regimen. All other therapy for malignancy was discontinued at least 4 weeks before CD30.CAR-T infusion. Seven patients had previously experienced disease progression while being treated with brentuximab. RESULTS: No toxicities attributable to CD30.CAR-Ts were observed. Of 7 patients with relapsed HL, 1 entered complete response (CR) lasting more than 2.5 years after the second infusion of CD30.CAR-Ts, 1 remained in continued CR for almost 2 years, and 3 had transient stable disease. Of 2 patients with ALCL, 1 had a CR that persisted 9 months after the fourth infusion of CD30.CAR-Ts. CD30.CAR-T expansion in peripheral blood peaked 1 week after infusion, and CD30.CAR-Ts remained detectable for over 6 weeks. Although CD30 may also be expressed by normal activated T cells, no patients developed impaired virus-specific immunity. CONCLUSION: CD30.CAR-Ts are safe and can lead to clinical responses in patients with HL and ALCL, indicating that further assessment of this therapy is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01316146. FUNDING: National Cancer Institute (3P50CA126752, R01CA131027 and P30CA125123), National Heart, Lung, and Blood Institute (R01HL114564), and Leukemia and Lymphoma Society (LLSTR 6227-08). PMID- 28805664 TI - Correlation and Comparison of Cortical and Hippocampal Neural Progenitor Morphology and Differentiation through the Use of Micro- and Nano-Topographies. AB - Neuronal morphology and differentiation have been extensively studied on topography. The differentiation potential of neural progenitors has been shown to be influenced by brain region, developmental stage, and time in culture. However, the neurogenecity and morphology of different neural progenitors in response to topography have not been quantitatively compared. In this study, the correlation between the morphology and differentiation of hippocampal and cortical neural progenitor cells was explored. The morphology of differentiated neural progenitors was quantified on an array of topographies. In spite of topographical contact guidance, cell morphology was observed to be under the influence of regional priming, even after differentiation. This influence of regional priming was further reflected in the correlations between the morphological properties and the differentiation efficiency of the cells. For example, neuronal differentiation efficiency of cortical neural progenitors showed a negative correlation with the number of neurites per neuron, but hippocampal neural progenitors showed a positive correlation. Correlations of morphological parameters and differentiation were further enhanced on gratings, which are known to promote neuronal differentiation. Thus, the neurogenecity and morphology of neural progenitors is highly responsive to certain topographies and is committed early on in development. PMID- 28805663 TI - YAP/TAZ regulates sprouting angiogenesis and vascular barrier maturation. AB - Angiogenesis is a multistep process that requires coordinated migration, proliferation, and junction formation of vascular endothelial cells (ECs) to form new vessel branches in response to growth stimuli. Major intracellular signaling pathways that regulate angiogenesis have been well elucidated, but key transcriptional regulators that mediate these signaling pathways and control EC behaviors are only beginning to be understood. Here, we show that YAP/TAZ, a transcriptional coactivator that acts as an end effector of Hippo signaling, is critical for sprouting angiogenesis and vascular barrier formation and maturation. In mice, endothelial-specific deletion of Yap/Taz led to blunted-end, aneurysm-like tip ECs with fewer and dysmorphic filopodia at the vascular front, a hyper-pruned vascular network, reduced and disarranged distributions of tight and adherens junction proteins, disrupted barrier integrity, subsequent hemorrhage in growing retina and brain vessels, and reduced pathological choroidal neovascularization. Mechanistically, YAP/TAZ activates actin cytoskeleton remodeling, an important component of filopodia formation and junction assembly. Moreover, YAP/TAZ coordinates EC proliferation and metabolic activity by upregulating MYC signaling. Overall, these results show that YAP/TAZ plays multifaceted roles for EC behaviors, proliferation, junction assembly, and metabolism in sprouting angiogenesis and barrier formation and maturation and could be a potential therapeutic target for treating neovascular diseases. PMID- 28805665 TI - The Role of Solvent-Accessible Leu-208 of Cold-Active Pseudomonas fluorescens Strain AMS8 Lipase in Interfacial Activation, Substrate Accessibility and Low Molecular Weight Esterification in the Presence of Toluene. AB - The alkaline cold-active lipase from Pseudomonas fluorescens AMS8 undergoes major structural changes when reacted with hydrophobic organic solvents. In toluene, the AMS8 lipase catalytic region is exposed by the moving hydrophobic lid 2 (Glu 148 to Gly-167). Solvent-accessible surface area analysis revealed that Leu-208, which is located next to the nucleophilic Ser-207 has a focal function in influencing substrate accessibility and flexibility of the catalytic pocket. Based on molecular dynamic simulations, it was found that Leu-208 strongly facilitates the lid 2 opening via its side-chain. The KM and Kcat/KM of L208A mutant were substrate dependent as it preferred a smaller-chain ester (pNP caprylate) as compared to medium (pNP-laurate) or long-chain (pNP-palmitate) esters. In esterification of ethyl hexanoate, L208A promotes a higher ester conversion rate at 20 degrees C but not at 30 degrees C, as a 27% decline was observed. Interestingly, the wild-type (WT) lipase's conversion rate was found to increase with a higher temperature. WT lipase AMS8 esterification was higher in toluene as compared to L208A. Hence, the results showed that Leu-208 of AMS8 lipase plays an important role in steering a broad range of substrates into its active site region by regulating the flexibility of this region. Leu-208 is therefore predicted to be crucial for its role in interfacial activation and catalysis in toluene. PMID- 28805666 TI - Multiple Cracks Detection in Pipeline Using Damage Index Matrix Based on Piezoceramic Transducer-Enabled Stress Wave Propagation. AB - Cracks in oil and gas pipelines cause leakage which results in property damage, environmental pollution, and even personal injury or loss of lives. In this paper, an active-sensing approach was conducted to identify the crack damage in pipeline structure using a stress wave propagation approach with piezoceramic transducers. A pipeline segment instrumented with five distributed piezoceramic transducers was used as the testing specimen in this research. Four cracks were artificially cut on the specimen, and each crack had six damage cases corresponding to different crack depths. In this way, cracks at different locations with different damage degrees were simulated. In each damage case, one piezoceramic transducer was used as an actuator to generate a stress wave to propagate along the pipeline specimen, and the other piezoceramic transducers were used as sensors to detect the wave responses. To quantitatively evaluate the crack damage status, a wavelet packet-based damage index matrix was developed. Experimental results show that the proposed method can evaluate the crack severity and estimate the crack location in the pipeline structure based on the proposed damage index matrix. The sensitivity of the proposed method decreases with increasing distance between the crack and the mounted piezoceramic transducers. PMID- 28805667 TI - The Effect of a Standardized Ginger Extract on Chemotherapy-Induced Nausea Related Quality of Life in Patients Undergoing Moderately or Highly Emetogenic Chemotherapy: A Double Blind, Randomized, Placebo Controlled Trial. AB - Ginger supplementation could be an effective adjuvant treatment for chemotherapy induced nausea (CIN). The aim of this clinical trial was to address significant methodological limitations in previous trials. Patients (N = 51) were randomly allocated to receive either 1.2 g of standardised ginger extract or placebo per day, in addition to standard anti-emetic therapy, during the first three cycles of chemotherapy. The primary outcome was CIN-related quality of life (QoL) measured with the Functional Living Index- Emesis (FLIE) questionnaire. Secondary outcomes included acute and delayed nausea, vomiting, and retching as well as cancer-related fatigue, nutritional status, and CIN and vomiting-specific prognostic factors. Over three consecutive chemotherapy cycles, nausea was more prevalent than vomiting (47% vs. 12%). In chemotherapy Cycle 1, intervention participants reported significantly better QoL related to CIN (p = 0.029), chemotherapy-induced nausea and vomiting (CINV)-related QoL (p = 0.043), global QoL (p = 0.015) and less fatigue (p = 0.006) than placebo participants. There were no significant results in Cycle 2. In Cycle 3, global QoL (p = 0.040) and fatigue (p = 0.013) were significantly better in the intervention group compared to placebo. This trial suggests adjuvant ginger supplementation is associated with better chemotherapy-induced nausea-related quality of life and less cancer related fatigue, with no difference in adverse effects compared to placebo. PMID- 28805668 TI - Locally Sustainable School Lunch Intervention Improves Hemoglobin and Hematocrit Levels and Body Mass Index among Elementary Schoolchildren in Rural West Java, Indonesia. AB - School lunch is not provided in public elementary schools in Indonesia, and students frequently buy and eat snacks at school. We hypothesized that providing a traditional Sundanese meal as school lunch would be beneficial for children in rural West Java. To test this hypothesis, we evaluated the effect of a 1-month school lunch intervention aiming at sustainability and based on children's nutritional intake, hemoglobin and hematocrit levels, and body mass index (BMI). A lunch (including rice, vegetable dish, animal protein dish, plant protein dish, and fruit) containing one-third of the recommended daily allowance of energy was offered every school day for 1 month, targeting 68 fourth-grade elementary schoolchildren. At baseline, the prevalence of anemia was 33.3%. The prevalence of stunting and underweight were 32.4% and 2.9%, respectively, whereas that of overweight and obesity combined was 17.6%, indicating a double burden of malnutrition among the subjects. During the intervention, intakes of protein (p < 0.05), calcium (p < 0.05), and vitamin C (p < 0.001) significantly increased, while that of fat significantly decreased (p < 0.001). After the intervention, hemoglobin (p < 0.05) and hematocrit (p < 0.05) levels were significantly improved, thereby almost halving the rate of anemia. These changes were significantly larger in the baseline anemic group than the non-anemic group (p < 0.01). BMI significantly increased in the baseline underweight/normal group (p < 0.001) but not in the overweight/obese group. The school lunch intervention significantly improved nutritional intakes and health statuses, implying its potential for reducing anemia and resolving the double burden of malnutrition among rural Indonesian schoolchildren. PMID- 28805669 TI - Effect of Mediterranean Diet and Antioxidant Formulation in Non-Alcoholic Fatty Liver Disease: A Randomized Study. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, characterized by liver fatty acid accumulation and fibrosis, not due to excessive alcohol consumption. Notably, nutritional habits have been reported to be implicated in the onset and severity of the hepatic damage, while the Mediterranean diet has shown beneficial effects on NAFLD. Free radicals and oxidative stress were suggested to be involved in the pathogenesis and progression of NAFLD, and several data highlighted the efficacy of antioxidant supplementation in its treatment. The aim of this study was to compare the effects of the Mediterranean diet, with or without an antioxidant complex supplement, in overweight patients suffering from NAFLD. In this prospective study, fifty Caucasian overweight patients were randomized into three groups (Groups A-C). A personalized moderately hypocaloric Mediterranean diet was prescribed to all patients included in the A and B groups. In addition to the diet, Group B was administered antioxidant supplementation daily and for the period of six months. Group C did not have any type of treatment. The study proved that the Mediterranean diet alone or in association with the antioxidant complex improved anthropometric parameters, lipid profile and reduced hepatic fat accumulation and liver stiffness. However, Group B patients, in which the diet was associated with antioxidant intake, showed not only a significant improvement in insulin sensitivity, but also a more consistent reduction of anthropometric parameters when compared with Group A patients. Taken together, these results support the benefit of antioxidant supplementation in overweight patients with NAFLD. PMID- 28805672 TI - Challenges in Estimating Vaccine Coverage in Refugee and Displaced Populations: Results From Household Surveys in Jordan and Lebanon. AB - Ensuring the sustained immunization of displaced persons is a key objective in humanitarian emergencies. Typically, humanitarian actors measure coverage of single vaccines following an immunization campaign; few measure routine coverage of all vaccines. We undertook household surveys of Syrian refugees in Jordan and Lebanon, outside of camps, using a mix of random and respondent-driven sampling, to measure coverage of all vaccinations included in the host country's vaccine schedule. We analyzed the results with a critical eye to data limitations and implications for similar studies. Among households with a child aged 12-23 months, 55.1% of respondents in Jordan and 46.6% in Lebanon were able to produce the child's EPI card. Only 24.5% of Syrian refugee children in Jordan and 12.5% in Lebanon were fully immunized through routine vaccination services (having received from non-campaign sources: measles, polio 1-3, and DPT 1-3 in Jordan and Lebanon, and BCG in Jordan). Respondents in Jordan (33.5%) and Lebanon (40.1%) reported difficulties obtaining child vaccinations. Our estimated immunization rates were lower than expected and raise serious concerns about gaps in vaccine coverage among Syrian refugees. Although our estimates likely under-represent true coverage, given the additional benefit of campaigns (not captured in our surveys), there is a clear need to increase awareness, accessibility, and uptake of immunization services. Current methods to measure vaccine coverage in refugee and displaced populations have limitations. To better understand health needs in such groups, we need research on: validity of recall methods, links between campaigns and routine immunization programs, and improved sampling of hard-to reach populations. PMID- 28805670 TI - Appetite and Gut Hormones Response to a Putative alpha-Glucosidase Inhibitor, Salacia Chinensis, in Overweight/Obese Adults: A Double Blind Randomized Controlled Trial. AB - Animal studies indicate Salacia reduces body weight, possibly due to its alpha glucosidase inhibitor (alpha-GI) properties, but this has not been examined previously. In this study, a randomized, placebo-controlled, three-way cross-over design was used to evaluate whether Salacia Chinensis (SC) reduces appetite in healthy overweight/obese individuals (body mass index 28.8 +/-3.6 kg/m2; 32 +/- 12 years). Forty-eight participants were fasted overnight and consumed a dose of SC (300 or 500 mg) or placebo with a fixed breakfast meal at each visit. Appetite sensations, glycemic indices and gastrointestinal peptides were measured. Results indicated that SC had no effect on postprandial appetite. However, in women, hunger was reduced by SC compared to placebo at multiple time points (300 mg; p < 0.05), but not in men. Area under the curve (AUC) for serum glucose, insulin and amylin was attenuated with SC compared to placebo (p < 0.05). Glucagon like peptide-1 had two peaks after the meal, but the AUC did not differ between groups. The AUC of peak areas for peptide YY and ghrelin were greater for SC than placebo (p < 0.05). These findings indicate that Salacia decreases glycemic indices supporting its role as an alpha-GI, and affects certain gastrointestinal peptides suggesting it may be an appetite modulator. PMID- 28805671 TI - The Roles of Vitamin C in Skin Health. AB - The primary function of the skin is to act as a barrier against insults from the environment, and its unique structure reflects this. The skin is composed of two layers: the epidermal outer layer is highly cellular and provides the barrier function, and the inner dermal layer ensures strength and elasticity and gives nutritional support to the epidermis. Normal skin contains high concentrations of vitamin C, which supports important and well-known functions, stimulating collagen synthesis and assisting in antioxidant protection against UV-induced photodamage. This knowledge is often used as a rationale for the addition of vitamin C to topical applications, but the efficacy of such treatment, as opposed to optimising dietary vitamin C intake, is poorly understood. This review discusses the potential roles for vitamin C in skin health and summarises the in vitro and in vivo research to date. We compare the efficacy of nutritional intake of vitamin C versus topical application, identify the areas where lack of evidence limits our understanding of the potential benefits of vitamin C on skin health, and suggest which skin properties are most likely to benefit from improved nutritional vitamin C intake. PMID- 28805673 TI - ALK Status Assessment with Liquid Biopsies of Lung Cancer Patients. AB - Patients with advanced stage non-small cell lung carcinoma (NSCLC) harboring an anaplastic lymphoma kinase ALK gene rearrangement, detected from a tissue sample, can benefit from targeted ALK inhibitor treatment. However, while treatment is initially effective in most cases, relapse or progression occurs due to different resistance mechanisms including mutations in the tyrosine kinase domain of echinoderm microtubule-associated protein-like 4 (EML44)-ALK. The liquid biopsy concept has recently radically changed the clinical care of NSCLC patients, in particular for those harboring an epidermal growth factor receptor (EGFR) gene mutation. Therefore, liquid biopsy is an alternative or complementary method to tissue biopsy for the detection of some resistance mutations in EGFR arising during tyrosine kinase inhibitor treatment. Moreover, in some frail patients, or if the tumor lesion is not accessible to a tissue biopsy, a liquid biopsy can also detect some activating mutations in EGFR on initial assessment. Recent studies have evaluated the possibility of also using a liquid biopsy approach to detect an ALK rearrangement and/or the emergence during inhibitor treatment of some resistance mutations in ALK. These assessments can be performed by studying circulating tumor cells by fluorescent in situ hybridization and by immunocytochemistry and/or after the isolation of RNA from plasma samples, free or associated with platelets. Thus, the liquid biopsy may be a complementary or sometimes alternative method for the assessment of the ALK status in certain NSCLC patients, as well as a non-invasive approach for early detection of ALK mutations. In this review, we highlight the current data concerning the role of the liquid biopsy for the ALK status assessment for NSCLC patients, and we compare the different approaches for this evaluation from blood samples. PMID- 28805674 TI - Hepatitis C Virus-Induced Autophagy and Host Innate Immune Response. AB - Autophagy is a catabolic process that is important for maintaining cellular homeostasis. This pathway in hepatocytes is stimulated and controlled by the hepatitis C virus (HCV)-upon infection-to promote its own replication. HCV induces autophagy indirectly and directly through different mechanisms and temporally controls the autophagic flux. This enables the virus to maximize its replication and attenuate the innate immune responses that it activates. In this review, we discuss the relationship between HCV and autophagy, and the crosstalk between HCV-induced autophagy and host innate immune responses. PMID- 28805675 TI - Changing Stem Cell Dynamics during Papillomavirus Infection: Potential Roles for Cellular Plasticity in the Viral Lifecycle and Disease. AB - Stem cells and cellular plasticity are likely important components of tissue response to infection. There is emerging evidence that stem cells harbor receptors for common pathogen motifs and that they are receptive to local inflammatory signals in ways suggesting that they are critical responders that determine the balance between health and disease. In the field of papillomaviruses stem cells have been speculated to play roles during the viral life cycle, particularly during maintenance, and virus-promoted carcinogenesis but little has been conclusively determined. I summarize here evidence that gives clues to the potential role of stem cells and cellular plasticity in the lifecycle papillomavirus and linked carcinogenesis. I also discuss outstanding questions which need to be resolved. PMID- 28805677 TI - Endocytosis of Albumin Induces Matrix Metalloproteinase-9 by Activating the ERK Signaling Pathway in Renal Tubule Epithelial Cells. AB - Matrix metalloproteinase-9 (MMP-9) is dysregulated in chronic kidney diseases including diabetic nephropathy. This study was performed to examine the expression of MMP-9 in renal tubule epithelial cells (TECs) under diabetic conditions and its regulatory mechanisms. We characterized MMP-9 protein in diabetic animals and primary cultured rat TECs exposed to exogenous albumin and high glucose. We also used specific inhibitors to determine if internalization of albumin and/or extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation were required for MMP-9 secretion. Immunostaining of kidney sections revealed enhanced MMP-9 signal in the damaged proximal tubules in Zucker diabetic fatty (ZDF) rats. ZDF rats also exhibited an albuminuria-related and age-dependent increase in MMP-9 excretion, which was prevented by rosiglitazone. In primary cultured rat TECs, high glucose exposure did not increase MMP-9 secretion. In contrast, administration of rat serum albumin (RSA, 0.1-0.5 mg/mL) resulted in a dose-dependent increase in MMP-9 expression and secretion by TECs, which was abolished in the presence of an ERK1/2-specific inhibitor, U0126. Simvastatin, an inhibitor of albumin endocytosis, also prevented MMP-9 secretion. Taken together, these results demonstrate that endocytosis of albumin stimulates MMP-9 secretion by TECs through the ERK signaling pathway. PMID- 28805676 TI - Inhibitors of Deubiquitinating Enzymes Block HIV-1 Replication and Augment the Presentation of Gag-Derived MHC-I Epitopes. AB - In recent years it has been well established that two major constituent parts of the ubiquitin proteasome system (UPS)-the proteasome holoenzymes and a number of ubiquitin ligases-play a crucial role, not only in virus replication but also in the regulation of the immunogenicity of human immunodeficiency virus type 1 (HIV 1). However, the role in HIV-1 replication of the third major component, the deubiquitinating enzymes (DUBs), has remained largely unknown. In this study, we show that the DUB-inhibitors (DIs) P22077 and PR-619, specific for the DUBs USP7 and USP47, impair Gag processing and thereby reduce the infectivity of released virions without affecting viral protease activity. Furthermore, the replication capacity of X4- and R5-tropic HIV-1NL4-3 in human lymphatic tissue is decreased upon treatment with these inhibitors without affecting cell viability. Most strikingly, combinatory treatment with DIs and proteasome inhibitors synergistically blocks virus replication at concentrations where mono-treatment was ineffective, indicating that DIs can boost the therapeutic effect of proteasome inhibitors. In addition, P22077 and PR-619 increase the polyubiquitination of Gag and thus its entry into the UPS and the major histocompatibility complex (MHC)-I pathway. In summary, our data point towards a model in which specific inhibitors of DUBs not only interfere with virus spread but also increase the immune recognition of HIV-1 expressing cells. PMID- 28805678 TI - Sodium Chloride and Its Influence on the Aroma Profile of Yeasted Bread. AB - The impact of sodium chloride (NaCl) concentration on the yeast activity in bread dough and its influence on the aroma profile of the baked bread was investigated. Key aroma compounds in the bread samples were analysed by two-dimensional high resolution gas chromatography-mass spectrometry in combination with solvent assisted flavour evaporation distillation. High-sensitivity proton-transfer reaction mass spectrometry was used to detect and quantify 2-phenylethanol in the headspace of the bread dough during fermentation. The analyses revealed significant (p < 0.05) changes in the aroma compounds 2-phenylethanol, (E)-2 nonenal, and 2,4-(E,E)-decadienal. Descriptive sensory analysis and discriminating triangle tests revealed that significant differences were only determinable in samples with different yeast levels but not samples with different NaCl concentrations. This indicates that a reduction in NaCl does not significantly influence the aroma profile of yeasted bread at levels above the odour thresholds of the relevant compounds, thus consumers in general cannot detect an altered odour profile of low-salt bread crumb. PMID- 28805679 TI - Controlling Blown Pack Spoilage Using Anti-Microbial Packaging. AB - Active (anti-microbial) packaging was prepared using three different formulations; Auranta FV; Inbac-MDA and sodium octanoate at two concentrations (2.5 and 3.5 times their minimum inhibitory concentration (MIC, the lowest concentration that will inhibit the visible growth of the organisms) against Clostridium estertheticum, DSMZ 8809). Inoculated beef samples were packaged using the active packaging and monitored for 100 days storage at 2 degrees C for blown pack spoilage. The time to the onset of blown pack spoilage was significantly (p < 0.01) increased using Auranta FV and sodium octanoate (caprylic acid sodium salt) at both concentrations. Moreover, sodium octanoate packs had significantly (p < 0.01) delayed blown pack spoilage as compared to Auranta FV. It was therefore concluded that Auranta FV or sodium octanoate, incorporated into the packaging materials used for vacuum packaged beef, would inhibit blown pack spoilage and in the case of the latter, well beyond the 42 days storage period currently required for beef primals. PMID- 28805680 TI - Broadband Ultra-Deep Sub-Diffraction-Limit Optical Focusing by Metallic Graded Index (MGRIN) Lenses. AB - The development of techniques for efficiently confining energy in the visible and infrared spectral regions to the deep subwavelength spatial scale with dimensions as small as a few nanometers would have great significance for scientific research and engineering practices. Such an ability to manipulate light is impossible for conventional dielectric lenses due to the diffraction limit. Here, we propose a metallic graded-index (MGRIN) lens formed by an array of coupled metallic waveguides with identical nanoscale widths embedded by index-varying dielectrics to enable the optical nanofocusing. The focusing mechanism of the MGRIN lens is theoretically investigated based on Hamiltonian optics, which are verified by the finite-difference time-domain (FDTD) method. Numerical results reveal that an ultra-deep subwavelength focus of 8 nm (lambda/500) with a long focal depth (1.93lambda) and enhanced field intensity can be achieved. Moreover, the nanofocusing capability of the MGRIN lens without redesigning the structure can be well kept when the incident wavelength changes over a broad range from visible to infrared. Our design of optical nanofocusing shows great potential for use in nano-optics and nanotechnology. PMID- 28805681 TI - Influenza Virus Infection, Interferon Response, Viral Counter-Response, and Apoptosis. AB - Human influenza A viruses (IAVs) cause global pandemics and epidemics, which remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral outbreaks, new treatments are urgently needed. Developing new virus control modalities requires better understanding of virus-host interactions. Here, we describe how IAV infection triggers cellular apoptosis and how this process can be exploited towards the development of new therapeutics, which might be more effective than the currently available anti-influenza drugs. PMID- 28805683 TI - Analysis and Comparison of the Antioxidant Component of Portulaca Oleracea Leaves Obtained by Different Solid-Liquid Extraction Techniques. AB - Portulaca oleracea is a wild plant pest of orchards and gardens, but is also an edible vegetable rich in beneficial nutrients. It possesses many antioxidant properties due to the high content of vitamins, minerals, omega-3 essential fatty acids and other healthful compounds; therefore, the intake of purslane and/or its bioactive compounds could help to improve the health and function of the whole human organism. Accordingly, in this work it was analyzed and compared to the extractive capacity of the antioxidant component of purslane leaves obtained by solid-liquid extraction techniques such as: hot-maceration, maceration with ultrasound, rapid solid-liquid dynamic extraction using the Naviglio extractor, and a combination of two techniques (mix extraction). The chromatographic analysis by High Performance Liquid Chromatography (HPLC) of the methanolic extract of dried purslane leaves allowed the identification of various polyphenolic compounds for comparison with the standards. In addition, the properties of the different extracts were calculated on dry matter and the antioxidant properties of the total polyphenol components analyzed by the DPPH (2,2-diphenyl-1-picrylhydrazyl) assay. The results showed that mix extraction was the most efficient compared to other techniques. In fact, it obtained a quantity of polyphenols amounting to 237.8 mg Gallic Acid Equivalents (GAE)/100 g of fresh weight, while in other techniques, the range varied from 60-160 mg GAE/100 g fresh weight. In addition, a qualitative analysis by Liquid Chromatography-Tandem Mass Spectrometry (LC/MS/MS) of the phenolic compounds present in the purslane leaves examined was carried out. The compounds were identified by comparison of their molecular weight, fragmentation pattern and retention time with those of standards, using the "Multiple Reaction Monitoring" mode (MRM). Therefore, this study allowed the re-evaluation of a little-known plant that possesses as its beneficial properties, a great potential for use in both the food and the nutraceuticals and cosmetic field. PMID- 28805682 TI - ALK in Non-Small Cell Lung Cancer (NSCLC) Pathobiology, Epidemiology, Detection from Tumor Tissue and Algorithm Diagnosis in a Daily Practice. AB - Patients with advanced-stage non-small cell lung carcinoma (NSCLC) harboring an ALK rearrangement, detected from a tissue sample, can benefit from targeted ALK inhibitor treatment. Several increasingly effective ALK inhibitors are now available for treatment of patients. However, despite an initial favorable response to treatment, in most cases relapse or progression occurs due to resistance mechanisms mainly caused by mutations in the tyrosine kinase domain of ALK. The detection of an ALK rearrangement is pivotal and can be done using different methods, which have variable sensitivity and specificity depending, in particular, on the quality and quantity of the patient's sample. This review will first highlight briefly some information regarding the pathobiology of an ALK rearrangement and the epidemiology of patients harboring this genomic alteration. The different methods used to detect an ALK rearrangement as well as their advantages and disadvantages will then be examined and algorithms proposed for detection in daily routine practice. PMID- 28805684 TI - Miniaturized Monitors for Assessment of Exposure to Air Pollutants: A Review. AB - Air quality has a huge impact on different aspects of life quality, and for this reason, air quality monitoring is required by national and international regulations. Technical and procedural limitations of traditional fixed-site stations for monitoring or sampling of air pollutants are also well-known. Recently, a different type of miniaturized monitors has been developed. These monitors, due to their characteristics (e.g., low cost, small size, high portability) are becoming increasingly important for individual exposure assessment, especially since this kind of instrument can provide measurements at high spatial and temporal resolution, which is a notable advantage when approaching assessment of exposure to environmental contaminants. The aim of this study is indeed to provide information regarding current knowledge regarding the use of miniaturized air pollutant sensors. A systematic review was performed to identify original articles: a literature search was carried out using an appropriate query for the search of papers across three different databases, and the papers were selected using inclusion/exclusion criteria. The reviewed articles showed that miniaturized sensors are particularly versatile and could be applied in studies with different experimental designs, helping to provide a significant enhancement to exposure assessment, even though studies regarding their performance are still sparse. PMID- 28805685 TI - Re-adaption on Earth after Spaceflights Affects the Mouse Liver Proteome. AB - Harsh environmental conditions including microgravity and radiation during prolonged spaceflights are known to alter hepatic metabolism. Our studies have focused on the analysis of possible changes in metabolic pathways in the livers of mice from spaceflight project "Bion-M 1". Mice experienced 30 days of spaceflight with and without an additional re-adaption period of seven days compared to control mice on Earth. To investigate mice livers we have performed proteomic profiling utilizing shotgun mass spectrometry followed by label-free quantification. Proteomic data analysis provided 12,206 unique peptides and 1,086 identified proteins. Label-free quantification using MaxQuant software followed by multiple sample statistical testing (ANOVA) revealed 218 up-regulated and 224 down-regulated proteins in the post-flight compared to the other groups. Proteins related to amino acid metabolism showed higher levels after re-adaption, which may indicate higher rates of gluconeogenesis. Members of the peroxisome proliferator-activated receptor pathway reconstitute their level after seven days based on a decreased level in comparison with the flight group, which indicates diminished liver lipotoxicity. Moreover, bile acid secretion may regenerate on Earth due to reconstitution of related transmembrane proteins and CYP superfamily proteins elevated levels seven days after the spaceflight. Thus, our study demonstrates reconstitution of pharmacological response and decreased liver lipotoxicity within seven days, whereas glucose uptake should be monitored due to alterations in gluconeogenesis. PMID- 28805686 TI - Lengths of the C-Terminus and Interconnecting Loops Impact Stability of Spider Derived Gating Modifier Toxins. AB - Spider gating modifier toxins (GMTs) are potent modulators of voltage-gated ion channels and have thus attracted attention as drug leads for several pathophysiological conditions. GMTs contain three disulfide bonds organized in an inhibitory cystine knot, which putatively confers them with high stability; however, thus far, there has not been a focused study to establish the stability of GMTs in physiological conditions. We examined the resistance of five GMTs including GpTx-1, HnTx-IV, HwTx-IV, PaurTx-3 and SgTx-1, to pH, thermal and proteolytic degradation. The peptides were stable under physiological conditions, except SgTx-1, which was susceptible to proteolysis, probably due to a longer C terminus compared to the other peptides. In non-physiological conditions, the five peptides withstood chaotropic degradation, and all but SgTx-1 remained intact after prolonged exposure to high temperature; however, the peptides were degraded in strongly alkaline solutions. GpTx-1 and PaurTx-3 were more resistant to basic hydrolysis than HnTx-IV, HwTx-IV and SgTx-1, probably because a shorter interconnecting loop 3 on GpTx-1 and PaurTx-3 may stabilize interactions between the C-terminus and the hydrophobic patch. Here, we establish that most GMTs are exceptionally stable, and propose that, in the design of GMT-based therapeutics, stability can be enhanced by optimizing the C-terminus in terms of length, and increased interactions with the hydrophobic patch. PMID- 28805687 TI - A Review of the Antiviral Role of Green Tea Catechins. AB - Over the centuries, infectious diseases caused by viruses have seriously threatened human health globally. Viruses are responsible not only for acute infections but also many chronic infectious diseases. To prevent diseases caused by viruses, the discovery of effective antiviral drugs, in addition to vaccine development, is important. Green tea catechins (GTCs) are polyphenolic compounds from the leaves of Camelliasinensis. In recent decades, GTCs have been reported to provide various health benefits against numerous diseases. Studies have shown that GTCs, especially epigallocatechin-3-gallate (EGCG), have antiviral effects against diverse viruses. The aim of this review is to summarize the developments regarding the antiviral activities of GTCs, to discuss the mechanisms underlying these effects and to offer suggestions for future research directions and perspectives on the antiviral effects of EGCG. PMID- 28805689 TI - Visual Servoing for an Autonomous Hexarotor Using a Neural Network Based PID Controller. AB - In recent years, unmanned aerial vehicles (UAVs) have gained significant attention. However, we face two major drawbacks when working with UAVs: high nonlinearities and unknown position in 3D space since it is not provided with on board sensors that can measure its position with respect to a global coordinate system. In this paper, we present a real-time implementation of a servo control, integrating vision sensors, with a neural proportional integral derivative (PID), in order to develop an hexarotor image based visual servo control (IBVS) that knows the position of the robot by using a velocity vector as a reference to control the hexarotor position. This integration requires a tight coordination between control algorithms, models of the system to be controlled, sensors, hardware and software platforms and well-defined interfaces, to allow the real time implementation, as well as the design of different processing stages with their respective communication architecture. All of these issues and others provoke the idea that real-time implementations can be considered as a difficult task. For the purpose of showing the effectiveness of the sensor integration and control algorithm to address these issues on a high nonlinear system with noisy sensors as cameras, experiments were performed on the Asctec Firefly on-board computer, including both simulation and experimenta results. PMID- 28805690 TI - Preparation of Magnetic Nanoparticles via a Chemically Induced Transition: Role of Treating Solution's Temperature. AB - Using FeOOH/Mg(OH)2 as precursor and FeCl2 as the treating solution, we prepared gamma-Fe2O3 based nanoparticles. The FeCl2 treating solution catalyzes the chemical reactions, dismutation and oxygenation, leading to the formation of products FeCl3 and Fe2O3, respectively. The treating solution (FeCl2) accelerates dehydration of the FeOOH compound in the precursor and transforms it into the initial seed crystallite gamma-Fe2O3. Fe2O3 grows epitaxially on the initial seed crystallite gamma-Fe2O3. The epitaxial layer has a magnetically silent surface, which does not have any magnetization contribution toward the breaking of crystal symmetry. FeCl3 would be absorbed to form the FeCl3.6H2O surface layer outside the particles to form gamma-Fe2O3/FeCl3.6H2O nanoparticles. When the treating solution's temperature is below 70 degrees C, the dehydration reaction of FeOOH is incomplete and the as-prepared samples are a mixture of both FeOOH and gamma Fe2O3/FeCl3.6H2O nanoparticles. As the treating solution's temperature increases from 70 to 90 degrees C, the contents of both FeCl3.6H2O and the epitaxial Fe2O3 increased in totality. PMID- 28805688 TI - 7-Dialkylaminocoumarin Oximates: Small Molecule Fluorescent "Turn-On" Chemosensors for Low-Level Water Content in Aprotic Organic Solvents. AB - The water sensing properties of two efficient two-component fluorescent "turn-on" chemo-sensors based on the 7-dialkylaminocoumarin oxime acid-base equilibrium were investigated. Interestingly, although simple frontier orbital analysis predicts an intramolecular photoinduced electron transfer quenching pathway in conjugated oximates, TD-DFT (Time-dependent density functional theory) quantum chemical calculations support non-radiative dark S1 excited state deactivation as a fluorescence quenching mechanism. Due to the acid-base sensing mechanism and sensitive "turn-on" fluorescent response, both studied coumarin aldoxime chemosensors exhibit rapid response to low-level water content in polar aprotic solvents, with detection limits comparable to chemodosimeters or chemosensors based on interpolymer pi-stacking aggregation. PMID- 28805691 TI - Structural and Neuronal Integrity Measures of Fatigue Severity in Multiple Sclerosis. AB - Fatigue is a common and disabling symptom in Multiple Sclerosis (MS). However, consistent neuroimaging correlates of its severity are not fully elucidated. In this article, we study the neuronal correlates of fatigue severity in MS. Forty three Relapsing Remitting MS (RRMS) patients with MS-related fatigue (Fatigue Severity Scale (FSS) range: 1-7) and Expanded Disability Status Scale (EDSS) <= 4, were divided into high fatigue (HF, FSS >= 5.1) and low fatigue groups (LF, FSS <= 3). We measured T2 lesion load using a semi-automated technique. Cortical thickness, volume of sub-cortical nuclei, and brainstem structures were measured using Freesurfer. Cortical Diffusion Tensor Imaging (DTI) parameters were extracted using a cross modality technique. A correlation analysis was performed between FSS, volumetric, and DTI indices across all patients. HF patients showed significantly lower volume of thalamus, (p = 0.02), pallidum (p = 0.01), and superior cerebellar peduncle ((SCP), p = 0.002). The inverse correlation between the FSS score and the above volumes was significant in the total study population. In the right temporal cortex (RTC), the Radial Diffusivity ((RD), p = 0.01) and Fractional Anisotropy ((FA), p = 0.01) was significantly higher and lower, respectively, in the HF group. After Bonferroni correction, thalamic volume, FA-RTC, and RD-RTC remained statistically significant. Multivariate regression analysis identified FA-RTC as the best predictor of fatigue severity. Our data suggest an association between fatigue severity and volumetric changes of thalamus, pallidum, and SCP. Early neuronal injury in the RTC is implicated in the pathogenesis of MS-related fatigue. PMID- 28805692 TI - Real-Time Rain Rate Evaluation via Satellite Downlink Signal Attenuation Measurement. AB - We present the NEFOCAST project (named by the contraction of "Nefele", which is the Italian spelling for the mythological cloud nymph Nephele, and "forecast"), funded by the Tuscany Region, about the feasibility of a system for the detection and monitoring of precipitation fields over the regional territory based on the use of a widespread network of new-generation Eutelsat "SmartLNB" (smart low noise block converter) domestic terminals. Though primarily intended for interactive satellite services, these devices can also be used as weather sensors, as they have the capability of measuring the rain-induced attenuation incurred by the downlink signal and relaying it on an auxiliary return channel. We illustrate the NEFOCAST system architecture, consisting of the network of ground sensor terminals, the space segment, and the service center, which has the task of processing the information relayed by the terminals for generating rain field maps. We discuss a few methods that allow the conversion of a rain attenuation measurement into an instantaneous rainfall rate. Specifically, we discuss an exponential model relating the specific rain attenuation to the rainfall rate, whose coefficients were obtained from extensive experimental data. The above model permits the inferring of the rainfall rate from the total signal attenuation provided by the SmartLNB and from the link geometry knowledge. Some preliminary results obtained from a SmartLNB installed in Pisa are presented and compared with the output of a conventional tipping bucket rain gauge. It is shown that the NEFOCAST sensor is able to track the fast-varying rainfall rate accurately with no delay, as opposed to a conventional gauge. PMID- 28805695 TI - Infants Investigated by the Child Welfare System: Exploring a Distinct Profile of Risks, Service Needs, and Referrals for Support in Ontario. AB - The science of early childhood development underscores that maltreatment and other adversities experienced during infancy heightens the risk for poor developmental and socio-emotional outcomes. Referrals to supportive services by the child welfare system are particularly critical during infancy given the rapidity of brain development and infants' sensitivity to their environment. The main objectives of the current study are to: (1) examine age-specific differences in clinical and case characteristics; (2) determine the factors associated with the service referral decision involving infants; and (3) explore the types of services families have been referred to at the conclusion of a maltreatment related investigation. Using data from the Ontario Incidence Study of Reported Child Abuse and Neglect for 2013, descriptive analyses were conducted, as was a logistic regression to identify factors associated with the decision to refer families of infants to supportive services. Overall, the findings reveal that the profile of infants and their families differs distinctly from those of older children with respect to risks, service needs, and service referrals, although this is rarely reflected in child welfare practice and policy. Investigations involving infants were most likely to have a referral made to supportive services, least likely to have an infant functioning concern identified; most likely to have a primary caregiver risk factor identified; and, the greatest likelihood of experiencing economic hardship. Multiple risks, identified for the primary caregiver of the infant are correlated to referral decisions for infants. However, the needs of the infant are likely under-identified and require cross sectorial collaboration. PMID- 28805694 TI - Progenitor Cells from Cartilage: Grade Specific Differences in Stem Cell Marker Expression. AB - Recent research has confirmed the presence of Mesenchymal stem cell (MSC)-like progenitors (MPC) in both normal and osteoarthritic cartilage. However, there is only limited information concerning how MPC markers are expressed with osteoarthritis (OA) progression. The purpose of this study was to compare the prevalence of various MPC markers in different OA grades. Human osteoarthritic tibial plateaus were obtained from ten patients undergoing total knee replacement. Each sample had been classified into a mild or severe group according to OARSI scoring. Tissue was taken from each specimen and mRNA expression levels of CD105, CD166, Notch 1, Sox9, Acan and Col II A1 were measured at day 0 and day 14 (2 weeks in vitro). Furthermore, MSC markers: Nucleostemin, CD90, CD73, CD166, CD105 and Notch 1 were studied by immunofluorescence. mRNA levels of MSC markers did not differ between mild and severe OA at day 0. At day 14, protein analysis showed that proliferated cells from both sources expressed all 6 MSC markers. Only cells from the mild OA subjects resulted in a significant increase of mRNA CD105 and CD166 after in vitro expansion. Moreover, cells from the mild OA subjects showed significantly higher levels of CD105, Sox9 and Acan compared with those from severe OA specimens. Results confirmed the presence of MSC markers in mild and severe OA tissue at both mRNA and protein levels. We found significant differences between cells obtained from mild compared to severe OA specimens suggests that mild OA derived cells may have a greater MSC potential. PMID- 28805693 TI - Glucose Sensing for Diabetes Monitoring: Recent Developments. AB - This review highlights recent advances towards non-invasive and continuous glucose monitoring devices, with a particular focus placed on monitoring glucose concentrations in alternative physiological fluids to blood. PMID- 28805696 TI - Licochalcone A Inhibits the Proliferation of Human Lung Cancer Cell Lines A549 and H460 by Inducing G2/M Cell Cycle Arrest and ER Stress. AB - Licochalcone A (LicA), a flavonoid isolated from the famous Chinese medicinal herb Glycyrrhiza uralensis Fisch, has wide spectrum of pharmacological activities. In this study, the anti-cancer effects and potential mechanisms of LicA in non-small cell lung cancer (NSCLC) cells were studied. LicA decreased cell viability and induced apoptosis in a dose-dependent manner in NSCLC cells. LicA inhibited lung cancer cells growth by blocking cell cycle progression at the G2/M transition and inducing apoptosis. LicA treatment decreased the expression of MDM2, Cyclin B1, Cdc2 and Cdc25C in H460 and A549 cancer cell lines. In addition, LicA induced caspase-3 activation and poly-ADP-ribose polymerase (PARP) cleavage, which displayed features of apoptotic signals. Furthermore, LicA increased the expression of endoplasmic reticulum (ER) stress related proteins, such as p-EIF2alpha and ATF4. These data provide evidence that LicA has the potential to be used in the treatment of lung cancer. PMID- 28805697 TI - Multiple Sclerosis and Schizophrenia. AB - The psychiatric and neurological aspects of health may present methodological challenges in the diagnosis and treatment of disease. This is especially true for patients whose symptoms indicate the coexistence of multiple sclerosis (MS) and schizophrenia (SCZ). These cases raise critical questions regarding the relationship between the mind and the brain. Studies have noted that patients with MS have an increased risk of developing SCZ or bipolar disorder (BD). It is suggested here that MS and a subgroup of SCZ have similar etiologies. Factors such as gender, ethnicity, geography and season also have an influence on the occurrence of MS and SCZ. This paper aims to examine the differences and similarities between SCZ and MS. For this purpose, scientific papers examining various factors associated with these disorders were reviewed, and similarities and differences in genetic, immunological, seasonal, geographical, and gender related risk factors and limited similarities in ethnic factors between the two diseases were identified. The findings suggest that subgroups of these two diseases may belong to the same class of disorders. PMID- 28805698 TI - Artemisia Iwayomogi Extract Attenuates High-Fat Diet-Induced Hypertriglyceridemia in Mice: Potential Involvement of the Adiponectin-AMPK Pathway and Very Low Density Lipoprotein Assembly in the Liver. AB - This study aimed to examine the protective effect of Artemisia iwayomogi extract (AI) against hypertriglyceridemia induced by a high-fat diet (HFD) in mice and to uncover the underlying molecular mechanisms. C57BL/6N mice were fed chow, HFD, HFD + 0.1% AI, HFD + 0.25% AI, or HFD + 0.5% AI for 10 weeks. The addition of 0.25% and 0.5% AI resulted in dose-dependent improvements in the major parameters of hypertriglyceridemia, including plasma triglyceride, free fatty acids, apolipoprotein B, and lipoprotein lipase, with parallel reductions in body weight gain, hepatic lipid accumulation, and insulin resistance. These beneficial effects were accompanied by the activation of adiponectin-adenosine monophosphate activated protein kinase (AMPK) mediated signaling cascades in the liver, which downregulated molecules involved in lipogenesis and concurrently upregulated molecules related to fatty acid oxidation. The downregulation of molecules involved in very low density lipoprotein assembly, which was associated with improved hepatic insulin signaling, also appeared to contribute to the AI-induced attenuation of hypertriglyceridemia. PMID- 28805700 TI - BILP-19-An Ultramicroporous Organic Network with Exceptional Carbon Dioxide Uptake. AB - Porous benzimidazole-based polymers (BILPs) have proven to be promising for carbon dioxide capture and storage. The polarity of their chemical structure in combination with an inherent porosity allows for adsorbing large amounts of carbon dioxide in combination with high selectivities over unpolar guest molecules such as methane and nitrogen. For this reason, among purely organic polymers, BILPs contain some of the most effective networks to date. Nevertheless, they are still outperformed by competitive materials such as metal organic frameworks (MOFs) or metal doped porous polymers. Here, we report the synthesis of BILP-19 and its exceptional carbon dioxide uptake of up to 6 mmol*g 1 at 273 K, making the network comparable to state-of-the-art materials. BILP-19 precipitates in a particulate structure with a strongly anisotropic growth into platelets, indicating a sheet-like structure for the network. It exhibits only a small microporous but a remarkable ultra-microporous surface area of 144 m2*g-1 and 1325 m2*g-1, respectively. We attribute the exceptional uptake of small guest molecules such as carbon dioxide and water to the distinct ultra-microporosity. Additionally, a pronounced hysteresis for both guests is observed, which in combination with the platelet character is probably caused by an expansion of the interparticle space, creating additional accessible ultra-microporous pore volume. For nitrogen and methane, this effect does not occur which explains their low affinity. In consequence, Henry selectivities of 123 for CO2/N2 at 298 K and 12 for CO2/CH4 at 273 K were determined. The network was carefully characterized with solid-state nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy, thermal gravimetry (TG) and elemental analyses as well as physisorption experiments with Ar, N2, CO2, CH4 and water. PMID- 28805699 TI - Predicting and Interpreting the Structure of Type IV Pilus of Electricigens by Molecular Dynamics Simulations. AB - Nanowires that transfer electrons to extracellular acceptors are important in organic matter degradation and nutrient cycling in the environment. Geobacter pili of the group of Type IV pilus are regarded as nanowire-like biological structures. However, determination of the structure of pili remains challenging due to the insolubility of monomers, presence of surface appendages, heterogeneity of the assembly, and low-resolution of electron microscopy techniques. Our previous study provided a method to predict structures for Type IV pili. In this work, we improved on our previous method using molecular dynamics simulations to optimize structures of Neisseria gonorrhoeae (GC), Neisseria meningitidis and Geobacter uraniireducens pilus. Comparison between the predicted structures for GC and Neisseria meningitidis pilus and their native structures revealed that proposed method could predict Type IV pilus successfully. According to the predicted structures, the structural basis for conductivity in G.uraniireducens pili was attributed to the three N-terminal aromatic amino acids. The aromatics were interspersed within the regions of charged amino acids, which may influence the configuration of the aromatic contacts and the rate of electron transfer. These results will supplement experimental research into the mechanism of long-rang electron transport along pili of electricigens. PMID- 28805702 TI - Study on the Status of Health Service Utilization among Caregivers of Left-Behind Children in Poor Rural Areas of Hunan Province: A Baseline Survey. AB - BACKGROUND: The caregivers of left-behind children (CLBC) in China's poor, rural areas are mostly elderly and women. Their health status and access to health services have not been previously characterized. This study aims to explore the status of CLBC in terms of their health service utilization and to provide a scientific basis for guiding effective implementation of health policy in rural Hunan. METHODS: Random cluster sampling was used to survey CLBC in two rural counties. Face-to-face interviews and questionnaires were used to collect data, including socioeconomic status and health service utilization. The two-week prevalence rate was used to reflect health service needs, while the two-week visiting rate, annual hospitalization rate and participation in basic public health services were used to evaluate health service utilization. RESULTS: Of the 518 respondents in the study, 95.9% were farmers and 88.4% were over 40 years old. The two-week prevalence rate was 36.1%. Furthermore, 40.1% of ill caregivers' activities were partly restricted by illness and 3.7% needed to be on bed rest. The two-week visiting rate was 21.0%. The main reasons for not seeing a doctor were "self-medication" (39.1%) or "financial difficulties" (32.6%). The annual hospitalization rate of the CLBC was 22.6% and the non-hospitalization rate of those who needed hospitalization was 41.5%. "Lack of time" (22.3%) and "financial difficulties" (50.5%) were the major factors affecting the utilization of hospitalization services. In terms of participation in basic public health services, only 35.1% CLBC clearly knew that township hospitals have established health records for them. Only 50.6% of caregivers received free health examinations in village clinics or township hospitals and 81.3% of the caregivers did not participate in health education or lectures organized by local health institutions in 2014. CONCLUSIONS: The utilization rate of health services was extremely low, which may affect the quality of care for left-behind children. Better public health education through multi-sector cooperation is urgently needed to improve health cognition among CLBC in rural China. PMID- 28805701 TI - A Pectic Polysaccharide from Sijunzi Decoction Promotes the Antioxidant Defenses of SW480 Cells. AB - Sijunzi Decoction (SJZD) is a formula used for the treatment of spleen deficiency and gastrointestinal diseases in Traditional Chinese Medicine. Polysaccharides are reported to be the main components of SJZD responsible for its bio-functions. However, highly purified and clearly characterized polysaccharides from SJZD are not well described. Here we obtained a purified polysaccharide (SJZDP-II-I) from SJZD using ion exchange chromatography and gel filtration. Structure analysis by FT-IR and NMR identified SJZDP-II-I as a typical pectic polysaccharide with homogalacturonan and rhamnogalacturonan type I regions and arabinogalactan type I and II as side chains. In vitro studies indicated that SJZDP-II-I treatment could significantly enhance the total antioxidant capacity of SW480 cells, resulting from the promoted expressions of antioxidant enzymes and their master regulator PGC-1alpha, which would be valuable for further research and applications. PMID- 28805703 TI - Thermo-Hydraulic Analysis of Heat Storage Filled with the Ceramic Bricks Dedicated to the Solar Air Heating System. AB - This article presents the results of a study into a packed bed filled with ceramic bricks. The designed storage installation is supposed to become part of a heating system installed in a single-family house and eventually to be integrated with a concentrated solar collector adapted to climate conditions in Poland. The system's working medium is air. The investigated temperature ranges and air volume flow rates in the ceramic bed were dictated by the planned integration with a solar air heater. Designing a packed bed of sufficient parameters first required a mathematical model to be constructed and heat exchange to be analyzed, since heat accumulation is a complex process influenced by a number of material properties. The cases discussed in the literature are based on differing assumptions and different formulas are used in calculations. This article offers a comparison of various mathematical models and of system operating parameters obtained from these models. The primary focus is on the Nusselt number. Furthermore, in the article, the thermo-hydraulic efficiency of the investigated packed bed is presented. This part is based on a relationship used in solar air collectors with internal storage. PMID- 28805704 TI - Effects of Adding Polysaccharides and Citric Acid into Sodium Dihydrogen Phosphate Mixing Solution on the Material Properties of Gelatin-Hybridized Calcium-Phosphate Cement. AB - We have succeeded in improving the material properties of a chelate-setting calcium-phosphate cement (CPC), which is composed of hydroxyapatite (HAp) the surface of which has been modified with inositol hexaphosphate (IP6) by adding alpha-tricalcium phosphate (alpha-TCP) powder. In order to create a novel chelate setting CPC with sufficient bioresorbability, gelatin particles were added into the IP6-HAp/alpha-TCP cement system to modify the material properties. The effects of adding polysaccharides (chitosan, chondroitin sulfate, and sodium alginate) into the sodium dihydrogen phosphate mixing solution on the material properties of the gelatin-hybridized CPC were evaluated. The results of mechanical testing revealed that chondroitin sulfate would be the most suitable for fabricating the hybridized CPC with higher compressive strength. Moreover, further addition of an appropriate amount of citric acid could improve the anti washout capability of the cement paste. In summary, a gelatin-hybridized IP6 HAp/alpha-TCP cement system prepared with a mixing solution containing chondroitin sulfate and citric acid is expected to be a beneficial CPC, with sufficient bioresorbability and material properties. PMID- 28805705 TI - Changes of Bone-Related Minerals during Denosumab Administration in Post Menopausal Osteoporotic Patients. AB - OBJECTIVES: This retrospective study included 21 patients with primary osteoporosis who were treated with the anti-resorption drug, denosumab. To date, there has been no detailed report on the changes of bone-related minerals after anti-resorption drug therapy. METHODS: Twenty-one post-menopausal females were retrospectively enrolled. Serum zinc (Zn), magnesium (Mg), iron (Fe), copper (Cu), grip strength, and estimated glomerular filtration rate (eGFR) were examined at one week and 1, 2, 4, 6, 8, 10, and 12 months. Lumbar spine (L1-4) bone mineral density (L-BMD) and bilateral total hip BMD (H-BMD) were examined before and at 4, 8, and 12 months after treatment commencement. RESULTS: Serum Zn tended to decrease at one week and one month, and tended to increase during 10 to 12 months. Serum Cu maintained during zero to eight months, then decreased at 10 and 12 months. Serum Fe gradually increased after four months. Serum Mg sharply increased at one week, then decreased further. Grip strength increased for two months, then slightly decreased and maintained 4 to 12 months. eGFR almost maintained for zero to eight months, then slightly decreased thereafter. L-BMD values significantly increased at eight (5.8%) (p < 0.01) and 12 months (9.8%) (p < 0.01). H-BMD increased during the period (at 12 months: 3.7%). CONCLUSIONS: These results suggest that at later phases of denosumab therapy, Zn and Fe tended to increase while Mg tended to decrease, all of which are important for bone metabolism. Thus, denosumab might improve Zn and Fe metabolism, and thereby likely increase BMD. Since denosumab may not improve Mg, it is better to obtain Mg supplementation during the therapy. PMID- 28805706 TI - Waveguide Plasmon Resonance of Arrayed Metallic Nanostructures Patterned on a Soft Substrate by Direct Contact Printing Lithography. AB - This paper presents a direct contact printing method to obtain arrayed metallic nanostructures on a soft polymer substrate. It utilizes a polydimethylsiloxane (PDMS) mold replicated from silicon molds to transfer metallic nanopatterns onto a polymer substrate based on differences in interfacial bonding energy. Arrayed metallic nanodisks with a disk diameter down to 180 nm and a center-to-center pitch around 400 nm are experimentally patterned on a PET substrate. The patterned metallic nanostructures are then spin-coated with a polymer layer; which mechanically secures the patterned nanostructures and optically allows waveguide plasmon resonance being excited by incident EM waves. Both experimental works and theoretical modeling are given to illustrate the behaviors of different types of plasmon resonance. These arrayed metallic nanostructures patterned on a soft polymer substrate and their tunable optical characteristics open up many possibilities in future engineering applications. PMID- 28805707 TI - Integrating Soil Silicon Amendment into Management Programs for Insect Pests of Drill-Seeded Rice. AB - Silicon soil amendment has been shown to enhance plant defenses against insect pests. Rice is a silicon-accumulating graminaceous plant. In the southern United States, the rice water weevil and stem borers are important pests of rice. Current management tactics for these pests rely heavily on the use of insecticides. This study evaluated the effects of silicon amendment when combined with current management tactics for these rice insect pests in the field. Field experiments were conducted from 2013 to 2015. Rice was drill-planted in plots subjected to factorial combinations of variety (conventional and hybrid), chlorantraniliprole seed treatment (treated and untreated), and silicon amendment (treated and untreated). Silicon amendment reduced densities of weevil larvae on a single sampling date in 2014, but did not affect densities of whiteheads caused by stem borers. In contrast, insecticidal seed treatment strongly reduced densities of both weevil larvae and whiteheads. Higher densities of weevil larvae were also observed in the hybrid variety in 2014, while higher incidences of whiteheads were observed in the conventional variety in 2014 and 2015. Silicon amendment improved rice yields, as did chlorantraniliprole seed treatment and use of the hybrid variety. PMID- 28805709 TI - Cyber Physical Systems for User Reliability Measurements in a Sharing Economy Environment. AB - As the sharing economic market grows, the number of users is also increasing but many problems arise in terms of reliability between providers and users in the processing of services. The existing methods provide shared economic systems that judge the reliability of the provider from the viewpoint of the user. In this paper, we have developed a system for establishing mutual trust between providers and users in a shared economic environment to solve existing problems. In order to implement a system that can measure and control users' situation in a shared economic environment, we analyzed the necessary factors in a cyber physical system (CPS). In addition, a user measurement system based on a CPS structure in a sharing economic environment is implemented through analysis of the factors to consider when constructing a CPS. PMID- 28805708 TI - Correlation of Leukocyte Telomere Length Measurement Methods in Patients with Dyskeratosis Congenita and in Their Unaffected Relatives. AB - Several methods have been employed to measure telomere length (TL) in human studies. It has been difficult to directly compare the results from these studies because of differences in the laboratory techniques and output parameters. We compared TL measurements (TLMs) by the three most commonly used methods, quantitative polymerase chain reaction (qPCR), flow cytometry with fluorescence in situ hybridization (flow FISH) and Southern blot, in a cohort of patients with the telomere biology disorder dyskeratosis congenita (DC) and in their unaffected relatives (controls). We observed a strong correlation between the Southern blot average TL and the flow FISH total lymphocyte TL in both the DC patients and their unaffected relatives (R2 of 0.68 and 0.73, respectively). The correlation between the qPCR average TL and that of the Southern blot method was modest (R2 of 0.54 in DC patients and of 0.43 in unaffected relatives). Similar results were noted when comparing the qPCR average TL and the flow FISH total lymphocyte TL (R2 of 0.49 in DC patients and of 0.42 in unaffected relatives). In conclusion, the strengths of the correlations between the three widely used TL assays (qPCR, flow FISH, and Southern blot) were significantly different. Careful consideration is warranted when selecting the method of TL measurement for research and for clinical studies. PMID- 28805710 TI - Analysis of the Pathogenic Factors and Management of Dry Eye in Ocular Surface Disorders. AB - The tear film represents the interface between the eye and the environment. The alteration of the delicate balance that regulates the secretion and distribution of the tear film determines the dry eye (DE) syndrome. Despite having a multifactorial origin, the main risk factors are female gender and advanced age. Likewise, morphological changes in several glands and in the chemical composition of their secretions, such as proteins, mucins, lipidics, aqueous tears, and salinity, are highly relevant factors that maintain a steady ocular surface. Another key factor of recurrence and onset of the disease is the presence of local and/or systemic inflammation that involves the ocular surface. DE syndrome is one of the most commonly encountered diseases in clinical practice, and many other causes related to daily life and the increase in average life expectancy will contribute to its onset. This review will consider the disorders of the ocular surface that give rise to such a widespread pathology. At the end, the most recent therapeutic options for the management of DE will be briefly discussed according to the specific underlying pathology. PMID- 28805712 TI - Health Risks Awareness of Electronic Waste Workers in the Informal Sector in Nigeria. AB - Insight into the health risk awareness levels of e-waste workers is important as it may offer opportunities for better e-waste recycling management strategies to reduce the health effects of informal e-waste recycling. Therefore, this study assessed the knowledge, attitude, and practices associated with occupational health risk awareness of e-waste workers compared with a control group (butchers) in the informal sector in Nigeria. A cross-sectional study was used to assess health risk awareness of 279 e-waste workers (repairers and dismantlers) and 221 butchers from the informal sector in three locations in Nigeria in 2015. A questionnaire was used to obtain information on socio-demographic backgrounds, occupational history, knowledge, attitude, and work practices. The data was analysed using Analysis of Variance. The three job designations had significantly different knowledge, attitude, and practice mean scores (p = 0.000), with butchers consistently having the highest mean scores. Only 43% of e-waste workers could mention one or more Personal Protective Equipment needed for their job compared with 70% of the butchers. The health risk awareness level of the e-waste workers was significantly lower compared with their counterparts in the same informal sector. A positive correlation existed between the workers' knowledge and their attitude and practice. Therefore, increasing the workers' knowledge may decrease risky practices. PMID- 28805711 TI - A Dereplication and Bioguided Discovery Approach to Reveal New Compounds from a Marine-Derived Fungus Stilbella fimetaria. AB - A marine-derived Stilbella fimetaria fungal strain was screened for new bioactive compounds based on two different approaches: (i) bio-guided approach using cytotoxicity and antimicrobial bioassays; and (ii) dereplication based approach using liquid chromatography with both diode array detection and high resolution mass spectrometry. This led to the discovery of several bioactive compound families with different biosynthetic origins, including pimarane-type diterpenoids and hybrid polyketide-non ribosomal peptide derived compounds. Prefractionation before bioassay screening proved to be a great aid in the dereplication process, since separate fractions displaying different bioactivities allowed a quick tentative identification of known antimicrobial compounds and of potential new analogues. A new pimarane-type diterpene, myrocin F, was discovered in trace amounts and displayed cytotoxicity towards various cancer cell lines. Further media optimization led to increased production followed by the purification and bioactivity screening of several new and known pimarane-type diterpenoids. A known broad-spectrum antifungal compound, ilicicolin H, was purified along with two new analogues, hydroxyl-ilicicolin H and ilicicolin I, and their antifungal activity was evaluated. PMID- 28805713 TI - Polyaspartamide-Based Nanoparticles Loaded with Fluticasone Propionate and the In Vitro Evaluation towards Cigarette Smoke Effects. AB - This paper describes the evaluation of polymeric nanoparticles (NPs) as a potential carrier for lung administration of fluticasone propionate (FP). The chosen polymeric material to produce NPs was a copolymer based on alpha,beta poly(N-2-hydroxyethyl)-d,l-aspartamide (PHEA) whose backbone was derivatised with different molecules, such as poly(lactic acid) (PLA) and polyethylenglycol (PEG). The chosen method to produce NPs from PHEA-PLA-PEG2000 was the method based on high-pressure homogenization and subsequent solvent evaporation by adding Pluronic F68 during the process and trehalose before lyophilisation. Obtained colloidal FP-loaded NPs showed a slightly negative surface charge and nanometric dimensions that are maintained after storage for one year at -20 degrees C and 5 degrees C. The FP loading was about 2.9 wt % and the drug was slowly released in simulated lung fluid. Moreover, the obtained NPs, containing the drug or not, were biocompatible and did not induce cell necrosis and cell apoptosis on bronchial epithelial cells (16-HBE). Further in vitro testing on cigarette smoke extract (CSE)-stimulated 16-HBE revealed that FP-loaded NPs were able to reduce the survivin expression, while either free FP or empty NPs were not able to significantly reduce this effect. PMID- 28805714 TI - Does Osmotic Stress Affect Natural Product Expression in Fungi? AB - The discovery of new natural products from fungi isolated from the marine environment has increased dramatically over the last few decades, leading to the identification of over 1000 new metabolites. However, most of the reported marine derived species appear to be terrestrial in origin yet at the same time, facultatively halo- or osmotolerant. An unanswered question regarding the apparent chemical productivity of marine-derived fungi is whether the common practice of fermenting strains in seawater contributes to enhanced secondary metabolism? To answer this question, a terrestrial isolate of Aspergillus aculeatus was fermented in osmotic and saline stress conditions in parallel across multiple sites. The ex-type strain of A. aculeatus was obtained from three different culture collections. Site-to-site variations in metabolite expression were observed, suggesting that subculturing of the same strain and subtle variations in experimental protocols can have pronounced effects upon metabolite expression. Replicated experiments at individual sites indicated that secondary metabolite production was divergent between osmotic and saline treatments. Titers of some metabolites increased or decreased in response to increasing osmolite (salt or glycerol) concentrations. Furthermore, in some cases, the expression of some secondary metabolites in relation to osmotic and saline stress was attributed to specific sources of the ex-type strains. PMID- 28805716 TI - Antioxidants in Food: The Significance of Characterisation, Identification, Chemical and Biological Assays in Determining the Role of Antioxidants in Food. AB - There is a vast research literature on the antioxidant activity in food. [...]. PMID- 28805715 TI - Identification and Analysis of Mitogen-Activated Protein Kinase (MAPK) Cascades in Fragaria vesca. AB - Mitogen-activated protein kinase (MAPK) cascades are highly conserved signaling modules in eukaryotes, including yeasts, plants and animals. MAPK cascades are responsible for protein phosphorylation during signal transduction events, and typically consist of three protein kinases: MAPK, MAPK kinase, and MAPK kinase kinase. In this current study, we identified a total of 12 FvMAPK, 7 FvMAPKK, 73 FvMAPKKK, and one FvMAPKKKK genes in the recently published Fragaria vesca genome sequence. This work reported the classification, annotation and phylogenetic evaluation of these genes and an assessment of conserved motifs and the expression profiling of members of the gene family were also analyzed here. The expression profiles of the MAPK and MAPKK genes in different organs and fruit developmental stages were further investigated using quantitative real-time reverse transcription PCR (qRT-PCR). Finally, the MAPK and MAPKK expression patterns in response to hormone and abiotic stresses (salt, drought, and high and low temperature) were investigated in fruit and leaves of F. vesca. The results provide a platform for further characterization of the physiological and biochemical functions of MAPK cascades in strawberry. PMID- 28805717 TI - The Fragility Index in a Cohort of Pediatric Randomized Controlled Trials. AB - Data suggest inadequacy of common statistical techniques for reporting outcomes in clinical trials. The Fragility Index can measure how many events the statistical significance hinges on, and may facilitate better interpretation of trial results. This study aimed to assess the Fragility Index in pediatric randomized controlled trials (RCTs) with statistically significant findings published in high-quality medical journals. A Fragility Index was calculated on included trials with dichotomous positive outcomes. Analysis of the relationship between trial characteristics and the Fragility Index was performed. Of the 429 abstracts screened, 17 met the inclusion criteria and underwent analysis. The median Fragility Index was 7 with an interquartile range of 2-11. In 41% of the studies, the number of patients lost to follow-up or withdrawn prior to analysis was equal to or greater than the Fragility Index. There was no correlation between the RCT sample size and the Fragility Index (r = 0.249, p = 0.335) nor the event group size and the Fragility Index (r = 0.250, p = 0.334). There was a strong negative correlation between the original p-value and the Fragility Index (r = -0.700, p = 0.002). The Fragility Index is a calculated metric that may assist in applying clinical relevance to statistically significant outcomes in pediatric randomized controlled trials with dichotomous outcomes. PMID- 28805719 TI - Factors Affecting Depressive Symptoms among North Korean Adolescent Refugees Residing in South Korea. AB - We examined factors affecting the depressive symptoms and the relationship between depression and quality of life among 131 North Korean adolescent refugees aged 12-24 years. We compared sociodemographic, social, and individual characteristics and perceived the quality of life between participants with and without depression. Thirty-seven refugees (28.2%) had clinically significant depressive symptoms. The refugees with depression were younger (t = 2.67; p = 0.009), more likely to be male (chi2 = 6.98; p = 0.009), and more likely to have a Chinese father (chi2 = 9.05; p = 0.003) than those without depression. The refugees with depression had lower levels of psychological social support (t = 2.96; p = 0.004) and resilience (t = 4.24; p < 0.001) and higher levels of alcohol problems (t = -2.08; p = 0.043), aggression (t = -3.15; p = 0.003), and post-traumatic stress disorder (PTSD; t = -2.89; p = 0.004). They also reported lower levels of life satisfaction (t = 3.31; p = 0.001) and had a more negative view of their future (t = 2.68; p = 0.010). Interventions to increase resilience, to decrease the impact of traumatic events, and to provide psychological support may be helpful for North Korean adolescent refugees at risk of depression. PMID- 28805720 TI - Theophylline-7beta-d-Ribofuranoside (Theonosine), a New Theophylline Metabolite Generated in Human and Animal Lung Tissue. AB - While assessing the ability of mammalian lung tissue to metabolize theophylline, a new metabolite was isolated and characterized. The metabolite was produced by the microsomal fraction of lungs from several species, including rat, rabbit, dog, pig, sheep and human tissue. Metabolite production was blocked by boiling the microsomal tissue. This new metabolite, theophylline-7beta-d-ribofuranoside (theonosine), was confirmed by several spectral methods and by comparison to an authentic synthetic compound. Tissue studies from rats, rabbits, dogs, and humans for cofactor involvement demonstrated an absolute requirement for NADP and enhanced metabolite production in the presence of magnesium ion. It remains to be demonstrated whether theonosine may contribute to the known pharmacological effects of theophylline. PMID- 28805718 TI - Myoclonic Disorders. AB - Few movement disorders seem to make a straightforward approach to diagnosis and treatment more difficult and frustrating than myoclonus, due to its plethora of causes and its variable classifications. Nevertheless, in recent years, exciting advances have been made in the elucidation of the pathophysiology and genetic basis of many disorders presenting with myoclonus. Here, we provide a review of all of the important types of myoclonus encountered in pediatric and adult neurology, with an emphasis on the recent developments that have led to a deeper understanding of this intriguing phenomenon. An up-to-date list of the genetic basis of all major myoclonic disorders is presented. Randomized studies are scarce in myoclonus therapy, but helpful pragmatic approaches at diagnosis as well as treatment have been recently suggested. PMID- 28805721 TI - Conformal Prediction Based on K-Nearest Neighbors for Discrimination of Ginsengs by a Home-Made Electronic Nose. AB - An estimate on the reliability of prediction in the applications of electronic nose is essential, which has not been paid enough attention. An algorithm framework called conformal prediction is introduced in this work for discriminating different kinds of ginsengs with a home-made electronic nose instrument. Nonconformity measure based on k-nearest neighbors (KNN) is implemented separately as underlying algorithm of conformal prediction. In offline mode, the conformal predictor achieves a classification rate of 84.44% based on 1NN and 80.63% based on 3NN, which is better than that of simple KNN. In addition, it provides an estimate of reliability for each prediction. In online mode, the validity of predictions is guaranteed, which means that the error rate of region predictions never exceeds the significance level set by a user. The potential of this framework for detecting borderline examples and outliers in the application of E-nose is also investigated. The result shows that conformal prediction is a promising framework for the application of electronic nose to make predictions with reliability and validity. PMID- 28805722 TI - Estrogen Repression of MicroRNAs Is Associated with High Guanine Content in the Terminal Loop Sequences of Their Precursors. AB - Widespread microRNA (miRNA) repression is a phenomenon observed in mammals after exposure to cigarette smoke and in many types of cancer. A comprehensive reduction in miRNA expression after treatment with the hormone estrogen has also previously been described. Here, we reveal a conserved association of miRNA downregulation after estrogen exposure in zebrafish, mouse, and human breast cancer cell line, with a high guanine content in the terminal loop sequences of their precursors, and offer a possible link between estrogen-related miRNA adducts formation and carcinogenesis. We also show common gene expression patterns shared by breast cancer tumors and estrogen-treated zebrafish, suggesting that this organism can be used as a powerful model system for the study of human breast cancer. PMID- 28805723 TI - Hitting the Holy Grail of Hematopoietic Cell Transplantation with Naive T-Cell Depleted Allografts-Graft Engineered Hematopoietic Stem Cell Transplant. AB - Hematopoietic cell transplant is a potentially curative procedure for many benign and malignant conditions. The efficacy of allogeneic transplant relies in part on the cytotoxicity of the conditioning regimen and the graft versus tumor effect mediated by alloreactive donor T cells; the same cells are also implicated in the development of graft versus host disease (GVHD). Selective identification and depletion of the T cells implicated in GVHD, while preserving the T cells responsible for graft versus tumor effect has been the focus of many research groups in the recent years. Here we briefly review the physiology of T cells in transplantation, and comment on a recent clinical trial published by Bleakly et al. using a novel way of graft engineered allograft via naive T cell depletion. PMID- 28805724 TI - Electroless Nickel Deposition for Front Side Metallization of Silicon Solar Cells. AB - In this work, nickel thin films were deposited on texture silicon by electroless plated deposition. The electroless-deposited Ni layers were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy dispersive x-ray spectroscopy (EDS), X-ray diffraction analysis (XRD), and sheet resistance measurement. The results indicate that the dominant phase was Ni2Si and NiSi in samples annealed at 300-800 degrees C. Sheet resistance values were found to correlate well with the surface morphology obtained by SEM and the results of XRD diffraction. The Cu/Ni contact system was used to fabricate solar cells by using two different activating baths. The open circuit voltage (Voc) of the Cu/Ni samples, before and after annealing, was measured under air mass (AM) 1.5 conditions to determine solar cell properties. The results show that open circuit voltage of a solar cell can be enhanced when the activation solution incorporated hydrofluoric acid (HF). This is mainly attributed to the native silicon oxide layer that can be decreased and/or removed by HF with the corresponding reduction of series resistance. PMID- 28805725 TI - Signal-to-Noise Ratio Enhancement Based on Empirical Mode Decomposition in Phase Sensitive Optical Time Domain Reflectometry Systems. AB - We propose a novel denoising method based on empirical mode decomposition (EMD) to improve the signal-to-noise ratio (SNR) for vibration sensing in phase sensitive optical time domain reflectometry (phi-OTDR) systems. Raw Rayleigh backscattering traces are decomposed into a series of intrinsic mode functions (IMFs) and a residual component using an EMD algorithm. High frequency noise is eliminated by removing several IMFs at the position without vibration selected by the Pearson correlation coefficient (PCC). When the pulse width is 50 ns, the SNR of location information for the vibration events of 100 Hz and 1.2 kHz is increased to as high as 42.52 dB and 39.58 dB, respectively, with a 2 km sensing fiber, which demonstrates the excellent performance of this new method. PMID- 28805726 TI - Chemical Identity of Interaction of Protein with Reactive Metabolite of Diosbulbin B In Vitro and In Vivo. AB - Diosbulbin B (DIOB), a hepatotoxic furan-containing compound, is a primary ingredient in Dioscorea bulbifera L., a common herbal medicine. Metabolic activation is required for DIOB-induced liver injury. Protein covalent binding of an electrophilic reactive intermediate of DIOB is considered to be one of the key mechanisms of cytotoxicity. A bromine-based analytical technique was developed to characterize the chemical identity of interaction of protein with reactive intermediate of DIOB. Cysteine (Cys) and lysine (Lys) residues were found to react with the reactive intermediate to form three types of protein modification, including Cys adduction, Schiff's base, and Cys/Lys crosslink. The crosslink showed time- and dose-dependence in animals given DIOB. Ketoconazole pretreatment decreased the formation of the crosslink derived from DIOB, whereas pretreatment with dexamethasone or buthionine sulfoximine increased such protein modification. These data revealed that the levels of hepatic protein adductions were proportional to the severity of hepatotoxicity of DIOB. PMID- 28805727 TI - Leaf Physiological and Proteomic Analysis to Elucidate Silicon Induced Adaptive Response under Salt Stress in Rosa hybrida 'Rock Fire'. AB - Beneficial effects of silicon (Si) on growth and development have been witnessed in several plants. Nevertheless, studies on roses are merely reported. Therefore, the present investigation was carried out to illustrate the impact of Si on photosynthesis, antioxidant defense and leaf proteome of rose under salinity stress. In vitro-grown, acclimatized Rosa hybrida 'Rock Fire' were hydroponically treated with four treatments, such as control, Si (1.8 mM), NaCl (50 mM), and Si+NaCl. After 15 days, the consequences of salinity stress and the response of Si addition were analyzed. Scorching of leaf edges and stomatal damages occurred due to salt stress was ameliorated under Si supplementation. Similarly, reduction of gas exchange, photosynthetic pigments, higher lipid peroxidation rate, and accumulation of reactive oxygen species under salinity stress were mitigated in Si treatment. Lesser oxidative stress observed was correlated with the enhanced activity and expression of antioxidant enzymes, such as superoxide dismutase, catalase, and ascorbate peroxidase in Si+NaCl treatment. Importantly, sodium transportation was synergistically restricted with the stimulated counter-uptake of potassium in Si+NaCl treatment. Furthermore, two-dimensional electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) results showed that out of 40 identified proteins, on comparison with control 34 proteins were down-accumulated and six proteins were up-accumulated due to salinity stress. Meanwhile, addition of Si with NaCl treatment enhanced the abundance of 30 proteins and downregulated five proteins. Differentially-expressed proteins were functionally classified into six groups, such as photosynthesis (22%), carbohydrate/energy metabolism (20%), transcription/translation (20%), stress/redox homeostasis (12%), ion binding (13%), and ubiquitination (8%). Hence, the findings reported in this work could facilitate a deeper understanding on potential mechanism(s) adapted by rose due to the exogenous Si supplementation during the salinity stress. PMID- 28805728 TI - Nano-Charged Polypropylene Application: Realistic Perspectives for Enhancing Durability. AB - Isotactic polypropylene/multi-walled carbon nanotube (iPP/MWCNTs) films have been exposed to accelerated weathering in a UV device for increasing times. The effect of UV irradiation on the structural and chemical changes has been investigated. The resistance to accelerated photooxidation of (iPP/MWCNTs) films has been compared to the photooxidation behaviour of unfilled polypropylene films with the same structural organization. The chemical and structural modifications resulting from photooxidation have been followed using infrared spectroscopy, calorimetric and diffractometric analysis. MWCNTs embedded in the polymeric matrix are able to strongly contrast the degradation mechanisms and the structural and morphological rearrangements caused by the UV treatment on the unfilled polymer. MWCNTs determine an induction period (IP) before the increase of the carbonyl and hydroxyl groups. The extent of the IP is strictly correlated to the amount of MWCNTs. The low electrical percolation threshold (EPT) and the electrical conductivity of the nanocomposites, together with their excellent thermal and photooxidative stability, make them promising candidates to fulfill many industrial requirements. PMID- 28805730 TI - Effect of Polymer Matrix on the Structure and Electric Properties of Piezoelectric Lead Zirconatetitanate/Polymer Composites. AB - Piezoelectric lead zirconatetitanate (PZT)/polymer composites were prepared by two typical polymer matrixes using the hot-press method. The micromorphology, microstructure, dielectric properties, and piezoelectric properties of the PZT/polymer composites were characterized and investigated. The results showed that when the condition of frequency is 103 Hz, the dielectric and piezoelectric properties of PZT/poly(vinylidene fluoride) were both better than that of PZT/polyvinyl chloride (PVC). When the volume fraction of PZT was 50%, PZT/PVDF prepared by the hot-press method had better comprehensive electric property. PMID- 28805729 TI - Systems Biology Approach to Bioremediation of Nitroaromatics: Constraint-Based Analysis of 2,4,6-Trinitrotoluene Biotransformation by Escherichia coli. AB - Microbial remediation of nitroaromatic compounds (NACs) is a promising environmentally friendly and cost-effective approach to the removal of these life threating agents. Escherichia coli (E. coli) has shown remarkable capability for the biotransformation of 2,4,6-trinitro-toluene (TNT). Efforts to develop E. coli as an efficient TNT degrading biocatalyst will benefit from holistic flux-level description of interactions between multiple TNT transforming pathways operating in the strain. To gain such an insight, we extended the genome-scale constraint based model of E. coli to account for a curated version of major TNT transformation pathways known or evidently hypothesized to be active in E. coli in present of TNT. Using constraint-based analysis (CBA) methods, we then performed several series of in silico experiments to elucidate the contribution of these pathways individually or in combination to the E. coli TNT transformation capacity. Results of our analyses were validated by replicating several experimentally observed TNT degradation phenotypes in E. coli cultures. We further used the extended model to explore the influence of process parameters, including aeration regime, TNT concentration, cell density, and carbon source on TNT degradation efficiency. We also conducted an in silico metabolic engineering study to design a series of E. coli mutants capable of degrading TNT at higher yield compared with the wild-type strain. Our study, therefore, extends the application of CBA to bioremediation of nitroaromatics and demonstrates the usefulness of this approach to inform bioremediation research. PMID- 28805731 TI - The Role of Visual Noise in Influencing Mental Load and Fatigue in a Steady-State Motion Visual Evoked Potential-Based Brain-Computer Interface. AB - As a spatial selective attention-based brain-computer interface (BCI) paradigm, steady-state visual evoked potential (SSVEP) BCI has the advantages of high information transfer rate, high tolerance to artifacts, and robust performance across users. However, its benefits come at the cost of mental load and fatigue occurring in the concentration on the visual stimuli. Noise, as a ubiquitous random perturbation with the power of randomness, may be exploited by the human visual system to enhance higher-level brain functions. In this study, a novel steady-state motion visual evoked potential (SSMVEP, i.e., one kind of SSVEP) based BCI paradigm with spatiotemporal visual noise was used to investigate the influence of noise on the compensation of mental load and fatigue deterioration during prolonged attention tasks. Changes in alpha, theta, theta + alpha powers, theta/alpha ratio, and electroencephalography (EEG) properties of amplitude, signal-to-noise ratio (SNR), and online accuracy, were used to evaluate mental load and fatigue. We showed that presenting a moderate visual noise to participants could reliably alleviate the mental load and fatigue during online operation of visual BCI that places demands on the attentional processes. This demonstrated that noise could provide a superior solution to the implementation of visual attention controlling-based BCI applications. PMID- 28805733 TI - First Detection of Rotavirus Group C in Asymptomatic Pigs of Smallholder Farms in East Africa. AB - Abstract: Group C rotavirus (RVC) has been described to be a causative agent of gastroenteritis in humans and animals including pigs, cows, and dogs. Fecal samples collected from asymptomatic pigs in smallholder swine farms in Kenya and Uganda were screened for the presence of group C rotaviruses (RVC) using a reverse transcription-polymerase chain reaction assay. A total of 446 samples were tested and 37 were positive (8.3%). A significantly larger (p < 0.05) number of RVC-positive samples was detected in groups of older pigs (5-6 months) than in younger piglets (1-2 months). There were no significant differences in the RVC detection rate between the pigs that were full time housed/tethered and those that were free range combined with housing/tethering. After compiling these data with diagnostic results for group A rotaviruses (RVA), 13 RVC-positive samples were also positive for RVA. This study provides the first evidence that porcine group C rotavirus may be detected frequently in asymptomatic piglets (aged < 1-6 months) in East Africa. The occurrence of RVC in mixed infections with RVA and other enteric pathogens requires further research to investigate the pathogenic potential of RVC in pigs. PMID- 28805732 TI - The Mechanistic Links between Insulin and Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Cl- Channel. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel belongs to the ATP-binding cassette (ABC) transporter superfamily and regulates Cl- secretion in epithelial cells for water secretion. Loss-of-function mutations to the CFTR gene cause dehydrated mucus on the apical side of epithelial cells and increase the susceptibility of bacterial infection, especially in the airway and pulmonary tissues. Therefore, research on the molecular properties of CFTR, such as its gating mechanism and subcellular trafficking, have been intensively pursued. Dysregulated CFTR trafficking is one of the major pathological hallmarks in cystic fibrosis (CF) patients bearing missense mutations in the CFTR gene. Hormones that activate cAMP signaling, such as catecholamine, have been found to regulate the intracellular trafficking of CFTR. Insulin is one of the hormones that regulate cAMP production and promote trafficking of transmembrane proteins to the plasma membrane. The functional interactions between insulin and CFTR have not yet been clearly defined. In this review article, I review the roles of CFTR in epithelial cells, its regulatory role in insulin secretion, and a mechanism of CFTR regulation by insulin. PMID- 28805734 TI - Grain Foods Are Contributors of Nutrient Density for American Adults and Help Close Nutrient Recommendation Gaps: Data from the National Health and Nutrition Examination Survey, 2009-2012. AB - The 2015-2020 Dietary Guidelines for Americans (2015-2020 DGA) maintains recommendations for increased consumption of whole grains while limiting intake of enriched/refined grains. A variety of enriched grains are sources of several shortfall nutrients identified by 2015-2020 DGA, including dietary fiber, folate, iron, and magnesium. The purpose of this study was to determine food sources of energy and nutrients for free-living U.S. adults using data from the National Health and Nutrition Examination Survey, 2009-2012. Analyses of grain food sources were conducted using a single 24-h recall collected in adults >=19 years of age (n = 10,697). Sources of nutrients contained in all grain foods were determined using United States Department of Agriculture nutrient composition databases and the food grouping scheme for grains (excluding mixed dishes). Mean energy and nutrient intakes from the total diet and from various grain food groups were adjusted for the sample design using appropriate weights. All grains provided 285 +/- 5 kcal/day or 14 +/- 0.2% kcal/day in the total diet in adult >=19 years of age. In the total daily diet, the grain category provided 7.2 +/- 0.2% (4.9 +/- 0.1 g/day) total fat, 5.4 +/- 0.2% (1.1 +/- 0.03 g/day) saturated fat, 14.6 +/- 0.3% (486 +/- 9 mg/day) sodium, 7.9 +/- 0.2% (7.6 +/- 0.2 g/day) total sugar, 22.8 +/- 0.4% (3.9 +/- 0.1 g/day) dietary fiber, 13.2 +/- 0.3% (122 +/- 3 mg/day) calcium, 33.6 +/- 0.5% (219 +/- 4 mcg dietary folate equivalents (DFE)/day) folate, 29.7 +/- 0.4% (5.3 +/- 0.1 mg/day) iron, and 13.9 +/- 0.3% (43.7 +/- 1.1 mg/day) magnesium. Individual grain category analyses showed that breads, rolls and tortillas and ready-to-eat cereals provided minimal kcal/day in the total diet in men and women >=19 years of age. Similarly, breads, rolls and tortillas, and ready-to-eat cereals supplied meaningful contributions of shortfall nutrients, including dietary fiber, folate and iron, while concurrently providing minimal amounts of nutrients to limit. Cumulatively, a variety of grain food groups consumed by American adults contribute to nutrient density in the total diet and have the potential to increase consumption of shortfall nutrients as identified by 2015-2020 DGA, particularly dietary fiber, folate, and iron. PMID- 28805735 TI - Dietary Propolis Ameliorates Dextran Sulfate Sodium-Induced Colitis and Modulates the Gut Microbiota in Rats Fed a Western Diet. AB - Propolis is an important hive product and considered beneficial to health. However, evidence of its potential for improving gut health is still lacking. Here we use rats to examine whether dietary supplementation with propolis could be used as a therapy for ulcerative colitis. Rats were fed with a Western style diet alone (controls) or supplemented with different amounts of Chinese propolis (0.1%, 0.2%, and 0.3%) to examine effects on acute colitis induced by 3% dextran sulphate sodium (DSS) in drinking water. Propolis at 0.3%, but not lower levels, significantly improved colitis symptoms compared with the control group, with a less pronounced disease activity index (DAI) (p < 0.001), a significant increase in colon length/weight ratio (p < 0.05) and an improved distal colon tissue structure as assessed by histology. Although short chain fatty acid levels in digesta were not altered by propolis supplementation, 16S rRNA phylogenetic sequencing revealed a significant increase in gut microbial diversity after 21 days of 0.3% propolis supplementation compared with controls including a significant increase in bacteria belonging to the Proteobacteria and Acidobacteria phyla. This is the first study to demonstrate that propolis can attenuate DSS-induced colitis and provides new insight into diet-microbiota interactions during inflammatory bowel disease. PMID- 28805736 TI - Artificial Structural Color Pixels: A Review. AB - Inspired by natural photonic structures (Morpho butterfly, for instance), researchers have demonstrated varying artificial color display devices using different designs. Photonic-crystal/plasmonic color filters have drawn increasing attention most recently. In this review article, we show the developing trend of artificial structural color pixels from photonic crystals to plasmonic nanostructures. Such devices normally utilize the distinctive optical features of photonic/plasmon resonance, resulting in high compatibility with current display and imaging technologies. Moreover, dynamical color filtering devices are highly desirable because tunable optical components are critical for developing new optical platforms which can be integrated or combined with other existing imaging and display techniques. Thus, extensive promising potential applications have been triggered and enabled including more abundant functionalities in integrated optics and nanophotonics. PMID- 28805737 TI - Effects of Short-Term Set-Aside Management Practices on Soil Microorganism and Enzyme Activity in China. AB - Set-aside farmland can effectively improve the self-rehabilitation of arable soil. Long-term set-asides however cannot satisfy provisionment, therefore the use of short-term set-asides to restore cultivated soil is a better option. Few studies have compared short-term set-aside patterns, and the effects of set asides on soil microbial community and enzyme enzymes. We analyzed the bacterial structure, microbial biomass carbon/nitrogen and enzyme activity of farmland soil under different set-aside regimes in the Yellow River Delta of China. Bacterial alpha diversity was relatively lower under only irrigation, and farmyard manure applications showed clear advantages. Set-asides should consider their influence on soil organic carbon and nitrogen, which were correlated with microbial community structure. Nitrospira (0.47-1.67%), Acidobacteria Gp6 (8.26-15.91%) and unclassified Burkholderiales (1.50-2.81%) were significantly altered (p < 0.01). Based on functions of these genera, some set-aside patterns led to a relative balance in nitrogen and carbon turnover. Partial treatments showed a deficiency in organic matter. In addition, farmyard manure may lead to the increased consumption of organic matter, with the exception of native plants set-asides. Conventional farming (control group) displayed a significant enzyme activity advantage. Set-aside management practices guided soil microbial communities to different states. Integrated soil microbiota and the content of carbon and nitrogen, native plants with farmyard manure showed an equilibrium state relatively, which would be helpful to improve land quality in the short-term. PMID- 28805738 TI - Vibroacoustic Impact on the Architectonic Heritage When Using Replicas of 16th Century Weapons. AB - The recreation of historical battles next to old buildings, walls, churches, fortifications or historical facades belonging to the historical heritage of a city, has always been a source of controversy and discussion. In the absence of a clear legislation about how these buildings can be affected by the use of blunderbusses and pyrotechnics, it is necessary to carry out practical experiments to test the effect of these celebrations on these buildings. For this reason, this paper presents a set of practical experiments where the vibroacoustic effect of using weapons such as blunderbusses and harquebuses is analyzed. To gather these measurements, we have used several sound level meters and 3-axis accelerometers placed on the facade of an old building. The tests have been carried out at the Moors and Christians festival of Villajoyosa (Spain) which is internationally famous for this festival. In order to carry out the tests, six harquebusiers shot their firearms and the sensors placed along the facade of the building at different height collected the data. The results of these devices allow us to study the vibroacoustic impact on the facade depending on the height. PMID- 28805739 TI - Four Bad Habits of Modern Psychologists. AB - Four data sets from studies included in the Reproducibility Project were re analyzed to demonstrate a number of flawed research practices (i.e., "bad habits") of modern psychology. Three of the four studies were successfully replicated, but re-analysis showed that in one study most of the participants responded in a manner inconsistent with the researchers' theoretical model. In the second study, the replicated effect was shown to be an experimental confound, and in the third study the replicated statistical effect was shown to be entirely trivial. The fourth study was an unsuccessful replication, yet re-analysis of the data showed that questioning the common assumptions of modern psychological measurement can lead to novel techniques of data analysis and potentially interesting findings missed by traditional methods of analysis. Considered together, these new analyses show that while it is true replication is a key feature of science, causal inference, modeling, and measurement are equally important and perhaps more fundamental to obtaining truly scientific knowledge of the natural world. It would therefore be prudent for psychologists to confront the limitations and flaws in their current analytical methods and research practices. PMID- 28805740 TI - ADP-ribosyl-N3: A Versatile Precursor for Divergent Syntheses of ADP-ribosylated Compounds. AB - Adenosine diphosphate-ribose (ADP-ribose) and its derivatives play important roles in a series of complex physiological procedures. The design and synthesis of artificial ADP-ribosylated compounds is an efficient way to develop valuable chemical biology tools and discover new drug candidates. However, the synthesis of ADP-ribosylated compounds is currently difficult due to structural complexity, easily broken pyrophosphate bond and high hydrophilicity. In this paper, ADP ribosyl-N3 was designed and synthesized for the first time. With ADP-ribosyl-N3 as the key precursor, a divergent post-modification strategy was developed to prepare structurally diverse ADP-ribosylated compounds including novel nucleotides and peptides bearing ADP-ribosyl moieties. PMID- 28805742 TI - Two New Tetravacant Organometallic Keggin-Type Heteropolyoxomolybdates-Supported Manganese Carbonyl Derivatives. AB - Two novel heteropolyoxomolybdate [XMo8O31]n- (X = Ge(1) or P(2)) manganese carbonyl derivatives [(CH3)4N]6H6{MnII(GeMo8O31)[MnI(CO)3]2}2.12H2O (1) and [(CH3)4N]4H6{MnII(PMo8O31)[MnI(CO)3]2}2.14H2O (2), have been successfully synthesized and characterized in the solid state by single crystal X-ray diffraction, IR and thermogravimetric analysis, and in solution by UV-Vis spectroscopy and electrochemistry. The two polyoxomolybdate-based organometallic compounds 1 and 2 represent rare examples of transition metal sandwich-based polyoxometalate metal carbonyl derivatives (PMCDs), in which the organic inorganic hybrids are composed of four Mn(CO)3+ groups symmetrically occupied the tetravacant sites of dimeric heteropolyoxomolybdate {Mn2(XMo8O31)2}n- through MnI O-Mo bonds. The carbonyl functionalized Mn atoms are octahedrally coordinated via three MU2-oxygens of the [XMo8O31]n- unit and three carbonyl carbon atoms. Interestingly, 1 and 2 form a psedocuboidal ring Mn(CO)3Mo3O12 with {Mn(CO)3}+ occupying the three fold axis of the Mo3O12 octahedral triad. Beside this, the two centrally placed adjacent MnII atoms show intramolecular Mn???Mn interactions of 3.11 and 3.16 A in 1 and 2, respectively. Significant n->pi* and O...O intermolecular interactions between the orthogonally aligned adjacent carbonyl groups through the overlap of lone-pair electrons on oxygen atoms with the antibonding orbital (pi*) of the adjacent carbony carbon atom of the subsequent units in 1 and 2 were observed. The electrochemical properties of the two compounds were also been investigated. PMID- 28805741 TI - Alcohol and Cancer: Mechanisms and Therapies. AB - Several scientific and clinical studies have shown an association between chronic alcohol consumption and the occurrence of cancer in humans. The mechanism for alcohol-induced carcinogenesis has not been fully understood, although plausible events include genotoxic effects of acetaldehyde, cytochrome P450 2E1 (CYP2E1) mediated generation of reactive oxygen species, aberrant metabolism of folate and retinoids, increased estrogen, and genetic polymorphisms. Here, we summarize the impact of alcohol drinking on the risk of cancer development and potential underlying molecular mechanisms. The interactions between alcohol abuse, anti tumor immune response, tumor growth, and metastasis are complex. However, multiple studies have linked the immunosuppressive effects of alcohol with tumor progression and metastasis. The influence of alcohol on the host immune system and the development of possible effective immunotherapy for cancer in alcoholics are also discussed here. The conclusive biological effects of alcohol on tumor progression and malignancy have not been investigated extensively using an animal model that mimics the human disease. This review provides insights into cancer pathogenesis in alcoholics, alcohol and immune interactions in different cancers, and scope and future of targeted immunotherapeutic modalities in patients with alcohol abuse. PMID- 28805743 TI - Inhibitors of the Detoxifying Enzyme of the Phytoalexin Brassinin Based on Quinoline and Isoquinoline Scaffolds. AB - The detoxification of the phytoalexin brassinin to indole-3-carboxaldehyde and S methyl dithiocarbamate is catalyzed by brassinin oxidase (BOLm), an inducible fungal enzyme produced by the plant pathogen Leptosphaeria maculans. Twenty-six substituted quinolines and isoquinolines are synthesized and evaluated for antifungal activity against L. maculans and inhibition of BOLm. Eleven compounds that inhibit BOLm activity are reported, of which 3-ethyl-6-phenylquinoline displays the highest inhibitory effect. In general, substituted 3 phenylquinolines show significantly higher inhibitory activities than the corresponding 2-phenylquinolines. Overall, these results indicate that the quinoline scaffold is a good lead to design paldoxins (phytoalexin detoxification inhibitors) that inhibit the detoxification of brassinin by L. maculans. PMID- 28805744 TI - Aptamer Cell-Based Selection: Overview and Advances. AB - Aptamers are high affinity single-stranded DNA/RNA molecules, produced by a combinatorial procedure named SELEX (Systematic Evolution of Ligands by Exponential enrichment), that are emerging as promising diagnostic and therapeutic tools. Among selection strategies, procedures using living cells as complex targets (referred as "cell-SELEX") have been developed as an effective mean to generate aptamers for heavily modified cell surface proteins, assuring the binding of the target in its native conformation. Here we give an up-to-date overview on cell-SELEX technology, discussing the most recent advances with a particular focus on cancer cell targeting. Examples of the different protocol applications and post-SELEX strategies will be briefly outlined. PMID- 28805745 TI - Insulin Resistance and NAFLD: A Dangerous Liaison beyond the Genetics. AB - Over the last decade, the understanding of the association between insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD) has dramatically evolved. There is clear understanding that carriers of some common genetic variants, i.e., the patatin-like phospholipase domain-containing 3 (PNPLA3) or the transmembrane 6 superfamily member 2 (TM6SF2) are at risk of developing severe forms of NAFLD even in the presence of reduced or absent IR. In contrast, there are obese patients with "metabolic" (non-genetically driven) NAFLD who present severe IR. Owing to the epidemic obesity and the high prevalence of these genetic variants in the general population, the number of pediatric cases with combination of genetic and metabolic NAFLD is expected to be very high. Gut dysbiosis, excessive dietary intake of saturated fats/fructose-enriched foods and exposure to some chemicals contribute all to both IR and NAFLD, adding further complexity to the understanding of their relationship. Once NAFLD is established, IR can accelerate the progression to the more severe form of liver derangement that is the non-alcoholic steatohepatitis. PMID- 28805747 TI - What Is Nutritious Snack Food? A Comparison of Expert and Layperson Assessments. AB - The term "nutritious" is being increasingly used by product manufacturers but the term is not currently regulated as a nutrition claim. It is unclear how lay consumers and experts define and interpret the term or how they evaluate the "nutritiousness" of various foods. To address this evidence gap, a mixed methods design was applied and both nutrition experts (n = 206) and lay participants (n = 269) provided definitions of the term "nutritious" and evaluated the "nutritiousness" of 20 different snack foods in a cross-sectional survey. Definitions were analysed using Leximancer and snack evaluations were compared both between groups and with nutrient profile scores (UK Ofcom and Australian Health Star Rating). Expert and lay definitions differed considerably, with experts using terms such as nutrient-density, macro- and micronutrients, kilojoules/Calories, while lay consumers used descriptions such as fuel, fresh, natural, body needs, and functioning. Snack evaluations were highly correlated between groups (Rs > 0.89, p < 0.001) and between nutrient profile scores (Rs > 0.75, p < 0.001). However, mean perceptions significantly differed for 18 out of 20 foods with the largest difference for yoghurts (p < 0.05). There are discrepancies between expert and lay perceptions of snack foods and the definition of the term "nutritious". The results highlight the need for an agreed definition and the potential regulation of the term "nutritious" in food marketing. PMID- 28805748 TI - Synthesis and Evaluation of Novel Benzofuran Derivatives as Selective SIRT2 Inhibitors. AB - A series of benzofuran derivatives were designed and synthesized, and their inhibitory activites were measured against the SIRT1-3. The enzymatic assay showed that all the compounds showed certain anti-SIRT2 activity and selective over SIRT1 and SIRT3 with IC50 (half maximal inhibitory concentration) values at the micromolar level. The preliminary structure-activity relationships were analyzed and the binding features of compound 7e (IC50 3.81 uM) was predicted using the CDOCKER program. The results of this research could provide informative guidance for further optimizing benzofuran derivatives as potent SIRT2 inhibitors. PMID- 28805749 TI - Food Addiction, Binge Eating Disorder, and Obesity: Is There a Relationship? AB - Existing research suggests that there is an overlap between binge eating disorder (BED) and the construct of 'food addiction' (FA). The objective of this study was to determine the overlapping features of BED and FA through a comparison of the individual scales of commonly used tools including the Binge Eating Scale (BES) and the Yale Food Addiction Scale (YFAS) in a sample of Australian adults. Adults (>18 years of age) were invited to complete an anonymous online survey on FA. Binge eating was assessed through the BES and addictive eating behaviours were assessed through the YFAS (n = 1344). The prevalence and severity of both FA and binge eating increased across weight categories. The overall correlation between the total score from the BES and FA symptoms was r = 0.76, p < 0.001; for females it was r = 0.77, p < 0.001, and for males it was r = 0.65, p < 0.001. Total BES score and the BES emotion factor were most often associated with FA symptoms, as was demonstrated to produce stronger correlations with FA symptoms. In contrast, the BES behaviour factor was less strongly associated to FA with the majority of correlations <0.6. This study demonstrates the overlap between BED and FA, and highlights the possible unique differences between the forms of disordered eating. PMID- 28805746 TI - Melanocortins, Melanocortin Receptors and Multiple Sclerosis. AB - The melanocortins and their receptors have been extensively investigated for their roles in the hypothalamo-pituitary-adrenal axis, but to a lesser extent in immune cells and in the nervous system outside the hypothalamic axis. This review discusses corticosteroid dependent and independent effects of melanocortins on the peripheral immune system, central nervous system (CNS) effects mediated through neuronal regulation of immune system function, and direct effects on endogenous cells in the CNS. We have focused on the expression and function of melanocortin receptors in oligodendroglia (OL), the myelin producing cells of the CNS, with the goal of identifying new therapeutic approaches to decrease CNS damage in multiple sclerosis as well as to promote repair. It is clear that melanocortin signaling through their receptors in the CNS has potential for neuroprotection and repair in diseases like MS. Effects of melanocortins on the immune system by direct effects on the circulating cells (lymphocytes and monocytes) and by signaling through CNS cells in regions lacking a mature blood brain barrier are clear. However, additional studies are needed to develop highly effective MCR targeted therapies that directly affect endogenous cells of the CNS, particularly OL, their progenitors and neurons. PMID- 28805750 TI - Inositol Derivatives and Phenolic Compounds from the Roots of Taraxacum coreanum. AB - In this study, the characterization of chemical constituents and biological activity of the roots of Taraxacum coreanum (Asteraceae) was attempted. Phytochemical investigation of the roots of T. coreanum led to the isolation of two new inositol derivatives, taraxinositols A (1) and B (2), and a new phenolic compound, taraxinol (16), together with twenty known compounds including four inositol derivatives, neo-inositol-1,4-bis (4-hydroxybenzeneacetate) (3), chiro inositol-1,5-bis(4- hydroxybenzeneacetate) (4), chiro-inositol-2,3-bis (4 hydroxybenzeneacetate) (5) and chiro-inositol- 1,2,3-tris (4 hydroxybenzeneacetate) (6), nine phenolic compounds: p-hydroxybenzaldehyde (7), vanillin (8), syringaldehyde (9), vanillic acid (10), 4-methoxyphenylacetic acid (11), 4-hydroxy- phenylacetic acid methyl ester (12), optivanin (13), isoferulic acid (14) and dihydroconiferyl alcohol (15), four coumarins: nodakenetin (17), decursinol (18), prangol (19) and isobyakangelicin (20), and three lignans: syringaresinol-4'-O-beta-d-glucoside (21), syringaresinol (22), and pinoresinol (23). The structures of isolated compounds were determined on the basis of spectroscopic analysis. Among the isolated compounds, vanillic acid, isoferulic acid and syringaresinol showed radical scavenging activity with IC50 values ranging from 30.4 to 75.2 MUM. PMID- 28805751 TI - Characterization of Quadratic Nonlinearity between Motion Artifact and Acceleration Data and its Application to Heartbeat Rate Estimation. AB - Accelerometers are applied to various applications to collect information about movements of other sensors deployed at diverse fields ranging from underwater area to human body. In this study, we try to characterize the nonlinear relationship between motion artifact and acceleration data. The cross bicoherence test and the Volterra filter are used as the approaches to detection and modeling. We use the cross bicoherence test to directly detect in the frequency domain and we indirectly identify the nonlinear relationship by improving the performance of eliminating motion artifact in heartbeat rate estimation using a nonlinear filter, the second-order Volterra filter. In the experiments, significant bicoherence values are observed through the cross bicoherence test between the photoplethysmogram (PPG) signal contaminated with motion artifact and the acceleration sensor data. It is observed that for each dataset, the heartbeat rate estimation based on the Volterra filter is superior to that of the linear filter in terms of average absolute error. Furthermore, the leave one out cross validation (LOOCV) is employed to develop an optimal structure of the Volterra filter for the total datasets. Due to lack of data, the developed Volterra filter does not demonstrate significant difference from the optimal linear filter in terms of t-test. Through this study, it can be concluded that motion artifact may have a quadaratical relationship with acceleration data in terms of bicoherence and more experimental data are required for developing a robust and efficient model for the relationship. PMID- 28805752 TI - Assessment of Typical Heavy Metals in Human Hair of Different Age Groups and Foodstuffs in Beijing, China. AB - Human hair of different age groups and foodstuff samples were collected in Beijing, China. The concerned metals-Cd, Cr, Pb, As, and Hg-were analyzed, and the metal levels in relation to age, gender, and dietary intake were further assessed. Results showed the highest level of the metals was shown by Pb, with an average concentration of 1.557 +/- 0.779 mg/kg, followed by Cr (0.782 +/- 0.394), Hg (0.284 +/- 0.094), As (0.127 +/- 0.078), and Cd (0.071 +/- 0.032), following a decreasing order of Pb > Cr > Hg > As > Cd, which were all below the upper limit of normal values in China. The heavy metal concentrations varied greatly among different age groups, and higher concentrations for Cd, Cr, Pb, and As appeared in female hair, whereas higher Hg concentration were found in male hair, suggesting that age and gender were not crucial factors for assessing metal concentrations in human hair. The ingestion of cereals and vegetables were the main route by which heavy metals in the environment create hazardous health effects for local inhabitants, but the estimated metal intakes through food consumption were all lower than the proposed limit of Provisional Tolerable Weekly Intake (PTWI), indicating that heavy metals posed no health risks for the inhabitants. Furthermore, little relationship was found between metal intakes and the corresponding metal levels in hair. Nevertheless, the results of this study can be used to analyze the internal heavy metal burden in the resident population of Beijing area and can also serve as reference for further studies. PMID- 28805753 TI - [Prognostic significance of leukocyte count in the venous blood in the acute stage of cerebral aneurism rupture]. AB - AIM: To determine a prognostic role of leukocyte count in the venous blood in the acute stage of cerebral aneurysm (CA) rupture. MATERIAL AND METHODS: Fifty-one patients with CA rupture, aged from 20 to 65 years, hospitalized in the first 72 h over the period from 01.10.12 to 01.02.16 were examined. The severity of disease and anatomical form of hemorrhage was corresponded to III-IV degree on the W. Hunt - R. Hess scale and Fisher scale. All patients underwent surgery. Outcomes after open and endovascular surgeries were similar. RESULTS: Normal leukocyte number in the venous blood at admission was identified in 12 (24%) of patients (on average 7.3+/-1.4.109/L), leukocytosis in 39 (76%) (14.3+/ 3.1.109/L) (p<0.0001). Leukocyte number in the acute stage of CA rupture was correlated with the frequency and severity of the vessel spasm. In 28 (55%) of patients with ischemic lesions of the brain matter, mean leukocyte number in the first 72 h after hemorrhage was higher by 2-24% (3+/-4.8.109/L) compared to patients without ischemia (11.9+/-2.5.109/L) (p=0.06). The level of leukocytes in survivors was lower by 3 - 28% (122+/-3.4.109/L) compared to patients with fatal outcome and patients with severe neurological deficit after the surgery (14.5+/ 3.9.109/L) (p>0.05). CONCLUSION: The increase in leukocyte number in the venous blood in the first 72 h after CA rupture >=10,1.109/L is a reliable risk factor of marked vessel spasm. The level of leukocytes in patients with cerebral ischemia and poor prognosis in the first 72h after aneurysmal hemorrhage was higher by 2-28% compared to survivors without neurological impairment or mild neurological deficit. PMID- 28805754 TI - [A phenomenological analysis of non-suicidal self-injuries in adolescents]. AB - AIM: To perform a phenomenological/clinical/psychopathological analysis of non suicidal self-injury behavior (NSSI) in adolescents. MATERIAL AND METHODS: The authors studied 155 adolescents, 140 girls and 15 boys, aged 12-17 years, including 111 with self-cutting, 5 with self-burning, 4 with self-beating. Other cases included combined, multiple and other variants of NSSI. RESULTS AND CONCLUSION: NSSI develop more often in female teenagers. NSSI may be a component of suicidal behavior or represent a relatively independent behavioral model existing out of a suicidal context. NSSI behavior can be considered as psychological defense as well as a coping strategy in response to nonspecific stress. PMID- 28805755 TI - [An analysis of postoperative cognitive dysfunction in different methods of coronary artery bypass]. AB - AIM: To evaluate changes in cognitive functions in patients with coronary heart disease before and after coronary artery bypass grafting (CABG) in a planned manner. MATERIAL AND METHODS: The study included 192 patients divided into 3 groups: in group 1 patients (n=88) underwent standard CABG; in group 2 (n=61) different methods of CABG were used; a control group consisted of 43 people. MMSE, FAB, Clock drawing test, Shultz tables, semantic verbal fluency, Wechsler adult intelligence scale were used for neurological testing. RESULTS AND CONCLUSION: Postoperative cognitive dysfunction develops 3.2 times more often in patients after standard CABG. Patients in the group with a differentiated approach show a trend towards the improvement of cognitive functions after surgery. PMID- 28805756 TI - [An experience of neurophysiological monitoring in neurosurgery]. AB - AIM: To evaluate the efficacy of neuromonitoring methods in prevention of postoperative neurological complications and estimation of predictive power of intraoperative changes in monitored characteristics. MATERIAL AND METHODS: Retrospective study examined 240 patients, operated in the years 2014-2015 using intraoperative neurophysiological monitoring. One hundred and seventy-three patients suffered from hemispheric lesions and 67 had lesions located in or near the brainstem. Somatosensory evoked potentials (SSEP) were monitored in 152 cases, visual in 32, brainstem acoustic in 22, transcranial motor in 36; stimulation mapping of motor cortex was performed in 69 surgeries, and cranial nerves identification in 27. EEG was recorded in 7 patients, and 3 of them were woke up during the surgery for speech mapping. RESULTS: The sensitivity of the SSEP in motor dysfunction detection was low (33%), while the specificity was relatively high (82%). These characteristics for visual and motor evoked potentials were close to 100% provided that the parameters of anesthesia met the corresponding requirements. The most effective methods in respect of prevention of postoperative dysfunctions were the stimulation mapping of functionally significant areas (motor and speech) and motor pathways mapping. CONCLUSION: Intraoperative neuromonitoring reduces a number of neurological complications after neurosurgical operations. The SSEP method is not sensitive enough in surgeries that could affect motor centers and/or pathways, and multimodal monitoring combining SSEP and motor responses recording during transcranial and/or direct electrical brain stimulation. Successful monitoring requires highly coordinated actions between neurophysiologists, neurosurgeons and anesthesiologists. PMID- 28805757 TI - [The influence of Cytoflavin therapy on the cerebral hemodynamics in patients with various stages of hypertensive disease]. AB - AIM: To study an influence of cytoflavin therapy on the cerebral hemodynamics in patients with various stages of hypertensive disease (HD). MATERIAL AND METHODS: One hundred and forty patients with HD, I-III stages, were randomized into 2 groups: patients of group 1 received complex treatment (antihypertensive therapy and cytoflavin), patients of group 2 were treated with antihypertensive therapy. The control group consisted of 30 healthy people. The changes in cerebral hemodynamics using the algorithm of the complex ultrasound study of cerebral vascular system were assessed. RESULTS: Disturbances of hemodynamics at all structural/functional levels of cerebral vascular system were found in all HD stages. There were a decrease in the blood flow through the common carotid, inner carotid, spinal and middle cerebral arteries, reactivity of veins of Rosenthal, blood flow through veins of Rosenthal and inner jugular veins and an increase of blood flow through spinal veins. The hemodynamic study showed that in group 1 there was the increase of blood flow through common carotid, inner carotid, middle cerebral arteries in stage I and through spinal arteries in stage I-II of HD; improvement of the reactivity of veins of Rosenthal, restoration of blood flow parameters through the veins of Rosenthal and inner jugular veins to control values, the decrease in blood flow velocity through the spinal veins in all HD stages. CONCLUSION: HD is accompanied by the damage of all structural/functional levels of cerebral vascular system. The use of cytoflavin in the complex therapy of HD exerts a positive influence on the cerebral hemodynamics reducing the severity of arterial insufficiency in the initial stages of disease, improving microcirculation and venous hemodynamics in all HD stages. PMID- 28805758 TI - [Preventive treatment of tension headache in children and adolescents]. AB - AIM: To assess the efficacy of noophen (gamma-amino-beta-phenylbutyric acid hydrochloride) in the preventive treatment of tension-type headache (TTH) in children and adolescents. MATERIAL AND METHODS: The study included 30 patients with TTH, aged from 8 to 16 years, treated with noophen in dose of 15-20 mg/kg per day (2-3 times perorally) during 2 month. Before and during the treatment characteristics of headache, its influence on daily activities were assessed with HIT-6 and PedMIDAS, anxiety disorders were assessed with SCAS, the dynamics of sleep disturbances in children were evaluated. RESULTS AND CONCLUSION: A significant decrease in the frequency, duration and intensity of TTH as well as positive changes in daily life activities and reduction of anxiety and sleep disorders manifestations, which are the risk factors for TTH, were demonstrated during the treatment with noophen. Starting from the first month of treatment, there was a significant decrease in the number of days completely lost because of headache and days with the reduced activity (a decrease in the productivity by >50%). PMID- 28805759 TI - [Diagnosis and treatment of dorsopathy in patients with connective tissue dysplasia]. AB - AIM: To study the pathogenesis, clinical manifestations and treatment of dorsopathy in patients with connective tissue dysplasia. MATERIAL AND METHODS: Thirty-six patients, aged from 18 to 45 years, with lumbar-sacral radiculopathies associated with connective tissue dysplasia were examined. Detailed neurological examination, X-ray visualization and MRI of lumbosacral spine section, electromyographic assessment were performed. A five-point scale of neuro vertebrological symptoms, the Numerical Rating Scale (NRS) and the Roland-Morris Low Back Pain and Disability Questionnaire were used. RESULTS AND CONCLUSION: The results contained own data on the pathogenesis, clinical manifestations and treatment of dorsopathies in connective tissue dysplasias. Inclusion of long acting pentoxifylline (vasonite) in the combined therapy in patients with dorsopathy associated with connective tissue dysplasia had a positive effect on disease course, decreased pain intensity and improved life activities. PMID- 28805760 TI - [Mapping of motor-points in the flexor muscles of the arm for the optimization of botulinum toxin injections in treatment of spasticity]. AB - AIM: To study the location and verification of motor points (MP) of the upper limbs for targeting botulinum toxin (BT) type A injections in the treatment of spasticity. MATERIAL AND METHODS: Twenty healthy people were examined. Using electromyography a complete study of the muscles of the upper limbs was conducted. RESULTS: Anatomical localization of MP was performed. The location of MP is identical and does not depend on sex, age and the dominant limb. Tables and maps of MP locations are presented. CONCLUSION: MP in the flexor muscles of the arm were identified. A surface map with MP location was created. This data may improve the clinical efficacy and feasibility of MP targeting, when injecting BT in spasticity. PMID- 28805761 TI - [Treatment of depression complicated by abuse and dependence on alcohol]. AB - AIM: To evaluate the efficacy of different treatment regimens of depression complicated by abuse and dependence on alcohol and to identify the most effective tactics of treatment. MATERIAL AND METHODS: One hundred patients with depression were studied. Examination of patients was conducted using clinical psychopathological method, the MADRS (at admission, on the 1st, 2nd, 4th and 6th week of treatment) and CGI scale (in the beginning of treatment and on 6th week). Data analysis using standard statistical indicators was performed. In accordance with the therapeutic tactics, patients were stratified into three groups: patients, treated with a combination of antidepressants, antipsychotics and mood stabilizers (group 1); antidepressants and antipsychotics (group 2); antidepressants and mood stabilizers (group 3). RESULTS: In group 1, a reduction in MADRS scores was significantly higher compared to other groups (8.53 points, p<=0.01). On the 6th week, 50% of the patients showed complete or almost complete remission, and the state of 44.7% patients was classified as 'mild disorders'. In group 3, serious condition remained in 16.7% of patients by the end of the 6th week. By the 6th week of treatment, 39.5% of patients of group 1 had 'very significant improvement'. The least treatment efficacy was noted in group 3. CONCLUSION: The use of the combination of antidepressants, antipsychotics and mood stabilizers demonstrates the greatest efficacy in terms of reduction of depressive symptoms. PMID- 28805762 TI - [A study of combination treatment with nacom (levodopa + carbodope) and citicoline in the model of Parkinson disease in rats]. AB - AIM: To evaluate the efficacy of the combined use of citicoline (neipilept) and levodopa/carbidopa (nakom) in the rotenone model of Parkinson's disease in rats. MATERIAL AND METHODS: Rotenone was administrated during 14 days in dose 2 mg/kg/day subcutaneously. The duration of treatment was 7 days, intragastrically. Alteration of locomotor behavior components, muscular rigidity in resistance to passive flexion in the ankle joint and signs of extrapyramidal disorders were assessed. RESULTS AND CONCLUSION: Combined therapy led to the decrease in muscle rigidity (the decrease of gibbosity in resistance to passive flexion in the ankle joint). There was a decrease in oligokinesia that emerged in higher vertical and horizontal locomotor activity of experimental animals, decrease in the time of head turning during climbing down the pole and total time of climbing down the pole. The combination of drugs had a more pronounced therapeutic effect on extrapyramidal disorders compared to monotherapy. PMID- 28805763 TI - [Angiogenesis mechanisms in the formation of structural changes of brain tissue in patients with progressive cerebrovascular disease]. AB - AIM: To study the correlation between expressiveness of focal changes of brain tissue and VEGF and MCP-1 levels in plasma and blood serum of patients with chronic cerebral ischemia (CCI). MATERIAL AND METHODS: Markers of inflammation (MCP-1, CRP) and angiogenesis (VEGF) in serum and blood plasma of 35 patients with CCI depending on expressiveness of structural changes of brain substance according to MRI were investigated. RESULTS: The increase in MCP-1 and CRP content in blood serum and simultaneous decrease in VEGF level in serum and blood plasma were correlated with the increase in the number of focal changes of substance of the brain in patients with CCI. PMID- 28805764 TI - [Behavioral phenotyping in rats during the experimental modeling of chronic cerebral circulation disorder]. AB - AIM: To describe motor, adaptive and cognitive disorders in rats with chronic cerebral circulatory deficiency caused by partial stenosis of the common carotid arteries (CCA). MATERIAL AND METHODS: A study was performed on 20 white outbred male rats. This manipulation led to 40-45% and 50-60% reduction of blood flow in CCA and in the brain, respectively. Twenty days after operation, animal's condition was assessed in the following tests: open field test, rotarod performance test, marble burying test and novel object recognition. RESULTS AND CONCLUSION: After 20 days of experimental CCA stenosis, animals demonstrated several signs of neuropsychiatric deficiency including coordination disorders, a decrease in locomotor activity as well as in explorative and protective behavior. The model of CCA partial stenosis could be used during further studies of the pathophysiology and pharmacology of chronic cerebral circulatory deficiency. PMID- 28805765 TI - [Systemic inflammatory markers in age-associated cognitive impairment and Alzheimer's disease]. AB - AIM: To determine a complex of immune markers reflecting various links of multicomponent inflammatory reactions in amnestic type of mild cognitive impairment (aMCI) in comparison with Alzheimer's disease (AD). MATERIAL AND METHODS: Sixty-seven patients with aMCI, aged 72 [63; 77] years, and 91 patients with Alzheimer's disease at the age of 74 [68; 79] years were examined. The aMCI was diagnosed according to the criteria of R.S. Petersen et al. (1999) and B. Dubois et al. (2014). The diagnosis of AD was established in accordance with the ICD-10 and NINCDS-ADRDA criteria. The degree of dementia severity was determined by clinical signs using the CDR (Clinical Dementia Rating) and the Mini Mental State Examination (MMSE) total score. The control group included 38 age- and sex matched individuals. Immune and biochemical parameters were determined in blood plasma. The activity of LE and alpha1-PI was determined by spectrophotometric method. Concentrations of IL-6 and CRP were measured by enzyme immunoassay. RESULTS: AD was characterized by the significant decrease in LE activity (p<0.0001) and increase in the activity/levels of alpha1-PI, CRP and IL-6 (p<0.001; p<0.05; p<0.01, respectively) compared to controls. CDR and MMSE scores were correlated with the LE activity (r=-0.38, r=0.31, p<0.05), i.e. cognitive decline was associated with decreased activity of LE. aMCI was characterized by the significant increase in the activity/level of alpha1-PI and IL-6 (p<0.0001; p<0.01). In 30% of patients with aMCI, a spectrum of inflammatory markers, typical for patients with AD, was determined. CONCLUSION: Based on the results of comparative analysis of aMCI and AD, one can suggest that one third of patients with aMCI represents a group of ultra-high risk of AD. These patients need a dynamic follow-up with a regular assessment of the state of cognitive functions and possibly preventive therapy. PMID- 28805766 TI - [Results of a clinical and genealogical analysis of pedigrees of children with cerebral palsy in the population of Rostov region]. AB - AIM: To perform clinical and genealogical pedigree analysis and determine the proportion of hereditary factors in the etiopathogenesis of cerebral palsy (CP) in children in the Rostov Region. MATERIAL AND METHODS: Pedigrees and the prevalence of CP, congenital malformations and other related diseases among relatives of I, II and III degrees of kinship of 229 probands with CP were studied. RESULTS AND CONCLUSION: The family concentration of the disease was detected in 15 (6.6%) cases. There were 96 (41.9%) pedigrees with probands with a family history and 118 (51.5%) without family history of CP. The frequency of CP was by 19.2 times higher in the relatives of probands in the families with a history of disease and 2.2 times higher in the siblings compared to the population frequency. The frequency of congenital malformations in the relatives of probands in this group was 23.8 times higher, while in the group of probands with a family history 14.9 times higher than the expected value. Miscarriages and stillbirths preceded the birth of children with CP in 29.2-33.3% of the mothers, and percentage of unrealized pregnancies ranged from 16.7 to 18.7%. CP in 51.5% of cases can be considered as a sporadic disease, and in 48.5% of cases it was genetically determined and can be attributed to a group of multifactorial diseases with polygenic determination of genetic predisposition components. PMID- 28805767 TI - [W. Griesinger - a famous European psychiatrist (the 200 anniversary of birth)]. AB - The article contains curriculum vitae of W. Griesinger and an analysis of the clinical-psychopathological approach developed by him for studying illnesses and their systematization. The stages of psychosis' progression in dynamics are shown. A clinical description of primary emerged dementia made by W. Griesinger as well as a description of the status of Grubelsucht, first discovered by the psychiatrist, are presented. The article emphasizes W. Griesinger' priority in the determination of reflexes' exclusive role in the appearance and further development of all types of mental disorders. W. Griesinger's conviction in the necessity of more close interaction of neurology and psychiatry is highlighted. PMID- 28805768 TI - [Organization of out-patient psychiatric care in dementia and cognitive impairment in aged. Part II: Clinical and economic efficacy of memory clinics and Alzheimer's disease centers]. AB - The part II of the review is focused on a history of developing of memory clinics and Alzheimer's disease centers as well as on the indices of their activity in various countries and in Russia. Approaches to the evaluation of clinical and economic efficacy of new technologies of organization of care and a role of the national programs in solving of the problem of old age dementias were considered. PMID- 28805769 TI - [New classifications of epilepsies and seizure types created by the International League against Epilepsy (2017)]. AB - This review presents the recently published revised classifications of epilepsies and seizure types developed by the International League Against Epilepsy (ILAE). The Classification of Epilepsies includes several diagnostic levels (steps): 1) from seizure type to epilepsy type (generalized/focal/combined generalized and focal/unknown), 2) diagnosis of epilepsy syndrome 3) etiology (genetic/ structural/ infectious/ metabolic/ immune/unknown). A clinician can use any level of the classification. Operational classification of seizure types is replaced by the previous classification that was grounded on the anatomical basis. Seizures are classified by the onset (focal, generalized or unknown). All types of seizures can be motor or non-motor. Focal seizure may evolve to bilateral tonic clonic (previously called secondary-generalized). Atonic, clonic, tonic, myoclonic seizures and epileptic spasms can be either of focal or generalized onset. Unclassified type of seizure was introduced. New types of seizures (absence with eyelid myoclonia, myoclonic absence, myoclonic atonic and clonic tonic-clonic seizures) were added. New terminology, definitions and some concepts developed by ILAE are presented. PMID- 28805770 TI - [Psychiatry of the future: an overview of foreign scientists opinions of the position of psychiatry in the modern world]. AB - First part of this review (Chapter 1) demonstrates an ambiguous attitude toward psychiatry among professionals and in society in recent decades. The articles of supporters and opponents of psychiatry are also quoted. The authors describe the dynamics of the reflection of psychopathology in the main widely accepted classifications and manuals. Critical and negative opinions regarding the DSM-5, due to its role in the 'medicalization' processes, for the movement 'World Mental Health', are mentioned. The history of antipsychiatry movement and its results for psychiatry and society are analyzed as well. An analysis of the articles on the scientific basis of psychiatry and its intersections with other sciences is presented. Several examples of studies on brain networks in correlation with clinical data, which may have possible implications for the future, are quoted. The authors call for the 'cure for dichotomy' between mind and brain before treatment of the patient. According to the analysis of available data, this problem seems too hard to be solved, as it requires theological knowledge, of which we probably have not enough knowledge. PMID- 28805771 TI - [Synergistic application of zinc and vitamin C to support memory, attention and the reduction of the risk of the neurological diseases]. AB - Zinc and vitamin C supplementation of the body is important for CNS functioning. Zinc ions are involved in the neurotransmission (signal transmission from acetylcholine, catecholamine, serotonin, prostaglandin receptors) and in ubiquitin-related protein degradation. Zinc deficits are associated with Alzheimer's disease and depression. Zinc supplementation (10-30 mg daily) improves neurologic recovery rate in patients with stroke and brain injury, has a positive impact on memory and reduces hyperactivity in children. Vitamin C, a zinc synergist, maintains antioxidant resources of the brain, synaptic activity and detoxification. Vitamin C in dose 130-500 mg daily should be used to prevent dementia and neurodegenerative pathology. PMID- 28805772 TI - [Diagnosis and treatment of extracranial internal carotid artery lesion combined with cerebrovascular malformation]. AB - AIM: To analyze own experience of diagnosis and treatment of patients with extracranial internal carotid artery lesion and cerebrovascular malformations. MATERIAL AND METHODS: There were 16 patients with combined lesion of extracranial and intracranial internal carotid artery for the period January 2013 - December 2014. Occlusive-stenotic lesion and tortuosity of ICA were observed in 11 and 5 cases respectively. RESULTS: Incidence of combined ICA lesion was 5.2% (16 out of 308 observations of extracranial internal carotid artery lesion). Surgical treatment was performed in 7 patients including two-stage intervention in 4 cases and simultaneous surgery in 3 cases. Mean time between neurosurgical and vascular stages was 6 months. Complications and mortality were absent. CONCLUSION: Two stage surgical approach with intracerebral vascular malformation correction followed by extracranial ICA reconstruction may be safe and effective in patients with combined lesion of ICA. Further trials are necessary for certain conclusions. PMID- 28805773 TI - [Comparative long-term results of surgical treatment of patients with diffuse toxic goiter]. AB - AIM: To analyze long-term outcomes of Graves' disease management. MATERIAL AND METHODS: There were 428 patients for the periods 2000-2004 and 2005-2010. Patients were called for examination and thyroid status control. 2 groups were compared: group 1 of 203 patients and group 2 of 225 patients. RESULTS: It was found that after subtotal resection by original technique (patent 1802309 of the Russian Federation, MPK 5 G01N1, 1/28) in group 1 euthyroid state was observed in more than half (59.4%) of patients, hypothyroidism - 30.3% and recurrence - in 10.3% 10 years postoperatively. At the same time most of patients of group 2 (71.6%) after predominant thyroidectomy had hypothyroidism, euthyroid state was only in 24%. Postoperative recurrent diffuse toxic goiter incidence was 4.7%. CONCLUSION: The dynamics of postoperative thyroid status depending on type of surgery and follow-up was presented. PMID- 28805774 TI - [Laparoscopic-assisted harvesting of omental flap in chest wall reconstruction for deep sternal wound infection]. AB - AIM: To present an experience of laparoscopic-assisted harvesting of omental flap in chest wall reconstruction for deep sternal wound infection. MATERIAL AND METHODS: It was made a prospective analysis of 14 patients aged 39-85 years after laparoscopic-assisted harvesting of omental flap in chest wall reconstruction for the period December 2014 - November 2016. Men/women ratio was 10/4. All patients had deep sternal wound infection grade IV (Oakley-Wright classification). RESULTS: Postoperative complications were observed in 2 (14.3%) of 14 (95% CI: 4.0-39.9%) cases that did not require re-operation. There were no 30-day postoperative mortality and significant complications as acute intestinal obstruction, postoperative ventral herniation and transplant rejection. Mean postoperative hospital-stay was 10.5 (9; 13) days. CONCLUSION: Laparoscopic assisted harvesting of omental flap is safe method for chest wall reconstruction in patients with severe sternal wound infection associated with soft tissue deficiency and high risk of local complications (bleeding, etc.). Laparoscopy significantly reduces incidence of postoperative complications after omental flap transposition and is feasible in majority of patients. PMID- 28805776 TI - [Diagnostic and curative bronchoscopy for purulent-destructive pulmonary diseases]. AB - AIM: To assess an efficacy of diagnostic and curative bronchoscopy in patients with purulent-destructive pulmonary diseases. MATERIAL AND METHODS: Diagnosis and treatment of 34 patients with purulent-destructive pulmonary diseases including small-focal destruction (14) and lung abscesses (19) were analyzed. 33 patients underwent diagnostic fibrobronchoscopy (FBS) with brush and transbronchial biopsy. Curative endoscopy included bronchial tree sanation, peribronchial administration of antibiotics (5) and transbronchial drainage of abscess (14). RESULTS: Atrophic bronchitis and cicatricial deformity of the 2-3rd segmental bronchi were revealed in 81.8% and 15.2% respectively. Transbronchial biopsy confirmed malignant neoplasms (15.2%) and pulmonary tuberculosis (6.1%). Peribronchial administration of amikacin in patients with small-focal pulmonary destruction and transbronchial drainage of abscesses accelerated pulmonary tissue repair and complete recovery. CONCLUSION: Transbronchial biopsy in patients with destructive pulmonary diseases verifies pathological process and excludes malignant and specific pulmonary damage. Complex use of endoscopic methods is associated with positive clinical result in all patients with pulmonary destruction. PMID- 28805775 TI - [The features of diagnosis and treatment of traumatic and non-traumatic pulmonary bleeding]. AB - AIM: To analyze an efficacy of differentiated approach for pulmonary bleeding of different etiology and severity. MATERIAL AND METHODS: The study included 134 cases of pulmonary bleeding for the period 2006-2015 including 53 patients with traumatic and 81 with non-traumatic etiology. Men/women ratio was 2.7:1, mean age was 43 years. Comparative retrospective analysis of X-ray and CT data in diagnosis of bleeding source was performed. Bronchoscopy was used to confirm these data. There were 43 endovascular examinations including 40 cases of bronchial arteriography (BAG). RESULTS AND DISCUSSION: X-ray and CT-signs of bleeding source were detected more often in case of traumatic pulmonary bleeding (62.3% and 93%) compared with non-traumatic (27.2 and 54%; p<0.05). Bronchoscopy revealed ongoing pulmonary bleeding in 40 (30%) patients, completed - in 94 (70%) patients. Indirect angiographic signs were the most frequent for pulmonary bleeding origin: hypervascularization (32.6%), bronchial-pulmonary shunts (23.2%) and bronchial artery dilatation (20.9%). 17 patients with ongoing bleeding underwent bronchial obstruction with adequate hemostasis in all cases. Endovascular interventions included bronchial arteries embolization (EBA) (33), occlusion of intercostal arteries (3) and segmental branches of low-lobar pulmonary artery (1), aortic stenting (1). Early efficacy of EBA was 97% with 2 month recurrence of pulmonary bleeding near 12.5%. Ongoing traumatic pulmonary bleeding was an indication for emergency thoracotomy in 18.9% compared with 12.3% for non-traumatic bleeding when surgery was made after endoscopic and endovascular hemostasis. CONCLUSION: Differentiated approach depending on etiology and severity of pulmonary bleeding improves outcomes and reduces the number of operations for ongoing severe bleeding. PMID- 28805777 TI - [Accelerated postoperative rehabilitation in patients undergoing pancreatoduodenectomy]. AB - AIM: To assess safety and clinical-economic effectiveness of complex postoperative rehabilitation after pancreatoduodenectomy. MATERIAL AND METHODS: 73 patients were included in the study. Main group consisted of 39 patients who underwent accelerated postoperative rehabilitation that was developed in our clinic. In the control group of 34 patients this protocol was not applied. The main components of rehabilitation were multicomponent analgesia, early enteral nutrition, physical rehabilitation by using of exercise therapy and physiotherapy. RESULTS: There were no significant differences in the incidence of postoperative complications and mortality (58.8% and 74.3%; p=0.213, 5.8% and 7.7%; p=0.678, respectively). Median of postoperative hospital-stay in the study group was 13 days (9; 16), in the control group - 15 days (9; 24). An estimated economic effect in the study group was 558 764, 84 rubles. CONCLUSION: Accelerated postoperative rehabilitation after pancreatoduodenectomy is safe and does not lead to increased number of postoperative complications and mortality. Developed protocol has clinical advantages and is cost-effective. PMID- 28805778 TI - [Metal self-expanding stents for malignant obstruction of stomach outlet and duodenum]. AB - AIM: To compare different types of self-expanding stents (partially coated or uncovered) for malignant pyloroduodenal obstruction (MPDO). MATERIAL AND METHODS: 89 MPDO patients underwent stenting at the Botkin City Hospital (Moscow) for the period 2008-2016. The causes of malignant obstruction were: stomach cancer - 53 (59.5%), pancreatic cancer - 31 (34.8%), compression by retroperitoneal lymph nodes - 3 (3.4%), duodenal cancer - 2 (2.2%). Patients were divided into two homogeneous groups. In group 1 (32 patients) partially coated stents were used, in group 2 (57 patients) - uncovered stents. Mean age was 68.3+/-6.2 and 64.3+/ 5.7 years in both groups respectively; male/female ratio 18/14 in group 1, 32/25 in group 2. Length of stricture was 51+/-5.1 mm in group 1, 48+/-4.8 mm in group 2. GOOSS score in group 1: 0-8, 1-13, 2-11, 3-0, in group 2 0-14, 1-25, 2-18, 3-0 (p=0.03). RESULTS AND DISCUSSION: Technical success was achieved in 32 patients of group 1 (100%) and in 57 patients of group 2 (100%). There were no procedure associated complications and mortality. Clinical success was observed in 29 (90.6%) patients of group 1 and in 50 (87.7%) patients of group 2. GOOSS score of group 1: 0-8, 1-8, 2-10, 3-12, group 2: 0-3, 1-15, 2-19, 3-20. There were 3 distal dislocations of the stent within 1 - days in group 1, in group 2 dislocations were absent. Postoperative chemotherapy was prescribed in 20 (62.5%) patients of group 1 and 38 (66.7%) patients of group 2 (p=0.08). 27 patients of group 1 and 49 patients of group 2 died due to progression of the disease, others are under observation. Mean life expectancy: group 1 (18 patients - 50 days, 9 patients - 100 days, 5 patients were alive by the moment of study); group 2 (32 patients - 50 days, 100 days - 17 patients, 8 patients were alive by the moment of study). 3 patients (9.4%) in group 1 and 7 (12.3%) patients in group 2 had stent dysfunction (p=0.02). Mean period of partially covered stent function was 138+/-3.9 days, uncovered stent - 96+/-4.8 days (r=0.003). CONCLUSION: Our study showed that time of stent function corresponds to median survival. Greater number of stent migration in group 1 is due to stent coverage, higher incidence of stent dysfunction in group 2 - due to malignant invasion. PMID- 28805779 TI - [Treatment of inflammatory complications of colic diverticular disease at the emergency surgical care hospital]. AB - AIM: To assess an effectiveness of minimally invasive and laparoscopic technologies in treatment of inflammatory complications of colic diverticular disease. MATERIAL AND METHODS: The study included 150 patients who were divided into control and main groups. Survey included ultrasound, X-ray examination and abdominal computerized tomography. In the main group standardized treatment algorithm including minimally invasive and laparoscopic technologies was used. RESULTS: In the main group 79 patients underwent conservative treatment, minimally invasive (ultrasound-assisted percutaneous drainage of abscesses) and laparoscopic surgery that was successful in 78 (98.7%) patients. CONCLUSION: Standardized algorithm reduces time of treatment, incidence of postoperative complications, mortality and the risk of recurrent inflammatory complications of colic diverticular disease. Also postoperative quality of life was improved. PMID- 28805780 TI - [Regional and peripheral blockades for prevention of chronic post-thoracotomy pain syndrome in oncosurgical practice]. AB - AIM: To compare an effectiveness of thoracic epidural anesthesia/analgesia, paravertebral and intercostal blockades in prevention of chronic post-thoracotomy pain syndrome (CPTPS) in oncosurgery. MATERIAL AND METHODS: There were 300 patients who underwent open surgery including lobectomy or pneumonectomy. Patients were randomized into 3 groups depending on type of anesthesia: TEA (n=100) - combined general and epidural anesthesia; PVB (n=50) - combined general and paravertebral anesthesia; ICB (n=50) - general anesthesia was supplemented by intercostal blockade after removal of the drug. RESULTS: CPTPS incidence was 34 and 40% in 6 months postoperatively after PVB and ICB, respectively (p>0.05). In TEA group this value was significantly lower compared with ICB group (23%, p<0.05). CONCLUSION: TEA contributes to significant reduction of CPTPS incidence, while paravertebral blockade does not affect the frequency of this complication. PMID- 28805782 TI - [Blunt chest trauma: possibilities to stabilize multiple and floating ribs fractures]. AB - AIM: To improve surgical treatment of patients with multiple and flotating ribs fractures. MATERIAL AND METHODS: A comparative analysis of two groups of victims with rib fractures was carried out. 148 patients of the control group underwent conservative treatment, mechanical ventilation, skeletal traction. In 167 patients of the main group we used advanced surgical tactics based on differentiated, stepwise and combined chest stabilization including osteosynthesis of ribs and thoracoscopy. RESULTS: Immediate results for each type of stabilization were evaluated. The most durable respiratory support was observed in case of ventilation alone - internal pneumatic stabilization without surgical stabilization. Osteosynthesis of the ribs had the best outcomes compared with other methods. An efficacy of developed tactics was confirmed by significantly reduced morbidity, mortality, mechanical ventilation time and ICU stay in main group. CONCLUSION: Surgical tactics in patients with multiple and flotating fractures of the ribs is determined by type of ribs and internal organs damage, combined trauma severity and conditions of medical care. Differentiated, stepwise and combined chest stabilization by using of high-tech methods of medical care (osteosynthesis, thoracoscopy) improves the outcomes in these patients. PMID- 28805781 TI - [Surgical treatment of hip subluxation and luxation in children with spinal hernia consequences]. AB - AIM: To determine surgical tactics for hip subluxation and luxation in children with spinal hernia consequences. MATERIAL AND METHODS: The study included 134 patients with hip subluxation and luxation with consequences of cerebrospinal hernias who were examined at the Turner Research Institute for Children's Orthopedics in 2006-2016. The main group consisted of 69 patients who received surgical treatment with hip joint stabilization. The control group included 65 children without surgery. Within each group patients were divided into 2 subgroups depending on level of spinal cord injury by using of Sharrard technique. RESULTS: In patients with high lesion (Th and LI-LII) surgical treatment led to impairment of motor function in most cases (71%) (archival material); in case of LIII-LIV and LV-SI segments 25 of 45 (55%) patients improved motor performance while in control group motor function was deteriorated in 13 of 35 (37%) cases. CONCLUSION: Neurosegmental level allows to predict the motor function and to determine surgical tactics. PMID- 28805783 TI - [Effect of the Cytoflavin on the distal polyneuropathy severity in patients with diabetic foot syndrome with arteries mediacalcinosis]. AB - : The aim of the study was to evaluate the effectiveness of cytoflavin in the complex treatment of patients with diabetic foot syndrome. MATERIAL AND METHODS: The research is based on the results of a comprehensive survey of 140 people with diabetic foot syndrome. Depending on the treatment, all patients were divided into 2 groups. The first group (n=35) received basic therapy. The second group (n=35) in addition to basic therapy received cytoflavin 10 ml (+200 ml 0.9% NaCl) for 10 days, followed by switching to the tablet form of the drug 2 tablets twice a day for 1 month. RESULTS: Analyzing the severity of polyneuropathy after treatment, we noted a more positive dynamic in patients who in addition to standard therapy received cytoflavin. PMID- 28805784 TI - [Short-term outcomes of complete mesocolic excision for right colon cancer]. AB - PURPOSE: Complete mesocolic excision (CME) appears to be a relatively new concept for colon cancer. The purpose is to evaluate the results of CME with high vascular ligation (D3 lymph node dissection) for right colon cancer. The presented study identifies possible risks and advantages of the proposed method, as well as the role of the laparoscopic approach. MATERIAL AND METHODS: The article included data from 39 patients with right colon cancer, TNM stage I-III, operated on between November 2015 and December 2016 in the oncoproctology Department of the Blokhin Cancer Research Center. The analysis of main intraoperative parameters, morbidity and mortality was carried out. RESULTS: There was no postoperative mortality. 17 (43.6%) of operations were performed by open and 22 - by laparoscopic approach. The conversion for laparoscopic approach was 1 (4.5%) in 22. The median duration of the operation was 180 (130-260) minutes for laparoscopic approach and 120 (90-280) minutes for open approach, r=0.0056. Median intraoperative blood loss was 30 (30-300) ml for laparoscopic approach, and 300 (30-500) ml for open approach (r=0.0001). The duration of lymphorrhoea, time to first bowel movement, time to start liquid and solid food intake were 5.1+/-2.4, 1.3+/-0.5, 1.26+/-0.4 and 3.2+/-0.7 days, respectively. The median number of removed lymph nodes was 35.7 (6-68), the median number of metastatic lymph nodes was 1.9 (0-16). The median number of removed apical lymph nodes was 10.3 (0-24). Metastases did not affect any of the lymph nodes of the apical group. CONCLUSION: Right mesocolic excision with D3 lymphadenectomy for right colon cancer is technically safe, and the laparoscopic approach provides all the benefits of minimally invasive surgery and excellent early treatment outcomes. Preliminary data shows no metastasis in apical lymphnodes for right colon cancer. Nonetheless, it is necessary to study the long-term results for the evaluation of oncological outcomes. PMID- 28805785 TI - [Endoscopic treatment of cicatricial stenoses of the 2-3 segmental bronchi]. PMID- 28805786 TI - [Surgical treatment of acute pancreatitis: possibilities of percutaneous therapy]. PMID- 28805787 TI - [About reduodenization of digestive tract in gastrectomy]. PMID- 28805788 TI - Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis. AB - Cancer cells are hallmarked by high proliferation and imbalanced redox consumption and signaling. Various oncogenic pathways such as proliferation and evading cell death converge on redox-dependent signaling processes. Nrf2 is a key regulator in these redox-dependent events and operates in cytoprotection, drug metabolism and malignant progression in cancer cells. Here, we show that patients with primary malignant brain tumors (glioblastomas, WHO degrees IV gliomas, GBM) have a devastating outcome and overall reduced survival when Nrf2 levels are upregulated. Nrf2 overexpression or Keap1 knockdown in glioma cells accelerate proliferation and oncogenic transformation. Further, activation of the Nrf2-Keap1 signaling upregulates xCT (aka SLC7A11 or system Xc-) and amplifies glutamate secretion thereby impacting on the tumor microenvironment. Moreover, both fostered Nrf2 expression and conversely Keap1 inhibition promote resistance to ferroptosis. Altogether, the Nrf2-Keap1 pathway operates as a switch for malignancy in gliomas promoting cell proliferation and resistance to cell death processes such as ferroptosis. Our data demonstrate that the Nrf2-Keap1 pathway is critical for cancer cell growth and operates on xCT. Nrf2 presents the Achilles' heel of cancer cells and thus provides a valid therapeutic target for sensitizing cancer for chemotherapeutics. PMID- 28805789 TI - Multiple myeloma with extramedullary disease: impact of autologous stem cell transplantation on outcome. PMID- 28805790 TI - Successful reduced intensity hematopoietic cell transplant in a patient with deficiency of adenosine deaminase 2. PMID- 28805791 TI - Low circulating mannan-binding lectin levels correlate with increased frequency and severity of febrile episodes in myeloma patients who undergo ASCT and do not receive antibiotic prophylaxis. AB - Patients with multiple myeloma (MM) who undergo autologous stem cell transplantation (ASCT) are susceptible to severe infections. Low levels of circulating mannan-binding lectin (MBL) are associated with increased risk of infection. In this prospective study, we evaluated 100 patients who underwent ASCT regarding the effect of MBL on the incidence and severity of febrile episodes. Seventeen patients had MBL levels <500 ng/mL (11 received antibiotic prophylaxis and 6 did not). Although there was no statistical difference regarding the development of febrile episodes between patients with low and normal MBL, among 17 patients with low MBL levels, six out of eleven patients who received antibiotic prophylaxis developed a febrile episode compared with six out of six patients who did not receive antibiotic prophylaxis and developed a febrile episode. Patients with low MBL levels who responded less frequently to first line antibiotic therapy required more frequent administration of a second more advanced line of antibiotics, independently of receiving or not prophylaxis, and required prolonged hospitalization. In the univariate analysis low MBL associated with shorter OS. Our results suggest that patient with low MBL levels should receive antibiotic prophylaxis to reduce the number of febrile episodes and raise the issue of MBL replacement for these patients. PMID- 28805792 TI - Immune reconstitution in patients with acquired severe aplastic anemia after haploidentical stem cell transplantation. AB - Immune recovery (IR) after haploidentical stem cell transplantation (haplo-SCT) in severe aplastic anemia (SAA) patients remains relatively unknown. In this study, we examined immune cell subset counts and immunoglobulins in 81 SAA patients from day 30 to day 365 after haplo-SCT. Simultaneously, we determined which factors influence IR and analyzed the effects of immune cell subsets on transplant outcomes. We found that: (i) The reconstitution of different immune cell subsets occurred at different rates after haplo-SCT. Monocytes were the first to recover, followed by CD8+ T and CD19+ B cells, and finally CD4+ T cells. (ii) In the multivariate analysis, lower recipient age, female gender, high mononuclear cell counts in the graft and absence of CMV reactivation were associated with improved IR after transplant. (iii) A CD4/CD8 ratio less than 0.567 on day 30 post transplantation was associated with higher overall survival after haplo-SCT in SAA patients. In conclusion, SAA patients showed a faster recovery of monocytes and CD8+ T cells after haplo-SCT, whereas the recovery of the CD4+ T-cell subset was delayed. Our results may provide insight into methods for better predicting and modulating IR of SAA patients and subsequently improving outcomes after transplantation. PMID- 28805793 TI - Conformational landscape of a virus by single-particle X-ray scattering. AB - Using a manifold-based analysis of experimental diffraction snapshots from an X ray free electron laser, we determine the three-dimensional structure and conformational landscape of the PR772 virus to a detector-limited resolution of 9 nm. Our results indicate that a single conformational coordinate controls reorganization of the genome, growth of a tubular structure from a portal vertex and release of the genome. These results demonstrate that single-particle X-ray scattering has the potential to shed light on key biological processes. PMID- 28805794 TI - Large-scale mapping of cortical synaptic projections with extracellular electrode arrays. AB - Understanding circuit computation in the nervous system requires sampling activity over large neural populations and maximizing the number of features that can be extracted. By combining planar arrays of extracellular electrodes with the three-layered cortex of turtles, we show that synaptic signals induced along individual axons as well as action potentials can be easily captured. Two types of information can be extracted from these signals, the neuronal subtype (inhibitory or excitatory)-whose identification is more reliable than with traditional measures such as action potential width-and a (partial) spatial map of functional axonal projections from individual neurons. Because our approach is algorithmic, it can be carried out in parallel on hundreds of simultaneously recorded neurons. Combining our approach with soma triangulation, we reveal an axonal projection bias among a population of pyramidal neurons in turtle cortex and confirm this bias through anatomical reconstructions. PMID- 28805795 TI - M3: an integrative framework for structure determination of molecular machines. AB - We present a broadly applicable, user-friendly protocol that incorporates sparse and hybrid experimental data to calculate quasi-atomic-resolution structures of molecular machines. The protocol uses the HADDOCK framework, accounts for extensive structural rearrangements both at the domain and atomic levels and accepts input from all structural and biochemical experiments whose data can be translated into interatomic distances and/or molecular shapes. PMID- 28805796 TI - Bifidobacterium breve as a delivery vector of IL-24 gene therapy for head and neck squamous cell carcinoma in vivo. AB - Beneficial bacteria are becoming ever more popular gene delivery method for hypoxia-tumor targeting in vivo. In this study we investigated the therapeutic effect of new recombinant Bifidobacterium breve strain expressing interleukin (IL)-24 gene (B. breve-IL24) on head and neck tumor xenograft in mice. Briefly, B. breve transformants were obtained through electro-transformation. Bacteria tumor-targeting ability were analyzed in vivo over different time points (1, 3 and 7 days post-bacteria injection). Furthermore, the therapeutic effect of bacteria on tumor cells in vivo were analyzed as follows: 30 Balb/c nude mice bearing subcutaneous tumor were randomly divided in three groups (Drug group, green fluorescent protein (GFP) group and Saline group). The therapy lasted for 2 weeks and included B. breve-IL24 administration via tail vein for Drug group, B. breve-GFP for GFP group and phosphate buffered saline for Saline group. The tumor growth was monitored using standard caliper technique, while the apoptosis induction in vivo was analyzed by Real-time Positron Emission Tomography/Computed Tomography (PET/CT) imaging ([18F]-ML-10 tracer). At the end of the experiment, tumor tissues were collected and analyzed by western blotting. Briefly, our results suggested that our new recombinant bacterium has the capability of targeting tumor tissue in vivo. As for the therapeutic effect, our new strain has revealed to be a promising therapeutic approach against tumor growth in vivo. Briefly, higher tumor growth inhibition and higher tumor cell apoptosis induction were observed in Drug group compared with the GFP and Saline groups. To conclude, a new recombinant strain B. breve-IL24 offers a novel, safe and clinically acceptable therapeutic approach for tumor therapy in vivo. PMID- 28805797 TI - Human genomics projects and precision medicine. AB - The completion of the Human Genome Project (HGP) in 2001 opened the floodgates to a deeper understanding of medicine. There are dozens of HGP-like projects which involve from a few tens to several million genomes currently in progress, which vary from having specialized goals or a more general approach. However, data generation, storage, management and analysis in public and private cloud computing platforms have raised concerns about privacy and security. The knowledge gained from further research has changed the field of genomics and is now slowly permeating into clinical medicine. The new precision (personalized) medicine, where genome sequencing and data analysis are essential components, allows tailored diagnosis and treatment according to the information from the patient's own genome and specific environmental factors. P4 (predictive, preventive, personalized and participatory) medicine is introducing new concepts, challenges and opportunities. This review summarizes current sequencing technologies, concentrates on ongoing human genomics projects, and provides some examples in which precision medicine has already demonstrated clinical impact in diagnosis and/or treatment. PMID- 28805799 TI - Kinetochore regulation: Let there be light. PMID- 28805798 TI - Repeated AAV-mediated gene transfer by serotype switching enables long-lasting therapeutic levels of hUgt1a1 enzyme in a mouse model of Crigler-Najjar Syndrome Type I. AB - Adeno-associated virus (AAV) -mediated gene therapy is a promising strategy to treat liver-based monogenic diseases. However, two major obstacles limit its success: first, vector dilution in actively dividing cells, such as hepatocytes in neonates/children, due to the non-integrating nature of the vector; second, development of an immune response against the transgene and/or viral vector. Crigler-Najjar Syndrome Type I is a rare monogenic disease with neonatal onset, caused by mutations in the liver-specific UGT1 gene, with toxic accumulation of unconjugated bilirubin in plasma, tissues and brain. To establish an effective and long lasting cure, we applied AAV-mediated liver gene therapy to a relevant mouse model of the disease. Repeated gene transfer to adults by AAV-serotype switching, upon neonatal administration, resulted in lifelong correction of total bilirubin (TB) levels in both genders. In contrast, vector loss over time was observed after a single neonatal administration. Adult administration resulted in lifelong TB levels correction in male, but not female Ugt1-/- mice. Our findings demonstrate that neonatal AAV-mediated gene transfer to the liver supports a second transfer of the therapeutic vector, by preventing the induction of an immune response and supporting the possibility to improve AAV-therapeutic efficacy by repeated administration. PMID- 28805800 TI - Optogenetic control of kinetochore function. AB - Kinetochores act as hubs for multiple activities during cell division, including microtubule interactions and spindle checkpoint signaling. Each kinetochore can act autonomously, and activities change rapidly as proteins are recruited to, or removed from, kinetochores. Understanding this dynamic system requires tools that can manipulate kinetochores on biologically relevant temporal and spatial scales. Optogenetic approaches have the potential to provide temporal and spatial control with molecular specificity. Here we report new chemical inducers of protein dimerization that allow us to both recruit proteins to and release them from kinetochores using light. We use these dimerizers to manipulate checkpoint signaling and molecular motor activity. Our findings demonstrate specialized properties of the CENP-E (kinesin-7) motor for directional chromosome transport to the spindle equator and for maintenance of metaphase alignment. This work establishes a foundation for optogenetic control of kinetochore function, which is broadly applicable to experimental probing of other dynamic cellular processes. PMID- 28805801 TI - Small-molecule studies identify CDK8 as a regulator of IL-10 in myeloid cells. AB - Enhancing production of the anti-inflammatory cytokine interleukin-10 (IL-10) is a promising strategy to suppress pathogenic inflammation. To identify new mechanisms regulating IL-10 production, we conducted a phenotypic screen for small molecules that enhance IL-10 secretion from activated dendritic cells. Mechanism-of-action studies using a prioritized hit from the screen, BRD6989, identified the Mediator-associated kinase CDK8, and its paralog CDK19, as negative regulators of IL-10 production during innate immune activation. The ability of BRD6989 to upregulate IL-10 is recapitulated by multiple, structurally differentiated CDK8 and CDK19 inhibitors and requires an intact cyclin C-CDK8 complex. Using a highly parallel pathway reporter assay, we identified a role for enhanced AP-1 activity in IL-10 potentiation following CDK8 and CDK19 inhibition, an effect associated with reduced phosphorylation of a negative regulatory site on c-Jun. These findings identify a function for CDK8 and CDK19 in regulating innate immune activation and suggest that these kinases may warrant consideration as therapeutic targets for inflammatory disorders. PMID- 28805802 TI - Colibactin assembly line enzymes use S-adenosylmethionine to build a cyclopropane ring. AB - Despite containing an alpha-amino acid, the versatile cofactor S adenosylmethionine (SAM) is not a known building block for nonribosomal peptide synthetase (NRPS) assembly lines. Here we report an unusual NRPS module from colibactin biosynthesis that uses SAM for amide bond formation and subsequent cyclopropanation. Our findings showcase a new use for SAM and reveal a novel biosynthetic route to a functional group that likely mediates colibactin's genotoxicity. PMID- 28805803 TI - Bisphosphoglycerate mutase controls serine pathway flux via 3-phosphoglycerate. AB - Lower glycolysis involves a series of reversible reactions, which interconvert intermediates that also feed anabolic pathways. 3-phosphoglycerate (3-PG) is an abundant lower glycolytic intermediate that feeds serine biosynthesis via the enzyme phosphoglycerate dehydrogenase, which is genomically amplified in several cancers. Phosphoglycerate mutase 1 (PGAM1) catalyzes the isomerization of 3-PG into the downstream glycolytic intermediate 2-phosphoglycerate (2-PG). PGAM1 needs to be histidine phosphorylated to become catalytically active. We show that the primary PGAM1 histidine phosphate donor is 2,3-bisphosphoglycerate (2,3-BPG), which is made from the glycolytic intermediate 1,3-bisphosphoglycerate (1,3-BPG) by bisphosphoglycerate mutase (BPGM). When BPGM is knocked out, 1,3-BPG can directly phosphorylate PGAM1. In this case, PGAM1 phosphorylation and activity are decreased, but nevertheless sufficient to maintain normal glycolytic flux and cellular growth rate. 3-PG, however, accumulates, leading to increased serine synthesis. Thus, one biological function of BPGM is controlling glycolytic intermediate levels and thereby serine biosynthetic flux. PMID- 28805804 TI - A genetically encoded tool for manipulation of NADP+/NADPH in living cells. AB - The redox coenzymes NADH and NADPH are broadly required for energy metabolism, biosynthesis and detoxification. Despite detailed knowledge of specific enzymes and pathways that utilize these coenzymes, a holistic understanding of the regulation and compartmentalization of NADH- and NADPH-dependent pathways is lacking, partly because of a lack of tools with which to investigate these processes in living cells. We have previously reported the use of the naturally occurring Lactobacillus brevis H2O-forming NADH oxidase (LbNOX) as a genetic tool for manipulation of the NAD+/NADH ratio in human cells. Here, we present triphosphopyridine nucleotide oxidase (TPNOX), a rationally designed and engineered mutant of LbNOX that is strictly specific to NADPH. We characterized the effects of TPNOX expression on cellular metabolism and used it in combination with LbNOX to show how the redox states of mitochondrial NADPH and NADH pools are connected. PMID- 28805805 TI - Whole tumor section quantitative image analysis maximizes between-pathologists' reproducibility for clinical immunohistochemistry-based biomarkers. AB - Pathologists have had increasing responsibility for quantitating immunohistochemistry (IHC) biomarkers with the expectation of high between-reader reproducibility due to clinical decision-making especially for patient therapy. Digital imaging-based quantitation of IHC clinical slides offers a potential aid for improvement; however, its clinical adoption is limited potentially due to a conventional field-of-view annotation approach. In this study, we implemented a novel solely morphology-based whole tumor section annotation strategy to maximize image analysis quantitation results between readers. We first compare the field of-view image analysis annotation approach to digital and manual-based modalities across multiple clinical studies (~120 cases per study) and biomarkers (ER, PR, HER2, Ki-67, and p53 IHC) and then compare a subset of the same cases (~40 cases each from the ER, PR, HER2, and Ki-67 studies) using whole tumor section annotation approach to understand incremental value of all modalities. Between reader results for each biomarker in relation to conventional scoring modalities showed similar concordance as manual read: ER field-of-view image analysis: 95.3% (95% CI 92.0-98.2%) vs digital read: 92.0% (87.8-95.8%) vs manual read: 94.9% (91.4-97.8%); PR field-of-view image analysis: 94.1% (90.3-97.2%) vs digital read: 94.0% (90.2-97.1%) vs manual read: 94.4% (90.9-97.2%); Ki-67 field-of-view image analysis: 86.8% (82.1-91.4%) vs digital read: 76.6% (70.9-82.2%) vs manual read: 85.6% (80.4-90.4%); p53 field-of-view image analysis: 81.7% (76.4-86.8%) vs digital read: 80.6% (75.0-86.0%) vs manual read: 78.8% (72.2-83.3%); and HER2 field-of-view image analysis: 93.8% (90.0-97.2%) vs digital read: 91.0 (86.6 94.9%) vs manual read: 87.2% (82.1-91.9%). Subset implementation and analysis on the same cases using whole tumor section image analysis approach showed significant improvement between pathologists over field-of-view image analysis and manual read (HER2 100% (97-100%), P=0.013 field-of-view image analysis and 0.013 manual read; Ki-67 100% (96.9-100%), P=0.040 and 0.012; ER 98.3% (94.1 99.5%), p=0.232 and 0.181; and PR 96.6% (91.5-98.7%), p=0.012 and 0.257). Overall, whole tumor section image analysis significantly improves between pathologist's reproducibility and is the optimal approach for clinical-based image analysis algorithms. PMID- 28805806 TI - Lung tumor exome files with T-cell receptor recombinations: a mouse model of T cell infiltrates reflecting mutation burdens. AB - Tumor exomes and RNASeq data were originally intended for obtaining tumor mutations and gene expression profiles, respectively. However, recent work has determined that tumor exome and RNAseq read files contain reads representing T cell and B-cell receptor (TcR and BcR) recombinations, presumably due to infiltrating lymphocytes. Furthermore, the recovery of immune receptor recombination reads has demonstrated correlations with specific, previously appreciated aspects of tumor immunology. To further understand the usefulness of recovering TcR and BcR recombinations from tumor exome files, we developed a scripted algorithm for recovery of reads representing these recombinations from a previously described mouse model of lung tumorigenesis. Results indicated that exomes representing lung adenomas reveal significantly more TcR recombinations than do exomes from lung adenocarcinomas; and that exome files representing high mutation adenomas, arising from chemical mutagens, have more TcR recombinations than do exome files from low mutation adenomas arising from an activating Kras mutation. The latter results were also consistent with a similar analysis performed on human lung adenocarcinoma exomes. The mouse and human results for obtaining TcR recombination reads from tumor specimen exomes are consistent with human tumor biology results indicating that adenomas and high mutation cancers are sites of high immune activity. The results indicate hitherto unappreciated opportunities for the use of tumor specimen exome files, particularly from experimental animal models, to study the connection between the adenoma stage of tumorigenesis, or high cancer mutation rates, and high level lymphocyte infiltrates. PMID- 28805807 TI - Notch signaling pathway and gene expression profiles during early in vitro differentiation of liver-derived mesenchymal stromal cells to osteoblasts. AB - Notch signaling is a key signaling pathway for cell proliferation and differentiation. Therefore, we formulated a working hypothesis that Notch signaling can be used to detect early osteoblastic differentiation of mesenchymal stromal cells. Changes in expression and distribution of Notch 1, 2, 3, and Delta1 in the cytoplasm and nuclei of rat liver-derived mesenchymal stromal cells differentiating into osteoblasts were investigated, together with the displacement of intracellular domains (ICDs) of the receptors. In addition, an oligonucleotide microarray was used to determine the expression of genes known to be linked to selected signaling pathways. Statistically significant changes in the number of cells expressing Notch1, Notch2, and Delta1, but not Notch3, and their activated forms were detected within 24 h of culture under osteogenic conditions. Although the number of cells expressing Notch3 remained unchanged, the number of cells with the activated receptor was significantly elevated. The number of cells positive for Notch3 was higher than that for the other Notch receptors even after 48 h of differentiation; however, a smaller fraction of cells contained activated Notch3. Culture mineralization was detected on day 4 of differentiation, and all analyzed receptors were present in the cells at that time, but only Delta1 was activated in twice as many cells than that before differentiation. Thus, the three analyzed receptors and ligand can serve as markers of very early stages of osteogenesis in stromal cells. These early changes in activation of the Notch signaling pathway were correlated with the transcription of several genes linked to osteogenesis, such as Bmps, Mmps, and Egfr, and with the regulation of cell cycle and apoptosis. PMID- 28805808 TI - Constraints and consequences of the emergence of amino acid repeats in eukaryotic proteins. AB - Proteins with amino acid homorepeats have the potential to be detrimental to cells and are often associated with human diseases. Why, then, are homorepeats prevalent in eukaryotic proteomes? In yeast, homorepeats are enriched in proteins that are essential and pleiotropic and that buffer environmental insults. The presence of homorepeats increases the functional versatility of proteins by mediating protein interactions and facilitating spatial organization in a repeat dependent manner. During evolution, homorepeats are preferentially retained in proteins with stringent proteostasis, which might minimize repeat-associated detrimental effects such as unregulated phase separation and protein aggregation. Their presence facilitates rapid protein divergence through accumulation of amino acid substitutions, which often affect linear motifs and post-translational modification sites. These substitutions may result in rewiring protein interaction and signaling networks. Thus, homorepeats are distinct modules that are often retained in stringently regulated proteins. Their presence facilitates rapid exploration of the genotype-phenotype landscape of a population, thereby contributing to adaptation and fitness. PMID- 28805809 TI - X-ray structures of endothelin ETB receptor bound to clinical antagonist bosentan and its analog. AB - Endothelin receptors (ETRs) have crucial roles in vascular control and are targets for drugs designed to treat circulatory-system diseases and cancer progression. The nonpeptide dual-ETR antagonist bosentan is the first oral drug approved to treat pulmonary arterial hypertension. Here we report crystal structures of human endothelin ETB receptor bound to bosentan and to the ETB selective analog K-8794, at 3.6-A and 2.2-A resolution, respectively. The K-8794 bound structure reveals the detailed water-mediated hydrogen-bonding network at the transmembrane core, which could account for the weak negative allosteric modulation of ETB by Na+ ions. The bosentan-bound structure reveals detailed interactions with ETB, which are probably conserved in the ETA receptor. A comparison of the two structures shows unexpected similarity between antagonist and agonist binding. Despite this similarity, bosentan sterically prevents the inward movement of transmembrane helix 6 (TM6), and thus exerts its antagonistic activity. These structural insights will facilitate the rational design of new ETR-targeting drugs. PMID- 28805810 TI - TRF2 binds branched DNA to safeguard telomere integrity. AB - Although t-loops protect telomeres, they are at risk of cleavage by Holliday junction (HJ) resolvases if branch migration converts the three-way t-loop junction into four-way HJs. T-loop cleavage is repressed by the TRF2 basic domain, which binds three- and four-way junctions and protects HJs in vitro. By replacing the basic domain with bacterial-protein domains binding three- and four way junctions, we demonstrated the in vivo relevance of branched-DNA binding. Branched-DNA binding also repressed PARP1, presumably by masking the PARP1 site in the t-loop junction. Although PARP1 recruits HJ resolvases and promotes t-loop cleavage, PARP1 activation alone did not result in t-loop cleavage, thus suggesting that the basic domain also prevents formation of HJs. Concordantly, removal of HJs by BLM helicase mitigated t-loop cleavage in response to loss of the basic domain. We propose that TRF2 masks and stabilizes the t-loop three-way junction, thereby protecting telomeres from detrimental deletions and PARP1 activation. PMID- 28805811 TI - Caveolin-1-dependent nanoscale organization of the BCR regulates B cell tolerance. AB - Caveolin-1 (Cav1) regulates the nanoscale organization and compartmentalization of the plasma membrane. Here we found that Cav1 controlled the distribution of nanoclusters of isotype-specific B cell antigen receptors (BCRs) on the surface of B cells. In mature B cells stimulated with antigen, the immunoglobulin M BCR (IgM-BCR) gained access to lipid domains enriched for GM1 glycolipids, by a process that was dependent on the phosphorylation of Cav1 by the Src family of kinases. Antigen-induced reorganization of nanoclusters of IgM-BCRs and IgD-BCRs regulated BCR signaling in vivo. In immature Cav1-deficient B cells, altered nanoscale organization of IgM-BCRs resulted in a failure of receptor editing and a skewed repertoire of B cells expressing immunoglobulin-MU heavy chains with hallmarks of poly- and auto-reactivity, which ultimately led to autoimmunity in mice. Thus, Cav1 emerges as a cell-intrinsic regulator that prevents B cell induced autoimmunity by means of its role in plasma-membrane organization. PMID- 28805812 TI - T-bet-dependent NKp46+ innate lymphoid cells regulate the onset of TH17-induced neuroinflammation. AB - The transcription factor T-bet has been associated with increased susceptibility to systemic and organ-specific autoimmunity, but the mechanism by which T-bet expression promotes neuroinflammation remains unknown. In this study, we demonstrate a cardinal role of T-bet-dependent NKp46+ innate lymphoid cells (ILCs) in the initiation of CD4+ TH17-mediated neuroinflammation. Loss of T-bet specifically in NKp46+ ILCs profoundly impaired the ability of myelin-reactive TH17 cells to invade central nervous system (CNS) tissue and protected the mice from autoimmunity. T-bet-dependent NKp46+ ILCs localized in the meninges and acted as chief coordinators of meningeal inflammation by inducing the expression of proinflammatory cytokines, chemokines and matrix metalloproteinases, which together facilitated T cell entry into CNS parenchyma. Our findings uncover a detrimental role of T-bet-dependent NKp46+ ILCs in the development of CNS autoimmune disease. PMID- 28805813 TI - Analysis of genome-wide association data highlights candidates for drug repositioning in psychiatry. AB - Knowledge of psychiatric disease genetics has advanced rapidly during the past decade with the advent of genome-wide association studies (GWAS). However, less progress has been made in harnessing these data to reveal new therapies. Here we propose a framework for drug repositioning by comparing transcriptomes imputed from GWAS data with drug-induced gene expression profiles from the Connectivity Map database and apply this approach to seven psychiatric disorders. We found a number of repositioning candidates, many supported by preclinical or clinical evidence. Repositioning candidates for a number of disorders were also significantly enriched for known psychiatric medications or therapies considered in clinical trials. For example, candidates for schizophrenia were enriched for antipsychotics, while those for bipolar disorder were enriched for both antipsychotics and antidepressants. These findings provide support for the usefulness of GWAS data in guiding drug discovery. PMID- 28805814 TI - Cerebellar granule cell replenishment postinjury by adaptive reprogramming of Nestin+ progenitors. AB - Regeneration of several organs involves adaptive reprogramming of progenitors, but the intrinsic capacity of the developing brain to replenish lost cells remains largely unknown. Here we found that the developing cerebellum has unappreciated progenitor plasticity, since it undergoes near full growth and functional recovery following acute depletion of granule cells, the most plentiful neuron population in the brain. We demonstrate that following postnatal ablation of granule cell progenitors, Nestin-expressing progenitors, specified during mid-embryogenesis to produce astroglia and interneurons, switch their fate and generate granule neurons in mice. Moreover, Hedgehog signaling in two Nestin expressing progenitor populations is crucial not only for the compensatory replenishment of granule neurons but also for scaling interneuron and astrocyte numbers. Thus, we provide insights into the mechanisms underlying robustness of circuit formation in the cerebellum and speculate that adaptive reprogramming of progenitors in other brain regions plays a greater role than appreciated in developmental regeneration. PMID- 28805816 TI - Selective attention within the foveola. AB - Efficient control of attentional resources and high-acuity vision are both fundamental for survival. Shifts in visual attention are known to covertly enhance processing at locations away from the center of gaze, where visual resolution is low. It is unknown, however, whether selective spatial attention operates where the observer is already looking-that is, within the high-acuity foveola, the small yet disproportionally important rod-free region of the retina. Using new methods for precisely controlling retinal stimulation, here we show that covert attention flexibly improves and speeds up both detection and discrimination at loci only a fraction of a degree apart within the foveola. These findings reveal a surprisingly precise control of attention and its involvement in fine spatial vision. They show that the commonly studied covert shifts of attention away from the fovea are the expression of a global mechanism that exerts its action across the entire visual field. PMID- 28805815 TI - AAV-mediated direct in vivo CRISPR screen identifies functional suppressors in glioblastoma. AB - A causative understanding of genetic factors that regulate glioblastoma pathogenesis is of central importance. Here we developed an adeno-associated virus-mediated, autochthonous genetic CRISPR screen in glioblastoma. Stereotaxic delivery of a virus library targeting genes commonly mutated in human cancers into the brains of conditional-Cas9 mice resulted in tumors that recapitulate human glioblastoma. Capture sequencing revealed diverse mutational profiles across tumors. The mutation frequencies in mice correlated with those in two independent patient cohorts. Co-mutation analysis identified co-occurring driver combinations such as B2m-Nf1, Mll3-Nf1 and Zc3h13-Rb1, which were subsequently validated using AAV minipools. Distinct from Nf1-mutant tumors, Rb1-mutant tumors are undifferentiated and aberrantly express homeobox gene clusters. The addition of Zc3h13 or Pten mutations altered the gene expression profiles of Rb1 mutants, rendering them more resistant to temozolomide. Our study provides a functional landscape of gliomagenesis suppressors in vivo. PMID- 28805817 TI - Room-temperature current blockade in atomically defined single-cluster junctions. AB - Fabricating nanoscopic devices capable of manipulating and processing single units of charge is an essential step towards creating functional devices where quantum effects dominate transport characteristics. The archetypal single electron transistor comprises a small conducting or semiconducting island separated from two metallic reservoirs by insulating barriers. By enabling the transfer of a well-defined number of charge carriers between the island and the reservoirs, such a device may enable discrete single-electron operations. Here, we describe a single-molecule junction comprising a redox-active, atomically precise cobalt chalcogenide cluster wired between two nanoscopic electrodes. We observe current blockade at room temperature in thousands of single-cluster junctions. Below a threshold voltage, charge transfer across the junction is suppressed. The device is turned on when the temporary occupation of the core states by a transiting carrier is energetically enabled, resulting in a sequential tunnelling process and an increase in current by a factor of ~600. We perform in situ and ex situ cyclic voltammetry as well as density functional theory calculations to unveil a two-step process mediated by an orbital localized on the core of the cluster in which charge carriers reside before tunnelling to the collector reservoir. As the bias window of the junction is opened wide enough to include one of the cluster frontier orbitals, the current blockade is lifted and charge carriers can tunnel sequentially across the junction. PMID- 28805818 TI - All-electric control of donor nuclear spin qubits in silicon. AB - The electronic and nuclear spin degrees of freedom of donor impurities in silicon form ultra-coherent two-level systems that are potentially useful for applications in quantum information and are intrinsically compatible with industrial semiconductor processing. However, because of their smaller gyromagnetic ratios, nuclear spins are more difficult to manipulate than electron spins and are often considered too slow for quantum information processing. Moreover, although alternating current magnetic fields are the most natural choice to drive spin transitions and implement quantum gates, they are difficult to confine spatially to the level of a single donor, thus requiring alternative approaches. In recent years, schemes for all-electrical control of donor spin qubits have been proposed but no experimental demonstrations have been reported yet. Here, we demonstrate a scalable all-electric method for controlling neutral 31P and 75As donor nuclear spins in silicon. Using coplanar photonic bandgap resonators, we drive Rabi oscillations on nuclear spins exclusively using electric fields by employing the donor-bound electron as a quantum transducer, much in the spirit of recent works with single-molecule magnets. The electric field confinement leads to major advantages such as low power requirements, higher qubit densities and faster gate times. Additionally, this approach makes it possible to drive nuclear spin qubits either at their resonance frequency or at its first subharmonic, thus reducing device bandwidth requirements. Double quantum transitions can be driven as well, providing easy access to the full computational manifold of our system and making it convenient to implement nuclear spin-based qudits using 75As donors. PMID- 28805819 TI - Donor qubits in silicon: Electrical control of nuclear spins. PMID- 28805820 TI - Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4. AB - The bromodomain and extraterminal (BET) family of proteins comprises four members BRD2, BRD3, BRD4 and the testis-specific isoform BRDT-that largely function as transcriptional coactivators and play critical roles in various cellular processes, including the cell cycle, apoptosis, migration and invasion. BET proteins enhance the oncogenic functions of major cancer drivers by elevating the expression of these drivers, such as c-Myc in leukemia, or by promoting the transcriptional activities of oncogenic factors, such as AR and ERG in prostate cancer. Pathologically, BET proteins are frequently overexpressed and are clinically linked to various types of human cancer; they are therefore being pursued as attractive therapeutic targets for selective inhibition in patients with cancer. To this end, a number of bromodomain inhibitors, including JQ1 and I BET, have been developed and have shown promising outcomes in early clinical trials. Although resistance to BET inhibitors has been documented in preclinical models, the molecular mechanisms underlying acquired resistance are largely unknown. Here we report that cullin-3SPOP earmarks BET proteins, including BRD2, BRD3 and BRD4, for ubiquitination-mediated degradation. Pathologically, prostate cancer-associated SPOP mutants fail to interact with and promote the degradation of BET proteins, leading to their elevated abundance in SPOP-mutant prostate cancer. As a result, prostate cancer cell lines and organoids derived from individuals harboring SPOP mutations are more resistant to BET-inhibitor-induced cell growth arrest and apoptosis. Therefore, our results elucidate the tumor suppressor role of SPOP in prostate cancer in which it acts as a negative regulator of BET protein stability and also provide a molecular mechanism for resistance to BET inhibitors in individuals with prostate cancer bearing SPOP mutations. PMID- 28805823 TI - Bronze-mean hexagonal quasicrystal. AB - The most striking feature of conventional quasicrystals is their non-traditional symmetry characterized by icosahedral, dodecagonal, decagonal or octagonal axes. The symmetry and the aperiodicity of these materials stem from an irrational ratio of two or more length scales controlling their structure, the best-known examples being the Penrose and the Ammann-Beenker tiling as two-dimensional models related to the golden and the silver mean, respectively. Surprisingly, no other metallic-mean tilings have been discovered so far. Here we propose a self similar bronze-mean hexagonal pattern, which may be viewed as a projection of a higher-dimensional periodic lattice with a Koch-like snowflake projection window. We use numerical simulations to demonstrate that a disordered variant of this quasicrystal can be materialized in soft polymeric colloidal particles with a core-shell architecture. Moreover, by varying the geometry of the pattern we generate a continuous sequence of structures, which provide an alternative interpretation of quasicrystalline approximants observed in several metal-silicon alloys. PMID- 28805821 TI - Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors. AB - It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood. Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP-CUL3 substrates that are preferentially degraded by endometrial cancer associated SPOP mutants. The resulting reduction of BET protein levels sensitized cancer cells to BET inhibitors. Conversely, prostate cancer-specific SPOP mutations resulted in impaired degradation of BETs, promoting their resistance to pharmacologic inhibition. These results uncover an oncogenomics paradox, whereby mutations mapping to the same domain evoke opposing drug susceptibilities. Specifically, we provide a molecular rationale for the use of BET inhibitors to treat patients with endometrial but not prostate cancer who harbor SPOP mutations. PMID- 28805822 TI - Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT-mTORC1 activation. AB - Bromodomain and extraterminal domain (BET) protein inhibitors are emerging as promising anticancer therapies. The gene encoding the E3 ubiquitin ligase substrate-binding adaptor speckle-type POZ protein (SPOP) is the most frequently mutated in primary prostate cancer. Here we demonstrate that wild-type SPOP binds to and induces ubiquitination and proteasomal degradation of BET proteins (BRD2, BRD3 and BRD4) by recognizing a degron motif common among them. In contrast, prostate cancer-associated SPOP mutants show impaired binding to BET proteins, resulting in decreased proteasomal degradation and accumulation of these proteins in prostate cancer cell lines and patient specimens and causing resistance to BET inhibitors. Transcriptome and BRD4 cistrome analyses reveal enhanced expression of the GTPase RAC1 and cholesterol-biosynthesis-associated genes together with activation of AKT-mTORC1 signaling as a consequence of BRD4 stabilization. Our data show that resistance to BET inhibitors in SPOP-mutant prostate cancer can be overcome by combination with AKT inhibitors and further support the evaluation of SPOP mutations as biomarkers to guide BET-inhibitor-oriented therapy in patients with prostate cancer. PMID- 28805824 TI - Flexible shape-memory scaffold for minimally invasive delivery of functional tissues. AB - Despite great progress in engineering functional tissues for organ repair, including the heart, an invasive surgical approach is still required for their implantation. Here, we designed an elastic and microfabricated scaffold using a biodegradable polymer (poly(octamethylene maleate (anhydride) citrate)) for functional tissue delivery via injection. The scaffold's shape memory was due to the microfabricated lattice design. Scaffolds and cardiac patches (1 cm * 1 cm) were delivered through an orifice as small as 1 mm, recovering their initial shape following injection without affecting cardiomyocyte viability and function. In a subcutaneous syngeneic rat model, injection of cardiac patches was equivalent to open surgery when comparing vascularization, macrophage recruitment and cell survival. The patches significantly improved cardiac function following myocardial infarction in a rat, compared with the untreated controls. Successful minimally invasive delivery of human cell-derived patches to the epicardium, aorta and liver in a large-animal (porcine) model was achieved. PMID- 28805825 TI - The processing and heterostructuring of silk with light. AB - Spider silk is a tough, elastic and lightweight biomaterial, although there is a lack of tools available for non-invasive processing of silk structures. Here we show that nonlinear multiphoton interactions of silk with few-cycle femtosecond pulses allow the processing and heterostructuring of the material in ambient air. Two qualitatively different responses, bulging by multiphoton absorption and plasma-assisted ablation, are observed for low- and high-peak intensities, respectively. Plasma ablation allows us to make localized nanocuts, microrods, nanotips and periodic patterns with minimal damage while preserving molecular structure. The bulging regime facilitates confined bending and microwelding of silk with materials such as metal, glass and Kevlar with strengths comparable to pristine silk. Moreover, analysis of Raman bands of microwelded joints reveals that the polypeptide backbone remains intact while perturbing its weak hydrogen bonds. Using this approach, we fabricate silk-based functional topological microstructures, such as Mobius strips, chiral helices and silk-based sensors. PMID- 28805826 TI - Violation of Ohm's law in a Weyl metal. AB - Ohm's law is a fundamental paradigm in the electrical transport of metals. Any transport signatures violating Ohm's law would give an indisputable fingerprint for a novel metallic state. Here, we uncover the breakdown of Ohm's law owing to a topological structure of the chiral anomaly in the Weyl metal phase. We observe nonlinear I-V characteristics in Bi0.96Sb0.04 single crystals in the diffusive limit, which occurs only for a magnetic-field-aligned electric field (E?B). The Boltzmann transport theory with the charge pumping effect reveals the topological in-origin nonlinear conductivity, and it leads to a universal scaling function of the longitudinal magnetoconductivity, which completely describes our experimental results. As a hallmark of Weyl metals, the nonlinear conductivity provides a venue for nonlinear electronics, optical applications, and the development of a topological Fermi-liquid theory beyond the Landau Fermi-liquid theory. PMID- 28805827 TI - Transcriptional risk scores link GWAS to eQTLs and predict complications in Crohn's disease. AB - Gene expression profiling can be used to uncover the mechanisms by which loci identified through genome-wide association studies (GWAS) contribute to pathology. Given that most GWAS hits are in putative regulatory regions and transcript abundance is physiologically closer to the phenotype of interest, we hypothesized that summation of risk-allele-associated gene expression, namely a transcriptional risk score (TRS), should provide accurate estimates of disease risk. We integrate summary-level GWAS and expression quantitative trait locus (eQTL) data with RNA-seq data from the RISK study, an inception cohort of pediatric Crohn's disease. We show that TRSs based on genes regulated by variants linked to inflammatory bowel disease (IBD) not only outperform genetic risk scores (GRSs) in distinguishing Crohn's disease from healthy samples, but also serve to identify patients who in time will progress to complicated disease. Our dissection of eQTL effects may be used to distinguish genes whose association with disease is through promotion versus protection, thereby linking statistical association to biological mechanism. The TRS approach constitutes a potential strategy for personalized medicine that enhances inference from static genotypic risk assessment. PMID- 28805831 TI - Elucidating "screw dislocation"-driven film formation of sodium thiosulphate with complex hierarchical molecular assembly. AB - Sodium thiosulphate (Na2S2O3) films were synthesized on carbon steel substrates through solution deposition, and a film formation growth mechanism is delineated in detail herein. Dislocation-driven film formation took place at the lower concentration of Na2S2O3 (0.1 M) studied, where screw dislocation loops were identified. Interestingly, we observed the co-existence of screw dislocation spiral loops and hierarchically-ordered molecular assembly in the film, and showed the importance of hierarchical morphology in the origin of screw dislocation. The screw dislocation loops were, however, distorted at the higher studied concentration of Na2S2O3 (0.5 M), and no hierarchical structures were formed. The mechanisms of film formation are discussed in detail and provide new insights into our understanding regarding morphology of the hierarchical molecular assembly, screw dislocation loop formation, and the role of chemical elements for their development. The main crystalline and amorphous phases in the surface films were identified as pyrite/mackinawite and magnetite. As sodium thiosulphate is widely used for energy, corrosion inhibition, nanoparticle synthesis and catalysis applications, the knowledge generated in this study is applicable to the fields of corrosion, materials science, materials chemistry and metallurgy. PMID- 28805832 TI - Encapsulation of flavonoids in liposomal delivery systems: the case of quercetin, kaempferol and luteolin. AB - The instability of dietary flavonoids is currently a challenge for their incorporation in functional foods. This study investigated the protective effects of liposome encapsulation on a variety of flavonoids and their interaction mechanisms. It was found that the incorporation of flavonoids into the liposomal membrane was strongly dependent on their structure and loading concentration. Liposomes loading quercetin and luteolin exhibited a relatively small size and homogeneous suspension compared to those loading kaempferol. Additionally, liposomes displayed a stronger retaining ability to quercetin and luteolin than kaempferol during preparation, storage, heating and pH shock. After encapsulation, quercetin displayed the strongest 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging and lipid peroxidation inhibition capacity, followed by kaempferol and luteolin. Raman and IR spectroscopy techniques demonstrated that flavonoids could modulate the dynamic and packing order of lipid chains, which were responsible for the stabilization of liposomes. Our findings should guide the rational design of liposomal encapsulation technology to efficiently deliver flavonoids in nutraceuticals and functional foods. PMID- 28805829 TI - Lineage-specific dynamic and pre-established enhancer-promoter contacts cooperate in terminal differentiation. AB - Chromosome conformation is an important feature of metazoan gene regulation; however, enhancer-promoter contact remodeling during cellular differentiation remains poorly understood. To address this, genome-wide promoter capture Hi-C (CHi-C) was performed during epidermal differentiation. Two classes of enhancer promoter contacts associated with differentiation-induced genes were identified. The first class ('gained') increased in contact strength during differentiation in concert with enhancer acquisition of the H3K27ac activation mark. The second class ('stable') were pre-established in undifferentiated cells, with enhancers constitutively marked by H3K27ac. The stable class was associated with the canonical conformation regulator cohesin, whereas the gained class was not, implying distinct mechanisms of contact formation and regulation. Analysis of stable enhancers identified a new, essential role for a constitutively expressed, lineage-restricted ETS-family transcription factor, EHF, in epidermal differentiation. Furthermore, neither class of contacts was observed in pluripotent cells, suggesting that lineage-specific chromatin structure is established in tissue progenitor cells and is further remodeled in terminal differentiation. PMID- 28805833 TI - Application of alpha-amino acids for the transition-metal-free synthesis of pyrrolo[1,2-a]quinoxalines. AB - A practical and concise protocol for the efficient synthesis of pyrrolo[1,2 a]quinoxalines from readily available alpha-amino acids and 2-(1H-pyrrol-1 yl)anilines under transition metal-free conditions has been established. This protocol, which includes the formation of new C-C and C-N bonds, features a wide substrate scope with a broad range of functional group tolerance. PMID- 28805830 TI - In vitro and in vivo analysis of visible light crosslinkable gelatin methacryloyl (GelMA) hydrogels. AB - Photocrosslinkable materials have been frequently used for constructing soft and biomimetic hydrogels for tissue engineering. Although ultraviolet (UV) light is commonly used for photocrosslinking such materials, its use has been associated with several biosafety concerns such as DNA damage, accelerated aging of tissues, and cancer. Here we report an injectable visible light crosslinked gelatin-based hydrogel for myocardium regeneration. Mechanical characterization revealed that the compressive moduli of the engineered hydrogels could be tuned in the range of 5-56 kPa by changing the concentrations of the initiator, co-initiator and co monomer in the precursor formulation. In addition, the average pore sizes (26-103 MUm) and swelling ratios (7-13%) were also shown to be tunable by varying the hydrogel formulation. In vitro studies showed that visible light crosslinked GelMA hydrogels supported the growth and function of primary cardiomyocytes (CMs). In addition, the engineered materials were shown to be biocompatible in vivo, and could be successfully delivered to the heart after myocardial infarction in an animal model to promote tissue healing. The developed visible light crosslinked hydrogel could be used for the repair of various soft tissues such as the myocardium and for the treatment of cardiovascular diseases with enhanced therapeutic functionality. PMID- 28805834 TI - Profiles of free and bound phenolics extracted from Citrus fruits and their roles in biological systems: content, and antioxidant, anti-diabetic and anti hypertensive properties. AB - This study of selected plants of the Rutaceae family was carried out to investigate their phenolic content, antioxidant activity, and the in vitro inhibitory potential of extracted phenolics towards enzymes relevant for hyperglycemia and hypertension. The phenolic content, antioxidant activity and phenolic extract-mediated inhibitory activities for alpha-glucosidase and alpha amylase were evaluated by spectrophotometry. The content of individual phenolics and the angiotensin I-converting enzyme (ACE) inhibitory activity of the phenolic extracts were evaluated by LC/MS-MS and RP-HPLC methods, respectively. A higher percentage of free phenolic content was seen for all the selected plants of the Rutaceae family (85.43-92.82% of the total phenolic content) than of the bound form (7.18-14.57% of total phenolic content). The major predominant bound phenolic in lemon and red blood orange was hesperidin. The major predominant bound phenolic in pummelo, shamouti and clementine was ferulic acid. The highest ACE and alpha-glucosidase inhibitory activity of the extracted phenolics from lemon was associated with free phenolic extracts obtained at 30 degrees C with values of 100% inhibition. Red blood orange free phenolic extract (30 degrees C) elicited the highest alpha-amylase inhibition activity (32.3%). In contrast, extracted bound phenolics after acid and base hydrolysis from all selected plants from the Citrus species were shown to induce activation of the ACE and alpha amylase enzymes. PMID- 28805835 TI - A comparison study on polysaccharides extracted from Laminaria japonica using different methods: structural characterization and bile acid-binding capacity. AB - In this study, the structural characterization and bile acid-binding capacity of Laminaria japonica polysaccharides (LP), obtained by seven different extraction methods, were investigated. The results indicated that extraction methods exhibited significant effects on extraction yield, molecular weight, monosaccharide composition and the content of neutral sugar, fucose, uronic acid and sulfate of LP. AFM analysis indicated that LP extracted by different methods exhibited certain different, flexible and worm-like chains with many branches. Rheological measurements showed that the LP, obtained by pressurized hot water extraction and acid assisted extraction, exhibited lower viscosity due to their lower molecular weight, compared to other extracted polysaccharides. The bile acid-binding capacity of acid assisted extracted LP was significantly higher than other LP samples tested, which was probably ascribed to its highly branched structure, low molecular weight, low viscosity and abundant uronic acid and fucose in total monosaccharides. The present study provides scientific evidence and advances in the preparation technology and a method for evaluating hypolipidemic activities of L. japonica polysaccharides. PMID- 28805836 TI - Dinuclear zinc complex catalyzed asymmetric methylation and alkynylation of aromatic aldehydes. AB - A general AzePhenol dinuclear zinc catalytic system has been successfully developed and introduced into the asymmetric addition of dimethylzinc and alkynylzinc to aromatic aldehydes. In this system, an azetidine derived chiral ligand has proven to be an effective enantioselective promoter. Under the optimal reaction conditions, a series of chiral 1-hydroxyethyl (up to 99% ee) and secondary propargylic alcohols (up to 96% ee) were generated with good yields and enantioselectivities. Additionally, this novel catalytic system showed good functional group compatibility. Remarkably, the substituent's electronic nature alone is not sufficient to allow for exclusive enantioselectivity, an additional substituent's location also had an effect. We proposed that the formation of a stable and structural rigid transition state by the chelation of ortho substituted benzaldehydes to the zinc atom was responsible for the observed higher enantioselectivity. The possible catalytic cycles of both transformations accounting for the stereoselectivity were described accordingly. PMID- 28805828 TI - Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly. AB - Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms. PMID- 28805837 TI - Synthesis of Cu-catalysed quinazolinones using a Csp3-H functionalisation/cyclisation strategy. AB - A series of 2,3-disubstituted-4(3H)-quinazolinones were synthesised via a copper catalysed Csp3-H functionalisation/cyclisation of 2-amino-N,N-dialkylbenzamides. In comparison to the reported methods this strategy allows an easy access to diversely substituted quinazolinones under mild conditions in air. The reaction also exhibits good functional group tolerance and would be of value to heterocyclic researchers as well as pharmaceutical process chemists. The reaction is proposed to proceed through a double SET type radical mechanism. PMID- 28805839 TI - CO2-Responsive polymer membranes with gas-tunable pore size. AB - We report a smart polymer membrane whose pore can be switched between the "closed" and "open" state just by passing CO2 and Ar in solution respectively. Compared with other stimuli, such as pH or temperature change, gas is an environmentally friendly and cost-effective stimulus for reversibly tuning the pore size and imparting the size selectivity of the membrane. PMID- 28805845 TI - Total syntheses of gerberinol I and the pterophyllins 2 and 4 using the Casnati Skattebol reaction under different conditions. AB - The concise and efficient total syntheses of the naturally-occurring coumarin derivatives gerberinol I, and the pterophyllins 2 and 4, from 5-methyl-4 hydroxycoumarin as a common precursor employing different Casnati-Skattebol reaction conditions, are reported. The synthesis of the key intermediate coumarin was achieved by the organocatalytic condensation of acetylacetone and crotonaldehyde followed by a LiCl-assisted cyclization, CuCl2-promoted aromatization and a final Et2CO3-mediated cyclization. A Casnati-Skattebol formylation under high-temperature conditions afforded gerberinol I, whereas milder conditions resulted in an unstable 3-formyl-4-hydroxycoumarin derivative, which was subjected to a basic alumina-mediated one pot O-alkylation with chloroacetone and intramolecular aldolization to furnish pterophyllin 4. Wittig methylenation of the latter conveniently afforded pterophyllin 2. PMID- 28805846 TI - A photochromic prototype based on difurylperhydrocyclopentene with remarkable photoswitching behavior and in vivo application. AB - A new strategy has been developed to synthesize difurylperhydrocyclopentene derivatives. The compound displays reversible photochromism in solution and thin film. The results show that furan is superior to thiophene in terms of strong fluorescence, higher photocyclization conversion and cyclization quantum yield, as well as better fatigue resistance. Owing to the molecule being derived absolutely from C, H, and O atoms, the compound exhibits no cytotoxicity, which enables it to potentially serve as a biodegradable and biorenewable material for in vivo applications. PMID- 28805847 TI - Probing nanoscale functionalities of metal-organic framework nanocrystals. AB - Experimental investigation of functional properties of metal-organic frameworks (MOFs) at nanoscale precision is challenging and rarely reported. In this study, we report the piezo- and ferroelectric properties of NUS-6 MOF nanocrystals using dual AC resonance tracking piezoresponse force microscopy and piezoresponse force spectroscopy for the first time. Both NUS-6-(Hf) and NUS-6-(Zr) nanocrystals displayed anomalous piezoelectricity with the calculated piezoelectric coefficient dzz constants of 2.0-3.5 pm V-1 and 1.5-2.5 pm V-1, respectively. Moreover, NUS-6-(Hf) showed much better polarization-switching behaviors (ferroelectricity) than NUS-6-(Zr), featured by very low coercive biases in the ferroelectric hysteresis (PR) loop. Furthermore, elasticity and thermal stability of the NUS-6 nanocrystals have been presented. The results have opened a realm of probing piezo- and ferro-electric properties as well as mechanical properties of MOF nanocrystals, which are promising materials for applications in integrated microelectromechanical systems (MEMS). PMID- 28805849 TI - Topology of polymer chains under nanoscale confinement. AB - Spatial confinement limits the conformational space accessible to biomolecules but the implications for bimolecular topology are not yet known. Folded linear biopolymers can be seen as molecular circuits formed by intramolecular contacts. The pairwise arrangement of intra-chain contacts can be categorized as parallel, series or cross, and has been identified as a topological property. Using molecular dynamics simulations, we determine the contact order distributions and topological circuits of short semi-flexible linear and ring polymer chains with a persistence length of lp under a spherical confinement of radius Rc. At low values of lp/Rc, the entropy of the linear chain leads to the formation of independent contacts along the chain and accordingly, increases the fraction of series topology with respect to other topologies. However, at high lp/Rc, the fraction of cross and parallel topologies are enhanced in the chain topological circuits with cross becoming predominant. At an intermediate confining regime, we identify a critical value of lp/Rc, at which all topological states have equal probability. Confinement thus equalizes the probability of more complex cross and parallel topologies to the level of the more simple, non-cooperative series topology. Moreover, our topology analysis reveals distinct behaviours for ring- and linear polymers under weak confinement; however, we find no difference between ring- and linear polymers under strong confinement. Under weak confinement, ring polymers adopt parallel and series topologies with equal likelihood, while linear polymers show a higher tendency for series arrangement. The radial distribution analysis of the topology reveals a non-uniform effect of confinement on the topology of polymer chains, thereby imposing more pronounced effects on the core region than on the confinement surface. Additionally, our results reveal that over a wide range of confining radii, loops arranged in parallel and cross topologies have nearly the same contact orders. Such degeneracy implies that the kinetics and transition rates between the topological states cannot be solely explained by contact order. We expect these findings to be of general importance in understanding chaperone assisted protein folding, chromosome architecture, and the evolution of molecular folds. PMID- 28805851 TI - On the shuttling mechanism of a chlorine atom in a chloroaluminum phthalocyanine based molecular switch. AB - An intermediate shuttling structure of a chloroaluminum phthalocyanine(ClAlPc) based molecular switch is transiently created and analyzed by combined scanning tunneling microcopy/spectroscopy and density-functional theory calculations, which suggests that the Cl atom is squeezed into the space between the central Al atom and the inner N-containing ring in ClAlPc. PMID- 28805850 TI - Dispersible oxygen microsensors map oxygen gradients in three-dimensional cell cultures. AB - Phase fluorimetry, unlike the more commonly used intensity-based measurement, is not affected by differences in light paths from culture vessels or by optical attenuation through dense 3D cell cultures and hydrogels thereby minimizing dependence on signal intensity for accurate measurements. This work describes the use of phase fluorimetry on oxygen-sensor microbeads to perform oxygen measurements in different microtissue culture environments. In one example, cell spheroids were observed to deplete oxygen from the cell-culture medium filling the bottom of conventional microwells within minutes, whereas oxygen concentrations remained close to ambient levels for several days in hanging-drop cultures. By dispersing multiple oxygen microsensors in cell-laden hydrogels, we also mapped cell-generated oxygen gradients. The spatial oxygen mapping was sufficiently precise to enable the use of computational models of oxygen diffusion and uptake to give estimates of the cellular oxygen uptake rate and the half-saturation constant. The results show the importance of integrated design and analysis of 3D cell cultures from both biomaterial and oxygen supply aspects. While this paper specifically tests spheroids and cell-laden gel cultures, the described methods should be useful for measuring pericellular oxygen concentrations in a variety of biomaterials and culture formats. PMID- 28805853 TI - The activity of lone pair contributing to SHG response in bismuth borates: a combination investigation from experiment and DFT calculation. AB - Second harmonic generation (SHG) response is one of the most essential properties of nonlinear optical (NLO) materials. To achieve relatively strong SHG response, a feasible strategy is to introduce stereochemically active lone pair (SCALP) cations, such as Bi3+. NLO materials with Bi3+ usually exhibit a huge difference in SHG response, the inner correlation between the activity of SCALP and SHG response still being unclear owing to the lack of quantization estimation of the intensity of SCALP. Based on the calculation results of density functional theory (DFT), we develop a theoretical method to compute the intensity of the Bi-6s SCALP, which could describe the stereochemical behavior and exert significantly influences on some apparent optical properties, such as SHG response. Using the method, we further analyze a series of bismuth borates which exhibit an apparent hierarchy in SHG response: BiB2O4F (12 * KDP), alpha-BiB3O6 (8.2 * KDP), Bi2ZnOB2O6 (4 * KDP), CaBi2B2O7 (2 * KDP), and Bi2B8O15 (1.2 * KDP). Combining the experimental measurements for the SHG responses, electronic structure analysis and the real-space atom cutting method, we explore the mechanism of the hierarchy in SHG response. PMID- 28805852 TI - The effect of sub-zero temperature on the formation and composition of secondary organic aerosol from ozonolysis of alpha-pinene. AB - This study presents a newly constructed temperature controlled cold-room smog chamber at Aarhus University, Denmark. The chamber is herein utilized to study the effect of sub-zero temperature on the formation and chemical composition of secondary organic aerosol (SOA) from ozone initiated oxidation of alpha-pinene. The chemical composition of alpha-pinene SOA formed from dark ozonolysis of alpha pinene at 293 K and 258 K was investigated using High-Resolution Time-of-Flight Aerosol Mass Spectrometry (HR-ToF-AMS) and Ultra-High Performance Liquid Chromatography/Electrospray Ionization Quadrupole Time-of-Flight Mass Spectrometry (UHPLC/ESI-qToF-MS). For comparison, an OH-initiated oxidation experiment was performed at 293 K. In ozonolysis experiments it was found that oxygen-to-carbon (O : C) ratios were higher in the particles formed at 293 K compared to 258 K. A total of 16 different organic acids and 30 dimers esters were quantified in the collected particles composing up to 34% of the total alpha pinene SOA mass with increased mass fraction of carboxylic acids in particles from alpha-pinene ozonolysis at 258 K compared to 293 K. In contrast, dimer esters showed suppressed formation at the sub-zero reaction temperature, thus contributing 3% to SOA mass at 258 K while contributing 9% at 293 K. SOA formed in the OH-initiated oxidation of alpha-pinene at 293 K resulted in low concentrations of dimer esters supporting Criegee intermediates as a possible pathway to dimer ester formation. Vapour pressure estimates of the identified carboxylic acids and dimer esters are presented and show how otherwise semi volatile carboxylic acids at sufficiently low temperatures may classify as low or even extremely low volatile organic compounds (ELVOC), thus may add to an enhanced particle formation observed at the sub-zero temperature through gas-to particle conversion. The change in chemical composition of the SOA particles with temperature is ascribed to a combination of effects: the decreased vapour pressures and hence increased condensation of carboxylic acids from the gas phase to the particle phase along with suppressed formation of the high molecular weight dimer esters and different gas and particle phase chemistry results in particles of different chemical composition as a consequence of low reaction temperatures. PMID- 28805855 TI - Rhodium(iii)-catalyzed and MeOH-involved regioselective mono-alkenylation of N arylureas with acrylates. AB - We herein disclose, for the first time, Rh(iii)-catalyzed and MeOH-involved regioselective mono-alkenylation of arenes with acrylates using NHCONMe2 as the transformable directing group, giving direct access to diverse ortho-acrylated N phenyl carbamates. The synthetic application of the obtained products to build privileged quinolin-2(1H)-ones and 3-(2-aminophenyl)acrylates has also been demonstrated in subsequent derivatization reactions. PMID- 28805858 TI - Optimal hydrogen storage in sodium substituted lithium fullerides. AB - Through the substitution of Li with Na in Li6C60, we synthesized a series of mixed alkali cluster intercalated fullerides, NaxLi6-xC60. These compounds share lattices of Na6C60 and Li6C60 with a cubic parameter linearly dependent on x. H2 absorption and desorption were studied by means of charge/discharge kinetic measurements and coupled calorimetric-manometric evaluation. By varying the stoichiometry, we found the best compromise among the absorption rate, temperature and amount of hydrogen for x = 0.5 and 1. Small concentrations of Na substituted to Li significantly lower the absorption temperature of Li6C60, improving the hydrogenation capacity, the kinetics, and the dehydrogenation enthalpy, the latter being 43.8 kJ mol-1 H2 for x = 1. This study moves further toward the utilization of intercalated fullerides for hydrogen storage applications. PMID- 28805859 TI - Thermo-responsive molecularly imprinted sensor based on the surface-enhanced Raman scattering for selective detection of R6G in the water. AB - In this study, a novel SERS sensor was successfully prepared by combining a molecular imprinted technique (MIT) with a SERS technique to improve the selectivity of the traditional SERS technique. Moreover, a thermo-sensitive technique was also introduced to confer stimuli-responsive properties to the materials. In a typical procedure, the Ag nanoparticles (NPs) were reduced on the surface of ZnO nanorods (NRs), and the ZnO/Ag heterostructures were used as the SERS substrates. Subsequently, a layer of thermo-sensitive imprinted polymer was coated on the surface of ZnO/Ag heterostructures to prepare the thermoresponsive ZnO/Ag/molecularly imprinted polymers (ZOA-TMIPs) by precipitation polymerization. Moreover, it was proven that the ZOA-TMIPs were regenerable and exhibited good reusability. The results proved that the materials in this study can be effectively used for residual organic dye detection in water. PMID- 28805860 TI - Synthesis of N-doped graphene quantum dots by pulsed laser ablation with diethylenetriamine (DETA) and their photoluminescence. AB - We report a facile, fast, and one-step approach to prepare N-doped graphene quantum dots (GQDs) using pulsed laser ablation with diethylenetriamine (DETA). The synthesized N-doped GQDs with an average size of about 3.4 nm and an N/C atomic ratio of 26% have been demonstrated. Compared to pristine GQDs, the N doped GQDs emit enhanced photoluminescence (PL) with a factor as high as 66, originated from the enhanced densities of pyridinic and graphitic N. The temperature-dependent PL of the N-doped GQDs was studied from cryogenic to room temperature. An anomalous temperature dependence of PL intensity was observed for the N-doped GQDs, which was ascribed to a carrier transfer mechanism from a dopant-induced state to the quantum-dot emitting state. PMID- 28805861 TI - Site-dependent effects of methylation on the electronic spectra of jet-cooled methylated xanthine compounds. AB - We obtained the electronic spectra of various methylated xanthine compounds including caffeine in a supersonic jet by resonant two-photon ionization spectroscopy. The methyl group in the tested methylated xanthine compounds has a distinct, site-dependent effect on the electronic spectrum. Methylation at the N3 position causes a significant red shift of the pipi* state, whereas methylation at the N1 position has only minimal effects on the electronic spectrum. The notably broad spectra of theobromine and caffeine result from methyl substitution at the N7 position, which causes a large displacement between the potential energy surfaces of the S0 and S1 states, and a strong vibronic coupling. We also investigated the internal rotation of the methyl group and its effect on the electronic spectrum of the methylated xanthine compounds. We found that the barrier height for the torsional motion in the ground state is significantly affected by a carbonyl or methyl group that lies close to the methyl group of interest. In contrast, the torsional barrier in the excited state is governed by the hyperconjugation interaction in the lowest unoccupied molecular orbital. The agreement between the experimental and simulated spectra of torsional vibronic bands suggested that the low frequency torsional vibrations arising from the tunneling splitting and the coupling between the torsional and molecular motions give theobromine and theophylline the multiplet nature of their origin bands. This study provides a new level of understanding for the methyl substitution effects on the electronically excited states of xanthine compounds, which may very well be applicable to many other methyl substituted biomolecules including DNAs and proteins. PMID- 28805862 TI - Lead(ii): Lewis acid and occasional base, as illustrated by its complex with 1,5 naphthalenedisulfonate and 5-methyl-1,10-phenanthroline. AB - A crystal structure determination of the Pb(ii) coordination polymer [Pb(Mephen)(1,5-nds)(H2O)]n provides not only evidence of the common action of Pb(ii) as a Lewis acid but also clear proof of its ability, in the solid state at least, to act as a Lewis base. This action as a base is attributed to the presence of a valence shell lone pair and its identification here is further evidence for the occasional but not universally detectable influence of the lone pair on the metal ion stereochemistry. PMID- 28805863 TI - Spin polynomial similarity transformation for repulsive Hamiltonians: interpolating between coupled cluster and spin-projected unrestricted Hartree Fock. AB - Our overarching goal is to be able to describe both weak and strong correlation with a single, computationally affordable method without sacrificing important qualities of the wavefunction, e.g. symmetries of the Hamiltonian. We know that coupled cluster theory with low-order excitations is excellent at describing weakly-correlated systems near equilibrium, but breaks down as systems become more strongly correlated. Projected Hartree-Fock on the other hand is inherently capable of describing multireference character, but misses weak correlation. We are thus exploring how best to combine coupled cluster and projected Hartree-Fock in our search for a computationally feasible method that is applicable across a wide range of correlation strengths. In this manuscript, we adapt our earlier work on the pairing Hamiltonian to repulsive Hamiltonians, resulting in the spin polynomial similarity transformation (SpinPoST) interpolation. SpinPoST parameterizes the wavefunction in order to interpolate between the coupled cluster and spin-projected unrestricted Hartree-Fock ansatze self consistently, and is a spin-symmetry adapted model which involves only single and double excitations. We employ a unique approach of optimizing the wavefunction by minimizing the effect of connected quadruple excitations, resulting in a method which is spin-symmetry adapted and is comparable energetically to coupled cluster with singles and doubles for weak correlation and spin-projected Hartree-Fock for strong correlation. PMID- 28805864 TI - Novel synthesis of magnetic, porous C/ZnFe2O4 photocatalyst with enhanced activity under visible light based on the Fenton-like reaction. AB - Magnetic visible-light-driven photocatalyst, porous C/ZnFe2O4 (denoted as C/ZFO CE) was fabricated via a CO2-mediated ethanol route. CO2-mediated ethanol route largely mitigated the solvent strength and facilitated the homogenous deposition of ZnFe2O4 (ZFO) through the coordination of metallic cation with CO32- and HCO3- anions, which were hydrolyzed from CO2 and H2O, thereby avoiding additional precipitant. Moreover, the HCO3-, CO32- and NO3- in the system acted as templates for the formation of porous C avoiding the additional organic mesoporous templates, thus reducing the synthesis cost. For the degradation of RhB and phenol, the C/ZFO-CE system in presence of minute H2O2 exhibited remarkably improved catalytic performance compared with the systems of H2O2, ZFO, C/ZFO-CE, C/ZFO-E (C/ZnFe2O4 synthesized in pure ethanol) and C/ZFO-E in the presence of minute H2O2. Furthermore, 2.0 mL of H2O2 (30%) combined with C/ZFO-CE obtained the maximum degradation efficiencies of 100% for RhB within 60 min and 91% for phenol within 120 min. The high efficiency for degradation of pollutants over C/ZFO-CE catalyst in the presence of minute H2O2 was possibly attributed to the strong harvest of visible light, the improved separation efficiency of the photoinduced charges and the overall OH production by the "photo-Fenton" process. The existence of OH during photodegradation process was evidenced via the PL-TA (photoluminescence-terephthalic acid) technique, ESR spectra and trapping experiments of active species using different scavengers. Furthermore, a possible reaction mechanism involving the Fenton-like reaction for the photodegradation of pollutants is proposed based on the experimental results. PMID- 28805866 TI - Low-spin [MII(L)2] and [MIII(L)2]+ (M = Fe and Co) complexes of tridentate azo containing pyridine/pyrazine amide ligands: structures, properties and redox potential correlations. AB - Using deprotonated forms of tridentate azo-containing pyridine-2-/pyrazine-2 carboxamide 2-[N-(2-phenylazo)carbamoyl]-pyridine/pyrazine, seven bis-ligand complexes of FeII/CoII and FeIII/CoIII have been synthesized. Molecular structures of six of them reveal that these six-coordinate complexes utilize all available donor sites of the ligands and assume MII/IIIN2(pyridine/pyrazine)N'2(amide)N''2(azo) coordination. Complexes of FeII and CoIII are diamagnetic and those of FeIII and CoII are paramagnetic (S = 1/2; room-temperature magnetic data and EPR spectra). Cyclic voltammetry experiments in CH2Cl2 reveal facile metal-centred FeIII/FeII and CoIII/CoII redox responses, and all complexes display quasireversible-to-irreversible ligand(azo)-centred redox processes. The E1/2 values of MIII/MII redox processes for Fe, Co and Ni (reported earlier) complexes of the pyridine amide ligand linearly correlate with those for six-coordinate [MIII(bpy)3]3+/[MII(bpy)3]2+, [MIII(terpy)2]3+/[MII(terpy)2]2+, [MIII(L)]+/[MII(L)]0 or [MIII(L')2]+/[MII(L')2]0 (bpy = 2,2'-bipyridine, terpy = 2,2':6',2''-terpyridine, hexadentate L(2-) = 1,4-bis[o-(pyridine-2-carboxamidophenyl)]-1,4-dithiobutane and tridentate L'(-) = {2-[2-(arylimino)phenylazo]-pyridine}) couples. Density functional theory (DFT) at the B3LYP level and time-dependent (TD)-DFT calculations rationalize the electronic structure of the present complexes and throw light on the origin of observed electronic transitions. PMID- 28805867 TI - Coumarin-containing thermoresponsive hyaluronic acid-based nanogels as delivery systems for anticancer chemotherapy. AB - Multi-stimuli responsive nanogels based on biocompatible hydrophilic polymers have emerged as promising drug delivery systems to improve anticancer therapy with hydrophobic drugs, through increase of circulating-time in the bloodstream, tumor-targeting and reduction of systemic toxicity. This paper reports on the synthesis, characterization and biological perspectives of light- and thermoresponsive hyaluronic acid (HA)-based nanogels containing coumarin as the photocleavable group. Newly synthesized nanogels exhibited interesting features: formation by a temperature-triggered self-assembly process, successful incorporation of poorly water-soluble molecules, light-responsiveness as demonstrated by a significant shift in the critical aggregation temperature after light irradiation, efficient internalization by cancer cells overexpressing the CD44 receptor of HA, ability to circulate for a prolonged period of time in the bloodstream after intravenous injection in mice and considerable detection in tumor tissues. Our findings indicate that coumarin-containing HA-based nanogels may be promising delivery systems for anticancer chemotherapy. PMID- 28805868 TI - A microfluidic flow cytometer enabling absolute quantification of single-cell intracellular proteins. AB - Quantification of single-cell proteomics provides key insights into cellular heterogeneity while conventional flow cytometry cannot provide absolute quantification of intracellular proteins of single cells due to the lack of calibration approaches. This paper presents a constriction channel (with a cross sectional area smaller than cells) based microfluidic flow cytometer, capable of collecting copy numbers of specific intracellular proteins. In this platform, single cells stained with fluorescence labelled antibodies were forced to squeeze through the constriction channel with the fluorescence intensities quantified and since cells fully filled the constriction channel during the squeezing process, solutions with fluorescence labelled antibodies were flushed into the constriction channel to obtain calibration curves. By combining raw fluorescence data and calibration curves, absolute quantification of intracellular proteins was realized. As a demonstration, copy numbers of beta-actin of single tumour cells were quantified to be 0.90 +/- 0.30 MUM (A549, ncell = 14 228), 2.34 +/- 0.70 MUM (MCF 10A, ncell = 2455), and 0.98 +/- 0.65 MUM (Hep G2, ncell = 6945). The travelling time for individual cells was quantified to be roughly 10 ms and thus a throughput of 100 cells per s can be achieved. This microfluidic system can be used to quantify the copy numbers of intracellular proteins in a high throughput manner, which may function as an enabling technique in the field of single-cell proteomics. PMID- 28805869 TI - Wrinkle-stabilized metal-graphene hybrid fibers with zero temperature coefficient of resistance. AB - The interfacial adhesion between graphene and metals is poor, as metals tend to generate superlubricity on smooth graphene surface. This problem renders the free assembly of graphene and metals to be a big challenge, and therefore, some desired conducting properties (e.g., stable metal-like conductivities in air, lightweight yet flexible conductors, and ultralow temperature coefficient of resistance, TCR) likely being realized by integrating the merits of graphene and metals remains at a theoretical level. This work proposes a wrinkle-stabilized approach to address the poor adhesion between graphene surface and metals. Cyclic voltammetry (CV) tests and theoretical analysis by Scharifker-Hills models demonstrate that multiscale wrinkles effectively induce nucleation of metal particles, locking in metal nuclei and guiding the continuous growth of metal islands in an instantaneous model on rough graphene surface. The universality and practicability of the wrinkle-stabilized approach is verified by our investigation through the electrodeposition of nine kinds of metals on graphene fibers (GF). The strong interface bonding permits metal-graphene hybrid fibers to show metal-level conductivities (up to 2.2 * 107 S m-1, a record high value for GF in air), reliable weatherability and favorable flexibility. Due to the negative TCR of graphene and positive TCR of metals, the TCR of Cu- and Au-coated GFs reaches zero at a wide temperature range (15 K-300 K). For this layered model, the quantitative analysis by classical theories demonstrates the suitable thickness ratio of graphene layer and metal layer to achieve zero TCR to be 0.2, agreeing well with our experimental results. This wrinkle-stabilized approach and our theoretical analysis of zero-TCR behavior of the graphene-metal system are conducive to the design of high-performance conducting materials based on graphene and metals. PMID- 28805870 TI - An enhanced degree of charge transfer in dye-sensitized solar cells with a ZnO TiO2/N3/Ag structure as revealed by surface-enhanced Raman scattering. AB - A number of recent studies have focused on improving the performance of dye sensitized solar cells (DSSCs). Cells with a ZnO-TiO2/N3/Ag structure have attracted particular attention because of their excellent power conversion efficiencies. Using a dendritic crystal ZnO-TiO2 composite semiconductor and Ag in conjunction leads to different charge-transfer (CT) processes, and this is the main theoretical basis for the improvement of DSSC performances. Thus, in the present study, TiO2/N3, ZnO/N3, ZnO-TiO2/N3, TiO2/N3/Ag, ZnO/N3/Ag, and ZnO TiO2/N3/Ag assemblies have been fabricated and their CT processes have been monitored by using surface-enhanced Raman scattering (SERS) spectra, with particular focus on the differences caused by the synergistic effect of the ZnO TiO2 component. The dye loading capacity of the dendritic crystal ZnO-TiO2 is much larger than that of TiO2. There are extra enhancements in the SERS intensity and degree of CT (rhoCT) in ZnO-TiO2/N3 compared to ZnO + TiO2/N3 (based on a simulation curve for the physically mixed TiO2 and ZnO semiconductors) with 476.5 nm excitation due to the synergistic effect of the ZnO-TiO2 component. And these enhancements in ZnO-TiO2/N3/Ag compared to ZnO + TiO2/N3/Ag appear with 476.5 and 532 nm excitation, which are particularly large with 532 nm excitation. Accordingly, the participation of Ag in this synergistic effect can reduce its energy threshold, which will make it easier to appear. Finally, to rationalize these extra enhancements, the models describing the CT mechanism have been proposed. Thus, the use of the dendritic crystal ZnO-TiO2 composite semiconductor in the semiconductor/N3/Ag system can improve the adsorption capacity of N3 compared to that with TiO2. Meanwhile, the synergistic effect of ZnO-TiO2 and Ag can promote the CT process, demonstrating that ZnO-TiO2/N3/Ag is an excellent structure for DSSCs. PMID- 28805871 TI - Asymmetric motion of magnetically actuated artificial cilia. AB - Most microorganisms use hair-like cilia with asymmetric beating to perform vital bio-physical processes. In this paper, we demonstrate a novel fabrication method for creating magnetic artificial cilia capable of such a biologically inspired asymmetric beating pattern essential for inducing microfluidic transport at low Reynolds number. The cilia are fabricated using a lithographic process in conjunction with deposition of magnetic nickel-iron permalloy to create flexible filaments that can be manipulated by varying an external magnetic field. A rotating permanent magnet is used to actuate the cilia. We examine the kinematics of a cilium and demonstrate that the cilium motion is defined by an interplay among elastic, magnetic, and viscous forces. Specifically, the forward stroke is induced by the rotation of the magnet which bends the cilium, whereas the recovery stroke is defined by the straightening of the deformed cilium, releasing accumulated elastic potential energy. This difference in dominating forces acting during the forward stroke and the recovery stroke leads to an asymmetric beating pattern of the cilium. Such magnetic cilia can find applications in microfluidic pumping, mixing, and other fluid handling processes. PMID- 28805872 TI - Microfluidic co-flow of Newtonian and viscoelastic fluids for high-resolution separation of microparticles. AB - The microfluidic passive control of microparticles largely relies on the hydrodynamic effects of the carrier media such as Newtonian fluids and viscoelastic fluids. Yet the viscoelastic/Newtonian interfacial effect has been scarcely investigated, especially for high-resolution particle separation. Here we report a microfluidic co-flow of Newtonian (water or PBS) and viscoelastic fluids (PEO) for the size-dependent separation of microparticles. The co-flow condition generates a stable viscoelastic/Newtonian interface, giving rise to the wall-directed elastic lift forces that compete with the center-directed lift forces, and efficiently hinders the migration of microparticles from the Newtonian to the viscoelastic fluid in a size-dependent manner. An almost complete separation of a binary mixture of 1 MUm and 2 MUm polystyrene particles is achieved by the co-flow of water and a very dilute PEO solution (100 ppm), whereas the sole use of water or PEO could not lead to an efficient separation. This co-flow microfluidic system is also applied for the separation of Staphylococcus aureus (1 MUm) from platelets (2-3 MUm) with >90% efficiencies and purities. PMID- 28805873 TI - Emission color tuning of core/shell upconversion nanoparticles through modulation of laser power or temperature. AB - Upconversion nanoparticles (UCNPs) are an excellent choice to construct security features against counterfeiting, owing to their unique NIR-to-VIS upconversion luminescence (UCL) characteristics. However, the application of upconversion materials is limited, due to their single and invariant emission colors. Herein, the temperature-dependent UCL properties of NaGdF4:Yb/Ho (or Tm) UCNPs in the solid state have been investigated. An anomalous UCL enhancement at higher temperatures has been demonstrated for these small-sized (<10 nm) UCNPs and the underlying mechanism is discussed herein. Meanwhile, effective UCL with tunable multicolor emissions has been realized by the rational incorporation of Ho3+ and Tm3+ emitters into a single nanostructure. The emission colors of these Ho/Tm co doped Na(Gd,Yb)F4 UCNPs can be tuned by changing the laser power or temperature, due to the different spectral sensitivities of the Tm3+ and Ho3+ emitters to the excitation power density and temperature. The power- and temperature-responsive color shifts of these Ho/Tm co-doped UCNPs are favorable for immediate recognition by the naked eye, but are hard to copy, offering the possibility of designing more secure anti-counterfeiting patterns. PMID- 28805875 TI - Frequency-selective electrokinetic enrichment of biomolecules in physiological media based on electrical double-layer polarization. AB - Proteomic biomarkers of interest to the early diagnosis of diseases and infections are present at trace levels versus interfering species. Hence, their selective enrichment is needed within bio-assays for speeding binding kinetics with receptors and for reducing signal interferences. While DC fields can separate biomolecules based on their electrokinetic mobilities, they are unable to selectively enrich biomarkers versus interfering species, which may possess like-charges. We present the utilization of AC electrokinetics to enable frequency-selective enrichment of nanocolloidal biomolecules, based on the characteristic time constant for polarization of their electrical double-layer, since surface conduction in their ion cloud depends on colloidal size, shape and surface charge. In this manner, using DC-offset AC fields, differences in frequency dispersion for negative dielectrophoresis are balanced against electrophoresis in a nanoslit channel to enable the selective enrichment of prostate specific antigen (PSA) versus anti-mouse immunoglobulin antibodies that cause signal interferences to immunoassays. Through coupling enrichment to capture by receptors on graphene-modified surfaces, we demonstrate the elimination of false positives caused by anti-mouse immunoglobulin antibodies to the PSA immunoassay. PMID- 28805876 TI - Few-layered MoS2/C with expanding d-spacing as a high-performance anode for sodium-ion batteries. AB - Sodium-ion batteries (SIBs) show great potential as alternative energy storage devices for next generation energy storage systems due to the deficiency of lithium resources. MoS2 is a promising anode material for SIBs due to its high theoretical sodium storage capability and large interspace for accommodating sodium ions with a larger ionic radius than lithium ions. However, bulk MoS2 exhibits a sluggish kinetics for the intercalation-deintercalation of sodium ions and large volume expansion, which result in poor cyclability and rate performance. In this study, we designed few-layered MoS2/C nanoflowers with expanded interspacing of MoS2-MoS2 planes using polyvinyl alcohol (PVA) as an intercalating reagent and a carbon precursor. Due to the unique nanostructure and larger interlayer spacing, the MoS2/C nanoflower electrode achieves a high reversible specific capacity of 400 mA h g-1 after 300 cycles at 500 mA g-1 for sodium-ion batteries (SIBs), showing a good cycling stability. The improved electrochemical performance suggests that the MoS2/C composite is a promising anode material for sodium ion storage. PMID- 28805877 TI - A DNA bipedal nanowalker with a piston-like expulsion stroke. AB - Artificial molecular walkers beyond burn-bridge designs are important for nanotechnology, but their systematic development remains difficult. Herein, we have reported a new rationally designed DNA walker-track system and experimentally verified a previously proposed general expulsion regime for implementing non-burn-bridge nanowalkers. The DNA walker has an optically powered engine motif that reversibly extends and contracts the walker via a quadruplex duplex conformational change. The walker's extension is an energy-absorbing and force-generating process, which drives the walker's leg dissociation off-track in a piston-like expulsion stroke. The unzipping-shearing asymmetry provides the expulsion stroke a bias, which decides the direction of the walker. Moreover, three candidate walkers of different sizes were fabricated. Fluorescence motility experiments indicated two of them as successful walkers and revealed a distinctive size dependence that was expected for these expulsive walkers, but was not observed in previously reported walkers. This study identifies unique technical requirements for expulsive nanowalkers. The present DNA design is readily adapted for making similar walkers from other molecules since the unzipping-shearing asymmetry is common. PMID- 28805874 TI - Microfluidic modeling of the biophysical microenvironment in tumor cell invasion. AB - Tumor cell invasion, whether penetrating through the extracellular matrix (ECM) or crossing a vascular endothelium, is a critical step in the cancer metastatic cascade. Along the way from a primary tumor to a distant metastatic site, tumor cells interact actively with the microenvironment either via biomechanical (e. g. ECM stiffness) or biochemical (e.g. secreted cytokines) signals. Increasingly, it is recognized that the tumor microenvironment (TME) is a critical player in tumor cell invasion. A main challenge for the mechanistic understanding of tumor cell TME interactions comes from the complexity of the TME, which consists of extracellular matrices, fluid flows, cytokine gradients and other cell types. It is difficult to control TME parameters in conventional in vitro experimental designs such as Boyden chambers or in vivo such as in mouse models. Microfluidics has emerged as an enabling tool for exploring the TME parameter space because of its ease of use in recreating a complex and physiologically realistic three dimensional TME with well-defined spatial and temporal control. In this perspective, we will discuss designing principles for modeling the biophysical microenvironment (biological flows and ECM) for tumor cells using microfluidic devices and the potential microfluidic technology holds in recreating a physiologically realistic tumor microenvironment. The focus will be on applications of microfluidic models in tumor cell invasion. PMID- 28805878 TI - Interfacial-entropy-driven thermophoretic tweezers. AB - Directed migration of particles and molecules in a temperature gradient field, which is known as thermophoresis or the Soret effect, is of fundamental importance for mass transfer in colloid science and life sciences. However, thermophoretic tweezers that enable versatile particle manipulation have remained elusive due to the complex underlying physical forces in thermophoresis and the lack of general thermophilic particles above room temperature. Herein, we exploit entropic response and permittivity gradient at the particle-solvent interface to optically generated thermal gradient to achieve the thermophoretic trapping and dynamic manipulation of charged particles over an optothermal-responsive substrate. Engineering the interfacial properties, i.e., the surface charge of particles and the ionic strength of the solvent, further enhances the trapping efficiency. Through the rational design of optothermal potential profiles and substrate geometries, we have achieved various tweezing functionalities, including particle assembly, alignment, rotation and guiding, as well as precise transport of single nanoparticles. Based on the general concept of entropic change of polarized molecules structured at the particle-solvent interlayer, the thermophoretic tweezers are applicable to various types of particles, biological cells, and molecules and a wide range of solvents. PMID- 28805879 TI - Downregulation of hepatic multi-drug resistance protein 1 (MDR1) after copper exposure. AB - Copper homeostasis is strictly regulated in mammalian cells. We investigated the adaptation of hepatocytes after long-term copper exposure. Copper-resistant hepatoma HepG2 cell lines lacking ATP7B were generated. Growth, copper accumulation, gene expression, and transport were determined. Hepatocyte-like cells derived from a Wilson disease (WD) patient and the liver of a WD animal model were also studied. The rapidly gained copper resistance was found to be stable, as subculturing of cells in the absence of added copper (weaning) did not restore copper sensitivity. Intracellular copper levels and the expression of MT1 and HSP70 were increased, whereas the expression of CTR1 was reduced. However, the values normalized after weaning. In contrast, downregulation of multi-drug resistance protein 1 (MDR1), encoding P-glycoprotein (P-gp), was shown to be permanent. Calcein assays confirmed the downregulation of MDR1 in the resistant cell lines. MDR1 knockdown by siRNA resulted in increased copper resistance and decreased intracellular copper. Treatment of the resistant cells with verapamil, a known inducer of MDR1, was followed by increased copper-induced toxicity. Downregulation of MDR1 was also observed in hepatocyte-like cells derived from a WD patient after copper exposure. In addition, MDR1 was downregulated in Long Evans Cinnamon rats when the liver copper was elevated. The results indicate that downregulation of MDR1 is an adaptation of hepatic cells after sustained copper exposure when ATP7B is non-functional. Our data add to the versatile functions of MDR1 in the hepatocyte and may have an impact on the treatment of copper-related diseases, prominently WD. PMID- 28805880 TI - Vacuum filling of complex microchannels with liquid metal. AB - This paper describes the utilization of vacuum to fill complex microchannels with liquid metal. Microchannels filled with liquid metal are useful as conductors for soft and stretchable electronics, as well as for microfluidic components such as electrodes, antennas, pumps, or heaters. Liquid metals are often injected manually into the inlet of a microchannel using a syringe. Injection can only occur if displaced air in the channels has a pathway to escape, which is usually accomplished using outlets. The positive pressure (relative to atmosphere) needed to inject fluids can also cause leaks or delamination of the channels during injection. Here we show a simple and hands-free method to fill microchannels with liquid metal that addresses these issues. The process begins by covering a single inlet with liquid metal. Placing the entire structure in a vacuum chamber removes the air from the channels and the surrounding elastomer. Restoring atmospheric pressure in the chamber creates a positive pressure differential that pushes the metal into the channels. Experiments and a simple model of the filling process both suggest that the elastomeric channel walls absorb residual air displaced by the metal as it fills the channels. Thus, the metal can fill dead-ends with features as small as several microns and branched structures within seconds without the need for any outlets. The method can also fill completely serpentine microchannels up to a few meters in length. The ability to fill dense and complex geometries with liquid metal in this manner may enable broader application of liquid metals in electronic and microfluidic applications. PMID- 28805881 TI - Carbon nanofiber high frequency nanomechanical resonators. AB - Carbon nanofibers (CNFs) synthesized using a plasma-enhanced chemical vapor deposition (PECVD) process are investigated as a new class of building blocks for high-frequency vibrating nanomechanical resonators. The CNF resonators are prototyped by using vertically oriented few-MUm-long cantilever-structured CNFs grown by PECVD. Undriven thermomechanical motions and photothermally driven resonances are measured in the frequency range of ~3-10 MHz, which exhibit quality (Q) factors of ~140-350 in moderate vacuum (milliTorr) at room temperature. Further, characteristics of CNF resonators after platinum deposition and intensive electron beam exposure are investigated, and resonance frequency shifts due to mass loading on the CNFs are clearly observed. In addition, extensive material characterization of the CNFs using techniques such as X-ray electron dispersive spectroscopy (XEDS) with spatial element-mapping reveals the structure and growth mechanism of the CNFs. PMID- 28805882 TI - Plant array chip for the germination and growth screening of Arabidopsis thaliana. AB - A screening process for the germination and growth of seed is generally required for plant research. Such a repetitive screening process is costly and time consuming, and its bulky setup requires a lot of space. In particular, the control of the variables, such as light, nutrients, hormones and temperature, is difficult due to the limited space for incubation. In addition, small seeds such as Arabidopsis thaliana are difficult to handle as they are hundreds of microns in diameter and require a more precisely controllable screening environment. However, conventional screening methods involve the seeding of multiple seeds on a single agarose plate without physical partitions. Such methods need to be improved because they lack control over the growth environment and the results are highly dependent on the researchers. To overcome the above-mentioned limitations, a novel seeding array chip has been developed which can be filled with conventional solid agarose while enabling more efficient screening. Individual seeds can be partitioned from each other and a number of different agarose conditions can be tested in a single plant array chip. As a demonstration, we tested the effect of various concentrations of Murashige and Skoog medium and a plant hormone (e.g., abscisic acid) on the growth of Arabidopsis. The chip can efficiently save the space required for screening by providing different conditions for ~400 seeds in a 59 * 55 mm chip, and it also provides easy observation and analysis of seed growth. The proposed plant array chip is expected to contribute to more efficient screening of essential phenotypes such as germination and growth for both academic and industrial purposes. PMID- 28805883 TI - A novel objective chute score interacts with monensin to affect growth of receiving cattle. AB - Growth in cattle may be related to animal temperament via alterations in intake or feed conversion. However, temperament is ill-defined, and different temperament measures may relate differently to production traits or interact with dietary factors in their effects. To examine relationships between diet, temperament, growth, and health, 160 crossbred steers (262 +/- 22 kg) were used in a 56-d RCBD experiment with a 2 * 2 * 2 factorial treatment structure with 5 pens/treatment. Steers were pen fed a corn silage-based diet with or without monensin (41.9 g/t DM), ad libitum. Temperament treatments (assigned on d -7) were exit velocity (EV; slow vs. fast) and objective chute score (OCS; low vs. high), a novel temperament measure, representing the CV of weights collected at 5 measures/s for 10 s while an animal's head was restrained in a chute. Both were measured on d -7, 0, 14, 28, 55, and 56. Subjective chute scores (SCS; visual estimates of animal activity obtained simultaneously with OCS measures) were measured on d -7 and d 56. Jugular blood samples from d 28 were analyzed for antibody response to leptospirosis vaccine and NEFA concentrations. No monensin * OCS * EV interactions were detected ( >= 0.11). There was a positive correlation between SCS and OCS ( < 0.01; = 0.57). Changes in OCS and EV across the duration of the study differed among treatments (treatment * day, < 0.10) and indicated that initial measures may be better proxies of growth than average measures. There were no interactions between EV and OCS ( >= 0.15) for any response variable and no interactions among treatments ( >= 0.31), nor main effects of temperament factors ( >= 0.12) for DMI (%BW). Monensin decreased DMI ( < 0.01) similarly across all levels of EV and OCS. Gains and G:F responses to monensin depended on OCS ( < 0.10) but not EV ( >= 0.80). Gain was reduced ( < 0.10) by monensin with low, but not high, OCS, and G:F was increased ( < 0.10) by monensin on high, but not low, OCS. Gain during the second 4 wk was lesser ( = 0.04) in fast, compared with slow, EV animals. Results provide novel indications that certain temperament measures can interact with dietary manipulation to influence animal performance. PMID- 28805884 TI - The effects of monensin in diets fed to finishing beef steers and heifers on growth performance and fecal shedding of Escherichia coli O157:H7. AB - Two experiments were conducted to study the effects of monensin dose on growth performance and O157:H7 shedding in finishing beef cattle. In Exp. 1, 198 heifers (298 +/- 1.1 kg BW) were allocated to 1 of 2 treatments consisting of 1) 200 mg/heifer daily of monensin and 2) 400 mg/heifer daily of monensin and fed for 151 d. In Exp. 2, 199 steers (430 +/- 1.9 kg BW) were stratified by BW and allocated to 1 of 2 treatments consisting of 1) 0 mg/steer daily of monensin and 2) 400 mg/steer daily of monensin and fed for 128 d. For both experiments, there were 4 pen replicates per treatment. For Exp. 1 and Exp. 2, the model included the fixed effect of treatment for growth performance measures and the fixed effects of treatment, time, and treatment * time interaction, respectively, for O157:H7 shedding. In Exp. 1, final BW was 1.9% greater for heifers fed 400 mg/d monensin than for heifers fed 200 mg/d monensin ( = 0.05). Furthermore, ADG was 4.9% greater ( = 0.05) and G:F was 3.1% greater ( = 0.04) when the heifers were fed 400 mg/d monensin vs. 200 mg/d monensin. Pen prevalence for O157:H7 ( = 0.96) and the percentage of animals in the pen shedding O157:H7 at enumerable levels ( = 0.82) did not differ between heifers fed 200 mg/d monensin and heifers fed 400 mg/d monensin over the 4 sampling periods. For Exp. 2, steers fed the supplement containing monensin had a 1.9% greater final BW ( = 0.04) and a 5.2% greater ADG ( = 0.02) than steers fed a control supplement without monensin. No differences in DMI or G:F were noted across the treatments ( >= 0.14). O157:H7 percentage of enumerable cattle within the pen was greater for the steers fed monensin than the control steers not fed monensin than the control steers not fed monensin ( = 0.02) over the 4 sampling periods. However, the percentage of animals in the pen shedding O157:H7 (prevalence positive) did not differ between treatments ( = 0.18), nor did the average fecal counts ( = 0.45). In conclusion, feeding a higher dose (400 mg/d) of monensin improved final BW and ADG compared with a low dose of monensin or a no-monensin control in steers and heifers across multiple years. The percentage of animals shedding O157:H7 at enumerable levels was greater for steers fed the monensin supplement than for steers fed the control supplement, yet the presence of monensin, irrespective of the dose, did not affect the percentage of animals in the pen shedding O157:H7. PMID- 28805885 TI - Effects of steeped or fermented distillers dried grains with solubles on growth performance in weanling pigs. AB - Coproduct feeding value may be improved by enzyme and microbial inoculant treatment in liquid diets. Three experiments were conducted to assess growth performance in newly weaned 20-d-old pigs fed corn- and soybean meal-based diets with untreated, steeped, or partially fermented distillers dried grains with solubles (DDGS) from day of weaning. In Exp. 1, conventionally dry fed diets with untreated DDGS (DDGS) or without DDGS (Control) were fed. In Exp. 2, liquid diets (25% DM [75% moisture]) were fed with enzymes (beta-glucanase and xylanase at 67.2 and 51.4 U/g DDGS, respectively) added to dry DDGS at the time of liquid feeding (UNSTP) or steeped with DDGS and added to liquid feed from d 5 to 12 of each batch prior to liquid feeding (STP). In Exp. 1 and 2 DDGS inclusion levels were 7.5% in phase 1 (d 0 to 7) and 25% in phase 2 (d 7 to 21) and phase 3 (d 21 to 35). In Exp. 3 liquid diets were fed with the Exp. 2 enzymes and silage inoculant (360,000 combined cfu and /g DDGS) added to dry DDGS at the time of liquid feeding (UNFER) or fermented with DDGS and added to liquid feed from d 1 to 7 of each batch before liquid feeding (FER). The inclusion levels of DDGS were 7.5% in phase 1 (d 0 to 7), 16.25% in phase 2 (d 7 to 21), and 25% in phase 3 (d 21 to 42 or 48). Experiment 3 diets were fed to light (LBW; 5.8 +/- 0.6 kg) or heavy (HBW; 7.6 +/- 0.8 kg) BW pigs at weaning, and results were analyzed separately. Pig BW and ADFI were measured weekly in each experiment. In Exp. 1, feeding diets with DDGS depressed ( < 0.05) ADFI on d 7 to 21 (491 vs. 375 +/- 21 g DM/pig) and d 0 to 35 (456 vs. 405 +/- 13 g DM/pig). In Exp. 2 growth performance was not affected. In Exp. 3 ADFI of HBW pigs was not affected. The HBW pigs fed FER had lower ( < 0.05) ADG and G:F on d 7 to 21 (323 vs. 264 +/- 15 g/pig and 0.86 vs. 0.72 +/- 0.02 g:g, respectively) and lower ( < 0.05) BW on d 21 (12.4 vs. 11.6 +/- 0.2 kg) compared with HBW pigs fed UNFER. The LBW pigs fed FER had lower ( < 0.05) ADFI on d 0 to 7 and 7 to 21 (190 vs. 168 +/- 3 and 318 vs. 273 +/- 13 g DM/pig, respectively) and had greater ( < 0.05) ADG on d 42 to 48 (773 vs. 941 +/- 60 g/pig) and BW on d 48 (24.5 vs. 25.8 +/- 0.5 kg) compared with LBW pigs fed UNFER. Results show that up to 25% DDGS inclusion in weaning pig diets did not affect overall growth performance. Liquid-fed partially fermented DDGS had an influence on the growth performance of weanling pigs, particularly during the extended nursery period of pigs of light weaning weight in this study. PMID- 28805886 TI - Effects of sunflower soap stocks on light lamb meat quality. AB - Thirty-two lambs were used to study the effect of sunflower soap stocks (SS), a by-product from the vegetable oil refinery industry, on meat chemical composition, fatty acid profile, volatile compounds, and consumer acceptability. Lambs were finished (average length of fattening period 35 +/- 7.3 d, 26.8 +/- 0.09 kg final BW) on a pelleted total mixed ration (TMR) with no SS (00SS) or including 15, 30 or 60 g SS/kg (15SS, 30SS, and 60SS, respectively). Sunflower soap stocks decreased the percentage of SFA, increased the proportion of -MUFA ( < 0.05), and modified the levels of several odor-active lipid-derived volatile compounds ( 0.05). Consumers were able to distinguish between control and 15SS meat samples in a triangular test ( < 0.05), but a well-defined preference for meat of any of these treatments was not exhibited ( > 0.05). Atherogenicity and saturation indexes decreased by 31% and 27%, respectively, in SS groups compared to control (linear 0.05). However, certain volatile compounds (benzene and toluene) and 10-18:1 fatty acid, known potential hazards for human health, were increased in meat from lambs fed TMR with SS. For this reason, only inclusion rates up to 15 g SS/kg TMR seem to sustain a satisfactory balance between beneficial and detrimental effects on lamb meat composition and quality. PMID- 28805887 TI - Characterizing ammonia emissions from horses fed different crude protein concentrations. AB - Evaluating impact of animal agriculture on air quality has been the focus of recent research. Ammonia (NH) volatilization occurs when undigested protein in feces and urea in urine is broken down by bacteria and enzymes. Information regarding NH emission from equine facilities is limited, and effects of CP intake on NH emissions have not been investigated. Nine mature geldings were used in a 3 * 3 replicated Latin square design study to determine effects of dietary CP on potential NH losses from feces and urine. We hypothesized feeding horses above the CP requirement would result in an increase in NH emissions from urine and feces and different bedding materials would affect NH emissions from urine. Diets were formulated using different ratios of bahiagrass () and Tifton-85 bermudagrass () hays, and a commercial vitamin mineral supplement to provide 3 different CP concentrations and labeled in relation to each other: LOW-CP, MED CP, and HIGH-CP (10.6%, 11.5%, and 12%, respectively). Each study period consisted of an 11-d diet adaptation phase, followed by a 3-d total collection of urine and feces. To determine total nitrogen (TN) and urea-N concentrations, samples were pooled by period ( = 9). For in vitro determination of NH concentrations, urine and fecal samples were pooled within period by diet ( = 3) and mixed with either wheat straw or wood shavings. Ammonia emission of these samples was measured using a vessel system with an airflow rate (2.5 L/min) at 20 degrees C over a 7-d period. Concentration of NH in each vessel was measured using a photoacoustic multigas analyzer. Temperature, airflow rate, and NH concentration in each vessel were used to calculate NH emission rate (ER). Data were analyzed using a mixed model ANOVA with repeated measures. Urinary TN and urea-N excretion increased as CP intake increased ( < 0.0001). Vessel urinary NH concentrations were not different across diets ( = 0.1225), ranging from 55.48 ppm (LOW-CP) to 101.14 ppm (HIGH-CP); however, they differed between bedding types ( < 0.0001), with straw higher than shavings (97 vs. 73.5 ppm, respectively). Cumulative urinary NH ER tended to be different across diets ( = 0.0550) ranging from 5.87 g/m to 9.97 g/m and bedding types ( = 0.0129), with straw being higher than shavings (11.1 vs. 6.9 g/m, respectively). Overfeeding CP to horses can lead to increased urinary TN and urea-N excretion, which could lead to greater of NH in the atmosphere. PMID- 28805888 TI - Development of small intestinal enzyme activities and their relationship with some gut regulatory peptides in grazing sheep. AB - Growth depends on an animal's capacity to digest and assimilate ingested nutrients, and insufficient supply and impairment will constrain lamb growth. Eight groups of Alpine Finewool lambs were harvested on 0, 3, 7, 14, 21, 28, 42, and 56 d to measure pH and enzymatic activities in the duodenum, proximal jejunum, middle jejunum, distal jejunum, and ileum mucosa or digesta. From the duodenum to the ileum the pH of intestinal mucosa and digesta increased, whereas pH changed very little with age. The trypsin, chymotrypsin, lipase, lactase, and alpha-amylase activities observed at birth decreased by d 3, followed by a nonuniform enzymatic response in the small intestine. The trypsin activity increased from d 3 to peak, at d 21, followed by a decline. Chymotrypsin activity followed the same general trend but with smaller responses in activities. Trypsin demonstrated greater enzymatic activity than chymotrypsin at the same age. The lipase activity of small intestinal mucosa and digesta changed little with age. The lactase activity was high at birth, decreased by d 3, and then increased, followed by a decrease as lambs approached weaning. alpha-Amylase activity was similar in the small intestinal mucosa and digesta at birth but increased with age for the duodenum and proximal jejunum. Plasma concentrations of cholecystokinin (CCK), secretin, and gastrin were positively correlated ( < 0.05) with ileal mucosa lipase activity. Plasma concentration of CCK, secretin, gastrin, and gastric inhibitory polypeptide (GIP) were positively correlated ( < 0.05) with ileal mucosa lactase activity. Plasma concentration of pancreatic polypeptide (PP) was negatively correlated ( < 0.05) with lactase activity in the middle jejunum and ileal mucosa. Plasma concentrations of CCK, secretin, gastrin, and GIP were positively correlated ( < 0.05) with alpha-amylase activity in the ileal mucosa but negatively correlated ( < 0.05) with duodenum, prejejunum, and middle jejunum. Plasma PP concentrations were positively correlated ( < 0.01) with alpha-amylase activity of duodenum, middle jejunum, and postjejunum mucosa but not with the enzyme activity of postjejunum and ileal mucosa ( > 0.05). Small intestinal enzymatic activities exist and may be sufficient to enhance lamb growth via appropriate nutrient supplementation. PMID- 28805889 TI - Oxytocin injections in the postpartal period affect mammary tight junctions in sows. AB - The potential impacts of injecting oxytocin (OXY) to sows in the early postpartum period on the quality of mammary tight junctions, milk composition, and immune status of sows and piglets were studied. Postparturient sows received i.m. injections of either saline (control [CTL]; = 10) or 75 IU of OXY ( = 10). Injections were given twice daily (0800 and 1630 h) starting on d 2 of lactation (i.e., between 12 and 20 h after birth of the last piglet), totaling 4 injections. Milk samples were obtained before the first injection (d 2 morning [AM]), before the second injection (d 2 afternoon [PM]), and on d 4 PM and d 5 PM. Blood samples were obtained from sows before milking on d 2 AM, d 2 PM, and d 5 PM. On d 5 of lactation, a blood sample was obtained from 3 piglets per litter. Circulating concentrations of prolactin, IGF-I, lactose, and IgA in sows did not differ between treatments at any time ( > 0.10), but OXY sows had less IgG than CTL sows ( < 0.01) on d 2 PM before the second OXY injection. There were differences in milk composition on d 2 PM, with OXY sows having more IGF-I ( < 0.01), solids ( < 0.05), protein ( < 0.01), energy ( < 0.05), and IgA ( < 0.01) and a greater Na:K ratio ( < 0.01) than CTL sows. These differences were not seen in the next 2 milk samples, except for protein and IgA that still tended ( < 0.10) to be greater in OXY vs. CTL sows on d 4 PM (for protein) and on d 5 PM (for IgA) after the last injection. Milk lactose content was lower in OXY vs. CTL sows on d 5 PM ( < 0.01). Values for immunoglobulin immunocrit, IgG, IgA, and IGF I in piglet blood did not differ between treatments ( > 0.10). Injecting OXY to sows in the early postpartum period increased leakiness of the mammary tight junctions, improved composition of early milk, and may potentially affect immune status of neonatal piglets. PMID- 28805890 TI - Effect of forage source included in total mixed ration on intake, sorting and feeding behavior of growing heifers fed high-concentrate diets. AB - The objective of this experiment was to compare the effects of using 2 different forage sources on intake and sorting and feeding behavior in growing heifers fed a high-concentrate diet offered as a total mixed ration (TMR). Eight Simmental heifers (initial BW of 148.1 +/- 4.83 kg) were used in a crossover design experiment. Treatment diets were a TMR with either barley straw (BS) or alfalfa hay (AH) as forage source. Diets were offered on an ad libitum basis, with a forage to concentrate ratio of 8 to 92. The experiment was performed in two 28-d periods, with 3 wk of diet adaptation and 1 wk of sampling in each period. Heifers were weighed before feeding on 2 consecutive days at the beginning and the end of the experiment, and in the sampling week. Feed and refusal samples were collected daily in the sampling week for DM determination and chemical analysis. Particle size separation was performed using the 3-screen Penn State Particle Separator. Dry matter digestibility was estimated using acid-insoluble ash as internal marker. Feeding behavior was recorded using an automated feeding system. Sorting behavior was measured with the intake of different particle size. Dry matter intake was greater ( < 0.05) in heifers fed BS (6.7 kg/d) than AH (5.8 kg/d) when these animals faced TMR for first time in period 1, but DMI did not differ between diets in period 2 when they were accustomed to the method of feeding. Apparent DM digestibility did not differ between diets (62.7 and 64.3% for BS and AH, respectively). Heifers fed BS sorted in both periods against long particle size ( < 0.01) and against medium particle size in period 2 ( < 0.01), a behavior that did not appear in heifers fed AH. Heifers sorted for short particle size in both diets in period 1, this behavior being maintained in period 2 for heifers fed BS, while it disappeared in heifers fed AH. This sorting behavior preferentially shown in heifers fed BS resulted in a tendency ( = 0.06) for greater length of each meal and a longer feeding time ( = 0.02). In conclusion, at 8% of incorporation, forage source affected intake in only 1 of the 2 experimental periods. Heifers fed BS showed a sorting behavior with preferential consumption for concentrate in the TMR, feeding time being greater in BS than in AH. In contrast, heifers fed AH sorted for short particle size when faced for the first time with a new method of feeding, this sorting behavior disappearing once heifers had got familiar with it. PMID- 28805891 TI - Increasing corn distillers solubles alters the liquid fraction of the ruminal microbiome. AB - Five ruminally fistulated steers were used in a 5 * 5 Latin square design to determine the effects of increasing dietary fat and sulfur from condensed distiller's solubles (CDS) on the ruminal microbiome. Treatments included a corn based control (CON) and 4 levels of CDS (0, 10, 19, and 27%) in a coproduct-based (corn gluten feed and soybean hulls) diet. Fat concentrations were 1.79, 4.43, 6.80, and 8.91% for diets containing 0, 10, 19, and 27% CDS, respectively. Steers were fed for ad libitum intake once daily. After feeding each diet for 18 d, ruminal samples were collected 3 h after feeding on d 19. Samples were separated into solid and liquid fractions. Microbial DNA was extracted for bacterial analysis using paired-end sequencing of the V3 through V4 region of the 16S rRNA gene on the MiSeq Illumina platform and quantitative PCR of selected species. Orthogonal contrasts were used to determine linear and quadratic effects of CDS inclusion. Increasing CDS inclusion decreased (linear, < 0.05) alpha-diversity and species richness in the liquid fraction. Analysis of Bray-Curtis similarity indicated a treatment effect ( = 0.01) in the liquid fraction. At the phyla level, relative abundance of Bacteroidetes decreased in steers fed increasing dietary inclusion of CDS as Firmicutes increased to 82% of sequences for the 27% CDS treatment. Family Ruminococcaceae increased (linear, < 0.01) 2-fold in the liquid fraction when feeding CDS increased from 0 to 27% CDS, yet genera tended ( = 0.09) to decrease in steers fed greater CDS. The most abundant family of sulfate-reducing bacteria, Desulfovibrionaceae, increased ( < 0.03) in the solid and liquid fraction in steers fed additional dietary CDS and sulfur. Relative abundance of family Veillonellaceae and were increased (linear, <= 0.02) in the solid fraction as steers were fed increasing CDS. There were no effects ( > 0.10) of feeding increasing dietary fat from CDS on fibroylytic genus in either fraction. Results demonstrate increasing fat and sulfur from CDS in a coproduct based diet markedly alters the liquid fraction ruminal microbiome but does not elicit negative effects on relative abundance of identified fiber-fermenting bacteria. PMID- 28805892 TI - Variance components for direct and maternal effects on body weights of Katahdin lambs. AB - The aim of this study was to estimate genetic parameters for BW in Katahdin lambs. Six animal models were used to study direct and maternal effects on birth weight (BWT), weaning weight (WWT), and postweaning weight (PWWT) using 41,066 BWT, 33,980 WWT, and 22,793 PWWT records collected over 17 yr in 100 flocks. Models included fixed effects of management group, dam age, type of birth (for BWT) or birth and rearing (for WWT and PWWT), and lamb age at weighing (fitted as a covariate for WWT and PWWT; all < 0.05). Variance components for random effects were estimated in sequentially more complex models and tested for significance with likelihood-ratio tests. A model that fitted only an additive animal effect overestimated additive variance for all BW, resulting in larger estimates of direct heritability than models that included maternal effects. Maternal effects explained variation ( < 0.05) in all BW. Heritability estimates for optimal models were 0.15 +/- 0.01 for BWT, 0.18 +/- 0.02 for WWT, and 0.20 +/- 0.02 for PWWT. Estimates of maternal heritabilities were 0.14 for BWT, 0.10 for WWT, and 0.06 for PWWT, with SE = 0.01. Permanent environmental maternal effects explained 4 to 6% (+/-1%) of total phenotypic variances for these BW. Litter effects included temporary environmental effects common to littermates and a proportion of the dominance genetic variance and accounted for 16 to 19% (+/-1%) of phenotypic variance. Correlations between additive direct and maternal genetic effects were -0.14 for BWT, -0.23 for WWT, and -0.04 for PWWT but differed from 0 ( < 0.05) only for WWT. The total heritability predicted the total response in direct and maternal genetic effects from mass selection and was 0.23 for BWT, 0.20 for WWT, and 0.23 for PWWT. Direct and maternal additive, maternal permanent environmental, residual, and phenotypic correlations between BWT and WWT were 0.53 +/- 0.05, 0.58 +/- 0.06, 0.51 +/- 0.06, 0.39 +/- 0.01, and 0.44 +/- 0.01, respectively; those between BWT and PWWT were 0.45 +/- 0.06, 0.58 +/- 0.08, 0.36 +/- 0.08, 0.33 +/- 0.01, and 0.37 +/- 0.01 respectively; and those between WWT and PWWT were 0.85, 0.99, 0.92, 0.77, and 0.81, respectively, with SE <= 0.02. Therefore, both direct and maternal effects had an important impact on BW in Katahdin lambs. Models that included both additive and permanent environmental maternal effects as well as a temporary environmental litter effect should result in more accurate estimates of breeding values and better selection decisions. PMID- 28805893 TI - BOARD INVITED REVIEW: The purebred-crossbred correlation in pigs: A review of theory, estimates, and implications. AB - Pig and poultry production relies on crossbreeding of purebred populations to produce production animals. In those breeding schemes, selection takes place within the purebred population to improve crossbred performance (CB performance). The genetic correlation between purebred performance (PB performance) and CB performance () is, however, lower than unity for many traits. When is low, the use of CB performance in selection is required to achieve sizable genetic progress. The objectives of this paper were to describe the different components and importance of , and to review existing literature that report estimates in pigs. The has 3 components: 1) genotype by genotype interactions, 2) genotype by environment interactions, and 3) differences in trait measurements. We theoretically showed that direct selection for CB performance reduces the response to selection in purebreds for. PMID- 28805895 TI - Genetic parameters of carcass and meat quality traits in different muscles (longissimus dorsi and semimembranosus) of Hanwoo (Korean cattle). AB - We estimated heritability () and genetic and phenotypic correlations for carcass and meat quality traits of longissimus dorsi (LD) and semimembranosus (SM) muscles in 30-mo-old Hanwoo steers. Variance and covariance components were estimated using REML procedures under univariate and bivariate models. The mean carcass weight (CWT), eye muscle area (EMA), back fat thickness (BFT), and marbling score (MS) were 428.20 +/- 46.30 kg, 87.38 +/- 8.54 cm2, 13.00 +/- 5.14 mm, and 5.21 +/- 1.56, respectively. The mean CIE reflectance of meat lightness (L*), redness (a*), and yellowness (b*) were 40.01 +/- 2.73, 22.37 +/- 2.18, and 10.35 +/- 1.46, respectively, in LD muscles and 36.33 +/- 2.44, 22.91 +/- 2.43, and 10.25 +/- 1.65, respectively, in SM muscles. The mean Warner-Bratzler shear force (WBSF), intramuscular fat content (IMF), water-holding capacity (WHC), and protein and ash content in LD and SM muscles were 3.84 +/- 0.96 and 6.52 +/- 1.21 kg, 15.91 +/- 4.39 and 5.10 +/- 1.94%, 62.07 +/- 3.38 and 71.61 +/- 2.06%, 20.01 +/- 1.39 and 21.34 +/- 0.89%, and 0.80 +/- 0.10 and 0.93 +/- 0.07, respectively. The estimates of CWT, EMA, BFT, and MS were 0.51 +/- 0.13, 0.45 +/- 0.13, 0.29 +/ 0.09, and 0.22 +/- 0.08, respectively. The estimates were moderate for meat quality traits and were 0.37 +/- 0.12, 0.40 +/- 0.12, 0.33 +/- 0.10, 0.33 +/- 0.10, 0.30 +/- 0.11, and 0.24 +/- 0.09 for L*, WBSF, IMF, WHC, and protein and ash content, respectively, in LD muscle; estimates from SM muscle were comparatively low (0.08 +/- 0.06 to 0.25 +/- 0.09). Estimates of for a* and b* were also low (0.08 +/- 0.06 to 0.13 +/- 0.07). Carcass weight had a moderate, positive genetic correlation with EMA (0.60 +/- 0.13) and a weak correlation with MS and BFT. The genetic correlations among the 3 colorimeter variants were strong and positive within and between muscles. Intramuscular fat content had moderate to strong and negative genetic correlations with WBSF (-0.49 +/- 0.18), WHC ( 0.99 +/- 0.01), and protein (-0.93 +/- 0.04) and ash content (-0.98 +/- 0.06) in LD muscle, whereas the associations were less pronounced in SM muscle. In general, CWT and EMA had low genetic and phenotypic correlations with meat quality traits, which suggests that the traits are independent and have distinct genetic contributions in each muscle. Conversely, with few exceptions, meat quality traits had genetic and phenotypic correlations with MS and BFT. In conclusion, the estimated genetic parameters for carcass and meat quality traits could be used for genetic evaluation and breeding programs in Korean Hanwoo cattle populations. PMID- 28805896 TI - The composition of dietary fat alters the transcriptional profile of pathways associated with lipid metabolism in the liver and adipose tissue in the pig. AB - The objective was to investigate the of effect chemical composition of dietary fat on transcription of genes involved in lipid metabolism in adipose tissue and the liver via transcriptional profiling in growing pigs. A total of 48 Genetiporc 6.0 * Genetiporc F25 (PIC, Inc., Hendersonville, TN) barrows (initial BW of 44.1 +/- 1.2 kg) were randomly allotted to 1 of 6 dietary treatments. Each experimental diet included 95% of a corn-soybean meal basal diet and 5% cornstarch (control; CNTR), animal-vegetable blend (AV), coconut oil (COCO), corn oil (COIL), fish oil (FO), or tallow (TAL). Pigs were sacrificed on d 10 (final BW of 51.2 +/- 1.7 kg) to collect tissues. Expression normalization across samples was performed by calculating a delta cycle threshold (DeltaCt) value using . Delta delta cycle threshold (DeltaDeltaCt) values were expressed relative to the CNTR treatment. In adipose tissue, adding dietary fat, regardless of the source, decreased the mRNA abundance of compared with the CNTR ( = 0.014). Pigs fed a COIL-based diet tended to have greater adipose tissue expression of ( = 0.071) than pigs fed the other dietary fat sources tested. Abundance of mRNA was greater in adipose tissue of barrows a fed COIL-based diet than barrows fed CNTR or FO-based diets ( = 0.047). In the liver, adding dietary fat, regardless of source, increased the mRNA abundance of , , , , , and ( <= 0.020) and tended to increase the abundance of ( = 0.071) and ( = 0.086) compared with the CNTR. Pigs fed a TAL-based diet had greater hepatic transcription of than pigs fed CNTR-, COCO-, or FO-based diets ( = 0.013). Hepatic transcription of tended to be greater in pigs fed COCO than in pigs fed other dietary fat sources ( = 0.074). Dietary omega-3 fatty acid content tended to negatively correlate with mRNA abundance of ( = 0.065) in adipose tissue and ( = 0.063) in the liver. Dietary fat SFA content was negatively correlated with in the liver ( <= 0.039). Dietary fat MUFA content tended to be positively correlated with , , and mRNA abundance in the liver ( <= 0.100). To conclude, the intake of omega-3 fatty acids suppressed the mRNA abundance of genes involved in lipolysis in both adipose tissue and the liver. Dietary SFA are greater inhibitors of lipogenesis in adipose tissue than omega-6 fatty acids. Intake of medium-chain fatty acids alters hepatic lipid metabolism differently than intake of long-chain fatty acids. PMID- 28805897 TI - Effects of grass silage quality and level of feed intake on enteric methane production in lactating dairy cows. AB - The objective of this study was to determine the effect of level of feed intake and quality of ryegrass silage as well as their interaction on enteric methane (CH) emission from dairy cows. In a randomized block design, 56 lactating dairy cows received a diet of grass silage, corn silage, and a compound feed meal (70:10:20 on DM basis). Treatments consisted of 4 grass silage qualities prepared from grass harvested from leafy through late heading stage, and offered to dairy cows at 96 +/- 2.4 (mean +/- SEM) days in milk (namely, high intake) and 217 +/- 2.4 d in milk (namely, low intake). Grass silage CP content varied between 124 and 286 g/kg of DM, and NDF content between 365 and 546 g/kg of DM. After 12 d of adaptation, enteric CH production of cows was measured in open-circuit climate controlled respiration chambers for 5 d. No interaction between DMI and grass quality on CH emission, or on milk production, diet digestibility, and energy, and N retention was found ( >= 0.17). Cows had a greater DMI (16.6 vs. 15.5 kg/d; SEM 0.46) and greater fat- and protein-corrected milk (FPCM) yield (29.9 vs. 25.4 kg/d; SEM 1.24) at high than low intake (both <= 0.001). Apparent total-tract nutrient digestibility was not affected ( >= 0.08) by DMI level. Total enteric CH production (346 +/- 10.9 g/d) was not affected ( = 0.15) by DMI level. A small, significant ( = 0.025) decrease at high compared with low intake occurred for CH yield (21.8 +/- 0.59 g/kg of DMI; -4%). Methane emission intensity (12.8 +/- 0.56 g/kg of FPCM; -12%) was considerably smaller ( <= 0.001) at high intake as a result of greater milk yields realized in early lactation. As grass quality decreased from leafy through late heading stage, FPCM yield and apparent total tract OM digestibility declined (-12%; <= 0.015), whereas total CH production (+13%), CH yield (+21%), and CH emission intensity (+28%) increased ( <= 0.001). Our results suggest that improving grass silage quality by cutting grass at an earlier stage considerably reduces enteric CH emissions from dairy cows, independent of DMI. In contrast, losses of N in manure increased for the earlier cut grass silage treatments. The small increase in DMI at high intake was associated with a small to moderate reduction in CH emission per unit of DMI and GE intake. This study confirmed that enteric CH emissions from dairy cows at distinct levels of feed intake depend on the nutritive value and chemical composition of the grass silage. PMID- 28805898 TI - Ability of garlic-derived diallyl disulfide and diallyl trisulfide supplemented by oral gavage to mitigate effects of an acute postweaning feed and water deprivation event in nursery pigs. AB - Compounds in garlic have been shown to contain anti-inflammatory, antioxidant, and immune modulatory properties that may be able to mitigate the effects of nursery pig stressors. The objective of the current experiment was to determine if oral gavage of garlic-derived diallyl disulfide (DADS) and diallyl trisulfide (DATS) could mitigate the effects of a 24-h postweaning feed + water deprivation event in nursery pigs. Pigs (6.0 +/- 0.05 kg and 21 d old) were allotted to 4 treatments in a randomized complete block design at weaning with 8 replicate pens per treatment that consisted of with or without a 24-h postweaning feed + water deprivation event and with or without an oral gavage containing 3.6 mg DADS + DATS/kg BW. Growth performance and morbidity were recorded throughout the experiment, and on 1, 6, and 21 d after weaning, 1 pig per pen was selected, blood was collected, the pig was euthanized, and a segment of the distal ileum was subsequently excised for morphological and gene and protein expression measurements. Mucosal gene expression was conducted by reverse transcription PCR for immune, antioxidant, and cellular integrity markers. Furthermore, activity of mucosal superoxide dismutase was measured by colorimetric assay. Immediately following the feed + water deprivation event, there was a decrease ( < 0.01) in growth performance and an increase ( = 0.01) in serum cortisol. The feed + water deprivation event tended ( = 0.10) to decrease ileal villus height and supplementation of DADS + DATS by oral gavage increased ( = 0.03) villus height 1 d after weaning. Supplementation of DADS + DATS by oral gavage decreased ( = 0.03) and tended to decrease ( = 0.08) gene expression of on 6 and 21 d after weaning, respectively. Furthermore, at 1 d after weaning, ileal mucosa SOD activity was decreased ( = 0.01) by the feed + water deprivation and increased ( = 0.04) by oral supplementation of DADS + DATS. Expression of the tight junction genes and were reduced ( <= 0.05) due to the feed + water deprivation event 1 d after weaning. Results from the current study show that an acute feed + water deprivation event can impact growth performance, intestinal characteristics, and antioxidant status in nursery pigs, which can be partially mitigated by oral supplementation of garlic compounds DADS + DATS. PMID- 28805899 TI - Effects of forage types on digestibility, methane emissions, and nitrogen utilization efficiency in two genotypes of hill ewes. AB - Thirty-six nonpregnant hill ewes (18 pure Scottish Blackface and 18 Swaledale * Scottish Blackface) aged 18 mo and weighing 48 +/- 4.8 kg were allocated to 3 forage treatments balanced for genotype and BW. Each genotype was offered 3 forages (pelleted ryegrass, fresh lowland grass, and fresh hill grass) ad libitum with 6 ewes for each of the 6 genotype * diet combination treatments. Pelleted ryegrass was sourced from a commercial supplier (Drygrass South Western Ltd, Burrington, UK). Fresh lowland grass was harvested daily in the morning from a third regrowth perennial ryegrass () sward. Fresh hill grass was harvested from a seminatural hill grassland every 2 d and stored in plastic bags at 4 to 5 degrees C until offered. The animals were individually housed in pens and offered experimental diets for 14 d before being transferred to 6 individual respiration chambers for a further 4 d, during which feed intake, fecal and urine outputs, and CH emissions were measured. There was no interaction between genotype and forage types on any variable measured. In a comparison of effects of the 3 forages, pelleted ryegrass had the greatest ( < 0.001) values in DMI, GE intake, CH emissions, N intake (NI), and fecal N (FN), urine N (UN), and manure N (MN) outputs, whereas hill grass had the lowest ( < 0.001) values in DMI, energy (GE, DE, and ME) intake, CH emissions, NI, UN, and MN. However, pelleted ryegrass had the lowest ratio in CH emissions per unit DMI ( = 0.022) or GE intake ( = 0.026) or UN excretion as a proportion of NI or MN ( < 0.001). Lowland grass had a greater ( < 0.001) digestibility of DM, OM, CP, NDF, ADF, and GE and a greater ( < 0.001) ME:GE ratio or retained N:NI ratio than pelleted ryegrass and hill grass. Genotypes of sheep had no effect on any variable in feed intake, digestibility, CH emissions, or N utilization. The CH conversion factors (CH energy/GE) for pelleted ryegrass, lowland grass, and hill grass were 4.4, 5.7, and 5.6%, respectively. All data were then pooled to develop regression equations between CH and DMI or between N excretions (FN, UN, and MN) and NI. Methane emissions and N excretions were positively related to DMI and NI ( < 0.001), respectively. However, increasing DMI could reduce CH emissions per kilogram DMI. These equations add new information in predicting enteric CH emissions and N utilization efficiency and can be used to quantify the environmental footprint of hill sheep production systems. PMID- 28805900 TI - Effects of dietary tannins on total and extractable nutrients from manure. AB - The effects of condensed tannins on N dynamics in ruminants have been a topic of research for some time, but much less work has focused on their impacts on other nutrients in manure. A 4 * 4 Latin square trial was used to determine if intake of sericea lespedeza (; SL; a condensed tannin source), at 0, 10, 20, or 40% of the diet (as-fed basis), would affect concentrations of nutrients in manure and patterns of total excretion when offered with alfalfa (; ALF) to sheep. With SL additions, average daily manure production increased linearly ( <= 0.01), from 40 to 50% of the diet mass. The concentrations of total C, total N, soluble P, total and soluble Na, total and soluble S, total and soluble Mn, and total and soluble B in feces increased ( <= 0.05) while soluble N, total Ca, total and soluble Mg, soluble Zn, total and soluble Fe, total and soluble Cu decreased ( <= 0.02). Total P, total and soluble K, soluble Ca, and total Zn were less affected ( > 0.05). Comparing diets containing 0 to 40% SL, average daily outputs of total C, total N, soluble P, soluble K, total and soluble Na, and total Mn increased linearly ( <= 0.01) by 42.0, 71.2, 93.3, 45.2, 111, 148, and 52.4 percentage points, respectively. Total K, total and soluble S, soluble Mn, and total and soluble B increased quadratically ( <= 0.02) by 26.1, 52.3, 26.7, 147, 100, and 19.5 percentage points, respectively. Conversely, outputs of soluble Zn and total Fe decreased linearly ( <= 0.01), by -51.5 and -24.8 percentage points, while total Ca, total and soluble Mg, soluble Fe, and soluble Cu decreased quadratically ( <= 0.05) by -15.7, -12.3, -40.0, -89.9, and -60.3 percentage points, respectively. Outputs of soluble N, total P, soluble Ca, total Zn, and total Cu remained unchanged ( >= 0.14). Ratios of manure outputs to feed inputs for C, N, K, and B increased ( <= 0.02) but those for P and Mg were unchanged ( >= 0.10). Ratios of soluble to total manure outputs (S:O) increased ( <= 0.01) for P, Ca, Na, Mn; decreased ( <= 0.05) for N, S, Mg, Zn, Fe, Cu, and B; and were unaffected by treatment ( <= 0.16) for K. Decreasing S:O ratios are consistent with the formation of complexes that adsorb these nutrients to insoluble fiber fractions of manure and could thus affect mineralization rates. This study suggests that dietary tannins, found in forages like SL, can alter the concentrations, total excretion rates and throughput efficiency of nutrients in manure. PMID- 28805901 TI - Effect of stocking density on performance, diet selection, total-tract digestion, and nitrogen balance among heifers grazing cool-season annual forages. AB - Grazing annual cool-season forages after oat grain harvest in South Dakota may allow an opportunity to increase efficient use of tillable land. However, data are limited regarding effects of stocking density on diet selection, nutrient digestion, performance, and N retention by cattle grazing annual cool-season forage. Heifers were blocked by initial BW (261 +/- 11.7 kg) and randomly assigned to 1 of 12 paddocks (1.1 ha) to graze a mixture of grass and brassica for 48 d. Each paddock contained 3, 4, or 5 heifers to achieve 4 replicates of each stocking density treatment. Ruminally cannulated heifers were used to measure diet and nutrient intake. Effects of stocking density on diet and nutrient selection were measured after 2, 24, and 46 d of grazing, and BW was measured at the beginning, middle, and end of the experiment as the average of d 1 and 2, d 22 and 23, and d 47 and 48 BW, respectively. Measures of DMI and DM, OM, NDF, and ADF digestion were collected from d 18 to 23. Increased stocking density increased intake of brassica relative to grass on d 24 (quadratic, = 0.02), but increased stocking density decreased (linear, <= 0.01) intake of brassica compared with grass on d 48 (stocking density * time, < 0.01). Increased stocking density increased DM (quadratic, < 0.01), OM (quadratic, = 0.01), and NDF (quadratic, = 0.05) digestion, and stocking density tended to increase DMI (quadratic, = 0.07). Additionally, increased stocking density quadratically increased ( = 0.05) N retention but did not affect overall BW gains. Increased stocking density did, however, contribute to linearly decreased ( = 0.05) BW gains from d 1 to 22 of grazing, but BW gains during the latter half of the experiment were greater than BW gains from d 1 to 22. Ruminal concentration of acetate:propionate was least on d 24 of grazing, and ruminal nitrate concentration tended to linearly decrease ( = 0.06) with greater amounts of time on pasture. Ruminal liquid and particulate fill and amounts of VFA were less (quadratic, <= 0.01) with greater amounts of time on pasture. Apparently, binary mixtures of brassica and grass planted after oat grain harvest can provide an opportunity to increase efficient use of land by providing forage resources. Increased stocking density may facilitate a more rapid adaptation to and intake of brassica among cattle grazing brassica-grass-based pastures. PMID- 28805902 TI - Enteric methane emissions from low- and high-residual feed intake beef heifers measured using GreenFeed and respiration chamber techniques. AB - The objectives of this study were to evaluate the relationship between residual feed intake (RFI; g/d) and enteric methane (CH) production (g/kg DM) and to compare CH and carbon dioxide (CO) emissions measured using respiration chambers (RC) and the GreenFeed emission monitoring (GEM) system (C-Lock Inc., Rapid City, SD). A total of 98 crossbred replacement heifers were group housed in 2 pens and fed barley silage ad libitum and their individual feed intakes were recorded by 16 automated feeding bunks (GrowSafe, Airdrie, AB, Canada) for a period of 72 d to determine their phenotypic RFI. Heifers were ranked on the basis of phenotypic RFI, and 16 heifers (8 with low RFI and 8 with high RFI) were randomly selected for enteric CH and CO emissions measurement. Enteric CH and CO emissions of individual animals were measured over two 25-d periods using RC (2 d/period) and GEM systems (all days when not in chambers). During gas measurements metabolic BW tended to be greater ( <= 0.09) for high-RFI heifers but ADG tended ( = 0.09) to be greater for low-RFI heifers. As expected, high-RFI heifers consumed 6.9% more feed ( = 0.03) compared to their more efficient counterparts (7.1 vs. 6.6 kg DM/d). Average CH emissions were 202 and 222 g/d ( = 0.02) with the GEM system and 156 and 164 g/d ( = 0.40) with RC for the low- and high-RFI heifers, respectively. When adjusted for feed intake, CH yield (g/kg DMI) was similar for high- and low-RFI heifers (GEM: 27.7 and 28.5, = 0.25; RC: 26.5 and 26.5, = 0.99). However, CH yield differed between the 2 measurement techniques only for the high-RFI group ( = 0.01). Estimates of CO yield (g/kg DMI) also differed between the 2 techniques ( <= 0.03). Our study found that high- and low efficiency cattle produce similar CH yield but different daily CH emissions. The 2 measurement techniques differ in estimating CH and CO emissions, partially because of differences in conditions (lower feed intakes of cattle while in chambers, fewer days measured in chambers) during measurement. We conclude that when intake of animals is known, the GEM system offers a robust and accurate means of estimating CH emissions from animals under field conditions. PMID- 28805903 TI - Chronic activation of AMP-activated protein kinase increases monocarboxylate transporter 2 and 4 expression in skeletal muscle. AB - Acute activation of AMP-activated protein kinase (AMPK) increases monocarboxylate transporter (MCT) expression in skeletal muscle. However, the impact of chronic activation of AMPK on MCT expression in skeletal muscle is unknown. To investigate, MCT1, MCT2, and MCT4 mRNA expression and protein abundance were measured in the longissimus lumborum (glycolytic), masseter (oxidative), and heart from wild-type (control) and AMPK gamma3 pigs. The AMPK gamma3 gain in function mutation results in AMPK being constitutively active in glycolytic skeletal muscle and increases energy producing pathways. The MCT1 and MCT2 mRNA expression in muscle was lower ( < 0.05) from both wild-type and AMPK gamma3 animals compared to other tissues. However, in both genotypes, MCT1 and MCT2 mRNA expression was greater ( < 0.05) in the masseter than the longissimus lumborum. The MCT1 protein was not detected in skeletal muscle, but MCT2 was greater ( < 0.05) in muscles with an oxidative muscle phenotype. Monocarboxylate transporter 2 was also detected in muscle mitochondria and may explain the differences between muscles. The MCT4 mRNA expression was intermediate among all tissues tested and greater ( < 0.05) in the longissimus lumborum than the masseter. Furthermore, MCT4 protein expression in the longissimus lumborum from AMPK gamma3 animals was greater ( < 0.05) than in the longissimus lumborum from wild-type animals. In totality, these data indicate that chronic AMPK activation simultaneously increases MCT2 and MCT4 expression in skeletal muscle. PMID- 28805904 TI - Higher dominance position does not result in higher reproductive success in female beef cattle. AB - The aim of this study was to investigate whether beef cows that achieve higher dominance status than their age-mates have prolonged reproductive life, increased number of offspring born and weaned, and/or heavier BW of the offspring. We also assessed whether maternal dominance rank affects the offspring sex ratio. We recorded data on 309 potential deliveries of female beef cows with known dominance status in a seasonally pastured herd over a 14-yr period and linked them with yearly records of dominance status of the cows assessed around feeding. We did not find any effect of age-corrected dominance index on cow reproductive success measured as delivery or weaning success, calf birth weight or weaning weight, survival of the cow to the following reproductive season, or sex of the conceived calf (generalized linear models, > 0.05). In conclusion, the results indicate that in a typical situation of pastured beef cattle, there might be no selection for individual striving to achieve higher dominance status. PMID- 28805905 TI - Standardized ileal digestible amino acids and digestible energy contents in high protein distiller's dried grains with solubles fed to growing pigs. AB - Chemical composition and, therefore, potential nutritive value of corn distiller's dried grains with solubles (DDGS) is constantly evolving as the ethanol industry innovates processing techniques. We determined standardized ileal digestibility (SID) of AA (Exp. 1) and DE (Exp. 2) contents in high-protein (HP; >40% on a DM basis) DDGS samples. Two HP DDGS (HP-A and HP-B) samples and 1 conventional DDGS (CON) sample were selected for this study. Three semipurified corn starch-based diets (minimum 18% CP, as-fed basis) were formulated with DDGS as the sole source of AA. A fourth, N-free diet was prepared to estimate basal ileal endogenous AA losses. The corn starch:sucrose:oil ratio was kept constant across diets to allow calculation of DE content in DDGS by the difference method. In Exp. 1, 8 ileal-cannulated barrows (23.9 kg initial BW) were used in a replicated 4 * 4 Latin square design ( = 8). Pigs were fed at 2.8 * maintenance energy requirement. In each period, pigs were adjusted to diets for 5 d followed by a 2 d of 8 h each grab continuous ileal digesta collection. In Exp. 2, 9 barrows (24.9 kg BW) were assigned to the 4 diets in a repeated 9 * 4 Youden square design to give 9 replicates per diet. In each period, pigs were adjusted to diets for 7 d followed by 5 d of fecal grab sample collection. The analyzed CP was 30.1, 42.3, and 43.1% (on a DM basis) in the CON, HP-A, and HP-B samples, respectively; the corresponding values for GE were 5,067, 5,425, and 5,407 kcal/kg DM, respectively. The concentrations of fat and NDF were comparable among the DDGS samples. Except for Arg and Val, the SID values for indispensable AA were not different ( > 0.05) among the 3 DDGS samples. However, HP samples had higher ( < 0.05) SID values for indispensable AA and CP compared with the CON sample. The SID of Lys content was 4.9, 6.1, and 7.4 g/kg DM for the CON, HP-A, and HP-B, respectively; the corresponding values for Met and Thr were 4.6, 6.8, and 7.4 g/kg DM, respectively, and 6.8, 9.5, and 10.7 g/kg DM, respectively. The DE content in HP samples was greater ( < 0.01) than in the CON (3,614, 4,494, and 4,555 kcal/kg DM for the CON, HP-A, and HP-B, respectively). In conclusion, HP DDGS had higher SID content of AA and DE compared with the CON. PMID- 28805906 TI - Technical note: Induction of pluripotent stem cell-like cells from chicken feather follicle cells. AB - Pluripotent stem cells including embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC) are regarded as representative tools for conservation of animal genetic resources. Although ESC have been established from chicken, it is very difficult to obtain enough embryos for isolation of stem cells for avian conservation in most wild birds. Therefore, the high feasibility of obtaining the pluripotent cell is most important in avian conservation studies. In this study, we generated induced pluripotent stem cell-like cells (iPSLC) from avian Feather Follicular cells (FFC). Avian FFC are one of the most easily accessible cell sources in most avian species, and their reprogramming into pluripotent stem cells can be an alternative system for preservation of avian species. Intriguingly, FFC had mesenchymal stromal cells (MSC)-like characteristics with regard to gene expression, protein expression, and adipocyte differentiation. Subsequently, we attempted to generate iPSLC from FFC using retroviral vectors. The FFC-iPSLC can proliferate with the stem pluripotent property and differentiate into several types of cells in vitro. Our results suggest that chicken FFC are an alternative cell source for avian cell reprogramming into pluripotent stem cells. This experimental strategy should be useful for conservation and restoration of endangered or high-value avian species without sacrificing embryos. PMID- 28805907 TI - Evaluation of essential oils and prebiotics for newborn dairy calves. AB - A blend of essential oils (EO; carvacrol, caryophyllene, -cymene, cineole, terpinene, and thymol) and prebiotics (arabinogalactans; Stay Strong; Ralco, Inc., Marshall, MN) was designed to promote immunity and stimulate appetite to diminish health challenges and stresses experienced by newborn calves. It was hypothesized that calves supplemented with the medium dose (2.5 g/feeding) of the commercial EO would demonstrate the optimal response. The study objective was to determine the optimal feeding rate of EO when added to a milk replacer (MR) compared with feeding a control or a yeast cell wall additive (YCW). One hundred Holstein calves from a commercial dairy farm were blocked by birth date and randomly assigned to 1 of 5 treatments. Treatments were a control (CON), a 24:20% CP:fat (as-fed basis) MR (24:20 MR) without EO; EO mixed into the 24:20 MR at a rate of 1.25 g/feeding (EO-0.5), EO mixed into the 24:20 MR at a rate of 2.5 g/feeding (EO-1.0), or EO mixed into the 24:20 MR at a rate of 3.75 g/feeding (EO 1.5); or 24:20 MR with YCW mixed in at a rate of 2 g/calf at each feeding. The 24:20 MR was fed in a bucket 2 times/d at a rate of 0.28 kg/calf daily for 14 d, which was increased to 0.43 kg/calf at 2 times/d until d 35 and then reduced to 1 time/d at d 36 to facilitate weaning at d 42. Decoquinate was added to the MR at 41.6 mg/kg for coccidiosis control. Calves were housed in individual hutches bedded with straw with ad libitum access to a 20% CP pelleted calf starter and water. All data were analyzed using PROC MIXED as a completely random design. Calves fed EO-0.5 demonstrated greater ( < 0.05) ADG (0.65, 0.71, 0.64, 0.64, and 0.63 kg/d for the CON, EO-0.5, EO-1.0, EO-1.5, and YCW, respectively) through d 56 compared with calves fed EO-1.0 and YCW and tended ( < 0.10) to have greater ADG than calves fed the CON and EO-1.5. Total BW gains were greater ( < 0.05) for calves fed EO-0.5 compared with calves fed EO-1.0 and YCW, with calves fed the CON and EO-1.5 being intermediate and similar. Body length and wither height gains (final - initial) were greater ( < 0.05) for calves fed EO-0.5 compared with calves fed the other treatments. Hip width gains were similar ( < 0.10) among treatments. Hip height gains were increased ( < 0.05) for calves fed EO-0.5 compared with calves fed the CON, EO-1.0, EO-1.5, and YCW. These results demonstrate that supplementing EO-0.5 (1.25 g/calf daily) in a 24:20 MR may be the optimal feeding rate to enhance growth rates compared with feeding a 24:20 MR and a 24:20 MR containing YCW or other inclusion rates of EO. PMID- 28805908 TI - Effects of encapsulated nitrate on growth performance, nitrate toxicity, and enteric methane emissions in beef steers: Backgrounding phase. AB - A long-term experiment was conducted to examine the effects of feeding encapsulated nitrate (EN) on growth, enteric methane production, and nitrate (NO) toxicity in beef cattle fed a backgrounding diet. A total of 108 crossbred steers (292 +/- 18 kg) were blocked by BW and randomly assigned to 18 pens. The pens (experimental unit; 6 animals per pen) received 3 dietary treatments: Control, a backgrounding diet supplemented with urea; 1.25% EN, control diet supplemented with 1.25% encapsulated calcium ammonium NO (i.e., EN) in dietary DM, which partially replaced urea; or 2.5% EN, control diet supplemented with 2.5% EN (DM basis) fully replacing urea. Additionally, 24 steers were located in 4 pens and randomly assigned to 1 of the above 3 dietary treatments plus a fourth treatment: 2.3% UEN, control diet supplemented with 2.3% unencapsulated calcium ammonium NO (UEN) fully replacing urea. Animals in the additional 4 pens were used for methane measurement in respiratory chambers, and the pens (except UEN) were also part of the performance study (i.e., = 7 pens/treatment). The experiment was conducted for 91 d in a randomized complete block design. During the experiment, DMI was not affected by inclusion of EN in the diet. Feeding EN had no effect on BW, ADG, and G:F ( >= 0.57). Methane production (g/d) tended to decrease ( = 0.099) with EN and UEN, but yield (g/kg DMI) did not differ ( = 0.56) among treatments. Inclusion of EN in the diet increased ( <= 0.02) sorting of the diets in favor of large and medium particles and against small and fine particles, resulting in considerable increases in NO concentrations of orts without affecting DMI. Plasma NO-N and NO-N concentrations increased ( <= 0.05) for EN compared with Control in a dose response manner, but blood methemoglobin levels were below the detection limit. Nitrate concentration in fecal samples slightly increased (from 0.01% to 0.14% DM; < 0.01) with increasing levels of EN in the diet. In conclusion, EN can be used as a feed additive replacing urea in beef cattle during a backgrounding phase in the long term without NO intoxication or any negative effects on growth performance. In addition, the study confirmed that feeding EN tended to decrease enteric methane production in the long term. PMID- 28805909 TI - Genomewide association study for production and meat quality traits in Canchim beef cattle. AB - The commercial value of the bovine carcass is determined by a set of traits, such as weight, yield, back fat thickness, and marbling; therefore, the genetic improvement of growth, meat, and carcass quality traits is an important tool to add value to the supply chain. Genomewide association studies (GWAS) enable the identification of loci that control phenotypic expression of quantitative traits (QTL). Therefore, the objective of this work was to perform a GWAS to identify genomic regions and genes associated with growth, carcass traits, and meat quality in Canchim beef cattle. These traits were yearling weight (YW), rib eye area (REA), back fat thickness (BFT), and marbling (MARB). To increase sample size and marker density, genotype imputation was performed, and only markers imputed with greater than 95% accuracy were used. Genomewide association study was performed using a Bayesian approach, by the Bayes B statistical method, incorporating genotypes and phenotypes from 614 animals from both the Canchim breed and the MA genetic group (offspring of Charolais bulls and one-half Canchim + one-half Zebu cows). This investigation identified 1 and 4 genomic regions explaining 0.23 and 7.35% of the genetic variance for REA and YW, respectively. These regions harbor a total of 19 genes, 7 of which were classified for biological functions by functional analysis. Significant associations were not observed for BFT and MARB. The identification of QTL that had been previously described in the literature reinforces associations found in this study. PMID- 28805910 TI - Evaluation of an intravaginal triptorelin acetate gel for inducing ovulation in mares. AB - The objective of these studies was to investigate the efficacy of an intravaginal triptorelin acetate (TA) gel as an ovulation-inducing agent in mares. In Exp. 1, 24 mares were blocked using a combination of parity and age and randomly assigned to 1 of 3 treatment groups: 5 mL TA gel (TA5), 10 mL TA gel (TA10), or 5 mL vehicle gel only (CON). Following the appearance of a follicle >= 25 mm, a blood sample was obtained for measurement of LH from each mare every 24 h until treatment administration. When a follicle >= 35 mm was observed, treatments were administered intravaginally. Following treatment, blood samples were collected for measurement of LH and ovaries were scanned via ultrasonography every 12 h until 48 h post-ovulation. Mares in both TA5 and TA10 tended ( = 0.08) to experience a brief surge in LH by 12 h post-treatment. There was a treatment by time interaction ( < 0.005). The interval from treatment to ovulation was not different between groups ( > 0.05). We hypothesized that duration of elevated LH was not sufficient to induce ovulation in most mares. In Exp. 2, 23 mares were blocked by parity/age and randomly assigned to 3 treatment groups: the CON ( = 7) and TA5 ( = 8) treatment groups remained the same, but the TA10 treatment was split into two 5-mL doses administered 24 h apart (TA5*2; = 8). Blood collection and ultrasonography occurred every 12 h on detection of a follicle >= 25 mm in diameter. Once a follicle >= 35 mm was detected, treatment was administered and ultrasonography and blood collection for measurement of LH occurred every 6 h until 48 h post-ovulation to get a more robust characterization of the effect of TA on LH and a more accurate timeframe in which ovulation was occurring. Mares in both TA5 and TA5*2 had an increase ( < 0.05) in LH by 6 h post-treatment, which was declining by 12 h post-treatment. Following the second dose in TA5*2, another rise in LH occurred, but to a lesser magnitude ( > 0.05) compared with the initial dose. Again there was a treatment by time interaction ( < 0.005) and in Exp. 2 the interval from treatment to ovulation was shorter in TA5 (61.5 +/- 8.8 h) and TA5*2 (61.5 +/- 9.6 h) compared with CON (123.1 +/- 21.7 h; < 0.01). In Exp. 2, administration of TA gel increased LH concentrations and hastened the interval from treatment to ovulation in mares, without an advantage in the timing of ovulation noted between the 5 or 10-mL doses, or administration of two 5-mL doses given 24 h apart. PMID- 28805911 TI - Effects of post-weaning growth rate and puberty induction protocol on reproductive performance of Bos indicus-influenced beef heifers. AB - A 3-yr study evaluated the effectiveness of puberty induction using exogenous reproductive hormones in beef heifers undergoing different post-weaning growth rates. On d 0 of each year, grazing Angus * Brahman heifers (60 heifers/yr) were stratified by initial BW and age (BW = 253 +/- 30 kg; age = 310 +/- 18 d), and randomly assigned, in a 3 * 2 factorial design, to achieve a low (LOW; 0.45 kg/d), medium (MED; 0.73 kg/d), or high (HIGH; 1.00 kg/d) growth rate from d 0 to 168 (5 heifers/pasture; 4 pastures/growth rate/yr). Dietary supplements were offered 3 times weekly (Mondays, Wednesdays, and Fridays) at 0800 h to provide 1.8, 2.9, and 4.4 kg of supplement DM per heifer daily from d 0 to 168. On d 0 of each year, 2 pastures/growth rate treatment were randomly assigned to receive (SYNC) or not (NOSYNC) a puberty induction protocol, which consisted of intravaginal controlled internal drug release (CIDR) insertion on d 65, CIDR removal on d 72, followed by 100-ug i.m. injection of GnRH on d 74, and 25-mg i.m. injection of PGF on d 84. Immediately after the puberty induction protocol, all heifers were grouped by growth rate treatment (1 group/growth rate/yr) into a single pasture and exposed to yearling Angus * Brahman bulls from d 84 to 168 (1 bull/group/yr). Interactions among growth rate and puberty induction protocol were not detected for any variable ( >= 0.26). Overall heifer ADG achieved only 51 to 56% of targeted ADG, and percentage of mature BW on d 84 did not differ between MED and HIGH heifers ( = 0.30), but both were heavier than LOW heifers ( < 0.01). Percentage of pubertal heifers on d 84 was greater for MED and HIGH vs. LOW heifers ( <= 0.05), whereas puberty induction protocol increased puberty attainment on d 84 ( < 0.01). Overall pregnancy and calving percentages after first breeding season were not affected by growth rate or puberty induction protocol ( >= 0.25). However, heifers calved 11 d earlier when enrolled in the puberty induction protocol ( = 0.02). In summary, puberty induction and HIGH and MED growth rates resulted in earlier attainment of puberty and pregnancy in influenced beef heifers. However, neither growth rate or puberty induction impacted overall heifer pregnancy and calving rates on their first breeding season. PMID- 28805912 TI - Prediction of fecal nitrogen and phosphorus excretion for Chinese Holstein lactating dairy cows. AB - Mathematical models for predicting nitrogen and phosphorus excretion play a key role in manure application and environment monitoring. An analysis for prediction of fecal nitrogen (FN, g/d) and fecal phosphorus (FP, g/d) excretion for Chinese Holstein lactating dairy cows was conducted using a data set from 15 dairy farms in northern China. The whole independent-variable data set, obtained with questionnaires, consisted of 110 sets of average diet nutrient compositions, including DMI (kg/d), CP content (% DM), OM intake (OMI, kg/d), nitrogen intake (NI, g/d), and phosphorus intake (PI, g/d), and animal characteristics, including average days in milk (DIM, d), average milk yield (MY, kg/d), and average BW (kg). In addition, 110 fecal samples in total were collected to analyze FN and FP excretions, which were considered dependent variables of prediction equations. Correlations between diet and animal variables were examined, and several variable subpools were derived that were used to develop equations to predict FN and FP excretions by stepwise regression analysis. The results showed that among all variables, OMI was the best predictor for FN excretion (root-mean-square prediction error [RMSPE] = 9.58%, = 0.70), followed by NI (RMSPE = 10.19%, = 0.67). However, when both DMI and CP were used as independent variables, the equation showed more accurate prediction for FN excretion (RMSPE = 8.55%, = 0.77) in comparison with univariate prediction equations. Simultaneously, PI was the best predictor of FP excretion (RMSPE = 10.28%, = 0.67). Evaluation results using 3-fold cross validation and comparison with extant equations indicated that the proposed equations were accurate with low prediction errors, which could be recommended for use to estimate FN and FP excretions from Chinese Holstein lactating dairy cows. PMID- 28805913 TI - Feeding distillers' grains, soybean hulls, or a mixture of both to cows as a forage replacement: Effects on intake, digestibility, and ruminal fermentation characteristics. AB - Coproduct feedstuffs offer a unique and potentially profitable avenue for cattle feeding strategies. However, research is lacking in the evaluation of varying coproducts on ruminal fermentation and digestive characteristics when included as the major component of the diet of cows. Our objective was to determine the effect of coproduct feedstuffs as a forage replacement on digestive and fermentative characteristics of cows. Eight ruminally fistulated cows (672 +/- 32.0 kg initial BW and approximately 9 yr of age) were stratified by BW and randomly allocated to 1 of 4 diets (2 cows?diet?period) in a 2-period study: soybean hulls (SH), distillers' dried grains with solubles (DG), an isoenergetic mixture of soybean hulls and distillers' dried grains with solubles (MX), or ad libitum hay plus 0.9 kg/d of an isoenergetic mixture of soybean hulls and distillers' dried grains with solubles (HY). Diets were formulated to meet the ME requirements of a similar, companion study. Coproduct amounts were increased over a 14-d period. This was followed by a 14-d adaptation to diet and facilities and 5 d of total fecal collections. On the final day of fecal collections, rumen fluid was sampled immediately prior to feeding and 2, 4, 6, 8, 10 and 12 h after feeding for measurement of rumen VFA and ammonia concentrations. Intake of DM and OM was not different ( >= 0.28) among treatments, but digestibilities of DM, OM, NDF, and ADF were improved ( < 0.05) by coproduct feeding and by MX vs. the mean of SH and DG. Ruminal DM and OM fill were greater ( < 0.05) for cows offered HY than for cows offered the coproduct diets, greater for cows offered SH than for cows offered DG, and for the mean of SH and DG vs. MX. Ruminal retention time was greater ( < 0.05) for HY vs. the coproduct diets and for SH vs. DG. Apparent N absorption tended ( < 0.10) to be greater for cows offered the coproduct diets than for cows offered HY and greater for cows offered DG than for cows offered SH. Total VFA averaged across sampling times were greatest ( < 0.05) for cows offered SH, and ruminal ammonia N was greatest ( < 0.05) for cows offered either DG or MX at all sampling times. Based on these data, coproduct feedstuffs may be fed to meet the energy requirement of cows without negative effects on digestion or ruminal fermentation. PMID- 28805914 TI - Genomic prediction for growth and reproduction traits in pig using an admixed reference population. AB - This study investigated the efficiency of genomic prediction using an admixed reference population comprising 3 Yorkshire populations with different genetic backgrounds. In total, 2,084 and 1,388 individuals with growth and reproduction records, respectively, were genotyped with a PorcineSNP80 marker panel. The corrected phenotypic values derived from conventional EBV of each population were taken as response variables. Three approaches, that is, a linear genomic BLUP (GBLUP) model, a Bayesian mixture model (BayesR), and single-step GBLUP (ssGBLUP), were implemented to predict genomic breeding values. Our results indicated that the accuracy of genomic prediction was increased by enlarging the reference population by admixing different populations. However, the improvement was lower than expected, because the relationships among individuals of different populations were not strong enough. Among the 3 approaches, for reproduction and growth traits, ssGBLUP produced 30 to approximately 38% and 23 to 31%, respectively, higher accuracy than GBLUP. And the ssGBLUP produced 28 to approximately 38% and 18 to approximately 31% higher accuracy than BayesR. In addition, ssGBLUP also yielded lower bias. In most situations, BayesR performed comparably to GBLUP for most traits. Our results indicated ssGBLUP using an admixed reference population is also meaningful for national joint genetic evaluation of Chinese pig breeding. PMID- 28805915 TI - Selection on resilience improves disease resistance and tolerance to infections. AB - Response to infection in animals has 2 main mechanisms: resistance (ability to control pathogen burden) and tolerance (ability to maintain performance given the pathogen burden). Selection on disease resistance and tolerance to infections seems a promising avenue to increase productivity of animals in the presence of disease infections, but it is hampered by a lack of records of pathogen burden of infected animals. Selection on resilience (ability to maintain performance regardless of pathogen burden) may, therefore, be an alternative pragmatic approach, because it does not need records of pathogen burden. Therefore, the aim of this study was to assess response to selection in resistance and tolerance when selecting on resilience compared with direct selection on resistance and tolerance. Monte Carlo simulation was used combined with selection index theory to predict responses to selection. Using EBV for resilience in the absence of records for pathogen burden resulted in favorable responses in resistance and tolerance to infections, with higher responses in tolerance than in resistance. If resistance and tolerance were unfavorably correlated, lower selection responses were obtained, especially in resistance. When the genetic correlation was very unfavorable, the selection response in tolerance became negative. Results showed that lower selection responses in resistance and tolerance were obtained when the frequency of disease outbreaks was 10% rather than 50% of the contemporary groups. The efficiency of selection on EBV for resilience compared with selection on EBV for resistance and tolerance was, however, not affected by the frequency of disease outbreaks. When records on pathogen burden were available, selection responses in resistance, tolerance, and the total breeding goal were 3 to 28%, 66 to 398%, and 2 to 11% higher, respectively, than when using the EBV for resilience, showing a clear benefit of recording pathogen burden. This study shows that selection on resilience is a pragmatic way of increasing disease resistance and tolerance to infections in the absence of records on pathogen burden, but recording pathogen burden would yield higher selection responses in resistance and tolerance. PMID- 28805916 TI - The reduction of starch in finishing diets supplemented with oil does not prevent the accumulation of trans-10 18:1 in lamb meat. AB - The experiment was conducted to test the hypothesis that the replacement of cereal with low-starch feed ingredients in lambs' finishing diets supplemented with oils could prevent the accumulation of -10-18:1 in meat. Forty lambs were fed 1 of 4 diets supplemented with soybean oil (5.9%) and fish oil (1%) for 6 wk before slaughter. The control (CON) diet contained 43% barley, and in the other diets, barley was completely replaced by dehydrated citrus pulp (DCP), dehydrated sugar beet pulp (DBP), or soybean hulls (SH). Growth performance, feed intake, and carcass and meat quality traits were analyzed. At slaughter, LM samples were collected for gene expression evaluation, and 3 d after slaughter, LM and subcutaneous (s.c.) fat samples were collected for fatty acid analysis. None of the diets affected meat quality, but the DCP diet reduced ADG ( < 0.05) and the DCP and SH diets decreased the feed-to-gain ratio ( < 0.01). The DCP diet increased ( < 0.05) the risk of parakeratosis and the severity of the lesions. Moreover, the DBP treatment led to increased a* (redness) and b* (yellowness) in s.c. fat compared with the CON treatment ( < 0.05). The lipid content of LM did not differ ( > 0.05) with treatment and averaged 34.4 g/kg of meat. Diets had no effect ( > 0.05) on SFA, PUFA, and -MUFA sums and on the -6:-3 ratio in both LM and s.c. fat. A lower expression of fatty acid synthase (FASN) was found with the DCP treatment than with the other treatments ( < 0.001). All treatments showed a high accumulation of -10-18:1, averaging 91 mg/g fatty acid in LM and 147 mg/g fatty acid in s.c. fat. The concentration of -11-18:1 in the tissues was considerably lower than that of -10-18:1, and thus the -10-18:1:-11-18:1 ratio was above 3 with all treatments. Despite this, the SH diet clearly promoted a larger deposition of -11-18:1 and -9,-11-18:2 in tissues compared with the other treatments. () gene expression and SCD activity index in LM were reduced with the SH diet compared with the CON and DCP diets. Overall, these results clearly showed, for the first time, that low-starch/high-NDF diets are not able to prevent the establishment of -10 shifted rumen biohydrogenation pathways, evaluated by the deposition of biohydrogenation intermediates in lamb meat and fat. PMID- 28805917 TI - Technical note: Impact of pedigree depth on convergence of single-step genomic BLUP in a purebred swine population. AB - In genomic evaluations, it is desirable to have low computing cost while retaining high accuracy of evaluation for young animals. When the population is large but only few animals have phenotypes, especially for low heritability traits, the convergence rate of BLUP or single-step genomic BLUP (ssGBLUP) can be very slow. This study investigates the effect of pedigree truncation on convergence rate and solutions of ssGBLUP for data exhibiting slow convergence. The data consisted of 216,000, 221,000, 732,000, and 579,000 phenotypes on 4 traits. Heritabilities were less than 0.1 for 2 traits and greater than 0.2 for the other 2 traits. The full pedigree consisted of 2.4 million animals. Genotypes were available for 33,000 animals and consisted of 60,000 SNP. Two bivariate animal models were fit using pedigree-based BLUP or ssGBLUP. Either a regular or the algorithm for proven and young (APY) inverse was used for the genomic relationship matrix. Different pedigree depths were analyzed including full pedigree and 1 to 5 ancestral generations. Pedigree depths were defined as n ancestral generations for animals with phenotypes. The number of animals in the reduced pedigrees varied from 226,000 and 760,000 for 1 generation to 228,000 and 767,000 for 5 generations. Genomic EBV (GEBV) for genotyped animals had correlations greater than 0.99 between runs with the full and reduced pedigrees with 2 to 5 generations. A single generation of pedigree was not sufficient to obtain the same GEBV as full pedigree. The convergence rate was the worst with the full pedigree and generally improved with reduced pedigrees. Using ssGBLUP with the APY inverse improved convergence without affecting accuracy. Reducing pedigrees and the APY are important tools to reduce the computational cost in the implementation of ssGBLUP. PMID- 28805918 TI - Effects of encapsulated nitrate on growth performance, carcass characteristics, nitrate residues in tissues, and enteric methane emissions in beef steers: Finishing phase. AB - A finishing feedlot study was conducted with beef steers to determine effects of encapsulated nitrate (EN) on growth performance, carcass characteristics, methane production, and nitrate (NO) residues in tissues. The 132 crossbred steers were backgrounded in a feedlot for 91 d and transitioned for 28 days to the high concentrate diets evaluated in the present study, maintaining the treatment and pen assignments designated at the start of the backgrounding period. The steers were initially assigned to 22 pens (6 animals per pen) in a randomized complete block design with BW (18 pens) and animals designated for methane measurement (4 pens) as blocking factors. Five animals in each pen designated for methane measurement (total of 20 animals) were monitored for methane emissions in respiratory chambers twice during the experiment. Pens received 3 dietary treatments (7 pens each): Control, a finishing diet supplemented with urea; 1.25% EN, control diet supplemented with 1.25% encapsulated NO in dietary DM that partially replaced urea; and 2.5% EN, control diet supplemented with 2.5% EN (DM basis) fully replacing urea. The final pen designated only for methane measurement received a fourth dietary treatment, 2.3% UEN, the control diet supplemented with unencapsulated NO (UEN) fully replacing urea. The cattle weighed 449 +/- SD 32 kg at the start of the 150-d finishing period. The 2.5% EN diet decreased ( < 0.01) DMI compared with Control and 1.25% EN diets. Feeding EN tended to increase ( = 0.092) ADG compared with Control, and G:F was improved ( < 0.01) for EN compared with Control. No differences in methane production (g/d) and yield (g/kg DMI) were observed among treatments. Inclusion of EN in the diets increased ( <= 0.03) sorting in favor of large and medium particles and against small and fine particles. Plasma NO and NO concentrations were elevated ( < 0.01) with EN in a dose-response manner, but total blood methemoglobin levels for all treatments were low, below the detection limit. Feeding EN increased ( < 0.01) NO concentrations of samples from muscle, fat, liver, and kidney; NO concentrations of these tissues were similar between 1.25% EN and 2.3% UEN. In conclusion, inclusion of 2.5% EN in a finishing diet (DM basis; about 2% NO) did not cause NO toxicity or any health problems in the long term. In comparison with supplemental urea, feeding EN improved feed efficiency despite increases in sorting against dietary EN. PMID- 28805919 TI - Cows exposed to heat stress during fetal life exhibit improved thermal tolerance. AB - Maternal heat stress during late gestation affects calf function during postnatal life. The objective of the present study was to evaluate whether calves that experience heat stress in utero have altered thermoregulatory responses to acute heat stress later in life. Specifically, the hypothesis was that heat stress in utero would improve the response to acute heat stress at maturity. Females were born to dams exposed to heat stress or cooled during late gestation preceding their birth. All animals were raised postnatally under identical management. Twelve lactating Holstein cows that were exposed to in utero heat stress (HT) and 12 that were exposed to in utero control (CON) were used. A heat stress challenge was conducted in 3 blocks using 4 HT and 4 CON cows matched according to milk yield, stage of lactation, and parity. Each challenge consisted of transfer from a barn with shade and evaporative cooling to one with shade but no additional cooling for 48 h. The challenge was replicated twice for each block. Sweating rate, respiration rate, rectal temperature (RT), and skin temperature were measured on each cow at 0900, 1100, 1300, 1500, and 1700 h for 2 consecutive days. Mean ambient temperature across 6 challenge days was 26.15 +/- 4.75 degrees C. Tendencies for differences at 1700 h were observed between treatments for RT (HT: 39.5 +/- 0.1; CON: 39.6 +/- 0.1 degrees C; = 0.065), however, there was no difference in respiration rate (HT: 77.6 +/- 1.6; CON: 79.5 +/- 1.6 bpm; = 0.85). Sweating rate for shaved skin (HT: 29.4 +/- 2.0; CON: 36.0 +/- 2.0 g/mh; = 0.057) and for non-shaved skin (HT: 22.5 +/- 1.5; CON: 29.2 +/- 1.2 g/mh; = 0.01) differed between groups. However, there was no effect on skin temperature at the shaved location (HT: 36.2 +/- 0.2; CON: 36.0 +/- 0.2 degrees C; = 0.81), but there was a tendency for differences for the non-shaved area (HT: 35.4 +/- 0.2; CON: 34.9 +/- 0.2 degrees C; = 0.097). Cows that underwent in utero heat stress had greater skin temperature at 1700 h vs. in utero control cows, which may be because HT cows increased skin perfusion, and consequently greater cooling via conduction. In utero HT cows would then have higher heat loss and reduced core body temperature, which results in lower rectal temperature and lower sweating rate when exposed to heat stress. These results support the hypothesis that heat stress in utero in late gestation increases heat tolerance at maturity by increasing capacity to dissipate heat to maintain core body temperature. PMID- 28805920 TI - Ground Juniperus pinchotii and urea in supplements fed to Rambouillet ewe lambs: I. Feedlot growth traits, blood serum parameters, and fecal characteristics. AB - Ground woody products and urea are low-cost roughage and N sources. Rambouillet ewe lambs ( = 48, 6 lambs/treatment; initial BW = 42 kg +/- 3.8) were used to evaluate effects of using ground (juniper) and urea in supplements on feedlot lamb growth traits, blood serum parameters, and fecal characteristics. In a randomized complete block design (40 d), lambs were individually fed an ad libitum basal sorghum-Sudangrass hay diet, which was fed separate from 1 of 8 supplemental diets (6 lambs/diet; 533 g of supplement/d, as-fed basis). Treatment structure was a 4 * 2 factorial: 4 concentrations of ground juniper (JN: 15%, 30%, 45%, or 60% of DM) and 2 concentrations of urea (UR: 1 or 3% of DM). Lamb growth traits were evaluated on d 0, 5, 12, 19, 26, 33, and 40; blood serum was evaluated on d 6 to 8, 20 to 22, and 34 (at h 3 and 6), and feces was evaluated on d 35. Compared to lambs fed all of the other treatments, lambs fed JN60UR1 or JN60UR3 had reduced supplement DMI (negative quadratic, = 0.007). Hay and total DMI were variable across day (JN * UR * day, < 0.04), but no linear or quadratic trends were detected ( > 0.10). A JN * day interaction was detected ( < 0.001) for lamb BW and the JN * day negative quadratic trend ( = 0.02) for BW was influenced by reduced ADG (linear decrease, < 0.001) of lambs fed JN60. Lambs supplemented with UR3 vs. UR1 tended ( = 0.06) to have reduced BW but had similar ( > 0.17) ADG and G:F. Lamb G:F fluctuated across day (JN * day, = 0.007), but the JN * day quadratic trend ( < 0.001) was mainly due to reduced G:F in lambs fed JN45 or JN60 diets. As the percentage of JN increased in the supplement, serum IGF-1 linearly decreased ( = 0.04), and serum urea N quadratically increased ( < 0.001). The UR * hour interaction ( < 0.001) for serum urea N resulted from a greater decline from 3 to 6 h after feeding in lambs supplemented with UR1 vs. UR3. Increasing JN concentration tended to quadratically increase ( = 0.09) fecal DM and linearly decrease ( = 0.002) fecal N, but an effect due to dietary UR was not detected ( > 0.34). Results indicated that daily supplement DMI was restricted only by using JN60. However, a 60% JN-based supplement will not make an effective rangeland supplement for growing ewe lambs, and using 3% UR should not be considered, especially since daily UR intake was not restricted enough to be considered safe. PMID- 28805921 TI - Bacterial flora of liver abscesses in crossbred beef cattle and Holstein steers fed finishing diets with or without tylosin. AB - Holstein steers raised for beef production consistently have a higher prevalence and more severe form of liver abscesses than cattle of beef breeds. A study was conducted to compare bacterial flora of liver abscesses collected from multiple abattoirs from 4 groups of cattle, arranged in a 2 * 2 factorial design, consisting of crossbred cattle and Holstein steers, and each group fed a finishing diet supplemented with or without tylosin. A total of 383 liver abscess samples, consisting of 94 and 81 from crossbred cattle and 89 and 119 from Holstein steers fed finishing diets with or without tylosin, respectively, were subjected for anaerobic and aerobic bacterial isolations. The minimum inhibitory concentrations (MIC) of tylosin to the predominant bacterial species were determined. The likelihood chi-square test was performed to assess unadjusted differences in bacterial prevalence proportions between the 2 types of cattle (crossbred and Holstein steers) and feed type (tylosin or no tylosin). There was no interaction between cattle type and tylosin inclusion on the prevalence of any of the bacterial species isolated. Liver abscesses from Holstein steers yielded a higher total number of isolates compared to liver abscesses from crossbred cattle (1060 vs. 788). subsp. was isolated from all abscesses. The prevalence of subsp. was 19.1% and was not affected by the cattle type or tylosin. The prevalence of was higher ( < 0.01) in crossbred cattle (73.7%) compared to Holstein steers (29.8%). Also, the prevalence of was higher in abscesses from tylosin-fed (66.1%) cattle than no tylosin-fed cattle (35%). The overall prevalence of was 25.3% and was similar ( = 0.58) between cattle type, but the prevalence was lower ( < 0.01) in tylosin-fed (16.9%) compared to no tylosin-fed group (33%). Mean MIC of tylosin for and were similar across both cattle types and tylosin inclusion. Although bacterial flora of liver abscesses from Holstein steers appeared to be more diverse than that of crossbred cattle, there was no difference in the prevalence of the and and in fact, prevalence of was higher in crossbred than Holstein steers. Therefore, the difference in bacterial flora is not the likely reason for higher prevalence and severity of liver abscesses in Holstein steers than crossbred beef cattle. PMID- 28805922 TI - Use of a complete starter feed in grain adaptation programs for feedlot cattle. AB - Four experiments evaluated the use of a complete starter feed (RAMP; Cargill Corn Milling, Blair, NE) for grain adaptation. In Exp. 1, 229 yearling steers (397 +/- 28.4 kg BW) were used to compare a traditional adaptation program (CON) with adapting cattle with RAMP in either a 1- (RAMP-1RS) or 2- (RAMP-2RS) ration system. From d 23 to slaughter, cattle were fed a common finishing diet. In Exp. 2, 390 yearling steers (341 +/- 14 kg BW) were used to compare accelerated grain adaptation programs with RAMP with 2 control treatments where RAMP was blended with a finishing diet containing either 25 (CON25) or 47.5% (CON47) Sweet Bran (Cargill Corn Milling) in 4 steps fed over 24 d to adapt cattle. Rapid adaptation treatments involved feeding RAMP for 10 d followed by a blend of RAMP and a 47% Sweet Bran finishing diet to transition cattle with 3 blends fed for 1 d each (3 1d), 2 blends fed for 2 d each (2-2d), or 1 blend fed for 4 d (1-4d). From d 29 to slaughter, all cattle were fed a common finishing diet. In Exp. 3, 300 steer calves (292 +/- 21 kg BW) were used to compare the CON47 and 1-4d adaptation programs with directly transitioning cattle from RAMP, which involved feeding RAMP for 10 d and then switching directly to F1 on d 11 (1-STEP). From d 29 until slaughter, F2 was fed to all cattle. In Exp. 4, 7 ruminally fistulated steers (482 +/- 49 kg BW) were used in a 35-d trial to compare the CON47 and 1-STEP adaptation programs. Ruminal pH and intake data from the first 6 d of F1and first 6 d of F2 were used to compare adaptation systems. Adaptation with RAMP-1RS and RAMP-2RS increased ( < 0.01) G:F compared with cattle adapted using CON in Exp. 1. Feeding RAMP-1RS increased ADG ( = 0.03) compared with CON. Intakes were similar ( = 0.39) among treatments. Daily gain, DMI, G:F, and carcass traits were similar ( > 0.11) among treatments in Exp. 2. Daily gain, DMI, and G:F were not different ( > 0.20) among treatments on d 39 or over the entire feeding period in Exp. 3. When F1 or F2 was being fed, DMI was similar ( >= 0.40) for CON47 and 1 STEP in Exp. 4. When F1 or F2 was being fed, 1-STEP cattle had lower average ruminal pH ( <= 0.03) and greater time below a pH of 5.3 ( <= 0.03). Using RAMP for grain adaptation improved performance compared with traditional adaptation. Rapid adaptation with RAMP decreased pH, but no performance differences were observed between long and rapid RAMP adaptation programs. Therefore, cattle started on RAMP do not require extensive adaptation before feeding a finishing diet with Sweet Bran. PMID- 28805924 TI - Measures of lamb production efficiency in a temperate grass-based system differing in ewe prolificacy potential and stocking rate. AB - The objective of this study was to quantify the effects of ewe prolificacy potential (PP; predicted number of lambs born ewe yr), as dictated by sire breed type, and stocking rate (SR; ewes ha) on ewe production efficiency (kg lamb live weight weaned:kg ewe live weight mated), lamb growth, lamb carcass output, and dry matter (DM; kg) and energy (UFL; unit of energy kg DM) consumption (in the form of both grazed and conserved herbage, concentrate supplementation, and total) in a temperate grass-based lamb production system. The study was a 2 * 3 factorial design, consisting of 2 differing ewe prolificacy potentials (medium prolificacy [MP]-Suffolk-sired crossbred ewes and high prolificacy [HP]-Belclare sired crossbred ewes) and 3 stocking rates: low (LSR; 10 ewes ha), medium (MSR; 12 ewes ha), and high (HSR: 14 ewes ha). Each treatment was managed in a 5 paddock rotational system for the duration of the study. The HP treatment weaned more lambs ewe and ha ( < 0.01), yielded a higher average daily live weight gain (ADG) ha ( < 0.001), produced an additional 50 kg of lamb carcass ha ( < 0.05), and required 13% less DM and UFL to produce a kg of lamb carcass ( < 0.001) compared to the MP treatment. High prolificacy potential ewes had a 4% higher production efficiency ( < 0.05) than MP ewes. Ewe prolificacy potential had no effect on the total quantity of DM and UFL consumed ewe and lamb unit ( > 0.05). Increasing stocking rate increased the number of lambs weaned ha ( < 0.001) and increased lifetime lamb ADG ha ( < 0.001). Lamb carcass output (kg) ha was highest at the HSR, intermediate at the MSR, and lowest at the LSR ( < 0.001). The quantity of DM and UFL consumed ewe and lamb unit and kg of lamb carcass produced ha increased as stocking rate increased ( < 0.001). In conclusion, results from this study demonstrate HP ewes to be more efficient in the production of lamb. Increasing stocking rate provides the opportunity to increase lamb carcass output ha; however, achieving this increase in output required additional DM and UFL ewe and lamb unit above 12 ewes ha. PMID- 28805925 TI - Evaluation of the prevalence of digital dermatitis and the effects on performance in beef feedlot cattle under organic trace mineral supplementation. AB - Bovine digital dermatitis (DD) is a contagious and multifactorial disease that leads to painful, ulcerative lesions of the skin near the heel-horn border of the foot, most commonly in dairy cattle. With regard to beef cattle, the pathogenesis and etiology of DD has not been widely reported or studied over the past several decades. A longitudinal field trial in a commercial feedlot was conducted to compare prevalence and effects of DD in beef steers provided a diet supplemented with a novel formulation of inorganic and organic trace mineral sources (OTM diet) compared to a diet provided with similar levels of trace minerals solely from inorganic sources (CON diet). A secondary objective was to evaluate the prevalence of DD and the potential effects on growth performance and carcass yield and quality. One thousand seventy-seven steers were assigned to 1 of the 2 treatment groups (CON diet or OTM diet) based on location of their home pens which were situated in 1 of 2 barns. All pens in the B barn (group B) were assigned to the OTM diet, and all pens in the A barn (group A) were assigned to the CON diet. The study was conducted in 2 phases: adaptation phase (AP) comprising the initial 60 d of feeding CON and OTM diets and postadaptation phase (PAP) which lasted until cattle were sent to harvest. In the AP, pens in group B had a greater proportion of steers (54.03%) with DD lesions compared to pens in group A (26.72%). During the PAP, the relative risk of observing an increased DD prevalence was significantly ( < 0.05) higher in CON group compared to OTM group. Growth performance, final live weight, and hot carcass weight were negatively impacted when steers were observed to have active DD lesions (M2 lesions) compared to steers with no M2 lesions over the study period. For ADG, a calculated loss per steer of 0.08 kg/d from type I (no M2 lesions) to type II (one M2 lesion; SE = 0.028; = 0.003) and loss of 0.14 kg/d from type I to type III (multiple M2 lesions; SE = 0.038; = 0.0003) were observed. A significant BW loss of approximately 10.06 kg (SE = 4.18; = 0.022) and a mean reduction of 5.5 kg per steer in HCW (SE = 2.74; = 0.043) were also found between type I and type II steers. PMID- 28805926 TI - Multiple-trait genomewide mapping and gene network analysis for scrotal circumference growth curves in Brahman cattle. AB - Fertility traits are economically important in cattle breeding programs. Scrotal circumference (SC) measures are repeatable, easily obtained, highly heritable, and positively correlated with female fertility traits and sperm quality traits in males. A useful approach to summarize SC measures over time is using nonlinear models, which summarize specific measures of SC in a few parameters with biological interpretation. This approach facilitates the selection of bulls with larger SC and maturity index (K), that is, early maturing animals. Because SC is a sex-limited trait, identifying the underlying genomics of growth curve parameters will allow selection across both males and females. We reported the first multitrait genomewide association study (GWAS) of estimated growth curve parameters for SC data in Brahman cattle. Five widely used nonlinear models were tested to fit a total of 3,612 SC records, measured at 6, 12, 18, and 24 mo of age. The von Bertalanffy model, individually fitted for each animal, best fit this SC data. Parameter estimates SC at maturity (A) and K as well as SC at all ages were jointly analyzed in a GWAS to identify 1-Mb regions most strongly associated with each trait. Heritabilities were 0.25 for K and 0.32 for A and ranged from 0.51 to 0.72 for SC at 6 (SC6), 12 (SC12), 18 (SC18), and 24 mo of age (SC24). An overlapping window on chromosome 14 explaining around 0.8% of genetic variance for K, SC12, SC18, and SC24 was observed. The major positional candidate genes within 1 Mb upstream and downstream of this overlapping window were , , , and . Windows of 1 Mb explaining more than 0.4% of each trait on chromosomes 1, 3, 6, 7, 14, 17, 18, 24, 25, and 26 were identified. Pathways and net-work analyses were indicated through transcription factors playing a role on fertility traits: , , , , , , and . Further validation studies on larger populations or other breeds are required to validate these findings and to improve our understanding of the biology and complex genetic architecture of traits associated with scrotal growth and male fertility in cattle. PMID- 28805927 TI - The relationship between different measures of feed efficiency and feeding behavior traits in Duroc pigs. AB - Utilization of feed in livestock species consists of a wide range of biological processes, and therefore, its efficiency can be expressed in various ways, including direct measurement, such as daily feed intake, as well as indicator measures, such as feeding behavior. Measuring feed efficiency is important to the swine industry, and its accuracy can be enhanced by using automated feeding systems, which record feed intake and associated feeding behavior of individual animals. Each automated feeder space is often shared among several pigs and therefore raises concerns about social interactions among pen mates with regard to feeding behavior. The study herein used a data set of 14,901 Duroc boars with individual records on feed intake, feeding behavior, and other off-test traits. These traits were modeled with and without the random spatial effect of Pen_Room, a concatenation of room and pen, or random social interaction among pen mates. The nonheritable spatial effect of common Pen-Room was observed for traits directly measuring feed intake and accounted for up to 13% of the total phenotypic variance in the average daily feeding rate. The social interaction effect explained larger proportions of phenotypic variation in all the traits studied, with the highest being 59% for ADFI in the group of feeding behaviors, 73% for residual feed intake (RFI; RFI4 and RFI6) in the feed efficiency traits, and 69% for intramuscular fat percentage in the off-test traits. After accounting for the social interaction effect, residual BW gain and RFI and BW gain (RIG) were found to have the heritability of 0.38 and 0.18, respectively, and had strong genetic correlations with growth and off-test traits. Feeding behavior traits were found to be moderately heritable, ranging from 0.14 (ADFI) to 0.52 (average daily occupation time), and some of them were strongly correlated with feed efficiency measures; for example, there was a genetic correlation of 0.88 between ADFI and RFI6. Our work suggested that accounting for the social common pen effect was important for estimating genetic parameters of traits recorded by the automated feeding system. Residual BW gain and RIG appeared to be two robust measures of feed efficiency. Feeding behavior measures are worth further investigation as indicators of feed efficiency. PMID- 28805928 TI - Effects of dietary fish oil supplementation on performance, meat quality, and cecal fermentation of growing rabbits. AB - The objective of this study was to investigate the effect of dietary supplementation with fish oil on growth performance (during all fatening period), carcass characteristics and fatty acid (FA) profile of muscle and fat tissues (at slaughter), as well as cecal fermentation and ileal mucosa morphology of growing rabbits (at 30, 45, and 60 d of age). Two isonitrogenous and isoenergetic diets, only differing in their fat source, were formulated and provided each to 24 does (12 per diet) and their offspring during pregnancy and lactation. The control diet contained 4.59 g of n-3 per 100 g of total FA, and the enriched diet contained 14.9 g of n-3 per 100 g of total FA. From weaning (30 d of age) to slaughter (60 d), the litters (12 per diet; 8 kits each) continued fed the corresponding experimental diet. There were no differences ( > 0.05) between groups in ADFI, ADG and G:F ratio during the growing period. At slaughter, BW, full gastrointestinal tract weight, carcass yield, meat color and pH, drip loss percentage, content of scapular fat and tissue composition of the left hind leg were similar between groups ( > 0.05), but perirenal fat was lower ( = 0.020) and skin weight and abdominal fat tended to be lower ( = 0.055 and = 0.063, respectively) in enriched rabbits than in control ones. Total PUFA content in both LM and perirenal fat was greater ( = 0.021 and < 0.001, respectively) in enriched rabbits, that also showed lower n-6/n-3 ratios in LM (1.61 vs. 5.80; < 0.001) and perirenal fat (4.71 vs. 12.0; < 0.001) than those fed the control diet. Cecal concentrations of total VFA were greater ( < 0.001) in enriched than in control group at 30, 45 and 60 d of age, but diet did not affect ( >= 0.332) VFA profile, with the exception of a lower ( = 0.013) proportion of minor VFA (sum of isobutyrate, isovalerate, and valerate) in control group. Diet did not affect ( > 0.255) either pH and NH-N concentrations in the cecum or ileal morphology (crypt depth and villi length). The results showed that dietary fish oil supplementation enhanced beneficial long-chain n-3 FA and decreased n-6/n-3 ratio in rabbit meat and fat, being healthier for human consumption, without having negative effects on growth performance, cecal fermentation, and ileal morphology or carcass characteristics. PMID- 28805929 TI - The impact of training strategies on the accuracy of genomic predictors in United States Red Angus cattle. AB - Genomic selection (GS) has become an integral part of genetic evaluation methodology and has been applied to all major livestock species, including beef and dairy cattle, pigs, and chickens. Significant contributions in increased accuracy of selection decisions have been clearly illustrated in dairy cattle after practical application of GS. In the majority of U.S. beef cattle breeds, similar efforts have also been made to increase the accuracy of genetic merit estimates through the inclusion of genomic information into routine genetic evaluations using a variety of methods. However, prediction accuracies can vary relative to panel density, the number of folds used for folds cross-validation, and the choice of dependent variables (e.g., EBV, deregressed EBV, adjusted phenotypes). The aim of this study was to evaluate the accuracy of genomic predictors for Red Angus beef cattle with different strategies used in training and evaluation. The reference population consisted of 9,776 Red Angus animals whose genotypes were imputed to 2 medium-density panels consisting of over 50,000 (50K) and approximately 80,000 (80K) SNP. Using the imputed panels, we determined the influence of marker density, exclusion (deregressed EPD adjusting for parental information [DEPD-PA]) or inclusion (deregressed EPD without adjusting for parental information [DEPD]) of parental information in the deregressed EPD used as the dependent variable, and the number of clusters used to partition training animals (3, 5, or 10). A BayesC model with pi set to 0.99 was used to predict molecular breeding values (MBV) for 13 traits for which EPD existed. The prediction accuracies were measured as genetic correlations between MBV and weighted deregressed EPD. The average accuracies across all traits were 0.540 and 0.552 when using the 50K and 80K SNP panels, respectively, and 0.538, 0.541, and 0.561 when using 3, 5, and 10 folds, respectively, for cross-validation. Using DEPD-PA as the response variable resulted in higher accuracies of MBV than those obtained by DEPD for growth and carcass traits. When DEPD were used as the response variable, accuracies were greater for threshold traits and those that are sex limited, likely due to the fact that these traits suffer from a lack of information content and excluding animals in training with only parental information substantially decreases the training population size. It is recommended that the contribution of parental average to deregressed EPD should be removed in the construction of genomic prediction equations. The difference in terms of prediction accuracies between the 2 SNP panels or the number of folds compared herein was negligible. PMID- 28805930 TI - Reliability of the qualitative behavior assessment as included in the Welfare Quality Assessment protocol for growing pigs. AB - Positive emotions constitute a very important part of animal welfare. They are, however, also the most challenging elements to be objectively measured. Due to its feasibility, the qualitative behavior assessment (QBA) is included in the Welfare Quality Assessment protocol for growing pigs as the animal-based measurement tool for positive emotions. Reliability testing on the QBA in the form as included in the protocols is, however, rare. Therefore, the present study aimed at the evaluation of the inter- and intraobserver as well as test-retest reliability of the QBA in growing pigs. This was done by trained observers based on 19 joint on-farm assessments, the repeated assessments of 24 farms during 2 growing periods, and 107 video sequences. The results were compared between the observers and the repeated farm visits. Therefore, millimeter values were directly compared by calculation of Spearman's rank correlation coefficients (RS), and furthermore, the results were subjected to a principal component analysis (PCA). The results identified 2 main principal components (PC; PC1 and PC2) together explaining from 42 to 75% of the variation in the recorded variables of the different PCA. The factor loadings that the adjectives reached on PC1 and PC2 were compared by calculation of RS between observers and farm visits, respectively. Reliability was interpreted as acceptable if at least a moderate correlation was detected; that is, RS was greater than or equal to 0.4. Regarding the on-farm assessments, and, therefore, under practical conditions, no sufficient interobserver reliability (RS = -0.16 for PC1 and RS = 0.13 for PC2) was found. In terms of the test-retest reliability, only 1 comparison of 2 farm visits showed a positive correlation for PC1 (RS = 0.79) as well as for PC2 (RS = 0.64). The other 5 comparisons presented negative to weak positive correlations. However, based on video sequences, good interobserver (RS = 0.67 for PC1 and RS = 0.60 for PC2) and intraobserver (RS = 0.94 for PC1 and RS = 0.44 for PC2) reliability was achieved. Therefore, the present study revealed good reliability for the QBA in the form as it is currently included in the Welfare Quality Assessment protocol for growing pigs based on video sequences but insufficient reliability for the application on the farm. PMID- 28805931 TI - MRP1 protein expression in leukemic stem cells as a negative prognostic marker in acute myeloid leukemia patients. AB - BACKGROUND: It is well established that expression of multi-drug resistance (MDR) proteins (MDR1, BCRP, MDR3, MRP1, and LRP) in leukemic blasts correlates with acute myeloid leukemia (AML) patients' clinical response. Assuming that leukemic stem cells (LSC) are resistant to chemotherapy and responsible for relapse, it might be clinically relevant to evaluate the expression level of MDR proteins in LSC and relate it to the clinical outcome. METHODS: Bone marrow samples from 26 patients with de novo AML were labeled with antibodies to distinguish CD34+CD38 CD123+ LSC population and with antibodies against MDR1, BCRP, MDR3, MRP1, or LRP proteins. Multicolor flow cytometry was applied to evaluate the expression of MDR proteins in blasts and LSC. RESULTS: Nine of 26 patients with AML attained CR (30%). High negative correlation was found between MDR1 and LRP expression in blasts and the patient's remission. MDR proteins were expressed more frequently in LSC than in leukemic blasts. High negative correlation was also observed between remission achievement and MRP1 expression in LSC. CONCLUSIONS: Our data present for the very first time the high negative correlation between MRP1 protein expression in LSC and AML patients' remission. It does strongly suggest that MRP1 expression in LSC is an adverse prognostic marker in patients with de novo AML. PMID- 28805933 TI - "...in anatomy it is better to have learned and lost than never to have learned at all". PMID- 28805932 TI - Muscle thickness correlates to muscle cross-sectional area in the assessment of strength training-induced hypertrophy. AB - Muscle thickness (MT) measured by ultrasound has been used to estimate cross sectional area (measured by CT and MRI) at a single time point. We tested whether MT could be used as a valid marker of MRI determined muscle anatomical cross sectional area (ACSA) and volume changes following resistance training (RT). Nine healthy, young, male volunteers (24 +/- 2 y.o., BMI 24.1 +/- 2.8 kg/m2 ) had vastus lateralis (VL) muscle volume (VOL) and ACSAmid (at 50% of femur length, FL) assessed by MRI, and VL MT measured by ultrasound at 50% FL. Measurements were taken at baseline and after 12 weeks of isokinetic RT. Differences between baseline and post-training were assessed by Student's paired t test. The relationships between MRI and ultrasound measurements were tested by Pearson's correlation. After RT, MT increased by 7.5 +/- 6.1% (P < .001), ACSAmid by 5.2 +/ 5% (P < .001), and VOL by 5.0 +/- 6.9% (P < .05) (values: means +/- SD). Positive correlations were found, at baseline and 12 weeks, between MT and ACSAmid (r = .82, P < .001 and r = .73, P < .001, respectively), and between MT and VOL (r = .76, P < .001 and r = .73, P < .001, respectively). The % change in MT with training was correlated with % change in ACSAmid (r = .69, P < .01), but not % change in VOL (r = .33, P > .05). These data support evidence that MT is a reliable index of muscle ACSAmid and VOL at a single time point. MT changes following RT are associated with parallel changes in muscle ACSAmid but not with the changes in VOL, highlighting the impact of RT on regional hypertrophy. PMID- 28805934 TI - Fragility of epidermis: acne and post-procedure lesional skin. AB - 'Fragile skin', or skin with lower resistance to aggressors, can be broadly classified into four causal categories: constitutional (age-dependent or associated with specific vulnerable locations on the body, e.g. eyelids), pathological (related to disease), circumstantial (related to environmental or internal factors, e.g. stress) and iatrogenic (caused by medical interventions or treatments). In this supplement, we focus on the fourth category, the iatrogenic origin of fragile skin and the role that dermo-cosmetics can have in restoring the natural protective function of the skin following treatments for skin diseases and medical interventions. We present epidemiological data on the prevalence of fragile skin in three different geographical regions, and the results of two randomized controlled studies investigating the efficacy and tolerability of dermo-cosmetics in combination with topical acne treatment and following physical skin damage. Overall, we found that prevalence across the three regions (23% in Germany, 41% in UAE, 56% in Taiwan) reflected previous global estimates (24-53%) across skin types, with significant associations found with environmental and lifestyle factors, such as stress, humidity and pollution. The iatrogenic effects of topical acne treatments can result in poor compliance or use of over-the-counter moisturizers, which may reduce treatment efficacy. Dermo-cosmetics were found to aid in restoration of fragile skin caused by the acne topical retinoid treatment adapalene 0.1% gel, by reducing transepidermal water loss and improving skin hydration, as well as reducing the side-effects such as skin irritation that are frequently associated with topical retinoids. Additionally, dermo-cosmetic products were found to accelerate wound closure following skin damage in a laser ablation model and reduced the duration of post procedural side-effects such as itching and burning. PMID- 28805935 TI - [UO2 Cl2 (phen)2 ], a Simple Uranium(VI) Compound with a Significantly Bent Uranyl Unit (phen=1,10-phenanthroline). AB - A simple synthesis based on UO2 Cl2 ?n H2 O and 1,10-phenanthroline (phen) resulted in the formation of a new uranyl(VI) complex [UO2 Cl2 (phen)2 ] (1), revealing a unique dodecadeltahedron coordination geometry around the uranium center with significant bending of the robust linear arrangement of the uranyl (O U-O) unit. Quantum chemical calculations on complex 1 indicated that the weak but distinct interactions between the uranyl oxygens and the adjacent hydrogens of phen molecules play an important role in forming the dodecadeltahedron geometry that fits to the crystal structure of 1, resulting in the bending the uranyl unit. The uranyl oxygens in 1 are anticipated to be activated as compared with those in other linear uranyl(VI) compounds. PMID- 28805937 TI - New data on hyperpigmentation disorders. AB - Recently visible light (VL) and vascularization triggered by infrared light (IR) play a role in hyperpigmentation disorders of the skin. The aim of this article is to provide an update on the aetiology of hyperpigmentation disorders and means of prevention against UV, visible (VL) and infrared light (IR). The author conducted a literature review of the most recent data about hyperpigmentation disorders and means of prevention and protection. VL impacts on pigmentation, especially in individuals with phototype III, IV or V and also causes the production of Reactive Oxygen Species (ROS), erythema and DNA damage through ROS production as well as photodermatoses. IR is supposed to be involved in melanogenesis throughout the activation of the endothelin receptor B and the mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK)1/2, and protein (p)38. To protect from hyperpigmentation caused by VL, sunscreens containing iron oxides are efficient. The development of systemic antioxidants and new UV-VL sunscreens which allow absorption of the energy in the VL spectrum without reflection may provide further protection. With no existing organic or non-organic filters able to absorb or reflect IR, topical antioxidants may be able to provide some protection against damage caused by IR. However, their clinical efficacy still needs to be confirmed. In conclusion, UV, VL and IR light induce pigmentation. To prevent hyperpigmentation, protection using adequate sunscreens on exposed areas is needed. To date, no efficient protection from IR light exists, but topical antioxidants may be able to provide some protection. PMID- 28805938 TI - What is new in the pathophysiology of acne, an overview. AB - Acne is a chronic inflammatory disease of the pilosebaceous unit. Its pathophysiology includes hyperseborrhoea, abnormal follicular keratinization and Propionibacterium acnes proliferation in the pilosebaceous unit. Recent research has shed some new light on the involvement of the sebaceous gland, as well as on the pro-inflammatory activity of the cutaneous microbiome. During puberty, alteration of the sebaceous lipid profile, called dysseborrhoea, stress, irritation, cosmetics and potential dietary factors lead to inflammation and formation of different types of acne lesions. Dysbiosis, the process leading to a disturbed skin barrier and disequilibrium of the cutaneous microbiome, resulting in the proliferation of P. acnes strains, is another important process that triggers acne. P. acnes activates the innate immunity via the expression of protease activated receptors (PARs), tumour necrosis factor (TNF) alpha and toll like receptors (TLRs), and the production of interferon (INF) gamma, interleukins (IL-8, IL12, IL-1), TNF, and matrix metalloproteinases (MMPs) by keratinocytes, resulting in the hyperkeratinization of the pilosebaceous unit. Rebalancing the natural microbiome of the skin by restoring the natural skin barrier, limiting the proliferation of P. acnes on the skin by using topical antibacterials which do not cause resistance and regulating quantity and quality of sebum will be the main acne treatment challenges in the future. The aim of this article to provide an update on the involvement of the sebaceous gland, the innate immunity and the cutaneous microbiome, how all of these factors promote acne and to illustrate their links with current and future treatments. PMID- 28805936 TI - Characterizing hypoxia in human glioma: A simultaneous multimodal MRI and PET study. AB - Hypoxia plays an important role for the prognosis and therapy response of cancer. Thus, hypoxia imaging would be a valuable tool for pre-therapeutic assessment of tumor malignancy. However, there is no standard validated technique for clinical application available yet. Therefore, we performed a study in 12 patients with high-grade glioma, where we directly compared the two currently most promising techniques, namely the MR-based relative oxygen extraction fraction (MR-rOEF) and the PET hypoxia marker H-1-(3-[18 F]-fluoro-2-hydroxypropyl)-2-nitroimidazole ([18 F]-FMISO). MR-rOEF was determined from separate measurements of T2 , T2 * and relative cerebral blood volume (rCBV) employing a multi-parametric approach for quantification of the blood-oxygenation-level-dependent (BOLD) effect. With respect to [18 F]-FMISO-PET, besides the commonly used late uptake between 120 and 130 min ([18 F]-FMISO120-130 min ), we also analyzed the hypoxia specific uptake rate [18 F]-FMISO-k3 , as obtained by pharmacokinetic modeling of dynamic uptake data. Since pharmacokinetic modeling of partially acquired dynamic [18 F] FMISO data was sensitive to a low signal-to-noise-ratio, analysis was restricted to high-uptake tumor regions. Individual spatial analyses of deoxygenation and hypoxia-related parameter maps revealed that high MR-rOEF values clustered in (edematous) peritumoral tissue, while areas with high [18 F]-FMISO120-130 min concentrated in and around active tumor with disrupted blood-brain barrier, i.e. contrast enhancement in T1 -weighted MRI. Volume-of-interest-based correlations between MR-rOEF and [18 F]-FMISO120-130 min as well as [18 F]-FMISO-k3 , and voxel-wise analyses in individual patients, yielded limited correlations, supporting the notion that [18 F]-FMISO uptake, even after 2 h, might still be influenced by perfusion while [18 F]-FMISO-k3 was severely hampered by noise. According to these results, vascular deoxygenation, as measured by MR-rOEF, and severe tissue hypoxia, as measured by [18 F]-FMISO, show a poor spatial correspondence. Overall, the two methods appear to rather provide complementary than redundant information about high-grade glioma biology. PMID- 28805939 TI - Molecular and cellular discoveries in inflammatory dermatoses. AB - It was no earlier than 1986 that T helper (Th)1 and Th2 cells were described for the first time, opening the field of lymphocyte diversity and the investigation of the physiopathology of inflammatory diseases such as atopic dermatitis and psoriasis. Since that time, much research has been carried out showing a very complex communication network leading to inflammatory responses. Nowadays, understanding the cellular and molecular components of the inflammatory network and of the different crosstalks not only for groups of diseases but also for the individual patient is mandatory for developing and personalizing treatments. The aim of the present proceeding was to provide an update concerning some of the most recent molecular and cellular discoveries in inflammatory skin diseases and especially of AD. PMID- 28805940 TI - New and current preventive treatment options in actinic keratosis. AB - Actinic keratosis (AK) is a characteristic skin lesion on skin areas of subjects with mainly phototype I and phototype II, or with specific genetic factors and who are exposed to prolonged ultraviolet radiation. AK may be considered a precursor of in situ squamous cell carcinoma (SCC), a type of non-melanoma skin cancer (NMSC). However, it is still not possible to predict which AK lesions will develop into SCC. Early treatment of AK is therefore recommended. Despite the increasing number of patients with AK developing into SCC, to date, there is still no clear suggestion of therapeutic strategy for AK. Current treatment consists of a multitude of topical lesion-directed or field-directed therapies or a combination of both. Recently, orally administered nicotinamide has shown to significantly reduce rates of new NMSC and AK in high-risk patients. This study aims to provide an update on the most relevant information about AK and to provide an insight into current and new treatment options. PMID- 28805941 TI - Comment on myocutaneous gracilis free flaps for unilateral breast reconstruction. PMID- 28805942 TI - Maternal and neonatal outcomes following abnormally invasive placenta: a population-based record linkage study. AB - INTRODUCTION: Abnormally invasive placenta involves abnormal adherence of the placenta to the myometrium and is associated with severe pregnancy complications such as blood transfusion and hysterectomy. Knowledge of outcomes has been limited by small sample sizes and a focus on maternal rather than neonatal outcomes. This study uses population-level data collected over 10 years to investigate maternal and neonatal outcomes and trends in incidence of abnormally invasive placenta (also known as placenta accreta, increta and percreta). MATERIAL AND METHODS: A population-based record linkage study was performed, including all women who gave birth in New South Wales, Australia, between 2003 and 2012. Data were obtained from birth records, hospital admissions and deaths registrations. Modified Poisson regression models, adjusted for confounding factors, were used to quantify the effect of abnormally invasive placenta on adverse maternal and neonatal outcomes. RESULTS: Abnormally invasive placenta was significantly associated with morbidity for mothers (adjusted relative risk 17.6, 99% confidence interval 14.5-21.2) and infants (adjusted relative risk 3.1, 99% confidence interval 2.7-3.5). Abnormally invasive placenta increased risk of stillbirth (relative risk 5.4, 99% confidence interval 4.0-7.3) and neonatal death (relative risk 8.0, 99% confidence interval 1.5-41.6). The overall rate of abnormally invasive placenta was 24.8 per 10 000 deliveries, and 22.7 per 10 000 among primiparae. Incidence increased by 30%, from 20.6 to 26.9 per 10 000, over the 10-year study period. CONCLUSIONS: Abnormally invasive placenta substantially increases the risk of severe adverse outcomes for mothers and babies, and the incidence is increasing. Delivery should occur in tertiary hospitals equipped with neonatal intensive care units. Clinicians should be cognizant of the risks, particularly to infants, and maintain a high index of suspicion of abnormally invasive placenta, including in primiparae. PMID- 28805943 TI - Issue Information-Declaration of Helsinki. PMID- 28805945 TI - Abstracts of the 2017 World Congress of Psycho-Oncology, 14-18 August 2017, Berlin, Germany. PMID- 28805944 TI - Suppression of acute and anticipatory nausea by peripherally restricted fatty acid amide hydrolase inhibitor in animal models: role of PPARalpha and CB1 receptors. AB - BACKGROUND AND PURPOSE: Effective treatments of nausea are limited. In this study we evaluated the ability of the peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor, URB937, to suppress acute and anticipatory nausea in rats and examined the pharmacological mechanism of this effect. EXPERIMENTAL APPROACH: We investigated the potential of URB937 (administered i.p.) to reduce the establishment of lithium chloride-induced conditioned gaping (model of acute nausea) and to reduce the expression of contextually-elicited conditioned gaping (model of anticipatory nausea) in rats. The role of CB1 receptors, CB2 receptors and PPARalpha in the anti-nausea effect of URB937 was examined. The potential of URB937 to suppress FAAH activity in tissue collected from the area postrema (AP), prefrontal cortex (PFC), liver and duodenum and to elevate levels of FAAH substrates - anandamide (AEA), N-oleoylethanolamide (OEO) and N palmitoylethanolamide (PEA) - in the AP was also evaluated. KEY RESULTS: URB937 reduced acute nausea by a PPARalpha-dependent mechanism and reduced anticipatory nausea by a CB1 receptor-dependent mechanism. The PPARalpha agonist, GW7647, similarly attenuated acute nausea. URB937 reduced FAAH activity in the liver and the duodenum but not in the PFC. In addition, URB937 reduced FAAH activity and elevated levels of fatty-acid ethanolamides in the AP, a brain region that is not protected by the blood-brain barrier. CONCLUSIONS AND IMPLICATIONS: The anti nausea action of URB937 may occur in the AP and may involve PPARalpha to suppress acute nausea and CB1 receptors to suppress anticipatory nausea. PMID- 28805946 TI - Racial entanglements and sociological confusions: repudiating the rehabilitation of integration. AB - In line with the broader nationalist advances currently remaking the Western political landscape, the concept of integration has witnessed a marked rehabilitation. Whilst many influential critiques of the sociology of integration are already available, this article contests the concept's renewed purchase through addressing its own internal incoherence. Based on research in Stockholm, this critique concerns the relationship between ethnic identity and cultural integration. It will be argued that integration and the production of difference are intertwined, entangled dualities, and far from being a benign entanglement, this duality is premised on the force and reach of everyday civic racisms. Of pivotal and unique analytical significance here is the observation that racism should not only be considered an exogenous process that impedes integration, but as a multifaceted phenomenon folded into integration. PMID- 28805947 TI - Penile neurovascular structure revisited: immunohistochemical studies with three dimensional reconstruction. AB - Penile erection is a neurovascular phenomenon that requires well coordinated and functional interaction between penile vascular and nervous systems. In order to provide a useful tool to examine pathologic changes in the erectile tissue, mainly focusing on penile neurovascular dysfunction, we established the technique to determine the differential distribution of endothelial cells, smooth muscle cells, pericytes, and nerve fibers in the mouse penis using immunohistochemical staining with three-dimensional reconstruction. Immunofluorescent staining of penile tissue was performed with antibodies against CD31 (an endothelial cell marker), smooth muscle alpha -actin (SMA, a smooth muscle cell marker), NG2 (a pericyte marker), or betaIII-tubulin (a neuronal marker). We reconstructed three dimensional images of penile vascular or neurovascular system from stacks of two dimensional images, which allows volume rendering and provides reliable anatomic information. CD31-positive endothelial cells, SMA-positive smooth muscle cells, and NG2-positive pericytes were evenly distributed and composed sinusoidal or venous wall. However, the endothelial layer of the cavernous artery or dorsal artery was mainly covered with smooth muscle cells and rarely associated with pericytes. The reconstructed three-dimensional images clearly visualized typical wavy appearance of nerve fibers that evenly innervate to cavernous sinusoids, cavernous artery, dorsal vein, and dorsal artery. We observed a significant decrease in CD31-positive endothelial cells, NG2-positive pericytes, and betaIII tubulin-positive nerve fibers in the penis of diabetic mice compared with those in normal condition. Our protocol for immunofluorescent staining with three dimensional reconstruction will allow a better understanding of the penile neurovascular anatomy and may constitute a standard technique to determine the efficacy of candidate therapeutics targeting therapeutic angiogenesis or neural regeneration. PMID- 28805948 TI - Pathogenic role of ADGRG2 in CBAVD patients replicated in Chinese population. AB - Congenital bilateral absence of the vas deferens (CBAVD) is an important cause of obstructive azoospermia and male infertility worldwide. Cystic fibrosis transmembrane conductance regulator (CFTR) mutations are the main pathogenic cause, although a proportion of cases are still unexplained. Recently, adhesion G protein-coupled receptor G2 (ADGRG2) gene, a novel pathogenic gene for CBAVD was identified. We did a single population replication study in Chinese CBAVD patients to replicate its role in CBAVD developing. In this study, we performed whole-exome sequencing in 18 unrelated CBAVD patients and identified two missense variants in two patients (c.G1709A, p.C570Y; and c.A2968G, p.K990E). Both variants were predicted to be deleterious and highly conserved in silico. The p.C570Y variant is located in the G protein-coupled receptor (GPCR) proteolysis site domain, which is functionally necessary for autoproteolysis, while the p.K990E variant is in the N-terminal fragment that may regulate activity of the adhesion GPCR. We did not find any potential pathogenic CFTR variants, implying the ADGRG2 variants are the genetic cause in these patients. To the best of our knowledge, these are the first two ADGRG2 variants to be identified in Chinese CBAVD patients, which further validate the disease-causing role of ADGRG2 in this congenital defect. PMID- 28805949 TI - The reversible P2Y12 antagonist ACT-246475 causes significantly less blood loss than ticagrelor at equivalent antithrombotic efficacy in rat. AB - The P2Y12 receptor is a validated target for prevention of major adverse cardiovascular events in patients with acute coronary syndrome. The aim of this study was to compare two direct-acting, reversible P2Y12 antagonists, ACT-246475 and ticagrelor, in a rat thrombosis model by simultaneous quantification of their antithrombotic efficacy and surgery-induced blood loss. Blood flow velocity was assessed in the carotid artery after FeCl3 -induced thrombus formation using a Doppler flow probe. At the same time, blood loss after surgical wounding of the spleen was quantified. Continuous infusions of ACT-246475 and ticagrelor prevented the injury-induced reduction of blood flow in a dose-dependent manner. High doses of both antagonists normalized blood flow and completely abolished thrombus formation as confirmed by histology. Intermediate doses restored baseline blood flow to >=65%. However, ACT-246475 caused significantly less increase of blood loss than ticagrelor; the difference in blood loss was 2.6-fold (P < 0.01) at high doses and 2.7-fold (P < 0.05) at intermediate doses. Potential reasons for this unexpected difference were explored by measuring the effects of ACT-246475 and ticagrelor on vascular tone. At concentrations needed to achieve maximal antithrombotic efficacy, ticagrelor compared with ACT-246475 significantly increased carotid blood flow velocity in vivo (P = 0.003), induced vasorelaxation of precontracted rat femoral arteries, and inhibited contraction of femoral artery induced by electrical field stimulation or by phenylephrine. Overall, ACT-246475 showed a significantly wider therapeutic window than ticagrelor. The absence of vasodilatory effects due to high selectivity of ACT 246475 for P2Y12 provides potential arguments for the observed safety advantage of ACT-246475 over ticagrelor. PMID- 28805951 TI - Plant reproduction: Recent discoveries from China. PMID- 28805950 TI - Management of osteonecrosis of the femoral head with pedicled iliac bone flap transfer: A multicenter study of 2190 patients. AB - BACKGROUND: Osteonecrosis of the femoral head (ONFH) often affects young active adults and leads to destruction of the hip joint and disabling arthritis. Several procedures have been developed to arrest the progress of osteonecrosis and postpone the procedure of total hip replacement especially in young patients. The aim of this multicenter study was to analyze the results of the use of the vascularized iliac bone flap transfer for management of ONFH. METHODS: From January 1985 to December 2012, a total of 2190 patients (2690 hips) with the mean age of 43.15 years (ranging from 18 to 65 years) underwent hip-preserving surgery with the pedilced iliac bone flap transfer for management of ONFH with Ficat and Arlet stage II-IV in 8 hospitals. There were 1733 hips in stage II, 776 hips in stage III, and 181 hips in stage IV preoperatively. The complications were recorded. The outcomes were evaluated by radiograph, the Harris hip-scoring system (HHS). RESULTS: Postoperative complications occurred in 128 patients (5.84%). Among them, 25 patients had deep venous thromboses, 16 patients had sensory deficits, 40 patients had superficial infection and hematoma, and 47 patients had wound dehiscence. A total of 1912 patients (2179 hips) were followed up with a median time of 12 years (ranging from 5 to 25 years). There were 1787 hips with no radiographic osteonecrotic progress during follow-up, while osteonecrosis progress was observed in 186 hips with stage II (13.1%), 170 hips with stage III (25.6%) and 36 hips with stage IV (36.4%; P < .001). Two hundred fifteen hips (9.87%) in 203 patients were converted to THA during follow-up, including 19 hips with stage II (1.34%), 162 hips with stage III (24.4%), and 34 hips with stage IV (34.3%).The mean HHS at the end of follow-up was significantly improved when compared to preoperative mean HHS (83.63 +/- 5.03 vs. 66.54 +/- 6.05, P < .001). CONCLUSIONS: In this evaluation of a large series of cases, the vascularized iliac bone flap transfer showed good results for arresting the osteonecrosis progress and improving the hip function of patients with pre collapse stages of ONFH. PMID- 28805952 TI - Constituents from Scutellaria barbata Inhibiting Nitric Oxide Production in LPS Stimulated Microglial Cells. AB - The arial parts of Scutellaria barbata D. Don (Lamiaceae) efficiently inhibited NO production in BV2 microglial cells, and the active constituents were further isolated based on activity-guided isolation using silica-gel column chromatography, RP-C18 MPLC and prep-HPLC. As the results, 2 flavonoids including 6-methoxynaringenin (1) and 6-O-methylscutellarein (5), and 6 neo-clerodane diterpenes such as scutebarbatine W (2), scutebatas B (3), scutebarbatine B (4), scutebarbatine A (6), 6-O-nicotinolylscutebarbatine G (7), and scutebarbatine X (8) were isolated. The structures of these compounds were elucidated based on NMR and MS data, and the comparison of literature values. All the compounds except compound 7 inhibited NO production efficiently with IC50 values of lower than 50 MUm. Particularly, compounds 1 and 8 were the most efficient with IC50 values of 25.8 and 27.4 MUm, respectively. This is the first report suggesting the potential of S. barbata on the reduction of neuroinflammation. PMID- 28805954 TI - Impact of caregiver burden on mental health in bereaved caregivers of cancer patients: A systematic review. AB - OBJECTIVE: Although caregiver burden may continue to influence the mental health of cancer patients' caregivers long after bereavement, few studies have examined this issue. METHODS: A systematic review was conducted to provide a summary of (1) operationalizations of caregiver burden used in this field and (2) the effect of caregiver burden on postbereavement mental health of adult caregivers of cancer patients. A systematic search of the electronic databases PubMed, Web of Science, and PsycINFO was conducted across empirical studies published in a peer reviewed journal up until April 2017. RESULTS: Caregiver burden was rarely defined, and it was operationalized in multiple and diverging ways. The 20 included papers present varying results but generally indicate that caregiver burden (especially emotional) has an adverse effect on postbereavement mental health. CONCLUSIONS: In future studies, researchers seeking to ascertain which aspects of caregiver burden may prove an appropriate target for prevention and intervention should first use a precise operational definition of the concept. PMID- 28805953 TI - Factors associated with physical activity among adolescent and young adult survivors of early childhood cancer: A report from the childhood cancer survivor study (CCSS). AB - OBJECTIVE: To evaluate concurrent and longitudinal associations between psychosocial functioning and physical activity in adolescent and young adult survivors of early childhood cancer. METHODS: Adolescent survivors of early childhood cancer (diagnosed before age four) participating in the Childhood Cancer Survivor Study completed the Coping Health and Illness Profile-Adolescent Edition (CHIP-AE; n = 303; mean age at survey: 17.6 years). A subset of these survivors (n = 248) completed a follow-up survey an average of 6.0 years later (range: 4-10). Logistic regression identified associations between psychosocial functioning in adolescence and physical activity levels in adolescence and young adulthood. RESULTS: Survivors reported low physical activity as adolescents (46.1% scored below CHIP-AE cut-point) and young adults (40.8% below Centers for Disease Control guidelines). Poor physical activity during adolescence was associated with female sex (OR = 2.06, 95% CI, 1.18-3.68), parents with less than a college education (OR = 1.91, 95% CI, 1.11-3.32), previous treatment with cranial radiation (OR = 3.35, 95% CI, 1.69-6.88), TV time (OR = 1.77, 95% CI, 1.00-3.14), and limitations of activity due to health or mobility restrictions (OR = 8.28, 95% CI, 2.87-30.34). Poor diet (OR = 1.84, 95% CI, 1.05-3.26) and low self-esteem (OR = 1.80, 95% CI, 0.99-3.31) during adolescence were associated with lower odds of meeting Centers for Disease Control physical activity guidelines in young adulthood. CONCLUSION: These findings provide targets for future interventional studies to improve physical activity in this high-risk population. PMID- 28805955 TI - Structural Modification of Stilbenoids from Acanthopanax leucorrhizus and Their Cytotoxic Activity. AB - A new cis-stilbenoid, 1,9-dihydroxy-10-methoxy-6H-dibenzo[b,f]oxocin-6-one (2) was isolated from the AcOEt extract of the stem barks of Acanthopanax leucorrhizus, along with three known stilbenoids, 9-hydroxy-10-methoxy-6H dibenzo[b,f]oxocin-6-one (1), 5-O-methyl-(E)-resveratrol 3-O-beta-d glucopyranoside (3), and (E)-resveratrol 3-O-beta-d-xylopyranoside (4). Two derivatives (2a and 2b) were synthesized by the structural modification of compound 2, which exhibited certain cytotoxic activities against HT-29 and HeLa cell lines in vitro. All compounds were structurally characterized by comprehensive analysis of their spectroscopic data and comparison with literature information, and evaluated for their cytotoxic activities against three human tumor cell lines (HL-60, HT-29, and HeLa) by the standard MTT assay in vitro. The results showed that derivatives 2a and 2b exhibited strong activities than compounds 2 against HT-29 and HeLa cell lines. PMID- 28805956 TI - Morphology and Postnatal Development of Lower Hindlimbs in Desmodus rotundus (Chiroptera: Phyllostomidae): A Comparative Study. AB - The hindlimbs in bats are functionally adapted to serve as a hook to attach to the mother from birth, and to roost during independent life. Although bats exhibit different terrestrial locomotion capabilities involving hindlimbs, hindlimb morphology and postnatal development have been poorly studied. We describe in detail the postnatal development and bone morphology of hindlimbs of the nimble walker vampire bat, Desmodus rotundus, and compare adult characters with the insectivorous Molossus molossus (erratic walker) and the frugivorous Artibeus lituratus (non-walker). The advanced ossification of most hindlimb elements of D. rotundus at the newborn stage is consistent with the functional role of this structure at birth in bats. The development completion events of hindlimb bone elements and bone processes in D. rotundus coincide with the cranial bone processes completion and suture closure events. Those events occur when individuals begin to feed by themselves. There are differences in the number and position of bone processes and sesamoids in adults among the compared species, most of which are described for the first time, and in the case of D. rotundus and M. molossus mostly related to a greater and tight articulation between elements. These facts seem to be closely associated with the different terrestrial locomotion capabilities, and in the case of the exclusively sanguivorous D. rotundus with specializations for obtaining food. Anat Rec, 300:2150-2165, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28805957 TI - Stroke or left atrial thrombus prediction using antithrombin III and mean platelet volume in patients with nonvalvular atrial fibrillation. AB - BACKGROUND: CHADS2 (congestive heart failure, hypertension, age >= 75 years, diabetes mellitus, stroke) and CHA2 DS2 -VASc (congestive heart failure, hypertension, age >= 75 years, diabetes mellitus, stroke, vascular disease, age 65 to 74 years, sex category) scores showed just moderate discrimination ability in predicting thromboembolic complications in patients with nonvalvular atrial fibrillation (AF). HYPOTHESIS: To determine the association of antithrombin III (AT-III) deficiency and mean platelet volume (MPV) with the development of stroke or left atrial (LA) thrombus in patients with AF. METHODS: AT-III and MPV were analyzed in 352 patients with AF. The primary endpoint was a composite of ischemic stroke event and incidental LA thrombus. RESULTS: There were 50 events (14.2%) during a mean 35.4 months of follow-up. A significantly higher stroke or LA thrombus rate was observed in the low-AT-III group (<70%) than that in the high-AT-III group (>=70%). A significantly higher stroke or LA thrombus rate was observed in the high-MPV group (>=7.0 fL) than that in the low-MPV group (<7.0 fL). AF patients with an MPV >=7.0 fL and AT-III deficiency had higher stroke or LA thrombus risk than those without an MPV >=7.0 fL and AT-III deficiency. In the Cox proportional hazard analysis, high MPV was found to be an independent predictor of stroke or LA thrombus risk (hazard ratio: 6.408; 95% confidence interval: 2.874-14.286). Although AT-III deficiency was not an independent predictor of stroke or LA thrombus risk, a trend was observed. CONCLUSIONS: High MPV and AT-III deficiency were predictive markers for stroke or LA thrombus. Their predictive power for stroke was independent of antiplatelet treatment, anticoagulation therapy, and a high CHA2 DS2 -VASc score in patients with AF. PMID- 28805958 TI - Large orbital defect reconstruction in the setting of globe-sparing maxillectomy: The titanium hammock and layered fibula technique. AB - INTRODUCTION: The purpose of our study was to describe a novel technique for reconstruction of orbital defects after maxillectomy using a non-anatomic titanium mesh suspension of orbital contents for both support and volume correction. This construct is then articulated with a layered fibula osteocutaneous free flap that restores orbital rim, zygoma, and maxillary alveolus. We herein present our application of this technique, including refinements over time and long-term outcomes. METHODS: A retrospective review was performed on 12 patients who underwent reconstruction of Brown class III orbitopalatomaxillary defects with extensive orbital involvement (at minimum complete orbital floor and rim absent) with titanium mesh sling and a layered fibula free flap. RESULTS: Primary reconstruction was accomplished in all 12 patients. The mean postoperative length of stay was 8 days (6-14 days). There were no free flap failures or perioperative re-explorations. Patients were routinely extubated on postoperative day #1 and began oral intake by postoperative day #3. At a mean follow-up length of 48 months, unrestricted eye function was accomplished in all patients. Midfacial symmetry was accomplished in 10 of 12 patients; 2 patients had moderate asymmetry due to extirpation of facial musculature and/or soft tissue. Minor revisions were necessary for lower lid ectropion and exposure of the titanium plate. Two patients required adipofascial free flap coverage of exposed intraoral bone after radiation therapy. CONCLUSIONS: This technique provides excellent restoration of eye position and function and also allows for implant-based prosthetic rehabilitation. It has become our procedure of choice for orbitomaxillary reconstruction. PMID- 28805959 TI - Fire ecology of a tree glacial refugium on a nunatak with a view on Alpine glaciers. AB - In paleoecology, the function of biomass as a fire driver has become a focus of attention in cold ecosystems, and concerns have been raised about climate in this context. Little is known about the fire frequency and fire-plant relationships during glaciation when woodlands were limited and the climate was cold. Fire history and tree biomass were reconstructed from sedimentary charcoal and macroremains, respectively, archived in lake sediments from the western Alps. Two nunataks were investigated, both with lacustrine sediments covering the last 21 000 yr at least. During the Last Glacial Maximum (LGM) and the Lateglacial, fires occurred only on the nunatak sheltering woody plants. Cembra pine (Pinus cembra) and larch (Larix decidua) survived above glaciers during the LGM, thus evidencing a biological refugium and supporting the nunatak theory. We highlighted a long term relationship between fires and dominant trees over the last 21 000 yr, where fire frequencies track the global climate and the local changes in tree biomass. Glacial climate (dry, cold) does not rule out fires. Fuel load and composition were significant fire drivers, with cembra pine dominating during colder periods with rare fires, and larch during the warmer Holocene with frequent fires. These findings increase knowledge of fire ecology in cold environments, and open perspectives in tree population genetics by considering new areas of tree glacial refugia in Europe. PMID- 28805960 TI - Factors associated with high pain intensity during wound care procedures: A model. AB - The most common wound care procedures (WPCs) performed on open wounds are dressing changes and wound cleansing. Dressing changes cause moderate to severe pain in 74% of patients, nearly half (36%) of whom experience severe pain (rated as 8-10 on a 10-point numeric rating scale). The purpose of this paper is to propose a model of clinically accessible factors that can be tested in order to develop a clinical tool to identify which patients are likely to experience high intensity pain during nonoperative WCPs, such as dressing changes. Although multiple factors are known to be associated with pain, the factors selected for this model were limited to those that (1) are supported based on evidence and/or pain mechanisms and (2) are readily accessible to clinicians/practitioners and can be tested as a prediction tool to be used prior to WCPs. This model may be helpful to identify those likely to experience high intensity pain during WCPs. In this way, use of aggressive pain management strategies, including specialty dressings, pharmacologic analgesics, and/or non-pharmacological strategies, such as high intensity transcutaneous electrical stimulation. PMID- 28805961 TI - Reducing Branded Prescription Drug Prices: A Review of Policy Options. AB - The high prices of specialty pharmaceuticals are causing some public programs to ration care and many private insurers, including Medicare drug plans, to place specialty drugs on high cost-sharing tiers. As a result, access to these drugs is often restricted, and only a small portion of the population with a disease may receive treatment. This concern has generated a wide range of proposed solutions. We conducted a literature review and identified 52 solutions in the peer-reviewed literature that we classified into five broad categories: revising the patent system, encouraging research to increase development of new drugs, altering pharmaceutical regulation, decreasing market demand, and developing innovative pricing strategies. We discuss the rationale for these five approaches and summarize the proposed solutions. We also discuss four empirical issues that are particularly important in any discussion of policy options. PMID- 28805962 TI - Medicago truncatula Molybdate Transporter type 1 (MtMOT1.3) is a plasma membrane molybdenum transporter required for nitrogenase activity in root nodules under molybdenum deficiency. AB - Molybdenum, as a component of the iron-molybdenum cofactor of nitrogenase, is essential for symbiotic nitrogen fixation. This nutrient has to be provided by the host plant through molybdate transporters. Members of the molybdate transporter family Molybdate Transporter type 1 (MOT1) were identified in the model legume Medicago truncatula and their expression in nodules was determined. Yeast toxicity assays, confocal microscopy, and phenotypical characterization of a Transposable Element from Nicotiana tabacum (Tnt1) insertional mutant line were carried out in the one M. truncatula MOT1 family member specifically expressed in nodules. Among the five MOT1 members present in the M. truncatula genome, MtMOT1.3 is the only one uniquely expressed in nodules. MtMOT1.3 shows molybdate transport capabilities when expressed in yeast. Immunolocalization studies revealed that MtMOT1.3 is located in the plasma membrane of nodule cells. A mot1.3-1 knockout mutant showed impaired growth concomitant with a reduction of nitrogenase activity. This phenotype was rescued by increasing molybdate concentrations in the nutritive solution, or upon addition of an assimilable nitrogen source. Furthermore, mot1.3-1 plants transformed with a functional copy of MtMOT1.3 showed a wild-type-like phenotype. These data are consistent with a model in which MtMOT1.3 is responsible for introducing molybdate into nodule cells, which is later used to synthesize functional nitrogenase. PMID- 28805963 TI - Recent advances in amino acid analysis by capillary electromigration methods: June 2015-May 2017. AB - In the tenth edition of this article focused on recent advances in amino acid analysis using capillary electrophoresis, we describe the most important research articles published on this topic during the period from June 2015 to May 2017. This article follows the format of the previous articles published in Electrophoresis. The new developments in amino acid analysis with CE mainly describe improvements in CE associated with mass spectrometry. Focusing on applications, we mostly describe clinical works, although metabolomics studies are also very important. Finally, works focusing on amino acids in food and agricultural applications are also described. PMID- 28805964 TI - Therapeutic drug monitoring of voriconazole for treatment and prophylaxis of invasive fungal infection in children. AB - Voriconazole therapeutic drug monitoring is not consistently recommended due to its high interpatient and intrapatient variability. Here, we aimed to describe our experience with voriconazole for treatment and prophylaxis of invasive fungal infections in paediatric patients. A fully validated high-performance liquid chromatography-mass spectrometry method was used to quantify voriconazole concentration in plasma, at the end of dosing interval. A high interindividual variability was shown. We enrolled 237 children, 83 receiving intravenous and 154 oral voriconazole. A positive correlation between drug dose and drug plasma exposure was observed. Considering intravenous route, patients with higher serum creatinine had higher voriconazole concentrations; a positive correlation was found among drug exposure and age. Sex significantly influenced drug levels: males had higher median drug concentrations than females (P < 0.001). Close voriconazole pharmacokinetics monitoring should help individualize antifungal therapy for children. PMID- 28805966 TI - Phyllodes tumour of the urinary bladder: a report of a unique case. PMID- 28805965 TI - The interplay of climate and land use change affects the distribution of EU bumblebees. AB - Bumblebees in Europe have been in steady decline since the 1900s. This decline is expected to continue with climate change as the main driver. However, at the local scale, land use and land cover (LULC) change strongly affects the occurrence of bumblebees. At present, LULC change is rarely included in models of future distributions of species. This study's objective is to compare the roles of dynamic LULC change and climate change on the projected distribution patterns of 48 European bumblebee species for three change scenarios until 2100 at the scales of Europe, and Belgium, Netherlands and Luxembourg (BENELUX). We compared three types of models: (1) only climate covariates, (2) climate and static LULC covariates and (3) climate and dynamic LULC covariates. The climate and LULC change scenarios used in the models include, extreme growth applied strategy (GRAS), business as might be usual and sustainable European development goals. We analysed model performance, range gain/loss and the shift in range limits for all bumblebees. Overall, model performance improved with the introduction of LULC covariates. Dynamic models projected less range loss and gain than climate-only projections, and greater range loss and gain than static models. Overall, there is considerable variation in species responses and effects were most pronounced at the BENELUX scale. The majority of species were predicted to lose considerable range, particularly under the extreme growth scenario (GRAS; overall mean: 64% +/ 34). Model simulations project a number of local extinctions and considerable range loss at the BENELUX scale (overall mean: 56% +/- 39). Therefore, we recommend species-specific modelling to understand how LULC and climate interact in future modelling. The efficacy of dynamic LULC change should improve with higher thematic and spatial resolution. Nevertheless, current broad scale representations of change in major land use classes impact modelled future distribution patterns. PMID- 28805967 TI - Prognostic value of exercise capacity among men undergoing pharmacologic treatment for erectile dysfunction: The FIT Project. AB - BACKGROUND: Vascular erectile dysfunction (ED) has been identified as a potentially useful risk factor for predicting future cardiovascular events, particularly in younger men. Because these men typically score more favorably on traditional cardiovascular disease risk assessment tools, there exists a gap in knowledge for how to most appropriately identify those men who would benefit from more aggressive treatments. To date, no studies have examined the impact of fitness on cardiovascular outcomes in men with ED. This study sought to examine the prognostic impact of maximal exercise capacity on cardiovascular-related outcomes in men ages 40 to 60 years being treated for ED. HYPOTHESIS: We hypothesized that there would be an independent association between higher baseline fitness level and lower cardiovascular events. METHODS: We analyzed 1152 men with pharmacy claims file-confirmed active pharmacologic treatment for ED from the Henry Ford Exercise Testing (FIT) Project (1991-2009). All patients were free of coronary heart disease and heart failure, and underwent clinician referred exercise stress testing, with fitness measured in metabolic equivalents of task (METs). Multivariable Cox proportional hazard models adjusted for traditional cardiovascular risk factors were used to study the association between fitness and all-cause mortality, major adverse cardiovascular events (MACE) (defined as myocardial infarction or revascularization), and incident type 2 diabetes mellitus. RESULTS: The mean age of the population was 53 years, with 39% African Americans. In multivariable analysis, each 1 MET of fitness was associated with a 16% lower risk of death (hazard ratio [HR]: 0.84, 95% confidence interval [CI]: 0.76-0.94, P = 0.002), and a nonsignificant reduction in MACE (HR: 0.89, 95% CI: 0.79-1.003, P = 0.048), and incident diabetes (HR: 0.92, 95% CI: 0.85-1.01, P = 0.129). CONCLUSIONS: Higher baseline fitness is associated with improved cardiovascular prognosis in a population of middle-aged men treated for ED. PMID- 28805968 TI - Protein turnover in the failing heart: an ever-changing landscape. PMID- 28805969 TI - Study of young patients with myocardial infarction: Design and rationale of the YOUNG-MI Registry. AB - The YOUNG-MI registry is a retrospective study examining a cohort of young adults age <= 50 years with a first-time myocardial infarction. The study will use the robust electronic health records of 2 large academic medical centers, as well as detailed chart review of all patients, to generate high-quality longitudinal data regarding the clinical characteristics, management, and outcomes of patients who experience a myocardial infarction at a young age. Our findings will provide important insights regarding prevention, risk stratification, treatment, and outcomes of cardiovascular disease in this understudied population, as well as identify disparities which, if addressed, can lead to further improvement in patient outcomes. PMID- 28805970 TI - A novel free fatty acid receptor 1 (GPR40/FFAR1) agonist, MR1704, enhances glucose-dependent insulin secretion and improves glucose homeostasis in rats. AB - Activation of G protein-coupled receptor 40/Free fatty acid receptor 1 (GPR40/FFAR1), which is highly expressed in pancreatic beta cells, is considered an important pharmacologic target for the treatment of type 2 diabetes mellitus. The aim of this study was to determine the effect of MR1704, a novel GPR40/FFAR1 agonist, on glucose homeostasis in rats. MR1704 is a highly potent and selective, orally bioavailable agonist with similar in vitro potencies among humans, mice, and rats. Treatment of rat islets with MR1704 increased glucose-dependent insulin secretion. Augmentation of glucose-dependent insulin secretion was abolished by adding a GPR40/FFAR1 antagonist. In mouse, insulinoma MIN6 cells, palmitic acid induced the activity of caspase 3/7 after a 72-h exposure, while pharmacologically active concentrations of MR1704 did not. In an oral glucose tolerance test in normal Sprague-Dawley rats, orally administered MR1704 (1-10 mg.kg-1 ) reduced plasma glucose excursion and enhanced insulin secretion, but MR1704 did not induce hypoglycemia, even at 300 mg.kg-1 , in fasted Sprague Dawley rats. In addition, orally administered MR1704 reduced plasma glucose excursion and enhanced insulin secretion in diabetic Goto-Kakizaki rats. Oral administration of MR1704 once daily to Goto-Kakizaki rats reduced their blood glucose levels during a 5-week treatment period without reducing pancreatic insulin content; as a result, hemoglobin A1C levels significantly decreased. These results suggest that MR1704 improves glucose homeostasis through glucose dependent insulin secretion with a low risk of hypoglycemia and pancreatic toxicity. MR1704 shows promise as a new, glucose-lowering drug to treat type 2 diabetes mellitus. PMID- 28805971 TI - Anticonvulsive evaluation of THIP in the murine pentylenetetrazole kindling model: lack of anticonvulsive effect of THIP despite functional delta-subunit containing GABAA receptors in dentate gyrus granule cells. AB - THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) is a GABAA receptor agonist with varying potencies and efficacies at gamma-subunit-containing receptors. More importantly, THIP acts as a selective superagonist at delta-subunit-containing receptors (delta-GABAA Rs) at clinically relevant concentrations. Evaluation of THIP as a potential anticonvulsant has given contradictory results in different animal models and for this reason, we reevaluated the anticonvulsive properties of THIP in the murine pentylenetetrazole (PTZ) kindling model. As loss of delta GABAA R in the dentate gyrus has been associated with several animal models of epilepsy, we first investigated the presence of functional delta-GABAA receptors. Both immunohistochemistry and Western blot data demonstrated that delta-GABAA R expression is not only present in the dentate gyrus, but also the expression level was enhanced in the early phase after PTZ kindling. Whole-cell patch-clamp studies in acute hippocampal brain slices revealed that THIP was indeed able to induce a tonic inhibition in dentate gyrus granule cells. However, THIP induced a tonic current of similar magnitude in the PTZ-kindled mice compared to saline treated animals despite the observed upregulation of delta-GABAA Rs. Even in the demonstrated presence of functional delta-GABAA Rs, THIP (0.5-4 mg/kg) showed no anticonvulsive effect in the PTZ kindling model using a comprehensive in vivo evaluation of the anticonvulsive properties. PMID- 28805972 TI - In vitro pharmacological characterization of a novel unbiased NOP receptor selective nonpeptide agonist AT-403. AB - Nociceptin/orphanin FQ (N/OFQ) regulates several biological functions via selective activation of the N/OFQ receptor (NOP), a member of the opioid receptor family. We recently identified a new high affinity and highly selective NOP agonist AT-403. In this study, we characterized the functional profile of AT-403 and compared it to other known nonpeptide NOP agonists Ro 65-6570, Ro 2q, SCH 221510, MCOPPB, AT-202 and SCH-486757, using the following assays: GTPgamma[35 S] stimulated binding, calcium mobilization assay in cells-expressing human NOP or classical opioid receptors and chimeric G proteins, bioluminescence resonance energy transfer (BRET) based assay for studying NOP receptor interaction with G protein and arrestin, and the electrically stimulated mouse vas deferens bioassay. All compounds behaved as NOP full agonists consistently showing the following rank order of potency MCOPPB > AT-403 > Ro 65-6570 = Ro 2q > SCH-221510 > AT-202 > SCH-486757. AT-403 and MCOPPB displayed the highest NOP selectivity both at human and murine receptors. Interestingly, while all the other nonpeptide NOP agonists displayed bias toward G protein-mediated signaling in the BRET assay, AT-403, similar to the natural ligand N/OFQ, behaved as an unbiased agonist, activating G-protein-mediated function as well as arrestin recruitment. AT-403 may be a useful nonpeptide tool compound to study the pharmacology of NOP activation in disease states. PMID- 28805973 TI - Experimental and clinical evidence of differential effects of magnesium sulfate on neuroprotection and angiogenesis in the fetal brain. AB - Clinical studies showed beneficial effects of magnesium sulfate regarding the risk of cerebral palsy. However, regimen protocols fluctuate worldwide and risks of adverse effects impacting the vascular system have been reported for human neonates, keeping open the question of the optimal dosing. Using clinically relevant concentrations and doses of magnesium sulfate, experiments consisted of characterizing, respectively, ex vivo and in vivo, the effects of magnesium sulfate on the nervous and vascular systems of mouse neonates by targeting neuroprotection, angiogenesis, and hemodynamic factors and in measuring, in human fetuses, the impact of a 4-g neuroprotective loading dose of magnesium sulfate on brain hemodynamic parameters. Preclinical experiments using cultured cortical slices from mouse neonates showed that the lowest and highest tested concentrations of magnesium sulfate were equally potent to prevent excitotoxic induced cell death, cell edema, cell burst, and intracellular calcium increase, whereas no side effects were found regarding apoptosis. In contrast, in vivo data revealed that magnesium sulfate exerted dose-dependent vascular effects on the fetal brain. In particular, it induced brain hypoperfusion, stabilization of Hif 1alpha, long-term upregulation of VEGF-R2 expression, impaired endothelial viability, and altered cortical angiogenesis. Clinically, in contrast to 6-g loading doses used in some protocols, a 4-g bolus of magnesium sulfate did not altered fetal brain hemodynamic parameters. In conclusion, these data provide the first mechanistic evidence of double-sword and dose-dependent actions of magnesium sulfate on nervous and vascular systems. They strongly support the clinical use of neuroprotection protocols validated for the lowest (4-g) loading dose of magnesium sulfate. PMID- 28805974 TI - Effect of single-nucleotide polymorphisms in ADH1B, ADH4, ADH1C, OPRM1, DRD2, BDNF, and ALDH2 genes on alcohol dependence in a Caucasian population. AB - Alcohol is a frequently used addictive substance worldwide. Aim of this study is to determine the frequency distribution of SNPs within ADH1B, ADH4, ADH1C, ALDH2, BDNF, OPRM1, and DRD2 genes in a southeastern European Caucasian population from Greece. For this purpose samples of 1276 volunteers were analyzed after deidentification and anonymization. The allele distribution of the examined polymorphisms in the present Greek population cohort was as follows: rs1229984 (ADH1B): GG(wt) = 64.14%, GA = 29.86%, AA = 4.00%; rs1693482 (ADH1C): CC(wt) = 57.45%, CT = 36.76%, TT = 5.80%; rs1799971 (OPRM1): AA(wt) = 72.43%, AG = 28.72%, GG = 1.89%; rs1800497 (DRD2): CC(wt) = 70.84%, CT = 27.18%, TT = 1.98%; rs1800759 (ADH4): CC(wt) = 34.25%, CA = 48.12%, AA = 17.63%; rs6265 (BDNF): GG(wt) = 65.99%, GA = 31.02%, AA = 2.99%; and rs671 (ALDH2): GG(wt) = 99.84% GA = 0.16%, AA = 0.00%. Mutant rs1229984 allele A was ~6.5* more frequent in the Greek than in the European population. Mutant rs1693482 allele T was ~1.7* more frequent in the European than in the Greek population. Mutant alleles for polymorphisms rs1800759 and rs1799971 show similar frequencies in both northern and southern Europeans. One rs671 mutant A allele was detected in the Greek population (0.08%). The mutant rs1800497 allele T was ~1.2* more frequent in the European than in the Greek population and the mutant rs6265 allele A was ~1.1* more frequent in the European than in the Greek population. An alcohol addiction specific algorithm was generated (TGS) that may predict alcohol addiction prevalence in a population. According to our findings, the analyzed Southeastern population may differ genetically from north Europeans due to influences from neighboring Asian and African populations and a calculated TGS score >50 indicates individuals with low susceptibility to develop alcohol addiction. PMID- 28805975 TI - Antofine suppresses endotoxin-induced inflammation and metabolic disorder via AMP activated protein kinase. AB - The inhibition of activated macrophages has been used to develop anti inflammatory agents for therapeutic intervention to human diseases that cause excessive inflammatory responses. Antofine, a phenanthroindolizidine alkaloid, has a potent anti-inflammatory effect. However, the molecular mechanisms of its anti-inflammatory activity have not yet been fully detailed. In this study, we comprehensively explored the anti-inflammatory effects of antofine on endotoxin induced inflammation in macrophages using cDNA microarray analysis, thereby elucidating the potential mechanism by which antofine suppresses inflammation. Antofine significantly suppressed the secretion of proinflammatory cytokines such as TNFalpha and IL-1beta and the production of iNOS in LPS-activated Raw264.7 macrophage cells. In addition, antofine can suppress the expressions of several inflammation-related genes (such as ARG-1, IL1F9, IL-10, and IL-33) and extracellular matrix genes (such as TNC and HYAL1), as well as a vasopressor gene (EDN1) in activated macrophage cells, that are induced by LPS stimulation. The gene expression profiles analyzed by GeneMANIA software showed that antofine not only contributed anti-inflammatory activity but also modulated the cellular metabolism via AMPK. Furthermore, antofine also modulated the activation of AMPK and caspase-1, the key regulator in inflammasome-mediated IL-1beta maturation, in activated macrophage cells. In conclusion, these data indicated that antofine potentially can not only contribute an anti-inflammatory effect but can also attenuate the metabolic disorders induced by inflammation via AMPK. PMID- 28805976 TI - Ethics of animal research in human disease remediation, its institutional teaching; and alternatives to animal experimentation. AB - Animals have been used in research and teaching for a long time. However, clear ethical guidelines and pertinent legislation were instated only in the past few decades, even in developed countries with Judeo-Christian ethical roots. We compactly cover the basics of animal research ethics, ethical reviewing and compliance guidelines for animal experimentation across the developed world, "our" fundamentals of institutional animal research ethics teaching, and emerging alternatives to animal research. This treatise was meticulously constructed for scientists interested/involved in animal research. Herein, we discuss key animal ethics principles - Replacement/Reduction/Refinement. Despite similar undergirding principles across developed countries, ethical reviewing and compliance guidelines for animal experimentation vary. The chronology and evolution of mandatory institutional ethical reviewing of animal experimentation (in its pioneering nations) are summarised. This is followed by a concise rendition of the fundamentals of teaching animal research ethics in institutions. With the advent of newer methodologies in human cell-culturing, novel/emerging methods aim to minimise, if not avoid the usage of animals in experimentation. Relevant to this, we discuss key extant/emerging alternatives to animal use in research; including organs on chips, human-derived three-dimensional tissue models, human blood derivates, microdosing, and computer modelling of various hues. PMID- 28805977 TI - Prevention against renal damage in rats with subtotal nephrectomy by sacubitril/valsartan (LCZ696), a dual-acting angiotensin receptor-neprilysin inhibitor. AB - Although patients with chronic kidney disease (CKD) are at increased risk for end stage renal disease and cardiovascular events, adequate drug therapies for preventing the deterioration of these conditions are still not established. This study was undertaken to evaluate a preventive effect of an angiotensin receptor neprilysin inhibitor sacubitril/valsartan (LCZ696), which is converted to sacubitril and valsartan in the body, against the progression of renal disease in rats with subtotal nephrectomy, an animal model of human CKD. Mean survival time after subtotal nephrectomy was about 100 days in Wistar rats with vehicle. LCZ696 (30 mg/kg) and valsartan-(15 mg/kg) prolonged the survival of these animals, and the effect of LCZ696 on survival was significantly greater than that of valsartan. Renoprotective effects of LCZ696 judged by serum creatinine and urinary protein excretions were larger than those of valsartan. Cardioprotective effects judged by cardiac left ventricular mass, fractional shortening, and fibrosis of LCZ696 and valsartan were not detected under the present condition. Thus, the renoprotective effect of LCZ696 was stronger than that of valsartan in rats with subtotal nephrectomy. This study provides the idea that, compared to valsartan, LCZ696 is more effective for the treatment of human CKD. PMID- 28805978 TI - Obeticholic acid, a selective farnesoid X receptor agonist, regulates bile acid homeostasis in sandwich-cultured human hepatocytes. AB - Farnesoid X receptor (FXR) is a master regulator of bile acid homeostasis through transcriptional regulation of genes involved in bile acid synthesis and cellular membrane transport. Impairment of bile acid efflux due to cholangiopathies results in chronic cholestasis leading to abnormal elevation of intrahepatic and systemic bile acid levels. Obeticholic acid (OCA) is a potent and selective FXR agonist that is 100-fold more potent than the endogenous ligand chenodeoxycholic acid (CDCA). The effects of OCA on genes involved in bile acid homeostasis were investigated using sandwich-cultured human hepatocytes. Gene expression was determined by measuring mRNA levels. OCA dose-dependently increased fibroblast growth factor-19 (FGF-19) and small heterodimer partner (SHP) which, in turn, suppress mRNA levels of cholesterol 7-alpha-hydroxylase (CYP7A1), the rate limiting enzyme for de novo synthesis of bile acids. Consistent with CYP7A1 suppression, total bile acid content was decreased by OCA (1 MUmol/L) to 42.7 +/- 20.5% relative to control. In addition to suppressing de novo bile acids synthesis, OCA significantly increased the mRNA levels of transporters involved in bile acid homeostasis. The bile salt excretory pump (BSEP), a canalicular efflux transporter, increased by 6.4 +/- 0.8-fold, and the basolateral efflux heterodimer transporters, organic solute transporter alpha (OSTalpha ) and OSTbeta increased by 6.4 +/- 0.2-fold and 42.9 +/- 7.9-fold, respectively. The upregulation of BSEP and OSTalpha and OSTbeta, by OCA reduced the intracellular concentrations of d8 -TCA, a model bile acid, to 39.6 +/- 8.9% relative to control. These data demonstrate that OCA does suppress bile acid synthesis and reduce hepatocellular bile acid levels, supporting the use of OCA to treat bile acid-induced toxicity observed in cholestatic diseases. PMID- 28805979 TI - Effects of mTOR inhibition on cardiac and adipose tissue pathology and glucose metabolism in rats with metabolic syndrome. AB - The mammalian target of rapamycin (mTOR) is a regulator of metabolism and is implicated in pathological conditions such as obesity and diabetes. We aimed to investigate the role of mTOR in obesity. A new animal model of metabolic syndrome (MetS), named DahlS.Z-Leprfa /Leprfa (DS/obese) rats was established previously in our laboratory. In this study, we used this model to evaluate the effects of mTOR inhibition on cardiac and adipose tissue pathology and glucose metabolism. DS/obese rats were treated with the mTOR inhibitor, everolimus, (0.83 mg/kg per day, per os) for 4 weeks at 9 weeks of age. Age-matched homozygous lean (DahlS.Z Lepr+ /Lepr+ or DS/lean) littermates of DS/obese rats were used as controls. Treatment with everolimus ameliorated hypertension, left ventricular (LV) hypertrophy and fibrosis, and LV diastolic dysfunction, and attenuated cardiac oxidative stress and inflammation in DS/obese rats, but had no effect on these parameters in DS/lean rats. Treatment with everolimus reduced Akt Thr308 phosphorylation in the heart of DS/obese rats. It also alleviated obesity, hyperphagia, adipocyte hypertrophy, and adipose tissue inflammation in DS/obese rats. Everolimus treatment exacerbated glucose intolerance, but did not affect Akt phosphorylation levels in the fat or liver in these rats. Pancreatic beta cell mass was increased in DS/obese rats compared with that in DS/lean rats and this effect was attenuated by everolimus. Activation of mTOR signaling contributes to the pathophysiology of MetS and its associated complications. And mTOR inhibition with everolimus ameliorated obesity as well as cardiac and adipose tissue pathology, but exacerbated glucose metabolism in rats with MetS. PMID- 28805980 TI - An environmental pollutant, 9,10-phenanthrenequinone, activates human TRPA1 via critical cysteines 621 and 665. AB - Transient receptor potential ankyrin 1 (TRPA1) is activated by noxious cold, mechanical stimulation, and irritant chemicals. In our recent study, 9, 10 phenanthrenequinone (9,10-PQ) is the most potent irritant for activation of NRF2 among 1395 cigarette smoke components and it may be, therefore, important to find its additional targets. Here, we show that 9,10-PQ functions as an activator of TRPA1 in human embryonic kidney (HEK) cells expressing human wild-type TRPA1 (HEK wTRPA1) and human alveolar A549 (A549) cells. Application of 9,10-PQ at 0.1-10 MUmol/L induced a concentration-dependent Ca2+ response as well as inward currents at -50 mV in HEK-wTRPA1 cells. The current response was blocked by TRPA1 antagonists, HC-030031 (HC) and A-967079. To test whether 9,10-PQ affects the cysteine residues of TRPA1, we expressed mutant TRPA1 channels in HEK cells (HEK muTRPA1) in which six different cysteine residues were replaced with serine. Among them, a mutation of cysteine 621 (C621S) abolished the 9,10-PQ-induced Ca2+ and current responses. The channel activity induced by 9,10-PQ was also abolished in excised inside-out patches isolated from HEK-muTRPA1 cells with the C621S substitution. Although a mutation of cysteine 665 (C665S) reduced the 9,10-PQ induced response, channel sensitization by pretreatment with Cu2+ plus 1,10 phenanthroline and by internal dialysis of 3 MUmol/L Ca2+ restored the response. However, a double mutant with C621S and C665S substitutions had little response to 9,10-PQ, even when sensitized by Ca2+ dialysis. In A549 cells, 9,10-PQ induced an HC-sensitive Ca2+ response. Our findings demonstrate that 9,10-PQ activation of human TRA1 is dependent on cysteine residues 621 and 665. PMID- 28805981 TI - Noncompetitive inhibition of human CYP2C9 in vitro by a commercial Rhodiola rosea product. AB - A commercial Rhodiola rosea (R. rosea) product has previously demonstrated CYP2C9 inhibition in humans. The purpose of this study was to provide in vitro inhibitory data for this particular interaction and to classify the mechanism of the interaction. Another aim was to examine the in vitro influence of ethanol on the CYP2C9 activity. Human CYP2C9 (wild type) isolated from a baculovirus infected cell system was incubated with 0.8 MUmol/L losartan for 20 min. Sulfaphenazole was used as a positive control. The commercial R. rosea product "Arctic Root" was used as test inhibitor. Formation of the CYP2C9-produced losartan metabolite EXP-3174 was determined by validated LC-MS/MS methodology. Possible mechanism-based (irreversible) inhibition was evaluated using time- and NADPH-dependent inhibition assays. Kinetic constants (Km , Vmax , and Ki ) were calculated from a Lineweaver-Burk plot. Mode of inhibition was determined. CYP2C9 was inhibited by "Arctic Root" with an IC50 (extract concentration yielding 50% reduction in enzyme activity) of 19.2 +/- 2.7 MUg/mL. Inhibitor concentrations of 20 MUg/mL and 40 MUg/mL yielded Ki values of 16.37 MUg/mL and 5.59 MUg/mL, respectively. The Lineweaver-Burk plot showed noncompetitive inhibition mode. No time- or NADPH-dependent inhibition was observed. The presence of ethanol inhibited CYP2C9 activity in a concentration-dependent manner. In conclusion, the commercial R. rosea product "Arctic Root" demonstrated noncompetitive inhibition of CYP2C9 in vitro. Further work identifying the constituents responsible for this inhibition is needed. PMID- 28805982 TI - A serious nightmare: psychiatric and neurologic adverse reactions to mefloquine are serious adverse reactions. AB - Mefloquine (originally marketed as Lariam) is a neurotoxic quinoline derivative antimalarial drug that is known to cause serious and potentially lasting neuropsychiatric adverse reactions. Since 2013, drug regulators in several jurisdictions, including the United States, the United Kingdom, Ireland, and Canada, have required their mefloquine labels be updated to warn that when used for malaria prophylaxis the drug should be discontinued at the onset of neurologic or psychiatric symptoms. These recent changes to the international labeling serve to imply that psychiatric and neurologic reactions to mefloquine prophylaxis may be an early warning of an impending more serious reaction that may further jeopardize the patient with continued use of the drug. To prevent these more serious effects, these drug labels now warn that mefloquine should be discontinued and that patients seek immediate medical intervention to obtain an alternative antimalarial drug when psychiatric or neurologic symptoms occur. When used correctly for malaria prophylaxis as the updated labeling now directs, it is reasonable to expect that mefloquine will be discontinued, and an alternative drug substituted, in each patient who develops psychiatric or neurologic symptoms. This opinion discusses the implications of this updated labeling for the reporting of adverse reactions and for the continued use of the drug in malaria prophylaxis. PMID- 28805983 TI - Challenges of measuring accurate estradiol levels in aromatase inhibitor-treated postmenopausal breast cancer patients on vaginal estrogen therapy. AB - Breast cancer patients who are taking adjuvant Aromatase Inhibitor (AI) therapy typically have extremely low estradiol levels, which are undetectable by routine clinical laboratories. Thus, it becomes difficult to assess the safety of interventions such as low-dose vaginal estrogen, which may increase estradiol levels. In this study, we aimed to assess the utility of enzyme-linked immunosorbent assay (ELISA) to measure low estradiol concentrations in breast cancer survivors on AI therapy treated with either vaginal estrogen or lubricant for atrophic vaginitis as a part of clinical trial. The samples were tested using two independent ELISA kits. Some of the samples were also evaluated using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for comparison. We found that while the results by ELISA were reproducible, they were not accurate when compared to LC-MS/MS. It is possible that medications or supplements may cross react with the ELISA reagents and confound the assessment; however, those were often not the reason for the discrepancy. Our results highlight the need for developing novel, reliable, and clinically accessible assays to measure ultra-low estradiol levels to improve care of breast cancer survivors. At this stage, based on our findings, we recommend using MS-based assays for estradiol quantitation for breast cancer survivors, whenever necessary. PMID- 28805984 TI - Self-medication misuse in the Middle East: a systematic literature review. AB - Regulations usually distinguish between prescription-only (POM) and over-the counter (OTC) medicines. The former requires medical prescription; the latter are available for SM of common minor or easily treated ailments. However, in the Eastern Mediterranean countries, theoretical prescription medicines can easily be purchased without a prescription, as self-medication (SM) resulting in potential misuse and unnecessary risk for patients. The magnitude of this activity is uncertain. The aim of this article, therefore, is to undertake a comprehensive review to identify the different types of medicines that can easily be purchased as SM in Middle East and recognized as misused. An extensive review of the published literature (1990-2015) was conducted using Pubmed, web of science, Cochrane, and Google Scholar databases, for OTC medicine misuse in the Middle East. A total of 72 papers were identified. Medicines involved in misuse included: codeine containing products, topical anesthetics, topical corticosteroids, antimalarial, and antibiotics. Self-medication misuse of medicines seemed widespread. Individual treatment patterns were not clearly identified. Studies were not standardized, limiting the comparability between studies and the estimation of the scale of misuse. Pharmacists, friends, or parents were found to be the main sources of SMs. Knowledge and attitudes are an important contributing factor in the misuse of these medications. Strategies and interventions to limit misuse were rarely identified in literature. In conclusion, a massive problem involving a range of medicines was found in Middle East. Standardization of studies is a prerequisite to the understanding and prevention of misuse of self-medication. PMID- 28805985 TI - Willingness to pay for antiretroviral drugs among HIV and AIDS clients in south east Nigeria. AB - BACKGROUND: The current trend of withdrawal of donor support for HIV/AIDS treatment in Nigeria may require that the cost of antiretroviral drugs be borne in part by infected people and their families. OBJECTIVE: This study was conducted to determine the economic value for free antiretroviral drugs (ARVs) expressed by clients receiving treatment for HIV/AIDS in a tertiary hospital. STUDY METHOD: The contingent valuation method was used to elicit the values attached to free ARVs from people living with HIV/AIDS that were receiving care in a public tertiary hospital in south-east Nigeria. Exit poll using a pre-tested questionnaire was undertaken with adult clients on treatment. The bidding game technique was used to elicit their willingness to pay (WTP) for ARVs for themselves and members of their households. Ordinary least squares (OLS) multiple regression analysis was used to test the construct validity of elicited WTP amounts. RESULTS: About a third of the respondents were willing to pay for a monthly supply of ARVs for themselves and household members. The mean WTP for monthly supply of ARVs for self was US$15.32 and for household member was US$15.26 (1US$=?160). OLS regression analysis showed that employment status and higher socio-economic status were positively associated with higher WTP. OLS showed that age and transport cost per clinic visit were negatively related to WTP. Knowing the risks of not adhering to treatment protocol was positively related to WTP. CONCLUSION: The respondents positively valued the free ARVs. This calls for greater financial support for the sustainable provision of the treatment service. However, holistic financing mechanisms should be explored to ensure sustained funding in the event of complete withdrawal of donor support. PMID- 28805987 TI - The case for empathy: Researchers differ on the finer points, but largely agree that stronger skills in empathy are needed for effective patient care. PMID- 28805988 TI - Are behaviors at one alternative in concurrent schedules independent of contingencies at the other alternative? AB - Some have reported changing the schedule at one alternative of a concurrent schedule changed responding at the other alternative (Catania, 1969), which seems odd because no contingencies were changed there. When concurrent schedules are programmed using two schedules, one associated with each alternative that operate continuously, changing the schedule at one alternative also changes the switch schedule at the other alternative. Thus, changes in responding at the constant alternative could be due to the change in the switch schedule. To assess this possibility, six rats were exposed to a series of conditions that alternated between pairs of interval schedules at both alternatives and a pair of interval schedules at one, constant, alternative and a pair of extinction schedules at the other alternative. Comparing run lengths, visit durations and response rates at the constant alternative in the alternating conditions did not show consistent increases and decreases when a strict criterion for changes was used. Using a less stringent definition (any change in mean values) showed changes. The stay/switch analysis suggests it may be inaccurate to apply behavioral contrast to procedures that change from concurrent variable-interval variable-interval schedules to concurrent variable-interval extinction schedules because the contingencies in neither alternative are constant. PMID- 28805986 TI - Histiocytic sarcoma: New insights into FNA cytomorphology and molecular characteristics. AB - BACKGROUND: Histiocytic sarcoma (HS) is a rare malignant neoplasm showing morphologic and immunophenotypic features of histiocytes. Molecular characteristics of HS and fine-needle aspiration (FNA) criteria for its diagnosis have not been established. METHODS: A case series of HS in 8 FNA samples from 6 patients was reviewed along with histopathologic and clinical data. Immunohistochemistry was performed on cell blocks (3 cases), core biopsies (5 cases), and surgical specimens (4 cases). Targeted-exome next-generation sequencing (NGS) was performed on surgical resection specimens in 4 cases. RESULTS: Four patients had a known history of hematolymphoid malignancy. Cytomorphologic features included variably cellular smears composed of large epithelioid cells with reniform nuclei and abundant vacuolated cytoplasm, in an inflammatory background, with occasional cytophagocytosis and lymphoglandular bodies. Marked pleomorphism, multinucleated monster cells, and binucleated histiocytoid cells with partially overlapping, eccentrically placed nuclei resembling Pac-Man were common. Most cases expressed histiocytic markers CD68 (6 of 7 cases), CD163 (5 of 5 cases), and PU.1 (3 of 4 cases). In 3 cases, NGS analysis revealed alterations in lysine methyltransferase 2D (KMT2D)/mixed lineage leukemia 2 (MLL2), a gene involved in chromatin regulation and previously implicated in the pathogenesis of follicular lymphoma. CONCLUSIONS: Although diagnosing HS with FNA alone is extremely challenging, the presence of pleomorphic and epithelioid large cells with binucleation and/or multinucleation in an inflammatory background should prompt the diagnosis of HS with judicious use of confirmatory histiocytic lineage markers. The detection of recurrent KMT2D/MLL2 alterations implicates epigenetic regulation in the pathogenesis of HS and supports the notion of transdifferentiation from a genetically similar but phenotypically distinct tumor of a different lineage. Cancer Cytopathol 2017;125:604-14. (c) 2017 American Cancer Society. PMID- 28805989 TI - Nitroxyl donors for acute heart failure: promising newcomers. PMID- 28805990 TI - Absence of JC polyomavirus (JCPyV) viremia in early post-transplant JCPyV nephropathy: A case report. AB - JC polyomavirus (JCPyV)-associated nephropathy (JCPyVAN) occurs in <3% of PVAN cases after renal transplantation. We report the first confirmed case to our knowledge of JCPyVAN diagnosed by kidney biopsy in the early 6 months post transplant in Thailand. In this case report, recovery of renal allograft function was not observed after reduction of immunosuppressive agents and administration of intravenous immunoglobulin and cidofovir. Despite persistent JCPyV viruria, no significant further decline in allograft function was documented at 15 months post transplant. PMID- 28805991 TI - Molecular Recognition-Mediated Transformation of Single-Chain Polymer Nanoparticles into Crosslinked Polymer Films. AB - We describe single-chain polymer nanoparticles (SCNPs) possessing intramolecular dynamic covalent crosslinks that can transform into polymer films through a molecular recognition-mediated crosslinking process. The SCNPs utilise molecular recognition with surface-immobilised proteins to concentrate upon a substrate, bringing the SCNPs into close spatial proximity with one another and allowing their dynamic covalent crosslinkers to undergo intra- to interpolymer chain crosslinking leading to the formation of polymeric film. SCNPs must possess both the capacity for specific molecular recognition and a dynamic nature to their intramolecular crosslinkers to form polymer films, and an investigation of the initial phase of film formation indicates it proceeds from features which form upon the surface then grow predominantly in the xy directions. This approach to polymer film formation presents a potential method to "wrap" surfaces displaying molecular recognition motifs-which could potentially include viral, cellular and bacterial surfaces or artificial surfaces displaying multivalent recognition motifs-within a layer of polymer film. PMID- 28805992 TI - A brief overview of cardiac resynchronization therapy and its current use in clinical practice. PMID- 28805993 TI - Self-Cleaning Catalyst Electrodes for Stabilized CO2 Reduction to Hydrocarbons. AB - A surface-restructuring strategy is presented that involves self-cleaning Cu catalyst electrodes with unprecedented catalytic stability toward CO2 reduction. Under the working conditions, the Pd atoms pre-deposited on Cu surface induce continuous morphological and compositional restructuring of the Cu surface, which constantly refreshes the catalyst surface and thus maintains the catalytic properties for CO2 reduction to hydrocarbons. The Pd-decorated Cu electrode can catalyze CO2 reduction with relatively stable selectivity and current density for up to 16 h, which is one of the best catalytic durability performances among all Cu electrocatalysts for effective CO2 conversion to hydrocarbons. The generality of this approach of utilizing foreign metal atoms to induce surface restructuring toward stabilizing Cu catalyst electrodes against deactivation by carbonaceous species accumulation in CO2 reduction is further demonstrated by replacing Pd with Rh. PMID- 28805994 TI - Monitoring Photosynthetic Activity in Microalgal Cells by Raman Spectroscopy with Deuterium Oxide as a Tracking Probe. AB - Microalgae offer great potential for the production of biofuel, but high photosynthetic activity is demanded for the practical realisation of microalgal biofuels. To this end, it is essential to evaluate the photosynthetic activity of single microalgal cells in a heterogeneous population. In this study, we present a method to monitor the photosynthetic activity of microalgae (in particular Euglena gracilis, a microalgal species of unicellular, photosynthetic, flagellate protists as our model organism) at single-cell resolution by Raman spectroscopy with deuterium from deuterium oxide (D2 O) as a tracking probe. Specifically, we replaced H2 O in culture media with D2 O up to a concentration of 20 % without disturbing the growth rate of E. gracilis cells and evaluated C-D bond formation as a consequence of photosynthetic reactions by Raman spectroscopy. We used the probe to monitor the kinetics of the C-D bond formation in E. gracilis cells by incubating them in D2 O media under light irradiation. Furthermore, we demonstrated Raman microscopy imaging of each single E. gracilis cell to discriminate deuterated cells from normal cells. Our results hold great promise for Raman-based screening of E. gracilis and potentially other microalgae with high photosynthetic activity by using D2 O as a tracking probe. PMID- 28805995 TI - Germline PMS2 and somatic POLE exonuclease mutations cause hypermutability of the leading DNA strand in biallelic mismatch repair deficiency syndrome brain tumours. AB - Biallelic mismatch repair deficiency (bMMRD) in tumours is frequently associated with somatic mutations in the exonuclease domains of DNA polymerases POLE or POLD1, and results in a characteristic mutational profile. In this article, we describe the genetic basis of ultramutated high-grade brain tumours in the context of bMMRD. We performed exome sequencing of two second-cousin patients from a large consanguineous family of Indian origin with early onset of high grade glioblastoma and astrocytoma. We identified a germline homozygous nonsense variant, p.R802*, in the PMS2 gene. Additionally, by genome sequencing of these tumours, we found extremely high somatic mutation rates (237/Mb and 123/Mb), as well as somatic mutations in the proofreading domain of POLE polymerase (p.P436H and p.L424V), which replicates the leading DNA strand. Most interestingly, we found, in both cancers, that the vast majority of mutations were consistent with the signature of POLE exo- , i.e. an abundance of C>A and C>T mutations, particularly in special contexts, on the leading strand. We showed that the fraction of mutations under positive selection among mutations in tumour suppressor genes is more than two-fold lower in ultramutated tumours than in other glioblastomas. Genetic analyses enabled the diagnosis of the two consanguineous childhood brain tumours as being due to a combination of PMS2 germline and POLE somatic variants, and confirmed them as bMMRD/POLE exo- disorders. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28805996 TI - What can we learn from pulmonary function testing in heart failure? AB - Pulmonary diseases frequently coexist in heart failure (HF), thus posing diagnostic and therapeutic challenges to cardiologists evaluating patients with overlapping symptoms and implementing recommended HF treatments. There is a growing body of evidence suggesting that pulmonary function testing might provide useful information for the best management of these patients. The availability of portable devices, allowing the measurement of spirometry and lung diffusion capacity for carbon monoxide outside of hospital-based pulmonary lung function laboratories, provides an opportunity for a more widespread use of these measures in the cardiology community, but their interpretation can be challenging. In this work, after a brief review of the methodologies, we discuss the interpretation of pulmonary function testing in patients with HF alone or associated with pulmonary diseases, and its contribution in differentiating cardiac and pulmonary symptoms and preventing acute cardiac decompensation. In addition, we examined recent evidence suggesting how the use of pulmonary function testing may provide independent prognostic information in HF patients with and without pulmonary disorders, and help therapeutic decisions to fill the treatment gap that still exists in HF patients with concomitant pulmonary diseases. PMID- 28805997 TI - Response to Nagai et al. PMID- 28805999 TI - Corrigendum. PMID- 28805998 TI - Franz Gerstenbrand - Obituary. PMID- 28806001 TI - Medical Student Petition Against the USMLE Step 2 Clinical Skills Examination. PMID- 28806002 TI - Midwest Science Festival: Exploring Students' and Parents' Participation in and Attitudes Toward Science. AB - INTRODUCTION: Compared to national numbers, South Dakota has a higher proportion of students interested in science, technology, engineering, and mathematics (STEM) fields. Interest in science can be influenced by exposure to science through formal and informal learning. Informal science activities (including exposures and participation) have been found to elicit higher levels of interest in science, likely impacting one's attitude towards science overall. The current study goal is to better understand the levels and relationships of attitude, exposure, and participation in science that were present among students and parents attending a free science festival. METHODS: The project collected survey data from 65 students and 79 parents attending a science festival ranging from age 6 to 65. RESULTS: Informal science participation is significantly related to science attitudes in students and informal science exposure is not. No relationship was found for parents between science attitudes and participation. CONCLUSIONS: Students who indicated high levels of informal science participation (i.e., reading science-themed books) were positively related to their attitudes regarding science. However, informal science exposures, such as attending the zoo or independently visiting a science lab, was not significantly associated with positive attitudes towards science. PMID- 28806003 TI - Rural United States Experience of Incorporation of a Technologically Advanced and Procedurally Complex Cardiovascular Program - the Sanford Trans-Catheter Aortic Valve Replacement Experience. AB - Trans-catheter aortic valve replacement (TAVR) was approved by the U.S. Food and Drug Administration in 2012 for treatment of severe symptomatic aortic stenosis in non-surgical and high risk patients. Implementation of this complex procedure requires a comprehensive heart team approach. Rural demographics in the Midwest pose many challenges related to low volumes of operations both at institutional and individual levels, leading to serious concerns about the quality of care delivered in such a setting. We compared the TAVR data at the University of South Dakota Sanford Medical Center to the national registry with the aim of looking at differences in outcomes of this procedure in a rural setting. PMID- 28806004 TI - Lymphangiectatic Variant of Eccrine Spiradenoma - A Diagnostic Challenge. AB - Conventional eccrine spiradenoma is a benign, slow growing and painful tumor of the skin. While the tumor does not usually present a diagnostic dilemma, a rare variant with marked stromal lymphedema can be a challenge to interpret. We present a case of lymphangiectatic variant of eccrine spiradenoma in an 82-year old white male who presented with a persistent left flank lesion for several months. The patient was initially asymptomatic and subsequently developed a suspected abscess that was excised to reveal a 6.5 cm subcutaneous mass. Microscopic examination reveals strands and cords of dark, epithelial, round to oval cells with inconspicuous nucleoli streaming between prominently dilated and congested vascular spaces. Within the cystic component there are small ductular structures. Additionally, prominent stromal lymphedema is present. To the best of our knowledge, there is only one reported case of this entity in the English literature. This case represents a diagnostic challenge and the purpose of reporting it is to alert surgical pathologists, dermatopathologists and dermatologists of the existence of this unusual variant of eccrine spiradenoma. PMID- 28806005 TI - New Oral Anticoagulants: What Prescribers Should Know; Differences and Similarities between Warfarin and "New Agents" (Dabigatran, Rivaroxaban, Apixaban, Edoxaban) - Review of Indications, Contraindications and Safety of Use. PMID- 28806006 TI - Procalcitonin as a Biomarker of Bacterial Infection. PMID- 28806007 TI - Quality Focus: Depression Screening Tools Improve Care. PMID- 28806008 TI - South Dakota Medicaid Implements Coverage for Immediate Postpartum Long-Acting Reversible Contraception. PMID- 28806009 TI - Regional Infant and Child Mortality Review Committee - 2015 Final Report. AB - The Regional Infant and Child Mortality Review Committee serves 10 counties in southeastern South Dakota and aims to use its reviews to prevent future loss of life during childhood. In 2015, the committee reviewed 24 deaths (compared to 32 cases in 2013 and 25 cases in 2014). Consistent with observations made in previous years, in 2015 all infants (n=7) who died during sleep did so with risks present in the sleep environment. Progress in decreasing these infant deaths in the region is not being observed, and in fact, may even be deteriorating. Two children died subsequent to a motor vehicle crash and neither were wearing a seat belt. The committee was pleased, however, to note that there were no childhood fatalities associated with teenaged drivers. One teen suicide in 2015 marked a decrease in the number observed in 2013 and 2014, but represents an ongoing concern about the safety of emotionally volatile adolescents. Further, one child homicide occurred in the region in 2015 reflecting the fragility of young in the presence of stressed and unstable home environments. The report provides the committee's recommendation for community action that could prevent future deaths of infants and children. PMID- 28806010 TI - Blastomycosis and Histoplasmosis in a Patient with Glioblastoma Receiving Temozolomide. AB - Malignant glioblastoma multiform (GBM) is the most common primary malignancy of the brain in the U.S. Temozolomide (TMZ) is the cornerstone of management along with surgical resection and radiotherapy. Because of the reduction in the CD4+ lymphocyte count as a side effect of TMZ use, this patient population is under risk for opportunistic infections like Pneumocystis jiroveci. A male patient with newly diagnosed glioblastoma multiform presented with non-productive cough and chest pain. Before presentation, the patient received the standard therapy including surgical resection, radiation and TMZ. Computerized tomography of the chest showed a very large cavitary lesion in the upper segment of the right lower lobe and multiple nodular lesions with some starting to cavitate. Cytology of the bronchioalveolar lavage with special stain showed large, broad based budding yeast-like cells, morphologically consistent with blastomyces and macrophages filled with yeast-like forms, morphologically consistent with histoplasma. The patient was treated with intraconazole intended for 12 months. To the best of our knowledge, our case represents the first documented case of lung infection with both blastomyces and histoplasma in a patient after receiving TMZ for newly diagnosed GBM. PMID- 28806011 TI - A Primer on Bleeding Risk and Management Strategies of Newer Oral Anti Platelet Agents in Cardiovascular Disease. AB - Aspirin, the first antiplatelet agent, has been around since the 19th century, and is one of the most established drugs in history. With the improvement of coronary interventions in the past few decades, there has been more reliance on oral antiplatelet agents to reduce complications of in-stent restenosis/thrombosis. Clopidogrel was initially introduced in 1997, and within the past seven years, two additional oral antiplatelet agents have been approved by the U.S. Food and Drug Administration. With more potent antiplatelet agents comes increased risks of adverse effects. Physicians of all fields should be aware of the common antiplatelet agents used today, and the basic landmark trials that allowed them to be on the market today. The focus of this review article is to evaluate each oral antiplatelet drug, its brief history, relevant trials, indications and management of complications through evidence based guidelines. PMID- 28806012 TI - New Age of Treatment for Fecal Incontinence: Sacral Nerve Modulation. PMID- 28806013 TI - Vaccines and Autism: A Misconception that Persists. PMID- 28806014 TI - Getting Ahead of Head Lice: Treatment in the Setting of Resistance. PMID- 28806015 TI - Quality Focus: Improving Adult Immunization Rates. PMID- 28806016 TI - Spacing Pregnancies Appropriately: Long-Acting Reversible Contraception in the Immediate Postpartum Period. PMID- 28806017 TI - Cardiac Presentation of Multiple Myeloma with Amyloidosis. AB - Amyloidosis is a rare disease encompassing the accumulation of abnormal and insoluble amyloids systemically or in specific organs. This is a case of a previously healthy 60-year-old male complaining of fatigue and chest pain who proceeded to rapidly decline in functional status within six months from the onset of these symptoms. Cardiac evaluation demonstrated characteristic changes on EKG and echocardiogram was consistent with cardiac amyloidosis. Muscle and gastrointestinal biopsies confirmed multisystem amyloidosis. Monoclonal kappa light chain was identified by serum electrophoresis and the diagnosis of multiple myeloma was confirmed by bone marrow biopsy. The process of amyloid deposition secondary to multiple myeloma was managed with chemotherapy after the patient was referred to a center specialized in amyloidosis treatment. This case highlights the diagnostic challenges, non-specific signs and symptoms, and treatment dilemmas involved in managing amyloid light-chain cardiac amyloidosis. PMID- 28806018 TI - Wolf in Sheep's Clothing Subdural Empyema: A Rare Complication of Acute Sinusitis. AB - The intent of this paper is to raise awareness to primary care and pediatric colleagues of how a clinically insignificant appearing condition like sinusitis can lead to a major complication. Subdural empyema is a rare but life-threatening complication of paranasal sinusitis, otitis media, or mastoid disease. We report a case of a 12-year-old male patient who originally presented with clinically insignificant symptoms and later developed intracranial abscess requiring aggressive neurosurgical intervention. We hope that this article will raise awareness among colleagues who can educate parents on high-alert symptoms to watch out for if the patient is discharged home after initial presentation. PMID- 28806019 TI - Metastatic Adenocarcinoma of the Prostate Diagnosed in a Colon Polyp: A Unique Clinicopathologic Scenario. AB - Adenocarcinoma of the prostate is the second most common cause of cancer-related deaths among males in the U.S. Metastatic disease commonly involves the bones, lymph nodes, lungs, liver, and brain. Rarely, colonic involvement is seen and it is generally due to direct extension to the rectum. It is exceedingly uncommon for distant metastasis to occur in the right colon and small bowel. We present a case of prostatic adenocarcinoma metastasizing to the appendiceal orifice in a 78 year-old male. Our patient had a history of adenocarcinoma of the prostate diagnosed four years prior to presentation. He also had a history of adenocarcinoma of the distal colon 30 years prior which resulted in a partial colectomy and permanent diverting colostomy. Prior to his presentation, follow-up colonoscopies failed to reveal disease progression or additional malignancy. During routine colonoscopy, he was found to have a 2.5 cm polyp near the appendiceal orifice. Histologically the polyp demonstrated colonic mucosa with an infiltration of the lamina propria by individual cells with abundant cytoplasm and round nuclei with prominent nucleoli. The neoplastic cells were strongly positive for PSA and negative for CK7, CK20, and CDX2 supporting a diagnosis of metastatic prostatic adenocarcinoma. Metastatic disease of extracolonic origin arising in a polyp is extremely uncommon, but metastases have been reported to involve breast, ovary, stomach, esophagus, and kidney. This case contributes to the scarce information available regarding metastatic spread of prostate cancer to the ascending colon and enlightens the community of pathologists, surgeons, gastroenterologists, and urologists about this unusual presentation of a common carcinoma. PMID- 28806020 TI - Physicians' Use of Compliance Gaining. AB - A qualitative analysis was conducted exploring physicians' use of compliance gaining strategies used in attempts to change patient behaviors. Analysis revealed six sets of perceptions that describe the ways physicians manage the difficult task of compliance gaining - recognition of failure, tolerance of outside credibility, labeling the "art of medicine," assigning patient responsibility, placing patients on "their journey," and acknowledging "the event." Analysis also identified three key sets of strategies that physicians use in compliance gaining: 1) message strategies (which include direct and strategic attempts to manage interactions about behavior change); 2) relational strategies (which emerge from the relationship shared by the physician and the patient); and 3) personal strategies (which include the individual physician's approaches to compliance gaining). Eight message strategies, three relational strategies, and two personal strategies are identified and described. PMID- 28806022 TI - Quality Focus: The Evolving World of Nursing Home Care. PMID- 28806021 TI - Is Digoxin Use Safe in Atrial Fibrillation? A Review of Contemporary Studies. PMID- 28806023 TI - Pharmacogenomics and Mental Illness. PMID- 28806024 TI - Atomoxetine Pharmacogenetics: Lessons Learned. PMID- 28806025 TI - Brain Tuberculoma: A Case Report and Literature Review. AB - We are reporting on a rare case of central nervous system tuberculosis (TB) in the state of South Dakota. Our case features one of the most infrequent forms of TB in the brain: multiple tuberculomas. A 44-year-old immunocompetent man was admitted complaining of a headache and fever for a week. His physical exam was unremarkable. A magnetic resonance imaging scan of his brain showed two ring enhancing lesions. The largest lesion was excised surgically and the histopathology exam was consistent with tuberculoma. We will discuss in this report various aspects of this rare disease in term of epidemiology, diagnosis, and treatment. PMID- 28806026 TI - Physician Perceptions of Barriers to Advance Care Planning. AB - BACKGROUND: Numerous studies have confirmed the importance of advance care planning. Despite the benefits of directed end-of-life discussions, a variety of barriers including discomfort with the topic, physician ideology, lack of time and reimbursement, delaying discussions, and lack of training impede physicians from facilitating these crucial conversations with their patients. This study aims to understand physicians' perceptions to additional barriers to advance care planning with patients and their families. METHODS: Interviews with 19 practicing physicians (seven women and 12 men). Their perceptions were noted in interviews that were audiotaped, transcribed, and analyzed (n = 19). RESULTS: Physicians continue to face barriers to advance care planning as well as struggle with additional challenges such as difficulty with families, lack of patient education, inconsistencies and accessibility of advance directive documents, and lack of physician-physician communication or agreement in care. Further analysis reveals contradictions regarding physician comfort level and the role of primary care. These results reveal the complexity of providing medical care and the continued need for improvements in physician-patient communication about end-of life care. CONCLUSIONS: Complex challenges in communication impede the delivery of successful end-of-life experiences for patients and their families. With improvements in the practices of advance care planning, many of these challenges can be removed - enabling individuals to remain in control as they near the end of their lives and preventing unnecessary pain and suffering on behalf of the patient and family. PMID- 28806027 TI - A Rare Case of Lymphadenopathy: Kikuchi-Fujimoto Disease. AB - A relatively unknown cause of cervical lymphadenopathy is Kikuchi-Fujimoto disease, also known as histiocytic necrotizing lymphadenitis. This is a rare and benign condition that presents with painful cervical lymphadenopathy, fevers, night sweats, and weight loss. This disease is most prevalent in Asian women between the age of 20-35 years. The diagnosis of Kikuchi Disease is made histologically and is characterized by paracortical areas of necrosis and a notable complete absence of neutrophils. The painful lymphadenopathy can be simply treated with antipyretics, but due to its presenting symptoms of Kikuchi disease, it is often mistaken for malignant lymphoma. As such, accurate diagnosis is required to avoid unnecessary testing. The evaluation of lymphadenopathy without an obvious cause can be quite challenging. When patients present with relapsing remitting lymphadenopathy, Kikuchi disease may warrant consideration. PMID- 28806028 TI - Treatment of Peritonsillar Abscess in Immunosuppressed Patients. AB - Peritonsillar abscess (PTA) is a common pathology in otolaryngology emergency. The treatment of PTA is usually bedside drainage or surgical removal of the tonsils (Quincy tonsillectomy) in combination with antibiotic treatment. However, patients with immune suppression might have a more difficult treatment course. Such difficulties may be further magnified within older patients. This case report will describe successful multi-modality treatment of two separate incidents of PTA developing in the context of immunosuppression. Two separate incidents of PTA occurring in immunosuppressed, thrombocytopenic, cancer patients after recent chemotherapy are presented. Early utilization of incision and drainage, antibiotics, and granulocyte colony stimulating factor (G-CSF, filgrastim) for PTA presenting in the setting of chemotherapy related neutropenia appears to be a viable option in patients with immunosuppression. Review of the current literature also demonstrates that reporting of PTA in older patients is important for future research efforts. PMID- 28806029 TI - Atrial Fibrillation Induced by Carbon Monoxide Poisoning and Successful Treatment with Hyperbaric Oxygen. AB - Carbon monoxide (CO) intoxication is one of the major public health hazards which may go unnoticed as this is a colorless, odorless and tasteless gas. The manifestations of the CO poisoning are far-reaching. Although CO affects almost every organ in the body, cerebral and myocardial involvement are predominant due to the hypoxia-induced cellular damage. The mainstay treatment is providing high flow oxygen and in some instances hyperbaric oxygen therapy. In the literature, there have been few cases of CO poisoning-induced atrial fibrillation (AF) reported. We hereby report an AF caused by CO toxicity in a young male patient and successful conversion to sinus rhythm with the hyperbaric therapy. PMID- 28806030 TI - Hepatitis C: Cured. PMID- 28806032 TI - Quality Focus: The Appropriate Use of Antipsychotic Medicine. PMID- 28806031 TI - Clinical Ethics With All Her Matter-of-Fact. PMID- 28806033 TI - 2016 Scholars Day Symposium Abstracts. PMID- 28806034 TI - A Primer for the Primary Care Physician: Management of Overactive Bladder Syndrome. AB - Overactive bladder syndrome affects millions of women in the U.S. and is defined by urinary urgency, urinary frequency, and small volume voids, with or without nocturia and incontinence. Overactive bladder is a diagnosis of exclusion, and several therapies exist for the management of this condition. This article outlines a systematic approach that the primary care physician can take when treating a patient with overactive bladder. PMID- 28806035 TI - A Primer on Diagnostic and Financial Implications of D-dimer Testing. AB - Given the high incidence of deep vein thrombosis/pulmonary embolism (DVT/PE) (300,000 to 600,000 per year in the U.S.) and the 30 percent mortality rate associated with undiagnosed PE, diagnostic evaluation is very important. One of the tools used to evaluate for DVT and PE is D-dimer testing. A negative D-dimer test, along with a low Wells clinical probability score, can safely rule out DVT/PE without the need for additional imaging. This approach can reduce cost; however, D-dimer testing is not indicated in all patients. D-dimers can be elevated in patients without DVT/PE, like the elderly. The consequences of over utilizing D-dimer testing can lead to excessive imaging, unnecessary contrast exposure, unnecessary exposure to radiation, and increased cost. In this primer, we provide a brief literature review of D-dimer testing for the diagnosis of DVT and PE. We also discuss the overutilization of D-dimer testing and its financial burden on the health care industry. PMID- 28806036 TI - FDA Issues New Fluoroquinolone Safety Warnings and Prescribing Restrictions. PMID- 28806037 TI - Quality Focus: Beneficiary and Family Engagement. PMID- 28806038 TI - Partnership Strategies of Community Health Centers: Building Capacity in Good Times and Bad. AB - Federally Qualified Health Centers--commonly referred to as Community Health Centers (CHCs)--serve as critical safety net providers for those who are uninsured or who may become uninsured. This policy brief reports the findings from the Remaining Uninsured Access to Community Health Centers (REACH) research project, which sought to identify the impact of the Affordable Care Act (ACA) on the ability of CHCs to serve the remaining uninsured. We examined strategies undertaken by CHCs in four states to reinforce the local safety net through partnerships, improvements to the local health system, and advocacy. With the uncertainties about whether Medicaid expansion will be continued or will be handed over to the states with limited oversight, partnerships both among CHCs and between CHCs and others in the health care system and beyond may become even more important. PMID- 28806045 TI - Electrolytes: Foreword. PMID- 28806046 TI - Electrolytes: Sodium Disorders. AB - Sodium disorders (ie, hyponatremia, hypernatremia) are common electrolyte disturbances in clinical medicine and are associated with increased rates of morbidity and mortality. Etiologies of hyponatremia are classified into four categories. The first is pseudohyponatremia, in which the sodium level is low due to hyperproteinemia, hyperlipidemia, or hyperglycemia. The other three categories are based on overall patient fluid status and include hypovolemic (commonly due to fluid loss), hypervolemic (commonly due to fluid retention from heart failure, cirrhosis, or renal failure), and euvolemic (most often because of syndrome of inappropriate secretion of antidiuretic hormone). Hypovolemic hyponatremia is managed by rehydration with isotonic saline. Hypervolemic hyponatremia is managed by addressing the underlying cause. Euvolemic hyponatremia is managed by restricting free water intake, addressing the underlying cause, and occasionally with drugs (eg, vasopressin receptor antagonists). Patients with severe or acutely symptomatic hyponatremia (eg, altered mental status, seizures), including those with acute symptomatic exercise-induced hyponatremia, require urgent treatment. This should consist of hypertonic saline administration along with monitoring of sodium levels to avoid overly rapid correction. Hypernatremia most often occurs because of water loss or inadequate water intake. Depending on severity, management involves oral or intravenous hypotonic fluids and addressing the underlying cause. PMID- 28806047 TI - Electrolytes: Potassium Disorders. AB - Hypokalemia (ie, potassium levels less than 3.5 mEq/L) occurs in fewer than 1% of healthy individuals, but is present in up to 20% of hospitalized patients, 40% of patients taking diuretics, and 17% of patients with cardiovascular conditions. Hypokalemia often is asymptomatic; symptoms are more common in older adults. Common symptoms are cardiac arrhythmias and muscle weakness or pain. Management consists of intravenous potassium replacement during cardiac monitoring for patients with marked symptoms, echocardiogram (ECG) abnormalities, or severe hypokalemia (ie, level less than 3.0 mEq/L). Oral replacement is appropriate for asymptomatic patients with less severe hypokalemia. Hyperkalemia (ie, level greater than 5.5 mEq/L) also can cause cardiac arrhythmias and muscle symptoms. Urgent management is warranted for patients with potassium levels of 6.5 mEq/L or greater, if ECG manifestations of hyperkalemia are present regardless of potassium levels, or if severe muscle symptoms occur. Urgent management includes intravenous calcium, intravenous insulin, and inhaled beta agonists. Hemodialysis can be used in urgent situations. For patients with less severe hyperkalemia, renal elimination drugs sometimes are used, as are gastrointestinal elimination drugs. For all patients with hypokalemia or hyperkalemia, drug regimens should be reevaluated and, when possible, hypokalemia- or hyperkalemia-causing drugs should be discontinued. PMID- 28806048 TI - Electrolytes: Calcium Disorders. AB - A normal serum calcium level is 8 to 10 mg/dL. The diagnosis of hypercalcemia (ie, levels 10.5 mg/dL or greater) should be confirmed with an albumin-adjusted or ionized calcium level. The two most common causes of hypercalcemia are hyperparathyroidism and malignancy. Drugs, notably lithium and thiazide diuretics, also can cause hypercalcemia. Patients with severe or symptomatic hypercalcemia should be treated initially with hydration to decrease calcium levels. The evaluation should include a parathyroid hormone (PTH) level. If the PTH level is low, cancer is a likely cause, particularly multiple myeloma, breast cancer, or lymphoma. If the PTH level is normal or elevated, hyperparathyroidism is the likely cause. Symptomatic patients with hyperparathyroidism and patients with certain clinical markers should be considered for surgery. For patients with mild disease, monitoring is an option. Hypocalcemia often is caused by vitamin D deficiency. Symptomatic patients and patients with calcium levels less than 7.6 mg/dL should be treated with intravenous calcium gluconate; concomitant magnesium deficiency should be addressed. There is no evidence that routine calcium and vitamin D supplementation reduces the risk of fractures, but studies have shown that vitamin D supplementation does decrease the number of falls in older adults at risk. PMID- 28806049 TI - Electrolytes: Oral Electrolyte Solutions. AB - Oral electrolyte solutions are used widely for rehydration in diarrheal illness and to maintain hydration during vigorous exercise. In diarrheal illness, an oral rehydration solution (ORS) typically is preferred over intravenous fluids except for patients with severe dehydration. The preferred ORS is one similar to the glucose-containing reduced osmolarity World Health Organization ORS. There also are polymer-based solutions that use rice or wheat as the source of carbohydrates but these are not widely recommended. Use of other liquids, such as sport drinks, juice, soft drinks, and chicken broth is not recommended, though these can be considered for patients with no or mild dehydration. For maintaining hydration during exercise, particularly vigorous high-intensity exercise, recommendations are to consume fluids (ie, 5 to 7 mL/kg) and a sodium-containing snack at least 4 hours before. During exercise, individuals require 200 to 800 mL/hour of liquid that should contain 20 to 30 mEq/L of sodium. Carbohydrate intake is recommended during high-intensity exercise. Intake of excessive sodium-free fluids should be avoided to prevent exercise-induced hyponatremia. Additional fluids (ie, 1.5 L/kg of weight lost) can be consumed after exercise to restore hydration. Vitamin and mineral supplements are not recommended routinely for athletes unless known deficiencies exist. PMID- 28806050 TI - Linking High-Throughput Screens to Identify MoAs and Novel Inhibitors of Mycobacterium tuberculosis Dihydrofolate Reductase. AB - Though phenotypic and target-based high-throughput screening approaches have been employed to discover new antibiotics, the identification of promising therapeutic candidates remains challenging. Each approach provides different information, and understanding their results can provide hypotheses for a mechanism of action (MoA) and reveal actionable chemical matter. Here, we describe a framework for identifying efficacy targets of bioactive compounds. High throughput biophysical profiling against a broad range of targets coupled with machine learning was employed to identify chemical features with predicted efficacy targets for a given phenotypic screen. We validate the approach on data from a set of 55 000 compounds in 24 historical internal antibacterial phenotypic screens and 636 bacterial targets screened in high-throughput biophysical binding assays. Models were built to reveal the relationships between phenotype, target, and chemotype, which recapitulated mechanisms for known antibacterials. We also prospectively identified novel inhibitors of dihydrofolate reductase with nanomolar antibacterial efficacy against Mycobacterium tuberculosis. Molecular modeling provided structural insight into target-ligand interactions underlying selective killing activity toward mycobacteria over human cells. PMID- 28806051 TI - Ordered Mesoporous NiCo2O4 Nanospheres as a Novel Electrocatalyst Platform for 1 Naphthol and 2-Naphthol Individual Sensing Application. AB - The novel ordered mesoporous NiCo2O4 (meso-NiCo2O4) nanospheres were synthesized by the nanocasting strategy followed by a calcination process for 2-naphthol (2 NAP) and 1-naphthol (1-NAP) individual sensing application. The as-obtained meso NiCo2O4 material possesses mesoporous structure in spinel crystalline type with a larger specific surface area than other structures. The meso-NiCo2O4-modified carbon paste electrode exhibited excellent electrocatalytic performance for NAP detection by amperometry measurement. The fabricated sensor of 2-NAP and 1-NAP has a wide linear detection range (0.02-300 and 0.02-20 MUM) with high sensitivity (1.822 and 1.510 MUA MUM-1 cm-2) and low limit of detection (0.007 and 0.007 MUM), respectively. In addition, the NAP sensors possess excellent reproducibility, stability, and selectivity. PMID- 28806052 TI - One-Step Sub-micrometer-Scale Electrohydrodynamic Inkjet Three-Dimensional Printing Technique with Spontaneous Nanoscale Joule Heating. AB - A one-step sub-micrometer-scale electrohydrodynamic (EHD) inkjet three dimensional (3D)-printing technique that is based on the drop-on-demand (DOD) operation for which an additional postsintering process is not required is proposed. Both the numerical simulation and the experimental observations proved that nanoscale Joule heating occurs at the interface between the charged silver nanoparticles (Ag-NPs) because of the high electrical contact resistance during the printing process; this is the reason why an additional postsintering process is not required. Sub-micrometer-scale 3D structures were printed with an above-35 aspect ratio via the use of the proposed printing technique; furthermore, it is evident that the designed 3D structures such as a bridge-like shape can be printed with the use of the proposed printing technique, allowing for the cost effective fabrication of a 3D touch sensor and an ultrasensitive air flow-rate sensor. It is believed that the proposed one-step printing technique may replace the conventional 3D conductive-structure printing techniques for which a postsintering process is used because of its economic efficiency. PMID- 28806053 TI - Deblurring Signal Network Dynamics. AB - To orchestrate the function and development of multicellular organisms, cells integrate intra- and extracellular information. This information is processed via signal networks in space and time, steering dynamic changes in cellular structure and function. Defects in those signal networks can lead to developmental disorders or cancer. However, experimental analysis of signal networks is challenging as their state changes dynamically and differs between individual cells. Thus, causal relationships between network components are blurred if lysates from large cell populations are analyzed. To directly study causal relationships, perturbations that target specific components have to be combined with measurements of cellular responses within individual cells. However, using standard single-cell techniques, the number of signal activities that can be monitored simultaneously is limited. Furthermore, diffusion of signal network components limits the spatial precision of perturbations, which blurs the analysis of spatiotemporal processing in signal networks. Hybrid strategies based on optogenetics, surface patterning, chemical tools, and protein design can overcome those limitations and thereby sharpen our view into the dynamic spatiotemporal state of signal networks and enable unique insights into the mechanisms that control cellular function in space and time. PMID- 28806054 TI - Tuning Porous Networks in Polyimide Aerogels for Airborne Nanoparticle Filtration. AB - The suitability of monolithic polyimide aerogels as filter media for removal of airborne nanoparticles was investigated in this work by considering two solvents, N-methylpyrrolidone (NMP) and dimethylformamide (DMF) for tuning of meso- and macropore content. Polyimide gels were synthesized from the chemical reactions between solutions of pyromellitic dianhydride, 2,2'-dimethylbenzidine, and 1, 3, 5-triaminophenoxylbenzene. The gels were dried via supercritical drying in CO2 to obtain the aerogels. The porosity of polyimide aerogels was varied by changing the initial concentration of the solids in the solutions in the range of 2.5-10 wt %. The resulting aerogels show high porosity (91-98%), high specific surface area (473-953 m2/g), low bulk density (0.025-0.12 g/cm3), and solvent dependent macro- and mesopore content. The monoliths with bulk density of >0.05 g/cm3 produced high values of nanoparticle filtration efficiency (>99.95%) with air permeability of the order of 10-10 m2. A strong proportional relationship was observed between the macropore content and air permeability and between the mesopore content and high filtration efficiency. Specimens prepared in DMF and NMP offered the same level of filtration efficiency, but the former provided a factor of 2 higher air permeability due to much greater proportion of macropores. PMID- 28806055 TI - Selective Release System for Antioxidative and Anti-Inflammatory Activities Using H2O2-Responsive Therapeutic Nanoparticles. AB - We developed nanoparticles that were degraded by H2O2, a reactive oxygen species (ROS), to study a drug delivery system that targets damaged skin cells with oxidative stress and inflammation. In this study, tyrosol-incorporated copolyoxalate (TPOX) was synthesized by using 1,4-cyclohexanedimethanol, 4-(2 hydroxyethyl)phenol (tyrosol), and oxalyl chloride (Mw ~ 8835 Da). In vitro drug release behavior was assessed by loading nile red, a lipophilic fluorescent material such as quercetin, into the TPOX nanoparticles. The results indicated that the release of TPOX nanopaticles depended on the H2O2 concentration, but was pH-independent. We confirmed that TPOX nanoparticles under oxidative conditions in oxidative- or inflammatory-damaged cells selectively released entrapped nile red through the degradation by H2O2 for contributing to antioxidant and anti inflammatory effects. For application, we prepared and evaluated the cytoprotective effect of quercetin-loaded TPOX (QTPOX) nanoparticles against oxidative and inflammatory stress. They showed a strong cytoprotective effect against H2O2-induced cell damage in HaCaT and RAW 264.7 cells. Also, QTPOX nanoparticles inhibited the main factors of LPS-induced inflammation, including iNOS, COX-2, IL-1, TNF-alpha, and NO production. These results suggest that QTPOX as H2O2-responsive therapeutic nanoparticles is highly potent and versatile as drug delivery system through selective and intensive drug release mechanism for the treatment of abnormal and inflammatory skin diseases. PMID- 28806056 TI - Self-Generation of Reactive Oxygen Species on Crystalline AgBiO3 for the Oxidative Remediation of Organic Pollutants. AB - In this study, we synthesized a novel perovskite nanomaterial consisting of AgBiO3 nanoparticles (NPs) via an ion-exchange method for remediation of polluted environments. The AgBiO3 NPs could self-produce significant amounts of reactive oxygen species (ROS) without light illumination or any other additional oxidant due to the controllable release of lattice oxygen from the crystalline AgBiO3, resulting in the formation of ROS somehow. The self-produced 1O2, O2*-, and *OH were confirmed by electron spin resonance spectroscopy using a spin trap technique. We found that the AgBiO3 NPs could be reused for the mineraliztion of most recalcitrant organic compounds alone, including Rhodamine B (RhB), phenol, 4 chlorophenol, 2,4-dichlorophenol, and bisphenol A. After the repeated eight cycles of continious treatment of RhB, AgBiO3 NPs still achieved 79% of degradation after 30 min of treatment. Characterization results revealved that the lattice oxygen inside AgBiO3 was activated to form active oxygen (O*), which resulted in consecutive formation of ROS. This study provides new insight on the lattice oxygen activation mechanism of silver bismuthate and its application to the remediation of polluted waters. PMID- 28806057 TI - Rational Design and Multibiological Profiling of Novel Donepezil-Trolox Hybrids against Alzheimer's Disease, with Cholinergic, Antioxidant, Neuroprotective, and Cognition Enhancing Properties. AB - A novel series of donepezil-trolox hybrids were designed, synthesized, and evaluated as multifunctional ligands against Alzheimer's disease (AD). Biological assays showed that these derivatives possessed moderate to good inhibitory activities against acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) as well as remarkable antioxidant effects. The optimal compound 6d exhibited balanced functions with good inhibition against hAChE (IC50 = 0.54 MUM) and hMAO B (IC50 = 4.3 MUM), significant antioxidant activity (41.33 MUM IC50 by DPPH method, 1.72 and 1.79 trolox equivalent by ABTS and ORAC methods), excellent copper chelation, and Abeta1-42 aggregation inhibition effect. Furthermore, cellular tests indicated that 6d has very low toxicity and is capable of combating oxidative toxin (H2O2, rotenone, and oligomycin-A) induced neurotoxicity. Most importantly, oral administration of 6d demonstrated notable improvements on cognition and spatial memory against scopolamine-induced acute memory deficit as well as d-galactose (d-gal) and AlCl3 induced chronic oxidative stress in a mouse model without acute toxicity and hepatotoxicity. In summary, both in vitro and in vivo results suggested that 6d is a valuable candidate for the development of a safe and effective anti-Alzheimer's drug. PMID- 28806059 TI - Bis(pyrene)-Doped Cationic Dipeptide Nanoparticles for Two-Photon-Activated Photodynamic Therapy. AB - At present, one of main problems for photodynamic therapy (PDT) is how to improve the treatment depth. Two-photon activated (TPA) developed recently provide a possible solution for it. In this work, we report the energy-transferring assembled cationic dipeptide nanoparticles for two-photon activated photodynamic therapy (TPA-PDT). In the nanoparticles, the coencapsulated two-photon fluorescent dye bis(pyrene) (BP) is an energy donor, and a photosensitizer rose bengal (RB) is an acceptor based on an intraparticle fluorescence resonance energy transfer (FRET) mechanism. BP in the nanoparticles can be excited by one- or two- photon laser. And then, the energy of BP was transferred to RB, which highly enhanced the generation of singlet oxygen. The cellular experiments indicated that this nanosystem can induce the cytotoxicity under one- and two photon irradiation, which allows further applications of FRET-based biomaterials for TPA-PDT. PMID- 28806058 TI - Metalloproteases of the Inner Mitochondrial Membrane. AB - The inner mitochondrial membrane (IM) is among the most protein-rich cellular compartments. The metastable IM subproteome where the concentration of proteins is approaching oversaturation creates a challenging protein folding environment with a high probability of protein malfunction or aggregation. Failure to maintain protein homeostasis in such a setting can impair the functional integrity of the mitochondria and drive clinical manifestations. The IM is equipped with a series of highly conserved, proteolytic complexes dedicated to the maintenance of normal protein homeostasis within this mitochondrial subcompartment. Particularly important is a group of membrane-anchored metallopeptidases commonly known as m-AAA and i-AAA proteases, and the ATP independent Oma1 protease. Herein, we will summarize the current biochemical knowledge of these proteolytic machines and discuss recent advances in our understanding of mechanistic aspects of their functioning. PMID- 28806060 TI - Smart DNA Machine for Carcinoembryonic Antigen Detection by Exonuclease III Assisted Target Recycling and DNA Walker Cascade Amplification. AB - A synthetic DNA machine performs quasi-mechanical movements in response to external intervention, suggesting the promise of constructing sensitive and specific biosensors. Herein, a smart DNA walker biosensor for label-free detection of carcinoembryonic antigen (CEA) is developed for the first time by a novel cascade amplification strategy of exonuclease (Exo) III-assisted target recycling amplification (ERA) and DNA walker. ERA as the first stage of amplification generates the walker DNA, while the autonomous traveling of the walker DNA on the substrate-modified silica microspheres as the second stage of amplification produces an ultrasensitive fluorescent signal with the help of N methylmesoporphyrin IX (NMM). The DNA machine as a biosensor could be applied for transducing and quantifying signals from isothermal molecular amplifications, avoiding the complicated reporter elements and thermal cycling. The present biosensor achieves a detection limit of 1.2 pg.mL-1 within a linear range of 10 pg.mL-1 to 100 ng.mL-1 for CEA, along with a favorable specificity. The practical applicability of the biosensor is demonstrated by the detection of CEA in human serum with satisfactory results; thus, it shows great potential in clinical diagnosis. PMID- 28806061 TI - Construction of a Polyhedral DNA 12-Arm Junction for Self-Assembly of Wireframe DNA Lattices. AB - A variety of different tiles for the construction of DNA lattices have been developed since the structural DNA nanotechnology field was born. The majority of these are designed for the realization of close-packed structures, where DNA helices are arranged in parallel and tiles are connected through sticky ends. Assembly of such structures requires the use of cation-rich buffers to minimize repulsion between parallel helices, which poses limits to the application of DNA nanostructures. Wireframe structures, on the other hand, are less susceptible to salt concentration, but the assembly of wireframe lattices is limited by the availability of tiles and motifs. Herein, we report the construction of a polyhedral 12-arm junction for the self-assembly of wireframe DNA lattices. Our approach differs from traditional assembly of DNA tiles through hybridization of sticky ends. Instead, the assembly approach presented here uses small polyhedral shapes as connecting points and branch points of wires in a lattice structure. Using this design principle and characterization techniques, such as transmission electron microscopy, single-particle reconstruction, patterning of gold nanoparticles, dynamic light scattering, UV melting analyses, and small-angle X ray scattering among others, we demonstrated formation of finite 12-way junction structures, as well as 1D and 2D short assemblies, demonstrating an alternative way of designing polyhedral structures and lattices. PMID- 28806063 TI - Inhibition of the Kinase Cascade Can Be Quantitative. PMID- 28806062 TI - Exploring Strategies for Labeling Viruses with Gold Nanoclusters through Non equilibrium Molecular Dynamics Simulations. AB - Biocompatible gold nanoclusters can be utilized as contrast agents in virus imaging. The labeling of viruses can be achieved noncovalently but site specifically by linking the cluster to the hydrophobic pocket of a virus via a lipid-like pocket factor. We have estimated the binding affinities of three different pocket factors of echovirus 1 (EV1) in molecular dynamics simulations combined with non-equilibrium free-energy calculations. We have also studied the effects on binding affinities with a pocket factor linked to the Au102pMBA44 nanocluster in different protonation states. Although the absolute binding affinities are over-estimated for all the systems, the trend is in agreement with recent experiments.3 Our results suggest that the natural pocket factor (palmitic acid) can be replaced by molecules pleconaril (drug) and its derivative Kirtan1 that have higher estimated binding affinities. Our results also suggest that including the gold nanocluster does not decrease the affinity of the pocket factor to the virus, but the affinity is sensitive to the protonation state of the nanocluster, i.e., to pH conditions. The methodology introduced in this work helps in the design of optimal strategies for gold-virus bioconjugation for virus detection and manipulation. PMID- 28806064 TI - Conditional Displacement Hybridization Assay for Multiple SNP Phasing. AB - The two chromosomal copies of the human genome are highly polymorphic, and the allelic content on each strand can dictate a person's biological outcomes. While many of the current diagnostic tools are able to detect the presence of multiple mutations at the same time, most cannot determine the phase of these mutations unless long-range PCR or sequencing techniques are used or if templates are compartmentalized into single copies prior to amplification. Here, an enzyme coupled hybridization assay, named conditional displacement hybridization assay (CDHA), is described for the concurrent and rapid determination of the presence and phase of SNP variants. In this approach, short DNA probes were utilized to first quantify the amount of SNPs on the templates using a two-channel fluorescence measurement. The hybrids formed between the probes and the templates then set up the right condition for the subsequent enzymatic displacement and quenching of a fluorophore-labeled strand, which happens only if both SNPs are present on the same strand. The drop in the fluorescence signal thereby indicates the phase of the two SNPs. As a proof of concept, we tested the assay on four variants of an arbitrary sequence-with or without mutation on two sites 100 nts apart. The assay described herein was able to determine the haplotype phase of the samples in less than 1 h. This method promises a direct, cost-effective, and laboratory-based test to extract further genetic information to determine and/or predict diseases and traits dependent on SNP phasing. PMID- 28806065 TI - Synthesis, Characterization, and Selective Delivery of DARPin-Gold Nanoparticle Conjugates to Cancer Cells. AB - We demonstrate that the designed ankyrin repeat protein (DARPin)_9-29, which specifically targets human epidermal growth factor receptor 2 (HER 2), binds tightly to gold nanoparticles (GNPs). Binding of the protein strongly increases the colloidal stability of the particles. The results of experimental analysis and molecular dynamics simulations show that approximately 35 DARPin_9-29 molecules are bound to the surface of a 5 nm GNP and that the binding does not involve the receptor-binding domain of the protein. The confocal fluorescent microscopy studies show that the DARPin-coated GNP conjugate specifically interacts with the surface of human cancer cells overexpressing epidermal growth factor receptor 2 (HER2) and enters the cells by endocytosis. The high stability under physiological conditions and high affinity to the receptors overexpressed by cancer cells make conjugates of plasmonic gold nanostructures with DARPin molecules promising candidates for cancer therapy. PMID- 28806066 TI - Thiol-Mediated Synthesis of Hyaluronic Acid-Epigallocatechin-3-O-Gallate Conjugates for the Formation of Injectable Hydrogels with Free Radical Scavenging Property and Degradation Resistance. AB - Hyaluronic acid (HA)-based biomaterials have demonstrated only limited in vivo stability as a result of rapid degradation by hyaluronidase and reactive oxidative species. The green tea catechin, (-)-epigallocatechin-3-O-gallate (EGCG), has received considerable attention because of its powerful antioxidant and enzyme-inhibitory activities. We describe here the synthesis of HA-EGCG conjugate using a thiol-mediated reaction and its use for the preparation of a long-lasting injectable hydrogel. HA-EGCG conjugates with tunable degrees of substitution were synthesized by the nucleophilic addition reaction between EGCG quinone and thiolated HA under mild conditions. Contrary to unmodified HA, the conjugates exhibited free radical scavenging and hyaluronidase-inhibitory activities. Peroxidase-catalyzed coupling reaction between EGCG moieties was employed to produce in situ forming HA-EGCG hydrogel with surprisingly high resistance to hyaluronidase-mediated degradation. When injected subcutaneously in mice, HA-EGCG hydrogel was retained much longer than HA-tyramine hydrogel with minimal inflammation. PMID- 28806067 TI - Immunosensor Employing Stable, Solid 1-Amino-2-naphthyl Phosphate and Ammonia Borane toward Ultrasensitive and Simple Point-of-Care Testing. AB - Biosensors for ultrasensitive point-of-care testing require dried reagents with long-term stability and a high signal-to-background ratio. Although ortho substituted diaromatic dihydroxy and aminohydroxy compounds undergo fast redox reactions, they are not used as electrochemical signaling species because they are readily oxidized and polymerized by dissolved oxygen. In this report, stable, solid 1-amino-2-naphthyl phosphate (1A2N-P) and ammonia-borane (H3N-BH3) are respectively employed as a substrate for alkaline phosphatase (ALP) and a reductant for electrochemical-chemical (EC) redox cycling. ALP converts 1A2N-P to 1-amino-2-naphthol (1A2N), which is then employed in EC redox cycling using H3N BH3. The oxidation and polymerization of 1A2N by dissolved oxygen is significantly prevented in the presence of H3N-BH3. The electrochemical measurement is performed without modification of indium-tin oxide (ITO) electrodes with electrocatalytic materials. For comparison, nine aromatic dihydroxy and aminohydroxy compounds, including 1A2N, are evaluated to achieve fast EC redox cycling, and four strong reductants, including H3N-BH3, are evaluated to achieve a low background level. The combination of 1A2N and H3N-BH3 allows the achievement of a very high signal-to-background ratio. When the newly developed combination is applied to the detection of creatine kinase-MB (CK-MB), the detection limit for CK-MB is ~80 fg/mL, indicating that the combination allows ultrasensitive detection. The concentrations of CK-MB in clinical serum samples, determined using the developed system, are in good agreement with the concentrations obtained using a commercial instrument. Thus, the use of stable, solid 1A2N-P and H3N-BH3 along with bare ITO electrodes is highly promising for ultrasensitive and simple point-of-care testing. PMID- 28806068 TI - In Situ Atomic-Scale Studies of the Formation of Epitaxial Pt Nanocrystals on Monolayer Molybdenum Disulfide. AB - Pt-nanocrystal:MoS2 hybrid materials have promising catalytic properties for hydrogen evolution, and understanding their detailed structures at the atomic scale is crucial to further development. Here, we use an in situ heating holder in an aberration-corrected transmission electron microscope to study the formation of Pt nanocrystals directly on the surface of monolayer MoS2 from a precursor on heating to 800 degrees C. Isolated single Pt atoms and small nanoclusters are observed after in situ heating, with two types of preferential alignment between the Pt nanocrystals and the underlying monolayer MoS2. Strain effects and thickness variations of the ultrasmall Pt nanocrystal supported on MoS2 are studied, revealing that single atomic planes are formed from a nonlayered face-centered cubic bulk Pt configuration with a lattice expansion of 7-10% compared to that of bulk Pt. The Pt nanocrystals are surrounded by an amorphous carbon layer and in some cases have etched the local surrounding MoS2 material after heating. Electron beam irradiation also initiates Pt nanocrystal etching of the local MoS2, and we study this process in real time at atomic resolution. These results show that the presence of carbon around the Pt nanocrystals does not affect their epitaxial relationship with the MoS2 lattice. Single Pt atoms within the carbon layer are also immobilized at high temperature. These results provide important insights into the formation of Pt:MoS2 hybrid materials. PMID- 28806069 TI - Oxidation Kinetics of Bromophenols by Nonradical Activation of Peroxydisulfate in the Presence of Carbon Nanotube and Formation of Brominated Polymeric Products. AB - This work demonstrated that bromophenols (BrPs) could be readily oxidized by peroxydisulfate (PDS) activated by a commercial carbon nanotube (CNT), while furfuryl alcohol (a chemical probe for singlet oxygen (1O2)) was quite refractory. Results obtained by radical quenching experiments, electron paramagnetic resonance spectroscopy, and Fourier transform infrared spectroscopy further confirmed the involvement of nonradical PDS-CNT complexes rather than 1O2. Bicarbonate and chloride ion exhibited negligible impacts on BrPs degradation by the PDS/CNT system, while a significant inhibitory effect was observed for natural organic matter. The oxidation of BrPs was influenced by solution pH with maximum rates occurring at neutral pH. Linear free energy relationships (LFERs) were established between the observed pseudo-first-order oxidation rates of various substituted phenols and the classical descriptor variables (i.e., Hammett constant sigma+, and half-wave oxidation potential E1/2). Products analyses by liquid chromatography tandem mass spectrometry clearly showed the formation of hydroxylated polybrominated diphenyl ethers and hydroxylated polybrominated biphenyls on CNT surface. Their formation pathway possibly involved the generation of bromophenoxyl radicals from BrPs one-electron oxidation and their subsequent coupling reactions. These results suggest that the novel nonradical PDS/CNT oxidation technology is a good alternative for selectively eliminating BrPs with alleviating toxic byproducts in treated water effluent. PMID- 28806070 TI - High Levels of Daytime Molecular Chlorine and Nitryl Chloride at a Rural Site on the North China Plain. AB - Molecular chlorine (Cl2) and nitryl chloride (ClNO2) concentrations were measured using chemical ionization mass spectrometry at a rural site over the North China Plain during June 2014. High levels of daytime Cl2 up to ~450 pptv were observed. The average diurnal Cl2 mixing ratios showed a maximum around noon at ~100 pptv. ClNO2 exhibited a strong diurnal variation with early morning maxima reaching ppbv levels and afternoon minima sustained above 60 pptv. A moderate correlation (R2 = 0.31) between Cl2 and sulfur dioxide was observed, perhaps indicating a role for power plant emissions in the generation of the observed chlorine. We also observed a strong correlation (R2 = 0.83) between daytime (10:00-20:00) Cl2 and ClNO2, which implies that both of them were formed from a similar mechanism. In addition, Cl2 production is likely associated with a photochemical mechanism as Cl2 concentrations varied with ozone (O3) levels. The impact of Cl2 and ClNO2 as Cl atom sources is investigated using a photochemical box model. We estimated that the produced Cl atoms oxidized slightly more alkanes than OH radicals and enhanced the daily concentrations of peroxy radicals by 15% and the O3 production rate by 19%. PMID- 28806071 TI - Contrasting Effects of Dissolved Organic Matter on Mercury Methylation by Geobacter sulfurreducens PCA and Desulfovibrio desulfuricans ND132. AB - Natural dissolved organic matter (DOM) affects mercury (Hg) redox reactions and anaerobic microbial methylation in the environment. Several studies have shown that DOM can enhance Hg methylation, especially under sulfidic conditions, whereas others show that DOM inhibits Hg methylation due to strong Hg-DOM complexation. In this study, we investigated and compared the effects of DOM on Hg methylation by an iron-reducing bacterium Geobacter sulfurreducens PCA and a sulfate-reducing bacterium Desulfovibrio desulfuricans ND132 under nonsulfidic conditions. The methylation experiment was performed with washed cells either in the absence or presence of DOM or glutathione, both of which form strong complexes with Hg via thiol-functional groups. DOM was found to greatly inhibit Hg methylation by G. Sulfurreducens PCA but enhance Hg methylation by D. desulfuricans ND132 cells with increasing DOM concentration. These strain dependent opposing effects of DOM were also observed with glutathione, suggesting that thiols in DOM likely played an essential role in affecting microbial Hg uptake and methylation. Additionally, DOM and glutathione greatly decreased Hg sorption by G. sulfurreducens PCA but showed little effect on D. desulfuricans ND132 cells, demonstrating that ND132 has a higher affinity to sorb or take up Hg than the PCA strain. These observations indicate that DOM effects on Hg methylation are bacterial strain specific, depend on the DOM:Hg ratio or site specific conditions, and may thus offer new insights into the role of DOM in methylmercury production in the environment. PMID- 28806072 TI - Modeling of the Passive Permeation of Mercury and Methylmercury Complexes Through a Bacterial Cytoplasmic Membrane. AB - Cellular uptake and export are important steps in the biotransformation of mercury (Hg) by microorganisms. However, the mechanisms of transport across biological membranes remain unclear. Membrane-bound transporters are known to be relevant, but passive permeation may also be involved. Inorganic HgII and methylmercury ([CH3HgII]+) are commonly complexed with thiolate ligands. Here, we have performed extensive molecular dynamics simulations of the passive permeation of HgII and [CH3HgII]+ complexes with thiolate ligands through a model bacterial cytoplasmic membrane. We find that the differences in free energy between the individual complexes in bulk water and at their most favorable position within the membrane are ~2 kcal mol-1. We provide a detailed description of the molecular interactions that drive the membrane crossing process. Favorable interactions with carbonyl and tail groups of phospholipids stabilize Hg containing solutes in the tail-head interface region of the membrane. The calculated permeability coefficients for the neutral compounds CH3S-HgII-SCH3 and CH3HgII-SCH3 are on the order of 10-5 cm s-1. We conclude that small, nonionized Hg-containing species can permeate readily through cytoplasmic membranes. PMID- 28806073 TI - Transformation among Aromatic Iodinated Disinfection Byproducts in the Presence of Monochloramine: From Monoiodophenol to Triiodophenol and Diiodonitrophenol. AB - Aromatic iodinated disinfection byproducts (DBPs) are a newly identified category of highly toxic DBPs. Among the identified aromatic iodinated DBPs, 2,4,6 triiodophenol and 2,6-diiodo-4-nitrophenol have shown relatively widespread occurrence and high toxicity. In this study, we found that 4-iodophenol underwent transformation to form 2,4,6-triiodophenol and 2,6-diiodo-4-nitrophenol in the presence of monochloramine. The transformation pathways were investigated, the decomposition kinetics of 4-iodophenol and the formation of 2,4,6-triiodophenol and 2,6-diiodo-4-nitrophenol were studied, the factors affecting the transformation were examined, the toxicity change during the transformation was evaluated, and the occurrence of the proposed transformation pathways during chloramination of source water was verified. The results revealed that 2,4,6 triiodophenol and 2,6-diiodo-4-nitrophenol, which could account for 71.0% of iodine in the transformed 4-iodophenol, were important iodinated transformation products of 4-iodophenol in the presence of monochloramine. The transformation pathways of 4-iodophenol in the presence of monochloramine were proposed and verified. The decomposition of 4-iodophenol in the presence of monochloramine followed a pseudo-second-order decay. Various factors including monochloramine dose, pH, temperature, nitrite concentration, and free chlorine contact time (before chloramination) affected the transformation. The cytotoxicity of the chloraminated 4-iodophenol samples increased continuously with contact time. The proposed transformation pathways occurred during chloramination of source water. PMID- 28806074 TI - Mechanical-Bond-Protected, Air-Stable Radicals. AB - Radical templation centered around a heterotrisradical tricationic inclusion complex DB*+?DAPQT2(*+), assembled from an equimolar mixture of a disubstituted 4,4'-bipyridinium radical cation (DB*+) and an asymmetric cyclophane bisradical dication (DAPQT2(*+)), affords a symmetric [2]catenane (SC.7PF6) and an asymmetric [2]catenane (AC.7PF6) on reaction of the 1:1 complex with diazapyrene and bipyridine, respectively. Both these highly charged [2]catenanes have been isolated as air-stable monoradicals and characterized by EPR spectroscopy. X-ray crystallography suggests that the unpaired electrons are delocalized in each case across two inner 4,4'-bipyridinium (BIPY2+) units forming a mixed-valence (BIPY2)*3+ state inside both [2]catenanes, an observation which is in good agreement with spin-density calculations using density functional theory. Electrochemical studies indicate that by replacing the BIPY2+ units in homo[2]catenane HC*7+-composed of two mechanically interlocked cyclobis(paraquat p-phenylene) rings-with "zero", one, and two more highly conjugated diazapyrenium dication (DAP2+) units, respectively, a consecutive series of five, six, and seven redox states can be accessed in the resulting SC.7PF6 (0, 4+, 6+, 7+, and 8+), HC.7PF6 (0, 2+, 4+, 6+, 7+, and 8+), and AC.7PF6 (0, 1+, 2+, 4+, 6+, 7+, and 8+), respectively. These unique [2]catenanes present a promising prototype for the fabrication of high-density data memories. PMID- 28806075 TI - Reversible On-Off Switching of a Single-Molecule Magnet via a Crystal-to-Crystal Chemical Transformation. AB - Dynamic molecular crystals are of high interest due to their potential applications. Herein we report the reversible on-off switching of single-molecule magnet (SMM) behavior in a [Mo(CN)7]4- based molecular compound. Upon dehydration and rehydration, the trinuclear Mn2Mo molecule [Mn(L)(H2O)]2[Mo(CN)7].2H2O (1) undergoes reversible crystal-to-crystal transformation to a hexanuclear Mn4Mo2 compound [Mn(L)(H2O)]2[Mn(L)]2[Mo(CN)7]2 (2). This structural transformation involves the breaking and reforming of coordination bonds which leads to significant changes in the color and magnetic properties. Compound 1 is an SMM with an energy barrier of 44.9 cm-1, whereas 2 behaves as a simple paramagnet despite its higher ground state spin value. The distortion of the pentagonal bipyramidal geometry of [Mo(CN)7]4- in 2 disrupts the anisotropic exchange interactions that lead to SMM behavior in 1. PMID- 28806077 TI - Structural Studies of Bulk to Nanosize Niobium Oxides with Correlation to Their Acidity. AB - Hydrated niobium oxides are used as strong solid acids with a wide variety of catalytic applications, yet the correlations between structure and acidity remain unclear. New insights into the structural features giving rise to Lewis and Bronsted acid sites are presently achieved. It appears that Lewis acid sites can arise from lower coordinate NbO5 and in some cases NbO4 sites, which are due to the formation of oxygen vacancies in thin and flexible NbO6 systems. Such structural flexibility of Nb-O systems is particularly pronounced in high surface area nanostructured materials, including few-layer to monolayer or mesoporous Nb2O5.nH2O synthesized in the presence of stabilizers. Bulk materials on the other hand only possess a few acid sites due to lower surface areas and structural rigidity: small numbers of Bronsted acid sites on HNb3O8 arise from a protonic structure due to the water content, whereas no acid sites are detected for anhydrous crystalline H-Nb2O5. PMID- 28806076 TI - Structure-Affinity Relationships and Structure-Kinetics Relationships of Pyrido[2,1-f]purine-2,4-dione Derivatives as Human Adenosine A3 Receptor Antagonists. AB - We expanded on a series of pyrido[2,1-f]purine-2,4-dione derivatives as human adenosine A3 receptor (hA3R) antagonists to determine their kinetic profiles and affinities. Many compounds showed high affinities and a diverse range of kinetic profiles. We found hA3R antagonists with very short residence time (RT) at the receptor (2.2 min for 5) and much longer RTs (e.g., 376 min for 27 or 391 min for 31). Two representative antagonists (5 and 27) were tested in [35S]GTPgammaS binding assays, and their RTs appeared correlated to their (in)surmountable antagonism. From a kon-koff-KD kinetic map, we divided the antagonists into three subgroups, providing a possible direction for the further development of hA3R antagonists. Additionally, we performed a computational modeling study that sheds light on the crucial receptor interactions, dictating the compounds' binding kinetics. Knowledge of target binding kinetics appears useful for developing and triaging new hA3R antagonists in the early phase of drug discovery. PMID- 28806078 TI - Time-Dependent Coupled Perturbed Hartree-Fock and Density-Functional-Theory Approach for Calculating Frequency-Dependent (Hyper)Polarizabilities with Nonorthogonal Localized Molecular Orbitals. AB - The time-dependent coupled perturbed Hartree-Fock/density-functional-theory (TDHF/TDDFT) approach has been reformulated based on nonorthogonal localized molecular orbitals (NOLMOs). Based on the NOLMO Fock equation, we have derived the corresponding NOLMO-TDHF/TDDFT equations up to the third order, and the formula for the frequency-dependent (hyper)polarizabilities has been given. Our approach has been applied to calculate both static and dynamic (hyper)polarizabilities of molecules varying from small molecules to large molecules. The NOLMO-TDHF/TDDFT approach can reproduce the reference canonical molecular orbital (CMO) results for all of our testing calculations. With the help of ongoing development of optimized local virtual molecular orbitals, the NOLMO-TDHF/TDDFT approach would be a very efficient method for large system calculations and tp achieve linear scaling. PMID- 28806080 TI - Dissociative Photoionization of the Elusive Vinoxy Radical. AB - These experiments report the dissociative photoionization of vinoxy radicals to m/z = 15 and 29. In a crossed laser-molecular beam scattering apparatus, we induce C-Cl bond fission in 2-chloroacetaldehyde by photoexcitation at 157 nm. Our velocity measurements, combined with conservation of angular momentum, show that 21% of the C-Cl photofission events form vinoxy radicals that are stable to subsequent dissociation to CH3 + CO or H + ketene. Photoionization of these stable vinoxy radicals, identified by their velocities, which are momentum matched with the higher-kinetic-energy Cl atom photofragments, shows that the vinoxy radicals dissociatively photoionize to give signal at m/z = 15 and 29. We calibrated the partial photoionization cross section of vinoxy to CH3+ relative to the bandwidth-averaged photoionization cross section of the Cl atom at 13.68 eV to put the partial photoionization cross sections on an absolute scale. The resulting bandwidth-averaged partial cross sections are 0.63 and 1.3 Mb at 10.5 and 11.44 eV, respectively. These values are consistent with the upper limit to the cross section estimated from a study by Savee et al. on the O(3P) + propene bimolecular reaction. We note that the uncertainty in these values is primarily dependent on the signal attributed to C-Cl primary photofission in the m/z = 35 (Cl+) time-of-flight data. While the value is a rough estimate, the bandwidth averaged partial photoionization cross section of vinoxy to HCO+ calculated from the signal at m/z = 29 at 11.53 eV is approximately half that of vinoxy to CH3+. We also present critical points on the potential energy surface of the vinoxy cation calculated at the G4//B3LYP/6-311++G(3df,2p) level of theory to support the observation of dissociative ionization of vinoxy to both CH3+ and HCO+. PMID- 28806081 TI - Chlorination Kinetics of 11-Nor-9-carboxy-Delta9-tetrahydrocannabinol: Effects of pH and Humic Acid. AB - The main psychoactive compound in marijuana, Delta9-tetrahydrocannabinol (THC), and its metabolites are emerging organic contaminants that have been detected in waste and surface waters. As legalization of marijuana for medical and recreational use continues, the effects of increased use and potency of marijuana on water and wastewater treatment processes and the environment should be considered. This study examined degradation kinetics of the main urinary metabolite of THC, 11-nor-9-carboxy-Delta9-tetrahydrocannabinol (THC-COOH) with chlorine. THC-COOH was rapidly removed from both deionized (DI) water at pH 5.6 +/- 0.2 and Suwannee River humic acid (SRHA) at pH 5.1 +/- 0.2 using low doses of chlorine (0.1 to 0.50 mg free Cl2/L), with half-lives calculated from second order kinetics constants (k2) of 8 s for DI and 42 s for DI with SRHA. Kinetic rates increased with an increase in pH from 5 to 9 in both DI water and SRHA and no interference from phosphate was observed. The chlorination pathway of electrophilic substitution of Cl at the ortho or para position of the phenol structure of THC-COOH was confirmed by detection of monochlorinated byproduct fragmentation ions using flow injection analysis with orbitrap mass spectrometry. PMID- 28806079 TI - Pilot in Vivo Structure-Activity Relationship of Dihydromethysticin in Blocking 4 (Methylnitrosamino)-1-(3-pyridyl)-1-butanone-Induced O6-Methylguanine and Lung Tumor in A/J Mice. AB - (+)-Dihydromethysticin was recently identified as a promising lung cancer chemopreventive agent, while (+)-dihydrokavain was completely ineffective. A pilot in vivo structure-activity relationship (SAR) was explored, evaluating the efficacy of its analogs in blocking 4-(methylnitrosamino)-1-(3-pyridyl)-1 butanone-induced short-term O6-methylguanine and long-term adenoma formation in the lung tissues in A/J mice. Both results revealed cohesive SARs, demonstrating that the methylenedioxy functional group in DHM is essential while the lactone functional group tolerates modifications. PMID- 28806083 TI - The Versatile Personality of Beryllium: Be(O2)1-2 vs Be(CO)1-2. AB - To reveal the diverse chemistry of beryllium, we employ multireference methodologies to study the ground and several excited electronic states of the titled beryllium oxides and carbonyls. The two types of complexes serve as model systems to describe the various ways that beryllium can form chemical bonds. Be(O2), its isomer OBeO, and Be(O2)2 are ionic compounds where beryllium is best represented in its Be(II) oxidation state. On the other hand, CO induces the excitation of one or two 2s electrons of beryllium to its 2p shell. In this manner, the beryllium core (Be2+) is exposed and enables the formation of dative bonds from the lone pair of carbonyls to Be. For all of the considered electronic states, we provide accurate optimal geometries and excitation energies. PMID- 28806085 TI - Resolving Discrepancy between Theory and Experiment in 4-Nitrotoluene Oxidation. AB - We have performed calculations of possible oxidation pathways of 4-nitrotoluene (4NT) by permanganate anion and evaluated relative contributions of oxidation of the methyl group and aromatic ring. Although a few theory levels matched the experimental results obtained by compound specific isotope analysis (CSIA) for 4NT, they failed in reproducing results for other nitrotoluene derivatives studied previously [Wijker, R.S.; Adamczyk, P.; Bolotin, J.; Paneth, P.; Hofstetter, T.B. Environ. Sci. Technol., 2013, 47, 13459-13468]. This discrepancy prompted us to reevaluate the experimental isotopic fractionation of carbon and hydrogen for 4NT on which the relative contributions of the oxidation channels has been based. Using position specific isotope analysis (PSIA) for hydrogen isotopic fractionation we have found that the previously determined value was incorrect. Reexamination of theory levels that are in agreement with these new findings indicated that while a better agreement for this particular case can be reached, overall, the previously used B3LYP functional expressed in the 6 31+G(d,p) basis set with inclusion of the polarized continuum model (PCM) of aqueous solution remains the theoretical level of choice in modeling oxidation of nitrotoluene derivatives by permanganate. PMID- 28806082 TI - The Discovery of Novel Antimalarial Aminoxadiazoles as a Promising Nonendoperoxide Scaffold. AB - Since the appearance of resistance to the current front-line antimalarial treatments, ACTs (artemisinin combination therapies), the discovery of novel chemical entities to treat the disease is recognized as a major global health priority. From the GSK antimalarial set, we identified an aminoxadiazole with an antiparasitic profile comparable with artemisinin (1), with no cross-resistance in a resistant strains panel and a potential new mode of action. A medicinal chemistry program allowed delivery of compounds such as 19 with high solubility in aqueous media, an acceptable toxicological profile, and oral efficacy. Further evaluation of the lead compounds showed that in vivo genotoxic degradants might be generated. The compounds generated during this medicinal chemistry program and others from the GSK collection were used to build a pharmacophore model which could be used in the virtual screening of compound collections and potentially identify new chemotypes that could deliver the same antiparasitic profile. PMID- 28806084 TI - Photochemical Activation of Tertiary Amines for Applications in Studying Cell Physiology. AB - Representative tertiary amines were linked to the 8-cyano-7-hydroxyquinolinyl (CyHQ) photoremovable protecting group (PPG) to create photoactivatable forms suitable for use in studying cell physiology. The photoactivation of tamoxifen and 4-hydroxytamoxifen, which can be used to activate Cre recombinase and CRISPR Cas9 gene editing, demonstrated that highly efficient release of bioactive molecules could be achieved through one- and two-photon excitation (1PE and 2PE). CyHQ-protected anilines underwent a photoaza-Claisen rearrangement instead of releasing amines. Time-resolved spectroscopic studies revealed that photorelease of the tertiary amines was extremely fast, occurring from a singlet excited state of CyHQ on the 70 ps time scale. PMID- 28806087 TI - Size-Dependent Relationships between Protein Stability and Thermal Unfolding Temperature Have Important Implications for Analysis of Protein Energetics and High-Throughput Assays of Protein-Ligand Interactions. AB - Changes in protein stability are commonly reported as changes in the melting temperature, Delta TM, or as changes in unfolding free energy at a particular temperature, DeltaDelta G degrees . Using data for 866 mutants from 16 proteins, we examine the relationship between DeltaDelta G degrees and Delta TM. A linear relationship is observed for each protein. The slopes of the plots of Delta TM vs DeltaDelta G degrees for different proteins scale as N-1, where N is the number of residues in the protein. Thus, a given change in Delta G degrees causes a much larger change in TM for a small protein relative to the effect observed for a large protein. The analysis suggests that reasonable estimates of DeltaDelta G degrees for a mutant can be obtained by interpolating measured values of TM. The relationship between DeltaDelta G degrees and Delta TM has implications for the design and interpretation of high-throughput assays of protein-ligand binding. So called thermal shift assays rely upon the increase in stability which results from ligand binding to the folded state. Quantitative relationships are derived which show that the observed thermal shift, Delta TM, scales as N-1. Hence, thermal shift assays are considerably less sensitive for ligand binding to larger proteins. PMID- 28806086 TI - Role of Electrostatics in Protein-RNA Binding: The Global vs the Local Energy Landscape. AB - U1A protein-stem loop 2 RNA association is a basic step in the assembly of the spliceosomal U1 small nuclear ribonucleoprotein. Long-range electrostatic interactions due to the positive charge of U1A are thought to provide high binding affinity for the negatively charged RNA. Short range interactions, such as hydrogen bonds and contacts between RNA bases and protein side chains, favor a specific binding site. Here, we propose that electrostatic interactions are as important as local contacts in biasing the protein-RNA energy landscape toward a specific binding site. We show by using molecular dynamics simulations that deletion of two long-range electrostatic interactions (K22Q and K50Q) leads to mutant-specific alternative RNA bound states. One of these states preserves short range interactions with aromatic residues in the original binding site, while the other one does not. We test the computational prediction with experimental temperature-jump kinetics using a tryptophan probe in the U1A-RNA binding site. The two mutants show the distinct predicted kinetic behaviors. Thus, the stem loop 2 RNA has multiple binding sites on a rough RNA-protein binding landscape. We speculate that the rough protein-RNA binding landscape, when biased to different local minima by electrostatics, could be one way that protein-RNA interactions evolve toward new binding sites and novel function. PMID- 28806088 TI - Giant Valley-Isospin Conductance Oscillations in Ballistic Graphene. AB - At high magnetic fields the conductance of graphene is governed by the half integer quantum Hall effect. By local electrostatic gating a p-n junction perpendicular to the graphene edges can be formed, along which quantum Hall channels copropagate. It has been predicted by Tworzidlo and co-workers that if only the lowest Landau level is filled on both sides of the junction, the conductance is determined by the valley (isospin) polarization at the edges and by the width of the flake. This effect remained hidden so far due to scattering between the channels copropagating along the p-n interface (equilibration). Here we investigate p-n junctions in encapsulated graphene with a movable p-n interface with which we are able to probe the edge-configuration of graphene flakes. We observe large quantum conductance oscillations on the order of e2/h which solely depend on the p-n junction position providing the first signature of isospin-defined conductance. Our experiments are underlined by quantum transport calculations. PMID- 28806089 TI - Spatially Resolved Magnetic Anisotropy of Cobalt Nanostructures on the Au(111) Surface. AB - Understanding the origin of perpendicular magnetic anisotropy in surface supported nanoclusters is crucial for fundamental research as well as data storage applications. Here, we investigate the perpendicular magnetic anisotropy energy (MAE) of bilayer cobalt islands on Au(111) substrate using spin-polarized scanning tunneling microscopy at 4.6 K and first-principles theoretical calculations. Au(111) substrate serves as an excellent model system to study the effect of nucleation site and stacking sequence on MAE. Our measurements reveal that the MAE of bilayer islands depends strongly on the crystallographic stacking of the two Co layers and nucleation of the third layer. Moreover, the MAE of Co atoms on Au(111) is enhanced by a factor of 1.75 as compared to that reported on Cu(111). Our first-principles calculations attribute this enhancement to the large spin-orbit coupling of the Au atoms. Our results highlight the strong impact of nanometer-scale structural changes in Co islands on MAE and emphasize the importance of spatially resolved measurements for the magnetic characterization of surface-supported nanostructures. PMID- 28806090 TI - Phonon Speed, Not Scattering, Differentiates Thermal Transport in Lead Halide Perovskites. AB - Thermal management plays a critical role in the design of solid state materials for energy conversion. Lead halide perovskites have emerged as promising candidates for photovoltaic, thermoelectric, and optoelectronic applications, but their thermal properties are still poorly understood. Here, we report on the thermal conductivity, elastic modulus, and sound speed of a series of lead halide perovskites MAPbX3 (X = Cl, Br, I), CsPbBr3, and FAPbBr3 (MA = methylammonium, FA = formamidinium). Using frequency domain thermoreflectance, we find that the room temperature thermal conductivities of single crystal lead halide perovskites range from 0.34 to 0.73 W/m.K and scale with sound speed. These results indicate that regardless of composition, thermal transport arises from acoustic phonons having similar mean free path distributions. A modified Callaway model with Born von Karmen-based acoustic phonon dispersion predicts that at least ~70% of thermal conductivity results from phonons having mean free paths shorter than 100 nm, regardless of whether resonant scattering is invoked. Hence, nanostructures or crystal grains with dimensions smaller than 100 nm will appreciably reduce thermal transport. These results are important design considerations to optimize future lead halide perovskite-based photovoltaic, optoelectronic, and thermoelectric devices. PMID- 28806091 TI - Sparsity-Based Super Resolution for SEM Images. AB - The scanning electron microscope (SEM) is an electron microscope that produces an image of a sample by scanning it with a focused beam of electrons. The electrons interact with the atoms in the sample, which emit secondary electrons that contain information about the surface topography and composition. The sample is scanned by the electron beam point by point, until an image of the surface is formed. Since its invention in 1942, the capabilities of SEMs have become paramount in the discovery and understanding of the nanometer world, and today it is extensively used for both research and in industry. In principle, SEMs can achieve resolution better than one nanometer. However, for many applications, working at subnanometer resolution implies an exceedingly large number of scanning points. For exactly this reason, the SEM diagnostics of microelectronic chips is performed either at high resolution (HR) over a small area or at low resolution (LR) while capturing a larger portion of the chip. Here, we employ sparse coding and dictionary learning to algorithmically enhance low-resolution SEM images of microelectronic chips-up to the level of the HR images acquired by slow SEM scans, while considerably reducing the noise. Our methodology consists of two steps: an offline stage of learning a joint dictionary from a sequence of LR and HR images of the same region in the chip, followed by a fast-online super resolution step where the resolution of a new LR image is enhanced. We provide several examples with typical chips used in the microelectronics industry, as well as a statistical study on arbitrary images with characteristic structural features. Conceptually, our method works well when the images have similar characteristics, as microelectronics chips do. This work demonstrates that employing sparsity concepts can greatly improve the performance of SEM, thereby considerably increasing the scanning throughput without compromising on analysis quality and resolution. PMID- 28806092 TI - Comparable Outcomes After Bucket-Handle Meniscal Repair and Vertical Meniscal Repair Can Be Achieved at a Minimum 2 Years' Follow-up. AB - BACKGROUND: Meniscal tears can lead to significant pain and disability, necessitating surgical treatment. Nondisplaced vertical tears are usually smaller in size and can be repaired in most cases; however, bucket-handle tears are usually larger and displaced, and the repair of these tears can be challenging. Purpose/Hypothesis: The purpose was to report the outcomes after inside-out vertical mattress suture meniscal repair of bucket-handle tears and to compare these outcomes with those of patients who underwent repair of nondisplaced vertical meniscal tears with a minimum of 2 years' follow-up. The hypothesis was that the outcomes of bucket-handle tear repair would be comparable with those of nondisplaced vertical meniscal tear repair. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Patients who underwent inside-out repair of a bucket-handle meniscal tear or a nondisplaced vertical meniscal tear with a minimum 2 years' follow-up were included in this study. Patients were excluded if they had a diagnosis of a meniscal root tear, underwent a concomitant procedure for a chondral injury, or underwent previous surgical treatment of the same meniscus. Subjective questionnaires were administered preoperatively and postoperatively, including the Lysholm score, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Short Form-12 (SF-12) physical component summary (PCS) and mental component summary (MCS), the Tegner activity scale, and patient satisfaction. RESULTS: Thirty-two patients underwent repair for vertical meniscal tears (mean, 7 sutures), while 38 patients underwent repair for bucket handle meniscal tears (mean, 11 sutures), with a mean follow-up of 3.1 years (range, 2-6 years). There were no significant differences in the preoperative outcome scores between the 2 groups. Significant improvements in patient-reported outcome scores from preoperatively to postoperatively were found in both groups. A direct comparison of the bucket-handle tear group to the vertical tear group did not exhibit significantly different SF-12 PCS scores (54.0 vs 51.6, respectively; P = .244), SF-12 MCS scores (55.3 vs 52.5, respectively; P = .165), WOMAC scores (8.1 vs 9.0, respectively; P = .729), Lysholm scores (84.6 vs 80.8, respectively; P = .276), Tegner scores (5.5 vs 5.5, respectively; P = .970), and patient satisfaction scores (7.4 vs 7.7, respectively; P = .570). Additionally, a comparison of acute and chronic bucket-handle tears demonstrated no significant difference in outcome scores. CONCLUSION: The repair of bucket-handle meniscal tears with multiple vertical mattress sutures using an inside-out technique yielded improved results and low failure rates, comparable with outcomes after repair of nondisplaced vertical meniscal tears. The findings of this study support repairing bucket-handle meniscal tears with multiple vertical mattress sutures when possible. PMID- 28806093 TI - Critical Shoulder Angle and Acromial Index Do Not Influence 24-Month Functional Outcome After Arthroscopic Rotator Cuff Repair. AB - BACKGROUND: Recent studies have shown a correlation between scapular geometry and the development of atraumatic rotator cuff tears. However, a paucity of literature is available on the effects of critical shoulder angle (CSA) and acromial index (AI) on functional outcomes after arthroscopic rotator cuff repair. Hypothesis/Purpose: The purpose was to investigate the influence of CSA and AI on 24-month functional outcomes after arthroscopic rotator cuff repair. The hypothesis was that a larger CSA or AI would result in poorer postoperative outcomes. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: The study included 147 patients who underwent arthroscopic double-row rotator cuff repair for radiologically documented full-thickness supraspinatus tears. An independent reviewer measured the CSA and AI on preoperative radiographs. These patients were prospectively enrolled and were evaluated preoperatively as well as at 3, 6, 12, and 24 months postoperatively. Functional outcome was assessed with the Constant Shoulder Score (CSS), Oxford Shoulder Score (OSS), and University of California at Los Angeles (UCLA) Shoulder Rating Scale. The patients were first divided based on CSA: (1) <=35 degrees (control CSA) and (2) >35 degrees (increased CSA); and then based on AI: (1) <=0.7 and (2) >0.7. The Student unpaired t test, Pearson chi-square test, and Pearson correlation were performed to examine the influence of CSA and AI on postoperative functional outcome scores. RESULTS: At 6 months of follow-up, the CSS, OSS, and UCLA Shoulder Rating Scale were 10 +/- 1, 4 +/- 2, and 3 +/- 1 points poorer in the increased CSA group compared with the control CSA group ( P = .005, P = .030, and P = .035, respectively). These scores were not significantly different between both AI groups. By 24 months of follow up, all outcome scores were comparable between both CSA groups as well as between both AI groups. No significant correlation was found between either CSA or AI when compared with CSS, OSS, or UCLA Shoulder Rating Scale at 24 months of follow up. CONCLUSION: CSA and AI do not appear to influence 24-month functional outcomes postoperatively and hence are not contraindications to arthroscopic rotator cuff repair. PMID- 28806094 TI - The Relationship of Throwing Arm Mechanics and Elbow Varus Torque: Within-Subject Variation for Professional Baseball Pitchers Across 82,000 Throws. AB - BACKGROUND: Likely due to the high level of strain exerted across the elbow during the throwing motion, elbow injuries are on the rise in baseball. To identify at-risk athletes and guide postinjury return-to-throw programs, a better understanding of the variables that influence elbow varus torque is desired. PURPOSE: To describe the within-subject relationship between elbow varus torque and arm slot and arm rotation in professional baseball pitchers. STUDY DESIGN: Descriptive laboratory study. METHODS: A total of 81 professional pitchers performed 82,000 throws while wearing a motusBASEBALL sensor and sleeve. These throws represented a combination of throw types, such as warm-up/catch, structured long-toss, bullpen throwing from a mound, and live game activity. Variables recorded for each throw included arm slot (angle of the forearm relative to the ground at ball release), arm speed (maximal rotational velocity of the forearm), arm rotation (maximal external rotation of the throwing arm relative to the ground), and elbow varus torque. Linear mixed-effects models and likelihood ratio tests were used to estimate the relationship between elbow varus torque and arm slot, arm speed, and arm rotation within individual pitchers. RESULTS: All 3 metrics-arm slot (chi2 = 428, P < .001), arm speed (chi2 = 57,683, P < .001), and arm rotation (chi2 = 1392, P < .001)-were found to have a significant relationship with elbow varus torque. Within individual athletes, a 1 N.m increase in elbow varus torque was associated with a 13 degrees decrease in arm slot, a 116 deg/s increase in arm speed, and an 8 degrees increase in arm rotation. CONCLUSION: Elbow varus torque increased significantly as pitchers increased their arm rotation during the arm cocking phase, increased the rotational velocity of their arm during the arm acceleration phase of throwing, and decreased arm slot at ball release. Thus, shoulder flexibility, arm speed, and elbow varus torque (and likely injury risk) are interrelated and should be considered collectively when treating pitchers. CLINICAL RELEVANCE: It is well established that elbow varus torque is related to ulnar collateral ligament injuries in overhead throwers. This study describes the relationship of arm slot, arm speed, and arm rotation to elbow varus torque in an attempt to identify modifiable risk factors for injury. PMID- 28806095 TI - A Midterm Evaluation of Postoperative Platelet-Rich Plasma Injections on Arthroscopic Supraspinatus Repair: A Randomized Controlled Trial. AB - BACKGROUND: Platelet-rich plasma (PRP) has been applied as an adjunct to rotator cuff repair to improve tendon-bone healing and potentially reduce the incidence of subsequent tendon retears. PURPOSE: To investigate whether the midterm clinical and radiographic outcomes of arthroscopic supraspinatus repair are enhanced after repeated postoperative applications of PRP. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 60 patients (30 control; 30 PRP) were initially randomized to receive 2 ultrasound guided injections of PRP to the tendon repair site at 7 and 14 days after double row arthroscopic supraspinatus repair or not. A total of 55 patients (91.7%) underwent a clinical review and magnetic resonance imaging (MRI) at a mean of 3.5 years after surgery (range, 36-51 months). Patient-reported outcome measures (PROMs) included the Constant score, Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) questionnaire, Oxford Shoulder Score (OSS), and visual analog scale (VAS) for pain. Global rating of change (GRC) scale and patient satisfaction scores were evaluated. Structural integrity of the surgical repair was assessed via MRI using the Sugaya classification system. RESULTS: At the midterm review, there was no difference between the groups for any of the PROMs. No differences between the groups were demonstrated for the subjective and range of motion subscales of the Constant score, although a significantly higher Constant strength subscale score was observed in the PRP group (3.3 points; 95% CI, 1.0-5.7; P = .006). There was no evidence for any group differences in MRI scores or retear rates, with 66.7% of PRP patients and 64.3% of control patients rated as Sugaya grade 1. Two control patients had symptomatic retears (both full thickness) within the first 16 weeks after surgery compared with 2 PRP patients, who suffered symptomatic retears (both partial thickness) between 16 weeks and a mean 3.5-year follow-up. CONCLUSION: Significant postoperative clinical improvements and high levels of patient satisfaction were observed in patients at the midterm review after supraspinatus repair. While pain-free, maximal abduction strength was greater in the midterm after PRP treatment, repeated applications of PRP delivered at 7 and 14 days after surgery provided no additional benefit to tendon integrity. PMID- 28806096 TI - Results of Anterior Cruciate Ligament Reconstruction With Patellar Tendon Autografts: Objective Factors Associated With the Development of Osteoarthritis at 20 to 33 Years After Surgery. AB - BACKGROUND: Few studies exist that report objective radiographic and physical examination results at >20 years after anterior cruciate ligament (ACL) reconstruction. HYPOTHESIS: The risk of osteoarthritis (OA) at >20 years after surgery would be statistically significantly higher if an increased severity of factors was present. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Between 1982 and 1994, 1428 knees met the inclusion criteria of being primary ACL surgery, having no existing OA or other ligamentous laxity, and having no known graft tear. Prospective data analyzed included demographics; meniscus and articular cartilage status; ratings of bilateral standing posteroanterior weightbearing, lateral, and Merchant view radiographs; KT-1000 arthrometer measurements; and range of motion measurements. Radiographs were graded for joint space narrowing, sclerosis, and osteophytes according to International Knee Documentation Committee (IKDC) criteria. Multivariate and univariate logistic models were used to determine the effect of potential predictors on the odds of having radiographic evidence of OA. IKDC and Cincinnati Knee Rating System (CKRS) subjective surveys were conducted. RESULTS: A minimum 20-year objective follow-up was obtained for 423 knees at a mean of 22.5 +/- 2.1 years postoperatively. If a patient lacked normal extension or flexion at discharge, the odds of lacking normal extension or flexion at follow-up were 19.7 and 7.97, respectively ( P < .001). Radiographic ratings were normal for 35.2%, nearly normal for 36.2%, abnormal for 20.1%, and severely abnormal for 8.5%. Multivariate analysis showed that the predictive factors for the presence of OA in the long-term were medial meniscectomy, older age at surgery, and less than normal knee extension at discharge. The odds ratios for statistically significant factors for the presence of any OA at follow-up were 2.02 for knee extension loss at discharge, 2.98 for medial meniscectomy, 1.65 for lateral meniscectomy, 1.06 for age at follow-up, 1.62 for chronic injury type, and 2.17 for articular cartilage damage. The IKDC and CKRS subjective scores were progressively and statistically significantly lower as the level of OA was greater. CONCLUSION: The prevalence rate of developing moderate to severe OA at >20 years after ACL reconstruction was 28.6%. Significant factors predictive of OA in the long-term were older age at surgery, medial meniscectomy, and knee extension loss. PMID- 28806097 TI - Opioid Demand Before and After Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: Surgeons and health care systems have received a call to action in an effort to curtail the current opioid epidemic. PURPOSE: To (1) define the natural history of opioid demand after anterior cruciate ligament reconstruction (ACLR), (2) consider how filling preoperative opioid prescriptions affects opioid demand after ACLR, and (3) evaluate the effect of additional procedures during ACLR and patient age on postoperative opioid demand. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: ACLRs performed in the Humana database between 2007 and 2014 were identified using Current Procedural Terminology code 29888. Patients were considered preoperative opioid users if they had filled an opioid prescription in the 3 months preceding surgery. Patients were defined as "chronic" opioid users if they had filled a prescription preoperatively at 1 to 3 months from surgery. Further categorization was performed by identifying patients who only underwent ACLR with no other procedures, those who underwent ACLR with meniscus repair, those who underwent ACLR with meniscectomy, and those who underwent ACLR with microfracture. Categorization by age was also performed. The relative risk (RR) of postoperative opioid use was calculated, and 95% CIs were determined. RESULTS: Over the course of the study period, 4946 ACLRs were performed. At 3 months after their procedure, 7.24% of patients were still filling opioid prescriptions. At 9 and 12 months postoperatively, 4.97% and 4.71% of patients, respectively, were still filling opioid prescriptions. Nearly 35% of patients (1716/4946) were filling opioid pain prescriptions in the 3 months before ACLR. Those filling preoperative opioid prescriptions were 5.35 (95% CI, 4.15-6.90) times more likely to be filling opioid prescriptions at 3 months after ACLR than nonusers (15.38% vs 2.88%, respectively). Those filling opioid prescriptions chronically before surgery were at a 10.50 (95% CI, 7.53-14.64) times increased risk of filling postoperative opioid prescriptions at 5 months. At 5 months postoperatively, patients undergoing ACLR with microfracture had a 1.96 (95% CI, 1.34-2.87) increased risk of filling opioid prescriptions compared with ACLR alone, 2.38 (95% CI, 1.48-3.82) increased risk compared with ACLR with meniscus repair, and 1.51 (95% CI, 1.04-2.19) increased risk compared with ACLR with meniscectomy. Patients younger than 25 years of age had an increased risk of filling opioid prescriptions after ACLR at all time points of the study. CONCLUSION: Opioid demand after ACLR dropped significantly in the vast majority of patients by the third postoperative month. Surprisingly, 35% of patients undergoing ACLR were observed to be using opioid medication preoperatively, and this study found preoperative opioid use to be a strong predictor of postoperative opioid demand with a 5- to 7-fold increased risk in this patient population. Patients who were filling opioid prescriptions 1 to 3 months from their surgical date were at the highest risk for postoperative opioid utilization. Patients undergoing ACLR with microfracture were at an increased risk of filling opioid prescriptions. Patients less than 25 years of age were at an elevated risk of filling opioid prescriptions at all time points postoperatively. PMID- 28806098 TI - Social Media Monitoring: 2016 Zika Response in NYC. AB - From the Field is a semi-regular column that explores what it means to be a local health professional on the front lines of an emergency. National Association of County and City Health Officials (NACCHO) members share their stories of preparing for and responding to disasters, epidemics, and other major health issues. Through exploring the analysis of the challenges faced and the solutions developed, readers can learn how these public health champions keep their communities safe even in extreme situations. Readers may submit topics of interest to the column's editor, Meghan McGinty, PhD, MPH, MBA, at mmcginty@naccho.org . PMID- 28806099 TI - Lessons from Interspecies Mammalian Chimeras. AB - As chimeras transform from beasts of Greek mythology into tools of contemporary bioscience, secrets of developmental biology and evolutionary divergence are being revealed. Recent advances in stem cell biology and interspecies chimerism have generated new models with extensive basic and translational applications, including generation of transplantable, patient-specific organs. PMID- 28806100 TI - Including the Copenhagen Adduction Exercise in the FIFA 11+ Provides Missing Eccentric Hip Adduction Strength Effect in Male Soccer Players: A Randomized Controlled Trial. AB - BACKGROUND: The FIFA 11+ was developed as a complete warm-up program to prevent injuries in soccer players. Although reduced hip adduction strength is associated with groin injuries, none of the exercises included in the FIFA 11+ seem to specifically target hip adduction strength. PURPOSE: To investigate the effect on eccentric hip adduction strength of the FIFA 11+ warm-up program with or without the Copenhagen adduction exercise. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: We recruited 45 eligible players from 2 U19 elite male soccer teams. Players were randomized into 2 groups; 1 group carried out the standard FIFA 11+ program, while the other carried out the FIFA 11+ but replaced the Nordic hamstring exercise with the Copenhagen adduction exercise. Both groups performed the intervention 3 times weekly for 8 weeks. Players completed eccentric strength and sprint testing before and after the intervention. Per protocol analyses were performed, and 12 players were excluded due to low compliance (<67% of sessions completed). The main outcome was eccentric hip adduction strength (N.m/kg). RESULTS: Between-group analyses revealed a significantly greater increase in eccentric hip adduction strength of 0.29 Nm/kg (8.9%; P = .01) in favor of the group performing the Copenhagen adduction exercise, whereas no within-group change was noted in the group that used the standard FIFA 11+ program (-0.02 N.m/kg [-0.7%]; P = .69). CONCLUSION: Including the Copenhagen adduction exercise in the FIFA 11+ program increases eccentric hip adduction strength, while the standard FIFA 11+ program does not. Registration: Registration: ISRCTN13731446 (International Standard Randomised Controlled Trial Number registry). PMID- 28806101 TI - Homeless women's service use, barriers, and motivation for participating in substance use treatment. AB - BACKGROUND: Homeless women are at high risk for substance use disorder (SUD), and are a growing proportion of the homeless population. However, homeless women experience barriers to engaging in substance use services. OBJECTIVES: Among homeless women with SUD, to explore service use, motivation to change, service barriers, and willingness to have substance use and mental health problems addressed in primary health care. METHODS: Women with SUD were sampled from 11 Health Care for the Homeless (HCH) primary care clinics in 9 states, yielding 241 with either an alcohol or drug use disorder who then completed questions about SUD services. RESULTS: Over 60% of women with dual alcohol and drug use disorders used some type of SUD service in the past year, while 52% with a drug only disorder, and 44% with an alcohol only disorder used services. The most mentioned barrier to service use was depression, but cost, wait time, where to find treatment, and facilities located too far away, were also frequently noted. A large proportion across all groups indicated high motivation for treatment and willingness to discuss their SUD in a primary care setting. CONCLUSION: There are continued barriers to SUD service use for homeless women despite high motivation for treatment, and willingness to be asked about SUD and mental health problems in primary care. HCH primary care sites should more systematically ask about SUD and mental health issues and address women's expressed need for support groups and alternative therapies to more holistically address their SUD needs. PMID- 28806102 TI - Effects of alcohol consumption on blood pressure in hypertensive women. AB - BACKGROUND: Problem drinking carries significant health burdens, including an increased risk of hypertension. The effect of chronic alcohol intake on blood pressure (BP) in women is understudied and poorly understood. OBJECTIVES: We sought to examine the relationships between drinking habits and BP in hypertensive women. METHODS: We analyzed drinking habits in 113 women followed in the Brigham and Women's Hospital Hypertension Clinic for at least one year. RESULTS: Among these women with well-controlled hypertension, baseline diastolic BP was significantly lower in moderate drinkers compared with women who rarely or never drank. Changes in both systolic and diastolic BP over 12 months showed a significant negative association with changes in percent drinking days. In contrast, there was a trend toward higher baseline systolic BP among those women who consumed more drinks per drinking day. CONCLUSIONS: Among these women with controlled hypertension, our data failed to demonstrate an association between drinking beyond recommended limits and higher disease burden. These findings parallel the widely reported difference between drinking frequency, associated with a host of positive health outcomes, and drinking intensity, associated with negative outcomes. Novel to this report is an observed reduction in blood pressure over the one-year follow-up period accompanying an increased drinking frequency in treated hypertensive women. Cautions include the suggestion that a greater number of drinks per drinking day was associated with higher baseline pressure. These data imply that drinking within sensible limits has no negative impact on chronic hypertension. In fact, for women with well-controlled hypertension, such a habit may impart benefit. PMID- 28806106 TI - The authors respond. PMID- 28806105 TI - Zika Virus in Ontario: Evaluating a Rapid Risk Assessment Tool. PMID- 28806104 TI - Repetitive transcranial magnetic stimulation (rTMS) administration to heavy cannabis users. AB - BACKGROUND: Cannabis use disorder (CUD) is a common condition with few treatments. Several studies in other substance use disorders have found that applying repetitive transcranial magnetic stimulation (rTMS) to the dorsolateral prefrontal cortex (DLPFC) decreases cue-elicited craving and possibly decreases use. To date, there have been no studies attempting to use rTMS in CUD. OBJECTIVES: This study was conducted to determine if rTMS could be feasibly delivered to a group of non-treatment seeking CUD participants. Secondarily, the study aimed to estimate the effect of rTMS on craving. METHODS: In a double blind, sham-controlled, crossover design, a single session of active or sham rTMS (Left DLPFC, 10 Hz, 110% rMT, 4000 pulses) was delivered during a validated cannabis cue paradigm. Participants crossed over to complete the other condition one week later. The feasibility and tolerability were measured by the rate of retention, and the percentage of participants able to tolerate full dose rTMS, respectively. Craving was measured using the Marijuana Craving Questionnaire (MCQ). RESULTS: Eighteen non-treatment seeking CUD participants were recruited from the community; 16 (three women) completed the trial (89% retained for the three study visits). All of the treatment completers tolerated rTMS at full dose without adverse effects. There was not a significant reduction in the total MCQ when participants received active rTMS as compared to sham rTMS. CONCLUSION: rTMS can be safely and feasibly delivered to CUD participants, and treatment is well tolerated. A single session of rTMS applied to the DLPFC may not reduce cue elicited craving in heavy cannabis users. PMID- 28806103 TI - Hsp83 loss suppresses proteasomal activity resulting in an upregulation of caspase-dependent compensatory autophagy. AB - The 2 main degradative pathways that contribute to proteostasis are the ubiquitin proteasome system and autophagy but how they are molecularly coordinated is not well understood. Here, we demonstrate an essential role for an effector caspase in the activation of compensatory autophagy when proteasomal activity is compromised. Functional loss of Hsp83, the Drosophila ortholog of human HSP90 (heat shock protein 90), resulted in reduced proteasomal activity and elevated levels of the effector caspase Dcp-1. Surprisingly, genetic analyses showed that the caspase was not required for cell death in this context, but instead was essential for the ensuing compensatory autophagy, female fertility, and organism viability. The zymogen pro-Dcp-1 was found to interact with Hsp83 and undergo proteasomal regulation in an Hsp83-dependent manner. Our work not only reveals unappreciated roles for Hsp83 in proteasomal activity and regulation of Dcp-1, but identifies an effector caspase as a key regulatory factor for sustaining adaptation to cell stress in vivo. PMID- 28806107 TI - The case for lymphoma-specific survival. PMID- 28806108 TI - The composition of a protein aggregate modulates the specificity and efficiency of its autophagic degradation. AB - The mechanism underlying autophagic degradation of a protein aggregate remains largely unknown. A family of receptor proteins that simultaneously bind to the cargo and the Atg8 family of autophagy proteins (such as the MAP1LC3/LC3 subfamily) has been shown to confer cargo selectivity. The selectivity and efficiency of protein aggregate removal is also modulated by scaffold proteins that interact with receptor proteins and ATG proteins. During C. elegans embryogenesis, autophagic clearance of the cargoes PGL-1 and PGL-3 requires the receptor protein SEPA-1 and the scaffold protein EPG-2. SEPA-1 and EPG-2 also form aggregates that are degraded by autophagy. Here we investigated the effect of composition and organization of PGL granules on their autophagic degradation. We found that depletion of PGL-1 or PGL-3 facilitates the degradation of SEPA-1 and EPG-2. Removal of EPG-2 is also promoted when SEPA-1 is absent. Depletion of PGL-1 or PGL-3 renders the degradation of SEPA-1 independent of EPG-2. We further showed that overexpression of SEPA-1 or EPG-2 as well as SQST-1 or EPG-7 (scaffold protein), which belong to different classes of aggregate, has no evident effect on the degradation of the other type. Our results indicate that the composition and organization of protein aggregates provide another layer of regulation to modulate degradation efficiency. PMID- 28806109 TI - Reflections on Leadership and Governance from the Incident Manager of Liberia's Ebola Response. AB - The 2014-2016 epidemic of Ebola virus disease occurred in a region with a recent history of civil war, unstable health systems, and widespread poverty. Despite these contextual challenges, the national Ebola response in Liberia controlled transmission under strong leadership that was able to rapidly coordinate activities, to manage local and international players, and to adapt upon recognizing missteps. Such leadership has persisted to improve public health capacity in post-Ebola Liberia. This article highlights the progress made toward developing a resilient health security system with capacity to prevent, detect, and respond to disease threats before they reach epidemic level. In particular, Liberia's development of a Global Health Security Agenda roadmap, a Joint External Evaluation (JEE) report for International Health Regulation (2005) core capacities, and recent establishment of a National Public Health Institute are described. To better protect the country's population and the greater global community from health threats, emerging institutions and policies in Liberia will depend on leadership and governance that draws from the successes and lessons learned during the Ebola outbreak. The author provides insight based on his role as incident manager of Liberia's Ebola response. PMID- 28806110 TI - [Anteposition in malignant hematologic diseases of siblings in Szabolcs-Szatmar Bereg county, Hungary. Analysis of data of a 34-year period]. AB - INTRODUCTION: In their previous works, the authors reported findings from familial hematologic malignancies in Szabolcs-Szatmar-Bereg county, Hungary. So far there are no other studies on this topic available in Hungary. AIM: Detailed analysis of epidemiologic features of hematologic malignancies of siblings. METHOD: During a 34-year period (between January 1, 1983 and December 31, 2016), 86 families with hematologic malignancies were recorded in Szabolcs-Szatmar-Bereg county. Among them, 19 cases of the affected siblings were registered. RESULTS: In one family there were three sisters with polycythaemia vera, hence the number of analysed disease associations was 21. In all of the 21 cases, the younger sibling's disease developed earlier. The average anteposition was 10.8 (1-33) years (median: 10 years). CONCLUSION: The anticipation was earlier observed in multigeneration hematological malignancies between direct and collateral descendants. On the basis of the above data, anteposition of the disease was observed in younger siblings. Orv Hetil. 2017; 158(33): 1283-1287. PMID- 28806111 TI - [Effectiveness of mindfulness-based cancer recovery (MBCR) program among Hungarian cancer patients]. AB - INTRODUCTION AND AIM: Employment of mindfulness-based programs and techniques in the treatment of cancer patients have spread exponentially in the past decade. A large number of studies have proved the effectiveness of the program in the reduction of stress symptoms, depression and anxiety, and the improvement of sleep and mood patterns. The present study was done at Firebird Foundation and examines the effectiveness of the complex, MBCR (mindfulness-based cancer recovery)-based psycho-social intervention in the treatment of cancer patients. METHOD: The experimental group consisted of 101 people with various types and states of cancer. The control group consisted of 72 adjusted people. We did measurements (PPS, HADS, FACT-G, POMS-SF, Freiburg Adaptation Questionnaire) before the intervention (T1), right after the 8-week intervention (T2), and 6 months after the intervention (T3). RESULTS: The experimental group showed significant improvement in the measured psychological variables, and in few aspects of life quality between T1 and T2. There was a decrease in levels of observed stress and depression, and an escalation in optimism and vitality. We found a decrease in depressive and minimizing coping scores as well. There was a significant improvement in two dimensions of quality of life, and all these positive changes remained present by the end of the follow-up period (T3). In the control group, we only found a significant increase in minimizing coping scores at the time of T3 measurements. This is the first impact assessment study done on cancer patients using MBCR techniques in Hungary. CONCLUSIONS: The MBCR program is a very effective psychosocial intervention among cancer patients; it has a long term significant impact on mood and quality of life. Orv Hetil. 2017; 158(33): 1293-1301. PMID- 28806114 TI - [Endoscopic ultra dream pulse laser surgery of laryngomalacia. Our experiences gained during the introduction of the method in Hungary]. AB - INTRODUCTION: Congenital stridor and dyspnoe are caused by laryngomalacia in most cases. AIM: In this article we present a new, surgical method for treating severe laryngomalacia in patients under the age of 1, where ultrapulsated (UDP) laser beam is used for supraglottoplasty. Ultra dream pulse laser creates lesser thermical side damage in the tissue, therefore the risk of postoperative laryngeal oedema and scarring is lower. METHOD: We present 10 cases and the endoscopic UDP-laser surgery of patients under the age of 1 with severe laryngomalacia. RESULTS: After the surgery the stridorous symptoms disappeared, and there was no evidence of postoperative laryngeal oedema, there was no need for reoperation or tracheotomy in any of the cases. CONCLUSION: UDP-laser surgery of laryngomalacia is proven to be a safe and effective surgial modality. During the follow up visits we experienced neither recurrence of stridor nor laryngeal scarring. Orv Hetil. 2017; 158(33): 1288-1292. PMID- 28806113 TI - [Hungarian Diet and Nutritional Status Survey - The OTAP2014 study. V. Vitamin intake of the Hungarian population]. AB - INTRODUCTION AND AIM: The Hungarian Diet and Nutritional Status Survey was implemented on a sub-sample of the European Health Interview Survey. In this paper, the authors present the data on the vitamin intake of the Hungarian population. METHOD: The survey represents the vitamin intake of the Hungarian non institutionalised adult population of 18 years and older. There are significant differences between men's and women's vitamin intake. RESULTS: The intake of all water-soluble vitamins except for vitamin C is higher in men than in women, and the difference between the genders regarding the intake of vitamin E and D is significant. The intake of vitamin B1, B2, B6, B12, niacin and vitamin C is in line with the recommendations, however, there is an unfavourable decrease in the intake of vitamin A and beta-carotene in the case of men compared to the previous survey. Vitamin D and folic acid intakes are critically low, particularly in the elderly, and mainly in case of vitamin D. The population's intake of panthotenic acid and biotin did not reach the recommendations. CONCLUSION: In order to reach the dietary reference intakes and to prevent deficiencies, it is necessary to inform the population and to make healthy food choices available. Orv Hetil. 2017; 158(33): 1302-1313. PMID- 28806115 TI - [Combined treatment of avulsion of maxillary central incisors]. AB - Avulsion of the permanent teeth is one of the most serious forms of traumatic dental injuries, which endangers the patients' quality of life. Therefore, the fast and proper treatment is crucial. In this case report we will discuss the supportive and definitive functional treatment and correct rehabilitation. The traumatic force can cause complex oral and maxillofacial injuries, which comprehensive treatment constitutes a major challenge for the dentist. Here we review functional restoration of dental injuries and their definitive aesthetic solution. Orv Hetil. 2017; 158(33): 1314-1318. PMID- 28806116 TI - Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. AB - Purpose Provide evidence-based recommendations updating the 2015 ASCO guideline on systemic therapy for patients with stage IV non-small-cell lung cancer (NSCLC). Methods The ASCO NSCLC Expert Panel made recommendations based on a systematic review of randomized controlled trials from February 2014 to December 2016 plus the Cancer Care Ontario Program in Evidence-Based Care's update of a previous ASCO search. Results This guideline update reflects changes in evidence since the previous guideline update. Fourteen randomized controlled trials provide the evidence base; earlier phase trials also informed recommendation development. Recommendations New or revised recommendations include the following. Regarding first-line treatment for patients with non-squamous cell carcinoma or squamous cell carcinoma (without positive markers, eg, EGFR/ALK /ROS1), if the patient has high programmed death ligand 1 (PD-L1) expression, pembrolizumab should be used alone; if the patient has low PD-L1 expression, clinicians should offer standard chemotherapy. All other clinical scenarios follow 2015 recommendations. Regarding second-line treatment in patients who received first-line chemotherapy, without prior immune checkpoint therapy, if NSCLC tumor is positive for PD-L1 expression, clinicians should use single-agent nivolumab, pembrolizumab, or atezolizumab; if tumor has negative or unknown PD-L1 expression, clinicians should use nivolumab or atezolizumab. All immune checkpoint therapy is recommended alone plus in the absence of contraindications. For patients who received a prior first-line immune checkpoint inhibitor, clinicians should offer standard chemotherapy. For patients who cannot receive immune checkpoint inhibitor after chemotherapy, docetaxel is recommended; in patients with nonsquamous NSCLC, pemetrexed is recommended. In patients with a sensitizing EGFR mutation, disease progression after first-line epidermal growth factor receptor tyrosine kinase inhibitor therapy, and T790M mutation, osimertinib is recommended; if NSCLC lacks the T790M mutation, then chemotherapy is recommended. Patients with ROS1 gene rearrangement without prior crizotinib may be offered crizotinib, or if they previously received crizotinib, they may be offered chemotherapy. PMID- 28806117 TI - Postdiagnosis Statin Use and Mortality in Danish Patients With Prostate Cancer. AB - Purpose Increasing evidence indicates that statin use may reduce mortality from prostate cancer. In this work, we examined whether postdiagnosis statin use was associated with reduced cancer-specific mortality or all-cause mortality among patients with prostate cancer in Denmark. Material and Methods From nationwide Danish registries, we identified all patients with incident prostate adenocarcinoma from 1998 to 2011 and retrieved data on tumor and patient characteristics, drug use, and primary treatment. We defined postdiagnosis use (two or more prescriptions) of statins as a time-varying covariate with 1-year lag. Cox proportional hazards regression models used to compute hazard ratios (HRs) for prostate cancer-specific mortality and all-cause mortality through 2013 associated with postdiagnosis statin use. In secondary and sensitivity analyses, we assessed statin use within exposure periods of 1 year or 5 years after prostate cancer diagnosis and evaluated the influence of prediagnosis statin use. Results Among 31,790 patients, 7,365 died of prostate cancer and 11,811 died from other causes during a median follow-up of 2.8 years (interquartile range, 1.3 to 5.1 years) from 1 year after diagnosis. Postdiagnosis statin use was associated with adjusted HRs of 0.83 (95% CI, 0.77 to 0.89) for prostate cancer mortality and 0.81 (95% CI, 0.76 to 0.85) for all-cause mortality. Similar results were observed in 1-year and 5-year sensitivity analyses. No substantial effect measure modification was found with estimated dose or type of statin, clinical stage, Gleason score, or with prediagnosis statin use; however, patients who were diagnosed early in the study period or who underwent radical prostatectomy or endocrine therapy exhibited slightly lower HRs for prostate cancer mortality with postdiagnosis statin use than did those in the overall analyses. Conclusion Postdiagnosis statin use was associated with reduced mortality from prostate cancer; however, it remains to be established whether this association is causal. PMID- 28806118 TI - Banter. PMID- 28806121 TI - Social Capital Accumulation in Location-Based Mobile Game Playing: A Multiple Process Approach. AB - In the summer of 2016, the widespread popularization of the game Pokemon Go brought the public's attention to the possible socialization benefits associated with location-based mobile games (LBMGs), yet no studies to date have investigated this issue. LBMGs deserve greater research attention because this type of game provides a unique gaming experience that encourages players to leave their homes and navigate around their neighborhood. This distinctive feature may promote more face-to-face interactions among LBMG players. Grounded in social capital theories, the present study compared the levels of both bridging and bonding social capital between LBMG and non-LBMG players. More important, we formulated a multiple-process model to explain the hypothesized psychological mechanisms underlying social capital accumulation among LBMG players. Participants were 349 U.S. participants (57 percent men; Mage = 32.40, SDage = 7.92, age range = 19-66). Results supported the proposed model by revealing that face-to-face interaction was crucial to the accrual of both bridging and bonding social capital among LBMG players, through enhancing their levels of communication frequency and self-disclosure. The present findings have implications for the utilization of LBMG as a potential tool to promote face-to face interactions and accumulate social capital. PMID- 28806122 TI - Sexual Attitudes of Classes of College Students Who Use Pornography. AB - Pornography is widely accepted and used as an appropriate sexual practice. Previous literature has suggested that pornography users may be best viewed through a heterogenetic lens that indicates specific classes of pornography users. Furthering this previous research, a latent profile analysis was conducted using a sample of 635 college students (mean age men 20.22 (standard deviation [SD] = 3.10); women 19.16 [SD = 2.12]) over two time points to not only identify unique classifications of pornography users, but also examine specific sexual attitudes 3 months later of each classification. When deriving types, the Pornography Consumption Inventory, frequency of pornography use, gradation of pornography acceptance, the Brief Sexual Attitudes Scale, and religiosity were used. For men, two classes of users were statistically derived based on the above variables: permissive porn explorers (n = 102) and sexual communion and dabbling porn users (n = 55). For women, two classes emerged: nonpermissive porn abstainers (n = 421) and instrumental, integrated porn users (n = 57). These results develop greater detail of different types of pornography users by exploring various sexual attitudes associated with their pornography use patterns. PMID- 28806119 TI - How Augmented Reality Is Poised to Outpace Virtual Reality. PMID- 28806123 TI - Identity Confusion and Materialism Mediate the Relationship Between Excessive Social Network Site Usage and Online Compulsive Buying. AB - This study investigates the mediating role of identity confusion and materialism in the relationship between social networking site (SNS) excessive usage and online compulsive buying among young adults. A total of 501 SNS users aged 17 to 23 years (M = 19.68, SD = 1.65) completed an online survey questionnaire. A serial multiple mediator model was developed and hypotheses were tested using structural equation modeling. The results showed that excessive young adult SNS users had a higher tendency toward compulsive buying online. This was partly because they experienced higher identity confusion and developed higher levels of materialism. Targeted psychological interventions seeking to gradually increase identity clarity to buffer the detrimental effects of SNS usage and identity confusion in young adults are suggested. PMID- 28806125 TI - Changing Avatars, Changing Selves? The Influence of Social and Contextual Expectations on Digital Rendition of Identity. AB - Avatar creation is an interesting topic for both video game and social network studies. Research has shown that the creation of avatars is influenced by individual, contextual, and cultural features. Avatars are used to represent aspects of users' personality, but multiple avatars are used in different virtual contexts, as self-presentation strategies may vary according to the different "audiences" to be met online (say: friends, or strangers). Moreover, avatar creation is also influenced by cultural variables, such as gender, as avatars embody stereotypical aspects of being a woman or a man. This research tested whether avatars, as digital self-representations, may change depending on the above-mentioned variables. Ninety-four participants created two avatars to be used in different contexts (video game and job-themed social network). Moreover, two groups of participants were told that they would have met friends or total strangers within the two virtual contexts. Results showed that avatars changed from the game to the job context. Changes involved avatars' transient features (Clothes) more than physical (Body) and symbolic (Accessories) ones, and females changed accessories more than males. Moreover, females who expected to meet friends changed their avatars' bodies significantly more than males in both virtual contexts. The findings are discussed based on literature about computer mediated communication and online self-disclosure. In conclusion, possible implications of the results for avatar-based interventions and the field of video games and social network design are reviewed. PMID- 28806126 TI - Development and Validation of an Instrument to Assess the Impact of Cyberbullying: The Cybervictimization Emotional Impact Scale. AB - Cyberbullying is a phenomenon with important adverse consequences on victims. The emotional impact of this phenomenon has been well established. However, there is to date no instrument with good psychometric properties tested to assess such impact. The objective of this study was developing and testing the psychometric properties of an instrument to assess the emotional impact of cyberbullying: the "Cybervictimization Emotional Impact Scale, CVEIS." The sample included 1,016 Compulsory Secondary Education students (52.9 percent female) aged between 12 and 18 (M = 13.86, DT = 1.33) from three schools in southern Spain. The study used Confirmatory Factor Analyses to test the structure of the questionnaire and robustness of the scale. Internal consistency was also tested. The results supported the suitability of a three-factor model: active, depressed, and annoyed. This model showed an optimal adjustment, which was better than its competing models. It also demonstrated strong invariance among cybervictims and non-cybervictims and also among gender. The internal consistency of each factor, and the total scale, was also appropriate. The article concludes by discussing research and practical implications of the scale. PMID- 28806128 TI - Exploring the Motivations for Body Piercing: A Pilot Study. PMID- 28806129 TI - Mental Health Issues and People who Identify as LGBTQSpecial issue of Issues in Mental Health Nursing on the topic of. PMID- 28806131 TI - How to tackle the orthopedic maze. PMID- 28806130 TI - Existential Risk and Cost-Effective Biosecurity. AB - In the decades to come, advanced bioweapons could threaten human existence. Although the probability of human extinction from bioweapons may be low, the expected value of reducing the risk could still be large, since such risks jeopardize the existence of all future generations. We provide an overview of biotechnological extinction risk, make some rough initial estimates for how severe the risks might be, and compare the cost-effectiveness of reducing these extinction-level risks with existing biosecurity work. We find that reducing human extinction risk can be more cost-effective than reducing smaller-scale risks, even when using conservative estimates. This suggests that the risks are not low enough to ignore and that more ought to be done to prevent the worst-case scenarios. PMID- 28806132 TI - Plight of the pore polar bar(rier). PMID- 28806133 TI - Autophagy dictates metabolism and differentiation of inflammatory immune cells. AB - The role of macroautophagy/autophagy, a conserved lysosomal degradation pathway, during cellular differentiation has been well studied over the last decade. In particular, evidence for its role during immune cell differentiation is growing. Despite the description of a variety of dramatic immune phenotypes in tissue specific autophagy knockout models, the underlying mechanisms are still under debate. One of the proposed mechanisms is the impact of autophagy on the altered metabolic states during immune cell differentiation. This concept is strengthened through novel molecular insights into how AMPK and MTOR signaling cascades affect both autophagy and metabolism. In this review, we discuss direct and indirect evidence linking autophagy, metabolic pathways and immune cell differentiation including T, B, and innate lymphocytes as well as in myeloid cells that are direct mediators of inflammation. Herein, we propose a model for autophagy-driven immunometabolism controlling immune cell differentiation. PMID- 28806135 TI - Changes in the Pseudogymnoascus destructans transcriptome during White-nose Syndrome reveal possible mechanisms for both virulence and host resistance. PMID- 28806134 TI - iLIR@viral: A web resource for LIR motif-containing proteins in viruses. AB - Macroautophagy/autophagy has been shown to mediate the selective lysosomal degradation of pathogenic bacteria and viruses (xenophagy), and to contribute to the activation of innate and adaptative immune responses. Autophagy can serve as an antiviral defense mechanism but also as a proviral process during infection. Atg8-family proteins play a central role in the autophagy process due to their ability to interact with components of the autophagy machinery as well as selective autophagy receptors and adaptor proteins. Such interactions are usually mediated through LC3-interacting region (LIR) motifs. So far, only one viral protein has been experimentally shown to have a functional LIR motif, leaving open a vast field for investigation. Here, we have developed the iLIR@viral database ( http://ilir.uk/virus/ ) as a freely accessible web resource listing all the putative canonical LIR motifs identified in viral proteins. Additionally, we used a curated text-mining analysis of the literature to identify novel putative LIR motif-containing proteins (LIRCPs) in viruses. We anticipate that iLIR@viral will assist with elucidating the full complement of LIRCPs in viruses. PMID- 28806137 TI - Thinking More or Feeling Less? Explaining the Foreign-Language Effect on Moral Judgment. AB - Would you kill one person to save five? People are more willing to accept such utilitarian action when using a foreign language than when using their native language. In six experiments, we investigated why foreign-language use affects moral choice in this way. On the one hand, the difficulty of using a foreign language might slow people down and increase deliberation, amplifying utilitarian considerations of maximizing welfare. On the other hand, use of a foreign language might stunt emotional processing, attenuating considerations of deontological rules, such as the prohibition against killing. Using a process dissociation technique, we found that foreign-language use decreases deontological responding but does not increase utilitarian responding. This suggests that using a foreign language affects moral choice not through increased deliberation but by blunting emotional reactions associated with the violation of deontological rules. PMID- 28806136 TI - Harnessing OLIG2 function in tumorigenicity and plasticity to target malignant gliomas. AB - Glioblastoma (GBM) is the most prevalent and malignant brain tumor, displaying notorious resistance to conventional therapy, partially due to molecular and genetic heterogeneity. Understanding the mechanisms for gliomagenesis, tumor stem/progenitor cell propagation and phenotypic diversity is critical for devising effective and targeted therapy for this lethal disease. The basic helix loop-helix transcription factor OLIG2, which is universally expressed in gliomas, has emerged as an important player in GBM cell reprogramming, genotoxic resistance, and tumor phenotype plasticity. In an animal model of proneural GBM, elimination of mitotic OLIG2+ progenitors blocks tumor growth, suggesting that these progenitors are a seeding source for glioma propagation. OLIG2 deletion reduces tumor growth and causes an oligodendrocytic to astrocytic phenotype shift, with PDGFRalpha downregulation and reciprocal EGFR signaling upregulation, underlying alternative pathways in tumor recurrence. In patient-derived glioma stem cells (GSC), knockdown of OLIG2 leads to downregulation of PDGFRalpha, while OLIG2 silencing results in a shift from proneural-to-classical gene expression pattern or a proneural-to-mesenchymal transition in distinct GSC cell lines, where OLIG2 appears to regulate EGFR expression in a context-dependent manner. In addition, post-translational modifications such as phosphorylation by a series of protein kinases regulates OLIG2 activity in glioma cell growth and invasive behaviors. In this perspective, we will review the role of OLIG2 in tumor initiation, proliferation and phenotypic plasticity in animal models of gliomas and human GSC cell lines, and discuss the underlying mechanisms in the control of tumor growth and potential therapeutic strategies to target OLIG2 in malignant gliomas. PMID- 28806138 TI - Lipid droplets and lipotoxicity during autophagy. AB - Lipid droplets (LDs) are neutral lipid storage organelles that provide a rapidly accessible source of fatty acids (FAs) for energy during periods of nutrient deprivation. Surprisingly, lipids released by the macroautophagic/autophagic breakdown of membranous organelles are packaged and stored in new LDs during periods of prolonged starvation. Why cells would store FAs during an energy crisis was unknown. In our recent study, we demonstrated that FAs released during MTORC1-regulated autophagy are selectively channeled by DGAT1 (diacylglycerol O acyltransferase 1) into triacylglycerol (TAG)-rich LDs. These DGAT1-dependent LDs sequester FAs and prevent the accumulation of acylcarnitines, which otherwise directly disrupt mitochondrial integrity. Our findings establish LD biogenesis as a general cellular response to periods of high autophagic flux that provide a lipid buffering system to mitigate lipotoxic cellular damage. PMID- 28806139 TI - Mask mitigates MAPT- and FUS-induced degeneration by enhancing autophagy through lysosomal acidification. AB - Accumulation of intracellular misfolded or damaged proteins is associated with both normal aging and late-onset degenerative diseases. Two cellular clearance mechanisms, the ubiquitin-proteasome system (UPS) and the macroautophagy/autophagy-lysosomal pathway, work in concert to degrade harmful protein aggregates and maintain protein homeostasis. Here we show that Mask, an Ankyrin-repeat and KH-domain containing protein, plays a key role in promoting autophagy flux and mitigating degeneration caused by protein aggregation or impaired UPS function. In Drosophila eye models of human tauopathy or amyotrophic lateral sclerosis diseases, loss of Mask function enhanced, while gain of Mask function mitigated, eye degenerations induced by eye-specific expression of human pathogenic MAPT/TAU or FUS proteins. The fly larval muscle, a more accessible tissue, was then used to study the underlying molecular mechanisms in vivo. We found that Mask modulates the global abundance of K48- and K63-ubiquitinated proteins by regulating autophagy-lysosome-mediated degradation, but not UPS function. Indeed, upregulation of Mask compensated the partial loss of UPS function. We further demonstrate that Mask promotes autophagic flux by enhancing lysosomal function, and that Mask is necessary and sufficient for promoting the expression levels of the proton-pumping vacuolar (V)-type ATPases in a TFEB independent manner. Moreover, the beneficial effects conferred by Mask expression on the UPS dysfunction and neurodegenerative models depend on intact autophagy lysosomal pathway. Our findings highlight the importance of lysosome acidification in cellular surveillance mechanisms and establish a model for exploring strategies to mitigate neurodegeneration by boosting lysosomal function. PMID- 28806140 TI - Adherent-Invasive E. coli enhances colonic hypersensitivity and P2X receptors expression during post-infectious period. AB - Irritable Bowel Syndrome (IBS) and Inflammatory Bowel Disease (IBD) are related gastrointestinal disorders characterized by abdominal pain associated with colonic hypersensitivity (CHS). Studies in humans have reported an abnormal colonization of Adherent-Invasive E. coli (AIEC) in the ileum of Crohn's disease (CD) patients associated with overexpression of the bacterial colonizing receptor CEACAM6. The aim of the present study was to investigate whether AIEC reference strain LF82 could induce intestinal impairment during infectious and/or post infectious periods and subsequently the development of CHS. Transgenic mice overexpressing human CEACAM6 protein (TG) and their wild-type littermates were gavaged by CD-associated AIEC bacteria (reference strain LF82) or PBS for 3 d. Colonic hypersensitivity was assessed by colorectal distension (CRD) test during infectious (D4) and post-infectious periods (D21). Several markers of intestinal inflammation were monitored and the colonic expression of purinergic P2X receptors was quantified. At D4, an increased visceromotor response (VMR) to the CRD test was observed in TG mice infected with CD-associated AIEC LF82 in comparison with non-infected TG mice and persisted in a subgroup of infected animals at D21 after bacteria clearance. Increased VMR was associated with low grade intestinal inflammation, increased intestinal permeability and expression of P2X 3, 4 and 7. This study shows that certain susceptible hosts infected with CD-associated AIEC bacteria can develop persistent CHS associated with low-grade inflammation and increased P2X receptors expression. Thus, CD-associated AIEC infection in CEACAM6 transgenic mice could be used as a novel post-infectious mouse model mimicking quiescent IBD with IBS-like symptoms such as visceral pain. PMID- 28806142 TI - Mucormycosis pathogenesis: Beyond Rhizopus. PMID- 28806144 TI - Particle size distributions of lead measured in battery manufacturing and secondary smelter facilities and implications in setting workplace lead exposure limits. AB - Inhalation plays an important role in exposures to lead in airborne particulate matter in occupational settings, and particle size determines where and how much of airborne lead is deposited in the respiratory tract and how much is subsequently absorbed into the body. Although some occupational airborne lead particle size data have been published, limited information is available reflecting current workplace conditions in the U.S. To address this data gap, the Battery Council International (BCI) conducted workplace monitoring studies at nine lead acid battery manufacturing facilities (BMFs) and five secondary smelter facilities (SSFs) across the U.S. This article presents the results of the BCI studies focusing on the particle size distributions calculated from Personal Marple Impactor sampling data and particle deposition estimates in each of the three major respiratory tract regions derived using the Multiple-Path Particle Dosimetry model. The BCI data showed the presence of predominantly larger-sized particles in the work environments evaluated, with average mass median aerodynamic diameters (MMADs) ranging from 21-32 um for the three BMF job categories and from 15-25 um for the five SSF job categories tested. The BCI data also indicated that the percentage of lead mass measured at the sampled facilities in the submicron range (i.e., <1 um, a particle size range associated with enhanced absorption of associated lead) was generally small. The estimated average percentages of lead mass in the submicron range for the tested job categories ranged from 0.8-3.3% at the BMFs and from 0.44-6.1% at the SSFs. Variability was observed in the particle size distributions across job categories and facilities, and sensitivity analyses were conducted to explore this variability. The BCI results were compared with results reported in the scientific literature. Screening-level analyses were also conducted to explore the overall degree of lead absorption potentially associated with the observed particle size distributions and to identify key issues associated with applying such data to set occupational exposure limits for lead. PMID- 28806145 TI - Technology? Yes. Useable? Not so fast. PMID- 28806141 TI - Cutaneous Leishmaniasis in Saudi Arabia: A Comprehensive Overview. AB - Despite the great efforts by health authorities in Kingdom of Saudi Arabia (KSA), Cutaneous leishmaniasis (CL) continues to be a major public health problem in the country. Many risk factors make KSA prone to outbreaks and epidemics; among these, rapid urbanization and the huge population movement are the most important. The disease is endemic in many parts of KSA, with the majority of cases concentrated in six regions, including Al-Qaseem, Riyadh, Al-Hassa, Aseer, Ha'il, and Al-Madinah. Leishmania major (L. major) and Leishmania tropica (L. tropica) are the main dermotropic species, and Phlebotomus papatasi (vector of L. major) and Phlebotomus sergenti (vector of L. tropica) are the proved vectors of the disease. Psammomys obesus and Meriones libycus have been defined as the principal reservoir hosts of zoonotic CL in Al-Hassa oasis, Al-Madinah, and Al Qaseem provinces. Clinically, males are affected more than females, and there is no variation between the Saudis and expatriates in terms of number of reported cases, but the disease tends to run a more severe course among non-Saudis. Face is the most commonly affected site, and ulcerative pattern accounts for 90% of lesions. Despite local and international recommendations of using laboratory diagnostics to confirm CL cases, most cases in KSA are diagnosed and treated on clinical grounds and local epidemiology. However, systemic parenteral sodium stibogluconate (SSG) is the first line of therapy and used to treat all CL patients irrespective of their clinical presentation or the incriminated species. In brief, more efforts are needed to combat this disease. Several aspects of the disease require more evaluation through encouragement of national and regional studies. Development of evidence based national diagnostic and management guidelines, as well as algorithms, is urgently needed to improve the practice of diagnosing and treating CL in KSA. PMID- 28806143 TI - Whose Preferences Matter? A Patient-Centered Approach for Eliciting Treatment Goals. AB - BACKGROUND: Patients facing a high-stakes clinical decision are often confronted with an overwhelming array of options. High-quality decisions about treatment should reflect patients' preferences as well as their clinical characteristics. Preference-assessment instruments typically focus on pre-selected clinical outcomes and attributes chosen by the investigator. OBJECTIVE: We sought to develop a patient-centered approach to elicit and compare the treatment goals of patients with multiple sclerosis (MS) and healthcare providers (HCPs). METHODS: We conducted five nominal group technique (NGT) meetings to elicit and prioritize treatment goals from patients and HCPs. Five to nine participants in each group responded silently to one question about their treatment goals. Responses were shared, consolidated, and ranked to develop a prioritized list for each group. The ranked lists were combined. Goals were rated and sorted into categories. Multidimensional scaling and hierarchical cluster analysis were used to derive a visual representation, or cognitive map, of the data and to identify conceptual clusters, reflecting how frequently items were sorted into the same category. RESULTS: Five NGT groups yielded 34 unique patient-generated treatment goals and 31 unique HCP-generated goals. There were differences between patients and HCPs in the goals generated and how they were clustered. Patients' goals tended to focus on the impact of specific symptoms on their day-to-day lives, whereas providers' goals focused on slowing down the course of disease progression. CONCLUSIONS: Differences between the treatment goals of patients and HCPs underscore the limitations of using HCP- or investigator-identified goals. This new adaptation of cognitive mapping is a patient-centered approach that can be used to generate and organize the outcomes and attributes for values clarification exercises while minimizing investigator bias and maximizing relevance to patients. PMID- 28806146 TI - * Three-Dimensional Bioprinting of Polycaprolactone Reinforced Gene Activated Bioinks for Bone Tissue Engineering. AB - Regeneration of complex bone defects remains a significant clinical challenge. Multi-tool biofabrication has permitted the combination of various biomaterials to create multifaceted composites with tailorable mechanical properties and spatially controlled biological function. In this study we sought to use bioprinting to engineer nonviral gene activated constructs reinforced by polymeric micro-filaments. A gene activated bioink was developed using RGD-gamma irradiated alginate and nano-hydroxyapatite (nHA) complexed to plasmid DNA (pDNA). This ink was combined with bone marrow-derived mesenchymal stem cells (MSCs) and then co-printed with a polycaprolactone supporting mesh to provide mechanical stability to the construct. Reporter genes were first used to demonstrate successful cell transfection using this system, with sustained expression of the transgene detected over 14 days postbioprinting. Delivery of a combination of therapeutic genes encoding for bone morphogenic protein and transforming growth factor promoted robust osteogenesis of encapsulated MSCs in vitro, with enhanced levels of matrix deposition and mineralization observed following the incorporation of therapeutic pDNA. Gene activated MSC-laden constructs were then implanted subcutaneously, directly postfabrication, and were found to support superior levels of vascularization and mineralization compared to cell-free controls. These results validate the use of a gene activated bioink to impart biological functionality to three-dimensional bioprinted constructs. PMID- 28806148 TI - Atrial Fibrillation Ablation. AB - The prevalence of atrial fibrillation (AF) has risen significantly over the past two decades. Catheter ablation is an increasingly utilized treatment strategy and has evolved significantly over the same time period. Successful ablation improves patient symptoms, reduces stroke risk, and can preserve or improve cardiac function. Recurrences following ablation can occur, particularly in patients with persistent AF. Procedural efficacy can best be improved through continued advancements in ablation technology and strategy, better understanding of the mechanisms of AF initiation and perpetuation, and rigorous integration of ablation into a multidisciplinary AF management approach. PMID- 28806149 TI - Detection of Nanophyetus salmincola in Water, Snails, and Fish Tissues by Quantitative Polymerase Chain Reaction. AB - We report the development and validation of two quantitative PCR (qPCR) assays to detect Nanophyetus salmincola DNA in water samples and in fish and snail tissues. Analytical and diagnostic validation demonstrated good sensitivity, specificity, and repeatability of both qPCR assays. The N. salmincola DNA copy number in kidney tissue was significantly correlated with metacercaria counts based on microscopy. Extraction methods were optimized for the sensitive qPCR detection of N. salmincola DNA in settled water samples. Artificially spiked samples suggested that the 1-cercaria/L threshold corresponded to an estimated log10 copies per liter >= 6.0. Significant correlation of DNA copy number per liter and microscopic counts indicated that the estimated qPCR copy number was a good predictor of the number of waterborne cercariae. However, the detection of real world samples below the estimated 1-cercaria/L threshold suggests that the assays may also detect other N. salmincola life stages, nonintact cercariae, or free DNA that settles with the debris. In summary, the qPCR assays reported here are suitable for identifying and quantifying all life stages of N. salmincola that occur in fish tissues, snail tissues, and water. Received April 13, 2017; accepted August 6, 2017. PMID- 28806147 TI - Phase variation of Clostridium difficile virulence factors. AB - Clostridium difficile is a leading cause of nosocomial infections, causing disease that ranges from mild diarrhea to potentially fatal colitis. A variety of surface proteins, including flagella, enable C. difficile colonization of the intestine. Once in the intestine, toxigenic C. difficile secretes two glucosylating toxins, TcdA and TcdB, which elicit inflammation and diarrheal disease symptoms. Regulation of colonization factors and TcdA and TcdB is an intense area of research in C. difficile biology. A recent publication from our group describes a novel regulatory mechanism that mediates the ON/OFF expression of co-regulated virulence factors of C. difficile, flagella and toxins. Herein, we review key findings from our work, present new data, and speculate the functional consequence of the ON/OFF expression of these virulence factors during host infection. PMID- 28806150 TI - The puncta enigma. AB - This Editor's Corner may sound like the title of a mystery novel, but it actually reflects a question I have about the puncta articles that appear in Autophagy (or rather, the ones that do not appear). In particular, I am surprised by the number of solicitations sent out for puncta that are either ignored, or, less frequently, declined. It is not that I expect the principal investigator (PI) to find the invitation to write a punctum undeniably attractive. Rather, it is the unilateral decision that it is not worthwhile for graduate students or postdocs who performed the work-and likely wrote at least the first draft of the paper-to write the punctum. In fact, time spent drafting a punctum yields considerable benefits: puncta provide more exposure for the lab, offer opportunities for young scientists to gain additional writing experience, and make a nice (albeit small) addition to a curriculum vitae. It is for the latter reason that I find it particularly disappointing that PIs decide to dismiss the opportunity to write a punctum. I fully understand that for many PIs, adding a punctum will not have a significant impact on a curriculum vitae. Yet for a student or a postdoc who might have a relatively small number of publications at this stage of their career, a punctum (even though it is not a full-fledged research article) can have a more meaningful impact on their C.V. PMID- 28806152 TI - Chicken HMGB1 Monoclonal Antibody. PMID- 28806151 TI - Establishment of a Monoclonal Antibody Against chGILZ. AB - The chicken glucocorticoid-induced leucine zipper (chGILZ) participates in the inflammation of avian immunosuppressive diseases. We aimed to establish a monoclonal antibody (MAb) against chGILZ and to investigate its distribution in clinical diagnosis. A gene cloned from chicken embryo fibroblast (CEF) cell was inserted into the expression vector pET-28a and pGEX-6p-1. The recombinant expression vectors were transformed into Escherichia coli BL21 (DE3). Then the recombinant proteins His-chGILZ and GST-chGILZ were successfully expressed and purified. The hybridomas were developed by fusing mouse myeloma cell line SP2/0 with splenocytes of immunized mice and screened with purified GST-chGILZ. Two hybridomas (1D3 and 3F4) were effective in detecting both recombinant and native chGILZ proteins and were isolated and characterized. The MAbs did not react with human GILZ protein, but could recognize chGILZ by Western blot assay. These data and reagents will be of great assistance to elucidate the molecular mechanism of avian immunosuppressive diseases, such as the infectious bursal disease. PMID- 28806154 TI - Monoclonal Antibody 1C11 Mouse Monoclonal Antibody Against Mortalin. PMID- 28806155 TI - Monoclonal Antibody 5F11G11. PMID- 28806153 TI - Expression, Purification, and Refolding of Human Lipocalin 6 and Production of a Monoclonal Antibody Against This Protein. AB - Human lipocalin 6 (hLCN6) is a member of the lipocalin family, which is a group of structurally conserved hydrophobic ligand binding proteins, and widely distributed in animal, plant, and bacteria. Specific expression of hLCN6 in the epididymis and localization of this protein on the surface of spermatozoa suggest a role played by hLCN6, which may function as a transporter to carry ligands in the epididymal channel. However, the role of hLCN6 in sperm maturation has been largely unknown due to the lack of effective antibodies. In this study, we report the prokaryotic expression, purification, and refolding of recombinant hLCN6. Purified hLCN6 protein was used to generate monoclonal antibody (mAb) against this protein using conventional hybridoma techniques. The sensitivity and specificity of the anti-hLCN6 mAb were determined based on their activities in enzyme-linked immunosorbent assay and Western blotting analysis using various human tissues. The results showed that the antibody induced by recombinant hLCN6 protein had high sensitivity and specificity. Taken together, the recombinant hLCN6 protein and mAb against this protein obtained from our study provided useful tools for further exploration of the biological functions and molecular mechanism, as well as pathological significance of LCN6 in human. PMID- 28806156 TI - Letter from the editor. PMID- 28806157 TI - Human Vaccines & Immunotherapeutics: News. PMID- 28806158 TI - Understanding the bell-ringing of concussion. PMID- 28806159 TI - Is spirometry necessary to diagnose and control asthma? PMID- 28806160 TI - Delirium in hospitalized patients: Risks and benefits of antipsychotics. AB - Consensus panel guidelines advocate for the judicious use of antipsychotic drugs to manage delirium in hospitalized patients when nonpharmacologic measures fail and the patient is in significant distress from symptoms, poses a safety risk to self or others, or is impeding essential aspects of his or her medical care. Here, we review the use of haloperidol, olanzapine, quetiapine, risperidone, and aripiprazole for this purpose. PMID- 28806161 TI - Concussion: Evaluation and management. AB - Concussion is a common problem often managed by nonneurologists. It is often accompanied by headaches, dizziness, sleep disturbance, psychiatric symptoms, and cognitive issues. Here, we outline how to evaluate and manage concussion, including treatment of the most common symptoms. PMID- 28806162 TI - Combined hormonal contraceptives and migraine: An update on the evidence. AB - Combined hormonal contraceptives are contraindicated in women who have migraine with aura, in whom these drugs can increase the risk of ischemic stroke. However, this contraindication is based on data from the 1960s and 1970s, when oral contraceptives contained much higher doses of estrogen. Stroke risk is not significantly increased with today's preparations, many of which contain less than 30 MUg of ethinyl estradiol. Further, in continuous regimens, ultra-low-dose formulations--those that contain less than 20 MUg of ethinyl estradiol--may help prevent menstrual migraine and reduce the frequency of aura. PMID- 28806163 TI - Necrotizing pancreatitis: Diagnose, treat, consult. AB - Necrosis significantly increases rates of morbidity and mortality in acute pancreatitis. Hospitalists and general internists are on the front lines in identifying severe cases and consulting the appropriate specialists for optimal multidisciplinary care. PMID- 28806164 TI - Weight loss, fatigue, and renal failure. PMID- 28806165 TI - Breast calcifications mimicking pulmonary nodules. PMID- 28806166 TI - Pseudo-Wellens syndrome after heavy marijuana use. PMID- 28806167 TI - A lump on the hip. PMID- 28806169 TI - Two views of the same stimulus. AB - Signals from two different membrane proteins are combined to modulate how strongly sensory neurons respond to mechanical force. PMID- 28806170 TI - Tips from the embryonic lung. AB - A new source of progenitor cells can now be used to study hidden aspects of human lung development and pediatric lung disease. PMID- 28806168 TI - Mapping the mouse Allelome reveals tissue-specific regulation of allelic expression. AB - To determine the dynamics of allelic-specific expression during mouse development, we analyzed RNA-seq data from 23 F1 tissues from different developmental stages, including 19 female tissues allowing X chromosome inactivation (XCI) escapers to also be detected. We demonstrate that allelic expression arising from genetic or epigenetic differences is highly tissue specific. We find that tissue-specific strain-biased gene expression may be regulated by tissue-specific enhancers or by post-transcriptional differences in stability between the alleles. We also find that escape from X-inactivation is tissue-specific, with leg muscle showing an unexpectedly high rate of XCI escapers. By surveying a range of tissues during development, and performing extensive validation, we are able to provide a high confidence list of mouse imprinted genes including 18 novel genes. This shows that cluster size varies dynamically during development and can be substantially larger than previously thought, with the Igf2r cluster extending over 10 Mb in placenta. PMID- 28806171 TI - The importance of remembering. AB - Creativity in science requires the ability to recall information and data, and will suffer if we rely too much on technology to remember things for us. PMID- 28806174 TI - Left Ventricular Apex Venting in High-Risk Redo Sternotomy With Severe Aortic Insufficiency: A Case Report. AB - Redo cardiac surgery in patients with severe aortic insufficiency can present unique challenges to the anesthesiologist. We report a case highlighting the challenge and importance of interdisciplinary planning between cardiothoracic surgeons and anesthesiologists prior to high-risk surgery. Failure to place an endoaortic balloon and percutaneous coronary sinus catheter due to anatomical abnormalities prompted the adoption of an alternate technique involving apical ventricular venting to assist sternal reentry. Apical left ventricular venting was successfully used to prevent ventricular dilation and dysfunction during institution of cardiopulmonary bypass with significant aortic regurgitation and hypothermia-induced ventricular fibrillation. PMID- 28806175 TI - Point-of-Care Ultrasound Facilitated Detection of Femoral Occlusive Septic Emboli During Mitral Valve Surgery: A Case Report. AB - Acute lower extremity ischemia from septic emboli is a surgical emergency. Timely diagnosis and management are critical to improve patient outcome. However, traditional diagnostic modalities such as intraoperative angiogram are time consuming, require special equipment and personnel, and introduce contrast exposure for critically ill patients. There are limited reports of utilization of point-of-care ultrasound to detect peripheral septic emboli. We present a case where femoral occlusive septic emboli were identified by point-of-care ultrasound after mitral valve replacement. This facilitated early surgical embolectomy and limb salvage. We suggest that perioperative point-of-care ultrasonography should be used as a first-line screening test in patients with acute lower extremity ischemia. PMID- 28806176 TI - Evaluating the Use of Ketamine for Pain Control With Sickle Cell Crisis in Pregnancy: A Report of 2 Cases. AB - Sickle cell crises occur frequently during pregnancy and are difficult to treat, even with high-dose opioids. Analgesia with ketamine has been suggested as an alternative, but its use during pregnancy is underreported. Two pregnant patients with uncontrolled sickle cell pain were treated with ketamine. Patient A reported no decrease in her pain, but her opioid requirements decreased. Patient B's pain resolved during ketamine administration. No serious maternal or neonatal adverse effects occurred. Ketamine may be considered as an adjunct analgesic in pregnant patients with sickle cell pain, although prospective clinical data are needed to fully assess its efficacy. PMID- 28806173 TI - The beta-alanine transporter BalaT is required for visual neurotransmission in Drosophila. AB - The recycling of neurotransmitters is essential for sustained synaptic transmission. In Drosophila, histamine recycling is required for visual synaptic transmission. Synaptic histamine is rapidly taken up by laminar glia, and is converted to carcinine. After delivered back to photoreceptors, carcinine is hydrolyzed to release histamine and beta-alanine. This histamine is repackaged into synaptic vesicles, but it is unclear how the beta-alanine is returned to the laminar glial cells. Here, we identified a new beta-alanine transporter, which we named BalaT (Beta-alanine Transporter). Null balat mutants exhibited lower levels of beta-alanine, as well as less beta-alanine accumulation in the retina. Moreover, BalaT is expressed and required in retinal pigment cells for maintaining visual synaptic transmission and phototaxis behavior. These results provide the first genetic evidence that retinal pigment cells play a critical role in visual neurotransmission, and suggest that a BalaT-dependent beta-alanine trafficking pathway is required for histamine homeostasis and visual neurotransmission. PMID- 28806177 TI - Laryngeal Mask Airway Embedded With Pharyngeal Suction Catheters for Rhinoplasty: A Case Report. AB - A flexible laryngeal mask airway device (LMAD) embedded with 2 pharyngeal suction catheters was used for a young female patient who underwent a revision rhinoplasty, septoplasty, and chin implant. The modified LMAD was constructed by attaching 2 suction catheters onto the back of the mask; it functioned well without signs of malfunction or complications, with a total of 71 mL of blood evacuated from the pharyngeal area during the five and a half hour surgery. The patient emerged from anesthesia without coughing or straining, and reported no sore throat or nausea/vomiting in the recovery room. PMID- 28806172 TI - Mobilization of LINE-1 retrotransposons is restricted by Tex19.1 in mouse embryonic stem cells. AB - Mobilization of retrotransposons to new genomic locations is a significant driver of mammalian genome evolution, but these mutagenic events can also cause genetic disorders. In humans, retrotransposon mobilization is mediated primarily by proteins encoded by LINE-1 (L1) retrotransposons, which mobilize in pluripotent cells early in development. Here we show that TEX19.1, which is induced by developmentally programmed DNA hypomethylation, can directly interact with the L1 encoded protein L1-ORF1p, stimulate its polyubiquitylation and degradation, and restrict L1 mobilization. We also show that TEX19.1 likely acts, at least in part, through promoting the activity of the E3 ubiquitin ligase UBR2 towards L1 ORF1p. Moreover, loss of Tex19.1 increases L1-ORF1p levels and L1 mobilization in pluripotent mouse embryonic stem cells, implying that Tex19.1 prevents de novo retrotransposition in the pluripotent phase of the germline cycle. These data show that post-translational regulation of L1 retrotransposons plays a key role in maintaining trans-generational genome stability in mammals. PMID- 28806178 TI - Vitamin D and osteosarcopenia: an update from epidemiological studies. AB - PURPOSE OF REVIEW: The review summarizes recent epidemiological studies that examined the relationship between osteoporosis and sarcopenia to assess the impact of vitamin D status or supplementation on health outcomes related to these two medical conditions. RECENT FINDINGS: Osteoporosis and sarcopenia are major public health problems, but whether these two diseases should be considered alone or combined into a single condition is not clear. No consensual definition of osteosarcopenia is largely accepted. Most observational studies demonstrate some relationship between muscle and bone health. Vitamin D status is generally lower in study participants with bone or muscle wasting. Studies on the effects of vitamin D supplementation on muscle or bone health have provided conflicting results, likely because of the heterogeneity between studies. However, the most positive results were observed in study participants with low vitamin D status and in studies that avoided massive boluses of vitamin D. SUMMARY: More observational and interventional studies are needed to confirm the exact role of vitamin D in the pathophysiology and treatment of osteosarcopenia. PMID- 28806180 TI - An Unusual Case of Levofloxacin Pill Aspiration Causing Respiratory Failure. PMID- 28806179 TI - Interpreting magnesium status to enhance clinical care: key indicators. AB - PURPOSE OF REVIEW: To update advances in identifying factors affecting magnesium (Mg) status that assist in providing improved evidence-based clinical decision making for assessing Mg status. RECENT FINDINGS: Findings from recent cohort studies, small randomized control trials, and multiple meta-analyses reinforce earlier work that serum Mg concentrations, urinary Mg excretion, and Mg dietary intakes are inversely associated with cardiovascular disease, chronic kidney disease, and diabetes. These studies indicate that the reference range for serum Mg needs updating, and that individuals with serum Mg in the range of 0.75-0.85 mmol/l and displaying changes in other factors associated with a low Mg status may be Mg deficient. Individuals with serum Mg concentrations below this range most likely are Mg deficient and, above this range, are most likely Mg sufficient. SUMMARY: The combined determination of serum Mg concentration, 24-h urinary Mg excretion, and dietary Mg intake is currently the most practical method to obtain a sound assessment of Mg status. The strong correlations of Mg deficiency with increased risk of several chronic diseases, some of which exist as comorbidities, indicate that Mg status should be ascertained in patients presenting such disorder. PMID- 28806181 TI - Impact of Perioperative Blood Transfusion on Survival Among Women With Breast Cancer: Potential Benefits of Blood-Saving Agent Desmopressin Use During Surgery. PMID- 28806182 TI - Nilotinib-Induced Ocular Toxicity: A Case Report. PMID- 28806183 TI - Taking Your ECMO With You: Continued Progress Toward an Ambulatory Goal. PMID- 28806184 TI - Noninfectious aortitis: what the cardiologist needs to know. AB - PURPOSE OF REVIEW: To sum up a group of noninfectious inflammatory diseases of the aorta and its branches relevant to a cardiologist's daily routine. To describe pathogenetic and clinical advances as well as modern diagnostic tools. To overview most recent treatment options and patient-tailored therapies. To provide an insight in future directions of research. RECENT FINDINGS: Pathophysiology of large vessel vasculitides (LVV) are still poorly defined. At least a certain number of patients with idiopathic periaortitis seem to part of the group of IgG4-related diseases which has implications for therapy. Modern diagnostic modalities as Positron-Emission-Tomography (PET)-computed tomography and PET-magnetic resonance tomography proof to be helpful to diagnose or excluded LVV and emerge as long-term surveillance tool. Biological therapy yields varying results but is reported to be important for patients nonresponding or relapsing under glucocorticoid therapy. SUMMARY: Owing to the multifactorial pathogenesis and the small number of cases of LVV further interdisciplinary efforts are necessary to elucidate the pathogenesis of this group of diseases. Technical progress in radiology and nuclear medicine supports clinical, histological, and laboratory findings to increase diagnostic precision. There are several therapies emerging that may have the potential to support patient-tailored treatment approaches in glucocorticoid refractory or relapsing disease. PMID- 28806185 TI - Graft quality verification in coronary artery bypass graft surgery: how, when and why? AB - PURPOSE OF REVIEW: The coronary artery bypass graft (CABG) operation is one of the few remaining operations/interventions on diseased arteries that are not routinely verified during or immediately after the procedure. This review answers the 'how', 'when' and 'why' of intraoperative CABG assessment. RECENT FINDINGS: More recent than new literature on this topic, is the increased interest in quality assurance of CABG. This is most likely due to reports in the last 5 years suggesting CABG superiority to percutaneous coronary intervention (PCI) for improved mid-term and long-term outcomes; for example, for patients with diabetes mellitus (Freedom Trial by Farkouh in 2012), and for patients with SYNTAX score >= 33 (SYNTAX Trial by Mohr in 2013). Possibly CABG is re-emerging from the era of-better-and-better-stents and is now deemed worthy of improvement. SUMMARY: In order to fully compliment PCI, the operative major adverse cardiac event rate of CABG must rival that of PCI. In order to reduce technical errors, it is best practice to perform intra-operative assessment of bypasses, especially since we have the tools. PMID- 28806186 TI - The impact of CYP2C19*2, CYP4F2*3, and clinical factors on platelet aggregation, CYP4F2 enzyme activity, and 20-hydroxyeicosatetraenoic acid concentration in patients treated with dual antiplatelet therapy. AB - : The aim of the current study was to evaluate the impact of CYP2C192 (rs4244285), CYP4F23 (rs2108622), and nongenetic factors on platelet aggregation and to investigate the mechanism of CYP4F2's effect on platelet aggregation in the patients treated with dual antiplatelet therapy. A total of 146 patients were included in this study. Ticagrelor or clopidogrel were administered in a loading dose of 180 mg and 600 mg, respectively, in combination with aspirin (300 mg). Blood samples for analysis were taken the next morning after antiplatelet therapy induction. Clopidogrel users with the CYP2C1912 variant had higher platelet aggregation values (median 43, range 30-54%) compared with 11 wild-type carriers (median 33, range 15-77%; P = 0.009). Carriers of the CYP4F213 variant had higher platelet aggregation values than carriers of the 33 variant (median 34, range 8 70% vs. median 24.5, range 10-47%, P = 0.016, respectively). Higher CYP4F2 concentrations were detected in clopidogrel users than in ticagrelor users (median 3.6, range 1.6-22.0 ng/ml vs. median 2.3, range 1.6-27.2 ng/ml, P = 0.056, respectively) and in carriers of the CYP4F213 variant compared with carriers of the 11 variant (median 4.3, range 1.6-27.2 ng/ml vs. median 2.4, range 1.6-22.0 ng/ml, P = 0.009, respectively). No correlation between plasma 20 hydroxyeicosatetraenoic acid and CYP4F2 enzyme concentrations were detected (r = 0.045, P = 0.587). Our results proved that CYP2C192 might significantly affect antiplatelet function of clopidogrel. Plasma CYP4F2 concentrations were significantly lower in ticagrelor users than in clopidogrel users. PMID- 28806187 TI - Pain is an underestimated symptom in cystic fibrosis. AB - PURPOSE OF REVIEW: Life expectancy is increasing in cystic fibrosis and new aspects of the disease have to be taken into account in cystic fibrosis care. RECENT FINDINGS: Pain is encountered among 70% of adult and pediatric patients with cystic fibrosis. This symptom is underestimated by the multidisciplinary team. It has been reported as impacting quality of life and adherence to treatments. The location of pain is inconstant among the different studies but the major symptoms are headaches, gastrointestinal, and chest pain. Pain is different for each patient and requires careful evaluation using questionnaires some of which specifically developed for patients with cystic fibrosis. Medical and nonmedical treatment such as ostheopathy or sophrology may relieve pain symptoms but have to be adjusted in the frame of a global personalized care. SUMMARY: Pain maybe an underestimated symptom among patients with cystic fibrosis and impacts negatively on quality of life. VIDEO ABSTRACT. PMID- 28806189 TI - The use of optical coherence tomography in neuro-ophthalmology. AB - PURPOSE OF REVIEW: In the last decade, with the advances of optical coherence tomography (OCT) technology, different imaging protocols and analysis algorithms have been introduced to maximize the potential of this diagnostic tool in the evaluation of different eye diseases. This review aims to provide an update on these additional features, with respect to the management of a diverse range of neuro-ophthalmologic conditions. RECENT FINDINGS: Macular ganglion cell complex (mGCC) analysis has been shown to be superior to peripapillary retinal nerve fiber layer (pRNFL) analysis in certain settings, such as differentiating Leber's hereditary optic neuropathy from functional visual loss; monitoring neurodegenerative diseases or multiple sclerosis; and predicting visual loss in nonarteritic ischemic optic neuropathy. mGCC analysis also demonstrates high correlation with perimetry and might serve as an early structural indicator of irreversible neuronal loss. Compared to pRNFL, retinal thickness analysis of the optic nerve head demonstrates better correlation with the severity of papilledema, thus enabling its possible application in detecting raised intracranial pressure, especially in the pediatric group. Upcoming research on emerging OCT technologies including OCT-angiography, enhanced depth imaging, retinal single-layer analysis and portable systems will hopefully further enhance the utility of OCT in the field. SUMMARY: It is crucial for neuro ophthalmologists to be updated and familiar with these newer OCT imaging protocols and to make appropriate choices for different clinical scenarios, in order to optimize the diagnostic sensitivity and specificity. PMID- 28806188 TI - Tubulointerstitial nephritis and uveitis. AB - PURPOSE OF REVIEW: Tubulointerstitial nephritis and uveitis (TINU) is an important yet underrecognized ocular inflammatory syndrome. This review summarizes key historical publications that identified and defined the syndrome, and more recent literature that reveal the importance of urinary beta2 microglobulin testing and kidney biopsy in the diagnostic evaluation of patients with TINU. Additionally, research studies providing new insights into disease pathogenesis are highlighted. RECENT FINDINGS: In contrast with initial reports of TINU manifesting exclusively as an anterior uveitis in pediatric patients, more recent reports have identified TINU in patients of all ages with a wide range of ocular manifestations. Urinary beta2-microglobulin has emerged as a sensitive and specific laboratory screening test, and the role of kidney biopsy in differentiating TINU from sarcoidosis continues to evolve. Genetic studies have identified HLA-DQA101, HLA-DQB105, and HLA-DRB101 as high-risk alleles and the identification of antimonomeric C-reactive protein antibodies suggests a role for humoral immunity in disease pathogenesis. Management strategies have evolved to include systemic anti-inflammatory treatment as a result of important outcome studies in patients with significant renal and ocular disease. SUMMARY: With greater recognition, understanding, and treatment of this syndrome, both ocular inflammation and renal disease can be better addressed. PMID- 28806190 TI - The challenges of proprotein convertase subtilisin-kexin-9 inhibitors for lipid guidelines and models of care. AB - PURPOSE OF REVIEW: The article reviews the challenges facing cardiovascular disease (CVD) guidelines committees. RECENT FINDINGS: Clinical trials in high risk populations have shown additional CVD event reduction with ezetimibe and proprotein convertase subtilisin-kexin-9 inhibitors. These trials recruit middle aged secondary prevention populations, whereas increasingly the population at risk of CVD comprises the elderly in primary prevention. Some major guidelines have moved from a lipid-target to a risk-based approach. Some guidelines wish to preserve treatment targets to optimize the risk profile of individual patients as opposed to using population-based approaches. A numbers needed to treat approach has been suggested as a way of prioritizing patients for treatment, while retaining an individual's LDL cholesterol risk. However, the main barrier to implementation of some novel therapies in medicine is not their efficacy or safety but their cost. Health economic approaches that consider both benefits and costs can help guideline committees to define populations mostly likely to benefit. SUMMARY: The efficacy and expense of novel treatments is challenging traditional guideline development. Previously guideline committees used only to review clinical efficacy and safety endpoints but now they also have to consider costs to derive recommendations that are practical to implement. PMID- 28806191 TI - A patient-centred approach to measuring quality in kidney care: patient-reported outcome measures and patient-reported experience measures. AB - PURPOSE OF REVIEW: Chronic kidney disease (CKD) is associated with symptoms that can significantly reduce the health-related quality of life (HRQOL) of patients. Patient-reported outcome and experience measures (PROMs and PREMs) may assist with the evaluation of HRQOL and quality of care from the patient perspective. This review focuses on evidence from recent studies exploring the role of PROMs and PREMs in the measurement of quality in CKD care. RECENT FINDINGS: PROMs are increasingly used in CKD research as measures of clinical effectiveness, whereas the current use of PROMs in routine clinical settings and PREMs in all settings is more limited. Electronic PROMs may be sensitive enough to detect clinically relevant patient-reported outcomes changes. Patients on frequent shorter-hours daily haemodialysis may experience better HRQOL compared with those on conventional haemodialysis. PROM data may correlate significantly with clinical parameters. PREMs are being utilized by healthcare professionals to inform service improvements. SUMMARY: PROMs and PREMs may facilitate the measurement of quality in renal care and aid the tailoring of care to individual patients. PROMs may have a potential role as prognostic markers. PMID- 28806192 TI - MicroRNAs as biomarkers in chronic kidney disease. AB - PURPOSE OF REVIEW: This review summarizes recent data supporting the concept that urinary microRNAs are a useful new class of biomarker. They may improve capacity to stratify patients with chronic kidney disease according to risk of progression, and may also inform about response to therapy. RECENT FINDINGS: MicroRNAs are present, stable and readily quantifiable in tissues and body fluids, including urine, and have widespread importance as regulators in the kidney. Urinary microRNAs are typically released from the nephron or downstream structures, and their abundance may reflect altered microRNA expression in the kidney, or release into the lumen by the cells comprising the different regions of the nephron. As a consequence, abundance of specific microRNAs in the urine may change in various pathological states. Large-scale studies are now needed, to test the capacity of specific microRNAs to inform about risk and response to therapy. SUMMARY: Urinary microRNAs appear useful sentinels for pathological processes occurring in the kidney and may enable a 'personalized medicine' approach to the management and stratification of renal disease. PMID- 28806194 TI - Paliperidone palmitate 3-month treatment results in symptomatic remission in patients with schizophrenia: a randomized, multicenter, double-blind, and noninferiority study. AB - The current analysis assessed symptomatic and functional remission achieved following paliperidone palmitate 3-month (PP3M) versus 1-month (PP1M) treatment in patients (age: 18-70 years) with schizophrenia, previously stabilized on PP1M. Following a less than or equal to 3-week screening, and a 17-week, flexible dosed, open-label phase [PP1M: day 1 (150 mg eq. deltoid), day 8 (100 mg eq. deltoid), weeks 5, 9, and 13 (50, 75, 100, or 150 mg eq., deltoid/gluteal)], clinically-stable patients were randomized (1 : 1) to PP3M (fixed-dose, 175, 263, 350, or 525 mg eq. deltoid/gluteal) or PP1M (fixed-dose, 50, 75, 100, or 150 mg eq. deltoid/gluteal) in 48-week double-blind (DB) phase. Symptomatic remission was assessed using Andreasen's criteria. Functional remission was assessed using Personal and Social Performance scale (PSP). More than 50% patients in both groups achieved symptomatic remission (PP3M: 50.3%; PP1M: 50.8%) during last 6 months of DB phase. Similar percentage of patients of both groups achieved functional remission (defined as PSP score>70, PP3M: 42.5%; PP1M: 43.9%) and combined remission (symptomatic and functional remission, PP3M: 25.1%; PP1M: 26.6%) during last 6 months of DB phase. Most patients who achieved remission at DB baseline maintained their remission status throughout the DB phase. PP3M and PP1M achieved comparable symptomatic and functional remissions during the DB phase. PMID- 28806193 TI - Speech Perception in Noise and Listening Effort of Older Adults With Nonlinear Frequency Compression Hearing Aids. AB - OBJECTIVES: The purpose of this laboratory-based study was to compare the efficacy of two hearing aid fittings with and without nonlinear frequency compression, implemented within commercially available hearing aids. Previous research regarding the utility of nonlinear frequency compression has revealed conflicting results for speech recognition, marked by high individual variability. Individual differences in auditory function and cognitive abilities, specifically hearing loss slope and working memory, may contribute to aided performance. The first aim of the study was to determine the effect of nonlinear frequency compression on aided speech recognition in noise and listening effort using a dual-task test paradigm. The hypothesis, based on the Ease of Language Understanding model, was that nonlinear frequency compression would improve speech recognition in noise and decrease listening effort. The second aim of the study was to determine if listener variables of hearing loss slope, working memory capacity, and age would predict performance with nonlinear frequency compression. DESIGN: A total of 17 adults (age, 57-85 years) with symmetrical sensorineural hearing loss were tested in the sound field using hearing aids fit to target (NAL-NL2). Participants were recruited with a range of hearing loss severities and slopes. A within-subjects, single-blinded design was used to compare performance with and without nonlinear frequency compression. Speech recognition in noise and listening effort were measured by adapting the Revised Speech in Noise Test into a dual-task paradigm. Participants were required trial by-trial to repeat the last word of each sentence presented in speech babble and then recall the sentence-ending words after every block of six sentences. Half of the sentences were rich in context for the recognition of the final word of each sentence, and half were neutral in context. Extrinsic factors of sentence context and nonlinear frequency compression were manipulated, and intrinsic factors of hearing loss slope, working memory capacity, and age were measured to determine which participant factors were associated with benefit from nonlinear frequency compression. RESULTS: On average, speech recognition in noise performance significantly improved with the use of nonlinear frequency compression. Individuals with steeply sloping hearing loss received more recognition benefit. Recall performance also significantly improved at the group level, with nonlinear frequency compression revealing reduced listening effort. The older participants within the study cohort received less recall benefit than the younger participants. The benefits of nonlinear frequency compression for speech recognition and listening effort did not correlate with each other, suggesting separable sources of benefit for these outcome measures. CONCLUSIONS: Improvements of speech recognition in noise and reduced listening effort indicate that adult hearing aid users can receive benefit from nonlinear frequency compression in a noisy environment, with the amount of benefit varying across individuals and across outcome measures. Evidence supports individualized selection of nonlinear frequency compression, with results suggesting benefits in speech recognition for individuals with steeply sloping hearing losses and in listening effort for younger individuals. Future research is indicated with a larger data set on the dual-task paradigm as a potential cognitive outcome measure. PMID- 28806195 TI - Antiretroviral combination use during pregnancy and the risk of major congenital malformations. AB - OBJECTIVE: To quantify the risk of major congenital malformations (MCMs) associated with gestational combination antiretroviral use. DESIGN: Population based prospective cohort study. METHODS: Using the Quebec Pregnancy Cohort from 1998 to 2015, we included women who were covered by the Quebec Drug Plan and had a singleton livebirth. All antiretroviral use alone or in combination were considered. MCMs overall and organ-specific malformations in the first year of life were identified. RESULTS: In total, 214 240 pregnancies met inclusion criteria; 0.09% (n = 198) occurred while on antiretroviral combinations during the first trimester; 169 HIV-positive women without antiretroviral treatment were included. Compared with the general population in this cohort, the prevalence of MCMs was significantly higher in unexposed HIV-positive women (14.8 vs. 8.6%, P = 0.004) but not in antiretroviral-exposed HIV-positive women (10.3%, P = 0.41). Adjusting for potential confounders, including maternal HIV status, antiretroviral use during the first trimester was not associated with the risk of MCMs (adjusted odds ratio 0.59, 95% confidence interval 0.33-1.06). However, antiretroviral combination use during the first trimester was associated with an increased risk of defects of the small intestine (adjusted odds ratio 10.32, 95% confidence interval 2.85-37.38, P = 0.0004). CONCLUSION: Antiretroviral therapy during the first trimester was not associated with the risk of overall MCMs but may be associated with an increased risk of defects of the small intestine. However, HIV-positive pregnant women who are not treated with antiretrovirals during pregnancy seem to have a higher risk of malformations; this is not seen among those who are treated, which could indicate that the underlying condition puts women at risk and not the treatment. PMID- 28806199 TI - Does Late Hip Dysplasia Occur After Normal Ultrasound Screening in Breech Babies? AB - BACKGROUND: Recent literature has raised concern regarding the occurrence of late dysplasia after normal screening in breech babies. One paper states a late dysplasia incidence of 29%. This finding is in contrast with other published work, which suggests breech presentation is predictive of spontaneous stabilization of the unstable neonatal hip. We decided to identify the rate of late dysplasia after normal screening in our patient cohort and also to investigate the use of a prophylactic abduction diaper. METHODS: During the study period of December 2012 to June 2014, breech babies referred to the screening program at our institution were identified. Ninety babies were prospectively enrolled into the study and randomized to either the observational arm or prophylactic treatment with the Healthy Hip Diaper (HALO, Minnetonka, MN). All babies had a normal initial clinical examination and ultrasound. Regular follow up including clinical and ultrasound examination was undertaken culminating in pelvic x-rays performed at 13+/-1 months. A total of 63% of patients elected against their randomization to prophylactic treatment, 28% opted for prophylactic treatment against their randomization to observation only, meaning a total of 40% of babies proceeded against their initial randomization. In total, 75% of recruited babies completed follow-up. Dysplasia was defined as an acetabular index >2 SD from the mean sex, age, and side-specific values. RESULTS: The overall rate of radiographic dysplasia at 13 months was 7.4%. The rate was 5% in those using a Healthy Hip Diaper and 8.3% in those under observation only. This was not a statistically significant difference. Two patients required operative intervention, one requiring capsulorraphy with acetabuloplasty, the other requiring an arthrogram. Overall compliance with the abduction diaper was low. CONCLUSIONS: We conclude that late radiographic dysplasia does occur after normal clinical and ultrasound screening in breech babies, although not to the same extent as recently published data. We cannot recommend prophylactic abduction devices for breech babies who have a normal hip ultrasound at 6 weeks of age. Consideration must be given to further clinical and radiographic follow-up for hip dysplasia when the risk factor of breech presentation is present. LEVEL OF EVIDENCE: Level II-prospective comparative trial. PMID- 28806200 TI - Quality of anticoagulation control and hemorrhage risk among African American and European American warfarin users. AB - OBJECTIVE: We evaluated whether percent time in target range (PTTR), risk of over anticoagulation [international normalized ratio (INR)>4], and risk of hemorrhage differ by race. As PTTR is a strong predictor of hemorrhage risk, we also determined the influence of PTTR on the risk of hemorrhage by race. PARTICIPANTS AND METHODS: Among 1326 warfarin users, PTTR was calculated as the percentage of interpolated INR values within the target range of 2.0-3.0. PTTR was also categorized as poor (PTTR<60%), good (60<=PTTR<70%), or excellent (PTTR>=70%) anticoagulation control. Over-anticoagulation was defined as INR more than 4 and major hemorrhages included serious, life-threatening, and fatal bleeding episodes. Logistic regression and survival analyses were carried out to evaluate the association of race with PTTR (>=60 vs. <60) and major hemorrhages, respectively. RESULTS: Compared with African Americans, European Americans had higher PTTR (57.6 vs. 49.1%; P<0.0001) and were more likely to attain 60<=PTTR<70% (22.9 vs. 13.1%; P<0.001) or PTTR of at least 70% (26.9 vs. 18.2%; P=0.001). Older (>65 years) patients without venous thromboembolism indication and chronic kidney disease were more likely to attain PTTR of at least 60%. After accounting for clinical and genetic factors, and PTTR, African Americans had a higher risk of hemorrhage [hazard ratio (HR)=1.58; 95% confidence interval (CI): 1.04-2.41; P=0.034]. Patients with 60<=PTTR<70% (HR=0.62; 95% CI: 0.38-1.02; P=0.058) and PTTR of at least 70% (HR=0.27; 95% CI: 0.15-0.49; P<0.001) had a lower risk of hemorrhage compared with those with PTTR less than 60%. CONCLUSION: Despite the provision of warfarin management through anticoagulation clinics, African Americans achieve a lower overall PTTR and have a significantly higher risk of hemorrhage. Personalized medicine interventions tailored to African American warfarin users need to be developed. PMID- 28806201 TI - Brain-Gut-Microbiota Axis and Mental Health. AB - OBJECTIVE: The brain-gut-microbiota axis has been put forward as a new paradigm in neuroscience, which may be of relevance to mental illness. The mechanisms of signal transmission in the brain-gut-microbiota axis are complex and involve bidirectional communications that enable gut microbes to communicate with the brain and the brain to communicate with the microbes. This review assesses the potential usefulness and limitations of the paradigm. METHODS: A selective literature review was conducted to evaluate the current knowledge in clinical and preclinical brain-gut-microbiota interactions as related to psychiatric disorders. RESULTS: Most published studies in the field are preclinical, and there is so far a lack of clinical studies. Preliminary studies in psychiatric populations support the view of a dysbiosis in some conditions, but studies are often small scale and marred by potential confounding variables. Preclinical studies support the view that psychobiotics ("bacteria which when ingested in adequate amounts have a positive mental health benefit") might be of use in treating some patients with mental health difficulties. To date, we have no well conducted studies in clinical populations, although there are some studies in healthy volunteers. A cocktail of probiotics has been shown to alter brain activity as monitored by functional magnetic resonance imaging, and Bifidobacterium longum was reported to alter brain electrical activity. CONCLUSIONS: It has yet to be convincingly demonstrated that the exciting findings of psychobiotic efficacy demonstrated in preclinical models of psychiatric illness will translate to patients. PMID- 28806202 TI - Alzheimer's Disease Caregivers' Health and Important Resources: Next Steps in Intervention Research. AB - In this issue of Psychosomatic Medicine, Mausbach and colleagues report that Alzheimer's disease caregivers who engage in more pleasant leisure activities had lower blood pressure for 5 years compared with those who engage in fewer leisure activities. This novel finding suggests that something as simple as taking more walks in the park or more time for reading books could protect the physical health of caregivers. In this editorial, we review possible mechanisms linking pleasant leisure activities with lower blood pressure in caregivers and discuss potential barriers that prevent caregivers from engaging in pleasant leisure activities. One possibility is that caregivers may not give themselves "permission" to take time away from caregiving, or feel guilty or selfish for doing so. Another impediment may be lack of outside assistance or support that would be needed to take time for leisure activities. Primary health care providers may play an important role in helping caregivers overcome these obstacles. In addition, public policy innovations are needed to meet the increasing societal demands on the psychological and medical consequences of caregiver burden. PMID- 28806204 TI - Preoxygenation Before Extubation: A Road to Patient Safety Less Traveled! PMID- 28806205 TI - Response to Dr O'Reilly-Shah et al. PMID- 28806206 TI - Chronic Pain and Associated Factors in India and Nepal: A Pilot Study of the Vanderbilt Global Pain Survey. AB - BACKGROUND: Evaluation and treatment of chronic pain worldwide are limited by the lack of standardized assessment tools incorporating consistent definitions of pain chronicity and specific queries of known social and psychological risk factors for chronic pain. The Vanderbilt Global Pain Survey (VGPS) was developed as a tool to address these concerns, specifically in the low- and middle-income countries where global burden is highest. METHODS: The VGPS was developed using standardized and cross-culturally validated metrics, including the Brief Pain Inventory and World Health Organization Disability Assessment Scale, as well as the Pain Catastrophizing Scale, the Fibromyalgia Survey Questionnaire along with queries about pain attitudes to assess the prevalence of chronic pain and disability along with its psychosocial and emotional associations. The VGPS was piloted in both Nepal and India over a 1-month period in 2014, allowing for evaluation of this tool in 2 distinctly diverse cultures. RESULTS: Prevalence of chronic pain in Nepal and India was consistent with published data. The Nepali cohort displayed a pain point prevalence of 48%-50% along with some form of disability present in approximately one third of the past 30 days. Additionally, 11% of Nepalis recorded pain in 2 somatic sites and 39% of those surveyed documented a history of a traumatic event. In the Indian cohort, pain point prevalence was approximately 24% to 41% based on the question phrasing, and any form of disability was present in 6 of the last 30 days. Of the Indians surveyed, 11% reported pain in 2 somatic sites, with only 4% reporting a previous traumatic event. Overall, Nepal had significantly higher chronic pain prevalence, symptom severity, widespread pain, and self-reported previous traumatic events, yet lower reported pain severity. CONCLUSIONS: Our findings confirm prevalent chronic pain, while revealing pertinent cultural differences and survey limitations that will inform future assessment strategies. Specific areas for improvement identified in this VGPS pilot study included survey translation methodology, redundancy of embedded metrics and cultural limitations in representative sampling and in detecting the prevalence of mental health illness, catastrophizing behavior, and previous traumatic events. International expert consensus is needed. PMID- 28806207 TI - Opportunities and Limitations in Mobile Technology. PMID- 28806208 TI - Systemic Hypotension Following Intravenous Administration of Nonionic Contrast Medium During Computed Tomography: Iopromide Versus Iodixanol. AB - BACKGROUND: In light of the increasing number of radiologic interventions performed under general anesthesia, the effects of contrast media (CM) on circulation and organ perfusion are of paramount importance. The objectives of this study were to systematically quantify effects on blood pressure, heart rate, and kidney function following intravenous administration of nonionic CM with normal and low osmolality. METHODS: In this controlled, double-blinded phase IV clinical trial, 40 consecutive patients were randomly assigned to receive repeated measures of either low-osmolar iopromide or iso-osmolar iodixanol. Normal saline solution (NSS) served as control. Blood pressure and heart rate were measured continuously from 1 minute before until 3 minutes after administration of CM and NSS. Urine output was recorded hourly. RESULTS: Administration of iopromide resulted in systemic hypotension lasting up to 300 seconds (105 +/- 61 seconds) with the lowest mean arterial pressure of 39 mm Hg (56.7 +/- 12.2 mm Hg). Iopromide caused a systolic/diastolic decrease of 31/26 mm Hg (P < .001), significant increase in heart rate (P = .042), and significant diuresis with a 2-fold higher per-hour urine output (P = .010). Administration of iodixanol and NSS had no significant influence on blood pressure (P > .640). CONCLUSIONS: Administration of low-osmolar iopromide was followed by a significant transient decrease in blood pressure and a rise in heart rate. Anesthetists and radiologists should be aware of these effects in patients in whom short episodes of disturbed tissue microcirculation may pose a clinical risk. PMID- 28806209 TI - Refractory Intracranial Hypertension: The Role of Decompressive Craniectomy. AB - Raised intracranial pressure (ICP) is associated with worse outcomes after acute brain injury, and clinical guidelines advocate early treatment of intracranial hypertension. ICP-lowering therapies are usually administered in a stepwise manner, starting with safer first-line interventions, while reserving higher-risk options for patients with intractable intracranial hypertension. Decompressive craniectomy is a surgical procedure in which part of the skull is removed and the underlying dura opened to reduce brain swelling-related raised ICP; it can be performed as a primary or secondary procedure. After traumatic brain injury, secondary decompressive craniectomy is most commonly undertaken as a last-tier intervention in a patient with severe intracranial hypertension refractory to tiered escalation of ICP-lowering therapies. Although decompressive craniectomy has been used in a number of conditions, it has only been evaluated in randomized controlled trials after traumatic brain injury and acute ischemic stroke. After traumatic brain injury, decompressive craniectomy is associated with lower mortality compared to medical management but with higher rates of vegetative state or severe disability. In patients with stroke-related malignant hemispheric infarction, hemicraniectomy significantly decreases mortality and improves functional outcome in adults <60 years of age. Surgery also reduces mortality in those >60 years, but results in a higher proportion of severely disabled survivors compared to medical therapy in this age group. Decisions to recommend decompressive craniectomy must always be made not only in the context of its clinical indications but also after consideration of an individual patient's preferences and quality of life expectations. This narrative review discusses the management of intractable intracranial hypertension in adults, focusing on the role of decompressive craniectomy in patients with traumatic brain injury and acute ischemic stroke. PMID- 28806210 TI - Risk Stratification for Major Postoperative Complications in Patients Undergoing Intra-abdominal General Surgery Using Latent Class Analysis. AB - BACKGROUND: Preoperative risk stratification is a critical element in assessing the risks and benefits of surgery. Prior work has demonstrated that intra abdominal general surgery patients can be classified based on their comorbidities and risk factors using latent class analysis (LCA), a model-based clustering technique designed to find groups of patients that are similar with respect to characteristics entered into the model. Moreover, the latent risk classes were predictive of 30-day mortality. We evaluated the use of latent risk classes to predict the risk of major postoperative complications. METHODS: An observational, retrospective cohort of patients undergoing intra-abdominal general surgery in the 2005 to 2010 American College of Surgeons National Surgical Quality Improvement Program was obtained. Known preoperative comorbidity and risk factor data were entered into LCA models to identify the latent risk classes. Complications were defined as: acute kidney injury, acute respiratory failure, cardiac arrest, deep vein thrombosis, myocardial infarction, organ space infection, pneumonia, postoperative bleeding, pulmonary embolism, sepsis/septic shock, stroke, unplanned reintubation, and/or wound dehiscence. Relative risk regression determined the associations between the latent classes and the 30-day complication risks, with adjustments for the surgical procedure. The area under the curve (AUC) of the receiver operator characteristic curve assessed model performance. RESULTS: LCA fit a 9-class model on 466,177 observations. The composite complication risk was 18.4% but varied from 7.7% in the lowest risk class to 56.7% in the highest risk class. After adjusting for procedure, the latent risk classes were significantly associated with complications, with risk ratios (95% confidence intervals) (compared to the class with the average risk) varying from 0.56 (0.54-0.58) in the lowest risk class to 2.15 (2.11-2.20) in the highest risk class, a 4-fold difference. In models incorporating surgical procedure, latent risk class, and the American Society of Anesthesiologists Physical Status, the AUC for composite complications was 0.76 (0.76-0.76). However, for individual complications, there was heterogeneity in model performance using these variables, with AUCs ranging from 0.70 (0.69-0.71) for pulmonary embolus to 0.90 (0.90-0.90) for acute respiratory failure. CONCLUSIONS: LCA can be used to classify patients undergoing intra-abdominal general surgery based on preoperative risk factors, and the classes are independently associated with postoperative complications. However, model performance is not uniform across individual complications, resulting in variations in the utility of preoperative risk stratification tools depending on the complication evaluated. PMID- 28806211 TI - The Opiorphin Analog STR-324 Decreases Sensory Hypersensitivity in a Rat Model of Neuropathic Pain. AB - BACKGROUND: Neuropathic pain represents a therapeutic challenge, and treatments with increased efficacy and tolerability still need to be developed. Opiorphin protects endogenous enkephalins from degradation, potentiating enkephalin dependent analgesia via the activation of opioid pathways. Enkephalins are natural ligands of opioid receptors, with strong affinity for delta-opioid receptors. Expression of functional delta-opioid receptors increases in sensory neurons after peripheral nerve injury in neuropathic pain models. In a postoperative pain model, opiorphin and its stable analog STR-324 have an analgesic potency comparable to that of morphine, but without adverse opioid related side effects. Consequently, administration of endogenous opiorphin peptides or STR-324 might be effective in managing peripheral neuropathic pain. METHODS: In this study, STR-324 was administered intravenously over the course of 7 days to rats with mononeuropathy induced by L5-L6 spinal nerve root ligation. The rats exhibited mechanical allodynia, thermal hyperalgesia, and spontaneous pain-related behavior throughout the testing period. RESULTS: Here, we report that the continuous administration of STR-324 significantly reduced mechanical allodynia and spontaneous pain-related behavior from day 2 to day 7 in animals that received 10 or 50 ug/h of STR-324 as compared to placebo-treated animals (P < .00001 and P < .0011, respectively, for mechanical allodynia; P = .028 and P = .0049, respectively, for spontaneous pain-related behavior). In addition, STR-324 reduced the pain-evoked expression of spinal c-Fos in this model, demonstrating that it acts at least in part through inhibition of endogenous nociceptive pathways. CONCLUSIONS: These observations suggested that STR-324 may be an effective addition to the multimodal approach for treating clinical neuropathic pain. PMID- 28806213 TI - MAINTENANCE OF GOOD VISUAL ACUITY IN BEST DISEASE ASSOCIATED WITH CHRONIC BILATERAL SEROUS MACULAR DETACHMENT. AB - PURPOSE: We describe the long-term follow-up of a patient with multifocal Best disease with chronic bilateral serous macular detachment and unusual peripheral findings associated with a novel mutation in the BEST1 gene. METHODS: Case report. RESULTS: A 59-year-old white woman was referred for an evaluation of her macular findings in 1992. There was a family history of Best disease in the patient's mother and a male sibling. Her medical history was unremarkable. Best corrected visual acuity was 20/20 in her right eye and 20/25 in her left eye. The anterior segment examination was normal in both eyes. Funduscopic examination showed multifocal hyperautofluorescent vitelliform deposits with areas of subretinal fibrosis in both eyes. An electrooculogram showed Arden ratios of 1.32 in the right eye and 1.97 in the left eye. Ultra-widefield color and fundus autofluorescence imaging showed degenerative retinal changes in areas throughout the entire fundus in both eyes. Optical coherence tomography, including annual eye-tracked scans from 2005 to 2016, showed persistent bilateral serous macular detachments. Despite chronic foveal detachment, visual acuity was 20/25 in her right eye and 20/40 in her left eye, 24 years after initial presentation. Genetic testing showed a novel c.238T>A (p.Phe80Ile) missense mutation in the BEST1 gene. CONCLUSION: Some patients with Best disease associated with chronic serous macular detachment can maintain good visual acuity over an extended follow-up. To our knowledge, this is the first report of Best disease associated with this mutation in the BEST1 gene. PMID- 28806214 TI - CHOROIDAL NEVI WITH FOCAL CHOROIDAL EXCAVATION AND POLYPOIDAL CHOROIDAL NEOVASCULARIZATION. AB - PURPOSE: To report two cases of choroidal nevi associated with focal choroidal excavation (FCE) and polypoidal choroidal neovascularization (PCN). METHODS: Report of two patients with choroidal nevi showing FCE and PCN who underwent multimodal imaging including color fundus photography, fluorescein angiography, indocyanine green angiography, fundus autofluorescence, spectral domain optical coherence tomography, swept-source optical coherence tomography, and optical coherence tomography angiography. RESULTS: Two patients presented with choroidal nevi associated with FCE and PCN. In the first case, a 74-year-old woman, the nevus had sharp margins, a deep FCE, surrounding drusen, and subretinal exudation at its inferior edge due to PCN that responded well to intravitreal anti-vascular endothelial growth factor therapy. In the second case, a 64-year-old woman, the nevus had ill-defined margins, a shallow FCE, and angiographic evidence of PCN without associated exudation. CONCLUSION: There have been several reports showing an association of either choroidal nevi or FCE with PCN. To our knowledge, there have been no previous reports of FCE identified within choroidal nevi, with or without associated PCN. Since, in one of our cases, the FCE was not apparent on clinical examination, the prevalence of FCE within nevi may be underdiagnosed. PMID- 28806215 TI - PREVALENCE OF VITREOMACULAR ADHESION IN PATIENTS WITHOUT MACULOPATHY OLDER THAN 40 YEARS. AB - PURPOSE: To determine the prevalence and factors influencing vitreomacular adhesion (VMA) or vitreomacular traction (VMT) in subjects without maculopathy older than age 40 years. METHODS: In a prospective cross-sectional study, 1,950 eyes in 1,090 participants aged 40 to 89 years representing various ethnic groups from 14 centers in the United States underwent a comprehensive eye examination, including spectral domain optical coherence tomography. A team of independent, masked readers classified the presence or absence of VMA/VMT on spectral domain optical coherence tomography based on the International Vitreomacular Traction Study Group rubric. RESULTS: Across all eyes, the prevalence of VMA or VMT was 39% or 1%, respectively. For every 1-year increase in age, there was a statistically significant 7% decreased odds of having VMA or VMT (95% confidence interval [CI]: 0.89-0.96; P < 0.001), whereas African Americans had 55% significantly reduced odds of having VMA or VMT when than whites (95% CI: 0.23 0.90; P = 0.025). Vitreomacular adhesion >1,500 MUm was significantly more likely than VMA <1,500 MUm in younger adults (95% CI: 0.70-0.86; P < 0.001), hyperopes versus emmetropes (95% CI: 1.49-35.9; P = 0.01), primary eye care versus tertiary practices (95% CI: 0.03-0.92; P = 0.04), and patients without hyperlipidemia (95% CI: 0.04-0.83; P = 0.03). CONCLUSION: Vitreomacular adhesion is highly prevalent among middle-aged adults. Diagnostic screening with spectral domain optical coherence tomography may help to accurately detect VMA or VMT, prompting routine monitoring and timely therapeutic intervention. PMID- 28806216 TI - Psoas Versus Femoral Blocks: A Registry Analysis of Risks and Benefits. AB - BACKGROUND AND OBJECTIVES: Psoas blocks are an alternative to femoral nerve blocks and have the potential advantage of blocking the entire lumbar plexus. However, the psoas muscle is located deeply, making psoas blocks more difficult than femoral blocks. In contrast, while femoral blocks are generally easy to perform, the inguinal region is prone to infection. We thus tested the hypothesis that psoas blocks are associated with more insertion-related complications than femoral blocks but have fewer catheter-related infections. METHODS: We extracted 22,434 surgical cases from the German Network for Regional Anesthesia registry (2007-2014) and grouped cases as psoas (n = 7593) and femoral (n = 14,841) blocks. Insertion-related complications (including single-shot blocks and catheter) and infectious complications (including only catheter) in each group were compared with chi tests. The groups were compared with multivariable logistic models, adjusted for potential confounding factors. RESULTS: After adjustment for potential confounding factors, psoas blocks were associated with more complications than femoral blocks including vascular puncture 6.3% versus 1.1%, with an adjusted odds ratio (aOR) of 3.6 (95% confidence interval [CI], 2.9 4.6; P < 0.001), and multiple skin punctures 12.6% versus 7.7%, with an aOR of 2.6 (95% CI, 2.1-3.3; P <0.001). Psoas blocks were also associated with fewer catheter-related infections: 0.3% versus 0.9% (aOR of 0.4; 95% CI, 0.2-0.8; P = 0.016), and with improved patient satisfaction (mean +/- SD 0- to 10-point scale score, 9.6 +/- 1.2 vs 8.4 +/- 2.9; P < 0.001). Results from a propensity-matched sensitivity analysis were similar. CONCLUSIONS: Psoas blocks are associated with more insertion-related complications but fewer infectious complications. CLINICAL TRIAL REGISTRATION: ID NCT02846610. PMID- 28806217 TI - The Effect of Ondansetron on Acute Opioid Tolerance in Patients Receiving Intrathecal Opioids Prior to Cesarean Delivery. AB - BACKGROUND: Multiple animal studies suggest that ondansetron ameliorates opioid induced hyperalgesia and tolerance. In this study, we aimed to determine if the administration of ondansetron prior to spinal anesthesia would have an effect on intrathecal opioid-induced acute opioid tolerance, postoperative pain, and analgesic requirements in patients undergoing cesarean delivery with spinal anesthesia. METHODS: Eighty-six patients undergoing elective cesarean delivery were recruited and randomly allocated to receive either 8 mg intravenous ondansetron (n = 44) or placebo (n = 42) in a prospective, double-blind design. All patients received spinal anesthesia consisting of 15 mg bupivacaine, 20 MUg of fentanyl, and 100 MUg of preservative-free morphine. We used linear mixed effects models to assess the difference in pain and opioid consumption in the first 24 hours after surgery between the 2 groups. RESULTS: No differences between the 2 groups were found in age, body mass index, American Society of Anesthesiologists physical status scores, duration of surgery, or sensory and motor block characteristics. There was no difference between the 2 groups in postoperative pain scores (P = 0.95) or opioid consumption (P = 0.68). CONCLUSIONS: In patients undergoing cesarean delivery under spinal anesthesia with intrathecal opioids, the administration of ondansetron prior to spinal anesthesia did not significantly affect postoperative pain scores or opioid consumption. Thus, the administration of ondansetron did not have an effect on acute opioid tolerance in our study. PMID- 28806218 TI - Hypoxemic Patients With Bilateral Infiltrates Treated With High-Flow Nasal Cannula Present a Similar Pattern of Biomarkers of Inflammation and Injury to Acute Respiratory Distress Syndrome Patients. AB - OBJECTIVE: To examine whether patients with acute hypoxemia and bilateral opacities treated with high-flow nasal cannula and acute respiratory distress syndrome patients who were directly mechanically ventilated are similar in terms of lung epithelial, endothelial, and inflammatory biomarkers. DESIGN: Prospective, multicenter study. SETTING: ICUs at three university tertiary hospitals. PATIENTS: Intubated and nonintubated patients admitted to the ICU with acute hypoxemia (PaO2/FIO2 <= 300) and bilateral opacities. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Either high-flow nasal cannula or mechanical ventilation was initiated, at the discretion of the attending physician. We measured plasma biomarkers of lung epithelial injury (receptor for advanced glycation end products and surfactant protein D) and endothelial injury (angiopoietin-2) and inflammation (interleukin-6, interleukin-8, and interleukin 33 and soluble suppression of tumorigenicity-2) within 24 hours of acute respiratory distress syndrome onset. Propensity score matching was performed using six different variables (Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment, PaO2/FIO2, origin of acute respiratory distress syndrome, steroids, renal failure and need for vasopressors). Nonhypoxemic mechanically ventilated critically ill patients and healthy volunteers served as controls. Of the 170 patients enrolled, 127 (74.7%) were intubated and 43 (25.3%) were treated with high-flow nasal cannula at acute respiratory distress syndrome onset. After propensity score matching (39 high flow nasal cannula patients vs 39 mechanical ventilation patients), no significant differences were observed in receptor for advanced glycation end products, surfactant protein D, angiopoietin-2, interleukin-6, interleukin-8, interleukin-33, and soluble suppression of tumorigenicity-2 between matched patients who were treated with high-flow nasal cannula and those who were intubated at acute respiratory distress syndrome onset. After matching, no differences in mortality or length of stay were observed. All biomarkers (with the exception of interleukin-33) were higher in both groups of matched acute respiratory distress syndrome patients than in both control groups. CONCLUSIONS: Acute hypoxemic patients with bilateral infiltrates treated with high-flow nasal cannula presented a similar pattern of biomarkers of inflammation and injury to acute respiratory distress syndrome patients undergoing direct mechanical ventilation. The results suggest that these high-flow nasal cannula patients should be considered as acute respiratory distress syndrome patients. PMID- 28806219 TI - Selective Activation of Basal Forebrain Cholinergic Neurons Attenuates Polymicrobial Sepsis-Induced Inflammation via the Cholinergic Anti-Inflammatory Pathway. AB - OBJECTIVES: Basal forebrain cholinergic neurons are proposed as a major neuromodulatory system in inflammatory modulation. However, the function of basal forebrain cholinergic neurons in sepsis is unknown, and the neural pathways underlying cholinergic anti-inflammation remain unexplored. DESIGN: Animal research. SETTING: University research laboratory. SUBJECTS: Male wild-type C57BL/6 mice and ChAT-ChR2-EYFP (ChAT) transgenic mice. INTERVENTIONS: The cholinergic neuronal activity of the basal forebrain was manipulated optogenetically. Cecal ligation and puncture was produced to induce sepsis. Left cervical vagotomy and 6-hydroxydopamine injection to the spleen were used. MEASUREMENTS AND MAIN RESULTS: Photostimulation of basal forebrain cholinergic neurons induced a significant decrease in the levels of tumor necrosis factor alpha and interleukin-6 in the serum and spleen. When cecal ligation and puncture was combined with left cervical vagotomy in photostimulated ChAT mice, these reductions in tumor necrosis factor-alpha and interleukin-6 were partly reversed. Furthermore, photostimulating basal forebrain cholinergic neurons induced a large increase in c-Fos expression in the basal forebrain, the dorsal motor nucleus of the vagus, and the ventral part of the solitary nucleus. Among them, 35.2% were tyrosine hydroxylase positive neurons. Furthermore, chemical denervation showed that dopaminergic neurotransmission to the spleen is indispensable for the anti inflammation. CONCLUSIONS: These results are the first to demonstrate that selectively activating basal forebrain cholinergic neurons is sufficient to attenuate systemic inflammation in sepsis. Specifically, photostimulation of basal forebrain cholinergic neurons activated dopaminergic neurons in dorsal motor nucleus of the vagus/ventral part of the solitary nucleus, and this dopaminergic efferent signal was further transmitted by the vagus nerve to the spleen. This cholinergic-to-dopaminergic neural circuitry, connecting central cholinergic neurons to the peripheral organ, might have mediated the anti inflammatory effect in sepsis. PMID- 28806220 TI - Association of Gender With Outcome and Host Response in Critically Ill Sepsis Patients. AB - OBJECTIVE: To determine the association of gender with the presentation, outcome, and host response in critically ill patients with sepsis. DESIGN AND SETTING: A prospective observational cohort study in the ICU of two tertiary hospitals between January 2011 and January 2014. PATIENTS: All consecutive critically ill patients admitted with sepsis, involving 1,815 admissions (1,533 patients). INTERVENTIONS: The host response was evaluated on ICU admission by measuring 19 plasma biomarkers reflecting organ systems implicated in sepsis pathogenesis (1,205 admissions) and by applying genome-wide blood gene expression profiling (582 admissions). MEASUREMENTS AND MAIN RESULTS: Sepsis patients admitted to the ICU were more frequently males (61.0%; p < 0.0001 vs females). Baseline characteristics were not different between genders. Urosepsis was more common in females; endocarditis and mediastinitis in men. Disease severity was similar throughout ICU stay. Mortality was similar up to 1 year after ICU admission, and gender was not associated with 90-day mortality in multivariate analyses in a variety of subgroups. Although plasma proteome analyses (including systemic inflammatory and cytokine responses, and activation of coagulation) were largely similar between genders, females showed enhanced endothelial cell activation; this difference was virtually absent in patients more than 55 years old. More than 80% of the leukocyte blood gene expression response was similar in male and female patients. CONCLUSIONS: The host response and outcome in male and female sepsis patients requiring ICU admission are largely similar. PMID- 28806221 TI - Admission to Intensive Care for Palliative Care or Potential Organ Donation: Demographics, Circumstances, Outcomes, and Resource Use. AB - OBJECTIVES: To describe the characteristics, circumstances, change over time, resource use, and outcomes of patients admitted to ICUs in Australia and New Zealand for the purposes of "palliative care of a dying patient" or "potential organ donation," and compare with actively managed ICU patients. DESIGN: A retrospective study of data from the Australian and New Zealand Intensive Care Society Adult Patient Database and a nested cohort analysis of a single center. SETTING: One hundred seventy-seven ICUs in Australia and New Zealand and a nested analysis of one university-affiliated hospital ICU in Melbourne, VIC, Australia. PATIENTS: Three thousand seven hundred "palliative care of a dying patient" and 1,115 "potential organ donation" patients from 2007 to 2016. The nested cohort included 192 patients. INTERVENTIONS: No interventions. Data extracted included patient demographics, diagnoses, length of stay, circumstances, and outcome of admission. MEASUREMENTS AND MAIN RESULTS: ICU admissions for "palliative care of a dying patient" and "potential organ donation" increased from 179 in 2007 to 551 in 2016 and from 44 in 2007 to 174 in 2016 in each respective group, though only the "potential organ donation" cohort showed an increase in proportion of total ICU admissions. Lengths of stay in ICU were a mean of 33.8 hours (median, 17.5; interquartile range, 6.4-38.8) and 44.7 hours (26.6; 16.0-44.6), respectively, compared with 74.2 hours (41.5; 21.7-77.0) in actively managed patients. Hospital mortality was 86.6% and 95.9%, respectively. In the nested cohort of 192 patients, facilitating family discussions about goals of treatment and organ donation represented the most common reason for ICU admission. CONCLUSIONS: Patients admitted to ICU to manage end-of-life care represent a small proportion of overall ICU admissions, with an increasing proportion of "potential organ donation" admissions. They have shorter ICU lengths of stay than actively managed patients, suggesting resource use for these patients is not disproportionate. PMID- 28806222 TI - Transient Receptor Potential Vanilloid 1 Antagonists Prevent Anesthesia-induced Hypothermia and Decrease Postincisional Opioid Dose Requirements in Rodents. AB - BACKGROUND: Intraoperative hypothermia and postoperative pain control are two important clinical challenges in anesthesiology. Transient receptor potential vanilloid 1 has been implicated both in thermoregulation and pain. Transient receptor potential vanilloid 1 antagonists were not advanced as analgesics in humans in part due to a side effect of hyperthermia. This study tested the hypothesis that a single, preincision injection of a transient receptor potential vanilloid 1 antagonist could prevent anesthesia-induced hypothermia and decrease the opioid requirement for postsurgical hypersensitivity. METHODS: General anesthesia was induced in rats and mice with either isoflurane or ketamine, and animals were treated with transient receptor potential vanilloid 1 antagonists (AMG 517 or ABT-102). The core body temperature and oxygen consumption were monitored during anesthesia and the postanesthesia period. The effect of preincision AMG 517 on morphine-induced reversal of postincision hyperalgesia was evaluated in rats. RESULTS: AMG 517 and ABT-102 dose-dependently prevented general anesthesia-induced hypothermia (mean +/- SD; from 1.5 degrees +/- 0.1 degrees C to 0.1 degrees +/- 0.1 degrees C decrease; P < 0.001) without causing hyperthermia in the postanesthesia phase. Isoflurane-induced hypothermia was prevented by AMG 517 in wild-type but not in transient receptor potential vanilloid 1 knockout mice (n = 7 to 11 per group). The prevention of anesthesia induced hypothermia by AMG 517 involved activation of brown fat thermogenesis with a possible contribution from changes in vasomotor tone. A single preincision dose of AMG 517 decreased the morphine dose requirement for the reduction of postincision thermal (12.6 +/- 3.0 vs. 15.6 +/- 1.0 s) and mechanical (6.8 +/- 3.0 vs. 9.5 +/- 3.0 g) withdrawal latencies. CONCLUSIONS: These studies demonstrate that transient receptor potential vanilloid 1 antagonists prevent anesthesia-induced hypothermia and decrease opioid dose requirements for the reduction of postincisional hypersensitivity in rodents. PMID- 28806223 TI - Images in Anesthesiology: Modified Cotton Swab Applicator for Nasal Sphenopalatine Ganglion Nerve Block. PMID- 28806224 TI - Bromodomain-containing Protein 4 Activates Voltage-gated Sodium Channel 1.7 Transcription in Dorsal Root Ganglia Neurons to Mediate Thermal Hyperalgesia in Rats. AB - BACKGROUND: Bromodomain-containing protein 4 binds acetylated promoter histones and promotes transcription; however, the role of bromodomain-containing protein 4 in inflammatory hyperalgesia remains unclear. METHODS: Male Sprague-Dawley rats received hind paw injections of complete Freund's adjuvant to induce hyperalgesia. The dorsal root ganglia were examined to detect changes in bromodomain-containing protein 4 expression and the activation of genes involved in the expression of voltage-gated sodium channel 1.7, which is a key pain related ion channel. RESULTS: The intraplantar complete Freund's adjuvant injections resulted in thermal hyperalgesia (4.0 +/- 1.5 s; n = 7). The immunohistochemistry and immunoblotting results demonstrated an increase in the bromodomain-containing protein 4-expressing dorsal root ganglia neurons (3.78 +/- 0.38 fold; n = 7) and bromodomain-containing protein 4 protein levels (2.62 +/- 0.39 fold; n = 6). After the complete Freund's adjuvant injection, histone H3 protein acetylation was enhanced in the voltage-gated sodium channel 1.7 promoter, and cyclin-dependent kinase 9 and phosphorylation of RNA polymerase II were recruited to this area. Furthermore, the voltage-gated sodium channel 1.7 mediated currents were enhanced in neurons of the complete Freund's adjuvant rats (55 +/- 11 vs. 19 +/- 9 pA/pF; n = 4 to 6 neurons). Using bromodomain-containing protein 4-targeted antisense small interfering RNA to the complete Freund's adjuvant-treated rats, the authors demonstrated a reduction in the expression of bromodomain-containing protein 4 (0.68 +/- 0.16 fold; n = 7), a reduction in thermal hyperalgesia (7.5 +/- 1.5 s; n = 7), and a reduction in the increased voltage-gated sodium channel 1.7 currents (21 +/- 4 pA/pF; n = 4 to 6 neurons). CONCLUSIONS: Complete Freund's adjuvant triggers enhanced bromodomain-containing protein 4 expression, ultimately leading to the enhanced excitability of nociceptive neurons and thermal hyperalgesia. This effect is likely mediated by the enhanced expression of voltage-gated sodium channel 1.7. PMID- 28806225 TI - Preventing Retained Central Venous Catheter Guidewires: A Randomized Controlled Simulation Study Using a Human Factors Approach. AB - BACKGROUND: Retained central venous catheter guidewires are never events. Currently, preventative techniques rely on clinicians remembering to remove the guidewire. However, solutions solely relying upon humans to prevent error inevitably fail. A novel locked procedure pack was designed to contain the equipment required for completing the procedure after the guidewire should have been removed: suture, suture holder, and antimicrobial dressings. The guidewire is used as a key to unlock the pack and to access the contents; thereby, the clinician must remove the guidewire from the patient to complete the procedure. METHODS: A randomized controlled forced-error simulation study replicated catheter insertion. We created a retained guidewire event and then determined whether clinicians would discover it, comparing standard practice against the locked pack. RESULTS: Guidewires were retrieved from 2/10 (20%) standard versus 10/10 (100%) locked pack, n = 20, P < 0.001. In the locked pack group, participants attempted to complete the procedure; however, when unable to access the contents, this prompted a search for the key (guidewire). Participants discovered the guidewire within the catheter lumen, recovered it, utilized it to unlock the pack, and finish the procedure. A structured questionnaire reported that the locked pack also improved subjective safety of central venous catheter insertion and allowed easy disposal of the sharps and guidewire (10/10). CONCLUSIONS: The locked pack is an engineered solution designed to prevent retained guidewires. Utilizing forced-error simulation testing, we have determined that the locked pack is an effective preventative device and is acceptable to clinicians for improving patient safety. PMID- 28806226 TI - NACNS Newsletter: President's Message. PMID- 28806227 TI - Looking Beyond the First Impression: Malnutrition in the Hospital Setting. PMID- 28806228 TI - Legal and Ethical Concerns of Big Data: Predictive Analytics. PMID- 28806229 TI - The Business of Interpersonal Team Relationships. PMID- 28806230 TI - A Multifaceted Model to Evaluate Interprofessional Education in Clinical Nurse Specialist Programs. AB - PURPOSE: Preparing students to engage in team-based healthcare is a major focus of clinical nurse specialist (CNS) education programs. A robust evaluation plan is needed to monitor achievement of key outcomes in this complex undertaking. DESCRIPTION: Informed by the work of Kirkpatrick and Stufflebeam, an evaluation model that incorporates multiple information sources about process and outcomes related to interprofessional (IP) education is proposed. OUTCOME: Improvements in scores on attitude and competency measures suggest that the program had the desired effects on students' attitudes and self-efficacy for IP collaboration and was validated by faculty clinical observations of IP communication and teamwork. Moreover, students indicated at both graduation and at 1-year follow-up surveys that they were prepared to function on IP teams, providing further evidence that the clinical nurse specialist (CNS) program prepared them in this key area of nursing practice. CONCLUSION: The evaluation plan guided the collection of quantitative and qualitative information that faculty could use to refine the CNS program. Congruent with the CNS role as change agents, future model refinements should incorporate systems change activities. PMID- 28806231 TI - Exploring the Role of Key Workers in Cancer Care: Patient and Staff Perspectives. AB - PURPOSE/AIMS: The key worker role in cancer services was established in England to improve the continuity of care for patients. We examined how the role has been implemented by clinical nurse specialists and how both cancer patients and nursing staff viewed its effectiveness to inform debate about the transfer of patients between clinical nurse specialists during cancer care. DESIGN: This study was questionnaire based, with separate surveys developed for patients and staff. METHOD: The questionnaires explored issues including implementation of the key worker role, modifications to it, and where the role was felt to have most impact. The questionnaires were completed by 101 staff members and 46 patients. The data were analyzed descriptively. RESULTS: Perspectives on the key worker role differed between nursing staff respondents and patient respondents. Overall, patient respondents were very positive, whereas staff respondents were less so. The following is a key difference related to patient handover: 71% of patient respondents wanted the same key worker throughout their treatment, but only 28% of staff respondents did. Staff respondents wanted more training to clarify the role. CONCLUSION: Continuity of care through an assigned key worker was highly valued by patients. Successful implementation could be better achieved through improved communication with both nursing staff and allied health professions. Where possible, cancer patients should be assigned a dedicated key worker at initial diagnosis. PMID- 28806232 TI - Assessment of Medical-Surgical Patients' Perception of Hospital Noises and Reported Ability to Rest. AB - OBJECTIVES: The purpose was to determine if an enhanced privacy curtain (1) impacted ability to rest while hospitalized in the acute care setting and (2) improved patient satisfaction associated with environmental noise. METHODS: The project evaluated a privacy curtain designed to increase speech privacy and intelligibility and reduce reverberation time (echo). The curtain was similar to the existing privacy curtain with 2 exceptions: the curtain panel had pocket inserts that absorbed sound, and curtain panels could be zipped together to reduce sound transmission through gaps. Curtains were evaluated on 2 medical surgical units. Patients with at least 2 nights' stay and were alert and oriented without behavioral concerns were asked to complete a 12-item restful environment assessment. RESULTS: The project demonstrated some impact on ability to rest. One unit saw an increase in the patient experience sleep measure score and demonstrated a small increase in the patient's self- reported ability to rest during the day and night when using the enhanced curtain. CONCLUSION: Patients on medical-surgical units were bothered by the noises typically heard in those units. Small improvements in patient experience with the enhanced curtain were outweighed by cost and increased housekeeping and laundry staff workload. PMID- 28806233 TI - Enhancing Key Competencies of Health Professionals in the Assessment and Care of Adults at Risk of Suicide Through Education and Technology. AB - PURPOSE: This article describes efforts undertaken to improve the clinical competencies of health professionals in the area of suicide risk assessment, documentation, and care planning. DESCRIPTION OF THE PROJECT: Best practices that fit the mental health and addictions setting were identified from the Registered Nurses' Association of Ontario Best Practice Guideline on Assessment and Care of Adults at Risk for Suicidal Ideation and Behaviour. A variety of methods were used to implement the guidelines at the Centre for Addiction and Mental Health in Toronto, Ontario, Canada. These included 3 in-person educational modules, an e learning module, and the creation of an electronic health record suicide risk assessment documentation form. OUTCOME: Results showed that interprofessional team members improved their suicide awareness and increased their confidence and knowledge in suicide risk assessment and the identification of interventions for clients at risk. Organizational level performance and quality improvement activities after implementation of the education and the electronic suicide risk assessment documentation form are being implemented through a collaboration between performance improvement, clinical education and informatics, and professional practice. CONCLUSION: The success of an interprofessional educational program of this nature is dependent on the collaboration of a number of stakeholders from a variety of areas of the organization. PMID- 28806234 TI - Delirium in the Critically Ill Child. AB - PURPOSE/OBJECTIVE: The purposes of this article are to describe the scientific literature on assessment, prevention, and management of delirium in critically ill children and to articulate the implications for clinical nurse specialists, in translating the evidence into practice. DESCRIPTION: A literature search was conducted in 4 databases-OvidMEDLINE, Cumulative Index to Nursing and Allied Health Literature, PsychINFO, and Web of Science-using the terms "delirium," "child," and "critically ill" for the period of 2006 to 2016. OUTCOME: The scientific literature included articles on diagnosis, prevalence, risk factors, adverse outcomes, screening tools, prevention, and management. The prevalence of delirium in critically ill children is up to 30%. Risk factors include age, developmental delay, severity of illness, and mechanical ventilation. Adverse outcomes include increased mortality, hospital length of stay, and cost for the critically ill child with delirium. Valid and reliable delirium screening tools are available for critically ill children. Prevention and management strategies include interventions to address environmental triggers, sleep disruption, integrated family care, and mobilization. CONCLUSION: Delirium is a common occurrence for the critically ill child. The clinical nurse specialist is accountable for leading the implementation of practice changes that are based on evidence to improve patient outcomes. Screening and early intervention for delirium are key to mitigating adverse outcomes for critically ill children. PMID- 28806235 TI - Research Priorities for Nursing Education: Application to Clinical Nurse Specialist Education. PMID- 28806236 TI - The Antidote to Indifference* Is Costly. PMID- 28806237 TI - Botulinum toxin use in rehabilitation clinics: a survey to highlight differences and similarities. AB - Spasticity is a complex condition and its management is multifaceted, involving physical therapies as well as interventions with botulinum toxin. There is currently no standard for best practice and also wide variation in spasticity service set-ups and the background of clinicians involved in treatment. This could potentially cause large differences in practice. The aim of this survey was to attempt to identify some of the common elements of service delivery as well as highlight any significant variations in service models. It was hoped that the results would assist healthcare professionals working with toxins to gauge or improve their own service provision in the light of any findings. A survey of 48 botulinum toxin experts was conducted at a national conference in the UK. Questions included (i) numbers of patients referred and diagnostic groups, (ii) staff composition of each clinic, (iii) methods of spasticity assessment, (iv) outcome measures and treatment goals commonly used and (v) follow-up arrangements. There were broad areas of agreement between experts such as methods of assessment of spasticity, treatment, injection guidance and follow-up arrangements. However, there were differences in diagnostic groups seen, staff composition and in outcome measurement across a wide range of clinic settings. There are considerable variations in practice between toxin experts. This survey may help practitioners identify areas of improvement in their services or explore alternative service arrangements. PMID- 28806238 TI - 68Ga-PSMA Uptake in Combined Hepatocellular Cholangiocarcinoma With Skeletal Metastases. AB - Ga-PSMA PET is a rapidly evolving imaging modality for whole-body staging of prostate cancer. We report a case of a 70-year-old man with mildly elevated prostate-specific antigen (8.1 MUg/L) and clinical suspicion of prostate cancer (osteoblastic metastases on radionuclide bone scan) who was referred for Ga-PSMA PET/CT for primary staging. Multiple Ga-PSMA-avid skeletal foci, mostly associated with lytic changes on low-dose CT, as well as hepatic foci of avid Ga PSMA uptake, were identified. No abnormal focus of avid Ga-PSMA uptake was identified in the prostate. On histopathological examination, the liver lesion proved to be combined hepatocellular cholangiocarcinoma. PMID- 28806239 TI - 18F-FDG PET/CT of Secondary Epithelioid Angiosarcoma of the Proximal Femur in a Patient With Polyostotic Fibrous Dysplasia. AB - Fibrous dysplasia rarely transforms into a secondary malignancy. We present the PET/CT findings at pretreatment and posttreatment in an exceedingly rare case of epithelioid angiosarcoma of the bone secondary to polyostotic fibrous dysplasia. PMID- 28806240 TI - Quality and Safety in Health Care, Part XXXI: Selected Risk Factors for Transcatheter Aortic Valve Replacement. AB - The Transcatheter Valve Therapy Registry has been very helpful in providing data to better understand patient risk factors for transcatheter aortic valve replacement (TAVR). The outcome of TAVR depends on many patient indicators, some of which are given in this article, including the age, dependence on oxygen, classification of pulmonary disease, gender, and the speed of walking. Patient characteristics also help determine which approach will be used to place the device. There are models for the outcome of the TAVR procedure now and more being developed. PMID- 28806241 TI - FDG PET/CT in Primary Splenic Angiosarcoma With Diffuse Involvement of the Spleen. AB - Primary splenic angiosarcoma is rare. A 44-year-old man presented with abdominal distension and malaise for 7 months. Laboratory tests showed anemia. Abdominal ultrasound showed enlargement of the spleen with multiple hypoechoic nodules. These nodules showed progressive enhancement on dynamic enhanced CT. Lymphoma was suspected. FDG PET/CT showed increased nonuniform FDG uptake with SUVmax of 11.6 of the entire spleen. Laparoscopic splenectomy was performed. The pathologic findings were consisted with angiosarcoma with replacement of the spleen. Eight months after surgery, multiple hepatic metastases were detected by follow-up abdominal CT. PMID- 28806242 TI - Generalized Lymph Node FDG Uptake as the First Manifestation of Systemic Lupus Erythematosus. AB - We report 2 cases of young patients referred for FDG PET/CT for peripheral lymphadenopathy and moderate fever associated with pericarditis in 1 patient and glomerulonephritis in the other patient. FDG PET/CT showed a very similar appearance in these 2 patients, with highly avid lymph nodes with axillary predominance and diffuse FDG uptake in spleen and bone marrow. Systemic lupus erythematosus with an unusual presentation of generalized lymphadenopathy was diagnosed in both patients. This FDG distribution pattern should be kept in mind when PET is performed for etiological investigation of fever of unknown origin. PMID- 28806243 TI - Ictal 18F-FDG PET/MRI in a Patient With Cortical Heterotopia and Focal Epilepsy. AB - A 19-year-old man with epilepsy underwent ictal F-FDG PET/MRI, showing a 5 mm heterotopic nodule in the periventricular white matter, adjacent to the frontal horn of the left lateral ventricle (SUVmax, 5.5; glucidic cerebral metabolic rate, 0.317 MUmol/mL). A repeated F-FDG PET/MRI, during seizure freedom, showed, at visual analysis, subtle decrease of the nodule metabolism. SUVmax and glucidic cerebral metabolic rate were clearly reduced to 3.7 and 0.226, respectively. Ictal F-FDG PET/MRI could be useful in epilepsy because of the added value of SUVmax and cerebral metabolic rate of glucose analysis to understand the relationship between heterotopy and epilepsy. PMID- 28806244 TI - Lymphoma Causing Gastrosplenic Fistula Revealed by FDG PET/CT. AB - A 73-year-old man presented with fatigue and weight loss. He had CT-proven splenic mass with fistulous connection to the greater curvature of the stomach, which suggested abscess. FDG PET/CT confirmed gastrosplenic fistula in addition to active lymph nodes in the gastrohepatic ligament and epigastric region. Pathological examination after the biopsy of the spleen was consistent with diffuse large B-cell lymphoma. Chemotherapy was administered with close clinical follow-up and resulted in the resolution of fistula without requirement for surgery. PMID- 28806245 TI - Gorham-Stout Disease Affecting the Mandible: Bone Scintigraphy and Computed Tomography Findings. AB - We present images of a 13-year-old boy with Gorham-Stout disease affecting the mandible. Initial bone scintigraphy showed poor visualization of Tc-methylene diphosphonate (Tc-MDP) uptake in the mandible body. However, abnormally increased Tc-MDP uptake was noted in the bilateral mandibular rami. In the follow-up examination a year later, bone scintigraphy indicated that the disease had progressed to the bilateral mandibular rami with no uptake. In addition, massive osteolysis of the mandible was noted that had progressed since the initial computed tomography. This report suggests that bone scintigraphy could be a useful imaging tool to evaluate disease activity and determine treatment response. PMID- 28806246 TI - Response Assessment of 223Ra Treatment: Should a Fluorocholine PET/CT Be Performed? AB - We present 3 cases of patients with castration-resistant prostate cancer and bone metastases treated with Ra, belonging to our prospective and multicenter ChoPET Rad study. All patients underwent clinical, hematological, and biochemical monitoring between each Ra administration. Initial and follow-up F-fluorocholine PET/CT and Tc-biphosphonate bone scintigraphy were performed previously and after the third Ra administration. Both techniques correctly established the response to treatment, in agreement to the biochemical response, although differences in the disease expression (concordant and discordant patterns) were found because of the different radiotracer biodistribution and molecular information derived from them. PMID- 28806247 TI - Glomus Tumor of the Neck Detected With 99mTc EDDA HYNIC-TOC. AB - A 54-year-old woman was referred to thyroid evaluation because of a lump on the left side of the neck. Ultrasound exam did not show any thyroid abnormality, but highly perfused nodule at the left common carotid artery bifurcation was found. Because of the specific location, somatostatin receptor scintigraphy with Tc EDDA HYNIC-TOC was performed, starting with perfusion images and followed with SPECT/CT imaging at 2 and 4 hours. Well-perfused nodule with intensive accumulation and no other visible pathology in the body raised suspicion of a glomus tumor, consistent with MR exam performed later. Subsequent surgical removal confirmed carotid paraganglioma. PMID- 28806248 TI - Bone SPECT/CT Localizes Increased Bone Metabolism and Subsequent Bone Resorption in Reflex Sympathetic Dystrophy. AB - A 64-year-old man with lung cancer with a history of revascularization of the occluded right femoral artery underwent bone scintigraphy, which showed intense uptake in the distal side of the right leg. The additional SPECT/CT clarified that the uptake was predominantly increased in the epiphyses of the right ankle and foot with possible osteopenia. One month later, follow-up SPECT/CT showed the manifestation of periosteal resorption in the hypermetabolic sites with slight decrease in bone metabolism. Radiological correlation between bone metabolism and subsequent bone resorption in addition to clinical symptoms in this patient suggested the diagnosis of reflex sympathetic dystrophy. PMID- 28806249 TI - Epidural Metastases From Follicular Thyroid Cancer Mimicking Meningiomas in 68Ga DOTATATE PET. AB - We report a woman with multifocal lesions suggestive of meningiomas in MRI, which also presented with high Ga-DOTATATE uptake in PET, a finding characteristic for meningioma. A whole-body staging due to a pathological fracture revealed multiple neoplastic lesions throughout the body without detection of a primary site. Subsequent pathological workup of a lung lesion revealed multifocal metastases from follicular thyroid cancer despite thyroidectomy 10 years ago (without pathological finding), and posttreatment scans after radioiodine therapy confirmed the multiple brain lesions to be metastases as well. Our case shows that epidural metastases from endocrine origin might represent a clinical pitfall in Ga-DOTATATE PET. PMID- 28806250 TI - Recurrent Leiomyosarcoma of External Oblique Muscle Detected on 99mTc-MDP SPECT/CT. AB - A Tc-MDP bone scintigraphy was performed in an 88-year-old man with a history of right external oblique muscle leiomyosarcoma, which was resected 8 months ago. The static images showed abnormal tracer uptake in the region of resection bed. SPECT/CT images demonstrated that the increased activity was from a partially calcified soft tissue mass in external oblique muscle. Subsequent pathological examination confirmed recurrent tumor. PMID- 28806251 TI - PET/CT in an 8-Year-Old Girl With Epstein-Barr Virus-Associated Smooth Muscle Tumor. AB - Epstein-Barr virus-associated smooth muscle tumor is a rare indolent neoplasm, which can occur in unusual locations. It has been reported in immunosuppressed individuals in only 3 settings: posttransplant, human immunodeficiency virus infection, and primary immunodeficiency. Here, we present CT, MRI, and F-FDG PET/CT findings of Epstein-Barr virus-associated smooth muscle tumor in an 8-year old girl with primary immunodeficiency and metachronous adrenal involvement. PMID- 28806252 TI - Quality and Safety in Health Care, Part XXX: Transcatheter Aortic Valve Therapy. AB - Initially, the transcatheter aortic valve replacement procedure was approved only for patients with aortic stenosis that was both severe and symptomatic who either also had too high a risk of aortic valve replacement surgery to have the surgery or who had a high risk for the surgery. Between the years 2012 and 2015, the death rate at 30 days declined from an initial rate of 7.5% to 4.6%. There has also been more use of the transfemoral approach over the years. In 2016, the transcatheter aortic valve replacement was approved for patients with aortic stenosis at intermediate risk of surgery. PMID- 28806253 TI - Variable MIBG Activity in the Same Renal Cyst. AB - A series of I-MIBG scanning was performed in a 33-year-old woman with a history of ganglioneuroblastoma and a known left renal cyst. The initial studies did not reveal any MIBG activity in the renal cyst. However, increased MIBG activity was noted in the same renal cyst in the subsequent follow-up scans. PMID- 28806254 TI - Rare Ileal Ewing Sarcoma/Primitive Neuroectodermal Tumor on 18F-FDG PET/CT. AB - A 24-year-old woman who had melena, dizziness, and fatigue and looked pale for 2 months was confirmed to have a microcytic hypochromic anemia in the local hospital. It was further revealed that the patient had splenomegaly and a small intestinal lump, and she was then referred to our hospital. The enhanced CT showed an ileal lesion with enhancement, which showed an increased F-FDG activity in further PET/CT scanning. Lymphoma was therefore suspected, and an uncomplicated surgical resection of the ileal lesion was then performed. Nevertheless, the histopathologic and immunohistochemical examination was finally proved to be a rare ileal Ewing sarcoma/primitive neuroectodermal tumor. PMID- 28806255 TI - Intra-articular Melanoma Metastasis in the Ankle Joint. AB - Intra-articular melanoma metastases are rare. We present a case of a 65-year-old woman with metastatic melanoma in the right ankle joint. F-FDG PET/CT was performed from the vertex to the toes, which demonstrated FDG-avid inguinal lymphadenopathy and an intensely FDG-avid soft tissue mass adjacent to the neck of the talus within the right ankle joint. The intra-articular mass was subsequently resected and histologically confirmed as metastatic melanoma. This case emphasizes the value of the contemporaneous CT in these studies for accurate anatomical localization in diagnostically challenging clinical scenarios. PMID- 28806256 TI - Recurrent Malignant Melanoma Detected on 18F-Fluciclovine PET/CT Imaging for Prostate Cancer. AB - A 66-year-old man presented with biochemical recurrence of prostate cancer and underwent F-fluciclovine PET/CT to detect sites of recurrence. He had a history of resected truncal stage IIIC malignant melanoma, with bilateral axillary node involvement on sentinel node biopsy, in complete remission for 3 years. F fluciclovine PET/CT demonstrated an incidental fluciclovine-avid right axillary node (SUVmax = 4.3). Diagnostic sampling confirmed recurrent malignant melanoma. PMID- 28806257 TI - Orbital Hemangiopericytoma in 68Ga-Prostate-Specific Membrane Antigen-HBED-CC PET/CT. AB - A 76-year-old man with biochemical relapse of prostate cancer underwent Ga prostate-specific membrane antigen PET/CT. Besides a local lymph node metastasis, a nodular structure inside the left orbit caudal to the optic nerve showed increased uptake. A metastasis in this location is unlikely. The subsequently performed MRI showed the structure being T1 hypointense, T2 indifferent, and strongly gadolinium contrast agent enhancing. Histopathologic examination after surgical removal identified the tumor as hemangiopericytoma, which rarely occurs in the orbit. Regarding the intense uptake observed, prostate-specific membrane antigen-targeting PET tracers could bear potential for staging purposes of this tumor entity. PMID- 28806258 TI - Recurrent Scapular Metastasis From Hepatoblastoma Shown on FDG PET/CT and F-DOPA PET/CT. AB - We report the case of a 4-year-old girl with a biochemical relapse (plasma alpha fetoprotein of 57,987.6 MUg/L) after hepatoblastoma and extrahepatic metastases removal and adjuvant chemotherapy. Abdominal ultrasound, CT, and MRI failed to determine the site of recurrence. F-FDG PET/CT showed increased activity in the region of left scapula and adjacent soft tissue, which was incorrectly interpreted as the postoperative repair or inflammatory change. F-DOPA PET/CT showed increased activity and noticeable progressed lesion in the same place. Finally, the left scapula was identified as the site of recurrent metastasis from hepatoblastoma by pathological examination. PMID- 28806259 TI - Serendipitous Discovery of Isolated Gastric Metastases From Adenocarcinoma of the Lung on Staging 18F-FDG PET-CT. AB - Gastric metastasis from lung cancer is rare. We here present the case of a 59 year-old man with lung adenocarcinoma where isolated gastric metastases were discovered on staging F-FDG PET-CT, confirmed with endoscopy and biopsy. PMID- 28806260 TI - 68Ga-PSMA-Ligand PET/CT Uptake in Anthracosilicosis. AB - This interesting image illustrates a case of biopsy-proven pulmonary anthracosilicosis, a mixed dust pneumoconiosis, associated with Ga-PSMA-ligand uptake. Prostate-specific membrane antigen (PSMA) is an emerging imaging biomarker, with clinical application in evaluation of prostate cancer using Ga PSMA-ligand PET/CT. Contrary to its name, PSMA is expressed in a number of other normal tissues and pathological states. Prostate-specific membrane antigen expression has been linked to tumor angiogenesis in various other epithelial neoplasms, as well as neovasculature associated with tissue regeneration and repair. Awareness of nonneoplastic inflammatory conditions associated with Ga PSMA-ligand uptake aids in patient assessment and management. PMID- 28806261 TI - Unexpected Fibrosing Mediastinitis Shown on FDG PET/CT in a Patient With IgG4 Related Disease. AB - A 66-year-old man presented to our hospital because of abdominal pain for 5 days. A contrast abdominal CT raised the possibility of pancreatic carcinoma. FDG PET/CT showed increased FDG accumulation not only in the pancreas and the retroperitoneum, but also in the posterior mediastinum, which was not typical of pancreatic carcinoma. The patient was subsequently diagnosed having immunoglobulin G4-related disease following the histopathologic examination. PMID- 28806262 TI - An Unusual Case of Penile Prostate Cancer Uncovered by Multiparametric MRI and PSMA-Targeted 18F-DCFPyL PET/CT. AB - Multiparametric MRI (mpMRI) is currently the test of choice for imaging sites of prostate cancer located within the pelvis. However, molecular imaging with PET radiotracers that bind to prostate-specific membrane antigen is increasingly being used for this purpose and may compliment mpMRI findings. We present a case of a 59-year-old man with elevated postprostatectomy serum prostate-specific antigen level who was found on both mpMRI and prostate-specific membrane antigen targeted PET to harbor residual prostate cancer in the corpus spongiosum along the proximal urethra. PMID- 28806264 TI - 18F-FDG PET/CT of Brown Adipose Tissue Hyperactivation Associated With Pregnancy and Paraganglioma. AB - This 32-year-old woman presented with pregnancy-related arterial hypertension unresponsive to antihypertensive therapy. During cesarean delivery, a lobulated retroperitoneal mass was discovered. F-FDG PET/CT performed 18 days postpartum demonstrated the hyperactive retroperitoneal mass and extensive hyperactivated brown adipose tissue. The mass was surgically removed, revealing a para-aortic multicentric paraganglioma. After surgery, blood pressure normalized, and serum chromogranin A and urinary metanephrines normalized. Brown adipose tissue hypermetabolism disappeared on follow-up FDG PET. Her initial FDG PET demonstrated brown adipose tissue hyperactivation, which may have been caused by the combination of hormonal changes in pregnancy and the paraganglioma. PMID- 28806263 TI - 18F-DCFBC Prostate-Specific Membrane Antigen-Targeted PET/CT Imaging in Localized Prostate Cancer: Correlation With Multiparametric MRI and Histopathology. AB - PURPOSE: To assess the ability of (N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-F fluorobenzyl-L-cysteine) (F-DCFBC), a prostate-specific membrane antigen-targeted PET agent, to detect localized prostate cancer lesions in correlation with multiparametric MRI (mpMRI) and histopathology. METHODS: This Health Insurance Portability and Accountability Act of 1996-compliant, prospective, institutional review board-approved study included 13 evaluable patients with localized prostate cancer (median age, 62.8 years [range, 51-74 years]; median prostate specific antigen, 37.5 ng/dL [range, 3.26-216 ng/dL]). Patients underwent mpMRI and F-DCFBC PET/CT within a 3 months' window. Lesions seen on mpMRI were biopsied under transrectal ultrasound/MRI fusion-guided biopsy, or a radical prostatectomy was performed. F-DCFBC PET/CT and mpMRI were evaluated blinded and separately for tumor detection on a lesion basis. For PET image analysis, MRI and F-DCFBC PET images were fused by using software registration; imaging findings were correlated with histology, and uptake of F-DCFBC in tumors was compared with uptake in benign prostatic hyperplasia nodules and normal peripheral zone tissue using the 80% threshold SUVmax. RESULTS: A total of 25 tumor foci (mean size, 1.8 cm; median size, 1.5 cm; range, 0.6-4.7 cm) were histopathologically identified in 13 patients. Sensitivity rates of F-DCFBC PET/CT and mpMRI were 36% and 96%, respectively, for all tumors. For index lesions, the largest tumor with highest Gleason score, sensitivity rates of F-DCFBC PET/CT and mpMRI were 61.5% and 92%, respectively. The average SUVmax for primary prostate cancer was higher (5.8 +/- 4.4) than that of benign prostatic hyperplasia nodules (2.1 +/- 0.3) or that of normal prostate tissue (2.1 +/- 0.4) at 1 hour postinjection (P = 0.0033). CONCLUSIONS: The majority of index prostate cancers are detected with F-DCFBC PET/CT, and this may be a prognostic indicator based on uptake and staging. However, for detecting prostate cancer with high sensitivity, it is important to combine prostate-specific membrane antigen PET/CT with mpMRI. PMID- 28806265 TI - Adult-Acquired Flatfoot Deformity: Etiology, Diagnosis, and Management. PMID- 28806266 TI - Bone Growth Stimulation: A Critical Analysis Review. PMID- 28806267 TI - Evaluation and Treatment of Femoral Osteolysis Following Total Hip Arthroplasty. PMID- 28806268 TI - Pharmacotherapy of eating disorders. AB - PURPOSE OF REVIEW: Medications are commonly prescribed in the treatment of eating disorders. In this review, we discuss relevant medications used for the treatment of bulimia nervosa, binge eating disorder (BED), and anorexia nervosa. We focus on recent research developments, where applicable, in addition to discussing important findings from older studies to provide a complete synopsis of the current evidence base for eating disorder treatment using pharmacologic agents. RECENT FINDINGS: Medications are generally useful for patients with bulimia nervosa and BED. For bulimia nervosa, antidepressant medications are the primary pharmacologic treatment and limited new research has been completed. For BED, lisdexamfetamine is reported to be generally well tolerated and effective, and is the first medication to be indicated by the US Food and Drug Administration for treatment of BED. For anorexia nervosa, there is limited evidence supporting benefits of medications. Second-generation antipsychotics, particularly olanzapine, appear to demonstrate some benefit for weight gain in anorexia nervosa, although are not advised as a stand-alone treatment. Transdermal administration of hormonal agents is also being explored for improving bone health in anorexia nervosa. SUMMARY: Although pharmacotherapy has established utility in bulimia nervosa and BED, further research on medications for the treatment of eating disorders, particularly anorexia nervosa, is necessary. PMID- 28806269 TI - Affective disorders and sexual function: from neuroscience to clinic. AB - PURPOSE OF REVIEW: Sexual dysfunction is a frequent issue in patients with affective disorders, affecting its quality of life and posing challenges to the approach of these patients. RECENT FINDINGS: In recent years, human sexuality has attracted interest from the scientific community, and today we have a much deeper knowledge of the mechanisms involved in the sexual response. Paraphilias or sexual dysfunctions like low sexual desire, premature ejaculation, and erectile dysfunction, are frequent in affective disorders, and the frequency of each sexual problem varies according to the affective disorder. Comparing what is currently known about the sexual response with the main neurobiological findings of depressive, anxiety, obsessive-compulsive and posttraumatic stress disorders, it is possible to better understand specific sexual complaints of patients with these disorders. SUMMARY: A better understanding of sexual function in affective disorders may help clinicians to choose treatments more suited to specific needs of these patients. Although the current state of science already allows us to have some understanding about sexual function in affective disorders, this critical area of research is still in its infancy, waiting for more investment. PMID- 28806270 TI - New clinical paradigms for treating and preventing antiplatelet gastrointestinal bleeding. AB - PURPOSE OF REVIEW: To quantify antiplatelet-related gastrointestinal bleeding (GIB), characterize patients at greatest risk and summarize risk-management strategies emphasizing evolving knowledge in acute management of antiplatelet related bleeding. RECENT FINDINGS: New paradigms for acute management of antiplatelet-related GIB exist in the domains of resuscitation and the transfusion of blood products, strategic use of proton pump therapy and identification and eradication of Helicobacter pylori. This review will also highlight the importance of prompt resumption of cardiac aspirin and dual antiplatelet therapy following endoscopic hemostasis to minimize the risk of future cardiac events. SUMMARY: This review will provide pragmatic strategies for the management of acute antiplatelet-related GIB. Emerging areas of clinical knowledge will be addressed and knowledge gaps requiring further research to inform clinical practice will be highlighted. PMID- 28806272 TI - Is there a standard-of-care for transfusion support of patients with haematological malignancies? AB - PURPOSE OF REVIEW: Patients with haematological malignancies are a high-user group for blood transfusions. Here, we describe the current evidence on transfusion policies in patients with haematological malignancies, based on recent systematic reviews of RCTs. RECENT FINDINGS: Results from six RCTs (1195 participants) suggest that prophylactic platelet transfusions reduce bleeding compared with therapeutic-only use, although the effects varied according to patient diagnosis/treatment plan. A meta-analysis of seven RCTs (1814 participants) reported that low-dose platelet transfusions (1.1 * 10/m +/- 25%) were noninferior to standard dose (2.2 * 10/m +/- 25%), or high dose (4.4 * 10/m +/- 25%). Three RCTs (499 participants) reported that restrictive platelet count thresholds (less than 10 * 10/l) were noninferior to liberal thresholds counts (less than 20-30 * 10/l). For red-cell transfusions, the data from completed RCTs was less advanced. A recent meta-analysis with four RCTs (240 participants) suggested that restrictive thresholds (less than 70-90 g/l) are noninferior to liberal thresholds (less than 80-120 g/l), but with more uncertainty for clinical outcomes. SUMMARY: There is support from randomised trials for using prophylactic platelet transfusions, in low-dose, and with restrictive thresholds. No large completed studies have been published for red-cell transfusions. Many studies overall were arguably underpowered and only offered low-to-medium grade level evidence. PMID- 28806271 TI - Luminal chemosensing in the gastroduodenal mucosa. AB - PURPOSE OF REVIEW: We report recently published knowledge regarding gut chemosensory mechanisms focusing on nutrient-sensing G protein-coupled receptors (GPCRs) expressed on gut enteroendocrine cells (EECs), tuft cells, and in afferent nerves in the gastroduodenal mucosa and submucosa. RECENT FINDINGS: Gene profiling of EECs and tuft cells have revealed expression of a variety of nutrient-sensing GPCRs. The density of EEC and tuft cells is altered by luminal environmental changes that may occur following bypass surgery or in the presence of mucosal inflammation. Some EECs and tuft cells are directly linked to sensory nerves in the subepithelial space. Vagal afferent neurons that innervate the intestinal villi express nutrient receptors, contributing to the regulation of duodenal anion secretion in response to luminal nutrients. Nutrients are also absorbed via specific epithelial transporters. SUMMARY: Gastric and duodenal epithelial cells are continually exposed to submolar concentrations of nutrients that activate GPCRs expressed on EECs, tuft cells, and submucosal afferent nerves and are also absorbed through specific transporters, regulating epithelial cell proliferation, gastrointestinal physiological function, and metabolism. The chemical coding and distribution of EECs and tuft cells are keys to the development of GPCR-targeted therapies. PMID- 28806273 TI - The changing landscape of gene editing in hematopoietic stem cells: a step towards Cas9 clinical translation. AB - PURPOSE OF REVIEW: Since the discovery two decades ago that programmable endonucleases can be engineered to modify human cells at single nucleotide resolution, the concept of genome editing was born. Now these technologies are being applied to therapeutically relevant cell types, including hematopoietic stem cells (HSC), which possess the power to repopulate an entire blood and immune system. The purpose of this review is to discuss the changing landscape of genome editing in hematopoietic stem cells (GE-HSC) from the discovery stage to the preclinical stage, with the imminent goal of clinical translation for the treatment of serious genetic diseases of the blood and immune system. RECENT FINDINGS: With the discovery that the RNA-programmable (sgRNA) clustered regularly interspace short palindromic repeats (CRISPR)-Cas9 nuclease (Cas9/sgRNA) systems can be easily used to precisely modify the human genome in 2012, a genome-editing revolution of hematopoietic stem cells (HSC) has bloomed. We have observed that over the last 2 years, academic institutions and small biotech companies are developing HSC-based Cas9/sgRNA genome-editing curative strategies to treat monogenic disorders, including beta-hemoglobinopathies and primary immunodeficiencies. We will focus on recent publications (within the past 2 years) that employ different genome-editing strategies to 'hijack' the cell's endogenous double-strand repair pathways to confer a disease-specific therapeutic advantage. SUMMARY: The number of genome-editing strategies in HSCs that could offer therapeutic potential for diseases of the blood and immune system have dramatically risen over the past 2 years. The HSC-based genome-editing field is primed to enter clinical trials in the subsequent years. We will summarize the major advancements for the development of novel autologous GE-HSC cell and gene therapy strategies for hematopoietic diseases that are candidates for curative allogeneic bone marrow transplantation. PMID- 28806275 TI - Effects of Creatine and Carbohydrate Loading on Cycling Time Trial Performance. AB - INTRODUCTION: Creatine (Cr) and carbohydrate loadings are dietary strategies used to enhance exercise capacity. This study examined the metabolic and performance effects of a combined CR and CHO loading regiment on time trial (TT) cycling bouts. METHODS: Eighteen well-trained (~65 mL.kg.min VO2peak) men completed three performance trials (PT) that comprised a 120-km cycling TT interspersed with alternating 1- and 4-km sprints (six sprints each) performed every 10 km followed by an inclined ride to fatigue (~90% VO2peak). Subjects were pair matched into either CR-loaded (20 g.d for 5 d + 3 g.d for 9 d) or placebo (PLA) groups (n = 9) after the completion of PT1. All subjects undertook a crossover application of the carbohydrate interventions, consuming either moderate (6 g.kg body mass (BM) per day; MOD) or CHO-loaded (12 g.kg BM.d; LOAD) diets before PT2 and PT3. Muscle biopsies were taken before PT1, 18 h after PT1, and before both PT2 and PT3. RESULTS: No significant differences in overall TT or inclined ride times were observed between intervention groups. PLA + LOAD improved power above baseline (P < 0.05) during the final 1-km sprint, whereas CR + MOD and CR + LOAD improved power (P < 0.05) during the final 4-km sprint. Greater power was achieved with MOD and LOAD compared with baseline with PLA (P < 0.05). CR increased pre-PT BM compared with PLA (+1.54% vs +0.99% from baseline). CR + LOAD facilitated greater [total CR] (P < 0.05 vs baseline) and muscle [glycogen] (P < 0.01 vs baseline and MOD) compared with PLA + LOAD. Mechanistic target of rapamycin decreased from baseline after glycogen depletion (~30%; P < 0.05). CONCLUSIONS: Power output in the closing sprints of exhaustive TT cycling increased with CR ingestion despite a CR-mediated increase in weight. CR cosupplemented with carbohydrates may therefore be beneficial strategy for late-stage breakaway moments in endurance events. PMID- 28806274 TI - Transfusion-related immunomodulation: a reappraisal. AB - PURPOSE OF REVIEW: This review summarizes current and prior observations regarding transfusion-related immunomodulation (TRIM) and puts these ideas into a modern immunological context, incorporating concepts from innate, adaptive, and nutritional immunity. We propose that TRIM research focus on determining whether there are specific, well-defined immunosuppressive effects from transfusing 'pure' red blood cells (RBCs) themselves, along with the by-products produced by the stored RBCs as a result of the 'storage lesion.' Macrophages are a key cell type involved in physiological and pathological RBC clearance and iron recycling. The plasticity and diversity of macrophages makes these cells potential mediators of immune suppression that could constitute TRIM. RECENT FINDINGS: Recent reports identified the capacity of macrophages and monocytes to exhibit 'memory.' Exposure to various stimuli, such as engulfment of apoptotic cells and interactions with beta-glucan and lipopolysaccharide, were found to induce epigenetic, metabolic, and functional changes in certain myeloid cells, particularly macrophages and monocytes. SUMMARY: Macrophages may mediate the immunosuppressive aspects of TRIM that arise as a result of transfused RBCs and their storage lesion induced by-products. PMID- 28806276 TI - Circulating Progenitor Cell Response to Exercise in Wheelchair Racing Athletes. AB - INTRODUCTION: Circulating progenitor cells (CPC) are a heterogeneous population of stem/progenitor cells in peripheral blood that participate in tissue repair. CPC mobilization has been well characterized in able-bodied persons but has not been previously investigated in wheelchair racing athletes. The purpose of this study was to characterize CPC and CPC subpopulation mobilization in elite wheelchair racing athletes in response to acute, upper-extremity aerobic exercise to determine whether CPC responses are similar to ambulatory populations. METHODS: Eight participants (three females; age = 27.5 +/- 4.0 yr, supine height = 162.5 +/- 18.6 cm, weight = 53.5 +/- 10.9 kg, VO2peak = 2.4 +/- 0.62 L.min, years postinjury = 21.5 +/- 6.2 yr) completed a 25-km time trial on a road course. Blood sampling occurred before and immediately after exercise for quantification of CPC (CD34), hematopoietic stem and progenitor cells (HSPC) (CD34/CD45), hematopoietic stem cells (HSC) (CD34/CD45/CD38), CD34 adipose tissue (AT)-derived mesenchymal stromal cells (MSC) (CD45/CD34/CD105/CD31), CD34 bone marrow (BM)-derived MSC (CD45/CD34/CD105/CD31), and endothelial progenitor cells (EPC) (CD45/CD34/VEGFR2) via flow cytometry. Blood lactate was measured before and after trial as an indicator of exercise intensity. RESULTS: CPC concentration increased 5.7-fold postexercise (P = 0.10). HSPC, HSC, EPC, and both MSC populations were not increased postexercise. Baseline HSPC populations were significantly positively correlated to absolute VO2peak (rho = 0.71, P < 0.05) with HSC trending to positively correlate to VO2peak (rho = 0.62, P = 0.10). AT MSC populations were trending to be negatively correlated to baseline VO2peak (rho = -0.62, P = 0.058). The change in CPC, EPC, and AT-MSC pre- and postexercise significantly positively correlated to the change in lactate concentrations (rho = 0.91 P = 0.002, 0.71 P = 0.047, 0.81 P = 0.02, respectively, all P < 0.05). CONCLUSION: These data suggest that CPC content in wheelchair racing athletes is related to cardiorespiratory fitness, and responses to exercise are positively related to exercise intensity. PMID- 28806277 TI - Nursing Faculty Attitudes and Practices Related to Online Teaching. AB - Online education as a teaching methodology is relatively new in higher education in comparison to traditional face-to-face instruction. There is often concern that the quality of online classes is inferior and that academic rigor is compromised when faculty are not engaged with students in a classroom. The purpose of this pilot study was to assess nursing faculty attitudes and practices regarding online teaching. Findings indicated that overall, faculty feel that achievement of student learning outcomes in online and hybrid settings is comparable to face-to-face and report excitement with most aspects of teaching online. PMID- 28806278 TI - CE: Original Research: The Experience of Transitioning to a Caregiving Role for a Family Member with Alzheimer's Disease or Related Dementia. AB - : : Background: Alzheimer's disease is a chronic, debilitating disease that currently affects an estimated 5.5 million Americans. The majority are being cared for at home by family caregivers, who are known to have higher levels of burden than any other group of caregivers. PURPOSE: The purpose of this phenomenological study was to explore the lived experiences of people who transition to the role of caregiver for a family member with Alzheimer's disease or a related dementia. METHODS: The study used purposeful sampling. Eight women and two men (mean age, 66.3 years) participated. Data were collected through in depth semistructured interviews, along with observational field notes. Data were analyzed using a hermeneutic phenomenological approach. RESULTS: The average duration of caregiving reported by participants was five years. Seven themes were uncovered: something is wrong; journey to diagnosis: ambiguity and negative emotions; shifting roles and relationships: losses and challenges; seeking knowledge and support: solutions and frustrations; adapting to the topsy-turvy world of caregiving: finding purpose; preserving self without guilt; and finding a way out. CONCLUSIONS: The study findings have implications for nursing education, research, and practice, with participants expressing needs for better communication and access to resources. The findings also suggest the importance of health care planning early in the disease process, and of raising awareness about nurses as a resource for family members. PMID- 28806279 TI - CE: Can Your Older Patients Drive Safely? AB - : In many areas of the world, driving is an essential part of life and for reasons of comfort, convenience, and security remains the primary mode of transportation among older adults. Both normal aging and diseases that are more prevalent in advanced age can substantially reduce older drivers' functional abilities, elevating their risk of involvement in motor vehicle accidents and serious injury or death. Identifying and intervening with older drivers at increased crash risk is an important aspect of preventive medicine. The authors discuss the specific driving risks adults face as they age and how nurses can raise older patients' awareness of these risks. They also discuss the importance of connecting older adults to community resources that may help them continue driving safely for a longer period or find alternative transportation options. PMID- 28806281 TI - Ventilator-associated Pneumonia in Neonatal Intensive Care Unit Due to Chryseobacterium indologenes. AB - Ventilator-associated pneumonia represents one of the most common nosocomial infections in neonatal intensive care units, increasing morbidity and mortality and associated costs. The authors report the case of a neonatal patient with ventilator-associated pneumonia secondary to Chryseobacterium indologenes and a review of the literature. The most effective empiric treatment for C. indologenes infection remains unclear due to limited data in the literature, and therefore, therapy should be adjusted in accordance with the result of the susceptibility profile. PMID- 28806282 TI - Adenovirus Infection in Children With Acute Myeloid Leukemia: A Report From the Canadian Infection in Acute Myeloid Leukemia Research Group. AB - BACKGROUND: Children with acute myeloid leukemia (AML) are at high risk of life threatening bacterial and fungal infection. However, little is known about the prevalence or severity of adenovirus infection in this population. Objective was to describe the characteristics, treatments and outcomes of adenovirus infection in children with newly diagnosed AML. METHODS: We performed a retrospective chart review based upon 2 multicenter cohort studies that focused on identifying risk factors for infection in children with AML. Inclusion criteria were patients with de novo AML who were <=18 years of age at diagnosis with a clinical specimen positive for adenovirus. RESULTS: Among the 235 patients with AML, 12 (5.1%) had positive adenovirus testing. The most common site of isolation was stool (n = 11, 91.6 %), and the most frequent symptom was diarrhea (n = 11, 91.6 %). Two patients received specific treatment for adenovirus, namely intravenous immunoglobulin only in 1 patient and both intravenous immunoglobulin and inhaled ribavirin in a second patient. In 11 patients, adenovirus resolved uneventfully without recurrence, including 10 that received no adenovirus-specific therapy. However, 1 patient developed sepsis syndrome in the setting of disseminated adenoviral infection and died from multiorgan failure. CONCLUSION: In children with AML, adenovirus infection was rare and typically not associated with severe disease, even without specific treatment. However, disseminated and fatal disease can occur in this population. Further investigations are needed to identify pediatric AML patients at particular risk for severe adenovirus infection and to determine optimal treatment approaches in these patients. PMID- 28806280 TI - Integrated Analysis of Biopsies from Inflammatory Bowel Disease Patients Identifies SAA1 as a Link Between Mucosal Microbes with TH17 and TH22 Cells. AB - BACKGROUND: Inflammatory bowel diseases (IBD) are believed to be driven by dysregulated interactions between the host and the gut microbiota. Our goal is to characterize and infer relationships between mucosal T cells, the host tissue environment, and microbial communities in patients with IBD who will serve as basis for mechanistic studies on human IBD. METHODS: We characterized mucosal CD4 T cells using flow cytometry, along with matching mucosal global gene expression and microbial communities data from 35 pinch biopsy samples from patients with IBD. We analyzed these data sets using an integrated framework to identify predictors of inflammatory states and then reproduced some of the putative relationships formed among these predictors by analyzing data from the pediatric RISK cohort. RESULTS: We identified 26 predictors from our combined data set that were effective in distinguishing between regions of the intestine undergoing active inflammation and regions that were normal. Network analysis on these 26 predictors revealed SAA1 as the most connected node linking the abundance of the genus Bacteroides with the production of IL17 and IL22 by CD4 T cells. These SAA1 linked microbial and transcriptome interactions were further reproduced with data from the pediatric IBD RISK cohort. CONCLUSIONS: This study identifies expression of SAA1 as an important link between mucosal T cells, microbial communities, and their tissue environment in patients with IBD. A combination of T cell effector function data, gene expression and microbial profiling can distinguish between intestinal inflammatory states in IBD regardless of disease types. PMID- 28806284 TI - Is extracorporeal cardiopulmonary resuscitation practical in severe chest trauma? A systematic review in single center of developing country. AB - BACKGROUND: We report our experience with extracorporeal cardiopulmonary resuscitation (ECPR) in patients with rupture of heart and major vessels caused by severe chest trauma. METHODS: From April 2015 to May 2016, 10 patients with suspected injuries to the heart and major vessels after focused assessment with sonography in trauma or computed tomography were selected from patients admitted at a Level I trauma center presenting with cardiac tamponade and tension hemothorax due to severe chest trauma. Patients were divided as follow: group A (n = 3), patients without cardiac arrest before entering the operating theatre; group B (n = 5), patients with cardiac arrest for whom ECPR was applied, and group C (n = 2), patients with cardiac arrest for whom ECPR was not applied. RESULTS: All patients underwent exploratory thoracotomy or sternotomy. Injuries included cardiac chamber ruptures (n = 8), lesions in the internal mammary arteries (n = 1), and lesions of the bronchial arteries (n = 1). In group B, extracorporeal membrane oxygenation (ECMO) was initiated and circulation was restored promptly with adequate extracorporeal blood flow in all five cases. These patients were weaned off ECMO uneventfully after controlling the bleeding in the operating theatre. Mean ECMO time was 142 +/- 48.2 minutes. Conversely, both patients in group C died, one due to low cardiac output on postoperative day 1, and the other due to multiple-organ failure on postoperative day 7. CONCLUSION: ECPR may be an option to rescue and stabilize patients with cardiac arrest due to severe chest trauma. LEVELS OF EVIDENCE: Therapeutic/Care Management, Level V. PMID- 28806286 TI - Aortic balloon occlusion and placenta percreta: Some concerns and clarifications. PMID- 28806285 TI - Peritoneal cavity lavage reduces the presence of mitochondrial damage associated molecular patterns in open abdomen patients. AB - BACKGROUND: Mitochondrial damage-associated molecular patterns (mtDAMPs), such as mitochondrial DNA and N-formylated peptides, are endogenous molecules released from tissue after traumatic injury. mtDAMPs are potent activators of the innate immune system. They have similarities with bacteria, which allow mtDAMPs to interact with the same pattern recognition receptors and mediate the development of systemic inflammatory response syndrome (SIRS). Current recommendations for management of an open abdomen include returning to the operating room every 48 hours for peritoneal cavity lavage until definitive procedure. These patients are often critically ill and develop SIRS. We hypothesized that mitochondrial DAMPs are present in the peritoneal cavity fluid in this setting, and that they accumulate in the interval between washouts. METHODS: We conducted a prospective pilot study of critically ill adult patients undergoing open abdomen management in the surgical and trauma intensive care units. Peritoneal fluid was collected daily from 10 open abdomen patients. Specimens were analyzed via quantitative polymerase chain reaction (qPCR) for mitochondrial DNA (mtDNA), via enzyme immunoassay for DNAse activity and via Western blot analysis for the ND6 subunit of the NADH: ubiquinone oxidoreductase, an N-formylated peptide. RESULTS: We observed a reduction in the expression of ND6 the day after lavage of the peritoneal cavity, that was statistically different from the days with no lavage (% change in ND6 expression, postoperative from washout: -50 +/- 11 vs. no washout day, 42 +/- 9; p < 0.05). Contrary to expectation, the mtDNA levels remained relatively constant from sample to sample. We then hypothesized that DNAse present in the effluent may be degrading mtDNA. CONCLUSION: These results indicate that the peritoneal cavity irrigation reduces the presence of mitochondrial DAMPs in the open abdomen. It is possible that increased frequency of peritoneal cavity lavage may lead to decreased systemic absorption of mtDAMPs, thereby reducing the risk of SIRS. LEVEL OF EVIDENCE: Prospective study, Case Series, Level V. PMID- 28806287 TI - A prospective human study of the hematologic, coagulative, and inflammatory characteristics of hemothorax. PMID- 28806288 TI - Acellular Dermal Matrix in Immediate Expander/Implant Breast Reconstruction: A Multicenter Assessment of Risks and Benefits. AB - BACKGROUND: Acellular dermal matrix has gained widespread acceptance in immediate expander/implant reconstruction because of perceived benefits, including improved expansion dynamics and superior aesthetic results. Although previous investigators have evaluated its risks, few studies have assessed the impact of acellular dermal matrix on other outcomes, including patient-reported measures. METHODS: The Mastectomy Reconstruction Outcomes Consortium Study used a prospective cohort design to evaluate patients undergoing postmastectomy reconstruction from 10 centers and 58 participating surgeons between 2012 and 2015. The analysis focused on women undergoing immediate tissue expander reconstruction following mastectomies for cancer treatment or prophylaxis. Medical records and patient-reported outcome data, using the BREAST-Q and Numeric Pain Rating Scale instruments, were reviewed. Bivariate analyses and mixed effects regression models were applied. RESULTS: A total of 1297 patients were evaluated, including 655 (50.5 percent) with acellular dermal matrix and 642 (49.5 percent) without acellular dermal matrix. Controlling for demographic and clinical covariates, no significant differences were seen between acellular dermal matrix and non-acellular dermal matrix cohorts in overall complications (OR, 1.21; p = 0.263), major complications (OR, 1.43; p = 0.052), wound infections (OR, 1.49; p = 0.118), or reconstructive failures (OR, 1.55; p = 0.089) at 2 years after reconstruction. There were also no significant differences between the cohorts in the time to expander/implant exchange (p = 0.78). No significant differences were observed in patient-reported outcome scores, including satisfaction with breasts, psychosocial well-being, sexual well being, physical well-being, and postoperative pain. CONCLUSIONS: In this multicenter, prospective analysis, the authors found no significant acellular dermal matrix effects on complications, time to exchange, or patient-reported outcome in immediate expander/implant breast reconstruction. Further studies are needed to develop criteria for more selective use of acellular dermal matrix in these patients. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 28806289 TI - Augmentation of the Nasal Dorsum Using the Multistrip Autologous Cartilage Technique. AB - Nasal augmentation is a popular modern technique requested by many Asian people. There are two kinds of autologous cartilage used to augment the nose at present: carved as a monobloc or diced into pieces. Each approach has its pros and cons. The authors performed their surgical technique on a group of 28 patients. Twenty of these patients had undergone rhinoplasties performed before referral to our hospital; eight of these patients had undergone a primary rhinoplasty. Bilateral conchal, nasal septum, or rib cartilage was harvested; deep temporal fascia or abdominal muscle fascia to be prepared for packing stripped cartilage was also removed at this time. The cartilage was placed on a plastic cutting board and cut into strips with a transverse section of 1 * 1 mm. Then, these strips were packed and covered by fascia to form the grafts. The median follow-up was 23 months (range, 12 to 48 months). Twenty-two patients were satisfied with their augmented noses. Through examinations, biopsies, and magnetic resonance imaging scans, less resorption was observed with the multistrip autologous cartilage technique. Junctional stepoffs, excessive prominence, and slanting grafts occurred in three patients, two of whom had revisions. Using multistrip autologous cartilage grafts is an easier method to perform and could be another alternative technique for augmentative and reconstructive rhinoplasties. PMID- 28806290 TI - Clinical and Quantitative Isokinetic Comparison of Abdominal Morbidity and Dynamics following DIEP versus Muscle-Sparing Free TRAM Flap Breast Reconstruction. AB - BACKGROUND: The deep inferior epigastric perforator (DIEP) flap, which is a modification of the muscle-sparing free transverse rectus abdominis musculocutaneous (TRAM) flap, is being more frequently used in an effort to reduce postoperative abdominal morbidity. However, there is no consensus as to which of these flaps is superior. The authors aimed to compare quantitative measurements of abdominal function obtained with an isokinetic dynamometer after DIEP and muscle-sparing free TRAM flap elevation. METHODS: Patients who underwent unilateral single-pedicled DIEP (n = 42) or muscle-sparing free TRAM flap (n = 36) breast reconstruction performed by a single surgeon were included in this study. Preoperative and postoperative trunk flexion parameters were measured prospectively using an isokinetic dynamometer in all patients. The occurrence of postoperative pain, stiffness, and bulging along with patient activity level were also investigated. RESULTS: At 3 months postoperatively, abdominal functions were decreased in both groups, with a larger decline in the muscle-sparing free TRAM flap group. However, at 6 months postoperatively, abdominal muscle function recovered to preoperative levels in both groups. These findings were consistent with the absence of a statistically significant difference in patient postoperative abdominal pain and stiffness, activity level, and the incidence of bulging between the two groups at 6 months postoperatively. CONCLUSION: From these results, we propose that the surgeon can select the muscle-sparing free TRAM flap, without hesitation or concern regarding abdominal morbidity, when a thick and reliable perforator does not exist and multiple thin perforators must be incorporated. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28806291 TI - Revisiting the Abdominal Donor Site: Introducing a Novel Nomenclature for Autologous Breast Reconstruction. AB - BACKGROUND: As abdominally based free flaps for breast reconstruction continue to evolve, significant effort has been invested in minimizing donor-site morbidity. The impact on the donor site remains a prevailing principle for breast reconstruction, and thus must be adequately reflected when classifying what is left behind following flap harvest. Although successful in describing the type of flap harvested, the existing nomenclature falls short of incorporating certain critical variables, such as degree of muscular preservation, fascial involvement, mesh implantation, and segmental nerve anatomy. METHODS: In an effort to expand on Nahabedian's 2002 classification system, this descriptive study revisits and critically reviews the existing donor-site classification system following abdominally based breast reconstruction. RESULTS: The authors propose a nomenclature system that emphasizes variability in flap harvest technique, degree of muscular violation, fascial resection, mesh implantation, and degree of nerve transection. CONCLUSION: With this revised classification system, reconstructive surgeons can begin reporting more clinically relevant and accurate information with regard to donor-site morbidity. PMID- 28806292 TI - Optimization and Standardization of the Immunodeficient Mouse Model for Assessing Fat Grafting Outcomes. AB - BACKGROUND: Animal models are often used to assess interventions that might improve fat grafting outcomes; however, there is great variability in the models. The authors sought to determine the predictive value of the immunocompromised mouse model for fat grafting so that experiments could be standardized and optimized. METHODS: Human lipoaspirate injections at different volumes and time points were assessed in a nude mouse model and compared with control injections of nonviable fat. Volume retention and explant histologic score were compared. In a separate study, interanimal reproducibility was determined by implanting a highly consistent hydrogel and measuring variability in volume retention. RESULTS: Injection volume significantly affects adipose resorption kinetics at 6 and 12 weeks. Masson trichrome staining revealed that macrophages were unable to infiltrate large (1 ml) grafts, and oil cysts were not absorbed by 18 weeks, which interfered with interpretation of volume retention data. Nonviable tissue was resorbed when grafts were 0.3 ml, and quantification of graft histologic viability correlated well with graft retention at all study time points. Interanimal variability was measured to be 8.44 percent of the mean retention volume for small graft volumes. CONCLUSIONS: Human fat graft retention in the immunodeficient mouse correlates with graft viability in small, 0.3-ml-volume grafts. However, centralized oil cysts in nonviable 1.0-ml grafts were not resorbed by 18 weeks and thus volume measurements were confounded and not significantly different from viable samples. In addition, tissue injury scores increased in initially healthy fat grafts at 18 weeks, possibly because of a delayed immune reaction. PMID- 28806293 TI - "Optimizing Your Post-Surgical Scars: A Systematic Review on Best Practices in Preventative Scar Management"1. AB - BACKGROUND: Scar management is critical for every plastic surgeon's practice and, ultimately, the patient's satisfaction with his or her aesthetic result. Despite the critical nature of this component of routine post-operative care, there has yet to be a comprehensive analysis of the available literature over the last decade to assess the best algorithmic approach to scar care. To this end, a systematic review of best practices in preventative scar management was conducted to elucidate the highest level of evidence available on this subject to date. METHODS: A computerized MEDLINE search was performed for clinical studies addressing scar management. The resulting publications were screened randomized clinical trials that met our specified inclusion/exclusion criteria. RESULTS: This systematic review was performed in May 2016. The initial search for MeSH term "cicatrix" and modifiers "therapy, radiotherapy, surgery, drug therapy, prevention and control" yielded 13,101 initial articles. Applying our inclusion/exclusion criteria resulted in 12 relevant articles. All included articles are randomized, controlled clinical trials. CONCLUSIONS: Optimal scar care requires taking into account factors such as incisional tension, anatomic location, and Fitzpatrick skin type. We present a streamlined algorithm for scar prophylaxis based on contemporary level I and II evidence to guide clinical practice. PMID- 28806294 TI - The Tissue-Engineered Tendon-Bone Interface: In Vitro and In Vivo Synergistic Effects of Adipose-Derived Stem Cells, Platelet-Rich Plasma, and Extracellular Matrix Hydrogel. AB - BACKGROUND: Suboptimal healing of the tendon-bone interface remains an unsolved problem. The authors hypothesized that (1) platelet-rich plasma and prolonged in vitro incubation will produce interface scaffolds with greater reseeding of viable adipose-derived stem cells; and (2) when implanted with extracellular matrix hydrogel, constructs will display superior in vivo strength repair and biocompatibility. METHODS: Achilles-calcaneal composite tendon-bone interface scaffold grafts were harvested from 30 Wistar rats. After physicochemical decellularization and lyophilization, scaffolds were revitalized in rat plasma or 100% activated rat platelet-rich plasma and reseeded with viable adipose-derived stem cells. For part 2 of the study, 90 Sprague-Dawley rats underwent reconstruction with one of five decellularized, lyophilized scaffold revitalization/reseeding conditions: (1) phosphate-buffered saline; (2) lyophilized, 100% activated platelet-rich plasma; (3) platelet-rich plasma and extracellular matrix hydrogel; (4) platelet-rich plasma and 14-day reseeding with ASC-luc2-eGFP cells; and (5) plasma, reseeding, and hydrogel. RESULTS: In part 1, platelet-rich plasma-revitalized grafts demonstrated greater live viable adipose derived stem cell loads at 3, 7, and 14 days and total adipose-derived stem cell loads at 7 and 14 days with visibly greater live surface cellularity, layering, migration, and penetration. In part 2, bioluminescence imaging confirmed cell viability to day 22 after implantation. Biomechanical strength testing demonstrated a significant increase in ultimate failure load for reseeded groups compared with all other groups at week 2, whereas only reseeded grafts with hydrogel remained significantly stronger at weeks 4 and 8. Histologic examination demonstrated most increased tendinous cellular invasion and fibrocartilage repopulation at 8 weeks in the reseeded group with hydrogel. Masson trichrome staining demonstrated persistence of the scaffold structure at week 8 and blinded ImageJ analysis demonstrated significantly more type III collagen in the reseeded/hydrogel group at 2, 4, and 8 weeks. CONCLUSIONS: Decellularized lyophilized allogeneic tendon-bone interface scaffolds can be optimized by revitalization in platelet-rich plasma, reseeding with viable adipose-derived stem cells, and supplemented by an extracellular matrix tendon hydrogel at the time of implantation. When this is done, they display greater repair strength and biocompatibility. PMID- 28806295 TI - Splenules Presenting as Incidental Gastric Fundic Masses on Endoscopy. PMID- 28806296 TI - The Risk of Necrotizing Enterocolitis Differs Among Preterm Pigs Fed Formulas With Either Lactose or Maltodextrin. AB - OBJECTIVES: When breast milk is unavailable for preterm infants, formulas are needed that won't increase the risk of necrotizing enterocolitis (NEC). Adding novel ingredients to formula to reduce NEC has not been effective clinically. Instead, we tested the prediction that NEC can be reduced by removing the maltodextrin now included in preterm formulas. METHODS: The preterm pig model of spontaneous NEC was used to evaluate growth, health, and intestinal responses to 6 to 7 days of feeding formulas that were identical except for the source of carbohydrate; either 100% lactose or maltodextrin; colostrum was used as the control. RESULTS: Formula with maltodextrin resulted in a 50% incidence of NEC with 30% mortality. The lactose formula and colostrum resulted in a 0% incidence of NEC. Growth was highest for pigs fed the formula with lactose, intermediate with maltodextrin, and minimal when bovine colostrum was fed (P < 0.05). Although the small intestine was larger when colostrum was fed (P < 0.05), because rates of glucose uptake were lower (P < 0.05), total small intestine capacities to transport glucose were similar for healthy pigs in all 3 groups. CONCLUSIONS: If lactose-based formulas reduce NEC clinically, the transition of preterm infants to enteral feeding can be accelerated, improving growth and development, and shortening reliance on parenteral nutrition. Although colostrum protects against NEC, chronic feeding does not promote body weight gain after preterm birth. The preterm pig can be used for preclinical studies that evaluate the mechanisms by which carbohydrates and other ingredients influence growth, development, health, and risk of NEC. PMID- 28806297 TI - Adherence to a Gluten-free Diet: Assessment by Dietician Interview and Serology. AB - We aimed to determine whether tissue transglutaminase (tTG) autoantibody positivity was associated with dietitian-assessed adherence to a gluten-free diet in pediatric patients with celiac disease and identify areas where adherence falters. We reviewed the records of children with celiac disease who had a standardized evaluation of adherence by a registered dietitian. A negative tTG value was not associated with good adherence (P = NS). Adherent and nonadherent children differed with respect to purposeful and accidental gluten exposure (P < 0.0001), knowledge (P = 0.003), cross-contact (P = 0.003), potential exposure via medications and cosmetics (P = 0.004), and potential exposure while at restaurants (P < 0.0001), but not with respect to potential exposure at school (P = NS). Based on our findings, we suggest that negative tTG levels are not necessarily indicative of good adherence to a gluten-free diet in pediatric patients with celiac disease. A separate assessment of adherence is needed focusing on knowledge, behavior while dining out, and intent to adhere. PMID- 28806298 TI - Effect of Cyproheptadine on Weight and Growth Velocity in Children With Silver Russell Syndrome. AB - OBJECTIVES: Nutritional management of children with Silver-Russell syndrome (SRS) is crucial, especially before initiating growth hormone therapy. Since cyproheptadine (CYP) has been reported to be orexigenic, we retrospectively investigated the effects of CYP on changes in weight and height in patients with SRS. METHODS: Anthropometric parameters (weight [W], length or height [H], weight on expected weight for height [W/H], and body mass index) were recorded for 34 children with SRS receiving CYP. We specifically analyzed the anthropometric parameters (expressed in median) in a group of 23 patients treated with CYP at baseline (M0-CYP) and every 3 months (M3 to M12-CYP) after the initiation of CYP treatment. RESULTS: The 23 children with SRS treated by CYP only had weight stagnation during the months preceding the start of treatment. Anthropometric parameters, especially the weight, differed significantly between M0-CYP and all other times (M3, M6, M9, M12-CYP). After 1 year of treatment, a gain in overall length/height and weight was observed (W: +1.1 standard deviations from the mean [SDS]; H: +0.5 SDS). At M3, significant improvements in W/H (74.9% vs 79.3% [P = 0.01]) and body mass index (-3.4 vs -2.4 SDS [P = 0.001]) were also observed. Twenty-one patients (91%) improved their weight by at least +0.5 SDS, and 12 (52%) by at least +1 SDS. CONCLUSIONS: Our results show that CYP can be effective in patients with SRS with significant improvements in growth velocity and nutritional status before initiation of growth hormone therapy. Further prospective studies are required to confirm these results. PMID- 28806299 TI - The Dynamic and Transient Immune Microenvironment in Locally Advanced Esophageal Adenocarcinoma Post Chemoradiation. AB - OBJECTIVE: The aim of this study was to assess the impact of chemoradiation on the immune microenvironment to influence and optimally design future neoadjuvant clinical trials. SUMMARY BACKGROUND DATA: Programmed death (PD)-1 inhibitors in metastatic gastroesophageal cancer have demonstrated response rates of approximately 25% in programmed death ligand-1 (PD-L1+) tumors. Unfortunately, the majority of patients do not respond. Therefore, a rationale strategy of combining immunotherapeutic agents with chemoradiation in earlier stage esophageal cancer may prevent metastatic disease in patients. METHODS: To determine the effects of chemoradiation on resected esophageal adenocarcinomas, we examined the immune microenvironment pre- and post-chemoradiation using immunohistochemistry, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and functional analysis of tumor-infiltrating lymphocytes. Additionally, to assess the duration and dependency of radiation-induced PD-L1 upregulation, a surgical rat reflux model of esophageal adenocarcinoma is used. First, tumor-bearing animals were dosed with single-fraction 13Gy or 16Gy radiation to determine safety, dose correlation, and PD-L1 upregulation using qRT PCR post-radiation. Next, longitudinal PD-L1 expression levels within individual animals were determined using serial endoscopic biopsies at baseline, 1, 5, and 9 weeks post 16Gy radiation. RESULTS: The majority of cancers displayed enhanced interferon gamma and activated CD8+ T lymphocytes at the tumor stroma interface. These tumors also demonstrated enhanced upregulation of PD-L1 and multiple other immune checkpoints including TIM3, GITR, IDO1, LAG3, OX40, and KIR. The animal model results indicated PD-L1 upregulation is dose-dependent and transiently elevated post radiation exposure. CONCLUSIONS: Collectively, these findings provide insights into the evolving immune landscape after chemoradiation and have significant implications for neoadjuvant trial designs that will combine radiotherapy with immune checkpoint inhibitors. PMID- 28806300 TI - Improving Benchmarks for Global Surgery: Nationwide Enumeration of Operations Performed in Ghana. AB - OBJECTIVE: To evaluate the operation rate in Ghana and characterize it by types of procedures and hospital level. BACKGROUND: The Lancet Commission on Global Surgery recommended an annual rate of 5000 operations/100,000 people as a benchmark at which low- and middle-income countries could achieve most of the population-wide benefits of surgery, but did not define procedure-type benchmarks. METHODS: Data on operations performed from June 2014 to May 2015 were obtained from representative samples of 48 of 124 district-level (first-level) hospitals, 9 of 11 regional (referral) hospitals, and 3 of 5 tertiary hospitals, and scaled-up to nationwide estimates. Operations were categorized into those deemed as essential procedures (most cost-effective, highest population impact) by the World Bank's Disease Control Priorities Project versus other. RESULTS: An estimated 232,776 [95% uncertainty interval (95% UI) 178,004 to 287,549] operations were performed nationally. The annual rate of operations was 869 of 100,000 (95% UI 664 to 1073). The rate fell well short of the benchmark. 77% of the estimated annual national surgical output was in the essential procedure category. Most operations (62%) were performed at district-level hospitals. Most district-level hospitals (54%) did not have fully trained surgeons, but nonetheless performed 36% of district-level hospital operations. CONCLUSION: The operation rate was short of the Lancet Commission benchmark, indicating large unmet need, although most operations were in the essential procedure category. Future global surgery benchmarking should consider both total numbers and priority levels. Most surgical care was delivered at district-level hospitals, many without fully trained surgeons. Benchmarking to improve surgical care needs to address both access deficiencies and hospital and provider level. PMID- 28806301 TI - Risk Adjustment in ALPPS Is Associated With a Dramatic Decrease in Early Mortality and Morbidity. AB - OBJECTIVE: To longitudinally assess whether risk adjustment in Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) occurred over time and is associated with postoperative outcome. BACKGROUND: ALPPS is a novel 2 stage hepatectomy enabling resection of extensive hepatic tumors. ALPPS has been criticized for its high mortality, which is reported beyond accepted standards in liver surgery. Therefore, adjustments in patient selection and technique have been performed but have not yet been studied over time in relation to outcome. METHODS: ALPPS centers of the International ALPPS Registry having performed >=10 cases over a period of >=3 years were assessed for 90-day mortality and major interstage complications (>=3b) of the longitudinal study period from 2009 to 2015. The predicted prestage 1 and 2 mortality risks were calculated for each patient. In addition, questionnaires were sent to all centers exploring center specific risk adjustment strategies. RESULTS: Among 437 patients from 16 centers, a shift in indications toward colorectal liver metastases from 53% to 77% and a reverse trend in biliary tumors from 24% to 9% were observed. Over time, 90-day mortality decreased from initially 17% to 4% in 2015 (P = 0.002). Similarly, major interstage complications decreased from 10% to 3% (P = 0.011). The reduction of 90-day mortality was independently associated with a risk adjustment in patient selection (P < 0.001; OR: 1.62; 95% CI: 1.36-1.93) and using less invasive techniques in stage-1 surgery (P = 0.019; OR: 0.39; 95% CI: 0.18-0.86). A survey indicated risk adjustment of patient selection in all centers and ALPPS technique in the majority (80%) of centers. CONCLUSIONS: Risk adjustment of patient selection and technique in ALPPS resulted in a continuous drop of early mortality and major postoperative morbidity, which has meanwhile reached standard outcome measures accepted for major liver surgery. PMID- 28806302 TI - Surgery for Primary Hyperparathyroidism: Adherence to Consensus Guidelines in an Academic Health System. AB - OBJECTIVE: To determine the extent to which consensus guidelines for surgery in patients with primary hyperparathyroidism (PHPT) are followed within an academic health system. BACKGROUND: Previous studies have shown that adherence to consensus guidelines in community practice is low. METHODS: Adults with biochemically confirmed PHPT who received primary care within an academic health system were identified from 2005 to 2015. Multivariable logistic regression was used to analyze predictors of parathyroidectomy (PTx). RESULTS: In 617 patients, the overall PTx rate was 30.8%. When individual consensus criteria were examined, age <50 (P<0.01), serum calcium >11.3 mg/dL (P < 0.01), and hypercalciuria (P = 0.02) were associated with PTx; while nephrolithiasis (P = 0.07) and osteoporosis (P = 0.34) did not affect the PTx rate. The PTx rate increased with the number of consensus criteria satisfied (1 criterion, 33%; 2 criteria, 45%; 3 or more criteria, 82%, P < 0.01). Independent predictors of PTx included male sex [odds ratio (OR) 1.7, 95% confidence interval (CI) 1.1-2.8], increasing serum parathyroid hormone (OR 1.1 per 10 pg/dL 95% CI 1.05-1.13), and endocrinologist evaluation (OR 1.6, 95% CI 1.1-2.4); while Black race (OR 0.4, 95% CI 0.2-0.8), lack of 24-hour urine calcium measurement (OR 0.5, 95% CI 0.3-0.8), Charlson Comorbidity Index >= 2 (OR 0.6, 95% CI 0.4-0.9), and age >=80 years (OR 0.2, 95% CI 0.1-0.4) predicted against PTx. CONCLUSION: Within an academic health system, consensus guidelines do appear to influence the decision for surgery in patients with PHPT. However, the level of compliance is generally low, and similar to that observed in community practice. PMID- 28806303 TI - Does a Combination of Laparoscopic Approach and Full Fast Track Multimodal Management Decrease Postoperative Morbidity?: A Multicenter Randomized Controlled Trial. AB - OBJECTIVE: The aim of this study was to assess whether association of laparoscopic approach and full fast track multimodal (FFT) management can reduce postoperative morbidity after colorectal cancer surgery, as compared to laparoscopic approach with limited fast-track program (LFT). SUMMARY OF BACKGROUND DATA: Recent advances in colorectal cancer surgery are introduction of laparoscopy and FFT implementation. METHODS: Patients eligible for elective laparoscopic colorectal cancer surgery were randomized into 2 groups: FFT or LFT care (with only early oral intake and mobilization starting on Day 1). Primary outcome was postoperative 30-day morbidity, according to Clavien-Dindo classification. RESULTS: Two hundred seventy patients were randomized and 263 were analyzed: 130 in FFT group and 133 in LFT group, including 106 colon (FFT: n = 52 and LFT: n = 54) and 157 rectal cancer (FFT: n = 78 and LFT: n = 79). Postoperative 30-day mortality was nil. Overall postoperative 30-day morbidity did not show any difference between the groups (FFT: 35% vs LFT: 29%, P = 0.290), neither regarding the overall population, nor in the colon (FFT: 23% vs LFT: 19%, P = 0.636) or rectal (FFT: 44% vs LFT: 35%, P = 0.330) cancer subgroups. Severe postoperative morbidity was also not different between groups (FFT: 12% vs LFT: 8%, P = 0.266). After multivariate regression analysis, only early intravenous catheter removal (on day 2) [odds ratio: 0.390; 95% confidence interval: (95% CI 0.181-0.842); P = 0.017] and the absence of intraoperative lidocaine intravenous perfusion (odds ratio: 0.182, 95% CI 0.042-0.788; P = 0.019) were identified as independent predictive factors of reduced postoperative morbidity. CONCLUSION: Addition of FFT multimodal management to laparoscopic approach with early oral intake and mobilization does not reduce postoperative morbidity after colorectal cancer surgery. PMID- 28806304 TI - Perceptions of Support Groups Among Older Breast Cancer Survivors: "I've Heard of Them, but I've Never Felt the Need to Go". AB - BACKGROUND: Cancer survivors transitioning from active treatment to posttreatment may lack critical support and information about their posttreatment care. Support groups have the potential to address this gap. OBJECTIVE: The aim of this study was to describe how breast cancer survivors 65 years and older perceived professionally led, in-person support groups. METHODS: Individual interviews with 54 women were analyzed using grounded theory informed by constructivism. RESULTS: Strong negative assumptions about cancer support groups were described. Tension existed between two opposing categories: participants' preconceptions of support groups and characterizations of their members and the women's perceptions of their own informational and emotional needs. Participants also described what sources of support they used in lieu of professionally led support groups. CONCLUSIONS: Despite awareness and availability, most participants did not use support groups as a resource during their primary or post-cancer treatment. IMPLICATIONS FOR PRACTICE: Structural changes can benefit existing models of support groups including how and when support needs and services are discussed with survivors and a shift toward the inclusion of practical information. PMID- 28806305 TI - Dimensions of Posttraumatic Growth in Patients With Cancer: A Mixed Method Study. AB - BACKGROUND: Posttraumatic growth (PTG) refers to positive outcomes after exposure to stressful events. Previous studies suggest cross-cultural differences in the nature and amount of PTG. OBJECTIVE: The aim of this study was to explore different dimensions of PTG in Iranian patients with cancer. METHODS: A mixed method study with convergent parallel design was applied to clarify and determine dimensions of PTG. Using the Posttraumatic Growth Inventory (PTGI), confirmatory factor analysis was used to quantitatively identify dimensions of PTG in 402 patients with cancer. Simultaneously, phenomenological methodology (in-depth interview with 12 patients) was used to describe and interpret the lived experiences of cancer patients in the qualitative part of the study. RESULTS: Five dimensions of PTGI were confirmed from the original PTGI. Qualitatively, new dimensions of PTG emerged including "inner peace and other positive personal attributes," "finding meaning of life," "being a role model," and "performing health promoting behaviors." CONCLUSION: Results of the study indicated that PTG is a 5-dimensional concept with a broad range of subthemes for Iranian cancer patients and that the PTGI did not reflect all growth dimensions in Iranian cancer patients. IMPLICATIONS FOR PRACTICE: Awareness of PTG dimensions can enable nurses to guide their use as coping strategies and provide context for positive changes in patients to promote quality care. PMID- 28806307 TI - Promoting Cardiovascular Health Worldwide: The Global Cardiovascular Nursing Leadership Forum. PMID- 28806308 TI - The False Paradigm of Equivalency: Conceptual Challenges to Collaborative Care. PMID- 28806309 TI - Single-center Experience of Over a Hundred Implantations of a Transcutaneous Bone Conduction Device. AB - OBJECTIVE: To assess outcomes with a novel passive transcutaneous bone conduction device (t-BCD). STUDY DESIGN: Prospective data collection and patient review. SETTING: Tertiary referral center. PATIENTS: Patients who underwent implantation with the t-BCD between November 2013 and September 2016. INTERVENTION: Implantation of BAHA Attract. MAIN OUTCOME MEASURES: Surgical outcome, patient reported outcomes including the "Glasgow Benefit Inventory" and the "Client Oriented Scale of Improvement" for adults and the "Speech, Spatial and Qualities of Hearing scale" (SSQ-12) for children. RESULTS: One hundred five patients were implanted. Numbness superior to the incision was commonly noticed. Four patients (3.8%) developed skin tenderness and redness that settled with conservative measures. Among those patients who had a conversion from a percutaneous Bone Conduction Hearing Device (BCHD) to the t-BCD (n=15), 1 (0.9%) developed seroma and 2 (1.9%) developed skin dehiscence at the edge of the implant magnet. Significant improvement in Client Oriented Scale of Improvement and Glasgow Benefit Inventory scores with a global satisfaction of 84% and 77.4% was observed for those previously aided and unaided respectively, with use of the device. A 22% improvement in SSQ-12 mean score was observed in the pediatric population. CONCLUSION: This is the largest single-center series reported on this t-BCD. The complication rate is small but caution is required in patients of conversion from a percutaneous BCHD. The patients' satisfaction is high and the need for aftercare is minimal. Cost-effectiveness evaluation of these devices, development of core outcome sets and well-designed, prospective trials to compare the different BCHDs should be the focus of future research. PMID- 28806310 TI - The Prevention of Recurrent Cholesteatoma in CWU Surgery: The Use of Titanium Sheeting. AB - OBJECTIVE: Assessment of the outcomes of a technique of prevention of recurrent cholesteatoma in canal wall up (CWU) mastoidectomy, using titanium sheeting to repair the external auditory canal wall. PATIENTS: Sixty four cholesteatoma cases were managed during a period from 2007 to 2015. The cases were unselected; the surgery was performed by the senior author. Cholesteatoma Patterns Were: Forty two attic, nine pars tensa, seven combined attic-pars tensa, three congenital, and three other. Primary surgery was undertaken in 33 cases. INTERVENTIONS: All cases underwent CWU surgery that employed canal wall repair using fine titanium sheeting combined with overlying organic material to repair canal wall defects. Drum repairs employed cymba conchae cartilage-perichondrium composite grafts. Chain reconstruction used Spanner struts or Grace Alto PORPs or TORPS. RESULTS: Two cases suffered mesotympanic residual disease, and three, mesotympanic recurrence one of which extended into the attic. Two other cases incurred atticomastoid residues. Transient myringitis occurred in three cases. CONCLUSION: The surgery was judged on its ability to avoid atticomastoid recurrence, and was regarded as highly successful. The titanium sheeting offers a relatively simple but effective technique. The mesotympanic complications are those also commonly found in both CWD and other CWU methods. As in other CWU procedures, the problems of the open cavity were avoided. PMID- 28806311 TI - Evaluation of Maximal Speech Intelligibility With Vibrant Soundbridge in Patients With Sensorineural Hearing Loss. AB - OBJECTIVE: The study investigated improvements in maximal speech intelligibility after Vibrant Soundbridge (VSB) implantation and analyzed the effect of the hearing loss pattern on maximal speech intelligibility represented by a phonetically balanced word score (PBmax). The effect of middle ear implants on PBmax has not been evaluated yet. STUDY DESIGN: Study. SETTING: Tertiary academic medical center. PATIENTS/INTERVENTIONS: Sixty patients who underwent VSB from December 2011 to January 2016 were retrospectively reviewed. All the patients had hearing aids preoperatively. MAIN OUTCOME MEASURES: Pure-tone and speech audiometry were checked with and without hearing aids and then with the VSB. The patients were divided into two groups: flat and down-sloping type of hearing loss. PBmax score was evaluated at the most comfortable listening level before and after VSB implantation and compared with scores with/without HA. RESULTS: PBmax for both conventional HA and VSB were significantly higher compared with the unaided condition. The improvement in speech recognition was significantly better using VSB than using HA (p = 0.003). However, there was no significant difference in the improvement provided by VSB and HA in patients with a flat hearing loss. Patients with a down-sloping audiogram showed significantly better improvement with VSB than with HA (p = 0.003). Moreover, patients with greater preoperative high-frequency hearing loss had greater improvement in PBmax after VSB implantation. CONCLUSION: Speech intelligibility can be significantly improved by VSB implantation, especially in patients with a down-sloping hearing loss. This finding can help select patients who will benefit most from VSB implantation. PMID- 28806312 TI - Neuro-Ophthalmology and Stroke. PMID- 28806313 TI - Patient Safety: Its History and Relevance to Neuro-Ophthalmology. PMID- 28806314 TI - Limitations of Current Methodology for Assessment of Compression of the Optic Chiasm by Macroadenoma: The Neuroradiologic Perspective. PMID- 28806315 TI - Nonarteritic Jaw Claudication. AB - A 60-year-old woman with decreased visual acuity in her right eye and right-sided jaw claudication was found to have ocular ischemic syndrome secondary to complete occlusion of the brachiocephalic artery. Although jaw claudication is often considered to be pathognomonic for giant cell arteritis, it has a broad differential diagnosis including both vascular and nonvascular conditions. PMID- 28806316 TI - Intracranial Displacement of the Eye After Blunt Trauma: Retraction. PMID- 28806317 TI - Quantitative Evaluation of Diffusion and Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Differentiation Between Primary Central Nervous System Lymphoma and Glioblastoma. AB - OBJECTIVE: This study aimed to evaluate the utility of diffusion and permeability parameters derived from diffusion-weighted imaging and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for differentiating primary central nervous system lymphoma (PCNSL) and glioblastoma multiforme (GBM) and to assess the correlation among these parameters. MATERIALS AND METHODS: Forty-two patients with GBM and 18 patients with PCNSL underwent conventional 3.0-T MRI, diffusion weighted imaging, and DCE-MRI before surgery. Normalized apparent diffusion coefficient ratio (rADC) and DCE-MRI-derived parameters (the volume transfer constant [K], the flux rate constant, the volume fraction of extravascular extracellular space [Ve], and the fractional plasma volume) were measured within the entire enhancing tumor and compared between the 2 groups. The diagnostic ability of each parameter and their optimal combination for differentiating between PCNSL and GBM, and the correlation among these parameters, were statistically analyzed. RESULTS: The PCNSLs demonstrated significantly lower rADC (P = 0.000), higher K (P = 0.000), and higher Ve (P = 0.001) than GBMs. With the combination of rADC and K, the diagnostic ability for discriminating between PCNSL and GBM was significantly improved (area under the receiver operating characteristic curve [AUC] = 0.930) as compared with rADC (AUC = 0.858) and K (AUC = 0.852) alone (P < 0.001 for both). The rADC did not correlate with K or Ve derived from DCE-MRI. CONCLUSIONS: Apparent diffusion coefficient ratio, K, and Ve are useful parameters for differentiating between PCNSL and GBM. The combination of rADC and K helps to improve the diagnostic accuracy. The rADC may not show correlation with K or Ve. PMID- 28806318 TI - Computed Tomography Image Quality Evaluation of a New Iterative Reconstruction Algorithm in the Abdomen (Adaptive Statistical Iterative Reconstruction-V) a Comparison With Model-Based Iterative Reconstruction, Adaptive Statistical Iterative Reconstruction, and Filtered Back Projection Reconstructions. AB - OBJECTIVE: The purpose of this study was to compare abdominopelvic computed tomography images reconstructed with adaptive statistical iterative reconstruction-V (ASIR-V) with model-based iterative reconstruction (Veo 3.0), ASIR, and filtered back projection (FBP). METHODS AND MATERIALS: Abdominopelvic computed tomography scans for 36 patients (26 males and 10 females) were reconstructed using FBP, ASIR (80%), Veo 3.0, and ASIR-V (30%, 60%, 90%). Mean +/ SD patient age was 32 +/- 10 years with mean +/- SD body mass index of 26.9 +/- 4.4 kg/m. Images were reviewed by 2 independent readers in a blinded, randomized fashion. Hounsfield unit, noise, and contrast-to-noise ratio (CNR) values were calculated for each reconstruction algorithm for further comparison. Phantom evaluation of low-contrast detectability (LCD) and high-contrast resolution was performed. RESULTS: Adaptive statistical iterative reconstruction-V 30%, ASIR-V 60%, and ASIR 80% were generally superior qualitatively compared with ASIR-V 90%, Veo 3.0, and FBP (P < 0.05). Adaptive statistical iterative reconstruction-V 90% showed superior LCD and had the highest CNR in the liver, aorta, and, pancreas, measuring 7.32 +/- 3.22, 11.60 +/- 4.25, and 4.60 +/- 2.31, respectively, compared with the next best series of ASIR-V 60% with respective CNR values of 5.54 +/- 2.39, 8.78 +/- 3.15, and 3.49 +/- 1.77 (P <0.0001). Veo 3.0 and ASIR 80% had the best and worst spatial resolution, respectively. CONCLUSIONS: Adaptive statistical iterative reconstruction-V 30% and ASIR-V 60% provided the best combination of qualitative and quantitative performance. Adaptive statistical iterative reconstruction 80% was equivalent qualitatively, but demonstrated inferior spatial resolution and LCD. PMID- 28806319 TI - Transient Segmental Enhancement of Pyogenic Liver Abscess: A Comparison Between Contrast-Enhanced Ultrasound and Computed Tomography. AB - OBJECTIVE: This study aimed to investigate the correlation between the transient segmental enhancement (TSE) of liver abscesses on contrast-enhanced ultrasound (CEUS) imaging and contrast-enhanced computed tomography (CT) scans. METHODS: In total, 42 abscesses in 38 patients were evaluated with real-time CEUS and contrast-enhanced CT imaging. The CT imaging and CEUS examinations were performed within one to 2 days of each other in all cases. The initial reports of the observations of TSE on CEUS scans were correlated later with the findings of TSE on contrast-enhanced CT images. Contrast-enhanced CT was used as the reference standard to evaluate the presence of TSE. Relationships between the 2 groups were analyzed using the chi test. P < 0.05 was considered to be statistically significant. RESULTS: In 16 patients, 16 typical TSE signs were shown by CEUS. Meanwhile, enhanced CT imaging showed 18 typical signs of TSE in 17 patients. We identified 38 patients with hepatic abscesses proven by needle aspiration (10 patients) or image-guided biopsy (28 patients). Ten patients had hepatobiliary cholelithiasis, 5 had diabetes mellitus type 2, and 2 had gastric cancer, whereas no evidence of underlying hepatobiliary or gastrointestinal diseases was found in the other 21 patients. Considering that enhanced CT is the reference standard for the diagnosis of hepatic abscesses, the sensitivity of CEUS in showing TSE was 89%, and the specificity was 100%. The chi test indicated that CEUS and enhanced CT were significantly correlated for detection of hepatic perfusion disorders (P < 0.05). CONCLUSIONS: The appearance of TSE in liver abscess was reliably detected by CEUS, which correlated well with the enhanced CT images (P < 0.05). PMID- 28806320 TI - The Value of Quality-Assured Magnetic Resonance Imaging of the Breast for the Early Detection of Breast Cancer in Asymptomatic Women. AB - PURPOSE: The aim of this study was to evaluate the exclusive performance of quality-assured high-resolution breast magnetic resonance imaging (MRI) for early detection of breast cancer in a population of asymptomatic women. MATERIALS AND METHODS: A total of 1189 MRI examinations performed in 789 asymptomatic women (mean age, 51.1 years) were evaluated. All examinations were performed using open bilateral surface coil, dedicated compression device, and high spatial resolution (matrix, 512 * 512). Digital mammography was available for all participants. Assessment included density types, artifact level, and Breast Imaging Reporting and Data System classification. Evaluation was performed by 2 readers. In addition, a computer-assisted diagnosis (CAD) system was used for image assessment. RESULTS: Breast MRI showed density types I and II in 87.6% and artifacts categories III and IV in 3.1%. Study included 32 carcinomas (8 ductal carcinoma in situ, 24 invasive tumors). Both readers detected 29 of 32 correctly (sensitivity 90.6%). The variation between the readers was low (reader 1: specificity, 94.4% and positive predictive value (PPV), 25.7%; reader 2: specificity, 97.6% and PPV, 34.1%). Sensitivity of CAD was 62.5% (specificity, 84.4%; PPV, 5.2%). Digital mammography detected 13 of 32 carcinomas (sensitivity, 56.3%; specificity, 98.4%; PPV, 32.1%). CONCLUSIONS: The exclusive use of quality assured breast MRI allows the early detection of breast cancer with a high sensitivity and specificity. The CAD analysis of MRI does not give additional information but shows results comparable with digital mammography. PMID- 28806321 TI - Liver Imaging Reporting and Data System: Discordance Between Computed Tomography and Gadoxetate-Enhanced Magnetic Resonance Imaging for Detection of Hepatocellular Carcinoma Major Features. AB - PURPOSE: The goal of this study was to compare agreement between computed tomography (CT) and magnetic resonance imaging (MRI) in the evaluation of the major Liver Imaging Reporting and Data System (LI-RADS) features used in assessment of hepatocellular carcinoma: arterial phase hyperenhancement (APHE), portal venous phase washout (WO), capsule appearance (capsule), and largest diameter (diameter). METHODS: Patients with liver protocol CT and gadoxetate enhanced MRI within 1 month of each other and at least 1 discrete untreated liver lesion were included. Two readers independently reviewed hepatic arterial phase and portal venous phase of each lesion on both CT and MRI, presented at random. The APHE, WO, capsule, and diameter were assessed for each lesion on CT and MRI. The LI-RADS category was assigned based on the recorded major features. Interobserver agreements between the readers for both imaging modalities and for each of the major features were assessed using kappa statistics. Agreement between CT and MRI for each reader and for each feature was assessed using kappa statistics. Agreement was interpreted based on kappa as follows: 0.20 or less, slight agreement; 0.21 to 0.40, fair agreement; 0.41 to 0.60, moderate agreement; 0.61 to 0.80, substantial agreement; and 0.81 to 1.00, almost perfect agreement. Intraclass correlation coefficient was used to assess concordance of diameter measurements. RESULTS: There were 42 patients (mean age, 62.2 +/- 7.0 years; 33 men [78.6%]) with 50 lesions. On CT, the interobserver agreement between the readers was almost perfect for APHE (kappa = 0.85), WO (kappa = 0.83), and capsule (kappa = 0.86). On MRI, the interobserver agreement between the readers was almost perfect for APHE (kappa = 0.86) and WO (kappa = 0.83) and moderate for capsule (kappa = 0.59). Intraclass correlation coefficient for diameter measurement was 0.99 for CT and 0.98 for MRI. For reader 1, the agreement between CT and MRI was fair for APHE (kappa = 0.39) and capsule (kappa = 0.26) and moderate for WO (kappa = 0.49). For reader 2, the agreement between CT and MRI was moderate for APHE (kappa = 0.43) and capsule (kappa = 0.43) and fair (kappa = 0.38) for WO. Agreement between readers for final LI-RADS category was substantial for CT (kappa = 0.79) and moderate for MRI (kappa = 0.60). Agreement for final LI-RADS categories between MRI and CT was fair for both reader 1 (kappa = 0.33) and reader 2 (kappa = 0.39). CONCLUSIONS: Interobserver agreement for the major LI-RADS features varies from moderate to almost perfect, for both CT and MRI. However, the agreement between CT and MRI for each of the major LI-RADS features is poor, ranging from fair to moderate. This poor agreement contributes to substantial differences between final LI-RADS category assigned on CT versus MRI. PMID- 28806323 TI - Interactive process of facial communication of pain. PMID- 28806322 TI - Reduced Field-of-View Diffusion-Weighted Magnetic Resonance Imaging of the Prostate at 3 Tesla: Comparison With Standard Echo-Planar Imaging Technique for Image Quality and Tumor Assessment. AB - OBJECTIVE: The purpose of this study was to compare image quality and tumor assessment at prostate magnetic resonance imaging (MRI) between reduced field-of view diffusion-weighted imaging (rFOV-DWI) and standard DWI (st-DWI). METHODS: A total of 49 patients undergoing prostate MRI and MRI/ultrasound fusion-targeted biopsy were included. Examinations included st-DWI (field of view [FOV], 200 * 200 mm) and rFOV-DWI (FOV, 140 * 64 mm) using a 2-dimensional (2D) spatially selective radiofrequency pulse and parallel transmission. Two readers performed qualitative assessments; a third reader performed quantitative evaluation. RESULTS: Overall image quality, anatomic distortion, visualization of capsule, and visualization of peripheral/transition zone edge were better for rFOV-DWI for reader 1 (P <= 0.002), although not for reader 2 (P >= 0.567). For both readers, sensitivity, specificity, and accuracy for tumor with a Gleason Score (GS) of 3 + 4 or higher were not different (P >= 0.289). Lesion clarity was higher for st-DWI for reader 2 (P = 0.008), although similar for reader 1 (P = 0.409). Diagnostic confidence was not different for either reader (P >= 0.052). Tumor-to-benign apparent diffusion coefficient ratio was not different (P = 0.675). CONCLUSIONS: Potentially improved image quality of rFOV-DWI did not yield improved tumor assessment. Continued optimization is warranted. PMID- 28806324 TI - Comparison of the Quality of Informal Care of Community-Dwelling Taiwanese Older People. AB - BACKGROUND: With social structures changing and the average life-span of individuals increasing, Taiwan is experiencing a steady rise in its elderly population. Thus, caring for older parentsis an urgent problem. Many foreign caregivers have been hired tocare for older parents.However, measuring the quality ofinformal care has not yet been fully explored in Taiwan, particularly among older people who are cared for by foreign caregivers in home settings. PURPOSE: The purposes of this study were to understand the differences in quality of care for older Taiwanese and to explore the predictors of quality of care in two types of caregiving. METHODS: A comparative descriptive study design was conducted. The study was held in several community healthcare centers in the middle and southern regions of Taiwan. Study data were collected over an 18-month period between 2012 and 2014. t Tests were used to compare continuous variables according to the types of caregiving. Multiple linear regressions with group analyses were performed to evaluate the underlying statistical assumptions. RESULTS: One hundred fifty-nine participants were included. The study results showed that age, activities of daily living level, and quality of care were significantly different between the two types of caregiving. Relationships with caregivers, social support, and depressive symptoms contributed to the quality of care in family caregiving, explaining 50.2% of the variance. Social support and depressive symptoms contributed to the quality of care in foreign caregiving, explaining 36.6% of the variance. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The study results support that the types of primary caregiving affect the quality of care that is received by elderly Taiwanese. This study may be used as a reference for families whose family members need long-term care when considering hiring foreign caregivers as an alternative option to Taiwanese caregivers. PMID- 28806325 TI - Parents' Reactions to the Diagnosis of Duchenne Muscular Dystrophy: Associations Between Resolution, Family Functioning, and Child Behavior Problems. AB - BACKGROUND: Duchenne muscular dystrophy (DMD) is the most frequent inherited form of muscular dystrophy during childhood. DMD is a severe and progressive disease. Children initially have no symptoms, but the diagnosis is often delayed until the child is about 5 years old. PURPOSE: Although few studies have addressed parent reactions to DMD, parental reactions to other serious childhood conditions have been documented. This study aims to understand the resolution styles that parents use in the context of their children with DMD. METHODS: Data were collected on 39 parents residing in central Italy, comprising 23 mothers and 16 fathers of children with DMD of a mean age of 12 years. The participants attended a single assessment session lasting 60-80 minutes in which they were interviewed and completed the questionnaire. The participants completed the Reaction to Diagnosis Interview, which is composed of five open-ended questions about parents' memories, thoughts, and feelings about their child's diagnosis. The interviews were videotaped, transcribed, and coded. The Reaction to Diagnosis Interview classifies parents into two main classifications: "resolved" and "unresolved." In addition, the participants responded to questions about their perceptions of family functioning and about the behavioral problems of their children. A hierarchical multiple regression analysis was used to examine the role of child characteristics, disease severity, resolution classification (yes/no), and family variables as predictors of child behavior problems. RESULTS: The proportion of the resolved cases found in this study (41%) was lower than the mean proportion of resolved cases (60%) found in previous studies. Within the resolved category, "thinking oriented" was the most prevalent subcategory. Resolved participants reported significantly higher scores for family functioning and family satisfaction than unresolved participants. No differences were found between the groups in terms of perceptions of family communication. The hierarchical multiple regression analysis showed that a lower level of family functioning was the strongest predictor of child behavior problems. Having a higher level of disease severity and being unresolved were also identified as predictors of child behavior problems. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Results highlight the relevance of parent resolution in the adjustment process of children. The findings of this study may assist professionals in the medical field to focus on family variables and the parent process of diagnosis resolution as the primary goals in the prevention of child behavior problems. PMID- 28806326 TI - Recurrent Vestibular Migraine Vertigo Attacks Associated With the Development of Profound Bilateral Vestibulopathy: A Case Series. AB - BACKGROUND: Bilateral vestibulopathy (BVP) is a debilitating condition characterized by gait ataxia, oscillopsia, and imbalance. OBJECTIVE: Case series of patients with migraine-linked vertigo spells and profound BVP. PATIENT 1:: A 69-year-old man presented with a history of recurrent severe vertigo spells lasting up to 3 days in duration associated with prostrating migraine headaches starting at age 60. His symptoms were misdiagnosed as an anxiety syndrome. At age 68, electronystagmography (ENG) revealed bilaterally absent caloric responses and complete BVP. His hearing was normal. PATIENT 2:: A 51-year-old man presented with a history of "earthquake-like" vertigo, sharp head pain, and phonophobia. These episodes occurred a handful of times over a 7-year period. Previous ENG testing at age 43 was normal. However, his ENG at age 48 revealed complete BVP. He was started on acetazolamide and noted improved balance, although subsequent ENG was unchanged. PATIENT 3:: A 49-year-old woman presented with a history of recurrent migraines with visual aura associated with vertigo lasting 1 hour. ENG at age 50 revealed complete BVP. Subjectively, she noted improved balance with acetazolamide and subsequent ENG demonstrated mild improvement. PATIENT 4:: A 43 year-old man presented with a 5-year history of optical migraines and recurrent vertigo spells, lasting 30 seconds, which was misdiagnosed as positional vertigo. He additionally had a 10-year history of oscillopsia. ENG at age 61 revealed complete BVP. CONCLUSION: In these cases, vestibular migraine was linked to recurrent vertigo spells that eventually led to complete bilateral vestibulopathy. PMID- 28806327 TI - Long-term Quality of Life Following Vestibular Schwannoma Excision Via the Translabyrinthine Approach. AB - OBJECTIVE: To assess postoperative quality of life (QOL) and other patient reported outcomes following surgery for vestibular schwannoma. STUDY DESIGN: Cross-sectional retrospective case review using postal questionnaires. SETTING: Tertiary referral center. PATIENTS: Five hundred consecutive patients undergoing surgery for vestibular schwannoma. INTERVENTION(S): Patients undergoing surgery via the translabyrinthine approach (excluding neurofibromatosis type 2) under the senior author, with a minimum of 5 years follow-up, were included. MAIN OUTCOME MEASURE(S): QOL was assessed using the Short Form 36 (SF-36) questionnaire and a disease-specific survey to assess patients' subjective outcomes. RESULTS: The SF 36 scores in this group were significantly lower than the general UK population, though 24% of respondents reported a subjective improvement in overall QOL. Tumors larger than 4 cm were related to a reduced SF-36 total mental component score (p = 0.037). Increased age at time of surgery correlated with a reduced physical component of QOL (correlation coefficient = -0.26) and an improved mental component (correlation coefficient = 0.26). Subjective reports of postoperative symptoms and return to work, driving and social activities were similar to other published studies. 35% of patients reported vivid dreams or nightmares following surgery; the first reported incidence of this phenomenon in a large group of vestibular schwannoma patients. CONCLUSIONS: Generic measures of QOL in patients following translabyrinthine surgery for vestibular schwannoma do not always match subjective reports, reflecting the complexity of QOL assessment and the range of outcomes in this group. Increased time since surgery appears to be associated with an improvement in mental health. PMID- 28806328 TI - Introduction to the 14th International Symposium on Cochlear Implants and other Implantable Auditory Technologies, Toronto, Canada, May 11 to 14, 2016. PMID- 28806329 TI - Physiological Mechanisms in Combined Electric-Acoustic Stimulation. AB - OBJECTIVE: Electrical stimulation is normally performed on ears that have no hearing function, i.e., lack functional hair cells. The properties of electrically-evoked responses in these cochleae were investigated in several previous studies. Recent clinical developments have introduced cochlear implantation (CI) in residually-hearing ears to improve speech understanding in noise. The present study documents the known physiological differences between electrical stimulation of hair cells and of spiral ganglion cells, respectively, and reviews the mechanisms of combined electric and acoustic stimulation in the hearing ears. DATA SOURCES: Literature review from 1971 to 2016. CONCLUSIONS: Compared with pure electrical stimulation the combined electroacoustic stimulation provides additional low-frequency information and expands the dynamic range of the input. Physiological studies document a weaker synchronization of the evoked activity in electrically stimulated hearing ears compared with deaf ears that reduces the hypersynchronization of electrically-evoked activity. The findings suggest the possibility of balancing the information provided by acoustic and electric input using stimulus intensity. Absence of distorting acoustic-electric interactions allows exploiting these clinical benefits of electroacoustic stimulation. PMID- 28806330 TI - NANOCI-Nanotechnology Based Cochlear Implant With Gapless Interface to Auditory Neurons. AB - : Cochlear implants (CI) restore functional hearing in the majority of deaf patients. Despite the tremendous success of these devices, some limitations remain. The bottleneck for optimal electrical stimulation with CI is caused by the anatomical gap between the electrode array and the auditory neurons in the inner ear. As a consequence, current devices are limited through 1) low frequency resolution, hence sub-optimal sound quality and 2), large stimulation currents, hence high energy consumption (responsible for significant battery costs and for impeding the development of fully implantable systems). A recently completed, multinational and interdisciplinary project called NANOCI aimed at overcoming current limitations by creating a gapless interface between auditory nerve fibers and the cochlear implant electrode array. This ambitious goal was achieved in vivo by neurotrophin-induced attraction of neurites through an intracochlear gel nanomatrix onto a modified nanoCI electrode array located in the scala tympani of deafened guinea pigs. Functionally, the gapless interface led to lower stimulation thresholds and a larger dynamic range in vivo, and to reduced stimulation energy requirement (up to fivefold) in an in vitro model using auditory neurons cultured on multi-electrode arrays. In conclusion, the NANOCI project yielded proof of concept that a gapless interface between auditory neurons and cochlear implant electrode arrays is feasible. These findings may be of relevance for the development of future CI systems with better sound quality and performance and lower energy consumption. The present overview/review paper summarizes the NANOCI project history and highlights achievements of the individual work packages. PMID- 28806331 TI - Cochlear Implants Meet Regenerative Biology: State of the Science and Future Research Directions. AB - : The cochlear implant, the first device to restore a human sense, is an electronic substitute for lost mechanosensory hair cells. It has been successful at providing hearing to people with severe to profound hearing loss and as of 2012, an estimated 324,000 patients worldwide have received cochlear implants. Users of cochlear implants however, suffer from difficulties in processing complex sounds such as music and in discriminating sounds in noisy environments. Recent advances in regenerative biology and medicine are opening new avenues for enhancing the efficacy of cochlear implants by improving the neural interface in the future and offer the possibility of an entirely biological solution for hearing loss in the long term. This report comprises the latest developments presented in the first Symposium on cochlear implants and regenerative biology, held at the 14th International Conference on Cochlear Implants in 2016 in Toronto, Canada. PMID- 28806332 TI - Linking Deafness and Dementia: Challenges and Opportunities. AB - : The rising incidence of dementia locally and worldwide has now reached a critical level. The associated costs associated with these individuals will ultimately be untenable to most societies. Furthermore there is a paucity of highly effective treatments. However, the recent discovery of the association of hearing loss and dementia may open many potential opportunities. Although we still are acquiring knowledge on the pathophysiology of this association, clinicians are hopeful that our current highly effective treatments of hearing loss may ultimately be shown to have a positive effect on those with dementia. PMID- 28806333 TI - What Does Music Sound Like for a Cochlear Implant User? AB - OBJECTIVE: Cochlear implant research and product development over the past 40 years have been heavily focused on speech comprehension with little emphasis on music listening and enjoyment. The relatively little understanding of how music sounds in a cochlear implant user stands in stark contrast to the overall degree of importance the public places on music and quality of life. The purpose of this article is to describe what music sounds like to cochlear implant users, using a combination of existing research studies and listener descriptions. We examined the published literature on music perception in cochlear implant users, particularly postlingual cochlear implant users, with an emphasis on the primary elements of music and recorded music. Additionally, we administered an informal survey to cochlear implant users to gather first-hand descriptions of music listening experience and satisfaction from the cochlear implant population. CONCLUSION: Limitations in cochlear implant technology lead to a music listening experience that is significantly distorted compared with that of normal hearing listeners. On the basis of many studies and sources, we describe how music is frequently perceived as out-of-tune, dissonant, indistinct, emotionless, and weak in bass frequencies, especially for postlingual cochlear implant users-which may in part explain why music enjoyment and participation levels are lower after implantation. Additionally, cochlear implant users report difficulty in specific musical contexts based on factors including but not limited to genre, presence of lyrics, timbres (woodwinds, brass, instrument families), and complexity of the perceived music. Future research and cochlear implant development should target these areas as parameters for improvement in cochlear implant-mediated music perception. PMID- 28806334 TI - Cochlear Implantation in Postlingual Adult Patients With Long-Term Auditory Deprivation. AB - OBJECTIVE: The role of long-term hearing deprivation in cochlear implant performance is not well established, and the limits for implanting an auditory deprived ear are still unknown. The objective of this study was to evaluate the effect of long-term auditory deprivation time on cochlear implant results. STUDY DESIGN: Retrospective case review study. SETTING: Cochlear implantation tertiary referral center. PATIENTS: Adult patients with postlingual deafness. INTERVENTION: Unilateral cochlear implantation between 2001 and January 2015. MAIN OUTCOME MEASURES: Age at implantation, sex, etiology of hearing loss, and duration of auditory deprivation in the implanted ear were collected. Cochlear implants results were expressed in terms of vowel identification, disyllabic word recognition, and sentence recognition.Spearman's correlation test was applied to determine the relationship between auditory deprivation time and speech recognition scores. Additionally, patients were divided according to their auditory deprivation time before implantation in group A (less than 10 yr) and group B (more than 10 yr). RESULTS: One hundred three patients met inclusion criteria for this study. There were 61 patients in group A, with a mean deprivation time of 2.52 years. There were 42 patients in group B, with a mean deprivation time of 19.67 years.There were no statistically significant differences between both groups regarding speech recognition scores.Deprivation time in the implanted ear was not statistically correlated with cochlear implantation performance. CONCLUSIONS: Long-term auditory deprivation in the ear to be implanted does not negatively influence cochlear implantation results and should not be considered criterion to reject cochlear implantation. PMID- 28806335 TI - A Smartphone Application for Customized Frequency Table Selection in Cochlear Implants. AB - HYPOTHESIS: A novel smartphone-based software application can facilitate self selection of frequency allocation tables (FAT) in postlingually deaf cochlear implant (CI) users. BACKGROUND: CIs use FATs to represent the tonotopic organization of a normal cochlea. Current CI fitting methods typically use a standard FAT for all patients regardless of individual differences in cochlear size and electrode location. In postlingually deaf patients, different amounts of mismatch can result between the frequency-place function they experienced when they had normal hearing and the frequency-place function that results from the standard FAT. For some CI users, an alternative FAT may enhance sound quality or speech perception. Currently, no widely available tools exist to aid real-time selection of different FATs. This study aims to develop a new smartphone tool for this purpose and to evaluate speech perception and sound quality measures in a pilot study of CI subjects using this application. METHODS: A smartphone application for a widely available mobile platform (iOS) was developed to serve as a preprocessor of auditory input to a clinical CI speech processor and enable interactive real-time selection of FATs. The application's output was validated by measuring electrodograms for various inputs. A pilot study was conducted in six CI subjects. Speech perception was evaluated using word recognition tests. RESULTS: All subjects successfully used the portable application with their clinical speech processors to experience different FATs while listening to running speech. The users were all able to select one table that they judged provided the best sound quality. All subjects chose a FAT different from the standard FAT in their everyday clinical processor. Using the smartphone application, the mean consonant-nucleus-consonant score with the default FAT selection was 28.5% (SD 16.8) and 29.5% (SD 16.4) when using a self-selected FAT. CONCLUSION: A portable smartphone application enables CI users to self-select frequency allocation tables in real time. Even though the self-selected FATs that were deemed to have better sound quality were only tested acutely (i.e., without long-term experience with them), speech perception scores were not inferior to those obtained with the clinical FATs. This software application may be a valuable tool for improving future methods of CI fitting. PMID- 28806336 TI - Musical Rehabilitation in Adult Cochlear Implant Recipients With a Self administered Software. AB - OBJECTIVE: The goal of this study was to determine if a self-administered computer-based rehabilitation program could improve music appreciation and speech understanding in adults who have a cochlear implant (CI). STUDY DESIGN: Prospective study. SETTING: Tertiary adult CI program. PATIENTS: Twenty-one postlingually deafened cochlear implant users between the ages of 27 and 79 years were recruited. INTERVENTIONS(S): A self-administered music rehabilitative software was designed to help improve the perception of musical patterns of increasing complexity, as well as pitch and timbre perception, premised on focused and divided attention. All participants completed a diagnostic music test before and after rehabilitative training, including tests of pitch and timbre perception and pattern identification with increasing levels of difficulty. Speech data in quiet and noise was also collected both pre- and post-training. Participants trained for a minimum of 3.5 hours a week, for 4 weeks. MAIN OUTCOME MEASURE(S): Mean changes in music perception and enjoyment as well as speech perception (IEEE sentence test in quiet and noise). RESULTS: Post-training diagnostic test scores, as compared with pretraining scores, indicated significant improvements in musical pattern perception. Tests of speech perception in quiet and in noise were significantly improved in a subset of this cohort. All of the training participants thought that the training helped to improve their recognition skills, and found the program to be beneficial. CONCLUSION: Despite the limitations of current CI technology, the results of this study suggest that auditory training can improve music perception skills, and possibly speech intelligibility, lending further support to rehabilitation being an integral part of the postimplantation paradigm. PMID- 28806337 TI - The Sound Quality of Cochlear Implants: Studies With Single-sided Deaf Patients. AB - OBJECTIVE: The goal of the present study was to assess the sound quality of a cochlear implant for single-sided deaf (SSD) patients fit with a cochlear implant (CI). BACKGROUND: One of the fundamental, unanswered questions in CI research is "what does an implant sound like?" Conventional CI patients must use the memory of a clean signal, often decades old, to judge the sound quality of their CIs. In contrast, SSD-CI patients can rate the similarity of a clean signal presented to the CI ear and candidate, CI-like signals presented to the ear with normal hearing. METHODS: For Experiment 1 four types of stimuli were created for presentation to the normal hearing ear: noise vocoded signals, sine vocoded signals, frequency shifted, sine vocoded signals and band-pass filtered, natural speech signals. Listeners rated the similarity of these signals to unmodified signals sent to the CI on a scale of 0 to 10 with 10 being a complete match to the CI signal. For Experiment 2 multitrack signal mixing was used to create natural speech signals that varied along multiple dimensions. RESULTS: In Experiment 1 for eight adult SSD-CI listeners, the best median similarity rating to the sound of the CI for noise vocoded signals was 1.9; for sine vocoded signals 2.9; for frequency upshifted signals, 1.9; and for band pass filtered signals, 5.5. In Experiment 2 for three young listeners, combinations of band pass filtering and spectral smearing lead to ratings of 10. CONCLUSION: The sound quality of noise and sine vocoders does not generally correspond to the sound quality of cochlear implants fit to SSD patients. Our preliminary conclusion is that natural speech signals that have been muffled to one degree or another by band pass filtering and/or spectral smearing provide a close, but incomplete, match to CI sound quality for some patients. PMID- 28806338 TI - Isolated Second Implant Adaptation Period in Sequential Cochlear Implantation in Adults. AB - OBJECTIVE: To determine if depriving the use of the first cochlear implant (CI1) impacts adaptation to a sequential implant (CI2). STUDY DESIGN: Prospective cohort. SETTING: Academic center. PATIENTS: Sixteen unilateral cochlear implant recipients undergoing contralateral implantation (sequential bilateral) were matched according to age, etiology, duration of deafness, device age, and delay between implants. INTERVENTION: During a 4-week adaptation period after CI2 activation, patients underwent deprivation of CI1 or were permitted continued use of it. MAIN OUTCOME MEASURES: Speech perception scores and subjective quality of life outcomes before CI2 and at 1, 3, 6, and 12-months following activation. RESULTS: Maximal CI2 speech perception scores in quiet were achieved by 1-month postactivation for the "deprivation" group (71.3% for hearing in noise test [HINT], p = 0.767 for change beyond 1-mo) compared with 6-months for the "continued use" group (67.9% for HINT, p = 0.064 for change beyond 6-mo). The "deprivation" group experienced a temporary drop in CI1 scores (67.9% for HINT in quiet at 1-mo versus 78.4% pre-CI2, p = 0.009) recovering to 77.3% by 3-months; unchanged from baseline levels (p = 1.0). A binaural advantage over the better hearing ear was present for HINT sentences with noise (72.4% versus 58.8% for "deprivation", p = 0.001; 71.5% versus 52.7% for "continued use," p = 0.01). Missing data precluded a meaningful analysis of subjective quality of life outcome scales. CONCLUSION: Bilateral cochlear implantation improves speech perception compared with one implant. A period of deprivation from CI1 shortens time to maximum speech perception by CI2 without long-term consequences on the performance of CI1. PMID- 28806339 TI - Cognitive Evaluation of Cochlear Implanted Adults Using CODEX and MoCA Screening Tests. AB - OBJECTIVE: The relationship between hearing loss and cognitive function has already been established. The objective of our study was to determine whether the two short cognitive tests, COgnitive Disorders EXamination (CODEX) and Montreal Cognitive Assessment (MoCA), could be used in daily clinical practice to detect cognitive impairment, and its changes after cochlear implantation. PATIENTS: Eighteen patients with severe to profound postlingual progressive hearing loss (mean age +/- SEM: 64 +/- 3.5 yr; range, 23-83 yr) were tested before, and 12 months after cochlear implantation, with adapted visual presentation of CODEX and MoCA tests. Auditory performance was tested under best-aided conditions in quiet and noise. RESULTS: Twelve months after cochlear implantation, hearing performance had clearly improved (paired t tests, p < 0.05). In addition, among the eight patients who had an abnormal cognitive score before implantation, four improved their cognitive performance, and were thus considered to be normal. No major alteration of cognitive performance was observed in the 10 patients who had normal cognitive performance before implantation. CONCLUSION: CODEX and MoCA are rapid tests that could be considered to be relevant cognitive performance screening tests. They could be used in daily clinical practice to improve the multidisciplinary sensory-cognitive monitoring of the elderly population. PMID- 28806340 TI - The Impact of Comorbidities in the Aging Population on Cochlear Implant Outcomes. AB - OBJECTIVES: Cochlear implants have been used for many years for bilateral profound hearing loss. General longevity has continued to increase and, therefore, the age at which cochlear implants are placed has concomitantly increased. Our purpose is to determine whether outcomes and complications are significantly different in the elderly. STUDY DESIGN: Retrospective, clinical review. SETTING: Tertiary referral center, primarily ambulatory setting. PATIENTS: One hundred and one patients with moderate-to-profound hearing loss who ranged in age from 18 to 89 years. Subjects were divided into younger (<69, n = 51) and older (>70, n = 50) groups for analysis. INTERVENTION: All patients received either a unilateral or bilateral multichannel cochlear implant. The change in hearing in noise testing and AZBio testing between pre and postimplantation was evaluated in each group. MAIN OUTCOME MEASURES: Primary outcome measures include preimplant and postimplant hearing in noise test (HINT) and/or AZBio speech perception testing. Preimplant HINT/AZBio was compared with postimplant HINT/AZBio for each patient and between the two groups. In addition, we reviewed the comorbidities between the two groups as well as complication rates between less than 70 and more than 70 group. RESULTS: Both the younger and the older group demonstrated a significant improvement in postimplant HINT and/or AZBio scores. No statistically significant difference was noted in precochlear implant HINT/AZBio testing (p = 0.65/p = 0.48) between the two groups or the postimplant HINT/AZBio testing (p = 0.19/p = 0.22) between the two groups. Although, more than 70 yo group had significantly more comorbidities, the complication rates between the groups were insignificant. There was no shown association of specific comorbidities to complications between the two groups. CONCLUSIONS: Both older and younger patients can receive a significant improvement in speech perception with cochlear implantation. Older patients tend to have more comorbidities compared with the younger patients, however, the complication rates are not higher in this population. PMID- 28806341 TI - Impact of Cochlear Implantation on Cognitive Functions of Older Adults: Pilot Test Results. AB - BACKGROUND: A significant relationship between hearing loss and cognitive impairment has been previously reported. Overall, improvement in speech perception in quiet and quality of life has been observed after cochlear implantation. However, the impact of hearing loss treatment using cochlear implantation on cognitive functions is yet to be fully elucidated. OBJECTIVE: To investigate the impact of cochlear implantation on cognitive and psychological functions of older adults. STUDY DESIGN: Prospective patient-control study. PARTICIPANTS: A total of 39 participants took part in the study: 23 cochlear implant (CI) candidates (M = 69.04 +/- 12.35 yr) and 16 CI recipients (M = 61.75 +/- 15.62 yr). All participants completed an assessment of hearing (pure-tone thresholds and speech perception in quiet), and a computerised, nonverbal test battery of cognitive function assessment, as well as a depression, anxiety, and stress scale. RESULTS: Independent-sample t test scores for the changes between 0 and 12 months revealed that CI recipients performed significantly better on measures of simple reaction time, cognitive flexibility, paired-associate learning, working memory, and strategy use (p < 0.05) compared with implant candidates. Compared with the candidates, recipients also showed significantly lower stress scores (p < 0.05) after 1 year use of a CI. CONCLUSION: Our results indicate that even in participants with a long duration, severe to profound hearing loss, cochlear implantation has some impact on improving a number of cognitive functions. This finding warrants future longitudinal investigations with a large sample size to examine if the observed cognitive enhancement benefits are sustainable. PMID- 28806343 TI - Pediatric Neuro-Ophthalmology: Coming of Age. PMID- 28806342 TI - Cognitive Abilities and Quality of Life After Cochlear Implantation in the Elderly. AB - OBJECTIVE: To evaluate quality of life (QoL) and cognitive function in elderly patients with cochlear implants relative to auditory improvement, using geriatric validated scales. STUDY DESIGN: Prospective observational study. SETTING: A tertiary referral center for cochlear implantation (CI) and a geriatric center in Nancy, France. PATIENTS: Sixteen consecutive patients were included, from 65 to 80 years old, with postlingual severe-to-profound deafness. MAIN OUTCOME MEASURES: Evaluations were conducted before and at 6 and 12 months after cochlear implant surgery. A monosyllabic word recognition test was used to measure speech perception. QoL was evaluated by the World Health Organization Quality of Life Assessment for elderly people; cognitive function was evaluated by the Mini Mental State Examination; depression was evaluated by the Hamilton Scale; autonomy was evaluated by the Instrumental Activities of Daily Living. RESULTS: Speech intelligibility evolved from 10% before surgery to 63% and 69% at 6 and 12 months after cochlear implant activation, respectively. QoL showed significant improvement in sensory abilities. The Mini-Mental State Examination evaluations remained stable and executive functions tended to improve. Autonomy improved significantly. CONCLUSION: Cochlear implantation improves autonomy and the QoL in the elderly. Cognitive functions are not influenced by surgery, but executive functions appear to benefit from implantation. Age should not be a limiting factor, and cochlear implantation can be proposed as an efficient treatment for severe-to-profound hearing loss in the elderly. PMID- 28806344 TI - Neuro-Ophthalmic Manifestations of Pediatric Neurodegenerative Disease. AB - The topic of pediatric neurodegenerative disease is broad and ever expanding. Children who suffer from neurodegenerative disease often have concomitant visual dysfunction. Neuro-ophthalmologists may become involved in clinical care to identify corroborating eye findings when a specific condition is suspected, to monitor for disease progression, and in some cases, to assess treatment efficacy. Ophthalmic findings also may be the harbinger of a neurodegenerative process so a keen awareness of the possible manifestations of these conditions is important. The purpose of this review is to highlight common examples of the neuro ophthalmic manifestations of pediatric neurodegenerative disease using a case based approach in an effort to provide a framework for approaching these complex patients. PMID- 28806345 TI - Pediatric Optic Neuritis: What Is New. AB - Few diseases blur the margins between their childhood and adult-onset varieties as much as optic neuritis. This report will review our state of knowledge of pediatric optic neuritis, as well as its relationship to the latest consensus definitions of neuroinflammatory disease. Current diagnostic and treatment options will be explored, as well as our potential to uncover an understanding of pediatric optic neuritis through systematic prospective studies. The risk of evolving multiple sclerosis is probably less than in adults, but pediatric optic neuritis is more likely to be an initial manifestation of acute disseminated encephalomyelitis. Steroids may hasten visual recovery, but they do not change visual outcome except in cases because of neuromyelitis optica. The role of puberty in modifying the presentation and risk associations is unknown. Prospective studies are required to resolve these diagnostic and management issues. PMID- 28806346 TI - Optic Pathway Gliomas in Neurofibromatosis Type 1: An Update: Surveillance, Treatment Indications, and Biomarkers of Vision. AB - Optic pathway gliomas (OPGs) occur in 15%-20% of children with neurofibromatosis type 1 (NF1), leading to visual deficits in fewer than half of these individuals. The goal of chemotherapy is to preserve vision, but vision loss in NF1-associated OPG can be unpredictable. Determining which child would benefit from chemotherapy and, equally important, which child is better observed without treatment can be difficult. Unfortunately, despite frequent imaging and ophthalmologic evaluations, some children experience progressive vision loss before treatment. Indications for chemotherapy usually are based on a comprehensive, quantitative assessment of vision, but reliable vision evaluation can be challenging in young children with NF1-OPG. The ability to identify and predict impending vision loss could potentially improve management decisions and visual outcomes. To address this challenge, ophthalmologic, electrophysiologic, and imaging biomarkers of vision in NF1-OPG have been proposed. We review current recommendations for the surveillance of children at risk for NF1-OPG, outline guidelines for initiating therapy, and describe the utility of proposed biomarkers for vision. PMID- 28806347 TI - Pediatric Pseudotumor Cerebri Syndrome. AB - Idiopathic intracranial hypertension, otherwise known as primary pseudotumor cerebri syndrome (PTCS), most frequently occurs in obese women of childbearing age. However, children may be affected as well. This review will address recent findings regarding demographics, diagnosis, and treatment of pediatric PTCS. Prepubertal children with primary PTCS have an equal sex distribution and less frequent obesity compared with adult patients. However, female gender and obesity are risk factors for primary PTCS in postpubertal children. Compared with adults, children with PTCS more frequently present with ocular motility deficits and more often have associated medical conditions that increase the risk of developing PTCS. Visual field testing may be unreliable, and the optimal modality to monitor visual function is unknown. MRI shows signs of elevated intracranial pressure (ICP) in children with PTCS similar to that of adults. It has now been established that elevated ICP in children <=18 years old is greater than 25 cm H20 in nonobese, nonsedated children, and greater than 28 cm H2O in the remainder. Optical coherence tomography (OCT) may be used to distinguish pseudopapilledema from papilledema, monitor response to treatment in preverbal children, and identify patients with PTCS at risk for permanent visual loss. However, the precise role of OCT in the management of pediatric PTCS remains to be determined. PMID- 28806348 TI - Radioprotective effect of vitamin E on salivary glands after radioiodine therapy for differentiated thyroid cancer: a randomized-controlled trial. AB - OBJECTIVES: This study aimed to examine the radioprotective effect of vitamin E on salivary glands after radioactive iodine (I) therapy in patients with differentiated thyroid cancer. PATIENTS AND METHODS: Eighty-two patients with differentiated thyroid cancer were enrolled in this study. They were divided randomly into four groups (control group: 22 cases, group A: 23 cases, group B: 22 cases, and group C: 15 cases) before postsurgical ablation therapy with 100 mCi I. The patients in groups A, B, and C received vitamin E 100, 200, and 300 mg/day orally, respectively, for a duration of 1 week before to 4 weeks after I therapy. Salivary gland function was assessed using salivary gland scintigraphy immediately before and 6 months after I therapy. Uptake fraction (UF), uptake index (UI), excretion fraction (EF), and excretion ratio (ER) of each salivary gland were measured and compared. RESULTS: On comparison between before and after I therapy in the control group, there was a significant decrease in UF of both right and left parotid glands (all P<0.01). In group A, a significant increase in EF of the right parotid gland (P<0.01) and UI of the right submandibular gland (P<0.05) was found. In group B, there was a significant increase in UI of the right parotid gland and both submandibular glands (all P<0.01). In group C, there was a significant increase in UF of the left parotid gland (P<0.05) and the right submandibular gland (P<0.01). Also, there was a statistical increase in UI in both submandibular glands (all P<0.01). However, on comparing the changes in the post-I therapy salivary scintigraphy parameters among the four groups, there was a significant difference in DeltaUI of the right parotid gland (P<0.05) and both submandibular glands (all P<0.01), as well as DeltaER of the left parotid gland (P<0.05) and DeltaUF of the left submandibular gland (P<0.05). CONCLUSION: Vitamin E exerts significant protective effects on the parotid and submandibular glands after I therapy. PMID- 28806349 TI - Dual-phase 99mTc-MIBI imaging and the expressions of P-gp, GST-pi, and MRP1 in hyperparathyroidism. AB - OBJECTIVE: The aim of this study was to further elucidate the mechanisms of dual phase technetium-99m methoxyisobutylisonitrile (Tc-MIBI) parathyroid imaging by exploring the association between early uptake results (EUR), delayed uptake results (DUR), and the retention index (RI) in dual-phase Tc-MIBI parathyroid imaging and P glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), and glutathione S-transferase-pi (GST-pi) expression in hyperparathyroidism (HPT). PATIENTS AND METHODS: Preoperative dual-phase (early and delayed) Tc-MIBI imaging was performed on 74 patients undergoing parathyroidectomy for HPT. EUR, DUR, and RI were calculated. P-gp, MRP1, and GST pi expressions were assessed using immunohistochemistry in resected tissue from HPT and control patients. The association between P-gp, MRP1, and GST-pi expressions and EUR, DUR, and RI in HPT was evaluated. RESULTS: The positive rate of dual-phase T c-MIBI imaging was 91.89% (68/74) and the false-negative rate was 8.11% (6/74). P-gp and GST-pi expressions were higher in tissues resected from control compared with HPT patients (47.37 and 81.5%, P<0.05); there was no difference in MRP1. EUR were associated with P-gp and GST-pi expressions, and DUR were associated with MRP1 expression. There was a significant difference in MRP1 expression between RI greater than or equal to 0 and RI less than 0. There was no relationship between the sensitivity of dual-phase Tc-MIBI imaging and P-gp, MRP1, and GST-pi expressions in resected parathyroid tissue. The six false negative HPT cases consisted of three P-gp (-)/MRP1 (-) tissues, three P-gp ( )/GST-pi (-) tissues, and four MRP1 (-)/GST-pi (-) tissues. CONCLUSION: As P-gp and GST-pi expressions were higher in tissues resected from control compared with HPT patients, Tc-MIBI may wash out faster from normal parathyroid tissue surrounding the lesion compared with the lesion itself, facilitating detection. PMID- 28806350 TI - Blood pressure variability is increasing from the first to the second day of the interdialytic interval in hemodialysis patients. AB - OBJECTIVES: Patients with end-stage renal-disease under hemodialysis have increased cardiovascular risk and experience severe blood pressure (BP) fluctuations during the dialysis session and the subsequent interdialytic period. BP variability (BPV) may be an additional risk factor for cardiovascular events and preliminary data suggest increased BPV with advancing stages of chronic kidney disease. This is the first study to examine BPV during the whole intradialytic and interdialytic period in hemodialysis patients with ambulatory BP monitoring. METHODS: A total of 160 patients receiving maintenance hemodialysis had 48-h ambulatory BP monitoring with the Mobil-O-Graph device during a regular dialysis session and the subsequent interdialytic interval. Brachial and aortic BPV were calculated with validated formulas and were compared between Days 1 and 2 of the interdialytic period (44-h), Days 1 and 2 of the total 48-h interval (including the dialysis session), and between the two respective daytime periods and night-time periods. RESULTS: All brachial SBPV indices [SD: 14.75 +/- 4.38 vs. 15.91 +/- 4.41, P = 0.001; weighted SD: 13.80 +/- 4.00 vs. 14.89 +/- 3.90, P < 0.001; coefficient of variation (CV): 11.34 +/- 2.91 vs. 11.93 +/- 2.94, P = 0.011; average real variability (ARV): 11.38 +/- 3.44 vs. 12.32 +/- 3.65, P < 0.001)] were increasing from Days 1 to 2 of the 44-h interdialytic period. Similarly, all indexes of DBPV were significantly increased in Day 2, except for CV. Aortic SBPV and DBPV indices displayed a similar pattern. Furthermore, all studied brachial SBPV and DBPV indexes were also lower during daytimes 1 than 2 (systolic ARV 11.56 +/- 3.98 vs. 12.44 +/- 4.03, P = 0.002); systolic ARV was lower in night-time 1 compared with night-time 2 (11.20 +/- 5.09 vs. 12.18 +/- 4.66, P = 0.045). In multivariate regression analysis prehemodialysis SBP, age and diabetes were independently associated with increased SBP ARV. CONCLUSION: BPV is increased in interdialytic Day 2 compared with Day 1 in hemodialysis patients; this could be another mechanism involved in the complex cardiovascular pathophysiology and increased cardiovascular mortality of these individuals. PMID- 28806353 TI - From lifestyle changes to outcomes in hypertension. PMID- 28806351 TI - Effects of a nationwide strategy to reduce salt intake in Samoa. AB - OBJECTIVE: Salt reduction is one of the most cost-effective interventions for the prevention of noncommunicable diseases, but there are no studies evaluating the effectiveness of national strategies in low or lower middle income countries. This study aimed to examine the effect of an 18-month nation-wide salt reduction strategy in Samoa. METHODS: Two nationally representative cross-sectional surveys of adults aged 18-64 years, measuring 24-h urinary salt excretion and salt related knowledge, attitudes and behaviours, were conducted before (2013) and after (2015) the intervention. RESULTS: There were 234 participants at baseline (response rate 47%) and 479 at 18 months (response rate 61%). There was no change in mean population salt intake between 2013 (7.31 g/day) and 2015 (7.50 g/day) (0.19, 95% confidence interval -0.50 to 0.88; P = 0.588). There were significant changes in the proportion of the population who always or often add discretionary salt when eating (-16.2%, P = 0.002), the proportion who understood the adverse effects of salt (+9.0%, P = 0.049) and the proportion using one or more methods to control their salt intake (+20.9%, P < 0.001). A total of 73% reported that they had heard or seen the salt reduction messages. CONCLUSION: With widespread awareness of the salt reduction message and some improvements in salt-related knowledge and behaviours following the intervention, Samoa is now well positioned to implement much-needed structural initiatives or policies to reduce salt in the food supply. PMID- 28806352 TI - Association between exposure to noise and risk of hypertension: a meta-analysis of observational epidemiological studies. AB - OBJECTIVE: An increasing amount of original studies suggested that exposure to noise could be associated with the risk of hypertension, but the results remain inconsistent and inconclusive. We aimed to synthesize available epidemiological evidence about the relationship between various types of noise and hypertension, and to explore the potential dose-response relationship between them in an up-to date meta-analysis. METHODS: We conducted a literature search of PubMed and Embase from these databases' inception through December 2016 to identify observational epidemiological studies examining the association between noise and risk of hypertension. A random effects model was used to combine the results of included studies. Dose-response meta-analysis was conducted to examine the potential dose-response relationship. RESULTS: In total, 32 studies (five cohort studies, one case-control study, and 26 cross-section studies) involving 264 678 participants were eligible for inclusion. Pooled result showed that living or working in environment with noise exposure was significantly associated with increased risk of hypertension (odds ratio 1.62; 95% confidence interval: 1.40 1.88). We found no evidence of a curve linear association between noise and risk of hypertension. A dose-response analysis suggested that, for an increment of per 10 dB(A) of noise, the combined odds ratio of hypertension was 1.06 (95% confidence interval: 1.04-1.08). CONCLUSION: Integrated epidemiological evidence supports the hypothesis that exposure to noise may be a risk factor of hypertension, and there is a positive dose-response association between them. PMID- 28806356 TI - Respiratory Viral Infections and Coinfections Caused by Human Metapneumovirus in Children With Cancer. PMID- 28806354 TI - Trends in Adult Chlamydia and Gonorrhea Prevalence, Incidence and Urethral Discharge Case Reporting in Morocco over 1995-2015-Estimates Using the Spectrum Sexually Transmitted Infection Model. AB - BACKGROUND: Evolving health priorities and resource constraints mean that countries require data on sexually transmitted infections (STI) trends to inform program planning and resource allocation. METHODS: The Spectrum modeling tool estimated prevalence and incidence of gonorrhea and chlamydia in Morocco's 15- to 49-year-old population, based on prevalence surveys. Incident cases, broken down between symptomatic and asymptomatic, and treated versus untreated, were compared with urethral discharge (UD) case reports, to estimate reporting completeness among treated UD cases. RESULTS: Gonorrhea prevalence was estimated at 0.37% (95% confidence interval [CI], 0.14-1.0%) in women and 0.32% (0.12-0.87%) in men in 2015; chlamydia prevalences were 3.8% (95% CI, 2.1-6.4%) and 3.0% (95% CI, 1.7 5.1%). Corresponding estimated numbers of new cases in women and men in 2015 were 79,598 (95% CI, 23,918-256,206) and 112,013 (95% CI, 28,700-307,433) for gonorrhea, and 291,908 (95% CI, 161,064-524,270) and 314,032 (95% CI, 186,076 559,133) for chlamydia. Gonorrhea and chlamydia prevalence had declined by an estimated 41% and 27%, respectively, over 1995 to 2015. Prevalence declines probably related to improved STI treatment coverage, and decreasing risk behaviors. Reporting completeness among treated UD cases was estimated at 46% to 77% in 2015. Reported UD cases corresponded to 13% of all estimated (symptomatic and asymptomatic) gonorrhea and chlamydia cases. CONCLUSIONS: STI declines and improvements in treatment coverage are consistent with Morocco's introduction of syndromic management in 2000, scale-up of prevention, and declining human immunodeficiency virus incidence. While gonorrhea is four-fold more common as cause of clinical UD cases than chlamydia, Morocco continues to suffer a large, untreated burden of chlamydia. Reliable monitoring of both STIs requires new periodic surveys and/or novel forms of affordable surveillance beyond high-risk populations. PMID- 28806355 TI - Seroprevalence of Anti-polio Antibodies in Children From Polio High-risk Areas of Pakistan: A Cross-Sectional Survey 2015-2016. AB - BACKGROUND: Pakistan is one of the 3 remaining wild poliovirus endemic countries. We collected sera from children to assess the prevalence of poliovirus antibodies in selected high-risk areas for poliovirus transmission. METHODS: Children in 2 age groups (6-11 and 36-48 months) were randomly selected between November 2015 and March 2016 in 6 areas of Pakistan (Sindh Province: Karachi and Kashmore; Khyber Pakhtunkhwa Province: Peshawar, Bannu and Nowshera; Punjab Province: Faisalabad). After obtaining informed consent, basic demographic and vaccination history data were collected, 1 peripheral venipuncture was obtained, and assays to detect poliovirus (PV)-neutralizing antibodies were performed. RESULTS: A total of 1301 children were enrolled and had peripheral blood drawn that analyzed. Study subjects were evenly distributed among survey sites and age groups. Anti-polio seroprevalence differed significantly among geographic areas (P < 0.001); in the 6-11 months group, it ranged between 89% and 98%, 58% and 95%, and 74% and 96% for PV serotypes 1, 2 and 3, respectively; in 36-48 months group, it ranged between 99% and 100%, 95% and 100%, and 92% and 100% for PV 1, 2, and 3, respectively. Having received inactivate poliovirus vaccine, malnourishment (stunting) and educational level of parents were found to be associated with presence of anti-polio antibodies. CONCLUSION: The polio eradication program achieved overall high serologic protection; however, immunity gaps in young children in the high polio risk areas remain. These gaps enable sustained circulation of wild poliovirus type 1, and pose risk for emergence of vaccine-derived polioviruses. Focusing on the lowest socioeconomic strata of society, where malnutrition is most prevalent, could accelerate poliovirus eradication. PMID- 28806358 TI - New Evidence Reflecting VA's Commitment to Achieve Health and Health Care Equity for All Veterans. PMID- 28806359 TI - The Role of VA Community Care in Addressing Health and Health Care Disparities. PMID- 28806360 TI - Achieving Health Equity: Federal Perspectives for 21st Century Health System Research Priorities. PMID- 28806361 TI - Health Disparities in Veterans: A Map of the Evidence. AB - BACKGROUND: Goals for improving the quality of care for all Veterans and eliminating health disparities are outlined in the Veterans Health Administration Blueprint for Excellence, but the degree to which disparities in utilization, health outcomes, and quality of care affect Veterans is not well understood. OBJECTIVES: To characterize the research on health care disparities in the Veterans Health Administration by means of a map of the evidence. RESEARCH DESIGN: We conducted a systematic search for research studies published from 2006 to February 2016 in MEDLINE and other data sources. We included studies of Veteran populations that examined disparities in 3 outcome categories: utilization, quality of health care, and patient health. MEASURES: We abstracted data on study design, setting, population, clinical area, outcomes, mediators, and presence of disparity for each outcome category. We grouped the data by population characteristics including race, disability status, mental illness, demographics (age, era of service, rural location, and distance from care), sex identity, socioeconomic status, and homelessness, and created maps illustrating the evidence. RESULTS: We reviewed 4249 citations and abstracted data from 351 studies which met inclusion criteria. Studies examining disparities by race/ethnicity comprised by far the vast majority of the literature, followed by studies examining disparities by sex, and mental health condition. Very few studies examined disparities related to lesbian, gay, bisexual, or transgender identity or homelessness. Disparities findings vary widely by population and outcome. CONCLUSIONS: Our evidence maps provide a "lay of the land" and identify important gaps in knowledge about health disparities experienced by different Veteran populations. PMID- 28806362 TI - Harnessing Implementation Science to Increase the Impact of Health Equity Research. AB - BACKGROUND: Health disparities are differences in health or health care between groups based on social, economic, and/or environmental disadvantage. Disparity research often follows 3 steps: detecting (phase 1), understanding (phase 2), and reducing (phase 3), disparities. Although disparities have narrowed over time, many remain. OBJECTIVES: We argue that implementation science could enhance disparities research by broadening the scope of phase 2 studies and offering rigorous methods to test disparity-reducing implementation strategies in phase 3 studies. METHODS: We briefly review the focus of phase 2 and phase 3 disparities research. We then provide a decision tree and case examples to illustrate how implementation science frameworks and research designs could further enhance disparity research. RESULTS: Most health disparities research emphasizes patient and provider factors as predominant mechanisms underlying disparities. Applying implementation science frameworks like the Consolidated Framework for Implementation Research could help disparities research widen its scope in phase 2 studies and, in turn, develop broader disparities-reducing implementation strategies in phase 3 studies. Many phase 3 studies of disparity-reducing implementation strategies are similar to case studies, whose designs are not able to fully test causality. Implementation science research designs offer rigorous methods that could accelerate the pace at which equity is achieved in real-world practice. CONCLUSIONS: Disparities can be considered a "special case" of implementation challenges-when evidence-based clinical interventions are delivered to, and received by, vulnerable populations at lower rates. Bringing together health disparities research and implementation science could advance equity more than either could achieve on their own. PMID- 28806363 TI - Clinical Epidemiology of Single Versus Multiple Substance Use Disorders: Polysubstance Use Disorder. AB - OBJECTIVE: While research on substance abuse has largely focused on people who have a single substance use disorder (SUD), many people abuse multiple substances. Studies have yet to examine the distinctive characteristics of patients diagnosed with more than 1 SUD and how those with polysubstance use disorder (PSUD) differ from those with a single SUD. METHODS: National Veterans Health Administration data from fiscal year 2012 were used to compare veterans diagnosed 1 SUD to veterans diagnosed with 2-3, and >3 SUDs on demographic characteristics, psychiatric and medical diagnoses, medical and psychiatric service utilization, and psychotropic medication fills. Comparisons of the 3 groups were based on bivariate and multiple logistic regression analyses. RESULTS: Of the 472,624 veterans with at least 1 diagnosed SUD, 346,329 (73.2%) had 1 disorder, 113,598 (24.0%) had 2-3, and 12,715 (2.7%) had >3 SUDs. Veterans with higher levels of PSUD were more likely to be black and homeless, were more likely to have hepatic disease as well as schizophrenia, bipolar disorder, major depressive disorder, and personality disorders. Higher levels of PSUD were associated with greater use of psychiatric inpatient care, residential and rehabilitative treatment, and with multiple psychotropic medication prescription fills. CONCLUSIONS: Veterans with PSUD have more severe problems along several dimensions and use more numerous and varied services than those with 1 SUD. This distinctive clinical profile warrants research to develop and evaluate methods for treating patients with complex multimorbid disorders that involve interactions between medical morbidity and psychosocial dysfunction. PMID- 28806364 TI - Racial and Ethnic Variation in Perceptions of VA Mental Health Providers are Associated With Treatment Retention Among Veterans With PTSD. AB - BACKGROUND: Veterans with posttraumatic stress disorder (PTSD) who seek mental health care in the Veterans Health Administration frequently discontinue treatment prematurely. Early discontinuation of mental health treatment is more common among Veterans with PTSD who are of minority race or ethnicity. OBJECTIVES: To determine whether retention in individual therapy or pharmacotherapy among Veterans with PTSD are associated with patients' ratings of their mental health providers, and if those associations differ depending on Veteran race or ethnicity. RESEARCH DESIGN: Latino, African American, and white Veterans (n=2452) who participated in a prospective national cohort study of Veterans with PTSD at the beginning of an episode of care were surveyed immediately following Veterans' PTSD diagnoses and 6 months later. Pharmacy and mental health service utilization were abstracted from Veterans Health Administration administrative databases for 6 months postdiagnosis. Retention in treatments were modeled using logistic regression among Veterans who initiated individual therapy or pharmacotherapy. Demographics, treatment need, treatment related beliefs, treatment process measures, and ratings of mental health providers were considered as predictors. RESULTS: Ratings of mental health providers, more than treatment beliefs, were associated with treatment retention. Among African American Veterans, retention in pharmacotherapy was reduced if the provider was perceived as not having helped manage medication side-effects (odds ratio, 0.36; confidence interval, 0.16-0.80). All Latino Veterans but one (99% or n=64) who rated their therapist as not caring discontinued individual psychotherapy. CONCLUSIONS: Ratings of mental health providers were associated with treatment retention. The salience of specific provider behaviors to treatment retention varied by Veteran race or ethnicity. PMID- 28806365 TI - Associations Between Perceived Race-based Discrimination and Contraceptive Use Among Women Veterans in the ECUUN Study. AB - OBJECTIVE: To describe perceived race-based discrimination in Veterans Affairs (VA) health care settings and assess its associations with contraceptive use among a sample of women Veterans. METHODOLOGY: This study used data from a national telephone survey of women Veterans aged 18-44 receiving health care in VA who were at risk of unintended pregnancy. Participants were asked about their perceptions of race-based discrimination while seeking VA health care and about their contraceptive use at last heterosexual intercourse. Logistic and multinomial regression analyses were used to examine associations between perceived race-based discrimination with use of prescription contraception. RESULTS: In our sample of 1341 women Veterans, 7.9% report perceived race-based discrimination when receiving VA care, with blacks and Hispanics reporting higher levels of perceived discrimination than white women (11.3% and 11.2% vs. 4.4%; P<0.001). In logistic and multinomial regression analyses adjusting for race/ethnicity, age, income, marital status, parity, and insurance, women who perceived race-based discrimination were less likely to use any prescription birth control than women who did not (odds ratio, 0.65; 95% confidence interval, 0.42-1.00), with the largest difference seen in rates of intrauterine device or implant use (odds ratio, 0.40; 95% confidence interval, 0.20-0.79). CONCLUSIONS: In this national sample of women Veterans, over 10% of racial/ethnic minority women perceived race-based discrimination when receiving care in VA settings, and perceived racial/ethnic discrimination was associated with lower likelihood of prescription contraception use, especially intrauterine devices and implants. VA efforts to enhance respectful interactions may not only improve patient health care experiences, but also represent an opportunity to improve reproductive health outcomes for women Veterans. PMID- 28806366 TI - African American Veterans Storytelling: A Multisite Randomized Trial to Improve Hypertension. AB - BACKGROUND: Disparities in hypertension control persist for African American Veterans. OBJECTIVE: To enhance cultural relevance of hypertension control self management education, in a multisite, stratified randomized trial, we tested an interactive Veteran-to-Veteran storytelling digital video disk (DVD) intervention created with Veteran partners, versus an education-only DVD comparison. METHODS: At 3 VA facilities, African American Veterans with uncontrolled hypertension were randomized to storytelling DVD intervention or didactic comparison DVD and followed for 6 months. We hypothesized that follow-up blood pressure (BP) would be lower among Veterans in the intervention group. RESULTS: African American Veterans (N=619) were 92% male, 39% over age 65, most had a high-school education, over 50% of both the intervention and comparison group reported a household income of <$20,000, and 40% had less than adequate health literacy. At baseline, mean intervention and comparison group BPs were 138/80 and 139/81 mm Hg, respectively; at 6 months, mean systolic BP (SBP) increased by 0.1 in the intervention group and by 1.9 for the comparison group; diastolic BP fell by 0.1 in the intervention group and rose by 0.2 in the comparison group. No differences between the intervention and control groups were statistically significant (all P>0.3). Site differences were large; at one, the intervention group improved while the comparison groups deteriorated, resulting in 6.3 and 3.9 mm Hg more improvement for the intervention group in SBP and diastolic BP (P=0.06 and 0.04), respectively; at the other 2 sites, there were positive and negative changes, all small, in the 2 measures, with minimal differences-one site favored the comparison group and the other, the intervention (these comparisons did not approach statistical significance (all P>0.20). In a secondary analysis stratified by baseline BP, there was no intervention effect among those with uncontrolled BP, but intervention patients who were in control at baseline were more likely to stay in control, compared with comparison [SBP increase by 6.3 mm Hg (SD=14.4) among intervention, and by 10.9 mm Hg (SD=16.9) in comparison, P=0.02]. CONCLUSIONS: In this multisite trial, we did not find a significant overall storytelling intervention effect (Clinicaltrials.gov Reg. #NCT01276197). PMID- 28806367 TI - Creating a Toolkit to Reduce Disparities in Patient Engagement. AB - BACKGROUND: Patient engagement has become a major focus of health care improvement efforts nationally. Although evidence suggests patient engagement can be beneficial to patients, it has not been consistently defined, operationalized, or translated into practice. OBJECTIVES: Our objective was to develop a toolkit to help providers increase patient engagement and reduce disparities in patient engagement. RESEARCH DESIGN: We used qualitative interviews and observations with staff at primary care sites nationally to identify patient engagement practices and resources used to engage patients. We then used a modified Delphi process, that included a series of conference calls and surveys, where stakeholders reduced lists of engagement practices based on perceived feasibility and importance to develop a toolkit for patient engagement. SAMPLING: Sites were selected for interviews and site visits based on the concentration of minority patients served and performance on a measure of patient engagement, with the goal of highlighting practices at sites that successfully serve minority patients. RESULTS: We created a toolkit consisting of patient engagement practices and resources. No identified practice or resource specifically targeted patient engagement of minorities or addressed disparities. However, high-performing, high minority-serving sites tended to describe more staff training opportunities and staff feedback mechanisms. In addition, low-performing and high-minority-serving sites more often reported barriers to implementation of patient engagement practices. CONCLUSIONS: Stakeholders agreed on feasible and important engagement practices. Implementation of this toolkit will be tracked to better understand patient engagement and its effect on patient-centered care and related disparities in care. PMID- 28806368 TI - Increased Health Care Utilization and Costs Among Veterans With a Positive Screen for Military Sexual Trauma. AB - BACKGROUND: The effects of sexual trauma on long-term health care utilization and costs are not well understood due to infrequent documentation of sexual trauma history in health care systems. The Veteran's Health Administration provides a unique opportunity to address this constraint as sexual trauma is actively screened for as part of routine care. METHODS: We used a retrospective cohort design to analyze Veteran's Health Administration mental health and medical service utilization and costs as a function of a positive screen for exposure to military sexual trauma (MST) among Veterans of recent conflicts in Iraq and Afghanistan. We computed adjusted 5-year estimates of overall utilization and costs, and utilization and costs determined not to be related to MST. RESULTS: The cohort included 426,223 men and 59,611 women. A positive MST screen was associated with 50% higher health care utilization and costs relative to a negative screen. Overall, a positive relative to negative MST screen was associated with a 5-year incremental difference of 34.6 encounters and $10,734 among women, and 33.5 encounters and $11,484 among men. After accounting for MST related treatment, positive MST screen was associated with 11.9 encounters and $4803 among women, and 19.5 encounters and $8001 among men. CONCLUSIONS: Results demonstrate significant and consistent differences in health care utilization and costs between Veterans with a positive relative to negative MST screen. Even after accounting for MST-related care, a positive screen was associated with significantly higher utilization and costs. MST-related needs may be more readily recognized in women relative to men. PMID- 28806369 TI - Intimate Partner Violence Victimization and Associated Implications for Health and Functioning Among Male and Female Post-9/11 Veterans. AB - BACKGROUND: There is increased emphasis on identifying patients who experience intimate partner violence (IPV) in Department of Veterans Affairs and other health care settings. A better understanding of IPV's implications for health and functioning is needed among post-911 Veterans, and especially male Veterans, to inform IPV screening and response. OBJECTIVES: To identify past 6-month IPV experienced among partnered post-9/11 Veterans and examine sex-based associations between IPV and health. RESEARCH DESIGN: A national sample of Veterans completed a survey that included measures of IPV victimization and health. Types of IPV and relationships with health and functioning were examined separately for male and female Veterans. SUBJECTS: In total, 407 post-9/11 Veterans (52% women) in intimate relationships. MEASURES: IPV victimization was assessed with the Conflict Tactics Scales-Revised. Health and functioning indicators included posttraumatic stress disorder (PCL-5) and depression (Beck Depression Inventory Primary Care) symptoms, physical health-related quality of life (Short-Form 12 item Health Survey), and occupational functioning (Inventory of Psychosocial Functioning). RESULTS: Nearly two thirds of both men and women reported past 6 month IPV, with greatest endorsement of psychological aggression (65% of men, 59% of women). A total of 8% of men and 7% of women reported physical IPV and 4% of men and 7% of women reported sexual IPV. Psychological aggression was strongly linked with mental health for both sexes and greater occupational impairment for men. Physical and sexual IPV were associated with more severe mental health symptoms for women while physical IPV was negatively associated with physical health-related quality of life for men. CONCLUSIONS: Recent IPV victimization, especially psychological aggression, is a key health issue for partnered male and female post-9/11 Veterans. Practice and research implications are discussed. PMID- 28806370 TI - Will Veterans Answer Sexual Orientation and Gender Identity Questions? AB - BACKGROUND: The Veterans Health Administration does not routinely collect and document sexual orientation and gender identity (SOGI) data, despite existing health disparities among sexual and gender minority Veterans. Because of the legacy of previous Department of Defense (DoD) policies that prohibited disclosure of sexual or gender minority identities among active duty personnel, Veterans may be reluctant to respond to SOGI questions. OBJECTIVES: This population-based study assesses item nonresponse to SOGI questions by Veteran status. RESEARCH DESIGN: This is a secondary analysis of data from a population based sample of adults in 20 US states that elected to administer a SOGI module in the 2014 Behavioral Risk Factor Surveillance System survey. Prevalence of SOGI refusals and responses of "don't know" were compared for Veterans and non Veterans. SUBJECTS: Veterans (n=22,587) and non-Veterans (n=146,475) were surveyed. RESULTS: Nearly all Veteran respondents (>=98%) completed the SOGI questions, with 95.4% identifying as heterosexual, 1.2% as gay or lesbian, 1.2% as bisexual, and 0.59% as transgender. A significantly lower proportion of Veterans than non-Veterans refuse to answer sexual orientation (1.5% vs. 1.9%). There was no difference between Veterans and non-Veterans in responses for gender identity. CONCLUSIONS: Veterans are just as likely as non-Veterans to complete SOGI items in survey research. Asking Veterans about SOGI is unlikely to yield significant nonresponse. These data suggest that future research should investigate Veterans' perspectives on being asked about SOGI in research settings and as part of routine clinical care. PMID- 28806371 TI - Transgender Veterans' Satisfaction With Care and Unmet Health Needs. AB - BACKGROUND: Transgender individuals are overrepresented among Veterans. However, little is known regarding their satisfaction with Veterans Administration (VA) care and unmet health needs. OBJECTIVES: This study examined transgender Veterans' satisfaction with VA medical and mental health care, prevalence of delaying care, and correlates of these outcomes. RESEARCH DESIGN: We used data from transgender Veterans collected in 2014 through an online, national survey. SUBJECTS: In total, 298 transgender Veterans living in the United States. MEASURES: We assessed patient satisfaction with VA medical and mental health care and self-reported delays in seeking medical and mental health care in the past year. Potential correlates associated with these 4 outcomes included demographic, health, and health care variables. RESULTS: Over half of the sample used VA (56%) since their military discharge. Among transgender Veterans who had used VA, 79% were satisfied with medical care and 69% with mental health care. Lower income was associated with dissatisfaction with VA medical care, and being a transgender man was associated with dissatisfaction with VA mental health care. A substantial proportion reported delays in seeking medical (46%) or mental (38%) health care in the past year (not specific to VA). Screening positive for depression and/or posttraumatic stress disorder was associated with delays in seeking both types of care. CONCLUSIONS: Although the majority of transgender Veterans are satisfied with VA health care, certain subgroups are less likely to be satisfied with care. Further, many report delaying accessing care, particularly those with depression and/or posttraumatic stress disorder symptoms. Adapting health care settings to better engage these vulnerable Veterans may be necessary. PMID- 28806372 TI - Exploring Rural Disparities in Medical Diagnoses Among Veterans With Transgender related Diagnoses Utilizing Veterans Health Administration Care. AB - OBJECTIVES: Research shows transgender individuals experience pronounced health disparities compared with their nontransgender peers. Yet, there remains insufficient research about health differences within transgender populations. This study seeks to fill this gap by exploring how current urban/rural status is associated with lifetime diagnosis of mood disorder, alcohol dependence disorder, illicit drug abuse disorder, tobacco use, posttraumatic stress disorder, human immunodeficiency virus, and suicidal ideation or attempt among veterans with transgender-related diagnoses. METHODS: This study used a retrospective review of The Department of Veterans Affairs (VA) administrative data for transgender patients who received VA care from 1997 through 2014. Transgender patients were defined as individuals that had a lifetime diagnosis of any of 4 International Classification of Diseases-9 diagnosis codes associated with transgender status. Independent multivariable logistic regression models were used to explore associations of rural status with medical conditions. RESULTS: Veterans with transgender-related diagnoses residing in small/isolated rural towns had increased odds of tobacco use disorder (adjusted odds ratio=1.39; 95% confidence intervals, 1.09-1.78) and posttraumatic stress disorder (adjusted odds ratio=1.33; 95% confidence intervals, 1.03-1.71) compared with their urban transgender peers. Urban/rural status was not significantly associated with other medical conditions of interest. CONCLUSIONS: This study contributes the first empirical investigations of how place of residence is associated with medical diagnoses among veterans with transgender-related diagnoses. The importance of place as a determinant of health is increasingly clear, but for veterans with transgender-related diagnoses this line of research is currently limited. The addition of self-reported sex identity data within VA electronic health records is one way to advance this line of research. PMID- 28806373 TI - Patient-aligned Care Team Engagement to Connect Veterans Experiencing Homelessness With Appropriate Health Care. AB - BACKGROUND: Veterans experiencing homelessness frequently use emergency and urgent care (ED). OBJECTIVE: To examine the effect of a Patient-aligned Care Team (PACT) model tailored to the unique needs of Veterans experiencing homelessness (H-PACT) on frequency and type of ED visits in Veterans Health Administration (VHA) medical facilities. RESEARCH DESIGN: During a 12-month period, ED visits for 3981 homeless Veterans enrolled in (1) H-PACT at 20 VHA medical centers (enrolled) were compared with those of (2) 24,363 homeless Veterans not enrolled in H-PACT at the same sites (nonenrolled), and (3) 23,542 homeless Veterans at 12 non-H-PACT sites (usual care) using a difference-in-differences approach. MEASURE(S): The primary outcome was ED and other health care utilization and the secondary outcome was emergent (not preventable/avoidable) ED visits. RESULTS: H PACT enrollees were predominantly white males with a higher baseline Charlson comorbidity index. In comparing H-PACT enrollees with usual care, there was a significant decrease in ED usage among the highest ED utilizers (difference-in differences, -4.43; P<0.001). The decrease in ED visits were significant though less intense for H-PACT enrollees versus nonenrolled (-0.29, P<0.001). H-PACT enrollees demonstrated a significant increase in the proportion of ED care visits that were not preventable/avoidable in the 6 months after enrollment, but had stable rates of primary care, mental health, social work, and substance abuse visits over the 12 months. CONCLUSIONS: Primary care treatment engagement can reduce ED visits and increase appropriate use of ED services in VHA for Veterans experiencing homelessness, especially in the highest ED utilizers. PMID- 28806375 TI - Physics and Histologic Evaluation of Rotary, Ultrasonic, and Sonic Instruments. AB - Rotary instruments (RIs) are the most commonly used to perform osteotomies in many fields of medicine. Owing to a new interest in performing a minimally invasive surgery, over last fifteen years new devices have been used in oral surgery such as ultrasonic instruments (UIs) and, lately, sonic instruments (SIs). Nowadays, bone preservation and regeneration are paramount in many clinical situations and, consequently, it is crucial to rely upon instruments, which cause the least tissue damage during the surgery. Concerning SIs, there is still few information about workload to be applied and related temperature increases; furthermore, there are no comparative in-vivo studies, which analyze the thermal and mechanical effects on bone. Thus, SIs have been compared with UIs and RIs in terms of heat generation, operating time, accuracy, and tissue damage. Decalcification and sectioning procedure resulted in no significant differences between the applied instruments in terms of bone damage. RIs resulted more efficient than UIs (P < 0.001), but demonstrated low accuracy (NRS 4.9), whereas SIs (P = 0.005) required more time to perform the osteotomy. The maximum temperature increase occurred in the ultrasonic group. Even though SI were the slowest, they have proved to be the most accurate (NRS 8.4) in comparison with UI (NRS 7.6) and RI (NRS 4.9). Within the limit of this study, sonic instruments could be considered a safe alternative to ultrasonic instruments. PMID- 28806376 TI - Classification of the Residual Cranial Defects and Selection of Reconstruction Materials. AB - The cranial defects are complex in nature and are due to various causes. Therefore, there is a need for a common term of reference to these defects. This requirement stood as a prime reason for proposing a classification system for cranial defects. The classification is based on 2 decades of experience in cranioplasty. This efficient and simple way of representation would fill the existing lacunae for a systematic communication on cranial defects. Over the ages the evolution of reconstruction and grafting had undergone a massive progress. Therefore, it is essential to enumerate all available graft and bio-materials for restoring the cranial defects. The aetiology for these defects, age and sex of the patient, site and size of the defect, associated systemic conditions, cost factor, and operator's choice are the factors that play key role in the selection of the reconstructive material. This article discusses on these factors in cranioplasty. High success rate with excellent function and cosmetic outcome in using a variety of materials, as shared in this article. The advantages of autografts cannot be matched by any existing alloplast. However, in case of larger defects, for a better cosmetic outcome and to reduce the donor site morbidity, alloplasts are the most widely preferred material of choice. PMID- 28806374 TI - Long-acting Reversible Contraception Among Homeless Women Veterans With Chronic Health Conditions: A Retrospective Cohort Study. AB - BACKGROUND: US women Veterans are at increased risk of homelessness and chronic health conditions associated with unintended pregnancy. Veterans Health Administration (VHA) provision of long-acting reversible contraception (LARC) can assist in healthy pregnancy planning. OBJECTIVES: To evaluate perinatal risk factors and LARC exposure in ever-homeless women Veterans. RESEARCH DESIGN: A retrospective cohort study of women Veterans using VHA administrative data from fiscal years 2002-2015. SUBJECTS: We included 41,747 ever-homeless women Veterans age 18-44 years and 46,391 housed women Veterans matched by military service period. A subgroup of 7773 ever-homeless and 8674 matched housed women Veterans deployed in Iraq and Afghanistan [Operations Enduring Freedom/Iraqi Freedom/New Dawn (OEF/OIF/OND)] conflicts comprised a second analytic cohort. MEASURES: Descriptive statistics compared demographic, military, health conditions, and LARC exposure in ever-homeless versus housed women Veterans. Multivariable logistic regression explored factors associated with LARC exposure in the OEF/OIF/OND subgroup. RESULTS: All health conditions were significantly higher in ever-homeless versus housed Veterans: mental health disorder in 84.5% versus 48.7% (P<0.001), substance abuse in 35.8% versus 8.6% (P<0.001), and medical conditions in 74.7% versus 55.6% (P<0.001). LARC exposure among all VHA users was 9.3% in ever-homeless Veterans versus 5.4% in housed Veterans (P<0.001). LARC exposure in the OEF/OIF/OND cohort was 14.1% in ever-homeless Veterans versus 8.2% in housed Veterans (P<0.001). In the OEF/OIF/OND cohort, homelessness along Veterans with medical and mental health indicators were leading LARC exposure predictors. CONCLUSIONS: The VHA is successfully engaging homeless women Veterans and providing LARC access. The prevalence of perinatal risk factors in ever homeless women Veterans highlights a need for further programmatic enhancements to improve reproductive planning. PMID- 28806377 TI - The Double Intravenous Catheter Technique for Single-Puncture Arthrocentesis. AB - Traditionally, arthrocentesis involves insertion of 2 needles into the joint space of which one acts as an inflow port and the other as the outflow port. These 2 needles must triangulate and be exactly placed in the upper joint space for the procedure to be effective. Due to the difficulty in maintaining the needle position, single-puncture arthrocentesis is gaining popularity. It is relatively easier to perform and less traumatic to the joint. The authors describe a simple technique of single-puncture arthrocentesis using parts of 2 peripheral intravenous catheters of different gauges. The outflow port is formed by the catheter tube of 1 cannula while the inflow port is formed by the needle of the second cannula. Besides beings easy to perform and cost-effective, our technique provides predictable joint lavage of the joint with minimal trauma to the tissues. PMID- 28806378 TI - Gummy Smile Correction Using Lingual Orthodontics and Augmented Corticotomy in Extremely Thin Alveolar Housing. AB - BACKGROUND: Tooth movement out of anatomic limitations was assisted by augmented corticotomy using deproteinized bovine bone mineral. METHODS: Lip protrusion can be reduced by premolar extraction followed by retraction of the anterior teeth. Surgical intervention is appropriate when the alveolar bone housing of the anterior region is insufficient for the tooth movement. In this patient, corticotomy in upper palatal area and anterior segmented osteotomy in the mandible were performed. Anatomic limitation to the retraction was expanded by xenograft. An antero-posterior lingual appliance was used to bodily retract the upper anterior teeth. The gummy smile was resolved by intrusion of upper entire arch using 2 mid-palatal temporary skeletal anchorage devices. RESULTS: New bone formation was observed on palatal side of upper anterior teeth. The teeth were moved into augmented area without fenestration or vitality loss. Lip protrusion was resolved, and the gummy smile was effectively improved. CONCLUSIONS: Orthodontic tooth movement beyond the limitation of the alveolar bone housing can be achieved with surgical assistance, which can be performed under local anesthesia. Without orthognathic surgery, the gummy smile can be reduced using an antero-posterior lingual retractor with mid-palatal skeletal anchorage. PMID- 28806379 TI - Evaluation of Protraction Face-Mask Therapy on the Craniofacial and Upper Airway Morphology in Unilateral Cleft Lip and Palate. AB - INTRODUCTION: The aim of the authors' study was to evaluate the effects of protraction face-mask therapy on the craniofacial and upper airway morphology in patients with unilateral cleft lip and palate (UCLP). METHODS: Twenty-three growing UCLP patients (mean age: 8.3 + 2.4) were enrolled in the study group. Protraction face-mask in combination with Hyrax appliance was applied for the correction of anterior crossbite and maxillary insufficiency. Twenty-six patients with maxillary retrusion (mean age: 8.1 + 2.5) were evaluated as the control group. The pharyngeal airway morphology was assessed via the area measurements of upper airway structures on the lateral cephalometric radiographs. RESULTS: The upper airway morphology was similar compared with the control group subjects at the beginning of the treatment. The pharyngeal airway area was increased significantly following the maxillary expansion and protraction. Nasopharyngeal area increased and the oropharyngeal area decreased significantly. There was an increase in the sagittal and vertical dimensions after the protraction therapy. CONCLUSION: The pharyngeal morphology in both UCLP patients and control group patients was similarly improved with the protraction face-mask therapy. PMID- 28806380 TI - Formation of the Philtral Column Using a Dermal Graft in Secondary Unilateral Cleft Lip. AB - INTRODUCTION: The philtral column has an important aesthetic significance and is especially important in patients with cleft lip. If the integrity of the philtrum cannot be preserved in patients of unilateral clefts, these patients will have profound abnormalities in their facial musculature. The purpose of this study was to analyze the effects of dermal grafting on the philtral column in patients with a unilateral alveolar cleft. METHODS: The authors retrospectively studied dermal grafts performed in Konkuk University Medical Center between January 2009 and January 2015. A total of 26 patients with unilateral cleft lip were included in this study; the authors measured philtral symmetry based on differences in convexity and angle using clinical photos. Additionally, panel evaluation was performed. RESULTS: Of 26 patients enrolled, 21 completed follow-up and had adequate photographs. Five patients who were lost to follow-up were excluded. The difference in convexity decreased from 0.25 to 0.15 (P < 0.005) and the difference in angle decreased from 10.76 to 6.43 (P < 0.005). The panel evaluation indicated that patient appearances were significantly improved (P < 0.001). DISCUSSION: In patients with secondary cleft lip deformity of the philtral depression, the authors' procedure may augment the thickness of the philtral ridge and have positive aesthetic outcomes. PMID- 28806381 TI - Congenital Salivary Fistula From Parotid Main Gland. AB - Congenital parotid fistulas are extremely rare diseases. Herein, the authors report a patient with congenital salivary fistula from parotid main gland in a 15 year-old boy. Therefore, clinicians should consider the possibility of congenital parotid fistula form parotid main gland. Surgical excision of the fistula and parotid gland can be effective treatment option of congenital parotid fistula. PMID- 28806382 TI - Orbital Cellulitis Following Orbital Blow-out Fracture. AB - Orbital cellulitis and abscess have been described in the literature as complication that usually occur secondary to infection in the maxillary, ethmoidal, and frontal sinuses. If left untreated, it can lead to blindness, cavernous sinus thrombosis, meningitis, or cerebral abscess. Orbital fractures are a common sequela of blunt orbital trauma, but are only rarely associated with orbital cellulitis. So, the authors present rare orbital cellulitis after orbital blow-out fracture. A 55-year-old Asian complains of severe orbital swelling and pain on the left side. These symptoms had started 2 days earlier and worsened within the 24 hours before hospital admission resulting in visual disturbances such as diplopia and photophobia. Contrast-enhanced computed tomography scan showed considerable soft tissue swelling and abscess formation on the left side. Patient was subjected to surgical drainage under general anesthesia in the operation room. In this case, the postoperative period was uneventful and the rapid improvement of symptoms was remarkable. In conclusion, the abscess of the orbit is a surgical emergency in patients whose impairment of vision or ocular symptoms cannot be controlled with medical therapy using antibiotics. In our case, orbital cellulitis can occur after blunt orbital trauma without predisposing sinusitis. Early and prompt diagnosis and surgical drainage before severe loss of visual acuity rescue or recover the vision in case of orbital cellulitis. PMID- 28806383 TI - Subependymal Heterotopia Mimicking Mass in Conventional Magnetic Resonance Imaging: Demonstration With 3T Advanced Neuroimages. AB - The authors reported a rare patient with large subependymal heterotopia mimicking cerebral neoplasia. A 22-year-old female was admitted with a history of right sided paresthesia accompanied by progressive headache. Cerebral magnetic resonance (MR) imaging showed a large solid lesion in the left frontal lobe. Advanced MR images proved that the lesion was compatible with subependymal heterotopia. Large subependymal heterotopia may mimick cerebral neoplasia. PMID- 28806384 TI - Transient Amaurosis and Diplopia After Inferior Alveolar Nerve Block. AB - A 40-year-old female patient was admitted to the authors' oral and maxillofacial clinic for removal of her lower left second molar under local anesthesia. The patient's medical history revealed that she had cardiac arhythmia and hypertension. Inferior alveolar nerve block was achieved using 2 mL of sefacaine (%3 mepivacaine HCL, without epinephrine). The patient complained of loss of vision in her left eye. All procedures were stopped immediately. Within 2 minutes the patient reported diplopia. All of the symptoms disappeared about 5 minutes after initial observation. Follow-up after 1 day revealed no complications. The procedure was then performed uneventfully. PMID- 28806385 TI - A Naturalistic Comparison of Methylphenidate and Risperidone Monotherapy in Drug Naive Youth With Attention-Deficit/Hyperactivity Disorder Comorbid With Oppositional Defiant Disorder and Aggression. AB - BACKGROUND/PURPOSE: Attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) are frequently co-occurring in youth, but data about the pharmacological management of this comorbidity are scarce, especially when impulsive aggression is prominent. Although stimulants are the first-line medication for ADHD, second-generation antipsychotics, namely, risperidone, are frequently used. We aimed to assess effectiveness and safety of monotherapy with the stimulant methylphenidate (MPH) and risperidone in a consecutive sample of 40 drug-naive male youths diagnosed as having ADHD-combined presentation, comorbid with ODD and aggression, without psychiatric comorbidities, according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria and a structured clinical interview (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version). METHODS: Twenty males treated with MPH (mean age, 8.95 +/- 1.67 years) and 20 males treated with risperidone (mean age, 9.35 +/- 2.72 years), followed up to 6 months, were assessed according to efficacy measures (Child Behavior Checklist [CBCL], Clinical Global Impression-Severity [CGI-S] and Improvement [CGI-I], Children Global Assessment Scale), and safety measures. At the end of the follow-up, both medications were similarly effective based on CBCL subscales of aggression and rule-breaking behaviors, on Diagnostic and Statistical Manual of Mental Disorders-oriented oppositional defiant problems and conduct problems, and on CGI-S, CGI-I, and Children Global Assessment Scale, but only MPH was effective on CBCL attention problems and attention deficit/hyperactivity problems. Risperidone was associated with weight gain and elevated prolactin levels. IMPLICATIONS/CONCLUSIONS: Although the nonrandomized, nonblind design limits the conclusions of our exploratory study, our findings suggest that when ADHD is comorbid with ODD and aggression MPH and risperidone are both effective on aggressive behavior, but only stimulants are effective on ADHD symptoms. PMID- 28806386 TI - Aripiprazole Improves Psychotic, Cognitive, and Motor Symptoms in a Patient With Lewy Body Dementia. PMID- 28806387 TI - Lurasidone-Associated Neuroleptic Malignant Syndrome. PMID- 28806388 TI - Naltrexone- or Nalmefene-Related Buprenorphine Withdrawal: Treat It With... More Buprenorphine. PMID- 28806389 TI - Staying Topical: An Unusual Case of Serotonin Syndrome. PMID- 28806390 TI - Combination Antipsychotic Therapies: An Analysis From a Longitudinal Pragmatic Trial. AB - BACKGROUND: Combination antipsychotics (CAs) are prescribed in schizophrenia despite limited evidence of efficacy. To explore the effect of switching from CA to monotherapy, we performed an exploratory analysis of the PROACTIVE (Preventing Relapse in Schizophrenia: Oral Antipsychotics Compared with Injectables: Evaluating Efficacy) study data, in which 305 patients with schizophrenia and schizoaffective disorder were followed for 30 months after randomization to long acting injectable (LAI) risperidone or second-generation oral antipsychotic (OA). METHODS: Patients who entered the PROACTIVE study on CA (n = 50), LAI (n = 20), or OA (n = 206) were compared in terms of time to relapse and clinical measures. FINDINGS: The OA group had significantly fewer hospitalizations than the CA group (P = 0.009) at baseline. In the CA group, 68% patients relapsed versus 53% in the LAI, and 52% in the OA groups. Although there was no significant difference in the relapse rate among groups on chi test (chi = 3.85, P = 0.146), the log-rank test showed a significant difference among the groups in time to first relapse (chi = 6.81, P = 0.033), with significantly longer time to relapse in the OA group (mean, 562.8 days) than in the CA group (mean, 409.5; P = 0.011). The LAI group's mean time to first relapse (594 days) was not significantly different from the other groups. However, after adjusting for number of hospitalizations, group was no longer significant (hazard ratio, 1.541; P = 0.052). IMPLICATIONS: Based on our exploratory analysis, taking antipsychotic combinations predicts earlier relapse and calls for additional treatment guidance in schizophrenia. PMID- 28806391 TI - What's New in Shock, September 2017? PMID- 28806392 TI - Kaempferol Alleviates the Interleukin-1beta-Induced Inflammation in Rat Osteoarthritis Chondrocytes via Suppression of NF-kappaB. AB - BACKGROUND This study was designed to examine the anti-inflammatory and anti osteoarthritis (OA) effects of kaempferol in rat articular chondrocytes stimulated with interleukin-1beta. MATERIAL AND METHODS Rat articular chondrocytes cultures were treated with interleukin-1beta alone or with kaempferol (25, 50, 100, and 200 MUM) and interleukin-1beta. The effect of kaempferol on chondrocyte cells viability was measured by MTT assay. The effect on prostaglandin E2 (PGE2) and nitric oxide (NO) level were also assessed using the ELISA and Griess reagent, respectively, for kaempferol activity. Moreover, the expression of iNOS, Cox-2 and activation of NF-kappaB under influence of kaempferol was also assessed by Western blot. RESULTS Kaempferol treatment (up to 100 MUM) in a concentration-dependent way caused reduction in the interleukin-1b stimulated formations of PGE2 and NO. Kaempferol also upregulated the expression of iNOS and Cox-2 in interleukin-1beta-stimulated rat OA chondrocytes. Additionally, kaempferol was found to inhibit the IkBa degradation and NF-kappaB activation in rat chondrocytes stimulated with interleukin-1beta. CONCLUSIONS Kaempferol significantly caused reduction in interleukin-1beta-stimulated pro inflammatory mediators in rat OA chondrocytes by inhibiting the NF-kappaB pathway. These results suggest that kaempferol had significant anti-inflammatory and anti-arthritis effects. Thus, kaempferol, as a novel therapeutic active agent, may prevent, stop, or retard the progression of OA. PMID- 28806393 TI - CRAF gene fusions in pediatric low-grade gliomas define a distinct drug response based on dimerization profiles. AB - Pediatric low-grade gliomas (PLGGs) are commonly associated with BRAF gene fusions that aberrantly activate the mitogen-activated protein kinase (MAPK) signaling pathway. This has led to PLGG clinical trials utilizing RAF- and MAPK pathway-targeted therapeutics. Whole-genome profiling of PLGGs has also identified rare gene fusions involving another RAF isoform, CRAF/RAF1, in PLGGs and cancers occuring in adults. Whereas BRAF fusions primarily dysregulate MAPK signaling, the CRAF fusions QKI-RAF1 and SRGAP3-RAF1 aberrantly activate both the MAPK and phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathways. Although ATP-competitive, first-generation RAF inhibitors (vemurafenib/PLX4720, RAFi) cause paradoxical activation of the MAPK pathway in BRAF-fusion tumors, inhibition can be achieved with 'paradox breaker' RAFi, such as PLX8394. Here we report that, unlike BRAF fusions, CRAF fusions are unresponsive to both generations of RAFi, vemurafenib and PLX8394, highlighting a distinct responsiveness of CRAF fusions to clinically relevant RAFi. Whereas PLX8394 decreased BRAF-fusion dimerization, CRAF-fusion dimerization is unaffected primarily because of robust protein-protein interactions mediated by the N-terminal non-kinase fusion partner, such as QKI. The pan-RAF dimer inhibitor, LY3009120, could suppress CRAF-fusion oncogenicity by inhibiting dimer mediated signaling. In addition, as CRAF fusions activate both the MAPK and PI3K/mTOR signaling pathways, we identify combinatorial inhibition of the MAPK/mTOR pathway as a potential therapeutic strategy for CRAF-fusion-driven tumors. Overall, we define a mechanistic distinction between PLGG-associated BRAF and CRAF/RAF1 fusions in response to RAFi, highlighting the importance of molecularly classifying PLGG patients for targeted therapy. Furthermore, our study uncovers an important contribution of the non-kinase fusion partner to oncogenesis and potential therapeutic strategies against PLGG-associated CRAF fusions and possibly pan-cancer CRAF fusions. PMID- 28806394 TI - SmgGDS is a transient nucleolar protein that protects cells from nucleolar stress and promotes the cell cycle by regulating DREAM complex gene expression. AB - The chaperone protein and guanine nucleotide exchange factor SmgGDS (RAP1GDS1) is a key promoter of cancer cell proliferation and tumorigenesis. SmgGDS undergoes nucleocytoplasmic shuttling, suggesting that it has both cytoplasmic and nuclear functions that promote cancer. Previous studies indicate that SmgGDS binds cytoplasmic small GTPases and promotes their trafficking to the plasma membrane. In contrast, little is known about the functions of SmgGDS in the nucleus, or how these nuclear functions might benefit cancer cells. Here we show unique nuclear localization and regulation of gene transcription pathways by SmgGDS. Strikingly, SmgGDS depletion significantly reduces expression of over 600 gene products that are targets of the DREAM complex, which is a transcription factor complex that regulates expression of proteins controlling the cell cycle. The cell cycle regulators E2F1, MYC, MYBL2 (B-Myb) and FOXM1 are among the DREAM targets that are diminished by SmgGDS depletion. E2F1 is well known to promote G1 cell cycle progression, and the loss of E2F1 in SmgGDS-depleted cells provides an explanation for previous reports that SmgGDS depletion characteristically causes a G1 cell cycle arrest. We show that SmgGDS localizes in nucleoli, and that RNAi mediated depletion of SmgGDS in cancer cells disrupts nucleolar morphology, signifying nucleolar stress. We show that nucleolar SmgGDS interacts with the RNA polymerase I transcription factor upstream binding factor (UBF). The RNAi mediated depletion of UBF diminishes nucleolar localization of SmgGDS and promotes proteasome-mediated degradation of SmgGDS, indicating that nucleolar sequestration of SmgGDS by UBF stabilizes SmgGDS protein. The ability of SmgGDS to interact with UBF and localize in the nucleolus is diminished by expressing DiRas1 or DiRas2, which are small GTPases that bind SmgGDS and act as tumor suppressors. Taken together, our results support a novel nuclear role for SmgGDS in protecting malignant cells from nucleolar stress, thus promoting cell cycle progression and tumorigenesis. PMID- 28806395 TI - RAD6 promotes DNA repair and stem cell signaling in ovarian cancer and is a promising therapeutic target to prevent and treat acquired chemoresistance. AB - Ovarian cancer (OC) is the most deadly gynecological cancer and unlike most other neoplasms, survival rates for OC have not significantly improved in recent decades. We show that RAD6, an ubiquitin-conjugating enzyme, is significantly overexpressed in ovarian tumors and its expression increases in response to carboplatin chemotherapy. RAD6 expression correlated strongly with acquired chemoresistance and malignant behavior of OC cells, expression of stem cell genes and poor prognosis of OC patients, suggesting an important role for RAD6 in ovarian tumor progression. Upregulated RAD6 enhances DNA damage tolerance and repair efficiency of OC cells and promotes their survival. Increased RAD6 levels cause histone 2B ubiquitination-mediated epigenetic changes that stimulate transcription of stem cell genes, including ALDH1A1 and SOX2, leading to a cancer stem cell phenotype, which is implicated in disease recurrence and metastasis. Downregulation of RAD6 or its inhibition using a small molecule inhibitor attenuated DNA repair signaling and expression of cancer stem cells markers and sensitized chemoresistant OC cells to carboplatin. Together, these results suggest that RAD6 could be a therapeutic target to prevent and treat acquired chemoresistance and disease recurrence in OC and enhance the efficacy of standard chemotherapy. PMID- 28806396 TI - Inhibiting MYC binding to the E-box DNA motif by ME47 decreases tumour xenograft growth. AB - Developing therapeutics to effectively inhibit the MYC oncoprotein would mark a key advance towards cancer patient care as MYC is deregulated in over 50% of human cancers. MYC deregulation is correlated with aggressive disease and poor patient outcome. Despite strong evidence in mouse models that inhibiting MYC would significantly impact tumour cell growth and patient survival, traditional approaches have not yet yielded the urgently needed therapeutic agents that directly target MYC. MYC functions through its interaction with MAX to regulate gene transcription by binding to E-box DNA response elements of MYC target genes. Here we used a structure-based strategy to design ME47, a small minimalist hybrid protein (MHP) able to disrupt the MAX:E-box interaction/binding and block transcriptional MYC activity. We show that inducing ME47 expression in established tumour xenografts inhibits tumour growth and decreases cellular proliferation. Mechanistically, we show by chromatin immunoprecipitation that ME47 binds to E-box binding sites of MYC target genes. Moreover, ME47 occupancy decreases MYC:DNA interaction at its cognate E-box binding sites. Taken together, ME47 is a prototypic MHP inhibitor that antagonizes tumour cell growth in vitro and in vivo and inhibits the interaction of MYC with DNA E-box elements. These results support ME47's role as a MYC inhibitor and suggest that MHPs provide an alternative therapeutic targeting system that can be used to target transcription factors important in human diseases, including cancer. PMID- 28806398 TI - Lysine-52 stabilizes the MYC oncoprotein through an SCFFbxw7-independent mechanism. AB - The oncogenic transcription factor c-MYC (MYC) is deregulated and often overexpressed in more than 50% of cancers. MYC deregulation is associated with poor prognosis and aggressive disease, suggesting that the development of therapeutic inhibitors targeting MYC would markedly impact patient outcome. MYC is highly regulated, with a protein and mRNA half-life of ~30 min. The most extensively studied pathway regulating MYC protein stability involves ubiquitylation and proteasomal degradation mediated by the E3-ligase, SCFFbxw7. Here we provide evidence for an SCFFbxw7-independent regulatory mechanism centred on the highly conserved lysine-52 (K52) within MYC Box I. This residue has been shown to be post-translationally modified by both ubiquitylation and SUMOylation, hinting at the interplay of post-translational modifications at this site and the importance of this residue. We demonstrate that mutation of K52 to arginine (R) renders the MYC protein more labile. Mechanistically, we show that the degradation pathway regulated by K52 is independent of the Cullin-RING ligase family of E3-ligases, which includes not only the canonical SCFFbxw7 but also other known MYC-targeting E3-ligases, such as SCFSkp2, SCFbetaTCRP, SCFFbxo28 and DCXTRUSS. Taken together, our data identify a novel regulatory pathway centred on K52 that may be exploited for the development of anti-MYC therapeutics. PMID- 28806397 TI - Mdm2 promotes Cdc25C protein degradation and delays cell cycle progression through the G2/M phase. AB - Upon different types of stress, the gene encoding the mitosis-promoting phosphatase Cdc25C is transcriptionally repressed by p53, contributing to p53's enforcement of a G2 cell cycle arrest. In addition, Cdc25C protein stability is also decreased following DNA damage. Mdm2, another p53 target gene, encodes a ubiquitin ligase that negatively regulates p53 levels by ubiquitination. Ablation of Mdm2 by siRNA led to an increase in p53 protein and repression of Cdc25C gene expression. However, Cdc25C protein levels were actually increased following Mdm2 depletion. Mdm2 is shown to negatively regulate Cdc25C protein levels by reducing its half-life independently of the presence of p53. Further, Mdm2 physically interacts with Cdc25C and promotes its degradation through the proteasome in a ubiquitin-independent manner. Either Mdm2 overexpression or Cdc25C downregulation delays cell cycle progression through the G2/M phase. Thus, the repression of the Cdc25C promoter by p53, together with p53-dependent induction of Mdm2 and subsequent degradation of Cdc25C, could provide a dual mechanism by which p53 can enforce and maintain a G2/M cell cycle arrest. PMID- 28806399 TI - Lymph node status have a prognostic impact in breast cancer patients with distant metastasis. AB - BACKGROUND: The objective of this retrospective study was to determine whether lymph node metastasis has a prognostic impact on patients with stage IV breast cancer. PATIENTS AND METHODS: Seven thousand three hundred and seventy-nine patients with de novo stage IV breast cancer diagnosed from 2004 to 2013 were identified. Kaplan-Meier estimate method was fitted to measure overall survival and breast cancer-specific survival (BCSS). Cox proportional hazard analysis was used to evaluate the association between N stage and BCSS after controlling variables such as other patient/tumor characteristics. RESULTS: The primary site of M1 tumors was mainly upper-outer quadrant and overlapping lesion of the breast. Patients with N1 disease had better overall survival and BCSS than did those without lymph node metastasis. The overall survival and BCSS of M1 patients with N3 disease were significantly lower than that of those with N0, N1 and N2 disease, whereas patients with N2 and N0/N1 involvement showed no significant difference with survival. Multivariate analysis showed that lymph node metastasis was an important prognostic factor for M1 patients (N1 versus N0, hazard ratio [HR] = 0.902, 95% confidence interval [CI]: 0.825-0.986, p = 0.023; N3 versus N0, HR = 1.161, 95% CI: 1.055-1.276, p = 0.002). For M1 patients, age, race, marital status, primary site, ER, PR and HER2 were the independent prognostic factors. CONCLUSIONS: The cohort study provides an insight into de novo stage IV breast cancer with lymph node metastasis. Our results indicated that accurate lymph node evaluation for stage IV patients is still necessary to obtain important prognostic information. PMID- 28806400 TI - Changes in the anterior segment after cycloplegia with a biometer using swept source optical coherence tomography. AB - The aim of this study was to investigate changes in the anterior segment of the eye after cycloplegia. A biometer combined with swept-source optical coherence tomography (SSOCT) was used for measurements. Patients with strabismus or amblyopia who underwent cycloplegia were included. The axial length, central corneal thickness, anterior chamber depth, and lens thickness were measured with the biometer-SSOCT system before and after cycloplegia. Altogether, 10 eyes of 10 patients (mean age 7.20 +/- 3.08 years, range 4-14 years) were evaluated. The mean measurements before cycloplegia were 22.75 +/- 0.96 mm axial length, 516 +/- 33 MUm central corneal thickness, 3.40 +/- 0.21 mm anterior chamber depth, and 3.77 +/- 0.26 mm lens thickness. The corresponding values after cycloplegia were 22.75 +/- 0.95 mm, 519 +/- 34 MUm, 3.68 +/- 0.16 mm, and 3.42 +/- 0.20 mm, respectively. The mean lens thickness had significantly decreased (P < 0.001) after cycloplegia, and the mean anterior chamber depth had significantly increased (P < 0.001). The means of the axial length (P = 0.66) and central corneal thickness (P = 0.17) had not changed significantly. The change in lens thickness was significantly correlated with the change in anterior chamber depth (r = -0.73, P = 0.02). The new biometer-SSOCT combination proved useful for accurately detecting changes in the anterior segment of the eye after cycloplegia in pediatric patients. The biometer's measurements indicated increased anterior chamber depth and decreased lens thickness after cycloplegia. The anterior chamber depth increased relative to the decrease in lens thickness. PMID- 28806401 TI - A GDF15 3' UTR variant, rs1054564, results in allele-specific translational repression of GDF15 by hsa-miR-1233-3p. AB - Growth differentiation factor 15 (GDF15) is a strong predictor of cardiovascular events and mortality in individuals with or without cardiovascular diseases. Single nucleotide polymorphisms (SNPs) in microRNA (miRNA) target sites, also known as miRSNPs, are known to enhance or weaken miRNA-mRNA interactions and have been linked to diseases such as cardiovascular disease and cancer. In this study, we aimed to elucidate the functional significance of the miRSNP rs1054564 in regulating GDF15 levels. Two rs1054564-containing binding sites for hsa-miR-873 5p and hsa-miR-1233-3p were identified in the 3' untranslated region (UTR) of the GDF15 transcript using bioinformatics tools. Their activities were further characterized by in vitro reporter assays. Bioinformatics prediction suggested that miRNA binding sites harboring the rs1054564-G allele had lower free energies than those with the C allele and therefore were better targets with higher affinities for both hsa-miR-873-5p and hsa-miR-1233-3p. Reporter assays showed that luciferase activity was significantly decreased by rs1054564-G-containing 3' UTRs for both miRNAs (P < 0.05) and was restored by miRNA inhibitors. Comparing the fold suppression of the two miRNAs, only that of hsa-miR-1233-3p showed significant changes between the rs1054564-G- and C-containing 3' UTRs (P = 0.034). In addition, western blots showed that transfection of both miRNA mimics significantly decreased endogenous GDF15 expression in a melanoma cell line (P < 0.05). Taken together, our findings demonstrate that GDF15 is a target of hsa-miR 873-5p and hsa-miR-1233-3p and that the rs1054564-C allele partially abolishes hsa-miR-1233-3p-mediated translational suppression of GDF15. These results suggest that rs1054564 confers allele-specific translational repression of GDF15 via hsa-miR-1233-3p. Our work thus provides biological insight into the previously reported clinical association between rs1054564 and plasma GDF15 levels. PMID- 28806403 TI - Th17 cells are associated with protection from ventilator associated pneumonia. AB - BACKGROUND: CD4+ T-helper 17 (Th17) cells and Interleukin (IL)-17A play an important role in clearing pathogens in mouse models of pneumonia. We hypothesized that numbers of Th17 cells and levels of IL-17A are associated with risk for nosocomial pneumonia in humans. METHODS: We collected bronchoalveolar lavage (BAL) fluid from mechanically ventilated (n = 25) patients undergoing quantitative bacterial culture to evaluate for ventilator associated pneumonia (VAP). We identified Th17 cells by positive selection of CD4+ cells, stimulation with ionomycin and PMA, then staining for CD4, CD45, CCR6, IL-17A, and IFN-gamma followed by flow cytometric analysis (n = 21). We measured inflammatory cytokine levels, including IL-17A, in BAL fluid by immunoassay. RESULTS: VAP was detected in 13 of the 25 subjects. We identified a decreased percentage of IL-17A producing Th17 cells in BAL fluid from patients with VAP compared to those without (p = 0.02). However, we found no significant difference in levels of IL 17A in patients with VAP compared to those without (p = 0.07). Interestingly, IL 17A levels did not correlate with Th17 cell numbers. IL-17A levels did show strong positive correlations with alveolar neutrophil numbers and total protein levels. CONCLUSIONS: Th17 cells are found at lower percentages in BAL fluid from mechanically ventilated patients with VAP and IL-17A levels correlated with Th17 cell percentages in non-VAP subjects, but not those with VAP. These findings suggest that Th17 cells may be protective against development of nosocomial pneumonia in patients receiving mechanical ventilation and that alveolar IL-17A in VAP may be derived from sources other than alveolar Th17 cells. PMID- 28806402 TI - Multi-functional mechanisms of immune evasion by the streptococcal complement inhibitor C5a peptidase. AB - The complement cascade is crucial for clearance and control of invading pathogens, and as such is a key target for pathogen mediated host modulation. C3 is the central molecule of the complement cascade, and plays a vital role in opsonization of bacteria and recruitment of neutrophils to the site of infection. Streptococcal species have evolved multiple mechanisms to disrupt complement mediated innate immunity, among which ScpA (C5a peptidase), a C5a inactivating enzyme, is widely conserved. Here we demonstrate for the first time that pyogenic streptococcal species are capable of cleaving C3, and identify C3 and C3a as novel substrates for the streptococcal ScpA, which are functionally inactivated as a result of cleavage 7 amino acids upstream of the natural C3 convertase. Cleavage of C3a by ScpA resulted in disruption of human neutrophil activation, phagocytosis and chemotaxis, while cleavage of C3 generated abnormally-sized C3a and C3b moieties with impaired function, in particular reducing C3 deposition on the bacterial surface. Despite clear effects on human complement, expression of ScpA reduced clearance of group A streptococci in vivo in wildtype and C5 deficient mice, and promoted systemic bacterial dissemination in mice that lacked both C3 and C5, suggesting an additional complement-independent role for ScpA in streptococcal pathogenesis. ScpA was shown to mediate streptococcal adhesion to both human epithelial and endothelial cells, consistent with a role in promoting bacterial invasion within the host. Taken together, these data show that ScpA is a multi-functional virulence factor with both complement-dependent and independent roles in streptococcal pathogenesis. PMID- 28806404 TI - RIG-I and IL-6 are negative-feedback regulators of STING induced by double stranded DNA. AB - The stimulator of interferon genes (STING) protein has emerged as a critical signal transduction molecule in the innate immune response. Sustained activation of the STING signaling induced by cytosolic DNA has been considered to be the cause of a variety of autoimmune diseases characterized by uncontrolled inflammation. Therefore, it is important to understand the molecular basis of the regulation of STING signaling pathway. Here we demonstrate that the STING protein undergoes a proteasome-mediated degradation in human diploid cell (HDC) lines including MRC-5 following the transfection of double-stranded DNA (dsDNA). The degradation of STING is accompanied by the increased expression of both RIG-I and IL-6. Employing the RIG-I siRNA knockdown and an IL-6 neutralizing antibody greatly inhibits the degradation of STING induced by dsDNA. We further demonstrate that both IL-6 and RIG-I are downstream molecules of STING along the DNA sensor pathway. Therefore, STING degradation mediated by RIG-I and IL-6 may serve as a negative feedback mechanism to limit the uncontrolled innate immune response induced by dsDNA. We have further shown that RIG-I and IL-6 promote STING degradation by activating/dephosphorylating UNC-51-like kinase (ULK1). Interestingly, the STING protein is not significantly affected by dsDNA in non HDC HEK293 cells. Our study thus has identified a novel signaling pathway for regulating STING in HDCs. PMID- 28806405 TI - Characterizing the influence of transportation infrastructure on Emergency Medical Services (EMS) in urban area-A case study of Seoul, South Korea. AB - In highly urbanized area where traffic condition fluctuates constantly, transportation infrastructure is one of the major contributing factors to Emergency Medical Service (EMS) availability and patient outcome. In this paper, we assess the impact of traffic fluctuation to the EMS first response availability in urban area, by evaluating the k-minute coverage under 21 traffic scenarios. The set of traffic scenarios represents the time-of-day and day-of week effects, and is generated by combining road link speed information from multiple historical speed databases. In addition to the k-minute area coverage calculation, the k-minute population coverage is also evaluated for every 100m by 100m grid that partitions the case study area of Seoul, South Korea. In the baseline case of traveling at the speed limit, both the area and population coverage reached nearly 100% when compared to the five-minute travel time national target. Employing the proposed LoST (Loss of Serviceability due to Traffic) index, which measures coverage reduction in percentage compared to the baseline case, we find that the citywide average LoST for area and population coverage are similar at 34.2% and 33.8%. However, district-wise analysis reveals that such reduction varies significantly by district, and the magnitude of area and population coverage reduction is not always proportional. We conclude that the effect of traffic variation is significant to successful urban EMS first response performance, and regional variation is evident among local districts. Complexity in the urban environment requires a more adaptive approach in public health resource management and EMS performance target determination. PMID- 28806406 TI - Terminal differentiation of T cells is strongly associated with CMV infection and increased in HIV-positive individuals on ART and lifestyle matched controls. AB - HIV-1-positive individuals on successful antiretroviral therapy (ART) are reported to have higher rates of age-associated non-communicable comorbidities (AANCCs). HIV-associated immune dysfunction has been suggested to contribute to increased AANCC risk. Here we performed a cross-sectional immune phenotype analysis of T cells in ART-treated HIV-1-positive individuals with undetectable vireamia (HIV-positives) and HIV-1-negative individuals (HIV-negatives) over 45 years of age. In addition, two control groups were studied: HIV negative adults selected based on lifestyle and demographic factors (Co-morBidity in Relation to AIDS, or COBRA) and unselected age-matched donors from a blood bank. Despite long term ART (median of 12.2 years), HIV-infected adults had lower CD4+ T-cell counts and higher CD8+ T-cell counts compared to well-matched HIV-negative COBRA participants. The proportion of CD38+HLA-DR+ and PD-1+ CD4+ T-cells was higher in HIV-positive cohort compared to the two HIV-negative cohorts. The proportion CD57+ and CD27-CD28- cells of both CD4+ and CD8+ T-cells in HIV-positives was higher compared to unselected adults (blood bank) as reported before but this difference was not apparent in comparison with well-matched HIV-negative COBRA participants. Multiple regression analysis showed that the presence of an increased proportion of terminally differentiated T cells was strongly associated with CMV infection. Compared to appropriately selected HIV-negative controls, HIV positive individuals on ART with long-term suppressed viraemia exhibited incomplete immune recovery and increased immune activation/exhaustion. CMV infection rather than treated HIV infection appears to have more consistent effects on measures of terminal differentiation of T cells. PMID- 28806407 TI - Low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet improves symptoms in adults suffering from irritable bowel syndrome (IBS) compared to standard IBS diet: A meta-analysis of clinical studies. AB - BACKGROUND: Irritable bowel syndrome (IBS) and functional digestive tract disorders, e.g. functional bloating, carbohydrate maldigestion and intolerances, are very common disorders frequently causing significant symptoms that challenge health care systems. A low Fermentable Oligosaccharides, Disaccharides, Monosaccharides and Polyols (FODMAP) diet is one of the possible therapeutic approaches for decreasing abdominal symptoms and improving quality of life. OBJECTIVES: We aimed to meta-analyze data on the therapeutic effect of a low FODMAP diet on symptoms of IBS and quality of life and compare its effectiveness to a regular, standard IBS diet with high FODMAP content, using a common scoring system, the IBS Symptom Severity Score (IBS-SSS). METHODS: A systematic literature search was conducted in PubMed, EMBASE and the Cochrane Library as well as in the references in a recent meta-analysis. Adult patients diagnosed with IBS according to the Rome II, Rome III, Rome IV or NICE criteria were included in the analysis. STATISTICAL METHODS: Mean differences with 95% confidence intervals were calculated from studies that contained means, standard deviation (SD) or mean differences and SD of differences and p-values. A random effect model was used because of the heterogeneity (Q test (chi2) and I2 indicator). A p-value of less than 0.05 was chosen to indicate a significant difference. RESULTS: The literature search yielded 902 publications, but only 10 were eligible for our meta-analysis. Both regular and low-FODMAP diets proved to be effective in IBS, but post-diet IBS-SSS values were significantly lower (p = 0.002) in the low-FODMAP group. The low-FODMAP diet showed a correlation with the improvement of general symptoms (by IBS-SSS) in patients with IBS. CONCLUSIONS: This meta-analysis provides high-grade evidence of an improved general symptom score among patients with irritable bowel syndrome who have maintained a low FODMAP diet compared to those on a traditional IBS diet, therefore showing its superiority to regular IBS dietary therapy. These data suggest that a low-FODMAP diet with dietitian control can be a candidate for first-line therapeutic modality in IBS. Because of a lack of data, well-planned randomized controlled studies are needed to ascertain the correlation between improvement of separate key IBS symptoms and the effect of a low-FODMAP diet. PMID- 28806408 TI - Microbiota of little penguins and short-tailed shearwaters during development. AB - The establishment and early colonisation of the gastrointestinal (GI) tract has been recognised as a crucial stage in chick development, with pioneering microbial species responsible for influencing the development of the GI tract and influencing host health, fitness and disease status throughout life. Development of the microbiota in long lived seabirds is poorly understood. This study characterised the microbial composition of little penguin and short-tailed shearwater chicks throughout development, using Quantitative Real Time PCR (qPCR) and 16S rRNA sequencing. The results indicated that microbial development differed between the two seabird species with the short-tailed shearwater microbiota being relatively stable throughout development whilst significant fluctuations in the microbial composition and an upward trend in the abundance of Firmicutes and Bacteroidetes were observed in the little penguin. When the microbial composition of adults and chicks was compared, both species showed low similarity in microbial composition, indicating that the adult microbiota may have a negligible influence over the chick's microbiota. PMID- 28806409 TI - The paradox of helping: Contradictory effects of scaffolding people with aphasia to communicate. AB - When interacting with people with aphasia, communication partners use a range of subtle strategies to scaffold, or facilitate, expression and comprehension. The present article analyses the unintended effects of these ostensibly helpful acts. Twenty people with aphasia and their main communication partners (n = 40) living in the UK were video recorded engaging in a joint task. Three analyses reveal that: (1) scaffolding is widespread and mostly effective, (2) the conversations are dominated by communication partners, and (3) people with aphasia both request and resist help. We propose that scaffolding is inherently paradoxical because it has contradictory effects. While helping facilitates performing an action, and is thus enabling, it simultaneously implies an inability to perform the action independently, and thus it can simultaneously mark the recipient as disabled. Data are in British English. PMID- 28806410 TI - The influence of speed abilities and technical skills in early adolescence on adult success in soccer: A long-term prospective analysis using ANOVA and SEM approaches. AB - Several talent development programs in youth soccer have implemented motor diagnostics measuring performance factors. However, the predictive value of such tests for adult success is a controversial topic in talent research. This prospective cohort study evaluated the long-term predictive value of 1) motor tests and 2) players' speed abilities (SA) and technical skills (TS) in early adolescence. The sample consisted of 14,178 U12 players from the German talent development program. Five tests (sprint, agility, dribbling, ball control, shooting) were conducted and players' height, weight as well as relative age were assessed at nationwide diagnostics between 2004 and 2006. In the 2014/15 season, the players were then categorized as professional (n = 89), semi-professional (n = 913), or non-professional players (n = 13,176), indicating their adult performance level (APL). The motor tests' prognostic relevance was determined using ANOVAs. Players' future success was predicted by a logistic regression threshold model. This structural equation model comprised a measurement model with the motor tests and two correlated latent factors, SA and TS, with simultaneous consideration for the manifest covariates height, weight and relative age. Each motor predictor and anthropometric characteristic discriminated significantly between the APL (p < .001; eta2 <= .02). The threshold model significantly predicted the APL (R2 = 24.8%), and in early adolescence the factor TS (p < .001) seems to have a stronger effect on adult performance than SA (p < .05). Both approaches (ANOVA, SEM) verified the diagnostics' predictive validity over a long-term period (~ 9 years). However, because of the limited effect sizes, the motor tests' prognostic relevance remains ambiguous. A challenge for future research lies in the integration of different (e.g., person-oriented or multilevel) multivariate approaches that expand beyond the "traditional" topic of single tests' predictive validity and toward more theoretically founded issues. PMID- 28806411 TI - Cross-sectional area of the femoral vein varies with leg position and distance from the inguinal ligament. AB - PURPOSE: The risk of complications associated with femoral venous catheterization could be potentially reduced if the procedure was performed at the location where the cross-sectional area (CSA) of the vessel is the largest. The diameter of the femoral vein depends on leg position as well as the distance from the inguinal ligament. We determined the CSA of the right femoral vein in three different leg positions at two distances from the inguinal ligament. SUBJECTS AND METHODS: Informed consent was given by 205 healthy volunteers aged 19-39 years, mean: 23+/ 3 years (108 women, 97 men). Ultrasonographic examinations were performed using a linear 14-MHz transducer with CSA measurements in three leg positions: abduction, abduction+external rotation, abduction+external rotation+90 degrees knee flexion/frog-leg position; at levels 20 mm caudally to the inguinal ligament, and 20 mm caudally to the inguinal crease. RESULTS: We found significant differences in mean values of CSA in three leg positions regardless of the measurement level. The largest mean CSA (114 mm2+/-35 mm2) was found at the proximal level in the frog-leg position. There was a significant association of the CSA with sex and height. The CSA in males was greater than in females in all leg positions at the level of 20 mm caudally to the inguinal crease, while 20 mm caudally to the inguinal ligament the CSA was larger in females. The CSA of 25% of the femoral vein was smaller than 45.0 mm2 at the proximal level, and 31.5 mm2 at the distal level, which refers to diameters of 5.3 mm, and 4.5 mm, respectively. CONCLUSIONS: The cross-sectional area of the femoral vein is the largest in the frog-leg position, and depends on gender. PMID- 28806412 TI - Missed opportunities for HIV control: Gaps in HIV testing for partners of people living with HIV in Lima, Peru. AB - INTRODUCTION: Based on the hypothesis that HIV programs struggle to deliver health services that harmonize necessities of treatment and prevention, we described the outcomes of routinely provided HIV testing to partners of people living with HIV (PLWH) through a secondary analysis of routine data collected at a public hospital in Lima, Peru. METHODS: Among PLWH enrolled in the study center's HIV program between 2005 and 2014, we identified index cases (IC): PLWH who reported a unique partner not previously enrolled. We grouped partners according to their HIV status as reported by IC and collected data on HIV testing, clinical characteristics and admissions. The main outcome was the frequency of HIV testing among partners with reported unknown/seronegative HIV status. RESULTS: Out of 1586 PLWH who reported a unique partner at enrollment, 171 had a previously enrolled partner, leaving 1415 (89%) IC. HIV status of the partner was reported as unknown in 571 (40%), seronegative in 325 (23%) and seropositive in 519 (37%). Out of 896 partners in the unknown/seronegative group, 72 (8%) had HIV testing, 42/72 (58%) tested within three months of IC enrollment. Among the 49/72 (68%) who tested positive for HIV, 33 (67%) were enrolled in the HIV program. The proportion in WHO clinical stage IV was lower in enrolled partners compared to IC (37% vs 9%, p = 0.04). Non-tested partners (824) were likely reachable by the hospital, as 297/824 (36%) of their IC were admitted in the study center at least once, 51/243 (21%) female IC had received pregnancy care at the study center, and 401/692 (64%) of IC on antiretroviral therapy had achieved viral suppression, implying frequent visits to the hospital for pill pick-up. CONCLUSION: In this setting, HIV testing of partners of PLWH was suboptimal, illustrating missed opportunities for HIV control. Integration of HIV strategies in primarily clinical-oriented services is a challenging need. PMID- 28806413 TI - Reply & Supply: Efficient crowdsourcing when workers do more than answer questions. AB - Crowdsourcing works by distributing many small tasks to large numbers of workers, yet the true potential of crowdsourcing lies in workers doing more than performing simple tasks-they can apply their experience and creativity to provide new and unexpected information to the crowdsourcer. One such case is when workers not only answer a crowdsourcer's questions but also contribute new questions for subsequent crowd analysis, leading to a growing set of questions. This growth creates an inherent bias for early questions since a question introduced earlier by a worker can be answered by more subsequent workers than a question introduced later. Here we study how to perform efficient crowdsourcing with such growing question sets. By modeling question sets as networks of interrelated questions, we introduce algorithms to help curtail the growth bias by efficiently distributing workers between exploring new questions and addressing current questions. Experiments and simulations demonstrate that these algorithms can efficiently explore an unbounded set of questions without losing confidence in crowd answers. PMID- 28806414 TI - Alpha-tocopherol attenuates the anti-tumor activity of crizotinib against cells transformed by NPM-ALK. AB - Anaplastic large cell lymphomas (ALCL) are mainly characterized by harboring the fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The ALK inhibitor, crizotinib specifically induced apoptosis in Ba/F3 cells expressing NPM-ALK by inhibiting the activation of NPM-ALK and its downstream molecule, signal transducer and activator of transcription factor 3 (STAT3). We found that alpha-tocopherol, a major component of vitamin E, attenuated the effects of crizotinib independently of its anti-oxidant properties. Although alpha tocopherol suppressed the inhibitory effects of crizotinib on the signaling axis including NPM-ALK and STAT3, it had no influence on the intake of crizotinib into cells. Crizotinib also directly inhibited the kinase activity of NPM-ALK; however, this inhibitory effect was not altered by the co-treatment with alpha tocopherol. Whereas the nuclear localization of NPM-ALK was disappeared by the treatment with crizotinib, the co-treatment with alpha-tocopherol swept the effect of crizotinib and caused the localization of NPM-ALK in nucleus. The administration of alpha-tocopherol attenuated the anti-tumor activity of crizotinib against NPM-ALK-provoked tumorigenesis in vivo. Furthermore, the alpha tocopherol-induced inhibition of crizotinib-caused apoptosis was also observed in NPM-ALK-positive cells derived from ALCL patients, namely, SUDHL-1 and Ki-JK. Collectively, these results not only revealed the novel mechanism underlying crizotinib-induced apoptosis in NPM-ALK-positive cells, but also suggest that the anti-tumor effects of crizotinib are attenuated when it is taken in combination with vitamin E. PMID- 28806415 TI - Synthetic mRNA is a more reliable tool for the delivery of DNA-targeting proteins into the cell nucleus than fusion with a protein transduction domain. AB - Cell reprogramming requires efficient delivery of reprogramming transcription factors into the cell nucleus. Here, we compared the robustness and workload of two protein delivery methods that avoid the risk of genomic integration. The first method is based on fusion of the protein of interest to a protein transduction domain (PTD) for delivery across the membranes of target cells. The second method relies on de novo synthesis of the protein of interest inside the target cells utilizing synthetic mRNA (syn-mRNA) as a template. We established a Cre/lox reporter system in three different cell types derived from human (PANC-1, HEK293) and rat (BRIN-BD11) tissues and used Cre recombinase to model a protein of interest. The system allowed constitutive expression of red fluorescence protein (RFP), while green fluorescence protein (GFP) was expressed only after the genomic action of Cre recombinase. The efficiency of protein delivery into cell nuclei was quantified as the frequency of GFP+ cells in the total cell number. The PTD method showed good efficiency only in BRIN-BD11 cells (68%), whereas it failed in PANC-1 and HEK293 cells. By contrast, the syn-mRNA method was highly effective in all three cell types (29-71%). We conclude that using synthetic mRNA is a more robust and less labor-intensive approach than using the PTD-fusion alternative. PMID- 28806416 TI - The impact of malignant nipple discharge cytology (NDc) in surgical management of breast cancer patients. AB - BACKGROUND: The role of nipple discharge cytology (NDc) in the surgical management of breast cancer patients is unclear. We aimed: (i) to evaluate the effect of malignant NDc on the surgical approach to the nipple-areola complex, and (ii) to verify the association between malignant NDc and nipple malignancy. METHODS: We retrospectively analyzed a case series of 139 patients with NDc who underwent breast surgery. The clinical and histological findings, types of surgery with emphasis on nipple-areola complex amputation, immunohistochemical phenotypes of the carcinomas and measurements of the tumor-nipple distance were recorded. Additionally, in patients who showed HER2-positive lesions on definitive surgery, we evaluated the HER2 immunocytochemistry of the NDc smears. RESULTS: Thirty-two malignant and 107 benign/borderline NDc diagnoses were identified. All 32 malignant-NDc cases were histologically confirmed as malignant. Thirty borderline/benign-NDc cases were histologically diagnosed as malignant (sensitivity 58%). The majority of the patients with malignant NDc were treated with nipple-areola complex amputations in both the mastectomy and conservative surgery groups (P<0.001, chi251.77). Nipple involvement was strongly associated with HER2-positive ductal carcinoma in-situ (P<0.001, chi211.98). HER2 immunocytochemistry on the NDc revealed a 100% correlation with the immunocytochemistry performed on the surgical tissues. CONCLUSIONS: Malignant NDc influenced surgical management. The association of malignant NDc with nipple involvement is highly related to ductal carcinoma in-situ with HER2 overexpression. In case of HER2 positive NDc, nipple-areola complex involvement is more likely than in HER2 negative cases. PMID- 28806417 TI - Phonetic complexity affects children's Mandarin tone production accuracy in disyllabic words: A perceptual study. AB - This is the first study to examine the effect of phonetic contexts on children's lexical tone production. Mandarin tones in disyllabic words produced by forty four 2- to 6-year-old children and twelve mothers were low-pass filtered to eliminate lexical information. Native Mandarin-speaking adults categorized the tones based on the pitch information in the filtered stimuli. All mothers' tones were categorized with ceiling accuracy. Counter to the findings in most previous studies on children's tone acquisition and the prevailing assumption in models of speech development that children acquire suprasegmental features much earlier than segmental features, this study found that children as old as six years of age have not mastered the production of Mandarin tones. Children's tones were judged with significantly lower accuracy than mothers' productions. Tone accuracy improved, while cross subject variability in tone accuracy decreased, with age. Children's tone accuracy was affected by the articulatory complexity of phonetic contexts. Children made more errors in tone combinations with more complex fundamental frequency (F0) contours than tone sequences with simpler F0 changes. When producing disyllabic tone sequences with complex F0 contours, children tended to shift the F0 contour of the first tone to reduce the F0 change, resulting in more tone errors in the first syllable than in the second syllable and showing substantially more anticipatory coarticulation than adults. The results provide further evidence that acquisition of lexical tones is a protracted process in children. Tones produced accurately by children in one phonetic context may not be produced correctly in another phonetic context. Children demonstrate more anticipatory coarticulation in their disyllabic productions than adults, which may be attributed to children's immature speech motor control in tone production, and is presumably a by-product of their inability to accomplish complex F0 changes within the syllable time-frame. PMID- 28806418 TI - Seasonality affects dietary diversity of school-age children in northern Ghana. AB - BACKGROUND AND OBJECTIVES: Dietary diversity score (DDS) is relatively easy to measure and is shown to be a very useful indicator of the probability of adequate micronutrient intake. Dietary diversity, however, is usually assessed during a single period and little is known about the effect of seasonality on it. This study investigates whether dietary diversity is influenced by seasonality. METHODS: Two cross-sectional surveys were conducted in two different seasons-dry season (October 2010) and rainy season (May 2011) among the same school-age children (SAC) in two rural schools in northern Ghana. The study population consisted of 228 school-age children. A qualitative 24-hour dietary recall was conducted in both seasons. Based on 13 food groups, a score of 1 was given if a child consumed a food item belonging to a particular food group, else 0. Individual scores were aggregated into DDS for each child. Differences in mean DDS between seasons were compared using linear mixed model analysis. RESULTS: The dietary pattern of the SAC was commonly plant foods with poor consumption of animal source foods. The mean DDS was significantly higher (P < 0.001) in the rainy season (6.95 +/- 0.55) compared to the dry season (6.44 +/- 0.55) after adjusting for potential confounders such as age, sex, occupation (household head and mother) and education of household head. The difference in mean DDS between dry and rainy seasons was mainly due to the difference in the consumption of Vitamin A-rich fruits and vegetables between the seasons. While vitamin A-rich fruits (64.0% vs. 0.9%; P < 0.0001) and vitamin A rich dark green leafy vegetables (52.6% vs. 23.3%, P < .0001) were consumed more during the rainy season than the dry season, more children consumed vitamin A-rich deep yellow, orange and red vegetables during the dry season than during the rainy season (73.7% vs. 36.4%, P <0.001). CONCLUSION: Seasonality has an effect on DDS and may affect the quality of dietary intake of SAC; in such a context, it would be useful to measure DDS in different seasons. Since DDS is a proxy indicator of micronutrient intake, the difference in DDS may reflect in seasonal differences in dietary adequacy and further studies are needed to establish this. PMID- 28806419 TI - Effects of short-term dry immersion on bone remodeling markers, insulin and adipokines. AB - BACKGROUND: Dry immersion (DI), a ground-based model of microgravity previously used in Russia, has been recently implemented in France. The aim of this study was to analyze early events in a short-term DI model in which all conditions are met to investigate who is first challenged from osteo- or adipo-kines and to what extent they are associated to insulin-regulating hormones. METHODS: Twelve healthy men were submitted to a 3-day DI. Fasting blood was collected during pre immersion phase for the determination of the baseline data collection (BDC), daily during DI (DI24h, DI48H and DI72h), then after recovery (R+3h and R+24h). Markers of bone turnover, phosphocalcic metabolism, adipokines and associated factors were measured. RESULTS: Bone resorption as assessed by tartrate-resistant acid phosphatase isoform 5b and N-terminal crosslinked telopeptide of type I collagen levels increased as early as DI24h. At the same time, total procollagen type I N- and C-terminal propeptides and osteoprotegerin, representing bone formation markers, decreased. Total osteocalcin [OC] was unaffected, but its undercarboxylated form [Glu-OC] increased from DI24h to R+3h. The early and progressive increase in bone alkaline phosphatase activities suggested an increased mineralization. Dickkopf-1 and sclerostin, as negative regulators of the Wnt-beta catenin pathway, were unaltered. No change was observed either in phosphocalcic homeostasis (calcium and phosphate serum levels, 25-hydroxyvitamin D, fibroblast growth factor 23 [FGF23]) or in inflammatory response. Adiponectemia was unchanged, whereas circulating leptin concentrations increased. Neutrophil gelatinase-associated lipocalin [lipocalin-2], a potential regulator of bone homeostasis, was found elevated by 16% at R+3h compared to DI24h. The secretory form of nicotinamide phosphoribosyl-transferase [visfatin] concentrations almost doubled after one day of DI and remained elevated. Serum insulin-like growth factor 1 levels progressively increased. Fasting insulin concentrations increased during the entire DI, whereas fasting glucose levels tended to be higher only at DI24h and then returned to BDC values. Changes in bone resorption parameters negatively correlated with changes in bone formation parameters. Percent changes of ultra-sensitive C-reactive protein positively correlated with changes in osteopontin, lipocalin-2 and fasting glucose. Furthermore, a positive correlation was found between changes in FGF23 and Glu OC, the two main osteoblast-/osteocyte-derived hormones. CONCLUSION: Our results demonstrated that DI induced an unbalanced remodeling activity and the onset of insulin resistance. This metabolic adaptation was concomitant with higher levels of Glu-OC. This finding confirms the role of bone as an endocrine organ in humans. Furthermore, visfatin for which a great responsiveness was observed could represent an early and sensitive marker of unloading in humans. PMID- 28806421 TI - The effect of Fe2O3 crystal phases on CO2 hydrogenation. AB - The effect of Fe2O3 crystal phases on their performance in CO2 hydrogenation was studied. alpha-Fe2O3 crystal was prepared by precipitation method from Fe(NO3)3.9H2O and (NH4)2CO3, and gamma-Fe2O3 was prepared by grinding Fe(NO3)3.9H2O and L(+)-Tartaric acid in agate mortar completely. The crystal phases of Fe2O3 influence the distribution of promoter Zn, K and Cu on catalysts. The dispersity of K on gamma-Fe2O3 surface is higher than alpha-Fe2O3. On the contrary, Cu and Zn are more dispersive on alpha-Fe2O3 surface than gamma-Fe2O3. The catalyst in gamma-Fe2O3 phase is easily reduced relative to the catalyst in alpha-Fe2O3 phase. The former presents higher CO2 conversion and C2+ hydrocarbon selectivity than the latter in CO2 hydrogenation. PMID- 28806420 TI - Perceptions of health risks of cigarette smoking: A new measure reveals widespread misunderstanding. AB - Most Americans recognize that smoking causes serious diseases, yet many Americans continue to smoke. One possible explanation for this paradox is that perhaps Americans do not accurately perceive the extent to which smoking increases the probability of adverse health outcomes. This paper examines the accuracy of Americans' perceptions of the absolute risk, attributable risk, and relative risk of lung cancer, and assesses which of these beliefs drive Americans' smoking behavior. Using data from three national surveys, statistical analyses were performed by comparing means, medians, and distributions, and by employing Generalized Additive Models. Perceptions of relative risk were associated as expected with smoking onset and smoking cessation, whereas perceptions of absolute risk and attributable risk were not. Additionally, the relation of relative risk with smoking status was stronger among people who held their risk perceptions with more certainty. Most current smokers, former smokers, and never smokers considerably underestimated the relative risk of smoking. If, as this paper suggests, people naturally think about the health consequences of smoking in terms of relative risk, smoking rates might be reduced if public understanding of the relative risks of smoking were more accurate and people held those beliefs with more confidence. PMID- 28806422 TI - Silver nanoparticles as a control agent against facades coated by aerial algae-A model study of Apatococcus lobatus (green algae). AB - Aerial algae are an important biological factor causing the biodegradation of building materials and facades. Conservation procedures aimed at the protection of historic and utility materials must be properly designed to avoid an increase of the degradation rate. The aim of the present study was to investigate the effect of silver nanoparticles (AgNP) synthetized with features contributing to the accessibility and toxicity (spherical shape, small size) on the most frequently occurring species of green algae in aerial biofilms and thus, the most common biodegradation factor-Apatococcus lobatus. Changes in the chloroplasts structure and the photosynthetic activity of the cells under AgNP exposure were made using confocal laser microscopy and digital image analysis and the estimation of growth inhibition rate was made using a biomass assay. In the majority of cases, treatment with AgNP caused a time and dose dependant degradation of chloroplasts and decrease in the photosynthetic activity of cells leading to the inhibition of aerial algae growth. However, some cases revealed an adaptive response of the cells. The response was induced by either a too low, or after a short time-too high concentration of AgNP. Taken together, the data suggest that AgNP may be used as a biocide against aerial algal coatings; however, with a proper caution related to the concentration of the nanoparticles. PMID- 28806423 TI - New synthetic lipid antigens for rapid serological diagnosis of tuberculosis. AB - BACKGROUND: During pulmonary tuberculosis (PTB) antibodies are generated to trehalose esters of mycolic acids which are cell wall lipids of Mycobacterium tuberculosis (Mtb). Attempts have been made to use these complex natural mixtures in serological tests for PTB diagnosis. AIM: The aim of this work was to determine whether a serological test based on a panel of defined individual trehalose esters of characteristic synthetic mycolic acids has improved diagnostic accuracy in distinguishing patients with culture positive PTB from individuals who were Mtb culture negative. METHOD: One hundred serum samples from well-characterized patients with presumptive tuberculosis, and diagnosed as having pulmonary smear and culture positive TB, or being culture and smear negative were evaluated by ELISA using different combinations of synthetic antigens and secondary antibodies. Using cut-off values determined from these samples, we validated this study blind in samples from a further 249 presumptive TB patients. RESULTS: With the first 100 samples, detailed responses depended both on the precise structure of the antigen and on the secondary antibody. Using a single antigen, a sensitivity/specificity combination for smear and culture positive PTB detection of 85 and 88% respectively was achieved; this increased to 96% and 95% respectively by a statistical combination of the results with seven antigens. In the blind study a sensitivity/specificity of 87% and 83% was reached with a single antigen. With some synthetic antigens, the responses from all 349 samples were significantly better than those with the natural mixture. Combining the results for seven antigens allowed a distinction between culture positive and negative with a ROC AUC of 0.95. CONCLUSION: We have identified promising antigen candidates for serological assays that could be used to diagnose PTB and which could be the basis of a much-needed, simple, rapid diagnostic test that would bring care closer to communities. PMID- 28806424 TI - Geometric Evaluation of the Effect of Prosthetic Rehabilitation on the Facial Appearance of Mandibulectomy Patients: A Preliminary Study. AB - PURPOSE: The purpose of this study was to geometrically evaluate the effect of prosthetic rehabilitation on the facial appearance of mandibulectomy patients. MATERIALS AND METHODS: Facial scans (with and without prostheses) were performed for 16 mandibulectomy patients using a noncontact three-dimensional (3D) digitizer, and 3D images were reconstructed with the corresponding software. The 3D datasets were geometrically evaluated and compared using 3D evaluation software. RESULTS: The mean difference in absolute 3D deviations for full face scans was 382.2 MUm. CONCLUSION: This method may be useful in evaluating the effect of conventional prostheses on the facial appearance of individuals with mandibulectomy defects. PMID- 28806425 TI - Impact of Different Surgeons on Dental Implant Failure. AB - PURPOSE: To assess the influence of several factors on the prevalence of dental implant failure, with special consideration of the placement of implants by different dental surgeons. MATERIALS AND METHODS: This retrospective study is based on 2,670 patients who received 10,096 implants at one specialist clinic. Only the data of patients and implants treated by surgeons who had inserted a minimum of 200 implants at the clinic were included. Kaplan-Meier curves were stratified with respect to the individual surgeon. A generalized estimating equation (GEE) method was used to account for the fact that repeated observations (several implants) were placed in a single patient. The factors bone quantity, bone quality, implant location, implant surface, and implant system were analyzed with descriptive statistics separately for each individual surgeon. RESULTS: A total of 10 surgeons were eligible. The differences between the survival curves of each individual were statistically significant. The multivariate GEE model showed the following variables to be statistically significant: surgeon, bruxism, intake of antidepressants, location, implant length, and implant system. The surgeon with the highest absolute number of failures was also the one who inserted the most implants in sites of poor bone and used turned implants in most cases, whereas the surgeon with the lowest absolute number of failures used mainly modern implants. Separate survival analyses of turned and modern implants stratified for the individual surgeon showed statistically significant differences in cumulative survival. CONCLUSION: Different levels of failure incidence could be observed between the surgeons, occasionally reaching significant levels. Although a direct causal relationship could not be ascertained, the results of the present study suggest that the surgeons' technique, skills, and/or judgment may negatively influence implant survival rates. PMID- 28806426 TI - Comparative Evaluation of the Effect of Laser Etching on the Shear Bond Strength of Crowns Cemented with Two Different Luting Agents: An In Vitro Study. AB - PURPOSE: The aim of this study was to compare the shear bond strength of crowns cemented on natural teeth after surface treatment of the enamel with an erbium doped yttrium aluminum garnet (Er:YAG) laser. MATERIALS AND METHODS: Crown preparation was done for 40 full-metal crowns, and wax patterns with loops were cast in a cobalt-chromium alloy. The Er:YAG laser was used for surface treatment of some teeth, and teeth without surface treatment acted as the control. Glass ionomer and self-adhesive resin luting cements were used for cementation. Shear bond strength was tested using a universal testing machine, and statistical analysis was done using paired t test. Scanning electron microscopy analysis was also carried out to study alterations of the enamel and dentin surfaces. RESULTS: Significant increase in shear strength was noted after laser etching the teeth with Er:YAG laser for both types of cement (P < .0001). CONCLUSION: The results showed that surface treatment using an Er:YAG laser resulted in significant increase in retention of crowns. PMID- 28806427 TI - Fixed Dental Prostheses and Single-Tooth Crowns Based on Ceria-Stabilized Tetragonal Zirconia/Alumina Nanocomposite Frameworks: Outcome After 2 Years in a Clinical Trial. AB - PURPOSE: This clinical trial tested bilayered restorations based on ceria stabilized tetragonal zirconia/alumina frameworks veneered with feldspathic ceramic. MATERIALS AND METHODS: A total of 67 crowns and 40 fixed dental prostheses (FDPs) were luted in 57 patients with self-etching/self-adhesive composite resin cement. Dental status and integrity of restorations were evaluated at 2 weeks, 6 months, and then annually. RESULTS: A total of 66 crowns and 36 FDPs (88% posterior) survived for success rates of 93.4% for crowns and 89% for FDPs at 2 years. In particular, 11 cohesive ceramic chippings were observed in 5 crowns and 6 FDPs. CONCLUSION: The material allows excellent marginal adaptation. Susceptibility to veneering failures might be due to framework design and the necessities of esthetics. PMID- 28806429 TI - Current Concepts of Bruxism. AB - Bruxism is a common phenomenon, and emerging evidence suggests that biologic, psychologic, and exogenous factors have greater involvement than morphologic factors in its etiology. Diagnosis should adopt the grading system of possible, probable, and definite. In children, it could be a warning sign of certain psychologic disorders. The proposed mechanism for the bruxism-pain relationship at the individual level is that stress sensitivity and anxious personality traits may be responsible for bruxism activities that may lead to temporomandibular pain, which in turn is modulated by psychosocial factors. A multiple-P (plates, pep talk, psychology, pills) approach involving reversible treatments is recommended, and adult prosthodontic management should be based on a common-sense cautionary approach. PMID- 28806428 TI - Antibacterial Effect of Provisional Cements with Incorporated Polyethyleneimine Nanoparticles: An In Vivo Study. AB - PURPOSE: Provisional restorations exhibit various degrees of microleakage when cemented. Incorporation of quaternized polyethyleneimine nanoparticles (QPEI) into provisional cements may be effective against bacteria in vivo. MATERIALS AND METHODS: Nine polymethylmethacrylate provisional restorations in human volunteers were evaluated after cementation with and without QPEI nanoparticles. Bacterial load in the provisional cement was assessed after 1 week of cementation. RESULTS: The number of colony-forming units in the cement with QPEI was significantly lower (P < .05) than in the control cement. CONCLUSION: The results of this in vivo study clearly indicate that provisional cement incorporating QPEI nanoparticles significantly reduces viable bacterial counts in the provisional cement in all patients. PMID- 28806430 TI - A Randomized Controlled Trial of Mastication with Complete Dentures Made by a Conventional or an Abbreviated Technique. AB - PURPOSE: The aim of this randomized clinical trial was to test the hypothesis that there are no statistically significant differences after 3 and 6 months in masticatory performance or chewing ability of people with new complete dentures made by an abbreviated or a conventional technique. MATERIALS AND METHODS: The trial included 20 edentulous participants at a dental school in Brazil assigned randomly to receive dentures made by either a conventional technique involving six clinical sessions or by an abbreviated technique involving three clinical sessions. At baseline with old dentures and at 3 and 6 months with new dentures, masticatory performance was measured by counting the number of chewing strokes and the time before participants had an urge to swallow and by calculating the medium particle size of a silicone material after 20 chewing strokes and at the urge to swallow. On each occasion, the participants recorded on visual analog scales their ability to chew five food textures. Statistical significance (P <= .05) of changes in masticatory performance and chewing ability during the trial were analyzed with generalized estimating equations. RESULTS: Both techniques improved masticatory performance between baseline and 6 months and the ability to bite and chew all foods apart from hard apples. CONCLUSION: There were no significant differences in masticatory performance or chewing ability after 6 months between complete dentures made by a conventional or an abbreviated technique. PMID- 28806431 TI - Association Between Personality Traits and Oral Health-Related Quality of Life: A Cross-Sectional Study. AB - PURPOSE: The aim of this study was to investigate the oral health-related quality of life (OHRQoL) among subjects with typical, atypically positive, and atypically negative personality trait scores within the five basic dimensions of personality (neuroticism, extroversion, openness, agreeableness, and conscientiousness). MATERIALS AND METHODS: A total of 235 subjects not seeking dental treatment were recruited from the families and acquaintances of dental students from the University of Salamanca. The 14-item Oral Health Impact Profile (OHIP-14) was used to capture the impact on their OHRQoL. The Neouroticism-Extroversion Openness Personality Inventory Revised was applied to assess personality profiles. People were classified as having negatively atypical, typical, or positively atypical (PAP) personality, depending on whether the sum of the Z scores was < -1, between -1 and 1, or > 1, respectively. Pearson correlation, analysis of variance, and logistic regression test were used for the statistical analyses. RESULTS: The sample was comprised of highly educated adults (aged 18-80 years) with good oral health habits. PAP subjects suffered significantly more in the dimension of psychologic discomfort (0.6 +/- 0.7) than did their counterparts (0.3 +/- 0.6), but the global impact in OHRQoL was comparable. Personality was weakly correlated with OHIP-14. The perception of dental treatment needs was found to be the major predictor of the impact on OHRQoL, but the number of negatively atypical deviated personality traits and the agreeableness raw score also had an effect. CONCLUSION: The risk of perceiving an impact on OHRQoL is significantly higher in individuals perceiving treatment needs and increases proportionally to the number of negatively atypical personality traits. PMID- 28806433 TI - Incorrect Number in Figure. PMID- 28806432 TI - Post-and-Core Restoration of Severely Damaged Permanent Posterior Teeth in Young Adolescents. AB - PURPOSE: This retrospective study evaluated the survival rates of postendodontic severely decayed posterior permanent teeth in young adolescents. MATERIALS AND METHODS: A total of 48 teeth (patient age range: 8.8-16.9 years) restored with a Kurer post- and core-system (Anchor System, Kurer K4) were assessed. Follow-up appointments 1 to 6 years posttreatment included radiographs and a clinical examination. RESULTS: A total of 5 teeth (10.4%) were extracted, and 13 restorations (27%) required repair. Average restoration-to-failure time was 27 months (SD 12.2 months). CONCLUSION: In view of these findings, clinicians should consider post-and-core restorations an alternative to extractions of endodontically treated severely damaged teeth in adolescents. PMID- 28806434 TI - Light Therapy Promoting Dopamine Release by Stimulating Retina in Parkinson Disease-Reply. PMID- 28806435 TI - Light Therapy Promoting Dopamine Release by Stimulating Retina in Parkinson Disease. PMID- 28806437 TI - Association Between Enactment of a "Stand Your Ground" Self-defense Law and Unlawful Homicides in Florida. PMID- 28806438 TI - Unnecessary Staging Imaging in Early-Stage Breast Cancer: A Teachable Moment. PMID- 28806436 TI - Effectiveness of a Timing and Coordination Group Exercise Program to Improve Mobility in Community-Dwelling Older Adults: A Randomized Clinical Trial. AB - Importance: Timing and coordination exercises may be an important addition to community-based health promotion exercise programs to improve walking in older adults. Objective: To compare the effectiveness of the On the Move group exercise program, which focuses on the timing and coordination of movement, with a seated strength, endurance, and flexibility program (usual care) at improving function, disability, and walking ability of older adults. Design, Setting, and Participants: Cluster-randomized, single-blind intervention trial. Thirty-two independent living facilities, senior apartment buildings, and senior community centers were randomized to On the Move (16 sites; 152 participants) or usual care (16 sites; 146 participants). Participants were 65 years or older, able to ambulate independently with a gait speed of at least 0.60 m/s, able to follow 2 step commands, and were medically stable. Interventions: Exercise classes were 50 minutes, twice a week for 12 weeks and had 10 or fewer participants per class. On the Move consisted of warm-up, timing and coordination (stepping and walking patterns), strengthening, and stretching exercises. The usual-care program consisted of warm-up, strength, endurance, and stretching exercises. Main Outcomes and Measures: The primary outcomes were self-report of function and disability (Late Life Function and Disability Instrument) and mobility (6-minute walk distance and gait speed) assessed by blinded individuals. Results: Participants (mean [SD] age, 80.0 [8.1] years) were mostly female (251 [84.2%]) and white (249 [83.6%]) and had a mean (SD) of 2.8 (1.4) chronic conditions. Intervention groups were similar on baseline characteristics. Postintervention, 142 (93.4%) participants in On the Move and 139 (95.2%) participants in usual care completed testing. On the Move had greater mean (SD) improvements than the usual-care group in gait speed (0.05 [0.13] vs -0.01 [0.11] m/s; adjusted difference = 0.05 [0.02] m/s; P = .002) and 6-minute walk distance (20.6 [57.1] vs 4.1 [55.6] m; adjusted difference = 16.7 [7.4] m; P = .03). Attendance was greater in the usual-care program compared with On the Move (95 [65.1%] vs 76 [50.0%] attended >=20 classes; P = .03). There were no significant differences in any of the other primary or secondary outcomes. Conclusions and Relevance: The On the Move group exercise program was more effective at improving mobility than a usual-care exercise program, despite lower attendance. Additional research examining the impact of the intervention on long-term disability outcomes is needed before recommending routine implementation into clinical practice. Trial Registration: clinicaltrials.gov Identifier: NCT01986647. PMID- 28806439 TI - Hazards of Neurological Nomenclature: Observations From Neurodevelopmental and Neurodegenerative Disorders. PMID- 28806440 TI - Considerations on the Off-label Use of Ketamine as a Treatment for Mood Disorders. PMID- 28806441 TI - Early-Onset Sepsis Calculator-Risk of Delaying Treatment. PMID- 28806443 TI - Addition of Open Access, Funding/Support, and Role of Funder/Sponsor Information. PMID- 28806442 TI - Communicating About Vaccines in a Fact-Resistant World. PMID- 28806444 TI - Eliminating Creatine Kinase-Myocardial Band Testing in Suspected Acute Coronary Syndrome: A Value-Based Quality Improvement. AB - Cardiac biomarker testing is estimated to occur in nearly 30 million emergency department visits nationwide each year in the United States. The American College of Cardiology/European Society of Cardiology indicate that cardiac troponin is the biomarker of choice owing to its nearly absolute myocardial tissue specificity and high clinical sensitivity for myocardial injury. Multiple academic medical centers have implemented interventions to eliminate the routine ordering of creatine kinase-myocardial band tests, with published patient safety outcomes data; however, creatine kinase-myocardial band testing is still ordered in many hospitals and emergency departments. Eliminating a simple laboratory test that provides no incremental value to patient care can lead to millions of health care dollars saved without adversely affecting patient care quality, and in this case potentially improving patient care. PMID- 28806445 TI - Use of Laboratory Markers in Addition to Symptoms for Diagnosis of Inflammatory Bowel Disease in Children: A Meta-analysis of Individual Patient Data. AB - Importance: Blood markers and fecal calprotectin are used in the diagnostic workup for inflammatory bowel disease (IBD) in pediatric patients. Any added diagnostic value of these laboratory markers remains unclear. Objective: To determine whether adding laboratory markers to evaluation of signs and symptoms improves accuracy when diagnosing pediatric IBD. Data Sources: A literature search of MEDLINE and EMBASE from inception through September 26, 2016. Studies were identified using indexing terms and free-text words related to child, target condition IBD, and diagnostic accuracy. Study Selection: Two reviewers independently selected studies evaluating the diagnostic accuracy of more than 1 blood marker or fecal calprotectin for IBD, confirmed by endoscopy and histopathology or clinical follow-up, in pediatric patients with chronic gastrointestinal symptoms. Studies that included healthy controls and/or patients with known IBD were excluded. Data Extraction and Synthesis: Individual patient data from each eligible study were requested from the authors. In addition, 2 reviewers independently assessed quality with Quality Assessment of Diagnostic Accuracy Studies-2. Mean Outcomes and Measures: Laboratory markers were added as a single test to a basic prediction model based on symptoms. Outcome measures were improvement of discrimination by adding markers as a single test and improvement of risk classification of pediatric patients by adding the best marker. Results: Of the 16 eligible studies, authors of 8 studies (n = 1120 patients) provided their data sets. All blood markers and fecal calprotectin individually significantly improved the discrimination between pediatric patients with and those without IBD, when added to evaluation of symptoms. The best marker fecal calprotectin-improved the area under the curve of symptoms by 0.26 (95% CI, 0.21-0.31). The second best marker-erythrocyte sedimentation rate-improved the area under the curve of symptoms by 0.16 (95% CI, 0.11-0.21). When fecal calprotectin was added to the model, the proportion of patients without IBD correctly classified as low risk of IBD increased from 33% to 91%. The proportion of patients with IBD incorrectly classified as low risk of IBD decreased from 16% to 9%. The proportion of the total number of patients assigned to the intermediate-risk category decreased from 55% to 6%. Conclusions and Relevance: In a hospital setting, fecal calprotectin added the most diagnostic value to symptoms compared with blood markers. Adding fecal calprotectin to the diagnostic workup of pediatric patients with symptoms suggestive of IBD considerably decreased the number of patients in the group in whom challenges in clinical decision making are most prevalent. PMID- 28806448 TI - Early-Onset Sepsis Calculator-Reply. PMID- 28806447 TI - Homocysteine Facilitates Prominent Polygonal Angiogenetic Networks of a Choroidal Capillary Sprouting Model. AB - Purpose: To investigate the effects of homocysteine on choroidal angiogenesis, we established an ex vivo choroidal sprouting explant model and examined the potential growth factors for angiogenesis. Methods: Choroid fragments with retinal pigment epithelium were isolated from mouse and embedded in Matrigel. Homocysteine at different concentrations were added to the culture mediums. The choroidal explants were observed at different time points, and the total area of choroidal sprouting was measured and analyzed. Results: Homocysteine evoked choroidal capillary sprouting by inducing capillary endothelial cell proliferation with pericyte formation and by facilitating polygonal angiogenetic networks. In some cases, vascular lumens were observed in the newly forming capillaries facilitated by homocysteine. The choroidal sprouting effect of homocysteine can only be observed at a certain range of homocysteine concentration, with 1-mM homocysteine exhibiting the most significantly increased choroidal sprouting areas. Isolectin overexpression was noted in the homocysteine treated group. Possible growth factors for angiogenesis were detected through immunofluorescent staining, which demonstrated the overexpression of platelet derived growth factor C and angiopoietin 1 in the homocysteine-treated preparations only. In these preparations, platelet-derived growth factor C was highly expressed in the tip cells of sprouting capillaries. Conclusions: We therefore conclude that platelet-derived growth factor C and angiopoietin 1 may play key roles in the choroid angiogenesis evoked by homocysteine. PMID- 28806446 TI - Sema3A Reduces Sprouting of Adult Rod Photoreceptors In Vitro. AB - Purpose: Rod photoreceptor terminals respond to retinal injury with retraction and sprouting. Since the guidance cue Semaphorin3A (Sema3A) is observed in the retina after injury, we asked whether Sema3A contributes to structural plasticity in rod photoreceptors. Methods: We used Western blots and alkaline phosphatase (AP)-tagged neuropilin-1 (NPN-1) to detect the expression of Sema3A in an organotypic model of porcine retinal detachment. We then examined Sema3A binding to cultured salamander rod photoreceptors using AP-tagged Sema3A. For functional analysis, we used a microspritzer to apply a gradient of Sema3A-Fc to isolated salamander rod photoreceptors over 24 hours. Results: Sema3A protein was biochemically detected in porcine retinal explants in the retina 7, 24, and 72 hours after detachment. In sections, NPN-1 receptor was bound to the inner and outer retina. For isolated rod photoreceptors, Sema3A localized to synaptic terminals and to neuritic processes after 1 week in vitro. In microspritzed rod photoreceptors, process initiation occurred away from high concentrations of Sema3A. Sema3A significantly decreased the number of processes formed by rod photoreceptors although the average length of processes was not affected. The cellular orientation of rod photoreceptors relative to the microspritzer also significantly changed over time; this effect was reduced with the Sema3A inhibitor, xanthofulvin. Conclusion: Sema3A is expressed in the retina after detachment, binds to rod photoreceptors, affects cell orientation, and reduces photoreceptor process initiation in vitro. Our results suggest that Sema3A contributes to axonal retraction in retinal injury, whereas rod neuritic sprouting and regenerative synaptogenesis may require a reduction in semaphorin signaling. PMID- 28806449 TI - Meeting the Needs of Patients for Specialty Care. PMID- 28806451 TI - Epidemiology of Sepsis Among Adolescents at Community Hospital Emergency Departments: Implications for Rory's Regulations. PMID- 28806452 TI - Sharing Experiences of Illness and Care. PMID- 28806450 TI - Evaluation of Combination Measles-Mumps-Rubella-Varicella Vaccine Introduction in Australia. AB - Importance: Incorporating combination vaccines, such as the measles-mumps-rubella varicella (MMRV) vaccine, into immunization schedules should be evaluated from a benefit-risk perspective. Use of MMRV vaccine poses challenges due to a recognized increased risk of febrile seizures (FSs) when used as the first dose in the second year of life. Conversely, completion by age 2 years of measles, mumps, rubella, and varicella immunization may offer improved disease control. Objective: To evaluate the effect on safety and coverage of earlier (age 18 months) scheduling of MMRV vaccine as the second dose of measles-containing vaccine (MCV) in Australia. Design, Setting, and Participants: Prospective active sentinel safety surveillance comparing the relative incidence (RI) of FSs in toddlers given MMRV and measles-mumps-rubella (MMR) and a national cohort study of vaccine coverage rates and timeliness before and after MMRV vaccine introduction were conducted. All Australian children aged 11 to 72 months were included in the coverage analysis, and 1471 Australian children aged 11 to 59 months were included in the FS analysis, with a focus on those aged 11 to 23 months. Main Outcomes and Measures: MMRV vaccine safety, specifically, the RI of FSs after MMRV vaccine at age 18 months, compared with risk following MMR vaccine and vaccine uptake for 2-dose MCV and single-dose varicella vaccine, focusing on timeliness. Results: Of the 1471 children, the median age at first FS was 21 months (interquartile range [IQR], 14-31 months). Three hundred ninety-one children were aged 11 to 23 months and had at least 1 FS included in the analysis; of these, 207 (52.9%) were male. A total of 278 children (71.1%) had received MMR followed by MMRV vaccine, 97 (24.8%) had received MMR vaccine only, and 16 (4.1%) had received neither vaccine. There was no increased risk of FSs (RI, 1.08; 95% CI, 0.55-2.13) in the 5 to 12 days following MMRV vaccine given as the second MCV to toddlers. Febrile seizures occurred after dose 1 of MMR vaccine at a known low increased risk (RI, 2.71; 95% CI, 1.71- 4.29). Following program implementation, 2-dose MCV coverage at age 36 months exceeded that obtained at age 60 months in historical cohorts recommended to receive MMR vaccine before school entry, and on-time vaccination increased by 13.5% (from 58.9% to 72.4%). Despite no change in the scheduled age of varicella vaccine, use of MMRV vaccine was associated with a 4.0% increase in 1-dose varicella vaccine coverage. Conclusions and Relevance: To our knowledge, this is the first study to provide evidence of the absence of an association between use of MMRV vaccine as the second dose of MCV in toddlers and an increased risk of FSs. Incorporation of MMRV vaccine has facilitated improvements in vaccine coverage that will potentially improve disease control. PMID- 28806454 TI - The Expanding Spectrum of Zika Virus Infections of the Nervous System. PMID- 28806453 TI - Neurologic Complications Associated With the Zika Virus in Brazilian Adults. AB - Importance: There are no prospective cohort studies assessing the incidence and spectrum of neurologic manifestations secondary to Zika virus (ZIKV) infection in adults. Objective: To evaluate the rates of acute ZIKV infection among patients hospitalized with Guillain-Barre syndrome (GBS), meningoencephalitis, or transverse myelitis. Design, Setting, and Participants: A prospective, observational cohort study was conducted at a tertiary referral center for neurological diseases in Rio de Janeiro, Brazil, between December 5, 2015, and May 10, 2016, among consecutive hospitalized adults (>18 years of age) with new onset acute parainfectious or neuroinflammatory disease. All participants were tested for a series of arbovirosis. Three-month functional outcome was assessed. Interventions: Samples of serum and cerebrospinal fluid were tested for ZIKV using real-time reverse-transcriptase-polymerase chain reaction and an IgM antibody-capture enzyme-linked immunosorbent assay. Clinical, radiographic (magnetic resonance imaging), electrophysiological, and 3-month functional outcome data were collected. Main Outcomes and Measures: The detection of neurologic complications secondary to ZIKV infection. Results: Forty patients (15 women and 25 men; median age, 44 years [range, 22-72 years]) were enrolled, including 29 patients (73%) with GBS (90% Brighton level 1 certainty), 7 (18%) with encephalitis, 3 (8%) with transverse myelitis, and 1 (3%) with newly diagnosed chronic inflammatory demyelinating polyneuropathy. Of these, 35 patients (88%) had molecular and/or serologic evidence of recent ZIKV infection in the serum and/or cerebrospinal fluid. Of the patients positive for ZIKV infection, 27 had GBS (18 demyelinating, 8 axonal, and 1 Miller Fisher syndrome), 5 had encephalitis (3 with concomitant acute neuromuscular disease), 2 had transverse myelitis, and 1 had chronic inflammatory demyelinating polyneuropathy. Admission to the intensive care unit was required for 9 patients positive for ZIKV infection (26%), and 5 (14%) required mechanical ventilation. Compared with admission during the period from December 5, 2013, to May 10, 2014 (before the Brazilian outbreak of ZIKV), admissions for GBS increased from a mean of 1.0 per month to 5.6 per month, admissions for encephalitis increased from 0.4 per month to 1.4 per month, and admissions for transverse myelitis remained constant at 0.6 per month. At 3 months, 2 patients positive for ZIKV infection (6%) died (1 with GBS and 1 with encephalitis), 18 (51%) had chronic pain, and the median modified Rankin score among survivors was 2 (range, 0-5). Conclusions and Relevance: In this single-center Brazilian cohort, ZIKV infection was associated with an increase in the incidence of a diverse spectrum of serious neurologic syndromes. The data also suggest that serologic and molecular testing using blood and cerebrospinal fluid samples can serve as a less expensive, alternative diagnostic strategy in developing countries, where plaque reduction neutralization testing is impractical. PMID- 28806456 TI - Using Disease Epidemiology to Optimize Immunization Schedules. PMID- 28806455 TI - Association of State Access Standards With Accessibility to Specialists for Medicaid Managed Care Enrollees. AB - Importance: Medicaid recipients have consistently reported less timely access to specialists than patients with other types of coverage. By 2018, state Medicaid agencies will be required by the Center for Medicare and Medicaid Services (CMS) to enact time and distance standards for managed care organizations to ensure an adequate supply of specialist physicians for enrollees; however, there have been no published studies of whether these policies have significant effects on access to specialty care. Objective: To compare ratings of access to specialists for adult Medicaid and commercial enrollees before and after the implementation of specialty access standards. Design, Setting, and Participants: We used Consumer Assessment of Healthcare Providers and Systems survey data to conduct a quasiexperimental difference-in-differences (DID) analysis of 20 163 nonelderly adult Medicaid managed care (MMC) enrollees and 54 465 commercially insured enrollees in 5 states adopting access standards, and 37 290 MMC enrollees in 5 matched states that previously adopted access standards. Main Outcomes and Measures: Reported access to specialty care in the previous 6 months. Results: Seven thousand six hundred ninety-eight (69%) Medicaid enrollees and 28 423 (75%) commercial enrollees reported that it was always or usually easy to get an appointment with a specialist before the policy implementation (or at baseline) compared with 11 889 (67%) of Medicaid enrollees in states that had previously implemented access standards. Overall, there was no significant improvement in timely access to specialty services for MMC enrollees in the period following implementation of standard(s) (adjusted difference-in-differences, -1.2 percentage points; 95% CI, -2.7 to 0.1), nor was there any impact of access standards on insurance-based disparities in access (0.6 percentage points; 95% CI, -4.3 to 5.4). There was heterogeneity across states, with 1 state that implemented both time and distance standards demonstrating significant improvements in access and reductions in disparities. Conclusions and Relevance: Specialty access standards did not lead to widespread improvements in access to specialist physicians. Meaningful improvements in access to specialty care for Medicaid recipients may require additional interventions. PMID- 28806460 TI - SIDS or SUID: The Emphasis on Risk Reduction. PMID- 28806461 TI - Talking to Adolescents About Social Media. AB - I see a large number of adolescents in my clinic with issues related to their social media use. These issues range from lack of sleep, to depression, to cyberbullying, and even sex trafficking, all secondary to constant social media exposure. Pediatricians should ask about social media use when they see children and adolescents who already have access to electronic devices. They should also ask parents about controls that are set in place to monitor social media use, content, and friend connections on those sites. They should ensure that their children know personally everyone they are connected to on social media and that their accounts are always private and not public. This will help reduce many of the issues associated with the potential consequences of social media use. [Pediatr Ann. 2017;46(8):e274-e276.]. PMID- 28806457 TI - Neurodevelopmental Disorders Caused by De Novo Variants in KCNB1 Genotypes and Phenotypes. AB - Importance: Knowing the range of symptoms seen in patients with a missense or loss-of-function variant in KCNB1 and how these symptoms correlate with the type of variant will help clinicians with diagnosis and prognosis when treating new patients. Objectives: To investigate the clinical spectrum associated with KCNB1 variants and the genotype-phenotype correlations. Design, Setting, and Participants: This study summarized the clinical and genetic information of patients with a presumed pathogenic variant in KCNB1. Patients were identified in research projects or during clinical testing. Information on patients from previously published articles was collected and authors contacted if feasible. All patients were seen at a clinic at one of the participating institutes because of presumed genetic disorder. They were tested in a clinical setting or included in a research project. Main Outcomes and Measures: The genetic variant and its inheritance and information on the patient's symptoms and characteristics in a predefined format. All variants were identified with massive parallel sequencing and confirmed with Sanger sequencing in the patient. Absence of the variant in the parents could be confirmed with Sanger sequencing in all families except one. Results: Of 26 patients (10 female, 15 male, 1 unknown; mean age at inclusion, 9.8 years; age range, 2-32 years) with developmental delay, 20 (77%) carried a missense variant in the ion channel domain of KCNB1, with a concentration of variants in region S5 to S6. Three variants that led to premature stops were located in the C-terminal and 3 in the ion channel domain. Twenty-one of 25 patients (84%) had seizures, with 9 patients (36%) starting with epileptic spasms between 3 and 18 months of age. All patients had developmental delay, with 17 (65%) experiencing severe developmental delay; 14 (82%) with severe delay had behavioral problems. The developmental delay was milder in 4 of 6 patients with stop variants and in a patient with a variant in the S2 transmembrane element rather than the S4 to S6 region. Conclusions and Relevance: De novo KCNB1 missense variants in the ion channel domain and loss-of-function variants in this domain and the C-terminal likely cause neurodevelopmental disorders with or without seizures. Patients with presumed pathogenic variants in KCNB1 have a variable phenotype. However, the type and position of the variants in the protein are (imperfectly) correlated with the severity of the disorder. PMID- 28806462 TI - Sudden Unexpected Infant Deaths: What Are We Learning and How Can We Reduce the Risks. PMID- 28806463 TI - The Evolving Understanding of Sudden Unexpected Infant Death. AB - Sudden unexpected infant death (SUID) is the leading cause for post-neonatal mortality in industrialized nations. Case-control studies have identified risk factors for SUID that have shaped research into studies of causation. Most current hypotheses for the mechanisms for SUID contribute to the "SUID sequence" hypoxia and/or hypercarbia in sleep to which a vulnerable infant fails to respond adequately and that results in death. Reducing vulnerability in infants and promoting safe sleep for infants is important for prevention and requires knowledge of the prevalence of risk factors within the target population and a culturally sensitive approach. [Pediatr Ann. 2017;46(8):e278-e283.]. PMID- 28806464 TI - Beyond "Back to Sleep": Ways to Further Reduce the Risk of Sudden Infant Death Syndrome. AB - Sudden infant death syndrome (SIDS) remains the leading cause of postneonatal mortality in the United States, despite reduction in rates of more than 50% since the initiation of the "Back to Sleep" (now called "Safe to Sleep") campaign in 1994. In recent years, the rate of decline in SIDS deaths has plateaued, even with the ongoing educational efforts that promote safe sleep and other risk reduction measures. The 2016 American Academy of Pediatrics guidelines for reducing the risk of SIDS focus heavily on sleep practices, bedding, and location, but also include factors that often receive less attention (ie, prenatal care, maternal smoking, alcohol and drug use, and childhood vaccinations). This review describes these factors that are less often addressed and identifies interventions that have resulted in positive behavioral changes that not only benefit infants, but also promote the health and well-being of their mothers. [Pediatr Ann. 2017;46(8):e284-e290.]. PMID- 28806465 TI - Safe Infant Sleep Practices: Parental Engagement, Education, and Behavior Change. AB - Although the incidence of sudden unexpected infant death declined by nearly 50% in the 1990s, there has been little improvement in the past 15 years. Significant disparities in infant sleep practices and sleep-associated death exist, particularly by maternal race/ethnicity. This article provides a brief overview of recent observational and intervention studies related to infant sleep practices to describe the context and motivation for the population-based Study of Attitudes and Factors Effecting Infant Care (SAFE). [Pediatr Ann. 2017;46(8):e291-e296.]. PMID- 28806466 TI - Medicolegal Death Investigation of Sudden Unexpected Infant Deaths. AB - This review article describes the role of the medicolegal death investigator and medical examiner or coroner (MEC) in the investigations of a sudden unexpected infant death (SUID) beginning with an introduction into the case types that should be investigated and how infant deaths fit into that legal framework. The article also provides an overview of the history of the Centers for Disease Control and Prevention SUID investigation guidelines and process. The article concludes with a description of how the MEC correlates the scene investigation with autopsy findings, as well as the role of the MEC in cause of death determinations. There is also a brief discussion on how infant mortality data are captured and subsequently used to decrease infant mortality. [Pediatr Ann. 2017;46(8):e297-e302.]. PMID- 28806467 TI - The History of Home Cardiorespiratory Monitoring. AB - Home cardiorespiratory monitoring has changed significantly since it was first introduced in the 1970s. It has improved from a simple alarm system to a sophisticated piece of equipment capable of monitoring the patient's electrocardiogram, respiratory effort, and oxygen saturations. In addition, the indications for using a monitor have also changed. The home monitor was initially used to reduce the incidence of sudden infant death syndrome (SIDS). Although there were several studies demonstrating the reduction of SIDS rates in communities where apnea programs existed, none was a prospective, double-blinded study or had adequate numbers to be clinically significant. Therefore, the American Academy of Pediatrics took the stance that monitors were not an effective way to reduce SIDS. However, when used appropriately, as part of a complete program (ie, the monitor is just one of many clinically based modalities), by a clinician with expertise in interpreting download tracings, home cardiorespiratory monitoring can be a useful, lifesaving, and economical tool to observe infants who are at increased risk of sudden death or increased morbidity secondary to intermittent hypoxia. [Pediatr Ann. 2017;46(8):e303 e308.]. PMID- 28806468 TI - An Overview of Hemophagocytic Lymphohistiocytosis. AB - Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by a dysregulated hyperinflammatory response associated with aberrant activation of lymphocytes and macrophages that results in hypercytokinemia. It is classically divided into two types: (1) primary or familial HLH and (2) secondary HLH. Familial HLH is generally an autosomal recessive condition, whereas secondary HLH is usually associated with infectious diseases, autoinflammatory and autoimmune diseases (where it is more commonly known as macrophage activation syndrome), malignancy, immunosuppression, hematopoietic stem cell transplantation, organ transplantation, HIV infection, and metabolic diseases. Although its clinical presentation is often similar to bacterial sepsis or systemic inflammatory response syndrome, HLH can be life threatening. As such, it is imperative to recognize and diagnose HLH in a timely manner to optimize care. [Pediatr Ann. 2017;46(8):e309-e313.]. PMID- 28806469 TI - Climate Change Effects on Respiratory Health: Implications for Nursing. AB - PURPOSE: Greenhouse gases are driving climate change. This article explores the adverse health effects of climate change on a particularly vulnerable population: children and adults with respiratory conditions. APPROACH: This review provides a general overview of the effects of increasing temperatures, extreme weather, desertification, and flooding on asthma, chronic obstructive lung disease, and respiratory infections. We offer suggestions for future research to better understand climate change hazards, policies to support prevention and mitigation efforts targeting climate change, and clinical actions to reduce individual risk. FINDINGS AND CONCLUSIONS: Climate change produces a number of changes to the natural and built environments that may potentially increase respiratory disease prevalence, morbidity, and mortality. Nurses might consider focusing their research efforts on reducing the effects of greenhouse gases and in directing policy to mitigate the harmful effects of climate change. Nurses can also continue to direct educational and clinical actions to reduce risks for all populations, but most importantly, for our most vulnerable groups. CLINICAL RELEVANCE: While advancements have been made in understanding the impact of climate change on respiratory health, nurses can play an important role in reducing the deleterious effects of climate change. This will require a multipronged approach of research, policy, and clinical action. PMID- 28806470 TI - Efficacy and safety of sugammadex versus neostigmine in reversing neuromuscular blockade in adults. AB - BACKGROUND: Acetylcholinesterase inhibitors, such as neostigmine, have traditionally been used for reversal of non-depolarizing neuromuscular blocking agents. However, these drugs have significant limitations, such as indirect mechanisms of reversal, limited and unpredictable efficacy, and undesirable autonomic responses. Sugammadex is a selective relaxant-binding agent specifically developed for rapid reversal of non-depolarizing neuromuscular blockade induced by rocuronium. Its potential clinical benefits include fast and predictable reversal of any degree of block, increased patient safety, reduced incidence of residual block on recovery, and more efficient use of healthcare resources. OBJECTIVES: The main objective of this review was to compare the efficacy and safety of sugammadex versus neostigmine in reversing neuromuscular blockade caused by non-depolarizing neuromuscular agents in adults. SEARCH METHODS: We searched the following databases on 2 May 2016: Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (WebSPIRS Ovid SP), Embase (WebSPIRS Ovid SP), and the clinical trials registries www.controlled-trials.com, clinicaltrials.gov, and www.centerwatch.com. We re-ran the search on 10 May 2017. SELECTION CRITERIA: We included randomized controlled trials (RCTs) irrespective of publication status, date of publication, blinding status, outcomes published, or language. We included adults, classified as American Society of Anesthesiologists (ASA) I to IV, who received non-depolarizing neuromuscular blocking agents for an elective in-patient or day-case surgical procedure. We included all trials comparing sugammadex versus neostigmine that reported recovery times or adverse events. We included any dose of sugammadex and neostigmine and any time point of study drug administration. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts to identify trials for eligibility, examined articles for eligibility, abstracted data, assessed the articles, and excluded obviously irrelevant reports. We resolved disagreements by discussion between review authors and further disagreements through consultation with the last review author. We assessed risk of bias in 10 methodological domains using the Cochrane risk of bias tool and examined risk of random error through trial sequential analysis. We used the principles of the GRADE approach to prepare an overall assessment of the quality of evidence. For our primary outcomes (recovery times to train-of-four ratio (TOFR) > 0.9), we presented data as mean differences (MDs) with 95 % confidence intervals (CIs), and for our secondary outcomes (risk of adverse events and risk of serious adverse events), we calculated risk ratios (RRs) with CIs. MAIN RESULTS: We included 41 studies (4206 participants) in this updated review, 38 of which were new studies. Twelve trials were eligible for meta-analysis of primary outcomes (n = 949), 28 trials were eligible for meta-analysis of secondary outcomes (n = 2298), and 10 trials (n = 1647) were ineligible for meta analysis.We compared sugammadex 2 mg/kg and neostigmine 0.05 mg/kg for reversal of rocuronium-induced moderate neuromuscular blockade (NMB). Sugammadex 2 mg/kg was 10.22 minutes (6.6 times) faster then neostigmine 0.05 mg/kg (1.96 vs 12.87 minutes) in reversing NMB from the second twitch (T2) to TOFR > 0.9 (MD 10.22 minutes, 95% CI 8.48 to 11.96; I2 = 84%; 10 studies, n = 835; GRADE: moderate quality).We compared sugammadex 4 mg/kg and neostigmine 0.07 mg/kg for reversal of rocuronium-induced deep NMB. Sugammadex 4 mg/kg was 45.78 minutes (16.8 times) faster then neostigmine 0.07 mg/kg (2.9 vs 48.8 minutes) in reversing NMB from post-tetanic count (PTC) 1 to 5 to TOFR > 0.9 (MD 45.78 minutes, 95% CI 39.41 to 52.15; I2 = 0%; two studies, n = 114; GRADE: low quality).For our secondary outcomes, we compared sugammadex, any dose, and neostigmine, any dose, looking at risk of adverse and serious adverse events. We found significantly fewer composite adverse events in the sugammadex group compared with the neostigmine group (RR 0.60, 95% CI 0.49 to 0.74; I2 = 40%; 28 studies, n = 2298; GRADE: moderate quality). Risk of adverse events was 28% in the neostigmine group and 16% in the sugammadex group, resulting in a number needed to treat for an additional beneficial outcome (NNTB) of 8. When looking at specific adverse events, we noted significantly less risk of bradycardia (RR 0.16, 95% CI 0.07 to 0.34; I2= 0%; 11 studies, n = 1218; NNTB 14; GRADE: moderate quality), postoperative nausea and vomiting (PONV) (RR 0.52, 95% CI 0.28 to 0.97; I2 = 0%; six studies, n = 389; NNTB 16; GRADE: low quality) and overall signs of postoperative residual paralysis (RR 0.40, 95% CI 0.28 to 0.57; I2 = 0%; 15 studies, n = 1474; NNTB 13; GRADE: moderate quality) in the sugammadex group when compared with the neostigmine group. Finally, we found no significant differences between sugammadex and neostigmine regarding risk of serious adverse events (RR 0.54, 95% CI 0.13 to 2.25; I2= 0%; 10 studies, n = 959; GRADE: low quality).Application of trial sequential analysis (TSA) indicates superiority of sugammadex for outcomes such as recovery time from T2 to TOFR > 0.9, adverse events, and overall signs of postoperative residual paralysis. AUTHORS' CONCLUSIONS: Review results suggest that in comparison with neostigmine, sugammadex can more rapidly reverse rocuronium-induced neuromuscular block regardless of the depth of the block. Sugammadex 2 mg/kg is 10.22 minutes (~ 6.6 times) faster in reversing moderate neuromuscular blockade (T2) than neostigmine 0.05 mg/kg (GRADE: moderate quality), and sugammadex 4 mg/kg is 45.78 minutes (~ 16.8 times) faster in reversing deep neuromuscular blockade (PTC 1 to 5) than neostigmine 0.07 mg/kg (GRADE: low quality). With an NNTB of 8 to avoid an adverse event, sugammadex appears to have a better safety profile than neostigmine. Patients receiving sugammadex had 40% fewer adverse events compared with those given neostigmine. Specifically, risks of bradycardia (RR 0.16, NNTB 14; GRADE: moderate quality), PONV (RR 0.52, NNTB 16; GRADE: low quality), and overall signs of postoperative residual paralysis (RR 0.40, NNTB 13; GRADE: moderate quality) were reduced. Both sugammadex and neostigmine were associated with serious adverse events in less than 1% of patients, and data showed no differences in risk of serious adverse events between groups (RR 0.54; GRADE: low quality). PMID- 28806471 TI - Limited uptake of ulcerative colitis "treat-to-target" recommendations in real world practice. AB - BACKGROUND AND AIMS: A "treat-to-target" approach has been proposed for ulcerative colitis (UC), with a target of combined clinical and endoscopic remission. The aim of the study was to evaluate the extent to which proposed targets are achieved in real-world care, along with clinician perceptions and potential challenges. METHODS: A multicentre, retrospective, cross-sectional review of patients with UC attending outpatient services in South Australia was conducted. Clinical and objective assessment of disease activity (endoscopy, histology, and/or biomarkers) was recorded. A survey evaluated gastroenterologists' perceptions of treat to target in UC. Statistical analysis included logistic regression and Fisher's exact tests. RESULTS: Of 246 patients with UC, 61% were in clinical remission (normal bowel habit and no rectal bleeding), 35% in clinical and endoscopic remission (Mayo endoscopic sub-score <= 1), and 16% in concordant clinical, endoscopic, and histological (Truelove and Richards' Index) remission. Rather than disease-related factors (extent/activity), clinician-related factors dominated outcome. Hospital location and the choice of therapy predicted combined clinical and endoscopic remission (OR 3.6, 95% CI 1.6-8.7, P < 0.001; OR 3.3, 95% CI 1.1-12.5, P = 0.04, respectively). Clinicians used C-reactive protein more often than endoscopy as a biomarker for disease activity (75% vs 47%, P < 0.001). In the survey, 45/61 gastroenterologists responded, with significant disparity between clinician estimates of targets achieved in practice and real-world data (P < 0.001 for clinical and endoscopic remission). CONCLUSIONS: Most patients with UC do not achieve composite clinical and endoscopic remission in "real-world" practice. Clinician uptake of proposed treat-to-target guidelines is a challenge to their implementation. PMID- 28806472 TI - Effects of clarithromycin on the pharmacokinetics of evogliptin in healthy volunteers. AB - WHAT IS KNOWN AND OBJECTIVE: Evogliptin (DA-1229), a novel dipeptidyl peptidase (DPP)-4 inhibitor with high potency and selectivity, was approved in Korea for the treatment of type 2 diabetes. Preclinical studies suggest that it is metabolized by cytochrome (CYP) P450 isozymes. Based on these findings, a clinical study was designed to investigate the pharmacokinetic (PK) interaction of evogliptin with a CYP inhibitor, clarithromycin. METHODS: An open-label, two phase, crossover study was conducted with 12 healthy subjects. On day 1, a single dose of evogliptin 5 mg was administered alone to assess the reference PK profile of evogliptin. On day 10, after a 2-day pretreatment with clarithromycin, evogliptin 5 mg was administered again to evaluate the effect of CYP inhibition on the PK profile of evogliptin. Administration of clarithromycin continued until day 14. Blood sampling in the reference and test phases was performed until 96 and 168 hours after dosing, respectively for PK assays. RESULTS: Eleven of the 12 subjects completed the study, and their data were analysed. In the presence of clarithromycin, exposure to evogliptin increased without any serious adverse events and the geometric mean peak plasma concentration (Cmax ) and area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-infinity ) of evogliptin increased by 116.5% and 89.6%, respectively. WHAT IS NEW AND CONCLUSION: Administration of clarithromycin significantly increased exposure to evogliptin in healthy subjects. PMID- 28806473 TI - Flavylium Polymethine Fluorophores for Near- and Shortwave Infrared Imaging. AB - Bright fluorophores in the near-infrared and shortwave infrared (SWIR) regions of the electromagnetic spectrum are essential for optical imaging in vivo. In this work, we utilized a 7-dimethylamino flavylium heterocycle to construct a panel of novel red-shifted polymethine dyes, with emission wavelengths from 680 to 1045 nm. Photophysical characterization revealed that the 1- and 3-methine dyes display enhanced photostability and the 5- and 7-methine dyes exhibit exceptional brightness for their respective spectral regions. A micelle formulation of the 7 methine facilitated SWIR imaging in mice. This report presents the first polymethine dye designed and synthesized for SWIR in vivo imaging. PMID- 28806474 TI - The benefit of sharing. PMID- 28806475 TI - Using the Washoe Language to Inform Hydrologic and Environmental Models. PMID- 28806476 TI - DNA Trojan Horses: Self-Assembled Floxuridine-Containing DNA Polyhedra for Cancer Therapy. AB - Based on their structural similarity to natural nucleobases, nucleoside analogue therapeutics were integrated into DNA strands through conventional solid-phase synthesis. By elaborately designing their sequences, floxuridine-integrated DNA strands were synthesized and self-assembled into well-defined DNA polyhedra with definite drug-loading ratios as well as tunable size and morphology. As a novel drug delivery system, these drug-containing DNA polyhedra could ideally mimic the Trojan Horse to deliver chemotherapeutics into tumor cells and fight against cancer. Both in vitro and in vivo results demonstrate that the DNA Trojan horse with buckyball architecture exhibits superior anticancer capability over the free drug and other formulations. With precise control over the drug-loading ratio and structure of the nanocarriers, the DNA Trojan horse may play an important role in anticancer treatment and exhibit great potential in translational nanomedicine. PMID- 28806477 TI - Curative salvage liver transplantation in patients with cirrhosis and hepatocellular carcinoma: An intention-to-treat analysis. AB - : The salvage liver transplantation (SLT) strategy was conceived for initially resectable and transplantable (R&T) hepatocellular carcinoma (HCC) patients, to try to obviate upfront liver transplantation, with the "safety net" of SLT in case of postresection recurrence. The SLT strategy is successful or curative when patients are recurrence free following primary resection alone, or after SLT for recurrence. The aim of the current study was to determine the SLT strategy's potential for cure in R&T HCC patients, and to identify predictors for its success. From 1994 to 2012, all R&T HCC patients with cirrhosis were enrolled in the SLT strategy. An intention-to-treat (ITT) analysis was used to determine this strategy's outcomes and predictors of success according to the above definition. In total, 110 patients were enrolled in the SLT strategy. Sixty-three patients (57%) had tumor recurrence after initial resection, and in 30 patients SLT could be performed (recurrence transplantability rate = 48%). From the time of initial resection, ITT 5-year overall and disease-free survival rates were 69% and 60%, respectively. The SLT strategy was successful in 60 patients (56%), either by resection alone (36%), or by SLT for recurrence (19%). Preresection predictors of successful SLT strategy at multivariate analysis included Model for End-Stage Liver Disease (MELD) score >10, and absence of neoadjuvant transarterial chemoembolization (TACE). Additional postresection predictive factors were absence of postresection morbidity, and T-stage 1-2 at the resection specimen. CONCLUSION: The SLT strategy is curative in only 56% of cases. Higher MELD score at inception of the strategy and no pre-resection TACE are predictors of successful SLT strategy. (Hepatology 2018;67:204-215). PMID- 28806478 TI - Successful stepdown treatment of pulmonary histoplasmosis with thrice-weekly liposomal amphotericin B in a hospital-associated, outpatient infusion centre: A case report. AB - WHAT IS KNOWN AND OBJECTIVE: Amphotericin is the preferred treatment for pulmonary histoplasmosis during pregnancy. The long half-life of amphotericin supports less than daily administration. CASE SUMMARY: A 28-year-old pregnant woman diagnosed with recurrent pulmonary histoplasmosis was initiated on liposomal amphotericin 250 mg (4 mg/kg) intravenously daily. After 2 weeks, the patient was discharged and successfully received 250 mg thrice weekly at a hospital-associated outpatient infusion centre. After 6 weeks of outpatient treatment, a chest X-ray demonstrated no remaining disease and therapy was discontinued. WHAT IS NEW AND CONCLUSION: Administration of thrice-weekly liposomal amphotericin in a hospital-associated, outpatient infusion centre may be a promising option for stepdown treatment in patients unable to take itraconazole. PMID- 28806479 TI - Zika Virus Disease in Children in Colombia, August 2015 to May 2016. AB - BACKGROUND: Children are considered a potentially vulnerable population for Zika virus infection. However, data on paediatric Zika virus infection are sparse. METHODS: We analysed data from Colombia's national surveillance system during the 2015-2016 Zika virus outbreak on patients meeting the clinical case definition of Zika virus disease (ZVD) among children aged 1 month to 18 years to estimate incidence by demographic characteristics and characterize the occurrence of selected complications. RESULTS: Between August 14, 2015, and May 28, 2016, there were 18 576 reported cases of postnatal ZVD among children aged 1 month to 18 years. Laboratory testing was prioritized for high-risk patients (infants, pregnant women, adults aged >=65 years, and persons with serious co-morbidities); among 1655 that were tested by real-time reverse transcriptase polymerase chain reaction, 1207 (72.9%) were positive. The cumulative incidence of reported ZVD was 114.4 per 100 000. The incidence differed by sex, depending on age group; the largest difference was observed for 15-18 year olds, with females having a higher incidence than males (cumulative incidence ratio 2.5, 95% confidence interval 2.3, 2.7). At the time of report to the surveillance system, 631 patients (3.4%) were hospitalised and 96 (0.5%) had a report of an accompanying neurological diagnosis, including Guillain-Barre syndrome in 40 patients. CONCLUSIONS: Only a small proportion of reported paediatric ZVD cases in Colombia were hospitalized or had reported neurological conditions following ZVD. However, the potential for some serious outcomes demonstrates the importance of preventing Zika virus infection in children. PMID- 28806480 TI - Aerosolized prostacyclins for acute respiratory distress syndrome (ARDS). AB - BACKGROUND: Acute respiratory distress syndrome (ARDS) is a critical condition that is associated with high mortality and morbidity. Aerosolized prostacyclin has been used to improve oxygenation despite the limited evidence available so far.This review was originally published in 2010 and updated in 2017. OBJECTIVES: To assess the benefits and harms of aerosolized prostacyclin in adults and children with ARDS. SEARCH METHODS: In this update, we searched CENTRAL (2017, Issue 4); MEDLINE (OvidSP), Embase (OvidSP), ISI BIOSIS Previews, ISI Web of Science, LILACS, CINAHL (EBSCOhost), and three trials registers. We handsearched the reference lists of the latest reviews, randomized and non-randomized trials, and editorials, and cross-checked them with our search of MEDLINE. We contacted the main authors of included studies to request any missed, unreported or ongoing studies. The search was run from inception to 5 May 2017. SELECTION CRITERIA: We included all randomized controlled trials (RCTs), irrespective of publication status, date of publication, blinding status, outcomes published or language. We contacted trial investigators and study authors to retrieve relevant and missing data. DATA COLLECTION AND ANALYSIS: Three authors independently abstracted data and resolved any disagreements by discussion. Our primary outcome measure was all cause mortality. We planned to perform subgroup and sensitivity analyses to assess the effect of aerosolized prostacyclin in adults and children, and on various clinical and physiological outcomes. We assessed the risk of bias through assessment of methodological trial components and the risk of random error through trial sequential analysis. MAIN RESULTS: We included two RCTs with 81 participants.One RCT involved 14 critically ill children with ARDS (very low quality of evidence), and one RCT involved 67 critically ill adults (very low quality evidence).Only one RCT (paediatric trial) provided data on mortality and found no difference between intervention and control. However, this trial was eligible for meta-analysis due to a cross-over design.We assessed the benefits and harms of aerosolized prostacyclin. One RCT found no difference in improvement of partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO2/FiO2) ratio (mean difference (MD) -25.35, 95% confidence interval (CI) 60.48 to 9.78; P = 0.16; 67 participants, very low quality evidence).There were no adverse events such as bleeding or organ dysfunction in any of the included trials. Due to the limited number of RCTs, we were unable to perform the prespecified subgroup and sensitivity analyses or trial sequential analysis. AUTHORS' CONCLUSIONS: We are unable to tell from our results whether the intervention has an important effect on mortality because the results were too imprecise to rule out a small or no effect. Therefore, no current evidence supports or refutes the routine use of aerosolized prostacyclin for people with ARDS. There is an urgent need for more RCTs. PMID- 28806481 TI - Paediatric Zika - Beyond Pregnant Women. PMID- 28806482 TI - Automated segmentation and quantification of actin stress fibres undergoing experimentally induced changes. AB - The actin cytoskeleton is a main component of cells and it is crucially involved in many physiological processes, e.g. cell motility. Changes in the actin organization can be effected by diseases or vice versa. Due to the nonuniform pattern, it is difficult to quantify reasonable features of the actin cytoskeleton for a significantly high cell number. Here, we present an approach capable to fully segment and analyse the actin cytoskeleton of 2D fluorescence microscopic images with a special focus on stress fibres. The extracted feature data include length, width, orientation and intensity distributions of all traced stress fibres. Our approach combines morphological image processing techniques and a trace algorithm in an iterative manner, classifying the segmentation result with respect to the width of the stress fibres and in nonfibre-like actin. This approach enables us to capture experimentally induced processes like the condensation or the collapse of the actin cytoskeleton. We successfully applied the algorithm to F-actin images of cells that were treated with the actin polymerization inhibitor latrunculin A. Furthermore, we verified the robustness of our algorithm by a sensitivity analysis of the parameters, and we benchmarked our algorithm against established methods. In summary, we present a new approach to segment actin stress fibres over time to monitor condensation or collapse processes. PMID- 28806483 TI - Mandate for the Nursing Profession to Address Climate Change Through Nursing Education. AB - PURPOSE: The adverse health effects from climate change demand action from the nursing profession. This article examines the calls to action, the status of climate change in nursing education, and challenges and recommendations for nursing education related to climate change and human health. ORGANIZING CONSTRUCT: Discussion paper. FINDINGS: The integration of climate change into nursing education is essential so that knowledge, skills, and insights critical for clinical practice in our climate-changing world are incorporated in curricula, practice, research, and policy. Our Ecological Planetary Health Model offers a framework for nursing to integrate relevant climate change education into nursing curricula and professional nursing education. Nursing education can offer a leadership role to address the mitigation, adaptation, and resilience strategies for climate change. CONCLUSIONS: An ecological framework is valuable for nursing education regarding climate change through its consideration of political, cultural, economic, and environmental interrelationships on human health and the health of the planet. Knowledge of climate change is important for integration into basic and advanced nursing education, as well as professional education for nurses to address adverse health impacts, climate change responses policy, and advocacy roles. CLINICAL RELEVANCE: For current and future nurses to provide care within a climate-changing environment, nursing education has a mandate to integrate knowledge about climate change issues across all levels of nursing education. Competence in nursing practice follows from knowledge and skill acquisition gained from integration of climate change content into nursing education. PMID- 28806484 TI - Tensions in perspectives on suicide prevention between men who have attempted suicide and their support networks: Secondary analysis of qualitative data. AB - BACKGROUND: Men generally have higher rates of suicide, despite fewer overt indicators of risk. Differences in presentation and response suggest a need to better understand why suicide prevention is less effective for men. OBJECTIVE: To explore the views of at-risk men, friends and family about the tensions inherent in suicide prevention and to consider how prevention may be improved. DESIGN: Secondary analysis of qualitative interview and focus group data, using thematic analysis techniques, alongside bracketing, construction and contextualisation. SETTING AND PARTICIPANTS: A total of 35 men who had recently made a suicide attempt participated in interviews, and 47 family and friends of men who had made a suicide attempt took part in focus groups. Participants recounted their experiences with men's suicide attempts and associated interventions, and suggested ways in which suicide prevention may be improved. RESULTS: Five tensions in perspectives emerged between men and their support networks, which complicated effective management of suicide risk: (i) respecting privacy vs monitoring risk, (ii) differentiating normal vs risky behaviour changes, (iii) familiarity vs anonymity in personal information disclosure, (iv) maintaining autonomy vs imposing constraints to limit risk, and (v) perceived need for vs failures of external support services. CONCLUSION: Tension between the different perspectives increased systemic stress, compounding problems and risk, thereby decreasing the effectiveness of detection of and interventions for men at risk of suicide. Suggested solutions included improving risk communication, reducing reliance on single source supports and increasing intervention flexibility in response to individual needs. PMID- 28806485 TI - A matrix-based method of moments for fitting multivariate network meta-analysis models with multiple outcomes and random inconsistency effects. AB - Random-effects meta-analyses are very commonly used in medical statistics. Recent methodological developments include multivariate (multiple outcomes) and network (multiple treatments) meta-analysis. Here, we provide a new model and corresponding estimation procedure for multivariate network meta-analysis, so that multiple outcomes and treatments can be included in a single analysis. Our new multivariate model is a direct extension of a univariate model for network meta-analysis that has recently been proposed. We allow two types of unknown variance parameters in our model, which represent between-study heterogeneity and inconsistency. Inconsistency arises when different forms of direct and indirect evidence are not in agreement, even having taken between-study heterogeneity into account. However, the consistency assumption is often assumed in practice and so we also explain how to fit a reduced model which makes this assumption. Our estimation method extends several other commonly used methods for meta-analysis, including the method proposed by DerSimonian and Laird (). We investigate the use of our proposed methods in the context of both a simulation study and a real example. PMID- 28806486 TI - Farmworker Vulnerability to Heat Hazards: A Conceptual Framework. AB - PURPOSE: To review factors that impact the effect of hot environments on the human body in order to develop a conceptual model of human biological response. METHODS: The organizing concept for the model development was the multilevel integration of three major factors, exposure to heat, sensitivity and adaptive capacity, and the heat stress response. Exposure of a vulnerable occupational group was used to illustrate the components of the model. FINDINGS: Components of this framework include the hazard (environmental heat stress), vulnerability factors (workplace exposure, sensitivity and adaptive capacity), and the heat stress response. The combination of the vulnerability factors of workplace exposure (work intensity, duration), sensitivity (age, gender, etc.), and adaptive capacity (hydration, clothing, work hygiene) mediate a worker's heat stress response to the hazard. A worker's heat stress response can be classified as progressing towards two outcomes: physiologic equilibrium or physiologic disequilibrium. CONCLUSIONS: This framework provides a starting point for the design and development of studies of heat-related illness (HRI) in farmworker and other vulnerable populations exposed to rising global temperatures. CLINICAL RELEVANCE: Identification of vulnerability factors to HRI, informs research designs which will lead to the development of public health interventions. PMID- 28806487 TI - Gut microbiome response to short-term dietary interventions in reactive hypoglycemia subjects. AB - BACKGROUND: Reactive hypoglycemia is a metabolic disorder that provokes severe hypoglycemic episodes after meals. Over recent years, the gut microbiota has been recognized as potential target for the control of metabolic diseases, and the possibility to correct gut microbiota dysbioses through diet, favouring the recovery of metabolic homeostasis, has been considered. METHODS: We investigate the impact of 2 short-term (3-day) nutritional interventions, based on the macrobiotic Ma-Pi 2 diet and a control Mediterranean diet, on the structure and functionality of the gut microbiota in 12 patients affected by reactive hypoglycemia. The gut microbiota composition was characterized by next-generation sequencing of the V3 to V4 region of the 16S rRNA gene, and the ecosystem functionality was addressed by measuring the faecal concentration of short-chain fatty acids (SCFAs). In order to measure the short-term physiological gut microbiota fluctuation, the microbiomes of 7 healthy people were characterized before and after 3 days of constant diet. RESULTS: While no convergence of the gut microbiota compositional profiles was observed, a significant increase in SCFA faecal levels was induced only in the Ma-Pi 2 diet group, suggesting the potential of this diet to support a short-term functional convergence of the gut microbiota, regardless of the individual compositional layout. CONCLUSIONS: The Ma-Pi 2 diet, with its high fibre load, was effective in increasing the production of SCFAs by the gut microbiota. Because these metabolites are known for their ability to counterbalance the metabolic deregulation in persons with glucose impairment disorders, their increased bioavailability could be of some relevance in reactive hypoglycemia. PMID- 28806489 TI - Characteristics of Spontaneous Births Attended by Midwives and Physicians in US Hospitals in 2014. AB - INTRODUCTION: This study compares characteristics and birth outcomes of women attended by certified nurse-midwives/certified midwives (midwives) and physicians in US hospitals in 2014. METHODS: Data reported in 2014 on the 2003 version of the US birth certificate were examined. Spontaneous vaginal births attributed to midwives and physicians and occurring in hospitals were included. Demographic and risk profiles and adjusted odds ratios for maternal and newborn outcomes were compared by provider type. RESULTS: Midwives attended 294,604 (12.21%) and physicians attended 2,117,376 (87.79%) of all spontaneous vaginal births occurring in 47 states. Small but statistically significant differences (P < .05) were evident in most characteristics. Substantively, profiles were remarkably similar along all demographic and many medical risk variables. Age, race, and insurance status varied by less than 2 percentage points; education status and Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) participation varied by less than one percentage point. Parity, body mass index, maternal weight gain, tobacco use, trimester care began, and average number of prenatal visits also varied by less than one to 2 percentage points. Midwives attended women with hypertension, diabetes, and infections in proportions similar to physicians. Physicians attended more women with preterm birth and multiple gestation. Midwives attended more women beyond 41 weeks' gestation. There were no differences in 5-minute Apgar scores, neonatal seizures, anomalous neonates, or those no longer living at the time of data collection. Third- or fourth-degree lacerations (odds ratio [OR], 0.81; 95% confidence interval [CI], 0.78-0.84), labor induction (OR, 0.76; 95% CI, 0.76-0.77), and epidural analgesia use (OR, 0.54; 95% CI, 0.53-0.54) were less likely in midwife-attended births. Birth at greater than 42 weeks' gestation was more likely (OR, 2.07; 95% CI, 1.97-2.17) among midwife-attended births. DISCUSSION: In 2014, midwives practicing in US hospitals attended women with a range of risks similar to those of women attended by physicians. Small but statistically significant differences were noted in most characteristics and should be controlled in comparative studies. This contrasts with earlier reports of midwives caring for disproportionately disadvantaged women compared to physicians. PMID- 28806490 TI - Challenges and Resources for Nurses Participating in a Hurricane Sandy Hospital Evacuation. AB - PURPOSE: Weather-related disasters have increased dramatically in recent years. In 2012, severe flooding as a result of Hurricane Sandy necessitated the mid storm patient evacuation of New York University Langone Medical Center. The purpose of this study was to explore, from the nurses' perspective, what the challenges and resources were to carrying out their responsibilities, and what the implications are for nursing education and preparation for disaster. DESIGN: This mixed-methods study included qualitative interviews with a purposive sample of nurses and an online survey of nurses who participated in the evacuation. METHODS: The interviews explored prior disaster experience and training, communication, personal experience during the evacuation, and lessons learned. The cross-sectional survey assessed social demographic factors, nursing education and experience, as well as potential challenges and resources in carrying out their disaster roles. FINDINGS: Qualitative interviews provided important contextual information about the specific challenges nurses experienced and their ability to respond effectively. Survey data identified important resources that helped nurses to carry out their roles, including support from coworkers, providing support to others, personal resourcefulness, and leadership. Nurses experienced considerable challenges in responding to this disaster due to limited prior disaster experience, training, and education, but drew on their personal resourcefulness, support from colleagues, and leadership to adapt to those challenges. CONCLUSIONS: Disaster preparedness education in schools of nursing and practice settings should include more hands-on disaster preparation exercises, more "low-tech" options to address power loss, and specific policies on nurses' disaster roles. CLINICAL RELEVANCE: Nurses play a critical role in responding to disasters. Learning from their disaster experience can inform approaches to nursing education and preparation. PMID- 28806488 TI - The role of 5-HT2B receptors in mitral valvulopathy: bone marrow mobilization of endothelial progenitors. AB - BACKGROUND AND PURPOSE: Valvular heart disease (VHD) is highly prevalent in industrialized countries. Chronic use of anorexigens, amphetamine or ergot derivatives targeting the 5-HT system is associated with VHD. Here, we investigated the contribution of 5-HT receptors in a model of valve degeneration induced by nordexfenfluramine, the main metabolite of the anorexigens, dexfenfluramine and benfluorex. EXPERIMENTAL APPROACH: Nordexfenfluramine was infused chronically (28 days) in mice ((WT and transgenic Htr2B -/- , Htr2A /- , and Htr2B/2A -/- ) to induce mitral valve lesions. Bone marrow transplantation was also carried out. Haemodynamics were measured with echocardiography; tissues and cells were analysed by histology, immunocytochemistry, flow cytometry and RT -qPCR. Samples of human prolapsed mitral valves were also analysed. KEY RESULTS: Chronic treatment of mice with nordexfenfluramine activated 5-HT2B receptors and increased valve thickness and cell density in a thick extracellular matrix, mimicking early steps of mitral valve remodelling. Lesions were prevented by 5-HT2A or 5-HT2B receptor antagonists and in transgenic Htr2B -/- or Htr2A/2B -/- mice. Surprisingly, valve lesions were mainly formed by numerous non-proliferative CD34+ endothelial progenitors. These progenitors originated from bone marrow (BM) as revealed by BM transplantation. The initial steps of mitral valve remodelling involved mobilization of BM-derived CD34+ CD31+ cells by 5-HT2B receptor stimulation. Analysis of human prolapsed mitral valves showing spontaneous degenerative lesions, demonstrated the presence of non-proliferating CD34+ /CD309+ /NOS3+ endothelial progenitors expressing 5-HT2B receptors. CONCLUSIONS AND IMPLICATIONS: BM-derived endothelial progenitor cells make a crucial contribution to the remodelling of mitral valve tissue. Our data describe a new and important mechanism underlying human VHD. PMID- 28806491 TI - The association between dysregulated adipocytokines in early pregnancy and development of gestational diabetes. AB - BACKGROUND: To investigate the association of adipocytokines and other inflammatory markers with development of GDM. METHODS: Serum adipocytokines and inflammatory markers were studied at 12 to 15 weeks gestation using biobanked control samples from a randomised trial. Study participants were identified as high risk for GDM using a validated clinical risk prediction tool. Markers were tested using commercial ELISA kits for high molecular weight (HMW) adiponectin, interleukin-6 (IL-6), plasminogen activator inhibitor-1, visfatin, omentin-1, sex hormone binding globulin, monocyte chemoattractant protein, and asymmetrical dimethylarginine. The association between each biomarker and development of GDM at 24 to 28 weeks was evaluated using multivariable logistic regression analysis adjusted for maternal factors. RESULTS: There were no differences in age, parity, country of birth, smoking, body mass index, or family history of diabetes in women with normal glucose tolerance (n = 78) and women who developed GDM (n = 25). Women with GDM were more likely to have a past history of GDM (P = 0.004). HMW adiponectin (odds ratio OR 0.37 [95% confidence interval 0.19-0.74]), omentin 1 (0.97 [0.94-0.99]), and IL-6 (1.87[1.03-3.37]) were associated with development of GDM, after adjustment for maternal age, body mass index, and past history of GDM. The other markers were not associated with GDM development. CONCLUSIONS: Decreased high molecular weight adiponectin and omentin-1 and increased IL-6 may enhance sensitivity of early risk prediction tools for women at high risk of GDM. This may allow early identification and opportunities for prevention of GDM and adverse outcomes. Further research is required in large validation studies to confirm these results. PMID- 28806492 TI - Evaluation of gastric and bladder tonometry as indicators of tissue perfusion in induced hypotension in dogs. AB - OBJECTIVE: To evaluate the use of gastric (PgCO2 ) and bladder (PbCO2 ) tonometry for assessing tissue hypoperfusion in dogs during sevoflurane-induced hypotension, and to compare these measurements with delivery of oxygen, arterial oxygen content, and plasma lactate concentration. DESIGN: Prospective experimental trial. SETTING: University veterinary teaching hospital. ANIMALS: Fourteen adult Beagle dogs. INTERVENTIONS: Anesthetic induction was performed by mask with sevoflurane and oxygen. Heart rate, direct arterial pressures, respiratory rate, and end-tidal carbon dioxide were recorded; arterial blood samples were taken to measure blood gases, and venous samples were sampled to measure plasma lactate. A tonometric catheter was introduced into the stomach to measure PgCO2 . Samples of saline from the balloon of a Foley catheter placed in the bladder were collected every 10 minutes and used to measure PbCO2 by gas analysis. Tonometry measurements, plasma lactate, and oxygen delivery and consumption were compared at 3 time points: at baseline, during hypotension, and during treatment periods. A hypotensive period (mean arterial pressure (MAP) < 60 mm Hg) of 15 minutes was induced by an overdose of sevoflurane, whereas during the treatment period, a constant-rate infusion of dopamine (10 MUg/kg/min) was administered intravenously for 40 minutes. MEASUREMENTS AND MAIN RESULTS: Values for PgCO2 and PbCO2 increased significantly during the hypotensive period, and correlations were found between these values and the delivery of oxygen. Gastric tonometry values had stronger correlations compared with bladder tonometry values. CONCLUSIONS: Gastric and bladder tonometry can be used to detect hypoperfusion. Further studies are warranted to determine the potential use of gastric and bladder tonometry in assessing dogs in clinical situations. PMID- 28806494 TI - Body Piercing: Motivations and Implications for Health. AB - Body piercing has evolved from a behavior once considered extreme to an accepted choice among the general population. Earlobe piercing is so common that it is now considered a normative behavior. The motivations for choosing body piercing have changed and are associated with piercing site and number of piercings chosen by the individual. Meanings ascribed to body piercing were traditionally related to enhanced sexual desirability and experience, but now range from the innocuous, such as a fashion statement, to the risk laden, such as nonsuicidal self-injury. Professional piercers are the primary providers of piercing services, and people will first turn to their professional piercer for advice when complications of the site arise, thus delaying entry into needed health care. Health care providers are often perceived as uninformed, dismissive, and biased against individuals, who are pierced particularly those with multiple piercings and piercings in intimate areas of the body. Common complications of piercing include infection, bleeding, and problems relating to tissue trauma and scarring, and are reported by nearly 50% of individuals who are pierced. Metal allergies can develop as a result of piercing, making the type of jewelry used for body adornment an important consideration. Additionally, management of the piercing site becomes critical under certain conditions, such as during pregnancy and birth, lactation, or surgery. This article provides information supporting midwives and other health care providers to offer anticipatory guidance and health care services in a nonjudgmental and supportive manner to individuals choosing body piercing. PMID- 28806495 TI - International Uptake of a Proven Intervention to Reduce Death and Dependency in Acute Stroke: A Cross-Sectional Survey Following the QASC Trial. AB - BACKGROUND: Uptake of proven interventions requires dedicated resources that may only result in local implementation, thus precluding international practice change. We explored international uptake through online dissemination of the fever, sugar, and swallow (FeSS) protocols from the Quality in Acute Stroke Care (QASC) trial, which showed decreased death and dependency by 15.7% 90-day poststroke. AIMS: To identify: (a) the clinical discipline of healthcare professionals who downloaded the QASC resources; (b) the purpose for downloading; (c) successful implementation of any or all the FeSS protocols; (d) barriers to implementation; and (e) associations with self-reported successful implementation. METHODS: A cross-sectional, online survey of those who downloaded the QASC resources between October 2011 and August 2013. Associations between implementation and participant characteristics were determined. RESULTS: One hundred and fifty-nine people from 21 countries participated. Nurses were the largest group to download the resources (n = 54, 38%), with the primary purpose to inform clinical practice (n = 97, 64%). Less than half (n = 77, 48%) downloaded, and less than a quarter (n = 38, 24%) attempted to implement all three protocols. Of those personally involved in implementation (n = 50) half reported doing so successfully for one or more protocols (n = 27, 54%) with 10 (20%) reporting successful implementation of all three protocols. Only about half (n = 13, 48%) used the proven implementation strategy with about one-third (n = 10, 29%) confirming successful uptake via audit. Implementation barriers were potential increase in nursing workload (n = 28, 56%) and lack of medical staff engagement (n = 27, 53%). Higher autonomy was associated with greater likelihood of implementation of all three protocols (p = .038). LINKING EVIDENCE TO ACTION: The QASC intervention required use of all three protocols. However, less than half downloaded them all and implementation was not guided by the proven implementation strategy. While encouraging that these resources were being used to drive practice change, piecemeal implementation of a proven intervention is unlikely to improve patient outcomes. PMID- 28806493 TI - Olaparib protects cardiomyocytes against oxidative stress and improves graft contractility during the early phase after heart transplantation in rats. AB - BACKGROUND AND PURPOSE: Olaparib, rucaparib and niraparib, potent inhibitors of poly(ADP-ribose) polymerase (PARP) are approved as anti-cancer drugs in humans. Considering the previously demonstrated role of PARP in various forms of acute and chronic myocardial injury, we tested the effects of olaparib in in-vitro models of oxidative stress in cardiomyocytes, and in an in vivo model of cardiac transplantation. EXPERIMENTAL APPROACH: H9c2-embryonic rat heart-derived myoblasts pretreated with vehicle or olaparib (10MUM) were challenged with either hydrogen peroxide (H2 O2 ) or with glucose oxidase (GOx, which generates H2 O2 in the tissue culture medium). Cell viability assays (MTT, lactate dehydrogenase) and Western blotting for PARP and its product, PAR was performed. Heterotopic heart transplantation was performed in Lewis rats; recipients were treated either with vehicle or olaparib (10 mg kg-1 ). Left ventricular function of transplanted hearts was monitored via a Millar catheter. Multiple gene expression in the graft was measured by qPCR. KEY RESULTS: Olaparib blocked autoPARylation of PARP1 and attenuated the rapid onset of death in H9c2 cells, induced by H2 O2 , but did not affect cell death following chronic, prolonged oxidative stress induced by GOx. In rats, after transplantation, left ventricular systolic and diastolic function were improved by olaparib. In the transplanted hearts, olaparib also reduced gene expression for c-jun, caspase-12, catalase, and NADPH oxidase-2. CONCLUSIONS AND IMPLICATIONS: Olaparib protected cardiomyocytes against oxidative stress and improved graft contractility in a rat model of heart transplantation. These findings raise the possibility of repurposing this clinically approved oncology drug, to be used in heart transplantation. LINKED ARTICLES: This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc. PMID- 28806496 TI - Anterior superior alveolar nerve injury after extended endoscopic medial maxillectomy: a preclinical study to predict neurological morbidity. AB - BACKGROUND: Endoscopic medial maxillectomies (EMMs) are used to optimize exposure of the maxillary sinus and retromaxillary areas. Although in type D EMM (Sturmann Canfield procedure) the anterior superior alveolar nerve (ASAN) is always at risk of injury, only 29% of patients complained of alveolar process and dental anesthesia. The purpose of this anatomical study is to assess the neural anastomotic network of the ASAN (ASAN-NAN) and describe different extensions of type D EMMs in a preclinical setting. METHODS: The ASAN and its medial anastomotic branches (MABs) and lateral anastomotic branches (LABs) were evaluated by cone-beam computerized tomography (CBCT). Five different extensions of type D (D1 to D5) EMMs were identified and nerves at risk of injury in each type were assessed by CBCT. Moreover, quantification of surgical corridors was performed on cadaver heads with a neuronavigation system. RESULTS: Fifty-seven CBCT scans were analyzed. The ASAN would be spared in 16.3% of cases with a type D1 EMM, while it would be injured in the majority of type D2 to D5 resections. At least 1 nerve of the ASAN-NAN was spared in 96.6%, 93%, 74.6%, 0%, and 65.8% of type D1 to D5 EMMs, respectively. Two cadaver heads were dissected and the incremental volume and number of maxillary subsites exposed was assessed in type D1 to D5 EMMs. CONCLUSION: ASAN function impairment is probably compensated by LABs and MABs. If this hypothesis will be validated in a prospective study on patients, preoperative CBCT evaluation could predict neurological morbidity after type D EMM, and allow tailoring the procedure to minimize impairment of the ASAN NAN. PMID- 28806497 TI - Tooth Morphogenesis and FGF4 Expression During Development of Molar Tooth in Three Muroid Rodents: Calomyscus elburzensis (Calomyscidae), Mesocricetus auratus (Cricetidae) and Mus musculus (Muridae). AB - To date, no studies have examined the tooth formation during developmental stages of brush-tailed mice (Calomyscidae) and true hamsters (Cricetidae). Herein, we compared the timing of tooth morphogenesis and FGF4 expression pattern during development of the first lower molar in Goodwin's brush-tailed mouse, Calomyscus elburzensis with two other muroid rodents; the house mouse, Mus musculus (Muridae), model organism for tooth morphogenesis, and the golden hamster, Mesocricetus auratus which shares great similarities in cusp pattern with brush tailed mice. All three species were bred in captivity and developing embryos were isolated at different embryonic days (E). Histological evaluation of lower molars was performed and spatiotemporal pattern of FGF4 expression was determined by immunohistochemistry. Results indicated that morphogenesis of the tooth cusps starts at the beginning of the cap stage of the first lower molar (E14 in house mouse, about E11.5 in golden hamster and E22 in Goodwin's brush-tailed mouse). During the cap to bell stage (E15 in house mouse, E12 in golden hamster and at about E24 in Goodwin's brush-tailed mouse), a decrease in the expression of FGF4 was observed in the mesenchyme, except for the cusp tips. According to our observations, the developmental process of the first lower molar formation in Goodwin's brush-tailed mouse began much later as compared with the other two species. Despite the differences in the temporal pattern of molar development between these three members of the same superfamily (Muroidea), the correlation in the expression of FGF4 with specific stages of tooth morphogenesis supported its regulatory function. Anat Rec, 300:2138-2149, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28806498 TI - Pacinian Corpuscles in Human Lymph Nodes. AB - The occurrence of Pacinian corpuscles associated to lymph nodes is an anatomical rarity and very scarce information exists in this regard. Here we examined immunohistochemically four Pacinian corpuscles found in the close vicinity of the hiliar blood vessels of lymph nodes (2 cervical, 1 axillary, and 1 inguinal) during routine surgical pathology. Pacinian corpuscles were normally arranged and displayed a pattern of protein distribution as follows: the axon was positive for neurofilament proteins and neuron specific enolase, the inner core cells showed intense S100 protein and vimentin immunostaining while they were negative for glial fibrillary acidic protein, type IV collagen and glucose transporter 1; vimentin, type IV collagen, and glucose transporter 1 were also observed also in the outer-core and the capsule. These results are in agreement with those reported for cutaneous Pacinian corpuscles, demonstrating that the immunohistochemical profile of these corpuscles is independent of its anatomical localization. The possible functional significance of Pacinian corpuscles in lymph nodes is discussed. Anat Rec, 300:2233-2238, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28806499 TI - Hibernating Little Pocket Mice Show Few Seasonal Changes in Bone Properties. AB - Periods of disuse or physical inactivity increases bone porosity and decreases bone mineral density, resulting in a loss of bone mechanical competence in many animals. Although large hibernators like bears and marmots prevent bone loss during hibernation, despite long periods of physical inactivity, some small hibernators do lose bone during hibernation. Little pocket mice (Perognathus longimembris) remain underground during winter hibernation and undergo bouts of torpor and interbout arousals, but the torpor bout duration is shorter than other rodent hibernators. Additionally, little pocket mice may enter torpor during summer estivation. In this study, cortical and trabecular bone architectural, mineral, and mechanical properties were analyzed for femurs from little pocket mice captured during 8 different months (March to October) to determine seasonal effects on bone. There were no differences in any bone properties between the pre hibernation month of October and the post-hibernation month of March, suggesting winter hibernation did not adversely affect bone properties. However, cortical area was higher in March than April, May, and June. Bone mechanical and osteocyte lacunar properties were not different between any months. Trabecular bone in the distal femoral epiphysis showed no changes between months. The distal femoral metaphyseal region showed higher trabecular spacing and lower trabecular number in May than August, otherwise, there were no differences in trabecular parameters. The few monthly differences in bone properties may be due to physical inactivity from periodic summer estivation or from the timing of birth and growth in spring and summer months. Anat Rec, 300:2175-2183, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28806501 TI - The innate immune system and beyond. PMID- 28806500 TI - Doxepin Mitigates Noise-induced Neuronal Damage in Primary Auditory Cortex of Mice via Suppression of Acid Sphingomyelinase/Ceramide Pathway. AB - Neuronal damage in primary auditory cortex (A1) underlies complex manifestations of noise exposure, prevention of which is critical for health maintenance. Acid sphingomyelinase (ASM) catalyzes generation of ceramide (Cer) which if over activated mediates neuronal disorders in various diseases. Tricyclic antidepressants (TCAs), by restraining ASM/Cer, benefits multiple neuronal anomalies, so we aimed to elucidate the effect of TCA on noise induced hearing loss and auditory cortex derangement, unraveling mechanism involved. The mice were exposed to noise with frequencies of 20-20 KHz and intensity of 95 dB. Doxepin hydrochloride (DOX), a kind of TCAs, was given intragastrically by 5 mg kg-1 days-1 . Morphology of neurons was examined using hematoxylin-eosin (HE) and Nissl staining. Apoptosis was assayed through transferase-mediated dUTP nick end labeling (TUNEL). The content of ASM, Cer or acid ceramidase (AC) was detected by western blot and immunohistochemistry analysis. We demonstrated intense, broad band noise caused upward shift of auditory brainstem response (ABR) threshold to sound over frequencies 4-32 KHz, with prominent morphologic changes and enhanced apoptosis in neurons of primary auditory cortex (A1) (P < 0.05). DOX partly restored noise-caused hearing loss alleviating morphologic changes or apoptosis remarkably (P < 0.05). Both ASM and Cer abundance were elevated significantly by noise which was reversed upon DOX treatment (P < 0.05), but neither noise nor DOX altered AC content. DOX had no influence on hearing, neuronal morphology or ASM/Cer in control mice. Our result suggests DOX palliates noise induced hearing loss and neuronal damage in auditory cortex by correcting over-activation of ASM/Cer without hampering intrinsic behavior of it. Anat Rec, 300:2220-2232, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28806502 TI - Efficacy of endoscopic sinus surgery for chronic rhinosinusitis following primary radiotherapy and concurrent chemotherapy for nasopharyngeal carcinoma. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is a downstream complication following radiotherapy or chemoradiation for nasopharyngeal carcinoma (NPC). Endoscopic sinus surgery (ESS) is an accepted therapy for medically refractory CRS, but its efficacy in addressing CRS symptoms in patients with previously irradiated NPC is unclear. METHODS: All patients at the Stanford Sinus Center with a history of radiation therapy or chemoradiation for NPC between 2006 and 2015 were reviewed. Patients without antecedent CRS prior to NPC treatment (n = 26) were retrospectively divided into 2 cohorts based on whether they developed postirradiation CRS and underwent ESS (surgical group, n = 13) or did not develop CRS (control, n = 13). Demographic and clinical characteristics were collected, and temporal changes in 22-item Sino-Nasal Outcome Test (SNOT-22) score were compared. RESULTS: The median time following primary irradiation to initial presentation was 6.8 and 6.5 years in the surgical and control groups, respectively. The surgical cohort had statistically greater baseline SNOT-22 scores than the control group (45 vs 14, p = 0.0198). At 6 to 12 months postoperatively, the surgical group demonstrated statistically significant and clinically meaningful improvements in SNOT-22 scores when compared to controls (15-point decrease vs 0, p = 0.0040), ultimately resulting in similar SNOT-22 scores for both groups (28 vs 18, p = 0.3687). The rhinologic, extranasal, and ear/face subdomain scores of the surgical group were significantly greater than those of the control group preoperatively (rhinologic: p = 0.0010; extranasal: p = 0.0179; ear/face: p = 0.0068), but these disparities resolved postoperatively (rhinologic: p = 0.1461; extranasal: p = 0.3131; ear/face: p = 0.3401). CONCLUSION: ESS appears to effectively manage recalcitrant CRS symptoms in patients previously treated with radiation therapy and concurrent chemotherapy for NPC. PMID- 28806503 TI - Identification of the Dimer Exchange Interface of the Bacterial DNA Damage Response Protein UmuD. AB - The Escherichia coli SOS response, an induced DNA damage response pathway, confers survival on bacterial cells by providing accurate repair mechanisms as well as the potentially mutagenic pathway translesion synthesis (TLS). The umuD gene products are upregulated after DNA damage and play roles in both nonmutagenic and mutagenic aspects of the SOS response. Full-length UmuD is expressed as a homodimer of 139-amino-acid subunits, which eventually cleaves its N-terminal 24 amino acids to form UmuD'. The cleavage product UmuD' and UmuC form the Y-family polymerase DNA Pol V (UmuD'2C) capable of performing TLS. UmuD and UmuD' exist as homodimers, but their subunits can readily exchange to form UmuDD' heterodimers preferentially. Heterodimer formation is an essential step in the degradation pathway of UmuD'. The recognition sequence for ClpXP protease is located within the first 24 amino acids of full-length UmuD, and the partner of full-length UmuD, whether UmuD or UmuD', is degraded by ClpXP. To better understand the mechanism by which UmuD subunits exchange, we measured the kinetics of exchange of a number of fluorescently labeled single-cysteine UmuD variants as detected by Forster resonance energy transfer. Labeling sites near the dimer interface correlate with increased rates of exchange, indicating that weakening the dimer interface facilitates exchange, whereas labeling sites on the exterior decrease the rate of exchange. In most but not all cases, homodimer and heterodimer exchange exhibit similar rates, indicating that somewhat different molecular surfaces mediate homodimer exchange and heterodimer formation. PMID- 28806504 TI - Designing Liposomes To Suppress Extracellular Matrix Expression To Enhance Drug Penetration and Pancreatic Tumor Therapy. AB - During pancreatic tumor development, pancreatic stellate cells (PSCs) proliferate exuberantly to secrete extracellular matrix (ECM) in the tumor stroma, which presents major barriers for drug delivery and penetration in tumor tissue. Thus, down-regulating ECM levels via regulation of the PSCs may allow enhanced penetration of therapeutic drugs and thereby enhancing their therapeutic efficacy. To regulate the PSCs, a matrix metalloproteinase-2 (MMP-2) responsive peptide-hybrid liposome (MRPL) was constructed via coassembly of a tailor designed MMP-2 responsive amphiphilic peptide and phospholipids. By utilizing the MMP-2-rich pathological environment, the pirfenidone (PFD) loaded MRPL (MRPL-PFD) can specifically release PFD at the pancreatic tumor site and down-regulate the multiple components of ECM expressed by the PSCs. This resulted in a significant increase in the penetration of gemcitabine into the tumor tissue and enhanced the efficacy of gemcitabine for pancreatic tumor. Our design tailored for antifibrosis of pancreatic cancer may provide a practical approach to build functional liposomes through supramolecular assembly, and regulation of ECM may be a promising adjuvant therapeutic strategy for pancreatic and other ECM-rich tumors. PMID- 28806505 TI - Co4N Nanowires: Noble-Metal-Free Peroxidase Mimetic with Excellent Salt- and Temperature-Resistant Abilities. AB - Compared to natural enzymes, nanomaterial-based artificial enzymes have attracted immense attention because of their high stability and cost-effectiveness. In this study, cobalt nitride (Co4N) as a noble-metal-free artificial enzyme exhibiting highly intrinsic peroxidase-like activity and good stability was reported. Kinetic studies revealed that the resultant Co4N nanowires (NWs) exhibited a stronger affinity for 3,3',5,5'-tetramethylbenzidine (TMB) and H2O2 than HRP. Compared to Co3O4 NWs, Co4N NWs exhibited highly improved catalytic activities, with H2O2 exhibiting an apparent Km approximately 2 orders of magnitude less than that of Co3O4. In particular, the peroxidase-like activity of Co4N was maintained well over a wide range of temperatures and ionic strength. A Co4N-based method was further developed for the detection of glucose with good sensitivity and reliability. Because of advantages such as easy storage, cost-effectiveness, high sensitivity, and outstanding stability, Co4N NWs demonstrate the potential for replacing noble-metal-based peroxidase mimetics in a wide range of promising applications. PMID- 28806506 TI - Quantifying Recycling and Losses of Cr and Ni in Steel Throughout Multiple Life Cycles Using MaTrace-Alloy. AB - Alloying metals are indispensable ingredients of high quality alloy steel such as austenitic stainless steel, the cyclical use of which is vital for sustainable resource management. Under the current practice of recycling, however, different metals are likely to be mixed in an uncontrolled manner, resulting in function losses and dissipation of metals with distinctive functions, and in the contamination of recycled steels. The latter could result in dilution loss, if metal scrap needed dilution with virgin iron to reduce the contamination below critical levels. Management of these losses resulting from mixing in repeated recycling of metals requires tracking of metals over multiple life cycles of products with compositional details. A new model (MaTrace-alloy) was developed that tracks the fate of metals embodied in each of products over multiple life cycles of products, involving accumulation, discard, and recycling, with compositional details at the level of both alloys and products. The model was implemented for the flow of Cr and Ni in the Japanese steel cycle involving 27 steel species and 115 final products. It was found that, under a high level of scrap sorting, greater than 70% of the initial functionality of Cr and Ni could be retained over a period of 100 years, whereas under a poor level of sorting, it could plunge to less than 30%, demonstrating the relevance of waste management technology in circular economy policies. PMID- 28806507 TI - Triboelectric Nanogenerator Enabled Body Sensor Network for Self-Powered Human Heart-Rate Monitoring. AB - Heart-rate monitoring plays a critical role in personal healthcare management. A low-cost, noninvasive, and user-friendly heart-rate monitoring system is highly desirable. Here, a self-powered wireless body sensor network (BSN) system is developed for heart-rate monitoring via integration of a downy-structure-based triboelectric nanogenerator (D-TENG), a power management circuit, a heart-rate sensor, a signal processing unit, and Bluetooth module for wireless data transmission. By converting the inertia energy of human walking into electric power, a maximum power of 2.28 mW with total conversion efficiency of 57.9% was delivered at low operation frequency, which is capable of immediately and sustainably driving the highly integrated BSN system. The acquired heart-rate signal by the sensor would be processed in the signal process circuit, sent to an external device via the Bluetooth module, and displayed on a personal cell phone in a real-time manner. Moreover, by combining a TENG-based generator and a TENG based sensor, an all-TENG-based wireless BSN system was developed, realizing continuous and self-powered heart-rate monitoring. This work presents a potential method for personal heart-rate monitoring, featured as being self-powered, cost effective, noninvasive, and user-friendly. PMID- 28806508 TI - Cubic Fluorite-Type CaH2 with a Small Bandgap. AB - A cubic variant of CaH2 adopting a fluorite-type crystal structure was synthesized by cationic substitution with La or Y, yielding the first alkaline earth hydride-based with fluorite-type framework. The material has a bandgap of ~2.5 eV (greenish yellow in color), which is much smaller than that of orthorhombic PbCl2-type CaH2 (4.4 eV) and is, in fact, the smallest among alkaline or alkaline earth metal hydrides reported to date. Analysis of the density functional theory band structure of cubic-CaH2 indicates that its conduction band minimum is formed mainly by the interaction between the Ca 3d eg orbitals around the crystallographic cavity defined by cubes of H- ions. The use of such cavities in the creation of low-lying conduction band minima by semiconductors is extremely rare, and has similarities to inorganic electrides. PMID- 28806509 TI - Two-Photon Probes for pH: Detection of Human Colon Cancer using Two-Photon Microscopy. AB - We have developed two-photon (TP) pH-sensitive probes (BH-2 and BHEt-1) that exhibit absorption and emission maxima at 370 and 466 nm, and TP absorption cross section values of 51 and 61 GM (1 GM = 10-50cm4s/photon), respectively, at 750 nm and pH 3.0 in a universal buffer (0.1 M citric acid, 0.1 M KH2PO4, 0.1 M Na2B4O7, 0.1 M Tris, 0.1 M KCl)/1,4-dioxane (7/3) solution. The TPM images of CCD-18co (a normal colon cell line) and HCT116 cells (a colon cancer cell line) labeled with BH-2 were too dim to be distinguished. When the same cells were labeled with BHEt 1, however, the TPM image of the HCT116 cells was much brighter than that of CCD 18co cells, and the relative proportion of the acidic vesicles (Pacid) of the former was 5-fold larger than that of latter. BHEt-1 could also differentiate HepG2 cells (a human liver cancer cell line) from LX-2 cells (a human hepatic stellate cell line) with a 6-fold larger Pacid value. Human colon cancer tissues labeled with BHEt-1 showed similar results, demonstrating much brighter TPM images and 6-fold larger Pacid values compared to normal tissue. These results suggest the potential utility of BHEt-1 for detecting colon cancer in human tissues using TPM. PMID- 28806510 TI - Reaction between Pyridine and CH3NH3PbI3: Surface-Confined Reaction or Bulk Transformation? AB - Pyridine molecules have been used to passivate surface Pb2+ sites of CH3NH3PbI3, to recrystallize CH3NH3PbI3, and to bleach CH3NH3PbI3. However, these results contradict each other, as recrystallization and optical-bleach require transformation of bulk CH3NH3PbI3, but surface passivation demands the confinement of the reaction at the surface region. The underlying mechanism for these seemly contradicting results is not yet understood. In this paper, we show, at 25 degrees C, partial pressure of pyridine vapor is a determining factor for its reaction behaviors with CH3NH3PbI3: one can modify the surface region of CH3NH3PbI3 by using pyridine vapor of pressure 1.15 torr or lower but can transform the whole bulk CH3NH3PbI3 film with a pyridine vapor of 1.3 torr or higher. Our result is the first demonstration that the reaction modes, i.e., surface-confined reaction and bulk transformation, are very sensitive to the partial pressure of under-saturated pyridine vapor. Despite the different reaction behaviors, it is interesting that in all pressure ranges, pyridinium ion is a main product from the reaction between pyridine and CH3NH3PbI3. The bulk transformation is due to the formation of a liquid-like film, which increases the mobility of species to catalyze the reaction between pyridine and CH3NH3PbI3. It is important to note 1.3 torr is much smaller than the saturated vapor pressure of pyridine (20 torr at 25 degrees C). These findings provide a guidance in applying pyridine and other amines to functionalize and transform CH3NH3PbI3 and other hybrid halide perovskites. It also highlights the critical role of fundamental studies in controllably modifying CH3NH3PbI3. PMID- 28806511 TI - Understanding and Reducing Photothermal Forces for the Fabrication of Au Nanoparticle Dimers by Optical Printing. AB - Optical printing holds great potential to enable the use of the vast variety of colloidal nanoparticles (NPs) in nano- and microdevices and circuits. By means of optical forces, it enables the direct assembly of NPs, one by one, onto specific positions of solid surfaces with great flexibility of pattern design and no need of previous surface patterning. However, for unclear causes it was not possible to print identical NPs closer to each other than 300 nm. Here, we show that the repulsion restricting the optical printing of close by NPs arises from light absorption by the printed NPs and subsequent local heating. By optimizing heat dissipation, it is possible to reduce the minimum separation between NPs. Using a reduced graphene oxide layer on a sapphire substrate, we demonstrate for the first time the optical printing of Au-Au NP dimers. Modeling the experiments considering optical, thermophoretic, and thermo-osmotic forces we obtain a detailed understanding and a clear pathway for the optical printing fabrication of complex nano structures and circuits based on connected colloidal NPs. PMID- 28806512 TI - Painkiller Isoxicam and Its Copper Complex Can Form Inclusion Complexes with Different Cyclodextrins: A Fluorescence, Fourier Transform Infrared Spectroscopy, and Nuclear Magnetic Resonance Study. AB - The interaction of a painkiller Isoxicam, belonging to the oxicam group of nonsteroidal anti-inflammatory drugs (NSAIDs) and its copper complex with different cyclodextrins (beta-CD, gamma-CD, HPbetaCD, and HPgammaCD), has been investigated in both solution and the solid state. Steady state and time-resolved fluorescence spectroscopy, fluorescence anisotropy, 1H NMR, and FTIR spectroscopy are used. Both the drug and its copper complex form a host-guest inclusion complex with all CDs. Fluorescence spectroscopy is used to determine binding constants and stoichiometries of the host-guest complex. The strongest binding is seen for gamma-CD. 1H NMR study showed that Isoxicam penetrates into the CD cavity from the more accessible wider side. For beta- and gamma-CD, Isoxicam showed one type of binding, i.e., formation of an inclusion complex, whereas, for HPbetaCD and HPgammaCD, it showed two types of binding, i.e., inclusion in the CD cavities and interaction with the outer surface of the CD molecules mainly near the hydroxy propyl group. Deeper penetration occurred into the larger diameter cavity of gamma-CD and HPgammaCD compared to beta-CD and HPbetaCD. From FTIR and 1H NMR study, it is seen that predominantly the pi-electron-rich benzene part of the drug and its complex penetrate into the host cavity. PMID- 28806513 TI - Intraperitoneal Delivery of Cisplatin via a Hyaluronan-Based Nanogel/in Situ Cross-Linkable Hydrogel Hybrid System for Peritoneal Dissemination of Gastric Cancer. AB - Intraperitoneal administration of chemotherapeutics is expected for the treatment of peritoneally disseminated gastric cancer because of poor migration of the drugs from the systemic circulation to the peritoneal cavity. In this study, for intraperitoneal delivery of cisplatin (CDDP), we developed a hyaluronan (HA) based hybrid system in which CDDP-loaded HA nanogels were either physically encapsulated in or chemically conjugated to injectable HA hydrogels. Physical encapsulation enabled sustained release of HA nanogels from the HA hydrogel matrix for over a week. This was a longer release period than that of encapsulated free CDDP, which released 80% of the drug in 2 days. The longer release was attributed to delayed diffusion of HA nanogels from the hydrogel matrix network. The release profile could be tuned by modifying the chemical conjugation of HA nanogels to the HA hydrogel matrix, as well as the type of chelating ligands used to load CDDP to the nanogel. Furthermore, intraperitoneally administered hybrid had significant antitumor activity in a mouse model of peritoneally disseminated gastric cancer, especially for nodules smaller than 1.0 mm. PMID- 28806514 TI - Phenolic Compounds Profiling of Virgin Olive Oils from Different Varieties Cultivated in Mendoza, Argentina, by Using Liquid Chromatography-Mass Spectrometry. AB - The aim of this work was to achieve a preliminary characterization of the profile of the phenolic fraction of virgin olive oils (VOOs) from Maipu (Mendoza, Argentina). Thus, 25 commercial VOO samples from Arauco, Arbequina, Picual, Frantoio, Changlot, Empeltre, Nevadillo, Manzanilla, and Coratina (both monovarietals and blends) were analyzed using LC-ESI-QTOF MS and LC-ESI-IT MS for identification and quantification purposes, respectively. A rapid LC method (15 min) accomplished quantitative information about a total of 40 phenolic compounds, including secoiridoid derivatives, which have not been evaluated before in samples coming from the subregion so-called Maipu (Mendoza province, Argentina). The results make evident that olive oils coming from Mendoza can be considered as important sources of phenolic bioactive compounds, exhibiting similar phenolic compound levels to those shown by oils from other typical world production regions. Moreover, some distinctive features of the Arauco variety (Argentinean autochthonous variety) were pointed out; indeed, a correlation between flavonoids content and botanical variety was established herewith. PMID- 28806515 TI - Redox-Triggered Coloration Mechanism of Electrically Tunable Colloidal Photonic Crystals. AB - Electrically tunable colloidal photonic crystals (ETPCs) have been investigated because of several merits such as easy color tunability, no discoloration, and clear color. The coloration mechanism of ETPCs has been explained in terms of only the electric field. Herein, we report on a new mechanism: electric field plus redox reaction. Specifically, the coloration behavior of ETPCs was investigated under electrically conductive or insulated conditions using current voltage, cyclic voltammetry, and zeta potential measurements, as well as scanning electron microscopy. Electrophoretic movement of ETPC particles toward the positive electrode was caused by the electric field due to the particles' negative surface charge. At the positive electrode, ETPC particles lost their electrons and formed a colloidal crystal structure. Finally, an ETPC transparent tube device was constructed to demonstrate the coloration mechanism. PMID- 28806516 TI - Scalable and Facile Preparation of Highly Stretchable Electrospun PEDOT:PSS@PU Fibrous Nonwovens toward Wearable Conductive Textile Applications. AB - Flexible and stretchable conductive textiles are highly desired for potential applications in wearable electronics. This study demonstrates a scalable and facile preparation of all-organic nonwoven that is mechanically stretchable and electrically conductive. Polyurethane (PU) fibrous nonwoven is prepared via the electrospinning technique; in the following step, the electrospun PU nonwoven is dip-coated with the conducting polymer poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS). This simple method enables convenient preparation of PEDOT:PSS@PU nonwovens with initial sheet resistance in the range of 35-240 Omega/sq (i.e., the electrical conductivity in the range of 30-200 S m-1) by varying the number of dip-coating times. The resistance change of the PEDOT:PSS@PU nonwoven under stretch is investigated. The PEDOT:PSS@PU nonwoven is first stretched and then released repeatedly under certain strain (denoted as prestretching strain); the resistance of PEDOT:PSS@PU nonwoven becomes constant after the irreversible change for the first 10 stretch release cycles. Thereafter, the resistance of the nonwoven does not vary appreciably under stretch as long as the strain is within the prestretching strain. Therefore, the PEDOT:PSS@PU nonwoven can be used as a stretchable conductor within the prestretching strain. Circuits using sheet and twisted yarn of the nonwovens as electric conductors are demonstrated. PMID- 28806517 TI - From Nonluminescent Cs4PbX6 (X = Cl, Br, I) Nanocrystals to Highly Luminescent CsPbX3 Nanocrystals: Water-Triggered Transformation through a CsX-Stripping Mechanism. AB - We report a novel CsX-stripping mechanism that enables the efficient chemical transformation of nonluminescent Cs4PbX6 (X = Cl, Br, I) nanocrystals (NCs) to highly luminescent CsPbX3 NCs. During the transformation, Cs4PbX6 NCs dispersed in a nonpolar solvent are converted into CsPbX3 NCs by stripping CsX through an interfacial reaction with water in a different phase. This process takes advantage of the high solubility of CsX in water as well as the ionic nature and high ion diffusion property of Cs4PbX6 NCs, and produces monodisperse and air stable CsPbX3 NCs with controllable halide composition, tunable emission wavelength covering the full visible range, narrow emission width, and high photoluminescent quantum yield (up to 75%). An additional advantage is that this is a clean synthesis as Cs4PbX6 NCs are converted into CsPbX3 NCs in the nonpolar phase while the byproduct of CsX is formed in water that could be easily separated from the organic phase. The as-prepared CsPbX3 NCs show enhanced stability against moisture because of the passivated surface. Our finding not only provides a new pathway for the preparation of highly luminescent CsPbX3 NCs but also adds insights into the chemical transformation behavior and stabilization mechanism of these emerging perovskite nanocrystals. PMID- 28806518 TI - In Vivo Biosynthesized Zinc and Iron Oxide Nanoclusters for High Spatiotemporal Dual-Modality Bioimaging of Alzheimer's Disease. AB - Alzheimer's disease is still incurable and neurodegenerative, and there is a lack of detection methods with high sensitivity and specificity. In this study, by taking different month old Alzheimer's mice as models, we have explored the possibility of the target bioimaging of diseased sites through the initial injection of zinc gluconate solution into Alzheimer's model mice post-tail vein and then the combination of another injection of ferrous chloride (FeCl2) solution into the same Alzheimer's model mice post-stomach. Our observations indicate that both zinc gluconate solution and FeCl2 solution could cross the blood-brain barrier (BBB) to biosynthesize the fluorescent zinc oxide nanoclusters and magnetic iron oxide nanoclusters, respectively, in the lesion areas of the AD model mice, thus enabling high spatiotemporal dual-modality bioimaging (i.e., including fluorescence bioimaging (FL) and magnetic resonance imaging (MRI)) of Alzheimer's disease for the first time. The result presents a novel promising strategy for the rapid and early diagnosis of Alzheimer's disease. PMID- 28806519 TI - Pluronic P85/F68 Micelles of Baicalein Could Interfere with Mitochondria to Overcome MRP2-Mediated Efflux and Offer Improved Anti-Parkinsonian Activity. AB - Overexpression of the drug efflux transporter multidrug resistance-associated protein 2 (MRP2) in the gastrointestinal tract and blood-brain barrier compromises the oral delivery of drugs to the circulation system and brain in the treatment of Parkinson's disease (PD). In this study, we aim to develop small sized Pluronic P85/F68 micelles loaded with baicalein (B-MCs) to overcome MRP2 mediated efflux and to investigate related mechanism, as well as the anti Parkinsonian efficacy. Spherical and sustained-release B-MCs have a mean particle size of 40.61 nm, a low critical micelle concentration (CMC) of 5.01 * 10-3 mg/mL with an encapsulation efficiency of 95.47% and a drug loading of 7.07%. In comparison with the free baicalein, the cellular uptake and apparent permeability coefficient (Papp) of B-MCs were significantly enhanced (p < 0.01). Fluorescence resonance energy transfer (FRET) analysis indicated that micelles carrying the hydrophobic fluorophores were internalized intact, followed by a rapid release of fluorophores inside the cells, and then the released free fluorophores were transported across the cell monolayers to the basolateral side. Further study on the MRP2 inhibitory effect showed that B-MCs could reverse the MRP2-mediated efflux of baicalein via interfering with the structure and function of mitochondria, i.e., reducing mitochondrial membrane potential and intracellular ATP level and influencing the respiration chain of mitochondria. In addition, B MCs exerted strong neuroprotective effects on zebrafish model of PD. In summary, Pluronic P85/F68 micelles could be considered as a promising drug delivery system to reverse MRP2-mediated efflux and improve the bioactivity of this MRP2 substrate, baicalein, for the treatment of PD. PMID- 28806520 TI - Tailoring the Doping Mechanisms at Oxide Interfaces in Nanoscale. AB - Here, we demonstrate the nanoscale manipulations of two types of charge transfer to the LaAlO3/SrTiO3 interfaces: one from surface adsorbates and another from oxygen vacancies inside LaAlO3 films. This method can be used to produce multiple insulating and metallic interface states with distinct carrier properties that are highly stable in air. By reconfiguring the patterning and comparing interface structures formed from different doping sources, effects of extrinsic and intrinsic material characters on the transport properties can be distinguished. In particular, a multisubband to single-subband transition controlled by the structural phases in SrTiO3 was revealed. In addition, the transient behaviors of nanostructures also provided a unique opportunity to study the nanoscale diffusions of adsorbates and oxygen vacancies in oxide heterostructures. Knowledge of such dynamic processes is important for nanodevice implementations. PMID- 28806521 TI - Determination of Caspase-3 Activity and Its Inhibition Constant by Combination of Fluorescence Correlation Spectroscopy with a Microwell Chip. AB - Caspase-3 is a key enzyme executing apoptosis during ontogenesis and homeostasis of multicellular organisms, and is a very important and potential drug target in treatment of apoptosis disturbance. So far, no commercial drugs for caspase-3 are available, and it is urgently necessitated to develop an effective method for caspase-3 activity assay and its inhibitor screening. In this paper, we propose a new method for determination of caspase-3 activity and its inhibition constant by combining single molecule fluorescence correlation spectroscopy (FCS) with a microwell chip. Its principle is based on measurement of the enzyme reaction kinetics and homogeneous detection of the reaction product by FCS. This system can reduce the requirement sample volume to 1 MUL level. The caspase-3 substrates are doubly labeled with fluorophore and biotin, the enzyme reaction can be quickly terminated in the presence of streptavidin, and the reaction products can be selectively detected by FCS. We established the model of caspase-3 inhibitor screening by combining the dynamics of enzyme reaction with FCS theory. This new method was successfully used for determination of inhibition constants of certain inhibitors and assay of drug-induced apoptosis. Compared to current methods, this method shows high sensitivity, small reagent dosage and short analysis time. We believe that this method will become an efficient platform for screening of caspase-3 inhibitors and detection of apoptosis. PMID- 28806523 TI - Production of Concentrated Pickering Emulsions with Narrow Size Distributions Using Stirred Cell Membrane Emulsification. AB - Stirred cell membrane emulsification (SCME) has been employed to prepare concentrated Pickering oil in water emulsions solely stabilized by fumed silica nanoparticles. The optimal conditions under which highly stable and low polydispersity concentrated emulsions using the SCME approach are highlighted. Optimization of the oil flux rates and the paddle stirrer speeds are critical to achieving control over the droplet size and size distribution. Investigating the influence of oil volume fraction highlights the criticality of the initial particle loading in the continuous phase on the final droplet size and polydispersity. At a particle loading of 4 wt %, both the droplet size and polydispersity increase with increasing of the oil volume fraction above 50%. As more interfacial area is produced, the number of particles available in the continuous phase diminishes, and coincidently a reduction in the kinetics of particle adsorption to the interface resulting in larger polydisperse droplets occurs. Increasing the particle loading to 10 wt % leads to significant improvements in both size and polydispersity with oil volume fractions as high as 70% produced with coefficient of variation values as low as ~30% compared to ~75% using conventional homogenization techniques. PMID- 28806522 TI - Development of a Recombinant Multifunctional Biomacromolecule for Targeted Gene Transfer to Prostate Cancer Cells. AB - The objective of this study was to genetically engineer a fully functional single chain fusion peptide composed of motifs from diverse biological and synthetic origins that can perform multiple tasks including DNA condensation, cell targeting, cell transfection, particle shielding from immune system and effective gene transfer to prostate tumors. To achieve the objective, a single chain biomacromolecule (vector) consisted of four repeatative units of histone H2A peptide, fusogenic peptide GALA, short elastin-like peptide, and PC-3 cell targeting peptide was designed. To examine the functionality of each motif in the vector sequence, it was characterized in terms of size and zeta potential by Zetasizer, PC-3 cell targeting and transfection by flowcytometry, IgG induction by immunogenicity assay, and PC-3 tumor transfection by quantitative live animal imaging. Overall, the results of this study showed the possibility of using genetic engineering techniques to program various functionalities into one single chain vector and create a multifunctional nonimmunogenic biomacromolecule for targeted gene transfer to prostate cancer cells. This proof-of-concept study is a significant step forward toward creating a library of vectors for targeted gene transfer to any cancer cell type at both in vitro and in vivo levels. PMID- 28806524 TI - Assessment of Effects of the Long-Term Exposure of Agricultural Crops to Carbon Nanotubes. AB - Carbon-based nanoparticles (CBNs) are nanomaterials that have been shown to be plant growth regulators. Here, we investigated the effects of long-term exposure to multi-walled carbon nanotubes (MWCNTs) on the growth of three important crops (barley, soybean, and corn). The tested species were cultivated in hydroponics supplemented with 50 MUg/mL MWCNTs. After 20 weeks of continuous exposure to the nanomaterials, no significant toxic effects on plant development were observed. Several positive phenotypical changes were recorded, in addition to the enhancement of photosynthesis in MWCNT-exposed crops. Raman spectroscopy with point-by-point mapping proved that the MWCNTs in the hydroponic solution moved into all tested species and were distributed in analyzed organs (leaves, stems, roots, and seeds). Our results confirmed the significant potential of CBN in plant agriculture. However, the documented presence of MWCNTs in different organs of all exposed crops highlighted the importance of detailed risk assessment of nanocontaminated plants moving into the food chain. PMID- 28806525 TI - Imaging the Localized Plasmon Resonance Modes in Graphene Nanoribbons. AB - We report a nanoinfrared (IR) imaging study of the localized plasmon resonance modes of graphene nanoribbons (GNRs) using a scattering-type scanning near-field optical microscope (s-SNOM). By comparing the imaging data of GNRs that are aligned parallel and perpendicular to the in-plane component of the excitation laser field, we observed symmetric and asymmetric plasmonic interference fringes, respectively. Theoretical analysis indicates that the asymmetric fringes are formed due to the interplay between the localized surface plasmon resonance (SPR) mode excited by the GNRs and the propagative surface plasmon polariton (SPP) mode launched by the s-SNOM tip. With rigorous simulations, we reproduce the observed fringe patterns and address quantitatively the role of the s-SNOM tip on both the SPR and SPP modes. Furthermore, we have seen real-space signatures of both the dipole and higher-order SPR modes by varying the ribbon width. PMID- 28806526 TI - Highly Selective Self-Powered Sensing Platform for p-Nitrophenol Detection Constructed with a Photocathode-Based Photocatalytic Fuel Cell. AB - A photocathode-based photocatalytic fuel cell (PFC) was fabricated and proposed as a self-powered sensor for p-nitrophenol (p-NP) detection. The PFC was comprised of a photocathode and an anode in separated chambers, which could generate suitable power output under photoirradiation to drive the sensing process. In this device, p-type PbS quantum dots-modified glass carbon electrode (GCE) served as the photocathode for the reduction of p-NP under photoirradiation while graphene-modified GCE was employed as the anode for the oxidation of ascorbic acid. In order to improve the selectivity of the PFC sensor, p-NP binding molecularly imprinted polymer (MIP) was introduced on the photocathode. Under optimal conditions, the open circuit voltage of the constructed PFC sensor was found to sensitively respond to p-NP in a wide concentration range from 0.05 MUM to 20 MUM. The proposed sensor exhibited high selectivity, good reproducibility, and stability, demonstrating the successful combination of MIP with photocathode in construction of high-performance PFC self-powered sensors for pollutant monitoring. PMID- 28806527 TI - A 2D Substitutional Solid Solution through Hydrogen Bonding of Molecular Building Blocks. AB - Two-dimensional (2D) molecular self-assembly allows for the formation of well defined supramolecular layers with tailored geometrical, compositional, and chemical properties. To date, random intermixing and entropic effects in these systems have largely been associated with crystalline disorder and glassy phases. Here we describe a 2D crystalline self-assembled molecular system that exhibits random incorporation of substitutional molecules. The lattice is formed from a mixture of trimesic acid (TMA) and terthienobenzenetricarboxylic acid (TTBTA), C3 symmetric hydrogen-bonding units of very different sizes (0.79 and 1.16 nm, respectively), at the solution-highly oriented pyrolitic graphite (HOPG) interface. Remarkably, the TTBTA substitutes into the TMA lattice at a fixed stoichiometry near 12%. The resulting lattice constant is consistent with Vegard's law prediction for an alloy with a composition TMA0.88TTBTA0.12, and the substrate orientation of the lattice is defined by an epitaxial relation with the HOPG substrate. The Gibbs free energy for the TMA/TTBTA lattice was elucidated by considering the entropy of intermixing, via Monte Carlo simulations of multiplicity of the substitutional lattices, and the enthalpy of intermixing, via density functional theory calculations. The latter show that both the bond enthalpy of the H-bonded lattice and the adsorption enthalpy of the molecule/substrate interactions play important roles. This work provides insight into the manifestation of entropy in a molecular crystal constrained by both epitaxy and intermolecular interactions and demonstrates that a randomly intermixed yet crystalline 2D solid can be formed through hydrogen bonding of molecular building blocks of very different size. PMID- 28806528 TI - Surface-Adaptive Gold Nanoparticles with Effective Adherence and Enhanced Photothermal Ablation of Methicillin-Resistant Staphylococcus aureus Biofilm. AB - Biofilms that contribute to the persistent bacterial infections pose serious threats to global public health, mainly due to their resistance to antibiotics penetration and escaping innate immune attacks by phagocytes. Here, we report a kind of surface-adaptive gold nanoparticles (AuNPs) exhibiting (1) a self adaptive target to the acidic microenvironment of biofilm, (2) an enhanced photothermal ablation of methicillin-resistant Staphylococcus aureus (MRSA) biofilm under near-infrared (NIR) light irradiation, and (3) no damage to the healthy tissues around the biofilm. Originally, AuNPs were readily prepared by surface modification with pH-responsive mixed charged zwitterionic self-assembled monolayers consisting of weak electrolytic 11-mercaptoundecanoic acid (HS-C10 COOH) and strong electrolytic (10-mercaptodecyl)trimethylammonium bromide (HS-C10 N4). The mixed charged zwitterion-modified AuNPs showed fast pH-responsive transition from negative charge to positive charge, which enabled the AuNPs to disperse well in healthy tissues (pH ~7.4), while quickly presenting strong adherence to negatively charged bacteria surfaces in MRSA biofilm (pH ~5.5). Simultaneous AuNP aggregation within the MRSA biofilm enhanced the photothermal ablation of MRSA biofilm under NIR light irradiation. The surrounding healthy tissues showed no damage because the dispersed AuNPs had no photothermal effect under NIR light. In view of the above advantages as well as the straightforward preparation, AuNPs developed in this work may find potential applications as a useful antibacterial agent in the areas of healthcare. PMID- 28806529 TI - Young at Heart: Is That Good Enough for Computed Tomography Screening? PMID- 28806530 TI - Reply: Tidal Carbon Dioxide as a Prognostic Feature in Inoperable Chronic Thromboembolic Pulmonary Hypertension. PMID- 28806531 TI - Tidal Carbon Dioxide as a Prognostic Feature in Inoperable Chronic Thromboembolic Pulmonary Hypertension. PMID- 28806532 TI - The impact of an acute oral phosphate load on endothelium dependent and independent brachial artery vasodilation in healthy males. AB - Serum phosphate levels are associated with cardiovascular morbidity and mortality in the general population and endothelial dysfunction may be mechanistically involved. The purpose of this study was to investigate the effects of acute phosphate supplementation on endothelial-dependent (flow-mediated dilation; FMD) and -independent (glyceryl trinitrate; GTN)) vasodilation in young, healthy males. Seventeen healthy male participants (age, 23 +/- 3 years) were exposed to an oral load of phosphate (PHOS; liquid supplement containing 1200 mg of phosphorous) and placebo (PLAC) over 2 experimental days. A brachial artery FMD test was performed pre-ingestion and at 20 min, 60 min, and 120 min following the ingestion of the phosphate load or the placebo. GTN tests were performed pre- and 140 min post-ingestion. Serum phosphate was not impacted differently by phosphate versus placebo ingestion (p = 0.780). In contrast, urinary phosphate excretion was markedly increased in the PHOS (p < 0.001) but not in the PLAC condition (p = 0.130) (Delta fractional excretion of phosphate in PHOS (29.2%) vs. PLAC (9.3%)). This indicates that circulating phosphate levels were homeostatically regulated. GTN-mediated vasodilation was not significantly affected by phosphate ingestion. In primary analysis no impact of phosphate ingestion on FMD was detected. However, when the shear stress stimulus was added as a covariate in a subset of participants, exploratory pairwise comparisons revealed a significantly lower FMD 20 min post-phosphate ingestion versus placebo (p = 0.024). The effects of phosphate ingestion on FMD and serum phosphate are in contrast with previous findings and the mechanisms that underlie the disparate results require further investigation. PMID- 28806533 TI - Reaching for the Holy Grail of Chronic Obstructive Pulmonary Disease Outcomes. Can Medications Modify Lung Function Decline? PMID- 28806534 TI - Knockdown of Snail inhibits epithelial-mesenchymal transition of human laryngeal squamous cell carcinoma Hep-2 cells through the vitamin D receptor signaling pathway. AB - It has been well documented that Snail plays a decisive role in various tumors. However, the direct effect of Snail on laryngeal squamous cell carcinoma (LSCC) has not been elaborated. In this study, we firstly detected the expression of Snail in 14 samples of patients with LSCC and found that its content was high in cancer tissues compared with adjacent tissues. Then we established LSCC Hep-2 cells with Snail silencing and validated the knockdown efficiency by Western blotting and real-time PCR. Results showed that silencing of Snail significantly inhibited the ability of adhesion, migration, and invasion of Hep-2 cells. Further study revealed that knockdown of Snail suppressed the epithelial mesenchymal transition (EMT) process of Hep-2 cells, as evidenced by downregulation of matrix metallopeptidase (MMP)-2, MMP-9, integrin subunit beta 1 (ITGbeta1), beta-catenin, vimentin, N-cadherin, and fibronectin and upregulation of vitamin D receptor (VDR) and E-cadherin. Additionally, transfection with the small interfering RNA of VDR reversed the effect induced by Snail silencing in Hep-2 cells. Taken together, these results demonstrate that knockdown of Snail can inhibit the EMT process of LSCC cells through the VDR signaling pathway in vitro. PMID- 28806535 TI - Interactions between genetic polymorphisms of glucose metabolizing genes and smoking and alcohol consumption in the risk of type 2 diabetes mellitus. AB - The impact of gene-environment interaction on diabetes remains largely unknown. We aimed to investigate if interaction between glucose metabolizing genes and lifestyle factors is associated with type 2 diabetes mellitus (T2DM). Interactions between genotypes of 4 glucose metabolizing genes (MTNR1B, KCNQ1, KLF14, and GCKR) and lifestyle factors were estimated in 722 T2DM patients and 759 controls, using multiple logistic regression. No significant associations with T2DM were detected for the single nucleotide polymorphisms of MTNR1B, KLF14 and GCKR. However, rs151290 (KCNQ1) polymorphisms were found to be associated with risk of T2DM. Compared with AA, the odds ratios (ORs) of AC or CC genotypes for developing T2DM were 1.545 (P = 0.0489) and 1.603 (P = 0.0383), respectively. In stratified analyses, the associations were stronger in smokers with CC than smokers with AA (OR = 3.668, P = 0.013); drinkers with AC (OR = 5.518, P = 0.036), CC (OR = 8.691, P = 0.0095), and AC+CC (OR = 6.764, P = 0.016) than drinkers with AA. Compared with nondrinkers with AA, drinkers who carry AC and CC had 12.072-fold (P = 0.0007) and 8.147-fold (P = 0.0052) higher risk of developing T2DM. In conclusions, rs151290 (KCNQ1) polymorphisms are associated with increased risk of T2DM, alone and especially in interaction with smoking and alcohol. PMID- 28806536 TI - A meta-analytic investigation of the impact of mindfulness-based interventions on post traumatic stress. AB - A number of studies have investigated the impact of mindfulness-based interventions on symptoms of post-traumatic stress (PTSD) compared to control conditions. The current meta-analysis consolidated findings from 18 studies reporting results for 21 samples of participants. Across studies, mindfulness based treatments compared to control conditions were effective in ameliorating symptoms of PTSD, with Hedges' g=-0.44. Hedges' g was -0.59 for comparison of mindfulness-based interventions to waitlist control conditions. Changes in mindfulness may underpin the effect of mindfulness-based interventions on PTSD symptoms and thus the meta-analysis examined findings regarding increases in mindfulness. The 12 studies that assessed mindfulness found that the interventions significantly increased mindfulness, Hedges' g=0.52. Moderator analyses indicated that interventions with longer mindfulness training were more efficacious in reducing symptoms of PTSD. Across studies, gender, age, veteran status, or length of time between the intervention and assessment of PTSD symptoms did not moderate the impact of mindfulness-based interventions. The results provide a foundation for future research directions and have implications for work with those impacted by trauma. PMID- 28806537 TI - Effect of Oral Hydration on External Cephalic Version at Term. AB - OBJECTIVE: To evaluate the effect of oral hydration on the success rate of external cephalic version (ECV). DESIGN: Randomized controlled and single-blind trial. SETTING: Academic tertiary hospital with approximately 3,000 births annually. PARTICIPANTS: One hundred sixty-four women at a gestational age of at least 37 weeks with breech-presenting fetuses and normal amniotic fluid indexes (AFIs). METHODS: Participants were randomly assigned to drink 2000 ml or no more than 100 ml of water in the 2 hours before undergoing ECV. The AFIs were assessed before and after treatment by the same sonographer, who was blinded to the treatment group. Data were collected on relevant maternal and fetal characteristics and ECV success. RESULTS: The mean AFI after hydration was significantly greater than that in the control group (15.5 cm vs. 13.4 cm, p = .003). The ECV success rate was 53.7% in the hydration group and 46.3% in the control group (odds ratio: 1.34, 95% confidence interval [0.69, 2.59]; p = .349). Hydration was well tolerated and there were no serious adverse events. CONCLUSION: Oral hydration significantly increased the AFIs but did not affect the success rate of ECVs. PMID- 28806538 TI - Surgical Safety Checklists Are Underutilized in Ambulatory Oral and Maxillofacial Surgery. AB - PURPOSE: The objective of this study was to determine attitudes toward and the prevalence of using a surgical safety checklist in ambulatory oral and maxillofacial surgery (OMS) practice. MATERIALS AND METHODS: The authors designed and implemented a cross-sectional study and enrolled a random sample of oral and maxillofacial surgeons. The predictor variable was years removed from residency. The primary outcome was the prevalence of surgical safety checklist usage in ambulatory OMS practice. The secondary outcome was to determine whether surgeons who do not currently use a checklist would be willing to do so if provided with one. Other demographic variables included age, gender, location of practice, type of practice, and number of ambulatory procedures performed per week. Appropriate uni- and bivariate statistics were computed and the level of significance set at .05; 95% confidence intervals also were calculated. RESULTS: The study sample was composed of 120 clinicians. Forty-two percent of respondents reported that they were not using a surgical safety checklist for ambulatory surgery. Ninety-three percent of those respondents not currently using a checklist reported they would consider implementing a surgical safety checklist in their practice if provided with one. In addition, 45.3% of surgeons performing more than 30 procedures a week reported not using a surgical safety checklist. Most respondents (67.9%) who had completed OMS training more than 20 years previously reported not using a checklist in their practice. CONCLUSION: According to this survey, most practicing oral and maxillofacial surgeons do not currently use surgical safety checklists. Although the response rate was only 12%, the survey does reflect a clear lack of use of checklists among practicing oral and maxillofacial surgeons despite its widespread acceptance in the medical community. PMID- 28806540 TI - Cystadenoma of Minor Salivary Gland With Cervical Metastasis: Benign or Malignant? AB - A cystadenoma originating in the salivary gland is a rare neoplasm that can originate from the major or minor salivary glands. Although this tumor has the potential to recur if it is incompletely excised, it has been regarded as a benign tumor because it has not been determined to be associated with local tissue destruction or metastasis. This report serves as an update to the current understanding of cystadenoma. The patient in this case study presented with a recurrent painless mass in her left retromolar and submandibular regions that had persisted for more than 2 years. Histologic analysis showed that this lesion was a recurrent cystadenoma of the minor salivary gland, with cervical lymph nodes testing positive for tumor cells. After more than 3 years of clinical follow-up, no signs of recurrence were observed. A case of cystadenoma with cervical metastasis is presented; further attention should be paid to patients with recurrent cystadenoma that also might contain lymph node metastasis. PMID- 28806539 TI - Clinical and Microstructural Findings in Paget Disease of the Entire Mandible. AB - Paget disease of bone (PDB) is a chronic progressive bone disorder characterized by localized increased bone turnover and focal areas of woven bone formation. Although skull involvement is common, PDB very rarely affects the mandible. This report describes the clinical and histologic findings in a 75-year-old patient with PDB involving the mandible. Microstructural analyses showed an altered quality of the bone microstructure and calcium depletion of the affected bone. Differential diagnosis of PDB affecting the mandible is discussed. PMID- 28806541 TI - Surgical Management of an Aggressive Multifocal Squamous Odontogenic Tumor. AB - Squamous odontogenic tumor is a rare benign epithelial odontogenic tumor of the jaw. Most are solitary lesions, although rare multifocal lesions have been described. Maxillary lesions have more aggressive behavior. Because of their benign character, these lesions are usually treated using a conservative surgical approach with curettage and surgical enucleation. This report describes the case of a 29-year-old woman with multifocal lesions who was initially treated with conservative surgical therapy. Early recurrence 6 months after surgery prompted more aggressive resection. This case is discussed in the context of current evidence related to the epidemiology, etiology, diagnosis, and therapy of squamous odontogenic tumors. PMID- 28806543 TI - 200 keV cold field emission source using carbon cone nanotip: Application to scanning transmission electron microscopy. AB - We report the use of a pyrolytic carbon cone nanotip as field emission cathode inside a modern 200 kV dedicated scanning transmission electron microscope. We show an unprecedented improvement in the probe current stability while maintaining all the fundamental properties of a cold field emission source such as a small angular current density together with a high brightness. We have also studied the influence of the low extraction voltage, as enabled by the nanosized apex of the cones, on the electron optics properties of the source that prevent the formation of a virtual beam cross-over of the gun. We have addressed this resolution-limiting issue by coming up with a new electron optical source design. PMID- 28806542 TI - Outcome of patients with lung adenocarcinoma with transformation to small-cell lung cancer following tyrosine kinase inhibitors treatment: A systematic review and pooled analysis. AB - BACKGROUND: Lung adenocarcinoma can transform to small-cell lung cancer (SCLC) when resistance to tyrosine kinase inhibitors (TKIs) develops. This phenomenon has repeatedly been described in several case reports and small patient series. The characteristics and treatment outcomes of this population, however, have not been comprehensively reported. METHODS: We performed a systematic review of the published literature to obtain explorative information on the clinical and pathological features and prognosis of the reported cases. RESULTS: Twenty-five eligible publications were identified, contributing to 39 patients. The median time from initial diagnosis of lung adenocarcinoma to the transformation to SCLC (ttSCLC) was 19months (range 1-61months). The median survival after SCLC diagnosis was 6months. Female gender was significantly associated with longer ttSCLC at the multivariable analysis. Smoking status seemed to be associated with worse prognosis after the diagnosis of SCLC. CONCLUSION: In this series of published cases, the transformation to a SCLC phenotype after an initial diagnosis of lung adenocarcinoma following TKI therapy appeared to be a late phenomenon. The prognosis after SCLC diagnosis is poor and current treatment strategies derived from primary SCLC seem to be largely inefficacious. New therapies are needed in the management of transformed SCLC. PMID- 28806544 TI - Decadal analysis of impact of future climate on wheat production in dry Mediterranean environment: A case of Jordan. AB - Different aspects of climate change, such as increased temperature, changed rainfall and higher atmospheric CO2 concentration, all have different effects on crop yields. Process-based crop models are the most widely used tools for estimating future crop yield responses to climate change. We applied APSIM crop simulation model in a dry Mediterranean climate with Jordan as sentinel site to assess impact of climate change on wheat production at decadal level considering two climate change scenarios of representative concentration pathways (RCP) viz., RCP4.5 and RCP8.5. Impact of climatic variables alone was negative on grain yield but this adverse effect was negated when elevated atmospheric CO2 concentrations were also considered in the simulations. Crop cycle of wheat was reduced by a fortnight for RCP4.5 scenario and by a month for RCP8.5 scenario at the approach of end of the century. On an average, a grain yield increase of 5 to 11% in near future i.e., 2010s-2030s decades, 12 to 16% in mid future i.e., 2040s-2060s decades and 9 to 16% in end of century period can be expected for moderate climate change scenario (RCP4.5) and 6 to 15% in near future, 13 to 19% in mid future and 7 to 20% increase in end of century period for a drastic climate change scenario (RCP8.5) based on different soils. Positive impact of elevated CO2 is more pronounced in soils with lower water holding capacity with moderate increase in temperatures. Elevated CO2 had greater positive effect on transpiration use efficiency (TUE) than negative effect of elevated mean temperatures. The change in TUE was in near perfect direct relationship with elevated CO2 levels (R2>0.99) and every 100-ppm atmospheric CO2 increase resulted in TUE increase by 2kgha-1mm-1. Thereby, in this environment yield gains are expected in future and farmers can benefit from growing wheat. PMID- 28806545 TI - Improvement of the drought indicators system in the Jucar River Basin, Spain. AB - Droughts are one of the gravest natural threats currently existing in the world and their occurrence and intensity might be exacerbated in the coming years due to climate change. The severe impacts that droughts cause to inland water resources and to the associated socio-economic activities justify the continuous monitoring of the drought. The case study presented shows a practical application of a distributed drought monitoring system implemented in a real river basin district, the Jucar River Basin District (43,000km2), where drought periods of marked intensity have occurred historically and the climate ranges from humid in the north to semiarid in the south. Five drought indices have been applied: Standardised Precipitation Index (SPI) for meteorological drought; Palmer Drought Severity Index (PDSI) and a new soil moisture index (HI), for edaphic drought; Normalised Difference Vegetation Index (NDVI) for the vegetation activity; and Spanish Status Index (SI), for the operational drought. All indices are standardised to compare them. The relationship between the standardised operational drought index SI and the long-term meteorological indices, SPI-12 or SPI-24, show that in a medium size basin the concept of "prolonged drought" required by the European Commission under the Water Framework Directive could be defined by the use of accumulated precipitation indices. The number of months to be accumulated depends on the size of the basin and the water management system properties. In large basins, such as the Jucar river basin (22,000km2), there are significant deviations due to the spatial distribution of the drought. The use of a unique aggregated indicator could hide a significant drought in a specific area, or on the other hand show a non-real drought. Evolution of drought indices for each water management system must be accompanied by spatially distributed drought maps to better understand the drought status and its evolution. PMID- 28806546 TI - Parental exposure to bisphenol A and its analogs influences zebrafish offspring immunity. AB - Transgenerational effects of environmental pollutants on humans and animals are complex. Thus, we used zebrafish to evaluate the effects of parental whole-life cycle exposure to bisphenol A and its analogs (bisphenol S and F) on offspring innate immunity. At adulthood, offspring were examined with/without continued chemicals treatment until 72h post-fertilization (hpf). To measure offspring immune function, larvae at 72 hpf were expose for 24h with/without the viral mimic polyinosinic-cytidylic acid (Poly I:C) or the bacterial mimic Pam3Cys-Ser Lys4 (PAM3CSK4). Data show modified immunity in offspring. Specifically, lysozyme activity was significantly induced in F1 larvae and respiratory burst response and oxidative defense genes were inhibited. Genes of the innate immune system including Toll-like receptors and their downstream molecules and inflammatory cytokines were significantly down-regulated, whereas matrix metalloproteinases were up-regulated in larvae. In addition, recombination-activating genes in the immature adaptive immune system were significantly reduced. Thus, immune defense is diminished by exposing parental generations of zebrafish to environmentally relevant concentration of bisphenols and this suggests that fish chronically exposed to bisphenols in the wild may be vulnerable to pathogens. PMID- 28806547 TI - Environmental life cycle assessment of seafood production: A case study of trawler catches in Tunisia. AB - The Gulf of Gabes is one of the most productive fishery areas in the southern Mediterranean Sea. It is archetypal of an ecosystem in which the effects of fisheries are most pronounced. Demersal trawling is the main fishing activity in the Gulf of Gabes. Life Cycle Assessment (LCA) was applied to assess the environmental performance landing 1t of seafood with wooden demersal trawlers in the Gulf of Gabes. Impact categories included in the study were abiotic depletion potential (ADP), acidification potential (AP), eutrophication potential (EP), global warming potential (GWP), ozone depletion potential (ODP), photochemical oxidant formation potential (POFP), human toxicity potential (HTP), marine eco toxicity potential (METP), terrestrial eco-toxicity potential (TETP), land occupation potential (LOP), and total cumulative energy demand (TCED). Demersal trawlers were classified based on their impact intensity. Results showed that 70% of the vessels had relatively low impacts. Impact intensity was proportional to the amount of fuel consumed to land 1t of seafood. Ships that fished less had the highest impacts per ton, due to lower fishing effort and catch per unit effort. This is likely to typify vessels that target highly valuable species such as shrimp. Onboard vessel activities contributed most to different environmental impacts (AP, EP, GWP and POFP), related to the high energy use of this fishery. Several impacts (ADP, ODP, METP, LOP and TCED) were associated mainly with fuel and lubricating oil production. Therefore, improvements must focus on minimizing fuel consumption. LCA is a valuable tool for assessing how to increase environmental sustainability of demersal trawling and it can help stakeholders identify the main operational issues that require improvement. PMID- 28806548 TI - Seasonal variation characteristic of inhalable microbial communities in PM2.5 in Beijing city, China. AB - Bacteria and fungi are primary constituents of airborne microbes in fine particulate matter (PM2.5) and significantly impact human health. However, hitherto, seasonal variation and effect of air pollution on microbial community composition and structure are poorly understood. This study analyzed the bacterial and fungal composition of PM2.5 under different air pollution levels during different seasons in Beijing. We altogether collected 75PM2.5 samples during four seasons from April 2014 to January 2015, under different air pollution levels and employed high-throughput sequencing methods to analyze microbial composition. The results showed that air pollution decreased species richness and community diversity of bacteria in PM2.5. The variation in bacterial and fungal community composition and structure was significantly related to the season but there was no correlation between their abundance and pollution levels. Pathogenic bacteria and fungi were more abundant in winter than other seasons. To best of our knowledge, this is the first study that demonstrates seasonal variation characteristics of bacteria and fungi in PM2.5 in heavy haze contaminated areas and highlights the effects of air pollution on the atmospheric microbial community. This study would be useful to other bioaerosol studies focusing on the role of the atmospheric particulate matter on human health. PMID- 28806549 TI - Liming impacts on soils, crops and biodiversity in the UK: A review. AB - Fertile soil is fundamental to our ability to achieve food security, but problems with soil degradation (such as acidification) are exacerbated by poor management. Consequently, there is a need to better understand management approaches that deliver multiple ecosystem services from agricultural land. There is global interest in sustainable soil management including the re-evaluation of existing management practices. Liming is a long established practice to ameliorate acidic soils and many liming-induced changes are well understood. For instance, short term liming impacts are detected on soil biota and in soil biological processes (such as in N cycling where liming can increase N availability for plant uptake). The impacts of liming on soil carbon storage are variable and strongly relate to soil type, land use, climate and multiple management factors. Liming influences all elements in soils and as such there are numerous simultaneous changes to soil processes which in turn affect the plant nutrient uptake; two examples of positive impact for crops are increased P availability and decreased uptake of toxic heavy metals. Soil physical conditions are at least maintained or improved by liming, but the time taken to detect change varies significantly. Arable crops differ in their sensitivity to soil pH and for most crops there is a positive yield response. Liming also introduces implications for the development of different crop diseases and liming management is adjusted according to crop type within a given rotation. Repeated lime applications tend to improve grassland biomass production, although grassland response is variable and indirect as it relates to changes in nutrient availability. Other indicators of liming response in grassland are detected in mineral content and herbage quality which have implications for livestock-based production systems. Ecological studies have shown positive impacts of liming on biodiversity; such as increased earthworm abundance that provides habitat for wading birds in upland grasslands. Finally, understanding of liming impacts on soil and crop processes are explored together with functional aspects (in terms of ecosystems services) in a new qualitative framework that includes consideration of how liming impacts change with time. This holistic approach provides insights into the far-reaching impacts that liming has on ecosystems and the potential for liming to enhance the multiple benefits from agriculturally managed land. Recommendations are given for future research on the impact of liming and the implications for ecosystem services. PMID- 28806550 TI - Discrepant responses of the electron transfer capacity of soil humic substances to irrigations with wastewaters from different sources. AB - An increasing area of agricultural land is irrigated with wastewater worldwide due to the scarcity of fresh water resources. Whether wastewater irrigations can affect the electron transfer capacity (ETC) of natural organic matter in soils is unclear. In this study, we assess the responses of the electron-accepting capacity (EAC) and electron-donating capacity (EDC) of soil humic substances (HS) to irrigations with wastewaters from different sources. We show that the EAC of soil HS increases and the EDC of soil HS decreases after irrigation with domestic wastewater. Conversely, the EAC of soil HS decreases and the EDC of soil HS increases after irrigation with industrial wastewater. The EAC and EDC of soil HS exert no changes after irrigation with pharmaceutical wastewater. Irrigations with wastewaters from different sources can cause the distinct directions of changes in the activities of lignin peroxidase and laccase by altering the content of labile organic carbon, heavy metals or antibiotics in soils, thereby changing the chemical structures and finally the ETC of HS along different directions. These results can provide insights into the role of HS in environmentally relevant processes in agricultural soils under the context of wastewater irrigations. PMID- 28806551 TI - Effects of agricultural land use on fluvial carbon dioxide, methane and nitrous oxide concentrations in a large European river, the Meuse (Belgium). AB - We report a data-set of CO2, CH4, and N2O concentrations in the surface waters of the Meuse river network in Belgium, obtained during four surveys covering 50 stations (summer 2013 and late winter 2013, 2014 and 2015), from yearly cycles in four rivers of variable size and catchment land cover, and from 111 groundwater samples. Surface waters of the Meuse river network were over-saturated in CO2, CH4, N2O with respect to atmospheric equilibrium, acting as sources of these greenhouse gases to the atmosphere, although the dissolved gases also showed marked seasonal and spatial variations. Seasonal variations were related to changes in freshwater discharge following the hydrological cycle, with highest concentrations of CO2, CH4, N2O during low water owing to a longer water residence time and lower currents (i.e. lower gas transfer velocities), both contributing to the accumulation of gases in the water column, combined with higher temperatures favourable to microbial processes. Inter-annual differences of discharge also led to differences in CH4 and N2O that were higher in years with prolonged low water periods. Spatial variations were mostly due to differences in land cover over the catchments, with systems dominated by agriculture (croplands and pastures) having higher CO2, CH4, N2O levels than forested systems. This seemed to be related to higher levels of dissolved and particulate organic matter, as well as dissolved inorganic nitrogen in agriculture dominated systems compared to forested ones. Groundwater had very low CH4 concentrations in the shallow and unconfined aquifers (mostly fractured limestones) of the Meuse basin, hence, should not contribute significantly to the high CH4 levels in surface riverine waters. Owing to high dissolved concentrations, groundwater could potentially transfer important quantities of CO2 and N2O to surface waters of the Meuse basin, although this hypothesis remains to be tested. PMID- 28806553 TI - Thiacloprid adsorption and leaching in soil: Effect of the composition of irrigation solutions. AB - Pressure on groundwater resources has increased during the last decades due to the growing demand, especially in arid and semiarid regions, such as the Mediterranean basin, with frequent drought periods. In order to partially remediate this environmental problem of world concern, irrigation of agricultural lands with adequately treated wastewaters (TWW) is becoming a common management practice. The complex composition of these low-quality waters may influence the behavior of organic contaminants in soils. A calcareous soil with low organic carbon content was selected for the assessment of the adsorption and leaching of the neonicotinoid insecticide thiacloprid (THC). Different solutions were evaluated: TWW after a secondary treatment, a saline solution and solutions with a range of dissolved organic carbon concentration (DOC, 3-300mgL-1). The addition of an organic fertilizer (fertiormont) to the soil was also assessed, in an attempt to reduce THC mobility. Sorption of thiacloprid, a relatively polar pesticide, was similar under all the conditions considered, though an adsorption decrease was observed when DOC concentration increased. The transport of THC through soil columns was retarded with all the treatments, with the lower effects corresponding to TWW and the saline solution. Addition of fertiormont and irrigation with DOC at 3mgL-1 resulted in a reduction of pesticide leached (34% and 38%, respectively) in comparison with the control (66%), but surprisingly not for DOC at high concentration (55%), possibly due to co-elution of the pesticide with DOC. Therefore the transport of polar compounds, like THC, could be affected by the composition of the irrigation solutions, altering their impact to environmental water resources. PMID- 28806552 TI - Exposure of engineered nanoparticles to Alexandrium tamarense (Dinophyceae): Healthy impacts of nanoparticles via toxin-producing dinoflagellate. AB - Human activities can enhance the frequency, intensity and occurrence of harmful algal blooms (HABs). Engineered nanoparticles (ENPs), contained in many materials, will inevitably enter coastal waters and thus cause unpredictable impacts on aquatic organisms. However, knowledge of the influence of ENPs on HAB species is still lacking. In this study, we examined the effects of titanium dioxide nanoparticles (nTiO2), zinc oxide nanoparticles (nZnO) and aluminum oxide nanoparticles (nAl2O3) on physiological changes and paralytic shellfish poisoning toxins (PSTs) production of Alexandrium tamarense. We found a dose-dependent decrease in photosynthetic activity of A. tamarense under all three ENPs and a significant growth inhibition induced by nZnO. The largest reactive oxygen species (ROS) production was induced by nTiO2, followed by nZnO and nAl2O3. Moreover, the PSTs production rate increased by 3.9-fold for nTiO2 (p<0.01) and 4.5-fold for nAl2O3 (p<0.01) at a concentration of 200mgL-1. The major component, C2 was transformed to its epimer C1 and the proportion of decarbamoyl toxins increased under 200mgL-1 of nZnO and nAl2O3. In addition, the proportion of carbamate toxins increased upon exposure to 2mgL-1 ENPs, while decreased upon exposure to 200mgL-1 ENPs. The changes in PSTs production and composition might be an adaptive response for A. tamarense to overcome the stress of ENPs exposure. This work brings the first evidence that ENP would affect PSTs production and profiles. PMID- 28806554 TI - Metal bioaccumulation and biomarkers of effects in caged mussels exposed in the Athabasca oil sands area. AB - The Athabasca oil sands deposit is the world's largest known reservoir of crude bitumen and the third-largest proven crude oil reserve. Mining activity is known to release contaminants, including metals, and to potentially impact the aquatic environment. The purpose of this study was to determine the impacts of oil sands mining on water quality and metal bioaccumulation in mussels from the Fort McMurray area in northern Alberta, Canada. The study presents two consecutive years of contrasting mussel exposure conditions (low and high flows). Native freshwater mussels (Pyganodon grandis) were placed in cages and exposed in situ in the Athabasca River for four weeks. Metals and inorganic elements were then analyzed in water and in mussel gills and digestive glands to evaluate bioaccumulation, estimate the bioconcentration factor (BCF), and determine the effects of exposure by measuring stress biomarkers. This study shows a potential environmental risk to aquatic life from metal exposure associated with oil sands development along with the release of wastewater from a municipal treatment plant nearby. Increased bioaccumulation of Be, V, Ni and Pb was observed in mussel digestive glands in the Steepbank River, which flows directly through the oil sands mining area. Increased bioaccumulation of Al, V, Cr, Co, Ni, Mo and Ni was also observed in mussel gills from the Steepbank River. These metals are naturally present in oil sands and generally concentrate and increase with the extraction process. The results also showed different pathways of exposure (particulate or dissolved forms) for V and Ni resulting from different river water flows, distribution coefficient (Kd) and BCF. Increasing metal exposure downstream of the oil sands mining area had an impact on metallothionein and lipid peroxidation in mussels, posing a potential environmental risk to aquatic life. These results confirm the bioavailability of some metals in mussel tissues associated with detoxification of metals (metallothionein levels), and oxidative stress in mussels located downstream of the oil sands mining area. These results highlight a potential ecotoxicological risk to biota and to the aquatic environment downstream of the oil sands mining area, even at low metal exposure levels. PMID- 28806555 TI - Environmental and socio-economic sustainability appraisal of contaminated land remediation strategies: A case study at a mega-site in China. AB - Green and sustainable remediation (GSR) has become a global trend in the contaminated land remediation field. Growing numbers of countries have adopted GSR procedures published in regulatory and/or technical guidance. China is fast becoming one of the largest remediation markets in the world, and is beginning to engage with GSR. Among other efforts, a taskforce is currently developing the first Chinese technical standard on GSR. This paper presents the context positioning and development of a sustainable remediation assessment indicator set for China. This sustainability indicator set was formed based on existing sustainable remediation guidelines and literature. LCA was used to evaluate environmental impacts, and the results combined with social and economic appraisal via MCA. The indicator set was applied to a remediation 'mega-site' in China. The results showed that compared to excavation and landfill, an alternative treatment strategy of soil washing, thermal desorption and S/S brought about relatively less waste generation, better worker safety, and preferable local impacts, leading to higher scores in the environmental and social-economic domains. However, the social-economic scores were limited by a lack of public engagement. The results of the case study have shown that the indicator set is valid, with lessons learnt and suggestions for improvement discussed. PMID- 28806556 TI - Persistent organic pollutants in fat of three species of Pacific pelagic longline caught sea turtles: Accumulation in relation to ingested plastic marine debris. AB - In addition to eating contaminated prey, sea turtles may be exposed to persistent organic pollutants (POPs) from ingesting plastic debris that has absorbed these chemicals. Given the limited knowledge about POPs in pelagic sea turtles and how plastic ingestion influences POP exposure, our objectives were to: 1) provide baseline contaminant levels of three species of pelagic Pacific sea turtles; and 2) assess trends of contaminant levels in relation to species, sex, length, body condition and capture location. In addition, we hypothesized that if ingesting plastic is a significant source of POP exposure, then the amount of ingested plastic may be correlated to POP concentrations accumulated in fat. To address our objectives we compared POP concentrations in fat samples to previously described amounts of ingested plastic from the same turtles. Fat samples from 25 Pacific pelagic sea turtles [2 loggerhead (Caretta caretta), 6 green (Chelonia mydas) and 17 olive ridley (Lepidochelys olivacea) turtles] were analyzed for 81 polychlorinated biphenyls (PCBs), 20 organochlorine pesticides, and 35 brominated flame-retardants. The olive ridley and loggerhead turtles had higher SigmaDDTs (dichlorodiphenyltrichloroethane and metabolites) than SigmaPCBs, at a ratio similar to biota measured in the South China Sea and southern California. Green turtles had a ratio close to 1:1. These pelagic turtles had lower POP levels than previously reported in nearshore turtles. POP concentrations were unrelated to the amounts of ingested plastic in olive ridleys, suggesting that their exposure to POPs is mainly through prey. In green turtles, concentrations of SigmaPCBs were positively correlated with the number of plastic pieces ingested, but these findings were confounded by covariance with body condition index (BCI). Green turtles with a higher BCI had eaten more plastic and also had higher POPs. Taken together, our findings suggest that sea turtles accumulate most POPs through their prey rather than marine debris. PMID- 28806557 TI - A highly sensitive and selective aptamer-based colorimetric sensor for the rapid detection of PCB 77. AB - A highly sensitive, specific and simple colorimetric sensor based on aptamer was established for the detection of polychlorinated biphenyls (PCB 77). The use of unmodified gold nanoparticles as a colorimetric probe for aptamer sensors enabled the highly sensitive and selective detection of polychlorinated biphenyls (PCB 77). A linear range of 0.5nM to 900nM was obtained for the colorimetric assay with a minimum detection limit of 0.05nM. In addition, by the methods of circular dichroism, UV and naked eyes, we found that the 35 base fragments retained after cutting 5 bases from the 5 'end of aptamer plays the most significant role in the PCB 77 specific recognition process. We found a novel way to truncated nucleotides to optimize the detection of PCB 77, and the selected nucleotides also could achieve high affinity with PCB 77. At the same time, the efficient detection of the PCB 77 by our colorimetric sensor in the complex environmental water samples was realized, which shows a good application prospect. PMID- 28806558 TI - Nanoscale zero-valent iron coated with rhamnolipid as an effective stabilizer for immobilization of Cd and Pb in river sediments. AB - Nanoremediation strategies applied to contaminated river sediments can induce changes in the mobility and bioavailability of metals with potential consequences on ecosystem health. In this study, the performance of rhamnolipid (RL) coated nanoscale zero-valent iron (NZVI) in immobilizing cadmium (Cd) and lead (Pb) from contaminated river sediments was investigated. We demonstrated that RNZVI was effective in transforming labile Cd and Pb to stable fraction (the maximum residual percentage of Cd and Pb increased by 56.40% and 43.10% after 42days of incubation, respectively), with the decrease of the mobility of metals. The increase of pH in NZVI and RNZVI treated sediment samples indicated the related mechanism for Cd and Pb immobilization. The contents of organic matter (OM) were higher than in control, with the initial addition of RL during 7days incubation, and then the contents gradually decreased and became stable, maybe resulting from the enhancement of the activity of microorganisms and the decomposition of OM. Urease and catalase activities were enhanced with the increase of incubation time, showing certain degrees of recovery in sediment metabolic function. This work provides a new insight into the potential effects of RNZVI applications on the Cd and Pb immobilization in contaminated river sediments. PMID- 28806559 TI - Assessment of chemicals released in the marine environment by dielectric elastomers useful as active elements in wave energy harvesters. AB - A series of elastomers, either natural or synthetic (some of them commercial, while others prepared in the laboratory), suitable for use as active elements in devices for wave energy harvesting, were evaluated concerning their behavior and effects on the marine environment. In this aim, the elastomer films, initially evaluated regarding their aspect, structure, surface wettability, and tolerance of microorganisms growth, were immersed in synthetic seawater (SSW) within six months for assessing compounds released. There were analyzed the changes occurred both in the elastomers and salt water in which they were immersed. For this, water samples taken at set time intervals were analyzed by using a sequence of sensitive spectral techniques: UV-vis, IR, and in relevant cases 1H NMR and electrospray ionization mass spectrometry (ESI-MS), able to detect and identify organic compounds, while after six months, they were also investigated from the point of view of aspect, presence of metal traces, pH, and biological activity. The changes in aspect, structure and morphology of the dielectric films at the end of the dipping period were also evaluated by visual inspection, IR spectroscopy by using spectral subtraction method, and SEM-EDX technique. PMID- 28806560 TI - TiO2/porous adsorbents: Recent advances and novel applications. AB - This article reviews two interrelated areas of research: the first is the use of TiO2-supported adsorbent materials as enhanced heterogeneous photocatalysts and their application to various reactions for organic pollutant removal from air and water; the second is the combination of adsorbent materials with TiO2 photocatalysts which aims to efficiently regenerate adsorbent materials using illumination. By reviewing both areas of research, the following topics are covered; (i) photocatalytic activation of TiO2; (ii) related properties of photocatalytic TiO2; (iii) shortcomings of photocatalytic processes; (iv) preparation methods of composite TiO2/adsorbent materials and their photocatalytic performance; (v) properties of common adsorbents and their applications for pollutant removal from air and water; (vi) adsorbent regeneration methods and their economic and operational issues; (vii) conclusions and future outlooks. This topic has not been previously reviewed to such an extent, and considerable knowledge can be gained from assembling the large number of studies on adsorption-photocatalysis combinations. As such, this review provides guidance for researchers working in the fields of environmental and chemical engineering focussing on organic pollutant removal and the engineering of new high performance photocatalytic TiO2-supported porous adsorbent materials. PMID- 28806561 TI - Delirium and exposure to psychoactive medications in critically ill adults: A multi-centre observational study. AB - PURPOSE: Investigate the relationship between psychoactive drugs and delirium. MATERIALS AND METHODS: Prospective observational study of 520 critically ill adult patients admitted >=24h to 6 intensive care units (ICUs). Data were collected on psychoactive drug exposure, use of sedation administration strategies, and incident delirium (Intensive Care Delirium Screening Checklist score>=4). RESULTS: Delirium was detected in 260 (50%) patients, median (IQR) duration 2 (1-5) days, and time to onset 3 (2-5) days. Delirious patients received more low-potency anticholinergic (P<0.0001), antipsychotic (P<0.0001), benzodiazepine (P<0.0001) and non-benzodiazepine sedative (P<0.0001), and opioid (P=0.0008) drugs. Primary regression (24-hours preceding drug exposure) revealed no association between any psychoactive drug and delirium. Post-hoc analysis (extended 48-hour exposure) revealed an association between delirium and high potency anticholinergic (HR 2.45, 95% CI 1.08-5.54) and benzodiazepine (HR 1.08 per 5mg midazolam-equivalent increment, 95% CI 1.04-1.12) drugs. Delirious patients had longer ICU (P<0.0001) and hospital (P<0.0001) length of stay, and higher ICU and hospital mortality (P=0.003 and P=0.007, respectively). CONCLUSIONS: The identification of psychoactive drugs as modifiable delirium risk factors plays an important role in the management of critically ill patients. This is particularly important given the burden of exposure and combinations of drugs used in this vulnerable patient population. PMID- 28806563 TI - Alteration of the number and percentage of innate immune cells in preschool children from an e-waste recycling area. AB - Heavy metal lead (Pb) and cadmium (Cd) are widespread environmental contaminants and exert detrimental effects on the immune system. We evaluated the association between Pb/Cd exposures and innate immune cells in children from an electronic waste (e-waste) recycling area. A total number of 294 preschool children were recruited, including 153 children from Guiyu (e-waste exposed group), and 141 from Haojiang (reference group). Pb and Cd levels in peripheral blood were measured by graphite furnace atomic absorption spectrophotometer, NK cell percentages were detected by flow cytometer, and other innate immune cells including monocytes, eosinophils, neutrophils and basophils were immediately measured by automated hematology analyzer. Results showed children in Guiyu had significantly higher Pb and Cd levels than in reference group. Absolute counts of monocytes, eosinophils, neutrophils and basophils, as well as percentages of eosinophils and neutrophils were significantly higher in the Guiyu group. In contrast, NK cell percentages were significantly lower in Guiyu group. Pb elicited significant escalation in counts of monocytes, eosinophils and basophils, as well as percentages of monocytes, but decline in percentages of neutrophils in different quintiles with respect to the first quintile of Pb concentrations. Cd induced significant increase in counts and percentages of neutrophils in the highest quintile compared with the first quintile of Cd concentrations. We concluded alteration of the number and percentage of innate immune cells are linked to higher levels of Pb and Cd, which indicates Pb and Cd exposures might affect the innate and adaptive immune response in Guiyu children. PMID- 28806562 TI - Zika virus-induced neurological critical illness in Latin America: Severe Guillain-Barre Syndrome and encephalitis. AB - : Zika virus (ZIKAV) is classically described as causing minor symptoms in adult patients, however neurologic complications have been recognized. The recent outbreak in Central and South America has resulted in serious illness in some adult patients. We report adult patients in Latin America diagnosed with ZIKAV infection admitted to Intensive Care Units (ICUs). METHODS: Multicenter, prospective case series of adult patients with laboratory diagnosis of ZIKAV in 16 ICUs in 8 countries. RESULTS: Between December 1st 2015 and April 2nd 2016, 16 ICUs in 8 countries enrolled 49 critically ill patients with diagnosis of ZIKAV infection. We included 10 critically ill patients with ZIKAV infection, as diagnosed with RT-PCR, admitted to the ICU. Neurologic manifestations concordant with Guillain-Barre Syndrome (GBS) were present in all patients, although 2 evolved into an encephalitis-like picture. 2 cases died, one due to encephalitis, the other septic shock. CONCLUSIONS: Differing from what was usually reported, ZIKAV infection can result in life-threatening neurologic illness in adults, including GBS and encephalitis. Collaborative reporting to identify severe illness from an emerging pathogen can provide valuable insights into disease epidemiology and clinical presentation, and inform public health authorities about acute care priorities. PMID- 28806564 TI - Tissue distribution and toxicity effects of myclobutanil enantiomers in lizards (Eremias argus). AB - In recent years, serious environmental pollution has caused a decrease in the abundance of many species worldwide. Reptiles are the most diverse group of terrestrial vertebrates. There are large amounts of toxicological data available regarding myclobutanil, but the adverse effects of myclobutanil on lizards has not been widely reported. In this study, treatment groups were orally administered a single-dose of myclobutanil (20mg/kg body weight (bw)). Subsequently, it was found that there were differences in myclobutanil levels between the different tissues and concentrations also changed with degradation time. The tissue concentrations of myclobutanil decreased in the order of: stomach > liver > lung > blood > testis > kidney > heart > brain. Based on our results, the liver and testis were considered to be the main target organs in lizards, indicating that the myclobutanil could induce potential hepatic and reproductive toxicity on lizards. Meanwhile, it was also demonstrated that the toxic effects of myclobutanil was different in different species, and the distribution of different pesticides in lizards were different. PMID- 28806565 TI - Implications of biological factors on accumulation of persistent organic pollutants in Antarctic notothenioid fish. AB - In the present study, the possible associations between selected persistent organic pollutants (POPs) and biological factors were assessed in different tissues of two Antarctic notothenioid fish: Notothenia rossii (NOR) and Trematomus newnesi (TRN) collected at Potter Cove, King George Island/Isla 25 de Mayo, South Shetland Islands. Specifically, association patterns between biological factors (body size, lipid content, body condition) and POP concentrations (polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethane (DDT) and metabolites, polybrominated diphenyl ethers (PBDEs), and hexachlorocyclohexane (HCH), hexachlorobenzene (HCB), chlordanes (CHLs) and methoxylated polybrominated diphenyl ethers (MeO-PBDEs)), were explored by using two approaches: multivariate analyses (principal component analysis: PCA) and intraspecific correlations. Integrating results suggest that biological factors such as size, KI and tissue type seemed to be associated to selective accumulation of POPs for immature specimens of N. rossii, and KI and tissue type for mature specimens of T. newnesi. Each particular factor should be considered when choosing N. rossii or T. newnesi as sentinels for POPs pollution in Antarctic marine environments. Further, both nototheniids showed a selective accumulation pattern in their gonads of penta-chlorinated biphenyls (penta-CBs; 55.5 and 29ngg-1 lw for N. rossii and T. newnesi, respectively) and organochlorine pesticides such as DDTs (199 and 13.3ngg-1 lw, for N. rossii and T. newnesi respectively), and of polybrominated diphenyl ethers (PBDEs) in gills (97.2 and 22.1 for ngg-1 lw, for N. rossii and T. newnesi, respectively), highlighting the importance of these tissues in monitoring studies of pollution in fish. The current study expands the knowledge concerning the biological factors to be investigated when specific pollutants are monitored and supports the importance of tissue type for the selective accumulation of POPs in Antarctic fish. Additionally, a contribution to the scarce data on concentration of MeO PBDEs in Antarctic marine organisms, particularly in the highly diverse perciform suborder Notothenioidei is provided. PMID- 28806566 TI - Volumetric adsorptive microsampling-liquid chromatography tandem mass spectrometry assay for the simultaneous quantification of four antibiotics in human blood: Method development, validation and comparison with dried blood spot. AB - In this paper we show the development and validation of a volumetric absorptive microsampling (VAMSTM)-LC-MS/MS method for the simultaneous quantification of four antibiotics: piperacillin-tazobactam, meropenem, linezolid and ceftazidime in 10MUL human blood. The novel VAMS-LC-MS/MS method has been compared with a dried blood spot (DBS)-based method in terms of impact of hematocrit (HCT) on accuracy, reproducibility, recovery and matrix effect. Antibiotics were extracted from VAMS and DBS by protein precipitation with methanol after a re-hydration step at 37 degrees C for 10min. LC-MS/MS was carried out on a Thermo ScientificTM TSQ QuantumTM Access MAX triple quadrupole coupled to an Accela TMUHPLC system. The VAMS-LC-MS/MS method is selective, precise and reproducible. In contrast to DBS, it allows an accurate quantification without any HCT influence. It has been applied to samples derived from pediatric patients under therapy. VAMS is a valid alternative sampling strategy for the quantification of antibiotics and is valuable in support of clinical PK/PD studies and consequently therapeutic drug monitoring (TDM) in pediatrics. PMID- 28806567 TI - Strategies to analyse data obtained from liquid intrusion experiments of loose porous materials. AB - Liquid intrusion remains one of the most common methods to measure the contact angle of liquids to powders. However, as there are two unknown variables in the Washburn equation: the material constant (that is, the pore structure of the powder bed) and the contact angle of the liquid to the powder, this method requires the use of two liquids-a liquid of interest (the probe liquid) and a reference liquid. The reference liquid should, ideally, make a contact angle of 0 degrees to the sample. However, in practice a low surface tension liquid is normally selected. This paper proposes a more standardised approach for the selection of the reference liquid based on experimental data. Additionally, a major assumption of the liquid intrusion method is that the pore structure, as measured by the material constant, C, is identical for all powder beds (provided that the same packing procedure is used for the same samples). In real systems, however, this is an approximation, and not likely to hold strictly true. Therefore, difficulties may arise with data analysis as there is a potential uncertainty in the most appropriate order to divide the gradient of the probe liquid by the gradient of the reference liquid. This paper proposes three specific methods of analysing such data, each with their own advantages and limitations. Hence, the selection of which method should be used is criteria based, assessed on the basis of the obtained data. PMID- 28806568 TI - A simple high performance liquid chromatography-mass spectrometry method for Therapeutic Drug Monitoring of isavuconazole and four other antifungal drugs in human plasma samples. AB - Triazoles chanced the prevention and treatment of invasive fungal infections, but their pharmacokinetic properties are still unclear. In particular, isavuconazole (ISC) is a new broad-spectrum antifungal triazole approved in 2015 as first-line treatment for intravenous and oral use against invasive aspergillosis and for mucormycosis. Nowadays, the optimal management of the treatments with triazoles requires the use of Therapeutic Drug Monitoring (TDM), in order to prevent sub therapeutic or toxic concentrations. In turn, the routine use of TDM requires reliable quantification methods The aim of this work was the development and full validation of a HPLC-mass spectrometry assay for the simultaneous quantification of fluconazole, itraconazole, isavuconazole, posaconazole and voriconazole in human samples. Both standards and quality controls were prepared in human plasma. After the addition of internal standard (6,7-dimethyl-2,3-di(2 pyridyl)quinaxoline for voriconazole, posaconazole and itraconazole; stable isotope labeled compounds for fluconazole and isavuconazole), protein precipitation with acetonitrile and dilution with water were performed. Chromatographic separation was performed on Atlantis(r) T3 5MUm 4.6*150mm column, with a gradient of water and acetonitrile, both added with 0.05% formic acid. Accuracy, intra-day and inter-day imprecision fitted FDA and EMA guidelines, while matrix effects and recoveries resulted stable between samples for each analyte. Stability results were in accordance with previously published data. Finally, we tested this method by monitoring plasma concentrations in real patients and using external quality controls with good results. This method resulted very simple, fast, cheap and very useful for TDM application, to improve clinical management of antifungal therapy in critically ill patients. PMID- 28806569 TI - Metabolic profiling of dehydrodiisoeugenol using xenobiotic metabolomics. AB - Dehydrodiisoeugenol (DDIE), a representative and major benzofuran-type neolignan in Myristica fragrans Houtt., shows anti-inflammatory and anti-bacterial actions. In order to better understand its pharmacological properties, xenobiotic metabolomics was used to determine the metabolic map of DDIE and its influence on endogenous metabolites. Total thirteen metabolites of DDIE were identified through in vivo and in vitro metabolism, and seven of them were reported for the first time in the present study. The identity of DDIE metabolites was achieved by comparison of the MS/MS fragmentation pattern with DDIE using ultra-performance chromatography electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI- QTOFMS). Demethylation and ring-opening reaction were the major metabolic pathways for in vivo metabolism of DDIE. Recombinant cytochrome P450s (CYPs) screening revealed that CYP1A1 is a primary enzyme contributing to the formation of metabolites D1-D4. More importantly, the levels of two endogenous metabolites 2,8-dihydroxyquinoline and its glucuronide were significantly elevated in mouse urine after DDIE exposure, which explains in part its modulatory effects on gut microbiota. Taken together, these data contribute to the understanding of the disposition and pharmacological activities of DDIE in vivo. PMID- 28806570 TI - Chiral separation of terbutaline and non-steroidal anti-inflammatory drugs by using a new lysine-bridged hemispherodextrin in capillary electrophoresis. AB - A method for the separation of a mixture of terbutaline and non-steroidal anti inflammatory drugs was developed using capillary electrophoresis with a new hemispherodextrin, ad hoc designed, the lysine - bridged hemispherodextrin (THLYSH). The use of lysine residues to bridge the trehalose capping unit moiety to the cyclodextrin cavity gives rise to a receptor with two long chains with amine nitrogen atoms, whose charge can be easily tuned as a function of the solution pH. The new hemispherodextrin was accurately characterised by ESI-MS and NMR spectroscopy, also highlighting its protonation behaviour. Circular dichroism and ESR spectroscopy measurements were also carried out to test its inclusion ability towards anthraquinone-3-sulfonate and its metal coordination ability towards copper(II) ion, respectively. Analogously to the other hemispherodextrins, the main skill of this new derivative lies in its chiral selector properties, as shown by the separation of the enantiomeric pairs of terbutaline and ibuprofen, flurbiprofen, suprofen and tiaprofenic acid by capillary electrophoresis. The focused use of the solution equilibria involved in the separations made it possible to understand the phenomena occurring in solution, and to finely tune the charge status of the receptor. In this way the chiral separation of the racemic mixture was successfully obtained, even if the receptor was individually used, differently by the other hemispherodextrins previously studied whose chiral separation capabilities are present only if used as binary mixtures. PMID- 28806571 TI - Separation and characterization of allergic polymerized impurities in cephalosporins by 2D-HPSEC*LC-IT-TOF MS. AB - Eleven unknown allergic impurities in cefodizime, cefmenoxime and cefonicid were separated and characterized by a trap-free two-dimensional high performance size exclusion chromatography (HPSEC) and reversed phase liquid chromatography (RP HPLC) coupled to high resolution ion trap/time-of-flight mass spectrometry (2D HPSEC*LC-IT-TOF MS) with positive and negative modes of electrospray ionization method. Separation and characterization the allergic polymerized impurities in beta-lactam antibiotics were on the basis of column-switching technique which effectively combined the advantages of HPSEC and the ability of RP-HPLC to identify the special impurities. In the first dimension HPSEC, the column was Xtimate SEC-120 analytical column (7.8mm*30cm, 5MUm), and the gradient elution used pH 7.0 buffer-acetonitrile as mobile phase And the second dimension analytical column was ZORBAX SB-C18 (4.6*150mm, 3.5MUm) with ammonium formate solution (10mM) and ammonium formate (8mM) in [acetonitrile-water (4:1, v/v)] solution as mobile phase. Structures of eleven unknown impurities were deduced based on the high resolution MSn data with both positive and negative modes, in which nine impurities were polymerized impurities. The forming mechanism of beta lactam antibiotic polymerization in cephalosporins was also studied. The question on incompatibility between non-volatile salt mobile phase and mass spectrometry was solved completely by multidimensional heart-cutting approaches and online demineralization technique, which was worthy of widespread use and application for the advantages of stability and repeatability. PMID- 28806572 TI - Globalization of psychosomatic medicine. PMID- 28806573 TI - Digital breast Tomosynthesis vacuum assisted biopsy for Tomosynthesis-detected Sonographically occult lesions. AB - PURPOSE: To assess the utility and pathological results from DBT VAB for lesions occult on 2D mammography and breast ultrasound (US). MATERIALS AND METHODS: A retrospective review of 1116 consecutive stereotactic biopsies was performed over 27months. DBT VAB was performed for 38 non-calcified lesions which were solely detected using DBT. Imaging findings and pathology results were reviewed. RESULTS: Pathologic findings were malignant in 8 of 38 lesions [masses (5) and distortion (3)]. High-risk findings found in 14 lesions. CONCLUSION: DBT VAB is easily performed and the majority of cases yield actionable pathologies. Therefore, perform DBT VAB primarily when available. PMID- 28806574 TI - Quantitative diffusion-weighted magnetic resonance imaging assessment of chemotherapy treatment response of pediatric osteosarcoma and Ewing sarcoma malignant bone tumors. AB - OBJECTIVE: Assessment of tumor response to chemotherapy is essential in managing malignant pediatric bone tumors prior to resection. SUBJECTS AND METHODS: Pre chemotherapy and post-chemotherapy osteosarcoma and Ewing sarcoma cases (n=18) were analyzed with apparent diffusion coefficient (ADC) values measured by two readers. RESULTS: Treated tumors demonstrated significantly greater ADC values compared to untreated tumors (p<0.001). Intraclass correlation coefficients ranged between 0.858 and 0.935. No significant tumor volume differences were observed. Regression analysis demonstrated average ADC as the best predictor of treatment. CONCLUSIONS: Our study suggests that ADC values may be useful for evaluating chemotherapeutic response of malignant pediatric bone tumors. PMID- 28806575 TI - Lessons from CTLA-4 deficiency and checkpoint inhibition. AB - CTLA-4 is a crucial negative regulator of immune responses. Absence of CTLA-4 in mice causes autoimmunity and lethal multiorgan lymphocytic infiltration and tissue destruction. Recently, heterozygous CTLA4 or biallelic LRBA mutations leading to functional CTLA-4 deficiency and autoimmunity have been discovered. LRBA was identified as a novel regulator of steady-state CTLA-4 protein levels in Tregs and activated T cells. CTLA-4 deficiency due to checkpoint blockade cancer immunotherapy has also been found to lead to autoimmune reactions. Studies investigating the variable efficacy and adverse autoimmune responses to checkpoint therapy elucidated a role of the microbiota in promoting antitumor and autoreactive immune responses that are regulated by CTLA-4. PMID- 28806576 TI - Allocentric and contra-aligned spatial representations of a town environment in blind people. AB - Evidence concerning the representation of space by blind individuals is still unclear, as sometimes blind people behave like sighted people do, while other times they present difficulties. A better understanding of blind people's difficulties, especially with reference to the strategies used to form the representation of the environment, may help to enhance knowledge of the consequences of the absence of vision. The present study examined the representation of the locations of landmarks of a real town by using pointing tasks that entailed either allocentric points of reference with mental rotations of different degrees, or contra-aligned representations. Results showed that, in general, people met difficulties when they had to point from a different perspective to aligned landmarks or from the original perspective to contra aligned landmarks, but this difficulty was particularly evident for the blind. The examination of the strategies adopted to perform the tasks showed that only a small group of blind participants used a survey strategy and that this group had a better performance with respect to people who adopted route or verbal strategies. Implications for the comprehension of the consequences on spatial cognition of the absence of visual experience are discussed, focusing in particular on conceivable interventions. PMID- 28806577 TI - Prevalence and predictors of cardiac and liver iron overload in patients with thalassemia: A multicenter study based on real-world data. AB - Prevalence of cardiac and liver iron overload in patients with thalassemia in real-world practice may vary among different regions especially in the era of widely-used iron chelation therapy. The aim of this study was to determine the prevalence of cardiac and liver iron overload in and the management patterns of patients with thalassemia in real-world practice in Thailand. We established a multicenter registry for patients with thalassemia who underwent magnetic resonance imaging (MRI) as part of their clinical evaluation. All enrolled patients underwent cardiac and liver MRI for assessment of iron overload. There were a total of 405 patients enrolled in this study. The mean age of patients was 18.8+/-12.5years and 46.7% were male. Two hundred ninety-six (73.1%) of patients received regular blood transfusion. Prevalence of cardiac iron overload (CIO) and liver iron overload (LIO) was 5.2% and 56.8%, respectively. Independent predictors for iron overload from laboratory information were serum ferritin and transaminase for both CIO and LIO. Serum ferritin can be used as a screening tool to rule-out CIO and to diagnose LIO. Iron chelation therapy was given in 74.6%; 15.3% as a combination therapy. PMID- 28806578 TI - Klotho dysfunction: A pathway linking the aging process to bipolar disorder? AB - AIM: Although accelerated aging profile has been described in bipolar disorder (BD), the biology linking BD and aging is still largely unknown. Reduced levels and/or activity of a protein named Klotho is associated with decreased life span, premature aging and occurrence of age-related diseases. Therefore, this study was designed to evaluate plasma levels of Klotho in BD patients and controls. METHODS: Forty patients with type 1 BD and 30 controls were enrolled in this study. After clinical evaluation, peripheral blood samples were drawn and plasma levels of Klotho were measured using enzyme-linked immunosorbent assay. RESULTS: Patients with BD and controls presented similar age and sex distribution. The mean +/- SD length of illness was 24.00 +/- 12.75 years. BD patients presented increased frequency of clinical comorbidities in comparison with controls, mainly arterial hypertension, diabetes mellitus, and hypothyroidism. Both patients with BD in remission and in mania exhibited increased plasma levels of Klotho in comparison with controls. There was no significant difference between patients in mania and patients in remission regarding the levels of Klotho. CONCLUSION: Klotho-related pathway is altered in BD. Contrary to our original hypothesis, our sample of patients with BD presented increased plasma levels of Klotho in comparison with controls. Elevated levels of Klotho in long-term BD patients may be associated with the disorder progression. Further studies are needed to better understand the role of Klotho in BD and other mood disorders. PMID- 28806579 TI - Access to emergency care services: a transversal ecological study about Brazilian emergency health care network. AB - OBJECTIVES: Studies of health geography are important in the planning and allocation of emergency health services. The geographical distribution of health facilities is an important factor in timely and quality access to emergency services; therefore, the present study analyzed the emergency health care network in Brazil, focusing the analysis at the roles of small hospitals (SHs). STUDY DESIGN: Cross-sectional ecological study. METHODS: Data were collected from 9429 hospitals of which 3524 were SHs and 5905 were high-complexity centers (HCCs). For analytical purposes, we considered four specialties when examining the proxies of emergency care capability: adult, pediatrics, neonatal, and obstetric. We analyzed the spatial distribution of hospitals, identifying municipalities that rely exclusively on SHs and the distance of these cities from HCCs. RESULTS: More than 14 and 30 million people were at least 120 km away from HCCs with an adult intensive care unit (ICU) and pediatric ICU, respectively. For neonatal care distribution, 12% of the population was more than 120 km away from a health facility with a neonatal ICU. The maternities situation is different from other specialties, where 81% of the total Brazilian population was within 1 h or less from such health facilities. CONCLUSION: Our results highlighted a polarization in distribution of Brazilian health care facilities. There is a concentration of hospitals in urban areas more developed and access gaps in rural areas and the Amazon region. Our results demonstrate that the distribution of emergency services in Brazil is not facilitating access to the population due to geographical barriers associated with great distances. PMID- 28806580 TI - The eco-toxic effects of pesticide and heavy metal mixtures towards earthworms in soil. AB - Earthworms are the key soil organisms, contribute to many positive ecological services that could be degraded by pesticides and other soil pollutants such as heavy metals. Chemicals usually occur as mixtures in the environmental systems which can lead synergistic effects. The assessment and characterization of soil pollutants that effects risks are very difficult due to the complexity of soil matrix, poor understanding about the fate and effects of chemical combinations like pesticide and metal mixtures in terrestrial systems, and scarcity of toxicological data on mixtures of pollutants. In this review we summarized the current studies on individual and joint effects of pesticides and metals on earthworms and indicate the mixture that cause the synergistic interactions. The review explores the methods and models used previously to evaluate the toxicity of chemical mixtures, and suggests the perspective approaches for a better knowledge of combine effects as well as research methods The summarized report indicates that pesticide and metal mixtures at all organization levels affect the earthworms negatively. Whereas, the combined pollution generated by mixtures of pesticides and metal ions could induce the DNA damage, disruption in enzyme activities, reduction in individual survival, production and growth rate, change in individual behavior such as feeding rate, and decrease in the total earthworm community biomass and density. Among the pesticides organophosphates were identified the most toxic pesticides causing the synergistic effects. The findings indicate the scarcity of toxicological data concerning the assessment of pesticide and metal mixtures at genome level; while the mechanisms causing synergism were still not sufficiently explored. PMID- 28806581 TI - Engineered systems for therapeutic angiogenesis. AB - Ischemic disease caused by insufficient blood supply leads to a lack of oxygen and nutrients and a build-up of waste products in the affected tissue. Therapeutic angiogenesis, as a means to enhance perfusion of tissues with an inadequate blood supply, holds great promise for the treatment of ischemic disease. A wide range of factors that play a key role in physiological angiogenesis have been identified and trialed as pro-angiogenic agents. However, as yet pro-angiogenic treatments have failed to be translated clinically, owing to both lack of efficacy and safety concerns regarding the use of doses considerably larger than is typical present under physiological conditions. Thus, there is a clear need for the design and development of systems to overcome these hurdles and allow for the translation of safe and efficacious treatments to induce angiogenesis. In this regard, much progress has been made in the development of biomaterials as delivery systems for angiogenic factors to control the delivery and release of angiogenic therapies to induce vascularization. Thus, we review progress towards the development of translatable biomaterial-based systems to deliver angiogenic therapies, and point towards burgeoning advances in the field. PMID- 28806582 TI - Beck's cognitive theory and the response style theory of depression in adolescents with and without mild to borderline intellectual disability. AB - AIM: This study tests the validity of Beck's cognitive theory and Nolen Hoeksema's response style theory of depression in adolescents with and without MBID. METHODS: The relationship between negative cognitive errors (Beck), response styles (Nolen-Hoeksema) and depressive symptoms was examined in 135 adolescents using linear regression. RESULTS: The cognitive error 'underestimation of the ability to cope' was more prevalent among adolescents with MBID than among adolescents with average intelligence. This was the only negative cognitive error that predicted depressive symptoms. There were no differences between groups in the prevalence of the three response styles. In line with the theory, ruminating was positively and problem-solving was negatively related to depressive symptoms. Distractive response styles were not related to depressive symptoms. The relationship between response styles, cognitive errors and depressive symptoms were similar for both groups. CONCLUSION: The main premises of both theories of depression are equally applicable to adolescents with and without MBID. The cognitive error 'Underestimation of the ability to cope' poses a specific risk factor for developing a depression for adolescents with MBID and requires special attention in treatment and prevention of depression. WHAT THIS PAPER ADDS?: Despite the high prevalence of depression among adolescents with MBID, little is known about the etiology and cognitive processes that play a role in the development of depression in this group. The current paper fills this gap in research by examining the core tenets of two important theories on the etiology of depression (Beck's cognitive theory and Nolen-Hoeksema's response style theory) in a clinical sample of adolescents with and without MBID. This paper demonstrated that the theories are equally applicable to adolescents with MBID, as to adolescents with average intellectual ability. However, the cognitive bias 'underestimation of the ability to cope' was the only cognitive error related to depressive symptoms, and was much more prevalent among adolescents with MBID than among adolescents with average intellectual ability. This suggests that underestimating one's coping skills may be a unique risk factor for depression among adolescents with MBID. This knowledge is important in understanding the causes and perpetuating mechanisms of depression in adolescents with MBID, and for the development of prevention- and treatment programs for adolescents with MBID. PMID- 28806583 TI - Plant genome-scale reconstruction: from single cell to multi-tissue modelling and omics analyses. AB - In this review, we present the latest developments in plant systems biology with particular emphasis on plant genome-scale reconstructions and multi-omics analyses. Understanding multicellular metabolism is far from trivial and 'omics' data are difficult to interpret in the absence of a systems framework. 'Omics' data appropriately integrated with genome-scale reconstructions and modelling facilitates our understanding of how individual components interact and influence overall cell, tissue or organisms function. Here we present examples of how plant metabolic reconstructions and modelling are used as a systems-based framework for improving our understanding of the plant metabolic processes in single cells and multiple tissues. PMID- 28806584 TI - Transfer of tritium into laying hen's meat and eggs at prolonged intake with atmospheric air, water and grass meal. AB - Following a continuous intake of tritium (T) by laying hens' over a 55 day period, an increase of NTO concentration both in eggs and meat was observed over the first 2 weeks for intakes via inhalation and ingestion of water and grass meal. After this time, equilibrium of the T in these products occurred. It was found that when the intake of HTO is from water, air and grass meal, the ratio of its activity concentration in muscular tissue to that in eggs does not exceed 1, 4, and 6 respectively. The ratio of OBT concentration to that of NTO in the meat of hens (OBT/HTO) when intakes were from water, air and grass meal were 0.08, 0.09 and 0.7, respectively. PMID- 28806585 TI - Relationship between craving and plasma leptin concentrations in patients with cocaine addiction. AB - BACKGROUND: There is robust evidence indicating an overlap between neurobiological circuitry and pathways that regulate addictions and those that regulate appetite and food intake. Rodent work suggests a role of the appetitive peptide leptin in cocaine-seeking behaviours. The goal of this study was to investigate the possible relationship between plasma leptin concentrations and cocaine craving and use in patients seeking treatment for cocaine dependence. METHODS: Patients (N=43) with a DSM-IV diagnosis of cocaine dependence were studied before starting detoxification (baseline; T0) and then again 14days after (T1; only those patients who abstained from cocaine during the study). Blood samples for plasma leptin concentrations were collected and cocaine craving was assessed using the Brief Cocaine Craving Questionnaire (Brief-CCQ). Food craving was also assessed using a food Visual Analogue Scale (f-VAS). Barratt Impulsiveness Scale (BIS) was used to evaluate impulsivity. RESULTS: Plasma leptin concentrations at T0 significantly correlated with baseline Brief-CCQ scores (r=0.34, p<0.05). Furthermore, plasma leptin concentrations at T1 significantly correlated with the baseline amount of cocaine used (r=0.5, p<0.05). There were no significant correlations between plasma leptin concentrations and f-VAS scores either at T0 or T1 (p's>0.05). CONCLUSIONS: The present study suggests a potential relationship between plasma leptin concentrations and cocaine craving and use. Future mechanistic studies are needed to determine whether manipulations of leptin signalling may lead to novel pharmacological approaches to treat cocaine addiction. PMID- 28806586 TI - The new frontier of strategic alliances in health care: New partnerships under accountable care organizations. AB - Accountable care organizations (ACOs) and similar reforms aim to improve coordination between health care providers; however, due to the fragmented nature of the US health care system, successful coordination will hinge in large part on the ability of health care organizations to successfully partner across organizational boundaries. Little is known about new partnerships formed under the ACO model. We use mixed methods data from the National Survey of ACOs, Medicare ACO performance data and interviews with executive leaders across 31 ACOs to examine the prevalence, characteristics, and capabilities of partnership ACOs and why and how ACO partnerships form. We find that a striking percentage of ACOs - 81% - involve new partnerships between independent health care organizations. These "partnership ACOs" generally report lower capabilities on care management, care coordination, and health information technology. Additionally, under Medicare ACO programs partnership ACO achieved somewhat lower quality performance. Qualitative interviews revealed that providers are motivated to partner for resource complementarity, risk reduction, and legislative requirements, and are using a variety of formal and informal accountability mechanisms. Most partnership ACOs were formed out of existing, positive relationships, but a minority of ACOs formed out of previously competitive or conflictual relationships. Our findings suggests that the success of the ACO model will hinge in large part upon the success of new partnerships, with important implications for understanding ACO readiness and capabilities, the relatively small savings achieved to date by ACO programs, and the path to providers bearing more risk for population health management. In addition, ACO partnerships may provide an important window to monitor a potential wave of health care consolidation or, in contrast, a new model of independent providers successfully coordinating patient care. PMID- 28806588 TI - Measurement of side effects of anti-epileptic drugs (AEDs) in adults with intellectual disability: A systematic review. PMID- 28806587 TI - Elucidation of host-pathogen protein-protein interactions to uncover mechanisms of host cell rewiring. AB - Infectious diseases are the result of molecular cross-talks between hosts and their pathogens. These cross-talks are in part mediated by host-pathogen protein protein interactions (HP-PPI). HP-PPI play crucial roles in infections, as they may tilt the balance either in favor of the pathogens' spread or their clearance. The identification of host proteins targeted by viral or bacterial pathogenic proteins necessary for the infection can provide insights into their underlying molecular mechanisms of pathogenicity, and potentially even single out pharmacological intervention targets. Here, we review the available methods to study HP-PPI, with a focus on recent mass spectrometry based methods to decipher bacterial-human infectious diseases and examine their relevance in uncovering host cell rewiring by pathogens. PMID- 28806589 TI - Novel clinical manifestations in patients with KCNA2 mutations. AB - PURPOSE: To report novel clinical manifestations of KCNA2 mutation related epileptic encephalopathy. METHODS: Blood samples were sent for whole exome and Sanger sequencing. Seizure types were characterized by clinical criteria and EEG recording. RESULTS: KCNA2 mutations have been reported in 10 cases who presented with focal, absence, generalized tonic-clonic or myoclonic astatic seizures. Here we describe 3 patients with previously unreported, more severe manifestations. Patient 1 is a 5 year-old male with a c.1214 C > T (p.Pro405Leu) mutation, previously reported to be disease causing. He presented at 1year of age with focal seizures and subsequently developed electrical status epilepticus of sleep at age 3. The latter finding to our knowledge has never been reported in patients with KCNA2 mutations. Patient 2 is a 7 year-old female with a novel c.1195 G > A (p.Val399Met) mutation not previously described. She presented with intermittent then continuous polymyoclonus and myoclonic-astatic and generalized tonic clonic seizures. Continuous polymyoclonus is another new manifestation in patients with KCNA2 mutations. Patient 3 is a 23 year-old male with a c.889C > T (p.Arg297Trp) mutation not previously described. He presented at 4 years of age with generalized tonic clonic seizures and later developed recurrent refractory status epilepticus episodes at ages 19, 22 and 23 years, the latter being a novel manifestation in patients with KCNA2 mutations. CONCLUSION: We identified 3 patients with KCNA2 mutations with novel characteristics, including electrical status epilepticus of sleep, continuous polymyoclonus and status epilepticus. These results expand KCNA2 mutation epileptic manifestations to include more severe, previously unreported phenotypes. PMID- 28806590 TI - How multi segmental patterns deviate in spastic diplegia from typical developed. AB - BACKGROUND: The relationship between gait features and coordination in children with Cerebral Palsy is not sufficiently analyzed yet. Principal Component Analysis can help in understanding motion patterns decomposing movement into its fundamental components (Principal Movements). This study aims at quantitatively characterizing the functional connections between multi-joint gait patterns in Cerebral Palsy. METHODS: 65 children with spastic diplegia aged 10.6 (SD 3.7) years participated in standardized gait analysis trials; 31 typically developing adolescents aged 13.6 (4.4) years were also tested. To determine if posture affects gait patterns, patients were split into Crouch and knee Hyperextension group according to knee flexion angle at standing. 3D coordinates of hips, knees, ankles, metatarsal joints, pelvis and shoulders were submitted to Principal Component Analysis. FINDINGS: Four Principal Movements accounted for 99% of global variance; components 1-3 explained major sagittal patterns, components 4-5 referred to movements on frontal plane and component 6 to additional movement refinements. Dimensionality was higher in patients than in controls (p<0.01), and the Crouch group significantly differed from controls in the application of components 1 and 4-6 (p<0.05), while the knee Hyperextension group in components 1-2 and 5 (p<0.05). INTERPRETATION: Compensatory strategies of children with Cerebral Palsy (interactions between main and secondary movement patterns), were objectively determined. Principal Movements can reduce the effort in interpreting gait reports, providing an immediate and quantitative picture of the connections between movement components. PMID- 28806591 TI - Immediate mechanical stability of threaded and porous implant systems. AB - BACKGROUND: Primary stability of a dental implant system is an essential factor to maintain its long-term success. Thus, the objective of this study was to examine whether primary stability is different between threaded and porous dental implant systems placed in artificial bone blocks and human cadaveric mandibular bone. MATERIALS AND METHODS: Forty-two threaded and 42 highly porous dental implants were placed in artificial polyurethane bone foams with 7 different thicknesses (3.5 to 12mm). In addition, 11 threaded and 11 porous implants were installed in 8 edentulous mandibles of human cadavers. Implant stability quotient values, insertion torque, static and dynamic stiffness, and viscoelastic tan delta of each implant system were measured. Mean gray values were obtained at the implantation sites in the human mandible. FINDINGS: The porous implant group had substantially lower implant stability quotient values and insertion torque values than the threaded implant group that were equal or >5.5mm in thickness of the artificial bone block (p<0.026) with the exception of 8.5mm thickness, while static and dynamic stiffness values were not different between the two implant groups greater than 5.5mm in thickness (p>0.132). Static and dynamic stiffness values of the porous group were significantly greater than the thread group in the human mandibular bone (p<0.015). INTERPRETATION: The porous layer supports axial loading better than lateral and shear loading of the dental implant system. This result indicates that trabecular shaped architecture of the porous layer may provide sufficient anchorage compromising reduction of the axial primary stability of the porous implant system to be comparable with the threaded implant system. PMID- 28806593 TI - Supporting people with young onset dementia and their families: An evaluation of a training course for care workers. AB - This article reports the findings of an evaluation of a training course for care workers who care for people with dementia in the community. Twenty-four care workers participated in the training which took place in London and Surrey, United Kingdom. The training had a significant positive impact on participants' confidence in understanding the experiences and social care needs of people with young onset dementia (YOD) and their families. Participants also perceived that the training would help them improve their working practice by furthering their understanding of practical approaches to supporting and caring for people with dementia in general. Additionally, participants reported many ways in which they perceived being able to specifically support and empower people with YOD. It was concluded that the short training course improved knowledge and confidence for care workers on dementia care, and specifically in understanding how to support people with YOD and their families. Dementia specific training should be considered by service managers as a way of potentially increasing care worker job satisfaction. PMID- 28806592 TI - Validation of simplified centre of mass models during gait in individuals with chronic stroke. AB - BACKGROUND: The feasibility of using a multiple segment (full-body) kinematic model in clinical gait assessment is difficult when considering obstacles such as time and cost constraints. While simplified gait models have been explored in healthy individuals, no such work to date has been conducted in a stroke population. The aim of this study was to quantify the errors of simplified kinematic models for chronic stroke gait assessment. METHODS: Sixteen individuals with chronic stroke (>6months), outfitted with full body kinematic markers, performed a series of gait trials. Three centre of mass models were computed: (i) 13-segment whole-body model, (ii) 3 segment head-trunk-pelvis model, and (iii) 1 segment pelvis model. Root mean squared error differences were compared between models, along with correlations to measures of stroke severity. FINDINGS: Error differences revealed that, while both models were similar in the mediolateral direction, the head-trunk-pelvis model had less error in the anteroposterior direction and the pelvis model had less error in the vertical direction. There was some evidence that the head-trunk-pelvis model error is influenced in the mediolateral direction for individuals with more severe strokes, as a few significant correlations were observed between the head-trunk-pelvis model and measures of stroke severity. INTERPRETATION: These findings demonstrate the utility and robustness of the pelvis model for clinical gait assessment in individuals with chronic stroke. Low error in the mediolateral and vertical directions is especially important when considering potential stability analyses during gait for this population, as lateral stability has been previously linked to fall risk. PMID- 28806594 TI - Signaling networks in the control of pluripotency. AB - Embryonic stem cells (ESCs) are characterized by their ability of unlimited self renewal in vitro and pluripotent developmental potential, which endows them with great values in basic research and future clinical application. However, realization of full potential of ESCs is dependent on the elucidation of molecular mechanisms governing ESCs, among which signaling pathways play critical roles. A great deal of efforts has been made in the past decades to understand what and how signaling pathways contribute to the establishment and maintenance of pluripotency. In this review, we discuss signaling networks in both mouse and human ESCs, focusing on signals involved in the control of self-renewal and differentiation. In addition, the modulation of signaling pathways by pluripotency-associated transcription factors is also briefly summarized. PMID- 28806595 TI - Advances in stem cell proteomics. AB - Stem cells are at the basis of organismal development, characterized by their potential to differentiate towards specific lineages upon receiving proper signals. To understand the molecular principles underlying gain and loss of pluripotency, proteomics plays an increasingly important role owing to technical developments in mass spectrometry and implementation of innovative biochemical approaches. Here we review how quantitative proteomics has been used to investigate protein expression, localization, interaction and modification in stem cells both in vitro and in vivo, thereby complementing other omics approaches to study fundamental properties of stem cell plasticity. PMID- 28806596 TI - Development of an effective dose coefficient database using a computational human phantom and Monte Carlo simulations to evaluate exposure dose for the usage of NORM-added consumer products. AB - After the Fukushima accident in Japan, the Korean Government implemented the "Act on Protective Action Guidelines Against Radiation in the Natural Environment" to regulate unnecessary radiation exposure to the public. However, despite the law which came into effect in July 2012, an appropriate method to evaluate the equivalent and effective doses from naturally occurring radioactive material (NORM) in consumer products is not available. The aim of the present study is to develop and validate an effective dose coefficient database enabling the simple and correct evaluation of the effective dose due to the usage of NORM-added consumer products. To construct the database, we used a skin source method with a computational human phantom and Monte Carlo (MC) simulation. For the validation, the effective dose was compared between the database using interpolation method and the original MC method. Our result showed a similar equivalent dose across the 26 organs and a corresponding average dose between the database and the MC calculations of < 5% difference. The differences in the effective doses were even less, and the result generally show that equivalent and effective doses can be quickly calculated with the database with sufficient accuracy. PMID- 28806597 TI - A nested multivariate chemometrics based calibration strategy for direct trace biometal analysis in soft tissue utilizing Energy Dispersive X-Ray Fluorescence (EDXRF) and scattering spectrometry. AB - Compton scatter-modulated fluorescence and multivariate chemometric (artificial neural network (ANN) and principal component regression (PCR)) calibration strategy was explored for direct rapid trace biometals (Mn, Fe, Cu, Zn, Se) analysis in "complex" matrices (model soft tissues). This involved spectral feature selection (multiple fluorescence signatures) normalized to or in conjunction with Compton scatter. ANN model resulted in more accurate trace biometal determination (R2>0.9) compared to PCR. Hybrid nested (ANN and PCR) approach led to optimized accurate biometals' concentrations in Oyster tissue (<= +/- 10%). PMID- 28806598 TI - Automated synthesis of 1-[11C]acetoacetate on a TRASIS AIO module. AB - We automated radiochemical synthesis of 1-[11C]acetoacetate in a commercially available radiochemistry module, TRASIS AllInOne by [11C]carboxylation of the corresponding enolate anion generated in situ from isopropenylacetate and MeLi, and purified by ion-exchange column resins.1-[11C]acetoacetate was synthesized with high radiochemical purity (95%) and specific activity (~ 66.6GBq/umol, n = 30) with 35% radiochemical yield, decay corrected to end of synthesis. The total synthesis required ~ 16min. PET imaging studies were conducted with 1 [11C]acetoacetate in vervet monkeys to validate the radiochemical synthesis. Tissue uptake distribution was similar to that reported in humans. PMID- 28806599 TI - Resting state functional connectivity of the anterior striatum and prefrontal cortex predicts reading performance in school-age children. AB - The current study investigated the neural basis of reading performance in 60 school-age Spanish-speaking children, aged 6 to 9years. By using a data-driven approach and an automated matching procedure, we identified a left-lateralized resting state network that included typical language regions (Wernicke's and Broca's regions), prefrontal cortex, pre- and post-central gyri, superior and middle temporal gyri, cerebellum, and subcortical regions, and explored its relevance for reading performance (accuracy, comprehension and speed). Functional connectivity of the left frontal and temporal cortices and subcortical regions predicted reading speed. These results extend previous findings on the relationship between functional connectivity and reading competence in children, providing new evidence about such relationships in previously unexplored regions in the resting brain, including the left caudate, putamen and thalamus. This work highlights the relevance of a broad network, functionally synchronized in the resting state, for the acquisition and perfecting of reading abilities in young children. PMID- 28806600 TI - Design, synthesis and evaluation of newer 5,6-dihydropyrimidine-2(1H)-thiones as GABA-AT inhibitors for anticonvulsant potential. AB - Several new 5,6-dihydropyrimidine-2(1H)-thione derivatives have been prepared and investigated for their potencies for anticonvulsant activity against maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) test in mice. The acute neurotoxicity was measured by rotarod test. Compounds 3c and 3l were found active in both of the animal models. Further, in vitro GABA-AT enzyme activity assay was carried out to investigate the possible mechanism of action through GABA-AT inhibition. The most potent compounds 3c and 3l showed inhibitory potency (IC50) of 18.42MUM and 19.23MUM, respectively. The molecular modeling was performed for all the synthesized compounds. The docking results were found in concordant with the observed animal studies. PMID- 28806601 TI - Influence of sublethal doses of acetamiprid and halosulfuron-methyl on metabolites of zebra fish (Brachydanio rerio). AB - Acetamiprid, a neonicotinoid pesticide, is reported to have adverse sublethal effects on non-target beneficial organisms. Halosulfuron-methyl (HM), one of the most widely used herbicides in agriculture, has high ecotoxicity to aquatic plants and animals. In this study, a GC-MS-based metabolomics approach was used to investigate the toxicity of acetamiprid and HM. The Automated Mass Spectral Deconvolution and Identification System (AMDIS) software program and the retention index method were used to identify 51 metabolites in zebra fish (Brachydanio rerio). Changes in metabolites showed that acetamiprid and HM disturbed amino acid (e.g., leucine, valine, serine, glycine, proline, and alanine) metabolism, the TCA cycle (malic acid and fumaric acid), and the balance of neurotransmitters (glutamic acid, taurine, and glycine). The change in metabolites in the liver, head, and blood indicated that metabolites in the liver were more sensitive than those in the head and blood. Overall, on the basis of the change in metabolites, we identified a potential risk to zebra fish exposed to sublethal doses of acetamiprid and/or HM. PMID- 28806602 TI - Exposure of European sea bass (Dicentrarchus labrax) to chemically dispersed oil has a chronic residual effect on hypoxia tolerance but not aerobic scope. AB - We tested the hypothesis that the chronic residual effects of an acute exposure of European sea bass (Dicentrarchus labrax) to chemically dispersed crude oil is manifest in indices of hypoxic performance rather than aerobic performance. Sea bass were pre-screened with a hypoxia challenge test to establish their incipient lethal oxygen saturation (ILOS), but on discovering a wide breadth for individual ILOS values (2.6-11.0% O2 saturation), fish were subsequently subdivided into either hypoxia sensitive (HS) or hypoxia tolerant (HT) phenotypes, traits that were shown to be experimentally repeatable. The HT phenotype had a lower ILOS and critical oxygen saturation (O2crit) compared with the HS phenotype and switched to glycolytic metabolism at a lower dissolved oxygen, even though both phenotypes accumulated lactate and glucose to the same plasma concentrations at ILOS. As initially hypothesized, and regardless of the phenotype considered, we found no residual effect of oil on any of the indices of aerobic performance. Contrary to our hypothesis, however, oil exposure had no residual effect on any of the indices of hypoxic performance in the HS phenotype. In the HT phenotype, on the other hand, oil exposure had residual effects as illustrated by the impaired repeatability of hypoxia tolerance and also by the 24% increase in O2crit, the 40% increase in scope for oxygen deficit, the 17% increase in factorial scope for oxygen deficit and the 57% increase in accumulated oxygen deficit. Thus, sea bass with a HT phenotype remained chronically impaired for a minimum of 167days following an acute 24-h oil exposure while the HS phenotypes did not. We reasoned that impaired oxygen extraction at gill due to oil exposure activates glycolytic metabolism at a higher dissolved oxygen, conferring on the HT phenotype an inferior hypoxia resistance that might eventually compromise their ability to survive hypoxic episodes. PMID- 28806603 TI - Cancer vaccines in the era of checkpoint blockade: the magic is in the adjuvant. AB - While T cell checkpoint blockade therapy of various cancers yields impressive clinical benefits, most patients are not cured. This is thought to result from insufficient spontaneous tumor-specific T cell responses, a situation that could be remedied with cancer-specific vaccination. Much work is underway to identify cancer-specific antigens, leaving open the question of how to formulate these antigens in a manner that provokes potent cancer-specific T cell responses. In this review I discuss paradigms guiding adjuvant development, and consider what may constitutes a clinically relevant T cell response. I also suggest that adjuvants providing multiple non-redundant signals may be the next frontier in the development of cancer vaccines that provide true clinical benefit when combined with T cell checkpoint blockade. PMID- 28806604 TI - Chemodiversity of tryptamine-derived alkaloids in six Costa Rican Palicourea species (Rubiaceae-Palicoureeae). AB - We report 14 harmala and tryptamine-iridoid alkaloids with various tri-, tetra- and pentacyclic cores from leaves and stem bark of six species of the large and complex neotropical genus Palicourea. Among them is the previously undescribed compound deoxostrictosamide which is related to strictosamide, a key intermediate in camptothecin biosynthesis. In addition, we describe the occurrence of 1,2,3,4 tetrahydronorharman-1-one for the first time within Rubiaceae and ophiorine A and B, two alkaloids with an unusual core bearing a betaine function and a zwitterion as new for the genus. Although the other compounds are already known from other species, their degree of structural diversity highlights the remarkable biosynthetic capabilities of the genus Palicourea. Furthermore, the present paper provides additional support for the hypothesis that tryptamine-iridoid alkaloids represent a distinct chemosystematic feature for the genus Palicourea. PMID- 28806605 TI - Phytochemistry of European Primula species. AB - The genus Primula is the largest among the Primulaceae and is widespread mainly in the cold and temperate regions of the Northern Hemisphere. Since the beginning of the Twentieth century, several studies on the phytochemical composition of different species of Primula have been carried out. The main constituents examined were tissue and epicuticular flavonoids and saponins, which are of therapeutic significance. Only in recent years studies of the volatiles emitted by leaves and flowers have been carried out as well, but they are restricted to a small number of species. Only a few authors have documented the morphology and function of glandular trichomes in relation to the production of flavonoids and volatile organic compounds (VOCs). The use of Primula in folk medicine is described in the literature. Investigation of the biological and pharmacological activities of Primula are reported. This study aims at providing a collection of publications on the genus Primula along with a critical revision of literature data. It focuses on the possible taxonomic significance of the secondary metabolites and on their ecological role as attractors for pollinators and deterrents against herbivores and parasites, in order to build the base for further studies. PMID- 28806606 TI - Imbalance between abstract and concrete repetitive thinking modes in schizophrenia. AB - OBJECTIVE: Repetitive thoughts can be divided in two modes: abstract/analytic (decontextualized and dysfunctional) and concrete/experiential (problem-focused and adaptive). They constitute a transdiagnostic process involved in many psychopathological states but have received little attention in schizophrenia, as earlier studies only indexed increased ruminations (related to dysfunctional repetitive thoughts) without jointly exploring both modes. This study explored the two repetitive thinking modes, beyond ruminations, to determine their imbalance in schizophrenia. METHODS: Thirty stabilized patients with schizophrenia and 30 matched controls completed the Repetitive Response Scale and the Mini Cambridge-Exeter Repetitive Thought Scale, both measuring repetitive thinking modes. Complementary measures related to schizophrenic symptomatology, depression and anxiety were also conducted. RESULTS: Compared to controls, patients with schizophrenia presented an imbalance between repetitive thinking modes, with increased abstract/analytic and reduced concrete/experiential thoughts, even after controlling for comorbidities. Schizophrenia is associated with stronger dysfunctional repetitive thoughts (i.e. abstract thinking) and impaired ability to efficiently use repetitive thinking for current problem solving (i.e. concrete thinking). CONCLUSION: This imbalance confirms the double faced nature of repetitive thinking modes, whose influence on schizophrenia's symptomatology should be further investigated. The present results also claim for evaluating these processes in clinical settings and for rehabilitating the balance between opposite repetitive thinking modes. PMID- 28806607 TI - Dissociation in patients with borderline personality disorder in acute inpatient care - A latent profile analysis. AB - PURPOSE: Dissociation is a common symptom in Borderline Personality disorder (BPD) and its consideration is important for the therapeutic outcome. The aim of this cross-sectional study was to scrutinize the co-occurrence of BPD symptoms and dissociative experiences. In particular, we were interested in the occurrence of specific symptom clusters characterizing qualitatively different patient groups in a clinical sample of BPD patients. BASIC PROCEDURES: We analyzed the data of 103 patients in a specialized acute inpatient care crisis intervention unit. Measures were the Borderline Symptom List (BSL-95), a German adaption of the Dissociative Experience Scale (FDS), and the Symptom Checklist SCL-90-R. We applied a Latent Profile Analysis (LPA) using the subscales of BSL-95 and FDS to investigate the existence of distinct latent classes of symptom profiles. Afterwards, we related the obtained profiles to other clinical and demographic characteristics. MAIN FINDINGS: Dissociative experiences of moderate to severe intensity were common among patients with BPD. LPA revealed that a model of three classes fitted the data best: one class was characterized by co-occurrence of severe borderline symptoms and frequent dissociative experiences, one class showed low symptom burden in both measures, and one class showed considerable borderline symptoms but only moderate dissociative experiences. The classes were closely related to the severity of other self-rated psychological problems and showed significantly different occurrences of stress-related comorbid disorders. PRINCIPAL CONCLUSIONS: The results underline that dissociation is an important factor in many (but not all) BPD patients. This should be addressed by increased attention to dissociative symptoms in the diagnostic process and the adjustment of treatment plans. PMID- 28806608 TI - Differential effects of childhood trauma subtypes on fatigue and physical functioning in chronic fatigue syndrome. AB - OBJECTIVE: There is wide consensus that childhood trauma plays an important role in the aetiology of chronic fatigue syndrome (CFS). The current study examines the differential effects of childhood trauma subtypes on fatigue and physical functioning in individuals suffering from CFS. METHODS: Participants were 155 well-documented adult, predominantly female CFS patients receiving treatment at the outpatient treatment centre for CFS of the Antwerp University Hospital in Belgium. Stepwise regression analyses were conducted with outcomes of the total score of the Checklist Individual Strength (CIS) measuring fatigue and the scores on the physical functioning subscale of the Medical Outcomes Short Form 36 Health Status Survey (SF-36) as the dependent variables, and the scores on the five subscales of the Traumatic Experiences Checklist (TEC) as the independent variables. RESULTS: The patients' fatigue (beta=1.38; p=0.025) and physical functioning scores (beta=-1.79; p=0.034) were significantly predicted by childhood sexual harassment. There were no significant effects of emotional neglect, emotional abuse, bodily threat, or sexual abuse during childhood. CONCLUSION: Of the childhood trauma subtypes investigated, sexual harassment emerged as the most important predictor of fatigue and poor physical functioning in the CFS patients assessed. These findings have to be taken into account in further clinical research and in the assessment and treatment of individuals coping with chronic fatigue syndrome. PMID- 28806609 TI - Sleep disturbances in young and middle-aged adults - Empirical patterns and related factors from an epidemiological survey. AB - BACKGROUND: Previous research suggests that sleep disorders are highly associated with other mental health problems. However, sleep problems even below the diagnostic threshold of sleep disorders are very common in the general population, which highly affects wellbeing and functioning. In order to broaden the focus beyond those severe cases we explored empirical patterns across the whole spectrum of sleep problems as well as associated clinical and other factors. METHOD: A representative community sample of N=1274 residents from the canton of Zurich was interviewed for sleep problems and diagnostic criteria for mental disorders as well as was given a number of mental health-related psychometrical checklists. Based on a broader spectrum of sleep problems we conducted a latent class analysis (LCA) to derive distinct classes of such disturbances. Classes were compared regarding their associations to mental health relevant and other risk factors. RESULTS: The LCA revealed four classes - no sleep disturbances (72.6%), difficulties initiating and maintaining sleep (15.8%), delayed sleep (5.3%), and severe sleep problems (6.4%). Severe sleep problems were related to female gender and generalized anxiety disorder, while depression was linked to all sleep problem classes. Persons with difficulties initiating and maintaining sleep and severe sleep problems reported higher levels of psychopathology, burnout and neuroticism, while all sleep problem types were tied to stress-related variables, but not alcohol use disorder. DISCUSSION: Sleep problems are highly prevalent among the young and middle-aged adults in our representative sample of young and middle-aged adults and as such represent a serious public mental health problem. Our findings indicate sleep problems to have a multi-dimensional structure with some differential associations. While all subtypes were associated with poorer mental health and particularly more depression, severe sleep problems appeared to be the sleep subtype seen in agoraphobia and GAD, while delayed sleep had no specific associations. The variety of associations assessed leads one to assume that likewise a variety of sleep interventions is required. PMID- 28806610 TI - Risk factors of transition from mild cognitive impairment to Alzheimer's disease and death: A cohort study. AB - BACKGROUND: Knowledge of risk factors is essential for developing strategies that prevent or minimise transitions from mild cognitive impairment (MCI) to Alzheimer's disease (AD) and death. The aim of this study was to assess risk factors for progression to AD and death among Chinese individuals with cognitive impairment. METHODS: We conducted a multisite, population-based cohort study on 437 community-dwelling elderly MCI residents in Taiyuan, China from 2010 to 2014. MCI, AD, death from AD and death from a cause other than AD were specified as disease states during the natural history of dementia. Transition-specific Cox model was fitted and hazard ratio (HR) with 95% confidence intervals (CIs) was estimated. RESULTS: Analyses showed that risk factors played different roles in affecting transitions to AD and death. Risk factors for transition from MCI to AD were being female (HR: 1.82; 95%CI: 1.20-2.77), older age (HR: 3.09; 95%CI: 1.81 5.25), reading occasionally (HR: 1.79; 95%CI: 1.11-2.89), current smoking (HR: 1.74; 95%CI: 1.15-2.65), light-moderate alcohol drinker (HR: 2.24; 95%CI: 1.42 3.53), cerebrovascular disease (HR: 2.70; 95%CI: 1.68-4.34), hyperlipidemia (HR: 1.87; 95%CI: 1.16-3.02) and diabetes (HR: 1.81; 95%CI: 1.18-2.77). Only cerebrovascular disease (HR: 3.04; 95%CI: 1.22-7.58) was a significant risk factor for transition from MCI to death from a cause other than AD. Older age (HR: 10.68; 95%CI: 1.16-97.93) and low level education (HR: 0.14; 95%CI: 0.05 0.44) were significant predictors for transition from AD to death from a cause other than AD. CONCLUSIONS: Participants with advanced age, low-level education, history of harmful alcohol consumption or smoking, cerebrovascular disease, hyperlipidemia, diabetes or who were female were at increased risk of transitioning to AD or death. Strategies to control modifiable risk factors in specific disease stage should be implemented to decrease the conversion to AD or death among Chinese patients with MCI. PMID- 28806611 TI - Automobile-dependency as a barrier to vision zero, evidence from the states in the USA. AB - With a traffic fatality rate of 10.6 per 100,000 as of 2013-more than triple that in the UK, the Netherlands, and Sweden-the United States has the worst traffic safety performance of all developed countries. Statewide variations are even more pronounced. North Dakota registers more than twice the national average and five times the rate of Massachusetts. We used panel models and annual data from 1997 to 2013 to capture the effect of seven separate sets of factors that influence traffic safety: exposure, travel behavior, socioeconomics, macroeconomics, safety policies, and mitigating factors such as health care. The results of our panel models and supplementary analysis of state effects show that two variables - Vehicle Miles Traveled and Vehicles per Capita-have the strongest impact on traffic fatality rates. This is closely followed by Infant Mortality Rates, the proxy that we used to represent the quality of health care. Policy levers such as Graduated Driver's Licenses (GDL) have improved safety, but to a limited extent. We also found that states with higher urban density and more walking are associated with lower traffic fatality rates. Taken as a whole, our findings suggest that if additional progress is to be made in reducing traffic fatalities, emphasis needs to move beyond simply focusing on policies such as GDL and seat belt laws, which have already been adopted by almost all jurisdictions across the United States. We need to also consider factors that focus on the type of urban form that we are creating to ensure that we are fostering environments that encourage multi-modal transportation such as walking to reduce the VMT and Vehicles per Capita, the two strongest predictors of traffic fatalities. PMID- 28806612 TI - Pilots using selective serotonin reuptake inhibitors compared to other fatally injured pilots. AB - Selective Serotonin Reuptake Inhibitors (SSRI) were a disqualifying medication for U.S. civil pilots before April 5, 2010. After this date, a Federal Aviation Administration policy was created that allowed airmen, on select SSRIs, a pathway to hold a valid medical certificate. The purpose of this study was to provide a detailed look at SSRIs in the U.S. pilot population since the inception of this new policy. We examined the toxicology results from fatally injured airmen in addition to outcomes concerning pilots who are participating in the program. This study examined data from the Civil Aerospace Medical Institute's Bioaeronautical Sciences Research Laboratory in conjunction with the Medical Analysis Tracking Registry and the Document Imaging and Workflow System. A count-based regression model quantified the relationships between positive SSRI findings with additional factors of interest. These factors included pilot rating, ethanol, and first generation antihistamines. There were 1484 fatally injured airmen over the six year study period, of which 44-tested positive for an SSRI. First-generation antihistamines were statistically associated with positive findings of SSRIs. PMID- 28806613 TI - Automatic blood vessels segmentation based on different retinal maps from OCTA scans. AB - The retinal vascular network reflects the health of the retina, which is a useful diagnostic indicator of systemic vascular. Therefore, the segmentation of retinal blood vessels is a powerful method for diagnosing vascular diseases. This paper presents an automatic segmentation system for retinal blood vessels from Optical Coherence Tomography Angiography (OCTA) images. The system segments blood vessels from the superficial and deep retinal maps for normal and diabetic cases. Initially, we reduced the noise and improved the contrast of the OCTA images by using the Generalized Gauss-Markov random field (GGMRF) model. Secondly, we proposed a joint Markov-Gibbs random field (MGRF) model to segment the retinal blood vessels from other background tissues. It integrates both appearance and spatial models in addition to the prior probability model of OCTA images. The higher order MGRF (HO-MGRF) model in addition to the 1st-order intensity model are used to consider the spatial information in order to overcome the low contrast between vessels and other tissues. Finally, we refined the segmentation by extracting connected regions using a 2D connectivity filter. The proposed segmentation system was trained and tested on 47 data sets, which are 23 normal data sets and 24 data sets for diabetic patients. To evaluate the accuracy and robustness of the proposed segmentation framework, we used three different metrics, which are Dice similarity coefficient (DSC), absolute vessels volume difference (VVD), and area under the curve (AUC). The results on OCTA data sets (DSC=95.04+/-3.75%, VVD=8.51+/-1.49%, and AUC=95.20+/-1.52%) show the promise of the proposed segmentation approach. PMID- 28806614 TI - Altered interaction with environmental reinforcers in major depressive disorder: Relationship to anhedonia. AB - Anhedonia-defined as loss of interest or pleasure-is one of two core symptoms of major depressive disorder (MDD). Anhedonia may involve decreased enjoyment of potentially rewarding activities and decreased motivation to engage in such activities. Increased engagement with reinforcers-activities with the potential to be positive experiences-is a frequent target of cognitive-behavioral therapies. Nevertheless, how environmental reinforcers are perceived, and how decisions to approach or avoid them are made by individuals with MDD, is largely unknown. We developed an experimental Behavioral Approach Motivation Paradigm to study how activities are evaluated and approached in MDD. Twenty-one MDD participants and 23 healthy controls performed an experimental task that rated activity words for their hedonic value, then engaged in an approach-avoidance joystick task with each individual's unique set of 'liked' and 'disliked' activity words. A negative correlation was observed between anhedonia and the number of 'liked' activities across participants. No significant difference between approach and avoidance behavior was found in direct comparisons between healthy controls and MDD participants; however, weaker avoidance and greater approach toward 'disliked' activities was found in MDD participants. This suggests negative bias in selecting environmental opportunities, potentially further compromising access to hedonic experiences in MDD. PMID- 28806615 TI - Graphene- gold based nanocomposites applications in cancer diseases; Efficient detection and therapeutic tools. AB - Early detection and efficient treatment of cancer disease remains a drastic challenge in 21st century. Throughout the bulk of funds, studies, and current therapeutics, cancer seems to aggressively advance with drug resistance strains and recurrence rates. Nevertheless, nanotechnologies have indeed given hope to be the next generation for oncology applications. According to US National cancer institute, it is anticipated to revolutionize the perspectives of cancer diagnosis and therapy. With such success, nano-hybrid strategy creates a marvelous preference. Herein, graphene-gold based composites are being increasingly studied in the field of oncology, for their outstanding performance as robust vehicle of therapeutic agents, built-in optical diagnostic features, and functionality as theranostic system. Additional modes of treatments are also applicable including photothermal, photodynamic, as well as combined therapy. This review aims to demonstrate the various cancer-related applications of graphene-gold based hybrids in terms of detection and therapy, highlighting the major attributes that led to designate such system as a promising ally in the war against cancer. PMID- 28806617 TI - Possible doubling of road traffic injury burden in Pakistan: findings from a population-based survey in 2013-2014. PMID- 28806616 TI - Parvovirus B19 integration into human CD36+ erythroid progenitor cells. AB - The pathogenic autonomous human parvovirus B19 (B19V) productively infects erythroid progenitor cells (EPCs). Functional similarities between B19V nonstructural protein (NS1), a DNA binding endonuclease, and the Rep proteins of Adeno-Associated Virus (AAV) led us to hypothesize that NS1 may facilitate targeted nicking of the human genome and B19 vDNA integration. We adapted an integration capture sequencing protocol (IC-Seq) to screen B19V infected human CD36+ EPCs for viral integrants, and discovered 40,000 unique B19V integration events distributed throughout the human genome. Computational analysis of integration patterns revealed strong correlations with gene intronic regions, H3K9me3 sites, and the identification of 41 base pair consensus sequence with an octanucleotide core motif. The octanucleotide core has homology to a single region of B19V, adjacent to the P6 promoter TATA box. We present the first direct evidence that B19V infection of erythroid progenitor cells disrupts the human genome and facilitates viral DNA integration. PMID- 28806618 TI - Public sentiment and discourse about Zika virus on Instagram. AB - OBJECTIVE: Social media have strongly influenced the awareness and perceptions of public health emergencies, and a considerable amount of social media content is now shared through images, rather than text alone. This content can impact preparedness and response due to the popularity and real-time nature of social media platforms. We sought to explore how the image-sharing platform Instagram is used for information dissemination and conversation during the current Zika outbreak. STUDY DESIGN: This was a retrospective review of publicly posted images about Zika on Instagram. METHODS: Using the keyword '#zika' we identified 500 images posted on Instagram from May to August 2016. Images were coded by three reviewers and contextual information was collected for each image about sentiment, image type, content, audience, geography, reliability, and engagement. RESULTS: Of 500 images tagged with #zika, 342 (68%) contained content actually related to Zika. Of the 342 Zika-specific images, 299 were coded as 'health' and 193 were coded 'public interest'. Some images had multiple 'health' and 'public interest' codes. Health images tagged with #zika were primarily related to transmission (43%, 129/299) and prevention (48%, 145/299). Transmission-related posts were more often mosquito-human transmission (73%, 94/129) than human-human transmission (27%, 35/129). Mosquito bite prevention posts outnumbered safe sex prevention; (84%, 122/145) and (16%, 23/145) respectively. Images with a target audience were primarily aimed at women (95%, 36/38). Many posts (60%, 61/101) included misleading, incomplete, or unclear information about the virus. Additionally, many images expressed fear and negative sentiment, (79/156, 51%). CONCLUSION: Instagram can be used to characterize public sentiment and highlight areas of focus for public health, such as correcting misleading or incomplete information or expanding messages to reach diverse audiences. PMID- 28806619 TI - A long-term recurrence-free survival of a patient with the mixed adeno neuroendocrine bile duct carcinoma: A case report and review of the literature. AB - INTRODUCTION: Neuroendocrine tumors arising primarily in the bile duct are rare. And among these tumors, mixed adeno-neuroendocrine carcinoma (MANEC) is quite uncommon. We report a patient with MANEC who achieved long-term recurrence-free survival. And our case report includes analysis previous case reports. PRESENTATION OF CASE: A 66-year-old man underwent investigation for persistent anorexia and fatigue. Laboratory tests showed that the values of hepatobiliary enzymes were increased. On CT, a 10mm*8mm hypervascular tumor was observed in the distal bile duct and the proximal bile duct was markedly dilated. Endoscopic retrograde cholangiography (ERC) also showed a stenosis with a long diameter of 10mm. Examination of a biopsy specimen obtained from the narrow site of the bile duct at the time of ERC revealed tubular adenocarcinoma. Therefore, pylorus preserving pancreaticoduodenectomy was performed under a preoperative diagnosis of distal bile duct carcinoma. Postoperative pathologic examination revealed alveolar structures and a mixture of moderately differentiated adenocarcinoma with synaptophysin-positive and chromogranin-A-positive neuroendocrine carcinoma. Therefore, the final diagnosis was MANEC, pT3, pN1, M0, pStage II B (TNM classification of the UICC). Curative resection was achieved and there has been no recurrence after 30 months. DISCUSSION: In the previous reports, only five patients (14.7%) survived for 24 months or longer. Median survival was longer (14 months) in the curative resection group and shorter (6 months) in the non curative resection group. CONCLUSION: Curative resection is essential to achieve long-term survival in patients with bile duct MANEC, even if these patients have lymph node metastasis. PMID- 28806620 TI - A novel intestinal rotation method for digestive reconstruction after combined pancreaticoduodenectomy and extended right hemicolectomy: A case report and surgical technique. AB - INTRODUCTION: Pancreaticoduodenectomy (PD) combined with extended right hemicolectomy (RH) is a challenging procedure for locally advanced malignancies. However, information concerning the reconstruction method of the digestive system is limited. Here, we present a case and surgical technique of a novel intestinal rotation method for digestive reconstruction after PD combined with RH. PRESENTATION OF CASE: A 62-year-old man with locally advanced pancreatic cancer received conversion surgery combined with PD and RH after preoperative chemotherapy. With respect to the reconstruction of the digestive system, the entire intestinal mesentery was rotated 180 degrees forward counterclockwise around the axis of the superior mesenteric artery, and then the reconstruction, according to Child's method, was performed. The patient recovered without problems in gastroenterological functions after the operation. DISCUSSION: With respect to the reconstruction of the digestive system in patients undergoing combined PD and RH, practitioners should pay close attention to twisting of the intestinal mesentery when bringing up the proximal jejunum for pancreatojejunostomy and hepatojejunostomy and the distal ileum for ileocolic anastomosis. This intestinal rotation method enables a smooth and uneventful reconstruction of the digestive system. CONCLUSION: This is the first detailed description of an intestinal rotation method for digestive reconstruction after combined PD and extended RH. The intestinal rotation method can be an alternative and helpful technical option for digestive reconstruction in patients with combined PD and RH. PMID- 28806621 TI - Traumatic common hepatic artery injury causing isolated right hepatic ischemia due to a left accessory artery. A case report. AB - INTRODUCTION: Hepatic arterial liver flow is renowned for its redundancy. Previous studies have demonstrated that the common hepatic artery is not essential for liver survival. We present a case of a 31year-old involved in a high-speed motor vehicle accident whose liver survived thanks to the presence of an accessory hepatic artery. PRESENTATON OF THE CASE: We present the case of a 31year-old male who sustained a traumatic injury of the proper hepatic artery following a motor vehicle accident. The patient suffered temporary right liver lobe ischemia due to the presence of an accessory left hepatic artery. This resulted in the selective formation of 'biliary lakes' distinctively within the territory of the right hepatic artery supply. Simultaneously the patient developed a pseudo-aneurysm of the proper hepatic artery which required radiology intervention. At the time of pseudo-aneurysm embolisation, a rich network of arterial collaterals had formed between the accessory left hepatic and the inferior phrenic artery. On follow up the biliary lakes to the right lobe had resolved, but a small area at the periphery of the right lobe had encountered atrophy. DISCUSSION: This case report is an 'in vivo' demonstration of liver resilience to arterial flow re-distribution and demonstrates the ability of the biliary epithelium to recover from and ischemic injury. CONCLUSION: Parenchymal liver survival is mostly independent from flow within the common hepatic artery. Acute and chronic liver parenchyma changes following interruption of hepatic artery flow can still occur. PMID- 28806622 TI - Case report on the non-operative management of a retrievable inferior vena cava filter perforating the duodenum. AB - INTRODUCTION: Deep vein thrombosis (DVT) continues to be a significant source of morbidity for surgical patients. Placement of a retrievable inferior vena cava (IVC) filter is used when patients have contraindications to anticoagulation or recurrent pulmonary embolism despite therapeutic anticoagulation. Although retrievable IVC filters are often used, they carry a unique set of risks. PRESENTATION OF CASE: A 67-year-old man presents to the Emergency Room (ER) following large volume melena and complaining of syncope. One year prior, the patient had been diagnosed with Glioblastoma multiforme, for which he underwent a craniotomy with near-total resection of the mass. He subsequently developed a deep vein thrombosis and underwent placement of a retrievable inferior vena cava (IVC) filter. Computerized tomography (CT) and esophagogastroduodenoscopy showed duodenal perforation by the retrievable IVC filter. The filter was successfully retrieved through an endovascular approach. DISCUSSION: Retrievable IVC filter placement is the preferred method of pulmonary embolism prevention in patients with significant risk for bleeding. Duodenal perforation by a retrievable IVC filter is a rare and serious complication. It is usually managed surgically, but can also be managed non-operatively. CONCLUSION: For patients with significant comorbidities or patients who are poor surgical candidates, non-operative management with close monitoring can serve as an initial approach to the patient with a caval enteric perforation secondary to a retrievable IVC filter. PMID- 28806623 TI - Retroperitoneal paraganglioma-Is pre operative embolization useful? AB - INTRODUCTION: Paragangliomas (PG) are rare tumors derived from chromaffin cells that are located outside the adrenal gland and are capable of producing catecholamines. The treatment is based on a surgical resection, and there is controversy regarding the usefulness of previously carrying out an embolization and what is the most adequate surgical approach. CLINICAL CASE: We will present a 17-year-old woman with a retroperitoneal tumour in contact with the aorta and the inferior vena cava, treated with embolization prior to the surgical resection via laparotomy. DISCUSSION: The PG tumors are very infrequent and originate in the extra-adrenal chromaffin cells that exist in the vicinity of the components of the autonomic nervous system. Most of them (86%) produce catecholamines, are unique, sporadic, benign and more frequent in middle-aged women. Since they are radioresistant tumors, the only possibility for a cure is by a complete surgical excision. The preoperative embolization has been described mainly as the treatment of cervical PG, although its use in abdominal PG is more controversial and is not done in a systematic manner. CONCLUSION: We can conclude that the embolization of abdominal PG is not free of risks and that it has not been demonstrated that it significantly reduces the peri-operative bleeding or the surgical time. Probably, the embolization should be reserved for intensively hypervascularized and larger PGs. PMID- 28806624 TI - Bcl-2/Bax protein and mRNA expression in yak (Bos grunniens) placentomes. AB - Placental function is complex and influenced by various factors; furthermore, it depends on a delicate balance between cell proliferation, cell differentiation, and cell death. Bcl-2 and Bax proteins are key apoptosis regulators and are considered to play an important role in the maintenance of both dynamic balance and integrity of many tissues. Changes in Bcl-2 and Bax expressions have been described during different developmental stages in normal human placentas. Studies furthermore indicated several pathological placental changes to be related to abnormal Bcl-2 and Bax expressions. In the present study, we investigated both expression and distribution of Bcl-2 and Bax in yak placentas. For this, we collected placentas of 35 yaks at different stages of pregnancy as well as cotyledonary villi of four postpartum yaks. Protein and mRNA expressions of both Bcl-2 and Bax were investigated via immunohistochemistry, Western blot, and real-time PCR. Immunoreactive Bcl-2 protein was mainly localized near the fetal villous trophoblast at various gestational stages and post-partum. The Positive Index (PI) of Bcl-2 protein expression significantly decreased with increasing gestational age. Early during pregnancy (<=2 months), the Bax protein was widely distributed in the fetal villous trophoblast layer, the maternal caruncular crypt epithelium, and the stroma. Subsequently, the Bax protein distribution gradually concentrated in the fetal villous trophoblast layer. The staining intensity of Bax increased from the 3rd month to the prepartum of gestation. The PI reached a minimum of 9.4 +/- 2.2 in fetal chorionic villi (FCV) and 1.3 +/- 0.8 in maternal caruncular crypts (MCC) of the three months group. Both Bcl-2 and Bax had maximum immunoreactivity in the fetal villous trophoblast layer of placentas collected form postpartum yaks (with PIs of 36.6 +/- 5.7 and 38.2 +/- 4.8, respectively). Protein and mRNA expression of Bcl-2 and Bax investigated via Western blot and real-time PCR demonstrated similar expression profiles than immunohistochemistry. These results demonstrated the dynamic expression of Bcl-2 and Bax during pregnancy and postpartum in yak placentas. The temporal and spatial expression patterns indicate that Bcl-2 and Bax may participate in physiological processes of the placenta, such as formation, maturation, and antepartum degeneration that are critical for fetal and placental development in yak. PMID- 28806625 TI - Association of changes among body condition score during the transition period with NEFA and BHBA concentrations, milk production, fertility, and health of Holstein cows. AB - Our objective was to evaluate the association between body condition score (BCS) change during the transition period with fertility, non-esterified fatty acids (NEFA) and beta-hydroxybutyrate (BHBA) concentrations, milk yield, and health problems of Holstein cows in a retrospective cohort study. Holstein cows (n = 232) were assessed for BCS (5 point scale; 0.25 point increments) and had blood collected at 21 and 7 d before, on the day of, and 7 and 21 d after calving. Blood samples were assayed for NEFA and BHBA concentrations. All cows received a timed artificial insemination (TAI) at 65 +/- 3 days in milk (DIM) following a Presynch-Ovsynch protocol with a progesterone implant during the Ovsynch protocol. Cows were grouped based on BCS change after calving as to whether they: 1) lost (L), 2) maintained (M), or 3) gained (G) BCS. Data were analyzed by logistic regression with GLIMMIX and ANOVA with repeated measures using the MIXED procedures of SAS. Both NEFA and BHBA concentrations after calving differed (P < 0.01) for cows that lost, maintained, or gained BCS from 21 d before to 21 d after calving (NEFA: 0.51 +/- 0.01; 0.45 +/- 0.01; 0.42 +/- 0.01 mmol/L; BHBA: 0.73 +/- 0.02; 0.70 +/- 0.02; 0.68 +/- 0.02 mmol/L; respectively; mean +/- SEM). By design, BCS change after calving differed (P < 0.01) among groups and was 0.38; 0.00; and 0.35 for cows in groups L, M, and G, respectively. At 21 d before and 21 d after calving, BCS differed (P < 0.01) among groups and was [before (2.97, 2.70, and 2.57) and after (2.54, 2.70, and 2.90)] for cows in groups L, M, and G, respectively. Between evaluated days, higher circulating NEFA and BHBA concentrations were observed 7 d after calving. Change in BCS affected (P < 0.01) pregnancy/AI (P/AI), days to first ovulation, and percentage of cyclic cows at 50 DIM. At 32 d after TAI, P/AI differed (P < 0.01) for cows that lost [18% (11/84)], maintained [33% (26/80)], or gained [47% (32/68)] BCS. Cows that lost BCS during the transition period had more health events (P < 0.01), than cows that gained or maintained BCS. In conclusion, changes in BCS during the transition period affected NEFA and BHBA concentrations, fertility, and occurrence of health problems during the lactation. PMID- 28806626 TI - Cryopreservation of cynomolgus macaque (Macaca fascicularis) sperm with glycerol and ethylene glycol, and its effect on sperm-specific ion channels - CatSper and Hv1. AB - The cryoprotective agent (CPA) is one of the most important factors that affects the cryosurvival of sperm. The aim of the present study was to compare two different CPAs, glycerol (Gly) and ethylene glycol (EG), on the cryopreservation of cynomolgus macaques sperm and evaluate the effects of cryopreservation on sperm motility, acrosomal integrity, DNA integrity, mitochondrial function and the sperm membrane ion channels CatSper and Hv1. Compared to fresh sperm, cryopreservation with either 0.7 M Gly or EG decreased the sperm motility (79.8 +/- 1.5% Vs. 47.3 +/- 1.8% and 47.6 +/- 1.4%), acrosomal integrity (89.6 +/- 1.2% Vs. 80.1 +/- 1.8% and 79.6 +/- 1.7%), DNA integrity (91.9 +/- 0.7% Vs. 82.9 +/- 1.0% and 82.3 +/- 1.0%) and mitochondrial membrane potential (87.9 +/- 1.8% Vs. 70.6 +/- 2.7% and 67.9 +/- 2.5%) and the quantity of the CatSper and Hv1 channels determined by Western Blot (p < 0.05), and EG showed equal cryoprotection to cynomolgus sperm in all of the sperm parameters. Our results indicated, for the first time, that cryopreservation decreases the quantity of sperm membrane ion channels (CatSper and Hv1), which might be one of the reasons that frozen sperm have a low fertilizing ability. The study will be beneficial to understand the biological process involved in sperm cryopreservation of nonhuman primates and contribute to improving cryopreservation protocols than can maintain sperm function and fertilizing ability. PMID- 28806627 TI - A novel clinical evaluation method using maximum angular velocity during knee extension to assess lower extremity muscle function of older adults. AB - The purpose of this study is to examine the utilities of maximum angular velocity (AV) assessment during knee extension (KE) using a gyroscope for clinical evaluation of exercise program for older adults. Two hundred and 4 community dwelling older adults underwent a 3-month exercise intervention program. Outcome measures included AV during KE and other physical functions (isometric strength (IS), walking abilities, and balance functions). A correlation coefficient was used to evaluate the relationships between AV and other physical functions at baseline. The differences of physical functions before and after intervention were evaluated and the effect size of each measurement was calculated after the program. The AV measurement was significantly correlated with IS during KE (r=0.303, P<0.01) and other physical functions. Most correlation coefficients of angular velocity were greater than that of IS. All of physical assessments were significantly improved. Also, effect size of AV was greater than that of IS (d=0.45 vs. 0.42). AV of the lower extremities is useful to evaluate the effects of exercise intervention in the elderly. PMID- 28806628 TI - Complete step section microscopic study of a Swan-Ganz catheter-related pulmonary artery rupture: a frequently lethal complication that to our knowledge has not had a comprehensive microscopic examination: case report and literature review. AB - BACKGROUND: Introduced in 1970, the Swan-Ganz catheter (SGC) soon became widely used because of its unique usefulness in managing intensive care patients. Unfortunately, SGC usage was complicated by pulmonary artery rupture (PAR) with a 50% mortality rate that led to a near banning of the SCG in the late 1980s. Increasing knowledge and decreasing incidence of SGC-related PARs (SGPARs) led to the current feeling that the present SGPAR incidence is now low enough to tolerate given the lives saved by SGC usage. However, an important unknown is that, to our knowledge, pathologists have never published a comprehensive microscopic description of a SGPAR. CASE REPORT: A 73-year-old woman with moderate pulmonary hypertension died from a SGPAR soon after single SGC measurements of right ventricular and pulmonary capillary wedge pressures. By using what we thought to be an appropriate method of dissection, we did a complete microscopic step section study of the 1.6 cm SGPAR revealing 12 relatively uniform longitudinal tears (one perforating) consistent with an overinflated SGC balloon or a weakened arterial wall. LITERATURE REVIEW: A MEDLINE search of 38 consecutive SGPARs from 2014 to 1980 found 52 cases in 38 papers. Analysis revealed that all 46 SGPARs suitable for study came from large institutions, and confirmed that elderly women were more likely to have SGPARs than elderly men. CONCLUSIONS: More and better data are needed before fully informed decisions can be made regarding future SGC usage. PMID- 28806629 TI - Aseptic meningitis in adults and children: Diagnostic and management challenges. AB - BACKGROUND: Aseptic meningitis represents a common diagnostic and management dilemma to clinicians. OBJECTIVES: To compare the clinical epidemiology, diagnostic evaluations, management, and outcomes between adults and children with aseptic meningitis. STUDY DESIGN: We conducted a retrospective study from January 2005 through September 2010 at 9 Memorial Hermann Hospitals in Houston, TX. Patients age>=2months who presented with community-acquired aseptic meningitis with a CSF white blood cell count >5cells/mm3 and a negative Gram stain and cultures were enrolled. Patients with a positive cryptococcal antigen, positive blood cultures, intracranial masses, brain abscesses, or encephalitis were excluded. RESULTS: A total of 509 patients were included; 404 were adults and 105 were children. Adults were most likely to be female, Caucasian, immunosuppressed, have meningeal symptoms (headache, nausea, stiff neck, photophobia) and have a higher CSF protein (P <0.05). In contrast, children were more likely to have respiratory symptoms, fever, and leukocytosis (P <0.05). In 410 (81%) patients, the etiologies remained unknown. Adults were more likely to be tested for and to have Herpes simplex virus and West Nile virus while children were more likely to be tested for and to have Enterovirus (P <0.001). The majority of patients were admitted (96.5%) with children receiving antibiotic therapy more frequently (P <0.001) and adults receiving more antiviral therapy (P=0.001). A total of 384 patients (75%) underwent head CT scans and 125 (25%) MRI scans; all were normal except for meningeal enhancement. All patients had a good clinical outcome at discharge. DISCUSSION: Aseptic meningitis in adults and children represent a management challenge as etiologies remained unknown for the majority of patients due to underutilization of currently available diagnostic techniques. PMID- 28806630 TI - Case report: Coincidental inclusion in a 17-locus Y-STR mixture, wrongful conviction and exoneration. AB - We report the case of a suspect (Suspect-3) who was convicted (and later exonerated) of participating in the multiple-attacker rape of two women. The forensic evidence against him was his inclusion in a 17-marker Y-STR mixture isolated from semen on one victim's clothing. The DNA inclusion produced a match statistic with a combined probability of inclusion of 1 in 741, and a Likelihood Ratio of 3296. While the defense team was told that Suspect-3 was included in the semen DNA mixture, they were not told that all of the Y-STR alleles could also be explained by just the other two accused attackers' haplotypes. Suspect-3 was subsequently freed after the Taiwan Association for Innocence requested re examination of the incriminating mixed DNA sample. The Criminal Investigation Bureau was then able to exclude him using an extended set of Y-STR markers (23 loci), leading to his exoneration. PMID- 28806631 TI - Unraveling complex relationships among dysphoric disorder, localization-related epilepsy, and mood disorders. AB - BACKGROUND: Dysphoric disorder (DD), characterized by intermittent pleomorphic symptoms, has been believed to be specific to epilepsy. However, our previous study revealed that DD in patients with localization-related epilepsy was associated with a lifetime diagnosis of mood disorders. The present study was conducted to estimate the prevalence of DD in patients with mood disorders, but not epilepsy, and to identify the clinical similarities and differences of DD in patients with either epilepsy or mood disorders. METHODS: Subjects consisted of 104 patients with localization-related epilepsy (group E) and 101 patients with DSM-IV mood disorders, but not with epilepsy (group M). After a diagnostic investigation for DD and the euthymic state, defined as the absence of any mood episodes during the last 12months, we compared the clinical characteristics of DD in patients from groups E and M. RESULTS: Dysphoric disorder was apparently more common in group M (56.4%) than in group E (21.2%). However, 86.0% of patients in group M showed a temporal overlap between DD and the noneuthymic state, while 68.2% of patients in group E did not show this overlap. Moreover, the noneuthymic state was significantly associated with symptoms of DD, indicating that the diagnosis of DD was more likely to be overestimated when the subjects were in a noneuthymic state. The prevalence of DD, temporally independent of the noneuthymic state (pure DD), was estimated at 13.4% and 7.0% in groups E and M, respectively, and pure DD was 1.91 times more common in patients with epilepsy than in those with mood disorders. Diagnosis of pure DD was significantly associated with increased suicidality in group E, but not group M. CONCLUSION: The present results suggest that DD is more familiar to epilepsy than mood disorders, although DD is not specific to epilepsy. Moreover, suicidality is specifically associated with DD in patients with epilepsy. PMID- 28806632 TI - Clinical utility of serum lactate levels for differential diagnosis of generalized tonic-clonic seizures from psychogenic nonepileptic seizures and syncope. AB - BACKGROUND: The differential diagnosis of generalized tonic-clonic seizures (GTCS), psychogenic nonepileptic seizures (PNES), and syncope constitutes a major challenge. Misdiagnosis rates up to 20 to 30% are reported in the literature. PURPOSE: To assess the clinical utility of serum lactate levels for differentiation of GTCS, PNES, and syncope based on gender differences. METHODS: Data from 270 patients were evaluated retrospectively. Only patients >=18 years old with the final diagnosis of GTCS, PNES, or syncope in their chart were recruited. Serum lactate levels were measured in the first 2h of the index event. RESULTS: Serum lactate levels in patients with GTCS (n=157) were significantly higher than in the patients with PNES (n=25) (p<0.001) and syncope (n=88) (p<0.001). When compared with the females, serum lactate levels in patients with GTCS were significantly higher in the male subgroup (p=0.004). In male patients the ROC analysis yielded a serum lactate value of 2.43mmol/l with a sensitivity of 0.85 and a specificity of 0.88 as the optimal cut-off value to distinguish GTCS from other events. The ROC analysis for the AUC yielded a high estimate of 0.94 (95% confidence interval: 0.91-0.98). When a cut-off value of 2.43mmol/l was chosen for the females, which was an optimal value for male patients, the specificity was 0.85, however, the sensitivity was 0.64. CONCLUSION: We propose that serum lactate level when measured in the first 2h after the index event has a high clinical utility in the differential diagnosis of GTCS, PNES, and syncope. With concomitant clinical signs and physical examination findings besides neuroimaging and EEG, elevated levels of lactate should be taken into account when evaluating a patient with impaired consciousness. On the other hand, the suggested cut-off value 2.43mmol/l might not have a discriminative effect between GTCS, PNES, and syncope in female patients. This finding should be verified in a prospectively designed study with a larger patient population. PMID- 28806633 TI - Provision of sudden unexpected death in epilepsy (SUDEP) information among Malaysian parents of children with epilepsy. AB - Sudden unexpected death in epilepsy (SUDEP) is an important cause of mortality in epilepsy. To date, there is only one published UK study evaluating information provision of SUDEP among parents of children with epilepsy (CWE), and there are no studies published from Asia. Although SUDEP information provision is recommended among parents of CWE, it is uncertain if these recommendations are applicable to Asian countries due to the different cultural attitude towards epilepsy. Our prospective cohort study consisted of multiethnic parents of children with epilepsy (CWE) seen in a tertiary hospital in Malaysia. Information on SUDEP was delivered to parents using an epilepsy educational software program. Participants completed a set of standardized questionnaire and Depression Anxiety Stress Scales-Short Form (DASS-21) immediately after and retested 3-6months after the SUDEP information provision. A total of 127 parents (84 mothers) participated in the study. The CWE consisted of 3 ethnic groups (38% Malay, 30% Chinese, 32% Indian) with a mean age of 9.6years. Majority (70.9%) felt positive after SUDEP information provision, 90.6% wanted SUDEP discussion for themselves with 70.1% wanted SUDEP discussion with their child, and a lower proportion (58.3%) would discuss SUDEP with their child. None of the participants reported increased symptoms of depression, stress or anxiety attributed to SUDEP information provision. Most parents took steps to reduce SUDEP risk, and most parents did not report an impact on their own functioning. However, there was an increase in parental report over time of impact on their child's functioning following SUDEP information (P<0.05). In conclusion, most Malaysian parents of CWE wanted SUDEP information. Following SUDEP information disclosure, majority did not report negative emotions; however, an increase in parents over time reported an impact on their child. Our findings reiterate that provision of SUDEP information should form part of care of CWE and parents should receive ongoing support as they undergo a period of parenting adjustment when dealing with the information provided. PMID- 28806634 TI - A correlation based bullet identification method using empirical mode decomposition. AB - The striations on bullet surface are 3D micro structures formed when a bullet is forcing its way out of barrel. Each barrel leaves individual striation patterns on bullets. Hence, the striation information of bullets is helpful for firearm identification. Common automatic identification methods process these images using linear time invariant (LTI) filters based on correlation. These methods do not consider the sensitivity of correlation based comparisons to nonlinear baseline drifts. The striations are undeniably random unique micro structures caused by random non-model-based imperfections in the tools used in rifling process, therefore any characteristic profile that is extracted from a bullet image is statistically non-stationary. Due to limitations of LTI filters, using them in smoothing bullet images and profiles may cause information loss and impact the process of identification. To address these problems, in this article, we consider bullet images as nonlinear non-stationary processes and propose a novel method which uses ensemble empirical mode decomposition (EEMD) as a preprocessing algorithm for smoothing and feature extraction. The features extracted by EEMD algorithm not only contain less noise, but also have no nonlinear baseline drifts. These improvements help the correlation based comparison methods to perform more robustly and efficiently. The experiments showed that our proposed method attained better results compared with two common methods in the field of automatic bullet identification. PMID- 28806635 TI - Oryong 501 sinking incident in the Bering Sea-International DVI cooperation in the Asia Pacific. AB - On December 1st, 2014, the sinking of Oryong 501 occurred in the Bering Sea off the east coast of Russia. A total of 60 crew members, including 35 Indonesians, 13 Filipinos, 11 South Koreans and 1 Russian inspector were on board out of which only seven survived. Through an international rescue operation, the dead bodies of 27 were found and the remaining 26 crew are still missing. After transferring the dead bodies to the Busan Harbor in South Korea, the operation to identify the deceased began involving DVI teams from three countries: Korea, Indonesia and the Philippines. When a deep sea fishing boat sinks, it is very difficult to obtain antemortem data of the crew who had been on board for a long time. This is especially so if the crews are multinational. Further, the accuracy of the antemortem data provided by the families may be questionable, and the provided data is often not standardized. Despite the fact that the antemortem data were received in different formats, the identification process for the bodies of the 27 crew from the Oryong sinking was quickly completed through the cooperation among the three DVI teams. This case is an excellent example of how efficiently a DVI operation can be conducted in the Asia Pacific region. Issues raised during this operation should enable even better preparation for similar events in the future. PMID- 28806636 TI - Blood or not blood-That is the question. A non-destructive method for the detection of blood-contaminated fingermarks. AB - Working in crime scenes presents a challenge to the forensic scientist, as some surfaces, such as floors and walls, cannot be transferred to the lab for further development and must, therefore, be processed at the crime scene itself. Two main types of latent fingermarks may be encountered in crime scenes: amino acids based and blood contaminated. One of the most common reagents, which are able to develop both types of fingermarks on porous surfaces, is ninhydrin. As blood contaminated fingermarks may be crucial in connecting the suspect to the crime it is important to be able to distinguish between them and natural fingermarks. More than a decade of experience in crime scene investigations led to the understanding that there is a clear visual distinction between natural and blood contaminated fingermarks that are developed by ninhydrin. This study attempted to translate the visual difference into a mobile, non-destructive spectrophotometric method that can be used in crime scenes. Three independent spectrophotometric approaches were examined. The first showed a clear difference between the UV-vis spectra of the solution of blood and ninhydrin versus that of Ruhemann's purple. The second introduced another method in the solid phase to better simulate a real exhibit found in crime scenes. Once establishing the scientific foundation for the visible difference, a third technique for colour measurements was used in order to provide a potentially fast, quantitative, accurate and non-destructive field test for blood determination at the crime scene. PMID- 28806637 TI - Want, need and habit as drivers of smoking behaviour: A preliminary analysis. AB - BACKGROUND AND AIMS: Models of tobacco smoking behaviour propose that anticipated pleasure or satisfaction, the need to alleviate a nicotine-induced drive state and a stimulus-driven impulse potentially play an important role. This study aimed to provide a preliminary assessment of how far urges to smoke are reported by smokers and whether the strength of such urges prior to a quit attempt predicts short-term success at quitting. METHODS: In a prospective study, 566 smokers attending a treatment programme to help smokers quit completed a written questionnaire covering frequency of different types of urge to smoke (automatic impulse - 'automatic urges', anticipated pleasure - 'pleasure urges', and fulfilling a need - 'need urges'). They were asked to rate this for whichever of these urges was dominant for them. The questionnaire also assessed daily cigarette consumption, time to first cigarette of the day, age and gender. Carbon monoxide verified smoking status was recorded at 1 and 4weeks after the target quit date. FINDINGS: A total of 47.9% (271) of smokers reported that automatic urges were dominant, 21.7% (123) reported pleasure urges to be dominant, and 30.4% (172) reported need urges to be dominant. The strength of automatic urges predicted abstinence at both 1week (OR=0.74, p=0.005, 95%CI=0.60-0.92) and 4weeks (OR=0.73, p=0.008, 95%CI=0.59-0.92). Associations between other urge types and abstinence were not statistically significant. CONCLUSIONS: A substantial proportion of smokers attending a clinic for help with quitting report that their dominant urges to smoke occur without any anticipation of pleasure or relief and the strength of the automatic urges predicts failure to sustain abstinence following a quit attempt. PMID- 28806638 TI - Patient preferences and extended-release naltrexone: A new opportunity to treat opioid use disorders in Ukraine. AB - BACKGROUND: Scaling up HIV prevention for people who inject drugs (PWID) using opioid agonist therapies (OAT) in Ukraine has been restricted by individual and structural factors. Extended-release naltrexone (XR-NTX), however, provides new opportunities for treating opioid use disorders (OUDs) in this region, where both HIV incidence and mortality continue to increase. METHODS: Survey results from 1613 randomly selected PWID from 5 regions in Ukraine who were currently, previously or never on OAT were analyzed for their preference of pharmacological therapies for treating OUDs. For those preferring XR-NTX, independent correlates of their willingness to initiate XR-NTX were examined. RESULTS: Among the 1613 PWID, 449 (27.8%) were interested in initiating XR-NTX. Independent correlates associated with interest in XR-NTX included: being from Mykolaiv (AOR=3.7, 95% CI=2.3-6.1) or Dnipro (AOR=1.8, 95% CI=1.1-2.9); never having been on OAT (AOR=3.4, 95% CI=2.1-5.4); shorter-term injectors (AOR=0.9, 95% CI 0.9-0.98); and inversely for both positive (AOR=0.8, CI=0.8-0.9), and negative attitudes toward OAT (AOR=1.3, CI=1.2-1.4), respectively. CONCLUSIONS: In the context of Eastern Europe and Central Asia where HIV is concentrated in PWID and where HIV prevention with OAT is under-scaled, new options for treating OUDs are urgently needed. FINDINGS: here suggest that XR-NTX could become an option for addiction treatment and HIV prevention especially for PWID who have shorter duration of injection and who harbor negative attitudes to OAT. Decision aids that inform patient preferences with accurate information about the various treatment options are likely to guide patients toward better, patient-centered treatments and improve treatment entry and retention. PMID- 28806640 TI - The importance of nutrition in aiding recovery from substance use disorders: A review. AB - BACKGROUND: Nutrition is a prerequisite for health; yet, there is no special nutritional assessment or guidance for drug and alcohol dependent individuals, despite the fact that their food consumption is often very limited, risking malnutrition. Further, the premise is examined that malnutrition may promote drug seeking and impede recovery from substance use disorders (SUD). METHOD: A narrative review addressed the relationship between substance use disorders and nutrition, including evidence for malnutrition, as well as their impact on metabolism and appetite regulation. The implications of the biopsychology of addiction and appetite for understanding the role of nutrition in SUD were also considered. RESULTS: The literature overwhelmingly finds that subjects with alcohol use disorder (AUD) and drug use disorder (DUD) typically suffer from nutrient deficiencies. These nutrient deficiencies may be complicit in the alcoholic myopathy, osteopenia and osteoporosis, and mood disorders including anxiety and depression, observed in AUD and DUD. These same individuals have also been found to have altered body composition and altered hormonal metabolic regulators. Additionally, brain processes fundamental for survival are stimulated both by food, particularly sweet foods, and by substances of abuse, with evidence supporting confusion (addiction transfer) when recovering from SUD between cravings for a substance and craving for food. CONCLUSION: Poor nutritional status in AUD and DUD severely impacts their physical and psychological health, which may impede their ability to resist substances of abuse and recover their health. This review contributes to a better understanding of interventions that could best support individuals with substance use disorders. PMID- 28806639 TI - A developmental etiological model for drug abuse in men. AB - BACKGROUND: We attempt to develop a relatively comprehensive structural model of risk factors for drug abuse (DA) in Swedish men that illustrates developmental and mediational processes. METHODS: We examined 20 risk factors for DA in 48,369 men undergoing conscription examinations in 1969-70 followed until 2011 when 2.34% (n=1134) of them had DA ascertained in medical, criminal and pharmacy registries. Risk factors were organized into four developmental tiers reflecting i) birth, ii) childhood/early adolescence, iii) late adolescence, and iv) young adulthood. Structural equational model fitting was performed using Mplus. RESULTS: The best fitting model explained 47.8% of the variance in DA. The most prominent predictors, in order, were: early adolescent externalizing behavior, early adult criminal behavior, early adolescent internalizing behavior, early adult unemployment, early adult alcohol use disorder, and late adolescent drug use. Two major inter-connecting pathways emerged reflecting i) genetic/familial risk and ii) family dysfunction and psychosocial adversity. Generated on a first and tested on a second random half of the sample, a model from these variables predicted DA with an ROC area under the curve of 83.6%. Fifty-nine percent of DA cases arose from subjects in the top decile of risk. CONCLUSIONS: DA in men is a highly multifactorial syndrome with risk arising from familial-genetic, psychosocial, behavioral and psychological factors acting and interacting over development. Among the multiple predisposing factors for DA, a range of psychosocial adversities, externalizing psychopathology and lack of social constraints in early adulthood are predominant. PMID- 28806641 TI - Acute ethanol administration results in a protective cytokine and neuroinflammatory profile in traumatic brain injury. AB - Ethanol intoxication is a common comorbidity in traumatic brain injury. To date, the effect of ethanol on TBI pathogenic cascades and resulting outcomes remains debated. A closed blunt weight-drop murine TBI model has been implemented to investigate behavioral (by sensorimotor and neurological tests), and neuro immunological (by tissue cytokine arrays and immuno-histology) effects of ethanol intoxication on TBI. The effect of the occurrence of traumatic intracerebral hemorrhage was also studied. The results indicate that ethanol pretreatment results in a faster and better recovery after TBI with reduced infiltration of leukocytes and reduced microglia activation. These outcomes correspond to reduced parenchymal levels of GM-CSF, IL-6 and IL-3 and to the transient upregulation of IL-13 and VEGF, indicating an early shift in the cytokine profile towards reduced inflammation. A significant difference in the cytokine profile was still observed 24h post injury in the ethanol pretreated mice, as shown by the delayed peak in IL-6 and by the suppression of GM-CSF, IFN-gamma, and IL-3. Seven days post injury, ethanol-pretreated mice displayed a significant decrease both in CD45+ cells infiltration and in microglial activation. On the other hand, in the case of traumatic intracerebral hemorrhage, the cytokine profile was dominated by KC, CCL5, M-CSF and several interleukins and ethanol pretreatment did not produce any modification. We can thus conclude that ethanol intoxication suppresses the acute neuro-inflammatory response to TBI, an effect which is correlated with a faster and complete neurological recovery, whereas, the presence of traumatic intracerebral hemorrhage overrides the effects of ethanol. PMID- 28806642 TI - Circulating follicular helper T cells presented distinctively different responses toward bacterial antigens in primary biliary cholangitis. AB - Primary biliary cholangitis (PBC) is a chronic and progressive cholestatic liver disease with unknown causes. The initiation of PBC is associated with bacterial infections and abnormal immune correlates, such as the presence of self-reactive anti-mitochondrial antibodies and shifted balance of T cell subsets. In particular, the CD4+CXCR5+ follicular helper T (Tfh) cells are highly activated in PBC patients and are significantly associated with PBC severity, but the underlying reasons are unknown. In this study, we found that the circulating CD4+CXCR5+ T cells were enriched with the interferon (IFN)-gamma-secreting Th1 subtype and the interleukin (IL)-17-secreting Th17-subtype, but not the IL-4 secreting Th2 subtype. We further demonstrated that a host of microbial motifs, including Pam3CSK4, poly(I:C), LPS, imiquimod, and CpG, could significantly stimulate IFN-gamma, IL-17, and/or IL-21 from circulating CD4+CXCR5+ T cells in PBC patients, especially in the presence of monocytes and B cells. Whole bacterial cells of Escherichia coli, Novosphingobium aromaticivorans, and Mycobacterium gordonae, could also potently stimulate IFN-gamma, IL-17, and/or IL 21 production from circulating CD4+CXCR5+ T cells. But interestingly, while the whole cell could potently stimulate circulating CD4+CXCR5+ T cells from both healthy controls and PBC patients, the cell protein lysate could only potently stimulate circulating CD4+CXCR5+ T cells from PBC patients, but not those from healthy controls, suggesting that circulating CD4+CXCR5+ T cells in PBC patients had distinctive antigen-specificity from those in healthy individuals. Together, these data demonstrated that bacterial antigen stimulation is a potential source of aberrant Tfh cell activation in PBC patients. PMID- 28806643 TI - Mixed ligand aroylhydrazone and N-donor heterocyclic Lewis base Cu(II) complexes as potential antiproliferative agents. AB - A series of four mixed ligand aroylhydrazone and N-donor heterocyclic Lewis base Cu(II) complexes [CuL(X)]2 [L refers to the dianionic form of (5-bromo-2 hydroxybenzylidene)-2-hydroxybenzohydrazide; X=pyrazine (Pz; 1), pyridine (Py; 2), imidazole (Imz; 3) and 3-pyridinecarbonitrile (3-PyCN; 4)] has been synthesized and characterized by elemental analysis, various spectroscopic techniques and X-ray crystallography (for 1, 2 and 4). The antiproliferative effect of complexes 1-4 was examined in 4 human tumor cell lines (ovarian carcinoma (A2780), colorectal carcinoma (HCT116), lung adenocarcinoma (A549) and breast adenocarcinoma (MCF7)) and in normal human primary Fibroblasts. Complex 4 exhibits a high cytotoxic activity against ovarian and colorectal carcinoma cells (A2780, HCT116 respectively), with IC50 much lower than those for normal primary fibroblasts. Complex 4 could induce cell death via apoptosis but not autophagy in colorectal carcinoma cells. PMID- 28806644 TI - Effects of the fluorine substituent positions of the intercalating ligands on the binding behavior and third-strand stabilization of two Ru(II) complexes toward poly(U)*poly(A)*poly(U) triplex RNA. AB - Two new Ru(II) polypyridyl complexes containing fluorine substituents, [Ru(bpy)2(o-fpip)]2+ (Ru1, bpy=2,2'-bipyridine, o-fpip=2-(2 fluorophenyl)imidazo[4,5-f] [1,10]phenanthroline) and [Ru(bpy)2(p-fpip)]2+ (Ru2, p-fpip=2-(4-fluorophenyl)imidazo[4,5-f] [1,10]phenanthroline) have been synthesized as binders for poly(U)*poly(A)*poly(U) triplex RNA. The binding of the two complexes with the triplex RNA has been investigated by spectroscopic methods and viscosity measurements. Analysis of the electronic absorption spectra indicates that the association of intercalating Ru2 with the triplex RNA is greater than that of Ru1, which is also supported by spectroscopic titrations and viscosity measurements. Thermal denaturation studies reflect that third-strand stabilization depend on the nature of the two complexes and Ru2 is more effective for stabilization of the triplex RNA. Circular dichroism spectra of the triplex RNA in the presence of metal complexes indicate that the binding-induced CD perturbation of the triplex structure is more obvious by Ru2. The main results obtained here suggest that the positions of fluorine substituent in the intercalating ligands have a significant effect on the two complexes stabilizing the third strand. PMID- 28806645 TI - Evaluation of the binding of four anti-tumor Casiopeinas(r) to human serum albumin. AB - The metal complexes designated by Casiopeinas(r) are mixed-ligand CuII-compounds some of them having promising antineoplastic properties. We report studies of binding of Cu(glycinato)(4,7-dimethyl-1,10-phenanthroline) (Cas-II-Gly (1)), Cu(acetylacetonato)(4,7-dimethyl-1,10-phenanthroline) (Cas-III-Ea (2)), Cu(glycinato)(4,4'-dimethyl-2,2'-bipyridine) (Cas-IV-Gly (3)) and Cu(acetylacetonato)(4,4'-dimethyl-2,2'-bipyridine) (Cas-III-ia (4)) to human serum albumin (HSA) by circular dichroism (CD), Electron paramagnetic resonance (EPR) and fluorescence spectroscopy. The results indicate that HSA may bind up to three molecules of the tested Casiopeinas. This is confirmed by inductively coupled plasma - atomic absorption spectroscopy measurements of samples of HSA Casiopeinas after passing by adequate size-exclusion columns. The binding of Cas II-Gly to HSA was also confirmed by MALDI-TOF mass spectrometric experiments. In the physiological range of concentrations the Casiopeinas form 1:1 adducts with HSA, with conditional binding constants of ca. 1*109 (1), 4*107 (2), 1*106 (3) and 2*105 (4), values determined from the CD spectra measured, and the fluorescence emission spectra indicates that the binding takes place close to the Trp214 residue. Overall, the data confirm that these Casiopeinas may bind to HSA and may be transported in blood serum by this protein; this might allow some selective tumor targeting, particularly in the case of Cas-II-Gly. In this work we also discuss aspects associated to the reliability of the frequently used methodologies to determine binding constants based on the measurement of fluorescence emission spectra of solutions containing low concentrations of proteins such as HSA and BSA, by titrations with solutions of metal complexes. PMID- 28806646 TI - Static flexural properties of hedgehog spines conditioned in coupled temperature and relative humidity environments. AB - Hedgehogs are agile climbers, scaling trees and plants to heights exceeding 10m while foraging insects. Hedgehog spines (a.k.a. quills) provide fall protection by absorbing shock and could offer insights for the design of lightweight, material-efficient, impact-resistant structures. There has been some study of flexural properties of hedgehog spines, but an understanding of how this keratinous biological material is affected by various temperature and relative humidity treatments, or how spine color (multicolored vs. white) affects mechanics, is lacking. To bridge this gap in the literature, we use three-point bending to analyze the effect of temperature, humidity, spine color, and their interactions on flexural strength and modulus of hedgehog spines. We also compare specific strength and stiffness of hedgehog spines to conventional engineered materials. We find hedgehog spine flexural properties can be finely tuned by modifying environmental conditioning parameters. White spines tend to be stronger and stiffer than multicolored spines. Finally, for most temperature and humidity conditioning parameters, hedgehog spines are ounce for ounce stronger than 201 stainless steel rods of the same diameter but as pliable as styrene rods with a slightly larger diameter. This unique combination of strength and elasticity makes hedgehog spines exemplary shock absorbers, and a suitable reference model for biomimicry. PMID- 28806647 TI - Mechanical reinforcement of bioceramics scaffolds via fracture energy dissipation induced by sliding action of MoS2 nanoplatelets. AB - The inherent brittleness of bioceramics restricts their applications in load bearing implant, although they possess good biocompatibility and bioactivity. In this study, molybdenum disulfide nanoplatelets (MSNPs) were used to reinforce bioceramics (Mg2SiO4/CaSiO3) scaffolds fabricated by selective laser sintering (SLS). The fracture mode of scaffolds was transformed from transgranular to mixed trans- and intergranular. It could be explained that MSNPs could slide easily due to their weak interlayer van der Waals interactions and provide elastic deformation due to their high elastic modulus. Such sliding action and elastic deformation synergistically induced crack bridging, crack deflection, pull-out and break of MSNPs. Those effects effectively increased the fracture energy dissipation and strain capacity as well as changed the fracture mode, contributing to high fracture toughness and compression strength. Additionally, the scaffolds with MSNPs not only formed a bioactive apatite layer in simulated body fluid, but also supported cell adhesion and proliferation. PMID- 28806648 TI - To embed or not to embed? A longitudinal study exploring the impact of curriculum design on the evidence-based practice profiles of UK pre-registration nursing students. AB - BACKGROUND: The use of Evidence-Based Practice (EBP) is increasingly emphasized within healthcare. However, little research has focused on nurses' pre registration training; particularly regarding the impact of curriculum-design on learning EBP. OBJECTIVES: This study compared the impact of embedding EBP throughout the curriculum, with modular-based teaching, on pre-registration nursing students' EBP profiles. DESIGN: A longitudinal panel study. SETTINGS AND PARTICIPANTS: A convenience sample of fifty-six pre-registration nursing students (55.4% studying an embedded EBP-curriculum and 44.6% studying a modular EBP curriculum), were recruited from a UK University between 2011 and 2014. METHODS: Participants completed the Student Evidence-Based Practice Questionnaire (S-EBPQ) in the first, second and third year of their course. This questionnaire measures four EBP domains: frequency of use, attitude, knowledge and skills in retrieving and reviewing evidence, and knowledge and skills in applying and sharing evidence. RESULTS: Two-way mixed between-within Analyses of Variance revealed significant improvements across all domains, except attitude (which remained broadly positive across all years), for both curriculum-groups. No significant differences in this improvement were identified between the two curricula overall. However, the direction and rate of change of scores on the retrieving and applying subscales (but not frequency of use) for the two groups differed across time; specifically those on the embedded curriculum showed a dip in scores on these subscales in year 2. This appeared to be related to associated features of the course such as the timing of placements and delivery of theory. CONCLUSIONS: Taking a modular or embedded approach to EBP may have little impact on students' final EBP profiles. However, careful consideration should be given to the timing of related course features which may play a key role in students' perceptions of their knowledge and skills in its application. Further research should explore how curriculum-design might build on students' initial positive attitudes towards EBP and its use in their practice. PMID- 28806649 TI - Firm performance and the role of environmental management. AB - This paper analyzes the interactions between three dimensions of firm performance - productivity, energy efficiency, and environmental performance - and especially sheds light on the role of environmental management. In this context, environmental management is investments to reduce environmental impact, which may also affect firm competitiveness, in terms of change in productivity, and spur more (or less) efficient use of energy. We apply data envelopment analysis (DEA) technique to calculate the Malmquist firm performance indexes, and a panel vector auto-regression (VAR) methodology is utilized to investigate the dynamic and causal relationship between the three dimensions of firm performance and environmental investment. Main results show that energy efficiency and environmental performance are integrated, and energy efficiency and productivity positively reinforce each other, signifying the cost saving property of more efficient use of energy. Hence, increasing energy efficiency, as advocated in many of today's energy policies, could capture multiple benefits. The results also show that improved environmental performance and environmental investments constrain next period productivity, a result that would be in contrast with the Porter hypothesis and strategic corporate social responsibility; both concepts conveying the notion that pro-environmental management can boost productivity and competitiveness. PMID- 28806650 TI - Floating rice-culture system for nutrient remediation and feed production in a eutrophic lake. AB - The increased inputs of nutrients have been demonstrated to be a major contributing factor to the eutrophication of lakes and reservoirs which can lead to the production of harmful algal/cyanobacterial blooms and deleteriously affect the aesthetics of water-bodies. Floating plant-culture systems have been widely used for the ecological remediation of eutrophic water in a cost-effective manner. We investigated the applicability of Korean japonica rice variety 'Nampyeong' in a floating-culture system in a eutrophic lake for nutrient uptake and biomass production. Chemical and organic compound compositions were analyzed two times during the growth stages of the rice plant: 98 DAT (days after transplanting) and 165 DAT. Total nitrogen and phosphorus contributed around 1.36 and 0.15 (% dry weight), respectively, in rice plant components at 165 DAT. Crude protein, lipids, fiber and ash were 4.35, 1.91, 23.66 and 5.55 (% dry weight), respectively. In addition, microcystin levels in the rice plant components ranged from 0.0008 to 0.002 MUg/g and did not exceed the recommended tolerable limits. These results suggested that the developed floating rice-culture system showed a good potential as a holistic management approach in terms of nutrient reduction, rice production for further use as feed and for bloom control. PMID- 28806651 TI - Changes in the process performance, sludge production and microbial activity in an activated sludge reactor with addition of a metabolic uncoupler under different operating conditions. AB - Sludge production in wastewater treatment plants is nowadays a big concern due to the high produced amounts and their characteristics. Consequently, the study of techniques that reduce the sludge generation in wastewater treatment plants is becoming of great importance. In this work, four laboratory sequencing batch reactors (SBRs), which treated municipal wastewater, were operated to study the effect of adding the metabolic uncoupler 3,3',4',5-tetrachlorosalicylanilide (TCS) on the sludge reduction, the SBRs performance and the microbial hydrolytic enzymatic activities (MHEA). In addition, different operating conditions of the SBRs were tested to study the effect of the TCS on the process: two dissolved oxygen (DO) concentrations (2 and 9 mg L-1) and two F/M ratio (0.18 and 0.35 g COD.g MLVSS-1.d-1). The sludge production decreased under high DO concentrations. At the same time, the DNA and EPS production increased in the four SBRs. After these stress conditions, the performance of the reactors were recovered when DO was around 2 mg L-1. From that moment on, results showed that TCS addition implied a reduction of the adenosine triphosphate (ATP) production, which implied a decrease in the sludge production. In spite of this reduction, the SBRs performances did not decay due to the increase in the global MHEA. Additionally, the sludge reduction was enhanced by the increase of the F/M ratio, achieving 28% and 60% of reduction for the low and the high F/M ratio, respectively. PMID- 28806652 TI - Applicability of alkaline precipitation for the recovery of EDDS spent solution. AB - This paper presents an innovative procedure for the recovery of SS ethylenediamine-N,N'-disuccinic acid (EDDS) solution used for soil washing processes. The procedure is derived from that applied for the recovery of ethylenediamine-tetraacetic acid (EDTA), modifying and optimizing the choice of the chemical agents used for the protonation of the chelant, the exchange of the metals, and the final precipitation of the unwanted compounds. To select the reagents and test the proposed approach, an experimental study was conducted on real EDDS spent solutions, obtained washing a Cu and Zn real contaminated soil. According to the results obtained, the precipitation ranges from 30% to more than 90% for both Cu and Zn, depending on the adopted reagent sequence, and on the molar ratio between the salt and the chelant contained in the spent solution. Data were in agreement with chemical equilibrium predicted in ideal conditions. The recovered solutions had a reduced ability to remove the contaminants when applied in a new soil washing cycle (15% less for Cu and 30% less for Zn) because of the high concentration of alkaline metal ions required for the precipitation. At the same time, they were more biodegradable compared to non-treated solutions, confirming that EDDS-metal chelates may represent a threat for biological wastewater processes. PMID- 28806653 TI - Novel microemulsion-based gels for topical delivery of indomethacin: Formulation, physicochemical properties and in vitro drug release studies. AB - HYPOTHESIS: Microemulsion-based semisolid systems may be considered as an interesting alternative to the traditional dosage forms applied in topical drug delivery. Mechanical properties of topical products are important both in terms of application and dosage form effectiveness. In this study we designed and evaluated novel microemulsion-based gels with indomethacin and analyzed the factors affecting their mechanical characteristics and drug release. EXPERIMENTS: The impact of the microemulsion composition on the extent of isotropic region was investigated with the use of pseudoternary phase diagrams. Selected microemulsions were analyzed in terms of electrical conductivity and surface tension in order to determine the microemulsion type. Microemulsions were transformed into polymer-based gels and subjected to rheological and textural studies. Finally, the indomethacin release from the analyzed gels was studied and compared to commercially available product. FINDINGS: The extent of isotropic domain in pseudoternary phase diagrams seems to be dependent on the polarity of the oil phase. The surface tension and conductivity monitored as a function of water content in microemulsion systems revealed possible structural transformations from w/o through bicontinuous systems into o/w. The mechanical properties of semisolid microemulsion-based systems depended on the composition of surface active agents and the drug presence. The drug release profiles observed in the case of the investigated gels differed from those recorded for the commercially available product which was most probably caused by the different structure of both systems. PMID- 28806654 TI - Magnetic separable chitosan microcapsules decorated with silver nanoparticles for catalytic reduction of 4-nitrophenol. AB - In the work, we have synthesized silver (Ag) nanoparticles deposited chitosan (CS) microcapsules with magnetic multiple Fe3O4 cores (denoted as Fe3O4/CS-Ag) as efficient catalysts for the reduction of 4-nitrophenol. The Fe3O4/CS-Ag catalysts are prepared by coating hydrophobic Fe3O4 nanoparticles with chitosan via a multiple emulsion-chemical crosslinking method and following in situ deposition of Ag nanoparticles onto the surfaces. The morphology and composition of the Fe3O4/CS-Ag microcapsules are characterized by Fourier transform infrared (FT-IR) spectra, scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), and X-ray photoelectron spectroscopy. Moreover, the catalytic activity of the Fe3O4/CS-Ag catalyst was investigated, which shows a conversion efficiency as high as 98% within 15min for the reduction of p-nitrophenol to p-aminophenol. At the same time, the recovered Fe3O4/CS-Ag catalyst with an external magnet can retain good activity after 10 cycles. These results indicate that the multiple emulsion-chemical crosslinking method is an efficient and simple way for the preparation of magnetic separable chitosan microcapsules, and the fabricated Fe3O4/CS-Ag is a promising catalytic material with excellent catalytic activity and convenient recovery ability. PMID- 28806655 TI - Magnetic reduced graphene oxide loaded hydrogels: Highly versatile and efficient adsorbents for dyes and selective Cr(VI) ions removal. AB - The formation of composites of reduced graphene oxide (rGO) and magnetic nanoparticles (MP) has flourished in recent years as they combine the advantages of both nanomaterials. Most of these composite materials are prepared by in situ formation of MP onto rGO or by the post-adsorption onto rGO. We report here on a simple and highly controlled method for the fabrication of different magnetic 3D rGO-loaded hydrogels. Cellulose bound magnetic nanoparticles (MP@cellulose) were synthesized by chemical co-precipitation and loaded together with rGO into poly(ethylene glycol) dimethacrylate based hydrogels during their fabrication using photo-polymerization. The magnetic rGO-loaded hydrogels proved to be highly adaptable to different applications. The as-formed composites allowed for efficient dye removal with an adsorption capacity of 111.9+/-4mgg-1 in the case of methylene blue (MB). Integration of poly(ethyleneimine) (PEI) allowed for the selective capturing of Cr6+ ions with an adsorption capacity of 313+/-12mgg-1. Most importantly, independent of the application, the magnetic rGO-loaded hydrogel can be regenerated without loss of its adsorption capacity. PMID- 28806656 TI - Sensitive surface-enhanced Raman scattering of TiO2/Ag nanowires induced by photogenerated charge transfer. AB - In this work, the semiconductor TiO2 nanowires were successfully coupled with plasmonic metal Ag nanoparticles to fabricate hybrid nanostructures with enhanced sensitive Raman substrate. The SERS activities of fabricated hybrid nanostructures were evaluated by detecting the Raman signals of R6G molecules. The fabricated TiO2/Ag nanowire/nanoparticle hybrid nanostructures show sensitive detection ability for R6G molecules. Based on the band structures of Ag nanoparticle, TiO2 nanowire and R6G molecule, the enhanced sensitive SERS activities of hybrid nanostructures is ascribed to an efficient charge transfer process, in which the photogenerated electrons transfer to the conduction band of TiO2 nanowires from metal Ag nanoparticles, and then to LUMO level of R6G molecules, leading to enhanced SERS activities. This efficient charge transfer process is achieved by the synergistic effects of plasmonic metal Ag nanoparticle, semiconductor TiO2 nanowire and R6G molecule. Furthermore, the transfer process of photoexcited electrons from metal Ag nanoparticle to conduction band of TiO2 nanowire is evidently confirmed by the photoresponse properties of hybrid nanostructures under illumination only with visible light (lambda>420nm). The findings achieved in this work demonstrate that efficient turning the charge transfer in plasmonic metal nanoparticle/semiconductor/molecule hybrid nanostructure can significantly enhance its SERS activity. PMID- 28806657 TI - Two-dimensional metal chalcogenides analogous NiSe2 nanosheets and its efficient electrocatalytic performance towards glucose sensing. AB - Recently, 2D layered transition-metal dichalcogenide materials have received great consideration because of their unique electronic properties, large surface area and high electrocatalytic activity. In this connection, for the first time the similar nanostructured material of NiSe2 nanosheets (NiSe2-NS) has been synthesized by a facile hydrothermal method for electrocatalytic applications. Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), X-ray Photoelectron Spectroscopy (XPS), Energy Dispersive X-ray analysis (EDX), X-ray diffraction spectrum (XRD) results confirmed the formation of NiSe2-NS with required stoichiometry and morphology. Electrochemical Impedance Spectroscopy (EIS) data indicate that electron transfer is facile at the NiSe2-NS modified glassy carbon electrode (GCE). It has been as an electrode modifier for glucose sensing applications. The electrochemical studies were performed for NiSe2-NS modified GCE using Cyclic Voltammetry (CV) and amperometric i-t techniques. The results are suggesting the effective response of NiSe2-NS/GCE with a very low limit of detection (LOD) and sensitivity of 23nM and 5.6MUAMUM-1cm-2 respectively. Moreover, the selectivity data exhibited excellent anti interference property of NiSe2-NS/GCE towards glucose in the presence of possible interfering agents viz. Ascorbic acid, dopamine, glucose. PMID- 28806658 TI - Hierarchically structured TiO2/PAN nanofibrous membranes for high-efficiency air filtration and toluene degradation. AB - Hierarchically structured, nanoparticle-on-nanofiber composite membranes were successfully prepared by electrospray of titanium dioxide (TiO2) suspensions and electrospinning of polyacrylonitrile (PAN) solution simultaneously. The results showed that the TiO2 nanoparticles were highly dispersed on the surface of PAN nanofibers to construct hierarchical nanostructures, which could not only endow the composite membrane with high photocatalytic activity but also further improve the filter efficiency of the composite membrane. Furthermore, the photocatalytic activities and filter efficiencies of composite membranes could be further tuned by controlling the TiO2/PAN mass ratios. Our study indicated that the combination of TiO2 nanoparticles and PAN nanofibers via simultaneous electrospinning-spray offers a new strategy to construct advanced multifunctional TiO2/PAN membranes with hierarchical nanostructures, which could not only perform well in decomposing toluene but also remove particulate matter in air effectively. PMID- 28806659 TI - Single step method to fabricate durable superliquiphobic coating on aluminum surface with self-cleaning and anti-fogging properties. AB - The development of self-cleaning and anti-fogging durable superliquiphobic coatings for aluminum surfaces has raised tremendous interest in materials science. In this study, a superliquiphobic coating is fabricated on an aluminum surface by a single-step dip-coating method using 1H,1H,2H,2H Perfluorooctyltrichlorosilane-modified SiO2 nanoparticles. The successful implementation of the aforesaid coating in different applications requires extensive investigations of its characteristics and stability. To understand the properties of the coating, surface morphology, contact angle, self-cleaning, anti fogging, and water repellency were investigated under perturbation conditions. Additionally, the dynamics of water and oil on the coated sample also were studied. Furthermore, the durability of the coating also was examined by performing thermal, chemical, and mechanical stability tests. It was found that the coating is superliquiphobic for water, ethylene glycol, glycerol and hexadecane, and shows thermal, chemical, and mechanical stability. Further, it exhibits self-cleaning and anti-fogging properties. This approach can be applied to any size and shape aluminum surface; thus, it has great industrial applications. PMID- 28806660 TI - Fluorescent carbon dot gated hollow mesoporous carbon for chemo-photothermal synergistic therapy. AB - An efficient and intelligent nano-carrier that combines cell imaging with near infrared (NIR) light and redox dual-responsive drug delivery was successfully prepared. The hollow mesoporous carbon (HMC) nanoparticles with high photothermal conversion ability were developed to increase the drug loading efficiency and realize chemotherapy and photothermal synergetic therapy. The photo-stable and luminescent carbon dots (CDs) were prepared from branched polyethyleneimine (PEI) by hydrothermal reaction. The PEI CDs (CDPEI) were grafted on the openings of HMC as the "gatekeepers" via disulfide units (HMC-SS-CDPEI) to prevent the premature release of doxorubicin (DOX). In the presence of GSH, the CDPEI separated from HMC due to the breakage of disulfide bonds, thus triggering the rapid release of the encapsulated drug. In addition, the release rate of DOX could be further accelerated by NIR light irradiation due to the increased temperature which would decrease the interaction between HMC and DOX. The fluorescence of the CDPEI is quenched when being attached to the HMC, while it is recovered when the CDPEI breaking away from HMC. Hence, the fluorescent CDPEI not only act as a gatekeeper to control drug release but also play a vital role in monitoring the process of the drug delivery. The developed HMC-SS-CDPEI showed dual-responsive drug release property and could be used as visible nano-platforms for chemo-photothermal synergistic therapy. PMID- 28806661 TI - Low cost and non-fluoride flowerlike superhydrophobic particles fabricated for both emulsions separation and dyes adsorption. AB - Green fluoride-free superhydrophobic hierarchical flowerlike iron-containing MnO2 particles were synthesized by a simple one-pot approach and subsequently modified by stearic acid. The special selective wettability toward water and oil makes the particle can be used in oil-in-water emulsion separation. In addition, the particle also can be applied as absorption material to remove dyes which are serious water contaminants. More importantly, as for the mixture of emulsion and dye, the particles also have the ability to remove both oil and dye, making the particles potential for wastewater purification in the future. PMID- 28806662 TI - Porous Co2P nanowires as high efficient bifunctional catalysts for 4-nitrophenol reduction and sodium borohydride hydrolysis. AB - The development of highly efficient and non-noble catalysts for both the reduction of 4-nitrophenol (4-NP) and NaBH4 hydrolysis is extraordinary attractive but it remains a tremendous challenge. In this work, self-assembled porous Co2P nanowires (NWs) have been successfully prepared via the low temperature hydrothermal method and the comprehensive experiments validate that the sample is a high efficient bifunctional catalyst for both the reduction of 4 nitrophenol and sodium borohydride hydrolysis. Specifically, the as-prepared porous Co2P NWs exhibit more excellent catalytic performance (knor=743s-1g-1) than that of other reported catalysts towards reduction of 4-nitrophenol. The catalytic activity of sodium borohydride hydrolysis is also investigated and the Co2P NWs show superior hydrogen generation rate (4028mLmin-1g-1) at 30 degrees C for sodium borohydride hydrolysis. Our results indicate that porous Co2P nanowires possess a potential application on both the sodium borohydride hydrolysis and reduction of 4-nitrophenol. PMID- 28806663 TI - Management of breast ductal carcinoma in situ in Catalonia, Spain: Results from the Grup Oncologic Calala-Occita-Catalonia survey with 9-year follow up. AB - INTRODUCTION: Reliable data on DCIS incidence and management are not available in many countries. The present study describes the management of DCIS in Catalonia, Spain in the year 2005 and compares these findings to data obtained in France. Local recurrence and late toxicity rates from 2005 through the end of 2014 are reported. MATERIALS AND METHODS: Observational survey of patients with pure DCIS (n = 270) diagnosed during 2005. A written questionnaire, the same as used in the French survey, was completed by 14 doctors at 12 cancer centres in Catalonia, Spain. RESULTS: Median patient age was 55 years (range, 29-89). Diagnosis was mammographic in 225 cases (83.3%). Treatment approaches included: mastectomy (10.4% of cases), breast-conserving surgery (BCS) alone (3.7%), and BCS plus radiotherapy (RT) (85.5%). Sentinel node biopsy and axillary dissection were performed in 27.4% and 5.6% of patients, respectively. Hormonotherapy was prescribed in 45.2% of cases. Tumour nuclear grade was as follows: low (16.7% of cases), intermediate (23%), and high (55.6%). Excision was complete (margins >=1 mm) in 75% of patients treated with BCS alone vs. 95.7% for BCS+RT. The treatment approach varied widely: mastectomy rates ranged from 7.1% to 26.7% of centres, BCS+RT from 55.5% to 87.8%, and hormonotherapy from 3.3% to 83.3%. At a median follow-up of 102.6 months, 14 patients (5.6%) presented ipsilateral breast tumour recurrence. CONCLUSIONS: These findings on DCIS management in Catalonia are consistent with previous international reports. The inter-centre differences observed are similar to those reported in other international surveys during the same period. PMID- 28806664 TI - Porous PLGA microparticles formed by "one-step" emulsification for pulmonary drug delivery: The surface morphology and the aerodynamic properties. AB - In the present study, by using a newly developed one-step emulsification technique, we tried to prepare porous PLGA particles having a proper diameter and surface morphology in order to achieve both a high efficient delivery of the particles to the lungs and a phagocytosis-avoidance ability. We found that our porous particles have the very low tapped density of 0.04g/cm3. Experimental and theoretical studies strongly suggest that the shape factor should not be determined only by the outline of the particles, although previous research assigned a value of 1 to the shape factor for particles regardless of the presence of pores and their distribution. We found the possibility that our porous particles both had specific internal structures induced by spontaneous emulsification and exhibited unusual aerodynamic performance. PMID- 28806665 TI - A sequential delivery system employing the synergism of EPO and NGF promotes sciatic nerve repair. AB - The different mechanisms of nerve growth factor (NGF) and erythropoietin (EPO) in promoting repair of peripheral nerve injuries suggest a potential therapeutic application through the synergism of the two. Yet NGF has also been reported to induce early nerve apoptosis after injury. To utilize the potential synergism of NGF and EPO while minimize the possible defect, in this study, we first confirmed the time dependency of NGF caused nerve apoptosis, and then established a sequential and sustained delivery system for NGF and EPO with poly(lactide-co glycolide) (PLGA), which has been approved by the US FDA for human use because of its injectable, biocompatible, and biodegradable properties. EPO was encapsulated in PLGA-microspheres (MS) for sustained releasing, while NGF was encapsulated in BSA-incorporated PLGA (B-PLGA) MS to postpone its release. In rat model of sciatic nerve injury, co-delivery of EPO/PLGA-MS and NGF/B-PLGA-MS resulted in significant nerve recovery. Hopefully, this sequential delivery system could provide a new therapeutic strategy for peripheral never injury. PMID- 28806666 TI - Doxorubicin-loaded environmentally friendly carbon dots as a novel drug delivery system for nucleus targeted cancer therapy. AB - Chemotherapy is widely applied against various kinds of carcinoma. Generally, chemotherapeutic agents, such as Doxorubicin (DOX), Paclitaxel (PTX), 5 Fluorouracil (5-FU), Methotrexate (MTX), and Vinblastine (VLB) are combined with a view to maximizing their efficacy. Unfortunately, chemotherapeutics are indiscriminate and also kill normal healthy cells, resulting in serious side effects. This non-productive and destructive distribution of chemotherapeutics is regarded as one of the largest problems associated with chemotherapy. Recently, the application of carbon dots (CDs) in cancer therapy has attracted considerable attention due to their attractive properties, such as biocompatibility and low toxicity. We report herein on the fabrication of CD-DOX antitumor drug complexes, from the combination of CDs and DOX, with a view to providing a novel and efficient strategy for cancer treatment. CDs were synthesized by hydrothermal treatment of milk, a simple and environmentally friendly synthetic process. DOX was conjugated to the CDs through electrostatic interactions via the multiple surface CD functional groups. The CD-DOX complexes exhibited pH-dependent DOX release behavior. A cytotoxicity study demonstrated that the CDs were non cytotoxic in the range of concentrations used. Compared to free DOX, the CD-DOX complexes were significantly more destructive to the adenoid cystic carcinoma cell line (ACC-2), but exhibited lower toxicity to a mouse fibroblast cell line (L929). Confocal microscopy and flow cytometry confirmed that CD-DOX complexes increased cancer therapy efficiency through the localization of a much higher quantity of drugs in the nuclei of tumor cells and induced a higher rate of apoptosis in ACC-2 cells, compared to DOX alone. PMID- 28806667 TI - Hydrophobic boron compound-loaded poly(l-lactide-co-glycolide) nanoparticles for boron neutron capture therapy. AB - Poly(DL-lactide-co-glycolide) (PLGA) has been widely used and studied because of its biocompatibility and biodegradability. Recently, the usefulness of nanoparticles using poly(L-lactide-co-glycolide) (PLLGA) having a higher glass transition temperature than PLGA was suggested. In this study, we investigated the availability of boron compound-loaded PLGA and PLLGA nanoparticles for boron neutron capture therapy (BNCT) by conducting biodistribution study using tumor bearing mice. o-Carborane, a hydrophobic boron compound, was used as a boron carrier, and o-carborane-albumin conjugate was used as a control. We prepared PLGA and PLLGA nanoparticles with diameters of 100nm and 150nm. In 100-nm PLLGA nanoparticles, the boron concentration in the tumor reached 113.9+/-15.8MUg/g of tissue at 8h after administration. This result indicated that 100-nm PLLGA nanoparticles were able to achieve an intratumoral 10B concentration of 20MUg/g without replacing the 11B with 10B. In addition, by nanoparticulation using PLGA7510 and PLLGA7510, intratumoral boron concentration was 1.7-3.2 and 3.5-4.2 times higher than that of the o-carborane-albumin conjugate, respectively. The tumor/blood ratios of boron concentration reached over 5 at 8-12h after injection. Boron atoms in nanoparticles were excreted mainly in the urine, and characteristic accumulation was not observed in other organs. These results suggested that 100-nm PLLGA nanoparticles were particularly useful for BNCT. PMID- 28806668 TI - Combination of electrochemical biosensor and textile threads: A microfluidic device for phenol determination in tap water. AB - Microfluidic devices constructed using low cost materials presents as alternative for conventional flow analysis systems because they provide advantages as low consumption of reagents and samples, high speed of analysis, possibility of portability and the easiness of construction and maintenance. Herein, is described for the first time the use of an electrochemical biosensor for phenol detection combined with a very simple and efficient microfluidic device based on commercial textile threads. Taking advantages of capillary phenomena and gravity forces, the solution transportation is promoted without any external forces or injection pump. Screen printed electrodes were modified with carbon nanotubes/gold nanoparticles followed by covalent binding of tyrosinase. After the biosensor electrochemical characterization by cyclic voltammetry technique, the optimization of relevant parameters such as pH, potential of detection and linear range for the biosensor performance was carried out; the system was evaluated for analytical phenol detection presenting limit of detection and limit of quantification 2.94nmolL-1 and 8.92nmolL-1 respectively. The proposed system was applied on phenol addition and recovery studies in drinking water, obtaining recoveries rates between 90% and 110%. PMID- 28806669 TI - Griess reaction-based paper strip for colorimetric/fluorescent/SERS triple sensing of nitrite. AB - This study demonstrates a novel strategy for colorimetric/fluorescent/surface enhanced Raman scattering (SERS) triple-mode sensing of nitrite based on Griess reaction modulated gold nanorods (GNRs)-Azo-gold nanoparticles (GNPs) (GNRs-Azo GNPs) assembly. The p-aminothiophenol (PATP)-capped GNRs (GNRs@PATP) and 1,8 diaminonaphthalene (DAP)-modified GNPs (GNPs@DAP) are first synthesized through Au-S and Au-N bonds, respectively. Upon being excited at 365nm, the dispersion of GNRs-GNPs (GNRs@PATP and GNPs@DAP) emits cyan fluorescence. Next, the addition of nitrite into the GNRs-GNPs induces the formation of GNRs-Azo-GNPs assembly, resulting in the enhancement of color and decrease of fluorescence. Therefore, the GNRs-Azo-GNPs assembly can not only be used as a naked-eye indicator of nitrite changed from orange-yellow to purple, but also as a highly selective ''fluorescence quenching'' probe due to the fluorescence resonance energy transfer (FRET) between azo-moiety and DAP. The limit of detection (LOD) for nitrite is 0.05MUM by colorimetry and 0.01MUM by fluorescence. Meanwhile, the GNRs-Azo-GNPs assembly possesses controllable core-satellites nanostructures and enables on-field SERS detection of nitrite with the LOD of 0.8nM. More importantly, the GNRs-GNPs sensing system can not only be used as a paper-based test strip for on-site fast screening of nitrite with a high sensitivity and selectivity, but also as a SERS substrate for reliable quantitative analysis of nitrite. This study offers a new method for on-site visual detection of nitrite in human urine and meat products, as well as provides a strategy for designing multi-mode sensing platform for various applications. PMID- 28806670 TI - Transmission surface plasmon resonance techniques and their potential biosensor applications. AB - Transmission surface plasmon resonance (TSPR) is an unusual extraordinary optical transmission that is more transparent at certain wavelengths than expected by classical theory. The three main plasmonic structures that providing this phenomenon are nanohole arrays, diffraction gratings, and nanoslit arrays. This extraordinary optical transmission phenomenon is produced as a result of surface plasmon excitations. The shifting in TSPR responses upon changing of dielectric environment at the surface of a metallic film was observed. After TSPR was discovered from metallic nanohole arrays in 1998, the number of papers about this topic rapidly increased. In the 20 years since, TSPR has been utilized to improve the detection limits, sensitivity, selectivity, and dynamic range of biosensing devices, resulting in them having greater potential for commercialization. This review gives a broad overview of the TSPR phenomenon, the development of this technique, and the typical experimental setups used to acquire TSPR signals; it also describes how they are applied in the field of research into biosensors. PMID- 28806671 TI - Characterization and health risk assessment of PM2.5-bound organics inside and outside of Chinese smoking lounges. AB - PM2.5 samples were collected at six indoor public places that contained dedicated smoking lounges. Samples were taken in the smoking lounges, at two indoor locations outside of the lounges, and in outdoor air near the venues. Organic carbon (OC), elemental carbon (EC), and non-polar organic compounds including polycyclic aromatic hydrocarbons (PAHs), n-alkanes (n-C16 to n-C40), iso/anteiso alkanes (C29 to C33), hopanes and phthalate esters (PAEs) were quantified. Average PM2.5 levels of 170.2 +/- 85.9 MUg/m3 in the lounges exceeded limits of 25 MUg/m3 set by World Health Organization (WHO); these levels were 5.4 and 3.9 times higher than those indoors and outdoors, respectively. High ratios of OC to PM2.5, OC to EC, and PAHs diagnostic ratios in the lounges indicated contributions from environmental tobacco smoke (ETS). The maximum carbon number (Cmax) and carbon preference indices (CPI) for n-alkanes showed ETS transport from the enclosed lounges to nearby indoor non-smoking areas. Iso/anteiso-alkanes in the lounges were 876.5 ng/m3, ~80 times higher than outdoor levels. 17alpha(H) 21beta(H),30-norhopane and 17alpha(H)-21beta(H),(22R)-homohopane were much higher in the lounges than outdoor air, but they cannot be directly attributed to ETS. Estimated carcinogenic risks of PAHs in the lounges exceeded the acceptable level of 10- 6. PMID- 28806672 TI - A novel approach for rapidly and cost-effectively assessing toxicity of toxic metals in acidic water using an acidophilic iron-oxidizing biosensor. AB - Contamination by heavy metals and metalloids is a serious environmental and health concern. Acidic wastewaters are often associated with toxic metals which may enter and spread into agricultural soils. Several biological assays have been developed to detect toxic metals; however, most of them can only detect toxic metals in a neutral pH, not in an acidic environment. In this study, an acidophilic iron-oxidizing bacterium (IOB) Strain Y10 was isolated, characterized, and used to detect toxic metals toxicity in acidic water at pH 2.5. The colorimetric acidophilic IOB biosensor was based on the inhibition of the iron oxidizing ability of Strain Y10, an acidophilic iron-oxidizing bacterium, by metals toxicity. Our results showed that Strain Y10 is acidophilic iron-oxidizing bacterium. Thiobacillus caldus medium (TCM) (pH 2.5) supplied with both S4O62- and glucose was the optimum growth medium for Strain Y10. The optimum temperature and pH for the growth of Strain Y10 was 45 degrees C and pH 2.5, respectively. Our study demonstrates that the color-based acidophilic IOB biosensor can be semi-quantitatively observed by eye or quantitatively measured by spectrometer to detect toxicity from multiple toxic metals at pH 2.5 within 45 min. Our study shows that monitoring toxic metals in acidic water is possible by using the acidophilic IOB biosensor. Our study thus provides a novel approach for rapid and cost-effective detection of toxic metals in acidic conditions that can otherwise compromise current methods of chemical analysis. This method also allows for increased efficiency when screening large numbers of environmental samples. PMID- 28806673 TI - Preservation and reactivation of Candidatus Jettenia asiatica and Anammoxoglobus propionicus using different preservative agents. AB - Anaerobic ammonium oxidation (anammox) bacteria have peculiar characteristics that make them difficult to cultivate. The conservation of these microorganisms in culture collections or laboratories requires successful preservation and reactivation techniques. Furthermore, studies have shown that successful reactivation may be preservative dependent. Considering this, the present study aimed to evaluate the preservation and reactivation of anammox consortia enriched from swine manure treatment lagoons, by using different preservative agents at different temperatures: KNO3 (at 4 degrees C), glycerol (-20 degrees C, -80 degrees C), and skimmed cow milk (-20 degrees C, -80 degrees C, -200 degrees C). After 4 months, the biomass was thawed (except for KNO3), and the reestablishment of anammox activity was evaluated by stoichiometric coefficients. Microbial community transformation during the reactivation process was also studied by 16S rDNA sequence analysis. The results showed that the anammox biomass preserved with glycerol or skimmed cow milk at -80 degrees C recovered activity, while the biomass preserved with other methodologies did not reestablish activity during the studied time (90 days). The bacterial community from the biomass with anammox activity was characterized and showed the presence of Candidatus Brocadia anammoxidans, Candidatus Jettenia asiatica, and Candidatus Anammoxoglobus propionicus. Preservation with skimmed cow milk at -80 degrees C favored the selection of Candidatus Anammoxoglobus propionicus, while preservation with glycerol at -80 degrees C was successful for Candidatus Jettenia asiatica. The present study was effective on anammox sludge preservation and reactivation using low-cost processes for anammox cultures preservation, which is important for biomass transport and deammonification reactor start up. PMID- 28806674 TI - Cadmium induces histopathological injuries and ultrastructural changes in the liver of freshwater turtle (Chinemys reevesii). AB - The study investigated the histopathological and ultrastructural lesions of liver of freshwater turtle Chinemys reevesii exposed to Cadmium (Cd). The animals were exposed to 0 mg kg-1 (0.85% normal saline (NS)), 7.5 mg kg-1, 15 mg kg-1, 30 mg kg-1 Cd chloride separately by intraperitoneal injection. Liver samples were collected for examination of lesions under light and electronic microscopes. Results showed that liver tissues from Cd -treated animals presented various degrees of histopathological lesions. Liver cells showed swollen, degeneration and necrosis with dose-dependent manner. Under electronic microscope, nucleus, mitochondria and rough endoplasmic reticulum presented various degrees of lesions with dose-dependent manner. In conclusion, Cd has significant toxicity on liver tissue of the freshwater turtle, which occurs in a dose-dependent manner. PMID- 28806675 TI - Biotransformation of NSAIDs by pig liver microsomes in vitro: Kinetics, metabolites identification and toxicity prediction. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most frequently used pharmaceuticals in animals. In the current study, the biotransformation of five NSAIDs by pig liver microsomes (PLMs) was studied. The pseudo-first-order kinetics mode was obtained for the metabolization of the studied NSAIDs by PLMs in vitro. The metabolites were identified by high performance liquid chromatography with a high-resolution LTQ-Orbitrap mass spectrometry. The hydroxylation of benzene was confirmed to be the dominating metabolic pathway. Finally, the toxicity of the metabolites was predicted by the Estimation Programs Interface Suite software based on quantitative structure-activity relationships. Decreased toxicity was expected for the most metabolites of the studied NSAIDs except flurbiprofen, whose main metabolite exhibited slightly more toxicity. The present study provided a preliminary foundation to understand the metabolites of some NSAIDs and their toxicity, which was of great significance in animal food safety. PMID- 28806676 TI - Occurrence and air-soil exchange of organochlorine pesticides and polychlorinated biphenyls at a CAWNET background site in central China: Implications for influencing factors and fate. AB - Ambient air and soil samples were collected between March 2012 and March 2013 at Jinsha, a regional background site in central China, to measure the concentrations of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs). The average concentrations of total OCPs and total PCBs were 191 +/- 107 and 39.4 +/- 27.1 pg/m3 in air (gaseous and particulate phase) and 0.585 +/- 0.437 and 0.083 +/- 0.039 ng/g in soil, respectively. The higher concentrations of p,p'-dichlorodiphenyltrichloroethane (p,p'-DDT) and p,p'-DDT/p,p'-DDE ratios in the soil indicated recent p,p'-DDT input to the soil. A strong positive temperature dependence and average fugacity fraction value > 0.5 were observed for p,p'-DDT, suggesting that volatilization of residual DDT in the soil was the main influencing factor on atmospheric p,p'-DDT. Highly average fugacity fractions (>0.7) of trans-chlordane (TC) and cis-chlordane (CC) and high TC/CC ratios both in the soil and atmosphere suggested fresh inputs. Higher gaseous concentrations of hexachlorobenzene (HCB) were observed in winter and negative temperature dependence was directly attributed to the surrounding ongoing source (e.g. fuel consuming activities), especially in winter. Overall, most targeted OCPs and PCBs were influenced by long-range transport, and fugacity fraction values indicated highly volatile compounds (e.g. alpha-hexachlorocyclohexane (alpha-HCH) and lower chlorinated PCBs) were volatilized and low volatility compounds (e.g. p,p'-DDE and higher chlorinated PCBs) were deposited at the air soil interface. Knowing the source and sink of OCPs and PCBs can help to control their pollution in this area and provide a reference for other studies. PMID- 28806677 TI - Influence of the residue from an iron mining dam in the growth of two macrophyte species. AB - On November 5th, 2015 the worst environmental disaster in Brazil spilled 60 million m3 of iron mining residue into Gualaxo do Norte River (Minas Gerais State), an affluent of the highest River Basin of the Brazilian Southeast (Doce River Basin), reaching the Atlantic Ocean. To assess the impact of the iron residue on the aquatic plant metabolism, we performed macrophyte growth experiments under controlled light and temperature conditions using two species (Egeria densa and Chara sp.). The plants' growth data were fitted in a kinetic model to obtain the biomass yields (K) and growth rates (MU). Turbidity and electrical conductivity of the water were measured over time. Both plants showed the highest growth rates in the contaminated condition (0.056 d-1 for E. densa and 0.45 d-1 for Chara sp.) and the biomass increased in the short-term (~20 days). The control condition (i.e. no impacted water) supported the biomass increasing over time and the development of vegetative buddings with high daily rates (1.75 cm d-1 for E. densa and 0.13 cm d-1 for Chara sp). Turbidity showed a sharp decrease in 48 h and had no effects in the plants growth in the contaminated condition. The contamination affected the plants' yields in the long term affecting the biomass development. This study provides preliminary information about the ecological consequences of a mining dam rupture aiming to collaborate with monitoring and risk assessments. PMID- 28806678 TI - The sorptive and reductive capacities of biochar supported nanoscaled zero-valent iron (nZVI) in relation to its crystallite size. AB - In this work, nZVI was immobilized by bamboo derived biochars (nZVI/BB), hydrogen peroxide (H2O2) (nZVI/PBB) and nitric acid (HNO3) (nZVI/HBB) modified BB. H2O2 and HNO3 deceased surface area and pore volume of pristine biochars. Total iron (Fe) contents were 16.50, 24.40, and 13.08% for nZVI/BB, nZVI/PBB and nZVI/HBB, respectively. The X-ray diffraction revealed that nZVI in biochar matrix was dominantly metallic Fe coated with Fe oxides. The transmission electron microscopy indicated nZVI particle sizes were 41.5, 30.5 and 6.1 nm for nZVI/BB, nZVI/HBB and nZVI/PBB, respectively. The removal capacities of arsenate (AsV) and silver ions (Ag+) by nZVI nanocomposites were compared in a batch experiment. Greater reductive removal of Ag+ (1217 g kg-1 nZVI) and sorptive removal of AsV (109.1 g kg-1 nZVI) were achieved in nZVI/PBB, indicating smaller-sized nZVI was more reactive. Thus, particle size of nZVI affected the sorptive and reductive capacities for AsV and Ag+. PMID- 28806679 TI - Development of a predictive model for lead, cadmium and fluorine soil-water partition coefficients using sparse multiple linear regression analysis. AB - In this study, we applied sparse multiple linear regression (SMLR) analysis to clarify the relationships between soil properties and adsorption characteristics for a range of soils across Japan and identify easily-obtained physical and chemical soil properties that could be used to predict K and n values of cadmium, lead and fluorine. A model was first constructed that can easily predict the K and n values from nine soil parameters (pH, cation exchange capacity, specific surface area, total carbon, soil organic matter from loss on ignition and water holding capacity, the ratio of sand, silt and clay). The K and n values of cadmium, lead and fluorine of 17 soil samples were used to verify the SMLR models by the root mean square error values obtained from 512 combinations of soil parameters. The SMLR analysis indicated that fluorine adsorption to soil may be associated with organic matter, whereas cadmium or lead adsorption to soil is more likely to be influenced by soil pH, IL. We found that an accurate K value can be predicted from more than three soil parameters for most soils. Approximately 65% of the predicted values were between 33 and 300% of their measured values for the K value; 76% of the predicted values were within +/-30% of their measured values for the n value. Our findings suggest that adsorption properties of lead, cadmium and fluorine to soil can be predicted from the soil physical and chemical properties using the presented models. PMID- 28806680 TI - Sequestration of Aluminium(III) by different natural and synthetic organic and inorganic ligands in aqueous solution. AB - The speciation of Al3+ in aqueous solutions containing organic and inorganic ligands important from a biological (citrate (Cit3-), gluconate (Gluc-), lactate (Lac-), silicate (H2SiO42-), carbonate (CO32-), fluoride (F-)) and industrial (Gantrez(r); polymethyl-vinyl-ether-co-maleic acids; GTZ S95 and GTZ AN169) point of view is reported. The stability constants of Al3+/Lz- complexes (Lz- = ligand with z- charge) were determined by potentiometry at T = 298.15 K and 0.10 <= I/M <= 1.00 in NaCl(aq) (in NaNO3(aq) only for Al3+/GTZ S95 and Al3+/Gluc- acid systems). For Al3+/Cit3-, Al3+/Lac- and Al3+/GTZ AN1694- systems, the investigations were also carried out at 283.15 <= T/K <= 318.15. The dependence of the thermodynamic parameters on ionic strength and temperature was modelled with a Debye-Huckel type equation. Different speciation schemes of Al3+/Lz- systems were obtained, including protonated, simple metal-ligand, polynuclear and hydrolytic mixed species. At I -> 0 M and T = 298.15 K the stability trend for the AlL(3-z) species is: 14.28 +/- 0.02, 13.99 +/- 0.03, 10.16 +/- 0.03, 3.16 +/- 0.08, 2.84 +/- 0.10 for GTZ S95, GTZ AN169, Cit3-, Gluc- and Lac-, respectively. From the investigations at different temperatures, it results that the entropic contribution is the driving force of the reactions. The sequestering ability of the ligands towards Al3+ was investigated determining the pL0.5 parameter at different experimental conditions, finding the following trend: Cit3- " Gluc- > GTZ S954- > GTZ AN1694- > Lac- for the organic ligands, and pL0.5: F- " CO32- > H2SiO42- for the inorganic ones. PMID- 28806681 TI - Human biomonitoring of polycyclic aromatic hydrocarbonsand metals in the general population residing near the municipal solid waste incinerator of Modena, Italy. AB - BACKGROUND AND OBJECTIVES: A cross-sectional biomonitoring study was carried out to investigate exposure to incinerator emission in relation to the body burden of selected biomarkers in the population living around the plant. METHODS: Approximately 500 people, aged 18-69 yrs, living within 4 km from the incinerator were randomly selected form the population register. Exposure was measured through fall-out maps of particulate matter (PM), used as tracer for incinerator emissions. Ten metabolized polycyclic aromatic hydrocarbons (PAHs), from naphthalene to chrysene, 1-hydroxypyrene and twelve metals (Cd, Cr, Cu, Hg, Ni, Pb, Ni, Zn, V, Tl, As, Sn) were measured in spot urine samples. Confounders, such as diet, smoking, traffic, occupation and personal characteristics were assessed by questionnaires and objective measurements, and included into multivariate linear regression models. RESULTS: Metal concentrations in urine were in line with or higher than Italian reference limits, besides Cr and V with more than twofold concentrations. Metal levels did not show clear association to exposure categories. Most abundant PAHs were naphthalene (median 26.2 ng/L) and phenanthrene (7.4 ng/L). All PAHs, but benz[a]anthracene and 1-hydroxypyrene, were found in more than 52% of samples, and included in regression models. Significant associations between urinary PAHs and exposure were found, strong for fluorene, and weaker for naphthalene, fluoranthene and pyrene. Results were confirmed by sensitivity analyses. Correlation with variables reported in literature were observed. CONCLUSIONS: The study indicates that the emissions were very low and highlights that specific urinary PAHs provided useful information about the internal dose arising from incinerator emission. PMID- 28806682 TI - Photolytic insertion of albumin on activated carbon modified with ozone. AB - 254nm photolyses of bovine serum albumin [BSA] in aqueous solutions, were carried out in the presence of activated carbons modified by reaction with ozone. The photolyses were monitored by fluorescence spectroscopy and UV spectrophotometry, and the products were characterized by elemental analysis, FTIR, TGA, total organic carbon analyses [TOC], and XPS. The ozonation reaction was carried out at room temperature with O3 under dry and wet conditions. The carbon characterization showed that the reaction increased the amount of epoxide and carbonyl groups on the carbon matrix. The activated carbon modified with dry O3 exhibited higher concentration of oxidized groups in its surface, smaller surface area and lower thermal stability. Characterization of the photolysis of ozonized carbons pointed to a small release of carbon organic groups during the reaction with elimination of epoxide groups and increase of carbonyl groups without change of thermal stability. Photolysis of BSA in aqueous solution occurred with fluorescence quenching due to changes of the local microenvironment and/or macromolecular conformational changes. Absorbance increase of the UV spectrum indicated a hyperchromic effect due to albumin structure modifications during photolysis. TGA analysis of the photolysed activated carbons in the presence of BSA suggested that ozonized carbon samples underwent insertion of BSA upon photolysis, in particular the sample ozonized under dry conditions. The changes observed for the FTIR and elemental analysis agreed with this conclusion, which was further supported by 13C SS-NMR, fluorescence emission and XPS. PMID- 28806683 TI - Asymmetric polyplex-nanocapsules loaded with photosentisizer for light-assisted gene transfer. AB - Inefficient intracellular gene delivery is still a limitation for the clinical translation of gene therapy. Recently, photochemical internalization (PCI) has emerged with the opportunity to overcome endo-lysosomal sequestration in gene delivery, which utilizes photosensitizer (PS) plus light generating reactive oxygen species (ROS) at sub-lethal level to facilitate intracellularly targeted drug delivery. In this work, asymmetric polyplex-nanocapsules were prepared based on the triblock copolymers of PEG-PCL-PEI by using the simple solvent-injection method. Subsequently, the hydrophobic PS was encapsulated in the hydrophobic layer of polyplex-nanocapsules through hydrophobic interaction. The results from agarose gel electrophoresis and fluorescence scanning spectroscopy show that DNA could be condensed effectively and the PS was encapsulated, resulting in the stable polyplex-nanocapsules. The obtained polyplex-nanocapsules were characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS) measurements with the average size ranging from 200 to 280nm and the negatively charged surface. Importantly, these polyplex-nanocapsules can be uptaken by Hela cells, resulting in improved gene transfection efficiency in comparison with the case without laser treatment due to the assistance of PCI effect. This work demonstrates a promising strategy to build the light-assisted gene delivery system containing PS and transporting genes simultaneously in one platform. PMID- 28806684 TI - Photochemical inactivation of lymphocytes by riboflavin with visible light for TA GVHD prevention. AB - Transfusion-associated graft-versus-host disease (TA-GVHD) is a life-threatening complication caused by the input of a number of immunocompetent allogeneic lymphocytes. This study focus on the photochemical effects of riboflavin excited by visible light (RB+L) treatment on human lymphocytes, to study the feasibility of using RB+L treatment to prevent adverse immune reactions caused by transfused lymphocytes. 100MUM riboflavin was added to lymphocyte suspensions. After exposure to 400-580nm visible light with a total energy of 40J/mL, cells were cultured and the ability of proliferation and cytokine secretion were assayed upon stimuli. Meanwhile, lymphocytes were also treated by gamma-irradiation as parallel to testify the inactivation effect of RB+L. Results showed that gamma irradiation and RB+L treated cells showed a decline in cell viability. After stimulation of phytohemagglutinin (PHA) or anti-CD3 together with anti-CD28, proliferative ability of RB+L treated cells was strongly inhibited when compared to untreated cells. The inhibitive rates of proliferation in RB+L group were also higher than those of cells treated by gamma-irradiation. Results of CFSE assays also illustrated hardly any cell division of RB+L and gamma-irradiation treated lymphocytes. Besides low level productions of IL-4 and IL-12, cytokine production of TNF-alpha, IFN-gamma and IL-10 by incubation with PHA or IL-1beta, IL-2, IL-6, IL-8, IL-10, TNF-alpha and IFN-gamma stimulated by anti-CD3 plus anti-CD28 were suppressed after treatment of RB+L significantly. It was suggested that RB+L/gamma-irradiation treatment induced cell apoptosis. These results indicated that RB+L treatment functionally inactivated lymphocytes by inhibiting cell proliferation and cytokine production. RB+L might be an alternative for TA-GVHD prevention. PMID- 28806685 TI - Ecofriendly gold nanoparticles - Lysozyme interaction: Thermodynamical perspectives. AB - In the featured work interaction between biosynthesized gold nanoparticles (GNP) and lysozyme (Lys) has been studied using multi-spectroscopic approach. A moderate association constant (Kapp) of 2.66*104L/mol has been observed indicative of interactive nature. The binding constant (Kb) was 1.99, 6.30 and 31.6*104L/mol at 291, 298 and 305K respectively and the number of binding sites (n) was found to be approximately one. Estimated values of thermodynamic parameters (Enthalpy change, DeltaH=141.99kJ/mol, entropy change, DeltaS=570J/mol/K, Gibbs free energy change, DeltaG=-27.86kJ/mol at 298K) suggest hydrophobic force as the main responsible factor for the Lys-GNP interaction and also the process of interaction is spontaneous. The average binding distance (r=3.06nm) and the critical energy transfer distance (Ro=1.84nm) between GNP and Lys was also evaluated using Forster's non-radiative energy transfer (FRET) theory and results clearly indicate that non-radiative type energy transfer is possible. Moreover, the addition of GNP does not show any significant change in the secondary structure of Lys as confirmed from circular dichroism (CD) spectra. Furthermore, NMR spectroscopy also indicates interaction between Lys and GNP. The resulting insight is important for the better understanding of structural nature and thermodynamic aspects of binding between the Lys and GNP. PMID- 28806686 TI - Simultaneous determination of 16 macrolide antibiotics and 4 metabolites in milk by using Quick, Easy, Cheap, Effective, Rugged, and Safe extraction (QuEChERS) and high performance liquid chromatography tandem mass spectrometry. AB - A novel analytical method was developed and validated for simultaneous analysis of 16 macrolide antibiotics and 4 metabolites in milk. A modified quick, easy, cheap, effective, rugged, and safe extraction method (QuEChERS) optimized by response surface methodology (RSM) was used for sample preparation. All the drugs were subsequently separated and detected by high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS), using roxithromycin as internal standards for maximum accuracy and precision. The method was validated following the guidelines specified in Commission Decision 2002/657/EC. The recoveries of all the analytes were in the range of 62.27%-115.28%. Most macrolide antibiotics and metabolites could be detected in the concentration of 1 100ng/mL with good correlation coefficient (r2>0.998). The LODs and LOQs of all analytes were in the range of 0.30-0.85MUg/kg and 1.1-4.0MUg/kg, respectively. The intra-day and inter-day precision were lower than 10% and 15%, respectively. The developed method has been successfully applied to screen these compounds in different milk products. PMID- 28806687 TI - Mineralization-defects are comparable in fluorotic impacted human teeth and fluorotic mouse incisors. AB - OBJECTIVE: Fluoride excess of 0.05-0.07mgF/kgbw/day in water or food additives like salt is the principal cause of endemic dental fluorosis. How fluoride causes these defects is not clear yet. Recent studies in rodents suggest that development of enamel fluorosis is associated with insufficient neutralization of protons released during the formation of hypermineralized lines. DESIGN: Here we examined whether hypermineralization could also be assessed by MicroCT in developing molar enamel of humans exposed to fluoride. RESULT: Micro-CT analysis of hypomineralized enamel from human fluorotic molars graded by the Thylstrup Fejerskov (TF) Index as III-IV showed weak hypermineralized lines and hypermineralized patches not seen in TF-I/II grade enamel. The mesio-distal sides of these molar teeth were significantly smaller (~18%, p=0.02) than in TF-I/II teeth. CONCLUSION: The patterns of changes observed in human fluorotic teeth were similar to those in fluorotic rodent incisors. The data are consistent with the hypothesis that also in developing human teeth fluoride-stimulated local acidification of enamel could be a mechanism for developing fluorotic enamel. PMID- 28806688 TI - Concentration dependent transcriptome responses of zebrafish embryos after exposure to cadmium, cobalt and copper. AB - Environmental metals are known to cause harmful effects to fish of which many molecular mechanisms still require elucidation. Particularly concentration dependence of gene expression effects is unclear. Focusing on this matter, zebrafish embryo toxicity tests were used in combination with transcriptomics. Embryos were exposed to three concentrations of copper (CuSO4), cadmium (CdCl2) and cobalt (CoSO4) from just after fertilization until the end of the 48hpf pre- and 96hpf post-hatch stage. The RNA was then analyzed on Agilent's Zebrafish (V3, 4*44K) arrays. Enrichment for GO terms of biological processes illustrated for cadmium that most affected GO terms were represented in all three concentrations, while for cobalt and copper most GO terms were represented in the lowest test concentration only. This suggested a different response to the non-essential cadmium than cobalt and copper. In cobalt and copper treated embryos, many developmental and cellular processes as well as the Wnt and Notch signaling pathways, were found significantly enriched. Also, different exposure concentrations affected varied functional networks. In contrast, the largest clusters of enriched GO terms for all three concentrations of cadmium included responses to cadmium ion, metal ion, xenobiotic stimulus, stress and chemicals. However, concentration dependence of mRNA levels was evident for several genes in all metal exposures. Some of these genes may be indicative of the mechanisms of action of the individual metals in zebrafish embryos. Real-time quantitative RT PCR (qRT-PCR) verified the microarray data for mmp9, mt2, cldnb and nkx2.2a. PMID- 28806689 TI - Fungal diversity of "Tomme d'Orchies" cheese during the ripening process as revealed by a metagenomic study. AB - Tomme d'Orchies is an artisanal pressed and uncooked cheese produced and marketed in the north of France. This study aimed at showing the fungal microbiota evolution of this cheese using a metagenetic based Illumina technology targeting the ITS2 domain of 5.8S fungal rDNAs. To this end, samples were taken from the rind and the core of different cheeses, after 0, 1, 3, 7, 14 and 21days of ripening. The data underpinned the prevalence of Yarrowia lipolytica and Galactomyces geotrichum for both microbiotas. Unusual species including Clavispora lusitaniae, Kazachstania unispora and Cladosporium cladosporioides were also detected, but their origins remain to be ascertained. The metagenomic revealed also the presence of Kluyveromyces and Debaryomyces species. PMID- 28806690 TI - Occurrence and distribution of halogenated flame retardants in an urban watershed: Comparison to polychlorinated biphenyls and organochlorine pesticides. AB - Due to restrictions on polybrominated diphenyl ethers (PBDEs), market demand for alternative flame retardants is projected to increase, worldwide. Information regarding the environmental behavior of these compounds is limited. The present study involved field measurements of several alternative halogenated flame retardants (HFRs), along with PBDEs and legacy persistent organic pollutants (POPs) in surface water, bottom sediments and suspended particulate matter (SPM) within a highly urbanized watershed in Singapore. Several alternative HFRs were detected in water and sediments. Dechlornane Plus stereoisomers (syn- and anti DP) were detected in all samples, exhibiting relatively high concentrations in water, sediments and SPM. The maximum syn-DP concentrations in water, sediments and SPM were 24.30 ng/L, 2.48 ng/g dry wt. and 7774 ng/g dry wt., respectively. 1,2-Bis(2,4,6-tribromophenoxy) ethane (BTBPE), pentabromotoluene (PBT), hexabromobenzene (HxBBz) and tetrabromoethylcyclohexane (TBECH) were routinely detected. PBDE concentrations were relatively low and often non-detectable. Polychlorinated biphenyl (PCB) concentrations ranged from 0.017 to 8.37 ng/L in water, 9.86-27.92 ng/g dry wt. in SPM, and 6.48-212.3 ng/g dry wt. in sediments. Congener and isomer patterns suggested no recent inputs of PBDEs or dichlorodiphenyltrichloroethane (DDT). Rainfall was found to be an important factor influencing temporal and spatial patterns of DPs, BTBPE, PBDEs and some organochlorines in surface water. Land use index was found to be important for several organochlorines, but not HFRs. The observed sediment-water partitioning behavior of the studied HFRs and legacy POPs was highly dependent on chemical hydrophobicity. The data demonstrate that the studied HFRs have a relatively high affinity for SPM and bottom sediments. For example, the log KOC,OBS for TBECH, syn-DP and anti-DP and BTBPE in bottom sediments ranged between 8.1 and 9.6. The findings will aid future studies regarding fate, transport and bioaccumulation of these current-use contaminants of concern. PMID- 28806692 TI - Microplastic pollution identified in deep-sea water and ingested by benthic invertebrates in the Rockall Trough, North Atlantic Ocean. AB - Microplastics are widespread in the natural environment and present numerous ecological threats. While the ultimate fate of marine microplastics are not well known, it is hypothesized that the deep sea is the final sink for this anthropogenic contaminant. This study provides a quantification and characterisation of microplastic pollution ingested by benthic macroinvertebrates with different feeding modes (Ophiomusium lymani, Hymenaster pellucidus and Colus jeffreysianus) and in adjacent deep water > 2200 m, in the Rockall Trough, Northeast Atlantic Ocean. Despite the remote location, microplastic fibres were identified in deep-sea water at a concentration of 70.8 particles m-3, comparable to that in surface waters. Of the invertebrates examined (n = 66), 48% ingested microplastics with quantities enumerated comparable to coastal species. The number of ingested microplastics differed significantly between species and generalized linear modelling identified that the number of microplastics ingested for a given tissue mass was related to species and not organism feeding mode or the length or overall weight of the individual. Deep-sea microplastics were visually highly degraded with surface areas more than double that of pristine particles. The identification of synthetic polymers with densities greater and less than seawater along with comparable quantities to the upper ocean indicates processes of vertical re-distribution. This study presents the first snapshot of deep ocean microplastics and the quantification of microplastic pollution in the Rockall Trough. Additional sampling throughout the deep-sea is required to assess levels of microplastic pollution, vertical transportation and sequestration, which have the potential to impact the largest global ecosystem. PMID- 28806691 TI - Mercury contamination level and speciation inventory in Lakes Titicaca & Uru-Uru (Bolivia): Current status and future trends. AB - Aquatic ecosystems of the Bolivian Altiplano (~3800 m a.s.l.) are characterized by extreme hydro-climatic constrains (e.g., high UV-radiations and low oxygen) and are under the pressure of increasing anthropogenic activities, unregulated mining, agricultural and urban development. We report here a complete inventory of mercury (Hg) levels and speciation in the water column, atmosphere, sediment and key sentinel organisms (i.e., plankton, fish and birds) of two endorheic Lakes of the same watershed differing with respect to their size, eutrophication and contamination levels. Total Hg (THg) and monomethylmercury (MMHg) concentrations in filtered water and sediment of Lake Titicaca are in the lowest range of reported levels in other large lakes worldwide. Downstream, Hg levels are 3-10 times higher in the shallow eutrophic Lake Uru-Uru than in Lake Titicaca due to high Hg inputs from the surrounding mining region. High percentages of MMHg were found in the filtered and unfiltered water rising up from <1 to ~50% THg from the oligo/hetero-trophic Lake Titicaca to the eutrophic Lake Uru-Uru. Such high %MMHg is explained by a high in situ MMHg production in relation to the sulfate rich substrate, the low oxygen levels of the water column, and the stabilization of MMHg due to abundant ligands present in these alkaline waters. Differences in MMHg concentrations in water and sediments compartments between Lake Titicaca and Uru-Uru were found to mirror the offset in MMHg levels that also exist in their respective food webs. This suggests that in situ MMHg baseline production is likely the main factor controlling MMHg levels in fish species consumed by the local population. Finally, the increase of anthropogenic pressure in Lake Titicaca may probably enhance eutrophication processes which favor MMHg production and thus accumulation in water and biota. PMID- 28806693 TI - Persistence of urban organic aerosols composition: Decoding their structural complexity and seasonal variability. AB - Organic Aerosols (OAs) are typically defined as highly complex matrices whose composition changes in time and space. Focusing on time vector, this work uses two-dimensional nuclear magnetic resonance (2D NMR) techniques to examine the structural features of water-soluble (WSOM) and alkaline-soluble organic matter (ASOM) sequentially extracted from fine atmospheric aerosols collected in an urban setting during cold and warm seasons. This study reveals molecular signatures not previously decoded in NMR-related studies of OAs as meaningful source markers. Although the ASOM is less hydrophilic and structurally diverse than its WSOM counterpart, both fractions feature a core with heteroatom-rich branched aliphatics from both primary (natural and anthropogenic) and secondary origin, aromatic secondary organics originated from anthropogenic aromatic precursors, as well as primary saccharides and amino sugar derivatives from biogenic emissions. These common structures represent those 2D NMR spectral signatures that are present in both seasons and can thus be seen as an "annual background" profile of the structural composition of OAs at the urban location. Lignin-derived structures, nitroaromatics, disaccharides, and anhydrosaccharides signatures were also identified in the WSOM samples only from periods identified as smoke impacted, which reflects the influence of biomass-burning sources. The NMR dataset on the H-C molecules backbone was also used to propose a semi quantitative structural model of urban WSOM, which will aid efforts for more realistic studies relating the chemical properties of OAs with their atmospheric behavior. PMID- 28806694 TI - What can neuronal populations tell us about cognition? AB - Nowadays, it is possible to record the activity of hundreds of cells at the same time in behaving animals. However, these data are often treated and analyzed as if they consisted of many independently recorded neurons. How can neuronal populations be uniquely used to learn about cognition? We describe recent work that shows that populations of simultaneously recorded neurons are fundamental to understand the basis of decision-making, including processes such as ongoing deliberations and decision confidence, which generally fall outside the reach of single-cell analysis. Thus, neuronal population data allow addressing novel questions, but they also come with so far unsolved challenges. PMID- 28806695 TI - Use of peptide aptamers, cationic peptides and artificial zinc finger proteins to generate resistance to plant viruses. AB - Various RNA/DNA viruses have caused severe infectious diseases in plants as well as animals, including humans, and been a threat to the production of agricultural crops. Therefore, prevention of plant virus infections is a major objective in crop protection. One attractive approach is to inhibit functions of viral proteins responsible for virus infections. In this review, I describe the status using such approaches to confer virus resistance to plants by three types of peptides/proteins: peptide aptamers, artificial zinc finger proteins and acidic peptides. These approaches vary in their specificity, broadness to other viruses, extent of protection and mechanisms of action. Additional ways to improve these approaches are also discussed. PMID- 28806696 TI - DFT approach to (benzylthio)acetic acid: Conformational search, molecular (monomer and dimer) structure, vibrational spectroscopy and some electronic properties. AB - The DFT studies were carried out with the B3LYP method utilizing the 6-31G and 6 311++G(d,p) basis sets depending on whether the aim of calculations was to gain the geometry at equilibrium, or to calculate the optimized molecular structure of (benzylthio)acetic acid (Hbta) in the forms of monomer and dimer. The minimum conformational energy search was followed by the potential energy surface (PES) scan of all rotary bonds existing in the acid molecule. The optimized geometrical monomeric and dimeric structures of the title compound were compared with the experimental structural data in the solid state. The detailed vibrational interpretation of experimental infrared and Raman bands was performed on the basis of theoretically simulated ESFF-scaled wavenumbers calculated for the monomer and dimer structures of Hbta. The electronic characteristics of Hbta is also presented in terms of Mulliken atomic charges, frontier molecular orbitals and global reactivity descriptors. Additionally, the MEP and ESP surfaces were computed to predict coordination sites for potential metal complex formation. PMID- 28806697 TI - Photoelectron spectra and biological activity of cinnamic acid derivatives revisited. AB - The electronic structures of several derivatives of cinnamic acid have been studied by UV photoelectron spectroscopy (UPS) and Green's function quantum chemical calculations. The spectra reveal the presence of dimers in the gas phase for p-coumaric and ferulic acids. The electronic structure analysis has been related to the biological properties of these compounds through the analysis of some structure-activity relationships (SAR). PMID- 28806698 TI - Fluorescence and electron paramagnetic resonance studies of norfloxacin and N donor mixed-ligand ternary copper(II) complexes: Stability and interaction with SDS micelles. AB - The stability of ternary copper(II) complexes of a heterocyclic ligand, L (L being 2,2'-bipyridine (bipy) or 1,10-phenanthroline (phen)) and the fluorescent antibacterial agent norfloxacin (NFX) as the second ligand was studied at pH7.4 and different ionic strengths. Fluorescence quenching upon titration of NFX with the binary complexes allowed to obtain stability constants for NFX binding, Kb, as a function of ionic strength. The Kb values vary by more than two orders of magnitude when buffer concentration varies from 0.5 to 100mM. It was observed that previously synthesized ternary complexes dissociate in buffer according with the obtained stability constants. This shows that equimolar solutions of NFX and binary complexes are equivalent to solutions of synthesized ternary complexes. The interaction of the ternary copper complexes with anionic SDS (sodium dodecyl sulfate) micelles was studied by fluorescence and electron paramagnetic resonance (EPR). Titration of NFX-loaded SDS micelles with the complexes Cu:L allowed to determine the stability constants inside the micelles. Fluorescence quenching demonstrated that SDS micelles increase the stability constants by factors around 50. EPR spectra gave details of the copper(II) local environment, and demonstrated that the structure of the ternary complexes inside SDS micelles is different from that in buffer. Mononuclear ternary complexes formed inside the micelles, while in buffer most ternary complexes are binuclear. The results show that anionic membrane interfaces increase formation of copper fluoroquinolone complexes, which can influence bioavailability, membrane diffusion, and mechanism of action of the antibiotics. PMID- 28806699 TI - A portable synthesis of water-soluble carbon dots for highly sensitive and selective detection of chlorogenic acid based on inner filter effect. AB - In this work, a simple and facile hydrothermal method for synthesis of water soluble carbon dots (CDs) with malic acid and urea, and were then employed as a high-performance fluorescent probe for selective and sensitive determination of chlorogenic acid (CGA) based on inner filter effect. The as-synthesized CDs was systematically characterized by Transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), Energy disperse spectroscopy (EDS), UV-vis absorption spectroscopy, spectrofluorophotometry, and the results indicated that the sizes of CDs were mainly distributed in the range of 1.0nm-3.0nm with an average diameter of 2.1nm. More significantly, the as-prepared CDs possessed remarkable selectivity and sensitivity towards CGA with the linear range of 0.15MUmolL-1-60MUmolL-1 and the detection limit for CGA was 45nmolL-1 (3sigma/k). The practical applications of CDs for detection of CGA have already been successfully demonstrated in Honeysuckle. This sensitive, selective method has a great application prospect in the pharmaceutical and biological analysis field owing to its simplicity and rapidity for the detection of CGA. PMID- 28806700 TI - A large Raman scattering cross-section molecular embedded SERS aptasensor for ultrasensitive Aflatoxin B1 detection using CS-Fe3O4 for signal enrichment. AB - With growing concern on oil safety problems, developing a simple and sensitive method to detect Aflatoxin B1 (AFB1), a common mycotoxin in peanut oil, is very necessary. In this study, Surface-enhanced Raman Scattering (SERS) aptasensor was developed for ultrasensitive AFB1 detection using the amino-terminal AFB1 aptamer (NH2-DNA1); and thiol-terminal AFB1 complementary aptamer (SH-DNA2) conjugated magnetic-beads (CS-Fe3O4) as enrichment nanoprobe and AuNR@DNTB@Ag nanorods (ADANRs) as reporter nanoprobe respectively. 5,5'-Dithiobis(2-nitrobenzoicacid) (DNTB) with large Raman scattering cross-section and no fluorescence interference was embedded in Au and Ag core/shell nanorods as Raman reporter molecules. CS Fe3O4 possessed excellent biocompatibility and superparamagnetism for rapid signal enrichment. Therefore, NH2-DNA1-CS-Fe3O4 and SH-DNA2-ADANRs were fabricated via the hybrid reaction between aptamers and complementary aptamers. When there is AFB1, AFB1 would competitively combine with the NH2-DNA1-CS-Fe3O4 inducing the dissociation of SH-DNA2-ADANRs from CS-Fe3O4 and further decreasing the SERS signal. Based on this developed SERS aptasensor, a low limit of 0.0036ng/mL and an effective linear detection range from 0.01 to 100ng/mL with the correlation coefficient up to 0.986 for AFB1 detection were obtained. Moreover, the specificity of this SERS aptasensor was demonstrated by detecting other two mycotoxins and its accuracy for AFB1 detection in real peanut oil was further confirmed by standard addition recovery test. PMID- 28806701 TI - Application of different spectrophotometric methods for simultaneous determination of elbasvir and grazoprevir in pharmaceutical preparation. AB - The first three UV spectrophotometric methods have been developed of simultaneous determination of two new FDA approved drugs namely; elbasvir and grazoprevir in their combined pharmaceutical dosage form. These methods include simultaneous equation, partial least squares with and without variable selection procedure (genetic algorithm). For simultaneous equation method, the absorbance values at 369 (lambdamax of elbasvir) and 253nm (lambdamax of grazoprevir) have been selected for the formation of two simultaneous equations required for the mathematical processing and quantitative analysis of the studied drugs. Alternatively, the partial least squares with and without variable selection procedure (genetic algorithm) have been applied in the spectra analysis because the synchronous inclusion of many unreal wavelengths rather than by using a single or dual wavelength which greatly increases the precision and predictive ability of the methods. Successfully assay of the drugs in their pharmaceutical formulation has been done by the proposed methods. Statistically comparative analysis for the obtained results with the manufacturing methods has been performed. It is noteworthy to mention that there was no significant difference between the proposed methods and the manufacturing one with respect to the validation parameters. PMID- 28806702 TI - HMGB1 redox during sepsis. AB - During sepsis, the alarmin HMGB1 is released from tissues and promotes systemic inflammation that results in multi-organ damage, with the kidney particularly susceptible to injury. The severity of inflammation and pro-damage signaling mediated by HMGB1 appears to be dependent on the alarmin's redox state. Therefore, we examined HMGB1 redox in kidney cells during sepsis. Using intravital microscopy, CellROX labeling of kidneys in live mice indicated increased ROS generation in the kidney perivascular endothelium and tubules during lipopolysaccharide (LPS)-induced sepsis. Subsequent CellROX and MitoSOX labeling of LPS-stressed endothelial and kidney proximal tubule cells demonstrated increased ROS generation in these cells as sepsis worsens. Consequently, HMGB1 oxidation increased in the cytoplasm of kidney cells during its translocation from the nucleus to the circulation, with the degree of oxidation dependent on the severity of sepsis, as measured in in vivo mouse samples using a thiol assay and mass spectrometry (LC-MS/MS). The greater the oxidation of HMGB1, the greater the ability of the alarmin to stimulate pro inflammatory cyto-/chemokine release (measured by Luminex Multiplex) and alter mitochondrial ATP generation (Luminescent ATP Detection Assay). Administration of glutathione and thioredoxin inhibitors to cell cultures enhanced HMGB1 oxidation during sepsis in endothelial and proximal tubule cells, respectively. In conclusion, as sepsis worsens, ROS generation and HMGB1 oxidation increases in kidney cells, which enhances HMGB1's pro-inflammatory signaling. Conversely, the glutathione and thioredoxin systems work to maintain the protein in its reduced state. PMID- 28806704 TI - Chiral pharmaceuticals: A review on their environmental occurrence and fate processes. AB - More than 50% of pharmaceuticals in current use are chiral compounds. Enantiomers of the same pharmaceutical have identical physicochemical properties, but may exhibit differences in pharmacokinetics, pharmacodynamics and toxicity. The advancement in separation and detection methods has made it possible to analyze trace amounts of chiral compounds in environmental media. As a result, interest on chiral analysis and evaluation of stereoselectivity in environmental occurrence, phase distribution and degradation of chiral pharmaceuticals has grown substantially in recent years. Here we review recent studies on the analysis, occurrence, and fate of chiral pharmaceuticals in engineered and natural environments. Monitoring studies have shown ubiquitous presence of chiral pharmaceuticals in wastewater, surface waters, sediments, and sludge, particularly beta-receptor antagonists, analgesics, antifungals, and antidepressants. Selective sorption and microbial degradation have been demonstrated to result in enrichment of one enantiomer over the other. The changes in enantiomer composition may also be caused by biologically catalyzed chiral inversion. However, accurate evaluation of chiral pharmaceuticals as trace environmental pollutants is often hampered by the lack of identification of the stereoconfiguration of enantiomers. Furthermore, a systematic approach including occurrence, fate and transport in various environmental matrices is needed to minimize uncertainties in risk assessment of chiral pharmaceuticals as emerging environmental contaminants. PMID- 28806703 TI - NOX4-mediated ROS production induces apoptotic cell death via down-regulation of c-FLIP and Mcl-1 expression in combined treatment with thioridazine and curcumin. AB - Thioridazine is known to have anti-tumor effects by inhibiting PI3K/Akt signaling, which is an important signaling pathway in cell survival. However, thioridazine alone does not induce apoptosis in head and neck squamous cell carcinoma (AMC-HN4), human breast carcinoma (MDA-MB231), and human glioma (U87MG) cells. Therefore, we investigated whether combined treatment with thioridazine and curcumin induces apoptosis. Combined treatment with thioridazine and curcumin markedly induced apoptosis in cancer cells without inducing apoptosis in human normal mesangial cells and human normal umbilical vein cells (EA.hy926). We found that combined treatment with thioridazine and curcumin had synergistic effects in AMC-HN4 cells. Among apoptosis-related proteins, thioridazine plus curcumin induced down-regulation of c-FLIP and Mcl-1 expression at the post-translational levels in a proteasome-dependent manner. Augmentation of proteasome activity was related to the up-regulation of proteasome subunit alpha 5 (PSMA5) expression in curcumin plus thioridazine-treated cells. Combined treatment with curcumin and thioridazine produced intracellular ROS in a NOX4-dependent manner, and ROS mediated activation of Nrf2/ARE signaling played a critical role in the up regulation of PSMA5 expression. Furthermore, ectopic expression of c-FLIP and Mcl 1 inhibited apoptosis in thioridazine and curcumin-treated cells. Therefore, we demonstrated that thioridazine plus curcumin induces proteasome activity by up regulating PSMA5 expression via NOX4-mediated ROS production and that down regulation of c-FLIP and Mcl-1 expression post-translationally is involved in apoptosis. PMID- 28806705 TI - Multiparametric monitoring of microbial faecal pollution reveals the dominance of human contamination along the whole Danube River. AB - The microbial faecal pollution of rivers has wide-ranging impacts on a variety of human activities that rely on appropriate river water quality. Thus, detailed knowledge of the extent and origin of microbial faecal pollution is crucial for watershed management activities to maintain safe water use. In this study, the microbial faecal pollution levels were monitored by standard faecal indicator bacteria (SFIB) along a 2580 km stretch of the Danube, the world's most international river, as well as the Danube's most important tributaries. To track the origin of faecal pollution, host-associated Bacteroidetes genetic faecal marker qPCR assays for different host groups were applied in concert with SFIB. The spatial resolution analysis was followed by a time resolution analysis of faecal pollution patterns over 1 year at three selected sites. In this way, a comprehensive faecal pollution map of the total length of the Danube was created, combining substantiated information on both the extent and origin of microbial faecal pollution. Within the environmental data matrix for the river, microbial faecal pollution constituted an independent component and did not cluster with any other measured environmental parameters. Generally, midstream samples representatively depicted the microbial pollution levels at the respective river sites. However, at a few, somewhat unexpected sites, high pollution levels occurred in the lateral zones of the river while the midstream zone had good water quality. Human faecal pollution was demonstrated as the primary pollution source along the whole river, while animal faecal pollution was of minor importance. This study demonstrates that the application of host-associated genetic microbial source tracking markers in concert with the traditional concept of microbial faecal pollution monitoring based on SFIB significantly enhances the knowledge of the extent and origin of microbial faecal pollution patterns in large rivers. It constitutes a powerful tool to guide target-oriented water quality management in large river basins. PMID- 28806706 TI - Auditory-cortex lesions impair contralateral tone-pattern detection under informational masking. AB - Impaired hearing contralateral to unilateral auditory-cortex lesions is typically only observed under conditions of perceptual competition, such as dichotic presentation or speech in noise. It remains unclear, however, if the source of this effect is direct competition in frequency-specific neurons, or if enhanced processing load in more distant frequencies can also impair auditory detection. To evaluate this question, we studied a group of patients with unilateral auditory-cortex lesions (N = 14, six left-hemispheric (LH), eight right hemispheric (RH); four females; age range 26-72 years) and a control group (N = 25; 15 females; age range 18-76 years) with a target-detection task in presence of a multi-tone masker, which can produce informational masking. The results revealed reduced sensitivity for monaural target streams presented contralateral to auditory-cortex lesions, with an approximately 10% higher error rate in the contra-lesional ear. A general, bilateral reduction of target detection was only observed in a subgroup of patients, who were classified as additionally suffering from auditory neglect. These results demonstrate that auditory-cortex lesions impair monaural, contra-lesional target detection under informational masking. The finding supports the hypothesis that neural mechanisms beyond direct competition in frequency-specific neurons can be a source of impaired hearing under perceptual competition in patients with unilateral auditory-cortex lesions. PMID- 28806708 TI - Predictive simulation of diabetic gait: Individual contribution of ankle stiffness and muscle weakening. AB - Diabetic neuropathic individuals present massive muscle strength reduction at the ankle plantar- and dorsiflexors and increased joint stiffness. Our aim is to investigate the adaptation strategies to these musculoskeletal alterations during walking by means of predictive simulations. We used a seven segment planar musculoskeletal model actuated by eight Hill-type muscles in each leg. The effect of all passive tissue in muscles and other joint structures was modeled by net passive joint moment curves. The predictive simulations were generated by solving an optimal control problem that minimized a cost function, including effort and tracking terms, using direct collocation and a commercial optimal control package. We simulate four conditions to represent the weakening of the distal muscles triceps sural (TS) and tibialis anterior (TA), and five conditions to represent the effect of increasing nonlinear ankle stiffness in flexion. The weakening of the distal muscles leads to a delayed action of the TS and a progressive decrease of the gastrocnemius peak force in the push-off phase. This distal deficit is compensated by a larger hip flexion moment resulting from an increase in the iliopsoas muscle force in this phase, known as the hip strategy. The adaptation mechanisms observed in response to an increase in ankle stiffness include the hip strategy and the exploitation of the passive joint structures as springs, which store energy during midstance and release it during push-off, reducing TS force and power in this phase and leading to a consistent decrease in the overall muscle force levels. PMID- 28806707 TI - Deviant functional activation and connectivity of the right insula are associated with lack of awareness of episodic memory impairment in nonamnesic alcoholism. AB - A disorder of metamemory, expressed as unawareness of mnemonic ability, is typically associated with the profound amnesia of Korsakoff's Syndrome (KS). A similar but less severe type of limited awareness can also occur in non-KS alcoholism and is observed as an impairment in generating Feeling-of-Knowing (FOK) predictions about future recognition performance. We previously found that FOK accuracy was selectively related to volumes of the insula in alcoholics involved in the present study. Unknown, however, are the neural substrates of unawareness of memory impairment in alcoholism. A task-activated fMRI paradigm served to identify neural nodes and networks implicated in inaccurate self estimation of mnemonic ability in sober alcoholics while they made prospective FOK judgments in an episodic memory paradigm. Lower activation in the right insula correlated with greater overestimations of future memory abilities in alcoholics. Weaker connectivity of the right insula with the left dorsal anterior cingulate cortex, a node of the salience network, and stronger connectivity of the right insula with the right ventromedial prefrontal cortex (vmPFC), a node of the default mode network (DMN), co-occurred in alcoholics relative to the controls. Specifically, alcoholics, who failed to desynchronize insula-vmPFC activity, had greater overestimation of their memory predictions and poorer recognition performance. This study provides novel support that deviant functional activation and connectivity involving the right insula, a hub of the salience network, appears to participate in disrupting metamemory functioning in alcoholics. Compromised FOK performance might result from disturbance of the switching mechanism between brain networks serving self-referential processes (i.e., DMN network) and networks serving externally-driven activities like memory monitoring (i.e., fronto-parietal network). Thus, compromise in insular network coupling could be a neural mechanism underlying anosognosia for subtle mnemonic impairment in nonamnesic alcoholism. PMID- 28806709 TI - In vivo kinematics of early-stage osteoarthritic knees during pivot and squat activities. AB - Kinematic changes have been shown to accompany severe knee osteoarthritis, but no studies have analyzed early-stage osteoarthritic knee kinematics in the transverse plane during functional activities. The purpose of this study was to analyze kinematics of early-stage osteoarthritic knees using model registration techniques. Fifteen early-stage osteoarthritic knees from eight females with a mean age of 52 years old (range, 43-57years old) were involved in this study. A radiologist confirmed with plain radiographs that knees had Kellgren-Lawrence grade-1 or -2 arthritic changes. Fluoroscopic images of squat and pivot activities were recorded for each subject. Three-dimensional surface models of the distal femur and proximal tibia were created from CT images, and anatomic coordinate systems were embedded in each model. The three-dimensional position and orientation of the femur and the tibia were determined using model-image registration techniques, and tibial anteroposterior translation and internal/external rotation relative to the femur were calculated. The contact points of the medial and lateral femoral condyle were also computed. Compared to healthy knees, osteoarthritic knees showed lateral contact points that were significantly shifted anteriorly in both pivot (P<0.001) and squat (P=0.001) activities and greater tibial external rotation in pivot activity (P=0.007). The medial contact point location was similar to healthy knees, but the amount of anteroposterior translation was smaller (P<0.001). These kinematic changes might change stress distributions in the medial compartment during weight-bearing activities. The changes in kinematics possibly have some influence on initiation or progression of knee osteoarthritis. PMID- 28806710 TI - Foot strike pattern in children during shod-unshod running. AB - The purpose of this study was to determine the foot strike patterns (FSPs) and neutral support (no INV/EVE and no foot rotation) in children, as well as to determine the influence of shod/unshod conditions and sex. A total of 713 children, aged 6 to 16 years, participated in this study (Age=10.28+/-2.71years, body mass index [BMI]=19.70+/-3.91kg/m2, 302 girls and 411 boys). A sagittal and frontal-plane video (240Hz) was recorded using a high-speed camcorder, to record the following variables: rearfoot strike (RFS), midfoot strike (MFS), forefoot strike (FFS), inversion/eversion (INV/EVE) and foot rotation on initial contact. RFS prevalence was similar between boys and girls in both shod and unshod conditions. In the unshod condition there was a significant reduction (p<0.001) of RFS prevalence both in boys (shod condition=83.95% vs. 62.65% unshod condition) and in girls (shod condition=87.85% vs. 62.70% unshod condition). No significant differences were found in INV/EVE and foot rotation between sex groups. In the unshod condition there was a significant increase (p<0.001) of neutral support (no INV/EVE) both in boys (shod condition=12.55% vs. 22.22% unshod condition) and in girls (shod condition=17.9% vs. 28.15% unshod condition). In addition, in the unshod condition there is a significant reduction (p<0.001) of neutral support (no foot rotation) both in boys (shod condition=21.55% vs. 11.10% unshod condition) and in girls (shod condition=21.05% vs. 11.95% unshod condition). In children, RFS prevalence is lower than adult's population. Additionally, barefoot running reduced the prevalence of RFS and INV/EVE, however increased foot rotation. PMID- 28806711 TI - The potential of an automated system to identify the upper limb component of a controlled sitting posture. AB - Full trunk control in sitting is demonstrated only when the head-trunk are aligned and upper limbs remain free of contact from mechanical support. These components represent a Controlled Kinetic Chain and can be evaluated in people with neuromotor disability using the Segmental Assessment of Trunk Control (SATCo) when a therapist provides manual trunk support at different segmental levels. However, the SATCo, as with other clinical assessments of control, is subjective. The SATCo was translated to objective rules relating the position of the hands and elbows to the head-trunk and then tested to determine the extent to which this automated objective method replicated the clinical judgement. Clinical evaluation used video to determine whether the upper limb was free of mechanical support while the objective evaluation used 3D motion capture of the trunk and upper limbs with a classification rule. The agreement between clinical and objective classification was calculated for three conditions of a distance-from support-surface threshold parameter in five healthy adults and five children with cerebral palsy. The unfitted (zero-threshold values) method replicated the clinical judgement in part (68.26%+/-15.7, adults, 48.3%+/-33.9 children). The fitted (level-of-support determined) agreement showed that the process could be refined using trial specific parameters (88.32%+/-5.3 adults, 89.84%+/-10.2 children). The fixed-values agreement showed high values when using general group parameters (80.80%+/-3.1 adults, 74.31%+/-21.5 children). This objective classification of the upper limb component of trunk control largely captures the clinical evaluation. It provides the first stages in development of a clinically friendly fully automated method. PMID- 28806712 TI - Association Between Background Parenchymal Enhancement and Pathologic Complete Remission Throughout the Neoadjuvant Chemotherapy in Breast Cancer Patients. AB - PURPOSE: To retrospectively investigate the quantitative background parenchymal enhancement (BPE) of the contralateral normal breast in patients with unilateral invasive breast cancer throughout multiple monitoring points of neoadjuvant chemotherapy (NAC) and to further determine whether BPE is associated with tumor response, especially at the early stage of NAC. MATERIALS AND METHODS: A total of 90 patients with unilateral breast cancer who then received six or eight cycles of NAC before surgery were analyzed retrospectively. BPE was measured in dynamic contrast-enhanced MRI at baseline and after 2nd, 4th, and 6th NAC, respectively. Correlation between BPE and tumor size was analyzed, and the association between pathologic complete remission (pCR) and BPE was also analyzed. RESULTS: The BPE of contralateral normal breast showed a constant reduction throughout NAC therapy regardless of the menopausal status (P<.001 in all). Both the BPEs and the changes of BPE in each of the three monitoring points were significantly correlated with those in tumor size (P<.05 in all), and the reduction of BPE after 2nd NAC had the largest diagnostic value for pCR (AUC=0.726, P<.001), particularly in hormonal receptor (HR)-negative patients (OR=0.243, 95%CI=0.083 to 0.706, P=.009). CONCLUSION: The BPE of contralateral normal breast had a constant decreased tendency similar to the change of tumor size in NAC. Reduction of BPE at the early stage of NAC was positively associated with pCR, especially in HR-negative status. PMID- 28806713 TI - Activity groups for persons with dementia: Personal predictors of participation, engagement and mood. AB - This study examined the relationship between personal characteristics and attendance, engagement, sleep, and mood outcomes of persons with dementia participating in group activities. The purpose of this study is to examine which persons with dementia benefit most from group interventions. Sixty-nine persons with dementia were observed by research and therapeutic recreation staff during 10 types of group activities (reading aloud with discussion, choral-singing, baking, creative storytelling, brain games, active games, exercise, reminiscence poetry, holiday newsletter, and holiday discussions) on multiple outcomes (attendance duration, sleep, engagement, active participation, attitude, and positive mood). Correlations between these outcomes and personal characteristics (demographics, functional and medical characteristics, personal preferences for group activities) were conducted. Variables with significant correlations were then entered into regression analyses. Many of the personal characteristics were significantly correlated with the outcomes. Cognitive function was the most consistent predictor of all outcomes. Personal characteristics, particularly cognitive function, can predict the responses of persons with dementia during group activities. PMID- 28806714 TI - F-norm distance metric based robust 2DPCA and face recognition. AB - Two-dimensional principal component analysis (2DPCA) employs squared F-norm as the distance metric for dimensionality reduction. It is commonly known that squared F-norm is sensitive to the presence of outliers. To address this problem, we use F-norm instead of squared F-norm as the distance metric in the objective function and develop a non-greedy algorithm, which has a closed-form solution in each iteration and can maximize the criterion function, to solve the optimal solution. Our approach not only is robust to outliers but also well characterizes the geometric structure of data. Experimental results on several face databases illustrate that our method is more effective and robust than the other robust 2DPCA algorithms. PMID- 28806715 TI - Recurrent networks with soft-thresholding nonlinearities for lightweight coding. AB - A long-standing and influential hypothesis in neural information processing is that early sensory networks adapt themselves to produce efficient codes of afferent inputs. Here, we show how a nonlinear recurrent network provides an optimal solution for the efficient coding of an afferent input and its history. We specifically consider the problem of producing lightweight codes, ones that minimize both l1 and l2 constraints on sparsity and energy, respectively. When embedded in a linear coding paradigm, this problem results in a non-smooth convex optimization problem. We employ a proximal gradient descent technique to develop the solution, showing that the optimal code is realized through a recurrent network endowed with a nonlinear soft thresholding operator. The training of the network connection weights is readily achieved through gradient-based local learning. If such learning is assumed to occur on a slower time-scale than the (faster) recurrent dynamics, then the network as a whole converges to an optimal set of codes and weights via what is, in effect, an alternative minimization procedure. Our results show how the addition of thresholding nonlinearities to a recurrent network may enable the production of lightweight, history-sensitive encoding schemes. PMID- 28806716 TI - Efficient hardware implementation of the subthalamic nucleus-external globus pallidus oscillation system and its dynamics investigation. AB - Modeling and implementation of the nonlinear neural system with physiologically plausible dynamic behaviors are considerably meaningful in the field of computational neuroscience. This study introduces a novel hardware platform to investigate the dynamical behaviors within the nonlinear subthalamic nucleus external globus pallidus system. In order to reduce the implementation complexities, a hardware-oriented conductance-based subthalamic nucleus (STN) model is presented, which can reproduce accurately the dynamical characteristics of biological conductance-based STN cells. The accuracy of the presented design is ensured by the investigation of the dynamical properties including bifurcation analysis and phase portraits. Hardware implementation on a field-programmable gate array (FPGA) demonstrates that the proposed digital system can mimic the relevant biological characteristics with higher performance, which means the resource cost is cut down and the computational efficiency is improved by introducing the multiplier-less techniques including novel "shift MUL" approach and piecewise linear approximation. The central pattern generator (CPG) coupled by the presented system is also investigated, which can be applied as an embedded intelligent system in the field of neuro-robotic engineering. PMID- 28806717 TI - Efficient construction of sparse radial basis function neural networks using L1 regularization. AB - This paper investigates the construction of sparse radial basis function neural networks (RBFNNs) for classification problems. An efficient two-phase construction algorithm (which is abbreviated as TPCLR1 for simplicity) is proposed by using L1 regularization. In the first phase, an improved maximum data coverage (IMDC) algorithm is presented for the initialization of RBF centers and widths. Then a specialized Orthant-Wise Limited-memory Quasi-Newton (sOWL-QN) method is employed to perform simultaneous network pruning and parameter optimization in the second phase. The advantages of TPCLR1 lie in that better generalization performance is guaranteed with higher model sparsity, and the required storage space and testing time are much reduced. Besides these, only the regularization parameter and the maximum number of function evaluations are required to be prescribed, then the entire construction procedure becomes automatic. The learning algorithm is verified by several classification benchmarks with different levels of complexity. The experimental results show that an appropriate value of the regularization parameter is easy to find without using costly cross validation, and the proposed TPCLR1 offers an efficient procedure to construct sparse RBFNN classifiers with good generalization performance. PMID- 28806718 TI - Stochastic separation theorems. AB - The problem of non-iterative one-shot and non-destructive correction of unavoidable mistakes arises in all Artificial Intelligence applications in the real world. Its solution requires robust separation of samples with errors from samples where the system works properly. We demonstrate that in (moderately) high dimension this separation could be achieved with probability close to one by linear discriminants. Based on fundamental properties of measure concentration, we show that for M1-theta, where 1>theta>0 is a given small constant. Exact values of a,b>0 depend on the probability distribution that determines how the random M-element sets are drawn, and on the constant theta. These stochastic separation theorems provide a new instrument for the development, analysis, and assessment of machine learning methods and algorithms in high dimension. Theoretical statements are illustrated with numerical examples. PMID- 28806719 TI - Comparison of reactive oxygen species metabolism during grape berry development between 'Kyoho' and its early ripening bud mutant 'Fengzao'. AB - Enzymes and non-enzyme elements related to the metabolism of reactive oxygen species (ROS), such as catalase (CAT), superoxide dismutase (SOD), ascorbic acid (AsA), glutathione (GSH), NADPH oxidase (NOX), hydrogen peroxide (H2O2), superoxide anion (O2-), lipoxygenase (LOX) and malondialdehyde (MDA), were measured in 'Kyoho' and its early ripening bud mutant 'Fengzao' to compare ROS level changes and investigate the potential roles of ROS in grape berry development and the ripening process. In addition, the anthocyanin and sugar contents as well as berry diameter were also investigated at different berry development stages. The results showed that the H2O2 content and LOX activity exhibited obviously different trends between 'Fengzao' and 'Kyoho' during the berry development stages. Before berry softening, the SOD activity, LOX activity and H2O2 content were significant lower in 'Fengzao' than in 'Kyoho', but there were no significant differences in the production rate of O2-, ROS scavengers (CAT, AsA, GSH) and MDA content between them, which indicated that the higher oxidation status in 'Fengzao'. It may promote the faster development of 'Fengzao' berry than 'Kyoho' before berry softening (EL31-33). The significant higher LOX and CAT activities at EL-34, as well as significant higher LOX activity and H2O2 content at EL-35 in 'Fengzao' than in 'Kyoho' indicated H2O2 was acted as the appropriate oxidative stress factor and the signal molecule to further accelerate the berry ripening of 'Fengzao'. The increasing O2- and H2O2 after EL-35 in 'Fengzao' further promoted the ripening process. Furthermore, after the spraying of 300 MUmol/L H2O2 solution on 'Kyoho' at EL-31 stage, the berries matured 15 days earlier than the untreated. Evidence in this study indicated that the overall oxidation status (ROS levels) in 'Fengzao' is higher than in 'Kyoho' and H2O2 could promote the early ripening of 'Kyoho' berry. PMID- 28806720 TI - Exploration of acute genotoxic effects and antigenotoxic potential of gambogic acid using Allium cepa assay. AB - The plant derived xanthanoid gambogic acid (GA) is well known for its anticancer activity. To date, biological actions of GA on plant system have not been reported. In the present study, we evaluated the potential acute genotoxic activity of GA, and its antigenotoxic potential against H2O2 induced genetic damage using Allium cepa root chromosomal aberration assay under hydroponic conditions. There was a significant decrease in the percentage of mitotic index/prophase index with the increase in clastogenicity percentage in a dose and time-dependent manner when Allium cepa bulbs were exposed to GA at 0.1 mM and 1 mM concentration for 1 h, 2 h, and 4 h. Total genomic DNA integrity analyzed by agarose gel electrophoresis and cell viability revealed pronounced DNA degradation and loss of viability when treated with 1 mM GA for 4 h. In situ histochemical localization by Schiff's staining and 3, 3-diaminobenzidine confirmed increased levels of lipid peroxide and H2O2 in GA treated roots respectively. Scanning electron microscopy and FT-IR suggested surface damage and biomolecular intervention of GA in root cells. In addition, possible antigenotoxic effect of GA at lower concentration was explored by employing standard assays using H2O2. We observed a higher percentage of nuclear lesions upon treatment with 3% H2O2 (97.21 +/- 0.76) that reduced significantly after modulatory treatment with 0.01 mM GA (70.44 +/- 4.42). The results suggest that GA is a Janus-faced compound as it demonstrates a genotoxic activity at higher doses and genoprotective action at lower precise doses. PMID- 28806721 TI - The effect of visual perturbation upon femoral acceleration during the single and bilateral squat. AB - OBJECTIVES: Record femoral accelerations using a smartphone accelerometer attached to the distal thigh during single-legged (SLS) and bilateral squats, and each squat condition occurred under two visual conditions: 1) normal vision and 2) visual perturbation with stroboscopic glasses. DESIGN: Repeated-measures cross over with counter-balanced order for four total conditions. SETTING: Laboratory. PARTICIPANTS: 22 females and 16 males without lower extremity pathologies. MAIN OUTCOME MEASURES: 2D video assessment of frontal plane projection angle, composite amplitude index of smartphone accelerometer measurements, and bivariate correlations between these two outcomes. RESULTS: A significant interaction was found for stance x vision as the difference occurred within the SLS stance condition between the visual conditions (Normal: 9.85 +/- 0.06; Stroboscopic: 9.86 +/- 0.07; p = 0.008 with an adjusted alpha of 0.25). Femoral accelerations were not associated (r = -0.07) with 2D video assessment of frontal plane projection angle. CONCLUSIONS: Similar to other studies using smartphone accelerometry to assess movement quality, we found that the device could detect movement variation via femoral accelerations during SLS with visual perturbation in healthy individuals. PMID- 28806722 TI - Spontaneous, modality-general abstraction of a ratio scale. AB - The existence of a generalized magnitude system in the human mind and brain has been studied extensively but remains elusive because it has not been clearly defined. Here we show that one possibility is the representation of relative magnitudes via ratio calculations: ratios are a naturally dimensionless or abstract quantity that could qualify as a common currency for magnitudes measured on vastly different psychophysical scales and in different sensory modalities like size, number, duration, and loudness. In a series of demonstrations based on comparisons of item sequences, we demonstrate that subjects spontaneously use knowledge of inter-item ratios within and across sensory modalities and across magnitude domains to rate sequences as more or less similar on a sliding scale. Moreover, they rate ratio-preserved sequences as more similar to each other than sequences in which only ordinal relations are preserved, indicating that subjects are aware of differences in levels of relative-magnitude information preservation. The ubiquity of this ability across many different magnitude pairs, even those sharing no sensory information, suggests a highly general code that could qualify as a candidate for a generalized magnitude representation. PMID- 28806723 TI - Prevalence and location of tobacco smoke exposure outside the home in adults and children in the United States. AB - OBJECTIVES: Tobacco smoke exposure (TSE) is associated with many adverse health outcomes. The goal of this study was to provide insight into the prevalence and location of self-reported TSE outside the home for US adults and children. STUDY DESIGN: Cross-sectional survey. METHODS: Data from a nationally representative sample of US adults from 2014 were included. Participants who responded that they smelled smoke during the past seven days in various settings were considered to have been exposed to TSE. Parents were asked about TSE exposure of their children. RESULTS: Sixty-nine percent of all adults reported TSE outside their home in the past seven days. The most common exposure location among adults was on a public sidewalk and outside the doorway of a building (both 33%). Thirty three percent of parents reported outside the home TSE for their children in the past seven days. Most commonly, the reported exposure was 'In some other place(s)' (16%), followed by at a relative's house (10%). CONCLUSIONS: This study reports on TSE outside the home in a wide variety of settings and a broad range of ages in a nationally representative US sample. A high proportion of US adults and children are exposed to TSE outside the home in indoor, outdoor, public, and private settings. Smoke-free laws, clinical interventions, education, and a change in social norms are required to stop TSE. PMID- 28806724 TI - One-star rating for a five-star program: evaluating 'Hospital Compare'. AB - OBJECTIVES: For healthcare systems of any size, it is important to minimize costs while maximizing outcomes. One idea of how to achieve these goals has been the reduction in hospital-related complications, including infection and surgical complications, among others. In the United States, policy makers recently adopted the 'Hospital Compare' program as a way to encourage consumers and improve hospitals. This article evaluates the effectiveness of this policy. STUDY DESIGN: This article uses an observed cohort study of most US hospitals across four different indices. METHODS: Each observed hospital was evaluated at least once each year over a span of three years for rates of hospital-acquired infections and compared to what reasonably ought to have been the rate based on hospital factors. Hospitals poorly rated in the base year were compared against remaining institutions for their ability to meet national benchmarks in future years. RESULTS: Despite government attempts to show individuals the comparative quality of hospitals, there is little evidence that these informed consumer choices were substantially enough to motivate changes. Across most metrics used, poorly rated hospitals were unlikely to improve at rates that the designers of Hospital Compare would have envisioned. CONCLUSIONS: Although it is possible that the effects could shift over time, it is unlikely that the Hospital Compare program properly understood and anticipated patient calculus for choosing a hospital. Technical complexity and other issues further undermined the program. Despite this, the goal of reducing complications is worthwhile, but a different strategy should be pursued. PMID- 28806725 TI - Link between perceived smoking behaviour at school and students smoking status: a large survey among Italian adolescents. AB - OBJECTIVES: To investigate a possible link between sociodemographic factors, the perception of smoking habits at school and smoking status of Italian adolescents attending secondary school. STUDY DESIGN: The study was a cross-sectional study. METHODS: An anonymous online survey was employed to gather information on age, gender, smoking status and to examine the perception of smoking behaviour on the school premises. Chi-squared and Kruskal-Wallis tests were performed for the univariate analysis and logistic and multinomial regressions for the multivariate analysis. RESULTS: The statistical analyses included 1889 students. Univariate analysis showed significant differences concerning knowledge between smoker and non-smoker concerning the harmfulness of smoking (P < 0.001). According to the multivariate analysis smokers had a higher perception of teacher, principal or janitor smoking at school (odds ratio: 1.54 [95% confidence interval 1.26-1.89]). Students older than 19 years most often begin smoking because their friends smoke compared with younger students (adjusted odds ratio: 1.18 [95% confidence interval 0.48-2.89]). CONCLUSION: School environment and behaviour of role models play a crucial part in student smoking. To prevent and reduce youth tobacco smoking, not merely the presence of preventive measures is important but greater attention needs to be placed on the enforcement of smoking policies. PMID- 28806726 TI - Replication fork slowing and stalling are distinct, checkpoint-independent consequences of replicating damaged DNA. AB - In response to DNA damage during S phase, cells slow DNA replication. This slowing is orchestrated by the intra-S checkpoint and involves inhibition of origin firing and reduction of replication fork speed. Slowing of replication allows for tolerance of DNA damage and suppresses genomic instability. Although the mechanisms of origin inhibition by the intra-S checkpoint are understood, major questions remain about how the checkpoint regulates replication forks: Does the checkpoint regulate the rate of fork progression? Does the checkpoint affect all forks, or only those encountering damage? Does the checkpoint facilitate the replication of polymerase-blocking lesions? To address these questions, we have analyzed the checkpoint in the fission yeast Schizosaccharomyces pombe using a single-molecule DNA combing assay, which allows us to unambiguously separate the contribution of origin and fork regulation towards replication slowing, and allows us to investigate the behavior of individual forks. Moreover, we have interrogated the role of forks interacting with individual sites of damage by using three damaging agents-MMS, 4NQO and bleomycin-that cause similar levels of replication slowing with very different frequency of DNA lesions. We find that the checkpoint slows replication by inhibiting origin firing, but not by decreasing fork rates. However, the checkpoint appears to facilitate replication of damaged templates, allowing forks to more quickly pass lesions. Finally, using a novel analytic approach, we rigorously identify fork stalling events in our combing data and show that they play a previously unappreciated role in shaping replication kinetics in response to DNA damage. PMID- 28806727 TI - Formation of friable embryogenic callus in cassava is enhanced under conditions of reduced nitrate, potassium and phosphate. AB - Agrobacterium-mediated transformation is an important research tool for the genetic improvement of cassava. The induction of friable embryogenic callus (FEC) is considered as a key step in cassava transformation. In the present study, the media composition was optimized for enhancing the FEC induction, and the effect of the optimized medium on gene expression was evaluated. In relative comparison to MS medium, results demonstrated that using a medium with reducing nutrition (a 10-fold less concentration of nitrogen, potassium, and phosphate), the increased amount of vitamin B1 (10 mg/L) and the use of picrolam led to reprogram non-FEC to FEC. Gene expression analyses revealed that FEC on modified media increased the expression of genes related to the regulation of polysaccharide biosynthesis and breakdown of cell wall components in comparison to FEC on normal CIM media, whereas the gene expression associated with energy flux was not dramatically altered. It is hypothesized that we reprogram non-FEC to FEC under low nitrogen, potassium and phosphate and high vitamin B1. These findings were more effective in inducing FEC formation than the previous protocol. It might contribute to development of an efficient transformation strategy in cassava. PMID- 28806728 TI - Costing evidence for health care decision-making in Austria: A systematic review. AB - BACKGROUND: With rising healthcare costs comes an increasing demand for evidence informed resource allocation using economic evaluations worldwide. Furthermore, standardization of costing and reporting methods both at international and national levels are imperative to make economic evaluations a valid tool for decision-making. The aim of this review is to assess the availability and consistency of costing evidence that could be used for decision-making in Austria. It describes systematically the current economic evaluation and costing studies landscape focusing on the applied costing methods and their reporting standards. Findings are discussed in terms of their likely impacts on evidence based decision-making and potential suggestions for areas of development. METHODS: A systematic literature review of English and German language peer reviewed as well as grey literature (2004-2015) was conducted to identify Austrian economic analyses. The databases MEDLINE, EMBASE, SSCI, EconLit, NHS EED and Scopus were searched. Publication and study characteristics, costing methods, reporting standards and valuation sources were systematically synthesised and assessed. RESULTS: A total of 93 studies were included. 87% were journal articles, 13% were reports. 41% of all studies were full economic evaluations, mostly cost-effectiveness analyses. Based on relevant standards the most commonly observed limitations were that 60% of the studies did not clearly state an analytical perspective, 25% of the studies did not provide the year of costing, 27% did not comprehensively list all valuation sources, and 38% did not report all applied unit costs. CONCLUSION: There are substantial inconsistencies in the costing methods and reporting standards in economic analyses in Austria, which may contribute to a low acceptance and lack of interest in economic evaluation informed decision making. To improve comparability and quality of future studies, national costing guidelines should be updated with more specific methodological guidance and a national reference cost library should be set up to allow harmonisation of valuation methods. PMID- 28806729 TI - ERK2 and JNK1 contribute to TNF-alpha-induced IL-8 expression in synovial fibroblasts. AB - Tumor necrosis factor alpha (TNF-alpha) induces the expression and secretion of interleukin 8 (IL-8), which contributes to synovitis in rheumatoid arthritis (RA). To elucidate the mechanism of the onset of RA, we used synovial fibroblasts without autoimmune inflammatory diseases and investigated MAPK signaling pathways in TNF-alpha-induced IL-8 expression. Synovial fibroblasts isolated from healthy dogs were characterized by flow cytometry, which were positive for the fibroblast markers CD29, CD44, and CD90 but negative for the hematopoietic cell markers CD14, CD34, CD45, and HLA-DR. TNF-alpha stimulated the secretion and mRNA expression of IL-8 in a time- and dose-dependent manner. ERK and JNK inhibitors attenuated TNF-alpha-induced IL-8 expression and secretion. TNF-alpha induced the phosphorylation of ERK1/2 and JNK1/2. TNF-alpha-induced IL-8 expression was attenuated both in ERK2- and JNK1-knockdown cells. TNF-alpha-induced ERK1/2 or JNK1/2 was observed in ERK2- or JNK1-knockdown cells, respectively, showing that there is no crosstalk between ERK2 and JNK1 pathways. These observations indicate that the individual activation of ERK2 and JNK1 pathways contributes to TNF-alpha induced IL-8 expression in synovial fibroblasts, which appears to be involved in the progress in RA. PMID- 28806730 TI - A systems approach reveals distinct metabolic strategies among the NCI-60 cancer cell lines. AB - The metabolic phenotype of cancer cells is reflected by the metabolites they consume and by the byproducts they release. Here, we use quantitative, extracellular metabolomic data of the NCI-60 panel and a novel computational method to generate 120 condition-specific cancer cell line metabolic models. These condition-specific cancer models used distinct metabolic strategies to generate energy and cofactors. The analysis of the models' capability to deal with environmental perturbations revealed three oxotypes, differing in the range of allowable oxygen uptake rates. Interestingly, models based on metabolomic profiles of melanoma cells were distinguished from other models through their low oxygen uptake rates, which were associated with a glycolytic phenotype. A subset of the melanoma cell models required reductive carboxylation. The analysis of protein and RNA expression levels from the Human Protein Atlas showed that IDH2, which was an essential gene in the melanoma models, but not IDH1 protein, was detected in normal skin cell types and melanoma. Moreover, the von Hippel-Lindau tumor suppressor (VHL) protein, whose loss is associated with non-hypoxic HIF stabilization, reductive carboxylation, and promotion of glycolysis, was uniformly absent in melanoma. Thus, the experimental data supported the predicted role of IDH2 and the absence of VHL protein supported the glycolytic and low oxygen phenotype predicted for melanoma. Taken together, our approach of integrating extracellular metabolomic data with metabolic modeling and the combination of different network interrogation methods allowed insights into the metabolism of cells. PMID- 28806731 TI - Climatic niche of Selinum alatum (Apiaceae, Selineae), a new invasive plant species in Central Europe and its alterations according to the climate change scenarios: Are the European mountains threatened by invasion? AB - In recent years, a few established populations of Selinum alatum have been found in the Eastern Carpathians outside its native range that is the Caucasus and the Armenian Highlands. The species is spreading predominantly in Poland where it can outcompete native plants in certain cases. This study addresses a potential climatic niche of the plant with the special aims to illuminate future spreading and indicate areas suitable for invasion. Our results show that the extent of the favourable habitat of the species is broader than currently known. This suggests that the plant has the ability to become a potential new element in some semi natural or disturbed ecosystems associated with mountainous areas, especially in Central and Southern Europe. Future (2070) models mostly rendered similar suitability maps, but showed slight differences over particular areas and a contraction of suitable habitats, mainly in the northern part of the non-native range. PMID- 28806733 TI - The interaction between endogenous 30S ribosomal subunit protein S11 and Cucumber mosaic virus LS2b protein affects viral replication, infection and gene silencing suppressor activity. AB - Cucumber mosaic virus (CMV) is a model virus for plant-virus protein interaction and mechanism research because of its wide distribution, high-level of replication and simple genome structure. The 2b protein is a multifunctional protein encoded by CMV that suppresses RNA silencing-based antiviral defense and contributes to CMV virulence in host plants. In this report, 12 host proteins were identified as CMV LS2b binding partners using the yeast two-hybrid screen system from the Arabidopsis thaliana cDNA library. Among the host proteins, 30S ribosomal subunit protein S11 (RPS11) was selected for further studies. The interaction between LS2b and full-length RPS11 was confirmed using the yeast two hybrid system. Bimolecular fluorescence complementation (BIFC) assays observed by confocal laser microscopy and Glutathione S-transferase (GST) pull-down assays were used to verify the interaction between endogenous NbRPS11 and viral CMVLS2b both in vivo and in vitro. TRV-based gene silencing vector was used to knockdown NbRPS11 transcription, and immunoblot analysis revealed a decline in infectious viral RNA replication and a decrease in CMV infection in RPS11 down-regulated Nicotiana benthamiana plants. Thus, the knockdown of RPS11 likely inhibited CMV replication and accumulation. The gene silencing suppressor activity of CMV2b protein was reduced by the RPS11 knockdown. This study demonstrated that the function of viral LS2b protein was remarkably affected by the interaction with host RPS11 protein. PMID- 28806732 TI - Loss of the chromatin modifier Kdm2aa causes BrafV600E-independent spontaneous melanoma in zebrafish. AB - KDM2A is a histone demethylase associated with transcriptional silencing, however very little is known about its in vivo role in development and disease. Here we demonstrate that loss of the orthologue kdm2aa in zebrafish causes widespread transcriptional disruption and leads to spontaneous melanomas at a high frequency. Fish homozygous for two independent premature stop codon alleles show reduced growth and survival, a strong male sex bias, and homozygous females exhibit a progressive oogenesis defect. kdm2aa mutant fish also develop melanomas from early adulthood onwards which are independent from mutations in braf and other common oncogenes and tumour suppressors as revealed by deep whole exome sequencing. In addition to effects on translation and DNA replication gene expression, high-replicate RNA-seq in morphologically normal individuals demonstrates a stable regulatory response of epigenetic modifiers and the specific de-repression of a group of zinc finger genes residing in constitutive heterochromatin. Together our data reveal a complex role for Kdm2aa in regulating normal mRNA levels and carcinogenesis. These findings establish kdm2aa mutants as the first single gene knockout model of melanoma biology. PMID- 28806734 TI - Mental health among single and partnered parents in South Korea. AB - OBJECTIVE: This study compares the mental health of single parents relative to partnered parents and assesses the contribution of the social and demographic factors to this difference, examining the gender difference in it. METHODS: We analyzed 12,024 single and partnered subjects, aged 30-59 years, living with children, aged 0-19 years, drawn from the 4th, 5th, and 6th Korea National Health and Nutrition Examination Survey (KNHANES) dataset in South Korea conducted from 2007-2013. Mental health was evaluated by self-reported questionnaires including depressive mood for recent two weeks, presence of suicidal ideation, and the Korean version of the Alcohol Use Disorder Identification Test. Covariates included age, physical illness, socioeconomic status (family income, recipient of national basic livelihood guarantees, educational level, house ownership, job, and residential area), family structure, and support (co-residence of another adult). Multiple logistic regression was carried out and the explained fractions of each covariate was calculated. RESULTS: Single parents had significantly poorer mental health than their partnered counterparts, with odds ratio (OR) of 2.02 (95% confidence interval (CI) 1.56-2.63) for depressive symptoms, 1.69 (95% CI 1.27-2.25) for suicidal ideation, and 1.74 (95% CI 1.38-2.20) for any of the three mental health statuses (suspicious depression, suicidal ideation, and alcohol dependence) after controlling for the covariates. The odds of depressive symptoms (OR = 3.13, 95% CI 2.50-3.93) and suicidal ideation (OR = 2.50, 95% CI 1.97-3.17) among both single fathers and mothers were higher than partnered parents. However, the odds of alcohol dependence were 3.6 times higher among single mothers than partnered mothers (OR = 3.58, 95% CI 1.81-7.08) and were 1.4 times greater among single fathers than partnered fathers (OR = 1.35, 95% CI 0.81 2.25). Socio-economic status explained more than 50% (except for substance use disorders) of the poorer mental health in single parents. These results were more remarkable for single fathers than for single mothers except for alcohol dependence. However, physical illness, family structure, and support made only minor contributions to single parents' mental health. CONCLUSIONS: This study demonstrates that single parents have poorer mental health than partnered parents. Although lower SES is an important factor explaining poorer mental health in single parents, there are other factors we cannot explain about their poor mental health. Therefore, we should pay proper regard to identifying other factors affecting mental health and to establishing policies to support single parents. PMID- 28806735 TI - Molecular characterization and multi-locus genotypes of Enterocytozoon bieneusi from captive red kangaroos (Macropus Rufus) in Jiangsu province, China. AB - Enterocytozoon bieneusi is the most common pathogen of microsporidian species infecting humans worldwide. Although E. bieneusi has been found in a variety of animal hosts, information on the presence of E. bieneusi in captive kangaroos in China is limited. The present study was aimed at determining the occurrence and genetic diversity of E. bieneusi in captive kangaroos. A total of 61 fecal specimens (38 from red kangaroos and 23 from grey kangaroos) were collected from Nanjing Hongshan Forest Zoo and Hongshan Kangaroo Breeding Research Base, Jiangsu province, China. Using the nested PCR amplification ITS gene of rRNA of E. bieneusi, totally 23.0% (14/61) of tested samples were PCR-positive with three genotypes (i.e. one known genotype, CHK1, and two novel genotypes, CSK1 and CSK2). Multi-locus sequence typing using three microsatellites (MS1, MS3, and MS7) and one minisatellite (MS4) revealed one, five, two, and one types at these four loci, respectively. In phylogenetic analysis, the two genotypes, CHK1 and CSK1, were clustered into a new group of unknown zoonotic potential, and the novel genotype CSK2 was clustered into a separate clade with PtEb and PtEbIX. To date, this is the first report on the presence of E. bieneusi in captive red kangaroos in Jiangsu province, China. Furthermore, a high degree of genetic diversity was observed in the E. bieneusi genotype and seven MLGs (MLG1-7) were found in red kangaroos. Our findings suggest that infected kangaroo may act as potential reservoirs of E. bieneusi and be source to transmit infections to other animal. PMID- 28806736 TI - Unravelling the interplay of sphingolipids and TGF-beta signaling in the human corneal stroma. AB - PURPOSE: To delineate the role of Sphingolipids (SPLs) in the human cornea and their cross-talks with transforming growth factor beta (TGF-beta) in order to develop novel, non-invasive therapies. METHODS: Human corneal fibroblasts (HCFs) were harvested from healthy donors, stimulated with Vitamin C to promote extracellular matrix assembly, treated with exogenous sphingosine-1-phosphate (S1P) or sphingosine kinase inhibitor 2 (SPHK I2) and isolated after 4 weeks for further analysis. RESULTS: Data showed that S1P led to a significant decrease in cellular migration where SPHK I2 just delayed it for 24h. Significant modulation of the sphingolipid pathway was also noted. Sphingosine kinase-1 (SphK1) was significantly downregulated upon exogenous stimulation with S1P at a concentration of 5MUM and Sphingosine kinase-2 (SphK2) was also significantly downregulated at concentrations of 0.01MUM, 0.1MUM, and 5MUM; whereas no effects were observed upon stimulation with SPHK I2. S1PR3 was significantly downregulated by 0.1MUM and 5MUM S1P and upregulated by 5MUM and 10MUM SPHK I2. Furthermore, both S1P and SPHK I2 regulated corneal fibrosis markers such as alpha-smooth muscle actin, collagen I, III, and V. We also investigated the interplay between two TGF-beta isoforms and S1P/SPHK I2 treatments and found that TGF-beta1 and TGF-beta3 were both significantly upregulated with the 0.1MUM S1P but were significantly downregulated with the 5MUM S1P concentration. When TGF beta1 was compared directly to TGF-beta3 expression, we observed that TGF-beta3 was significantly downregulated compared to TGF-beta1 in the 5MUM concentration of S1P. No changes were observed upon SPHK I2 treatment. CONCLUSION: Our study delineates the role of sphingolipids in the human cornea and highlights their different activities based on the cell/tissue type. PMID- 28806737 TI - Effectiveness of the 13-valent pneumococcal conjugate vaccine in preventing invasive pneumococcal disease in children aged 7-59 months. A matched case control study. AB - BACKGROUND: The 13-valent pneumococcal conjugate vaccine (PCV13) was licensed based on the results of immunogenicity studies and correlates of protection derived from randomized clinical trials of the 7-valent conjugate pneumococcal vaccine. We assessed the vaccination effectiveness (VE) of the PCV13 in preventing invasive pneumococcal disease (IPD) in children aged 7-59 months in a population with suboptimal vaccination coverage of 55%. METHODS: The study was carried out in children with IPD admitted to three hospitals in Barcelona (Spain) and controls matched by hospital, age, sex, date of hospitalization and underlying disease. Information on the vaccination status was obtained from written medical records. Conditional logistic regression was made to estimate the adjusted VE and 95% confidence intervals (CI). RESULTS: 169 cases and 645 controls were included. The overall VE of >=1 doses of PCV13 in preventing IPD due to vaccine serotypes was 75.8% (95% CI, 54.1-87.2) and 90% (95% CI, 63.9 97.2) when >=2 doses before 12 months, two doses on or after 12 months or one dose on or after 24 months, were administered. The VE of >=1 doses was 89% (95% CI, 42.7-97.9) against serotype 1 and 86.0% (95% CI, 51.2-99.7) against serotype 19A. Serotype 3 showed a non-statistically significant effectiveness (25.9%; 95% CI, -65.3 to 66.8). CONCLUSIONS: The effectiveness of >=1 doses of PCV13 in preventing IPD caused by all PCV13 serotypes in children aged 7-59 months was good and, except for serotype 3, the effectiveness of >=1 doses against the most frequent PCV13 serotypes causing IPD was high when considered individually. PMID- 28806738 TI - Partial IGF-1 deficiency is sufficient to reduce heart contractibility, angiotensin II sensibility, and alter gene expression of structural and functional cardiac proteins. AB - Circulating levels of IGF-1 may decrease under several circumstances like ageing, metabolic syndrome, and advanced cirrhosis. This reduction is associated with insulin resistance, dyslipidemia, progression to type 2 diabetes, and increased risk for cardiovascular diseases. However, underlying mechanisms between IGF-1 deficiency and cardiovascular disease remain elusive. The specific aim of the present work was to study whether the partial IGF-1 deficiency influences heart and/or coronary circulation, comparing vasoactive factors before and after of ischemia-reperfusion (I/R). In addition, histology of the heart was performed together with cardiac gene expression for proteins involved in structure and function (extracellular matrix, contractile proteins, active peptides); carried out using microarrays, followed by RT-qPCR confirmation of the three experimental groups. IGF-1 partial deficiency is associated to a reduction in contractility and angiotensin II sensitivity, interstitial fibrosis as well as altered expression pattern of genes involved in extracellular matrix proteins, calcium dynamics, and cardiac structure and function. Although this work is descriptive, it provides a clear insight of the impact that partial IGF-1 deficiency on the heart and establishes this experimental model as suitable for studying cardiac disease mechanisms and exploring therapeutic options for patients under IGF-1 deficiency conditions. PMID- 28806739 TI - Combined effects of O3 and UV radiation on secondary metabolites and endogenous hormones of soybean leaves. AB - Enhanced ultraviolet radiation (UV) and elevated tropospheric ozone (O3) may individually cause reductions in the growth and productivity of important agricultural crops. However, research regarding their combined effects on important agricultural crops is still scarce, especially on changes in secondary metabolites and endogenous hormones, which are important protective substances and signal components that control plant responses to environment stresses. In this study, using an experimental setup of open top chambers, we monitored the responses of seed yield per plant, leaf secondary metabolites and leaf endogenous hormones under the stress of elevated O3 and enhanced UV radiation individually, as well as their combined stress. The results indicated that elevated O3 (110 +/- 10 nmol mol-1 for 8 hours per day) and enhanced UV radiation (1.73 kJ h-1 m-2) significantly decreased seed yield per plant. Concentrations of rutin, queretin and total flavonoids were significantly increased under the elevated O3 treatment or the enhanced UV radiation treatment or the combination treatment at flowering and podding stages, and concentrations of rutin, queretin and total flavonoids showed significant correlations with seed yield per plant. Concentrations of ABA and IAA decreased under the three treatments. There was a significant positive correlation between the ABA concentration and seed yield and a negative correlation between the IAA concentration and seed yield. We concluded that the combined stress of elevated O3 and UV radiation significantly decreased seed yield per plant. Yield reduction was associated with changes in the concentrations of flavonoids, ABA and IAA in soybean leaves. The effects of the combined O3 and UV stress were always greater than those of the individual stresses alone. PMID- 28806740 TI - Community- and government-managed marine protected areas increase fish size, biomass and potential value. AB - Government-managed marine protected areas (MPAs) can restore small fish stocks, but have been heavily criticized for excluding resource users and creating conflicts. A promising but less studied alternative are community-managed MPAs, where resource users are more involved in MPA design, implementation and enforcement. Here we evaluated effects of government- and community-managed MPAs on the density, size and biomass of seagrass- and coral reef-associated fish, using field surveys in Kenyan coastal lagoons. We also assessed protection effects on the potential monetary value of fish; a variable that increases non linearly with fish body mass and is particularly important from a fishery perspective. We found that two recently established community MPAs (< 1 km2 in size, <= 5 years of protection) harbored larger fish and greater total fish biomass than two fished (open access) areas, in both seagrass beds and coral reefs. As expected, protection effects were considerably stronger in the older and larger government MPAs. Importantly, across management and habitat types, the protection effect on the potential monetary value of the fish was much stronger than the effects on fish biomass and size (6.7 vs. 2.6 and 1.3 times higher value in community MPAs than in fished areas, respectively). This strong effect on potential value was partly explained by presence of larger (and therefore more valuable) individual fish, and partly by higher densities of high-value taxa (e.g. rabbitfish). In summary, we show that i) small and recently established community-managed MPAs can, just like larger and older government-managed MPAs, play an important role for local conservation of high-value fish, and that ii) these effects are equally strong in coral reefs as in seagrass beds; an important habitat too rarely included in formal management. Consequently, community-managed MPAs could benefit both coral reef and seagrass ecosystems and provide spillover of valuable fish to nearby fisheries. PMID- 28806741 TI - Risk of cancer in patients with genital warts: A nationwide, population-based cohort study in Taiwan. AB - BACKGROUND: Condyloma acuminata currently affects around 1% of sexually active adults, and its incidence is increasing. The coexistence of genital warts (GW) and certain cancers and an association between human papillomavirus (HPV) and various malignancies have been reported. Therefore, we conducted this large national study to analyze the risk of malignancies among men and women with GW in Taiwan. METHODS AND FINDINGS: Between January 2000 and December 2013, approximately 3 million patients were reported to the National Health Insurance Research Database of Taiwan. Of these patients, 21,763 were diagnosed with GW. In the same time period, a total of 213,541 cancer cases were reported to the registry, of which 1002 were recorded among patients with GW. The age-specific incidence rates of GW and standardized incidence ratios (SIRs) of malignancies compared to the general population were calculated. Women acquired GW earlier than men, with a mean age at diagnosis of 32.63+/-12.78 years. The highest incidence rate for both genders peaked at 20-29 years. Of the 1002 patients with GW and malignancies, the SIR was 1.95 (95%CI 1.83-2.07). The most markedly increased risk was found for HPV-related cancers, with a SIR of 9.74 (95%CI 3.70 15.77). Significantly elevated risks were also noted for smoking-related cancers, anogenital cancers, cervix in situ, colon, rectum, lung, kidney, and prostate cancers. Most cancers developed within 10 years after the diagnosis of GW. CONCLUSIONS: Patients with GW have an increased risk of HPV-related cancers, especially anogenital malignancies in Taiwan. The elevated risk of other cancers highlights differences in exposure and risk factors among patients with GW compared to the general population. Cancer screening and HPV vaccination programs should be emphasized for at-risk patients. PMID- 28806743 TI - Correction: Gene expression and immunohistochemical analyses of mKast suggest its late pupal and adult-specific functions in the honeybee brain. AB - [This corrects the article DOI: 10.1371/journal.pone.0176809.]. PMID- 28806742 TI - Dissociating maternal responses to sad and happy facial expressions of their own child: An fMRI study. AB - BACKGROUND: Maternal sensitive behavior depends on recognizing one's own child's affective states. The present study investigated distinct and overlapping neural responses of mothers to sad and happy facial expressions of their own child (in comparison to facial expressions of an unfamiliar child). METHODS: We used functional MRI to measure dissociable and overlapping activation patterns in 27 healthy mothers in response to happy, neutral and sad facial expressions of their own school-aged child and a gender- and age-matched unfamiliar child. To investigate differential activation to sad compared to happy faces of one's own child, we used interaction contrasts. During the scan, mothers had to indicate the affect of the presented face. After scanning, they were asked to rate the perceived emotional arousal and valence levels for each face using a 7-point Likert-scale (adapted SAM version). RESULTS: While viewing their own child's sad faces, mothers showed activation in the amygdala and anterior cingulate cortex whereas happy facial expressions of the own child elicited activation in the hippocampus. Conjoint activation in response to one's own child happy and sad expressions was found in the insula and the superior temporal gyrus. CONCLUSIONS: Maternal brain activations differed depending on the child's affective state. Sad faces of the own child activated areas commonly associated with a threat detection network, whereas happy faces activated reward related brain areas. Overlapping activation was found in empathy related networks. These distinct neural activation patterns might facilitate sensitive maternal behavior. PMID- 28806744 TI - Sustainability of knowledge implementation in a low- and middle- income context: Experiences from a facilitation project in Vietnam targeting maternal and neonatal health. AB - BACKGROUND: In a previous trial in Vietnam, a facilitation strategy to secure evidence-based practice in primary care resulted in reduced neonatal mortality over a period of three years. While little is known as to what ensures sustainability in the implementation of community-based strategies, the aim of this study was to investigate factors promoting or hindering implementation, and sustainability of knowledge implementation strategies, by means of the former Neonatal Knowledge Into Practice (NeoKIP) trial. METHODS: In 2014 we targeted all levels in the Vietnamese healthcare system: six individual interviews with representatives at national, provincial and district levels, and six focus group discussions with representatives at the commune level. The interviews were transcribed verbatim, translated to English, and analysed using inductive and deductive thematic analysis. RESULTS: To achieve successful implementation and sustained effect of community-based knowledge implementation strategies, engagement of leaders and key stakeholders at all levels of the healthcare system is vital-prior to, during and after a project. Implementation and sustainability require thorough needs assessment, tailoring of the intervention, and consideration of how to attain and manage funds. The NeoKIP trial was characterised by a high degree of engagement at the primary healthcare system level. Further, three years post trial, maternal and neonatal care was still high on the agenda for healthcare workers and leaders, even though primary aspects such as stakeholder engagement at all levels, and funding had been incomplete or lacking. CONCLUSIONS: The current study illustrates factors to support successful implementation and sustain effects of community-based strategies in projects in low- and middle-income settings; some but not all factors were represented during the post-NeoKIP era. Most importantly, trials in this and similar contexts require deliberate management throughout and beyond the project lifetime, and engagement of key stakeholders, in order to promote and sustain knowledge implementation. PMID- 28806745 TI - Persistent mycobacteria evade an antibacterial program mediated by phagolysosomal TLR7/8/MyD88 in human primary macrophages. AB - Pathogenic mycobacteria reside in macrophages where they avoid lysosomal targeting and degradation through poorly understood mechanisms proposed to involve arrest of phagosomal maturation at an early endosomal stage. A clear understanding of how this relates to host defenses elicited from various intracellular compartments is also missing and can only be studied using techniques allowing single cell and subcellular analyses. Using confocal imaging of human primary macrophages infected with Mycobacterium avium (Mav) we show evidence that Mav phagosomes are not arrested at an early endosomal stage, but mature to a (LAMP1+/LAMP2+/CD63+) late endosomal/phagolysosomal stage where inflammatory signaling and Mav growth restriction is initiated through a mechanism involving Toll-like receptors (TLR) 7 and 8, the adaptor MyD88 and transcription factors NF-kappaB and IRF-1. Furthermore, a fraction of the mycobacteria re-establish in a less hostile compartment (LAMP1-/LAMP2-/CD63-) where they not only evade destruction, but also recognition by TLRs, growth restriction and inflammatory host responses that could be detrimental for intracellular survival and establishment of chronic infections. PMID- 28806746 TI - Selective small-chemical inhibitors of protein arginine methyltransferase 5 with anti-lung cancer activity. AB - Protein arginine methyltransferase 5 (PRMT5) plays critical roles in a wide variety of biological processes, including tumorigenesis. By screening a library of small chemical compounds, we identified eight compounds that selectively inhibit the PRMT5 enzymatic activity, with IC50 values ranging from 0.1 to 6 MUM. Molecular docking simulation and site-directed mutagenesis indicated that identified compounds target the substrate-binding site in PRMT5. Treatment of lung cancer cells with identified inhibitors led to inhibition of the symmetrical arginine methylation of SmD3 and histones and the cellular proliferation. Oral administration of the inhibitor demonstrated antitumor activity in a lung tumor xenograft model. Thus, identified PRMT5-specific small-molecule inhibitors would help elucidate the biological roles of PRMT5 and serve as lead compounds for future drug development. PMID- 28806748 TI - Temperature effects on gene expression and morphological development of European eel, Anguilla anguilla larvae. AB - Temperature is important for optimization of rearing conditions in aquaculture, especially during the critical early life history stages of fish. Here, we experimentally investigated the impact of temperature (16, 18, 20, 22 and 24 degrees C) on thermally induced phenotypic variability, from larval hatch to first-feeding, and the linked expression of targeted genes [heat shock proteins (hsp), growth hormone (gh) and insulin-like growth factors (igf)] associated to larval performance of European eel, Anguilla anguilla. Temperature effects on larval morphology and gene expression were investigated throughout early larval development (in real time from 0 to 18 days post hatch) and at specific developmental stages (hatch, jaw/teeth formation, and first-feeding). Results showed that hatch success, yolk utilization efficiency, survival, deformities, yolk utilization, and growth rates were all significantly affected by temperature. In real time, increasing temperature from 16 to 22 degrees C accelerated larval development, while larval gene expression patterns (hsp70, hsp90, gh and igf-1) were delayed at cold temperatures (16 degrees C) or accelerated at warm temperatures (20-22 degrees C). All targeted genes (hsp70, hsp90, gh, igf-1, igf-2a, igf-2b) were differentially expressed during larval development. Moreover, expression of gh was highest at 16 degrees C during the jaw/teeth formation, and the first-feeding developmental stages, while expression of hsp90 was highest at 22 degrees C, suggesting thermal stress. Furthermore, 24 degrees C was shown to be deleterious (resulting in 100% mortality), while 16 degrees C and 22 degrees C (~50 and 90% deformities respectively) represent the lower and upper thermal tolerance limits. In conclusion, the high survival, lowest incidence of deformities at hatch, high yolk utilization efficiency, high gh and low hsp expression, suggest 18 degrees C as the optimal temperature for offspring of European eel. Furthermore, our results suggest that the still enigmatic early life history stages of European eel may inhabit the deeper layer of the Sargasso Sea and indicate vulnerability of this critically endangered species to increasing ocean temperature. PMID- 28806747 TI - Low lamin A expression in lung adenocarcinoma cells from pleural effusions is a pejorative factor associated with high number of metastatic sites and poor Performance status. AB - The type V intermediate filament lamins are the principal components of the nuclear matrix, including the nuclear lamina. Lamins are divided into A-type and B-type, which are encoded by three genes, LMNA, LMNB1, and LMNB2. The alternative splicing of LMNA produces two major A-type lamins, lamin A and lamin C. Previous studies have suggested that lamins are involved in cancer development and progression. A-type lamins have been proposed as biomarkers for cancer diagnosis, prognosis, and/or follow-up. The aim of the present study was to investigate lamins in cancer cells from metastatic pleural effusions using immunofluorescence, western blotting, and flow cytometry. In a sub-group of lung adenocarcinomas, we found reduced expression of lamin A but not of lamin C. The reduction in lamin A expression was correlated with the loss of epithelial membrane antigen (EMA)/MUC-1, an epithelial marker that is involved in the epithelial to mesenchymal transition (EMT). Finally, the lamin A expression was inversely correlated with the number of metastatic sites and the WHO Performance status, and association of pleural, bone and lung metastatic localizations was more frequent when lamin A expression was reduced. In conclusion, low lamin A but not lamin C expression in pleural metastatic cells could represent a major actor in the development of metastasis, associated with EMT and could account for a pejorative factor correlated with a poor Performance status. PMID- 28806749 TI - Defining the genetic susceptibility to cervical neoplasia-A genome-wide association study. AB - A small percentage of women with cervical HPV infection progress to cervical neoplasia, and the risk factors determining progression are incompletely understood. We sought to define the genetic loci involved in cervical neoplasia and to assess its heritability using unbiased unrelated case/control statistical approaches. We demonstrated strong association of cervical neoplasia with risk and protective HLA haplotypes that are determined by the amino-acids carried at positions 13 and 71 in pocket 4 of HLA-DRB1 and position 156 in HLA-B. Furthermore, 36% (standard error 2.4%) of liability of HPV-associated cervical pre-cancer and cancer is determined by common genetic variants. Women in the highest 10% of genetic risk scores have approximately >7.1% risk, and those in the highest 5% have approximately >21.6% risk, of developing cervical neoplasia. Future studies should examine genetic risk prediction in assessing the risk of cervical neoplasia further, in combination with other screening methods. PMID- 28806751 TI - The relative age effect reversal among the National Hockey League elite. AB - Like many sports in adolescence, junior hockey is organized by age groups. Typically, players born after December 31st are placed in the subsequent age cohort and as a result, will have an age advantage over those players born closer to the end of the year. While this relative age effect (RAE) has been well established in junior hockey and other professional sports, the long-term impact of this phenomenon is not well understood. Using roster data on North American National Hockey League (NHL) players from the 2008-2009 season to the 2015-2016 season, we document a RAE reversal-players born in the last quarter of the year (October-December) score more and command higher salaries than those born in the first quarter of the year. This reversal is even more pronounced among the NHL "elite." We find that among players in the 90th percentile of scoring, those born in the last quarter of the year score about 9 more points per season than those born in the first quarter. Likewise, elite players in the 90th percentile of salary who are born in the last quarter of the year earn 51% more pay than players born at the start of the year. Surprisingly, compared to players at the lower end of the performance distribution, the RAE reversal is about three to four times greater among elite players. PMID- 28806750 TI - Characterization of novel bangle lectin from Photorhabdus asymbiotica with dual sugar-binding specificity and its effect on host immunity. AB - Photorhabdus asymbiotica is one of the three recognized species of the Photorhabdus genus, which consists of gram-negative bioluminescent bacteria belonging to the family Morganellaceae. These bacteria live in a symbiotic relationship with nematodes from the genus Heterorhabditis, together forming a complex that is highly pathogenic for insects. Unlike other Photorhabdus species, which are strictly entomopathogenic, P. asymbiotica is unique in its ability to act as an emerging human pathogen. Analysis of the P. asymbiotica genome identified a novel fucose-binding lectin designated PHL with a strong sequence similarity to the recently described P. luminescens lectin PLL. Recombinant PHL exhibited high affinity for fucosylated carbohydrates and the unusual disaccharide 3,6-O-Me2-Glcbeta1-4(2,3-O-Me2)Rhaalpha-O-(p-C6H4)-OCH2CH2NH2 from Mycobacterium leprae. Based on its crystal structure, PHL forms a seven-bladed beta-propeller assembling into a homo-dimer with an inter-subunit disulfide bridge. Investigating complexes with different ligands revealed the existence of two sets of binding sites per monomer-the first type prefers l-fucose and its derivatives, whereas the second type can bind d-galactose. Based on the sequence analysis, PHL could contain up to twelve binding sites per monomer. PHL was shown to interact with all types of red blood cells and insect haemocytes. Interestingly, PHL inhibited the production of reactive oxygen species induced by zymosan A in human blood and antimicrobial activity both in human blood, serum and insect haemolymph. Concurrently, PHL increased the constitutive level of oxidants in the blood and induced melanisation in haemolymph. Our results suggest that PHL might play a crucial role in the interaction of P. asymbiotica with both human and insect hosts. PMID- 28806753 TI - Accelerometer-derived physical activity and sedentary time by cancer type in the United States. AB - The 2003-2004 and 2005-2006 cycles of the National Health and Nutrition Examination Survey (NHANES) were among the first population-level studies to incorporate objectively measured physical activity and sedentary behavior, allowing for greater understanding of these behaviors. However, there has yet to be a comprehensive examination of these data in cancer survivors, including short and long-term survivors of all cancer types. Therefore, the purpose of this analysis was to use these data to describe activity behaviors in short- and long term cancer survivors of various types. A secondary aim was to compare activity patterns of cancer survivors to that of the general population. Cancer survivors (n = 508) and age-matched individuals not diagnosed with cancer (n = 1,016) were identified from a subsample of adults with activity measured by accelerometer. Physical activity and sedentary behavior were summarized across cancer type and demographics; multivariate regression was used to evaluate differences between survivors and those not diagnosed with cancer. On average, cancer survivors were 61.4 (95% CI: 59.6, 63.2) years of age; 57% were female. Physical activity and sedentary behavior patterns varied by cancer diagnosis, demographic variables, and time since diagnosis. Survivors performed 307 min/day of light-intensity physical activity (95% CI: 295, 319), 16 min/day of moderate-vigorous intensity activity (95% CI: 14, 17); only 8% met physical activity recommendations. These individuals also reported 519 (CI: 506, 532) minutes of sedentary time, with 86 (CI: 84, 88) breaks in sedentary behavior per day. Compared to non-cancer survivors, after adjustment for potential confounders, survivors performed less light-intensity activity (P = 0.01), were more sedentary (P = 0.01), and took fewer breaks in sedentary time (P = 0.04), though there were no differences in any other activity variables. These results suggest that cancer survivors are insufficiently active. Relative to adults of similar age not diagnosed with cancer, they engage in more sedentary time with fewer breaks. As such, sedentary behavior and light-intensity activity may be important intervention targets, particularly for those for whom moderate-to-vigorous activity is not well accepted. PMID- 28806752 TI - The ESCRT-III pathway facilitates cardiomyocyte release of cBIN1-containing microparticles. AB - Microparticles (MPs) are cell-cell communication vesicles derived from the cell surface plasma membrane, although they are not known to originate from cardiac ventricular muscle. In ventricular cardiomyocytes, the membrane deformation protein cardiac bridging integrator 1 (cBIN1 or BIN1+13+17) creates transverse tubule (t-tubule) membrane microfolds, which facilitate ion channel trafficking and modulate local ionic concentrations. The microfold-generated microdomains continuously reorganize, adapting in response to stress to modulate the calcium signaling apparatus. We explored the possibility that cBIN1-microfolds are externally released from cardiomyocytes. Using electron microscopy imaging with immunogold labeling, we found in mouse plasma that cBIN1 exists in membrane vesicles about 200 nm in size, which is consistent with the size of MPs. In mice with cardiac-specific heterozygous Bin1 deletion, flow cytometry identified 47% less cBIN1-MPs in plasma, supporting cardiac origin. Cardiac release was also evidenced by the detection of cBIN1-MPs in medium bathing a pure population of isolated adult mouse cardiomyocytes. In human plasma, osmotic shock increased cBIN1 detection by enzyme-linked immunosorbent assay (ELISA), and cBIN1 level decreased in humans with heart failure, a condition with reduced cardiac muscle cBIN1, both of which support cBIN1 release in MPs from human hearts. Exploring putative mechanisms of MP release, we found that the membrane fission complex endosomal sorting complexes required for transport (ESCRT)-III subunit charged multivesicular body protein 4B (CHMP4B) colocalizes and coimmunoprecipitates with cBIN1, an interaction enhanced by actin stabilization. In HeLa cells with cBIN1 overexpression, knockdown of CHMP4B reduced the release of cBIN1-MPs. Using truncation mutants, we identified that the N-terminal BAR (N-BAR) domain in cBIN1 is required for CHMP4B binding and MP release. This study links the BAR protein superfamily to the ESCRT pathway for MP biogenesis in mammalian cardiac ventricular cells, identifying elements of a pathway by which cytoplasmic cBIN1 is released into blood. PMID- 28806754 TI - Short-term prediction of solar energy in Saudi Arabia using automated-design fuzzy logic systems. AB - Solar energy is considered as one of the main sources for renewable energy in the near future. However, solar energy and other renewable energy sources have a drawback related to the difficulty in predicting their availability in the near future. This problem affects optimal exploitation of solar energy, especially in connection with other resources. Therefore, reliable solar energy prediction models are essential to solar energy management and economics. This paper presents work aimed at designing reliable models to predict the global horizontal irradiance (GHI) for the next day in 8 stations in Saudi Arabia. The designed models are based on computational intelligence methods of automated-design fuzzy logic systems. The fuzzy logic systems are designed and optimized with two models using fuzzy c-means clustering (FCM) and simulated annealing (SA) algorithms. The first model uses FCM based on the subtractive clustering algorithm to automatically design the predictor fuzzy rules from data. The second model is using FCM followed by simulated annealing algorithm to enhance the prediction accuracy of the fuzzy logic system. The objective of the predictor is to accurately predict next-day global horizontal irradiance (GHI) using previous-day meteorological and solar radiation observations. The proposed models use observations of 10 variables of measured meteorological and solar radiation data to build the model. The experimentation and results of the prediction are detailed where the root mean square error of the prediction was approximately 88% for the second model tuned by simulated annealing compared to 79.75% accuracy using the first model. This results demonstrate a good modeling accuracy of the second model despite that the training and testing of the proposed models were carried out using spatially and temporally independent data. PMID- 28806755 TI - Acquired von Willebrand syndrome in cardiogenic shock patients on mechanical circulatory microaxial pump support. AB - Early use of mechanical circulatory support, e.g. veno-arterial extracorporeal membrane oxygenation (ECMO) or left ventricular unloading by microaxial pump in refractory cardiogenic shock is recommended in current guidelines. Development of acquired von Willebrand Syndrome (AVWS) in patients with left ventricular assist devices (LVADs) and ECMO has been reported. There is an increasing number of patients treated with the Impella(r) CP microaxial pump for left ventricular unloading. However, the prevalence of AVWS in these high risk patients is unknown and needs to be determined. We therefore screened 21 patients (68 +/- 11years) treated with Impella(r) (17 for cardiogenic shock, 4 for protected PCI) for the presence of AVWS by determining von Willebrand factor multimers, VWF collagen binding capacity and VWF antigen. During the time course of Impella(r) support, 20/21 patients (95%) developed AVWS (mean duration of support: 135 +/- 114 hours, mean time from device implantation to first diagnosis of AVWS: 10.6 +/- 10.8 hours). Our data indicate that AVWS is a common phenomenon during left ventricular unloading via microaxial pump support. Thus, AVWS has to be considered as contributing factor for potential bleeding complications in this high risk patient population, especially in the context of dual antiplatelet therapy. PMID- 28806756 TI - Generic, scalable and decentralized fault detection for robot swarms. AB - Robot swarms are large-scale multirobot systems with decentralized control which means that each robot acts based only on local perception and on local coordination with neighboring robots. The decentralized approach to control confers number of potential benefits. In particular, inherent scalability and robustness are often highlighted as key distinguishing features of robot swarms compared with systems that rely on traditional approaches to multirobot coordination. It has, however, been shown that swarm robotics systems are not always fault tolerant. To realize the robustness potential of robot swarms, it is thus essential to give systems the capacity to actively detect and accommodate faults. In this paper, we present a generic fault-detection system for robot swarms. We show how robots with limited and imperfect sensing capabilities are able to observe and classify the behavior of one another. In order to achieve this, the underlying classifier is an immune system-inspired algorithm that learns to distinguish between normal behavior and abnormal behavior online. Through a series of experiments, we systematically assess the performance of our approach in a detailed simulation environment. In particular, we analyze our system's capacity to correctly detect robots with faults, false positive rates, performance in a foraging task in which each robot exhibits a composite behavior, and performance under perturbations of the task environment. Results show that our generic fault-detection system is robust, that it is able to detect faults in a timely manner, and that it achieves a low false positive rate. The developed fault-detection system has the potential to enable long-term autonomy for robust multirobot systems, thus increasing the usefulness of robots for a diverse repertoire of upcoming applications in the area of distributed intelligent automation. PMID- 28806757 TI - Impact of interaction style and degree on the evolution of cooperation on Barabasi-Albert scale-free network. AB - In this work, we study an evolutionary prisoner's dilemma game (PDG) on Barabasi Albert scale-free networks with limited player interactions, and explore the effect of interaction style and degree on cooperation. The results show that high degree preference interaction, namely the most applicable interaction in the real world, is less beneficial for emergence of cooperation on scale-free networks than random interaction. Besides, cooperation on scale-free networks is enhanced with the increase of interaction degree regardless whether the interaction is high-degree preference or random. If the interaction degree is very low, the cooperation level on scale-free networks is much lower than that on regular ring networks, which is against the common belief that scale-free networks must be more beneficial for cooperation. Our analysis indicates that the interaction relations, the strategy and the game payoff of high-connectivity players play important roles in the evolution of cooperation on scale-free networks. A certain number of interactions are necessary for scale-free networks to exhibit strong capability of facilitating cooperation. Our work provides important insight for members on how to interact with others in a social organization. PMID- 28806758 TI - Developmental vascular remodeling defects and postnatal kidney failure in mice lacking Gpr116 (Adgrf5) and Eltd1 (Adgrl4). AB - GPR116 (ADGRF5) and ELTD1 (ADGRL4) belong to different subfamilies of the adhesion G-protein-coupled receptor group but are both expressed in endothelial cells. We therefore analyzed their functions in mice lacking these receptors. While loss of GPR116 or ELTD1 alone had no obvious effect on cardiovascular or kidney function, mice lacking both, GPR116 and ELTD1, showed malformations of the aortic arch arteries and the cardiac outflow tract leading to perinatal lethality in about 50% of the mutants. In addition to cardiovascular malformations, surviving mice developed renal thrombotic microangiopathy as well as hemolysis and splenomegaly, and their lifespan was significantly reduced. Loss of GPR116 and ELTD1 specifically in endothelial cells or neural crest-derived cells did not recapitulate any of the phenotypes observed in GPR116-ELTD1 double deficient mice, indicating that loss of GPR116 and ELTD1 expressed by other cells accounts for the observed cardiovascular and renal defects. PMID- 28806759 TI - Peculiar Genes Selection: A new features selection method to improve classification performances in imbalanced data sets. AB - High-Throughput technologies provide genomic and trascriptomic data that are suitable for biomarker detection for classification purposes. However, the high dimension of the output of such technologies and the characteristics of the data sets analysed represent an issue for the classification task. Here we present a new feature selection method based on three steps to detect class-specific biomarkers in case of high-dimensional data sets. The first step detects the differentially expressed genes according to the experimental conditions tested in the experimental design, the second step filters out the features with low discriminative power and the third step detects the class-specific features and defines the final biomarker as the union of the class-specific features. The proposed procedure is tested on two microarray datasets, one characterized by a strong imbalance between the size of classes and the other one where the size of classes is perfectly balanced. We show that, using the proposed feature selection procedure, the classification performances of a Support Vector Machine on the imbalanced data set reach a 82% whereas other methods do not exceed 73%. Furthermore, in case of perfectly balanced dataset, the classification performances are comparable with other methods. Finally, the Gene Ontology enrichments performed on the signatures selected with the proposed pipeline, confirm the biological relevance of our methodology. The download of the package with the implementation of Peculiar Genes Selection, 'PGS', is available for R users at: http://github.com/mbeccuti/PGS. PMID- 28806760 TI - Endothelial activation and dysfunction in severe fever with thrombocytopenia syndrome. AB - BACKGROUND: Pathogenesis of severe fever with thrombocytopenia syndrome (SFTS) has not been well described yet. Recent studies indicate that SFTSV could replicate in endothelial cells. Here we performed a case-control study to determine whether endothelial activation/dysfunction occurred in SFTSV infection and to identify the biomarkers reflecting endothelial dysfunction. METHODOLOGY/PRINCIPAL FINDINGS: In a case-control study of 134 SFTS patients and 68 healthy controls, serum levels of plasminogen activator inhibitor 1, tissue plasminogen activator, P-selectin, platelet endothelial cell adhesion molecular, CD40 ligand, E-selectin, vascular endothelial growth factor A, serum amyloid antigen 1 (SAA-1) and vascular cell adhesion molecular 1 were significantly enhanced in the patients than the controls (all P<0.05), indicating the occurrence of endothelial activation/dysfunction in SFTS. The intercellular adhesion molecular 1 (ICAM-1) and SAA-1 at the convalescent phase were also significantly associated with severe patients, after adjusting for the potential confounders. The odds ratio was estimated to be 3.364 (95% CI 1.074-10.534) for ICAM-1, and 1.881 (95% CI 1.166-3.034) for SAA-1, respectively. Cutoff value of 1.1*107 pg/mL SAA-1 or 1.2*106 pg/mL ICAM-1 were found to have moderate power of predicting fatal cases. CONCLUSIONS: The endothelial dysfunction may be one of the pathogenic mechanism of SFTS. The serum levels of ICAM-1 and SAA-1 might be used to predict adverse outcome. PMID- 28806761 TI - Transcriptome analysis of PDGFRalpha+ cells identifies T-type Ca2+ channel CACNA1G as a new pathological marker for PDGFRalpha+ cell hyperplasia. AB - Platelet-derived growth factor receptor alpha (PDGFRalpha)+ cells are distributed into distinct morphological groups within the serosal, muscular, and submucosal layers as well as the myenteric and deep muscular plexi. PDGFRalpha+ cells directly interact with interstitial cells of Cajal (ICC) and smooth muscle cells (SMC) in gastrointestinal smooth muscle tissue. These three cell types, SMC, ICC, and PDGFRalpha+ cells (SIP cells), form an electrical syncytium, which dynamically regulates gastrointestinal motility. We have previously reported the transcriptomes of SMC and ICC. To complete the SIP cell transcriptome project, we obtained transcriptome data from jejunal and colonic PDGFRalpha+ cells. The PDGFRalpha+ cell transcriptome data were added to the Smooth Muscle Genome Browser that we previously built for the genome-scale gene expression data of ICC and SMC. This browser provides a comprehensive reference for all transcripts expressed in SIP cells. By analyzing the transcriptomes, we have identified a unique set of PDGFRalpha+ cell signature genes, growth factors, transcription factors, epigenetic enzymes/regulators, receptors, protein kinases/phosphatases, and ion channels/transporters. We demonstrated that the low voltage-dependent T type Ca2+ channel Cacna1g gene was particularly expressed in PDGFRalpha+ cells in the intestinal serosal layer in mice. Expression of this gene was significantly induced in the hyperplasic PDGFRalpha+ cells of obstructed small intestine in mice. This gene was also over-expressed in colorectal cancer, Crohn's disease, and diverticulitis in human patients. Taken together, our data suggest that Cacna1g exclusively expressed in serosal PDGFRalpha+ cells is a new pathological marker for gastrointestinal diseases. PMID- 28806762 TI - A Becn1 mutation mediates hyperactive autophagic sequestration of amyloid oligomers and improved cognition in Alzheimer's disease. AB - Impairment of the autophagy pathway has been observed during the pathogenesis of Alzheimer's disease (AD), a neurodegenerative disorder characterized by abnormal deposition of extracellular and intracellular amyloid beta (Abeta) peptides. Yet the role of autophagy in Abeta production and AD progression is complex. To study whether increased basal autophagy plays a beneficial role in Abeta clearance and cognitive improvement, we developed a novel genetic model to hyperactivate autophagy in vivo. We found that knock-in of a point mutation F121A in the essential autophagy gene Beclin 1/Becn1 in mice significantly reduces the interaction of BECN1 with its inhibitor BCL2, and thus leads to constitutively active autophagy even under non-autophagy-inducing conditions in multiple tissues, including brain. Becn1F121A-mediated autophagy hyperactivation significantly decreases amyloid accumulation, prevents cognitive decline, and restores survival in AD mouse models. Using an immunoisolation method, we found biochemically that Abeta oligomers are autophagic substrates and sequestered inside autophagosomes in the brain of autophagy-hyperactive AD mice. In addition to genetic activation of autophagy by Becn1 gain-of-function, we also found that ML246, a small-molecule autophagy inducer, as well as voluntary exercise, a physiological autophagy inducer, exert similar Becn1-dependent protective effects on Abeta removal and memory in AD mice. Taken together, these results demonstrate that genetically disrupting BECN1-BCL2 binding hyperactivates autophagy in vivo, which sequestrates amyloid oligomers and prevents AD progression. The study establishes new approaches to activate autophagy in the brain, and reveals the important function of Becn1-mediated autophagy hyperactivation in the prevention of AD. PMID- 28806763 TI - Genome-wide regulation of electro-acupuncture on the neural Stat5-loss-induced obese mice. AB - Acupuncture is reported to be effective in treating obesity related illnesses, but its mechanism is still unclear. To investigate this mechanism we applied electro-acupuncture (EA) in a mouse model of obesity and used RNA-seq to identify molecular consequences. Deletion of the transcription factor STAT5 from neurons (Stat5NKO) led to obesity. Acupuncture, in turn, reduced body weight and the ratio of epididymal white adipose tissue (Epi-WAT) to body weight, and it also decreased plasma concentrations of glucose, triglyceride, and cholesterol. In addition, EA increased cold endurance of Stat5NKO obese mice. EA reversed altered gene expressions in the hypothalamus and Epi-WAT, especially in the hypothalamus in Stat5NKO obese mice. This study provides, for the first time, insight into genomic networks of obesity and their modulation by electro-acupuncture, which in turn reveals potential mechanisms that explain acupuncture-induced weight-loss. PMID- 28806764 TI - Do labeled versus unlabeled treatments of alternatives' names influence stated choice outputs? Results from a mode choice study. AB - Discrete choice experiments have been widely applied to elicit behavioral preferences in the literature. In many of these experiments, the alternatives are named alternatives, meaning that they are naturally associated with specific names. For example, in a mode choice study, the alternatives can be associated with names such as car, taxi, bus, and subway. A fundamental issue that arises in stated choice experiments is whether to treat the alternatives' names as labels (that is, labeled treatment), or as attributes (that is, unlabeled treatment) in the design as well as the presentation phases of the choice sets. In this research, we investigate the impact of labeled versus unlabeled treatments of alternatives' names on the outcome of stated choice experiments, a question that has not been thoroughly investigated in the literature. Using results from a mode choice study, we find that the labeled or the unlabeled treatment of alternatives' names in either the design or the presentation phase of the choice experiment does not statistically affect the estimates of the coefficient parameters. We then proceed to measure the influence toward the willingness-to pay (WTP) estimates. By using a random-effects model to relate the conditional WTP estimates to the socioeconomic characteristics of the individuals and the labeled versus unlabeled treatments of alternatives' names, we find that: a) Given the treatment of alternatives' names in the presentation phase, the treatment of alternatives' names in the design phase does not statistically affect the estimates of the WTP measures; and b) Given the treatment of alternatives' names in the design phase, the labeled treatment of alternatives' names in the presentation phase causes the corresponding WTP estimates to be slightly higher. PMID- 28806765 TI - PKA activity is essential for relieving the suppression of hyphal growth and appressorium formation by MoSfl1 in Magnaporthe oryzae. AB - In the rice blast fungus Magnaporthe oryzae, the cAMP-PKA pathway regulates surface recognition, appressorium turgor generation, and invasive growth. However, deletion of CPKA failed to block appressorium formation and responses to exogenous cAMP. In this study, we generated and characterized the cpk2 and cpkA cpk2 mutants and spontaneous suppressors of cpkA cpk2 in M. oryzae. Our results demonstrate that CPKA and CPK2 have specific and overlapping functions, and PKA activity is essential for appressorium formation and plant infection. Unlike the single mutants, the cpkA cpk2 mutant was significantly reduced in growth and rarely produced conidia. It failed to form appressoria although the intracellular cAMP level and phosphorylation of Pmk1 MAP kinase were increased. The double mutant also was defective in plant penetration and Mps1 activation. Interestingly, it often produced fast-growing spontaneous suppressors that formed appressoria but were still non-pathogenic. Two suppressor strains of cpkA cpk2 had deletion and insertion mutations in the MoSFL1 transcription factor gene. Deletion of MoSFL1 or its C-terminal 93-aa (MoSFL1DeltaCT) was confirmed to suppress the defects of cpkA cpk2 in hyphal growth but not appressorium formation or pathogenesis. We also isolated 30 spontaneous suppressors of the cpkA cpk2 mutant in Fusarium graminearum and identified mutations in 29 of them in FgSFL1. Affinity purification and co-IP assays showed that this C-terminal region of MoSfl1 was essential for its interaction with the conserved Cyc8-Tup1 transcriptional co-repressor, which was reduced by cAMP treatment. Furthermore, the S211D mutation at the conserved PKA-phosphorylation site in MoSFL1 partially suppressed the defects of cpkA cpk2. Overall, our results indicate that PKA activity is essential for appressorium formation and proper activation of Pmk1 or Mps1 in M. oryzae, and phosphorylation of MoSfl1 by PKA relieves its interaction with the Cyc8-Tup1 co-repressor and suppression of genes important for hyphal growth. PMID- 28806766 TI - Sublingual immunotherapy (SLIT) for house dust mites does not prevent new allergen sensitization and bronchial hyper-responsiveness in allergic rhinitis children. AB - INTRODUCTION: The aim of this study is to identify the effects of sublingual immunotherapy (SLIT) on immunologic parameters and bronchial-hyper-responsiveness in children with allergic rhinitis to house-dust mite (HDM), through long-term follow-up cohort. METHODS: Among the Allergic Rhinitis Cohort Study for Kids, pediatric patients who visited the hospital for rhinitis symptoms and proven allergy to HDM through skin prick test were studied. In this cohort, 37 patients received SLIT more than 3-years (SLIT group), and 184 patients received only pharmacologic therapy (non-SLIT group) were included in this study. The results of skin prick test, eosinophil percent and count, total immunoglobulin E (IgE), and bronchial provocation test at initial and 3-year followed-up were compared in the two groups. RESULTS: After 3 year follow-up, only the serum eosinophil percent decreased more significantly in SLIT group than that in the non-SLIT group. New-sensitization rate other than HDM between SLIT and non-SLIT group did not show any significant differences. The distribution of sensitized allergen other than HDM showed increasing tendency after 3 years in both groups. Older age and a small number of sensitized allergen affected the improvement of bronchial hyper-responsiveness regardless of SLIT. CONCLUSION: HDM SLIT in allergic rhinitis children for 3 years in Korea does not affect prevention of new sensitization and poly-sensitization rate increment, and improvement of bronchial hyper-responsiveness. PMID- 28806767 TI - Hydrodynamic repulsion of spheroidal microparticles from micro-rough surfaces. AB - Isolation of microparticles and biological cells from mixtures and suspensions is a central problem in a variety of biomedical applications. This problem, for instance, is of an immense importance for microfluidic devices manipulating with whole blood samples. It is instructive to know how the mobility and dynamics of rigid microparticles is altered by the presence of micrometer-size roughness on walls. The presented theoretical study addresses this issue via computer simulations. The approach is based on a combination of the Lattice Boltzmann method for calculating hydrodynamics and the Lagrangian Particle dynamics method to describe the dynamics of cell membranes. The effect of the roughness on the mobility of spheroidal microparticles in a shear fluid flow was quantified. We conclude that mechanical and hydrodynamic interactions lift the particles from the surface and change their mobility. The effect is sensitive to the shape of particles. PMID- 28806768 TI - Design and fabrication of a realistic anthropomorphic heterogeneous head phantom for MR purposes. AB - OBJECTIVE: The purpose of this study is to design an anthropomorphic heterogeneous head phantom that can be used for MRI and other electromagnetic applications. MATERIALS AND METHODS: An eight compartment, physical anthropomorphic head phantom was developed from a 3T MRI dataset of a healthy male. The designed phantom was successfully built and preliminarily evaluated through an application that involves electromagnetic-tissue interactions: MRI (due to it being an available resource). The developed phantom was filled with media possessing electromagnetic constitutive parameters that correspond to biological tissues at ~297 MHz. A preliminary comparison between an in-vivo human volunteer (based on whom the anthropomorphic head phantom was created) and various phantoms types, one being the anthropomorphic heterogeneous head phantom, were performed using a 7 Tesla human MRI scanner. RESULTS: Echo planar imaging was performed and minimal ghosting and fluctuations were observed using the proposed anthropomorphic phantom. The magnetic field distributions (during MRI experiments at 7 Tesla) and the scattering parameter (measured using a network analyzer) were most comparable between the anthropomorphic heterogeneous head phantom and an in-vivo human volunteer. CONCLUSION: The developed anthropomorphic heterogeneous head phantom can be used as a resource to various researchers in applications that involve electromagnetic-biological tissue interactions such as MRI. PMID- 28806769 TI - Effects of statin therapy on clinical outcomes after acute myocardial infarction in patients with advanced renal dysfunction: A propensity score-matched analysis. AB - OBJECTIVE: Lipid lowering therapy is widely used for the prevention of cardiovascular complications after acute myocardial infarction (AMI). However, some studies show that this benefit is uncertain in patients with renal dysfunction, and the role of statins is based on the severity of renal dysfunction. In this study, we investigated the impact of statin therapy on major adverse cardiac events (MACEs) and all-cause mortality in patients with advanced renal dysfunction undergoing percutaneous coronary intervention (PCI) after AMI. METHODS: This study was based on the Korea Acute Myocardial Infarction Registry database. We included 861 patients with advanced renal dysfunction from among 33,205 patients who underwent PCI after AMI between November 2005 and July 2012. Patients were divided into two groups: a statin group (n = 537) and a no-statin group (n = 324). We investigated the 12-month MACEs (cardiac death, myocardial infarction, repeated PCI or coronary artery bypass grafting) and all-cause mortality of each group. Subsequently, a propensity score-matched analysis was performed. RESULTS: In the total population studied, no significant differences were observed between the two groups with respect to the rate of recurrent MI, repeated PCI, coronary artery bypass grafting (CABG), or all-cause mortality. However, the cardiac death rate was significantly lower in the statin group (p = 0.009). Propensity score-matched analysis yielded 274 pairs demonstrating, results similar to those obtained from the total population. However, there was no significant difference in the cardiac death rate in the propensity score matched population (p = 0.103). Cox-regression analysis revealed only left ventricular ejection fraction to be an independent predictor of 12-month MACEs (Hazard ratio [HR] of 0.979, 95% confidence interval [CI], 0962-0.996, p = 0.018). CONCLUSIONS: Statin therapy was not significantly associated with a reduction in the 12-month MACEs or all-cause mortality in patients with advanced renal dysfunction undergoing PCI after AMI. PMID- 28806771 TI - Effect of knee alignment on the quadriceps femoris muscularity: Cross-sectional comparison of trained versus untrained individuals in both sexes. AB - Knee alignment is suggested to be a factor affecting each quadriceps femoris muscle size, and knee alignment such as Q-angle differs between men and women. Also, training can induce inhomogeneous hypertrophy among the quadriceps femoris, thereby leading to different component characteristics of the muscles. If Q-angle is a major determinant of the quadriceps femoris muscularity, it is hypothesized that the sex-related difference in the quadriceps femoris muscularity, if any, is further highlighted in trained individuals, being associated with Q-angle. We tested this hypothesis. Magnetic resonance images of the right thigh were obtained from 26 varsity rowers as trained subjects (13 for each sex) and 34 untrained individuals as controls (17 for each sex). From the images, muscle volume of each constituent of the quadriceps femoris (vastus lateralis, VL; medialis, VM; intermedius; rectus femoris) was determined. The Q-angle was measured during quiet bilateral standing with hand support as needed. Percent volume of VM to the total quadriceps femoris was greater in female rowers than male rowers and female controls, and that of VL was greater in male rowers than male controls. There were no correlations between Q-angle and percent muscle volume in any muscles regardless of rowing experience or sex. The current study revealed that well-trained rowers have sex-related quadriceps femoris muscularity but no significant correlations between percent muscle volume in any muscles and Q-angle. Our findings suggest that Q-angle is not a major determinant of the quadriceps femoris muscularity in either well-trained or untrained individuals. PMID- 28806770 TI - Increasing creatine kinase activity protects against hypoxia / reoxygenation injury but not against anthracycline toxicity in vitro. AB - The creatine kinase (CK) phosphagen system is fundamental to cellular energy homeostasis. Cardiomyocytes express three CK isoforms, namely the mitochondrial sarcomeric CKMT2 and the cytoplasmic CKM and CKB. We hypothesized that augmenting CK in vitro would preserve cell viability and function and sought to determine efficacy of the various isoforms. The open reading frame of each isoform was cloned into pcDNA3.1, followed by transfection and stable selection in human embryonic kidney cells (HEK293). CKMT2- CKM- and CKB-HEK293 cells had increased protein and total CK activity compared to non-transfected cells. Overexpressing any of the three CK isoforms reduced cell death in response to 18h hypoxia at 1% O2 followed by 2h re-oxygenation as assayed using propidium iodide: by 33% in CKMT2, 47% in CKM and 58% in CKB compared to non-transfected cells (P<0.05). Loading cells with creatine did not modify cell survival. Transient expression of CK isoforms in HL-1 cardiac cells elevated isoenzyme activity, but only CKMT2 over-expression protected against hypoxia (0.1% for 24h) and reoxygenation demonstrating 25% less cell death compared to non-transfected control (P<0.01). The same cells were not protected from doxorubicin toxicity (250nM for 48h), in contrast to the positive control. These findings support increased CK activity as protection against ischaemia-reperfusion injury, in particular, protection via CKMT2 in a cardiac-relevant cell line, which merits further investigation in vivo. PMID- 28806772 TI - Microhabitats and canopy cover moderate high summer temperatures in a fragmented Mediterranean landscape. AB - Extreme heat events will become more frequent under anthropogenic climate change, especially in Mediterranean ecosystems. Microhabitats can considerably moderate (buffer) the effects of extreme weather events and hence facilitate the persistence of some components of the biodiversity. We investigate the microclimatic moderation provided by two important microhabitats (cavities formed by the leaves of the grass-tree Xanthorrhoea semiplana F.Muell., Xanthorrhoeaceae; and inside the leaf-litter) during the summer of 2015/16 on the Fleurieu Peninsula of South Australia. We placed microsensors inside and outside these microhabitats, as well as above the ground below the forest canopy. Grass tree and leaf-litter microhabitats significantly buffered against high temperatures and low relative humidity, compared to ground-below-canopy sensors. There was no significant difference between grass-tree and leaf-litter temperatures: in both microhabitats, daily temperature variation was reduced, day temperatures were 1-5 degrees C cooler, night temperatures were 0.5-3 degrees C warmer, and maximum temperatures were up to 14.4 degrees C lower, compared to ground-below-canopy sensors. Grass-tree and leaf-litter microhabitats moderated heat increase at an average rate of 0.24 degrees C temperature per 1 degrees C increase of ambient temperature in the ground-below-canopy microhabitat. The average daily variation in temperature was determined by the type (grass-tree and leaf-litter versus ground-below-canopy) of microhabitat (explaining 67%), the amount of canopy cover and the area of the vegetation fragment (together explaining almost 10% of the variation). Greater canopy cover increased the amount of microclimatic moderation provided, especially in the leaf-litter. Our study highlights the importance of microhabitats in moderating macroclimatic conditions. However, this moderating effect is currently not considered in species distribution modelling under anthropogenic climate change nor in the management of vegetation. This shortcoming will have to be addressed to obtain realistic forecasts of future species distributions and to achieve effective management of biodiversity. PMID- 28806773 TI - Quantitative accuracy of 177Lu SPECT imaging for molecular radiotherapy. AB - The purpose of this study is to investigate the optimal reference geometry for gamma camera calibration. Yet another question of interest was to assess the influence of the number of 3D Ordered Subsets Expectation Maximization (3D-OSEM) updates on activity quantification for SPECT imaging with 177Lu. The accuracy of 177Lu activity quantification was assessed both in small and in large objects. Two different reference geometries, namely a cylindrical homogeneous phantom and a Jaszczak 16 ml sphere surrounded by cold water, were used to determine the gamma camera calibration factor of a commercial SPECT/CT system. Moreover, the noise level and the concentration recovery coefficient were evaluated as a function of the number of 3D-OSEM updates by using the SPECT/CT images of the reference geometry phantoms and those of a cold Jaszczak phantom with three hot spheres (16ml, 8ml and 4ml), respectively. The optimal choice of the number of 3D OSEM updates was based on a compromise between the noise level achievable in the reconstructed SPECT images and the concentration recovery coefficients. The quantitative accuracy achievable was finally validated on a test phantom, where a spherical insert composed of two concentric spheres was used to simulate a lesion in a warm background. Our data confirm and extend previous observations. Using the calibration factor obtained with the cylindrical homogeneous phantom and the Jaszczak 16 ml sphere, the recovered activity in the test phantom was underestimated by -16.4% and -24.8%, respectively. Our work has led us to conclude that gamma camera calibration performed with large homogeneous phantom outperforms calibration executed with the Jaszczak 16ml sphere. Furthermore, the results obtained support the assumption that approximately 50 OSEM updates represent a good trade-off to reach convergence in small volumes, meanwhile minimizing the noise level. PMID- 28806774 TI - Fibroblast growth factor receptor-1 mediates internalization of pathogenic spotted fever rickettsiae into host endothelium. AB - Rickettsial infections continue to cause serious morbidity and mortality in severe human cases around the world. Host cell adhesion and invasion is an essential requisite for intracellular growth, replication, and subsequent dissemination of pathogenic rickettsiae. Heparan sulfate proteoglycans [HSPGs] facilitate the interactions between fibroblast growth factor(s) and their tyrosine kinase receptors resulting in receptor dimerization/activation and have been implicated in bacterial adhesion to target host cells. In the present study, we have investigated the contributions of fibroblast growth factor receptors [FGFRs] in rickettsial entry into the host cells. Inhibition of HSPGs by heparinase and FGFRs by AZD4547 (a selective small-molecule inhibitor) results in significant reduction in rickettsial internalization into cultured human microvascular endothelial cells (ECs), which represent the primary targets of pathogenic rickettsiae during human infections. Administration of AZD4547 during R. conorii infection in a murine model of endothelial-target spotted fever rickettsiosis also diminishes pulmonary rickettsial burden in comparison to mock treated controls. Silencing of FGFR1 expression using a small interfering RNA also leads to similar inhibition of R. rickettsii invasion into ECs. Consistent with these findings, R. rickettsii infection of ECs also results in phosphorylation of tyrosine 653/654, suggesting activation of FGFR1. Using isobaric tag for relative and absolute quantitation [iTRAQ]-based proteomics approach, we further demonstrate association of beta-peptide of rickettsial outer membrane protein OmpA with FGFR1. Mechanistically, FGFR1 binds to caveolin-1 and mediates bacterial entry via caveolin-1 dependent endocytosis. Together, these results identify host cell FGFR1 and rickettsial OmpA as another novel receptor ligand pair contributing to the internalization of pathogenic rickettsiae into host endothelial cells and the potential application of FGFR-inhibitor drugs as adjunct therapeutics against spotted fever rickettsioses. PMID- 28806775 TI - Depression screening with patient-targeted feedback in cardiology: The cost effectiveness of DEPSCREEN-INFO. AB - BACKGROUND: Although depression is common in patients with heart disease, screening for depression is much debated. DEPSCREEN-INFO showed that a patient targeted feedback in addition to screening results in lower depression level six months after screening. The purpose of this analysis was to perform a cost effectiveness analysis of DEPSCREEN-INFO. METHODS: Patients with coronary heart disease or arterial hypertension were included. Participants in both groups were screened for depression. Participants in the intervention group additionally received a patient-targeted feedback of their result and recommended treatment options. A cost-utility analysis using quality-adjusted life years (QALY) based on the EQ-5D was performed. The time horizon was 6 months. Resource utilization was assessed by a telephone interview. Multiple imputation using chained equations was used. Net-benefit regressions controlled for prognostic variables at baseline were performed to construct cost-effectiveness acceptability curves. Different sensitivity analyses were performed. RESULTS: 375 participants (intervention group: 155; control group: 220) were included at baseline. After 6 months, in the intervention group adjusted total costs were lower (-?2,098; SE: ?1,717) and more QALY were gained (0.0067; SD: 0.0133); yet differences were not statistically significant. The probability of cost-effectiveness was around 80% independent of the willingness-to-pay (range: ?0/QALY-?130,000/QALY). The results were robust. CONCLUSIONS: A patient-targeted feedback in addition to depression screening in cardiology is cost-effective with a high probability. This underpins the use of the patient-targeted feedbacks and the PHQ-9 that are both freely available and easy to implement in routine care. PMID- 28806776 TI - The very low-frequency band of heart rate variability represents the slow recovery component after a mental stress task. AB - The very low-frequency (VLF) band of heart rate variability (HRV) has different characteristics compared with other HRV components. Here we investigated differences in HRV changes after a mental stress task. After the task, the high frequency (HF) band and ratio of high- to low-frequency bands (LF/HF) immediately returned to baseline. We evaluated the characteristics of VLF band changes after a mental stress task. We hypothesized that the VLF band decreases during the Stroop color word task and there would be a delayed recovery for 2 h after the task (i.e., the VLF change would exhibit a "slow recovery"). Nineteen healthy, young subjects were instructed to rest for 10 min, followed by a Stroop color word task for 20 min. After the task, the subjects were instructed to rest for 120 min. For all subjects, R-R interval data were collected; analysis was performed for VLF, HF, and LF/HF ratio. HRV during the rest time and each 15-min interval of the recovery time were compared. An analysis of the covariance was performed to adjust for the HF band and LF/HF ratio as confounding variables of the VLF component. HF and VLF bands significantly decreased and the LF/HF ratio significantly increased during the task compared with those during rest time. During recovery, the VLF band was significantly decreased compared with the rest time. After the task, the HF band and LF/HF ratio immediately returned to baseline and were not significantly different from the resting values. After adjusting for HF and LF/HF ratio, the VLF band had significantly decreased compared with that during rest. The VLF band is the "slow recovery" component and the HF band and LF/HF ratio are the "quick recovery" components of HRV. This VLF characteristic may clarify the unexplained association of the VLF band in cardiovascular disease prevention. PMID- 28806777 TI - A 'synthetic-sickness' screen for senescence re-engagement targets in mutant cancer backgrounds. AB - Senescence is a universal barrier to immortalisation and tumorigenesis. As such, interest in the use of senescence-induction in a therapeutic context has been gaining momentum in the past few years; however, senescence and immortalisation remain underserved areas for drug discovery owing to a lack of robust senescence inducing agents and an incomplete understanding of the signalling events underlying this complex process. In order to address this issue we undertook a large-scale morphological siRNA screen for inducers of senescence phenotypes in the human melanoma cell line A375P. Following rescreen and validation in a second cancer cell line, HCT116 colorectal carcinoma, a panel of 16 of the most robust hits were selected for further validation based on significance and the potential to be targeted by drug-like molecules. Using secondary assays for detection of senescence biomarkers p21, 53BP1 and senescence associated beta-galactosidase (SAbetaGal) in a panel of HCT116 cell lines carrying cancer-relevant mutations, we show that partial senescence phenotypes can be induced to varying degrees in a context dependent manner, even in the absence of p21 or p53 expression. However, proliferation arrest varied among genetic backgrounds with predominantly toxic effects in p21 null cells, while cells lacking PI3K mutation failed to arrest. Furthermore, we show that the oncogene ECT2 induces partial senescence phenotypes in all mutant backgrounds tested, demonstrating a dependence on activating KRASG13D for growth suppression and a complete senescence response. These results suggest a potential mechanism to target mutant KRAS signalling through ECT2 in cancers that are reliant on activating KRAS mutations and remain refractory to current treatments. PMID- 28806778 TI - Serum resistin as an independent marker of aortic stiffness in patients with coronary artery disease. AB - BACKGROUND: Subjects with higher carotid-femoral pulse wave velocity (cfPWV) will be at an increased risk for cardiovascular (CV) events in future. Resistin is an inflammatory mediator and a biomarker of CV diseases. We evaluated the association between serum resistin and aortic stiffness in patients with coronary artery disease (CAD). METHODS: A total of 104 patients with CAD were enrolled in this study. cfPWV was measured using the SphygmoCor system. Patients with cfPWV >10 m/s were defined as the high aortic stiffness group. RESULTS: Thirty-seven patients (35.6%) had high aortic stiffness and higher percentages of diabetes (p = 0.001), were of older age (p = 0.001) and had higher waist circumference (p < 0.001), systolic blood pressure (p = 0.027), pulse pressure (p = 0.013), high sensitivity C-reactive protein (p < 0.001) and resistin levels (p < 0.001) but lower estimated glomerular filtration rate (p = 0.009) compared to subjects with low aortic stiffness. After adjusting for factors significantly associated with aortic stiffness by multivariate logistic regression analysis, serum resistin (odds ratio = 1.275, 95% confidence interval: 1.065-1.527, p = 0.008) was also found to be an independent predictor of aortic stiffness in patients with CAD. CONCLUSIONS: Serum resistin level is a biomarker for aortic stiffness in patients with CAD. PMID- 28806779 TI - A mutation in Nischarin causes otitis media via LIMK1 and NF-kappaB pathways. AB - Otitis media (OM), inflammation of the middle ear (ME), is a common cause of conductive hearing impairment. Despite the importance of the disease, the aetiology of chronic and recurrent forms of middle ear inflammatory disease remains poorly understood. Studies of the human population suggest that there is a significant genetic component predisposing to the development of chronic OM, although the underlying genes are largely unknown. Using N-ethyl-N-nitrosourea mutagenesis we identified a recessive mouse mutant, edison, that spontaneously develops a conductive hearing loss due to chronic OM. The causal mutation was identified as a missense change, L972P, in the Nischarin (NISCH) gene. edison mice develop a serous or granulocytic effusion, increasingly macrophage and neutrophil rich with age, along with a thickened, inflamed mucoperiosteum. We also identified a second hypomorphic allele, V33A, with only modest increases in auditory thresholds and reduced incidence of OM. NISCH interacts with several proteins, including ITGA5 that is thought to have a role in modulating VEGF induced angiogenesis and vascularization. We identified a significant genetic interaction between Nisch and Itga5; mice heterozygous for Itga5-null and homozygous for edison mutations display a significantly increased penetrance and severity of chronic OM. In order to understand the pathological mechanisms underlying the OM phenotype, we studied interacting partners to NISCH along with downstream signalling molecules in the middle ear epithelia of edison mouse. Our analysis implicates PAK1 and RAC1, and downstream signalling in LIMK1 and NF kappaB pathways in the development of chronic OM. PMID- 28806781 TI - The advantage of being slow: The quasi-neutral contact process. AB - According to the competitive exclusion principle, in a finite ecosystem, extinction occurs naturally when two or more species compete for the same resources. An important question that arises is: when coexistence is not possible, which mechanisms confer an advantage to a given species against the other(s)? In general, it is expected that the species with the higher reproductive/death ratio will win the competition, but other mechanisms, such as asymmetry in interspecific competition or unequal diffusion rates, have been found to change this scenario dramatically. In this work, we examine competitive advantage in the context of quasi-neutral population models, including stochastic models with spatial structure as well as macroscopic (mean-field) descriptions. We employ a two-species contact process in which the "biological clock" of one species is a factor of alpha slower than that of the other species. Our results provide new insights into how stochasticity and competition interact to determine extinction in finite spatial systems. We find that a species with a slower biological clock has an advantage if resources are limited, winning the competition against a species with a faster clock, in relatively small systems. Periodic or stochastic environmental variations also favor the slower species, even in much larger systems. PMID- 28806780 TI - The AraC Negative Regulator family modulates the activity of histone-like proteins in pathogenic bacteria. AB - The AraC Negative Regulators (ANR) comprise a large family of virulence regulators distributed among diverse clinically important Gram-negative pathogens, including Vibrio spp., Salmonella spp., Shigella spp., Yersinia spp., Citrobacter spp., and pathogenic E. coli strains. We have previously reported broad effects of the ANR members on regulators of the AraC/XylS family. Here, we interrogate possible broader effects of the ANR members on the bacterial transcriptome. Our studies focused on Aar (AggR-activated regulator), an ANR family archetype in enteroaggregative E. coli (EAEC) isolate 042. Transcriptome analysis of EAEC strain 042, 042aar and 042aar(pAar) identified more than 200 genes that were differentially expressed (+/- 1.5 fold, p<0.05). Most of those genes are located on the bacterial chromosome (195 genes, 92.85%), and are associated with regulation, transport, metabolism, and pathogenesis, based on the predicted annotation; a considerable number of Aar-regulated genes encoded for hypothetical proteins (46 genes, 21.9%) and regulatory proteins (25, 11.9%). Notably, the transcriptional expression of three histone-like regulators, H-NS (orf1292), H-NS homolog (orf2834) and StpA, was down-regulated in the absence of aar and may explain some of the effects of Aar on gene expression. By employing a bacterial two-hybrid system, LacZ reporter assays, pull-down and electrophoretic mobility shift assay (EMSA) analysis, we demonstrated that Aar binds directly to H-NS and modulates H-NS-induced gene silencing. Importantly, Aar was highly expressed in the mouse intestinal tract and was found to be necessary for maximal H-NS expression. In conclusion, this work further extends our knowledge of genes under the control of Aar and its biological relevance in vivo. PMID- 28806782 TI - The use of 18F-Fluoro-deoxy-glucose positron emission tomography (18F-FDG PET) as a non-invasive pharmacodynamic biomarker to determine the minimally pharmacologically active dose of AZD8835, a novel PI3Kalpha inhibitor. AB - BACKGROUND: The phosphatidyl inositol 3 kinase (PI3K), AKT and mammalian target of rapamycin (mTOR) signal transduction pathway is frequently de-regulated and activated in human cancer and is an important therapeutic target. AZD8835 is a PI3K inhibitor, with selectivity against PI3K alpha and delta isoforms, which is currently in Phase 1 clinical trials. 18F-Fluoro-deoxy-glucose positron emission tomography (18F-FDG PET) is a non-invasive pharmacodynamic imaging biomarker that has become an integral part of drug development. It has been used widely with PI3K inhibitors both clinically and pre-clinically because of the role of the PI3K pathway in glucose metabolism. In this study we investigated the potential of 18F-FDG PET as a non-invasive pharmacodynamic biomarker for AZD8835. We sought to understand if 18F-FDG PET could determine the minimally effective dose of AZD8835 and correlate with other pharmacodynamic biomarkers for validation of its use in clinical development. 18F-FDG PET scans were performed in nude mice in the BT474C breast xenograft model. Mice were fasted prior to imaging and static 18F FDG PET was performed. Treatment groups received AZD8835 by oral gavage at a dose volume of 10ml/kg. Treatment groups received either 3, 6, 12.5, 25 or 50mg/kg AZD8835. Tumour growth was monitored throughout the study, and at the end of the imaging procedure, tumours were taken and a full pharmacodynamic analysis was performed. RESULTS: Results showed that AZD8835 reduced 18F-FDG uptake at a dose of 12.5, 25 and 50mg/kg with no significant reduction at doses of 3 and 6mg/kg. These results were consistent with other pharmacodynamics biomarkers measured and show 18F-FDG PET as a sensitive biomarker with the ability to determine the minimal effective dose of AZD8835. CONCLUSIONS: Our pre-clinical studies support the use of 18F-FDG PET imaging as a sensitive and non- invasive pharmacodynamic biomarker (understanding the role of PI3K signalling in glucose uptake) for AZD8835 with a decrease in 18F-FDG uptake observed at only two hours post treatment. The decrease in 18F-FDG uptake was dose dependent and data showed excellent PK/PD correlation. This data supports and parallels observations obtained with this class of compounds in patients. PMID- 28806783 TI - The utilization of critical care ultrasound to assess hemodynamics and lung pathology on ICU admission and the potential for predicting outcome. AB - AIM: Critical care ultrasound (CCUS) has been used by many Intensive Care Units(ICUs) worldwide, so as to guiding the diagnosis and the treatment. However, none of the publications currently systematically describe the utilization of CCUS to analyze the characteristics of hemodynamics and lung pathology upon the new admission to ICU and its potential role in patients' prognosis prediction. In this retrospective clinical study, we have demonstrated and analyzed the characteristics of hemodynamics and lung pathology assessed by CCUS and investigated its potential to predict patient outcome. METHODS: We have described and analyzed the epidemic characteristics of hemodynamics and lung pathology assessed by CCUS on ICU admission, which based on our database of 451 cases from the biggest medical center in Western China, between November 2014 and October 2015. The patients' demographics, clinical characteristics, prognosis and ultrasonic pattern of hemodynamics and lung pathology had been analyzed. A bivariate logistic regression model was established to identify the correlation between the ultrasonic variables on admission and the ICU mortality. RESULTS: The mean age of the 451 patients was 56.7+/-18.7 years; the mean APACHE II score was 19.0+/-7.9, the ICU mortality was 30.6%. Patients received CCUS examination of pericardial, right ventricle (RV) wall motion, left ventricle (LV) wall motion, LV systolic function, LV diastolic function, lung and volume of inferior vena cava (IVC) were 423(93.8%), 418(92.7%), 392(86.9%), 389(86.3%), 383(84.9%), 440(97.6%), 336(74.5%), respectively; The univariate analysis revealed that length of mechanical ventilation was significantly correlated with the diameter of IVC, tricuspid annular plane systolic excursion(TAPSE), mitral annular plane systolic excursion(MAPSE), early diastolic transmitral velocity to early mitral annulus diastolic velocity(E/e') (p = 0.016, 0.011, 0.000, 0.049, respectively); The TAPSE, ejection fraction(EF), MAPSE, lung ultrasound score (LUS score) (p = 0.000, 0.028, 0.000, 0.011, respectively) were significantly related to ICU mortality. The multivariate analysis demonstrated that APACHE II, age, TAPSE, E/e' are the independent risk factors for ICU mortality in our study. CONCLUSION: CCUS examination on ICU admission which performed by the experienced physician provide valuable information to assist the caregivers in understanding the comprehensive outlook of the characteristics of hemodynamics and lung pathology. Those key variables obtained by CCUS predict the possible prognosis of patients, hence deserve more attention in clinical decision making. PMID- 28806784 TI - Structural analysis of P. falciparum KAHRP and PfEMP1 complexes with host erythrocyte spectrin suggests a model for cytoadherent knob protrusions. AB - Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) and Knob-associated Histidine-rich Protein (KAHRP) are directly linked to malaria pathology. PfEMP1 and KAHRP cluster on protrusions (knobs) on the P. falciparum-infected erythrocyte surface and enable pathogenic cytoadherence of infected erythrocytes to the host microvasculature, leading to restricted blood flow, oxygen deprivation and damage of tissues. Here we characterize the interactions of PfEMP1 and KAHRP with host erythrocyte spectrin using biophysical, structural and computational approaches. These interactions assist knob formation and, thus, promote cytoadherence. We show that the folded core of the PfEMP1 cytosolic domain interacts broadly with erythrocyte spectrin but shows weak, residue specific preference for domain 17 of alpha spectrin, which is proximal to the erythrocyte cytoskeletal junction. In contrast, a protein sequence repeat region in KAHRP preferentially associates with domains 10-14 of beta spectrin, proximal to the spectrin-ankyrin complex. Structural models of PfEMP1 and KAHRP with spectrin combined with previous microscopy and protein interaction data suggest a model for knob architecture. PMID- 28806785 TI - Adherence to ivermectin is more associated with perceptions of community directed treatment with ivermectin organization than with onchocerciasis beliefs. AB - BACKGROUND: The fight against onchocerciasis in Africa has boomed thanks to the Community Directed Treatment with Ivermectin (CDTI) program. However, in Cameroon, after more than 15 years of mass treatment, onchocerciasis prevalence is still above the non-transmission threshold. This study aimed to explore a possible association between people's beliefs/perceptions of onchocerciasis and of CDTI program, and their adherence to ivermectin in three regions of Cameroon. METHODOLOGY/PRINCIPAL FINDINGS: A cross sectional survey was carried out in three health districts with persistent high onchocerciasis prevalence. Participants were randomly selected in 30 clusters per district. Adherence to ivermectin was comparable between Bafang and Bafia (55.0% and 48.8%, respectively, p>0.05) and lower in Yabassi (40.7%). Among all factors related to program perceptions and disease representations that were studied, perceptions of the program are the ones that were most determinant in adherence to ivermectin. People who had a "not positive" opinion of ivermectin distribution campaigns were less compliant than those who had a positive opinion about the campaigns (40% vs 55% in Bafang, and 48% vs 62% in Bafia, p<0.01), as well as those who had a negative appreciation of community drug distributors' commitment (22% vs 53% in Bafang, 33% vs 59% in Bafia, 27% vs 47% in Yabassi; p<0.01). The most common misconception about onchocerciasis transmission was the lack of hygiene, especially in Bafia and Yabassi. In Bafang, high proportions of people believed that onchocerciasis was due to high consumption of sugar (31% vs less than 5% in Bafia and Yabassi, p<0.001). CONCLUSION/SIGNIFICANCE: There are still frequent misconceptions about onchocerciasis transmission in Cameroon. Perceptions of ivermectin distribution campaigns are more strongly associated to adherence. In addition to education/sensitisation on onchocerciasis during the implementation of the CDTI program, local health authorities should strive to better involve communities and more encourage community distributors' work. PMID- 28806786 TI - An economic evaluation of vector control in the age of a dengue vaccine. AB - INTRODUCTION: Dengue is a rapidly emerging vector-borne Neglected Tropical Disease, with a 30-fold increase in the number of cases reported since 1960. The economic cost of the illness is measured in the billions of dollars annually. Environmental change and unplanned urbanization are conspiring to raise the health and economic cost even further beyond the reach of health systems and households. The health-sector response has depended in large part on control of the Aedes aegypti and Ae. albopictus (mosquito) vectors. The cost-effectiveness of the first-ever dengue vaccine remains to be evaluated in the field. In this paper, we examine how it might affect the cost-effectiveness of sustained vector control. METHODS: We employ a dynamic Markov model of the effects of vector control on dengue in both vectors and humans over a 15-year period, in six countries: Brazil, Columbia, Malaysia, Mexico, the Philippines, and Thailand. We evaluate the cost (direct medical costs and control programme costs) and cost effectiveness of sustained vector control, outbreak response and/or medical case management, in the presence of a (hypothetical) highly targeted and low cost immunization strategy using a (non-hypothetical) medium-efficacy vaccine. RESULTS: Sustained vector control using existing technologies would cost little more than outbreak response, given the associated costs of medical case management. If sustained use of existing or upcoming technologies (of similar price) reduce vector populations by 70-90%, the cost per disability-adjusted life year averted is 2013 US$ 679-1331 (best estimates) relative to no intervention. Sustained vector control could be highly cost-effective even with less effective technologies (50-70% reduction in vector populations) and in the presence of a highly targeted and low cost immunization strategy using a medium-efficacy vaccine. DISCUSSION: Economic evaluation of the first-ever dengue vaccine is ongoing. However, even under very optimistic assumptions about a highly targeted and low cost immunization strategy, our results suggest that sustained vector control will continue to play an important role in mitigating the impact of environmental change and urbanization on human health. If additional benefits for the control of other Aedes borne diseases, such as Chikungunya, yellow fever and Zika fever are taken into account, the investment case is even stronger. High burden endemic countries should proceed to map populations to be covered by sustained vector control. PMID- 28806787 TI - Antagonism of proteasome inhibitor-induced heme oxygenase-1 expression by PINK1 mutation. AB - PTEN-induced putative kinase 1 (PINK1) is an integral protein in the mitochondrial membrane and maintains mitochondrial fidelity. Pathogenic mutations in PINK1 have been identified as a cause of early-onset autosomal recessive familial Parkinson's disease (PD). The ubiquitin proteasome pathway is associated with neurodegenerative diseases. In this study, we investigated whether mutations of PINK1 affects the cellular stress response following proteasome inhibition. Administration of MG132, a peptide aldehyde proteasome inhibitor, significantly increased the expression of heme oxygenase-1 (HO-1) in rat dopaminergic neurons in the substantia nigra and in the SH-SY5Y neuronal cell line. The induction of HO-1 expression by proteasome inhibition was reduced in PINK1 G309D mutant cells. MG132 increased the levels of HO-1 through the Akt, p38, and Nrf2 signaling pathways. Compared with the cells expressing WT-PINK1, the phosphorylation of Akt and p38 was lower in those cells expressing the PINK1 G309D mutant, which resulted in the inhibition of the nuclear translocation of Nrf2. Furthermore, MG132-induced neuronal death was enhanced by the PINK1 G309D mutation. In this study, we demonstrated that the G309D mutation impairs the neuroprotective function of PINK1 following proteasome inhibition, which may be related to the pathogenesis of PD. PMID- 28806790 TI - Opening the Book on Maintenance of Certification. PMID- 28806789 TI - Cannabis for Pain and Posttraumatic Stress Disorder: More Consensus Than Controversy or Vice Versa? PMID- 28806791 TI - Effect of Access to an Electronic Medical Resource on Performance Characteristics of a Certification Examination: A Randomized Controlled Trial. AB - Background: Electronic resources are increasingly used in medical practice. Their use during high-stakes certification examinations has been advocated by many experts, but whether doing so would affect the capacity to differentiate between high and low abilities is unknown. Objective: To determine the effect of electronic resources on examination performance characteristics. Design: Randomized controlled trial. Setting: Medical certification program. Participants: 825 physicians initially certified by the American Board of Internal Medicine (ABIM) who passed the Internal Medicine Certification examination or sat for the Internal Medicine Maintenance of Certification (IM MOC) examination in 2012 to 2015. Intervention: Participants were randomly assigned to 1 of 4 conditions: closed book using typical or additional time, or open book (that is, UpToDate [Wolters Kluwer]) using typical or additional time. All participants took the same modified version of the IM-MOC examination. Measurements: Primary outcomes included item difficulty (how easy or difficult the question was), item discrimination (how well the question differentiated between high and low abilities), and average question response time. Secondary outcomes included examination dimensionality (that is, the number of factors measured) and test-taking strategy. Item response theory was used to calculate question characteristics. Analysis of variance compared differences among conditions. Results: Closed-book conditions took significantly less time than open-book conditions (mean, 79.2 seconds [95% CI, 78.5 to 79.9 seconds] vs. 110.3 seconds [CI, 109.2 to 111.4 seconds] per question). Mean discrimination was statistically significantly higher for open-book conditions (0.34 [CI, 0.32 to 0.35] vs. 0.39 [CI, 0.37 to 0.41] per question). A strong single dimension showed that the examination measured the same factor with or without the resource. Limitation: Only 1 electronic resource was evaluated. Conclusion: Inclusion of an electronic resource with time constraints did not adversely affect test performance and did not change the specific skill or factor targeted by the examination. Further study on the effect of resource inclusion on other examinations is warranted. Primary Funding Source: ABIM Foundation. PMID- 28806788 TI - Chronic unpredictable stress exacerbates surgery-induced sickness behavior and neuroinflammatory responses via glucocorticoids secretion in adult rats. AB - METHODS: Sprague-Dawley adult male rats (12-14 weeks old) were exposed to 14-day CUS and then subjected to partial hepatectomy 24 h after the last stress session. The rats were pretreated with an antagonist of the glucocorticoids (GCs) receptor RU486 (30 mg/kg, i.p.) 1 h prior to stress exposure. The behavioral changes were evaluated with open field test and elevated plus-maze test. The hippocampal cytokines interleukin (IL)-1beta and IL-6 were measured on postoperative days 1, 3 and 7. Ionized calcium binding adaptor protein (Iba)-1, microglial M2 phenotype marker Arg1, brain derived neurotrophic factor (BDNF) and CD200 were also examined at each time point. RESULTS: CUS exacerbated surgery-induced sickness behavior. Exposure to CUS alone failed to alter the levels of pro-inflammatory cytokines in the brain. However, CUS exaggerated surgery-induced pro-inflammatory cytokines expression (e.g. IL-1beta and IL-6) and upregulated the levels of Iba-1 on postoperative days 1 and 3. An additional significant decreased BDNF, CD200 and a lower level of Arg1 were also observed in the stressed rats following surgical procedure. Pretreatment with RU486 blunted the potentiating effects of CUS on surgery-induced sickness behavior and neuroinflammatory responses. CONCLUSION: Chronic unpredictable stress enhanced surgery-induced sickness behavior and neuroinflammatory responses. Stress-induced GCs played a pivotal role in enhancing surgery-induced neuroinflammatory processes by modulation of microglia functions. PMID- 28806792 TI - Moving to Measures That Matter and Motivate Change. PMID- 28806793 TI - Holding Providers Accountable for Health Care Outcomes. AB - Federal public reporting and payment programs have increasingly emphasized the measurement of outcomes (such as readmission, health care-associated infections, and mortality). Yet, the criteria for assessing whether outcome measures are accurate and valid enough to use for public reporting, payment, and accreditation are not well-defined. An outcome measure should be used only if the outcome can be influenced substantially by providers (that is, a strong process-outcome link exists) and statistical adjustment can be made for differences in patient populations across providers so that differences in outcomes are truly attributable to differences in the care provided. Validly distinguishing differences in quality of care across providers requires precision in both the design of the outcome measure and the actual recording of all the measure's elements. Four criteria are proposed to assess outcome measures. First, strong evidence should exist that good medical care leads to improvement in the outcome within the time period for the measure. Second, the outcome should be measurable with a high degree of precision. Third, the risk-adjustment methodology should include and accurately measure the risk factors most strongly associated with the outcome. Fourth, implementation of the outcome measure must have little chance of inducing unintended adverse consequences. These criteria were applied to 10 outcome measures currently used or proposed for accountability programs. Three measures met all 4 criteria; 5, including all 4 claims-based 30-day mortality measures, failed to meet 1 or more criteria. Patient-reported outcome measures are problematic, because low response rates may cause bias. These findings raise concerns and suggest the need for a national dialogue about how to judge outcome measures currently in use or proposed for the future. PMID- 28806794 TI - Benefits and Harms of Plant-Based Cannabis for Posttraumatic Stress Disorder: A Systematic Review. AB - Background: Cannabis is available from medical dispensaries for treating posttraumatic stress disorder (PTSD) in many states of the union, yet its efficacy in treating PTSD symptoms remains uncertain. Purpose: To identify ongoing studies and review existing evidence regarding the benefits and harms of plant-based cannabis preparations in treating PTSD in adults. Data Sources: MEDLINE, the Cochrane Library, and other sources from database inception to March 2017. Study Selection: English-language systematic reviews, trials, and observational studies with a control group that reported PTSD symptoms and adverse effects of plant-based cannabis use in adults with PTSD. Data Extraction: Study data extracted by 1 investigator was checked by a second reviewer; 2 reviewers independently assessed study quality, and the investigator group graded the overall strength of evidence by using standard criteria. Data Synthesis: Two systematic reviews, 3 observational studies, and no randomized trials were found. The systematic reviews reported insufficient evidence to draw conclusions about benefits and harms. The observational studies found that compared with nonuse, cannabis did not reduce PTSD symptoms. Studies had medium and high risk of bias, and overall evidence was judged insufficient. Two randomized trials and 6 other studies examining outcomes of cannabis use in patients with PTSD are ongoing and are expected to be completed within 3 years. Limitation: Very scant evidence with medium to high risk of bias. Conclusion: Evidence is insufficient to draw conclusions about the benefits and harms of plant-based cannabis preparations in patients with PTSD, but several ongoing studies may soon provide important results. Primary Funding Source: U.S. Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Quality Enhancement Research Initiative. (PROSPERO: CRD42016033623). PMID- 28806795 TI - In older adults with subclinical hypothyroidism, levothyroxine did not improve symptoms or tiredness. PMID- 28806796 TI - In type 1 diabetes, education with either insulin pumps or daily injections did not differ for HbA1c at 2 y. PMID- 28806797 TI - Dexamethasone did not increase resolution of acute sore throat symptoms at 24 hours. PMID- 28806798 TI - In high-risk patients with arthritis and previous upper GI bleeding, celecoxib vs naproxen reduced recurrent bleeding. PMID- 28806799 TI - Review: CPAP improves QoL in obstructive sleep apnea; effects not as clear for mandibular advancement devices. PMID- 28806800 TI - Review: Osteoporosis drugs may improve BMD and reduce fractures in some patients with CKD. PMID- 28806801 TI - Short-term use of oral corticosteroids was linked to increased risk for sepsis, VTE, and fractures. PMID- 28806802 TI - In nonvalvular AF, DOAC-related risk for GI bleeding was lower with apixaban than dabigatran or rivaroxaban. PMID- 28806803 TI - In patients with chest pain, HEART score-guided and usual care did not differ for MACE or health care use. PMID- 28806804 TI - Review: A single hs-cTnT with a cutpoint < limit of detection plus a nonischemic ECG can rule out acute MI. PMID- 28806805 TI - Pharmacologic Treatment of Hypertension in Adults Aged 60 Years or Older. PMID- 28806806 TI - Pharmacologic Treatment of Hypertension in Adults Aged 60 Years or Older. PMID- 28806807 TI - Pharmacologic Treatment of Hypertension in Adults Aged 60 Years or Older. PMID- 28806808 TI - Intensive Blood Pressure Treatment in Adults Aged 60 Years or Older. PMID- 28806810 TI - Correction: The Relationship of Obesity to Hospice Use and Expenditures. PMID- 28806809 TI - Intensive Blood Pressure Treatment in Adults Aged 60 Years or Older. PMID- 28806811 TI - Correction: Effectiveness of a Multicomponent Quality Improvement Strategy to Improve Achievement of Diabetes Care Goals. PMID- 28806812 TI - Web Exclusives. Annals for Hospitalists Inpatient Notes - Sensemaking-Fostering a Shared Understanding in Clinical Teams. PMID- 28806813 TI - Web Exclusives. Annals Consult Guys - Is It Statin Myalgia? What a Pain! PMID- 28806816 TI - The Determinants of Dying Where We Choose: An Analysis of Coordinate My Care. PMID- 28806818 TI - Comprehensive Nicotine Regulation to End the Combustible Tobacco Epidemic. PMID- 28806817 TI - The Effects of Cannabis Among Adults With Chronic Pain and an Overview of General Harms: A Systematic Review. AB - Background: Cannabis is increasingly available for the treatment of chronic pain, yet its efficacy remains uncertain. Purpose: To review the benefits of plant based cannabis preparations for treating chronic pain in adults and the harms of cannabis use in chronic pain and general adult populations. Data Sources: MEDLINE, Cochrane Database of Systematic Reviews, and several other sources from database inception to March 2017. Study Selection: Intervention trials and observational studies, published in English, involving adults using plant-based cannabis preparations that reported pain, quality of life, or adverse effect outcomes. Data Extraction: Two investigators independently abstracted study characteristics and assessed study quality, and the investigator group graded the overall strength of evidence using standard criteria. Data Synthesis: From 27 chronic pain trials, there is low-strength evidence that cannabis alleviates neuropathic pain but insufficient evidence in other pain populations. According to 11 systematic reviews and 32 primary studies, harms in general population studies include increased risk for motor vehicle accidents, psychotic symptoms, and short-term cognitive impairment. Although adverse pulmonary effects were not seen in younger populations, evidence on most other long-term physical harms, in heavy or long-term cannabis users, or in older populations is insufficient. Limitation: Few methodologically rigorous trials; the cannabis formulations studied may not reflect commercially available products; and limited applicability to older, chronically ill populations and patients who use cannabis heavily. Conclusion: Limited evidence suggests that cannabis may alleviate neuropathic pain in some patients, but insufficient evidence exists for other types of chronic pain. Among general populations, limited evidence suggests that cannabis is associated with an increased risk for adverse mental health effects. Primary Funding Source: U.S. Department of Veterans Affairs. (PROSPERO: CRD42016033623). PMID- 28806819 TI - Indicators of Dysphagia in Aged Care Facilities. AB - Purpose: The current cross-sectional study aimed to investigate risk factors for dysphagia in elderly individuals in aged care facilities. Method: A total of 878 individuals from 42 aged care facilities were recruited for this study. The dependent outcome was speech therapist-determined swallowing function. Independent factors were Eating Assessment Tool score, oral motor assessment score, Mini-Mental State Examination, medical history, and various functional status ratings. Binomial logistic regression was used to identify independent variables associated with dysphagia in this cohort. Results: Two statistical models were constructed. Model 1 used variables from case files without the need for hands-on assessment, and Model 2 used variables that could be obtained from hands-on assessment. Variables positively associated with dysphagia identified in Model 1 were male gender, total dependence for activities of daily living, need for feeding assistance, mobility, requiring assistance walking or using a wheelchair, and history of pneumonia. Variables positively associated with dysphagia identified in Model 2 were Mini-Mental State Examination score, edentulousness, and oral motor assessments score. Conclusions: Cognitive function, dentition, and oral motor function are significant indicators associated with the presence of swallowing in the elderly. When assessing the frail elderly, case file information can help clinicians identify frail elderly individuals who may be suffering from dysphagia. PMID- 28806820 TI - Didactic training vs. computer-based self-learning in the prediction of diminutive colon polyp histology by trainees: a randomized controlled study. AB - Background and study aim Experts can accurately predict diminutive polyp histology, but the ideal method to train nonexperts is not known. The aim of the study was to compare accuracy in diminutive polyp histology characterization using narrow-band imaging (NBI) between participants undergoing classroom didactic training vs. computer-based self-learning. Participants and methods Trainees at two institutions were randomized to classroom didactic training or computer-based self-learning. In didactic training, experienced endoscopists reviewed a presentation on NBI patterns for adenomatous and hyperplastic polyps and 40 NBI videos, along with interactive discussion. The self-learning group reviewed the same presentation of 40 teaching videos independently, without interactive discussion. A total of 40 testing videos of diminutive polyps under NBI were then evaluated by both groups. Performance characteristics were calculated by comparing predicted and actual histology. Fisher's exact test was used and P < 0.05 was considered significant. Results A total of 17 trainees participated (8 didactic training and 9 self-learning). A larger proportion of polyps were diagnosed with high confidence in the classroom group (66.5 % vs. 50.8 %; P < 0.01), although sensitivity (86.9 % vs. 95.0 %) and accuracy (85.7 % vs. 93.9 %) of high-confidence predictions were higher in the self-learning group. However, there was no difference in overall accuracy of histology characterization (83.4 % vs. 87.2 %; P = 0.19). Similar results were noted when comparing sensitivity and specificity between the groups. Conclusion The self learning group showed results on a par with or, for high-confidence predictions, even slightly superior to classroom didactic training for predicting diminutive polyp histology. This approach can help in widespread training and clinical implementation of real-time polyp histology characterization. PMID- 28806821 TI - Endoscopic submucosal dissection of colitis-related dysplasia. AB - Background and study aims Endoscopic submucosal dissection (ESD) offers en bloc resection of lesions, allowing precise pathological assessment. Although possible in ulcerative colitis (UC) patients, the chronic inflammation may increase the procedural risks and reduce the complete resection rate. The aim of this study was to assess the feasibility of ESD for UC and to consider the factors contributing to its technical difficulty. Patients and methods Multicenter experiences of ESD for UC were retrospectively analyzed by reviewing endoscopic videos, pictures, reports, and clinical notes. Results A total of 32 dysplastic lesions were included (23 in British patients, 9 in Japanese patients). The lesions were macroscopically flat or with subtle extension macroscopically in 30 patients (94 %), with a median size of 33 mm (range 12 - 73 mm), and were located in the distal colon, including one on a pouch anastomosis. Submucosal fibrosis and adipose deposition were observed in 31 (97 %) and 13 lesions (41 %), respectively. En bloc resection was possible in 29/32 lesions (91 %). One patient had delayed bleeding. Advanced pathology was observed in 11 lesions (35 %). Recurrence was observed in only one patient (after a median of 33 months [range 6 - 76 months]); however, three patients developed metachronous lesions. Conclusions ESD is feasible for UC dysplasia without an increased rate of complications. Submucosal fibrosis and fat deposition were frequently observed and contributed to the technical complexity. Careful and intensive follow-up should be organized to detect metachronous lesions. PMID- 28806822 TI - [Multiple Myeloma - Current Status in Diagnostic Testing and Therapy]. AB - Background Multiple myeloma is a haematological blood cancer of the bone marrow and is classified by the World Health Organisation (WHO) as a plasma cell neoplasm. In multiple myeloma, normal plasma cells transform into malignant myeloma cells and produce large quantities of an abnormal immunoglobulin called monoclonal protein or M protein. This ultimately causes multiple myeloma symptoms such as bone damage or kidney problems. The annual worldwide incidence of multiple myeloma is estimated to be 6 - 7/100,000 and accounts for 1% of all cancer. In Germany, there are about 6,000 cases of newly diagnosed multiple myeloma per annum. In the current era of new agents, such as immunomodulatory drugs and proteasome inhibitors and antibodies, enormous progress has been achieved in the therapy of multiple myeloma. In orthopaedics, it is essential to be able to recognise the of alarming symptoms of multiple myeloma in clinical routine and to be aware of basic diagnostic features to confirm this disease. Surgical treatment of myeloma-related bone lesions - such as stabilisation of pathological fractures - is an important domain of tumour orthopaedic surgery. Methods A comprehensive literature search was performed in PubMed using the keywords "multiple myeloma" and "diagnostic" or "therapy". This served to evaluate the available primary and secondary literature on the current status of the diagnostic testing and therapy of multiple myeloma. Systematic reviews, meta analyses and clinical studies as well as international recommendations in therapy were included until the spring of 2016. Results There are now very sensitive screening methods for the diagnosis of multiple myeloma. Accurate diagnosis is generally based on several factors, including physical evaluation, patient history, symptoms, and diagnostic testing results. The standards for initial diagnostic tests are determined by blood and urine tests as well as a bone marrow biopsy and skeletal imaging, such as X-rays, CT scans and MRI scans. Major and minor criteria are required to confirm the diagnosis of multiple myeloma and help to determine the classification and staging of multiple myeloma, and whether it is smoldering myeloma (asymptomatic), symptomatic myeloma, or a monoclonal gammopathy of undetermined significance (MGUS). Multiple myeloma treatment options have increased significantly over the last 10 years. Standard of basic myeloma treatment consists of high dose chemotherapy in combination with autologous stem cell transplantation. Several factors may determine multiple myeloma treatment, such as age and general health, results of laboratory and cytogenetic (genomic) tests as well as symptoms and disease complications. After evaluation of these factors, an individual and often multimodal treatment plan is created and implemented in interdisciplinary cooperation. Conventional treatment options have to be evaluated for older patients (> 70 - 75 years), who are not eligible for high dose chemotherapy and autologous stem cell transplantation due to their age and/or severe comorbidities. It is essential to include supportive therapy in the integral treatment concept, in order to control pain or retain function or mobility. Supportive drugs such as bisphosphonates but also radiation therapy and orthopaedic surgery may be required in order to manage complications of the disease as well as side effects of treatment. Conclusion Current studies show promising results in the treatment of multiple myeloma, due to new agents such as immunomodulatory drugs, proteasome inhibitors and antibodies, which may improve prognosis and survival rate among myeloma patients in the future. However treatment algorithms have become more complex and expensive. PMID- 28806823 TI - Propensity Score Adjusted Comparison of Minimally Invasive versus Open Thymectomy in the Management of Early Stage Thymoma. AB - BACKGROUND: The benefits of minimally invasive versus open thymectomy for the management of thymoma are debatable. Further, patient factors contributing to the selection of operative technique are not well elucidated. We aim to identify the association between baseline patient characteristics with choice of surgical approach. METHODS: Medical records of early stage thymoma (stages I and II) patients undergoing thymectomy between 2005 and 2015 at a single center were identified. Baseline characteristics and surgical outcomes such as prolonged length of stay (LOS >= 4 days), 90-day postoperative morbidity, completeness of resection, and recurrence or mortality free rates were compared by surgical approach. RESULTS: Fifty-three patients underwent thymectomy (34 open [64.15%] vs. 19 minimally invasive [35.85%]). There were no statistical differences between the two surgical approaches in demographic variables, smoking status, lung function, comorbidity, tumor size, or staging. Open thymectomy had significantly prolonged LOS (>=4 days) compared with minimally invasive procedures (odds ratio: 11.65; p < 0.01). There were no significant differences in postoperative composite morbidity (p = 0.56), positive margin (p = 0.40), tumor within 0.1 cm of resection margin (p = 0.38), and survival probability estimates (log rank test; p = 0.48) between the two groups. CONCLUSION: Baseline patient characteristics were not associated with surgical approach selected for thymectomy. Minimally invasive thymectomy patients had shorter LOS but no significant differences in 90-day composite morbidity and recurrence or mortality. Larger multicenter studies are needed to evaluate factors contributing to patient selection for each approach, which may include surgeon preference. PMID- 28806824 TI - Surgical Treatment of Ebstein's Anomaly. AB - Surgical repair of the tricuspid valve is a milestone in the medical history of patientswith Ebstein's anomaly. The timely alleviation of the insufficiency has an importantimpact on the prognosis. In this review, we describe features of the disease relevant tosurgical correction and the evolution of surgical techniques over six decades. Wecompare the results of different repair and replacement techniques. Additionally, wediscuss concomitant antiarrhythmic surgery and bailout strategies for postoperativeright ventricular failure. Finally, we review the surgical options in symptomaticneonates with Ebstein's disease. PMID- 28806825 TI - [Completeness and reproducibility of surgical reports: A retrospective analysis of documentation quality using the example of Dupuytren's disease]. AB - Background A surgical report is the surgeon's postoperative documentation of the procedure undertaken. The purpose of this study was to evaluate the completeness and accuracy of data extracted from surgical reports, using the example of Dupuytren's disease. Material and Methods Between 1999 and 2007, surgical data were retrospectively collected from all primary Dupuytren's disease procedures performed at an academic department for plastic and reconstructive surgery and analysed for completeness. A surgical report was assessed as complete if data on indication, affected side and finger(s), tourniquet, type of incision and surgical procedure were stated. Surgical reports of residents and consultants were compared with respect to completeness. For the assessment of accuracy, total fasciectomy procedure reports were compared with intra- and postoperative photo documentation. Results 424 surgical reports of 366 patients were analysed, 275 created by consultants, 149 by residents. Although 49.5 % of all surgical reports were complete, the indication for surgery was omitted in 53 cases. Information on the affected side and finger(s) was missing in 13 and 6 cases, respectively. In 29 reports, no documentation on tourniquet was found, in 5 the surgical method and in 82 reports the type of incision was lacking. A significant difference between surgical reports of residents and consultants was found for documentation of indication and severity of the Dupuytren's disease, as well as the tourniquet, in favour of residents (p < 0.0001). In 37 surgical reports, total fasciectomy was performed, 26 with intra- or postoperative photodocumentation. By comparison, in 11 of 26 cases (42 %), total fasciectomy could not have been performed. Conclusion Surgical reports are sometimes incomplete and imprecise, independently of whether they were created by residents or consultants. Although they are intended as documentation for doctors and not for forensic reasons, it should be in the surgeon's interest to create complete and exact reports. As surgical reports are part of the patient's chart, surgical associations should develop guidlines with information that should manditorily included in surgical reports. PMID- 28806826 TI - [Treatment of Dupuytren's disease with collagenase injections in Germany: efficacy and adverse effects in 110 treated joints]. AB - Background Since 2011, a new minimally-invasive treatment for Dupuytren's disease has been available in the form of injectable collagenase (Xiapex(r), Pfizer). Purpose Our aim is to report about the results and adverse effects of injectable collagenase for the treatment of Dupuytren's disease in Germany. Patients and Methods We treated 78 patients (61 male, 17 female) with 87 injections in 87 digits (little finger n = 40, ring finger n = 37, middle finger n = 8 and index n = 2). We documented the range of motion before treatment, after 6 weeks and after 6 months. We were able to include 39 patients (32 male, 7 female) in the 6-month follow-up. Results The initial correction in MCP joints (n = 26) was from an average 51 degrees to 0 degrees (p < 0.05). After 6 months there was an average reduction of contracture in MCP joints (n = 16) from 52 degrees to 0 degrees (p < 0.05). The initial correction in PIP joints (n = 28) was from an average of 63 degrees to 15 degrees (p < 0.05). After 6 months, PIP joints (n = 12) exhibited an average correction from 70 degrees auf 40 degrees (p < 0.05). In combined contractures of MCP und PIP joints (n = 33), there was a mean reduction from 96 degrees to 13 degrees (p < 0.05). In the 6-month follow-up, the correction of combined contractures (n = 16) was from 91 degrees to 61 degrees (p < 0.05). Common adverse effects were local oedema (n = 36), followed by haematoma (n = 25), temporary livid discolouration (n = 17) and skin tears (n=16). There were no severe complications such as tendon ruptures, vessel or nerve injuries. The most severe complications comprised 4 little skin defects that healed with conservative wound care. Conclusion Our results are comparable with previous international studies. Very good success has been achieved with single injection treatment for high-grade preoperative contractures in MCP joints, while treatment success for combined contractures of MCP and PIP joints has been satisfactory. There have been no severe complications. Common adverse effects have been similar to previous studies. In our opinion, collagenase injection is a safe and efficient treatment for Dupuytren's disease. Further studies are needed to compare long-term efficacy with percutaneous needle aponeurotomy und partial fasciectomy. PMID- 28806827 TI - [Functional outcome following high-pressure injection injuries of the hand]. AB - Background High-pressure injection injuries are devastating injuries that often lead to an amputation of the primarily affected finger. The available literature mainly focuses on amputation rates, while there is a lack of knowledge regarding functional results. Patients and Methods Between 1998 and 2016, 47 cases of high pressure injection injuries of the hand were registered in our department. Out of these, data of 26 patients, all men with an average age of 42 (18-62) years, were included in a retrospective follow-up examination after 4 (1-12) years. We recorded DASH scores, pain intensity on visual analogue scales (VAS, 1-10), fingertip-to-palm distance, active range of wrist motion, grip strength, and two point-discrimination ability (2PD). The statistical analysis was descriptive and was performed by analysis of correlation. Results The average DASH score of these 26 patients was 45 (30-93), pain intensity was 2.5 (0-9) on the VAS, fingertip-to palm distance was 1 (0-4) cm. Active range of wrist motion was 99 (77-122) % of the contralateral side. Average grip strength was reduced to 67 (0-164) % of the contralateral side. Average 2PD was 9 (2-25) mm. Nineteen out of 26 patients returned to work. An amputation was necessary in 7 out of 26 cases. These patients had more pain and less grip strength. High latency from injury to operative treatment impaired functional outcome, which was statistically significant for DASH (p < 0.05). A trend to poorer outcomes was noted in cases of a more distal lesion and injection of toxic substances, whereas high injection pressure had no negative influence. Conclusion High-pressure injection injuries have serious consequences regarding hand function and frequently cause chronic pain. This affects patients with finger preservation as well as patients requiring an amputation. A further evaluation of prognostic factors requires a metaanalysis of functional parameters. The DASH score seems to be an expedient assessment tool. PMID- 28806828 TI - [Prophylactic plexus catheter treatment in operations following complex regional pain syndrome (CRPS)]. AB - Background This paper investigates and discusses the effect of perioperative plexus catheter treatment in former CRPS patients. Patients and Methods A retrospective matched-pair analysis was conducted on 10 CRPS patients with comparable injuries, who underwent surgery in the disease-free interval. In 10 cases, the procedure was performed with perioperative plexus catheter treatment (intervention group), whereas 10 patients did not receive perioperative plexus catheter treatment (control group). Results In the intervention group, after a follow-up time of 105 (20-184) days after the last surgical procedure, pain intensity on the visual analogue scale (VAS; 0 to 10) was 6.4 (4-8), fingertip-to palm distance averaged 3.2 (0-7.6) cm, active range of wrist motion was 47.5 (0 95), and grip strength was 9.2 (2.1-16.6) kg. In the control group, after a follow-up time of 129 (19-410) days since the last surgical procedure, pain intensity on the visual analogue scale was 6 (3-10), fingertip-to-palm distance averaged 2.7 (0-4.5) cm, active range of wrist-motion was 64 (0-125), and grip strength was 12.4 (0.8-23.8) kg. There was no significant difference between the groups. There was no recurrence of CRPS disease in either group after surgery. Conclusion There is no evidence so far for perioperative plexus catheter treatment to prevent recurrence in former CRPS patients. PMID- 28806829 TI - [Lundborg's resection arthroplasty vs. Pyrocarbon spacer (Pyrocardan(r)) for the treatment of trapeziometacarpal joint osteoarthritis: a two-centre study]. AB - Background Various operative approaches exist for osteoarthritis of the trapeziometacarpal joint. The aim of this two-centre study was to compare the results of Lundsborg's resection arthroplasty with the implantation of the Pyrocardan(r) spacer. Patients and methods We treated 20 patients with symptomatic osteoarthritis of the trapeziometacarpal joint in stage III / IV (Eaton-Littler classification). Twelve patients received Lundsborg's resection arthroplasty (centre 1), and in 8 patients a Pyrocardan(r) spacer was implanted (centre 2). Both groups were comparable regarding patients' age, the preoperative pain level, the osteoarthritis stage according to Eaton-Littler, and the duration from the onset of symptoms until surgery. Patient data were retrospectively collected from patient records, and we performed a follow-up examination at least 18 months postoperatively, thereby evaluating the DASH sore, the postoperative time until freedom of symptoms, the pain level according to the visual analogue scale, grip force (Jamar dynamometer), pinch force, and patients' treatment satisfaction (0-10; 10 = highest satisfaction). Results Both groups had a similar length of follow-up with 23.6 +/- 5.2 months for the resection group and 26.1 +/- 4.0 months for the spacer group. The duration of the operation was 31 +/- 5 min for the resection group and 29 +/- 7 min for the spacer group (p > 0.05). The DASH score was 21.9 +/- 6.2 in the resection group and 18.3 +/- 5.0 in the spacer group (p > 0.05). The pain level at the current follow-up was 1.5 +/- 0.83 in the spacer group and 1.0 +/- 0.74 in the resection group (p > 0.05). The time until freedom of symptoms was significantly shorter in the spacer group with 3.7 +/- 1.9 months compared to the resection group with 5.7 +/- 3.1 months (p = 0.0001). Grip force and pinch force were not significantly different between both groups. Treatment satisfaction was 9.3 +/- 1.6 in the resection group and 7.4 +/- 3.0 in the spacer group (p > 0.05). Conclusion Over a follow-up period of 1.5 years, both techniques resulted in a satisfactory usability of the operated hand and a clear reduction of symptoms. The implantation of the Pyrocardan(r) spacer seems to have slight advantages regarding a shorter time until freedom of symptoms. However, the implantation of the spacer is associated with additional material costs of a few hundred Euros, which are not incurred in resection arthroplasties. The implantation of the Pyrocardan(r) spacer seems to have slight advantages regarding a shorter time until freedom of symptoms. PMID- 28806830 TI - [The size and proportion of the interphalangeal finger joints: an anatomic study]. AB - Background This study aimed to evaluate the size of the joint surfaces of the proximal and distal interphalangeal finger joints. Material and Methods 117 proximal and distal interphalangeal joints of 30 formalin-fixed hands of body donors were included in this study. The size of the articular surface was determined for each joint. Results The mean size of the proximal joint surface of the distal interphalangeal joint is 56.1 mm2; the distal joint surface averages 30.9 mm2 (ratio: 1.8:1). The size of the proximal articular surface of the proximal interphalangeal joint is 92.5 mm2. The size of the distal articular surface averages 52.4 mm2 (ratio 1.7:1). Conclusions This is the first study to describe the articular surface area of the proximal and distal interphalangeal joints of the hand. PMID- 28806831 TI - Clinical Sign for Missed Decompression of a Separate Extensor Pollicis Brevis Compartment in de Quervain's Disease. AB - Persistent pain despite previous surgery for de Quervain's disease might be due to an overlooked septum between the abductor pollicis longus tendon slips and the extensor pollicis brevis tendon, or an overlooked completely separate compartment for the extensor pollicis brevis tendon alone. In both of these instances, extension of the MP joint of the thumb against resistance elicits pain at the distal level of the first extensor compartment of the wrist. When this sign is positive, revisional surgery and decompression of the remaining septum or separate compartment is indicated. PMID- 28806832 TI - [Dorsal ligamentoplasty for posttraumatic scapholunate dissociation]. AB - Scapholunate dissociation in stages 2 and 3 may lead to posttraumatic damage if left untreated. Different types of treatment have been described, including capsulodesis, tenodesis, and others. The purpose of all procedures is to avoid palmar shift of the distal scaphoid resulting in secondary arthritis (SLAC wrist). This study aimed to evaluate a modified dorsal ligamentoplasty in second- and third-degree scapholunate dissociation in a prospective study design. Furthermore, the study aimed to find out if there is a correlation between radiological and clinical parameters at follow-up and whether or not a SLAC wrist can be avoided. From 2007 to 2011 we performed 29 dorsal ligamentoplasties in our hospital in patients with second- and third-degree scapholunate dissociation. In a prospective study design, 25 patients were followed up after an average period of 18 months. Parameters recorded preoperatively included ROM, the radiological parameters SL diastasis, SL diastasis in power grip and SL angle, the DASH score, and the VAS score. The postoperative evaluation additionally included power grip, the Mayo wrist score, and patients' subjective satisfaction. The average subjective satisfaction after surgery was good. The average postoperative ROM was 83.8 % of the ROM of the healthy wrist and decreased by 11 % compared with the preoperative level. The average postoperative grip strength was 85.7 % of the strength of the healthy hand. The VAS score was 2.7 with a significant reduction from 6.7 preoperatively. The average DASH score decreased significantly from 60 preoperatively to 22.5 postoperatively. The average Mayo wrist score after surgery was 73. All radiological parameters at follow-up were significantly better than preoperatively, although they remained in a pathological range. The Pearson correlation analysis showed no relevant correlation between clinical and radiological scores. Three cases (12 %) required revision surgery. The described modified dorsal ligamentoplasty at the carpus can be recommended in second- and third-degree scapholunate dissociation. Clinical results are comparable to other techniques, but there is only a single approach required and the complication rate is very low. The short average follow-up of 18 months must be viewed critically as the rate of SLAC wrists might be higher during longer follow-up periods. PMID- 28806834 TI - [Extracorporeal loss of lunate in perilunar transscaphoidal fracture dislocation]. PMID- 28806833 TI - [Dynamic correction of scapholunate instability using an ECRL tendon strip and a free PL interponat]. AB - The present article describes our technique of correction of static reduceable scapholunate instability. PMID- 28806835 TI - [Median nerve compression neuropathy due to a closed osteocartilaginous tunnel at the distal upper arm: a case report]. PMID- 28806836 TI - [Complication of an Elbow Prosthesis: Screw Breakage of the Ulnar cap and Gout Arthropathy]. PMID- 28806837 TI - [Zum Beitrag: Die Technik der erweiterten perkutanen Nadelfasziotomie (PNF+) bei der Dupuytren'schen Kontraktur]. PMID- 28806839 TI - [Psychoanalysis and Psychiatrie-Enquete: expert interviews and document analysis]. AB - Background The purpose of this paper is to analyse the perception of the role of psychoanalysis and psychoanalysts in the coming about of the Psychiatrie-Enquete in the Federal Republic of Germany (West Germany). Methods We performed a qualitative content analysis of expert interviews with persons involved in the Enquete (or witnessing the events as mental health professionals active at the time), a selective literature review and an analysis of documents on the Enquete process. Results Expert interviews, relevant literature and documents point to a role of psychoanalysis in the Enquete process. Psychoanalysts were considered to have been effective in the run-up to the Enquete and the work of the commission. Conclusion Psychoanalysis and a small number of psychoanalysts were perceived as being relevant in the overall process of the Psychiatrie-Enquete in West Germany. PMID- 28806840 TI - Changes of Sagittal and Axial Alignments of Patella after Open- and Closed-Wedge High-Tibial Osteotomy: A Systematic Review and Meta-Analysis. AB - The present systematic review and meta-analysis were aimed to verify the effect of open-wedge (OW) and closed-wedge (CW) high-tibial osteotomy (HTO) on sagittal and axial alignments of the patella. A vigorous search was performed for studies that compared the changes of sagittal and axial alignments of patella after OW and CW HTO. After evaluating publication bias and heterogeneity, we aggregated variables by using the random-effects model. The weighted mean differences in sagittal and axial alignment of patella were estimated with 95% confidence intervals. Also, we analyzed the changes in sagittal alignment of various OW HTO techniques, such as uniplanar, biplanar, and retrotubercle osteotomy. Overall, 20 studies that included 831 OW HTOs and 206 CW HTOs were included in this study. Patellar height decreased after OW HTO based on the Blackburne-Peel index (BPI, mean: -0.10), and Caton-Deschamps index (CDI, mean: -0.08). However, the patellar height after CW HTO showed no change after surgery (BPI [mean: -0.02], and CDI [mean: 0.02]). Among OW HTO techniques, the retrotubercle osteotomy showed the least change in patellar height after surgery. The lateral patellar tilt decreased by 1.74 degrees, and lateral patellar shift showed no change after OW HTO. However, there was a lack of evidence to conclude the change of axial alignment of patella after CW HTO. Our results supported that the sagittal alignment of patella lowered after OW HTO. However, CW HTO maintained the constant sagittal position of the patella. Among OW HTO techniques, the retrotubercle osteotomy had the least effect on the sagittal alignment of the patella. Regarding the axial alignment of the patella, OW HTO resulted in a little change of lateral patellar tilt; however, there was little evidence to confirm the change of the axial alignment of patella after CW HTO. PMID- 28806841 TI - Genetic Polymorphisms as Predictive Markers of Response to Growth Hormone Therapy in Children with Growth Hormone Deficiency. AB - Objective Growth hormone (GH) deficiency (GHD) is commonly treated with recombinant human GH (rhGH). Individual response to rhGH therapy varies widely and there is evidence that variations in growth-related genes, e. g. the GH receptor (GHR) gene, may impact treatment response. We aimed to identify genetic polymorphisms which could serve as predictive markers of response to rhGH therapy. Methods We conducted a genetic analysis of single nucleotide polymorphisms (SNPs) and the GHR exon 3 deletion in 101 paediatric GHD patients receiving rhGH. Patients were analysed for 13 known SNPs in 11 genes of the GH axis (SOS1, IGFR1, GAB1, LHX4, IGFBP3, GRB10, GHRHR, GHSR), growth plate (VDR, ESR1) and cell cycle (CDK4). Individual index of responsiveness (IoR) values were compared by genotype. We also analysed the potential association between the IoR and the GHR exon 3 deletion. IoRs were analysed by genotype by one-way analysis of variance and unpaired t-test. Results Variations in two SNPs, rs2888586 (SOS1) and rs2069502 (CDK4), and the GHR exon 3 deletion were significantly associated with response to rhGH treatment. Conclusions Genetic variations are potentially suitable as predictive markers of rhGH treatment response in GHD. Genetic analysis provides a starting point for individualised treatment of GHD. PMID- 28806842 TI - Clowns in Paediatric Surgery: Less Anxiety and More Oxytocin? A Pilot Study. AB - Background Hospital stays and medical interventions are accompanied by worries and anxiety in children and parents. Recent studies show that hospital clowns may reduce anxiety and enhance well-being. However, so far studies are based solely on subjective measures and clowns are usually not integrated in medical routine. With this pilot study, we aim to provide both psychological and physiological evidence of positive effects of clowns' interventions in hospitalized children. Patients/Method In a consecutive randomized intervention-control group design with 31 children aged 4 to 13 years, 17 patients were accompanied by a clown prior to surgery or during ward round (intervention group) and 14 were not (control group). Saliva samples for oxytocin measurement were taken from all patients before hospitalization (T1) and prior to surgery or after ward round (T2). Self- and parents-reports were obtained at T1, T2 as well as at time of discharge from hospital (T3) regarding children's anxiety (STAI), worries and well-being. Clowns evaluated their success in cheering up the child. Health professionals were asked for their acceptance of clowns in hospitals. Results Children in the intervention group had lower anxiety ratings and a higher oxytocin concentration at T2 as compared with T1; the control group showed no changes. Parents rated the well-being of their children higher if their child had clown's contact and were more willing to recommend the hospital. The staff judged the clowns as helpful for patients. Discussion Consistent psychological and physiological results suggest the positive impact of a clown's intervention in hospitalized children. PMID- 28806843 TI - Congenital Jejunal Membrane Causing Transient Pseudohypoaldosteronism and Hypoprothrombinemia in a 7-Week-Old Infant. PMID- 28806844 TI - [Treatment of Morbus Hodgkin in a Child with Congenital Lamellar Ichthyosis]. PMID- 28806845 TI - [Effectivity of Inpatient Psychosomatic Treatment - Results of a Naturalistic Two Year Survey in a Psychosomatic Service at a General Hospital]. AB - BACKGROUND: Hospital psychosomatic treatment matches care expectations of a modern society. Evidence of its effectiveness through investigation in different settings is of importance because of prominent role of psychotherapy in German Healthcare System. OBJECTIVE: First, to explore whether clinical as well as personal resources could improve significantly due to a hospital psychosomatic treatment. Second, to assess possible associations between outcome variables and other variables from the multidimensional profile of the sample. METHOD: The sample consists of all 2014 - 2015 admitted patients who agree with investigation (N=283). Pre-post comparisons of results from validated questionnaires were performed by means of t-tests, including effect sizes. Associations between outcome variables (pre-post differences of clinical and resources related variables) and variables from the multidimensional profile were performed by means of bivariate and multivariate regression tests. Outcome differences were assessed by means of logistic regression models. RESULTS: Drop-out-rate due to refusal of participation amounts 11.8%; from remaining participants uncompleted datasets additional 6.9%; due to declining further participation during hospitalisation additional 4.1% (total drop-out rate amounted 22.8%). Functionality, self-efficacy, disease severity, psychological as well as physical symptom burden, depressiveness, interpersonal concerns, and embitterment improved significantly (p<0.001) displaying effect sizes between 0.39 and 1.42 (average level for clinical variables 0.98). Considerable associations between clinical and resources related variables in both directions were found. 10% of patients reported worsening. DISCUSSION: Psychosomatic hospital treatment is effective according to clinical improvement as well as to perceived quality of treatment. Clinical and resources related variables are positively bidirectional associated notwithstanding the kind of working causality. Robust prognostic factors are hard to identify. CONCLUSIONS: Inpatient psychosomatic treatment is effective when the admission is indicated and the unit accomplishes mandatory quality criteria. The outcome occurs individually and is hard to be predicted. Depressiveness and embitterment could be considered as epiphenomena of all psychosomatic illnesses. PMID- 28806846 TI - The Oxytocin Product Correlates with Total Oxytocin Received during Labor: A Research Methods Study. AB - OBJECTIVE: Total dose of oxytocin received during labor is an important variable in studies of human labor but is difficult to calculate. We sought to identify a surrogate measure for total dose of oxytocin received. STUDY DESIGN: For each subject receiving oxytocin during labor, the oxytocin total dose received in labor was calculated as the area under the curve. Maximal oxytocin infusion rate, total duration of oxytocin infusion, and the product of both, defined as the oxytocin product, were then each correlated with the total dose of oxytocin received using the Pearson's correlation coefficient. RESULTS: Oxytocin dosing data were available from 402 women at Duke and 6,907 women from Pithagore6. The two variables alone, or combined as the oxytocin product, demonstrated a high correlation with the oxytocin total dose (r > 0.7), with the oxytocin product demonstrating the highest (r > 0.9). This was true whether labor was induced or augmented and whether delivery was vaginal or cesarean. CONCLUSION: The oxytocin product, composed of two easily obtained variables, demonstrated a very high correlation with total oxytocin dose received in labor and represents a simple and accurate surrogate for total dose of oxytocin received during labor. The oxytocin product can be used in clinical studies in which oxytocin dose is an important variable. PMID- 28806847 TI - Interhospital Transfers of Maternal Patients: Cohort Analysis of Nationwide Inpatient Sample, 2011. AB - OBJECTIVE: The objective of this study was to estimate the annual rate of interhospital transfers of pregnant and postpartum women in the United States and analyze associated patient and health system characteristics as measures of regionalized perinatal care performance. METHODS: Separate weighted univariate analyses of the 2011 Nationwide Inpatient Sample (NIS) were performed for all maternal discharges, in-hospital deaths, and transfers. Multivariable logistic regression analyses for transfer dispositions adjusted for health system characteristics, maternal demographics, and diagnoses were performed. Additional perinatal service characteristics were analyzed using NIS merged with the 2011 American Hospital Association Annual Survey database. RESULTS: An estimated 18,082 patients, 0.43% of maternal hospitalizations, were transferred to an acute care hospital; 81% occurred without childbirth delivery before transfer. Transfers were toward larger, urban teaching hospitals and hospitals with higher levels of obstetrical and neonatal care and were more likely in states with >=4.0 maternal-fetal medicine specialists/10,000 live births. Blacks and Native Americans were more likely and Hispanics and Asians were less likely than white patients to be transferred. Privately insured women were less likely to be transferred than were others. Transfers were associated with life-threatening maternal diagnoses and fetal indications. CONCLUSION: Transfers reflected a risk based regionalized system of perinatal care, with racial and payer differences. PMID- 28806848 TI - Comparison of Live Rat Femoral Artery Model with Intraoperative Microvascular Anastomosis. PMID- 28806849 TI - Effect of Monopolar Cutting Mode against Bipolar Diathermy on Surgical Dissection of Microvessels. PMID- 28806850 TI - The Global Initiative for Children's Surgery: Optimal Resources for Improving Care. AB - BACKGROUND: The Lancet Commission on Global Surgery reported that 5 billion people lack access to safe, affordable surgical care. The majority of these people live in low-resource settings, where up to 50% of the population is children. The Disease Control Priorities (Debas HTP, Donkor A, Gawande DT, Jamison ME, Kruk, and Mock CN, editors. Essential Surgery. Disease Control Priorities. Third Edition, vol 1. Essential Surgery. Washington, DC: World Bank; 2015) on surgery included guidelines for the improvement of access to surgical care; however, these lack detail for children's surgery. AIM: To produce guidance for low- and middle-income countries (LMICs) on the resources required for children's surgery at each level of hospital care. METHODS: The Global Initiative for Children's Surgery (GICS) held an inaugural meeting at the Royal College of Surgeons in London in May 2016, with 52 surgical providers from 21 countries, including 27 providers from 18 LMICs. Delegates engaged in working groups over 2 days to prioritize needs and solutions for optimizing children's surgical care; these were categorized into infrastructure, service delivery, training, and research. At a second GICS meeting in Washington in October 2016, 94 surgical care providers, half from LMICs, defined the optimal resources required at primary, secondary, tertiary, and national referral level through a series of working group engagements. RESULTS: Consensus solutions for optimizing children's surgical care included the following: . Establishing standards and integrating them into national surgical plans.. . Each country should have at least one children's hospital.. . Designate, facilitate, and support regional training hubs covering all. . children's surgical specialties.. . Establish regional research support centers.. An "Optimal Resources" document was produced detailing the facilities and resources required at each level of care. CONCLUSION: The Optimal Resources document has been produced by surgical providers from LMICs who have the greatest insight into the needs and priorities in their population. The document will be refined further through online GICS Working Groups and the World Health Organization for broad application to ensure all children have timely access to safe surgical care. PMID- 28806851 TI - Production of Single Contracting Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes: Matrigel Mattress Technique. AB - This unit describes the published Matrigel mattress method. Briefly, we describe the preparation of the mattress, replating of the human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) on the Matrigel mattress, and hiPSC-CM mattress maintenance. Adherence to this protocol will yield individual, robustly shortening hiPSC-CMs, which can be used for downstream applications. (c) 2017 by John Wiley & Sons, Inc. PMID- 28806852 TI - Generation of Oligodendrogenic Spinal Neural Progenitor Cells From Human Induced Pluripotent Stem Cells. AB - This unit describes protocols for the efficient generation of oligodendrogenic neural progenitor cells (o-NPCs) from human induced pluripotent stem cells (hiPSCs). Specifically, detailed methods are provided for the maintenance and differentiation of hiPSCs, human induced pluripotent stem cell-derived neural progenitor cells (hiPS-NPCs), and human induced pluripotent stem cell oligodendrogenic neural progenitor cells (hiPSC-o-NPCs) with the final products being suitable for in vitro experimentation or in vivo transplantation. Throughout, cell exposure to growth factors and patterning morphogens has been optimized for both concentration and timing, based on the literature and empirical experience, resulting in a robust and highly efficient protocol. Using this derivation procedure, it is possible to obtain millions of oligodendrogenic NPCs within 40 days of initial cell plating which is substantially shorter than other protocols for similar cell types. This protocol has also been optimized to use translationally relevant human iPSCs as the parent cell line. The resultant cells have been extensively characterized both in vitro and in vivo and express key markers of an oligodendrogenic lineage. (c) 2017 by John Wiley & Sons, Inc. PMID- 28806853 TI - Development of Hepatocyte-like Cell Derived from Human Induced Pluripotent Stem cell as a Host for Clinically Isolated Hepatitis C Virus. AB - This unit describes protocols to develop hepatocyte-like cells (HLCs) starting from mesenchymal stem cells (MSCs) as a natural host for hepatitis C virus (HCV). These include the preparation of MSCs from bone marrow, the reprogramming of MSCs into induced pluripotent stem cells (iPSCs), and the differentiation of iPSCs into HLCs. This unit also incorporates the characterization of the resulting cells at each stage. Another section entails the preparations of HCV. The sources of HCV are either the clinically isolated HCV (HCVser) and the conventional JFH-1 genotype. The last section is the infection protocol coupled with the measurement of viral titer. (c) 2017 by John Wiley & Sons, Inc. PMID- 28806854 TI - Generation of Xeno-Free, cGMP-Compliant Patient-Specific iPSCs from Skin Biopsy. AB - This unit describes protocols for the generation of clinical-grade patient specific induced pluripotent stem cell (iPSC)-derived retinal cells from patients with inherited retinal degenerative blindness. Specifically, we describe how, using xeno-free reagents in an ISO class 5 environment, one can isolate and culture dermal fibroblasts, generate iPSCs, and derive autologous retinal cells via 3-D differentiation. The universal methods described herein for the isolation of dermal fibroblasts and generation of iPSCs can be employed regardless of disease, tissue, or cell type of interest. (c) 2017 by John Wiley & Sons, Inc. PMID- 28806855 TI - Functional Stem Cell Integration into Neural Networks Assessed by Organotypic Slice Cultures. AB - Re-formation or preservation of functional, electrically active neural networks has been proffered as one of the goals of stem cell-mediated neural therapeutics. A primary issue for a cell therapy approach is the formation of functional contacts between the implanted cells and the host tissue. Therefore, it is of fundamental interest to establish protocols that allow us to delineate a detailed time course of grafted stem cell survival, migration, differentiation, integration, and functional interaction with the host. One option for in vitro studies is to examine the integration of exogenous stem cells into an existing active neural network in ex vivo organotypic cultures. Organotypic cultures leave the structural integrity essentially intact while still allowing the microenvironment to be carefully controlled. This allows detailed studies over time of cellular responses and cell-cell interactions, which are not readily performed in vivo. This unit describes procedures for using organotypic slice cultures as ex vivo model systems for studying neural stem cell and embryonic stem cell engraftment and communication with CNS host tissue. (c) 2017 by John Wiley & Sons, Inc. PMID- 28806857 TI - Structure elucidation, total assignment of the 1 H and 13 C chemical shifts, and absolute configuration by NMR techniques of dammarane-type triterpenes from Hippocratea volubilis. PMID- 28806856 TI - Direct Cell Labeling to Image Transplanted Stem Cells in Real Time Using a Dual Contrast MRI Technique. AB - Exogenous direct cell labeling with superparamagnetic iron oxide nanoparticles (SPIONs) is currently the most employed cell-labeling technique for tracking transplanted cells using magnetic resonance imaging (MRI). Although SPION-based cell labeling is effective for monitoring cell delivery and migration, monitoring cell survival is still a challenge. This unit describes an MRI technique that permits detection of the delivery, migration, and death of transplanted cells. This dual-contrast technique involves labeling cells with two different classes of MRI contrast agents, possessing different diffusion coefficients: SPIONs (T2 /T2* contrast agents, with lower diffusion coefficients) and gadolinium chelates (T1 contrast agents, with higher diffusion coefficients). In live cells, where both agents are in close proximity, the T2 /T2* contrast predominates and the T1 contrast is quenched. In dead cells, where the cell membrane is breached, gadolinium chelates diffuse from the SPIONs and generate a signature T1 contrast enhancement in the vicinity of dead cells. (c) 2017 by John Wiley & Sons, Inc. PMID- 28806858 TI - The haemtrack home therapy reporting system: Design, implementation, strengths and weaknesses: A report from UK Haemophilia Centre Doctors Organisation. AB - INTRODUCTION: Haemtrack is an electronic home treatment diary for patients with inherited bleeding disorders, introduced in 2008. It aimed to improve the timeliness and completeness of patient-reported treatment records, to facilitate analysis of treatment and outcome trends. The system is easy to use, responsive and accessible. METHODS: The software uses Microsoft technologies with a SQL Server database and an ASP.net website front-end, running on personal computers, android and I-phones. Haemtrack interfaces with the UK Haemophilia Centre Information System and the National Haemophilia Database (NHD). Data are validated locally by Haemophilia Centres and centrally by NHD. Data collected include as follows: treatment brand, dose and batch number, time/date of bleed onset and drug administration, reasons for treatment (prophylaxis, bleed, follow up), bleed site, severity, pain-score and outcome. RESULTS: Haemtrack was used by 90% of haemophilia treatment centres (HTCs) in 2015, registering 2683 patients using home therapy of whom 1923 used Haemtrack, entering >17 000 treatments per month. This included 68% of all UK patients with severe haemophilia A. Reporting compliance varied and 55% of patients reported >=75% of potential usage. Centres had a median 78% compliance overall. A strategy for progressively improving compliance is in place. Age distribution and treatment intensity were similar in Haemtrack users/non-users with severe haemophilia treated prophylactically. CONCLUSION: The Haemtrack system is a valuable tool that may improve treatment compliance and optimize treatment regimen. Analysis of national treatment trends and large-scale longitudinal, within-patient analysis of changes in regimen and/or product will provide valuable insights that will guide future clinical practice. PMID- 28806859 TI - Analysis of low molecular weight compounds using MALDI- and LDI-TOF-MS: Direct detection of active pharmaceutical ingredients in different formulations. AB - Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) is a high throughput, easy to use analytical technique. The simple sample preparation of this technique and its tolerance to the presence of contaminants are among its advantages. In contrast, depending on the matrix used, MALDI can ionize and generates ions in the low m/z range that complicate the interpretation of the spectra of low molecular weight compounds. To address this issue, one can envisage the use of tunable ionic matrices that can reduce the low m/z interferents. In this work, the ionic matrices triethylammonium alpha-cyano-4 hydroxycinnamate and diisopropylammonium alpha-cyano-4-hydroxycinnamate were used to directly analyze 14 pharmaceutical drugs in different formulations (coated tablets, noncoated tablets, capsules, and solutions). This methodology enabled the detection of their active compounds with minimum sample preparation, thus providing a straightforward approach for the forensic analysis of pharmaceutical drugs in the quest for detecting counterfeits. LDI-MS experiments were also performed, and the active ingredient in all of the medicines analyzed were detected. However, MALDI-MS spectra for the medicines analyzed herein showed less or no fragmentation than LDI-MS, which makes the analysis easier. PMID- 28806860 TI - Patient, caregiver, and provider perceptions of pain and pain management in adolescents and young adults with bleeding disorders. AB - INTRODUCTION: Recurrent bleeding and associated pain are critical components in the management of bleeding disorders, yet scant data describe perceptions of pain in this patient population. OBJECTIVE: This study assessed perceptions of pain and pain management in adolescents and young adults (AYAs) with haemophilia or von Willebrand disease (VWD) to determine agreement/disagreement between patients, caregivers and health care providers. METHODS: Using an online questionnaire, AYA patients (N=89), their caregivers (N=77), and providers (N=54) reported on pain perception, pain treatment and pain control. Acute and chronic pain was measured in patients via the Faces Pain Scale-Revised (FPS-R). Questionnaires queried about pharmacologic and non-pharmacologic pain management methods and how well providers and caregivers helped to manage pain. RESULTS: Poor agreement existed between patients and caregivers across all pain levels, perception of pain control and effectiveness of pain management. Specifically for chronic pain, poor agreement was noted between patients and caregivers (kappa=0.04; 29% agreement) and patients and providers (kappa=-0.07; 21.4% agreement). Among patients reporting acute or chronic pain, only 67% and 43%, respectively, utilized medication for their specific pain. Patients used more opioid medications than expected by their providers. On average, AYAs reported initial use of pain medications for chronic pain at 11.5 years. CONCLUSIONS: Ongoing research is needed in haemophilia and VWD pain management, and on the differences in pain perception between patients, caregivers and providers. As chronic pain often begins at an early age, optimal pain management should include acknowledging patient complaints, exploring pharmacologic and non-pharmacologic options, and optimizing prophylaxis. PMID- 28806861 TI - IMPACT OF JOINT ATTENTION ON SOCIAL-COMMUNICATION SKILLS IN INTERNATIONALLY ADOPTED CHILDREN. AB - Internationally adopted (IA) children have often experienced early adversity and are at risk for long-term deficiencies in multiple developmental domains. This study examined the association between IA children's joint attention (JA) soon after arrival and later cognitive, communicative, and socioemotional competency 6 months' postadoption. We expected a child's initial JA would positively predict later cognitive, communication, and social ability. IA children (n = 63) adopted from Eastern Europe were seen soon after their arrival into the United States to assess their JA. Their socioemotional competency, social communication, and cognitive abilities were measured at a follow-up session 6 months' postadoption. We found that higher order JA was positively associated with measures of social relatedness. Furthermore, individual hierarchical regressions of each measure of JA (higher order JA, initiating JA, responding to JA, and initiating behavior requests [BR]) considered with age-at-adoption showed that each measure was an independent and positive predictor of Mullen outcomes in the receptive and expressive language domains. These results suggest that JA may be a sensitive predictor of subsequent functioning in the social, communicative, and cognitive domains. Thus, assessing JA soon after arrival has the potential to identify at risk IA children, and interventions targeting JA may support those children in overcoming the negative impacts of early adversity. PMID- 28806862 TI - FEASIBILITY AND EFFECTIVENESS OF DYADIC PROLONGED EXPOSURE INTERVENTION FOR PREVENTING POSTTRAUMATIC GRIEF IN YOUNG CHILDREN: A CASE REPORT OF TWO SIBLINGS. AB - This article highlights the feasibility of a dyadic prolonged exposure (DPE) intervention (L. Rachamim, I. Mirochnik, L. Helpman, N. Nacasch, & E. Yadin, ) in a 3-year-old preschooler and in a 6-year-old kindergartener immediately following the traumatic death of their younger sibling. It presents a detailed case description of the DPE treatment addressing traumatic grief and includes transcribed treatment dialogue. At the time of treatment termination, both children and caregivers resumed normal functioning. The results suggest that DPE intervention may ameliorate posttraumatic grief symptoms in young children. Controlled studies of preventive interventions for this population are clearly warranted. PMID- 28806863 TI - Influence of gender, working field and psychosocial factors on the vulnerability for burnout in mental hospital staff: results of an Austrian cross-sectional study. AB - INTRODUCTION: According to the European Agency for Safety and Health at Work (EU OSHA), hospitals represent a work environment with high job strain. Prolonged perceived occupational stress may result in symptoms of burnout, such as emotional exhaustion (EE), depersonalisation (DP) and reduced personal accomplishment (PA). Understanding which factors may reduce vulnerability for burnout is an important requirement for well-targeted occupational stress prevention in mental hospital staff. OBJECTIVE: To identify the influence of gender, age, working field, family structure, education, voluntarily occupational training during holidays and length of stay on job on occupational stress perception. METHODS: In a cross-sectional design, 491 employees (311 female, 180 male) of an Austrian mental health centre participated in the study. The extent of perceived occupational stress was assessed by the Maslach Burnout Inventory (MBI) with the scales for emotional exhaustion, depersonalisation and personal accomplishment. Participants were divided according to their working field in those working with/without patients. FINDINGS: Prevalence of emotional exhaustion was higher in women working with patients compared to men working with patients (25% vs. 18%, p = 0.003). Age above 45 years was significantly associated with decreased vulnerability for burnout in men (EE p = 0.040, DP p = 0.010, PA p = 0.007), but not in women. A lower level of education had a significant impact on depersonalisation in both sexes (p = 0.001 for men, p = 0.048 for women). Length of stay on job showed a significant influence on emotional exhaustion. No significant relationship was found between family structure and vulnerability for burnout. CONCLUSION: Gender had a differential effect on perceived occupational stress indicating a need for gender-tailored preventive strategies. Age, working field, education, voluntarily occupational training during holidays and length of stay on job affect vulnerability for burnout in mental hospital staff. PMID- 28806865 TI - Study Break: Glucose-Sensitive Holographic (Bio)Sensors: Fundamentals and Applications PMID- 28806864 TI - Study of physical function in adolescents with haemophilia: The SO-FIT study. AB - INTRODUCTION: Contemporary haemophilia care demands Patient-Reported Outcomes. SO FIT is a UK multi-centre study, assessing self-reported function, health-related quality of life (HRQoL) and joint health in boys with severe haemophilia. METHODS: Subjective physical function (PedHAL, HEP-Test-Q) and HRQoL (Haemo-QoL Short Form [SF]) were assessed alongside joint health using the objective Haemophilia Joint Health Score (HJHS v2.1). Demographic and clinical data were collected. RESULTS: Data from 127 boys mean age 12.38 +/- 2.5 (range 8-17) treated at 16 sites were analysed. One-hundred-and-thirteen had haemophilia A, 25/9 past/current inhibitor, 124 were treated prophylactically (46.8% primary) and three on-demand. In the preceding 6 months, boys reported median 0 joint bleeds (range 0-8) with a median HJHS score of 1 (range 0-30). Boys reported good physical functioning; HEP-Test-Q (M = 80.32 +/- 16.1) showed the highest impairments in the domain "endurance" (72.53 +/- 19.1), in PedHAL (M = 85.44 +/- 18.9) highest impairments were in the domains "leisure activities & sports" (M = 82.43 +/- 23.4) and "lying/sitting/kneeling/standing" (M = 83.22 +/- 20.3). Boys reported generally good HRQoL in Haemo-QoL SF SF (M = 22.81 +/- 15.0) with highest impairments in the domains "friends" (M = 28.81 +/- 30.5) and "sports & school" (M = 26.14 +/- 25.1). HJHS revealed low correlations with the Haemo-QoL SF (r = .251, P < .006), the PedHAL (r = -.397, P < .0001) and the HEP-Test-Q (r = -.323, P < .0001). A moderate correlation was seen between HEP-Test-Q and Haemo QoL SF of r = -.575 (P < .0001) and between PedHAL and Haemo-QoL SFr = -.561 (P < .0001) implying that good perceived physical function is related to good HRQoL. CONCLUSIONS: The SO-FIT study has demonstrated that children with severe haemophilia in the UK report good HRQoL and have good joint health as reflected in low HJHS scores. PMID- 28806866 TI - Molecular Screening and Single Nucleotide Polymorphism Typing of Molluscum Contagiosum Virus (MCV) from Genital Specimens, between 2012 and 2015 AB - Background: The present study is the first comprehensive report of the Molluscum contagiosum virus (MCV) in Iran based on the molecular technique for differentiation and typing of the MCV1 and MCV2. Methods: Patients were diagnosed as having tumor-like genital warts less than 5 mm in diameter, and HIV seronegative samples were chosen for this cross-sectional study. TaqMan real-time PCR was used to identify MCV following clinical examination. Typing of the MCV positive specimens was performed in the SNP A27451G region of MC021L gene. Results: Of 1470 samples, 114 (7.75%) samples were positive for the MCV. From MCV positive samples, 71.05% sequences were found to be related to the MCV1 and 28.95% to the MCV2. Conclusion: This assay constitutes a reliable method for identification and typing of the MCV genomic variants that could be valuable for reviewing the pathogenesis, molecular epidemiology, and the natural history of MCV-related situations. PMID- 28806867 TI - Death by maladministration: An important category of patient mortality PMID- 28806868 TI - Mechanistic Investigation of Thermal and Photoreactions between Boron and Silane. AB - Density functional theory and high-level ab initio calculations were performed to elucidate the detailed reaction mechanism from B and SiH4 to a structure with two bridging H atoms (Si(MU-H2)BH2, silicon tetrahydroborate). On the basis of the calculated results, this reaction mechanism includes both thermal and photochemical reactions. Especially, thermal conversion of silylene dihydroborate (H2B?SiH2) to Si(MU-H2)BH2 is not feasible because two high energetic barriers must be overcome. In contrast, the reverse reaction is feasible because it is effectively only necessary to overcome a single barrier. The characteristics of the excited states of H2B?SiH2 and Si(MU-H2)BH2 have been identified. Two successive conical intersections (CIs) are involved in the photochemical reaction. The BSiH4 bending coordinate is almost parallel to the reaction coordinate near the regions from the second CI to Si(MU-H2)BH2. The activated BSiH4 bending mode lift the degeneracy of the second CI, thereby the reaction readily proceeds to Si(MU-H2)BH2. All calculated results in this work reasonably well describe the recent experimental observations. PMID- 28806870 TI - Catalytic Reductive Vinylidene Transfer Reactions. AB - Methylenecyclopropanes are important synthetic intermediates that possess strain energies exceeding those of saturated cyclopropanes by >10 kcal/mol. This report describes a catalytic reductive methylenecyclopropanation reaction of simple olefins, utilizing 1,1-dichloroalkenes as vinylidene precursors. The reaction is promoted by a dinuclear Ni catalyst, which is proposed to access Ni2(vinylidenoid) intermediates via C-Cl oxidative addition. PMID- 28806872 TI - Di- and Trivalent Metal-Ion Solution Studies with the Phosphinate-Containing Heterocycle DEDA-(PO). AB - A 7-membered triprotic heterocycle, DEDA-(PO), was synthesized, characterized, and tested for its solution properties with three trivalent lanthanides (La3+, Gd3+, and Lu3+) and three biologically relevant divalent metal ions (Ca2+, Zn2+, and Cu2+). The ligand synthesis has been reported once before; however, the characterization results were previously misinterpreted to correspond to a larger, 14-membered heterocycle, TETA-(PO)2. This manuscript serves to correct the original paper. Potentiometric titrations were carried out with each of the metal ions, and the thermodynamic stability values in terms of log beta and log KML were calculated showing a 1:1 metal-to-ligand ratio preference for the divalent metal ions and a 1:2 ratio for the lanthanides. The stability of the 1:2 complexes decreased across the lanthanide series, presumed to be a steric effect. Further resolution to the potentiometry results was given via pH-dependent NMR spectrometry (with La3+) and pH-dependent UV-vis spectroscopy (with Cu2+), and the pM values were calculated for all metal ions. The solid-state structure of the 1:1 Cu2+-DEDA-(PO) complex was further characterized by X-ray crystallography. PMID- 28806871 TI - Bioreducible Hydrophobin-Stabilized Supraparticles for Selective Intracellular Release. AB - One of the main hurdles in nanomedicine is the low stability of drug-nanocarrier complexes as well as the drug delivery efficiency in the region-of-interest. Here, we describe the use of the film-forming protein hydrophobin HFBII to organize dodecanethiol-protected gold nanoparticles (NPs) into well-defined supraparticles (SPs). The obtained SPs are exceptionally stable in vivo and efficiently encapsulate hydrophobic drug molecules. The HFBII film prevents massive release of the encapsulated drug, which, instead, is activated by selective SP disassembly triggered intracellularly by glutathione reduction of the protein film. As a consequence, the therapeutic efficiency of an encapsulated anticancer drug is highly enhanced (2 orders of magnitude decrease in IC50). Biodistribution and pharmacokinetics studies demonstrate the high stability of the loaded SPs in the bloodstream and the selective release of the payloads once taken up in the tissues. Overall, our results provide a rationale for the development of bioreducible and multifunctional nanomedicines. PMID- 28806873 TI - Super-Resolving the Actual Position of Single Fluorescent Molecules Coupled to a Plasmonic Nanoantenna. AB - Plasmonic nanoparticles (NPs) enhance the radiative decay rate of adjacent dyes and can significantly increase fluorescence intensity for improved spectroscopy. However, the NP nanoantenna complicates super-resolution imaging by introducing a mislocalization between the emitter position and its super-resolved emission position. The mislocalization magnitude depends strongly on the dye/NP coupling geometry. It is therefore crucial to quantify mislocalization to recover the actual emitter position in a coupled system. Here, we super-resolve in two and three dimensions the distance-dependent emission mislocalization of single fluorescent molecules coupled to gold NPs with precise distance tuning via double stranded DNA. We develop an analytical framework to uncover detailed spatial information when direct 3D imaging is not accessible. Overall, we demonstrate that by taking measurements on a single, well-defined, and symmetric dye/NP assembly and by accounting explicitly for artifacts from super-resolution imaging, we can measure the true nanophotonic mislocalization. We measure up to 50 nm mislocalizations and show that smaller separation distances lead to larger mislocalizations, also verified by electromagnetic calculations. Overall, by quantifying the distance-dependent mislocalization shift in this gold NP/dye coupled system, we show that the actual physical position of a coupled single emitter can be recovered. PMID- 28806874 TI - The Molecular Basis for Binding of an Electron Transfer Protein to a Metal Oxide Surface. AB - Achieving fast electron transfer between a material and protein is a long standing challenge confronting applications in bioelectronics, bioelectrocatalysis, and optobioelectronics. Interestingly, naturally occurring extracellular electron transfer proteins bind to and reduce metal oxides fast enough to enable cell growth, and thus could offer insight into solving this coupling problem. While structures of several extracellular electron transfer proteins are known, an understanding of how these proteins bind to their metal oxide substrates has remained elusive because this abiotic-biotic interface is inaccessible to traditional structural methods. Here, we use advanced footprinting techniques to investigate binding between the Shewanella oneidensis MR-1 extracellular electron transfer protein MtrF and one of its substrates, alpha-Fe2O3 nanoparticles, at the molecular level. We find that MtrF binds alpha Fe2O3 specifically, but not tightly. Nanoparticle binding does not induce significant conformational changes in MtrF, but instead protects specific residues on the face of MtrF likely to be involved in electron transfer. Surprisingly, these residues are separated in primary sequence, but cluster into a small 3D putative binding site. This binding site is located near a local pocket of positive charge that is complementary to the negatively charged alpha Fe2O3 surface, and mutational analysis indicates that electrostatic interactions in this 3D pocket modulate MtrF-nanoparticle binding. Strikingly, these results show that binding of MtrF to alpha-Fe2O3 follows a strategy to connect proteins to materials that resembles the binding between donor-acceptor electron transfer proteins. Thus, by developing a new methodology to probe protein-nanoparticle binding at the molecular level, this work reveals one of nature's strategies for achieving fast, efficient electron transfer between proteins and materials. PMID- 28806876 TI - Retraction of "Synthesis and Solution Studies of the Complexes of Trivalent Lanthanides with the Tetraazamacrocycle TETA-(PO)2". PMID- 28806875 TI - Homologous Series of 2D Chalcogenides Cs-Ag-Bi-Q (Q = S, Se) with Ion-Exchange Properties. AB - Four new layered chalcogenides Cs1.2Ag0.6Bi3.4S6, Cs1.2Ag0.6Bi3.4Se6, Cs0.6Ag0.8Bi2.2S4, and Cs2Ag2.5Bi8.5Se15 are described. Cs1.2Ag0.6Bi3.4S6 and Cs1.2Ag0.6Bi3.4Se6 are isostructural and have a hexagonal P63/mmc space group; their structures consist of [Ag/Bi]2Q3 (Q = S, Se) quintuple layers intercalated with disordered Cs cations. Cs0.6Ag0.8Bi2.2S4 also adopts a structure with the hexagonal P63/mmc space group and its structure has an [Ag/Bi]3S4 layer intercalated with a Cs layer. Cs1.2Ag0.6Bi3.4S6 and Cs0.6Ag0.8Bi2.2S4 can be ascribed to a new homologous family Ax[MmS1+m] (m = 1, 2, 3...). Cs2Ag2.5Bi7.5Se15 is orthorhombic with Pnnm space group, and it is a new member of the A2[M5+nSe9+n] homology with n = 6. The Cs ions in Cs1.2Ag0.6Bi3.4S6 and Cs0.6Ag0.8Bi2.2S4 can be exchanged with other cations, such as Ag+, Cd2+, Co2+, Pb2+, and Zn2+ forming new phases with tunable band gaps between 0.66 and 1.20 eV. Cs1.2Ag0.6Bi3.4S6 and Cs0.6Ag0.8Bi2.2S4 possess extremely low thermal conductivity (<0.6 W.m-1.K-1). PMID- 28806877 TI - Electrochemically Mediated Surface-Initiated de Novo Growth of Polymers for Amplified Electrochemical Detection of DNA. AB - The development of convenient and efficient strategies without involving any complex nanomaterials or enzymes for signal amplification is of great importance in bioanalytical applications. In this work, we report the use of electrochemically mediated surface-initiated atom transfer radical polymerization (SI-eATRP) as a novel amplification strategy based on the de novo growth of polymers (dnGOPs) for the electrochemical detection of DNA. Specifically, the capture of target DNA (tDNA) by the immobilized peptide nucleic acid (PNA) probes provides a high density of phosphate groups for the subsequent attachment of ATRP initiators onto the electrode surface by means of the phosphate-Zr4+-carboxylate chemistry, followed by the de novo growth of electroactive polymer via the SI eATRP. De novo growth of long polymeric chains enables the labeling of numerous electroactive probes, which in turn greatly improves the electrochemical response. Moreover, it circumvents the slow kinetics and poor coupling efficiency encountered when nanomaterials or preformed polymers are used and features sufficient flexibility and simplicity in controlling the degree of signal amplification. Under optimal conditions, it allows a highly sensitive and selective detection of tDNA within a broad linear range from 0.1 fM to 0.1 nM (R2 = 0.996), with the detection limit down to 0.072 fM. Compared with the unamplified method, more than 1.2 * 106-fold sensitivity improvement in DNA detection can be achieved. By virtue of its simplicity, high efficiency, and cost effectiveness, the proposed dnGOPs-based signal amplification strategy holds great potential in bioanalytical applications for the sensitive detection of biological molecules. PMID- 28806878 TI - Transmission Electron Microscopy for Chemists. PMID- 28806879 TI - Major Advances in the Development of Vectors for Clinical Gene Therapy of Hematopoietic Stem Cells from European Groups over the Last 25 Years. AB - The first attempts at hematopoietic stem cell-based gene therapy (HSC-GT) were reported >25 years ago for primary immune deficiencies, marking the beginning of a vibrant field of translational and therapeutic research. Since then, many HSC GT studies have been conducted in diverse genetic diseases. The approach has been improved over time, showing biological and therapeutic efficacy with an overall excellent safety record. Within a defined regulatory and ethical landscape, the field of HSC-GT has reached industrialization and commercialization stages, with a landmark recent approval by the European Medicines Agency of the first HSC-GT medicine for human use. At such a pivotal stage, it is important to look back at 25 years of European applied research in this field. This review highlights some of the key contributions of European teams to the field of HSC-GT, focusing in particular on the development of safer gene transfer vectors and international cooperation. PMID- 28806880 TI - Temporal Changes in Thyroid Nodule Volume: Lack of Effect on Paranodular Thyroid Tissue Volume. AB - BACKGROUND: The term "nodular goiter" has long been used to refer to a nodular thyroid gland, based on the assumption that nodule growth may be associated with hyperplasia of the surrounding non-nodular tissue. The aim of this prospective, multicenter, observational study was to determine whether nodule growth is accompanied by growth in the non-nodular tissue. METHODS: Eight Italian thyroid disease referral centers enrolled 992 consecutive patients with one to four benign nodules. Nodular and non-nodular thyroid tissue volumes were assessed for five years with annual ultrasound examinations. RESULTS: In participants whose nodules remained stable (n = 839), thyroid volumes did not change (baseline 15.0 mL [confidence interval (CI) 14.5-15.6]; five-year evaluation 15.1 mL [CI 14.5 15.7]). In participants with significant growth of one or more nodule (n = 153), thyroid volumes increased and by year 5 were significantly greater than those of the former group (17.4 mL [CI 16-18.7]). In 76 individuals with unilateral nodules that grew, the mean nodular lobe volume significantly exceeded that of the contralateral lobe (8.6 mL [CI 7.4-9.8] vs. 6.7 mL [CI 6-7.4]). The unaffected lobe volumes remained stable over time, while nodular lobes grew steadily and were significantly greater at the end of follow-up (10.1 mL [CI 8.9 11.3]). Excluding the volume of the largest growing nodule in these cases, the remaining volume of the affected lobe remained virtually unchanged with respect to its baseline value. Furthermore, there was no significant difference in the non-nodular tissue volume between the unaffected lobe and the affected lobe (with the largest growing nodule volume subtracted), both at baseline and at the end of follow-up. CONCLUSIONS: The growth of thyroid nodules is a local process, not associated with growth of the surrounding non-nodular tissue. Therefore, a normal sized thyroid containing nodules should be referred to as a "uni- or multinodular thyroid gland" and considered a distinct entity from "uni- or multinodular goiter." PMID- 28806882 TI - Long-Term Outcomes of Lateral Neck Dissection in Patients with Recurrent or Persistent Well-Differentiated Thyroid Cancer. AB - BACKGROUND: Well-differentiated thyroid carcinoma (WDTC) has a high predilection for regional metastatic spread. Rates for WDTC lateral neck recurrence are reported to be as high as 24% in patients after initial thyroidectomy, lateral neck surgery, and adjuvant radioactive (RAI) iodine treatment. The objective of the study was to evaluate the efficacy, safety, and long-term outcome of comprehensive lateral neck dissection (LND) of levels II-V for recurrent or persistent WDTC in a tertiary referral center. METHODS: This study retrospectively analyzed the standardized approach of LND for recurrent WDTC in the lateral neck compartment. Survival was analyzed by Cox regression analysis. RESULTS: Three hundred and seven patients underwent 429 LND for cytopathology confirmed lateral neck recurrent WDTC at the University of Texas MD Anderson Cancer Center between 1994 and 2012. The vast majority (90%) of patients were originally treated elsewhere. Multilevel lateral neck dissection had been originally performed in 80% of patients, with 17% having undergone at least two previous operations. Two hundred and sixty-seven (87%) patients had previous RAI. The most common levels of recurrence were levels III and IV (33% and 33%, respectively). Postoperative complications were seen in 7% of patients. Median follow-up was 7.2 years. In-field lateral neck control was 96% at 10 years. Overall lateral neck regional control, overall survival (OS), and disease specific survival (DSS) at 10 years was 88%, 78%, and 91%, respectively. When stratifying by age (<24 years, 24-50 years, and >50 years), OS and DSS was significantly better in patients <50 years (OS: p < 0.001; DSS: p < 0.001). However, there was worse overall lateral neck control in the younger group (<24 years; p = 0.04). Regional recurrence after salvage LND occurred within a median time interval of 20.0 months (2.9-121.3 months), of which 2% (8/429) developed in field lateral neck recurrences. Of those with any lateral neck recurrence after salvage LND, 24/30 (80%) patients successfully underwent another LND, resulting in an ultimate 98% lateral neck regional control rate. CONCLUSIONS: Expert comprehensive LND of levels II-V is associated with few perioperative complications and results in very high in-field regional control rate and ultimate lateral neck control in recurrent/persistent WDTC. PMID- 28806881 TI - Cancer Risk Stratification of Indeterminate Thyroid Nodules: A Cytological Approach. AB - BACKGROUND: Management recommendations for thyroid nodules rely primarily on the cytological diagnosis. However, 25% of biopsies render an indeterminate cytology for which management decision is more challenging due to heterogeneity of the specimens. This study aimed to stratify the cancer risk through subcategorization of indeterminate cytology. METHODS: The indeterminate cytological specimens (Bethesda-III or IV) of 518 thyroid nodules consecutively evaluated at our academic cancer center between October 2008 and September 2015, blinded to the histological outcome, were retrospectively reviewed. Cytological specimens were subclassified into four groups: aspirates exhibiting nuclear atypia (n = 158; 31%); architectural atypia (n = 222; 43%); oncocytic features (n = 120; 23%); or other types of atypia (n = 18; 3%). The prevalence of malignancy and odds ratio for malignancy were calculated in 323 nodules with histological confirmation. RESULTS: The prevalence of malignancy was 26% overall (20% in Bethesda-III and 29% in Bethesda-IV; p = 0.07), and 47%, 12%, 24%, and 25% for aspirates with nuclear atypia, architectural atypia, oncocytic features, or other types of atypia, respectively. The OR of nuclear atypia over architectural atypia was 6.4 (3.4-12.2; p < 0.001), and 2.7 over oncocytic features (1.4-5.1; p = 0.01), whereas the OR of architectural atypia over oncocytic features was 0.4 (0.2-0.9; p = 0.03). Results were similar for Bethesda-III and IV aspirates when analyzed independently. Furthermore, cytological subcategories improved cytology-histology correlation, as they were associated with distinct profiles of histological diagnoses (p < 0.001). CONCLUSIONS: Cytological subcategories can effectively stratify the risk of malignancy of thyroid nodules with indeterminate cytology and improve cytology-histology correlation. PMID- 28806883 TI - Genome and Epigenome Editing to Treat Disorders of the Hematopoietic System. AB - The possibility of editing complex genomes in a targeted fashion has revolutionized basic research as well as biomedical and biotechnological applications in the last 5 years. The targeted introduction of genetic changes has allowed researchers to create smart model systems for basic research, bio engineers to modify crops and farm animals, and translational scientists to develop novel treatment approaches for inherited and acquired disorders for which curative treatment options are not yet available. With the rapid development of genome editing tools, in particular zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the CRISPR-Cas system, a wide range of therapeutic options have been-and will be-developed at an unprecedented speed, which will change the clinical routine of various disciplines in a revolutionary way. This review summarizes the fundamentals of genome editing and the current state of research. It particularly focuses on the advances made in employing engineered nucleases in hematopoietic stem cells for the treatment of primary immunodeficiencies and hemoglobinopathies, provides a perspective of combining gene editing with the chimeric antigen receptor T cell technology, and concludes by presenting targeted epigenome editing as a novel potential treatment option. PMID- 28806884 TI - Severe bilateral cerebellar edema from ingestion of ketamine: case report. AB - The use of ketamine as a drug of abuse has increased and so too has the risk of accidental overdose. Here, the authors report the case of a 10-month-old infant who inadvertently ingested ketamine. The child demonstrated severe cerebellar swelling that required emergency surgical intervention. The authors describe the clinical course of this child and present the radiographic characteristics of the brain. The imaging characteristics were not consistent with purely anoxic injury, thus suggesting a specific effect of this drug. To the authors' knowledge, similar imaging characteristics in this context have not been described. PMID- 28806885 TI - Adenovirus Particle Quantification in Cell Lysates Using Light Scattering. AB - Adenoviral vector production for therapeutic applications is a well-established routine process. However, current methods for measurement of adenovirus particle titers as a quality characteristic require highly purified virus preparations. While purified virus is typically obtained in the last step of downstream purification, rapid and reliable methods for adenovirus particle quantification in intermediate products and crude lysates to allow for optimization and validation of cell cultures and intermediate downstream processing steps are currently not at hand. Light scattering is an established process to measure virus particles' size, though due to cell impurities, adequate quantification of adenovirus particles in cell lysates by light scattering has been impossible until today. This report describes a new method using light scattering to measure virus concentration in nonpurified cell lysates. Here we report application of light scattering, a routine method to measure virus particle size, to virus quantification in enzymatically conditioned crude lysates. Samples are incubated with phospholipase A2 and benzonase and filtered through a 0.22 MUm filter cartridge prior to quantification by light scattering. Our results show that this treatment provides a precise method for fast and easy determination of total adenovirus particle numbers in cell lysates and is useful to monitor virus recovery throughout all downstream processing. PMID- 28806886 TI - Rs6586282 of the CBS Gene: Its Lack of Eff ect on Homocysteine Concentrations, and Interaction Eff ects on Body Weight in Elderly Women. AB - The aim of the present study is to evaluate the effect of the rs6586282 polymorphism of the cystathionine-beta-synthase (CBS) gene, and of the intake of B vitamins on anthropometric parameters, tHcy levels, and lipoprotein levels in women over 60 years of age. 122 volunteers were supplemented with 400 MUg/day folic acid for 8 weeks. The intake of B vitamins above the median value was associated with lower levels of blood biomarkers: folate with tHcy post supplementation (6.21 +/- 0.24 MUM vs 7.11 +/- 0.32 MUM; p < 0.05), vitamin B6 with baseline triacylglycerol (TAG, 107.3 +/- 5.5 mg/dL vs 127.2 +/- 6.4 mg/dL; p < 0.05) and glucose (82.3 +/- 1.1 mg/dL vs 86.9 +/- 1.5 mg/dL; p < 0.05); and vitamin B12 with baseline TAG (106.8 +/- 5.5 mg/dL vs 127.7 +/- 6.3 mg/dL; p < 0.01). Women with a T allele consuming lower amounts of folate had higher body weight (72.3 +/- 2.3 kg vs 64.0 +/- 1.7 kg; p < 0.05), body mass index (28.7 +/- 0.8 vs 25.2 +/- 0.7; p < 0.05), waist (0.90 +/- 0.02 m vs 0.82 +/- 0.01 m; p < 0.01), and hip circumference (1.08 +/- 0.02 vs 1.02 +/- 0.01 m; p < 0.01) than the CC homozygotes. Intake of vitamin B6 or B12 may infl uence blood TAG and glucose concentrations in elderly women, but the rs6586282 polymorphism of the CBS gene does not alter either tHcy or the effectiveness of folic acid supplementation. The CBS SNP at rs6586282 may infl uence anthropometric parameters, though only in case of low folate intake. PMID- 28806887 TI - Chemically Contaminated Eel Fed to Pregnant and Lactating Mouse Dams Causes Hyperactivity in Their Offspring. AB - This study examined whether perinatal exposure to polluted eels (Anguilla anguilla L.) induces changes in the locomotor activity of offspring mice across lifespan (post-natal days (PNDs) 47 - 329), using the open field and the home cage activity tests. Dams were exposed during gestation and lactation, through diets enriched in eels naturally contaminated with pollutants including PCBs. Analysis of the eel muscle focused on the six non-dioxin-like (NDL) indicator PCBs (Sigma6 NDL-PCBs: 28, 52, 101, 138, 153 and 180). Four groups of dams (n = 10 per group) received either a standard diet without eels or eels (0.8 mg/kg/day) containing 85, 216, or 400 ng/kg/day of epsilon6 NDL-PCBs. The open field test showed that early-life exposure to polluted eels increased locomotion in female offspring of exposed dams but not in males, compared to controls. This hyperlocomotion appeared later in life, at PNDs 195 and 329 (up to 32 % increase, p < 0.05). In addition, overactivity was observed in the home cage test at PND 305: exposed offspring females showed a faster overall locomotion speed (3.6 - 4.2 cm/s) than controls (2.9 cm/s, p <0.05); again, males remained unaffected. Covered distances in the home cage test were only elevated significantly in offspring females exposed to highest PCB concentrations (3411 +/- 590 cm vs. 1377 +/- 114 cm, p < 0.001). These results suggest that early-life exposure to polluted eels containing dietary contaminants including PCBs caused late, persistent and gender-dependent neurobehavioral hyperactive effects in offspring mice. Furthermore, female hyperactivity was associated with a significant inhibition of acetylcholinesterase activity in the hippocampus and the prefrontal cortex. PMID- 28806888 TI - Breakfast Skipping Is an Independent Predictor of Obesity but not Overweight Among Children in a Southeastern European Population. AB - AIM: To assess the association of breakfast skipping with overweight and obesity among children in Albania, a post-communist country in the Western Balkans, which is undergoing a long and difficult political and socioeconomic transition towards a market-oriented economy. METHODS: A nationwide cross-sectional study was carried out in Albania in 2013 including a representative sample of 5810 children aged 7.0 - 9.9 years (49.5% girls aged 8.4 +/- 0.6 years and 51.5% boys aged 8.5 +/- 0.6 years; overall response rate: 97%). Children were measured for height and weight, and body mass index (BMI) calculated. Cut-off BMI values of the World Health Organization (WHO) and the International Obesity Task Force (IOTF) were used to define overweight and obesity in children. Demographic data were also collected. RESULTS: Upon adjustment for age, sex, and place of residence, breakfast skipping was positively related to obesity (WHO criteria: OR = 1.5, 95% CI = 1.3-1.9; IOTF criteria: OR = 1.9, 95% CI = 1.4-2.5), but not overweight (OR = 1.1, 95% CI = 0.9-1.3 and OR = 1.1, 95% CI = 0.9-1.4, respectively). Furthermore, breakfast skipping was associated with a higher BMI (multivariable adjusted OR = 1.05, 95% CI = 1.02-1.07). CONCLUSIONS: Our findings point to a strong and consistent positive relationship between breakfast skipping and obesity, but not overweight, among children in this transitional southeastern European population. Future studies in Albania and other transitional settings should prospectively examine the causal role of breakfast skipping in the development of overweight and obesity. PMID- 28806889 TI - Effects of the 2013 Psychiatric Current Procedural Terminology Codes Revision on Psychotherapy in Psychiatric Billing. AB - OBJECTIVE: The purpose of this study was to determine whether the changes to the psychiatric Current Procedural Terminology (CPT) codes implemented in 2013 were associated with changes in types of services for which psychiatrists billed. METHODS: Analyses were conducted using paid private insurance claims from a large commercial database. The participant cohort comprised psychiatrists with at least one psychiatry visit reported in the database in each calendar year studied: 2012 (N of visits=778,445), 2013 (N=748,317), and 2014 (N=754,760). RESULTS: The percentage of visits in which psychiatrists billed for psychotherapy declined from 51.4% in 2012 to 42.1% in 2014. The decline held after the analyses adjusted for patient characteristics, plan type, and region. CONCLUSIONS: The update to CPT codes resulted in a decrease in visits for which psychiatrists billed for psychotherapy. Further research should explore whether the change in billing corresponds to changes in service delivery. PMID- 28806890 TI - Impact of State Psychiatric Hospital Waitlists on Monthly Admissions. AB - OBJECTIVE: This study estimated the effects of a waitlist policy on the monthly number and case mix of admissions to state psychiatric hospitals (SPHs) in North Carolina (NC). METHODS: Descriptive analyses compared pre/postwaitlist differences in the monthly number and case mix of nonforensic adult admissions (N=72,035) to NC's four SPHs by using data from the three years before and the three years after the waitlist announcement. Hospital-level fixed-effects regression models further evaluated the waitlist policy's impact on the number and case mix of admissions. RESULTS: Regression results confirmed that the waitlist policy was associated with both fewer admissions and changes to the case mix of admissions, including a 4.2% decrease in the percentage of monthly admissions by patients with diagnoses of substance abuse disorders (p=.002) across all months postwaitlist (partially offset by an increase of patients with diagnoses of severe mental illness alone). CONCLUSIONS: Waitlists led to reduced monthly admissions and altered case mix following implementation at NC SPHs. PMID- 28806891 TI - Racial-Ethnic Differences in Off-Label Antidepressant Use, by Insurance Type. AB - OBJECTIVE: The objective of this study was to examine whether and to what extent racial-ethnic differences exist in off-label use of antidepressant drugs by insurance type (Medicare, Medicaid, private coverage, and uninsured). METHODS: Multiyear data (2000-2010) from Medical Expenditure Panel Surveys were used. Logistic and negative binomial regressions were used for the likelihood and frequency analyses, respectively. RESULTS: The likelihood of filling prescriptions for off-label use of antidepressants was greater among blacks than among whites in all insurance groups (Medicare [N=6,470], adjusted odds ratio [AOR]=1.68; Medicaid [N=3,076], AOR=1.76; private coverage [N=9,918], AOR=2.10; and uninsured [N=1,826], AOR=1.88). Only in the uninsured group were Hispanics more likely than whites to use antidepressants off label (AOR=1.58). Among off label antidepressant users, blacks and Hispanics with private coverage filled significantly fewer off-label antidepressant prescriptions than whites (blacks, incidence rate ratio [IRR]=.81; Hispanics, IRR=.88). CONCLUSIONS: Off-label use of antidepressants was more likely among blacks than among whites in all insurance groups; however, once whites initiated off-label use of antidepressants, they tended to fill off-label antidepressant prescriptions more frequently than blacks or Hispanics. Because off-label use may be inappropriate, clinical and policy efforts should aim to reduce off-label antidepressant use, with particular attention to racial-ethnic differences. PMID- 28806892 TI - Addressing Complexity and Improving Access in Community Mental Health Services: An Inner-City Adaptation of Flexible ACT. AB - To serve a wider range of patients with serious mental illness and develop more integrated, flexible services, investigators in Toronto redesigned a high fidelity assertive community treatment (ACT) team according to flexible ACT (FACT) principles. FACT, developed in the Netherlands, merges ACT and intensive case management (ICM) services. This model holds the promise of an affordable approach to addressing unmet service needs in community mental health, particularly for patients with complex health issues, by widening the ACT admission criteria. This enables the team to serve more patients and provide both ACT and ICM services according to patients' needs while allowing continuity of care. PMID- 28806893 TI - Enhanced Primary Care Treatment of Behavioral Disorders With ECHO Case-Based Learning. AB - The Extension for Community Healthcare Outcomes (ECHO) model offers a way for primary care providers to develop expertise in addressing behavioral health issues of primary care patients. It provides an alternative to traditional continuing medical education (CME) for ongoing training and support for health care providers. ECHO uses videoconferencing to connect multiple primary care teams simultaneously with academic specialists and builds capacity via mentorship and case-based learning. ECHO aims to expand access to care by developing capacity to treat common, complex conditions in underserved areas. Participants in an integrated addictions and psychiatry teleECHO program reported that when they presented a patient case, the feedback they received was highly valuable and led them to change their care plans more than 75% of the time. ECHO is an effective model for teaching primary care teams about behavioral health and may be more effective than traditional CME approaches. PMID- 28806894 TI - Effectiveness of Mental Health Courts in Reducing Recidivism: A Meta-Analysis. AB - OBJECTIVE: Mental health courts (MHCs) were developed to address the overrepresentation of adults with mental illnesses in the U.S. criminal justice system through diversion into community-based treatment. Research on MHCs has proliferated in recent years, and there is a need to synthesize contemporary literature on MHC effectiveness. The authors conducted a meta-analytic investigation of the effect on criminal recidivism of adult MHC participation compared with traditional criminal processing. METHODS: Systematic search of three databases yielded 17 studies (N=16,129) published between 2004 and 2015. Study characteristics and potential moderators (that is, publication type, recidivism outcome, and length and timing of follow-up) were independently extracted by two of four raters for each study. Two raters coded each study for quality and extracted between-group effect sizes for measures of recidivism (that is, arrest, charge, conviction, and jail time; k=25). Results were synthesized by using random-effects meta-analysis. Heterogeneity and publication bias were also assessed. RESULTS: Results showed a small effect of MHC participation on recidivism (d=-.20) relative to traditional criminal processing. MHCs were most effective with respect to jail time and charge outcomes compared with arrest and conviction, in studies measuring recidivism after MHC exit rather than at entry, and in lower-quality studies compared with moderate- and high-quality studies. Results showed significant heterogeneity in effect sizes across studies (I2=73.33) but little evidence of publication bias. CONCLUSIONS: Overall, a small effect of MHC participation on recidivism was noted, compared with traditional criminal processing. Findings suggest the need for research to identify additional sources of variability in the effectiveness of MHCs. PMID- 28806895 TI - Expanding the Mental Health Workforce in China: Narrowing the Mental Health Service Gap. AB - There is a significant gap between mental health service coverage and the need for these services in China. In particular, workforce shortages impair several aspects of China's national mental health service system, including access to timely diagnosis and treatment in rural areas, expansion of general hospital psychiatric consultation-liaison services, and leadership in establishing a collaborative stepped-care system. This column focuses on China's ongoing efforts to develop its mental health workforce to ensure a sustainable supply of psychiatrists and allied mental health professionals. PMID- 28806896 TI - The U.S. Department of State's Mental Health Services: A Model for Integrated Care. AB - Since it was established in 1979, the U.S. Department of State's mental health service has functioned as a unique program of care for U.S. diplomats and their family members, currently encompassing more than 250 U.S. embassies and consulates worldwide. Such an approach has allowed for rapid delivery of high quality care in collaboration with regional medical officers, nurse practitioners, physician assistants, nurses, and local assets. Data from the past three decades indicate that the program has had low rates of medical evacuation and repatriation and low rates of mortality. Building from its roots in disaster and crisis response, the program now offers integrated mental health care in a geographically distributed, worldwide program to address the general medical and behavioral health needs of an expanding U.S. diplomatic presence in increasingly remote, challenging, and dangerous environments. PMID- 28806897 TI - Evaluation of Intrathecal Routes of Administration for Adeno-Associated Viral Vectors in Large Animals. AB - Delivery of adeno-associated viral (AAV) vectors into the cerebrospinal fluid (CSF) can achieve gene transfer to cells throughout the brain and spinal cord, potentially making many neurological diseases tractable gene therapy targets. Identifying the optimal route of CSF access for intrathecal AAV delivery will be a critical step in translating this approach to clinical practice. We previously demonstrated that vector injection into the cisterna magna is a safe and effective method for intrathecal AAV delivery in nonhuman primates; however, this procedure is not commonly used in clinical practice. More routine methods of administration into the CSF are now being explored, including intracerebroventricular (ICV) injection and injection through a lumbar puncture. In this study, we compared ICV and intracisternal (IC) AAV administration in dogs. We also evaluated vector administration via lumbar puncture in nonhuman primates, with some animals placed in the Trendelenburg position after injection, a maneuver that has been suggested to improve cranial distribution of vector. In the dog study, ICV and IC vector administration resulted in similarly efficient transduction throughout the brain and spinal cord. However, animals in the ICV cohort developed encephalitis associated with a T-cell response to the transgene product, a phenomenon that was not observed in the IC cohort. In the nonhuman primate study, transduction efficiency was not improved by placing animals in the Trendelenburg position after injection. These findings illustrate important limitations of commonly used methods for CSF access in the context of AAV delivery, and will be important for informing the selection of a route of administration for first-in-human studies. PMID- 28806898 TI - * Microcomputed Tomography Technique for In Vivo Three-Dimensional Fat Tissue Volume Evaluation After Polymer Injection. AB - Tissue engineering technologies are new and promising techniques in fat tissue reconstruction. However, to assess their efficacy before any clinical application, in vivo experiments are mandatory. This study assesses whether microcomputed tomography (CT) scan imaging is suitable to analyze in vivo the behavior of injected engineered polymer and changes in fat tissue. The volume of mice inguinal fat pads and the resorption rate of different polymers were analyzed by CT scan for up to 3 months. Different biomaterials were used, including our innovative microspheres loaded with oleic acid. We were able to follow in vivo the polymer and the fat volume of the same animals during a long term follow-up of 90 days. Semiautomatic three-dimensional quantification allowed to determine the fat volume enhancement after injection, as well as the resorption rate of our product compared to other biomaterials (i.e., polylactic and hyaluronic acid) until 90 days. Our results demonstrate the encouraging proof of-principle evidence for the application of micro-CT scan technology to follow in vivo biodegradable polymers in a fat tissue engineering approach. This noninvasive technique offers the advantages of the long-term follow-up of fat tissue and synthetic materials in the same animals, which allows both a scientific evaluation of the measurements and the reduction of the number of animals used in in vivo protocols in accordance with the 3 "R" principles governing the use of animals in science. PMID- 28806899 TI - Executive functioning in Cornelia de Lange syndrome: domain asynchrony and age related performance. AB - BACKGROUND: The aim of this study was to examine executive functioning in adolescents and adults with Cornelia de Lange syndrome (CdLS) to identify a syndrome and age-related profile of cognitive impairment. METHODS: Participants were 24 individuals with CdLS aged 13-42 years (M = 22; SD = 8.98), and a comparable contrast group of 21 individuals with Down syndrome (DS) aged 15-33 years (M = 24; SD = 5.82). Measures were selected to test verbal and visual fluency, inhibition, perseverance/flexibility, and working memory and comprised both questionnaire and performance tests. RESULTS: Individuals with CdLS showed significantly greater impairment on tasks requiring flexibility and inhibition (rule switch) and on forwards span capacity. These impairments were also reported in the parent/carer-rated questionnaire measures. Backwards Digit Span was significantly negatively correlated with chronological age in CdLS, indicating increased deficits with age. This was not identified in individuals with DS. CONCLUSIONS: The relative deficits in executive functioning task performance are important in understanding the behavioural phenotype of CdLS. Prospective longitudinal follow-up is required to examine further the changes in executive functioning with age and if these map onto observed changes in behaviour in CdLS. Links with recent research indicating heightened responses to oxidative stress in CdLS may also be important. PMID- 28806901 TI - Polymorphism rs189037C > T in the promoter region of the ATM gene may associate with reduced risk of T2DM in older adults in China: a case control study. AB - BACKGROUND: Recent evidence indicates that ataxia telangiectasia mutated (ATM) is a cytoplasmic protein that involves in insulin signaling pathways. When ATM gene is mutated, this event appears to contribute to the development of insulin resistance and type 2 diabetes mellitus (T2DM). Up to date, little information about the relationship between ATM gene polymorphism and T2DM is available. This study aimed to explore potential association between a genetic variant [single nucleotide polymorphism (SNP), i.e. rs189037C > T] in the ATM promoter region and T2DM in older adults in China. METHODS: We conducted a 1:1 age- and sex-matched case-control study. It enrolled 160 patients including 80 type 2 diabetic and 80 nondiabetic patients who were aged 60 years and above. Genotyping of the polymorphism rs189037 in the promoter of the ATM gene was performed using polymerase chain reaction-restriction fragment length polymorphism. Chi-square test or Fisher's exact test (when an expected cell count was <5) and unpaired Student's t test were used for categorical and continuous variables, respectively. Logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) with adjustment for factors associated with T2DM. RESULTS: Significant association was found between the genotypes of the ATM rs189037 polymorphism and T2DM (P = 0.037). The frequency of CT genotype is much higher in patients without T2DM than in diabetics (60.0% versus 40.0%, P = 0.012). After adjustment of the major confounding factors, such difference remained significant (OR for non-T2DM is 2.62, 95%CI = 1.05-6.53, P = 0.038). Similar effect of CT genotype on T2DM was observed in male population (adjusted: OR = 0.27, 95%CI = 0.09-0.84, P = 0.024). In addition, the percentage of TT genotype in diabetics with coronary artery disease (CAD) was considerably lower than in those without CAD (17.9% versus 61.5%, P = 0.004). CONCLUSIONS: Our study suggests that the ATM rs189037 polymorphism is associated with reduced risk of T2DM in older adult population in China. Specifically, CT heterozygote seems to be associated with a lower risk of T2DM than CC or TT genotype, especially in male older adults. Moreover, TT genotype may reduce the risk of CAD in diabetic patients. PMID- 28806900 TI - Drift, selection, or migration? Processes affecting genetic differentiation and variation along a latitudinal gradient in an amphibian. AB - BACKGROUND: Past events like fluctuations in population size and post-glacial colonization processes may influence the relative importance of genetic drift, migration and selection when determining the present day patterns of genetic variation. We disentangle how drift, selection and migration shape neutral and adaptive genetic variation in 12 moor frog populations along a 1700 km latitudinal gradient. We studied genetic differentiation and variation at a MHC exon II locus and a set of 18 microsatellites. RESULTS: Using outlier analyses, we identified the MHC II exon 2 (corresponding to the beta-2 domain) locus and one microsatellite locus (RCO8640) to be subject to diversifying selection, while five microsatellite loci showed signals of stabilizing selection among populations. STRUCTURE and DAPC analyses on the neutral microsatellites assigned populations to a northern and a southern cluster, reflecting two different post glacial colonization routes found in previous studies. Genetic variation overall was lower in the northern cluster. The signature of selection on MHC exon II was weaker in the northern cluster, possibly as a consequence of smaller and more fragmented populations. CONCLUSION: Our results show that historical demographic processes combined with selection and drift have led to a complex pattern of differentiation along the gradient where some loci are more divergent among populations than predicted from drift expectations due to diversifying selection, while other loci are more uniform among populations due to stabilizing selection. Importantly, both overall and MHC genetic variation are lower at northern latitudes. Due to lower evolutionary potential, the low genetic variation in northern populations may increase the risk of extinction when confronted with emerging pathogens and climate change. PMID- 28806902 TI - Monitoring, documenting and reporting the quality of antibiotic use in the Netherlands: a pilot study to establish a national antimicrobial stewardship registry. AB - BACKGROUND: The Dutch Working Party on Antibiotic Policy is developing a national antimicrobial stewardship registry. This registry will report both the quality of antibiotic use in hospitals in the Netherlands and the stewardship activities employed. It is currently unclear which aspects of the quality of antibiotic use are monitored by antimicrobial stewardship teams (A-teams) and can be used as indicators for the stewardship registry. In this pilot study we aimed to determine which stewardship objectives are eligible for the envisioned registry. METHODS: We performed an observational pilot study among five Dutch hospitals. We assessed which of the 14 validated stewardship objectives (11 process of care recommendations and 3 structure of care recommendations) the A-teams monitored and documented in individual patients. They provided, where possible, data to compute quality indicator (QI) performance scores in line with recently developed QIs to measure appropriate antibiotic use in hospitalized adults for the period of January 2015 through December 2015 RESULTS: All hospitals had a local antibiotic guideline describing recommended antimicrobial use. All A-teams monitored the performance of bedside consultations in Staphylococcus aureus bacteremia and the prescription of restricted antimicrobials. Documentation and reporting were the best for the use of restricted antimicrobials: 80% of the A teams could report data. Lack of time and the absence of an electronic medical record system enabling documentation during the daily work flow were the main barriers hindering documentation and reporting. CONCLUSIONS: Five out of 11 stewardship objectives were actively monitored by A-teams. Without extra effort, 4 A-teams could report on the quality of use of restricted antibiotics. Therefore, this aspect of antibiotic use should be the starting point of the national antimicrobial stewardship registry. Our registry is expected to become a powerful tool to evaluate progress and impact of antimicrobial stewardship programs in hospitals. PMID- 28806903 TI - Service provider perceptions of transitioning from audio to video capability in a telehealth system: a qualitative evaluation. AB - BACKGROUND: Telephone consultation and triage services are increasingly being used to deliver health advice. Availability of high speed internet services in remote areas allows healthcare providers to move from telephone to video telehealth services. Current approaches for assessing video services have limitations. This study aimed to identify the challenges for service providers associated with transitioning from audio to video technology. METHODS: Using a mixed-method, qualitative approach, we observed training of service providers who were required to switch from telephone to video, and conducted pre- and post training interviews with 15 service providers and their trainers on the challenges associated with transitioning to video. Two full days of simulation training were observed. Data were transcribed and analysed using an inductive approach; a modified constant comparative method was employed to identify common themes. RESULTS: We found three broad categories of issues likely to affect implementation of the video service: social, professional, and technical. Within these categories, eight sub-themes were identified; they were: enhanced delivery of the health service, improved health advice for people living in remote areas, safety concerns, professional risks, poor uptake of video service, system design issues, use of simulation for system testing, and use of simulation for system training. CONCLUSIONS: This study identified a number of unexpected potential barriers to successful transition from telephone to the video system. Most prominent were technical and training issues, and personal safety concerns about transitioning from telephone to video media. Addressing identified issues prior to implementation of a new video telehealth system is likely to improve effectiveness and uptake. PMID- 28806904 TI - A falls prevention programme to improve quality of life, physical function and falls efficacy in older people receiving home help services: study protocol for a randomised controlled trial. AB - BACKGROUND: Falls and fall-related injuries in older adults are associated with great burdens, both for the individuals, the health care system and the society. Previous research has shown evidence for the efficiency of exercise as falls prevention. An understudied group are older adults receiving home help services, and the effect of a falls prevention programme on health-related quality of life is unclear. The primary aim of this randomised controlled trial is to examine the effect of a falls prevention programme on quality of life, physical function and falls efficacy in older adults receiving home help services. A secondary aim is to explore the mediating factors between falls prevention and health-related quality of life. METHODS: The study is a single-blinded randomised controlled trial. Participants are older adults, aged 67 or older, receiving home help services, who are able to walk with or without walking aids, who have experienced at least one fall during the last 12 months and who have a Mini Mental State Examination of 23 or above. The intervention group receives a programme, based on the Otago Exercise Programme, lasting 12 weeks including home visits and motivational telephone calls. The control group receives usual care. The primary outcome is health-related quality of life (SF-36). Secondary outcomes are leg strength, balance, walking speed, walking habits, activities of daily living, nutritional status and falls efficacy. All measurements are performed at baseline, following intervention at 3 months and at 6 months' follow-up. Sample size, based on the primary outcome, is set to 150 participants randomised into the two arms, including an estimated 15-20% drop out. Participants are recruited from six municipalities in Norway. DISCUSSION: This trial will generate new knowledge on the effects of an exercise falls prevention programme among older fallers receiving home help services. This knowledge will be useful for clinicians, for health managers in the primary health care service and for policy makers. TRIAL REGISTRATION: ClinicalTrials.gov . NCT02374307 . First registration, 16/02/2015. PMID- 28806905 TI - Evaluation of the cervix tissue homogeneity by ultrasound elastography in infertile women for the prediction of embryo transfer ease: a diagnostic accuracy study. AB - BACKGROUND: Ultrasound elastography is a non-invasive medical imaging technique able to quantitatively characterize the stiffness of a given tissue. It has been shown to predict the risk for cervical insufficiency and preterm delivery, and to allow differentiation of malignancy from normal tissue. The present study sought to evaluate whether cervical tissue dishomogeneity, as assessed by cervical ultrasound elastography, may predict the embryo transfer (ET) ease in infertile women undergoing IVF/ICSI. METHODS: We evaluated 154 infertile patients with no history of previous ET or intrauterine insemination. Cervical stiffness was evaluated in six regions of interest (ROI), compared two by two to obtain strain ratio (SR) values. Since a SR value of 1 was suggestive of tissue homogeneity, we computed 1-SR/SR-1 values to obtain a measure of the degree of cervical tissue dishomogeneity that we named "dishomogeneity index" (DI). Ultrasound-guided ET was performed by an expert operator blinded to the results of cervical elastography. The prediction ability of elastography on ET ease was evaluated by binary logistic regression, and the predictive accuracy of the independent variables was quantified with area under the curve (AUC) estimates derived from receiver operating characteristic (ROC) curve. RESULTS: ET resulted to be easy in 99 out of 154 patients (64,2%), difficult in 54 patients (35%), and impossible in one. DI values in cervical medial lips region correctly classified 86.9% of patients, according to binary logistic regression, with a sensitivity of 81.4% and a specificity of 89,9%, positive likelihood ratio (LR) 8.07 and negative LR of 0.21. A DI cut-off value of 0.29 predicted a difficulty of ET with a sensitivity of 88,9% and a specificity of 85%. CONCLUSIONS: Cervical ultrasound elastography, by allowing the identification of cervical tissue dishomogeneity, may be of help in predicting the ET ease in infertile women candidates to IVF/ICSI. PMID- 28806906 TI - Age-associated mRNA expression changes in bovine endometrial cells in vitro. AB - BACKGROUND: Endometrial cells secrete various cytokines and the dysfunction of endometrial cells may directly lead to infertility. Interferon tau (IFNT) secreted by trophoblast cells, a well-known pregnancy recognition signal in ruminants, acts on the uterus to prepare for pregnancy. Aging causes cellular and organ dysfunction, and advanced maternal age is associated with reduced fertility. However, few studies have investigated age-dependent changes in the uterus. METHODS: Using next generation sequencing and real-time PCR, we examined mRNA expression in bovine endometrial cells in vitro obtained from young (mean 45.2 months) and aged (mean 173.5 months) animals and the effects of IFNT depending on the age. RESULTS: We showed that inflammation-related (predicted molecules are IL1A, C1Qs, DDX58, NFKB, and CCL5) and interferon-signaling (predicted molecules are IRFs, IFITs, STATs, and IFNs) pathways were activated in endometrial cells obtained from aged compared to young cows. Also, the activation of "DNA damage checkpoint regulation" and the inhibition of "mitotic mechanisms" in endometrial cells obtained from aged cows were evident. Moreover, we showed lower cell viability levels in endometrial cells obtained from aged compared to young cows. Although treatment with IFNT upregulated various types of interferon stimulated genes both in endometrial cells obtained from young and aged cows, the rate of increase by IFNT stimulus was obviously lower in endometrial cells obtained from aged compared to young cows. CONCLUSIONS: Endometrial cells obtained from aged cows exhibited higher levels of inflammatory- and IFN signaling, and dysfunction of cell division compared with young cows. In addition, a high basal level of IFN-related genes in endometrial cells of aged cows is suggested a concept of "inflammaging". PMID- 28806907 TI - Effect of acupuncture and its influence on cerebral activity in perimenopausal insomniacs: study protocol for a randomized controlled trial. AB - BACKGROUND: Perimenopausal insomnia is one of the core symptoms of the menopausal transition. Acupuncture is considered to exert a positive effect on restoring the normal sleep-wake cycle. However, there is little intuitive evidence besides evaluation using clinical effectiveness scales. We therefore designed this study, aiming to use more intuitive and reliable detection techniques such as functional magnetic resonance imaging before and after applying acupuncture to provide neuroimaging evidence, as well as to verify the effectiveness with other curative effect indicators. METHODS/DESIGN: This study is a randomized, assessor statistician-blinded, positive medicine controlled trial involving 40 participants. A total of 40 eligible patients with perimenopausal insomnia will be randomly assigned to two groups in a 1:1 ratio as an intervention group using acupuncture and a control group taking estazolam. Participants in the intervention group will receive six acupuncture treatment sessions per week for 4 consecutive weeks, for a total of 24 sessions during the study. Meanwhile, the medicine control group will be prescribed estazolam 1-2 mg/day to be taken 30 minutes before sleep for 4 weeks. The primary outcome is the Pittsburgh Sleep Quality Index. Secondary outcomes are the micro-movement sensitive mattress-type sleep monitoring system, the Hamilton Depression Scale, and the Hamilton Anxiety Scale. All outcomes will be evaluated before and after treatment. The safety of interventions will be assessed at every visit. DISCUSSION: The results of this trial, which will be available in 2018, will investigate the impact of acupuncture treating perimenopausal insomnia from assessment of the sleep architecture, hormone level, and emotional-circuit neurological function, and will uncover the effective mechanism of acupuncture regulating the emotional center integrated effect. TRIAL REGISTRATION: Chinese Clinical Trials Register, ChCTR-IPC-16007832 . Registered on 26 January 2016. PMID- 28806908 TI - Changing the default for tobacco-cessation treatment in an inpatient setting: study protocol of a randomized controlled trial. AB - BACKGROUND: Most health care providers do not treat tobacco dependence routinely. This may in part be due to the treatment "default." Current treatment guidelines recommend that providers (1) ask patients if they are willing to quit and (2) provide cessation-focused medications and counseling only to smokers who state that they are willing to quit. The default is that patients have to "opt in" to receive cessation assistance: providers ask smokers if they are willing to quit, and only offer medications and cessation support to those who say "yes." This drastically limits the reach of cessation services because, at any given encounter, only one in three smokers say that they are ready to quit. The objective of this study is to determine the impact of providing all smokers with tobacco-cessation treatment unless they refuse it (OPT OUT) versus current practice-screening for readiness and only offering treatment to smokers who say they are ready to quit (OPT IN). METHODS: This individually randomized clinical trial is conducted in a tertiary-care hospital. We will conduct the trial among up to 1000 randomly selected hospitalized smokers to determine the population impact of changing the treatment default, identify mediators of outcome, and determine the cost-effectiveness of this new, highly proactive approach. This is a population-based study that targets an endpoint of vital interest; applies minimal eligibility criteria to broaden generalizability; and utilizes hospital staff for interventions to ensure long-term sustainability. The study employs delayed consent and an innovative Bayesian adaptive design to evaluate a major shift in our approach to care. If effective, this change would expand the reach of tobacco-cessation treatment from 30% to 100% of smokers. DISCUSSION: Regardless of outcome, the trial will provide a model of how to alter and evaluate the impact of health care defaults. If OPT OUT proves to be more effective, it will expand the population eligible for cessation treatment by over 300%. It will also simplify the tobacco-cessation treatment algorithm, and relieve busy health care providers of the burden of evaluating readiness to quit. TRIAL REGISTRATION: Clinical Trials Registration, ID: NCT02721082 . Registered on 22 March 2016. PMID- 28806909 TI - Tumor-derived exosomes induce CD8+ T cell suppressors. AB - BACKGROUND: The suppressive nature of immune cells in the tumor microenvironment plays a major role in regulating anti-tumor immune responses. Our previous work demonstrated that a soluble factor from tumor cells is able to induce a suppressor phenotype (SP) in human CD8+ T cells typified by loss of CD27/CD28 expression and acquisition of a potent suppressor function. The present study hypothesized that the soluble mechanism that is inducing the SP in CD8+ T cells are tumor-derived exosomes (TDEs). METHODS: Membrane vesicles and TDEs from multiple head and neck cancer cell line's conditioned growth media were isolated by ultracentrifugation and precipitation, respectively. Human purified CD3+CD8+ T cells were assessed for their induction of the T cell SP by flow cytometry identifying loss of CD27/CD28 expression and in vitro suppression assays. Furthermore, the T cell SP was characterized for the attenuation of IFN-gamma production. To delineate exosomal proteins contributing to T cell SP, mass spectrometry was used to identify unique proteins that were present in TDEs. CRISPR/Cas9 knockout constructs were used to examine the role of one of these proteins, galectin-1. To assess the role of exosomal RNA, RNA purified from TDEs was nucleofected into CD8+ T cells followed by suppression analysis. RESULTS: Using fractionated conditioned growth media, factors >200 kDa induced CD8+ T cell SP, which was determined to be an exosome by mass spectrometry analysis. Multiple head and neck cancer-derived cell lines were found to secrete T cell SP-inducing exosomes. Mass spectrometry analysis revealed that an immunoregulatory protein, galectin-1 (Gal-1), was expressed in those exosomes, but not in TDEs unable to induce T cell SP. Galectin-1 knockout cells were found to be less able to induce T cell SP. Furthermore, RNA purified from the T cell SP-inducing exosomes were found to partially induce the SP when transfected into normal CD8+ T cells. CONCLUSIONS: For the first-time, TDEs have been identified to induce a SP in CD8+ T cells and their mode of action may be synergistic effects from exosomal proteins and RNA. One protein in particular, galectin-1, appears to play a significant role in inducing T cell SP. Therefore, tumor-derived immunosuppressive exosomes are a potential therapeutic target to prevent T cell dysfunction and enhance anti-tumor immune responses. PMID- 28806910 TI - Multi-target chimaeric VLP as a therapeutic vaccine in a model of colorectal cancer. AB - BACKGROUND: Colorectal cancer is responsible for almost 700,000 deaths annually worldwide. Therapeutic vaccination is a promising alternative to conventional treatment for colorectal cancer, using vaccines to induce targeted immune responses against tumour-associated antigens. In this study, we have developed chimaeric virus-like particles (VLP), a form of non-infectious non-replicative subunit vaccine consisting of rabbit haemorrhagic disease virus (RHDV) VP60 capsid proteins containing recombinantly inserted epitopes from murine topoisomerase IIalpha and survivin. These vaccines were developed in mono- (T.VP60, S.VP60) and multi-target (TS.VP60) forms, aiming to elucidate the potential benefits from multi-target vaccination. METHODS: Chimaeric RHDV VLP were developed by recombinantly inserting immune epitopes at the N-terminus of VP60. Vaccines were tested against a murine model of colorectal cancer by establishing MC38-OVA tumours subcutaneously. Unmethylated CpG DNA oligonucleotides (CpGs) were used as a vaccine adjuvant. Statistical tests employed included the Mantel-Cox log-rank test, ANOVA and unpaired t-tests depending on the data analysed, with a post hoc Bonferroni adjustment for multiple measures. RESULTS: Chimaeric RHDV VLP were found to form a composite particle in the presence of CpGs. Overall survival was significantly improved amongst mice bearing MC38-OVA tumours following vaccination with T.VP60 (60%, 9/15), S.VP60 (60%, 9/15) or TS.VP60 (73%, 11/15). TS.VP60 significantly prolonged the vaccine-induced remission period in comparison to each mono therapy. CONCLUSIONS: Chimaeric VLP containing multiple epitopes were found to confer an advantage for therapeutic vaccination in a model of colorectal cancer based on the prolongation of remission prior to tumour escape. PMID- 28806911 TI - Predictors of delayed care seeking for tuberculosis in southern India: an observational study. AB - BACKGROUND: Reducing delay to accessing care is necessary to reduce the Tuberculosis (TB) burden in high incidence countries such as India. This study aimed to identify factors associated with delays in seeking care for TB in Southern India. METHODS: We analyzed data from newly diagnosed, smear-positive, culture-confirmed, pulmonary TB patients in the Regional Prospective Observational Research for TB (RePORT) cohort in Puducherry and Tamil Nadu, India. Data were collected on demographic characteristics, symptom duration, and TB knowledge, among other factors. Delay was defined as cough >=4 weeks before treatment initiation. Risky alcohol use was defined by the AUDIT-C score which incorporates information about regular alcohol use and binge drinking. TB knowledge was assessed by knowing transmission mode or potential curability. RESULTS: Of 501 TB patients, 369 (73.7%) subjects delayed seeking care. In multivariable analysis, risky alcohol use was significantly associated with delay (aOR 2.20, 95% CI: 1.31, 3.68). Delay was less likely in lower versus higher income groups (<3000 versus >10,000 rupees/month, aOR 0.31, 95% CI: 0.12, 0.78). TB knowledge was not significantly associated with delay. CONCLUSIONS: Local TB programs should consider that risky alcohol users may delay seeking care for TB. Further studies will be needed to determine why patients with higher income delay in seeking care. PMID- 28806912 TI - Genome-wide comparative analysis of DNA methylation between soybean cytoplasmic male-sterile line NJCMS5A and its maintainer NJCMS5B. AB - BACKGROUND: DNA methylation is an important epigenetic modification. It can regulate the expression of many key genes without changing the primary structure of the genomic DNA, and plays a vital role in the growth and development of the organism. The genome-wide DNA methylation profile of the cytoplasmic male sterile (CMS) line in soybean has not been reported so far. RESULTS: In this study, genome-wide comparative analysis of DNA methylation between soybean CMS line NJCMS5A and its maintainer NJCMS5B was conducted by whole-genome bisulfite sequencing. The results showed 3527 differentially methylated regions (DMRs) and 485 differentially methylated genes (DMGs), including 353 high-credible methylated genes, 56 methylated genes coding unknown protein and 76 novel methylated genes with no known function were identified. Among them, 25 DMRs were further validated that the genome-wide DNA methylation data were reliable through bisulfite treatment, and 9 DMRs were confirmed the relationship between DNA methylation and gene expression by qRT-PCR. Finally, 8 key DMGs possibly associated with soybean CMS were identified. CONCLUSIONS: Genome-wide DNA methylation profile of the soybean CMS line NJCMS5A and its maintainer NJCMS5B was obtained for the first time. Several specific DMGs which participated in pollen and flower development were further identified to be probably associated with soybean CMS. This study will contribute to further understanding of the molecular mechanism behind soybean CMS. PMID- 28806913 TI - Proteomics informed by transcriptomics for characterising differential cellular susceptibility to Nelson Bay orthoreovirus infection. AB - BACKGROUND: Nelson Bay orthoreovirus (NBV) is a fusogenic bat borne virus with an unknown zoonotic potential. Previous studies have shown that NBV can infect and replicate in a wide variety of cell types derived from their natural host (bat), as well as from human, mouse and monkey. Within permissive cells, NBV induced significant cytopathic effects characterised by cell-cell fusion and syncytia formation. To understand the molecular events that underpin NBV infection we examined the host transcriptome and proteome response of two cell types, derived from bat (PaKiT03) and mouse (L929), to characterise differential cellular susceptibility to NBV. RESULTS: Despite significant differences in NBV replication and cytopathic effects in the L929 and PaKiT03 cells, the host response was remarkably similar in these cells. At both the transcriptome and proteome level, the host response was dominated by IFN production and signalling pathways. The majority of proteins up-regulated in L929 and PaKiT03 cells were also up-regulated at the mRNA (gene) level, and included many important IFN stimulated genes. Further functional experimentation demonstrated that stimulating IFN signalling prior to infection, significantly reduced NBV replication in PaKiT03 cells. Moreover, inhibiting IFN signalling (through specific siRNAs) increased NBV replication in L929 cells. In line with the significant cytopathic effects seen in PaKiT03 cells, we also observed a down regulation of genes involved in cell-cell junctions, which may be related to the fusogenic effects of NBV. CONCLUSIONS: This study provides new multi-dimensional insights into the host response of mammalian cells to NBV infection. We show that IFN activity is capable of reducing NBV replication, although it is unlikely that this is solely responsible for the reduced replication of NBV in L929 cells. The molecular events that underpin the fusogenic cytopathic effects described here will prove valuable for identifying potential therapeutic targets against fusogenic orthoreovirus. PMID- 28806914 TI - Expansion and evolutionary patterns of cysteine-rich peptides in plants. AB - BACKGROUND: Cysteine-rich peptides (CRPs) are gaining recognition as regulators of cell-cell communication in plants. RESULTS: We identified 9556 CRPs in 12 plant species and analysed their evolutionary patterns. In most angiosperm plants, whole genome duplication and segmental duplication are the major factors driving the expansion of CRP family member genes, especially signal peptides. About 30% of the CRP genes were found clustered on the chromosomes, except in maize (Zea mays). Considerable collinearities between CRP genes between or within species reveal several syntenic regions on the chromosomes. Different subfamilies display diverse evolutionary rates, suggesting that these subfamilies are subjected to different selective pressures. CRPs in different duplication models also show contrasting evolutionary rates, although the underlying mechanism is unclear because of the complexity of gene evolution. The 1281 positively selected genes identified are probably generated within a certain period of time. While most of these belonged to maize and sorghum (Sorghum bicolor), new CRP functions would also be expected. Up-regulation of 10 CRPs was observed in self-pollinated pear pistils and pollen tubes under self S-RNase treatments in vitro. The expression divergence between different CRP gene duplication types suggests that different duplication mechanisms affected the fate of the duplicated CRPs. CONCLUSION: Our analyses of the evolution of the CRP gene family provides a unique view of the evolution of this large gene family. PMID- 28806915 TI - Evaluating the maintenance of disease-associated variation at the blood group related gene B4galnt2 in house mice. AB - BACKGROUND: B4galnt2 is a blood group-related glycosyltransferase that displays cis-regulatory variation for its tissue-specific expression patterns in house mice. The wild type allele, found e.g. in the C57BL/6 J strain, directs intestinal expression of B4galnt2, which is the pattern observed among vertebrates, including humans. An alternative allele class found in the RIIIS/J strain and other mice instead drives expression in blood vessels, which leads to a phenotype similar to type 1 von Willebrand disease (VWD), a common human bleeding disorder. We previously showed that alternative B4galnt2 alleles are subject to long-term balancing selection in mice and that variation in B4galnt2 expression influences host-microbe interactions in the intestine. This suggests that the costs of prolonged bleeding in RIIIS/J allele-bearing mice might be outweighed by benefits associated with resistance against gastrointestinal pathogens. However, the conditions under which such trade-offs could lead to the long-term maintenance of disease-associated variation at B4galnt2 are unclear. RESULTS: To explore the persistence of B4galnt2 alleles in wild populations of house mice, we combined B4galnt2 haplotype frequency data together with a mathematical model based on an evolutionary game framework with a modified Wright Fisher process. In particular, given the potential for a heterozygote advantage as a possible explanation for balancing selection, we focused on heterozygous mice, which express B4galnt2 in both blood vessels and the gastrointestinal tract. We show that B4galnt2 displays an interesting spatial allelic distribution in Western Europe, likely due to the recent action of natural selection. Moreover, we found that the genotype frequencies observed in nature can be produced by pathogen-driven selection when both heterozygotes and RIIIS/J homozygotes are protected against infection and the fitness cost of bleeding is roughly half that of infection. CONCLUSION: By comparing the results of our models to the patterns of polymorphism at B4galnt2 in natural populations, we are able to recognize the long-term maintenance of the RIIIS/J allele through host pathogen interactions as a viable hypothesis. Further, our models identify that a putative dominant-, yet unknown protective function of the RIIIS/J allele appears to be more likely than a protective loss of intestinal B4galnt2 expression in RIIIS/J homozygotes. PMID- 28806916 TI - Assessment of tuberculosis spatial hotspot areas in Antananarivo, Madagascar, by combining spatial analysis and genotyping. AB - BACKGROUND: Tuberculosis (TB) remains a public health problem in Madagascar. A crucial element of TB control is the development of an easy and rapid method for the orientation of TB control strategies in the country. Our main objective was to develop a TB spatial hotspot identification method by combining spatial analysis and TB genotyping method in Antananarivo. METHODS: Sputa of new pulmonary TB cases from 20 TB diagnosis and treatment centers (DTCs) in Antananarivo were collected from August 2013 to May 2014 for culture. Mycobacterium tuberculosis complex (MTBC) clinical isolates were typed by spoligotyping on a Luminex(r) 200 platform. All TB patients were respectively localized according to their neighborhood residence and the spatial distribution of all pulmonary TB patients and patients with genotypic clustered isolates were scanned respectively by the Kulldorff spatial scanning method for identification of significant spatial clustering. Areas exhibiting spatial clustering of patients with genotypic clustered isolates were considered as hotspot TB areas for transmission. RESULTS: Overall, 467 new cases were included in the study, and 394 spoligotypes were obtained (84.4%). New TB cases were distributed in 133 of the 192 Fokontany (administrative neighborhoods) of Antananarivo (1 to 15 clinical patients per Fokontany) and patients with genotypic clustered isolates were distributed in 127 of the 192 Fokontany (1 to 13 per Fokontany). A single spatial focal point of epidemics was detected when ignoring genotypic data (p = 0.039). One Fokontany of this focal point and three additional ones were detected to be spatially clustered when taking genotypes into account (p < 0.05). These four areas were declared potential TB transmission hotspots in Antananarivo and will be considered as priority targets for surveillance in the future. CONCLUSION: This method, combining spatial analysis and TB genotyping will now be used for further focused clinical and epidemiological studies in Madagascar and will allow better TB control strategies by public health authorities. PMID- 28806918 TI - Systemic LPS resulted in a transient hippocampus malfunction but a prolonged corpus callosum injury. AB - BACKGROUND: To investigate the effect of systemic lipopolysaccharide (LPS) on function of hippocampus and corpus callosum (CC) in adult rats. METHODS: Adult rats with mature white matter tract were divided into systemic LPS and saline injection groups. Animal were euthanized following 3 daily injections (day 3) and 3-day after cessation of injections (day 6). At both time points, hippocampal long term potentiation (LTP) and CC compound action potentials (CAP) were recorded, beta amyloid precursor protein (beta-APP) level in CC tissue was measured by Western blot, and microglia activation was examined by immunostaining and proportional area analysis. RESULTS: Systemic LPS significantly decreased amplitude of both post tetanic potentiation (PTP) and LTP at day 3, but PTP and LTP turned to be normal at day 6. CAP was significantly declined at day 3 but was further declined at day 6. The beta-APP levels in CC tissues of LPS injected rats were significantly higher than that of saline group at both time-points. Interestingly, proportional area measurement disclosed that microglial areas in both hippocampus and CC significantly expanded at day3, but at the day 6, microglial area decreased in hippocampus but further increased in CC. CONCLUSION: Systemic LPS resulted in a transient hippocampus malfunction but a prolonged CC injury. Microglia activation may correlate with such LPS induced white matter injury. PMID- 28806917 TI - Study protocol: pragmatic randomized control trial of an internet-based intervention (My tools 4 care) for family carers. AB - BACKGROUND: Family carers of older persons with Alzheimer's' disease and related dementia (ADRD) and multiple chronic conditions (MCC) experience significant, complex, and distressing transitions such as changes to their environment, roles and relationships, physical health, and mental health. An online intervention (My Tools 4 Care) was developed for family carers of persons with ADRD and MCC living at home, with the aim of supporting these carers through transitions and increasing their self-efficacy, hope, and health related quality of life (HRQoL). This study will evaluate My Tools 4 Care (MT4C) by asking the following research questions: 1. Does use of MT4C result in a 3 month (immediately post intervention) and 6-month (3 months after intervention) increase in HRQoL, self efficacy, and hope, in carers of persons with ADRD and MCC compared to an educational control group? 2. Does use of MT4C help carers of community-dwelling older adults with ADRD and MCC deal with significant changes they experience as carers? and 3. Are the effects/benefits of the MT4C intervention achieved at no additional cost compared to an educational control group? METHODS/DESIGN: Using a pragmatic mixed methods randomized controlled trial design, 180 family carers of community dwelling older persons (65 years of age and older) with ADRD and MCC will participate in the study. Data will be collected from the intervention and an educational control group at four time points: baseline, 1 month, 3 and 6 months. We expect to find that family carers using MT4C will show greater improvement in hope, self-efficacy and HRQoL, at no additional cost from a societal perspective, compared to those in the educational control group. General estimating equations will be used to determine differences between groups and over time. DISCUSSION: Data collection began in Ontario and Alberta Canada in June 2015 and is expected to be completed in June 2017. The results will inform policy and practice as MT4C can be easily revised for local contexts and is scalable in terms of posting on websites such as those hosted by the Alzheimer Society. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02428387. PMID- 28806919 TI - Integrated analysis of mRNA-seq and miRNA-seq reveals the potential roles of sex biased miRNA-mRNA pairs in gonad tissue of dark sleeper (Odontobutis potamophila). AB - BACKGROUND: The dark sleeper (Odontobutis potamophila) is an important commercial fish species which shows a sexually dimorphic growth pattern. However, the lack of sex transcriptomic data is hindering further research and genetically selective breeding of the dark sleeper. In this study, integrated analysis of mRNA and miRNA was performed on gonad tissue to elucidate the molecular mechanisms of sex determination and differentiation in the dark sleeper. RESULTS: A total of 143 differentially expressed miRNAs and 16,540 differentially expressed genes were identified. Of these, 8103 mRNAs and 75 miRNAs were upregulated in testes, and 8437 mRNAs and 68 miRNAs were upregulated in ovaries. Integrated analysis of miRNA and mRNA expression profiles predicted more than 50,000 miRNA-mRNA interaction sites, and among them 27,583 negative miRNA-mRNA interactions. A number of sex related genes were targeted by sex-biased miRNAs. The relationship between 15 sex-biased genes and 15 sex-biased miRNAs verified by using qRT-PCR were described. Additionally, a number of SNPs were revealed through the transcriptome data. CONCLUSIONS: The overall results of this study facilitate our understanding of the molecular mechanism underlying sex determination and differentiation and provide valuable genomic information for selective breeding of the dark sleeper. PMID- 28806921 TI - Using classification and regression tree modelling to investigate response shift patterns in dentine hypersensitivity. AB - BACKGROUND: Dentine hypersensitivity (DH) affects people's quality of life (QoL). However changes in the internal meaning of QoL, known as Response shift (RS) may undermine longitudinal assessment of QoL. This study aimed to describe patterns of RS in people with DH using Classification and Regression Trees (CRT) and to explore the convergent validity of CRT with the then-test and ideals approaches. METHODS: Data from an 8-week clinical trial of mouthwashes for dentine hypersensitivity (n = 75) using the Dentine Hypersensitivity Experience Questionnaire (DHEQ) as the outcome measure, were analysed. CRT was used to examine 8-week changes in DHEQ total score as a dependent variable with clinical status for DH and each DHEQ subscale score (restrictions, coping, social, emotional and identity) as independent variables. Recalibration was inferred when the clinical change was not consistent with the DHEQ change score using a minimally important difference for DHEQ of 22 points. Reprioritization was inferred by changes in the relative importance of each subscale to the model over time. RESULTS: Overall, 50.7% of participants experienced a clinical improvement in their DH after treatment and 22.7% experienced an important improvement in their quality of life. Thirty-six per cent shifted their internal standards downward and 14.7% upwards, suggesting recalibration. Reprioritization occurred over time among the social and emotional impacts of DH. CONCLUSIONS: CRT was a useful method to reveal both, the types and nature of RS in people with a mild health condition and demonstrated convergent validity with design based approaches to detect RS. PMID- 28806922 TI - Hepatitis B reactivation characterized by HBsAg negativity and anti-HbsAg antibodies persistence in haematopoietic stem cell transplanted patient after lamivudine withdrawal. AB - BACKGROUND: HBV reactivation is associated with high mortality rates in hematopoietic stem cell transplantation (HSCT) and prophylactic lamivudine (LMV) treatment is suggested to prevent this phenomenon. However, the duration of LMV treatment in HSCT patients is not fully defined and the time of immune recovery is considered the best parameter for a drug to be safely interrupted. In patients undergoing allogeneic HSCT, the time of immune recovery is not easy to define and may take years after transplantation and prolonged LMV treatments, which can lead to drug-resistant viral strains. CASE PRESENTATION: An anti-HBc-positive hematological patient who was undergoing prolonged immunosuppression and who experienced HBV reactivation 3 months after the suspension of a prolonged LMV prophylaxis is described. HBV-DNA matching an atypical serological profile characterized by HbsAg negativity and anti-HBs positivity was detected in the patient. The genotypic analysis of the HBV strain identified T127P, F170FL and S204R mutations of HbsAg, which can hinder HBsAg recognition in a diagnostic assay. CONCLUSIONS: HBV reactivation in the HSCT host can be sustained by HBsAg viral variants with characteristics of altered immunogenicity that cannot be detected by usual laboratory tests. This clinical case description suggests the importance of screening for serum HBV-DNA levels in the diagnosis of HBV reactivation and monitoring HBV-DNA after prophylaxis suspension, particularly in HSCT subjects who have undergone prolonged periods of LMV treatment. PMID- 28806923 TI - Historical biogeography and ecological niche modelling of the Asimina-Disepalum clade (Annonaceae): role of ecological differentiation in Neotropical-Asian disjunctions and diversification in Asia. AB - BACKGROUND: The Asimina-Disepalum clade (Annonaceae subfam. Annonoideae tribe Annoneae) includes a major Neotropical-Asian biogeographical disjunction. We evaluate whether this disjunction can be explained by the Eocene boreotropics hypothesis, which relies on the existence of extensive boreotropical forests during the Late Palaeocene-Early Eocene thermal maximum (52-50 Ma), followed by disruption of boreotropical vegetation during post-Eocene cooling. Molecular dating using an uncorrelated relaxed molecular clock (UCLD) model with two fossil calibrations, ancestral range estimation, and ecological niche modelling across evolutionary time were performed. Our focus was the geographical origin of Disepalum and general biogeographic patterns within this genus. Comparison of ecological tolerance among extant species and niche reconstructions at ancestral nodes within the clade enabled insights in likely migration routes of lineages, as well as evaluating the role of bioclimatic ecological differentiation in the diversification of Disepalum within Southeast Asia. RESULTS: The inferred vicariance event associated with the Asimina-Disepalum disjunction is estimated to have originated ca. 40 Mya [95% highest posterior density (HPD): 44.3-35.5 Mya]. The Disepalum crown lineage is estimated to have originated ca. 9 Mya (95% HPD: 10.6-7.6), either in western Malesia and continental Southeast Asia, or exclusively in western Malesia. Ecological niche modelling shows that seasonality of temperature and precipitation are major contributors determining the geographical range of species. Ancestral niche modelling furthermore indicates that the ancestor of the Asimina-Disepalum clade likely had bioclimatic preferences close to conditions found in current tropical and subtropical climates across Asia, whereas the ancestors of the Asimina and Disepalum crown groups are projected onto the more subtropical and tropical regions, respectively. CONCLUSIONS: The vicariance event associated with the Neotropical Asian disjunction within the Asimina-Disepalum clade likely coincided with climatic deterioration at the Eocene-Oligocene boundary. Although detrended component analyses (DCA) indicate that altitude and seasonality of temperature and precipitation have the greatest influence in determining the geographical range of species, isolation due to palaeogeographic and palaeoclimatic events appears to be of greater significance than climate niche differentiation in driving diversification in Disepalum. PMID- 28806920 TI - Specific ion channels contribute to key elements of pathology during secondary degeneration following neurotrauma. AB - BACKGROUND: Following partial injury to the central nervous system, cells beyond the initial injury site undergo secondary degeneration, exacerbating loss of neurons, compact myelin and function. Changes in Ca2+ flux are associated with metabolic and structural changes, but it is not yet clear how flux through specific ion channels contributes to the various pathologies. Here, partial optic nerve transection in adult female rats was used to model secondary degeneration. Treatment with combinations of three ion channel inhibitors was used as a tool to investigate which elements of oxidative and structural damage related to long term functional outcomes. The inhibitors employed were the voltage gated Ca2+ channel inhibitor Lomerizine (Lom), the Ca2+ permeable AMPA receptor inhibitor YM872 and the P2X7 receptor inhibitor oxATP. RESULTS: Following partial optic nerve transection, hyper-phosphorylation of Tau and acetylated tubulin immunoreactivity were increased, and Nogo-A immunoreactivity was decreased, indicating that axonal changes occurred acutely. All combinations of ion channel inhibitors reduced hyper-phosphorylation of Tau and increased Nogo-A immunoreactivity at day 3 after injury. However, only Lom/oxATP or all three inhibitors in combination significantly reduced acetylated tubulin immunoreactivity. Most combinations of ion channel inhibitors were effective in restoring the lengths of the paranode and the paranodal gap, indicative of the length of the node of Ranvier, following injury. However, only all three inhibitors in combination restored to normal Ankyrin G length at the node of Ranvier. Similarly, HNE immunoreactivity and loss of oligodendrocyte precursor cells were only limited by treatment with all three ion channel inhibitors in combination. CONCLUSIONS: Data indicate that inhibiting any of a range of ion channels preserves certain elements of axon and node structure and limits some oxidative damage following injury, whereas ionic flux through all three channels must be inhibited to prevent lipid peroxidation and preserve Ankyrin G distribution and OPCs. PMID- 28806924 TI - Essential genome of Campylobacter jejuni. AB - BACKGROUND: Campylobacter species are a leading cause of bacterial foodborne illness worldwide. Despite the global efforts to curb them, Campylobacter infections have increased continuously in both developed and developing countries. The development of effective strategies to control the infection by this pathogen is warranted. The essential genes of bacteria are the most prominent targets for this purpose. In this study, we used transposon sequencing (Tn-seq) of a genome-saturating library of Tn5 insertion mutants to define the essential genome of C. jejuni at a high resolution. RESULT: We constructed a Tn5 mutant library of unprecedented complexity in C. jejuni NCTC 11168 with 95,929 unique insertions throughout the genome and used the genomic DNA of the library for the reconstruction of Tn5 libraries in the same (C. jejuni NCTC 11168) and different strain background (C. jejuni 81-176) through natural transformation. We identified 166 essential protein-coding genes and 20 essential transfer RNAs (tRNA) in C. jejuni NCTC 11168 which were intolerant to Tn5 insertions during in vitro growth. The reconstructed C. jejuni 81-176 library had 384 protein coding genes with no Tn5 insertions. Essential genes in both strain backgrounds were highly enriched in the cluster of orthologous group (COG) categories of 'Translation, ribosomal structure and biogenesis (J)', 'Energy production and conversion (C)', and 'Coenzyme transport and metabolism (H)'. CONCLUSION: Comparative analysis among this and previous studies identified 50 core essential genes of C. jejuni, which can be further investigated for the development of novel strategies to control the spread of this notorious foodborne bacterial pathogen. PMID- 28806925 TI - Genomic data illuminates demography, genetic structure and selection of a popular dog breed. AB - BACKGROUND: Genomic methods have proved to be important tools in the analysis of genetic diversity across the range of species and can be used to reveal processes underlying both short- and long-term evolutionary change. This study applied genomic methods to investigate population structure and inbreeding in a common UK dog breed, the Labrador Retriever. RESULTS: We found substantial within-breed genetic differentiation, which was associated with the role of the dog (i.e. working, pet, show) and also with coat colour (i.e. black, yellow, brown). There was little evidence of geographical differentiation. Highly differentiated genomic regions contained genes and markers associated with skull shape, suggesting that at least some of the differentiation is related to human-imposed selection on this trait. We also found that the total length of homozygous segments (runs of homozygosity, ROHs) was highly correlated with inbreeding coefficient. CONCLUSIONS: This study demonstrates that high-density genomic data can be used to quantify genetic diversity and to decipher demographic and selection processes. Analysis of genetically differentiated regions in the UK Labrador Retriever population suggests the possibility of human-imposed selection on craniofacial characteristics. The high correlation between estimates of inbreeding from genomic and pedigree data for this breed demonstrates that genomic approaches can be used to quantify inbreeding levels in dogs, which will be particularly useful where pedigree information is missing. PMID- 28806926 TI - Evaluation of vaccination herd immunity effects for anogenital warts in a low coverage setting with human papillomavirus vaccine-an interrupted time series analysis from 2005 to 2010 using health insurance data. AB - BACKGROUND: Shortly after the human papillomavirus (HPV) vaccine recommendation and hence the reimbursement of vaccination costs for the respective age groups in Germany in 2007, changes in the incidence of anogenital warts (AGWs) were observed, but it was not clear at what level the incidence would stabilize and to what extent herd immunity would be present. Given the relatively low HPV vaccination coverage in Germany, we aimed to assess potential vaccination herd immunity effects in the German setting. METHODS: A retrospective open cohort study with data from more than nine million statutory health insurance members from 2005 to 2010 was conducted. AGW cases were identified using ICD-10-codes. The incidence of AGWs was estimated by age, sex, and calendar quarter. Age and sex specific incidence rate ratios were estimated comparing the years 2009-2010 (post-vaccination period) with 2005-2007 (pre-vaccination period). RESULTS: Incidence rate ratio of AGWs for the post-vaccination period compared to the pre vaccination period showed a u-shaped decrease among the 14- to 24-year-old females and males which corresponds well with the reported HPV vaccination uptake in 2008. A maximum reduction of up to 60% was observed for the 16- to 20-year-old females and slightly less pronounced (up to 50%) for the 16- and 18-year-old males. Age groups outside of the range 14-24 years demonstrated no decrease. The decrease of incidence occurred in both sexes early after the vaccine recommendation and stabilized at lower levels in 2009-2010. CONCLUSIONS: A relative reduction of up to 50% among males of approximately similar age groups as that of females receiving the HPV vaccination suggests herd protection resulting from assortative mixing by age. The early decrease among males can be reduced over time due to partner change. PMID- 28806927 TI - Mapping of a major QTL for salt tolerance of mature field-grown maize plants based on SNP markers. AB - BACKGROUND: Salt stress significantly restricts plant growth and production. Maize is an important food and economic crop but is also a salt sensitive crop. Identification of the genetic architecture controlling salt tolerance facilitates breeders to select salt tolerant lines. However, the critical quantitative trait loci (QTLs) responsible for the salt tolerance of field-grown maize plants are still unknown. RESULTS: To map the main genetic factors contributing to salt tolerance in mature maize, a double haploid population (240 individuals) and 1317 single nucleotide polymorphism (SNP) markers were employed to produce a genetic linkage map covering 1462.05 cM. Plant height of mature maize cultivated in the saline field (SPH) and plant height-based salt tolerance index (ratio of plant height between saline and control fields, PHI) were used to evaluate salt tolerance of mature maize plants. A major QTL for SPH was detected on Chromosome 1 with the LOD score of 22.4, which explained 31.2% of the phenotypic variation. In addition, the major QTL conditioning PHI was also mapped at the same position on Chromosome 1, and two candidate genes involving in ion homeostasis were identified within the confidence interval of this QTL. CONCLUSIONS: The detection of the major QTL in adult maize plant establishes the basis for the map-based cloning of genes associated with salt tolerance and provides a potential target for marker assisted selection in developing maize varieties with salt tolerance. PMID- 28806928 TI - Colour polymorphic lures exploit innate preferences for spectral versus luminance cues in dipteran prey. AB - BACKGROUND: Theory predicts that colour polymorphism may be favored by variation in the visual context under which signals are perceived. The context encompasses all environmental determinants of light availability and propagation, but also the dynamics of perception in receivers. Color vision involves the neural separation of information into spectral versus luminance channels, which often differentially guide specific tasks. Here we explicitly tested whether this discrete perceptual basis contributes to the maintenance of polymorphism in a prey-luring system. The orb-weaving spider Gasteracantha fornicata is known to attract a broad community of primarily dipteran prey due to their conspicuous banded dorsal signal. They occur in two morphs ("white" and "yellow") which should, respectively, generate greater luminance and color contrast in the dipteran eye. Given that arthropods often rely upon luminance-versus-spectral cues for relatively small-versus-large stimulus detection, we predicted a switch in relative attractiveness among morphs according to apparent spider size. RESULTS: Our experimental tests used colour-naive individuals of two known prey species (Drosophila hydei and Musca domestica) in replicate Y-maze choice trials designed to manipulate the apparent size of spider models via the distance at which they are viewed. Initial trials confirmed that flies were attracted to each G. fornicata morph in single presentations. When given a simultaneous choice between morphs against a viewing background typical of those encountered in nature, flies exhibited no preference regardless of the visual angle subtended by models. However, when backgrounds were adjusted to nearer the extremes of those of each morph in the wild, flies were more attracted by white morphs when presented at longer range (consistent with a reliance on achromatic cues), yet were unbiased in their close-range choice. CONCLUSION: While not fully consistent with predictions (given the absence of a differential preference for stimuli at close range), our results demonstrate an effect of apparent stimulus size upon relative morph attractiveness in the direction anticipated from present knowledge of fly visual ecology. This implies the potential tuning of G. fornicata morph signal structure according to a perceptual feature that is likely common across their breadth of arthropod prey, and complements recent observational work in suggesting a candidate mechanism for the maintenance of deceptive polymorphism through the exploitation of different visual channels in prey. PMID- 28806930 TI - Factors associated with change in objectively measured physical activity in older people - data from the physical activity cohort Scotland study. AB - BACKGROUND: Cross-sectional relationships between physical activity and health have been explored extensively, but less is known about how physical activity changes with time in older people. The aim of this study was to assess baseline predictors of how objectively measured physical activity changes with time in older people. METHODS: Longitudinal cohort study using data from the Physical Activity Cohort Scotland. A sample of community-dwelling older people aged 65 and over were recruited in 2009-2011, then followed up 2-3 years later. Physical activity was measured using Stayhealthy RT3 accelerometers over 7 days. Other data collected included baseline comorbidity, health-related quality of life (SF 36), extended Theory of Planned Behaviour Questionnaire and Social Capital Module of the General Household Survey. Associations between follow-up accelerometer counts and baseline predictors were analysed using a series of linear regression models, adjusting for baseline activity levels and follow-up time. RESULTS: Follow up data were available for 339 of the original 584 participants. The mean age was 77 years, 185 (55%) were female and mean follow up time was 26 months. Mean activity counts fell by between 2% per year (age < =80, deprivation decile 5 10) and 12% per year (age > 80, deprivation decile 5-10) from baseline values. In univariate analysis age, sex, deprivation decile, most SF-36 domains, most measures of social connectedness, most measures from the extended Theory of Planned Behaviour, hypertension, diabetes mellitus, chronic pain and depression score were significantly associated with adjusted activity counts at follow-up. In multivariate regression age, satisfactory friend network, SF-36 physical function score, and the presence of diabetes mellitus were independent predictors of activity counts at follow up after adjustment for baseline count and duration of follow up. CONCLUSIONS: Health status and social connectedness, but not extended Theory of Planned Behaviour measures, independently predicted changes in physical activity in community dwelling older people. PMID- 28806929 TI - Myelination is delayed during postnatal brain development in the mdx mouse model of Duchenne muscular dystrophy. AB - BACKGROUND: In Duchenne muscular dystrophy (DMD), the loss of the dystrophin component of the dystrophin-glycoprotein complex (DGC) compromises plasma membrane integrity in skeletal muscle, resulting in extensive muscle degeneration. In addition, many DMD patients exhibit brain deficits in which the cellular etiology remains poorly understood. We recently found that dystroglycan, a receptor component of the DGC that binds intracellularly to dystrophin, regulates the development of oligodendrocytes, the myelinating glial cells of the brain. RESULTS: We investigated whether dystrophin contributes to oligodendroglial function and brain myelination. We found that oligodendrocytes express up to three dystrophin isoforms, in conjunction with classic DGC components, which are developmentally regulated during differentiation and in response to extracellular matrix engagement. We found that mdx mice, a model of DMD lacking expression of the largest dystrophin isoform, have delayed myelination and inappropriate oligodendrocyte progenitor proliferation in the cerebral cortex. When we prevented the expression of all oligodendroglial dystrophin isoforms in cultured oligodendrocytes using RNA interference, we found that later stages of oligodendrocyte maturation were significantly delayed, similar to mdx phenotypes in the developing brain. CONCLUSIONS: We find that dystrophin is expressed in oligodendrocytes and influences developmental myelination, which provides new insight into potential cellular contributors to brain dysfunction associated with DMD. PMID- 28806931 TI - Draft de novo transcriptome assembly and proteome characterization of the electric lobe of Tetronarce californica: a molecular tool for the study of cholinergic neurotransmission in the electric organ. AB - BACKGROUND: The electric organ of Tetronarce californica (an electric ray formerly known as Torpedo californica) is a classic preparation for biochemical studies of cholinergic neurotransmission. To broaden the usefulness of this preparation, we have performed a transcriptome assembly of the presynaptic component of the electric organ (the electric lobe). We combined our assembled transcriptome with a previous transcriptome of the postsynaptic electric organ, to define a MetaProteome containing pre- and post-synaptic components of the electric organ. RESULTS: Sequencing yielded 102 million paired-end 100 bp reads. De novo Trinity assembly was performed at Kmer 25 (default) and Kmers 27, 29, and 31. Trinity, generated around 103,000 transcripts, and 78,000 genes per assembly. Assemblies were evaluated based on the number of bases/transcripts assembled, RSEM-EVAL scores and informational content and completeness. We found that different assemblies scored differently according to the evaluation criteria used, and that while each individual assembly contained unique information, much of the assembly information was shared by all assemblies. To generate the presynaptic transcriptome (electric lobe), while capturing all information, assemblies were first clustered and then combined with postsynaptic transcripts (electric organ) downloaded from NCBI. The completness of the resulting clustered predicted MetaProteome was rigorously evaluated by comparing its information against the predicted proteomes from Homo sapiens, Callorhinchus milli, and the Transporter Classification Database (TCDB). CONCLUSIONS: In summary, we obtained a MetaProteome containing 92%, 88.5%, and 66% of the expected set of ultra conserved sequences (i.e., BUSCOs), expected to be found for Eukaryotes, Metazoa, and Vertebrata, respectively. We cross-annotated the conserved set of proteins shared between the T. californica MetaProteome and the proteomes of H. sapiens and C. milli, using the H. sapiens genome as a reference. This information was used to predict the position in human pathways of the conserved members of the T. californica MetaProteome. We found proteins not detected before in T. californica, corresponding to processes involved in synaptic vesicle biology. Finally, we identified 42 transporter proteins in TCDB that were detected by the T. californica MetaProteome (electric fish) and not selected by a control proteome consisting of the combined proteomes of 12 widely diverse non-electric fishes by Reverse-Blast-Hit Blast. Combined, the information provided here is not only a unique tool for the study of cholinergic neurotransmission, but it is also a starting point for understanding the evolution of early vertebrates. PMID- 28806932 TI - The impact of the lookback period and definition of confirmatory events on the identification of incident cancer cases in administrative data. AB - BACKGROUND: This cohort study examined the impact of the lengths of lookback and confirmation periods as well as the definition of confirmatory events on the number of incident cancer cases identified and age-standardized cumulative incidences (ACI) estimated in administrative data using German cancer registry data as a benchmark. METHODS: ACI per 100,000 insured persons for breast, prostate and colorectal cancer were estimated using BARMER Statutory Health Insurance claims data. Incident cancer cases were defined as having an in- or outpatient diagnosis in 2013, no diagnosis in a lookback period of 1 year and a second diagnosis (or death) in a confirmation period of 1 quarter. We varied lookback periods from 1 to 7 years, confirmation periods from 1 to 4 quarters as well as the definition of confirmatory events and compared ACI estimates to cancer registry data. RESULTS: ACI were higher for breast (138.7) and prostate (103.6) but lower for colorectal cancer (42.1) when compared to cancer registries (119.3, 98.0 and 45.5, respectively). Extending the lookback period to 7 years reduced ACI to 129.0, 95.1 and 38.3. An extended confirmation period of 4 quarters increased ACI to 151.3, 114.9 and 46.8. Including breast and colorectal surgeries as a confirmatory event reduced ACI to 114.9 and 37.1, respectively. CONCLUSIONS: The choice of lookback and confirmation periods and the definition of confirmatory events have considerable impact on the number of incident cancer cases identified and ACI estimated. Researchers need to be aware of potential misclassification when identifying incident cancer cases in administrative data. Further validation studies as well as studies using administrative data to estimate cancer incidences should consider several choices of the lookback and confirmation periods and the definition of confirmatory events to show how these parameters impact the validity and robustness of their results. PMID- 28806933 TI - The evolutionary and coevolutionary consequences of defensive microbes for host parasite interactions. AB - BACKGROUND: Animal and plant species can harbour microbes that provide them with protection against enemies. These beneficial microbes can be a significant component of host defence that complement or replaces a repertoire of immunity, but they can also be costly. Given their impact on host and parasite fitness, defensive microbes have the potential to influence host-parasite interactions on an evolutionary timescale. RESULTS: Using a phenotypic framework, we explore the evolutionary and coevolutionary dynamics of a host-parasite interaction in the presence of defensive microbes. We show that costs of host-defensive microbe systems are critical in determining whether a defensive microbe based system or an immune system provides better host protection investment. Partitioning the coevolutionary dynamics yields testable predictions. The density of defensive microbes influences the strength of selection resulting from host - defensive microbe - parasite coevolutionary interactions. We find that they lessen the negative effects of infection on hosts and reduce infectivity by directly competing with parasites. CONCLUSIONS: Defensive microbes might thus play a central role in host-parasite interactions, by outright replacing host-based defences, engaging in within-host competition with parasites, and ultimately driving tripartite coevolutionary dynamics. PMID- 28806934 TI - Development and evaluation of the content validity, practicability and feasibility of the Innovative dementia-oriented Assessment system for challenging behaviour in residents with dementia. AB - BACKGROUND: One of the most difficult issues for care staff is the manifestation of challenging behaviour among residents with dementia. The first step in managing this type of behaviour is analysing its triggers. A structured assessment instrument can facilitate this process and may improve carers' management of the situation. This paper describes the development of an instrument designed for this purpose and an evaluation of its content validity and its feasibility and practicability in nursing homes. METHODS: The development process and evaluation of the content validity were based on Lynn's methodology (1998). A literature review (steps 1 + 2) provided the theoretical framework for the instrument and for item formation. Ten experts (step 3) evaluated the first version of the instrument (the Innovative dementia-oriented Assessment (IdA(r))) regarding its relevance, clarity, meaningfulness and completeness; content validity indices at the scale-level (S-CVI) and item-level (I-CVI) were calculated. Health care workers (step 4) evaluated the second version in a workshop. Finally, the instrument was introduced to 17 units in 11 nursing homes in a field study (step 5), and 60 care staff members assessed its practicability and feasibility. RESULTS: The IdA(r) used the need-driven dementia-compromised behaviour (NDB) model as a theoretical framework. The literature review and expert-based panel supported the content validity of the IdA(r). At the item level, 77% of the ratings had a CVI greater than or equal to 0.78. The majority of the question-ratings (84%, n = 154) and answer-ratings (69%, n = 122) showed valid results, with none below 0.50. The health care workers confirmed the understandability, completeness and plausibility of the IdA(r). Steps 3 and 4 led to further item clarification. The carers in the study considered the instrument helpful for reflecting challenging behaviour and beneficial for the care of residents with dementia. Negative ratings referred to the time required and the lack of effect on residents' behaviour. CONCLUSIONS: There was strong evidence supporting the content validity of the IdA(r). Despite the substantial length and time requirement, the instrument was considered helpful for analysing challenging behaviour. Thus, further research on the psychometric qualities, implementation aspects and effectiveness of the IdA(r) in understanding challenging behaviour is needed. PMID- 28806935 TI - Association between Charlson comorbidity index score and outcome in patients with stage IIIB-IV non-small cell lung cancer. AB - BACKGROUND: This retrospective study investigated the association between the Charlson comorbidity index (CCI) score and the survival of patients with stage IIIB-IV (advanced, non-resectable) non-small cell lung cancer (NSCLC) who also did not have gene mutations in epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK). METHODS: The records of 165 patients (28-80 y, median 61 y) who met the above criteria and were admitted to Beijing Friendship Hospital Capital Medical University from 1 May 2010 to 1 October 2014were reviewed. Associations between baseline variables and the CCI score were assessed via univariate and multivariate logistic regression analysis. Overall survival was defined as the time from the first clinic visit to death from any cause, or to the end of follow-up. Survival curves were estimated via the Kaplan-Meier method and compared with the log-rank test. RESULTS: Logistic regression analyses indicated that smoking and performance status were independently associated with the CCI score. Smoking was associated with an increased risk of mortality (odds ratio (OR) 4.12 (95% confidence interval [CI] 1.92-8.84) compared to non smokers), as was performance status 2 (ambulatory, capable of self-care, unable to perform any work activities; active for >50% of waking hours) (OR 2.22 (95% CI, 1.14-4.33) compared to performance status 1). Univariate Cox's regression analyses showed that the hazard ratios were significantly associated with the CCI score (P = 0.009), smoking (P = 0.042), and male gender (P = 0.021). CONCLUSION: The CCI score is an important prognostic factor for the prediction of overall survival in patients with stage IIIB-IV NSCLC who are negative for EGFR and ALK gene mutations. PMID- 28806936 TI - Enhancement of hepatitis virus immunoassay outcome predictions in imbalanced routine pathology data by data balancing and feature selection before the application of support vector machines. AB - BACKGROUND: Data mining techniques such as support vector machines (SVMs) have been successfully used to predict outcomes for complex problems, including for human health. Much health data is imbalanced, with many more controls than positive cases. METHODS: The impact of three balancing methods and one feature selection method is explored, to assess the ability of SVMs to classify imbalanced diagnostic pathology data associated with the laboratory diagnosis of hepatitis B (HBV) and hepatitis C (HCV) infections. Random forests (RFs) for predictor variable selection, and data reshaping to overcome a large imbalance of negative to positive test results in relation to HBV and HCV immunoassay results, are examined. The methodology is illustrated using data from ACT Pathology (Canberra, Australia), consisting of laboratory test records from 18,625 individuals who underwent hepatitis virus testing over the decade from 1997 to 2007. RESULTS: Overall, the prediction of HCV test results by immunoassay was more accurate than for HBV immunoassay results associated with identical routine pathology predictor variable data. HBV and HCV negative results were vastly in excess of positive results, so three approaches to handling the negative/positive data imbalance were compared. Generating datasets by the Synthetic Minority Oversampling Technique (SMOTE) resulted in significantly more accurate prediction than single downsizing or multiple downsizing (MDS) of the dataset. For downsized data sets, applying a RF for predictor variable selection had a small effect on the performance, which varied depending on the virus. For SMOTE, a RF had a negative effect on performance. An analysis of variance of the performance across settings supports these findings. Finally, age and assay results for alanine aminotransferase (ALT), sodium for HBV and urea for HCV were found to have a significant impact upon laboratory diagnosis of HBV or HCV infection using an optimised SVM model. CONCLUSIONS: Laboratories looking to include machine learning via SVM as part of their decision support need to be aware that the balancing method, predictor variable selection and the virus type interact to affect the laboratory diagnosis of hepatitis virus infection with routine pathology laboratory variables in different ways depending on which combination is being studied. This awareness should lead to careful use of existing machine learning methods, thus improving the quality of laboratory diagnosis. PMID- 28806937 TI - Prognostic value of pretreatment serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) ratio and gamma glutamyltransferase (GGT) in patients with esophageal squamous cell carcinoma. AB - BACKGROUND: The levels of liver function tests (LFTs) are often used to assess liver injury and non-liver disease-related mortality. In our study, the relationship between pretreatment serum LFTs and overall survival (OS) was evaluated in esophageal squamous cell carcinoma (ESCC) patients. METHODS: Our purpose was to investigate the prognostic value of the preoperative alanine aminotransferase/aspartate aminotransferase (ALT/AST) ratio and gamma glutamyltransferase (GGT) in ESCC patients. A retrospective study was performed in 447 patients with ESCC, and follow-up period was at least 60 months until death. The prognostic significance of serum LFTs were determined by univariate and multivariate Cox hazard models. RESULTS: LFTs including ALT, AST, LSR, GGT, TBA and LDH were analyzed. Serum LSR (HR: 0.592, 95% CI = 0.457-0.768, p < 0.001 and GGT (HR: 1.507, 95% CI = 1.163-1.953, p = 0.002) levels were indicated as significant predictors of OS. The 5-year OS among patients with higher LSR levels was longer compared with those patients with decreased LSR levels, not only in the whole cohort but also in the subgroups stratified by pathological stage (T1 T2 subgroup, T3-T4 subgroup, N0 subgroup and M0 subgroup). We also found that patients with a higher GGT might predict worse OS than patients with a normal GGT, not only in the whole cohort but also in the subgroups stratified by pathological stage (T3-T4 subgroup and N1-N2 subgroup). CONCLUSIONS: Both increased levels of LSR and decreased levels of GGT might predict shorter overall survival in ESCC patients. Our findings suggest that serum LSR and GGT levels could be used as a key predictor of survival in patients with ESCC. PMID- 28806938 TI - Cystoid macular oedema associated with Rosai-Dorfman disease: a case report. AB - BACKGROUND: The aim of this study is to report a case of cystoid macular oedema (CME) associated with Rosai-Dorfman Disease (RDD). CASE PRESENTATION: A 52-year old male initially presented with a two-month history of a congested left eye. At presentation, visual acuity was 20/20 in the right eye and 20/80 in the left eye. Biomicroscopy showed conjunctival hyperaemia in the left eye with a slight elevation, suggesting a subconjunctival mass. Retinal fluorescein angiography and optical coherence tomography (OCT) revealed the presence of CME in the left eye. A clinical examination revealed nodular lesions in the ears and a lump in the subcutaneous tissue of the left arm. A biopsy of the subcutaneous lesion showed histological and immunohistochemical characteristics of RDD. The patient was treated with intravitreal triamcinolone (0.1 mL/4 mg). One month after treatment, there was complete regression of the oedema with a significant improvement in visual acuity to 20/20. CONCLUSIONS: This is the first reported case of RDD associated with cystoid macular oedema. Macular oedema responded to intravitreal treatment with triamcinolone. PMID- 28806939 TI - Effect of electromagnetic fields on human osteoarthritic and non-osteoarthritic chondrocytes. AB - BACKGROUND: Studies of the effects of electromagnetic fields (EMFs) on cartilaginous cells show a broad range of outcomes. However EMFs are not yet clinically applied as standard treatment of osteoarthritis, as EMF effects are showing varying outcomes in the literature. The aim of this study was to examine effects of EMFs (5 mT or 8 mT) on osteoarthritic (OA) and non-OA chondrocytes in order to investigate whether EMF effects are related to chondrocyte and EMF quality. METHODS: Pellets of human OA and non-OA chondrocytes were exposed to a sinusoidal 15 Hz EMF produced by a solenoid. Control groups were cultivated without EMF under standard conditions for 7 days. Cultures were examined by staining, immunohistochemistry and quantitative real-time PCR for RNA corresponding to cartilage specific proteins (COL2A1, ACAN, SOX9). RESULTS: OA chondrocytes increased the expression of COL2A1 and ACAN under 5 mT EMF compared to control. In contrast no changes in gene expression were observed in non-OA chondrocytes. OA and non-OA chondrocytes showed no significant changes in gene expression under 8 mT EMF. CONCLUSION: A 5 mT EMF increased the expression of cartilage specific genes in OA chondrocytes whereas in non-OA chondrocytes no changes in gene expression were observed. An 8 mT EMF however showed no effect altogether. This suggests that EMF effects are related to EMF but also to chondrocyte quality. Further studies about the clinical relevance of this effect are necessary. PMID- 28806940 TI - Evaluation of the implementation of an intervention to improve the street environment and promote walking for transport in deprived neighbourhoods. AB - BACKGROUND: Levels of physical activity remain low, particularly in deprived areas. Improving the street environment to promote walking for transport using a community engagement approach is a potential strategy to increase physical activity. An understanding of the implementation of this intervention approach is needed to facilitate further research, replication and scale-up. The aim of this study was to evaluate the implementation of the Fitter for Walking (FFW) intervention in deprived neighbourhoods. METHODS: FFW was delivered in five regions of England between August 2008 and March 2012 and aimed to use a community engagement approach to improve the street environment to promote walking for transport. Implementation was assessed in relation to reach; dosage; implementation processes and adaptation; and factors influencing implementation. Three data sources were used: focus groups and face-to-face interviews with coordinators; implementation logs; and participation records. RESULTS: Reach: 155 community groups participated in FFW engaging 30,230 local residents. Dosage: A wide variety of environmental improvements were implemented by local authorities (LAs) (42 projects) and by communities (46 projects). Examples of LA-led improvements included removal of encroaching vegetation, new/improved pedestrian signage, new dropped kerbs/kerb improvements and new, repaired or improved footpaths. Examples of community-led improvements included planting bulbs, shrubs or bedding plants, clean-up days and litter pick-ups. In 32 projects, no environmental improvements were implemented. Promotional and awareness-raising activities were undertaken in 81 projects. Examples included led walks, themed walks, development of maps/resources to promote improved routes and community events. Processes and adaptation: The need for a planning phase, a preparatory phase, and a delivery phase with a four step process were identified. Adaptability to local context was important. Factors influencing implementation: Five key themes were identified in relation to the barriers and facilitators of implementing FFW: local knowledge and contacts; intervention delivery; coordinator role; working with LAs and other partners; and working with communities. CONCLUSIONS: FFW is one of few reported interventions which have used a community engagement approach to change the street environment to promote walking for transport in deprived neighbourhoods. Delivering these types of interventions is complex and requires considerable resource and time. A set of recommendations and an implementation framework are proposed for future delivery of this and similar types of programme. PMID- 28806941 TI - Androgen receptor is expressed in mouse cardiomyocytes at prenatal and early postnatal developmental stages. AB - BACKGROUND: Previous studies show that androgens are involved in hypertrophy and excitability of cardiomyocytes and that their effects are mediated through their receptor. The aim of this study was to evaluate the presence of androgen receptor (AR) in mouse heart during prenatal and early postnatal stages. RESULTS: The expression of AR and related genes, alpha myosin heavy chain -Myh6-, beta myosin heavy chain -Myh7- and atrial natriuretic factor -Nppa- was simultaneously evaluated by semiquantitative RT-PCR. AR was also detected by immunohistochemistry. Androgen receptor mRNA was detected in hearts from 10.5 days post coitum to 16 postnatal days. A higher expression of AR mRNA in atria compared to ventricles was observed in neonatal mouse. A positive correlation between mRNA levels of AR and Nppa was observed in mouse heart at early postnatal development. Androgen receptor expression is similar in males and females during cardiac development. Finally, androgen receptor protein was observed by immunohistochemistry in myocardial cells of atria and ventricles from 12.5 days onwards and restricted after 16.5 days post-coitum to nuclei of cardiomyocytes. CONCLUSION: Present results provide evidence that androgen receptor is expressed from prenatal stages in mouse heart, supporting the proposition that androgens could be involved in mammalian heart development. PMID- 28806942 TI - Impact of inpatient Care in Emergency Department on outcomes: a quasi experimental cohort study. AB - BACKGROUND: Hospitals around the world are faced with the issue of boarders in emergency department (ED), patients marked for admission but with no available inpatient bed. Boarder status is known to be associated with delayed inpatient care and suboptimal outcomes. A new care delivery system was developed in our institution where boarders received full inpatient care from a designated medical team, acute medical team (AMT), while still residing at ED. The current study examines the impact of this AMT intervention on patient outcomes. METHODS: We conducted a retrospective quasi-experimental cohort study to analyze outcomes between the AMT intervention and conventional care in a 1250-bed acute care tertiary academic hospital in Singapore. Study participants included patients who received care from the AMT, a matched cohort of patients admitted directly to inpatient wards (non-AMT) and a sample of patients prior to the intervention (pre AMT group). Primary outcomes were length of hospital stay (LOS), early discharges (within 24 h) and bed placement. Secondary outcomes included unplanned readmissions within 3 months, and patient's bill size. chi2- and Mann-Whitney U tests were used to test for differences between the cohorts on dichotomous and continuous variables respectively. RESULTS: The sample comprised of 2279 patients (1092 in AMT, 1027 in non-AMT, and 160 in pre-AMT groups). Higher rates of early discharge (without significant differences in the readmission rates) and shorter LOS were noted for the AMT patients. They were also more likely to be admitted into a ward allocated to their discipline and had lower bill size compared to non AMT patients. CONCLUSIONS: The AMT intervention improved patient outcomes and resource utilization. This model was noted to be sustainable and provides a potential solution for hospitals' ED boarders who face a gap in inpatient care during their crucial first few hours of admissions while waiting for an inpatient bed. PMID- 28806943 TI - Gender differences and similarities in medical students' experiences of mistreatment by various groups of perpetrators. AB - BACKGROUND: Mistreatment of medical students during medical education is a widespread concern. Studies have shown that medical students report the most mistreatment compared to students of other study programs and that the prevalence of mistreatment peaks during clinical training. For this reason, a study was conducted to assess prevalence of mistreatment among medical students committed by various groups of people. The focus was to identify whether gender was associated with the experience of mistreatment. Additionally, students' perception of university climate for reporting sexual harassment was assessed. METHOD: In the study 88 medical students (45 women, 43 men) participated. A modified version of the Questionnaire on Student Abuse was used to assess students' experience of various types of mistreatment and associated distress during medical education. To explore factors that could be associated with this experience the organizational climate for reporting sexual harassment was assessed with the Psychological Climate for Sexual Harassment. RESULT: The most often cited perpetrators of mistreatment were strangers (79.5%), friends (75.0%) and university staff (68.2%). Strangers mostly committed psychological mistreatment and sexual harassment, whereas friends additionally engaged in physical mistreatment of medical students. The most common form of mistreatment conducted by university staff was humiliation of students. These kinds of psychological mistreatment were reported to be distressing (43%). Gender differences were found in the prevalence of mistreatment. Women experienced more sexual harassment and humiliation than did men. On the other hand, men experienced more physical mistreatment than did women. Women reported experiencing more distress from mistreatment experiences than did men and also more often reported being mistreated by university staff than did men. Women perceived a greater risk in reporting sexual harassment to the organization than did men. CONCLUSION: Mistreatment of female and male students should be focused on using a gender perspective because types of mistreatment can differ by gender. Additionally, interventions should include the societal level as there was a high prevalence of mistreatment perpetrated by strangers. Also the issue of trust in the university needs to be addressed and the organization is called on to visibly demonstrate that it represents and protects its students as well as its staff. PMID- 28806944 TI - Real-world costs of autosomal dominant polycystic kidney disease in the Nordics. AB - BACKGROUND: There is limited real-world data on the economic burden of patients with autosomal dominant polycystic kidney disease (ADPKD). The objective of this study was to estimate the annual direct and indirect costs of patients with ADPKD by severity of the disease: chronic kidney disease (CKD) stages 1-3; CKD stages 4 5; transplant recipients; and maintenance dialysis patients. METHODS: A retrospective study of ADPKD patients was undertaken April-December 2014 in Denmark, Finland, Norway and Sweden. Data on medical resource utilisation were extracted from medical charts and patients were asked to complete a self administered questionnaire. RESULTS: A total of 266 patients were contacted, 243 (91%) of whom provided consent to participate in the study. Results showed that the economic burden of ADPKD was substantial at all levels of the disease. Lost wages due to reduced productivity were large in absolute terms across all disease strata. Mean total annual costs were highest in dialysis patients, driven by maintenance dialysis care, while the use of immunosuppressants was the main cost component for transplant care. Costs were twice as high in patients with CKD stages 4-5 compared to CKD stages 1-3. CONCLUSIONS: Costs associated with ADPKD are significant and the progression of the disease is associated with an increased frequency and intensity of medical resource utilisation. Interventions that can slow the progression of the disease have the potential to lead to substantial reductions in costs for the treatment of ADPKD. PMID- 28806945 TI - Tumor microenvironment conditions alter Akt and Na+/H+ exchanger NHE1 expression in endothelial cells more than hypoxia alone: implications for endothelial cell function in cancer. AB - BACKGROUND: Chronic angiogenesis is a hallmark of most tumors and takes place in a hostile tumor microenvironment (TME) characterized by hypoxia, low nutrient and glucose levels, elevated lactate and low pH. Despite this, most studies addressing angiogenic signaling use hypoxia as a proxy for tumor conditions. Here, we compared the effects of hypoxia and TME conditions on regulation of the Na+/H+ exchanger NHE1, Ser/Thr kinases Akt1-3, and downstream effectors in endothelial cells. METHODS: Human umbilical vein endothelial cells (HUVEC) and Ea.hy926 endothelial cells were exposed to simulated TME (1% hypoxia, low serum, glucose, pH, high lactate) or 1% hypoxia for 24 or 48 h, with or without NHE1 inhibition or siRNA-mediated knockdown. mRNA and protein levels of NHE1, Akt1-3, and downstream effectors were assessed by qPCR and Western blotting, vascular endothelial growth factor (VEGF) release by ELISA, and motility by scratch assay. RESULTS: Within 24 h, HIF-1alpha level and VEGF mRNA level were increased robustly by TME and modestly by hypoxia alone. The NHE1 mRNA level was decreased by both hypoxia and TME, and NHE1 protein was reduced by TME in Ea.hy926 cells. Akt1-3 mRNA was detected in HUVEC and Ea.hy926 cells, Akt1 most abundantly. Akt1 protein expression was reduced by TME yet unaffected by hypoxia, while Akt phosphorylation was increased by TME. The Akt loss was partly reversed by MCF-7 human breast cancer cell conditioned medium, suggesting that in vivo, the cancer cell secretome may compensate for adverse effects of TME on endothelial cells. TME, yet not hypoxia, reduced p70S6 kinase activity and ribosomal protein S6 phosphorylation and increased eIF2alpha phosphorylation, consistent with inhibition of protein translation. Finally, TME reduced Retinoblastoma protein phosphorylation and induced poly-ADP-ribose polymerase (PARP) cleavage consistent with inhibition of proliferation and induction of apoptosis. NHE1 knockdown, mimicking the effect of TME on NHE1 expression, reduced Ea.hy926 migration. TME effects on HIF-1alpha, VEGF, Akt, translation, proliferation or apoptosis markers were unaffected by NHE1 knockdown/inhibition. CONCLUSIONS: NHE1 and Akt are downregulated by TME conditions, more potently than by hypoxia alone. This inhibits endothelial cell migration and growth in a manner likely modulated by the cancer cell secretome. PMID- 28806946 TI - Improving access to mental health care in an Orthodox Jewish community: a critical reflection upon the accommodation of otherness. AB - BACKGROUND: The English National Health Service (NHS) has significantly extended the supply of evidence based psychological interventions in primary care for people experiencing common mental health problems. Yet despite the extra resources, the accessibility of services for 'under-served' ethnic and religious minority groups, is considerably short of the levels of access that may be necessary to offset the health inequalities created by their different exposure to services, resulting in negative health outcomes. This paper offers a critical reflection upon an initiative that sought to improve access to an NHS funded primary care mental health service to one 'under-served' population, an Orthodox Jewish community in the North West of England. METHODS: A combination of qualitative and quantitative data were drawn upon including naturally occurring data, observational notes, e-mail correspondence, routinely collected demographic data and clinical outcomes measures, as well as written feedback and recorded discussions with 12 key informants. RESULTS: Improvements in access to mental health care for some people from the Orthodox Jewish community were achieved through the collaborative efforts of a distributed leadership team. The members of this leadership team were a self-selecting group of stakeholders which had a combination of local knowledge, cultural understanding, power to negotiate on behalf of their respective constituencies and expertise in mental health care. Through a process of dialogic engagement the team was able to work with the community to develop a bespoke service that accommodated its wish to maintain a distinct sense of cultural otherness. CONCLUSIONS: This critical reflection illustrates how dialogic engagement can further the mechanisms of candidacy, concordance and recursivity that are associated with improvements in access to care in under-served sections of the population, whilst simultaneously recognising the limits of constructive dialogue. Dialogue can change the dynamic of community engagement. However, the full alignment of the goals of differing constituencies may not always be possible, due the complex interaction between the multiple positions and understandings of stakeholders that are involved and the need to respect the other'-s' autonomy. PMID- 28806947 TI - Conessine as a novel inhibitor of multidrug efflux pump systems in Pseudomonas aeruginosa. AB - BACKGROUND: Holarrhena antidysenterica has been employed as an ethnobotanical plant for the treatment of dysentery, diarrhoea, fever, and bacterial infections. Biological activities of the principle compound, conessine including anti diarrhoea and anti-plasmodial effects were documented. Our previous study reported potency of Holarrhena antidysenterica extract and conessine as resistance modifying agents against extensively drug-resistant Acinetobacter baumannii. This study aimed to investigate (i) whether conessine, a steroidal alkaloid compound, could act as a resistance modifying agent against multidrug resistant Pseudomonas aeruginosa, and (ii) whether MexAB-OprM efflux pump involved in the mechanism. METHODS: Conessine combined with various antibiotics were determined for synergistic activity against P. aeruginosa PAO1 strain K767 (wild-type), K1455 (MexAB-OprM overexpressed), and K1523 (MexB deletion). H33342 accumulation assay was used to evaluate efflux pump inhibition while NPN uptake assay was assessed membrane permeabilization. RESULTS: Conessine significantly reduced MICs of all antibiotics by at least 8-fold in MexAB-OprM overexpressed strain. The levels were comparable to those obtained in wild-type strain for cefotaxime, levofloxacin, and tetracycline. With erythromycin, novobiocin, and rifampicin, MICs were 4- to 8-fold less than MICs of the wild-type strain. Loss of MexAB-OprM due to deletion of mexB affected susceptibility to almost all antibiotics, except novobiocin. Synergistic activities between other antibiotics (except novobiocin) and conessine observed in MexB deletion strain suggested that conessine might inhibit other efflux systems present in P. aeruginosa. Inhibition of H33342 efflux in the tested strains clearly demonstrated that conessine inhibited MexAB-OprM pump. In contrast, the mode of action as a membrane permeabilizer was not observed after treatment with conessine as evidenced by no accumulation of 1-N-phenylnaphthylamine. CONCLUSIONS: The results suggested that conessine could be applied as a novel efflux pump inhibitor to restore antibiotic activity by inhibiting efflux pump systems in P. aeruginosa. The findings speculated that conessine may also have a potential to be active against homologous resistance-nodulation-division (RND) family in other Gram-negative pathogens. PMID- 28806948 TI - Assessment of lower urinary symptom flare with overactive bladder symptom score and International Prostate Symptom Score in patients treated with iodine-125 implant brachytherapy: long-term follow-up experience at a single institute. AB - BACKGROUND: The aim of this study was to evaluate the combined use of the overactive bladder symptom score (OABSS) and International Prostate Symptom Score (IPSS) as an assessment tool for urinary symptom flare after iodine-125 (125I) implant brachytherapy. The association between urinary symptom flare and prostate specific antigen (PSA) bounce was investigated. METHODS: Changes in the IPSS and OABSS were prospectively recorded in 355 patients who underwent seed implantation. The percentage distribution of patients according to the difference between the flare peak and post-implant nadir was plotted to define significant increases in the scores. The clinicopathologic characteristics, treatment parameters, and post-implant dosimetric parameters were compared between the non flare and flare groups. PSA bounce was defined as an elevation of >=0.1 ng/mL or >=0.4 ng/mL compared to the previous lowest value, followed by a decrease to a level at or below the pre-bounce value. RESULTS: A clinically significant increase required an IPSS increase of at least 12 points and an OABSS increase of at least 6 points based on a time-course analysis of total scores and the QOL index. Assessment only by IPSS failed to detect 40 patients (11%) who had urinary symptom flare according to the OABSS. Univariate and multivariate analyses revealed that patients treated with higher biologically effective doses and those without diabetes mellitus had higher risks of urinary flare. There was no statistical correlation between the incidence and time of urinary symptom flare onset and that of a PSA bounce. CONCLUSIONS: To our knowledge, this is the first report to prove the clinical potential of the OABSS as an assessment tool for urinary symptom flare after seed implantation. Our findings showed that persistent lower urinary tract symptoms after seed implantation were attributed to storage rather than to voiding issues. We believe that assessment with the OABSS combined with the IPSS would aid in decision-making in terms of timing, selection of a treatment intervention, and assessment of the outcome. PMID- 28806949 TI - Case report of ocular Kaposi's sarcoma. AB - BACKGROUND: Kaposi's sarcoma (KS) is generally considered a neoplastic disorder of vascular origin and occurs in patients with acquired immunodeficiency syndrome (AIDS) or who have received immunosuppressive treatments after an organ transplant (Soulier et al., Blood 86(4):1276-80, 1995; Viejo-Borbolla and Schulz, AIDS Rev 5(4):222-9, 2003; Schulz, J Antimicrob Chemother 45(Suppl T3):15-27, 2000; Aversa et al. Crit Rev Oncol Hematol 53(3):253-65, 2005; Mbulaiteye and Engels, Int J Cancer 119(11):2685-91, 2006; Tessari et al., Eur J Dermatol 16(5):553-7, 2006). Several Kaposi's sarcoma case reports involving eyelids and conjunctiva have been published (Bavishi et al., Int J STD AIDS 23(3):221-2, 2012; Baumann et al., Ger J Ophthalmol 4(4):239-45, 1995). CASE PRESENTATION: we report a 13 years old asian male patient rare case of ocular KS that was initiated from the sclera and progressed into the cornea and conjunctiva without an human Immunodeificiency Virus (HIV) or HHV-8 infection after a peripheral blood stem cells transplantation. In this case, anti- vascular endothelial growth factor (VEGF) therapy was attempted to stop the advance of ocular lesions and failed. Eventually, the KS was cured by a limbo-corneal lamellar graft, an amniotic membrane and scleral allograft transplantation plus intraoperative mitomycin C(MMC) after the complete excision of the tumors. CONCLUSION: A compete surgical excision combined with the intraoperative application of MMC, as well as grafts to repair the scleral, conjunctival, and corneal surfaces, could prevent a recurrence of KS. PMID- 28806950 TI - Precision medicine approaches to lung adenocarcinoma with concomitant MET and HER2 amplification. AB - BACKGROUND: Patient-derived xenograft (PDX) models are important tools in precision medicine and for the development of targeted therapies to treat cancer patients. This study aimed to evaluate our precision medicine strategy that integrates genomic profiling and preclinical drug-screening platforms, in order to personalize cancer treatments using PDX models. METHODS: We performed array comparative genomic hybridization, microarray, and targeted next-generation sequencing analyses, in order to determine the oncogenic driver mutations. PDX cells were obtained from PDXs and subsequently screened in vitro with 17 targeted agents. RESULTS: PDX tumors recapitulated the histopathologic and genetic features of the patient tumors. Among the samples from lung cancer patients that were molecularly-profiled, copy number analysis identified unique focal MET amplification in one sample, 033 T, without RTK/RAS/RAF oncogene mutations. Although HER2 amplification in 033 T was not detected in the cancer panel, the selection of HER2-amplified clones was found in PDXs and PDX cells. Additionally, MET and HER2 overexpression were found in patient tumors, PDXs, and PDX cells. Crizotinib or EGFR tyrosine kinase inhibitor treatments significantly inhibited cell growth and impaired tumor sphere formation in 033 T PDX cells. CONCLUSIONS: We established PDX cell models using surgical samples from lung cancer patients, and investigated their preclinical and clinical implications for personalized targeted therapy. Additionally, we suggest that MET and EGFR inhibitor-based therapy can be used to treat MET and HER2-overexpressing lung cancers, without receptor tyrosine kinase /RAS/RAF pathway alterations. PMID- 28806951 TI - Phytochemical analysis and in vitro anthelmintic activity of Lophira lanceolata (Ochnaceae) on the bovine parasite Onchocerca ochengi and on drug resistant strains of the free-living nematode Caenorhabditis elegans. AB - BACKGROUND: Onchocerciasis is one of the tropical neglected diseases (NTDs) caused by the nematode Onchocerca volvulus. Control strategies currently in use rely on mass administration of ivermectin, which has marked activity against microfilariae. Furthermore, the development of resistance to ivermectin was observed. Since vaccine and safe macrofilaricidal treatment against onchocerciasis are still lacking, there is an urgent need to discover novel drugs. This study was undertaken to investigate the anthelmintic activity of Lophira lanceolata on the cattle parasite Onchocerca ochengi and the anthelmintic drug resistant strains of the free living nematode Caenorhabditis elegans and to determine the phytochemical profiles of the extracts and fractions of the plants. METHODS: Plant was extracted in ethanol or methanol-methylene chloride. O. ochengi, C. elegans wild-type and C. elegans drug resistant strains were cultured in RPMI-1640 and NGM-agar respectively. Drugs diluted in dimethylsulphoxide/RPMI or M9-Buffer were added in assays and monitored at 48 h and 72 h. Worm viability was determined by using the MTT/formazan colorimetric method. Polyphenol, tannin and flavonoid contents were determined by dosage of gallic acid and rutin. Acute oral toxicity was evaluated using Swiss albino mice. RESULTS: Ethanolic and methanolic-methylene chloride extracts killed O. ochengi with LC50 values of 9.76, 8.05, 6.39 MUg/mL and 9.45, 7.95, 6.39 MUg/mL respectively for leaves, trunk bark and root bark after 72 h. The lowest concentrations required to kill 50% of the wild-type of C. elegans were 1200 and 1890 MUg/mL with ethanolic crude extract, 1000 and 2030 MUg/mL with MeOH-CH2Cl2 for root bark and trunk bark of L. lanceolata, respectively after 72 h. Leave extracts of L. lanceolata are lethal to albendazole and ivermectin resistant strains of C. elegans after 72 h. Methanol/methylene chloride extracted more metabolites. Additionally, extracts could be considered relatively safe. CONCLUSION: Ethanolic and methanolic methylene chloride crude extracts and fractions of L. lanceolata showed in vitro anthelmintic activity. The extracts and fractions contained polyphenols, tannins, flavonoids and saponins. The mechanism of action of this plant could be different from that of albendazole and ivermectin. These results confirm the use of L. lanceolata by traditional healers for the treatment of worm infections. PMID- 28806953 TI - A Fast Healthcare Interoperability Resources (FHIR) layer implemented over i2b2. AB - BACKGROUND: Standards and technical specifications have been developed to define how the information contained in Electronic Health Records (EHRs) should be structured, semantically described, and communicated. Current trends rely on differentiating the representation of data instances from the definition of clinical information models. The dual model approach, which combines a reference model (RM) and a clinical information model (CIM), sets in practice this software design pattern. The most recent initiative, proposed by HL7, is called Fast Health Interoperability Resources (FHIR). The aim of our study was to investigate the feasibility of applying the FHIR standard to modeling and exposing EHR data of the Georges Pompidou European Hospital (HEGP) integrating biology and the bedside (i2b2) clinical data warehouse (CDW). RESULTS: We implemented a FHIR server over i2b2 to expose EHR data in relation with five FHIR resources: DiagnosisReport, MedicationOrder, Patient, Encounter, and Medication. The architecture of the server combines a Data Access Object design pattern and FHIR resource providers, implemented using the Java HAPI FHIR API. Two types of queries were tested: query type #1 requests the server to display DiagnosticReport resources, for which the diagnosis code is equal to a given ICD 10 code. A total of 80 DiagnosticReport resources, corresponding to 36 patients, were displayed. Query type #2, requests the server to display MedicationOrder, for which the FHIR Medication identification code is equal to a given code expressed in a French coding system. A total of 503 MedicationOrder resources, corresponding to 290 patients, were displayed. Results were validated by manually comparing the results of each request to the results displayed by an ad-hoc SQL query. CONCLUSION: We showed the feasibility of implementing a Java layer over the i2b2 database model to expose data of the CDW as a set of FHIR resources. An important part of this work was the structural and semantic mapping between the i2b2 model and the FHIR RM. To accomplish this, developers must manually browse the specifications of the FHIR standard. Our source code is freely available and can be adapted for use in other i2b2 sites. PMID- 28806952 TI - Socio-cultural contexts of end- of- life conversations and decisions: bereaved family cancer caregivers' retrospective co-constructions. AB - BACKGROUND: End-of-life communication becomes increasingly difficult in terminal cancer, which inevitably entails conversations around dying and death. In resource-limited areas, the context of end-of-life communication is usually home based palliative care comprising mostly women in the family who play critical roles as informal caregivers. This article examined the content and contexts of family end-of-life conversations and decisions based on the retrospective accounts of a sample of bereaved women family cancer caregivers in Nairobi, Kenya. METHOD: An interpretative phenomenological analysis approach was utilized to explore pertinent end-of-life communication themes. Four mini focus group interviews with a total of 13 participants [n = 5; n = 3; n = 3; n = 2] were conducted. RESULTS: Two end-of-life themes, advance directives as preparedness for death, and initiating death talk were examined. Findings (a) illustrate the role of family dynamics in influencing the nature of end-of-life conversations and decisions (b) demonstrate the transitional nature of family caregiver roles, and (c) underscore the paradox of the critical role played by family members in palliative care versus their ill preparedness in dealing with end-of-life issues. CONCLUSIONS: Findings are relevant in informing palliative psychosocial interventions and specifically the concerns and decisions of cancer patients and their families. This prompts further engagement with the question of how to equip family caregivers in resource-limited contexts for end of life care. Methodologically, these results demonstrate the possibility of simultaneous elucidation of individual experiences, interactive co-constructions and the socio cultural contexts of experiences and meaning making processes in IPA research. PMID- 28806954 TI - "Usability of data integration and visualization software for multidisciplinary pediatric intensive care: a human factors approach to assessing technology". AB - BACKGROUND: Intensive care clinicians use several sources of data in order to inform decision-making. We set out to evaluate a new interactive data integration platform called T3TM made available for pediatric intensive care. Three primary functions are supported: tracking of physiologic signals, displaying trajectory, and triggering decisions, by highlighting data or estimating risk of patient instability. We designed a human factors study to identify interface usability issues, to measure ease of use, and to describe interface features that may enable or hinder clinical tasks. METHODS: Twenty-two participants, consisting of bedside intensive care physicians, nurses, and respiratory therapists, tested the T3TM interface in a simulation laboratory setting. Twenty tasks were performed with a true-to-setting, fully functional, prototype, populated with physiological and therapeutic intervention patient data. Primary data visualization was time series and secondary visualizations were: 1) shading out-of-target values, 2) mini-trends with exaggerated maxima and minima (sparklines), and 3) bar graph of a 16-parameter indicator. Task completion was video recorded and assessed using a use error rating scale. Usability issues were classified in the context of task and type of clinician. A severity rating scale was used to rate potential clinical impact of usability issues. RESULTS: Time series supported tracking a single parameter but partially supported determining patient trajectory using multiple parameters. Visual pattern overload was observed with multiple parameter data streams. Automated data processing using shading and sparklines was often ignored but the 16-parameter data reduction algorithm, displayed as a persistent bar graph, was visually intuitive. However, by selecting or automatically processing data, triggering aids distorted the raw data that clinicians use regularly. Consequently, clinicians could not rely on new data representations because they did not know how they were established or derived. CONCLUSIONS: Usability issues, observed through contextual use, provided directions for tangible design improvements of data integration software that may lessen use errors and promote safe use. Data-driven decision making can benefit from iterative interface redesign involving clinician-users in simulated environments. This study is a first step in understanding how software can support clinicians' decision making with integrated continuous monitoring data. Importantly, testing of similar platforms by all the different disciplines who may become clinician users is a fundamental step necessary to understand the impact on clinical outcomes of decision aids. PMID- 28806956 TI - MiRNAs regulate oxidative stress related genes via binding to the 3' UTR and TATA box regions: a new hypothesis for cataract pathogenesis. AB - BACKGROUND: Age-related cataracts are related to oxidative stress. However, the genome-wide screening of cataract related oxidative stress related genes are not thoroughly investigated. Our study aims to identify cataract regulated miRNA target genes that are related to oxidative stress and to propose a new possible mechanism for cataract formation. METHODS: Microarrays were used to determine the mRNA expression profiles of both transparent and cataractous lenses. The results were analyzed by significance analyses performed by the microarray software, and bioinformatics analysis was further conducted using Molecular Annotation System. The Eukaryotic Promoter Database (EPD) was used to retrieve promoter sequences and identify TATA-box motifs. Online resource miRWalk was exploited to screen for validated miRNAs targeting mRNAs related to oxidative stress. RNAhybrid online tool was applied to predict the binding between significantly regulated miRNAs in cataract lenses and target mRNAs. RESULTS: Oxidative stress pathway was significantly regulated in cataractous lens samples. Pro-oxidative genes were half up-regulated (11/20), with a small number of genes down-regulated (4/20) and the rest of them with no significant change (5/20). Anti-oxidative genes were partly up-regulated (17/69) and partly down-regulated (17/69). Four down regulated miRNAs (has-miR-1207-5p, has-miR-124-3p, has-miR-204-3p, has-miR-204 5p) were found to target 3' UTR of pro-oxidative genes and could also bind to the TATA-box regions of anti-oxidative genes (with the exception of has-miR-204-3p), whilst two up-regulated miRNAs (has-miR-222-3p, has-miR-378a-3p) were found to target 3' UTR of anti-oxidative genes and could simultaneously bind to the TATA box regions of pro-oxidative genes. CONCLUSIONS: We propose for the first time a hypothesis that cataract regulated miRNAs could contribute to cataract formation not only by targeting 3' UTR but also by targeting TATA-box region of oxidative stress related genes. This results in the subsequent elevation of pro-oxidative genes and inhibition of anti-oxidative genes. This miRNA-TATA-box/3' UTR-gene regulation network may contribute to cataract pathogenesis. PMID- 28806955 TI - Reducing the socioeconomic gradient in uptake of the NHS bowel cancer screening Programme using a simplified supplementary information leaflet: a cluster randomised trial. AB - BACKGROUND: Uptake of colorectal cancer screening is low in the English NHS Bowel Cancer Screening Programme (BCSP). Participation in screening is strongly associated with socioeconomic status. The aim of this study was to determine whether a supplementary leaflet providing the 'gist' of guaiac-based Faecal Occult Blood test (gFOBt) screening for colorectal cancer could reduce the socioeconomic status (SES) gradient in uptake in the English NHS BCSP. METHODS: The trial was integrated within routine BCSP operations in November 2012. Using a cluster randomised controlled design all adults aged 59-74 years who were being routinely invited to complete the gFOBt were randomised based on day of invitation. The Index of Multiple Deprivation was used to create SES quintiles. The control group received the standard information booklet ('SI'). The intervention group received the SI booklet and the Gist leaflet ('SI + Gist') which had been designed to help people with lower literacy engage with the invitation. Blinding of hubs was not possible and invited subjects were not made aware of a comparator condition. The primary outcome was the gradient in uptake across IMD quintiles. RESULTS: In November 2012, 163,525 individuals were allocated to either the 'SI' intervention (n = 79,104) or the 'SI + Gist' group (n = 84,421). Overall uptake was similar between the intervention and control groups (SI: 57.3% and SI + Gist: 57.6%; OR = 1.02, 95% CI: 0.92-1.13, p = 0.77). Uptake was 42.0% (SI) vs. 43.0% (SI + Gist) in the most deprived quintile and 65.6% vs. 65.8% in the least deprived quintile (interaction p = 0.48). The SES gradient in uptake was similar between the study groups within age, gender, hub and screening round sub-groups. CONCLUSIONS: Providing supplementary simplified information in addition to the standard information booklet did not reduce the SES gradient in uptake in the NHS BCSP. The effectiveness of the Gist leaflet when used alone should be explored in future research. TRIAL REGISTRATION: ISRCTN74121020 , registered: 17/20/2012. PMID- 28806957 TI - Clinical and molecular surveillance of artemisinin resistant falciparum malaria in Myanmar (2009-2013). AB - BACKGROUND: Emergence of artemisinin-resistant malaria in Southeast Asian countries threatens the global control of malaria. Although K13 kelch propeller has been assessed for artemisinin resistance molecular marker, most of the mutations need to be validated. In this study, artemisinin resistance was assessed by clinical and molecular analysis, including k13 and recently reported markers, pfarps10, pffd and pfmdr2. METHODS: A prospective cohort study in 1160 uncomplicated falciparum patients was conducted after treatment with artemisinin based combination therapy (ACT), in 6 sentinel sites in Myanmar from 2009 to 2013. Therapeutic efficacy of ACT was assessed by longitudinal follow ups. Molecular markers analysis was done on all available day 0 samples. RESULTS: True recrudescence treatment failures cases and day 3 parasite positivity were detected at only the southern Myanmar sites. Day 3 positive and k13 mutants with higher prevalence of underlying genetic foci predisposing to become k13 mutant were detected only in southern Myanmar since 2009 and comparatively fewer mutations of pfarps10, pffd, and pfmdr2 were observed in western Myanmar. K13 mutations, V127M of pfarps10, D193Y of pffd, and T448I of pfmdr2 were significantly associated with day 3 positivity (OR: 6.48, 3.88, 2.88, and 2.52, respectively). CONCLUSIONS: Apart from k13, pfarps10, pffd and pfmdr2 are also useful for molecular surveillance of artemisinin resistance especially where k13 mutation has not been reported. Appropriate action to eliminate the resistant parasites and surveillance on artemisinin resistance should be strengthened in Myanmar. Trial registration This study was registered with ClinicalTrials.gov, identifier NCT02792816. PMID- 28806958 TI - Responses of Synechocystis sp. PCC 6803 to heterologous biosynthetic pathways. AB - BACKGROUND: There are an increasing number of studies regarding genetic manipulation of cyanobacteria to produce commercially interesting compounds. The majority of these works study the expression and optimization of a selected heterologous pathway, largely ignoring the wholeness and complexity of cellular metabolism. Regulation and response mechanisms are largely unknown, and even the metabolic pathways themselves are not fully elucidated. This poses a clear limitation in exploiting the rich biosynthetic potential of cyanobacteria. RESULTS: In this work, we focused on the production of two different compounds, the cyanogenic glucoside dhurrin and the diterpenoid 13R-manoyl oxide in Synechocystis PCC 6803. We used genome-scale metabolic modelling to study fluxes in individual reactions and pathways, and we determined the concentrations of key metabolites, such as amino acids, carotenoids, and chlorophylls. This allowed us to identify metabolic crosstalk between the native and the introduced metabolic pathways. Most results and simulations highlight the metabolic robustness of cyanobacteria, suggesting that the host organism tends to keep metabolic fluxes and metabolite concentrations steady, counteracting the effects of the heterologous pathway. However, the amino acid concentrations of the dhurrin producing strain show an unexpected profile, where the perturbation levels were high in seemingly unrelated metabolites. CONCLUSIONS: There is a wealth of information that can be derived by combining targeted metabolite identification and computer modelling as a frame of understanding. Here we present an example of how strain engineering approaches can be coupled to 'traditional' metabolic engineering with systems biology, resulting in novel and more efficient manipulation strategies. PMID- 28806959 TI - Second-line therapy for Helicobacter pylori eradication causing antibiotic associated hemorrhagic colitis. AB - OBJECTIVE: Helicobacter pylori (H. pylori) eradication rarely develops into antibiotic-associated hemorrhagic colitis (AAHC), in which the etiology of colitis remains unclear. We herein report a rare case of AAHC caused by second line therapy for H. pylori eradication. RESULTS: A 65-year-old female was administered second-line therapy for H. pylori composed of 1500 mg of amoxicillin, 500 mg of metronidazole and 40 mg of vonoprazan for 7 days because of first-line therapy failure. A day after completing second-line therapy, she complained of abdominal pain and hematochezia. Colonoscopy revealed a hemorrhage and edematous mucosa with no transparent vascular pattern in the transverse colon. A bacterial culture detected Klebsiella oxytoca (K. oxytoca), but no other pathogenic bacteria. A drug-induced lymphocyte stimulation test (DLST) showed positive reactions for both amoxicillin and metronidazole. According to these findings, the patient was diagnosed with AAHC. Bowel rest for 6 days relieved her abdominal pain and hematochezia. CONCLUSIONS: The present case developed AAHC caused by second-line therapy for H. pylori eradication. The pathogenesis is considered to be associated with microbial substitution as well as a delayed-type allergy to antibiotics, suggesting that AAHC is a potential adverse event of second-line therapy for H. pylori eradication. PMID- 28806960 TI - 16-Channel biphasic current-mode programmable charge balanced neural stimulation. AB - BACKGROUND: Neural stimulation is an important method used to activate or inhibit action potentials of the neuronal anatomical targets found in the brain, central nerve and peripheral nerve. The neural stimulator system produces biphasic pulses that deliver balanced charge into tissue from single or multichannel electrodes. The timing and amplitude of these biphasic pulses are precisely controlled by the neural stimulator software or imbedded algorithms. Amplitude mismatch between the anodic current and cathodic current of the biphasic pulse will cause permanently damage for the neural tissues. The main goal of our circuit and layout design is to implement a 16-channel biphasic current mode programmable neural stimulator with calibration to minimize the current mismatch caused by inherent complementary metal oxide semiconductor (CMOS) manufacturing processes. METHODS: This paper presents a 16-channel constant current mode neural stimulator chip. Each channel consists of a 7-bit controllable current DAC used as sink and source current driver. To reduce the LSB quantization error and the current mismatch, an automatic calibration circuit and flow diagram is presented in this paper. There are two modes of operation of the stimulator chip-namely, stimulation mode and calibration mode. The chip also includes a digital interface used to control the stimulator parameters and calibration levels specific for each individual channel. RESULTS: This stimulator Application Specific Integrated Circuit (ASIC) is designed and fabricated in a 0.18 MUm High-Voltage CMOS technology that allows for +/-20 V power supply. The full-scale stimulation current was designed to be at 1 mA per channel. The output current was shown to be constant throughout the timing cycles over a wide range of electrode load impedances. The calibration circuit was also designed to reduce the effect of CMOS process variation of the P channel metal oxide semiconductor (PMOS) and N-channel metal oxide semiconductor (NMOS) devices that will result in charge delivery to have less than 0.13% error. CONCLUSIONS: A 16-channel integrated biphasic neural stimulator chip with calibration is presented in this paper. The stimulator circuit design was simulated and the chip layout was completed. The chip layout was verified using design rules check (DRC) and layout versus schematic (LVS) design check using computer aided design (CAD) software. The test results we presented show constant current stimulation with charge balance error within 0.13% least-significant-bit (LSB). This LSB error was consistent throughout a variety stimulation patterns and electrode load impedances. PMID- 28806961 TI - Molecular analysis demonstrates high prevalence of chloroquine resistance but no evidence of artemisinin resistance in Plasmodium falciparum in the Chittagong Hill Tracts of Bangladesh. AB - BACKGROUND: Artemisinin resistance is present in the Greater Mekong region and poses a significant threat for current anti-malarial treatment guidelines in Bangladesh. The aim of this molecular study was to assess the current status of drug resistance in the Chittagong Hill Tracts of Bangladesh near the Myanmar border. METHODS: Samples were obtained from patients enrolled into a Clinical Trial (NCT02389374) conducted in Alikadam, Bandarban between August 2014 and January 2015. Plasmodium falciparum infections were confirmed by PCR and all P. falciparum positive isolates genotyped for the pfcrt K76T and pfmdr1 N86Y markers. The propeller region of the kelch 13 (k13) gene was sequenced from isolates from patients with delayed parasite clearance. RESULTS: In total, 130 P. falciparum isolates were available for analysis. The pfcrt mutation K76T, associated with chloroquine resistance was found in 81.5% (106/130) of cases and the pfmdr1 mutation N86Y in 13.9% (18/130) cases. No single nucleotide polymorphisms were observed in the k13 propeller region. CONCLUSION: This study provides molecular evidence for the ongoing presence of chloroquine resistant P. falciparum in Bangladesh, but no evidence of mutations in the k13 propeller domain associated with artemisinin resistance. Monitoring for artemisinin susceptibility in Bangladesh is needed to ensure early detection and containment emerging anti-malarial resistance. PMID- 28806962 TI - Oncofertility in patients with stage I epithelial ovarian cancer: fertility sparing surgery in young women of reproductive age. AB - BACKGROUND: Fertility-sparing surgery is indicated for patients with stage I epithelial ovarian cancers. We sought to evaluate the clinical outcomes and oncofertility in a cohort of patients of reproductive age with stage I epithelial ovarian cancer (EOC). METHODS: Overall, 108 patients of reproductive age (<= 40 years) diagnosed with stage I EOC who were treated at Peking Union Medical College Hospital between 1999 and 2013 were included in the study. The Kaplan Meier model and Cox regression analyses were used for the survival analysis. RESULTS: The type of surgery included fertility-sparing surgery (FSS) (48.1%) and radical surgery (RS) (51.9%). After a median follow-up of 83 months, we observed that grade 3 or clear-cell carcinoma was the only independent risk factor for disease-free survival and tumor-specific survival in the multivariate analysis. Patients with grade 3 or clear-cell carcinoma tended to be older than 30 years, have endometriosis, and undergo RS (p < 0.05). Fertility-sparing surgery did not affect disease-free survival or tumor-specific survival among patients of reproductive age with stage I EOC and among high-risk patients with stage IC2-3, grade 3, or clear-cell carcinoma. Thirty-four out of 52 (65.4%) FSS patients attempted to get pregnant. Twenty-eight (82.4%) achieved a successful pregnancy with a full-term delivery. CONCLUSIONS: Grade 3 or clear-cell carcinoma was the only independent risk factor for survival of patients of reproductive age with stage I EOC. FSS can be safely performed on patients of reproductive age with grade 1-2, stage I EOC. The safety of FSS for grade 3 and clear-cell carcinoma warrants further investigation. PMID- 28806963 TI - Effectiveness outcomes and health related quality of life impact of disease progression in patients with advanced nonsquamous NSCLC treated in real-world community oncology settings: results from a prospective medical record registry study. AB - BACKGROUND: Treatment options for advanced nonsquamous non-small cell lung cancer (NSCLC) in the first line include platinum-based doublet therapy with or without bevacizumab. This study examined efficacy outcomes and patient reported outcomes (PROs) in a community oncology patient sample. METHODS: Advanced nonsquamous NSCLC patients from 34 U.S. community oncology practices treated in first line with bevacizumab regimens (A platinum doublet; gemcitabine doublet; pemetrexed with platinum) or non-bevacizumab regimens (B platinum doublet; gemcitabine doublet; C pemetrexed with platinum) were recruited for this prospective study. Patient characteristics and clinical outcomes were accessed from routine care records. Three validated and widely used PRO measures of health related quality of life (HRQOL) and symptom burden were collected prospectively at each visit and up to one-year follow-up. Effectiveness outcomes were progression free survival (PFS) and overall survival (OS) assessed by Kaplan-Meier and Cox regression methods. PROs were analyzed with linear mixed model regression to examine changes over time, and the effect of disease progression. RESULTS: Of 147 patients in the study, 145 provided PRO data. Patients in treatment groups were: A (n = 66, 44.9%); B (n = 25, 17.0%); C (n = 56, 38.1%). A was associated with significantly longer OS than B (HR = 0.341, p = 0.0012), and significantly longer than C (HR = 0.602, p = 0.0354). PFS results were similar. Irrespective of regimen group and on 12/32 measures, patients showed significant and clinically meaningful worsening of symptoms and HRQOL at disease progression. After disease progression, the pattern of symptom and HRQOL change showed continued worsening. CONCLUSIONS: Bevacizumab-containing regimens were associated with longer PFS and OS compared with non-bevacizumab regimens. PRO measures show disease progression is associated with worsening HRQOL. Delaying disease progression can sustain better HRQL and reduce symptom burden. PMID- 28806964 TI - Intervention Now to Eliminate Repeat Unintended Pregnancy in Teenagers (INTERUPT): a systematic review of intervention effectiveness and cost effectiveness, and qualitative and realist synthesis of implementation factors and user engagement. AB - BACKGROUND: Unintended repeat conceptions can result in emotional, psychological and educational harm to young women, often with enduring implications for their life chances. This study aimed to identify which young women are at the greatest risk of repeat unintended pregnancies; which interventions are effective and cost effective; and what are the barriers to and facilitators for the uptake of these interventions. METHODS: We conducted a mixed-methods systematic review which included meta-analysis, framework synthesis and application of realist principles, with stakeholder input and service user feedback to address this. We searched 20 electronic databases, including MEDLINE, Excerpta Medica database, Applied Social Sciences Index and Abstracts and Research Papers in Economics, to cover a broad range of health, social science, health economics and grey literature sources. Searches were conducted between May 2013 and June 2014 and updated in August 2015. RESULTS: Twelve randomised controlled trials (RCTs), two quasi-RCTs, 10 qualitative studies and 53 other quantitative studies were identified. The RCTs evaluated psychosocial interventions and an emergency contraception programme. The primary outcome was repeat conception rate: the event rate was 132 of 308 (43%) in the intervention group versus 140 of 289 (48%) for the control group, with a non-significant risk ratio (RR) of 0.92 [95% confidence interval (CI) 0.78-1.08]. Four studies reported subsequent birth rates: 29 of 237 (12%) events for the intervention arm versus 46 out of 224 (21%) for the control arm, with an RR of 0.60 (95% CI 0.39-0.93). Many repeat conceptions occurred in the context of poverty, low expectations and aspirations and negligible opportunities. Qualitative and realist evidence highlighted the importance of context, motivation, future planning and giving young women a central and active role in the development of new interventions. CONCLUSIONS: Little or no evidence for the effectiveness or cost-effectiveness of any of the interventions to reduce repeat pregnancy in young women was found. Qualitative and realist evidence helped to explain gaps in intervention design that should be addressed. More theory-based, rigorously evaluated programmes need to be developed to reduce unintended repeat pregnancy in young women. TRIAL REGISTRATION: PROSPERO, CRD42012003168 . Cochrane registration number: i = fertility/0068. PMID- 28806965 TI - Decreased circulating dihomo-gamma-linolenic acid levels are associated with total mortality in patients with acute cardiovascular disease and acute decompensated heart failure. AB - BACKGROUND: Polyunsaturated fatty acids (PUFAs) have important roles in the pathogenesis of cardiovascular diseases. However, the clinical significance of omega-6 PUFAs in acute cardiovascular disease remains unknown. METHODS: We enrolled 417 consecutive patients with acute cardiovascular disease admitted to the cardiac intensive care unit at Juntendo University Hospital between April 2012 and October 2013. We investigated the association between serum PUFA levels and long-term mortality. Blood samples were collected after an overnight fast, within 24 h of admission. We excluded patients who received eicosapentaenoic acid therapy and those with malignancy, end-stage kidney disease, chronic hepatic disease, and connective tissue disease. RESULTS: Overall, 306 patients (mean age: 66.4 +/- 15.0 years) were analysed. During the follow-up period of 2.4 +/- 1.2 years, 50 patients (16.3%) died. The dihomo-gamma-linolenic acid (DGLA) levels, arachidonic acid (AA) levels, and DGLA/AA ratio were significantly lower in the nonsurvivor group than in the survivor group (DGLA: 23.2 +/- 9.8 vs. 31.5 +/- 12.0 MUg/ml, AA: 151.1 +/- 41.6 vs. 173.3 +/- 51.6 MUg/ml, and DGLA/AA: 0.16 +/- 0.05 vs. 0.19 +/- 0.06, all p < 0.01). Kaplan-Meier curves showed that survival rates were significantly higher in the higher DGLA, AA, and DGLA/AA groups than in their lower counterparts (DGLA and AA; p < 0.01, DGLA/AA; p = 0.01), although omega-3 PUFAs were not associated with prognosis. Furthermore, in patients with acute decompensated heart failure (ADHF), survival rates were significantly higher in the higher DGLA, AA, and DGLA/AA groups than in their lower counterparts (DGLA and AA; p < 0.01, DGLA/AA; p = 0.04). However, among patients with acute coronary syndrome, none of the PUFA levels were associated with prognosis. Among patients with ADHF, after controlling for confounding variables, DGLA and DGLA/AA were associated with long-term mortality [DGLA: hazard ratio (HR), 0.94; 95% confidence interval (CI), 0.88-0.99; p = 0.01 and DGLA/AA: HR, 0.87; 95% CI, 0.77-0.97; p < 0.01], whereas AA was not associated with prognosis. CONCLUSION: Low omega-6 PUFA levels, particularly DGLA, and a low DGLA/AA ratio predict long-term mortality in patients with acute cardiovascular disease and ADHF. TRIAL REGISTRATION: UMIN-CTR; UMIN000007555 . PMID- 28806966 TI - An exploratory study assessing psychological distress of indigents in Burkina Faso: a step forward in understanding mental health needs in West Africa. AB - BACKGROUND: Poverty is known as an important determinant of health, but empirical data are still missing on the relationships between poverty, other adverse living conditions, and psychological distress, particularly in low-income countries. This study aimed to assess mental health needs and psychological distress among the poorest in rural settings in Burkina Faso where food security and access to water, electricity, schooling, and healthcare are limited. METHODS: We randomly selected 2000 individuals previously identified as indigents by a community targeting process. Interviewers visited participants (n = 1652) in their homes and completed a questionnaire on mental health variables that included presence and intensity of anxious, depressive, psychotic, and aggressive symptoms, as well as level of psychological distress. Descriptive statistics, Spearman correlations, and logistic regressions were performed. RESULTS: In all, 40.2% of the sample reported 10 or more anxious/depressive symptoms in the past 30 days, and 25.5% reported having experienced at least one psychotic symptom over their lifetime, 65.6% of whom had had those symptoms for many years. The number of anxious and depressive symptoms was significantly associated with the level of psychological distress (r = 0.423, p < .001). Predictors of distress level included: poor health condition (F(1) = 23.743, p <. 001), being a woman (F(1) = 43.926, p < .001), not having any income (F(1) = 16.185, p < .001), having begged for food in the past 30 days (F(1) = 12.387, p < .001), being illiterate, and being older (F(1) = 21.487, p < .001). Approximately one third of respondents reporting anxious/depressive or psychotic symptoms (28.2 and 30.0%, respectively) had not talked about their symptoms to anyone in their social network. CONCLUSIONS: These results suggest alarmingly high levels of psychological distress and reported symptoms among the poorest in rural settings in Burkina Faso, which can be explained by their difficult living conditions. However, these results must be interpreted from a transcultural perspective to avoid decontextualized misinterpretations. Ethnographic works are needed to document the larger context within which these distress results can be analyzed. PMID- 28806967 TI - MicroRNA-181c inhibits cigarette smoke-induced chronic obstructive pulmonary disease by regulating CCN1 expression. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an obstinate pulmonary disease, causing irreversible alveoli collapse and increasing the risk for cardiovascular disease. Accumulating evidence has shown that the dysregulation of miRNAs is crucially involved in the pathogenesis and development of COPD. However, the effects and role of microRNA-181c (miR-181c) have not been investigated in a murine model of COPD. METHODS: miR-181c expression was detected in human lung tissue samples of 34 patients, an in vivo murine model of CS exposure, and primary human bronchial epithelial cells (HBECs) by qRT-PCR. Degeneration of lung tissue, necrosis, infiltration and neutrophil cells were assessed with H&E and flow cytometry. Interleukin (IL)-6 and IL-8 levels were determined by an enzyme-linked immunosorbent assay and qRT-PCR. Luciferase reporter assay and correlation analyses were used to confirm and measure the levels between miR-181c and its target CCN1. RESULTS: We showed that miR-181c was significantly down-regulated in lung tissues from patients with COPD compared to individuals who had never smoked (p < 0.01). We also observed a down-regulation of miR-181c in HBECs and a mouse model after cigarette smoke (CS) exposure. Functional assays demonstrated that miR-181c over-expression decreased the inflammatory response, neutrophil infiltration, reactive oxygen species (ROS) generation, and inflammatory cytokines induced by CS, while its down-regulation produced the opposite effects. Subsequent investigation found that CCN1 was a direct target of miR-181c. CCN1 expression was increased in lung tissues of COPD patients, and was negatively correlated with miR-181c expression in human COPD samples (p < 0.01). CONCLUSIONS: Taken together, our data suggest the critical roles of miR-181c and its target CCN1 in COPD development, and provide potential therapeutic targets for COPD treatment. PMID- 28806969 TI - Pharmacokinetic and urinary profiling reveals the prednisolone/cortisol ratio as a valid biomarker for prednisolone administration. AB - BACKGROUND: In Europe, synthetic corticosteroids are not allowed in animal breeding for growth-promoting purposes. Nevertheless, a high prevalence of non compliant urine samples was recently reported for prednisolone, however, without any indication of unauthorized use. Within this context, 20beta dihydroprednisolone and the prednisolone/cortisol ratio have been suggested as potential tools to discriminate between exogenous and endogenous urinary prednisolone. In this study, the validity of these strategies was verified by investigating the plasma pharmacokinetic and urinary excretion profiles of relevant glucocorticoids in bovines, subjected to exogenous prednisolone treatment or tetracosactide hexaacetate administration to induce endogenous prednisolone formation. Bovine urine and plasma samples were analysed by liquid chromatography and mass spectrometry. RESULTS: Based on the plasma pharmacokinetics and urinary profiles, 20beta-dihydroprednisolone was confirmed as the main prednisolone-derived metabolite, being detected in the biological fluids of all 12 bovines (plasma AUC0-inf of 121 h MUg L-1 and urinary concentration > 0.695 MUg L-1). However, this metabolite enclosed no potential as discriminative marker as no significant concentration differences were observed upon exogenous prednisolone treatment or tetracosactide hexaacetate administration under all experimental conditions. As a second marker tool, the prednisolone/cortisol ratios were assessed along the various treatments, taking into account that endogenous prednisolone formation involves the hypothalamic pituitary-adrenal axis and is associated with an increased cortisol secretion. Significantly lower ratios were observed in case of endogenous prednisolone formation (i.e. ratios ranging from 0.00379 to 0.129) compared to the exogenous prednisolone treatment (i.e. ratios ranging from 0.0603 to 36.9). On the basis of these findings, a discriminative threshold of 0.260 was proposed, which allowed classification of urine samples according to prednisolone origin with a sensitivity of 94.2% and specificity of 99.0%. CONCLUSION: The prednisolone/cortisol ratio was affirmed as an expedient strategy to discriminate between endogenous and exogenous prednisolone in urine. Although the suggested threshold value was associated with high specificity and sensitivity, a large scale study with varying experimental conditions is designated to optimize this value. PMID- 28806968 TI - Cardamom powder supplementation prevents obesity, improves glucose intolerance, inflammation and oxidative stress in liver of high carbohydrate high fat diet induced obese rats. AB - BACKGROUND: Cardamom is a well-known spice in Indian subcontinent, used in culinary and traditional medicine practices since ancient times. The current investigation was untaken to evaluate the potential benefit of cardamom powder supplementation in high carbohydrate high fat (HCHF) diet induced obese rats. METHOD: Male Wistar rats (28 rats) were divided into four different groups such as Control, Control + cardamom, HCHF, HCHF + cardamom. High carbohydrate and high fat (HCHF) diet was prepared in our laboratory. Oral glucose tolerance test, organs wet weight measurements and oxidative stress parameters analysis as well as liver marker enzymes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) activities were assayed on the tissues collected from the rats. Plasma lipids profiles were also measured in all groups of animals. Moreover, histological staining was also performed to evaluate inflammatory cells infiltration and fibrosis in liver. RESULTS: The current investigation showed that, HCHF diet feeding in rats developed glucose intolerance and increased peritoneal fat deposition compared to control rats. Cardamom powder supplementation improved the glucose intolerance significantly (p > 0.05) and prevented the abdominal fat deposition in HCHF diet fed rats. HCHF diet feeding in rats also developed dyslipidemia, increased fat deposition and inflammation in liver compared to control rats. Cardamom powder supplementation significantly prevented the rise of lipid parameters (p > 0.05) in HCHF diet fed rats. Histological assessments confirmed that HCHF diet increased the fat deposition and inflammatory cells infiltration in liver which was normalized by cardamom powder supplementation in HCHF diet fed rats. Furthermore, HCHF diet increased lipid peroxidation, decreased antioxidant enzymes activities and increased advanced protein oxidation product level significantly (p > 0.05) both in plasma and liver tissue which were modulated by cardamom powder supplementation in HCHF diet fed rats. HCHF diet feeding in rats also increased the ALT, AST and ALP enzyme activities in plasma which were also normalized by cardamom powder supplementation in HCHF diet fed rats. Moreover, cardamom powder supplementation ameliorated the fibrosis in liver of HCHF diet fed rats. CONCLUSION: This study suggests that, cardamom powder supplementation can prevent dyslipidemia, oxidative stress and hepatic damage in HCHF diet fed rats. PMID- 28806970 TI - Transcriptomic analysis of the response of Acropora millepora to hypo-osmotic stress provides insights into DMSP biosynthesis by corals. AB - BACKGROUND: Dimethylsulfoniopropionate (DMSP) is a small sulphur compound which is produced in prodigious amounts in the oceans and plays a pivotal role in the marine sulfur cycle. Until recently, DMSP was believed to be synthesized exclusively by photosynthetic organisms; however we now know that corals and specific bacteria can also produce this compound. Corals are major sources of DMSP, but the molecular basis for its biosynthesis is unknown in these organisms. RESULTS: Here we used salinity stress, which is known to trigger DMSP production in other organisms, in conjunction with transcriptomics to identify coral genes likely to be involved in DMSP biosynthesis. We focused specifically on both adults and juveniles of the coral Acropora millepora: after 24 h of exposure to hyposaline conditions, DMSP concentrations increased significantly by 2.6 fold in adult corals and 1.2 fold in juveniles. Concomitantly, candidate genes enabling each of the necessary steps leading to DMSP production were up-regulated. CONCLUSIONS: The data presented strongly suggest that corals use an algal-like pathway to generate DMSP from methionine, and are able to rapidly change expression of the corresponding genes in response to environmental stress. However, our data also indicate that DMSP is unlikely to function primarily as an osmolyte in corals, instead potentially serving as a scavenger of ROS and as a molecular sink for excess methionine produced as a consequence of proteolysis and osmolyte catabolism in corals under hypo-osmotic conditions. PMID- 28806971 TI - Factors contributing to the variability of a predictive score for cranial cruciate ligament deficiency in Labrador Retrievers. AB - BACKGROUND: We recently reported that a conformation score derived from the tibial plateau angle (TPA) and the femoral anteversion angle (FAA), best discriminates limbs predisposed to, or affected by cranial cruciate ligament disease (CCLD), from those that are at low risk for CCLD. The specificity and sensitivity of this score were high enough to support further investigations toward its use for large-scale screening of dogs by veterinarians. The next step, which is the objective of the current study, is to determine inter-observer variability of that CCLD score in a large population of Labrador Retrievers. A total of 167 Labradors were enrolled in this cross-sectional study. Limbs of normal dogs over 6 years of age with no history of CCLD were considered at low risk for CCLD. Limbs of dogs with CCLD were considered at high risk for CCLD. Tibial plateau and femoral anteversion angles were measured independently by two investigators to calculate a CCLD score for each limb. Kappa statistics were used to determine the extent of agreement between investigators. Pearson's correlation and intraclass coefficients were calculated to evaluate the correlation between investigators and the relative contribution of each measurement to the variability of the CCLD score. RESULTS: The correlation between CCLD scores calculated by investigators was good (correlation coefficient = 0.68 p < 0.0001). However, interobserver agreement with regards to the predicted status of limbs was fair (kappa value = 0.28), with 37% of limbs being assigned divergent classifications. Variations in CCLD scores correlated best with those of TPA, which was the least consistent parameter between investigators. Absolute interobserver differences were two times greater for FAAs (4.19 degrees +/- 3.15) than TPAs (2.23 degrees +/- 1.91). CONCLUSIONS: The reproducibility of the CCLD score between investigators is fair, justifying caution when interpreting individual scores. Future studies should focus on improving the reproducibility of TPA and FAA measurements, as strategies to improve the agreement between CCLD scores. PMID- 28806972 TI - Overexpression of Arabidopsis P3B increases heat and low temperature stress tolerance in transgenic sweetpotato. AB - BACKGROUND: Sweetpotato (Ipomoea batatas [L.] Lam) is suitable for growth on marginal lands due to its abiotic stress tolerance. However, severe environmental conditions including low temperature pose a serious threat to the productivity and expanded cultivation of this crop. In this study, we aimed to develop sweetpotato plants with enhanced tolerance to temperature stress. RESULTS: P3 proteins are plant-specific ribosomal P-proteins that act as both protein and RNA chaperones to increase heat and cold stress tolerance in Arabidopsis. Here, we generated transgenic sweetpotato plants expressing the Arabidopsis ribosomal P3 (AtP3B) gene under the control of the CaMV 35S promoter (referred to as OP plants). Three OP lines (OP1, OP30, and OP32) were selected based on AtP3B transcript levels. The OP plants displayed greater heat tolerance and higher photosynthesis efficiency than wild type (WT) plants. The OP plants also exhibited enhanced low temperature tolerance, with higher photosynthesis efficiency and less membrane permeability than WT plants. In addition, OP plants had lower levels of hydrogen peroxide and higher activities of antioxidant enzymes such as peroxidase and catalase than WT plants under low temperature stress. The yields of tuberous roots and aerial parts of plants did not significantly differ between OP and WT plants under field cultivation. However, the tuberous roots of OP transgenic sweetpotato showed improved storage ability under low temperature conditions. CONCLUSIONS: The OP plants developed in this study exhibited increased tolerance to temperature stress and enhanced storage ability under low temperature compared to WT plants, suggesting that they could be used to enhance sustainable agriculture on marginal lands. PMID- 28806973 TI - Protective effects of orange (Citrus sinensis L.) peel aqueous extract and hesperidin on oxidative stress and peptic ulcer induced by alcohol in rat. AB - BACKGROUND: Massive alcohol drinking can lead to gastric ulcer. In the present study we investigated the gastroprotective effect of Citrus sinensis peel aqueous extract (CSPE) and Hesperidin (H) in ethanol (EtOH) induced oxidative stress and peptic ulcer in rats. METHODS: Seventy adult male Wistar rats were divided into seven groups of 10 each: control, EtOH (4 g/kg b.w.), EtOH + various doses of CSPE (100, 200 and 400 mg/kg, b.w.), EtOH + Hesperidin (50 mg/kg, p.o.) and EtOH + Omeprazole (OM, 20 mg/kg, p.o.). Animals were perorally (p.o.) pre-treated with CSPE during 15 days and intoxicated with a single oral administration of EtOH (4 g/kg b.w.) during 2 h. Gastric ulcer was induced in rats with a single dose of ethanol (EtOH). Ulcer index, gene expression of gastric cyclooxygenase-2 (COX-2), tumor necrosis factor alpha (TNF-alpha), malondialdhyde (MDA), hydrogen peroxide H2O2 and Thiol groups (-SH) content in stomach and antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and gluthation peroxidise (GPx) were measured. Furthermore, histopathological examinations were performed. RESULTS: The results showed that ethanol induced gastric damage, improving oxidative stress markers level such as MDA (121 +/- 4.45 nmol/mg proteins) and H2O2 (24.62 +/- 1.04 MUmol/mg proteins), increased pro-inflammatory cytokine (TNF-alpha level), as well as the expression of COX-2 in the ethanol group. However, a significant depletion of enzymatic and non-enzymatic antioxidants were observed, such as, GPx (72%), SOD (57.5%), CAT (41.6%) and -SH (50%). The lesions were associated with severe histopathological damage. The both Citrus sinensis peel aqueous extract (CSPE) and hesperidin significantly protect against all gastric damages caused by ethanol administration in rats. CONCLUSIONS: We propose that CSPE and hesperidin exhibit protective effects in EtOH-induced peptic ulcer in rat. This protection might be related in to part its antioxidant properties as well as its opposite effects on some studied intracellular mediators. PMID- 28806974 TI - Association of plasma fatty acid alteration with the severity of coronary artery disease lesions in Tunisian patients. AB - BACKGROUND: Some factors related to diet are known to be involved in the progression of atherosclerosis in humans. METHODS: The relationship between plasma fatty acid (FA) levels and the severity of coronary artery disease (CAD), evaluated by Gensini score (GS), was investigated in CAD Tunisian patients compared to controls. Lipid profiles were analyzed, GS was calculated in CAD and non-CAD patients and compared to controls. RESULTS: CAD patients showed an alteration of conventional lipid parameters. In fact, a significant increase of plasmatic triglycerides (TG) level, atherogenic lipid ratios (TC/HDL-C,TG/HDL-C, LDL-C/HDL-C); and ApoB/ApoA1 was observed in the CAD group comparatively to controls (p < 0.001). Gensini score was showed to be a good indicator to evaluate cholesterol metabolism disorders associated with HDL-C since a negative association was found between HDL-C levels and GS for the two groups of patients. In addition, in the relation with FA and classes of FA, a negative association was found as expected, between Gensini score and total MUFA, PUFA n-3, total PUFA, GLA, DGLA and DHA. Furthermore, a positive association with stearic and erucic acid was found. Suggests that, GS is also a good indicator to evaluate FA metabolic disorders. Higher elongation index and modifications of desaturation index (D5D, D6D and D9D) were observed in patients compared to controls, supporting FA metabolism modifications. CONCLUSIONS: In conclusion, although that Tunisian population appears to follow the Mediterranean diet, variations of plasmatic FA levels and desaturase activities in CAD patients highlights an alteration of FA metabolism and suggests an important implication of certain FA in the development of atherosclerosis. PMID- 28806975 TI - Admission blood glucose and 10-year mortality among patients with or without pre existing diabetes mellitus hospitalized with heart failure. AB - BACKGROUND: High admission blood glucose (ABG) level has been associated with a poor short-term outcome among non-diabetic patients with heart failure (HF). We aimed to investigate the association between ABG levels and long-term (10 years) mortality in patients with or without pre-existing diabetes mellitus (DM) admitted with HF. METHODS: We analyzed data on 1811 patients with DM and 2182 patients without pre-existing DM who were hospitalized with HF during a prospective national survey. The relationship between ABG and 10-year mortality was assessed using the Cox proportional hazard model adjusting for multiple variables. ABG was analyzed both as a categorical (<110, 110-140, 140-200, and >200 mg/dL) and as a continuous variable. RESULTS: At 10 years of follow-up the cumulative probability of mortality was 85 and 78% among patients with DM and patients with no pre-existing DM (p < 0.001), respectively. Among patients with no pre-existing DM, glucose levels of 110-140, 140-200 and >=200 mg/dL were associated with 9% (p = 0.140), 16% (p = 0.031) and 53% (p < 0.001) increased mortality risk compared to ABG < 110 mg/dL. Each 18-mg/dL (1-mmol/L) increase in glucose level was associated with a 5% increased risk of mortality (p < 0.001) among patients with no-pre-existing DM. In contrast, among patients with DM, only those with glucose levels >200 mg/dL had an increased mortality risk (>200 mg/dL versus <110 mg/dL; HR = 1.20, p = 0.032). CONCLUSION: Among hospitalized HF patients with no pre-existing DM there is a linear relationship between ABG level and long-term mortality, whereas among patients with DM only ABG level >200 mg/dL is associated with increased mortality risk. PMID- 28806976 TI - Quantitative detection of human Malawi polyomavirus in nasopharyngeal aspirates, sera, and feces in Beijing, China, using real-time TaqMan-based PCR. AB - BACKGROUND: Human Malawi polyomavirus (MWPyV) was discovered in 2012, but its prevalence and clinical characteristics are largely unknown. METHODS: We used real-time TaqMan-based PCR to detect MWPyV in the feces (n = 174) of children with diarrhea, nasopharyngeal aspirates (n = 887) from children with respiratory infections, and sera (n = 200) from healthy adults, and analyzed its clinical characteristics statistically. All the MWPyV-positive specimens were also screened for other common respiratory viruses. RESULTS: Sixteen specimens were positive for MWPyV, including 13 (1.47%) respiratory samples and three (1.7%) fecal samples. The samples were all co-infected with other respiratory viruses, most commonly with influenza viruses (69.2%) and human coronaviruses (30.7%). The MWPyV-positive children were diagnosed with bronchopneumonia or viral diarrhea. They ranged in age from 12 days to 9 years, and the most frequent symptoms were cough and fever. CONCLUSIONS: Real-time PCR is an effective tool for the detection of MWPyV in different types of samples. MWPyV infection mainly occurs in young children, and fecal-oral transmission is a possible route of its transmission. PMID- 28806977 TI - A tandem simulation framework for predicting mapping quality. AB - Read alignment is the first step in most sequencing data analyses. Because a read's point of origin can be ambiguous, aligners report a mapping quality, which is the probability that the reported alignment is incorrect. Despite its importance, there is no established and general method for calculating mapping quality. I describe a framework for predicting mapping qualities that works by simulating a set of tandem reads. These are like the input reads in important ways, but the true point of origin is known. I implement this method in an accurate and low-overhead tool called Qtip, which is compatible with popular aligners. PMID- 28806978 TI - Transcriptome sequencing in pediatric acute lymphoblastic leukemia identifies fusion genes associated with distinct DNA methylation profiles. AB - BACKGROUND: Structural chromosomal rearrangements that lead to expressed fusion genes are a hallmark of acute lymphoblastic leukemia (ALL). In this study, we performed transcriptome sequencing of 134 primary ALL patient samples to comprehensively detect fusion transcripts. METHODS: We combined fusion gene detection with genome-wide DNA methylation analysis, gene expression profiling, and targeted sequencing to determine molecular signatures of emerging ALL subtypes. RESULTS: We identified 64 unique fusion events distributed among 80 individual patients, of which over 50% have not previously been reported in ALL. Although the majority of the fusion genes were found only in a single patient, we identified several recurrent fusion gene families defined by promiscuous fusion gene partners, such as ETV6, RUNX1, PAX5, and ZNF384, or recurrent fusion genes, such as DUX4-IGH. Our data show that patients harboring these fusion genes displayed characteristic genome-wide DNA methylation and gene expression signatures in addition to distinct patterns in single nucleotide variants and recurrent copy number alterations. CONCLUSION: Our study delineates the fusion gene landscape in pediatric ALL, including both known and novel fusion genes, and highlights fusion gene families with shared molecular etiologies, which may provide additional information for prognosis and therapeutic options in the future. PMID- 28806980 TI - Factors influencing outcomes after medial hamstring lengthening with semitendinosus transfer in patients with cerebral palsy. AB - BACKGROUND: Although several studies have investigated the outcomes after distal hamstring lengthening (DHL), no study has undertaken an approach that included all or most of the important factors that could influence the results. This study was performed to evaluate the outcomes after DHL and analyze the factors that influence the improvement and serial change in knee motion after surgery in patients with cerebral palsy (CP), using a linear mixed model (LMM). METHODS: The study included 314 ambulatory CP patients (594 limbs) with spsastic diplegia who were followed up after undergoing DHL as part of a single-event multilevel surgery and who underwent preoperative and postoperative 3-dimensional (3D) gait analyses. Relevant kinematic values, including knee flexion at initial contact, minimum knee flexion in the stance phase, knee range of motion (ROM), mean pelvic tilt and gait deviation index (GDI) score, were the outcome measures. Changes in knee motion and the GDI score were adjusted for multiple factors, such as sex, the Gross Motor Function Classification System (GMFCS) level, and concomitant surgeries as fixed effects, and follow-up duration, laterality, and each subject as random effects, using a LMM. RESULTS: We found significant improvements in knee flexion at initial contact, minimum knee flexion in the stance phase, knee ROM, and GDI score 2 years after DHL. In patients with GMFCS level I and II, improvement in all sagittal knee kinematics was maintained during follow-up. In addition, GDI score, which represents overall gait pathology, consistently improved throughout the follow-up duration (1.2 per year, p = 0.008). CONCLUSION: Medial hamstring lengthening with semitendinosus transfer, as a part of a SEMLS, was effective procedure in treating flexed knee gait with regard to sagittal knee kinematics and GDI score in spastic CP with flexed knee gait. PMID- 28806979 TI - Breath-giving cooperation: critical review of origin of mitochondria hypotheses : Major unanswered questions point to the importance of early ecology. AB - : The origin of mitochondria is a unique and hard evolutionary problem, embedded within the origin of eukaryotes. The puzzle is challenging due to the egalitarian nature of the transition where lower-level units took over energy metabolism. Contending theories widely disagree on ancestral partners, initial conditions and unfolding of events. There are many open questions but there is no comparative examination of hypotheses. We have specified twelve questions about the observable facts and hidden processes leading to the establishment of the endosymbiont that a valid hypothesis must address. We have objectively compared contending hypotheses under these questions to find the most plausible course of events and to draw insight on missing pieces of the puzzle. Since endosymbiosis borders evolution and ecology, and since a realistic theory has to comply with both domains' constraints, the conclusion is that the most important aspect to clarify is the initial ecological relationship of partners. Metabolic benefits are largely irrelevant at this initial phase, where ecological costs could be more disruptive. There is no single theory capable of answering all questions indicating a severe lack of ecological considerations. A new theory, compliant with recent phylogenomic results, should adhere to these criteria. REVIEWERS: This article was reviewed by Michael W. Gray, William F. Martin and Purificacion Lopez-Garcia. PMID- 28806981 TI - Understanding the potentiality of accelerator based-boron neutron capture therapy for osteosarcoma: dosimetry assessment based on the reported clinical experience. AB - BACKGROUND: Osteosarcoma is the most frequent primary malignant bone tumour, and its incidence is higher in children and adolescents, for whom it represents more than 10% of solid cancers. Despite the introduction of adjuvant and neo-adjuvant chemotherapy that markedly increased the success rate in the treatment, aggressive surgery is still needed and a considerable percentage of patients do not survive due to recurrences or early metastases. Boron Neutron Capture Therapy (BNCT), an experimental radiotherapy, was investigated as a treatment that could allow a less aggressive surgery by killing infiltrated tumour cells in the surrounding healthy tissues. BNCT requires an intense neutron beam to ensure irradiation times of the order of 1 h. In Italy, a Radio Frequency Quadrupole (RFQ) proton accelerator has been designed and constructed for BNCT, and a suitable neutron spectrum was tailored by means of Monte Carlo calculations. This paper explores the feasibility of BNCT to treat osteosarcoma using this neutron source based on accelerator. METHODS: The therapeutic efficacy of BNCT was analysed evaluating the dose distribution obtained in a clinical case of femur osteosarcoma. Mixed field dosimetry was assessed with two different formalisms whose parameters were specifically derived from radiobiological experiments involving in vitro UMR-106 osteosarcoma cell survival assays and boron concentration assessments in an animal model of osteosarcoma. A clinical case of skull osteosarcoma treated with BNCT in Japan was re-evaluated from the point of view of dose calculation and used as a reference for comparison. RESULTS: The results in the case of femur osteosarcoma show that the RFQ beam would ensure a suitable tumour dose painting in a total irradiation time of less than an hour. Comparing the dosimetry between the analysed case and the treated patient in Japan it turns out that doses obtained in the femur tumour are at least as good as the ones delivered in the skull osteosarcoma. The same is concluded when the comparison is carried out taking into account osteosarcoma irradiations with photon radiation therapy. CONCLUSIONS: The possibility to apply BNCT to osteosarcoma would allow a multimodal treatment consisting in neo-adjuvant chemotherapy, high-LET selective radiation treatment and a more conservative surgery. PMID- 28806982 TI - Software-guided versus nurse-directed blood glucose control in critically ill patients: the LOGIC-2 multicenter randomized controlled clinical trial. AB - BACKGROUND: Blood glucose control in the intensive care unit (ICU) has the potential to save lives. However, maintaining blood glucose concentrations within a chosen target range is difficult in clinical practice and holds risk of potentially harmful hypoglycemia. Clinically validated computer algorithms to guide insulin dosing by nurses have been advocated for better and safer blood glucose control. METHODS: We conducted an international, multicenter, randomized controlled trial involving 1550 adult, medical and surgical critically ill patients, requiring blood glucose control. Patients were randomly assigned to algorithm-guided blood glucose control (LOGIC-C, n = 777) or blood glucose control by trained nurses (Nurse-C, n = 773) during ICU stay, according to the local target range (80-110 mg/dL or 90-145 mg/dL). The primary outcome measure was the quality of blood glucose control, assessed by the glycemic penalty index (GPI), a measure that penalizes hypoglycemic and hyperglycemic deviations from the chosen target range. Incidence of severe hypoglycemia (<40 mg/dL) was the main safety outcome measure. New infections in ICU, duration of hospital stay, landmark 90-day mortality and quality of life were clinical safety outcome measures. RESULTS: The median GPI was lower in the LOGIC-C (10.8 IQR 6.2-16.1) than in the Nurse-C group (17.1 IQR 10.6-26.2) (P < 0.001). Mean blood glucose was 111 mg/dL (SD 15) in LOCIC-C versus 119 mg/dL (SD 21) in Nurse-C, whereas the median time-in-target range was 67.0% (IQR 52.1-80.1) in LOGIC-C versus 47.1% (IQR 28.1-65.0) in the Nurse-C group (both P < 0.001). The fraction of patients with severe hypoglycemia did not differ between LOGIC-C (0.9%) and Nurse-C (1.2%) (P = 0.6). The clinical safety outcomes did not differ between groups. The sampling interval was 2.3 h (SD 0.5) in the LOGIC-C group versus 3.0 h (SD 0.8) in the Nurse-C group (P < 0.001). CONCLUSIONS: In a randomized controlled trial of a mixed critically ill patient population, the use of the LOGIC-Insulin blood glucose control algorithm, compared with blood glucose control by expert nurses, improved the quality of blood glucose control without increasing hypoglycemia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02056353 . Registered on 4 February 2014. PMID- 28806983 TI - Profiling of metalloprotease activities in cerebrospinal fluids of patients with neoplastic meningitis. AB - BACKGROUND: Neoplastic invasion into leptomeninges and subarachnoid space, resulting in neoplastic meningitis (NM) is a fatal complication of advanced solid and hematological neoplasms. Identification of malignant involvement of the cerebrospinal fluid (CSF) early in the disease course has crucial prognostic and therapeutic implications, but remains challenging. As indicators of extracellular matrix (ECM) degradation and breakdown of the blood-brain-barrier, Matrix Metalloproteases (MMPs) and A Disintegrin and Metalloproteases (ADAMs) are potential analytes for cerebral pathophysiology and metastatic dissemination of tumor cells into the CSF. METHODS: We compared protease activities in CSF samples from patients with NM and control individuals using FRET-based metalloprotease substrates with distinct enzyme selectivity profiles in a real-time, multiplex approach termed "proteolytic activity matrix assay" (PrAMA). Protease activity dynamics can be tracked by fluorescence changes over time. By simultaneously monitoring a panel of 5 FRET-substrate cleavages, a proteolytic signature can be identified and analyzed to infer the activities of multiple specific proteases. Distinct patterns of substrate cleavage comparing disease vs. control samples allow rapid, reproducible and sensitive discrimination even in small volumes of CSF. RESULTS: Individual substrate cleavage rates were linked to distinct proteases, and PrAMA computational inference implied increased activities of MMP 9, ADAM8 and ADAM17 (4-5-fold on average) in CSF samples from NM patients that were inhibitable by the metalloprotease inhibitor batimastat (BB-94). The activities of these proteases correlated with blood-brain barrier impairment. Notably, CSF cell counts were not found to directly reflect the protease activities observed in CSF samples from NM patients; this may explain the frequent clinical observation of negative cytology in NM patients. CONCLUSION: PrAMA analysis of CSF samples is a potential diagnostic method for sensitive detection of NM and may be suitable for the clinical routine. PMID- 28806984 TI - Fatigue in the general population- associations to age, sex, socioeconomic status, physical activity, sitting time and self-rated health: the northern Sweden MONICA study 2014. AB - BACKGROUND: Fatigue is widespread in the population and a common complaint in primary care. Little is known about prevalence of fatigue in the population and its predictors. We aimed to describe the pattern of fatigue in the general population and to explore the associations with age, sex, socioeconomic status, self-reported physical activity, sitting time and self-rated health. METHODS: One thousand, five hundred and fifty-seven out of 2500 invited subjects in the Northern Sweden MONICA Study 2014, aged 25-74 years, filled out the Multidimensional Fatigue Inventory (MFI-20), consisting of four subscales: General fatigue (GF), Physical fatigue (PF), Reduced activity (RA) and Mental fatigue (MF). Questions regarding age, sex, socioeconomic status, physical activity, sitting time and self-rated health were also included. RESULTS: Higher age correlated significantly with lower fatigue scores for the GF and MF subscales. Women had higher fatigue scores than men on all subscales (p < 0.05). Among men, higher socioeconomic status was related to lower fatigue for the GF, PF and RA subscales (age adjusted p < 0.05). Among women, higher socioeconomic status was related to lower fatigue for the PF and MF subscales (age adjusted p < 0.05). Higher physical activity was connected to lower levels of fatigue for all subscales (age and sex adjusted p < 0.001) except for MF. Longer time spent sitting was also related to more fatigue on all subscales (age and sex adjusted p < 0.005) except for MF. Better self-rated health was strongly associated with lower fatigue for all subscales (age and sex adjusted p < 0.001). CONCLUSION: Older, highly educated, physically active men, with little sedentary behavior are generally the least fatigued. Self-rated health is strongly related to fatigue. Interventions increasing physical exercise and reducing sedentary behavior may be important to help patients with fatigue and should be investigated in prospective studies. PMID- 28806985 TI - Parents' and teachers' views on sexual health education and screening for sexually transmitted infections among in-school adolescent girls in Kenya: a qualitative study. AB - BACKGROUND: To successfully develop and implement school-based sexual health interventions for adolescent girls, such as screening for Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis, it is important to understand parents' and teachers' attitudes towards sexual health education and acceptability of sexually transmitted infection (STI) screening interventions. METHODS: In this qualitative study, we approached parents and teachers from three high schools to participate in in-depth interviews (IDIs) and focus-group discussions (FGDs). Parents and teachers were asked about their general knowledge of STIs and sexual health education. In addition, they were asked whether they would support utilizing outreach to schools to facilitate provision of sexual health education and screening for STIs in adolescent girls. Data were audio recorded, transcribed, and translated into English. An initial coding matrix was developed and refined throughout the coding process. Transcripts were coded by two researchers and analyzed using the content analysis approach. RESULTS: We conducted 10 IDIs (5 parents and 5 teachers) and 4 FGDs (2 with parents, 2 with teachers, total of 26 participants). Most parents reported few or no discussions regarding STIs with their adolescent girls. Parents were more comfortable discussing consequences of sexual activity including loss of virginity and the potential for pregnancy. Parents tended to place responsibility for sexual health education with teachers. The teachers, in turn, provided basic sexual and reproductive health education including puberty, abstinence, and overview of STIs. Both parents and teachers found the idea of screening for STIs in adolescent girls to be acceptable, and were comfortable with research staff contacting girls through informational meetings at schools. Parents felt that adolescents' STI screening results should be shared with their parents. CONCLUSION: In this African setting, parents and teachers provide limited sexual health education, with a focus on negative consequences including loss of virginity, pregnancy, and risk for STIs. Nonetheless, both parents and teachers were supportive of STI screening for adolescent girls, beginning with school based informational meetings for the girls. Research and programs that aim to provide STI screening in this setting must offer treatment and address the issue of whether results will be disclosed to parents. PMID- 28806986 TI - Antihyperlipidaemic and hepatoprotective activities of acidic and enzymatic hydrolysis exopolysaccharides from Pleurotus eryngii SI-04. AB - BACKGROUND: Hyperlipidaemia is the major risk factor contributing to the development and progression of atherosclerosis, fatty liver and cerebrovascular disease. Pleurotus eryngii (P. eryngii) is rich in biologically active components, especially polysaccharides that exhibit various biological activities, including reducing blood lipids. In the present study, three novel polysaccharide types, including exopolysaccharides (EPS), enzymatic EPS (EEPS) and acidic EPS (AEPS) were isolated, and the hypolipidaemic and hepatoprotective effects were investigated to better understand possible hypolipidaemic mechanisms and their hepatoprotective effects. METHODS: The EPS was hydrolysed by snailase (dissolved in 1% acetic acid, pH = 6) and H2SO4 (1 M) to obtain EEPS and AEPS, respectively. The in vitro antioxidant activities were measured by investigating the reducing power and the scavenging effects on radicals of hydroxyl, 1,1 diphenyl-2-picrylhydrazyl (DPPH) and superoxide anion. The hyperlipidaemic mice were induced by perfusing a high-fat emulsion. In addition to the hepatic histopathology, the following biochemical analyses were performed to investigate the antioxidative effects, including the activities of alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT). Triacylglycerol (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), malondialdehyde (MDA) and lipid peroxidation (LPO) levels were also measured in serum and liver homogenate. RESULTS: Supplementation of EPS, EEPS and AEPS could significantly improve blood lipid levels (TC, TG, HDL-C, and LDL-C), hepatic lipid levels (TC and TG), hepatic enzyme activities (ALP, ALT, and AST) and antioxidant status (GSH-Px, SOD, T-AOC, MDA, and LPO). In addition, histopathological observations indicated that these polysaccharides had potential effects in attenuating hepatocyte damage. CONCLUSION: These results demonstrated that both EPS and its hydrolysates EEPS and AEPS might effectively reduce serum lipid levels and protect against high-fat diet-induced hyperlipidaemia, indicating that they could be used as functional foods and natural hepatoprotectants. PMID- 28806987 TI - A prospective study to evaluate the risk malignancy index and its diagnostic implication in patients with suspected ovarian mass. AB - BACKGROUND: There is no universal screening method for discrimination between benign and malignant adnexal masses yet. Various authors have tried tumor markers, imaging studies, cytology but no one yet is a definite method for screening of cancer ovary, for which a combined diagnostic modality has come to practice in form of RMI. With this background we conducted our study "Evaluation of risk malignancy index and its diagnostic value in patients with adnexal masses". METHODS: The aim of the study was to determine the effectiveness of risk of malignancy index (RMI-3) in preoperative discrimination between benign and malignant masses and also to reveal the most suitable cut off value. We have conducted a prospective study between November 2014 to October 2016. We included the parameters like menopausal status, ultrasound features, and serum levels of tumor marker like CA-125 for calculating RMI 3. Then RMI was compared with the histopathological report which was taken as gold standard. RESULTS: In the present study malignant tumors constitute 54.76% (69/126) & benign tumors 45.24% (57/126). Bilaterality in adnexal masses and multilocularity is higher in malignant tumors than benign tumor, but a P -value >0.005 failed to be proved significant in our study. Solid area is seen in 24.69% (20/81) of benign and 75.30% (61/81) of malignant tumor. Similarly ascites was found in 38.09% (48/126) of cases. Out of which 18.75% (9/48) cases were found to be benign and malignancy was confirmed in 81.25% (39/48) patients. There is statistically significant number of malignant ovarian cancer patients where ascites and solid area is seen in USG findings (p = 0.000). Risk of Malignancy Index compared with individual parameters of Ultrasound score, CA-125 or menopausal score and a cut-off point of 236 shows a very high sensitivity (72.5%), specificity (98.2%), positive predictive value (98.1%), negative predictive value (74.7%) and diagnostic accuracy (84.13%) for discriminating malignant and benign pelvic masses. CONCLUSION: Simplicity and applicability of the method in the primary evaluation of patients with pelvic masses makes it a good option in daily clinical practice in non-specialized gynecologic departments and also in developing countries where access to a gynaecologist oncologist is limited. PMID- 28806988 TI - Subjective safety and self-confidence in prehospital trauma care and learning progress after trauma-courses: part of the prospective longitudinal mixed-methods EPPTC-trial. AB - BACKGROUND: Prehospital trauma care is stressful and requires multi-professional teamwork. A decrease in the number of accident victims ultimately affects the routine and skills and underlines the importance of effective training. Standardized courses, like PHTLS, are established for health care professionals to improve the prehospital care of trauma patients. The aim of the study was to investigate the subjective safety in prehospital trauma care and learning progress by paramedics in a longitudinal analysis. METHODS: This was a prospective intervention trial and part of the mixed-method longitudinal EPPTC trial, evaluating subjective and objective changes among participants and real patient care as a result of PHTLS courses. Participants were evaluated with pre/post questionnaires as well as one year after the course. RESULTS: We included 236 datasets. In the pre/post comparison, an increased performance could be observed in nearly all cases. The result shows that the expectations of the participants of the course were fully met even after one year (p = 0.002). The subjective safety in trauma care is significantly better even one year after the course (p < 0.001). Regression analysis showed that (ABCDE)-structure is decisive (p = 0.036) as well as safety in rare and common skills (both p < 0.001). Most skills are also rated better after one year. Knowledge and specific safety are assessed as worse after one year. CONCLUSION: The courses meet the expectations of the participants and increase the subjective safety in the prehospital care of trauma patients. ABCDE-structure and safety in skills are crucial. In the short term, both safety in skills and knowledge can be increased, but the courses do not have the power to maintain knowledge and specific subjective safety issues over a year. TRIAL REGISTRATION: German Clinical Trials Register, ID DRKS00004713 , registered 14. February 2014. PMID- 28806989 TI - Maximising value from a United Kingdom Biomedical Research Centre: study protocol. AB - BACKGROUND: Biomedical Research Centres (BRCs) are partnerships between healthcare organisations and universities in England. Their mission is to generate novel treatments, technologies, diagnostics and other interventions that increase the country's international competitiveness, to rapidly translate these innovations into benefits for patients, and to improve efficiency and reduce waste in healthcare. As NIHR Oxford BRC (Oxford BRC) enters its third 5-year funding period, we seek to (1) apply the evidence base on how best to support the various partnerships in this large, multi-stakeholder research system and (2) research how these partnerships play out in a new, ambitious programme of translational research. METHODS: Organisational case study, informed by the principles of action research. A cross-cutting theme, 'Partnerships for Health, Wealth and Innovation' has been established with multiple sub-themes (drug development, device development, business support and commercialisation, research methodology and statistics, health economics, bioethics, patient and public involvement and engagement, knowledge translation, and education and training) to support individual BRC research themes and generate cross-theme learning. The 'Partnerships' theme will support the BRC's goals by facilitating six types of partnership (with patients and citizens, clinical services, industry, across the NIHR infrastructure, across academic disciplines, and with policymakers and payers) through a range of engagement platforms and activities. We will develop a longitudinal progress narrative centred around exemplar case studies, and apply theoretical models from innovation studies (Triple Helix), sociology of science (Mode 2 knowledge production) and business studies (Value Co-creation). Data sources will be the empirical research studies within individual BRC research themes (who will apply separately for NHS ethics approval), plus documentary analysis and interviews and ethnography with research stakeholders. This study has received ethics clearance through the University of Oxford Central University Research Ethics Committee. DISCUSSION: We anticipate that this work will add significant value to Oxford BRC. We predict accelerated knowledge translation; closer alignment of the innovation process with patient priorities and the principles of responsible, ethical research; reduction in research waste; new knowledge about the governance and activities of multi-stakeholder research partnerships and the contexts in which they operate; and capacity-building that reflects the future needs of a rapidly-evolving health research system. PMID- 28806990 TI - DVH- and NTCP-based dosimetric comparison of different longitudinal margins for VMAT-IMRT of esophageal cancer. AB - PURPOSE: To cover the microscopic tumor spread in squamous cell carcinoma of the esophagus (SCC), longitudinal margins of 3-4 cm are used for radiotherapy (RT) protocols. However, smaller margins of 2-3 cm might be reasonable when advanced diagnostic imaging is integrated into target volume delineation. Purpose of this study was to compare the dose distribution and deposition to the organs at risk (OAR) for different longitudinal margins using a DVH- and NTCP-based approach. METHODS: Ten patients with SCC of the middle or lower third were retrospectively selected. Three planning target volumes (PTV) with longitudinal margins of 4 cm, 3 cm and 2 cm and an axial margin of 1.5 cm to the gross target volume (GTV) were defined for each patient. For each PTV two treatment plans with total doses of 41.4 Gy (neoadjuvant treatment) and 50.4 Gy (definite treatment) were calculated. Dose to the lungs, heart, myelon and liver were then evaluated and compared between different PTVs. RESULTS: When using a longitudinal margin of 3 cm instead of 4 cm, all dose parameters (Dmin, Dmean, Dmedian and V5-V35), except Dmax could be significantly reduced for the lungs. Regarding the heart, a significant reduction was seen for Dmean and V5, but not for Dmin, Dmax, Dmedian and V10-V35. When comparing a longitudinal margin of 4 cm to a longitudinal margin of 2 cm, a significant difference was calculated for Dmin, Dmean, Dmedian and V5-V35 of the lungs and for Dmax, Dmean and V5-V35 of the heart. Nevertheless, no difference was seen for median heart dose. An additional dose reduction for V10 of the heart was achieved for definite treatment plans when using a longitudinal margin of 3 cm. The NTCP-based risk of pneumonitis was significantly reduced by a margin reduction to 2 cm for neoadjuvant and definite treatment plans. CONCLUSION: Reduction of longitudinal margins from 4 cm to 3 cm can significantly reduce the dose to lungs and Dmean of the heart. Despite clinical benefit and oncologic outcome remain unclear, reduction of the longitudinal margins might provide the opportunity to reduce side effects of chemoradiation (CRT) for SCC in upcoming studies. PMID- 28806991 TI - The impact of an educational program on recognition, treatment and report of child abuse. AB - BACKGROUND: Pediatricians play a crucial role in the identification and management of child abuse and neglect (CAN) but they often don't have a formal specialized training. METHODS: We analysed retrospectively data about patients, 0 - 18 years of age, victims of CAN between 1 April 2005 and 30 April 2015. The aim of the study was to evaluate the effect of a multidisciplinary educational program, "CAN: prevention strategies, individuation and treatment", on the knowledge, case recognition, treatment and follow-up of physicians of Gemelli University Hospital in Rome, regarding physical, sexual abuse and neglect. This program, in 3 different editions biannually, respectively in May-July 2010, November-January 2012 and February-May 2014, was based on 4 sessions, each one of 2 days. RESULTS: Considering the number of victims of CAN between 2005 and 2015 we observed 66 cases of maltreatment. We divided the study population in 2 groups: group A, before the educational programs, patients evaluated from 1 April 2005 to 30 July 2010; group B, after the educational program from 1 August 2010 to 30 April 2015. We observed 23 children in group A and 43 children in group B with an improvement of 87%. Analyzing our data about sex, nationality, type of perpetrators, we found that: 37/66 (56%) of children were females compared to 29/66 (44%) males; 41/66 (62%) of children came from Italy compared to 25/66 (38%) of foreign children; 52/66 (79%) of the perpetrators of abuse were parents or family members compared to acquaintances 10/66 (15%) and to strangers 4/66 (6%). CONCLUSIONS: Considering the prevalence of CAN, the need to develop clinically competent clinicians and the improving of residency education in child maltreatment is imperative. Improving the clinical skills of pediatricians to identify and evaluate CAN may lead to reduce morbidity and mortality of these children. PMID- 28806992 TI - Comparison of an alternative schedule of extended care contacts to a self directed control: a randomized trial of weight loss maintenance. AB - BACKGROUND: Behavioral interventions for obesity produce clinically meaningful weight loss, but weight regain following treatment is common. Extended care programs attenuate weight regain and improve weight loss maintenance. However, less is known about the most effective ways to deliver extended care, including contact schedules. METHODS: We compared the 12-month weight regain of an extended care program utilizing a non-conventional, clustered campaign treatment schedule and a self-directed program among individuals who previously achieved >=5% weight reductions. Participants (N = 108; mean age = 51.6 years; mean weight = 92.6 kg; 52% African American; 95% female) who achieved >=5% weight loss during an initial 16-week behavioral obesity treatment were randomized into a 2-arm, 12-month extended care trial. A clustered campaign condition included 12 group-based visits delivered in three, 4-week clusters. A self-directed condition included provision of the same printed intervention materials but no additional treatment visits. The study was conducted in a U.S. academic medical center from 2011 to 2015. RESULTS: Prior to randomization, participants lost an average of -7.55 +/- 3.04 kg. Participants randomized to the 12-month clustered campaign program regained significantly less weight (0.35 +/- 4.62 kg) than self-directed participants (2.40 +/- 3.99 kg), which represented a significant between-group difference of 2.28 kg (p = 0.0154) after covariate adjustments. This corresponded to maintaining 87% and 64% of lost weight in the clustered campaign and self directed conditions, respectively, which was a significant between-group difference of 29% maintenance of lost weight after covariate adjustments, p = 0.0396. CONCLUSIONS: In this initial test of a clustered campaign treatment schedule, this novel approach effectively promoted 12-month maintenance of lost weight. Future trials should directly compare the clustered campaigns with conventional (e.g., monthly) extended care schedules. TRIAL REGISTRATION: Clinicaltrials.gov NCT02487121 . Registered 06/26/2015 (retrospectively registered). PMID- 28806993 TI - Successful intravenous thrombolysis for ischemic stroke after reversal of dabigatran anticoagulation with idarucizumab: a case report. AB - BACKGROUND: Non-vitamin K antagonist oral anticoagulants, including dabigatran, are currently widely used for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. Recently, idarucizumab, a monoclonal antibody fragment for immediate reversal of dabigatran-induced anticoagulation, has been introduced into the market to be used in life threatening bleeding or urgent surgery, allowing for rapid normalization of clotting parameters. The use of idarucizumab is not yet well established in patients presenting with acute ischemic stroke on dabigatran who are candidates for thrombolytic therapy. CASE PRESENTATION: We report the case of a 71-year-old hypertensive Caucasian woman with non-valvular atrial fibrillation treated with dabigatran 150 mg twice daily, who presented with acute ischemic stroke causing right-sided hemiparesis and aphasia. Two hours after presentation to the emergency department, a decision was made to administer idarucizumab for achieving complete reversal of any potential anticoagulant effect of dabigatran and, in the absence of any contraindications, our patient underwent successful thrombolysis. At discharge, our patient was able to walk unassisted and had only residual aphasia. Twenty days later, she had completely recovered motor function of her right side, with further progressive improvement of aphasia. Repeat cranial computed tomography confirmed the absence of hemorrhage, and anticoagulant therapy with dabigatran 150 mg twice daily was resumed. CONCLUSIONS: Our case report adds to the evidence that idarucizumab administration is safe in the setting of patients with atrial fibrillation treated with dabigatran who develop acute ischemic stroke requiring thrombolysis. PMID- 28806994 TI - Patterns of locoregional failure following post-operative intensity-modulated radiotherapy to oral cavity cancer: quantitative spatial and dosimetric analysis using a deformable image registration workflow. AB - BACKGROUND: We sought to identify spatial/dosimetric patterns of failure for oral cavity cancer patients receiving post-operative IMRT (PO-IMRT). METHODS: Two hundred eighty-nine OCC patients receiving PO-IMRT were retrospectively reviewed from 2000 to 2012. Diagnostic CT documenting recurrence (rCT) was co-registered with planning CT (pCT) using a validated deformable image registration software. Manually segmented recurrent gross disease (rGTV) was deformed to co-registered pCTs. Mapped rGTVs were compared dosimetrically to planned dose and spatially to planning target volumes using centroid-based approaches. Failures types were classified using combined spatial/dosimetric criteria: A (central high-dose), B (peripheral high-dose), C (central intermediate/low-dose), D (peripheral intermediate/low-dose), and E (extraneous-dose). RESULTS: Fifty-four patients with recurrence were analyzed; 26 local recurrence, 19 regional recurrence, and 9 both local and regional recurrence. Median time to recurrence was 4 months (range 0-71). Median rGTVs volume was 3.7 cm3 (IQR 1.4-10.6). For spatial and dosimetric analysis of the patterns of failure, 30 patients (55.5%) were classified as type A (central high-dose). Non-central high dose failures were distributed as follows: 2 (3.7%) type B, 10 (18.5%) type C, 1 (1.8%) type D, and 9 (16.7%) type E. Non-IMRT failure in the matching low-neck field was seen in two patients. No failures were noted at the IMRT-supraclavicular field match-line. CONCLUSIONS: Approximately half of patients with local/regional failure had non-central high dose recurrence. Peripheral high dose misses were uncommon reflecting adequate delineation and dose delivery. Future strategies are needed to reduce types C and E failures. PMID- 28806995 TI - Robot-supported assessment of balance in standing and walking. AB - Clinically useful and efficient assessment of balance during standing and walking is especially challenging in patients with neurological disorders. However, rehabilitation robots could facilitate assessment procedures and improve their clinical value. We present a short overview of balance assessment in clinical practice and in posturography. Based on this overview, we evaluate the potential use of robotic tools for such assessment. The novelty and assumed main benefits of using robots for assessment are their ability to assess 'severely affected' patients by providing assistance-as-needed, as well as to provide consistent perturbations during standing and walking while measuring the patient's reactions. We provide a classification of robotic devices on three aspects relevant to their potential application for balance assessment: 1) how the device interacts with the body, 2) in what sense the device is mobile, and 3) on what surface the person stands or walks when using the device. As examples, nine types of robotic devices are described, classified and evaluated for their suitability for balance assessment. Two example cases of robotic assessments based on perturbations during walking are presented. We conclude that robotic devices are promising and can become useful and relevant tools for assessment of balance in patients with neurological disorders, both in research and in clinical use. Robotic assessment holds the promise to provide increasingly detailed assessment that allows to individually tailor rehabilitation training, which may eventually improve training effectiveness. PMID- 28806996 TI - Improved passive catheter tracking with positive contrast for CMR-guided cardiac catheterization using partial saturation (pSAT). AB - BACKGROUND: Cardiac catheterization is a common procedure in patients with congenital heart disease (CHD). Although cardiovascular magnetic resonance imaging (CMR) represents a promising alternative approach to fluoroscopy guidance, simultaneous high contrast visualization of catheter, soft tissue and the blood pool remains challenging. In this study, a novel passive tracking technique is proposed for enhanced positive contrast visualization of gadolinium filled balloon catheters using partial saturation (pSAT) magnetization preparation. METHODS: The proposed pSAT sequence uses a single shot acquisition with balanced steady-state free precession (bSSFP) readout preceded by a partial saturation pre-pulse. This technique was initially evaluated in five healthy subjects. The pSAT sequence was compared to conventional bSSFP images acquired with (SAT) and without (Non-SAT) saturation pre-pulse. Signal-to-noise ratio (SNR) of the catheter balloon, blood and myocardium and the corresponding contrast-to-noise ratio (CNR) are reported. Subjective assessment of image suitability for CMR-guidance and ideal pSAT angle was performed by three cardiologists. The feasibility of the pSAT sequence is demonstrated in two adult patients undergoing CMR-guided cardiac catheterization. RESULTS: The proposed pSAT approach provided better catheter balloon/blood contrast and catheter balloon/myocardium contrast than conventional Non-SAT sequences. It also resulted in better blood and myocardium SNR than SAT sequences. When averaged over all volunteers, images acquired with a pSAT angle of 20 degrees to 40 degrees enabled simultaneous visualization of the catheter balloon and the cardiovascular anatomy (blood and myocardium) and were found suitable for CMR-guidance in >93% of cases. The pSAT sequence was successfully used in two patients undergoing CMR guided diagnostic cardiac catheterization. CONCLUSIONS: The proposed pSAT sequence offers real-time, simultaneous, enhanced contrast visualization of the catheter balloon, soft tissues and blood. This technique provides improved passive tracking capabilities during CMR-guided catheterization in patients. PMID- 28806997 TI - Stathmin is overexpressed and regulated by mutant p53 in oral squamous cell carcinoma. AB - BACKGROUND: The aim of this study was to investigate the oncogenic function and regulatory mechanism of stathmin in oral squamous cell carcinoma (OSCC). METHODS: Two-dimensional electrophoresis and liquid chromatography-tandem mass chromatography were applied to screen differentiated proteins during carcinogenesis in OSCC. Cell Counting Kit-8 (CCK-8) assays, colony formation, migration, flow cytometry, immunofluorescence and a xenograft model were used to detect the function of stathmin. The correlation between stathmin and p53 expression was analyzed using immunohistochemistry. Mutant/wild type p53 plasmids and small interfering RNA were used to examine the regulation of stathmin. Chromatin immunoprecipitation assays and luciferase assays were performed to detect the transcriptional activation of stathmin by p53. RESULTS: Overexpression of stathmin was screened and confirmed in OSCC patients and cell lines. Silencing expression of stathmin inhibited proliferation, colony formation and migration and promoted apoptosis. Poly ADP ribose polymerase (PARP) and cyclin-dependent kinase 1 (cdc2) were activated after silencing the expression of stathmin. Suppression of tumorigenicity was also confirmed in vivo. Mutant p53 transcriptionally activated the expression of stathmin in HN6 and HN13 cancer cells, but not in HN30 cells harboring wild type p53. CONCLUSIONS: These results suggest that stathmin acts as an oncogene and is transcriptionally regulated by mutant p53, but not by wild-type p53. Stathmin could be a potential anti-tumor therapeutic target in OSCC. PMID- 28806998 TI - First report of Sneathia sanguinegens together with Mycoplasma hominis in postpartum prosthetic valve infective endocarditis: a case report. AB - BACKGROUND: The presence of more than one bacterial agent is relatively rare in infective endocarditis, although more common in prosthetic cases. Molecular diagnosis from a removed heart tissue is considered a quick and effective way to diagnose fastidious or intracellular agents. CASE PRESENTATION: Here we describe the case of postpartum polymicrobial prosthetic valve endocarditis in a young woman. Sneathia sanguinegens and Mycoplasma hominis were simultaneously detected from the heart valve sample using broad range 16S rRNA polymerase chain reaction (PCR) followed by sequencing while culture remained negative. Results were confirmed by independent PCR combined with denaturing gradient gel electrophoresis. Before the final agent identification, the highly non-compliant patient left from the hospital against medical advice on empirical intravenous treatment with aminopenicillins, clavulanate and gentamicin switched to oral amoxycillin and clavulanate. Four months after surgery, no signs of inflammation were present despite new regurgitation and valve leaflet flail was detected. However, after another 5 months the patient died from sepsis and recurrent infective endocarditis of unclarified etiology. CONCLUSIONS: Mycoplasma hominis is a rare causative agent of infective endocarditis. To the best of our knowledge, presented case is the first report of Sneathia sanguinegens detected in this condition. Molecular techniques were shown to be useful even in polymicrobial infective endocarditis samples. PMID- 28806999 TI - Trading certainty for speed - how much uncertainty are decisionmakers and guideline developers willing to accept when using rapid reviews: an international survey. AB - BACKGROUND: Decisionmakers and guideline developers demand rapid syntheses of the evidence when time sensitive evidence-informed decisions are required. A potential trade-off of such rapid reviews is that their results can have less reliability than results of systematic reviews that can lead to an increased risk of making incorrect decisions or recommendations. We sought to determine how much incremental uncertainty about the correctness of an answer guideline developers and health policy decisionmakers are willing to accept in exchange for a rapid evidence-synthesis. METHODS: Employing a purposive sample, we conducted an international web-based, anonymous survey of decisionmakers and guideline developers. Based on a clinical treatment, a public health, and a clinical prevention scenario, participants indicated the maximum risk of getting an incorrect answer from a rapid review that they would be willing to accept. We carefully reviewed data and performed descriptive statistical analyses. RESULTS: In total, 325 (58.5%) of 556 participants completed our survey and were eligible for analysis. The median acceptable incremental risk for getting an incorrect answer from a rapid review across all three scenarios was 10.0% (interquartile range [IQR] 5.0-15.0). Acceptable risks were similar for the clinical treatment (n = 313, median 10.0% [IQR 5.0-15.0]) and the public health scenarios (n = 320, median 10.0% [IQR 5.0-15.0]) and lower for the clinical prevention scenario (n = 312, median 6.5% [IQR 5.0-10.5]). CONCLUSIONS: Findings suggest that decisionmakers are willing to accept some trade-off in validity in exchange for a rapid review. Nevertheless, they expect the validity of rapid reviews to come close to that of systematic reviews. PMID- 28807000 TI - Necrotizing streptococcal myositis of the upper extremity: a case report. AB - BACKGROUND: Necrotizing myositis is a rare but life-threatening soft-tissue infection characterized by rapidly spreading inflammation and subsequent necrosis of the affected tissue. The myositis is often caused by toxin-producing, virulent bacteria such as group A beta-hemolytic streptococcus and associated with severe systemic toxicity. It is rapidly fatal unless diagnosed promptly and treated aggressively. However, necrotizing myositis is often initially misdiagnosed as a more benign soft-tissue infection as such fulminant, invasive muscle infections are rare with no more than 30 cases reported over the last century. CASE PRESENTATION: We illustrate the case of a 74-year-old male Caucasian initially presenting with a progressing swelling and gradually oncoming pain of the upper right extremity. Rapidly, livid discolorations of the skin, blisters, hypoesthesia and severe pain resistant to analgesics treatment developed accompanied by disruption of the arterial blood flow. Due to a manifest compartment syndrome the patient was admitted to theater for fasciotomy of the arm. After multiple revision surgeries wound closure was achieved using a pedicled, fasciocutaneous parascapular flap and a free, ipsilateral anterolateral thigh flap. Microbiological analysis revealed group A beta-hemolytic streptococcus, histology a bacterial interstitial myositis with necrotic muscular fibers. CONCLUSIONS: A high degree of clinical suspicion is necessary to avert potentially disastrous consequences of necrotizing myositis. Timely diagnosis, broad-spectrum antibiotic therapy, and aggressive surgical debridement of affected tissue are keys to the treatment of this serious, often life-threatening infection. PMID- 28807002 TI - High resolution measurement of DUF1220 domain copy number from whole genome sequence data. AB - BACKGROUND: DUF1220 protein domains found primarily in Neuroblastoma BreakPoint Family (NBPF) genes show the greatest human lineage-specific increase in copy number of any coding region in the genome. There are 302 haploid copies of DUF1220 in hg38 (~160 of which are human-specific) and the majority of these can be divided into 6 different subtypes (referred to as clades). Copy number changes of specific DUF1220 clades have been associated in a dose-dependent manner with brain size variation (both evolutionarily and within the human population), cognitive aptitude, autism severity, and schizophrenia severity. However, no published methods can directly measure copies of DUF1220 with high accuracy and no method can distinguish between domains within a clade. RESULTS: Here we describe a novel method for measuring copies of DUF1220 domains and the NBPF genes in which they are found from whole genome sequence data. We have characterized the effect that various sequencing and alignment parameters and strategies have on the accuracy and precision of the method and defined the parameters that lead to optimal DUF1220 copy number measurement and resolution. We show that copy number estimates obtained using our read depth approach are highly correlated with those generated by ddPCR for three representative DUF1220 clades. By simulation, we demonstrate that our method provides sufficient resolution to analyze DUF1220 copy number variation at three levels: (1) DUF1220 clade copy number within individual genes and groups of genes (gene-specific clade groups) (2) genome wide DUF1220 clade copies and (3) gene copy number for DUF1220-encoding genes. CONCLUSIONS: To our knowledge, this is the first method to accurately measure copies of all six DUF1220 clades and the first method to provide gene specific resolution of these clades. This allows one to discriminate among the ~300 haploid human DUF1220 copies to an extent not possible with any other method. The result is a greatly enhanced capability to analyze the role that these sequences play in human variation and disease. PMID- 28807001 TI - The MEK inhibitor selumetinib complements CTLA-4 blockade by reprogramming the tumor immune microenvironment. AB - BACKGROUND: T-cell checkpoint blockade and MEK inhibitor combinations are under clinical investigation. Despite progress elucidating the immuno-modulatory effects of MEK inhibitors as standalone therapies, the impact of MEK inhibition on the activity of T-cell checkpoint inhibitors remains incompletely understood. Here we sought to characterize the combined effects of MEK inhibition and anti CTLA-4 mAb (anti-CTLA-4) therapy, examining effects on both T-cells and tumor microenvironment (TME). METHODS: In mice, the effects of MEK inhibition, via selumetinib, and anti-CTLA-4 on immune responses to keyhole limpet haemocyanin (KLH) immunization were monitored using ex vivo functional assays with splenocytes. In a KRAS-mutant CT26 mouse colorectal cancer model, the impact on the tumor microenvironment (TME) and the spleen were evaluated by flow cytometry. The TME was further examined by gene expression and immunohistochemical analyses. The combination and sequencing of selumetinib and anti-CTLA-4 were also evaluated in efficacy studies using the CT26 mouse syngeneic model. RESULTS: Anti-CTLA-4 enhanced the generation of KLH specific immunity following KLH immunization in vivo; selumetinib was found to reduce, but did not prevent, this enhancement of immune response by anti-CTLA-4 in vivo. In the CT26 mouse model, anti-CTLA-4 treatment led to higher expression levels of the immunosuppressive mediators, Cox 2 and Arg1 in the TME. Combination of anti-CTLA-4 with selumetinib negated this up-regulation of Cox-2 and Arg1, reduced the frequency of CD11+ Ly6G+ myeloid cells, and led to the accumulation of differentiating monocytes at the Ly6C+ MHC+ intermediate state in the tumor. We also report that MEK inhibition had limited impact on anti-CTLA-4-mediated increases in T-cell infiltration and T-cell activation in CT26 tumors. Finally, we show that pre-treatment, but not concurrent treatment, with selumetinib enhanced the anti-tumor activity of anti CTLA-4 in the CT26 model. CONCLUSION: These data provide evidence that MEK inhibition can lead to changes in myeloid cells and immunosuppressive factors in the tumor, thus potentially conditioning the TME to facilitate improved response to anti-CTLA-4 treatment. In summary, the use of MEK inhibitors to alter the TME as an approach to enhance the activities of immune checkpoint inhibitors warrants further investigation in clinical trials. PMID- 28807003 TI - Overexpression of miR-21 in stem cells improves ovarian structure and function in rats with chemotherapy-induced ovarian damage by targeting PDCD4 and PTEN to inhibit granulosa cell apoptosis. AB - BACKGROUND: Chemotherapy-induced premature ovarian failure (POF) is a severe complication affecting tumor patients at a childbearing age. Mesenchymal stem cells (MSCs) can partially restore the ovarian structure and function damaged by chemotherapy. miR-21 is a microRNA that can regulate cell apoptosis. This study discusses the repair effect and mechanism of MSCs overexpressing miR-21 on chemotherapy-induced POF. METHODS: Rat MSCs and granulosa cells (GCs) were isolated in vitro. MSCs were transfected with miR-21 lentiviral vector (LV-miR 21) to obtain MSCs stably expressing miR-21 (miR-21-MSCs). The microenvironment of an ovary receiving chemotherapy was mimicked by adding phosphamide mustard (PM) into the cellular culture medium. The apoptosis rate and the mRNA and protein expression of target genes PTEN and PDCD4 were detected in MSCs. Apoptosis was induced by adding PM into the culture medium for GCs, which were cocultured with miR-21-MSCs. The apoptosis rate and the mRNA and protein expression of PTEN and PDCD4 were detected. The chemotherapy-induced POF model was built into rats by intraperitoneal cyclophosphamide injection. miR-21-MSCs were transplanted into the bilateral ovary. The rats were sacrificed at 15, 30, 45, and 60 days after the last injection. The ovarian weights, follicle count, estrous cycle, and sex hormone levels (estradiol (E2) and follicle-stimulating hormone (FSH)) were detected. Apoptosis of GCs was determined by TUNEL assay. The miR-21 and mRNA and protein expression of PTEN and PDCD4 were determined. RESULTS: The apoptosis decreased in MSCs transfected with miR-21. The mRNA and protein expression of target genes PTEN and PDCD4 was downregulated. GCs cocultured with miR-21-MSCs showed a decreased apoptosis, an upregulation of miR 21, and a downregulation of PTEN and PDCD4. Following the injection of miR-21 MSCs, the ovarian weight and follicle counts increased; E2 levels increased while FSH levels decreased, with less severe apoptosis of GCs. The miR-21 expression in the ovaries was upregulated, while the mRNA expression and protein expression of PTEN and PDCD4 were downregulated. CONCLUSIONS: Overexpression of miR-21 in MSCs promoted efficacy against chemotherapy-induced POF and its improvement of the repair effect was related to the inhibition of GC apoptosis by targeting PTEN and PDCD4. PMID- 28807004 TI - Predictive role of PD-L1 expression in the response of renal Medullary carcinoma to PD-1 inhibition. AB - BACKGROUND: Renal medullary carcinoma is one of the rarest malignancies arising from the kidney. Despite various aggressive therapeutic regimens, mortality remains significantly high (95%) with a median overall survival of 5 months. Furthermore, the scarcity of this malignancy renders randomized clinical trials impossible. We examined the expression of programmed death ligand 1 (PD-L1) in two new renal medullary carcinoma cases, investigated their responses to the PD L1 inhibitor nivolumab and explored the predictive role of the rate of PD-L1 expression in such response. CASE PRESENTATION: Two African-American patients (male and female) with sickle cell trait who presented to our center with hematuria and flank pain were diagnosed with metastatic renal medullary carcinoma. PD-L1 was expressed at rate of 25% and 60% in patient 1 and 2 respectively. Following nephrectomy, they were started on nivolumab. Patient 1 initially responded to the treatment with regression of metastatic lesions. However, following this early response, patient 1 who has been receiving nivolumab for more than 15 months, was noted to have a disease progression. Patient 2 had disease progression after 3 months of nivolumab therapy. CONCLUSIONS: Although PD-L1 is expressed in these patients with renal medullary carcinoma, response to nivolumab was only observed in patient 1 whose tumor has the lowest rate of PD-L1 expression. This may suggest that in RMC, response to PD L1 inhibition therapy may not correlate with the rate of PD-L1 expression. PMID- 28807005 TI - First records of Triatoma rubrofasciata (De Geer, 1773) (Hemiptera, Reduviidae) in Foshan, Guangdong Province, Southern China. AB - BACKGROUND: Triatomines, also known as kissing bugs, which are found throughout the world and especially in Latin America, are well known natural vectors that transmit American trypanosomiasis, also called Chagas disease. In China, the presence of two species of Triatoma (Triatoma rubrofasciata and T. sinica) was recorded in the past. Due to the growing population and the increasing risk of the global spread of Chagas disease, triatomines became a potential public health nuisance, and in 2016, we started monitoring triatomine activities in southern China. METHODS: Triatomine specimens were collected by the National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, and identified by their morphological characteristics under a dissecting microscope. In addition to morphological analysis, the genomic DNA of the specimens was extracted, and the mitochondrial 16S rRNA, the cytochrome b (CytB) gene and the nuclear ribosomal 28S rRNA gene were PCR-amplified to analyze and confirm the species genetically. RESULTS: One female adult insect and one male adult insect were collected in a dwelling in the rural area of Shunde County, Foshan City, Guangdong Province, China (22 degrees 42'44.63"N, 113 degrees 08'45.34"E). The results from the morphological and genetic analyses indicated that these triatomines were T. rubrofasciata. CONCLUSIONS: This is the first time that the occurrence of T. rubrofasciata has been confirmed in Foshan City, Guangdong Province in southern China. Further studies are needed to reach a clearer understanding of the ecology of this species of triatomine, since it has been found to be naturally infected by Trypanosoma cruzi and T. conorhini and there is evidence of its domiciliation capabilities. PMID- 28807006 TI - The impact of active stakeholder involvement on recruitment, retention and engagement of schools, children and their families in the cluster randomised controlled trial of the Healthy Lifestyles Programme (HeLP): a school-based intervention to prevent obesity. AB - BACKGROUND: Recruitment and retention of participants is crucial for statistical power and internal and external validity and participant engagement is essential for behaviour change. However, many school-based interventions focus on programme content rather than the building of supportive relationships with all participants and tend to employ specific standalone strategies, such as incentives, to improve retention. We believe that actively involving stakeholders in both intervention and trial design improves recruitment and retention and increases the chances of creating an effective intervention. METHODS: The Healthy Lifestyles Programme, HeLP (an obesity prevention programme for children 9-10 years old) was developed using intervention mapping and involved extensive stakeholder involvement in both the design of the trial and the intervention to ensure that: (i) delivery methods were suitably engaging, (ii) deliverers had the necessary skills and qualities to build relationships and (iii) the intervention dovetailed with the National Curriculum. HeLP was a year-long intervention consisting of 4 multi-component phases using a range of delivery methods. We recruited 1324 children from 32 schools from the South West of England to a cluster-randomised controlled trial to determine the effectiveness of HeLP in preventing obesity. The primary outcome was change in body mass index standard deviation score (BMI SDS) at 24 months post randomisation. Secondary outcomes included additional anthropometric and behavioural (physical activity and diet) measures at 18 and 24 months. RESULTS: Anthropometric and behavioural measures were taken in 99%, 96% and 94% of children at baseline, 18 and 24 months, respectively, with no differential follow up between the control and intervention groups at each time point. All children participated in the programme and 92% of children and 77% of parents across the socio-economic spectrum were considered to have actively engaged with HeLP. CONCLUSIONS: We attribute our excellent retention and engagement results to the high level of stakeholder involvement in both trial and intervention design, the building of relationships using appropriate personnel and creative delivery methods that are accessible to children and their families across the social spectrum. TRIAL REGISTRATION: International Standard Randomised Controlled Trials Register, ISRCTN15811706 . Registered on 1 May 2012. PMID- 28807007 TI - TNF-alpha-induced miR-155 regulates IL-6 signaling in rheumatoid synovial fibroblasts. AB - BACKGROUND: MicroRNAs (miRNAs) are important regulators of a variety of inflammatory mediators. The present study was undertaken to elucidate the role of miRNAs in the rheumatoid cytokine network. METHODS: We analyzed miRNA expression in rheumatoid synovial fibroblasts (RASFs). miRNA array-based screening was used to identify miRNAs differentially expressed between tumor necrosis factor-alpha (TNF-alpha)-activated RASFs and untreated RASFs. Transfection of RASFs with miR 155 was used to analyze the function of miR-155. Real-time polymerase chain reaction (PCR) was used to measure the levels of miR-155 in RASFs. RESULTS: miRNA microarray analysis revealed that miR-155-5p was the most highly induced miRNA in TNF-alpha-stimulated RASFs. TNF-alpha-induced miR-155 expression in RASFs was time-dependent and TNFalpha dose-dependent, whereas, IL-6 stimulation did not affect miR-155 expression in RASFs. Transfection of miR-155 mimics into RASFs resulted in the decrease JAK2/STAT3 phosphorylation in IL-6-treated RASFs. CONCLUSIONS: The current results demonstrate that TNF-alpha modulated miRNA expressions in RASFs. Our data showed that miR-155, which is highly induced by TNF-alpha stimulation, inhibits IL-6-mediated JAK2/STAT3 activation in RASFs. These findings suggest that miR-155 contributes to the cross-regulation between TNF-alpha and IL-6-mediated inflammatory pathways in RA. PMID- 28807008 TI - Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders. AB - BACKGROUND: De novo missense variants in CDK13 have been described as the cause of syndromic congenital heart defects in seven individuals ascertained from a large congenital cardiovascular malformations cohort. We aimed to further define the phenotypic and molecular spectrum of this newly described disorder. METHODS: To minimise ascertainment bias, we recruited nine additional individuals with CDK13 pathogenic variants from clinical and research exome laboratory sequencing cohorts. Each individual underwent dysmorphology exam and comprehensive medical history review. RESULTS: We demonstrate greater than expected phenotypic heterogeneity, including 33% (3/9) of individuals without structural heart disease on echocardiogram. There was a high penetrance for a unique constellation of facial dysmorphism and global developmental delay, as well as less frequently seen renal and sacral anomalies. Two individuals had novel CDK13 variants (p.Asn842Asp, p.Lys734Glu), while the remaining seven unrelated individuals had a recurrent, previously published p.Asn842Ser variant. Summary of all variants published to date demonstrates apparent restriction of pathogenic variants to the protein kinase domain with clustering in the ATP and magnesium binding sites. CONCLUSIONS: Here we provide detailed phenotypic and molecular characterisation of individuals with pathogenic variants in CDK13 and propose management guidelines based upon the estimated prevalence of anomalies identified. PMID- 28807009 TI - Adverse mental health outcomes in breast cancer survivors compared to women who did not have cancer: systematic review protocol. AB - BACKGROUND: Recent increasing trends in breast cancer incidence and survival have resulted in unprecedented numbers of cancer survivors in the general population. A cancer diagnosis may have a profound psychological impact, and breast cancer treatments often cause long-term physical sequelae, potentially affecting women's mental health. The aim of this systematic review is to identify and summarise all studies that have compared mental health outcomes in breast cancer survivors, versus women who did not have cancer. METHODS: This study will be a systematic review of the literature. Four databases, including MEDLINE and PsycINFO, will be searched to identify potentially relevant studies. The search expressions will use a Boolean logic, including terms for the target population (women who have had breast cancer), outcomes (psychiatric disorders) and comparators (e.g. risk, hazard). All mental disorders will be eligible, except those with onset normally occurring during childhood or strong genetic basis (e.g. Huntington disease). The eligibility of the studies will be assessed in two phases: (1) considering the information provided in the title and abstract; (2) evaluating the full text. Studies including women diagnosed with breast cancer 1 year or more ago and that provide original data on mental health outcomes will be eligible. Studies in which all women were undergoing surgery, chemotherapy or radiotherapy, or hospitalised or institutionalised, will be excluded, as well as studies that include patients selected on the basis of symptomatology. Two investigators will do the screening of the references and the data extraction independently, with results compared and discrepancies resolved by involving a third investigator when necessary. Study quality and risk of bias will be assessed across six broad domains. Results will be summarised by outcome, and summary measures of frequency and/or association will be computed if possible. DISCUSSION: This review will summarise the evidence on the mental health outcomes of women who have been diagnosed with breast cancer. This information can be used to motivate further research and increase understanding of the most common mental health conditions affecting this growing population of women. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017056946. PMID- 28807010 TI - Angiogenic potency evaluation of cell therapy candidates by a novel application of the in vitro aortic ring assay. AB - BACKGROUND: Due to limitations of current angiogenesis assays, we aimed to develop a novel application of the rat aortic ring assay to assess the angiogenic potential of mesenchymal stromal cells (MSCs). First-trimester human umbilical cord-derived perivascular cells (FTM HUCPVCs) have multipotent characteristics and previously demonstrated angiogenic potential. We compared the effect of this young source of MSCs and adult bone marrow stromal cells (BMSCs) on ex vivo aortic endothelial network formation. METHODS: Thoracic segments of adult rat aortas were isolated, sectioned and embedded into MatrigelTM. Fluorophore-labeled FTM HUCPVC lines and BMSCs (N = 3) were cocultured with developing endothelial networks (day 0). MSC integration, tube formation and endothelial network growth were monitored daily using phase-contrast and fluorescence microscopy. Quantification of endothelial networks was performed using ImageJ network analysis software on day 5 of coculture. RESULTS: FTM HUCPVCs from two umbilical cord samples migrated toward and integrated with developing aortic ring tubular networks while displaying elongated morphologies (day 1). In contrast, BMSCs did not show targeted migration and maintained spherical morphologies with limited physical interactions. Within 1 week of coculture, FTM HUCPVC lines contributed to significantly greater radial network growth and network loop formation when compared to BMSCs and untreated networks. CONCLUSIONS: We have developed a novel potency assay to assess the angiogenic potential of cell therapy candidates. Favorable properties of FTM HUCPVCs over BMSCs that we observed with this assay and which merit further study include chemotaxis, affinity for developing vasculature, and physical supportive interactions contributing to the development of endothelial networks. PMID- 28807011 TI - Changes in proteinuria and the risk of myocardial infarction in people with diabetes or pre-diabetes: a prospective cohort study. AB - BACKGROUND: The relationship between changes in proteinuria and myocardial infarction (MI) remains unclear in people with diabetes or pre-diabetes. We aimed to evaluate the predictive value and independent role of changes in proteinuria over a 2-year period in the incidence of MI in people with diabetes or pre diabetes. METHODS: Based on the baseline and 2-year dipstick screening results from the Kailuan prospective cohort study, participants were divided into four categories: no proteinuria, remittent proteinuria, incident proteinuria, and persistent proteinuria. Four multivariable Cox proportional hazard models were built to adjust for the effects of different confounding covariates. RESULTS: Among the 17,625 participants in this study, there were a total of 238 incidents of MI during a median follow-up of 6.69 years. After adjusting for demography factors and laboratory indices, the association between persistent proteinuria and MI incidence was maintained (hazard ratio [HR] 2.50, 95% confidence interval [CI] 1.48-4.22). Every decrease of proteinuria from 2006 to 2008 was observed to be responsible for a 21% decline of MI incidence (HR 0.79, 95% CI 0.68-0.90). The interaction between changes in proteinuria and diabetes was confirmed with no effect on MI (P = 0.3371). CONCLUSIONS: Persistent proteinuria is an independent risk factor for MI incidence in the pre-diabetic and diabetic population. These findings may help clinicians to interpret proteinuria changes in the outpatient setting and provide possible preventive approaches for people with pre-diabetes or diabetes. PMID- 28807012 TI - Protein deubiquitinase USP7 is required for osteogenic differentiation of human adipose-derived stem cells. AB - BACKGROUND: Human adipose-derived stem cells (hASCs) are multipotent progenitor cells with self-renewal capabilities and multilineage differentiation potential, including osteogenesis. Although protein deubiquitinases have been linked to stem cell fate determination, whether protein deubiquitination contributes to lineage commitment during osteogenic differentiation of hASCs remains to be investigated. The objective of this study was to evaluate the effects of the ubiquitin specific protease 7 (USP7) on osteogenic differentiation of hASCs. METHODS: An osteocalcin promoter driven luciferase reporter system was established to initially discover the potential association between USP7 and hASC osteogenesis. To further characterize the function of USP7 in osteogenic differentiation of hASCs, a combination of in vitro and in vivo experiments were carried out through genetic depletion or overexpression of USP7 using a lentiviral strategy. Moreover, HBX 41,108, a cyanoindenopyrazine-derived deubiquitinase inhibitor of USP7, was utilized at different doses to further examine whether USP7 regulated osteogenic differentiation of hASCs through its enzymatic activity. RESULTS: We demonstrated that USP7 depletion was associated with remarkable downregulation of the reporter gene activity. Genetic depletion of USP7 by lentiviral RNAi markedly suppressed hASC osteogenesis both in vitro and in vivo, while overexpression of USP7 enhanced the osteogenic differentiation of hASCs. Notably, chemical blockade via the small molecular inhibitor HBX 41,108 could efficiently mimic the effects of USP7 genetic depletion in a dose-dependent manner. CONCLUSIONS: Taken together, our study revealed that protein deubiquitinase USP7 is an essential player in osteogenic differentiation of hASCs through its catalytic activity, and supported the pursuit of USP7 as a potential target for modulation of hASC-based stem cell therapy and bone tissue engineering. PMID- 28807013 TI - Microneedle physical contact as a therapeutic for abnormal scars. AB - BACKGROUND: Abnormal (keloid and hypertrophic) scars are a significant affliction with no satisfactory single modality therapy to-date. Available options are often ineffective, painful, potentially hazardous, and require healthcare personnel involvement. Herein a self-administered microneedle device based on drug-free physical contact for inhibiting abnormal scars is reported. Its therapeutic activity through microneedle contact eliminates hazards associated with toxic anti-scarring drugs while self-treatment enables administration flexibility. METHODS: The microneedle patch was fabricated with FDA-approved liquid crystalline polymer under good manufacturing practice. It was first tested to ascertain its ability to inhibit (keloid) fibroblast proliferation. Later the microneedle patch was examined on the rabbit ear hypertrophic scar model to explore its potential in inhibiting the generation of abnormal scars post-injury. Finally, the microneedle patch was applied to the caudal region of a hypertrophic scar located on a female patient's dorsum to verify clinical efficacy. RESULTS: On untreated control cultures, barely any non-viable fibroblasts could be seen. After 12-h treatment with the microneedle patch, the non-viable proportion increased to 83.8 +/- 11.96%. In rabbit ear hypertrophic scar model, 100% of the control wounds without the presence of patches on rabbit ears generated regions of raised dermis originating from the wound site (3/3), whereas microneedle treatment prevented dermis tissue thickening in 83.33% of the wounds (15/18). In the clinical test, the microneedle patch was well tolerated by the patient. Compared to the untreated region, microneedle treatment decreased the number of infiltrated inflammatory cells, with less disrupted dermis tissue architecture and more flattened appearance. CONCLUSIONS: A self-administered, drug-free microneedle patch appears highly promising in reducing abnormal scarring as observed from in vitro, in vivo and clinical experiments. Larger cohort clinical studies need to be performed to validate its efficacy on abnormal scars. PMID- 28807014 TI - Epigenetic reprogramming converts human Wharton's jelly mesenchymal stem cells into functional cardiomyocytes by differential regulation of Wnt mediators. AB - BACKGROUND: Lineage commitment of mesenchymal stem cells (MSCs) to cardiac differentiation is controlled by transcription factors that are regulated by epigenetic events, mainly histone deacetylation and promoter DNA methylation. Here, we studied the differentiation of human Wharton's jelly MSCs (WJMSCs) into the cardiomyocyte lineage via epigenetic manipulations. METHODS: We introduced these changes using inhibitors of DNA methyl transferase and histone deacetylase, DC301, DC302, and DC303, in various combinations. We characterized for cardiogenic differentiation by assessing the expression of cardiac-specific markers by immunolocalization, quantitative RT-PCR, and flow cytometry. Cardiac functional studies were performed by FURA2AM staining and Greiss assay. The role of Wnt signaling during cardiac differentiation was analyzed by quantitative RT PCR. In-vivo studies were performed in a doxorubicin-induced cardiotoxic mouse model by injecting cardiac progenitor cells. Promoter methylation status of the cardiac transcription factor Nkx2.5 and the Wnt antagonist, secreted frizzled related protein 4 (sFRP4), after cardiac differentiation was studied by bisulfite sequencing. RESULTS: By induction with DC301 and DC302, WJMSCs differentiated into cardiomyocyte-like structures with an upregulation of Wnt antagonists, sFRP3 and sFRP4, and Dickkopf (Dkk)1 and Dkk3. The cardiac function enhancer, vinculin, and DDX20, a DEAD-box RNA helicase, were also upregulated in differentiated cardiomyocytes. Additionally, bisulfite sequencing revealed, for the first time in cardiogenesis, that sFRP4 is activated by promoter CpG island demethylation. In vivo, these MSC-derived cardiac progenitors could not only successfully engraft to the site of cardiac injury in mice with doxorubicin-induced cardiac injury, but also form functional cardiomyocytes and restore cardiac function. CONCLUSION: The present study unveils a link between Wnt inhibition and epigenetic modification to initiate cardiac differentiation, which could enhance the efficacy of stem cell therapy for ischemic heart disorders. PMID- 28807016 TI - Endogenous controls of gene expression in N-methyl-N-nitrosourea-induced T-cell lymphoma in p53-deficient mice. AB - BACKGROUND: Real-time polymerase chain reaction (PCR) has become an increasingly important technique for gene expression profiling because it can provide insights into complex biological and pathological processes and be used to predict disease or treatment outcomes. Although normalized data are necessary for an accurate estimation of mRNA expression levels, several pieces of evidence suggest that the expression of so-called housekeeping genes is not stable. This study aimed to validate reference genes for the normalization of real-time PCR in an N-methyl-N nitrosourea (MNU)-induced T-cell lymphoma mouse model. METHODS: T-cell lymphomas were generated in p53-deficient mice by treatment with 37.5 mg/kg MNU. Thymus and spleen were identified as the primary target organs with the highest incidences of lymphomas. We analyzed the RNA expression levels of eight potential endogenous reference genes (Gapdh, Rn18s, Actb, Hprt, B2M, Rplp0, Gusb, Ctbp1). The expression stabilities of these reference genes were tested at different time points after MNU treatment using geNorm and NormFinder algorithms. RESULTS: A total of 65% of MNU-treated mice developed T-cell lymphomas, with the spleen and thymus as the major target organs. All candidate reference genes were amplified efficiently by quantitative reverse-transcription polymerase chain reaction (RT qPCR). Gene stability evaluation after MNU treatment and during lymphomagenesis revealed that Ctbp1 and Rplp0 were the most stably expressed genes in the thymus and spleen, respectively. RT-PCR of thymus RNA using two additional sets of primer confirmed that Ctbp1 was the most stable of all the candidate reference genes. CONCLUSIONS: We provided suitable endogenous controls for gene expression studies in the T-cell lymphoma model. PMID- 28807015 TI - Genomic upregulation of cardiac Cav1.2alpha and NCX1 by estrogen in women. AB - BACKGROUND: Women have a higher risk of lethal arrhythmias than men in long QT syndrome type 2 (LQTS2), but the mechanisms remain uncertain due to the limited availability of healthy control human tissue. We have previously reported that in female rabbits, estrogen increases arrhythmia risk in drug-induced LQTS2 by upregulating L-type Ca2+ (ICa,L) and sodium-calcium exchange (INCX) currents at the base of the epicardium by a genomic mechanism. This study investigates if the effects of estrogen on rabbit ICa,L and INCX apply to human hearts. METHODS: Postmortem human left ventricular tissue samples were probed with selective antibodies for regional heterogeneities of ion channel protein expression and compared to rabbit myocardium. Functionally, ICa,L and INCX were measured from female and male cardiomyocytes derived from human induced pluripotent stem cells (iPS-CMs) with the voltage-clamp technique from control and estrogen-treated iPS CMs. RESULTS: In women (n = 12), Cav1.2alpha (primary subunit of the L-type calcium channel protein 1) and NCX1 (sodium-calcium exchange protein) levels were higher at the base than apex of the epicardium (40 +/- 14 and 81 +/- 30%, respectively, P < 0.05), but not in men (n = 6) or postmenopausal women (n = 6). Similarly, in cardiomyocytes derived from female human iPS-CMs, estrogen (1 nM, 1 2 days) increased ICa,L (31%, P < 0.05) and INCX (7.5-fold, - 90 mV, P < 0.01) and their mRNA levels (P < 0.05). Moreover, in male human iPS-CMs, estrogen failed to alter ICa,L and INCX. CONCLUSIONS: The results show that estrogen upregulates cardiac ICa,L and INCX in women through genomic mechanisms that account for sex differences in Ca2+ handling and spatial heterogeneities of repolarization due to base-apex heterogeneities of Cav1.2alpha and NCX1. By analogy with rabbit studies, these effects account for human sex-difference in arrhythmia risk. PMID- 28807017 TI - The urinary microbiota of men and women and its changes in women during bacterial vaginosis and antibiotic treatment. AB - BACKGROUND: The urinary microbiota is similarly complex as the vaginal and penile microbiota, yet its role as a reservoir for pathogens and for recurrent polymicrobial biofilm diseases like bacterial vaginosis (BV) is not clear. RESULTS: Here, we analysed the urinary microbiota of healthy men and women and compared it with that of women during BV and after antibiotic treatment using next-generation sequencing of the 16S rRNA gene V1-V2 regions. Eight different community types, so called urotypes (UT), were identified in healthy humans, all of which were shared between men and women, except UT 7, dominated in relative abundance by Lactobacillus crispatus, which was found in healthy women only. Orally applied metronidazole significantly reduced Shannon diversity and the mean relative abundance of Gardnerella vaginalis, Atopobium vaginae, and Sneathia amnii, while L. iners increased to levels twofold higher than those found in healthy women. Although individual urine microbial profiles strongly responded to the antibiotic, the healthy community could not be restored. The correlation between urinary and vaginal fluid microbiota was generally weak and depending on UT and BV status. It was highest in UT 1 in acute BV (59% of samples), but after metronidazole treatment, only 3 out of 35 women showed a significant correlation between their urinary and vaginal microbiota composition. CONCLUSIONS: Urethra and bladder thus harbor microbial communities distinct from the vagina. The high abundance of BV related species in the urine of both men and women suggests that urine may act as a reservoir of pathogens and contribute to recurrence. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02687789. PMID- 28807018 TI - The neglected burden of snakebites in Cameroon: a review of the epidemiology, management and public health challenges. AB - OBJECTIVES: Snakebite is an underestimated medical and surgical emergency in developing countries responsible for a high disease burden. Optimal management of snake envenomation in these resource-limited settings is precluded by several public health challenges. In this review, we discuss the disease burden of snakebites in Cameroon and the public health challenges of its management in view of making recommendations essential for policy-making. MEDLINE, African Journals Online and Google Scholar were searched from January 1990 to February 2017 for studies addressing snakebite in Cameroon. Our search extended to include grey literature from book chapters, conference proceedings, theses and documents from organizations. RESULTS: Our results suggest that snakebites pose a significant health and economic burden in Cameroon. A composite of factors contributes to the challenge of managing snakebites in Cameroon and include: inadequate disease surveillance; poor health-seeking behaviours of patients; under-production and scarcity of anti-venom serum and the relatively high cost of anti-venom serum. There is an urgent need to revamp the current health policies through health education, promotion and building of sustainable health systems. Disease surveillance and management can be improved by providing refresher courses for healthcare providers and subsidization of the prices of anti-venom serum in pharmacies in the country. PMID- 28807019 TI - Barriers and facilitators to the implementation of antenatal syphilis screening and treatment for the prevention of congenital syphilis in the Democratic Republic of Congo and Zambia: results of qualitative formative research. AB - BACKGROUND: The impact of untreated syphilis during pregnancy on neonatal health remains a major public health threat worldwide. Given the high prevalence of syphilis during pregnancy in Zambia and Democratic Republic of Congo (DRC), the Preventive Congenital Syphilis Trial (PCS Trial), a cluster randomized trial, was proposed to increase same-day screening and treatment of syphilis during antenatal care visits. To design an accepted and feasible intervention, we conducted a qualitative formative research. Our objective was to identify context-specific barriers and facilitators to the implementation of antenatal screening and treatment during pregnancy. METHODS: Qualitative research included in-depth semi-structured interviews with clinic administrators, group interviews with health care providers, and focus groups with pregnant women in primary care clinics (PCCs) in Kinshasa (DRC) and Lusaka (Zambia). RESULTS: A total of 112 individuals participated in the interviews and focus groups. Barriers for the implementation of syphilis testing and treatment were identified at the a) system level: fragmentation of the health system, existence of ANC guidelines in conflict with proposed intervention, poor accessibility of clinics (geographical and functional), staff and product shortages at the PCCs; b) healthcare providers' level: lack of knowledge and training about evolving best practices, reservations regarding same-day screening and treatment; c) Pregnant women level: late enrollment in ANC, lack of knowledge about consequences and treatment of syphilis, and stigma. Based on these results, we developed recommendations for the design of the PCS Trial intervention. CONCLUSION: This research allowed us to identify barriers and facilitators to improve the feasibility and acceptability of a behavioral intervention. Formative research is a critical step in designing appropriate and effective interventions by closing the "know-do gap". PMID- 28807020 TI - Feasibility study of strengthening the public-private partnership for tuberculosis case detection in Bandung City, Indonesia. AB - OBJECTIVE: Private practitioner's (PPs) collaboration for detection, diagnosis and treatment of tuberculosis (TB) is recommended by the World Health Organization and encouraged by the Indonesian National TB control programme. TB case management by PPs, however, are mostly not in line with current guidelines. Therefore, we developed an intervention package for PPs comprising of TB training, implementation of a mobile phone application for notification of TB cases and a 6-month regular follow-up with PPs. This study aimed to evaluate the feasibility of the intervention package to increase TB case detection and notification rates among PPs in five community health centre areas in Bandung City, Indonesia. RESULTS: A total of 87 PPs were registered within the study area of whom 17 attended the training and 12 had the mobile phone application successfully installed. The remaining five PPs had phones that did not support the application. During the follow-up period, five PPs registered patients with TB symptoms and cases into the application. A total of 36 patients with TB symptoms were identified and 17 were confirmed TB positive. PMID- 28807021 TI - Serological and morphological prognostic factors in patients with interstitial pneumonia with autoimmune features. AB - BACKGROUND: To identify the prognostic factors for survival in patients with interstitial pneumonia with autoimmune features (IPAF) who meet the serological domain of the IPAF criteria. METHODS: We retrospectively analysed 99 IPAF patients who met the serological domain and were hospitalised at the Respiratory Medicine Unit of Kurashiki Central Hospital from 1999 to 2015. The high resolution computed tomography findings were usual interstitial pneumonia (UIP; n = 1), non-specific interstitial pneumonia (NSIP; n = 63), NSIP with organizing pneumonia (OP) overlap (n = 15), and OP (n = 20). One patient who had radiological UIP pattern, and met the serological and clinical domains was excluded. The clinical characteristics, radiological findings, administered therapy, and prognosis of the remaining 98 IPAF patients who met the serological and morphological domains were analysed. RESULTS: The median age of the 98 IPAF patients was 68 years, and 41 (41.8%) of them were men. Twelve (12.2%) of the 98 IPAF patients developed other characteristics and were diagnosed with connective tissue disease (CTD) later during the median follow-up of 4.5 years. Univariate Cox analysis revealed systemic sclerosis (SSc)-specific and SSc-associated antibodies (ANA nucleolar pattern, ANA centromere pattern, anti-ribonucleoprotein and anti-Scl-70) positive IPAF, radiological NSIP pattern, bronchoalveolar lavage fluid lymphocytes >15%, and age as significant prognostic factors for survival. Multivariate Cox analysis revealed radiological NSIP pattern (hazard ratio [HR], 4.48; 95% confidence interval [CI], 1.28-15.77, p = 0.02) and age (HR, 1.07; 95% CI, 1.02-1.11, p = 0.01) were significantly associated with worse survival. CONCLUSIONS: We confirmed that radiological NSIP pattern and age are poor prognostic factors for the survival of IPAF patients. This study suggested that the autoantibodies that are highly specific for certain connective tissue diseases might be less important for the prognosis of IPAF compared with the radiological-pathological patterns. The relatively high proportion of IPAF patients who developed CTD later suggests the importance of careful observation for evolution to CTD in IPAF. PMID- 28807022 TI - Ethical issues of informed consent in malaria research proposals submitted to a research ethics committee in Thailand: a retrospective document review. AB - BACKGROUND: The informed-consent process should be one of meaningful information exchange between researchers and study participants. One of the responsibilities of research ethics committees is to oversee appropriate informed consent. The committee must consider various matters before deciding whether the process is appropriate, including the adequacy and completeness of the written information provided to study participants, and the process of obtaining informed consent. This study aimed to identify, quantitatively and qualitatively, consent-related issues in different types of malaria proposals submitted to the Faculty of Tropical Medicine, Ethics Committee. METHODS: This study reviewed proposal documentation submitted to two panels of the Ethics Committee of the Faculty of Tropical Medicine, Mahidol University, from 2011 to 2015. The documentation included proposals, notifications to researchers of review outcomes and ethical issues of concern to committee members. Each element of the informed-consent process was identified and analyzed by study classification, design, and specimen use, including whether the study involved a vulnerable population. Summative content analysis was used to analyze patterns of common issues raised in reviews. RESULTS: Of the 112 proposals reviewed, 63 required an informed consent process. All researchers proposed communicating with their study participants; however, about two-thirds needed to improve their explanations of study procedures (study activities and specimen/data-collection process) to participants. About 40% of the proposals attracted comments on informed-consent process elements--risk and discomfort, vulnerable status, and compensation. Studies that planned to collect or use new/linked specimens raised more issues around informed consent than studies using linked data/records. Studies that involved vulnerable populations raised more issues than those that did not. The committee usually asked researchers to clarify, elaborate, revise, or paraphrase the consent process elements that were considered to involve inadequate information exchange between researcher and study participant. CONCLUSIONS: This study aimed to describe lessons for malaria researchers about common informed-consent process issues in different types of malaria proposals. The information and analysis of informed consent elements should assist the preparation of malaria-research proposals. PMID- 28807023 TI - Local measles vaccination gaps in Germany and the role of vaccination providers. AB - BACKGROUND: Measles elimination in Europe is an urgent public health goal, yet despite the efforts of its member states, vaccination gaps and outbreaks occur. This study explores local vaccination heterogeneity in kindergartens and municipalities of a German county. METHODS: Data on children from mandatory school enrolment examinations in 2014/15 in Reutlingen county were used. Children with unknown vaccination status were either removed from the analysis (best case) or assumed to be unvaccinated (worst case). Vaccination data were translated into expected outbreak probabilities. Physicians and kindergartens with statistically outstanding numbers of under-vaccinated children were identified. RESULTS: A total of 170 (7.1%) of 2388 children did not provide a vaccination certificate; 88.3% (worst case) or 95.1% (best case) were vaccinated at least once against measles. Based on the worst case vaccination coverage, <10% of municipalities and <20% of kindergartens were sufficiently vaccinated to be protected against outbreaks. Excluding children without a vaccination certificate (best case) leads to over-optimistic views: the overall outbreak probability in case of a measles introduction lies between 39.5% (best case) and 73.0% (worst case). Four paediatricians were identified who accounted for 41 of 109 unvaccinated children and for 47 of 138 incomplete vaccinations; GPs showed significantly higher rates of missing vaccination certificates and unvaccinated or under-vaccinated children than paediatricians. CONCLUSIONS: Missing vaccination certificates pose a severe problem regarding the interpretability of vaccination data. Although the coverage for at least one measles vaccination is higher in the studied county than in most South German counties and higher than the European average, many severe and potentially dangerous vaccination gaps occur locally. If other federal German states and EU countries show similar vaccination variability, measles elimination may not succeed in Europe. PMID- 28807024 TI - Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of bladder carcinoma. AB - The standard of care for most patients with non-muscle-invasive bladder cancer (NMIBC) is immunotherapy with intravesical Bacillus Calmette-Guerin (BCG), which activates the immune system to recognize and destroy malignant cells and has demonstrated durable clinical benefit. Urologic best-practice guidelines and consensus reports have been developed and strengthened based on data on the timing, dose, and duration of therapy from randomized clinical trials, as well as by critical evaluation of criteria for progression. However, these reports have not penetrated the community, and many patients do not receive appropriate therapy. Additionally, several immune checkpoint inhibitors have recently been approved for treatment of metastatic disease. The approval of immune checkpoint blockade for patients with platinum-resistant or -ineligible metastatic bladder cancer has led to considerations of expanded use for both advanced and, potentially, localized disease. To address these issues and others surrounding the appropriate use of immunotherapy for the treatment of bladder cancer, the Society for Immunotherapy of Cancer (SITC) convened a Task Force of experts, including physicians, patient advocates, and nurses, to address issues related to patient selection, toxicity management, clinical endpoints, as well as the combination and sequencing of therapies. Following the standard approach established by the Society for other cancers, a systematic literature review and analysis of data, combined with consensus voting was used to generate guidelines. Here, we provide a consensus statement for the use of immunotherapy in patients with bladder cancer, with plans to update these recommendations as the field progresses. PMID- 28807025 TI - Changes in tibialis anterior architecture affect the amplitude of surface electromyograms. AB - BACKGROUND: Variations in the amplitude of surface electromyograms (EMGs) are typically considered to advance inferences on the timing and degree of muscle activation in different circumstances. Surface EMGs are however affected by factors other than the muscle neural drive. In this study, we use electrical stimulation to investigate whether architectural changes in tibialis anterior (TA), a key muscle for balance and gait, affect the amplitude of surface EMGs. METHODS: Current pulses (500 MUs; 2 pps) were applied to the fibular nerve of ten participants, with the ankle at neutral, full dorsi and full plantar flexion positions. Ultrasound images were collected to quantify changes in TA architecture with changes in foot position. The peak-to-peak amplitude of differential M waves, detected with a grid of surface electrodes (16 * 4 electrodes; 10 mm inter-electrode distance), was considered to assess the effect of changes in TA architecture on the surface recordings. RESULTS: On average, both TA pennation angle and width increased by respectively 7 deg. and 9 mm when the foot moved from plantar to dorsiflexion (P < 0.02). M-wave amplitudes changed significantly with ankle position. M waves elicited in dorsiflexion and neutral positions were ~25% greater than those obtained during plantar flexion, regardless of where they were detected in the grid (P < 0.001). This figure increased to ~50% when considering bipolar M waves. CONCLUSIONS: Findings reported here indicate the changes in EMG amplitude observed during dynamic contractions, especially when changes in TA architecture are expected (e.g., during gait), may not be exclusively conceived as variations in TA activation. PMID- 28807026 TI - Circulating microRNAs in malaria infection: bench to bedside. AB - Severe malaria has a poor prognosis with a morbidity rate of 80% in tropical areas. The early parasite detection is one of the effective means to prevent severe malaria of which specific treatment strategies are limited. Many clinical characteristics and laboratory testings have been used for the early diagnosis and prediction of severe disease. However, a few of these factors could be applied to clinical practice. MicroRNAs (miRNAs) were demonstrated as useful biomarkers in many diseases such as malignant diseases and cardiovascular diseases. Recently it was found that plasma miR-451 and miR-16 were downregulated in malaria infection at parasitic stages or with multi-organ failure involvement. MiR-125b, -27a, -23a, -150, 17-92 and -24 are deregulated in malaria patients with multiple organ failures. Here, the current findings of miRNAs were reviewed in relation to clinical severity of malaria infection and emphasized that miRNAs are potential biomarkers for severe malaria infection. PMID- 28807027 TI - Health-related quality of life in the Brazilian Amazon: a population-based cross sectional study. AB - BACKGROUND: To analyze perceptions of health-related quality of life and associated factors in populations from the Manaus Metropolitan Region. METHODS: We conducted a population-based cross-sectional study from May to August 2015. Adults aged 18 years and older were selected using probabilistic three-phase cluster sampling and stratified by sex and age, based on official estimates. Quality of life data were collected using the European Quality of Life 5 Dimensions 3-Levels (EQ-5D-3L) along with socioeconomic, demographic, and health perception data. Utility scores were calculated using the Brazilian version of the EQ-5D-3L. Descriptive statistics were derived, and a multivariate Tobit regression model with correction for complex sampling was performed to identify the variables that influence utility levels. RESULTS: A total of 4001 participants were included. The average utility score was 0.886 (95% confidence interval [CI]: 0.881-0.890) with significant differences according to living area (the capital (0.882 +/- 0.144) or inner cities (0.908 +/- 0.122; p < 0.001)). The dimension for which the highest proportion of people reported moderate to severe problems was pain/discomfort (39%), followed by anxiety/depression (18%). Men had a higher quality of life than women (beta = 0.041, p < 0.001). Not working was a factor that increased quality of life compared with being formally employed (beta = 0.031, p = 0.037). The poorest people had a lower quality of life than the richest people (beta = -0.118, p < 0.001). Better health perceptions increased utility scores (p < 0.001), while being separated decreased the scores (beta = 0.052, p = 0.001). CONCLUSION: Health-related quality of life in the Manaus Metropolitan Region was high, as expected for the general population, and was higher among individuals who lived in the inner cities, men and those in higher social classes. Gender discrepancies and differences in quality of life between the capital and inner cities should be further investigated. PMID- 28807028 TI - Connectivity, not region-intrinsic properties, predicts regional vulnerability to progressive tau pathology in mouse models of disease. AB - Spatiotemporal tau pathology progression is regarded as highly stereotyped within each type of degenerative condition. For instance, AD has a progression of tau pathology consistently beginning in the entorhinal cortex, the locus coeruleus, and other nearby noradrenergic brainstem nuclei, before spreading to the rest of the limbic system as well as the cingulate and retrosplenial cortices. Proposed explanations for the consistent spatial patterns of tau pathology progression, as well as for why certain regions are selectively vulnerable to exhibiting pathology over the course of disease generally focus on transsynaptic spread proceeding via the brain's anatomic connectivity network in a cell-independent manner or on cell-intrinsic properties that might render some cell populations or regions uniquely vulnerable. We test connectivity based explanations of spatiotemporal tau pathology progression and regional vulnerability against cell intrinsic explanation, using regional gene expression profiles as a proxy. We find that across both exogenously seeded and non-seeded tauopathic mouse models, the connectivity network provides a better explanation than regional gene expression profiles, even when such profiles are limited to specific sets of tau risk-related genes only. Our results suggest that, regardless of the location of pathology initiation, tau pathology progression is well characterized by a model positing entirely cell-type and molecular environment independent transsynaptic spread via the mouse brain's connectivity network. These results further suggest that regional vulnerability to tau pathology is mainly governed by connectivity with regions already exhibiting pathology, rather than by cell-intrinsic factors. PMID- 28807029 TI - Development of a new Rasch-based scoring algorithm for the National Eye Institute Visual Functioning Questionnaire to improve its interpretability. AB - BACKGROUND: The NEI VFQ-25 has undergone psychometric evaluation in patients with varying ocular conditions and the general population. However, important limitations which may affect the interpretation of clinical trial results have been previously identified, such as concerns with reliability and validity. The purpose of this study was to evaluate the National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25) and make recommendations for a revised scoring structure, with a view to improving its psychometric performance and interpretability. METHODS: Rasch Measurement Theory analyses were conducted in two stages using pooled baseline NEI VFQ-25 data for 2487 participants with retinal diseases enrolled in six clinical trials. In stage 1, we examined: scale to-sample targeting; thresholds for item response options; item fit statistics; stability; local dependence; and reliability. In stage 2, a post-hoc revision of the scoring structure (VFQ-28R) was created and psychometrically re-evaluated. RESULTS: In stage 1, we found that the NEI VFQ-25 was mis-targeted to the sample, and had disordered response thresholds (15/25 items) and mis-fitting items (8/25 items). However, items appeared to be stable (differential item functioning for three items), have minimal item dependency (one pair of items) and good reliability (person-separation index, 0.93). In stage 2, the modified Rasch scored NEI VFQ-28-R was assessed. It comprised two broad domains: Activity Limitation (19 items) and Socio-Emotional Functioning (nine items). The NEI VFQ 28-R demonstrated improved performance with fewer disordered response thresholds (no items), less item misfit (three items) and improved population targeting (reduced ceiling effect) compared with the NEI VFQ-25. CONCLUSIONS: Compared with the original version, the proposed NEI VFQ-28-R, with Rasch-based scoring and a two-domain structure, appears to offer improved psychometric performance and interpretability of the vision-related quality of life scale for the population analysed. PMID- 28807030 TI - Combined effect of metformin with ascorbic acid versus acetyl salicylic acid on diabetes-related cardiovascular complication; a 12-month single blind multicenter randomized control trial. AB - BACKGROUND: We aimed to investigate the efficacy of ascorbic acid and acetylsalicylic acid among type II diabetes mellitus patients using metformin (only) for diabetes management therapy. METHOD: A 12-month single blinded multicenter randomized control trial was designed to investigate the measured variables [Glycated Hemoglobin (HbA1c), Renal function, Albumin Creatinine Ratio (ACR) etc.]. The trial was randomized into 2 experimental parallel arms (ascorbic acid vs acetylsalicylic acid) were blinded with study supplements in combination with metformin and findings were compared to control arm with metformin alone and blinded with placebo. Withdrawal criteria was defined to maintain the equity and balance in the participants in the whole trial. FINDING: Patients with metformin and ascorbic acid (parallel arm I) was twice more likely to reduce HbA1c than metformin alone (control arm) in a year (OR 2.31 (95% CI 1.87-4.42) p < 0.001). Also Parallel arm I was ten times more likely to reduced risk factors contributing to long-term diabetes complications than participants of arm II in a year (OR 10.38 (95% CI 6.91-15.77) p < 0.001). In contrast, parallel arm II patients were seven times more effective to reduce the risk of expected CVD development in 10 years than arm I (OR 7.54 (95% CI 3.76-10.32) p < 0.001). CONCLUSIONS: The trial concluded that ascorbic acid with metformin is more effective against reducing risks for diabetes related long-term complications (including ACR). TRIAL details Registration No: NTR-6100, Registry Name: Netherlands Trial Registry, URL: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6100 , Date of Registration: 20th October, 2016, Date of first Enrollment: 1 November, 2015. PMID- 28807031 TI - Inflammation and pro-resolution inflammation after hepatobiliary surgery. AB - BACKGROUND: The magnitude of the perioperative inflammatory response plays a role in surgical outcomes. However, few studies have explored the mechanisms of the resolution of inflammation in the context of surgery. Here, we described the temporal kinetics of interleukin-6, cortisol, lipoxin A4, and resolvin D in patients who underwent oncologic liver resections. METHODS: All patients gave written informed consent. Demographic and perioperative surgical data were collected, along with blood samples, before surgery and on the mornings of postoperative days 1, 3, and 5. Interleukin-6, cortisol, lipoxin-A4, and resolvin D were measured in plasma. A P value < 0.05 was considered statistically significant. RESULTS: Forty-one patients were included in the study. Liver resection for colorectal metastatic disease was the most commonly performed surgery. The plasma concentrations of interleukin-6 were highest on day 1 after surgery and remained higher than the baseline up to postoperative day 1. Postoperative complications occurred in 14 (24%) patients. Cortisol concentrations spiked on postoperative day 1. The concentrations of lipoxin A4 and resolvin D were lowest on day 1 after surgery. CONCLUSIONS: The inflammatory response associated with hepatobiliary surgery is associated with low circulating concentrations of lipoxin A4 and resolvin D that mirror, in an opposite manner, the kinetics of interleukin 6 and cortisol. TRIAL REGISTRATION: NCT01438476. PMID- 28807032 TI - Liquid chromatography mass spectrometry-based profiling of phosphatidylcholine and phosphatidylethanolamine in the plasma and liver of acetaminophen-induced liver injured mice. AB - BACKGROUND: Acetaminophen (APAP) overdose is one of the most common causes of acute liver failure in many countries. The aim of the study was to describe the profiling of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) in the plasma and liver of Acetaminophen -induced liver injured mice. METHODS: A time course study was carried out using C57BL/6 mice after intraperitoneal administration of 300 mg/kg Acetaminophen 1 h, 3 h, 6 h, 12 h and 24 h. A high throughput liquid chromatography mass spectrometry (LC-MS) lipidomic method was utilized to detect phosphatidylcholine and phosphatidylethanolamine species in the plasma and liver. The expressions of phosphatidylcholine and phosphatidylethanolamine metabolism related genes in liver were detected by quantitative Reverse transcription polymerase chain reaction (qRT-PCR) and Western-blot. RESULTS: Following Acetaminophen treatment, the content of many PC and PE species in plasma increased from 1 h time point, peaked at 3 h or 6 h, and tended to return to baseline at 24 h time point. The relative contents of almost all PC species in liver decreased from 1 h, appeared to be lowest at 6 h, and then return to normality at 24 h, which might be partly explained by the suppression of phospholipases mRNA expressions and the induction of choline kinase (Chka) expression. Inconsistent with PC profile, the relative contents of many PE species in liver increased upon Acetaminophen treatment, which might be caused by the down-regulation of phosphatidylethanolamine N-methyltransferase (Pemt). CONCLUSIONS: Acetaminophen overdose induced dramatic change of many PC and PE species in plasma and liver, which might be caused by damaging hepatocytes and interfering the phospholipid metabolism in Acetaminophen -injured liver. PMID- 28807033 TI - Sponsorship bias and quality of randomised controlled trials in veterinary medicine. AB - BACKGROUND: Randomised controlled trials (RCTs) are considered the gold standard form of evidence for assessing treatment efficacy, but many factors can influence their reliability including methodological quality, reporting quality and funding source. The aim of this study was to examine the relationship between funding source and positive outcome reporting in veterinary RCTs published in 2011 and to assess the risk of bias in the RCTs identified. METHODS: A structured search of PubMed was used to identify feline, canine, equine, bovine and ovine clinical trials examining the efficacy of pharmaceutical interventions published in 2011. Funding source and outcomes were extracted from each RCT and an assessment of risk of bias made using the Cochrane risk of bias tool. RESULTS: Literature searches returned 972 papers, with 86 papers (comprising 126 individual RCTs) included in the analysis. There was found to be a significantly higher proportion of positive outcomes reported in the pharmaceutical funding group (P) compared to the non-pharmaceutical (NP) and 'no funding source stated' (NF) groups (P = 56.9%, NP = 34.9%, NF = 29.1%, p < 0.05). A high proportion of trials had an unclear risk of bias across the five criteria examined. CONCLUSIONS: We found evidence that veterinary RCTs were more likely to report positive outcomes if they have pharmaceutical industry funding or involvement. Consistently poor reporting of trials, including non-identification of funding source, was found which hinders the use of the available evidence. PMID- 28807034 TI - Exosomes from embryonic mesenchymal stem cells alleviate osteoarthritis through balancing synthesis and degradation of cartilage extracellular matrix. AB - BACKGROUND: Mesenchymal stem cell therapy for osteoarthritis (OA) has been widely investigated, but the mechanisms are still unclear. Exosomes that serve as carriers of genetic information have been implicated in many diseases and are known to participate in many physiological processes. Here, we investigate the therapeutic potential of exosomes from human embryonic stem cell-induced mesenchymal stem cells (ESC-MSCs) in alleviating osteoarthritis (OA). METHODS: Exosomes were harvested from conditioned culture media of ESC-MSCs by a sequential centrifugation process. Primary mouse chondrocytes treated with interleukin 1 beta (IL-1beta) were used as an in vitro model to evaluate the effects of the conditioned medium with or without exosomes and titrated doses of isolated exosomes for 48 hours, prior to immunocytochemistry or western blot analysis. Destabilization of the medial meniscus (DMM) surgery was performed on the knee joints of C57BL/6 J mice as an OA model. This was followed by intra articular injection of either ESC-MSCs or their exosomes. Cartilage destruction and matrix degradation were evaluated with histological staining and OARSI scores at the post-surgery 8 weeks. RESULTS: We found that intra-articular injection of ESC-MSCs alleviated cartilage destruction and matrix degradation in the DMM model. Further in vitro studies illustrated that this effect was exerted through ESC-MSC-derived exosomes. These exosomes maintained the chondrocyte phenotype by increasing collagen type II synthesis and decreasing ADAMTS5 expression in the presence of IL-1beta. Immunocytochemistry revealed colocalization of the exosomes and collagen type II-positive chondrocytes. Subsequent intra-articular injection of exosomes derived from ESC-MSCs successfully impeded cartilage destruction in the DMM model. CONCLUSIONS: The exosomes from ESC-MSCs exert a beneficial therapeutic effect on OA by balancing the synthesis and degradation of chondrocyte extracellular matrix (ECM), which in turn provides a new target for OA drug and drug-delivery system development. PMID- 28807035 TI - Artemisinin combination therapy mass drug administration in a setting of low malaria endemicity: programmatic coverage and adherence during an observational study in Zanzibar. AB - BACKGROUND: Mass drug administration (MDA) appears to be effective in reducing the risk of malaria parasitaemia. This study reports on programmatic coverage and compliance of MDA using artemisinin-based combination therapy (ACT) in four shehias (smallest administration unit) that had been identified as hotspots through Zanzibar's malaria case notification surveillance system. METHODS: Mass drug administration was done in four shehias selected on the basis of: being an established malaria hot spot; having had mass screening and treatment (MSaT) 2-6 weeks previously; and exceeding the epidemic alert threshold of 5 cases within a week even after MSaT. Communities were sensitized and MDA was conducted using a house-to-house approach. All household members, except pregnant women and children aged less than 2 months, were provided with ACT medicine. Two weeks after the MDA campaign, a survey was undertaken to investigate completion of ACT doses. RESULTS: A total of 8816 [97.1% of eligible; 95% confidence interval (CI) 96.8-97.5] people received ACT. During post MDA surveys, 2009 people were interviewed: 90.2% reported having completed MDA doses; 1.9% started treatment but did not complete dosage; 4.7% did not take treatment; 2.0% were absent during MDA and 1.2% were ineligible (i.e. infants <2 months and pregnant women). Main reasons for failure to complete treatment were experience of side-effects and forgetting to take subsequent doses. Failure to take treatment was mainly due to fear of side-effects, reluctance due to lack of malaria symptoms and caregivers forgetting to give medication to children. CONCLUSION: Mass drug administration for malaria was well accepted by communities at high risk of malaria in Zanzibar, with high participation and completion rates. Further work to investigate the potential of MDA in accelerating Zanzibar's efforts towards malaria elimination should be pursued. PMID- 28807036 TI - T-Time: A data repository of T cell and calcium release-activated calcium channel activation imagery. AB - BACKGROUND: A fundamental understanding of live-cell dynamics is necessary in order to advance scientific techniques and personalized medicine. For this understanding to be possible, image processing techniques, probes, tracking algorithms and many other methodologies must be improved. Currently there are no large open-source datasets containing live-cell imaging to act as a standard for the community. As a result, researchers cannot evaluate their methodologies on an independent benchmark or leverage such a dataset to formulate scientific questions. FINDINGS: Here we present T-Time, the largest free and publicly available data set of T cell phase contrast imagery designed with the intention of furthering live-cell dynamics research. T-Time consists of over 40 GB of imagery data, and includes annotations derived from these images using a custom T cell identification and tracking algorithm. The data set contains 71 time-lapse sequences containing T cell movement and calcium release activated calcium channel activation, along with 50 time-lapse sequences of T cell activation and T reg interactions. The database includes a user-friendly web interface, summary information on the time-lapse images, and a mechanism for users to download tailored image datasets for their own research. T-Time is freely available on the web at http://ttime.mlatlab.org . CONCLUSIONS: T-Time is a novel data set of T cell images and associated metadata. It allows users to study T cell interaction and activation. PMID- 28807037 TI - Selepressin, a novel selective vasopressin V1A agonist, is an effective substitute for norepinephrine in a phase IIa randomized, placebo-controlled trial in septic shock patients. AB - BACKGROUND: Vasopressin is widely used for vasopressor support in septic shock patients, but experimental evidence suggests that selective V1A agonists are superior. The initial pharmacodynamic effects, pharmacokinetics, and safety of selepressin, a novel V1A-selective vasopressin analogue, was examined in a phase IIa trial in septic shock patients. METHODS: This was a randomized, double-blind, placebo-controlled multicenter trial in 53 patients in early septic shock (aged >=18 years, fluid resuscitation, requiring vasopressor support) who received selepressin 1.25 ng/kg/minute (n = 10), 2.5 ng/kg/minute (n = 19), 3.75 ng/kg/minute (n = 2), or placebo (n = 21) until shock resolution or a maximum of 7 days. If mean arterial pressure (MAP) >=65 mmHg was not maintained, open-label norepinephrine was added. Co-primary endpoints were maintenance of MAP >60 mmHg without norepinephrine, norepinephrine dose, and proportion of patients maintaining MAP >60 mmHg with or without norepinephrine over 7 days. Secondary endpoints included cumulative fluid balance, organ dysfunction, pharmacokinetics, and safety. RESULTS: A higher proportion of the patients receiving 2.5 ng/kg/minute selepressin maintained MAP >60 mmHg without norepinephrine (about 50% and 70% at 12 and 24 h, respectively) vs. 1.25 ng/kg/minute selepressin and placebo (p < 0.01). The 7-day cumulative doses of norepinephrine were 761, 659, and 249 MUg/kg (placebo 1.25 ng/kg/minute and 2.5 ng/kg/minute, respectively; 2.5 ng/kg/minute vs. placebo; p < 0.01). Norepinephrine infusion was weaned more rapidly in selepressin 2.5 ng/kg/minute vs. placebo (0.04 vs. 0.18 MUg/kg/minute at 24 h, p < 0.001), successfully maintaining target MAP and reducing norepinephrine dose vs. placebo (first 24 h, p < 0.001). Cumulative net fluid balance was lower from day 5 onward in the selepressin 2.5 ng/kg/minute group vs. placebo (p < 0.05). The selepressin 2.5 ng/kg/minute group had a greater proportion of days alive and free of ventilation vs. placebo (p < 0.02). Selepressin (2.5 ng/kg/minute) was well tolerated, with a similar frequency of treatment-emergent adverse events for selepressin 2.5 ng/kg/minute and placebo. Two patients were infused at 3.75 ng/kg/minute, one of whom had the study drug infusion discontinued for possible safety reasons, with subsequent discontinuation of this dose group. CONCLUSIONS: In septic shock patients, selepressin 2.5 ng/kg/minute was able to rapidly replace norepinephrine while maintaining adequate MAP, and it may improve fluid balance and shorten the time of mechanical ventilation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01000649 . Registered on September 30, 2009. PMID- 28807038 TI - NLR, MLP, SVM, and LDA: a comparative analysis on EMG data from people with trans radial amputation. AB - BACKGROUND: Currently, the typically adopted hand prosthesis surface electromyography (sEMG) control strategies do not provide the users with a natural control feeling and do not exploit all the potential of commercially available multi-fingered hand prostheses. Pattern recognition and machine learning techniques applied to sEMG can be effective for a natural control based on the residual muscles contraction of amputated people corresponding to phantom limb movements. As the researches has reached an advanced grade accuracy, these algorithms have been proved and the embedding is necessary for the realization of prosthetic devices. The aim of this work is to provide engineering tools and indications on how to choose the most suitable classifier, and its specific internal settings for an embedded control of multigrip hand prostheses. METHODS: By means of an innovative statistical analysis, we compare 4 different classifiers: Nonlinear Logistic Regression, Multi-Layer Perceptron, Support Vector Machine and Linear Discriminant Analysis, which was considered as ground truth. Experimental tests have been performed on sEMG data collected from 30 people with trans-radial amputation, in which the algorithms were evaluated for both performance and computational burden, then the statistical analysis has been based on the Wilcoxon Signed-Rank test and statistical significance was considered at p < 0.05. RESULTS: The comparative analysis among NLR, MLP and SVM shows that, for either classification performance and for the number of classification parameters, SVM attains the highest values followed by MLP, and then by NLR. However, using as unique constraint to evaluate the maximum acceptable complexity of each classifier one of the typically available memory of a high performance microcontroller, the comparison pointed out that for people with trans-radial amputation the algorithm that produces the best compromise is NLR closely followed by MLP. This result was also confirmed by the comparison with LDA with time domain features, which provided not significant differences of performance and computational burden between NLR and LDA. CONCLUSIONS: The proposed analysis would provide innovative engineering tools and indications on how to choose the most suitable classifier based on the application and the desired results for prostheses control. PMID- 28807039 TI - The impact of the recent AAP changes in palivizumab authorization on RSV-induced bronchiolitis severity and incidence. AB - Following the most recent modification by the American Academy of Pediatrics, based on American studies on RSV epidemiology, the Italian Drug Agency (AIFA) decided to limit the total financial coverage of the palivizumab prescription by the National Health Service only to the < 29 wGA group and age <= 12 months at the beginning of the RSV epidemic season. However, the vulnerability of otherwise healthy premature infants >= 29 wGA has been demonstrated in Italian analyses. We retrospectively reviewed records from children <= 1 years of age admitted for RSV induced ALRI at the Gaslini Hospital, over three consecutive RSV epidemic seasons (RES) (2014-2017). We found that the prescription limitation on RSV immunoprophylaxis in preterms was associated in the 2016-2017 RES with: a) a high proportion of admission for the < 36 wGA infants, the great majority born at 33- < 36 wGA and a chronological age of < 6 months; b) a high proportion of preterms treated with high flow nasal cannula ventilation. These results strongly point to a need to reevaluate the role of palivizumab prophylaxis in the >= 29 wGA subpopulation when specific risk factors are present. PMID- 28807040 TI - Management of upper gastrointestinal bleeding in emergency departments, from bleeding symptoms to diagnosis: a prospective, multicenter, observational study. AB - BACKGROUND: Upper gastrointestinal bleeding (UGB) is common in emergency departments (EDs) and can be caused by many eso-gastro-duodenal lesions. Most available epidemiological data and data on the management of UGB comes from specialized departments (intensive care units or gastroenterology departments), but little is known from the ED perspective. We aimed to determine the distribution of symptoms revealing UGB in EDs and the hemorrhagic lesions identified by endoscopy. We also describe the characteristics of patients consulting for UGB, UGB management in the ED and patients outcomes. METHOD: This was a prospective, observational, multicenter study covering 4 consecutive days in November 2013. Participating EDs were part of the Initiatives de Recherche aux Urgences network coordinated by the French Society of Emergency Medicine. All patients with suspected UGB in these EDs were included. RESULTS: In total, 110 EDs participated, including 194 patients with suspected UGB (median age 66 years [Q1-Q3: 51-81]). Overall, 104 patients (54%) had hematemesis and 75 (39%) melena. Endoscopy revealed lesions in 121 patients, mainly gastroduodenal ulcer or ulcerations (41%) or bleeding lesions due to portal hypertension (20%). The final diagnosis of UGB was reversed by endoscopy in only 3% of cases. Overall, 67 patients (35%) had at least one severity sign. Twenty-one patients died (11%); 40 (21%) were hospitalized in intensive care units and 126 (65%) in medicine departments; 28 (14%) were outpatients. Mortality was higher among patients with clinical and biological severity signs. CONCLUSION: Most of the UGB cases in EDs are revealed by hematemesis. The emergency physician diagnosis of UGB is rarely challenged by the endoscopic findings. PMID- 28807041 TI - The feasibility and RE-AIM evaluation of the TAME health pilot study. AB - BACKGROUND: Conducting 5 A's counseling in clinic and utilizing technology-based resources are recommended to promote physical activity but little is known about how to implement such an intervention. This investigation aimed to determine the feasibility and acceptability, using the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework, of a pragmatic, primary care-based intervention that incorporated 5 A's counseling and self-control through an activity monitor. METHODS: Primary care patients (n = 40) 55-74 years of age were recruited and randomized to receive a pedometer or an electronic activity monitor (EAM), Jawbone UP24, to monitor activity for 12 weeks. Participants were also invited to a focus group after completing the intervention. Stakeholders (n = 36) were recruited to provide feedback. RESULTS: The intervention recruitment rate was 24.7%. The attrition rate was 20% with a significantly higher rate for the pedometer group (p = 0.02). The EAM group increased their minutes of physical activity by 11.1 min/day while the pedometer maintained their activity (0.2 min/day), with no significant group difference. EAM participants liked using their monitor and would continue wearing it while the pedometer group was neutral to these statements (p < 0.05). Over the 12 weeks there were 490 comments and 1094 "likes" given to study peers in the corresponding application for the UP24 monitor. Some EAM participants enjoyed the social interaction feature while others were uncomfortable talking to strangers. Participants stated they would want counseling from a counselor and not their physician or a nurse. Other notable comments included incorporating multiple health behaviors, more in-person counseling with a counselor, and having a funding source for sustainability. CONCLUSIONS: Overall, the study was well-received but the results raise a number of considerations. Practitioners, counselors, and researchers should consider the following before implementing a similar intervention: 1) utilize PA counselors, 2) target multiple health behaviors, 3) form a social support group, 4) identify a funding source for sustainability, and 5) be mindful of concerns with technology. TRIAL REGISTRATION: clinicaltrials.gov- NCT02554435 . Registered 24 August 2015. PMID- 28807042 TI - Incidence, prevalence, and management of MRSA bacteremia across patient populations-a review of recent developments in MRSA management and treatment. AB - Methicillin-resistant Staphylococcus aureus (MRSA) infection is still a major global healthcare problem. Of concern is S. aureus bacteremia, which exhibits high rates of morbidity and mortality and can cause metastatic or complicated infections such as infective endocarditis or sepsis. MRSA is responsible for most global S. aureus bacteremia cases, and compared with methicillin-sensitive S. aureus, MRSA infection is associated with poorer clinical outcomes. S. aureus virulence is affected by the unique combination of toxin and immune-modulatory gene products, which may differ by geographic location and healthcare- or community-associated acquisition. Management of S. aureus bacteremia involves timely identification of the infecting strain and source of infection, proper choice of antibiotic treatment, and robust prevention strategies. Resistance and nonsusceptibility to first-line antimicrobials combined with a lack of equally effective alternatives complicates MRSA bacteremia treatment. This review describes trends in epidemiology and factors that influence the incidence of MRSA bacteremia. Current and developing diagnostic tools, treatments, and prevention strategies are also discussed. PMID- 28807043 TI - An equine herpesvirus type 1 (EHV-1) vector expressing Rift Valley fever virus (RVFV) Gn and Gc induces neutralizing antibodies in sheep. AB - Rift Valley fever virus (RVFV) is an arthropod-borne bunyavirus that can cause serious and fatal disease in humans and animals. RVFV is a negative-sense RNA virus of the Phlebovirus genus in the Bunyaviridae family. The main envelope RVFV glycoproteins, Gn and Gc, are encoded on the M segment of RVFV and known inducers of protective immunity. In an attempt to develop a safe and efficacious RVF vaccine, we constructed and tested a vectored equine herpesvirus type 1 (EHV-1) vaccine that expresses RVFV Gn and Gc. The Gn and Gc genes were custom synthesized after codon optimization and inserted into EHV-1 strain RacH genome. The rH_Gn-Gc recombinant virus grew in cultured cells with kinetics that were comparable to those of the parental virus and stably expressed Gn and Gc. Upon immunization of sheep, the natural host, neutralizing antibodies against RVFV were elicited by rH_Gn-Gc and protective titers reached to 1:320 at day 49 post immunization but not by parental EHV-1, indicating that EHV-1 is a promising vector alternative in the development of a safe marker RVFV vaccine. PMID- 28807044 TI - MetaMeta: integrating metagenome analysis tools to improve taxonomic profiling. AB - BACKGROUND: Many metagenome analysis tools are presently available to classify sequences and profile environmental samples. In particular, taxonomic profiling and binning methods are commonly used for such tasks. Tools available among these two categories make use of several techniques, e.g., read mapping, k-mer alignment, and composition analysis. Variations on the construction of the corresponding reference sequence databases are also common. In addition, different tools provide good results in different datasets and configurations. All this variation creates a complicated scenario to researchers to decide which methods to use. Installation, configuration and execution can also be difficult especially when dealing with multiple datasets and tools. RESULTS: We propose MetaMeta: a pipeline to execute and integrate results from metagenome analysis tools. MetaMeta provides an easy workflow to run multiple tools with multiple samples, producing a single enhanced output profile for each sample. MetaMeta includes a database generation, pre-processing, execution, and integration steps, allowing easy execution and parallelization. The integration relies on the co occurrence of organisms from different methods as the main feature to improve community profiling while accounting for differences in their databases. CONCLUSIONS: In a controlled case with simulated and real data, we show that the integrated profiles of MetaMeta overcome the best single profile. Using the same input data, it provides more sensitive and reliable results with the presence of each organism being supported by several methods. MetaMeta uses Snakemake and has six pre-configured tools, all available at BioConda channel for easy installation (conda install -c bioconda metameta). The MetaMeta pipeline is open-source and can be downloaded at: https://gitlab.com/rki_bioinformatics . PMID- 28807045 TI - A randomized, multi-center, prospective study comparing best medical treatment versus best medical treatment plus renal artery stenting in patients with hemodynamically relevant atherosclerotic renal artery stenosis (RADAR) - one-year results of a pre-maturely terminated study. AB - BACKGROUND: The indications for conservative "best medical treatment" (BMT) versus additional renal artery stenting are a matter of ongoing debate. The RADAR study aimed to evaluate the impact of percutaneous renal artery stenting on the impaired renal function in patients with hemodynamically significant atherosclerotic renal artery stenosis (RAS). METHODS: RADAR is an international, prospective, randomized (1:1) controlled study comparing BMT alone versus BMT plus renal artery stenting in patients with duplex sonographic hemodynamically relevant RAS. Follow-up assessments were at 2, 6, and 12 months and at 3 years. The primary endpoint was change in estimated glomerular filtration rate (eGFR) at 12 months. RESULTS: Due to slow enrollment, RADAR was terminated early after inclusion of 86 of the scheduled 300 patients (28.7%). Change in eGFR between baseline and 12 months was 4.3 +/- 15.4 ml/min/1.73 m2 (stent group) and 3.0 +/- 14.9 ml/min/1.73 m2 (BMT group), p > 0.999. Clinical event rates were low with a 12-month composite of cardiac death, stroke, myocardial infarction, and hospitalization for congestive heart failure of 2.9% in the stent and 5.3% in the BMT group, p = 0.526, and a 3-year composite of 14.8% and 12.0%, p = 0.982. At 3 years, target vessel (re-)vascularization occurred in one patient (3.0%) in the stent group and in 8 patients (29.4%) in the BMT group. CONCLUSION: In RADAR, outcomes of renal artery stenting were similar to BMT. These results have to be interpreted with the caveat that the study did not reach its statistically based sample size. TRIAL REGISTRATION: Clinicaltrials.gov, NCT00640406. Registered on 17 March 2008. PMID- 28807046 TI - A comprehensive evaluation of the sl1p pipeline for 16S rRNA gene sequencing analysis. AB - BACKGROUND: Advances in next-generation sequencing technologies have allowed for detailed, molecular-based studies of microbial communities such as the human gut, soil, and ocean waters. Sequencing of the 16S rRNA gene, specific to prokaryotes, using universal PCR primers has become a common approach to studying the composition of these microbiota. However, the bioinformatic processing of the resulting millions of DNA sequences can be challenging, and a standardized protocol would aid in reproducible analyses. METHODS: The short-read library 16S rRNA gene sequencing pipeline (sl1p, pronounced "slip") was designed with the purpose of mitigating this lack of reproducibility by combining pre-existing tools into a computational pipeline. This pipeline automates the processing of raw 16S rRNA gene sequencing data to create human-readable tables, graphs, and figures to make the collected data more readily accessible. RESULTS: Data generated from mock communities were compared using eight OTU clustering algorithms, two taxon assignment approaches, and three 16S rRNA gene reference databases. While all of these algorithms and options are available to sl1p users, through testing with human-associated mock communities, AbundantOTU+, the RDP Classifier, and the Greengenes 2011 reference database were chosen as sl1p's defaults based on their ability to best represent the known input communities. CONCLUSIONS: sl1p promotes reproducible research by providing a comprehensive log file, and reduces the computational knowledge needed by the user to process next generation sequencing data. sl1p is freely available at https://bitbucket.org/fwhelan/sl1p . PMID- 28807047 TI - Adverse outcomes associated with opioid prescription for acute low back pain: a systematic review protocol. AB - BACKGROUND: Acute low back pain (ALBP) is the top cause of global disability, demonstrating a significant impact on individuals and society and demanding the need for appropriate management. There is a trend towards an increasing number of opioid prescriptions for ALBP despite the lack of investigation for its various short- and long-term outcomes. The objective of this review is to examine adverse outcomes associated with opioid use for ALBP. METHODS/DESIGN: Using a search strategy, the search will be conducted using the following electronic databases: PubMed/MEDLINE, EMBASE, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, Cochrane Library, the National Institutes for Health Clinical Trials Registry and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP). We will include randomized clinical trials and observational studies investigating the impact of opioid use in ALBP in the adult population. All phases of screening, data extraction and assessment of methodological quality will be performed by two independent reviewers. We will perform quality and risk of bias assessment for the included articles and compare high and low risk of bias with a sensitivity analysis. We will conduct random- and fixed-effects meta-analyses with heterogeneity calculated using the I 2 statistic and evaluate publication bias. DISCUSSION: There are current guidelines published to alert clinicians in prescribing opioids for ALBP due to its likelihood of misuse, yet there is little change in prescribing patterns. To date, there is an absence of systematic information about the outcomes of prescription opioid in patients with ALBP. We will address this gap by providing evidence that will be useful for clinical practice. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016033090. PMID- 28807048 TI - Response to single agent PD-1 inhibitor after progression on previous PD-1/PD-L1 inhibitors: a case series. AB - BACKGROUND: Monoclonal antibodies targeting the PD-1/PD-L1 axis have gained increasing attention across many solid tumors and hematologic malignancies due to their efficacy and favorable toxicity profile. With more than 1 agent now FDA approved in a wide variety of tumor types, and with others in clinical trials, it is becoming more common that patients present to clinic for potential treatment with a second PD-1/PD-L1 inhibitor. CASE PRESENTATION: In this report, we present two patients with renal cell carcinoma and one with melanoma who received PD-1/PD L1 inhibitors. Upon progression on their first-line PD-1/PD-L1 inhibitors, these patients received a different PD-1 inhibitor (nivolumab in all cases) and all had progressive disease as their best response to the subsequent PD-1 inhibitor. The reported clinical information focuses on the course of the disease and the responses to all treatment regimens. CONCLUSIONS: Clinicians should refrain from using multiple PD-1/PD-L1 inhibitors sequentially outside of clinical trials until there is sufficient data to support this practice routinely. Prospective studies that allow prior treatment with PD-1/PD-L1 are needed to validate the efficacy and safety of these drugs in the second line or later setting. Furthermore, ongoing efforts that aim to identify mechanisms of resistance to immunotherapy will be informative and may ultimately assist physicians in select the optimal treatment following progression on PD-1/PD-L1 inhibitor. PMID- 28807049 TI - Oral manifestations, dental management, and a rare homozygous mutation of the PRDM12 gene in a boy with hereditary sensory and autonomic neuropathy type VIII: a case report and review of the literature. AB - BACKGROUND: Hereditary sensory and autonomic neuropathy type VIII is a rare autosomal recessive inherited disorder. Chen et al. recently identified the causative gene and characterized biallelic mutations in the PR domain-containing protein 12 gene, which plays a role in the development of pain-sensing nerve cells. Our patient's family was included in Chen and colleagues' study. We performed a literature review of the PubMed library (January 1985 to December 2016) on hereditary sensory and autonomic neuropathy type I to VIII genetic disorders and their orofacial manifestations. This case report is the first to describe the oral manifestations, and their treatment, of the recently discovered hereditary sensory and autonomic neuropathy type VIII in the medical and dental literature. CASE PRESENTATION: We report on the oral manifestations and dental management of an 8-month-old white boy with hereditary sensory and autonomic neuropathy-VIII over a period of 16 years. Our patient was homozygous for a mutation of PR domain-containing protein 12 gene and was characterized by insensitivity to pain and thermal stimuli, self-mutilation behavior, reduced sweat and tear production, absence of corneal reflexes, and multiple skin and bone infections. Oral manifestations included premature loss of teeth, associated with dental traumata and self-mutilation, severe soft tissue injuries, dental caries and submucosal abscesses, hypomineralization of primary teeth, and mandibular osteomyelitis. CONCLUSIONS: The lack of scientific knowledge on hereditary sensory and autonomic neuropathy due to the rarity of the disease often results in a delay in diagnosis, which is of substantial importance for the prevention of many complications and symptoms. Interdisciplinary work of specialized medical and dental teams and development of a standardized treatment protocols are essential for the management of the disease. There are many knowledge gaps concerning the management of patients with hereditary sensory and autonomic neuropathy-VIII, therefore more research on an international basis is needed. PMID- 28807050 TI - Cooperative binding mitigates the high-dose hook effect. AB - BACKGROUND: The high-dose hook effect (also called prozone effect) refers to the observation that if a multivalent protein acts as a linker between two parts of a protein complex, then increasing the amount of linker protein in the mixture does not always increase the amount of fully formed complex. On the contrary, at a high enough concentration range the amount of fully formed complex actually decreases. It has been observed that allosterically regulated proteins seem less susceptible to this effect. The aim of this study was two-fold: First, to investigate the mathematical basis of how allostery mitigates the prozone effect. And second, to explore the consequences of allostery and the high-dose hook effect using the example of calmodulin, a calcium-sensing protein that regulates the switch between long-term potentiation and long-term depression in neurons. RESULTS: We use a combinatorial model of a "perfect linker protein" (with infinite binding affinity) to mathematically describe the hook effect and its behaviour under allosteric conditions. We show that allosteric regulation does indeed mitigate the high-dose hook effect. We then turn to calmodulin as a real life example of an allosteric protein. Using kinetic simulations, we show that calmodulin is indeed subject to a hook effect. We also show that this effect is stronger in the presence of the allosteric activator Ca 2+/calmodulin-dependent kinase II (CaMKII), because it reduces the overall cooperativity of the calcium calmodulin system. It follows that, surprisingly, there are conditions where increased amounts of allosteric activator actually decrease the activity of a protein. CONCLUSIONS: We show that cooperative binding can indeed act as a protective mechanism against the hook effect. This will have implications in vivo where the extent of cooperativity of a protein can be modulated, for instance, by allosteric activators or inhibitors. This can result in counterintuitive effects of decreased activity with increased concentrations of both the allosteric protein itself and its allosteric activators. PMID- 28807051 TI - Mesenchymal stromal cells ameliorate oxidative stress-induced islet endothelium apoptosis and functional impairment via Wnt4-beta-catenin signaling. AB - BACKGROUND: Islet dysfunction and destruction are the common cause for both type 1 and type 2 diabetes mellitus (T2DM). The islets of Langerhans are highly vascularized miniorgans, and preserving the structural integrity and full function of the microvascular endothelium is vital for protecting the islets from the infiltration of immune cells and secondary inflammatory attack. Mesenchymal stromal cell (MSC)-based therapies have been proven to promote angiogenesis of the islets; however, the underlying mechanism for the protective role of MSCs in the islet endothelium is still vague. METHODS: In this study, we used MS-1, a murine islet microvascular endothelium cell line, and an MSC-MS1 transwell culturing system to investigate the protective mechanism of rat bone marrow derived MSCs under oxidative stress in vitro. Cell apoptosis was detected by TUNEL staining, annexin V/PI flow cytometry analysis, and cleaved caspase 3 western blotting analysis. Endothelial cell activation was determined by expression of intercellular cell adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM), as well as eNOS phosphorylation/activation. The changes of VCAM-1, eNOS, and the beta-catenin expression were also tested in the isolated islets of T2DM rats infused with MSCs. RESULTS: We observed that treating MS-1 cells with H2O2 triggered significant apoptosis, induction of VCAM expression, and reduction of eNOS phosphorylation. Importantly, coculturing MS-1 cells with MSCs prevented oxidative stress-induced apoptosis, eNOS inhibition, and VCAM elevation in MS-1 cells. Similar changes in VCAM-1 and eNOS phosphorylation could also be observed in the islets isolated from T2DM rats infused with MSCs. Moreover, MSCs cocultured with MS-1 in vitro or their administration in vivo could both result in an increase of beta-catenin, which suggested activation of the beta-catenin-dependent Wnt signaling pathway. In MS-1 cells, activation of the beta-catenin-dependent Wnt signaling pathway partially mediated the protective effects of MSCs against H2O2-induced apoptosis and eNOS inhibition. Furthermore, MSCs produced a significant amount of Wnt4 and Wnt5a. Although both Wnt4 and Wnt5a participated in the interaction between MSCs and MS-1 cells, Wnt4 exhibited a protective role while Wnt5a seemed to show a destructive role in MS-1 cells. CONCLUSIONS: Our observations provide evidence that the orchestration of the MSC-secreted Wnts could promote the survival and improve the endothelial function of the injured islet endothelium via activating the beta-catenin dependent Wnt signaling in target endothelial cells. This finding might inspire further in-vivo studies. PMID- 28807052 TI - Whole-blood RNA transcript-based models can predict clinical response in two large independent clinical studies of patients with advanced melanoma treated with the checkpoint inhibitor, tremelimumab. AB - BACKGROUND: Tremelimumab is an antibody that blocks CTLA-4 and demonstrates clinical efficacy in a subset of advanced melanoma patients. An unmet clinical need exists for blood-based response-predictive gene signatures to facilitate clinically effective and cost-efficient use of such immunotherapeutic interventions. METHODS: Peripheral blood samples were collected in PAXgene(r) tubes from 210 treatment-naive melanoma patients receiving tremelimumab in a worldwide, multicenter phase III study (discovery dataset). A central panel of radiologists determined objective response using RECIST criteria. Gene expression for 169 mRNA transcripts was measured using quantitative PCR. A 15-gene pre treatment response-predictive classifier model was identified. An independent population (N = 150) of refractory melanoma patients receiving tremelimumab after chemotherapy enrolled in a worldwide phase II study (validation dataset). The classifier model, using the same genes, coefficients and constants for objective response and one-year survival after treatment, was applied to the validation dataset. RESULTS: A 15-gene pre-treatment classifier model (containing ADAM17, CDK2, CDKN2A, DPP4, ERBB2, HLA-DRA, ICOS, ITGA4, LARGE, MYC, NAB2, NRAS, RHOC, TGFB1, and TIMP1) achieved an area under the curve (AUC) of 0.86 (95% confidence interval 0.81 to 0.91, p < 0.0001) for objective response and 0.6 (95% confidence interval 0.54 to 0.67, p = 0.0066) for one-year survival in the discovery set. This model was validated in the validation set with AUCs of 0.62 (95% confidence interval 0.54 to 0.70 p = 0.0455) for objective response and 0.68 for one-year survival (95% confidence interval 0.59 to 0.75 p = 0.0002). CONCLUSIONS: To our knowledge, this is the largest blood-based biomarker study of a checkpoint inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA classifier model that predicts clinical response. The data suggest that the model captures a biological signature representative of genes needed for a robust anti cancer immune response. It also identifies non-responders to tremelimumab at baseline prior to treatment. PMID- 28807053 TI - Regulation of inflammation in Japanese encephalitis. AB - BACKGROUND: Uncontrolled inflammatory response of the central nervous system is a hallmark of severe Japanese encephalitis (JE). Although inflammation is necessary to mount an efficient immune response against virus infections, exacerbated inflammatory response is often detrimental. In this context, cells of the monocytic lineage appear to be important forces driving JE pathogenesis. MAIN BODY: Brain-infiltrating monocytes, macrophages and microglia play a major role in central nervous system (CNS) inflammation during JE. Moreover, the role of inflammatory monocytes in viral neuroinvasion during JE and mechanisms of cell entry into the CNS remains unclear. The identification of cellular and molecular actors in JE inflammatory responses may help to understand the mechanisms behind excessive inflammation and to develop therapeutics to treat JE patients. This review addresses the current knowledge about mechanisms of virus neuroinvasion, neuroinflammation and therapeutics critical for JE outcome. CONCLUSION: Understanding the regulation of inflammation in JE is challenging. Elucidation of the remaining open questions will help to the development of therapeutic approaches avoiding detrimental inflammatory responses in JE. PMID- 28807054 TI - Transcriptomic profile of tobacco in response to Tomato zonate spot orthotospovirus infection. AB - BACKGROUND: Tomato zonate spot virus (TZSV), a dominant species of thrips transmitted orthotospoviruses in Yunnan and Guangxi provinces in China, causes significant loss of yield in lots of crops and is a major threat to incomes of rural families. However, the detailed molecular mechanism of crop disease caused by TZSV remains obscure. METHODS: Next-generation sequencing (NGS)-based transcriptome analysis (RNA-seq) was performed to investigate and compare the gene expression changes in systemic leaves of tobacco upon infection with TZSV and mock-inoculated plants as a control. RESULTS: De novo assembly and analysis of tobacco transcriptome data by RNA-Seq identified 135,395 unigenes. 2102 differentially expressed genes (DEGs) were obtained in tobacco with TZSV infection, among which 1518 DEGs were induced and 584 were repressed. Gene Ontology enrichment analysis revealed that these DEGs were associated with multiple biological functions, including metabolic process, oxidation-reduction process, photosynthesis process, protein kinase activity. The KEGG pathway analysis of these DEGs indicated that pathogenesis caused by TZSV may affect multiple processes including primary and secondary metabolism, photosynthesis and plant-pathogen interactions. CONCLUSION: Our global survey of transcriptional changes in TZSV infected tobacco provides crucial information into the precise molecular mechanisms underlying pathogenesis and symptom development. This is the first report on the relationships in the TZSV-plant interaction using transcriptome analysis. Findings of present study will significantly help enhance our understanding of the complicated mechanisms of plant responses to orthotospoviral infection. PMID- 28807055 TI - Transcriptomic profiling of microbe-microbe interactions reveals the specific response of the biocontrol strain P. fluorescens In5 to the phytopathogen Rhizoctonia solani. AB - BACKGROUND: Few studies to date report the transcriptional response of biocontrol bacteria toward phytopathogens. In order to gain insights into the potential mechanism underlying the antagonism of the antimicrobial producing strain P. fluorescens In5 against the phytopathogens Rhizoctonia solani and Pythium aphanidermatum, global RNA sequencing was performed. METHODS: Differential gene expression profiling of P. fluorescens In5 in response to either R. solani or P. aphanidermatum was investigated using transcriptome sequencing (RNA-seq). Total RNA was isolated from single bacterial cultures of P. fluorescens In5 or bacterial cultures in dual-culture for 48 h with each pathogen in biological triplicates. RNA-seq libraries were constructed following a default Illumina stranded RNA protocol including rRNA depletion and were sequenced 2 * 100 bases on Illumina HiSeq generating approximately 10 million reads per sample. RESULTS: No significant changes in global gene expression were recorded during dual culture of P. fluorescens In5 with any of the two pathogens but rather each pathogen appeared to induce expression of a specific set of genes. A particularly strong transcriptional response to R. solani was observed and notably several genes possibly associated with secondary metabolite detoxification and metabolism were highly upregulated in response to the fungus. A total of 23 genes were significantly upregulated and seven genes were significantly downregulated with at least respectively a threefold change in expression level in response to R. solani compared to the no fungus control. In contrast, only one gene was significantly upregulated over threefold and three transcripts were significantly downregulated over threefold in response to P. aphanidermatum. Genes known to be involved in synthesis of secondary metabolites, e.g. non-ribosomal synthetases and hydrogen cyanide were not differentially expressed at the time points studied. CONCLUSION: This study demonstrates that genes possibly involved in metabolite detoxification are highly upregulated in P. fluorescens In5 when co cultured with plant pathogens and in particular the fungus R. solani. This highlights the importance of studying microbe-microbe interactions to gain a better understanding of how different systems function in vitro and ultimately in natural systems where biocontrol agents can be used for the sustainable management of plant diseases. PMID- 28807056 TI - Agonist anti-GITR antibody significantly enhances the therapeutic efficacy of Listeria monocytogenes-based immunotherapy. AB - BACKGROUND: We previously demonstrated that in addition to generating an antigen specific immune response, Listeria monocytogenes (Lm)-based immunotherapy significantly reduces the ratio of regulatory T cells (Tregs)/CD4+ and myeloid derived suppressor cells (MDSCs) in the tumor microenvironment. Since Lm-based immunotherapy is able to inhibit the immune suppressive environment, we hypothesized that combining this treatment with agonist antibody to a co stimulatory receptor that would further boost the effector arm of immunity will result in significant improvement of anti-tumor efficacy of treatment. METHODS: Here we tested the immune and therapeutic efficacy of Listeria-based immunotherapy combination with agonist antibody to glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) in TC-1 mouse tumor model. We evaluated the potency of combination on tumor growth and survival of treated animals and profiled tumor microenvironment for effector and suppressor cell populations. RESULTS: We demonstrate that combination of Listeria-based immunotherapy with agonist antibody to GITR synergizes to improve immune and therapeutic efficacy of treatment in a mouse tumor model. We show that this combinational treatment leads to significant inhibition of tumor-growth, prolongs survival and leads to complete regression of established tumors in 60% of treated animals. We determined that this therapeutic benefit of combinational treatment is due to a significant increase in tumor infiltrating effector CD4+ and CD8+ T cells along with a decrease of inhibitory cells. CONCLUSION: To our knowledge, this is the first study that exploits Lm-based immunotherapy combined with agonist anti-GITR antibody as a potent treatment strategy that simultaneously targets both the effector and suppressor arms of the immune system, leading to significantly improved anti-tumor efficacy. We believe that our findings depicted in this manuscript provide a promising and translatable strategy that can enhance the overall efficacy of cancer immunotherapy. PMID- 28807057 TI - Inhibitory effects of HNF4alpha on migration/maltransformation of hepatic progenitors: HNF4alpha-overexpressing hepatic progenitors for liver repopulation. AB - BACKGROUND: Although they are expandable in vitro, hepatic progenitors are immature cells and share many immunomarkers with hepatocellular carcinoma, raising potential concerns regarding maltransformation after transplantation. This study investigated the effects of hepatic nuclear factor (HNF) 4alpha on the proliferation, migration, and maltransformation of hepatic progenitors and determined the feasibility of using these manipulated cells for transplantation. METHODS: The effects of HNF4alpha on rat hepatic progenitors (i.e. hepatic oval cells) were analyzed by HNF4alpha overexpression and HNF4alpha shRNA. Nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice injured by carbon chloride (CCl4) were then transplanted with control, HNF4alpha-overexpressing or HNF4alpha-suppressing hepatic oval cells. Finally, the engraftment of these cells in the recipient liver was analyzed. RESULTS: Rat hepatic progenitors (i.e. hepatic oval cells) expressed HNF4alpha, although less than that in hepatocytes. When HNF4alpha was overexpressed in these cells, the proliferation and migration of hepatic oval cells were reduced; but when HNF4alpha was suppressed by shRNA, the proliferation and migration, and even anchorage-independent growth, of these cells were accelerated. RNA microarray and gene functional analysis revealed that suppressing HNF4alpha not only impaired many biosynthesis and metabolism pathways of hepatocytes but also increased pathways for cancer. When transplanted into CCl4-injured NOD/SCID mice, few HNF4alpha-suppressing hepatic oval cells localized into the liver, while control cells and HNF4alpha-overexpressing cells engrafted into the liver and differentiated into albumin-positive hepatocytes. Interestingly, the hepatocytes derived from HNF4alpha-overexpressing cells were less migrative and expressed less c-Myc than the cells derived from control cells. CONCLUSION: HNF4alpha constrains proliferation, migration, and maltransformation of hepatic progenitors, and HNF4alpha-overexpressing hepatic progenitors serve as an optimal candidate for cell transplantation. PMID- 28807059 TI - Lower education predicts poor response to dietary intervention in pregnancy, regardless of neighbourhood affluence: secondary analysis from the ROLO randomised control trial. AB - OBJECTIVE: To determine if response to a low glycaemic index (GI) dietary intervention, measured by changes in dietary intake and gestational weight gain, differed across women of varying socio-economic status (SES). DESIGN: Secondary data analysis of the ROLO randomised control trial. The intervention consisted of a two-hour low-GI dietary education session in early pregnancy. Change in GI was measured using 3 d food diaries pre- and post-intervention. Gestational weight gain was categorised as per the 2009 Institute of Medicine guidelines. SES was measured using education and neighbourhood deprivation. SETTING: The National Maternity Hospital, Dublin, Ireland. SUBJECTS: Women (n 625) recruited to the ROLO randomised control trial. RESULTS: The intervention significantly reduced GI and excess gestational weight gain (EGWG) among women with third level education residing in both disadvantaged (GI, mean (sd), intervention v. control: -3.30 (5.15) v. -0.32 (4.22), P=0.024; EGWG, n (%), intervention v. control: 7 (33.6) v. 22 (67.9); P=0.022) and advantaged areas (GI: -1.13 (3.88) v. 0.06 (3.75), P=0.020; EGWG: 41 (34.1) v. 58 (52.6); P=0.006). Neither GI nor gestational weight gain differed between the intervention and control group among women with less than third level education, regardless of neighbourhood deprivation. CONCLUSIONS: A single dietary education session was not effective in reducing GI or gestational weight gain among less educated women. Multifaceted, appropriate and practical approaches are required in pregnancy interventions to improve pregnancy outcomes for less educated women. PMID- 28807058 TI - Role of metabolites of cyclophosphamide in cardiotoxicity. AB - BACKGROUND: The dose-limiting toxic effect of cyclophosphamide (CY) is cardiotoxicity. The pathogenesis of myocardial damage is poorly understood, and there is no established means of prevention. In previous studies, we suggested that for CY-induced cardiotoxicity, whereas acrolein is the key toxic metabolite, carboxyethylphosphoramide mustard (CEPM) is protective. We sought to verify that acrolein is the main cause of cardiotoxicity and to investigate whether aldehyde dehydrogenase (ALDH), which is associated with greater CEPM production, is involved in the protective effect for cardiotoxicity. We also evaluated the protective effect of N-acetylcysteine (NAC), an amino acid with antioxidant activity and a known acrolein scavenger. METHODS: H9c2 cells were exposed to CY metabolites HCY (4-hydroxy-cyclophosphamide), acrolein or CEPM. The degree of cytotoxicity was evaluated by MTT assay, lactate dehydrogenase (LDH) release, and the production of reactive oxygen species (ROS). We also investigated how the myocardial cellular protective effects of CY metabolites were modified by NAC. To quantify acrolein levels, we measured the culture supernatants using high performance liquid chromatography. We measured ALDH activity after exposure to HCY or acrolein and the same with pre-treatment with NAC. RESULTS: Exposure of H9c2 cells to CEPM did not cause cytotoxicity. Increased ROS levels and myocardial cytotoxicity, however, were induced by HCY and acrolein. In cell cultures, HCY was metabolized to acrolein. Less ALDH activity was observed after exposure to HCY or acrolein. Treatment with NAC reduced acrolein concentrations. CONCLUSIONS: Increased ROS generation and decreased ALDH activity confirmed that CY metabolites HCY and acrolein are strongly implicated in cardiotoxicity. By inhibiting ROS generation, increasing ALDH activity and decreasing the presence of acrolein, NAC has the potential to prevent CY-induced cardiotoxicity. PMID- 28807060 TI - Current dietary supplement use of Australian military veterans of Middle East operations. AB - OBJECTIVE: To assess patterns and levels of dietary supplement use among Australian Defence Forces, previously deployed to the Middle East Area of Operations. DESIGN: A cross-sectional study. Participants of a large survey self completed questions about dietary supplement use, health status, personal and job related characteristics, and lifestyle factors. Frequency of current use of supplements was assessed in three categories (bodybuilding, energy and weight loss). SETTING: Middle East Area of Operations post-deployment health survey. SUBJECTS: Current and ex-serving Australian Defence Force personnel (n 14 032) who deployed to the Middle East between 2001 and 2009. RESULTS: Bodybuilding supplements were used by 17.5 % of participants, energy supplements by 24.5 % and weight-loss supplements by 7.6 %. Overall, 32.3 % of participants used any of these supplements. Bodybuilding and energy supplements were more often used by men, younger persons and those in the Army, while weight-loss supplements were more commonly used by women and Navy personnel. Supplements in all three categories were more commonly used by persons in lower ranks, active service and combat roles. Users of bodybuilding supplements had healthier lifestyles and better health status, while users of energy and weight-loss supplements had less healthy lifestyles and poorer mental and physical health status. Overall, 11.7 % of participants used supplements containing caffeine and 3.6 % used a creatine containing product. CONCLUSIONS: Use of dietary supplements among Australian Defence Force personnel is common, and patterned by lifestyle factors and health status. PMID- 28807061 TI - The incidence of hyperthermia during cochlear implant surgery in children. AB - BACKGROUND: Inadvertent hyperthermia during anaesthesia is a rare but life threatening complication. We have encountered several cases of severe hyperthermia in paediatric patients undergoing anaesthesia for cochlear implantation. METHODS: This study aimed to describe the clinical characteristics of children who developed hyperthermia while undergoing cochlear implantation, and to explore possible mechanisms and predisposing factors. The anaesthetic charts of all patients aged under 18 years who underwent cochlear implantation, or mastoid or ophthalmic surgery, between 1 January 2006 and 31 December 2009, at Soroka Medical Center in Beer Sheva, Israel, were reviewed. Patients undergoing mastoid and ophthalmic surgical procedures were used as controls. RESULTS: A larger percentage of patients who underwent cochlear implant surgery (10 per cent) developed hyperthermia compared to controls (0.7 per cent, p < 0.05). In five of the seven cases, hyperthermia appeared in combination with tachycardia and hypercapnia, adhering to the clinical triad of malignant hyperthermia. CONCLUSION: Patients undergoing cochlear implantation are susceptible to developing intra-operative hyperthermia. This article describes the hyperthermic events that occur during paediatric cochlear implantation, and attempts to identify potential triggers of hyperthermia. PMID- 28807062 TI - Neuropsychiatric characteristics of antiterrorist operation combatants in the Donbass (Ukraine). AB - OBJECTIVE: The present paper aimed to explore the neuropsychiatric characteristics of the antiterrorism (ATO) combatants in the Donets Basin (Donbass) and to propose therapeutic strategies for managing their mental healthcare. METHODS: A total of 54 ATO combatants were included in our study and compared with four groups of subjects exposed to other emergencies, including the Chernobyl disaster and the war in Afghanistan. The neuropsychiatric features were assessed through psychopathological assessments, neurological examinations, and quantitative electroencephalography (qEEG). RESULTS: The ATO combatants were characterized by low health self-estimation, somatic concerns, a high prevalence of posttraumatic stress disorder, anxiety, insomnia, depression, social dysfunction, mild cognitive impairment, and neurological soft signs, similar to individuals involved in the Chernobyl disaster and veterans of the Afghan War. Quantitative EEG showed abnormalities suggestive of irritation of the corticolimbic system and diencephalic structures. Some post-conflict personality changes in ATO combatants were recorded. The treatment of ATO combatants included a comprehensive strategy: from psychotropic drugs to different psychotherapies. CONCLUSIONS: On the basis of 30 years of experience in the management of the consequences of Chernobyl disaster and the available studies on war veterans, the authors proposed a method for assessment and an approach to providing mental healthcare for ATO combatants, refugees, and migrants from the Donbass, which perhaps can be used as guidelines for other conflicts. Taken together, the findings of the study suggest that voluntary participation in war may decrease but does not eliminate the risk of developing the neuropsychiatric consequences caused by such conflicts. A comprehensive strategy-one that would encompass psychopharmacological, psychological, and rehabilitation techniques-seems to be the most successful approach to managing the main symptoms and disorders involved. PMID- 28807063 TI - Performance of a Novel Non-Fit-Tested HEPA Filtering Face Mask. PMID- 28807064 TI - Stage is a prognostic factor for surgically treated patients with early-stage lip cancer for whom a 'wait and see' policy in terms of neck status has been implemented. AB - OBJECTIVES: To determine the locoregional control and survival rates (in terms of risk factors) of patients who underwent surgical resection of early-stage lip cancer and for whom a 'wait and see' policy in terms of neck status had been implemented. METHODS: The sociodemographic data, tumour stage, tumour characteristics and histopathological features of 41 patients with early-stage lip cancer were evaluated. Factors predictive of survival and locoregional recurrence were analysed. The five-year overall survival and disease-free survival rates were determined, and the prognostic risk factors were compared. RESULTS: The mean follow-up period was 60.5 months (range, 4-92 months). Age, sex, tumour stage, tumour thickness and volume, and perineural involvement were not predictive of locoregional recurrence or survival. Pathological tumour stage (T1 vs T2) was a prognostic factor for both five-year overall survival (87.3 vs 65.6 per cent, p = 0.042) and disease-free survival (88.6 vs 65.6 per cent, p = 0.037). CONCLUSION: Tumour stage was clearly a major factor affecting the prognosis of surgically treated patients with early-stage lip cancer for whom a 'wait and see' policy in terms of neck status had been implemented. PMID- 28807066 TI - Laser-assisted management of a symptomatic anterior pharyngeal diverticulum. AB - BACKGROUND: Dysphagia is a relatively common symptom following laryngectomy. An anterior pharyngeal diverticulum is a rare cause of post-laryngectomy dysphagia. However, it is often an incidental finding on rigid telescopic examination. METHODS AND RESULTS: This article describes two patients with a symptomatic anterior pharyngeal diverticulum. They were treated by transoral micro-endoscopic potassium titanyl phosphate 532 nm laser assisted resection. Both patients could take feeds orally after the procedure without any difficulty. One patient died one and a half years after the procedure because of secondary lung cancer. The other patient died after three years as a result of regional recurrence. The patients were able to swallow during their survival period post treatment. CONCLUSION: Laser-assisted micro-endoscopic resection is a relatively safe, quick and effective procedure for the management of anterior pharyngeal diverticulum. PMID- 28807065 TI - Possible role of Dickkopf-1 protein in the pathogenesis of tympanosclerosis in a rat model. AB - OBJECTIVES: This study aimed to investigate the expression of DKK1 protein in an experimental model of tympanosclerosis and its possible role in the pathogenesis of this disorder. METHODS: Forty Sprague Dawley rats were included in the study: 20 in the control group (which received no treatment) and 20 in the experimental group (which received an incision to induce tympanosclerosis). Otomicroscopy was performed to observe the development of myringosclerosis. Haematoxylin and eosin staining was performed to observe the morphological changes. Western blot analysis and immunohistochemistry were performed to assess the expression of DKK1 protein. RESULTS: At day 15, sclerotic lesions were observed in 70 per cent of the tympanic membranes. Inflammatory infiltration and hyaline degeneration markedly appeared in the tympanic membranes and middle-ear mucosa. DKK1 protein was mainly distributed in the cytoplasm of epithelial cells, which were widely distributed in the tympanic membranes and middle-ear mucosa. The expression of DKK1 protein was significantly decreased in the calcified experimental ears. CONCLUSION: DKK1 protein is involved in the pathogenesis of tympanosclerosis by regulating the Wnt/beta-catenin signalling pathway. PMID- 28807067 TI - Iterative Fecal Microbiota Transplantations for Eradicating Digestive Colonization With Carbapenemase-Producing Enterobacteriaceae: Is It Worth It? PMID- 28807068 TI - Secular trends in dietary patterns of young children in Brazil from 1996 to 2006. AB - OBJECTIVE: To describe dietary patterns (DP) from 1996 to 2006 and in the first 5 years of life and to explore individual and contextual characteristics associated with each DP. DESIGN: DP were defined by principal component analysis. The association between DP and individual (sociodemographic, maternal and child) and contextual (geographic regional and year) characteristics was analysed by multilevel analysis. SETTING: Two complex probabilistic Brazilian Demographic and Health Surveys (BDHS 1996, 2006). SUBJECTS: Brazilian children under 5 years of age. RESULTS: DP1 included yoghurt, vegetables, fruits, tubers, red meat. DP2 included liquids, milk, fruits, egg/chicken/fish, red meat, breast milk (negative loading). DP3 included fruit juices, 'papilla', yoghurt, red meat (negative loading). DP4 included formulas, milk, enriched 'papilla', egg/chicken/fish (negative loading). DP prevalence within the age range from 1996 to 2006 remained constant for DP1; increased after 12 and 6 months, respectively, for DP2 and DP3; and decreased for DP4. DP1 was explained by higher maternal education, wealth, lower number of children at home; DP2 by living in rural area and younger mothers; and DP4 by lower maternal education and wealth. The total variance of the model attributable to geographic region was 30.2, 20.7 and 54.2 % for DP2, DP3 and DP4, respectively. CONCLUSIONS: DP trends observed from 1996 to 2006 show positive aspects, such as: maintenance of DP1 as the main DP after 12 months; an increase in the prevalence of DP2 and DP3 followed by a decrease of DP4 after 6 months. DP1 is explained mainly by socio-economic factors, regardless of contextual characteristics, and DP2, DP3, DP4 are partially explained by contextual effects. PMID- 28807069 TI - A Pilot Project Demonstrating that Combat Medics Can Safely Administer Parenteral Medications in the Emergency Department. AB - : Introduction Select units in the military have improved combat medic training by integrating their functions into routine clinical care activities with measurable improvements in battlefield care. This level of integration is currently limited to special operations units. It is unknown if regular Army units and combat medics can emulate these successes. The goal of this project was to determine whether US Army combat medics can be integrated into routine emergency department (ED) clinical care, specifically medication administration. Project Design This was a quality assurance project that monitored training of combat medics to administer parenteral medications and to ensure patient safety. Combat medics were provided training that included direct supervision during medication administration. Once proficiency was demonstrated, combat medics would prepare the medications under direct supervision, followed by indirect supervision during administration. As part of the quality assurance and safety processes, combat medics were required to document all medication administrations, supervising provider, and unexpected adverse events. Additional quality assurance follow-up occurred via complete chart review by the project lead. Data During the project period, the combat medics administered the following medications: ketamine (n=13), morphine (n=8), ketorolac (n=7), fentanyl (n=5), ondansetron (n=4), and other (n=6). No adverse events or patient safety events were reported by the combat medics or discovered during the quality assurance process. CONCLUSIONS: In this limited case series, combat medics safely administered parenteral medications under indirect provider supervision. Future research is needed to further develop this training model for both the military and civilian setting. Schauer SG , Cunningham C W, Fisher AD , DeLorenzo RA . A pilot project demonstrating that combat medics can safely administer parenteral medications in the emergency department. Prehosp Disaster Med. 2017;32(6):679 681. PMID- 28807070 TI - Evaluation of cardiovascular risks and recovery of idiopathic sudden sensorineural hearing loss in hospitalised patients: comparison between complete and partial sudden sensorineural hearing loss. AB - OBJECTIVE: To evaluate the presence of cardiovascular risk factors and recovery of idiopathic sudden sensorineural hearing loss in hospitalised patients. METHODS: A single-centre retrospective study of 80 patients hospitalised for idiopathic sudden sensorineural hearing loss was conducted over a 6-year period. Mean pure tone hearing thresholds were assessed by pure tone audiometry. RESULTS: Twenty-three of 80 patients (28.75 per cent) initially had no cardiovascular risk factors. Forty-five patients had hyperlipidaemia, 22 patients had hypertension, 7 patients had diabetes mellitus and 7 patients were obese. No statistically significant difference was observed between patients with complete versus partial sudden sensorineural hearing loss (p = 0.0708) concerning the cardiovascular risk factors. At long-term follow up, the hearing recovery rate was not significantly different between the two groups of patients (p = 0.7541). CONCLUSION: The lack of a clear relationship between idiopathic sudden sensorineural hearing loss and cardiovascular risk factors suggests that sudden sensorineural hearing loss has a predominantly multifactorial disease profile regardless of hearing impairment severity. PMID- 28807071 TI - Single Rescuer Ventilation Using a Bag Valve Mask with Removable External Handle: A Randomized Crossover Trial. AB - : Introduction Ventilation with a bag valve mask (BVM) is a challenging but critical skill for airway management in the prehospital setting. Hypothesis Tidal volumes received during single rescuer ventilation with a modified BVM with supplemental external handle will be higher than those delivered using a standard BVM among health care volunteers in a manikin model. METHODS: This study was a randomized crossover trial of adult health care providers performing ventilation on a manikin. Investigators randomized participants to perform single rescuer ventilation, first using either a BVM modified by addition of a supplemental external handle or a standard unmodified BVM (Spur II BVM device; Ambu; Ballerup, Denmark). Participants performed mask placement and delivery of 10 breaths per minute for three minutes, as guided by a metronome. After a three-minute rest period, they performed ventilation using the alternative device. The primary outcome measure was mean received tidal volume as measured by the manikin (IngMar RespiTrainer model; IngMar Medical; Pittsburgh, Pennsylvania USA). Secondary outcomes included subject device preference. RESULTS: Of 70 recruited participants, all completed the study. The difference in mean received tidal volume between ventilations performed using the modified BVM with external handle versus standard BVM was 20 ml (95% CI, -16 to 56 ml; P=.28). There were no significant differences in mean received tidal volume based on the order of study arm allocation. The proportion of participants preferring the modified BVM over the standard BVM was 47.1% (95% CI, 35.7 to 58.6%). CONCLUSIONS: The modified BVM with added external handle did not result in greater mean received tidal volume compared to standard BVM during single rescuer ventilation in a manikin model. Reed P , Zobrist B , Casmaer M , Schauer SG , Kester N , April MD . Single rescuer ventilation using a bag valve mask with removable external handle: a randomized crossover trial. Prehosp Disaster Med. 2017;32(6):625-630. PMID- 28807072 TI - Clavicle fracture with osteomyelitis after neck dissection and post-operative radiotherapy: case report. AB - BACKGROUND: Non-traumatic bone fractures in cancer patients are usually pathological fractures due to bone metastases. In head and neck cancer patients, clavicle stress fractures may occur as a result of atrophy of the trapezius muscle after neck dissection in which the accessory nerve becomes structurally or functionally damaged. CASE REPORT: A 71-year-old man underwent modified radical neck dissection with accessory nerve preservation and post-operative radiotherapy for submandibular lymph node metastases of tongue cancer. Four weeks after the radiotherapy, a clavicle fracture, with osteomyelitis and abscess formation in the pectoralis major muscle, occurred. Unlike in simple stress fracture, long term antibiotic administration and drainage surgery were required to suppress the inflammation. CONCLUSION: As seen in the present patient, clavicle stress fractures may occur even after neck dissection in which the accessory nerve is preserved, and may be complicated by osteomyelitis and abscess formation owing to risk factors such as radiotherapy, tracheostomy and contiguous infection. PMID- 28807073 TI - A Comparison of Paramedic First Pass Endotracheal Intubation Success Rate of the VividTrac VT-A 100, GlideScope Ranger, and Direct Laryngoscopy Under Simulated Prehospital Cervical Spinal Immobilization Conditions in a Cadaveric Model. AB - OBJECTIVE: The primary goal of this study was to compare paramedic first pass success rate between two different video laryngoscopes and direct laryngoscopy (DL) under simulated prehospital conditions in a cadaveric model. METHODS: This was a non-randomized, group-controlled trial in which five non-embalmed, non frozen cadavers were intubated under prehospital spinal immobilization conditions using DL and with both the GlideScope Ranger (GL; Verathon Inc, Bothell, Washington USA) and the VividTrac VT-A100 (VT; Vivid Medical, Palo Alto, California USA). Participants had to intubate each cadaver with each of the three devices (DL, GL, or VT) in a randomly assigned order. Paramedics were given 31 seconds for an intubation attempt and a maximum of three attempts per device to successfully intubate each cadaver. Confirmation of successful endotracheal intubation (ETI) was confirmed by one of the six on-site physicians. RESULTS: Successful ETI within three attempts across all devices occurred 99.5% of the time overall and individually 98.5% of the time for VT, 100.0% of the time for GL, and 100.0% of the time for DL. First pass success overall was 64.4%. Individually, first pass success was 60.0% for VT, 68.8% for GL, and 64.5% for DL. A chi-square test revealed no statistically significant difference amongst the three devices for first pass success rates (P=.583). Average time to successful intubation was 42.2 seconds for VT, 38.0 seconds for GL, and 33.7 for seconds for DL. The average number of intubation attempts for each device were as follows: 1.48 for VT, 1.40 for GL, and 1.42 for DL. CONCLUSION: The was no statistically significant difference in first pass or overall successful ETI rates between DL and video laryngoscopy (VL) with either the GL or VT (adult). Hodnick R , Zitek T , Galster K , Johnson S , Bledsoe B , Ebbs D . A comparison of paramedic first pass endotracheal intubation success rate of the VividTrac VT A 100, GlideScope Ranger, and direct laryngoscopy under simulated prehospital cervical spinal immobilization conditions in a cadaveric model. Prehosp Disaster Med. 2017;32(6):621-624. PMID- 28807074 TI - A Model to Predict Central-Line-Associated Bloodstream Infection Among Patients With Peripherally Inserted Central Catheters: The MPC Score. AB - BACKGROUND Peripherally inserted central catheters (PICCs) are associated with central-line-associated bloodstream infections (CLABSIs). However, no tools to predict risk of PICC-CLABSI have been developed. OBJECTIVE To operationalize or prioritize CLABSI risk factors when making decisions regarding the use of PICCs using a risk model to estimate an individual's risk of PICC-CLABSI prior to device placement. METHODS Using data from the Michigan Hospital Medicine Safety consortium, patients that experienced PICC-CLABSI between January 2013 and October 2016 were identified. A Cox proportional hazards model with robust sandwich standard error estimates was then used to identify factors associated with PICC-CLABSI. Based on regression coefficients, points were assigned to each predictor and summed for each patient to create the Michigan PICC-CLABSI (MPC) score. The predictive performance of the score was assessed using time-dependent area-under-the-curve (AUC) values. RESULTS Of 23,088 patients that received PICCs during the study period, 249 patients (1.1%) developed a CLABSI. Significant risk factors associated with PICC-CLABSI included hematological cancer (3 points), CLABSI within 3 months of PICC insertion (2 points), multilumen PICC (2 points), solid cancers with ongoing chemotherapy (2 points), receipt of total parenteral nutrition (TPN) through the PICC (1 point), and presence of another central venous catheter (CVC) at the time of PICC placement (1 point). The MPC score was significantly associated with risk of CLABSI (P<.0001). For every point increase, the hazard ratio of CLABSI increased by 1.63 (95% confidence interval, 1.56 1.71). The area under the receiver-operating-characteristics curve was 0.67 to 0.77 for PICC dwell times of 6 to 40 days, which indicates good model calibration. CONCLUSION The MPC score offers a novel way to inform decisions regarding PICC use, surveillance of high-risk cohorts, and utility of blood cultures when PICC-CLABSI is suspected. Future studies validating the score are necessary. Infect Control Hosp Epidemiol 2017;38:1155-1166. PMID- 28807075 TI - Relationship between chronic otitis media with effusion and overweight or obesity in children. AB - OBJECTIVES: Otitis media with effusion and obesity are both common in childhood and might share some immunological alterations. This study aimed to investigate the relationship between chronic otitis media with effusion and childhood overweight or obesity, including the potential effects of adenoid or tonsillar hypertrophy on that relationship. METHODS: This study included 60 children with chronic otitis media with effusion and 86 healthy children aged from 2 to 10 years. Measures of height and weight were used to calculate the body mass index, weight for height and weight z score. RESULTS: The prevalence of overweight or obesity was higher in children with chronic otitis media with effusion, according to the weight for height percentiles (p = 0.012). However, neither the presence of adenoid or tonsillar hypertrophy nor the degree of adenoid hypertrophy was associated with overweight or obesity. CONCLUSION: Overweight and obesity might be risk factors for developing chronic otitis media with effusion, or vice versa. PMID- 28807076 TI - Review: Behavioral signs of estrus and the potential of fully automated systems for detection of estrus in dairy cattle. AB - Efficient detection of estrus is a permanent challenge for successful reproductive performance in dairy cattle. In this context, comprehensive knowledge of estrus-related behaviors is fundamental to achieve optimal estrus detection rates. This review was designed to identify the characteristics of behavioral estrus as a necessary basis for developing strategies and technologies to improve the reproductive management on dairy farms. The focus is on secondary symptoms of estrus (mounting, activity, aggressive and agonistic behaviors) which seem more indicative than standing behavior. The consequences of management, housing conditions and cow- and environmental-related factors impacting expression and detection of estrus as well as their relative importance are described in order to increase efficiency and accuracy of estrus detection. As traditional estrus detection via visual observation is time-consuming and ineffective, there has been a considerable advancement of detection aids during the last 10 years. By now, a number of fully automated technologies including pressure sensing systems, activity meters, video cameras, recordings of vocalization as well as measurements of body temperature and milk progesterone concentration are available. These systems differ in many aspects regarding sustainability and efficiency as keys to their adoption for farm use. As being most practical for estrus detection a high priority - according to the current research - is given to the detection based on sensor-supported activity monitoring, especially accelerometer systems. Due to differences in individual intensity and duration of estrus multivariate analysis can support herd managers in determining the onset of estrus. Actually, there is increasing interest in investigating the potential of combining data of activity monitoring and information of several other methods, which may lead to the best results concerning sensitivity and specificity of detection. Future improvements will likely require more multivariate detection by data and systems already existing on farms. PMID- 28807077 TI - Cochlear implantation in Malawi: report of the first four cases. AB - OBJECTIVE: This paper reports on the first four cochlear implant cases in Malawi. CASE REPORTS: Three patients were deafened from infectious diseases and one from an unknown cause. They all had post-lingual deafness. Six months after the last implant, they are all progressing well. CONCLUSION: Despite significant practical difficulties, it has proved possible, with the right support, to carry out cochlear implantation in one of the world's poorest countries. The project has also raised awareness of deafness in Malawi and highlighted significant public health issues relating to the aetiology of deafness in developing countries. PMID- 28807078 TI - The relationship between lung function and the clinical and histopathological features in Chinese patients with nasal polyps. AB - OBJECTIVE: To investigate lung function in Chinese patients suffering from chronic rhinosinusitis with nasal polyps and examine its association with histopathological features. METHODS: The lung function of 99 patients with nasal polyps was measured. Haematoxylin and eosin and immunohistochemistry staining were performed to evaluate any inflammatory cells and epithelial tissue remodelling. RESULTS: Predicted maximal expiratory flow rate at 25 per cent vital capacity was reduced (p < 0.05) in epithelial hyperplasia, and predicted maximal expiratory flow rate at 50 per cent vital capacity was reduced (p < 0.05) in goblet cell hyperplasia. Both peripheral blood eosinophilia and tissue eosinophilia nasal polyps manifested significantly reduced: forced expiratory volume in 1 second/forced vital capacity ratio, predicted maximal expiratory flow rate at 25, 50 and 75 per cent of vital capacity, and predicted maximal mid expiratory flow. Peripheral blood eosinophils were negatively correlated with predicted maximal expiratory flow rate at 25 and 50 per cent of vital capacity, and predicted maximal mid-expiratory flow. Eosinophils in tissue were negatively correlated with all lung function parameters investigated except predicted forced vital capacity. CONCLUSION: Clinicians should be aware of lung function decline in nasal polyps patients, especially in those with tissue eosinophilia. PMID- 28807079 TI - Syncope During Competitive Events: Interrogating Heart Rate Monitor Watches May Be Useful! AB - This is a case report of a 45-year-old man who reported complete amnesia during the very first kilometer of a 10-km run. He was wearing a heart rate monitor (HRM). The interrogation of his HRM watch showed 200 bpm tachycardia beginning in the first kilometer and increasing up to 220 bpm during the last kilometer. The patient was asked to wear a Holter-monitor (Holter Research Laboratory; Helena, Montana USA) electrocardiogram (ECG) while practicing a training session. This examination allowed for the diagnosis of an adrenergic paroxysmal atrial fibrillation (AF) with an impressive auriculo-ventricular conduction over 260 bpm. This case highlights that non-medical devices, such as connected watches, can be helpful to diagnose arrhythmias. Thabouillot O , Bostanci K , Bouvier F , Dumitrescu N , Stefuriac M , Paule P , Roche NC . Syncope during competitive events: interrogating heart rate monitor watches may be useful! Prehosp Disaster Med. 2017;32(6):691-693. PMID- 28807080 TI - A Descriptive Analysis of Traction Splint Utilization and IV Analgesia by Emergency Medical Services. AB - : Study Objectives Traction splinting has been the prehospital treatment of midshaft femur fracture as early as the battlefield of the First World War (1914 1918). This study is the assessment of these injuries and the utilization of a traction splint (TS) in blunt and penetrating trauma, as well as intravenous (IV) analgesia utilization by Emergency Medical Services (EMS) in Miami, Florida (USA). METHODS: This is a retrospective study of patients who sustained a midshaft femur fracture in the absence of multiple other severe injuries or severe physiologic derangement, as defined by an injury severity score (ISS) <20 and a triage revised trauma score (T-RTS)>=10, who presented to an urban, Level 1 trauma center between September 2008 and September 2013. The EMS patient care reports were assessed for physical exam findings and treatment modality. Data were analyzed descriptively and statistical differences were assessed using odds ratios and Z-score with significance set at P<=.05. RESULTS: There were 170 patients studied in the cohort. The most common physical exam finding was a deformity +/- shortening and rotation in 136 patients (80.0%), followed by gunshot wound (GSW) in 22 patients (13.0%), pain or tenderness in four patients (2.4%), and no findings consistent with femur fracture in three patients (1.7%). The population was dichotomized between trauma type: blunt versus penetrating. Of 134 blunt trauma patients, 50 (37.0%) were immobilized in traction, and of the 36 penetrating trauma victims, one (2.7%) was immobilized in traction. Statistically significant differences were found in the application of a TS in blunt trauma when compared to penetrating trauma (OR=20.83; 95% CI, 2.77-156.8; P <.001). Intravenous analgesia was administered to treat pain in only 35 (22.0%) of the patients who had obtainable IV access. Of these patients, victims of blunt trauma were more likely to receive IV analgesia (OR=6.23; 95% CI, 1.42-27.41; P=.0067). CONCLUSION: Although signs of femur fracture are recognized in the majority of cases of midshaft femur fracture, only 30% of patients were immobilized using a TS. Statistically significant differences were found in the utilization of a TS and IV analgesia administration in the setting of blunt trauma when compared to penetrating trauma. Nackenson J , Baez AA , Meizoso JP . A descriptive analysis of traction splint utilization and IV analgesia by Emergency Medical Services.Prehosp Disaster Med. 2017;32(6):631-635. PMID- 28807081 TI - Emergency Medical Technician Education in Saudi Arabia: History and Challenges. AB - Alamri Y . Emergency medical technician education in Saudi Arabia: history and challenges. Prehosp Disaster Med. 2017;32(6):699. PMID- 28807082 TI - Hearing status in patients with rheumatoid arthritis. AB - OBJECTIVE: Rheumatoid arthritis is thought to induce conductive hearing loss and/or sensorineural hearing loss. This study evaluated the function of the middle ear and cochlea, and the related factors. METHODS: Pure tone audiometry, speech reception thresholds, speech discrimination scores, tympanometry, acoustic reflexes, and distortion product otoacoustic emissions were assessed in rheumatoid arthritis patients and healthy volunteers. RESULTS: Pure tone audiometry results revealed a higher bone conduction threshold in the rheumatoid arthritis group, but there was no significant difference when evaluated according to the sensorineural hearing loss definition. Distortion product otoacoustic emissions related prevalence of conductive or mixed hearing loss, tympanometry values, acoustic reflexes, and speech discrimination scores were not significantly different between the two groups. Sensorineural hearing loss was significantly more prevalent in patients who used azathioprine, cyclosporine and etanercept. CONCLUSION: Higher bone conduction thresholds in some frequencies were detected in rheumatoid arthritis patients that were not clinically significant. Sensorineural hearing loss is significantly more prevalent in refractory rheumatoid arthritis patients. PMID- 28807083 TI - MicroRNA let-7a up-regulates OPN expression in a mouse model of allergic rhinitis. AB - OBJECTIVE: To investigate the effect of microRNA let-7a on OPN expression in a mouse model of allergic rhinitis. METHODS: Thirty-two mature female C57BL/6 mice were randomly divided into four groups, with eight mice in each group: microRNA let-7a, microRNA control, OVA and phosphate-buffered saline groups. The microRNA let-7a, microRNA control and OVA groups were sensitised with OVA to establish a mouse model of allergic rhinitis. Nose-scratching events were counted. Nasal mucosa was used to evaluate histological changes of goblet cell hyperplasia. Interleukins 5 and 13 were detected. Interferon-gamma levels in the nasal lavage fluid were assayed with enzyme-linked immunosorbent assay. OPN expression was estimated with polymerase chain reaction. RESULTS: Compared with microRNA control mice, microRNA let-7a treated mice had a significantly increased number of nose scratching events, nasal mucosal eosinophilia and goblet cell hyperplasia (p 0.05). In addition, microRNA let-7a treated mice had significantly enhanced OPN expression in nasal mucosa (p < 0.05). CONCLUSION: MicroRNA let-7a can promote allergic rhinitis development partly by regulating OPN expression. PMID- 28807084 TI - Linseed plus nitrate in the diet for fattening bulls: effects on methane emission, animal health and residues in offal. AB - The combination of linseed and nitrate is known to decrease enteric methane emission in dairy cows but few studies have been carried out in fattening cattle for animal liveweight gain, enteric methane emission, animal health and presence of residues in beef products. To address this gap, 16 young bulls received a control (C) diet between weaning at 9 months and 14 months, then were split into two groups of eight balanced on feed intake, BW gain and methane emission to receive either the C diet or a diet moderately supplemented with extruded linseed and calcium nitrate (LN) for 2 months before being slaughtered. On a dry matter (DM) basis, the C diet contained 70% baled grass silage and 30% concentrate mainly made of maize, wheat and rapeseed meal. In the LN diet, rapeseed meal and a fraction of cereals were replaced by 35% extruded linseed and 6% calcium nitrate; linseed fatty acids and nitrate supply in the LN diet were 1.9% and 1.0%, respectively. Methane emission was measured continuously using the GreenFeed system. Methaemoglobin was determined every week in peripheral blood from bulls receiving the LN diet. Nitrate and nitrite concentrations were determined in rumen, liver and tongue sampled at slaughter. Dry matter intake tended to be lower for LN diet (P=0.10). Body weight gain was lower for LN diet (P=0.01; 1.60 and 1.26 kg/day for C and LN diet, respectively). Daily methane emission was 9% lower (P<0.001) for LN than C diet (249 and 271 g/day, respectively) but methane yield did not differ between diets (24.1 and 23.2 g/kg DM intake for C and LN diet, respectively, P=0.34). Methaemoglobin was under the limit of detection (<2% of total haemoglobin) for most animals and was always lower than 5.6%, suggesting an absence of risk to animal health. Nitrite and nitrate concentrations in offal did not differ between C and LN diets. In conclusion, a moderate supply of linseed and nitrate in bull feed failed to decrease enteric methane yield and impaired bull liveweight gain but without adverse effects for animal health and food safety. PMID- 28807085 TI - Variation in bacterial endosymbionts associated with the date palm hopper, Ommatissus lybicus populations. AB - The date palm hopper, Ommatissus lybicus, is a key pest of the date palm, which is expected to be comprised of many allopatric populations. The current study was carried out to determine bacterial endosymbiont diversity in the different populations of this pest. Ten date palm hopper populations were collected from the main date palm growing regions in Iran and an additional four samples from Pakistan, Oman, Egypt and Tunisia for detection of primary and secondary endosymbionts using polymerase chain reaction (PCR) assay with their specific primers. The PCR products were directly sequenced and edited using SeqMan software. The consensus sequences were subjected to a BLAST similarity search. The results revealed the presence of 'Candidatus Sulcia muelleri' (primary endosymbiont) and Wolbachia, Arsenophonus and Enterobacter (secondary endosymbionts) in all populations. This assay failed to detect 'Candidatus Nasuia deltocephalinicola' and Serratia in these populations. 'Ca. S. muelleri' exhibited a 100% infection frequency in populations and Wolbachia, Arsenophonus and Enterobacter demonstrated 100, 93.04 and 97.39% infection frequencies, respectively. The infection rate of Arsenophonus and Enterobacter ranged from 75 to 100% and 62.5 to 100%, respectively, in different populations of the insect. The results demonstrated multiple infections by 'Ca. Sulcia muelleri', Wolbachia, Arsenophonus and Enterobacter in the populations and may suggest significant roles for these endosymbionts on date palm hopper population fitness. This study provides an insight to endosymbiont variation in the date palm hopper populations; however, further investigation is needed to examine how these endosymbionts may affect host fitness. PMID- 28807086 TI - Oral steroids alone or followed by intranasal steroids versus watchful waiting in the management of otitis media with effusion. AB - OBJECTIVE: To evaluate the effects of oral steroids alone or followed by intranasal steroids versus watchful waiting on the resolution of otitis media with effusion in children aged 2-11 years. METHODS: A total of 290 children with bilateral otitis media with effusion were assigned to 3 groups: group A was treated with oral steroids followed by intranasal steroids, group B was treated with oral steroids alone and group C was managed with watchful waiting. Patients were evaluated with audiometry and tympanometry. RESULTS: The complete resolution rates of otitis media with effusion were higher in groups A and B than in group C at six weeks. There were no significant differences in otitis media with effusion resolution rates between the groups at three, six and nine months. CONCLUSION: Oral steroids lead only to a quick resolution of otitis media with effusion, with no long-term benefits. There was no benefit of using intranasal steroids in the management of otitis media with effusion. PMID- 28807087 TI - Allergic Bronchopulmonary Mycosis due to Exposure to Eurotium herbariorum after the Great East Japan Earthquake. AB - BACKGROUND: Indoor mold levels typically increase after natural disasters, flooding, and water damage. Eurotium herbariorum is the sexual stage of Aspergillus glaucus. Case Presentation A 66-year-old, Japanese male, ex-smoker had been diagnosed with bronchial asthma when he was five years old; he achieved remission at the age of 13 years. He was displaced from his home during the Great East Japan Earthquake on March 11, 2011 and moved to temporary housing in Miyagi Prefecture in June 2011. He experienced the first episode of chest tightness, coughing, and wheezing in February 2012, when he again was diagnosed as having bronchial asthma. Mycofloral surveillance detected high counts of Eurotium in the air of his bedroom, kitchen, and living room, with a maximal fungal count of 163,200 colony-forming units per cubic meter (CFU/m3). Although Cladosporium and Penicillium typically predominate in the indoor air of residential dwellings, only low levels of these organisms were present in the patient's home. Morphologic identification confirmed the isolates as E. herbariorum. The patient had positive reactions to E. herbariorum in skin prick testing and the presence of antigen-specific precipitating antibodies to E. herbariorum. Computed tomography of the chest in August 2013 revealed central bronchiectasis and bronchial wall thickening. The patient experienced late reactions after provocation testing with E. herbariorum. CONCLUSION: This report presents the rare case of a patient who developed allergic bronchopulmonary mycosis (ABPM) due to exposure to E. herbariorum during temporary housing after the Great East Japan Earthquake. Oshikata C , Watanabe M , Saito A , Ishida M , Kobayashi S , Konuma R , Kamata Y , Terajima J , Cho J , Yanai M , Tsurikisawa N . Allergic bronchopulmonary mycosis due to exposure to eurotium herbariorum after the Great East Japan Earthquake. Prehosp Disaster Med. 2017;32(6):688-690. PMID- 28807088 TI - Posterior translacrimal approach to the maxillary sinus. AB - BACKGROUND: This study aimed to compare the view into the maxillary sinus using the posterior translacrimal approach compared with grade 3 antrostomy. METHODS: Grade 3 antrostomy followed by a posterior translacrimal approach was performed on four cadavers. The maximum intramaxillary view was documented endoscopically guided by electromagnetic navigation. Representative screenshots were evaluated in a blinded manner by three independent sinus surgeons. In addition, a prospective investigation of specific complications in the post-operative course of consecutive patients was performed. RESULTS: In the cadaver study, the posterior translacrimal approach provided a significantly better view into the maxillary sinus compared with grade 3 antrostomy. In the clinical study, only 1 out of 20 patients reported on a minor problem with lacrimal drainage at 6 months. CONCLUSION: The posterior translacrimal approach to visualising the maxillary sinus should be considered a strong alternative to more radical techniques. PMID- 28807089 TI - Supramolecular-Based Ultrasonic-Assisted Dispersion Solidification Liquid-Liquid Microextraction of Copper and Cobalt Prior to Their Flame Atomic Absorption Spectrometry Determination. AB - In the present work, a simple, efficient, and environmentally friendly method was proposed for the simultaneous preconcentration and determination of minute quantities of copper and cobalt in water samples and serum by a supramolecular based ultrasonic-assisted dispersion solidification liquid-liquid microextraction (DSLLME) procedure coupled with flame atomic absorption spectrometry. The procedure is based on the DSLLME of copper and cobalt with decanoic acid tetrahydrofuran supramolecular solvent (SUPRAS) in the presence of sodium diethyldithiocarbamate, as the complexing agent. SUPRAS is a nanostructured liquid generated from amphiphiles through a sequential self-assembly process occurring on two scales, molecular and nano. Several variables that affect the extraction efficiency-including pH, concentration of complexing agent, volume of the extraction and dispersive solvents (volume of SUPRAS), sonication time, and ionic strength-were investigated and optimized. The method provided enrichment factors of 23.31 and 22.38 for copper and cobalt, respectively. The preconcentration factor for the two analytes was 20.00. Calibration plots were linear in the range of 5.00-700.00 ng/mL for copper and 5.00-500.00 ng/mL for cobalt, with correlations of determination of 0.9973 and 0.9981. The precision of the method were expressed as RSDs for six replicate measurements and LODs and found to be +/-4.10 and +/-2.30% for copper and 2.90 and 3.50 ng/mL for cobalt. The proposed method was successfully applied to the simultaneous determination of trace copper and cobalt in real water samples and serum with satisfactory results. PMID- 28807090 TI - Mass Spectral Characterization and UPLC Quantitation of 3-Deoxyanthocyanidins in Sorghum bicolor Varietals. AB - A quantitative ultra-performance LC (UPLC) method was developed and validated to successfully separate, identify, and quantitate the major polyphenolic compounds present in different varieties of sorghum (Sorghum bicolor) feedstock. The method was linear from 3.2 to 320 ppm, with an r2 of 0.99999 when using luteolinidin chloride as the external standard. Method accuracy was determined to be 99.5%, and precision of replicate preparations was less than 1% RSD. Characterization by UPLC-MS determined that the predominant polyphenolic components of the sorghum varietals were 3-deoxyanthocyanidins (3-DXAs). High-throughput screening for 3 DXA identified four unique classes within the sorghum varieties. Certain feedstock varieties have been found to have a high potential to not only be plant based colorants, but also provide significant amounts of bioactive 3-DXAs, making them of unique interest to the dietary supplement industry. PMID- 28807091 TI - Rapid and Sensitive Determination of 13 Components in a Traditional Chinese Medicine Formula of Da-Huang-Gan-Cao Decoction by High-Performance Liquid Chromatography Coupled with Triple Quadrupole Mass Spectrometry. AB - Da-Huang-Gan-Cao decoction (DHGCD), which is a classic formula in traditional Chinese medicine, has been clinically used for the treatment of vomiting, constipation, pancreatitis, and cholelithiasis in China and Japan. In this study, a rapid and validated method using HPLC coupled with triple quadrupole MS was developed for the simultaneous determination of 13 components in DHGCD. Separation was performed on an XBridge BEH C18 column (50 * 2.1 mm, 2.5 MUm) with a gradient elution of acetonitrile and 0.1% formic acid in water. All calibration curves showed good linear regression (r > 0.9981) within the test range. LODs and LOQs were in the range of 1.0-20 and 2.6-69 ng/mL, respectively. The proposed method was applied for the analysis of the target compounds in 10 batches of DHGCD within a total time of 10 min. This method was conducive for the QC of DHGCD. PMID- 28807092 TI - Extraction and Determination of Trace Amounts of p-Coumaric Acid in Vinegar, Carrot Juice, and Seed Extract from Silybum marianum (L.) Gaertn. AB - In this study, for the monitoring and quantification of p-coumaric acid (p-CA) in vinegar, carrot juice, and seed extract from the plant species Silybum marianum (L.) Gaertn, an efficient and low-cost analytical method has been applied. For this purpose, a dispersive liquid-liquid microextraction (DLLME) method, followed by UV-Vis spectrophotometric detection, was used. To form a cloudy solution, a binary mixture containing ethanol as a disperser solvent and chloroform as an extraction solvent was rapidly injected by syringe into a sample solution containing p-CA. After centrifugation, dilution of the obtained organic phase was done with the proper amount of ethanol, and the phase was transferred into a micro cell for subsequent measurement. Some effective parameters for the DLLME method, such as the volume of disperser solvent and extraction solvent, pH, and salt concentration were inspected by a 24 full factorial central composite design using design Export Software. Under the optimized conditions, linearity was between 10 and 150 ng/mL, and the LOD was 2.3 ng/mL. The results of the proposed method were similar to the obtained results using a GC with flame-ionization detection method. PMID- 28807093 TI - MC-Media Pad SA (Sanita-kun SA) for the Enumeration of Staphylococcus aureus in a Variety of Foods. AB - MC-Media Pad SA (formerly known as Sanita-kun SA) is a dry rehydratable film medium for the enumeration of Staphylococcus aureus. The performance of the method in a variety of foods was compared with that of ISO 6888-1:1999, Microbiology of Food and Animal Feeding Stuffs - Horizontal Method for the Enumeration of Coagulase-Positive Staphylococci (Staphylococcus aureus and Other Species) - Part 1: Technique Using Baird-Parker Agar Medium. The validated matrixes included pastrami, a sliced cooked chicken roll, cooked prawns, cold smoked salmon, pasta salad, sandwich spread, fresh uncooked pasta, infant cereal, custard, and raw-milk Brie cheese. In the matrix study, five replicates at each of three contamination levels were tested as paired test portions. Across all matrixes, the difference in mean log10 values ranged from -0.32 to 0.10, which was within the acceptable range of -0.50 to 0.50. Thus, all 10 matrixes met the acceptance criterion at all concentration levels. Further, only two matrixes, cooked prawns and raw-milk Brie cheese, had 95% confidence limits outside the 0.50 to 0.50 criterion, and these were at the lowest concentration level for each matrix. The candidate method sr varied from 0.03 to 0.22 log10 CFU/g. This compares favorably with the reference method SD, which ranged from 0.06 to 0.30 log10 CFU/g. The candidate and reference methods detected 51 of 53 inclusivity strains, with both methods not detecting the same two strains. The candidate method did not detect any of the 32 exclusivity strains, whereas the reference method did not detect 30 of the 32 exclusivity strains; the 2 strains detected by the reference method were S. delphini and S. hyicus, both developing atypical colonies on Baird-Parker plates. The product consistency study demonstrated no significant difference between lots of product and supported the 1 year shelf life. Robustness testing yielded no significant differences when small variations were made in sample volume, incubation temperature, and incubation time. Thus, the data show equivalent or better performance of the Sanita-kun SA/MC-Media Pad SA method compared with the International Organization for Standardization reference method, in support of AOAC Performance Tested MethodSM certification. PMID- 28807094 TI - Mesonia maritima sp. nov., isolated from seawater of the South Sea of Korea. AB - A yellow-pigmented bacterial strain, originally designated 15-S14-6T, was isolated from the southern coastal waters of Korea and was subjected to taxonomic study using a polyphasic approach. Strain 15-S14-6T was Gram-staining-negative, flagellated, rod-shaped and aerobic. The strain grew optimally at 25-30 degrees C, in the presence of 2 % (w/v) NaCl and at pH 7.5-8.0. The results of phylogenetic analysis based on 16S rRNA gene sequences indicated that 15-S14-6T represented a member of the genus Mesonia and exhibited the highest sequence similarity (98.0 %) with Mesonia aquimarina IMCC1021T, followed by Mesonia mobilis KMM 6059T (96.7 %) and Mesonia phycicola MDSW-25T (96.1 %). DNA-DNA relatedness between 15-S14-6T and M. aquimarina IMCC1021T was 11.2+/-1.6 % (12.3+/-0.3 % in a reciprocal experiment). Strain 15-S14-6T had a DNA G+C content of 34.4 mol% and had MK-6 as the predominant menaquinone. Furthermore, iso-C15 : 0, iso-C17 : 0 3-OH and summed feature 3 were identified as the major fatty acids. Phosphatidylethanolamine, two unknown aminolipids, an unknown phospholipid and four other unknown lipids were determined to be the major polar lipids. Based on phenotypic properties and phylogenetic data presented here, 15-S14-6T represents a novel species within the genus Mesonia , for which the name Mesonia maritima sp. nov. is proposed. The type strain is 15-S14-6T (= KCCM 43197T, NCAIM B.02633T, CGMCC 1.16020T). PMID- 28807095 TI - Simultaneous Detection of 13 Key Bacterial Respiratory Pathogens by Combination of Multiplex PCR and Capillary Electrophoresis. AB - OBJECTIVE: Lower respiratory tract infections continue to pose a significant threat to human health. It is important to accurately and rapidly detect respiratory bacteria. To compensate for the limits of current respiratory bacteria detection methods, we developed a combination of multiplex polymerase chain reaction (PCR) and capillary electrophoresis (MPCE) assay to detect thirteen bacterial pathogens responsible for lower respiratory tract infections, including Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, Mycoplasma pneumoniae, Legionella spp., Bordetella pertussis, Mycobacterium tuberculosis complex, Corynebacterium diphtheriae, and Streptococcus pyogenes. METHODS: Three multiplex PCR reactions were built, and the products were analyzed by capillary electrophoresis using the high-throughput DNA analyzer. The specificity of the MPCE assay was examined and the detection limit was evaluated using DNA samples from each bacterial strain and the simulative samples of each strain. This assay was further evaluated using 152 clinical specimens and compared with real-time PCR reactions. For this assay, three nested-multiplex-PCRs were used to detect these clinical specimens. RESULTS: The detection limits of the MPCE assay for the 13 pathogens were very low and ranged from 10-7 to 10-2 ng/MUL. Furthermore, analysis of the 152 clinical specimens yielded a specificity ranging from 96.5%-100.0%, and a sensitivity of 100.0% for the 13 pathogens. CONCLUSION: This study revealed that the MPCE assay is a rapid, reliable, and high-throughput method with high specificity and sensitivity. This assay has great potential in the molecular epidemiological survey of respiratory pathogens. PMID- 28807096 TI - A Five-year Surveillance of Carbapenemase-producing Klebsiella pneumoniae in a Pediatric Hospital in China Reveals Increased Predominance of NDM-1. AB - OBJECTIVE: To characterize carbapenem (CPM)-non-susceptible Klebsiella pneumoniae (K. pneumoniae) and carbape-nemase produced by these strains isolated from Beijing Children's Hospital based on a five-year surveillance. METHODS: The Minimal Inhibition Concentration values for 15 antibiotics were assessed using the Phonix100 compact system. PCR amplification and DNA sequencing were used to detect genes encoding carbapenemases. WHONET 5.6 was finally used for resistance analysis. RESULTS: In total, 179 strains of CPM-non-susceptible K. pneumoniae were isolated from January, 2010 to December, 2014. The rates of non-susceptible to imipenem and meropenem were 95.0% and 95.6%, respectively. In the 179 strains, 95 (53.1%) strains carried the blaIMP gene, and IMP-4 and IMP-8 were detected in 92 (96.8%) and 3 (3.2%) IMP-producing isolates, respectively. 65 (36.3%) strains carried the blaNDM-1 gene. 6 (3.4%) strains carried the blaKPC gene, and KPC-2 were detected in 6 KPC-producing isolates. In addition, New Delhi-Metallo-1 (NDM 1) producing isolates increased from 7.1% to 63.0% in five years and IMP-4 producing isolates decreased from 75.0% to 28.3%. CONCLUSION: High frequencies of multiple resistances to antibiotics were observed in the CPM-non-susceptible K. pneumoniae strains isolated from Beijing Children's Hospital. The production of IMP-4 and NDM-1 metallo-beta-lactamases appears to be an important mechanism for CPM-non- susceptible in K. pneumoniae. PMID- 28807097 TI - Genotypic Characterization of Methicillin-resistant Staphylococcus aureus Isolated from Pigs and Retail Foods in China. AB - OBJECTIVE: To investigate the genotypic diversity of Methicillin-resistant Staphylococcus aureus (MRSA) isolated from pigs and retail foods from different geographical areas in China and further to study the routes and rates of transmission of this pathogen from animals to food. METHODS: Seventy-one MRSA isolates were obtained from pigs and retail foods and then characterized by multi locus sequencing typing (MLST), spa typing, multiple-locus variable number of tandem repeat analysis (MLVA), pulsed-field gel electrophoresis (PFGE), and antimicrobial susceptibility testing. RESULTS: All isolated MRSA exhibited multi drug resistance (MDR). Greater diversity was found in food-associated MRSA (7 STs, 8 spa types, and 10 MLVA patterns) compared to pig-associated MRSA (3 STs, 1 spa type, and 6 MLVA patterns). PFGE patterns were more diverse for pig associated MRSA than those of food-associated isolates (40 vs. 11 pulse types). Among the pig-associated isolates, CC9-ST9-t899-MC2236 was the most prevalent clone (96.4%), and CC9-ST9-t437-MC621 (20.0%) was the predominant clone among the food-associated isolates. The CC9-ST9 isolates showed significantly higher antimicrobial resistance than other clones. Interestingly, CC398-ST398-t034 clone was identified from both pig- and food-associated isolates. Of note, some community- and hospital-associated MRSA strains (t030, t172, t1244, and t4549) were also identified as food-associated isolates. CONCLUSION: CC9-ST9-t899-MC2236 MDR was the most predominant clone in pigs, but significant genetic diversity was observed in food-associated MRSA. Our results demonstrate the great need for improved surveillance of MRSA in livestock and food and effective prevention strategies to limit MDR-MRSA infections in China. PMID- 28807098 TI - Protective Effect of Ozone against Hemiscorpius lepturus Envenomation in Mice. AB - OBJECTIVE: Scorpion (Hemiscorpius lepturus) stings are a public health concern in Iran, particularly in south and southwestern regions of Iran. The gold standard for the treatment of a scorpion sting is anti-venom therapy. However, immunotherapy can have serious side effects, such as anaphylactic shock (which can sometimes even lead to death). The aim of the current study was to demonstrate the protective effect of ozone against toxicity induced by Hemiscorpius lepturus (H. lepturus) venom in mice. METHODS: Eight hours after the injection of ozone to the experimental design groups, the male mice were decapitated and mitochondria were isolated from five different tissues (liver, kidney, heart, brain, and spinal cord) using differential ultracentrifugation. Then, assessment of mitochondrial parameters including mitochondrial reactive oxidative species (ROS) production, mitochondrial membrane potential (MMP), ATP level, and the release of cytochrome c from the mitochondria was performed. RESULTS: Our results showed that H. lepturus venom-induced oxidative stress is related to ROS production and MMP collapse, which is correlated with cytochrome c release and ATP depletion, indicating the predisposition to the cell death signaling. CONCLUSION: In general, ozone therapy in moderate dose can be considered as clinically effective for the treatment of H. lepturus sting as a protective and antioxidant agent. PMID- 28807099 TI - Role of Endoplasmic Reticulum Stress in Silica-induced Apoptosis in RAW264.7 Cells. AB - OBJECTIVE: We investigated the role of endoplasmic reticulum stress (ERS) in silica-induced apoptosis in alveolar macrophages in vitro. METHODS: RAW264.7 cells were incubated with 200 MUg/mL silica for different time periods. Cell viability was assayed by the MTT assay. Cell apoptosis was evaluated by DAPI staining, flow cytometry analysis, and Western blot analysis of caspase-3. Morphological changes in the endoplasmic reticulum were observed by transmission electron microscopy. The expression of ERS markers binding protein (BiP) and CCAAT-enhancer-binding protein homologous protein (CHOP) was examined by Western blotting and real-time PCR. As an inhibitor of ERS, 4-phenylbutyric acid (4-PBA) was used in the experiments. RESULTS: Silica exposure induced nuclear condensation and caspase-3 expression in RAW264.7 cells. The number of apoptotic cells increased after silica exposure in a time-dependent manner. Silica treatment induced expansion of the endoplasmic reticulum. In addition, the expression of BiP and CHOP increased in silica-stimulated cells. Furthermore, 4 PBA treatment inhibited silica-induced endoplasmic reticulum expansion and the expression of BiP and CHOP. Moreover, 4-PBA treatment attenuated nuclear condensation, reduced apoptotic cells, and downregulated caspase-3 expression in silica-stimulated cells. CONCLUSION: Silica-induced ERS is involved in the apoptosis of alveolar macrophages. PMID- 28807100 TI - Two Cases of Multi-antibiotic Resistant Cronobacter spp. Infections of Infants in China. AB - Infections by Cronobacter spp. are hazardous to infants since they can lead to neonatal meningitis, bacteremia, and necrotizing enterocolitis. Cronobacter spp. are frequently resistant to beta-lactam derivatives, macrolides, and aminoglycosides. In addition, multi-resistant strains have also been detected. In China, the isolation rate of Cronobacter spp. from commercial powdered infant formula (PIF) or follow-up formula (FUF) is relatively high. Nevertheless, clinical cases of Cronobacter infection have been ignored to date. Here we describe two cases of Cronobacter infection detected at the Wuhan Women and Children Medical Care Center Hospital (Wuhan City, China). We provide the genomic analysis of the isolates and the antibiotic-resistance profiles of the two strains. The Cronobacter strains identified in this study were not susceptible to third-generation cephalosporins, aminoglycoside, and/or trimethoprim sulfamethoxazole. Whole genome sequencing revealed various genes known to encode antibiotic resistance. Future studies are needed to determine whether the genes predicted in this study are functional. As with Enterobacter spp., the antibiotic resistance of Cronobacter is a serious issue that requires more attention. PMID- 28807101 TI - Examine the Correlation between Heat Shock Protein IbpA and Heat Tolerance in Cronobacter sakazakii. AB - We used a proteomic approach to identify IbpA in Cronobacter sakazakii (C. sakazaki), which is related to heat tolerance in this strain. The abundance of IbpA in C. sakazakii strains strongly increased after heat shock. C. sakazakii CMCC 45402 ibpA deletion mutants were successfully constructed. The C. sakazakii CMCC 45402 DeltaibpA and wild-type strains could not be distinguished based on colony morphology on LB agar plates or biochemical assays. The growth of the C. sakazakii CMCC 45402 DeltaibpA mutant in heat shock conditions was indistinguishable from that of the isogenic wild-type, but showed greater heat resistance than E. coli O157:H7 strain CMCC 44828. This study suggests that the absence of a single ibpA gene has no obvious effect on the phenotype or heat resistance of the strain C. sakazakii CMCC 45402. PMID- 28807102 TI - Bitter Melon Powder Protects against Obesity-associated Fatty Liver Disease by Improving Colonic Microenvironment in Rats with High-fat Diet-induced Obesity. AB - This study explored how bitter melon powder (BMP) alters the colonic microenvironment during the development of obesity-associated fatty liver in rats. We observed that BMP effectively inhibited the body weight gain and lipid accumulation in the liver, ameliorated glucose intolerance, and increased the colon weight after an 8-week treatment compared to that in the high-fat diet (HFD) group. BMP significantly decreased fecal water toxicity towards HT-29 cells, as revealed by the cell counting kit (CCK)-8 assay results, and the mRNA expression of Toll-like receptor 4 (TLR4) in colon mucosa. Additionally, gut permeability in the BMP group was restored to normal levels. Finally, BMP alleviated the inflammatory state of the rat colon mucosa and liver tissues as well as the systemic inflammation. PMID- 28807103 TI - Research Progress in Occupational Health Risk Assessment Methods in China. PMID- 28807104 TI - Understanding practitioner professionalism in Aboriginal and Torres Strait Islander health: lessons from student and registrar placements at an urban Aboriginal and Torres Strait Islander primary healthcare service. AB - Aboriginal and Torres Strait Islander peoples continue to be pathologised in medical curriculum, leaving graduates feeling unequipped to effectively work cross-culturally. These factors create barriers to culturally safe health care for Aboriginal and Torres Strait Islander peoples. In this pilot pre-post study, the learning experiences of seven medical students and four medical registrars undertaking clinical placements at an urban Aboriginal and Torres Strait Islander primary healthcare service in 2014 were followed. Through analysis and comparison of pre- and post-placement responses to a paper-based case study of a fictitious Aboriginal patient, four learning principles for medical professionalism were identified: student exposure to nuanced, complex and positive representations of Aboriginal peoples; positive practitioner role modelling; interpersonal skills that build trust and minimise patient-practitioner relational power imbalances; and knowledge, understanding and skills for providing patient-centred, holistic care. Though not exhaustive, these principles can increase the capacity of practitioners to foster culturally safe and optimal health care for Aboriginal peoples. Furthermore, competence and effectiveness in Aboriginal health care is an essential component of medical professionalism. PMID- 28807105 TI - RIPK1-RIPK3-MLKL-dependent necrosis promotes the aging of mouse male reproductive system. AB - A pair of kinases, RIPK1 and RIPK3, as well as the RIPK3 substrate MLKL cause a form of programmed necrotic cell death in mammals termed necroptosis. We report here that male reproductive organs of both Ripk3- and Mlkl-knockout mice retain 'youthful' morphology and function into advanced age, while those of age-matched wild-type mice deteriorate. The RIPK3 phosphorylation of MLKL, the activation marker of necroptosis, is detected in spermatogonial stem cells in the testes of old but not in young wild-type mice. When the testes of young wild-type mice are given a local necroptotic stimulus, their reproductive organs showed accelerated aging. Feeding of wild-type mice with an RIPK1 inhibitor prior to the normal onset of age-related changes in their reproductive organs blocked the appearance of signs of aging. Thus, necroptosis in testes promotes the aging-associated deterioration of the male reproductive system in mice. PMID- 28807106 TI - Developmental adaptations of trypanosome motility to the tsetse fly host environments unravel a multifaceted in vivo microswimmer system. AB - The highly motile and versatile protozoan pathogen Trypanosoma brucei undergoes a complex life cycle in the tsetse fly. Here we introduce the host insect as an expedient model environment for microswimmer research, as it allows examination of microbial motion within a diversified, secluded and yet microscopically tractable space. During their week-long journey through the different microenvironments of the fly's interior organs, the incessantly swimming trypanosomes cross various barriers and confined surroundings, with concurrently occurring major changes of parasite cell architecture. Multicolour light sheet fluorescence microscopy provided information about tsetse tissue topology with unprecedented resolution and allowed the first 3D analysis of the infection process. High-speed fluorescence microscopy illuminated the versatile behaviour of trypanosome developmental stages, ranging from solitary motion and near-wall swimming to collective motility in synchronised swarms and in confinement. We correlate the microenvironments and trypanosome morphologies to high-speed motility data, which paves the way for cross-disciplinary microswimmer research in a naturally evolved environment. PMID- 28807107 TI - Etiologies and management of cutaneous flushing: Nonmalignant causes. AB - The flushing phenomenon may represent a physiologic or a pathologic reaction. Although flushing is usually benign, it is prudent that the physician remains aware of potentially life-threatening conditions associated with cutaneous flushing. A thorough investigation should be performed if the flushing is atypical or not clearly associated with a benign underlying process. The diagnosis often relies on a pertinent history, review of systems, physical examination, and various laboratory and imaging modalities, all of which are discussed in the 2 articles in this continuing medical education series. This article reviews flushing associated with fever, hyperthermia, emotions, menopause, medications, alcohol, food, hypersensitivity reactions, rosacea, hyperthyroidism, dumping syndrome, superior vena cava syndrome, and neurologic etiologies. PMID- 28807108 TI - Etiologies and management of cutaneous flushing: Malignant causes. AB - The second article in this 2-part continuing medical education series reviews the following malignant causes of flushing: mastocytosis, medullary thyroid carcinoma, pheochromocytoma, carcinoid tumors, gastroenteropancreatic neuroendocrine tumors, bronchogenic carcinoma, vasointestinal polypeptide secreting tumors, and renal cell carcinoma. The information provided will allow physicians to better distinguish patients who have worrisome presentations that require a more thorough investigation. Appropriate diagnostic workup and treatment options for these malignancies are reviewed. PMID- 28807109 TI - Psoriasis and suicidality: A systematic review and meta-analysis. AB - BACKGROUND: Psoriasis is associated with psychiatric comorbidities; however, the relationship between psoriasis and suicidality is not well understood. OBJECTIVE: To perform a systematic review and meta-analysis that elucidates the relationship between psoriasis and suicidality. METHODS: Applying the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we systematically searched the PubMed, EMBASE, PsycINFO, and Cochrane databases. We searched literature published between 1946 and 2017. RESULTS: We identified 18 studies with a total of 1,767,583 participants, of whom 330,207 had psoriasis. On the basis of random effects modeling, the pooled odds ratio (OR) for suicidal ideation among patients with psoriasis was 2.05 (95% confidence interval [CI], 1.54-2.74). Patients with psoriasis were more likely to exhibit suicidal behaviors (combined attempted and completed suicides) with a pooled OR of 1.26 (95% CI, 1.13-1.40). Subgroup analysis showed that patients with psoriasis were more likely to attempt suicides (OR, 1.32; 95% CI, 1.14-1.54) and complete suicide (OR, 1.20; 95% CI, 1.04-1.39) than those without psoriasis. More severe psoriasis and younger age were associated with greater likelihood of suicidality. LIMITATIONS: There are few studies examining suicidality in conjunction with psoriasis severity. CONCLUSIONS: Patients with psoriasis have a significantly higher likelihood of suicidal ideation, suicide attempts, and completed suicides. Among patients with psoriasis, those who are younger and whose psoriasis is more severe are at particular risk for suicidality. PMID- 28807110 TI - How similar are the treatment responses to biosimilars in patients with psoriasis? A systematic review of statistical margins in comparative clinical trials. PMID- 28807111 TI - Prevalence of chronic hepatitis B and C in psoriasis patients: A cross-sectional study in a large US population. PMID- 28807112 TI - Smoking and risk of psoriasis: A nationwide cohort study. PMID- 28807113 TI - Circulating vitamin D-binding protein and free 25-hydroxyvitamin D concentrations in patients with melanoma: A case-control study. PMID- 28807115 TI - Correlation between HPV status via in situ hybridization testing on genital squamous papillomas and risk for cervical dysplasia or other anogenital HPV related complications: A case-control study. PMID- 28807116 TI - Keratinocyte carcinoma data for Hispanic patients undergoing Mohs micrographic surgery in Miami, Florida from 2011 to 2014. PMID- 28807117 TI - Efficacy of curettage alone for invasive cutaneous squamous cell carcinoma: A retrospective cohort study. PMID- 28807114 TI - A prospective, randomized, double-blinded, split-face/chest study of prophylactic topical dapsone 5% gel versus moisturizer for the prevention of cetuximab-induced acneiform rash. PMID- 28807118 TI - Efficacy of autologous platelet-rich plasma combined with hyaluronic acid on skin facial rejuvenation: A prospective study. PMID- 28807119 TI - Gifts: Are there strings attached? PMID- 28807120 TI - Spontaneous upper eyelid ecchymosis: A cutaneous clue to increased intracranial pressure. PMID- 28807121 TI - Fractional carbon dioxide laser in combination with topical corticosteroid: An innovative treatment for hypertrophic lichen planus. PMID- 28807122 TI - Fractionated cryotherapy. PMID- 28807123 TI - A simple and effective technique for hair control in dermatologic surgery. PMID- 28807124 TI - The pinch stitch. PMID- 28807125 TI - Nail debridement after ablative fractional laser treatment and occlusive dressing with urea 20% cream: An alternative to nail extraction. PMID- 28807126 TI - Radiation therapy for nonmelanoma skin cancer, a cost comparison: 2016 coding changes to radiation therapy. PMID- 28807127 TI - Measuring ultraviolet A protection in sunscreen products. PMID- 28807128 TI - Partial biopsies and persistent nevi: Communicate clearly and proceed with caution. PMID- 28807129 TI - Reply: Do moderately dysplastic nevi with positive histologic margins need to be reexcised? PMID- 28807130 TI - Response to: "The role of cannabinoids in dermatology". PMID- 28807131 TI - In reply. PMID- 28807132 TI - Primary health care workers' knowledge and attitudes towards depression and its management in the MeHPric-P project, Lagos, Nigeria. AB - OBJECTIVE: This study aimed to evaluate the knowledge, perceived challenges and attitude of primary health care (PHC) workers in Lagos to depression and its management in the PHC. METHODS: Health workers (n=607) from 49 "flagship" PHCs in Lagos were evaluated for their level of knowledge, experience, competence, attitude and perceived challenges to managing depression in the primary care using a case vignette. RESULTS: More than half (56.2%) of the health workers correctly diagnosed depression. The most endorsed causative factors were "Psycho social" (77.3%), but "spiritual factors" were endorsed by 36.2%. While only 39.4% agreed that the depressed patient is best managed in a PHC, 86.2% would support treating the patient in their PHC if their capacity is enhanced. Top identified challenges were "heavy work schedule" (68.5%) and "lack of competence of the PHC staff" (67.5%). Over 42% had poor attitude towards depressed patient. Having a mental health training was the major factor that predicted good knowledge (OR 4.52, 95%CI 2.96-7.00) and good attitude (OR 2.17, 95% CI 1.48-3.17). CONCLUSIONS: For successful scale up of mental health services in LMICs, the design of mental health training curriculum for PHC workers should consider their knowledge, experience, competence level, perception and attitudes. PMID- 28807133 TI - The tense, the hostile and the distressed: multidimensional psychosocial risk profiles based on the ESC interview in coronary artery disease patients - the THORESCI study. AB - BACKGROUND: While single psychosocial factors have been associated with cardiovascular outcomes, it is still unclear how they cluster. Therefore, we examined whether latent multidimensional psychosocial risk profiles could be identified in the European Society of Cardiology (ESC) psychosocial screening interview. Additionally we examined whether these profiles were associated with specific sociodemographic, clinical, and psychosocial characteristics. METHOD: 681 coronary artery disease patients (age=64.9+/-10.6; 80% men) completed the ESC interview, comprising 15 items on 7 predefined components. Multiple self-report questionnaires focusing on demographics, mood symptoms, personality, coping, and life events were used. Clinical information was extracted from patients' medical records. RESULTS: Latent class analysis identified four psychological classes: 1. Low psychological distress (62%), 2. High hostility (19%), 3. High tension (11%), 4. High psychological distress (8%), and two social classes: Low chronic stress (81%), and High work stress (%19). Characteristics increasing the odds to belong to the "High hostility" class were male sex, negative affectivity, and psychiatric history. "High tension" membership was associated with female sex, being single, a sedentary lifestyle, seeking social support, NA, early adverse life-events, depression, anxiety, and psychiatric history. "High psychological stress" characteristics were younger age, smoking, a sedentary lifestyle, NA, depression, anxiety, early adverse life-events, psychiatric history. Being younger, alcohol use and avoidance-oriented coping increased the odds to be in the "High work stress" class. CONCLUSIONS: This study characterized four psychological and two social latent risk profiles. Results indicate the importance of a multidimensional psychosocial screening, potentially uncovering differential mechanistic pathways, which also may prove beneficial in clinical practice and in risk prevention strategies. PMID- 28807134 TI - Classification of suicide attempters in schizophrenia using sociocultural and clinical features: A machine learning approach. AB - OBJECTIVE: Suicide is a major concern for those afflicted by schizophrenia. Identifying patients at the highest risk for future suicide attempts remains a complex problem for psychiatric interventions. Machine learning models allow for the integration of many risk factors in order to build an algorithm that predicts which patients are likely to attempt suicide. Currently it is unclear how to integrate previously identified risk factors into a clinically relevant predictive tool to estimate the probability of a patient with schizophrenia for attempting suicide. METHODS: We conducted a cross-sectional assessment on a sample of 345 participants diagnosed with schizophrenia spectrum disorders. Suicide attempters and non-attempters were clearly identified using the Columbia Suicide Severity Rating Scale (C-SSRS) and the Beck Suicide Ideation Scale (BSS). We developed four classification algorithms using a regularized regression, random forest, elastic net and support vector machine models with sociocultural and clinical variables as features to train the models. RESULTS: All classification models performed similarly in identifying suicide attempters and non-attempters. Our regularized logistic regression model demonstrated an accuracy of 67% and an area under the curve (AUC) of 0.71, while the random forest model demonstrated 66% accuracy and an AUC of 0.67. Support vector classifier (SVC) model demonstrated an accuracy of 67% and an AUC of 0.70, and the elastic net model demonstrated and accuracy of 65% and an AUC of 0.71. CONCLUSION: Machine learning algorithms offer a relatively successful method for incorporating many clinical features to predict individuals at risk for future suicide attempts. Increased performance of these models using clinically relevant variables offers the potential to facilitate early treatment and intervention to prevent future suicide attempts. PMID- 28807135 TI - Suicidal ideation and suicidal self-directed violence following clinician initiated prescription opioid discontinuation among long-term opioid users. AB - OBJECTIVE: Little is known about patient outcomes following discontinuation of opioid therapy, which may include suicidal ideation (SI) and suicidal self directed violence (SSV). The purpose of this study was to examine correlates of SI and non-fatal SSV in a sample of patients discontinued from long-term opioid therapy (LTOT). METHOD: Five hundred-nine Veterans Health Administration (VHA) patients whose clinicians discontinued them from LTOT were selected from a national cohort of VHA patients who discontinued opioids in 2012. The sample comprised patients with a substance use disorder and matched controls. Patient electronic health records were manually reviewed to identify discontinuation reasons and the presence of SI or SSV in the 12months following discontinuation. RESULTS: Forty-seven patients (9.2%) had SI only, while 12 patients (2.4%) had SSV. In covariate-adjusted logistic regression models, mental health diagnoses associated with having SI/SSV included post-traumatic stress disorder (aOR=2.56, 95% CI=1.23-5.32) and psychotic disorders (aOR=3.19, 95% CI=1.14-8.89). Other medical comorbidities, substance use disorder and pain diagnoses, opioid dose, and benzodiazepine prescriptions were unrelated to SI/SSV. CONCLUSIONS: Among patients with a substance use disorder and matched controls, there are high rates of SI/SSV following opioid discontinuation, suggesting that these "high risk" patients may require close monitoring and risk prevention. PMID- 28807136 TI - Misuse of prescription opioids among chronic pain patients suffering from anxiety: A cross-sectional analysis. AB - OBJECTIVE: In the past two decades, chronic pain has been increasingly treated with prescription opioids, particularly in developed countries. This has drawn public concern of possible risks associated with the potential misuse of prescriptions opioids. Previous research has indicated that this may be particularly true among individuals suffering from co-occurring psychiatric disorders. The present study sought to explore rates of misuse among chronic pain patients prescribed opioids, comparing individuals with and without anxiety. METHODS: Chronic pain patients receiving prescription opioids (N=554) were screened for anxiety using the Generalized Anxiety Disorder (GAD-7) scale and for opioid misuse using the Current Opioid Misuse Measure (COMM). RESULTS: Among patients who screened positive for anxiety (GAD-7>=10), 50% also screened positive for opioid misuse, compared to 10% among those without anxiety. After controlling for possible confounding sociodemographic and clinical variables, patients with anxiety were significantly more prone to screen positive for opioid misuse (Adjusted Odds Ratio (AOR)=2.18; 95% Confidence Interval (CI)=1.37-4.17) compared to those without anxiety. This was maintained when conducting separate comparisons for severe, but not mild or moderate, level of anxiety. CONCLUSIONS: These findings highlight the importance of detecting and addressing co-occurring anxiety when treating patients with chronic pain who receive prescription opioids. PMID- 28807137 TI - Association of anxiety sensitivity-physical concerns and FVC with dyspnea severity in sarcoidosis. AB - OBJECTIVE: The purpose of the study was to evaluate the relationship of an objective functional lung parameter (FVC) and a subjective psychological factor (physical symptom concerns) with dyspnea in sarcoidosis. Dyspnea constitutes one of the most common and burdensome symptoms in sarcoidosis, yet little is known about its mechanisms and, in particular, psychological. METHOD: A total of 107 hospitalized sarcoidosis patients (Female=50, Mage=45.3years) volunteered to take part in the correlational research study. Participants underwent spirometry and completed the MRC Dyspnea Scale and the Anxiety Sensitivity Index-3 (ASI) questionnaire. Linear hierarchical regression analysis was used to determine the relationship between the studied predictors and dyspnea severity. RESULTS: The best fitting model predicted 18% of variance in dyspnea severity. Physical symptom concerns subscale of ASI (beta=0.24) and FVC (beta=-0.23) were significantly related to dyspnea MRC severity, but only physical concerns remained significantly related to dyspnea when both predictors were in the model. CONCLUSIONS: The current results suggest that both psychological and physiological factors should be taken into account when explaining subjective dyspnea severity in sarcoidosis. More specifically, these findings call for including cognitive vulnerability factors related to anxiety (physical symptom concerns) into the diagnostic procedures and management of dyspnea in sarcoidosis. PMID- 28807138 TI - Prevalence and predictors of post-stroke mood disorders: A meta-analysis and meta regression of depression, anxiety and adjustment disorder. AB - OBJECTIVE: To ascertain the prevalence and predictors of mood disorders, determined by structured clinical interviews (ICD or DSM criteria) in people after stroke. METHODS: Major electronic databases were searched from inception to June 2016 for studies involving major depression (MDD), minor depression (MnD), dysthymia, adjustment disorder, any depressive disorder (any depressive disorder) and anxiety disorders. Studies were combined using both random and fixed effects meta-analysis and results were stratified as appropriate. RESULTS: Depression was examined on 147 occasions from 2days to 7years after stroke (mean 6.87months, N=33 in acute, N=43 in rehabilitation and N=69 in the community/outpatients). Across 128 analyses involving 15,573 patients assessed for major depressive disorder (MDD), the point prevalence of depression was 17.7% (95% CI=15.6% to 20.0%) 0.65 analyses involving 9720 patients determined MnD was present in 13.1% in all settings (95% CI=10.9% to 15.8%). Dysthymia was present in 3.1% (95% CI=2.1% to 5.3%), adjustment disorder in 6.9% (95% CI=4.6 to 9.7%) and anxiety in 9.8% (95% CI=5.9% to 14.8%). Any depressive disorder was present in 33.5% (95% CI=30.3% to 36.8%). The relative risk of any depressive disorder was higher following left (dominant) hemisphere stroke, aphasia, and among people with a family history and past history of mood disorders. CONCLUSION: Depression, adjustment disorder and anxiety are common after stroke. Risk factors are aphasia, dominant hemispheric lesions and past personal/family history of depression but not time since stroke. PMID- 28807139 TI - Recognition of anxiety, depression, and PTSD in patients with COPD and CHF: Who gets missed? AB - OBJECTIVE: This study sought to identify patient factors associated with mental health (MH) recognition and treatment in medically ill Veterans. METHOD: Retrospective data from patient electronic medical records (EMR) and self-report data were reviewed for 180 Veterans with cardiopulmonary conditions who met diagnostic criteria for anxiety, depression, or posttraumatic stress disorder on the Mini-International Neuropsychiatric Interview. Multivariate logistic regression examined the association of medical record MH recognition and MH service use with patient factors, including anxiety and depression severity, self efficacy, locus of control, coping, illness intrusiveness, and health-related quality of life (QOL). RESULTS: Seventy veterans (39%) had an MH diagnosis documented in their EMR, and 101 (56%) received at least one MH service (>=1 MH encounter or psychiatric medications). Greater depression (p=0.047) and adaptive coping (p=0.012) were associated with increased likelihood of EMR documentation of MH diagnoses. EMR MH diagnosis (p<0.001), higher internal locus of control (p=0.037), and poorer physical health-related QOL (p=0.014) were associated with greater likelihood of MH service use. DISCUSSION: Veterans with cardiopulmonary conditions experiencing MH problems are under-recognized. Improved MH screening is needed, particularly for patients with poor adaptive coping skills, low internal locus of control, or poor physical health-related QOL. PMID- 28807140 TI - Acute psychological trauma in the critically ill: Patient and family perspectives. AB - OBJECTIVE: Post-intensive care syndrome (PICS), which encompasses profound psychological morbidity, affects many survivors of critical illness. We hypothesize that acute psychological stress during the intensive care unit (ICU) confinement likely contributes to PICS. In order to develop strategies that mitigate PICS associated psychological morbidity, it is paramount to first characterize acute ICU psychological stress and begin to understand its causative and protective factors. METHODS: A structured interview study was administered to adult critical illness survivors who received >=48h of mechanical ventilation in medical and surgical ICUs of a tertiary care center, and their families. RESULTS: Fifty patients and 44 family members were interviewed following ICU discharge. Patients reported a high level of psychological distress. The families' perception of patient's stress level correlated with the patient's self-estimated stress level both in daily life (rho=0.59; p<0.0001) and in ICU (rho=0.45; p=0.002). 70% of patients experienced fear of death, 38% had additional other fears, 48% had hallucinations. Concerns included inability to communicate (34%), environmental factors (30%), procedures and restraints (24%), and being intubated (12%). Emotional support of family/friend/staff/clergy (86%), and physical therapy/walking (14%) were perceived to be important mitigating factors. Clinicians' actions that were perceived to be very constructive included reassurance (54%), explanations (32%) and physical touch (8%). CONCLUSIONS: Fear, hallucinations, and the inability to communicate, are identified as central contributors to psychological stress during an ICU stay; the presence of family, and physician's attention are categorized as important mitigating factors. Patients and families identified several practical recommendations which may help assuage the psychological burden of the ICU stay. PMID- 28807141 TI - Psychosocial predictors of quality of life and weight loss two years after bariatric surgery: Results from the Toronto Bari-PSYCH study. AB - OBJECTIVES: Studies exploring the impact of pre-surgery psychiatric status as a predictor of health related quality of life (QOL) after bariatric surgery have been limited to short-term follow-up and variable use of psychosocial measures. We examined the effect of pre-operative psychiatric factors on QOL and weight loss 2-years after surgery. METHODS: 156 patients participated in this prospective cohort study, the Toronto Bariatric Psychosocial Cohort Study, between 2010 and 2014. Patients were assessed pre-surgery for demographic factors, weight, psychiatric diagnosis using the MINI International Neuropsychiatric Interview and symptom measures for QOL, depression and anxiety at pre-surgery and at 1 and 2years post-surgery. RESULTS: At 2-years post bariatric surgery, patients experienced a significant decrease in mean weight ( 48.43kg, 95% [-51.1, -45.76]) and an increase only in physical QOL (+18.91, 95% [17.01, 20.82]) scores as compared to pre-surgery. Multivariate regression analysis identified pre-surgery physical QOL score (p<0.001), younger age (p=0.005), and a history of a mood disorder as significant predictors of physical QOL. Only a history of a mood disorder (p=0.032) significantly predicted mental QOL (p=0.006). Pre-surgery weight (p<0.001) and a history of a mood disorder (p=0.047) were significant predictors of weight loss 2-years post-surgery. CONCLUSIONS: Bariatric surgery had a sustained impact on physical QOL but not mental QOL at 2-years post-surgery. A history of mood disorder unexpectedly increased physical QOL scores and weight loss following surgery. Further research is needed to determine if these results are due to bariatric surgery candidate selection within this program. PMID- 28807142 TI - Efficacy of lurasidone in the treatment of agitation: A post hoc analysis of five short-term studies in acutely ill patients with schizophrenia. AB - OBJECTIVE: This post hoc analysis evaluated the effect of lurasidone on agitation in acutely ill patients with schizophrenia. METHOD: Patient-level data were pooled from five 6-week, randomized, double-blind, placebo-controlled studies of fixed-dose, once-daily, oral lurasidone (40, 80, 120, or 160 mg/d). Agitation was assessed with the Positive and Negative Syndrome Scale-Excited Component (PANSS EC) score, utilizing a mixed model for repeated measurement analysis. RESULTS: In patients with higher levels of agitation at baseline (PANSS-EC score>=14; n=773), lurasidone was associated with significantly greater improvement in least-squares (LS) mean PANSS-EC scores versus placebo at Day 3/4 (-1.6 vs -1.0; p<0.05), Day 7 (-2.3 vs -1.6; p<0.05), and at Week 6 endpoint (-5.5 vs -3.8; p<0.001; effect size=0.43). In patients with lower agitation at baseline (PANSS-EC score<14; n=754), LS mean PANSS-EC score change was significantly greater for lurasidone compared with placebo at Day 7 (-0.8 vs -0.1; p<0. 01) through Week 6 endpoint ( 1.9 vs -0.9; p<0.001; effect size=0.31). Higher doses of lurasidone were notably more effective than lower doses in patients with more severe agitation at study baseline. CONCLUSION: In this pooled analysis of 5 short-term studies, lurasidone provided early and sustained reduction in agitation, assessed using the PANSS-EC score, in patients with an acute exacerbation of schizophrenia. Higher doses of lurasidone were particularly effective in patients with more severe agitation at study baseline. Overall, these results suggest that lurasidone may be a useful treatment option for patients exhibiting agitation associated with acute psychotic symptoms of schizophrenia. ClinicalTrials.gov Identifiers: NCT00088634 (Study D1050196); NCT00549718 (Study D1050229), NCT00615433 (Study D1050231); NCT00790192 (Study D1050233). Study D1050006 was completed prior to the requirement to register trials. PMID- 28807143 TI - Lifestyle interventions for weight loss among overweight and obese adults with serious mental illness: A systematic review and meta-analysis. AB - OBJECTIVE: To conduct a systematic review and meta-analysis to estimate effects of lifestyle intervention participation on weight reduction among overweight and obese adults with serious mental illness. METHOD: We systematically searched electronic databases for randomized controlled trials comparing lifestyle interventions with other interventions or usual care controls in overweight and obese adults with serious mental illness, including schizophrenia spectrum or mood disorders. Included studies reported change in weight [kg] or body mass index (BMI) [kg/m2] from baseline to follow-up. Standardized mean differences (SMD) were calculated for change in weight from baseline between intervention and control groups. RESULTS: Seventeen studies met inclusion criteria (1968 participants; 50% male; 66% schizophrenia spectrum disorders). Studies were grouped by intervention duration (<=6-months or >=12-months). Lifestyle interventions of <=6-months duration showed greater weight reduction compared with controls as indicated by effect size for weight change from baseline (SMD= 0.20; 95% CI=-0.34, -0.05; 10 studies), but high statistical heterogeneity (I2=90%). Lifestyle interventions of >=12-months duration also showed greater weight reduction compared with controls (SMD=-0.24; 95% CI=-0.36, -0.12; 6 studies) with low statistical heterogeneity (I2=0%). CONCLUSION: Lifestyle interventions appear effective for treating overweight and obesity among people with serious mental illness. Interventions of >=12-months duration compared to <=6-months duration appear to achieve more consistent outcomes, though effect sizes are similar for both shorter and longer duration interventions. PMID- 28807145 TI - A benzothiadiazine derivative and methylprednisolone are novel and selective activators of transient receptor potential canonical 5 (TRPC5) channels. AB - The transient receptor potential canonical channel 5 (TRPC5) is a Ca2+-permeable ion channel, which is predominantly expressed in the brain. TRPC5-deficient mice exhibit a reduced innate fear response and impaired motor control. In addition, outgrowth of hippocampal and cerebellar neurons is retarded by TRPC5. However, pharmacological evidence of TRPC5 function on cellular or organismic levels is sparse. Thus, there is still a need for identifying novel and efficient TRPC5 channel modulators. We, therefore, screened compound libraries and identified the glucocorticoid methylprednisolone and N-[3-(adamantan-2-yloxy)propyl]-3-(6-methyl 1,1-dioxo-2H-1lambda6,2,4-benzothiadiazin-3-yl)propanamide (BTD) as novel TRPC5 activators. Comparisons with closely related chemical structures from the same libraries indicate important substructures for compound efficacy. Methylprednisolone activates TRPC5 heterologously expressed in HEK293 cells with an EC50 of 12MUM, while BTD-induced half-maximal activation is achieved with 5 fold lower concentrations, both in Ca2+ assays (EC50=1.4MUM) and in electrophysiological whole cell patch clamp recordings (EC50=1.3 MUM). The activation resulting from both compounds is long lasting, reversible and sensitive to clemizole, a recently established TRPC5 inhibitor. No influence of BTD on homotetrameric members of the remaining TRPC family was observed. On the main sensory TRP channels (TRPA1, TRPV1, TRPM3, TRPM8) BTD exerts only minor activity. Furthermore, BTD can activate heteromeric channel complexes consisting of TRPC5 and its closest relatives TRPC1 or TRPC4, suggesting a high selectivity of BTD for channel complexes bearing at least one TRPC5 subunit. PMID- 28807144 TI - Regulation of L-type CaV1.3 channel activity and insulin secretion by the cGMP PKG signaling pathway. AB - cGMP is a second messenger widely used in the nervous system and other tissues. One of the major effectors for cGMP is the serine/threonine protein kinase, cGMP dependent protein kinase (PKG), which catalyzes the phosphorylation of a variety of proteins including ion channels. Previously, it has been shown that the cGMP PKG signaling pathway inhibits Ca2+ currents in rat vestibular hair cells and chromaffin cells. This current allegedly flow through voltage-gated CaV1.3L-type Ca2+ channels, and is important for controlling vestibular hair cell sensory function and catecholamine secretion, respectively. Here, we show that native L type channels in the insulin-secreting RIN-m5F cell line, and recombinant CaV1.3 channels heterologously expressed in HEK-293 cells, are regulatory targets of the cGMP-PKG signaling cascade. Our results indicate that the CaValpha1 ion conducting subunit of the CaV1.3 channels is highly expressed in RIN-m5F cells and that the application of 8-Br-cGMP, a membrane-permeable analogue of cGMP, significantly inhibits Ca2+ macroscopic currents and impair insulin release stimulated with high K+. In addition, KT-5823, a specific inhibitor of PKG, prevents the current inhibition generated by 8-Br-cGMP in the heterologous expression system. Interestingly, mutating the putative phosphorylation sites to residues resistant to phosphorylation showed that the relevant PKG sites for CaV1.3 L-type channel regulation centers on two amino acid residues, Ser793 and Ser860, located in the intracellular loop connecting the II and III repeats of the CaValpha1 pore-forming subunit of the channel. These findings unveil a novel mechanism for how the cGMP-PKG signaling pathway may regulate CaV1.3 channels and contribute to regulate insulin secretion. PMID- 28807146 TI - TRP channel pores and local calcium signals. AB - Calcium signals control a plethora of essential cellular functions ranging from secretion and contraction to gene expression and sensory signaling cascades. An essential part of intracellular calcium signals originates from the transmembrane flux of calcium ions, which is mainly mediated through different calcium permeable cation channels with variable calcium selectivity. Opening of individual calcium permeable channels induces a local cytosolic calcium rise that can be highly restricted in time and space. Here, we provide a short overview of the current knowledge about calcium permeation and localized calcium signals in transient receptor potential (TRP) channels. We also present a brief survey of some fundamental theoretical aspects of the local calcium signals generated upon opening of single calcium-permeable channels, and compare theoretical predictions with published experimental data on TRP channel-mediated local calcium signals. PMID- 28807147 TI - TRPP2 ion channels: Critical regulators of organ morphogenesis in health and disease. AB - Ion channels control the membrane potential and mediate transport of ions across membranes. Archetypical physiological functions of ion channels include processes such as regulation of neuronal excitability, muscle contraction, or transepithelial ion transport. In that regard, transient receptor potential ion channel polycystin 2 (TRPP2) is remarkable, because it controls complex morphogenetic processes such as the establishment of properly shaped epithelial tubules and left-right-asymmetry of organs. The fascinating question of how an ion channel regulates morphogenesis has since captivated the attention of scientists in different disciplines. Four loosely connected key insights on different levels of biological complexity ranging from protein to whole organism have framed our understanding of TRPP2 physiology: 1) TRPP2 is a non-selective cation channel; 2) TRPP2 is part of a receptor-ion channel complex; 3) TRPP2 localizes to primary cilia; and 4) TRPP2 is required for organ morphogenesis. In this review, we will discuss the current knowledge in these key areas and highlight some of the challenges ahead. PMID- 28807148 TI - Acetylcholine induces intracellular Ca2+ oscillations and nitric oxide release in mouse brain endothelial cells. AB - Basal forebrain neurons increase cortical blood flow by releasing acetylcholine (Ach), which stimulates endothelial cells (ECs) to produce the vasodilating gasotransmitter, nitric oxide (NO). Surprisingly, the mechanism whereby Ach induces NO synthesis in brain microvascular ECs is unknown. An increase in intracellular Ca2+ concentration recruits a multitude of endothelial Ca2+ dependent pathways, such as Ca2+/calmodulin endothelial NO synthase (eNOS). The present investigation sought to investigate the role of intracellular Ca2+ signaling in Ach-induced NO production in bEND5 cells, an established model of mouse brain microvascular ECs, by conventional imaging of cells loaded with the Ca2+-sensitive dye, Fura-2/AM, and the NO-sensitive fluorophore, DAF-DM diacetate. Ach induced dose-dependent Ca2+ oscillations in bEND5 cells, 300 MUM being the most effective dose to generate a prolonged Ca2+ burst. Pharmacological manipulation revealed that Ach-evoked Ca2+ oscillations required metabotropic muscarinic receptor (mAchR) activation and were patterned by a complex interplay between repetitive ER Ca2+ release via inositol-1,4,5-trisphosphate receptors (InsP3Rs) and store-operated Ca2+ entry (SOCE). A comprehensive real time polymerase chain reaction analysis demonstrated the expression of the transcripts encoding for M3-mAChRs, InsP3R1 and InsP3R3, Stim1-2 and Orai2. Next, we found that Ach-induced NO production was hindered by L-NAME, a selective NOS inhibitor, and BAPTA, a membrane permeable intracellular Ca2+ buffer. Moreover, Ach-elicited NO synthesis was blocked by the pharmacological abrogation of the accompanying Ca2+ spikes. Overall, these data shed novel light on the molecular mechanisms whereby neuronally-released Ach controls neurovascular coupling in blood microvessels. PMID- 28807149 TI - Muscling in on TRP channels in vascular smooth muscle cells and cardiomyocytes. AB - The human TRP protein family comprises a family of 27 cation channels with diverse permeation and gating properties. The common theme is that they are very important regulators of intracellular Ca2+ signaling in diverse cell types, either by providing a Ca2+ influx pathway, or by depolarising the membrane potential, which on one hand triggers the activation of voltage-gated Ca2+ channels, and on the other limits the driving force for Ca2+ entry. Here we focus on the role of these TRP channels in vascular smooth muscle and cardiac striated muscle. We give an overview of highlights from the recent literature, and highlight the important and diverse roles of TRP channels in the pathophysiology of the cardiovascular system. The discovery of the superfamily of Transient Receptor Potential (TRP) channels has significantly enhanced our knowledge of multiple signal transduction mechanisms in cardiac muscle and vascular smooth muscle cells (VSMC). In recent years, multiple studies have provided evidence for the involvement of these channels, not only in the regulation of contraction, but also in cell proliferation and remodeling in pathological conditions. The mammalian family of TRP cation channels is composed by 28 genes which can be divided into 6 subfamilies groups based on sequence similarity: TRPC (Canonical), TRPM (Melastatin), TRPML (Mucolipins), TRPV (Vanilloid), TRPP (Policystin) and TRPA (Ankyrin-rich protein). Functional TRP channels are believed to form four unit complexes in the plasma, each of them expressed with six transmembrane domain and intracellular N and C termini. Here we review the current knowledge on the expression of TRP channels in both muscle types, and discuss their functional properties and role in physiological and pathophysiological processes. PMID- 28807151 TI - Exocytotic fusion pores as a target for therapy. AB - Regulated exocytosis can be split into a sequence of steps ending with the formation and the dilation of a fusion pore, a neck-like connection between the vesicle and the plasma membrane. Each of these steps is precisely controlled to achieve the optimal spatial and temporal profile of the release of signalling molecules. At the level of the fusion pore, tuning of the exocytosis can be achieved by preventing its formation, by stabilizing the unproductive narrow fusion pore, by altering the speed of fusion pore expansion and by completely closing the fusion pore. The molecular structure and dynamics of fusion pores have become a major focus of cell research, especially as a promising target for therapeutic strategies. Electrophysiological, optical and electrochemical methods have been used extensively to illuminate how cells regulate secretion at the level of a single fusion pore. Here, we describe recent advances in the structure and mechanisms of the initial fusion pore formation and the progress in therapeutic strategies with the focus on exocytosis. PMID- 28807150 TI - Two EF-hand motifs in ryanodine receptor calcium release channels contribute to isoform-specific regulation by calmodulin. AB - The mammalian ryanodine receptor Ca2+ release channel (RyR) has a single conserved high affinity calmodulin (CaM) binding domain. However, the skeletal muscle RyR1 is activated and cardiac muscle RyR2 is inhibited by CaM at submicromolar Ca2+. This suggests isoform-specific domains are involved in RyR regulation by CaM. To gain insight into the differential regulation of cardiac and skeletal muscle RyRs by CaM, RyR1/RyR2 chimeras and mutants were expressed in HEK293 cells, and their single channel activities were measured using a lipid bilayer method. All RyR1/RyR2 chimeras and mutants were inhibited by CaM at 2MUM Ca2+, consistent with CaM inhibition of RyR1 and RyR2 at micromolar Ca2+ concentrations. An RyR1/RyR2 chimera with RyR1 N-terminal amino acid residues (aa) 1-3725 and RyR2 C-terminal aa 3692-4968 were inhibited by CaM at <1MUM Ca2+ similar to RyR2. In contrast, RyR1/RyR2 chimera with RyR1 aa 1-4301 and RyR2 4254 4968 was activated at <1MUM Ca2+ similar to RyR1. Replacement of RyR1 aa 3726 4298 with corresponding residues from RyR2 conferred CaM inhibition at <1MUM Ca2+, which suggests RyR1 aa 3726-4298 are required for activation by CaM. Characterization of additional RyR1/RyR2 chimeras and mutants in two predicted Ca2+ binding motifs in RyR1 aa 4081-4092 (EF1) and aa 4116-4127 (EF2) suggests that both EF-hand motifs and additional sequences in the large N-terminal regions are required for isoform-specific RyR1 and RyR2 regulation by CaM at submicromolar Ca2+ concentrations. PMID- 28807152 TI - Structure of thrombospondin type 3 repeats in bacterial outer membrane protein A reveals its intra-repeat disulfide bond-dependent calcium-binding capability. AB - Eukaryotic thrombospondin type 3 repeat (TT3R) is an efficient calcium ion (Ca2+) binding motif only found in mammalian thrombospondin family. TT3R has also been found in prokaryotic cellulase Cel5G, which was thought to forfeit the Ca2+ binding capability due to the formation of intra-repeat disulfide bonds, instead of the inter-repeat ones possessed by eukaryotic TT3Rs. In this study, we have identified an enormous number of prokaryotic TT3R-containing proteins belonging to several different protein families, including outer membrane protein A (OmpA), an important structural protein connecting the outer membrane and the periplasmic peptidoglycan layer in gram-negative bacteria. Here, we report the crystal structure of the periplasmic region of OmpA from Capnocytophaga gingivalis, which contains a linker region comprising five consecutive TT3Rs. The structure of OmpA TT3R exhibits a well-ordered architecture organized around two tightly coordinated Ca2+ and confirms the presence of abnormal intra-repeat disulfide bonds. Further mutagenesis studies showed that the Ca2+-binding capability of OmpA-TT3R is indeed dependent on the proper formation of intra-repeat disulfide bonds, which help to fix a conserved glycine residue at its proper position for Ca2+ coordination. Additionally, despite lacking inter-repeat disulfide bonds, the interfaces between adjacent OmpA-TT3Rs are enhanced by both hydrophobic and conserved aromatic-proline interactions. PMID- 28807153 TI - C1q/tumor necrosis factor-related protein-3 enhances the contractility of cardiomyocyte by increasing calcium sensitivity. AB - C1q/tumor necrosis factor-related protein-3 (CTRP3) is an adipokine that protects against myocardial infarction-induced cardiac dysfunction through its pro angiogenic, anti-apoptotic, and anti-fibrotic effects. However, whether CTRP3 can directly affect the systolic and diastolic function of cardiomyocytes remains unknown. Adult rat cardiomyocytes were isolated and loaded with Fura-2AM. The contraction and Ca2+ transient data was collected and analyzed by IonOptix system. 1 and 2MUg/ml CTRP3 significantly increased the contraction of cardiomyocytes. However, CTRP3 did not alter the diastolic Ca2+ content, systolic Ca2+ content, Ca2+ transient amplitude, and L-type Ca2+ channel current. To reveal whether CTRP3 affects the Ca2+ sensitivity of cardiomyocytes, the typical phase-plane diagrams of sarcomere length vs. Fura-2 ratio was performed. We observed a left-ward shifting of the late relaxation trajectory after CTRP3 perfusion, as quantified by decreased Ca2+ content at 50% sarcomere relaxation, and increased mean gradient (MUm/Fura-2 ratio) during 500-600ms (-0.163 vs. 0.279), 500-700ms (-0.159 vs. -0.248), and 500-800ms (-0.148 vs. -0.243). Consistently, the phosphorylation level of cardiac troponin I at Ser23/24 was reduced by CTRP3, which could be eliminated by preincubation of okadaic acid, a type 2A protein phosphatase inhibitor. In summary, CTRP3 increases the contraction of cardiomyocytes by increasing the myofilament Ca2+ sensitivity. CTRP3 might be a potential endogenous Ca2+ sensitizer that modulates the contractility of cardiomyocytes. PMID- 28807155 TI - Effects of Lycium barbarum on the Visual System. AB - Lycium barbarum (wolfberry, gogi berry, gouqizi, ) is one of the most widely used Chinese herbal medicines (CHMs) and is also one of the most scientifically studied. Indeed, the polysaccharide component of this berry (LBP) has been shown to have antioxidant, antiinflammatory, antiexcitotoxic, and antiapoptotic properties. These properties make it a particularly useful treatment option for the ocular environment. Although there are a handful of studies investigating the use of LBP to treat diseases affecting the lens, the vast majority of the published literature investigating LBP in the visual system focus on the retina. In this chapter, we have described what is currently understood concerning the effects of LBP treatment on various retinal diseases, including glaucoma, ischemia/reperfusion, age-related macular degeneration, retinitis pigmentosa, and diabetic retinopathy. We then describe the functions attributed to LBP using other cellular contexts to elucidate the full mechanisms this CHM utilizes in the retina. By making connections between what is known about the function of LBP in a variety of tissues and its function as a therapy for retinal degenerative diseases, we hope to further emphasize the continued use of this CHM in clinical medicine in addition to providing a platform for additional study. PMID- 28807156 TI - Metabolic Factors and Adult Neurogenesis: Impacts of Chinese Herbal Medicine on Brain Repair in Neurological Diseases. AB - Adult neurogenesis plays the important roles in animal cognitive and emotional behaviors. Abnormal proliferation and differentiation of neural stem cells (NSCs) usually associate with the neural dysfunctions induced by different brain disorders. Therefore, targeting neurogenic factors could be a promoting strategy for neural regeneration and brain repair. Importantly, epidemiological studies suggest metabolism disorders like diabetes and obesity significantly increase the risk of neurological and psychiatric diseases. A large number of studies indicate that metabolic factors could serve as the modulators to adult neurogenesis, providing the potentials of metabolic factors to regulate NSCs growth and neural regeneration therapy. This chapter reviews the current studies on the roles of metabolic factors in modulating adult neurogenesis and evaluates the potentials of Chinese Herbal Medicine (CHM) for the treatment of neurological or psychiatric disorders by targeting the metabolic factors. Traditional Chinese Medicine (TCM) including CHM and acupuncture is now widely applied for the treatment of metabolic diseases, and neurological diseases in Asia, because its' therapeutic principles meet the multiple targets and complexity characteristics of most neurological disorders. Different studies indicate that there are many active compounds perform the regulations to metabolic factors and promoting neurogenesis. This chapter systematically summarizes the current progress and understanding of the active compounds and their underlying mechanisms of CHM formulas for promoting neurogenesis. Many CHM formulas and their active ingredients that originally used for metabolic disorders show the promising effects on mediating neurogenesis and brain repair for the treatments of neurodegenerative diseases. Therefore, further investigations about the relationship between neurogenesis and metabolic regulations of CHM will bring new insights into understanding the mechanisms of adult neurogenesis and provide great opportunities to develop new therapeutic strategies for neurological diseases. Those studies will provide scientific guidance to develop the drugs from TCM resource. PMID- 28807154 TI - Total internal reflectance fluorescence imaging of genetically engineered ryanodine receptor-targeted Ca2+ probes in rat ventricular myocytes. AB - The details of cardiac Ca2+ signaling within the dyadic junction remain unclear because of limitations in rapid spatial imaging techniques, and availability of Ca2+ probes localized to dyadic junctions. To critically monitor ryanodine receptors' (RyR2) Ca2+ nano-domains, we combined the use of genetically engineered RyR2-targeted pericam probes, (FKBP-YCaMP, Kd=150nM, or FKBP-GCaMP6, Kd=240nM) with rapid total internal reflectance fluorescence (TIRF) microscopy (resolution, ~80nm). The punctate z-line patterns of FKBP,2-targeted probes overlapped those of RyR2 antibodies and sharply contrasted to the images of probes targeted to sarcoplasmic reticulum (SERCA2a/PLB), or cytosolic Fluo-4 images. FKBP-YCaMP signals were too small (~20%) and too slow (2-3s) to detect Ca2+ sparks, but the probe was effective in marking where Fluo-4 Ca2+ sparks developed. FKBP-GCaMP6, on the other hand, produced rapidly decaying Ca2+ signals that: a) had faster kinetics and activated synchronous with ICa3 but were of variable size at different z-lines and b) were accompanied by spatially confined spontaneous Ca2+ sparks, originating from a subset of eager sites. The frequency of spontaneously occurring sparks was lower in FKBP-GCaMP6 infected myocytes as compared to Fluo-4 dialyzed myocytes, but isoproterenol enhanced their frequency more effectively than in Fluo-4 dialyzed cells. Nevertheless, isoproterenol failed to dissociate FKBP-GCaMP6 from the z-lines. The data suggests that FKBP GCaMP6 binds predominantly to junctional RyR2s and has sufficient on-rate efficiency as to monitor the released Ca2+ in individual dyadic clefts, and supports the idea that beta-adrenergic agonists may modulate the stabilizing effects of native FKBP on RyR2. PMID- 28807157 TI - Antiinflammatory and Hepatoprotective Medicinal Herbs as Potential Substitutes for Bear Bile. AB - Practitioners of traditional Chinese medicine (TCM) commonly prescribe medicinal formulations relying on the purported synergism of a combination of plant species, sometimes incorporating animal parts and minerals. Bear bile, obtained from either wild or farmed bears, is a commonly used constituent of traditional medicine formulations. With several bear species now listed under Convention on International Trade in Endangered Species of Wild Fauna and Flora as threatened with extinction and with bear farming being actively campaigned against on ethical grounds, it is important to seek and promote alternatives to the use of bear bile as medicine. This chapter describes and evaluates the scientific data relating to the efficacy of bear bile and potential alternatives to its use, including the use of bile from other animal species, the use of synthetic chemical alternatives, and the use of herbal substitutes. Scientific studies have confirmed the efficacy of bear bile as an antiinflammatory and a hepatoprotective agent. Ursodeoxycholic acid (UDCA), the active component of bear bile is used in a synthetic form in Western medicine and can serve as an alternative to bear bile in the treatment and management of certain cholestatic liver conditions. In TCM practice, bile from domesticated animal species (such as cattle, chicken, and pig) has been used as a substitute for bear bile. Following evaluation of TCM literature and pharmacological/clinical data, the authors propose six plant species, either as single herbs or in combination, Gardenia jasminoides (zhi zi; ), Scutellaria baicalensis (huang qin; ), Coptis chinensis (huang lian, ), Phellodendron amurense (huang bai; ), Andrographis paniculata (chuan xin lian; ), and Rheum palmatum (da huang; ), two medicinal Kampo formulations, Orengedokuto, Dia-Orengedokuto (which originated from traditional Chinese herbal formula Huanglian Jiedu Tang, ), and two individual phytochemicals (berberine and andrographolide) as alternatives to bear bile. The proposed herbal alternatives are frequently found listed in traditional formulations also containing bear bile, usually with different therapeutic roles ascribed to them. The existing evidence base for the effectiveness of herbal alternatives is sufficiently strong for TCM practitioners and consumers to consider using these without the addition of bear bile. This consideration is driven by the imperative to protect populations of bears from overexploitation in the wild and when farmed. However, for the identified alternatives to be accepted by users, it is essential that researchers and TCM practitioners collaborate effectively to initiate consumer behavior change. PMID- 28807158 TI - Effect of Chinese Herbal Medicine on Molecular Imaging of Neurological Disorders. AB - Chinese herbal medicine has been used to treat a wide variety of neurological disorders including stroke, Alzheimer's disease, and Parkinson's disease. However, its mechanism behind the effectiveness remains unclear. Recently, molecular imaging technology has been applied for this purpose, since it can assess the cellular or molecular function in a living subject by using specific imaging probes and/or radioactive tracers, which enable efficient analysis and monitoring the therapeutic response repetitively. This chapter reviews the in vivo functional and metabolic changes after administration of Chinese herbal medicine in various neurological disorders and provides perspectives on the future evaluations of therapeutic response of Chinese herbal medicine. PMID- 28807159 TI - Herb-Drug Interactions of Commonly Used Chinese Medicinal Herbs. AB - With more and more popular use of traditional herbal medicines, in particular Chinese herbal medicines, herb-drug interactions have become a more and more important safety issue in the clinical applications of the conventional drugs. Researches in this area are increasing very rapidly. Herb-drug interactions are complicated due to the fact that multiple chemical components are involved, and these compounds may possess diverse pharmacological activities. Interactions can be in both pharmacokinetics and pharmacodynamics. Abundant studies focused on pharmacokinetic interactions of herbs and drugs. Herbs may affect the behavior of the concomitantly used drugs by changing their absorption, distribution, metabolism, and excretion. Studies on pharmacodynamics interactions of herbs and drugs are still very limited. Herb-drug interactions are potentially causing changes in drug levels and drug activities and leading to either therapeutic failure or toxicities. Sometime it can be fatal. The exposures to drugs, lacking of knowledge in the potential adverse herb-drug interactions, will put big risk to patients' safety in medical services. On the contrary, some interactions may be therapeutically beneficial. It may be used to help develop new therapeutic strategies in the future. This chapter is trying to review the development in the area of herb-drug interactions based on the recently published research findings. Information on the potential interactions among the commonly used Chinese medicinal herbs and conventional drugs is summarized in this chapter. PMID- 28807160 TI - Treatment of Chinese Herbal Medicine for Female Infertility. AB - Female infertility is when a woman of reproductive age and sexual active, without contraception, cannot get pregnant after a year and more or keeps having miscarriages. Although conventional treatments for infertility such as hormone therapy, in vitro fertilization and many more, helped many female patients with infertility get pregnant during past a few decades, it is far from satisfactory with prolonging treatment time frames and emotional and financial burden. In recent years, more patients with infertile problems are seeking to alternative and complementary medicines to achieve a better outcome. In particular, Chinese herbal medicine (CHM) is increasingly popular for treating infertility due to its effectiveness and complimentary with conventional treatments. However, the mechanisms of action of CHM in treating female infertility are not well understood. In this chapter authors reviewed research development of CHM applied in many infertile models and CHM clinical studies in many conditions associated with female infertility, published in past 15 years. The data of review showed that CHM has either specific target mechanisms of action or multitarget mechanisms of action, via regulating relevant hormone levels in female reproductive system, improving ovary function, enhancing uterine receptivity. More studies are warranted to explore the new drugs from CHM and ensure safety, efficacy, and consistency of CHM. PMID- 28807161 TI - Phytochemical Modulation of Apoptosis and Autophagy: Strategies to Overcome Chemoresistance in Leukemic Stem Cells in the Bone Marrow Microenvironment. AB - Advances in scientific research and targeted treatment regimes have improved survival rates for many cancers over the past few decades. However, for some types of leukemia, including acute lymphoblastic and acute myeloid leukemia, mortality rates have continued to rise, with chemoresistance in leukemic stem cells (LSCs) being a major contributing factor. Most cancer drug therapies act by inducing apoptosis in dividing cells but are ineffective in targeting quiescent LSCs. Niches in the bone marrow, known as leukemic niches, behave as "sanctuaries" where LSCs acquire drug resistance. This review explores the role of the bone marrow environment in the maintenance of LSCs and its contribution to chemoresistance and considers current research on the potential use of phytochemicals to overcome chemoresistance through the modulation of signaling pathways involved in the survival and death of leukemic clonal cells and/or leukemic stem cells. Phytochemicals from traditional Chinese medicine, namely baicalein, chrysin, wogonin (constituents of Scutellaria baicalensis; huang qin; ), curcumin (a constituent of Curcuma longa, jiang huang, ), and resveratrol (a constituent of Polygonum cuspidatum; hu zhang, ) have been shown to induce apoptosis in leukemic cell lines, with curcumin and resveratrol also causing cell death via the induction of autophagy (a nonapoptotic pathway). In order to be effective in eliminating LSCs, it is important to target signaling pathways (such as Wnt/beta-catenin, Notch, and Hedgehog). Resveratrol has been reported to induce apoptosis in leukemic cells through the inhibition of the Notch and Sonic hedgehog signaling pathways, therefore showing potential to affect LSCs. While these findings are of interest, there is a lack of reported research on the modulatory effect of phytochemicals on the autophagic cell death pathway in leukemia, and on the signaling pathways involved in the maintenance of LSCs, highlighting the need for further work in these areas. PMID- 28807162 TI - Chinese Herbal Medicine for the Treatment of Drug Addiction. AB - This chapter summarizes recent developments in preclinical and clinical research on Chinese herbal medicines and their neurochemical mechanism of action for the treatment of drug addiction. We searched Chinese and English scientific literature and selected several kinds of Chinese herbal medicines that have beneficial effects on drug addiction. Ginseng (Renshen) may be clinically useful for the prevention of opioid abuse and dependence. Rhizoma Corydalis (Yanhusuo) may be used to prevent relapse to chronic drug dependence. Alkaloids of Uncaria rhynchophylla (Gouteng) appear to have positive effects on methamphetamine and ketamine addiction. Both Salvia miltiorrhiza (Danshen) and Radix Pueraiae (Gegen) have beneficial inhibitory effects on alcohol intake. Sinomenine has been shown to have preventive and curative effects on opioid dependence. l-Stepholidine, an alkaloid extract of the Chinese herb Stephania intermedia (Rulan), attenuated the acquisition, maintenance, and reacquisition of morphine-induced conditioned place preference and antagonized the heroin-induced reinstatement of heroin seeking. Traditional Chinese herbal medicines may be used to complement current treatments for drug addiction, including withdrawal and relapse. As the molecular mechanisms of action of traditional Chinese herbal medicines are elucidated, further advances in their use for the treatment of drug addiction are promising. PMID- 28807163 TI - Effect of Chinese Herbal Medicine on Alzheimer's Disease. AB - Alzheimer's disease (AD) is reaching epidemic proportions yet treatment strategies are limited and are restricted to providing symptomatic relief for the cognitive and behavioral and psychological symptoms of dementia (BPSD). Chinese herbal medicine (CHM) has been a valuable source of medicines for centuries and research has burgeoned in recent years to understand the scientific basis for their use. Some plants have been used in CHM for AD symptoms (e.g., Polygala tenuifolia), while others are CHMs for different conditions, but they show mechanistic effects relevant to AD (e.g., Salvia miltiorrhiza). Some CHMs (e.g., Ginkgo biloba extract, and huperzine A from Huperzia serrata) show pharmacological activities relevant to AD, and promising effects on cognitive functions in clinical trials. Other CHMs show effects relevant to BPSD (e.g., Crocus sativus). This chapter discusses available scientific evidence for CHM plants and formulae that have been used both traditionally for AD, and those that have been used traditionally but not specifically for AD symptoms, and encompasses chemical, pharmacological and clinical studies. The ethnopharmacological approach to understanding the use of CHMs for AD is also discussed. PMID- 28807164 TI - Effect of Chinese Herbal Medicine on Male Infertility. AB - Male infertility normally refers a male's inability to cause pregnancy in a fertile female partner after 1 year of unprotected intercourse. Male infertility in recent years has been attracting increasing interest from public due to the evidence in decline in semen quality. There are many factors contributing to the male infertility including abnormal spermatogenesis; reproductive tract anomalies or obstruction; inadequate sexual and ejaculatory functions; and impaired sperm motility, imbalance in hormone levels, and immune system dysfunction. Although conventional treatments such as medication, surgical operation, and advanced techniques have helped many male with infertility cause pregnancy in their female partners, effectiveness is not satisfactory and associated with adverse effects. Chinese herbal medicine (CHM) has been used to improve male infertility in China for a very long time and has now been increasingly popular in Western countries for treating infertility. In this chapter we summarized recent development in basic research and clinical studies of CHM in treating male infertility. It has showed that CHM improved sperm motility and quality, increased sperm count and rebalanced inadequate hormone levels, and adjusted immune functions leading to the increased number of fertility. Further, CHM in combination with conventional therapies improved efficacy of conventional treatments. More studies are needed to indentify the new drugs from CHM and ensure safety, efficacy, and consistency of CHM. PMID- 28807165 TI - Effect and Mechanism of Chinese Herbal Medicine on Parkinson's Disease. AB - Parkinson's disease is a progressive neurodegenerative disorder. Although both genetic and environmental factors are implicated in the development of Parkinson's disease, the cause of the disease is still unclear. So far conventional treatments to Parkinson's are symptomatic relief and focused mainly on motor symptoms. Chinese herbal medicine has been used to treat many conditions in China, Korea, Japan, and many Southeast Asian countries for 1000 years. During past a few decades, Chinese herbal medicine has gained wider and increasing acceptance within both public and medical profession due to its effectiveness on many conditions in western countries. In this chapter, mechanisms of action of many Chinese herbal compounds/extracts and Chinese herb formulas on the models of Parkinson's were reviewed. Further, reports of effectiveness of Chinese herb formulas on patients with Parkinson's were summarized. It was shown that both Chinese herbal compounds/extracts and herb formulas have either specific target mechanisms of action or multitargets mechanisms of action, as antioxidant, antiinflammatory, and antiapoptosis agents. Clinical studies showed that Chinese herb formulas as an adjunct improved both motor and nonmotor symptoms, and reduced dose of dopaminergic drugs and occurrence of dyskinesia. The evidence from the studies suggests that Chinese herb medicine has potential, acting as neuroprotective to slow down the progression of Parkinson's, and it is able to simultaneously treat both motor and nonmotor symptoms of Parkinson's. More studies are needed to explore the new compounds/extracts derived from Chinese herbs, in particular, their mechanisms of action. It is hopeful that new drugs developed from Chinese herb compounds/extracts and Chinese herb formulas will lead to better and complimentary therapy to PD. PMID- 28807166 TI - Neurobiology of Chinese Herbal Medicine on Major Depressive Disorder. AB - Major depressive disorder, or depression, becomes a serious public health problem globally. As current mainstream conventional antidepressants have limitations in unsatisfied response and remission rate, late onset of efficacy and side effects, increasing attention has been drawn to traditional Chinese medicine (TCM), in which mixture of herbs is commonly prescribed after the clinicians make pattern identification for diagnosis. Here, the principle of herbal formulation for TCM (Chinese herbal medicine, CHM) on depression as well as some clinical outcome research is briefly introduced. The neurobiological mechanisms underlying antidepressant effects of CHM, including enhancement of monoamine, dehyperactivation of hypothalamic-pituitary-adrenal axis, neuroimmune response, and neurotrophic factors are discussed. Additionally, the results from emerging research into rapid antidepressant efficacy using CHM formula Yueju, as well as the associated neuroplastical mechanisms, are summarized. The in-depth study of the antidepressant efficacy, and underlying chemical substrates, as well as the molecular and systems neurobiological mechanisms may shed new lights for better understanding the mechanisms of CHM and improving the therapy. PMID- 28807168 TI - Preface. PMID- 28807167 TI - Treatment of Insomnia With Traditional Chinese Herbal Medicine. AB - Insomnia is a condition with sleep problems and many people suffered from it. Chronic insomnia can last for long time and it will severely affect people's health and the quality of life. In conventional medicine, the most commonly used the medicine is benzodiazepine. It is effective but also has significant side effects. Patients try to use some kinds of alternative medicines. Chinese medicinal herbs and formulas have been used in the treatment of insomnia for more than 2000 years in China. In recent decades, Chinese herbal medicine has been widely used in the Western countries. Many clinical studies including randomized controlled clinical trials and research on pharmacological action mechanisms of the herbs for treatment of insomnia have been conducted. It is very important and very helpful to review the published research papers to gather the available information for a critical analysis. This chapter evaluated the data from both of clinical studies and pharmacological researches on the therapeutic formulas and on some key herbs used in the treatment of insomnia. Clinical studies showed a very wide spectrum of herbs that were used in clinical treatment of insomnia. This was due to different syndrome patterns happened with insomnia. This brought complexity and difficulties to identify which are the essential key herbs or formulas. It was found Suanzaoren decoction (Ziziphus spinose decoction ) is the most frequently used formula for the treatment of insomnia. Based on the clinical data, several herbs were identified as most frequently used sedative and hypnotic herbs in Chinese herbal medicine including Suanzaoren (Ziziphus spinose ), Fuling (Poria cocos ), and Gancao (Glycyrrhiza uralensis ). The underlying pharmacological action mechanisms discovered in the studies on some key herbs used in the treatment of insomnia were evaluated. The major pharmacological action mechanisms shared by most of the sedative herbs are to act through the neurotransmitter gamma-aminobutyric acid (GABA) or via stimulation of GABAAA receptor. Some herbs exert sedative activities via inhibition of 5 hydroxytryptamine 1A receptor. Another mechanism shown by some herbs is to upregulate the expression of orexin-A, leptin, orexin receptor-1, and leptin receptor in the brain, reducing insomnia-induced negative consequences, and thus indirectly help improvement of insomnia. PMID- 28807169 TI - Suicide prevention: keeping the momentum. PMID- 28807170 TI - Tuberculosis in children: under-counted and under-treated. PMID- 28807171 TI - Incentives to improve couples' HIV testing uptake and cost-effectiveness. PMID- 28807172 TI - Mortality and socioeconomic status: the vicious cycle between poverty and ill health. PMID- 28807173 TI - Cassava, konzo, and neurotoxicity. PMID- 28807174 TI - Improving the quality of WHO guidelines over the last decade: progress and challenges. PMID- 28807175 TI - Joint external evaluation process: bringing multiple sectors together for global health security. PMID- 28807176 TI - Lychee-associated acute hypoglycaemic encephalopathy outbreaks in Muzaffarpur, India. PMID- 28807177 TI - Lychee-associated acute hypoglycaemic encephalopathy outbreaks in Muzaffarpur, India - Author's reply. PMID- 28807178 TI - Routine fruit washing to prevent acute toxic encephalopathy. PMID- 28807179 TI - Routine fruit washing to prevent acute toxic encephalopathy - Authors' reply. PMID- 28807180 TI - Lychee-associated encephalopathy in China and its reduction since 2000. PMID- 28807182 TI - Bringing all together for research capacity building in LMICs. PMID- 28807181 TI - Community health systems: allowing community health workers to emerge from the shadows. PMID- 28807183 TI - Obligations under global health partnerships in LMICs should be contractual. PMID- 28807184 TI - Bringing all together for research capacity building in LMICs - Authors' reply. PMID- 28807185 TI - Gender myths in global health. PMID- 28807187 TI - Correction to Lancet Glob Health 2017; 5: e593-603. PMID- 28807186 TI - Gender myths in global health - Authors' reply. PMID- 28807188 TI - The global burden of tuberculosis mortality in children: a mathematical modelling study. AB - BACKGROUND: Tuberculosis in children is increasingly recognised as an important component of the global tuberculosis burden, with an estimated 1 million cases in 2015. Although younger children are vulnerable to severe forms of tuberculosis disease, no age-disaggregated estimates of paediatric tuberculosis mortality exist, and tuberculosis has never been included in official estimates of under-5 child mortality. We aimed to produce a global mortality burden estimate in children using a complementary approach not dependent on vital registration data. METHODS: In this mathematical modelling study, we estimated deaths in children younger than 5 years and those aged 5-14 years for 217 countries and territories using a case-fatality-based approach. We used paediatric tuberculosis notification data and HIV and antiretroviral treatment estimates to disaggregate the WHO paediatric tuberculosis incidence estimates by age, HIV, and treatment status. We then applied systematic review evidence on corresponding case-fatality ratios. FINDINGS: We estimated that 239 000 (95% uncertainty interval [UI] 194 000-298 000) children younger than 15 years died from tuberculosis worldwide in 2015; 80% (191 000, 95% UI 132 000-257 000) of these deaths were in children younger than 5 years. More than 70% (182 000, 140 000-239 000) of deaths occurred in the WHO southeast Asia and Africa regions. We estimated that 39 000 (17%, 23 000-73 000) paediatric tuberculosis deaths worldwide were in children with HIV infections, with 31 000 (36%, 19 000-59 000) in the WHO Africa region. More than 96% (230 000, 185 000-289 000) of all tuberculosis deaths occurred in children not receiving tuberculosis treatment. INTERPRETATION: Tuberculosis is a top ten cause of death in children worldwide and a key omission from previous analyses of under-5 mortality. Almost all these deaths occur in children not on tuberculosis treatment, implying substantial scope to reduce this burden. FUNDING: UNITAID, National Institutes of Health, and National Institute for Health Research. PMID- 28807189 TI - Effect of non-monetary incentives on uptake of couples' counselling and testing among clients attending mobile HIV services in rural Zimbabwe: a cluster randomised trial. AB - BACKGROUND: Couples' HIV testing and counselling (CHTC) is associated with greater engagement with HIV prevention and care than individual testing and is cost-effective, but uptake remains suboptimal. Initiating discussion of CHTC might result in distrust between partners. Offering incentives for CHTC could change the focus of the pre-test discussion. We aimed to determine the impact of incentives for CHTC on uptake of couples testing and HIV case diagnosis in rural Zimbabwe. METHODS: In this cluster-randomised trial, 68 rural communities (the clusters) in four districts receiving mobile HIV testing services were randomly assigned (1:1) to incentives for CHTC or not. Allocation was not masked to participants and researchers. Randomisation was stratified by district and proximity to a health facility. Within each stratum random permutation was done to allocate clusters to the study groups. In intervention communities, residents were informed that couples who tested together could select one of three grocery items worth US$1.50. Standard mobilisation for testing was done in comparison communities. The primary outcome was the proportion of individuals testing with a partner. Analysis was by intention to treat. 3 months after CHTC, couple-testers from four communities per group individually completed a telephone survey to evaluate any social harms resulting from incentives or CHTC. The effect of incentives on CHTC was estimated using logistic regression with random effects adjusting for clustering. The trial was registered with the Pan African Clinical Trial Registry, number PACTR201606001630356. FINDINGS: From May 26, 2015, to Jan 29, 2016, of 24 679 participants counselled with data recorded, 14 099 (57.1%) were in the intervention group and 10 580 (42.9%) in the comparison group. 7852 (55.7%) testers in the intervention group versus 1062 (10.0%) in the comparison group tested with a partner (adjusted odds ratio 13.5 [95% CI 10.5-17.4]). Among 427 (83.7%) of 510 eligible participants who completed the telephone survey, 11 (2.6%) reported that they were pressured or themselves pressured their partner to test together; none regretted couples' testing. Relationship unrest was reported by eight individuals (1.9%), although none attributed this to incentives. INTERPRETATION: Small non-monetary incentives, which are potentially scalable, were associated with significantly increased CHTC and HIV case diagnosis. Incentives did not increase social harms beyond the few typically encountered with CHTC without incentives. The intervention could help achieve UNAIDS 90-90-90 targets. FUNDING: The study was funded by the UK Department for International Development, Irish AID, and Swedish SIDA, through Population Services International Zimbabwe under the Integrated Support Program. PMID- 28807190 TI - Socioeconomic differences in mortality in the antiretroviral therapy era in Agincourt, rural South Africa, 2001-13: a population surveillance analysis. AB - BACKGROUND: Understanding the effects of socioeconomic disparities in health outcomes is important to implement specific preventive actions. We assessed socioeconomic disparities in mortality indicators in a rural South African population over the period 2001-13. METHODS: We used data from 21 villages of the Agincourt Health and socio-Demographic Surveillance System (HDSS). We calculated the probabilities of death from birth to age 5 years and from age 15 to 60 years, life expectancy at birth, and cause-specific and age-specific mortality by sex (not in children <5 years), time period, and socioeconomic status (household wealth) quintile for HIV/AIDS and tuberculosis, other communicable diseases (excluding HIV/AIDS and tuberculosis) and maternal, perinatal, and nutritional causes, non-communicable diseases, and injury. We also quantified differences with relative risk ratios and relative and slope indices of inequality. FINDINGS: Between 2001 and 2013, 10 414 deaths were registered over 1 058 538 person-years of follow-up, meaning the overall crude mortality was 9.8 deaths per 1000 person years. We found significant socioecomonic status gradients for mortality and life expectancy at birth, with outcomes improving with increasing socioeconomic status. An inverse relation was seen for HIV/AIDS and tuberculosis mortality and socioeconomic status that persisted from 2001 to 2013. Deaths from non communicable diseases increased over time in both sexes, and injury was an important cause of death in men and boys. Neither of these causes of death, however, showed consistent significant associations with household socioeconomic status. INTERPRETATION: The poorest people in the population continue to bear a high burden of HIV/AIDS and tuberculosis mortality, despite free antiretroviral therapy being made available from public health facilities. Associations between socioeconomic status and increasing burden of mortality from non-communicable diseases is likely to become prominent. Integrated strategies are needed to improve access to and uptake of HIV testing, care, and treatment, and management of non-communicable diseases in the poorest populations. FUNDING: Wellcome Trust, South African Medical Research Council, and University of the Witwatersrand, South Africa. PMID- 28807191 TI - Cognitive and motor performance in Congolese children with konzo during 4 years of follow-up: a longitudinal analysis. AB - BACKGROUND: Konzo is an irreversible upper-motor neuron disorder affecting children dependent on bitter cassava for food. The neurocognitive ability of children with konzo over time has yet to be fully documented. METHODS: We did a longitudinal study in a konzo outbreak zone continuously affected by konzo since 1990, in the district of Kahemba, southern Bandundu Province, Congo. We enrolled children with a record of neurological diagnosis of konzo in Kahemba town. For all study children with konzo enrolled in the final sample for the baseline assessment, a neurological exam was done by neurologists to confirm konzo diagnosis using the 1996 WHO criteria at 2 years and 4 years. In the initial baseline sample for each child with konzo, we attempted to get consent from a comparison child without konzo (1996 WHO criteria) within 2 years of age, from a neighbouring household who met inclusion criteria. The neuropsychological assessments were the Kaufman Assessment Battery for Children, second edition (KABC-II), and the Bruininks-Oseretsky Test of Motor Proficiency, second edition (BOT-2). FINDINGS: Data collection occurred between Oct 12, 2011, and Aug 14, 2015, in the town of Kahemba. 123 children from the Congo with konzo and 87 presumably healthy children without konzo from neighbouring households were enrolled. The planned assessments were completed by 76 children with konzo and 82 children without konzo at 2-year follow-up, and by 55 children with konzo and 33 children without konzo at 4-year follow-up. Boys with konzo did worse than those without konzo on the KABC-II Learning (p=0.0424) and on the Mental Processing Index (MPI; p=0.0111) assessments at 2-year follow-up, but girls did not. These differences observed in boys might have been caused by stunting. At 4-year follow up, the difference in KABC-II MPI score between boys or girls with or without konzo was not significant. Both boys and girls with konzo had lower scores on BOT 2 than children without konzo at both follow-up times (p<0.0001). These differences were not attenuated when controlling for physical growth. Boys with and without konzo declined on BOT-2 fine motor proficiency at 2-year follow-up (boys with konzo p=0.0076; boys without konzo p=0.0224) and KABC-II MPI performance at 2-year follow-up and 4-year follow-up (2 years: boys with konzo p<0.0001, boys without konzo p=0.0213; 4 years: boys with konzo p=0.0256, boys without konzo p=0.10), but that was not the case for the girls with scores remaining stable regardless of konzo status. For boys, increases in urinary thiocyanate concentration was significantly associated with reductions in BOT-2 motor proficiency (p=0.0321), but was not significantly associated in girls and urinary thiocyanate concentration was not associated with KABC-II MPI score for either boys or girls. INTERPRETATION: Motor and cognitive performance continues to be significantly impaired in boys with konzo at 2-year follow-up compared with boys without konzo. Because these impairments are associated in part with exposure to poorly processed cassava as measured by urinary thiocyanate, interventions are urgently needed to ensure improved processing of cassava to detoxify this food source. FUNDING: US National Institutes of Health. PMID- 28807192 TI - Does compliance with antibiotic prophylaxis in pediatric simple appendicitis matter? AB - BACKGROUND: Institutional protocols for preincisional antibiotic prophylaxis can standardize care and improve outcomes. However, challenges remain in compliance with such protocols for urgent or emergent operations. We hypothesized that compliance with an institutional protocol for antibiotic prophylaxis for appendectomy for appendicitis in pediatric patients results in reduced surgical site infections (SSIs) after simple appendectomy. METHODS: This retrospective study assessed all pediatric patients (<=18 y) who underwent appendectomy for confirmed simple appendicitis at a tertiary children's hospital between 2012 and 2015. Demographic, admission, and outcome data were recorded. Compliance with the protocol was assessed. Univariate analyses were performed to identify factors associated with any SSI and protocol noncompliance. RESULTS: Overall compliance with antibiotic prophylaxis occurred in 590 of 697 patients (85%). Compliance was high with timing (91%), spectrum (95%), and protocol-recommended drug (87%). Admission antibiotics alone were administered in 65 patients (9%), preincisional antibiotics alone in 254 patients (36%), and both in 378 patients (55%). Patients included in the analysis received a median of 2 (range 1-6) doses of antibiotics preoperatively. Ten patients (1.4%) developed an SSI. Only receipt of any antibiotics within an hour of incision was associated with decreased odds of SSI (odds ratio 0.22, 95% confidence interval 0.06-0.87). No factors were associated with noncompliance. CONCLUSIONS: An institutional appendicitis protocol yields high compliance with prophylactic antibiotic administration and associated low SSI rates, but at a cost of antibiotic over-administration. Further efforts are necessary to sustain compliance while also practicing appropriate antibiotic stewardship. PMID- 28807193 TI - Does increased prehospital time lead to a "trial of life" effect for patients with blunt trauma? AB - BACKGROUND: Variance in prehospital time among severely injured blunt trauma patients is dependent upon numerous factors. Effects on subsequent mortality and trauma team activation (TTA) rates are also unclear. The primary aim of this study was to evaluate the relationship between prehospital time and mortality at level I trauma referral centers amongst critically blunt injured patients. MATERIALS AND METHODS: This multiinstitutional study from three geographically distinct level I trauma centers analyzed all severely blunt injured patients (Injury Severity Score [ISS] >=12). The relationship between prehospital time and survival was evaluated. Secondary outcomes included the association between prehospital time and TTA. Standard statistical methodology was used (P < 0.05 = significance). RESULTS: Between January 1, 2011, and January 1, 2016, 5375 severely blunt injured patients (mean ISS = 25; mean length of stay = 16.3 d) were analyzed (center 1 = 3376; center 2 = 2401; and center 3 = 1104). As prehospital time interval increased, overall mortality decreased (0-30 min = 24.1%; 31-60 min = 14.7%; 61-90 min = 10.3%; 91-120 min = 10.4%; 121-150 min = 10.2%; P < 0.05). This pattern was especially strong for patients with an arrival measurement of hypotension, despite corrections for ISS (P < 0.05). TTA and patient outcomes were extremely variable across intervals and centers (P < 0.05). CONCLUSIONS: A trial of life effect is present for severely blunt injured patients who arrive with vital signs. Despite arrival measurements of hypotension, patients with prolonged prehospital times have a substantially lower risk of subsequent mortality. This concept should contribute to decision-making with regard to TTA. PMID- 28807194 TI - The impact of Glasgow Coma Scale-age prognosis score on geriatric traumatic brain injury outcomes. AB - BACKGROUND: As the population ages, increasing number of geriatric patients sustain traumatic brain injury (TBI). Communication of accurate prognostic information is crucial for making informed decisions on behalf of such patients. Therefore, the aim of our study was to develop a simple and clinically applicable tool that accurately predicts the prognosis in geriatric TBI patients. METHODS: We performed a 1-y (2011) retrospective analysis of isolated geriatric TBI patients (age >=65 y, head abbreviated injury score [AIS] >= 3, and other body AIS < 3) in the National Trauma Data Bank. We calculated a Glasgow Coma Scale (GCS)-age prognosis (GAP) score (age/GCS score) for all patients. Outcome measures were in-hospital adverse outcomes (mortality and Rehab/skilled nursing facility discharge disposition). Regression analysis and receiver operator characteristic curve analysis were performed to determine the discriminatory power of GAP score. RESULTS: A total of 8750 geriatric patients with TBI were included. Mean age was 77.8 +/- 7.1 y, the median (interquartile range) GCS was 15 (13-15), and the median (interquartile range) head AIS was 4 (3-4). The overall in-hospital mortality rate was 12.7%, and 34.2% of the patients were discharged home. As the GAP score increased, the mortality rate increased and discharge to-home decreased. Receiver operator characteristic curve analysis revealed excellent discriminatory power for mortality (area under the curve: 0.826). Above a GAP score of 12, the mortality rate was >50% and more than 45% of the patients were discharged to Rehab/skilled nursing facility. CONCLUSIONS: For geriatric patients with TBI, a simple GAP score reliably predicts outcomes. A score above 12 results in a drastic increase in mortality and an adverse discharge disposition. This simple tool may help clinicians provide accurate prognostic information to patients' families. PMID- 28807195 TI - Characterizing the relationship between age and venous thromboembolism in adult trauma patients: findings from the National Trauma Data Bank and the National Inpatient Sample. AB - BACKGROUND: Venous thromboembolism (VTE) is a tremendous burden in health care. However, current guidelines lack recommendations regarding the prevention of VTE in older adult trauma patients. Furthermore, the appropriate method of modeling of age in VTE models is currently unclear. METHODS: Patients included in the National Trauma Data Bank (NTDB) between the years 2008 and 2014 and patients included in the National Inpatient Sample (NIS) between 2009 and 2013 were analyzed. Multiple logistic regression of VTE on age was performed. RESULTS: Of 3,598,881 patients in the NTDB, 34,202 (1.0%) were diagnosed with VTE compared to 5405 (1.1%) of the 505,231 patients in NIS. In both the fully adjusted NTDB and NIS model, age was positively associated with odds of VTE diagnosis under 65 years (NTDB, adjusted odds ratio [aOR]: 1.018, 95% confidence interval [CI]: 1.017-1.019, P < 0.001; NIS, aOR: 1.025, 95% CI 1.022-1.027, P < 0.001). In patients aged >=65 years, age was negatively associated with odds of VTE diagnosis in the NTDB (aOR: 0.995, 95% CI: 0.992-0.999, P = 0.006) but not in the NIS (aOR: 0.998, 95% CI 0.994-1.002, P = 0.26). CONCLUSIONS: Incidence of VTE among adult trauma patients steadily increases with age until 65 years, after which the odds of VTE appear to level off or even slightly decrease. These findings should be applied for improved modeling of VTE in trauma patients. The mechanism behind these findings should be explored before using them to update guidelines for standardized VTE prevention in older adults. PMID- 28807196 TI - Trauma patients meeting both Centers for Disease Control and Prevention's definitions for ventilator-associated pneumonia had worse outcomes than those meeting only one. AB - BACKGROUND: The Centers for Disease Control and Prevention's National Healthcare Safety Network (NHSN) replaced its old definition for ventilator-associated pneumonia (VAP) with the ventilator-associated events algorithm in 2013. We sought to compare the outcome of trauma patients meeting the definitions for VAP in the two modules. METHODS: Trauma patients with blunt or penetrating injuries and with at least 2 d of ventilator support were identified from the trauma registry from 2013 to 2014. VAP was determined using two methods: (1) VAP as defined by the "old," clinically based NHSN definition and (2) possible VAP as defined by the updated "new" NHSN definition. Cohen's kappa statistic was determined to compare the two definitions for VAP. To compare demographic and clinical outcomes, the chi-square and Student's t-tests were used for categorical and continuous variables, respectively. RESULTS: From 2013 to 2014, there were 1165 trauma patients admitted who had at least 2 d of ventilator support. Seventy eight patients (6.6%) met the "new" NHSN definition for possible VAP, 361 patients (30.9%) met the "old" definition of VAP, and 68 patients (5.8%) met both definitions. The kappa statistic between VAP as defined by the "new" and "old" definitions was 0.22 (95% confidence interval, 0.17-0.27). There were no differences in age, gender, race, or injury severity score when comparing patients who met the different definitions. Those satisfying both definitions had longer ventilator support days (P = 0.0009), intensive care unit length of stay (LOS; P = 0.0003), and hospital LOS (P = 0.0344) when compared with those meeting only one definition. There was no difference in mortality for those meeting both and those meeting the old definition for VAP; patients meeting both definitions had higher respiratory rate at arrival (P = 0.0178). CONCLUSIONS: There was no difference in mortality between patients meeting the "old" and "new" NHSN definitions for VAP; those who met "both" definitions had longer ventilator support days, intensive care unit, and hospital LOS. PMID- 28807197 TI - Perioperative blood transfusion and complications in children undergoing surgery for solid tumors. AB - BACKGROUND: The objective was to assess whether perioperative blood transfusion (PBT) is associated with postoperative complications in children undergoing surgery for a solid tumor. METHODS: Using 2012-2014 National Surgical Quality Improvement Program Pediatric data, we identified patients aged 0-18 years who underwent surgery (biopsy or resection) for solid tumors. We compared demographic, clinical, and 30-day outcome characteristics between children who did and did not receive a PBT within 72 hours after surgery. Propensity score matched analyses were used to estimate the effect of PBT on postoperative complications, in the overall cohort, the subgroup undergoing resection, and the subgroup with liver tumors. RESULTS: Of 961 patients who underwent surgery for solid tumors, 27.8% required PBT. Patients requiring PBT were more likely to have preoperative risk factors, including ventilator dependence, hematologic disorders, chemotherapy, sepsis, transfusion before surgery, and an American Society of Anesthesiologists class >=3 (all P <= 0.01). In propensity score matched analyses, PBT was not associated with overall complication risk (odds ratio [OR]: 1.50, P = 0.07) but was associated with an increased risk of postoperative mechanical ventilation (OR: 3.78, P < 0.001). Of the 750 patients undergoing tumor resection, 36.3% required PBT. After propensity matching, PBT was associated with overall postoperative complications (OR: 1.76, P = 0.02). Of 163 patients with liver tumors, 52.8% required PBT. After propensity matching, PBT was not associated with postoperative complications (OR: 2.00, P = 0.09). PBT was associated with a longer postoperative length of stay in all three analyses (all P < 0.01). CONCLUSIONS: PBT was associated with higher risks for postoperative complications in children undergoing surgery for solid tumors. PMID- 28807198 TI - Encapsulated follicular variant of papillary thyroid cancer: are these tumors really benign? AB - BACKGROUND: Recent studies suggest that the encapsulated form of follicular variant of papillary thyroid cancer (eFVPTC) behaves more similarly to benign lesions and can be treated with thyroid lobectomy alone instead of total thyroidectomy. To distinguish aggressive cancers from more benign lesions more clearly, the objective of this study was to determine if the eFVPTC behaves less aggressively than the nonencapsulated variant (neFVPTC). METHODS: A prospectively collected endocrine surgery database in our institution was reviewed for all patients with FVPTC on surgical pathology from 1999 to 2012. Samples were rereviewed to determine if the tumor was eFVPTC or neFVPTC, which were correlated with patient outcomes. RESULTS: Of the 68 patients, 59 (87%) had eFVPTC and 9 (13%) had neFVPTC. The mean age was 48 y and 63% were female. Fifty-four of 64 patients (84%) who had a total thyroidectomy received radioactive iodine. The eFVPTC group had lower rates of cervical LN involvement (5% versus 22%, P = 0.2504). The median follow-up time was 3 y (0-13 y) and only two patients had recurrence, one with eFVPTC and one with neFVPTC. None of the patients had distant metastasis or died of their disease. CONCLUSIONS: eFVPTCs appear to have a lower rate of cervical lymph node metastases compared with neFVPTCs, but recurrent disease may be seen in both subtypes. These findings suggest eFVPTC can be managed more conservatively. PMID- 28807199 TI - Prediction of difficult laparoscopic cholecystectomy for acute cholecystitis. AB - BACKGROUND: No report has described the predictive factor of surgical difficulty for laparoscopic cholecystectomy (LC) by preoperative computed tomography (CT) findings. This study aimed to investigate whether dynamic CT findings can predict the difficulty of LC for acute cholecystitis. MATERIALS AND METHODS: Fifty-seven patients who underwent emergency LC and dynamic CT preoperatively were enrolled. Difficult LC (DLC) was defined as any patient with an operative time >=3 h, bleeding volume >=300 mL, common bile duct injury, partial cholecystectomy, the need for a second surgeon, and/or conversion to open surgery. Patients were assigned to either the DLC (+) or DLC (-) group. We determined the CT attenuation ratio of the arterial phase (ARAP) to represent the degree of transient focal enhancement of the liver adjacent to the gallbladder. The ARAP cutoff value for a DLC predictor was determined using receiver operating characteristic curve analysis. Patients' characteristics and CT findings, including the ARAP, were compared between the groups. The Fisher exact test for categorical variables and the Mann-Whitney U test for continuous variables with Bonferroni correction were used to evaluate the significance of differences. RESULTS: Fifteen patients were assigned to the DLC (+) group. The ARAP was significantly higher in the DLC (+) group than in the DLC (-) group (P = 0.006). The ARAP cutoff value was 1.55. Regarding the CT findings, an ARAP >=1.55 (P = 0.005) was significantly correlated with DLC. CONCLUSIONS: Among dynamic CT findings, an increased ARAP is a predictive factor for DLC. PMID- 28807200 TI - A sequential assessment of the preservation injury in porcine intestines. AB - BACKGROUND: Clinical and experimental evidence strongly suggest that ischemia reperfusion injury after intestinal transplantation has deleterious short- and long-term effects and finding means to reduce ischemia-reperfusion injury is a major research area. The anatomical and physiological similarities between the human and porcine digestive tract favor its use as a preclinical model for translational research. Intriguingly, no systematic appraisal of the development of the intestinal preservation injury in pigs is available. MATERIALS AND METHODS: Intestinal procurement was performed in nine pigs using histidine tryptophan-ketoglutarate solution as preservation fluid. Ileal biopsies were obtained after 8, 14, and 24 h of static cold storage (SCS), and the preservation injury was assessed morphologically (Chiu score) as well as on the molecular level. Tight junction (zonula occludens, claudin-3 and 4, tricellulin, and occludin) and adherens junctions (E-cadherin) proteins were studied using immunofluorescence and Western blot. RESULTS: Eight hours of SCS induced minimal mucosal changes (Chiu grade 1) that advanced to significant subepithelial edema (Chiu grade 3) after 24 h; progressive Goblet cell depletion was also noted. Apoptosis (studied by cleaved caspase-3 staining significantly increased after 24 h of SCS. Significant molecular changes with decreasing expression of zonula occludens, tricellulin, and occludin were evident already after 8 h of SCS and continuously worsened. Claudin-3 and Claudin-4 and E-cadherin expression remained relatively unaltered during SCS. CONCLUSIONS: Important molecular alterations precede histologic changes during SCS of the porcine intestine and may be used as more sensitive injury markers than histologic changes in intestinal ischemia and transplantation. PMID- 28807201 TI - Overexpression of Thioredoxin1 enhances functional recovery in a mouse model of hind limb ischemia. AB - BACKGROUND: There is keen interest in finding nonsurgical treatments for peripheral vascular disease (PVD). Previously, we demonstrated that selective activation of Thioredoxin1 (Trx1), a 12-kDa cytosolic protein, initiates redox dependent signaling and promotes neovascularization after ischemic heart disease. Therefore, Trx1 might possess immense potential to not only treat murine hind limb ischemia (HLI) through effective angiogenesis but also provide PVD patients with nonsurgical therapy to enhance neovascularization and improve blood perfusion. METHODS: To determine whether activation of Trx1 increases blood perfusion in HLI, two different strategies were used-gene therapy and transgenic model system. In adenoviral-mediated gene therapy, 8- to 12-wk-old mice were divided into two groups: (1) control Adeno-LacZ (Ad-LacZ) and (2) Adeno Thiroedoxin1 (Ad-Trx1). The mice underwent surgical intervention to induce right HLI followed by injection with Ad-LacZ or Ad-Trx1, respectively. In the second strategy, we used wild-type and transgenic mice overexpressing Trx1 (Trx1Tg/+). All the animals underwent Doppler imaging for the assessment of limb perfusion followed by immunohistochemistry and Western blot analysis. RESULTS: Significant increases in perfusion ratio were observed in all the Trx1 overexpressed groups compared with their corresponding controls. Expressions of heme oxygenase-1, vascular endothelial growth factor, and the vascular endothelial growth factor receptors Flk-1 and Flt-1 were increased in Trx1 overexpressed mice compared with their respective controls. Blood perfusion in the ischemic limb gradually improved and significantly recovered in Trx1Tg/+ and Ad-Trx1 groups compared with their corresponding controls. The capillary and arteriolar density in the ischemic zone were found to be higher in Trx1Tg/+ group compared with wild type. CONCLUSIONS: The overall outcomes of our study demonstrate that Trx1 enhances blood perfusion and increases angiogenic protein expression in a rodent HLI model. These results suggest that Trx1 is a potential target for clinical trials and drug therapy for the treatment of PVD. PMID- 28807202 TI - Do acute-care surgeons follow best practices for breast abscess management? A single-institution analysis of 325 consecutive cases. AB - BACKGROUND: The breast surgery community has adopted needle aspiration as the standard of care for breast abscesses, which have a size less than 5 cm on ultrasound, no skin changes, and fewer than 5 days of symptoms. Our acute-care surgery (ACS) service manages all breast abscess consults at our urban safety-net hospital. We undertook this descriptive study to identify the rate of operative incisions and drainage performed by ACS surgeons which were not compatible with best practices for breast abscess management. METHODS: We performed a retrospective review of the electronic health records of all patients on whom the ACS service was consulted for a breast abscess at our urban safety-net hospital between January 2010 and December 2014. We collected data on patient demographics, breast skin characteristics, length of symptoms, ultrasound results, and treatment modality. RESULTS: A total of 325 patients with breast abscesses were evaluated by ACS, of whom 21 met the breast community's indications for needle aspiration. Of the overall 325 subject sample, 281 (86.5%) underwent incision and drainage (I&D), and 44 (13.5%) underwent bedside needle aspiration. Of the 281 patients that underwent I&D, 269 (95.7%) met the breast surgery community's indications for I&D due to either skin changes (n = 90, 33.5%), abscess >5 cm on ultrasound (n = 88, 32.7%), or symptoms >5 days (n = 238, 88.5%). Of the 44 patients that underwent needle aspiration, only 9 (20.5%) met the current practice indications for aspiration. Of the 44 patients that underwent aspiration, 28 (63.6%) failed and went on to have an operation. The majority of these failed aspirations had symptoms >5 days (23 patients, 82.1%) or had skin changes at presentation (1 patient, 3.6%) or an abscess >5 cm on ultrasound (5 patients, 17.9%). CONCLUSIONS: As judged by best practices promulgated by the breast surgery community, ACS surgeons do not show excessive rates of operative I&D of breast abscess and in fact seem to overutilize needle aspiration. To our knowledge, this is the largest single institution series of the management of breast abscesses by ACS surgeons in the literature. PMID- 28807203 TI - Utilizing stricture indices to predict dilation of strictures after esophageal atresia repair. AB - BACKGROUND: Anastomotic stricture is the most common postoperative complication in infants undergoing repair of esophageal atresia with or without tracheoesophageal fistula (EA/TEF). Stricture indices (SIs) are used to predict infants at risk for stricture requiring dilation. We sought to determine the most accurate SI and optimal timing for predicting anastomotic dilation. MATERIALS AND METHODS: A retrospective study of infants undergoing repair of EA/TEF between 2008 and 2013 was performed. Esophagrams were used to calculate four SIs (upper pouch esophageal anastomotic stricture index [U-EASI], lower pouch esophageal anastomotic stricture index [L-EASI], lateral SI, and anterior/posterior SI). The best performing SI was identified. Logistic regression analysis was performed to determine if a first or second esophagram SI threshold was associated with dilation. A receiver operating characteristic curve measured the accuracy of the model using SIs to predict dilation. RESULTS: Of 45 EA/TEF infants included, 20 (44%) had postoperative strictures requiring dilation. As the best performing SI, logistic regression analysis showed that U-EASI as a continuous variable was predictive of dilation (P = 0.03) but was not significant at U-EASI <= 0.37. However, U-EASI <= 0.37 was associated with needing earlier dilation. On second esophagram (median, 38 days), U-EASI of <=0.39 was significantly associated with dilation (OR: 7.8, 95% CI: 1.05-57.58, P = 0.04). The area under the receiver operating characteristic curve of the U-EASI model controlling for days to esophagram demonstrated improved predictive ability from first (AUC 0.73) to second esophagram (AUC 0.81). CONCLUSIONS: Calculation of the SI utilizing a U EASI <= 0.39 on the delayed esophagram is associated with future anastomotic dilation. A multi-institutional study is necessary to confirm the predictive ability of the U-EASI. PMID- 28807204 TI - Anti-inflammatory effect of dexmedetomidine combined with hypothermia on acute respiratory distress syndrome in rats. AB - BACKGROUND: To investigate the protective effect of combination of dexmedetomidine and hypothermia on lipopolysaccharide (LPS) induced acute respiratory distress syndrome in rats. METHODS: Fifty male Wistar rats were randomly divided into five groups, with 10 rats in each group. The acute respiratory distress syndrome model was reproduced by LPS injected into the right external jugular vein (L group); only saline was injected into the right external jugular vein for control group (C group). In hypothermia group (T group), the body temperature was lowered to 32.5 degrees C-33.0 degrees C after 1 h of LPS injection, and 10 rats were sacrificed at 8 h. Group dexmedetomidine (D group) and dexmedetomidine combined with hypothermia group (DT group) received intraperitoneal dexmedetomidine 30 min before LPS was injected. The arterial blood gas was determined in all the groups before and 8 h after instillation of saline or LPS, and the oxygenation index (PaO2/FiO2) was calculated. The pro inflammatory cytokines TNF-alpha (TNF-alpha) and interleukin- 6 (IL-6) levels were determined by enzyme-linked immunosorbent assay. The expression of inflammatory signaling proteins in bronchial alveolar lavage fluid was determined by Western blot. RESULTS: Compared with group L, TNF-alpha and IL-6 levels in serum of rats were significantly lower (P < 0.05), the expression of toll-like receptors 4 and phosphorylated c-Jun N-terminal kinase was significantly lower (P < 0.05), and the p-Akt level was significantly higher (P < 0.05). Moreover, the dexmedetomidine combined with hypothermia treated was superior to the single method. CONCLUSIONS: The combination of dexmedetomidine and hypothermia could alleviate acute lung injury in rats. PMID- 28807205 TI - Facilitating surgeon understanding of complex anatomy using a three-dimensional printed model. AB - BACKGROUND: 3-dimensional prints (3DP) anecdotally facilitate surgeon understanding of anatomy and decision-making. However, the actual benefit to surgeons or patients has not been quantified. This study investigates how surgeon understanding of complex anatomy is altered by a 3DP compared to computed tomography (CT) scan or CT + digital reconstruction (CT + DR). MATERIALS AND METHODS: Key anatomic features were segmented from a CT-abdomen/pelvis of pygopagus twins to build a DR and printed in color on a 3D printer. Pediatric surgery trainees and attendings (n = 21) were tested regarding anatomy identification and their understanding of point-to-point distances, scale, and shape. RESULTS: There was no difference between media regarding point-to-point distances. The 3DP led to an increased number of correct answers for questions of scale and shape compared to CT (P < 0.05). CT + DR performance was intermediate but not statistically different from 3DP or CT. Identification of anatomy was inconsistent between media; however, answers were significantly closer to correct when using the 3DP. Participants completed the test faster with the 3DP (6.6 +/- 0.5 min) (P < 0.05) than with CT (18.9 +/- 2.5 min) or CT + 3DR (14.9 +/- 1.5 min). CONCLUSIONS: Although point-to-point measurements were not different, 3DP increased the understanding of shape, scale, and anatomy. It enabled understanding significantly faster than other media. In difficult surgical cases with complex anatomy and a need for efficient multidisciplinary coordination, 3D printed models should be considered for surgical planning. PMID- 28807206 TI - Graft loss: Review of a single burn center's experience and proposal of a graft loss grading scale. AB - BACKGROUND: There exists neither a consensus definition of burn "graft loss" nor a scale with which to grade severity. We introduced an institutional scale in 2014 for quality improvement. MATERIALS AND METHODS: We reviewed all burned patients with graft loss on departmental Morbidity and Mortality reports between July 2014 and July 2016. Graft loss grades were assigned during the course of clinical care per institutional scale. Chronic nonhealing wounds and nonburn wounds were excluded. Data abstracted included demographics, medical history, injury details, surgical procedures, graft loss, and lengths of stay (LOS). Photos of affected areas were graded by two blinded surgeons, and a linear weighted kappa was calculated to assess interrater agreement. RESULTS: Graft loss was noted in 50 patients, with 43 remaining after exclusions. Mean age was 50.1 y. The majority were male (58.1%) and African American (41.9%). Smoking (30.2%) and diabetes (27.9%) were prevalent. Total body surface area involvement ranged from 0.5% to 51.0% (11.8 +/- 12.3%). Grade I graft loss was documented on one patient (2.3%), Grade II in 15 (34.9%), Grade III in 12 (27.9%), and Grade IV in 15 (34.9%). Reoperation was performed in 20 (46.5%). Hospital LOS was longer than predicted in 38 patients (88.4%). Seven had significant morbidity, including two amputations. Moderate agreement was reached between blinded surgeons (kappa = 0.44, P = 0.004). CONCLUSIONS: Graft loss is a major source of morbidity in burn patients. In this cohort, reoperation was common and hospital LOS was extended. Use of a grading scale improves dialog among providers and enables improved understanding of risk factors. PMID- 28807207 TI - Effect of bevacizumab on acetic acid-induced ulcerative colitis in rats. AB - BACKGROUND: The aim of this study was to examine the effect of intraperitoneally administered bevacizumab on colitis induced by acetic acid. METHODS: An experimental model of acetic acid-induced colitis was introduced in rats. After the induction of colitis, bevacizumab was administered intraperitoneally at two different daily doses of low (2.5 mg/kg) or high (5 mg/kg) concentration. Control groups were included for colitis and bevacizumab. After 7 d, the rats were sacrificed, and colonic tissues were harvested for macroscopic and microscopic examination of colonic damage. Tumor necrosis factor alpha, interleukin 1 beta (IL-1beta), IL-6, myeloperoxidase, malondialdehyde, glutathione, and superoxidismutase values were measured biochemically. RESULTS: There was no statistically significant macroscopic improvement in damage to the colon tissues (P > 0.05). The severity of inflammation was significantly reduced (0.98 +/- 0.22) in the low-dose bevacizumab-treated rat group compared with the control group (P < 0.001). The decrease in the inflammation score in the high-dose bevacizumab-treated rat group was not statistically significant (1.40 +/- 0.33). In addition, although there was no significant change in the myeloperoxidase levels biochemically, IL-6 and malondialdehyde levels decreased in the low-dose treatment group (P = 0.014, P = 0.002, respectively). A significant decrease was found at both treatment doses in IL-1beta (P < 0.001, P = 0.010), tumor necrosis factor alpha (P < 0.001, P = 0.015), superoxidismutase (P = 0.046, P = 0.011), and glutathione (P = 0.012 and P < 0.001) levels. CONCLUSIONS: Both treatment doses of bevacizumab were observed to have a protective effect in an experimental colitis model, and the dosage of 2.5 mg/kg bevacizumab was found to have a more prominent effect. PMID- 28807208 TI - Imaging for acute appendicitis at nonpediatric centers exposes children to excess radiation. AB - BACKGROUND: Radiation exposure is the reason for the decreased utilization of computed tomography (CT) in pediatric centers (PCs). We sought to compare the radiation dose exposure of CT imaging performed at outside hospitals (OH) versus PC in pediatric patients with acute appendicitis (AA). MATERIAL AND METHODS: A retrospective review of all patients managed at our PC for AA from January 2011 to March 2016 was performed. Patients who had CT imaging for AA at OH were compared to those who underwent CT for appendicitis at our PC. Radiation dosing was compared using the dose index (CTDI [mGY]) and dose length product (DLP [mGYcm]). Independent t-test samples were used to compare means for radiation dose. RESULTS: 379 patients met inclusion criteria. There were 59.4% (225) patients imaged at our PC and 40.6% (154) patients were transferred from an OH. When performed at OH, 6.5% of CTs were considered inadequate as they were done without intravenous contrast compared to 1.3% in our PC. Mean CTDI was 6.9 at our PC and 11.8 at OH (P < 0.0001). Mean DLP at PC was 296.2 versus 456.8 at OH (P < 0.0001). An excess radiation dose of 4.9 mGY and 160.5 mGYcm was noted when CT scan was performed at OH versus PC. CONCLUSIONS: Using DLP as a gauge of radiation exposure, CT imaging performed at OH has a 44% higher radiation rate relative to the exposure at PC. In cases of suspected AA at a facility without pediatric surgeons, early transfer to PC prior to imaging is advocated. PMID- 28807209 TI - Induction of autophagy reduces ischemia/reperfusion injury in steatotic rat livers. AB - BACKGROUND: Steatotic livers are particularly vulnerable to ischemia/reperfusion injury (IRI). One of the reasons is an underlying impairment of autophagy. Autophagy is regulated by glycogen synthase kinase 3b (GSK3b) and extracellular signal-regulated kinases (ERK1/2) pathways. Both of them are target proteins of a cell-protective drug, lithium chloride. Lithium chloride treatment reduces IRI in many organs including liver. Therefore, we aimed to investigate the effect of lithium chloride treatment on autophagy induction in steatotic rat livers. We also wanted to evaluate the related cell-protective effects on the enhanced hepatic IRI. MATERIALS AND METHODS: After inducing hepatic steatosis, rats were injected with lithium chloride or normal saline for 3 d before being subjected to 70% selective warm ischemia for 60 min. After reperfusion, rats were observed for 30 min, 6, 24, and 48 h. RESULTS: Lithium chloride appeared to protect hepatocytes from IRI via its ability to induce autophagy by modulation of both GSK3b and ERK1/2 pathways. Hepatic damage was significantly decreased in the treatment group as indicated by a reduced inflammatory response, less apoptosis, less necrosis, and lower liver enzyme levels. CONCLUSIONS: Simultaneous modulation of GSK3b and ERK1/2 pathways might be an interesting strategy to reduce IRI in steatotic livers with an impairment of autophagy. PMID- 28807210 TI - Personalized treatment in patients with colorectal liver metastases. AB - BACKGROUND: Precision Medicine Initiative is a new research effort aiming to offer personalized treatment in many diseases, including cancer. The aim of the present article is to offer novel insights about the role of personalized treatment in patients with colorectal liver metastases (CRLM). METHODS: A review of the literature regarding personalized medicine and colorectal liver metastases was performed mainly in the MEDLINE/PubMed database. RESULTS: Surgical resection remains the only hope for cure of CRLM. Improved surgical strategies to optimize remnant liver volume are recently introduced and gaining ground. Following resection of CRLM scoring systems have been developed by combining certain preoperative factors such as microsatellite instability KRAS expression and sensitivity to immunotherapy with Programmed Death-1 inhibitor. CONCLUSIONS: Multidisciplinary management of patients with CRLM has markedly contributed to increased survival. While the last several decades have been characterized by these important developments, future advances for patients with CRLM will depend on a better understanding of genomics and molecular biology to facilitate characterization of a specific tumor "identity" so that individualized treatment for each CRLM patient becomes the rule, and not the exception. PMID- 28807211 TI - Let us cut to the core: is core biopsy enough for subcentimeter breast cancer? AB - BACKGROUND: Breast conservation therapy has become a preferred method of treating early-stage breast cancer. As care continues to evolve, certain lesions allowed less invasive treatment options. A simplified explanation of early breast cancer care is detection, biopsy, surgery, and adjuvant therapy. The authors look to challenge that algorithm for a specific type of disease. METHODS: A retrospective review was performed to identify all subcentimeter breast cancer that underwent surgery after core biopsy. These cases (n = 115) were analyzed for biopsy technique and outcome of final surgical excision to find when no residual disease was found on final pathology, potentially rendering the surgical resection an unneeded procedure. RESULTS: The authors found that 17 of 115 patients (14.8%) who underwent biopsy for subcentimeter breast cancer had no residual disease found on final surgical resection. Although the subsets were small, the largest core needle resulted in negative pathology two of three times, while the smallest gauge, never resulted in negative resection at time of surgery. CONCLUSIONS: Nearly, fifteen percent of patients were found to have no residual disease on final surgical pathology. These results were obtained when the radiologist was simply trying to get tissue diagnosis. The authors postulate that this percentage could be even higher if protocols were initiated to biopsy these small lesions with larger core biopsies and possibly alleviate the need for formal surgery in these specific, small lesion. PMID- 28807213 TI - Turkey model for flexor tendon research: in vitro comparison of human, canine, turkey, and chicken tendons. AB - BACKGROUND: Flexor tendon injuries are one of the most common hand injuries and remain clinically challenging for functional restoration. Canine and chicken have been the most commonly used animal models for flexor tendon-related research but possess several disadvantages. The purpose of this study was to explore a potential turkey model for flexor tendon research. METHODS: The third digit from human cadaveric hands, canine forepaws, turkey foot, and chicken foot were used for this study. Six digits in each of four species were studied in detail, comparing anatomy of the flexor apparatus, joint range of motion tendon excursion, tendon cross-sectional area, work of flexion, gliding resistance at the level of the A2 pulley, modulus of elasticity, suture retention strength, and histology across species. RESULTS: Anatomically, the third digit in the four species displayed structural similarities; however, the tendon cross-sectional area of the turkey and human were similar and larger than canine and chicken. Furthermore, the turkey digit resembles the human's finger with the lack of webbing between digits, similar vascularization, tendon excursion, work of flexion, gliding resistance, mechanical properties, and suture holding strength. More importantly, human and turkey tendons were most similar in histological appearance. CONCLUSIONS: Turkey flexor tendons have many properties that are comparable to human flexor tendons which would provide a clinically relevant, economical, nonhuman companion large animal model for flexor tendon research. PMID- 28807212 TI - Comparison of normothermic and hypothermic perfusion in porcine kidneys donated after cardiac death. AB - BACKGROUND: Normothermic machine perfusion (NMP) is an alternative strategy for preserving kidneys donated after cardiac death (DCD). The relative efficacy of prolonged NMP compared to hypothermic machine perfusion (HMP) in DCD kidneys with moderate ischemic injury is undetermined. This study compares NMP and HMP kidney preservation in a porcine DCD model. METHODS: Ten porcine kidneys underwent NMP or HMP preservation following 45 minutes of warm ischemia and 5 hours of cold ischemia. After 8 hours of machine preservation, hemodynamic stability, renal function, perfusate biomarkers, and histologic integrity were assessed in a simulated reperfusion model. RESULTS: During simulated reperfusion, no differences were observed in oxygen consumption, urine production, creatinine clearance, fractional excretion of sodium, proteinuria, and perfusate levels of lactate dehydrogenase and aspartate aminotransferase. Resistance was no different after 30 minutes of simulated reperfusion. Histologically, NMP kidneys demonstrated increased vacuolization after preservation and greater loss of tubular integrity after simulated reperfusion. Perfusate levels of alkaline phosphatase (AP) and gamma glutamyltransferase (GGT) were higher in NMP kidneys during preservation, but upon simulated reperfusion, AP and GGT levels were higher in HMP-preserved kidneys. Peak AP and GGT during simulated reperfusion of HMP kidneys were over 14 times higher than peak AP and GGT during preservation of NMP kidneys. CONCLUSIONS: NMP provided comparable preservation of renal function as HMP and minimized AP and GGT release upon reperfusion. PMID- 28807215 TI - Long-term survival based on pathologic response to neoadjuvant therapy in esophageal cancer. AB - BACKGROUND: Neoadjuvant treatment is standard for locally advanced esophageal cancer. However, whether the addition of radiation to neoadjuvant regimen improves survival remains unclear. The aim of this study was to compare survival in locally advanced esophageal cancer treated with neoadjuvant chemotherapy versus chemoradiation. MATERIALS AND METHODS: A prospectively maintained database of esophagectomies (1999-2012) was analyzed. We identified 297 patients with locally advanced esophageal cancer that underwent either neoadjuvant chemotherapy (n = 231) or chemoradiation (n = 66) followed by esophagectomy. Pretreatment and pathologic staging were compared to assess response. Overall survival was recorded. RESULTS: Most patients in the chemotherapy and chemoradiation groups had pretreatment stage III disease (66.7% versus 65.2%; P = 0.44). Median follow up was 79.3 and 64.9 mo for chemotherapy and chemoradiation cohorts, respectively. Complete response rate was higher in chemoradiation than chemotherapy groups (30.3% versus 13.8%; P < 0.001). Overall survival was similar between complete responders in both groups (median not reached versus 121.1 mo; chemotherapy versus chemoradiation). However, partial responders in the chemotherapy cohort had improved median survival (147.2 mo) versus those in the chemoradiation cohort (83.7 mo, P < 0.03). Within the chemotherapy-only group, partial responders had improved survival compared with nonresponders (P = 0.041); however, there was no difference in survival between partial and complete responders (P = 0.36). CONCLUSIONS: In patients undergoing esophagectomy for locally advanced esophageal cancer, neoadjuvant chemotherapy was associated with an equivalent overall survival, when compared with neoadjuvant chemoradiotherapy. Adding neoadjuvant radiation may enhance complete response rates but does not appear to be associated with improved survival. PMID- 28807214 TI - Early geriatric consultation increases adherence to TQIP Geriatric Trauma Management Guidelines. AB - BACKGROUND: The American College of Surgeons' Trauma Quality Improvement Program (TQIP) Geriatric Trauma Management Guidelines recommend geriatric consultation for injured older adults. However it is not known how or whether geriatric consultation improves compliance to these quality measures. METHODS: This study is a retrospective chart review of our institutional trauma databank. Adherence to quality measures was compared before and after implementation of specific triggers for geriatric consultation. Secondary analyses evaluated adherence by service: trauma service (Trauma) or a trauma service with early geriatric consultation (GeriTrauma). RESULTS: The average age of the 245 patients was 76.7 years, 47% were women, and mean Injury Severity Score was 9.5 (SD +/-8.1). Implementation of the GeriTrauma collaborative increased geriatric consultation rates from 2% to 48% but had minimal effect on overall adherence to TQIP quality measures. A secondary analysis comparing those in the post implementation group who received geriatric consultation (n = 94) to those who did not (n = 103) demonstrated higher rates of delirium diagnosis (36.2% vs 14.6%, P < 0.01) and better documentation of initial living situation, code status, and medication list in the GeriTrauma group. Physical therapy was consulted more frequently for GeriTrauma patients (95.7% vs 68.0%, P < 0.01) Documented goals of care discussions were rare and difficult to abstract. A subgroup analysis of only patients with fall-related injuries demonstrated similar outcomes. CONCLUSIONS: Early geriatric consultation increases adherence to TQIP guidelines. Further research into the long term significance and validity of these geriatric trauma quality indicators is needed. PMID- 28807216 TI - Early resuscitation with exendin-4 alleviates acute lung injury after hemorrhagic shock in rats. AB - BACKGROUND: Oxidative stress induced by hemorrhagic shock (HS) is known to initiate a systemic inflammatory response, which leads to subsequent acute lung injury. This study is aimed to assess the efficacy of exendin-4 (Ex-4) in attenuating lung injury in a rat model of HS and resuscitation (HS/R). METHODS: HS was induced in sodium pentobarbital-anesthetized adult male Wistar rats by withdrawing blood to maintain a mean arterial pressure of 30-35 mm Hg for 50 min. Then, the animals received Ex-4 (5 MUg/kg) or vehicle (saline) intravenously and were resuscitated with a volume of normal saline 1.5 times that of the shed blood volume. Mean arterial pressure was measured throughout the experiment, and acid base status, oxidative stress, inflammation, and lung injury were evaluated at 2 h after resuscitation. RESULTS: Ex-4 infusion reduced the methemoglobin content, the malondialdehyde content, the myeloperoxidase activity, and the expression of tumor necrosis factor-alpha and interleukin-6 in the lungs. The histologic injury was also markedly decreased in the Ex-4 group compared with the vehicle group. CONCLUSIONS: Ex-4 ameliorates the oxidative stress, inflammatory response, and subsequent acute lung injury occurring after HS/R. Although future studies are required to elucidate the underlying mechanism, our results indicate that Ex-4 infusion may be a promising strategy for improving lung injury in the treatment of HS. PMID- 28807217 TI - Adenosine triphosphate as a molecular mediator of the vascular response to injury. AB - BACKGROUND: Human saphenous veins used for arterial bypass undergo stretch injury at the time of harvest and preimplant preparation. Vascular injury promotes intimal hyperplasia, the leading cause of graft failure, but the molecular events leading to this response are largely unknown. This study investigated adenosine triphosphate (ATP) as a potential molecular mediator in the vascular response to stretch injury, and the downstream effects of the purinergic receptor, P2X7R, and p38 MAPK activation. MATERIALS AND METHODS: A subfailure stretch rat aorta model was used to determine the effect of stretch injury on release of ATP and vasomotor responses. Stretch-injured tissues were treated with apyrase, the P2X7R antagonist, A438079, or the p38 MAPK inhibitor, SB203580, and subsequent contractile forces were measured using a muscle bath. An exogenous ATP (eATP) injury model was developed and the experiment repeated. Change in p38 MAPK phosphorylation after stretch and eATP tissue injury was determined using Western blotting. Noninjured tissue was incubated in the p38 MAPK activator, anisomycin, and subsequent contractile function and p38 MAPK phosphorylation were analyzed. RESULTS: Stretch injury was associated with release of ATP. Contractile function was decreased in tissue subjected to subfailure stretch, eATP, and anisomycin. Contractile function was restored by apyrase, P2X7R antagonism, and p38-MAPK inhibition. Stretch, eATP, and anisomycin-injured tissue demonstrated increased phosphorylation of p38 MAPK. CONCLUSIONS: Taken together, these data suggest that the vascular response to stretch injury is associated with release of ATP and activation of the P2X7R/P38 MAPK pathway, resulting in contractile dysfunction. Modulation of this pathway in vein grafts after harvest and before implantation may reduce the vascular response to injury. PMID- 28807218 TI - Teduglutide effects on gene regulation of fibrogenesis on an animal model of intestinal anastomosis. AB - BACKGROUND: Teduglutide is an enterotrophic analog of glucagon-like peptide 2 approved for the rehabilitation of short-bowel syndrome. This study aims to analyze the effects of teduglutide administration on the gene regulation of fibrogenesis during the intestinal anastomotic healing on an animal model. METHODS: Wistar rats (n = 62) were assigned into four groups: "Ileal Resection and Anastomosis" or "Laparotomy," each one subdivided into "Postoperative Teduglutide Administration" or "No Treatment," and sacrificed at the third or at the seventh days, with ileal sample harvesting. Gene expression of matrix components and remodeling factors (matrix metalloproteinases [Mmp] and tissue inhibitors of metalloproteinases [Timp]) and growth factors was studied by real time polymerase chain reaction. Net collagen deposition was assessed through the Collagen-to-Mmp-to-Timp ratio of fold change of relative gene expression. RESULTS: Gene expression profiles revealed a balance toward net degradation of collagen at the third day of the intestinal anastomotic healing. Teduglutide appeared to be associated with an overall accumulation of collagen at the third day of the anastomotic repair, attributable to the upregulation of Collagen type 1 alpha 1, Collagen type 3 alpha 1, and Collagen type 4 alpha 1, Timp1, and Timp2 and downregulation of Mmp13 and to a net degradation of collagen at the seventh day, derived from repression of Collagen type 3 alpha 1, Collagen type 5 alpha 1 and Timp1 expression. CONCLUSIONS: Teduglutide appeared to be associated with a favorable influence on fibrogenesis at the third day of the intestinal anastomotic repair and to a trend to fibrolysis at the seventh day. PMID- 28807219 TI - Effects of p38 mitogen-activated protein kinase on lung ischemia-reperfusion injury in diabetic rats. AB - BACKGROUND: Lung ischemia-reperfusion injury (LIRI) is a pathologic process that is observed in several clinical conditions, and p38 mitogen-activated protein kinase (MAPK) is involved. Diabetes mellitus (DM) results in an increased incidence of ischemia-induced organ damage. The aims of this study were to examine the effects of DM on LIRI in a rat model of DM and to explore the possible mechanisms in relation to the p38 MAPK pathway. METHODS: Forty rats were randomly divided into the following five groups (n = 8 each): a control + sham group, a control + IR group (CIR), a DM + sham group, a DM + IR group (DIR), and a DM + IR + SB203580 group. The control and streptozotocin-induced diabetic rats underwent a sham operation or left hilum occlusion for 90 min followed by reperfusion for 4 h. SB203580 was used to inhibit the p38 MAPK pathway. The pulmonary oxygenation index, inflammatory cytokines in the serum, lung edema, histopathology, oxidant stress, apoptosis, and phosphorylated/total-p38 MAPK protein levels were measured. RESULTS: The DIR group displayed greater concentrations of tumor necrosis factor-alpha, interleukin-6, and intercellular adhesion molecule-1 and increases in the wet weight-to-dry weight ratio, lung injury scores, malondialdehyde levels, and cellular apoptosis, and these effects were accompanied by lower pulmonary oxygenation compared with the CIR group (P < 0.05). In the DIR group, the expression levels of p38 MAPK protein were significantly upregulated compared with those of the CIR group. Additionally, all of these alterations were attenuated in the DM + IR + SB203580 group compared with the DIR group. CONCLUSIONS: Diabetes exacerbates LIRI by activating the p38 MAPK pathway. PMID- 28807220 TI - Health characteristics of heart transplant recipients surviving into their 80s. AB - BACKGROUND: Heart transplantation (HTx) is the preferred treatment for patients with end-stage heart failure and has been successful for >30 y. The clinical course of recipients at the extreme of age is unknown. We reviewed our experience to determine the overall health and prevalence of Tx-related medical problems for recipients in their ninth decade. METHODS: We reviewed the UCTP experience from 1985 to present to identify patients who survived into their 80s and matched (1:1) with other recipients for gender and age at HTx, but did not survive to >=80 y. The end point was the prevalence of medical problems. RESULTS: Since 1985, 1129 adult HTx have been performed and 14 patients (1.2%) survived to >=80 y old. The mean age at HTx was 63 +/- 4 y. Of octogenarians, the majority were males with ischemic cardiomyopathy. The average survival after transplant was 19 +/- 5 y in the octogenarians and 5 +/- 5 y in the controls (P < 0.01). Over time, the prevalence of comorbidities increased. Compared with nonoctogenarians, we observed higher prevalence of dyslipidemia (P = 0.02), and chronic renal insufficiency (P = 0.02) during follow-up. Cardiac function was normal (ejection fraction > 55%) for all octogenarians at age 80 y. CONCLUSIONS: Despite improvements in posttransplant care, survival of HTx patients into the ninth decade is rare (1%). For those surviving into their 80s, cardiac function is preserved but dyslipidemia, renal insufficiency, and skin cancers are common. As the age of Htx patients continues to increase, posttransplant care should be tailored to minimize post-HTx complications and further extend survival. PMID- 28807221 TI - Identification of processed Chinese medicinal materials using DNA mini-barcoding. AB - Most of Chinese medicinal herbs are subjected to traditional processing procedures, including stir-frying, charring, steaming, boiling, and calcining before they are released into dispensaries. The marketing and identification of processed medicinal materials is a growing issue in the marketplace. However, conventional methods of identification have limitations, while DNA mini barcoding, based on the sequencing of a short-standardized region, has received considerable attention as a new potential means to identify processed medicinal materials. In the present study, six DNA barcode loci including ITS2, psbA-trnH, rbcL, matK, trnL (UAA) intron and its P6 loop, were employed for the authentication of 45 processed samples belonging to 15 species. We evaluated the amplification efficiency of each locus. We also examined the identification accuracy of the potential mini-barcode locus, of trnL (UAA) intron P6 loop. Our results showed that the five primary barcode loci were successfully amplified in only 8.89%-20% of the processed samples, while the amplification rates of the trnL (UAA) intron P6 loop were higher, at 75.56% successful amplification. We compared the mini-barcode sequences with Genbank using the Blast program. The analysis showed that 45.23% samples could be identified to genus level, while only one sample could be identified to the species level. We conclude that trnL (UAA) p6 loop is a candidate mini-barcode that has shown its potential and may become a universal mini-barcode as complementary barcode for authenticity testing and will play an important role in medicinal materials control. PMID- 28807222 TI - Polymyxin B as an inhibitor of lipopolysaccharides contamination of herb crude polysaccharides in mononuclear cells. AB - Lipopolysaccharides (LPS) contamination in herbal crude polysaccharides is inevitable. The present study was performed to explore the effect of polymyxin B on abolishing the influence of LPS contamination in mononuclear cells. LPS was pretreated with polymyxin B sulfate (PB) at different concentrations for 1, 5 or 24 h, and then used to stimulate RAW264.7 and mouse peritoneal macrophages (MPMs). The nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) in cell culture supernatant, as the indications of cell response, were assayed. Bupleurum chinensis polysaccharides (BCPs) with trace amount contamination of LPS was treated with PB. 30 MUg.mL-1 of PB, treating LPS (10 and 1 000 ng.mL-1 in stimulating RAW264.7 and MPMs respectively) at 37 degrees C for 24 h, successfully abolished the stimulating effect of LPS on the cells. When the cells were stimulated with LPS, BCPs further promoted NO production. However, pretreated with PB, BCPs showed a suppression of NO production in MPMs and no change in RAW264.7. In the in vitro experiments, LPS contamination in polysaccharide might bring a great interference in assessing the activity of drug. Pretreatment with PB (30 MUg.mL-1) at 37 degrees C for 24 h was sufficient to abolish the effects of LPS contamination (10 and 1 000 ng.mL-1). PMID- 28807223 TI - GTS40, an active fraction of Gou Teng-San (GTS), protects PC12 from H2O2-induced cell injury through antioxidative properties. AB - Oxidative stress, a predominant cause of apoptosis cascades triggered in neurodegenerative disorders, has been regarded as a critical inducement in the pathogenesis of Alzheimer's disease (AD). Gou Teng-San (GTS) is a traditional Chinese herbs preparation commonly utilized to alleviate cognitive dysfunction and psychological symptoms of patients with dementia. The present study aimed to investigate the protective effects of GTS40, an active fraction of GTS, on H2O2 induced oxidative damage and identify the potential active ingredients. Our results revealed that GTS40 exhibited radical scavenging activity, elevated cell viability, decreased the levels of intracellular reactive oxygen species (ROS), and stabilized mitochondrial transmembrane potential (MMP) in H2O2-treated PC12 cells. In addition, GTS40 blocked the apoptotic cascade by reversing the imbalance of Bcl-2/Bax and inhibiting the activity of caspase-3. Furthermore, an HPLC-QTOFMS method was developed to characterize major chemical constituents in GTS40. Our results revealed twenty-seven identified or tentatively characterized compounds through comparing their retention time (tR) and MS spectra with reference standards. These results suggested that GTS40 was a promising active fraction that may be beneficial in the prevention and treatment of oxidative stress-mediated neurodegenerative disorders. PMID- 28807225 TI - Differences in anti-inflammatory effects between two specifications of Scutellariae Radix in LPS-induced macrophages in vitro. AB - Scutellariae Radix (SR), the root of Scutellaria baicalensis Georgi, is used as an antipyretic drug and has been demonstrated to have anti-inflammatory activity. SR is divided into two specifications, "Ku Qin" (KQ) and "Zi Qin" (ZQ), for use against different symptoms (upper energizer heat or lower portion of the triple energizer), according to the theory of traditional Chinese medicine (TCM). However, differences in the efficacies of these two specifications have not been determined. In the present study, we aimed to characterize the differences in the anti-inflammatory activities between KQ and ZQ and to explore how their differences are manifested in lipopolysaccharide (LPS)-induced macrophages. Our results showed that, in RAW264.7 cells (a mouse macrophage cell line derived from ascites), KQ and ZQ displayed anti-inflammatory effects by inhibiting the release of nitric oxide (NO), inducible NOS (iNOS), and nuclear factor-kappaB (NF-kappaB) in a dose-dependent manner without distinction. In NR8383 cells (a rat alveolar macrophage cell line), KQ and ZQ displayed similar effects on NO, iNOS, and NF kappaB as seen in RAW264.7 cells, but KQ showed a higher inhibition rate for NO and iNOS than that shown by ZQ at the same concentration. These results indicated that there were differences in efficacy between KQ and ZQ in treating lung inflammation. Our findings provided an experimental evidence supporting the different uses of KQ and ZQ in clinic, as noted in ancient herbal records. PMID- 28807224 TI - Mesua ferrea stem bark extract induces apoptosis and inhibits metastasis in human colorectal carcinoma HCT 116 cells, through modulation of multiple cell signalling pathways. AB - Considering the great potential of natural products as anticancer agents, the present study was designed to explore the molecular mechanisms responsible for anticancer activities of Mesua ferrea stem bark extract against human colorectal carcinoma. Based on MTT assay results, bioactive sub-fraction (SF-3) was selected for further studies using HCT 116 cells. Repeated column chromatography resulted in isolation of less active alpha-amyrin from SF-3, which was identified and characterized by GC-MS and HPLC methods. alpha-amyrin and betulinic acid contents of SF-3 were measured by HPLC methods. Fluorescent assays revealed characteristic apoptotic features, including cell shrinkage, nuclear condensation, and marked decrease in mitochondrial membrane potential in SF-3 treated cells. In addition, increased levels of caspases-9 and -3/7 levels were also observed in SF-3 treated cells. SF-3 showed promising antimetastatic properties in multiple in vitro assays. Multi-pathway analysis revealed significant down-regulation of WNT, HIF 1alpha, and EGFR with simultaneous up-regulation of p53, Myc/Max, and TGF-beta signalling pathways in SF-3 treated cells. In addition, promising growth inhibitory effects were observed in SF-3 treated HCT 116 tumour spheroids, which give a hint about in vivo antitumor efficacy of SF-3 phytoconstituents. In conclusion, these results demonstrated that anticancer effects of SF-3 towards colon cancer are through modulation of multiple molecular pathways. PMID- 28807226 TI - Liver metabolomics study reveals protective function of Phyllanthus urinaria against CCl4-induced liver injury. AB - Phyllanthus Urinaria L. (PUL) is a traditional Chinese medicine used to treat hepatic and renal disorders. However, the mechanism of its hepatoprotective action is not fully understood. In the present study, blood biochemical indexes and liver histopathological changes were used to estimate the extent of hepatic injury. GC/MS and LC/MS-based untargeted metabolomics were used in combination to characterize the potential biomarkers associated with the protective activity of PUL against CCl4-induced liver injury in rats. PUL treatment could reverse the increase in ALT, AST and ALP induced by CCl4 and attenuate the pathological changes in rat liver. Significant changes in liver metabolic profiling were observed in PUL-treated group compared with liver injury model group. Seventeen biomarkers related to the hepatoprotective effects of PUL against CCl4-induced liver injury were screened out using nonparametric test and Pearson's correlation analysis (OPLS-DA). The results suggested that the potential hepatoprotective effects of PUL in attenuating CCl4-induced hepatotoxicity could be partially attributed to regulating L-carnitine, taurocholic acid, and amino acids metabolism, which may become promising targets for treatment of liver toxicity. In conclusion, this study provides new insights into the mechanism of the hepatoprotection of Phyllanthus Urinaria. PMID- 28807227 TI - In vivo and in vitro anti-sepsis effects of physcion 8-O-beta-glucopyranoside extracted from Rumex japonicus. AB - The present study was designed to investigate the anti-sepsis effects of physcion 8-O-beta-glucopyranoside (POG) isolated from Rumex japonicas and explore its possible pharmacological mechanisms. POG was extracted from R. japonicas by bioactivity-guided isolation with the anti-sepsis agents. Survival analysis in septic mouse induced by LPS and heat-killed Escherichia coli were used to evaluate the protective effect of POG (40 mg.kg-1, i.p.) on sepsis. Cytokines including TNF-alpha, IL-1beta and IL-6 in RAW 264.7 cells induced by LPS (100 ng.mL-1) were determined by ELISA. In addition, the proteins expressions of TLR2 and TLR4 were determined by Western blotting assay. Our results demonstrated that POG (40 mg.kg-1, i.p.) possessed significant protective activity on the endotoxemic mice. The POG treatment (20, 40, and 80 MUg.mL-1) significantly decreased the TNF-alpha, IL-1beta and IL-6 induced by LPS (P < 0.01) in a concentration-dependent manner. Furthermore, the TLR4 and TLR2 proteins were also down-regulated by POG at 20 (P < 0.01), 40 (P < 0.01), and 80 MUg.mL-1 (P < 0.01). The present study demonstrated that the POG extracted from R. japonicas possessed significant anti-sepsis effect on endotoxemic mice, and can be developed as a novel drug for treating sepsis in the future. PMID- 28807228 TI - Antibacterial steroidal alkaloids from Holarrhena antidysenteriaca. AB - Two new steroidal alkaloids, isoconkuressine and N-formylconessimine, together with 6 known steroidal alkaloids including conkuressine, conessine, isoconessimine, conimine, conarrhimine, and funtudienine, were isolated from the seeds of Holarrhena antidysenteriaca Wall.ex A.DC. Their intrinsic antibacterial activities and synergistic effects with penicillin and vancomycin were analyzed in methicillin sensitive staphylococcus aureus (MSSA) and methicillin resistant staphylococcus aureus (MRSA). Two of the steroidal alkaloids including one new compound (N-formylconessimine) showed potential antibacterial activity and possessed synergistic effects with penicillin and vancomycin, respectively. PMID- 28807229 TI - Tagetones A and B, new cytotoxic monocyclic diterpenoids from flowers of Tagetes minuta. AB - Tagetones A (1) and B (2), two new monocyclic diterpenoids were isolated from the n-hexane fraction of fresh flowers of Tagetes minuta L. (Asteraceae). Their structures were established by multiple spectroscopic methods (IR, HR-ESI-MS, and 1D-, and 2D-NMR), in addition to comparison with literature data. Compound 1 showed cytotoxic activity towards MCF7 and A549 cancer cells with IC50 values being 4.68 and 4.24 umol.L-1, respectively, compared to doxorubicin (IC50 0.13 and 1.12 umol.L-1, respectively). Compound 2 also exhibited significant activity against HCT116 cancer cells (IC50, 6.30 umol.L-1). PMID- 28807230 TI - Global identification of chemical constituents and rat metabolites of Si-Miao-Wan by liquid chromatography-electrospray ionization/quadrupole time-of-flight mass spectrometry. AB - Si-Miao-Wan (SMW), a tradiational Chinese medicinal formula consisting of Atractylodis Rhizoma, Phellodendri Chinensis Cortex, Coicis Semen, and Achyranthis Bidentatae Radix, has been used for the treatment of gout and gouty arthritis for many years. In the present study, a liquid chromatography quadrupole-time-of-flight mass spectrometry (LC-Q-TOF/MS) method was established to identify the multiple constituents of SMW and its metabolites in rat biological samples after oral administration. A total of 48 compounds in SMW, including 21 alkaloids, 12 organic acids, 2 terpenes, 3 lactones, 2 phytosterols, and 8 other compounds, were tentatively characterized with the diagnostic-ion filtering strategy. Based on the diagnostic ions applied to identify compounds in SMW, 28 prototype compounds and 10 metabolic compounds were detected in the biological samples. This was the first comprehensive drug metabolism investigation of SMW in rats. The developed method could be a useful means for identifying the multi-components in SMW and the metabolic components. The results may help explore the possible metabolic processes and mechanism of action for SMW in vivo. PMID- 28807231 TI - Bartholin gland cancer. AB - INTRODUCTION: Bartholin gland carcinoma is an extremely rare condition. Because of its, phase III trials have not been carried out, there exists no unanimous consensus on treatment and guidelines are missing. METHODS: All studies reporting cases of Bartholin cancer were collected and screened for the evaluations. Baseline characteristics of studies were extracted and were queried in a database. RESULTS: A total number of 133 manuscripts collected were available for the review process, representing a total number of 275 reported cases. The histological type of Bartholin gland cancer was specified in 90.4% cases: 30.7% cases were squamous cell carcinoma, 29.6% adenoid cystic carcinoma, 25% adenocarcinomas. At multivariate analysis adenocarcinoma histotype and positive lymph node were statistical correlated with worse prognosis. CONCLUSION: Bartholin gland cancer remains a challenge for gynecologic oncologists. To better understand and treat this disease, centralization to referral centers and design of multi institutional trials is crucial. PMID- 28807232 TI - Ovarian cancer: Novel molecular aspects for clinical assessment. AB - Ovarian cancer is a very heterogeneous tumor which has been traditionally characterized according to the different histological subtypes and differentiation degree. In recent years, innovative molecular screening biotechnologies have allowed to identify further subtypes of this cancer based on gene expression profiles, mutational features, and epigenetic factors. These novel classification systems emphasizing the molecular signatures within the broad spectrum of ovarian cancer have not only allowed a more precise prognostic prediction, but also proper therapeutic strategies for specific subgroups of patients. The bulk of available scientific data and the high refinement of molecular classifications of ovarian cancers can today address the research towards innovative drugs with the adoption of targeted therapies tailored for single molecular profiles leading to a better prediction of therapeutic response. Here, we summarize the current state of knowledge on the molecular bases of ovarian cancer, from the description of its molecular subtypes derived from wide high-throughput analyses to the latest discoveries of the ovarian cancer stem cells. The latest personalized treatment options are also presented with recent advances in using PARP inhibitors, anti-angiogenic, anti-folate receptor and anti cancer stem cells treatment approaches. PMID- 28807233 TI - Overcoming obstacles in the design of cancer anorexia/weight loss trials. AB - Most advanced cancer patients suffer loss of appetite (anorexia) and loss of weight. Despite the fact that cancer anorexia and weight loss are associated with a poor prognosis and detract from quality of life, no interventions have been demonstrated to palliate this syndrome in its entirety, particularly in patients with treatment-refractory malignancies. Recently, two registration trials - one with anamorelin and another with enobosarm - failed to reach their primary endpoints, thus raising questions. Were both these agents ineffective? Alternatively, did study design issues compromise the ability of these trials to identify effective agents? Thus, this review is timely insofar it serves as an introduction to study design, offers guidance on how to test promising agents for cancer anorexia/weight loss, and provides advice for overcoming trial design obstacles. PMID- 28807234 TI - Third generation EGFR TKIs in EGFR-mutated NSCLC: Where are we now and where are we going. AB - The therapeutic landscape of Non Small Lung Cancer (NSCLC) has been profoundly changed over the last decade with the clinical introduction of Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) and the discovery of EGFR activating mutations as the major predictive factor to these agents. Despite impressive clinical activity against EGFR-mutated NSCLCs, the benefit seen with 1st and 2nd generation EGFR TKIs is usually transient and virtually all patients become resistant. Several different mechanisms of acquired resistance have been reported to date, but the vast majority of patients develop a secondary exon 20 mutation in the ATP-binding site of EGFR, namely T790M. The discovery of mutant selective EGFR TKIs that selectively inhibit EGFR-mutants, including T790M harboring NSCLCs, while sparing EGFR wild type, provide the opportunity for overcoming the major mechanism of acquired resistance to 1st and 2nd generation EGFR TKIs, with a relatively favorable toxicity profile. The development of this novel class of EGFR inhibitors poses novel challenges in the rapidly evolving therapeutic paradigm of EGFR-mutated NSCLCs and the next few years will witness the beginning of a new era for EGFR inhibition in lung cancer. The aim of this paper is to provide a comprehensive overview of the increasing body of data emerging from the ongoing clinical trials with this promising novel therapeutic class of EGFR inhibitors. PMID- 28807235 TI - Stereotactic ablative radiation therapy in renal cell carcinoma: From oligometastatic to localized disease. AB - Renal Cell Carcinoma (RCC) has historically been considered a radioresistant cancer, and radiotherapy was usually delivered with a palliative goal. Stereotactic ablative radiotherapy (SABR) allows the delivery of high doses on small treatment volumes in a safe and effective way, thus opening the doors to new applicationsof radiotherapy both in the treatment of the primary and oligometastasic disease. Aim of the current review is to explore the state of art of SABR in the therapeutic approach to RCC. PMID- 28807236 TI - Overcoming barriers to treating iron overload in patients with lower-risk myelodysplastic syndrome. AB - Myelodysplastic syndromes (MDS) constitute a group of heterogeneous hematopoietic neoplasms characterized by ineffective erythropoiesis, anemia, and/or cytopenias. Supportive care for patients with MDS involves frequent red blood cell transfusions, which places patients with ongoing transfusional dependence (TD) at risk for iron overload (IO). Development of IO and tissue iron deposition can increase the risk of cardiac, hepatic, and endocrine toxicities, infection, and progression to acute myeloid leukemia. Iron chelation therapy (ICT) is an option for lower-risk MDS patients to reduce their degree of IO and possibly improve survival; use of these agents in thalassemia patients with TD and IO has been associated with reduced IO-associated complications and better survival. At present, there are several barriers to the regular use of ICT, such as a lack of randomized trial evidence and consistent guidance on diagnosis of IO and when to implement ICT, as well as barriers in adherence to/tolerability of ICT. PMID- 28807237 TI - Mitochondrial dysfunctions in bladder cancer: Exploring their role as disease markers and potential therapeutic targets. AB - Bladder cancer (BC) is a major cause of mortality worldwide as it currently lacks fully reliable markers of disease outcome and effective molecular targets for therapy. Mitochondria play a key role in cell metabolism but the role of mitochondrial dysfunctions in BC has been scarcely investigated. In this review, we explored current evidence for the potential role of mitochondrial DNA (mtDNA) alterations (point mutations and copy number) as disease markers in BC. Some germline mtDNA mutations detectable in blood could represent a non-invasive tool to predict the risk of developing BC. MtDNA copy number and tumor specific mtDNA mutations and RNAs showed encouraging results as novel molecular markers for early detection of BC in body fluids. Moreover, mitochondrial proteins Lon protease, Mitofusin-2, and TFAM may have prognostic/predictive value and may represent potential therapeutic targets. A deeper understanding of mitochondrial dysfunctions in BC could therefore provide novel opportunities for targeted therapeutic strategies. PMID- 28807238 TI - Unravelling the complexity of signalling networks in cancer: A review of the increasing role for computational modelling. AB - Cancer induction is a highly complex process involving hundreds of different inducers but whose eventual outcome is the same. Clearly, it is essential to understand how signalling pathways and networks generated by these inducers interact to regulate cell behaviour and create the cancer phenotype. While enormous strides have been made in identifying key networking profiles, the amount of data generated far exceeds our ability to understand how it all "fits together". The number of potential interactions is astronomically large and requires novel approaches and extreme computation methods to dissect them out. However, such methodologies have high intrinsic mathematical and conceptual content which is difficult to follow. This review explains how computation modelling is progressively finding solutions and also revealing unexpected and unpredictable nano-scale molecular behaviours extremely relevant to how signalling and networking are coherently integrated. It is divided into linked sections illustrated by numerous figures from the literature describing different approaches and offering visual portrayals of networking and major conceptual advances in the field. First, the problem of signalling complexity and data collection is illustrated for only a small selection of known oncogenes. Next, new concepts from biophysics, molecular behaviours, kinetics, organisation at the nano level and predictive models are presented. These areas include: visual representations of networking, Energy Landscapes and energy transfer/dissemination (entropy); diffusion, percolation; molecular crowding; protein allostery; quinary structure and fractal distributions; energy management, metabolism and re-examination of the Warburg effect. The importance of unravelling complex network interactions is then illustrated for some widely used drugs in cancer therapy whose interactions are very extensive. Finally, use of computational modelling to develop micro- and nano- functional models ("bottom up" research) is highlighted. The review concludes that computational modelling is an essential part of cancer research and is vital to understanding network formation and molecular behaviours that are associated with it. Its role is increasingly essential because it is unravelling the huge complexity of cancer induction otherwise unattainable by any other approach. PMID- 28807239 TI - Corrigendum to "High-level over-expression, purification, and crystallization of a novel phospholipase C/sphingomyelinase from Pseudomonas aeruginosa" [Protein Expr. Purif. 90 (2013) 40-46]. PMID- 28807240 TI - Role of exosomes in treatment of hepatocellular carcinoma. AB - Exosomes are nanovesicles that may play a role in intercellular communication by acting as carriers of functional contents such as proteins, lipids, RNA molecules and circulating DNA from donor to recipient cells. In addition, exosomes may play a potential role in immunosurveillance and tumor pathogenesis and progression. Recently, research has increasingly focused on the role of exosomes in hepatocellular carcinoma (HCC), the most common primary liver malignancy. We herein review data on emerging experimental and clinical studies focused on the role of exosomes in the pathogenesis, diagnosis, progression and chemotherapy response of patients with HCC. Beyond their diagnostic value in HCC, exosomes are involved in different mechanisms of HCC tumor pathogenesis and progression including angiogenesis and immune escape. Moreover, exosomes have been demonstrated to change the tumor microenvironment to a less tolerogenic state, favoring immune response and tumor suppression. These results underline a practical and potentially feasible role of exosomes in the treatment of patients with HCC, both as a target and a vehicle for drug design. Future studies will need to further elucidate the exact role and reliability of exosomes as screening, diagnostic and treatment targets in patients with HCC. PMID- 28807241 TI - The impact of radiofrequency-assisted transection on local hepatic recurrence after resection of colorectal liver metastases. AB - Resection is the gold standard in the treatment of liver metastases from colorectal cancer. An internal cooled radiofrequency electrode was described to achieve tissue coagulation to a greater margin width. The aim of this study is to determinate if a RF-assisted transection device (RFAT) has any effect on local hepatic recurrence (LHER) compared to conventional technologies. A study population of 103 patients who had undergone a hepatic surgical resection was retrospectively analysed. Patients were classified into two groups according to the device used: a RF-assisted device (RFAT group; n = 45) and standard conventional devices (control group; n = 58). LHER was defined as any growing or enhancing tumour in the margin of hepatic resection during follow-up. Cox proportional models were constructed and variables were eliminated only if p > 0.20 to protect against residual confounding. To assess the stability of Cox's regression model and its internal validity, a bootstrap investigation was also performed. Baseline and operative characteristics were similar in both groups. With a mean follow-up of 28.5 months (range 2-106), in patients with positive margins, we demonstrated 0% of LHER in RFAT vs. 27% in control group (p = 0.032). In the multivariate analysis five factors demonstrated significant influence on the final model of LHER: RFAT group, size of the largest metastases, number of resected metastases, positive margin and usage of Pringle-manoeuvre. This study suggests that parenchymal transection using a RFAT able to create deep thermal lesions may reduce LHER especially in case of margin invasion during transection. PMID- 28807242 TI - Efficacy and safety of combination therapy of chemoembolization and radiofrequency ablation with different time intervals for hepatocellular carcinoma patients. AB - BACKGROUND AND OBJECTIVES: Combination of transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) has become an effective alternative therapy for hepatocellular carcinoma (HCC). In clinical practice, the choice of time interval between TACE and RFA is a key point for curative effect, but optimal time interval is uncertain in guidelines. We aim to explore the optimal time interval for HCC patients of Child-Pugh classification A or B. METHODS: Two hundred and thirty-three HCC patients of Child A or B who had undergone TACE and RFA were enrolled and divided into seven groups according to different time intervals (1-7weeks). Tumor damage, liver function, complications and survival time of patients after treatment were analyzed. RESULTS: Complete remission rate and total effective rate decreased in groups with the prolonged time interval (p < 0.05). Average Child-Pugh score of patients in first three groups significantly increased one month after combination treatment (p < 0.01). While that not happened in other groups. Complications occurred in 16.7% patients, similarly occurred in groups (p > 0.1). Median survival time in groups four and five were 42 months, longer than other groups (p < 0.01). CONCLUSION: A period of 3-5 weeks is the optimal time interval between TACE and RFA for HCC patients of Child-Pugh classification A or B. PMID- 28807243 TI - Is hyperthermic intraperitoneal chemotherapy (HIPEC) safe for healthcare workers? AB - BACKGROUND: During hyperthermic intraperitoneal chemotherapy (HIPEC), caregivers are exposed by different routes to cytotoxic drugs. This review proposes an overview of the safety of HIPEC by assessing existing data on protection procedures, biological and non-biological samples. Based on these data, relevant good practices, eventual irrelevant overprotection procedures and missing data to implement adapted protections are highlighted. MATERIALS AND METHODS: Data were extracted from a systematic review of literature from 1980 till 2016: number and type of surgical procedure, healthcare professionals present, protective equipment, samples, pre-analytical method and analytical method. RESULTS AND DISCUSSION: Only 55 HIPEC procedures have been evaluated. The majority of antineoplastic drugs used have all required characteristics to penetrate the organism and are recognized as very dangerous. Moreover, a great heterogeneity in protective equipment used, either individual or collective is observed. Environmental contamination occurs during HIPEC, especially for all surfaces in the operating room. Compounds penetration into caregivers lungs cannot be excluded. Priority remains to prove professionals contamination by focusing on biological samples. Biological material is rarely sampled or samples are not necessarily adapted. CONCLUSION: Repeated blood tests should be preferred using appropriate sampling schedules and validated sensitive analytical methods. Furthermore, there is a great need of new biological indicators to monitor caregivers exposure. During hyperthermic intraperitoneal chemotherapy (HIPEC), healthcare workers are exposed by different routes to cytotoxic drugs. There are currently few available occupational exposure data and environmental monitoring and biomonitoring must be improved in order to ensure optimal protection against antineoplastic drugs. PMID- 28807244 TI - Endoscopic management of upper tract urothelial carcinoma: Improved prediction of invasive cancer using a ureteroscopic scoring model. AB - BACKGROUND: The aim of this study was to investigate clinical and ureteroscopic factors considered as important for the prediction of invasive upper tract urothelial carcinoma (UTUC) and establish a model using a new ureteroscopic scoring. METHODS: We analyzed tumor depth and grade from ureteroscopic biopsies in 172 patients who underwent imaging studies, urine cytology, and radical nephroureterectomy. Invasive UTUC was defined as muscle-invasive or non-organ confined tumors. Ureteroscopic scoring was defined as sum of the risk factors, lamina propria invasion, or presence of a high-grade tumor. RESULTS: In the multivariate analysis, lamina propria invasion was a significant factor associated with an increased risk of invasive UTUC. Positive urine cytology, hydronephrosis, and local invasion on imaging were also significant. Presence of a high-grade tumor was not significant due to interaction with lamina propria invasion (P < 0.001). In the ureteroscopic scoring model, the odds ratio of invasive UTUC was significantly related to the ureteroscopic scoring number (30.9% (56/81), 66.7% (14/42), and 83.7% (41/49) according to the sum of risk factors 0 to 2, respectively, (P < 0.001). Positive predictive value (PPV) for invasive UTUC was increased in relation to the number of risk factors including urine cytology, hydronephrosis, local invasion on imaging, and any abnormal ureteroscopic finding (lamina propria invasion or presence of high-grade tumors). The PPV gradually increased as follows: 6.3%, 33.3%, 52.1%, 81.6%, to 92.9% for 0 to 4 positive risk factors, respectively (P < 0.001). CONCLUSIONS: When lamina propria invasion and presence of a high-grade tumor were incorporated, our novel ureteroscopic scoring model was highly predictive of invasive UTUC. PMID- 28807245 TI - Portal vein ligation versus portal vein embolization for induction of hypertrophy of the future liver remnant: A systematic review and meta-analysis. AB - An important risk of major hepatic resection is postoperative liver failure, which is directly related to insufficient future liver remnant (FLR). Portal vein embolization (PVE) and portal vein ligation (PVL) can minimize this risk by inducing hypertrophy of the FLR. The aim of this systematic review and meta analysis was to compare the efficacy and safety of PVE and PVL for FLR hypertrophy. A systematic search was conducted on the17th of January 2017. The methodological quality of the studies was assessed using the Oxford Critical Appraisal Skills Program for cohort studies. The primary endpoint was the relative rate of hypertrophy of the FLR. Number of cancelled hepatic resection and postoperative morbidity and mortality were secondary endpoints. For meta analysis, the pooled hypertrophy rate was calculated for each intervention. The literature search identified 21 eligible studies with 1953 PVE and 123 PVL patients. All studies were included in the meta-analysis. No significant differences were found regarding the rate of FLR hypertrophy (PVE 43.2%, PVL 38.5%, p = 0.39). The number of cancelled hepatic resections due to inadequate hypertrophy was significantly lower after PVL (p = 0.002). No differences were found in post-intervention mortality and morbidity. This meta-analysis demonstrated no significant differences in safety and rate of FLR hypertrophy between PVE and PVL. PVE should be considered as the preferred strategy, since it is a minimally invasive procedure. However, during a two-stage procedure, PVL can be performed with expected comparable outcome as PVE. PMID- 28807246 TI - Hepatic intra-arterial injection of irinotecan drug eluting beads (DEBIRI) for patients with unresectable colorectal liver metastases: A systematic review. AB - PURPOSE: To systematically review the safety and efficacy of transarterial drug eluting beads, irinotecan (DEBIRI) for the treatment of pretreated patients with unresectable colorectal liver metastases (CRLM). METHODS: A systematic search of the current literature was conducted to extract publications reporting on the use of DEBIRI for CRLM. Data on the safety and efficacy was extracted and tabulated. Weighted average values (WAV) were calculated for each variable to provide a single value representing the pooled safety and efficacy data. RESULTS: 13 studies (15 treatment arms) were evaluated, comprising a total of 850 patients. There were 6 prospective phase I/II trials, 5 retrospective trials and 2 randomized control trials. All papers involved patients previously treated with systemic chemotherapy. The weighted average all-grade toxicity rate was 35.2% (range; 6-100%). The high-grade WAV toxicity rate was 10.1% (range; 0-32%). Weighted average response rates were 56.2% and 51.1% according to RECIST (Response Evaluation Criteria in Solid Tumors) and modified RECIST/EASL (European Association for the Study of the Liver) response criteria respectively. The weighted average progression-free survival and overall survival were 8.1 months and 16.8 months, respectively. CONCLUSION: Transarterial DEBIRI is safe and effective in the treatment of unresectable CRLM to the liver. Further studies are warranted to better define its role in the treatment algorithm of this patient subset. PMID- 28807248 TI - Tumor model for surgical simulation to assess a minimally invasive endoscopic approach for midcheek mass removal. AB - INTRODUCTION: The midcheek is considered one of the most important facial area due to its involvement in mimic expression and communication. Pathology of this district is complex due to the variety of soft tissue belonging to the face. We propose a surgical simulation, to assess the feasibility of a new minimally invasive endoscopic approach for midcheek mass removal. TECHNICAL REPORT: This study was performed on four cadavers, at the Anatomy Laboratory of the University of Tubingen. In all the cadavers 3 cm3 of Acquasil Dent Sply Ultra were injected via trans-cutaneous along the nasolabial fold to simulate a midcheek mass. Three incisions in concealed areas were performed to create an access to reach the anterior compartment of the face. By using the Optical Dissector with distal spatula and a 30 degrees endoscope we provided a wide surgical window and a greater exposure to isolate, dissect and remove the midcheek tumor model safely. CONCLUSION: The proposed endoscopic technique allowed us to visualize and preserve all the key anatomic structures of the midcheek region. Due to its nature, the suggested material may provide a valid tumor model for surgical training also in other districts. PMID- 28807247 TI - Interleukins as new prognostic genetic biomarkers in non-small cell lung cancer. AB - BACKGROUND: Surgery is the standard treatment for early-stage NSCLC, and platinum based chemotherapy remains as the treatment of choice for advanced-stage NSCLC patients with naive EGFR status. However, overall 5-years relative survival rates are low. Interleukins (ILs) are crucial for processes associated with tumor development. In NSCLC, IL1B, IL6, IL12A, IL13 and IL16 gene polymorphisms may contribute to individual variation in terms of patient survival. The purpose of this study was to evaluate the association between IL gene polymorphisms and survival in NSCLC patients. METHODS: A prospective cohorts study was performed, including 170 NSCLC patients (114 Stage IIIB-IV, 56 Stage I-IIIA). IL1B (C > T; rs1143634), IL1B (C > T; rs12621220), IL1B (C > G; rs1143623), IL1B (A > G; rs16944), IL1B (C > T; rs1143627), IL6 (C > G; rs1800795), IL12A (C > T; rs662959), IL13 (A > C; rs1881457) and IL16 (G > T; rs7170924) gene polymorphisms were analyzed by PCR Real-Time. RESULTS: Patients with IL16 rs7170924-GG genotype were in higher risk of death (p = 0.0139; HR = 1.82; CI95% = 1.13-2.94) Furthermore, carriers of the TT genotype for IL12A rs662959 presented higher risk of progression in the non-resected NSCLC patient subgroup (p = 0.0412; HR = 4.49; CI95% = 1.06-18.99). The rest of polymorphisms showed no effect of on outcomes. CONCLUSIONS: Our results suggest that IL16 rs7170924-GG and IL12A rs662959-TT genotypes predict higher risk of death and progression, respectively, in NSCLC patients. No influence of IL1B rs12621220, IL1B rs1143623, IL1B rs16944, IL1B rs1143627, IL6 rs1800795, IL13 rs1881457 on NSCLC clinical outcomes was found in our patients. PMID- 28807249 TI - Current trends in multimodality treatment of esophageal and gastroesophageal junction cancer - Review article. AB - PURPOSE: Multimodality treatment has now been widely introduced in the curatively intended treatment of esophageal and gastroesophageal junction cancer. We aim to give an overview of the scientific evidence for the available treatment strategies and to describe which trends that are currently developing. METHODS: We conducted a review of the scientific evidence for the different curatively intended treatment strategies that are available today. Relevant articles of randomized controlled trials, cohort studies, and meta analyses were included. RESULTS: After a systematic search of relevant papers we have included 64 articles in the review. The results show that adenocarcinomas and squamous cell carcinomas of the esophagus and gastroesophageal junction are two separate entities and should be analysed and studied as two different diseases. Neoadjuvant treatment followed by surgical resection is the gold standard of the curatively intended treatment today. There is no scientific evidence to support the use of chemoradiotherapy over chemotherapy in the neoadjuvant setting for esophageal or junctional adenocarcinoma. There is reasonable evidence to support definitive chemoradiotherapy as a treatment option for squamous cell carcinoma of the esophagus. CONCLUSION: The evidence base for curatively intended treatments of esophageal and gastroesophageal junction cancer is not very strong. Several on going trials have the potential to change the gold standard treatments of today. PMID- 28807250 TI - A systematic review on radiofrequency assisted laparoscopic liver resection: Challenges and window to excel. AB - Laparoscopic liver resection has progressively gained acceptance as a safe and effective procedure in the treatment of benign and malignant liver neoplasms. However, blood loss remains the major challenge in liver surgery. Several techniques and devices have been introduced in liver surgery in order to minimize intraoperative haemorrhage during parenchymal transection. Radiofrequency (RF) assisted liver resection has been shown to be an effective method to minimize bleeding in open and laparoscopic liver resection. A number of RF devices for parenchymal transection have been designed to assist laparoscopic liver resections. Here we have reviewed the results of various RF devices in laparoscopic liver resection. A total 15 article were considered relevant for the evaluation of technical aspects and outcomes of RF-assisted liver resections in laparoscopic procedures. In these studies, 176 patients had laparoscopic liver resection using RF-assisted parenchymal coagulation. Two monopolar and three bipolar devices were employed. Blood loss was limited in most of the studies. The need of blood transfusions was limited to two cases in all the series. Conversion was necessary due to bleeding in 3 cases. Operative and transection times varied between studies. However, RF-assisted resection with bipolar devices appeared to have taken less time in comparison to other RF devices. RF-related complications were minimum, and only one case of in-hospital death due to hepatic failure was reported. Although RF has been used in a small minority of laparoscopic liver resections, laparoscopic RF-assisted liver resection for benign and malignant disease is a safe and feasible procedure associated with reduction in blood loss, low morbidity, and lower hospital mortality rates. PMID- 28807251 TI - How to conduct a high-quality original study on a diagnostic research topic. AB - As health research methodologists and journal reviewers, we noticed that the methodological rigor of many publications on diagnostic or prognostic topics in the medical literature could be improved. We present a concise and clear series of reviews to help clinicians and health researchers to master the basic key components of how to conduct a high-quality original study or systematic review on a diagnostic or prognostic research topic from a methodological perspective. This is the first review of the series, which focuses on how to conduct a high quality diagnostic study. We are introducing four aspects: clarifying the objectives; generating an appropriate research question; planning the study design; and reporting and analyzing data. This review highlights that diagnostic test accuracy outcomes are surrogates for patient outcomes, a diagnostic test has three roles, the "PIRO" components should be included in a diagnostic research question, a new study should be registered, multiple index tests can be compared in one study, and prevalence affects test accuracy outcomes. This review also emphasizes reporting any thresholds, calculating sample size, and performing a two-by-three table to calculate diagnostic outcomes. PMID- 28807252 TI - Role of hepatic trisectionectomy in advanced hepatocellular carcinoma. AB - BACKGROUND: Advanced hepatocellular carcinoma (HCC) with underlying cirrhosis poses a major operative challenge. Patients have a dismal prognosis without curative resection. The role of hepatic trisectionectomy in these patients is not established. The aim of this study was to analyze and compare the perioperative outcome and prognosis of patients undergoing trisectionectomy with hepatic resection of a lesser extent. METHODS: From 2000 to 2014, 48 patients underwent hepatic trisectionectomy for HCC with background cirrhosis or chronic hepatitis (Group A). Another (Group B) 520 patients underwent liver resection of a lesser extent. Patient demographics, clinicopathological data, perioperative outcome and long-term survival were compared between the 2 groups. RESULTS: Intraoperative bloodloss, operating time and total hospital stay were significantly higher in trisectionectomy patients. Tumors were larger and more advanced in group A. The morbidity rate was 43.8% in group A compared to 27.5% in group B, p = 0.027. In hospital mortality was 6.3% for group A. Group A had a significantly shorter time to recurrence (4.5months vs 6.2months, p = 0.036), as well as a poorer disease free survival (DFS) than group B (6.3 months vs 15.7 months, p = 0.02). Overall survival was comparable. Tumor number, size, albumin, INR, microvascular invasions and positive resection margins were predictors of disease-free survival. CONCLUSION: Hepatic trisectionectomy may be associated with a higher morbidity and lower DFS. However, these patients would not be suitable candidates for ablative therapy or liver transplantation. With careful patient selection and meticulous surgical technique, trisectionectomy is feasible and gives these patients the only hope of cure. PMID- 28807253 TI - Interdisciplinary reconstruction of oncological resections at the skull base, scalp and facial region. AB - Extensive bone and soft tissue defects of the skull require unique plastic and reconstructive techniques to avoid and optimize aesthetic appearance following oncological resections. Procedures are ideally planned in an interdisciplinary board composed of neurosurgery, otorhinolaryngology, plastic and reconstructive surgery to facilitate reconstructive procedures of soft tissue and bone as early as possible in one approach. Large resections may require plastic surgery involvement from the beginning. Herein, we describe the function of a multidisciplinary approach to complex oncologic resections of the cranial base, scalp, and facial regions for neuro-oncologic patients. PMID- 28807254 TI - Minimally invasive gastrectomy for gastric cancer: A national perspective on oncologic outcomes and overall survival. AB - BACKGROUND: Minimally invasive (MI) gastrectomy has become increasingly common as a resection technique for gastric cancer; however, data are limited regarding peri-operative morbidity, oncologic outcomes and long-term survival, particularly in the Western patient population. STUDY DESIGN: The 2010-2012 National Cancer Data Base was queried for adult patients who underwent gastrectomy for localized, intestinal-type gastric adenocarcinoma. Patients were classified by surgical approach (MI vs. open gastrectomy) on an intent-to-treat basis. Groups were propensity score matched using a 1:1 nearest neighbor algorithm, and outcomes were compared. Survival was estimated using the Kaplan-Meier method. RESULTS: Among 5420 patients, 1423 (26%) underwent MI gastrectomy. Following adjustment with propensity matching, all baseline characteristics were highly similar between 1175 patients in each treatment group. Between propensity-matched groups, MI gastrectomy patients had similar rates of margin-negative resections (91 vs. 90%, p = 0.447), median lymph node harvest (16 vs. 15, p = 0.104), and utilization of adjuvant therapies (28 vs. 28%, p = 0.748). MI gastrectomy was associated with shorter hospital stay (8 vs. 9 days, p < 0.001) without an increase in unplanned readmissions (7 vs. 6%, p = 0.456) or 30-day mortality (2 vs. 3%, p = 0.655). There was no difference in 3-year overall survival (50 vs. 55%, p = 0.359). CONCLUSIONS: On a national level, MI gastrectomy for gastric cancer appears to be associated with similar perioperative and long-term outcomes compared to the traditional open approach. While prospective studies remain essential, these data provide greater equipoise for ongoing trials and institutional efforts to further implement and evaluate this technique. PMID- 28807257 TI - Revisiting the determinants of the glomerular filtration barrier: what goes round must come round. AB - The glomerular filtration barrier (GFB) is characterized by a very high hydraulic permeability, combined with a marked permselectivity that excludes macromolecules such as albumin. Thus, the GFB retains most of the plasma proteins, with only 0.06% of albumin getting across the basement membrane. The GFB consists of 3 layers: fenestrated endothelial cells, the glomerular basement membrane, and podocytes. Injury to any of these components can result in the development of proteinuria. The contribution of the major components of the GFB has recently been reexamined and is discussed in the context of our past and present understanding. PMID- 28807256 TI - Climate change and kidney disease-threats and opportunities. PMID- 28807258 TI - How low can you go? Achieved blood pressure and cardiovascular outcomes. AB - The benefits of controlling blood pressure to levels < 140/90 mm Hg are well established, but the risks and benefits of further reductions in blood pressure are less clear. A recent observational study using pooled data from 2 large randomized trials of renin-angiotensin system blockers suggested no added benefit and some increased risk of cardiovascular events with achieved blood pressures < 120 mm Hg systolic or 70 mm Hg diastolic. Caveats of observational studies notwithstanding, these results add to the ongoing controversy over the optimal blood pressure target for high-risk individuals. PMID- 28807259 TI - Is osteocyte Klotho bad for bone health? AB - The recent identification of alphaKlotho protein (Klotho) in osteocytes led to the generation of an experimental mouse model with osteocyte-specific Klotho ablation. This enabled Komaba et al. to assess the contribution to bone structure and function of osteocyte Klotho per se as compared with that of the systemic fibroblast growth factor 23-Klotho axis. Surprisingly, unlike the osteopenia and low bone turnover of systemic Klotho deletion, osteocyte-specific Klotho ablation resulted in increased osteoblastic activity and bone formation rate. PMID- 28807260 TI - ANCA in anti-GBM disease: moving beyond a one-dimensional clinical phenotype. AB - McAdoo et al. propose that patients with both circulating antiglomerular basement membrane antibody and antineutrophil cytoplasm antibody demonstrate a phenotype that lies between that of single-positive antiglomerular basement membrane disease and antineutrophil cytoplasm antibody-associated vasculitis. Specifically, there may be a subset of "double-positives" that have a more favorable response to therapy. These observations, along with reports of "atypical" antiglomerular basement membrane disease, challenge us to look beyond antiglomerular basement membrane disease as a 1-dimensional entity, and better characterize its clinical spectrum. PMID- 28807261 TI - Association between hepatitis C virus and chronic kidney disease: heterogeneity begets heterogeneity. AB - Epidemiologic studies examining the association between hepatitis C virus and chronic kidney disease have yielded conflicting findings. Analyzing data from a Taiwanese cohort, Lai and colleagues report a novel finding that the odds of chronic kidney disease were nearly 3-fold higher in hepatitis C virus-infected persons with genotype 2 compared with genotype 1. Hepatitis C virus genotype distributions differ in regions around the world. Can genotypic differences in chronic kidney disease risk explain some of the heterogeneity in prior studies? PMID- 28807262 TI - Heavy metal nephropathy: considerations for exposure analysis. AB - Epidemiologic studies have yielded conflicting results regarding the role of heavy metal exposure in recent epidemics of chronic kidney disease (CKD). In this issue of Kidney International, Tsai et al. examined the combined effects of chromium, lead, and cadmium on kidney function using data from the Nutrition and Health Survey in Taiwan. We add this report to our growing understanding of contemporary epidemics of CKD and highlight considerations for exposure analysis in CKD epidemiologic studies. PMID- 28807263 TI - The growth of AKI: half empty or half full, it's the size of the glass that matters. AB - Previous data suggest rapid growth in the population incidence of acute kidney injury (AKI). In this study, Kashani et al. report data from the Mayo Clinic Hospital indicating slowing to stabilization of AKI rates in Olmsted County, Minnesota, from 2006 through 2014. More studies are needed to confirm this trend, and if this trend exists, reasons behind it. Further, strategies to optimally care for vulnerable populations in which AKI rates remain high, including the elderly, are warranted. PMID- 28807264 TI - Deconstructing interstitial fibrosis and tubular atrophy: a step toward precision medicine in renal transplantation. AB - The prerequisite for successful treatment is an accurate diagnosis, a concept coined precision medicine. Progression of interstitial fibrosis and tubular atrophy is widely considered the natural course for all transplanted kidneys. In this issue, Gosset et al. describe discrete disease entities in individual patients and their contribution to interstitial fibrosis and tubular atrophy and its progression. This represents a major step forward in stratifying patients for targeted treatment trials (i.e., a step toward precision medicine in renal transplantation). PMID- 28807265 TI - Proliferative glomerulonephritis with monotypic IgA-kappa deposits in a 10-year old. PMID- 28807266 TI - Warfarin in CKD patients with atrial fibrillation. PMID- 28807267 TI - The Authors Reply. PMID- 28807268 TI - The Authors Reply. PMID- 28807269 TI - Renal functional reserve and pregnancy outcomes. PMID- 28807270 TI - Decleves A-E, Zolkipli Z, Satriano J, et al. Regulation of lipid accumulation by AMK-activated kinase in high fat diet-induced kidney injury. Kidney Int. 2014;85:611-623. PMID- 28807271 TI - Yan Y, Ma L, Zhou X, et al. Src inhibition blocks renal interstitial fibroblast activation and ameliorates renal fibrosis. Kidney Int. 2016;89:68-81. PMID- 28807272 TI - The role of mammography in calcific uremic arteriolopathy. PMID- 28807273 TI - Treatment dilemma-bilateral renal artery aneurysms. PMID- 28807274 TI - Isolation of viable Toxoplasma gondii, molecular characterization, and seroprevalence in elk (Cervus canadensis) in Pennsylvania, USA. AB - Toxoplasmosis is a worldwide zoonosis. The ingestion of uncooked/undercooked meat and consumption of water contaminated with Toxoplasma gondii oocysts excreted by felids are the main modes of transmission of this parasite. T. gondii has been reported in multiple cervid species; however, little is known of the parasite in North American elk (Cervus canadensis). In the present study, antibodies to T. gondii were detected in serum of wild elk from Pennsylvania collected during 2013 2016 by the modified agglutination test (MAT, cut-off 1:25); 221 of 317 (69.7%) had MAT titers of 1:25 in 19, 1:50 in 28, 1:100 in 34, and 1:200 or higher in 140. Thus most (44.1%) elk had relatively high titers. Seroprevalence was slightly higher in males (76.9%) than females (67.5%, not statistically significant, Chi-square tests, P<0.0001) and was higher in adults (76.5%) than yearlings (46.4%, Odds ratio 3.82; 95% CL 1.72-8.47; P=0.001) or calves (21.7%, Odds ratio 12.58; 95% CL 4.51-35.10; P<0.0001). Annual seroprevalence was relatively stable throughout the period tested and ranged from 66.6% to 72.2%. Of the 101 elk harvested in 2016, hearts were bioassayed from 20 elk and tongues were bioassayed from 56; all tongue samples were negative. Viable T. gondii was isolated from hearts of two female elk, one of these was a seronegative adult and the other was a calf with no serum available for testing. Both T. gondii isolates were cultivated in cell culture and DNA derived from tachyzoites was characterized using the PCR-RFLP markers including SAG1, SAG2 (5'- 3'SAG2 and altSAG2), SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, and Apico. One isolate belongs to ToxoDB PCR-RFLP genotype #2 and the other is genotype #5. Both genotypes are frequently identified in animals in North America. PMID- 28807275 TI - Recombinant Miro domain-containing protein of Haemonchus contortus (rMiro-1) activates goat peripheral blood mononuclear cells in vitro. AB - In our previous proteomics study, we identified Miro domain-containing protein (Miro-1), an excretory and secretory product of the pole worm, Haemonchus contortus, binds to goat peripheral blood mononuclear cells (PBMCs) in vivo. However, our understanding of the role of Miro-1and its potential immune impact on goat PBMCs is limited. The aim of the present study was to evaluate the effects of Miro-1 on functions of goat PBMCs in vitro. Recombinant protein (rMiro 1) was expressed in a prokaryote and incubated with goat PBMCs. Western blot analysis showed that rMiro-1 is successfully recognized by goat sera infected with H. contortus. Immunofluorescence analysis using rat antibodies against rMiro 1 indicated that this protein binds to goat PBMCs in vitro. Treatment of goat PBMCs/monocytes with various concentrations of rMiro-1 resulted in the upregulation of IL-2, IL-4, and IL-17, which in turn promoted cell proliferation, migration, the release of NO in PBMCs, and enhancement of phagocytosis of monocytes. These findings suggested that rMiro-1 stimulates PBMCs activity. PMID- 28807276 TI - Establishment rate of cattle gastrointestinal nematodes in farmed red deer (Cervus elaphus). AB - Red deer can be infected with some gastrointestinal nematodes (GIN) of cattle but it is unknown to what extent. An indoor study was conducted to determine the establishment rate of cattle GIN in young deer. Five young calves and 5 young red deer were used. They were effectively treated with anthelmintics when housed and then infected 2 weeks later. After four weeks they were killed for total worm counts. Establishment rates were assessed comparing worm counts to the infective dose which were identified morphologically, and to the relative establishment rate of different species. The establishment rates (%) in cattle and deer respectively were H. contortus (8.0, 18.7, p=0.18), Ostertagia ostertagi (30.8, 0.7, p<0.001), Cooperia spp. (72.3, 2.3, p<0.001) and Trichostrongylus spp. (19.0, 25.3, p=0.12). The majority (>98%) of Trichostrongylus spp. were Trichostrongylus axei in both hosts and there were no differences between hosts for this species (p=0.11). In cattle >98% of Cooperia were Cooperia oncophora and the mean burden was much higher than in deer (p<0.01) where there were similar proportions of Cooperia oncophora, Cooperia punctata and C. curticei. Small numbers of Oesophagostomum venulosum were also present with 3X as many found in deer as in cattle (p<0.05). This study has shown that some cattle-origin GIN can establish in red deer. In particular, the establishment of H. contortus and T. axei could allow sufficient burdens to build up to be clinically significant. Importantly, almost no cattle Ostertagia species or small intestinal species established in deer. PMID- 28807277 TI - Recovery of bovine Babesia spp. after long-term cryostorage and comparison of bovine donor erythrocytes and serum. AB - Cultured Babesia bovis and Babesia bigemina were recovered from liquid nitrogen storage nearly 30 years after they were cryopreserved. Four cattle were compared as donors of erythrocytes and serum for microaerophilous stationary phase (MASP) cultures for recovery of B. bigemina. Erythrocytes and serum from only one (#913) of the four animals supported growth of B. bigemina. Two B. bigemina (frozen in 1986 and 1987) and two B. bovis (both frozen in 1986) cryostocks were recovered from liquid nitrogen storage and all four recovered and thrived in #913 erythrocytes and serum. In the third passage after recovery, B. bovis cultures were cryopreserved. Six months later they were successfully recovered using #913 erythrocytes and serum. This study shows that B. bovis and B. bigemina stored nearly 30 years in liquid nitrogen can be successfully recovered in the MASP system. This study also confirms previous observations that selection of a suitable bovine donor of erythrocytes and serum is critical to the success of the culture. PMID- 28807278 TI - Helminth infections on organic dairy farms in Spain. AB - The aim of this study was to assess the prevalence of the major helminth infections affecting organic dairy cattle in northern Spain. Milk and faecal samples were obtained from 443 milking cows. Ostertagia ostertargi and Fasciola hepatica exposure was assessed by detection of specific antibodies in milk samples and F. hepatica infection was diagnosed by the detection of coproantigens in faecal samples. Dictyocaulus viviparus and Calicophoron daubneyi infections were diagnosed by conventional coprological techniques. The prevalence of infections caused by F. hepatica was considerable low, but similar to data reported from conventional farming in the same area. The prevalence rate of C. daubneyi infection was higher than previous data mirroring an increase of the prevalence that was also reported in other European countries in recent years. Specific antibodies against O. ostertargi were detected in all herds and the median levels of antibodies, determined by ELISA, exceeded the thresholds indicating milk production losses. The prevalence of D. viviparus was almost negligible. For each parasite, an ordinal logistic-regression analysis was used to assess the risk of infection by taking into account the administration of effective anthelmintics and the number of lactations. Treatment of cows with fasciolicides decreased the risk of F. hepatica infection in multiparous cows, whereas treatment with oxiclozanide or albendazol did not decrease the risk of C. daubneyi infection or O. ostertargi exposure, respectively. The study findings demonstrate that helminth infection in organic dairy farming is similar or even lower than previous data reported from conventional farming. Special attention should be paid to the impact of these infections on milk production. PMID- 28807279 TI - Acaricidal activity of fluralaner against Ornithodoros moubata and Ornithodoros erraticus argasid ticks evaluated through in vitro feeding. AB - Ornithodoros erraticus and Ornithodoros moubata are argasid tick vectors that transmit severe diseases such as African swine fever and human relapsing fever. Elimination of the synanthropic populations of these vectors would facilitate the control of these diseases. Fluralaner is a novel isoxazoline that selectively blocks the GABA- and glutamate-gated channels, providing potent insecticidal and acaricidal activity. The aim of the current study was to provide quantitative data on the susceptibility of males, females and third nymphal instar of O. erraticus and O. moubata to fluralaner through in vitro feeding exposure. Fluralaner activity against these developmental stages and species was assessed by feeding the ticks on ovine blood medicated with decreasing fluralaner concentrations between 1 and 10-8MUg/mL. Tick mortality was measured at 4, 24 and 48h and 1, 2 and 3 weeks post-feeding. Tests included solvent-treated and untreated blood controls. Fluralaner was extremely active against O. erraticus, with mean lethal concentrations 50 (LC50) and 95 (LC95) of 2.0*10-8 and 5.4*10 8MUg/mL, respectively. Fluralaner was also highly active against O. moubata, showing a mean LC50 of 1.5*10-6MUg/mL and a mean LC95 of 1.8*10-3MUg/mL. In the latter species, the most susceptible life stages were the females (LC95 1.4*10 4MUg/mL). Fluralaner demonstrated potent acaricidal activity against all developmental stages of O. erraticus and O. moubata tested, in the first 48h after in vitro feeding. Therefore, fluralaner has the potential to provide very high acaricidal efficacy to multiple argasid tick species via feeding exposure and could be included as an acaricidal agent in integrated programmes for the control of argasid tick vectors and argasid tick-borne diseases. PMID- 28807280 TI - Immunization with inactivated antigens of Neospora caninum induces toll-like receptors 3, 7, 8 and 9 in maternal-fetal interface of infected pregnant heifers. AB - Neospora caninum is an obligate parasite and a major cause of abortion in cattle. Pregnancy failures appear to be associated with weak innate defences on the maternal-fetal interface during infection with N. caninum. Herein, we studied the gene expression of Toll-like receptors (TLRs) in pregnant heifers immunized with different vaccine formulations against N. caninum before mating and then challenged the heifers with live N. caninum on day 70 of gestation. TLR7 and TLR8 expression was upregulated in the placental caruncle of infected-pregnant heifers previously exposed to live N. caninum as immunogen. However, TLR7 and 8 expression in both placenta and caruncle as well as, TLR3 and 9 expression in caruncle were upregulated when heifers were previously immunized with inactivated soluble whole antigens and recombinant NcSAG1, NcHSP20 and NcGRA7 proteins. All dams were carrying viable fetuses when they were culled at day 104 of gestation. Upregulation of TLR7 and IFNgamma expression was detected in fetal spleen when their mothers where previously vaccinated with soluble antigens and recombinant NcSAG1, NcHSP20 and NcGRA7 proteins. These studies demonstrate that soluble or recombinant NcSAG1, NcHSP20 and NcGRA7 antigens induce key TLRs expression at the maternal-fetal interface, probably triggering damaging inflammatory cellular immune responses associated with abortion. Previous infection with N. caninum seems to attenuate the innate immune response at the maternal-fetal interface, which could favour pregnancy maintenance and perpetuation of the disease. This finding represents novel information on how N. caninum vaccination and infection modulate TLRs expression at the placenta and fetal spleen, the possible role in the pregnancy outcomes and transplacental transmission of the protozoa. PMID- 28807281 TI - Toxoplasma gondii in the Cornigliese sheep breed in Italy: Meat juice serology, in vitro isolation and genotyping. AB - Toxoplasma gondii is considered one of the most important food-borne parasitic zoonoses globally and sheep are important intermediate hosts of the parasite. Meat and milk from infected sheep are considered an important source of infection for humans. Here, the authors evaluated T. gondii infection in the Italian Cornigliese sheep breed using meat juice ELISA, and in vitro assay for followed by Real Time-PCR and PCR-RFLP. Twenty-one hearts were collected at slaughter. Meat juice serology was carried out on all samples, while eleven hearts with the highest antibody titres were subjected to acid-peptic digestion and seeding onto Vero cells. DNA was extracted at three different time points following seeding. PCR-positive samples were then genotyped by PCR-RFLP. All the meat juice samples were positive for IgG antibodies against p30 protein of T. gondii. Five of the 11 samples, seeded onto Vero cells, were positive in PCR made on DNA extracted after 21days of culture and the PCR-RFLP revealed a Type-II or Type II variant profile at 9/10 loci. Two out of five samples showed an increase in terms of parasite growth by comparing the Cq values at three different time points. To the authors' knowledge, this is the first report of in vitro cultivation of T. gondii from muscle tissue of naturally-infected sheep. In vitro assays may be a promising alternative to bioassays and further studies are necessary in order to improve assay performance and to identify possible early markers of parasite proliferation. PMID- 28807282 TI - Age of Haemonchus contortus third stage infective larvae is a factor influencing the in vitro assessment of anthelmintic properties of tannin containing plant extracts. AB - The larval exsheathment inhibition assay (LEIA) of infective larvae (L3) is an in vitro method used to evaluate the anthelmintic (AH) activity of tannin-containing plant extracts against different species of gastrointestinal nematodes, including Haemonchus contortus. Some conditions remain to be defined in order to standardize the LEIA, i.e. the optimal age of larvae produced from donor animals to use in the assays. Therefore, this study aimed at identifying the effect of age and age-related vitality of H. contortus infective larvae produced under tropical conditions, on the in vitro AH activity measured with the LEIA. The same acetone:water (70:30) extract from Acacia pennatula leaves was used to perform respective LEIA tests with H. contortus L3 of different ages (1-7 weeks). Each week, the L3 were tested against different concentrations of extract (1200, 600, 400, 200, 100, 40MUg/mL of extract) plus a PBS control. Bioassays were performed with a benzimidazole (Bz) resistant H. contortus (Paraiso) strain. In order to identify changes in L3 vitality on different weeks (1-7), two assays testing larval motility were included only with PBS: the larval migration assay (LMA) and the larval motility observation assay (LMOA). Mean effective concentrations causing 50% and 90% exsheathment inhibition (EC50, EC90) were obtained for every week using respective Probit analyses. On the first week, the larvae had lowest EC50 and EC90 (39.4 and 65.6MUg/mL) compared to older larvae (P<0.05). The EC50 and EC90 for weeks 2-5 were similar (P>0.05), while older larvae tended to show higher EC50 and EC90 (P<0.05). Motility showed strong negative correlations with age of larvae (r>=-0.83; P <0.05) and EC50 (r>=-0.80; P<0.05), suggesting that the lower extract efficacy could be associated with decaying vitality of larvae associated with age. More stable efficacy results were found between two to five weeks of age. PMID- 28807283 TI - Neospora caninum ROP16 play an important role in the pathogenicity by phosphorylating host cell STAT3. AB - Neospora caninum is a common cause of abortions in cattle and nervous system dysfunctions in dogs. Our analysis shows that NcROP16 and TgROP16 have similar structures and may have similar functions. To our surprise, we found that similar to the T. gondii RH strain, the N. caninum Nc-1 strain could phosphorylate STAT3Y705, but in contrast to T. gondii, N. caninum Nc-1 could not phosphorylate STAT6Y641. We constructed a gene-knockout plasmid and screened DeltaNcROP16 strains at the gene, protein and transcription levels. Plaque assays, invasion assays and intracellular proliferation tests indicated that the DeltaNcROP16 strain phenotypes had changed, resulting in smaller plaques and slower intracellular growth. A virulence analysis showed that the cerebral loads of the parasite in mice infected with the DeltaNcROP16 strain were significantly reduced compared to the loads in mice infected with the Nc-1 strain. In contrast, the overexpression of ROP16 led to the largest number of parasites observed in the mouse brains. Similarly, the overexpression of ROP16 caused the most powerful virulence in mice. In addition, NcROP16 takes part in the STAT3 signaling pathway in different host cells. This occurs by the secretion of NcROP16 into the host cell, where it phosphorylates STAT3, and phosphorylated STAT3 then migrates to the cell nucleus. NcROP16 can enter the host nucleus and continuously phosphorylate STAT3, resulting in the induction of host cell apoptosis. The parasites engineered to over express the NcROP16 induce the increased transcription of apoptotic-related genes, such as Fas, FasL and Bax and enhanced ANA1 cell apoptosis. The results show that NcROP16 is a key virulence factor in N. caninum, promoting the host cell apoptosis and enhancing the pathogenicity of the parasites for the host by phosphorylating STAT3. PMID- 28807284 TI - First description of Cryptosporidium parvum in carrier pigeons (Columba livia). AB - The carrier pigeon and the domestic pigeon are different breeds of the species Columba livia. Carrier pigeons are used for recreational activities such as bird contests and exhibitions. Due to the close contact with humans, these birds may potentially represent a public health risk, since they can host and disseminate zoonotic parasites, such as those belonging to the genus Cryptosporidium (phylum Apicomplexa). The purpose of this work was the detection by microscopic and molecular techniques of Cryptosporidium spp. oocysts in fecal samples of carrier pigeons, and subsequently to sequence the 18S ribosomal RNA marker of positive samples to identify the species. A total of 100 fecal samples were collected individually in two pigeon breeding facilities from Formiga and Aracatuba, cities located in Minas Gerais state and Sao Paulo state, Brazil, respectively. The age of the birds ranged from one to 12 years; 56 were females and 44 males. Fecal smears were stained with negative malachite green, whereas the molecular characterization was based on the sequence of a ~800bp fragment of the 18S rRNA gene. Microscopic examination of fecal smears revealed 4% (4/100) oocyst positivity. On the other hand, 7% (7/100) of positivity were found using nested PCR. Three samples were 99% to 100% similar to Cryptosporidium parvum 18S rDNA type A (Genbank AH006572) and the other three samples had 99% to 100% similarity to C. parvum 18S rDNA type B (Genbank AF308600). To our knowledge, this is the first report of C. parvum oocysts in carrier pigeons. PMID- 28807285 TI - Sarcoptes scabiei alters follicular dynamics in female Iberian ibex through a reduction in body weight. AB - Normal development of the ovarian cycle is a key factor in ensuring female reproductive success. Sarcoptes scabiei has been shown to induce changes in host physiology, although the effects of this mite on the female reproductive cycle are still unknown. In an attempt to clarify this issue, the number of ovarian structures (primary follicles, secondary follicles, Graaf follicles, corpus luteum and corpus albicans) in female Iberian ibex (Capra pyrenaica) affected by sarcoptic mange was explored by histological analysis of samples taken from 102 females selectively harvested in the Sierra Nevada Natural Space, southern Spain. The effect of mange status, body weight (corrected for age), age and year of sampling on the number of ovarian structures was assessed using generalized linear models. Our results provide evidence that sarcoptic mange alters follicular dynamics through a reduction in host body weight, whose main consequences are noted in follicular maturation and ovulatory capacity. PMID- 28807286 TI - Prevalence and risk factors associated with endoparasitic infection in dogs from Transylvania (Romania): A retrospective study. AB - During six years (April 2010-April 2016) we examined individual feces samples collected from 1314 dogs located in Center and Northwest Romania (Transylvania). Stool samples were analyzed by saturated salt flotation, sedimentation technique and modified Ziehl-Nielsen staining method. The overall prevalence of endoparasitic infections was 66.6% (n=875). Sixteen species/genera of endoparasites were identified. The most prevalent species were Ancylostoma caninum/Uncinaria stenocephala (33.0%) (p=0.0001) followed by Trichocephalus vulpis (25.0%). Mixed infections, were significantly more frequent (p=0.0001) than single species infections. The age and the living condition/service of dogs were identified as the main risk factors for infection with endoparasites. PMID- 28807287 TI - An ELISA for the early diagnosis of acute canine babesiosis detecting circulating antigen of large Babesia spp. AB - Babesia canis is the predominant Babesia species in dogs in Europe and is responsible for a severe and fatal disease. An increase in global pet tourism and a widening of the geographic distribution of the tick vector has led to the emergence of infections in areas where previously only imported cases have been reported. Due to the potential for rapid and serious disease progression, direct parasite detection by stained blood smears and light microscopy or DNA-based methods have traditionally been used for the diagnosis of acute infections. This study describes the production of a murine monoclonal antibody ('mAb BcFIII 7/1/2') that reacts to a 65kDa corpuscular epitope present in B. canis-infected erythrocytes and can be used in an ELISA to detect circulating Babesia antigen during acute infections. The sensitivity of the ELISA was 100% (95%CI: 84.5-100) as determined using blood lysate samples from 27 dogs with acute B. canis infections. Sensitivity was reduced to 53.8% in 13 patent Babesia vogeli infections (95%CI: 26.1-79.6) based on the current test design using convalescent serum from a B. canis-infected dog. The specificity was determined to be 86.4% (95%CI: 64-96.4) using 22 samples from healthy canine blood donors. In the course of acute B. canis infections, the ELISA showed a positive result at the same time as a positive PCR result was recorded. This was 24-48h before parasites could be detected by light microscopy. Convalescent samples collected from 6 B. canis infected dogs at least 14days post treatment resulted in negative ELISA reactions. The hyper-acute to acute phase of a B. canis infection represents an emergency situation with high mortality. To increase the chances of survival, a fast and accurate diagnosis and immediate treatment is required. The current study demonstrates the opportunity of an early and specific detection of acute infections by an AgELISA that is potentially translatable to a rapid diagnostic test design. PMID- 28807288 TI - Prevalence of Tritrichomonas foetus in tennessee bulls. AB - The prevalence of bovine trichomonosis (BT) in TN bulls was estimated through both active screening of bulls and review of previous laboratory records. During the active bull screening, preputial smegma specimens were collected from 458 TN beef bulls at 2 cattle slaughterhouses and 2 stockyards, which serve most beef bulls in TN, between March 2014 and June 2015. Each specimen was cultured for Tritrichomonas foetus (T. foetus) as well as evaluated microscopically every other day for seven days for any protozoa resembling T. foetus. An aliquot of the culture media from each specimen was used for DNA extraction and subsequent qPCR testing. Two specimens were considered suspect on microscopic evaluation, but all specimens were negative for T. foetus on qPCR. This suggests that the 2 specimens were most likely contaminated by fecal trichomonads. Retrospectively, 1979 T. foetus test records from 2 major TN diagnostic laboratories were reviewed between October 2013 and September 2016. True prevalence of BT in TN beef bulls was estimated at <0.01% from the laboratory records, although the county prevalence differed in 2 TN counties (Marshal: 0.09% and Bedford: 0.5%). Overall, the prevalence of BT in TN is low, and the current screening efforts to help control BT disease in TN are acceptable. Future efforts should focus on educating cattle stakeholders on the importance of optimal specimen collection and handling as well as routine testing for BT before cattle movement. In addition, cattle producers should be reminded of leading risk factors associated with BT in cattle. PMID- 28807289 TI - Neglected intravascular pathogens, Babesia vulpes and haemotropic Mycoplasma spp. in European red fox (Vulpes vulpes) population. AB - Wild animals, especially canids, are important reservoirs of vector-borne pathogens, that are transmitted by the ticks and other bloodsucking arthropods. In total, 300 red foxes (Vulpes vulpes), shot by the hunters in eastern and northern Slovakia, were screened for the presence of vector-borne pathogens by PCR-based methods Blood samples were obtained from nine red foxes and tissue samples originated from 291 animals (the liver tissue samples from 49 foxes and spleen samples from 242 red foxes). Babesia vulpes and haemotropic Mycoplasma species were identified by amplification and sequencing of 18S rRNA and 16S rRNA gene fragments, respectively. Overall, the presence of these pathogens was recorded in 12.3% of screened DNA samples. Altogether 9.7% (29/300) of investigated foxes carried DNA of Babesia spp. In total, 12 out of 29 Babesia spp. PCR - positive amplicons were further sequenced and identified as B. vulpes (41.4%; 12/29), remaining 17 samples are referred as Babesia sp. (58.6%; 17/29). Overall prevalence of B. vulpes reached 4.0% (n=300). Thirteen (4.3%) samples tested positive for distinct Mycoplasma species. To the best of our knowledge, this study brings the first information on B. vulpes infection in red foxes in Slovakia, and the first data on the prevalence and diversity of haemotropic Mycoplasma spp. in European red fox population. Moreover, co-infections with B. vulpes and Mycoplasma spp. were confirmed in 1.7% of tested DNA samples. The relatively high rates of blood pathogen' prevalence and species diversity in wild foxes indicate the role of the fox population in the maintenance of the parasites in sylvatic cycles and strengthen the assumption that foxes play an important role in spreading of infectious microorganisms within and outside the natural foci. PMID- 28807290 TI - Exposure to vector-borne pathogens in privately owned dogs living in different socioeconomic settings in Brazil. AB - This survey was conducted in four Brazilian cities, from three federative units (Pernambuco, Minas Gerais, and Federal District), representing different socioeconomic settings, to determine the presence of antibodies to or antigens and DNA of selected pathogens in privately owned dogs. From January to April 2015, blood and serum samples were collected and assayed using different tests. In particular, antibodies to Anaplasma spp., Borrelia burgdorferi sensu lato, and Ehrlichia spp., and antigens of Dirofilaria immitis were detected using a rapid enzyme-linked immunosorbent assay, whereas antibodies to Babesia spp. were detected by an immunofluorescence antibody assay. Moreover, the presence of Leishmania DNA in blood samples was assessed by real-time polymerase chain reaction. Overall, 208 (69.3%) out of 300 dogs were positive for at least one tested pathogen (intended here as antibodies, antigen or DNA, as abovementioned), with 139 (66.8%) of them being positive to two or more pathogens. No dog presented antibodies to B. burgdorferi s.l., and D. immitis antigens were detected exclusively in dogs from Pernambuco. Among positive dogs, the most common clinical signs were lymphadenomegaly (45.2%), onychogryphosis (41.3%), dermatitis (34.1%), pale mucous membranes (19.7%), weight loss (14.9%), fever (12.5%), alopecia (11.1%), and lethargy (4.8%). Tick and flea infestations were recorded in 41.7% and 29.3% of the dogs, respectively, with 49 (16.3%) dogs being co-infested by both ticks and fleas. Most of the tick- and flea-infested dogs presented high level of infestation (>10 ticks and >20 fleas). The level of tick infestation varied significantly among federative units, being highest in Minas Gerais (68.0%), followed by Pernambuco (36.0%) and Federal District (21.0%). On the other hand, the level of flea infestation was higher in Pernambuco (50.0%), followed by Minas Gerais (29.0%) and Federal District (9.0%). The number of dog owners reporting the use of ectoparasiticides (on dogs and/or in the environment) varied significantly, ranging from 6.0% in Pernambuco to 60.0% in Federal District. This study reveals disparate results in terms of dog exposure to fleas and ticks in the studied communities, which may be related to factors such as the owners' capability/willingness to afford the use of ectoparasiticides on their dogs and the dog's level of restriction. Further research is needed to establish the relationship between dog owners' socioeconomic situation and the level of exposure to ectoparasites and their transmitted pathogens. PMID- 28807291 TI - Toxocara canis: Analysis of the kinetics of antigen release and antibody production in an in vivo model for the detection of past or present infection. AB - Worldwide, Toxocara canis is an important zoonotic nematode of public health concern. This soil-transmitted helminth causes visceral larva and ocular larva migrans in paratenic hosts. The detection of T. canis larva migrans is complicated because current immunological tests detect only IgG antibodies, which can cross-react with antigens from other parasites and cannot distinguish between the past and present infection. Analysis of antigen release and antibody production could help improve the detection of larva migrans. Here, we report the kinetics of antigen release, IgM and IgG production in an in vivo model for the detection of past or present infection. We used four groups of seven mice: two groups infected orally with 50 or 100 embryonated eggs, and the other two infected intraperitoneally with 50 or 100 live larvae. We obtained blood samples at 0, 3, 7, and 14days and, then, every two weeks until day 140. Sandwich ELISA and indirect ELISA were performed for antigen capture and the detection of immunoglobulins, respectively. Mice inoculated with larvae developed an immune response faster than those inoculated with eggs. In all groups, antigen capture was positive starting at 3days until 140days post-inoculation (dpi). Detection of immunoglobulins was at 14 or 28dpi in mice inoculated with larvae or eggs, respectively. Negative IgM values were detected at days 98 and 112. The samples remained positive for IgG until the last day of the experiment. Data suggest that in mice inoculated with T canis eggs, some larvae did not hatch, others died or never reached the bloodstream. Based on our model, we propose that there is early infection when only antigens are present, and active larva migrans when antigen and immunoglobulins are detected, implying an immune response of the host against the antigen. Our study offers a view into the parasite-host relationship and enables us to infer if there are live larvae. Additionally, these findings provide a foundation for the diagnosis and differentiation of recent infection and active larva migrans. PMID- 28807292 TI - Development of a bead-agglutination assay for rapid detection of Tritrichomonas foetus. AB - Tritrichomonas foetus is a flagellated protozoan parasite that causes inflammation of the reproductive tract leading to early embryonic death and abortion in cattle, thereby resulting in significant economic losses. Testing and culling infected bulls is an important strategy for parasite control. Routine testing is mainly limited to bulls that are traveling across state lines or within states that have specific control programs. Both culture and PCR detection methods are available, but they are not typically conducted as part of a yearly breeding soundness program and are not easily conducted in the field. In the present study, we developed a bead agglutination assay for detection of T. foetus antigens. Our experiments revealed that latex beads conjugated to T. foetus lipophosphoglycan-binding antibodies visibly clump in the presence of T. foetus. The detection limit of the assay, determined using both field and laboratory isolates of the parasite, was 0.25MUg/mL and 1.0MUg/mL total T. foetus antigen, respectively. Our results indicate that an antigen detection test could offer a tool for screening bulls under field conditions. PMID- 28807293 TI - Sarcocystis neurona and Neospora caninum in Brazilian opossums (Didelphis spp.): Molecular investigation and in vitro isolation of Sarcocystis spp. AB - Sarcocystis neurona and Neospora spp. are protozoan parasites that induce neurological diseases in horses and other animal species. Opossums (Didelphis albiventris and Didelphis virginiana) are definitive hosts of S. neurona, which is the major cause of equine protozoal myeloencephalitis (EPM). Neospora caninum causes abortion in cattle and infects a wide range of animal species, while N. hughesi is known to induce neurologic disease in equids. The aims of this study were to investigate S. neurona and N. caninum in tissues from opossums in the northeastern Brazil, and to isolate Brazilian strains of Sarcocystis spp. from wild opossums for comparison with previously isolated strains. Carcasses of 39 opossums from Bahia state were available for molecular identification of Sarcocystis spp. and N. caninum in their tissues, and for sporocyst detection by intestinal scraping. In addition, Sarcocystis-like sporocysts from nine additional opossums, obtained in Sao Paulo state, were tested. Sarcocystis DNA was found in 16 (41%) of the 39 opossums' carcasses; N. caninum DNA was detected in tissues from three opossums. The sporocysts from the nine additional opossums from Sao Paulo state were tested by bioassay and induced infection in nine budgerigars, but in none of the gamma-interferon knockout mice. In vitro isolation was successful using tissues from all nine budgerigars. The isolated strains were maintained in CV-1 and Vero cells. Three of nine isolates presented contamination in cell culture and were discarded. Analysis of six isolates based on five loci showed that these parasites were genetically different from each other and also distinct from S. neurona, S. falcatula, S. lindsayi, and S. speeri. In conclusion, opossums in the studied regions were infected with N. caninum and Sarcocystis spp. and represent a potential source of infection to other animals. This is the first report of N. caninum infection in tissues from black-eared opossum (D. aurita or D. marsupialis) and white-eared opossum (D. albiventris). Brazilian opossums are probably infected by different Sarcocystis spp. distinct from S. neurona and S. falcatula, or present a high level of genetic recombination. PMID- 28807294 TI - Recombinase polymerase amplification (RPA) combined with lateral flow (LF) strip for detection of Toxoplasma gondii in the environment. AB - Toxoplasma gondii infects all warm-blooded vertebrates, resulting in a great threat to human health and significant economic loss to the livestock industry. Ingestion of infectious oocysts of T. gondii from the environment is the major source of transmission. Detection of T. gondii oocysts by existing methods is laborious, time-consuming and expensive. The objective of the present study was to develop a recombinase polymerase amplification (RPA) method combined with a lateral flow (LF) strip for detection of T. gondii oocysts in the soil and water. The DNA of T. gondii oocysts was amplified by a pair of specific primers based on the T. gondii B1 gene over 15min at a constant temperature ranging from 30 degrees C to 45 degrees C using RPA. The amplification product was visualized by the lateral flow (LF) strip within 5min using the specific probe added to the RPA reaction system. The sensitivity of the established assay was 10 times higher than that of nested PCR with a lower detection limit of 0.1 oocyst per reaction, and there was no cross-reactivity with other closely related protozoan species. Fifty environmental samples were further assessed for the detection validity of the LF-RPA assay (B1-LF-RPA) and compared with nested PCR based on the B1 gene sequence. The B1-LF-RPA and nested PCR both showed that 5 out of the 50 environmental samples were positive. The B1-LF-RPA method was also proven to be sufficiently tolerant of existing inhibitors in the environment. In addition, the advantages of simple operation, speediness and cost-effectiveness make B1-LF-RPA a promising molecular detection tool for T. gondii. PMID- 28807295 TI - Anthelmintic effects of forage chicory (Cichorium intybus) against free-living and parasitic stages of Cooperia oncophora. AB - Chicory shows great promise as an anthelmintic forage for grazing ruminants that can reduce reliance on anti-parasitic drugs. Recently, we reported potent anthelmintic effects of chicory-based diets in infected cattle with significant reductions in worm burdens of the abomasal nematode Ostertagia ostertagi, whilst no apparent activity was observed against the small intestinal parasite Cooperia oncophora. To explore this discrepancy, we investigated direct anthelmintic effects of forage chicory against C. oncophora in vitro. Chicory leaves (cultivar 'Spadona') were extracted with methanol in a Soxhlet apparatus and the resulting extract was purified by solid-phase extraction to concentrate bioactive phytochemicals such as sesquiterpene lactones. C. oncophora eggs and adult worms from mono-infected donor calves were exposed to decreasing concentrations of the chicory extract. In an egg hatch assay, the chicory extract induced a marked and dose-dependent inhibition of egg hatching, with 95% inhibition at 2500MUg extract/mL (EC50=619 [95% CI: 530-722] MUg extract/mL). In the adult motility inhibition assays, the chicory extract induced a potent and dose-dependent worm paralysis. At 12h of incubation, worms exposed to chicory showed a total paralysis at >=500MUg extract/mL, while after 48h of incubation a complete inhibition of worm motility was observed at >=250MUg extract/mL (EC50=80 [95% CI: 67-95] MUg extract/mL). We have demonstrated that forage chicory can induce potent inhibitory effects on the egg hatching and exert direct anthelmintic activity against parasitic stages of C. oncophora. These results suggest that the previously reported absence of in vivo effects of chicory towards C. oncophora in infected animals may be related with host-mediated factors and/or inhibitory digestive conditions, rather than an inherent inactivity of chicory and its bioactive phytochemicals. PMID- 28807296 TI - Myiasis of domestic and wild ruminants caused by Hypodermatinae in the Mediterranean and Indian subcontinent. AB - Myiasis caused by Hypodermatinae flies is an economically important disease affecting domesticated and wild ruminants in countries of the Mediterranean and Indian subcontinent. The adult flies have a short life span of 1 week, and they spread disease by laying their eggs on the coat of animals. Hypoderma spp. primarily lay their eggs on cattle, buffalo, roe deer, red deer and reindeer, while Przhevalskiana spp. lay eggs on the coat of goats. The larvae live as tissue parasites, inducing myiasis in the host, and have a major impact on the productivity and welfare of infested animals. Diagnosis of myiasis is mainly based on clinical examination of the animal and immunodiagnosis using serum and milk samples. Chemical control of this pest is considered the best treatment option. Treatment with microdoses of ivermectin (2MUg/kg body weight) combined with immunosurveillance strategies has led to the eradication of bovine hypodermosis in a few countries; however, these flies are still prevalent throughout the northern hemisphere. This paper reviews the current status, diagnosis and control measures for Hypodermatinae myiasis of domestic and wild ruminants in the Indian subcontinent and Mediterranean region. PMID- 28807297 TI - Cutaneous leishmaniosis in naturally infected dogs in Parana, Brazil, and the epidemiological implications of Leishmania (Viannia) braziliensis detection in internal organs and intact skin. AB - Environmental changes have occurred over the years, altering the eco epidemiological pattern of leishmaniosis in the State of Parana, Brazil, involving the pillars of the cycle (parasite, vectors, reservoir, and environment) and their interaction. Much has been discussed about the dog's role as a reservoir of the Leishmania (Viannia) braziliensis Vianna, 1911 transmission cycle. However, this question remains unanswered. The purpose of this study was to investigate, using parasitological and molecular methods, different samples in eight naturally infected dogs from an endemic rural locality where only L. (V.) braziliensis is present, and where human cases have been previously notified. Blood and biopsied organ samples from naturally infected dogs were analyzed by culture media, PCR, random amplified polymorphic DNA and sequencing methodologies. Only skin lesions from all dogs yielded positive cultures and when PCR was performed, L. (V.) braziliensis DNA was amplified from intact skin, peripheral blood, bone marrow, spleen, liver and lymph nodes. RAPD was also applied to isolates from the skin lesions, exhibiting the genetic variability of the parasite identified. To confirm which species of Leishmania was amplified in PCR, the sequencing method was performed, verifying 100% similarity with the Viannia subgenus. This study showed that L. (V.) braziliensis can spread to other sites besides the ulcerous lesions, such as intact skin, peripheral blood and internal organs, making it possibility for dogs to serve as active sources of parasite transmission. For definitive proof, xenodiagnostic test on intact skin of infected dogs, should be done. PMID- 28807298 TI - Using a rule-based envelope model to predict the expansion of habitat suitability within New Zealand for the tick Haemaphysalis longicornis, with future projections based on two climate change scenarios. AB - Haemaphysalis longicornis is the only species of tick present in New Zealand which infests livestock and is also the only competent vector for Theileria orientalis. Since 2012, New Zealand has suffered from an epidemic of infectious bovine anaemia associated with T. orientalis, an obligate intracellular protozoan parasite of cattle and buffaloes. The aim of this study was to predict the spatial distribution of habitat suitability of New Zealand for the tick H. longicornis using a simple rule-based climate envelope model, to validate the model against published data and use the validated model to project an expansion in habitat suitability for H. longicornis under two alternative climate change scenarios for the periods 2046-2065 and 2081-2100, relative to the climate of 1981-2010. A rule-based climate envelope model was developed based on the environmental requirements for off-host tick survival. The resulting model was validated against a maximum entropy environmental niche model of environmental suitability for T. orientalis transmission and against a H. longicornis occurrence map. Validation was completed using the I-similarity statistic and by linear regression. The H. longicornis climate envelope model predicted that 75% of cattle farms in the North Island, 3% of cattle farms in the South Island and 54% of cattle farms in New Zealand overall have habitats potentially suitable for the establishment of H. longicornis. The validation methods showed an acceptable level of agreement between the envelope model and published data. Both of the climate change scenarios, for each of the time periods, projected only slight to moderate increases in the average farm habitat suitability scores for all the South Island regions. However, only for the West Coast, Marlborough, Tasman, and Nelson regions did these increases in environmental suitability translate into an increased proportion of cattle farms with low or high H. longicornis habitat suitability. These results will have important implications for the geographical progression of Theileria-associated bovine anaemia (TABA) in New Zealand and will also be of interest to Haemaphysalis longicornis researchers in Australia, Japan, Korea and New Zealand. PMID- 28807299 TI - Seasonality and circadian variation of microfilaremia in dogs experimentally infected with Dirofilaria immitis. AB - Periodicity, the cyclical rise and fall in microfilaria (mff) numbers in the peripheral blood over time, is observed in many filarial infections. It is correlated with the necessity for these larval stages to be ingested by the blood feeding vector before they can be transmitted to a new vertebrate host. Microfilariae of the dog heartworm Dirofilaria immitis have been described to show periodicity, but the circadian pattern does not seem to be consistent. Most publications describe the lowest mff-concentrations in the peripheral blood in the early morning, while the highest counts occurred either in the afternoon, in the late evening or shortly after midnight. Sixteen dogs were experimentally infected with D. immitis isolates originating from Italy (one isolate, 14 dogs), and the USA (two isolates, one dog each). The dogs were housed indoors with a natural light source (windows) and heating that prevented temperature-drops below 20 degrees C during winter. When patency was reached, blood samples were collected at weekly and monthly intervals over a period of up to 3 years, and at given hours of the day (morning, noon, evening) for the duration of one year in order to determine seasonal, as well as daily variations of microfilaremia. Despite the fact that the dogs were kept indoors, there was an apparent seasonality of the D. immitis-microfilaremia, with peaks in summer and 5-49-times lower counts in winter. This difference was statistically significant and the ratio remained constant over the years, regardless of the fact that the mff counts increased from the first to the second year of patency. Since the temperature was kept constantly in a range between 20 to 26 degrees C (with some single outliners in both directions) the climatic conditions may not explain this observation. Therefore, day length may be the most obvious reason for the seasonality in the given study set-up. Interestingly, the Italian D. immitis isolate lost seasonality after three passages of experimental infections in dogs. The circadian cycle of mff in the peripheral blood varied considerably between dogs and season. There was no consistent or apparent pattern, which led to the conclusion that many individual factors seem to influence the appearance of mff in the peripheral blood, even, or especially, under standardized environmental conditions. PMID- 28807300 TI - Echinococcus felidis in hippopotamus, South Africa. AB - Hydatid cysts of Echinococcus felidis are described from the hippopotamus (Hippopotamus amphibius) from Mpumalanga Province, South Africa. Among six hippopotami investigated, hepatic hydatids were found in three. The identification was based on mitochondrial and nuclear DNA sequences. In addition, the rostellar hook morphology was analysed. This is the first morphological description of the metacestode of E. felidis, and the first molecularly confirmed report of the intermediate host of E. felidis in South Africa. The definitive host of E. felidis in South Africa is the lion (Panthera leo). PMID- 28807301 TI - A candidate recombinant antigen for diagnosis of schistosomiasis japonica in domestic animals. AB - Domestic animals infected with Schistosoma japonicum are a major source of infection and play an important role in transmission to humans. A key strategy for the elimination of schistosomiasis is to control the sources of infection. In the present study, we identified a candidate diagnostic antigen-encoding gene, SjMRP1, the putative multidrug resistance protein 1 gene, by screening a cDNA phage display library from 44-day-old S. japonicum worms using IgGs from goat, cattle, and buffalo infected with S. japonicum. We cloned and expressed the fragment of SjMRP1 and subsequently evaluated the diagnostic potential of the recombinant protein rSjMRP1. In the enzyme-linked immunosorbent assay of rSjMRP1 (rSjMRP1-ELISA), the sensitivity in goat, cattle, and buffalo was 95.6% (86/90), 100% (22/22), and 90% (81/90), respectively, and the specificity was 100% (30/30) in goat and cattle and 96.67% (29/30) in buffalo. These results were not significantly different from soluble egg antigen (SEA)-ELISA results. Notably, rSjMRP1-ELISA has no cross reaction with Haemonchus contortus, a most common nematode seen in goat and bovine in China, in 13 infected goats, and with Orientobilhazia turkestanica, which is genetically under Schistosoma, in 36 infected goats; whereas SEA-ELISA showed false positive rate of 15.38% and 83.33% in the two respective animal groups. The results obtained here suggest that rSjMRP1 may be used for diagnosis of S. japonicum infection of domestic animals. PMID- 28807302 TI - Targeted overexpression of cyclic AMP-dependent protein kinase subunit in Toxoplasma gondii promotes replication and virulence in host cells. AB - Toxoplasma gondii (T. gondii) is one of the most common parasite that can infect almost any warm-blooded animals including humans. The cyclic nucleotide-dependent protein kinase (PKA) regulates a spectrum of intracellular signal pathways in many organisms. Protein kinase catalytic subunit (PKAC) is the core of the whole protein, and plays an important role in the life cycle of T.gondii. Here, T.gondii PKAC (TgPKAC) overexpression strain (TgPKAC-OE) was constructed. The growth of the TgPKAC-OE, RH?Ku80, and TgPKAC inhibition strains (TgPKAC-H89) were analysed by SYBR-green real-time PCR, and the ultrastructure was observed by transmission electron microscopy. The survival rate in mice was also recorded to analyse the virulence of the parasites. We also investigated the subcellular localization of TgPKAC in Vero cells by laser scanning microscope. We found that TgPKAC-OE strain exhibited obviously increased growth rate in Vero cells in vitro, and infected mice survived for a shorter time compared to wild type strain. Ultrastructural analysis found more autophagosomes-like structures in TgPKAC-H89 parasite compared to RH?Ku80 strain, and the relative expression level of Toxoplasma gondii autophagy-related protein (ATG8) in TgPKAC-H89 parasite was higher than wild type parasite. Laser confocal results showed that TgPKAC was mainly expressed in the cytoplasm of Vero cells. In conclusion, we hypothesized that inhibition of TgPKAC could cause autophagy of Toxoplasma gondii and then influence the replication of the parasite. TgPKAC plays an important role in parasite virulence in vivo, and the subcellular localization was successfully detected in Vero cells. Our data will provide a basis for further study of TgPKAC function and help screen drug targets of T. gondii. PMID- 28807303 TI - Helminth egg excretion in horses kept under tropical conditions-Prevalence, distribution and risk factors. AB - Increasing levels of anthelmintic resistance observed in equine cyathostomin parasites have led to recommendations of selective anthelmintic treatment strategies to lower the selection pressure favoring resistant populations. This principle is based on determining strongyle fecal egg counts from all herd members, and treating those exceeding a predetermined treatment cutoff. However, epidemiological information is lacking from horses kept under tropical conditions, where parasite burdens may be of a different composition and magnitude compared to those of horses kept under temperate climate conditions. The aim of the present work was to characterize the strongylid fauna in horses kept in tropical Camaguey, Cuba and identify risk factors associated with strongylid and ascarid egg counts. A total of 396 horses from eight different establishments were included in the study. Coprocultures revealed that Strongylus vulgaris and cyathostomins, sensu lato, were detected in all of those establishments. Prevalence and mean value of strongylid eggs per gram of feces were 97% and 1436, respectively. Eggs of Parascaris spp. were observed in 10% of horses. A multivariate mixed linear model identified sex (p=0.022), month (p=0.044), operation type (p=0.037) and time since last deworming (p<0.001) to be significantly associated in with the magnitude of strongylid fecal egg counts. A multivariate logistic regression identified horses less than two years of age (p=0.010) and horses not receiving anthelmintic treatment (p<0.001) to be significantly more likely to harbor Parascaris spp. parasites. The high magnitude and prevalence of strongylid fecal egg counts observed and the common occurrence of S. vulgaris suggest that strongylid parasite burdens are substantially different from those typically observed in managed equines kept under more temperate conditions. PMID- 28807304 TI - Association between mast cells, tissue remodelation and parasite burden in the skin of dogs with visceral leishmaniasis. AB - Canine visceral leishmaniosis (CVL) is a zoonosis of major public health impact caused by organisms of the genus Leishmania which is transmitted to human and animals by phlebotomine sand flies. The skin is the first point of contact with Leishmania parasites for sandy fly vectors and it is considered an important reservoir compartment in infected dogs. The aim of this study was to determine the main histophatologic alterations in ear skin of dogs naturally infected by Leishmania infantum with different clinical status and different degrees of parasitism. Therefore, thirty-four dogs naturally infected with L. infantum were grouped according to their clinical status in asymptomatic (AD, n=11), oligosymptomatic (OD, n=11) and symptomatic dogs (SD, n=12) as well as their degrees of parasite load in the skin as low (LP, n=11), median (MP, n=11) and high (HP, n=12) parasitism. Additionally, ten dogs were used as control (CD, n=10). At necropsy, skin samples were collected for further histological and parasitological analysis. The OD and SD groups presented higher parasite burden than AD group. The inflammation was higher in SD group when compared to OD and AD. The LP, MP and HP groups showed an increasing inflammatory process, indicating that a great parasite load is accompanied by a major inflammatory process in the skin. The number of mast cells was higher in the OD and LP groups than CD group, suggesting that these cells may be involved in tissue remodeling, since that an increase of type III collagen fibers and decrease type I collagen fibers were observed in these groups. Taken together, our results enable a better understanding of the alterations in skin of CVL dogs and consequently new insights about the pathogenesis of CVL. PMID- 28807305 TI - Evaluation of the PrioCHECKTM Trichinella AAD Kit for the digestion and recovery of larvae in pork, horse meat and wild meat. AB - The artificial digestion magnetic stirrer method using pepsin protease and hydrochloric acid is the standard assay for the detection of Trichinella larvae in muscle of infected animals. Recently, an alternative enzyme, serine protease, was employed in the development of a commercially available digestion kit (PrioCHECKTM Trichinella AAD Kit). This assay requires a higher digestion temperature of 60 degrees C which kills the larvae during the digestion process, mitigating the risk of environmental contamination from the parasite. The present study was conducted to determine the performance of the PrioCHECKTM Trichinella AAD Kit compared to the conventional pepsin/HCl digestion. Replicate paired 115g samples of Trichinella-negative pork diaphragm and masseter, and of horse tongue and masseter, were used to compare the two methods for tissue digestibility. Similarly, paired 100g samples of pork diaphragm and horse tongue were spiked with proficiency samples containing known numbers of Trichinella spiralis first stage larvae to compare larval recoveries for the two methods. Masseter samples from wild bears and wolves naturally infected with Trichinella nativa or T6 were also used to compare the performance of the methods. The results of the study showed that the PrioCHECKTM Trichinella AAD Kit, when used according to the manufacturer's instructions, was effective in detecting Trichinella infection in all samples that contained 0.05 or more larvae per gram of tissue. Although there was no significant difference between the Kit method and the standard pepsin/HCl digestion procedure in the average number of larvae recovered from spiked pork diaphragm, 38% fewer larvae were recovered from similarly spiked samples of horse tongue by digestion using serine protease (one way ANOVA, P value <0.001). Additional clarification was also more often required for both horse meat and pork when using the Kit compared to the pepsin/HCl method. The results of testing wildlife samples were similar for the two methods. Overall, the performance of the Kit method was suitable for the digestion of muscle samples and recovery of Trichinella larvae, according to international standards. It also provides advantages of faster digestion, safer reagents and recovered parasites that are non-hazardous for analysts and the environment. PMID- 28807306 TI - Managing anthelmintic resistance-Variability in the dose of drug reaching the target worms influences selection for resistance? AB - The concentration profile of anthelmintic reaching the target worms in the host can vary between animals even when administered doses are tailored to individual liveweight at the manufacturer's recommended rate. Factors contributing to variation in drug concentration include weather, breed of animal, formulation and the route by which drugs are administered. The implications of this variability for the development of anthelmintic resistance was investigated using Monte-Carlo simulation. A model framework was established where 100 animals each received a single drug treatment. The 'dose' of drug allocated to each animal (i.e. the concentration-time profile of drug reaching the target worms) was sampled at random from a distribution of doses with mean m and standard deviation s. For each animal the dose of drug was used in conjunction with pre-determined dose response relationships, representing single and poly-genetic inheritance, to calculate efficacy against susceptible and resistant genotypes. These data were then used to calculate the overall change in resistance gene frequency for the worm population as a result of the treatment. Values for m and s were varied to reflect differences in both mean dose and the variability in dose, and for each combination of these 100,000 simulations were run. The resistance gene frequency in the population after treatment increased as m decreased and as s increased. This occurred for both single and poly-gene models and for different levels of dominance (survival under treatment) of the heterozygote genotype(s). The results indicate that factors which result in lower and/or more variable concentrations of active reaching the target worms are more likely to select for resistance. The potential of different routes of anthelmintic administration to play a role in the development of anthelmintic resistance is discussed. PMID- 28807307 TI - Significance of anti-CarLA salivary IgA antibody in first grazing season cattle naturally infected with gastrointestinal nematodes. AB - A carbohydrate larval surface antigen (CarLA) present on infective larvae of all trichostrongylid nematodes is a target antigen for host immunoglobulins (Ig). Levels of anti-CarLA salivary IgA antibody (CarLA-IgA) have been shown to be correlated to the level of protective immunity to GIN in sheep and deer but no information is available in cattle. The first objective of this study was to assess the pattern of CarLA-IgA response in 7 groups (G1-G7) of first grazing season cattle (FGSC) naturally infected with gastrointestinal nematodes. The second objective was to assess the phenotypic correlations between CarLA-IgA level, 3 parasitological indicators (faecal egg count-FEC, pepsinogen level, serum anti-O. ostertagi IgG antibody level-OstertagiaIgG), a clinical indicator (diarrhea score) and average daily weight gain (ADWG). Overall, CarLA-IgA response gradually increased over grazing season and showed large variations in speed and magnitude both between and within groups. Based on the mean group CarLA IgA response pattern, the 7 groups could be allocated to 3 different classes: (i) 'Late High' class characterized by a high response at housing (G1 and G2); (ii) 'Low' class with a low response over time (G3, G4 and G5); and (iii) 'Early' class with an high initial then stable response (G6 and G7). This classification was consistent with the grazing management practices. In the 'Late High' class, the mean CarLA-IgA at housing was 6.05units/mL and negatively correlated with FEC while no correlation was seen with the other indicators nor ADWG. In the 'Low' class, CarLA response at housing was low (1.95units/mL) and mainly positively correlated with OstertagiaIgG. In the 'Early' class, mean CarLA-IgA ranged from 1.32 to 1.86units/mL during the grazing season and positive correlations were seen with parasitological and clinical indicators. These results suggest that, according to the intensity of larval challenge occurring during the first grazing season, CarLA-IgA response in cattle could be either an indicator of the early manifestation of immunity (FEC decreases) or the reflection of exposure to GIN. PMID- 28807308 TI - Presence and species identity of rumen flukes in cattle and sheep in the Netherlands. AB - The purpose of the study was to gain knowledge about the prevalence and identity of rumen flukes (RF) in cattle and sheep in the Netherlands. Routine faecal examinations of diagnostic submissions between May 2009 and September 2014 showed a mean annual herd or flock RF prevalence of 15.8% for cattle and 8.0% for sheep. Prevalence in cattle was higher after 2012 than before, which may reflect a change in detection method as well as an increase in true prevalence. During November and December 2014, an abattoir survey was conducted to allow for scoring of rumen fluke burden and to obtain specimens for molecular species characterization. Over 8 visits to 5 abattoirs in areas deemed to pose a high risk for trematode infection, 116 cows and 41 sheep from 27 herds and 10 flocks were examined. Prevalence of RF was higher in beef cattle than in dairy cattle and higher in cattle than in sheep. Median fluke burden was >100 specimens per animal for most positive animals. Using a semi-quantitative RF density score as a gold standard, sensitivity and specificity of a modified quantitative Dorsman egg counting method were estimated at 82.6% and 83.3%, respectively. Of 14 collected adult rumen flukes, twelve (8 bovine and 4 ovine specimens) were identified as Calicophoron daubneyi. The other two, of bovine origin, were identified as Paramphistomum leydeni, which was unexpected as in other European countries all recently collected rumen flukes in both cattle and sheep were identified as C. daubneyi. The findings implicate that multiple rumen fluke species, intermediate host species and transmission cycles may play a role in rumen fluke infections in the Netherlands. PMID- 28807309 TI - Synergistic interaction of ten essential oils against Haemonchus contortus in vitro. AB - Anthelmintic resistance in sheep gastrointestinal nematodes is a worldwide problem. Multi-drug resistant haemonchosis is the most serious impediment for small ruminant systems, and there are no new drug candidates currently under development. Molecules from natural sources have demonstrated anthelmintic activity against parasites. In this work, the monoterpenoids carvacrol, carvone, cineole, linalool, limonene, and thymol and the phenylpropanoids cinnamaldehyde, anethole, vanillin, and eugenol were assessed individually or in mixtures of ten binary, three ternary, and three quaternary combinations using the in vitro egg hatch assay with eggs of a multi-drug resistant strain of Haemonchus contortus. The main objective of this study was to identify the most effective interaction among essential oils with the greatest individual anthelmintic efficacy and to determine the most powerful combinations. The essential oils were ranked by their 50% lethal concentration (LC50) as follows (mg/mL): cinamaldehyde (0.018), anethole (0.070), carvone (0.085), carvacrol (0.11), thymol (0.13), linalool (0.29), vanillin (0.57), eugenol (0.57), cineole (4.74), and limonene (207.5). Quantification of synergism, additive effect, and antagonism were calculated for binary, ternary, and quaternary combinations. The best anthelmintic effect resulting from synergistic activity among 16 different combinations was for cinnamaldehyde:carvacrol (CL50 0.012mg/mL) and anethole:carvone (CL50 0.013mg/mL). These results indicate that these binary combinations would be promising to be tested in sheep infected with H. contortus. PMID- 28807310 TI - The sustained speed of kill of ticks (Rhipicephalus sanguineus) and fleas (Ctenocephalides felis felis) on dogs by a spot-on combination of fipronil and permethrin (Effitix(r)) compared with oral afoxolaner (NexGard(r)). AB - The rapid speed of kill of a spot-on, combination of fipronil-permethrin (Effitix(r), Virbac) was shown against infestations of Rhipicephalus sanguineus and Ctenocephalides felis on dogs. Efficacy was determined against new infestations at weekly intervals for one month after treatment. Dogs were allocated randomly to either an untreated control or to a single administration, given on Day 0, of either topical fipronil-permethrin (6.7-13.4mg/kg and 60 120mg/kg, respectively) or oral afoxolaner (2.72-6.8mg/kg), based on pre treatment, host-suitability flea counts. Dogs were infested with 50, unfed, adult R. sanguineus on Days 7, 14, 21 and 28, and with 100C. felis on Days 8, 15, 22 and 29. Tick counts were performed 0.5, 2, 6, 12 and 24h, and flea counts were performed 0.5 and 24h after each infestation. No treatment-related adverse reactions occurred. Dogs in the untreated group maintained viable infestations throughout the study. Following infestation, live tick and flea counts for dogs treated with fipronil-permethrin compared with untreated dogs were rapidly and significantly reduced with efficacy apparent at 0.5h after infestation. Flea efficacies (arithmetic mean counts) at 0.5h after infestation on Day 7 (Day 28) were significantly greater for fipronil-permethrin, 70% (34%) compared with 8% (18%) for afoxolaner (P<=0.05). Tick efficacies at 2h on Day 7 (Day 28) were 74% (63%) for fipronil-permethrin compared with 10% (0%) for afoxolaner (P<=0.05). Efficacies for tick repellency as indicated by counts of ticks off the dogs at 2h on Day 7 (Day 28) were greater for fipronil-permethrin, 32% (22%) compared with afoxolaner, 0% (0%) (P<=0.05). Anti-attachment efficacies at 12h were greater for fipronil-permethrin compared with afoxolaner. Tick efficacies at 24h, based on arithmetic (geometric) means, were significantly greater on Day 28 for fipronil permethrin compared with afoxolaner (P<=0.05), 74% (87%) and 45% (60%), respectively, and were similar (P >0.05) on Days 7, 14 and 21. Flea efficacies, 24h after infestation were >98% and similar for both treated groups on all infestation days (P >0.05). The topically applied fipronil-permethrin containing ectoparasiticide Effitix(r) offers rapid efficacy against R. sanguineus and C. felis which persists for one month after a single administration in dogs. Afoxolaner is also effective although speed of kill is slower. The rapid and sustained speed of kill of both parasites by fipronil-permethrin should contribute to effective management not only of these parasites and their direct adverse effects including irritancy and allergy, but also to reducing the risk of transmitting infections. PMID- 28807311 TI - Mitochondrial genomes of Australian chicken Eimeria support the presence of ten species with low genetic diversity among strains. AB - Modern molecular approaches have vastly improved diagnostic capabilities for differentiating among species of chicken infecting Eimeria. Consolidating information from multiple genetic markers, adding additional poultry Eimeria species and increasing the size of available data-sets is improving the resolving power of the DNA, and consequently our understanding of the genus. This study adds information from 25 complete mitochondrial DNA genomes from Australian chicken Eimeria isolates representing all 10 species known to occur in Australia, including OTU-X, -Y and -Z. The resulting phylogeny provides a comprehensive view of species relatedness highlighting where the OTUs align with respect to others members of the genus. All three OTUs fall within the Eimeria clade that contains only chicken-infecting species with close affinities to E. maxima, E. brunetti and E. mitis. Mitochondrial genetic diversity was low among Australian isolates likely reflecting their recent introduction to the country post-European settlement. The lack of observed genetic diversity is a promising outcome as it suggests that the currently used live vaccines should continue to offer widespread protection against Eimeria outbreaks in all states and territories. Flocks were frequently found to host multiple strains of the same species, a factor that should be considered when studying disease epidemiology in the field. PMID- 28807312 TI - Ectoparasite Caligus rogercresseyi modifies the lactate response in Atlantic salmon (Salmo salar) and Coho salmon (Oncorhynchus kisutch). AB - Although Caligus rogercresseyi negatively impacts Chilean salmon farming, the metabolic effects of infection by this sea louse have never been completely characterized. Therefore, this study analyzed lactate responses in the plasma, as well as the liver/muscle lactate dehydrogenase (LDH) activity and gene expression, in Salmo salar and Oncorhynchus kisutch infested by C. rogercresseyi. The lactate responses of Atlantic and Coho salmon were modified by the ectoparasite. Both salmon species showed increasing in plasma levels, whereas enzymatic activity increased in the muscle but decreased in the liver. Gene expression was overexpressed in both Coho salmon tissues but only in the liver for Atlantic salmon. These results suggest that salmonids need more energy to adapt to infection, resulting in increased gene expression, plasma levels, and enzyme activity in the muscles. The responses differed between both salmon species and over the course of infection, suggesting potential species-specific responses to sea-lice infection. PMID- 28807313 TI - Severe impact of sarcoptic mange on the movements and space use for one of its most important vector species, the raccoon dog. AB - Sarcoptic mange is a highly contagious zoonotic skin disease that can have severe effect on population dynamics of many wild mammals. However, very little is known about its effect on the activity and space use of infected animals. In this study we equipped two raccoon dogs (Nyctereutes procyonoides) in a mange outbreak area with radio-collars and observed the spatial and temporal effects of sarcoptic mange to these individuals. Initially, the raccoon dogs had no external symptoms of mange infection, but developed these during the study period. One of the raccoon dogs died just 32 and the other 52days after collaring. During a relatively short period before their death, there was an abrupt and drastic decline in their home range size. For one of the animals it started about 1 month before its death and the home range size reduced >1000*, whereas for the other raccoon dog it took place within the last week, decreasing >200*. The daily covered distances also declined considerably. These results indicate that at the later stage sarcoptic mange affected the physiological state of the diseased animals so forcefully that made them almost immobile. Our results show for the first time how rapid and severe could the impact of sarcoptic mange be for one of its most important reservoir and vector species. PMID- 28807314 TI - A candidate gene approach to study nematode resistance traits in naturally infected sheep. AB - Sheep naturally acquire a degree of resistant immunity to parasitic worm infection through repeated exposure. However, the immune response and clinical outcome vary greatly between animals. Genetic polymorphisms in genes integral to differential T helper cell polarization may contribute to variation in host response and disease outcome. A total of twelve single nucleotide polymorphisms (SNPs) were sequenced in IL23R, RORC2 and TBX21 from genomic DNA of Scottish Blackface lambs. Of the twelve SNPs, six were non-synonymous (missense), four were within the 3' UTRs and two were intronic. The association between nine of these SNPs and the traits of body weight, faecal egg count (FEC) and relative T. circumcincta L3-specific IgA antibody levels was assessed in a population of domestic Scottish Blackface ewe lambs and a population of free-living Soay ewe lambs both naturally infected with a mixture of nematodes. There were no significant associations identified between any of the SNPs and phenotypes recorded in either of the populations after adjustment for multiple testing (Bonferroni corrected P value<=0.002). In the Blackface lambs, there was a nominally significant association (P=0.007) between IL23R p.V324M and weight at 20 weeks. This association may be worthy of further investigation in a larger sample of sheep. PMID- 28807315 TI - Genetic homogeneity of Fascioloides magna in Austria. AB - The large American liver fluke, Fascioloides magna, is an economically relevant parasite of both domestic and wild ungulates. F. magna was repeatedly introduced into Europe, for the first time already in the 19th century. In Austria, a stable population of F. magna has established in the Danube floodplain forests southeast of Vienna. The aim of this study was to determine the genetic diversity of F. magna in Austria. A total of 26 individuals from various regions within the known area of distribution were investigated for their cytochrome oxidase subunit 1 (cox1) and nicotinamide dehydrogenase subunit 1 (nad1) gene haplotypes. Interestingly, all 26 individuals revealed one and the same haplotype, namely concatenated haplotype Ha5. This indicates a homogenous population of F. magna in Austria and may argue for a single introduction. Alternatively, genetic homogeneity might also be explained by a bottleneck effect and/or genetic drift. PMID- 28807316 TI - Vaccination with Eimeria tenella elongation factor-1alpha recombinant protein induces protective immunity against E. tenella and E. maxima infections. AB - Avian coccidiosis is caused by multiple species of the apicomplexan protozoan, Eimeria, and is one of the most economically devastating enteric diseases for the poultry industry worldwide. Host immunity to Eimeria infection, however, is relatively species-specific. The ability to immunize chickens against different species of Eimeria using a single vaccine will have a major beneficial impact on commercial poultry production. In this paper, we describe the molecular cloning, purification, and vaccination efficacy of a novel Eimeria vaccine candidate, elongation factor-1alpha (EF-1alpha). One day-old broiler chickens were given two subcutaneous immunizations one week apart with E. coli-expressed E. tenella recombinant (r)EF-1alpha protein and evaluated for protection against challenge infection with E. tenella or E. maxima. rEF-1alpha-vaccinated chickens exhibited increased body weight gains, decreased fecal oocyst output, and greater serum anti-EF-1alpha antibody levels following challenge infection with either E. tenella or E. maxima compared with unimmunized controls. Vaccination with EF 1alpha may represent a new approach to inducing cross-protective immunity against avian coccidiosis in the field. PMID- 28807317 TI - Validation of the FAMACHA(c) system in South American camelids. AB - Haemonchus contortus resistant to multiple anthelmintics threaten the viability of the small ruminant industry in areas where this parasite is prevalent. In response to this situation, the FAMACHA(c) system was developed and validated for use with small ruminants as a way to detect clinical anemia associated with haemonchosis. Given that H. contortus and multiple anthelmintic resistance is a similar problem in camelids, the FAMACHA(c) system might also provide the same benefits. To address this need, a validation study of the FAMACHA(c) system was conducted on 21 alpaca and llama farms over a 2-year period. H. contortus was the predominant nematode parasite on 17 of the 21 farms (10 alpaca and 7 llama farms) enrolled in the study, based on fecal culture results. The FAMACHA(c) card was used to score the color of the lower palpebral (lower eye lid) conjunctiva on a 1 5 scale. Packed cell volume (PCV) values were measured and compared to FAMACHA(c) scores using FAMACHA(c) score cutoffs of >=3 or >=4 and with anemia defined as a PCV <=15%, <=17%, or<=20%. PCV was significantly associated with FAMACHA(c) score, fecal egg count (FEC), and body condition score (BCS), regardless of the FAMACHA(c) cutoff score or the PCV% chosen to define clinical anemia (p<0.01 in all cases). The use of FAMACHA(c) scores >=3 and PCV >= 15% indicating anemia provided the best sensitivity (96.4% vs 92.9% for FAMACHA(c) >=4), whereas FAMACHA scores >= 4 and PCV <=20% provided the best specificity (94.2% vs 69.1% for FAMACHA(c) >=3). The data from this study support the FAMACHA(c) system as a useful tool for detecting clinical anemia in camelids suffering from haemonchosis. Parameters for making treatment decisions based on FAMACHA(c) score in camelids should mirror those established for small ruminants. PMID- 28807319 TI - Erratum to "Short communication: Analysis of health and survival in a population of Ontario Holstein heifer calves" (J. Dairy Sci. 96:1800-1885). PMID- 28807318 TI - Application of a specific quantitative real-time PCR (qPCR) to identify Leishmania infantum DNA in spleen, skin and hair samples of wild Leporidae. AB - The aim of this study was to compare a quantitative real-time PCR (qPCR) validated for the detection of Leishmania infantum in dogs with a nested PCR but in wild Leporidae. Additionally, L. infantum results from indirect immunofluorescent antibody test (IFAT) and in vitro culture were also compared with qPCR. Different samples (spleen, skin and hair) recovered from 224 European rabbits and 70 Iberian hares from two green areas of Madrid Council were analysed for the detection of L. infantum. The presence of Leishmania kDNA was detected by qPCR in 58 out of 221 (26.24%), 162 out of 203 (79.8%) and 22 out of 33 (66.67%) analysed rabbits on spleen, skin and hair samples, respectively; and in 7 out of 69 (10.14%), 39 out of 70 (55.71%) and 17 out of 32 (53.13%) test hares on spleen, skin and hair samples, respectively. The qPCR in all test samples resulted to be more sensitive than nested PCR, with a limit of detection of 1.43 fg/reaction (0.039 parasites) for L. infantum genomic DNA. Additionally, the percentage of positive animals detected by qPCR in at least two out of three samples (n=221 rabbits and 70 hares) tested was higher than those detected by IFAT (n=190 rabbits and 61 hares) and isolation (n=75 rabbits and 20 hares). The highest level of agreement was obtained by nested PCR on spleen/skin (89%/83%) samples and qPCR on spleen samples (81%), followed by IFAT (48%) and qPCR on skin (32%) samples. Our results demonstrate this qPCR is a suitable method for detecting L. infantum DNA in different samples suggesting hair could be considered an adequate sample for direct, reliable and non-invasive diagnosis of L. infantum in wild animals. PMID- 28807320 TI - Source of Bias in the Spanish Language Version of the WPAI:PSO (Work Productivity and Activity Impairment-Psoriasis v. 2.0) Questionnaire. PMID- 28807321 TI - Folliculitis Decalvans Caused by Bacterial Superinfection Secondary to Erlotinib. PMID- 28807322 TI - Corrigendum to "Quantitative meta-analytic approaches to the systematic synthesis of data and hazard identification: A case-study of decreased pain sensitivity due to trimethylbenzene exposure" [Environ. Res. 158C (2017) 598-609]. PMID- 28807323 TI - Inlay butterfly miringoplasty. Our experience. AB - INTRODUCTION: Multiple surgical techniques have been proposed to close tympanic perforations. Eavey, two decades ago, described a technique aimed at closing central perforations in children. For this, he designed a butterfly-shaped cartilage graft that was placed between the tympanic membrane in an inlay manner. This technique showed great effectiveness for the closure of perforations as well as low morbidity, rapidity and great economic difference. METHODS: We performed a descriptive study of a series of cases analysing 32 interventions in children and adults with the modified Eavey technique, during the period from January 2012 to November 2016. We evaluated the surgical and audiometric functional results. RESULTS: Surgical success was achieved in 93% of cases, including complete closures in 27 patients (84%) and 3 cases in which minimal asymptomatic dehiscences occurred. There was rejection of the graft and persistence of the perforation in only one case. No major surgical or postoperative complications associated with the procedure were described. The mean improvement in the audiometric gap was from 17dB preoperatively to 7dB after the intervention. CONCLUSIONS: The modified Eavey technique is a low morbidity, cost-effective procedure with a technical facility that proves effective for the closure of tympanic perforations in adults and children. PMID- 28807324 TI - Spontaneous rupture of cervical thoracic duct: A case report. PMID- 28807325 TI - Radioguided surgery in primary hyperparathyroidism: Results and correlation with intraoperative histopathologic diagnosis. AB - INTRODUCTION AND OBJECTIVES: Radioguided surgery is a minimally invasive surgical technique for the treatment of primary hyperparathyroidism. The goals of our study were to evaluate the rate of success and compare the results with intraoperative histological analysis. METHODS: We retrospectively studied 84 patients with primary parathyroidism who had undergone radioguided surgery. All the patients had a positive parathyroid scintigraphy prior to surgery. An intravenous injection of Tc-99m sestamibi was administered before surgery, and radioguided location of the pathologic parathyroid tissue was performed using an intraoperative gamma probe, applying the "20% rule". All resected specimens underwent intraoperative histologic analysis. All patients were followed up for at least 6 months. Positive predictive values of both parathyroid scintigraphy and cervical ultrasonography were also compared. RESULTS: Radioguided surgery success rate was 99%. Sensitivity, specificity, positive and negative predictive values for gamma probe were 99, 73, 97 and 89%, respectively. After surgery, 83 of 84 patients were eucalcaemic (99%) and parathyroid hormone normalised in 77 of 84 patients (92%). Ultrasonography showed low positive predictive value (41%) when compared with scintigraphy. CONCLUSIONS: Radioguided surgery is a minimally invasive surgical technique with excellent results for the treatment of primary hyperparathyroidism and could replace both intraoperative histological analysis and intraoperative parathyroid hormone assay. Further studies are needed to confirm these findings. PMID- 28807326 TI - The end of the line: Antagonistic attentional weightings in unilateral neglect. AB - The line bisection task is widely used in the study of neglect. Some years ago, McIntosh, Schindler, Birchall, & Milner (2005) proposed a radical reframing of this ubiquitous task. Rather than using the traditional measure of directional bisection error, they quantified the sensitivities of the response to the changing locations of the left and right endpoints of the line, expressing these as 'endpoint weightings'. A novel prediction generated from their analysis was that manipulations increasing attention to the left end of the line should cause an increase in the left endpoint weighting and a corresponding reduction in the right endpoint weighting. The present study fulfilled this prediction, using a forced-report cueing method in a group of 12 patients with left neglect. The data confirm an antagonistic relationship between endpoint weightings, consistent with the idea that they represent the sharing of a finite resource. It is argued that the endpoint weightings model of line bisection offers a sensitive and uniquely useful framework for studying competitive lateral biases of attention in neglect, and may also provide insight into non-lateralised attentional impairments. PMID- 28807327 TI - Problems of artificial neural network. PMID- 28807328 TI - Corrigendum to: Neural networks underlying language and social cognition during self-other processing in autism spectrum disorders [Neuropsychologia 102 (2017) 116-123]. PMID- 28807330 TI - ? PMID- 28807329 TI - Impact of thio-urethane additive and filler type on light-transmission and depth of polymerization of dental composites. AB - OBJECTIVE: This study evaluated the effects of filler type and the addition of thio-urethane oligomers on light-transmission, polymerization kinetics and depth of cure of resin composites. METHODS: BisGMA:UDMA:TEGMA (5:3:2wt%) were mixed with 0 (control) or 20wt% thio-urethane. Fillers with various sizes and refractive indices were included and refractive index (RI) measured. Unfilled resins were used as controls. The RIs of materials were measured before and after polymerization. The irradiance reaching the bottom of 3-mm thick specimens was measured during the polymerization. Degree of conversion to a depth of 5mm was mapped. An optical bench was used to simultaneously follow conversion and light transmission. RESULTS: The addition of thio-urethane increased the RI for all composites. As expected, RI also increased with conversion for all materials. The one exception was for the material filled with OX-50, in which the RI of the composite decreased with conversion. In this case, the irradiance at the bottom of the 3mm specimen was also the lowest among all groups. The addition of thio urethanes had only minimal effect on light transmission within a filler type, but led to increased conversion in depth for all groups. The filler type itself had a greater effect on light transmission, and that correlated well with the degree of conversion. SIGNIFICANCE: The effect of the thio-urethane addition on degree of conversion in depth was dependent on filler type. The additive can be tailored to improve the RI match with the filler to optimize light transmission in dental composites. PMID- 28807331 TI - Health insurance subsidies and deductible choice: Evidence from regional variation in subsidy schemes. AB - The extent to which premium subsidies can influence health insurance choices is an open question. In this paper, we explore the regional variation in subsidy schemes in Switzerland, designed as either in-kind or cash transfers, to study their impact on the choice of health insurance deductibles. Using health survey data and a difference-in-differences methodology, we find that in-kind transfers increase the likelihood of choosing a low deductible plan by approximately 4 percentage points (or 7%). Our results indicate that the response to in-kind transfers is strongest among women, middle-aged and unmarried individuals, which we explain by differences in risk-taking behavior, health status, financial constraints, health insurance and financial literacy. We discuss our results in the light of potential extra-marginal effects on the demand for health care services, which are however not supported by our data. PMID- 28807332 TI - Synthetic biology regulation and governance: Lessons from TAPIC for the United States, European Union, and Singapore. AB - Synthetic biology is an emerging technology with potential benefits to various fields, yet also contains potential risks to human and environmental health. The field remains in an emerging state with limited quantitative guidance and a small but growing population of international researchers that conduct work within this field. Given the uncertain nature of this technology, an adaptive and anticipatory governance framework may be necessary to balance the potential benefits that may accrue from the technology's continued research alongside a desire to reduce or eliminate potential risks that may arise. However, such developments must account for the unique political and institutional factors that form a government's risk culture - something that can facilitate or impede the development of adaptive synthetic biology governance moving forward. The TAPIC framework helps illustrate those factors that are essential to develop good governance for emerging technologies like synthetic biology. Specifically, an application of TAPIC to synthetic biology governance indicates that the factors of accountability, participation, and integrity must be bolstered to improve technology governance in governments like with the United States, European Union, and Singapore. PMID- 28807333 TI - Update on maximal anabolic response to dietary protein. AB - The anabolic response to dietary protein can be defined as the difference between protein synthesis and breakdown, or the net protein balance, in response to ingestion of protein alone or a mixed meal containing protein. Others have concluded that a maximal anabolic response can be achieved with ingestion of 20 35 g of a high quality protein, leading to the formulation of a popular concept that the maximal anabolic response can be achieved by distributing the total protein intake evenly throughout the day, rather than eating a majority of dietary protein with dinner. However, this concept was based entirely on the measurement of muscle protein synthesis and thus ignored the potential contributions of suppression of protein breakdown to the anabolic response, as well as the possibility that tissues and organs other than muscle may also play a role in the anabolic response. In this review we discuss the factors comprising the total anabolic response, discuss relevant methodological issues, derive a theoretical maximal anabolic response based on current literature values, and interpret recent papers addressing the issue of maximal anabolic response as well as meal distribution of dietary protein. We conclude that it is not likely that there is a practical limit to the maximal anabolic response to a single meal, and the most efficient way in which to maximize the total anabolic response over a 24 h period is to increase dietary protein at breakfast and lunch without reducing protein intake with dinner. PMID- 28807334 TI - A semi-quantitative World Health Organization grading scheme evaluating worst tumor differentiation predicts disease-free survival in oral squamous carcinoma patients. AB - We investigated World Health Organization (WHO) grading and pattern of invasion based histological schemes as independent predictors of disease-free survival, in oral squamous carcinoma patients. Tumor resection slides of eighty-seven oral squamous carcinoma patients [pTNM: I&II/III&IV-32/55] were evaluated. Besides examining various patterns of invasion, invasive front grade, predominant and worst (highest) WHO grade were recorded. For worst WHO grading, poor undifferentiated component was estimated semi-quantitatively at advancing tumor edge (invasive growth front) in histology sections. Tumor recurrence was observed in 31 (35.6%) cases. The 2-year disease-free survival was 47% [Median: 656; follow-up: 14-1450] days. Using receiver operating characteristic curves, we defined poor-undifferentiated component exceeding 5% of tumor as the cutoff to assign an oral squamous carcinoma as grade-3, when following worst WHO grading. Kaplan-Meier curves for disease-free survival revealed prognostic association with nodal involvement, tumor size, worst WHO grading; most common pattern of invasion and invasive pattern grading score (sum of two most predominant patterns of invasion). In further multivariate analysis, tumor size (>2.5cm) and worst WHO grading (grade-3 tumors) independently predicted reduced disease-free survival [HR, 2.85; P=0.028 and HR, 3.37; P=0.031 respectively]. The inter-observer agreement was moderate for observers who semi-quantitatively estimated percentage of poor-undifferentiated morphology in oral squamous carcinomas. Our results support the value of semi-quantitative method to assign tumors as grade-3 with worst WHO grading for predicting reduced disease-free survival. Despite limitations, of the various histological tumor stratification schemes, WHO grading holds adjunctive value for its prognostic role, ease and universal familiarity. PMID- 28807335 TI - Recent updates on grading and classification of neuroendocrine tumors. AB - Neuroendocrine tumors (NETs) are originating from neuroendocrine cells in diffuse endocrine systems. NETs are diagnosed by characteristic histologic features and immunoprofiles. Recent 2010 WHO classification for gastroenteropancreatic NETs introduced grading system based on mitotic count and Ki-67 proliferation index. Gastroenteropancreatic NETs are classified as NET grade 1, NET grade 2, and neuroendocrine carcinoma (NET grade 3). However, the carcinoid is still used in classification of NETs of the lung and uterine cervix. Some issues with grading system such as methodologies for evaluation of Ki-67 index and subclassification of neuroendocrine carcinoma (NET grade 3) are arising. The importance of Ki-67 labeling index is emerging in differential diagnosis of lung carcinoids. In this review, we focus on recent grading and classification of NETs and related issues in various organs, including gastrointestinal tract, pancreas, lung, and female reproductive organs. PMID- 28807336 TI - Programmed death-1 (PD-1) receptor/PD-1 ligand (PD-L1) expression in fumarate hydratase-deficient renal cell carcinoma. AB - Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare and aggressive tumor affecting mostly younger patients. This is the first study to assess the expression of programmed death-1 (PD-1) receptor/PD-1 ligand (PD-L1) in FH-RCC. Formalin-fixed paraffin-embedded samples from 13 FH-RCCs collected in an international multi-institutional study, were evaluated by immunohistochemistry (IHC) for PD-1/PD-L1 reactivity in tumor cells and tumor infiltrating lymphocytes (TILs). PD-1/PD-L1 expression was further evaluated by qPCR. By IHC, PD-1 was negative in tumor cells in all 13 cases. PD-L1 was positive in tumor cells in 2/13 cases, weak positive in 7/13, and negative in 4/13 cases, respectively. In TILs, PD-1 was positive in 1/13, weak positive in 3/13, and negative in 9/13 cases. In TILs, PD-L1 was weak positive by IHC in 5/13, and negative in 8/13 cases, respectively. qPCR confirmed the result for 2 of 3 IHC weak positive PD-1 samples. Of 7 IHC weak positive samples (in tumor cells), PD-L1 mRNA was detected in all 7 tumors. The majority of FH-RCCs did not express PD-1/PD-L1 by IHC, which was confirmed by molecular analysis. PD-1/PD-L1 expression in FH-RCC is restricted to a proportion of cases which may benefit from targeted therapies. PMID- 28807337 TI - Evaluation of CD43 expression in non-hematopoietic malignancies. AB - OBJECTIVES: CD43 is normally expressed only on the surface of leukocytes, and is considered a sensitive and specific marker for hematologic malignancies. As such, it may have diagnostic utility in confirming hematolymphoid lineage in cases that are negative for CD45. Aberrant CD43 expression has been described in non hematopoietic tumors, although literature data on this topic is variable and sometimes contradictory. To clarify and expand on existing literature findings, we evaluated CD43 expression by immunohistochemistry (IHC) in a large cohort (307) of non-hematopoietic neoplasms, including poorly differentiated malignancies. METHODS: 17 tissue microarrays and sections from 19 individual cases were stained with CD43 (clone DF-T1) monoclonal antibody. The proportion of positive cells, stain localization (nuclear, cytoplasmic or membranous), and intensity (compared to internal leukocyte controls) were recorded in all cases. RESULTS: There were 98/307 (32%) positive cases, that showed focal weak nuclear staining in 1-25% of cells, including 23/25 (92%) pancreatic ductal adenocarcinomas; 31/34 (91%) breast invasive ductal carcinomas; 13/15 (87%) papillary thyroid carcinomas; 3/4 (75%) follicular thyroid carcinomas; 6/15 (40%) renal cell carcinomas; 9/28 (32%) lung adenocarcinomas; 1/13 (8%) lung squamous cell carcinomas (SCCs); 2/8 (25%) prostate adenocarcinomas; 8/62 (13%) colon adenocarcinomas; and 2/21 (10%) neuroendocrine neoplasms. None of the positive cases demonstrated strong, membranous CD43 expression comparable to that seen in background mature lymphocytes or segmented neutrophils. Negative cases included 11 cervical SCCs, 12 cervical adenocarcinomas, 19 urothelial carcinomas, 10 lung small cell carcinomas, 11 sarcomas, and 19 poorly differentiated carcinomas from various tissue sites. CONCLUSIONS: In our cohort, most non-hematopoietic neoplasms are negative for CD43 expression, with a subset showing focal, weak nuclear positivity. This data indicates that uniform and strong membranous staining appears to be specific to hematopoietic neoplasms. PMID- 28807338 TI - Molecular pathology diagnosis of diffuse large B cell lymphoma using BIOMED-2 clonal gene rearrangements. AB - BACKGROUND: Clonality testing for immunoglobulin gene rearrangement analysis could be implemented effectively as a useful technique for conventional diagnosis of lymphoma. The European Biomedicine and Health Concerted Action Project BMH4 CT98-3936 (BIOMED-2) have been suggested a gold standard method to clonality detection. OBJECTIVES: We tested empirically clonality rearrangements of IGH and incomplete IGH D-J, on formalin-fixed, paraffin embedded (FFPE) tissue of patients with diffuse large B cell lymphoma (DLBCL). MATERIAL AND METHODS: This appraisal was conveyed on 50 sequential FFPE specimens of patients with DLBCL. We carried out a standard multiplex PCR and heteroduplex techniques to analysis of IGH and incomplete IGH D-J clonal gene rearrangements. RESULTS: In our investigation, we were identified a total positive monoclonality of 96% (48/50) for IGH and 58% (29/50) for incomplete IGH D-J. The percentage of positive clonality was detected in three frameworks (FRI, II, III) of IGH revealed 50% (25/50), 28% (14/50) and 18% (9/50) to FRIII, FRII and FRI, respectively. Analysis of incomplete IGH D-J showed 34% (17/50) and 24% (12/50) rates of positive clonality for DH1-6-JH and DH7-JH, respectively. In the 4% (2/50) of cases was no detected any gene rearrangements in both of IGH and incomplete IGH D J genes. CONCLUSIONS: Analysis of molecular clonality gene rearrangements on FFPE tissues disclosed that using BIOMED-2 protocols, could be improvement significant clinicopathological diagnosis of DLBCL. Clonality testing is believable that to suggest as a helpful and credible technique for clonality detection in the routine diagnosis of DLBCL and other lymphoproliferative disorders. PMID- 28807339 TI - Primary collision tumors of the kidney composed of oncocytoma and papillary renal cell carcinoma: A review. AB - BACKGROUND: There are well known cases of hybrid tumors of chromophobe renal cell carcinoma (RCC) and oncocytoma in kidney, where both tumors have the same cell of origin - intercalated cell of the collecting duct. However, collision tumors composed of neoplasms originating from different cell lineages such as oncocytoma and papillary RCC are extremely rare. Herein, we made a collective literature review of reported cases of collision tumors composed of oncocytoma and papillary RCC, adding a case that we recently experienced. MATERIAL AND METHODS: A PubMed database was search for collision tumors of the kidney composed of oncocytoma and papillary RCC and a collective literature review was made. To this cohort, we also added a recently encountered case with similar, confirmed by immunohistochemistry, morphological features. RESULTS: To date 8 cases of a collision tumor composed of papillary RCC and oncocytoma have been described in the literature. All of them had a smaller papillary RCC component present within a larger oncocytoma. CONCLUSION: Because of a few cases of such a collision tumors reported, it is difficult to make classification and right clinical management of these patients. None of the reported cases had tumor recurrence or progression on a follow-up. The presence of only small portion of papillary RCC in a large oncocytoma raises a possibility of under-sampling of malignant component in large oncocytomas in core biopsy or surgically resected specimens. We recommend better sampling, particularly at the periphery of otherwise classic oncocytomas to unveil this possible association. PMID- 28807340 TI - Unusual locations of hydatid disease: A 10-year experience from a tertiary reference center in Western Turkey. AB - INTRODUCTION: Hydatid disease is an endemic parasitic infection caused by Echinococcus granulosus mostly seen in the Mediterranean countries. The most affected organ is the liver, however hydatidosis can be found anywhere in the human body. METHODS: The records of patients who were diagnosed with hydatid disease in our hospital from December 2005 to February 2016 were analyzed retrospectively. The cases were evaluated and recorded depending on their gender, age and the localization of the cysts. RESULTS: A total of 329 patients diagnosed over a 10-year period were included in our study. There were 202 females (61.4%) and 127 males (38.6%). The hydatid cysts were located in the liver in 257 (78.1%) patients and in unusual locations in 72 (21.9%) patients. The most common unusual site for hydatid cysts was the spleen followed by bones, central nervous system, soft tissue, the kidney and the gall bladder. Amongst these 72 patients who had hydatid cysts in unusual locations; 33 patients had concomitant liver hydatidosis, whereas 39 patients had primary involvement of unusual sites. Two patients with malignancies also had hydatid cysts in different locations. CONCLUSION: Hydatid disease affects many organs in the body and therefore it can pose a major diagnostic dilemma and it may mimic other entities. In endemic areas, a differential diagnosis of hydatid disease should be considered for cystic masses in any anatomical location. PMID- 28807341 TI - Ultrastructural examination of skin biopsies may assist in diagnosing mitochondrial cytopathy when muscle biopsies yield negative results. AB - Ultrastructural evaluation of skin biopsies has been utilized for diagnosis of mitochondrial disease. This study investigates how frequently skin biopsies reveal mitochondrial abnormalities, correlates skin and muscle biopsy findings, and describes clinical diagnoses rendered following the evaluation. A retrospective review of surgical pathology reports from 1990 to 2015 identified skin biopsies examined by electron microscopy for suspected metabolic disease. A total of 630 biopsies were included from 615 patients. Of these patients, 178 also underwent a muscle biopsy. Of the 630 skin biopsies, 75 (12%) showed ultrastructural abnormalities and 34 (5%) specifically showed mitochondrial abnormalities including increased size (n=27), reduced or abnormal cristae (n=23), dense matrices (n=20), and increased number (n=8). Additional findings included lysosomal abnormalities (n=13), lipid accumulation (n=2) or glycogen accumulation (n=1). Of the 34 patients with mitochondrial abnormalities on skin biopsy, 20 also had muscle biopsies performed and nine showed abnormalities suggestive of a mitochondrial disorder including absent cytochrome oxidase staining (n=2), increased subsarcolemmal NADH, SDH, or cytochrome oxidase staining (n=1), or ultrastructural findings including large mitochondrial size (n=5), abnormal mitochondrial structure (n=5), and increased mitochondrial number (n=4). The most common presenting symptoms were intellectual disability (n=13), seizures (n=12), encephalopathy (n=9), and gastrointestinal disturbances (n=9). At last known follow-up, 12 patients had a definitive diagnosis of a mitochondrial disorder. One patient each had Complex I deficiency, Complex III deficiency, Charcot-Marie-Tooth disease, pyruvate dehydrogenase deficiency, and Phelan-McDermid syndrome. Our results suggest that skin biopsy sometimes yields diagnostic clues suggestive of a mitochondrial cytopathy in cases with a negative muscle biopsy. PMID- 28807342 TI - Accuracy and interobserver agreement of retroareolar frozen sections in nipple sparing mastectomies. AB - In the last decades, surgical treatment of breast cancer has enormously changed. As a result, nipple-sparing mastectomy (NSM) has evolved as an oncologically safe and cosmetic approach. NSM includes a subareolar frozen section to evaluate malignancy. We determined the accuracy of subareolar frozen section diagnosis, analyzed the discrepancy factor, and estimated the interobserver agreement of frozen section in NSM. A retrospective review of all NSMs at our institution from 2009 to 2015 was performed. Frozen sections were compared to the final diagnoses to analyze the accuracy of subareolar frozen sections. Discordant results were rigorously evaluated to identify discrepancy factors. Some cases were randomly chosen to assess the interobserver agreement (kappa) among pathologists. The agreement results were evaluated with and without knowledge of the tumor morphology. Among 34 NSMs, the frozen section false-negative and false-positive rate was 5.9% and 8.8%, respectively. The sensitivity and specificity was 77.8% and 88.0%, respectively. Sampling errors and diathermy artifacts explained our false-negative diagnoses. Freezing artifacts and an intraductal papilloma explained our false-positive diagnoses. The interobserver agreement between breast and general pathologists was 0.87 (p<0.0001) and 0.31 (p=0.0001), respectively. The interobserver agreement increased to 0.35 (p<0.0001) in general pathologists with knowledge of the tumor morphology. Subareolar frozen section showed to be a specific test with moderate sensitivity. Papillary lesions can mimic atypical cells and influence the frozen section interpretation. Frozen section in NSM had a better performance in breast pathologists (almost perfect) versus general pathologists (fair). Interobserver agreement may improve with knowledge of tumor morphology. PMID- 28807343 TI - Anisometric cell lipoma: Insight from a case series and review of the literature on adipocytic neoplasms in survivors of retinoblastoma suggest a role for RB1 loss and possible relationship to fat-predominant ("fat-only") spindle cell lipoma. AB - The term "anisometric cell lipoma" (ACL) has been proposed recently by Evans for a lipoma variant characterized by striking variation in size and shape of adipocytes but little or no cytological atypia. One patient with multiple ACL had a history of retinoblastoma. The current study analyzed six patients with ACL (4 males and two females aged 34 to 87years; median, 58); all seen in consultation. Five patients presented with solitary and one with multiple subcutaneous masses measuring 5 to 9cm (median, 7.5cm). Affected sites were upper arm (3), shoulder (2), neck (1), trunk (1) and chest wall (1). Surgical excision was the treatment in all cases. No recurrence was recorded at last follow-up (1-17months). Submitted diagnoses were atypical lipomatous tumor (n=3), lipoma with regressive changes (n=1) and unclassified lipomatous neoplasm (n=2). In all cases, the striking variation in size of adipocytes was mentioned as the most or sole worrisome feature justifying external consultation. Histology was similar in all cases. All fulfilled the features reported by Evans as stated above and lacked any conventional spindle cell lipoma-like areas. Multi-vacuolated (lipoblast like) cells were seen in three cases. MDM2/CDK4 were negative by immunohistochemistry and MDM2 amplification was absent by FISH in all cases. RB1 immunoexpression was lost in 5/5 cases. Rb1 FISH analysis revealed copy number aberrations in 3 of 4 cases (heterozygous deletions in two cases and homozygous deletion in one). In conclusion, ACL shares similar clinicopathological, demographic and molecular features as spindle cell lipoma suggesting related diseases. In the light of the available literature on adipocytic neoplasms in retinoblastoma survivors (>30 patients with multiple lipomas following retinoblastoma reported), it is probably that retinoblastoma-associated lipomas belong to the ACL category. Thus, it seems that Somatic RB1 loss probably drives sporadic ACL in a comparable way to post-retinoblastoma lipomas which were shown to be driven by LOH of the RB1 wild-type allele. PMID- 28807344 TI - Pituicytoma: Review of commonalities and distinguishing features among TTF-1 positive tumors of the central nervous system. AB - Pituicytoma is a rare low-grade glial neoplasm that originates in the distribution of the neurohypophysis, including the posterior pituitary lobe and infundibular stalk. The tumor cells resemble pituicytes, which are specialized glial cells of the neurohypophysis. Pituicytoma can be misdiagnosed pre operatively as a pituitary adenoma due to overlapping clinical and neuroimaging features between these two entities. Pituicytoma can also mimic other neoplasms of the sellar and parasellar regions microscopically - meningioma, schwannoma and pilocytic astrocytoma - and shares immunohistochemical expression of TTF-1 with spindle cell oncocytoma and granular cell tumor of the sellar region, suggesting a common histogenesis. In this short review, we present the key features of pituicytoma, discuss commonalities and distinguishing features from other neoplasms of the sellar and parasellar regions and highlight the importance of recognizing this tumor entity for clinical and surgical management. PMID- 28807345 TI - AMPK expression patterns are significantly associated with poor prognosis in breast cancer patients. AB - Many investigators have examined the functions of AMP-activated protein kinase (AMPK) in cancer biology and its anti-neoplastic features in cancer models. The goal of this research is to assess the association of the immunohistochemical expression of AMPK in human mammary tumours with the clinical data of breast cancer patients. 449 cases of previously diagnosed breast cancer, and 27 tissue samples of fibroadenomas and normal breast were utilized for detection of AMPK expression using tissue microarrays and immunohistochemistry. Brownish nuclear and cytoplasmic staining were present in epithelial cells and stromal cells in 333 (74.16%) and 348 (77.5%) cancer cases respectively indicating AMPK expression. Twenty two (81.48%) control cases showed AMPK immunoexpression in both epithelial and stromal cells. Significant statistical association has been found between advanced stages of breast cancer and increased intensity of AMPK immunostaining only in epithelial cells (p-value=0.0001). Histotypes have been correlated with AMPK immunostaining in epithelial cells only (p-value=0.029). Low AMPK immunostaining scores were more dominant in DCIS, ductal and mixed type's ductal and mucinous histotypes, while high intense staining was more common in the lobular type. Furthermore, breast tumour cases with lymph node metastases showed significant AMPK expression in both epithelial and stromal cells (p value=0.0001 and p-value=0.026). Low scores of AMPK immunostaining were common in breast cancer cases with positive vascular invasion (p-value=0.007) and disease recurrence (p-value=0.008). No significant differences in survival behavior distributions were observed for the different categories of AMPK immunostaining in epithelial and stromal cells. In conclusion, our results showed decreased AMPK expression in breast cancer in comparison with the control group. AMPK expression was significantly correlated with some clinicopathological factors like advanced stage, lymph node involvement, vascular invasion and disease recurrence which give indications for poor clinical outcomes. Immunohistochemical staining of AMPK protein is a valuable method which could predict cases of breast cancer with poor prognosis. PMID- 28807346 TI - Application of a time-resolved fluoroimmunoassay for detection of p16INK4a in cervix. AB - OBJECTIVE: To establish a time-resolved fluoroimmunoassay (TRFIA) method to detect p16INK4a. METHODS: 119 cases of exfoliative cells following Thinprep cytologic test (TCT) test were selected for TRFIA and biopsy tissues of these patients according to TCT results were collected for immunohistochemical (IHC) staining. RESULTS: There were 40 cases with cervicitis, 16 cases of cervical intraepithelial neoplasia grade 1 (CIN1), 15 cases of CIN2, 26 cases of CIN3, and 22 cases of squamous cell carcinoma (SCC). For each group, TCT results displaying above ASC-US were 7, 6, 12, 23, and 21 cases. IHC results were positive for 2, 13, 14, 26, and 21 cases, while the TRFIA results were positive for 5, 12, 13, 25, and 21 cases, respectively. The sensitivity and specificity were not significantly different between TCT and TRFIA test due to the limited cases. Significantly more CIN1 cases were positive by TRFIA, as compared with cervicitis (75.00% vs. 12.50%, chi2=21.116, p<0.001). Most (93.65%) CIN2/3 and SCC cases were positive for p16INK4a (higher than CIN1, chi2=4.877 and p=0.027). CONCLUSION: Detecting p16INK4a protein by TRFIA is suitable to discriminate cervical dysplastic/neoplastic lesions from cervicitis. A commercial kit which created in the future might be a rapid, simple, and low-cost method to obtain objective results with an instrument automatically on a large scale. PMID- 28807347 TI - Dorsoradial Instability of the Thumb Metacarpophalangeal Joint: A Biomechanical Investigation. AB - PURPOSE: To define the role of the dorsal capsule and associated dorsal fibrocartilage (DFC) and their interactions with the radial collateral ligament (RCL) as a thumb metacarpophalangeal (MCP) joint stabilizer. METHODS: Eight cadaveric thumbs were mounted onto a custom jig with 20 N of muscle load applied. The thumb position in space was digitized to measure ulnar-radial, pronation supination, and volar-dorsal laxity at 0 degrees , 30 degrees , and 60 degrees MCP joint flexion. Serial sectioning was performed and measurements were repeated for the intact state, proper RCL insufficiency, proper and accessory (complete) RCL insufficiency, complete RCL with 50% DFC (radial) insufficiency, and complete RCL with complete DFC insufficiency. RESULTS: Ulnar-radial deviation, pronation supination, and volar-dorsal translation significantly changed at 30 degrees and 60 degrees MCP joint flexion when comparing complete RCL insufficiency with complete RCL with 50% DFC insufficiency. At 30 degrees flexion, significant increases were found in ulnar deviation, pronation, and volar translation, and there was a decrease in supination. At 60 degrees flexion, ulnar deviation, pronation, and volar translation increased and radial deviation decreased significantly. At 30 degrees flexion, the resting position significantly pronated and translated volarly. At 60 degrees flexion, the resting position significantly shifted ulnarly, pronated, and translated volarly. CONCLUSIONS: The DFC acts as a secondary stabilizer of the thumb MCP joint, working in tandem with the RCL. It acts by stabilizing the MCP joint dorsoradially when external forces are applied across the joint. This cadaveric study shows that RCL insufficiency with a concomitant DFC injury is less likely to be stable than RCL injuries alone, and that this effect is more pronounced with MCP joint flexion. CLINICAL RELEVANCE: Increasing incompetence of the secondary stabilizers of the RCL, such as the DFC, will likely result in increased clinical instability upon physical examination. The results of this study also suggest the need to consider repair of the DFC at the time of RCL repair. PMID- 28807348 TI - A Biomechanical Comparison Between Asymmetric Pennington Technique and Conventional Core Suture Techniques: 6-Strand Flexor Tendon Repair. AB - PURPOSE: To evaluate the fatigue strength and gap sizes of the asymmetric Pennington technique compared with 2 conventional 6-strand core suture techniques: the triple-looped suture and the Yoshizu #1. METHODS: We recorded the fatigue strength (forces * cycles) and gap sizes of a 6-strand flexor tendon repair with different core suture techniques under cyclic loading in 30 porcine tendons. The asymmetric Pennington technique was performed with a Pennington repair of equal suture purchase in the 2 tendon stumps, with the 2 other Pennington repairs shifted by 3 mm, respectively, along the longitudinal axis of the tendon in relation to the first Pennington repair. The triple-looped suture technique was made with triple Tsuge sutures. The Yoshizu #1 technique was performed with a combined Pennington repair (using a double strand) and Tsuge suture. RESULTS: The asymmetric Pennington technique showed significantly greater fatigue strength and significantly smaller gaps in comparison to the triple looped suture and Yoshizu #1 techniques. CONCLUSIONS: This study demonstrated that the asymmetric Pennington technique generated increased fatigue strength and reduced gap sizes compared with 2 conventional 6-strand core suture techniques, the triple-looped suture and Yoshizu #1. CLINICAL RELEVANCE: The asymmetric Pennington technique may permit an early active motion rehabilitation protocol similar to the triple-looped suture and Yoshizu #1 techniques. PMID- 28807349 TI - Reply to Erfan Ayubi and Saeid Safiri's Letter to the Editor re: Sungmin Woo, Chong Hyun Suh, Sang Youn Kim, Jeong Yeon Cho, Seung Hyup Kim. Diagnostic Performance of Prostate Imaging Reporting and Data System Version 2 for Detection of Prostate Cancer: A Systematic Review and Diagnostic Meta-analysis. Eur Urol 2017;72:177-88. PMID- 28807350 TI - One Strategy Does Not Fit All: The Era of Personalised Medicine for the Treatment of Male Lower Urinary Tract Symptoms Is upon Us. PMID- 28807351 TI - Cost Effectiveness of Nivolumab in Advanced Renal Cell Carcinoma. AB - BACKGROUND: In recent years, new drugs have been introduced for second-line treatment of advanced renal cell carcinoma (RCC). Nivolumab increases overall survival and is associated with less toxicity compared to everolimus in this setting according to the CheckMate 025 study. However, because of the high cost of nivolumab, there is a need to define its value by considering both efficacy and cost. OBJECTIVE: To estimate the cost effectiveness of nivolumab for second line treatment of advanced RCC from the US payer perspective. DESIGN, SETTING, AND PARTICIPANTS: A Markov model was developed to compare the costs and effectiveness of nivolumab with those of everolimus and placebo in second-line treatment of advanced RCC. Health outcomes were measured in life-years (LYs) and quality-adjusted LYs (QALYs). Drug costs were based on 2016 Medicare reimbursement rates. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Model robustness was assessed in univariable and probabilistic sensitivity analyses. We addressed the issue of the extensive duration of immunotherapy treatment among long-term survivors, which may or may not be approved by payers. RESULTS AND LIMITATIONS: The total mean cost per patient was $101 070 for nivolumab and $50 935 for everolimus. Nivolumab generated a gain of 0.24 LYs (0.34 QALYs) compared to everolimus. The incremental cost-effectiveness ratio (ICER) for nivolumab was $146 532/QALY versus everolimus and $226 197/QALY versus placebo. Limiting the maximal treatment duration of nivolumab to 2 yr reduced the ICER to $121 788/QALY versus everolimus. The analysis is limited by data availability and our assumptions. CONCLUSIONS: Our analysis established that with a willingness-to-pay threshold of $100 000 to $150 000 per QALY, nivolumab is estimated to be cost effective versus everolimus, but not cost-effective versus placebo. PATIENT SUMMARY: We assessed the cost effectiveness of nivolumab in previously treated metastatic kidney cancer. In the USA, it would cost $146 532 to gain one quality adjusted life-year with nivolumab versus everolimus, or $226 197 versus placebo. Nivolumab is considered cost-effective versus everolimus, but not versus placebo. PMID- 28807352 TI - Unusual digoxin toxicity with myocardial injury. AB - A 38-year-old healthy male presented with vomiting and profuse diarrhea, associated with blurry and yellow coloration of the vision (xanthopsia). Laboratory workup was unremarkable, except for hyperkalemia (K 5.2 mEq/L) and mildly elevated troponin level 0.11 ng/mL (cut-off value 0.08). An electrocardiogram showed sinus bradycardia with deep scooping of the T waves. Although the patient denied intake of any drugs, herbs, consumption of plants, a digoxin level was drawn and was significantly elevated >5ng/mL (therapeutic range 0.8-2.0). Further questioning revealed that the patient was a pharmacist mixing raw material to fabricate medication, and that he could have incidentally ingested contaminated water. His symptoms improved with parallel improvement in the electrocardiogram T wave abnormalities. An echocardiogram was normal. The positive troponin was felt to be secondary to severe digoxin toxicity. Review of the literature however showed no report of elevated troponin in the setting of digoxin toxicity. PMID- 28807353 TI - Incidence rates, correlates, and prognosis of electrocardiographic P-wave abnormalities - a nationwide population-based study. AB - BACKGROUND: Scant data exist on incidence rates, correlates, and prognosis of electrocardiographic P-wave abnormalities in the general population. METHODS: We recorded ECG and measured conventional cardiovascular risk factors in 5667 Finns who were followed up for incident atrial fibrillation (AF). We obtained repeat ECGs from 3089 individuals 11years later. RESULTS: The incidence rates of prolonged P-wave duration, abnormal P terminal force (PTF), left P-wave axis deviation, and right P-wave axis deviation were 16.0%, 7.4%, 3.4%, and 2.2%, respectively. Older age and higher BMI were associated with incident prolonged P wave duration and abnormal PTF (P<=0.01). Higher blood pressure was associated with incident prolonged P-wave duration and right P-wave axis deviation (P<=0.01). During follow-up, only prolonged P-wave duration predicted AF (multivariable-adjusted hazard ratio, 1.38; P=0.001). CONCLUSIONS: Modifiable risk factors associate with P-wave abnormalities that are common and may represent intermediate steps of atrial cardiomyopathy on a pathway leading to AF. PMID- 28807354 TI - Penaloza-Tranchesi sign secondary to ascending aortic aneurysm and not due to right atrium enlargement. AB - Low QRS amplitude in V1, with relative three-to-fourfold or greater increase in V2, is considered an indirect sign of right atrium enlargement (Penaloza Tranchesi sign). We describe a patient with Penaloza-Tranchesi sign caused by an ascending aortic aneurysm, with normalization of the QRS complex amplitude in V1 after aortic replacement. PMID- 28807356 TI - High Flow Nasal Cannula Flow Rates: New Data Worth the Weight. PMID- 28807355 TI - Hydrogen-rich pure water prevents cigarette smoke-induced pulmonary emphysema in SMP30 knockout mice. AB - Chronic obstructive pulmonary disease (COPD) is predominantly a cigarette smoke (CS)-triggered disease with features of chronic systemic inflammation. Oxidants derived from CS can induce DNA damage and stress-induced premature cellular senescence in the respiratory system, which play significant roles in COPD. Therefore, antioxidants should provide benefits for the treatment of COPD; however, their therapeutic potential remains limited owing to the complexity of this disease. Recently, molecular hydrogen (H2) has been reported as a preventive and therapeutic antioxidant. Molecular H2 can selectively reduce hydroxyl radical accumulation with no known side effects, showing potential applications in managing oxidative stress, inflammation, apoptosis, and lipid metabolism. However, there have been no reports on the efficacy of molecular H2 in COPD patients. In the present study, we used a mouse model of COPD to investigate whether CS-induced histological damage in the lungs could be attenuated by administration of molecular H2. We administered H2-rich pure water to senescence marker protein 30 knockout (SMP30-KO) mice exposed to CS for 8 weeks. Administration of H2-rich water attenuated the CS-induced lung damage in the SMP30-KO mice and reduced the mean linear intercept and destructive index of the lungs. Moreover, H2-rich water significantly restored the static lung compliance in the CS-exposed mice compared with that in the CS-exposed H2-untreated mice. Moreover, treatment with H2-rich water decreased the levels of oxidative DNA damage markers such as phosphorylated histone H2AX and 8-hydroxy-2' deoxyguanosine, and senescence markers such as cyclin-dependent kinase inhibitor 2A, cyclin-dependent kinase inhibitor 1, and beta-galactosidase in the CS-exposed mice. These results demonstrated that H2-rich pure water attenuated CS-induced emphysema in SMP30-KO mice by reducing CS-induced oxidative DNA damage and premature cell senescence in the lungs. Our study suggests that administration of molecular H2 may be a novel preventive and therapeutic strategy for COPD. PMID- 28807358 TI - Pulmonary Calcification in a Congenital Cytomegalovirus Infection. PMID- 28807359 TI - Physical Therapy for Fecal Incontinence in Children with Pelvic Floor Dyssynergia. AB - OBJECTIVES: To determine the efficacy of physical therapy (PT) for fecal incontinence in children with pelvic floor dyssynergia (PFD). STUDY DESIGN: Retrospective chart review of children with PFD completing >1 PT session for fecal incontinence at a quaternary children's hospital. The frequency of fecal incontinence (primary outcome), constipation-related medication use, number of bowel movements (in those with <3 per week at baseline) and pelvic floor muscle (PFM) function were captured at baseline and at the final PT visit. Outcomes were categorized as excellent (complete continence), good (>50% decrease in fecal incontinence frequency), fair (not worsening but <50% fecal incontinence frequency decrease), and poor (more frequent fecal incontinence). Compliance with PT was determined by the percentage of attended PT appointments. RESULTS: Children included met the following primary outcomes: 27 (42.2%) excellent, 24 (37.5%) good, 11 (17.1%) fair, and 2 (3.1%) poor. Factors associated with an excellent or good outcome included improved PFM functioning and good (>=70% PT attendance) compliance. Children with a history of surgically corrected tethered spinal cord were more likely to have a fair outcome (P = .015). Use of constipation-related medications decreased (1.9 +/- 0.7 vs 1.5 +/- 0.9, P = .005). Weekly bowel movement frequency increased (1.6 +/- 0.6 vs 6.4 +/- 4.8, P < .001) in those with infrequent bowel movements (n = 26) at baseline. CONCLUSIONS: Pelvic floor PT is effective in the majority of children with fecal incontinence related to PFD. Factors associated with PT efficacy include improved PFM functioning, good compliance with PT, and history of tethered cord. PMID- 28807360 TI - Introducing the Cancer Research UK Advanced Radiotherapy Technologies Network (ART-NET). PMID- 28807361 TI - Challenges to Treating Older Glioblastoma Patients: the Influence of Clinical and Tumour Characteristics on Survival Outcomes. AB - AIMS: There is now evidence to support giving single-agent chemotherapy, radiotherapy or hypofractionated concurrent chemoradiotherapy to older patients with glioblastoma (GBM). However, the clinical basis on which treatment decisions are made is under-researched and not standardised. This retrospective, multicentre study assessed whether pre-morbid characteristics or tumour imaging features could predict for overall survival in a cohort of older patients with GBM. MATERIALS AND METHODS: Patients aged > 70 years, diagnosed with GBM at three neuro-oncology centres from 2010 to 2015 were retrospectively analysed. Demographic, clinical, radiological and treatment details were included in a multivariate model to examine for predictors of overall survival. RESULTS: In total, 339 patients were included with a median overall survival of 3.8 months. One and 2 year overall survival rates were 13% and 4%, respectively. The median age at diagnosis was 75 years. Pre-treatment characteristics predicting for overall survival included Eastern Cooperative Oncology Group performance status over 0 (performance status 1, hazard ratio 1.66, P = 0.042; performance status 2, hazard ratio 1.78, P = 0.031; performance status 3, hazard ratio 2.20, P = 0.008; performance status 4, hazard ratio 2.40, P = 0.021), radiological evidence of mass effect (hazard ratio 1.31, P = 0.049), multifocal tumours (hazard ratio 3.419, P = 0.013), presenting with seizures (hazard ratio 0.63, P = 0.008) and tumours confined to the cerebral hemisphere (hazard ratio 0.59, P = 0.048). Subtotal resection decreased risk of death by 37% (P = 0.019) and total tumour resection by 44% (P = 0.019). Palliative radiotherapy decreased risk of death by 41% (P = 0.005), temozolomide alone by 60% (P = 0.004) and radical chemoradiotherapy by 81% (P < 0.001). CONCLUSION: Clinical presentation, performance status and imaging characteristics are independent prognostic indicators of overall survival in older GBM patients, irrespective of age or treatment received. PMID- 28807362 TI - Leg movement tracking in automatic video-based one-leg stance evaluation. AB - Falls are a major risk in elder population. Early diagnosis is therefore an important step towards increasing the safety of elders. One of the common diagnostic tests is the Berg Balance Scale (BBS), consisting of 14 exercises arranged from the easiest (sitting-to-standing) to the most demanding (one-leg stance). In this study a novel approach to the automatic assessment of the time in which the patient can remain in the one-leg stance position without loosing balance is introduced. The data is collected using a regular video camera. No markers, special garments, or system calibration are required. Two groups are examined. The first group consists of 16 students: healthy, young adults (12 female, 4 male, avg. 20yrs+/-1). The second group consists of 50 elders (39 female, 11 male, avg. 78.8yrs+/-5.9). Data (short, one minute recordings) are collected in a controlled environment using a digital video recorder (50fps, 1920*1080) fixed to a tripod. Data are processed off-line. First, the region of interest is determined. Next, the Kanade-Lucas-Tomasi tracking is performed. Best tracks are selected based on the registered vertical movement and two tracks are obtained corresponding to the left and right leg movements. Tracks are later subjected to the sparse signal baseline estimation, denoising and thresholding to detect the raised leg. Results are compared frame-wise to the ground truth reference obtained in the manual processing procedure. Both legs are evaluated in the elder group (in all cases several attempts featuring both legs were registered), resulting in 89.18%+/-11.27% DICE, 93.07%+/-5.43% sensitivity and 96.94%+/-6.11% specificity values for both legs. The signal of a single leg is evaluated in the student group (in all cases only one attempt was needed to perform the full examination) resulting in 98.96%+/-1.2% DICE, 98.78%+/-1.65% sensitivity and 98.73%+/-2.69% specificity values. This is the first step towards a video-based system enabling the automatic assessment of the four last, most vital tasks of the Berg Balance Scale evaluation. PMID- 28807357 TI - Development and Initial Validation of the Macrophage Activation Syndrome/Primary Hemophagocytic Lymphohistiocytosis Score, a Diagnostic Tool that Differentiates Primary Hemophagocytic Lymphohistiocytosis from Macrophage Activation Syndrome. AB - OBJECTIVE: To develop and validate a diagnostic score that assists in discriminating primary hemophagocytic lymphohistiocytosis (pHLH) from macrophage activation syndrome (MAS) related to systemic juvenile idiopathic arthritis. STUDY DESIGN: The clinical, laboratory, and histopathologic features of 362 patients with MAS and 258 patients with pHLH were collected in a multinational collaborative study. Eighty percent of the population was assessed to develop the score and the remaining 20% constituted the validation sample. Variables that entered the best fitted model of logistic regression were assigned a score, based on their statistical weight. The MAS/HLH (MH) score was made up with the individual scores of selected variables. The cutoff in the MH score that discriminated pHLH from MAS best was calculated by means of receiver operating characteristic curve analysis. Score performance was examined in both developmental and validation samples. RESULTS: Six variables composed the MH score: age at onset, neutrophil count, fibrinogen, splenomegaly, platelet count, and hemoglobin. The MH score ranged from 0 to 123, and its median value was 97 (1st-3rd quartile 75-123) and 12 (1st-3rd quartile 11-34) in pHLH and MAS, respectively. The probability of a diagnosis of pHLH ranged from <1% for a score of <11 to >99% for a score of >=123. A cutoff value of >=60 revealed the best performance in discriminating pHLH from MAS. CONCLUSION: The MH score is a powerful tool that may aid practitioners to identify patients who are more likely to have pHLH and, thus, could be prioritized for functional and genetic testing. PMID- 28807363 TI - Deducing magnetic resonance neuroimages based on knowledge from samples. AB - PURPOSE: Because individual variance always exists, using the same set of predetermined parameters for magnetic resonance imaging (MRI) may not be exactly suitable for each participant. We propose a knowledge-based method that can repair MRI data of undesired contrast as if a new scan were acquired using imaging parameters that had been individually optimized. METHODS: The method employed a strategy called analogical reasoning to deduce voxel-wise relaxation properties using morphological and biological similarity. The proposed framework involves steps of intensity normalization, tissue segmentation, relaxation time deducing, and image deducing. RESULTS: This approach has been preliminarily validated using conventional MRI data at 3T from several examples, including 5 normal and 9 clinical datasets. It can effectively improve the contrast of real MRI data by deducing imaging data using optimized imaging parameters based on deduced relaxation properties. The statistics of deduced images shows a high correlation with real data that were actually collected using the same set of imaging parameters. CONCLUSION: The proposed method of deducing MRI data using knowledge of relaxation times alternatively provides a way of repairing MRI data of less optimal contrast. The method is also capable of optimizing an MRI protocol for individual participants, thereby realizing personalized MR imaging. PMID- 28807364 TI - Initial results of the oesophageal and gastric cancer registry from the Comunidad Valenciana. AB - AIMS: To evaluate the initial results of the oesophagogastric cancer registry developed for the Sociedad Valenciana de Cirugia and the Health Department of the Comunidad Valenciana (Spain). METHODS: Fourteen of the 24 public hospitals belonging to the Comunidad Valenciana participated. All patients with diagnosis of oesophageal or gastric carcinomas operated from January 2013 to December 2014 were evaluated. Demographic, clinical and pathological data were analysed. RESULTS: Four hundred and thirty-four patients (120 oesophageal carcinomas and 314 gastric carcinomas) were included. Only two hospitals operated more than 10 patients with oesophageal cancer per year. Transthoracic oesophaguectomy was the most frequent approach (84.2%) in tumours localized within the oesophagus. A total gastrectomy was performed in 50.9% patients with gastroesophageal junction (GOJ) carcinomas. Postoperative 30-day and 90-day mortality were 8% and 11.6% in oesophageal carcinoma and 5.9 and 8.6% in gastric carcinoma. Before surgery, middle oesophagus carcinomas were treated mostly (76,5%) with chemoradiotherapy. On the contrary, lower oesophagus and GOJ carcinomas were treated preferably with chemotherapy alone (45.5 and 53.4%). Any neoadjuvant treatment was administered to 73.6% of gastric cancer patients. Half patients with oesophageal carcinoma or gastric carcinoma received no adjuvant treatment. CONCLUSIONS: This registry revealed that half patients with oesophageal cancer were operated in hospitals with less than 10 cases per year at the Comunidad Valenciana. Also, it detected capacity improvement for some clinical outcomes of oesophageal and gastric carcinomas. PMID- 28807365 TI - [The breakthrough of personalized medicine, new hopes and new challenges]. AB - The development of personalized medicine in oncology is based on biomarkers that help select populations for more efficient and less toxic therapies. The onset of molecular biology led to new paradigms in drug development, with efficacy data reported in early clinical trials and accelerated approvals. Multiple clinical trials, including SHIVA, SAFIR-01 and MOSCATO-01, have been developed to evaluate the interest of treatment decision-making based on tumor molecular profiling, with the ambition to replace historical clinical and pathological classifications. Targeted molecular therapies have also drastically enhanced the prognosis of patients in several cancer subtypes, with increased use in the context of advanced palliative care. Breaking through those boundaries might lead to a true precision medicine in oncology, which implementation in clinical routine is now expected by patients and physicians. PMID- 28807366 TI - Prospective screening with the validated Opioid Risk Tool demonstrates gynecologic oncology patients are at low risk for opioid misuse. AB - OBJECTIVE: To characterize risk for opioid misuse among gynecologic oncology patients. METHODS: The Opioid Risk Tool (ORT), a validated screen for opioid misuse risk, was administered to a convenience sample of patients with gynecologic cancer receiving opioid prescriptions in gynecologic oncology or palliative care clinics from January 2012-June 2016. Demographic and clinical information was abstracted on chart review. The primary outcome was ORT risk level (low vs. moderate or high). Chi-square tests were performed for categorical variables. RESULTS: A total of 118 women were screened. Most women were Caucasian (79%) with a median age of 57years. Ovarian cancer patients comprised 46% of the cohort with fewer endometrial (25%), cervical (23%), vulvar (4%), and vaginal (2%) cancer patients. The median ORT score was 1.0 (range, 0-10) out of a possible 26. Overall, 87% of patients were categorized as low-risk for opioid misuse, 7% as moderate-risk, and 6% as high-risk. Patients who were at moderate or high-risk of opioid misuse were significantly younger (47 vs. 58years, p=0.02), more likely to have cervical cancer (p=0.02), be smokers (p=0.01) and be uninsured or on Medicare (p=0.03). CONCLUSIONS: Most gynecologic oncology patients in our cohort were low-risk for opioid misuse (87%). Cervical cancer patients were more likely to be moderate to high-risk for misuse. Future screening efforts for opioid misuse may have the highest utility in this subset of patients. PMID- 28807368 TI - Membrane interactions and antimicrobial effects of inorganic nanoparticles. AB - Interactions between nanoparticles and biological membranes are attracting increasing attention in current nanomedicine, and play a key role both for nanotoxicology and for utilizing nanomaterials in diagnostics, drug delivery, functional biomaterials, as well as combinations of these, e.g., in theranostics. In addition, there is considerable current interest in the use of nanomaterials as antimicrobial agents, motivated by increasing resistance development against conventional antibiotics. Here, various nanomaterials offer opportunities for triggered functionalites to combat challenging infections. Although the performance in these diverse applications is governed by a complex interplay between the nanomaterial, the properties of included drugs (if any), and the biological system, nanoparticle-membrane interactions constitute a key initial step and play a key role for the subsequent biological response. In the present overview, the current understanding of inorganic nanomaterials as antimicrobial agents is outlined, with special focus on the interplay between antimicrobial effects and membrane interactions, and how membrane interactions and antimicrobial effects of such materials depend on nanoparticle properties, membrane composition, and external (e.g., light and magnetic) fields. PMID- 28807369 TI - An Interview with Ruth Nussinov. PMID- 28807367 TI - An evaluation of progression free survival and overall survival of ovarian cancer patients with clear cell carcinoma versus serous carcinoma treated with platinum therapy: An NRG Oncology/Gynecologic Oncology Group experience. AB - PURPOSE: We examined disparities in prognosis between patients with ovarian clear cell carcinoma (OCCC) and serous epithelial ovarian cancer (SOC). METHODS: We reviewed data from FIGO stage I-IV epithelial ovarian cancer patients who participated in 12 prospective randomized GOG protocols. Proportional hazards models were used to compare progression-free survival (PFS) and overall survival (OS) by cell type (clear cell versus serous). RESULTS: There were 10,803 patients enrolled, 9531 were eligible, evaluable and treated with platinum, of whom 544 (6%) had OCCC, 7054 (74%) had SOC, and 1933 (20%) had other histologies and are not included further. In early stage (I-II) patients, PFS was significantly better in OCCC than in SOC patients. For late stage (III, IV) patients, OCCC had worse PFS and OS compared to SOC, OS HR=1.66 (1.43, 1.91; p<0.001). After adjusting for age and stratifying by protocol and treatment arm, stage, performance status, and race, OCCC had a significantly decreased OS, HR=1.53 (1.33, 1.76; p<0.001). In early stage cases, there was a significantly decreased treatment effect on PFS for consolidative therapy with weekly Paclitaxel versus observation in OCCC compared to SOC (p=0.048). CONCLUSIONS: This is one of the largest analyses to date of OCCC treated on multiple cooperative group trials. OCCC histology is more common than SOC in early stage disease. When adjusted for prognostic factors, in early stage patients, PFS was better for OCCC than for SOC; however, in late-stage patients, OCCC was significantly associated with decreased OS. Finally, treatment effect was influenced by histology. PMID- 28807370 TI - Descriptive Analysis of Factors Associated with External Cervical Resorption. AB - INTRODUCTION: The aim of this study was to perform a descriptive analysis of the occurrence of external cervical resorption (ECR) in relation to the patients' characteristics (sex, age, and tooth type) and the potentially involved predisposing factors. METHODS: This study includes data on 284 patients (337 teeth with evidence of ECR) referred to the University Hospital Leuven (Leuven, Belgium) and Endo Rotterdam (Rotterdam, the Netherlands) for diagnosis and treatment from 2010 to 2015. The medical history, existing radiographs, and dental records were available for evaluation. Each patient was then interviewed followed by a thorough clinical and radiographic examination. Intraoral pictures using a dental operating microscope and digital camera were taken during clinical examination. The radiographic examination consisted of digital periapical radiography and/or cone-beam computed tomographic imaging. A review of existing literature provided a potential predisposing factor checklist for ECR. The clinical data were correlated with the dental and medical history of each patient in an attempt to identify some potential predisposing factor(s) that could contribute to ECR. The frequency of the occurrence of ECR was correlated with tooth type, sex and age of the patient, and each 1 of the recorded potential predisposing factor(s). RESULTS: From the examined teeth (337) with ECR, 175 (54%) were found in male patients and 162 (46%) were found in female patients. In 59% of the cases, more than 1 potential predisposing factor was identified. Most ECR cases were observed on maxillary central incisors (29%) followed by maxillary canines (14%), mandibular molars (14%), and maxillary premolars (11%). In addition, most ECR cases were observed on maxillary teeth (72%). The most frequently appearing factor was orthodontics (45.7%). Other frequently observed factors were trauma (28.5%), parafunctional habits (23.2%), poor oral health (22.9%), malocclusion (17.5%), and extraction of a neighboring tooth (14%). CONCLUSIONS: The data indicate that ECR is not related to patient sex. ECR occurs most often in the maxillary central incisor. In the majority of the cases, more than 1 potential predisposing factor was identified, indicating that ECR may be mainly multifactorial. The most frequently appearing factors were orthodontics, iatrogenic or accidental trauma, and poor oral health. This information may be helpful in diagnosing ECR at an early stage when screening patients presenting with these predisposing factors. PMID- 28807371 TI - Treatment Outcome Following Direct Pulp Capping Using Bioceramic Materials in Mature Permanent Teeth with Carious Exposure: A Pilot Retrospective Study. AB - INTRODUCTION: The aim of this study was to investigate the sequelae of direct pulp capping (DPC) using mineral trioxide aggregate (MTA) and Biodentine in mature permanent teeth with carious exposure. METHODS: Clinical records of 30 patients (15 each with MTA and Biodentine) treated with DPC technique from January 2015 to June 2015 were retrieved. Success rates (based on symptoms, sensibility tests, and radiographic analysis) and adverse events were analyzed. RESULTS: The patients were reviewed at 1, 3, 6, 12, and 18 months after treatment. Four cases (2 each of MTA and Biodentine) were lost to follow-up. MTA and Biodentine groups showed success rates of 84.6% and 92.3%, respectively, with overall success rate of 88.5%. Radiographically visible dentin bridge formation was observed in 69.2% (9/13) and 61.5% (8/13) of cases done with MTA and Biodentine, respectively. The cases done with MTA showed coronal discoloration on review. Diffuse calcifications of the pulp chamber were observed in 1 (7.7%) case done with MTA and 3 (23.1%) cases done with Biodentine. CONCLUSIONS: The advent of bioceramic materials with better biocompatibility and sealing properties can make the outcome of DPC technique in mature permanent teeth with carious exposure more predictable. The success rate observed in this study should be confirmed through randomized controlled trials with long follow-up periods. Effects of adverse events like coronal discoloration and calcifications of the pulp chamber also need to be evaluated. PMID- 28807372 TI - Accuracy of Orthopantomography for Apical Periodontitis without Endodontic Treatment. AB - INTRODUCTION: This study aimed to evaluate the diagnostic accuracy of orthopantomography (OPT) for the detection of clinically/surgically confirmed apical periodontitis (AP) without endodontic treatment using cone-beam computed tomographic (CBCT) imaging as the reference standard. METHODS: One hundred twenty patients without endodontically treated AP (diseased group) were detected via CBCT imaging using the periapical index system. They were divided into groups of 10 each according to the size of the lesion (2-4.5 mm and 4.6-7 mm) and the anatomic area (incisor, canine/premolar, and molar) in both the upper and lower arches. Another 120 patients with a healthy root and periapex (healthy group) were selected. Each diseased and healthy patient underwent OPT first and a CBCT scan within 40 days of the OPT. The periapical index system was also used to assess AP by OPT. Sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy for OPT images with respect to CBCT imaging were analyzed. The k value was calculated to assess both the interobserver reliability for OPT and the agreement between OPT and CBCT imaging. RESULTS: OPT showed low sensitivity (34.2), negative predictive value (59.3), and diagnostic accuracy (65.0) and high specificity (95.8) and positive predictive value (89.1). Interobserver reliability for OPT was substantial (k = 0.71), and agreement between OPT and CBCT imaging was fair (k = 0.30). The best and worst identified AP were located in the lower molar area and the upper/lower incisor area, respectively. CONCLUSIONS: OPT showed high specificity and positive predictive value. However, overall, it was not an accurate imaging technique for the detection of untreated AP, especially in the incisor area. PMID- 28807373 TI - Usefulness of cocaine drops in investigating infant anisocoria. AB - INTRODUCTION: Whereas apraclonidine has eclipsed cocaine test in the exploration of unilateral miosis in adults, its use in infants is avoided because of the risk of central nervous system depression. This chart review evaluates the usefulness of cocaine drops in infants. METHODS: Infants under the age of one referred for unilateral miosis between November 1, 2009 and November 1, 2015, were reviewed. Patients underwent the following protocol: (1) in case of isolated miosis, cocaine test was performed. If the miotic pupil did not dilate, imaging was performed. Dilation in both eyes led to simple clinical follow-up. (2) In case of miosis associated with ptosis or iris heterochromia, imaging of the brain, neck and chest was directly performed. RESULTS: Twenty-six children were included. Twenty-two presented an isolated miosis; three had ipsilateral ptosis, and one had no pupillary light reflex in the miotic eye. Cocaine tests performed in the 22 patients led to imaging in four, which was always normal. No side effect of the test was noticed. Imaging found one neuroblastoma and one intraorbital hemolymphangioma in two patients presenting miosis plus another sign. Imaging was avoided for 18 patients thanks to negative cocaine test. DISCUSSION: Urgent imaging is mandatory in infants presenting with miosis associated with other localizing sign on the sympathetic nerve pathway (Horner syndrome). Since the uselessness of complementary investigations in isolated infantile miosis cannot be proven so far, cocaine test remains the gold standard, as it is safe, cheaper and less stressful than systematic imaging. PMID- 28807374 TI - Design and application of discrete wavelet packet transform based multiresolution controller for liquid level system. AB - A new controller based on discrete wavelet packet transform (DWPT) for liquid level system (LLS) has been presented here. This controller generates control signal using node coefficients of the error signal which interprets many implicit phenomena such as process dynamics, measurement noise and effect of external disturbances. Through simulation results on LLS problem, this controller is shown to perform faster than both the discrete wavelet transform based controller and conventional proportional integral controller. Also, it is more efficient in terms of its ability to provide better noise rejection. To overcome the wind up phenomenon by considering the saturation due to presence of actuator, anti-wind up technique is applied to the conventional PI controller and compared to the wavelet packet transform based controller. In this case also, packet controller is found better than the other ones. This similar work has been extended for analogous first order RC plant as well as second order plant also. PMID- 28807375 TI - The four-tank control problem: Comparison of two disturbance rejection control solutions. AB - The paper aims to compare and prove a pair of disturbance/uncertainty rejection control laws for the well-known four-tank control problem. The control requirements are expressed in terms of a set point sequence as usual in the literature. The uncertainty class is defined as the union of four sub-classes: unknown disturbance, parametric uncertainty, measurement errors and neglected dynamics. Modelling and design give insight on the dynamic properties of the problem. Two theorems, which fix the range of application, are presented. These theorems are confirmed by the simulated results, and indicate the correct way to further broaden the control design applicability. The disturbance rejection design is deployed using the Embedded Model Control methodology. Accordingly, only the unknown disturbance and parametric uncertainty can be rejected, whereas the effects of neglected dynamics must be filtered. As a result, simple performance and stability inequality can be formulated in the frequency domain: they guide the closed-loop pole placement. These inequalities reveal whether pole placement is feasible and how feasibility can be recovered. The latter is an issue, which at the authors' knowledge, is rarely encountered in the literature. Simulated runs prove the effectiveness of the design procedure. PMID- 28807376 TI - Robust adaptive fault-tolerant control for leader-follower flocking of uncertain multi-agent systems with actuator failure. AB - In this work, we study the flocking problem of multi-agent systems with uncertain dynamics subject to actuator failure and external disturbances. By considering some standard assumptions, we propose a robust adaptive fault tolerant protocol for compensating of the actuator bias fault, the partial loss of actuator effectiveness fault, the model uncertainties, and external disturbances. Under the designed protocol, velocity convergence of agents to that of virtual leader is guaranteed while the connectivity preservation of network and collision avoidance among agents are ensured as well. PMID- 28807377 TI - CREM-transgene mice: An animal model of atrial fibrillation and thrombogenesis. AB - BACKGROUND: The molecular pathomechanisms underlying atrial thrombogenesis are multifactorial and still require detailed investigations. Transgenic mice with cardiomyocyte-directed expression of the transcriptional repressor CREM-IbDeltaC X (CREM-TG) represent an experimental model of atrial fibrillation (AF) that shows a gradual, age-dependent progression from atrial ectopy to persistent AF. Importantly, this model develops biatrial thrombi. The molecular characteristics related to the thrombogenesis in CREM-TG mice have not been studied, yet. METHODS: The inflammatory and prothrombotic state was evaluated at the transcriptional (qRT-PCR) and protein level in the left (LA) and right atria (RA) from CREM-TG mice at the age of 20weeks and compared to wild-type controls. Moreover, histological analyses of atrial thrombi were performed. RESULTS: The endocardial dysfunction was mirrored by diminished levels of eNOS-mRNA in both atria (RA: 0.79+/-0.04, LA: 0.72+/-0.06; each P<0.05). Moreover, the PAI-1/t-PA mRNA ratio was significantly increased in both atria (RA: 3.6+/-0.6; P<0.01, LA: 4.0+/-1.0; P<0.05) indicating a high risk of thrombus formation. However, the inflammatory phenotype was more pronounced in the RA and was reflected by a significant increase in the mRNA levels encoding adhesion molecules ICAM-1 (2.1+/ 0.2; P<0.01), VCAM-1 (2.3+/-0.5; P<0.05), and selectin P (3.6+/-0.5: P<0.05). CONCLUSIONS: CREM-TG mice represent a valuable model for studying atrial thrombogenesis and assessing therapeutic approaches preventing embolic events in the systemic and pulmonary circulation. PMID- 28807379 TI - Surgical Correction of Haglund's Triad Using a Central Tendon-Splitting Approach: A Retrospective Outcomes Study. AB - We evaluated the surgical outcomes of Haglund's triad using a central tendon splitting approach, with Achilles tendon partial detachment and debridement, excision of the retrocalcaneal bursa, resection of Haglund's prominence, and reattachment of the Achilles tendon. The medical records of 22 patients (22 heels) who had undergone surgical correction of Haglund's triad from January 2010 to December 2015 were reviewed retrospectively. The visual analog scale pain score, American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot scale score, and 36-item Short-Form Health Survey physical and mental component scores were prospectively collected preoperatively, 6 months postoperatively, and at the last visit. The scores of a subjective question involving satisfaction were prospectively collected at the last visit. Possible risk factors were also evaluated. We reviewed the data from 12 females and 10 males, with the mean age of 59.2 +/- 7.3 years and a mean follow-up duration of 15.1 +/- 4.6 months. Significant improvement was found in the mean visual analog scale pain score, average American Orthopaedic Foot and Ankle Society Ankle-Hindfoot scale score, and 36-item Short-Form Health Survey physical component scale score. The overall satisfaction rate was 77.3% (17 of 22). Postoperative complications included 2 cases of delayed wound healing and 1 case of sensation loss over the heel wound. No Achilles tendon rupture or wound infection developed. Gender and body mass index did not affect the surgical outcomes. The surgical technique we used for Haglund's triad provided effective pain relief, function improvement, and overall enhancement of patients' health condition. More research is required to further evaluate the outcomes of our surgical approach to treat Haglund's triad and the possible risk factors. PMID- 28807380 TI - Reconstruction After Osteomyelitis of the Midfoot From High-Pressure Washer Injury. AB - Reports of ballistic injures to the extremities typically include those involving gunshot wounds. However, high-pressure washer injuries frequently lead to equally damaging injuries. These injuries should not be overlooked, because they can result in high morbidity and complication rates. Similar to the open fracture protocol, these injuries require prompt debridement and irrigation with administration of antibiotics to avoid limb loss. The present case report identified a delay in the treatment protocol that left limited options for the patient. However, the patient agreed to undergo staged reconstruction consisting of serial debridement, implantation of a polymethylmethacrylate antibiotic spacer, and eventual interpositional iliac crest arthrodesis of the midfoot. At a follow-up point >5 years from the initial injury, the patient was walking with minimal pain and no limitations in his daily activities. PMID- 28807381 TI - Postoperative initial 2-day blood pressure management facilitates the shrinkage of abdominal aortic aneurysm after endovascular aneurysm repair by reducing the incidence of type II endoleak. AB - OBJECTIVE: The aim of this study was to evaluate the effect of initial 2-day blood pressure management (BPM) after endovascular aneurysm repair (EVAR) for the incidence of subsequent type II endoleak (T2E) and shrinkage of abdominal aortic aneurysm (AAA) sac diameter. METHODS: We reviewed 136 patients who underwent EVAR for atherosclerotic AAA between July 2008 and July 2014 with one of three stent grafts (Excluder [W. L. Gore & Associates, Flagstaff, Ariz], Powerlink [Endologix Inc, Irvine, Calif], and Endurant [Medtronic Vascular, Santa Rosa, Calif]). Starting from 2013, the mean blood pressure of 76 participating patients (treatment group) was maintained at 75 to 90 mm Hg for the initial 48 hours after EVAR. The incidence of T2E at 7 days and AAA sac diameter 12 months after EVAR were evaluated using computed tomography scanning. The results so obtained were then compared with those of the control group composed of 60 consecutive patients who underwent EVAR before 2013. RESULTS: The incidence of T2E at 7 days was significantly lower in patients who received treatment (treatment group, 19.7%; control group, 40.0%; P = .013), and AAA sac diameter at 12 months in the treatment group had a mean decrease of 5.1 mm compared with the mean 2.2 mm in the control group (P = .004). In multivariate regression analysis, BPM was significantly related to the reduction of incidence of T2E at 7 days (odds ratio, 0.31; P = .007) and a decrease in AAA sac diameter at 12 months (P = .005). In addition, although the use of Endurant had less effect, the use of Excluder under controlled blood pressure conditions improved the incidence of T2E from 80% to 23% compared with those under normal postoperative management (P = .001). CONCLUSIONS: The initial 2-day postoperative BPM might have positive effects, such as lower incidence of T2E and facilitation of AAA sac shrinkage. PMID- 28807382 TI - Association between statin therapy and amputation-free survival in patients with critical limb ischemia in the CRITISCH registry. AB - OBJECTIVE: Secondary prevention in patients with critical limb ischemia (CLI) is crucial for the reduction of cardiovascular morbidity and mortality. Nonetheless, current recommendations are extrapolated from other high-risk populations because of the lack of CLI-dedicated trials. The aim of this explorative study was to evaluate the association of statin therapy with the outcomes of CLI patients. METHODS: The First-Line Treatments in Patients With Critical Limb Ischemia (CRITISCH) registry is a prospective multicenter registry analyzing the effectiveness of all available treatment strategies in 1200 CLI patients. For the purposes of this analysis, patients were divided into two groups based on statin administration. Treatment crossovers and nonadherent patients were excluded from analysis. The primary composite end point of this study was the amputation-free survival (AFS). Major adverse cardiovascular and cerebral events (MACCEs), time to death, and time to major amputation were also analyzed. RESULTS: Statin therapy was applied in 445 individuals (37%), 371 (31%) patients received no statins, and 384 subjects were excluded from analysis (treatment crossovers). Patients receiving statins were more likely to be younger (P < .001) and to have a history of coronary heart disease (P < .001) or previous intervention at index limb (P < .001). Patients receiving statin therapy had a lower hazard regarding AFS (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.34-0.63; P < .001) and death (HR, 0.40; 95% CI, 0.24-0.66; P < .001) as well as lower odds of MACCE (odds ratio, 0.41; 95% CI, 0.23-0.69; P = .001). However, statin therapy was not associated with reduced amputation rates (HR, 1.02; 95% CI, 0.67-1.56; P = .922). Statin effect on AFS was consistent among diabetics (HR, 0.47; 95% CI, 0.31-0.70; P < .001), patients with chronic kidney disease (HR, 0.53; 95% CI, 0.32-0.87; P = .012), and patients older than 75 years (HR, 0.40; 95% CI, 0.26-0.60; P < .001). Statin administration was also associated with an improved AFS in patients with antiplatelet medication (HR, 0.64; 95% CI, 0.41-0.99; P = .049) and without antiplatelet medication (HR, 0.26; 95% CI, 0.12-0.57; P = .001) and after both endovascular therapy (HR, 0.51; 95% CI, 0.34-0.76; P = .001) and bypass revascularization (HR, 0.38; 95% CI, 0.21-0.68; P = .001). CONCLUSIONS: Statin therapy in CLI patients is associated with an increased AFS and lower rates of mortality and MACCEs without improving, however, the salvage rates of the affected limb. PMID- 28807383 TI - Prediction of major cardiac events after vascular surgery. AB - OBJECTIVE: Predicting cardiac events is essential to provide patients with the best medical care and to assess the risk-benefit ratio of surgical procedures. The aim of our study was to evaluate the performance of the Revised Cardiac Risk Index (Lee) and the Vascular Study Group of New England Cardiac Risk Index (VSG) scores for the prediction of major cardiac events in unselected patients undergoing arterial surgery and to determine whether the inclusion of additional risk factors improved their accuracy. METHODS: The study prospectively enrolled 954 consecutive patients undergoing arterial vascular surgery, and the Lee and VSG scores were calculated. Receiver operating characteristic curves for each cardiac risk score were constructed and the areas under the curve (AUCs) compared. Two logistic regression models were done to determine new variables related to the occurrence of major cardiac events (myocardial infarction, heart failure, arrhythmias, and cardiac arrest). RESULTS: Cardiac events occurred in 120 (12.6%) patients. Both scores underestimated the rate of cardiac events across all risk strata. The VSG score had AUC of 0.63 (95% confidence interval [CI], 0.58-0.68), which was higher than the AUC of the Lee score (0.58; 95% CI, 0.52-0.63; P = .03). Addition of preoperative anemia significantly improved the accuracy of the Lee score to an AUC of 0.61 (95% CI, 0.58-0.67; P = .002) but not that of the VSG score. CONCLUSIONS: The Lee and VSG scores have low accuracy and underestimate the risk of major perioperative cardiac events in unselected patients undergoing vascular surgery. The Lee score's accuracy can be increased by adding preoperative anemia. Underestimation of major cardiac complications may lead to incorrect risk-benefit assessments regarding the planned operation. PMID- 28807384 TI - External validation of Vascular Study Group of New England risk predictive model of mortality after elective abdominal aorta aneurysm repair in the Vascular Quality Initiative and comparison against established models. AB - OBJECTIVE: The purpose of this study is to externally validate a recently reported Vascular Study Group of New England (VSGNE) risk predictive model of postoperative mortality after elective abdominal aortic aneurysm (AAA) repair and to compare its predictive ability across different patients' risk categories and against the established risk predictive models using the Vascular Quality Initiative (VQI) AAA sample. METHODS: The VQI AAA database (2010-2015) was queried for patients who underwent elective AAA repair. The VSGNE cases were excluded from the VQI sample. The external validation of a recently published VSGNE AAA risk predictive model, which includes only preoperative variables (age, gender, history of coronary artery disease, chronic obstructive pulmonary disease, cerebrovascular disease, creatinine levels, and aneurysm size) and planned type of repair, was performed using the VQI elective AAA repair sample. The predictive value of the model was assessed via the C-statistic. Hosmer Lemeshow method was used to assess calibration and goodness of fit. This model was then compared with the Medicare, Vascular Governance Northwest model, and Glasgow Aneurysm Score for predicting mortality in VQI sample. The Vuong test was performed to compare the model fit between the models. Model discrimination was assessed in different risk group VQI quintiles. RESULTS: Data from 4431 cases from the VSGNE sample with the overall mortality rate of 1.4% was used to develop the model. The internally validated VSGNE model showed a very high discriminating ability in predicting mortality (C = 0.822) and good model fit (Hosmer-Lemeshow P = .309) among the VSGNE elective AAA repair sample. External validation on 16,989 VQI cases with an overall 0.9% mortality rate showed very robust predictive ability of mortality (C = 0.802). Vuong tests yielded a significant fit difference favoring the VSGNE over then Medicare model (C = 0.780), Vascular Governance Northwest (0.774), and Glasgow Aneurysm Score (0.639). Across the 5 risk quintiles, the VSGNE model predicted observed mortality significantly with great accuracy. CONCLUSIONS: This simple VSGNE AAA risk predictive model showed very high discriminative ability in predicting mortality after elective AAA repair among a large external independent sample of AAA cases performed by a diverse array of physicians nationwide. The risk score based on this simple VSGNE model can reliably stratify patients according to their risk of mortality after elective AAA repair better than other established models. PMID- 28807385 TI - External validation of a 5-year survival prediction model after elective abdominal aortic aneurysm repair. AB - OBJECTIVE: The benefit of prophylactic repair of abdominal aortic aneurysms (AAAs) is based on the risk of rupture exceeding the risk of death from other comorbidities. The purpose of this study was to validate a 5-year survival prediction model for patients undergoing elective repair of asymptomatic AAA <6.5 cm to assist in optimal selection of patients. METHODS: All patients undergoing elective repair for asymptomatic AAA <6.5 cm (open or endovascular) from 2002 to 2011 were identified from a single institutional database (validation group). We assessed the ability of a prior published Vascular Study Group of New England (VSGNE) model (derivation group) to predict survival in our cohort. The model was assessed for discrimination (concordance index), calibration (calibration slope and calibration in the large), and goodness of fit (score test). RESULTS: The VSGNE derivation group consisted of 2367 patients (70% endovascular). Major factors associated with survival in the derivation group were age, coronary disease, chronic obstructive pulmonary disease, renal function, and antiplatelet and statin medication use. Our validation group consisted of 1038 patients (59% endovascular). The validation group was slightly older (74 vs 72 years; P < .01) and had a higher proportion of men (76% vs 68%; P < .01). In addition, the derivation group had higher rates of advanced cardiac disease, chronic obstructive pulmonary disease, and baseline creatinine concentration (1.2 vs 1.1 mg/dL; P < .01). Despite slight differences in preoperative patient factors, 5 year survival was similar between validation and derivation groups (75% vs 77%; P = .33). The concordance index of the validation group was identical between derivation and validation groups at 0.659 (95% confidence interval, 0.63-0.69). Our validation calibration in the large value was 1.02 (P = .62, closer to 1 indicating better calibration), calibration slope of 0.84 (95% confidence interval, 0.71-0.97), and score test of P = .57 (>.05 indicating goodness of fit). CONCLUSIONS: Across different populations of patients, assessment of age and level of cardiac, pulmonary, and renal disease can accurately predict 5-year survival in patients with AAA <6.5 cm undergoing repair. This risk prediction model is a valid method to assess mortality risk in determining potential overall survival benefit from elective AAA repair. PMID- 28807386 TI - No Effect of Pretreatment Breast MRI on the Timing of Surgical Treatment of Newly Diagnosed Breast Cancer. AB - BACKGROUND: Although breast MRI has been shown to be more sensitive in the diagnosis of breast cancer than conventional mammography, one criticism breast MRI has faced in the preoperative treatment planning is that it can delay treatment. METHODS: A retrospective analysis was performed of all women diagnosed and treated for breast cancer over three consecutive years at an American university hospital. The subjects were divided into two groups: those who received preoperative breast MRI and those who did not. There were 189 patients included in this study, of whom 109 (57.67%) received pretreatment breast MRI. RESULTS: Median time to treatment was not significantly different between pretreatment MRI and no pretreatment MRI groups (32 days versus 34.5 days, P = .950). Adjusting for age, detection method, stage, and histology type did not change this conclusion. CONCLUSIONS: At this institution, preoperative breast MRI for patients with newly diagnosed breast cancer seemed to have no significant effect on the timing of surgical treatment in cases of newly diagnosed breast cancer. PMID- 28807387 TI - Financial Education for Radiology Residents: Significant Improvement in Measured Financial Literacy After a Targeted Intervention. PMID- 28807388 TI - Building a Hospital Core Resource for Clinical Research Imaging: Lessons for Driving Change Within Complex Organizations. PMID- 28807389 TI - The opportunity costs of caring for people with dementia in Southern Spain. AB - OBJECTIVE: The aim of this paper is to study the opportunity costs (OC) that are involved in being a caregiver and to compare them with the direct costs assumed by the State and the families. We evaluate direct cost (those that imply a payment-out-of-pocket) and indirect cost (those that imply a dedication in time). We hypothesized that costs increase with the severity of the dementia, with the educational level and active occupational situation of caregiver. They are greater if the caregiver is male, but if the patient and caregiver cohabit they are reduced. METHOD: 778 surveys were analyzed. Data was collected using a questionnaire specifically designed for the purpose, with the collaboration of Alzheimer's Diseases Associations in Andalusia (Spain). For the indirect cost, we used the reveal preferences method. For the comparison between groups an ANOVA and a MANOVA was done. RESULTS: The hypotheses were confirmed. The OC exponentially increases with severity. More than 55% of costs are assumed by families. Occupied people have higher educational level and incomes and contract more external support. Costs are significantly higher for male caregivers. Cohabiting reduces all kinds of costs. CONCLUSIONS: The relationship between educational level and employment situation lead to think that if these variables are greater more people will seek professional support. Cultural reasons still maintain women as main caregivers for all educational levels. The existence of these informal caregivers as the main care providers is a saving for the State, and a brake for the development of professional supply. PMID- 28807390 TI - Vancomycin-resistant Enterococcus faecium ST17 outbreak in a Neonatal Unit. PMID- 28807391 TI - Pelvic inflammatory disease due to Streptococcus pneumoniae. PMID- 28807392 TI - Candidemia and colonization by Candida auris, a diagnostic challenge. PMID- 28807393 TI - Treatment Trends, Effectiveness, and Safety of Statins on Lipid Goal Attainment in Chinese Percutaneous Coronary Intervention Patients: a Multicenter, Retrospective Cohort Study. AB - PURPOSE: Limited data exist on the use of statins in Chinese patients with coronary artery disease (CAD) treated with percutaneous coronary intervention (PCI). We therefore conducted this study to observe the usage trend and the effectiveness of statins on LDL-C goal attainment and other lipid parameters among PCI-treated patients. METHODS: This multicenter, retrospective, observational, longitudinal cohort study was conducted in PCI-treated patients with CAD between July 1, 2011, and February 28, 2015. Primary study outcomes included statin treatment pattern after PCI and proportion of patients achieving target (LDL-C) levels 1 month after PCI and initiating statin therapy. FINDINGS: Data were analyzed for 2708 patients (mean age, 59 [10] years; median body mass index, 25.6 [4.0] kg/m2). From baseline to the end of 1 month, atorvastatin and rosuvastatin were the most prescribed statins; 20 mg and 10 mg were the most prescribed doses and therefore chosen for efficacy comparisons. In patients without dose changes, LDL-C reduction with rosuvastatin 10 mg was significantly greater compared with atorvastatin 20 mg (-0.67 mmol/L [from 2.44 mmol/L to 1.77 mmol/L] vs -0.54 mmol/L [from 2.40 mmol/L to 1.86 mmol/L]; P = 0.008). However, there was no difference in HDL-C, triglyceride, or total cholesterol values between groups. Age and LDL-C levels at baseline were significantly associated with target LDL-C achievement. IMPLICATIONS: In real-world, PCI-treated Chinese patients, atorvastatin and rosuvastatin were the most prescribed statins. Compared with atorvastatin 20 mg, rosuvastatin 10 mg was associated with greater LDL-C reductions and achievement of LDL-C targets in a higher percentage of patients. This analysis of real-world data shows that both rosuvastatin and atorvastatin were well tolerated and seemed to be suitable drugs for controlling lipid levels and preventing CVD risk in post-PCI Chinese patients with CAD. PMID- 28807395 TI - Clinical validation of pinopode as a marker of endometrial receptivity: a randomized controlled trial. AB - OBJECTIVE: To determine the clinical value of pinopodes in the human. DESIGN: Randomized controlled trial. SETTING: Academic fertility center. PATIENT(S): From December 2014 to December 2016, in a phase I trial, 363 patients were recruited in their first IVF cycles. In a phase II trial, 136 patients with at least two previous embryo implantation failures were recruited. INTERVENTION(S): In the phase I trial, in the midluteal phase, endometrial tissues were obtained for scanning electron microscopy, and their IVF treatment outcomes were followed up. In the phase II trial, participants were allocated into two groups by random number table, and the experimental group had twice the number of the control group. Individual ETs (iETs) were performed in the experimental group, while frozen-thawed embryos were routinely transferred in the control group. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate (CPR) and ongoing pregnancy rate (OPR). RESULT(S): In the phase I trial, through receiver operation characteristic curve analysis, the optimal pinopode scoring for successful clinical pregnancy was determined to be 85. The CPR (74.29% vs. 19.77%) and OPR (62.86% vs 11.86%) were significantly higher in the patients whose pinopode scoring was >85. In the phase II trial, the CPR was dramatically higher in the iET group (33.82% vs. 8.11%). CONCLUSION(S): Pinopode scoring is a reliable marker of endometrial receptivity, and iET based on pinopode scoring is a promising solution for recurrent implantation failure. TRIAL REGISTRATION NUMBERS: ChiCTR-OOC-14005617; ChiCTR-OOC-15005882. PMID- 28807396 TI - Polycystic ovary morphology: age-based ultrasound criteria. AB - OBJECTIVE: To determine age-based criteria for polycystic ovary morphology. DESIGN: Cross-sectional, case-control design. SETTING: Outpatient setting. SUBJECT(S): Women with polycystic ovary syndrome (PCOS) defined by hyperandrogenism and irregular menses (n = 544) and controls with regular menses and no evidence of hyperandrogenism (n = 666) participated. Parameters were tested in a second cohort of women with PCOS (n = 105) and controls (n = 32) meeting the same criteria. INTERVENTION(S): Subjects underwent a pelvic ultrasound documenting ovarian volume and maximum follicle number in a single plane. MAIN OUTCOME MEASURE(S): A receiver operating characteristic curve was constructed to determine the ovarian volume and follicle number with the best sensitivity and specificity to define PCOS for age groups at approximately 5-year intervals from age 18 to >44 years. RESULT(S): The best sensitivity and specificity were obtained using a threshold volume of 12 mL and 13 follicles for ages <=24 years, 10 mL and 14 follicles for ages 25-29 years, 9 mL and 10 follicles for ages 30-34 years, 8 mL and 10 follicles for ages 35-39 years, 10 mL and 9 follicles for ages 40-44 years, and 6 mL and 7 follicles for ages >44 years. Data from a second cohort confirmed the need to decrease volume and follicle number with increasing age to diagnose PCOS. Polycystic ovary morphology was most accurate at predicting the PCOS diagnosis for women ages 30-39 years. CONCLUSION(S): The ovarian volume and follicle number threshold to define polycystic ovary morphology should be lowered starting at age 30. PMID- 28807394 TI - Preterm prelabor rupture of the membranes: A disease of the fetal membranes. AB - Preterm prelabor rupture of the membranes (pPROM) remains a significant obstetric problem that affects 3-4% of all pregnancies and precedes 40-50% of all preterm births. pPROM arises from complex, multifaceted pathways. In this review, we summarize some old concepts and introduce some novel theories related to pPROM pathophysiology. Specifically, we introduce the concept that pPROM is a disease of the fetal membranes where inflammation-oxidative stress axis plays a major role in producing pathways that can lead to membrane weakening through a variety of processes. In addition, we report microfractures in fetal membranes that are likely sites of tissue remodeling during gestation; however, increase in number and morphometry (width and depth) of these microfractures in pPROM membranes suggests reduced remodeling capacity of membranes. Microfractures can act as channels for amniotic fluid leak, and inflammatory cell and microbial migration. Further studies on senescence activation and microfracture formation and their role in maintaining membrane homeostasis are needed to fill the knowledge gaps in our understanding of pPROM as well as provide better screening (biomarker and imaging based) tools for predicting women at high risk for pPROM and subsequent preterm birth. PMID- 28807397 TI - Colorectal endometriosis-associated infertility: should surgery precede ART? AB - OBJECTIVE: To compare the impact of first-line assisted reproductive technology (ART; intracytoplasmic sperm injection [ICSI]-IVF) and first-line colorectal surgery followed by ART on fertility outcomes in women with colorectal endometriosis-associated infertility. DESIGN: Retrospective matched cohort study using propensity score (PS) matching (PSM) analysis. SETTING: University referral centers. PATIENT(S): A total of 110 women were analyzed from January 2005 to June 2014. A PSM was generated using a logistic regression model based on the age, antimullerian hormone (AMH) serum level, and presence of adenomyosis to compare the treatment strategy. INTERVENTION(S): First-line surgery group followed by ART versus exclusive ART with in situ colorectal endometriosis. MAIN OUTCOME MEASURE(S): After PSM, pregnancy rates (PRs), live-birth rates (LBRs), and cumulative rates (CRs) were estimated. RESULT(S): After PSM, in the whole population, the total LBR and PR were 35.4% (39/110) and 49% (54/110), respectively. The specific cumulative LBR at the first ICSI-IVF cycle in the first-line surgery group compared with the first-line ART was, respectively, 32.7% versus 13.0%; at the second cycle, 58.9% versus 24.8%; and at the third cycle, 70.6% versus 54.9%. The cumulative LBRs were significantly higher for women who underwent first-line surgery followed by ART compared with first-line ART in the subset of women with good prognosis (age <= 35 years and AMH >= 2 ng/mL and no adenomyosis) and women with AMH serum level < 2 ng/mL. CONCLUSION(S): First-line surgery may be a good option for women with colorectal endometriosis-associated infertility. PMID- 28807398 TI - Which Latitudinal Gradients for Genetic Diversity? AB - A recent global analysis of GenBank DNA sequences from amphibians and mammals indicated consistent poleward decrease of intraspecific genetic diversity in both classes. We highlight that this result was biased by not accounting for distance decay of similarity and reanalyse the datasets, revealing distinct latitudinal gradients in mammals and amphibians. PMID- 28807399 TI - Wound Closure, Tension-Relieving Techniques, and Local Flaps. AB - Wounds are often addressed by primary or delayed primary closure. Although many skin wounds could go on to heal by second intention, this results in a less cosmetic outcome, takes longer, and in the long run, is often more expensive. As a general rule, the simplest method of wound closure that is likely to succeed should be chosen. If tension is present at the wound edges, wound dehiscence is likely to occur. Using specific techniques to relieve tension on wound edges and recruiting local flaps from neighboring regions are useful ways to achieve wound closure. PMID- 28807400 TI - IncX3 plasmid harboring a non-Tn4401 genetic element (NTEKPC) in a hospital associated clone of KPC-2-producing Klebsiella pneumoniae ST340/CG258. AB - IncX-type plasmids have achieved clinical significance for their contribution in the dissemination of genes confering resistance to carbapenems (most blaKPC- and blaNDM-type genes) and polymyxins (mcr-type genes), both antibiotics considered last resort for multidrug-resistant Gram-negative infections. In this study, we report the identification and complete sequence analysis of an IncX3 plasmid (designated pKP1194a) carrying a non-Tn4401 genetic element (NTEKPC) of tnpR-tnpA (partial)-blaKPC-2-DeltaISKpn6/traN, originating from a hospital-associated lineage of K. pneumoniae belonging to the ST340/CG258, with epidemiological link to Brazil. PMID- 28807401 TI - Newer GFR Estimating Equations Require Validation in Different Populations. PMID- 28807402 TI - In Reply to 'Newer GFR Estimating Equations Require Validation in Different Populations'. PMID- 28807403 TI - Prevalence of Hyperuricemia in Patients With Acute Heart Failure With Either Reduced or Preserved Ejection Fraction. AB - The relation between uric acid (UA) and heart failure has been described; however, there is little detail concerning acute heart failure (AHF) in patients with reduced versus preserved ejection fraction heart failure (HFrEF, HFpEF). We studied 324 consecutive AHF patients screened from interventional Diur-HF Trial (NCT01441245) from January 2011 to February 2016, and divided into HFrEF (EF <50%) and HFpEF (EF >=50%). We defined hyperuricemia as serum UA >=7.0 mg/dL in men and >=6 mg/dL in women. Patients were followed up for 6 months after discharge. The primary outcome was heart failure hospitalization or death. Among 173 HFrEF and 151 HFpEF cases, hyperuricemia was found in 43% and 57%, respectively (p = 0.01). Hyperuricemia was also more frequent in women (74% vs 60%; p = 0.008), those with diabetes (39% vs 19%; p <0.001), hypertension (62% vs 43%; p = 0.001), and atrial fibrillation (48% vs 34%; p = 0.01). In patients with HFrEF, univariate analysis found that hyperuricemia (hazard ratio [HR] 1.48, 95% confidence interval [CI] 1.02 to 2.15; p = 0.04) and congestion score >=3 (HR 2.83, 95% CI 1.52 to 5.28; p <0.001) were associated with the primary end point; after adjustment, only congestion score >=3 (HR 2.08, 95% CI 1.06 to 4.10; p = 0.03) confirmed this trend. Conversely, in patients with HFpEF, hyperuricemia was the only significant predictor of the primary end point both in univariate (HR 2.25, 95% CI 1.44 to 3.50; p <0.001) and multivariate analyses (HR 2.38, 95% CI 1.32 to 4.28; p = 0.004). In conclusion, in AHF hyperuricemia is common in both in HFrEF and in HFpEF. In the HFpEF subgroup, hyperuricemia was the only independent predictor of heart failure hospitalization or death. PMID- 28807404 TI - Prognostic Usefulness of Cardiac Stress Test Modalities in Patients With Type 2 Diabetes Mellitus Who Underwent Myocardial Perfusion Scintigraphy (from the Basel Asymptomatic High-Risk Diabetics' Outcome Trial). AB - Our study aimed to assess predictors of the stress test technique used and to evaluate the impact of exercise level achieved on risk stratification in patients with asymptomatic type 2 diabetes without a previous coronary artery disease. Little is known whether co-morbidities of these patients predict the stress technique and whether physical performance provides risk stratification: 400 patients underwent clinical evaluation and myocardial perfusion scintigraphy (MPS) using physical or pharmacological stress. Physical patients were divided into 2 groups: achieving <6 and >=6 METs, respectively. The mean follow-up time was 2 years. Major cardiac events (MACEs) included myocardial infarction and/or cardiac death. Independent predictors of pharmacological stress were a body mass index of >30 kg/m2 (hazard ratio 1.076, 95% confidence interval 1.027 to 1.127, p = 0.002) and a peripheral arterial disease (hazard ratio 2.888, 95% confidence interval 1.446 to 5.769, p = 0.003). Pharmacological patients had more MACE than physical patients (3.2% vs 1.0%, p = 0.03). Patients achieving <6 METs had a similar MACE rate as pharmacological patients (3.0% vs 3.2%, p = not significant) and more MACE than patients achieving >=6 METs (3.0% vs 0.4%, p = 0.01). In patients achieving <6 METs and in pharmacological patients, MPS added an incremental prognostic value to pretest information (p values for global chi square 0.012 and 0.04, respectively). In high-risk asymptomatic diabetic patients, co-morbidities were predictive of the stress technique used. Pharmacological patients had more MACE, similar to those unable to achieve 6 METs. MPS provided an incremental prognostic value in pharmacological patients and in patients with <6METs. In contrast, patients who were able to achieve >=6 METs were at low risk and do not need further risk stratification. PMID- 28807405 TI - Initiation of a Multidisciplinary, Rapid Response Team to Massive and Submassive Pulmonary Embolism. AB - Pulmonary embolism (PE) can result in rapid clinical decompensation in many patients. With increasing patient complexity and advanced treatment options for PE, multidisciplinary, rapid response teams can optimize risk stratification and expedite management strategies. The Massive And Submassive Clot On-call Team (MASCOT) was created at our institution, which comprised specialists from cardiology, pulmonology, hematology, interventional radiology, and cardiac surgery. MASCOT offers rapid consultation 24 hours a day with a web-based conference call to review patient data and discuss management of patients with high-risk PE. We reviewed patient data collected from MASCOT's registry to analyze patient clinical characteristics and outcomes and describe the composition and operation of the team. Between August 2015 and September 2016, MASCOT evaluated 72 patients. Seventy of the 72 patients were admitted to our institution, accounting for 32% of all patients discharged with a primary diagnosis of PE. Average age was 62 +/- 17 years with a female predominance (63%). Active malignancy (31%), recent surgery or trauma (21%), and recent hospitalization (24%) were common. PE clinical severity was massive in 16% and submassive in 83%. Patients were managed with anticoagulation alone in 65% (n = 46), systemic fibrinolysis in 11% (n = 8), catheter-directed therapy in 18% (n = 13), extracorporeal membrane oxygenation in 3% (n = 2), and an inferior vena cava filter was placed in 15% (n = 11). Thirteen percent (n = 9) experienced a major bleed with no intracranial hemorrhage. Survival to discharge was 89% (64% with massive PE and 93% with submassive PE). In conclusion, multidisciplinary, rapid response PE teams offer a unique coordinated approach to patient care. PMID- 28807406 TI - Longitudinal Changes in Segmental Aortic Stiffness Determined by Cardiac Magnetic Resonance in Children and Young Adults With Connective Tissue Disorders (the Marfan, Loeys-Dietz, and Ehlers-Danlos Syndromes, and Nonspecific Connective Tissue Disorders). AB - Aortic stiffness measured by cardiac magnetic resonance (CMR) in connective tissue disorder (CTD) patients has been previously shown to be abnormal and to be associated with adverse aortic outcomes. The rate of increase in aortic stiffness with normal aging has been previously described. However, longitudinal changes in aortic stiffness have not been characterized in CTD patients. We examined longitudinal changes in CMR-derived aortic stiffness in children and young adults with CTDs. A retrospective analysis of 50 children and young adults (median age, 20 years; range, 0.2 to 49; 40% < 18 years old) with a CTD, and with at least 2 CMR examinations (total 152 examinations) over a median duration of 3.9 (1 to 13.2) years was performed. Aortic stiffness measures (strain, distensibility, and beta stiffness index) were calculated on each examination at the aortic root (AoR), ascending aorta, and descending aorta. Longitudinal changes in parameters were analyzed using linear mixed-effects models. Aortic strain and distensibility decreased with age, whereas the beta stiffness index increased at all aortic segments. The average rates of decline in distensibility (x10-3 mm Hg-1 per 10 year increase in age) were 0.7, 1.3, and 1 at the AoR, ascending aorta, and descending aorta, respectively. The rates of decline in distensibility were not associated with the rates of AoR dilation or surgical AoR replacement. In conclusion, on serial CMR measurements in children and young adults with CTDs, aortic stiffness progressively increased with age, with rates of change only slightly higher than those previously reported in healthy adults. PMID- 28807407 TI - Infrarenal aorta as the donor site for bypasses to the superior mesenteric artery for chronic mesenteric ischemia: A prospective clinical series of 24 patients. AB - BACKGROUND: Treatment of symptomatic, chronic mesenteric ischemia is indicated to relieve symptoms and prevent acute ischemia and death. Current therapeutic options include endovascular and open surgery. The purpose of this prospective study was to evaluate the results of bypasses to the superior mesenteric artery arising from the infrarenal aorta or infrarenal aortic grafts. METHODS: From January 1999 to December 2016, 24 consecutive patients with a mean age of 61 years underwent a prosthetic bypass to the superior mesenteric artery. Nine patients (37%) presented with an associated clinically important stenosis of the celiac artery and 10 (42%) of the inferior mesenteric artery. Five patients (21%) received preoperative parenteral nutrition. Four patients (17%) underwent dual antiplatelet treatment. The donor site was the infrarenal aorta in 19 patients (79%) and an infrarenal, Dacron graft was used in 5 (21%). The origin of the bypass was from the distal infrarenal aorta or Dacron graft in 19 patients (79%) and from the proximal infrarenal aorta in 5 patients (21%). The graft material consisted of 7 mm polytetrafluoroethylene in 19 cases (79%) and 7 mm Dacron in 5 cases (21%). A concomitant bypass to the inferior mesenteric artery was performed in 4 patients (17%). The primary end points were postoperative mortality, morbidity, graft infection, late survival, primary patency, and symptom-free rate. The secondary end point was postoperative hemorrhagic complications. RESULTS: No postoperative mortality occurred. Postoperative morbidity included a prolonged postoperative ileus in 4 patients (17%), transitory postoperative increases in serum creatinine concentrations in 3 patients (12%), and myocardial ischemia in 2 patients (8%). No postoperative hemorrhagic complications or graft infection were observed. Overall, the cumulative survival rate was 77% at 60 months. The overall late-patency rate and freedom from recurrence of symptoms were both 87% at 60 months. CONCLUSION: Infrarenal aorta and infrarenal aortic grafts are an excellent source for the revascularization of the superior mesenteric artery. Bypasses to the superior mesenteric artery from the infrarenal aorta, either isolated or associated with adjunctive bypass to the inferior mesenteric artery, yield results that are comparable with those obtained with complete digestive artery revascularization using other donor sources. PMID- 28807409 TI - A decade of imaging surgeons' brain function (part I): Terminology, techniques, and clinical translation. AB - BACKGROUND: Functional neuroimaging has the potential to deepen our understanding of technical and nontechnical skill acquisition in surgeons, particularly as established assessment tools leave unanswered questions about inter-operator differences in ability that seem independent of experience. METHODS: In this first of a 2-part article, we aim to utilize our experience in neuroimaging surgeons to orientate the nonspecialist reader to the principles of brain imaging. Terminology commonly used in brain imaging research is explained, placing emphasis on the "activation response" to an surgical task and its effect on local cortical hemodynamic parameters (neurovascular coupling). RESULTS: Skills learning and subsequent consolidation and refinement through practice lead to reorganization of the functional architecture of the brain (known as "neuroplasticity"), evidenced by changes in the strength of regional activation as well as alterations in connectivity between brain regions, culminating in more efficient use of neural resources during task performance. CONCLUSION: Currently available neuroimaging techniques that either directly (ie, measure electrical activity) or indirectly (ie, measure tissue hemodynamics) assess brain function are discussed. Finally, we highlight the important practical considerations when conducting brain imaging research in surgeons. PMID- 28807408 TI - Reply to a letter to the editor regarding the International Study Group on Pancreatic Surgery definition and classification of chyle leak after pancreatic operation. PMID- 28807410 TI - Macrofaunal community structure in Bahia Concepcion (Chile) before and after the 8.8 Mw Maule mega-earthquake and tsunami. AB - Faunal assemblages of subtidal sedimentary environments are key components of coastal ecosystems. Benthic communities inhabiting the coastal zone near urban centers in Concepcion Bay (Chile) have been described as highly disturbed (i.e. impoverished in diversity and species richness). This is due to the frequent presence of hypoxic conditions at the bottom due to the intrusion of low oxygen Equatorial Subsurface Water, high natural productivity and the high load of organic matter generated by several anthropogenic activities. A mega-earthquake (8.8 Mw) and subsequent tsunami occurred on the coast of south-central Chile on February 27, 2010 (27F), heavily impacting Concepcion Bay, which is located 30 km south of the epicenter. The objectives of the present study are: (i) to evaluate the effect produced by the mega-earthquake and tsunami on the benthic community, and (ii) to assess dissimilarity in macrofauna composition and abundance in Concepcion Bay at an inter-decadal time scale based on a comparison between our sampling conducted between 2010 and 2013 and information published since 1969. Our results show that the benthic macrofauna of Concepcion Bay was disturbed by the 27F (i.e. high community dissimilarity in 2010). Changes in community structure were observed at an inter-annual scale (i.e. diminished community dissimilarity in 2013), suggesting a recovery post-27F. At an inter-decadal scale, community structure post-27F was dissimilar to the structure described for the 1980's and 1990's but more similar to that reported for 1969. The reducing conditions of the sediments due to the high input of organic matter that took place in the 1980's and 1990's may explain this dissimilarity. PMID- 28807411 TI - TIMP3 is Regulated by Pericytes upon Shear Stress Detection Leading to a Modified Endothelial Cell Response. AB - OBJECTIVES: Atherosclerosis is a hallmark of cardiovascular disease. Shear stress on endothelial cells has been linked to atherogenesis and to fibrous cap thinning and rupture. Pericytes reside in the sub-endothelial space of vessels and have vasoprotective effects. They are subjected to shear stress when endothelial cell integrity is disrupted. The aim was to investigate the susceptibility and response of pericytes to shear stress. METHODS: Endothelial cells and pericytes were seeded in two dimensional monocultures and co-cultures, and in a novel three dimensional co-culture system and were subjected to no, low and high shear stress (0, 10, 30 dyne/cm2) for 48 h. The morphological response to flow was assessed by histology and the expression of extracellular matrix proteins was analysed using quantitative polymerase chain reaction, immunoblotting, and ELISA. RESULTS: While endothelial cells aligned into flow direction, pericytes aligned perpendicularly (p < .001), indicating that they must be capable of sensing flow. When pericytes were embedded into a 3D matrix they showed similar alignment and pericytes built long processes towards the lumen. Under shear stress endothelial cells upregulated "a disintegrin and metalloproteinase with thrombospondin motif 1" (ADAMTS-1) (p < .01) and pericytes upregulated "tissue inhibitor of matrix metalloproteinase" (TIMP) 3 (p < .05), an inhibitor of ADAMTS-1, meanwhile differential expression of extracellular matrix (ECM) proteins could be detected in co-cultures of both cells. For TIMP3 expression direct cell-cell contact between endothelial cells and pericytes was required. CONCLUSION: The experiments highlight that pericytes are able to sense direct flow thereby regulating ECM proteins known to be involved in vascular remodelling. Furthermore, pericytes counter-regulate endothelial ADAMTS-1 by protective TIMP3 expression to prevent matrix degradation and maintain vascular stability. For this protective effect direct cell contact was necessary. This observation might represent an adaptive, protective mechanism of pericytes to counteract endothelial damage in the onset of atherosclerosis. PMID- 28807412 TI - Recruitment rates in orthopaedic trauma trials: Zen or the art of riding dead horses. PMID- 28807413 TI - Corrigendum to "A portable low-cost long-term live-cell imaging platform for biomedical research and education" [Biosens. Bioelectron. 64 (2015) 639-649]. PMID- 28807414 TI - Transient receptor potential vanilloid 4-expressing macrophages and keratinocytes contribute differentially to allergic and nonallergic chronic itch. AB - BACKGROUND: Chronic itch is a highly debilitating symptom that underlies many medical disorders with no universally effective treatments. Although unique neuronal signaling cascades in the sensory ganglia and spinal cord have been shown to critically promote the pathogenesis of chronic itch, the role of skin associated cells remains poorly understood. OBJECTIVE: We sought to examine the cutaneous mechanisms underlying transient receptor potential vanilloid 4 (TRPV4) mediated allergic and nonallergic chronic itch. METHODS: Expression of TRPV4 in chronic itch and healthy control skin preparations was examined by using real time RT-PCR. Trpv4eGFP mice were used to study the expression and function of TRPV4 in the skin by means of immunofluorescence staining, flow cytometry, calcium imaging, and patch-clamp recordings. Genetic and pharmacologic approaches were used to examine the role and underlying mechanisms of TRPV4 in mouse models of dry skin-associated chronic itch and spontaneous scratching associated with squaric acid dibutylester-induced allergic contact dermatitis. RESULTS: TRPV4 is selectively expressed by dermal macrophages and epidermal keratinocytes in mice. Lineage-specific deletion of TRPV4 in macrophages and keratinocytes reduces allergic and nonallergic chronic itch in mice, respectively. Importantly, TRPV4 expression is significantly increased in skin biopsy specimens from patients with chronic idiopathic pruritus in comparison with skin from healthy control subjects. Moreover, TRPV4-dependent chronic itch requires 5-hydroxytryptamine (5 HT) signaling secondary to activation of distinct 5-HT receptors in mice with allergic and those with nonallergic chronic itch conditions. CONCLUSION: Our study reveals previously unrecognized mechanisms by which TRPV4-expressing epithelial and immune cells in the skin critically and dynamically mediate chronic itch and unravels novel targets for therapeutics in the setting of chronic itch. PMID- 28807415 TI - The impact of seismic air gun exposure on the haemolymph physiology and nutritional condition of spiny lobster, Jasus edwardsii. AB - There is a critical knowledge gap regarding the impacts of seismic air gun signals on the physiology of adult crustaceans. We conducted four controlled field experiments to examine the impact of seismic acoustic signals on spiny lobster, Jasus edwardsii. Seismic air gun exposure suppressed total haemocyte count (THC) for up to 120days post-exposure, suggesting a chronic negative impact of immune competency. THC levels after 365days post-exposure, were elevated two fold, potentially indicating an immune response to infection. Haemolymph refractive index was reduced after 120days post exposure in one experiment, suggesting a chronic impairment of nutritional condition. There was no effect of air gun exposure on 24 haemolymph biochemical parameters, hepatopancreas index or survival. Collectively these results indicate that the biochemical haematological homeostasis of J. edwardsii is reasonably resilient to seismic acoustic signals, however, air gun exposure may negatively influence the lobster's nutritional condition and immunological capacity. PMID- 28807416 TI - Phthalates, heavy metals and PAHs in an overpopulated coastal region: Inferences from Abruzzo, central Italy. AB - Phthalates are an emerging class of environmental pollutants whose distribution and effects in aquatic environments are not well characterized. We analyzed intertidal and emerged beach sediments from the Abruzzo coastline, along the Adriatic Sea, finding significant phthalate concentrations in marine sediments. Phthalate baseline levels in the intertidal environment, marked by substantial interplay of sediment, water and air, were determined. We used statistical rank methods to select representative phthalate compositions, for which we derived risk levels for ingestion, dermal absorption and inhalation. Our study shows that phthalates are a major cause of pollution along the Abruzzo coast, with river transport of sediments a continuous source of replenishment. Phthalate concentrations in two specific sites were determined to be of the same order of magnitude as the safety, remediation-warranting, threshold set by Italian law. Phthalates, heavy metals, PAHs appear to be correlated. We discuss possible intervention and mitigation strategies. PMID- 28807417 TI - Fate and stability of polyamide-associated bacterial assemblages after their passage through the digestive tract of the blue mussel Mytilus edulis. AB - We examined whether bacterial assemblages inhabiting the synthetic polymer polyamide are selectively modified during their passage through the gut of Mytilus edulis in comparison to the biopolymer chitin with focus on potential pathogens. Specifically, we asked whether bacterial biofilms remained stable over a prolonged period of time and whether polyamide could thus serve as a vector for potential pathogenic bacteria. Bacterial diversity and identity were analysed by 16S rRNA gene fingerprints and sequencing of abundant bands. The experiments revealed that egested particles were rapidly colonised by bacteria from the environment, but the taxonomic composition of the biofilms on polyamide and chitin did not differ. No potential pathogens could be detected exclusively on polyamide. However, after 7days of incubation of the biofilms in seawater, the species richness of the polyamide assemblage was lower than that of the chitin assemblage, with yet unknown impacts on the functioning of the biofilm community. PMID- 28807418 TI - Assessment of metallic trace elements in the muscles and fins of four landed elasmobranchs from Kuala Terengganu Waters, Malaysia. AB - A study had been carried out to determine Cu, Zn, Cd, Hg and Pb concentrations in the muscle and fins of four elasmobranchs species namely spot-tail sharks, milk sharks, whitespotted bamboo sharks and whitespotted guitarfish from Pulau Kambing LKIM Fishery Complex, Kuala Terengganu, Malaysia. Zinc level was found to have the highest concentration whereas Cd had the lowest concentration in both organs. By comparing both organs, metals concentrations in fins of all elasmobranchs species were higher than muscle. Result obtained was compared with the guidelines set by Malaysian Food Regulation and the provisional tolerable weekly intake was also determined. Current study recommends that the muscle of whitespotted bamboo shark from Kuala Terengganu Waters is likely not to be consumed due to it exceeded the allowable consumption guideline. Finding of this paper is very useful as it provides the baseline data on the pollution status of elasmobranchs in Kuala Terengganu Waters. PMID- 28807419 TI - A method to assess the evolution and recovery of heavy metal pollution in estuarine sediments: Past history, present situation and future perspectives. AB - A methodology to assess the historical evolution and recovery of heavy metal pollution in estuarine sediments was developed and is presented here. This approach quantifies the distribution of heavy metals in sediment cores, and investigates the influence of anthropogenic activities and/or core locations on the heavy metal pollution, by proposing and using sediment quality indices and polynomial regressions. The method has been applied to the Suances Estuary confirming its suitability as a comprehensive and practical management tool. In this estuary, the evolution of heavy metal pollution (since 1997-1998 to 2015) pointed out the deeper the sediments, the more polluted, indicating a recovery at the upper layers due to the closure and ending of washing discharges from mining, and the reduction of metal loads from industrial wastewaters. In terms of global pollution, the intertidal and subtidal sediments will require 43.1+/-2.8 and 8.6+/-0.6years to be unpolluted, respectively. PMID- 28807420 TI - How the dispersant Corexit impacts the formation of sinking marine oil snow. AB - The vertical transport of sinking marine oil snow (MOS) and oil-sediment aggregations (OSA) during the Deepwater Horizon (DwH) spill contributed appreciably to the unexpected, and exceptional accumulation of oil on the seafloor. However, the role of the dispersant Corexit in mediating oil sedimentation is still controversial. Here we demonstrate that the formation of diatom MOS is enhanced by chemically undispersed oil, but inhibited by Corexit dispersed oil. Nevertheless, the sedimentation rate of oil may at times be enhanced by Corexit application, because of an elevated oil content per aggregate when Corexit is used. A conceptual framework explains the seemingly contradictory effects of Corexit application on the sedimentation of oil and marine particles. The redistribution of oil has central ecological implications, and future decisions on mediating measures or damage assessment will have to take the formation of sinking, oil-laden, marine snow into account. PMID- 28807421 TI - Seagrass science is growing: A report on the 12th International Seagrass Biology Workshop. AB - This conference report describes the programme of the 12th International Seagrass Biology Workshop, its highlights, areas of growth for the workshop, and potential future directions for the workshop series. The report is written with an eye toward where it fits within the field of seagrass research. PMID- 28807422 TI - Assessment of heavy metal pollution in surficial sediments from a tropical river estuary-shelf system: A case study of Kelantan River, Malaysia. AB - To understand the source-to-sink of pollutants in the Kelantan River estuary and the adjacent shelf area in Malaysia, a total of 42 surface sediment samples were collected in the Kelantan River-estuary-shelf system to analyze for grain size, total organic carbon (TOC) content, Al and heavy metals (Cr, Ni, Cu, Zn, Cd and Pb). The surficial sediments were mainly composed of clayey silt and the TOC content in sediments decreased from the river to the shelf. The surficial sediments experienced Pb pollution; Cr only showed a certain level of pollution in the coastal area of the estuary but not in other areas, and Ni, Cu, Zn, and Cd showed no pollution. The heavy metals mainly originated from natural weathering and erosion of rocks and soils in the catchment and enriched near the river mouth. Total organic carbon can promote the enrichment of heavy metals in sediments. PMID- 28807423 TI - Coping with the Stress in the Cardiac Intensive Care Unit: Can Mindfulness Be the Answer? AB - BACKGROUND: Mothers of infants with complex congenital heart disease are exposed to increased stress which has been associated with numerous adverse health outcomes. The coping mechanisms these mothers use critically effect the familial illness adaptation and most likely infant outcomes. Currently no data-based strategies have been developed for mothers to facilitate their coping, and proactively promote their adaptation in the critical care settings. A potential strategy is mindfulness which is currently used in other clinical settings with stress-reduction effects. PURPOSE: (1) To investigate coping mechanisms of mothers whose infant with complex CHD is admitted in the CICU, and (2) to explore the acceptability and feasibility of mindfulness as a potential stress-reduction intervention for these mothers. DESIGN AND METHODS: A descriptive qualitative study obtained perspectives from 14 mothers during three focus groups. A qualitative conventional content analysis was performed using ATLAS.ti. RESULTS: In congruence with the Stress and Coping framework, themes identified mostly emotion-regulatory coping mechanisms including both active and passive strategies such as positive thinking, denial, distraction, relying on support systems, and focusing on baby. Mindfulness was an acceptable and feasible approach for most participants, however, practice unfamiliarity, time and space concerns, and personal preferences were identified as potential barriers for future dissemination. CONCLUSIONS: Mindfulness can potentially promote illness adaptation by utilization of active coping mechanisms. Early interventions can provide immediate, and potentially long-term stress relief. Intervention settings, format, and time-frame should be flexibly tailored to the trajectory of parental distress and familial adjustment. PMID- 28807424 TI - A national collaborative approach to reduce catheter-associated urinary tract infections in nursing homes: A qualitative assessment. AB - BACKGROUND: Reducing health care-associated infections (HAIs), such as catheter associated urinary tract infection (CAUTI), is a critical performance improvement target in nursing homes. The Agency for Healthcare Research and Quality Safety Program for Long-term Care: Health Care-Associated Infections/Catheter-Associated Urinary Tract Infection, a national performance improvement program, was designed to promote implementation of a CAUTI prevention program through state-based or regional collaboratives in more than 500 nursing homes across the United States. METHODS: Qualitative interviews were conducted with 8 purposefully selected organizational leads (who led implementation activities for a group of facilities) and 8 facility leads (who led implementation activities at a given facility) to understand implementation successes and challenges and experiences of participants involved in the program. Key themes were identified using a rapid analysis approach. RESULTS: Key themes related to general perceptions, changes due to program participation, and factors influencing program implementation were identified. In general, the program was viewed positively by organizational and facility leads with changes in catheter care practices, staff empowerment, and improvements in knowledge identified as benefits. Implementation challenges included the time required for program start-up as well as issues with staff and physician support, logistic barriers, and staffing turnover. CONCLUSIONS: Despite some challenges, the observed program success and positive views of those participating suggest that collaboratives are an important strategy for providing nursing homes with enhanced expertise and support to prevent HAIs and ensure resident safety. PMID- 28807425 TI - Clinical outcome of dual colistin- and carbapenem-resistant Klebsiella pneumoniae bloodstream infections: A single-center retrospective study of 75 cases in India. AB - In this study, we retrospectively evaluated clinical outcomes of 75 patients with dual colistin- and carbapenem-resistant Klebsiella pneumoniae bloodstream infections over a 5-year period in a single tertiary care hospital in India. We observed a high in-hospital mortality rate of 69.3%. Our findings indicate the urgent need for new antibiotics to treat these infections. PMID- 28807426 TI - Clinical usefulness of catheter-drawn blood samples and catheter tip cultures for the diagnosis of catheter-related bloodstream infections in neonatology: A systematic review. AB - OBJECTIVES: Neonatal sepsis is the most frequent health care-associated infection in neonatal units. This study aimed to analyze articles on the clinical usefulness of catheter-drawn blood samples and catheter tip cultures for the diagnosis of intravascular catheter-related bloodstream infection (CRBSI) in neonates. METHODS: A systematic search was performed for studies published from 1987-2017, without language restriction. Observational studies carried out in neonates with CRBSI diagnosed using catheter-drawn blood samples or catheter tip cultures were included. RESULTS: A total of 412 articles were identified in the databases and 10 articles were included. The 7 studies that evaluated central venous catheter tip cultures and cultures of catheter fragments presented sensitivities ranging from 58.5%-100% and specificities ranging from 60%-95.7%. Three studies that evaluated catheter-drawn blood cultures, paired with peripheral blood cultures, reported sensitivity and specificity of 94% and 71% when evaluated for the differential time to positivity. When quantitative evaluation was performed, the sensitivity and specificity were 80% and 99.4%. CONCLUSIONS: Most of the studies analyzed cultures from the central venous catheter tip and catheter fragments for the diagnosis of CRBSI in neonatal populations. The results of this review suggest that the analysis of the catheter drawn blood samples and catheter tip cultures, paired with peripheral blood cultures, are efficient methods for the diagnosis of CRBSI in neonates. PMID- 28807427 TI - Paediatric fracture clinic re-design: Incorporating a virtual fracture clinic. AB - INTRODUCTION: The use of virtual fracture clinics (VFCs) and home management protocols is increasing. The main aim of this research is to determine whether a paediatric home management programme and VFC can be used safely to manage a range of suitable fractures in children. MATERIALS AND METHODS: Protocols for the home management of stable paediatric fractures were designed by two consultant paediatric orthopaedic surgeons. These were for children between the ages of 18 months and 15 years 364 days. A new tariff was negotiated with the clinical commissioning groups (CCGs) for a VFC new patient review. A prospective analysis was performed for the first 2 months of the programme. Further review periods were undertaken 6 months later and 12 months after that. RESULTS: Sixty-five patients were reviewed in the first 10 VFCs (mean 6.5 cases per week). After 6 months, 164 patients were reviewed in a 3-month period in the VFC, a mean of 11 cases per week. A year later the number of patients reviewed in the VFC had continued to increase with a total of 253 patients in 3 months, mean 21 cases per week. This gave a saving to the CCG of L45,000 per year and to the hospital of L106,000 per year. There were no serious adverse consequences to any patients from the use of the pathway. DISCUSSION AND CONCLUSION: We have reported on the introduction of a paediatric VFC and a home management programme for stable paediatric fractures. We are not aware of any reports in the orthopaedic literature that have described such a comprehensive and innovative re organisation of paediatric fracture services. We estimate that the NHS could save approximately L10.1 million if all hospitals in England introduced this. PMID- 28807428 TI - Decreased mortality in patients with isolated severe blunt traumatic brain injury receiving higher plasma to packed red blood cells transfusion ratios. AB - INTRODUCTION: Higher transfusion ratios of plasma to packed red blood cells (PRBC) and platelets (PLT) to PRBC have been shown to be associated with decreased mortality in major trauma patients. However, little is known about the effect of transfusion ratios on mortality in patients with isolated severe traumatic brain injury (TBI). The aim of this study was to investigate the effect of transfusion ratios on mortality in patients with isolated severe blunt TBI. We hypothesized that higher transfusion ratios of plasma to PRBC and PLT to PRBC are associated with a lower mortality rate in these patients. METHODS: Retrospective observational study. Patients with isolated severe blunt TBI (AIS head>=3, AIS extracranial <3) admitted to an urban level I trauma centre were included. Clinical data were extracted from the institution's trauma registry, blood transfusion data from the blood bank database. The effect of higher transfusion ratios on in-hospital mortality was analysed using univariate and multivariable regression analysis. RESULTS: A total of 385 patients were included. Median age was 32 years (IQR 2-50), 71.4% were male, and 76.6% had an ISS>=16. Plasma:PRBC transfusion ratios>=1 were identified as an independent predictor for decreased in-hospital mortality (adjusted OR 0.43 [CI 0.22-0.81]). PLT:PRBC transfusion ratios>=1 were not significantly associated with mortality (adjusted OR 0.39 [CI 0.08-1.92]). CONCLUSION: This study revealed plasma to PRBC transfusion ratios>=1 as an independent predictor for decreased in-hospital mortality in patients with isolated severe blunt TBI. PMID- 28807429 TI - The incidence and trauma mechanisms of acetabular fractures: A nationwide study in Finland between 1997 and 2014. AB - PURPOSE: Information on the incidence of acetabular fractures of the pelvis is limited. Epidemiological data is often based on specific trauma registers, individual trauma centres or on trends of all pelvic fractures grouped together. The primary aim of this study was to determine the incidence and trends of hospital-treated acetabular fractures in the Finnish population from 1997 to 2014. The secondary aim was to assess the trauma mechanisms involved. METHODS: The Finnish National Hospital Discharge Register collects inpatient data from all public and private medical institutions in Finland and covers the entire Finnish population of 5.5 million. For this study, we selected all persons 18 years of age or older who were admitted to hospital for the treatment of an acetabular fracture between 1997 and 2014. The main outcome variable was the annual number of patients hospitalised with a main or secondary diagnosis of acetabular fracture of the pelvis. RESULTS: The overall crude incidence of acetabular fractures increased slightly (from 6.4/100 000 persons/year to 8.1/100 000 persons/year) from 1997 to 2014 while the age-standardised incidence rate remained at a similar level (7.1/100 000/persons/year in 1997 and 7.2/100 000/persons/year in 2014). An incidence increase was observed in the elderly population, whereas the incidence of acetabular fractures in the younger population (mostly high energy traumas) remained stable. The most frequent trauma mechanism for acetabular fractures was fall on the same level (47%). CONCLUSIONS: The incidence of acetabular fractures increased slightly in Finland between 1997 and 2014. This increase was observed especially in the elderly population and the ageing of the population largely explains the rise. The incidence of acetabular fractures in the younger population decreased. The most common trauma mechanism was falling on the same level. PMID- 28807430 TI - Letter to the editor concerning "Factors associated with pain intensity and physical limitations after lateral ankle sprains". PMID- 28807431 TI - A prospective analysis of injury rates, patterns and causes in Cliff and Splash Diving. AB - INTRODUCTION: Information about injuries and its differences in Cliff Diving (CD) and Splash Diving (SD) are unknown. It was the aim to analyse (1) injury rates, patterns and causes; (2) differences (in injuries) between both disciplines; and to (3) identify targets for future injury prevention interventions. METHODS: From April to November 2013, 81 cliff and 51 splash divers were prospectively surveyed with an encrypted, monthly e-mail-based questionnaire. RESULTS: During a total of 7857h diving with an average diving height of 13 (+/-7)m, an overall injury rate of 7.9 injuries/1000h of sport exposure was reported. Cliff divers most commonly suffered from injuries of the foot and ankle (18%; n=24) and neck and cervical spine (14%; n=19). In SD, the lower limb (52%; n=43) and lower back (23%; n=19) were most frequently involved. In 79% (n=49) of the cases, the injury happened while entering the water. Cliff divers were in 52% (n=15) of the injuries in a feet-first and in 14% (n=4) in a head-first position. Splash divers were in 45% (n=9) of the injuries in a back- or buttocks-first position. Most of the injuries were bruises (47%; n=104) and muscle strains (13%; n=28). The injury risk during practice was significantly higher than in competition (11.3 vs. 4.5 injuries/1000h; OR 2.5; p=0.001). The injury risk of experts (15.4/1000h exposure) was significantly higher than in professionals (6.3/1000h exposure; OR 2.4; 95% CI, 3.3-1.9; p<0.001), although the average diving height was significantly higher in professionals (19m+/-8 vs. 12m+/-6; p<0.001). Significantly more professionals performed dryland training compared to experts (p=0.006). CONCLUSION: Most of the injuries are related to the water entry. The entry position plays a key role in injury patterns with pursuant differences comparing CD with SD. Although most of the injuries involved soft-tissue only, severe injuries have been reported. Targets for future injury prevention strategies include protection for the increased impaction at entry; adaption of the diving conditions in practice to those in competition; dryland training courses; and instruction of non-professional divers to teach appropriate diving techniques. PMID- 28807432 TI - Non neurologic burst thoracolumbar fractures fixation: Case-control study. AB - STUDY DESIGN: Burst fractures not associated with any neurological deficits are frequent but not therapeutic agreement on their management is available to date. This case-control study was conducted to try to help guide therapeutic decision in the treatment of such fractures. MATERIALS AND METHODS: This case-control study includes consecutive retrospective evaluation of 25 case-patients treated by posterior short-segment fixation associated with kyphoplasty (SFK) in the treatment of A3 thoracolumbar unstable fractures, as compared to a control-group composed of 82 patients treated by long-segment (LF) pedicle screws. RESULTS: SFK patients bled significantly less than the LF patients (p=0.04). Assessment of deformation progression, vertebral height restoration and reduction of the regional kyphotic angle in the SFK and LF groups revealed no statistically significant superiority of one approach on another. In contrast, the height of endplates was significantly increased in the SFK group (p=0.006). The patients' pain levels were significantly improved in the SFK group (p=0.002). However, patients from the SFK group stood earlier postoperatively (1.7 vs 3.7days, p=0.001). CONCLUSION: We believe that SFK in vertebral fractures is as efficient as LF for bone consolidation and spine stabilization. In addition, SFK patients may use fewer analgesics. PMID- 28807433 TI - Influences on Decision-Making Regarding Antipsychotic Prescribing in Nursing Home Residents With Dementia: A Systematic Review and Synthesis of Qualitative Evidence. AB - BACKGROUND: Antipsychotic prescribing is prevalent in nursing homes for the management of behavioral and psychological symptoms of dementia (BPSD), despite the known risks and limited effectiveness. Many studies have attempted to understand this continuing phenomenon, using qualitative research methods, and have generated varied and sometimes conflicting findings. To date, the totality of this qualitative evidence has not been systematically collated and synthesized. AIMS: To synthesize the findings from individual qualitative studies on decision-making and prescribing behaviors for antipsychotics in nursing home residents with dementia, with a view to informing intervention development and quality improvement in this field. METHODS: A systematic review and synthesis of qualitative evidence was conducted (PROSPERO protocol registration CRD42015029141). Six electronic databases were searched systematically from inception through July 2016 and supplemented by citation, reference, and gray literature searching. Studies were included if they used qualitative methods for both data collection and analysis, and explored antipsychotic prescribing in nursing homes for the purpose of managing BPSD. The Critical Appraisal Skills Program assessment tool was used for quality appraisal. A meta-ethnography was conducted to synthesize included studies. The Confidence in the Evidence from Reviews of Qualitative research approach was used to assess the confidence in individual review findings. All stages were conducted by at least 2 independent reviewers. RESULTS: Of 1534 unique records identified, 18 met the inclusion criteria. Five key concepts emerged as influencing decision-making: organizational capacity; individual professional capability; communication and collaboration; attitudes; regulations and guidelines. A "line of argument" was synthesized and a conceptual model constructed, comparing this decision-making process to a dysfunctional negative feedback loop. Our synthesis indicates that when all stakeholders come together to communicate and collaborate as equal and empowered partners, this can result in a successful reduction in inappropriate antipsychotic prescribing. CONCLUSIONS: Antipsychotic prescribing in nursing home residents with dementia occurs in a complex environment involving the interplay of various stakeholders, the nursing home organization, and external influences. To improve the quality of antipsychotic prescribing in this cohort, a more holistic approach to BPSD management is required. Although we have found the issue of antipsychotic prescribing has been extensively explored using qualitative methods, there remains a need for research focusing on how best to change the prescribing behaviors identified. PMID- 28807434 TI - Nutritional Strategies in the Management of Alzheimer Disease: Systematic Review With Network Meta-Analysis. AB - BACKGROUND: Alzheimer disease (AD) is the major cause of dependency and disability in the elderly. Numerous studies have sought to achieve its prevention and/or management examining a role for modifiable risk factors, such as nutrition. This work aims to investigate the effects of food and/or nutrients in the management of AD at different stages. METHODS: Electronic databases were searched for clinical trials examining the effect of nutrient intervention in individuals with AD, compared with placebo, published up to 2014. The outcomes investigated were neuropsychological assessment scales, neuroimaging, and biomarkers. The Cochrane tool was employed to assess risk of bias. Pairwise meta analyses were performed in a random-effect model by estimating the weighted mean differences with 95% confidence interval (CI) for each outcome measure. The Network meta-analysis was undertaken on cognitive outcome. RESULTS: Selected studies used antioxidants, B-vitamins, inositol, medium-chain triglyceride, omega 3, polymeric formulas, polypeptide, and vitamin D. AD outcome measurements were mainly restricted to cognitive state and functional abilities. Estimate treatment effects from pairwise meta-analyses showed large but nonsignificant effect in the supplementation with proline-rich polypeptide [weighted mean difference 6.93 (95% CI -3.04, 16.89); P = .17] and B-vitamins [weighted mean difference 0.52 (95% CI 0.05, 1.09); P = .07) on cognitive function measured by the Mini-Mental State Examination. The other nutrients supplementation did not show any significant effect on any outcome measures. CONCLUSIONS: Isolated nutrient supplementations show no convincing evidence of providing a significant benefit on clinical manifestations or neuropathology of AD. During the initial stages of AD, nutrient supplementation did not show any effect when delivered individually, probably because of their synergistic function on brain, at different domains. PMID- 28807435 TI - Team working is crucial in the battle against stroke. PMID- 28807436 TI - Simple and efficient knockdown of His-tagged proteins by ternary molecules consisting of a His-tag ligand, a ubiquitin ligase ligand, and a cell-penetrating peptide. AB - We designed and synthesized hybrid molecules for a protein knockdown method based on the recognition of a His-tag fused to a protein of interest (POI). The synthesized target protein degradation inducers contained three functional moieties: a His-tag ligand (nickel nitrilotriacetic acid [Ni-NTA]), an E3 ligand (bestatin [BS] or MV1), and a carrier peptide (Tat or nonaarginine [R9]). The designed hybrid molecules, BS-Tat-Ni-NTA, MV1-Tat-Ni-NTA, BS-R9-Ni-NTA, and MV1 R9-Ni-NTA, efficiently degraded His-tagged cellular retinoic acid binding protein 2 via the ubiquitin-proteasome system (UPS). This system will become a useful tool for research into selective protein degradation inducers that act via the UPS. PMID- 28807437 TI - Aminosquaraines as potential photodynamic agents: Synthesis and evaluation of in vitro cytotoxicity. AB - The synthesis of several aminosquaraine cationic dyes displaying strong absorption within the so-called phototherapeutic window (650-850nm) is described. Their cytotoxicity, under dark and illuminated conditions, was tested against several human tumor cell lines (breast, lung, cervical and hepatocellular carcinomas) and non-tumor porcine liver primary cells. All compounds showed to inhibit the growth of the tumor cells upon irradiation more than in the absence of light, in more or less extension, clearly exhibiting photodynamic activity. The photosensitizing ability against some cell lines, together with the low toxicity for the non-tumor primary PLP2 cells displayed by some of the compounds synthetized, turns them into potential candidates as photosensitizers for PDT. PMID- 28807438 TI - Synthesis, conformational study and antiviral activity of l-like neplanocin derivatives. AB - The l-like enantiomer of 9-(trans-2', trans-3'-dihydroxycyclopent-4'-enyl)-3 deazaadenine (DHCDA) (1), its 3-deaza-3-bromo derivative (3), and the conformational restricted methanocarba (MC) nucleoside analogues (2 and 4) were synthesized. X-ray crystal structures showed the L isomer MC analogue 4 adopts a similar North-like locked conformation as conventional D-MC nucleosides, while the DHCDA analogue 3 preferred south-like conformer. Compounds 1 and 4 showed potent antiviral activity against norovirus, while compound 2 and 3 were less potent or inactive. The conformational behavior of "sugar" puckering (north/south) and nucleobase orientation (syn /anti) may contribute to the antiviral activity differences. For compound 3, antiviral activity was also found against Ebola virus. PMID- 28807439 TI - Tetrahydrobenzothiophene carboxamides: Beyond the kinase domain and into the fatty acid realm. AB - A series of tetrahydrobenzothiophene carboxamides, inspired by structural features present in kinase and SCD1 inhibitors, are presented here. Prototype compound 8 (MMDD13) modulates fatty acid elongase and desaturase indexes, lipid accumulation, while preserving kinase inhibitory activity. This chemotype represents a stepping stone towards chemical probes to study the consequences of lipid metabolism modulation through non-redundant pathways. PMID- 28807440 TI - Synthesis of 3-[4-(dimethylamino)phenyl]alkyl-2-oxindole derivatives and their effects on neuronal cell death. AB - Novel 3-[4-(dimethylamino)phenyl]alkyl-2-oxindole analogs were synthesized by either of the following two pathways: (1) a sequence of Knoevenagel condensation of oxindole with (4-dimethylamino)cinnamaldehyde-hydrogenation, or (2) alkylation of oxindole dianion with [(4-dimethylamino)phenyl]alkyl halides. Subsequent alkylation at C-3 and/or N-1 of the oxindole skeleton by anion-based methods provided additional substituted derivatives for structure-activity relationship studies. Their effects on neuronal cell death induced by oxidative stress were evaluated by lactate dehydrogenase assay. Compounds with the alkyl chain length of 2-4 significantly suppressed the neuronal cell death. No significant change occurred in the activity by substitution with less-polar groups. The stereochemistry at C-3 of the oxindole core was also irrelevant for the neuroprotective effects of these compounds. PMID- 28807441 TI - Whole-body dose and energy measurements in radiotherapy by a combination of LiF:Mg,Cu,P and LiF:Mg,Ti. AB - PURPOSE: Long-term survivors of cancer who were treated with radiotherapy are at risk of a radiation-induced tumor. Hence, it is important to model the out-of field dose resulting from a cancer treatment. These models have to be verified with measurements, due to the small size, the high sensitivity to ionizing radiation and the tissue-equivalent composition, LiF thermoluminescence dosimeters (TLD) are well-suited for out-of-field dose measurements. However, the photon energy variation of the stray dose leads to systematic dose errors caused by the variation in response with radiation energy of the TLDs. We present a dosimeter which automatically corrects for the energy variation of the measured photons by combining LiF:Mg,Ti (TLD100) and LiF:Mg,Cu,P (TLD100H) chips. METHODS: The response with radiation energy of TLD100 and TLD100H compared to 60Co was taken from the literature. For the measurement, a TLD100H was placed on top of a TLD100 chip. The dose ratio between the TLD100 and TLD100H, combined with the ratio of the response curves was used to determine the mean energy. With the energy, the individual correction factors for TLD100 and TLD100H could be found. The accuracy in determining the in- and out-of-field dose for a nominal beam energy of 6MV using the double-TLD unit was evaluated by an end-to-end measurement. Furthermore, published Monte Carlo (M.C.) simulations of the mean photon energy for brachytherapy sources, stray radiation of a treatment machine and cone beam CT (CBCT) were compared to the measured mean energies. Finally, the photon energy distribution in an Alderson phantom was measured for different treatment techniques applied with a linear accelerator. Additionally, a treatment plan was measured with a cobalt machine combined with an MRI. RESULTS: For external radiotherapy, the presented double-TLD unit showed a relative type A uncertainty in doses of -1%+/-2% at the two standard deviation level compared to an ionization chamber. The type A uncertainty in dose was in agreement with the theoretically calculated type B uncertainty. The measured energies for brachytherapy sources, stray radiation of a treatment machine and CBCT imaging were in agreement with M.C. simulations. A shift in energy with increasing distance to the isocenter was noticed for the various treatment plans measured with the Alderson phantom. The calculated type B uncertainties in energy were in line with the experimentally evaluated type A uncertainties. CONCLUSION: The double-TLD unit is able to predict the photon energy of scatter radiation in external radiotherapy, X-ray imagine and brachytherapy sources. For external radiotherapy, the individual energy correction factors enabled a more accurate dose determination compared to conventional TLD measurements. PMID- 28807442 TI - Age is related to neurological outcome in patients with out-of-hospital cardiac arrest (OHCA) receiving therapeutic hypothermia (TH). AB - INTRODUCTION: In this study, we retrospectively reviewed the patients' outcomes after cardiac arrest based on age in one center, to determine whether geriatric patients had worse outcomes. METHODS: This was a single-center, retrospective cohort study. The patients admitted to the intensive care unit on successful resuscitation after OHCA were retrospectively identified and evaluated. RESULTS: This was a retrospective cohort study of patients over 18years of-age with return of spontaneous circulation (ROSC) (>24h) after cardiac arrest who were admitted to the emergency intensive care unit (EICU) and received post-cardiac arrest care between March 2007 and December 2013. Finally, a total of 295 patients were enrolled during the study period; of these, 79 patients (36.6%) had a good cerebral performance category (CPC). In stepwise multivariate analysis, young age (per 10years) (odds ratio [OR] 1.42, 95% CI 1.00-1.99, p=0.044), high hemoglobin level (per 1g/dL) (OR 1.31, 95% CI 1.07-1.60, p=0.008), non-diabetic patients (OR 15.21, 95% CI 1.85-125.3, p=0.01), cardiogenic cardiac arrest (OR 8.68, 95% CI 3.72-20.30, p<0.001), pre-hospital cardiopulmonary resuscitation (CPR) by bystander (OR 3.61, 95% CI 1.23-10.57, p=0.019), short time from collapsed to ACLS (per 1min) (OR 1.12, 95% CI 1.06-1.18, p<0.001) had good CPC at 6-month post admission. CONCLUSION: Elderly patients with OHCA had a poor neurological outcome; but several other factors were also related with the outcome. In decision-making for resuscitation, physicians should consider the patients' physiologic factors as well as age. PMID- 28807443 TI - Acute massive pulmonary embolism associated with olanzapine. AB - Treatment with low-potency anti-psychotic agents is an important risk factor in the development of pulmonary embolism (PE). We report a case of 74years old female patient receiving olanzapine for psychotic depression admitted to the emergency service with the complaints of chest pain and shortness of breath. She had tachypnea, hypotension and tachycardia. Arterial blood gas analysis showed hypoxemia-hypocapnia and D-dimer level was high. Computed tomographic pulmonary angiography (CTPA) demonstrated pulmonary embolism in both main pulmonary arteries, through lobar and segmental branches. Tissue plasminogen activator (t PA) was administered in intensive care unit. As the only possible risk factor for PE was olanzapine, olanzapine treatment was terminated with pyschiatry consultation. During the 12-month follow-up of the patient; malignancy was not observed. Diagnosis and prevention of PE are the important goals to reduce morbidity and mortality in subjects receiving olanzapine. PMID- 28807444 TI - Response to: "Response to: Medication errors with push dose pressors in the ED and ICU". PMID- 28807445 TI - Emergency physician accuracy using ultrasonography to diagnose lateral malleolar fracture. AB - OBJECTIVE: Many studies in the literature related to the investigation of the sensitivity and specificity of ultrasound examinations in lateral malleolar fractures is limited. The aim of this study is to investigate the sensitivity and specificity of ultrasound examinations performed by emergency physicians in fractures who are presented to the emergency department with blunt lateral malleolar trauma. METHOD: Patients over 18years of age who were admitted to the ED with lateral malleolar tenderness were enrolled to this study with convenience sampling. Ultrasonographic examination was performed by emergency physicians. Following the ultrasound examination, a two-sided X-ray was performed. In the case of inconsistency between the US exam and the X-ray evaluated by the emergency physician, a CT was performed on the patients. The X-ray or CT imaging evaluation of an orthopedic surgeon was accepted as the gold standard. RESULTS: A hundred-twenty patients were included in the study. Fractures in the lateral malleolus were detected in 47 patients. The sensitivity of X-ray in the diagnosis of lateral malleolar fractures was 92.8%, (95% CI, 79.4-98.1) and the specificity was 100% (95% CI, 89.5-100), while the sensitivity of US exam was 100% (95% CI, 94.1-100), and the specificity was 93% (95% CI, 85-97.6). X-ray gave false negative results in 3 patients, whereas US gave false positive results in 5 patients. CONCLUSION: In patients admitted to ED with lateral malleolus tenderness, the sensitivity of the ultrasound examination performed by emergency physicians regarding diagnosis of lateral malleolar fracture is higher than X ray. PMID- 28807446 TI - Karadeniz clinical decision rules for the use of radiography in wrist trauma. PMID- 28807447 TI - Role of Reactive Oxygen Species during Low-Intensity Pulsed Ultrasound Application in MC-3 T3 E1 Pre-osteoblast Cell Culture. AB - We evaluated the activation of mitogen-activated protein kinase (MAPK) activation through reactive oxygen species (ROS) by application of low-intensity ultrasound (LIPUS) to MC-3 T3 E1 pre-osteoblasts. The cells were subjected to one LIPUS application for either 10 or 20 min, and the control group was exposed to a sham transducer. For ROS inhibition, 10 MUM diphenylene iodonium (DPI) was added to the cells an hour before LIPUS application. Samples were collected 1, 3, 6, 12 and 24 h after LIPUS application, and cells were evaluated for ROS generation, cell viability, gene expression and MAPK activation by immunoblot analyses. LIPUS caused a significant increase in ROS and cell viability in the non-DPI-treated group. Expression of RUNX2, OCN and OPN mRNA was higher in the LIPUS-treated groups at 1 h in both the DPI-treated and non-DPI-treated groups; RUNX2 and OCN mRNA levels increased at 6 h. ERK1/2 activation was increased in the LIPUS treated groups. These results indicate that LIPUS activates MAPK by ROS generation in MC-3 T3 E1 pre-osteoblasts. PMID- 28807448 TI - Assessing Hepatic Fibrosis Using 2-D Shear Wave Elastography in Patients with Liver Tumors: A Prospective Single-Center Study. AB - The purpose of this study was to investigate the diagnostic performance of 2-D shear wave elastography (2-D-SWE) in evaluations of liver stiffness in patients with liver tumors before resection. A total of 121 consecutive patients with hepatocellular carcinoma (HCC) (n = 93), intra-hepatic cholangiocarcinoma (n = 6), mixed hepatocellular carcinoma and intra-hepatic cholangiocarcinoma (n = 6), liver metastases (n = 10) and benign tumors (n = 6) were prospectively enrolled in this study from June 2015 to March 2016. Three valid 2-D-SWE measurements for each patient and median liver stiffness values were calculated. Fibrosis staging was evaluated according to the METAVIR scoring system. A receiver operating characteristic curve analysis was used to assess diagnostic performance. In this study, we found that median liver stiffness values were significantly higher in patients with primary liver tumors than in those with liver metastases and benign tumors (11.80 kPa vs. 5.85 kPa, p < 0.001). In addition, liver stiffness, assessed using 2-D-SWE, was highly correlated with pathologically confirmed liver fibrosis stage. Liver fibrosis stage and liver stiffness values were analyzed using Spearman's correlation (0.708, p < 0.001). The median liver stiffness values were as follows: F1, 6.7 kPa; F2, 6.33 kPa; F3, 9.2 kPa; F4, 13.7 kPa. The area under the receiver operating characteristic curves of the liver stiffness values that predicted significant fibrosis (>=F2), severe fibrosis (>=F3) and cirrhosis (=F4) were 83.5%, 91.6% and 88.1%, respectively. According to the Youden index, the optimal cutoff values for predicting significant fibrosis (>=F2), severe fibrosis (>=F3) and cirrhosis (=F4) were 7.05 kPa (sensitivity = 74.6%, specificity = 100.0%), 9.45 kPa (sensitivity = 78.8%, specificity = 100.0%) and 11.1 kPa (sensitivity = 83.1%, specificity = 89.3%), respectively. We conclude that 2-D-SWE is a useful, accurate and non-invasive method for evaluating hepatic fibrosis in patients with liver tumors adapted to hepatectomy (ClinicalTrials.gov ID: NCT02958592). PMID- 28807450 TI - Role of Contrast-Enhanced Ultrasound in the Pre-operative Diagnosis of Cervical Lymph Node Metastasis in Patients with Papillary Thyroid Carcinoma. AB - The objective of this study was to prospectively evaluate the diagnostic accuracy of contrast-enhanced ultrasonography (CEUS) in differentiating between benign and metastatic cervical lymph nodes in patients with papillary thyroid cancer (PTC). Three hundred nineteen cervical lymph nodes (162 metastatic from PTC and 157 benign) were evaluated using conventional ultrasonography (US) and CEUS before biopsy or surgery. Metastatic lymph nodes more often manifested centripetal or asynchronous perfusion, hyper-enhancement, heterogeneous enhancement, perfusion defects and ring-enhancing margins than benign lymph nodes at pre-operative CEUS (all p values < 0.001). The area under the receiver operating characteristic curve (AUC) for the combination of conventional US and CEUS (0.983, 95% confidence interval [CI]: 0.971-0.994) was higher than that of conventional US alone (0.929, 95% CI: 0.899-0.958) and CEUS (0.911, 95% CI: 0.876-0.947). In conclusion, CEUS is a promising tool in conjunction with conventional US for the pre-operative prediction of metastatic cervical lymph nodes in patients with PTC. PMID- 28807449 TI - Non-Invasive Intra-cardiac Pressure Measurements Using Subharmonic-Aided Pressure Estimation: Proof of Concept in Humans. AB - This study evaluated the feasibility of employing non-invasive intra-cardiac pressure estimation using subharmonic signals from ultrasound contrast agents in humans. This institutional review board-approved proof-of-concept study included 15 consenting patients scheduled for left and right heart catheterization. During the catheterization procedure, Definity was infused intra-venously at 4-10 mL/min. Ultrasound scanning was performed with a Sonix RP using pulse inversion, three incident acoustic output levels and 2.5-MHz transmit frequency. Radiofrequency data were processed and subharmonic amplitudes were compared with the pressure catheter data. The correlation coefficient between subharmonic signals and pressure catheter data ranged from -0.3 to -0.9. For acquisitions with optimum acoustic output, pressure errors between the subharmonic technique and catheter were as low as 2.6 mmHg. However, automatically determining optimum acoustic output during scanning for each patient remains to be addressed before clinical applicability can be decided. PMID- 28807451 TI - The 137Cs activity concentration of suspended and dissolved fractions in irrigation waters collected from the 80 km zone around TEPCO's Fukushima Daiichi Nuclear Power Station. AB - Fifty-four samples of irrigation water were collected in 2014 from agricultural ponds, rivers, and dams within the 80 km zone around TEPCO's Fukushima Daiichi Nuclear Power Station (FDNPS). The samples were filtered with a 0.45 MUm pore size membrane filter to produce suspended and dissolved fractions. The 137Cs activity concentration of the suspended fraction varied from 1.5 to 300 Bq g-1 dry weight and was significantly higher than that in the soil around each sampling site. The range of 137Cs activity concentrations in the dissolved fraction varied over three orders of magnitude at 0.0075-6.7 Bq l-1, which was a larger range than that of the suspended fraction; the higher values for samples were from within the 20 km zone. In the dissolved fraction 87 +/- 9% of the 137Cs (n = 37) was in a monovalent cationic form (Cs+) and therefore potentially mobile. The distribution coefficient (Kd) ranged from 4100 to 2,100,000; the geometric mean value (110,000) was higher than that reported by the IAEA (2010). The geometric mean Kd of samples collected from the 20 km zone was 61,000 (n = 27), which was significantly lower than that collected from 20 to 80 km zone (200,000, n = 27). The Kd-value was negative correlated with the concentration of stable 133Cs and the electric conductivity in the dissolved fraction. This shows relatively higher mobility of radiocaesium in irrigation waters may occur when there are higher contents of cations present. PMID- 28807452 TI - Corrigendum to "The role of calcitonin receptor signalling in polyethylene particle-induced osteolysis" [Acta Biomater. 14 (2015) 125-132]. PMID- 28807453 TI - Corrigendum to "Thiolated silicone oil: Synthesis, gelling and mucoadhesive properties" [Acta Biomater. 16 (2015) 169-177]. PMID- 28807454 TI - Reconsidering olfactory bulb magnetic resonance patterns in Kallmann syndrome. AB - OBJECTIVE: The aim of this retrospective study was to perform magnetic resonance imaging assessment of olfactory pathway and skull base abnormalities in Kallmann syndrome (KS) patients with hypogonadotropic hypogonadism and olfaction disorder. METHODS: Magnetic resonance brain patterns were retrospectively studied in 19 patients clinically classified as KS. Qualitative assessment of olfactory bulb region comprised bulb atrophy and rectus and medial orbital gyrus ptosis; quantitative assessment measured olfactory fossa depth and width, sulcus depth and ethmoid angle. Results were compared to an age- and sex-matched control population (n=19) with no impairment in the region of interest. Sixteen of the 19 KS patients were genetically screened for mutations associated with KS. RESULTS: On the above qualitative criteria, 15 of the 19 patients presented either unilateral (n=2) or bilateral (n=13) olfactory bulb agenesis; 16 showed tract agenesis and 16 showed gyrus malformation (ptosis or absence). On the quantitative criteria, 18 of the 19 patients showed abnormal sulcus depth and/or olfactory fossa malformation and/or abnormal ethmoid angle. CONCLUSION: The presence of malformation abnormalities in the olfactory fossae of 18 of the 19 patients appears to be a key factor for etiological diagnosis of hypogonadotropic hypogonadism, and should enable targeted study of genes involved in KS. PMID- 28807455 TI - 34e Congres SFE Poitiers 2017. PMID- 28807456 TI - Post-hospitalization experiences of older adults diagnosed with diabetes: "It was daunting!" AB - Multimorbidity combined with geriatric syndromes in older adults with diabetes exacerbate their risks for poor post-discharge outcomes. The purpose of this study was to examine self-described hospital-to-home transition challenges encountered by older adults with a diagnosis of diabetes within the first 30 days following discharge. The qualitative responses for this paper emerged from a larger mixed methods study (n = 96) in which participants provided free responses specifying transition challenges during follow-up telephone interviews on the 7th day (n = 67) and 30th day (n = 55) post-discharge. Using inductive content analysis techniques four major themes emerged: a) "The daily stuff is difficult"; b) engineering care at home is complex; c) "life is very difficult"; and d) managing complex health problems is difficult. Findings suggest existing system level metrics such as readmission rates fail to capture the complex and dynamic interplay of personal, family and social factors which complicate hospital-to home transitions of older adults with pre-existing diabetes. PMID- 28807457 TI - Identification of pseudobulbar affect symptoms in the nursing home setting: Development and assessment of a screening tool. AB - Pseudobulbar Affect (PBA) is a neurologic condition characterized by involuntary outbursts of crying and/or laughing disproportionate to patient mood or social context. Although an estimated 9% of nursing home residents have symptoms suggestive of PBA, they are not routinely screened. Our goal was to develop an electronic screening tool based upon characteristics common to nursing home residents with PBA identified through medical record data. Nursing home residents with PBA treated with dextromethorphan hydrobromide/quinidine sulfate (n = 140) were compared to age-, gender-, and dementia-diagnosis-matched controls without PBA or treatment (n = 140). Comparative categories included diagnoses, medication use and symptom documentation. Using a multivariable regression and best decision rule analysis, we found PBA in nursing home residents was associated with chart documentation of uncontrollable crying, presence of a neurologic disorder (e.g., Parkinson's disease), or by the documented presence of at least 2 of the following: stroke, severe cognitive impairment, and schizophrenia. Based on these risk factors, an electronic screening tool was created. PMID- 28807458 TI - Caveolin 3 deficiency myopathy associated with dyslipidemia: Treatment challenges and possible pathophysiological association. AB - We report the case of a patient treated at the lipid clinic because of high cholesterol levels with consistently elevated creatine kinase concentrations that precluded statin treatment. Electromyography showed a rippling muscle disease pattern. A muscle biopsy confirmed caveolin 3 deficiency, and a missense mutation in the CAV3 gene was identified. The patient could be properly managed with ezetimibe and cholestyramine, which reduced the low-density lipoprotein cholesterol by 30%. He remains asymptomatic after 10 years of follow-up. Caveolae and caveolins are essential to membrane integrity, and their deficit has been associated with insulin resistance and hypercholesterolemia in animal models. Therefore, a putative pathophysiological association between myopathy and lipid metabolism mediated by functional alterations of membrane receptors is considered. PMID- 28807459 TI - Rapidly progressive atherosclerosis after domino liver transplantation from a teenage donor with homozygous familial hypercholesterolemia. AB - Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by impaired clearance of low-density lipoprotein cholesterol. Given limitations in pharmacologic therapy and the significant morbidity and mortality associated with this disease, liver transplantation may be offered to select homozygous FH patients in childhood in an effort to slow progression of atherosclerotic cardiovascular disease. In rare cases, domino liver transplantation can be performed, transplanting the livers of patients with various metabolic disorders into elderly recipients whose projected survival precludes prolonged waiting on the transplant list. Herein, we report a case of domino liver transplantation using the liver of a 14-year-old boy with homozygous FH into a 65-year-old man with primary sclerosing cholangitis and cirrhosis who developed rapidly progressive atherosclerotic cardiovascular disease involving the arteries of his proximal bilateral lower extremities, carotid arteries and superior mesenteric artery. PMID- 28807460 TI - Metabolic syndrome cluster does not provide incremental prognostic information in patients with stable cardiovascular disease: A post hoc analysis of the AIM-HIGH trial. AB - BACKGROUND: Metabolic syndrome (MS) is a well-known risk factor for the development of cardiovascular (CV) disease; yet, controversy persists whether it adds incremental prognostic value in patients with established CV disease. OBJECTIVES: This study was performed to determine if MS is associated with worse CV outcomes in patients with established CV disease treated intensively with statins. METHODS: We performed a post hoc analysis of the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes trial, in which patients with established CV disease and atherogenic dyslipidemia (n = 3414) were randomly assigned to receive extended release niacin or placebo during a mean 36-month follow-up, to assess whether the presence of MS or the number of MS components contributed to CV outcomes. RESULTS: The composite primary end point of CV events occurred in 15.1% of patients without MS vs 13.8%, 16.9%, and 16.8% of patients with MS in the subsets with 3, 4, and 5 MS components, respectively (corresponding adjusted hazard ratios 0.9, 1.1, and 1.1 relative to patients without MS), P = .55. Comparing subgroups with 3 vs 4 or 5 MS components, there was no significant difference in either the composite primary end point or secondary end points. Patients with diabetes mellitus had higher event rates, with or without the presence of MS. CONCLUSIONS: The presence of MS was not associated with worse CV outcomes in the AIM-HIGH population. The rate of CV events in statin-treated Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes patients with MS was not significantly influenced by the number of MS components. PMID- 28807462 TI - Is it time to get serious about cholesterol screening? PMID- 28807461 TI - The effects of statins on exercise and physical activity. AB - OBJECTIVE: We sought to review studies examining the effect of statins on symptoms of exercise tolerance, markers of muscle injury and activity levels in physical active individuals. BACKGROUND: Statin therapy reduces atherosclerotic cardiovascular disease (CVD) events. Regular physical activity is also associated with reduced CVD events, but statin therapy can produce muscle complaints, which may be more frequent in physically active individuals. We reviewed the literature to determine the effects of statins on symptoms, exercise performance and activity levels in physically active individuals. METHODS: We performed a PubMed search to identify English language articles reporting on statins and their effect on athletic/exercise performance, and symptoms in active individuals. RESULTS: We identified 65 articles, 32 of which provided sufficient information to be included in this review. Seventeen of the 32 studies examined the incidence of myalgia while exercising on statins, and showed that myalgia was increased in 8 of the 17 (47%) of these studies. Of the 17 studies examining the effects of statin therapy on muscle injury, 6 (35%) studies reported that statins augment the increase in creatine kinase (CK) produced by exercise. There were 10 studies that examined statin effects on aerobic exercise performance, only 3 of which (33%) concluded that statins decreased performance. Two (25%) of the 8 studies examined the effects of statins on muscular strength and suggested that statins decreased muscular strength, whereas 2 (25%) reported increased strength. Statins did not consistently affect physical activity levels since statins were associated with an increase in activity in 3 of the 5 studies examining habitual exercise. None of the studies showed a relationship between statins use and exercise and an increase in myalgia or a decrease in exercise performance. There was also no correlation between intensity of statin therapy and an effect on these variables. CONCLUSION: Statins may increase the incidence of exercise related muscle complaints and in some studies augment the exercise-induced rise in muscle enzymes, but statins do not consistently reduce muscle strength, endurance, overall exercise performance or physical activity. PMID- 28807463 TI - Clinical analysis of MatrixMANDIBLE Preformed Reconstruction Plate design. AB - MatrixMANDIBLE Preformed Reconstruction Plates (MMPRPs) were developed to overcome laborious bending procedures of conventional reconstruction plates. The design comprises three sizes with a nonbendable centerpiece and two bendable sections (proximal and distal). According to the surgical protocol unnecessary parts are trimmed after the last used screw hole. In the present retrospective study postoperative radiographs from 130 patients (average age 63 years) that received treatment with MMPRPs were assessed. There was no statistical correlation between plate-size, location (left/right) or age. 82.98% of the small and 91.80% of the medium MMPRPs were trimmed by at least the terminal screw hole of the ramus part. In all patients receiving a large MMPRP, the terminal screw hole of the ramus was unused accordingly all inserted large MMPRPs were trimmed by at least the terminal screw hole. The majority of the bridged defects were located within the area of the body indicating a feasible plate design. With the emergence of solid free form fabrication of Ti-alloys and economic need to reduce the waste of resources this study may help to further improve the MMPRP design and prevent the loss of medical-grade titanium. PMID- 28807464 TI - Sex estimation using dimensions around the nutrient foramen of the long bones of the arm and forearm in South Africans. AB - South Africa has had an increase in rates of crime, interpersonal violence and homicide since the introduction of democracy in 1994. Forensic osteological standards was lacking for South Africans of different population groups necessitating the generation of new standards for forensic identification of individuals from skeletal remains. For these reasons, there is a concerted demand for methods of identifying skeletal remains with sex being amongst the most important of the biological characteristics required. The nutrient foramen has been used to estimate sex in lower limb long bones with much accuracy but this has not been demonstrated in the upper limb long bones. The aim of this study was to develop osteometric standards for sex estimation from measurements around the nutrient foramen of the arm and forearm bones of South Africans of different population affinities. A total of 660 bones consisting of humeri, radii and ulnae of black South Africans and white South Africans were assessed for sex estimation using dimensions related to the nutrient foramen. Sex was correctly classified with a range of 84-85% for the humerus and 83-88% for the arm bones. The study showed that length measurements were more sexually dimorphic than width dimensions in South Africans, as length was consistently selected as the best predictor of sex in all bones. However, the average accuracy increased when length was used in combination with measurements related to the nutrient foramen. In conclusion, the dimensions of upper limb long bones that are directly related to the nutrient foramen are sexually dimorphic and are useful in the estimation of sex in South Africans, with the highest accuracy shown in the white South African population group. PMID- 28807465 TI - New techniques in interventional neuroradiology: Should we really randomize the first patient? PMID- 28807466 TI - Midwives being 'with woman': An integrative review. AB - BACKGROUND: Midwives being 'with woman' is embedded in professional philosophy, standards of practice and partnerships with women. In light of the centrality of being 'with woman' to the profession of midwifery, it is timely to review the literature to gain a contemporary understanding of this phenomenon. AIM: This review synthesises research and theoretical literature to report on what is known and published about being 'with woman'. METHODS: A five step framework for conducting an integrative literature reviews was employed. A comprehensive search strategy was utilised that incorporated exploration in electronic databases CINAHL, Scopus, Proquest, Science Direct and Pubmed. The initial search resulted in the retrieval of 2057 publications which were reduced to 32 through a systematic process. FINDINGS: The outcome of the review revealed three global themes and corresponding subthemes that encompassed 'with woman': (1) philosophy, incorporated two subthemes relating to midwifery philosophy and philosophy and models of care; (2) relationship, that included the relationship with women and the relationship with partners; and (3) practice, that captured midwifery presence, care across the childbirth continuum and practice that empowers women. CONCLUSION: Research and theoretical sources support the concept that being 'with woman' is a fundamental construct of midwifery practice as evident within the profession's philosophy. Findings suggest that the concept of midwives being 'with woman' is a dynamic and developing construct. The philosophy of being 'with woman' acts as an anchoring force to guide, inform and identify midwifery practice in the context of the rapidly changing modern maternity care landscapes. Gaps in knowledge and recommendations for further research are made. PMID- 28807467 TI - Sleeping for two: The importance of good sleep during pregnancy. PMID- 28807468 TI - Are Revision Hip Arthroplasty Patients at Higher Risk for Venous Thromboembolic Events Than Primary Hip Arthroplasty Patients? AB - BACKGROUND: The purpose of this study is to determine whether revision total hip arthroplasty (THA) is associated with increased rates of deep vein thrombosis (DVT) and pulmonary embolism (PE) when compared to primary THA. METHODS: We queried the American College of Surgeons National Surgical Quality Improvement Program database for all primary and revision THA cases from 2011 to 2014. Demographic data, medical comorbidities, and venous thromboembolic rates within 30 days of surgery were compared between the primary and revision THA groups. RESULTS: Revision THA had a higher rate of DVT than the primary THA (0.6% vs 0.4%, P = .016), but there was no difference in the rate of PE (0.3% vs 0.2%, P = .116). When controlling for confounding variables, revision surgery alone was not a risk factor for DVT (odds ratio 0.833, 95% confidence interval 0.564-1.232) or PE (odds ratio 1.009, 95% confidence interval 0.630-1.616). Independent risk factors for DVT include age >70 years, malnutrition, infection, operating time >3 hours, general anesthesia, American Society of Anesthesiologists classification 4 or greater, and kidney disease (all P < .05). Probability of DVT ranged from 0.2% with zero risk factors to 10% with all risk factors. Independent risk factors for PE included age >70 years, African American ethnicity, and operating time >3 hours (all P < .05) with probabilities of PE postoperatively ranging from 0.2% to 1.1% with all risk factors. CONCLUSION: Revision surgery alone is not a risk factor for venous thromboembolism after hip arthroplasty. Surgeons should weigh the risks and benefits of more aggressive anticoagulation in certain high-risk patients. PMID- 28807469 TI - Hip Fractures: Appropriate Timing to Operative Intervention. AB - BACKGROUND: The purpose of this study is to (1) identify the incidence of surgical delay in hip fractures, (2) evaluate the time point surgical delay puts patients at increased risk for complications, and (3) identify risk factors for surgical delay in the setting of surgical management of hip fractures. METHODS: A multi-center database was queried for patients of 60 years of age or older undergoing surgical treatment of a hip fracture. Surgical delay was defined by days from admission until surgical intervention. Univariate analyses and multivariate analyses were performed on all groups. RESULTS: A total of 4215 patients underwent surgery for their hip fracture. Of those experiencing surgical delay, 3304 (78%) patients experienced surgical delay of >=1 day, 1314 (31%) had delay of >=2 days, and 480 (11%) experienced delay of >=3 days. There was a significant difference in complications if patients experienced surgical delay of >=2 days (P <= .01). Multivariate analyses identified multiple risk factors for delay of >=2 days including congestive heart failure (odds ratio 3.09, 95% confidence interval 2.04-4.66) and body mass index >=40 (odds ratio 2.31, 95% confidence interval 1.31-4.08). Subgroup analysis identified that patients undergoing total hip arthroplasty were not at risk for complications with surgical delay of >=2 days. CONCLUSION: Surgical delay of >=2 days in the setting of hip fractures is common and confers an increased risk of complications in those undergoing non-total hip arthroplasty procedures. We recommend surgical intervention prior to 48 hours from hospital admission when possible. Healthcare systems can utilize our non-modifiable risk factors when performing quality assessment and cost accounting. PMID- 28807470 TI - Persistent Pulmonary Embolism Rates Following Total Knee Arthroplasty Even With Prophylactic Anticoagulants. AB - BACKGROUND: Symptomatic pulmonary embolism (PE), a significant and life threatening complication following total knee arthroplasty (TKA), has been described as a "never event." Despite a number of advancements in care, PE continues to occur following TKA. This study evaluates symptomatic PE rates over time in TKA patients enrolled in multicenter randomized clinical trials assessing the efficacy of venous thromboembolism prophylaxis regimens. METHODS: The MEDLINE and Cochrane Central Register of Controlled Trials were searched to identify clinical trials assessing prophylactic anticoagulation in patients undergoing TKA between January 1995 and December 2016. A random effect model was used to combine PE rates across studies. The pooled proportion of symptomatic PEs was calculated and heterogeneity was quantified with the I2 statistic. A 95% prediction interval was constructed to examine what the expected range in the proportion of symptomatic PEs would be in future studies. Meta-regression was used to explore the effect of time on the rate of symptomatic PEs. RESULTS: A total of 18 studies representing 27,073 patients were included in the meta-analysis. The symptomatic PE rate was 0.37% (95% confidence interval, 0.24%-0.52%). There was significant heterogeneity across studies, I2 = 66%. Between 1996 and 2010, the proportion of PEs did not change in the regression analysis. The 95% prediction interval was 0.0002 to 0.0106, indicating that in similar future studies, the true proportion of symptomatic PEs would range from 0.02% to 1.06%. CONCLUSION: Over a 14-year period, the symptomatic PE rate after TKA was relatively constant even when patients received potent anticoagulation. These results suggest that some patients may have a genetic predisposition to develop a PE and more effective risk stratification protocols need to be developed to make sure patients receive appropriate anticoagulation. PMID- 28807471 TI - Corrigendum to "Oxidative stress effects of titanium dioxide nanoparticle aggregates in zebrafish" [Sci. Total Environ. Volumes 470-471, 1 February 2014, Pages 379-389]. PMID- 28807473 TI - Water Treatment by Magnetic Field Increases Bone Mineral Density of Rats. AB - Water treatment using a magnetic field is an attractive but controversial issue with regard to its effects on human health. This study aimed to investigate the effects of water treatment using a magnetic field on the bone mineral density (BMD), bone mineral content (BMC), bone area (BA), bone resistance (BR), blood gas analysis, blood viscosity, and blood biochemical profile of rats. Forty-eight Wistar rats were divided into 2 groups: control (n = 24) and magnetic water treated (n = 24). Each of these groups was subdivided into 3 groups to evaluate 3 consumption periods (15, 30, and 45 d). The animals were kept in metabolic cages throughout the experiment. A completely randomized design distributed to a 2 * 3 factorial arrangement was used. No significant difference was found in the water intake, dry matter intake, BA, or femoral head resistance between the groups. However, higher anion gap and lower CHCO3 were found in the arterial blood of the magnetic water-treated group. There was significant interaction between the water consumption period and the BR, BMD, and BMC. With 15 d of consumption, there was no difference in the BMC and BR. With 30 d of consumption, the BR (midshaft), BMD, and BMC showed increases; the increases were greater with 45 d of consumption. In adulthood, every month of the animal is approximately equivalent to 2.5 human years. The consumption of water treated by magnetic field for 45 d provided an effective way to improve BMD, BMC and BR in rats. PMID- 28807472 TI - A survey of domestic wells and pit latrines in rural settlements of Mali: Implications of on-site sanitation on the quality of water supplies. AB - On-site sanitation is generally advocated as a means to eradicate the health hazards associated with open defecation. While this has provided a welcome upgrade to the livelihoods of millions of people in low-income countries, improved sanitation facilities are increasingly becoming a threat to domestic groundwater-based supplies. Within this context, a survey of pit latrines, domestic wells and improved water sources was carried out in a large rural village of southern Mali. All households were surveyed for water, sanitation and hygiene habits. Domestic wells and improved water sources were georeferenced and sampled for water quality (pH, electric conductivity, temperature, turbidity, total dissolved solids, thermotolerant coliforms, chloride and nitrate) and groundwater level, while all latrines were inspected and georeferenced. A GIS database was then used to evaluate the proportion of water points within the influence area of latrines, as well as to underpin multiple regression models to establish the determinants for fecal contamination in drinking supplies. Moreover, an appraisal of domestic water treatment practices was carried out. This revealed that nearly two-thirds of the population uses bleach to purify drinking supplies, but also that domestic-scale treatment as currently implemented by the population is far from effective. It is thus concluded that existing habits could be enhanced as a means to make water supplies safer. Furthermore, population, well and latrine density were all identified as statistically significant predictors for fecal pollution at different spatial scales. These findings are policy-relevant in the context of groundwater dependent human settlements, since many countries in the developing world currently pursue the objective of eliminating open defecation. PMID- 28807475 TI - Temporary Rumenostomy for the Treatment of Forestomach Diseases and Enteral Nutrition. AB - Temporary rumenostomy is a useful procedure for the treatment, management, and support of patients with forestomach disease of various types. The rumenostomy provides a mechanism for relief of chronic rumen tympany or distention, removal of rumen contents and lavage of the rumen, removal of some rumen foreign bodies, administration of rumen fluid transfaunation, and administration of enteral nutrition or other medications. When the rumenostomy is no longer necessary, it can be allowed to close by second intention or by surgical resection. PMID- 28807474 TI - Rumen Function and Development. AB - The ruminal epithelium is a complex tissue that serves as an important protective barrier as well as a metabolically important tissue for whole-animal energy metabolism. Up to 70% of the energetic needs of mature animals are absorbed as short-chain fatty acids through the stratified squamous epithelium, and it serves as the primary producer of ketones in fed animals. Both physical and metabolic development are incomplete at birth and are triggered by short-chain fatty acids. Regulatory control of the proliferation and differentiation necessary for normal development is a useful model for the scientific investigation of nutrient-gene interactions. PMID- 28807477 TI - Echocardiographic Features and Clinical Outcomes of Flail Mitral Leaflet without Severe Mitral Regurgitation. AB - BACKGROUND: Flail mitral leaflet is a common complication of degenerative mitral regurgitation (MR) and is generally equated with severe MR. However, a flail mitral leaflet is not always associated with severe MR. The hemodynamic and clinical significance of a flail leaflet in the absence of severe MR has not been characterized. The authors identified cases of flail mitral leaflet associated with only mild or moderate MR and evaluated their echocardiographic features and clinical outcomes. METHODS: The echocardiography database at Cedars-Sinai Medical Center was queried for reports of flail mitral valve leaflet. Cases of possible flail and <=3+ MR were identified and adjudicated for the presence of definite flail and <=2+ MR. These patients were retrospectively evaluated by chart review to determine clinical outcomes. RESULTS: Seven hundred six cases of possible flail were identified, of which 143 were identified as having <=3+ MR. Of these, 14 cases were identified with definitive echocardiographic evidence of a flail mitral leaflet and <=2+ MR. Over a median of 361 days of follow-up, MR progressed in severity in only one patient, in association with endocarditis and death. All other patients were free of progression of MR, heart failure, or mortality during follow-up. CONCLUSIONS: A flail mitral leaflet is not synonymous with severe MR and can be associated with only mild or moderate MR. Furthermore, patients with flail mitral leaflet and only mild to moderate MR were clinically stable. Thus, an integrated, multiparametric approach should be used to assess MR severity, even in the presence of a flail mitral leaflet. PMID- 28807476 TI - A model for a career in a specialty of general surgery: One surgeon's opinion. AB - BACKGROUND: The integration of general and endocrine surgery was studied as a potential career model for fellowship trained general surgeons. METHODS: Case logs collected from 1991-2016 and academic milestones were examined for a single general surgeon with a focused interest in endocrine surgery. Operations were categorized using CPT codes and the 2017 ACGME "Major Case Categories" and there frequencies were determined. RESULTS: 10,324 operations were performed on 8209 patients. 412.9 +/- 84.9 operations were performed yearly including 279.3 +/- 42.7 general and 133.7 +/- 65.5 endocrine operations. A high-volume endocrine surgery practice and a rank of tenured professor were achieved by years 11 and 13, respectively. At year 25, the frequency of endocrine operations exceeded general surgery operations. CONCLUSION: Maintaining a foundation in broad-based general surgery with a specialty focus is a sustainable career model. Residents and fellows can use the model to help plan their careers with realistic expectations. PMID- 28807478 TI - Role of lipid mediators in the regulation of oxidative stress and inflammatory responses in dairy cattle. AB - Periparturient dairy cows experience an increased incidence and severity of several inflammatory-based diseases such as mastitis and metritis. Factors associated with the physiological adaptation to the onset of lactation can impact the efficiency of the inflammatory response at a time when it is most needed to eliminate infectious pathogens that cause these economically important diseases. Oxidative stress, for example, occurs when there is an imbalance between the production of oxygen radicals during periods of high metabolic demand and the reduced capabilities of the host's antioxidant defenses. The progressive development of oxidative stress in early lactation cows is thought to be a significant underlying factor leading to dysfunctional inflammatory responses. Reactive oxygen species (ROS) are also produced by leukocytes during inflammation resulting in positive feedback loops that can further escalate oxidative stress during the periparturient period. During oxidative stress, ROS can modify polyunsaturated fatty acids (PUFA) associated with cellular membranes, resulting in the biosynthesis of oxidized products called oxylipids. Depending on the PUFA substrate and oxidation pathway, oxylipids have the capacity of either enhancing or resolving inflammation. In mediating their effects, oxylipids can directly or indirectly target sites of ROS production and thus control the degree of oxidative stress. This review discusses the evidence supporting the roles of oxylipids in the regulation of oxidative stress and the subsequent development of uncontrolled inflammatory responses. Further, the utility of some of the oxylipids as oxidative stress markers that can be exploited in developing and monitoring therapies for inflammatory-based diseases in dairy cattle is discussed. Understanding of the link between some oxylipids and the development or resolution of oxidative stress could provide novel therapeutic targets to limit immunopathology, reduce antibiotic usage, and optimize the resolution of inflammatory-based diseases in periparturient dairy cows. PMID- 28807479 TI - Multifactorial analyses revealed optimal aquaculture modalities improving husbandry fitness without clear effect on stress and immune status of pikeperch Sander lucioperca. AB - High mortality and impairment in growth rate during pikeperch (Sander lucioperca) ongrowing are among the major bottlenecks for its development in aquaculture. These failures may be related to high stress responsiveness since the rearing conditions are not yet optimized for this species. The objectives were to characterize the stress and immunological responses of pikeperch to major aquaculture modalities, and to identify the optimal aquaculture conditions for improving its welfare status. In a screening experiment, eight factors considered as relevant for the welfare of pikeperch were compared in two modalities using a fractional multifactorial design (28-4). Each experimental unit represented a combination of 8 factors in two modalities including grading, stocking density (15 vs 30kg.m-3), feed type (sinking vs mid-floating), light intensity (10 vs 100 lux), light spectrum (red vs white), photoperiod (long vs short), dissolved oxygen (60 vs 90%) and temperature (21 vs 26 degrees C). Fish sampling occurred on days 36 and 63. Stress markers (glucose, cortisol and brain serotonergic activity), innate immune parameters (plasma lysozyme and complement activities) and expression of some immune genes were assessed. Light intensity and the type of feed clearly appeared as directive factors for pikeperch culture. A strong effect of the feed type was observed on growth parameters while survival was impacted by high light intensity. Light characteristics (intensity, spectrum and photoperiod) and temperature were identified as determining factors for physiological and immune markers. No obvious relation was established between stress status and growth parameters and further investigations are needed to improve management strategies of pikeperch culture and knowledge on the relations between environmental conditions, stress and immunity in percid fish. PMID- 28807480 TI - Opportunities and challenges in screening for childhood sexual abuse. AB - Retrospective studies suggest 1 in 4 girls and 1 in 6 boys will experience sexual abuse before 18 years of age, resulting in future morbidity. Successful interventions exist, however, victims are reluctant to disclose. Screening for childhood sexual abuse (CSA) may provide an opportunity to overcome this barrier, yet no current model for universal CSA screening exists. We sought to understand the perspective of key stakeholders on CSA screening through qualitative research. Eight focus groups of 7-10 participants each (n=62) were conducted from April-September 2016. Stakeholders included school nurses, school teachers, counselors and administrators, pediatric providers, and parents. The interview guide focused on reporting suspected CSA and impressions of a CSA screening tool. Sessions were audiotaped and transcribed. Researchers used qualitative content analysis to develop conceptual categories that related to CSA screening and reporting. Two research team members independently open-coded 20% of the data for interrater reliability (kappa=0.98) prior to completing the coding process. Three major categories emerged to inform CSA screening. First, early screening (e.g. kindergarten) was preferred. Confidentiality was a concern, specifically privacy in the school-setting. As CSA perpetrators are often known to the child, parental presence in the medical office was also a concern. Finally, refinement of the screening process was discussed starting with routine education on safe touch and defining "normal." Rather than direct questioning, consistent and repeated offering of opportunities to disclose CSA and identification of a trusted adult were suggested. Next steps should involve partnering with evidence-based CSA prevention programs to incorporate and evaluate the aforementioned elements. PMID- 28807481 TI - Necrotic mucosal CD30-positive ulcer on the oral mucosa: a self-healing lymphoma. PMID- 28807482 TI - Postoperative complications after head and neck operations that require free tissue transfer - prevalent, morbid, and costly. AB - To understand and reduce the impact of postoperative complications, we studied 568 patients who had had operations over 72 months in our hospital. Multivariate analysis indicated that factors indicative of coexisting conditions (including activated systemic inflammation) and the complexity of the operation are primary determinants of postoperative complications. The enhanced recovery after surgery (ERAS) care pathway did not have an effect on their occurrence or severity. Systematic study of patients' toleration of major head and neck operations is required, as optimal perioperative care pathways remain elusive. PMID- 28807483 TI - The potential efficacy of GABAB antagonists in depression. AB - Evidence for the potential utility of GABAB antagonists has been assembled from a variety of sources, including clinical experience with the GABAB agonist baclofen, murine genetic GABAB knock-outs, rodent studies of GABAB receptor expression and function following treatment with antidepressant therapies, animal models of depression, and some functional and post mortem data from human subjects. Definitive testing of GABAB antagonists in depression, however, still awaits the development of potent, selective and brain-penetrant compounds for human testing. PMID- 28807484 TI - Impact of drought on human health. PMID- 28807486 TI - Gender, Social Networks, and Stroke Preparedness in the Stroke Warning Information and Faster Treatment Study. AB - BACKGROUND AND PURPOSE: The study aimed to investigate the effect of gender on the association between social networks and stroke preparedness as measured by emergency department (ED) arrival within 3 hours of symptom onset. METHODS: As part of the Stroke Warning Information and Faster Treatment study, baseline data on demographics, social networks, and time to ED arrival were collected from 1193 prospectively enrolled stroke/transient ischemic attack (TIA) patients at Columbia University Medical Center. Logistic regression was conducted with arrival to the ED <=3 hours as the outcome, social network characteristics as explanatory variables, and gender as a potential effect modifier. RESULTS: Men who lived alone or were divorced were significantly less likely to arrive <=3 hours than men who lived with a spouse (adjusted odds ratio [aOR]: .31, 95% confidence interval [CI]: .15-0.64) or were married (aOR: .45, 95% CI: .23-0.86). Among women, those who lived alone or were divorced had similar odds of arriving <=3 hours compared with those who lived with a spouse (aOR: 1.25, 95% CI: .63 2.49) or were married (aOR: .73, 95% CI: .4-1.35). CONCLUSIONS: In patients with stroke/TIA, living with someone or being married improved time to arrival in men only. Behavioral interventions to improve stroke preparedness should incorporate gender differences in how social networks affect arrival times. PMID- 28807487 TI - Exploring how prison-based drug rehabilitation programming shapes racial disparities in substance use disorder recovery. AB - Prison-based therapeutic community (TC) programming is derived from the perspective that drug addiction is primarily symptomatic of cognitive dysfunction, poor emotional management, and underdeveloped self-reliance skills, and can be addressed in a collaborative space where a strong ideological commitment to moral reform and personal responsibility is required of its members. In this space, evidence of rehabilitation is largely centered on the client's relationship to language and the public adoption of a "broken self" narrative. Failure to master these linguistic performances can result in the denial of material and symbolic resources, thus participants learn how to use TC language to present themselves in ways that support existing institutionalized hierarchies, even if that surrender spells their self-denigration. This research examines the interview narratives of 300 former prisoners who participated in a minimum of 12 months of prison-based TC programming, and described how programming rhetoric impacted their substance abuse treatment experiences. While many of the respondents described distressing experiences as TC participants, White respondents were more likely to eventually embrace the "addict" label and speak of privileges and reintegrative support subsequently received. Black respondents were more likely to defy the treatment rhetoric, and either fail to complete the program or simulate a deficit-based self-narrative without investing in the content of those stories. The following explores the significance of language and identity construction in these carceral spaces, and how treatment providers as well as agency agendas are implicated in the reproduction of racial disparities in substance abuse recovery. PMID- 28807488 TI - Changes at Applied Ergonomics. PMID- 28807485 TI - Influence of Dietary Salt Knowledge, Perceptions, and Beliefs on Consumption Choices after Stroke in Uganda. AB - BACKGROUND: Previous research on Uganda's poststroke population revealed that their level of dietary salt knowledge did not lead to healthier consumption choices. PURPOSE: Identify barriers and motivators for healthy dietary behaviors and evaluate the understanding of widely accepted salt regulation mechanisms among poststroke patients in Uganda. METHODS: Convergent parallel mixed methods triangulation design comprised a cross-sectional survey (n = 81) and 8 focus group discussions with 7-10 poststroke participants in each group. We assessed participant characteristics and obtained insights into their salt consumption attitudes, perceptions, and knowledge. Qualitative responses were analyzed using an inductive approach with thematic analytic procedures. Relationships between healthy dietary salt compliance, dietary salt knowledge, and participant characteristics were assessed using logistic regression analyses. RESULTS: Healthy dietary salt consumption behaviors were associated with basic salt knowledge (P < .0001), but no association was found between compliance and salt disease-related knowledge (P = .314). Only 20% and 7% obtained health-related salt knowledge from their health facility and educational sources, respectively, whereas 44% obtained this information from media personalities; 92% of participants had no understanding of nutrition labels, and only 25% of the study population consumed potash-an inexpensive salt substitute that is both rich in potassium and low in sodium. CONCLUSION: One barrier to healthy dietary consumption choices among Uganda's stroke survivors is a lack of credible disease related information. Improving health-care provider stroke-related dietary knowledge in Uganda and encouraging the use of potash as a salt substitute would help reduce hypertension and thereby lower the risk of stroke. PMID- 28807489 TI - A model to estimate survival in ambulatory patients with hepatocellular carcinoma: Can it predict the natural course of hepatocellular carcinoma? AB - BACKGROUND: Several hepatocellular carcinoma (HCC) staging systems are available including the newly developed staging system, the Model to Estimate Survival in Ambulatory HCC patients (MESIAH); however, whether these staging systems could predict the natural course of HCC is largely unknown. METHODS: 1013 patients with history of HCC treatment and 111 patients without any history of treatment till death or last follow-up at a single tertiary hospital were included. RESULTS: The MESIAH score showed a better discrimination ability, with a C-statistic of 0.835 [95% confidence interval (CI), 0.810-0.861] in the group of treated patients compared to the Barcelona Clinic Liver Cancer (BCLC) staging system [0.739 (95% CI, 0.709-0.769)] before propensity score matching. However, the MESIAH score failed to stratify patients according to their risk of death in the group of untreated patients unlike the BCLC staging system. Propensity score matching analysis confirmed that the MESIAH score was most strongly influenced by whether treatment was given or not. CONCLUSIONS: Although the MESIAH score provided better prognostic stratification than other staging systems in treated HCC patients, it was not helpful in predicting the natural course of HCC. Since the treatment affects patient outcome and prognosis, it is necessary to develop a new staging system that can also reflect the natural course of HCC. PMID- 28807490 TI - FABP1 and Hepar expression levels in Barrett's esophagus and associated neoplasia in an Asian population. AB - INTRODUCTION: Barrett's esophagus (BE) is a premalignant condition associated with esophageal adenocarcinoma (EAC). Evidence highlights that EAC is associated with an estimated 5-year survival of approximately 10-15%. Therefore, there is a need to determine which biomarkers are of value in the diagnosis of BE and beyond. The aim of our study was to evaluate the clinical significance of markers known to be expressed across BE and associated neoplasia. METHODS: Retrospective tissues were obtained from columnar lined esophagus (CLE) without goblet cells (n=22), BE (n=29), dysplasia (n=14), and EAC (n=10). Standardised immunohistochemistry for FABP1, Hepar, CDH17, and CDX2 were performed followed by quantitative staining and statistical analysis. RESULTS: FABP1 expression was negligible in CLE and was highest in BE, with a further decrease in expression in dysplasia and EAC. Hepar expression was also negligible in CLE and was highest in dysplasia and BE, with a reduced expression in EAC. CDH17 and CDX2 showed a significantly higher expression in BE, dysplasia, and EAC compared to CLE. CONCLUSION: All 4 markers were excellent diagnostic panels to clearly discriminate BE from CLE. Moreover, as FABP1 and Hepar have different expression levels in dysplasia and EAC, these markers could function as key diagnostic aids in helping to determine the state of disease progression. PMID- 28807491 TI - Adenosine A2A receptor signaling affects IL-21/IL-22 cytokines and GATA3/T-bet transcription factor expression in CD4+ T cells from a BTBR T+ Itpr3tf/J mouse model of autism. AB - Autism is a complex heterogeneous neurodevelopmental disorder; previous studies have identified altered immune responses among individuals diagnosed with autism. An imbalance in the production of pro- and anti-inflammatory cytokines and transcription factors plays a role in neurodevelopmental behavioral and autism disorders. BTBR T+ Itpr3tf/J (BTBR) mice are used as a model for autism, as they exhibit social deficits, communication deficits, and repetitive behaviors compared with C57BL/6J (B6) mice. The adenosine A2A receptor (A2AR) appears to be a potential target for the improvement of behavioral, inflammatory, immune, and neurological disorders. We investigated the effects of the A2AR antagonist SCH 5826 (SCH) and agonist CGS 21680 (CGS) on IL-21, IL-22, T-bet, T-box transcription factor (T-bet), GATA3 (GATA Binding Protein 3), and CD152 (CTLA-4) expression in BTBR mice. Our results showed that BTBR mice treated with SCH had increased CD4+IL-21+, CD4+IL-22+, CD4+GATA3+, and CD4+T-bet+ and decreased CD4+CTLA-4+ expression in spleen cells compared with BTBR control mice. Moreover, CGS efficiently decreased CD4+IL-21+, CD4+IL-22+, CD4+GATA3+, and CD4+T-bet+ and increased CD4+CTLA-4 production in spleen cells compared with SCH-treated and BTBR control mice. Additionally, SCH treatment significantly increased the mRNA and protein expression levels of IL-21, IL-22, GATA3, and T-bet in brain tissue compared with CGS-treated and BTBR control mice. The augmented levels of IL-21/IL 22 and GATA3/T-bet could be due to altered A2AR signaling. Our results indicate that A2AR agonists may represent a new class of compounds that can be developed for use in the treatment of autistic and neuroimmune dysfunctions. PMID- 28807492 TI - Neuropsychiatric involvement in lupus is associated with the Nogo-a/NgR1 pathway. AB - Neuroinflammation- and neurodegeneration-induced nerve injury may represent important components of neuropsychiatric lupus (NPSLE). Myelin-associated neurite outgrowth inhibitor (Nogo)-a and its receptor, NgR1, limit recovery of the adult central nervous system after injury. We detected a soluble Nogo-a product in the cerebral spinal fluid of patients with NPSLE. In a mouse model of lupus, aging was associated with an increase in Nogo-a positive neurons, diminished myelin sheaths, enhanced pro-inflammatory cytokines, and impaired cognition and memory. Treatment with the Nogo-66 antagonist promoted myelin repair, improved cognition and memory, and downregulated pro-inflammatory factors. Our data imply the Nogo a/NgR1 pathway is involved in NPSLE. PMID- 28807493 TI - Homocysteine and cognitive function in Parkinson's disease. AB - INTRODUCTION: Increased plasma homocysteine (HC) is a risk factor for dementia in the general population. Levodopa therapy causes increased plasma HC, but it remains unclear whether elevated plasma HC is associated with cognitive impairment in Parkinson's disease (PD). METHODS: The study population includes all participants in the Pacific Northwest Udall Center (PANUC) Clinical cohort at the time of the study, consisting of 294 individuals with PD who had a standardized neuropsychological assessment and plasma collection for HC measurement. We tested the hypothesis that elevated plasma HC is inversely related to cognitive function in patients with PD. RESULTS: As expected, plasma HC was positively associated with age, disease duration, disease severity, and levodopa usage, while cognitive function was associated with age, education, gender, and APOE genotype, so subsequent analyses controlled for these covariates. When plasma HC was dichotomized as normal (<14 MUmol/L) or elevated (>=14 MUmol/L), subjects with hyper-homocysteinemia had lower scores on Digit Symbol (p = 0.031), Hopkins Verbal Learning Task (HVLT) Delayed Recall (p = 0.004), and semantic verbal fluency (p = 0.049). When examined as a continuous variable, plasma HC was inversely associated with HVLT Delayed Recall (p = 0.009)) and semantic verbal fluency (p = 0.004), but was not significantly related to Digit symbol, Trail-making test, Judgment of Line Orientation, phonemic verbal fluency, MMSE, or MOCA. When analysis was restricted to non demented subjects (n = 231), the findings were unchanged. CONCLUSIONS: We conclude that plasma HC is significantly associated with some aspects of cognitive function in PD, and may represent a treatable risk factor for cognitive decline in PD. PMID- 28807494 TI - Relationship between GWAS-linked three new loci in Essential tremor and risk of Parkinson's disease in Chinese population. PMID- 28807495 TI - The colorful spectrum of Tourette syndrome and its medical, surgical and behavioral therapies. AB - Tourette syndrome (TS) is a common neuropsychiatric disorder, more common in males than females, with onset before age 18. TS is characterized by multiple motor tics and one or more vocal/phonic tics, persisting for more than a year. Tics are unvoluntary, abrupt, rapid, repetitive, but non-rhythmic movements or sounds (vocalizations). They are preceded by an inner urge. Tics can be temporarily suppressed, but this leads to a powerful re-emergence. The performance of tics results in immediate but transient relief. Motor and vocal tics are classified as simple or complex. Tics emerge many times during the day and display spontaneous fluctuations in frequency, type, severity and complexity. Tics improve during concentration, worsen during relaxation or when under stress and occasionally are persistent in sleep. Psychiatric comorbidities such as attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD) and others frequently are present. Patients, families and teachers benefit from receiving instruction regarding the character of TS and its specific symptoms and from receiving counseling. Pharmacological treatment is not always necessary. Atypical antipsychotics (e.g. risperidone, ziprasidone, olanzapine, aripiprazole) are often the first-line treatment; typical antipsychotics (e.g. haloperidol, pimozide, fluphenazine), benzodiazepines (clonazepam) and tetrabenazine are employed less frequently. Alpha adrenergic agonists (clonidine, guanfacine), the selective noradrenaline re-uptake inhibitor, atomoxetine, and the amphetamine-like stimulant, methylphenidate, are useful in patients with tics and ADHD; selective serotonin re-uptake inhibitors can be useful in individuals with tics and OCD. Botulinum toxin can be effective in focal tics. In severe, treatment-resistant TS, deep brain stimulation may be beneficial. PMID- 28807497 TI - Characterisation of the porcine cytokines which activate the CD131betac common sub-unit, for potential immune-augmentation. AB - Early acting cytokines and growth factors such as those of the CD131 betac subunit, may offer an alternative method to the current use of antibiotics and chemicals such as anthelmintics in maintaining Porcine (Po) health. Thus far, the recombinant Po (rPo) Granulocyte-macrophage colony-stimulating factor (GM-CSF), rPo interleukin-3 (IL-3) and rPo interleukin-5 (IL-5) proteins have been identified and cloned and the biological activity of each cytokine has been confirmed in vitro, however, in vivo immune system regulation and hematopoietic stem cell (HSC) augmentation are regulated by numerous cytokines and cellular signals within the bone marrow (BM) niche. In order to quantify the use of recombinant cytokines in augmenting the immune response, it is necessary to determine the stages of hematopoiesis induced by each cytokine and possible areas of synergy requiring further investigation. Here we used the chemotherapeutic agent 5-fluorouracil (5-FU), to chemically induce a state of myelosuppression in young pigs. This allowed for the monitoring of both the autologous BM reconstitution and recombinant cytokine induced BM repopulation, precursor cell proliferation and cellular differentiation. The recombinant cytokines PoGM-CSF, PoIL-3 and PoIL-5 were administered by intramuscular injections (i.m.) following confirmation of 5-FU induced leukocytopenia. Blood and BM samples were collected and then analysed for cell composition. Statistically significant results were observed in several blood cell populations including eosinophils for animals treated with rPoIL-5, rPoGM-CSF and basophils for animals treated with rPoIL-3. BM analysis of CD90+ and CD172a+ cells confirmed myelosuppression in week one with significant results observed between rPoIL-3 and the 5-FU control group in week two and for the rPoGM-CSF group in week three. These results have demonstrated the effects of each of these rPo cytokines within the hematopoietic processes of the pig and may demonstrate similar outcomes in other mammalian models including human. PMID- 28807496 TI - CD4 effector T cell differentiation is controlled by IL-15 that is expressed and presented in trans. AB - T cells are both producers and consumers of cytokines, and autocrine cytokine signaling plays a critical role in T cell immunity. IL-15 is a homeostatic cytokine for T cells that also controls inflammatory immune responses. An autocrine role of T cell-derived IL-15, however, remains unclear. Here we examined IL-15 expression and signaling upon effector T cell differentiation in mice, and, surprisingly, found that CD4 T cells did not express IL-15. CD4 T cells lacked Il15 gene reporter activity, did not contain IL-15 transcripts, and did not produce IL-15Ralpha, the proprietary IL-15 receptor required for IL-15 trans-presentation. Moreover, IL-15 failed to inhibit Th17 cell differentiation and failed to generate Foxp3+ Treg cells in vitro. IL-2, which utilizes the same IL-2Rbeta/gammac receptor complex, however, successfully did so. Exogenous IL-15 only exerted bioactivity and controlled T cell differentiation when it was trans presented by IL-15Ralpha. Consequently, IL-15Ralpha-bound IL-15, but not free IL 15, suppressed Th17 cell differentiation and induced Treg cell generation. Collectively, these results reveal the absence of an IL-15 autocrine loop in CD4 T cells and strongly suggest that IL-15 trans-presentation by non-CD4 T cells is the primary mechanism via which IL-15 controls CD4 effector T cell differentiation. PMID- 28807498 TI - Vascular Pathology and Trajectories of Late-Life Major Depressive Disorder in Secondary Psychiatric Care. AB - OBJECTIVE: To examine 5-year trajectories of psychiatrist-treated late-life major depressive disorder (MDD), and evaluate whether previous vascular pathology is associated with more severe trajectories of late-life MDD. METHODS: Data were obtained from nationally representative civil, psychiatric, hospital, and prescription registers in Denmark. The sample included 11,092 older adults (>=60 years) who received their first diagnosis of MDD in a psychiatric facility in Denmark between 2000 and 2007. Trajectories of inpatient or outpatient contact at psychiatric hospitals for MDD over the 5-year period following index MDD diagnosis were modeled using latent class growth analysis. Measures of vascular disease (stroke, heart disease, vascular dementia) and vascular risk factors (hypertension, diabetes) were defined based on medication prescriptions and hospital-based diagnoses. Other predictors included demographic characteristics and characteristics of the index MDD diagnosis. RESULTS: The final model included 4 trajectories with consistently low (66% of the sample), high decreasing (19%), consistently high (9%), and moderate fluctuating (6%) probabilities of contact at a psychiatric hospital for MDD during the 5-year period following the index MDD diagnosis. We found no significant associations between any form of vascular pathology and trajectory class membership. Relative to the consistently low class, older age, greater severity and >12 months of prior antidepressant medication use predicted membership in the other three classes. CONCLUSIONS: A notable proportion (34%) of individuals diagnosed with MDD in late-life require secondary psychiatric treatment for extended time periods. We did not find evidence that vascular pathology predicts hospital contact trajectories in secondary-treated late-life MDD. PMID- 28807499 TI - Making the hard decisions: Ethical care decisions in wartime nursing practice. AB - BACKGROUND: Codes of ethics set forth standards of ethical conduct for nurses. However, nurses involved in wartime operations, or disasters, may often have their moral compass challenged by the patient care decisions necessary under adverse conditions. Reverse triage, resource allocation, and promotion of patient autonomy present multiple challenges to meeting commonly applied ethical principles. PURPOSE: The purpose of this study was to use the International Council of Nursing code of ethics as a framework to organize the ethical issues emerging from wartime nursing. METHODS: This article represents a secondary analysis of two studies using thematic analysis to identify ethical issues encountered by military nurses during the recent conflicts in Iraq and Afghanistan. Data were collected from nurses deployed from 2002 to 2015 and from 111 military nurses during focused interviews. DISCUSSION: Across both studies, issues such as resource allocation, patient triage, cultural differences, and equitable treatment for all emerged as challenges within the wartime environment. Nurses were at a loss at times as to how best to manage the situations and recommended that more education is needed in ethical decision making before, during, and after deployment as a debriefing strategy. Similar issues have been documented in military and disaster literature indicating that such challenges are not limited to the recent conflicts but cross time and location. CONCLUSION: By better understanding how nurses define, assess, and manage the ethical situations they encounter in wartime nursing practice, military nurses can better prepare for future conflicts, provide mentorship and targeted education to hopefully reducing any feelings of moral distress, and promote ethical decision making that will best promote outcomes in accordance with nursing's ethical codes. PMID- 28807500 TI - Twenty-five years of the TriService Nursing Research Program: Standing on the shoulders of giants. PMID- 28807501 TI - The COMT Val158Met polymorphism exerts a common influence on avoidant attachment and inhibited personality, with a pattern of positive heterosis. PMID- 28807502 TI - Cranial size and shape variation in isolated populations of the Olkhon mountain vole (Alticola olchonensis Litvinov, 1960). AB - The Olkhon mountain vole (Alticola olchonensis) is an endemic species of the Lake Baikal area with an extremely restricted range. We investigated the pattern of differentiation of cranial shape and size in five isolated insular populations of A. olchonensis from the Baikal islands (Olkhon, Hubyn, Borokchin, Ogoy, and Zamogoy). The ventral aspect of the cranium was analysed using landmark-based geometric morphometric methods While the sexes of A. olchonensis did not differ regarding cranium size and shape, multivariate statistical analyses showed that there were inter-island differences in skull morphology. Voles from the four small islands were similar in cranium size; the large skull size of voles inhabiting the Olkhon Island may be due to the more favourable habitat conditions on Olkhon. Shape differences among island populations were not associated with the geographic distances between islands. The voles from Borokchin Island differ the most in skull shape compared to other island populations. The combination of reduced gene flow among island populations (due to isolation and drift during population fluctuations) may be a suitable explanation for the significant differences in skull shape among island populations of A. olchonensis. PMID- 28807503 TI - Morphological, physiological and dietary covariation in migratory and resident adult brown trout (Salmo trutta). AB - The causes and consequences of trait relationships within and among the categories of physiology, morphology, and life-history remain poorly studied. Few studies cross the boundaries of these categories, and recent reviews have pointed out not only the dearth of evidence for among-category correlations but that trait relationships may change depending on the ecological conditions a population faces. We examined changes in mean values and correlations between traits in a partially migrant population of brown trout when migrant sea-run and resident stream forms were breeding sympatrically. Within each sex and life history strategy group, we used carbon and nitrogen stable isotopes to assess trophic level and habitat use; assessed morphology which reflects swimming and foraging ability; measured circulating cortisol as it is released in response to stressors and is involved in the transition from salt to freshwater; and determined oxidative status by measuring oxidative stress and antioxidants. We found that sea-run trout were larger and had higher values of stable isotopes, cortisol and oxidative stress compared to residents. Most groups showed some correlations between morphology and diet, indicating individual resource specialization was occurring, and we found consistent correlations between morphology and cortisol. Additionally, relationships differed between the sexes (cortisol and oxidative status were related in females but not males) and between life-history strategies (habitat use was related to oxidative status in male sea run trout but not in either sex of residents). The differing patterns of covariation between the two life-history strategies and between the sexes suggest that the relationships among phenotypic traits are subjected to different selection pressures, illustrating the importance of integrating multiple phenotypic measures across different trait categories and contrasting life history strategies. PMID- 28807504 TI - Bone up: craniomandibular development and hard-tissue biomineralization in neonate mice. AB - The presence of regional variation in the osteogenic abilities of cranial bones underscores the fact that the mechanobiology of the mammalian skull is more complex than previously recognized. However, the relationship between patterns of cranial bone formation and biomineralization remains incompletely understood. In four strains of mice, micro-computed tomography was used to measure tissue mineral density during perinatal development in three skull regions (calvarium, basicranium, mandible) noted for variation in loading environment, embryological origin, and ossification mode. Biomineralization levels increased during perinatal ontogeny in the mandible and calvarium, but did not increase in the basicranium. Tissue mineral density levels also varied intracranially, with density in the mandible being highest, in the basicranium intermediate, and in the calvarium lowest. Perinatal increases in, and elevated levels of, mandibular biomineralization appear related to the impending postweaning need to resist elevated masticatory stresses. Similarly, perinatal increases in calvarial biomineralization may be linked to ongoing brain expansion, which is known to stimulate sutural bone formation in this region. The lack of perinatal increase in basicranial biomineralization could be a result of earlier developmental maturity in the cranial base relative to other skull regions due to its role in supporting the brain's mass throughout ontogeny. These results suggest that biomineralization levels and age-related trajectories throughout the skull are influenced by the functional environment and ontogenetic processes affecting each region, e.g., onset of masticatory loads in the mandible, whereas variation in embryology and ossification mode may only have secondary effects on patterns of biomineralization. Knowledge of perinatal variation in tissue mineral density, and of normal cranial bone formation early in development, may benefit clinical therapies aiming to correct developmental defects and traumatic injuries in the skull, and more generally characterize loading environments and skeletal adaptations in mammals by highlighting the need for multi-level analyses for evaluating functional performance of cranial bone. PMID- 28807505 TI - Delayed Ejaculation and Associated Complaints: Relationship to Ejaculation Times and Serum Testosterone Levels. AB - BACKGROUND: Although delayed ejaculation (DE) is typically characterized as a persistently longer than anticipated or desired time to ejaculation (or orgasm) during sexual activity, a timing-based definition of DE and its association with serum testosterone has not been established in a large cohort. AIM: To examine in an observational study estimated intravaginal ejaculatory latency time (IELT) and masturbatory ejaculation latency time (MELT) in men self-reporting DE, assess the association of IELT and MELT with serum testosterone levels, and determine whether correlation with demographic and sexual parameters exist. METHODS: Men who resided in the United States, Canada, and Mexico were enrolled from 2011 to 2013. Self-estimated IELT and MELT were captured using an Ejaculatory Function Screening Questionnaire in a sample of 988 men screened for possible inclusion in a randomized clinical trial assessing testosterone replacement therapy for ejaculatory dysfunction (EjD) and who self-reported the presence or absence of DE and symptoms of hypogonadism. Additional comorbid EjDs (ie, anejaculation, perceived decrease in ejaculate volume, and decreased force of ejaculation) were recorded. Men with premature ejaculation were excluded from this analysis. IELT and MELT were compared between men self-reporting DE and men without DE. The associations of IELT and MELT with serum testosterone were measured. OUTCOMES: IELT, MELT, and total testosterone levels. RESULTS: Sixty-two percent of screened men self-reported DE with or without comorbid EjDs; 38% did not report DE but did report at least one of the other EjDs. Estimated median IELTs were 20.0 minutes for DE vs 15 minutes for no DE (P < .001). Estimated median MELTs were 15.0 minutes for DE vs 8.0 minutes for no DE (P < .001). Ejaculation time was not associated with serum testosterone levels. Younger men and those with less severe erectile dysfunction had longer IELTs and MELTs. CLINICAL IMPLICATIONS: Estimated ejaculation times during vaginal intercourse and/or masturbation were not associated with serum testosterone levels in this study; thus, routine androgen evaluation is not indicated in these men. STRENGTHS AND LIMITATIONS: This large systematic analysis attempted to objectively assess the ejaculation latency in men with self-reported DE. Limitations were that ejaculation time estimates were self-reported and were queried only once; the questionnaire did not distinguish between failure to achieve orgasm and ejaculation; and assessment of DE was limited to heterosexual vaginal intercourse and masturbation. CONCLUSION: IELT and MELT were longer in men with DE, and there was no association of ejaculation times with serum testosterone levels in this study population. Morgentaler A, Polzer P, Althof S, et al. Delayed Ejaculation and Associated Complaints: Relationship to Ejaculation Times and Serum Testosterone Levels. J Sex Med 2017;14:1116-1124. PMID- 28807506 TI - Altered vulnerability to asthma at various levels of ambient Benzo[a]Pyrene by CTLA4, STAT4 and CYP2E1 polymorphisms. AB - BACKGROUND: Within fossil- and solid-fuel dependent geographic locations, mechanisms of air pollution-induced asthma remains unknown. In particular, sources of greater genetic susceptibility to airborne carcinogen, namely, benzo[a]pyrene (B[a]P) has never been investigated beyond that of a few well known genes. OBJECTIVES: To deepen our understanding on how the genotypic variations within the candidate genes contribute to the variability in the children's susceptibility to ambient B[a]P on doctor-diagnosed asthma. METHODS: Clinically confirmed asthmatic versus healthy control children (aged, 7-15) were enrolled from historically polluted and rural background regions in Czech Republic. Contemporaneous ambient B[a]P concentration was obtained from the routine monitoring network. The sputum DNA was genotyped for 95 genes. B[a]P interaction with SNPs was studied by two-stage, semi-agnostic screening of 621 SNPs. RESULTS: The median B[a]P within the highly polluted urban center was 8 times higher than that in the background region (7.8 vs. 1.1 ng/m3) during the period of investigation. Within the baseline model, which considered B[a]P exposure-only, the second tertile range was associated with a significantly reduced odds (aOR = 0.28) of asthma (95% CI, 0.16 to 0.50) compared to those at the lowest range. However, the highest range of B[a]P was associated with 3.18 times greater odds of the outcome (95% CI, 1.77 to 5.71). Within the gene environment interaction models, joint occurrence of a high B[a]P exposure range and having a high-risk genotype at CTLA4 gene (rs11571316) was associated with 9 times greater odds (95% CI, 4.56-18.36) of the asthma diagnosis. Similarly, rs11571319 at CTLA4 and a high B[a]P exposure range was associated with a 8-times greater odds (95% CI, 3.95-14.27) of asthma diagnosis. Furthermore, having TG + GG genotypes on rs1031509 near STAT4 was associated with 5-times (95% CI, 3.03 8.55) greater odds of asthma diagnosis at the highest B[a]P range, compared to the odds at the reference range. Also CYP2E1 AT + TT genotypes (rs2070673) was associated with 5-times (95% CI, 3.1-8.8) greater odds of asthma diagnosis at the highest B[a]P exposure. CONCLUSIONS: The children, who jointly experience a high B[a]P exposure (6.3-8.5 ng/m3) as well as susceptible genotypes in CTLA4 (rs11571316 and rs11571319), STAT4 (rs1031509), and CYP2E1 (rs2070673), respectively, are associated with a significantly greater odds of having doctor diagnosed asthma, compared to those with neither risk factors. PMID- 28807507 TI - Optimizing Arthroscopy for Osteochondral Lesions of the Talus: The Effect of Ankle Positions and Distraction During Anterior and Posterior Arthroscopy in a Cadaveric Model. AB - PURPOSE: To quantify arthroscopic accessibility of the talar dome with predefined ankle positions through anterior and posterior approaches. METHODS: Fourteen below-knee cadaver specimens underwent preoperative range of motion assessments. A 30 degrees 2.7-mm arthroscopic camera was used to mark accessible areas at varying ankle positions. Accessible regions were quantified using a surface laser scanner and digital 3 * 3 grid. Statistical analyses were performed to detect differences in arthroscopic accessibility between different flexion angles and noninvasive distraction. RESULTS: The mean arthroscopic accessibility of the talus was 58.5% and 49.8% for the anterior and posterior approaches, respectively (P < .001). During anterior arthroscopy, accessibility increased with up to 30 degrees of plantarflexion (P < .001). There were no significant differences in accessibility between flexion groups for the posterior approach. There was significantly greater central zone accessibility for anterior arthroscopy (87.7%) when compared with posterior arthroscopy (74.3%; P = .002). Arthroscopic accessibility increased with increasing ankle distraction for both the anterior and posterior approaches (parameter estimates +/- standard error): anterior = 6.5% +/- 1.3%/mm of distraction, P < .001; and posterior = 7.0% +/- 2.8%/mm, P = .026. Frequency analysis showed that the posterior third of the talus was completely inaccessible in 7 out of 14 of ankles during anterior arthroscopy. The anterior third of the talus during posterior arthroscopy was inaccessible in 11 out of 14 ankles during posterior arthroscopy. CONCLUSIONS: Ankle plantarflexion up to 30 degrees may be adequate for anterior arthroscopy for osteochondral lesions of the talus (OLTs). Noninvasive distraction also increases accessibility during both anterior and posterior arthroscopy. Anterior arthroscopy should be used for central third OLTs due to greater accessibility. CLINICAL RELEVANCE: Ankle positioning is an important consideration for anterior arthroscopy. Surgical approach used should match with the location of the OLTs. PMID- 28807508 TI - Incidence and risk factors of venous thromboembolism: Peculiarities in psychiatric institutions. AB - INTRODUCTION: The objectives of this study were to assess the incidence and risk factors for venous thromboembolism (VTE) in a population of patients hospitalized in a psychiatric setting. MATERIAL AND METHODS: Episodes of VTE occurring in patients hospitalized at the Erstein Hospital (France), specialized in psychiatry, were retrospectively identified from a computerized database. The clinical, somatic, psychiatric and therapeutic characteristics of each patient were analyzed in comparison with a control population composed of patients of similar age and sex, hospitalized during the same period in a psychiatric setting but who did not suffer from VTE. RESULTS: Between January 2012 and October 2015, 12,320 patients were hospitalized. Forty-one patients experienced an episode of VTE, giving an incidence of 47.8per1000patient-years (3.32 cases per 1000 patients). Restriction of mobility (restraint or confinement), somatic clinical profile, psychiatric diagnosis or psychotropic treatment were not associated with an increased risk of VTE. The event occurred within the first 48h of hospitalization for 31.7% of patients, and within the first week for 56.1%. Time to onset for the occurrence of VTE between admission and the end of the first week was significantly associated with acute decompensation of a chronic psychiatric pathology (p=0.003). CONCLUSION: The incidence of VTE in a psychiatric setting is high. Acute decompensation of a chronic psychiatric pathology is associated with a risk of VTE. PMID- 28807509 TI - 18F-FDG-PET/CT angiography in the diagnosis of infective endocarditis and cardiac device infection in adult patients with congenital heart disease and prosthetic material. AB - OBJECTIVES: Infective endocarditis (IE) and cardiac device infection (CDI) are a major complication in the growing number of patients with congenital heart disease (CHD) reaching adulthood. We aimed to evaluate the added value of 18F-FDG PET/CT angiography (PET/CTA) in the diagnosis of IE-CDI in adults with CHD and intravascular or intracardiac prosthetic material, in whom echocardiography (ECHO) and modified Duke Criteria (DC) have limitations because of the patients' complex anatomy. METHODS: A prospective study was conducted in a referral center with multidisciplinary IE and CHD Units. PET/CTA and ECHO findings were compared in consecutive adult (>=18years) patients with CHD who have prosthetic material and suspected IE-CDI. The initial diagnosis using the DC and the diagnosis with the additional PET/CTA data (DC+PET/CTA) were compared with the final diagnostic consensus established by an expert team at three months. RESULTS: Between November-2012 and April-2017, 25 patients (15 men; median age 40years) were included. Cases were initially classified as definite in 8 (32%), possible in 14 (56%) and rejected in 3 (12%). DC+PET/CTA allowed reclassification of 12/14 (86%) cases initially identified as possible IE. The sensitivity, specificity, PPV, NPV, and accuracy of DC at IE suspicion were 39.1%/83.3%/90.4%/25.5%/61.2%, respectively. The diagnostic performance increased significantly with addition of PET/CTA data: 87%/83.3%/95.4%/61.5%/85.1%, respectively. PET/CTA also provided an alternative diagnosis in 3 patients with rejected IE, and detected pulmonary embolisms in 3 patients. CONCLUSIONS: PET/CTA was a useful diagnostic tool in the complex group of adult patients with CHD who have cardiac or intravascular prosthetic material and suspected IE or CDI, providing added diagnostic value to the modified DC (increased sensitivity) and improving case classification. PMID- 28807510 TI - Angina after percutaneous coronary intervention: The need for precision medicine. AB - Persistence or recurrence of angina after successful percutaneous coronary intervention (PCI) represent an important clinical issue involving from one fifth to one third of patients undergoing myocardial revascularization at one-year follow-up. A systematic approach to this syndrome is strongly needed. Precision medicine is particularly important in addressing angina after successful PCI because of the multiple underlying causes. Restenosis or coronary atherosclerosis progression explain symptom recurrence after successful PCI in some patients, while functional causes, including vasomotor abnormalities of epicardial coronary arteries and/or coronary microvascular dysfunction, explain symptoms in the remaining patients. In this review, we summarize the mechanisms of persistent or recurrent angina after PCI, proposing a diagnostic algorithm and a systematic therapeutic approach. PMID- 28807511 TI - Prevalence and predictors of inappropriate anticoagulation in patients with a CHA2DS2-VASc score of 0 and atrial fibrillation. AB - BACKGROUND: Previous studies have shown underutilization of anticoagulation therapy in patients with atrial fibrillation and a CHA2DS2-VASc score >=2; however there exists little data regarding the inappropriate use of anticoagulation in patients with a CHA2DS2-VASc score of 0. We aimed to determine the true prevalence and predictors of inappropriate anticoagulation therapy in patients with atrial fibrillation and a CHA2DS2-VASc score of 0. METHODS: A retrospective chart review was performed on all patients with atrial fibrillation and a CHA2DS2-VASc score of 0 in our institution from January 2009 to January 2016. Demographic and clinical data were collected from the electronic medical record. We utilized multivariable logistic regression analysis to determine independent clinical predictors of inappropriate anticoagulation administration. RESULTS: 512 patients were identified with a CHA2DS2-VASc score of 0 and a diagnosis of atrial fibrillation. Of the 137 patients prescribed anticoagulation, 64 patients were identified as inappropriately treated with anticoagulation therapy after assessing for other indications of warfarin or novel anticoagulant therapy. Independent variables associated with inappropriate anticoagulation administration were age (OR 1.07; 95% CI 1.03-1.10), body mass index (OR 1.06; 95% CI 1.01-1.10), absence of current aspirin use (OR 13.50; 95% CI 6.00-30.54) and persistent atrial fibrillation (OR 2.34; 95% CI 1.11-4.94). CONCLUSIONS: Our study shows that 12% of patients with a CHA2DS2-VASc score of 0 were inappropriately prescribed anticoagulant therapy. Independent predictors of unnecessary anticoagulation were age, body mass index, absence of current aspirin use and persistent atrial fibrillation. PMID- 28807512 TI - Non-linear finite element model to assess the effect of tendon forces on the foot ankle complex. AB - A three-dimensional foot finite element model with actual geometry and non-linear behavior of tendons is presented. The model is intended for analysis of the lower limb tendon forces effect in the inner foot structure. The geometry of the model was obtained from computational tomographies and magnetic resonance images. Tendon tissue was characterized with the first order Ogden material model based on experimental data from human foot tendons. Kinetic data was employed to set the load conditions. After model validation, a force sensitivity study of the five major foot extrinsic tendons was conducted to evaluate the function of each tendon. A synergic work of the inversion-eversion tendons was predicted. Pulling from a peroneus or tibialis tendon stressed the antagonist tendons while reducing the stress in the agonist. Similar paired action was predicted for the Achilles tendon with the tibialis anterior. This behavior explains the complex control motion performed by the foot. Furthermore, the stress state at the plantar fascia, the talocrural joint cartilage, the plantar soft tissue and the tendons were estimated in the early and late midstance phase of walking. These estimations will help in the understanding of the functional role of the extrinsic muscle-tendon-units in foot pronation-supination. PMID- 28807513 TI - Second generation prototype of a variable stiffness transverse plane adapter for a lower limb prosthesis. AB - The prescription and fitting of a traditional lower limb prosthesis often focuses on straight walking, neglecting maneuvers such as turning and pivoting that require flexibility in the transverse plane. Current devices that allow transverse plane movement only offer a fixed stiffness and are incapable of adapting to varying daily activities. Pilot testing of a first-generation variable stiffness torsion adapter (VSTA I) showed a benefit for individuals with lower limb amputation by reducing peak transverse plane moments at the residual limb which could lead to increased comfort, but testing was limited due to excessive device height and mass. The VSTA II, a second-generation prototype, is capable of discrete stiffness variation from 0.31 to 1.29 Nm/ degrees in 0.25 Nm/ degrees increments with +/-30 degrees of motion in addition to fully locked operation. Stiffness variation is enabled by five independent spring subunits that can be combined in parallel to create different, linear, stiffness settings. The VSTA II features a reduced mass (51% reduction) and height (42% reduction) compared to its predecessor along with a tether-free controller and power system. These improvements will permit greater recruitment for amputee studies, and allow for advanced testing both in and out of the lab. PMID- 28807515 TI - The Yin and Yang of the Non-Specific Effects of Vaccines. PMID- 28807514 TI - Highly Selective Activation of Heat Shock Protein 70 by Allosteric Regulation Provides an Insight into Efficient Neuroinflammation Inhibition. AB - Heat shock protein 70 (Hsp70) is widely involved in immune disorders, making it as an attractive drug target for inflammation diseases. Nonselective induction of Hsp70 upregulation for inflammation therapy could cause extensive interference in inflammation-unrelated protein functions, potentially resulting in side effects. Nevertheless, direct pharmacological activation of Hsp70 via targeting specific functional amino acid residue may provide an insight into precise Hsp70 function regulation and a more satisfactory treatment effect for inflammation, which has not been extensively focused. Here we show a cysteine residue (Cys306) for selective Hsp70 activation using natural small-molecule handelin. Covalent modification of Cys306 significantly elevates Hsp70 activity and shows more satisfactory anti-neuroinflammation effects. Mechanism study reveals Cys306 modification by handelin induces an allosteric regulation to facilitate adenosine triphosphate hydrolysis capacity of Hsp70, which leads to the effective blockage of subsequent inflammation signaling pathway. Collectively, our study offers some insights into direct pharmacological activation of Hsp70 by specially targeting functional cysteine residue, thus providing a powerful tool for accurately modulating neuroinflammation pathogenesis in human with fewer undesirable adverse effects. PMID- 28807516 TI - Quantification of annual sediment deposits for sustainable sand management in Aghanashini river estuary. AB - Sedimentation involving the process of silt transport also carries nutrients from upstream to downstream of a river/stream. Sand being one of the important fraction of these sediments is extracted in order to cater infrastructural/housing needs in the region. This communication is based on field research in the Aghanshini river basin, west coast of India. Silt yield in the river basin and the sedimentation rate assessed using empirical techniques supplemented with field quantifications using soundings (SONAR), show the sediment yield of 1105-1367 kilo cum per year and deposition of sediment of 61 (2016) to 71 (2015) cm. Quantifications of extractions at five locations, reveal of over exploitation of sand to an extent of 30% with damages to the breeding ground of fishes, reduced productivity of bivalves, etc., which has affected dependent people's livelihood. This study provides vital insights towards sustainable sand harvesting through stringent management practices. PMID- 28807517 TI - TRIM21 and the Function of Antibodies inside Cells. AB - Therapeutic antibodies targeting disease-associated antigens are key tools in the treatment of cancer and autoimmunity. So far, therapeutic antibodies have targeted antigens that are, or are presumed to be, extracellular. A largely overlooked property of antibodies is their functional activity inside cells. The diverse literature dealing with intracellular antibodies emerged historically from studies of the properties of some autoantibodies. The identification of tripartite motif (TRIM) 21 as an intracellular Fc receptor linking cytosolic antibody recognition to the ubiquitin proteasome system brings this research into sharper focus. We review critically the research related to intracellular antibodies, link this to the TRIM21 effector mechanism, and highlight how this work is exposing the previously restricted intracellular space to the potential of therapeutic antibodies. PMID- 28807518 TI - High income countries should be more aware of self-immolation in asylum seekers. PMID- 28807519 TI - Lower-order anxiety sensitivity and intolerance of uncertainty dimensions operate as specific vulnerabilities for social anxiety and depression within a hierarchical model. AB - Within a hierarchical framework for depressive and anxiety disorders, negative affect (NA) is posited to be indirectly related to social anxiety and depression through cognitive vulnerabilities, including intolerance of uncertainty (IU) and anxiety sensitivity (AS). However, few prior studies have considered whether the lower-order dimensions of IU (i.e., prospective and inhibitory IU) and AS (i.e., physical, cognitive, and social concerns) better explain the indirect relation between NA and social anxiety and depression. The indirect relations between NA and social anxiety and depression through these cognitive vulnerabilities were examined using structural equation modeling in a clinical sample (N=298). NA and social anxiety symptoms were indirectly related through AS social concerns and inhibitory IU, although a direct effect of NA was also found. Only AS social concerns explained the relation between NA and a social anxiety disorder diagnosis. AS cognitive concerns was the only cognitive vulnerability factor to indirectly explain the relation between NA and depressive symptoms, although a direct effect of NA was also found. These findings suggest that the lower-order dimensions of AS and IU demonstrate more specific and less transdiagnostic associations with social anxiety and depression. PMID- 28807521 TI - Erratum. PMID- 28807520 TI - EGFR-amplification plus gene expression profiling predicts response to combined radiotherapy with EGFR-inhibition: A preclinical trial in 10 HNSCC-tumour xenograft models. AB - BACKGROUND AND PURPOSE: Improvement of the results of radiotherapy by EGFR inhibitors is modest, suggesting significant intertumoural heterogeneity of response. To identify potential biomarkers, a preclinical trial was performed on ten different human squamous cell carcinoma xenografts of the head and neck (HNSCC) studying in vivo and ex vivo the effect of fractionated irradiation and EGFR inhibition. Local tumour control and tumour growth delay were correlated with potential biomarkers, e.g. EGFR gene amplification and radioresponse associated gene expression profiles. MATERIAL AND METHODS: Local tumour control 120days after end of irradiation was determined for fractionated radiotherapy alone (30f, 6weeks) or after simultaneous EGFR-inhibition with cetuximab. The EGFR gene amplification status was determined using FISH. Gene expression analyses were performed using an in-house gene panel. RESULTS: Six out of 10 investigated tumour models showed a significant increase in local tumour control for the combined treatment of cetuximab and fractionated radiotherapy compared to irradiation alone. For 3 of the 6 responding tumour models, an amplification of the EGFR gene could be demonstrated. Gene expression profiling of untreated tumours revealed significant differences between amplified and non-amplified tumours as well as between responder and non-responder tumours to combined radiotherapy and cetuximab. CONCLUSION: The EGFR amplification status, in combination with gene expression profiling, may serve as a predictive biomarker for personalized interventional strategies regarding combined treatment of cetuximab and fractionated radiotherapy and should, as a next step, be clinically validated. PMID- 28807522 TI - Orthostatic Hypotension: A Practical Approach to Investigation and Management. AB - The maintenance of blood pressure upon the assumption of upright posture depends on rapid cardiovascular adaptations driven primarily by the autonomic nervous system. Failure of these compensatory mechanisms can result in orthostatic hypotension (OH), defined as sustained reduction in systolic blood pressure > 20 mm Hg or diastolic blood pressure > 10 mm Hg within 3 minutes of standing or > 60 degrees head-up tilt. OH is a common finding, particularly in elderly populations, associated with cardiovascular and cerebrovascular morbidity and mortality. Therefore, it is important to identify OH in the clinical setting. The detection of OH requires blood pressure measurements in the supine and standing positions. A more practical approach in clinics might be measurement of seated and standing blood pressure, but this can produce smaller depressor responses because of reduced gravitational stress. Heart rate responses to standing should be concomitantly measured to assess integrity of baroreflex function. Patients with OH can present with symptoms of cerebral hypoperfusion on standing predisposing to syncope and falls; however, many patients are asymptomatic. When the diagnosis of OH is established, it is important to document potentially deleterious medications and comorbidities and to assess for neurogenic autonomic impairment to establish underlying causes. Treatment should be initiated in a structured and stepwise approach starting with nonpharmacological interventions (eg, lifestyle modifications and physical countermanoeuvres), and adding pharmacological interventions as needed in patients with severe OH (eg, midodrine, droxidopa, fludrocortisone). The treatment goal in OH should be to improve symptoms and functional status, and not to target arbitrary blood pressure values. PMID- 28807523 TI - Multidisciplinary Heart Failure Clinics Are Associated With Lower Heart Failure Hospitalization and Mortality: Systematic Review and Meta-analysis. AB - BACKGROUND: Heart failure (HF) clinics (HFCs) are an integral aspect of the strategy for community HF care. METHODS: A systematic search was conducted to retrieve studies. We searched for candidate articles in the PubMed, EMBASE, and Cochrane databases from 1990 to January 2017. RESULTS: We included 16 randomized controlled trials in the meta-analysis with 3999 patients. The HFC group had a lower incidence of the primary composite end point of HF hospitalization and all cause mortality (odds ratio [OR], 0.58; P = 0.0003). The benefit was maintained when stratified according to non-nurse led HFCs (OR, 0.52; P = 0.003), clinics that followed-up patients >= 3 months (OR, 0.51; P = 0.0009), patients with mean ejection fraction <= 30% (OR, 0.39; P = 0.02), and ejection fraction > 30% (OR, 0.72; P = 0.02), and patients with recent hospitalization for HF (OR, 0.51; P = 0.0001). There was no benefit in patients who were seen in HFCs with limited follow-up <= 3 months (OR, 0.91; P = 0.69), patients with stable HF without recent hospitalization (OR, 0.95; P = 0.70), and studies published after 2008 (OR, 0.89; P = 0.31). Patients in the HFC group had lower HF hospitalization rates (OR, 0.68; P = 0.003), however, no significant difference in all-cause hospitalization (OR, 1.04; P = 0.33). There was lower all-cause mortality in the HFC group (OR, 0.71; P = 0.006). CONCLUSIONS: The results of our analysis show a benefit of HFC to reduce HF hospitalization, and all-cause mortality. This was a cumulative benefit of all randomized clinical trials that assessed the benefit of HFC, with additional analysis showing a greater benefit among patients with recent emergency room visit or hospitalization, and patients seen frequently in follow-up >= 3 months. PMID- 28807524 TI - Peak linear and rotational acceleration magnitude and duration effects on maximum principal strain in the corpus callosum for sport impacts. AB - Concussion has been linked to the presence of injurious strains in the brain tissues. Research investigating severe brain injury has reported that strains in the brain may be affected by two parameters: magnitude of the acceleration, and duration of that acceleration. However, little is known how this relationship changes in terms of creating risk for brain injury for magnitudes and durations of acceleration common in sporting environments. This has particular implications for the understanding and prevention of concussive risk of injury in sporting environments. The purpose of this research was to examine the interaction between linear and rotational acceleration and duration on maximum principal strain in the brain tissues for loading conditions incurred in sporting environments. Linear and rotational acceleration loading curves of magnitudes and durations similar to those from impact in sport were used as input to the University College Brain Trauma Model and maximum principal strain (MPS) was measured for the different curves. The results demonstrated that magnitude and duration do have an effect on the strain incurred by the brain tissue. As the duration of the acceleration increases, the magnitude required to achieve strains reflecting a high risk of concussion decreases, with rotational acceleration becoming the dominant contributor. The magnitude required to attain a magnitude of MPS representing risk of brain injury was found to be as low as 2500rad/s2 for impacts of 10-15ms; indicating that interventions to reduce the risk of concussion in sport must consider the duration of the event while reducing the magnitude of acceleration the head incurs. PMID- 28807525 TI - Experimental and computational analysis of micromotions of an uncemented femoral knee implant using elastic and plastic bone material models. AB - It is essential to calculate micromotions at the bone-implant interface of an uncemented femoral total knee replacement (TKR) using a reliable computational model. In the current study, experimental measurements of micromotions were compared with predicted micromotions by Finite Element Analysis (FEA) using two bone material models: linear elastic and post-yield material behavior, while an actual range of interference fit was simulated. The primary aim was to investigate whether a plasticity model is essential in order to calculate realistic micromotions. Additionally, experimental bone damage at the interface was compared with the FEA simulated range. TKR surgical cuts were applied to five cadaveric femora and micro- and clinical CT- scans of these un-implanted specimens were made to extract geometrical and material properties, respectively. Micromotions at the interface were measured using digital image correlation. Cadaver-specific FEA models were created based on the experimental set-up. The average experimental micromotion of all specimens was 53.1+/-42.3um (mean+/ standard deviation (SD)), which was significantly higher than the micromotions predicted by both models, using either the plastic or elastic material model (26.5+/-23.9um and 10.1+/-10.1um, respectively; p-value<0.001 for both material models). The difference between the two material models was also significant (p value<0.001). The predicted damage had a magnitude and distribution which was comparable to the experimental bone damage. We conclude that, although the plastic model could not fully predict the micro motions, it is more suitable for pre-clinical assessment of a press-fit TKR implant than using an elastic bone model. PMID- 28807527 TI - Does CT help in predicting preepiglottic space invasion in laryngeal carcinoma? AB - OBJECTIVE: Evaluating preepiglottic space involvement in laryngeal cancer by CT may lead misinterpretation. We sought to understand the causes of misinterpretation in evaluating the preepiglottic space by CT and assessed the effects of misinterpretation in treatment plans of patients with laryngeal squamous cell carcinomas. METHODS: Specimen histopathology reports of 102 (99 male, 3 female) patients who underwent total or partial laryngectomy due to supraglottic and/or transglottic laryngeal carcinoma were reviewed. Neck CTs were also re-assessed for preepiglottic space involvement by three radiologists. The initial surgical treatment choices were re-examined according to the current radiological evaluation in combination with pathological results of the specimens and physical examination findings in the patients. Interobserver agreement regarding image interpretation was based on a kappa analysis. RESULTS: The interclass correlation coefficient in predicting preepiglottic space invasion was 0.74; this was considered 'good.' Among the three radiologists, sensitivity, specificity, accuracy of CT in detecting preepiglottic space involvement were 86 93%, 75-93%, and 77-93%, respectively, while the negative and positive predictive values were 97-98% and 38-50%, respectively. Given the previous treatments applied, false-positive diagnoses for PES involvement resulted in overtreatment in 2.9% of cases. False-negative diagnoses of PES involvement (1.9% of cases) did not result in any undertreatment. CONCLUSIONS: Although CT is a practical and inexpensive imaging tool for evaluating laryngeal carcinomas, the PPV of CT in assessing preepiglottic space invasion, especially in advanced tumors, is low and may lead to overtreatment. PMID- 28807526 TI - The effect of fixed charge density and cartilage swelling on mechanics of knee joint cartilage during simulated gait. AB - The effect of swelling of articular cartilage, caused by the fixed charge density (FCD) of proteoglycans, has not been demonstrated on knee joint mechanics during simulated walking before. In this study, the influence of the depth-wise variation of FCD was investigated on the internal collagen fibril strains and the mechanical response of the knee joint cartilage during gait using finite element (FE) analysis. The FCD distribution of tibial cartilage was implemented from sodium (23Na) MRI into a 3-D FE-model of the knee joint ("Healthy model"). For comparison, models with decreased FCD values were created according to the decrease in FCD associated with the progression of osteoarthritis (OA) ("Early OA" and "Advanced OA" models). In addition, a model without FCD was created ("No FCD" model). The effect of FCD was studied with five different collagen fibril network moduli of cartilage. Using the reference fibril network moduli, the decrease in FCD from "Healthy model" to "Early OA" and "Advanced OA" models resulted in increased axial strains (by +2 and +6%) and decreased fibril strains (by -3 and -13%) throughout the stance, respectively, calculated as mean values through cartilage depth in the tibiofemoral contact regions. Correspondingly, compared to the "Healthy model", the removal of the FCD altogether in "NoFCD model" resulted in increased mean axial strains by +16% and decreased mean fibril strains by -24%. This effect was amplified as the fibril network moduli were decreased by 80% from the reference. Then mean axial strains increased by +6, +19 and +49% and mean fibril strains decreased by -9, -20 and -32%, respectively. Our results suggest that the FCD in articular cartilage has influence on cartilage responses in the knee during walking. Furthermore, the FCD is suggested to have larger impact on cartilage function as the collagen network degenerates e.g. in OA. PMID- 28807528 TI - Clinical course of incidental parathyroidectomy: Single center experience. AB - OBJECTIVE: Thyroidectomy is a very common surgical procedure. Regardless of surgeon experience, incidental parathyroidectomy is a complication of thyroidectomy. The aim of this study was to identify the clinical course of incidental parathyroidectomies after thyroidectomy. METHODS: Patients who underwent thyroidectomy between January 2010 and June 2014 were evaluated retrospectively. Pathology reports were reviewed for the presence of parathyroid tissue in the thyroidectomy pathology specimens. Information regarding demographic, laboratory variables, operative details, and postoperative complications were collected. RESULTS: Incidental parathyroidectomy was found in 178 out of 3022 patients who had thyroidectomy (5.8%). Types of surgeries performed for 178 patients were total thyroidectomy (TT) in 132(74.2%) cases, TT and central lymph node dissection(CLND) in 30 (16.9%) cases, lobectomy in seven cases (3.9%), completion thyroidectomy in five (2.8%) patients and modified cervical lymph node dissection in four (2.2%)patients. One and two parathyroid glands were accidentally removed in 152 (85.3%) and 26 (14.7%) patients, respectively. In the entire series, biochemical temporary postoperative hypocalcemia occurred in 75(42.1%) patients and permanent hypocalcemia occured in 12 (6.7%) patients with incidental parathyroidectomy. There was not a statistically significant difference regarding the occurrence of postoperative permanent hypocalcemia between the patients who had incidental parathyroidectomy of one gland and the patients with two incidental parathyroidectomies (p=0.114). CONCLUSION: Incidental parathyroidectomy is not uncommon during thyroidectomy. No association between inadvertent parathyroidectomy and postoperative permanent hypocalcemia was found. PMID- 28807529 TI - Correlation of soft palate length with velum obstruction and severity of obstructive sleep apnea syndrome. AB - OBJECTIVE: Our aim in this study was to analyze whether soft palate length and velum obstruction during sleep are correlated and to determine the effects of related parameters on obstructive sleep apnea syndrome (OSAS) severity. We used computed tomography to measure soft palate length and drug-induced sleep endoscopy (DISE) to evaluate velum obstruction severity. Patients also underwent polysomnography (PSG) for evaluation of OSAS severity. METHODS: A retrospective cohort of 67 patients with OSAS treated between May 1st, 2013 and July 31st, 2016 was analyzed. Each patient underwent DISE, PSG, and computed tomography. Using DISE, velum obstruction was categorized by the VOTE classification method. Using computed tomography, soft palate length was measured as the length of the posterior nasal spine to the uvula. Correlations of velum obstruction in DISE and PSG parameters (obstructive apnea, hypopnea, apnea hypopnea index (AHI), respiratory effort related arousal (RERA), respiratory disturbance index (RDI), baseline SaO2, and minimum SaO2) with soft palate length were also analyzed. RESULTS: Among the 67 patients, the average PNS-U length was 39.90+/-4.19mm. Length was significantly different by age but not by other demographic characteristics such as sex, past history, or BMI. DISE revealed a statistically significant difference of velum obstruction degree; the cutoff value for PNS-U was 39.47mm. The PSG results, obstructive apnea, AHI, RDI, baseline SaO2, and minimum SaO2 were correlated with PNS-U length, while other results such as hypopnea and RERA showed no correlation. CONCLUSION: Analysis of soft palate length showed that increased PNS-U length was associated with higher rates of obstructive apnea, AHI, and RDI as assessed by PSG. In contrast, lower baseline SaO2 and minimum SaO2 values were seen by PSG; more severe velum obstruction was seen by DISE. We propose that when a soft palate is suspected in OSAS, computed tomography measurement of soft palate length is a valid method for estimating the degree of velum obstruction and the severity of OSAS. PMID- 28807530 TI - Cervical mass as the first clinical manifestation of unsuspected metastatic seminoma. AB - The authors reported a case of a 27-year-old man with a nontender left neck mass that had grown quite rapidly within few weeks. FNAB and CT were not consistent to establish the definite diagnosis. After excisional biopsy, the histopathological examination and the immunohistochemical study of the specimen revealed a cervical metastasis of seminoma. The patient was treated with chemotherapy with a complete clinical remission. This uncommon case-report can represent a great diagnostic and therapeutic challenge and should be considered in the differential diagnosis of every cervical masses occurring in young males patients. Diagnostic delays are unfortunately common and may lead to metastatic spread and worse prognosis. PMID- 28807531 TI - Absent cardiac and muscle sympathetic nerve activities involvement in Ross syndrome: A follow-up study. AB - PURPOSE: Ross syndrome (RS) is characterized by selective involvement of post ganglionic skin sympathetic nerve fibres. We report a follow-up study in 4 patients to clarify whether in RS autonomic dysfunction spreads affecting also cardiovascular system. METHODS: The patients underwent cardiovascular reflexes (CVR) and microneurography recording of muscle sympathetic nerve activity (MSNA) for a follow-up mean period of 5years. RESULTS: CVR and MSNA were normal at baseline and unchanged over the follow-up. CONCLUSIONS: Cardiovascular autonomic system is spared in RS differently from skin autonomic activity dysfunction which progress over time. However, before drawing any definite conclusion, a large cohort of patients needs to be studied. PMID- 28807532 TI - Multicenter Evaluation of Biochemical Relapse-Free Survival Outcomes for Intraoperatively Planned Prostate Brachytherapy Using an Automated Delivery System. AB - PURPOSE: To report biochemical recurrence in prostate cancer treated with intraoperatively planned low-dose-rate prostate brachytherapy using an automated delivery system (IO-LDRB). METHODS AND MATERIALS: Between 2003 and 2013, 2608 patients from 3 centers were treated with IO-LDRB as single-modality treatment for low or low-tier intermediate-risk prostate cancer. Databases from the 3 centers have been analyzed. These independent databases were collected prospectively. Patient, tumor, and treatment characteristics were then compared, Kaplan-Meier survival estimates of biochemical relapse-free survival (bRFS) were generated, and the Cox proportional hazards model was used to determine factors predicting for relapse. RESULTS: A total of 2608 patients with a median follow-up of 4.7 (interquartile range, 3.1-6.9) years were analyzed. Median age was 64 (range, 42-84) years. In these patients, median initial prostate-specific antigen was 5.5 ng/mL, 74% were T1, and 26% were T2; 73% were Gleason 6, and 25% Gleason 7. Median percentage of biopsy cores positive was 33%, and median gland volume was 34.2 cm3. Eleven percent of patients received hormones for a median of 3.0 months before implantation. Median seed activity was 0.437 mCi, D90 (dose covering 90% of the prostate volume) was 186.7 Gy, and V100 was 99.37%. Biochemical relapse was observed in 124 patients (4.8%), and median time to failure was 4.0 years. Predicted bRFS was 93% at 7 years. On Cox regression bRFS was dependent only on D90 at the time of implantation and prostate-specific antigen density. CONCLUSIONS: This study demonstrates that IO-LDRB is an effective treatment option for patients with low and low-tier intermediate-risk prostate cancer. Rates of biochemical relapse remain low several years after treatment. These results compared favorably to published manual preplan technique results. PMID- 28807533 TI - Evaluation of the Effects of Prostate Radiation Therapy on Occludin Expression and Ultrasonography Characteristics of the Bladder. AB - PURPOSE: To evaluate the effects of radiation dose in prostate radiation therapy (RT) on occludin expression and ultrasonography characteristics of the bladder. METHODS AND MATERIALS: Urine samples of 64 prostate RT patients were collected before, at regular intervals during, and 3 months after RT. Occludin expression analysis was performed, and bladder wall echogenicity and echotexture were investigated by ultrasound and the gray-scale histogram analysis method. The bladder equivalent uniform dose (EUD) was derived from individually produced dose treatment plan for each patient. Clinical scoring for bladder-specific symptoms was done using the Radiation Therapy Oncology Group Acute Radiation Morbidity Scoring Criteria Scale. RESULTS: Thirty patients (47%) experienced at least 1 of the studied bladder symptoms (grade >=1 endpoints), including urinary pain, frequency, urgency, straining, incontinence, hematuria, dysuria, and nocturia. For these patients there were significant changes in urine occludin levels after starting the treatment compared with the baseline urine samples (P=.023). The mean bladder EUD that caused a significant change in occludin level, which occurred after the 15th RT session, was 26.9 Gy (range, 13.2-36.5 Gy, P=.020). In all patients a significant reduction in bladder echogenicity (P=.0137) and a significant change in its echotexture (P=.047) was found after the 10th RT session, after which the EUD to the bladder reached 17.9 Gy (range, 8.8-24.3 Gy). CONCLUSIONS: Significant changes in occludin expression level and bladder wall echogenicity and echotexture occurred during prostate RT. Our findings suggest that a significant reduction in bladder echogenicity and increase in occludin expression during treatment can be associated with acute urinary complications. PMID- 28807535 TI - Department of Error. PMID- 28807534 TI - Computed Tomography Radiomics Predicts HPV Status and Local Tumor Control After Definitive Radiochemotherapy in Head and Neck Squamous Cell Carcinoma. AB - PURPOSE: This study aimed to predict local tumor control (LC) after radiochemotherapy of head and neck squamous cell carcinoma (HNSCC) and human papillomavirus (HPV) status using computed tomography (CT) radiomics. METHODS AND MATERIALS: HNSCC patients treated with definitive radiochemotherapy were included in the retrospective study approved by the local ethical commission (93 and 56 patients in the training and validation cohorts, respectively). Three hundred seventeen CT radiomic features, including those based on shape, intensity, texture, and wavelet transform, were calculated in the primary tumor region. Cox and logistic regression models were built to predict LC and HPV status, respectively. The best-performing features in the univariable analysis were included in the multivariable analysis after the exclusion of redundant features. The quality of the models was assessed using the concordance index (CI) for modeling of LC and receiver operating characteristics area under the curve (AUC) for HPV status prediction. The radiomics LC model was compared to a model incorporating clinical parameters (tumor stage, volume, and HPV status) and a mixed model. RESULTS: A radiomic signature comprising 3 features was significantly associated with LC (CItraining = 0.75 and CIvalidation = 0.78), showing that tumors with a more heterogeneous CT density distribution are at risk for decreased LC. The addition of clinical parameters to the radiomics model slightly improved the model in the training cohort but not in the validation cohort. Another radiomic signature showed good performance in HPV status prediction (AUCtraining = 0.85 and AUCvalidation = 0.78) and indicated that HPV positive tumors have a more homogenous CT density distribution. CONCLUSIONS: Heterogeneity of HNSCC tumor density, quantified by CT radiomics, is associated with LC after radiochemotherapy and HPV status. PMID- 28807537 TI - Learning from a negative trial of lockable pesticide storage. PMID- 28807536 TI - Effectiveness of household lockable pesticide storage to reduce pesticide self poisoning in rural Asia: a community-based, cluster-randomised controlled trial. AB - BACKGROUND: Agricultural pesticide self-poisoning is a major public health problem in rural Asia. The use of safer household pesticide storage has been promoted to prevent deaths, but there is no evidence of effectiveness. We aimed to test the effectiveness of lockable household containers for prevention of pesticide self-poisoning. METHODS: We did a community-based, cluster-randomised controlled trial in a rural area of North Central Province, Sri Lanka. Clusters of households were randomly assigned (1:1), with a sequence computer-generated by a minimisation process, to intervention or usual practice (control) groups. Intervention households that had farmed or had used or stored pesticide in the preceding agricultural season were given a lockable storage container. Further promotion of use of the containers was restricted to community posters and 6 monthly reminders during routine community meetings. The primary outcome was incidence of pesticide self-poisoning in people aged 14 years or older during 3 years of follow-up. Identification of outcome events was done by staff who were unaware of group allocation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT1146496. FINDINGS: Between Dec 31, 2010, and Feb 2, 2013, we randomly assigned 90 rural villages to the intervention group and 90 to the control group. 27 091 households (114 168 individuals) in the intervention group and 26 291 households (109 693 individuals) in the control group consented to participate. 20 457 household pesticide storage containers were distributed. In individuals aged 14 years or older, 611 cases of pesticide self-poisoning had occurred by 3 years in the intervention group compared with 641 cases in the control group; incidence of pesticide self-poisoning did not differ between groups (293.3 per 100 000 person-years of follow-up in the intervention group vs 318.0 per 100 000 in the control group; rate ratio [RR] 0.93, 95% CI 0.80-1.08; p=0.33). We found no evidence of switching from pesticide self-poisoning to other forms of self-harm, with no significant difference in the number of fatal (82 in the intervention group vs 67 in the control group; RR 1.22, 0.88-1.68]) or non-fatal (1135 vs 1153; RR 0.97, 0.86-1.08) self-harm events involving all methods. INTERPRETATION: We found no evidence that means reduction through improved household pesticide storage reduces pesticide self poisoning. Other approaches, particularly removal of highly hazardous pesticides from agricultural practice, are likely to be more effective for suicide prevention in rural Asia. FUNDING: Wellcome Trust, with additional support from the American Foundation for Suicide Prevention, Lister Institute of Preventive Medicine, Chief Scientist Office of Scotland, University of Copenhagen, and NHMRC Australia. PMID- 28807540 TI - Necessity of preoperative activated partial thromboplastin time test as a predictor for surgical hemorrhage in obstetric and gynecological patients in China. AB - BACKGROUND: On an international scale, the necessity of preoperative coagulation screen remains controversial, yet in China, coagulation screen is still a routine test before surgery required by the Ministry of Health of China. METHODS: A retrospective review of 26,807 patients >18y presenting with problems related to the areas of gynecology and obstetrics from March 2013 to July 2015 was performed, and the rate of major bleeding and the amount of blood lost during surgery were compared among groups of patients grouped according to the values of preoperative APTT, the departments the patients belonged to, or the measures for intervention. RESULTS: Groups with increased APTT had higher rates of major bleeding (9.80% & 26.14% vs 2.77%, P<0.001) and more blood loss (862.9 and 1455.6ml vs 194.0ml, P<0.001). And the same conclusion could be induced in both the obstetric and gynecological patients when they were taken into account separately. For obstetric patients, once those with high bleeding risks, e.g., placental abruption, placental implantation, or preoperative massive hemorrhage were excluded, groups with increased APTT would no longer demonstrated the higher rate of major bleeding (0.91% & 2.38% vs 0%, P=0.409 & 0.833) and would even have a lower amount of blood loss (202.76 and 228.09ml vs 322.13ml, P=0.003 and 0.027). In increased APTT patients without bleeding or bleeding tendency, FFP intervention would not make a difference in the rate of major bleeding (7.69% vs 8.37%, P=0.203) and the amount of blood loss (271.35ml vs 306.63, P=0.865). CONCLUSION: For Chinese patients from the Obstetrics and Gynecology Departments, APTT is a good screen test to predict surgical hemorrhage. PMID- 28807538 TI - Lactose malabsorption and taste aversion learning. AB - Consumption of foods can be suppressed by two feeding system defense mechanisms: conditioned taste aversion (CTA) or taste avoidance learning (TAL). There is a debate in the literature about which form of intake suppression is caused by various aversive stimuli. For instance, illness-inducing stimuli like lithium chloride are the gold standard for producing CTA and external (or peripheral) painful stimuli, such as footshock, are the traditional model of TAL. The distinction between CTA and TAL, which have identical effects on intake, is based on differential effects on palatability. That is, CTA involves a decrease in both intake and palatability, whereas TAL suppresses intake without influencing palatability. We evaluated whether lactose, which causes gastrointestinal pain in adult rats, produces CTA or TAL. Using lick pattern analysis to simultaneously measure intake and palatability (i.e., lick cluster size and initial lick rate), we found that pairing saccharin with intragastric infusions of lactose suppressed both the intake and palatability of saccharin. These results support the conclusion that gastrointestinal pain produced by lactose malabsorption produces a CTA, not TAL as had previously been suggested. Furthermore, these findings encourage the view that the CTA mechanism is broadly tuned to defend against the ingestion of foods with aversive post-ingestive effects. PMID- 28807539 TI - Murine models for mucosal tolerance in allergy. AB - Immunity is established by a fine balance to discriminate between self and non self. In addition, mucosal surfaces have the unique ability to establish and maintain a state of tolerance also against non-self constituents such as those represented by the large numbers of commensals populating mucosal surfaces and food-derived or air-borne antigens. Recent years have seen a dramatic expansion in our understanding of the basic mechanisms and the involved cellular and molecular players orchestrating mucosal tolerance. As a direct outgrowth, promising prophylactic and therapeutic models for mucosal tolerance induction against usually innocuous antigens (derived from food and aeroallergen sources) have been developed. A major theme in the past years was the introduction of improved formulations and novel adjuvants into such allergy vaccines. This review article describes basic mechanisms of mucosal tolerance induction and contrasts the peculiarities but also the interdependence of the gut and respiratory tract associated lymphoid tissues in that context. Particular emphasis is put on delineating the current prophylactic and therapeutic strategies to study and improve mucosal tolerance induction in allergy. PMID- 28807541 TI - Urinary RNA-based biomarkers for prostate cancer detection. AB - Prostate cancer (PCa) is the commonest malignancy in the male population worldwide. Serum prostate specific antigen (PSA) test is the most important biomarker for the detection, follow-up and therapeutic monitoring of PCa. Defects in PSA specificity have elicited research for new biomarkers to improve early diagnosis and avoid false-positive results. This review evaluates urinary RNA based biomarkers. Urine is a versatile body fluid for non-invasive biomarker detection in case of urological malignancies. The importance of RNA-based biomarkers has been demonstrated by the current use of PCA3, a long non coding RNA biomarker already approved by the Food and Drugs Administration. Through the years, other urinary RNA biomarkers have been evaluated, including the well-known TMPRSS2:ERG transcript, as well as many messenger RNAs, long non coding RNAs and micro-RNA. Validation of a specific urinary RNA-based marker or an algorithm of different biomarkers levels as diagnostic markers for PCa could be useful to avoid unnecessary prostate biopsies. PMID- 28807542 TI - Rapid and simple analysis of disease-associated biomarkers of Taiwanese patients with schizophrenia using matrix-assisted laser desorption ionization mass spectrometry. AB - BACKGROUND: Matrix-assisted laser desorption ionization/time-of-flight mass spectrometry (MALDI-TOF MS) is an extremely sensitive analytical tool for characterizing biological compounds in bio samples. In this study, we applied MALDI-TOF MS to assess potential protein biomarkers in the peripheral blood mononuclear cells (PBMCs) of patients with schizophrenia in the acute phase, recovery phase and healthy controls in Taiwan. METHODS: We recruited 40 participants, including 20 pairs of patients diagnosed with schizophrenia in the acute phase, after four-week treatment with drug in the recovery phase, and 20 healthy controls. The schizophrenic patients were diagnosed using Structured Clinical Interview for DSM-IV Axis I Disorders (SCID), and severity was assessed by a positive and negative symptom scale at baseline and at endpoint following four-week treatment with drug. The patients' PBMCs biomarkers were rapidly measured using a technique that combines MALDI-TOF MS and principle component analysis. A receiver operating characteristic curve was created for the evaluated biomarker. RESULTS: Significant differences in alpha-defensins 1-3 were found between the patients in acute phase with schizophrenia and the healthy controls, but not between the schizophrenic patients in recovery phase and healthy controls or between the schizophrenic patients in acute phase and in recovery phase. CONCLUSIONS: alpha-Defensins can be biomarkers of Taiwanese patients with schizophrenia, thus supporting the hypothesis that the inflammatory response and immunity system is correlated with the pathophysiology of schizophrenia. Moreover, the result also implies that alpha-defensins may be related in schizophrenia-associated disease not in efficacy of drug-treatment. PMID- 28807543 TI - Is the diagnosis of acute luminal appendicitis clinically meaningful? PMID- 28807544 TI - Use and misuse of drugs in perinatology and neonatology. PMID- 28807545 TI - Bronchopulmonary dysplasia: Myths of pharmacologic management. AB - Bronchopulmonary dysplasia (BPD) is the leading cause of long-term respiratory morbidity in newborns who require respiratory support at birth. BPD is a multifactorial disorder, and infants are frequently subjected to treatment with multiple pharmacologic agents of dubious efficacy and questionable safety, including diuretics, bronchodilators, corticosteroids, anti-reflux medications, and pulmonary vasodilators. These agents, with narrow therapeutic indices, are widely used despite the lack of an evidence base, and some may do more harm than good. It is incumbent on the clinician to establish a risk:benefit ratio and to avoid drugs that have little efficacy and a high rate of toxicity. PMID- 28807546 TI - Epigenetic drivers of tumourigenesis and cancer metastasis. AB - Since the completion of the first human genome sequence and the advent of next generation sequencing technologies, remarkable progress has been made in understanding the genetic basis of cancer. These studies have mainly defined genetic changes as either causal, providing a selective advantage to the cancer cell (a driver mutation) or consequential with no selective advantage (not directly causal, a passenger mutation). A vast unresolved question is how a primary cancer cell becomes metastatic and what are the molecular events that underpin this process. However, extensive sequencing efforts indicate that mutation may not be a causal factor for primary to metastatic transition. On the other hand, epigenetic changes are dynamic in nature and therefore potentially play an important role in determining metastatic phenotypes and this area of research is just starting to be appreciated. Unlike genetic studies, current limitations in studying epigenetic events in cancer metastasis include a lack of conceptual understanding and an analytical framework for identifying putative driver and passenger epigenetic changes. In this review, we discuss the key concepts involved in understanding the role of epigenetic alterations in the metastatic cascade. We particularly focus on driver epigenetic events, and we describe analytical approaches and biological frameworks for distinguishing between "epi-driver" and "epi-passenger" events in metastasis. Finally, we suggest potential directions for future research in this important area of cancer research. PMID- 28807547 TI - Gas chromatography-mass spectrometry and high-performance liquid chromatography diode array detection for dating of paper ink. AB - An extraction and determination method is shown for the analysis of dyes and solvents present in two types of ballpoint pen inks that are deposited onto paper. Ink extracts are analysed using a combination of gas chromatography with mass spectrometry (GC-MS), and high-pressure liquid chromatography with photodiode array detection (HPLC-DAD), within a single sample extraction procedure. Seventeen solvents and thirteen dyes contained in two Montblanc(r) inks (black and blue) were monitored for 45 months at monthly intervals, in order to determine variations in the concentrations of the compounds over time. We also studied the relative variations between different compounds and the generation of degradation products such as phenol. The concentration data obtained from these compounds during their exposure have been analysed and a multiple regression model is developed for each ink type that allows an estimate of the exposure time of the ink on paper with a maximum error of between 4 and 7 months. PMID- 28807548 TI - Application of a simple column-switching ion chromatography technique for removal of matrix interferences and sensitive fluorescence determination of acidic compounds (pharmaceutical drugs) in complex samples. AB - This work illustrates the introduction of a simple, rugged and flexible column switching ion chromatography (IC) technique for an automated on-line QuEChERS extracted samples extracts washing followed by sensitive fluorescence (FLD) determination of five acidic pharmaceutical drugs namely; clofibric acid (CLO), ibuprofen (IBU), aspirin (ASP), naproxen (NAP) and flurobrofen (FLU) in three complex samples (spinach, apple and hospital sewage sludge). An old anion exchange column IonPac(r) AS11-HC was utilized as a pre-treatment column for on line washing of inorganic and organic interferences followed by isocratic separation of five acidic drugs with another anion exchange IonPac(r) AS12A analytical column by exploiting the column-switching technique. This novel method exhibited good linearity with correlation coefficients (r2) for all drugs were in the range 0.976-0.996. The limit of detection and quantification of all five acidic drugs were in the range 0.024MUg/kg to 8.70MUg/kg and 0.082MUg/kg to 0.029mg/kg, respectively, and better recoveries in the range 81.17-112.5% with percentage relative standard deviations (RSDs) less than 17.8% were obtained. This on-line sample pre-treatment method showed minimum matrix effect in the range of 0.87-1.25 except for aspirin. This simple rugged and flexible column switching system required only 28min for maximum elimination of matrices and interferences in three complex samples extracts, isocratic separation of five acidic drugs and for the continuous regeneration of pre-treatment column prior to every subsequent analysis. Finally, this simple automated IC system was appeared so rugged and flexible, which can eliminate and wash out most of interference, impurities and matrices in complex samples, simply by adjusting the NaOH and acetonitrile concentration in washing mobile phase with maximum recoveries of acidic analytes of interest. PMID- 28807549 TI - A multiplexed microfluidic toolbox for the rapid optimization of affinity-driven partition in aqueous two phase systems. AB - Antibodies and other protein products such as interferons and cytokines are biopharmaceuticals of critical importance which, in order to be safely administered, have to be thoroughly purified in a cost effective and efficient manner. The use of aqueous two-phase extraction (ATPE) is a viable option for this purification, but these systems are difficult to model and optimization procedures require lengthy and expensive screening processes. Here, a methodology for the rapid screening of antibody extraction conditions using a microfluidic channel-based toolbox is presented. A first microfluidic structure allows a simple negative-pressure driven rapid screening of up to 8 extraction conditions simultaneously, using less than 20MUL of each phase-forming solution per experiment, while a second microfluidic structure allows the integration of multi step extraction protocols based on the results obtained with the first device. In this paper, this microfluidic toolbox was used to demonstrate the potential of LYTAG fusion proteins used as affinity tags to optimize the partitioning of antibodies in ATPE processes, where a maximum partition coefficient (K) of 9.2 in a PEG 3350/phosphate system was obtained for the antibody extraction in the presence of the LYTAG-Z dual ligand. This represents an increase of approx. 3.7 fold when compared with the same conditions without the affinity molecule (K=2.5). Overall, this miniaturized and versatile approach allowed the rapid optimization of molecule partition followed by a proof-of-concept demonstration of an integrated back extraction procedure, both of which are critical procedures towards obtaining high purity biopharmaceuticals using ATPE. PMID- 28807550 TI - Decreased gene expression of fatty acid binding protein 3 in the atrium of patients with new onset of atrial fibrillation in cardiac perioperative phase. AB - BACKGROUND: Post-operative atrial fibrillation (POAF) frequently occurs after cardiac surgery. However, the mechanisms of POAF have not been fully elucidated. We aimed to examine whether pre-operative atrial gene expression related to cardiac metabolism is changed in patients with POAF. METHODS: Right atrial tissue was obtained during surgery from 38 patients who underwent cardiac surgery from 2013 to 2015. Atrial expression levels were determined by reverse transcription polymerase chain reaction for the following genes: glucose transporter type 4, peroxisome proliferator-activated receptor-alpha, fatty acid translocase, carnitine palmitoyltransferase 1B, and fatty acid binding protein 3 (FABP3). To investigate fatty acid beta-oxidation and tricarboxylic acid cycle capacities in the mitochondria, beta-hydroxyacyl CoA dehydrogenase and citrate synthase activity levels were spectrophotometrically determined. RESULTS: POAF within 7 days after surgery was observed in 18 (47%) patients. POAF patients were significantly older, had a larger left atrial diameter, and had reduced expression of FABP3, a fatty acids transport gene in the cytosol, compared to those in the non-POAF group. Reduced FABP3 expression predicted POAF independent of age and atrial size. In contrast, fatty acid beta-oxidation enzymatic activity was comparable between the groups. CONCLUSIONS: FABP3 gene expression in the atrium was reduced in patients with POAF. These findings suggest a potential link between altered fatty acid transport in the atrium and increased AF onset after cardiac surgery. PMID- 28807551 TI - The optimal cut-off of blood pressure related to left ventricular diastolic dysfunction and remodeling in Asian diabetic patients. AB - BACKGROUND: Although a recent randomized trial found no difference between intensive and standard blood pressure (BP) control in patients with diabetes mellitus (DM), the debate over the optimal BP target continues. Thus, the present study investigated the effect of BP on the subclinical left ventricular (LV) function and structural changes in diabetic patients. METHOD: A total of 2649 patients with DM who received echocardiography were enrolled in this study. Study population was stratified by three groups according to BP and presence of hypertension (normal, <130/80mmHg; prehypertension, >=130/80mmHg without hypertension; hypertension, >=140/90mmHg or history of hypertension). The odds ratios (ORs) of impaired LV diastolic function and LV remodeling were analyzed using multivariate logistic regression analysis. The adjusted mean values of echocardiographic parameters related to LV diastolic function and remodeling were also evaluated. RESULT: When normal group was set as reference, the adjusted ORs [95% confidential interval (CI)] for impaired LV diastolic function was 2.45 (95% CI 1.84-3.24) in prehypertension, 3.51 (95% CI 2.57-4.80) in hypertension group. Adjusted ORs for LV remodeling only showed significant result in hypertension group [1.82 (95% CI 1.23-2.69)]. The adjusted mean value of LV diastolic function and structure also demonstrated LV deterioration in prehypertension and hypertension groups. CONCLUSION: Our study showed the adverse influence of prehypertension and hypertension on subclinical LV deterioration. This finding suggested the potential clinical benefits of intensive BP control (<130/80mmHg) in patients with DM. PMID- 28807552 TI - Assessment of deformation of the mitral valve complex during off-pump coronary artery bypass surgery using three-dimensional echocardiography in a porcine model. AB - BACKGROUND: This study aimed to assess the deformation of the mitral valve complex during the displacement of the beating heart by using three-dimensional echocardiography in a porcine off-pump coronary artery bypass grafting (OPCAB) model. METHODS: In nine healthy swine, we positioned the beating heart as an OPCAB model, i.e. control, left anterior descending artery (LAD), right coronary artery (RCA), and left circumflex artery (LCX) positions. In each position, three dimensional echocardiography was performed to assess the mitral valve complex with hemodynamic parameters. We analyzed the deformation of the mitral valve and the three-dimensional coordinates of the papillary muscles. RESULTS: There was a significant increase in maximum tenting length and tenting volume (control 0.70+/ 0.30, LAD 0.65+/-0.27, RCA 0.79+/-0.23, LCX 0.95+/-0.34cm3, p<0.05) in the LCX position compared with the other positions. The posterior papillary muscle (PPM) angle had a significant relationship with the tenting volume (r=-0.643, p<0.001). The PPM was displaced to the medial side in the LAD and LCX positions (p<0.01). CONCLUSIONS: The prime cause of the deformation of the mitral leaflets is suggested to be the displacement of the PPM associated with the change in geometry of the left ventricle in a porcine model. PMID- 28807554 TI - Grassroots Technological Resistance: The People's Power Project and the Impossible Dream of Wireless Transmission of Energy. AB - In 1972, the Minnesota United Power Association (UPA) teamed up with the Minnesota Cooperative Power Association (CPA) to initiate an electrification project designed to bring power from North Dakota to the Twin Cities area. A significant backlash and protest began once farmers across the state became aware of the plan and the potential impending land seizure. In the midst of these actions, one group sought to create an alternative to the power line transmission system by designing a system of wireless energy transmission based on the plans of Nikola Tesla. This self-funded conglomeration of farmers and amateur researchers formed the People's Power Project (PPP) and set about building Tesla's system for the wireless transmission of energy. Using archival documents, this paper recounts this episode and argues that, in this case, the potential for successful grassroots action was derailed by the influence of longstanding myths about Tesla and his devices. PMID- 28807553 TI - Coronary artery segmentation in X-ray angiograms using gabor filters and differential evolution. AB - Segmentation of coronary arteries in X-ray angiograms represents an essential task for computer-aided diagnosis, since it can help cardiologists in diagnosing and monitoring vascular abnormalities. Due to the main disadvantages of the X-ray angiograms are the nonuniform illumination, and the weak contrast between blood vessels and image background, different vessel enhancement methods have been introduced. In this paper, a novel method for blood vessel enhancement based on Gabor filters tuned using the optimization strategy of Differential evolution (DE) is proposed. Because the Gabor filters are governed by three different parameters, the optimal selection of those parameters is highly desirable in order to maximize the vessel detection rate while reducing the computational cost of the training stage. To obtain the optimal set of parameters for the Gabor filters, the area (Az) under the receiver operating characteristics curve is used as objective function. In the experimental results, the proposed method achieves an Az=0.9388 in a training set of 40 images, and for a test set of 40 images it obtains the highest performance with an Az=0.9538 compared with six state-of-the art vessel detection methods. Finally, the proposed method achieves an accuracy of 0.9423 for vessel segmentation using the test set. In addition, the experimental results have also shown that the proposed method can be highly suitable for clinical decision support in terms of computational time and vessel segmentation performance. PMID- 28807555 TI - Improving biogas production from anaerobic co-digestion of sewage sludge with a thermal dried mixture of food waste, cheese whey and olive mill wastewater. AB - Anaerobic co-digestion of sewage sludge and other organic wastes at a wastewater treatment plant (WWTP) is a promising method for both energy and material recovery. However, transportation and storage of wastes to WWTP may be the bottleneck for the successful implementation of this technology. In case of wet wastes and wastewater it is possible to reduce their volume and as a result the transportation and storage cost by using a drying process. During this study, the optimization of biogas production from sewage sludge (SS) was attempted by co digesting with a dried mixture of food waste, cheese whey and olive mill wastewater (FCO). A series of laboratory experiments were performed in continuously-operating reactors at 37 degrees C, fed with thermal dried mixtures of FCO at concentrations of 3%, 5% and 7%. The overall process was designed with a hydraulic retention time (HRT) of 24days. FCO addition can boost biogas yields if the mixture exceeds 3% (v/v) concentration in the feed. Any further increase of 5% FCO causes a small increase in biogas production. The reactor treating the sewage sludge produced 287ml CH4/Lreactor/d before the addition of FCO and 815ml CH4/Lreactor/d (5% v/v in the feed). The extra FCO-COD added (7% FCO v/v) to the feed did not have a negative effect on reactor performance, but seemed to have the same results. In all cases, the estimated biodegradability of mixtures was over 80%, while the VS removal was 22% for the maximum biomethane production (5% v/v). Moreover, co-digestion improved biogas production by 1.2-2.7 times. PMID- 28807556 TI - Long-term weight loss in laparoscopic sleeve gastrectomy. AB - INTRODUCTION: Laparoscopic sleeve gastrectomy (LSG) has become an option as a bariatric surgical technique. There is a lack of long-term results of this procedure in the literature. The aim of this study is to present weight loss results of LSG for up to 7 years of follow-up. METHODS: A retrospective series of patients who underwent LSG between 2008 and 2011 was examined. The primary endpoint was weight loss: percentage of excess weight loss (%EWL), percentage of total weight loss (%TWL), and body mass index (BMI) were reported. Failure was defined as %EWL<50%. Multivariate analysis for weight loss was performed. The complications rate was reported. RESULTS: A total of 148 patients met the inclusion criteria; 76.3% were female. Mean preoperative BMI was 36 +/- 4 kg/m2. Mean operative time was 89.3 +/- 3.2 minutes. Follow-up at 5, 6, and 7 years was 77.7%, 83.3%, and 82.2%, respectively. Mean %EWL and %TWL at 1, 3, 5, and 7 years was 93.2%, 80.7%, 70.6%, and 51.7%, and 27.2%, 23.3%, 20.4%, and 16.3%, respectively. The failure rate was 30.4% at the fifth year and 51.4% at the seventh year. High preoperative BMI was related to worse %EWL (P<0.001) but not to %TWL. Preoperative BMI<35 kg/m2 was associated with better %EWL but not with %TWL (P = 0.003). Four leaks (2.7%) and no mortalities were reported. CONCLUSIONS: LSG is an acceptable surgical technique for weight loss, but in this series, up to one third of the patients fail at the fifth year and half fail in the seventh year. %EWL is better in patients with BMI<35 kg/m2, but this difference disappears when we express outcomes with %TWL. PMID- 28807557 TI - The role of toll-like receptor 3 in chronic contact hypersensitivity induced by repeated elicitation. AB - BACKGROUND: Accumulating evidence suggests that Toll-like receptor (TLR)-3 signaling is involved in non-infectious immune and inflammatory reactions as well as in viral infections. The skin of patients with atopic dermatitis (AD) is often infected with virus and bacteria, leading to the aggravation of atopic symptoms. These findings suggest TLR3 signaling may be involved in the pathogenesis of AD, but the exact role of TLR3 in AD remains to be defined. OBJECTIVE: The purpose of this study was to investigate the role of TLR3 in chronic contact hypersensitivity reactions induced by repeated elicitation, resembling the features of AD. METHODS: Wild-type (WT) and Toll-like receptor 3 knockout (Tlr3 KO) mice were sensitized, and chronic contact hypersensitivity reactions were elicited in their ear skin via repeated application of a hapten, 2,4,6-trinitro-1 chlorobenzene (TNCB) or oxazolone. RESULTS: The Tlr3 KO mice exhibited less ear swelling, less leukocyte infiltration into the skin, and lower serum total IgE levels than WT mice after hapten challenge. The Tlr3 KO mice also displayed lower expression levels of inflammatory cytokines (interleukin (IL)-33, IL-4, IL-10, and interferon-? in their TNCB-treated ear skin than WT mice. CONCLUSION: These results showed that TLR3 deficiency suppressed the development of chronic contact hypersensitivity reactions, suggesting that TLR3 signaling may participate in the pathogenesis of AD. PMID- 28807559 TI - World Apheresis Association: Member-Society Updates. PMID- 28807558 TI - Cost of asthma in Portuguese adults: A population-based, cost-of-illness study. AB - INTRODUCTION: Asthma is one of the most frequent chronic diseases, putting a considerable economic burden on societies and individuals. We aimed to estimate the total cost of adult asthma in Portugal, as well as the extent to which direct and indirect costs are influenced by the level of asthma control. METHODS: A nationwide, prevalence-based, cost-of-illness study using a bottom-up approach to calculate direct and indirect costs of asthma was conducted, using participant data from the Portuguese National Asthma Survey (INAsma). Direct (healthcare service usage, diagnostic tests and treatment) and indirect (absenteeism and transportation) costs were measured. Decision analytic modelling was used to perform multivariate deterministic sensitivity analysis. RESULTS: On average, each adult costs 708.16? (95%CI: 594.62-839.30) a year, with direct costs representing 93% (658.46?; 95%CI: 548.99-791.29) and indirect costs representing 7% (49.70?; 95%CI: 32.08-71.56). This amounts to a grand total of 386,197,211.25? (95%CI: 324,279,674.31-457,716,500.18), with direct costs being 359,093,559.82? (95%CI: 299,391,930.03-431,533,081.07). Asthma direct costs are 2.04% of the total Portuguese healthcare expense in 2010. The major cost domains were acute care usage (30.7%) and treatment (37.4%). Asthma control was significantly associated with higher costs throughout several domains, most notably in acute medical care. CONCLUSIONS: Asthma in adults poses a significant economic burden on the Portuguese healthcare system, accounting for over 2% of the total healthcare expenditure in Portugal in 2010. It is important to note that a considerable portion of this burden might be eased by improving asthma control in patients, as uncontrolled patients' costs are more than double those of controlled asthma patients. PMID- 28807560 TI - Morphologic and molecular characterization of seven species of the remarkably diverse and widely distributed metopid genus Urostomides Jankowski, 1964 (Armophorea, Ciliophora). AB - The free-living ciliates of the order Metopida Jankowski, 1980 are pivotal players in the microbial food web of the sulfuretum, acting as hosts to prokaryotic endo- and ectosymbionts. They are also of interest in the study of the function and evolution of their mitochondrion-related organelle, the hydrogenosome. The taxonomy and phylogeny of this group remains confused, due, in large part, to the fact that most of its taxa have not been characterized by modern methods including molecular sequencing. In this report we provide morphologic and molecular characterization of seven taxa from the poorly-known resurrected genus Urostomides obtained in the course of broad geographic sampling. Foissner (2016) established the family Apometopidae to include Apometopus (a junior synonym of Urostomides) and Cirranter Jankowski, 1964. These two genera differ from all other metopid genera in having a four-rowed perizonal ciliary stripe, the only currently recognizable morphologic synapomorphy for the family. The members of Urostomides show remarkable morphologic diversity. The genus has a broad geographic distribution, occurring on six continents. Urostomides species form a strongly supported clade in phylogenetic analyses. Relationships within the genus itself are less clearly resolved. The diagnoses of Apometopidae and Urostomides are emended. PMID- 28807561 TI - Mass spectrometry analysis of intact Francisella bacteria identifies lipid A structure remodeling in response to acidic pH stress. AB - Structural modification of lipid A, the lipid anchor of LPS, is one of the strategies used by Gram-negative bacteria to evade host innate immunity. Francisella tularensis is a human pathogen that infects and replicates within phagocytic cells. It produces an atypical lipid A, whose structure precludes an efficient recognition by both innate immune players, TLR4 and cationic antimicrobial peptides. Interestingly, a recent report indicates that the lipid A of Francisella (LVS vaccinal strain) undergoes polar modifications when bacteria are grown in human macrophages as compared to in broth. To characterize the structural modifications of lipid A that may be induced intracellularly, Francisella novicida, a surrogate strain for the highly virulent F. tularensis, was submitted to different stress conditions mimicking the harsh environment encountered in the macrophages. To analyze lipid A directly from intact bacteria without any chemical treatment or purification steps, we used a rapid and sensitive MALDI-TOF mass spectrometry approach. Among the many conditions tested, only bacteria exposure to acidic pHs (from 6 to 5) induced a change in lipid A structure. These changes were characterized by an increase in the relative abundance of molecular species bearing an additional hexose unit on the diglucosamine backbone, similar to species present when bacteria are grown under reduced environmental temperature. This lipid A glyco-form, which is observed in trace amounts in normal in vitro growth conditions at 37 degrees C, may contribute to the intracellular parasitism of macrophages by Francisella. PMID- 28807562 TI - Targeting signal transducers and activators of transcription (STAT) in human cancer by dietary polyphenolic antioxidants. AB - Over the course of the last three decades, a large body of evidence has shown that polyphenols, the secondary metabolites occurring in plant foods and beverages, exert protective effects due to their antioxidant activity mediated through different mechanisms ranging from direct radical scavenging and metal chelating activities, to the capacity to inhibit pro-oxidant enzymes and to target specific cell-signalling pathways. In the last decade, dietary components, and polyphenols in particular have gained considerable attention as chemopreventive agents against different types of cancer. The signal transducers and activators of transcription (STAT) family is a group of cytoplasmic transcription factors which interact with specific sequences of DNA, inducing the expression of specific genes which in turn give rise to adaptive and highly specific biological responses. Growing evidence suggests that, of the seven STAT members identified, STAT3 is over-expressed in many human tumors (i.e. solid tumors and hematological malignancies) promoting the onset and development of cancer in humans by inhibiting apoptosis or by inducing cell proliferation, angiogenesis, invasion, and metastasis. This review article aims to assess the most recent studies on the role of STATs, with focus on STAT3, in oncogenesis, and the promising effects of some polyphenols on STAT expression. Moreover, the mechanisms behind the anti-inflammatory and antioxidant activities of polyphenols which have an influence on STAT expression are discussed, with a focus on their ability to target specific cell-signalling pathways. PMID- 28807563 TI - The complex co-translational processing of glycoprotein GP5 of type 1 porcine reproductive and respiratory syndrome virus. AB - GP5 and M, the major membrane proteins of porcine reproductive and respiratory syndrome virus (PRRSV), are the driving force for virus budding and a target for antibodies. We studied co-translational processing of GP5 from an European PRRSV 1 strain. Using mass spectrometry, we show that in virus particles of a Lelystad variant, the signal peptide of GP5 was absent due to cleavage between glycine-34 and asparagine-35. This cleavage site removes an epitope for a neutralizing monoclonal antibody, but leaves intact another epitope recognized by neutralizing pig sera. Upon ectopic expression of this GP5 in cells, signal peptide cleavage was however inefficient. Complete cleavage occurred when cysteine-24 was changed to proline or an unused glycosylation site involving asparagine-35 was mutated. Insertion of proline at position 24 also caused carbohydrate attachment to asparagine-35. Glycosylation sites introduced downstream of residue 35 were used, but did not inhibit signal peptide processing. Co-expression of the M protein rescued this processing defect in GP5, suggesting a novel function of M towards GP5. We speculate that a complex interplay of the co-translational modifications of GP5 affect the N-terminal structure of the mature proteins and hence its antigenicity. PMID- 28807564 TI - Reduced metallic artefacts in 3 T knee MRI using fast spin-echo multi-point Dixon compared to fast spin-echo T2-weighted sequences. AB - AIM: To compare multi-point Dixon magnetic resonance imaging (MRI) and fast spin echo (FSE) T2-weighted imaging (WI) with regard to the size of metallic artefacts when imaging the knee joint. MATERIALS AND METHODS: A total of 42 patients who underwent anterior cruciate ligament (ACL) reconstruction and follow-up imaging with 3 T MRI using the multi-point Dixon technique was included in this retrospective study. The maximal distance of the image distortion area around the metallic artefact was measured (interference screw of femoral tunnel area) on sagittal images of both FSE T2WI (T2WI and fat-suppressed [FS] T2WI) and multi point Dixon (water only image and in-phase image) sequences. The maximal distance of the image distortion were compared using paired t-tests across the image sequences (multi-point Dixon water only image versus FS T2WI and multi-point Dixon in-phase image versus T2WI). RESULTS: The mean distance of the image distortion from metallic artefacts regardless of the image sequence ranged from 16.6 mm to 24.5 mm (Table 2). The mean distances measured by two readers on multi point Dixon (water only image) sequences were significantly shorter than those in FS T2WI sequences (p<0.001). In contrast, the mean distances measured by two readers on multi-point Dixon (in-phase image) sequences did not differ from those of T2WI (p>0.05) sequences. CONCLUSION: The water-only image of multi-point Dixon technique reduces the amount of metallic artefacts compared to that in FS FSE T2WI sequences; however, the metallic artefacts were not significantly different between in-phase images of multi-point Dixon and FSE T2WI. PMID- 28807565 TI - Disrupted day-night pattern of cardiovascular death in obstructive sleep apnea. AB - BACKGROUND: Obstructive sleep apnea (OSA) patients who suffer sudden cardiac death die predominantly during the night. We aimed to investigate whether all cardiovascular-related deaths display the same night-time peak as sudden cardiac death. METHODS: Data from a large cohort of adults who underwent full-night polysomnography between 1985 and 2015 in a university-affiliated sleep clinic were analyzed. Time and cause of death of these patients and of persons from the general population were identified in death certificates from the State Health Secretariat. The day-night pattern of cardiovascular death was compared among groups of non-OSA, OSA (apnea-hypopnea index, AHI >=5), CPAP users, and persons from the general population. RESULTS: Among 619 certificates, 160 cardiovascular related deaths were identified. The time of death of the 142 persons with OSA was uniformly distributed over 24 h, with neither an identifiable peak nor a circadian pattern (Rayleigh test; P = 0.8); the same flat distribution was seen in those with purported CPAP use (n = 49). Non-OSA individuals presented a morning peak and a night nadir of deaths, clearer when analyzed in eight-hour intervals. The same pattern was observed in 92 836 certificates from the State general population, with cardiovascular deaths showing the expected morning peak, night nadir, and a significant circadian pattern (Rayleigh test; P < 0.001). CONCLUSIONS: In OSA patients, the distribution of cardiovascular-related deaths throughout the 24-h period is virtually flat, in contrast with the described nighttime peak of sudden cardiac death. OSA-related phenomena during nighttime might be blunting the mechanisms, arrhythmic or not, behind the morning peak of cardiovascular-related deaths. PMID- 28807566 TI - Electrospun collagen-based nanofibres: A sustainable material for improved antibiotic utilisation in tissue engineering applications. AB - For the creation of scaffolds in tissue engineering applications, it is essential to control the physical morphology of fibres and to choose compositions which do not disturb normal physiological function. Collagen, the most abundant protein in the human body, is a well-established biopolymer used in electrospinning compositions. It shows high in-vivo stability and is able to maintain a high biomechanical strength over time. In this study, the effects of collagen type I in polylactic acid-drug electrospun scaffolds for tissue engineering applications are examined. The samples produced were subsequently characterised using a range of techniques. Scanning electron microscopy analysis shows that the fibre morphologies varied across PLA-drug and PLA-collagen-drug samples - the addition of collagen caused a decrease in average fibre diameter by nearly half, and produced nanofibres. Atomic force microscopy imaging revealed collagen-banding patterns which show the successful integration of collagen with PLA. Solid-state characterisation suggested a chemical interaction between PLA and drug compounds, irgasan and levofloxacin, and the collagen increased the amorphous regions within the samples. Surface energy analysis of drug powders showed a higher dispersive surface energy of levofloxacin compared with irgasan, and contact angle goniometry showed an increase in hydrophobicity in PLA-collagen-drug samples. The antibacterial studies showed a high efficacy of resistance against the growth of both E. coli and S. Aureus, except with PLA-collagen-LEVO which showed a regrowth of bacteria after 48h. This can be attributed to the low drug release percentage incorporated into the nanofibre during the in vitro release study. However, the studies did show that collagen helped shift both drugs into sustained release behaviour. These ideal modifications to electrospun scaffolds may prove useful in further research regarding the acceptance of human tissue by inhibiting the potential for bacterial infection. PMID- 28807567 TI - A New Promoter Allows Optogenetic Vision Restoration with Enhanced Sensitivity in Macaque Retina. AB - The majority of inherited retinal degenerations converge on the phenotype of photoreceptor cell death. Second- and third-order neurons are spared in these diseases, making it possible to restore retinal light responses using optogenetics. Viral expression of channelrhodopsin in the third-order neurons under ubiquitous promoters was previously shown to restore visual function, albeit at light intensities above illumination safety thresholds. Here, we report (to our knowledge, for the first time) activation of macaque retinas, up to 6 months post-injection, using channelrhodopsin-Ca2+-permeable channelrhodopsin (CatCh) at safe light intensities. High-level CatCh expression was achieved due to a new promoter based on the regulatory region of the gamma-synuclein gene (SNCG) allowing strong expression in ganglion cells across species. Our promoter, in combination with clinically proven adeno-associated virus 2 (AAV2), provides CatCh expression in peri-foveolar ganglion cells responding robustly to light under the illumination safety thresholds for the human eye. On the contrary, the threshold of activation and the proportion of unresponsive cells were much higher when a ubiquitous promoter (cytomegalovirus [CMV]) was used to express CatCh. The results of our study suggest that the inclusion of optimized promoters is key in the path to clinical translation of optogenetics. PMID- 28807570 TI - Albumin-bilirubin grade predicts the outcomes of liver resection versus radiofrequency ablation for very early/early stage of hepatocellular carcinoma. AB - BACKGROUND AND PURPOSE: Whether liver resection or ablation should be the first line treatment for very early/early hepatocellular carcinoma (HCC) in patients who are candidates for both remains controversial. The aim of this study was to determine if the newly-developed Albumin-Bilirubin (ALBI) grade might help in treatment selections and to evaluate the survival of patients treated with liver resection and radiofrequency ablation (RFA). METHODS: Patients with BCLC stage 0/A HCC who were treated with curative liver resection and RFA from 2003 to 2013 were included. Baseline clinical and laboratory parameters were retrieved and reviewed from the hospital database. Liver function and its impact on survival was assessed by the ALBI score. Overall and disease-free survivals were compared between the two groups. RESULTS: 488 patients underwent liver resection (n = 318) and RFA (n = 170) for BCLC stage 0/A HCC during the study period. Liver resection offered superior survival to RFA in patients with BCLC stage 0/A HCC in the whole cohort. After propensity score matching, liver resection offered superior overall survival and disease-free survival to RFA in patients with ALBI grade 1 (P = 0.0002 and P < 0.0001 respectively). In contrast, there were no significant differences in overall survival and disease-free survival between liver resection and RFA in patients with ALBI grade 2 (P = 0.7119 and 0.3266, respectively). CONCLUSIONS: Liver resection offered superior survival to RFA in patients with BCLC stage 0/A HCC. The ALBI grade could identify those patients with worse liver function who did not gain any survival advantage from curative liver resection. PMID- 28807571 TI - Radiofrequency ablation for osteoid osteoma - Recurrence rates and predictive factors. AB - BACKGROUND AND PURPOSE: Osteoid osteoma is an infrequent but debilitating benign bone lesion which can be successfully managed by percutaneous radiofrequency ablation (RFA). There are few studies investigating the efficacy and follow-up of this treatment. An arbitrary upper limit of 15 mm has been used to differentiate between osteoid osteoma and osteoblastoma with surgery used for lesions above this limit. We aimed to analyse the cases identified from our prospectively maintained database over a ten year period since adoption of this technique in our unit. The primary objectives were to investigate factors which influenced recurrence and the time period at which patients are at risk of this. BASIC PROCEDURES: Consecutive patients with confirmed osteoid osteoma were included. Patient demographics, complications, and recurrence were recorded and multiple regression analysis was performed to investigate causation. MAIN FINDINGS: Within a minimum follow up of 21 months (mean 72), a recurrence rate of 16.3% was noted, higher than the published literature. Cox regression analysis to predict chance of recurrence revealed a relationship between larger lucent diameter and recurrence (p = 0.049, CI 95%, hazard ratio 1.33). CONCLUSIONS: The traditional cut off between osteoid osteoma and osteoblastoma appears less rigidly defined than previously thought and probably represents a progressive scale with larger lesions responding less well to RFA. This study indicates that each millimetre increase represents a *1.33 chance of recurrence. Clinicians should counsel patients accordingly with lesions approaching the larger limits of this diagnosis. PMID- 28807568 TI - Function of Novel Anti-CD19 Chimeric Antigen Receptors with Human Variable Regions Is Affected by Hinge and Transmembrane Domains. AB - Anti-CD19 chimeric antigen receptor (CAR) T cells have caused remissions of B cell malignancies, but problems including cytokine-mediated toxicity and short persistence of CAR T cells in vivo might limit the effectiveness of anti-CD19 CAR T cells. Anti-CD19 CARs that have been tested clinically had single-chain variable fragments (scFvs) derived from murine antibodies. We have designed and constructed novel anti-CD19 CARs containing a scFv with fully human variable regions. T cells expressing these CARs specifically recognized CD19+ target cells and carried out functions including degranulation, cytokine release, and proliferation. We compared CARs with CD28 costimulatory moieties along with hinge and transmembrane domains from either the human CD28 molecule or the human CD8alpha molecule. Compared with T cells expressing CARs with CD28 hinge and transmembrane domains, T cells expressing CARs with CD8alpha hinge and transmembrane domains produced lower levels of cytokines and exhibited lower levels of activation-induced cell death (AICD). Importantly, CARs with hinge and transmembrane regions from either CD8alpha or CD28 had similar abilities to eliminate established tumors in mice. In anti-CD19 CARs with CD28 costimulatory moieties, lower levels of inflammatory cytokine production and AICD are potential clinical advantages of CD8alpha hinge and transmembrane domains over CD28 hinge and transmembrane domains. PMID- 28807569 TI - IL-10-Engineered Human CD4+ Tr1 Cells Eliminate Myeloid Leukemia in an HLA Class I-Dependent Mechanism. AB - T regulatory cells (Tregs) play a key role in modulating T cell responses. Clinical trials showed that Tregs modulate graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, their ability to mediate anti-leukemic activity (graft-versus-leukemia [GvL]) is largely unknown. Enforced interleukin-10 (IL-10) expression converts human CD4+ T cells into T regulatory type 1 (Tr1)-like (CD4IL-10) cells that suppress effector T cells in vitro and xenoGvHD in humanized mouse models. In the present study, we show that CD4IL-10 cells mediate anti-leukemic effects in vitro and in vivo in a human leukocyte antigen (HLA) class I-dependent but antigen-independent manner. The cytotoxicity mediated by CD4IL-10 cells is granzyme B (GzB) dependent, is specific for CD13+ target cells, and requires CD54 and CD112 expression on primary leukemic target blasts. CD4IL-10 cells adoptively transferred in humanized mouse models directly mediate anti-tumor and anti-leukemic effects. In addition, when co-transferred with peripheral blood mononuclear cells (PBMCs), CD4IL-10 cells contribute to the GvL activity but suppress xenoGvHD mediated by the PBMCs. These findings provide for the first time a strong rationale for CD4IL 10 cell immunotherapy to prevent GvHD and promote GvL in allo-HSCT for myeloid malignancies. PMID- 28807572 TI - Identification of highly selective and potent orexin receptor 1 antagonists derived from a dual orexin receptor 1/2 antagonist based on the structural framework of pyrazoylethylbenzamide. AB - The design, synthesis, and structure activity relationships of the novel class of pyrazolylethylbenzamide orexin receptor 1-selective antagonists are described. Further derivatization of the prototype dual orexin receptor 1/2 antagonist lead (1) by installing a (S)-methyl group into the ethyl linker moiety between the pyrazole ring and benzamide resulted in an increase of the antagonist potency against orexin receptor 1/2 receptors. Optimization of the benzamide and pyrazole parts of compounds 2 and 9b led to the identification of N-ethyl-5-fluoro-N-{(2S) 1-[5-(4-fluorophenyl)-2H-tetrazol-2-yl]propan-2-yl}-2-(pyrimidin-2-yl)benzamide (24), which exhibited excellent antagonistic activity against orexin receptor 1 with an IC50 of 2.01nM and a 265-fold selectivity for orexin receptor 1 over orexin receptor 2. PMID- 28807573 TI - Axially substituted silicon(IV) phthalocyanine and its quaternized derivative as photosensitizers towards tumor cells and bacterial pathogens. AB - Axially di-(alpha,alpha-diphenyl-4-pyridylmethoxy) silicon(IV) phthalocyanine (3) and its quaternized derivative (3Q) were synthesized and tested as photosensitizers against tumor and bacterial cells. These new phthalocyanines were characterized by elemental analysis, and different spectroscopic methods such as FT-IR, UV-Vis, MALDI-TOF and 1H NMR. The photophysical properties such as absorption and fluorescence, and the photochemical properties such as singlet oxygen generation of both phthalocyanines were investigated in solutions. The obtained values were compared to the values obtained with unsubstituted silicon(IV) phthalocyanine dichloride (SiPcCl2). The addition of two di (alpha,alpha-diphenyl-4-pyridylmethanol) groups as axial ligands showed an improvement of the photophysical and photochemical properties and an increasement of the singlet oxygen quantum yield (PhiDelta) from 0.15 to 0.33 was determined. The photodynamic efficacy of synthesized photosensitizers (3 and 3Q) were evaluated with promising photocytotoxicity (17% cell survival for 3 and 28% for 3Q) against the cervical cancer cell line (HeLa). The photodynamic inactivation of pathogenic bacterial strains Streptococcus mutans, Staphylococcus aureus, and Pseudomonas aeruginosa suggested a high susceptibility with quaternized derivative (3Q). The both Gram-positive bacterial strains were fully photoinactivated with 11MUM 3Q and mild light dose 50J.cm-2. In case of P. aeruginosa the effect was negligible for concentrations up to 22MUM 3Q and light dose 100J.cm-2. The results suggested that the novel axially substituted silicon(IV) phthalocyanines have promising characteristic as photosensitizer towards tumor cells. The quaternized derivative 3Q has high potential for photoinactivation of pathogenic bacterial species. PMID- 28807574 TI - Synthesis and evaluation of analogs of 5'-(((Z)-4-amino-2-butenyl)methylamino)-5' deoxyadenosine (MDL 73811, or AbeAdo) - An inhibitor of S-adenosylmethionine decarboxylase with antitrypanosomal activity. AB - We describe our efforts to improve the pharmacokinetic properties of a mechanism based suicide inhibitor of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (AdoMetDC), essential for the survival of the eukaryotic parasite Trypanosoma brucei responsible for Human African Trypanosomiasis (HAT). The lead compound, 5'-(((Z)-4-amino-2-butenyl)methylamino)-5'-deoxyadenosine (1, also known as MDL 73811, or AbeAdo), has curative efficacy at a low dosage in a hemolymphatic model of HAT but displayed no demonstrable effect in a mouse model of the CNS stage of HAT due to poor blood-brain barrier permeation. Therefore, we prepared and evaluated an extensive set of analogs with modifications in the aminobutenyl side chain, the 5'-amine, the ribose, and the purine fragments. Although we gained valuable structure-activity insights from this comprehensive dataset, we did not gain traction on improving the prospects for CNS penetration while retaining the potent antiparasitic activity and metabolic stability of the lead compound 1. PMID- 28807575 TI - Triple reuptake inhibitors: Design, synthesis and structure-activity relationship of benzylpiperidine-tetrazoles. AB - Monoamine transporters are important targets in the treatment of various central nervous disorders. Several limitations of traditional reuptake inhibitors, like delayed onset of action, insomnia, and sexual dysfunction, have compelled the search for safer, more effective compounds. In this study, we have sought to identify novel monoamine reuptake inhibitors. Based upon the docking study of compounds that we had reported previously, aromatic rings (A1) were modified to generate a novel series of benzylpiperidine-tetrazoles. Thirty-one compounds were synthesized and evaluated for their triple reuptake inhibition of serotonin, norepinephrine and dopamine. Triple reuptake inhibitor, compound 2q, in particular, showed potent serotonin reuptake inhibition, validating our design approach. PMID- 28807576 TI - Evaluation of three tidal volumes (10, 12 and 15 mL kg-1) in dogs for controlled mechanical ventilation assessed by volumetric capnography: a randomized clinical trial. AB - OBJECTIVE: To evaluate three routinely used tidal volumes (VT; 10, 12 and 15 mL kg-1) for controlled mechanical ventilation (CMV) in lung-healthy anaesthetized dogs by assessing alveolar ventilation (VTalv) and dead space (DS). STUDY DESIGN: Prospective, randomized clinical trial. ANIMALS: A total of 36 client-owned dogs. METHODS: Dogs were randomly allocated to a VT of 10 (G10), 12 (G12) or 15 (G15) mL kg-1. After induction CMV was started. End-tidal carbon dioxide tension was maintained at 4.7-5.3 kPa by changing the respiratory frequency (fR; 630. VTalv kg-1 (p=0.001) increased and VDBohr (p=0.002) decreased with greater VT. VTCO2,br (p=0.017) increased and VDaw/VT (p=0.006), VDBE (p=0.008) and fR (p=0.002) decreased between G10 and G15. PIP (p=0.013) was significantly higher in G15 compared with that in G10 and G12. No changes were observed in MawP. CONCLUSIONS AND CLINICAL RELEVANCE: A VT of 15 mL kg-1 is most appropriate for CMV in lung-healthy dogs (as evaluated by respiratory mechanics and VCap) and does not impair cardiovascular variables. PMID- 28807578 TI - Heparin-Induced Thrombocytopenia and Vascular Surgery. PMID- 28807577 TI - A Comparison of Inflammatory Responses Between Robotically Enhanced Coronary Artery Bypass Grafting and Conventional Coronary Artery Bypass Grafting: Implications for Hybrid Revascularization. AB - OBJECTIVE: The inflammatory response elicited by robotically enhanced coronary artery bypass grafting (r-CABG) has not been well described. When r-CABG is performed as part of hybrid coronary revascularization, the inflammatory milieu and the timing of percutaneous coronary intervention may affect the stent patency negatively in the short and long term. The goal of this study was to describe the extent and time course of cytokine release after r-CABG compared with conventional CABG (c-CABG) and to elucidate the optimal timing for r-CABG in the setting of hybrid coronary revascularization for a future study. DESIGN: Prospective, observational study. SETTING: Tertiary-care center in a university hospital. PARTICIPANTS: The study comprised patients scheduled to undergo r-CABG or c-CABG from October 2012 to November 2014. INTERVENTIONS: Cytokine levels of interleukin (IL)-6, IL-8, IL-10; tumor necrosis factor-alpha; and C-reactive protein (CRP) were measured at the following time points: preprocedure; at the end of the procedure; and at 4, 8, 12, 24, and 48 hours after the procedure. MEASUREMENTS AND MAIN RESULTS: Twenty-eight patients undergoing r-CABG and 10 patients undergoing c-CABG were enrolled. The levels of cytokines after r-CABG and c-CABG were compared using the mixed-effect linear regression model for longitudinal data. Cytokine release in the r-CABG group was comparatively less for IL-6, IL-10, tumor necrosis factor, and CRP levels. They all trended toward the baseline by the 48th hour in both groups, except CRP levels, which reached their peak at 48 hours in both groups. CONCLUSIONS: The inflammatory response to r-CABG was blunted compared with that of c-CABG. The high CRP levels on the second postoperative day after r-CABG were a cause for concern in regard to percutaneous coronary intervention performed at that time period, but additional studies are necessary. PMID- 28807579 TI - Hemodilution on Cardiopulmonary Bypass and Its Impact on TEG Patterns and Coagulation: Is the Evidence Dilute? PMID- 28807580 TI - Markers of Right Ventricular Dysfunction in Adult Cardiac Surgical Patients. PMID- 28807581 TI - Right Heart Function During and After Community-Acquired Pneumonia in Adults. AB - BACKGROUND: New-onset or worsening heart failure is the most common extra pulmonary complication of community-acquired pneumonia (CAP) during the first 30 days after diagnosis. METHODS: We evaluated the changes in the right ventricular function amongst adult CAP survivors from the time of acute infection to its resolution. We performed comprehensive transthoracic echocardiographic examinations to assess right heart function during the acute illness and the convalescent period (4 to 6 weeks after hospital discharge). RESULTS: Twenty-six patients underwent acute measurements, of which convalescent measurements were completed in 19 subjects. There was no significant change in any of the right heart function parameters from the acute to convalescent stage of CAP. CONCLUSIONS: Our results suggest that right ventricular function does not meaningfully change in the transition from the acute to convalescent stage of CAP in non-critically ill adult CAP survivors. PMID- 28807582 TI - Comparative Efficacy of Angiotensin II Antagonists in Essential Hypertension: Systematic Review and Network Meta-Analysis of Randomised Controlled Trials. AB - BACKGROUND: Evidence on the long-term clinical benefits of individual members of angiotensin II receptor blockers is limited given the lack of head-to-head studies. We conducted a network meta-analysis to determine the comparative efficacy of different members within this drug class with respect to outcomes of (i) blood pressure reduction (at 24 and 52 weeks) and (ii) prevention of cardiovascular disease (>104 weeks). METHODS: A systematic literature review was conducted - Protocol registration: (PROSPERO - CRD42014007067) - to identify relevant literature from the following databases: Cochrane Library, PubMed, Medline and EMBASE; searched from inception to July 2016. Randomised controlled trials (RCTs) were included if they reported long-term effectiveness relating to blood pressure, mortality, myocardial infarction or stroke. Eligible studies included those with placebo or specific active-treatment comparators (either another angiotensin II receptor blockers or hydrochlorothiazide). A Bayesian random-effects network model was used to combine direct within-trial comparisons between treatment groups with indirect evidence from other trials. RESULTS: Thirty-six studies were identified, representing 28 unique trials. Blood pressure reduction, based on 12 studies (n=807) with fixed dosing regimen, was found to be similar amongst members of the angiotensin receptor blocker drug class at both 24 and 52 weeks. A network meta-analysis of five studies (n=16,716) with a treat-to target approach found that prevention of all-cause mortality, stroke and myocardial infarction was similar across the angiotensin-receptor blockers therapies initiated. CONCLUSIONS: Current evidence is insufficient to show differences in any members within the angiotensin II receptor blocker drug class with respect to blood pressuring lowering effects or a reduction in cardiovascular diseases. PMID- 28807583 TI - Lung Cancer Surgery in the xxi Century. PMID- 28807584 TI - World Lung Day. PMID- 28807585 TI - SCCT President's Page: So many to thank, so much to do! PMID- 28807586 TI - Correction to Lancet Glob Health 2017; 5: e757. PMID- 28807587 TI - Prevention of suicide with regulations aimed at restricting access to highly hazardous pesticides: a systematic review of the international evidence. AB - BACKGROUND: Pesticide self-poisoning accounts for 14-20% of suicides worldwide. Regulation aimed at restricting access to pesticides or banning highly hazardous pesticides is one approach to reducing these deaths. We systematically reviewed the evidence of the effectiveness of pesticide regulation in reducing the incidence of pesticide suicides and overall suicides. METHODS: We did a systematic review of the international evidence. We searched MEDLINE, PsycINFO, and Embase for studies published between Jan 1, 1960, and Dec 31, 2016, which investigated the effect of national or regional bans, and sales or import restrictions, on the availability of one or more pesticides and the incidence of suicide in different countries. We excluded other interventions aimed at limiting community access to pesticides. We extracted data from studies presenting pesticide suicide data and overall suicide data from before and after national sales restrictions. Two reviewers independently assessed papers for inclusion, extracted data, and assessed risk of bias. We undertook a narrative synthesis of the data in each report, and where data were available for the years before and after a ban, we pooled data for the 3 years before and the 3 years after to obtain a crude estimate of the effect of the ban. This study is registered through PROSPERO, number CRD42017053329. FINDINGS: We identified 27 studies undertaken in 16 countries-five low-income or middle-income countries (Bangladesh, Colombia, India, Jordan and Sri Lanka), and 11 high-income countries (Denmark, Finland, Germany, Greece, Hungary, Ireland, Japan, South Korea, Taiwan, UK, and USA). Assessments largely focused on national bans of specific pesticides (12 studies of bans in six countries-Jordan, Sri Lanka, Bangladesh, Greece [Crete], South Korea, and Taiwan) or sales restrictions (eight studies of restrictions in five countries- India, Denmark, Ireland, the UK and the USA). Only five studies used optimum analytical methods. National bans on commonly ingested pesticides in five of the six countries studied, including four studies using optimum analytical methods, were followed by reductions in pesticide suicides and, in three of these countries, falls in overall suicide mortality. Greece was the only country studied that did not show a decrease in pesticide suicide following a ban. There were no high-quality studies of restricting sales to people for occupational uses; four of the seven studies (in three of the five countries studied-India, Denmark, and the USA) showed sales restrictions were followed by decreases in pesticide suicides; one of the two studies investigating trends in overall suicide mortality reported a fall in deaths in Denmark, but there were also decreases in suicide deaths from other methods. INTERPRETATION: National bans on highly hazardous pesticides, which are commonly ingested in acts of self-poisoning, seem to be effective in reducing pesticide-specific and overall suicide rates. Evidence is less consistent for sales restrictions. A worldwide ban on the use of highly hazardous pesticides is likely to prevent tens of thousands of deaths every year. FUNDING: None. PMID- 28807588 TI - Regulatory control of highly hazardous pesticides to prevent self-poisoning. PMID- 28807589 TI - Differences in Texture Analysis Parameters Between Active Alveolitis and Lung Fibrosis in Chest CT of Patients with Systemic Sclerosis: A Feasibility Study. AB - RATIONALE AND OBJECTIVES: This study aimed to determine the diagnostic aid of computed tomography (CT) features for the differentiation of active alveolitis and fibrosis using a CT texture analysis (CTTA) prototype and CT densitometry in patients with systemic sclerosis (SSc) using ancillary high-resolution computed tomography (HRCT) features and their longitudinal course as standard of reference. MATERIALS AND METHODS: We retrospectively analyzed thin-slice noncontrast chest CT image data of 43 patients with SSc (18 men, mean age 51.55 +/- 15.52 years; range 23-71 years). All of them had repeated noncontrast enhanced HRCT of the lung. Classification into active alveolitis or fibrosis was done on HRCT based on classical HRCT findings (active alveolitis [19; 44.2%] and fibrosis [24; 55.8%]) and their course at midterm. Results were compared to pulmonary functional tests and were followed up by CT. Ground glass opacity was considered suggestive of alveolitis, whereas coarse reticulation with parenchymal distortion, traction bronchiectasis, and honeycombing were assigned to fibrosis. RESULTS: Statistically significant differences in CTTA were found for first-order textural features (mean intensity, average, deviation, skewness) and second-order statistics (entropy of co-occurrence matrix, mean number of nonuniformity (NGLDM), entropy of NGLDM, entropy of heterogeneity, intensity, and average). Cut off value for the prediction of fibrosis at baseline was significant for entropy of intensity (P value < .001) and for mean deviation (P value < .001), and for prediction of alveolitis was significant for uniformity of intensity (P value < .001) and for NGLDM (P value < .001). At pulmonary functional tests, forced expiratory volume in 1 second and single-breath diffusion capacity for carbon monoxide were significantly lower in fibrosis than in alveolitis 2.03 +/- 0.78 vs. 2.61 +/- 0.83, P < .016 and 4.51 +/- 1.61 vs. 6.04 +/- 1.75, P < .009, respectively. Differences in CT densitometry between alveolitis and fibrosis were not significant. CONCLUSIONS: CTTA parameters are significantly different in active alveolitis vs. fibrosis in patients with SSc and may be helpful for differentiation of these two entities. PMID- 28807590 TI - Re: Impact of the method and success of pharyngeal reconstruction on the outcome of treating laryngeal and hypopharyngeal cancers with pharyngolaryngectomy: A national analysis. PMID- 28807591 TI - Comment on: Impact of the method and success of pharyngeal reconstruction on the outcome of treating laryngeal and hypopharyngeal cancers with pharyngolaryngectomy: A national analysis. PMID- 28807592 TI - Ligand migration and steered molecular dynamics in drug discovery: Comment on "Ligand diffusion in proteins via enhanced sampling in molecular dynamics" by Jakub Rydzewski and Wieslaw Nowak. PMID- 28807593 TI - Numerical solution of generalised kinetic models for active particles: Comment on "Modeling human behavior in economics and social science" by Marina Dolfin, Leone Leonida and Nisrine Outada. PMID- 28807594 TI - Thyroid Hormone Receptor-beta Agonist GC-1 Inhibits Met-beta-Catenin-Driven Hepatocellular Cancer. AB - The thyromimetic agent GC-1 induces hepatocyte proliferation via Wnt/beta-catenin signaling and may promote regeneration in both acute and chronic liver insufficiencies. However, beta-catenin activation due to mutations in CTNNB1 is seen in a subset of hepatocellular carcinomas (HCC). Thus, it is critical to address any effect of GC-1 on HCC growth and development before its use can be advocated to stimulate regeneration in chronic liver diseases. In this study, we first examined the effect of GC-1 on beta-catenin-T cell factor 4 activity in HCC cell lines harboring wild-type or mutated-CTNNB1. Next, we assessed the effect of GC-1 on HCC in FVB mice generated by hydrodynamic tail vein injection of hMet S45Y-beta-catenin, using the sleeping beauty transposon-transposase. Four weeks following injection, mice were fed 5 mg/kg GC-1 or basal diet for 10 or 21 days. GC-1 treatment showed no effect on beta-catenin-T cell factor 4 activity in HCC cells, irrespective of CTNNB1 mutations. Treatment with GC-1 for 10 or 21 days led to a significant reduction in tumor burden, associated with decreased tumor cell proliferation and dramatic decreases in phospho-(p-)Met (Y1234/1235), p extracellular signal-related kinase, and p-STAT3 without affecting beta-catenin and its downstream targets. GC-1 exerts a notable antitumoral effect on hMet-S45Y beta-catenin HCC by inactivating Met signaling. GC-1 does not promote beta catenin activation in HCC. Thus, GC-1 may be safe for use in inducing regeneration during chronic hepatic insufficiency. PMID- 28807595 TI - Sphingosine Kinase-2 Deficiency Ameliorates Kidney Fibrosis by Up-Regulating Smad7 in a Mouse Model of Unilateral Ureteral Obstruction. AB - Kidney fibrosis is a hallmark of chronic kidney disease and leads to extracellular matrix accumulation, organ scarring, and loss of kidney function. In this study, we investigated the role of sphingosine kinase-2 (SPHK2) on the progression of tubular fibrosis by using a mouse unilateral ureteral obstruction (UUO) model. We found that SPHK2 protein and activity are up-regulated in fibrotic renal tissue. Functionally, Sphk2-deficient (Sphk2-/-) mice showed an attenuated fibrotic response to UUO compared with wild-type mice, as demonstrated by reduced collagen abundance and decreased expression of fibronectin-1, collagen I, alpha-smooth muscle actin, connective tissue growth factor (CTGF), and plasminogen activator inhibitor (PAI-1). More important, these changes were associated with increased expression of the antifibrotic protein Smad7 and higher levels of sphingosine in Sphk2-/- UUO kidneys. Mechanistically, sphingosine ameliorates transforming growth factor-beta-induced collagen accumulation, CTGF, and PAI-1 expression, but enhances Smad7 protein expression in primary kidney fibroblasts. In a complementary approach, in human Sphk2-overexpressing mice, UUO resulted in exacerbated signs of fibrosis with increased collagen accumulation, higher expression levels of fibronectin-1, collagen I, alpha-smooth muscle actin, CTGF, and PAI-1, but decreased Smad7 expression. SPHK2 plays an important role in kidney fibrogenesis by modulating transforming growth factor-beta signaling. Thus, SPHK2 might be an attractive new target for the treatment of fibrosis in chronic kidney disease. PMID- 28807596 TI - The Role of Angiotensin II in Parietal Epithelial Cell Proliferation and Crescent Formation in Glomerular Diseases. AB - Crescentic glomerulonephritis (GN) is a devastating disease with rapidly progressive deterioration in kidney function, which, histologically, manifests as crescent formation in most glomeruli. We previously found that crescents derive from the aberrant proliferation and migration of parietal epithelial cells (PECs)/progenitor cells, and that the angiotensin (ang) II/ang II type-1 (AT1) receptor pathway may participate, together with the stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor 4 axis, in the development of those lesions. Herein, we elucidated sequential events and cellular and molecular interactions occurring during crescentic lesion onset and evolution. By analyzing kidney biopsy specimens of patients with extracapillary GN, divided according to the grade of glomerular lesions, we found that the accumulation of macrophages expressing matrix metalloproteinase-12 started manifesting in glomeruli affected by early-stage lesions, whereas AT1 receptor expression could not be detected. In glomeruli with advanced lesions, AT1 receptor expression increased markedly, and the up-regulation of SDF-1, and its receptor C-X-C chemokine receptor 7, was documented on podocytes and PECs, respectively. In vitro studies were instrumental to demonstrating the role of ang II in inducing podocyte SDF-1 production, which ultimately activates PECs. The present findings support the possibility that angiotensin-converting enzyme inhibitor treatment might limit PEC activation and reduce the frequency and extension of crescents in extracapillary GN. PMID- 28807597 TI - Reference values of intrinsic muscle strength of the hand of adolescents and young adults. AB - STUDY DESIGN: A cross-sectional clinical measurement study. INTRODUCTION: Measuring intrinsic hand muscle strength helps evaluate hand function or therapeutic outcomes. However, there are no established normative values in adolescents and young adults between 13 and 20 years of age. PURPOSE OF THE STUDY: To measure hand intrinsic muscle strength and identify associated factors that may influence such in adolescents and young adults through use of the Rotterdam intrinsic hand myometer. METHODS: A total of 131 participants (male: 63; female: 68) between 13 and 20 years of age completed the strength measurements of abductor pollicis brevis, first dorsal interosseus (FDI), deep head of FDI and lumbrical of second digit, flexor pollicis brevis (FPB), and abductor digiti minimi. Two trials of the measurements of each muscle were averaged for analyses. Self-reported demographic data were used to examine the influences of age, sex, and body mass index (BMI) on intrinsic hand muscle strength. RESULTS: Normative values of intrinsic hand muscle strength were presented by age groups (13, 14, 15-16, 17-18, 19-20 year olds) for each sex category (male, female). A main effect of sex, but not age, on all the muscles on both the dominant (FPB: P = .02, others: P < .001) and non-dominant (FDI: P = .005, FPB: P = .01, others: P < .001) sides was found. A significant effect of BMI was found on dominant (P = .009) and non-dominant abductor pollicis brevis (P = .002). In addition, FDI (P = .005) and FPB (P = .002) were stronger on the dominant side than the non-dominant side. DISCUSSION: Intrinsic hand muscle strength may be influenced by different factors including sex, BMI, and hand dominance. A larger sample is needed to rigorously investigate the influence of age on intrinsic strength in male and female adolescents and young adults. CONCLUSION: The results provide reference values and suggest factors to be considered when evaluating hand function and therapeutic outcomes in both clinical and research settings. Further study is recommended. LEVEL OF EVIDENCE: VI. PMID- 28807598 TI - Effectiveness of edema management techniques for subacute hand edema: A systematic review. AB - STUDY DESIGN: Systematic review. INTRODUCTION: Prolonged hand edema can have detrimental effects on range of motion and function. There is no consensus on how best to manage traumatic subacute edema. This is the first systematic review which examines the clinical effectiveness of edema treatments on hand volume. PURPOSE OF THE STUDY: The purpose of this systematic review was to examine the evidence of effectiveness of treatments for sub-acute hand edema. METHODS: A literature search of AMED, CINAHL, Embase, and OVID MEDLINE (from inception to August 2015) was undertaken. Studies were selected if they met the following inclusion criteria: randomized controlled or controlled trials in adults who have subacute swelling after a recent upper limb musculoskeletal trauma or cerebral vascular attack or after surgery. Two independent assessors rated study quality and risk of bias using the 24-point MacDermid Structured Effectiveness Quality Evaluation Scale (SEQES). RESULTS: Ten studies met the inclusion criteria. Study quality ranged from 23 to 41 out of 48 points on the SEQES. A total of 16 edema interventions were evaluated across the studies. Due to heterogeneity of the patient characteristics, interventions, and outcomes assessed, it was not possible to pool the results from all studies. Therefore, a narrative best evidence synthesis was undertaken. There is low to moderate quality evidence with limited confidence in the effect estimate to support the use of manual edema mobilization methods in conjunction with standard therapy to reduce problematic hand edema. CONCLUSION: Manual edema mobilization techniques should be considered in conjunction with conventional therapies, in cases of excessive edema or when the edema has not responded to conventional treatment alone; however, manual edema mobilization is not advocated as a routine intervention. LEVEL OF EVIDENCE: 2b. PMID- 28807599 TI - Relationship of the Patient-Specific Functional Scale to commonly used clinical measures in hand osteoarthritis. AB - STUDY DESIGN: Prospective cohort correlation study. INTRODUCTION: There is no known published research on correlations between the Patient-Specific Functional Scale (PSFS), hand grip strength, and the Disability of the Arm, Shoulder and Hand (DASH) in a population with hand osteoarthritis (OA). PURPOSE: The purpose of this study is to establish reliability of the PSFS and to evaluate the relationship between the PSFS, hand grip strength, and the DASH for a population with hand OA. METHODS: Thirty-five participants in 4 hand clinics completed the PSFS, hand grip strength testing, and the DASH at the onset of therapy and at discharge. Eighteen participants enrolled at the primary investigator's site completed a baseline PSFS one week before the pretreatment collection with data used to establish relative and absolute reliability. Data were analyzed separately at pretreatment and posttreatment with Spearman's rho correlation (P < .05). Intraclass correlation (2, 1), standard error of the measurement, and minimum detectable change (MDC90 and MDC95) were calculated from the repeated baseline and pretreatment PSFS. RESULTS: Intraclass correlation for PSFS was (r = 0.80) with the standard error of the measurement = 0.56, MDC90 = 1.30, and MDC95 = 1.56. Small correlation between the PSFS and DASH scores was found pretreatment (rho = -0.10) and change scores (rho = 0.13). CONCLUSION: Excellent reliability with small measurement error has established clinical utility of the PSFS for the population with hand OA. These outcome measures were shown to measure different constructs and therefore should not be used interchangeably. LEVEL OF EVIDENCE: 3. PMID- 28807600 TI - Methylglyoxal synthase regulates cell elongation via alterations of cellular methylglyoxal and spermidine content in Bacillus subtilis. AB - Methylglyoxal regulates cell division and differentiation through its interaction with polyamines. Loss of their biosynthesizing enzyme causes physiological impairment and cell elongation in eukaryotes. However, the reciprocal effects of methylglyoxal and polyamine production and its regulatory metabolic switches on morphological changes in prokaryotes have not been addressed. Here, Bacillus subtilis methylglyoxal synthase (mgsA) and polyamine biosynthesizing genes encoding arginine decarboxylase (SpeA), agmatinase (SpeB), and spermidine synthase (SpeE), were disrupted or overexpressed. Treatment of 0.2mM methylglyoxal and 1mM spermidine led to the elongation and shortening of B. subtilis wild-type cells to 12.38+/-3.21MUm (P<0.05) and 3.24+/-0.73MUm (P<0.01), respectively, compared to untreated cells (5.72+/-0.68MUm). mgsA-deficient (mgsA ) and -overexpressing (mgsAOE) mutants also demonstrated cell shortening and elongation, similar to speB- and speE-deficient (speB- and speE-) and overexpressing (speBOE and speEOE) mutants. Importantly, both mgsA-depleted speBOE and speEOE mutants (speBOE/mgsA- and speEOE/mgsA-) were drastically shortened to 24.5% and 23.8% of parental speBOE and speEOE mutants, respectively. These phenotypes were associated with reciprocal alterations of mgsA and polyamine transcripts governed by the contents of methylglyoxal and spermidine, which are involved in enzymatic or genetic metabolite-control mechanisms. Additionally, biophysically detected methylglyoxal-spermidine Schiff bases did not affect morphogenesis. Taken together, the findings indicate that methylglyoxal triggers cell elongation. Furthermore, cells with methylglyoxal accumulation commonly exhibit an elongated rod-shaped morphology through upregulation of mgsA, polyamine genes, and the global regulator spx, as well as repression of the cell division and shape regulator, FtsZ. PMID- 28807601 TI - UBX domain-containing proteins are involved in lipid homeostasis and stress responses in Pichia pastoris. AB - Ubiquitin regulatory X (UBX) domain-containing proteins constitute a family of proteins and are substrate adaptors of AAA ATPase Cdc48. UBX proteins can bind to the N-terminal region of Cdc48 to perform endoplasmic reticulum associated protein degradation (ERAD). In this study, we identified two UBX domain containing proteins, Ubx1 and Ubx2, in Pichia pastoris and found that the two proteins could recover the growth defect of Saccharomyces cerevisiae in ubx2Delta. Our results revealed that Ubx1 and Ubx2 play critical roles in synthesis of unsaturated fatty acids by affecting Spt23. In addition, the results demonstrated that both Ubx1 and Ubx2 are involved in lipid droplet formation and protein degradation. Deletion of UBX1 led to increased sensitivity to oxidative stress and disruption of UBX2 impaired cell viability under osmotic stress. The phenotypes of ubx1Delta+UBX2, ubx2Delta+UBX1 and ubx1Deltaubx2Delta and RNA-seq data suggested that Ubx1 and Ubx2 play different roles in cell functions, and the roles of Ubx1 may be more numerous than Ubx2. In summary, our findings provide new insights into the relationship between lipid homeostasis and cell functions in the oil-producing organism P. pastoris. PMID- 28807602 TI - Neutralization of IFN-gamma reverts clinical and laboratory features in a mouse model of macrophage activation syndrome. AB - BACKGROUND: The pathogenesis of macrophage activation syndrome (MAS) is not clearly understood: a large body of evidence supports the involvement of mechanisms similar to those implicated in the setting of primary hemophagocytic lymphohistiocytosis. OBJECTIVE: We sought to investigate the pathogenic role of IFN-gamma and the therapeutic efficacy of IFN-gamma neutralization in an animal model of MAS. METHODS: We used an MAS model established in mice transgenic for human IL-6 (IL-6TG mice) challenged with LPS (MAS mice). Levels of IFN-gamma and IFN-gamma-inducible chemokines were evaluated by using real-time PCR in the liver and spleen and by means of ELISA in plasma. IFN-gamma neutralization was achieved by using the anti-IFN-gamma antibody XMG1.2 in vivo. RESULTS: Mice with MAS showed a significant upregulation of the IFN-gamma pathway, as demonstrated by increased mRNA levels of Ifng and higher levels of phospho-signal transducer and activator of transcription 1 in the liver and spleen and increased expression of the IFN-gamma-inducible chemokines Cxcl9 and Cxcl10 in the liver and spleen, as well as in plasma. A marked increase in Il12a and Il12b expression was also found in livers and spleens of mice with MAS. In addition, mice with MAS had a significant increase in numbers of liver CD68+ macrophages. Mice with MAS treated with an anti-IFN-gamma antibody showed a significant improvement in survival and body weight recovery associated with a significant amelioration of ferritin, fibrinogen, and alanine aminotransferase levels. In mice with MAS, treatment with the anti-IFN-gamma antibody significantly decreased circulating levels of CXCL9, CXCL10, and downstream proinflammatory cytokines. The decrease in CXCL9 and CXCL10 levels paralleled the decrease in serum levels of proinflammatory cytokines and ferritin. CONCLUSION: These results provide evidence for a pathogenic role of IFN-gamma in the setting of MAS. PMID- 28807603 TI - Stem cell industry update: 2012 to 2016 reveals accelerated investment, but market capitalization and earnings lag. AB - Treatments based on stem cells have long been heralded for their potential to drive the future of regenerative medicine and have inspired increasing medical and business interest. The stem cell therapy market has been expanding since 2012, but earnings and profitability still lag the broader health care sector (compounded annual growth rate in annual financing of 31.5% versus 13.4%, respectively). On the basis of historical financial data, approximately $23 billion has been invested in stem cell companies since 1994, with more than 80% of this raised from 2011 through 2016. This reflects a marked acceleration in capital investment, as companies began late-stage clinical trials, initiate partnerships or are acquired by large pharmaceutical companies. All of these data reflect a field that is emerging from infancy, which will demand more time and capital to mature. This update is relevant to researchers, clinicians and investors who wish to quantify the potential in this field. PMID- 28807604 TI - Focusing on the implementation of 21st century vaccines for adults. AB - Adult immunization is a priority for public health, particularly in countries where an aging population has become increasingly more numerous. Protection against diseases which typically affect adults (like flu, pneumococcal diseases and Herpes zoster), the shift of age of infections which originally affected children (like measles), the decreasing protection with time for infections which need periodical booster doses of vaccines (Tdap), the availability of vaccines which can also impact on adult health (HPV) are only some examples of the importance of implementing targeted vaccination strategies. The possibility to reach high coverage with immunizations that can guarantee a fundamental improvement of health for adults and the elderly can only be achieved through a coordinated effort where all stakeholders, under the coordination of public health, contribute to issue recommendations; create a functioning database for vaccine coverage registration; promote formative courses for healthcare workers and continuous information for the public; increase vaccines uptake among healthcare workers, who need to give the first testimony on the relevance of immunization. PMID- 28807606 TI - Effectiveness of different vaccine schedules for heptavalent and 13-valent conjugate vaccines against pneumococcal disease in the Community of Madrid. AB - INTRODUCTION: The heptavalent pneumococcal conjugate vaccine (PCV-7) was added to the childhood routine vaccination program in the Community of Madrid in November of 2006 with 3+1 recommended doses and a catch-up for those under 2years old. In June 2010, PCV-7 was replaced by 13-valent vaccine (PCV-13) with 2+1 recommended doses. In July of 2012, the PCV-13 was removed from the funded program and reintroduced again (2+1 recommended doses) in December 2014. In between, children were vaccinated privately with 3+1 recommended doses of PCV-13. The aim of this study was to evaluate the effectiveness of each vaccination schedule used in the Community of Madrid. METHODS: We included all cases of invasive pneumococcal disease (IPD) reported between 2007 and 2015 to the Notifiable Diseases Surveillance System. Vaccination information was obtained from the Immunization Registry. Vaccine effectiveness (VE) was estimated using the indirect cohort design for cases with serotype information. RESULTS: A total 779 cases were included in the study. Among them 47.6% of the cases were primo-vaccinated with booster, 20% primo-vaccinated, 15.9% incompletely primo-vaccinated and 16.5% not vaccinated. The VE for >=1 doses of any PCV was 82% (CI 95%: 67.8-89.9%): 91.9% (CI 95%: 76.5-97.2%) for PCV-7 and 77.2% (48.6-89.9%) for PCV-13. VE in those receiving the full 2+1 or 3+1 schedules was 100% for both vaccines. CONCLUSIONS: A high number of vaccine failures were reported in children before they had the opportunity to receive the booster dose, especially due to PCV-13-non-PCV-7 serotypes. VE was higher for PCV-7 compared to PCV-13, except for those that received the complete schedule with booster that achieved 100% of VE, which shows the relevance of the vaccines and complying with all doses scheduled. PMID- 28807605 TI - Adjuvant HPV vaccination for anal cancer prevention in HIV-positive men who have sex with men: The time is now. AB - IMPORTANCE: Outcomes of treating high-grade squamous intraepithelial lesions (HSIL), a precursor to anal cancer, remain uncertain. Emerging evidence shows that post HSIL treatment adjuvant quadrivalent human papillomavirus (qHPV) vaccination improves the effectiveness of treatment. However, no recommendations exist regarding the use of qHPV vaccine as an adjuvant form of therapy. Our objective was to determine whether post-treatment adjuvant vaccination should be adopted in HIV-infected MSM (individuals at highest risk for anal cancer) on the basis of cost-effectiveness determined using existing evidence or whether future research is needed. METHODS: We developed a Markov (state-transition) cohort model to assess the cost-effectiveness of post-treatment adjuvant HPV vaccination of 27years or older HIV-infected MSM. We first estimated cost-effectiveness and then performed value-of-information (VOI) analysis to determine whether future research is required by estimating the expected value of perfect information (EVPI). We also estimated expected value of partial perfect information (EVPPI) to determine what new evidences should have highest priority. RESULTS: With the incremental cost-effectiveness ratio (ICER) of $71,937/QALY, "treatment plus vaccination" was the most cost-effective HSIL management strategy using the willingness-to-pay threshold of 100,000/QALY. We found that population-level EVPI for conducting future clinical research evaluating HSIL management approaches was US$12 million (range $6-$20 million). The EVPPI associated with adjuvant qHPV vaccination efficacy estimated in terms of hazards of decreasing HSIL recurrence was $0 implying that additional data from a future study evaluating efficacy of adjuvant qHPV vaccination will not change our policy conclusion that "treatment plus vaccination" was cost-effective. Both the ICER and EVPI were sensitive to HSIL treatment compliance. CONCLUSION: Post-treatment adjuvant qHPV vaccination in HIV-infected MSM aged 27 or above is likely to be cost-effective. Use of adjuvant qHPV vaccination could be considered as a potential strategy to reduce rising anal cancer burden among these high-risk individuals. PMID- 28807608 TI - Benefits of flu vaccination for persons with diabetes mellitus: A review. AB - Diabetes mellitus imposes a significant and increasing burden on society, with major consequences for human health, welfare and the economy worldwide. Persons with diabetes mellitus are at increased risk of developing severe complications after influenza virus infection and guidelines advise vaccination. The present evidence for influenza vaccine effectiveness in persons with diabetes mellitus is mainly based on observational studies with clinical endpoints like hospitalization and death, indicating a beneficial reduction of morbidity and mortality. Further supportive evidence comes from serological studies, in which persons with diabetes mellitus usually develop similar antibody levels after vaccination as healthy people. Observational studies may be prone to selection bias, and serological studies may not completely mirror vaccine effectiveness in the field. Although more controlled trials in persons with diabetes mellitus with laboratory-confirmed, influenza-specific outcomes would be desirable to better estimate the effect of vaccination, the currently available data justify routine influenza vaccination in persons with diabetes mellitus. As in this risk group, the use of influenza vaccine is far below target worldwide, efforts should be made to increase vaccination coverage. PMID- 28807607 TI - Plasma cell and serum antibody responses to influenza vaccine in preterm and full term infants. AB - BACKGROUND: Preterm (PT) infants are at greater risk for severe influenza infection and experience decrements in long-term antibody responses to vaccines. This may related to defects in antibody secreting cell (ASC) generation. OBJECTIVE: To investigate the relationships among the frequencies of influenza specific antibody secreting cells, ASC numbers and subsets, and antibody responses to influenza vaccines (IV) among PT and full-term (FT) infants. DESIGN/METHODS: We enrolled 11 former PT (<=32weeks' gestation, <=1500 g' birth weight) and 11FT infants, 6-17months of age, receiving their first influenza immunizations. Infants received two doses of inactivated trivalent (T)IV or quadrivalent (Q)IV during the 2012-2013 and 2013-2014 influenza seasons, respectively, at 0 and 28days, and blood was drawn at 0, 10, 35, and 56days and 9months. Vaccine-specific antibody was measured by hemagglutination inhibition (HAI) at 0 and 56days and 9months, vaccine-specific ASC numbers by enzyme linked immunospot (ELISPOT) at 10 and 35days, and ASC subsets by flow cytometry at 0, 10 and 35days. RESULTS: PT infants had post-vaccine HAI titers to all 4 vaccine strains at least equal to FT infants at 56days and 9months after beginning immunization. Influenza-specific ASC ELISPOT responses at 35days were higher among PT than FT infants (median 100 v. 30 per 106 PBMC, p=0.04). ASC numbers at 35days were positively correlated with serum HAI titers at 56days (rho=0.50 0.80). There were no statistical differences between PT and FT infants in the frequency of five ASC subsets and no specific ASC subset correlated with durability of serum antibody titers. CONCLUSIONS: Influenza-specific ASC numbers in both FT and PT infants correlated with peak antibody titers, but ASC subsets did not correlate with durability of antibody response. PMID- 28807609 TI - CspB of an arctic bacterium, Polaribacter irgensii KOPRI 22228, confers extraordinary freeze-tolerance. AB - Freezing temperatures are a major challenge for life at the poles. Decreased membrane fluidity, uninvited secondary structure formation in nucleic acids, and protein cold-denaturation all occur at cold temperatures. Organisms adapted to polar regions possess distinct mechanisms that enable them to survive in extremely cold environments. Among the cold-induced proteins, cold shock protein (Csp) family proteins are the most prominent. A gene coding for a Csp-family protein, cspB, was cloned from an arctic bacterium, Polaribacter irgensii KOPRI 22228, and overexpression of cspB greatly increased the freeze-survival rates of Escherichia coli hosts, to a greater level than any previously reported Csp. It also suppressed the cold-sensitivity of an E. coli csp-quadruple deletion strain, BX04. Sequence analysis showed that this protein consists of a unique domain at its N-terminal end and a well conserved cold shock domain at its C-terminal end. The most common mechanism of Csp function in cold adaption is melting of the secondary structures in RNA and DNA molecules, thus facilitating transcription and translation at low temperatures. P. irgensii CspB bound to oligo(dT) cellulose resins, suggesting single-stranded nucleic acid-binding activity. The unprecedented level of freeze-tolerance conferred by P. irgensii CspB suggests a crucial role for this protein in survival in polar environments. PMID- 28807610 TI - Genome sequencing of two Bacillus anthracis strains: a virulent strain and a vaccinal strain. AB - Bacillus anthracis strain SPV842_15 was isolated from bovine fetus, while B. anthracis strain Brazilian vaccinal was recovered from a commercial vaccine. We report here the genome sequences of both strains. The SPV842_15 genome is composed of a single circular chromosome with a length of 5,228,664 base pairs, and comprises 5911 coding sequences. In turn, the Brazilian vaccinal genome remains in 201 contigs with 5733 coding sequences. Both genomes have an overall C+G content of 35.4%, and 11 genes encoding the ribosomal RNAs (rRNAs) 5S, 16S and 23S. Only the plasmid pX01 sequence, which carries genes for toxins synthesis, was detected and completely assembled for both strains. These plasmids have a length of 181,684 base pairs and a C+G content of 32.5%. These genomic data generate insights about vaccinal B. anthracis virulence. PMID- 28807611 TI - Initial Treatment for Nonsyndromic Early-Life Epilepsy: An Unexpected Consensus. AB - OBJECTIVE: There are no evidence-based guidelines on the preferred approach to treating early-life epilepsy. We examined initial therapy selection in a contemporary US cohort of children with newly diagnosed, nonsyndromic, early-life epilepsy (onset before age three years). METHODS: Seventeen pediatric epilepsy centers participated in a prospective cohort study of children with newly diagnosed epilepsy with onset under 36 months of age. Details regarding demographics, seizure types, and initial medication selections were obtained from medical records. RESULTS: About half of the 495 enrolled children with new-onset, nonsyndromic epilepsy were less than 12 months old at the time of diagnosis (n = 263, 53%) and about half (n = 260, 52%) had epilepsy with focal features. Of 464 who were treated with monotherapy, 95% received one of five drugs: levetiracetam (n = 291, 63%), oxcarbazepine (n = 67, 14%), phenobarbital (n = 57, 12%), topiramate (n = 16, 3.4%), and zonisamide (n = 13, 2.8%). Phenobarbital was prescribed first for 50 of 163 (31%) infants less than six months old versus seven of 300 (2.3%) of children six months or older (P < 0.0001). Although the first treatment varied across study centers (P < 0.0001), levetiracetam was the most commonly prescribed medication regardless of epilepsy presentation (focal, generalized, mixed/uncertain). Between the first and second treatment choices, 367 (74%) of children received levetiracetam within the first year after diagnosis. CONCLUSIONS: Without any specific effort, the pediatric epilepsy community has developed an unexpectedly consistent approach to initial treatment selection for early-life epilepsy. This suggests that a standard practice is emerging and could be utilized as a widely acceptable basis of comparison in future drug studies. PMID- 28807612 TI - The role of trimethylamine N-oxide as a mediator of cardiovascular complications in chronic kidney disease. AB - Patients with chronic kidney disease (CKD) have an enhanced risk of cardiovascular (CV) morbidity and mortality when compared with age- and gender matched individuals with normal kidney function. Trimethlyamine N-oxide (TMAO) is a gut-derived amine oxide that has been implicated in the causation of CV diseases. Plasma TMAO is cleared by the kidney, and TMAO levels are elevated in CKD. Experimental studies have identified pathogenic mechanisms by which TMAO may contribute to CV disease through dysregulation of lipid metabolism, enhanced macrophage foam cell formation, and platelet dysfunction. Safe and well-tolerated therapeutic interventions such as pre- and probiotics, which modify the gut microbiome, offer the opportunity for interventional studies. This review examines the pathogenicity of TMAO, its value as a biomarker, and its potential as a therapeutic target in the context of CKD. PMID- 28807614 TI - WITHDRAWN: Oxysterols and phytosterols in human health. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/ 10.1016/j.chemphyslip.2017.08.003. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal. PMID- 28807613 TI - Identification and quantification and antioxidant activity of flavonoids in different strains of silk cocoon, Bombyx mori. AB - Silk cocoon is produced from silkworm (Bombyx mori) to protect itself from outer environment. Various strains of cocoon contain different forms and amounts of flavonoids, which may affect on their antioxidant activity. Moreover, the extraction method would influence the amount of flavonoids extracted. Therefore, the objectives of this study were to identify and quantify the flavonoids in 3 strains of bivoltine Bombyx mori silk cocoon (Chul 1/1; white cocoon, Chul 3/2; greenish cocoon, and Chul 4/2; yellow cocoon) extracted by 6 different solvents including acetone, ethyl acetate, dimethyl sulfoxide (DMSO), ethanol, methanol, and purified water. The flavonoids extracted were identified and quantified by liquid chromatography-mass spectrometry (LC-MS). The antioxidant activity of flavonoids extracted was also investigated by visible spectroscopy at 517 nm. The results showed that Chul 3/2 silk cocoon contained the highest amount of flavonoids. Purified water seemed to be the best solvent that preserved most antioxidant activity of the flavonoids extracted. Flavonoids in Chul 1/1 and Chul 4/2 silk cocoon were rarely found, however they contained some antioxidant activities. The data from this study can provide basic information for flavonoid extraction from silk cocoon which can also apply for other flavonoid-containing natural biomaterials. PMID- 28807615 TI - Interfacial properties of avian stratum corneum monolayers investigated by Brewster angle microscopy and vibrational sum frequency generation. AB - The outermost layer of skin, the stratum corneum (SC), contains a complex mixture of lipids, which controls the rate of cutaneous water loss (CWL) in reptiles, mammals, and birds. However, the molecular structure of SC lipids and how molecular configurations influence CWL is poorly understood. Here, the organization and structure of SC lipids extracted from birds were investigated by means of Langmuir films. Properties of lipids from the SC of arid and semi-arid adapted larks, known to have a low CWL, were compared with lipids extracted from the SC of mesic lark species with higher CWL to gain insight into how structure impacts CWL. Film properties were probed with surface pressure-area isotherms, Brewster angle microscopy (BAM), and vibrational sum frequency generation (VSFG). Results indicate organization and ordering of SC lipids in the arid-adapted hoopoe lark was vastly different from all other species, forming a miscible, rigid monolayer, whereas monolayers from semi-arid and mesic species were immiscible and disordered. Probing of interfacial water structure reveals that film morphology determines organization of water molecules near the monolayer; monolayers with a porous morphology had an increased population of water molecules that are weakly hydrogen-bonded. In general, CWL appears related to the miscibility and ordering of lipid components within the SC, as well as the ability of these lipids to interact with water molecules. From a broader perspective, CWL in larks appears linked to both the SC lipid composition and the aridity of the species' environment. PMID- 28807616 TI - Problem Representation, Background Evidence, Analysis, Recommendation: An Oral Case Presentation Tool to Promote Diagnostic Reasoning. AB - Oral case presentations provide an opportunity for trainees to communicate diagnostic reasoning at the bedside. However, few tools exist to enable faculty to provide effective feedback. We developed a tool to assess diagnostic reasoning and communication during oral case presentations. PMID- 28807617 TI - Measurement of peripheral venous catheter-related phlebitis: a cross-sectional study. AB - BACKGROUND: Many instruments for measurement of peripheral venous catheter (PVC) related phlebitis are available, but no consensus exists on their applicability in clinical practice. This absence of consensus affects the ability to identify and compare proportions of PVCs causing phlebitis within and across hospitals as the range varies between 2% and 62% in previous studies. We hypothesised that the instruments' ability to identify phlebitis varies. The aim of this study is to illustrate the complexity of application of phlebitis instruments to a clinical dataset. METHODS: In this cross-sectional study, we applied 17 instruments for phlebitis identification (divided into three groups [instruments using definitions, severity rating systems, and scoring systems]) to PVCs in adult patients admitted to 12 inpatient units at Karolinska University Hospital in Sweden. We calculated the proportion of PVCs causing phlebitis on the basis of each instrument's minimum criterion for phlebitis. We also analysed each instrument's face validity. We compared proportions using the Z test. FINDINGS: On the basis of data collected between Feb 2, 2009, and Feb 20, 2009, May 18, 2009, and June 5, 2009, and Feb 8, 2010, and Feb 26, 2010, we applied 17 instruments for phlebitis identification (eight instruments using definitions, seven severity rating systems, and two scoring systems) to 1175 observed PVCs in 1032 patients. The highest number of PVCs causing phlebitis generated by definitions was 137 (11.7%), by severity rating systems was 395 (33.6%), and by scoring systems was 363 (30.9%). The proportion generated by instruments using definitions was significantly different to that of both the severity rating (difference 21.9% [95% CI 18.6-25.2]; p<0.0001) and scoring (19.2% [12.0-26.4]; p<0.0001) systems. Proportions did not differ significantly between severity rating systems and scoring system (difference 2.7% [95% CI -1.1 to 6.6]; p=0.16). The proportion within instruments ranged from less than 1% to 28%. We identified face validity issues, such as use of indistinct or complex measurements and inconsistent measurements or definitions. INTERPRETATION: Our study highlights several concerns regarding instruments to measure phlebitis published in the scientific community. From a work environment and patient safety perspective, clinical staff engaged in PVC management should be aware of the absence of adequately validated instruments for phlebitis assessment. We suggest that researchers within the field of PVC come together in a joint research programme aiming to develop valid and reliable methods that accurately identify PVC-related adverse events that also includes decision support for clinical staff concerning clinical indications for PVC removal. Such actions could lead to a revised view on what is best practice for management of PVCs. FUNDING: None. PMID- 28807618 TI - Repeatability of the infant food reinforcement paradigm: Implications of individual and developmental differences. AB - The relative reinforcing value of food versus engagement in other behaviors may be related to the development of obesity, and interventions to reduce FRR may prevent the development of obesity. Our laboratory recently developed a paradigm to measure the reinforcing value of food versus an alternative behavior (i.e., playing with bubbles) in infants using a computerized laboratory task, during which infants press a button to earn reinforcers following a progressive ratio schedule of reinforcement. The primary purpose of this study was to examine the short-term (within 2 weeks) repeatability of this measure, specifically the outcome of infant food reinforcing ratio (FRR), or how hard infants will work for food relative to the alternative. The secondary aim was to examine whether infant age and temperament dimensions related to novelty responsiveness (high intensity pleasure and approach) moderated the repeatability of FRR. Thirty-seven infants aged 9-18 months completed this study. Repeated measures analysis of variance (ANOVA) showed no differences between time 1 and time 2 in responding for food (F = 0.463, p = 0.501), bubbles (F = 1.793, p = 0.189), or overall FRR (F = 0.797, p = 0.378). Regression models showed the association between BUB Pmax at time 1 and time 2 were moderated by infant age (p = 0.04), with greater repeatability in older infants. Linear regression models also demonstrated that the infant temperamental dimension of high intensity pleasure significantly predicted BUB Pmax at time 1 (beta = 2.89, p = 0.01), but not at time 2. Overall, our findings support the repeatability of this measure for food portion of the reinforcement task, but demonstrated that the measure of non-food portion of the task required modification, in particular among children younger than 13 months old. PMID- 28807619 TI - Neuroplasticity-related mechanisms underlying the antidepressant-like effects of traditional herbal medicines. AB - Traditional herbal medicine can offer efficacious and safe alternative pharmacotherapies for depression. The ability of an herbal medicine to produce neuroadaptive processes, that enhance neuroplasticity and cellular resilience in response to chronic stress, may point to its antidepressant potential. We suggest that among many investigated herbal medicines, those that can enhance neuroplasticity may have stronger therapeutic potential. The current article presents a summary of traditional herbal medicines, which are thought to exert antidepressant-like effects in chronic stress models via neuroplasticity enhancement. Brain-derived neurotrophic factor (BDNF) is a biomarker for neuroplasticity-related mechanisms compromised in depression and recovered by conventional antidepressants, including synaptic plasticity, cell survival, neurogenesis and spine formation. We therefore presumed that if an herbal medicine up-regulates BDNF in the hippocampus and/or prefrontal cortex (PFC), its antidepressant-like effect is mediated, at least partially, via neuroplasticity related mechanisms. Literature search was performed using the general terms depression, stress, neuroplasticity and herbal medicines. Screening of retrieved preclinical studies revealed 30 traditional herbal medicines: 8 single herbs, 15 bioactive constituents, and 7 herbal formulas. The antidepressant-like effects of these medicines were associated with reversal of chronic stress-induced impairment in neuroplasticity, most notably by BDNF up-regulation, activation of BDNF downstream signaling pathways and increase in neurogenesis in the hippocampus and/or PFC/frontal cortex. In light of the ability of these medicines to enhance neuroplasticity, we suggest that they may be suitable candidates for clinical investigation in depressed individuals. Once their efficacy, tolerability and safety will be substantiated, they may serve as natural alternatives to conventional antidepressants. PMID- 28807620 TI - Muscarinic acetylcholine receptor but not nicotinic acetylcholine receptor plays a role in morphine-induced behavioral sensitization in rats. AB - : Background and Aim The cholinergic system can affect drug reward. The present study aimed to examine the roles of muscarinic acetylcholine receptor (mAChR) and nicotinic acetylcholine receptor (nAChR) in morphine-induced behavioral sensitization. METHODS: To analyze the roles of mAChR and nAChR in behavioral sensitization induced by morphine (5mg/kg), seven experiments were designed. Experiments 1 and 2 examined the effects of 3, 1, and 0.3 mg/kg scopolamine and 0.2, 0.1, and 0.05mg/kg scopolamine, respectively, on the locomotor activity when administered alone. Experiments 3 and 4 explored the effect of scopolamine on morphine-induced behavioral sensitization. Experiment 5 studied the effect of mecamylamine on morphine-induced behavioral sensitization. Experiments 6 and 7 investigated the effects of scopolamine+huperzine A and mecamylamine+huperzine A, respectively, on morphine-induced behavioral sensitization. RESULTS: The results revealed that 3mg/kg scopolamine, which significantly enhanced locomotor activity when administered alone, inhibited the acquisition of morphine-induced sensitization. However, mecamylamine (0.5, 1, 2mg/kg) did not have these effects. The co-administration of scopolamine (0.05 mg/kg)+huperzine A (0.4mg/kg) or mecamylamine (1mg/kg)+huperzine A (0.4mg/kg) did not affect the acquisition of morphine-induced behavioral sensitization. Scopolamine (0.05mg/kg) which did not affect the locomotor activity when administered alone, but not mecamylamine (1mg/kg), reversed the acute attenuation effect of huperzine A (0.4mg/kg) on morphine-induced locomotor activity at the acquisition stage and reversed the inhibition of huperzine A on the expression of morphine-induced sensitization. CONCLUSION: The mAChR might play a more important role in morphine-induced locomotor activity and the expression of morphine-induced behavioral sensitization. The mechanisms of mAChR and nAChR were relatively separate in morphine-induced sensitization. PMID- 28807621 TI - Antitoxin therapy of natural avian botulism outbreaks occurred in Brazil. AB - Botulism commonly affects water birds and it has recently been observed to be emerging in poultry production. In the present work, outbreaks of botulism in wild native species, such as the black-fronted Piping-guan (Aburria jacutinga), wild duck (Cairina moschata) and its crosses with mallard (Anas platyrhynchos), and domestic chickens (Gallus gallus domesticus) are described. Following treatments with a commercial botulism antitoxin CD, 28 (96.5%) out of 29 animals fully recovered after 24-72 h. The antitoxin therapy was shown to be a useful option for the treatment of affected birds, including those that were severely affected. PMID- 28807623 TI - Spatio-temporal variability of the epidemic 027 Clostridium difficile strains in France based on MLVA typing. AB - MLVA analysis of 103 PCR ribotype 027 strains showed a regional specificity and the persistence of the same clone within a hospital several years apart. Capillary electrophoresis PCR ribotyping led to the identification of seven 027 variant strains and five 176 strains, four of them being implicated in an outbreak. PMID- 28807622 TI - Community-associated Clostridium difficile infection in emergency department patients in Western Australia. AB - Clostridium difficile infection (CDI) is primarily associated with hospitalised patients, however, community-associated CDI (CA-CDI) has increased in Australia. We aimed to investigate the epidemiology and outcomes of CA-CDI cases presenting to hospital emergency departments in Western Australia (WA). A retrospective case control study of CA-CDI cases presenting at six emergency departments in WA from July 2013 to June 2014 was performed. Clinical signs, recent medication, hospitalisations and potential risk factors for CA-CDI were investigated for cases (n = 34) and unmatched controls (n = 62) who were infected with another gastrointestinal pathogen, including Campylobacter spp., Salmonella spp., Aeromonas spp., Shigella sonnei and Escherichia coli O157. Elevated white cell count (31.3% vs 8.2%, p < 0.01), female gender (67.6% vs 41.9%, p < 0.05), age >=65 years (41.2% vs 21.0%, p < 0.05) and antimicrobial use in the previous month (41.2% vs 11.3%, p < 0.01) were significantly more frequent among cases compared to controls. After multivariable analysis, antibiotic use (odds ratio 8.49, 95% confidence interval 2.75-26.21) and age >=65 years (3.03, 1.05-8.75) were significantly associated with CA-CDI. Ribotype (RT) 014/020 was most common (40.7%) among 27 C. difficile isolates followed by RTs 002 (14.8%), 001, 056 and 244 (all 7.4%). CA-CDI was associated with advanced age and recent antibiotic use compared to those infected with other gastrointestinal pathogens. RT 014 has also recently been found at high prevalence in public lawn spaces, and previously RT 014 strains from humans and pigs in Australia were closely genetically related, suggesting CA-CDI may be linked with these community reservoirs. PMID- 28807624 TI - A new chapter of JCMA: On the go. PMID- 28807625 TI - Role of urodynamics in management of urethral diverticulum in females. AB - BACKGROUND: Few studies have focused on the urodynamic findings of urethral diverticula (UD). We characterized the symptoms and urodynamic findings in women with UD. METHODS: A retrospective review of all women in a single center having surgical treatment for symptomatic UD between May 2004 and September 2014 was done. Lower urinary tract symptoms were evaluated with International Prostate Symptom Score and Overactive Bladder Symptom Score questionnaires. All patients underwent magnetic resonance imaging and videourodynamic study (VUDS) prior to surgery, and postoperative evaluation with VUDS. RESULTS: A total of 20 female patients were enrolled into the study. 12 (60%) UD patients presented with symptoms of stress urinary incontinence (SUI). However, there were merely 3 (15%) patients diagnosed as urodynamic SUI. 15 (75%) patients exhibited low catheter free uroflow. Detrusor overactivity was demonstrated in 4 (20%) patients. Bladder outlet obstruction (BOO) was diagnosed in 8 (40%) cases. Postoperative VUDS revealed persistent BOO in 50% of patients with preoperative BOO. Of these, residual diverticulum was noted by VUDS in one patient. CONCLUSION: For UD patients with urinary incontinence or voiding dysfunction, VUDS is helpful in accurately characterizing these symptoms. PMID- 28807626 TI - What will it take to end human suffering from measles? PMID- 28807627 TI - Measles immunity gaps and the progress towards elimination: a multi-country modelling analysis. AB - BACKGROUND: The persistent circulation of measles in both low-income and high income countries requires a better characterisation of present epidemiological trends and existing immunity gaps across different sociodemographic settings. Serological surveys, which provide direct measures of population protection against the infection, are underexploited and often supply fragmentary estimates of population immunity. This study aims to investigate how measles immunity has changed over time across different socioeconomic settings, as a result of demographic changes and past immunisation policies. METHODS: For this multi country modelling analysis, we developed a transmission model to simulate measles circulation during the past 65 years in nine countries with distinct demographic and vaccination histories. The model was calibrated on historical serological data and used to estimate the reduction of disease burden as a result of vaccination and present age-specific residual susceptibility. FINDINGS: Our model shows that estimated residual susceptibility to measles ranges from 3% in the UK to more than 10% in Kenya and Ethiopia. In high-income countries, such as Italy, Singapore, and South Korea, where routine first-dose administration produced more than 90% of immunised individuals, only about 20% of susceptible individuals are younger than 5 years. We also observed that the reduction in fertility that has occurred during the past decades in high-income countries has contributed to almost half of the reduction in measles incidence. In low-income countries, where fertility is high, the population is younger and routine vaccination has been suboptimum. Susceptible individuals are concentrated in early childhood, with about 60% of susceptible individuals in Ethiopia younger than 10 years. In these countries, Supplementary Immunization Activities (SIAs) were responsible for more than 25% of immunised individuals (up to 45% in Ethiopia), mitigating the consequences of suboptimum routine vaccination coverage. INTERPRETATION: Future vaccination strategies in high-fertility countries should focus on increasing childhood immunisation rates, either by raising first-dose coverage or by making erratic SIAs more frequent and regular. Immunisation campaigns targeting adolescents and adults are required in low-fertility countries, where the susceptibility in these age groups will otherwise sustain measles circulation. FUNDING: European Research Council. PMID- 28807628 TI - Vertebral alveolar echinococcosis-a case report, systematic analysis, and review of the literature. AB - Alveolar echinococcosis caused by Echinococcus multilocularis is an infrequent zoonosis with a high degree of disability, morbidity, and mortality, especially in disease clusters of the northern hemisphere. The diagnosis is complicated by extended incubation time, diverse clinical manifestations, and mimicking of differential diagnoses. The primary organ affected is the liver, but extrahepatic disease is possible, with vertebral involvement in only a few dozen cases described worldwide. Although vertebral alveolar echinococcosis seems to be rare, it might be under diagnosed, and it might be seen more often as the number of people with immunocompromised conditions increases. Recognition of this syndrome is crucial, because advances in medical and surgical management strategies since the introduction of benzimidazole in 1976 have controlled and relieved symptoms in most cases. In this Grand Round, we present the case of a 75-year-old woman who was referred for biopsy of a lumbar lesion 3 months after she was diagnosed with chronic myeloid leukaemia. The diagnosis of hepatic alveolar echinococcosis with metastasis to the lumbar spine and paravertebral region as well as the brain was confirmed by biopsy, PCR, and serology. The patient was given albendazole and referred for palliative surgery with the aim of pain control. Clinical features of the case are presented and discussed in the context of the literature. This case and review illustrate the complexity of extrahepatic alveolar echinococcosis manifestations and the necessity of an interdisciplinary approach. PMID- 28807629 TI - Genetic polymorphism of 17 autosomal STR loci in the Lahu ethnic minority from Yunnan Province, Southwest China. PMID- 28807630 TI - Haplotype data for 27 Y-chromosomal STR loci in the Chaoshan Han population, South China. PMID- 28807631 TI - Chitosan hydrochloride has no detrimental effect on bladder urothelial cancer cells. AB - Bladder cancer is among the most common and aggressive human malignant carcinomas, thus targeting and removal of bladder cancer cells is still a challenge. Although it is well known that chitosan hydrochloride (CH-HCl) causes desquamation of normal urothelial cells, its effect on cancer urothelial cells has not been recognized yet. In this in vitro study, we analyzed the cytotoxicity of 0.05% CH-HCl on three urothelial models: two cancer urothelial models, i.e. invasive and papillary urothelial neoplasms, and a normal urothelial model. The cytotoxicity of CH-HCl was evaluated with viability tests, transepithelial resistance (TER) measurements, and electron microscopy. TER measurements showed that 15-minute treatment with CH-HCl caused no reduction in TER of the cancer models, whereas the TER of the normal urothelial model significantly decreased. Furthermore, after CH-HCl treatment, the viability of cancer cells was reduced by only 5%, whereas the viability of normal cells was reduced by 30%. Ultrastructural analysis revealed necrotic cell death in all cases. We have demonstrated that although CH-HCl increases the mortality of cancer urothelial cells, it increases the mortality of normal urothelial cells even more so. However, shorter 2-minute CH-HCl treatment only temporarily increases the permeability of normal urothelial model, i.e. disrupts tight junctions and reduces TER without comprising cell viability, and enables the complete recovery of the permeability barrier after 24h. Overall, our results suggest that CH-HCl cannot be used as a self-sufficient anticancer agent for urothelial bladder cancer treatment; nevertheless a possibility of its use as an enhancer of cytostatic treatment is discussed. PMID- 28807633 TI - Evaluating the effectiveness of prophylactic central neck dissection with total thyroidectomy for cN0 papillary thyroid carcinoma: An updated meta-analysis. AB - BACKGROUND: The effectiveness of prophylactic central neck dissection (pCND) following total thyroidectomy (TT) in patients with clinical node-negative (cN0) papillary thyroid carcinoma (PTC) is still controversial. The aim of this meta analysis is to evaluate the outcome of pCND and to provide quantitative evidence. METHOD: A detailed literature search of PubMed, EMBASE, ClinicalTrails.gov and Cochrane Library electronic databases for articles published up to October 2016 was carried out. This meta-analysis was performed by the random method (Mantel Haenszel) model. Locoregional recurrence (LRR) and surgical complications were analyzed. RESULTS: Twenty-two studies comparing pCND + TT (combined) and TT alone in cN0 PTC patients were analyzed. A total of 6930 cases were enrolled, including 2381 cases in the combined group and 4009 cases in the TT-alone group. Compared with TT alone, patients in the combined group showed a significantly lower rate of overall LRR (OR = 0.66, 95% CI = 0.48-0.89) and central compartment recurrence (OR = 0.40, 95% CI = 0.22-0.73). There was no statistical difference in the rate of lateral compartment recurrence. However, the combined group showed a significantly higher rate of temporary and permanent hypoparathyroidism (OR = 2.28, 95% CI = 1.92-2.27/OR = 1.84, 95% CI = 1.15-2.95) and temporary recurrent laryngeal nerve injury (LNR) (OR = 1.53, 95% CI = 1.08-2.16). There was no statistical difference in the rate of permanent LNR, hematoma, hemorrhage or wound infection. CONCLUSIONS: This meta-analysis revealed that pCND with TT was a significantly efficient way to reduce the risk of LRR. However, pCND + TT increased the incidence rate of temporary and permanent hypoparathyroidism and temporary LNR. PMID- 28807634 TI - [Severity assessment strategies based on administrative data using stroke as an example]. AB - BACKGROUND AND OBJECTIVES: Information on disease severity is relevant for many studies with claims data in health service research, but only limited information is available in routine data. Stroke serves as an example to analyse whether the combination of different information in claims data can provide insight into the severity of a disease. METHOD: As a first step, a literature search was conducted. Strategies to assess the severity of a disease by means of routine data were examined with regard to approval and applicability to German sickness fund data. In order to apply and extend the identified procedures, the statutory health insurance sample AOK Hessen/KV Hessen (VSH) served as data source. It is an 18.75 % random sample of persons insured by the AOK Hessen, with 2013 being the most recent year. Stroke patients were identified by the ICD-10 GM code I63 and I64. Patients with said diagnoses being coded as a hospital discharge diagnosis in 2012 were included due to an acute event in 2012 (n=944). The follow up time was one year. RESULTS: Ten studies covering seven different methods to assess stroke severity were identified. Codes for coma (4.2 % of stroke patients in the SHI sample) as well as coma and/or the application of a PEG tube (9.8 % of the stroke patients) were applied as a proxy for disease severity of acute cases. Taking age, sex and comorbidity into consideration, patients in a coma show a significantly increased risk of mortality compared to those without coma. Three operationalisations were chosen as possible proxies for disease severity of stroke in the further course of disease: i) sequelae (hemiplegia, neurological neglect), ii) duration of the index inpatient stay, and iii) nursing care/ care level 3 for the first time after stroke. The latter proxy has the highest explanatory value for SHI costs. CONCLUSION: The studies identified use many variables mainly based on hospital information in order to describe disease severity. With the exception of coma, these proxies were neither validated nor did the authors provide more detailed grounds for their use. An identified score for stroke severity could not be applied to SHI data. To develop a comparable score requires a linkage of clinical and administrative data. Since routine data include information from all sectors of care, it should be explored whether these data (for example, the patients' care needs) are suitable to assess disease severity. For validation, separate databases and, optimally, primary patient data are necessary. PMID- 28807632 TI - Development of an in vitro co-culture model to mimic the human intestine in healthy and diseased state. AB - The intestine forms the largest interface between the environment and the human organism. Its integrity and functioning are crucial for the uptake of nutrients while preventing access of harmful antigens. Inflammatory conditions can significantly change the normal functioning of the intestine. In vitro models that adequately reproduce both healthy and inflamed intestinal tissue could provide a useful tool for studying the mechanisms of intestinal inflammation and investigating new therapeutic drugs. We established a co-culture of Caco-2 and PMA-differentiated THP-1 cells that mimics the intestine in healthy and controlled inflamed states. In homoeostatic conditions without stimulation, Caco 2 and THP-1 cells were co-cultured for 48h without affecting the barrier integrity and with no increase in the release of cytokines, nitric oxide or lactate dehydrogenase. To simulate the inflamed intestine, the Caco-2 barrier was primed with IFN-gamma and THP-1 cells were pre-stimulated with LPS and IFN-gamma. In these conditions a significant but temporary reduction in barrier integrity was measured, and large concentrations of pro-inflammatory cytokines and cytotoxicity markers detected. With its ability to feature numerous hallmarks of intestinal inflammation the presented co-culture model of epithelial cells and macrophages offers a unique possibility to study exposure effects in relation to the health status of the intestine. PMID- 28807637 TI - A Need for Empirical Evidence Concerning the Accuracy of Joint Parent-Child Reports of Children's Dietary Intake. PMID- 28807635 TI - Sustained Benefits of Ranibizumab with or without Laser in Branch Retinal Vein Occlusion: 24-Month Results of the BRIGHTER Study. AB - PURPOSE: To evaluate the long-term (24-month) efficacy and safety of ranibizumab 0.5 mg administered pro re nata (PRN) with or without laser using an individualized visual acuity (VA) stabilization criteria in patients with visual impairment due to macular edema secondary to branch retinal vein occlusion (BRVO). DESIGN: Phase IIIb, open-label, randomized, active-controlled, 3-arm, multicenter study. PARTICIPANTS: A total of 455 patients. METHODS: Patients were randomized (2:2:1) to ranibizumab 0.5 mg (n = 183), ranibizumab 0.5 mg with laser (n = 180), or laser (with optional ranibizumab 0.5 mg after month 6; n = 92). After initial 3 monthly injections, patients in the ranibizumab with or without laser arms received VA stabilization criteria-driven PRN treatment. Patients assigned to the laser arm received laser at the investigator's discretion. MAIN OUTCOME MEASURES: Mean (and mean average) change in best-corrected visual acuity (BCVA) and central subfield thickness (CSFT) from baseline to month 24, and safety over 24 months. RESULTS: A total of 380 patients (83.5%) completed the study. Ranibizumab with or without laser led to superior BCVA outcomes versus laser (monotherapy and combined with ranibizumab from month 6; 17.3/15.5 vs. 11.6 letters; P < 0.0001). Ranibizumab with laser was noninferior to ranibizumab monotherapy (mean average BCVA change: 15.4 vs. 15.0 letters; P < 0.0001). However, addition of laser did not reduce the number of ranibizumab injections (mean injections: 11.4 vs. 11.3; P = 0.4259). A greater reduction in CSFT was seen with ranibizumab with or without laser versus laser monotherapy over 24 months from baseline (ranibizumab monotherapy -224.7 MUm, ranibizumab with laser 248.9 MUm, laser [monotherapy and combined with ranibizumab from month 6] -197.5 MUm). Presence of macular ischemia did not affect BCVA outcome or treatment frequency. There were no reports of neovascular glaucoma or iris neovascularization. No new safety signals were identified. CONCLUSIONS: The BRIGHTER study results confirmed the long-term efficacy and safety profile of PRN dosing driven by individualized VA stabilization criteria using ranibizumab 0.5 mg in patients with BRVO. Addition of laser did not lead to better functional outcomes or lower treatment need. The safety results were consistent with the well-established safety profile of ranibizumab. PMID- 28807636 TI - Visual Outcomes and Complications of Type I Boston Keratoprosthesis in Children: A Retrospective Multicenter Study and Literature Review. AB - PURPOSE: To report outcomes and complications of Boston type 1 keratoprosthesis (KPro) implantation in children. DESIGN: Retrospective, multicenter case series. PARTICIPANTS: All children 16 years of age or younger who underwent KPro surgery at 3 ophthalmology centers in Canada between January 2010 and November 2014. METHODS: Records of patients having undergone KPro implantation were reviewed. Data on preoperative characteristics, surgical procedure(s) performed, and postoperative outcomes were collected and analyzed. MAIN OUTCOME MEASURES: Intraoperative and postoperative complications, device retention, and best corrected visual acuity (BCVA). RESULTS: The KPro was implanted in 11 eyes of 11 patients 0.9 to 15.5 years of age, with 6 being primary corneal procedures. Best corrected visual acuity recorded before surgery ranged from 20/600 to light perception (LP), and vision in 2 eyes was fix and follow. All patients had been diagnosed with glaucoma and 6 eyes had glaucoma drainage devices (GDDs) inserted before KPro implantation. At last follow-up (mean, 41.8 months; range, 6.5-85.0 months), 2 eyes retained BCVA of 20/400 or better, whereas 5 eyes lost LP. Postoperative complications included retroprosthetic membrane (9 eyes), corneal melt (5 eyes), infectious keratitis (3 eyes), endophthalmitis (3 eyes), GDD erosion (2 eyes), and retinal detachment (5 eyes). The initial KPro was retained in 4 eyes (36.4%). CONCLUSIONS: Boston type 1 keratoprosthesis implantation in children is associated with a substantially higher rate of complications, higher chance of device failure, and worse visual outcomes than observed in adults. In view of these results, the authors do not recommend the use of the KPro in the pediatric population. PMID- 28807638 TI - Food Waste in the National School Lunch Program 1978-2015: A Systematic Review. AB - BACKGROUND: Food waste studies have been used for more than 40 years to assess nutrient intake, dietary quality, menu performance, food acceptability, cost, and effectiveness of nutrition education in the National School Lunch Program (NSLP). OBJECTIVE: Describe methods used to measure food waste and respective results in the NSLP across time. METHODS: A systematic review using PubMed, Science Direct, Informaworld, and Institute of Scientific Information Web of Knowledge was conducted using the following search terms: waste, school lunch, plate waste, food waste, kitchen, half method, quarter method, weight, and photography. Studies published through June 2015 were included. The systematic review followed preferred reporting items for systematic reviews and meta-analyses recommendations. RESULTS: The final review included 53 articles. Food waste methodologies included in-person visual estimation (n=11), digital photography (n=11), direct weighing (n=23), and a combination of in-person visual estimation, digital photography, and/or direct weighing (n=8). A majority of studies used a pre-post intervention or cross-sectional design. Fruits and vegetables were the most researched dietary component on the lunch tray and yielded the greatest amount of waste across studies. CONCLUSIONS: Food waste is commonly assessed in the NSLP, but the methods are diverse and reporting metrics are variable. Future research should focus on establishing more uniform metrics to measure and report on food waste in the NSLP. Consistent food waste measurement methods will allow for better comparisons between studies. Such measures may facilitate better decision making about NSLP practices, programs, and policies that influence student consumption patterns across settings and interventions. PMID- 28807639 TI - A survey of caesarean section surgical site infections with PICOTM Single Use Negative Pressure Wound Therapy System in high-risk patients in England and Ireland. AB - This article reports audit data from the introduction of the PICOTM System for caesarean section patients with high body mass index (BMI) in four hospitals in the UK and Ireland. PICO was used on closed surgical incisions following caesarean section in 399 patients with BMI >=35kg/m2. Thirty-six out of 399 patients (9.0%) developed signs of surgical site infection (SSI), a rate lower than a previously reported incidence of 19.3% in a similar population. The readmission incidence was 0.8%. Therefore the use of PICO on closed surgical incisions may be associated with low incidence of SSI and readmission in this high-risk group. PMID- 28807640 TI - Rogue Nuns Grow Services to Combat Growing Problems. AB - This paper tells the story of how an experiment in caring for the children of poor, working mothers became a multimillion-dollar early learning center. It follows the evolution of two nuns who began providing day care in a church and came to realize that children living in poverty need a much greater range of services. It covers how the sisters broke with the Catholic Church and engaged alternative and unorthodox sources to help the operation survive and to extend its reach. It documents how far the sisters went to keep the doors open and how they sustained success. PMID- 28807641 TI - A Novel Partnership Disrupts the Norm in Early Childhood Education and Pediatric Health Care. AB - Children living in poverty in the United States in 2016 face a devastating combination of psychological problems. Their neighborhoods are often violent. They have no place to get healthy food. It is not safe to play outside, even on playgrounds. The children who grow up in this environment, not surprisingly, have many adverse childhood experiences (ACEs). ACEs cause toxic stress. Toxic stress leads to long-term physical and psychological problems. For many pediatricians, children's hospitals, civic leaders, and public health officials, it is difficult to know how to intervene. While the science on causation is indisputable, there are fewer data about treatment. We know that intervention should start early, but the types of interventions that are being proposed require extensive collaboration between social services, health care, and education. Such collaborations require a new sort of cooperation among professionals in disciplines that have not traditionally worked closely together. But they need to start. No one group will be able to solve this problem. This issue of Current Problems in Pediatric and Adolescent Health Care essentially provides a case study of one community's attempt to develop such a collaboration. PMID- 28807642 TI - Alterations of apoptosis and autophagy in developing brain of rats with epilepsy: Changes in LC3, P62, Beclin-1 and Bcl-2 levels. AB - Current studies have indicated that apoptotic and autophagic signaling pathways are triggered by epileptic seizures, but the precise roles of these processes in epilepsy-induced neuronal loss remain unclear. Identifying a concrete molecular mechanism may help researchers develop relevant epilepsy therapies that are more effective than existing treatments. Autophagy is a type of conserved degradation that contributes to cellular homeostasis. The involved signaling pathways allow us to observe alterations in autophagy and apoptosis during epileptic seizures over time. This study investigated the time-dependent changes in autophagy, apoptosis and neuronal morphology in developing brain of epilepsy model rats. At 48h after epileptic seizure onset, the number of neurons in neocortex decreased, and the number of apoptotic cells in neocortex increased. The ratio of microtubule-associated protein 1 light chain 3 (LC3) II to LC3 I and Beclin-1 protein levels increased from 12h to 48h after epileptic seizure onset. P62 protein and Bcl-2 protein levels decreased from 24h to 48h after epileptic seizure onset. The changes in the levels of these autophagy and apoptosis markers indicate that autophagy starts before apoptosis in rats with epilepsy, demonstrating a potential role of autophagy in epilepsy-induced neuronal loss in developing brain. PMID- 28807643 TI - [Use of subcutaneous route for comfort care in neonatal palliative population: Systematic review and survey of practices in France]. AB - INTRODUCTION: Subcutaneous hydration (hypodermoclysis) and drug administration is a widely used method of analgesic therapy in adult palliative care medicine. Very little is known about its use in neonatal medicine. Evidence-based guidelines do not exist due to a lack of data. In this study, the advantages of subcutaneous analgesic therapy in terms of comfort in neonatal palliative care situations were investigated. METHODS: This report details the results of a systematic review associated with a survey in neonatal intensive care units (NICUs) and pediatric palliative care departments (PPCTs) in France. RESULTS: No article was available in the Medline database. In Google(r), we found six guidelines that described the use of the subcutaneous route in the pediatric palliative population. The participation rate in the survey was approximately 83 % for French NICUs and 74 % for PPCTs. Eleven percent of NICUs and 27 % of PPCTs had already used subcutaneous drug administration for palliative care, mainly for analgesia and terminal sedation. Limiting factors of its use were mainly alternative options and the lack of data. Nevertheless, 76 % of NICUs and 73 % of PPCTs expressed an interest in the use of the subcutaneous route in NICUs. Ninety-one percent of French NICUs and 80 % of PPCTs were interested in elaborating a protocol using the subcutaneous route for analgesia, anxiolysis, or terminal sedation. CONCLUSION: The subcutaneous route can be advantageous for comfort care in the neonatal palliative population. Studies are needed to define the modalities, pharmacodynamics, and pharmacokinetics of therapeutics in this population. PMID- 28807644 TI - Predictors of Infectious Complications after Targeted Prophylaxis for Prostate Needle Biopsy. AB - PURPOSE: The incidence of infectious complications after transrectal ultrasound guided prostate needle biopsy is rising. We sought to identify the incidence and predictors of infection in a large cohort of men undergoing biopsy who receive targeted prophylaxis. MATERIALS AND METHODS: We retrospectively reviewed the records of 5,214 consecutive patients who underwent transrectal ultrasound guided prostate needle biopsy from January 2013 to December 2014 at UroPartners, a large urology group comprising 28 clinics in metropolitan Chicago. At 1 microbiology laboratory all swabs were processed, the presence of fluoroquinolone resistant gram-negative rods was identified and sensitivity tests were performed. Prophylaxis for biopsy was guided by rectal swab culture. Characteristics of patients with and without infectious complications were compared using the Kruskal-Wallis and chi-square tests. Multivariable logistic regression was done to determine predictors of infectious complications. Analyses were performed with R, version 2.14.2 (https://www.r-project.org/). RESULTS: Of the 5,214 biopsies performed 56 infectious (1.1%) and 24 sepsis complications (0.46%) were found. On univariable analysis nonCaucasian race and fluoroquinolone resistant microbes were predictors of infection (p <0.05). On multivariable analysis fluoroquinolone resistant rectal vault flora (OR 9.98, 95% CI 3.79-26.3) and the number of biopsy cores taken (OR 1.28 per core, 95% CI 1.04-1.54) were independent predictors of infection. CONCLUSIONS: Despite targeted prophylaxis patients with fluoroquinolone resistant rectal vault flora have higher odds of infectious complications following transrectal ultrasound guided prostate needle biopsy. In these patients one should consider using other biopsy approaches or techniques to minimize risk. PMID- 28807645 TI - A Behavioral Weight Loss Program and Nonurinary Incontinence Lower Urinary Tract Symptoms in Overweight and Obese Women with Urinary Incontinence: A Secondary Data Analysis of PRIDE. AB - PURPOSE: We sought to determine whether a behavioral weight reduction intervention would improve nonurinary incontinence lower urinary tract storage symptoms at 6 months, including urinary frequency, nocturia and urgency, compared to a structured education program serving as the control group among overweight and obese women with urinary incontinence. MATERIALS AND METHODS: PRIDE (Program to Reduce Incontinence by Diet and Exercise) was a randomized clinical trial performed in 338 overweight or obese women with urinary incontinence. Participants were randomized, including 226 to 6-month behavioral weight loss intervention and 112 to the control group. All participants received a self-help behavioral treatment booklet to improve bladder control. On this secondary data analysis we examined changes in nonurinary incontinence lower urinary tract storage symptoms from baseline to 6 months and the impact of treatment allocation (intervention vs control), weight loss and physical activity. RESULTS: Nonurinary incontinence lower urinary tract storage symptoms were common at baseline, varying from 48% to 62%. In the 2 groups combined women experienced significant improvement in nocturia, urgency and International Prostate Symptom Score at 6 months (all p <0.001). However, lower urinary tract storage symptom outcomes at 6 months did not differ between the intervention and control groups. Similarly no difference was observed in the amount of weight lost (5% or greater vs less than 5%) or physical activity (1,500 kcal or greater expenditure per week compared to less than 1,500 kcal). CONCLUSIONS: Lower urinary tract storage symptoms were common among overweight and obese women with urinary incontinence. The prevalence decreased significantly after 6 months independent of treatment group assignment, amount of weight lost or physical activity. These improvements may have been due to self-help behavioral educational materials, trial participation or repeat assessment of symptoms. PMID- 28807646 TI - Elevated Renal Pelvic Pressures during Percutaneous Nephrolithotomy Risk Higher Postoperative Pain and Longer Hospital Stay. AB - PURPOSE: Renal pelvic pressure may vary during percutaneous nephrolithotomy. We sought to determine the relationship of postoperative pain to endoscope caliber, renal pelvic pressure and hospital stay. MATERIALS AND METHODS: We reviewed the records of 20 percutaneous nephrolithotomies done under ureteroscopic guidance with renal pelvic pressure monitoring. The ureteroscope working channel was connected to a pressure transducer and used to determine renal pelvic pressure at baseline, when irrigating with a 26Fr rigid nephroscope and a 16Fr flexible nephroscope, and during suction. Patient demographics, operative characteristics, Likert pain scores and length of hospital stay were compared as stratified by average renal pelvic pressure. The Mann-Whitney U and Fisher exact tests were used with p <0.05 considered significant. RESULTS: A total of 220 measurements were recorded in 20 patients undergoing single access percutaneous nephrolithotomy. Mean patient age was 55.2 years (range 20 to 77) and mean body mass index was 32.4 kg/m2 (range 18 to 53.3). Rigid nephroscopy resulted in significantly higher average renal pelvic pressure than flexible nephroscopy (30.3 vs 12.9 mm Hg, p = 0.007). Average renal pelvic pressure was 30 mm Hg or greater in 7 patients (35%) undergoing rigid nephroscopy and in none (0%) undergoing flexible nephroscopy (p <0.01). Patients exposed to an average renal pelvic pressure of 30 mm Hg or greater during rigid nephroscopy had significantly higher average pain scores (p = 0.004) and longer hospital stays (p = 0.04) than patients with renal pelvic pressure less than 30 mm Hg. Average renal pelvic pressure 30 mm Hg or greater during rigid nephroscopy was also associated with a longer skin to calyx distance (105.5 vs 79.7 mm, p = 0.03). CONCLUSIONS: Knowledge of the factors that influence renal pelvic pressure and methods to control pressure extremes may improve patient outcomes during percutaneous nephrolithotomy. PMID- 28807647 TI - Endogenous visuospatial attention increases visual awareness independent of visual discrimination sensitivity. AB - Visuospatial attention often improves task performance by increasing signal gain at attended locations and decreasing noise at unattended locations. Attention is also believed to be the mechanism that allows information to enter awareness. In this experiment, we assessed whether orienting endogenous visuospatial attention with cues differentially affects visual discrimination sensitivity (an objective task performance) and visual awareness (the subjective feeling of perceiving) during the same discrimination task. Gabor patch targets were presented laterally, either at low contrast (contrast stimuli) or at high contrast embedded in noise (noise stimuli). Participants reported their orientation either in a 3 alternative choice task (clockwise, counterclockwise, unknown) that allowed for both objective and subjective reports, or in a 2-alternative choice task (clockwise, counterclockwise) that provided a control for objective reports. Signal detection theory models were fit to the experimental data: estimated perceptual sensitivity reflected objective performance; decision criteria, or subjective biases, were a proxy for visual awareness. Attention increased sensitivity (i.e., improved objective performance) for the contrast, but not for the noise stimuli. Indeed, with the latter, attention did not further enhance the already high target signal or reduce the already low uncertainty on its position. Interestingly, for both contrast and noise stimuli, attention resulted in more liberal criteria, i.e., awareness increased. The noise condition is thus an experimental configuration where people think they see the targets they attend to better, even if they do not. This could be explained by an internal representation of their attentional state, which influences awareness independent of objective visual signals. PMID- 28807648 TI - Not all visual symmetry is equal: Partially distinct neural bases for vertical and horizontal symmetry. AB - Visual mirror symmetry plays an important role in visual perception in both human and animal vision; its importance is reflected in the fact that it can be extracted automatically during early stages of visual processing. However, how this extraction is implemented at the cortical level remains an open question. Given the importance of symmetry in visual perception, one possibility is that there is a network which extracts all types of symmetry irrespective of axis of orientation; alternatively, symmetry along different axes might be encoded by different brain regions, implying that there is no single neural mechanism for symmetry processing. Here we used fMRI-guided transcranial magnetic stimulation (TMS) to compare the neural basis of the two main types of symmetry found in the natural world, vertical and horizontal symmetry. TMS was applied over either right Lateral Occipital Cortex (LO), right Occipital Face Area (OFA) or Vertex while participants were asked to detect symmetry in low-level dot configurations. Whereas detection of vertical symmetry was impaired by TMS over both LO and OFA, detection of horizontal symmetry was delayed by stimulation of LO only. Thus, different types of visual symmetry rely on partially distinct cortical networks. PMID- 28807649 TI - Effects of dietary Tenebrio molitor meal on the growth performance, immune response and disease resistance of yellow catfish (Pelteobagrus fulvidraco). AB - This study evaluated the influence of diets containing mealworm (Tenebrio molitor) meal in partial substitution of fishmeal on growth performance and immune responses of juvenile yellow catfish (Pelteobagrus fulvidraco). Four diets were formulated to contain 0 (the control diet), 9, 18 and 27 g mealworm meal per 100 g diet with 0%, 25%, 50% and 75% of fishmeal replacement, respectively. Yellow catfish were randomly divided into 4 groups with 3 replicates in each group. The fish in each group were fed with one of the four experimental diets for 5 weeks. Growth performance, plasma parameters (SOD, MDA, IgM, C3, lysozyme) and immune related genes (MHC II, IL-1, CypA, IgM, HE) of yellow catfish were determined at the end of the feeding trial, as well as 24 h post bacterial (Edwardsiella ictaluri) challenge. The present results showed that dietary inclusion of mealworm meal (MW) had no negative effects on the growth performance of the juvenile yellow catfish, compared to the control group. At the end of the feeding trial, plasma MDA contents of MW supplemented groups were significant lower than the control group. Plasma SOD activities increased significantly with the increasing dietary MW contents at the end of feeding trial (pre-challenge) and 24 h post challenge with E. ictaluri. Significant increase of plasma lysozyme activity was found in MW supplemented groups compared to the control group 24 h post bacterial challenge. Plasma IgM levels increased significantly with the increasing dietary MW contents at the end of feeding trial. Compared with the control group, the immune related genes of MHC II, IL-1, IgM and HE of the fish in the MW supplemented groups significantly upregulated pre-challenge or 24 h post bacterial challenge. Finally, it was observed that the survival rate of the 27% MW group was significant higher (P < 0.05) than the control group but was not significantly differed from the 18% MW group. The present results indicated that dietary inclusion level of at least 18% MW could improve the immune response and the bacterial resistance of yellow catfish without any negative growth effects. PMID- 28807650 TI - Current state of biosimilars in Mexico: The position of the Mexican College of Rheumatology, 2016. AB - The present document is a position statement of the Mexican College of Rheumatology on the use of biosimilars in rheumatic diseases. This position considers that biosimilars should be considered as interchangeable, that automatic substitution without previous notice in stable patients during follow up is not ethical, that the approval of a biosimilar should only be given after exhaustive review of preclinical and clinical data marked by Mexican regulations, that it should be clearly stated in the nomenclature of biologic drugs which is the innovator and which is the biosimilar, that it is not correct to choose a biosimilar as treatment based only on economic reasons or extrapolate indications based only on the approval of the innovator and in the absence of safety and efficacy data for the biosimilar. PMID- 28807651 TI - Recommendations for the prescription of physical exercise for patients with spondyloarthritis. AB - OBJECTIVE: To develop expert-based recommendations on physical activity and exercise for patients with spondyloarthritis (SpA). METHODS: Two discussion groups, one of physical therapists, rehabilitation physicians, and professionals of physical activity and sports, and another of rheumatologists interested in SpA, were held to discuss the results of a survey of rheumatologists on exercise and two focus groups with patients on barriers to exercise. Preliminary recommendations were drafted. These were submitted to the opinion of the experts in both groups according to a two round Delphi methodology. RESULTS: Twenty one recommendations covering general aspects of exercise, adaptation to patient, how to deliver messages, pain management, and type of exercise and monitoring were issued. The level of agreement varied slightly between expert groups but it was high overall. Items with poor agreement were removed from the consensus. CONCLUSIONS: We present recommendations on when and how to prescribe and monitor exercise in patients with SpA based on the opinion of experts in exercise and in SpA. We must now test whether these recommendations are useful for clinical practice and have an effect on patients with SpA seen by rheumatologists. PMID- 28807652 TI - Severity indices in rheumatoid arthritis: A systematic review. AB - OBJECTIVE: To identify tools designed to evaluate the severity of patients with rheumatoid arthritis (RA) in order to use them in the investigation of prognostic markers in early arthritis. METHODS: We conducted a systematic review of studies that developed/validated an index for RA disease severity. They were analyzed using the COSMIN checklist to assess their methodological quality. In addition, all the variables included were evaluated for their clarity of definition, feasibility and probability of being present in each outcome during the first 2 years of the disease course. To estimate redundancy, variables were grouped by domains. RESULTS: After reviewing 3,519 articles, 3 studies were included. The first study, the PAS, assessed whether current and lifetime treatment with disease-modifying antirheumatic drugs and/or biologics accurately predicted RA severity, as measured by the patient-reported PAS. Treatment variables did not fully distinguish patients in the highest and lowest quartiles of PAS scores. Another severity index, the Claims-Based Index for RA Severity (CIRAS), included the variables age, sex, Felty's syndrome, number of rehabilitation and rheumatology visits, test for inflammatory markers, number of chemistry panels/platelet counts ordered and rheumatoid factor test. The correlation was low (r=0.56) with an index previously validated by the same research group, the RA medical records-based index of severity (RARBIS), with Disease Activity Score C-reactive protein (DAS28-PCR) (r=0.07) and Multidimensional Health Assessment Questionnaire (MD-HAQ) (r=0.008). Finally, the RARBIS, used to validate the CIRAS, was devised as an RA severity index based on medical records. It includes as domains surgery, radiology, extra-articular manifestations, clinical and laboratory variables, previously chosen by an expert panel. RARBIS had a weak correlation with treatment intensity (r=0.35) and with DAS28 (r=0.41). CONCLUSION: There is no index to assess the severity of RA based on the course of the first 2 years of follow-up that is adapted to the current strategy of therapeutic management of this disease. Therefore, we believe it is reasonable to develop a new ad hoc severity index for patients with early arthritis. PMID- 28807653 TI - Editorial Comment. PMID- 28807654 TI - Editorial Comment. PMID- 28807655 TI - First Clinical Consensus and National Recommendations on Tracheostomized Children of the Brazilian Academy of Pediatric Otorhinolaryngology (ABOPe) and Brazilian Society of Pediatrics (SBP). AB - INTRODUCTION: Tracheostomy is a procedure that can be performed in any age group, including children under 1year of age. Unfortunately health professionals in Brazil have great difficulty dealing with this condition due to the lack of standard care orientation. OBJECTIVE: This clinical consensus by Academia Brasileira de Otorrinolaringologia Pediatrica (ABOPe) and Sociedade Brasileira de Pediatria (SBP) aims to generate national recommendations on the care concerning tracheostomized children. METHODS: A group of experts experienced in pediatric tracheostomy (otorhinolaryngologists, intensive care pediatricians, endoscopists, and pediatric pulmonologists) were selected, taking into account the different regions of Brazil and following inclusion and exclusion criteria. RESULTS: The results generated from this document were based on the agreement of the majority of participants regarding the indications, type of cannula, surgical techniques, care, and general guidelines and decannulation. CONCLUSION: These guidelines can be used as directives for a wide range of health professionals across the country that deal with tracheostomized children. PMID- 28807656 TI - Opportunities for model-based precision dosing in the treatment of sickle cell anemia. AB - Hydroxyurea is the primary pharmacotherapy to prevent complications of sickle cell anemia (SCA). Accumulated clinical experience across multiple age ranges has suggested that the use of an individualized maximum tolerated dose (MTD) will achieve optimal benefit of hydroxyurea treatment. However, the current empirical and trial-and-error approach for dose escalation often results in a lengthy titration process and is not strictly implemented in many clinics. Opportunities exist for pharmacokinetics model-based precision dosing of hydroxyurea to quickly achieve individual MTD. This review intends to introduce the use of a quantitative modeling approach including a Bayesian adaptive control strategy for the precision dosing of hydroxyurea. The rationale and practical considerations for the implementation of this approach are discussed. Future research directions with a focus on integrating specific safety and other clinical outcome endpoints into dose selection decision making are also discussed. PMID- 28807657 TI - Prediabetes, diabetes and unemployment. PMID- 28807658 TI - Self-reported participation in voluntary nonprescription syringe sales in California's Central Valley. AB - OBJECTIVES: California Senate Bill 41 (SB41), effective January 2012, is a human immunodeficiency virus/hepatitis C virus prevention measure designed to expand syringe access among injection drug users (IDUs) by allowing pharmacies to sell syringes without a prescription. This study assesses self-reported implementation of SB41 and characterizes barriers amenable to intervention. DESIGN: Interviewer administered survey. SETTING AND PARTICIPANTS: Fresno and Kern Counties, CA. Pharmacists and other pharmacy staff (n = 404) at 212 pharmacies. OUTCOME MEASURE: Self-reported nonprescription pharmacy sales to known or suspected IDUs. RESULTS: Overall, 29.3% of participants said their pharmacy would sell nonprescription syringes to a known or suspected IDU, whereas a far higher proportion (79.3%) would sell nonprescription syringes to a person with diabetes. More than one-half said that their pharmacy requires nonprescription syringe purchasers to enter their signature and name and address in a log book although that is not required under SB41. Fewer than 2 out of 3 participants (61.1%) knew that it is legal to sell nonprescription syringes to IDUs. That knowledge, as well as having syringe sales practices based on both store policy and discretion, were positively associated with IDU syringe sales after controlling for other factors. Working at an independent pharmacy, agreeing that only people with "medical conditions" such as diabetes should be able to buy syringes, and viewing syringe sales to IDUs as "not good business" were independently but negatively associated with IDU syringe sales. CONCLUSION: This study complements an earlier syringe purchase trial documenting low participation in voluntary nonprescription syringe sales under SB41 in Fresno and Kern Counties. In the absence of legislation requiring mandatory syringe sales, interventions should be developed to increase knowledge of the law and frame addiction as a medical condition, with a special focus on independent pharmacies. Informational interventions should stress the need to eliminate log book documentation requirements, which may serve as a barrier to IDU purchase. PMID- 28807659 TI - Expanding state laws and a growing role for pharmacists in vaccination services. AB - OBJECTIVES: Gaps in vaccination coverage leave populations vulnerable to illnesses. Since the 1990s, there has been a growing movement to improve vaccination access by giving pharmacists the authority to administer vaccines according to state laws. Understanding the variation of pharmacist vaccination laws over time is critical to understanding the effect of improving access to vaccination services. METHODS: We identified relevant statutes and regulations with the use of Westlaw legal databases. A 4-stage coding process identified 220 legal variables of pharmacist vaccination authority. Each jurisdiction's laws were coded against these 220 legal variables. The resulting legal dataset was then evaluated to determine whether jurisdictions expanded or restricted pharmacist vaccination authorities over time. RESULTS: From 1971 to 2016, jurisdictions made 627 changes to statutes and regulations relating to pharmacist vaccination authority. There were 85 expansions, 3 restrictions, and 22 regulatory clarifications. Eight changes were deemed to be unclear, and 479 changes did not substantively alter the scope of pharmacist vaccination authority. CONCLUSION: Collectively, the laws in 50 states and DC paint a clear picture: the scope of pharmacists' vaccination authority is expanding. Jurisdictions are allowing pharmacists to administer more vaccines to younger patients with less direct prescriber oversight. This clear expansion of pharmacist vaccination authority stands in contrast to the reservations expressed by some physician groups for pharmacists as vaccination providers. However, laws in some states still do not permit pharmacists to vaccinate according to the Advisory Committee on Immunization Practices recommendations. PMID- 28807660 TI - The changing cost to prevent diabetes: A retrospective analysis of the Diabetes Prevention Program. AB - OBJECTIVES: Diabetes prevention interventions are poorly implemented. While health care costs generally increase, 2 factors affect the relative cost of diabetes prevention interventions: the declining cost of metformin (even without insurance) and the new recommendation for vitamin B12 monitoring during metformin treatment. The study's objective was to update the relative health system cost estimate of metformin for diabetes prevention by incorporating the current health system cost of metformin and the cost of addressing potential metformin associated vitamin B12 deficiency. The study was designed to assess whether metformin with vitamin B12 supplementation is a cost-saving measure for diabetes prevention and for the updated cost estimate to be useful in assessing future implementation studies. METHODS: In 2012, the Diabetes Prevention Program Research Group published detailed per capita total direct health system costs for the Diabetes Prevention Program (DPP) and the Diabetes Prevention Program Outcomes Study (DPPOS). The present analysis incorporated the declining cost of metformin and the increasing cost of metformin monitoring into the detailed per capita health system costs found in the DPP and DPPOS. The updated costs were used to assess the total cost of metformin use for diabetes prevention relative to placebo and lifestyle intervention. RESULTS: The current health system cost to acquire metformin ranges from $0 to $72 per year. The estimated health system cost to address potential metformin-associated vitamin B12 deficiency is $28 per metformin-treated patient per year. The 10-year total health system cost for metformin in diabetes prevention can decrease by $329 or increase by $21 depending on the cost to acquire metformin. Compared with placebo, the unadjusted cost savings of metformin is generally maintained, although it may double or quadruple depending on how metformin is acquired by patients. Metformin with vitamin B12 supplementation remained less costly and less effective than lifestyle intervention. CONCLUSION: Metformin is generally more cost-saving for diabetes prevention than previously reported because of decreasing costs for patients to acquire metformin. The cost savings was increased despite increased management cost associated with addressing metformin-associated vitamin B12 deficiency. PMID- 28807661 TI - State programs assisting pharmacy professionals with substance use disorders. AB - OBJECTIVES: To identify which states currently have substance use disorder (SUD) programs to facilitate the return of pharmacy professionals (including technicians, interns, and student pharmacists) to active practice, to identify the operational structures used by the states in providing these services and compare them with those reported previously, and to compile the most current and accurate contact information for each state SUD program. METHODS: Information specific to each state program was identified from Internet resources including state pharmacy associations, licensing boards, and professional associations. Each state's site was evaluated for currency within 2016-2017. Direct contact by e-mail or telephone using the program information, or association, or licensing board contacts was pursued to identify the current program status. RESULTS: Five states with no program in 1990 have since developed programs, and 2 states with programs in 1990 have closed their programs. Overall, 4 states do not currently have a program, 2 of which have never had one. One of the 2 states has recent authorization from their legislature to develop a program. Three other programs are currently in transition from 1 model to another, resulting in website inaccuracies. The operational models have undergone significant shifts with a decrease in the association (+/- [with or without] Foundation) model toward a group health care association or organization model including other health- or all state-licensed professionals. CONCLUSION: Currently, 46 states have programs for assisting pharmacy professionals. Information presented in this article provides the most current contact information and model structure used by states with programs. Frequent updating of program information is critical for those who might decide to seek assistance. Expansion to include a central database that enables rigorous evaluation of outcomes and specific features is viewed as desirable. PMID- 28807662 TI - A preliminary study of osmotic dehydration in zebrafish embryos: Implications for vitrification and ultra-fast laser warming. AB - To date, traditional cryopreservation techniques have not been amenable to zebrafish (Danio rerio) embryos, due in part to their large yolky eggs, which have a low surface to volume ratio and limited permeability to water and cryoprotectants. However, recent vitrification and ultra-rapid warming studies in mice have demonstrated successful preservation by dehydrating 85% or more of their total water content. We hypothesized that this approach may help overcome the barriers to embryo cryopreservation among D. rerio. The purpose of this study was to determine the osmotic tolerance limit of D. rerio embryos under conditions relevant to cryopreservation. We found that embryos undergoing gastrulation (30% 70% epiboly) were particularly sensitive to osmotic dehydration/rehydration. By contrast, a subset of embryos dehydrated during or after segmentation (20-22 somite, prim 5) survived 3 h in a 2 M sucrose solution but exhibit developmental delay, edema and trunk necrosis 2-4 days post-treatment. PMID- 28807663 TI - Incidence and predictors of late atrioventricular conduction recovery among patients requiring permanent pacemaker for complete heart block after cardiac surgery. AB - BACKGROUND: New-onset complete heart block (CHB) commonly complicates cardiac surgery, for which some patients require a permanent pacemaker (PPM). Little is known regarding late atrioventricular (AV) conduction recovery. OBJECTIVE: The purpose of this study was to characterize the incidence and predictors of late AV conduction recovery among patients requiring PPM after cardiac surgery. METHODS: Consecutive patients receiving PPM for CHB after cardiac surgery at a high-volume U.S. center from 2000 to 2014 were evaluated. The primary outcome was late AV conduction recovery, defined as a reduction in ventricular pacing requirement to <10% beyond 1 month postimplant. Regression analysis was performed to evaluate predictors of AV recovery. RESULTS: Among 301 patients evaluated over 4 +/- 4 years of follow-up, the incidence of late AV conduction recovery was 12% (n = 37), for whom the median ventricular pacing requirement decreased from 96% at implant to <1% at 6 months and persisted throughout study follow-up. AV recovery was less common when preoperative conduction abnormalities were present, including no recovery among patients with preoperative PR >200 ms and QRS >120 ms (n = 42). Multivariable analysis identified only female sex and transient AV conduction postoperatively as independent predictors of recovery (odds ratio 3.5; P <.01 for each). Neither cardiac surgery subtype nor PPM implant timing postoperatively was significantly associated with recovery. CONCLUSION: Late AV conduction recovery is not uncommon after cardiac surgery, occurring in 1 of 8 patients within 6 months postoperatively. Preoperative AV conduction abnormalities were associated with decreased recovery, whereas female sex and transient postoperative AV conduction were associated with increased recovery. PMID- 28807665 TI - A comparative study of care practices for young boys with Duchenne muscular dystrophy between Japan and European countries: Implications of early diagnosis. AB - Early diagnosis of Duchenne muscular dystrophy (DMD) is widely advocated to initiate proactive interventions and genetic counselling. Genetic testing now allows the diagnosis of DMD even prior to the onset of symptoms. However, little is known about care practices and their impact on young DMD boys and families after receiving an early diagnosis. We analysed 64 young boys (Japan, 19; the United Kingdom, 10; Germany, 18; Hungary, 6; Poland, 5; and the Czech Republic, 6) aged <5 years and diagnosed at <=2 years old among the participants of the cross-sectional study about care practice in DMD. A combination of elevated serum creatine kinase and genetic testing usually led to the diagnosis (n = 31, 48%); 41 boys visited neuromuscular clinics more than once a year. Early diagnosis did not generally result in higher satisfaction among DMD families, and country specific differences were observed. Psychosocial support following early diagnosis was perceived as insufficient in most countries, and deficits in access and uptake of genetic counselling resulted in lower satisfaction in the Japanese cohort. In conclusion, seamless and comprehensive support for DMD families following early diagnosis at presymptomatic stages should be taken into consideration if early genetic testing or newborn screening is made available more widely. PMID- 28807664 TI - Social interaction modulates the neuroinflammatory response to global cerebral ischemia in male mice. AB - Social isolation is a risk factor for cardiovascular and cerebrovascular diseases, although the underlying mechanisms remain underspecified. Considering the potential of microglia to become sensitized by stressors and their role in neuroinflammation, we hypothesized that social isolation primes microglia, resulting in an exaggerated neuroimmune response to experimental cerebral ischemia. First, major histocompatibility complex II (MHC II) gene expression, an indicator of microglial priming, was compared between mice that were socially isolated or pair-housed. MHC II increased in the hippocampus and cortex of socially isolated mice, which is suggestive of isolation-induced microglial priming. In experiment 2, isolated and pair-housed mice underwent ~8min of global cerebral ischemia. Hippocampal mRNA expression of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) was significantly increased among both isolated and pair-housed ischemia groups relative to sham controls. Hippocampal expression of interleukin 1 beta (IL-1beta) and cortical TNF-alpha, IL-1beta and IL-6, were significantly increased 24-h post ischemia in isolated mice, but not pair-housed mice, relative to controls. Ischemia-induced increases in microglial cell body area and percent area fraction of ionized calcium binding adaptor molecule 1 (Iba-1) positive staining were also observed in isolated, but not pair housed mice, relative to controls. For experiment 3, brain sections from socially isolated and pair-housed mice underwent 15min of oxygen glucose deprivation (OGD), an ex vivo model of cerebral ischemia. IL-6 gene expression was significantly elevated following OGD only in hippocampi from mice that had been socially isolated, indicating that isolation prior to ischemia is sufficient to modulate the neuroinflammatory response. Together, these data suggest microglial priming as a possible mechanism underlying the detrimental effects of social isolation on cerebral ischemia outcome. PMID- 28807666 TI - MicroRNA-132 with Therapeutic Potential in Chronic Wounds. AB - Chronic wounds represent a major and rising health and economic burden worldwide. There is a continued search toward more effective wound therapy. We found significantly reduced microRNA-132 (miR-132) expression in human diabetic ulcers compared with normal skin wounds and also in skin wounds of leptin receptor deficient (db/db) diabetic mice compared with wild-type mice. Local replenishment of miR-132 in the wounds of db/db mice accelerated wound closure effectively, which was accompanied by increased proliferation of wound edge keratinocytes and reduced inflammation. The pro-healing effect of miR-132 was further supported by global transcriptome analysis, which showed that several inflammation-related signaling pathways (e.g., NF-kappaB, NOD-like receptor, toll-like receptor, and tumor necrosis factor signaling pathways) were the top ones regulated by miR-132 in vivo. Moreover, we topically applied liposome-formulated miR-132 mimics mixed with pluronic F-127 gel on human ex vivo skin wounds, which promoted re epithelialization. Together, our study showed the therapeutic potential of miR 132 in chronic wounds, which warrants further evaluation in controlled clinical trials. PMID- 28807667 TI - Inhibition of beta-Catenin Signaling in the Skin Rescues Cutaneous Adipogenesis in Systemic Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial of C 82. AB - Several studies have suggested that Wnts might contribute to skin fibrosis in systemic sclerosis (SSc) by affecting the differentiation of pluripotent dermal cells. We tested C-82, a therapeutic that inhibits canonical Wnt signaling by blocking the interaction of the protein CBP with beta-Catenin and inhibiting Wnt activated genes. We used a trial design formulating C-82 for topical application and conducting a placebo-controlled, double-blinded clinical trial in which patients with diffuse cutaneous SSc were treated with C-82 or placebo on opposite forearms. C-82- compared with placebo-treated forearms did not show any clinical effect. Skin biopsies performed before and after treatment showed a very weak trend toward improvement in the C-82-treated skin of biomarkers of local skin disease, THBS1 and COMP. However, on microarray analysis C-82 treatment strongly up-regulated two clusters of genes that correlate negatively with the severity of SSc skin disease. These clusters are highly associated with metabolism and one gene, PLIN2, expressed only by sebocytes and subcutaneous fat cells. These changes in gene expression strongly support a role for Wnts in differentiation of pluripotent cells into profibrotic fibroblasts and the potential for C-82 with longer treatment to promote fat regeneration in SSc skin. PMID- 28807668 TI - Evidence that blood flukes (Trematoda: Aporocotylidae) of chondrichthyans infect bivalves as intermediate hosts: indications of an ancient diversification of the Schistosomatoidea. AB - Blood flukes (Aporocotylidae) of actinopterygians (bony fishes) have been shown to infect freshwater gastropods and marine polychaetes as intermediate hosts. However, no life cycle is known for any aporocotylid of chondrichthyans (cartilaginous fishes) and no adult aporocotylid has been linked to a cercaria infecting a bivalve. Here we report two novel infections that fill these gaps. Cercariae consistent with the family Aporocotylidae were found developing in sporocysts in the gonad of the surf pipi, Donax deltoides Lamarck, 1818 (Bivalvia: Donacidae), from Stockton Beach, central New South Wales, Australia. Adult aporocotylids were found in the heart of the giant shovelnose ray, Glaucostegus typus (Anonymous [Bennett], 1830), from Moreton Bay, southeastern Queensland, Australia. Phylogenetic analyses of the 28S rDNA region generated from the new specimens resulted in phylograms in which the two parasites form a strongly supported clade with Chimaerohemecus trondheimensis van der Land, 1967, the only aporocotylid known from a holocephalan and the only other chondrichthyan infecting aporocotylid for which sequence data are available. Most marine aporocotylids of actinopterygians also form a strongly supported clade. These findings lead us to hypothesise that the aporocotylids of chondrichthyans are distinct from all other blood flukes in infecting bivalves as intermediate hosts. Putative cophyly between three major blood fluke clades and both definitive and intermediate host groups is consistent with diversification of the Schistosomatoidea over 400million years ago. PMID- 28807669 TI - T cells and Parkinson's disease. PMID- 28807670 TI - What is the evidence for a link between digit ratio (2D:4D) and direct measures of prenatal sex hormones? PMID- 28807671 TI - Selective inhibition of extra-synaptic alpha5-GABAA receptors by S44819, a new therapeutic agent. AB - In the mammalian central nervous system (CNS) GABAA receptors (GABAARs) mediate neuronal inhibition and are important therapeutic targets. GABAARs are composed of 5 subunits, drawn from 19 proteins, underpinning expression of 20-30 GABAAR subtypes. In the CNS these isoforms are heterogeneously expressed and exhibit distinct physiological and pharmacological properties. We report the discovery of S44819, a novel tricyclic oxazolo-2,3-benzodiazepine-derivative, that selectively inhibits alpha5-subunit-containing GABAARs (alpha5-GABAARs). Current alpha5 GABAAR inhibitors bind to the "benzodiazepine site". However, in HEK293 cells expressing recombinant alpha5-GABAARs, S44819 had no effect on 3H-flumazenil binding, but displaced the GABAAR agonist 3H-muscimol and competitively inhibited the GABA-induced responses. Importantly, we reveal that the alpha5-subunit selectivity is uniquely governed by amino acid residues within the alpha-subunit F-loop, a region associated with GABA binding. In mouse hippocampal CA1 neurons, S44819 enhanced long-term potentiation (LTP), blocked a tonic current mediated by extrasynaptic alpha5-GABAARs, but had no effect on synaptic GABAARs. In mouse thalamic neurons, S44819 had no effect on the tonic current mediated by delta GABAARs, or on synaptic (alpha1beta2gamma2) GABAARs. In rats, S44819 enhanced object recognition memory and reversed scopolamine-induced impairment of working memory in the eight-arm radial maze. In conclusion, S44819 is a first in class compound that uniquely acts as a potent, competitive, selective antagonist of recombinant and native alpha5-GABAARs. Consequently, S44819 enhances hippocampal synaptic plasticity and exhibits pro-cognitive efficacy. Given this profile, S44819 may improve cognitive function in neurodegenerative disorders and facilitate post-stroke recovery. PMID- 28807672 TI - Pharmacological characterization of novel synthetic opioids (NSO) found in the recreational drug marketplace. AB - Novel synthetic opioids (NSO) are increasingly encountered in illicit heroin and counterfeit pain pills. Many NSO are resurrected from older biomedical literature or patent applications, so limited information is available about their biological effects. Here we examined the pharmacology of three structurally distinct NSO found in the recreational drug market: N-(1-(2-phenylethyl)-4 piperidinyl)-N-phenylbutyramide (butyrylfentanyl), 3,4-dichloro-N-[(1R,2R)-2 (dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) and 1-cyclohexyl-4-(1,2 diphenylethyl)piperazine (MT-45). Radioligand binding and GTPgammaS functional assays were carried out in cells transfected with murine mu- (MOR-1), delta- (DOR 1) or kappa-opioid receptors (KOR-1). Antinociceptive effects were determined using the radiant heat tail flick technique in mice, and opioid specificity was assessed with the mu-opioid antagonist naloxone. Butyrylfentanyl, U-47700 and MT 45 displayed nM affinities at MOR-1, but were less potent than morphine, and had much weaker effects at DOR-1 and KOR-1. All NSO exhibited agonist actions at MOR 1 in the GTPgammaS assay. Butyrylfentanyl and U-47700 were 31- and 12-fold more potent than morphine in the tail flick assay, whereas MT-45 was equipotent with morphine. Analgesic effects were reversed by naloxone and absent in genetically engineered mice lacking MOR-1. Our findings confirm that butyrylfentanyl, U-47700 and MT-45 are selective MOR-1 agonists with in vitro affinities less than morphine. However, analgesic potencies vary more than 30-fold across the compounds, and in vitro binding affinity does not predict in vivo potency. Taken together, our findings highlight the risks to humans who may unknowingly be exposed to these and other NSO when taking adulterated heroin or counterfeit pain medications. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.' PMID- 28807673 TI - GPR55: A therapeutic target for Parkinson's disease? AB - The GPR55 receptor is expressed abundantly in the brain, especially in the striatum, suggesting it might fulfill a role in motor function. Indeed, motor behavior is impaired in mice lacking GPR55, which also display dampened inflammatory responses. Abnormal-cannabidiol (Abn-CBD), a synthetic cannabidiol (CBD) isomer, is a GPR55 agonist that may serve as a therapeutic agent in the treatment of inflammatory diseases. In this study, we explored whether modulating GPR55 could also represent a therapeutic approach for the treatment of Parkinson's disease (PD). The distribution of GPR55 mRNA was first analyzed by in situ hybridization, localizing GPR55 transcripts to neurons in brain nuclei related to movement control, striatum, globus pallidus, subthalamic nucleus, substantia nigra and cortex. Striatal expression of GPR55 was downregulated in parkinsonian conditions. When Abn-CBD and CBD (5 mg/kg) were chronically administered to mice treated over 5 weeks with 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine and probenecid (MPTPp), Abn-CBD but not CBD prevented MPTPp induced motor impairment. Although Abn-CBD protected dopaminergic cell bodies, it failed to prevent degeneration of the terminals or preserve dopamine levels in the striatum. Both compounds induced morphological changes in microglia that were compatible with an anti-inflammatory phenotype that did not correlate with a neuroprotective activity. The symptomatic relief of Abn-CBD was further studied in the haloperidol-induced catalepsy mouse model. Abn-CBD had an anti-cataleptic effect that was reversed by CBD and PSB1216, a newly synthesized GPR55 antagonist, and indeed, two other GPR55 agonists also displayed anti-cataleptic effects (CID1792197 and CID2440433). These results demonstrate for the first time that activation of GPR55 might be beneficial in combating PD. PMID- 28807674 TI - Phenylglycine analogs are inhibitors of the neutral amino acid transporters ASCT1 and ASCT2 and enhance NMDA receptor-mediated LTP in rat visual cortex slices. AB - The N-methyl-d-aspartate receptor (NMDA) co-agonist d-serine is a substrate for the neutral amino acid transporters ASCT1 (SLC1A4) and ASCT2 (SLC1A5). We identified l-phenylglycine (PG) and its analogs as inhibitors of ASCT1 and ASCT2. PG analogs were shown to be non-substrate inhibitors of ASCT1 and ASCT2 with a range of activities relative to other amino acid transport systems, including sodium-dependent glutamate transporters, the sodium-independent d-serine transporter asc-1 and system L. L-4-chloroPG was the most potent and selective ASCT1/2 inhibitor identified. The PG analogs facilitated theta-burst induced long term potentiation in rat visual cortex slices in a manner that was dependent on extracellular d-serine. For structurally-related PG analogs, there was an excellent correlation between ASCT1/2 transport inhibition and enhancement of LTP which was not the case for inhibition of asc-1 or system L. The ability of PG analogs to enhance LTP is likely due to inhibition of d-serine transport by ASCT1/2, leading to elevated extracellular levels of d-serine and increased NMDA receptor activity. These results suggest that ASCT1/2 may play an important role in regulating extracellular d-serine and NMDA receptor-mediated physiological effects and that ASCT1/2 inhibitors have the potential for therapeutic benefit. PMID- 28807675 TI - Substantial protection against MPTP-associated Parkinson's neurotoxicity in vitro and in vivo by anti-cancer agent SU4312 via activation of MEF2D and inhibition of MAO-B. AB - We have previously demonstrated the unexpected neuroprotection of the anti-cancer agent SU4312 in cellular models associated with Parkinson's disease (PD). However, the precise mechanisms underlying its neuroprotection are still unknown, and the effects of SU4312 on rodent models of PD have not been characterized. In the current study, we found that the protection of SU4312 against 1-methyl-4 phenylpyridinium ion (MPP+)-induced neurotoxicity in PC12 cells was achieved through the activation of transcription factor myocyte enhancer factor 2D (MEF2D), as evidenced by the fact that SU4312 stimulated myocyte enhancer factor 2 (MEF2) transcriptional activity and prevented the inhibition of MEF2D protein expression caused by MPP+, and that short hairpin RNA (ShRNA)-mediated knockdown of MEF2D significantly abolished the neuroprotection of SU4312. Additionally, Western blotting analysis revealed that SU4312 potentiated pro-survival PI3-K/Akt pathway to down-regulate MEF2D inhibitor glycogen synthase kinase-3beta (GSK3beta). Furthermore, using the in vivo PD model of C57BL/6 mice insulted with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we found that intragastrical administration of SU4312 (0.2 and 1 mg/kg) greatly ameliorated Parkinsonian motor defects, and restored protein levels of MEF2D, phosphorylated-Ser473-Akt and phosphorylated-Ser9-GSK3beta. Meanwhile, SU4312 effectively reversed the decrease in protein expression of tyrosine hydroxylase in substantia nigra pars compacta dopaminergic neurons, inhibited oxidative stress, maintained mitochondrial biogenesis and partially prevented the depletion of dopamine and its metabolites. Very encouragingly, SU4312 was able to selectively inhibit monoamine oxidase-B (MAO-B) activity both in vitro and in vivo, with an IC50 value of 0.2 MUM. These findings suggest that SU4312 provides therapeutic benefits in cellular and animal models of PD, possibly through multiple mechanisms including enhancement of MEF2D through the activation of PI3-K/Akt pathway, maintenance of mitochondrial biogenesis and inhibition of MAO-B activity. SU4312 thus may be an effective drug candidate for the prevention or even modification of the pathological processes of PD. PMID- 28807676 TI - CRF modulates glutamate transmission in the central amygdala of naive and ethanol dependent rats. AB - Corticotropin-releasing factor (CRF) signaling in the central nucleus of the amygdala (CeA) is hypothesized to drive the development of alcohol dependence, as it regulates ethanol intake and several anxiogenic behaviors linked to withdrawal. Excitatory glutamatergic neurotransmission contributes to alcohol reinforcement, tolerance and dependence. Therefore, in this study we used in vitro slice electrophysiology to investigate the effects of CRF and its receptor subtype (CRF1 and CRF2) antagonists on both evoked and spontaneous action potential-independent glutamatergic transmission in the CeA of naive and ethanol dependent Sprague-Dawley rats. We found that CRF (25-200 nM) concentration dependently diminished evoked compound excitatory postsynaptic potentials (EPSPs), but increased miniature excitatory postsynaptic current (mEPSC) frequencies similarly in CeA neurons of both naive and ethanol-dependent rats, indicating reduced evoked glutamatergic responses and enhanced vesicular glutamate release, respectively. This CRF-induced vesicular glutamate release was prevented by the CRF1/2 antagonist (Astressin B) and the CRF1 antagonist (R121919), but not by the CRF2 antagonist (Astressin 2B). Similarly, CRF's effects on evoked glutamatergic responses were completely blocked by CRF1 antagonism, but only slightly decreased in the presence of the CRF2 antagonist. Moreover, CRF1 antagonism reveals a tonic facilitation of vesicular glutamate, whereas the CRF2 antagonism revealed a tonic inhibition of vesicular glutamate release. Collectively our data show that CRF primarily acts at presynaptic CRF1 to produce opposite effects on CeA evoked and spontaneous glutamate release and that the CRF system modulates CeA glutamatergic synapses throughout the development of alcohol dependence. PMID- 28807680 TI - Patient characteristics and cancer prevalence in the Danish cancer patient pathway for patients with serious non-specific symptoms and signs of cancer-A nationwide, population-based cohort study. AB - BACKGROUND: A new cancer patient pathway for patients presenting with non specific signs and symptoms (NSSC-CPP) was implemented nationally in Denmark in 2012. This study aims to describe, on a national level, the characteristics of patients referred to the Danish NSSC-CPP, and to estimate the prevalence and distribution of cancers and other diagnosis in this population. METHODS: A population-based cohort study using the Danish national registries, including all patients who completed a diagnostic course through the NSSC-CPP between 2012 and 2015. Cancer prevalence is presented as the percentage of included patients who were diagnosed with cancer after completing a NSSC-CPP diagnostic course. Associations between patient characteristics and cancer diagnosis were estimated in a multivariate logistic regression model. RESULTS: The mean age of the 23,934 patients included in the analysis was 64.6 years and 47% where male. In total, 11% of all patients received a cancer diagnosis after completing a diagnostic course in the NSSC-CPP; the most common types were breast cancer (18%) hematopoietic and lymphoid tissue cancer (15%), and malignant melanoma (12%). The most common non-cancer diagnosis was non-specific symptoms/observation (54%). Fifty-five patients were diagnosed with cancer within six months following a non cancer diagnosis in the NSSC-CPP. CONCLUSIONS: The prevalence of cancer in the NSSC-CPP was 11%. The most common cancer diagnosis was breast cancer, hematopoietic and lymphoid cancer and malignant melanoma. A small proportion of patients receiving a non-cancer diagnosis in the NSSC-CPP were diagnosed with cancer in the six months following their NSSC-CPP course. PMID- 28807678 TI - Metformin lowers alpha-synuclein phosphorylation and upregulates neurotrophic factor in the MPTP mouse model of Parkinson's disease. AB - In spite of the massive research for the identification of neurorestorative or neuroprotective intervention for curing Parkinson's disease (PD), there is still lack of clinically proven neuroprotective agents. Metformin, a common anti hyperglycemic drug has been known to possess neuroprotective properties. However, specific mechanisms by which metformin protects neurons from 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity remain to be elucidated. In this study, we assessed the neuroprotective effects of metformin in the subchronic MPTP model of PD, and explored its feasible mechanisms for neuroprotection. Animals received saline or MPTP injection (30 mg/kg/day) for the first 7 days, and then saline or metformin (200 mg/kg/day) for the next 7 days. Immunohistochemical stainings showed that metformin rescued the tyrosine hydroxylase-positive neurons and attenuated astroglial activation in the nigrostriatal pathway. In parallel, metformin restored dopamine depletion and behavioral impairments exerted by MPTP. Western blot analysis revealed that metformin ameliorated MPTP-induced alpha-synuclein phosphorylation which was accompanied by increased methylation of protein phosphatase 2A (PP2A), a phosphatase related to alpha-synuclein dephosphorylation. Moreover, the metformin regimen significantly increased the level of brain derived neurotrophic factor in the substantia nigra, and activated signaling pathways related to cell survival. Proof of concept study revealed that inhibition of PP2A or tropomyosin receptor kinase B reversed neuroprotective property of metformin in SH-SY5Y cells. Our results indicate that metformin provides neuroprotection against MPTP neurotoxicity, which might be mediated by inhibition of alpha-synuclein phosphorylation and induction of neurotrophic factors. PMID- 28807681 TI - Seasonal changes in activity patterns of Japanese flying squirrel Pteromys momonga. AB - Seasonal changes of activity patterns are an important survival strategy for several species. Seasonal changes in the activity patterns of Japanese flying squirrels (Pteromys momonga) were studied at Daibosatsu Mountain on Honshu Island, Japan from 2 June to 20 November 2007 and 11 April to 14 November 2008, to discuss their survival strategy based on the change. Activity patterns were assessed using long-term sensor camera traps at 214 sites for 14 months of a 2 year period. The cameras were placed for a total of 7317 camera trap nights over which total of 90 photographs of this species were collected from 22 of the 214 sites. Although distinct nocturnal activity was detected throughout the study period, activity patterns differed between temperate (June-September) and cold (April, May, October, and November) seasons. So, activity peaks were found to be bimodal during the temperate seasons and trimodal during the cold seasons. It is possible that the squirrels reduce their activity times per bout during the cold seasons to reduce energy loss arising from prolonged exposure to cold temperatures, as a survival strategy. PMID- 28807677 TI - Phosphodiesterase 4b expression plays a major role in alcohol-induced neuro inflammation. AB - It is increasingly evident that alcohol-induced, gut-mediated peripheral endotoxemia plays a significant role in glial cell activation and neuro inflammation. Using a mouse model of chronic alcohol feeding, we examined the causal role of endotoxin- and cytokine-responsive Pde4 subfamily b (Pde4b) expression in alcohol-induced neuro-inflammation. Both pharmacologic and genetic approaches were used to determine the regulatory role of Pde4b. In C57Bl/6 wild type (WT) alcohol fed (WT-AF) animals, alcohol significantly induced peripheral endotoxemia and Pde4b expression in brain tissue, accompanied by a decrease in cAMP levels. Further, along with Pde4b, there was a robust activation of astrocytes and microglia accompanied by significant increases in the inflammatory cytokines (Tnfalpha, Il-1beta, Mcp-1 and Il-17) and the generalized inflammatory marker Cox-2. At the cellular level, alcohol and inflammatory mediators, particularly LPS, Tnfalpha and Hmgb1 significantly activated microglial cells (Iba-1 expression) and selectively induced Pde4b expression with a minimal to no change in Pde4a and d isoforms. In comparison, the alcohol-induced decrease in brain cAMP levels was completely inhibited in WT mice treated with the Pde4 specific pharmacologic inhibitor rolipram and in Pde4b-/- mice. Moreover, all the observed markers of alcohol-induced brain inflammation were markedly attenuated. Importantly, glial cell activation induced by systemic endotoxemia (LPS administration) was also markedly decreased in Pde4b-/- mice. Taken together, these findings strongly support the notion that Pde4b plays a critical role in coordinating alcohol-induced, peripheral endotoxemia mediated neuro-inflammation and could serve as a significant therapeutic target. PMID- 28807679 TI - Identification and characterization of 5alpha-cyprinol-sulfating cytosolic sulfotransferases (Sults) in the zebrafish (Danio rerio). AB - 5alpha-Cyprinol 27-sulfate is the major biliary bile salt present in cypriniform fish including the zebrafish (Danio rerio). The current study was designed to identify the zebrafish cytosolic sulfotransferase (Sult) enzyme(s) capable of sulfating 5alpha-cyprinol and to characterize the zebrafish 5alpha-cyprinol sulfating Sults in comparison with human SULT2A1. Enzymatic assays using zebrafish homogenates showed 5alpha-cyprinol-sulfating activity. A systematic analysis, using a panel of recombinant zebrafish Sults, revealed two Sult2 subfamily members, Sult2st2 and Sult2st3, as major 5alpha-cyprinol-sulfating Sults. Both enzymes showed higher activities using 5alpha-cyprinol as the substrate, compared to their activity with DHEA, a representative substrate for mammalian SULT2 family members, particularly SULT2A1. pH-Dependence and kinetics experiments indicated that the catalytic properties of zebrafish Sult2 family members in mediating the sulfation of 5alpha-cyprinol were different from those of either zebrafish Sult3st4 or human SULT2A1. Collectively, these results imply that both Sult2st2 and Sult2st3 have evolved to sulfate specifically C27-bile alcohol, 5alpha-cyprinol, in Cypriniform fish, whereas the enzymatic characteristics of zebrafish Sult3 members, particularly Sult3st4, correlated with those of human SULT2A1. PMID- 28807682 TI - Evaluation and Treatment of Minors. AB - Many patients under the age of majority present to emergency departments (EDs) without parents or guardians. This may create concern in regard to evaluation of these patients without formal consent to treat. The Emergency Medical Treatment and Labor Act mandates that all patients presenting to EDs receive a medical screening examination and does not exclude these minors. Standards for who can provide consent for a patient vary from state to state and address important issues such as consent by parent surrogates, as well as adolescent emancipation, reproductive health, mental health, and substance use. This document addresses current federal and state legal implications of providing emergency care to minors, as well as guidance in obtaining consent, maintaining confidentiality, and addressing refusal of care. PMID- 28807683 TI - Nano-sized drug carriers: Extravasation, intratumoral distribution, and their modeling. AB - Navigating intratumoral drug distribution has proven to be one of the most challenging aspects of drug delivery. The barriers are significant and varied; increased diffusional distances, elevated interstitial fluid pressure, regions of dense extracellular matrix and high cell density, and overall heterogeneity. Such a long list imposes significant requirements on nano-sized carriers. Unfortunately, other capabilities are eclipsed by the distribution requirements. A drug can do no good until it reaches its target. Numerous strategies to improve drug distribution have been developed, taking account of various unique characteristics of solid tumors, including some mechanisms that are still not fully understood. Most of these strategies were from small animal tumor models which are our primary tool for understanding cancer physiology. The small animal tumor model is the most versatile and effective means of understanding tumor transport, but its prevalence belies some of its weaknesses. Tumors grown under lab conditions are developed much more quickly than naturally developed cancers, potentially impacting tumor heterogeneity, blood vessel development, extracellular matrix organization, cell diversity, and many other features of structure and physiology that may impact transport. These problems come in addition to the difficulties of making precise measurements within a living tumor. Resolving these problems is best done by improving our analysis methods, and by finding complementary models that can clarify and expound the details. In this review, we will first discuss some of the strategies employed to improve transport and then highlight some of the new models that have recently been developed in the Bae lab and how they may aid in the study of tumor transport in the future. PMID- 28807684 TI - Influence of Velotron chainring size on Wingate anaerobic test. AB - OBJECTIVES: This study compared an 85-tooth versus the standard 62-tooth chainring for power outputs during a Wingate test using a Velotron electromagnetically-braked cycle ergometer. DESIGN: All participants completed trials using both chainring sizes in a repeated-measures cross-over design. METHODS: Resistance-trained male participants (n=20, 24.6+/-4.5years) performed two Wingate tests separated by at least 48h. Peak power (PP), mean power (MP), fatigue index (FI), peak cadence, mean cadence, and total work (TW) were recorded. RESULTS: Peak power was not significantly different (p=0.10) between trials (62-tooth=1111+/-187W vs. 85-tooth=1188+/-103W). However, MP, mean cadence, and TW were significantly greater (p<0.01) for the 85-tooth trial (869+/ 114W, 131+/-16rpm, and 26,063+/-3418J) compared to the 62-tooth test (673+/-136W, 102+/-24rpm, and 20,199+/-4066J). Fatigue index was reduced during the 85-tooth trial (49.9+/-9.1% vs. 61.6+/-8.8%; p<0.01). Agreement was poor with most ICCs~0.19 and large SEMs. CONCLUSIONS: The two options for chainrings on Velotron cycle ergometers should not be interchangeably used with the Wingate test software; the 62-tooth ring is recommended for most applications. Individuals who can attain peak cadence >180rpm have less variability and tend to achieve higher power outputs on the 62-tooth ring. We suspect that the manufacturer's software limits peak cadence to 182rpm when using the 85-tooth chainring. PMID- 28807686 TI - Adsorption of Zn(II) ions by chitosan coated diatomaceous earth. AB - In this work, chitosan coated diatomaceous earth (CCDE) beads were synthesized by a drop-wise method and characterized by FTIR, BET, SEM, EDS, and zeta potential for Zn(II) ion removal from aqueous solution in batch and continuous processes. Several parameters have been studied such as solution-pH, initial Zn(II) ion concentration, temperature, flow rate, and contact time to investigate the Zn(II) ion uptake. The maximum adsorption capacity of Zn(II) ion onto CCDE beads was 127.4mg/g in batch studies. The adsorption followed Pseudo second order and was well fitted to Langmuir model, indicating monolayer adsorption behavior. The continuous adsorption studies showed decreasing breakthrough and exhausted time with increasing flow rate of solution. The breakthrough points were 220 and 115min at flow rate 3 and 6mL/min, respectively. Loaded CCDE beads with Zn(II) ions were successfully regenerated by 0.2M NaOH without damaging the adsorbents and up to 87% recovery in the fourth cycle. Anions in the solution had an insignificant effect on Zn(II) ion uptake by CCDE beads. Overall results suggested that the prepared adsorbents could be employed as a low-cost, sustainable, and excellent alternative material for Zn(II) ion removal from wastewater. PMID- 28807685 TI - An RNA polymerase II-driven Ebola virus minigenome system as an advanced tool for antiviral drug screening. AB - Ebola virus (EBOV) causes a severe disease in humans with the potential for significant international public health consequences. Currently, treatments are limited to experimental vaccines and therapeutics. Therefore, research into prophylaxis and antiviral strategies to combat EBOV infections is of utmost importance. The requirement for high containment laboratories to study EBOV infection is a limiting factor for conducting EBOV research. To overcome this issue, minigenome systems have been used as valuable tools to study EBOV replication and transcription mechanisms and to screen for antiviral compounds at biosafety level 2. The most commonly used EBOV minigenome system relies on the ectopic expression of the T7 RNA polymerase (T7), which can be limiting for certain cell types. We have established an improved EBOV minigenome system that utilizes endogenous RNA polymerase II (pol II) as a driver for the synthesis of minigenome RNA. We show here that this system is as efficient as the T7-based minigenome system, but works in a wider range of cell types, including biologically relevant cell types such as bat cells. Importantly, we were also able to adapt this system to a reliable and cost-effective 96-well format antiviral screening assay with a Z-factor of 0.74, indicative of a robust assay. Using this format, we identified JG40, an inhibitor of Hsp70, as an inhibitor of EBOV replication, highlighting the potential for this system as a tool for antiviral drug screening. In summary, this updated EBOV minigenome system provides a convenient and effective means of advancing the field of EBOV research. PMID- 28807688 TI - Hypochlorous acid induced structural and conformational modifications in human DNA: A multi-spectroscopic study. AB - Hypochlorous acid (HOCl) is generated by activated phagocytes at the site of inflammation. Exposure of DNA to HOCl results in base and nucleotide modifications causing DNA damage, which is one of the leading causes of various pathological conditions including carcinogenesis. In the present work, various biophysical techniques were used to study HOCl induced structural and conformational changes in human placental DNA. The HOCl modified DNA showed hyperchromicity, reduced fluorescence and decrease in melting temperature. Circular dichorism (CD) and Fourier transform infra-red (FT-IR) studies exhibited conformational changes and shift in band positions of DNA, respectively, suggesting structural changes. Agarose gel electrophoresis and scanning electron microscopy showed strand breakage and decreased aggregation. These results suggest that HOCl causes conformational and structural perturbations in mammalian DNA, which may consequentially lead to DNA mutations resulting in perturbation of epigenetic signals leading to cancer and autoimmune diseases. PMID- 28807687 TI - Influence of Tween-80 on the production and structure of water-insoluble curdlan from Agrobacterium sp. AB - In order to explore the mechanism by which Tween-80 enhances the production of curdlan produced by Agrobacterium sp., the effects of Tween-80 on the production and structure of curdlan and Agrobacterium sp. were evaluated. Maximum curdlan production (51.94g/L) was achieved when 16g/L Tween-80 was added at the beginning of the cell growth stage. The addition of Tween-80 at higher concentration inhibited cell growth. However, the addition of 16g/L Tween-80 enhanced the production of curdlan with a looser ultrastructure, significantly weakened the envelopment of curdlan on Agrobacterium sp., altered the fine structure of cell membrane, and increased the cell membrane permeability. Moreover, the efficiency of oxygen and mass transport, respiration intensity, UTP regeneration, ATP regeneration, activity of curdlan synthetase, capacity of stress response and energy supply of Agrobacterium sp. were all greatly improved by the addition of Tween-80. These findings demonstrate the mechanisms by which Tween-80 enhances curdlan production and provide a cheap and feasible approach to weaken the envelopment of water-insoluble polysaccharides on bacteria. PMID- 28807689 TI - Effects of polysaccharides from abalone viscera (Haliotis discus hannai Ino) on MGC 803 cells proliferation. AB - The polysaccharides (AVP) was obtained from abalone (Haliotis discus hannai Ino) viscera, using the alkaline protease to enzymolysis, sevage method and repeated freezing and thawing method to remove protein and hydrogen peroxide method to depigment. The total sugar content was 46.27+/-1.5% and uronic acid, sulfate radical, hexosamine and protein contents were 17.44+/-0.22%, 16.98+/-0.15%, 0.65+/-0.02% and 1.64+/-0.13% in AVP respectively. The main monosaccharide compositions of AVP were d-galactose, d-xylose, d-mannose, d-glucose and d glucuronic acid. MTT assay showed AVP had a significant anti-tumor activity to gastric carcinoma cells, especially to MGC 803, while it had no influence upon proliferation of normal stomach cells GES 1. The results of Morphological changes, cell migration ability and AO/EB staining indicated that MGC803 cells underwent apoptosis in a dose-dependent manner induced by AVP. Moreover, the western blotting results showed that the expressions of survivin, Bcl-2 and VEGF were decreased, while the expression of Bax and p53 were increased in a dose dependent manner of AVP. The results suggested that AVP might be a potential anti tumor agent securely and naturally. PMID- 28807690 TI - Synergistic effect of quercetin and pH-responsive DEAE-chitosan carriers as drug delivery system for breast cancer treatment. AB - Amphiphilic chitosans, which may self-assemble in aqueous solution to form nanoaggregates with different conformations depending to the environmental pH, can be used as drug transport and delivery agents, when the target pH differs from the delivery medium pH. In this study, quercetin, a bioactive flavonoid, was encapsulated in a pH-responsive system based on amphiphilic chitosan. The hydrophilic reagent 2-chloro-N,N-diethylethylamine hydrochloride (DEAE), also known to inhibit the proliferation of cancer cells, was used as a grafting agent. Drug loading experiments (DL ~5%) showed a quercetin entrapment efficiency of 73 and 78% for the aggregates. The sizes of blank aggregates measured by dynamic light scattering (DLS) varied from 169 to 263nm and increased to ~410nm when loaded with quercetin. The critical aggregation concentration, zeta potential and morphology of the aggregates were determined. pH had a dominant role in the release process and Fickian diffusion was the controlling factor in drug release according to the Korsmeyer-Peppas mathematical model. In vitro studies indicated that the DEAE-modified chitosan nanoaggregates showed a synergistic effect with quercetin on the control of the viability of MCF-7 cells. Therefore, DEAE modified chitosan nanoaggregates with pH-sensibility can be used as optimized nanocarriers in cancer therapy. PMID- 28807691 TI - Size optimization and in vitro biocompatibility studies of chitosan nanoparticles. AB - Chitosan (CS), an amino polysaccharide has fascinating scientific applications due to its many flexible properties. The advantages of Chitosan tend to increase when it was modified. Thus, in the present research work, to improve the properties of chitosan, it was converted into chitosan nanoparticles (CS-NPs) through the ionic gelation method using sodium tripoyphosphate (TPP) and sodium hexametaphosphate (SHMP) as a crosslinker. The size optimization was done by varying the parameters such as crosslinker concentration, agitation method and rate, agitation time, temperature and drying method. The prepared samples were characterized using FTIR, TGA, XRD, SEM, TEM and DLS. Also the prepared CS-NPs with TPP and SHMP had been evaluated in vitro for determining its hemocompatibility, biodegradability, serum stability, cytotoxicity and cell viability. The results showed the significant participation of all the parameters in obtaining the nanoparticles in 20-30nm and 5-10nm for CS-NPs-TPP air dried and freeze dried samples and around 60-80nm and 20-30nm for CS-NPs-SHMP air dried and freeze dried samples. The in vitro biological studies revealed that the nanoparticles are non-toxic with a good degree of biodegradability, blood compatibility and stability. PMID- 28807692 TI - Community Use of Physical and Occupational Therapy After Stroke and Risk of Hospital Readmission. AB - OBJECTIVES: To determine whether receipt of therapy and number and timing of therapy visits decreased hospital readmission risk in stroke survivors discharged home. DESIGN: Retrospective cohort analysis of Medicare claims (2010-2013). SETTING: Acute care hospital and community. PARTICIPANTS: Patients hospitalized for stroke who were discharged home and survived the first 30 days (N=23,413; mean age +/- SD, 77.6+/-7.5y). INTERVENTIONS: Physical and occupational therapist use in the home and/or outpatient setting in the first 30 days after discharge (any use, number of visits, and days to first visit). MAIN OUTCOME MEASURES: Hospital readmission 30 to 60 days after discharge. Covariates included demographic characteristics, proxy variables for functional status, hospitalization characteristics, comorbidities, and prior health care use. Multivariate logistic regression analyses were conducted to examine the relation between therapist use and readmission. RESULTS: During the first 30 days after discharge, 31% of patients saw a therapist in the home, 11% saw a therapist in an outpatient setting, and 59% did not see a therapist. Relative to patients who had no therapist contact, those who saw an outpatient therapist were less likely to be readmitted to the hospital (odds ratio, 0.73; 95% confidence interval, 0.59 0.90). Although the point estimates did not reach statistical significance, there was some suggestion that the greater the number of therapist visits in the home and the sooner the visits started, the lower the risk of hospital readmission. CONCLUSIONS: After controlling for observable demographic-, clinical-, and health related differences, we found that individuals who received outpatient therapy in the first 30 days after discharge home after stroke were less likely to be readmitted to the hospital in the subsequent 30 days, relative to those who received no therapy. PMID- 28807694 TI - Reviewing evidence for systematic transcriptional deletions, nucleotide exchanges, and expanded codons, and peptide clusters in human mitochondria. AB - Polymerization sometimes transforms sequences by (a) systematic deletions of mono , dinucleotides after trinucleotides, or (b) 23 systematic nucleotide exchanges (9 symmetric, X<>Y, e.g. G<>T, 14 asymmetric, X > Y > Z > X, e.g. A > G > T > A), producing del- and swinger RNAs. Some peptides correspond to del- and swinger RNA translations, also according to tetracodons, codons expanded by a silent nucleotide. Here new analyzes assume different proteolytic patterns, partially alleviating false negative peptide detection biases, expanding noncanonical mitoproteome profiles. Mito-genomic, -transcriptomic and -proteomic evidence for noncanonical transcriptions and translations are reviewed and clusters of del- and swinger peptides (also along tetracodons) are described. Noncanonical peptide clusters indicate regulated expression of cryptically encoded mitochondrial protein coding genes. These candidate noncanonical proteins don't resemble known proteins. PMID- 28807693 TI - Safety and Feasibility of Rehabilitation Interventions in Children Undergoing Hematopoietic Stem Cell Transplant With Thrombocytopenia. AB - OBJECTIVE: To analyze the relation between platelet counts, intensities of physical therapy (PT) and occupational therapy (OT) services received, and frequencies of bleeding complications in children undergoing hematopoietic stem cell transplant (HSCT) during a period of severe thrombocytopenia. DESIGN: Retrospective review study. SETTING: Tertiary care hospital. PARTICIPANTS: Children (N=63; age, <18y) hospitalized for HSCT in 2010 and 2011 who received PT and OT services while markedly thrombocytopenic (platelet count, <=50K/mcL). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Intensities of PT and OT interventions, patients' platelet counts on specific therapy days, and any bleeding events (minor or major) that occurred during or shortly after rehabilitation interventions. RESULTS: Sixty-two patients (accounting for 63 HSCTs) met the criteria for analysis. Fifty-six of these patients (57 HSCTs) underwent PT and/or OT while markedly thrombocytopenic. There was no correlation between platelet counts and intensities of rehabilitation interventions. There were no major bleeding events. There was no association between minor bleeding events and intensities of PT or OT interventions and no association between minor bleeding events and platelet counts. Only 5 minor bleeding events occurred during or after moderate or intensive therapy out of 346 PT and OT sessions (1.5%). CONCLUSIONS: The results of our study suggest that bleeding complications during or after mobilization and supervised exercise during PT and OT in children with severe thrombocytopenia undergoing HSCT are minor and relatively rare. These are encouraging results for both patients and rehabilitation specialists treating this population who is at high risk of developing immobility-related complications. PMID- 28807695 TI - Doxorubicin enhances oxysterol levels resulting in a LXR-mediated upregulation of cardiac cholesterol transporters. AB - The anthracycline-mediated cardiotoxicity is still not completely understood. To examine the impact of cholesterol metabolism and transport in this context, cholesterol and oxysterol levels as well as the expression of the cholesterol transporters ABCA1 and ABCG1 were analyzed in doxorubicin-treated HL-1 murine cardiomyocytes as well as in mouse model for acute doxorubicin-induced cardiotoxicity. Doxorubicin-treated HL-1 cells exhibited enhanced cholesterol (153+/-20% of control), oxysterol (24S-hydroxycholesterol: 206+/-29% of control) and cholesterol precursor levels (lathosterol: 122+/-12% of control; desmosterol: 188+/-10% of control) indicating enhanced cholesterol synthesis. Moreover, abca1 and abcg1 were upregulated on mRNA, protein and functional level caused by a doxorubicin-mediated activation of the nuclear receptor LXR. In addition, the oxysterols not only induced the abca1 and abcg1 in HL-1 cells but also enhanced the expression of endothelin-1 and transforming growth factor-beta, which have already been identified as important factors in doxorubicin-induced cardiotoxicity. These in vitro findings were verified in a murine model for acute doxorubicin-induced cardiotoxicity, demonstrating elevated cardiac (2.1+/-0.2vs. 3.6+/-1.0ng/mg) and systemic cholesterol levels (105.0+/-8.4vs. 130.0+/ 4.3mg/dl), respectively, as well as enhanced oxysterol levels such as cardiac 24S hydroxycholesterol (2.1+/-0.2vs. 3.6+/-1.0ng/mg). In line with these findings cardiac mRNA expression of abca1 (303% of control) and abcg1 (161% of control) was induced. Taken together, our data demonstrate enhanced cholesterol and oxysterol levels by doxorubicin, resulting in a LXR-dependent upregulation of abca1 and abcg1. In this context, the cytotoxic effects of oxysterols and their impact on cardiac gene expression should be considered as an important factor in doxorubicin-induced cardiotoxicity. PMID- 28807696 TI - A tailored intervention to improving the quality of intrahospital nursing handover. AB - INTRODUCTION: Nursing handover is a process central to the delivery of high quality and safe care. We aimed to improve the quality of nursing handover from the emergency department to ward and intensive care unit (ICU). METHODS: A quasi experimental non-equivalent control group pre-test - post-test design was applied. Handover quality was measured using the Handover Evaluation Scale (HES). A tailored intervention, inspired by appreciative inquiry, was designed to improve the implementation of an existing handover form and procedure. RESULTS: In total 130 nurses participated, 66 before and 64 after the intervention. Initial structure of the HES showed no good fit to our data; the questions were reshaped into 3 dimensions: Quality of information, Interaction and support, and Relevance of information. Following the intervention, mean changes in HES factor scores ranged from -3.99 to +15.9. No significant difference in factor scoring by ward and ICU nurses was found. Emergency department nurses, however, perceived Interaction and support to be improved following the intervention. CONCLUSION: The intervention did not result in an improved perception of handover quality by ward and ICU nurses. There was improvement in the perception of Interaction and support among emergency department nurses. The intervention positively effected teamwork and mutual understanding concerning nursing handover practice amongst emergency nurses. In order to improve intrahospital nursing handover, hospital wide interventions are suggested. These interventions should be aimed at creating a generative story, improving mutual understanding, and establishing a supportive attitude regarding standardised procedures to reduce human error. PMID- 28807697 TI - First do no harm: Echocardiography during cardiac arrest may increase pulse check duration. PMID- 28807698 TI - Cross-Cultural Adaptation and Psychometric Evaluation of the Turkish Version of the Cancer Behavior Inventory-Brief Version. AB - CONTEXT: Cancer Behavior Inventory-Brief Version (CBI-B) is a simple and non burdensome tool used to evaluate the self-efficacy of the cancer patients. OBJECTIVES: The aim of this study was to examine the psychometric properties of the Turkish version of the CBI-B. METHODS: This methodologic study was conducted on 143 cancer patients who received radiotherapy at the Department of Radiation Oncology at a Training and Research Hospital in Turkey. Data were collected using Medical and Demographic Information Form, CBI-B, Satisfaction With Life Scale, and European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30). Descriptive statistics, exploratory factor analysis, and correlation coefficients were used for the analysis of data. RESULTS: Exploratory factor analysis confirmed four-factor structure explaining 74.7% of the total variance: 1) Maintaining Independence and Positive Attitude, 2) Participating in Medical Care, 3) Coping and Stress Management, and 4) Managing Affect. The CBI-B had acceptable internal consistency (Cronbach alpha = 0.87) and test-retest reliability (intraclass correlation coefficient = 0.961) and concurrent validity with Satisfaction With Life Scale and EORTC QLQ-C30 scores. The measures of life satisfaction and quality of life were positively correlated with CBI-B, whereas the symptom levels and the functions (with the exception of the role function) were negatively correlated. CONCLUSION: The CBI-B was found to be a valid and reliable inventory for assessing the self-efficacy of Turkish cancer patients. The CBI-B, is a simple and brief measure of self efficacy for coping with cancer, could be easily used in clinical and research settings. PMID- 28807699 TI - Communication Challenges of Oncologists and Intensivists Caring for Pediatric Oncology Patients: A Qualitative Study. AB - CONTEXT: The families of oncology patients requiring intensive care often face increasing complexity in communication with their providers, particularly when patients are cared for by providers from different disciplines. OBJECTIVE: The objective of this study was to describe experiences and challenges faced by pediatric oncologists and intensivists and how the oncologist-intensivist relationship impacts communication and initiation of goals of care discussions (GCDs). METHODS: We conducted semi-structured interviews with a convenience sample of 10 physicians, including pediatric oncology and intensive care attendings and fellows. RESULTS: We identified key themes (three barriers and four facilitators) to having GCDs with families of oncology patients who have received intensive care. Barriers included challenges to communication within teams because of hierarchy and between teams due to incomplete sharing of information and confusion about who should initiate GCDs; provider experiences of internal conflict about how to engage parents in decision-making and about the "right thing to do" for patients; and lack of education and training in communication. Facilitators included team preparation for family meetings; skills for partnering with families; the presence of palliative care specialists; and informal education in communication and willingness for further training in communication. Notably, the education theme was identified as both a barrier and resource. CONCLUSION: We identified barriers to communication with families both within and between teams and for individual physicians. Formal communication training and processes that standardize communication to ensure completeness and role delineation between clinical teams may improve oncologists' and intensivists' ability to initiate GCDs, thereby fulfilling their ethical obligations of decision support. PMID- 28807700 TI - Unfinished Business in Families of Terminally Ill With Cancer Patients. AB - CONTEXT: Unfinished business often causes psychological issues after bereavement. Providing care for families of terminally ill patients with cancer to prevent unfinished business is important. OBJECTIVES: To clarify the prevalence and types of unfinished business in families of end-of-life patients with cancer admitted to palliative care units (PCUs), explore depression and grief associated with unfinished business, and explore the factors affecting unfinished business. METHODS: We conducted a cross-sectional, anonymous, self-report questionnaire survey with 967 bereaved families of patients with cancer admitted to PCUs. The questionnaire assessed the presence or the absence of unfinished business, content of unfinished business, depression, grief, process of preparedness, condition of the family and patient, and the degree of involvement of health care professionals. RESULTS: Questionnaires were sent to 967 families, and 73.0% responded. In total, 26.0% of families had some unfinished business, with improvement of the patient-family relationship being a common type of unfinished business. Families with unfinished business had significantly higher depression and grief scores after bereavement compared with those without. Factors that influenced the presence or the absence of unfinished business were preparedness for the patient's death (P = 0.001), discussion between the patient and family about the disease trajectory and way to spend daily life (P < 0.001), good patient-family relationship (P = 0.011), and family and health care professionals considering together the appropriate timing to accomplish the family's wishes (P = 0.021). CONCLUSION: Many families have unfinished business. Health care professionals should coordinate the appropriate timing for what the family wishes to do, with consideration of family dynamics, including the family's preparedness, communication pattern, and relationships. PMID- 28807702 TI - Factors Associated With the Use of U.S. Community-Based Palliative Care for Children With Life-Limiting or Life-Threatening Illnesses and Their Families: An Integrative Review. AB - CONTEXT: As children with life-limiting illnesses (LLIs) and life-threatening illnesses (LTIs) live longer, challenges to meeting their complex health care needs arise in homes and communities, as well as in hospitals. Integrated knowledge regarding community-based pediatric palliative care (CBPPC) is needed to strategically plan for a seamless continuum of care for children and their families. OBJECTIVES: The purpose of this integrative review article is to explore factors that are associated with the use of CBPPC for U.S. children with LLIs and LTIs and their families. METHODS: A literature search of PubMed, CINAHL, Scopus, Google Scholar, and an ancestry search was performed to identify empirical studies and program evaluations published between 2000 and 2016. The methodological protocol included an evaluation of empirical quality and explicit data collection of synthesis procedures. RESULTS: Forty peer-reviewed quantitative and qualitative methodological interdisciplinary articles were included in the final sample. Patient characteristics such as older age and a solid tumor cancer diagnosis and interpersonal factors such as family support were associated with higher CBPPC use. Organizational features were the most frequently discussed factors that increased CBPPC, including the importance of interprofessional hospice services and interorganizational care coordination for supporting the child and family at home. Finally, geography, concurrent care and hospice eligibility regulations, and funding and reimbursement mechanisms were associated with CBPPC use on a community and systemic level. CONCLUSION: Multilevel factors are associated with increased CBPPC use for children with LLIs or LTIs and their families in the U.S. PMID- 28807701 TI - Late-Life Suicide in Terminal Cancer: A Rational Act or Underdiagnosed Depression? AB - CONTEXT: Previous studies have reported significantly elevated standardized mortality rates in older people with cancer. Terminally ill people represent a unique group where suicide may be considered as rational. OBJECTIVES: The aims of this study are to compare the sociodemographic and clinical characteristics of older people with and without terminal cancer who died by suicide and analyze the suicide motives of those with terminal cancer to determine whether they represent rational suicide. METHODS: The New Zealand Coronial Services provided records of all older people (aged 65 years and older) who died by suicide between July 2007 and December 2012. Sociodemographic and clinical data were extracted from the records. Using the characteristics for defining rational suicide, we determined whether the motives in terminal cancer cases represented rational suicide. RESULTS: Of the 214 suicide cases, 23 (10.7%) older people were diagnosed with a terminal cancer. Univariate analysis found that older people with terminal cancer who died by suicide were less likely to have a diagnosis of depression (8.7% vs. 46.6%; P = 0.001) or previous contact with mental health services (4.5% vs. 35.0%; P = 0.004) than those without terminal cancer. About 82.6% of the terminal cancer cases had a motivational basis that would be understandable to uninvolved observers. CONCLUSION: A high proportion of those with terminal cancer had motives suggestive of rational suicide. Future studies are needed to clarify whether the low rate of depression is secondary to underdiagnosis of depression or people with terminal cancer choosing to end their life as a rational act to alleviate suffering. PMID- 28807703 TI - Is Early Palliative Care Feasible in Patients With Multiple Myeloma? AB - CONTEXT: Evidence for the benefits of early palliative care (EPC) in patients with solid tumors is strong, but EPC has received scant attention in hematologic malignancies. OBJECTIVE: To assess the benefits of outpatient-based EPC for symptom control in patients with multiple myeloma. METHODS: Retrospective study of patients attending the Multiple Myeloma Palliative Care Clinic at our hospital in the year 2013 (February 1-December 31). The following symptoms were assessed at baseline and at three follow-up consultations using a Numerical Visual Scale (0 = no symptoms; 10 = worst possible): pain, anorexia, constipation, insomnia, nausea/vomiting, dyspnea, anxiety, and sadness. Physical and emotional symptom burden scores were calculated. Pain interference with general activity, sleep, and mood was also evaluated. RESULTS: About 67 patients were included. The proportion of patients reporting moderate-to-severe pain (Numerical Visual Scale >=5) decreased significantly from baseline to the final follow-up: worst pain decreased from 57% to 18% (P < 0.0001), whereas average pain fell from 24% to 2% (P < 0.0001). The percentage of patients reporting no pain interference increased significantly from baseline: general activity (52% vs. 82%; P = 0.0001), sleep (73% vs. 91%; P = 0.01), and mood (52% vs. 87.5%; P = 0.0001). Physical and emotional symptom burden also improved, with significantly fewer patients reporting depression (13% vs. 5%; P = 0.001). Most patients (86.6%) were alive and still attending the Multiple Myeloma Palliative Care Clinic at study end. CONCLUSIONS: These findings indicate that EPC is feasible in patients with multiple myeloma. Pain and other symptoms were well controlled. PMID- 28807704 TI - Palliative Care-Albania. AB - Sixty percent of cancer patients are diagnosed with advanced stages of disease and those diagnosed in early stages face challenges to receive adequate treatment. Palliative care has had significant developments in recent years in Albania because of a close partnership with the Ministry of Health, local nonprofit organizations, and the Open Society Foundation Albania. In 2011, a five year action plan for palliative care as one of four parts of the National Cancer Control Plan was approved. At the end of 2014, the first palliative care law was approved by Parliament. Palliative care by-laws, documents, standards, clinical protocols, and guidelines for adults and children have been developed. Training and education are being provided to primary care professionals. Curricula on palliative care have been developed for the faculty of medicine, nursing high schools, and social work. About 80% of essential medications used in palliative care are available in Albania, 50% of these are paid for and have some access restrictions, and meanwhile the opiophobia still remains an enormous barrier. In the last three years, significant progress has been made in service provision. From only one public palliative care service in 2013, there are now eight palliative care services in eight of the 11 regional hospitals. By the end of 2016, it is expected that palliative care services will be available in all regional hospitals in the country. PMID- 28807705 TI - Psychometric Properties of the Fatigue Questionnaire EORTC QLQ-FA12 in a Sample of Female Cancer Patients. AB - CONTEXT: Cancer patients frequently suffer from fatigue. Recently, the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life group developed a new 12-item fatigue assessment instrument. OBJECTIVES: The aim of this study was to psychometrically test this questionnaire in comparison with the three-item fatigue scale of the EORTC QLQ-C30. METHODS: A sample of 354 patients who were being treated for breast cancer or gynecologic cancer were examined using the new fatigue questionnaire EORTC QLQ-FA12 and the EORTC QLQ-C30 during their hospital stay (t1) and three months after hospital discharge (t2). Confirmatory factorial analyses, item analyses, test-retest reliability analyses, and correlation analyses were performed. RESULTS: The analyses roughly supported the three-factorial structure of the FA12, which comprised the subscales physical, emotional, and cognitive fatigue. The fit indices of the confirmatory factorial analysis were worse than those of the original article but nevertheless acceptable. Cronbach alpha of the total scale was 0.92; the coefficients of the subscales were between 0.79 and 0.93. The correlation between the EORTC QLQ-FA12 total scale and the fatigue scale of the EORTC QLQ-C30 was 0.69 and the correlation between the t1 and t2 scores was 0.45 for the EORTC QLQ-FA12 total scale and between 0.37 and 0.47 for the subscales. CONCLUSION: The psychometric coefficients justify the calculation of a sum score, which can be used by clinicians to assess the general degree of fatigue. Although the three-item fatigue scale of the EORTC QLQ-C30 stresses the physical aspect of fatigue, the new EORTC QLQ-FA12 covers its emotional and cognitive aspects as well. PMID- 28807708 TI - The Great Imitator: Visual Changes in a 37-Year-Old Man with HIV. PMID- 28807707 TI - Quality Improvement Pearls for the Palliative Care and Hospice Professional. AB - Rapid changes in how palliative care clinicians are evaluated and paid present an imperative for clinicians to adeptly and routinely perform quality improvement in usual practice. Like empathic communication and facilitating goals of care discussions, quality improvement skills must be learned, honed, and practiced, so identifying problems and brainstorming solutions becomes a natural component of delivering serious illness care. Using our experience in both failures and successes in performing quality improvement, here we provide a prioritized list of 10 pearls specifically aimed to palliative care and hospice professionals. We aim to demystify quality improvement, highlight areas where rigor and a systematic approach are needed for success, and offer our own lessons learned and mistakes made to promote success for our colleagues and our field. PMID- 28807706 TI - The Relationship Between Psychological Symptoms and Ventricular Assist Device Implantation. AB - CONTEXT: Ventricular assist devices (VADs) improve quality of life in advanced heart failure patients, but there are little data exploring psychological symptoms in this population. OBJECTIVE: This study examined the prevalence of psychiatric symptoms and disease over time in VAD patients. METHODS: This prospective multicenter cohort study enrolled patients immediately before or after VAD implant and followed them up to 48 weeks. Depression and anxiety were assessed with Patient-Reported Outcomes Measurement Information System Short Form 8a questionnaires. The panic disorder, acute stress disorder (ASD) and post traumatic stress disorder (PTSD) modules of the Structured Clinical Interview for the DSM were used. RESULTS: Eighty-seven patients were enrolled. After implant, depression and anxiety scores decreased significantly over time (P = 0.03 and P < 0.001, respectively). Two patients met criteria for panic disorder early after implantation, but symptoms resolved over time. None met criteria for ASD or PTSD. CONCLUSIONS: Our study suggests VADs do not cause serious psychological harms and may have a positive impact on depression and anxiety. Furthermore, VADs did not induce PTSD, panic disorder, or ASD in this cohort. PMID- 28807709 TI - Gunshot to the Head. PMID- 28807710 TI - Inferior Vena Cava Filters in Stable Patients with Acute Pulmonary Embolism Who Receive Thrombolytic Therapy. AB - BACKGROUND: There is a need for further analyses of subgroups of patients with pulmonary embolism who might benefit from vena cava filters. In the present investigation, we analyze mortality with vena cava filters in the subgroup of stable patients with pulmonary embolism who received thrombolytic therapy. We use a different database than used previously, and we analyze data in more recent years. METHODS: Administrative data were analyzed from the Premier Healthcare Database, 2010-2014, in hospitalized stable patients with pulmonary embolism who received thrombolytic therapy and may or may not have received a vena cava filter. Patients were identified on the basis of International Classification of Disease, Ninth Revision, Clinical Modification codes. RESULTS: In-hospital all cause mortality in stable patients who received a vena cava filter in addition to thrombolytic therapy was 139 of 2660 (5.2%), compared with 697 of 4332 (16.1%) who did not receive a filter (P < .0001) (relative risk .32). Mortality was lower with a filter every decade of age >= 31 years. CONCLUSION: Among stable patients with acute pulmonary embolism who receive thrombolytic therapy, irrespective of the reason, the additional use of an inferior vena cava filter results in a lower in-hospital mortality. PMID- 28807711 TI - Delayed Diagnosis of Cast Nephropathy. PMID- 28807712 TI - Cerebellar Hemangioblastoma. PMID- 28807713 TI - Opioid Drug Use and Acute Cardiac Events Among Pregnant Women in the United States. AB - BACKGROUND: Cardiovascular disease remains a leading cause of pregnancy associated deaths in the United States. The extent to which increasing opioid use among pregnant women contributes to fatal cardiovascular events is unknown. We examined trends in opioid use among pregnant women over the previous decade and the association between changes in temporal trends in opioid drug use and the incidence of acute cardiac events among mothers. METHODS: In this retrospective analysis of the Healthcare and Cost Utilization Project, we used a 2-stage stratified cluster sampling of all inpatient hospital discharges from nonfederal hospitals from January 1, 2002 through December 31, 2014. The study population comprised pregnant women aged 13-49 years and related hospitalizations, including delivery. The primary exposure of interest was opioid use during pregnancy. The primary outcome was the occurrence of acute myocardial infarction or cardiac arrest during pregnancy or childbirth. RESULTS: Among the estimated 57.4 million pregnancy-related inpatient hospitalizations, 511,469 (approximately 1%) had documented use of opioids, cocaine, and/or amphetamines. There was a 300% increase in the use of opioids during pregnancy over the study period, whereas cocaine consumption significantly decreased and that of amphetamine remained stable. Over the 13-year period, the rise in opioid use paralleled a 50% increase in the incidence of acute cardiac events among mothers. CONCLUSION: Over the previous decade opioid use during pregnancy increased significantly, in parallel with the rise in the incidence of acute cardiac events in pregnancy and childbirth. An effective national policy is needed to address this emerging public health challenge. PMID- 28807714 TI - Systemic Immunoglobulin G4-Related Disease in an Asymptomatic Patient. PMID- 28807715 TI - Chrodrimanins O-S from the fungus Penicillium sp. SCS-KFD09 isolated from a marine worm, Sipunculusnudus. AB - Five new meroterpenoids, chrodrimanins O-S (1-5), as well as a known one (6), were isolated from the fermentation broth of Penicillium sp. SCS-KFD09 isolated from a marine worm, Sipunculusnudus, from Haikou Bay, China. The structures including the absolute configurations of the new compounds were unambiguously elucidated by spectroscopic data and ECD spectra analysis along with quantum ECD calculations. Among them, compound 1 represents the first example of an unusual trichlorinated meroterpenoid with an unique dichlorine functionality. Compounds 1 and 4-6 displayed inhibitory activity of protein tyrosine phosphatase 1B (PTP1B) with IC50 values of 71.6, 62.5, 63.1, and 39.6MUM, respectively, and showed no apparent activity against three tumor cell lines (A549, HepG2, and Hela) and human umbilical vein endothelial cells (HUVEC) at 10MUM. PMID- 28807716 TI - Iritectol G, a novel iridal-type triterpenoid from Iris tectorum displays anti epileptic activity in vitro through inhibition of sodium channels. AB - Iritectol G, a novel iridal-type triterpenoid containing an uncommon tetrahydrofuran moiety, was isolated from the rhizomes of Iris tectorum. The structure was elucidated by comprehensive spectroscopic analysis. Iritectol G inhibited spontaneous and 4-aminopyridine-evoked calcium oscillations in primary cultured neocortical neurons with IC50 values of 8.2MUM and 12.5MUM, respectively. Further electrophysiological study demonstrated that iritectol G preferred to interact with inactivated state of voltage-gated sodium channel with an IC50 value of 7.0MUM. These data demonstrated that iritectol G was a novel sodium channel inhibitor. PMID- 28807718 TI - Autonomic regulation of systemic inflammation in humans: A multi-center, blinded observational cohort study. AB - OBJECTIVE: Experimental animal models demonstrate that autonomic activity regulates systemic inflammation. By contrast, human studies are limited in number and exclusively use heart rate variability (HRV) as an index of cardiac autonomic regulation. HRV measures are primarily dependent on, and need to be corrected for, heart rate. Thus, independent autonomic measures are required to confirm HRV based findings. Here, the authors sought to replicate the findings of preceding HRV-based studies by using HRV-independent, exercise-evoked sympathetic and parasympathetic measures of cardiac autonomic regulation to examine the relationship between autonomic function and systemic inflammation. METHODS: Sympathetic function was assessed by measuring heart rate changes during unloaded pedaling prior to onset of exercise, divided into quartiles; an anticipatory heart rate (AHRR) rise during this period is evoked by mental stress in many individuals. Parasympathetic function was assessed by heart rate recovery (HRR) 60s after finishing cardiopulmonary exercise testing, divided into quartiles. Parasympathetic dysfunction was defined by delayed heart rate recovery (HRR) <=12.beats.min-1, a threshold value associated with higher cardiovascular morbidity/mortality in the general population. Systemic inflammation was primarily assessed by neutrophil-lymphocyte ratio (NLR), where a ratio >4 is prognostic across several inflammatory diseases and correlates strongly with elevated plasma levels of pro-inflammatory cytokines. High-sensitivity C-reactive protein (hsCRP) was also measured. RESULTS: In 1624 subjects (65+/-14y; 67.9% male), lower HRR (impaired vagal activity) was associated with progressively higher NLR (p=0.004 for trend across quartiles). Delayed HRR, recorded in 646/1624 (39.6%) subjects, was associated with neutrophil-lymphocyte ratio >4 (relative risk: 1.43 (95%CI: 1.18-1.74); P=0.0003). Similar results were found for hsCRP (p=0.045). By contrast, AHRR was not associated with NLR (relative risk: 1.24 (95%CI: 0.94-1.65); P=0.14). CONCLUSIONS: Delayed HRR, a robust measure of parasympathetic dysfunction, is independently associated with leukocyte ratios indicative of systemic inflammation. These results further support a role for parasympathetic modulation of systemic inflammation in humans. PMID- 28807719 TI - Maternal hypothyroidism: An overview of current experimental models. AB - Maternal hypothyroidism (MH) is the most common cause of transient congenital hypothyroidism. Different animal models are used for assessing developmental effects of MH in offspring. The severity and status of hypothyroidism in animal models must be a reflection of the actual conditions in humans. To obtain comparable results with different clinical conditions, which lead to MH in humans, several factors have been suggested for researchers to consider before designing the experimental models. Regarding development of fetal body systems during pregnancy, interference at different times provides different results and the appropriate time for induction of hypothyroidism should be selected based on accurate time of development of the system under assessment. Other factors that should be taken into consideration include, physiological and biochemical differences between humans and other species, thyroid hormone-independent effects of anti-thyroid drugs, circadian rhythms in TSH secretion, sex differences, physical and psychological stress. This review addresses essential guidelines for selecting and managing the optimal animal model for MH as well as discussing the pros and cons of currently used models. PMID- 28807720 TI - Comparison of the therapeutic effects of sildenafil citrate, heparin and neuropeptides in a rat model of acetic acid-induced gastric ulcer. AB - AIMS: The purpose of our investigative work has been to determine whether there can be therapeutic roles in the administration of sildenafil citrate, heparin and several neuropeptides on an animal model where gastric ulcers were induced with acetic acid, and to compare their efficacy. MATERIALS AND METHODS: The animals were divided into 13 groups, with 4 animals in each. Gastric ulcers was induced in the animals of 12 groups with one untreated group being left as the control (Group I - control; given normal saline (NS)). The other groups were: Group II (ulcer+NS); Group III (5mg/kg sildenafil citrate, low dose); Group IV (10mg/kg sildenafil citrate, high dose); Group V (0.6mg/kg heparin, low dose); Group VI (6mg/kg heparin, high dose); Group VII (20nmol/kg des-acyl ghrelin); Group VIII (40nmol/kg des-acyl ghrelin); Group IX (4nmol/kg acyl ghrelin); Group X (8nmol/kg acly ghrelin); Group XI (20pmol/kg Nesfatin-1); Group XII (15nmol/kg Obestatin) and Group XIII (5nmol/kg Neuropeptide Y). Gastric neuropeptide expression was measured using an immunohistochemical method, and the amount in circulation was detected using ELISA. To compare with no treatment, the controls and other treatment groups, we recorded loss of the surface epithelium of the stomach, erosion, bleeding and inflammatory cell infiltration in the upper halves of the gastric glands. KEY FINDINGS: The muscularis and the layers beneath it were, however, apparently normal. The gastric mucosa healed with little or no inflammation when sildenafil citrate, low dose heparin, ghrelin, NUCB2/Nesfatin 1, obestatin, Neuropeptide Y were administered. SIGNIFICANCE: Overall the data indicate that low dose heparin, and especially sildenafil citrate and neuropeptides, can be used clinically as an alternative approach in the treatment of the gastric ulcer. PMID- 28807721 TI - Selenopheno quinolinones and coumarins promote cancer cell apoptosis by ROS depletion and caspase-7 activation. AB - AIM: This study was designed to investigate the mechanism underlying cancer cell apoptosis caused by selenophenoquinolinones and coumarins. MATERIALS AND METHODS: Twelve derivatives were studied according to their ability to suppress the proliferation of cancer cells in vitro (i.e., HepG2, MH-22A, MCF-7), induce cell apoptosis, modulate cellular antioxidant enzyme system activities (i.e., SOD, GPx, TrxR), influence the level of ROS, and modulate caspase activity. RESULTS: A plausible mechanism of apoptosis is presented. The lack of change in the activity of caspase-8 demonstrates that these compounds affect the intrinsic rather than the extrinsic pathway; moreover, the absence of caspase-9 activation suggests that the studied compounds are involved in the intrinsic pathway of apoptosis in a non-canonical manner. Provisionally, the increase in Smac/Diablo released from the mitochondria removes the inhibitory effect and activates caspase-7, leading to apoptosis. Additionally, the activation of caspase-1 activates effector caspase-7, thereby increasing the amount of cytochrome c and Smac/Diablo released from the mitochondria and ultimately leading to apoptosis. CONCLUSION: This present study provides scientific evidence that selenopheno quinolinones and coumarins promote cancer cell apoptosis by ROS depletion and caspase-7 activation in malignant cells. PMID- 28807722 TI - Coronary microvascular dysfunction is not associated with a history of reproductive risk factors in women with angina pectoris-An iPOWER substudy. AB - BACKGROUND: Reproductive risk factors such as preeclampsia and recurrent miscarriages have been associated with adverse cardiovascular (CV) events. Underlying coronary microvascular dysfunction (CMD) may be a common denominator. PURPOSE: We investigated whether a history of reproductive risk factors was associated with CMD in women with angina pectoris and no obstructive coronary artery disease (CAD). METHODS: Participants from the iPOWER study, including women with angina pectoris and no obstructive CAD (<50% stenosis), were invited to complete an electronic survey regarding reproductive risk factors: recurrent miscarriages, gestational diabetes, preeclampsia, rhesus immunity, polycystic ovary syndrome and menopausal status as well as migraine and Raynaud phenomenon. CMD was assessed by transthoracic Doppler echocardiography with measurement of coronary flow velocity reserve (CFVR) during high-dose dipyridamole infusion, and analyzed in three categories with cut-off points at 2.0 and 2.5. Associations between CFVR and a history of reproductive risk factors were examined by age adjusted trend test. RESULTS: The questionnaire was completed by 613 women (73% of those invited), of whom 550 had a successful CFVR measurement. There was no significant difference in baseline characteristics between participants and non participants. Median (interquartile range (IQR)) age was 62.8 (54.8; 68.7) years, median (IQR) BMI 26.2 (23.2; 29.8) kg/m2, and 81.5% were postmenopausal. We did not find any significant associations between any of the reproductive risk factors, Raynaud's phenomenon or migraine and CFVR. CONCLUSION: The lack of association between coronary microvascular function and a history of reproductive risk factors, migraine and Raynaud's phenomenon suggests that a common vascular pathophysiological mechanism underlying these conditions is unlikely. PMID- 28807723 TI - Identifying consistent disease subnetworks using DNet. AB - It is critical to identify disease-specific subnetworks from the vastly available genome-wide gene expression data for elucidating how genes perform high-level biological functions together. Various algorithms have been developed for disease gene identification. However, the topological structure of the disease networks (or even the fraction of the networks) has been left largely unexplored. In this article, we present DNet, a method for the identification of significant disease subnetworks by integrating both the network structure and gene expression information. Our work will lead to the identification of missing key disease genes, which are be highly expressed in a disease-specific gene expression dataset. The experimental evaluation of our method on both the Leukemia and the Duchenne Muscular Dystrophy gene expression datasets show that DNet performs better than the existing state-of-the-art methods. In addition, literature supports were found for the discovered disease subnetworks in a case study. PMID- 28807724 TI - The versatile functions of LRR-only proteins in mollusk Chlamys farreri. AB - Leucine-rich repeat (LRR)-only proteins are involved in the innate immune responses as they mediate protein-ligand interactions. In the present study, three novel LRR-only proteins, CfLRRop-4, CfLRRop-5 and CfLRRop-6, were identified and characterized from Zhikong scallop Chlamys farreri. They all contained LRR motifs with consensus signature sequences of LxxLxLxxNxL or LxxLxLxxCxxL. All the mRNA transcripts of three CfLRRops were high abundant in hepatopancreas, gills and gonads, and their mRNA transcripts in hemocytes could respond to the stimulations of different microbes, including Vibrio anguillarum, Micrococcus luteus and Pichia pastoris. These three CfLRRops exhibited similar ligand binding and recognition characteristics as Toll-like receptors (TLRs) and NOD-like receptors (NLRs). The immune effectors, including tumor necrosis factor alpha, superoxide dismutase, catalase and lysozyme, varied significantly after the scallops were stimulated by recombinant LRR-only proteins. All these results indicated that LRR-only proteins are functionally differentiated and exhibit different immunomodulation activities on various downstream immune effectors. PMID- 28807717 TI - Myofibroblast transdifferentiation: The dark force in ocular wound healing and fibrosis. AB - Wound healing is one of the most complex biological processes to occur in life. Repair of tissue following injury involves dynamic interactions between multiple cell types, growth factors, inflammatory mediators and components of the extracellular matrix (ECM). Aberrant and uncontrolled wound healing leads to a non-functional mass of fibrotic tissue. In the eye, fibrotic disease disrupts the normally transparent ocular tissues resulting in irreversible loss of vision. A common feature in fibrotic eye disease is the transdifferentiation of cells into myofibroblasts that can occur through a process known as epithelial-mesenchymal transition (EMT). Myofibroblasts rapidly produce excessive amounts of ECM and exert tractional forces across the ECM, resulting in the distortion of tissue architecture. Transforming growth factor-beta (TGFbeta) plays a major role in myofibroblast transdifferentiation and has been implicated in numerous fibrotic eye diseases including corneal opacification, pterygium, anterior subcapsular cataract, posterior capsular opacification, proliferative vitreoretinopathy, fibrovascular membrane formation associated with proliferative diabetic retinopathy, submacular fibrosis, glaucoma and orbital fibrosis. This review serves to introduce the pathological functions of the myofibroblast in fibrotic eye disease. We also highlight recent developments in elucidating the multiple signaling pathways involved in fibrogenesis that may be exploited in the development of novel anti-fibrotic therapies to reduce ocular morbidity due to scarring. PMID- 28807725 TI - The RNF146 E3 ubiquitin ligase is required for the control of Wnt signaling and body pattern formation in Xenopus. AB - The RING finger protein Rnf146 encodes an E3 ubiquitin ligase capable of targeting poly-ADP-ribosylated substrates for proteasomal degradation. Rnf146 has been identified as a critical regulator of Axin1 and thus of Wnt/beta-catenin signaling. However its physiological significance in vertebrate embryonic development remains to be demonstrated. In this study, we take advantages of early Xenopus embryos to demonstrate that Rnf146 is essential for embryonic pattern formation. Depletion of zygotic Rnf146 using a translation blocking morpholino oligo (MO) results in anteriorized development and increased expression the anterior marker gene Otx2, consistent the notion that Rnf146 is a positive regulator of Wnt/beta-catenin signaling through negatively regulating Axin1 expression. This notion is further supported by examination of the role of maternal Rnf146 in the context of Spemann organizer formation and dorsal axis development. Depletion of maternal Rnf146 using an antisense oligodeoxynucleic acid (ODN) leads to ventralized development and diminished expression of organizer genes. Together, we have provided evidence for the first time that Rnf146 is a critical regulator of embryonic pattern formation in vertebrates. PMID- 28807726 TI - The value of venous blood gas analysis in the diagnosis of diabetic ketoacidosis. AB - BACKGROUND & AIM: Newer blood gas analyzers have the ability to report electrolyte values and glucose in addition to pH, so this diagnostic process could be condensed in diagnosing diabetic ketoacidosis (DKA). We aimed to assess the accuracy of the venous blood gas (VBG) analysis with electrolytes for diagnosing DKA. METHODS: This study prospectively identified a convenience sample of (60 patients) presented with DKA and tested their VBG and serum electrolytes. The diagnosis of DKA was made according to American Diabetes Association criteria. Serum chemistry electrolyte values were considered to be the criterion standard. Sensitivity and specificity of VBG electrolytes results were compared against this standard. In addition, correlation coefficients for individual electrolytes between VBG electrolytes and laboratory chemistry electrolytes were calculated. RESULTS: Paired VBG and serum chemistry panels were available for 60 patients, only 49 patients were included, In this study; 20% of cases were newly diagnosed diabetes mellitus. The total number of diabetic ketoacidosis was 14 patients (28.5%). The sensitivity and specificity of the VBG and electrolytes for diagnosing DKA was 92.9% (95% confidence interval [CI]=89% to 99%) and 97.1% (95% CI=92% to 100%), respectively. Correlation coefficients between VBG and serum chemistry were 0.91, 0.47, 0.61, 0.65, and 0.58 for blood sugar, sodium, potassium, chloride, and creatinine respectively. CONCLUSIONS: Findings of this study offer preliminary support for the possibility of using VBG sample rather than VBG sample and serum chemistry electrolytes together to rule out diabetic ketoacidosis. PMID- 28807727 TI - Association between PARK16 and Parkinson's disease: A meta-analysis. AB - Recent years, several case-control studies reported that two polymorphisms (rs947211 and 1572913) within the PARK16 locus were associated with the Parkinson's disease (PD). However, the results were still controversial. Herein, we conducted a comprehensive meta-analysis to estimate the associations between two polymorphisms and PD. Seven databases (PubMed, Google Scholar, EMBASE, Web of Science, CNKI (China National Knowledge Infrastructure), VIP and Wanfang) were searched to identify the eligible studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the associations of two polymorphisms with PD susceptibility. Totally, 15 studies with 6637 cases and 6774 controls were included in our meta-analysis. The results showed that rs947211 variants were associated with a decreased risk of PD in overall population. Stratified analysis found that rs947211 variants were associated with a significantly decreased risk of PD in Northeast Asian population, but a slightly decreased risk of PD in Southeast Asian and Caucasian population. With regard to rs1572913 polymorphism, the results suggested that rs1572913 variants contribute to decrease the risk of PD. Therefore, our meta-analysis suggested that rs947211 variants (A allele, AG and GG genotypes) may decrease the risk of PD in overall population, particularly in Northeast Asian population; and T allele, TC and TT genotypes of rs1572913 variants contributed to decrease the risk of PD. PMID- 28807728 TI - Vestibulo-ocular reflex abnormality in Parkinson's disease detected by video head impulse test. AB - BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disease characterized by dopaminergic neuronal loss. The underlying cause of PD is unknown. OBJECTIVE: To assess the clinical relevance of vestibular-ocular reflex (VOR) gain in patients with PD, especially those in the early stages. METHODS: Sixty-three PD patients and 56 control healthy individuals were enrolled in this study between Mar 2015 and Aug 2015. VOR gains were determined by video head impulse test (vHIT) device. Statistical analysis was performed to assess the difference in VOR gains between PD patients and normal people. The relationship of VOR gain with age, duration and severity of disease was also assessed. RESULTS: In the control group, average VOR gain was 0.98+/-0.09 on the left side and 0.99+/-0.16 on the right side. No statistically significant difference was observed between the two sides in the control group (P>0.05). In the PD group, average VOR gain was 1.20+/-0.22 on the left side and 1.23+/-0.23 on the right side. No statistically significant difference was observed between the two sides in the PD group (P>0.05). There was a significant difference in VOR gain between the PD (both in early and mid-late stages) and the control group (P<0.05). A weak correlation was observed between VOR gain and the motor Unified Parkinson Disease Rating Scale score. No correlation of VOR gain with age, duration of disease or the Hoehn and Yahr Scale score was observed. VOR gains in PD patients were found to be higher than normal, especially in the early stages of the disease. CONCLUSION: vHIT is a potential tool to determine the VOR gain in PD patients and may help detect PD at an early stage. PMID- 28807729 TI - CpG demethylation in the neurotoxicity of 1-methyl-4-phenylpyridinium might mediate transcriptional up-regulation of alpha-synuclein in SH-SY5Y cells. AB - The accumulation of alpha-synuclein is the primary pathological hallmark of Parkinson's disease (PD). In PD patients, CpG demethylation of intron-1 has been reported to be associated with alpha-synuclein up-regulation. Environmental factor, for example neurotoxin, is a major etiological risk factor in PD pathogenesis. However, the role of CpG methylation in neurotoxin-induced PD has not been addressed completely yet. To explore CpG methylation associating with alpha-synuclein transcription and its underlying mechanisms in the neurotoxin induced PD pathology, human neuroblastoma SH-SY5Y cells were treated with neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP+). Results showed that MPP+ induced demethylation of the whole length of the CpG island around SNCA promoter, and both 6-OHDA and MPP+ resulted in up-regulation of SNCA transcription. The CpG demethylation around promoter resulted in up regulation of SNCA transcriptional activity. In addition, 6-OHDA and MPP+ induced the reduced levels of DNA methyltransferase (DNMT) 3a and DNMT3b but not DNMT1. These data suggested that CpG demethylation was induced by MPP+ and might mediate up-regulation of SNCA transcription in neurotoxin-induced PD. And down-regulation of both DNMT3a and DNMT3b, but not DNMT1, might contribute to CpG demethylation of the SNCA promoter. PMID- 28807730 TI - Development of a dual reporter screening assay for distinguishing the inhibition of HIV Tat-mediated transcription from off-target effects. AB - Human immunodeficiency virus (HIV) encodes a transcription trans-activator (Tat) with an essential role in the transcriptional elongation of viral RNA based on the viral promoter long terminal repeat (LTR). Tat-mediated transcription is conserved and can be distinguished from host transcription, so it is a therapeutic target for combating HIV replication. Traditional screening assays for Tat-mediated transcriptional inhibitors are based on the biochemical properties of Tat and transactivation-responsive RNA. We developed an inducible system based on two lentiviral expression cassettes for doxycycline (Dox) inducible Tat and Renilla luciferase (R-Luc) using TZM-bl cells harboring LTR driven firefly luciferase (F-Luc). The cells simultaneously expressed both Tat induced F-Luc and R-Luc, so it was possible to recognize off-target effects in the presence of Dox. The system was validated with known inhibitors: CYC202 obtained high sensitivity and specificity, whereas 6Bio and DRB had off-target effects. The MTT-based cytotoxicity test indicated the resistance of the system even at concentrations with off-target effects. The specificity of the system was confirmed using antiretroviral drugs. Our dual reporter system can simply detect Tat inhibitory effects, as well as precisely discriminate between the inhibitory and off-target effects of inhibitors, and may be useful for the development of a therapeutic anti-HIV drug. PMID- 28807731 TI - Time-resolved generation of membrane potential by ba3 cytochrome c oxidase from Thermus thermophilus coupled to single electron injection into the O and OH states. AB - Two electrogenic phases with characteristic times of ~14MUs and ~290MUs are resolved in the kinetics of membrane potential generation coupled to single electron reduction of the oxidized "relaxed" O state of ba3 oxidase from T. thermophilus (O->E transition). The rapid phase reflects electron redistribution between CuA and heme b. The slow phase includes electron redistribution from both CuA and heme b to heme a3, and electrogenic proton transfer coupled to reduction of heme a3. The distance of proton translocation corresponds to uptake of a proton from the inner water phase into the binuclear center where heme a3 is reduced, but there is no proton pumping and no reduction of CuB. Single-electron reduction of the oxidized "unrelaxed" state (OH->EH transition) is accompanied by electrogenic reduction of the heme b/heme a3 pair by CuA in a "fast" phase (~22MUs) and transfer of protons in "middle" and "slow" electrogenic phases (~0.185ms and ~0.78ms) coupled to electron redistribution from the heme b/heme a3 pair to the CuB site. The "middle" and "slow" electrogenic phases seem to be associated with transfer of protons to the proton-loading site (PLS) of the proton pump, but when all injected electrons reach CuB the electronic charge appears to be compensated by back-leakage of the protons from the PLS into the binuclear site. Thus proton pumping occurs only to the extent of ~0.1 H+/e-, probably due to the formed membrane potential in the experiment. PMID- 28807733 TI - Early Trabeculotomy Ab Externo in Treatment of Sturge-Weber Syndrome. AB - PURPOSE: To evaluate the intermediate-term efficacy and safety of trabeculotomy in infant Sturge-Weber syndrome (SWS). DESIGN: Retrospective cohort study. METHODS: All SWS-induced glaucoma patients less than 12 months of age who underwent trabeculotomy at our Ophthalmology Department from August 2011 to March 2017 were reviewed. Baseline demographics, intraocular pressure (IOP), cup-to disc ratio (C/D), and cornea diameters were noted before surgery. The IOP, success probabilities, and medication usage were recorded during follow-up until the last visit. RESULTS: Overall, 34 eyes (32 patients) were included, with a median surgery age of 3 months and a median follow-up time of 15.5 months. The mean preoperative IOP, asymmetry between 2 eyes, cornea diameter, and median C/D were 21.5 +/- 6.6 mm Hg, 10.1 +/- 4.9 mm Hg, 12.6 +/- 0.7 mm, and 0.65 (interquartile range [IQR]: 0.55, 0.80), respectively. The IOP was significantly reduced from the preoperative baseline at 1 week, 3 months, 6 months, 1 year, and 2 years after the surgery (P < .05). At the last follow-up, the cumulative proportions of overall and complete success were 86.6% and 66.0%, respectively. Complications included a transient shallow anterior chamber. Thirty of the 34 eyes had intraoperative hyphema, 27 of which lasted less than 3 days. No other complications were noted during the follow-up. CONCLUSIONS: Compared to previous studies with a later diagnosis of glaucoma in SWS patients, better outcomes were achieved with an early diagnosis of glaucoma in SWS patients. Early trabeculotomy ab externo was safe and led to good intermediate-term surgical outcomes for early onset glaucoma in SWS patients. Higher preoperative IOP and corneal edema were associated with a greater risk of surgery failure. PMID- 28807734 TI - MicroRNAs, promising biomarkers in the diagnosis of Xp11 translocation RCC. PMID- 28807732 TI - Diagnostic Capability of Peripapillary Three-dimensional Retinal Nerve Fiber Layer Volume for Glaucoma Using Optical Coherence Tomography Volume Scans. AB - PURPOSE: To determine the diagnostic capability of peripapillary 3-dimensional (3D) retinal nerve fiber layer (RNFL) volume measurements from spectral-domain optical coherence tomography (OCT) volume scans for open-angle glaucoma (OAG). DESIGN: Assessment of diagnostic accuracy. METHODS: Setting: Academic clinical setting. STUDY POPULATION: Total of 180 patients (113 OAG and 67 normal subjects). OBSERVATION PROCEDURES: One eye per subject was included. Peripapillary 3D RNFL volumes were calculated for global, quadrant, and sector regions, using 4 different-size annuli. Peripapillary 2D RNFL thickness circle scans were also obtained. MAIN OUTCOME MEASURES: Area under the receiver operating characteristic curve (AUROC) values, sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios. RESULTS: Among all 2D and 3D RNFL parameters, best diagnostic capability was associated with inferior quadrant 3D RNFL volume of the smallest annulus (AUROC value 0.977). Otherwise, global 3D RNFL volume AUROC values were comparable to global 2D RNFL thickness AUROC values for all 4 annulus sizes (P values: .0593 to .6866). When comparing the 4 annulus sizes for global RNFL volume, the smallest annulus had the best AUROC values (P values: .0317 to .0380). The smallest-size annulus may have the best diagnostic potential, partly owing to having no areas excluded for being larger than the 6 * 6 mm2 scanned region. CONCLUSION: Peripapillary 3D RNFL volume showed excellent diagnostic performance for detecting glaucoma. Peripapillary 3D RNFL volume parameters have the same or better diagnostic capability compared to peripapillary 2D RNFL thickness measurements, although differences were not statistically significant. PMID- 28807735 TI - Effect of Parent-Daughter Communication about Sex on the Use of Less Effective Contraception among Women from Ages 15-24 Years in France. AB - STUDY OBJECTIVE: Most women begin sexual activity as teenagers but nearly 20% of women in France younger than 25 years rely on less effective contraceptive methods (condoms or methods such as withdrawal or periodic abstinence). We sought to analyze the association with less effective contraception among women aged 15 24 years in France and communication about sex and contraception with their parents. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: The analyses focused on 713 sexually active women who did not currently want a child, were using contraception, and were interviewed in 2010 in a national cross sectional probability survey (FEcondite CONtraception Dysfonctions sexuelles [FECOND]) when they were 15-24 years old. Associations between the use of less effective contraception, social and demographic characteristics, sexual activity, health characteristics, and communication with parents and friends about sexuality and contraception were tested with logistic regression models according to age group. RESULTS AND CONCLUSION: Less effective contraception (condoms, and barrier or natural methods) is used more often by younger women: 27.5% of 15- to 19-year-old women and 14.7% of 20- to 24-year-old women (P < .001). After adjustment for demographic characteristics and aspects of their sex lives (regularity and frequency of intercourse), women who reported difficulty discussing contraception and sex with their mothers at age 15 years were more likely than those with easier communication to use less effective contraception (for those 15-19 years, odds ratio = 1.97; 95% confidence interval, 0.94-4.10, and for those 20-24 years, odds ratio = 2.36; 95% confidence interval, 1.31 4.26). Difficulty in communicating with their parents, especially their mothers, about sex, is associated with young women's choice of less effective contraception. PMID- 28807737 TI - Serrated Colorectal Neoplasia: From Sideshow to Center Stage. PMID- 28807736 TI - Uterine Didelphys with Bilateral Cervical Agenesis in a 15-Year-Old Girl. AB - BACKGROUND: Isolated uterine didelphys requires no treatment in contrast to cervical agenesis, which requires a hysterectomy. Because of this, correct diagnosis of Mullerian anomalies is paramount for making recommendations for patient care. CASE: A 15-year-old girl presented to clinic with pelvic pain and primary amenorrhea. Uterine didelphys with bilateral cervical agenesis was diagnosed using imaging. Hysterectomy was recommended and diagnosis was confirmed at surgery and according to anatomic pathology. SUMMARY AND CONCLUSION: Our patient with uterine didelphys with bilateral cervical agenesis presented a diagnostic challenge, because, to our knowledge, it has never been reported before in the literature. Her pattern of anomalies had significant implications for future fertility. Radiology exam was vital to confirming this diagnosis in a young, virginal female patient. PMID- 28807738 TI - Observed benefit and safety of aflibercept in elderly patients with metastatic colorectal cancer: An age-based analysis from the randomized placebo-controlled phase III VELOUR trial. AB - OBJECTIVES: Aflibercept (ziv-aflibercept) significantly improves progression-free (PFS) and overall survival (OS) when added to 5-fluorouracil, leucovorin and irinotecan (FOLFIRI), compared with FOLFIRI alone, in patients with metastatic colorectal cancer previously treated with oxaliplatin-based therapy. This subset analysis of the VELOUR study investigates aflibercept plus FOLFIRI versus placebo plus FOLFIRI according to age. METHODS: Efficacy and safety were analyzed by treatment arm and age (>= or <65years). RESULTS: Overall, 443 patients were >=65years old (205 in aflibercept arm; 238 in placebo arm) and 783 were <65years old (407 in aflibercept arm; 376 in placebo arm). Median OS was 12.6 versus 11.3months (hazard ratio [HR]: 0.85; 95.34% CI 0.68-1.07) in patients >=65years old and 14.5 versus 12.5months (HR: 0.80; 95.34% CI 0.67-0.95) in those patients <65years old, for patients receiving FOLFIRI plus aflibercept or placebo, respectively. There was no interaction between treatment and age. Treatment emergent adverse events (AEs) were comparable for patients <65years and >=65years old. The incidence of grade 3/4 AEs was higher for patients >=65years old than for those <65years old in both the aflibercept (89.3% versus 80.5%) and placebo (67.4% versus 59.4%) arms. Interaction tests for grade 3/4 antiangiogenic agent related AEs suggested no heterogeneity between the older and younger patient populations (p>0.1). CONCLUSION: A limited but consistent benefit on both OS and PFS was associated with the addition of aflibercept to FOLFIRI compared with placebo in patients <65 and >=65years old, with a marked but manageable increase in the toxicity profile in older patients. TRIAL REGISTRATION: clinicaltrials.govNCT00561470. PMID- 28807741 TI - Importance of orthopedic research and the 32nd Annual Research Meeting of the Japanese Orthopaedic Association. PMID- 28807739 TI - Community-based participatory research to design a faith-enhanced diabetes prevention program: The Better Me Within randomized trial. AB - Reducing obesity positively impacts diabetes and cardiovascular risk; however, evidence-based lifestyle programs, such as the diabetes prevention program (DPP), show reduced effectiveness in African American (AA) women. In addition to an attenuated response to lifestyle programs, AA women also demonstrate high rates of obesity, diabetes, and cardiovascular disease. To address these disparities, enhancements to evidence-based lifestyle programs for AA women need to be developed and evaluated with culturally relevant and rigorous study designs. This study describes a community-based participatory research (CBPR) approach to design a novel faith-enhancement to the DPP for AA women. A long-standing CBPR partnership designed the faith-enhancement from focus group data (N=64 AA adults) integrating five components: a brief pastor led sermon, memory verse, in class or take-home faith activity, promises to remember, and scripture and prayer integrated into participant curriculum and facilitator materials. The faith components were specifically linked to weekly DPP learning objectives to strategically emphasize behavioral skills with religious principles. Using a CBPR approach, the Better Me Within trial was able to enroll 12 churches, screen 333 AA women, and randomize 221 (Mage=48.8+/-11.2; MBMI=36.7+/-8.4; 52% technical or high school) after collection of objective eligibility measures. A prospective, randomized, nested by church, design will be used to evaluate the faith-enhanced DPP as compared to a standard DPP on weight, diabetes and cardiovascular risk, over a 16-week intervention and 10-month follow up. This study will provide essential data to guide enhancements to evidence-based lifestyle programs for AA women who are at high risk for chronic disease. PMID- 28807740 TI - Outcomes of HIV-positive patients with cryptococcal meningitis in the Americas. AB - BACKGROUND: Cryptococcal meningitis (CM) is associated with substantial mortality in HIV-infected patients. Optimal timing of antiretroviral therapy (ART) in persons with CM represents a clinical challenge, and the burden of CM in Latin America has not been well described. Studies suggest that early ART initiation is associated with higher mortality, but data from the Americas are scarce. METHODS: HIV-infected adults in care between 1985-2014 at participating sites in the Latin America (the Caribbean, Central and South America network (CCASAnet)) and the Vanderbilt Comprehensive Care Clinic (VCCC) and who had CM were included. Survival probabilities were estimated. Risk of death when initiating ART within the first 2 weeks after CM diagnosis versus initiating between 2-8 weeks was assessed using dynamic marginal structural models adjusting for site, age, sex, year of CM, CD4 count, and route of HIV transmission. FINDINGS: 340 patients were included (Argentina 58, Brazil 138, Chile 28, Honduras 27, Mexico 34, VCCC 55) and 142 (42%) died during the observation period. Among 151 patients with CM prior to ART 56 (37%) patients died compared to 86 (45%) of 189 with CM after ART initiation (p=0.14). Patients diagnosed with CM after ART had a higher risk of death (p=0.03, log-rank test). The probability of survival was not statistically different between patients who started ART within 2 weeks of CM (7/24, 29%) vs. those initiating between 2-8 weeks (14/53, 26%) (p=0.96), potentially due to lack of power. INTERPRETATION: In this large Latin-American cohort, patients with CM had very high mortality rates, especially those diagnosed after ART initiation. This study reflects the overwhelming burden of CM in HIV-infected patients in Latin America. PMID- 28807742 TI - A cost-utility analysis of Dynesys dynamic stabilization versus instrumented fusion for the treatment of degenerative lumbar spine diseases. AB - BACKGROUND: Symptomatic chronic low back and leg pain resulting from lumbar spine degenerative disorders is highly prevalent in China, and for some patients, surgery is the final option for improvement. Several techniques for spinal non fusion have been introduced to reduce the side-effects of fusion methods and hasten postoperative recovery. In this study, the authors have evaluated the cost effectiveness of Dynesys posterior dynamic stabilization system (DY) compared with lumbar fusion techniques in the treatment of single-level degenerative lumbar spinal conditions. METHODS: A total of 221 patients undergoing single level elective primary surgery for degenerative lumbar pathology were included. 2 Year postoperative health outcomes of Visual Analogue Scale (VAS) for back and leg pain, Oswestry Disability Index (ODI), 36-Item Short Form Health Survey (SF 36) and EuroQol-5 Dimensions (EQ-5D) questionnaires were recorded. 2-Year back related medical resource use, missed work, and health-state values (Quality adjusted life-year [QALY]) were assessed. Cost-effectiveness was determined by the incremental cost per QALY gained. RESULTS: At each follow-up point, both cohorts were associated with significant improvements in VAS scores, ODI, SF-36 scores and EQ-5D QALY scores, which persisted at the 2-year evaluation. The 2 year total mean cost per patient were significantly lower for Dynesys system ($20,150) compared to fusion techniques ($25,581, $27,862 and $27,314, respectively) (P < 0.001). Using EQ-5D, the mean cumulative 2-year QALYs gained were statistically equivalent between the four groups (0.28, 0.27, 0.30 and 0.30 units, respectively) (P = 0.74). Results indicate that patients implanted with the DY system derive lower total costs and more utility, on average, than those treated with fusion. CONCLUSIONS: The Dynesys dynamic stabilization system is cost effective compared to instrumented lumbar fusion for treatment of single level degenerative lumbar disorders. It is not possible to state whether DY or lumbar fusion is more cost-effective after 2 years. PMID- 28807743 TI - Two decades of experience with laparoscopic varicocele repair in children: Standardizing the technique. AB - BACKGROUND: Controversy still exists about the indications and the gold standard approach for varicocele treatment in pediatric population. OBJECTIVE: The authors report their 23 years of experience in laparoscopic varicocele repair in the pediatric population. STUDY DESIGN: We retrospectively evaluated the data of 345 consecutive patients who underwent laparoscopic left varicocelectomy from January 1993 to December 2015. Average patient age was 12.5 years (range 8-17). Seven out of 345 patients (2%) had a recurrent varicocele, and five out of 345 patients (1.4%) had a varicocele on a single testis. In 335/345 patients (97.1%) we performed a Palomo procedure, and in 10/345 patients (2.9%) an artery-sparing Palomo procedure. After 2010, in 105/345 patients (30.4%) we performed a lymphatic sparing procedure using isosulfan blue injection preoperatively. RESULTS: All procedures were completed in laparoscopy (Figure), without conversions or intraoperative complications. The average operative time was 17 min (range 14-45) for the Palomo procedure and 26 min (range 18-50) for artery sparing Palomo. In 45/345 patients (13%) we performed additional procedures. We recorded 4/345 (1.3%) recurrences/persistences in patients undergoing Palomo, while we recorded 1/10 (10%) recurrence/persistence after artery-sparing Palomo. On 230 Palomo procedures performed in the pre-isosulfan blue era, we recorded 25 cases of hydrocele (10.8%), 13 of these were treated with transcrotal puncture and 12 required surgical operation. The last 105 patients undergoing isosulfan blue injection had no postoperative hydrocele. We also reported 10 other complications (I grade Clavien-Dindo) such as umbilical granuloma or instrumental problems. DISCUSSION: Analyzing the international literature of the last 25 years, most papers focused on the minimally invasive treatment of pediatric varicocele. There are several reasons to perform laparoscopic repair of pediatric varicocele. First of all, it is technically easy to perform, the average operative time is very short, and it has excellent outcome in regard to varicocele persistence/recurrence. In addition it has a very low complication rate, and in particular adopting the intradartoic/intratesticular isosulfan blue injection before surgery we recorded no postoperative hydrocele. CONCLUSION: On the basis of our 23 years of experience with varicocele repair, we clearly believe that laparoscopic Palomo lymphatic sparing varicocelectomy should be considered the standard of care for the treatment of pediatric patients with varicocele. Laparoscopic varicocelectomy is technically easy and quick to perform, painless, and scarless, with a recurrence rate of about 1%. The use of a preoperative injection of isosulfan blue completely eliminates postoperative hydrocele formation. PMID- 28807744 TI - Primary Stenting Is Not Necessary in Benign Central Venous Stenosis. AB - BACKGROUND: The aim of this study is to evaluate central venous stenosis (CVS) etiologies and presentation within a vascular surgery practice. We evaluated endovascular treatment modalities and the patency rates of our interventions. METHODS: Five-year retrospective review of endovascular intervention for CVS. Patient demographics, medical comorbidities, and variables were collected including etiology, indwelling device, previous upper extremity (UE) deep venous thrombosis, long-term UE indwelling device (defined as >30 days), malignancy status, hypercoagulable disorders, history of radiation or mediastinal fibrosis or masses, and anticoagulation and/or antiplatelet therapy. Follow-up variables included symptoms, imaging, and anticoagulation and/or antiplatelet utilization. Living patients without recent follow-up were contacted with a telephone survey regarding current symptoms. Patency was evaluated by imaging or clinically by recurrence of signs or symptoms through January 2016. RESULTS: A total of 61 patients underwent attempted endovascular CVS interventions from January 2007 to 2013. Forty-seven (83%) patients had successful interventions. There were 22 (36%) end-stage renal disease (ESRD) patients. The primary etiology in 79% of patients was benign CVS secondary to an indwelling device. Eighty-nine percent of the interventions were primary angioplasty (PTA). The overall primary patency rates at 6, 12, and 24 months were 49%, 34%, and 24%, respectively. Secondary patency rates at 6, 12, and 24 months were 97%, 93%, and 88%, respectively. There were no statistical differences in demographics or outcomes in patients treated successfully with PTA or those requiring stenting. There was no statistical difference in the patency rates between ESRD and non-ESRD patients. Previous interventions were not a predictor of loss of patency. CONCLUSIONS: Our study supported the rising trend of benign CVS predominantly secondary to indwelling devices. We demonstrated acceptable secondary patency with PTA alone. This study adds further support for a primary angioplasty strategy in treating benign CVS. The optimal endovascular treatment for benign CVS is still undefined. PMID- 28807746 TI - 20-HETE regulated PSMB5 expression via TGF-beta/Smad signaling pathway. AB - We previously found that 20-hydroxyeicosatetraeonic acid (20-HETE) showed an effect on proteasome activity in cytochrome P450 F2 (CYP4F2) transgenic mice. Proteasome subunit beta5 (PSMB5) is a primary subunit of the proteasome. In the current study, we examine whether 20-HETE has any affect on PSMB5. We found that PSMB5 was upregulated in the liver, but downregulated in the kidney of transgenic mice, when compared with wild-type mice. Luciferase reporter gene experiments and electrophoretic mobility shift assays (EMSA) suggested that Smad3 directly associated with the putative Smad binding element (SBE) of the Psmb5 promoter. Furthermore, the binding affinity was different between the liver and kidney, and can be regulated by 20-HETE. Compared to wild mice, both TGF-beta1 and Smad3 phosphorylation were increased in the liver but decreased in the kidney of transgenic mice. SB431542, an inhibitor of TGF-beta receptor I kinase activity, can reverse the changes induced in PSMB5 by 20-HETE in vitro. Taken together, our data demonstrated that 20-HETE upregulated the expression of PSMB5 by activating the TGF-beta/Smad signaling pathway in the liver, but downregulated the expression of PSMB5 by inhibiting the TGF-beta/Smad signaling pathway in the kidney of transgenic mice. PMID- 28807745 TI - Acute toxicity of functionalized single wall carbon nanotubes: A biochemical, histopathologic and proteomics approach. AB - Recently carbon nanotubes (CNTs) showed promising potentials in different biomedical applications but their safe use in humans and probable toxicities are still challenging. The aim of this study was to determine the acute toxicity of functionalized single walled carbon nanotubes (SWCNTs). In this project, PEGylated and Tween functionalized SWCNTs were prepared. BALB/c mice were randomly divided into nine groups, including PEGylated SWCNTs (75,150MUg/mouse) and PEG, Tween80 suspended SWCNTs, Tween 80 and a control group (intact mice). One or 7 days after intravenous injection, the mice were killed and serum and livers were collected. The oxidative stress markers, biochemical and histopathological changes were studied. Subsequently, proteomics approach was used to investigate the alterations of protein expression profiles in the liver. Results showed that there were not any significant differences in malondealdehyde (MDA), glutathione (GSH) levels and biochemical enzymes (ALT and AST) between groups, while the histopathological observations of livers showed some injuries. The results of proteomics analysis revealed indolethylamine N-Methyltransferase (INMT), glycine N-Methyltransferase (GNMT), selenium binding protein (Selenbp), thioredoxin peroxidase (TPx), TNF receptor associated protein 1(Trap1), peroxiredoxin-6 (Prdx6), electron transport flavoprotein (Etf-alpha), regucalcin (Rgn) and ATP5b proteins were differentially expressed in functionalized SWCNTs groups. Western blot analyses confirmed that the changes in Prdx6 were consistent with 2-DE gel analysis. In summary, acute toxicological study on two functionalized SWCNTs did not show any significant toxicity at selected doses. Proteomics analysis also showed that following exposure to functionalized SWCNTs, the expression of some proteins with antioxidant activity and detoxifying properties were increased in liver tissue. PMID- 28807747 TI - Pretreatment 3T multiparametric MRI staging predicts for biochemical failure in high-risk prostate cancer treated with combination high-dose-rate brachytherapy and external beam radiotherapy. AB - PURPOSE: To determine whether pretreatment 3T multiparametric MRI (mpMRI) staging impacts biochemical recurrence-free survival (BRFS) or distant metastasis-free survival (DMFS) for men with high-risk prostate cancer treated with combination high-dose-rate (HDR) brachytherapy and external beam radiation therapy (EBRT). MATERIALS AND METHODS: This institutional review board-approved retrospective study included a cohort of 37 men with high-risk prostate cancer treated with HDR brachytherapy and EBRT after 3T mpMRI. Kaplan-Meier analysis was used to evaluate whether mpMRI evidence of extracapsular extension or seminal vesicle invasion (SVI) resulted in differences in BRFS or DMFS. Pretreatment and treatment-related variables were evaluated for association with biochemical failure (Phoenix definition) and distant metastatic failure using univariate Cox regression analysis. RESULTS: The median prostate-specific antigen at diagnosis was 9 ng/mL (range 2-100). Biopsy Gleason score (bGS) was <=8 in 38% and nine in 62%. Clinical T-category was T1-T2 in 89%, T3a in 8%, and T3b in 3%. With a median followup of 30.6 months, actuarial 3-year BRFS and DMFS were 76% and 86%, respectively. Kaplan-Meier analysis revealed that mpMRI evidence of extracapsular extension or SVI resulted in significantly higher rates of both biochemical recurrence and distant failure. Using Cox regression analysis, only mpMRI evidence of SVI vs. no SVI predicted for biochemical failure (hazard ratio 13.98, p = 0.0055). CONCLUSIONS: For high-risk prostate cancer treated with combination HDR brachytherapy and EBRT, mpMRI evidence of SVI predicted for biochemical failure, whereas traditional pretreatment variables did not. Therefore, pretreatment 3T mpMRI appears useful for identifying men who may benefit from treatment intensification. PMID- 28807748 TI - Dosimetric analysis and preliminary clinical result of image-guided brachytherapy with or without hybrid technique for cervical cancer using VariSource titanium ring applicator with "Siriraj Ring Cap". AB - PURPOSE: Titanium ring cap applicator (VariSource) was applied in treating cervical cancer patients by using image-guided brachytherapy (IGBT). However, its sizes appeared to be relatively large for most of our patients. Thus, we have developed a specific applicator "Siriraj Ring Cap," which is slightly smaller and more suitable for our patients. This study was to evaluate effectiveness of this equipment. METHODS AND MATERIALS: Locally advanced cervical cancer patients were treated with external beam radiation therapy with or without concomitant chemotherapy. Siriraj Ring Cap was applied in all of the patients for at least one fraction. Dosimetric analysis was performed in each fraction of IGBT. Clinical outcomes of these patients were evaluated. RESULTS: Twenty-nine patients with 117 dosimetric planning were evaluated between January and December of 2014. Siriraj Ring Cap was fit to all patients in this study. By using this applicator, radiation doses to the targets (D90 high-risk clinical target volume and D90 intermediate-risk clinical target volume) were higher in each fraction. There were no statistically differences of radiation doses to the bladder, rectum, sigmoid colon, and small bowel. Within 2-year followup, 3 patients (10.3%) developed locoregional recurrence. Two-year disease-free survival and overall survival were 75.9% and 89.7%, respectively. According to RTOG/EORTC complication criteria, Grade 1, 2, and 3 gastrointestinal complications were developed in 2 (6.9%), 4 (13.8%), and 1 (3.4%) patients, respectively. For genitourinary complications, 3 patients (10.3%) and 1 patient (3.4%) had Grades 1 and 2, respectively. CONCLUSIONS: Siriraj Ring Cap is feasible for IGBT in cervical cancer patients with narrow vagina. Dosimetry and clinical outcomes were satisfactory by using our specific applicator. PMID- 28807749 TI - High-dose-rate interstitial brachytherapy boost in inoperable locally advanced tongue carcinoma. AB - PURPOSE: Locally advanced tongue carcinomas (LATCs) in inoperable lesions are managed with external beam radiation therapy (EBRT) and chemotherapy. In our institution, the boost to the gross tumor volume is delivered with high-dose-rate brachytherapy (HDR-BT) after EBRT. We review the outcome of these patients when HDR-BT is added as a boost. METHODS AND MATERIALS: From May 2000 to December 2014, a total of 24 patients with LATC, nonsurgical oral tongue, and base of tongue carcinomas were treated with EBRT and with interstitial plastic tubes for brachytherapy; median dose was 18-24 Gy in 6-8 fractions after 50-60 Gy of EBRT. Mean age was 60 years, 20 men and 4 women. The distribution by stages was 11 patients in Stage III and 13 patients in Stage IV. All cases but one received chemotherapy. RESULTS: With a median followup of 44 months, local control (LC) rate at 4 years was 80% for the entire group, 78% in Stage III, and 90% in Stage IV. The cause-specific survival was 68% at 4 years; the regional control was 76%. Four patients developed distant metastasis with disease free from distant metastasis of 77% at 4 years. The overall survival was 68% at 4 years. CONCLUSIONS: HDR-BT yields similar results to low dose rate in treatment of patients with LATC, with better results than those reported with exclusive EBRT. HDR-BT allows to increase the local dose, with good LC rates. In patients with large tumors requiring very mutilating surgery and patients who refuse surgery, EBRT with HDR-BT boost is a good option to increase the LC and cause-specific survival while keeping a better functional outcome. PMID- 28807750 TI - High resolution simultaneous imaging of intracranial and extracranial arterial wall with improved cerebrospinal fluid suppression. AB - PURPOSE: To develop a technique for three dimensional (3D) high resolution joint imaging of intracranial and extracranial arterial walls with improved cerebrospinal fluid (CSF) suppression and good blood suppression based on T1 weighted sampling perfection with application optimized contrast using different angle evolutions (T1w-SPACE) and to compare this technique (hereafter, iSPACE) with alternating with nutation for tailored excitation (DANTE) prepared SPACE sequence (DANTE-SPACE) for their CSF suppression performance around the mid cerebral arteries (MCA) and blood suppression at carotid arteries. MATERIALS AND METHODS: Eight volunteers and twelve patients were prospectively recruited in this institutional review board approved study. A custom designed 32-channel coil set covering the intracranial and extracranial arteries was used for signal reception. Imaging was performed in each subject using DANTE-SPACE and iSPACE. Signal-to-noise ratios (SNR) of the vessel walls at the MCA and carotid arteries, and contrast-to-noise ratios (CNR) between vessel wall and CSF at the MCA and between vessel wall and lumen at carotid arteries from the two sequences were compared. RESULTS: In volunteers, contrast between CSF and white matter (surrogate for vessel wall signal) at the M2 segments in iSPACE was 67.9% higher than in DANTE-SPACE. At the carotid region, the SNR of vessel wall in iSPACE was 11.6% higher than DANTE-SPACE while the CNR in iSPACE was 13% higher than DANTE SPACE. In patients, images with 0.6mm isotropic resolution were obtained in 7.5min. iSPACE showed 70.9% improvement in CNR between plaque and CSF at the M2 segments compared to DANTE-SPACE. CONCLUSION: Simultaneous extracranial and intracranial arterial wall imaging using iSPACE improved CSF suppression significantly at the M2 segment of MCA while blood suppression was comparable to DANTE-SPACE. The technique achieved 3D images with 0.6mm isotropic spatial resolution and took 7.5min using a custom made coil set. Using this technique, intracranial plaque visualization was improved with no observable image SNR degradation. PMID- 28807751 TI - A novel PMCA3 mutation in an ataxic patient with hypomorphic phosphomannomutase 2 (PMM2) heterozygote mutations: Biochemical characterization of the pump defect. AB - The neuron-restricted isoform 3 of the plasma membrane Ca2+ ATPase plays a major role in the regulation of Ca2+ homeostasis in the brain, where the precise control of Ca2+ signaling is a necessity. Several function-affecting genetic mutations in the PMCA3 pump associated to X-linked congenital cerebellar ataxias have indeed been described. Interestingly, the presence of co-occurring mutations in additional genes suggest their synergistic action in generating the neurological phenotype as digenic modulators of the role of PMCA3 in the pathologies. Here we report a novel PMCA3 mutation (G733R substitution) in the catalytic P-domain of the pump in a patient affected by non-progressive ataxia, muscular hypotonia, dysmetria and nystagmus. Biochemical studies of the pump have revealed impaired ability to control cellular Ca2+ handling both under basal and under stimulated conditions. A combined analysis by homology modeling and molecular dynamics have revealed a role for the mutated residue in maintaining the correct 3D configuration of the local structure of the pump. Mutation analysis in the patient has revealed two additional function-impairing compound heterozygous missense mutations (R123Q and G214S substitution) in phosphomannomutase 2 (PMM2), a protein that catalyzes the isomerization of mannose 6-phosphate to mannose 1-phosphate. These mutations are known to be associated with Type Ia congenital disorder of glycosylation (PMM2-CDG), the most common group of disorders of N-glycosylation. The findings highlight the association of PMCA3 mutations to cerebellar ataxia and strengthen the possibility that PMCAs act as digenic modulators in Ca2+-linked pathologies. PMID- 28807752 TI - Vasectomy Practice Patterns Among Family Medicine Physicians and Compliance With the American Urological Association 2012 Vasectomy Guidelines. AB - OBJECTIVE: To survey urologists and family medicine physicians (FMPs) within a single institution to determine current vasectomy practice patterns and determine compliance with 2012 American Urological Association (AUA) vasectomy guidelines. METHODS: In 2016, a single-institution survey was conducted to understand the vasectomy practice patterns among urologists and nonurologists. The survey questions and 3 clinical scenarios were designed based on the 2012 AUA vasectomy guidelines. Results of the survey were compiled between urologists and nonurologists and then compared with the guideline recommendations. RESULTS: A total of 23 FMPs and 6 urologists responded. Fewer prevasectomy counseling topics were discussed by FMPs compared with urologists. A variety of vasectomy techniques were used among FMPs. Vas deferens segments were more likely to be sent for histology by FMPs than urologists (65% vs 17%, P = .02). FMPs were more likely to send postvasectomy semen analyses earlier than urologists (P = .02) and more likely to send multiple postvasectomy semen analyses (P = .006) before forgoing alternative contraceptive methods. Regarding the clinical scenario questions, FMPs were more likely to answer discordantly from guideline recommendations compared with urologists. CONCLUSION: Significant vasectomy practice pattern heterogeneity still exists among nonurologists surveyed within our institution. The 2012 AUA vasectomy guidelines have yet to be broadly implemented within nonurology practices. Further studies are warranted to investigate national trends in nonurologist vasectomy practice patterns and determine how the guidelines can be better implemented in nonurologic practices. PMID- 28807754 TI - Transgenerational effects of early environmental insults on aging and disease incidence. AB - Adverse early life experiences are major influences on developmental trajectories with potentially life-long consequences. Prenatal or early postnatal exposure to stress, undernutrition or environmental toxicants may reprogram brain development and increase risk of behavioural and neurological disorders later in life. Not only experience within a single lifetime, but also ancestral experience affects health trajectories and chances of successful aging. The central mechanism in transgenerational programming of a disease may be the formation of epigenetic memory. This review explores transgenerational effects of early adverse experience on health and disease incidence in older age. First, we address mechanisms of developmental and transgenerational programming of disease and inheritance. Second, we discuss experimental and clinical findings linking early environmental determinants to adverse aging trajectories in association with possible parental contributions and sex-specific effects. Third, we outline the main mechanisms of age-related functional decline and suggest potential interventions to reverse negative effects of transgenerational programming. Thus, strategies that support healthy development and successful aging should take into account the potential influences of transgenerational inheritance. PMID- 28807755 TI - Antimicrobial susceptibility of pathogens in acute uncomplicated cystitis cases in the urology department of a community hospital in Japan: Comparison with treatment outcome and hospital-wide antibiogram. AB - We hypothesized that cases of uncomplicated cystitis treated in a Urology Department would display higher antimicrobial susceptibility than those reported by the hospital antibiogram. This would suggest narrow spectrum antibiotics could still be an effective treatment for uncomplicated cystitis despite this era of antimicrobial resistance. The objective of this study was thus to evaluate the rates of antimicrobial susceptibility of isolates cultured from uncomplicated cystitis cases that presented to the Urology Department of a community hospital in Japan. We evaluated the efficacy of cefaclor, a narrow spectrum antibiotic, for uncomplicated cystitis. We further compared the rates of antimicrobial susceptibility of isolates from uncomplicated cystitis cases to those reported in a hospital-wide antibiogram. A retrospective chart review was performed of patients diagnosed with uncomplicated cystitis in the Urology Department. The patients were mainly treated orally by cefaclor at 750 mg/day for seven days. Significantly greater susceptibilities to cefazolin (87.0% vs 65.7%), trimethoprim-sulfamethoxazole (89.4% vs 79.1%) and levofloxacin (84.6% vs 66.9%) were observed in a cystitis antibiogram for Escherichia coli compared with a hospital-wide antibiogram. The clinical efficacy of cefaclor for acute cystitis was also demonstrated. The greater susceptibility of Escherichia coli to antimicrobials observed in this study supports the hypothesis that antimicrobial susceptibility rates in uncomplicated cystitis cases that present to the Urology Department would be greater than those reported in the hospital antibiogram. Therefore, uncomplicated acute cystitis can be treated by narrow spectrum antibiotics such as cefaclor even in this ''antimicrobial resistance era''. PMID- 28807756 TI - First time identification of Acanthamoeba genotypes in the cornea samples of wild birds; Is Acanthamoeba keratitis making the predatory birds a target? AB - Acanthamoeba is a free-living amoeba which can be isolated from environment and among others well known as an opportunist protozoan parasite causing infections in humans and animals. Eyes are extremely important for the wild birds and losing sight ability due to Acanthamoeba can be dangerous. The studies on Acanthamoeba infection in wild birds is very few in world and Turkey therefore we aimed to screen deceased wild birds found in Izmir and Manisa provinces located in western Turkey using PCR and non-nutrition agar (NNA) plate method. Cornea samples were obtained from 18 deceased wild birds. During the external examination, signs of keratitis were observed in two Eurasian sparrowhawks (Accipiter nisus). All of the corneal samples were analyzed by two PCR methods and NNA plate. According to results, the Acanthamoeba positivity in corneal samples was 16.6% and 5.5% by PCR and plate method, respectively. According to sequencing data, two of isolates belonged to genotype T5 and one was genotype T4. In conclusion, Acanthamoeba infection was detected in wild bird cornea samples with/without keratitis for the first time in the world. The result of this study also show that Acanthamoeba can be a cause of keratitis in wild birds of Turkey and thus these predator birds can be a target of other wild animals due to loss of sight ability. In terms of public health, these results show the importance of wild birds as a source of Acanthamoeba infection in nature. PMID- 28807757 TI - Strategies to counter transmission of "superbugs" by targeting free-living amoebae. AB - Bacterial infections have remained significant despite our advances in the development of a plethora of disinfectants as well as antimicrobial chemotherapy. This is in part due to our incomplete understanding of the prevalence of bacterial pathogens in the environmental and clinical settings. Several lines of evidence suggest that Acanthamoeba is one of the most ubiquitous/resilient protists that also acts as a host/reservoir for pathogenic microbes. Thus targeting the hardy host, which harbour microbial pathogens, offer a potential avenue to counter infection transmission, particularly hospital/community acquired infections. This will complement existing approach of applying disinfectants that are targeted against bacterial pathogens directly. PMID- 28807758 TI - Insulinoma enucleation after echoendoscopic fiducial placement. PMID- 28807753 TI - A critical evaluation of validity and utility of translational imaging in pain and analgesia: Utilizing functional imaging to enhance the process. AB - Assessing clinical pain and metrics related to function or quality of life predominantly relies on patient reported subjective measures. These outcome measures are generally not applicable to the preclinical setting where early signs pointing to analgesic value of a therapy are sought, thus introducing difficulties in animal to human translation in pain research. Evaluating brain function in patients and respective animal model(s) has the potential to characterize mechanisms associated with pain or pain-related phenotypes and thereby provide a means of laboratory to clinic translation. This review summarizes the progress made towards understanding of brain function in clinical and preclinical pain states elucidated using an imaging approach as well as the current level of validity of translational pain imaging. We hypothesize that neuroimaging can describe the central representation of pain or pain phenotypes and yields a basis for the development and selection of clinically relevant animal assays. This approach may increase the probability of finding meaningful new analgesics that can help satisfy the significant unmet medical needs of patients. PMID- 28807759 TI - Development of a highly resolved loop-mediated isothermal amplification method to detect the N526K ftsI mutation of beta-lactamase-negative ampicillin-resistant Haemophilus influenzae. AB - Rapid and easy detection of sequence polymorphisms, including nucleotide point mutations of bacterial pathogens responsible for amino acid substitutions linked to drug resistance, is essential for the proper use of antimicrobial agents. Here, a detection method using loop-mediated amplification (LAMP) combined with amplification refractory mutation system (ARMS) to accurately distinguish a different single nucleotide in the target sequence was established, named ARMS SNP LAMP. This procedure is capable of species-specific detection of a nucleotide (1578T) in the ftsI gene on Haemophilus influenzae without amplifying the sequence carrying the point mutations (T1578G/A) in beta-lactamase-negative ampicillin resistant (BLNAR) strains. Reactions were performed at 61 degrees C for 45min. Successful target gene amplifications were detected by measuring real time turbidity using a turbidimeter and visual detection. The assay had a detection limit of 10.0pg of genomic DNA per reaction and showed specificity against 52 types of pathogens, whereas amplifications were completely blocked in even 100.0ng/MUL of genomic DNA with point mutations at T1578G and T1578A. The expected ARMS-SNP LAMP products were confirmed through identical melting curves in real-time LAMP procedures. This novel procedure was also used to analyze 57 clinical isolates of H. influenzae. All 25 clinical isolates with the naive sequence of 1578T gave positive results. In addition, concordant negative results were obtained for 31 of the BLNAR strains with the T1578G mutation and one strain with the T1578A mutation. The ARMS-SNP LAMP method is a simple and rapid method for SNP-genotyping of a clinical isolate as point-of-care testing (POCT) technology. It is suitable for use in both resource-limited situations and well equipped clinical settings because of its simplicity and convenience. PMID- 28807760 TI - A simple methodology to collect culturable bacteria from feces of Anopheles darlingi (Diptera: Culicidae). AB - A simple methodology based in a modified mosquito cage with a Petri dish containing culture medium was successfully used as an alternative method to the traditional digestive tract dissection protocol to collect bacteria from the feces of the mosquito Anopheles darlingi. PMID- 28807761 TI - Mycoplasma hyopneumoniae detection in nylon-flocked and rayon-bud swabs. AB - The objective of this study was to compare the absorption and M. hyopneumoniae detection by real-time PCR using nylon-flocked and rayon-bud swabs. Results of this study showed that absorption and detection of M. hyopneumoniae were significantly higher in nylon-flocked swabs with Ct differences only ranging from 0.5 to 1.7. PMID- 28807762 TI - Diagnostic exome sequencing identifies a heterozygous MBD5 frameshift mutation in a family with intellectual disability and epilepsy. AB - Methyl-CpG-binding domain 5 (MBD5)-associated neurodevelopmental disorder caused by 2q23.1 or MBD5-specific mutation has been recently identified as a genetic disorder associated with autism spectrum disorders. Phenotypic features of 2q23.1 deletion or disruption of MBD5 gene include severe intellectual disability, seizure, significant speech impairment, sleep disturbance, and autistic-like behavioural problems. Here we report a 7-year-old girl with intellectual disability and epilepsy without previous clinical diagnosis. Diagnostic exome sequencing identified a novel frameshift mutation c.254_255delGA (p.Arg85Asnfs*6) in the MBD5 gene of the proband and her father. The proband's father with normal intelligence showed subclinical manifestations observed in subsequent investigations. Clinical manifestations, disease course, and molecular findings of the involvement of MBD5 gene in this family suggest an unusual MBD5-related neurodevelopmental disorder. Moreover, this report demonstrates the critical role of next-generation sequencing technique in characterizing such a rare disorder with variable or no clinical manifestation and providing opportunity to develop effective preventive measures such as pre-implantation genetic diagnosis. PMID- 28807763 TI - Effects of 2,2',4,4'-tetrabromodiphenyl ether on neurobehavior and memory change and bcl-2, c-fos, grin1b and lingo1b gene expression in male zebrafish (Danio rerio). AB - Polybrominated diphenyl ethers (PBDEs) are persistent organic pollutants in various environmental matrices and organisms and pose a threat to neural systems of organisms. However, though quite a few studies have explored the effect of PBDEs on neural behaviors such as learning and memory abilities in animals, their mechanisms are less known. We used the zebrafish model to evaluate neurotoxicity of PBDEs and observe changes in behavior and related gene expression. In behavioral testing, 50 zebrafish were divided into five groups treated with different concentrations of BDE-47. T-maze exploration was used for learning and memory testing, which was recorded by camera every 7days. After 21days, all fish were killed, and the gene expression of c-fos, bcl-2, lingo1b and grin1b in brain tissue was analyzed by RT-qPCR. The behavioral changes (latency to leave the start zone, reach the reward zone, and stay in the reward zone; accuracy in choosing the right maze arm, accumulation of freezing bouts, etc.) were related to BDE-47 concentration and had a time-effect relation with increasing exposure days, especially with 500MUg/L BDE-47. BDE-47 elevated brain bcl-2, grin1b and lingo1b expression. The expression of c-fos showed an increase with 50 and 100MUg/L BDE-47 exposure. The PBDE BDE-47 had a negative impact on the neurobehaviors of zebrafish and affected the expression of c-fos, bcl-2, lingo1b and grin1b in zebrafish brain tissue. PMID- 28807764 TI - Staphylococcal enterotoxin C2 mutant drives T lymphocyte activation through PI3K/mTOR and NF-KB signaling pathways. AB - Staphylococcal enterotoxin C2 (SEC2), a superantigen, causes rapid clonal expansion of lymphocytes and secretion of T cell growth factors, leading to a severe inflammatory response within tissues. Although previous studies have shown that ST-4, a SEC2 mutant with enhanced recognition of Vbeta regions of T-cell receptors (TCRVbeta), can activate an increased number of T cells and produce more cytokines than SEC2. However, the signaling mechanisms of SEC2/ST-4-mediated immune activation have not been addressed. In this study, we showed that the phosphatidylinositide-3-kinase (PI-3K) inhibitor LY294002, mammalian target of rapamycin (mTOR) inhibitor rapamycin, and nuclear factor kappa-light-chain enhancer of activated B cells (NF-kappaB) inhibitor Bay11-7085 could suppress SEC2/ST-4-induced proliferation, CD69/CD25 expression, cell-cycle progression, and IL-2 production in BALB/c mouse splenocytes. In addition, we observed significantly upregulated expression of p70S6K, cyclin E, cyclin D3, and NF KB/p65, but downregulated expression of p27kip during SEC2/ST-4-driven T cells activation. However, SEC2/ST-4-induced changes in cell cycle and PI3K/mTOR signaling were significantly relieved by either LY294002 or rapamycin, and the induction of NF-KB/p65 induced was significantly downregulated by Bay11-7085. Moreover, we found that IL-2 secretion was positively associated with p65 expression in a time- and dose-dependent manner. Taken together, our findings demonstrate the involvement of PI3K/mTOR and NF-kappaB signaling pathways in SEC2/ST-4-induced T cell activation. ST-4 intensifies PI3K/mTOR and NF-KB signaling transduction, ultimately leading to enhance T cell activation. These results provide a theoretical mechanism for future immunotherapy using ST-4. PMID- 28807766 TI - Chikungunya virus: A new endemic in Pakistan? PMID- 28807765 TI - SGLT2-inhibitor and DPP-4 inhibitor improve brain function via attenuating mitochondrial dysfunction, insulin resistance, inflammation, and apoptosis in HFD induced obese rats. AB - Dipeptidyl peptidase-4 inhibitor (vildagliptin) has been shown to exert beneficial effects on insulin sensitivity and neuroprotection in obese-insulin resistance. Recent studies demonstrated the neuroprotection of the sodium-glucose co-transporter 2 inhibitor (dapagliflozin) in diabetes. However, the comparative effects of both drugs and a combination of two drugs on metabolic dysfunction and brain dysfunction impaired by the obese-insulin resistance have never been investigated. Forty male Wistar rats were divided into two groups, and received either a normal-diet (ND, n=8) or a high-fat diet (HFD, n=32) for 16weeks. At week 13, the HFD-fed rats were divided into four subgroups (n=8/subgroup) to receive either a vehicle, vildagliptin (3mg/kg/day) dapagliflozin (1mg/kg/day) or combined drugs for four weeks. ND rats were given a vehicle for four weeks. Metabolic parameters and brain function were investigated. The results demonstrated that HFD rats developed obese-insulin resistance and cognitive decline. Dapagliflozin had greater efficacy on improved peripheral insulin sensitivity and reduced weight gain than vildagliptin. Single therapy resulted in equally improved brain mitochondrial function, insulin signaling, apoptosis and prevented cognitive decline. However, only dapagliflozin improved hippocampal synaptic plasticity. A combination of the drugs had greater efficacy in improving brain insulin sensitivity and reducing brain oxidative stress than the single drug therapy. These findings suggested that dapagliflozin and vildagliptin equally prevented cognitive decline in the obese-insulin resistance, possibly through some similar mechanisms. Dapagliflozin had greater efficacy than vildagliptin for preserving synaptic plasticity, thus combined drugs could be the best therapeutic approach for neuroprotection in the obese-insulin resistance. PMID- 28807767 TI - A New Clinicobiological Scoring System for the Prediction of Infection-Related Mortality and Survival after Allogeneic Hematopoietic Stem Cell Transplantation. AB - Infection-related mortality (IRM) is a substantial component of nonrelapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (allo HSCT). No scores have been developed to predict IRM before transplantation. Pretransplantation clinical and biochemical data were collected from a study cohort of 607 adult patients undergoing allo-HSCT between January 2009 and February 2017. In a training set of 273 patients, multivariate analysis revealed that age >60 years (P = .003), cytomegalovirus host/donor serostatus different from negative/negative (P < .001), pretransplantation IgA level <1.11 g/L (P = .004), and pretransplantation IgM level <.305 g/L (P = .028) were independent predictors of increased IRM. Based on these results, we developed and subsequently validated a 3-tiered weighted prognostic index for IRM in a retrospective set of patients (n = 219) and a prospective set of patients (n = 115). Patients were assigned to 3 different IRM risk classes based on this index score. The score significantly predicted IRM in the training set, retrospective validation set, and prospective validation set (P < .001, .044, and .011, respectively). In the training set, 100-day IRM was 5% for the low-risk group, 11% for the intermediate-riak group, and 16% for the high-risk groups. In the retrospective validation set, the respective 100-day IRM values were 7%, 17%, and 28%, and in the prospective set, they were 0%, 5%, and 7%. This score predicted also overall survival (P < .001 in the training set, P < 041 in the retrospective validation set, and P < .023 in the prospective validation set). Because pretransplantation levels of IgA/IgM can be modulated by the supplementation of enriched immunoglobulins, these results suggest the possibility of prophylactic interventional studies to improve transplantation outcomes. PMID- 28807768 TI - European Group for Blood and Marrow Transplantation Risk Score Predicts the Outcome of Patients with Acute Leukemia Receiving Single Umbilical Cord Blood Transplantation. AB - The European Group for Blood and Marrow Transplantation (EBMT) risk score has been implemented as an important tool to predict patient outcomes after allogeneic hematopoietic stem cell transplantation. However, to our knowledge, this score has never been applied in cases of single umbilical cord blood transplantation (sUCBT). We retrospectively analyzed 207 consecutive patients with acute leukemia who received sUCBT at our center between February 2011 and December 2015. The probabilities of 3-year overall survival (OS) and leukemia free survival (LFS) of the entire cohort were 65.0% and 59.8%, respectively, whereas the cumulative incidences of 3-year nonrelapse mortality (NRM) and relapse rate were 19.5% and 20.3%, respectively. In the univariate analysis, a higher EBMT risk score was associated with worse OS and LFS and higher NRM and relapse rate, ranging from 81.7%, 75.9%, 7.3%, and 15.3%, respectively, for patients with a score of 1 to 43.8%, 44.3%, 31.7%, and 23.9%, respectively, for patients with scores of 4 to 6. Hazard ratios of OS, LFS, and NRM all steadily increased for each additional score point. Importantly, the prognostic value of the EBMT risk score on OS, LFS, NRM, and relapse was maintained in the multivariate analysis. Moreover, considering the univariate analysis results of donor-recipient gender and mismatched allele-level HLA-A, -B, -C, and -DRB1 loci on patient outcomes and the fairly strong interaction between time from diagnosis to sUCBT and disease status, we developed a modified sUCBT-EBMT risk score by using degrees of 8-allele HLA match instead of donor type, donor-recipient gender combination, and time from diagnosis to sUCBT, and found that the modified score could also be used as a predictor for patient outcomes after sUCBT. The EBMT risk score is a good predictor of outcomes of patients with leukemia after sUCBT. The modified sUCBT-EBMT risk score can also be used as a pretransplant risk assessment, but this metric still requires further evaluation with a larger cohort. PMID- 28807770 TI - GSTA1 Genetic Variants and Conditioning Regimen: Missing Key Factors in Dosing Guidelines of Busulfan in Pediatric Hematopoietic Stem Cell Transplantation. AB - Busulfan (Bu) is a key component of conditioning regimens used before hematopoietic stem cell transplantation (SCT) in children. Different predictive methods have been used to calculate the first dose of Bu. To evaluate the necessity of further improvements, we retrospectively analyzed the currently available weight- and age-based guidelines to calculate the first doses in 101 children who underwent allogenic SCT in CHU Sainte-Justine, Montreal, after an intravenous Bu-containing conditioning regimen according to genetic and clinical factors. The measured areas under the curve (AUCs) were within target (900 to 1500 uM/min) in 38.7% of patients after the administration of the first dose calculated based on age and weight, as locally recommended. GSTA1 diplotypes linked to poor Bu metabolism (G3) and fludarabine-containing regimens were the only factors associated with AUC within target (OR, 4.7 [95% CI, 1.1 to 19.8, P = .04]; and OR, 9.9 [95% CI, 1.6 to 61.7, P = .01], respectively). From the 11 methods selected for dose calculation, the percentage of AUCs within the target varied between 16% and 74%. In some models G3 was associated with AUCs within the therapeutic and the toxic range, whereas rapid metabolizers (G1) were correlated with subtherapeutic AUCs when different methods were used. These associations were confirmed by clearance-prediction analysis, in which GSTA1 diplotypes consistently influenced the prediction errors of the methods. These findings suggest that these factors should be considered in Bu dose prediction in addition to the anthropometric data from patients. Furthermore, our data indicated that GSTA1 diplotypes was a factor that should be included in future population pharmacokinetic models, including similar conditioning regiments, to improve the prediction of Bu exposure after its initial dose. PMID- 28807771 TI - Increase of Intermediate Monocytes in Graft-versus-Host Disease: Correlation with MDR1+Th17.1 Levels and the Effect of Prednisolone and 1alpha,25-Dihydroxyvitamin D3. AB - Graft-versus-host disease (GVHD) remains one of the major complications after allogeneic hematopoietic stem cell transplantation that is mainly treated with glucocorticoids such as prednisolone. In this study the influence of monocyte subpopulations, prednisolone, and 1alpha,25-dihydroxyvitamin D3 (1alpha,25 (OH)2D3) on the induction of a proinflammatory subset of Th17 cells (MDR+Th17.1) characterized by CCR6+CXCR3hiCCR4loCCR10-CD161+ and stable expression of the multidrug resistance protein type 1 (MDR1) was investigated. Our results demonstrate that intermediate monocytes are increased in patients with acute GVHD, promoting the induction of proinflammatory MDR1+Th17.1 cells. Furthermore, prednisolone induces the development of MDR1+Th17.1 cells, whereas 1alpha,25 (OH)2D3 acts as an anti-inflammatory, leading to diminished percentages of proinflammatory MDR1+Th17.1 cells in the presence of prednisolone after stimulation with the TLR4-ligand S100A8/S100A9. Moreover, 1alpha,25-(OH)2D3 decreased the expression level of the targets JAK2 and CD74, both associated with T cell activation, in monocytes. Thus, in steroid-resistant GVHD, 1alpha,25 (OH)2D3 could be an important regulator in monocyte-induced development of proinflammatory MDR1+Th17.1 cells and might therefore be a potential therapeutic agent in combination with glucocorticoids for GVHD treatment. PMID- 28807772 TI - Streptococcus agalactiae impairs cerebral bioenergetics in experimentally infected silver catfish. AB - It is becoming evident that bacterial infectious diseases affect brain energy metabolism, where alterations of enzymatic complexes of the mitochondrial respiratory chain and creatine kinase (CK) lead to an impairment of cerebral bioenergetics which contribute to disease pathogenesis in the central nervous system (CNS). Based on this evidence, the aim of this study was to evaluate whether alterations in the activity of complex IV of the respiratory chain and CK contribute to impairment of cerebral bioenergetics during Streptococcus agalactiae infection in silver catfish (Rhamdia quelen). The activity of complex IV of the respiratory chain in brain increased, while the CK activity decreased in infected animals compared to uninfected animals. Brain histopathology revealed inflammatory demyelination, gliosis of the brain and intercellular edema in infected animals. Based on this evidence, S. agalactiae infection causes an impairment in cerebral bioenergetics through the augmentation of complex IV activity, which may be considered an adaptive response to maintain proper functioning of the electron respiratory chain, as well as to ensure ongoing electron flow through the electron transport chain. Moreover, inhibition of cerebral CK activity contributes to lower availability of ATP, contributing to impairment of cerebral energy homeostasis. In summary, these alterations contribute to disease pathogenesis linked to the CNS. PMID- 28807769 TI - Reduced-Intensity Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Solid Tumors in Pediatric and Young Adult Patients. AB - High-risk, recurrent, or refractory solid tumors in pediatric, adolescent, and young adult (AYA) patients have an extremely poor prognosis despite current intensive treatment regimens. We piloted an allogeneic bone marrow transplant platform using reduced-intensity conditioning (RIC) and partially HLA-mismatched (haploidentical) related donors for this population of pediatric and AYA solid tumor patients. Sixteen patients received fludarabine, cyclophosphamide, melphalan, and low-dose total body irradiation RIC haploidentical BMT (haploBMT) followed by post-transplantation cyclophosphamide (PTCy), mycophenolate mofetil, and sirolimus. All assessable patients were full donor chimeras on day 30 with a median neutrophil recovery of 19 days and platelet recovery of 21 days. One patient (7%) exhibited secondary graft failure associated with concomitant infection. The median follow-up time was 15 months. Overall survival was 88%, 56%, and 21% at 6, 12, and 24 months, respectively. Median survival from transplant date was 14 months with a median progression-free survival 7 months. We observed limited graft-versus-host disease in 3 patients and nonrelapse mortality in 1 patient. We demonstrated that RIC haploBMT with PTCy is feasible and has acceptable toxicities in patients with incurable pediatric and AYA solid tumors; thus, this approach serves as a platform for post-transplant strategies to prevent relapse and optimize progression-free survival. PMID- 28807773 TI - Influence of oxidative stress on the antibacterial activity of betulin, betulinic acid and ursolic acid. AB - Contribution of reactive oxygen species and oxidative stress in the antibacterial activities of betulin, betulinic acid and ursolic acid against Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus was investigated. The minimum inhibitory concentrations of betulin, betulinic acid and ursolic acid against E. coli, P. aeruginosa and S. aureus are 1024-, 256- and 1024-MUg/mL; 512-, 256- and 256 MUg/mL; 256-, 256- and 64 MUg/mL respectively. Cell viability of betulin-, betulinic acid- and ursolic acid-treated bacteria decrease in time dependent manner. Treatment of bacteria in the presence of 2,2'-bipyrydyl increased cell viability. Superoxide anion radical production increased significantly (p < 0.05) in bacterial cells-treated with betulin, betulinic acid and ursolic acid. Furthermore, NAD+/NADH ratio increased significantly (p < 0.05) in betulin-, betulinic acid- and ursolic acid-treated bacteria. Similarly, level of reduced glutathione in E. coli, P. aeruginosa and S. aureus decreased significantly with corresponding increase in glutathione disulphide, malondialdehyde and fragmented DNA following betulin, betulinic acid and ursolic acid treatments. It is evident from the above findings that betulin, betulinic acid and ursolic acid enhanced electron transport chain activity in E. coli, P. aeruginosa and S. aureus leading to increased ROS generation, Fenton reaction, lipid peroxidation, fragmented DNA and consequentially bacterial death. PMID- 28807774 TI - Chlorin e6-mediated photodynamic therapy promotes collagen production and suppresses MMPs expression via modulating AP-1 signaling in P. acnes-stimulated HaCaT cells. AB - BACKGROUND: Photodynamic therapy (PDT) is a clinically approved therapeutic for cancers and non-neoplastic diseases, based on the use of a photosensitizer activated by light. The feasibility of PDT depends on several factors, such as PDT dose, photosensitizer efficacy, type of light source, and target tissue irradiated. METHODS: In this study, the second generation photosensitizer chlorin e6 (Ce6) and halogen light were used to investigate their PDT effect on the collagen production and MMPs expression of heat killed P. acnes-stimulated HaCaT cells. The mRNA levels of COL1A1, c-Jun, and c-Fos were detected by RT-PCR. The protein levels of MMPs, ERK and JNK were detected by western blot. The transactivation of AP-1 was detected by luciferase assay. RESULTS: Ce6-based PDT markedly upregulated the mRNA level of COL1A1 and type I procollagen level; and at the same time downregulated the expression of MMPs in P. acnes-infected HaCaT cells. Moreover, Ce6-mediated PDT, in a dose dependent manner, inhibited P. acnes induced phosphorylation of JNK and ERK, as wells as the phosphorylation of their downstream targets c-Jun and c-Fos. P. acnes-induced mRNA expression of c-Jun and c-Fos were also suppressed by Ce6-mediated PDT. The transactivation of AP-1 induced by P. acnes infection was also downregulated. CONCLUSION: These results indicated that Ce6-mediated PDT with halogen light enhanced collagen production, but inhibited the expression of MMPs in P. acnes-infected HaCaT cells, by regulating AP-1 signals. This investigation provided the first molecular basis for the increase in collagen production by Ce6-mediated PDT, suggesting its potential use for scar amelioration and skin rejuvenation in acne treatment. PMID- 28807775 TI - The potential benefits of glucagon-like peptide-1 receptor agonists for diabetic retinopathy. AB - For a long time, diabetic retinopathy (DR) has been one of the most severe complications of diabetes. The early treatment of DR is not clearly recognized. The additional benefit of hypoglycemic agents for DR has become a new research field. Glucagon-like peptide-1 receptor (GLP-1R) has been shown to be widely expressed in tissues including retina. Glucagon-like peptide-1 receptor agonists (GLP-1RA) have been generally used in the treatment of diabetic patients. Studies shows that GLP-1RA could inhibit nerve damage by decrease apoptosis of nerve cells and activation of glial cells. In addition, GLP-1RA plays a protective role for tight junction (TJ) and cells of blood retinal barrier (BRB). It also protects retina from BRB damage. In this review, we discuss the potential protective mechanisms of GLP-1RA for DR beyond the hypoglycemic effects. PMID- 28807776 TI - Sleep behaviors in children with different frequencies of parental-reported sleep bruxism. AB - OBJECTIVE: Knowledge on the relationship between sleep bruxism (SB) and sleep behaviors in children is still fragmental, especially when socioeconomic factors are concerned. To assess sleep behaviors in children with different frequencies of proxy-reported SB. METHODS: Parents of 1475 Colombian children, aged 9.8+/ 1.6years, belonging to 3 different social layers, filled out a questionnaire on their childrens sleep (Childrens Sleep Habits Questionnaire [CSHQ]). Differences in sleep behaviors were assessed for the total sample and the three socioeconomic layers, using one-way ANOVA and Bonferroni post-hoc tests or Kruskal-Wallis and Dunn's post-hoc tests, based on the normality of outcome variables. RESULTS: Most sleep patterns and daytime sleepiness were similar for children with different frequencies of proxy-reported SB, without differences among socioeconomic layers, whilst sleep disorders and parasomnias increased with the frequency of proxy reported SB, independently on the socioeconomic layer (Bonferroni post hoc<0.001). The association between sleep-related habits and the frequency of proxy-reported SB was different for each socioeconomic layer. CONCLUSION: Among the various sleep behaviors under investigation, some sleep disorders and parasomnias seem to be associated with parental-reported SB in children. The influence of socioeconomic conditions on sleep behaviors seems not relevant. Based on these results, more specific studies on the association between different sleep behaviors are needed. CLINICAL SIGNIFICANCE: Sleep behaviors, sociodemographic and socioeconomic features are correlated with SB in adults. However, in children, good evidence about this topic is lacking. This article give information to help clinicians evaluating sleep behaviors, sociodemographic and socioeconomic characteristics, when assessing sleep bruxism, based on evidence. PMID- 28807777 TI - Bilateral Temporal Myofascial Flap for the Reconstruction of Frontal Sinus Defects. AB - BACKGROUND: A frontal sinus infection, following a transsinus skull base procedure, portends potentially life-threatening complications, making surgical revision mandatory in refractory infections. The authors describe the application of the bilateral temporal myofascial flap (BTMF) as a valuable option for frontal sinus reconstruction, when pericranial or galeal-frontalis myofascial flap (GFMF) is no longer available. METHODS: A microanatomic laboratory cadaver investigation was conducted to obtain anthropometric measurements. Surgical technique is described, and intraoperative images are provided. RESULTS: The surgical steps of this technique and the related intraoperative images are reported. One case illustration regarding frontal sinus reconstruction following a postoperative infection, as a complication after a transsinus procedure, is reported. CONCLUSION: The BTMF should be considered as a valuable option for frontal sinus reconstruction after transsinus skull base procedures when GFMF is not available. PMID- 28807778 TI - Cervical Cord-Canal Mismatch: A New Method for Identifying Predisposition to Spinal Cord Injury. AB - The risk for spinal cord injuries (SCIs) ranging from devastating traumatic injuries, compression because of degenerative pathology, and neurapraxia is increased in patients with congenital spinal stenosis. Classical diagnostic criteria include an absolute anteroposterior diameter of <12-13 mm or a Torg Pavlov ratio of <0.80-0.82; however, these factors do not take into account the size of the spinal cord, which varies across patients, independent of canal size. Recent large magnetic resonance imaging studies of population cohorts have allowed newer methods to emerge that account for both cord and canal size by measuring a spinal cord occupation ratio (SCOR). A SCOR defined as >=70% on midsagittal imaging or >=80% on axial imaging appears to be an effective method of identifying cord-canal mismatch, but requires further validation. Cord-canal size mismatch predisposes patients to SCI because of 1) less space within the canal lowering the amount of degenerative changes needed for cord compression, and 2) less cerebrospinal fluid surrounding the spinal cord decreasing the ability to absorb kinetic forces directed at the spine. Patients with cord-canal mismatch have been reported to be at a substantially higher risk of traumatic SCI, and present with degenerative cervical myelopathy at a younger age than patients without cord-canal mismatch. However, neurologic outcome after SCI has occurred does not appear to be different in patients with or without a cord-canal mismatch. Recognition that canal and cord size are both factors which predispose to SCI supports that cord-canal size mismatch rather than a narrow cervical canal in isolation should be viewed as the underlying mechanism predisposing to SCI. PMID- 28807779 TI - Syringo-Subarachnoid Shunt for the Treatment of Persistent Syringomyelia Following Decompression for Chiari Type I Malformation: Surgical Results. AB - BACKGROUND: Approximately 30% of patients treated with foramen magnum decompression (FMD) for Chiari I-associated syringomyelia will show persistence, recurrence, or progression of the syrinx. OBJECTIVE: This study evaluates the clinical and radiologic outcomes of syringo-subarachnoid shunt (SSS) as the treatment for persistent syringomyelia after FMD. METHODS: Data were collected retrospectively. The primary outcome measurement was neurologic function (assessed with the Modified Japanese Orthopedic Association [mJOA] scale). Secondary outcome measurements were surgical complications, reoperation rate, and syrinx status on magnetic resonance imaging (MRI). RESULTS: Twenty-one patients (14 females [66.7%]) underwent SSS, either concurrent to the FMD or at a later stage. Two minor surgical complications were seen: a wound dehiscence and postoperative kyphosis, both requiring revision surgery. No major complication or mortality occurred. The median change in the mJOA score was an improvement of 3 out of a possible 17 points on the scale (mean follow-up, 24.9 months). Expressed as a percentage, overall improvement was 11.8% (95% confidence interval [CI], 5.9 17.6; P < 0.001). On postoperative MRI, shrinkage of the syrinx was seen in all but 1 patient in whom the syrinx remained unchanged. Expressed as percentage, the improvement of the syrinx surface was 76.3% (95% CI, 65.0-87.7; P < 0.001), and the improvement of syrinx span was 36.4% (95% CI, 21.8-50.9; P = 0.05). CONCLUSION: SSS for persistent, recurrent, or increasing syrinx following FMD for Chiari I malformation is a safe and effective surgical treatment when performed selectively by an experienced neurosurgeon. PMID- 28807780 TI - MGL-1 on AIY neurons translates starvation to reproductive plasticity via neuropeptide signaling in Caenorhabditis elegans. AB - Reproductive plasticity is the ability of an animal to modulate its reproductive functions in response to environmental changes. For example, Caenorhabditis elegans, a free-living nematode, can adjust the onsets of oogenesis and embryogenesis under harsh environmental conditions, including starvation. However, the molecular mechanisms used to perceive and translate environmental signals into reproductive functional adjustments remain largely uncharacterized. We discovered that in C. elegans, the glutamate receptor homolog MGL-1 initiated reproductive plasticity in response to starvation. A genetic analysis of the mutant gene, mgl-1(tm1811), suggested that starvation delayed the onsets of oogenesis and embryogenesis via MGL-1. Cell-specific rescues of mgl-1 deletion mutants, which used transgenic lines designed to express MGL-1 in different neurons (e.g., RMD, AIA, AIY, and NSM), suggested that only AIY-rescued animals exhibited normal delays in oogenesis and embryogenesis equivalent to those of wild-type animals, suggesting recovery. Furthermore, in AIY neurons, MGL-1 appears to use neuropeptide signaling, rather than glutamate, to translate starvation stimuli into delayed oogenesis and embryogenesis. Our findings, which reveal molecular linkages between starvation signals and reproductive alterations, may provide a basis for understanding energy reallocation mechanisms, as the mgl-1 deletion mutant exhibited more severe reductions in lifespan and fat accumulation than did wild-type animals under starvation conditions. Taken together, MGL-1 is the molecular driver underlying the translation of starvation signals to reproduction plasticity in an AIY neuron specific manner. PMID- 28807781 TI - Engrailed controls epaxial-hypaxial muscle innervation and the establishment of vertebrate three-dimensional mobility. AB - Chordates are characterised by contractile muscle on either side of the body that promotes movement by side-to-side undulation. In the lineage leading to modern jawed vertebrates (crown group gnathostomes), this system was refined: body muscle became segregated into distinct dorsal (epaxial) and ventral (hypaxial) components that are separately innervated by the medial and hypaxial motors column, respectively, via the dorsal and ventral ramus of the spinal nerves. This allows full three-dimensional mobility, which in turn was a key factor in their evolutionary success. How the new gnathostome system is established during embryogenesis and how it may have evolved in the ancestors of modern vertebrates is not known. Vertebrate Engrailed genes have a peculiar expression pattern as they temporarily demarcate a central domain of the developing musculature at the epaxial-hypaxial boundary. Moreover, they are the only genes known with this particular expression pattern. The aim of this study was to investigate whether Engrailed genes control epaxial-hypaxial muscle development and innervation. Investigating chick, mouse and zebrafish as major gnathostome model organisms, we found that the Engrailed expression domain was associated with the establishment of the epaxial-hypaxial boundary of muscle in all three species. Moreover, the outgrowing epaxial and hypaxial nerves orientated themselves with respect to this Engrailed domain. In the chicken, loss and gain of Engrailed function changed epaxial-hypaxial somite patterning. Importantly, in all animals studied, loss and gain of Engrailed function severely disrupted the pathfinding of the spinal motor axons, suggesting that Engrailed plays an evolutionarily conserved role in the separate innervation of vertebrate epaxial-hypaxial muscle. PMID- 28807783 TI - Aggregation and Its Influence on the Immunomodulatory Activity of Synthetic Innate Defense Regulator Peptides. AB - There is increasing interest in developing cationic host defense peptides (HDPs) and their synthetic derivatives as antimicrobial, immunomodulatory, and anti biofilm agents. These activities are often evaluated without considering biologically relevant concentrations of salts or serum; furthermore certain HDPs have been shown to aggregate in vitro. Here we examined the effect of aggregation on the immunomodulatory activity of a synthetic innate defense regulator peptide, 1018 (VRLIVAVRIWRR-NH2). A variety of salts and solutes were screened to determine their influence on 1018 aggregation, revealing that this peptide "salts out" of solution in an anion-specific and concentration-dependent manner. Furthermore, the immunomodulatory activity of 1018 was found to be inhibited under aggregation-promoting conditions. A series of 1018 derivatives were synthesized with the goal of disrupting this self-assembly process. Indeed, some derivatives exhibited reduced aggregation while maintaining certain immunomodulatory functions, demonstrating that it is possible to engineer optimized synthetic HDPs to avoid unwanted peptide aggregation. PMID- 28807784 TI - Gabapentin prevents cortical spreading depolarization-induced disinhibition. AB - Cortical spreading depolarization (CSD) has an important role in brain diseases such as stroke, subarachnoid hemorrhage, migraine with aura, and epilepsy. Several anti-epileptic drugs (AEDs) are used to treat paroxysmal brain diseases and are thus known to suppress CSD. One of these AEDs is gabapentin (GBP) which has been traditionally used for treatment of some CSD-related neurological diseases. We applied intra- and extracellular recordings to investigate the effect of CSD on inhibitory post synaptic potentials (IPSPs) and synaptic properties of rodent neocortex after application of GBP. Application of GBP after CSD increased the amplitude of IPSPs. In addition, GBP inhibited induction of long-term potentiation after CSD. These data support an effect of GBP on GABA mediated inhibition in the late hyperexcitable phase of CSD. Modulations of synaptic properties and post-CSD GABAergic function are likely GBP's mechanisms of action in CSD-related disorders. These mechanisms could be targeted for further drug discovery in CSD-related diseases. PMID- 28807782 TI - Modulating Protein-Protein Interactions of the Mitotic Polo-like Kinases to Target Mutant KRAS. AB - Mutations activating KRAS underlie many forms of cancer, but are refractory to therapeutic targeting. Here, we develop Poloppin, an inhibitor of protein-protein interactions via the Polo-box domain (PBD) of the mitotic Polo-like kinases (PLKs), in monotherapeutic and combination strategies to target mutant KRAS. Poloppin engages its targets in biochemical and cellular assays, triggering mitotic arrest with defective chromosome congression. Poloppin kills cells expressing mutant KRAS, selectively enhancing death in mitosis. PLK1 or PLK4 depletion recapitulates these cellular effects, as does PBD overexpression, corroborating Poloppin's mechanism of action. An optimized analog with favorable pharmacokinetics, Poloppin-II, is effective against KRAS-expressing cancer xenografts. Poloppin resistance develops less readily than to an ATP-competitive PLK1 inhibitor; moreover, cross-sensitivity persists. Poloppin sensitizes mutant KRAS-expressing cells to clinical inhibitors of c-MET, opening opportunities for combination therapy. Our findings exemplify the utility of small molecules modulating the protein-protein interactions of PLKs to therapeutically target mutant KRAS-expressing cancers. PMID- 28807785 TI - Blocking the CD38/cADPR pathway plays a double-edged role in LPS stimulated microglia. AB - Whether the CD38/cyclic ADP-ribose (cADPR) pathway plays a protective or detrimental role in neuroinflammation remains controversial. This study aimed to determine the role of CD38 in neuroinflammation using lipopolysaccharide (LPS) stimulated BV2 microglial cells and co-cultured Neuro-2a (N2a) cells. In monoculture experiments, BV2 cells were divided into control, CD38 interference (CD38Ri), negative control (NC), LPS, CD38Ri+LPS, NC+LPS and 8-Br-cADPR+LPS groups. In co-culture experiments, N2a cells were co-cultured with BV2 cells for 48h. Nicotinamide adenine dinucleotide (NAD+), cADPR and intracellular Ca2+ levels and CD38 expression increased significantly in LPS-stimulated BV2 cells. CD38 knockdown or 8-Br-cADPR treatment significantly reduced NAD+, cADPR and intracellular Ca2+ levels. CD38 knockdown increased iNOS and NO levels in BV2 cells without LPS treatment; however, CD38 knockdown or 8-Br-cADPR treatment reduced iNOS and NO levels in BV2 cells with LPS treatment. CD38 knockdown increased the ratio of TUNEL-positive cells and cleaved Caspase 3/Caspase 3 ratio, and decreased the Bcl-2/Bax ratio in BV2 cells without LPS treatment; however, CD38 knockdown reduced the TUNEL positivity in BV2 cells with LPS treatment. CD38 knockdown or 8-Br-cADPR inhibited TNF-alpha, IL-6 (interleukin-6) and IL-1beta levels in LPS-stimulated BV2 cells. Co-culture with CD38 knockdown or 8-Br-cADPR-treated BV2 cells did not influence apoptosis or iNOS expression in N2a cells. In conclusion, our results indicate that blocking the CD38/cADPR pathway reduces intracellular Ca2+, NO and the secretion of proinflammatory cytokines. CD38 knockdown exerted a detrimental effect in apoptosis and NO production in normal microglia, but played a protective role in apoptosis and NO production in LPS-stimulated microglia. PMID- 28807786 TI - Dexmedetomidine prolongs levobupivacaine analgesia via inhibition of inflammation and p38 MAPK phosphorylation in rat dorsal root ganglion. AB - Following tissue injury, phosphorylation of p38 MAPK in the primary afferent neurons drives sensitization of peripheral nerve. Dexmedetomidine extends the duration of reginal analgesia by local anesthetics. The effect of regional analgesia on the peripheral nerve sensitization is not known. The aim of this study is to investigate the effect of regional analgesia by levobupivacaine with or without dexmedetomidine on the p38 MAPK phosphorylation in the dorsal root ganglion (DRG) and inflammatory reaction in the peripheral tissue. A plantar incision was made in the hind paws of Sprague-Dawley rats. Prior to incision, levobupivacaine with or without dexmedetomidine was injected to the plantar aspect of the paws and ankles. A behavioral study was performed to investigate pain hypersensitivity. Phosphorylation of p38 MAPK in the DRG was assessed by immunohistochemistry and Western blotting. Macrophage accumulation, NGF, and TNF alpha in the DRG and plantar tissue were measured using immunohistochemistry, real-time PCR and ELISA. Pain hypersensitivity was induced immediately after the plantar incision. Treatment with levobupivacaine inhibited the development of pain hypersensitivity for two hours. Adjunctive dexmedetomidine extended the anti hyperalgesic duration for four hours. Levobupivacaine without dexmedetomidine could not inhibit p38 MAPK phosphorylation in the DRG completely. However, Levobupivacaine and dexmedetomidine completely inhibited p38 MAPK phosphorylation, and reduced macrophage accumulation and TNF-alpha amount in the plantar tissue. Inhibition of p38 MAPK phosphorylation via TNF-alpha suggests dexmedetomidine has a peripheral mechanism of anti-inflammatory action when used asan adjunct to local anesthetics, and provides a molecular basis for the prevention of peripheral sensitization following surgery. PMID- 28807787 TI - Trigeminal nerve stimulation induces Fos immunoreactivity in selected brain regions, increases hippocampal cell proliferation and reduces seizure severity in rats. AB - Sites and mechanisms by which trigeminal nerve stimulation (TNS) exerts beneficial effects on symptoms of drug-resistant epilepsy and depression are still unknown. Effects of short-term TNS on brain regions involved in the physiopathology of these disorders were investigated in this study. Forty male rats were assigned to three groups: TNS (undergoing electrical stimulation of the left infraorbitary nerve via surgically implanted cuff electrodes); Sham (undergoing surgical procedure but without a stimulation); Naive rats. The effects of TNS (3-hour session; 30-s ON, 5-min OFF; 30Hz; 500MUs; 2mA) were evaluated on: (i) behavioral pattern of pentylenetetrazole (PTZ)-induced seizures as measured by the Racine scale; (ii) c-Fos-like immunoreactivity in discrete brain areas; (iii) hippocampal cell proliferation by bromodeoxyuridine (BrdU) like immunoreactivity. In comparison with Sham groups, TNS significantly decreased the duration of PTZ-induced seizures (p<0.05) and promoted a faster recovery (p<0.001) by reducing the most severe seizure types. In the TNS group the number of c-Fos-labeled cells was significantly increased (p<0.001) in the trigeminal nuclear complex, nucleus of the solitary tract, locus coeruleus, dorsal raphe nucleus, hippocampus, amygdala, endopiriform nucleus, entorhinal cortex and sensorimotor cortex. In the TNS group the number of BrdU-positive cells in the dentate gyrus was significantly greater with respect to both Naive and Sham groups. Data show that acute TNS effectively counteracted PTZ-induced seizures and boosted hippocampal cell proliferation in rats. TNS increased c-Fos like immunoreactivity in brainstem and forebrain structures which play a pivotal role in the physiopathology of epilepsy and depression. PMID- 28807789 TI - The expression of ERK and JNK in patients with an endemic osteochondropathy, Kashin-Beck disease. AB - Kashin-Beck disease (KBD) is a chronic, endemic osteochondropathy. Its etiopathogenesis is still obscure until now. Epidemiological observation has shown that low selenium play a crucial role in the pathogenesis of KBD. Extracellular signal-regulated kinases (ERKs) and C-Jun N-terminal kinase (JNK), members of the mitogen-activated protein kinase (MAPK) superfamily, play an important role in cell proliferation and differentiation. Nuclear factor-KB (NF KB), an important signaling mediator for inflammatory and immune responses, is involved in the regulation of osteoclastogenesis. In the present study, we investigated the expression of ERK and JNK signal molecular, as well as nuclear factor-KB in the pathogenesis of Kashin-Beck disease, evaluated the effect of selenium on ERK signal pathway. The expression levels of ERK and JNK signal pathway, as well as nuclear factor-KB were investigated for 218 patients and 209 controls by immunoblot analysis in whole blood. Evaluated the effect of selenium on ERK signal pathway by Na2SeO3 treatment. The protein levels of pRaf-1, pMek1/2 and pErk1/2 decreased significantly in KBD patients, p-JNK and NF-KB increased in KBD patients. Furthermore, Na2SeO3 treatment improved the reduction of proteins in ERK signal pathway. These findings indicated that ERK and JNK signaling pathways, as well as the expression level of NF-kappaB signaling molecular are important contributor to the pathogenesis of KBD. Selenium stimulates the phosphorylation of the ERK signaling pathway. PMID- 28807788 TI - Adolescent binge ethanol exposure alters specific forebrain cholinergic cell populations and leads to selective functional deficits in the prefrontal cortex. AB - Adolescence has been identified as a vulnerable developmental time period during which exposure to drugs can have long-lasting, detrimental effects. Although adolescent binge-like ethanol (EtOH) exposure leads to a significant reduction in forebrain cholinergic neurons, EtOH's functional effect on acetylcholine (ACh) release during behavior has yet to be examined. Using an adolescent intermittent ethanol exposure model (AIE), rats were exposed to binge-like levels of EtOH from postnatal days (PD) 25 to 55. Three weeks following the final EtOH exposure, cholinergic functioning was assessed during a spontaneous alternation protocol. During maze testing, ACh levels increased in both the hippocampus and prefrontal cortex. However, selectively in the prefrontal cortex, AIE rats displayed reduced levels of behaviorally relevant ACh efflux. We found no treatment differences in spatial exploration, spatial learning, spatial reversal, or novel object recognition. In contrast, AIE rats were impaired during the first attentional set shift on an operant set-shifting task, indicative of an EtOH-mediated deficit in cognitive flexibility. A unique pattern of cholinergic cell loss was observed in the basal forebrain following AIE: Within the medial septum/diagonal band there was a selective loss (30%) of choline acetyltransferase (ChAT)-positive neurons that were nestin negative (ChAT+/nestin-); whereas in the Nucleus basalis of Meynert (NbM) there was a selective reduction (50%) in ChAT+/nestin+. These results indicate that early adolescent binge EtOH exposure leads to a long lasting frontocortical functional cholinergic deficit, driven by a loss of ChAT+/nestin+ neurons in the NbM, which was associated with impaired cognitive flexibility during adulthood. PMID- 28807790 TI - The functional domains for Bax?2 aggregate-mediated caspase 8-dependent cell death. AB - Bax?2 is a functional pro-apoptotic Bax isoform having alterations in its N terminus, but sharing the rest of its sequence with Baxalpha. Bax?2 is unable to target mitochondria due to the loss of helix alpha1. Instead, it forms cytosolic aggregates and activates caspase 8. However, the functional domain(s) responsible for BaxDelta2 behavior have remained elusive. Here we show that disruption of helix alpha1 makes Baxalpha mimic the behavior of Bax?2. However, the other alterations in the Bax?2 N-terminus have no significant impact on aggregation or cell death. We found that the hallmark BH3 domain is necessary but not sufficient for aggregation-mediated cell death. We also noted that the core region shared by Baxalpha and Bax?2 is required for the formation of large aggregates, which is essential for BaxDelta2 cytotoxicity. However, aggregation by itself is unable to trigger cell death without the C-terminus. Interestingly, the C-terminal helical conformation, not its primary sequence, appears to be critical for caspase 8 recruitment and activation. As Bax?2 shares core and C-terminal sequences with most Bax isoforms, our results not only reveal a structural basis for Bax?2 induced cell death, but also imply an intrinsic potential for aggregate-mediated caspase 8-dependent cell death in other Bax family members. PMID- 28807792 TI - Anti-science in the 21st century. PMID- 28807791 TI - Effects of Bosutinib Treatment on Renal Function in Patients With Philadelphia Chromosome-Positive Leukemias. AB - BACKGROUND: The purpose of the study was to assess renal function in patients with Philadelphia chromosome-positive leukemias receiving bosutinib or imatinib. PATIENTS AND METHODS: Patients received first-line bosutinib (n = 248) or imatinib (n = 251; phase III trial), or second-line or later bosutinib (phase I/II trial; n = 570). Adverse events (AEs) and changes from baseline in estimated glomerular filtration rate (eGFR) and serum creatinine were assessed. RESULTS: Time from the last patient's first dose to data cutoff was >= 48 months. Renal AEs were reported in 73/570 patients (13%) receiving second-line or later bosutinib, and in 22/248 (9%) and 16/251 (6%) receiving first-line bosutinib and imatinib, respectively. eGFR in patients receiving bosutinib declined over time with more patients developing Grade >= 3b eGFR (< 45 mL/min/1.73 m2 according to the Modification of Diet in Renal Disease method) with second-line or later bosutinib (139/570, 24%) compared with first-line bosutinib (26/248, 10%) and imatinib (25/251, 10%); time to Grade >= 3b eGFR was shortest with second-line or later bosutinib. Similar proportions of patients receiving second-line or later bosutinib (74/139, 53%), first-line bosutinib (15/26, 58%), and first-line imatinib (15/25, 60%) improved to >= 45 mL/min/1.73 m2 eGFR as of the last follow up. In a regression analysis, first-line treatment with bosutinib versus imatinib was not a significant predictor of Grade >= 3b eGFR. CONCLUSION: Long-term bosutinib treatment is associated with an apparently reversible decline in renal function with frequency and characteristics similar to renal decline observed with long-term imatinib treatment. Patients with risk factors for Grade >= 3b eGFR should be monitored closely. PMID- 28807793 TI - Interests. PMID- 28807794 TI - Flavor and object recognition memory impairment induced by excitotoxic lesions of the perirhinal cortex. AB - Recognition memory is based on the ability to assess the familiarity of a previously encountered stimulus. It can be approached using tests for different sensorial modalities. Excitotoxic lesions of the perirhinal cortex (Prh) were performed in order to assess the relevance of its integrity for object and flavor recognition memory. Object recognition memory was impaired with a 24h retention interval. Flavor neophobia attenuation was prevented on a second encounter with the tastant. These results support a role of the perirhinal cortex in mediating the transition from novel to familiar, both in object and flavor recognition memory. PMID- 28807795 TI - d-Cycloserine facilitates extinction learning and enhances extinction-related brain activation. AB - Extinction learning is modulated by N-methyl d-aspartate receptors (NMDAR) particularly in prefrontal and hippocampal brain regions. The use of of NMDA agonists in exposure therapy of anxiety disorders has been investigated in various patient groups. Behavioral results showed beneficial effects of pre learning administration of the partial NMDAR agonist d-Cycloserine (DCS) on therapy success. However, the impact of DCS upon non-fear-related contextual extinction, and associated recruitment of extinction-relevant brain regions is as yet unknown. In the present fMRI study, healthy human participants performed a context-related associative learning and extinction task. A single dose of DCS, administered prior to extinction learning, enhanced extinction learning performance in an identical context, and increased activation in prefrontal, temporal as well as hippocampal/insular regions, compared to placebo controls. In contrast, DCS did not affect extinction learning in a novel context, nor the renewal effect, which describes the recovery of an extinguished response if the context of extinction differs from the context of recall. Our findings demonstrate a specific involvement of prefrontal and hippocampal NMDAR in the modification of established stimulus-outcome associations in identical contexts and thus their role in behavioral flexibility, underlining their potential for enhancing AAA extinction learning. PMID- 28807796 TI - High-content image analysis (HCIA) assay has the highest correlation with direct counting cell suspension compared to the ATP, WST-8 and Alamar blue assays for measurement of cytotoxicity. AB - INTRODUCTION: Various cytotoxicity assays measuring indicators such as enzyme activity, dye uptake, or cellular ATP content are often performed using 96-well microplates. However, recent reports show that cytotoxicity assays such as the ATP assay and MTS assay underestimate cytotoxicity when compounds such as anti cancer drugs or mutagens induce cell hypertrophy whilst increasing intracellular ATP content. Therefore, we attempted to evaluate the reliability of a high content image analysis (HCIA) assay to count cell number in a 96-well microplate automatically without using a cell-number indicator. METHODS: We compared cytotoxicity results of 25 compounds obtained from ATP, WST-8, Alamar blue, and HCIA assays with those directly measured using an automatic cell counter, and repeating individual experiments thrice. RESULTS: The number of compounds showing low correlation in cell viability measured using cytotoxicity assays compared to automatic cell counting (r2<0.8, at least 2 of 3 experiments) were follows: ATP assay; 7; WST-8 assay, 2; Alamar blue assay, 3; HCIA cytotoxicity assay, 0. Compounds for which correlation was poor in 3 assays, except the HCIA assay, induced an increase in nuclear and cell size. However, correlation between cell viability measured by automatic cell counter and the HCIA assay was strong regardless of nuclear and cell size. Additionally, correlation coefficients between IC50 values obtained from automatic cell counter and from cytotoxicity assays were as follows: ATP assay, 0.80; WST-8 assay, 0.84; Alamar blue assay, 0.84; and HCIA assay, 0.98. DISCUSSION: From the above, we showed that the HCIA cytotoxicity assay produces similar data to the automatic cell counter and is highly accurate in measuring cytotoxicity. PMID- 28807797 TI - Fresnel Prism Intraocular Lens and Scharioth Macula Lens. PMID- 28807798 TI - Clinically undetected retinal breaks causing retinal detachment: A review of options for management. AB - The successful detection of retinal breaks is a critical step in rhegmatogenous retinal detachment surgery in order to prevent persistent/recurrent retinal detachments. Not all retinal breaks causing retinal detachments are obvious. Retinal breaks may be obscured by opacities that are either anterior segment related, lens related, or posterior segment related. Rules to identify breaks based on subretinal fluid configuration are more difficult to apply in pseudophakic, aphakic, and scleral buckle encircled eyes-and in eyes with repeat detachments and those with proliferative vitreoretinopathy. Exudative detachments exhibit characteristic features and must be ruled out. A thorough clinical examination preoperatively is important even if a vitrectomy is planned. We review the incidence and causes of undetected breaks, along with preoperative/clinical issues that may hinder break detection. We review the literature with respect to investigative approaches and techniques that are available to the vitreoretinal surgeon when primary breaks remain clinically undetected during the preoperative examination. We broadly divide the surgical approaches into ones where the surgeon utilizes techniques to pursue actively a search for breaks versus adopting a purely speculative approach. Advantages and disadvantages of various techniques are appraised. Intuitively one might argue that an encircling scleral buckle combined with vitrectomy would give higher single operation success than pars plana vitrectomy alone because "undetected" retinal breaks would be addressed by a 360 degrees plombage. We could not confirm this concept. Newer techniques, such as pars plana vitrectomy augmented with dye extrusion or endoscopic-assisted pars plana vitrectomy, show encouraging results. Technological advances such as intraoperative optical coherence tomography will also help to broaden the vitreoretinal surgeon's armamentarium. At this time, there is no gold standard in terms of the recommended approach, and this is reflected in the many options that are available for management. The surgeon must consider the benefits versus the risk of their preferred approach. PMID- 28807799 TI - The influence of yttrium-segregation-dependent phase partitioning and residual stresses on the aging and fracture behaviour of 3Y-TZP ceramics. AB - : The yttrium-segregation-dependent phase partitioning and residual stress development that influence both the aging and the fracture behaviour in 3Y-TZP bioceramics were studied by sintering alumina-free 3Y-TZP, varying the sintering temperature and the time, to yield ceramics with identical grain size distributions, but with different phase compositions. The structure and stability of the resulting tetragonal phases, in the form of transformable, yttria-lean t ZrO2 (YLZ) and non-transformable, yttria-rich t"-ZrO2 and/or t'-ZrO2 (YRZ), were studied by X-ray diffraction (XRD) and focused ion beam scanning electron microscopy (FIB-SEM). The accelerated aging kinetics was fitted to the Mehl Avrami-Johnson equation. The specimen sintered at the lowest sintering temperature but with the longest dwell time contained the smallest and the largest concentrations of yttria in the YLZ and YRZ phases, respectively, as well as the largest amount of YRZ. As a consequence, it exhibited the fastest linear aging kinetics accompanied by more extensive micro-cracking of the transformed layer, as well as largest amount of intergranular fracture and the greatest resistance to fracture. These properties were ascribed to the increased transformability of the YLZ phase and the greatest propensity of the YRZ phase to relax the accumulated residual stresses during transformation (tetragonal to monoclinic, t-m) manifested asa~2.4% unit-cell volume increase. The observed relaxation provides additional understanding of the t-m transformation mechanism, which governs both the aging and fracture behaviour of 3Y-TZP. STATEMENT OF SIGNIFICANCE: A novel approach to understanding the effect of yttrium segregation on t-m transformation of 3Y-TZP zirconia bioceramics is presented. Carefully designed sintering strategy facilitated fabrication of ceramics with identical grain size distributions but with different yttrium concentrations. The influence of phase partitioning on stability and structure of transformable yttria-lean tetragonal phase (YLZ) and non-transformable yttria-rich phases (YRZ; t"- and t' prime) and on the formation of residual stresses in YRZ were investigated. It is shown that YRZ phases are under compressive stresses in YLZ matrix, since a systematic relaxation after ageing was observed and explained for the first time. It puts additional perspective on the understanding of the t-m transformation mechanism ultimately governing both the ageing and fracture behaviour of 3Y-TZP. PMID- 28807800 TI - The synergistic effects of Sr and Si bioactive ions on osteogenesis, osteoclastogenesis and angiogenesis for osteoporotic bone regeneration. AB - : Bioactive ions released from bioceramics play important roles in bone regeneration; however, it is unclear how each ionic composition in complex bioceramics exerts its specific effect on bone regeneration. The aim of this study is to elucidate the functional effects of Sr and Si ions in bioceramics on the regeneration of osteoporotic bone. A model bioceramic with Sr- and Si containing components (SMS) was successfully fabricated and the effects of ionic products from SMS bioceramics on the osteogenic, osteoclastic and angiogenic differentiation of rBMSCs-OVX and RANKL-induced osteoclasts were investigated. The results showed that SMS bioceramics could enhance ALP activity and expression of Col 1, OCN, Runx2, and angiogenic factors including VEGF and Ang-1. SMS bioceramics not only rebalanced the OPG/RANKL ratio of rBMSCs-OVX at early stage, but also repressed RANKL-induced osteoclast formation and expression of TRAP, DC STAMP, V-ATPase a3, and NFATc1. The synergistic effects of Sr and Si ions were further investigated as compared with those of similar concentrations of Sr and Si ions alone. Sr and Si ions possessed synergistic effects on osteogenesis, osteoclastogenesis, and angiogenesis, attributed to the dominant effects of Sr ions on enhancing angiogenesis and repressing osteoclastogenesis, and the dominant effects of Si ions on stimulating osteogenesis. The in vivo study using critical-size mandibular defects of OVX rat models showed that SMS bioceramics could significantly enhance bone formation and mineralization compared with beta TCP bioceramics. Our results are the first to elucidate the specific effect of each ion from bioceramics on osteogenesis, osteoclastogenesis and angiogenesis for osteoporotic bone regeneration, paving the way for the design of functional biomaterials with complex compositions for tissue engineering and regenerative medicine. STATEMENT OF SIGNIFICANCE: Bioactive ions released from bioceramics play important roles for bone regeneration; however, it is unclear how each of ionic compositions in complex bioceramics exerts its specific effect on bone regeneration. The aim of present study is to elucidate the functional effects of Sr and Si ions in complex bioceramics on the regeneration of osteoporotic bone. A model bioceramic with Sr and Si-containing components (SMS) was successfully fabricated and the effects of ionic products from SMS bioceramics on the osteogenic, osteoclastic and angiogenic differentiation of rBMSCs-OVX and RANKL induced osteoclasts were investigated. The results showed that SMS bioceramics could enhance ALP activity and expression of Col 1, OCN, Runx2 and angiogenic factors including VEGF and Ang-1. SMS bioceramics not only rebalanced the ratio of OPG/RANKL of OVX-BMSCs at early stage, but also repressed RANKL-induced osteoclast formation and expression of TRAP, DC-STAMP, V-ATPase a3, and NFATc1. The synergistic effects of Sr and Si ions were further investigated as compared with the similar concentration of Sr and Si ions alone. It was found that Sr and Si ions possessed synergistic effects on osteogenesis, osteoclastogenesis and angiogenesis, attributed to the dominant effects of Sr ions on enhancing angiogenesis and repressing osteoclastogenesis, and the dominant effects of Si ions on stimulating osteogenesis. The in vivo study using critical-size mandibular defects of OVX rat models showed that SMS bioceramics could significantly enhance bone formation and mineralization as compared with beta-TCP bioceramics. It is suggested that SMS bioceramics may be a promising biomaterial for osteoporotic bone regeneration. To our knowledge, this is the first time to elucidate the specific effect of each ion from bioceramics on osteogenesis, osteoclastogenesis and angiogenesis for osteoporotic bone regeneration, paving the way to design functional biomaterials with complex compositions for tissue engineering and regenerative medicine. PMID- 28807801 TI - Effect of diabetes mellitus on clinical outcomes and quality of life after transcatheter aortic valve implantation for severe aortic valve stenosis. AB - BACKGROUND: Diabetes mellitus (DM) is considered a marker of poor prognosis after cardiac surgery. We sought to investigate the effect of DM on clinical outcomes and quality of life (QoL) after transcatheter aortic valve implantation (TAVI). METHODS: A total of 148 consecutive patients with symptomatic, severe aortic stenosis who underwent TAVI were included. Baseline characteristics, procedural and long-term clinical outcomes, and the results of frailty and QoL assessment with EQ-5D-3L questionnaire were compared between patients with and without DM. RESULTS: DM was present in 48 of 148 (32.4%) patients. No differences in periprocedural risk (Logistic Euroscore and Society of Thoracic Surgeons (STS) scale) between groups were observed. There were no differences in 30-day and 12 month all-cause mortality between groups [DM(-) vs. DM(+): 7 (7.0%) vs. 5 (10.4%), p = 0.53 and 12 (12.0%) vs. 10 (20.8%), p = 0.16, respectively]. No influence of DM presence on the risk of death was confirmed after adjustment for age and gender (for 30-day mortality, age/gender-adjusted OR 1.55, 95%CI 0.47 5.17; for 12-month mortality, age/gender-adjusted OR 2.05, 95%CI 0.79-5.32). Similarly, at the longest available follow-up, mortality did not differ between groups [14 (29.2%) vs. 19 (19.0%), p = 0.16; age/gender-adjusted OR 1.81, 95%CI 0.80-4.08]. Similar rates of other complications after TAVI were noted. Frailty measured with the 5-meter walking test was more frequently reported in patients with DM [11 (22.9%) vs. 10 (10.0%), p = 0.035]. No differences in QoL parameters at baseline and 12 months were noted. CONCLUSIONS: Patients with DM undergoing TAVI demonstrated similar mortality, complication rates, and QoL outcomes compared to patients without DM. PMID- 28807802 TI - Characteristics of the transRADIAL approach for coronary angiography and angioplasty in GREECE: the RADIAL-GREECE registry. PMID- 28807803 TI - Effect of depression on long-term prognosis after successful coronary stenting. PMID- 28807805 TI - Laparoscopic Sentinel Node Mapping in Cervical and Endometrial Malignancies: A Case-Control Study Comparing Two Near-Infrared Fluorescence Systems. AB - STUDY OBJECTIVE: The goal of this study was to evaluate the intraoperative and perioperative surgical outcomes of 2 different florescence systems commonly used for sentinel lymph node (SLN) mapping in women with early-stage cervical cancer or endometrial cancer. DESIGN: Case-control study (Canadian Task Force classification II-2). SETTING: The Gynecology Oncology Surgical Unit of the San Gerardo Hospital, Italy. PATIENTS: Thirty-four consecutive women with early stage cervical cancer (stage IA-1B1) or apparent confined stage I endometrial cancer were included in the study. INTERVENTIONS: Between October 2016 and May 2017, 34 patients underwent laparoscopic surgery with SLN mapping using indocyanine green dye: 22 women were mapped with the Storz 1S system (Karl Storz Endoscopy, Tuttlingen, Germany; Group A), whereas 12 women underwent planned surgery with the Novadaq PinPoint system (Novadaq, Mississauga, Ontario, Canada; Group B). MEASUREMENT AND MAIN RESULTS: We compared the surgical and perioperative outcomes of Group A and Group B. Patients in Group B had a shorter duration of the SLN mapping time than those in Group A (p = .0003). The median number of SLNs removed was 2 (range, 0-5) in Group A and 2 (range, 1-3) in Group B (p = .501). Bilateral mapping was 77.3% in Group A and 83.3% in Group B (p = .334), respectively. No differences were recorded in terms of body mass index, length of hospital stay, type of tumor, bilateral mapping, or number of lymph nodes removed. Body mass index was found to have no impact on the duration of the mapping (p = .353). CONCLUSION: From our preliminary experience we can conclude that both fluorescence systems are valid and applicable for SLN detection in the case of early-stage cervical or endometrial cancer. The PinPoint system seems to allow surgeons easier and faster identification of the SLNs, particularly in endometrial cancer patients. PMID- 28807804 TI - Joint parameter estimation in the QTL mapping of ordinal traits. AB - With the rapid development of statistical genetics, the deep researches of ordinal traits have been gradually emphasized. The data of these traits bear relatively less information than those of continuous phenotypes, therefore it is more complex to map the quantitative trait loci (QTL) of ordinal traits. In this paper, the multiple-interval mapping method is considered in the genetic mapping of ordinal traits. By combining threshold model and statistical model, we build a cumulative logistic regression model to express the relationship between the ordinal data and the QTL genotypes. In order to make the interval mapping more straightforward, we treat the recombination rates as unknown parameters, and then simultaneously obtain the estimates of QTL positions, QTL effects and threshold parameters via the EM algorithm. We perform simulation experiments to investigate and compare the proposed method. We also present a real example to test the reasonableness of the considered model and estimate both model parameters and QTL parameters. Both results of simulations and example show that the method we proposed is reasonable and effective. PMID- 28807806 TI - Removal of Retained Multiple Fetal Bones by Hysteroscopy. PMID- 28807807 TI - In Vitro Fertilization Success Rates after Surgically Treated Endometriosis and Effect of Time Interval between Surgery and In Vitro Fertilization. AB - STUDY OBJECTIVE: To evaluate the impact of endometriosis staging and endometriomas on in vitro fertilization (IVF) outcome and to assess the optimal time interval between laparoscopy and IVF. DESIGN: A retrospective clinical study (Canadian Task Force classification II1). SETTING: A university-affiliated private infertility clinic. PATIENTS: Two hundred sixteen infertile patients with endometriosis and 209 infertile patients without endometriosis. INTERVENTIONS: Laparoscopy, IVF. MEASUREMENTS AND MAIN RESULTS: Patients with endometriosis were classified according to American Society for Reproductive Medicine criteria; 58, 67, 63, and 28 patients had stages 1 through 4 disease, respectively. Patients with endometriosis had significantly lower estradiol on trigger day (9986 +/- 6710 vs 12 220 +/- 9414 pg/mL, respectively) and number of retrieved oocytes (12.7 +/- 8.6 vs 14.0 +/- 10, respectively) compared with controls. We found a consistent decline in clinical and ongoing pregnancy rates with increasing stage of endometriosis. The presence of endometrioma in patients with stages 3 and 4 endometriosis did not alter IVF outcome. Patients with a time interval of 7 to 12 and 13 to 25 months after surgery had a favorable outcome. CONCLUSION: IVF pregnancy rate was negatively correlated with endometriosis severity. The presence of endometriomas had no impact on IVF clinical outcome. The optimal time to perform IVF appears to be between 7 and 25 months after endometriosis surgery. PMID- 28807808 TI - Safety and Efficacy of Amnion Graft in Preventing Reformation of Intrauterine Adhesions. AB - STUDY OBJECTIVE: To determine the safety and efficacy of amnion grafts in preventing the recurrence of intrauterine adhesions after hysteroscopic adhesiolysis in women with severe intrauterine adhesions. DESIGN: A retrospective matched cohort study including 120 patients treated during 62 months (Canadian Task Force classification II-2). SETTING: A tertiary referral center. PATIENTS: A total of 120 patients who underwent intrauterine adhesiolysis for severe intrauterine adhesions: 40 patients in the treatment group and 80 patients in the control group matched for age and adhesion scores. The mean duration of follow-up was 14.6 months. INTERVENTION: A Foley balloon with/without a fresh amnion graft was introduced into the uterine cavity after hysteroscopic adhesiolysis. MEASUREMENTS AND MAIN RESULTS: In both groups, the balloon was kept in place for 7 days, cyclic hormone treatment was given for 3 months, and second-look and third-look hysteroscopies were performed 1 and 3 months after the operation. Outcome measures included the incidence of the recurrence of intrauterine adhesions, the score of intrauterine adhesions (if present), and the impact of the surgery on the amount of menstrual flow. In the study group, the menstrual score at the end of 3 months was significantly higher, and the intrauterine adhesion score at third-look hysteroscopy was significantly lower compared with those in the control group. The incidences of the recurrence of intrauterine adhesions at third-look hysteroscopy in the treatment and control groups were 30% and 48.7%, respectively (p = .05). The adhesion scores at third-look hysteroscopy in the treatment and control groups were 1.3 and 2.1, respectively (p < .05). CONCLUSION: The use of an amnion graft after intrauterine adhesiolysis appears to be beneficial in improving menstruation and reducing the recurrence of adhesion reformation. PMID- 28807809 TI - Paraureteral Endometriosis with Bilateral Gross Hydroureters and Left Renal Compromise. PMID- 28807810 TI - Unique Learning System for Uterine Artery Embolization for Symptomatic Myoma and Adenomyosis for Obstetrician-Gynecologists in Cooperation with Interventional Radiologists: Evaluation of UAE From the Point of View of Gynecologists Who Perform UAE. AB - STUDY OBJECTIVE: To evaluate a unique learning system for uterine artery embolization (UAE) and examine its feasibility and clinical outcomes for the treatment of symptomatic uterine leiomyomas and adenomyosis when performed by obstetrician-gynecologists in cooperation with interventional radiologists (IVRs). DESIGN: Retrospective study (Canadian Task Force classification II-2). SETTING: University hospital. PATIENTS: One hundred seventy-three patients who underwent UAE for symptomatic leiomyomas and adenomyosis. INTERVENTIONS: We examined the medical records of patients who underwent UAE for symptomatic uterine leiomyomas and adenomyosis at our department between 2003 and 2012 using our learning system for UAE for obstetrician-gynecologists in cooperation with IVRs. The charts of all patients were reviewed, and data on etiologic factors, past medical history of leiomyomas and adenomyosis, symptoms, details of UAE, and clinical outcomes after UAE were extracted. MEASUREMENTS AND MAIN RESULTS: A total of 173 patients who underwent 177 UAEs were identified, including 4 patients who underwent embolization twice because of primary treatment failure or symptom recurrence. During the study period, 2 gynecologists successfully acquired endovascular skills. The technical success rate was 97.7% (174 of 177). The duration of fluoroscopy in procedures performed by obstetrician-gynecologists who acquired endovascular skills was not significantly different from that in procedures performed by IVRs at our institution; however, this duration was significantly longer in procedures performed by obstetrician-gynecologists who did not have sufficient experience with our learning protocol for UAE because of inadequate live observation of UAEs performed by skilled IVRs. Complications that necessitated discontinuation of the procedure occurred in 2.3% of cases (4 of 177). The clinical outcomes were similar to those reported in previous studies. Adverse events after UAE included myeloid passages in 7.0% (11 of 158), infections in 2.5% (4 of 158), vaginal discharge in 2.5% of patients with leiomyomas (4 of 158), and vaginal discharge in 7.1% of patients with adenomyosis (1 of 14). All the adverse events were adequately treated by the obstetrician gynecologists themselves. The timing of hysterectomy due to complications or recurrence of symptoms after UAE varied widely. CONCLUSION: UAE performed by obstetrician-gynecologists in cooperation with radiologists can be achieved safely and successfully with acceptable clinical outcomes. Live observation of the procedure performed by skilled IVRs is essential to improving the skills and reducing the fluoroscopic time of obstetrician-gynecologists. PMID- 28807811 TI - Clinical Validation of a Genome-Wide DNA Methylation Assay for Molecular Diagnosis of Imprinting Disorders. AB - Genomic imprinting involves a DNA methylation-dependent and parent-of-origin specific regulation of gene expression. Clinical assays for imprinting disorders are genomic locus, disorder, and molecular defect specific. We aimed to clinically validate a genome-wide approach for simultaneous testing of common imprinting disorders in a single assay. Using genome-wide DNA methylation arrays, epigenetic profiles from peripheral blood of patients with Angelman, Prader Willi, Beckwith-Wiedemann, or Silver-Russell syndromes were compared to a reference cohort of 361 unaffected individuals. The analysis was of developmental delay and intellectual disabilities. This approach has allowed 100% sensitivity and specificity in detecting imprinting defects in all 28 patients and enabled identification of defects beyond the classically tested imprinted loci. Analysis of the cohort of patients with developmental delay and intellectual disabilities identified two patients with Prader-Willi syndrome, one with Beckwith-Wiedemann syndrome, and several other patients with DNA methylation defects in novel putative imprinting loci. These findings demonstrate clinical validation of a sensitive and specific genome-wide DNA methylation array-based approach for molecular testing of imprinting disorders to allow simultaneous assessment of genome-wide epigenetic defects in a single analytical procedure, enabling replacement of multiple locus-specific molecular tests while allowing discovery of novel clinical epigenomic associations and differential diagnosis of other epigenomic disorders. PMID- 28807812 TI - Evaluation and Clinical Validation of Two Field-Deployable Reverse Transcription Insulated Isothermal PCR Assays for the Detection of the Middle East Respiratory Syndrome-Coronavirus. AB - Middle East respiratory syndrome (MERS) is an emerging zoonotic viral respiratory disease that was first identified in Saudi Arabia in 2012. In 2015, the largest MERS outbreak outside of the Middle East region occurred in the Republic of Korea. The rapid nosocomial transmission of MERS-coronavirus (MERS-CoV) in Korean health care settings highlighted the importance and urgent need for a rapid and reliable on-site diagnostic assay to implement effective control and preventive measures. Here, the evaluation and validation of two newly developed reverse transcription-insulated isothermal PCR (RT-iiPCR) methods targeting the ORF1a and upE genes of MERS-CoV are described. Compared with World Health Organization recommended singleplex real-time quantitative RT-PCR (RT-qPCR) assays, both RT iiPCR assays had comparable analytical sensitivity for the detection of MERS-CoV RNA in tissue culture fluid and in sputum samples spiked with infectious virus. Furthermore, clinical evaluation was performed with sputum samples collected from subjects with acute and chronic respiratory illnesses, including patients infected with MERS-CoV. The overall agreement values between the two RT-iiPCR assays and the reference RT-qPCR assays were 98.06% (95% CI, 94.43%-100%; kappa = 0.96) and 99.03% (95% CI, 95.88%-100%; kappa = 0.99) for ORF1a and upE assays, respectively. The ORF1a and upE MERS-CoV RT-iiPCR assays coupled with a field deployable system provide a platform for a highly sensitive and specific on-site tool for diagnosis of MERS-CoV infections. PMID- 28807813 TI - Norovirus Loads in Stool Specimens of Cancer Patients with Norovirus Gastroenteritis. AB - In immunocompromised patients with norovirus (NoV) gastroenteritis, the relationship between fecal NoV load and clinical complications has not been examined. In this study, a validated real-time quantitative PCR assay was used to determine viral loads for NoV genogroup I and II (GI and GII) in NoV-positive stool specimens of cancer patients. A total of 234 specimens from 152 patients were positive for NoV, including 201 of GII and 33 of GI. Geometric mean of logarithmic copies per gram of stool (w/w) of NoV-GII were 9.03 +/- 1.71 (means +/- SD), which was significantly higher than that of NoV-GI [7.87 +/- 1.49; odd ratio (OR), 3.22; 95% CI, 1.33-7.76; P = 0.009]. Among 152 patients with gastroenteritis, the fecal NoV geometric mean of logarithmic copy was correlated with mild (n = 85; 7.97 +/- 1.55), moderate (n = 23; 9.09 +/- 1.38), and severe (n = 44; 10.39 +/- 0.91) episodes of severity by modified Vesikari scoring system, respectively. Multivariate analysis revealed that high level of NoV load was correlated with GII infections (OR, 4.13; 95% CI, 1.62-10.55; P = 0.003) and associated with development of severe clinical symptom (OR, 5.53; 95% CI, 2.00 7.24; P = 0.001) at the time of diagnosis. Infection with GII strains was more common than GI infection in cancer patients with viral gastroenteritis. PMID- 28807814 TI - Development of a Chromosomal Microarray Test for the Detection of Abnormalities in Formalin-Fixed, Paraffin-Embedded Products of Conception Specimens. AB - Testing the products of conception (POCs) provides information about the cause of fetal loss and helps determine the recurrence risk of future losses and chromosome abnormalities in subsequent pregnancies. Historically, the Mayo Clinic Cytogenetics Laboratory performed targeted fluorescent in situ hybridization (FISH) testing to identify aneuploidy of only certain chromosomes in formalin fixed, paraffin-embedded (FFPE) POC samples. Chromosomal microarray studies using the Affymetrix OncoScan FFPE Assay can detect copy number changes across the genome. We validated the utility of the OncoScan assay using 25 archival FFPE POC specimens with previous FISH results (five normal, 12 trisomy, six triploidy, two monosomy). Of the five normal samples, four had no clinically relevant findings, and one sample was found to have trisomy 9, which is not detectable by the FISH test. For the 20 samples with abnormal FISH results, the OncoScan assay identified all reported abnormalities along with additional findings. A sample with trisomy 22 was also found to have trisomy 7. Another sample reported as triploidy was found to have four copies of chromosome 16. In conclusion, we verified the performance characteristics of OncoScan on FFPE POC specimens and found it acceptable for clinical use. Additional information was identified in 3 of 25 cases (12%) that would explain the pregnancy loss or provide recurrence risk for the family. PMID- 28807815 TI - Bcl-xL knockout attenuates mitochondrial respiration and causes oxidative stress that is compensated by pentose phosphate pathway activity. AB - Bcl-xL is an anti-apoptotic protein that localizes to the outer mitochondrial membrane and influences mitochondrial bioenergetics by controlling Ca2+ influx into mitochondria. Here, we analyzed the effect of mitochondrial Bcl-xL on mitochondrial shape and function in knockout (KO), wild type and rescued mouse embryonic fibroblast cell lines. Mitochondria of KO cells were more fragmented, exhibited a reduced ATP concentration, and reduced oxidative phosphorylation (OXPHOS) suggesting an increased importance of ATP generation by other means. Under steady-state conditions, acidification of the growth medium as a readout for glycolysis was similar, but upon inhibition of ATP synthase with oligomycin, KO cells displayed an instant increase in glycolysis. In addition, forced energy production through OXPHOS by replacing glucose with galactose in the growth medium rendered KO cells more susceptible to mitochondrial toxins. KO cells had increased cellular reactive oxygen species and were more susceptible to oxidative stress, but had higher glutathione levels, which were however more rapidly consumed under conditions of oxidative stress. This coincided with an increased activity and protein abundance of the pentose phosphate pathway protein glucose-6 phosphate dehydrogenase, which generates NADPH necessary to regenerate reduced glutathione. KO cells were also less susceptible to pharmacological inhibition of the pentose phosphate pathway. We conclude that mitochondrial Bcl-xL is involved in maintaining mitochondrial respiratory capacity. Its deficiency causes oxidative stress, which is associated with an increased glycolytic capacity and balanced by an increased activity of the pentose phosphate pathway. PMID- 28807817 TI - Assessment of glutathione/glutathione disulphide ratio and S-glutathionylated proteins in human blood, solid tissues, and cultured cells. AB - Glutathione (GSH) is the major non-protein thiol in humans and other mammals, which is present in millimolar concentrations within cells, but at much lower concentrations in the blood plasma. GSH and GSH-related enzymes act both to prevent oxidative damage and to detoxify electrophiles. Under oxidative stress, two GSH molecules become linked by a disulphide bridge to form glutathione disulphide (GSSG). Therefore, assessment of the GSH/GSSG ratio may provide an estimation of cellular redox metabolism. Current evidence resulting from studies in human blood, solid tissues, and cultured cells suggests that GSH also plays a prominent role in protein redox regulation via S -glutathionylation, i.e., the conjugation of GSH to reactive protein cysteine residues. A number of methodologies that enable quantitative analysis of GSH/GSSG ratio and S glutathionylated proteins (PSSG), as well as identification and visualization of PSSG in tissue sections or cultured cells are currently available. Here, we have considered the main methodologies applied for GSH, GSSG and PSSG detection in biological samples. This review paper provides an up-to-date critical overview of the application of the most relevant analytical, morphological, and proteomics approaches to detect and analyse GSH, GSSG and PSSG in mammalian samples as well as discusses their current limitations. PMID- 28807818 TI - Novel concentrated water-in-oil emulsions based on a non-ionic silicone surfactant: Appealing application properties and tuneable viscoelasticity. AB - Silicone excipients are non-irritating ingredients that are extensively used in topical formulations. In the present study, innovative water-in-oil emulsions with a high water content stabilised by a non-ionic silicone surfactant were developed. Effects of formulation composition on its properties and stability were investigated. It was possible to prepare highly stable emulsions with a water volume fraction of up to 80%. The emulsions exhibited desirable application properties such as non-sticky and cooling qualities. A dependency of the viscosity on the water fraction was found; this offers the opportunity to create emulsions with fine-tuned rheological properties. Furthermore, it could be shown in skin studies that the in vitro release of a hydrophilic model drug is influenced by the configuration of the oil phase. The penetration of the silicone surfactant and the other deployed additives was monitored using combined tape stripping and ATR-FTIR experiments, revealing that the compounds remain in the superficial layers of the stratum corneum, thus minimising the risk for skin irritation. PMID- 28807816 TI - mTOR in Down syndrome: Role in Abeta and tau neuropathology and transition to Alzheimer disease-like dementia. AB - The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase involved in the regulation of protein synthesis and degradation, longevity and cytoskeletal formation. The mTOR pathway represents a key growth and survival pathway involved in several diseases such as cancer, obesity, cardiovascular disease and neurodegenerative diseases. Numerous studies linked the alterations of mTOR pathway to age-dependent cognitive decline, pathogenesis of Alzheimer disease (AD) and AD-like dementia in Down syndrome (DS). DS is the most frequent chromosomal abnormality that causes intellectual disability. The neuropathology of AD in DS is complex and involves impaired mitochondrial function, defects in neurogenesis, increased oxidative stress, altered proteostasis and autophagy networks as a result of triplication of chromosome 21(chr 21). The chr21 gene products are considered a principal neuropathogenic moiety in DS. Several genes involved respectively in the formation of senile plaques and neurofibrillary tangles (NFT), two main pathological hallmarks of AD, are mapped on chr21. Further, in subjects with DS the activation of mTOR signaling contributes to Abeta generation and the formation of NFT. This review discusses recent research highlighting the complex role of mTOR associated with the presence of two hallmarks of AD pathology, senile plaques (composed mostly of fibrillar Abeta peptides), and NFT (composed mostly of hyperphosphorylated tau protein). Oxidative stress, associated with chr21-related Abeta and mitochondrial alterations, may significantly contribute to this linkage of mTOR to AD-like neuropathology in DS. PMID- 28807819 TI - Carrier characteristics influence the kinetics of passive drug loading into lipid nanoemulsions. AB - Passive loading as a novel screening approach is a material-saving tool for the efficient selection of a suitable colloidal lipid carrier system for poorly water soluble drug candidates. This method comprises incubation of preformed carrier systems with drug powder and subsequent determination of the resulting drug load of the carrier particles after removal of excess drug. For reliable routine use and to obtain meaningful loading results, information on the kinetics of the process is required. Passive loading proceeds via a dissolution-diffusion-based mechanism, where drug surface area and drug water solubility are key parameters for fast passive loading. While the influence of the drug characteristics is mostly understood, the influence of the carrier characteristics remains unknown. The aim of this study was to examine how the lipid nanocarriers' characteristics, i.e. the type of lipid, the lipid content and the particle size, influence the kinetics of passive loading. Fenofibrate was used as model drug and the loading progress was analyzed by UV spectroscopy. The saturation solubility in the nanocarrier particles, i.e. the lipid type, did not influence the passive loading rate constant. Low lipid content in the nanocarrier and a small nanocarrier particle size both increased passive loading speed. Both variations increase the diffusivity of the nanocarrier particles, which is the primary cause for fast loading at these conditions: The quicker the carrier particles diffuse, the higher is the speed of passive loading. The influence of the diffusivity of the lipid nanocarriers and the effect of drug dissolution rate were included in an overall mechanistic model developed for similar processes (A. Balakrishnan, B.D. Rege, G.L. Amidon, J.E. Polli, Surfactant-mediated dissolution: contributions of solubility enhancement and relatively low micelle diffusivity, J. Pharm. Sci. 93 (2004) 2064-2075). The resulting mechanistic model gave a good estimate of the speed of passive loading in nanoemulsions. Whilst the drug's characteristics - apart from drug surface area - are basically fixed, the lipid nanocarriers can be customized to improve passive loading speed, e.g. by using small nanocarrier particles. The knowledge of the loading mechanism now allows the use of passive loading for the straightforward, material-saving selection of suitable lipid drug nanocarriers. PMID- 28807820 TI - The biology, function and clinical implications of exosomes in lung cancer. AB - Exosomes are 30-100 nm small membrane vesicles of endocytic origin that are secreted by all types of cells, and can also be found in various body fluids. Increasing evidence implicates that exosomes confer stability and can deliver their cargos such as proteins and nucleic acids to specific cell types, which subsequently serve as important messengers and carriers in lung carcinogenesis. Here, we describe the biogenesis and components of exosomes mainly in lung cancer, we summarize their function in lung carcinogenesis (epithelial mesenchymal transition, oncogenic cell transformation, angiogenesis, metastasis and immune response in tumor microenvironment), and importantly we focus on the clinical potential of exosomes as biomarkers and therapeutics in lung cancer. In addition, we also discuss current challenges that might impede the clinical use of exosomes. Further studies on the functional roles of exosomes in lung cancer requires thorough research. PMID- 28807821 TI - POPDC1 is suppressed in human breast cancer tissues and is negatively regulated by EGFR in breast cancer cell lines. AB - Breast cancer molecular heterogeneity has resulted in disparities in therapeutic response and targeting of molecular subtypes of breast cancer. This necessitates identification and validation of novel therapeutic targets for breast cancer treatment. Suppression of Popeye domain-containing (POPDC) proteins is hypothesized to promote malignant cell behaviour and poor clinical outcomes in various cancers. We aimed to determine whether POPDC proteins are suppressed in human ductal carcinoma tissues and if this correlates to clinical progression and Her2 status. We further assessed if the EGFR regulated POPDC1 in breast cancer. Here we show significant suppression of POPDC1 in malignant breast cancer tissues without correlation to clinical progression. Interestingly, POPDC2 and POPDC3 were highly expressed in malignant breast tissues. Furthermore, HER2+ status significantly correlated with high POPDC2 and POPDC3, but not POPDC1 expression. We further show for the first time that low POPDC1 correlates to high EGFR expression in breast cancer tissues and that EGFR negatively regulates POPDC1 expression in MCF7, MDA231 and SKBR3 breast cancer cells. Furthermore, overexpression of POPDC1 in MCF7, MDA231 and SKBR3 cells attenuated EGF-mediated cell migration and proliferation. These findings show that POPDC1 is suppressed in breast cancer and can potentially be targeted to inhibit EGFR-mediated cell migration and proliferation. PMID- 28807822 TI - Does long-term androgen deficiency lead to metabolic syndrome in middle-aged rats? AB - Evidence from clinical observational studies and animal experiments suggests that hypogonadism is associated with the metabolic syndrome. In most of the experiments, androgen deficiency is induced by gonadectomy in the adulthood and relatively short-term effects of hypogonadism on metabolic parameters are usually observed. The purpose of this study was to evaluate the metabolic effects of long term androgen deficiency starting before puberty in middle-aged male rats. The components of the metabolic syndrome were examined in male, female and gonadectomized male rats at the age of 18months. Sex differences were observed in plasma testosterone, cholesterol, high-density lipoproteins and also in body weight and in glycemia dynamics during oral glucose tolerance test. Gonadectomy and long-term hypogonadism did not affect most of the analyzed metabolic parameters such as blood pressure, glycemia, plasma insulin and uric acid. The only exception was the significantly higher liver enzymes in plasma and triacylglycerol in liver found in gonadectomized males. Except low-density lipoprotein, neither treatment of middle-aged males and females with letrozole, nor supplementation of estradiol as the metabolite of testosterone in gonadectomized male rats changed any of the observed metabolic parameters. Our results suggest that long-term hypogonadism started before puberty does not induce metabolic syndrome in middle-aged male rats, but may affect the liver. Sex differences in metabolic parameters in middle-aged rats are not mediated by testosterone. Whether hypogonadism predispose to metabolic syndrome in combination with other risk factors needs further clarification. PMID- 28807823 TI - Dietary supplementation with acetyl-l-carnitine counteracts age-related alterations of mitochondrial biogenesis, dynamics and antioxidant defenses in brain of old rats. AB - We previously reported the ability of dietary supplementation with acetyl-l carnitine (ALCAR) to prevent age-related decreases of mitochondrial biogenesis in skeletal muscle and liver of old rats. Here, we investigate the effects of ALCAR supplementation in cerebral hemispheres and cerebellum of old rats by analyzing several parameters linked to mitochondrial biogenesis, mitochondrial dynamics and antioxidant defenses. We measured the level of the coactivators PGC-1alpha and PGC-1beta and of the factors regulating mitochondrial biogenesis, finding an age related decrease of PGC-1beta, whereas PGC-1alpha level was unvaried. Twenty eight-month old rats supplemented with ALCAR for one and two months showed increased levels of both factors. Accordingly, the expression of the two transcription factors NRF-1 and TFAM followed the same trend of PGC-1beta. The level of mtDNA, ND1 and the activity of citrate synthase, were decreased with aging and increased following ALCAR treatment. Furthermore, ALCAR counteracted the age-related increase of deleted mtDNA. We also analyzed the content of proteins involved in mitochondrial dynamics (Drp1, Fis1, OPA1 and MNF2) and found an age-dependent increase of MFN2 and of the long form of OPA1. ALCAR treatment restored the content of the two proteins to the level of the young rats. No changes with aging and ALCAR were observed for Drp1 and Fis1. ALCAR reduced total cellular levels of oxidized PRXs and counteracted the age-related decrease of PRX3 and SOD2. Overall, our findings indicate a systemic positive effect of ALCAR dietary treatment and a tissue specific regulation of mitochondrial homeostasis in brain of old rats. Moreover, it appears that ALCAR acts as a nutrient since in most cases its effects were almost completely abolished one month after treatment suspension. Dietary supplementation of old rats with this compound seems a valuable approach to prevent age-related mitochondrial dysfunction and might ultimately represent a strategy to delay age-associated negative consequences in mitochondrial homeostasis. PMID- 28807824 TI - Flavan 3-ol delays the progression of disuse atrophy induced by hindlimb suspension in mice. AB - Periods of skeletal muscle disuse, for example due to a sedentary lifestyle or bed rest, are associated with aging and can lead to muscle atrophy. We previously found that the flavan 3-ol fraction derived from cocoa (FL) enhanced energy expenditure with metabolic changes in skeletal muscle. In the present study, we examined the effect of FL on disuse muscle atrophy induced by hindlimb suspension in mice. Male C57BL/6J mice were assigned to four groups as follows: unsuspended vehicle, unsuspended-FL, suspended-vehicle, and suspended-FL. Mice in the vehicle treatment groups were administered distilled water and those in the FL treatment groups were dosed with FL (50mg/kg/day) for 2weeks. The weights of the gastrocnemius (GC), tibialis anterior (TA), and soleus (SOL), but not the extensor digitorum longus (EDL), decreased significantly in mice with hindlimb suspension (-11.8%, -16.5%, and -41.0%, respectively). This reduction in GC, TA, and SOL mass was inhibited by FL (-5.3%, +2.0%, and -16.6%, respectively). The FL increased the EDL weight >20% with or without hindlimb suspension. The protein level of the ubiquitin ligase, muscle ring finger-1, in the SOL was significantly increased by hindlimb suspension, but inhibited by treatment with FL. Protein expression of p70S6 kinase in the SOL was significantly decreased by hindlimb suspension, and FL treatment inhibited this change. These results suggested that FL delayed disuse muscle atrophy by metabolic alteration. PMID- 28807825 TI - USP3 stabilizes p53 protein through its deubiquitinase activity. AB - p53 is the guardian of the genome integrity and the degradation of p53 protein is mediated by MDM2. Here we report that USP3 interacts with p53 and regulates p53 stability. Depletion of USP3 lead to accelerated degradation of p53 in normal cells thereby enhanced cell proliferation and transformation. Reconstitution of wildtype USP3, but not the USP3 C168S mutant, restored the stability of p53 protein and inhibited cell proliferation and transformation. These findings suggest that USP3 is an important regulator of p53 and regulates normal cell transformation. PMID- 28807826 TI - Structural plasticity of T4 transcription co-activator gp33 revealed by a protease-resistant unfolded state. AB - Gene 33 protein (gp33) is a transcriptional coactivator for late genes of the T4 bacteriophage. gp33 possesses a 5-helix bundle core, with unstructured N- and C terminal regions that account for >50% of the protein sequence. It plays a unique role of interacting with host RNA polymerase, couples transcription with DNA replication, and plays the dual function as repressor and co-activator in phage transcription. Here, we identify protein structural plasticity as the molecular basis of the dual nature in gp33. We find that gp33 has the peculiar property of remaining protease insensitive in its urea-unfolded state. Using NMR studies with spectroscopic measurements, we propose that intra-protein interactions are replaced by protein-urea interactions in gp33. This process not only unfolds gp33 but also renders it protease-resistant. Our studies shed new light on the unique structural malleability of gp33 that might be important in its transition from a repressor to a late transcription co-activator. PMID- 28807828 TI - Identification of novel direct protein-protein interactions by irradiating living cells with femtosecond UV laser pulses. AB - The identification of protein-protein interaction networks in living cells is becoming increasingly fundamental to elucidate main biological processes and to understand disease molecular bases on a system-wide level. We recently described a method (LUCK, Laser UV Cross-linKing) to cross-link interacting protein surfaces in living cells by UV laser irradiation. By using this innovative methodology, that does not require any protein modification or cell engineering, here we demonstrate that, upon UV laser irradiation of HeLa cells, a direct interaction between GAPDH and alpha-enolase was "frozen" by a cross-linking event. We validated the occurrence of this direct interaction by co immunoprecipitation and Immuno-FRET analyses. This represents a proof of principle of the LUCK capability to reveal direct protein interactions in their physiological environment. PMID- 28807827 TI - The endotoxemia cardiac dysfunction is attenuated by AMPK/mTOR signaling pathway regulating autophagy. AB - AMP-activated protein kinase (AMPK), an enzyme that plays a role in cellular energy homeostasis, modulates myocardial signaling in the heart. Myocardial dysfunction is a common complication of sepsis. Autophagy is involved in the aging related cardiac dysfunction. However, the role of AMPK in sepsis-induced cardiotoxicity has yet to be clarified, especially in aging. In this study, we explored the role of AMPK in lipopolysaccharide (LPS)-induced myocardial dysfunction and elucidated the potential mechanisms of AMPK/mTOR pathway regulating autophagy in young and aged mice. We harvested cardiac tissues by intraperitoneal injection of LPS treatment. The results by echocardiography, pathology, contractile and intracellular Ca2+ property as well as western blot analysis revealed that LPS induced remarkable cardiac dysfunction and cardiotoxicity in mice hearts and cardiomyocytes, which were more seriously in the aged mice. Western blot analysis indicated that the underlying mechanisms included inhibition autophagy mediated by AMPK/mTOR activation. LPS overtly promoted the expression of AMPK upstream regulator PP2A and PP2Calpha. Pharmacological activation of AMPK improved cardiac function and upregulated cardiac autophagy induced by LPS in the aged mice. Collectively, our findings suggest that upregulation of autophagy by administration of AMPK could attenuate LPS-induced cardiotoxicity, which enhances our knowledge to explore new drugs and strategies for combating cardiac dysfunction induced by sepsis. PMID- 28807829 TI - The Magnaporthe oryzae Alt A 1-like protein MoHrip1 binds to the plant plasma membrane. AB - MoHrip1, a protein isolated from Magnaporthe oryzae, belongs to the Alt A 1 (AA1) family. mohrip1 mRNA levels showed inducible expression throughout the infection process in rice. To determine the location of MoHrip1 in M. oryzae, a mohrip1-gfp mutant was generated. Fluorescence microscopy observations and western blotting analysis showed that MoHrip1 was both present in the secretome and abundant in the fungal cell wall. To obtain MoHrip1 protein, we carried out high-yield expression of MoHrip1 in Pichia pastoris. Treatment of tobacco plants with MoHrip1 induced the formation of necrosis, accumulation of reactive oxygen species and expression of several defense-related genes, as well as conferred disease resistance. By fusion to green fluorescent protein, we showed that MoHrip1 was able to bind to the tobacco and rice plant plasma membrane, causing rapid morphological changes at the cellular level, such as cell shrinkage and chloroplast disorganization. These findings indicate that MoHrip1 is a microbe associated molecular pattern that is perceived by the plant immune system. This is the first study on an AA1 family protein that can bind to the plant plasma membrane. PMID- 28807831 TI - Note of caution: Contaminations of hepatocellular cell lines. PMID- 28807830 TI - USP5 promotes tumorigenesis and progression of pancreatic cancer by stabilizing FoxM1 protein. AB - Increased ubiquitin-specific protease 5 (USP5) has been associated with tumorigenesis of malignancy including glioblastoma, melanoma and hepatocellular carcinoma. However, the role of USP5 in tumorigenesis of pancreatic ductal adenocarcinoma (PDAC) has not been studied yet. In this study, we demonstrated that USP5 was significantly upregulated in a panel of PDAC cell lines and correlated with FoxM1 protein expression. USP5 knockdown inhibited proliferation of PANC-1 and SW1990, two PDAC cell lines. In the mouse xenografted pancreatic tumor model, suppression of USP5 significantly decreased tumor growth, correlated with down regulation of FoxM1. Additionally, we found that overexpression of USP5 stabilized the FoxM1 protein in PDAC cells. Overexpression of USP5 extended the half-life of FoxM1. Knockdown of USP5 in PANC-1 cells decreased FoxM1 protein level while the proteasome inhibitor MG-132 treatment restored FoxM1 expression. We also found that endogenous USP5 was coimmunoprecipitated with an endogenous FoxM1 from PANC-1 cells while FoxM1 was also coimmunoprecipitated with USP5. Furthermore, we also confirmed that USP5 regulated proliferation of PDAC via FoxM1 by rescuing the inhibitory effect of USP5 knockdown with ectopic expression of FoxM1 in USP5-depleted cells. Taken together, our study demonstrates that USP5 plays a critical role in tumorigenesis and progression of pancreatic cancer by stabilizing FoxM1 protein, and provides a rationale for USP5 being a potential therapeutic approach against PDAC. PMID- 28807832 TI - Pattern of exposure to information and its impact on seasonal influenza vaccination uptake in nurses. AB - BACKGROUND: Uptake of annual influenza vaccination of healthcare workers (HCWs) varies, and remains at a suboptimal level in many countries. As HCWs are often exposed to a variety of information about vaccination, the pattern of exposure may impact their decision; this deserves further investigation. METHODS: Practising nurses in Hong Kong were invited to participate in an anonymous online survey in February 2016, after the winter seasonal peak. The questionnaire covered demographics, work nature and experiences, vaccination uptake history and reasons for vaccination decisions. Two behavioural categories for access to information were defined - passive exposure to information and active information seeking - differentiated by the source, type and nature of information accessed. Chi-squared test, Mann-Whitney U-test and logistic regression were performed to compare vaccinated and unvaccinated nurses. RESULTS: In total, 1177 valid returns were received from nurses. The median age of respondents was 32 years and 86% were female. The overall vaccination rate was 33%. Passive exposure to information from the workplace, professional body and social network was not predictive of vaccination decision, but passive exposure to information from mass media was predictive [odds ratio (OR) 1.78]. Active information-seeking, such as consulting a senior (OR 2.46), organizing promotional activities (OR 2.85) and undertaking an information search (OR 2.43), was significantly associated with increased vaccination uptake. A cumulative effect could be demonstrated for active information-seeking (OR 1.86), but not for passive exposure to information. CONCLUSION: The current strategy of promotions and campaigns for seasonal influenza vaccination in HCWs may not be effective in increasing vaccination coverage. Measures targeting information-seeking behaviours may serve as an alternative approach. PMID- 28807833 TI - Following trends in steam sterilizer performance by quantitative monitoring of non-condensable gases. AB - Standards require a daily steam penetration test before starting production with a steam sterilizer. In many cases the results of steam penetration tests are not used for improvements or optimization of processes. This study aimed to detect whether trend analysis with an objective and quantifying steam penetration test has added value for the end-user. The databases of an objective quantifying steam penetration test, from the hospital and the manufacturer, are coupled and analysed. In this study, the databases included five steam sterilizers and approximately a four-year period. Based on the analysis, the process of the sterilizers was optimized. The results of the steam penetration tests became more stable over longer periods. This may result in lengthened periods between maintenance and validation. The analysis demonstrates that an objective, quantifying steam penetration test delivers more insights and knowledge of the functioning of the steam sterilization process. This knowledge may be used to optimize the process and reduce costs for the end-user. PMID- 28807834 TI - A predictive model of days from infection to discharge in patients with healthcare-associated urinary tract infections: a structural equation modelling approach. AB - BACKGROUND: Length of stay (LOS) in hospital is an important component of describing how costs change in relation to healthcare-associated infection and this variable underpins models used to evaluate cost. It this therefore imperative that estimations of LOS associated with infections are performed accurately. AIM: To test the relationships between the size of hospital, age, and patient comorbidity on days from admission to infection and days from infection to discharge in patients with a healthcare-associated urinary tract infection (HAUTI), using structural equation modelling (SEM). METHODS: A non-current cohort study in eight hospitals in New South Wales, Australia. All patients admitted to the hospital for >48 h and who acquired a HAUTI were included. FINDINGS: From the 162,503 eligible patient admissions, 2821 (1.73%) acquired a HAUTI. SEM showed that the proposed model had acceptable fit indices for the combined sample (GFI = 1.00; AGFI = 1.00; NFI = 1.00; CFI = 1.00; RMSEA = 0.000). The main findings showed that age of patient had a direct association with days from admission to infection and with days from infection to discharge. Patient comorbidity had direct links to the variables days from admission to infection and days from infection to discharge. Multi-group analysis indicated that the age of male patients was more influential on the factor days from admission to infection when compared to female patients. Furthermore, the number of comorbidities was significantly more influential on days from admission to infection in male patients than in female patients. CONCLUSION: As the first published study to use SEM to explore a healthcare-associated infection and the predictors of days from infection to discharge in hospital, we can confirm that accounting for the timing of infection during hospitalization is important and that patient comorbidity influences the timing of infection. PMID- 28807835 TI - Role of antimicrobial stewardship programmes in children: a systematic review. AB - The United Nations and the World Health Organization have designated antimicrobial resistance (AMR) as a major health priority and developed action plans to reduce AMR in all healthcare settings. Establishment of institutional antimicrobial stewardship programmes (ASPs) is advocated as a key intervention to reduce antibiotic consumption in hospitals and address high rates of multi-drug resistant (MDR) bacteria. PUBMED and the Cochrane Database of Systematic Reviews (January 2007-March 2017) were searched to identify studies reporting the effectiveness of ASPs in general paediatric wards and paediatric intensive care units (PICUs) for reducing antibiotic consumption, use of broad spectrum/restricted antibiotics, and antibiotic resistance and healthcare associated infections (HAIs). Neonatal units and antifungal agents were excluded. Of 2509 titles and abstracts, nine articles were eligible for inclusion in the final analysis. All studies reported a reduction in the use of broad spectrum/restricted antibiotics or antibiotic consumption. One study reported a reduction in HAIs in a PICU, and another study evaluated bacterial resistance, showing no effect following ASP implementation. Prospective audit on antibiotic use was the most common ASP core component (eight of nine studies). Antibiotic pre-authorization was described in two studies. Other described interventions were the provision of guidelines or written information (five of nine studies), and training of healthcare professionals (one study). There is limited evidence for a reduction in antibiotic consumption and use of broad-spectrum/restricted agents following ASP implementation specifically in PICUs. Data evaluating the impact of ASPs on HAIs and AMR in PICUs are lacking. In addition, there is limited information on effective components of a successful ASP in PICUs. PMID- 28807836 TI - Development and evaluation of the automated risk assessment system for multidrug resistant organisms (autoRAS-MDRO). AB - BACKGROUND: A high proportion of infections acquired in hospitals are caused by multidrug-resistant organisms (MDROs). The priority in MDRO prevention is to detect high-risk patients and implement preventive intervention as soon as possible. AIM: To develop an automated risk assessment system for MDROs (autoRAS MDRO) to screen for patients at MDRO infection risk and evaluate the predictive validity of the autoRAS-MDRO. METHODS: Data for 4200 variables were extracted from the electronic health records (EHRs) for constructing the MDRO risk-scoring algorithm, which was based on a logistic regression model. The autoRAS-MDRO was designed such that the MDRO risk classification (high, moderate, low risk) could be automatically displayed on the nursing Kardex screen in the EHRs system. For the development of the MDRO risk-scoring algorithm, 1000 patients with MDROs and 4000 patients without MDROs were selected; similarly, for the evaluation, 2173 and 8692 patients with and without MDROs, respectively, were selected. FINDINGS: The predictive validity of the autoRAS-MDRO was as follows: (i) at the 6-month evaluation: sensitivity, 81%; specificity, 79%; positive predictive value (PPV), 49%; negative predictive value (NPV), 94%; and Youden index, 0.60; (ii) at the 12 month evaluation: sensitivity 79%, specificity 78%, PPV 47%, NPV 94%, and Youden index, 0.57. CONCLUSION: The autoRAS-MDRO had moderate predictive validity. It could be useful in redirecting nurses' time and efforts required for MDRO risk assessment and implementation of infection control measures, and in reducing the incidence of MDRO infection in hospitals, thereby contributing to patient safety. PMID- 28807838 TI - Large BTK gene mutation in a child with X-linked agammaglobulinemia and polyarthritis. PMID- 28807837 TI - Characterization of two odorant binding proteins in Spodoptera exigua reveals functional conservation and difference. AB - As the first biochemical step of olfactory reception and recognition, odorant binding proteins (OBPs) have been demonstrated to be essential. Considering functional diversities of OBPs within a single species, we here extended the characterization of two other OBPs from Spodoptera exigua, belonging to insect Classic OBPs. With a combination of transcriptome and Rapid Amplification of cDNA End (RACE) approaches, two OBP genes in S. exigua were identified, namely SexiOBP1 and OBP7. Expression pattern analysis revealed that both of them exhibited a distinct expression pattern, where OBP1 was broadly and highly expressed in several tissues including antennae of adults whereas OBP7 was abundant only in the antennae of both sexes, strongly indicative of olfactory roles. Further, binding assays showed that the two SexiOBPs shared a common odorant-response spectrum with considerable affinities to host odorants of acetophenone, farnesol and beta-ionone (Ki<20MUM). Specially, OBP1 could strongly bind an insect attractant beta-caryophyllene (Ki=2.76MUM) released by maize. Intriguingly, the major sex pheromone of S. exigua, Z9,E12-14:Ac, was the best ligand for OBP7 with Ki value of 7.58MUM. Ligand structural analysis revealed that the two SexiOBPs were capable of accommodating different types of ligands in shape and size, possibly implying the plasticity of binding pockets. Ultimately, comparison of binding properties among 10 SexiOBPs including the two OBPs in this study implied a cross-talk in functions, i.e. different OBPs are also suitable to accept some common odorants except for unique ligands. Taken together, this study has provided evidence for their involvements in seeking and orientation of host plants, and meanwhile indicates functional conservation and differences between OBP1 and OBP7 from S. xigua. PMID- 28807839 TI - Characterization of FM2382 from Fulvimarina manganoxydans sp. Nov. 8047 with potential enzymatic decontamination of sulfur mustard. AB - Sulfur mustard (SM) can be hydrolyzed by haloalkane dehalogenases such as DhaA, LinB and DmbA. However, the low resistance to the elevated temperatures limited the practical application of haloalkane dehalogenases. Here we reported a new thermotolerant dehalogenase FM2382 from Fulvimarina manganoxydans sp. nov. 8047. The specific activity of FM2382 to SM is 0.6 U/mg. FM2382 possessed high heat stability (45 degrees C) in slight alkali environment (pH 7.5) and retained approximately 50% activity after incubation at 70 degrees C for 40 min. The catalytic activity of FM2382 was activated by Co2+ and Mg2+, and inhibited by Zn2+, Cu2+ and Fe3+. Furthermore, site-specific mutagenesis proved that D34, K207 D232, D237 were amino acid residues related to the catalytic activity of SM. In conclusion, we found a thermostable haloacid dehalogenases (HAD) family dehalogenase showing SM-degradation activity, which may be useful for practical application in the future. PMID- 28807840 TI - The heterologous expression strategies of antimicrobial peptides in microbial systems. AB - Antimicrobial peptides (AMPs) consist of molecules acting on the defense systems of numerous organisms toward tumor and multiple pathogens, such as bacteria, fungi, viruses, and parasites. Compared to traditional antibiotics, AMPs are more stable and have lower propensity for developing resistance through functioning in the innate immune system, thus having important applications in the fields of medicine, food and so on. However, despite of their high economic values, the low yield and the cumbersome extraction process in AMPs production are problems that limit their industrial application and scientific research. To conquer these obstacles, optimized heterologous expression technologies were developed that could provide effective ways to increase the yield of AMPs. In this review, the research progress on heterologous expression of AMPs using Escherichia coli, Bacillus subtilis, Pichia pastoris and Saccharomyces cerevisiae as host cells was mainly summarized, which might guide the expression strategies of AMPs in these cells. PMID- 28807842 TI - A Rare Complication of Infliximab. PMID- 28807843 TI - Unusual Cause of Elevated Liver Enzymes in a Female Patient. PMID- 28807844 TI - An Unusual Gastric Antral Mass. PMID- 28807841 TI - Racial Disparity in Gastrointestinal Cancer Risk. AB - Cancer from the gastrointestinal tract and its associated excretory organs will occur in more than 300,000 Americans in 2017, with colorectal cancer responsible for >40% of that burden; there will be more than 150,000 deaths from this group of cancers in the same time period. Disparities among subgroups related to the incidence and mortality of these cancers exist. The epidemiology and risk factors associated with each cancer bear out differences for racial groups in the United States. Esophageal adenocarcinoma is more frequent in non-Hispanic whites, whereas esophageal squamous cell carcinoma with risk factors of tobacco and alcohol is more frequent among blacks. Liver cancer has been most frequent among Asian/Pacific Islanders, chiefly due to hepatitis B vertical transmission, but other racial groups show increasing rates due to hepatitis C and emergence of cirrhosis from non-alcoholic fatty liver disease. Gastric cancer incidence remains highest among Asian/Pacific Islanders likely due to gene-environment interaction. In addition to esophageal squamous cell carcinoma, cancers of the small bowel, pancreas, and colorectum show the highest rates among blacks, where the explanations for the disparity are not as obvious and are likely multifactorial, including socioeconomic and health care access, treatment, and prevention (vaccination and screening) differences, dietary and composition of the gut microbiome, as well as biologic and genetic influences. Cognizance of these disparities in gastrointestinal cancer risk, as well as approaches that apply precision medicine methods to populations with the increased risk, may reduce the observed disparities for digestive cancers. PMID- 28807845 TI - 1-Hz rTMS in the treatment of tinnitus: A sham-controlled, randomized multicenter trial. AB - BACKGROUND: Chronic tinnitus is a frequent, difficult to treat disease with high morbidity. OBJECTIVE: This multicenter randomized, sham-controlled trial investigated the efficacy and safety of 1-Hz repetitive transcranial magnetic stimulation (rTMS) applied to the left temporal cortex in patients with chronic tinnitus. METHODS: Tinnitus patients were randomized to receive 10 sessions of either real or sham 1-Hz-rTMS (2000 stimuli, 110% motor threshold) to the left temporal cortex. The primary outcome was the change in the sum score of the tinnitus questionnaire (TQ) of Goebel and Hiller from baseline to end of treatment. RESULTS: A total of 163 patients were enrolled in the study (real rTMS: 75; sham rTMS: 78). At day 12, the baseline mean of 43.1 TQ points in 71 patients assigned to real rTMS changed by -0.5 points; it changed by 0.5 points from a baseline of 42.1 in 75 patients randomized to sham rTMS (adjusted mean difference between groups: -1.0; 95.19% confidence interval: -3.2 to 1.2; p = 0.36). All secondary outcome measures including measures of depression and quality of life showed no significant differences either (p > 0.11). The number of participants with side-effects or adverse events did not differ between groups. CONCLUSION: Real 1-Hz-rTMS over the left temporal cortex was well tolerated but not superior compared with sham rTMS in improving tinnitus severity. These findings are in contrast to results from studies with smaller sample sizes and put the efficacy of this rTMS protocol for treatment of chronic tinnitus into question. TRIAL REGISTRATION: Controlled Trials: http://www.isrctn.com/ISRCTN89848288. PMID- 28807847 TI - Novel method of altering stimulus parameter to facilitate seizure induction during electroconvulsive therapy. PMID- 28807846 TI - The reliability of commonly used electrophysiology measures. AB - BACKGROUND: Electrophysiological measures can help understand brain function both in healthy individuals and in the context of a disease. Given the amount of information that can be extracted from these measures and their frequent use, it is essential to know more about their inherent reliability. OBJECTIVE/HYPOTHESIS: To understand the reliability of electrophysiology measures in healthy individuals. We hypothesized that measures of threshold and latency would be the most reliable and least susceptible to methodological differences between study sites. METHODS: Somatosensory evoked potentials from 112 control participants; long-latency reflexes, transcranial magnetic stimulation with resting and active motor thresholds, motor evoked potential latencies, input/output curves, and short-latency sensory afferent inhibition and facilitation from 84 controls were collected at 3 visits over 24 months at 4 Track-On HD study sites. Reliability was assessed using intra-class correlation coefficients for absolute agreement, and the effects of reliability on statistical power are demonstrated for different sample sizes and study designs. RESULTS: Measures quantifying latencies, thresholds, and evoked responses at high stimulator intensities had the highest reliability, and required the smallest sample sizes to adequately power a study. Very few between-site differences were detected. CONCLUSIONS: Reliability and susceptibility to between-site differences should be evaluated for electrophysiological measures before including them in study designs. Levels of reliability vary substantially across electrophysiological measures, though there are few between-site differences. To address this, reliability should be used in conjunction with theoretical calculations to inform sample size and ensure studies are adequately powered to detect true change in measures of interest. PMID- 28807848 TI - Hydroalcoholic extract from bark of Persea major (Meisn.) L.E. Kopp (Lauraceae) exerts antiulcer effects in rodents by the strengthening of the gastric protective factors. AB - ETHOPHARMACOLOGICAL RELEVANCE: The Persea major (Meisn.) L.E. Kopp (Lauraceae) (botanical synonym: Persea pyrifolia (D. Don) Spreng, Persea pyrifolia Nees and Mart., Persea cordata var. major (Meisn.) Mez and Persea willdenovii Kosterm) is a medicinal plant native in the south of Brazil, where is popularly known as Pau de Andrade, Macaranduba or Abacate-do-Mato. Its barks are commonly used to prepare an infusion which is administered orally or topically to treat ulcers and wounds, respectively. Thus, this study has been undertaken to contribute to the validation of the popular use of P. major to treat of ulcerative disorders from gastrointestinal system, using different experimental models in rodents. MATERIAL AND METHODS: Firstly, ultra-performance liquid chromatography coupled to a mass spectrophotometer has been performed. Next, the potential gastroprotective of hydroalcoholic extract of P. major barks (HEPM) (30-300mg/kg) has been evaluated in ulcer models acute as: ethanol, ethanol/HCl and indomethacin-induced ulcer. The extract (300mg/kg) has been also tested in acetic acid-induced chronic ulcer model. Histological, toxicological, histochemical, oxidative stress and gastric secretion parameters were analyzed. RESULTS: The main compounds found in HEPM were polyphenols as condensed tannins, flavonoids heterosides derivatives from quercetin and kaempferol. HEPM (300mg/kg, p.o) prevented gastric lesions induced by ethanol or indomethacin in rats by 58.98% and 97.48%, respectively, compared to vehicle group (148.00+/-14.83mm2 and 12.07+/-1.61mm2, respectively). In acetic acid-induced chronic ulcer model the HEPM (300mg/kg, p.o) reduced the ulcer are by 40.58%, compared to vehicle group (127.90+/-12.04mm2). The healing effect was confirmed histologically, by an increase in mucin content and by the reduction in oxidative and inflammatory parameters at the ulcer site. Neither significant effect on gastric acid secretion nor toxicological effects and cytotoxicity were provoked by administration of HEPM. CONCLUSIONS: The results allows to conclude that HEPM exerts gastroprotective and gastric cicatrizing effects favoring on protective defenses, but not possess antisecretory effect in contrast to the current antiulcer therapy, besides the extract present good tolerability and absence of cytotoxicity. Moreover, the results presented here contribute to the validation to the popular use of the P. major in the treatment of gastric ulcer. PMID- 28807849 TI - Danshen improves survival of patients with colon cancer and dihydroisotanshinone I inhibit the proliferation of colon cancer cells via apoptosis and skp2 signaling pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Danshen (Salvia miltiorrhiza Bunge) is widely used in traditional Chinese medicine. However, it's definite clinical effect and mechanism on colon carcinoma is unclear. AIM OF THE STUDY: To test the hypothesis that the protective effect of danshen on colon cancer and discover the bioactive compounds through in vitro study. MATERIALS AND METHODS: We conducted a nationwide cohort study by using population-based data from the Taiwan National Health Insurance Research Database (NHIRD). The study cohort comprised patients diagnosed with malignant neoplasm of colon (ICD-9-CM codes:153) in catastrophic illness database between January 1, 2000, and December 31, 2010. We used the Kaplan-Meier method to estimate lung cancer cumulative incidences. Next, human colon cancer cells (HCT 116 cells and HT29 cells) were used to investigate the effect of dihydroisotanshinone I (DT) on the proliferation and apoptosis of human colon cancer cells and the underlying mechanism through XTT assay and flow cytometry. The in vivo effect of DT treatment was investigated through a xenograft nude mouse model. RESULTS: In our study, the in vivo protective effect of danshen in the different stage of colon cancer patients was validated through data from the National Health Insurance Research Database in Taiwan. In vitro, we found that dihydroisotanshinone I (DT), a bioactive compound present in danshen, can inhibit the proliferation of colon carcinoma cells, HCT 116 cells and HT-29 cells. Moreover, DT induced apoptosis of colorectal cancer cells. DT also repressed the protein expression of Skp2 (S-Phase Kinase Associated Protein 2) and the mRNA levels of its related gene, Snail1 (Zinc finger protein SNAI1) and RhoA (Ras homolog gene family, member A). In addition, DT also blocked the colon cancer cells recruitment ability of macrophage by decreasing CCL2 secretion in macrophages. DT treatment also significantly inhibited the final tumor volume in a xenograft nude mouse model. CONCLUSION: Danshen has protective effects in colon cancer patients, which could be attributed to DT through blocking the proliferation of colon cancer cells through apoptosis. PMID- 28807850 TI - Anti-HIV activity of southern African plants: Current developments, phytochemistry and future research. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The African continent is home to a large number of higher plant species used over centuries for many applications, which include treating and managing diseases such as HIV. Due to the overwhelming prevalence and incidence rates of HIV, especially in sub-Saharan Africa, it is necessary to develop new and affordable treatments. AIM OF THE STUDY: The article provides an extensive overview of the status on investigation of plants from the southern African region with ethnobotanical use for treating HIV or HIV-related symptoms, or the management of HIV. The review also provide an account of the in vitro assays, anti-viral activity and phytochemistry of these plants. MATERIALS AND METHODS: Peer-reviewed articles investigating plants with ethnobotanical information for the treatment or management of HIV or HIV-related symptoms from the southern African region were acquired from Science Direct, PubMed central and Google Scholar. The selection criteria was that (1) plants should have a record of traditional/popular use for infectious or viral diseases, HIV treatment or symptoms similar to HIV infection, (2) if not traditionally/popularly used, plants should be closely related to plants with popular use and HIV activity identified by means of in vitro assays, (3) plants should have been identified scientifically, (4) should be native to southern African region and (5) anti-HIV activity should be within acceptable ranges. RESULTS: Many plants in Africa and specifically the southern African region have been used for the treatment of HIV or HIV related symptoms and have been investigated suing various in vitro techniques. In vitro assays using HIV enzymes such as reverse transcriptase (RT), integrase (IN) and protease (PR), proteins or cell-based assays have been employed to validate the use of these plants with occasional indication of the selectivity index (SI) or therapeutic index (TI), with only one study, that progressed to in vivo testing. The compounds identified from plants from southern Africa is similar to compounds identified from other regions of the world, and the compounds have been divided into three groups namely (1) flavonoids and flavonoid glycosides, (2) terpenoids and terpenoid glycosides and (3) phenolic acids and their conjugated forms. CONCLUSIONS: An investigation of the plants from southern Africa with ethnobotanical use for the treatment of HIV, management of HIV or HIV-related symptoms, therefore provide a very good analysis of the major assays employed and the anti-viral compounds and compound groups identified. The similarity in identified anti-viral compounds worldwide should support the progression from in vitro studies to in vivo testing in development of affordable and effective anti-HIV agents for countries with high infection and mortality rates due to HIV/AIDS. PMID- 28807851 TI - Toxic pyrrolizidine alkaloids provide a warning sign to overuse of the ethnomedicine Arnebia benthamii. AB - ETHNOPHARMACOLOGICAL RELEVANCE: From early times man has used medicinal plants for the treatment of various ailments and basic health care needs. The use of herbal medicines has increased day by day and with this, so do reports of adverse events, poisoning, and suspected toxicity. Similarly, the indigenous communities of Neelum Valley in Azad Kashmir commonly use Arnebia benthamii (Wall. ex G.Don) I.M.Johnst. for medicinal purposes to treat various human aliments. Besides their medicinal uses, it also contains hepatotoxic pyrrolizidine alkaloids (PAs). AIM OF THE STUDY: This explorative study underscores two major aspects about this herbal medicine. Firstly we aimed to document the traditional therapeutic uses of Arnebia benthamii in Neelum Valley, Azad Kashmir. Secondly, to determine the presence or absence of hepatotoxic pyrrolizidine alkaloids and if they are within the suggested limit for the use of herbs in excess. MATERIALS AND METHODS: Interviews, group discussions, and inquiries were carried out from July to September 2016 with local indigenous and elder people. In the laboratory, the plant was investigated for pyrrolizidine alkaloids by using high performance liquid chromatography (HPLC). RESULTS: A total of 30 respondents were interviewed. They explained the preferred preparation, parts used, and treatment indications. Treatment of fever along with kidney and liver problems are the three principle uses. Among the different parts of Arnebia benthamii, 43% respondents preferred aerial parts for the herbal formulation, followed by whole plants, and leaves. Decoction was the major mode of preparation and all herbal preparations were administrated orally. This study reports, for the first time according to our literature review, a study of Arnebia benthamii with regard to PA determination. By using column Zorbax SB-Aq and acetonitrile-water gradient as the mobile phase, HPLC results showed that the aerial parts of the plant were PA positive, and (1) Europine, Heliotrine (2), Lycopsamine (3), and Echimidine (4) were identified. CONCLUSIONS: This study has revealed two new findings of significance to herbal medicine producers, practitioners, and consumers of Arnebia benthamii First, local knowledge regarding the medicinal uses of Arnebia benthamii were documented in five sites of Neelum Valley, Azad Kashmir. The use of this plant by a large part of the population in the study area shows the importance for their therapeutic benefits. Unfortunately, the second finding of this study shows that Arnebia benthamii contains hepatotoxic PAs. Hence, we advised to the government regulatory authorities and non-governmental organizations that use of this plant as herbal medicine should be excluded before more accurate quality control tests. PMID- 28807852 TI - Extracts of Equisetum giganteum L and Copaifera reticulate Ducke show strong antiviral activity against the sexually transmitted pathogen herpes simplex virus type 2. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Equisetum giganteum L and Copaifera reticulate Ducke have been traditionally used by women of the Tacana tribe in the Bolivian Amazonas for genital hygiene and for treatment of genital infection/inflammation. AIM OF THE STUDY: To assess the ability of extracts from Equisetum giganteum L and Copaifera reticulate Ducke to block genital viral infection by herpes simplex virus type 2. MATERIALS AND METHODS: Equisetum giganteum L and Copaifera reticulate Ducke were collected from the Amazon region of La Paz, Bolivia. Extracts were prepared and screened for anti-viral activity against herpes simplex virus type 2 (HSV-2) using both in vitro and in in vivo models of infection. RESULTS: Equisetum giganteum L and Copaifera reticulate Ducke efficiently blocked HSV-2 infection of cell cultures without major cell cytotoxic effects. Extracts of Equisetum giganteum L and Copaifera reticulate Ducke could prevent HSV-2 disease development when administered together with virus in a mouse model of genital HSV-2 infection. In vitro analyses revealed that both plant extracts exerted their anti-HSV-2 effects by interfering with viral cell attachment and entry, but could not block viral replication post entry. CONCLUSIONS: These studies show that extracts of Equisetum giganteum L and Copaifera reticulate Ducke have potent antiviral activities against HSV-2 comparable to those two previously identified plants, Croton lechleri Mull. Arg. and Uncaria tomentosa (Willd. ex Schult.) DC. These studies confirm that plants used by the Tacana tribe could be explored further for the development of novel topical antiviral microbicides. PMID- 28807853 TI - Aqueous extract from pecan nut [Carya illinoinensis (Wangenh) C. Koch] shell show activity against breast cancer cell line MCF-7 and Ehrlich ascites tumor in Balb C mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In Brazil many health disorders are treated with the consumption of different varieties of tea. Shell extracts of pecan nut (Carya illinoinensis), which have significant amounts of phenolic compounds in their composition, are popularly taken as tea to prevent diverse pathologies. AIM OF THE STUDY: Phenolic compounds from pecan nut shell extract have been associated with diverse biological effects but the effect on tumor cells has not been reported yet. The aim of the current work was to evaluate the relationship between DNA fragmentation, cell cycle arrest and apoptosis induced by pecan nut shell extract and its antitumor activity. MATERIALS AND METHODS: Cytotoxicity, proliferation, cell death and cell cycle were evaluated in MCF-7 cells by MTT, colony assay, differential coloring and flow cytometry assays, respectively. DNA damage effects were evaluated through intercalation into CT-DNA and plasmid DNA cleavage. Tumor growth inhibition, survival time increase, apoptosis and cell cycle arrest were assessed in Ehrlich ascites tumor in Balb/C mice. RESULTS: The cytotoxic effect of pecan nut shell extracts, the induction of cell death by apoptosis and also the cell cycle arrest in MCF-7 cells have been demonstrated. The survival time in mice with Ehrlich ascites tumor increased by 67%. DNA damage was observed in the CT-DNA, plasmid DNA and comet assays. The mechanism involved in the antitumor effect of pecan nut shell extracts may be related to the activation of key proteins involved in apoptosis cell death (Bcl-XL, Bax and p53) and on the cell cycle regulation (cyclin A, cyclin B and CDK2). CONCLUSIONS: These results were attributed to the phenolic profile of the extract, which presented compounds such as gallic, 4-hydroxybenzoic, chlorogenic, vanillic, caffeic and ellagic acid, and catechin, epicatechin, epigallocatechin and epicatechin gallate. The results indicated that pecan nut shell extracts are effective against tumor cells growth and may be considered as an alternative to the treatment of cancer. PMID- 28807854 TI - A.D.T. PMID- 28807855 TI - Spatial Organization and Molecular Interactions of the Schizosaccharomyces pombe Ccq1-Tpz1-Poz1 Shelterin Complex. AB - The shelterin complex is a macromolecular assembly of proteins that binds to and protects telomeric DNA, which composes the ends of all linear chromosomes. Shelterin proteins prevent chromosome ends from fusing together and from eliciting erroneous induction of DNA damage response pathways. In addition, shelterin proteins play key roles in regulating the recruitment and activation of telomerase, an enzyme that extends telomeric DNA. In fission yeast, Schizosaccharomyces pombe, interactions between the shelterin proteins Ccq1, Tpz1, and Poz1 are important for regulating telomerase-mediated telomere synthesis and thus telomere length homeostasis. Here, we used electron microscopy combined with genetic labeling to define the three-dimensional arrangement of the S. pombe Ccq1-Tpz1-Poz1 (CTP) complex. Crosslinking mass spectrometry was used to identify individual residues that are in proximity to the protein-protein interfaces of the assembled CTP complex. Together, our data provide a first glimpse into the architectural design of the CTP complex and reveals unique interactions that are important in maintaining the S. pombe telomere in a non extendible state. PMID- 28807856 TI - Low levels of genetic diversity associated with evidence of negative selection on the Babesia bovis apical membrane antigen 1 from parasite populations in Thailand. AB - Babesia bovis, a parasite infecting cattle and buffalo, continues to spread throughout the developing world. The babesial vaccine was developed to be a sustainable alternative treatment to control the parasite. However, genetic diversity is a major obstacle for designing and developing a safe and effective vaccine. The apical membrane antigen 1 (AMA-1) is considered to be a potential vaccine candidate antigen among immunogenic genes of B. bovis. To gain a more comprehensive understanding of B. bovis AMA-1 (BbAMA-1), three B. bovis DNA samples were randomly selected to characterize in order to explore genetic diversity and natural selection and to predict the antigen epitopes. The sequence analysis revealed that BbAMA-1 has a low level of polymorphism and is highly conserved (95.46-99.94%) among Thai and global isolates. The majority of the polymorphic sites were observed in domains I and III. Conversely, domain II contained no polymorphic sites. We report the first evidence of strong negative or purifying selection across the full length of the gene, especially in domain I, by demonstrating a significant excess of the average number of synonymous (dS) over the non-synonymous (dN) substitutions. Finally, we also predict the linear and conformational B-cell epitope. The predicted B-cell epitopes appeared to be involved with the amino acid changes. Collectively, the results suggest that the conserved BbAMA-1 may be used to detect regional differences in the B. bovis parasite. Importantly, the limitation of BbAMA-1 diversity under strong negative selection indicates strong functional constraints on this gene. Thus, the gene could be a valuable target vaccine candidate antigen. PMID- 28807857 TI - Prevalence and genetic characterization of Toxoplasma gondii in donkeys in northeastern China. AB - Toxolasma gondii is one of the most important obligate intracellular protozoan parasites. Recently, toxoplasmosis is of increasing concerns because T. gondii not only has a worldwide distribution but also can infect virtually all warm blooded hosts including donkeys. However, limited information is available concerning the genetic characterization of T. gondii in donkeys in northeastern China. In this study, a total of 302 brain tissue samples collected from donkeys from Jilin (n=108) and Liaoning (n=194) provinces, northeastern China, were examined for T. gondii infection by semi-nested PCR of B1 gene. The positive samples were genotyped at 11 loci (i.e., SAG1, alternative SAG2, 5'-and 3'-SAG2, SAG3, L358, BTUB, c22-8, GRA6, c29-2, PK1 and Apico) using polymerase chain reaction-restriction fragment length polymorphism technology. Of 302 brain tissue samples, 19 (6.29%) were PCR-positive for T. gondii. The prevalence rates of T. gondii were 6.48% (7/108) and 6.19% (12/194) in Jilin Province and Liaoning Province, respectively. The prevalence of T. gondii in different season groups varied from 5.56% to 7.41%. The prevalence of T. gondii in "Cage-free" donkeys was higher than that in "Captive" donkeys. Of the 19 positive samples, only two isolates were successfully genotyped at all loci, three were genotyped at 9 loci. In total, four samples belong to ToxoDB genotype #9, one belong to ToxoDB genotype #10. This is firstly characterized the T. gondii isolates from donkeys in northeastern China. The results of the present study will improve the information of the distribution of T. gondii genotypes in China. PMID- 28807858 TI - Host specificity, pathogen exposure, and superinfections impact the distribution of Anaplasma phagocytophilum genotypes in ticks, roe deer, and livestock in a fragmented agricultural landscape. AB - Anaplasma phagocytophilum is a bacterial pathogen mainly transmitted by Ixodes ricinus ticks in Europe. It infects wild mammals, livestock, and, occasionally, humans. Roe deer are considered to be the major reservoir, but the genotypes they carry differ from those that are found in livestock and humans. Here, we investigated whether roe deer were the main source of the A. phagocytophilum genotypes circulating in questing I. ricinus nymphs in a fragmented agricultural landscape in France. First, we assessed pathogen prevalence in 1837 I. ricinus nymphs (sampled along georeferenced transects) and 79 roe deer. Prevalence was dramatically different between ticks and roe deer: 1.9% versus 76%, respectively. Second, using high-throughput amplicon sequencing, we characterized the diversity of the A. phagocytophilum genotypes found in 22 infected ticks and 60 infected roe deer; the aim was to determine the frequency of co-infections. Only 22.7% of infected ticks carried genotypes associated with roe deer. This finding fits with others suggesting that cattle density is the major factor explaining infected tick density. To explore epidemiological scenarios capable of explaining these patterns, we constructed compartmental models that focused on how A. phagocytophilum exposure and infection dynamics affected pathogen prevalence in roe deer. At the exposure levels predicted by the results of this study and the literature, the high prevalence in roe deer was only seen in the model in which superinfections could occur during all infection phases and when the probability of infection post exposure was above 0.43. We then interpreted these results from the perspective of livestock and human health. PMID- 28807859 TI - Widespread functional opsin transduction in the rat cortex via convection enhanced delivery optimized for horizontal spread. AB - BACKGROUND: Widespread opsin expression in the cortex of rats, where transgenic models have not been established, is not practical to achieve with the traditional diffusion-based virus transduction methods (DBD). NEW METHOD: We developed protocols for convection-enhanced delivery (CED) of virus for optogenetic transduction of the rat cortex. Targeting the motor forelimb area as an example, we performed dual-site CED (6MUL of virus per site, 3mm pitch between sites) in the rat motor cortex. RESULTS: We identified injection parameters optimized for horizontal spread of infusate in the agarose gel model and then demonstrated in vivo widespread opsin expression over the cortical area (7.4+/ 1.0mm in the AP direction, 4.4+/-1.1mm in the ML direction, N=13 rats) using CED. The optogenetic transduction was also functionally robust, in which both optical modulation of neuronal activity and elicitation of overt motor responses was reliably observed. COMPARISON WITH EXISTING METHOD(S): CED led to about 24-fold increase in the volume of opsin expression, compared with the conventional DBD method. The total injection time was also reduced by at least 10 times, if similar extent of expression were to be achieved with the conventional DBD method. CONCLUSIONS: CED is a reliable and effective method of virus delivery for optogenetic transduction of planar superficial structures, such as the cortex in rats. PMID- 28807860 TI - Hidden Markov modeling of frequency-following responses to Mandarin lexical tones. AB - BACKGROUND: The frequency-following response (FFR) is a scalp-recorded electrophysiological potential reflecting phase-locked activity from neural ensembles in the auditory system. The FFR is often used to assess the robustness of subcortical pitch processing. Due to low signal-to-noise ratio at the single trial level, FFRs are typically averaged across thousands of stimulus repetitions. Prior work using this approach has shown that subcortical encoding of linguistically-relevant pitch patterns is modulated by long-term language experience. NEW METHOD: We examine the extent to which a machine learning approach using hidden Markov modeling (HMM) can be utilized to decode Mandarin tone-categories from scalp-record electrophysiolgical activity. We then assess the extent to which the HMM can capture biologically-relevant effects (language experience-driven plasticity). To this end, we recorded FFRs to four Mandarin tones from 14 adult native speakers of Chinese and 14 of native English. We trained a HMM to decode tone categories from the FFRs with varying size of averages. RESULTS AND COMPARISONS WITH EXISTING METHODS: Tone categories were decoded with above-chance accuracies using HMM. The HMM derived metric (decoding accuracy) revealed a robust effect of language experience, such that FFRs from native Chinese speakers yielded greater accuracies than native English speakers. Critically, the language experience-driven plasticity was captured with average sizes significantly smaller than those used in the extant literature. CONCLUSIONS: Our results demonstrate the feasibility of HMM in assessing the robustness of neural pitch. Machine-learning approaches can complement extant analytical methods that capture auditory function and could reduce the number of trials needed to capture biological phenomena. PMID- 28807862 TI - Comment to the manuscript by Bacalhau et al. on "In silico prediction is insufficient to assess pathogenicity of mtDNA variants". PMID- 28807861 TI - Comparing brain graphs in which nodes are regions of interest or independent components: A simulation study. AB - BACKGROUND: A key challenge in building a brain graph using fMRI data is how to define the nodes. Spatial brain components estimated by independent components analysis (ICA) and regions of interest (ROIs) determined by brain atlas are two popular methods to define nodes in brain graphs. It is difficult to evaluate which method is better in real fMRI data. NEW METHOD: Here we perform a simulation study and evaluate the accuracies of a few graph metrics in graphs with nodes of ICA components, ROIs, or modified ROIs in four simulation scenarios. RESULTS: Graph measures with ICA nodes are more accurate than graphs with ROI nodes in all cases. Graph measures with modified ROI nodes are modulated by artifacts. The correlations of graph metrics across subjects between graphs with ICA nodes and ground truth are higher than the correlations between graphs with ROI nodes and ground truth in scenarios with large overlapped spatial sources. Moreover, moving the location of ROIs would largely decrease the correlations in all scenarios. COMPARISON WITH EXISTING METHOD (S): Evaluating graphs with different nodes is promising in simulated data rather than real data because different scenarios can be simulated and measures of different graphs can be compared with a known ground truth. CONCLUSION: Since ROIs defined using brain atlas may not correspond well to real functional boundaries, overall findings of this work suggest that it is more appropriate to define nodes using data-driven ICA than ROI approaches in real fMRI data. PMID- 28807863 TI - Prenatal diagnosis of complex phenotype in a 13-week-old fetus with an interstitial multigene deletion 20q13.13.-q13.2 by chromosomal microarray. AB - We report the first trimester three-dimensional ultrasonographic findings in a 13 week-old fetus with complex phenotype and a de novo 4.7 Mb multigene deletion encompassing chromosome region 20q13.13-q13.2 detected by chromosomal microarray. Fetal sonography detected radial-ray anomalies in the form of bilateral absence of thumbs and the left club hand deformity. The presence of single atrioventricular canal instead of the atrial septal defect typical for Holt-Oram syndrome pointed us to rather suspect the SALL4 related diseases. Central nervous system anomaly in the form of enlarged lateral brain ventricles with choroid plexus shifted backwards was not previously reported as a part of SALL4 related disorders. The pregnancy was terminated at 14 + 3 weeks of pregnancy and the autopsy confirmed ultrasonographic findings. Deleted region included 38 genes, where only SALL4, ADNP and KCNB1 heterozygote pathogenic variants were described to be cause of syndromic forms. Radial ray anomalies are common part of clinical picture of SALL4 related disorders. Despite the lack of prenatally described cases, we hypothesized that maldevelopment of lateral brain ventriculomegaly could be very early sonographic sign of disturbed ADNP expression causing Helsmoortel-Van der Aa syndrome, but in some extent also of KCNB1 related early onset epileptic encephalopathy. Furthermore, the possible dosage-dependent influence of recessive genes located in this region cannot be also excluded. The use of genome-wide technologies enables the detection of subtle chromosomal imbalances and more precise familial genetic counseling regarding actual and future pregnancies. PMID- 28807864 TI - Reducing diagnostic turnaround times of exome sequencing for families requiring timely diagnoses. AB - BACKGROUND AND OBJECTIVE: Whole-exome sequencing (WES) has now entered medical practice with powerful applications in the diagnosis of rare Mendelian disorders. Although the usefulness and cost-effectiveness of WES have been widely demonstrated, it is essential to reduce the diagnostic turnaround time to make WES a first-line procedure. Since 2011, the automation of laboratory procedures and advances in sequencing chemistry have made it possible to carry out diagnostic whole genome sequencing from the blood sample to molecular diagnosis of suspected genetic disorders within 50 h. Taking advantage of these advances, the main objective of the study was to improve turnaround times for sequencing results. METHODS: WES was proposed to 29 patients with severe undiagnosed disorders with developmental abnormalities and faced with medical situations requiring rapid diagnosis. Each family gave consent. The extracted DNA was sequenced on a NextSeq500 (Illumina) instrument. Data were analyzed following standard procedures. Variants were interpreted using in-house software. Each rare variant affecting protein sequences with clinical relevance was tested for familial segregation. RESULTS: The diagnostic rate was 45% (13/29), with a mean turnaround time of 40 days from reception of the specimen to delivery of results to the referring physician. Besides permitting genetic counseling, the rapid diagnosis for positive families led to two pre-natal diagnoses and two inclusions in clinical trials. CONCLUSIONS: This pilot study demonstrated the feasibility of rapid diagnostic WES in our primary genetics center. It reduced the diagnostic odyssey and helped provide support to families. PMID- 28807865 TI - Novel compound heterozygous mutations identified by whole exome sequencing in a Japanese patient with geroderma osteodysplastica. AB - Geroderma osteodysplastica (GO) is a subtype of cutis laxa syndrome characterized by congenital wrinkly skin, a prematurely aged face, extremely short stature, and osteoporosis leading to recurrent fractures. GO exhibits an autosomal recessive inheritance pattern and is caused by loss-of-function mutations in GORAB, which encodes a protein important for Golgi-related transport. Using whole exome sequencing, we identified novel compound heterozygous nonsense mutations in the GORAB in a GO patient. The patient was a 14-year-old Japanese boy. Wrinkled skin and joint laxity were present at birth. At 1 year of age, he was clinically diagnosed with cutis laxa syndrome based on recurrent long bone fractures and clinical features, including wrinkled skin, joint laxity, and a distinctive face. He did not show retarded gross motor and cognitive development. At 11 years of age, he was treated with oral bisphosphonate and vitamin D owing to recurrent multiple spontaneous fractures of the vertebral and extremity bones associated with a low bone mineral density (BMD). Bisphosphonate treatment improved his BMD and fracture rate. Whole exome sequencing revealed two novel compound heterozygous nonsense mutations in the GORAB gene (p.Arg60* and p.Gln124*), and the diagnosis of GO was established. GO is a rare connective tissue disorder. Approximately 60 cases have been described to date, and this is the first report of a patient from Japan. Few studies have reported the effects of bisphosphonate treatment in GO patients with recurrent spontaneous fractures. Based on this case study, we hypothesize that oral bisphosphonate and vitamin D are effective and safe treatment options for the management of recurrent fractures in GO patients. It is important to establish a precise diagnosis of GO to prevent recurrent fractures and optimize treatment plans. PMID- 28807866 TI - BRCA1/2 missense mutations and the value of in-silico analyses. AB - INTRODUCTION: The clinical implications of genetic variants in BRCA1/2 in healthy and affected individuals are considerable. Variant interpretation, however, is especially challenging for missense variants. The majority of them are classified as variants of unknown clinical significance (VUS). Computational (in-silico) predictive programs are easy to access, but represent only one tool out of a wide range of complemental approaches to classify VUS. With this single-center study, we aimed to evaluate the impact of in-silico analyses in a spectrum of different BRCA1/2 missense variants. METHODS: We conducted mutation analysis of BRCA1/2 in 523 index patients with suspected hereditary breast and ovarian cancer (HBOC). Classification of the genetic variants was performed according to the German Consortium (GC)-HBOC database. Additionally, all missense variants were classified by the following three in-silico prediction tools: SIFT, Mutation Taster (MT2) and PolyPhen2 (PPH2). RESULTS: Overall 201 different variants, 68 of which constituted missense variants were ranked as pathogenic, neutral, or unknown. The classification of missense variants by in-silico tools resulted in a higher amount of pathogenic mutations (25% vs. 13.2%) compared to the GC-HBOC classification. Altogether, more than fifty percent (38/68, 55.9%) of missense variants were ranked differently. Sensitivity of in-silico-tools for mutation prediction was 88.9% (PPH2), 100% (SIFT) and 100% (MT2). CONCLUSION: We found a relevant discrepancy in variant classification by using in-silico prediction tools, resulting in potential overestimation and/or underestimation of cancer risk. More reliable, notably gene-specific, prediction tools and functional tests are needed to improve clinical counseling. PMID- 28807867 TI - Impairment of different protein domains causes variable clinical presentation within Pitt-Hopkins syndrome and suggests intragenic molecular syndromology of TCF4. AB - Pitt-Hopkins syndrome is a neurodevelopmental disorder characterized by severe intellectual disability and a distinctive facial gestalt. It is caused by haploinsufficiency of the TCF4 gene. The TCF4 protein has different functional domains, with the NLS (nuclear localization signal) domain coded by exons 7-8 and the bHLH (basic Helix-Loop-Helix) domain coded by exon 18. Several alternatively spliced TCF4 variants have been described, allowing for translation of variable protein isoforms. Typical PTHS patients have impairment of at least the bHLH domain. To which extent impairment of the remaining domains contributes to the final phenotype is not clear. There is recent evidence that certain loss-of function variants disrupting TCF4 are associated with mild ID, but not with typical PTHS. We describe a frameshift-causing partial gene deletion encompassing exons 4-6 of TCF4 in an adult patient with mild ID and nonspecific facial dysmorphisms but without the typical features of PTHS, and a c.520C > T nonsense variant within exon 8 in a child presenting with a severe phenotype largely mimicking PTHS, but lacking the typical facial dysmorphism. Investigation on mRNA, along with literature review, led us to suggest a preliminary phenotypic map of loss-of-function variants affecting TCF4. An intragenic phenotypic map of loss-of-function variants in TCF4 is suggested here for the first time: variants within exons 1-4 and exons 4-6 give rise to a recurrent phenotype with mild ID not in the spectrum of Pitt-Hopkins syndrome (biallelic preservation of both the NLS and bHLH domains); variants within exons 7-8 cause a severe phenotype resembling PTHS but in absence of the typical facial dysmorphism (impairment limited to the NLS domain); variants within exons 9-19 cause typical Pitt-Hopkins syndrome (impairment of at least the bHLH domain). Understanding the TCF4 molecular syndromology can allow for proper nosology in the current era of whole genomic investigations. PMID- 28807868 TI - Response to "In silico prediction is insufficient to assess pathogenicity of mtDNA variants". PMID- 28807869 TI - A novel mutation in SMOC1 and variable phenotypic expression in two patients with Waardenburg anophthalmia syndrome. AB - Waardenburg anophthalmia syndrome (WAS) is a rare disorder that mostly affects the eyes and distal limbs. In the current study we reported two Iranian patients with WAS. The first case was a 26-year-old girl with unilateral anophthalmia, bilateral camptodactyly and clinodactyly in her hands, oligodactly in her left foot and syndactyly of the second to fifth toes in her right foot. She also had severe hearing loss in both ears. The second case was a 12-year-old boy with bilateral anophthalmia, camptodactyly in his right hand, oligodactyly in his foot, clubfoot, and cryptorchidism. Both patients were mentally normal. To detect the causative mutation all exons and exon-intron boundaries of SMOC1 gene were sequenced in patients and other normal family members. We found a homozygous missense mutation (NM_001034852.2(SMOC1):c.367T > C) in exon 3 of SMOC1 gene in both patients. As the mutation segregated with the disease in the family, it should be the causative mutation. Our study extended the mutation spectrum of SMOC1 gene related to WAS. PMID- 28807870 TI - An open, multi-vendor, multi-field-strength brain MR dataset and analysis of publicly available skull stripping methods agreement. AB - This paper presents an open, multi-vendor, multi-field strength magnetic resonance (MR) T1-weighted volumetric brain imaging dataset, named Calgary Campinas-359 (CC-359). The dataset is composed of images of older healthy adults (29-80 years) acquired on scanners from three vendors (Siemens, Philips and General Electric) at both 1.5 T and 3 T. CC-359 is comprised of 359 datasets, approximately 60 subjects per vendor and magnetic field strength. The dataset is approximately age and gender balanced, subject to the constraints of the available images. It provides consensus brain extraction masks for all volumes generated using supervised classification. Manual segmentation results for twelve randomly selected subjects performed by an expert are also provided. The CC-359 dataset allows investigation of 1) the influences of both vendor and magnetic field strength on quantitative analysis of brain MR; 2) parameter optimization for automatic segmentation methods; and potentially 3) machine learning classifiers with big data, specifically those based on deep learning methods, as these approaches require a large amount of data. To illustrate the utility of this dataset, we compared to the results of a supervised classifier, the results of eight publicly available skull stripping methods and one publicly available consensus algorithm. A linear mixed effects model analysis indicated that vendor (p-value<0.001) and magnetic field strength (p-value<0.001) have statistically significant impacts on skull stripping results. PMID- 28807871 TI - Mentalizing regions represent distributed, continuous, and abstract dimensions of others' beliefs. AB - The human capacity to reason about others' minds includes making causal inferences about intentions, beliefs, values, and goals. Previous fMRI research has suggested that a network of brain regions, including bilateral temporo parietal junction (TPJ), superior temporal sulcus (STS), and medial prefrontal cortex (MPFC), are reliably recruited for mental state reasoning. Here, in two fMRI experiments, we investigate the representational content of these regions. Building on existing computational and neural evidence, we hypothesized that social brain regions contain at least two functionally and spatially distinct components: one that represents information related to others' motivations and values, and another that represents information about others' beliefs and knowledge. Using multi-voxel pattern analysis, we find evidence that motivational versus epistemic features are independently represented by theory of mind (ToM) regions: RTPJ contains information about the justification of the belief, bilateral TPJ represents the modality of the source of knowledge, and VMPFC represents the valence of the resulting emotion. These representations are found only in regions implicated in social cognition and predict behavioral responses at the level of single items. We argue that cortical regions implicated in mental state inference contain complementary, but distinct, representations of epistemic and motivational features of others' beliefs, and that, mirroring the processes observed in sensory systems, social stimuli are represented in distinct and distributed formats across the human brain. PMID- 28807872 TI - Cortical representation of persistent visual stimuli. AB - Research into visual neural activity has focused almost exclusively on onset- or change-driven responses and little is known about how information is encoded in the brain during sustained periods of visual perception. We used intracranial recordings in humans to determine the degree to which the presence of a visual stimulus is persistently encoded by neural activity. The correspondence between stimulus duration and neural response duration was strongest in early visual cortex and gradually diminished along the visual hierarchy, such that is was weakest in inferior-temporal category-selective regions. A similar posterior anterior gradient was found within inferior temporal face-selective regions, with posterior but not anterior sites showing persistent face-selective activity. The results suggest that regions that appear uniform in terms of their category selectivity are dissociated by how they temporally represent a stimulus in support of ongoing visual perception, and delineate a large-scale organizing principle of the ventral visual stream. PMID- 28807874 TI - Docosahexaenoic acid increases the expression of oxidative stress-induced growth inhibitor 1 through the PI3K/Akt/Nrf2 signaling pathway in breast cancer cells. AB - Oxidative stress-induced growth inhibitor 1 (OSGIN1), a tumor suppressor, inhibits cell proliferation and induces cell death. N-6 and n-3 PUFAs protect against breast cancer, but the molecular mechanisms of this effect are not clear. We investigated the effect of n-6 and n-3 PUFAs on OSGIN1 expression and whether OSGIN1 is involved in PUFA-induced apoptosis in breast cancer cells. We used 100 MUM of n-6 PUFAs including arachidonic acid, linoleic acid, and gamma-linolenic acid and n-3 PUFAs including alpha-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid (DHA). Only DHA significantly induced OSGIN1 protein and mRNA expression. DHA triggered reactive oxygen species (ROS) generation and nuclear translocation of Nrf2. LY294002, a PI3K inhibitor, suppressed DHA-induced OSGIN1 protein expression and nuclear accumulation of Nrf2. Nrf2 knockdown attenuated DHA-induced OSGIN1 expression. N-Acetyl-l-cysteine, a ROS scavenger, abrogated the DHA-induced increases in Akt phosphorylation, Nrf2 nuclear accumulation, and OSGIN1 expression. DHA induced the Bax/Bcl-2 ratio, mitochondrial accumulation of OSGIN1 and p53, and cytochrome c release; knockdown of OSGIN1 diminished these effects. In conclusion, induction of OSGIN1 by DHA is at least partially associated with increased ROS production, which activates PI3K/Akt/Nrf2 signaling. Induction of OSGIN1 may be involved in DHA-induced apoptosis in breast cancer cells. PMID- 28807875 TI - Bioactive isoflavones from Pueraria lobata root and starch: Different extraction techniques and carbonic anhydrase inhibition. AB - Kudzu, the dried root of an important edible plant (Pueraria lobata), is used in Traditional Chinese Medicine for the important nutritional value strictly related to its isoflavone derivatives. These compounds characterize the quality of kudzu contained in different preparations, as pharmaceutical ingredient as well as dietary/food supplement (e.g. starch). The optimization of the isoflavones recovery, monitored by HPLC-PDA, through different innovative and conventional extraction techniques, e.g. microwave-assisted, ultrasound-assisted and conventional extraction, represented a suitable challenge in food industry and natural products evaluation. The impact on the isoflavone extraction by using an ionic liquid-assisted procedure was also considered. Furthermore, the inhibitory activity of the most representative isoflavones, isolated from kudzu, was evaluated using four isoforms (I, II, IX and XII) of human carbonic anhydrase (hCA) due to their role in several physiopathological processes. PMID- 28807876 TI - Molecular insights on xenoestrogenic potential of zearalenone-14-glucoside through a mixed in vitro/in silico approach. AB - The mycotoxin zearalenone may contaminate food and feed worldwide upon infections by Fusarium spp. of plants and raw materials intended for human and animal consumption. Currently, contamination by zearalenone and congeners pose concern for health due to xenoestrogenic effects. However, while zearalenone and the main reduced metabolites are well-known xenoestrogens, some plant metabolites that may enter the food chain have been observed aside. Among them, zearalenone-14 glucoside may be abundant in the edible parts of infected plants, thereby entering significantly the human diet and animal feeding. On the basis of previous works, the lack of xenoestrogenicity for this compound per se was taken for granted, while neglecting the direct proof of estrogenic activity and considering the hydrolysis as a possible source of estrogenically active metabolites. The present work investigated the xenoestrogenicity of zearalenone 14-glucoside, in comparison to zearalenone, deepening the underlying molecular mechanisms through an integrated in vitro/in silico approach. On the basis of our results, zearalenone-14-glucoside effectively stimulated a xenoestrogenic response in cells, but such stimulus can be entirely attributable to the hydrolysis phenomenon, as the glycosylated form turned out to be unable to effectively bind and activate the estrogens receptors. PMID- 28807873 TI - Neurophysiologically-informed markers of individual variability and pharmacological manipulation of human cortical gamma. AB - The ability to quantify synaptic function at the level of cortical microcircuits from non-invasive data would be enormously useful in the study of neuronal processing in humans and the pathophysiology that attends many neuropsychiatric disorders. Here, we provide proof of principle that one can estimate inter-and intra-laminar interactions among specific neuronal populations using induced gamma responses in the visual cortex of human subjects - using dynamic causal modelling based upon the canonical microcircuit (CMC; a simplistic model of a cortical column). Using variability in induced (spectral) responses over a large cohort of normal subjects, we find that the predominant determinants of gamma responses rest on recurrent and intrinsic connections between superficial pyramidal cells and inhibitory interneurons. Furthermore, variations in beta responses were mediated by inter-subject differences in the intrinsic connections between deep pyramidal cells and inhibitory interneurons. Interestingly, we also show that increasing the self-inhibition of superficial pyramidal cells suppresses the amplitude of gamma activity, while increasing its peak frequency. This systematic and nonlinear relationship was only disclosed by modelling the causes of induced responses. Crucially, we were able to validate this form of neurophysiological phenotyping by showing a selective effect of the GABA re uptake inhibitor tiagabine on the rate constants of inhibitory interneurons. Remarkably, we were able to recover the pharmacodynamics of this effect over the course of several hours on a per subject basis. These findings speak to the possibility of measuring population specific synaptic function - and its response to pharmacological intervention - to provide subject-specific biomarkers of mesoscopic neuronal processes using non-invasive data. Finally, our results demonstrate that, using the CMC as a proxy, the synaptic mechanisms that underlie the gain control of neuronal message passing within and between different levels of cortical hierarchies may now be amenable to quantitative study using non invasive (MEG) procedures. PMID- 28807877 TI - Cryptotanshinone promotes commitment to the brown adipocyte lineage and mitochondrial biogenesis in C3H10T1/2 mesenchymal stem cells via AMPK and p38 MAPK signaling. AB - Although white adipose tissue (WAT) stores triglycerides and contributes to obesity, brown adipose tissue (BAT) dissipates energy as heat. Therefore, browning of WAT is regarded as an attractive way to counteract obesity. Our previous studies have revealed that treatment with cryptotanshinone (CT) during adipogenesis of 3T3-L1 cells inhibits their differentiation. Here, we found that pretreatment of C3H10T1/2 mesenchymal stem cells with CT before exposure to adipogenic hormonal stimuli promotes the commitment of these mesenchymal stem cells to the adipocyte lineage as confirmed by increased triglyceride accumulation. Furthermore, CT treatment induced the expression of early B-cell factor 2 (Ebf2) and bone morphogenetic protein 7 (Bmp7), which are known to drive differentiation of C3H10T1/2 mesenchymal stem cells toward preadipocytes and to the commitment to brown adipocytes. Consequently, CT treatment yielded brown adipocyte-like features as evidenced by elevated expression of brown-fat signature genes including Ucp1, Prdm16, Pgc-1alpha, Cidea, Zic1, and beige-cell specific genes such as CD137, Hspb7, Cox2, and Tmem26. Additionally, CT treatment induced mitochondrial biogenesis through upregulation of Sirt1, Tfam, Nrf1, and Cox7a and increased mitochondrial mass and DNA content. Our data also showed that cotreatment with CT and BMP4 was more effective at activating brown-adipocyte specific genes. Mechanistic experiments revealed that treatment with CT activated AMPKalpha and p38-MAPK via their phosphorylation: the two major signaling pathways regulating energy metabolism. Thus, these findings suggest that CT is a candidate therapeutic agent against obesity working via activation of browning and mitochondrial biogenesis in C3H10T1/2 mesenchymal stem cells. PMID- 28807878 TI - Sex-dependent changes in lipid metabolism, PPAR pathways and microRNAs that target PPARs in the fetal liver of rats with gestational diabetes. AB - Gestational diabetes mellitus (GDM) is a prevalent disease that impairs fetal metabolism and development. We have previously characterized a rat model of GDM induced by developmental programming. Here, we analyzed lipid content, the levels of the three PPAR isotypes and the expression of microRNAs that regulate PPARs expression in the liver of male and female fetuses of control and GDM rats on day 21 of pregnancy. We found increased levels of triglycerides and cholesterol in the livers of male fetuses of GDM rats compared to controls, and, oppositely, reduced levels of triglycerides, cholesterol, phospholipids and free fatty acids in the livers of female fetuses of GDM rats compared to controls. Although GDM did not change PPARalpha levels in male and female fetal livers, PPARgamma was increased in the liver of male fetuses of GDM rats, a change that occurred in parallel to a reduction in the expression of miR-130, a microRNA that targets PPARgamma. In livers of female fetuses of GDM rats, no changes in PPARgamma and miR-130 were evidenced, but PPARdelta was increased, a change that occurred in parallel to a reduction in the expression of miR-9, a microRNA that targets PPARdelta, and was unchanged in the liver of male fetuses of GDM and control rats. These results show clear sex-dependent changes in microRNAs that target different PPAR isotypes in relation to changes in the levels of their targets and the differential regulation of lipid metabolism evidenced in fetal livers of GDM pregnancies. PMID- 28807880 TI - Broad-spectrum bactericidal activity of a new bioactive grafting material (F18) against clinically important bacterial strains. AB - Infection is the most relevant surgical complication in implant or grafting procedures. Osteomyelitis and other chronic conditions pose a constant challenge in current medical practice. In this context, a grafting biomaterial that possesses antibacterial properties combined with bioactivity could have great clinical impact. Researchers at the Vitreous Materials Laboratory (LaMaV-UFSCar) recently developed a glass composition, named F18, that presents an improved workability range combined with high bioactivity. With F18, one can easily manufacture complex shapes, such as scaffolds, continuous fibres and coat implants. This biomaterial has proven to be a viable alternative for bone and skin regeneration in in vivo tests, however its antimicrobial properties have not been explored. Hence, the purpose of this study was to systematically investigate the antibacterial activity of F18 in powder and fibre forms according to the JIS Z 2801:2010 standard. Whether incorporation of silver into F18 glass could impact its antimicrobial activity was also evaluated. Four clinically relevant Gram positive and Gram-negative pathogenic bacterial strains (Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli and Pseudomonas aeruginosa) were used in this study. In both powder and fibre forms, F18 presented extremely efficient bactericidal activity against all strains tested, eliminating virtually 100% of the bacterial cells after 24 h. Kinetic tests showed that silver doping further increased the bactericidal activity, leading to S. aureus eradication in only 30 min after incubation. Both doped and non-doped glasses demonstrated very high bactericidal activity, making F18 a promising infection-preventing alternative for bone and wound regeneration in clinical practice. PMID- 28807879 TI - Apigenin-induced ABCC1-mediated efflux of glutathione from mature erythrocytes inhibits the proliferation of Plasmodium falciparum. AB - Plasmodium falciparum infection of mature erythrocytes leads to heightened oxidative stress that is tolerated in normal erythrocytes but not in erythrocytes from sickle cell, beta-thalassaemia and glucose-6-phosphate dehydrogenase (G6PD) deficiency hosts. In this report, it was of interest to perturb the redox homeostasis of normal erythrocytes through drug-induced active efflux of glutathione via erythrocyte ABCC1, a member of the C-subfamily of the human ATP binding cassette (ABC) transporters. To achieve this objective, we made use of apigenin (API), shown previously to activate ABCC1 glutathione efflux in mature erythrocytes. Our results show that API increased ABCC1-mediated efflux of calcein-AM from uninfected erythrocytes, which was reversed with MK571, an inhibitor of ABCC1 drug efflux. Similarly, addition of API to uninfected normal erythrocytes led to a dramatic increase in reactive oxygen species coupled with a significant decrease in intracellular glutathione. Moreover, using P. falciparum infected normal erythrocytes, we demonstrate that increasing concentrations of API inhibited the proliferation of chloroquine-susceptible (3D7) and -resistant (Dd2) parasites in culture with similar 50% inhibitory concentration (IC50) values (36.02 +/- 2.4 uM and 34.45 +/- 2.4 uM, respectively). Interestingly, the presence of API (25 uM) led to a three-fold decrease in the IC50 of artemisinin compared with artemisinin alone (2.8 +/- 0.7 nM vs. 7.09 +/- 1.5 nM, respectively). Taken together, the findings of this study demonstrate the feasibility of our proposed approach for the development of novel antimalarials by modulating host protein functions that leads to heightened oxidative stress in P. falciparum-infected erythrocytes and inhibits parasite proliferation. PMID- 28807881 TI - Taking the Initiative: Risk-Reduction Strategies and Decreased Malpractice Costs. AB - BACKGROUND: To heighten awareness of attending and resident surgeons regarding strategies for defense against malpractice claims, a series of risk reduction initiatives have been carried out in our Department of Surgery. We hypothesized that emphasis on certain aspects of risk might be associated with decreased malpractice costs. The relative impact of Department of Surgery initiatives was assessed when compared with malpractice experience for the rest of the Clinical Practices of the University of Pennsylvania (CPUP). STUDY DESIGN: Surgery and CPUP malpractice claims, indemnity, and expenses were obtained from the Office of General Counsel. Malpractice premium data were obtained from CPUP finance. The Department of Surgery was assessed in comparison with all other CPUP departments. Cost data (yearly indemnity and expenses), and malpractice premiums (total and per physician) were expressed as a percentage of the 5-year mean value preceding implementation of the initiative program. RESULTS: Surgery implemented 38 risk reduction initiatives. Faculty participated in 27 initiatives; house staff participated in 10 initiatives; and advanced practitioners in 1 initiative. Department of Surgery claims were significantly less than CPUP (74.07% vs 81.07%; p < 0.05). The mean yearly indemnity paid by the Department of Surgery was significantly less than that of the other CPUP departments (84.08% vs 122.14%; p < 0.05). Department of Surgery-paid expenses were also significantly less (83.17% vs 104.96%; p < 0.05), and surgical malpractice premiums declined from baseline, but remained significantly higher than CPUP premiums. CONCLUSIONS: The data suggest that educating surgeons on malpractice and risk reduction may play a role in decreasing malpractice costs. Additional extrinsic factors may also affect cost data. Emphasis on risk reduction appears to be cumulative and should be part of an ongoing program. PMID- 28807882 TI - Control of nucleus positioning in mouse oocytes. AB - The position of the nucleus in a cell can instruct morphogenesis in some cases, conveying spatial and temporal information and abnormal nuclear positioning can lead to disease. In oocytes from worm, sea urchin, frog and some fish, nucleus position regulates embryo development, it marks the animal pole and in Drosophila it defines the future dorso-ventral axis of the embryo and of the adult body plan. However, in mammals, the oocyte nucleus is centrally located and does not instruct any future embryo axis. Yet an off-center nucleus correlates with poor outcome for mouse and human oocyte development. This is surprising since oocytes further undergo two extremely asymmetric divisions in terms of the size of the daughter cells (enabling polar body extrusion), requiring an off-centering of their chromosomes. In this review we address not only the bio-physical mechanism controlling nucleus positioning via an actin-mediated pressure gradient, but we also speculate on potential biological relevance of nuclear positioning in mammalian oocytes and early embryos. PMID- 28807883 TI - Simultaneous AFM topography and recognition imaging at the plasma membrane of mammalian cells. AB - Elucidation the nano-organization of membrane proteins at/within the plasma membrane is probably the most demanding and still challenging task in cell biology since requires experimental approaches with nanoscale resolution. During last decade, atomic force microscopy (AFM)-based simultaneous topography and recognition imaging (TREC) has become a powerful tool to quickly obtain local receptor nano-maps on complex heterogeneous biosurfaces such as cells and membranes. Here we emphasize the TREC technique and explain how to unravel the nano-landscape of mammalian cells. We describe the procedures for all steps of the experiment including tip functionalization with ligand molecules, sample preparation, and localization of key molecules on the cell surface. We also discuss the current limitations and future perspectives of this technique. PMID- 28807884 TI - ESCRT and autophagies: Endosomal functions and beyond. AB - ESCRT (endosomal sorting complex required for transport) machinery has been initially identified for its role during endocytosis, which allows membrane proteins and lipids to be degraded in the lysosome. ESCRT function is required to form intraluminal vesicles permitting internalization of cytosolic components or membrane embedded cargoes and promoting endosome maturation. ESCRT machinery also contributes to multiple key cell mechanisms in which it reshapes membranes. In addition, ESCRT actively participates in different types of autophagy processes for degrading cytosolic components, such as endosomal microautophagy and macroautophagy. During macroautophagy, ESCRT promotes formation of multivesicular bodies, which can fuse with autophagosomes to generate amphisomes. This latter fusion probably brings to autophagosomes key membrane molecules necessary for the subsequent fusion with lysosomes. Interestingly, during macroautophagy, ESCRT proteins could be involved in non-canonical functions such as vesicle tethering or phagophore membrane sealing. Additionally, ESCRT subunits could directly interact with key autophagy related proteins to build a closer connection between endocytosis and autophagy pathways. PMID- 28807885 TI - Biogenesis and function of ESCRT-dependent extracellular vesicles. AB - From bacteria to humans, cells secrete a large variety of membrane-bound extracellular vesicles. Only relatively recently has it however started to become clear that the exovesicular transport of proteins and RNAs is important for normal physiology and numerous pathological conditions. Extracellular vesicles can be formed through the release of the intralumenal vesicles of multivesicular endosomes as so-called exosomes, or through direct, ectosomal, budding from the cell surface. Through their ability to promote the bending of membranes away from the cytoplasm, the components of the Endosomal Sorting Complex Required for Transport (ESCRT) have been implicated in both exo- and ectosomal biogenesis. Studies of the ESCRT machinery may therefore provide important insights into the formation and function of extracellular vesicles. In the present review, we first describe the cell biological mechanisms through which ESCRT components contribute to the biogenesis of different types of extracellular vesicles. We then discuss how recent functional studies have started to uncover important roles of ESCRT dependent extracellular vesicles in a wide variety of processes, including the transport of developmental signaling molecules and embryonic morphogenesis, the regulation of social behavior and host-pathogen interactions, as well as the etiology and progression of neurodegenerative pathologies and cancer. PMID- 28807887 TI - An integrative system biology approach to unravel potential drug candidates for multiple age related disorders. AB - Aging, though an inevitable part of life, is becoming a worldwide social and economic problem. Healthy aging is usually marked by low probability of age related disorders. Good therapeutic approaches are still in need to cure age related disorders. Occurrence of more than one ARD in an individual, expresses the need of discovery of such target proteins, which can affect multiple ARDs. Advanced scientific and medical research technologies throughout last three decades have arrived to the point where lots of key molecular determinants affect human disorders can be examined thoroughly. In this study, we designed and executed an approach to prioritize drugs that may target multiple age related disorders. Our methodology, focused on the analysis of biological pathways and protein protein interaction networks that may contribute to the pharmacology of age related disorders, included various steps such as retrieval and analysis of data, protein-protein interaction network analysis, and statistical and comparative analysis of topological coefficients, pathway, and functional enrichment analysis, and identification of drug-target proteins. We assume that the identified molecular determinants may be prioritized for further screening as novel drug targets to cure multiple ARDs. Based on the analysis, an online tool named as 'ARDnet' has been developed to construct and demonstrate ARD interactions at the level of PPI, ARDs and ARDs protein interaction, ARDs pathway interaction and drug-target interaction. The tool is freely made available at http://genomeinformatics.dtu.ac.in/ARDNet/Index.html. PMID- 28807886 TI - Mechanistic insights into F420-dependent glucose-6-phosphate dehydrogenase using isotope effects and substrate inhibition studies. AB - F420-dependent glucose-6-phosphate dehydrogenase (FGD) is involved in the committed step of the pentose phosphate pathway within mycobacteria, where it catalyzes the reaction between glucose-6-phosphate (G6P) and the F420 cofactor to yield 6-phosphogluconolactone and the reduced cofactor, F420H2. Here, we aim to probe the FGD reaction mechanism using dead-end inhibition experiments, as well as solvent and substrate deuterium isotope effects studies. The dead-end inhibition studies performed using citrate as the inhibitor revealed competitive and uncompetitive inhibition patterns for G6P and F420 respectively, thus suggesting a mechanism of ordered addition of substrates in which the F420 cofactor must first bind to FGD before G6P binding. The solvent deuterium isotope effects studies yielded normal solvent kinetic isotope effects (SKIE) on kcat and kcat/Km for both G6P and F420. The proton inventory data yielded a fractionation factor of 0.37, suggesting that the single proton responsible for the observed SKIE is likely donated by Glu109 and protonates the cofactor at position N1. The steady state substrate deuterium isotope effects studies using G6P and G6P-d1 yielded KIE of 1.1 for both kcat and kcat/Km, while the pre-steady state KIE on kobs was 1.4. Because the hydride transferred to C5 of F420 was the one targeted for isotopic substitution, these KIE values provide further evidence to support our previous findings that hydride transfer is likely not rate-limiting in the FGD reaction. PMID- 28807888 TI - Spectroscopic and calorimetric assays reveal dependence on dCTP and two metals (Zn2++Mg2+) for enzymatic activity of Schistosoma mansoni deoxycytidylate (dCMP) deaminase. AB - The parasite Schistosoma mansoni possess all pathways for pyrimidine biosynthesis, whereby deaminases play an essential role in the thymidylate cycle, a crucial step to controlling the ratio between cytidine and uridine nucleotides. In this study, we heterologously expressed and purified the deoxycytidylate (dCMP) deaminase from S. mansoni to obtain structural, biochemical and kinetic information. Small-angle X-ray scattering of this enzyme showed that it is organized as a hexamer in solution. Isothermal titration calorimetry was used to determine the kinetic constants for dCMP-dUMP conversion and the role of dCTP and dTTP in enzymatic regulation. We evaluated the metals involved in activating the enzyme and show for the first time the dependence of correct folding on the interaction of two metals. This study provides information that may be useful for understanding the regulatory mechanisms involved in the metabolic pathways of S. mansoni. Thus, improving our understanding of the function of these essential pathways for parasite metabolism and showing for the first time the hitherto unknown deaminase function in this parasite. PMID- 28807889 TI - Activity Trackers Implement Different Behavior Change Techniques for Activity, Sleep, and Sedentary Behaviors. AB - BACKGROUND: Several studies have examined how the implementation of behavior change techniques (BCTs) varies between different activity trackers. However, activity trackers frequently allow tracking of activity, sleep, and sedentary behaviors; yet, it is unknown how the implementation of BCTs differs between these behaviors. OBJECTIVE: The aim of this study was to assess the number and type of BCTs that are implemented by wearable activity trackers (self-monitoring systems) in relation to activity, sleep, and sedentary behaviors and to determine whether the number and type of BCTs differ between behaviors. METHODS: Three self monitoring systems (Fitbit [Charge HR], Garmin [Vivosmart], and Jawbone [UP3]) were each used for a 1-week period in August 2015. Each self-monitoring system was used by two of the authors (MJD and BM) concurrently. The Coventry, Aberdeen, and London-Refined (CALO-RE) taxonomy was used to assess the implementation of 40 BCTs in relation to activity, sleep, and sedentary behaviors. Discrepancies in ratings were resolved by discussion, and interrater agreement in the number of BCTs implemented was assessed using kappa statistics. RESULTS: Interrater agreement ranged from 0.64 to 1.00. From a possible range of 40 BCTs, the number of BCTs present for activity ranged from 19 (Garmin) to 33 (Jawbone), from 4 (Garmin) to 29 (Jawbone) for sleep, and 0 (Fitbit) to 10 (Garmin) for sedentary behavior. The average number of BCTs implemented was greatest for activity (n=26) and smaller for sleep (n=14) and sedentary behavior (n=6). CONCLUSIONS: The number and type of BCTs implemented varied between each of the systems and between activity, sleep, and sedentary behaviors. This provides an indication of the potential of these systems to change these behaviors, but the long-term effectiveness of these systems to change activity, sleep, and sedentary behaviors remains unknown. PMID- 28807890 TI - Vulnerable Youth as Prosumers in HIV Prevention: Studies Using Participatory Action Research. AB - BACKGROUND: Stigma, voicelessness, and legislative and rights barriers, coupled with top-down decision making, are the common experiences of vulnerable youth populations that limit their opportunities to participate in vital health promotion efforts such as HIV prevention. OBJECTIVE: To consider new opportunities arising from a digital society for youth to creatively shape HIV prevention. METHODS: Drawing on research with vulnerable youth in Busoga, Uganda; Bulawayo, Zimbabwe; Bangkok, Thailand; and Bali, Indonesia, we explore current youth participation, in theory and practice, while considering new opportunities arising from a digital society for youth to creatively shape HIV prevention. RESULTS: Collaborative commons and prosumer models are defined as people employing new technology to codesign toward a common goal. Within the context of a diminishing role of the traditional institution and the rise of digitized networks, such models offer exciting new directions for youth as electronic health promotion prosumers to participate in difficult challenges such as HIV prevention in the 21st century. CONCLUSIONS: It is time for institutions to embrace such opportunities, especially in areas where access to technology is widening, while continuing to champion youth and advocate for supportive social environments. PMID- 28807891 TI - A Collaborative Approach to Identifying Social Media Markers of Schizophrenia by Employing Machine Learning and Clinical Appraisals. AB - BACKGROUND: Linguistic analysis of publicly available Twitter feeds have achieved success in differentiating individuals who self-disclose online as having schizophrenia from healthy controls. To date, limited efforts have included expert input to evaluate the authenticity of diagnostic self-disclosures. OBJECTIVE: This study aims to move from noisy self-reports of schizophrenia on social media to more accurate identification of diagnoses by exploring a human machine partnered approach, wherein computational linguistic analysis of shared content is combined with clinical appraisals. METHODS: Twitter timeline data, extracted from 671 users with self-disclosed diagnoses of schizophrenia, was appraised for authenticity by expert clinicians. Data from disclosures deemed true were used to build a classifier aiming to distinguish users with schizophrenia from healthy controls. Results from the classifier were compared to expert appraisals on new, unseen Twitter users. RESULTS: Significant linguistic differences were identified in the schizophrenia group including greater use of interpersonal pronouns (P<.001), decreased emphasis on friendship (P<.001), and greater emphasis on biological processes (P<.001). The resulting classifier distinguished users with disclosures of schizophrenia deemed genuine from control users with a mean accuracy of 88% using linguistic data alone. Compared to clinicians on new, unseen users, the classifier's precision, recall, and accuracy measures were 0.27, 0.77, and 0.59, respectively. CONCLUSIONS: These data reinforce the need for ongoing collaborations integrating expertise from multiple fields to strengthen our ability to accurately identify and effectively engage individuals with mental illness online. These collaborations are crucial to overcome some of mental illnesses' biggest challenges by using digital technology. PMID- 28807893 TI - Optimizing the Use of Electronic Health Records to Identify High-Risk Psychosocial Determinants of Health. AB - BACKGROUND: Care coordination programs have traditionally focused on medically complex patients, identifying patients that qualify by analyzing formatted clinical data and claims data. However, not all clinically relevant data reside in claims and formatted data. Recently, there has been increasing interest in including patients with complex psychosocial determinants of health in care coordination programs. Psychosocial risk factors, including social determinants of health, mental health disorders, and substance abuse disorders, are less amenable to rapid and systematic data analyses, as these data are often not collected or stored as formatted data, and due to US Health Insurance Portability and Accountability Act (HIPAA) regulations are often not available as claims data. OBJECTIVE: The objective of our study was to develop a systematic approach using word recognition software to identifying psychosocial risk factors within any part of a patient's electronic health record (EHR). METHODS: We used QPID (Queriable Patient Inference Dossier), an ontology-driven word recognition software, to scan adult patients' EHRs to identify terms predicting a high-risk patient suitable to be followed in a care coordination program in Massachusetts, USA. Search terms identified high-risk conditions in patients known to be enrolled in a care coordination program, and were then tested against control patients. We calculated precision, recall, and balanced F-measure for the search terms. RESULTS: We identified 22 EHR-available search terms to define psychosocial high-risk status; the presence of 9 or more of these terms predicted that a patient would meet inclusion criteria for a care coordination program. Precision was .80, recall .98, and balanced F-measure .88 for the identified terms. For adult patients insured by Medicaid and enrolled in the program, a mean of 14 terms (interquartile range [IQR] 11-18) were present as identified by the search tool, ranging from 2 to 22 terms. For patients enrolled in the program but not insured by Medicaid, a mean of 6 terms (IQR 3-8) were present as identified by the search tool, ranging from 1 to 21. CONCLUSIONS: Selected informatics tools such as word recognition software can be leveraged to improve health care delivery, such as an EHR-based protocol that identifies psychosocially complex patients eligible for enrollment in a care coordination program. PMID- 28807892 TI - Parent-Mediated Intervention Training Delivered Remotely for Children With Autism Spectrum Disorder Living Outside of Urban Areas: Systematic Review. AB - BACKGROUND: Parent training programs for families living outside of urban areas can be used to improve the social behavior and communication skills in children with autism spectrum disorder (ASD). However, no review has been conducted to investigate these programs. OBJECTIVE: The aim of this study was to (1) systematically review the existing evidence presented by studies on parent mediated intervention training, delivered remotely for parents having children with ASD and living outside of urban areas; (2) provide an overview of current parent training interventions used with this population; (3) and provide an overview of the method of delivery of the parent training interventions used with this population. METHODS: Guided by the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement, we conducted a comprehensive review across 5 electronic databases (CINAHL, Embase, ERIC, PsycINFO, and Pubmed) on July 4, 2016, searching for studies investigating parent-mediated intervention training for families living outside of urban centers who have a child diagnosed with ASD. Two independent researchers reviewed the articles for inclusion, and assessment of methodological quality was based on the Kmet appraisal checklist. RESULTS: Seven studies met the eligibility criteria, including 2 prepost cohort studies, 3 multiple baseline studies, and 2 randomized controlled trials (RCTs). Interventions included mostly self-guided websites: with and without therapist assistance (n=6), with training videos, written training manuals, and videoconferencing. Post intervention, studies reported significant improvements (P<.05) in parent knowledge (n=4), parent intervention fidelity (n=6), and improvements in children's social behavior and communication skills (n=3). A high risk of bias existed within all of the studies because of a range of factors including small sample sizes, limited use of standardized outcome measures, and a lack of control groups to negate confounding factors. CONCLUSIONS: There is preliminary evidence that parent-mediated intervention training delivered remotely may improve parent knowledge, increase parent intervention fidelity, and improve the social behavior and communication skills for children with ASD. A low number of RCTs, difficulty in defining the locality of the population, and a paucity of standardized measures limit the generalization of the findings to the target population. Future studies should investigate the appropriateness and feasibility of the interventions, include RCTs to control for bias, and utilize standard outcome measures. PMID- 28807894 TI - Advances in the diagnosis and management of neck pain. AB - Neck pain imposes a considerable personal and socioeconomic burden-it is one of the top five chronic pain conditions in terms of prevalence and years lost to disability-yet it receives a fraction of the research funding given to low back pain. Although most acute episodes resolve spontaneously, more than a third of affected people still have low grade symptoms or recurrences more than one year later, with genetics and psychosocial factors being risk factors for persistence. Nearly half of people with chronic neck pain have mixed neuropathic-nociceptive symptoms or predominantly neuropathic symptoms. Few clinical trials are dedicated solely to neck pain. Muscle relaxants and non-steroidal anti-inflammatory drugs are effective for acute neck pain, and clinical practice is mostly guided by the results of studies performed for other chronic pain conditions. Among complementary and alternative treatments, the strongest evidence is for exercise, with weaker evidence supporting massage, acupuncture, yoga, and spinal manipulation in different contexts. For cervical radiculopathy and facet arthropathy, weak evidence supports epidural steroid injections and radiofrequency denervation, respectively. Surgery is more effective than conservative treatment in the short term but not in the long term for most of these patients, and clinical observation is a reasonable strategy before surgery. PMID- 28807896 TI - Fgf10+ progenitors give rise to the chick hypothalamus by rostral and caudal growth and differentiation. AB - Classical descriptions of the hypothalamus divide it into three rostro-caudal domains but little is known about their embryonic origins. To investigate this, we performed targeted fate-mapping, molecular characterisation and cell cycle analyses in the embryonic chick. Presumptive hypothalamic cells derive from the rostral diencephalic ventral midline, lie above the prechordal mesendoderm and express Fgf10Fgf10+ progenitors undergo anisotropic growth: those displaced rostrally differentiate into anterior cells, then those displaced caudally differentiate into mammillary cells. A stable population of Fgf10+ progenitors is retained within the tuberal domain; a subset of these gives rise to the tuberal infundibulum - the precursor of the posterior pituitary. Pharmacological approaches reveal that Shh signalling promotes the growth and differentiation of anterior progenitors, and also orchestrates the development of the infundibulum and Rathke's pouch - the precursor of the anterior pituitary. Together, our studies identify a hypothalamic progenitor population defined by Fgf10 and highlight a role for Shh signalling in the integrated development of the hypothalamus and pituitary. PMID- 28807895 TI - The miR-124 family of microRNAs is crucial for regeneration of the brain and visual system in the planarian Schmidtea mediterranea. AB - Brain regeneration in planarians is mediated by precise spatiotemporal control of gene expression and is crucial for multiple aspects of neurogenesis. However, the mechanisms underpinning the gene regulation essential for brain regeneration are largely unknown. Here, we investigated the role of the miR-124 family of microRNAs in planarian brain regeneration. The miR-124 family (miR-124) is highly conserved in animals and regulates neurogenesis by facilitating neural differentiation, yet its role in neural wiring and brain organization is not known. We developed a novel method for delivering anti-miRs using liposomes for the functional knockdown of microRNAs. Smed-miR-124 knockdown revealed a key role for these microRNAs in neuronal organization during planarian brain regeneration. Our results also demonstrated an essential role for miR-124 in the generation of eye progenitors. Additionally, miR-124 regulates Smed-slit-1, which encodes an axon guidance protein, either by targeting slit-1 mRNA or, potentially, by modulating the canonical Notch pathway. Together, our results reveal a role for miR-124 in regulating the regeneration of a functional brain and visual system. PMID- 28807898 TI - Hypothalamic sonic hedgehog is required for cell specification and proliferation of LHX3/LHX4 pituitary embryonic precursors. AB - Sonic hedgehog (SHH) is an essential morphogenetic signal that dictates cell fate decisions in several developing organs in mammals. In vitro data suggest that SHH is required to specify LHX3+/LHX4+ Rathke's pouch (RP) progenitor identity. However, in vivo studies have failed to reveal such a function, supporting instead a crucial role for SHH in promoting proliferation of these RP progenitors and for differentiation of pituitary cell types. Here, we have used a genetic approach to demonstrate that activation of the SHH pathway is necessary to induce LHX3+/LHX4+ RP identity in mouse embryos. First, we show that conditional deletion of Shh in the anterior hypothalamus results in a fully penetrant phenotype characterised by a complete arrest of RP development, with lack of Lhx3/Lhx4 expression in RP epithelium at 9.0 days post coitum (dpc) and total loss of pituitary tissue by 12.5 dpc. Conversely, overactivation of the SHH pathway by conditional deletion of Ptch1 in RP progenitors leads to severe hyperplasia and enlargement of the Sox2+ stem cell compartment by the end of gestation. PMID- 28807899 TI - Pitx1 directly modulates the core limb development program to implement hindlimb identity. AB - Forelimbs (FLs) and hindlimbs (HLs) develop complex musculoskeletal structures that rely on the deployment of a conserved developmental program. Pitx1, a transcription factor gene with expression restricted to HL and absent from FL, plays an important role in generating HL features. The genomic mechanisms by which Pitx1 effects HL identity remain poorly understood. Here, we use expression profiling and analysis of direct Pitx1 targets to characterize the HL- and FL restricted genetic programs in mouse and situate the Pitx1-dependent gene network within the context of limb-specific gene regulation. We show that Pitx1 is a crucial component of a narrow network of HL-restricted regulators, acting on a developmental program that is shared between FL and HL. Pitx1 targets sites that are in a similar chromatin state in FL and HL and controls expression of patterning genes as well as the chondrogenic program, consistent with impaired chondrogenesis in Pitx1-/- HL. These findings support a model in which multifactorial actions of a limited number of HL regulators redirect the generic limb development program in order to generate the unique structural features of the limb. PMID- 28807897 TI - Cytoplasmic poly (A)-binding protein critically regulates epidermal maintenance and turnover in the planarian Schmidtea mediterranea. AB - Identifying key cellular events that facilitate stem cell function and tissue organization is crucial for understanding the process of regeneration. Planarians are powerful model system to study regeneration and stem cell (neoblast) function. Here, using planaria, we show that the initial events of regeneration, such as epithelialization and epidermal organization are critically regulated by a novel cytoplasmic poly A-binding protein, SMED-PABPC2. Knockdown of smed-pabpc2 leads to defects in epidermal lineage specification, disorganization of epidermis and ECM, and deregulated wound healing, resulting in the selective failure of neoblast proliferation near the wound region. Polysome profiling suggests that epidermal lineage transcripts, including zfp-1, are translationally regulated by SMED-PABPC2. Together, our results uncover a novel role for SMED-PABPC2 in the maintenance of epidermal and ECM integrity, critical for wound healing and subsequent processes for regeneration. PMID- 28807900 TI - Heart morphogenesis gene regulatory networks revealed by temporal expression analysis. AB - During embryogenesis the heart forms as a linear tube that then undergoes multiple simultaneous morphogenetic events to obtain its mature shape. To understand the gene regulatory networks (GRNs) driving this phase of heart development, during which many congenital heart disease malformations likely arise, we conducted an RNA-seq timecourse in zebrafish from 30 hpf to 72 hpf and identified 5861 genes with altered expression. We clustered the genes by temporal expression pattern, identified transcription factor binding motifs enriched in each cluster, and generated a model GRN for the major gene batteries in heart morphogenesis. This approach predicted hundreds of regulatory interactions and found batteries enriched in specific cell and tissue types, indicating that the approach can be used to narrow the search for novel genetic markers and regulatory interactions. Subsequent analyses confirmed the GRN using two mutants, Tbx5 and nkx2-5, and identified sets of duplicated zebrafish genes that do not show temporal subfunctionalization. This dataset provides an essential resource for future studies on the genetic/epigenetic pathways implicated in congenital heart defects and the mechanisms of cardiac transcriptional regulation. PMID- 28807901 TI - Differing contributions of the first and second pharyngeal arches to tympanic membrane formation in the mouse and chick. AB - We have proposed that independent origins of the tympanic membrane (TM), consisting of the external auditory meatus (EAM) and first pharyngeal pouch, are linked with distinctive middle ear structures in terms of dorsal-ventral patterning of the pharyngeal arches during amniote evolution. However, previous studies have suggested that the first pharyngeal arch (PA1) is crucial for TM formation in both mouse and chick. In this study, we compare TM formation along the anterior-posterior axis in these animals using Hoxa2 expression as a marker of the second pharyngeal arch (PA2). In chick, the EAM begins to invaginate at the surface ectoderm of PA2, not at the first pharyngeal cleft, and the entire TM forms in PA2. Chick-quail chimera that have lost PA2 and duplicated PA1 suggest that TM formation is achieved by developmental interaction between a portion of the EAM and the columella auris in PA2, and that PA1 also contributes to formation of the remaining part of the EAM. By contrast, in mouse, TM formation is highly associated with an interdependent relationship between the EAM and tympanic ring in PA1. PMID- 28807903 TI - Transgelin-expressing myofibroblasts orchestrate ventral midline closure through TGFbeta signalling. AB - Ventral body wall (VBW) defects are among the most common congenital malformations, yet their embryonic origin and underlying molecular mechanisms remain poorly characterised. Transforming growth factor beta (TGFbeta) signalling is essential for VBW closure, but the responding cells are not known. Here, we identify in mouse a population of migratory myofibroblasts at the leading edge of the closing VBW that express the actin-binding protein transgelin (TAGLN) and TGFbeta receptor (TGFbetaR). These cells respond to a temporally regulated TGFbeta2 gradient originating from the epithelium of the primary body wall. Targeted elimination of TGFbetaR2 in TAGLN+ cells impairs midline closure and prevents the correct subsequent patterning of the musculature and skeletal components. Remarkably, deletion of Tgfbr2 in myogenic or chondrogenic progenitor cells does not manifest in midline defects. Our results indicate a pivotal significance of VBW myofibroblasts in orchestrating ventral midline closure by mediating the response to the TGFbeta gradient. Altogether, our data enable us to distinguish highly regulated epithelial-mesenchymal signalling and successive cellular migration events in VBW closure that explain early morphological changes underlying the development of congenital VBW defects. PMID- 28807902 TI - H2Av facilitates H3S10 phosphorylation but is not required for heat shock-induced chromatin decondensation or transcriptional elongation. AB - A model has been proposed in which JIL-1 kinase-mediated H3S10 and H2Av phosphorylation is required for transcriptional elongation and heat shock-induced chromatin decondensation. However, here we show that although H3S10 phosphorylation is indeed compromised in the H2Av null mutant, chromatin decondensation at heat shock loci is unaffected in the absence of JIL-1 as well as of H2Av and that there is no discernable decrease in the elongating form of RNA polymerase II in either mutant. Furthermore, mRNA for the major heat shock protein Hsp70 is transcribed at robust levels in both H2Av and JIL-1 null mutants. Using a different chromatin remodeling paradigm that is JIL-1 dependent, we provide evidence that ectopic tethering of JIL-1 and subsequent H3S10 phosphorylation recruits PARP-1 to the remodeling site independently of H2Av phosphorylation. These data strongly suggest that H2Av or H3S10 phosphorylation by JIL-1 is not required for chromatin decondensation or transcriptional elongation in Drosophila. PMID- 28807904 TI - No Clinically Relevant Drug-Drug Interactions between Methadone or Buprenorphine Naloxone and Antiviral Combination Glecaprevir and Pibrentasvir. AB - The combination of glecaprevir (formerly ABT-493), a nonstructural protein 3/4A (NS3/4A) protease inhibitor, and pibrentasvir (formerly ABT-530), an NS5A protein inhibitor, is being developed as treatment for HCV genotype 1 to 6 infection. The pharmacokinetics, pharmacodynamics, safety, and tolerability of methadone or buprenorphine-naloxone when coadministered with the glecaprevir-pibrentasvir combination in HCV-negative subjects on stable opioid maintenance therapy were investigated in a phase 1, single-center, two-arm, multiple-dose, open-label sequential study. Subjects received methadone (arm 1) or buprenorphine-naloxone (arm 2) once daily (QD) per their existing individual prescriptions alone (days 1 to 9) and then in combination with glecaprevir at 300 mg QD and pibrentasvir at 120 mg QD (days 10 to 16) each morning. Dose-normalized exposures were similar with and without glecaprevir and pibrentasvir for (R)- and (S)-methadone (<=5% difference) and for buprenorphine and naloxone (<=24% difference); the norbuprenorphine area under the curve was 30% higher with glecaprevir and pibrentasvir, consistent with maximum and trough plasma concentrations that increased by 21% to 25%. No changes in pupil response, short opiate withdrawal scale score, or desire for drugs questionnaire were observed when glecaprevir and pibrentasvir were added to methadone or buprenorphine-naloxone therapy. No dose adjustment is required when glecaprevir and pibrentasvir are coadministered with methadone or buprenorphine-naloxone. PMID- 28807905 TI - Pulmonary Pharmacokinetics of Colistin following Administration of Dry Powder Aerosols in Rats. AB - Colistin has been administered via nebulization for the treatment of respiratory tract infections. Recently, dry powder inhalation (DPI) has attracted increasing attention. The current study aimed to investigate the pharmacokinetics (PK) of colistin in epithelial lining fluid (ELF) and plasma following DPI and intravenous (i.v.) administration in healthy Sprague-Dawley rats. Rats were given colistin as DPI intratracheally (0.66 and 1.32 mg base/kg of body weight) or i.v. injection (0.66 mg base/kg). Histopathological examination of lung tissue was performed at 24 h. Colistin concentrations in both ELF and plasma were quantified, and a population PK model was developed and compared to a previously published PK model of nebulized colistin in rats. A two-compartment structural model was developed to describe the PK of colistin in both ELF and plasma following pulmonary or i.v. administration. The model-estimated clearance from the central plasma compartment was 0.271 liter/h/kg (standard error [SE] = 2.51%). The transfer of colistin from the ELF compartment to the plasma compartment was best described by a first-order rate constant (clearance of colistin from the ELF compartment to the plasma compartment = 4.03 * 10-4 liter/h/kg, SE = 15%). DPI appeared to have a higher rate of absorption (time to the maximum concentration in plasma after administration of colistin by DPI, <=10 min) than nebulization (time to the maximum concentration in plasma after administration of colistin by nebulization, 20 to 30 min), but the systemic bioavailabilities by the two routes of administration were similar (~46.5%, SE = 8.43%). Histopathological examination revealed no significant differences in inflammation in lung tissues between the two treatments. Our findings suggest that colistin DPI is a promising alternative to nebulization considering the similar PK and safety profiles of the two forms of administration. The PK and histopathological information obtained is critical for the development of optimal aerosolized colistin regimens with activity against lung infections caused by Gram-negative bacteria. PMID- 28807906 TI - Impact of Type III Secretion Effectors and of Phenoxyacetamide Inhibitors of Type III Secretion on Abscess Formation in a Mouse Model of Pseudomonas aeruginosa Infection. AB - Pseudomonas aeruginosa is a leading cause of intra-abdominal infections, wound infections, and community-acquired folliculitis, each of which may involve macro- or microabscess formation. The rising incidence of multidrug resistance among P. aeruginosa isolates has increased both the economic burden and the morbidity and mortality associated with P. aeruginosa disease and necessitates a search for novel therapeutics. Previous work from our group detailed novel phenoxyacetamide inhibitors that block type III secretion and injection into host cells in vitro In this study, we used a mouse model of P. aeruginosa abscess formation to test the in vivo efficacy of these compounds against the P. aeruginosa type III secretion system (T3SS). Bacteria used the T3SS to intoxicate infiltrating neutrophils to establish abscesses. Despite this antagonism, sufficient numbers of functioning neutrophils remained for proper containment of the abscesses, as neutrophil depletion resulted in an increased abscess size, the formation of dermonecrotic lesions on the skin, and the dissemination of P. aeruginosa to internal organs. Consistent with the specificity of the T3SS-neutrophil interaction, P. aeruginosa bacteria lacking a functional T3SS were fully capable of causing abscesses in a neutropenic host. Phenoxyacetamide inhibitors attenuated abscess formation and aided in the immune clearance of the bacteria. Finally, a P. aeruginosa strain resistant to the phenoxyacetamide compound was fully capable of causing abscess formation even in the presence of the T3SS inhibitors. Together, our results further define the role of type III secretion in murine abscess formation and demonstrate the in vivo efficacy of phenoxyacetamide inhibitors in P. aeruginosa infection. PMID- 28807907 TI - Original Chemical Series of Pyrimidine Biosynthesis Inhibitors That Boost the Antiviral Interferon Response. AB - De novo pyrimidine biosynthesis is a key metabolic pathway involved in multiple biosynthetic processes. Here, we identified an original series of 3-(1H-indol-3 yl)-2,3-dihydro-4H-furo[3,2-c]chromen-4-one derivatives as a new class of pyrimidine biosynthesis inhibitors formed by two edge-fused polycyclic moieties. We show that identified compounds exhibit broad-spectrum antiviral activity and immunostimulatory properties, in line with recent reports linking de novo pyrimidine biosynthesis with innate defense mechanisms against viruses. Most importantly, we establish that pyrimidine deprivation can amplify the production of both type I and type III interferons by cells stimulated with retinoic acid inducible gene 1 (RIG-I) ligands. Altogether, our results further expand the current panel of pyrimidine biosynthesis inhibitors and illustrate how the production of antiviral interferons is tightly coupled to this metabolic pathway. Functional and structural similarities between this new chemical series and dicoumarol, which was reported before to inhibit pyrimidine biosynthesis at the dihydroorotate dehydrogenase (DHODH) step, are discussed. PMID- 28807909 TI - Development and Use of Personalized Bacteriophage-Based Therapeutic Cocktails To Treat a Patient with a Disseminated Resistant Acinetobacter baumannii Infection. AB - Widespread antibiotic use in clinical medicine and the livestock industry has contributed to the global spread of multidrug-resistant (MDR) bacterial pathogens, including Acinetobacter baumannii We report on a method used to produce a personalized bacteriophage-based therapeutic treatment for a 68-year old diabetic patient with necrotizing pancreatitis complicated by an MDR A. baumannii infection. Despite multiple antibiotic courses and efforts at percutaneous drainage of a pancreatic pseudocyst, the patient deteriorated over a 4-month period. In the absence of effective antibiotics, two laboratories identified nine different bacteriophages with lytic activity for an A. baumannii isolate from the patient. Administration of these bacteriophages intravenously and percutaneously into the abscess cavities was associated with reversal of the patient's downward clinical trajectory, clearance of the A. baumannii infection, and a return to health. The outcome of this case suggests that the methods described here for the production of bacteriophage therapeutics could be applied to similar cases and that more concerted efforts to investigate the use of therapeutic bacteriophages for MDR bacterial infections are warranted. PMID- 28807910 TI - 24-Hour Pharmacokinetic Relationships for Vancomycin and Novel Urinary Biomarkers of Acute Kidney Injury. AB - Vancomycin has been associated with acute kidney injury in preclinical and clinical settings; however, the precise exposure profiles associated with vancomycin-induced acute kidney injury have not been defined. We sought to determine pharmacokinetic/pharmacodynamics indices associated with the development of acute kidney injury using sensitive urinary biomarkers. Male Sprague-Dawley rats received clinical-grade vancomycin or normal saline as an intraperitoneal injection. Total daily doses between 0 and 400 mg/kg of body weight were administered as a single dose or 2 divided doses over a 24-h period. At least five rats were utilized for each dosing protocol. A maximum of 8 plasma samples per rat were obtained, and urine was collected over the 24-h period. Kidney injury molecule-1 (KIM-1), clusterin, osteopontin, cystatin C, and neutrophil gelatinase-associated lipocalin levels were determined using Milliplex multianalyte profiling rat kidney panels. Vancomycin plasma concentrations were determined via a validated high-performance liquid chromatography methodology. Pharmacokinetic analyses were conducted using the Pmetrics package for R. Bayesian maximal a posteriori concentrations were generated and utilized to calculate the 24-h area under the concentration-time curve (AUC), the maximum concentration (Cmax), and the minimum concentration. Spearman's rank correlation coefficient (rs ) was used to assess the correlations between exposure parameters, biomarkers, and histopathological damage. Forty-seven rats contributed pharmacokinetic and toxicodynamic data. KIM-1 was the only urinary biomarker that correlated with both composite histopathological damage (rs = 0.348, P = 0.017) and proximal tubule damage (rs = 0.342, P = 0.019). The vancomycin AUC and Cmax were most predictive of increases in KIM-1 levels (rs = 0.438 and P = 0.002 for AUC and rs = 0.451 and P = 0.002 for Cmax). Novel urinary biomarkers demonstrate that kidney injury can occur within 24 h of vancomycin exposure as a function of either AUC or Cmax. PMID- 28807908 TI - Activity of the beta-Lactamase Inhibitor LN-1-255 against Carbapenem-Hydrolyzing Class D beta-Lactamases from Acinetobacter baumannii. AB - The number of infections caused by Gram-negative pathogens carrying carbapenemases is increasing, and the group of carbapenem-hydrolyzing class D beta-lactamases (CHDLs) is especially problematic. Several clinically important CHDLs have been identified in Acinetobacter baumannii, including OXA-23, OXA 24/40, OXA-58, OXA-143, OXA-235, and the chromosomally encoded OXA-51. The selection and dissemination of carbapenem-resistant A. baumannii strains constitutes a serious global threat. Carbapenems have been successfully utilized as last-resort antibiotics for the treatment of multidrug-resistant A. baumannii infections. However, the spread of OXA carbapenemases is compromising the continued use of these antimicrobials. In response to this clinical issue, it is necessary and urgent to design and develop new specific inhibitors with efficacy against these enzymes. The aim of this work was to characterize the inhibitory activity of LN-1-255 (a 6-alkylidene-2-substituted penicillin sulfone) and compare it to that of two established inhibitors (avibactam and tazobactam) against the most relevant enzymes of each group of class D carbapenemases in A. baumannii The beta-lactamase inhibitor LN-1-255 demonstrated excellent microbiological synergy and inhibition kinetics parameters against all tested CHDLs and a significantly higher activity than tazobactam and avibactam. A combination of carbapenems and LN-1-255 was effective against A. baumannii class D carbapenemases. Docking assays confirmed the affinity of LN-1-255 for the active site of these enzymes. LN-1-255 represents a potential new beta-lactamase inhibitor that may have a significant role in eradicating infections caused by A. baumannii isolates carrying CHDLs. PMID- 28807911 TI - Systematic Review and Meta-analyses of the Effect of Chemotherapy on Pulmonary Mycobacterium abscessus Outcomes and Disease Recurrence. AB - In pharmacokinetic/pharmacodynamic models of pulmonary Mycobacterium abscessus complex, the recommended macrolide-containing combination therapy has poor kill rates. However, clinical outcomes are unknown. We searched the literature for studies published between 1990 and 2017 that reported microbial outcomes in patients treated for pulmonary M. abscessus disease. A good outcome was defined as sustained sputum culture conversion (SSCC) without relapse. Random effects models were used to pool studies and estimate proportions of patients with good outcomes. Odds ratios (OR) and 95% confidence intervals (CI) were computed. Sensitivity analyses and metaregression were used to assess the robustness of findings. In 19 studies of 1,533 patients, combination therapy was administered to 508 patients with M. abscessus subsp. abscessus, 204 with M. abscessus subsp. massiliense, and 301 with M. abscessus with no subspecies specified. Macrolide containing regimens achieved SSCC in only 77/233 (34%) new M. abscessus subsp. abscessus patients versus 117/141 (54%) M. abscessus subsp. massiliense patients (OR, 0.108 [95% CI, 0.066 to 0.181]). In refractory disease, SSCC was achieved in 20% (95% CI, 7 to 36%) of patients, which was not significantly different across subspecies. The estimated recurrent rates per month were 1.835% (range, 1.667 to 3.196%) for M. abscessus subsp. abscessus versus 0.683% (range, 0.229 to 1.136%) for M. abscessus subsp. massiliense (OR, 6.189 [95% CI, 2.896 to 13.650]). The proportion of patients with good outcomes was 52/223 (23%) with M. abscessus subsp. abscessus versus 118/141 (84%) with M. abscessus subsp. massiliense disease (OR, 0.059 [95% CI, 0.034 to 0.101]). M. abscessus subsp. abscessus pulmonary disease outcomes with the currently recommended regimens are atrocious, with outcomes similar to those for extensively drug-resistant tuberculosis. Therapeutically, the concept of nontuberculous mycobacteria is misguided. There is an urgent need to craft entirely new treatment regimens. PMID- 28807912 TI - Phase 2 Randomized Trial of the Safety and Efficacy of MHAA4549A, a Broadly Neutralizing Monoclonal Antibody, in a Human Influenza A Virus Challenge Model. AB - MHAA4549A, a human monoclonal antibody targeting the hemagglutinin stalk region of influenza A virus (IAV), is being developed as a therapeutic for patients hospitalized with severe IAV infection. The safety and efficacy of MHAA4549A were assessed in a randomized, double-blind, placebo-controlled, dose-ranging study in a human IAV challenge model. One hundred healthy volunteers were inoculated with A/Wisconsin/67/2005 (H3N2) IAV and, 24 to 36 h later, administered a single intravenous dose of either placebo, MHAA4549A (400, 1,200, or 3,600 mg), or a standard oral dose of oseltamivir. Subjects were assessed for safety, pharmacokinetics (PK), and immunogenicity. The intent-to-treat-infected (ITTI) population was assessed for changes in viral load, influenza symptoms, and inflammatory biomarkers. MHAA4549A was well tolerated in all IAV challenge subjects. The 3,600-mg dose of MHAA4549A significantly reduced the viral burden relative to that of the placebo as determined by the area under the curve (AUC) of nasopharyngeal virus infection, quantified using quantitative PCR (98%) and 50% tissue culture infective dose (TCID50) (100%) assays. Peak viral load, duration of viral shedding, influenza symptom scores, mucus weight, and inflammatory biomarkers were also reduced. Serum PK was linear with a half-life of ~23 days. No MHAA4549A-treated subjects developed anti-drug antibodies. In conclusion, MHAA4549A was well tolerated and demonstrated statistically significant and substantial antiviral activity in an IAV challenge model. (This study has been registered at ClinicalTrials.gov under identifier NCT01980966.). PMID- 28807913 TI - Reducing Antibacterial Development Risk for GSK1322322 by Exploring Potential Human Dose Regimens in Nonclinical Efficacy Studies Using Immunocompetent Rats. AB - Directly testing proposed clinical dosing regimens in nonclinical studies can reduce the risk during the development of novel antibacterial agents. Optimal dosing regimens can be identified in animal models by testing recreated human pharmacokinetic profiles. An example of this approach using continuous intravenous infusions of GSK1322322 in immunocompetent rats to evaluate recreated human exposures from phase I trials in pneumonia models with Streptococcus pneumoniae and Haemophilus influenzae and an abscess model with Staphylococcus aureus is presented. GSK1322322 was administered via continuous intravenous infusion to recreate 1,000- or 1,500-mg oral doses every 12 h in humans. Significant reductions (P <= 0.05 for all comparisons) in bacterial numbers compared with those for the baseline controls were observed for S. pneumoniae and H. influenzae (mean log10 reductions, 1.6 to >=2.7 and 1.8 to 3.3 CFU/lungs, respectively) with the recreated 1,000-mg oral dose. This profile was also efficacious against S. aureus (mean log10 reduction, 1.9 to 2.4 CFU/abscess). There was a nonsignificant trend for improved efficacy against S. aureus with the 1,500-mg oral dose (mean log10 reduction, 2.4 to 3.1 CFU/abscess). These results demonstrate that the human oral 1,000- or 1,500-mg exposure profiles of GSK1322322 recreated in rats were effective against representative community associated pathogens and supported selection of the 1,500-mg oral dose given every 12 h for a phase II clinical skin infection study. Furthermore, this work exemplifies how the testing of recreated human pharmacokinetic profiles can be incorporated into the development process and serve as an aid for selecting optimal dosing regimens prior to conducting large-scale clinical studies. PMID- 28807914 TI - Amplification of Antimicrobial Resistance in Gut Flora of Patients Treated with Ceftriaxone. AB - Although antibacterial therapy has an impact on human intestinal flora and the emergence of resistant bacteria, its role in the amplification of antimicrobial resistance and the quantitative exposure-effect relationship is not clear. An observational prospective study was conducted to determine whether and how ceftriaxone exposure is related to amplification of resistance in non-intensive care unit (non-ICU) patients. Serial stool samples from 122 extended-spectrum beta-lactamase-positive (ESBL+) hospitalized patients were analyzed by quantitative real-time PCR to quantify the resistant gene blaCTX-M Drug exposure was calculated for each patient by using a population pharmacokinetic model. Multi- and univariate regression and classification regression tree (CART) analyses were used to explore relationships between measures of exposure and amplification of blaCTX-M genes. Amplification of blaCTX-M was observed in 0% (0/11) of patients with no treatment and 33% (20/61) of patients treated with ceftriaxone. Stepwise regression analysis showed a significant association between amplification of blaCTX-M and the plasma area under the concentration time curve from 0 to 24 h for the unbound fraction of the drug (fAUC0-24), the maximum concentration of drug in serum for the unbound fraction of the drug (fCmax), and the duration of ceftriaxone therapy. Using CART analysis, amplification of blaCTX-M was observed in 11/16 (69%) patients treated for >14 days and in 9/40 (23%) patients treated for <=14 days (P = 0.0019). In the latter group, amplification was observed in 5/7 (71%) patients with an fAUC0-24 of >=222 mg . h/liter and in 4/33 (12%) patients with lower drug exposures (P = 0.0033). A similar association was found for an fCmax of >=30 mg/liter (63% versus 13%, P = 0.0079). A significant association was found between the amplification of blaCTX M resistance genes and exposure to ceftriaxone. Both duration of treatment and degree of ceftriaxone exposure have a significant impact on the amplification of resistance genes. (The project described in this paper has been registered at ClinicalTrials.gov under identifier NCT01208519.). PMID- 28807915 TI - A Randomized Controlled Trial Shows that both 14-Day Hybrid and Bismuth Quadruple Therapies Cure Most Patients with Helicobacter pylori Infection in Populations with Moderate Antibiotic Resistance. AB - Hybrid therapy is a novel two-step treatment achieving a high eradication rate for Helicobacter pylori infection. Currently, whether this new therapy achieves a higher eradication rate than bismuth quadruple therapy remains an unanswered question. The aim of this prospective, randomized comparative study was to investigate the efficacies of 14-day hybrid therapy and bismuth quadruple therapy in the treatment of H. pylori infection. From July 2013 to June 2015, eligible H. pylori-infected subjects were randomly assigned to receive either 14-day bismuth quadruple therapy (pantoprazole, bismuth subcitrate, tetracycline, and metronidazole for 14 days) or 14-day hybrid therapy (a 7-day dual therapy with pantoprazole plus amoxicillin, followed by a 7-day quadruple therapy with pantoprazole plus amoxicillin, clarithromycin, and metronidazole). H. pylori status was examined 6 weeks after the end of treatment. Three hundred thirty H. pylori-infected participants were randomized to receive 14-day bismuth quadruple therapy (n = 164) or 14-day hybrid therapy (n = 166). The eradication rates by intention-to-treat analysis were similar: 93.9% versus 92.8%, respectively (95% confidence interval [CI], -4.3% to 5.4%; P = 0.68). Per-protocol analysis yielded similar results (96.7% versus 94.9%, respectively; P = 0.44). However, bismuth quadruple therapy had a higher frequency of adverse events than hybrid therapy (55.5% versus 15.7%, respectively; 95% CI, 30.4% to 49.2%; P < 0.001). The two treatments exhibited comparable drug adherence (93.9% versus 97%, respectively). The resistance rates of antibiotics were: clarithromycin, 16.7% of patients; amoxicillin, 1.3%; metronidazole, 25%; and tetracycline, 0%. In the bismuth quadruple therapy group, the eradication rate of metronidazole-resistant strains was lower than that of metronidazole-susceptible strains (70.0% versus 96.4%, respectively; P = 0.04). In the hybrid therapy group, no significant impact of clarithromycin or metronidazole resistance on eradication rates was identified. Both 14-day hybrid and bismuth quadruple therapies cure most patients with H. pylori infection in populations with moderate antibiotic resistance. However, the 14-day hybrid therapy has fewer adverse effects than the bismuth quadruple therapy. (This study has been registered at ClinicalTrials.gov under identifier NCT02541864.). PMID- 28807916 TI - Inhibition of Calcineurin or IMP Dehydrogenase Exerts Moderate to Potent Antiviral Activity against Norovirus Replication. AB - Norovirus is a major cause of acute gastroenteritis worldwide and has emerged as an important issue of chronic infection in transplantation patients. Since no approved antiviral is available, we evaluated the effects of different immunosuppressants and ribavirin on norovirus and explored their mechanisms of action by using a human norovirus (HuNV) replicon-harboring model and a surrogate murine norovirus (MNV) infectious model. The roles of the corresponding drug targets were investigated by gain- or loss-of-function approaches. We found that the calcineurin inhibitors cyclosporine (CsA) and tacrolimus (FK506) moderately inhibited HuNV replication. Gene silencing of their cellular targets, cyclophilin A, FKBP12, and calcineurin, significantly inhibited HuNV replication. A low concentration, therapeutically speaking, of mycophenolic acid (MPA), an uncompetitive IMP dehydrogenase (IMPDH) inhibitor, potently and rapidly inhibited norovirus replication and ultimately cleared HuNV replicons without inducible resistance following long-term drug exposure. Knockdown of the MPA cellular targets IMPDH1 and IMPDH2 suppressed HuNV replication. Consistent with the nucleotide-synthesizing function of IMPDH, exogenous guanosine counteracted the antinorovirus effects of MPA. Furthermore, the competitive IMPDH inhibitor ribavirin efficiently inhibited norovirus and resulted in an additive effect when combined with immunosuppressants. The results from this study demonstrate that calcineurin phosphatase activity and IMPDH guanine synthase activity are crucial in sustaining norovirus infection; thus, they can be therapeutically targeted. Our results suggest that MPA shall be preferentially considered immunosuppressive medication for transplantation patients at risk of norovirus infection, whereas ribavirin represents as a potential antiviral for both immunocompromised and immunocompetent patients with norovirus gastroenteritis. PMID- 28807917 TI - Bedaquiline Inhibits the ATP Synthase in Mycobacterium abscessus and Is Effective in Infected Zebrafish. AB - Pulmonary infections caused by Mycobacterium abscessus are emerging as a global threat, especially in cystic fibrosis patients. Further intensifying the concern of M. abscessus infection is the recent evidence of human-to-human transmission of the infection. M. abscessus is a naturally multidrug-resistant fast-growing pathogen for which pharmacological options are limited. Repurposing antitubercular drugs represents an attractive option for the development of chemotherapeutic alternatives against M. abscessus infections. Bedaquiline (BDQ), an ATP synthase inhibitor, has recently been approved for the treatment of multidrug-resistant tuberculosis. Herein, we show that BDQ has a very low MIC against a vast panel of clinical isolates. Despite being bacteriostatic in vitro, BDQ was highly efficacious in a zebrafish model of M. abscessus infection. Remarkably, a very short period of treatment was sufficient to protect the infected larvae from M. abscessus-induced killing. This was corroborated with reduced numbers of abscesses and cords, considered to be major pathophysiological signs in infected zebrafish. Mode-of-action studies revealed that BDQ triggered a rapid depletion of ATP in M. abscessusin vitro, consistent with the drug targeting the FoF1 ATP synthase. Importantly, despite a failure to select in vitro for spontaneous mutants that are highly resistant to BDQ, the transfer of single nucleotide polymorphisms leading to D29V or A64P substitutions in atpE conferred high resistance, thus resolving the target of BDQ in M. abscessus Overall, this study indicates that BDQ is active against M. abscessusin vitro and in vivo and should be considered for clinical use against the difficult-to-manage M. abscessus pulmonary infections. PMID- 28807918 TI - Relationships of Vancomycin Pharmacokinetics to Body Size and Composition Using a Novel Pharmacomorphomic Approach Based on Medical Imaging. AB - Antibiotics such as vancomycin are empirically dosed on the basis of body weight, which may not be optimal across the expanding adult body size distribution. Our aim was to compare the relationships between morphomic parameters generated from computed tomography images to conventional body size metrics as predictors of vancomycin pharmacokinetics (PK). This single-center retrospective study included 300 patients with 1,622 vancomycin concentration (52% trough) measurements. Bayesian estimation was used to compute individual vancomycin volume of distribution of the central compartment (Vc) and clearance (CL). Approximately 45% of patients were obese with an overall median (5th, 95th percentile) weight and body mass index of 87.2 (54.7, 123) kg and 28.8 (18.9, 43.7) kg/m2, respectively. Morphomic parameters of body size such as body depth, total body area, and torso volume of the twelfth thoracic through fourth lumbar vertebrae (T12 to L4) correlated with Vc. The relationship of vancomycin Vc was poorly predicted by body size but was stronger with T12-to-L4 torso volume (coefficient of determination [R2] = 0.11) than weight (R2 = 0.04). No relationships between vancomycin CL and traditional body size metrics could be discerned; however, relationships with skeletal muscle volume and total psoas area were found. Vancomycin CL independently correlated with total psoas area and inversely correlated with age. Thus, vancomycin CL was significantly related to total psoas area over age (R2 = 0.23, P < 0.0001). This proof-of-concept study suggests a potential role for translation of radiographic information into parameters predictive of drug pharmacokinetics. Prediction of individual antimicrobial pharmacokinetic parameters using analytic morphomics has the potential to improve antimicrobial dose selection and outcomes of obese patients. PMID- 28807919 TI - Drug Susceptibility and Replicative Capacity of Multidrug-Resistant Recombinant Human Cytomegalovirus Harboring Mutations in UL56 and UL54 Genes. AB - Letermovir is an investigational antiviral agent with a novel mechanism of action involving the viral terminase (pUL56). We evaluated the impact of the V236M mutation in the UL56 gene alone and in combination with the E756K mutation in the UL54 gene on drug susceptibility and viral replicative capacity of recombinant human cytomegalovirus. The double mutant exhibited at least borderline resistance to all antivirals tested (ganciclovir, foscarnet, cidofovir, brincidofovir, and letermovir) and replicated less efficiently than the wild-type virus in vitro. PMID- 28807920 TI - Mediator Tail Module Is Required for Tac1-Activated CDR1 Expression and Azole Resistance in Candida albicans. AB - The human fungal pathogen Candida albicans develops drug resistance after long term exposure to azole drugs in the treatment of chronic candidiasis. Gain-of function (GOF) mutations in the transcription factor Tac1 and the consequent expression of its targets, drug efflux pumps Cdr1 and Cdr2, are a common mechanism by which C. albicans acquires fluconazole resistance. The mechanism by which GOF mutations hyperactivate Tac1 is currently unknown. Here, we define a transcriptional activation domain (TAD) at the C terminus of Tac1. GOF mutations within the Tac1 TAD, outside the context of full-length Tac1, generally do not enhance its absolute potential as a transcriptional activator. Negative regulation of the Tac1 TAD by the Tac1 middle region is necessary for the activating effect of GOF mutations or fluphenazine to be realized. We have found that full-length Tac1, when hyperactivated by xenobiotics or GOF mutations, facilitates the recruitment of the Mediator coactivator complex to the CDR1 promoter. Azole resistance and the activation of Tac1 target genes, such as CDR1, are dependent on the Tac1 TAD and subunits of the Mediator tail module. The dependence of different Tac1 target promoters on the Mediator tail module, however, varies widely. Lastly, we show that hyperactivation of Tac1 is correlated with its Mediator-dependent phosphorylation, a potentially useful biomarker for Tac1 hyperactivation. The role of Mediator in events downstream of Tac1 hyperactivation in fluconazole-resistant clinical isolates is complex and provides opportunities and challenges for therapeutic intervention. PMID- 28807922 TI - Using Population Pharmacokinetic Modeling and Monte Carlo Simulations To Determine whether Standard Doses of Piperacillin in Piperacillin-Tazobactam Regimens Are Adequate for the Management of Febrile Neutropenia. AB - Changes in the pharmacokinetics of piperacillin in febrile neutropenic patients have been reported to result in suboptimal exposures. This study aimed to develop a population pharmacokinetic model for piperacillin and perform dosing simulation to describe optimal dosing regimens for hematological malignancy patients with febrile neutropenia. Concentration-time data were obtained from previous prospective observational pharmacokinetic and interventional therapeutic drug monitoring studies. Nonparametric population pharmacokinetic analysis and Monte Carlo dosing simulations were performed with the Pmetrics package for R. A two compartment model, with between-subject variability for clearance (CL), adequately described the data from 37 patients (21 males, age of 59 +/- 12 years [means +/- standard deviations] and weight of 77 +/- 16 kg). Parameter estimates were CL of 18.0 +/- 4.8 liters/h, volume of distribution of the central compartment of 14.3 +/- 7.3 liters, rate constant for piperacillin distribution from the central to peripheral compartment of 1.40 +/- 1.35 h-1, and rate constant for piperacillin distribution from the peripheral to central compartment of 4.99 +/- 7.81 h-1 High creatinine clearance (CLCR) was associated with reduced probability of target attainment (PTA). Extended and continuous infusion regimens achieved a high PTA of >90% for an unbound concentration of piperacillin remaining above the MIC (fT>MIC) of 50%. Only continuous regimens achieved >90% PTA for 100% fT>MIC when CLCR was high. The cumulative fraction of response (FTA, for fractional target attainment) was suboptimal (<85%) for conventional regimens for both empirical and directed therapy considering 50% and 100% fT>MIC FTA was maximized with prolonged infusions. Overall, changes in piperacillin pharmacokinetics and the consequences on therapeutic dosing requirements appear similar to those observed in intensive care patients. Guidelines should address the altered dosing needs of febrile neutropenic patients exhibiting high CLCR or with known/presumed infections from high-MIC bacteria. PMID- 28807921 TI - Candida albicans Swi/Snf and Mediator Complexes Differentially Regulate Mrr1 Induced MDR1 Expression and Fluconazole Resistance. AB - Long-term azole treatment of patients with chronic Candida albicans infections can lead to drug resistance. Gain-of-function (GOF) mutations in the transcription factor Mrr1 and the consequent transcriptional activation of MDR1, a drug efflux coding gene, is a common pathway by which this human fungal pathogen acquires fluconazole resistance. This work elucidates the previously unknown downstream transcription mechanisms utilized by hyperactive Mrr1. We identified the Swi/Snf chromatin remodeling complex as a key coactivator for Mrr1, which is required to maintain basal and induced open chromatin, and Mrr1 occupancy, at the MDR1 promoter. Deletion of snf2, the catalytic subunit of Swi/Snf, largely abrogates the increases in MDR1 expression and fluconazole MIC observed in MRR1GOF mutant strains. Mediator positively and negatively regulates key Mrr1 target promoters. Deletion of the Mediator tail module med3 subunit reduces, but does not eliminate, the increased MDR1 expression and fluconazole MIC conferred by MRR1GOF mutations. Eliminating the kinase activity of the Mediator Ssn3 subunit suppresses the decreased MDR1 expression and fluconazole MIC of the snf2 null mutation in MRR1GOF strains. Ssn3 deletion also suppresses MDR1 promoter histone displacement defects in snf2 null mutants. The combination of this work with studies on other hyperactive zinc cluster transcription factors that confer azole resistance in fungal pathogens reveals a complex picture where the induction of drug efflux pump expression requires the coordination of multiple coactivators. The observed variations in transcription factor and target promoter dependence of this process may make the search for azole sensitivity restoring small molecules more complicated. PMID- 28807924 TI - Thyroid cancer incidence in Canada: a national cancer registry analysis. AB - BACKGROUND: Thyroid cancer incidence rates are increasing in many developed countries while mortality rates remain stable. International evidence shows that the increase in incidence rates is mostly caused by overdiagnosis of small papillary cancers. We sought to describe how thyroid cancer incidence has changed and how it varies between provinces in Canada. METHODS: Data were obtained from the National Cancer Incidence Reporting System, causes of death tables and the Canadian Cancer Registry using the 1991 census population structure. We report thyroid cancer incidence by sex, age and province and mortality by sex from 1970 to 2012. RESULTS: Since 1970, age-standardized thyroid cancer incidence rates have increased in women from 3.9 to 23.4 per 100 000 and in men from 1.5 to 7.2 per 100 000 while mortality rates have remained stable at around 0.5 per 100 000 for both sexes. In 2012, incidence rates for both women and men were highest in Ontario (31.5 and 9.2 per 100 000, respectively) and lowest in British Columbia (13.2 and 4.5 per 100 000, respectively). Age-specific incidence rates were the highest in Ontarian women aged 50-54 years, at 65.2 per 100 000. INTERPRETATION: The rapid increase in thyroid cancer incidence especially since 1990, the variation among provinces and the peak in middle-aged women does not correspond to any known cause or risk factor for disease, although the lack of change in mortality rates suggests that serious thyroid cancer has not increased. The likely cause of the increase in incidence is an overdiagnosis epidemic for clinically unimportant lesions detected by modern diagnostic imaging. To reduce the harms of overtreatment, overdiagnosis should be reduced, through more judicious use of diagnostic imaging. PMID- 28807923 TI - PBP4 Mediates beta-Lactam Resistance by Altered Function. AB - Penicillin binding protein 4 (PBP4) can provide high-level beta-lactam resistance in Staphylococcus aureus A series of missense and promoter mutations associated with pbp4 were detected in strains that displayed high-level resistance. We show here that the missense mutations facilitate the beta-lactam resistance mediated by PBP4 and the promoter mutations lead to overexpression of pbp4 Our results also suggest a cooperative interplay among PBPs for beta-lactam resistance. PMID- 28807925 TI - What is the evidence for different management options for difficult to treat severe asthma? PMID- 28807927 TI - US declares opioid epidemic a "national emergency". PMID- 28807926 TI - Use of Antihypertensive Medications and Risk of Adverse Breast Cancer Outcomes in a SEER-Medicare Population. AB - Background: It is unclear if use of common antihypertensive medications influences the risk of adverse breast cancer outcomes.Methods: Using the linked Surveillance, Epidemiology and End-Results (SEER)-Medicare database, we identified 14,766 women between ages 66 and 80 years diagnosed with incident stage I/II breast cancer between 2007 and 2011. Medicare Part D data were obtained to characterize women's post-cancer use of various antihypertensive medications. Outcomes included a second breast cancer event (SBCE; a composite outcome defined as the first of a recurrence or a second contralateral primary breast cancer), breast cancer recurrence, and breast cancer-specific mortality. Time-varying Cox proportional hazard models were used to estimate hazard ratios (HR) and their associated 95% confidence intervals (CI).Results: There were 791 SBCEs, 627 breast cancer recurrences, and 237 breast cancer deaths identified over a median follow-up of 3 years. Use of diuretics (n = 8,517) after breast cancer diagnosis was associated with 29% (95% CI, 1.10-1.51), 36% (95% CI, 1.14 1.63) and 51% (95% CI, 1.11-2.04) higher risks of a SBCE, recurrence, and breast cancer death, respectively. Compared with nonusers, beta-blockers users (n = 7,145) had a 41% (95% CI, 1.07-1.84) higher risk of breast cancer death. Use of angiotensin II receptor blockers, calcium channel blockers and angiotensin converting enzyme inhibitors were not associated with risks of breast cancer outcomes.Conclusions: Use of diuretics and beta-blockers may be associated with increased risk of breast cancer outcomes among older women.Impact: Most antihypertensive medications are safe with respect to breast cancer outcomes, but more research is needed for diuretics and beta-blockers. Cancer Epidemiol Biomarkers Prev; 26(11); 1603-10. (c)2017 AACR. PMID- 28807928 TI - Role of Translesion Synthesis DNA Polymerases in DNA Replication in the Presence of a Weak DNA Polymerase delta in Saccharomyces cerevisiae. PMID- 28807929 TI - Human mucosal-associated invariant T (MAIT) cells possess capacity for B cell help. AB - Mucosal-associated invariant T (MAIT) cells are an innate-like T cell subset, restricted by the nonclassic MHC class I-related protein MR1 and enriched at mucosal sites. Human studies have shown an association between MAIT cells and pathogen-specific antibody responses. In this study, we investigate the effect of human MAIT cells on B cells ex vivo. We found that supernatants from microbe- or cytokine-stimulated MAIT cells, when added to purified autologous B cells, increase frequencies of plasmablasts and promote IgA, IgG, and IgM production. We found effects to be mostly MR1-dependent and that the increases in plasmablasts are likely a result of increased differentiation from memory B cells. Furthermore, microbe-activated MAIT cell supernatant contains multiple cytokines known to stimulate B cells, including IL-6, -10, and -21. This study thus provides the first direct evidence of a newly identified role of MAIT cells in providing help to B cells. PMID- 28807930 TI - Transcriptome Association Identifies Regulators of Wheat Spike Architecture. AB - The architecture of wheat (Triticum aestivum) inflorescence and its complexity is among the most important agronomic traits that influence yield. For example, wheat spikes vary considerably in the number of spikelets, which are specialized reproductive branches, and the number of florets, which are spikelet branches that produce seeds. The large and repetitive nature of the three homologous and highly similar subgenomes of wheat has impeded attempts at using genetic approaches to uncover beneficial alleles that can be utilized for yield improvement. Using a population-associative transcriptomic approach, we analyzed the transcriptomes of developing spikes in 90 wheat lines comprising 74 landrace and 16 elite varieties and correlated expression with variations in spike complexity traits. In combination with coexpression network analysis, we inferred the identities of genes related to spike complexity. Importantly, further experimental studies identified regulatory genes whose expression is associated with and influences spike complexity. The associative transcriptomic approach utilized in this study allows rapid identification of the genetic basis of important agronomic traits in crops with complex genomes. PMID- 28807931 TI - Identification of Novel Growth Regulators in Plant Populations Expressing Random Peptides. AB - The use of chemical genomics approaches allows the identification of small molecules that integrate into biological systems, thereby changing discrete processes that influence growth, development, or metabolism. Libraries of chemicals are applied to living systems, and changes in phenotype are observed, potentially leading to the identification of new growth regulators. This work describes an approach that is the nexus of chemical genomics and synthetic biology. Here, each plant in an extensive population synthesizes a unique small peptide arising from a transgene composed of a randomized nucleic acid sequence core flanked by translational start, stop, and cysteine-encoding (for disulfide cyclization) sequences. Ten and 16 amino acid sequences, bearing a core of six and 12 random amino acids, have been synthesized in Arabidopsis (Arabidopsis thaliana) plants. Populations were screened for phenotypes from the seedling stage through senescence. Dozens of phenotypes were observed in over 2,000 plants analyzed. Ten conspicuous phenotypes were verified through separate transformation and analysis of multiple independent lines. The results indicate that these populations contain sequences that often influence discrete aspects of plant biology. Novel peptides that affect photosynthesis, flowering, and red light response are described. The challenge now is to identify the mechanistic integrations of these peptides into biochemical processes. These populations serve as a new tool to identify small molecules that modulate discrete plant functions that could be produced later in transgenic plants or potentially applied exogenously to impart their effects. These findings could usher in a new generation of agricultural growth regulators, herbicides, or defense compounds. PMID- 28807932 TI - Reducing Inflammatory Cytokine Production from Renal Collecting Duct Cells by Inhibiting GATA2 Ameliorates Acute Kidney Injury. AB - Acute kidney injury (AKI) is a leading cause of chronic kidney disease. Proximal tubules are considered to be the primary origin of pathogenic inflammatory cytokines in AKI. However, it remains unclear whether other cell types, including collecting duct (CD) cells, participate in inflammatory processes. The transcription factor GATA2 is specifically expressed in CD cells and maintains their cellular identity. To explore the pathophysiological function of GATA2 in AKI, we generated renal tubular cell-specific Gata2 deletion (G2CKO) mice and examined their susceptibility to ischemia reperfusion injury (IRI). Notably, G2CKO mice exhibited less severe kidney damage, with reduced granulomacrophagic infiltration upon IRI. Transcriptome analysis revealed that a series of inflammatory cytokine genes were downregulated in GATA2-deficient CD cells, suggesting that GATA2 induces inflammatory cytokine expression in diseased kidney CD cells. Through high-throughput chemical library screening, we identified a potent GATA inhibitor. The chemical reduces cytokine production in CD cells and protects the mouse kidney from IRI. These results revealed a novel pathological mechanism of renal IRI, namely, that CD cells produce inflammatory cytokines and promote IRI progression. In injured kidney CD cells, GATA2 exerts a proinflammatory function by upregulating inflammatory cytokine gene expression. GATA2 can therefore be considered a therapeutic target for AKI. PMID- 28807934 TI - A novel, bounding gait in swimming turtles: implications for aquatic locomotor diversity. AB - Turtles are an iconic lineage in studies of animal locomotion, typifying the use of slow, alternating footfalls during walking. Alternating movements of contralateral limbs are also typical during swimming gaits for most freshwater turtles. Here, we report a novel gait in turtles, in which the pleurodire Emydura subglobosa swims using a bounding gait that coordinates bilateral protraction of both forelimbs with bilateral retraction of both hindlimbs. Use of this bounding gait is correlated with increased limb excursion and decreased stride frequency, but not increased velocity when compared with standard swimming strokes. Bounding by E. subglobosa provides a second example of a non-mammalian lineage that can use bounding gaits, and may give insight into the evolution of aquatic flapping. Parallels in limb muscle fascicle properties between bounding turtles and crocodylids suggest a possible musculoskeletal mechanism underlying the use of bounding gaits in particular lineages. PMID- 28807933 TI - Mice Deficient in lysophosphatidic acid acyltransferase delta (Lpaatdelta)/acylglycerophosphate acyltransferase 4 (Agpat4) Have Impaired Learning and Memory. AB - We previously characterized LPAATdelta/AGPAT4 as a mitochondrial lysophosphatidic acid acyltransferase that regulates brain levels of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylinositol (PI). Here, we report that Lpaatdelta-/- mice display impaired spatial learning and memory compared to wild-type littermates in the Morris water maze and our investigation of potential mechanisms associated with brain phospholipid changes. Marker protein immunoblotting suggested that the relative brain content of neurons, glia, and oligodendrocytes was unchanged. Relative abundance of the important brain fatty acid docosahexaenoic acid was also unchanged in phosphatidylserine, phosphatidylglycerol, and cardiolipin, in agreement with prior data on PC, PE and PI. In phosphatidic acid, it was increased. Specific decreases in ethanolamine containing phospholipids were detected in mitochondrial lipids, but the function of brain mitochondria in Lpaatdelta-/- mice was unchanged. Importantly, we found that Lpaatdelta-/- mice have a significantly and drastically lower brain content of the N-methyl-d-asparate (NMDA) receptor subunits NR1, NR2A, and NR2B, as well as the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1, compared to wild-type mice. However, general dysregulation of PI mediated signaling is not likely responsible, since phospho-AKT and phospho-mTOR pathway regulation was unaffected. Our findings indicate that Lpaatdelta deficiency causes deficits in learning and memory associated with reduced NMDA and AMPA receptors. PMID- 28807935 TI - Function of the hypobranchial muscles and hyoidiomandibular ligament during suction capture and bite processing in white-spotted bamboo sharks, Chiloscyllium plagiosum. AB - Suction feeding in teleost fish is a power-dependent behavior, requiring rapid and forceful expansion of the orobranchial cavity by the hypobranchial and trunk muscles. To increase power production for expansion, many species employ in series tendons and catch mechanisms to store and release elastic strain energy. Suction feeding sharks such as Chiloscyllium plagiosum lack large in-series tendons on the hypobranchials, yet two of the hypobranchials, the coracohyoideus and coracoarcualis (CH and CA; hyoid depressors), are arranged in-series, and run deep and parallel to a third muscle, the coracomandibularis (CM, jaw depressor). The arrangement of the CH and CA suggests that C. plagiosum is using the CH muscle rather than a tendon to store and release elastic strain energy. Here we describe the anatomy of the feeding apparatus, and present data on hyoid and jaw kinematics and fascicle shortening in the CM, CH and CA quantified using sonomicrometry, with muscle activity and buccal pressure recorded simultaneously. Results from prey capture show that prior to jaw and hyoid depression the CH is actively lengthened by shortening of the in-series CA. The active lengthening of the CH and pre-activation of the CH and CA suggest that the CH is functioning to store and release elastic energy during prey capture. Catch mechanisms are proposed involving a dynamic moment arm and four-bar linkage between the hyoidiomandibular ligament (LHML), jaws and ceratohyals that is influenced by the CM. Furthermore, the LHML may be temporarily disengaged during behaviors such as bite processing to release linkage constraints. PMID- 28807936 TI - Genomic Alterations in Circulating Tumor DNA from Diverse Cancer Patients Identified by Next-Generation Sequencing. AB - Noninvasive genomic profiling of tumors may be possible with next-generation sequencing (NGS) of blood-derived circulating tumor DNA (ctDNA), but proof of concept in a large cohort of patients with diverse cancers has yet to be reported. Here we report the results of an analysis of plasma-derived ctDNA from 670 patients with diverse cancers. The tumors represented in the patient cohort were mainly gastrointestinal (31.8%), brain (22.7%), or lung (20.7%). ctDNA obtained from most patients [N = 423 (63%)] displayed at least one alteration. The most frequent alterations seen, as characterized mutations or variants of unknown significance, occurred in TP53 (32.5% of patients), EGFR (13%), KRAS (12.5%), and PIK3CA (9.1%); for characterized alterations, 30.7% (TP53), 7.6% (EGFR), 12.2% (KRAS), and 7.7% (PIK3CA). We found that 32% of brain tumors had at least one ctDNA alteration. Head and neck tumors were independently associated with a higher number of alterations in a multivariable analysis (P = 0.019). Notably, 320/670 (48%) of patients displayed potentially actionable alterations, with 241 patients possible candidates for on-label or off-label treatment with an FDA-approved drug. Several illustrations of the clinical utility of the information obtained for improving treatment of specific patients is provided. Our findings demonstrate the feasibility and impact of genomic profiling of tumors by ctDNA NGS, greatly encouraging broader investigations of the application of this technology for precision medicine in cancer management. Cancer Res; 77(19); 5419-27. (c)2017 AACR. PMID- 28807937 TI - HNF1B Loss Exacerbates the Development of Chromophobe Renal Cell Carcinomas. AB - Chromophobe renal cell carcinoma (ChRCC) is characterized by major changes in chromosomal copy number (CN). No model is available to precisely elucidate the molecular drivers of this tumor type. HNF1B is a master regulator of gene expression. Here, we report that the transcription factor HNF1B is downregulated in the majority of ChRCC and that the magnitude of HNF1B loss is unique to ChRCC. We also observed a strong correlation between reduced HNF1B expression and aneuploidy in ChRCC patients. In murine embryonic fibroblasts or ACHN cells, HNF1B deficiency reduced expression of the spindle checkpoint proteins MAD2L1 and BUB1B, and the cell-cycle checkpoint proteins RB1 and p27. Furthermore, it altered the chromatin accessibility of Mad2l1, Bub1b, and Rb1 genes and triggered aneuploidy development. Analysis of The Cancer Genome Atlas database revealed TP53 mutations in 33% of ChRCC where HNF1B expression was repressed. In clinical specimens, combining HNF1B loss with TP53 mutation produced an association with poor patient prognosis. In cells, combining HNF1B loss and TP53 mutation increased cell proliferation and aneuploidy. Our results show how HNF1B loss leads to abnormal mitotic protein regulation and induction of aneuploidy. We propose that coordinate loss of HNF1B and TP53 may enhance cellular survival and confer an aggressive phenotype in ChRCC. Cancer Res; 77(19); 5313-26. (c)2017 AACR. PMID- 28807938 TI - S100A4 Is a Biomarker and Regulator of Glioma Stem Cells That Is Critical for Mesenchymal Transition in Glioblastoma. AB - Glioma stem cells (GSC) and epithelial-mesenchymal transition (EMT) are strongly associated with therapy resistance and tumor recurrence, but the underlying mechanisms are incompletely understood. Here, we show that S100A4 is a novel biomarker of GSCs. S100A4+ cells in gliomas are enriched with cancer cells that have tumor-initiating and sphere-forming abilities, with the majority located in perivascular niches where GSCs are found. Selective ablation of S100A4-expressing cells was sufficient to block tumor growth in vitro and in vivo We also identified S100A4 as a critical regulator of GSC self-renewal in mouse and patient-derived glioma tumorspheres. In contrast with previous reports of S100A4 as a reporter of EMT, we discovered that S100A4 is an upstream regulator of the master EMT regulators SNAIL2 and ZEB along with other mesenchymal transition regulators in glioblastoma. Overall, our results establish S100A4 as a central node in a molecular network that controls stemness and EMT in glioblastoma, suggesting S100A4 as a candidate therapeutic target. Cancer Res; 77(19); 5360-73. (c)2017 AACR. PMID- 28807939 TI - PRC2-Mediated Transcriptomic Alterations at the Embryonic Stage Govern Tumorigenesis and Clinical Outcome in MYCN-Driven Neuroblastoma. AB - Pediatric cancers such as neuroblastoma are thought to involve a dysregulation of embryonic development. However, it has been difficult to identify the critical events that trigger tumorigenesis and differentiate them from normal development. In this study, we report the establishment of a spheroid culture method that enriches early-stage tumor cells from TH-MYCN mice, a preclinical model of neuroblastoma. Using this method, we found that tumorigenic cells were evident as early as day E13.5 during embryo development, when the MYC and PRC2 transcriptomes were significantly altered. Ezh2, an essential component of PRC2, was expressed in embryonic and postnatal tumor lesions and physically associated with N-MYC and we observed that H3K27me3 was increased at PRC2 target genes. PRC2 inhibition suppressed in vitro sphere formation, derepressed its target genes, and suppressed in situ tumor growth. In clinical specimens, expression of MYC and PRC2 target genes correlated strongly and predicted survival outcomes. Together, our findings highlighted PRC2-mediated transcriptional control during embryogenesis as a critical step in the development and clinical outcome of neuroblastoma. Cancer Res; 77(19); 5259-71. (c)2017 AACR. PMID- 28807940 TI - Mitotic Vulnerability in Triple-Negative Breast Cancer Associated with LIN9 Is Targetable with BET Inhibitors. AB - Triple-negative breast cancers (TNBC) are highly aggressive, lack FDA-approved targeted therapies, and frequently recur, making the discovery of novel therapeutic targets for this disease imperative. Our previous analysis of the molecular mechanisms of action of bromodomain and extraterminal protein inhibitors (BETi) in TNBC revealed these drugs cause multinucleation, indicating BET proteins are essential for efficient mitosis and cytokinesis. Here, using live cell imaging, we show that BET inhibition prolonged mitotic progression and induced mitotic cell death, both of which are indicative of mitotic catastrophe. Mechanistically, the mitosis regulator LIN9 was a direct target of BET proteins that mediated the effects of BET proteins on mitosis in TNBC. Although BETi have been proposed to function by dismantling super-enhancers (SE), the LIN9 gene lacks an SE but was amplified or overexpressed in the majority of TNBCs. In addition, its mRNA expression predicted poor outcome across breast cancer subtypes. Together, these results provide a mechanism for cancer selectivity of BETi that extends beyond modulation of SE-associated genes and suggest that cancers dependent upon LIN9 overexpression may be particularly vulnerable to BETi. Cancer Res; 77(19); 5395-408. (c)2017 AACR. PMID- 28807941 TI - The Rac GTPase in Cancer: From Old Concepts to New Paradigms. AB - Rho family GTPases are critical regulators of cellular functions that play important roles in cancer progression. Aberrant activity of Rho small G-proteins, particularly Rac1 and their regulators, is a hallmark of cancer and contributes to the tumorigenic and metastatic phenotypes of cancer cells. This review examines the multiple mechanisms leading to Rac1 hyperactivation, particularly focusing on emerging paradigms that involve gain-of-function mutations in Rac and guanine nucleotide exchange factors, defects in Rac1 degradation, and mislocalization of Rac signaling components. The unexpected pro-oncogenic functions of Rac GTPase-activating proteins also challenged the dogma that these negative Rac regulators solely act as tumor suppressors. The potential contribution of Rac hyperactivation to resistance to anticancer agents, including targeted therapies, as well as to the suppression of antitumor immune response, highlights the critical need to develop therapeutic strategies to target the Rac pathway in a clinical setting. Cancer Res; 77(20); 5445-51. (c)2017 AACR. PMID- 28807944 TI - What's the prognosis, Doc? PMID- 28807942 TI - Nuclear FAK and Runx1 Cooperate to Regulate IGFBP3, Cell-Cycle Progression, and Tumor Growth. AB - Nuclear focal adhesion kinase (FAK) is a potentially important regulator of gene expression in cancer, impacting both cellular function and the composition of the surrounding tumor microenvironment. Here, we report in a murine model of skin squamous cell carcinoma (SCC) that nuclear FAK regulates Runx1-dependent transcription of insulin-like growth factor binding protein 3 (IGFBP3), and that this regulates SCC cell-cycle progression and tumor growth in vivo Furthermore, we identified a novel molecular complex between FAK and Runx1 in the nucleus of SCC cells and showed that FAK interacted with a number of Runx1-regulatory proteins, including Sin3a and other epigenetic modifiers known to alter Runx1 transcriptional function through posttranslational modification. These findings provide important new insights into the role of FAK as a scaffolding protein in molecular complexes that regulate gene transcription. Cancer Res; 77(19); 5301 12. (c)2017 AACR. PMID- 28807945 TI - ? PMID- 28807943 TI - Chromatin-Associated Protein SIN3B Prevents Prostate Cancer Progression by Inducing Senescence. AB - Distinguishing between indolent and aggressive prostate adenocarcinoma remains a priority to accurately identify patients who need therapeutic intervention. SIN3B has been implicated in the initiation of senescence in vitro Here we show that in a mouse model of prostate cancer, SIN3B provides a barrier to malignant progression. SIN3B was required for PTEN-induced cellular senescence and prevented progression to invasive prostate adenocarcinoma. Furthermore, SIN3B was downregulated in human prostate adenocarcinoma correlating with upregulation of its target genes. Our results suggest a tumor suppressor function for SIN3B that limits prostate adenocarcinoma progression, with potential implications for the use of SIN3B and its target genes as candidate diagnostic markers to distinguish indolent from aggressive disease. Cancer Res; 77(19); 5339-48. (c)2017 AACR. PMID- 28807946 TI - Figure 8 strategy: Practical guide to finding your niche in a community engagement initiative. PMID- 28807948 TI - Approach to GERD. PMID- 28807947 TI - ? PMID- 28807949 TI - True reconciliation. PMID- 28807951 TI - Correction. PMID- 28807950 TI - Time off work. PMID- 28807952 TI - Emerging role of HPV self-sampling in cervical cancer screening for hard-to-reach women: Focused literature review. AB - OBJECTIVE: To provide a focused critical review of the literature on the acceptability, feasibility, and uptake of human papillomavirus (HPV) self sampling among hard-to-reach women. QUALITY OF EVIDENCE: A focused search to obtain relevant literature published in English between 1997 and 2015 was done using PubMed and EMBASE using search terms including HPV self-test or HPV self sample or HPV kit in combination with acceptability or feasibility. Only studies that focused on never-screened or underscreened populations were included in this review. MAIN MESSAGE: Human papillomavirus self-sampling was found to be highly acceptable and feasible among these hard-to-reach women across most studies. Mailing of self-sampling kits has been shown to increase participation among hard to reach women. Some concerns remain regarding adherence to further follow-up among high-risk women with positive test results for HPV after screening. CONCLUSION: There is a strong body of evidence to support the usefulness of HPV self-sampling in increasing participation of hard-to-reach women in screening programs (level I evidence). Convenience, privacy, ease of use, and, likely, cost effectiveness of HPV self-sampling are driving forces in its emerging role in cervical cancer screening among hard-to-reach women. Key barriers to participation could be addressed by overcoming disparities in HPV-related knowledge and perceptions about cervical cancer screening. PMID- 28807953 TI - Developing family practice to respond to global health challenges: The Besrour Papers: a series on the state of family medicine in the world. AB - OBJECTIVE: To assess family medicine's role in developing strong, coordinated, community-based, integrated health care systems in low-resource settings globally. COMPOSITION OF THE COMMITTEE: A subgroup of the Besrour Centre of the College of Family Physicians of Canada developed connections with selected international colleagues with expertise in international family medicine practice, health systems and capacity building, and teaching to map family medicine globally and give a bird's eye view of family medicine internationally. METHODS: Following a background literature review, the authors collectively reflected on their substantial international experience to attempt to describe best practices for various contexts. REPORT: With the failure of vertical, disease-oriented models to provide sustained improvements in health outcomes, the need to develop integrated primary care involving the most appropriate health professionals for differing contexts is becoming apparent worldwide. Health system planning is required to develop policies on health professional training to achieve this. Advocating and offering appropriate incentives for, and coordination of, local opportunities within the health system also becomes paramount. The adaptability and generalist nature of family medicine allows it to respond to the unique needs of a given population. Family physicians with adequate financial and physical resources can function most effectively as members of interdisciplinary teams, thus providing valuable, comprehensive health services in any area of the world. PMID- 28807954 TI - Acetylsalicylic acid for children with Kawasaki disease. AB - Question A 7-year-old child in my office was recently discharged from the hospital after receiving intravenous immunoglobulin for Kawasaki disease. Should I continue treatment with acetylsalicylic acid (ASA), and if so, what is the appropriate dose? Answer The role of ASA for Kawasaki disease during the acute febrile phase has recently been called into question. According to several studies, ASA might reduce the duration of fever but it does not appear to directly reduce the incidence of coronary artery complications. However, with no high-quality randomized controlled trials, the evidence is scarce and more studies with good methodology are needed to determine the value of ASA in the treatment of Kawasaki disease. Currently, guidelines recommending the use of ASA should be followed. PMID- 28807955 TI - Bilateral pathologic mid-tibial stress fractures: Initial presentation of mild primary hyperparathyroidism. PMID- 28807956 TI - Trouble sleeping: spend less time in bed? PMID- 28807957 TI - Emerging clone of meningococcal bacterium affecting middle-aged and older adults. PMID- 28807958 TI - Management of impetigo and cellulitis: Simple considerations for promoting appropriate antibiotic use in skin infections. PMID- 28807959 TI - Referral processes and wait times in primary care. AB - OBJECTIVE: To evaluate the response times to requests for consultations from FPs and the wait times for patient appointments. DESIGN: Mailed invitation to participate in a survey about non-FP specialist consultation requests from April 28 to May 9, 2014. SETTING: Hamilton, Ont. PARTICIPANTS: All active physicians with community practices from the Department of Family Medicine at St Joseph's Healthcare Hamilton and Hamilton Health Sciences. MAIN OUTCOME MEASURES: All non FP specialist consultation requests for a 2-week period. RESULTS: Thirty-four practices (9.6% response rate) collected data on 816 consultation requests. Requests for referrals were most commonly made to the following 5 specialties: dermatology, surgery, gastroenterology, orthopedics, and obstetrics and gynecology. Overall, 36.4% of the requests for consultation received no response from the non-FP specialist's office by the end of the follow-up period. The mean wait time for a patient appointment was 60.1 days (range 23.3 to 168.5 days). Five specialties had particularly lengthy wait times of 105.9 to 168.5 days. CONCLUSION: Allowing 5 to 7 weeks for a response from a non-FP specialist, there was still a 36.4% nonresponse rate (similar to a pilot survey administered in 2010). Patient and physician frustration is certainly heightened and more office time and energy is expended when no acknowledgment of a referral is received within 7 weeks. This gives our community wait times much longer than those reported by any of the national bodies. PMID- 28807960 TI - Stethoscopes and stories. PMID- 28807961 TI - Poisoned perfection: Welling concerns about arsenic, drinking water, and public health in rural Newfoundland. PMID- 28807964 TI - ? PMID- 28807963 TI - Dual vision. PMID- 28807962 TI - Podcasts on the 99 priority topics for family medicine residents. PMID- 28807965 TI - ? PMID- 28807966 TI - Fatigue risk management revisited. PMID- 28807968 TI - ? PMID- 28807967 TI - ? PMID- 28807969 TI - ? PMID- 28807970 TI - ? PMID- 28807971 TI - ? PMID- 28807972 TI - Young women describe the ideal first pelvic examination: Qualitative research using semistructured interviews. AB - OBJECTIVE: To explore representations of the first pelvic examination (PE) among adolescents who had not yet had this examination and to identify their criteria for a positive experience of it. DESIGN: Qualitative study using semistructured interviews. SETTING: Midi-Pyrenees and Auvergne in France. PARTICIPANTS: Adolescents aged 15 to 19 years who had never had a PE. METHODS: Participants were recruited through snowball sampling and targeted sampling until data saturation was reached. Maximum variation was sought in the profiles of the study participants. Open-ended questions dealt with the interviewee's sources of information, knowledge of the PE, criteria for a positive PE experience, and representations of the PE itself. Verbatim transcripts were immediately subjected to longitudinal analysis with the context (researchers' notes) and key themes of the interview. Cross-sectional analysis was then performed. MAIN FINDINGS: Many adolescents lack knowledge about the PE and believe that it is mandatory. According to study participants, the ideal PE would take place when they felt ready. They would be given adequate information in advance and the option of being accompanied by a friend or family member. They described the ideal examining room as warm, comfortable, and reassuring. The quality of their relationship with the examining physician would also affect their acceptance of this examination. CONCLUSION: An information session before the consultation for the PE would make it possible to reduce the patient's apprehension, improve her level of knowledge, and set the right tone for the upcoming PE, both for her and for the physician. PMID- 28807973 TI - Prevention of delayed referrals through the Champlain BASE eConsult service. AB - OBJECTIVE: To identify the proportion and evaluate the content of eConsults (electronic consultations) in which the Champlain BASE (Building Access to Specialists through eConsultation) eConsult process prompted a referral to a specialist that was not originally contemplated by the primary care provider (PCP). DESIGN: Cross-sectional study of all eConsults submitted between April 15, 2011, and January 31, 2015. SETTING: Champlain Local Health Integration Network, a large health region in eastern Ontario. PARTICIPANTS: Primary care providers registered to use the Champlain BASE eConsult service. MAIN OUTCOME MEASURES: Answers from a close-out survey-completed by PCPs at the conclusion of each eConsult-stating that specialist referral was not originally contemplated but that the eConsult process had prompted referral. The logs containing the communication exchanged between the PCPs and the specialists were reviewed, and each prompted referral case was categorized by the type of question asked, if pharmaceutical advice was given, if the referral was redirected to a different specialty group, and if the referral was urgent. RESULTS: A total of 188 (3.4%) of 5601 eConsults completed during the study period were cases in which PCPs stated that they had originally not contemplated referring the patient to a specialist but that the Champlain BASE eConsult process had prompted referral. Prompted referrals were most often directed to cardiologists (10.6%), dermatologists (10.6%), infectious disease specialists (9.0%), hematologists (9.0%), and urologists (8.5%). The most common questions were about diagnosis (34.0%), drug treatment (18.0%), and management (15.0%). Pharmaceutical advice was given in 28.0% of prompted referral cases, and in 26.0% of cases, the face-to face referral was redirected to another specialty group. In 5.0% of cases, the specialist stated the referral was urgent. The median specialist response time was 0.96 days (interquartile range 0.17 to 3.80 days). CONCLUSION: By providing PCPs with increased access to specialists, the Champlain BASE eConsult service serves an important role in identifying and preventing the potential detrimental consequences of delayed medical referrals across specialty groups. PMID- 28807975 TI - ? PMID- 28807976 TI - ? PMID- 28807974 TI - Exploring family physicians' reasons to continue or discontinue providing intrapartum care: Qualitative descriptive study. AB - OBJECTIVE: To examine the reasons why family physicians continue or discontinue providing intrapartum care in their clinical practice. DESIGN: Qualitative descriptive study. SETTING: Two hospitals located in a multicultural area of Montreal, Que, in November 2011 to June 2012. PARTICIPANTS: Sixteen family physicians who were current or former providers of obstetric care. METHODS: Data were collected using semistructured qualitative interviews. Thematic analysis was used to analyze the interview transcripts. MAIN FINDINGS: Three overarching themes that help create understanding of why family doctors continue to provide obstetric care were identified: their attraction, often initiated by role models early in their careers, to practising complete continuity of care and accompanying patients in a special moment in their lives; the personal, family, and organizational pressures experienced while pursuing a family medicine career that includes obstetrics; and their ongoing reflection about continuing to practise obstetrics. CONCLUSION: The practice of obstetrics was very attractive to family physician participants whether they provided intrapartum care or decided to stop. More professional support and incentives might help keep family doctors practising obstetrics. PMID- 28807978 TI - High-Sensitivity Troponin: Star Player but No Lone Hero. PMID- 28807977 TI - Can Secure Patient-Provider Messaging Improve Diabetes Care? AB - OBJECTIVE: Internet-based secure messaging between patients and providers through a patient portal is now common in the practice of modern medicine. There is limited evidence on how messaging is associated with use and clinical quality measures among patients with type 2 diabetes. We examine whether messaging with physicians for medical advice is associated with fewer face-to-face visits and better diabetes management. RESEARCH DESIGN AND METHODS: Patients with diabetes who were enrolled in an online portal of an outpatient health care organization in 2011-2014 were studied (N = 37,762 patient-years). Messages from/to primary care physicians or diabetes-related specialists for medical advice were considered. We estimated the association of messaging with diabetes quality measures, adjusting for patient and provider characteristics and patient-level clustering. RESULTS: Most patients (72%) used messaging, and those who made frequent visits were also more likely to message. Given visit frequency, no (vs. any) messaging was negatively associated with the likelihood of meeting an HbA1c target of <8% (64 mmol/mol) (odds ratio [OR] 0.83 [95% CI 0.77, 0.90]). Among message users, additional messages (vs. 1) were associated with better outcome (two more messages: OR 1.17 [95% CI 1.06, 1.28]; three more messages: 1.38 [1.25, 1.53]; four more messages: 1.55 [1.43, 1.69]). The relationship was stronger for noninsulin users. Message frequency was also positively associated, but to a smaller extent, with process measures (e.g., eye examination). Physician initiated messages had effects similar to those for patient-initiated messages. CONCLUSIONS: Patients with diabetes frequently used secure messaging for medical advice in addition to routine visits to care providers. Messaging was positively associated with better diabetes management in a large community outpatient practice. PMID- 28807979 TI - Single-Stranded DNA Library Preparation Does Not Preferentially Enrich Circulating Tumor DNA. PMID- 28807980 TI - CD177 modulates human neutrophil migration through activation-mediated integrin and chemoreceptor regulation. AB - CD177 is a glycosylphosphatidylinositol (GPI)-anchored protein expressed by a variable proportion of human neutrophils that mediates surface expression of the antineutrophil cytoplasmic antibody antigen proteinase 3. CD177 associates with beta2 integrins and recognizes platelet endothelial cell adhesion molecule 1 (PECAM-1), suggesting a role in neutrophil migration. However, CD177pos neutrophils exhibit no clear migratory advantage in vivo, despite interruption of in vitro transendothelial migration by CD177 ligation. We sought to understand this paradox. Using a PECAM-1-independent transwell system, we found that CD177pos and CD177neg neutrophils migrated comparably. CD177 ligation selectively impaired migration of CD177pos neutrophils, an effect mediated through immobilization and cellular spreading on the transwell membrane. Correspondingly, CD177 ligation enhanced its interaction with beta2 integrins, as revealed by fluorescence lifetime imaging microscopy, leading to integrin-mediated phosphorylation of Src and extracellular signal-regulated kinase (ERK). CD177 driven cell activation enhanced surface beta2 integrin expression and affinity, impaired internalization of integrin attachments, and resulted in ERK-mediated attenuation of chemokine signaling. We conclude that CD177 signals in a beta2 integrin-dependent manner to orchestrate a set of activation-mediated mechanisms that impair human neutrophil migration. PMID- 28807981 TI - Delineation of the timing of second-line therapy post-autologous stem cell transplant in patients with AL amyloidosis. AB - Among patients with immunoglobulin light chain (AL) amyloidosis, there is little consensus on when reinstitution of chemotherapy should occur. We conducted a retrospective study to evaluate the patterns of relapse or progression (R/P) and the timing of reinitiating therapy among 235 patients initially treated with autologous stem cell transplant (ASCT) at Mayo Clinic. The median time from ASCT to second-line therapy was 24.3 months. At the time of restarting therapy, median difference of free light chain (dFLC) was 9.9 mg/dL (42% of diagnosis value), 32% had a dFLC <5 mg/dL, and 63% met criteria for organ R/P. The indications for retreatment were (1) clinical suspicion of R/P, 10%; 92) hematologic R/P only, 23%; (3) organ R/P only, 32%; (4) both hematologic and organ R/P, 31%; and (5) suboptimal response to ASCT and second-line therapy as consolidation, 4%. Patients with organ progression at the time of second-line therapy had inferior survival. Although a dFLC of >5 mg/dL at the time of reinstituting therapy was associated with risk, patients relapsing from very good partial response (VGPR) or better had a longer time to develop organ progression after hematologic R/P (24.2 vs 3.2 months, P = .007). These data suggest that the best candidates for clinical trials testing novel plasma cell-directed chemotherapy beyond first line may be those patients who are either relapsing from VGPR or better (dFLC at diagnosis was >5 mg/dL) or having inadequate response to prior therapy. This strategy should allow for hematologic response assessment while avoiding the risk of deleterious organ progression. Implementation of more stringent progression criteria may also be warranted. PMID- 28807984 TI - Bureaucracy of changing gender. PMID- 28807982 TI - C/EBPbeta is required for survival of Ly6C- monocytes. AB - The transcription factor CCAAT/enhancer-binding protein beta (C/EBPbeta) is highly expressed in monocytes/macrophages. However, its roles in monopoiesis are largely unknown. Here, we investigated the roles of C/EBPbeta in monopoiesis. Further subdivision of monocytes revealed that Cebpb messenger RNA was highly upregulated in Ly6C- monocytes in bone marrow. Accordingly, the number of Ly6C- monocytes was significantly reduced in Cebpb-/- mice. Bone marrow chimera experiments and Mx1-Cre-mediated deletion of Cebpb revealed a cell-intrinsic and monocyte-specific requirement for C/EBPbeta in monopoiesis. In Cebpb-/- mice, turnover of Ly6C- monocytes was highly accelerated and apoptosis of Ly6C- monocytes was increased. Expression of Csf1r, which encodes a receptor for macrophage colony-stimulating factor, was significantly reduced in Ly6C- monocytes of Cebpb-/- mice. C/EBPbeta bound to positive regulatory elements of Csf1r and promoted its transcription. Collectively, these results indicate that C/EBPbeta is a critical factor for Ly6C- monocyte survival, at least in part through upregulation of Csf1r. PMID- 28807985 TI - Inhaled Carbon Monoxide: From Toxin to Therapy. AB - Carbon monoxide (CO) is usually recognized as a toxic gas that can be used to assess lung function in the pulmonary function laboratory. The toxicity of CO relates to its high affinity for hemoglobin and other heme molecules, producing carboxyhemoglobin (HbCO). Despite that blood HbCO levels are commonly measured in patients with CO poisoning, the clinical presentation often does not correlate with the HbCO level, and clinical improvement in the patient's condition does not correlate with HbCO clearance. In patients with CO poisoning, administration of 100% O2 is standard practice. If available, hyperbaric O2 can be used, although this is controversial. Measurement of exhaled CO might be useful to estimate HbCO, such as in smoking cessation programs, but assessment of HbCO using pulse oximetry can be misleading. Endogenous CO is generated as the result of heme oxygenase activity. It is becoming increasingly recognized that the results of heme oxygenase activity, specifically CO production, might have important physiologic functions. These include effects on vascular function, inflammation, apoptosis, cell proliferation, and signaling pathways. Given the abundance of basic science supporting a therapeutic role for CO, clinical trials are exploring this potential. PMID- 28807983 TI - Cancer-associated pathways and biomarkers of venous thrombosis. AB - Cancer patients have an increased risk of venous thromboembolism (VTE). In this review, we summarize common and cancer type-specific pathways of VTE in cancer patients. Increased levels of leukocytes, platelets, and tissue factor-positive (TF+) microvesicles (MVs) are all potential factors that alone or in combination increase cancer-associated thrombosis. Patients with lung or colorectal cancer often exhibit leukocytosis. Neutrophils could increase VTE in cancer patients by releasing neutrophil extracellular traps whereas monocytes may express TF. Thrombocytosis is often observed in gastrointestinal, lung, breast, and ovarian cancer and this could decrease the threshold required for VTE. Soluble P-selectin has been identified as a biomarker of cancer-associated thrombosis in a general cancer population and may reflect activation of the endothelium. P-selectin expression by the endothelium may enhance VTE by increasing the recruitment of leukocytes. Studies in patients with pancreatic or brain cancer suggest that elevated levels of PAI-1 may contribute to VTE. Although elevated levels of TF+ MVs have been observed in patients with different types of cancer, an association between TF+ MVs and VTE has been observed only in pancreatic cancer. Podoplanin expression is associated with VTE in patients with brain cancer and may activate platelets. Future studies should measure multiple biomarkers in each cancer type to determine whether combinations of biomarkers can be used as predictors of VTE. A better understanding of the pathways that increase VTE in cancer patients may lead to the development of new therapies to reduce the morbidity and mortality associated with thrombosis. PMID- 28807986 TI - A Turbine-Driven Ventilator Improves Adherence to Advanced Cardiac Life Support Guidelines During a Cardiopulmonary Resuscitation Simulation. AB - BACKGROUND: Research has shown that increased breathing frequency during cardiopulmonary resuscitation is inversely correlated with systolic blood pressure. Rescuers often hyperventilate during cardiopulmonary resuscitation (CPR). Current American Heart Association advanced cardiac life support recommends a ventilation rate of 8-10 breaths/min. We hypothesized that a small, turbine-driven ventilator would allow rescuers to adhere more closely to advanced cardiac life support (ACLS) guidelines. METHODS: Twenty-four ACLS-certified health-care professionals were paired into groups of 2. Each team performed 4 randomized rounds of 2-min cycles of CPR on an intubated mannikin, with individuals altering between compressions and breaths. Two rounds of CPR were performed with a self-inflating bag, and 2 rounds were with the ventilator. The ventilator was set to deliver 8 breaths/min, pressure limit 22 cm H2O. Frequency, tidal volume (VT), peak inspiratory pressure, and compression interruptions (hands-off time) were recorded. Data were analyzed with a linear mixed model and Welch 2-sample t test. RESULTS: The median (interquartile range [IQR]) frequency with the ventilator was 7.98 (7.98-7.99) breaths/min. Median (IQR) frequency with the self-inflating bag was 9.5 (8.2-10.7) breaths/min. Median (IQR) ventilator VT was 0.5 (0.5-0.5) L. Median (IQR) self-inflating bag VT was 0.6 (0.5-0.7) L. Median (IQR) ventilator peak inspiratory pressure was 22 (22-22) cm H2O. Median (IQR) self-inflating bag peak inspiratory pressure was 30 (27-35) cm H2O. Mean +/ SD hands-off times for ventilator and self-inflating bag were 5.25 +/- 2.11 and 6.41 +/- 1.45 s, respectively. CONCLUSIONS: When compared with a ventilator, volunteers ventilated with a self-inflating bag within ACLS guidelines. However, volunteers ventilated with increased variation, at higher VT levels, and at higher peak pressures with the self-inflating bag. Hands-off time was also significantly lower with the ventilator. (ClinicalTrials.gov registration NCT02743299.). PMID- 28807987 TI - Use of Noninvasive Ventilation During Feeding Tube Placement. AB - Parenteral nutrition is indicated in amyotrophic lateral sclerosis (ALS) when dysphagia, loss of appetite, and difficulty protecting the airways cause malnutrition, severe weight loss, dehydration, and increased risk of aspiration pneumonia. The aim of this review is to compare percutaneous endoscopic gastrostomy (PEG), radiologically inserted G-tube (RIG), and percutaneous radiologic gastrostomy (PRG) in patients with ALS, performed with or without noninvasive ventilation (NIV). We searched PubMed, MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), the EBSCO Online Research Database, and Scopus up to December 2015. A priori selection included all randomized controlled trials (RCTs), quasi-randomized trials, and prospective and retrospective studies. The primary outcome was 30-d survival. We found no RCTs or quasi-RCTs. Seven studies about the implementation of the PEG/RIG procedure during the use of NIV and 5 studies without NIV were included. In another study of 59 subjects undergoing open gastrostomy, all with vital capacity < 30% of normal, 18 of whom were dependent on continuous NIV at full ventilatory support settings, there were no respiratory complications. Thus, the use of NIV during the implementation of these procedures, especially when used at full ventilatory support settings of pressure preset 18-25 cm H2O, can support alveolar ventilation before, during, and after the procedures and prevent respiratory complications. The procedures investigated appear equivalent, but the methodological quality of the studies could be improved. Possible benefits with regard to nutrition parameters, quality of life, and psychological features need to be further investigated. PMID- 28807988 TI - High-Flow Nasal Cannula Therapy Versus Intermittent Noninvasive Ventilation in Obese Subjects After Cardiothoracic Surgery. AB - BACKGROUND: Obese patients are considered at risk of respiratory failure after cardiothoracic surgery. High-flow nasal cannula has demonstrated its non inferiority after cardiothoracic surgery compared to noninvasive ventilation (NIV), which is the recommended treatment in obese patients. We hypothesized that NIV was superior to high-flow nasal cannula for preventing or resolving acute respiratory failure after cardiothoracic surgery in this population. METHODS: We performed a post hoc analysis of a randomized, controlled trial. Obese subjects were randomly assigned to receive NIV for at least 4 h/d (inspiratory pressure, 8 cm H2O; expiratory pressure, 4 cm H2O; FIO2 , 0.5) or high-flow nasal cannula delivered continuously (flow, 50 L/min, FIO2 0.5). RESULTS: Treatment failure (defined as re-intubation, switch to the other treatment, or premature discontinuation) occurred in 21 of 136 (15.4%, 95% CI 9.8-22.6%) subjects with NIV compared to 18 of 135 (13.3%, 95% CI 8.1-20.3%) subjects with high-flow nasal cannula (P = .62). No significant differences were found for dyspnea and comfort scores. Skin breakdown was significantly more common with NIV after 24 h (9.2%, 95% CI 5.0-16.0 vs 1.6%, 95% CI 1.0-6.0; P = .01). No significant differences were found for ICU mortality (5.9% for subjects with NIV vs 2.2% for subjects with high-flow nasal cannula, P = .22) or for any of the other secondary outcomes. CONCLUSIONS: Among obese cardiothoracic surgery subjects with or without respiratory failure, the use of continuous high-flow nasal cannula compared to intermittent NIV (8/4 cm H2O) did not result in a worse rate of treatment failure. Because high-flow nasal cannula presents some advantages, it may be used instead of NIV in obese patients after cardiothoracic surgery. PMID- 28807989 TI - Coaxial Tubing Systems Increase Artificial Airway Resistance and Work of Breathing. AB - BACKGROUND: Tubing systems are an essential component of the ventilation circuit, connecting the ventilator to the patient's airways. Coaxial tubing systems incorporate the inspiratory tube within the lumen of the expiratory one. We hypothesized that by design, these tubing systems increase resistance to air flow compared with conventional ones. METHODS: We investigated the flow-dependent pressure gradient across coaxial, conventional disposable, and conventional reusable tubing systems from 3 different manufacturers. Additionally, the additional work of breathing and perception of resistance during breathing through the different devices were determined in 18 healthy volunteers. RESULTS: The pressure gradient across coaxial tubing systems was up to 6 times higher compared with conventional ones (1.90 +/- 0.03 cm H2O vs 0.34 +/- 0.01 cm H2O, P < .001) and was higher during expiration compared with inspiration (P < .001). Additional work of breathing and perceived breathing resistance were highest in coaxial tubing systems, accordingly. CONCLUSIONS: Our findings suggest that the use of coaxial tubing systems should be carefully considered with respect to their increased resistance. PMID- 28807990 TI - Investigating the Genetic Causes of Sudden Unexpected Death in Children Through Targeted Next-Generation Sequencing Analysis. AB - BACKGROUND: Inherited arrhythmia syndromes are responsible for a significant portion of autopsy-negative sudden unexpected death (SUD) cases, but molecular autopsy used to identify potentially causal variants is not routinely included in SUD investigations. We collaborated with a medical examiner's office to assist in finding a diagnosis for their autopsy-negative child SUD cases. METHODS AND RESULTS: 191 child SUD cases (<5 years of age) were selected for analyses. Our next generation sequencing panel incorporated 38 inherited arrhythmia syndrome candidate genes and another 33 genes not previously investigated for variants that may underlie SUDY pathophysiology. Overall, we identified 11 potentially causal disease-associated variants in 12 cases, for an overall yield of 6.3%. We also identified 31 variants of uncertain significance in 36 cases and 16 novel variants predicted to be pathogenic in silico in 15 cases. The disease-associated variants were reported to the medical examiner to notify surviving relatives and recommend clinical assessment. CONCLUSIONS: We have identified variants that may assist in the diagnosis of at least 6.3% of autopsy-negative child SUD cases and reduce risk of future SUD in surviving relatives. We recommend a cautious approach to variant interpretation. We also suggest inclusion of cardiomyopathy genes as well as other candidate SUD genes in molecular autopsy analyses. PMID- 28807991 TI - Torque depression following active shortening is associated with a modulation of cortical and spinal excitation: a history-dependent study. AB - The reduction in steady-state isometric torque following a shortening muscle action when compared to a purely isometric contraction at the same muscle length and level of activation is termed torque depression (TD). The purpose of this study was to investigate spinal and supraspinal neural responses during the TD state of a maximal voluntary activation of the ankle dorsiflexors. Thirteen subjects (10 male) were recruited for the study. To explore alterations in corticospinal excitability during voluntary muscle activation in the TD state, motor evoked potentials (MEPs), cervicomedullary motor evoked potentials (CMEPs), and maximal compound muscle action potentials (Mmax) were elicited during the isometric steady-state following active shortening (i.e., TD) and the purely isometric condition. A 15% reduction in steady-state isometric torque (P < 0.05) was observed following isokinetic shortening at 40 degrees /sec. Although mean evoked responses (MEP and CMEP) were not different in the TD state as compared with purely isometric state, the changes in evoked responses were inversely related to one another depending on the level of TD These findings indicate that supraspinal and spinal responses are interrelated in the TD state. Furthermore, antagonist muscle coactivation during the isometric reference contraction was positively related to TD These findings suggest the possibility of a relationship between the central nervous system and TD in humans. Further work should be performed to definitively link TD to specific spinal interneurons. PMID- 28807992 TI - A Midsummer Night's Strange Reality. AB - After GOP efforts to repeal and replace the ACA collapsed in the Senate, attention is focused on whether cost-sharing reduction payments will continue. PMID- 28807993 TI - Nine unanswered questions about cytokinesis. AB - Experiments on model systems have revealed that cytokinesis in cells with contractile rings (amoebas, fungi, and animals) depends on shared molecular mechanisms in spite of some differences that emerged during a billion years of divergent evolution. Understanding these fundamental mechanisms depends on identifying the participating proteins and characterizing the mechanisms that position the furrow, assemble the contractile ring, anchor the ring to the plasma membrane, trigger ring constriction, produce force to form a furrow, disassemble the ring, expand the plasma membrane in the furrow, and separate the daughter cell membranes. This review reveals that fascinating questions remain about each step. PMID- 28807994 TI - A Novel Computational Model Predicts Key Regulators of Chemokine Gradient Formation in Lymph Nodes and Site-Specific Roles for CCL19 and ACKR4. AB - The chemokine receptor CCR7 drives leukocyte migration into and within lymph nodes (LNs). It is activated by chemokines CCL19 and CCL21, which are scavenged by the atypical chemokine receptor ACKR4. CCR7-dependent navigation is determined by the distribution of extracellular CCL19 and CCL21, which form concentration gradients at specific microanatomical locations. The mechanisms underpinning the establishment and regulation of these gradients are poorly understood. In this article, we have incorporated multiple biochemical processes describing the CCL19 CCL21-CCR7-ACKR4 network into our model of LN fluid flow to establish a computational model to investigate intranodal chemokine gradients. Importantly, the model recapitulates CCL21 gradients observed experimentally in B cell follicles and interfollicular regions, building confidence in its ability to accurately predict intranodal chemokine distribution. Parameter variation analysis indicates that the directionality of these gradients is robust, but their magnitude is sensitive to these key parameters: chemokine production, diffusivity, matrix binding site availability, and CCR7 abundance. The model indicates that lymph flow shapes intranodal CCL21 gradients, and that CCL19 is functionally important at the boundary between B cell follicles and the T cell area. It also predicts that ACKR4 in LNs prevents CCL19/CCL21 accumulation in efferent lymph, but does not control intranodal gradients. Instead, it attributes the disrupted interfollicular CCL21 gradients observed in Ackr4-deficient LNs to ACKR4 loss upstream. Our novel approach has therefore generated new testable hypotheses and alternative interpretations of experimental data. Moreover, it acts as a framework to investigate gradients at other locations, including those that cannot be visualized experimentally or involve other chemokines. PMID- 28807995 TI - Regulation of the Cell Cycle and Inflammatory Arthritis by the Transcription Cofactor LBH Gene. AB - Rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) display unique aggressive behavior, invading the articular cartilage and promoting inflammation. Using an integrative analysis of RA risk alleles, the transcriptome and methylome in RA FLS, we recently identified the limb bud and heart development (LBH) gene as a key dysregulated gene in RA and other autoimmune diseases. Although some evidence suggests that LBH could modulate the cell cycle, the precise mechanism is unknown and its impact on inflammation in vivo has not been defined. Our cell cycle analysis studies show that LBH deficiency in FLS leads to S-phase arrest and failure to progress through the cell cycle. LBH-deficient FLS had increased DNA damage and reduced expression of the catalytic subunit of DNA polymerase alpha. Decreased DNA polymerase alpha was followed by checkpoint arrest due to phosphorylation of checkpoint kinase 1. Because DNA fragments can increase arthritis severity in preclinical models, we then explored the effect of LBH deficiency in the K/BxN serum transfer model. Lbh knockout exacerbated disease severity, which is associated with elevated levels of IL-1beta and checkpoint kinase 1 phosphorylation. These studies indicate that LBH deficiency induces S phase arrest that, in turn, exacerbates inflammation. Because LBH gene variants are associated with type I diabetes mellitus, systemic lupus erythematosus, RA, and celiac disease, these results suggest a general mechanism that could contribute to immune-mediated diseases. PMID- 28807996 TI - Klhl6 Deficiency Impairs Transitional B Cell Survival and Differentiation. AB - Klhl6 belongs to the KLHL gene family, which is composed of an N-terminal BTB-POZ domain and four to six Kelch motifs in tandem. Several of these proteins function as adaptors of the Cullin3 E3 ubiquitin ligase complex. In this article, we report that Klhl6 deficiency induces, as previously described, a 2-fold reduction in mature B cells. However, we find that this deficit is centered on the inability of transitional type 1 B cells to survive and to progress toward the transitional type 2 B cell stage, whereas cells that have passed this step generate normal germinal centers (GCs) upon a T-dependent immune challenge. Klhl6 deficient type 1 B cells showed a 2-fold overexpression of genes linked with cell proliferation, including most targets of the anaphase-promoting complex/cyclosome complex, a set of genes whose expression is precisely downmodulated upon culture of splenic transitional B cells in the presence of BAFF. These results thus suggest a delay in the differentiation process of Klhl6-deficient B cells between the immature and transitional stage. We further show, in the BL2 Burkitt's lymphoma cell line, that KLHL6 interacts with Cullin3, but also that it binds to HBXIP/Lamtor5, a protein involved in cell-cycle regulation and cytokinesis. Finally, we report that KLHL6, which is recurrently mutated in B cell lymphomas, is an off-target of the normal somatic hypermutation process taking place in GC B cells in both mice and humans, thus leaving open whether, despite the lack of impact of Klhl6 deficiency on GC B cell expansion, mutants could contribute to the oncogenic process. PMID- 28807997 TI - Phosphoantigen-induced conformational change of butyrophilin 3A1 (BTN3A1) and its implication on Vgamma9Vdelta2 T cell activation. AB - Human Vgamma9Vdelta2 T cells respond to microbial infections as well as certain types of tumors. The key initiators of Vgamma9Vdelta2 activation are small, pyrophosphate-containing molecules called phosphoantigens (pAgs) that are present in infected cells or accumulate intracellularly in certain tumor cells. Recent studies demonstrate that initiation of the Vgamma9Vdelta2 T cell response begins with sensing of pAg via the intracellular domain of the butyrophilin 3A1 (BTN3A1) molecule. However, it is unknown how downstream events can ultimately lead to T cell activation. Here, using NMR spectrometry and molecular dynamics (MD) simulations, we characterize a global conformational change in the B30.2 intracellular domain of BTN3A1 induced by pAg binding. We also reveal by crystallography two distinct dimer interfaces in the BTN3A1 full-length intracellular domain, which are stable in MD simulations. These interfaces lie in close proximity to the pAg-binding pocket and contain clusters of residues that experience major changes of chemical environment upon pAg binding. This suggests that pAg binding disrupts a preexisting conformation of the BTN3A1 intracellular domain. Using a combination of biochemical, structural, and cellular approaches we demonstrate that the extracellular domains of BTN3A1 adopt a V-shaped conformation at rest, and that locking them in this resting conformation without perturbing their membrane reorganization properties diminishes pAg-induced T cell activation. Based on these results, we propose a model in which a conformational change in BTN3A1 is a key event of pAg sensing that ultimately leads to T cell activation. PMID- 28807999 TI - Role of co-occurring competition and facilitation in plant spacing hydrodynamics in water-limited environments. AB - Plant performance (i.e., fecundity, growth, survival) depends on an individual's access to space and resources. At the community level, plant performance is reflected in observable vegetation patterning (i.e., spacing distance, density) often controlled by limiting resources. Resource availability is, in turn, strongly dependent on plant patterning mediated by competitive and facilitative plant-plant interactions. Co-occurring competition and facilitation has never been specifically investigated from a hydrodynamic perspective. To address this knowledge gap, and to overcome limitations of field studies, three intermediate scale laboratory experiments were conducted using a climate-controlled wind tunnel-porous media test facility to simulate the soil-plant-atmosphere continuum. The spacing between two synthetic plants, a design consideration introduced by the authors in a recent publication, was varied between experiments; edaphic and mean atmospheric conditions were held constant. The strength of the above- and belowground plant-plant interactions changed with spacing distance, allowing the creation of a hydrodynamic conceptual model based on established ecological theories. Greatest soil water loss was observed for the experiment with the smallest spacing where competition dominated. Facilitation dominated at the intermediate spacing; little to no interactions were observed for the largest plant spacing. Results suggest that there exists an optimal spacing distance range that lowers plant environmental stress, thus improving plant performance through reduced atmospheric demand and conservation of available soil water. These findings may provide a foundation for improving our understanding of many climatological, ecohydrological, and hydrological problems pertaining to the hydrodynamics of water-limited environments where plant-plant interactions and community self-organization are important. PMID- 28807998 TI - Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) is a lineage C betacoronavirus that since its emergence in 2012 has caused outbreaks in human populations with case-fatality rates of ~36%. As in other coronaviruses, the spike (S) glycoprotein of MERS-CoV mediates receptor recognition and membrane fusion and is the primary target of the humoral immune response during infection. Here we use structure-based design to develop a generalizable strategy for retaining coronavirus S proteins in the antigenically optimal prefusion conformation and demonstrate that our engineered immunogen is able to elicit high neutralizing antibody titers against MERS-CoV. We also determined high-resolution structures of the trimeric MERS-CoV S ectodomain in complex with G4, a stem directed neutralizing antibody. The structures reveal that G4 recognizes a glycosylated loop that is variable among coronaviruses and they define four conformational states of the trimer wherein each receptor-binding domain is either tightly packed at the membrane-distal apex or rotated into a receptor accessible conformation. Our studies suggest a potential mechanism for fusion initiation through sequential receptor-binding events and provide a foundation for the structure-based design of coronavirus vaccines. PMID- 28808000 TI - Vibrio cholerae type 6 secretion system effector trafficking in target bacterial cells. AB - The type 6 secretion system (T6SS) is used by many Gram-negative bacterial species to deliver toxic effector proteins into nearby bacteria prey cells to kill or inhibit their growth. VgrG proteins are core conserved secretion substrates of the T6SS and one subset of T6SS effectors consists of VgrG proteins with C-terminal extension domains carrying various enzymatic activities. In Vibrio cholerae, VgrG3 has a hydrolase extension domain and degrades peptidoglycan in the periplasm of target bacteria. In this study, we replaced this domain with a nuclease domain from Salmonella enterica subsp. arizonae This modified V. cholerae strain was able to kill its parent using its T6SS. This result also demonstrated that V. cholerae T6SS is capable of delivering effectors that could attack substrates found either in the periplasm or cytosol of target bacteria. Additionally, we found that effectors VgrG3 and TseL, despite lacking a classical Sec or TAT secretion signal, were able to reach the periplasm when expressed in the bacterial cytosol. This effector trafficking likely represents an evolutionary strategy for T6SS effectors to reach their intended substrates regardless of which subcellular compartment in the target cell they happen to be delivered to by the T6SS apparatus. PMID- 28808001 TI - Two transmembrane dimers of the bovine papillomavirus E5 oncoprotein clamp the PDGF beta receptor in an active dimeric conformation. AB - The dimeric 44-residue E5 protein of bovine papillomavirus is the smallest known naturally occurring oncoprotein. This transmembrane protein binds to the transmembrane domain (TMD) of the platelet-derived growth factor beta receptor (PDGFbetaR), causing dimerization and activation of the receptor. Here, we use Rosetta membrane modeling and all-atom molecular dynamics simulations in a membrane environment to develop a chemically detailed model of the E5 protein/PDGFbetaR complex. In this model, an active dimer of the PDGFbetaR TMD is sandwiched between two dimers of the E5 protein. Biochemical experiments showed that the major PDGFbetaR TMD complex in mouse cells contains two E5 dimers and that binding the PDGFbetaR TMD to the E5 protein is necessary and sufficient to recruit both E5 dimers into the complex. These results demonstrate how E5 binding induces receptor dimerization and define a molecular mechanism of receptor activation based on specific interactions between TMDs. PMID- 28808002 TI - Optimized strategy for in vivo Cas9-activation in Drosophila. AB - While several large-scale resources are available for in vivo loss-of-function studies in Drosophila, an analogous resource for overexpressing genes from their endogenous loci does not exist. We describe a strategy for generating such a resource using Cas9 transcriptional activators (CRISPRa). First, we compare a panel of CRISPRa approaches and demonstrate that, for in vivo studies, dCas9-VPR is the most optimal activator. Next, we demonstrate that this approach is scalable and has a high success rate, as >75% of the lines tested activate their target gene. We show that CRISPRa leads to physiologically relevant levels of target gene expression capable of generating strong gain-of-function (GOF) phenotypes in multiple tissues and thus serves as a useful platform for genetic screening. Based on the success of this CRISRPa approach, we are generating a genome-wide collection of flies expressing single-guide RNAs (sgRNAs) for CRISPRa. We also present a collection of more than 30 Gal4 > UAS:dCas9-VPR lines to aid in using these sgRNA lines for GOF studies in vivo. PMID- 28808003 TI - Signaling from the plasma-membrane localized plant immune receptor RPM1 requires self-association of the full-length protein. AB - Plants evolved intracellular immune receptors that belong to the NOD-like receptor (NLR) family to recognize the presence of pathogen-derived effector proteins. NLRs possess an N-terminal Toll-like/IL-1 receptor (TIR) or a non-TIR domain [some of which contain coiled coils (CCs)], a central nucleotide-binding (NB-ARC) domain, and a C-terminal leucine-rich repeat (LRR). Activation of NLR proteins results in a rapid and high-amplitude immune response, eventually leading to host cell death at the infection site, the so-called hypersensitive response. Despite their important contribution to immunity, the exact mechanisms of NLR activation and signaling remain unknown and are likely heterogenous. We undertook a detailed structure-function analysis of the plasma membrane (PM) localized CC NLR Resistance to Pseudomonas syringae pv. maculicola 1 (RPM1) using both stable transgenic Arabidopsis and transient expression in Nicotiana benthamiana We report that immune signaling is induced only by activated full length PM-localized RPM1. Our interaction analyses demonstrate the importance of a functional P-loop for in planta interaction of RPM1 with the small host protein RPM1-interacting protein 4 (RIN4), for constitutive preactivation and postactivation self-association of RPM1 and for proper PM localization. Our results reveal an additive effect of hydrophobic conserved residues in the CC domain for RPM1 function and RPM1 self-association and their necessity for RPM1 RIN4 interaction. Thus, our findings considerably extend our understanding of the mechanisms regulating NLR activation at, and signaling from, the PM. PMID- 28808004 TI - Critical structural fluctuations of proteins upon thermal unfolding challenge the Lindemann criterion. AB - Internal subnanosecond timescale motions are key for the function of proteins, and are coupled to the surrounding solvent environment. These fast fluctuations guide protein conformational changes, yet their role for protein stability, and for unfolding, remains elusive. Here, in analogy with the Lindemann criterion for the melting of solids, we demonstrate a common scaling of structural fluctuations of lysozyme protein embedded in different environments as the thermal unfolding transition is approached. By combining elastic incoherent neutron scattering and advanced molecular simulations, we show that, although different solvents modify the protein melting temperature, a unique dynamical regime is attained in proximity of thermal unfolding in all solvents that we tested. This solvation shell-independent dynamical regime arises from an equivalent sampling of the energy landscape at the respective melting temperatures. Thus, we propose that a threshold for the conformational entropy provided by structural fluctuations of proteins exists, beyond which thermal unfolding is triggered. PMID- 28808005 TI - Conformational dynamics of 1-deoxy-d-xylulose 5-phosphate synthase on ligand binding revealed by H/D exchange MS. AB - The enzyme 1-deoxy-d-xylulose 5-phosphate synthase (DXPS) is a key enzyme in the methylerythritol 4-phosphate pathway and is a target for the development of antibiotics, herbicides, and antimalarial drugs. DXPS catalyzes the formation of 1-deoxy-d-xylulose 5-phosphate (DXP), a branch point metabolite in isoprenoid biosynthesis, and is also used in the biosynthesis of thiamin (vitamin B1) and pyridoxal (vitamin B6). Previously, we found that DXPS is unique among the superfamily of thiamin diphosphate (ThDP)-dependent enzymes in stabilizing the predecarboxylation intermediate, C2-alpha-lactyl-thiamin diphosphate (LThDP), which has subsequent decarboxylation that is triggered by d-glyceraldehyde 3 phosphate (GAP). Herein, we applied hydrogen-deuterium (H/D) exchange MS (HDX-MS) of full-length Escherichia coli DXPS to provide a snapshot of the conformational dynamics of this enzyme, leading to the following conclusions. (i) The high sequence coverage of DXPS allowed us to monitor structural changes throughout the entire enzyme, including two segments (spanning residues 183-238 and 292-317) not observed by X-ray crystallography. (ii) Three regions of DXPS (spanning residues 42-58, 183-199, and 278-298) near the active center displayed both EX1 (monomolecular) and EX2 (bimolecuar) H/D exchange (HDX) kinetic behavior in both ligand-free and ligand-bound states. All other peptides behaved according to the common EX2 kinetic mechanism. (iii) The observation of conformational changes on DXPS provides support for the role of conformational dynamics in the DXPS mechanism: The closed conformation of DXPS is critical for stabilization of LThDP, whereas addition of GAP converts DXPS to the open conformation that coincides with decarboxylation of LThDP and DXP release. PMID- 28808006 TI - Impact of catch shares on diversification of fishers' income and risk. AB - Many fishers diversify their income by participating in multiple fisheries, which has been shown to significantly reduce year-to-year variation in income. The ability of fishers to diversify has become increasingly constrained in the last few decades, and catch share programs could further reduce diversification as a result of consolidation. This could increase income variation and thus financial risk. However, catch shares can also offer fishers opportunities to enter or increase participation in catch share fisheries by purchasing or leasing quota. Thus, the net effect on diversification is uncertain. We tested whether diversification and variation in fishing revenues changed after implementation of catch shares for 6,782 vessels in 13 US fisheries that account for 20% of US landings revenue. For each of these fisheries, we tested whether diversification levels, trends, and variation in fishing revenues changed after implementation of catch shares, both for fishers that remained in the catch share fishery and for those that exited but remained active in other fisheries. We found that diversification for both groups was nearly always reduced. However, in most cases, we found no significant change in interannual variation of revenues, and, where changes were significant, variation decreased nearly as often as it increased. PMID- 28808007 TI - Early photosynthetic eukaryotes inhabited low-salinity habitats. AB - The early evolutionary history of the chloroplast lineage remains an open question. It is widely accepted that the endosymbiosis that established the chloroplast lineage in eukaryotes can be traced back to a single event, in which a cyanobacterium was incorporated into a protistan host. It is still unclear, however, which Cyanobacteria are most closely related to the chloroplast, when the plastid lineage first evolved, and in what habitats this endosymbiotic event occurred. We present phylogenomic and molecular clock analyses, including data from cyanobacterial and chloroplast genomes using a Bayesian approach, with the aim of estimating the age for the primary endosymbiotic event, the ages of crown groups for photosynthetic eukaryotes, and the independent incorporation of a cyanobacterial endosymbiont by Paulinella Our analyses include both broad taxon sampling (119 taxa) and 18 fossil calibrations across all Cyanobacteria and photosynthetic eukaryotes. Phylogenomic analyses support the hypothesis that the chloroplast lineage diverged from its closet relative Gloeomargarita, a basal cyanobacterial lineage, ~2.1 billion y ago (Bya). Our analyses suggest that the Archaeplastida, consisting of glaucophytes, red algae, green algae, and land plants, share a common ancestor that lived ~1.9 Bya. Whereas crown group Rhodophyta evolved in the Mesoproterozoic Era (1,600-1,000 Mya), crown groups Chlorophyta and Streptophyta began to radiate early in the Neoproterozoic (1,000 542 Mya). Stochastic mapping analyses indicate that the first endosymbiotic event occurred in low-salinity environments. Both red and green algae colonized marine environments early in their histories, with prasinophyte green phytoplankton diversifying 850-650 Mya. PMID- 28808008 TI - Mathematical model reveals role of nucleotide signaling in airway surface liquid homeostasis and its dysregulation in cystic fibrosis. AB - Mucociliary clearance is composed of three components (i.e., mucin secretion, airway surface hydration, and ciliary-activity) which function coordinately to clear inhaled microbes and other foreign particles from airway surfaces. Airway surface hydration is maintained by water fluxes driven predominantly by active chloride and sodium ion transport. The ion channels that mediate electrogenic ion transport are regulated by extracellular purinergic signals that signal through G protein-coupled receptors. These purinoreceptors and the signaling pathways they activate have been identified as possible therapeutic targets for treating lung disease. A systems-level description of airway surface liquid (ASL) homeostasis could accelerate development of such therapies. Accordingly, we developed a mathematical model to describe the dynamic coupling of ion and water transport to extracellular purinergic signaling. We trained our model from steady-state and time-dependent experimental measurements made using normal and cystic fibrosis (CF) cultured human airway epithelium. To reproduce CF conditions, reduced chloride secretion, increased potassium secretion, and increased sodium absorption were required. The model accurately predicted ASL height under basal normal and CF conditions and the collapse of surface hydration due to the accelerated nucleotide metabolism associated with CF exacerbations. Finally, the model predicted a therapeutic strategy to deliver nucleotide receptor agonists to effectively rehydrate the ASL of CF airways. PMID- 28808009 TI - A protein complex regulates RNA processing of intronic heterochromatin-containing genes in Arabidopsis. AB - In several eukaryotic organisms, heterochromatin (HC) in the introns of genes can regulate RNA processing, including polyadenylation, but the mechanism underlying this regulation is poorly understood. By promoting distal polyadenylation, the bromo-adjacent homology (BAH) domain-containing and RNA recognition motif containing protein ASI1 and the H3K9me2-binding protein EDM2 are required for the expression of functional full-length transcripts of intronic HC-containing genes in Arabidopsis Here we report that ASI1 and EDM2 form a protein complex in vivo via a bridge protein, ASI1-Immunoprecipitated Protein 1 (AIPP1), which is another RNA recognition motif-containing protein. The complex also may contain the Pol II CTD phosphatase CPL2, the plant homeodomain-containing protein AIPP2, and another BAH domain protein, AIPP3. As is the case with dysfunction of ASI1 and EDM2, dysfunction of AIPP1 impedes the use of distal polyadenylation sites at tested intronic HC-containing genes, such as the histone demethylase gene IBM1, resulting in a lack of functional full-length transcripts. A mutation in AIPP1 causes silencing of the 35S-SUC2 transgene and genome-wide CHG hypermethylation at gene body regions, consistent with the lack of full-length functional IBM1 transcripts in the mutant. Interestingly, compared with asi1, edm2, and aipp1 mutations, mutations in CPL2, AIPP2, and AIPP3 cause the opposite effects on the expression of intronic HC-containing genes and other genes, suggesting that CPL2, AIPP2, and AIPP3 may form a distinct subcomplex. These results advance our understanding of the interplay between heterochromatic epigenetic modifications and RNA processing in higher eukaryotes. PMID- 28808011 TI - Behavioral responses to annual temperature variation alter the dominant energy pathway, growth, and condition of a cold-water predator. AB - There is a pressing need to understand how ecosystems will respond to climate change. To date, no long-term empirical studies have confirmed that fish populations exhibit adaptive foraging behavior in response to temperature variation and the potential implications this has on fitness. Here, we use an unparalleled 11-y acoustic telemetry, stable isotope, and mark-recapture dataset to test if a population of lake trout (Salvelinus namaycush), a cold-water stenotherm, adjusted its use of habitat and energy sources in response to annual variations in lake temperatures during the open-water season and how these changes translated to the growth and condition of individual fish. We found that climate influenced access to littoral regions in spring (data from telemetry), which in turn influenced energy acquisition (data from isotopes), and growth (mark-recapture data). In more stressful years, those with shorter springs and longer summers, lake trout had reduced access to littoral habitat and assimilated less littoral energy, resulting in reduced growth and condition. Annual variation in prey abundance influenced lake trout foraging tactics (i.e., the balance of the number and duration of forays) but not the overall time spent in littoral regions. Lake trout greatly reduced their use of littoral habitat and occupied deep pelagic waters during the summer. Together, our results provide clear evidence that climate-mediated behavior can influence the dominant energy pathways of top predators, with implications ranging from individual fitness to food web stability. PMID- 28808010 TI - Voltage-gated calcium flux mediates Escherichia coli mechanosensation. AB - Electrically excitable cells harness voltage-coupled calcium influx to transmit intracellular signals, typically studied in neurons and cardiomyocytes. Despite intense study in higher organisms, investigations of voltage and calcium signaling in bacteria have lagged due to their small size and a lack of sensitive tools. Only recently were bacteria shown to modulate their membrane potential on the timescale of seconds, and little is known about the downstream effects from this modulation. In this paper, we report on the effects of electrophysiology in individual bacteria. A genetically encoded calcium sensor expressed in Escherichia coli revealed calcium transients in single cells. A fusion sensor that simultaneously reports voltage and calcium indicated that calcium influx is induced by voltage depolarizations, similar to metazoan action potentials. Cytoplasmic calcium levels and transients increased upon mechanical stimulation with a hydrogel, and single cells altered protein concentrations dependent on the mechanical environment. Blocking voltage and calcium flux altered mechanically induced changes in protein concentration, while inducing calcium flux reproduced these changes. Thus, voltage and calcium relay a bacterial sense of touch and alter cellular lifestyle. Although the calcium effectors remain unknown, these data open a host of new questions about E. coli, including the identity of the underlying molecular players, as well as other signals conveyed by voltage and calcium. These data also provide evidence that dynamic voltage and calcium exists as a signaling modality in the oldest domain of life, and therefore studying electrophysiology beyond canonical electrically excitable cells could yield exciting new findings. PMID- 28808012 TI - BDNF-TrkB controls cocaine-induced dendritic spines in rodent nucleus accumbens dissociated from increases in addictive behaviors. AB - Chronic cocaine use is associated with prominent morphological changes in nucleus accumbens shell (NACsh) neurons, including increases in dendritic spine density along with enhanced motivation for cocaine, but a functional relationship between these morphological and behavioral phenomena has not been shown. Here we show that brain-derived neurotrophic factor (BDNF) signaling through tyrosine kinase B (TrkB) receptors in NACsh neurons is necessary for cocaine-induced dendritic spine formation by using either localized TrkB knockout or viral-mediated expression of a dominant negative, kinase-dead TrkB mutant. Interestingly, augmenting wild-type TrkB expression after chronic cocaine self-administration reverses the sustained increase in dendritic spine density, an effect mediated by TrkB signaling pathways that converge on extracellular regulated kinase. Loss of TrkB function after cocaine self-administration, however, leaves spine density intact but markedly enhances the motivation for cocaine, an effect mediated by specific loss of TrkB signaling through phospholipase Cgamma1 (PLCgamma1). Conversely, overexpression of PLCgamma1 both reduces the motivation for cocaine and reverses dendritic spine density, suggesting a potential target for the treatment of addiction in chronic users. Together, these findings indicate that BDNF-TrkB signaling both mediates and reverses cocaine-induced increases in dendritic spine density in NACsh neurons, and these morphological changes are entirely dissociable from changes in addictive behavior. PMID- 28808013 TI - Disaggregating sorghum yield reductions under warming scenarios exposes narrow genetic diversity in US breeding programs. AB - Historical adaptation of sorghum production to arid and semiarid conditions has provided promise regarding its sustained productivity under future warming scenarios. Using Kansas field-trial sorghum data collected from 1985 to 2014 and spanning 408 hybrid cultivars, we show that sorghum productivity under increasing warming scenarios breaks down. Through extensive regression modeling, we identify a temperature threshold of 33 degrees C, beyond which yields start to decline. We show that this decline is robust across both field-trial and on-farm data. Moderate and higher warming scenarios of 2 degrees C and 4 degrees C resulted in roughly 17% and 44% yield reductions, respectively. The average reduction across warming scenarios from 1 to 5 degrees C is 10% per degree Celsius. Breeding efforts over the last few decades have developed high-yielding cultivars with considerable variability in heat resilience, but even the most tolerant cultivars did not offer much resilience to warming temperatures. This outcome points to two concerns regarding adaption to global warming, the first being that adaptation will not be as simple as producers' switching among currently available cultivars and the second being that there is currently narrow genetic diversity for heat resilience in US breeding programs. Using observed flowering dates and disaggregating heat-stress impacts, both pre- and postflowering stages were identified to be equally important for overall yields. These findings suggest the adaptation potential for sorghum under climate change would be greatly facilitated by introducing wider genetic diversity for heat resilience into ongoing breeding programs, and that there should be additional efforts to improve resilience during the preflowering phase. PMID- 28808014 TI - Adaptive benefit of cross-modal plasticity following cochlear implantation in deaf adults. AB - It has been suggested that visual language is maladaptive for hearing restoration with a cochlear implant (CI) due to cross-modal recruitment of auditory brain regions. Rehabilitative guidelines therefore discourage the use of visual language. However, neuroscientific understanding of cross-modal plasticity following cochlear implantation has been restricted due to incompatibility between established neuroimaging techniques and the surgically implanted electronic and magnetic components of the CI. As a solution to this problem, here we used functional near-infrared spectroscopy (fNIRS), a noninvasive optical neuroimaging method that is fully compatible with a CI and safe for repeated testing. The aim of this study was to examine cross-modal activation of auditory brain regions by visual speech from before to after implantation and its relation to CI success. Using fNIRS, we examined activation of superior temporal cortex to visual speech in the same profoundly deaf adults both before and 6 mo after implantation. Patients' ability to understand auditory speech with their CI was also measured following 6 mo of CI use. Contrary to existing theory, the results demonstrate that increased cross-modal activation of auditory brain regions by visual speech from before to after implantation is associated with better speech understanding with a CI. Furthermore, activation of auditory cortex by visual and auditory speech developed in synchrony after implantation. Together these findings suggest that cross-modal plasticity by visual speech does not exert previously assumed maladaptive effects on CI success, but instead provides adaptive benefits to the restoration of hearing after implantation through an audiovisual mechanism. PMID- 28808015 TI - A p53-dependent response limits the viability of mammalian haploid cells. AB - The recent development of haploid cell lines has facilitated forward genetic screenings in mammalian cells. These lines include near-haploid human cell lines isolated from a patient with chronic myelogenous leukemia (KBM7 and HAP1), as well as haploid embryonic stem cells derived from several organisms. In all cases, haploidy was shown to be an unstable state, so that cultures of mammalian haploid cells rapidly become enriched in diploids. Here we show that the observed diploidization is due to a proliferative disadvantage of haploid cells compared with diploid cells. Accordingly, single-cell-sorted haploid mammalian cells maintain the haploid state for prolonged periods, owing to the absence of competing diploids. Although the duration of interphase is similar in haploid and diploid cells, haploid cells spend longer in mitosis, indicative of problems in chromosome segregation. In agreement with this, a substantial proportion of the haploids die at or shortly after the last mitosis through activation of a p53 dependent cytotoxic response. Finally, we show that p53 deletion stabilizes haploidy in human HAP1 cells and haploid mouse embryonic stem cells. We propose that, similar to aneuploidy or tetraploidy, haploidy triggers a p53-dependent response that limits the fitness of mammalian cells. PMID- 28808016 TI - Hydrodynamics of microbial filter feeding. AB - Microbial filter feeders are an important group of grazers, significant to the microbial loop, aquatic food webs, and biogeochemical cycling. Our understanding of microbial filter feeding is poor, and, importantly, it is unknown what force microbial filter feeders must generate to process adequate amounts of water. Also, the trade-off in the filter spacing remains unexplored, despite its simple formulation: A filter too coarse will allow suitably sized prey to pass unintercepted, whereas a filter too fine will cause strong flow resistance. We quantify the feeding flow of the filter-feeding choanoflagellate Diaphanoeca grandis using particle tracking, and demonstrate that the current understanding of microbial filter feeding is inconsistent with computational fluid dynamics (CFD) and analytical estimates. Both approaches underestimate observed filtration rates by more than an order of magnitude; the beating flagellum is simply unable to draw enough water through the fine filter. We find similar discrepancies for other choanoflagellate species, highlighting an apparent paradox. Our observations motivate us to suggest a radically different filtration mechanism that requires a flagellar vane (sheet), something notoriously difficult to visualize but sporadically observed in the related choanocytes (sponges). A CFD model with a flagellar vane correctly predicts the filtration rate of D. grandis, and using a simple model we can account for the filtration rates of other microbial filter feeders. We finally predict how optimum filter mesh size increases with cell size in microbial filter feeders, a prediction that accords very well with observations. We expect our results to be of significance for small-scale biophysics and trait-based ecological modeling. PMID- 28808017 TI - Antitumor effect of Batf2 through IL-12 p40 up-regulation in tumor-associated macrophages. AB - The development of effective treatments against cancers is urgently needed, and the accumulation of CD8+ T cells within tumors is especially important for cancer prognosis. Although their mechanisms are still largely unknown, growing evidence has indicated that innate immune cells have important effects on cancer progression through the production of various cytokines. Here, we found that basic leucine zipper transcription factor ATF-like 2 (Batf2) has an antitumor effect. An s.c. inoculated tumor model produced fewer IL-12 p40+ macrophages and activated CD8+ T cells within the tumors of Batf2-/- mice compared with WT mice. In vitro studies also revealed that the IL-12 p40 expression was significantly lower in Batf2-/- macrophages following their stimulation by toll-like receptor ligands, such as R848. Additionally, we found that BATF2 interacts with p50/p65 and promotes IL-12 p40 expression. In conclusion, Batf2 has an antitumor effect through the up-regulation of IL-12 p40 in tumor-associated macrophages, which eventually induces CD8+ T-cell activation and accumulation within the tumor. PMID- 28808018 TI - A genome Tree of Life for the Fungi kingdom. AB - Fungi belong to one of the largest and most diverse kingdoms of living organisms. The evolutionary kinship within a fungal population has so far been inferred mostly from the gene-information-based trees ("gene trees"), constructed commonly based on the degree of differences of proteins or DNA sequences of a small number of highly conserved genes common among the population by a multiple sequence alignment (MSA) method. Since each gene evolves under different evolutionary pressure and time scale, it has been known that one gene tree for a population may differ from other gene trees for the same population depending on the subjective selection of the genes. Within the last decade, a large number of whole-genome sequences of fungi have become publicly available, which represent, at present, the most fundamental and complete information about each fungal organism. This presents an opportunity to infer kinship among fungi using a whole genome information-based tree ("genome tree"). The method we used allows comparison of whole-genome information without MSA, and is a variation of a computational algorithm developed to find semantic similarities or plagiarism in two books, where we represent whole-genomic information of an organism as a book of words without spaces. The genome tree reveals several significant and notable differences from the gene trees, and these differences invoke new discussions about alternative narratives for the evolution of some of the currently accepted fungal groups. PMID- 28808019 TI - Next step in the ongoing arms race between myxoma virus and wild rabbits in Australia is a novel disease phenotype. AB - In host-pathogen arms races, increases in host resistance prompt counteradaptation by pathogens, but the nature of that counteradaptation is seldom directly observed outside of laboratory models. The best-documented field example is the coevolution of myxoma virus (MYXV) in European rabbits. To understand how MYXV in Australia has continued to evolve in wild rabbits under intense selection for genetic resistance to myxomatosis, we compared the phenotypes of the progenitor MYXV and viral isolates from the 1950s and the 1990s in laboratory rabbits with no resistance. Strikingly, and unlike their 1950s counterparts, most virus isolates from the 1990s induced a highly lethal immune collapse syndrome similar to septic shock. Thus, the next step in this canonical case of coevolution after a species jump has been further escalation by the virus in the face of widespread host resistance. PMID- 28808020 TI - KCNE1 and KCNE3 modulate KCNQ1 channels by affecting different gating transitions. AB - KCNE beta-subunits assemble with and modulate the properties of voltage-gated K+ channels. In the heart, KCNE1 associates with the alpha-subunit KCNQ1 to generate the slowly activating, voltage-dependent potassium current (IKs) in the heart that controls the repolarization phase of cardiac action potentials. By contrast, in epithelial cells from the colon, stomach, and kidney, KCNE3 coassembles with KCNQ1 to form K+ channels that are voltage-independent K+ channels in the physiological voltage range and important for controlling water and salt secretion and absorption. How KCNE1 and KCNE3 subunits modify KCNQ1 channel gating so differently is largely unknown. Here, we use voltage clamp fluorometry to determine how KCNE1 and KCNE3 affect the voltage sensor and the gate of KCNQ1. By separating S4 movement and gate opening by mutations or phosphatidylinositol 4,5-bisphosphate depletion, we show that KCNE1 affects both the S4 movement and the gate, whereas KCNE3 affects the S4 movement and only affects the gate in KCNQ1 if an intact S4-to-gate coupling is present. Further, we show that a triple mutation in the middle of the transmembrane (TM) segment of KCNE3 introduces KCNE1-like effects on the second S4 movement and the gate. In addition, we show that differences in two residues at the external end of the KCNE TM segments underlie differences in the effects of the different KCNEs on the first S4 movement and the voltage sensor-to-gate coupling. PMID- 28808021 TI - Kinetic and high-throughput profiling of epigenetic interactions by 3D-carbene chip-based surface plasmon resonance imaging technology. AB - Chemical modifications on histones and DNA/RNA constitute a fundamental mechanism for epigenetic regulation. These modifications often function as docking marks to recruit or stabilize cognate "reader" proteins. So far, a platform for quantitative and high-throughput profiling of the epigenetic interactome is urgently needed but still lacking. Here, we report a 3D-carbene chip-based surface plasmon resonance imaging (SPRi) technology for this purpose. The 3D carbene chip is suitable for immobilizing versatile biomolecules (e.g., peptides, antibody, DNA/RNA) and features low nonspecific binding, random yet function retaining immobilization, and robustness for reuses. We systematically profiled binding kinetics of 1,000 histone "reader-mark" pairs on a single 3D-carbene chip and validated two recognition events by calorimetric and structural studies. Notably, a discovery on H3K4me3 recognition by the DNA mismatch repair protein MSH6 in Capsella rubella suggests a mechanism of H3K4me3-mediated DNA damage repair in plant. PMID- 28808022 TI - Genomic evidence reveals a radiation of placental mammals uninterrupted by the KPg boundary. AB - The timing of the diversification of placental mammals relative to the Cretaceous Paleogene (KPg) boundary mass extinction remains highly controversial. In particular, there have been seemingly irreconcilable differences in the dating of the early placental radiation not only between fossil-based and molecular datasets but also among molecular datasets. To help resolve this discrepancy, we performed genome-scale analyses using 4,388 loci from 90 taxa, including representatives of all extant placental orders and transcriptome data from flying lemurs (Dermoptera) and pangolins (Pholidota). Depending on the gene partitioning scheme, molecular clock model, and genic deviation from molecular clock assumptions, extensive sensitivity analyses recovered widely varying diversification scenarios for placental mammals from a given gene set, ranging from a deep Cretaceous origin and diversification to a scenario spanning the KPg boundary, suggesting that the use of suboptimal molecular clock markers and methodologies is a major cause of controversies regarding placental diversification timing. We demonstrate that reconciliation between molecular and paleontological estimates of placental divergence times can be achieved using the appropriate clock model and gene partitioning scheme while accounting for the degree to which individual genes violate molecular clock assumptions. A birth death-shift analysis suggests that placental mammals underwent a continuous radiation across the KPg boundary without apparent interruption by the mass extinction, paralleling a genus-level radiation of multituberculates and ecomorphological diversification of both multituberculates and therians. These findings suggest that the KPg catastrophe evidently played a limited role in placental diversification, which, instead, was likely a delayed response to the slightly earlier radiation of angiosperms. PMID- 28808023 TI - Prefrontal cortex modulates posterior alpha oscillations during top-down guided visual perception. AB - Conscious visual perception is proposed to arise from the selective synchronization of functionally specialized but widely distributed cortical areas. It has been suggested that different frequency bands index distinct canonical computations. Here, we probed visual perception on a fine-grained temporal scale to study the oscillatory dynamics supporting prefrontal-dependent sensory processing. We tested whether a predictive context that was embedded in a rapid visual stream modulated the perception of a subsequent near-threshold target. The rapid stream was presented either rhythmically at 10 Hz, to entrain parietooccipital alpha oscillations, or arrhythmically. We identified a 2- to 4 Hz delta signature that modulated posterior alpha activity and behavior during predictive trials. Importantly, delta-mediated top-down control diminished the behavioral effects of bottom-up alpha entrainment. Simultaneous source reconstructed EEG and cross-frequency directionality analyses revealed that this delta activity originated from prefrontal areas and modulated posterior alpha power. Taken together, this study presents converging behavioral and electrophysiological evidence for frontal delta-mediated top-down control of posterior alpha activity, selectively facilitating visual perception. PMID- 28808024 TI - Structural and functional studies of pyruvate carboxylase regulation by cyclic di AMP in lactic acid bacteria. AB - Cyclic di-3',5'-adenosine monophosphate (c-di-AMP) is a broadly conserved bacterial second messenger that has been implicated in a wide range of cellular processes. Our earlier studies showed that c-di-AMP regulates central metabolism in Listeria monocytogenes by inhibiting its pyruvate carboxylase (LmPC), a biotin dependent enzyme with biotin carboxylase (BC) and carboxyltransferase (CT) activities. We report here structural, biochemical, and functional studies on the inhibition of Lactococcus lactis PC (LlPC) by c-di-AMP. The compound is bound at the dimer interface of the CT domain, at a site equivalent to that in LmPC, although it has a distinct binding mode in the LlPC complex. This binding site is not well conserved among PCs, and only a subset of these bacterial enzymes are sensitive to c-di-AMP. Conformational changes in the CT dimer induced by c-di-AMP binding may be the molecular mechanism for its inhibitory activity. Mutations of residues in the binding site can abolish c-di-AMP inhibition. In L. lactis, LlPC is required for efficient milk acidification through its essential role in aspartate biosynthesis. The aspartate pool in L. lactis is negatively regulated by c-di-AMP, and high aspartate levels can be restored by expression of a c-di AMP-insensitive LlPC. LlPC has high intrinsic catalytic activity and is not sensitive to acetyl-CoA activation, in contrast to other PC enzymes. PMID- 28808025 TI - Knee osteoarthritis has doubled in prevalence since the mid-20th century. AB - Knee osteoarthritis (OA) is believed to be highly prevalent today because of recent increases in life expectancy and body mass index (BMI), but this assumption has not been tested using long-term historical or evolutionary data. We analyzed long-term trends in knee OA prevalence in the United States using cadaver-derived skeletons of people aged >=50 y whose BMI at death was documented and who lived during the early industrial era (1800s to early 1900s; n = 1,581) and the modern postindustrial era (late 1900s to early 2000s; n = 819). Knee OA among individuals estimated to be >=50 y old was also assessed in archeologically derived skeletons of prehistoric hunter-gatherers and early farmers (6000-300 B.P.; n = 176). OA was diagnosed based on the presence of eburnation (polish from bone-on-bone contact). Overall, knee OA prevalence was found to be 16% among the postindustrial sample but only 6% and 8% among the early industrial and prehistoric samples, respectively. After controlling for age, BMI, and other variables, knee OA prevalence was 2.1-fold higher (95% confidence interval, 1.5 3.1) in the postindustrial sample than in the early industrial sample. Our results indicate that increases in longevity and BMI are insufficient to explain the approximate doubling of knee OA prevalence that has occurred in the United States since the mid-20th century. Knee OA is thus more preventable than is commonly assumed, but prevention will require research on additional independent risk factors that either arose or have become amplified in the postindustrial era. PMID- 28808026 TI - Superior colliculus encodes visual saliency before the primary visual cortex. AB - Models of visual attention postulate the existence of a bottom-up saliency map that is formed early in the visual processing stream. Although studies have reported evidence of a saliency map in various cortical brain areas, determining the contribution of phylogenetically older pathways is crucial to understanding its origin. Here, we compared saliency coding from neurons in two early gateways into the visual system: the primary visual cortex (V1) and the evolutionarily older superior colliculus (SC). We found that, while the response latency to visual stimulus onset was earlier for V1 neurons than superior colliculus superficial visual-layer neurons (SCs), the saliency representation emerged earlier in SCs than in V1. Because the dominant input to the SCs arises from V1, these relative timings are consistent with the hypothesis that SCs neurons pool the inputs from multiple V1 neurons to form a feature-agnostic saliency map, which may then be relayed to other brain areas. PMID- 28808027 TI - De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis. AB - Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 * 10-11). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity. PMID- 28808028 TI - Immune evasion by a staphylococcal inhibitor of myeloperoxidase. AB - Staphylococcus aureus is highly adapted to its host and has evolved many strategies to resist opsonization and phagocytosis. Even after uptake by neutrophils, S. aureus shows resistance to killing, which suggests the presence of phagosomal immune evasion molecules. With the aid of secretome phage display, we identified a highly conserved protein that specifically binds and inhibits human myeloperoxidase (MPO), a major player in the oxidative defense of neutrophils. We have named this protein "staphylococcal peroxidase inhibitor" (SPIN). To gain insight into inhibition of MPO by SPIN, we solved the cocrystal structure of SPIN bound to a recombinant form of human MPO at 2.4-A resolution. This structure reveals that SPIN acts as a molecular plug that prevents H2O2 substrate access to the MPO active site. In subsequent experiments, we observed that SPIN expression increases inside the neutrophil phagosome, where MPO is located, compared with outside the neutrophil. Moreover, bacteria with a deleted gene encoding SPIN showed decreased survival compared with WT bacteria after phagocytosis by neutrophils. Taken together, our results demonstrate that S. aureus secretes a unique proteinaceous MPO inhibitor to enhance survival by interfering with MPO-mediated killing. PMID- 28808029 TI - Elucidating crosstalk mechanisms between phosphorylation and O-GlcNAcylation. AB - Proteins can be modified by multiple posttranslational modifications (PTMs), creating a PTM code that controls the function of proteins in space and time. Unraveling this complex PTM code is one of the great challenges in molecular biology. Here, using mass spectrometry-based assays, we focus on the most common PTMs-phosphorylation and O-GlcNAcylation-and investigate how they affect each other. We demonstrate two generic crosstalk mechanisms. First, we define a frequently occurring, very specific and stringent phosphorylation/O-GlcNAcylation interplay motif, (pSp/T)P(V/A/T)(gS/gT), whereby phosphorylation strongly inhibits O-GlcNAcylation. Strikingly, this stringent motif is substantially enriched in the human (phospho)proteome, allowing us to predict hundreds of putative O-GlcNAc transferase (OGT) substrates. A set of these we investigate further and show them to be decent substrates of OGT, exhibiting a negative feedback loop when phosphorylated at the P-3 site. Second, we demonstrate that reciprocal crosstalk does not occur at PX(S/T)P sites, i.e., at sites phosphorylated by proline-directed kinases, which represent 40% of all sites in the vertebrate phosphoproteomes. PMID- 28808030 TI - Oxytocin-enforced norm compliance reduces xenophobic outgroup rejection. AB - Never before have individuals had to adapt to social environments defined by such magnitudes of ethnic diversity and cultural differentiation. However, neurobiological evidence informing about strategies to reduce xenophobic sentiment and foster altruistic cooperation with outsiders is scarce. In a series of experiments settled in the context of the current refugee crisis, we tested the propensity of 183 Caucasian participants to make donations to people in need, half of whom were refugees (outgroup) and half of whom were natives (ingroup). Participants scoring low on xenophobic attitudes exhibited an altruistic preference for the outgroup, which further increased after nasal delivery of the neuropeptide oxytocin. In contrast, participants with higher levels of xenophobia generally failed to exhibit enhanced altruism toward the outgroup. This tendency was only countered by pairing oxytocin with peer-derived altruistic norms, resulting in a 74% increase in refugee-directed donations. Collectively, these findings reveal the underlying sociobiological conditions associated with outgroup-directed altruism by showing that charitable social cues co-occurring with enhanced activity of the oxytocin system reduce the effects of xenophobia by facilitating prosocial behavior toward refugees. PMID- 28808031 TI - Changes in aggregation states of light-harvesting complexes as a mechanism for modulating energy transfer in desert crust cyanobacteria. AB - In this paper we propose an energy dissipation mechanism that is completely reliant on changes in the aggregation state of the phycobilisome light-harvesting antenna components. All photosynthetic organisms regulate the efficiency of excitation energy transfer (EET) to fit light energy supply to biochemical demands. Not many do this to the extent required of desert crust cyanobacteria. Following predawn dew deposition, they harvest light energy with maximum efficiency until desiccating in the early morning hours. In the desiccated state, absorbed energy is completely quenched. Time and spectrally resolved fluorescence emission measurements of the desiccated desert crust Leptolyngbya ohadii strain identified (i) reduced EET between phycobilisome components, (ii) shorter fluorescence lifetimes, and (iii) red shift in the emission spectra, compared with the hydrated state. These changes coincide with a loss of the ordered phycobilisome structure, evident from small-angle neutron and X-ray scattering and cryo-transmission electron microscopy data. Based on these observations we propose a model where in the hydrated state the organized rod structure of the phycobilisome supports directional EET to reaction centers with minimal losses due to thermal dissipation. In the desiccated state this structure is lost, giving way to more random aggregates. The resulting EET path will exhibit increased coupling to the environment and enhanced quenching. PMID- 28808032 TI - Mechanical constraint from growing jaw facilitates mammalian dental diversity. AB - Much of the basic information about individual organ development comes from studies using model species. Whereas conservation of gene regulatory networks across higher taxa supports generalizations made from a limited number of species, generality of mechanistic inferences remains to be tested in tissue culture systems. Here, using mammalian tooth explants cultured in isolation, we investigate self-regulation of patterning by comparing developing molars of the mouse, the model species of mammalian research, and the bank vole. A distinct patterning difference between the vole and the mouse molars is the alternate cusp offset present in the vole. Analyses of both species using 3D reconstructions of developing molars and jaws, computational modeling of cusp patterning, and tooth explants cultured with small braces show that correct cusp offset requires constraints on the lateral expansion of the developing tooth. Vole molars cultured without the braces lose their cusp offset, and mouse molars cultured with the braces develop a cusp offset. Our results suggest that cusp offset, which changes frequently in mammalian evolution, is more dependent on the 3D support of the developing jaw than other aspects of tooth shape. This jaw-tooth integration of a specific aspect of the tooth phenotype indicates that organs may outsource specific aspects of their morphology to be regulated by adjacent body parts or organs. Comparative studies of morphologically different species are needed to infer the principles of organogenesis. PMID- 28808033 TI - Multiplex, quantitative cellular analysis in large tissue volumes with clearing enhanced 3D microscopy (Ce3D). AB - Organ homeostasis, cellular differentiation, signal relay, and in situ function all depend on the spatial organization of cells in complex tissues. For this reason, comprehensive, high-resolution mapping of cell positioning, phenotypic identity, and functional state in the context of macroscale tissue structure is critical to a deeper understanding of diverse biological processes. Here we report an easy to use method, clearing-enhanced 3D (Ce3D), which generates excellent tissue transparency for most organs, preserves cellular morphology and protein fluorescence, and is robustly compatible with antibody-based immunolabeling. This enhanced signal quality and capacity for extensive probe multiplexing permits quantitative analysis of distinct, highly intermixed cell populations in intact Ce3D-treated tissues via 3D histo-cytometry. We use this technology to demonstrate large-volume, high-resolution microscopy of diverse cell types in lymphoid and nonlymphoid organs, as well as to perform quantitative analysis of the composition and tissue distribution of multiple cell populations in lymphoid tissues. Combined with histo-cytometry, Ce3D provides a comprehensive strategy for volumetric quantitative imaging and analysis that bridges the gap between conventional section imaging and disassociation-based techniques. PMID- 28808034 TI - Feedback amplification loop drives malignant growth in epithelial tissues. AB - Interactions between cells bearing oncogenic mutations and the surrounding microenvironment, and cooperation between clonally distinct cell populations, can contribute to the growth and malignancy of epithelial tumors. The genetic techniques available in Drosophila have contributed to identify important roles of the TNF-alpha ligand Eiger and mitogenic molecules in mediating these interactions during the early steps of tumor formation. Here we unravel the existence of a tumor-intrinsic-and microenvironment-independent-self reinforcement mechanism that drives tumor initiation and growth in an Eiger independent manner. This mechanism relies on cell interactions between two functionally distinct cell populations, and we present evidence that these cell populations are not necessarily genetically different. Tumor-specific and cell autonomous activation of the tumorigenic JNK stress-activated pathway drives the expression of secreted signaling molecules and growth factors to delaminating cells, which nonautonomously promote proliferative growth of the partially transformed epithelial tissue. We present evidence that cross-feeding interactions between delaminating and nondelaminating cells increase each other's sizes and that these interactions can explain the unlimited growth potential of these tumors. Our results will open avenues toward our molecular understanding of those social cell interactions with a relevant function in tumor initiation in humans. PMID- 28808035 TI - Fission yeast myosin Myo2 is down-regulated in actin affinity by light chain phosphorylation. AB - Studies in fission yeast Schizosaccharomyces pombe have provided the basis for the most advanced models of the dynamics of the cytokinetic contractile ring. Myo2, a class-II myosin, is the major source of tension in the contractile ring, but how Myo2 is anchored and regulated to produce force is poorly understood. To enable more detailed biochemical/biophysical studies, Myo2 was expressed in the baculovirus/Sf9 insect cell system with its two native light chains, Rlc1 and Cdc4. Milligram yields of soluble, unphosphorylated Myo2 were obtained that exhibited high actin-activated ATPase activity and in vitro actin filament motility. The fission yeast specific chaperone Rng3 was thus not required for expression or activity. In contrast to nonmuscle myosins from animal cells that require phosphorylation of the regulatory light chain for activation, phosphorylation of Rlc1 markedly reduced the affinity of Myo2 for actin. Another unusual feature of Myo2 was that, unlike class-II myosins, which generally form bipolar filamentous structures, Myo2 showed no inclination to self-assemble at approximately physiological salt concentrations, as analyzed by sedimentation velocity ultracentrifugation. This lack of assembly supports the hypothesis that clusters of Myo2 depend on interactions at the cell cortex in structural units called nodes for force production during cytokinesis. PMID- 28808036 TI - Reducing posttreatment relapse in cleft lip palatal expansion using an injectable estrogen-nanodiamond hydrogel. AB - Patients with cleft lip and/or palate (CLP), who undergo numerous medical interventions from infancy, can suffer from lifelong debilitation caused by underdeveloped maxillae. Conventional treatment approaches use maxillary expansion techniques to develop normal speech, achieve functional occlusion for nutrition intake, and improve esthetics. However, as patients with CLP congenitally lack bone in the cleft site with diminished capacity for bone formation in the expanded palate, more than 80% of the patient population experiences significant postexpansion relapse. While such relapse has been a long standing battle in craniofacial care of patients, currently there are no available strategies to address this pervasive problem. Estrogen, 17beta estradiol (E2), is a powerful therapeutic agent that plays a critical role in bone homeostasis. However, E2's clinical application is less appreciated due to several limitations, including its pleiotropic effects and short half-life. Here, we developed a treatment strategy using an injectable system with photo-cross linkable hydrogel (G) and nanodiamond (ND) technology to facilitate the targeted and sustained delivery of E2 to promote bone formation. In a preclinical expansion/relapse model, this functionalized E2/ND/G complex substantially reduced postexpansion relapse by nearly threefold through enhancements in sutural remodeling compared with unmodified E2 administration. The E2/ND/G group demonstrated greater bone volume by twofold and higher osteoblast number by threefold, compared with the control group. The E2/ND/G platform maximized the beneficial effects of E2 through its extended release with superior efficacy and safety at the local level. This broadly applicable E2 delivery platform shows promise as an adjuvant therapy in craniofacial care of patients. PMID- 28808037 TI - Separate mesocortical and mesolimbic pathways encode effort and reward learning signals. AB - Optimal decision making mandates organisms learn the relevant features of choice options. Likewise, knowing how much effort we should expend can assume paramount importance. A mesolimbic network supports reward learning, but it is unclear whether other choice features, such as effort learning, rely on this same network. Using computational fMRI, we show parallel encoding of effort and reward prediction errors (PEs) within distinct brain regions, with effort PEs expressed in dorsomedial prefrontal cortex and reward PEs in ventral striatum. We show a common mesencephalic origin for these signals evident in overlapping, but spatially dissociable, dopaminergic midbrain regions expressing both types of PE. During action anticipation, reward and effort expectations were integrated in ventral striatum, consistent with a computation of an overall net benefit of a stimulus. Thus, we show that motivationally relevant stimulus features are learned in parallel dopaminergic pathways, with formation of an integrated utility signal at choice. PMID- 28808038 TI - The Phosphatidylinositol 3-Kinase Pathway as a Potential Therapeutic Target in Bladder Cancer. AB - Purpose: Activation of the PI3K pathway occurs in over 40% of bladder urothelial cancers. The aim of this study is to determine the therapeutic potential, the underlying action, and the resistance mechanisms of drugs targeting the PI3K pathway.Experimental Design: Urothelial cancer cell lines and patient-derived xenografts (PDXs) were analyzed for alterations of the PI3K pathway and for their sensitivity to the small-molecule inhibitor pictilisib alone and in combination with cisplatin and/or gemcitabine. Potential predictive biomarkers for pictilisib were evaluated, and RNA sequencing was performed to explore drug resistance mechanisms.Results: The bladder cancer cell line TCCSUP, which harbors a PIK3CA E545K mutation, was sensitive to pictilisib compared to cell lines with wild-type PIK3CA Pictilisib exhibited stronger antitumor activity in bladder cancer PDX models with PI3KCA H1047R mutation or amplification than the control PDX model. Pictilisib synergized with cisplatin and/or gemcitabine in vitro, significantly delayed tumor growth, and prolonged survival compared with single-drug treatment in the PDX models. The phosphorylation of ribosomal protein S6 correlated with response to pictilisib both in vitro and in vivo, and could potentially serve as a biomarker to predict response to pictilisib. Pictilisib activated the compensatory MEK/ERK pathway that likely contributed to pictilisib resistance, which was reversed by cotreatment with the RAF inhibitor sorafenib. RNA sequencing of tumors resistant to treatment suggested that LSP1 downregulation correlated with drug resistance.Conclusions: These preclinical results provide new insights into the therapeutic potential of targeting the PI3K pathway for the treatment of bladder cancer. Clin Cancer Res; 23(21); 6580-91. (c)2017 AACR. PMID- 28808039 TI - Preclinical Evaluation of Intravesical Cisplatin Nanoparticles for Non-Muscle Invasive Bladder Cancer. AB - Purpose: Prior clinical trials evaluating cisplatin for non-muscle-invasive bladder cancer (NMIBC) were stopped due to local and systemic toxicity. Currently, there is still a need for improved intravesical therapies, and nanoparticle-based CDDP may be efficacious without the toxicity of free cisplatin observed in the past.Experimental Design: Cisplatin nanoparticles (CDDP NPs) were developed using biocompatible poly(l-aspartic acid sodium salt; PAA), both with and without low and high grafting density of methoxy-polyethylene glycol (PEG). In vitro cytotoxicity studies confirmed activity of CDDP NPs and CDDP solution against a papillary bladder cancer cell line. Local toxicity was assessed by three weekly intravesical administrations of CDDP formulations. CDDP NPs and CDDP solution were evaluated for bladder absorption in murine models 1 and 4 hours after intravesical administration. In vivo efficacy was evaluated in an immunocompetent carcinogen model of NMIBC.Results: CDDP NPs showed decreased local toxicity, as assessed by bladder weight, compared with CDDP solution. Furthermore, >2 MUg/mL of platinum was observed in mouse serum after intravesical administration of CDDP solution, whereas serum platinum was below the limit of quantification after intravesical administration of CDDP NPs. CDDP NPs provided significantly increased (P < 0.05) drug levels in murine bladders compared with CDDP solution for at least 4 hours after intravesical administration. In vivo, CDDP NPs reduced cancer cell proliferation compared with untreated controls, and was the only treatment group without evidence of invasive carcinoma.Conclusions: Cisplatin-loaded PAA NPs have the potential to improve intravesical treatment of NMIBC while reducing local and systemic side effects. Clin Cancer Res; 23(21); 6592-601. (c)2017 AACR. PMID- 28808042 TI - 50 years on ... the discovery of tubulin continues to advance cancer treatment. PMID- 28808040 TI - Evaluating the longitudinal risk of social vigilance on atherosclerosis: study protocol for the North Texas Heart Study. AB - INTRODUCTION: Psychosocial factors are increasingly recognised as important determinants of cardiovascular disease risk. The North Texas Heart Study aims to understand the mechanisms responsible for this association with a focus on social vigilance (ie, scanning the environment for social threats). There is also growing interest in supplementing traditional methods (eg, survey assessment of psychosocial risk paired with cross-sectional and longitudinal health outcomes) with daily or repeated momentary assessment of psychosocial factors. However, there are relatively few longitudinal studies directly comparing these approaches with hard endpoints. METHODS AND ANALYSIS: The North Texas Heart Study proposes a longitudinal measurement burst design to examine psychosocial determinants of subclinical atherosclerosis. A sample of 300 healthy community participants, stratified by age and gender, will complete survey measures, as well as 2 days of ecological momentary assessment at baseline and at a 2-year follow-up. A range of psychosocial and behavioural factors, objective biomarkers, as well as carotid intima-media thickness (cIMT) will be assessed at both time points. Unadjusted and adjusted models will evaluate cross-sectional associations and determinants of change in the cIMT. ETHICS AND DISSEMINATION: The Institutional Review Board at the study coordinating institute (University of North Texas) has approved this study. Positive, negative or inconclusive primary and ancillary findings will be disseminated in scientific journals and conferences. PMID- 28808043 TI - Allosteric alterations in the androgen receptor and activity in prostate cancer. AB - Organisms have evolved to generate biological complexity in their proteome and transcriptome from a limited number of genes. This concept holds true for the androgen receptor, which displays a diversity of inclusion/exclusion events in its structural motifs as a mechanism of resistance to the most forefront anti androgen therapies. More than 20 androgen receptor variants that lack various portions of ligand-binding domain have been identified in human prostate cancer (PCa) samples. Most of the variants are inactive on their own, with a few exceptions displaying constitutive activity. The full-length receptor and one or more variants can be co-expressed in the same cell under many circumstances, which raises the question of how these variants physically and functionally interact with the full-length receptor or one another in the course of PCa progression. To address this issue, in this review, we will characterize and discuss androgen receptor variants, including the novel variants discovered in the last couple of years (i) individually, (ii) with respect to their physical and functional interaction with one another and (iii) in clinical relevance. Here, we also introduce the very recent understanding of AR-Vs obtained through successful development of some AR-V-specific antibodies as well as identification of novel AR-Vs by data mining approaches. PMID- 28808044 TI - Germline mutation contribution to chromosomal instability. AB - Genomic instability is a feature of cancer that fuels oncogenesis through increased frequency of genetic disruption, leading to loss of genomic integrity and promoting clonal evolution as well as tumor transformation. A form of genomic instability prevalent across cancer types is chromosomal instability, which involves karyotypic changes including chromosome copy number alterations as well as gross structural abnormalities such as transversions and translocations. Defects in cellular mechanisms that are in place to govern fidelity of chromosomal segregation, DNA repair and ultimately genomic integrity are known to contribute to chromosomal instability. In this review, we discuss the association of germline mutations in these pathways with chromosomal instability in the background of related cancer predisposition syndromes. We will also reflect on the impact of genetic predisposition to clinical management of patients and how we can exploit this vulnerability to promote catastrophic genomic instability as a therapeutic strategy. PMID- 28808045 TI - Fighting tubulin-targeting anticancer drug toxicity and resistance. AB - Tubulin-targeting drugs, like taxanes and vinca alkaloids, are among the most effective anticancer therapeutics used in the clinic today. Specifically, anti microtubule cancer drugs (AMCDs) have proven to be effective in the treatment of castration-resistant prostate cancer and triple-negative breast cancer. AMCDs, however, have limiting toxicities that include neutropenia and neurotoxicity, and, in addition, tumor cells can become resistant to the drugs after long-term use. Co-targeting mitotic progression/slippage with inhibition of the protein kinases WEE1 and MYT1 that regulate CDK1 kinase activity may improve AMCD efficacy, reducing the acquisition of resistance by the tumor and side effects from the drug and/or its vehicle. Other possible treatments that improve outcomes in the clinic for these two drug-resistant cancers, including new formulations of the AMCDs and pursuing different molecular targets, will be discussed. PMID- 28808046 TI - CAR T Cells Drive CLL Remissions. AB - A new study shows that chimeric antigen receptor T cells produce objective responses in 71% of patients with chronic lymphocytic leukemia whose disease progressed despite receiving ibrutinib or who are unable to tolerate the drug. Cancer cells were undetectable in the bone marrow in 81% of tested patients, and 64% of tested patients showed complete lymph node responses. Most patients experienced adverse effects, however. PMID- 28808052 TI - A small-molecule modulator of cardiac myosin acts on multiple stages of the myosin chemomechanical cycle. AB - Mavacamten, formerly known as MYK-461 is a recently discovered novel small molecule modulator of cardiac myosin that targets the underlying sarcomere hypercontractility of hypertrophic cardiomyopathy, one of the most prevalent heritable cardiovascular disorders. Studies on isolated cells and muscle fibers as well as intact animals have shown that mavacamten inhibits sarcomere force production, thereby reducing cardiac contractility. Initial mechanistic studies have suggested that mavacamten primarily reduces the steady-state ATPase activity by inhibiting the rate of phosphate release of beta-cardiac myosin-S1, but the molecular mechanism of action of mavacamten has not been described. Here we used steady-state and presteady-state kinetic analyses to investigate the mechanism of action of mavacamten. Transient kinetic analyses revealed that mavacamten modulates multiple steps of the myosin chemomechanical cycle. In addition to decreasing the rate-limiting step of the cycle (phosphate release), mavacamten reduced the number of myosin-S1 heads that can interact with the actin thin filament during transition from the weakly to the strongly bound state without affecting the intrinsic rate. Mavacamten also decreased the rate of myosin binding to actin in the ADP-bound state and the ADP-release rate from myosin-S1 alone. We, therefore, conclude that mavacamten acts on multiple stages of the myosin chemomechanical cycle. Although the primary mechanism of mavacamten mediated inhibition of cardiac myosin is the decrease of phosphate release from beta-cardiac myosin-S1, a secondary mechanism decreases the number of actin binding heads transitioning from the weakly to the strongly bound state, which occurs before phosphate release and may provide an additional method to modulate myosin function. PMID- 28808053 TI - Navigating the conformational landscape of G protein-coupled receptor kinases during allosteric activation. AB - G protein-coupled receptors (GPCRs) are essential for transferring extracellular signals into carefully choreographed intracellular responses controlling diverse aspects of cell physiology. The duration of GPCR-mediated signaling is primarily regulated via GPCR kinase (GRK)-mediated phosphorylation of activated receptors. Although many GRK structures have been reported, the mechanisms underlying GRK activation are not well-understood, in part because it is unknown how these structures map to the conformational landscape available to this enzyme family. Unlike most other AGC kinases, GRKs rely on their interaction with GPCRs for activation and not phosphorylation. Here, we used principal component analysis of available GRK and protein kinase A crystal structures to identify their dominant domain motions and to provide a framework that helps evaluate how close each GRK structure is to being a catalytically competent state. Our results indicated that disruption of an interface formed between the large lobe of the kinase domain and the regulator of G protein signaling homology domain (RHD) is highly correlated with establishment of the active conformation. By introducing point mutations in the GRK5 RHD-kinase domain interface, we show with both in silico and in vitro experiments that perturbation of this interface leads to higher phosphorylation activity. Navigation of the conformational landscape defined by this bioinformatics-based study is likely common to all GPCR-activated GRKs. PMID- 28808054 TI - MST4 kinase phosphorylates ACAP4 protein to orchestrate apical membrane remodeling during gastric acid secretion. AB - Digestion in the stomach depends on acidification of the lumen. Histamine elicited acid secretion is triggered by activation of the PKA cascade, which ultimately results in the insertion of gastric H,K-ATPases into the apical plasma membranes of parietal cells. Our recent study revealed the functional role of PKA MST4-ezrin signaling axis in histamine-elicited acid secretion. However, it remains uncharacterized how the PKA-MST4-ezrin signaling axis operates the insertion of H,K-ATPases into the apical plasma membranes of gastric parietal cells. Here we show that MST4 phosphorylates ACAP4, an ARF6 GTPase-activating protein, at Thr545 Histamine stimulation activates MST4 and promotes MST4 interaction with ACAP4. ACAP4 physically interacts with MST4 and is a cognate substrate of MST4 during parietal cell activation. The phosphorylation site of ACAP4 by MST4 was mapped to Thr545 by mass spectrometric analyses. Importantly, phosphorylation of Thr545 is essential for acid secretion in parietal cells because either suppression of ACAP4 or overexpression of non-phosphorylatable ACAP4 prevents the apical membrane reorganization and proton pump translocation elicited by histamine stimulation. In addition, persistent overexpression of MST4 phosphorylation-deficient ACAP4 results in inhibition of gastric acid secretion and blockage of tubulovesicle fusion to the apical membranes. Significantly, phosphorylation of Thr545 enables ACAP4 to interact with ezrin. Given the location of Thr545 between the GTPase-activating protein domain and the first ankyrin repeat, we reason that MST4 phosphorylation elicits a conformational change that enables ezrin-ACAP4 interaction. Taken together, these results define a novel molecular mechanism linking the PKA-MST4-ACAP4 signaling cascade to polarized acid secretion in gastric parietal cells. PMID- 28808055 TI - Dynamin-dependent amino acid endocytosis activates mechanistic target of rapamycin complex 1 (mTORC1). AB - The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of protein synthesis and potential target for modifying cellular metabolism in various conditions, including cancer and aging. mTORC1 activity is tightly regulated by the availability of extracellular amino acids, and previous studies have revealed that amino acids in the extracellular fluid are transported to the lysosomal lumen. There, amino acids induce recruitment of cytoplasmic mTORC1 to the lysosome by the Rag GTPases, followed by mTORC1 activation by the small GTPase Ras homolog enriched in brain (Rheb). However, how the extracellular amino acids reach the lysosomal lumen and activate mTORC1 remains unclear. Here, we show that amino acid uptake by dynamin-dependent endocytosis plays a critical role in mTORC1 activation. We found that mTORC1 is inactivated when endocytosis is inhibited by overexpression of a dominant-negative form of dynamin 2 or by pharmacological inhibition of dynamin or clathrin. Consistently, the recruitment of mTORC1 to the lysosome was suppressed by the dynamin inhibition. The activity and lysosomal recruitment of mTORC1 were rescued by increasing intracellular amino acids via cycloheximide exposure or by Rag overexpression, indicating that amino acid deprivation is the main cause of mTORC1 inactivation via the dynamin inhibition. We further show that endocytosis inhibition does not induce autophagy even though mTORC1 inactivation is known to strongly induce autophagy. These findings open new perspectives for the use of endocytosis inhibitors as potential agents that can effectively inhibit nutrient utilization and shut down the upstream signals that activate mTORC1. PMID- 28808056 TI - The crystal structure of full-length Sizzled from Xenopus laevis yields insights into Wnt-antagonistic function of secreted Frizzled-related proteins. AB - The Wnt-signaling pathway is crucial to cell proliferation, differentiation, and migration. The secreted Frizzled-related proteins (sFRPs) represent the largest family of secreted Wnt inhibitors. However, their function in antagonizing Wnt signaling has remained somewhat controversial. Here, we report the crystal structure of Sizzled from Xenopus laevis, the first full-length structure of an sFRP. Tethered by an inter-domain disulfide bond and a linker, the N-terminal cysteine-rich domain (CRD) and the C-terminal netrin-like domain (NTR) of Sizzled are arranged in a tandem fashion, with the NTR domain occluding the groove of CRD for Wnt accessibility. A Dual-Luciferase assay demonstrated that removing the NTR domain and replacing the CRD groove residues His-116 and His-118 with aromatic residues may significantly enhance antagonistic function of Sizzled in inhibiting Wnt3A signaling. Sizzled is a monomer in solution, and Sizzled CRD exhibited different packing in the crystal, suggesting that sFRPs do not have a conserved CRD dimerization mode. Distinct from the canonical NTR domain, the Sizzled NTR adopts a novel alpha/beta folding with two perpendicular helices facing the central mixed beta-sheet. The subgroup of human sFRP1/2/5 and Sizzled should have a similar NTR domain that features a highly positively charged region, opposite the NTR-CRD interface, suggesting that the NTR domain in human sFRPs, at least sFRP1/2/5, is unlikely to bind to Wnt but is likely involved in biphasic Wnt signaling modulation. In summary, the Sizzled structure provides the first insights into how the CRD and the NTR domains relate to each other for modulating Wnt-antagonistic function of sFRPs. PMID- 28808057 TI - A kidney-specific genetic control module in mice governs endocrine regulation of the cytochrome P450 gene Cyp27b1 essential for vitamin D3 activation. AB - The vitamin D endocrine system regulates mineral homeostasis through its activities in the intestine, kidney, and bone. Terminal activation of vitamin D3 to its hormonal form, 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3), occurs in the kidney via the cytochrome P450 enzyme CYP27B1. Despite its importance in vitamin D metabolism, the molecular mechanisms underlying the regulation of the gene for this enzyme, Cyp27b1, are unknown. Here, we identified a kidney-specific control module governed by a renal cell-specific chromatin structure located distal to Cyp27b1 that mediates unique basal and parathyroid hormone (PTH)-, fibroblast growth factor 23 (FGF23)-, and 1,25(OH)2D3-mediated regulation of Cyp27b1 expression. Selective genomic deletion of key components within this module in mice resulted in loss of either PTH induction or FGF23 and 1,25(OH)2D3 suppression of Cyp27b1 gene expression; the former loss caused a debilitating skeletal phenotype, whereas the latter conferred a quasi-normal bone mineral phenotype through compensatory homeostatic mechanisms involving Cyp24a1 We found that Cyp27b1 is also expressed at low levels in non-renal cells, in which transcription was modulated exclusively by inflammatory factors via a process that was unaffected by deletion of the kidney-specific module. These results reveal that differential regulation of Cyp27b1 expression represents a mechanism whereby 1,25(OH)2D3 can fulfill separate functional roles, first in the kidney to control mineral homeostasis and second in extra-renal cells to regulate target genes linked to specific biological responses. Furthermore, we conclude that these mouse models open new avenues for the study of vitamin D metabolism and its involvement in therapeutic strategies for human health and disease. PMID- 28808059 TI - Linchpin DNA-binding residues serve as go/no-go controls in the replication factor C-catalyzed clamp-loading mechanism. AB - DNA polymerases depend on circular sliding clamps for processive replication. Clamps must be loaded onto primer-template DNA (ptDNA) by clamp loaders that open and close clamps around ptDNA in an ATP-fueled reaction. All clamp loaders share a core structure in which five subunits form a spiral chamber that binds the clamp at its base in a twisted open form and encloses ptDNA within, while binding and hydrolyzing ATP to topologically link the clamp and ptDNA. To understand how clamp loaders perform this complex task, here we focused on conserved arginines that might play a central coordinating role in the mechanism because they can alternately contact ptDNA or Walker B glutamate in the ATPase site and lie close to the clamp loader-clamp-binding interface. We mutated Arg-84, Arg-88, and Arg 101 in the ATPase-active B, C, and D subunits of Saccharomyces cerevisiae replication factor C (RFC) clamp loader, respectively, and assessed the impact on multiple transient events in the reaction: proliferating cell nuclear antigen (PCNA) clamp binding/opening/closure/release, ptDNA binding/release, and ATP hydrolysis/product release. The results show that these arginines relay critical information between the PCNA-binding, DNA-binding, and ATPase sites at all steps of the reaction, particularly at a checkpoint before RFC commits to ATP hydrolysis. Moreover, their actions are subunit-specific with RFC-C Arg-88 serving as an accelerator that enables rapid ATP hydrolysis upon contact with ptDNA and RFC-D Arg-101 serving as a brake that confers specificity for ptDNA as the correct substrate for loading PCNA. PMID- 28808058 TI - Reductions in the mitochondrial ABC transporter Abcb10 affect the transcriptional profile of heme biosynthesis genes. AB - ATP-binding cassette subfamily B member 10 (Abcb10) is a mitochondrial ATP binding cassette (ABC) transporter that complexes with mitoferrin1 and ferrochelatase to enhance heme biosynthesis in developing red blood cells. Reductions in Abcb10 levels have been shown to reduce mitoferrin1 protein levels and iron import into mitochondria, resulting in reduced heme biosynthesis. As an ABC transporter, Abcb10 binds and hydrolyzes ATP, but its transported substrate is unknown. Here, we determined that decreases in Abcb10 did not result in protoporphyrin IX accumulation in morphant-treated zebrafish embryos or in differentiated Abcb10-specific shRNA murine Friend erythroleukemia (MEL) cells in which Abcb10 was specifically silenced with shRNA. We also found that the ATPase activity of Abcb10 is necessary for hemoglobinization in MEL cells, suggesting that the substrate transported by Abcb10 is important in mediating increased heme biosynthesis during erythroid development. Inhibition of 5-aminolevulinic acid dehydratase (EC 4.2.1.24) with succinylacetone resulted in both 5-aminolevulinic acid (ALA) accumulation in control and Abcb10-specific shRNA MEL cells, demonstrating that reductions in Abcb10 do not affect ALA export from mitochondria and indicating that Abcb10 does not transport ALA. Abcb10 silencing resulted in an alteration in the heme biosynthesis transcriptional profile due to repression by the transcriptional regulator Bach1, which could be partially rescued by overexpression of Alas2 or Gata1, providing a mechanistic explanation for why Abcb10 shRNA MEL cells exhibit reduced hemoglobinization. In conclusion, our findings rule out that Abcb10 transports ALA and indicate that Abcb10's ATP hydrolysis activity is critical for hemoglobinization and that the substrate transported by Abcb10 provides a signal that optimizes hemoglobinization. PMID- 28808060 TI - The human RNA-binding protein and E3 ligase MEX-3C binds the MEX-3-recognition element (MRE) motif with high affinity. AB - MEX-3 is a K-homology (KH) domain-containing RNA-binding protein first identified as a translational repressor in Caenorhabditis elegans, and its four orthologs (MEX-3A-D) in human and mouse were subsequently found to have E3 ubiquitin ligase activity mediated by a RING domain and critical for RNA degradation. Current evidence implicates human MEX-3C in many essential biological processes and suggests a strong connection with immune diseases and carcinogenesis. The highly conserved dual KH domains in MEX-3 proteins enable RNA binding and are essential for the recognition of the 3'-UTR and post-transcriptional regulation of MEX-3 target transcripts. However, the molecular mechanisms of translational repression and the consensus RNA sequence recognized by the MEX-3C KH domain are unknown. Here, using X-ray crystallography and isothermal titration calorimetry, we investigated the RNA-binding activity and selectivity of human MEX-3C dual KH domains. Our high-resolution crystal structures of individual KH domains complexed with a noncanonical U-rich and a GA-rich RNA sequence revealed that the KH1/2 domains of human MEX-3C bound MRE10, a 10-mer RNA (5'-CAGAGUUUAG-3') consisting of an eight-nucleotide MEX-3-recognition element (MRE) motif, with high affinity. Of note, we also identified a consensus RNA motif recognized by human MEX-3C. The potential RNA-binding sites in the 3'-UTR of the human leukocyte antigen serotype (HLA-A2) mRNA were mapped with this RNA-binding motif and further confirmed by fluorescence polarization. The binding motif identified here will provide valuable information for future investigations of the functional pathways controlled by human MEX-3C and for predicting potential mRNAs regulated by this enzyme. PMID- 28808061 TI - Structural analyses of the bacterial primosomal protein DnaB reveal that it is a tetramer and forms a complex with a primosomal re-initiation protein. AB - The DnaB primosomal protein from Gram-positive bacteria plays a key role in DNA replication and restart as a loader protein for the recruitment of replisome cascade proteins. Previous investigations have established that DnaB is composed of an N-terminal domain, a middle domain, and a C-terminal domain. However, structural evidence for how DnaB functions at the atomic level is lacking. Here, we report the crystal structure of DnaB, encompassing the N-terminal and middle domains (residues 1-300), from Geobacillus stearothermophilus (GstDnaB1-300) at 2.8 A resolution. Our structure revealed that GstDnaB1-300 forms a tetramer with two basket-like architectures, a finding consistent with those from solution studies using analytical ultracentrifugation. Furthermore, our results from both GST pulldown assays and analytical ultracentrifugation show that GstDnaB1-300 is sufficient to form a complex with PriA, the primosomal reinitiation protein. Moreover, with the aid of small angle X-ray scattering experiments, we also determined the structural envelope of full-length DnaB (GstDnaBFL) in solution. These small angle X-ray scattering studies indicated that GstDnaBFL has an elongated conformation and that the protruding density envelopes originating from GstDnaB1-300 could completely accommodate the GstDnaB C-terminal domain (residues 301-461). Taken together with biochemical assays, our results suggest that GstDnaB uses different domains to distinguish the PriA interaction and single stranded DNA binding. These findings can further extend our understanding of primosomal assembly in replication restart. PMID- 28808062 TI - Ablating the protein TBC1D1 impairs contraction-induced sarcolemmal glucose transporter 4 redistribution but not insulin-mediated responses in rats. AB - TBC1 domain family member 1 (TBC1D1), a Rab GTPase-activating protein and paralogue of Akt substrate of 160 kDa (AS160), has been implicated in both insulin- and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase-mediated glucose transporter type 4 (GLUT4) translocation. However, the role of TBC1D1 in contracting muscle remains ambiguous. We therefore explored the metabolic consequence of ablating TBC1D1 in both resting and contracting skeletal muscles, utilizing a rat TBC1D1 KO model. Although insulin administration rapidly increased (p < 0.05) plasma membrane GLUT4 content in both red and white gastrocnemius muscles, the TBC1D1 ablation did not alter this response nor did it affect whole-body insulin tolerance, suggesting that TBC1D1 is not required for insulin-induced GLUT4 trafficking events. Consistent with findings in other models of altered TBC1D1 protein levels, whole-animal and ex vivo skeletal muscle fat oxidation was increased in the TBC1D1 KO rats. Although there was no change in mitochondrial content in the KO rats, maximal ADP stimulated respiration was higher in permeabilized muscle fibers, which may contribute to the increased reliance on fatty acids in resting KO animals. Despite this increase in mitochondrial oxidative capacity, run time to exhaustion at various intensities was impaired in the KO rats. Moreover, contraction-induced increases in sarcolemmal GLUT4 content and glucose uptake were lower in the white gastrocnemius of the KO animals. Altogether, our results highlight a critical role for TBC1D1 in exercise tolerance and contraction-mediated translocation of GLUT4 to the plasma membrane in skeletal muscle. PMID- 28808063 TI - Phylogenetic sequence analysis and functional studies reveal compensatory amino acid substitutions in loop 2 of human ribonucleotide reductase. AB - Eukaryotic class I ribonucleotide reductases (RRs) generate deoxyribonucleotides for DNA synthesis. Binding of dNTP effectors is coupled to the formation of active dimers and induces conformational changes in a short loop (loop 2) to regulate RR specificity among its nucleoside diphosphate substrates. Moreover, ATP and dATP bind at an additional allosteric site 40 A away from loop 2 and thereby drive formation of activated or inactive hexamers, respectively. To better understand how dNTP binding influences specificity, activity, and oligomerization of human RR, we aligned >300 eukaryotic RR sequences to examine natural sequence variation in loop 2. We found that most amino acids in eukaryotic loop 2 were nearly invariant in this sample; however, two positions co varied as nonconservative substitutions (N291G and P294K; human numbering). We also found that the individual N291G and P294K substitutions in human RR additively affect substrate specificity. The P294K substitution significantly impaired effector-induced oligomerization required for enzyme activity, and oligomerization was rescued in the N291G/P294K enzyme. None of the other mutants exhibited altered ATP-mediated hexamerization; however, certain combinations of loop 2 mutations and dNTP effectors perturbed ATP's role as an allosteric activator. Our results demonstrate that the observed compensatory covariation of amino acids in eukaryotic loop 2 is essential for its role in dNTP-induced dimerization. In contrast, defects in substrate specificity are not rescued in the double mutant, implying that functional sequence variation elsewhere in the protein is necessary. These findings yield insight into loop 2's roles in regulating RR specificity, allostery, and oligomerization. PMID- 28808064 TI - Obesity and aging diminish sirtuin 1 (SIRT1)-mediated deacetylation of SIRT3, leading to hyperacetylation and decreased activity and stability of SIRT3. AB - Sirtuin 3 (SIRT3) deacetylates and regulates many mitochondrial proteins to maintain health, but its functions are depressed in aging and obesity. The best studied sirtuin, SIRT1, counteracts aging- and obesity-related diseases by deacetylating many proteins, but whether SIRT1 has a role in deacetylating and altering the function of SIRT3 is unknown. Here we show that SIRT3 is reversibly acetylated in the mitochondria and unexpectedly is a target of SIRT1 deacetylation. SIRT3 is hyperacetylated in aged and obese mice, in which SIRT1 activity is low, and SIRT3 acetylation at Lys57 inhibits its deacetylase activity and promotes protein degradation. Adenovirus-mediated expression of SIRT3 or an acetylation-defective SIRT3-K57R mutant in diet-induced obese mice decreased acetylation of mitochondrial long-chain acyl-CoA dehydrogenase, a known SIRT3 deacetylation target; improved fatty acid beta-oxidation; and ameliorated liver steatosis and glucose intolerance. These SIRT3-mediated beneficial effects were not observed with an acetylation-mimic SIRT3-K57Q mutant. Our findings reveal an unexpected mechanism for SIRT3 regulation via SIRT1-mediated deacetylation. Improving mitochondrial SIRT3 functions by inhibiting SIRT3 acetylation may offer a new therapeutic approach for obesity- and aging-related diseases associated with mitochondrial dysfunction. PMID- 28808066 TI - Maternal mRNAs with distinct 3' UTRs define the temporal pattern of Ccnb1 synthesis during mouse oocyte meiotic maturation. AB - The final stages of female gamete maturation occur in the virtual absence of transcription, with gene expression driven by a program of selective unmasking, translation, and degradation of maternal mRNAs. Here we demonstrate that the timing of Ccnb1 mRNA translation in mouse oocytes is dependent on the presence of transcripts with different 3' untranslated regions (UTRs). This 3' UTR heterogeneity directs distinct temporal patterns of translational activation or repression. Inclusion or exclusion of cis-acting elements is responsible for these divergent regulations. Our findings reveal an additional layer of translation control through alternative polyadenylation usage required to fine tune the timing of meiosis progression. PMID- 28808065 TI - The punctilious RNA polymerase II core promoter. AB - The signals that direct the initiation of transcription ultimately converge at the core promoter, which is the gateway to transcription. Here we provide an overview of the RNA polymerase II core promoter in bilateria (bilaterally symmetric animals). The core promoter is diverse in terms of its composition and function yet is also punctilious, as it acts with strict rules and precision. We additionally describe an expanded view of the core promoter that comprises the classical DNA sequence motifs, sequence-specific DNA-binding transcription factors, chromatin signals, and DNA structure. This model may eventually lead to a more unified conceptual understanding of the core promoter. PMID- 28808067 TI - Childhood Socioeconomic Status and Arterial Stiffness in Adulthood: The Cardiovascular Risk in Young Finns Study. AB - Increasing evidence supports the importance of socioeconomic factors in the development of atherosclerotic cardiovascular disease. However, the association of childhood socioeconomic status (SES) with arterial stiffness in adulthood has not been reported. Our aim was to determine whether higher childhood family-level SES is associated with lower arterial stiffness in adulthood. The analyses were performed using data gathered within the longitudinal Young Finns Study. The sample comprised 2566 participants who had data concerning family SES at ages 3 to 18 years in 1980 and arterial pulse wave velocity and carotid artery distensibility measured 21 or 27 years later in adulthood. Higher family SES in childhood was associated with lower arterial stiffness in adulthood; carotid artery distensibility being higher (beta value+/-SE, 0.029+/-0.0089%/10 mm Hg; P=0.001) and pulse wave velocity lower (beta value+/-SE, -0.062+/-0.022 m/s; P=0.006) among those with higher family SES in a multivariable analysis adjusted with age, sex, and conventional childhood cardiometabolic risk factors. The association remained significant after further adjustment for participant's SES in adulthood (beta value+/-SE, 0.026+/-0.010%/10 mm Hg; P=0.01 for carotid artery distensibility and beta value+/-SE, -0.048+/-0.023 m/s; P=0.04 for pulse wave velocity) but attenuated after adjustment for adulthood cardiometabolic risk factors (beta value+/-SE, 0.015+/-0.008%/10 mm Hg; P=0.08 for carotid artery distensibility and beta value+/-SE, -0.019+/-0.02 m/s; P=0.38 for pulse wave velocity). In conclusion, we observed an association between higher family SES in childhood and lower arterial stiffness in adulthood. Our findings suggest that special attention could be paid to children from low SES families to prevent cardiometabolic diseases primordially. PMID- 28808068 TI - Deletion of Angiotensin-Converting Enzyme-2 Promotes Hypertensive Nephropathy by Targeting Smad7 for Ubiquitin Degradation. AB - Angiotensin-converting enzyme-2 (ACE2) is downregulated in hypertensive nephropathy. The present study investigated the mechanisms whereby loss of ACE2 promoted angiotensin II-induced hypertensive nephropathy in ACE2 gene knockout mice. We found that compared with wild-type animals, mice lacking ACE2 developed much more severe hypertensive nephropathy in response to chronic angiotensin II infusion, including higher levels of blood pressure, urinary protein excretion, serum creatinine, and progressive renal fibrosis and inflammation. Mechanistic studies revealed that worsening kidney injury in ACE2 knockout mice was associated with an increase in Smurf2 (Smad-specific E3 ubiquitin protein ligase 2), a decrease in renal Smad7, and marked activation of TGF-beta (transforming growth factor beta)/Smad3 and NF-kappaB (nuclear factor kappa-light-chain enhancer of activated B cells) signaling, suggesting that Smurf2-dependent Smad7 ubiquitin degradation may be a key mechanism whereby loss of ACE2 promotes angiotensin II-induced TGF-beta/Smad3 and NF-kappaB-mediated hypertensive nephropathy. This was validated by restoring Smad7 locally in the kidneys of ACE2 knockout mice to block angiotensin II-induced TGF-beta/Smad3-mediated renal fibrosis and NF-kappaB-driven renal inflammation. Moreover, we found that angiotensin II could induce microRNA-21 in the mouse kidney and in cultured mesangial cells via a Smad3-dependent mechanism, which was enhanced by deleting ACE2 but inhibited by overexpressing renal Smad7. In conclusion, loss of ACE2 promotes angiotensin II-induced renal injury by targeting Smad7 for degradation via a Smurf2-dependent mechanism. Overexpression of renal Smad7 protects against hypertensive nephropathy by inactivating angiotensin II-induced TGF-beta/Smad3 and NF-kappaB pathways and by targeting the Smad3-dependent microRNA-21 axis. PMID- 28808070 TI - Chicken or the Egg? Hyperuricemia, Insulin Resistance, and Hypertension. PMID- 28808069 TI - Endothelial Function Is Impaired in Patients Receiving Antihypertensive Drug Treatment Regardless of Blood Pressure Level: FMD-J Study (Flow-Mediated Dilation Japan). AB - Hypertension is associated with endothelial dysfunction. Blood pressure significantly correlates with endothelial function in antihypertensive drug-naive subjects. The purpose of this study was to determine whether treatment status affects the relationship between blood pressure and endothelial function. We measured flow-mediated vasodilation (FMD) in 2297 subjects, including 1822 antihypertensive drug-naive subjects and 475 treated hypertensive patients. FMD significantly decreased in relation to increase in systolic blood pressure (8.2+/ 3.1% in subjects with systolic blood pressure of <120 mm Hg, 7.5+/-2.8% for 120 129 mm Hg, 7.1+/-2.8% for 130-139 mm Hg, and 6.7+/-2.6% for >=140 mm Hg; P<0.001). Systolic blood pressure was independently associated with FMD in untreated subjects. In contrast, there was no significant relationship between systolic blood pressure and FMD in treated hypertensive patients (4.6+/-3.1% in treated hypertensives with systolic blood pressure of <120 mm Hg, 4.8+/-2.7% for 120-129 mm Hg, 4.9+/-2.8% for 130-139 mm Hg, and 4.5+/-2.3% for >=140 mm Hg; P=0.77). Propensity score matching analysis revealed that the prevalence of endothelial dysfunction defined as FMD of less than the division point for the lowest tertile, and the middle tertile of FMD was significantly higher in treated hypertensive patients than in untreated subjects in all systolic blood pressure categories. Endothelial function assessed by FMD was impaired regardless of the level of blood pressure achieved by antihypertensive drug treatment in hypertensive patients. PMID- 28808071 TI - Temporal Relationship Between Hyperuricemia and Insulin Resistance and Its Impact on Future Risk of Hypertension. AB - Although hyperuricemia and insulin resistance significantly correlated, their temporal sequence and how the sequence influence on future risk of hypertension are largely unknown. This study assessed temporal relationship between uric acid and insulin resistance and its impact on future risk of hypertension by examining a longitudinal cohort including 8543 subjects aged 20 to 74 years from China, with an average follow-up of 5.3 years. Measurements of fasting uric acid, as well as fasting and 2-hour serum glucose and insulin, were obtained at baseline and follow-up. Indicators of hepatic and peripheral insulin resistance were calculated. Cross-lagged panel and mediation analysis were used to examine the temporal relationship between uric acid and insulin resistance and its impact on follow-up hypertension. After adjusting for covariates, the cross-lagged path coefficients (beta1 values) from baseline uric acid to follow-up insulin resistance indices were significantly greater than path coefficients (beta2 values) from baseline insulin resistance indices to follow-up uric acid (beta1=0.110 versus beta2=0.017; P<0.001, for hepatic insulin resistance; beta1= 0.208 versus beta2=-0.021; P<0.001, for peripheral insulin resistance). The path coefficients from baseline uric acid to follow-up insulin resistance indices in the hypertensive group were significantly greater than that in the normotensive group (P<0.001 for the difference of beta1 values in the 2 groups). Insulin resistance partially mediated the effect of uric acid on subsequent hypertension, and the mediation effect of peripheral insulin resistance was significantly greater than that of hepatic insulin resistance (31.3% versus 13.2%; P<0.001, for the difference of mediation effects). These findings provide evidence that higher uric acid levels probably precede insulin resistance, and peripheral insulin resistance likely plays a more important role in the development of hypertension than hepatic insulin resistance does. PMID- 28808072 TI - Vaccines and Outpatient Antibiotic Stewardship. PMID- 28808073 TI - Unintentional Cannabis Intoxication in Toddlers. AB - BACKGROUND AND OBJECTIVES: In France, cannabis consumption is illegal. The health impact of its increasing use and higher tetrahydrocannabinol (THC) concentrations is still poorly documented, particularly that of unintentional pediatric intoxications. We sought to evaluate the French national trend of admissions for unintentional cannabis intoxication in children over an 11-year period (2004 2014). METHODS: A retrospective, national, multicenter, observational study of a pediatric cohort. All children aged <6 years admitted to a tertiary-level pediatric emergency department (PED) for proven cannabis intoxication (compatible symptoms and positive toxicological screening results) during the reference period were included. RESULTS: Twenty-four PEDs participated in our study; 235 children were included, and 71% of the patients were 18 months old or younger. Annual admissions increased by a factor of 13. Hashish resin was the main form ingested (72%). During the study period, the evolution was characterized by a national increase in intoxications, younger intoxicated children (1.28 +/- 0.4 vs 1.7 +/- 0.7 years, P = .005), and more comas (n = 38) (P = .05, odds ratio 3.5 [1.02-11.8]). Compared with other intoxications, other PED admissions, and the same age population, cannabis-related admissions were greater. There was a potential link between the increased incidence of comas and increased THC concentration in resin seized in France over the period. CONCLUSIONS: Children are collateral victims of changing trends in cannabis use and a prevailing THC concentration. Intoxicated children are more frequent, are younger, and have intoxications that are more severe. This raises a real issue of public health. PMID- 28808074 TI - Trends in Antibiotic Use by Birth Season and Birth Year. AB - OBJECTIVES: We examined 2 birth cohort effects on antibiotic prescribing during the first year of life (henceforth, infancy) in Denmark: (1) the birth season effect on timing and overall occurrence of antibiotic prescribing, and (2) the birth year effect amid emerging nationwide pneumococcal vaccination programs and changing prescribing guidelines. METHODS: We linked data for all live births in Denmark from 2004 to 2012 (N = 561 729) across the National Health Service Prescription Database, Medical Birth Registry, and Civil Registration System. Across birth season and birth year cohorts, we estimated 1-year risk, rate, and burden of redeemed antibiotic prescriptions during infancy. We used interrupted time series methods to assess prescribing trends across birth year cohorts. Graphical displays of all birth cohort effect data are included. RESULTS: The 1 year risk of having at least 1 redeemed antibiotic prescription during infancy was 39.5% (99% confidence interval [CI]: 39.3% to 39.6%). The hazard of a first prescription increased with age throughout infancy and varied by season; subsequently, Kaplan-Meier-derived risk functions varied by birth season cohort. After rollout of a first vaccination program and new antibiotic prescribing guidelines, 1-year risk decreased by 4.4% over 14 months (99% CI: 3.4% to 5.5%); it decreased again after rollout of a second vaccination program by 6.9% over 3 years (99% CI: 4.4% to 9.3%). CONCLUSIONS: In Denmark, birth season and birth year cohort effects influenced timing and risk of antibiotic prescribing during infancy. Future studies of antibiotic stewardship, effectiveness, and safety in children should consider these cohort effects, which may render some children inherently more susceptible than others to downstream antibiotic effects. PMID- 28808075 TI - Symptom response to antibiotic prescribing strategies in acute sore throat in adults: the DESCARTE prospective cohort study in UK general practice. AB - BACKGROUND: A delayed or 'just in case' prescription has been identified as having potential to reduce antibiotic use in sore throat. AIM: To determine the symptomatic outcome of acute sore throat in adults according to antibiotic prescription strategy in routine care. DESIGN AND SETTING: A secondary analysis of the DESCARTE (Decision rule for the Symptoms and Complications of Acute Red Throat in Everyday practice) prospective cohort study comprising adults aged >=16 years presenting with acute sore throat (<=2 weeks' duration) managed with treatment as usual in primary care in the UK. METHOD: A random sample of 2876 people from the full cohort were requested to complete a symptom diary. A brief clinical proforma was used to collect symptom severity and examination findings at presentation. Outcome details were collected by notes review and a detailed symptom diary. The primary outcome was poorer 'global' symptom control (defined as longer than the median duration or higher than median symptom severity). Analyses controlled for confounding by indication (propensity to prescribe antibiotics). RESULTS: A total of 1629/2876 (57%) of those requested returned a symptom diary, of whom 1512 had information on prescribing strategy. The proportion with poorer global symptom control was greater in those not prescribed antibiotics 398/587 (68%) compared with those prescribed immediate antibiotics 441/728 (61%) or delayed antibiotic prescription 116/197 59%); adjusted risk ratio (RR) (95% confidence intervals [CI]): immediate RR 0.87 (95% CI = 0.70 to 0.96), P = 0.006; delayed RR 0.88 (95% CI = 0.78 to 1.00), P = 0.042. CONCLUSION: In the routine care of adults with sore throat, a delayed antibiotic strategy confers similar symptomatic benefits to immediate antibiotics compared with no antibiotics. If a decision is made to prescribe an antibiotic, a delayed antibiotic strategy is likely to yield similar symptomatic benefit to immediate antibiotics. PMID- 28808076 TI - Influence of the duration of penicillin prescriptions on outcomes for acute sore throat in adults: the DESCARTE prospective cohort study in UK general practice. AB - BACKGROUND: Guidelines recommend 10-day treatment courses for acute sore throat, but shorter courses may be used in practice. AIM: To determine whether antibiotic duration predicts adverse outcome of acute sore throat in adults in routine care. DESIGN AND SETTING: A secondary analysis of the DESCARTE (Decision rule for the Symptoms and Complications of Acute Red Throat in Everyday practice) prospective cohort study of 12 829 adults presenting in UK general practice with acute sore throat. METHOD: A brief clinical proforma was used to collect symptom severity and examination findings at presentation. Outcomes were collected by notes review, a sample also completed a symptom diary. The primary outcome was re consultation with new/non-resolving symptoms within 1 month. The secondary outcome was 'global' poorer symptom control (longer than the median duration or higher than median severity). RESULTS: Antibiotics were prescribed for 62% (7872/12 677) of participants. The most commonly prescribed antibiotic was phenoxymethylpenicillin (76%, 5656/7474) and prescription durations were largely for 5 (20%), 7 (57%), or 10 (22%) days. Compared with 5-day courses, those receiving longer courses were less likely to re-consult with new or non-resolving symptoms (5 days 15.3%, 7 days 13.9%, 10 days 12.2%, 7-day course adjusted risk ratio (RR) 0.92 [95% confidence interval [CI] = 0.76 to 1.11] and 10-days RR 0.86 [95% CI = 0.59 to 1.23]) but these differences did not reach statistical significance. CONCLUSION: In adults prescribed antibiotics for sore throat, the authors cannot rule out a small advantage in terms of reduced re-consultation for a 10-day course of penicillin, but the effect is likely to be small. PMID- 28808077 TI - GPs' knowledge, use, and confidence in national physical activity and health guidelines and tools: a questionnaire-based survey of general practice in England. AB - BACKGROUND: Physical activity (PA) brief advice in health care is effective at getting individuals active. It has been suggested that one in four people would be more active if advised by a GP or nurse, but as many as 72% of GPs do not discuss the benefits of physical activity with patients. AIM: To assess the knowledge, use, and confidence in national PA and Chief Medical Officer (CMO) health guidelines and tools among GPs in England. DESIGN AND SETTING: Online questionnaire-based survey of self-selecting GPs in England that took place over a 10-day period in March 2016. METHOD: The questionnaire consisted of six multiple-choice questions and was available on the Doctors.net.uk (DNUK) homepage. Quotas were used to ensure good regional representation. RESULTS: The final analysis included 1013 responses. Only 20% of responders were broadly or very familiar with the national PA guidelines. In all, 70% of GPs were aware of the General Practice Physical Activity Questionnaire (GPPAQ), but 26% were not familiar with any PA assessment tools, and 55% reported that they had not undertaken any training with respect to encouraging PA. CONCLUSION: The majority of GPs in England (80%) are unfamiliar with the national PA guidelines. Awareness of the recommended tool for assessment, GPPAQ, is higher than use by GPs. This may be because it is used by other clinical staff, for example, as part of the NHS Health Check programme. Although brief advice in isolation by GPs on PA will only be a part of the behaviour change journey, it is an important prompt, especially if repeated as part of routine practice. This study highlights the need for significant improvement in knowledge, skills, and confidence to maximise the potential for PA advice in GP consultations. PMID- 28808078 TI - Relationship of Kidney Injury Biomarkers with Long-Term Cardiovascular Outcomes after Cardiac Surgery. AB - Clinical AKI, measured by serum creatinine elevation, is associated with long term risks of adverse cardiovascular (CV) events and mortality in patients after cardiac surgery. To evaluate the relative contributions of urine kidney injury biomarkers and plasma cardiac injury biomarkers in adverse events, we conducted a multicenter prospective cohort study of 968 adults undergoing cardiac surgery. On postoperative days 1-3, we measured five urine biomarkers of kidney injury (IL 18, NGAL, KIM-1, L-FABP, and albumin) and five plasma biomarkers of cardiac injury (NT-proBNP, H-FABP, hs-cTnT, cTnI, and CK-MB). The primary outcome was a composite of long-term CV events or death, which was assessed via national health care databases. During a median 3.8 years of follow-up, 219 (22.6%) patients experienced the primary outcome (136 CV events and 83 additional deaths). Compared with patients without postsurgical AKI, patients who experienced AKI Network stage 2 or 3 had an adjusted hazard ratio for the primary composite outcome of 3.52 (95% confidence interval, 2.17 to 5.71). However, none of the five urinary kidney injury biomarkers were significantly associated with the primary outcome. In contrast, four out of five postoperative cardiac injury biomarkers (NT-proBNP, H-FABP, hs-cTnT, and cTnI) strongly associated with the primary outcome. Mediation analyses demonstrated that cardiac biomarkers explained 49% (95% confidence interval, 1% to 97%) of the association between AKI and the primary outcome. These results suggest that clinical AKI at the time of cardiac surgery is indicative of concurrent CV stress rather than an independent renal pathway for long-term adverse CV outcomes. PMID- 28808081 TI - ? Eluxadoline for IBS-D. AB - Irritable bowel syndrome (IBS) is a chronic relapsing gastrointestinal problem characterised by intestinal pain and associated alterations of defecation and/or bowel habit (constipation: IBS-C or diarrhoea: IBS-D).1,2 Opioid receptors in the gut have a role in gastrointestinal motility, secretion and sensation.3 Tau Eluxadoline (Truberzi-Allergan) is a locally acting, mixed opioid receptor agonist/antagonist licensed for the treatment of IBS-D in adults.4 Here, we consider the evidence for eluxadoline and how it fts with current management strategies for IBS-D. PMID- 28808080 TI - Characterization of the human thyroid epigenome. AB - The thyroid gland, necessary for normal human growth and development, functions as an essential regulator of metabolism by the production and secretion of appropriate levels of thyroid hormone. However, assessment of abnormal thyroid function may be challenging suggesting a more fundamental understanding of normal function is needed. One way to characterize normal gland function is to study the epigenome and resulting transcriptome within its constituent cells. This study generates the first published reference epigenomes for human thyroid from four individuals using ChIP-seq and RNA-seq. We profiled six histone modifications (H3K4me1, H3K4me3, H3K27ac, H3K36me3, H3K9me3, H3K27me3), identified chromatin states using a hidden Markov model, produced a novel quantitative metric for model selection and established epigenomic maps of 19 chromatin states. We found that epigenetic features characterizing promoters and transcription elongation tend to be more consistent than regions characterizing enhancers or Polycomb repressed regions and that epigenetically active genes consistent across all epigenomes tend to have higher expression than those not marked as epigenetically active in all epigenomes. We also identified a set of 18 genes epigenetically active and consistently expressed in the thyroid that are likely highly relevant to thyroid function. Altogether, these epigenomes represent a powerful resource to develop a deeper understanding of the underlying molecular biology of thyroid function and provide contextual information of thyroid and human epigenomic data for comparison and integration into future studies. PMID- 28808083 TI - Strontium ranelate discontinued. PMID- 28808079 TI - The impact of IUGR on pancreatic islet development and beta-cell function. AB - Placental insufficiency is a primary cause of intrauterine growth restriction (IUGR). IUGR increases the risk of developing type 2 diabetes mellitus (T2DM) throughout life, which indicates that insults from placental insufficiency impair beta-cell development during the perinatal period because beta-cells have a central role in the regulation of glucose tolerance. The severely IUGR fetal pancreas is characterized by smaller islets, less beta-cells, and lower insulin secretion. Because of the important associations among impaired islet growth, beta-cell dysfunction, impaired fetal growth, and the propensity for T2DM, significant progress has been made in understanding the pathophysiology of IUGR and programing events in the fetal endocrine pancreas. Animal models of IUGR replicate many of the observations in severe cases of human IUGR and allow us to refine our understanding of the pathophysiology of developmental and functional defects in islet from IUGR fetuses. Almost all models demonstrate a phenotype of progressive loss of beta-cell mass and impaired beta-cell function. This review will first provide evidence of impaired human islet development and beta-cell function associated with IUGR and the impact on glucose homeostasis including the development of glucose intolerance and diabetes in adulthood. We then discuss evidence for the mechanisms regulating beta-cell mass and insulin secretion in the IUGR fetus, including the role of hypoxia, catecholamines, nutrients, growth factors, and pancreatic vascularity. We focus on recent evidence from experimental interventions in established models of IUGR to understand better the pathophysiological mechanisms linking placental insufficiency with impaired islet development and beta-cell function. PMID- 28808082 TI - Tau Eluxadoline for IBS-D. PMID- 28808084 TI - Glycopyrronium for severe drooling in children. AB - Drooling of saliva is common in children with physical, intellectual and learning disability, and with poor neuromuscular coordination and oral control.1 It can cause skin breakdown, damage to clothes and equipment and psychosocial problems for the child and family. For many years, glycopyrronium has been prescribed off label using the injection solution given orally or tablets crushed and suspended in water, or as unlicensed products that were imported or manufactured as pharmaceutical specials.2,3 In January 2017, a glycopyrronium oral solution (Sialanar-Proveca Limited) became available in the UK as the first licensed product for the treatment of severe drooling (sialorrhoea) in children and adolescents aged 3 years and older with chronic neurological disorders.4-6 Here, we consider the place of this new product in the management of severe drooling. PMID- 28808086 TI - A pharmacological study of Arabidopsis cell fusion between the persistent synergid and endosperm. AB - Cell fusion is a pivotal process in fertilization and multinucleate cell formation. A plant cell is ubiquitously surrounded by a hard cell wall, and very few cell fusions have been observed except for gamete fusions. We recently reported that the fertilized central cell (the endosperm) absorbs the persistent synergid, a highly differentiated cell necessary for pollen tube attraction. The synergid-endosperm fusion (SE fusion) appears to eliminate the persistent synergid from fertilized ovule in Arabidopsis thaliana Here, we analyzed the effects of various inhibitors on SE fusion in an in vitro culture system. Different from other cell fusions, neither disruption of actin polymerization nor protein secretion impaired SE fusion. However, transcriptional and translational inhibitors decreased the SE fusion success rate and also inhibited endosperm division. Failures of SE fusion and endosperm nuclear proliferation were also induced by roscovitine, an inhibitor of cyclin-dependent kinases (CDK). These data indicate unique aspects of SE fusion such as independence of filamentous actin support and the importance of CDK-mediated mitotic control. PMID- 28808085 TI - Sub-mitochondrial localization of the genetic-tagged mitochondrial intermembrane space-bridging components Mic19, Mic60 and Sam50. AB - Each mitochondrial compartment contains varying protein compositions that underlie a diversity of localized functions. Insights into the localization of mitochondrial intermembrane space-bridging (MIB) components will have an impact on our understanding of mitochondrial architecture, dynamics and function. By using the novel visualizable genetic tags miniSOG and APEX2 in cultured mouse cardiac and human astrocyte cell lines and performing electron tomography, we have mapped at nanoscale resolution three key MIB components, Mic19, Mic60 and Sam50 (also known as CHCHD3, IMMT and SAMM50, respectively), in the environment of structural landmarks such as cristae and crista junctions (CJs). Tagged Mic19 and Mic60 were located at CJs, distributed in a network pattern along the mitochondrial periphery and also enriched inside cristae. We discovered an association of Mic19 with cytochrome c oxidase subunit IV. It was also found that tagged Sam50 is not uniformly distributed in the outer mitochondrial membrane and appears to incompletely overlap with Mic19- or Mic60-positive domains, most notably at the CJs. PMID- 28808087 TI - The Drosophila LC8 homolog cut up specifies the axonal transport of proteasomes. AB - Because of their functional polarity and elongated morphologies, microtubule based transport of proteins and organelles is critical for normal neuronal function. The proteasome is required throughout the neuron for the highly regulated degradation of a broad set of protein targets whose functions underlie key physiological responses, including synaptic plasticity and axonal degeneration. Molecularly, the relationship between proteasome transport and the transport of the targets of proteasomes is unclear. The dynein motor complex is required for the microtubule-based motility of numerous proteins and organelles in neurons. Here, we demonstrate that microtubule-based transport of proteasomes within the neuron in Drosophila utilizes a different dynein light chain to that used by synaptic proteins. Live imaging of proteasomes and synaptic vesicle proteins in axons and synapses finds that these cargoes traffic independently, and that proteasomes exhibit significantly reduced retrograde transport velocities compared to those of synaptic vesicle proteins. Genetic and biochemical analyses reveals that the Drosophila homolog of the LC8 dynein light chains (mammalian DYNLL1 and DYNLL2), called Cut up, binds proteasomes and functions specifically during their transport. These data support the model that Cut up functions to specify the dynein-mediated transport of neuronal proteasomes. PMID- 28808088 TI - The armadillo protein p0071 controls KIF3 motor transport. AB - We here report a novel function of the armadillo protein p0071 (also known as PKP4) during transport mediated by the KIF3 transport complex. Secretion of chromogranin A and matrix metallopeptidase 9 from pancreatic neuroendocrine tumor cells or pancreatic cancer cells, respectively, was substantially reduced following knockdown of p0071. Vesicle tracking indicated that there was impaired directional persistence of vesicle movement upon p0071 depletion. This suggests a disturbed balance between plus- and minus-end directed microtubule transport in cells lacking p0071. p0071 directly interacts with the KIF3 motor subunit KIF3B. Our data indicate that p0071 also interacts with the kinesin cargo adaptor protein KAP3 (also known as KIFAP3) acting as a stabilizing linker between KIF3B and its KAP3 cargo-binding entity. Thus, p0071 is required for directional vesicle movement and secretion of different KIF3-transported carriers, thereby regulating the transport of intracellular membrane vesicles along microtubules. PMID- 28808089 TI - BAG3-mediated proteostasis at a glance. AB - Cellular and organismal survival depend on the ability to maintain the proteome, even under conditions that threaten protein integrity. BCL2-associated athanogene 3 (BAG3) is essential for protein homeostasis (proteostasis) in stressed cells. Owing to its multi-domain structure, it engages in diverse processes that are crucial for proteome maintenance. BAG3 promotes the activity of molecular chaperones, sequesters and concentrates misfolded proteins, initiates autophagic disposal, and balances transcription, translation and degradation. In this Cell Science at a Glance article and the accompanying poster, we discuss the functions of this multi-functional proteostasis tool with a focus on mechanical stress protection and describe the importance of BAG3 for human physiology and pathophysiology. PMID- 28808090 TI - The wisdom of crowds: regulating cell function through condensed states of living matter. AB - Our understanding of cells has progressed rapidly in recent years, mainly because of technological advances. Modern technology now allows us to observe molecular processes in living cells with high spatial and temporal resolution. At the same time, we are beginning to compile the molecular parts list of cells. However, how all these parts work together to yield complex cellular behavior is still unclear. In addition, the established paradigm of molecular biology, which sees proteins as well-folded enzymes that undergo specific lock-and-key type interactions, is increasingly being challenged. In fact, it is now becoming clear that many proteins do not fold into three-dimensional structures and additionally show highly promiscuous binding behavior. Furthermore, proteins function in collectives and form condensed phases with different material properties, such as liquids, gels, glasses or filaments. Here, I examine emerging evidence that the formation of macromolecular condensates is a fundamental principle in cell biology. I further discuss how different condensed states of living matter regulate cellular functions and decision-making and ensure adaptive behavior and survival in times of cellular crisis. PMID- 28808092 TI - Training and Experience Matter: Improving Athlete ECG Screening, Interpretation, and Reproducibility. PMID- 28808091 TI - Inter-Rater Reliability and Downstream Financial Implications of Electrocardiography Screening in Young Athletes. AB - BACKGROUND: Preparticipation screening for cardiovascular disease in young athletes with electrocardiography is endorsed by the European Society of Cardiology and several major sporting organizations. One of the concerns of the ECG as a screening test in young athletes relates to the potential for variation in interpretation. We investigated the degree of variation in ECG interpretation in athletes and its financial impact among cardiologists of differing experience. METHODS AND RESULTS: Eight cardiologists (4 with experience in screening athletes) each reported 400 ECGs of consecutively screened young athletes according to the 2010 European Society of Cardiology recommendations, Seattle criteria, and refined criteria. Cohen kappa coefficient was used to calculate interobserver reliability. Cardiologists proposed secondary investigations after ECG interpretation, the costs of which were based on the UK National Health Service tariffs. Inexperienced cardiologists were more likely to classify an ECG as abnormal compared with experienced cardiologists (odds ratio, 1.44; 95% confidence interval, 1.03-2.02). Modification of ECG interpretation criteria improved interobserver reliability for categorizing an ECG as abnormal from poor (2010 European Society of Cardiology recommendations; kappa=0.15) to moderate (refined criteria; kappa=0.41) among inexperienced cardiologists; however, interobserver reliability was moderate for all 3 criteria among experienced cardiologists (kappa=0.40-0.53). Inexperienced cardiologists were more likely to refer athletes for further evaluation compared with experienced cardiologists (odds ratio, 4.74; 95% confidence interval, 3.50-6.43) with poorer interobserver reliability (kappa=0.22 versus kappa=0.47). Interobserver reliability for secondary investigations after ECG interpretation ranged from poor to fair among inexperienced cardiologists (kappa=0.15-0.30) and fair to moderate among experienced cardiologists (kappa=0.21-0.46). The cost of cardiovascular evaluation per athlete was $175 (95% confidence interval, $142-$228) and $101 (95% confidence interval, $83-$131) for inexperienced and experienced cardiologists, respectively. CONCLUSIONS: Interpretation of the ECG in athletes and the resultant cascade of investigations are highly physician dependent even in experienced hands with important downstream financial implications, emphasizing the need for formal training and standardized diagnostic pathways. PMID- 28808094 TI - Photosynthesis solutions to enhance productivity. AB - The concept that photosynthesis is a highly inefficient process in terms of conversion of light energy into biomass is embedded in the literature. It is only in the past decade that the processes limiting photosynthetic efficiency have been understood to an extent that allows a step change in our ability to manipulate light energy assimilation into carbon gain. We can therefore envisage that future increases in the grain yield potential of our major crops may depend largely on increasing the efficiency of photosynthesis. The papers in this issue provide new insights into the nature of current limitations on photosynthesis and identify new targets that can be used for crop improvement, together with information on the impacts of a changing environment on the productivity of photosynthesis on land and in our oceans.This article is part of the themed issue 'Enhancing photosynthesis in crop plants: targets for improvement'. PMID- 28808093 TI - Are Disagreements in Caregiver and Patient Assessment of Patient Health Associated with Increased Caregiver Burden in Caregivers of Older Adults with Cancer? AB - BACKGROUND: As patients age, caregivers increasingly provide essential support and patient information. We sought to determine if patient-caregiver assessments of patient health differ and if differences contribute to burden in caregivers of older adults with cancer. MATERIALS AND METHODS: One hundred patients, aged >=65, and their caregivers independently assessed patient function, comorbidity, nutrition, social activity, social support, and mental health. Caregivers completed the Caregiver Strain Index (CSI). Patient-caregiver assessments were compared using the Wilcoxon signed rank test and paired t test. Association between caregiver burden and differences between patient-caregiver assessments was examined using generalized linear regression. RESULTS: Median patient age was 70 (range 65-91) and 70% had advanced disease. Sixty percent of patients reported requiring help with instrumental activities of daily living (IADLs); most had good social support (median Medical Outcomes Study [MOS]-Social Support Survey score 92) and mental health (median Mental Health Inventory score 85).Caregivers were a median age of 66 (range 28-85), 73% female, 68% spousal caregivers, and 79% lived with the patient. Caregivers rated patients as having poorer physical function (more IADLs dependency [p = .008], lower Karnofsky Performance Status [p = .02], lower MOS-Physical Function [p < .0001]), poorer mental health (p = .0002), and having more social support (p = .03) than patients themselves. Three quarters of caregivers experienced some caregiver burden (mean CSI score 3.1). Only differences in patient-caregiver assessment of the patient's need for help with IADLs were associated with increased caregiver burden (p = .03). CONCLUSION: Patient-caregiver assessments of patient function, mental health, and social support differ. However, only differences in assessment of IADLs dependency were associated with increased caregiver burden. IMPLICATIONS FOR PRACTICE: As patients age, there is a higher incidence of frailty and cognitive impairments. As a result, caregivers play an increasingly vital role in providing information about patient health to healthcare providers, which is used to help healthcare providers tailor treatments and optimize patient health. These findings highlight that caregiver reporting in older adults with cancer may not replace patient reporting in those older adults who are otherwise able to self-report. Furthermore, clinicians should check for caregiver burden in caregivers who report providing more help with instrumental activities of daily living than patients themselves report and provide appropriate support as needed. PMID- 28808095 TI - What limits photosynthetic energy conversion efficiency in nature? Lessons from the oceans. AB - Constraining photosynthetic energy conversion efficiency in nature is challenging. In principle, two yield measurements must be made simultaneously: photochemistry, fluorescence and/or thermal dissipation. We constructed two different, extremely sensitive and precise active fluorometers: one measures the quantum yield of photochemistry from changes in variable fluorescence, the other measures fluorescence lifetimes in the picosecond time domain. By deploying the pair of instruments on eight transoceanic cruises over six years, we obtained over 200 000 measurements of fluorescence yields and lifetimes from surface waters in five ocean basins. Our results revealed that the average quantum yield of photochemistry was approximately 0.35 while the average quantum yield of fluorescence was approximately 0.07. Thus, closure on the energy budget suggests that, on average, approximately 58% of the photons absorbed by phytoplankton in the world oceans are dissipated as heat. This extraordinary inefficiency is associated with the paucity of nutrients in the upper ocean, especially dissolved inorganic nitrogen and iron. Our results strongly suggest that, in nature, most of the time, most of the phytoplankton community operates at approximately half of its maximal photosynthetic energy conversion efficiency because nutrients limit the synthesis or function of essential components in the photosynthetic apparatus.This article is part of the themed issue 'Enhancing photosynthesis in crop plants: targets for improvement'. PMID- 28808096 TI - Strategies and tools to improve crop productivity by targeting photosynthesis. AB - Crop productivity needs to substantially increase to meet global food and feed demand for a rapidly growing world population. Agricultural technology developers are pursuing a variety of approaches based on both traditional technologies such as genetic improvement, pest control and mechanization as well as new technologies such as genomics, gene manipulation and environmental modelling to develop crops that are capable of meeting growing demand. Photosynthesis is a key biochemical process that, many suggest, is not yet optimized for industrial agriculture or the modern global environment. We are interested in identifying control points in maize photoassimilation that are amenable to gene manipulation to improve overall productivity. Our approach encompasses: developing and using novel gene discovery techniques, translating our discoveries into traits and evaluating each trait in a stepwise manner that reflects a modern production environment. Our aim is to provide step change advancement in overall crop productivity and deliver this new technology into the hands of growers.This article is part of the themed issue 'Enhancing photosynthesis in crop plants: targets for improvement'. PMID- 28808097 TI - Photoprotection through ultrafast charge recombination in photochemical reaction centres under oxidizing conditions. AB - Engineering natural photosynthesis to address predicted shortfalls in food and energy supply requires a detailed understanding of its molecular basis and the intrinsic photoprotective mechanisms that operate under fluctuating environmental conditions. Long-lived triplet or singlet excited electronic states have the potential to cause photodamage, particularly in the presence of oxygen, and so a variety of mechanisms exist to prevent formation of such states or safely dissipate their energy. Here, we report a dramatic difference in spectral evolution in fully reduced and partially oxidized Rhodobacter sphaeroides reaction centres (RCs) following excitation of the monomeric bacteriochlorophyll (BChl) cofactors at 805 nm. Three types of preparation were studied, including RCs purified as protein/lipid nanodiscs using the copolymer styrene maleic acid. In fully reduced RCs such excitation produces membrane-spanning charge separation. In preparations of partially oxidized RCs the spectroscopic signature of this charge separation is replaced by that of an energy dissipation process, including in the majority sub-population of reduced RCs. This process, which appears to take place on both cofactor branches, involves formation of a BChl+/bacteriopheophytin- radical pair that dissipates energy via recombination to a vibrationally hot ground state. The possible physiological role of this dissipative process under mildly oxidizing conditions is considered.This article is part of the themed issue 'Enhancing photosynthesis in crop plants: targets for improvement'. PMID- 28808098 TI - Overexpression of plastid terminal oxidase in Synechocystis sp. PCC 6803 alters cellular redox state. AB - Cyanobacteria are the most ancient organisms performing oxygenic photosynthesis, and they are the ancestors of plant plastids. All plastids contain the plastid terminal oxidase (PTOX), while only certain cyanobacteria contain PTOX. Many putative functions have been discussed for PTOX in higher plants including a photoprotective role during abiotic stresses like high light, salinity and extreme temperatures. Since PTOX oxidizes PQH2 and reduces oxygen to water, it is thought to protect against photo-oxidative damage by removing excess electrons from the plastoquinone (PQ) pool. To investigate the role of PTOX we overexpressed rice PTOX fused to the maltose-binding protein (MBP-OsPTOX) in Synechocystis sp. PCC 6803, a model cyanobacterium that does not encode PTOX. The fusion was highly expressed and OsPTOX was active, as shown by chlorophyll fluorescence and P700 absorption measurements. The presence of PTOX led to a highly oxidized state of the NAD(P)H/NAD(P)+ pool, as detected by NAD(P)H fluorescence. Moreover, in the PTOX overexpressor the electron transport capacity of PSI relative to PSII was higher, indicating an alteration of the photosystem I (PSI) to photosystem II (PSII) stoichiometry. We suggest that PTOX controls the expression of responsive genes of the photosynthetic apparatus in a different way from the PQ/PQH2 ratio.This article is part of the themed issue 'Enhancing photosynthesis in crop plants: targets for improvement'. PMID- 28808099 TI - Enhancing (crop) plant photosynthesis by introducing novel genetic diversity. AB - Although some elements of the photosynthetic light reactions might appear to be ideal, the overall efficiency of light conversion to biomass has not been optimized during evolution. Because crop plants are depleted of genetic diversity for photosynthesis, efforts to enhance its efficiency with respect to light conversion to yield must generate new variation. In principle, three sources of natural variation are available: (i) rare diversity within extant higher plant species, (ii) photosynthetic variants from algae, and (iii) reconstruction of no longer extant types of plant photosynthesis. Here, we argue for a novel approach that outsources crop photosynthesis to a cyanobacterium that is amenable to adaptive evolution. This system offers numerous advantages, including a short generation time, virtually unlimited population sizes and high mutation rates, together with a versatile toolbox for genetic manipulation. On such a synthetic bacterial platform, 10 000 years of (crop) plant evolution can be recapitulated within weeks. Limitations of this system arise from its unicellular nature, which cannot reproduce all aspects of crop photosynthesis. But successful establishment of such a bacterial host for crop photosynthesis promises not only to enhance the performance of eukaryotic photosynthesis but will also reveal novel facets of the molecular basis of photosynthetic flexibility.This article is part of the themed issue 'Enhancing photosynthesis in crop plants: targets for improvement'. PMID- 28808100 TI - Hacking the thylakoid proton motive force for improved photosynthesis: modulating ion flux rates that control proton motive force partitioning into Deltapsi and DeltapH. AB - There is considerable interest in improving plant productivity by altering the dynamic responses of photosynthesis in tune with natural conditions. This is exemplified by the 'energy-dependent' form of non-photochemical quenching (qE), the formation and decay of which can be considerably slower than natural light fluctuations, limiting photochemical yield. In addition, we recently reported that rapidly fluctuating light can produce field recombination-induced photodamage (FRIP), where large spikes in electric field across the thylakoid membrane (Deltapsi) induce photosystem II recombination reactions that produce damaging singlet oxygen (1O2). Both qE and FRIP are directly linked to the thylakoid proton motive force (pmf), and in particular, the slow kinetics of partitioning pmf into its DeltapH and Deltapsi components. Using a series of computational simulations, we explored the possibility of 'hacking' pmf partitioning as a target for improving photosynthesis. Under a range of illumination conditions, increasing the rate of counter-ion fluxes across the thylakoid membrane should lead to more rapid dissipation of Deltapsi and formation of DeltapH. This would result in increased rates for the formation and decay of qE while resulting in a more rapid decline in the amplitudes of Deltapsi spikes and decreasing 1O2 production. These results suggest that ion fluxes may be a viable target for plant breeding or engineering. However, these changes also induce transient, but substantial mismatches in the ATP : NADPH output ratio as well as in the osmotic balance between the lumen and stroma, either of which may explain why evolution has not already accelerated thylakoid ion fluxes. Overall, though the model is simplified, it recapitulates many of the responses seen in vivo, while spotlighting critical aspects of the complex interactions between pmf components and photosynthetic processes. By making the programme available, we hope to enable the community of photosynthesis researchers to further explore and test specific hypotheses.This article is part of the themed issue 'Enhancing photosynthesis in crop plants: targets for improvement'. PMID- 28808101 TI - Increased SBPase activity improves photosynthesis and grain yield in wheat grown in greenhouse conditions. AB - To meet the growing demand for food, substantial improvements in yields are needed. This is particularly the case for wheat, where global yield has stagnated in recent years. Increasing photosynthesis has been identified as a primary target to achieve yield improvements. To increase leaf photosynthesis in wheat, the level of the Calvin-Benson cycle enzyme sedoheptulose-1,7-biphosphatase (SBPase) has been increased through transformation and expression of a Brachypodium distachyon SBPase gene construct. Transgenic lines with increased SBPase protein levels and activity were grown under greenhouse conditions and showed enhanced leaf photosynthesis and increased total biomass and dry seed yield. This showed the potential of improving yield potential by increasing leaf photosynthesis in a crop species such as wheat. The results are discussed with regard to future strategies for further improvement of photosynthesis in wheat.This article is part of the themed issue 'Enhancing photosynthesis in crop plants: targets for improvement'. PMID- 28808102 TI - Recruitment of pre-existing networks during the evolution of C4 photosynthesis. AB - During C4 photosynthesis, CO2 is concentrated around the enzyme RuBisCO. The net effect is to reduce photorespiration while increasing water and nitrogen use efficiencies. Species that use C4 photosynthesis have evolved independently from their C3 ancestors on more than 60 occasions. Along with mimicry and the camera like eye, the C4 pathway therefore represents a remarkable example of the repeated evolution of a highly complex trait. In this review, we provide evidence that the polyphyletic evolution of C4 photosynthesis is built upon pre-existing metabolic and genetic networks. For example, cells around veins of C3 species show similarities to those of the C4 bundle sheath in terms of C4 acid decarboxylase activity and also the photosynthetic electron transport chain. Enzymes of C4 photosynthesis function together in gluconeogenesis during early seedling growth of C3Arabidopsis thaliana Furthermore, multiple C4 genes appear to be under control of both light and chloroplast signals in the ancestral C3 state. We, therefore, hypothesize that relatively minor rewiring of pre-existing genetic and metabolic networks has facilitated the recurrent evolution of this trait. Understanding how these changes are likely to have occurred could inform attempts to install C4 traits into C3 crops.This article is part of the themed issue 'Enhancing photosynthesis in crop plants: targets for improvement'. PMID- 28808103 TI - A bioarchitectonic approach to the modular engineering of metabolism. AB - Dissociating the complexity of metabolic processes into modules is a shift in focus from the single gene/gene product to functional and evolutionary units spanning the scale of biological organization. When viewing the levels of biological organization through this conceptual lens, modules are found across the continuum: domains within proteins, co-regulated groups of functionally associated genes, operons, metabolic pathways and (sub)cellular compartments. Combining modules as components or subsystems of a larger system typically leads to increased complexity and the emergence of new functions. By virtue of their potential for 'plug and play' into new contexts, modules can be viewed as units of both evolution and engineering. Through consideration of lessons learned from recent efforts to install new metabolic modules into cells and the emerging understanding of the structure, function and assembly of protein-based organelles, bacterial microcompartments, a structural bioengineering approach is described: one that builds from an architectural vocabulary of protein domains. This bioarchitectonic approach to engineering cellular metabolism can be applied to microbial cell factories, used in the programming of members of synthetic microbial communities or used to attain additional levels of metabolic organization in eukaryotic cells for increasing primary productivity and as the foundation of a green economy.This article is part of the themed issue 'Enhancing photosynthesis in crop plants: targets for improvement'. PMID- 28808104 TI - Interaction between photosynthetic electron transport and chloroplast sinks triggers protection and signalling important for plant productivity. AB - The photosynthetic light reactions provide energy that is consumed and stored in electron sinks, the products of photosynthesis. A balance between light reactions and electron consumption in the chloroplast is vital for plants, and is protected by several photosynthetic regulation mechanisms. Photosystem I (PSI) is particularly susceptible to photoinhibition when these factors become unbalanced, which can occur in low temperatures or in high light. In this study we used the pgr5 Arabidopsis mutant that lacks DeltapH-dependent regulation of photosynthetic electron transport as a model to study the consequences of PSI photoinhibition under high light. We found that PSI damage severely inhibits carbon fixation and starch accumulation, and attenuates enzymatic oxylipin synthesis and chloroplast regulation of nuclear gene expression after high light stress. This work shows that modifications to regulation of photosynthetic light reactions, which may be designed to improve yield in crop plants, can negatively impact metabolism and signalling, and thereby threaten plant growth and stress tolerance.This article is part of the themed issue 'Enhancing photosynthesis in crop plants: targets for improvement'. PMID- 28808105 TI - Inhibitor-induced oxidation of the nucleus and cytosol in Arabidopsis thaliana: implications for organelle to nucleus retrograde signalling. AB - Concepts of organelle-to-nucleus signalling pathways are largely based on genetic screens involving inhibitors of chloroplast and mitochondrial functions such as norflurazon, lincomycin (LINC), antimycin A (ANT) and salicylhydroxamic acid. These inhibitors favour enhanced cellular oxidation, but their precise effects on the cellular redox state are unknown. Using the in vivo reduction-oxidation (redox) reporter, roGFP2, inhibitor-induced changes in the glutathione redox potentials of the nuclei and cytosol were measured in Arabidopsis thaliana root, epidermal and stomatal guard cells, together with the expression of nuclear encoded chloroplast and mitochondrial marker genes. All the chloroplast and mitochondrial inhibitors increased the degree of oxidation in the nuclei and cytosol. However, inhibitor-induced oxidation was less marked in stomatal guard cells than in epidermal or root cells. Moreover, LINC and ANT caused a greater oxidation of guard cell nuclei than the cytosol. Chloroplast and mitochondrial inhibitors significantly decreased the abundance of LHCA1 and LHCB1 transcripts. The levels of WHY1, WHY3 and LEA5 transcripts were increased in the presence of inhibitors. Chloroplast inhibitors decreased AOXA1 mRNA levels, while mitochondrial inhibitors had the opposite effect. Inhibitors that are used to characterize retrograde signalling pathways therefore have similar general effects on cellular redox state and gene expression.This article is part of the themed issue 'Enhancing photosynthesis in crop plants: targets for improvement'. PMID- 28808106 TI - Quantifying the efficiency of photoprotection. AB - A novel emerging technology for the assessment of the photoprotective 'power' of non-photochemical fluorescence quenching (NPQ) has been reviewed and its insightful outcomes are explained using several examples. The principles of the method are described in detail as well as the work undertaken for its justification. This pulse amplitude modulated chlorophyll fluorescence approach has been applied for the past 5 years to quantify the photoprotective effectiveness of the NPQ and the light tolerance in Arabidopsis plants grown under various light conditions, during ontogenetic development as well as in a range of mutants impaired in carotenoid and protein biosynthesis. The future applications of this approach for the assessment of crop plant light tolerance are outlined. The perspective of obtaining detailed information about how the extent of photoinhibition and photoprotection can affect plant development, growth and productivity is highlighted, including the potential for us to predict the influence of environmental elements on plant performance and yield of crops. The novel methodology can be used to build up comprehensive light tolerance databases for various current and emerging varieties of crops that are grown outdoors as well as in artificial light environments, in order to optimize for the best environmental conditions that enable high crop productivity.This article is part of the themed issue 'Enhancing photosynthesis in crop plants: targets for improvement'. PMID- 28808107 TI - Structure of Psb29/Thf1 and its association with the FtsH protease complex involved in photosystem II repair in cyanobacteria. AB - One strategy for enhancing photosynthesis in crop plants is to improve their ability to repair photosystem II (PSII) in response to irreversible damage by light. Despite the pivotal role of thylakoid-embedded FtsH protease complexes in the selective degradation of PSII subunits during repair, little is known about the factors involved in regulating FtsH expression. Here we show using the cyanobacterium Synechocystis sp. PCC 6803 that the Psb29 subunit, originally identified as a minor component of His-tagged PSII preparations, physically interacts with FtsH complexes in vivo and is required for normal accumulation of the FtsH2/FtsH3 hetero-oligomeric complex involved in PSII repair. We show using X-ray crystallography that Psb29 from Thermosynechococcus elongatus has a unique fold consisting of a helical bundle and an extended C-terminal helix and contains a highly conserved region that might be involved in binding to FtsH. A similar interaction is likely to occur in Arabidopsis chloroplasts between the Psb29 homologue, termed THF1, and the FTSH2/FTSH5 complex. The direct involvement of Psb29/THF1 in FtsH accumulation helps explain why THF1 is a target during the hypersensitive response in plants induced by pathogen infection. Downregulating FtsH function and the PSII repair cycle via THF1 would contribute to the production of reactive oxygen species, the loss of chloroplast function and cell death.This article is part of the themed issue 'Enhancing photosynthesis in crop plants: targets for improvement'. PMID- 28808108 TI - Chloroplast thioredoxin systems: prospects for improving photosynthesis. AB - Thioredoxins (TRXs) are protein oxidoreductases that control the structure and function of cellular proteins by cleavage of a disulphide bond between the side chains of two cysteine residues. Oxidized thioredoxins are reactivated by thioredoxin reductases (TR) and a TR-dependent reduction of TRXs is called a thioredoxin system. Thiol-based redox regulation is an especially important mechanism to control chloroplast proteins involved in biogenesis, in regulation of light harvesting and distribution of light energy between photosystems, in photosynthetic carbon fixation and other biosynthetic pathways, and in stress responses of plants. Of the two plant plastid thioredoxin systems, the ferredoxin dependent system relays reducing equivalents from photosystem I via ferredoxin and ferredoxin-thioredoxin reductase (FTR) to chloroplast proteins, while NADPH dependent thioredoxin reductase (NTRC) forms a complete thioredoxin system including both reductase and thioredoxin domains in a single polypeptide. Chloroplast thioredoxins transmit environmental light signals to biochemical reactions, which allows fine tuning of photosynthetic processes in response to changing environmental conditions. In this paper we focus on the recent reports on specificity and networking of chloroplast thioredoxin systems and evaluate the prospect of improving photosynthetic performance by modifying the activity of thiol regulators in plants.This article is part of the themed issue 'Enhancing photosynthesis in crop plants: targets for improvement'. PMID- 28808110 TI - Moving point of GMC registration is "out of remit" of training review body. PMID- 28808109 TI - Slow induction of photosynthesis on shade to sun transitions in wheat may cost at least 21% of productivity. AB - Wheat is the second most important direct source of food calories in the world. After considerable improvement during the Green Revolution, increase in genetic yield potential appears to have stalled. Improvement of photosynthetic efficiency now appears a major opportunity in addressing the sustainable yield increases needed to meet future food demand. Effort, however, has focused on increasing efficiency under steady-state conditions. In the field, the light environment at the level of individual leaves is constantly changing. The speed of adjustment of photosynthetic efficiency can have a profound effect on crop carbon gain and yield. Flag leaves of wheat are the major photosynthetic organs supplying the grain of wheat, and will be intermittently shaded throughout a typical day. Here, the speed of adjustment to a shade to sun transition in these leaves was analysed. On transfer to sun conditions, the leaf required about 15 min to regain maximum photosynthetic efficiency. In vivo analysis based on the responses of leaf CO2 assimilation (A) to intercellular CO2 concentration (ci) implied that the major limitation throughout this induction was activation of the primary carboxylase of C3 photosynthesis, ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco). This was followed in importance by stomata, which accounted for about 20% of the limitation. Except during the first few seconds, photosynthetic electron transport and regeneration of the CO2 acceptor molecule, ribulose-1,5 bisphosphate (RubP), did not affect the speed of induction. The measured kinetics of Rubisco activation in the sun and de-activation in the shade were predicted from the measurements. These were combined with a canopy ray tracing model that predicted intermittent shading of flag leaves over the course of a June day. This indicated that the slow adjustment in shade to sun transitions could cost 21% of potential assimilation.This article is part of the themed issue 'Enhancing photosynthesis in crop plants: targets for improvement'. PMID- 28808111 TI - Interferon-tau promotes luteal endothelial cell survival and inhibits specific luteolytic genes in bovine corpus luteum. AB - Interferon-tau (IFNT), a maternal recognition of pregnancy (MRP) signals in domestic ruminants, suppresses the release of luteolytic pulses of uterine prostaglandin F2a (PGF2a), thus extending the corpus luteum (CL) life span. We hypothesized that IFNT also exerts anti-luteolytic actions in bovine CL. To examine the direct effects of IFNT on bovine CL, luteal slices and enriched luteal endothelial cells (LECs) were utilized. We found that recombinant ovine IFNT (roIFNT) markedly elevates interferon-associated genes (STAT1, STAT2 and IRF9) and interferon-stimulated genes (ISGs: MX2, ISG15 and OAS1Y) in both models. Furthermore, IFNT time-dependently induced STAT1 phosphorylation in LECs without affecting total STAT1. roIFNT-stimulated viable LECs numbers and the knockdown of protein inhibitor of activated STAT1 (PIAS1) abolished this effect, suggesting that PIAS1 may mediate the proliferative effect of IFNT. IFNT significantly downregulated luteolytic genes such as TGFB1, thrombospondin-1 (THBS1), endothelin-1 (EDN1) and serpin family E member-1 (SERPINE1) in LECs. However, less robust effects were observed in luteal slices. Moreover, PGF2a alone induced THBS1, SERPINE1 and EDN1 mRNA in CL slices whereas in the presence of IFNT, THBS1 and SERPINE1 stimulation was abolished. Collectively, these results indicate that IFNT acts via STAT1- IRF9-dependent and independent pathways and affects diverse luteal functions. Most interestingly, this study suggests the existence of an anti-luteolytic effect of IFNT in bovine CL, namely, inhibiting key PGF2a-induced luteolytic genes. The proliferative effect of IFNT may constitute an additional mechanism that promotes luteal cell survival, thus, extending the luteal life span during early pregnancy in cows. PMID- 28808112 TI - Regulation of perforin activation and pre-synaptic toxicity through C-terminal glycosylation. AB - Perforin is a highly cytotoxic pore-forming protein essential for immune surveillance by cytotoxic lymphocytes. Prior to delivery to target cells by exocytosis, perforin is stored in acidic secretory granules where it remains functionally inert. However, how cytotoxic lymphocytes remain protected from their own perforin prior to its export to secretory granules, particularly in the Ca2+-rich endoplasmic reticulum, remains unknown. Here, we show that N-linked glycosylation of the perforin C-terminus at Asn549 within the endoplasmic reticulum inhibits oligomerisation of perforin monomers and thus protects the host cell from premature pore formation. Subsequent removal of this glycan occurs through proteolytic processing of the C-terminus within secretory granules and is imperative for perforin activation prior to secretion. Despite evolutionary conservation of the C-terminus, we found that processing is carried out by multiple proteases, which we attribute to the unstructured and exposed nature of the region. In sum, our studies reveal a post-translational regulatory mechanism essential for maintaining perforin in an inactive state until its secretion from the inhibitory acidic environment of the secretory granule. PMID- 28808114 TI - Anesthetic neurotoxicity and the developing brain. PMID- 28808113 TI - LncRNA GAS5 inhibits microglial M2 polarization and exacerbates demyelination. AB - The regulation of inflammation is pivotal for preventing the development or reoccurrence of multiple sclerosis (MS). A biased ratio of high-M1 versus low-M2 polarized microglia is a major pathological feature of MS Here, using microarray screening, we identify the long noncoding RNA (lncRNA) GAS5 as an epigenetic regulator of microglial polarization. Gain- and loss-of-function studies reveal that GAS5 suppresses microglial M2 polarization. Interference with GAS5 in transplanted microglia attenuates the progression of experimental autoimmune encephalomyelitis (EAE) and promotes remyelination in a lysolecithin-induced demyelination model. In agreement, higher levels of GAS5 are found in amoeboid shaped microglia in MS patients. Further, functional studies demonstrate that GAS5 suppresses transcription of TRF4, a key factor controlling M2 macrophage polarization, by recruiting the polycomb repressive complex 2 (PRC2), thereby inhibiting M2 polarization. Thus, GAS5 may be a promising target for the treatment of demyelinating diseases. PMID- 28808116 TI - Living kidney donation. PMID- 28808115 TI - Human papillomavirus in oropharyngeal cancer in Canada: analysis of 5 comprehensive cancer centres using multiple imputation. AB - BACKGROUND: The incidence of oropharyngeal cancer has risen over the past 2 decades. This rise has been attributed to human papillomavirus (HPV), but information on temporal trends in incidence of HPV-associated cancers across Canada is limited. METHODS: We collected social, clinical and demographic characteristics and p16 protein status (p16-positive or p16-negative, using this immunohistochemistry variable as a surrogate marker of HPV status) for 3643 patients with oropharyngeal cancer diagnosed between 2000 and 2012 at comprehensive cancer centres in British Columbia (6 centres), Edmonton, Calgary, Toronto and Halifax. We used receiver operating characteristic curves and multiple imputation to estimate the p16 status for missing values. We chose a best-imputation probability cut point on the basis of accuracy in samples with known p16 status and through an independent relation between p16 status and overall survival. We used logistic and Cox proportional hazard regression. RESULTS: We found no temporal changes in p16-positive status initially, but there was significant selection bias, with p16 testing significantly more likely to be performed in males, lifetime never-smokers, patients with tonsillar or base-of tongue tumours and those with nodal involvement (p < 0.05 for each variable). We used the following variables associated with p16-positive status for multiple imputation: male sex, tonsillar or base-of-tongue tumours, smaller tumours, nodal involvement, less smoking and lower alcohol consumption (p < 0.05 for each variable). Using sensitivity analyses, we showed that different imputation probability cut points for p16-positive status each identified a rise from 2000 to 2012, with the best-probability cut point identifying an increase from 47.3% in 2000 to 73.7% in 2012 (p < 0.001). INTERPRETATION: Across multiple centres in Canada, there was a steady rise in the proportion of oropharyngeal cancers attributable to HPV from 2000 to 2012. PMID- 28808117 TI - Thrombosed persistent sciatic artery presenting with pain in the buttock. PMID- 28808118 TI - Adverse health outcomes in transgender people. PMID- 28808119 TI - The authors respond to "Adverse health outcomes in transgender people". PMID- 28808120 TI - Expert forum releases roadmap for drug reform. PMID- 28808121 TI - July Effect? Maybe not. PMID- 28808122 TI - Dramatic budget increase for hepatitis treatment in federal prisons. PMID- 28808123 TI - "I didn't know I needed a poet". PMID- 28808124 TI - Rapid RNase L-driven arrest of protein synthesis in the dsRNA response without degradation of translation machinery. AB - Mammalian cells respond to double-stranded RNA (dsRNA) by activating a translation-inhibiting endoribonuclease, RNase L. Consensus in the field indicates that RNase L arrests protein synthesis by degrading ribosomal RNAs (rRNAs) and messenger RNAs (mRNAs). However, here we provide evidence for a different and far more efficient mechanism. By sequencing abundant RNA fragments generated by RNase L in human cells, we identify site-specific cleavage of two groups of noncoding RNAs: Y-RNAs, whose function is poorly understood, and cytosolic tRNAs, which are essential for translation. Quantitative analysis of human RNA cleavage versus nascent protein synthesis in lung carcinoma cells shows that RNase L stops global translation when tRNAs, as well as rRNAs and mRNAs, are still intact. Therefore, RNase L does not have to degrade the translation machinery to stop protein synthesis. Our data point to a rapid mechanism that transforms a subtle RNA cleavage into a cell-wide translation arrest. PMID- 28808125 TI - Insights into substrate promiscuity of human seryl-tRNA synthetase. AB - Seryl-tRNA synthetase (SerRS) attaches L-serine to the cognate serine tRNA (tRNASer) and the noncognate selenocysteine tRNA (tRNASec). The latter activity initiates the anabolic cycle of selenocysteine (Sec), proper decoding of an in frame Sec UGA codon, and synthesis of selenoproteins across all domains of life. While the accuracy of SerRS is important for overall proteome integrity, it is its substrate promiscuity that is vital for the integrity of the selenoproteome. This raises a question as to what elements in the two tRNA species, harboring different anticodon sequences and adopting distinct folds, facilitate aminoacylation by a common aminoacyl-tRNA synthetase. We sought to answer this question by analyzing the ability of human cytosolic SerRS to bind and act on tRNASer, tRNASec, and 10 mutant and chimeric constructs in which elements of tRNASer were transposed onto tRNASec We show that human SerRS only subtly prefers tRNASer to tRNASec, and that discrimination occurs at the level of the serylation reaction. Surprisingly, the tRNA mutants predicted to adopt either the 7/5 or 8/5 fold are poor SerRS substrates. In contrast, shortening of the acceptor arm of tRNASec by a single base pair yields an improved SerRS substrate that adopts an 8/4 fold. We suggest that an optimal tertiary arrangement of structural elements within tRNASec and tRNASer dictate their utility for serylation. We also speculate that the extended acceptor-TPsiC arm of tRNASec evolved as a compromise for productive binding to SerRS while remaining the major recognition element for other enzymes involved in Sec and selenoprotein synthesis. PMID- 28808126 TI - Growth- and Stress-Induced PASTA Kinase Phosphorylation in Enterococcus faecalis. AB - Transmembrane Ser/Thr kinases containing extracellular PASTA domains are ubiquitous among Actinobacteria and Firmicutes Such PASTA kinases regulate critical processes, including antibiotic resistance, cell division, toxin production, and virulence, and are essential for viability in certain organisms. Based on in vitro studies with purified extracellular and intracellular fragments of PASTA kinases, a model for signaling has been proposed, in which the extracellular PASTA domains bind currently undefined ligands (typically thought to be peptidoglycan, or fragments thereof) to drive kinase dimerization, which leads to enhanced kinase autophosphorylation and enhanced phosphorylation of substrates. However, this model has not been rigorously tested in vivoEnterococcus faecalis is a Gram-positive intestinal commensal and major antibiotic-resistant opportunistic pathogen. In E. faecalis, the PASTA kinase IreK drives intrinsic resistance to cell wall-active antimicrobials, suggesting that such antimicrobials may trigger IreK signaling. Here we show that IreK responds to cell wall stress in vivo by enhancing its phosphorylation and that of a downstream substrate. This response requires both the extracellular PASTA domains and specific phosphorylatable residues in the kinase domain. Thus, our results provide in vivo evidence, with an intact full-length PASTA kinase in its native physiological environment, that supports the prevailing model of PASTA kinase signaling. In addition, we show that IreK responds to a signal associated with growth and/or cell division, in the absence of cell wall-active antimicrobials. Surprisingly, the ability of IreK to respond to growth and/or division does not require the extracellular PASTA domains, suggesting that IreK monitors multiple parameters for sensory input in vivoIMPORTANCE Transmembrane Ser/Thr kinases containing extracellular PASTA domains are ubiquitous among Actinobacteria and Firmicutes and regulate critical processes. The prevailing model for signaling by PASTA kinases proposes that the extracellular PASTA domains bind ligands to drive kinase dimerization, enhanced autophosphorylation, and enhanced phosphorylation of substrates. However, this model has not been rigorously tested in vivo We show that the PASTA kinase IreK of Enterococcus faecalis responds to cell wall stress in vivo by enhancing its phosphorylation and that of a downstream substrate. This response requires the PASTA domains and phosphorylatable residues in the kinase domain. Thus, our results provide in vivo evidence, with an intact full-length PASTA kinase in its native physiological environment, that supports the prevailing model of PASTA kinase signaling. PMID- 28808127 TI - The components of the unique Zur regulon of Cupriavidus metallidurans mediate cytoplasmic zinc handling. AB - Zinc is an essential trace element and at the same time it is toxic at high concentrations. In the beta-proteobacterium Cupriavidus metallidurans the highly efficient removal of surplus zinc from the periplasm is responsible for its outstanding metal resistance. Rather than having a typical Zur-dependent, high affinity ATP-binding cassette transporter of the ABC protein superfamily for zinc uptake at low concentrations, C. metallidurans instead has the secondary zinc importer ZupT of the ZRT/IRT (ZIP) family. It is important to understand, therefore, how this zinc-resistant bacterium copes when it is exposed to low zinc concentrations. Members of the Zur regulon in C. metallidurans were identified by comparing the transcriptomes of a Deltazur mutant and its parent strain. The consensus sequence of the Zur-binding box was derived for the zupTp promoter regulatory region using a truncation assay. The motif was used to predict possible Zur-boxes upstream of Zur regulon members. Binding of Zur to these boxes was confirmed. Two Zur-boxes upstream of the cobW1 gene, encoding a putative zinc chaperone, proved to be required for complete repression of cobW1 and its downstream genes in cells cultivated in mineral salts medium. A Zur box upstream of each of zur-cobW2, cobW3 and zupT permitted low-expression level of these genes plus their up-regulation under zinc starvation conditions. This demonstrates a compartmentalization of zinc homeostasis in C. metallidurans with the periplasm being responsible for removal of surplus zinc and cytoplasmic components for management of zinc as an essential co-factor, with both compartments connected by ZupT.Importance Elucidating zinc homeostasis is necessary to understand both host-pathogen interactions and performance of free living bacteria in their natural environment. Escherichia coli acquires zinc under low zinc concentrations by the Zur-controlled ZnuABC importer of the ABC superfamily, and this was also the paradigm for other bacteria. In contrast, the heavy metal-resistant bacterium C. metallidurans achieves high tolerance to zinc due to sophisticated zinc handling and efflux systems operating on periplasmic zinc ions, so that removal of surplus zinc is a periplasmic feature in this bacterium. It is shown here that this process is augmented by management of zinc through cytoplasmic zinc chaperones, whose syntheses are controlled by the Zur regulator. This demonstrates a new mechanism to organize zinc homeostasis through compartmentalization. PMID- 28808128 TI - Conjugative Plasmid Transfer in Xylella fastidiosa Is Dependent on tra and trb Operon Functions. AB - The insect-transmitted plant pathogen Xylella fastidiosa is capable of efficient horizontal gene transfer (HGT) and recombination. Natural transformation occurs at high rates in X. fastidiosa, but there also is evidence that certain strains of X. fastidiosa carry native plasmids equipped with transfer and mobilization genes, suggesting conjugation as an additional mechanism of HGT in some instances. Two operons, tra and trb, putatively encoding a conjugative type IV secretion system, are found in some but not all X. fastidiosa isolates, often on native plasmids. X. fastidiosa strains that carry the conjugative transfer genes can belong to different subspecies and frequently differ in host ranges. Using X. fastidiosa strain M23 (X. fastidiosa subsp. fastidiosa) or Dixon (X. fastidiosa subsp. multiplex) as the donor strain and Temecula (X. fastidiosa subsp. fastidiosa) as the recipient strain, plasmid transfer was characterized using the mobilizable broad-host-range vector pBBR5pemIK. Transfer of plasmid pBBR5pemIK was observed under in vitro conditions with both donor strains and was dependent on both tra and trb operon functions. A conjugative mechanism likely contributes to gene transfer between diverse strains of X. fastidiosa, possibly facilitating adaptation to new environments or different hosts.IMPORTANCEXylella fastidiosa is an important plant pathogen worldwide, infecting a wide range of different plant species. The emergence of new diseases caused by X. fastidiosa, or host switching of existing strains, is thought to be primarily due to the high frequency of HGT and recombination in this pathogen. Transfer of plasmids by a conjugative mechanism enables movement of larger amounts of genetic material at one time, compared with other routes of gene transfer such as natural transformation. Establishing the prevalence and functionality of this mechanism in X. fastidiosa contributes to a better understanding of HGT, adaptation, and disease emergence in this diverse pathogen. PMID- 28808130 TI - Meeting report on the ASM Conference on Mechanisms of Interbacterial Cooperation and Competition. AB - The ASM Conference on Mechanisms of Interbacterial Cooperation and Competition was held in Washington DC, from 1 to 4 March 2017. The conference provided an international forum for sociomicrobiologists from different disciplines to present and discuss new findings. The meeting covered a wide range of topics, spanning molecular mechanisms, ecology, evolution, computation and manipulation of interbacterial interactions, and encompassed social communities in medicine, the natural environment, and industry. This report summarizes the presentations and emerging themes. PMID- 28808129 TI - Gene Duplication in Pseudomonas aeruginosa Improves Growth on Adenosine. AB - The laboratory strain of Pseudomonas aeruginosa, PAO1, activates genes for catabolism of adenosine using quorum sensing (QS). However, this strain is not well-adapted for growth on adenosine, with doubling times greater than 40 h. We previously showed that when PAO1 is grown on adenosine and casein, variants emerge that grow rapidly on adenosine. To understand the mechanism by which this adaptation occurs, we performed whole-genome sequencing of five isolates evolved for rapid growth on adenosine. All five genomes had a gene duplication amplification (GDA) event covering several genes, including the quorum-regulated nucleoside hydrolase gene, nuh, and PA0148, encoding an adenine deaminase. In addition, two of the growth variants also exhibited a nuh promoter mutation. We recapitulated the rapid growth phenotype with a plasmid containing six genes common to all the GDA events. We also showed that nuh and PA0148, the two genes at either end of the common GDA, were sufficient to confer rapid growth on adenosine. Additionally, we demonstrated that the variant nuh promoter increased basal expression of nuh but maintained its QS regulation. Therefore, GDA in P. aeruginosa confers the ability to grow efficiently on adenosine while maintaining QS regulation of nucleoside catabolism.IMPORTANCEPseudomonas aeruginosa thrives in many habitats and is an opportunistic pathogen of humans. In these diverse environments, P. aeruginosa must adapt to use myriad potential carbon sources. P. aeruginosa PAO1 cannot grow efficiently on nucleosides, including adenosine; however, it can acquire this ability through genetic adaptation. We show that the mechanism of adaptation is by amplification of a specific region of the genome and that the amplification preserves the regulation of the adenosine catabolic pathway by quorum sensing. These results demonstrate an underexplored mechanism of adaptation by P. aeruginosa, with implications for phenotypes such as development of antibiotic resistance. PMID- 28808131 TI - Intercellular communication via the comX-Inducing Peptide (XIP) of Streptococcus mutans. AB - Gram-positive bacteria utilize exported peptides to coordinate genetic and physiological processes required for biofilm formation, stress responses and ecological competitiveness. One example is activation of natural genetic competence by ComR and the comX-inducing peptide (XIP) in Streptococcus mutans Although the competence pathway can be activated by addition of synthetic XIP in defined medium, the hypothesis that XIP is able to function as an intercellular signal molecule has not been rigorously tested. Co-culture model systems were developed that included a "sender" strain that overexpressed the XIP precursor (ComS) and a "responder" strain harboring a GFP reporter fusion to a ComR activated gene (comX) promoter. The ability of the sender strain to provide a signal to activate GFP expression was monitored at the individual cell and population levels using i) planktonic culture systems, ii) cells suspended in an agarose matrix or iii) cells growing in biofilms. XIP was shown to be freely diffusible and XIP signaling between the S. mutans sender and responder strains did not require cell-to-cell contact. The presence of a sucrose-derived exopolysaccharide matrix diminished the efficiency of XIP signaling in biofilms, possibly by affecting spatial distribution of XIP senders and potential responders. Intercellular signaling was greatly impaired in a strain lacking the primary autolysin, AtlA, and was substantially greater when the sender strain underwent lysis. Collectively, these data provide evidence that S. mutans XIP can indeed function as a peptide signal between cells and highlight the importance of studying signaling with endogenously-produced peptide(s) in populations in various environments and physiologic states.IMPORTANCE The comX-inducing peptide (XIP) of Streptococcus mutans is a key regulatory element in the activation of genetic competence, which allows cells to take up extracellular DNA. XIP has been found in cell culture fluids and addition of synthetic XIP to physiologically receptive cells can robustly induce competence gene expression. However, there is a lack of consensus as to whether XIP can function as an intercellular communication signal. Here, we show that XIP indeed signals between cells in S. mutans, but that cell lysis may be a critical factor, as opposed to a dedicated secretion/processing system, in allowing for release of XIP into the environment. The results have important implications in the context of the ecology, virulence and evolution of a ubiquitous human pathogen and related organisms. PMID- 28808132 TI - Defining Electron Bifurcation in the Electron-Transferring Flavoprotein Family. AB - Electron bifurcation is the coupling of exergonic and endergonic redox reactions to simultaneously generate (or utilize) low- and high-potential electrons. It is the third recognized form of energy conservation in biology and was recently described for select electron-transferring flavoproteins (Etfs). Etfs are flavin containing heterodimers best known for donating electrons derived from fatty acid and amino acid oxidation to an electron transfer respiratory chain via Etf quinone oxidoreductase. Canonical examples contain a flavin adenine dinucleotide (FAD) that is involved in electron transfer, as well as a non-redox-active AMP. However, Etfs demonstrated to bifurcate electrons contain a second FAD in place of the AMP. To expand our understanding of the functional variety and metabolic significance of Etfs and to identify amino acid sequence motifs that potentially enable electron bifurcation, we compiled 1,314 Etf protein sequences from genome sequence databases and subjected them to informatic and structural analyses. Etfs were identified in diverse archaea and bacteria, and they clustered into five distinct well-supported groups, based on their amino acid sequences. Gene neighborhood analyses indicated that these Etf group designations largely correspond to putative differences in functionality. Etfs with the demonstrated ability to bifurcate were found to form one group, suggesting that distinct conserved amino acid sequence motifs enable this capability. Indeed, structural modeling and sequence alignments revealed that identifying residues occur in the NADH- and FAD-binding regions of bifurcating Etfs. Collectively, a new classification scheme for Etf proteins that delineates putative bifurcating versus nonbifurcating members is presented and suggests that Etf-mediated bifurcation is associated with surprisingly diverse enzymes.IMPORTANCE Electron bifurcation has recently been recognized as an electron transfer mechanism used by microorganisms to maximize energy conservation. Bifurcating enzymes couple thermodynamically unfavorable reactions with thermodynamically favorable reactions in an overall spontaneous process. Here we show that the electron transferring flavoprotein (Etf) enzyme family exhibits far greater diversity than previously recognized, and we provide a phylogenetic analysis that clearly delineates bifurcating versus nonbifurcating members of this family. Structural modeling of proteins within these groups reveals key differences between the bifurcating and nonbifurcating Etfs. PMID- 28808133 TI - The rph-1-Encoded Truncated RNase PH Protein Inhibits RNase P Maturation of Pre tRNAs with Short Leader Sequences in the Absence of RppH. AB - RNase PH, encoded by the rph gene, is a 3'->5' exoribonuclease that in E. coli participates primarily in the 3' maturation of pre-tRNAs and the degradation of rRNA in stationary-phase cells. Interestingly, the routinely used laboratory strains of MG1655 and W3110 have naturally acquired the rph-1 allele, encoding a truncated catalytically inactive RNase PH protein which is widely assumed to be benign. Contrary to this assumption, we show that the rph-1-encoded Rph-1 protein inhibits RNase P-mediated 5'-end maturation of primary pre-tRNAs with leaders of <5 nucleotides in the absence of RppH, an RNA pyrophosphohydrolase. In contrast, RppH is not required for 5'-end maturation of endonucleolytically generated pre tRNAs in the rph-1 strain and for any tRNAs in Deltarph mutant or rph+ strains. We propose that the Rph-1 protein bound to the 3' end of the substrate creates a steric hindrance that in the presence of a triphosphate at the 5' end reduces the ability of RNase P to bind to the pre-tRNA.IMPORTANCE In this paper, we demonstrate that the rph-1 mutation found in commonly used E. coli strains leads to the synthesis of a truncated functionally inactive RNase PH protein that interferes with the 5'-end maturation of specific tRNAs with short 5' leaders by RNase P in the absence of RppH, an RNA pyrophosphohydrolase that converts primary 5' triphosphates into 5' monophosphates. The data presented indicate that the presence of the triphosphate interferes with RNase P binding to the pre-tRNA. PMID- 28808134 TI - VPS9a Activates the Rab5 GTPase ARA7 to Confer Distinct Pre- and Postinvasive Plant Innate Immunity. AB - Plant innate immunity can effectively prevent the proliferation of filamentous pathogens. Papilla formation at the site of attack is essential for preinvasive immunity; in postinvasive immunity, the encasement of pathogen structures inside host cells can hamper disease. Whereas papillae are highly dependent on transcytosis of premade material, little is known about encasement formation. Here, we show that endosome-associated VPS9a, the conserved guanine-nucleotide exchange factor activating Rab5 GTPases, is required for both pre- and postinvasive immunity against a nonadapted powdery mildew fungus (Blumeria graminis f. sp hordei) in Arabidopsis thaliana Surprisingly, VPS9a acts in addition to two previously well-described innate immunity components and thus represents an additional step in the regulation of how plants resist pathogens. We found VPS9a to be important for delivering membrane material to the encasement and VPS9a also plays a predominant role in postinvasive immunity. GTP-bound Rab5 GTPases accumulate in the encasement, but not the papillae, suggesting that two independent pathways form these defense structures. VPS9a also mediates defense to an adapted powdery mildew fungus, thus regulating a durable type of defense that works in both host and nonhost resistance. We propose that VPS9a plays a conserved role in organizing cellular endomembrane trafficking, required for delivery of defense components in response to powdery mildew fungi. PMID- 28808135 TI - Mutations in eIF5B Confer Thermosensitive and Pleiotropic Phenotypes via Translation Defects in Arabidopsis thaliana. AB - The conserved eukaryotic translation initiation factor 5B, eIF5B, is a GTPase that acts late in translation initiation. We found that an Arabidopsis thaliana mutant sensitive to hot temperatures 3 (hot3-1), which behaves as the wild type in the absence of stress but is unable to acclimate to high temperature, carries a missense mutation in the eIF5B1 gene (At1g76810), producing a temperature sensitive protein. A more severe, T-DNA insertion allele (hot3-2) causes pleiotropic developmental phenotypes. Surprisingly, Arabidopsis has three other eIF5B genes that do not substitute for eIF5B1; two of these appear to be in the process of pseudogenization. Polysome profiling and RNA-seq analysis of hot3-1 plants show delayed recovery of polysomes after heat stress and reduced translational efficiency (TE) of a subset of stress protective proteins, demonstrating the critical role of translational control early in heat acclimation. Plants carrying the severe hot3-2 allele show decreased TE of auxin regulated, ribosome-related, and electron transport genes, even under optimal growth conditions. The hot3-2 data suggest that disrupting specific eIF5B interactions on the ribosome can, directly or indirectly, differentially affect translation. Thus, modulating eIF5B interactions could be another mechanism of gene-specific translational control. PMID- 28808136 TI - ePlant: Visualizing and Exploring Multiple Levels of Data for Hypothesis Generation in Plant Biology. AB - A big challenge in current systems biology research arises when different types of data must be accessed from separate sources and visualized using separate tools. The high cognitive load required to navigate such a workflow is detrimental to hypothesis generation. Accordingly, there is a need for a robust research platform that incorporates all data and provides integrated search, analysis, and visualization features through a single portal. Here, we present ePlant (http://bar.utoronto.ca/eplant), a visual analytic tool for exploring multiple levels of Arabidopsis thaliana data through a zoomable user interface. ePlant connects to several publicly available web services to download genome, proteome, interactome, transcriptome, and 3D molecular structure data for one or more genes or gene products of interest. Data are displayed with a set of visualization tools that are presented using a conceptual hierarchy from big to small, and many of the tools combine information from more than one data type. We describe the development of ePlant in this article and present several examples illustrating its integrative features for hypothesis generation. We also describe the process of deploying ePlant as an "app" on Araport. Building on readily available web services, the code for ePlant is freely available for any other biological species research. PMID- 28808137 TI - Regulatory RNPs: a novel class of ribonucleoproteins that potentially contribute to ribosome heterogeneity. AB - Many ribonucleoproteins (RNPs), which are comprised of noncoding RNA and associated proteins, are involved in essential cellular processes such as translation and pre-mRNA splicing. One class of RNP is the small Cajal body specific RNP (scaRNP), which contributes to the biogenesis of small nuclear RNPs (snRNPs) that are central components of the spliceosome. Three scaRNAs are internally processed, generating stable nucleolus-enriched RNAs of unknown function. Here, we provide data that show that these RNAs become part of RNPs we term regulatory RNPs (regRNPs). Most modifications within rRNA (predominantly pseudouridylation and ribose 2'-O-methylation) are conducted by small nucleolar RNPs (snoRNPs), and we provide evidence that the activity of at least some of these snoRNPs is under the control of regRNPs. Because modifications within rRNA can vary in different physiological or pathological situations, rRNA modifications are thought to be the major source of ribosome heterogeneity. Our identification of regRNPs thus provides a potential mechanism for how ribosome heterogeneity may be accomplished. This work also provides additional functional connections between the Cajal body and the nucleolus. PMID- 28808138 TI - An AMPK-dependent regulatory pathway in tau-mediated toxicity. AB - Neurodegenerative tauopathies are characterised by accumulation of hyperphosphorylated tau aggregates primarily degraded by autophagy. The 5'AMP activated protein kinase (AMPK) is expressed in most cells, including neurons. Alongside its metabolic functions, it is also known to be activated in Alzheimer's brains, phosphorylate tau, and be a critical autophagy activator. Whether it plays a neurotoxic or neuroprotective role remains unclear. In tauopathies stress conditions can result in AMPK activation, enhancing tau mediated toxicity. Paradoxically, in these cases AMPK activation does not always lead to protective autophagic responses. Using a Drosophila in vivo quantitative approach, we have analysed the impact of AMPK and autophagy on tau-mediated toxicity, recapitulating the AMPK-mediated tauopathy condition: increased tau phosphorylation, without corresponding autophagy activation. We have demonstrated that AMPK binding to and phosphorylating tau at Ser-262, a site reported to facilitate soluble tau accumulation, affects its degradation. This phosphorylation results in exacerbation of tau toxicity and is ameliorated via rapamycin-induced autophagy stimulation. Our findings support the development of combinatorial therapies effective at reducing tau toxicity targeting tau phosphorylation and AMPK-independent autophagic induction. The proposed in vivo tool represents an ideal readout to perform preliminary screening for drugs promoting this process. PMID- 28808139 TI - Differential expression of sirtuin 2 and adipocyte maturation restriction: an adaptation process during hypoxia in fish. AB - Sirtuins have received widespread attention due to their diverse physiological role in metabolism. Among sirtuins, SIRT2 is more abundant in adipocytes and exerts effects on adipocyte differentiation, a process which involves conversion of preadipocytes to mature adipocytes orchestrated by adipokines and adipogenic transcription factors. Grey mullet (Mugil cephalus) was chosen as a study organism due to its excellent service as a biomonitor. Adipocytes isolated from natural field conditions were termed as field-hypoxic (Ennore) and -normoxic (Kovalam) based on dissolved oxygen (DO) level in the estuary. A previous study portrayed the hypoxic instance of Ennore estuary (low DO) and grey mullet [HIF1alpha in adipocytes, brain endothelial cell (EC) and hepatocytes] inhabiting this estuary ( Padmini et al., 2016a, b; Padmini and Tharani, 2015). In this context, fish adipocytes of both conditions were subjected to in vitro hypoxia for 1 h (in the pre/trigassed incubator with the supply of 1% O2; 94% N2; 5% CO2) and were analysed for the expression of adipokines, adipogenic transcription factors and anti-adipogenic markers in fish adipocytes. Elevation of asymmetric dimethylarginine (ADMA), TNFalpha and leptin along with decreased adiponectin, adipogenic transcription factors and altering sirtuins were observed in test adipocytes and in control adipocytes on in vitro hypoxia. This suggests that adipocytes may follow internal caloric restriction as portrayed from cytomorphological/ultrastructural analysis, limiting adipocyte maturation process, one of the adaptive mechanisms triggered by adipocyte of fish surviving in Ennore estuary. Prolonged exposure to hypoxia (test on in vitro hypoxia for 1 h) showed a drastic alteration in these components leading to both structural and biological fluctuation when compared to limited hypoxic condition (field-hypoxic and control on in vitro hypoxia). Our study concludes that hypoxia may serve as the chief molecular cue in eliciting adipocyte maturation restriction though metabolic reprogramming and it also shows the significance of adipocyte maturation restriction in imparting survival mechanism. PMID- 28808140 TI - Amyloid-beta and islet amyloid pathologies link Alzheimer's disease and type 2 diabetes in a transgenic model. AB - Alzheimer's disease (AD) and type 2 diabetes (T2D) present a significant risk to each other. AD and T2D are characterized by deposition of cerebral amyloid-beta (Abeta) and pancreatic human islet amyloid polypeptide (hIAPP), respectively. We investigated the role of amyloidogenic proteins in the interplay between these diseases. A novel double transgenic mouse model combining T2D and AD was generated and characterized. AD-related amyloid transgenic mice coexpressing hIAPP displayed peripheral insulin resistance, hyperglycemia, and glucose intolerance. Abeta and IAPP amyloid co-deposition increased tau phosphorylation, and a reduction in pancreatic beta-cell mass was detected in islets. Increased brain Abeta deposition and tau phosphorylation and reduced insulin levels and signaling were accompanied by extensive synaptic loss and decreased neuronal counts. Abeta immunization rescued the peripheral insulin resistance and hyperglycemia, suggesting a role for Abeta in T2D pathogenesis for individuals predisposed to AD. These findings demonstrate that Abeta and IAPP are key factors in the overlapping pathologies of AD and T2D.-Wijesekara, N., Ahrens, R., Sabale, M., Wu, L., Ha, K., Verdile, G., Fraser, P. E. Amyloid-beta and islet amyloid pathologies link Alzheimer's disease and type 2 diabetes in a transgenic model. PMID- 28808142 TI - Reflections of the Editor-in-Chief. PMID- 28808143 TI - Charting Our Future Together: Turning Discovery Science Into Cardiovascular Health. PMID- 28808141 TI - A critical role for plasma kallikrein in the pathogenesis of autoantibody-induced arthritis. AB - The plasma kallikrein-kinin system (KKS) consists of serine proteases, prekallikrein (pKal) and factor XII (FXII), and a cofactor, high-MW kininogen (HK). Upon activation, activated pKal and FXII cleave HK to release bradykinin. Activation of this system has been noted in patients with rheumatoid arthritis, and its pathogenic role has been characterized in animal arthritic models. In this study, we generated 2 knockout mouse strains that lacked pKal and HK and determined the role of KKS in autoantibody-induced arthritis. In a K/BxN serum transfer-induced arthritis (STIA) model, mice that lacked HK, pKal, or bradykinin receptors displayed protective phenotypes in joint swelling, histologic changes in inflammation, and cytokine production; however, FXII-deficient mice developed normal arthritis. Inhibition of Kal ameliorated arthritis severity and incidence at early stage STIA and reduced the levels of major cytokines in joints. In addition to releasing bradykinin from HK, Kal directly activated monocytes to produce proinflammatory cytokines, up-regulated their C5aR and FcRIII expression, and released C5a. Immune complex increased pKal activity, which led to HK cleavage. The absence of HK is associated with a decrease in joint vasopermeability. Thus, we identify a critical role for Kal in autoantibody induced arthritis with pleiotropic effects, which suggests that it is a new target for the inhibition of arthritis.-Yang, A., Zhou, J., Wang, B., Dai, J., Colman, R. W., Song, W., Wu, Y. A critical role for plasma kallikrein in the pathogenesis of autoantibody-induced arthritis. PMID- 28808145 TI - "Stressed" About Air Pollution: Time for Personal Action. PMID- 28808146 TI - Thrombolytic Potential of N-Acetylcysteine: Evidence for Significant Benefit in Mitigating Arterial Thrombosis. PMID- 28808144 TI - Particulate Matter Exposure and Stress Hormone Levels: A Randomized, Double Blind, Crossover Trial of Air Purification. AB - BACKGROUND: Exposure to ambient particulate matter (PM) is associated with a number of adverse health outcomes, but potential mechanisms are largely unknown. Metabolomics represents a powerful approach to study global metabolic changes in response to environmental exposures. We therefore conducted this study to investigate changes in serum metabolites in response to the reduction of PM exposure among healthy college students. METHODS: We conducted a randomized, double-blind crossover trial in 55 healthy college students in Shanghai, China. Real and sham air purifiers were placed in participants' dormitories in random order for 9 days with a 12-day washout period. Serum metabolites were quantified by using gas chromatography-mass spectrometry and ultrahigh performance liquid chromatography-mass spectrometry. Between-treatment differences in metabolites were examined using orthogonal partial least square-discriminant analysis and mixed-effect models. Secondary outcomes include blood pressure, corticotropin releasing hormone, adrenocorticotropic hormone, insulin resistance, and biomarkers of oxidative stress and inflammation. RESULTS: The average personal exposure to PMs with aerodynamic diameters <=2.5 MUm was 24.3 MUg/m3 during the real purification and 53.1 MUg/m3 during the sham purification. Metabolomics analysis showed that higher exposure to PMs with aerodynamic diameters <=2.5 MUm led to significant increases in cortisol, cortisone, epinephrine, and norepinephrine. Between-treatment differences were also observed for glucose, amino acids, fatty acids, and lipids. We found significantly higher blood pressure, hormones, insulin resistance, and biomarkers of oxidative stress and inflammation among individuals exposed to higher PMs with aerodynamic diameters <=2.5 MUm. CONCLUSIONS: This study suggests that higher PM may induce metabolic alterations that are consistent with activations of the hypothalamus-pituitary adrenal and sympathetic-adrenal-medullary axes, adding potential mechanistic insights into the adverse health outcomes associated with PM. Furthermore, our study demonstrated short-term reductions in stress hormone following indoor air purification. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02712333. PMID- 28808147 TI - Eleventh Oriental Congress of Cardiology. PMID- 28808149 TI - Acute Coronary Syndrome: What Is the Affected Artery? Where Is the Occlusion Located? And How Important Is the Myocardial Mass Involved? PMID- 28808150 TI - Letter by Rowshani et al Regarding Article, "Gene Expression Profiling for the Identification and Classification of Antibody-Mediated Heart Rejection". PMID- 28808151 TI - Letter by Moayedi et al Regarding Article, "Gene Expression Profiling for the Identification and Classification of Antibody-Mediated Heart Rejection". PMID- 28808152 TI - Response by Loupy et al to Letters Regarding Article, "Gene Expression Profiling for the Identification and Classification of Antibody-Mediated Heart Rejection". PMID- 28808153 TI - History of Aneurysmal Spontaneous Subarachnoid Hemorrhage. PMID- 28808154 TI - Practicing Evidence-Based Stroke Medicine. PMID- 28808155 TI - RocA Is an Accessory Protein to the Virulence-Regulating CovRS Two-Component System in Group A Streptococcus. AB - Regulating gene expression during infection is critical to the ability of pathogens to circumvent the immune response and cause disease. This is true for the group A Streptococcus (GAS), a pathogen that causes both invasive (e.g., necrotizing fasciitis) and noninvasive (e.g., pharyngitis) diseases. The control of virulence (CovRS) two-component system has a major role in regulating GAS virulence factor expression. The regulator of cov (RocA) protein, which is a predicted kinase, functions in an undetermined manner through CovRS to alter gene expression and reduce invasive disease virulence. Here, we show that the ectopic expression of a truncated RocA derivative, harboring the membrane-spanning domains but not the dimerization or HATPase domain, is sufficient to complement a rocA mutant strain. Coupled with a previous bioinformatic study, the data are consistent with RocA being a pseudokinase. RocA reduces the ability of serotype M1 GAS isolates to express capsule and to evade killing in human blood, phenotypes that are not observed for M3 or M18 GAS due to isolates of these serotypes naturally harboring mutant rocA alleles. In addition, we found that varying the RocA concentration attenuates the regulatory activity of Mg2+ and the antimicrobial peptide LL-37, which positively and negatively regulate CovS function, respectively. Thus, we propose that RocA is an accessory protein to the CovRS system that influences the ability of GAS to modulate gene expression in response to host factors. A model of how RocA interacts with CovRS, and of the regulatory consequences of such activity, is presented. PMID- 28808156 TI - Identification of Staphylococcus aureus Factors Required for Pathogenicity and Growth in Human Blood. AB - Staphylococcus aureus is a human commensal but also has devastating potential as an opportunistic pathogen. S. aureus bacteremia is often associated with an adverse outcome. To identify potential targets for novel control approaches, we have identified S. aureus components that are required for growth in human blood. An ordered transposon mutant library was screened, and 9 genes involved specifically in hemolysis or growth on human blood agar were identified by comparing the mutants to the parental strain. Three genes (purA, purB, and pabA) were subsequently found to be required for pathogenesis in the zebrafish embryo infection model. The pabA growth defect was specific to the red blood cell component of human blood, showing no difference from the parental strain in growth in human serum, human plasma, or sheep or horse blood. PabA is required in the tetrahydrofolate (THF) biosynthesis pathway. The pabA growth defect was found to be due to a combination of loss of THF-dependent dTMP production by the ThyA enzyme and increased demand for pyrimidines in human blood. Our work highlights pabA and the pyrimidine salvage pathway as potential targets for novel therapeutics and suggests a previously undefined role for a human blood factor in the activity of sulfonamide antibiotics. PMID- 28808157 TI - Cytosolic Phospholipase A2alpha Promotes Pulmonary Inflammation and Systemic Disease during Streptococcus pneumoniae Infection. AB - Pulmonary infection by Streptococcus pneumoniae is characterized by a robust alveolar infiltration of neutrophils (polymorphonuclear cells [PMNs]) that can promote systemic spread of the infection if not resolved. We previously showed that 12-lipoxygenase (12-LOX), which is required to generate the PMN chemoattractant hepoxilin A3 (HXA3) from arachidonic acid (AA), promotes acute pulmonary inflammation and systemic infection after lung challenge with S. pneumoniae As phospholipase A2 (PLA2) promotes the release of AA, we investigated the role of PLA2 in local and systemic disease during S. pneumoniae infection. The group IVA cytosolic isoform of PLA2 (cPLA2alpha) was activated upon S. pneumoniae infection of cultured lung epithelial cells and was critical for AA release from membrane phospholipids. Pharmacological inhibition of this enzyme blocked S. pneumoniae-induced PMN transepithelial migration in vitro Genetic ablation of the cPLA2 isoform cPLA2alpha dramatically reduced lung inflammation in mice upon high-dose pulmonary challenge with S. pneumoniae The cPLA2alpha deficient mice also suffered no bacteremia and survived a pulmonary challenge that was lethal to wild-type mice. Our data suggest that cPLA2alpha plays a crucial role in eliciting pulmonary inflammation during pneumococcal infection and is required for lethal systemic infection following S. pneumoniae lung challenge. PMID- 28808158 TI - Influence of the Gut Microbiota Composition on Campylobacter jejuni Colonization in Chickens. AB - The Campylobacter jejuni-host interaction may be affected by the host's gut microbiota through competitive exclusion, metabolites, or modification of the immune response. To understand this interaction, C. jejuni colonization and local immune responses were compared in chickens with different gut microbiota compositions. Birds were treated with an antibiotic cocktail (AT) (experiments 1 and 2) or raised under germfree (GF) conditions (experiment 3). At 18 days posthatch (dph), they were orally inoculated either with 104 CFU of C. jejuni or with diluent. Cecal as well as systemic C. jejuni colonization, T- and B-cell numbers in the gut, and gut-associated tissue were compared between the different groups. Significantly higher numbers of CFU of C. jejuni were detected in the cecal contents of AT and GF birds, with higher colonization rates in spleen, liver, and ileum, than in birds with a conventional gut microbiota (P < 0.05). Significant upregulation of T and B lymphocyte numbers was detected in cecum, cecal tonsils, and bursa of Fabricius of AT or GF birds after C. jejuni inoculation compared to the respective controls (P < 0.05). This difference was less clear in birds with a conventional gut microbiota. Histopathological gut lesions were observed only in C. jejuni-inoculated AT and GF birds but not in microbiota-colonized C. jejuni-inoculated hatchmates. These results demonstrate that the gut microbiota may contribute to the control of C. jejuni colonization and prevent lesion development. Further studies are needed to identify key players of the gut microbiota and the mechanisms behind their protective role. PMID- 28808159 TI - Chronic Brucella Infection Induces Selective and Persistent Interferon Gamma Dependent Alterations of Marginal Zone Macrophages in the Spleen. AB - The spleen is known as an important filter for blood-borne pathogens that are trapped by specialized macrophages in the marginal zone (MZ): the CD209+ MZ macrophages (MZMs) and the CD169+ marginal metallophilic macrophages (MMMs). Acute systemic infection strongly impacts MZ populations and the location of T and B lymphocytes. This phenomenon has been linked to reduced chemokine secretion by stromal cells. Brucella spp. are the causative agent of brucellosis, a widespread zoonotic disease. Here, we used Brucella melitensis infection as a model to investigate the impact of chronic stealth infection on splenic MZ macrophage populations. During the late phase of Brucella infection, we observed a loss of both MZMs and MMMs, with a durable disappearance of MZMs, leading to a reduction of the ability of the spleen to take up soluble antigens, beads, and unrelated bacteria. This effect appears to be selective as every other lymphoid and myeloid population analyzed increased during infection, which was also observed following Brucella abortus and Brucella suis infection. Comparison of wild-type and deficient mice suggested that MZ macrophage population loss is dependent on interferon gamma (IFN-gamma) receptor but independent of T cells or tumor necrosis factor alpha receptor 1 (TNF-alphaR1) signaling pathways and is not correlated to an alteration of CCL19, CCL21, and CXCL13 chemokine mRNA expression. Our results suggest that MZ macrophage populations are particularly sensitive to persistent low-level IFN-gamma-mediated inflammation and that Brucella infection could reduce the ability of the spleen to perform certain MZM- and MMM-dependent tasks, such as antigen delivery to lymphocytes and control of systemic infection. PMID- 28808160 TI - Incremental Contributions of FbaA and Other Impetigo-Associated Surface Proteins to Fitness and Virulence of a Classical Group A Streptococcal Skin Strain. AB - Group A streptococci (GAS) are highly prevalent human pathogens whose primary ecological niche is the superficial epithelial layers of the throat and/or skin. Many GAS strains with a strong tendency to cause pharyngitis are distinct from strains that tend to cause impetigo; thus, genetic differences between them may confer host tissue-specific virulence. In this study, the FbaA surface protein gene was found to be present in most skin specialist strains but largely absent from a genetically related subset of pharyngitis isolates. In an DeltafbaA mutant constructed in the impetigo strain Alab49, loss of FbaA resulted in a slight but significant decrease in GAS fitness in a humanized mouse model of impetigo; the DeltafbaA mutant also exhibited decreased survival in whole human blood due to phagocytosis. In assays with highly sensitive outcome measures, Alab49DeltafbaA was compared to other isogenic mutants lacking virulence genes known to be disproportionately associated with classical skin strains. FbaA and PAM (i.e., the M53 protein) had additive effects in promoting GAS survival in whole blood. The pilus adhesin tip protein Cpa promoted Alab49 survival in whole blood and appears to fully account for the antiphagocytic effect attributable to pili. The finding that numerous skin strain-associated virulence factors make slight but significant contributions to virulence underscores the incremental contributions to fitness of individual surface protein genes and the multifactorial nature of GAS-host interactions. PMID- 28808161 TI - Listeria monocytogenes has both a bd-type and an aa3 -type terminal oxidase which allow growth in different oxygen levels and both are important in infection. AB - Listeria monocytogenes is a food borne pathogen responsible for a number of life threatening infections of humans. During an infection it invades epithelial cells before spreading from the intestine to the cells of the liver and spleen. This requires an ability to adapt to varying oxygen levels. Here we demonstrate that L. monocytogenes has two terminal oxidases, a cytochrome bd-type (CydAB) and a cytochrome aa3 -type menaquinol oxidase (QoxAB) and that both are used for respiration under different oxygen tensions. Furthermore, we show that possession of both terminal oxidases is important in infection. In air, the CydAB bd-type oxidase is essential for aerobic respiration and intracellular replication, and cydAB mutants are highly attenuated in mice. In contrast, the QoxAB aa3 -type oxidase is neither required for aerobic respiration in air nor for intracellular growth. However, the qoxAB mutants are attenuated in mice with both a delay in the onset of disease signs and with increased survival time, indicating a role for the QoxAB aa3 -type oxidase in the initial stages of infection. Growth of bacteria under defined oxygen conditions revealed that at 1% (v/v) both oxidases are functional and the presence of either is sufficient for aerobic respiration and intracellular replication. However at 0.2% (v/v) both oxidases are necessary for maximum growth. These findings are consistent with the ability of L. monocytogenes to switch between terminal oxidases under different oxygen conditions providing an exquisite adaptation to different conditions encountered within the infected host. PMID- 28808162 TI - Listeria monocytogenes and Shigella flexneri Activate the NLRP1B Inflammasome. AB - Activation of the innate immune receptor NLRP1B leads to the formation of an inflammasome, which induces autoproteolytic processing of pro-caspase-1, and ultimately to the release of inflammatory cytokines and to the execution of pyroptosis. One of the signals to which NLRP1B responds is metabolic stress that occurs in cells deprived of glucose or treated with metabolic inhibitors. NLRP1B might therefore sense microbial infection, as intracellular pathogens such as Listeria monocytogenes and Shigella flexneri cause metabolic stress as a result of nutrient scavenging and host cell damage. Here we addressed whether these pathogens activate the NLRP1B inflammasome. We found that Listeria infection activated the NLRP1B inflammasome in a reconstituted fibroblast model. Activation of NLRP1B by Listeria was diminished in an NLRP1B mutant shown previously to be defective at detecting energy stress and was dependent on the expression of listeriolysin O (LLO), a protein required for vacuolar escape. Infections of either Listeria or Shigella activated NLRP1B in the RAW264.7 murine macrophage line, which expresses endogenous NLRP1B. We conclude that NLRP1B senses cellular infection by distinct invasive pathogens. PMID- 28808164 TI - Supranuclear gaze palsy and horizontal ocular oscillations in Creutzfeldt-Jakob disease. PMID- 28808165 TI - Editors' Note. PMID- 28808166 TI - Letter re: Hyperbaric oxygen: B-Level evidence in mild traumatic brain injury clinical trials. PMID- 28808167 TI - Author response: Hyperbaric oxygen: B-Level evidence in mild traumatic brain injury clinical trials. PMID- 28808168 TI - Letter re: Autopsy validation of 123I-FP-CIT dopaminergic neuroimaging for the diagnosis of DLB. PMID- 28808163 TI - Role for FimH in Extraintestinal Pathogenic Escherichia coli Invasion and Translocation through the Intestinal Epithelium. AB - The translocation of bacteria across the intestinal epithelium of immunocompromised patients can lead to bacteremia and life-threatening sepsis. Extraintestinal pathogenic Escherichia coli (ExPEC), so named because this pathotype infects tissues distal to the intestinal tract, is a frequent cause of such infections, is often multidrug resistant, and chronically colonizes a sizable portion of the healthy population. Although several virulence factors and their roles in pathogenesis are well described for ExPEC strains that cause urinary tract infections and meningitis, they have not been linked to translocation through intestinal barriers, a fundamentally distant yet important clinical phenomenon. Using untransformed ex situ human intestinal enteroids and transformed Caco-2 cells, we report that ExPEC strain CP9 binds to and invades the intestinal epithelium. ExPEC harboring a deletion of the gene encoding the mannose-binding type 1 pilus tip protein FimH demonstrated reduced binding and invasion compared to strains lacking known E. coli virulence factors. Furthermore, in a murine model of chemotherapy-induced translocation, ExPEC lacking fimH colonized at levels comparable to that of the wild type but demonstrated a statistically significant reduction in translocation to the kidneys, spleen, and lungs. Collectively, this study indicates that FimH is important for ExPEC translocation, suggesting that the type 1 pilus is a therapeutic target for the prevention of this process. Our study also highlights the use of human intestinal enteroids in the study of enteric diseases. PMID- 28808170 TI - Escalation therapy for multiple sclerosis in Austria: Analysis of gender differences in the nationwide registry. PMID- 28808171 TI - The role of genetics in ethanol-induced cell death in the forebrain and brainstem. PMID- 28808169 TI - Author response: Autopsy validation of 123I-FP-CIT dopaminergic neuroimaging for the diagnosis of DLB. PMID- 28808172 TI - Child Neurology: Childhood basilar artery occlusion and stroke. PMID- 28808173 TI - Clinical Reasoning: A demure teenager and her dystonic foot. PMID- 28808174 TI - Journal Club: Long-term functional outcome in patients with acquired infections after acute spinal cord injury. PMID- 28808175 TI - Teaching NeuroImages: Classic Ramsay Hunt syndrome and associated MRI findings. PMID- 28808176 TI - Teaching Video NeuroImages: Trapezius muscle hypertrophy in multifocal motor neuropathy. PMID- 28808177 TI - Teaching Video NeuroImages: The underrecognized diphasic dyskinesia of Parkinson disease. PMID- 28808179 TI - Aggf1 attenuates hepatic inflammation and activation of hepatic stellate cells by repressing Ccl2 transcription. AB - Liver injury represents a continuum of pathophysiological processes involving a complex interplay between hepatocytes, macrophages, and hepatic stellate cells. The mechanism whereby these intercellular interactions contribute to liver injury and fibrosis is not completely understood. We report here that angiogenic factor with G patch and FHA domains 1 (Aggf1) was downregulated in the livers of cirrhotic patients compared to healthy controls and in primary hepatocytes in response to carbon tetrachloride (CCl4) stimulation. Overexpression of Aggf1 attenuated macrophage chemotaxis. Aggf1 interacted with NF-kappaB to block its binding to the Ccl2 gene promoter and repressed Ccl2 transcription in hepatocytes. Macrophages cultured in the conditioned media collected from Aggf1 overexpressing hepatocytes antagonized HSC activation. Taken together, our data illustrate a novel role for Aggf1 in regulating hepatic inflammation and provide insights on the development of interventional strategies against cirrhosis. PMID- 28808178 TI - Metabolomic profiles of plasma, exhaled breath condensate, and saliva are correlated with potential for air toxics detection. AB - INTRODUCTION: Advances in the development of high-resolution metabolomics (HRM) have provided new opportunities for their use in characterizing exposures to environmental air pollutants and air pollution-related disease etiologies. Exposure assessment studies have considered blood, breath, and saliva as biological matrices suitable for measuring responses to air pollution exposures. The current study examines comparability among these three matrices using HRM and explores their potential for measuring mobile-source air toxics. METHODS: Four participants provided saliva, exhaled breath concentrate (EBC), and plasma before and after a 2 h road traffic exposure. Samples were analyzed on a Thermo Scientific QExactive MS system in positive electrospray ionization mode and resolution of 70 000 full-width at half-maximum with C18 chromatography. Data were processed using an apLCMS and xMSanalyzer on the R statistical platform. RESULTS: The analysis yielded 7110, 6019, and 7747 reproducible features in plasma, EBC, and saliva, respectively. Correlations were moderate-to-strong (R = 0.41-0.80) across all pairwise comparisons of feature intensity within profiles, with the strongest between EBC and saliva. The associations of mean intensities between matrix pairs were positive and significant, controlling for subject and sampling time effects. Six out of 20 features shared in all three matrices putatively matched a list of known mobile-source air toxics. CONCLUSIONS: Plasma, saliva, and EBC have largely comparable metabolic profiles measurable through HRM. These matrices have the potential to be used in identification and measurement of exposures to mobile-source air toxics, though further, targeted study is needed. PMID- 28808180 TI - White adipose tissue browning and obesity. PMID- 28808181 TI - Screening of Fabry disease in patients with end-stage renal disease of unknown etiology: the first Thailand study. AB - We aimed to explore the prevalence of Fabry disease in Thai patients who were diagnosed with end-stage renal disease (ESRD) of an unknown origin. Venous blood samples were collected from ESRD patients for biochemical and molecular studies. Alpha-galactosidase A (alpha-GAL A) screening was performed from dried-blood spots using fluorometry. Molecular confirmation was performed using DNA sequencing of the GLA gene. A total of 142 male and female patients were included in this study. Ten patients (7.04%) exhibited a significant decrease in alpha-GAL A activity. There were no definitive pathogenic mutations observed in the molecular study. However, four patients revealed a novel nucleotide variant at c.1 -10 C>T, which was identified as a benign variant following screening in the normal population. In conclusion, the alpha-GAL A assay utilizing dried-blood spots revealed a significant false positive rate. There was no definitive Fabry disease confirmed in Thai patients diagnosed with ESRD of unknown etiology. PMID- 28808182 TI - Determination of serum biomarkers in osteoarthritis patients: a previous interventional imaging study revisited. AB - To evaluate in an interventional trial on knee osteoarthritis (OA) the level and change of two serum biomarkers and their correlation with imaging parameters. The previously reported interventional OA study (ClinicalTrials.gov: NCT00536302) identified a positive effect of collagen hydrolysate (CH) on cartilage morphology in patients with knee OA using delayed gadolinium enhanced magnetic resonance imaging (dGEMRIC). It was the objective in this research project to evaluate in an interventional clinical trial on knee OA the level and change of two serum biomarkers and their correlation with imaging parameters. In blood samples of study participants, we determined the concentration of procollagen type II N terminal propeptide (PIIANP) and aggrecan chondroitin sulfate 846 epitope (CS846) at baseline (BL) and at the follow-up (FU) visits at 24 and 48 weeks. We measured the level and change of biomarker concentrations in both study groups, and the correlation of those changes with changes in dGEMRIC. For the biomarker PIIANP, we observed a significantly greater increase in the CH group (29.9% vs. 1.2% at week 24, P= 0.001). For CS846, the mean concentration was lower among the CH treated participants at 24 weeks (78% vs. 96%, P= 0.045). Consistent correlations of changes in biomarkers PIIANP and CS846 with changes of the dGEMRIC score could not be observed. In this study, different changes per treatment group, CH and placebo were seen for dGEMRIC and PIIANP BL to 24 weeks FU, but only weak correlations between changes in dGEMRIC and biochemical markers. PMID- 28808183 TI - Indoor tanning bed use and risk of food addiction based on the modified Yale Food Addiction Scale. AB - The popularity of indoor tanning may be partly attributed to the addictive characteristics of tanning for some individuals. We aimed to determine the association between frequent indoor tanning, which we view as a surrogate for tanning addiction, and food addiction. A total of 67,910 women were included from the Nurses' Health Study II. In 2005, we collected information on indoor tanning during high school/college and age 25-35 years, and calculated the average use of indoor tanning during these periods. Food addiction was defined as >=3 clinically significant symptoms plus clinically significant impairment or distress, assessed in 2009 using a modified version of the Yale Food Addiction Scale. Totally 23.3% (15,822) of the participants reported indoor tanning at high school/college or age 25-35 years. A total of 5,557 (8.2%) women met the criteria for food addiction. We observed a dose-response relationship between frequency of indoor tanning and the likelihood of food addiction (Ptrend<0.0001), independent of depression, BMI, and other confounders. Compared with never indoor tanners, the odds ratio (95% confidence interval) of food addiction was 1.07 (0.99-1.17) for average indoor tanning 1-2 times/year, 1.25 (1.09-1.43) for 3-5 times/year, 1.34 (1.14-1.56) for 6-11 times/year, 1.61 (1.35-1.91) for 12-23 times/year, and 2.98 (1.95-4.57) for 24 or more times/year. Frequent indoor tanning before or at early adulthood is associated with prevalence of food addiction at middle age. Our data support the addictive property of frequent indoor tanning, which may guide intervention strategies to curb indoor tanning and prevent skin cancer. PMID- 28808184 TI - Obesity is associated with the Arg389Gly ADRB1 but not with the Trp64Arg ADRB3 polymorphism in children from San Luis PotosI and Leon, Mexico. AB - This research was designed to analyze the possible associations of Arg389Gly ADRB1 and Trp64Arg ADRB3 polymorphisms in children with obesity. A cross sectional study included 1,046 school-age Mexican participants (6-12 years old) from the cities of San Luis PotosI and Leon. Children were classified as non obese or obese according to their body mass index (BMI) percentile; obese children had a BMI>=95th percentile for sex and age. Biochemical data were collected. Polymorphisms were detected using TaqMan qPCR assay. A logistic regression analysis was used to calculate the risk of obesity based on genotypes. Differences were found between groups where obese children had a significant increase in systolic and diastolic blood pressure, fasting plasma glucose, insulin, HOMA-IR, LDL-cholesterol, triglycerides, and lower HDL-cholesterol compared with the normal weight group (P<0.05). The distribution of allele frequency in the population was Arg= 87.4 and Gly= 12.6 (Hardy Weinberg equilibrium c2 = 3.16 , P = 0.07 ); Trp= 81.5 and Arg= 18.5 (Hardy Weinberg equilibrium c2 = 2.2, P = 0.14 ) for ADRB1 and ADRB3, respectively. Even though no different frequencies of Arg389Gly polymorphism between groups were found (P = 0.08), children carriers of one Gly389 ADRB1 allele had a risk for obesity of OR=1.40 (95%CI, 1.03-1.90, P = 0.03) after adjustment for age and gender. No other association was found for Trp64Arg ADRB3 polymorphism. Only the Arg389Gly ADRB1 polymorphism was associated with risk for obesity in Mexican children. PMID- 28808185 TI - Establishment of a rat model with diet-induced coronary atherosclerosis. AB - Coronary atherosclerotic disease is a serious disease in humans, but no suitable animal model is available currently for further studies. We used apolipoprotein E gene knockout (ApoE KO) rats to induce hypercholesterolemia through a special high cholesterol/bile salt diet (Paigen diet), then analyzed aortic and coronary atherosclerosis lesions and the myocardial injury in order to establish a novel small animal model of coronary atherosclerosis. Plasma cholesterol of ApoE KO rats increased 7.6-fold compared with wild-type rats after 8 weeks on the Paigen diet. After 10 to 12 weeks of subsisting on the Paigen diet, ApoE KO rats developed mild aortic atherosclerosis with severe coronary atherosclerosis. Hematoxilyn and eosin staining showed that 11 out of 12 ApoE KO male rats had right coronary artery atherosclerosis, 7 of them were>70% occluded. Oil Red O (Lipid Stain), Mac2 immuno-staining and Masson's trichrome staining demonstrated substantial amounts of lipid, macrophages and collagen fibers in coronary atherosclerosis plaques. In addition, ApoE KO male rats had severe myocardial focal lesions with cholesterol ester as the main component in the lesions. In conclusion, ApoE KO rats developed severe hypercholesterolemia, coronary atherosclerosis and myocardial cholesterol ester deposition after subsisting on the Paigen diet and can be used as a novel animal model for studies on cholesterol metabolism and coronary atherosclerotic disease. PMID- 28808186 TI - Oxygenation, inflammatory response and lung injury during one lung ventilation in rabbits using inspired oxygen fraction of 0.6 vs. 1.0. AB - Maintaining adequate oxygenation during one-lung ventilation (OLV) requires high inspired oxygen fraction (FiO2). However, high FiO2 also causes inflammatory response and lung injury. Therefore, it remains a great interest to clinicians and scientists to optimize the care of patients undergoing OLV. The aim of this study was to determine and compare oxygenation, inflammatory response and lung injury during OLV in rabbits using FiO2 of 0.6 vs. 1.0. After 30 minutes of two lung ventilation (TLV) as baseline, 30 rabbits were randomly assigned to three groups receiving mechanical ventilation for 3 hours: the sham group, receiving TLV with 0.6 FiO2; the 1.0 FiO2 group, receiving OLV with 1.0 FiO2; the 0.6 FiO2 group, receiving OLV with 0.6 FiO2. Pulse oximetry was continuously monitored and arterial blood gas analysis was intermittently conducted. Histopathologic study of lung tissues was performed and inflammatory cytokines and the mRNA and protein of nuclear factor kappa B (NF-kappaB) p65 were determined. Three of the 10 rabbits in the 0.6 FiO2 group suffered hypoxemia, defined by pulse oximetric saturation (SpO2) less than 90%. Partial pressure of oxygen (PaO2), acute lung injury (ALI) score, myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF alpha), interleukin-6 (IL-6), mRNA and protein of NF-kappaB p65 were lower in the 0.6 FiO2 group than in the 1.0 FiO2 group. In conclusion, during OLV, if FiO2 of 0.6 can be tolerated, lung injury associated with high FiO2 can be minimized. Further study is needed to validate this finding in human subjects. PMID- 28808187 TI - G-Aminobutyric acid promotes methionine-choline deficient diet-induced nonalcoholic steatohepatitis. AB - Nonalcoholic steatohepatitis (NASH) is one of the most common liver diseases and a major cause of liver fibrosis worldwide. G-Aminobutyric acid (GABA) is one of the most abundant inhibitory neurotransmitters in the central nervous system. Recently, it has been reported that GABAergic signaling pathways are found in various non-neuronal tissues including the immune system and play a functional role. In the present study, we investigated whether administration of GABA has effects on NASH through its immunomodulatory effects. To test this hypothesis, C57BL/6 mice were fed a methionine-choline-deficient (MCD) diet for 8 weeks. After four weeks into MCD feeding, mice were provided with plain water (control) or water containing 2 mg/mL of GABA for the subsequent 4 weeks. Using this MCD diet-induced NASH model, we found that mice receiving GABA showed more severe steatohepatitis and liver fibrosis than control mice. This increased liver damage was confirmed by higher levels of serum alanine transaminase (ALT) and aspartate aminotransferase (AST) compared to the control group. In accordance with increased liver steatohepatitis, NASH-related and inflammatory gene expression (collagen alpha1, tissue inhibitor of metalloproteinase-1, TNF-alpha) in the liver was markedly increased in GABA-treated mice. Furthermore, GABA directly enhanced production of inflammatory cytokines including IL-6 and TNF-alpha in LPS activated RAW macrophage cells and increased TIB-73 hepatocyte death. Such effects were abolished when GABA was treated with bicuculline, a competitive antagonist of GABA receptors. These results suggest that oral administration of GABA may be involved in changes of the liver immune milieu and conferred detrimental effects on NASH progression. PMID- 28808188 TI - Endovascular repair of thoracic aortic dissection associated with right-sided aortic arch: report of four cases. PMID- 28808189 TI - What is "normal" intraoperative blood pressure and do deviations from it really affect postoperative outcome? PMID- 28808190 TI - Cholesterol crystal embolization following plaque rupture: a systemic disease with unusual features. AB - Cholesterol crystal embolic (CCE) syndrome is often a clinically challenging condition that has a poor prognostic implication. It is a result of plaque rupture with release of cholesterol crystals into the circulation that embolize into various tissue organs. Plaque rupture seems to be triggered by an expanding necrotic core during cholesterol crystallization forming sharp tipped crystals that perforate and tear the fibrous cap. Embolizing cholesterol crystals then initiate both local and systemic inflammation that eventually lead to vascular fibrosis and obstruction causing symptoms that can mimic other vasculitic conditions. In fact, animal studies have demonstrated that cholesterol crystals can trigger an inflammatory response via NLRP3 inflammasome similar to that seen with gout. The diagnosis of CCE syndrome often requires a high suspicion of the condition. Serum inflammation biomarkers including elevated sedimentation rate, abnormal renal function tests and eosinophilia are useful but non-specific. Common target organ involvement includes the skin, kidney, and brain. Various testing including fundoscopic eye examination and other non-invasive procedures such as trans-esophageal echocardiography and magnetic resonance imaging may be helpful in identifying the embolic source. Treatment includes aspirin and clopidogrel, high dose statin and possibly steroids. In rare cases, mechanical intervention using covered stents may help isolate the ruptured plaque. Anticoagulation with warfarin is not recommended and might even be harmful. Overall, CCE syndrome is usually a harbinger of extensive and unstable atherosclerotic disease that is often associated with acute cardiovascular events. PMID- 28808192 TI - Classification of facial wrinkles among Chinese women. AB - It is generally recognized that Caucasians and Asians have different skin aging features. The aim of this study was to develop a facial wrinkle grading scale for Chinese women. Standard photographs were taken of 242 Chinese women. Six sets of 0 to 9 wrinkle scales with reference photographs and descriptions were selected, including grading scales for resting and hyperkinetic crow's feet, frontalis lines, glabellar frown lines, and nasolabial folds. To identify the scale by objective quantitative measurement, skin surface measurements from the Visioscan(r) VC98 were used. To test the reliability and validity of our wrinkle scale, a multi-rater consensus method was used. A double-blind, randomized, vehicle-controlled 12-week study was conducted to use this clinical photo-score to evaluate the efficacy and safety of Centella triterpenes cream(r) in treating crow's feet. A newly developed 10-point photographic and descriptive scale emerged from this study. The final atlas of these photographs contained a total of 6 sets with 10 pictures each. From 0 to 9, surface evaluation of smoothness (SEsm) parametric measurements decreased progressively, indicating that the scale increased inversely. Weighted kappa coefficients for intra-assessor were between 0.75-0.87. The overall Kendall's coefficient is 0.86 on the first rating and 0.87 on the second rating. Thirty-six volunteers were recruited and 35 subjects completed a 12-week trial. Clinical photo-score by investigator showed a significant difference (P<0.05) between the treatment side and control side after 4 weeks. Use of these scales in clinical settings to evaluate facial wrinkles in Asians individuals is recommended. PMID- 28808191 TI - Shunts, channels and lipoprotein endosomal traffic: a new model of cholesterol homeostasis in the hepatocyte. AB - The liver directs cholesterol metabolism in the organism. All the major fluxes of cholesterol within the body involve the liver: dietary cholesterol is directed to the liver; cholesterol from peripheral cells goes to the liver; the liver is a major site of cholesterol synthesis for the organism; cholesterol is secreted from the liver within the bile, within apoB lipoproteins and translocated to nascent HDL. The conventional model of cholesterol homeostasis posits that cholesterol from any source enters a common, rapidly exchangeable pool within the cell, which is in equilibrium with a regulatory pool. Increased influx of cholesterol leads rapidly to decreased synthesis of cholesterol. This model was developed based on in vitro studies in the fibroblast and validated only for LDL particles. The challenges the liver must meet in vivo to achieve cholesterol homeostasis are far more complex. Our model posits that the cholesterol derived from three different lipoproteins endosomes has three different fates: LDL derived cholesterol is largely recycled within VLDL with most of the cholesterol shunted through the hepatocyte without entering the exchangeable pool of cholesterol; high density lipoprotein-derived CE is transcytosed into bile; and chylomicron remnant-derived cholesterol primarily enters the regulatory pool within the hepatocyte. These endosomal channels represent distinct physiological pathways and hepatic homeostasis represents the net result of the outcomes of these distinct channels. Our model takes into account the distinct physiological challenges the hepatocyte must meet, underlie the pathophysiology of many of the apoB dyslipoproteinemias and account for the sustained effectiveness of therapeutic agents such as statins. PMID- 28808193 TI - Evaluation of atherosclerotic lesions in cholesterol-fed mice during treatment with paclitaxel in lipid nanoparticles: a magnetic resonance imaging study. AB - Cholesterol-core nanoparticles (LDE) have been shown to be recognized by low density lipoprotein receptors (LDLR) after administration; therefore, LDE is an ideal vehicle to deliver drug with targeting property. Paclitaxel, when incorporated into LDE, promotes atherosclerosis regression with reduced drug toxicity in rabbits through LDLR. Here, we tested whether LDE-paclitaxel could still be effective in reducing diet-induced atherosclerosis in a mouse model without LDLR. Nineteen LDLR knockout male mice were fed 1% cholesterol for 12 weeks. Then, 12 animals received 4-weekly intraperitoneal LDE-paclitaxel (4 mg/kg) while 7 controls received saline solution. On week 12 and 16, in vivo MRI of the aortic roots was performed. Aorta macroscopy was made after euthanasia. Reduction of atherosclerotic lesions was observed. LDE-paclitaxel treatment resulted in reduction of wall area (14%) and stenosis (22%) by MRI and 33% by macroscopy. Thus, LDE-paclitaxel may produce pharmacological effects through LDE uptake by mechanisms other than LDLR. PMID- 28808194 TI - Comparative effects of plant oils and trans-fat on blood lipid profiles and ischemic stroke in rats. AB - Since plant oils are believed to be better than animal fats for cerebrovascular and cardiovascular diseases, the effects of various plant oils and trans-fat on blood lipid profiles and ischemic stroke were investigated. Sprague-Dawley rats were fed a diet containing the oils or trans-fat, and then body weights, blood lipids, and effects on brain infarction and physical dysfunction induced by middle cerebral artery occlusion (MCAO) were analyzed. All the oils and trans fat, except perilla oil, significantly increased body fats and body weight gain. Sesame oil and trans-fat specifically increased blood cholesterols and triglycerides, respectively, while perilla oil decreased both cholesterols and triglycerides. Perilla oil not only attenuated cerebral infarction, but also restored locomotor activity and rota-rod performances of MCAO rats. It is suggested that perilla oil among oils and fats could be the first choice to reduce the risk of metabolic syndrome and ischemic stroke. PMID- 28808195 TI - Effect of exposure to ambient PM2.5 pollution on the risk of respiratory tract diseases: a meta-analysis of cohort studies. AB - The International Agency for Research on Cancer and the World Health Organization have designated airborne particulates, including particulates of median aerodynamic diameter <= 2.5 MUm (PM2.5), as Group 1 carcinogens. It has not been determined, however, whether exposure to ambient PM2.5 is associated with an increase in respiratory related diseases. This meta-analysis assessed the association between exposure to ambient fine particulate matter (PM2.5) and the risk of respiratory tract diseases, using relevant articles extracted from PubMed, Web of Science, and Embase. In results, of the 1,126 articles originally identified, 35 (3.1%) were included in this meta-analysis. PM2.5 was found to be associated with respiratory tract diseases. After subdivision by age group, respiratory tract disease, and continent, PM2.5 was strongly associated with respiratory tract diseases in children, in persons with cough, lower respiratory illness, and wheezing, and in individuals from North America, Europe, and Asia. The risk of respiratory tract diseases was greater for exposure to traffic related than non-traffic-related air pollution. In children, the pooled relative risk (RR) represented significant increases in wheezing (8.2%), cough (7.5%), and lower respiratory illness (15.3%). The pooled RRs in children were 1.091 (95%CI: 1.049, 1.135) for exposure to <25 MUg/m3 PM2.5, and 1.126 (95%CI: 1.067, 1.190) for exposure to >= 25 MUg/m3 PM2.5. In conclusion, exposure to ambient PM2.5 was significantly associated with the development of respiratory tract diseases, especially in children exposed to high concentrations of PM2.5. PMID- 28808196 TI - Antioxidant mediated response of Scoparia dulcis in noise-induced redox imbalance and immunohistochemical changes in rat brain. AB - Noise has been regarded as an environmental/occupational stressor that causes damages to both auditory and non-auditory organs. Prolonged exposure to these mediators of stress has often resulted in detrimental effect, where oxidative/nitrosative stress plays a major role. Hence, it would be appropriate to examine the possible role of free radicals in brain discrete regions and the "antioxidants" mediated response of S. dulcis. Animals were subjected to noise stress for 15 days (100 dB/4 hours/day) and estimation of endogenous free radical and antioxidant activity were carried out on brain discrete regions (the cerebral cortex, cerebellum, brainstem, striatum, hippocampus and hypothalamus). The result showed that exposure to noise could alleviate endogenous free radical generation and altered antioxidant status in brain discrete regions when compared to that of the control groups. This alleviated free radical generation (H2O2 and NO) is well supported by an upregulated protein expression on immunohistochemistry of both iNOS and nNOS in the cerebral cortex on exposure to noise stress. These findings suggest that increased free radical generation and altered anti-oxidative status can cause redox imbalance in the brain discrete regions. However, free radical scavenging activity of the plant was evident as the noise exposed group treated with S. dulcis[200 mg/(kg.b.w)] displayed a therapeutic effect by decreasing the free radical level and regulate the anti oxidative status to that of control animals. Hence, it can be concluded that the efficacy of S. dulcis could be attributed to its free radical scavenging activity and anti-oxidative property. PMID- 28808197 TI - Effect of zeaxanthin on porcine embryonic development during in vitro maturation. AB - Zeaxanthin is a common carotenoid, which is a powerful antioxidant that protects against damage caused by reactive oxygen species. The aim of the present study was to investigate the effects of zeaxanthin supplementation on in vitro maturation of porcine embryo development. We investigated nuclear maturation, intracellular glutathione (GSH), and reactive oxygen species (ROS) levels during in vitro maturation, and subsequent embryonic development following parthenogenetic activation and in vitro fertilization (IVF). The oocytes were maturated and used at the metaphase II stage. After 42 hours of in vitro maturation, the zeaxanthin-treated group (0.5 mmol/L) showed significant increases in nuclear maturation (89.6%) than the control group (83.4%) (P<0.05). The intracellular GSH levels increased significantly (P<0.05) as zeaxanthin concentrations increased; ROS generation levels decreased with increased zeaxanthin concentrations, but there were no significant differences. There were no significant differences in subsequent embryonic development, cleavage rate, blastocyst stage rate, and total blastocyst cell numbers following parthenogenetic activation and IVF when in vitro maturation media was supplemented with zeaxanthin. These results suggest that treatment with zeaxanthin during in vitro maturation improved the nuclear maturation of porcine oocytes by increasing the intracellular GSH level, thereby slightly decreasing the intracellular ROS level. PMID- 28808198 TI - Ultrasonographic evaluation of enthesitis in patients with ankylosing spondylitis. AB - The aim of this study was to assess sensitivity and responsiveness of power Doppler ultrasound (PDUS) in detecting enthesitis for ankylosing spondylitis (AS) patients compared to clinical examinations. Twenty AS patients initiating etanerceptunderwent clinical and PDUS examinations of six bilateral entheseal sites at baseline and after 1, 2 and 3 months of treatment. Clinical and PDUS examinations identified at least one entheseal lesion in nine (45%) and 19 (95%) patients, respectively. Furthermore, of 240 entheseal sites examined in these 20 patients, PDUS detected 123 entheseal lesions (51.3% of sites), compared with only 47 entheseal lesions (19.6%) detected by clinical examination (P<0.05). The entheseal lesions found on PDUS were most commonly identified by calcification (33.3%), tendon edema (29.2%), abnormal blood flow (25.8%), a thickened tendon (22.1%), cortical irregularity (12.9%), bony erosions (9.6%) and bursitis at the tendon insertion to the bone cortex (7.1%). Improvements in clinical symptoms and laboratory parameters, and significant decreases in PDUS scores were observed following treatment with etanercept. Improvements in PDUS scores continued during follow-up in patients who entered remission following treatment. In conclusion, PDUS improves detection of structural and inflammatory abnormalities of the enthesis in AS compared to physical examination. In addition, PDUS may be useful inascertaining medications. PMID- 28808199 TI - Cost and value in medical education: the role of statistical process control. PMID- 28808201 TI - Thalamic paramagnetic iron by T2* relaxometry correlates with severity of multiple sclerosis. AB - Iron can contribute to the pathogenesis and progression of multiple sclerosis (MS) due to its accumulation in the human brain. We focus on the thalamus as an information transmitter between various subcortical and cortical areas. Thalamic iron seems to follow different rules than iron in other deep gray matter structures and its relation to the clinical outcomes of MS is still indistinct. In our study, we investigated a connection between thalamic iron and patients' disability and course of the disease. The presence of paramagnetic substances in the tissues was tracked by T2* quantification. Twenty-eight subjects with definite MS and 15 age-matched healthy controls underwent MRI examination with a focus on gradient echo sequence. We observed a non-monotonous course of T2* values with age in healthy controls. Furthermore, T2* distribution in MS patients was significantly wider than that of age matched healthy volunteers (P<0.001). A strong significant correlation was demonstrated between T2* distribution spread and the expanded disability status scale (EDSS) (left thalamus:P<0.00005; right thalamus: P<0.005), and multiple sclerosis severity scale (MSSS) (left thalamus: P<0.05; right thalamus: P<0.005). The paramagnetic iron distribution in the thalamus in MS was not uniform and this inhomogeneity may be considered as an indicator of thalamic neurodegeneration in MS. PMID- 28808200 TI - Acute-on-chronic liver failure: recent update. AB - Acute on chronic liver failure (ACLF) was first described in 1995 as a clinical syndrome distinct to classic acute decompensation. Characterized by complications of decompensation, ACLF occurs on a background of chronic liver dysfunction and is associated with high rates of organ failure and significant short-term mortality estimated between 45% and 90%. Despite the clinical relevance of the condition, it still remains largely undefined with continued disagreement regarding its precise etiological factors, clinical course, prognostic criteria and management pathways. It is concerning that, despite our relative lack of understanding of the condition, the burden of ACLF among cirrhotic patients remains significant with an estimated prevalence of 30.9%. This paper highlights our current understanding of ACLF, including its etiology, diagnostic and prognostic criteria and pathophysiology. It is evident that further refinement of the ACLF classification system is required in order to detect high-risk patients and improve short-term mortality rates. The field of metabolomics certainly warrants investigation to enhance diagnostic and prognostic parameters, while the use of granulocyte-colony stimulating factor is a promising future therapeutic intervention for patients with ACLF. PMID- 28808202 TI - (+)-Borneol is neuroprotective against permanent cerebral ischemia in rats by suppressing production of proinflammatory cytokines. AB - Stroke is one of the leading causes of disability and death globally. It occurs when a major artery is occluded in the brain and leads to death of cells within the injured tissue. (+)-Borneol, a simple bicyclic monoterpene extracted from traditional Chinese medicine, is widely used in various types of diseases. However, no study has proved the effects of (+)-borneol on functional recovery from permanent ischemic stroke and the mechanism is still unknown. Here, we report that in the rat model of permanent cerebral ischemia, we found that (+) borneol (1.0 mg/kg) significantly ameliorated infarct size and neurological scoresvia reducing the expression of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) in a dose dependent manner. Notably, (+) borneol showed long-term effects on the improvement of sensorimotor functions in the photothrombotic model of stroke, which decreased the number of foot faults in the grid-walking task and forelimb asymmetry scores in the cylinder task, at least in part through reducing loss of dendritic spines in the length, brunch number and density. These findings suggest that (+)-borneol could serve as a therapeutic target for ischemic stroke. PMID- 28808203 TI - Clinical application of simultaneous detection of cystatin C, cathepsin S, and IL 1 in classification of coronary artery disease. AB - : Cystatin C, cathepsin S, and IL-1 are three important biomarkers of atherosclerosis. Previous studies emphasized the relationship between individual biomarkers in coronary artery disease (CAD) patients and severity of atherosclerostic lesions of the coronary arteries, while combined cystatin C, cathepsin S, and IL-1 have not been reported for clinical classification of CAD. We aimed to establish a link between cystatin C, cathepsin S, IL-1 and CAD in this cohort study. Totally 112 subjects were enrolled and divided into the stable angina pectoris group, the unstable angina pectoris group and the acute myocardial infarction (AMI) groups, and 50 healthy adults served as controls. The levels of the three biomarkers were detected by ELISA. The results showed that serum level of cystatin C (mg/L) was higher in CAD patients compared with those in the healthy controls (AMIvs. unstable angina pectoris vs. stable angina pectoris vs. CONTROLS: 1.27+/-0.18 vs. 1.09+/-0.19 vs. 0.91+/-0.05 vs. 0.78+/ 0.07, all P<0.01). Cathepsin S (ng/mL) was also significantly different among the groups (AMI vs. unstable angina pectoris vs. stable angina pectoris vs. CONTROLS: 67.30+/-8.36 vs. 56.90+/-7.16 vs. 49.8+/-2.72 vs. 67.30+/-8.36, all P<0.01). IL-1 (pg/mL) was significantly different among the groups as well (AMIvs. unstable angina pectoris vs. stable angina pectoris vs. CONTROLS: 2.96+/-0.57 vs. 2.46+/ 0.24 vs. 2.28+/-0.09 vs. 2.02+/-0.13, all P<0.01). Spearman's correlation test revealed positive correlation between cystatin C, cathepsin S, IL-1 and Gensini score (r=0.451, 0.491, 0.397, respectively). It is suggested that simultaneous detection of cystatin C, cathepsin S, and IL-1 in serum may be useful in clinical classification and assessment of severity of CAD. PMID- 28808204 TI - Safety, immunogenicity, and cross-species protection of a plasmid DNA encoding Plasmodium falciparum SERA5 polypeptide, microbial epitopes and chemokine genes in mice and olive baboons. AB - Incorporation of biomolecular epitopes to malarial antigens should be explored in the development of strain-transcending malarial vaccines. The present study sought to determine safety, immunogenicity and cross-species efficacy ofPlasmodium falciparum serine repeat antigen 5 polypeptide co-expressed with epitopes of Bacille-Calmette Guerin (BCG), tetanus toxoid (TT) and a chemokine gene. Olive baboons and BALB/c mice were randomly assigned into vaccine and control groups. The vaccine group animals were primed and boosted twice with pIRES plasmids encoding the SERA5+ BCG+ TT alone, or with either CCL5 or CCL20 and the control group with pIRES plasmid vector backbone. Mice and baboons were challenged withP. berghei ANKA and P. knowlesi H strain parasites, respectively. Safety was determined by observing for injection sites reactogenicities, hematology and clinical chemistry. Parasitaemia and survivorship profiles were used to determine cross-species efficacy, and T cell phenotypes, Th1-, Th2-type, T-regulatory immune responses and antibody responses were assessed to determine vaccine immunogenicity. The pSeBCGTT plasmid DNA vaccines were safe and induced Th1-, Th2-type, and T-regulatory responses vaccinated animals showed enhanced CD4+ (P<0.01), CD 8+ T cells (P<0.001) activation and IgG anti-SE36 antibodies responses (P<0.001) at week 4 and 8 post vaccination compared to the control group. Vaccinated mice had a 31.45-68.69% cumulative parasite load reduction and 60% suppression in baboons (P<0.05) and enhanced survivorship (P<0.001) with no clinical signs of malaria compared to the control group. The results showed that the vaccines were safe, immunogenic and conferred partial cross-species protection. PMID- 28808205 TI - Farnesol inhibits development of caries by augmenting oxygen sensitivity and suppressing virulence-associated gene expression inStreptococcus mutans. AB - Streptococcus mutans is a primary etiological agent of dental caries. Farnesol, as a potential antimicrobial agent, inhibits the development ofS. mutans biofilm. In this study, we hypothesized that farnesol inhibits caries development in vitro and interferes with biofilm formation by regulating virulence-associated gene expression. The inhibitory effects of farnesol to S. mutans biofilms on enamel surfaces were investigated by determining micro-hardness and calcium measurements. Additionally, the morphological changes ofS. mutans biofilms were compared using field emission scanning electron microscopy and confocal laser scanning microscopy, and the vitality and oxygen sensitivity ofS. mutans biofilms were compared using MTT assays. To investigate the molecular mechanisms of farnesol's effects, expressions of possible target genesluxS, brpA, ffh, recA, nth, and smx were analyzed using reverse-transcription polymerase chain reaction (PCR) and quantitative PCR. Farnesol-treated groups exhibited significantly higher micro-hardness on the enamel surface and lower calcium concentration of the supernatants as compared to the-untreated control. Microscopy revealed that a thinner film with less extracellular matrix formed in the farnesol-treated groups. As compared to the-untreated control, farnesol inhibited biofilm formation by 26.4% with 500 umol/L and by 37.1% with 1,000 umol/L (P<0.05). Last, decreased transcription levels of luxS, brpA, ffh, recA, nth, and smx genes were expressed in farnesol-treated biofilms. In vitrofarnesol inhibits caries development and S. mutans biofilm formation. The regulation of luxS, brpA, ffh, recA, nth, and smx genes may contribute to the inhibitory effects of farnesol. PMID- 28808207 TI - Moringa oleifera-based diet protects against nickel-induced hepatotoxicity in rats. AB - Multiple health-promoting effects have been attributed to the consumption of Moringa oleifera leaves, as part of diet without adequate scientific credence. This study evaluated the effect of M. oleifera-based diets on nickel (Ni) - induced hepatotoxicity in rats. Male rats assigned into six groups were given oral administration of 20 mg/kg body weight nickel sulfate in normal saline and either fed normal diet orM. oleifera-based diets for 21 days. All animals were sacrificed under anesthesia 24 hours after the last treatment. Ni exposure elevated the rat plasma activities of alanine transaminase, aspartate transaminase and alkaline phosphatase significantly. Ni exposure also raised the levels of triglyceride, total cholesterol and low-density lipoprotein cholesterol while depleting the high-density lipoprotein cholesterol concentration. Further, Ni exposure raised rat plasma malondialdehyde but depleted reduced glutathione concentrations. The histopathological presentations revealed inflammation and cellular degeneration caused by Ni exposure. We show evidence thatM. oleifera based diets protected against Ni-induced hepatotoxicity by improving the rat liver function indices, lipid profile as well as restoring cellular architecture and integrity. Study lends credence to the health-promoting value ofM. oleifera as well as underscores its potential to attenuate hepatic injury. PMID- 28808206 TI - The effect of sunblock against oxidative stress in farmers: a pilot study. AB - Farmers are frequently exposed to ultraviolet (UV) radiation which causes various diseases by inducing oxidative stress. This study aimed to assess the effects of sunblock on oxidative stress in the body. Eighty-seven farmers were divided into two groups: those who wore sunblock for five days and those who did not. The total antioxidant capacity (TAC) in urine, which is an antioxidant indicator, and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels in urine, an oxidative stress indicator, were measured. The urinary TAC of sunblock users was significantly higher than that of non-users, but urinary 8-OHdG levels were not significantly different. Even after adjustment for potential confounders, urinary TAC was found to be markedly increased with sunblock usage. These results suggest that sunblock is effective in preventing oxidative stress among farmers. In addition, they show that urinary TAC can be used as a good effect marker of oxidative stress caused by UV exposure. PMID- 28808209 TI - Herpes zoster in breast cancer: a case report. AB - There is little information on herpes zoster infection in breast cancer patients as a complication during adjuvant chemotherapy. We report a case of herpes zoster in a 65-year-old woman presented with low grade fever and vital signs together with skin symptoms such as severe edema, irritation and itching in the left breast where there was wound drainage. PCR test revealed varicella zoster virus. To the best of our knowledge, the histologic features coupled with PCR led to a diagnosis of herpes zoster. PMID- 28808208 TI - Effects of bisphenol compounds on the growth and epithelial mesenchymal transition of MCF-7 CV human breast cancer cells. AB - Bisphenol-A (BPA) has been considered as an endocrine disrupting chemical (EDC) because it can exert estrogenic properties. For bisphenol-S (BPS) and bisphenol-F (BPF) that are BPA analogs and substitutes, their risk to estrogen-dependent cancer has been reported rarely compared with the numerous cases of BPA. In this study, we examined whether BPA, BPS, and BPF can lead to the proliferation, migration, and epithelial mesenchymal transition (EMT) of MCF-7 clonal variant (MCF-7 CV) breast cancer cells expressing estrogen receptors (ERs). In a cell viability assay, BPA, BPS, and BPF significantly increased proliferation of MCF-7 CV cells compared to control (DMSO) as did 17beta-estradiol (E2). In Western blotting assay, BPA, BPS, and BPF enhanced the protein expression of cell cycle progression genes such as cyclin D1 and E1. In addition, MCF-7 CV cells lost cell to cell contacts and acquired fibroblast-like morphology by the treatment of BPA, BPS, or BPF for 24 hours. In cell migration assay, BPA, BPS, and BPF accelerated the migration capability of MCF-7 CV cells as did E2. In relation with the EMT process, BPA, BPS, and BPF increased the protein expression ofN-cadherin, while they decreased the protein expression of E-cadherin. When BPA, BPS, and BPF were co-treated with ICI 182,780, an ER antagonist, proliferation effects were reversed, the expression of cyclin D1 and cyclin E1 was downregulated, and the altered cell migration and expression ofN-cadherin and E-cadherin by BPA, BPS, and BPF were restored to the control level. Thus, these results imply that BPS and BPF also have the risk of breast cancer progression as much as BPA in the induction of proliferation and migration of MCF-7 CV cells by regulating the protein expression of cell cycle-related genes and EMT markersvia the ER dependent pathway. PMID- 28808210 TI - Acute-on-chronic liver failure: recent update. AB - Acute on chronic liver failure (ACLF) was first described in 1995 as a clinical syndrome distinct to classic acute decompensation. Characterized by complications of decompensation, ACLF occurs on a background of chronic liver dysfunction and is associated with high rates of organ failure and significant short-term mortality estimated between 45% and 90%. Despite the clinical relevance of the condition, it still remains largely undefined with continued disagreement regarding its precise etiological factors, clinical course, prognostic criteria and management pathways. It is concerning that, despite our relative lack of understanding of the condition, the burden of ACLF among cirrhotic patients remains significant with an estimated prevalence of 30.9%. This paper highlights our current understanding of ACLF, including its etiology, diagnostic and prognostic criteria and pathophysiology. It is evident that further refinement of the ACLF classification system is required in order to detect high-risk patients and improve short-term mortality rates. The field of metabolomics certainly warrants investigation to enhance diagnostic and prognostic parameters, while the use of granulocyte-colony stimulating factor is a promising future therapeutic intervention for patients with ACLF. PMID- 28808211 TI - Chinese medical service and medical education in urgent need of reform in the context of public welfare-based medical reform. PMID- 28808212 TI - Recent advances in arsenic trioxide encapsulated nanoparticles as drug delivery agents to solid cancers. AB - Since arsenic trioxide was first approved as the front line therapy for acute promyelocytic leukemia 25 years ago, its anti-cancer properties for various malignancies have been under intense investigation. However, the clinical successes of arsenic trioxide in treating hematological cancers have not been translated to solid cancers. This is due to arsenic's rapid clearance by the body's immune system before reaching the tumor site. Several attempts have henceforth been made to increase its bioavailability toward solid cancers without increasing its dosage albeit without much success. This review summarizes the past and current utilization of arsenic trioxide in the medical field with primary focus on the implementation of nanotechnology for arsenic trioxide delivery to solid cancer cells. Different approaches that have been employed to increase arsenic's efficacy, specificity and bioavailability to solid cancer cells were evaluated and compared. The potential of combining different approaches or tailoring delivery vehicles to target specific types of solid cancers according to individual cancer characteristics and arsenic chemistry is proposed and discussed. PMID- 28808213 TI - The interaction between the Wnt/beta-catenin signaling cascade and PKG activation in cancer. AB - The activation of the Wnt/beta-catenin signaling cascade has been well studied and documented in colorectal cancer (CRC). The long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to reduce the incidence and risk of death from CRC in numerous epidemiological studies. The NSAID sulindac has also been reported to cause regression of precancerous adenomas in individuals with familial adenomatous polyposis who are at high risk of developing CRC. The mechanism responsible for cancer chemopreventive activity of NSAIDs is not well understood but may be unrelated to their cyclooxygenase inhibitory activity. Emerging evidence suggests that sulindac inhibits the growth of colon tumor cells by suppressing the activity of certain phosphodiesterase isozymes to activate cGMP-dependent protein kinase, PKG, through the elevation of the second messenger cyclic guanosine monophosphote, cGMP. PKG activation has been shown to inhibit the nuclear translocation of beta-catenin, reduce beta-catenin mRNA and protein levels, and suppress the transcriptional activity of beta-catenin. This review describes the relationship between the Wnt/beta-catenin signaling cascade and the activation of PKG through PDE inhibition and elevation of intracellular cGMP levels. PMID- 28808214 TI - Association of three single nucleotide polymorphisms of ESR1with breast cancer susceptibility: a meta-analysis. AB - Expression of estrogen receptors is correlated with breast cancer risk, but inconsistent results have been reported. To clarify potential estrogen receptor (ESR)-related breast cancer risk, we analyzed genetic variants ofESR1 in association with breast cancer susceptibility. We performed a meta-analysis to investigate the association between rs2234693, rs1801132, and rs2046210 (single nucleotide polymorphisms ofESR1), and breast cancer risk. Our analysis included 44 case-control studies. For rs2234693, the CC genotype had a higher risk of breast cancer compared to the TT or CT genotype. For rs2046210, the AA, GA, or GA+ GG genotype had a much higher risk compared to the GG genotype. No significant association was found for the rs1801132 polymorphism with breast cancer risk. This meta-analysis demonstrates association between the rs2234693 and rs2046210 polymorphisms ofESR1 and breast cancer risk. The correlation strength between rs2234693 and breast cancer susceptibility differs in subgroup assessment by ethnicity. PMID- 28808215 TI - Ginkgol C17:1 inhibits tumor growth by blunting the EGF- PI3K/Akt signaling pathway. AB - Ginkgol C17:1 has been shown to inhibit apoptosis and migration of cancer cells, but the underlying mechanisms are not fully elucidated. In this study, we explored whether the inhibitory effects of Ginkgol C17:1 were associated with epidermal growth factor receptor (EGFR) and PI3K/Akt signaling. The results showed that EGF treatment increased the phosphorylation of EGFR, PI3K, Akt, mTOR and NF-kB, and also enhanced the proliferation, migration and invasion of HepG2 cells. Ginkgol C17:1 dose-dependently inhibited EGF-induced phosphorylation/activation of all the key components including EGFR, PI3K, Akt, mTOR and NF-kB, leading to a significant reduction either of proliferation or migration and invasion of HepG2 cells. Notably, treatment with Ginkgol C17:1 in mice suppressed the growth of tumor massin vivo, and expression of EGFR in the tumor tissue. The results suggest that Ginkgol C17:1 is a potent tumor inhibiting compound that acts on EGF-induced signal transduction of the PI3K/Akt signaling pathways, and may represent a clinically interesting candidate for cancer therapy. PMID- 28808216 TI - Modeling and validating three dimensional human normal cervix and cervical cancer tissues in vitro. AB - The use of three dimensional in vitro systems in cancer research is a promising path for developing effective anticancer therapies. The aim of this study was to engineer a functional 3-Din vitro model of normal and cancerous cervical tissue.Normal epithelial and immortalized cervical epithelial carcinoma cell lines were used to construct 3-D artificial normal cervical and cervical cancerous tissues. De-epidermised dermis (DED) was used as a scaffold for both models. Morphological analyses were conducted by using hematoxylin and eosin staining and characteristics of the models were studied by analyzing the expression of different structural cytokeratins and differential protein marker Mad1 using immunohistochemical technique.Haematoxylin and eosin staining results showed that normal cervical tissue had multi epithelial layers while cancerous cervical tissue showed dysplastic changes. Immunohistochemistry staining results revealed that for normal cervix model cytokeratin 10 was expressed in the upper stratified layer of epithelium while cytokeratin 5 was expressed mainly in the middle and basal layer. Cytokeratin 19 was weakly expressed in a few basal cells. Cervical cancer model showed cytokeratin 19 expression in different epithelial layers and weak or no expression for cytokeratin 5 and cytokeratin 10. Mad1 expression was detected in some suprabasal cells.The 3-Din vitro models showed stratified epithelial layers and expressed the same types and patterns of differentiation marker proteins as seen in correspondingin vivo tissue in either normal cervical or cervical cancerous tissue. Findings imply that they can serve as functional normal and cervical cancer models. PMID- 28808217 TI - Electromyography and Fos immunostaining study establish a possible functional link between trigeminal proprioception and the oculomotor system in rats. AB - The objective of this study was to explore whether there was a functional link between trigeminal proprioception and the oculomotor system mediated through jaw muscle afferents. Electromyography (EMG) was undertaken of the levator palpebrae (LP) and superior rectus (SR), and Fos expression was detected in the brainstem following consecutive down-stretching of the lower jaw at 2-4 Hz in rats. Retrograde tracing was undertaken of the interstitial nucleus of Cajal and Darkschewitsch nucleus (INC/DN) pre-oculomotor neurons. EMG-like responses were recorded from the LP/SR during down-stretching of the lower jaw at 2-4 Hz in 3 out of 11 rats. Fos expression was induced by consecutive down-stretching of the lower jaw at 2-4 Hz for 20-30 seconds. Interestingly, Fos expression was distributed mainly in the bilateral INC/DN area. We also examined Fos-like immunoreactivity in central mesencephalic and paramedian pontine reticular formation that harbors premotor neurons controlling horizontal eye movement, but no Fos-like staining was observed therein. By injection of retrograde tracers into the oculomotor nucleus combined with Fos immunostaining, double labeled pre oculomotor neurons were visualized to distribute in the INC/DN. In conclusions, there may exist a trigeminal proprioceptive - oculomotor system neural circuit through jaw muscle afferents in rats. Judging from Fos distribution pattern, this pathway might be related to vertical and torsional eye movements. PMID- 28808218 TI - Setting kinetics and mechanical properties of flax fibre reinforced glass ionomer restorative materials. AB - Regardless of the excellent properties of glass ionomer cements, their poor mechanical properties limit their applications to non-load bearing areas. This study aimed to investigate the effect of incorporated short, chopped and randomly distributed flax fibers (0, 0.5, 1, 2.5, 5 and 25 wt%) on setting reaction kinetics, and mechanical and morphological properties of glass ionomer cements. Addition of flax fibers did not significantly affect the setting reaction extent. According to their content, flax fibers increased the compressive (from 148 to 250 MPa) and flexure strength (from 20 to 42 MPa). They also changed the brittle behavior of glass ionomer cements to a plastic one. They significantly reduced the compressive (from 3 to 1.3 GPa) and flexure modulus (from 19 to 14 GPa). Accordingly, flax fiber-modified glass ionomer cements could be potentially used in high-stress bearing areas. PMID- 28808219 TI - Spindle cell carcinoma of the mandible: a case report. AB - Spindle cell carcinoma is a rare highly malignant squamous cell carcinoma. Here, we describe a case of a 74-year-old Chinese female who presented with a 2-week history of pain and swelling in the left retromolar region. Surgical resection and titanium plate prosthesis were performed and histological analysis revealed spindle squamous cell carcinoma. PMID- 28808220 TI - Insensitivity of PI3K/Akt/GSK3 signaling in peripheral blood mononuclear cells of age-related macular degeneration patients. AB - Our recent studies with cultured retinal pigment epithelium cells suggested that overexpression of interleukin 17 receptor C (IL-17RC), a phenomenon observed in peripheral blood and chorioretinal tissues with age-related macular degeneration (AMD), was associated with altered activation of phosphatidylinositide 3-kinase (PI3K), Akt, and glycogen synthase kinase 3 (GSK3). We wondered whether or not altered PI3K, Akt, and GSK3 activities could be detected in peripheral blood mononuclear cells (PBMC) obtained from AMD patients. In the patients' PBMC, absent or reduced serine-phosphorylation of GSK3alpha or GSK3beta was observed, which was accompanied with increased phosphorylation of GSK3 substrates (e.g. CCAAT enhancer binding protein alpha, insulin receptor substrate 1, and TAU), indicative of enhanced GSK3 activation. In addition, decreased protein mass of PI3K85alpha and tyrosine-phosphorylation of PI3K50alpha was present in PBMC of the AMD patients, suggesting impaired PI3K activation. Moreover, abnormally lowered molecular weight forms of Akt and GSK3 were detected in PBMC of the AMD patients. These data demonstrate that despite the presence of high levels of IL 17RC, Wnt-3a and vascular endothelial growth factor, the PI3K/Akt/GSK3 signaling pathway is insensitive to these stimuli in PBMC of the AMD patients. Thus, measurement of PI3K/Akt/GSK3 expression and activity in PBMC may serve as a surrogate biomarker for AMD. PMID- 28808221 TI - Genetic variation of the PSCA gene (rs2294008) is not associated with the risk of prostate cancer. AB - Prostate stem cell antigen (PSCA) is a cell-membrane glycoprotein consisting of 123 amino acids and highly expressed in the prostate, but there have been few reports on the relationship between rs2294008 ofPSCA and prostate cancer in the literature. Therefore, we evaluated the association between rs2294008 and the risk of prostate cancer. A total of 240 prostate cancer patients and 306 controls (patients with benign prostatic hyperplasia) were enrolled. Genotype analysis of rs2294008 ofPSCA was performed using PCR. Logistic regression analysis was performed according to the genotype ofPSCA rs2294008. We found that CT and TT genotypes were associated with an insignificant risk of prostate cancer compared with the CC genotype (P= 0.627 and 0.397, respectively). In addition, there was no significant difference in rs2294008 according to clinicopathological parameters, such as age, Gleason score, prostate-specific antigen (PSA), stage, and metastasis in prostate cancer (P>0.05 for each). Age, Gleason score, PSA, pathologic stage, and metastasis did not modify the association between PSCA and the risk of prostate cancer (each P>0.05 for each). Taken together, the genetic polymorphism of PSCA rs2294008 was not associated with the risk of prostate cancer. Our results suggest that rs2294008 may not play a role in prostate carcinogenesis. PMID- 28808223 TI - Metastasis-Associated Protein 1 Deficiency Results in Compromised Pulmonary Alveolar Capillary Angiogenesis in Mice. AB - BACKGROUND The aim of this study was to investigate the effects of metastasis associated protein 1 (MTA1) deficiency during angiogenesis of pulmonary alveolar capillaries in mice and to determine the molecular mechanisms involved. MATERIAL AND METHODS The expressions of MTA1, CD34, vascular endothelial growth factor (VEGF), alpha smooth muscle actin (alpha-SMA), and HIF-1alpha were analyzed in the lungs of MTA1-knockout (KO) and wild-type mice at embryonic day 18.5 and 2 months by quantitative PCR, immunoblotting, and immunohistochemistry. The morphological changes were investigated during pulmonary alveolar capillary formation. The heart weight/body weight (HW/BW) ratio and the size of the right ventricular wall cardiomyocytes were also measured. Regulation of MTA1 on HIF 1alpha was determined in vitro. RESULTS MTA1 deficiency reduced the number of pulmonary alveolar capillaries compared to the wild-type mice. MTA1-KO mice exhibited a decreased expression of HIF-1alpha and VEGF in the lungs. The retarded growth of the MTA1-KO mice was also noticed during the first week after birth. Accordingly, MTA1 deficiency resulted in increased infant mortality. In surviving adult mice, MTA1 deficiency induced myocardial hypertrophy, highlighted by an increased heart weight/body weight ratio and larger cardiomyocytes. In cultured cells, HIF-1alpha and VEGF levels were significantly upregulated upon MTA1 overexpression, suggesting a close relationship between all 3 molecules. CONCLUSIONS MTA1 participates in the formation of pulmonary capillaries via stabilization of HIF-1alpha. This finding sheds new light on the function of MTA1 in lung development, opening new avenues for the diagnosis/treatment of related pulmonary diseases. PMID- 28808224 TI - Off-Label Use of Crizotinib as a Neoadjuvant Treatment for a Young Patient When Conventional Chemotherapy Gave No Benefits in Stage IIIA Non-Small Cell Lung Cancer. AB - BACKGROUND The treatment of locally advanced non-small cell lung cancer involves a combination of chemotherapy, surgery, and radiotherapy. Each case is discussed and the best strategy is chosen individually, following international guidelines. CASE REPORT A 37-year-old man was diagnosed with locally advanced broncho pulmonary adenocarcinoma (stage IIIA). The disease was stable after 2 cycles of cisplatin plus Navelbine used as neoadjuvant therapy. FISH analysis revealed an ALK rearrangement. The patient then received unlicensed crizotinib as second-line neoadjuvant treatment, which led to an almost complete radiological and metabolic response. A left upper lobectomy was performed, followed by post-operative chemotherapy and radiotherapy. At 18 months post-surgery, the patient is still disease-free according to the last CT scan. CONCLUSIONS Targeted therapy was an alternative solution when chemotherapy was not helping. Randomized studies are needed to define its precise role in the neoadjuvant scheme. PMID- 28808222 TI - Perioperative "remote" acute lung injury: recent update. AB - Perioperative acute lung injury (ALI) is a syndrome characterised by hypoxia and chest radiograph changes. It is a serious post-operative complication, associated with considerable mortality and morbidity. In addition to mechanical ventilation, remote organ insult could also trigger systemic responses which induce ALI. Currently, there are limited treatment options available beyond conservative respiratory support. However, increasing understanding of the pathophysiology of ALI and the biochemical pathways involved will aid the development of novel treatments and help to improve patient outcome as well as to reduce cost to the health service. In this review we will discuss the epidemiology of peri-operative ALI; the cellular and molecular mechanisms involved on the pathological process; the clinical considerations in preventing and managing perioperative ALI and the potential future treatment options. PMID- 28808225 TI - Congestive Preconditioning by Portal Venous Clamping: A Novel Preventive Concept for Small Intestinal Congestive Re-Outflow Injury. AB - BACKGROUND Congestion of the small intestine, which induces mucosal damage via apoptosis, is a common pathophysiological change in hepato-biliary-pancreatic surgery, including liver transplantation. Small intestinal mucosal damage can trigger postoperative complications via various pathways. Therefore, we investigated the efficacy of intermittent portal venous clamping, which we named congestive preconditioning (CPC), for decreasing congestive re-outflow injury (CRoI) of the small intestine. MATERIAL AND METHODS Small intestinal CRoI was induced in rats by clamping the portal vein (PV) for 30 min, followed by re outflow. The CPC group underwent 3 episodes of 5 min PV clamping and 5 min re outflow before CRoI. The Control group underwent CRoI after 30 min simple laparotomy without any preconditioning. Survival and histological changes in the small intestine after CRoI were analyzed. The histological changes were compared CPC group to Control group using a scoring system that expressed histopathological severity. Also, small intestinal apoptosis and expression of apoptosis-related genes were analyzed by immunohistochemistry. RESULTS The survival rate of the CPC group was significantly higher than Control group. Histological scoring of small intestinal damage was significantly lower in the CPC group after 6 h of CRoI. Expression of anti-apoptotic gene, Bcl-xL was significantly increased, but pro-apoptotic gene caspase-3 and apoptotic cells did not differ significantly between the CPC group and Control group. CONCLUSIONS Induction of CPC for small intestinal CRoI was effective, which suggests that an anti-apoptotic pathway is involved in the beneficial mechanism. PMID- 28808227 TI - Exactly solvable model for a velocity jump observed in crack propagation in viscoelastic solids. AB - Needs to impart appropriate elasticity and high toughness to viscoelastic polymer materials are ubiquitous in industries such as concerning automobiles and medical devices. One of the major problems to overcome for toughening is catastrophic failure linked to a velocity jump, i.e., a sharp transition in the velocity of crack propagation occurred in a narrow range of the applied load. However, its physical origin has remained an enigma despite previous studies over 60 years. Here, we propose an exactly solvable model that exhibits the velocity jump incorporating linear viscoelasticity with a cutoff length for a continuum description. With the exact solution, we elucidate the physical origin of the velocity jump: it emerges from a dynamic glass transition in the vicinity of the propagating crack tip. We further quantify the velocity jump together with slow- and fast-velocity regimes of crack propagation, which would stimulate the development of tough polymer materials. PMID- 28808226 TI - ATR inhibition facilitates targeting of leukemia dependence on convergent nucleotide biosynthetic pathways. AB - Leukemia cells rely on two nucleotide biosynthetic pathways, de novo and salvage, to produce dNTPs for DNA replication. Here, using metabolomic, proteomic, and phosphoproteomic approaches, we show that inhibition of the replication stress sensing kinase ataxia telangiectasia and Rad3-related protein (ATR) reduces the output of both de novo and salvage pathways by regulating the activity of their respective rate-limiting enzymes, ribonucleotide reductase (RNR) and deoxycytidine kinase (dCK), via distinct molecular mechanisms. Quantification of nucleotide biosynthesis in ATR-inhibited acute lymphoblastic leukemia (ALL) cells reveals substantial remaining de novo and salvage activities, and could not eliminate the disease in vivo. However, targeting these remaining activities with RNR and dCK inhibitors triggers lethal replication stress in vitro and long-term disease-free survival in mice with B-ALL, without detectable toxicity. Thus the functional interplay between alternative nucleotide biosynthetic routes and ATR provides therapeutic opportunities in leukemia and potentially other cancers.Leukemic cells depend on the nucleotide synthesis pathway to proliferate. Here the authors use metabolomics and proteomics to show that inhibition of ATR reduced the activity of these pathways thus providing a valuable therapeutic target in leukemia. PMID- 28808228 TI - Loss of Usp9x disrupts cell adhesion, and components of the Wnt and Notch signaling pathways in neural progenitors. AB - Development of neural progenitors depends upon the coordination of appropriate intrinsic responses to extrinsic signalling pathways. Here we show the deubiquitylating enzyme, Usp9x regulates components of both intrinsic and extrinsic fate determinants. Nestin-cre mediated ablation of Usp9x from embryonic neural progenitors in vivo resulted in a transient disruption of cell adhesion and apical-basal polarity and, an increased number and ectopic localisation of intermediate neural progenitors. In contrast to other adhesion and polarity proteins, levels of beta-catenin protein, especially S33/S37/T41 phospho-beta catenin, were markedly increased in Usp9x -/Y embryonic cortices. Loss of Usp9x altered composition of the beta-catenin destruction complex possibly impeding degradation of S33/S37/T41 phospho-beta-catenin. Pathway analysis of transcriptomic data identified Wnt signalling as significantly affected in Usp9x /Y embryonic brains. Depletion of Usp9x in cultured human neural progenitors resulted in Wnt-reporter activation. Usp9x also regulated components of the Notch signalling pathway. Usp9x co-localized and associated with both Itch and Numb in embryonic neocortices. Loss of Usp9x led to decreased Itch and Numb levels, and a concomitant increase in levels of the Notch intracellular domain as well as, increased expression of the Notch target gene Hes5. Therefore Usp9x modulates and potentially coordinates multiple fate determinants in neural progenitors. PMID- 28808229 TI - Bioenergy application of Dunaliella salina SA 134 grown at various salinity levels for lipid production. AB - The biofuels are receiving considerable attention as a substitute for petro diesel. For microalgae, the cell density or biomass and lipid contents are key components for biodiesel production. This study was conducted to develop favorable culture conditions for Dunaliella salina to maximize its biomass and lipid accumulation. The effect of salinity (0.5 to 2.5 M NaCl) on the cell population, biochemical composition, and lipid output of Dunaliella salina was examined under a controlled environment for 21 days. Maximum growth (6.57 * 107 to 7.17 * 107cells mL-1) potentials were observed at 1.5 to 2 M NaCl. The photosynthetic pigments and carbohydrates also showed trends similar to growth. The maximum carotenoid level (5.16 mg L-1) was recorded at 2 M NaCl. Almost all physicochemical parameters increased with increases in salinity, biomass (1231.66 +/- 1.26 mg L-1) and lipid content (248.33 mg L-1), as recorded at 2 M NaCl. Based on fluorescence intensity, the highest values (11.84 * 107cells/ml) of neutral lipids and total lipids (22.28%) were recorded at optimum salinity levels. The present study suggests that a high biomass and lipid accumulation of Dunaliella salina SA 134 could be obtained at the 2 M NaCl level. PMID- 28808230 TI - Environmental drivers of a microbial genomic transition zone in the ocean's interior. AB - The core properties of microbial genomes, including GC content and genome size, are known to vary widely among different bacteria and archaea 1,2 . Several hypotheses have been proposed to explain this genomic variability, but the fundamental drivers that shape bacterial and archaeal genomic properties remain uncertain 3-7 . Here, we report the existence of a sharp genomic transition zone below the photic zone, where bacterial and archaeal genomes and proteomes undergo a community-wide punctuated shift. Across a narrow range of increasing depth of just tens of metres, diverse microbial clades trend towards larger genome size, higher genomic GC content, and proteins with higher nitrogen but lower carbon content. These community-wide changes in genome features appear to be driven by gradients in the surrounding environmental energy and nutrient fields. Collectively, our data support hypotheses invoking nutrient limitation as a central driver in the evolution of core bacterial and archaeal genomic and proteomic properties. PMID- 28808231 TI - A synthetic analysis of greenhouse gas emissions from manure amended agricultural soils in China. AB - Application of manure has been recommended as an effective strategy to to mitigate climate change. However, the magnitude of greenhouse gases emission derived by application of manure to agricultural soils across environmental conditions still remains unclear. Here, we synthesized data from 379 observations in China and quantified the responses of soil nitrous oxide (N2O), carbon dioxide (CO2) and methane (CH4) emissions to manure (Org-M) in comparison to chemical fertilizers (Min-F) or non-fertilizers (Non-F). The results showed that N2O, CO2 and CH4 emissions were significantly affected by Org-M compared to Min-F (percentage change: -3, +15 and +60%, P < 0.05) and Non-F (percentage change: +289, +84 and +83%, P < 0.05), respectively. However, at the same amount of total N input, Org-M decreased soil N2O emission by 13% and CH4 emission by 12%, and increased soil CO2 emission by 26% relative to Min-F in upland soils. For paddy soils, N2O, CO2 and CH4 emissions differed by -3%, -36% and +84% between Org-M and Min-F (i.e., Org-M minus Min-F). Thus, practices such as application of manure instead of chemical fertilizer and decreasing nitrogen input rate need to be highly considered and optimized under different soils and climate conditions to mitigate GHGs emission in China. PMID- 28808232 TI - Analysis of the ATR-Chk1 and ATM-Chk2 pathways in male breast cancer revealed the prognostic significance of ATR expression. AB - The ATR-Chk1 and ATM-Chk2 pathways are central in DNA damage repair (DDR) and their over-activation may confer aggressive molecular features, being an adaptive response to endogenous DNA damage and oncogene-induced replication stress. Herein we investigated the ATR-Chk1 and ATM-Chk2 signalings in male breast cancer (MBC). The expression of DDR kinases (pATR, pATM, pChk1, pChk2, and pWee1) and DNA damage markers (pRPA32 and gamma-H2AX) was evaluated by immunohistochemistry in 289 MBC samples to assess their association. Survival analyses were carried out in 112 patients. Survival curves were estimated with the Kaplan-Meier method and compared by log-rank test. Cox proportional regression models were generated to identify variables impacting survival outcomes. The expression of pATR conferred poorer survival outcomes (log rank p = 0.013, p = 0.007 and p = 0.010 for overall, 15- and 10-year survival, respectively). Multivariate Cox models of 10 year survival and overall indicated that pATR expression, alone or combined with pChk2, was an independent predictor of adverse outcomes (10-year survival: pATR: HR 2.74, 95% CI: 1.23-6.10; pATR/pChk2: HR 2.92, 95% CI: 1.35-6.33; overall survival: pATR: HR 2.58, 95% CI: 1.20-5.53; pATR/pChk2: HR 2.89, 95% CI: 1.37 6.12). Overall, the ATR/ATM-initiated molecular cascade seems to be active in a fraction of MBC patients and may represent a negative prognostic factor. PMID- 28808234 TI - Cascaded counter-propagating nonlinear interactions in highly-efficient sub-um periodically poled crystals. AB - Mirrorless optical parametric oscillators (MOPOs) are very attractive parametric devices that rely on the nonlinear interaction of counter-propagating photons to inherently establish distributed feedback, without the use of external mirrors or surface coatings. These devices offer unique spectral and coherence properties that will benefit a large variety of applications ranging from spectroscopy to quantum communications. The major obstacle in exploiting their full potential is ascribed to the difficulty in engineering a nonlinear material in which the generation of counter-propagating waves can be phase matched. Here we present a reliable and consistent technique for fabrication of highly-efficient sub micrometer periodically poled Rb-doped KTiOPO4. We experimentally demonstrate the first cascaded counter-propagating interactions in which the generated forward signal serves as a pump for a secondary MOPO process, reaching pump depletion larger than 60%. The cascaded process exemplifies the high efficiency of our nonlinear photonic structures. Our domain-engineering technique paves the way to realize counter-propagating schemes and devices that have been deemed unfeasible until now. PMID- 28808233 TI - The influence of affective state on exogenous attention to emotional distractors: behavioral and electrophysiological correlates. AB - The interplay between exogenous attention to emotional distractors and the baseline affective state has not been well established yet. The present study aimed to explore this issue through behavioral measures and event-related potentials (ERPs). Participants (N = 30) completed a digit categorization task depicted over negative, positive or neutral distractor background pictures, while they experienced negative, positive and neutral affective states elicited by movie scenes. Behavioral results showed higher error rates and longer reaction times for negative distractors than for neutral and positive ones, irrespective of the current emotional state. Neural indices showed that the participants' affective state modulated N1 amplitudes, irrespective of distractor type, while the emotional charge of distractors modulated N2, irrespective of the emotional state. Importantly, an interaction of state and distractor type was observed in LPP. These results demonstrate that exogenous attention to emotional distractors is independent from modulating effects of the emotional baseline state at early, automatic stages of processing. However, attention to emotional distractors and affective state interact at later latencies. PMID- 28808235 TI - Direct Ink Write (DIW) 3D Printed Cellulose Nanocrystal Aerogel Structures. AB - Pure cellulose nanocrystal (CNC) aerogels with controlled 3D structures and inner pore architecture are printed using the direct ink write (DIW) technique. While traditional cellulosic aerogel processing approaches lack the ability to easily fabricate complete aerogel structures, DIW 3D printing followed by freeze drying can overcome this shortcoming and can produce CNC aerogels with minimal structural shrinkage or damage. The resultant products have great potential in applications such as tissue scaffold templates, drug delivery, packaging, etc., due to their inherent sustainability, biocompatibility, and biodegradability. Various 3D structures are successfully printed without support material, and the print quality can be improved with increasing CNC concentration and printing resolution. Dual pore CNC aerogel scaffolds are also successfully printed, where the customizable 3D structure and inner pore architecture can potentially enable advance CNC scaffold designs suited for specific cell integration requirements. PMID- 28808236 TI - Decreased high density lipoprotein cholesterol is an independent predictor for persistent organ failure, pancreatic necrosis and mortality in acute pancreatitis. AB - High density lipoprotein cholesterol (HDL-C) has been reported as a significant indicator of systemic inflammation. The association underlying HDL-C and persistent organ failure (POF), pancreatic necrosis (PNec) and mortality in acute pancreatitis (AP) has not been evaluated. From 2007 to 2016, consecutive AP patients with admission lipid profiles assessment were included in this study. The association of HDL-C value and other lipids with outcomes was explored with Cox proportional regression models, which were adjusted for confounding factors. 1131 consecutive AP patients were clinically eligible. Overall, 17.9% of the patients developed with POF, 27.1% experienced PNec, and 6.7% died during hospitalization. Lower HDL-C median (<1.06 mmol/L) was identified as an independent prognostic factor of the outcomes. Moreover, there was a positive trend for the association across increasing HDL-C quartiles and POF, PNec and mortality after multivariable analysis (p values were <0.001, <0.001 and 0.043, respectively). The AUC of HDL-C for the outcomes were comparable to that of Ranson score for diagnosing POF (0.778 vs. 0.678; P < 0.001), PNec (0.734 vs. 0.701; P = 0.143) and mortality (0.768 vs. 0.745; P = 0.516). Decreased HDL-C value is an independent risk factor for the incidence of POF, PNec and in hospital mortality in AP. PMID- 28808238 TI - RNA-Seq using bulked recombinant inbred line populations uncovers the importance of brassinosteroid for seed longevity after priming treatments. AB - Seed priming is a commercially used technique for improving seed performance including germination. However, the treatment sometimes reduces seed longevity as a side effect, limiting the storable period or longevity of the seeds. To overcome this problem, molecular mechanisms involved in the loss of seed longevity during priming were analyzed using natural variations of Arabidopsis thaliana. We found that the Est-1 accession retained longevity for longer after priming compared to the reference accession Col-0. QTL analysis using 279 recombinant inbred lines (RILs) derived from the Est-1 * Col-0 detected three QTL regions associated with the loss of seed longevity during priming. Bulked transcriptome analysis (RNA-Seq with bulked RIL populations) revealed that genes related to brassinosteroid (BR) biosynthesis/signaling and cell wall modification were highly expressed in primed seeds with shorter longevity. After priming, BR deficient mutants cyp85a1/a2 and det2 showed significantly longer longevity than the wild type (WT). Moreover, tetrazolium staining indicated that mutant seed coats were less permeable after priming than those of WT. We suggest that the loss of seed longevity in primed seed is due to increased seed coat permeability, which is positively regulated, at least partly, via BR signaling. PMID- 28808237 TI - Coding and small non-coding transcriptional landscape of tuberous sclerosis complex cortical tubers: implications for pathophysiology and treatment. AB - Tuberous Sclerosis Complex (TSC) is a rare genetic disorder that results from a mutation in the TSC1 or TSC2 genes leading to constitutive activation of the mechanistic target of rapamycin complex 1 (mTORC1). TSC is associated with autism, intellectual disability and severe epilepsy. Cortical tubers are believed to represent the neuropathological substrates of these disabling manifestations in TSC. In the presented study we used high-throughput RNA sequencing in combination with systems-based computational approaches to investigate the complexity of the TSC molecular network. Overall we detected 438 differentially expressed genes and 991 differentially expressed small non-coding RNAs in cortical tubers compared to autopsy control brain tissue. We observed increased expression of genes associated with inflammatory, innate and adaptive immune responses. In contrast, we observed a down-regulation of genes associated with neurogenesis and glutamate receptor signaling. MicroRNAs represented the largest class of over-expressed small non-coding RNA species in tubers. In particular, our analysis revealed that the miR-34 family (including miR-34a, miR-34b and miR 34c) was significantly over-expressed. Functional studies demonstrated the ability of miR-34b to modulate neurite outgrowth in mouse primary hippocampal neuronal cultures. This study provides new insights into the TSC transcriptomic network along with the identification of potential new treatment targets. PMID- 28808239 TI - Compound A influences gene regulation of the Dexamethasone-activated glucocorticoid receptor by alternative cofactor recruitment. AB - The glucocorticoid receptor (GR) is a transcription factor of which the underlying gene regulatory mechanisms are complex and incompletely understood. The non-steroidal anti-inflammatory Compound A (CpdA), a selective GR modulating compound in various cell models, has been shown to favour GR-mediated gene repression but not GR-mediated gene activation. Shifting balances towards only a particular subset of GR gene regulatory events may be of benefit in the treatment of inflammatory diseases. We present evidence to support that the combination of CpdA with Dexamethasone (DEX), a classic steroidal GR ligand, can shape GR function towards a unique gene regulatory profile in a cell type-dependent manner. The molecular basis hereof is a changed GR phosphorylation status concomitant with a change in the GR cofactor recruitment profile. We subsequently identified and confirmed the orphan nuclear receptor SHP as a coregulator that is specifically enriched at GR when CpdA and DEX are combined. Combining CpdA with DEX not only leads to stronger suppression of pro-inflammatory gene expression, but also enhanced anti-inflammatory GR target gene expression in epithelial cells, making ligand combination strategies in future a potentially attractive alternative manner of skewing and fine-tuning GR effects towards an improved therapeutic benefit. PMID- 28808241 TI - Specific calpain inhibition protects kidney against inflammaging. AB - Calpains are ubiquitous pro-inflammatory proteases, whose activity is controlled by calpastatin, their specific inhibitor. Transgenic mice over-expressing rabbit calpastatin (CalpTG) are protected against vascular remodelling and angiotensin II-dependent inflammation. We hypothesized that specific calpain inhibition would protect against aging-related lesions in arteries and kidneys. We analysed tissues from 2-months and 2-years-old CalpTG and wild-type mice and performed high throughput RNA-Sequencing of kidney tissue in aged mice. In addition, we analysed inflammatory response in the kidney of aged CalpTG and wild-type mice, and in both in vivo (monosodium urate peritonitis) and in vitro models of inflammation. At two years, CalpTG mice had preserved kidney tissue, less vascular remodelling and less markers of senescence than wild-type mice. Nevertheless, CalpTG mice lifespan was not extended, due to the development of lethal spleen tumors. Inflammatory pathways were less expressed in aged CalpTG mice, especially cytokines related to NF-kappaB and NLRP3 inflammasome activation. CalpTG mice had reduced macrophage infiltration with aging and CalpTG mice produced less IL-1alpha and IL-1beta in vivo in response to inflammasome activators. In vitro, macrophages from CalpTG mice produced less IL-1alpha in response to particulate activators of inflammasome. Calpains inhibition protects against inflammaging, limiting kidney and vascular lesions related to aging. PMID- 28808242 TI - Unusual dynamic precipitation softening induced by dislocation glide in biomedical beta-titanium alloys. AB - Softening of metallic materials containing precipitates during cyclic deformation occurs through dissolution of the precipitates, because the to-and-fro motion of the dislocation causes dissolution of the precipitate particles by cutting them. Here, however, we found the completely opposite phenomenon for the first time; a "dynamic precipitation softening" phenomenon. In a Ti-35Nb-10Ta-5Zr body-centered cubic structured beta-Ti alloy single crystal developed for biomedical implant, the to-and-fro motion of the dislocation "induced" the selective precipitation of the omega-phase whose c-axis is parallel to the Burgers vector of the moving dislocation, which led to the significant cyclic softening of the crystal. The formation of the omega-phase is generally believed to induce significant hardening of beta-Ti alloys. However, the present results suggest that this is not always true, and control of the anisotropic features of the omega-phase via control of crystal orientation can induce unusual mechanical properties in beta Ti alloys. The unique anisotropic mechanical properties obtained by the cyclic deformation-induced oriented omega-phase formation could be useful for the development of "single-crystalline beta-Ti implant materials" with advanced mechanical performance. PMID- 28808240 TI - Micro-epidemiology and spatial heterogeneity of P. vivax parasitaemia in riverine communities of the Peruvian Amazon: A multilevel analysis. AB - Malaria has steadily increased in the Peruvian Amazon over the last five years. This study aimed to determine the parasite prevalence and micro-geographical heterogeneity of Plasmodium vivax parasitaemia in communities of the Peruvian Amazon. Four cross-sectional active case detection surveys were conducted between May and July 2015 in four riverine communities in Mazan district. Analysis of 2785 samples of 820 individuals nested within 154 households for Plasmodium parasitaemia was carried out using light microscopy and qPCR. The spatio-temporal distribution of Plasmodium parasitaemia, dominated by P. vivax, was shown to cluster at both household and community levels. Of enrolled individuals, 47% had at least one P. vivax parasitaemia and 10% P. falciparum, by qPCR, both of which were predominantly sub-microscopic and asymptomatic. Spatial analysis detected significant clustering in three communities. Our findings showed that communities at small-to-moderate spatial scales differed in P. vivax parasite prevalence, and multilevel Poisson regression models showed that such differences were influenced by factors such as age, education, and location of households within high-risk clusters, as well as factors linked to a local micro-geographic context, such as travel and occupation. Complex transmission patterns were found to be related to human mobility among communities in the same micro-basin. PMID- 28808243 TI - Comparison of error correction algorithms for Ion Torrent PGM data: application to hepatitis B virus. AB - Ion Torrent Personal Genome Machine (PGM) technology is a mid-length read, low cost and high-speed next-generation sequencing platform with a relatively high insertion and deletion (indel) error rate. A full systematic assessment of the effectiveness of various error correction algorithms in PGM viral datasets (e.g., hepatitis B virus (HBV)) has not been performed. We examined 19 quality-trimmed PGM datasets for the HBV reverse transcriptase (RT) region and found a total error rate of 0.48% +/- 0.12%. Deletion errors were clearly present at the ends of homopolymer runs. Tests using both real and simulated data showed that the algorithms differed in their abilities to detect and correct errors and that the error rate and sequencing depth significantly affected the performance. Of the algorithms tested, Pollux showed a better overall performance but tended to over correct 'genuine' substitution variants, whereas Fiona proved to be better at distinguishing these variants from sequencing errors. We found that the combined use of Pollux and Fiona gave the best results when error-correcting Ion Torrent PGM viral data. PMID- 28808244 TI - The N-P-K soil nutrient balance of Portuguese cropland in the 1950s: The transition from organic to chemical fertilization. AB - Agricultural nutrient balances have been receiving increasing attention in both historical and nutrient management research. The main objectives of this study were to further develop balance methodologies and to carry out a comprehensive assessment of the functioning and nutrient cycling of 1950s agroecosystems in Portugal. Additionally, the main implications for the history of agriculture in Portugal were discussed from the standpoint of soil fertility. We used a mass balance approach that comprises virtually all nitrogen (N), phosphorus (P) and potassium (K) inputs and outputs from cropland topsoil for average conditions in the period 1951-56. We found a consistent deficit in N, both for nationwide (-2.1 kg.ha-1.yr-1) and arable crops (-1.6 kg.ha-1.yr-1) estimates, that was rectified in the turn to the 1960 decade. P and K were, in contrast, accumulating in the soil (4.2-4.6 kg.ha-1.yr-1 and 1.0-3.0 kg.ha-1.yr-1, respectively). We observed that the 1950s is the very moment of inflection from an agriculture fertilized predominantly through reused N in biomass (livestock excretions plus marine, plant and human waste sources) to one where chemical fertilizers prevailed. It is suggested that N deficiency played an important role in this transition. PMID- 28808245 TI - Structural characterization of CAS SH3 domain selectivity and regulation reveals new CAS interaction partners. AB - CAS is a docking protein downstream of the proto-oncogene Src with a role in invasion and metastasis of cancer cells. The CAS SH3 domain is indispensable for CAS-mediated signaling, but structural aspects of CAS SH3 ligand binding and regulation are not well understood. Here, we identified the consensus CAS SH3 binding motif and structurally characterized the CAS SH3 domain in complex with ligand. We revealed the requirement for an uncommon centrally localized lysine residue at position +2 of CAS SH3 ligands and two rather dissimilar optional anchoring residues, leucine and arginine, at position +5. We further expanded the knowledge of CAS SH3 ligand binding regulation by manipulating tyrosine 12 phosphorylation and confirmed the negative role of this phosphorylation on CAS SH3 ligand binding. Finally, by exploiting the newly identified binding requirements of the CAS SH3 domain, we predicted and experimentally verified two novel CAS SH3 binding partners, DOK7 and GLIS2. PMID- 28808246 TI - How context alters value: The brain's valuation and affective regulation system link price cues to experienced taste pleasantness. AB - Informational cues such as the price of a wine can trigger expectations about its taste quality and thereby modulate the sensory experience on a reported and neural level. Yet it is unclear how the brain translates such expectations into sensory pleasantness. We used a whole-brain multilevel mediation approach with healthy participants who tasted identical wines cued with different prices while their brains were scanned using fMRI. We found that the brain's valuation system (BVS) in concert with the anterior prefrontal cortex played a key role in implementing the effect of price cues on taste pleasantness ratings. The sensitivity of the BVS to monetary rewards outside the taste domain moderated the strength of these effects. These findings provide novel evidence for the fundamental role that neural pathways linked to motivation and affective regulation play for the effect of informational cues on sensory experiences. PMID- 28808247 TI - Social learning promotes nicotine self-administration by facilitating the extinction of conditioned aversion in isogenic strains of rats. AB - Both social environment and genetic factors are critical for smoking initiation and nicotine addiction. We reported that rats developed conditioned flavor (i.e., taste and odor) aversion to intravenously self-administered (IVSA) nicotine, and that social learning promoted nicotine IVSA with flavor cues. We thus tested the hypothesis that socially acquired nicotine IVSA is a heritable trait by using female rats of six inbred strains and six F1 hybrids. Each strain was tested for 10 daily IVSA sessions. We found that the intake of nicotine (15 and 30 MUg/kg/inf) varied among these strains by 33.7-56.6-fold. The heritability of nicotine intake was estimated to be 0.54-0.65. Further, there was a strong correlation in nicotine intake (R2 = 0.85, p < 0.0001) between the two nicotine doses. Another cohort of rats was given three daily IVSA sessions followed by five sessions that tested conditioned flavor aversion. Nicotine intake was highly correlated with the extinction of the conditioned aversion (R2 = 0.58, p < 0.005). These data showed that nicotine intake in the socially acquired nicotine self-administration model is controlled by genetic factors and that the role of social learning is likely in facilitating the extinction of conditioned aversive response to nicotine. PMID- 28808248 TI - Half-spaced substrate integrated spoof surface plasmon polaritons based transmission line. AB - In this paper, a new spoof surface plasmon polaritons (SPPs) based transmission line (TL) with semi-open structure is proposed, which is implemented on a single layer substrate with metallized via holes planted on a ground plane. The electromagnetic (EM) power propagates along it in the form of controlled slow surface wave, which is the same with its existing counterparts. The proposed TL can adjust the degree of EM energy confinement, and thus balance its performance in every characteristic, in particular attenuation and interference. As the TL is semi-open (i.e., EM energy distributes in the half space above the ground plane), it is less vulnerable to the nearby interference compared with its former counterparts, which are fully-open structure (i.e., EM energy distributes in the full space). Prototypes working at Ka band are fabricated and measured. Bianco Parodi (BP) method is used to derive the attenuation of the proposed TL from the measured S-parameters. The proposed structure can be easily scaled for THz applications, which opens the door for future high performance THz components and systems. PMID- 28808249 TI - Magnetic moment evolution and spin freezing in doped BaFe2As2. AB - Fe-K beta X-ray emission spectroscopy measurements reveal an asymmetric doping dependence of the magnetic moments MU bare in electron- and hole-doped BaFe2As2. At low temperature, MU bare is nearly constant in hole-doped samples, whereas it decreases upon electron doping. Increasing temperature substantially enhances MU bare in the hole-doped region, which is naturally explained by the theoretically predicted crossover into a spin-frozen state. Our measurements demonstrate the importance of Hund's-coupling and electronic correlations, especially for hole doped BaFe2As2, and the inadequacy of a fully localized or fully itinerant description of the 122 family of Fe pnictides. PMID- 28808250 TI - Polarization tunable all-dielectric color filters based on cross-shaped Si nanoantennas. AB - Polarization sensitive and insensitive color filters have important applications in the area of nano-spectroscopy and CCD imaging applications. Metallic nanostructures provide an efficient way to design and engineer ultrathin color filters. These nanostructures have capability to split the white light into fundamental colors and enable color filters with ultrahigh resolution but their efficiency can be restricted due to high losses in metals especially at the visible wavelengths. In this work, we demonstrate all-dielectric color filters based on Si nanoantennas, which are sensitive to incident-wave polarization and, thus, tunable with the aid of polarization angle variation. Two different information can be encoded in two different polarization states in one nanostructure. The nanoantenna based pixels are highly efficient and can provide high quality of colors, in particular, due to low losses in Si at optical frequencies. We experimentally demonstrate that a variety of colors can be achieved by changing the physical size of the nonsymmetric cross-shaped nanoantennas. The proposed devices allow to cover an extended gamut of colors on CIE-1931 chromaticity diagram owing to the existence of high-quality resonances in Si nanoantennas. Significant tunability of the suggested color filters can be achieved by varying polarization angle in both transmission and reflection mode. Additional tunability can be obtained by switching between transmission and reflection modes. PMID- 28808251 TI - Continuous Production of Macroporous Films: an Alternative to Breath Figure Assembly. AB - Despite the need for sophisticated instrumentation, breath figure assembly (BFA) methods are restricted to produce macroporous films on a tiny scale so far. The current study narrates the fabrication of macroporous films in hollow fiber geometry which extends to adopt the method for continuous production of isoporous surfaces from commercially available low-priced polymer materials. The fabrication of the films in the hollow fiber geometry is carried out by a co centric quadruple orifice spinneret through which four different liquids are co extruded simultaneously: bore fluid (to fill the lumen of the fiber), support layer solution, glycerol, and an isoporous film forming solution through the outer most orifice. The extruded entities plunge into a coagulation bath after passing a definite air gap. The implementation of the concept of diffuse-in, droplet formation, and then condense-out behavior of glycerol in a co-extrusion method of hollow fiber spinning makes macroporous film formation possible in an interminable way sidestepping the use of breath figure assembly method. Moreover, the continuous film formation by the proposed mechanism is also authenticated in flat sheet geometry by employing two casting blades in a casting machine. The structure of the films is analyzed by scanning electron microscopy (SEM). PMID- 28808252 TI - Altered awareness of action in Parkinson's disease: evaluations by explicit and implicit measures. AB - Deficits in the integration of motor prediction and its feedback have been reported in Parkinson's disease. Conscious awareness of action is proposed to emerge under the integration of motor prediction and its feedback. Thus, it may lead to changes in the awareness of the authorship of action (in other words, the sense of agency) in Parkinson's disease. We have employed both explicit and implicit measures to assess the awareness of action in Parkinson's disease and matched controls. As an explicit measure, an action recognition task requiring explicit judgments was used. Patients showed less attribution of their movements to non-biased and angular-biased visual feedbacks. As an implicit measure, the temporal attraction between the perceived time of actions and their effects, which is known as intentional binding task, was used. While action-effect association was observed in the control group, actions were not experienced as having shifted towards their subsequent effects in the patient group. These tendencies were consistent regardless of the side of the asymmetrical motor symptoms. These results may reflect an underlying abnormality in the awareness of voluntary action in Parkinson's disease. PMID- 28808253 TI - Species distribution models of two critically endangered deep-sea octocorals reveal fishing impacts on vulnerable marine ecosystems in central Mediterranean Sea. AB - Deep-sea coral assemblages are key components of marine ecosystems that generate habitats for fish and invertebrate communities and act as marine biodiversity hot spots. Because of their life history traits, deep-sea corals are highly vulnerable to human impacts such as fishing. They are an indicator of vulnerable marine ecosystems (VMEs), therefore their conservation is essential to preserve marine biodiversity. In the Mediterranean Sea deep-sea coral habitats are associated with commercially important crustaceans, consequently their abundance has dramatically declined due to the effects of trawling. Marine spatial planning is required to ensure that the conservation of these habitats is achieved. Species distribution models were used to investigate the distribution of two critically endangered octocorals (Funiculina quadrangularis and Isidella elongata) in the central Mediterranean as a function of environmental and fisheries variables. Results show that both species exhibit species-specific habitat preferences and spatial patterns in response to environmental variables, but the impact of trawling on their distribution differed. In particular F. quadrangularis can overlap with fishing activities, whereas I. elongata occurs exclusively where fishing is low or absent. This study represents the first attempt to identify key areas for the protection of soft and compact mud VMEs in the central Mediterranean Sea. PMID- 28808254 TI - Ikk2 regulates cytokinesis during vertebrate development. AB - NFkappaB signaling has a pivotal role in regulation of development, innate immunity, and inflammation. Ikk2 is one of the two critical kinases that regulate the NFkappaB signaling pathway. While the role of Ikk2 in immunity, inflammation and oncogenesis has received attention, an understanding of the role of Ikk2 in vertebrate development has been compounded by the embryonic lethality seen in mice lacking Ikk2. We find that despite abnormal angiogenesis in IKK2 zygotic mutants of zebrafish, the maternal activity of Ikk2 supports embryogenesis and maturation of fertile animals and allows to study the role of IKK2 in development. Maternal-zygotic ikk2 mutants represent the first vertebrates globally devoid of maternal and zygotic Ikk2 activity. They are defective in cell proliferation as evidenced by abnormal cytokinesis, nuclear enlargement and syncytialisation of a significant portion of blastoderm. We further document that reduced phosphorylation of Aurora A by Ikk2 could underlie the basis of these defects in cell division. PMID- 28808256 TI - SpotOn: High Accuracy Identification of Protein-Protein Interface Hot-Spots. AB - We present SpotOn, a web server to identify and classify interfacial residues as Hot-Spots (HS) and Null-Spots (NS). SpotON implements a robust algorithm with a demonstrated accuracy of 0.95 and sensitivity of 0.98 on an independent test set. The predictor was developed using an ensemble machine learning approach with up sampling of the minor class. It was trained on 53 complexes using various features, based on both protein 3D structure and sequence. The SpotOn web interface is freely available at: http://milou.science.uu.nl/services/SPOTON/ . PMID- 28808255 TI - Critical role for arginase 2 in obesity-associated pancreatic cancer. AB - Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDA). Despite recent identification of metabolic alterations in this lethal malignancy, the metabolic dependencies of obesity-associated PDA remain unknown. Here we show that obesity-driven PDA exhibits accelerated growth and a striking transcriptional enrichment for pathways regulating nitrogen metabolism. We find that the mitochondrial form of arginase (ARG2), which hydrolyzes arginine into ornithine and urea, is induced upon obesity, and silencing or loss of ARG2 markedly suppresses PDA. In vivo infusion of 15N-glutamine in obese mouse models of PDA demonstrates enhanced nitrogen flux into the urea cycle and infusion of 15N-arginine shows that Arg2 loss causes significant ammonia accumulation that results from the shunting of arginine catabolism into alternative nitrogen repositories. Furthermore, analysis of PDA patient tumors indicates that ARG2 levels correlate with body mass index (BMI). The specific dependency of PDA on ARG2 rather than the principal hepatic enzyme ARG1 opens a therapeutic window for obesity-associated pancreatic cancer.Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDA). Here the authors show that obesity induces the expression of the mitochondrial form of arginase ARG2 in PDA and that ARG2 silencing or loss results in ammonia accumulation and suppression of obesity driven PDA tumor growth. PMID- 28808257 TI - Stochastic model of contact inhibition and the proliferation of melanoma in situ. AB - Contact inhibition is a central feature orchestrating cell proliferation in culture experiments; its loss is associated with malignant transformation and tumorigenesis. We performed a co-culture experiment with human metastatic melanoma cell line (SKMEL- 147) and immortalized keratinocyte cells (HaCaT). After 8 days a spatial pattern was detected, characterized by the formation of clusters of melanoma cells surrounded by keratinocytes constraining their proliferation. In addition, we observed that the proportion of melanoma cells within the total population has increased. To explain our results we propose a spatial stochastic model (following a philosophy of the Widom-Rowlinson model from Statistical Physics and Molecular Chemistry) which considers cell proliferation, death, migration, and cell-to-cell interaction through contact inhibition. Our numerical simulations demonstrate that loss of contact inhibition is a sufficient mechanism, appropriate for an explanation of the increase in the proportion of tumor cells and generation of spatial patterns established in the conducted experiments. PMID- 28808259 TI - Combination of chemical fingerprint and bioactivity evaluation to explore the antibacterial components of Salvia miltiorrhizae. AB - The aim of this study was to explore the possible antibacterial components of Salvia miltiorrhizae on Pseudomonas aeruginosa using a combination of chemical fingerprint and bioactivity evaluation. The chemical fingerprints of 32 batches of S. miltiorrhizae samples from different sources were developed using high performance liquid chromatography with diode array detection, and then were evaluated by similarity analysis and hierarchical clustering analysis. Anti-P. aeruginosa activity was determined by microcalorimetry. Some crucial thermokinetic parameters obtained from the heat-flow power-time curves of P. aeruginosa growth in the absence or presence of these S. miltiorrhizae samples were evaluated using principal component analysis. Thereafter, multiple linear regression analysis was used to analyze the fingerprint-activity relationship between the chemical fingerprints and anti-P. aeruginosa activity. This established the related equation between the inhibition ratio (I, %) of S. miltiorrhizae samples on P. aeruginosa and the peak areas of the common peaks. The results showed that the 32S. miltiorrhizae samples could be grouped into three clusters according to their chemical fingerprints and anti-P. aeruginosa activities. Protocatechualdehyde, salvianolic acid B, together with three unidentified compounds might be the major components that contributed largely to the antibacterial properties of S. miltiorrhizae and should be the focus of S. miltiorrhizae quality control. Thus, this study provided a preferred way for exploring the bioactive components of medicinal plants. PMID- 28808260 TI - Transcriptional profiling identifies differential expression of long non-coding RNAs in Jo-1 associated and inclusion body myositis. AB - Myositis is characterised by muscle inflammation and weakness. Although generally thought to be driven by a systemic autoimmune response, increasing evidence suggests that intrinsic changes in the muscle might also contribute to the pathogenesis. Long non-coding RNAs (lncRNAs) are a family of novel genes that regulate gene transcription and translation. To determine the potential role of lncRNAs, we employed next generation sequencing to examine the transcriptome in muscle biopsies obtained from two histologically distinct patient populations, inclusion body myositis (IBM) and anti-Jo-1-associated myositis (Jo-1). 1287 mRNAs and 1068 mRNAs were differentially expressed in the muscle from Jo-1 and IBM patients, respectively. Pathway analysis showed the top canonical pathway in both Jo-1 and IBM was oxidative phosphorylation and mitochondrial dysfunction. We identified 731 known and 325 novel lncRNAs in the muscles biopsies. Comparison with controls showed 55 and 46 lncRNAs were differentially expressed in IBM and Jo-1 myositis, respectively. Of these, 16 lncRNAs were differentially expressed in both IBM and Jo-1 myositis and included upregulated H19, lncMyoD and MALAT1. Given that these are known to regulate muscle proliferation and differentiation, we speculate that changes in lncRNAs might contribute to the phenotypic changes in Jo-1 and IBM myositis. PMID- 28808258 TI - Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity. AB - Antimalarial compounds with dual therapeutic and transmission-blocking activity are desired as high-value partners for combination therapies. Here, we report the identification and characterization of hexahydroquinolines (HHQs) that show low nanomolar potency against both pathogenic and transmissible intra-erythrocytic forms of the malaria parasite Plasmodium falciparum. This activity translates into potent transmission-blocking potential, as shown by in vitro male gamete formation assays and reduced oocyst infection and prevalence in Anopheles mosquitoes. In vivo studies illustrated the ability of lead HHQs to suppress Plasmodium berghei blood-stage parasite proliferation. Resistance selection studies, confirmed by CRISPR-Cas9-based gene editing, identified the digestive vacuole membrane-spanning transporter PfMDR1 (P. falciparum multidrug resistance gene-1) as a determinant of parasite resistance to HHQs. Haemoglobin and haem fractionation assays suggest a mode of action that results in reduced haemozoin levels and might involve inhibition of host haemoglobin uptake into intra erythrocytic parasites. Furthermore, parasites resistant to HHQs displayed increased susceptibility to several first-line antimalarial drugs, including lumefantrine, confirming that HHQs have a different mode of action to other antimalarials drugs for which PfMDR1 is known to confer resistance. This work evokes therapeutic strategies that combine opposing selective pressures on this parasite transporter as an approach to countering the emergence and transmission of multidrug-resistant P. falciparum malaria. PMID- 28808262 TI - Generation of broadband ultraviolet frequency-entangled photons using cavity quantum plasmonics. AB - Application of quantum entangled photons is now extending to various fields in physics, chemistry and biology. In particular, in terms of application to molecular science, broadband ultraviolet frequency-entangled photons are desired because molecules inducing photochemical reactions of interest often have electronic transition energies in the ultraviolet region. Recent standard method for generating such entangled photons is a chirped quasi-phase-matching method, however this method is not suitable for the generation of ultraviolet frequency entangled photons because it requires down-conversion of a photon with a wavelength shorter than ultraviolet into an entangled photon pair. Here we propose a simple method for generating broadband ultraviolet frequency-entangled photons using cavity quantum plasmonics, in which conventional cavity quantum electrodynamics theory is applied to quantum plasmonics. We introduce a cavity plasmon system in which localised surface plasmon (LSP) is coupled to the cavity fields of a state-of-the-art microcavity. Using this system, we theoretically show that broadband ultraviolet frequency-entangled photons can be generated simply by utilising the absorption saturation effect of LSP. PMID- 28808263 TI - Ising Ferromagnets on Proximity Graphs with Varying Disorder of the Node Placement. AB - We perform Monte Carlo simulations to determine the critical temperatures of Ising Ferromagnets (IFM) on different types of two-dimensional proximity graphs, in which the distribution of their underlying node sets has been changed systematically by means of a parameter sigma. This allows us to interpolate between regular grids and proximity graphs based on complete random placement of nodes. Each edge of the planar proximity graphs carries a weighted ferromagnetic coupling. The coupling strengths are determined via the Euclidean distances between coupled spins. The simulations are carried out on graphs with N = 162 to N = 1282 nodes utilising the Wolff cluster algorithm and parallel tempering method in a wide temperature range around the critical point to measure the Binder cumulant in order to obtain the critical temperature for different values of sigma. Interestingly, the critical temperatures depend partially non monotonously on the disorder parameter sigma, corresponding to a non-monotonous change of the graph structure. For completeness, we further verify using finite size scaling methods that the IFM on proximity graphs is for all values of the disorder in the same universality class as the IFM on the two-dimensional square lattice. PMID- 28808261 TI - Atomic Force Microscopy micro-rheology reveals large structural inhomogeneities in single cell-nuclei. AB - During growth, differentiation and migration of cells, the nucleus changes size and shape, while encountering forces generated by the cell itself and its environment. Although there is increasing evidence that such mechanical signals are employed to control gene expression, it remains unclear how mechanical forces are transduced through the nucleus. To this end, we have measured the compliance of nuclei by applying oscillatory strains between 1 and 700 Hz to individual nuclei of multiple mammalian cell-lines that were compressed between two plates. The quantitative response varied with more than one order of magnitude and scaled with the size of the nucleus. Surprisingly, the qualitative behaviour was conserved among different cell-lines: all nuclei showed a softer and more viscous response towards the periphery, suggesting a reduced degree of crosslinking of the chromatin. This may be an important feature to regulate transcription via mechano-transduction in this most active and dynamic region of the nucleus. PMID- 28808264 TI - Knockdown of lncRNA MIR31HG inhibits adipocyte differentiation of human adipose derived stem cells via histone modification of FABP4. AB - Adipogenesis plays an important role in the regulation of whole-body energy homeostasis and is inextricably related to obesity. Several studies have highlighted the relevance of microRNAs in adipocyte differentiation, but the contributions of long non-coding RNAs (lncRNAs) are still largely uncharacterized. Here, we determined that lncRNA MIR31HG is related to adipocyte lineage commitment. We demonstrated that knockdown of MIR31HG inhibited adipocyte differentiation, whereas overexpression of MIR31HG promoted adipogenesis in vitro and in vivo. Furthermore, inhibition of MIR31HG reduced the enrichment of active histone markers, histone H3 lysine 4 trimethylation (H3K4me3) and acetylation (AcH3), in the promoter of the adipogenic-related gene, fatty acid binding protein 4 (FABP4), leading to suppression of its expression and adipogenesis. These results provide new insights into the molecular mechanisms of MIR31HG in terms of adipogenesis and may have implications for obesity and associated disorders. PMID- 28808265 TI - Study of dynamical heterogeneities in colloidal nanoclay suspensions approaching dynamical arrest. AB - The dynamics of aqueous Laponite clay suspensions slow down with increasing sample waiting time (t w ). This behavior, and the material fragility that results, closely resemble the dynamical slowdown in fragile supercooled liquids with decreasing temperature, and are typically ascribed to the increasing sizes of distinct dynamical heterogeneities in the sample. In this article, we characterize the dynamical heterogeneities in Laponite suspensions by invoking the three-point dynamic susceptibility formalism. The average time-dependent two point intensity autocorrelation and its sensitivity to t w are probed in dynamic light scattering experiments. Distributions of relaxation time scales, deduced from the Kohlrausch-Williams-Watts equation, are seen to widen with increasing t w . The calculated three-point dynamic susceptibility of Laponite suspensions exhibits a peak, with the peak height increasing with evolving t w at fixed volume fraction or with increasing volume fraction at fixed t w , thereby signifying the slowdown of the sample dynamics. The number of dynamically correlated particles, calculated from the peak-height, is seen to initially increase rapidly with increasing t w , before eventually slowing down close to the non-ergodic transition point. This observation is in agreement with published reports on supercooled liquids and hard sphere colloidal suspensions and offers a unique insight into the colloidal glass transition of Laponite suspensions. PMID- 28808267 TI - Novel twin-roll-cast Ti/Al clad sheets with excellent tensile properties. AB - Pure Ti or Ti alloys are recently spot-lighted in construction industries because they have excellent resistance to corrosions, chemicals, and climates as well as various coloring characteristics, but their wide applications are postponed by their expensiveness and poor formability. We present a new fabrication process of Ti/Al clad sheets by bonding a thin Ti sheet on to a 5052 Al alloy melt during vertical-twin-roll casting. This process has merits of reduced production costs as well as improved tensile properties. In the as-twin-roll-cast clad sheet, the homogeneously cast microstructure existed in the Al alloy substrate side, while the Ti/Al interface did not contain any reaction products, pores, cracks, or lateral delamination, which indicated the successful twin-roll casting. When this sheet was annealed at 350 degrees C~600 degrees C, the metallurgical bonding was expanded by interfacial diffusion, thereby leading to improvement in tensile properties over those calculated by a rule of mixtures. The ductility was also improved over that of 5052-O Al alloy (25%) or pure Ti (25%) by synergic effect of homogeneous deformation due to excellent Ti/Al bonding. This work provides new applications of Ti/Al clad sheets to lightweight-alloy clad sheets requiring excellent formability and corrosion resistance as well as alloy cost saving. PMID- 28808266 TI - In silico analysis of Glanzmann variants of Calf-1 domain of alphaIIbbeta3 integrin revealed dynamic allosteric effect. AB - Integrin alphaIIbbeta3 mediates platelet aggregation and thrombus formation. In a rare hereditary bleeding disorder, Glanzmann thrombasthenia (GT), alphaIIbbeta3 expression / function are impaired. The impact of deleterious missense mutations on the complex structure remains unclear. Long independent molecular dynamics (MD) simulations were performed for 7 GT variants and reference structure of the Calf-1 domain of alphaIIb. Simulations were analysed using a structural alphabet to describe local protein conformations. Common and flexible regions as well as deformable zones were observed in all the structures. The most flexible region of Calf-1 (with highest B-factor) is rather a rigid region encompassed into two deformable zones. Each mutated structure barely showed any modifications at the mutation sites while distant conformational changes were observed. These unexpected results question the relationship between molecular dynamics and allostery; and the role of these long-range effects in the impaired alphaIIbbeta3 expression. This method is aimed at studying all alphaIIbbeta3 sub-domains and impact of missense mutations at local and global structural level. PMID- 28808268 TI - Change of precipitation characteristics in the water-wind erosion crisscross region on the Loess Plateau, China, from 1958 to 2015. AB - Precipitation plays an important and crucial role in processes in the water-wind erosion crisscross region of the Loess Plateau than in other parts of the region. We analyzed precipitation data and standardized precipitation index (SPI) at 14 representative synoptic stations from 1958 to 2015 used trend-free prewhitening, linear trend estimation, Spearman's rho test, the Mann-Kendall trend test, the Mann-Kendall abrupt change test and rescaled range analysis. The following conclusions were drawn. First, the analysis of monthly precipitation at all stations suggested that precipitation during the rainy season (July, August, September), especially rain in July and August, exhibited a general decreasing trend, while both increasing and decreasing trends were observed in other months. Moreover, the annual precipitation of all stations continued to exhibit decreasing trends except Wuzhai. Erosive rainfall frequency in the rainy season and the annual scale was weakly reduced but erosive force of single rainfall has been enhanced. Second, the SPI exhibited different increasing degrees in winter, while decreasing trends were observed in other seasons. Additionally, the annual scale SPI at most stations exhibited a stable and sustained downward trend. Therefore, this region is currently associated with a drought trend, and the drought degree will likely continue to increase. PMID- 28808269 TI - Delivery of large transgene cassettes by foamy virus vector. AB - Viral vectors are effective tools in gene therapy, but their limited packaging capacity can be restrictive. Larger clinically-relevant vectors are needed. Foamy viruses have the largest genomes among mammalian retroviruses and their vectors have shown potential for gene therapy in preclinical studies. However, the effect of vector genome size on titre has not been determined. We inserted increasing lengths of the dystrophin open reading frame in a foamy virus vector and quantified packaged vector RNA and integrated DNA. For both measures, a semi logarithmic reduction in titre was observed as genome size increased. Concentrated titres were reduced 100-fold to approximately 106 transducing units per ml when vector genomes harboured a 12 kb insert, approximately twice that reported for lentivirus vectors in a comparable study. This potential was applied by optimising foamy virus vectors carrying the full-length dystrophin open reading frame for transduction of human muscle derived cells. Full-length dystrophin protein was expressed and transduced cells remained able to form myotubes in vitro. Foamy virus vectors are well-suited for stable delivery of large transgene cassettes and warrant further investigation for development as a therapy for Duchenne or Becker muscular dystrophy. PMID- 28808270 TI - A Low Permeability Microfluidic Blood-Brain Barrier Platform with Direct Contact between Perfusable Vascular Network and Astrocytes. AB - A novel three dimensional blood brain barrier (BBB) platform was developed by independently supplying different types of media to separate cell types within a single device. One channel (vascular channel, VC) is connected to the inner lumen of the vascular network while the other supplies media to the neural cells (neural channel, NC). Compared to co-cultures supplied with only one type of medium (or 1:1 mixture), best barrier properties and viability were obtained with culturing HUVECs with endothelial growth medium (EGM) and neural cells with neurobasal medium supplemented with fetal bovine serum (NBMFBS) independently. The measured vascular network permeability were comparable to reported in vivo values (20 kDa FITC-dextran, 0.45 +/- 0.11 * 10-6 cm/s; 70 kDa FITC-dextran, 0.36 +/- 0.05 * 10-6 cm/s) and a higher degree of neurovascular interfacing (astrocytic contact with the vascular network, GFAP-CD31 stain overlap) and presence of synapses (stained with synaptophysin). The BBB platform can dependably imitate the perivascular network morphology and synaptic structures characteristic of the NVU. This microfluidic BBB model can find applications in screening pharmaceuticals that target the brain for in neurodegenerative diseases. PMID- 28808271 TI - Dynamic modulation of Poincare beams. AB - Generation of complex Poincare beams is enabled by amplitude and phase modulation accompanied by simultaneous spatially polarization structuring. A holographic system to tailor complex light fields and optical angular momentum structures forecasts promising applications in quantum communication and optical trapping. Experimental results are presented together with simulations of complex Poincare beams embedding different types of polarization singularities. Additionally, parameters of the dynamic polarization modulation system are discussed and analyzed to demonstrate the enormous capability of the method. PMID- 28808273 TI - Financial fluctuations anchored to economic fundamentals: A mesoscopic network approach. AB - We demonstrate the existence of an empirical linkage between nominal financial networks and the underlying economic fundamentals, across countries. We construct the nominal return correlation networks from daily data to encapsulate sector level dynamics and infer the relative importance of the sectors in the nominal network through measures of centrality and clustering algorithms. Eigenvector centrality robustly identifies the backbone of the minimum spanning tree defined on the return networks as well as the primary cluster in the multidimensional scaling map. We show that the sectors that are relatively large in size, defined with three metrics, viz., market capitalization, revenue and number of employees, constitute the core of the return networks, whereas the periphery is mostly populated by relatively smaller sectors. Therefore, sector-level nominal return dynamics are anchored to the real size effect, which ultimately shapes the optimal portfolios for risk management. Our results are reasonably robust across 27 countries of varying degrees of prosperity and across periods of market turbulence (2008-09) as well as periods of relative calmness (2012-13 and 2015 16). PMID- 28808272 TI - A combinatorial approach for the discovery of cytochrome P450 2D6 inhibitors from nature. AB - The human cytochrome P450 2D6 (CYP2D6) enzyme is part of phase-I metabolism and metabolizes at least 20% of all clinically relevant drugs. Therefore, it is an important target for drug-drug interaction (DDI) studies. High-throughput screening (HTS) assays are commonly used tools to examine DDI, but show certain drawbacks with regard to their applicability to natural products. We propose an in silico - in vitro workflow for the reliable identification of natural products with CYP2D6 inhibitory potential. In order to identify candidates from natural product-based databases that share similar structural features with established inhibitors, a pharmacophore model was applied. The virtual hits were tested for the inhibition of recombinant human CYP2D6 in a bioluminescence-based assay. By controlling for unspecific interferences of the test compounds with the detection reaction, the number of false positives were reduced. The success rate of the reported workflow was 76%, as most of the candidates identified in the in silico approach were able to inhibit CYP2D6 activity. In summary, the workflow presented here is a suitable and cost-efficient strategy for the discovery of new CYP2D6 inhibitors with natural product libraries. PMID- 28808274 TI - Temperature-dependent birefringence of lithium triborate, LBO in the THz regime. AB - Optical properties of lithium triborate (LBO) in the terahertz regime (0.2-2 THz) were characterized using broadband terahertz time-domain spectroscopy. The frequency dependence of refractive index and absorption coefficient of the LBO crystal was experimentally investigated over the temperature range of 77-297 K, which the experimental results indicated that LBO has very low optical absorption coefficient at terahertz frequencies especially for the beam polarization along the crystal's principal dielectric axis X. Moreover, a giant birefringence was observed, and the refractive index difference between the axis X and Z gradually decreased with decreasing temperature, which is attributed to the behavior of the TO phonon modes of B1 and B2 symmetries at low frequencies at different temperatures. As potential applications, LBO can be exemplarily used as terahertz wave shapers, beam splitters, terahertz wave plates, circular polarizers and other polarization devices. PMID- 28808275 TI - Screening drug-target interactions with positive-unlabeled learning. AB - Identifying drug-target interaction (DTI) candidates is crucial for drug repositioning. However, usually only positive DTIs are deposited in known databases, which challenges computational methods to predict novel DTIs due to the lack of negative samples. To overcome this dilemma, researchers usually randomly select negative samples from unlabeled drug-target pairs, which introduces a lot of false-positives. In this study, a negative sample extraction method named NDTISE is first developed to screen strong negative DTI examples based on positive-unlabeled learning. A novel DTI screening framework, PUDTI, is then designed to infer new drug repositioning candidates by integrating NDTISE, probabilities that remaining ambiguous samples belong to the positive and negative classes, and an SVM-based optimization model. We investigated the effectiveness of NDTISE on a DTI data provided by NCPIS. NDTISE is much better than random selection and slightly outperforms NCPIS. We then compared PUDTI with 6 state-of-the-art methods on 4 classes of DTI datasets from human enzymes, ion channels, GPCRs and nuclear receptors. PUDTI achieved the highest AUC among the 7 methods on all 4 datasets. Finally, we validated a few top predicted DTIs through mining independent drug databases and literatures. In conclusion, PUDTI provides an effective pre-filtering method for new drug design. PMID- 28808276 TI - Growing-up (habitually) barefoot influences the development of foot and arch morphology in children and adolescents. AB - The development of the human foot is crucial for motor learning in children and adolescents as it ensures the basic requirements for bipedal locomotion and stable standing. Although there is an ongoing debate of the advantages and disadvantages of early and permanent footwear use, the influence of regular barefootness on foot characteristics in different stages of child development has not been extensively evaluated. A multicenter epidemiological study was conducted to compare the foot morphology between habitually barefoot children and adolescents (N = 810) to age-, sex- and ethnicity-matched counterparts that are used to wearing shoes. While controlling for confounders, we found that habitual footwear use has significant effects on foot-related outcomes in all age groups, such as a reduction in foot arch and hallux angles. The results indicate an impact of habitual footwear use on the development of the feet of children and adolescents. Therefore, growing up barefoot or shod may play an important role for childhood foot development, implying long-term consequences for motor learning and health later in life. PMID- 28808277 TI - Age- and sex-dependency of the association between systemic antioxidant potential and glaucomatous damage. AB - Systemic oxidative stress is thought to be an important factor in the pathogenesis of glaucoma. In particular, low systemic antioxidative capacity, which normally counters oxidative stress, may contribute to glaucoma. Thus, we investigated the association between biological antioxidant potential (BAP), a biomarker of systemic antioxidative capacity, and glaucoma severity in patients with open-angle glaucoma (OAG). This study included 480 eyes of 240 patients with OAG and 66 healthy control eyes. We measured the BAP serum level with a free radical analyzer and compared it with a weighted estimate of the number of retinal ganglion cells (wrgc), derived from circumpapillary retinal nerve fiber layer thickness and visual field mean deviation. We found that wrgc was uncorrelated with BAP in the overall, male, and female OAG patients, but was correlated in young (aged <= 65 years) male OAG patients (better eye: r = 0.33, P = 0.02; worse eye: r = 0.27, P = 0.047). Furthermore, a mixed-effects regression analysis revealed that BAP was an independent contributing factor to wrgc in young male OAG patients (P = 0.02). Thus, systemic antioxidant capacity was associated with glaucomatous damage in relatively young male patients, suggesting that anti-oxidant therapy might be more effective in these patients. PMID- 28808278 TI - Elevated Long Term Resting Heart Rate Variation is Associated with Increased Risk of All-cause Mortality in Northern China. AB - Elevated resting heart rate (RHR) predicts all-cause death. However, the relationship between RHR variation over years and mortality are still unknown. We aimed to analyze the association between RHR variation and all-cause mortality in the general population without cardiovascular diseases. A total of 46,873 subjects were included from the Kailuan Study (2006-2011). RHR readings were taken during three separate examinations and the RHR variation was defined using the standard deviation (RHR-SD) and the coefficient of variation. Participants were divided into four groups according to the quartiles of RHR-SD. All subjects were followed for a median of 49.4 months from the date of the 3rd examination to December 31, 2014. Up until the follow-up examinations, 973 (2.08%) participants had died. In a multivariate analysis, adjusting for variables potentially associated with death, the highest quartile of RHR-SD remained an independent predictor of all-cause mortality (Hazards ratio = 1.43, 95% confidence interval 1.18-1.74, P < 0.001). These findings suggest that an elevated long-term RHR variation is an independent risk marker for all-cause mortality in the general population without known cardiovascular diseases. PMID- 28808279 TI - Fine tuning and MOND in a metamaterial "multiverse". AB - We consider the recently suggested model of a multiverse based on a ferrofluid. When the ferrofluid is subjected to a modest external magnetic field, the nanoparticles inside the ferrofluid form small hyperbolic metamaterial domains, which from the electromagnetic standpoint behave as individual "Minkowski universes" exhibiting different "laws of physics", such as different strength of effective gravity, different versions of modified Newtonian dynamics (MOND) and different radiation lifetimes. When the ferrofluid "multiverse" is populated with atomic or molecular species, and these species are excited using an external laser source, the radiation lifetimes of atoms and molecules in these "universes" depend strongly on the individual physical properties of each "universe" via the Purcell effect. Some "universes" are better fine-tuned than others to sustain the excited states of these species. Thus, the ferrofluid-based metamaterial "multiverse" may be used to study models of MOND and to illustrate the fine tuning mechanism in cosmology. PMID- 28808281 TI - Surveillance Bias in Cancer Risk After Unrelated Medical Conditions: Example Urolithiasis. AB - We analysed cancer risks in patients with urinary tract stones but some features of the generated results alarmed us about possible surveillance bias, which we describe in this report. We used nationwide Swedish hospital records to identify patients with urinary tract stones (N = 211,718) and cancer registration data for cancer patients for years 1987 to 2012. Standardized incidence ratios (SIRs) for cancer were calculated after the last medical contact for urinary tract stones. All cancers were increased after kidney (SIR 1.54, 95%CI: 1.50-1.58), ureter (1.44, 1.42-1.47), mixed (1.51, 1.44-1.58) and bladder stones (1.63, 1.57-1.70). The risk of kidney cancer was increased most of all cancers after kidney, ureter and mixed stones while bladder cancer was increased most after bladder stones. All SIRs decreased steeply in the course of follow-up time. Tumour sizes were smaller in kidney cancer and in situ colon cancers were more common in patients diagnosed after urinary tract stones compared to all patients. The results suggest that surveillance bias influenced the result which somewhat surprisingly appeared to extend past 10 years of follow-up and include cancers at distant anatomical sites. Surveillance bias may be difficult to avoid in the present type of observational studies in clinical settings. PMID- 28808280 TI - Influence of different aluminum salts on the photocatalytic properties of Al doped TiO2 nanoparticles towards the degradation of AO7 dye. AB - Three kinds of Al-TiO2 samples and pure TiO2 samples were synthesized via a modified polyacrylamide gel route using different aluminum salts, including Al2(SO4)3?18H2O, AlCl3, and Al(NO3)3?9H2O under identical conditions. The influence of different aluminum salts on the phase purity, morphologies, thermal stability of anatase and photocatalytic properties of the as-prepared Al-TiO2 nanoparticles were studied. The energy gap (Eg) of Al-TiO2 nanoparticles decreases due to Al ion doping into TiO2. The photocatalytic activities of the Al TiO2 samples were investigated by the degradation of acid orange 7 dye in aqueous solution under simulated solar irradiation. The Al-TiO2 nanoparticles prepared from Al(NO3)3?9H2O exhibit the best photocatalytic activity among the four kinds of samples, followed in turn by the Al-TiO2 nanoparticles prepared with AlCl3, Al2(SO4)3?18H2O and pure TiO2. The different performances are attributed to complex effects of Eg, particle size, surface morphology, phase purity and the defect sites of the Al-TiO2 nanoparticles. PMID- 28808282 TI - Health care claims for primary open-angle glaucoma and retinal vein occlusion from an 11-year nationwide dataset. AB - To evaluate the risk of retinal vein occlusion (RVO) development after primary open-angle glaucoma (POAG) and the risk of POAG development after RVO, we conducted a nationwide, population-based 11-year longitudinal study. National registry data were collected from the Korean National Health Insurance Research Database, comparing 1 025 340 (~2.2%) subjects who were selected from 46 605 433 Korean residents in 2002. Each sampled patients was tracked until 2013. POAG developed in 0.92% of the RVO group (n = 6 826) and in 0.22% of the comparison group. RVO developed in 0.99% of the POAG group (n = 4 138) and in 0.37% of the comparison group. RVO was associated with an increased risk of POAG development (hazard ratio [HR], 3.25; 95% confidence interval [CI], 2.39-4.42) and POAG was associated with an increased risk of RVO development (HR, 5.05; 95% CI, 3.94 6.47). Comorbidity of systemic hypertension and diabetes mellitus further increased the risk of POAG development in the RVO group (HR, 3.58 and HR, 5.98, respectively). Patients with RVO exhibit a significantly higher risk of POAG development and patients with POAG exhibit a significantly higher risk of RVO development, based on an 11-year follow-up period. PMID- 28808283 TI - Drug-induced Extrapyramidal Symptoms Scale (DIEPSS) Serbian Language version: Inter-rater and Test-retest Reliability. AB - Drug-induced Extrapyramidal Symptoms Scale (DIEPSS) is developed in the era of second-generation antipsychotics and is suitable for evaluation of the low incidence of extrapyramidal symptoms occurring in the treatment of atypical antipsychotics, as well as the relationship between personal and social functioning. The study was carried out at the Institute of Mental Health in Serbia in 2015 Study used the 127 DIEPSS video clips material, recorded from 1987 till 2015. Four raters performed the assessment simultaneously, individually rating one assigned item immediately after seeing the video clip. For the purpose of evaluating test-retest reliability the second assessment of the same material was performed nine months after the first assessment. Inter-rater reliability was high for each individual item, with ICCs ranging from 0.769 to 0.949. The inter rater reliability was highest for akathisia item and lowest for dyskinesia. The test-retest reliability was high for each individual item, with ICC ranging from 0.713 to 0.935. The test-retest reliability was highest for bradykinesia item and lowest for dystonia. The Serbian version of DIEPSS has high level of inter-rater and test-retest reliability. High values of concordance rates (ICC > 0.7) for each evaluated individual item suggest that items of DIEPSS are well defined. PMID- 28808284 TI - Molecular Rationale behind the Differential Substrate Specificity of Bacterial RND Multi-Drug Transporters. AB - Resistance-Nodulation-cell Division (RND) transporters AcrB and AcrD of Escherichia coli expel a wide range of substrates out of the cell in conjunction with AcrA and TolC, contributing to the onset of bacterial multidrug resistance. Despite sharing an overall sequence identity of ~66% (similarity ~80%), these RND transporters feature distinct substrate specificity patterns whose underlying basis remains elusive. We performed exhaustive comparative analyses of the putative substrate binding pockets considering crystal structures, homology models and conformations extracted from multi-copy MUs-long molecular dynamics simulations of both AcrB and AcrD. The impact of physicochemical and topographical properties (volume, shape, lipophilicity, electrostatic potential, hydration and distribution of multi-functional sites) within the pockets on their substrate specificities was quantitatively assessed. Differences in the lipophilic and electrostatic potentials among the pockets were identified. In particular, the deep pocket of AcrB showed the largest lipophilicity convincingly pointing out its possible role as a lipophilicity-based selectivity filter. Furthermore, we identified dynamic features (not inferable from sequence analysis or static structures) such as different flexibilities of specific protein loops that could potentially influence the substrate recognition and transport profile. Our findings can be valuable for drawing structure (dynamics)-activity relationship to be employed in drug design. PMID- 28808285 TI - Differentiating peripheral cholangiocarcinoma in stages T1N0M0 and T2N0M0 from hepatic hypovascular nodules using dynamic contrast-enhanced MRI. AB - Because cholangiocarcinoma shows no specific clinical signs or symptoms and presents with non-specific biological and tumor markers in the early stages, MRI findings often lack typical features before this lesion becomes symptomatic and might be mistaken for other liver lesions. An evaluation of relevant radiological findings in nodular cholangiocarcinoma (<=3 cm) in stages T1N0M0 and T2N0M0 is urgently needed. In our study, we compared two groups of liver hypovascular nodules and found that a distinct margin and enhanced area/nodule size >2/3 in the delayed phase were more frequently observed in cholangiocarcinoma cases than in metastatic nodule cases in which markedly high signal intensity on T2WI was common (p < 0.05). The results also revealed that in the both the portal and delayed phases, an enhanced area/nodule size >2/3 favored cholangiocarcinoma, whereas the presence of regional markedly higher SI on T2WI favored benign nodules. Furthermore, signs of peripheral washout in the delayed phase only appeared in cholangiocarcinoma cases. PMID- 28808286 TI - Source and dynamics of a volcanic caldera unrest: Campi Flegrei, 1983-84. AB - Despite their importance for eruption forecasting the causes of seismic rupture processes during caldera unrest are still poorly reconstructed from seismic images. Seismic source locations and waveform attenuation analyses of earthquakes in the Campi Flegrei area (Southern Italy) during the 1983-1984 unrest have revealed a 4-4.5 km deep NW-SE striking aseismic zone of high attenuation offshore Pozzuoli. The lateral features and the principal axis of the attenuation anomaly correspond to the main source of ground uplift during the unrest. Seismic swarms correlate in space and time with fluid injections from a deep hot source, inferred to represent geochemical and temperature variations at Solfatara. These swarms struck a high-attenuation 3-4 km deep reservoir of supercritical fluids under Pozzuoli and migrated towards a shallower aseismic deformation source under Solfatara. The reservoir became aseismic for two months just after the main seismic swarm (April 1, 1984) due to a SE-to-NW directed input from the high attenuation domain, possibly a dyke emplacement. The unrest ended after fluids migrated from Pozzuoli to the location of the last caldera eruption (Mt. Nuovo, 1538 AD). The results show that the high attenuation domain controls the largest monitored seismic, deformation, and geochemical unrest at the caldera. PMID- 28808287 TI - Rare Earth Extraction from NdFeB Magnet Using a Closed-Loop Acid Process. AB - There is considerable interest in extraction of rare earth elements from NdFeB magnets to enable recycling of these elements. In practical extraction methods using wet processes, the acid waste solution discharge is a problem that must be resolved to reduce the environmental impact of the process. Here, we present an encouraging demonstration of rare earth element extraction from a NdFeB magnet using a closed-loop hydrochloric acid (HCl)-based process. The extraction method is based on corrosion of the magnet in a pretreatment stage and a subsequent ionic liquid technique for Fe extraction from the HCl solution. The rare earth elements are then precipitated using oxalic acid. Triple extraction has been conducted and the recovery ratio of the rare earth elements from the solution is approximately 50% for each extraction process, as compared to almost 100% recovery when using a one-shot extraction process without the ionic liquid but with sufficient oxalic acid. Despite its reduced extraction efficiency, the proposed method with its small number of procedures at almost room temperature is still highly advantageous in terms of both cost and environmental friendliness. This study represents an initial step towards realization of a closed-loop acid process for recycling of rare earth elements. PMID- 28808288 TI - In vivo evaluation of radiotracers targeting the melanin-concentrating hormone receptor 1: [11C]SNAP-7941 and [18F]FE@SNAP reveal specific uptake in the ventricular system. AB - The MCHR1 is involved in the regulation of energy homeostasis and changes of the expression are linked to a variety of associated diseases, such as diabetes and adiposity. The study aimed at the in vitro and in vivo evaluation of [11C]SNAP 7941 and [18F]FE@SNAP as potential PET-tracers for the MCHR1. Competitive binding studies with non-radioactive derivatives and small-animal PET/CT and MRI brain studies were performed under baseline conditions and tracer displacement with the unlabelled MCHR1 antagonist (+/-)-SNAP-7941. Binding studies evinced high binding affinity of the non-radioactive derivatives. Small-animal imaging of [11C]SNAP 7941 and [18F]FE@SNAP evinced high tracer uptake in MCHR1-rich regions of the ventricular system. Quantitative analysis depicted a significant tracer reduction after displacement with (+/-)-SNAP-7941. Due to the high binding affinity of the non-labelled derivatives and the high specific tracer uptake of [11C]SNAP-7941 and [18F]FE@SNAP, there is strong evidence that both radiotracers may serve as highly suitable agents for specific MCHR1 imaging. PMID- 28808289 TI - Gene editing in clinical isolates of Candida parapsilosis using CRISPR/Cas9. AB - Candida parapsilosis is one of the most common causes of candidiasis, particularly in the very young and the very old. Studies of gene function are limited by the lack of a sexual cycle, the diploid genome, and a paucity of molecular tools. We describe here the development of a plasmid-based CRISPR-Cas9 system for gene editing in C. parapsilosis. A major advantage of the system is that it can be used in any genetic background, which we showed by editing genes in 20 different isolates. Gene editing is carried out in a single transformation step. The CAS9 gene is expressed only when the plasmid is present, and it can be removed easily from transformed strains. There is theoretically no limit to the number of genes that can be edited in any strain. Gene editing is increased by homology-directed repair in the presence of a repair template. Editing by non homologous end joining (NHEJ) also occurs in some genetic backgrounds. Finally, we used the system to introduce unique tags at edited sites. PMID- 28808290 TI - Molecular MR imaging of fibrosis in a mouse model of pancreatic cancer. AB - Fibrosis with excessive amounts of type I collagen is a hallmark of many solid tumours, and fibrosis is a promising target in cancer therapy, but tools for its non-invasive quantification are missing. Here we used magnetic resonance imaging with a gadolinium-based probe targeted to type I collagen (EP-3533) to image and quantify fibrosis in pancreatic ductal adenocarcinoma. An orthotopic syngeneic mouse model resulted in tumours with 2.3-fold higher collagen level compared to healthy pancreas. Animals were scanned at 4.7 T before, during and up to 60 min after i.v. injection of EP-3533, or of its non-binding isomer EP-3612. Ex-vivo quantification of gadolinium showed significantly higher uptake of EP-3533 compared to EP-3612 in tumours, but not in surrounding tissue (blood, muscle). Uptake of EP-3533 visualized in T1-weighted MRI correlated well with spatial distribution of collagen determined by second harmonic generation imaging. Differences in the tumour pharmacokinetic profiles of EP-3533 and EP-3612 were utilized to distinguish specific binding to tumour collagen from non-specific uptake. A model-free pharmacokinetic measurement based on area under the curve was identified as a robust imaging biomarker of fibrosis. Collagen-targeted molecular MRI with EP-3533 represents a new tool for non-invasive visualization and quantification of fibrosis in tumour tissue. PMID- 28808291 TI - GLP-1 Inhibits High-Glucose-Induced Oxidative Injury of Vascular Endothelial Cells. AB - The aim of this work was to evaluate the effects of glucagon-like peptide-1 (GLP 1) on high-glucose-induced oxidative stress and investigate the possible mechanisms underlying this process. We measured reactive oxygen species (ROS) production, cell apoptosis, the expression of NOX4 and its subunits, and p47phox translocation in human umbilical vein endothelial cells (HUVECs). An experimental type 2 diabetes model was induced using streptozotocin in male Sprague-Dawley rats. Fasting blood glucose (FBG), fasting insulin (FINS), total cholesterol (TC), triglycerides (TGs), and free fatty acid (FFA) were measured. Histomorphological analysis of the aorta was performed using hematoxylin-eosin staining. NOX4 and VCAM-1 expression in the aorta was measured. We found that high-glucose-induced ROS production and apoptosis were inhibited by GLP-1 treatment. High glucose caused upregulation of NOX4, p47phox, and Rac-1 and translocation of p47phox but had no effect on the cells pretreated with GLP-1. Furthermore, in the diabetic group, FBG, FINS, TG, TC, and FFA were increased, and NOX4 and VCAM-1 levels were also elevated. However, GLP-1 attenuated all these changes. GLP-1 ameliorated high-glucose-induced oxidative stress by inhibiting NOX4, p47phox, and Rac-1 expression and translocation of p47phox, suggesting its clinical usefulness in diabetic vascular complications. PMID- 28808292 TI - Binding of the Helicobacter pylori OipA causes apoptosis of host cells via modulation of Bax/Bcl-2 levels. AB - The H. pylori outer inflammatory protein A (OipA) is an outer membrane protein that contributes to gastric inflammation. OipA is believed to affect intra cellular signalling and modulate the host signalling pathways. The aim of the current study was to clarify the role of OipA in H. pylori pathogenesis and its effect on host cell signalling pathways. To this end, the oipA gene was isolated and inserted into cloning and expression vectors. The recombinant plasmid was transferred into an expression host to produce OipA, which was subsequently purified by affinity chromatography and used for antibody production. A confluent monolayer of gastric cell lines was treated with various concentrations of OipA and investigated for attachment, toxicity, and apoptosis and alterations in signalling pathways. OipA bound to gastric cell lines confirming its role in the attachment of H. pylori to host cells. The ratio of Bax/Bcl-2 and caspase3, 8, FasL in the host cells were assessed and the results showed that the Bax/Bcl-2 ratio as well as the level of cleaved-caspase 3 was elevated in OipA-treated cells. These findings suggest that OipA can bind and induce toxic events as well as triggering apoptotic cascade in host gastric cells through intrinsic pathway. PMID- 28808294 TI - Te-based chalcogenide materials for selector applications. AB - The implementation of dense, one-selector one-resistor (1S1R), resistive switching memory arrays, can be achieved with an appropriate selector for correct information storage and retrieval. Ovonic threshold switches (OTS) based on chalcogenide materials are a strong candidate, but their low thermal stability is one of the key factors that prevents rapid adoption by emerging resistive switching memory technologies. A previously developed map for phase change materials is expanded and improved for OTS materials. Selected materials from different areas of the map, belonging to binary Ge-Te and Si-Te systems, are explored. Several routes, including Si doping and reduction of Te amount, are used to increase the crystallization temperature. Selector devices, with areas as small as 55 * 55 nm2, were electrically assessed. Sub-threshold conduction models, based on Poole-Frenkel conduction mechanism, are applied to fresh samples in order to extract as-processed material parameters, such as trap height and density of defects, tailoring of which could be an important element for designing a suitable OTS material. Finally, a glass transition temperature estimation model is applied to Te-based materials in order to predict materials that might have the required thermal stability. A lower average number of p electrons is correlated with a good thermal stability. PMID- 28808293 TI - Targeting Apolipoprotein E/Amyloid beta Binding by Peptoid CPO_Abeta17-21 P Ameliorates Alzheimer's Disease Related Pathology and Cognitive Decline. AB - Inheritance of the apolipoprotein E4 (apoE4) genotype has been identified as the major genetic risk factor for late onset Alzheimer's disease (AD). Studies have shown that apoE, apoE4 in particular, binds to amyloid-beta (Abeta) peptides at residues 12-28 of Abeta and this binding modulates Abeta accumulation and disease progression. We have previously shown in several AD transgenic mice lines that blocking the apoE/Abeta interaction with Abeta12-28 P reduced Abeta and tau related pathology, leading to cognitive improvements in treated AD mice. Recently, we have designed a small peptoid library derived from the Abeta12-28 P sequence to screen for new apoE/Abeta binding inhibitors with higher efficacy and safety. Peptoids are better drug candidates than peptides due to their inherently more favorable pharmacokinetic properties. One of the lead peptoid compounds, CPO_Abeta17-21 P, diminished the apoE/Abeta interaction and attenuated the apoE4 pro-fibrillogenic effects on Abeta aggregation in vitro as well as apoE4 potentiation of Abeta cytotoxicity. CPO_Abeta17-21 P reduced Abeta-related pathology coupled with cognitive improvements in an AD APP/PS1 transgenic mouse model. Our study suggests the non-toxic, non-fibrillogenic peptoid CPO_Abeta17-21 P has significant promise as a new AD therapeutic agent which targets the Abeta related apoE pathway, with improved efficacy and pharmacokinetic properties. PMID- 28808295 TI - Testing Association between Mixed Type Outcomes and Covariates Jointly by the Use of a Latent Variable. AB - Multiple outcomes are often collected simultaneously in biomedical fields in order to identify whether a continuous response and an ordinal response are associated with some covariates simultaneously. Here we propose a joint statistical model by the use of a latent variable underlying the ordinal response. Asymptotic results are obtained and a jointly test is proposed for testing the continuous response and the ordinal response are associated with some covariates simultaneously. Extensive simulations and real data analysis results indicate more efficient performances of the proposed method than that of the combined p-values method. PMID- 28808296 TI - Effects of latitude and depth on the beta diversity of New Zealand fish communities. AB - Marine ecosystems are difficult to sample quantitatively at increasing depth. Hence, few studies attempt to measure patterns of beta diversity for ecological communities in the deep sea. Here we (i) present and quantify large-scale gradients in fish community structure along depth and latitude gradients of the New Zealand EEZ, (ii) obtain rigorous quantitative estimates of these depth (50 1200 m) and latitudinal effects (29.15-50.91 degrees S) and their interaction, and (iii) explicitly model how latitudinal beta diversity of fishes varies with depth. The sampling design was highly structured, replicated and stratified for latitude and depth, using data obtained from 345 standardised baited remote underwater stereo-video deployments. Results showed that gradients in fish community structure along depth and latitude were strong and interactive in New Zealand waters; latitudinal variation in fish communities progressively decreased with depth following an exponential decay (r 2 = 0.96), revealing increasingly similar fish communities with increasing depth. In contrast, variation in fish community structure along the depth gradient was of a similar magnitude across all of the latitudes investigated here. We conclude that an exponential decay in beta diversity vs depth exists for fish communities present in areas shallower than the New Zealand upper continental slope. PMID- 28808297 TI - Secretory phospholipase A2 modified HDL rapidly and potently suppresses platelet activation. AB - Levels of secretory phospholipases A2 (sPLA2) highly increase under acute and chronic inflammatory conditions. sPLA2 is mainly associated with high-density lipoproteins (HDL) and generates bioactive lysophospholipids implicated in acute and chronic inflammatory processes. Unexpectedly, pharmacological inhibition of sPLA2 in patients with acute coronary syndrome was associated with an increased risk of myocardial infarction and stroke. Given that platelets are key players in thrombosis and inflammation, we hypothesized that sPLA2-induced hydrolysis of HDL associated phospholipids (sPLA2-HDL) generates modified HDL particles that affect platelet function. We observed that sPLA2-HDL potently and rapidly inhibited platelet aggregation induced by several agonists, P-selectin expression, GPIIb/IIIa activation and superoxide production, whereas native HDL showed little effects. sPLA2-HDL suppressed the agonist-induced rise of intracellular Ca2+ levels and phosphorylation of Akt and ERK1/2, which trigger key steps in promoting platelet activation. Importantly, sPLA2 in the absence of HDL showed no effects, whereas enrichment of HDL with lysophosphatidylcholines containing saturated fatty acids (the main sPLA2 products) mimicked sPLA2-HDL activities. Our findings suggest that sPLA2 generates lysophosphatidylcholine-enriched HDL particles that modulate platelet function under inflammatory conditions. PMID- 28808298 TI - Standards for arsenic in drinking water: Implications for policy in Mexico. AB - Global concern about arsenic in drinking water and its link to numerous diseases make translation of evidence-based research into national policy a priority. Delays in establishing a maximum contaminant level (MCL) to preserve health have increased the burden of disease and caused substantial and avoidable loss of life. The current Mexican MCL for arsenic in drinking water is 25 MUg/l (2.5 times higher than the World Health Organization (WHO) recommendation from 1993). Mexico's struggles to set its arsenic MCL offer a compelling example of shortcomings in environmental health policy. We explore factors that might facilitate policy change in Mexico: scientific evidence, risk communication and public access to information, economic and technological resources, and politics. To raise awareness of the health, societal, and economic implications of arsenic contamination of drinking water in Mexico, we suggest action steps for attaining environmental policy change and better protect population health. PMID- 28808299 TI - Gut-homing Delta42PD1+Vdelta2 T cells promote innate mucosal damage via TLR4 during acute HIV type 1 infection. AB - The innate immune cells underlying mucosal inflammatory responses and damage during acute HIV-1 infection remain incompletely understood. Here, we report a Vdelta2 subset of gut-homing gammadelta T cells with significantly upregulated Delta42PD1 (a PD1 isoform) in acute (~20%) HIV-1 patients compared to chronic HIV 1 patients (~11%) and healthy controls (~2%). The frequency of Delta42PD1+Vdelta2 cells correlates positively with plasma levels of pro-inflammatory cytokines and fatty-acid-binding protein before detectable lipopolysaccharide in acute patients. The expression of Delta42PD1 can be induced by in vitro HIV-1 infection and is accompanied by high co-expression of gut-homing receptors CCR9/CD103. To investigate the role of Delta42PD1+Vdelta2 cells in vivo, they were adoptively transferred into autologous humanized mice, resulting in small intestinal inflammatory damage, probably due to the interaction of Delta42PD1 with its cognate receptor Toll-like receptor 4 (TLR4). In addition, blockade of Delta42PD1 or TLR4 successfully reduced the cytokine effect induced by Delta42PD1+Vdelta2 cells in vitro, as well as the mucosal pathological effect in humanized mice. Our findings have therefore uncovered a Delta42PD1-TLR4 pathway exhibited by virus induced gut-homing Vdelta2 cells that may contribute to innate immune activation and intestinal pathogenesis during acute HIV-1 infection. Delta42PD1+Vdelta2 cells may serve as a target for the investigation of diseases with mucosal inflammation. PMID- 28808301 TI - The study of electronic nematicity in an overdoped (Bi, Pb)2Sr2CuO6+delta superconductor using scanning tunneling spectroscopy. AB - The pseudogap (PG) state and its related intra-unit-cell symmetry breaking remain the focus in the research of cuprate superconductors. Although the nematicity has been studied in Bi2Sr2CaCu2O8+delta, especially underdoped samples, its behavior in other cuprates and different doping regions is still unclear. Here we apply a scanning tunneling microscope to explore an overdoped (Bi, Pb)2Sr2CuO6+delta with a large Fermi surface (FS). The establishment of a nematic order and its real space distribution is visualized as the energy scale approaches the PG. PMID- 28808300 TI - Pterostilbene exerts anticancer activity on non-small-cell lung cancer via activating endoplasmic reticulum stress. AB - Pterostilbene (PT), the natural dimethylated analog of resveratrol (RSV), is a potent anticarcinogen for non-small-cell lung cancer (NSCLC), but its anti-NSCLC mechanisms remain unclear. In this study, we show that PT treatment time- and dose-dependently enhanced the endoplasmic reticulum stress (ERS) signaling (i.e., p-PERK, IRE1, ATF4, CHOP), thus decreasing the cell viability and inducing apoptosis in human PC9 and A549 NSCLC cell lines. Moreover, the decreased migratory and adhesive abilities, downregulation of intracellular glutathione (GSH) level, enhanced reactive oxygen species (ROS) generation, Caspase 3 activity and mitochondrial membrane depolarization were observed in NSCLC cells treated with PT. These effects were reversed by CHOP siRNA which inhibited the ERS signaling pathway, but were promoted by thapsigargin (a classical ERS inducer) in vitro. Besides, in vivo studies also verify that PT exerted anticancer activity by mobilizing ERS signaling and apoptosis-related proteins, and these effects were enhanced by thapsigargin. Therefore, ERS activation may represent a new mechanism of anti-NSCLC action by PT, and a novel therapeutic intervention for lung cancer. PMID- 28808302 TI - Effects of One-Week Empirical Antibiotic Therapy on the Early Development of Gut Microbiota and Metabolites in Preterm Infants. AB - The early postnatal period is the most dynamic and vulnerable stage in the assembly of intestinal microbiota. Antibiotics are commonly prescribed to newborn preterm babies and are frequently used for a prolonged duration in China. We hypothesized that the prolonged antibiotic therapy would affect the early development of intestinal microbiota and their metabolites. To test this hypothesis, we analyzed the stool microbiota and metabolites in 36 preterm babies with or without antibiotic treatment. These babies were divided into three groups, including two groups treated with the combination of penicillin and moxalactam or piperacillin-tazobactam for 7 days, and the other group was free of antibiotics. Compared to the antibiotic-free group, both antibiotic-treated groups had distinct gut microbial communities and metabolites, including a reduction of bacterial diversity and an enrichment of harmful bacteria such as Streptococcus and Pseudomonas. In addition, there was a significant difference in the composition of gut microbiota and their metabolites between the two antibiotic-treated groups, where the piperacillin-tazobactam treatment group showed an overgrowth of Enterococcus. These findings suggest that prolonged antibiotic therapy affects the early development of gut microbiota in preterm infants, which should be considered when prescribing antibiotics for this population. PMID- 28808303 TI - NLRP3 inflammasome activation results in liver inflammation and fibrosis in mice infected with Schistosoma japonicum in a Syk-dependent manner. AB - Granulomatous and fibrosing inflammation in response to soluble egg antigen (SEA) from Schistosoma japonicum (S. japonicum) is the main pathological process of S. japonicum infection. Inflammasome activation has recently been implicated in the pathogenesis of liver disease. However, the role of inflammasome activation in schistosomiasis-associated liver fibrosis (SSLF) has not been extensively studied. In this study, it is demonstrated that the NLRP3 inflammasome is markedly activated in mouse HSCs both in vivo and in vitro during S. japonicum infection. Furthermore, it is demonstrated that inhibition of NLRP3 inflammasome significantly alleviates the liver inflammation and collagen deposition that are induced by infection with S. japonicum. The mechanism of SEA-induced NLRP3 inflammasome activation is studied in isolated, cultured mouse HSCs and it is shown that SEA-induced NLRP3 inflammasome activation in HSCs is dependent upon the activities of spleen tyrosine kinase (Syk), an enzyme usually associated with a pathogen recognition receptor for fungal pathogens. Moreover, it is demonstrated that Dectin-1 and JNK signaling are also involved in SEA-induced NLRP3 inflammasome activation in HSCs. These data shed new light on the mechanisms of NLRP3 inflammasome activation during an infection with S. japonicum, and further characterize its role in schistosomiasis-associated liver fibrosis (SSLF). PMID- 28808305 TI - Multipolar second harmonic generation in a symmetric nonlinear metamaterial. AB - Optical nonlinearities are intimately related to the spatial symmetry of the nonlinear media. For example, the second order susceptibility vanishes for centrosymmetric materials under the dipole approximation. The latter concept has been naturally extended to the metamaterials' realm, sometimes leading to the (erroneous) hypothesis that second harmonic (SH) generation is negligible in highly symmetric meta-atoms. In this work we aim to show that such symmetric meta atoms can radiate SH light efficiently. In particular, we investigate in-plane centrosymmetric meta-atom designs where the approximation for meta-atoms breaks down. In a periodic array this building block allows us to control the directionality of the SH radiation. We conclude by showing that the use of symmetry considerations alone allows for the manipulation of the nonlinear multipolar response of a meta-atom, resulting in e.g. dipolar, quadrupolar, or multipolar emission on demand. This is because the size of the meta-atom is comparable with the free-space wavelength, thus invalidating the dipolar approximation for meta-atoms. PMID- 28808304 TI - Hypoxia-induced TET1 facilitates trophoblast cell migration and invasion through HIF1alpha signaling pathway. AB - Low oxygen is a typical extrinsic factor for the regulation of trophoblast biological function, including cell migration, invasion and proliferation. Ten eleven translocation methylcytosine dioxygenase 1 (TET1), an enzyme converting 5 methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), is transcriptionally activated by hypoxia in cancer cells. Therefore, we focus on the role of TET1 on trophoblast function in a physiologically hypoxic environment (3% oxygen), which is related to early placentation. Here, we found that TET1 was highly expressed in first trimester villi compared with normal term placentas. In vitro, both TET1 mRNA and protein expression levels in JEG3 cells were increased following exposure to 3% oxygen, and the migration and invasion capacities of JEG3 cells were up-regulated. Furthermore, TET1 knockdown decreased the migration, invasion and proliferation of JEG3 cells exposed to 3% oxygen, and the expression of HIF1alpha and its downstream target genes was also decreased, which was related to hyper-methylation of the HIF1alpha promoter. Finally, increased HIF1alpha protein expression reversed the inhibitory effect of TET1 knockdown on the migration and invasion of JEG3 cells exposed to 3% oxygen. These data show that hypoxia-induced TET1 expression facilitates trophoblast cell migration and invasion through the HIF1alpha signaling pathway, which plays an important role during placentation. PMID- 28808306 TI - PHF20 positively regulates osteoblast differentiation via increasing the expression and activation of Runx2 with enrichment of H3K4me3. AB - Plant homeodomain finger protein 20 (PHF20), a methyl lysine effector protein, is a component MOF-NSL lysine acetyltranferase complex. Global deletion of PHF20 has shown spinal bone defects and reduced skeletal formation. However, the molecular basis of PHF20 involved in skeletal development has not been elucidated yet. The objective of this study was to determine the role of PHF20 in osteoblast differentiation and mineralization. Expression of PHF20 was gradually increased during osteoblast differentiation. Overexpression of PHF20 enhanced ALP activity and mineralized nodule formation as well as the expression of osteogenic markers including Runx2. In contrast, inhibition of PHF20 expression reduced osteoblast differentiation and mineralization. Mechanistically, PHF20 increased the promoter activity of osteogenic genes including Og2, Alp, and Bsp through direct association with Runx2. Moreover, PHF20 increased the enrichment of H3K4me3 on the promoter of Runx2 followed by increased Runx2 promoter activity. Interestingly, Bix-01294, a histone methylation inhibitor, decreased mineralized nodule formation through decreasing the levels of H3K4me3 and Runx2. Overexpression of PHF20 restored the Bix-01294 effects. Taken together, these results indicate that methyl lysine-binding protein PHF20 might be a novel regulator of osteoblast differentiation. PMID- 28808307 TI - LC3A Silencing Hinders Aggresome Vimentin Cage Clearance in Primary Choroid Plexus Carcinoma. AB - Aggresomes are transient microtubule-dependent inclusion bodies that sequester misfolded proteins and are ultimately removed by autophagy. Here we report the generation of a choroid plexus carcinoma cell line; Children's Cancer Hospital Egypt (CCHE)-45, which is characterized by the constitutive formation of aggresomes. When examining the autophagy pathway as the main route for aggresomes clearance, CCHE-45 cells displayed increased autophagy flux mediated by MAP1LC3B. MAP1LC3A-Variant1 gene expression was silenced by promoter methylation. Restoring MAP1LC3A-Variant1 expression resulted in the formation of MAP1LC3A positive autophagosmes and the disruption of the aggresomes' vimentin cage independent of MAP1LC3B positive autophagosomes. Our data supports the notion that basal quality control autophagy and vimentin cage clearance in CCHE-45 are mediated by MAP1LC3A. Hence we propose that absence of MAP1LC3A disrupts the autophagic pathway and leads to the failure of aggresome vimentin cage degradation. Consequently, this could represent a targetable pathway in autophagy-dependent cancers. PMID- 28808308 TI - On the potential alternate binding change mechanism in a dimeric structure of Pyruvate Phosphate Dikinase. AB - The pyruvate phosphate dikinase (PPDK) reaction mechanism is characterized by a distinct spatial separation of reaction centers and large conformational changes involving an opening-closing motion of the nucleotide-binding domain (NBD) and a swiveling motion of the central domain (CD). However, why PPDK is active only in a dimeric form and to what extent an alternate binding change mechanism could underlie this fact has remained elusive. We performed unbiased molecular dynamics simulations, configurational free energy computations, and rigidity analysis to address this question. Our results support the hypothesis that PPDK dimerization influences the opening-closing motion of the NBDs, and that this influence is mediated via the CDs of both chains. Such an influence would be a prerequisite for an alternate binding change mechanism to occur. To the best of our knowledge, this is the first time that a possible explanation has been suggested as to why only dimeric PPDK is active. PMID- 28808309 TI - Defluoridation technology for drinking water and tea by green synthesized Fe3O4/Al2O3 nanoparticles coated polyurethane foams for rural communities. AB - Fluoride (F) contaminated ground water poses a serious public health concern to rural population with unaffordable purification technologies. Therefore, development of a cost-effective, portable, environment and user-friendly defluoridation technique is imperative. In the present study, we report on the development of a green and cost-effective method that utilizes Fe3O4 and Al2O3 nanoparticles (NPs) that were synthesized using jojoba defatted meal. These NPs were impregnated on to polyurethane foam (PUF) and made into tea infusion bags. The Al2O3 NPs-PUF displayed a higher water defluoridation capacity of 43.47 mg g 1 of F as compared to 34.48 mg g-1 of F with Fe3O4 NPs-PUF. The synthesized Al2O3 PUF infusion bags removed the F that was under the permissible limit of 1.5 mg L 1. The sorption experiments were conducted to verify the effect of different parameters such as pH, contact time, size of PUF and initial F concentration. The different properties of adsorbent were characterized using a combination of FESEM, EDX, XRD and FTIR techniques, respectively. The calculated total cost per NPs-PUF pouch developed is as low as US $0.05, which makes the technology most suitable for rural communities. This paper will be beneficial for researchers working toward further improvement in water purification technologies. PMID- 28808310 TI - Genome-scale analysis identifies NEK2, DLGAP5 and ECT2 as promising diagnostic and prognostic biomarkers in human lung cancer. AB - This study aims to identify promising biomarkers for the early detection of lung cancer and evaluate the prognosis of lung cancer patients. Genome-wide mRNA expression data obtained from the Gene Expression Omnibus (GSE19188, GSE18842 and GSE40791), including 231 primary tumor samples and 210 normal samples, were used to discover differentially expressed genes (DEGs). NEK2, DLGAP5 and ECT2 were found to be highly expressed in tumor samples. These results were experimentally confirmed by quantitative reverse transcription-polymerase chain reaction (qRT PCR). The elevated expression of the three candidate genes was also validated using the Cancer Genome Atlas (TCGA) datasets, which consist of 349 tumor and 58 normal tissues. Furthermore, we performed receiver operating characteristics (ROC) analysis to assess the diagnostic value of these lung cancer biomarkers, and the results suggested that NEK2, DLGAP5 and ECT2 expression levels could robustly distinguish lung cancer patients from normal subjects. Finally, Kaplan Meier analysis revealed that elevated NEK2, DLGAP5 and ECT2 expression was negatively correlated with both overall survival (OS) and relapse-free survival (RFS). Taken together, these findings indicate that these three genes might be used as promising biomarkers for the early detection of lung cancer, as well as predicting the prognosis of lung cancer patients. PMID- 28808312 TI - The synchronous improvement of strength and plasticity (SISP) in new Ni-Co based disc superalloys by controling stacking fault energy. AB - It is a great challenge to improve the strength of disc superalloys without great loss of plasticity together since the microstructures benefiting the strength always do not avail the plasticity. Interestingly, this study shows that the trade-off relationship between strength and plasticity can be broken through decreasing stacking fault energy (SFE) in newly developed Ni-Co based disc superalloys. Axial tensile tests in the temperature range of 25 to 725 degrees C were carried out in these alloys with Co content ranging from 5% to 23% (wt.%). It is found that the ultimate tensile strength (UTS) and uniform elongation (UE) are improved synchronously when microtwinning is activated by decreasing the SFE at 650 and 725 degrees C. In contrast, only UTS is improved when stacking fault (SF) dominates the plastic deformation at 25 and 400 degrees C. These results may be helpful for designing advanced disc superalloys with relatively excellent strength and plasticity simultaneously. PMID- 28808311 TI - Antitumor properties of Coenzyme Q0 against human ovarian carcinoma cells via induction of ROS-mediated apoptosis and cytoprotective autophagy. AB - Coenzyme Q0 (CoQ0, 2,3-dimethoxy-5-methyl-1,4-benzoquinone) has been reported to exert anticancer properties against human breast/lung cancer cells. This study investigated the in vitro and in vivo anticancer properties of CoQ0 on human ovarian carcinoma (SKOV-3) cells and xenografted nude mice, and revealed the underlying molecular mechanism. CoQ0 induced G2/M arrest through downregulation of cyclin B1/A and CDK1/K2 expressions. CoQ0-induced autophagy as a survival mechanism was evidenced by increased accumulation of LC3-II, GFP-LC3 puncta, AVOs formation and Beclin-1/Bcl-2 dysregulation. Increased TUNEL-positive cells and Annexin-V/PI stained cells indicated CoQ0-induced late apoptosis. Both mitochondrial (caspase-3, PARP and Bax/Bcl-2 dysregulation) and ER stress (caspase-12 and Hsp70) signals are involved in execution of apoptosis. Interestingly, CoQ0-induced apoptosis/autophagy is associated with suppression of HER-2/neu and PI3K/AKT signalling cascades. CoQ0 triggered intracellular ROS production, whereas antioxidant N-acetylcysteine prevented CoQ0-induced apoptosis, but not autophagy. Inhibition of apoptosis by Z-VAD-FMK suppressed CoQ0-induced autophagy (diminished LC3-II/AVOs), indicates CoQ0-induced apoptosis led to evoke autophagy. Contrary, inhibition of autophagy by 3-MA/CQ potentiated CoQ0-induced apoptosis (increased DNA fragmentation/PARP cleavage). Furthermore, CoQ0 treatment to SKOV-3 xenografted nude mice reduced tumor incidence and burden. Histopathological analyses confirmed that CoQ0 modulated xenografted tumor progression by apoptosis induction. Our findings emphasize that CoQ0 triggered ROS-mediated apoptosis and cytoprotective autophagy. PMID- 28808313 TI - Controllable oscillatory lateral coupling in a waveguide-microdisk-resonator system. AB - We report a theoretical and experimental study of coupling between a whispering gallery-mode (WGM) microdisk resonator and a fiber taper which exchange energies at two distinct regions. We observe an oscillatory behavior in the coupling strength as a function of the distance between the two coupling regions when a fiber taper is moved laterally above the resonator at fixed vertical distance. This oscillation is clearly seen in the linewidth of the resonance as well as in the on-resonance transmission. A theoretical model considering for two-point coupling successfully explains the experimental observations as being a result of the interference between the light fields coupled into and out of the resonator at two distinct regions and the light transmitted through the waveguide. Critical coupling in two-region coupling is a collective result of the coupling at two different coupling regions, and does not require critical coupling at both or at any one of the two coupling regions. This relaxes the conditions for achieving critical coupling in waveguide-resonator systems. The discovery of this previously unnoticed oscillatory behavior in two-region coupling between a WGM resonator and a waveguide will benefit both fundamental studies and practical applications based on WGM resonators. PMID- 28808314 TI - Cellular toxicity pathways of inorganic and methyl mercury in the green microalga Chlamydomonas reinhardtii. AB - Contamination by mercury (Hg) is a worldwide concern because of Hg toxicity and biomagnification in aquatic food webs. Nevertheless, bioavailability and cellular toxicity pathways of inorganic (IHg) and methyl-Hg (MeHg) remain poorly understood. We analyzed the uptake, transcriptomic, and physiological responses in the microalga Chlamydomonas reinhardtii exposed to IHg or MeHg. Bioavailability of MeHg was up to 27* higher than for IHg. Genes involved in cell processes, energy metabolism and transport were dysregulated by both Hg species. Physiological analysis revealed an impact on photosynthesis and reduction oxidation reaction metabolism. Nevertheless, MeHg dysregulated a larger number of genes and with a stronger fold-change than IHg at equivalent intracellular concentration. Analysis of the perturbations of the cell's functions helped to derive a detailed mechanistic understanding of differences in cellular handling of IHg and MeHg resulting in MeHg having a stronger impact. This knowledge is central for the prediction of impact of toxicants on organisms. PMID- 28808315 TI - Modular Serial Flow Through device for pulsed electric field treatment of the liquid samples. AB - In biotechnology, medicine, and food processing, simple and reliable methods for cell membrane permeabilization are required for drug/gene delivery into the cells or for the inactivation of undesired microorganisms. Pulsed electric field treatment is among the most promising methods enabling both aims. The drawback in current technology is controllable large volume operation. To address this challenge, we have developed an experimental setup for flow through electroporation with online regulation of the flow rate with feedback control. We have designed a modular serial flow-through co-linear chamber with a smooth inner surface, the uniform cross-section geometry through the majority of the system's length, and the mesh in contact with the electrodes, which provides uniform electric field distribution and fluid velocity equilibration. The cylindrical cross-section of the chamber prevents arching at the active treatment region. We used mathematical modeling for the evaluation of electric field distribution and the flow profile in the active region. The system was tested for the inactivation of Escherichia coli. We compared two flow-through chambers and used a static chamber as a reference. The experiments were performed under identical experimental condition (product and similar process parameters). The data were analyzed in terms of inactivation efficiency and specific energy consumption. PMID- 28808316 TI - Habituation based synaptic plasticity and organismic learning in a quantum perovskite. AB - A central characteristic of living beings is the ability to learn from and respond to their environment leading to habit formation and decision making. This behavior, known as habituation, is universal among all forms of life with a central nervous system, and is also observed in single-cell organisms that do not possess a brain. Here, we report the discovery of habituation-based plasticity utilizing a perovskite quantum system by dynamical modulation of electron localization. Microscopic mechanisms and pathways that enable this organismic collective charge-lattice interaction are elucidated by first-principles theory, synchrotron investigations, ab initio molecular dynamics simulations, and in situ environmental breathing studies. We implement a learning algorithm inspired by the conductance relaxation behavior of perovskites that naturally incorporates habituation, and demonstrate learning to forget: a key feature of animal and human brains. Incorporating this elementary skill in learning boosts the capability of neural computing in a sequential, dynamic environment.Habituation is a learning mechanism that enables control over forgetting and learning. Zuo, Panda et al., demonstrate adaptive synaptic plasticity in SmNiO3 perovskites to address catastrophic forgetting in a dynamic learning environment via hydrogen induced electron localization. PMID- 28808317 TI - Bumblebee colony development following chronic exposure to field-realistic levels of the neonicotinoid pesticide thiamethoxam under laboratory conditions. AB - Neonicotinoid pesticides are used in agriculture to reduce damage from crop pests. However, beneficial insects such as bees can come into contact with these pesticides when foraging in treated areas, with potential consequences for bee declines and pollination service delivery. Honeybees are typically used as a model organism to investigate insecticide impacts on bees, but relatively little is known about impacts on other taxa such as bumblebees. In this experiment, we chronically exposed whole mature bumblebee (Bombus terrestris) colonies to field realistic levels of the neonicotinoid thiamethoxam (2.4ppb & 10ppb) over four weeks, and compared colony growth under laboratory conditions. We found no impact of insecticide exposure on colony weight gain, or the number or mass of sexuals produced, although colonies exposed to 2.4ppb produced larger males. As previous studies have reported pesticide effects on bumblebee colony growth, this may suggest that impacts on bumblebee colonies are more pronounced for colonies at an earlier stage in the reproductive cycle. Alternatively, it may also indicate that thiamethoxam differs in toxicity compared to previously tested neonicotinoids in terms of reproductive effects. In either case, assessing bumblebee colony development under field conditions is likely more informative for real world scenarios than tests conducted in laboratory conditions. PMID- 28808318 TI - Stress Induced Polarization of Immune-Neuroendocrine Phenotypes in Gallus gallus. AB - Immune-neuroendocrine phenotypes (INPs) stand for population subgroups differing in immune-neuroendocrine interactions. While mammalian INPs have been characterized thoroughly in rats and humans, avian INPs were only recently described in Coturnix coturnix (quail). To assess the scope of this biological phenomenon, herein we characterized INPs in Gallus gallus (a domestic hen strain submitted to a very long history of strong selective breeding pressure) and evaluated whether a social chronic stress challenge modulates the individuals' interplay affecting the INP subsets and distribution. Evaluating plasmatic basal corticosterone, interferon-gamma and interleukin-4 concentrations, innate/acquired leukocyte ratio, PHA-P skin-swelling and induced antibody responses, two opposite INP profiles were found: LEWIS-like (15% of the population) and FISCHER-like (16%) hens. After chronic stress, an increment of about 12% in each polarized INP frequency was found at expenses of a reduction in the number of birds with intermediate responses. Results show that polarized INPs are also a phenomenon occurring in hens. The observed inter-individual variation suggest that, even after a considerable selection process, the population is still well prepared to deal with a variety of immune-neuroendocrine challenges. Stress promoted disruptive effects, leading to a more balanced INPs distribution, which represents a new substrate for challenging situations. PMID- 28808319 TI - IP-10 Levels as an Accurate Screening Tool to Detect Acute HIV Infection in Resource-Limited Settings. AB - Acute HIV infection (AHI) is the period prior to seroconversion characterized by high viral replication, hyper-transmission potential and commonly, non-specific febrile illness. AHI detection requires HIV-RNA viral load (VL) determination, which has very limited access in low-income countries due to restrictive costs and implementation constraints. We sought to identify a biomarker that could enable AHI diagnosis in scarce-resource settings, and to evaluate the feasibility of its implementation. HIV-seronegative adults presenting at the Manhica District Hospital, Mozambique, with reported-fever were tested for VL. Plasma levels of 49 inflammatory biomarkers from AHI (n = 61) and non-HIV infected outpatients (n = 65) were determined by Luminex and ELISA. IP-10 demonstrated the best predictive power for AHI detection (AUC = 0.88 [95%CI 0.80-0.96]). A cut-off value of IP-10 >= 161.6 pg/mL provided a sensitivity of 95.5% (95%CI 85.5-99.5) and a specificity of 76.5% (95%CI 62.5-87.2). The implementation of an IP-10 screening test could avert from 21 to 84 new infections and save from US$176,609 to US$533,467 to the health system per 1,000 tested patients. We conclude that IP-10 is an accurate biomarker to screen febrile HIV-seronegative individuals for subsequent AHI diagnosis with VL. Such an algorithm is a cost-effective strategy to prevent disease progression and a substantial number of further HIV infections. PMID- 28808320 TI - Carotid Body-Mediated Chemoreflex Drive in The Setting of low and High Output Heart Failure. AB - Enhanced carotid body (CB) chemoreflex function is strongly related to cardiorespiratory disorders and disease progression in heart failure (HF). The mechanisms underlying CB sensitization during HF are not fully understood, however previous work indicates blood flow per se can affect CB function. Then, we hypothesized that the CB-mediated chemoreflex drive will be enhanced only in low output HF but not in high output HF. Myocardial infarcted rats and aorto caval fistulated rats were used as a low output HF model (MI-CHF) and as a high output HF model (AV-CHF), respectively. Blood flow supply to the CB region was decreased only in MI-CHF rats compared to Sham and AV-CHF rats. MI-CHF rats exhibited a significantly enhanced hypoxic ventilatory response compared to AV CHF rats. However, apnea/hypopnea incidence was similarly increased in both MI CHF and AV-CHF rats compared to control. Kruppel-like factor 2 expression, a flow sensitive transcription factor, was reduced in the CBs of MI-CHF rats but not in AV-CHF rats. Our results indicate that in the setting of HF, potentiation of the CB chemoreflex is strongly associated with a reduction in cardiac output and may not be related to other pathophysiological consequences of HF. PMID- 28808321 TI - The proteasome deubiquitinase inhibitor b-AP15 enhances DR5 activation-induced apoptosis through stabilizing DR5. AB - b-AP15 and its derivatives block proteasome deubiquitinase (DUB) activity and have been developed and tested in the clinic as potential cancer therapeutic agents. b-AP15 induces apoptosis in cancer cells, but the underlying mechanisms are largely undefined. The current study focuses on studying the modulatory effects of b-AP15 on death receptor 5 (DR5) levels and DR5 activation-induced apoptosis as well as on understanding the underlying mechanisms. Treatment with b AP15 potently increased DR5 levels including cell surface DR5 in different cancer cell lines with limited or no effects on the levels of other related proteins including DR4, c-FLIP, FADD, and caspase-8. b-AP15 substantially slowed the degradation of DR5, suggesting that it stabilizes DR5. Moreover, b-AP15 effectively augmented apoptosis when combined with TRAIL or the DR5 agonistic antibody AMG655; these effects are DR5-dependent because DR5 deficiency abolished the ability of b-AP15 to enhance TRAIL- or AMG655-induced apoptosis. Therefore, it is clear that b-AP15, and possibly its derivatives, can stabilize DR5 and increase functional cell surface DR5 levels, resulting in enhancement of DR5 activation-induced apoptosis. Our findings suggest that b-AP15 and its derivatives may have potential in sensitizing cancer cells to DR5 activation based cancer therapy. PMID- 28808322 TI - Neuroinflammation alters cellular proteostasis by producing endoplasmic reticulum stress, autophagy activation and disrupting ERAD activation. AB - Proteostasis alteration and neuroinflammation are typical features of normal aging. We have previously shown that neuroinflammation alters cellular proteostasis through immunoproteasome induction, leading to a transient decrease of proteasome activity. Here, we further investigated the role of acute lipopolysaccharide (LPS)-induced hippocampal neuroinflammation in cellular proteostasis. In particular, we focused on macroautophagy (hereinafter called autophagy) and endoplasmic reticulum-associated protein degradation (ERAD). We demonstrate that LPS injection induced autophagy activation that was dependent, at least in part, on glycogen synthase kinase (GSK)-3beta activity but independent of mammalian target of rapamycin (mTOR) inhibition. Neuroinflammation also produced endoplasmic reticulum (ER) stress leading to canonical unfolded protein response (UPR) activation with a rapid activating transcription factor (ATF) 6alpha attenuation that resulted in a time-dependent down-regulation of ERAD markers. In this regard, the time-dependent accumulation of unspliced X-box binding protein (XBP) 1, likely because of decreased inositol-requiring enzyme (IRE) 1alpha-mediated splicing activity, might underlie in vivo ATF6alpha attenuation. Importantly, lactacystin-induced activation of ERAD was abolished in both the acute neuroinflammation model and in aged rats. Therefore, we provide a cellular pathway through which neuroinflammation might sensitize cells to neurodegeneration under stress situations, being relevant in normal aging and other disorders where neuroinflammation is a characteristic feature. PMID- 28808324 TI - Spatially modulated thermal light in atomic medium for enhanced ghost imaging. AB - Recent years have seen vast progress in image modulation based on atomic media, with potential applications in both classical optical imaging and quantum imaging regions. However, there have been few investigations of how thermal light images interact with an electromagnetically induced transparent medium. In this letter, we experimentally demonstrate pseudo-thermal light modulation on coherent population trapping conditions in 87 Rb vapor. By introducing the Laguerre Gaussian beam as the control beam and the encoded speckle as the probe beam, we obtained sharper speckle patterns after the atom cell compared with that in free space. The spatially modulated thermal light was then used to enhance the image resolution in ghost imaging of which the resolution was enhanced by factor 3, since the ghost image resolution is heavily reliant on the speckle's transverse coherent length. Our results are promising for potential applications in high resolution ghost imaging and image metrology, image processing and biomedical imaging. PMID- 28808323 TI - Stress hormone rapidly tunes synaptic NMDA receptor through membrane dynamics and mineralocorticoid signalling. AB - Stress hormones, such as corticosteroids, modulate the transmission of hippocampal glutamatergic synapses and NMDA receptor (NMDAR)-dependent synaptic plasticity, favouring salient behavioural responses to the environment. The corticosterone-induced synaptic adaptations partly rely on changes in NMDAR signalling, although the cellular pathway underlying this effect remains elusive. Here, we demonstrate, using single molecule imaging and electrophysiological approaches in hippocampal neurons, that corticosterone specifically controls GluN2B-NMDAR surface dynamics and synaptic content through mineralocorticoid signalling. Strikingly, extracellular corticosterone was sufficient to increase the trapping of GluN2B-NMDAR within synapses. Functionally, corticosterone induced potentiation of AMPA receptor content in synapses required the changes in NMDAR surface dynamics. These high-resolution imaging data unveiled that, in hippocampal networks, corticosterone is a natural, potent, fast and specific regulator of GluN2B-NMDAR membrane trafficking, tuning NMDAR-dependent synaptic adaptations. PMID- 28808325 TI - Phytoremediation potential of Acorus calamus in soils co-contaminated with cadmium and polycyclic aromatic hydrocarbons. AB - Phytoremediation is a promising technology for the remediation of sites co contaminated with inorganic (heavy metal) and organic pollutants. A greenhouse experiment was conducted to investigate the independent and interactive effects of cadmium (Cd) and polycyclic aromatic hydrocarbons (PAHs) on the growth of the wetland plant Acorus calamus and its ability to uptake, accumulate, and remove pollutants from soils. Our results showed that growth and biomass of A. calamus were significantly influenced by the interaction of Cd and PAHs after 60 days of growth. The combined treatment of low Cd and low PAHs increased plant biomass and Cd accumulation in plant tissues, thus enhancing Cd removal. Dissipation of PAHs from soils was not significantly influenced by Cd addition or by the presence of plants. Correlation analysis also indicated a positive relationship between residual concentrations of phenantherene and pyrene (PAHs), whereas enzyme activities (dehydrogenase and polyphenol oxidase) were negatively correlated with each other. Cluster analysis was used to evaluate the similarity between different treatments during phytoremediation of Cd and PAHs. Our results suggest that A. calamus might be useful for phytoremediation of co-contaminated soil. PMID- 28808326 TI - The importance of the nutritive value of old bones in the diet of Bearded vultures Gypaetus barbatus. AB - Vultures are central-place foragers and need to optimize their foraging behaviour to offset travel costs by increasing their energy gain. This process is more obvious in certain vulture species that do not feed their young by regurgitation and so must carry food items back to the nest. The Bearded Vulture Gypaetus barbatus is the only species with a bone-diet based. We analysed the chemical composition of bones and the age-related changes in their nutritive value to assess the differences in energy content between bones of differing age, body part and species. We found differences between specific anatomical parts, species and the age of the bones. Fresh bones contain 108% as much energy as fresh meat and, interestingly, dry bones retain 90% of the protein found in fresh bones. Dry femurs weighing 140 g retain enough protein to be comparable to 111 g of fresh meat, in energy terms. Compared to meat-eating species, the specialized osteophagous diet of the Bearded Vulture seems to have certain advantages. A better understanding of nutrient levels in food remains could help to improve theoretical foraging models, assist in conservation management, and even improve our understanding of the use of bones by early hominids. PMID- 28808327 TI - Spontaneous detachment of Streptococcus mutans biofilm by synergistic effect between zwitterion and sugar alcohol. AB - A biofilm, a community of microorganisms, is highly resistant to antibiotics, resulting in massive losses in various areas. We herein present a strategy to remove Streptococcus mutans biofilms through a spontaneous exfoliation by the synergistic effect between zwitterion and sugar alcohols. It is assumed that the anionic site of zwitterion can be coupled with sugar alcohols and the cationic site remains in the state of lacking electrons. The cationic site allows the complexes to be delivered to negatively charged exopolysaccharides of biofilms. This strategy facilitates a significant increase in the ability of sugar alcohols to disperse aggregated exopolysaccharides. In this work, it was demonstrated that the mixture of betaine and erythritol existed as a complex in water and that the complex induced a spontaneous detachment of biofilms from the surface to which the biofilms had been adhered. This detachment resulted from a reduction in adhesive forces of the biofilms due to an increase in solubility of bacterial exopolysaccharides. The effects triggered by the formation of complex between zwitterion and sugar alcohol provide a simple and safe way to remove biofilms without antibiotics and physical forces. PMID- 28808328 TI - Light Guided In-vivo Activation of Innate Immune Cells with Photocaged TLR 2/6 Agonist. AB - The complexity of the immune system creates challenges in exploring its importance and robustness. To date, there have been few techniques developed to manipulate individual components of the immune system in an in vivo environment. Here we show a light-based dendritic cell (DC) activation allowing spatial and temporal control of immune activation in vivo. Additionally, we show time dependent changes in RNA profiles of the draining lymph node, suggesting a change in cell profile following DC migration and indicating that the cells migrating have been activated towards antigen presentation. PMID- 28808329 TI - Resonance optimization of polychromatic light in disordered structures. AB - Disorder offers rich possibilities for manipulating the phase and intensity of light and designing photonic devices for various applications including random lasers, light storage, and speckle-free imaging. Disorder-based optical systems can be implemented in one-dimensional structures based on random or pseudo-random alternating layers with different refractive indices. Such structures can be treated as sequences of scatterers, in which spatial light localization is characterized by random sets of spectral transmission resonances, each accompanied by a relatively high-intensity concentration. The control and manipulation of resonances is the key element in designing disorder-based photonic systems. In this work, we introduce a method of controlling disorder induced resonances by using the established non-trivial interconnection between the symmetry of bi-directional light propagation properties and the features of the resonant transmissions. Considering a fiber with resonant Bragg gratings as an example, the mechanism of enhancing or suppressing the resonant transmission of polychromatic light and the effectiveness of the method have been demonstrated both theoretically and experimentally. The proposed algorithm of controlling disorder-induced resonances is general and applicable to classical waves and quantum particles, for disordered systems both with and without gain. PMID- 28808330 TI - Generation and characterization of a mouse line for monitoring translation in dopaminergic neurons. AB - We developed a mouse line targeting midbrain dopamine neurons for Translating Ribosome Affinity Purification(TRAP). Here, we briefly report on the basic characterization of this mouse line including confirmation of expression of the transgene in midbrain dopamine neurons and validation of its effectiveness in capturing mRNA from these cells. We also report a translational profile of these neurons which may be of use to investigators studying the gene expression of these cells. Finally, we have provided the line to Jackson Laboratories for distribution and use in future studies. PMID- 28808331 TI - Pro- and anti-inflammatory responses of peripheral blood mononuclear cells induced by Staphylococcus aureus and Pseudomonas aeruginosa phages. AB - The ability of bacteriophages to kill bacteria is well known, as is their potential use as alternatives to antibiotics. As such, bacteriophages reach high doses locally through infection of their bacterial host in the human body. In this study we assessed the gene expression profile of peripheral blood monocytes from six donors for twelve immunity-related genes (i.e. CD14, CXCL1, CXCL5, IL1A, IL1B, IL1RN, IL6, IL10, LYZ, SOCS3, TGFBI and TNFA) induced by Staphylococcus aureus phage ISP and four Pseudomonas aeruginosa phages (i.e. PNM, LUZ19, 14-1 and GE-vB_Pae-Kakheti25). The phages were able to induce clear and reproducible immune responses. Moreover, the overall immune response was very comparable for all five phages: down-regulation of LYZ and TGFBI, and up-regulation of CXCL1, CXCL5, IL1A, IL1B, IL1RN, IL6, SOCS3 and TNFA. The observed immune response was shown to be endotoxin-independent and predominantly anti-inflammatory. Addition of endotoxins to the highly purified phages did not cause an immune response comparable to the one induced by the (endotoxin containing) phage lysate. In addition, the use of an intermediate level of endotoxins tipped the immune response to a more anti-inflammatory response, i.e. up-regulation of IL1RN and a strongly reduced expression of CXCL1 and CXCL5. PMID- 28808332 TI - Magnetic microsphere-based portable solid phase extraction device for on-site pre concentration of organics from large-volume water samples. AB - In this research a new magnetic material called M88 was fully synthetized and characterized for the extraction of pharmaceutical and personal care products in water samples. In addition, a portable prototype of magnetic solidphase extraction (MSPE) device was developed for the onsite preconcentration. The MSPE coupling with high performance liquid chromatography-Diode array detector (HPLC DAD) method was developed and validated for simultaneous analysis of 11 PPCPs (mefenamic acid, chloroamphenicol, ketoprofen, clofibric acid, indometacin, acetylsalicylic acid, bisphenol A, phenylphenol, gemfibrozil, triclosan, and ibuprofen) in environmental water samples. Experimental parameters affecting the extraction efficiencies, such as the amount of M88, desorption solvent, extraction time, and solution pH and sample volume were investigated. Under the optimal conditions, the limits of detection (LODs, S/N = 3) for the selected PPCPs were found to be in the range of 0.7-9.4 ng/L, with good linear correlation coefficients. It is also shown that the extraction efficiency of M88 was comparable to that of the commercial Oasis HLB and was evidently higher than that of the C18 cartridge. The optimised method was further verified by performing spiking experiments in water samples from Taihu Lake, with good recovery and reproducibility for all the compounds. PMID- 28808333 TI - Noise of a superconducting magnetic flux sensor based on a proximity Josephson junction. AB - We demonstrate simultaneous measurements of DC transport properties and flux noise of a hybrid superconducting magnetometer based on the proximity effect (superconducting quantum interference proximity transistor, SQUIPT). The noise is probed by a cryogenic amplifier operating in the frequency range of a few MHz. In our non-optimized device, we achieve minimum flux noise ~4 MUPhi0/Hz1/2, set by the shot noise of the probe tunnel junction. The flux noise performance can be improved by further optimization of the SQUIPT parameters, primarily minimization of the proximity junction length and cross section. Furthermore, the experiment demonstrates that the setup can be used to investigate shot noise in other nonlinear devices with high impedance. This technique opens the opportunity to measure sensitive magnetometers including SQUIPT devices with very low dissipation. PMID- 28808334 TI - Cardiorespiratory optimization during improvised singing and toning. AB - We evaluated the effect of different forms of singing on cardiorespiratory physiology, and we aimed at disentangling the role of breathing from that of vocal production. Cardiorespiratory recordings were obtained from 20 healthy adults at rest and during: a) singing of familiar slow songs as in the standard form of Western culture; b) improvised vocalization of free vowel sounds, known as toning. To disentangle the role of breathing from that of vocal production, we compared the vocal conditions with matched breathing-only conditions. Toning significantly improved heart rate variability, ventilatory efficiency and slowed respiration to almost exactly six breaths per minute (p < 0.001), a pattern that is known to optimize cardiovascular function and that coincides with the period of endogenous circulatory rhythms. Singing songs also positively impacted cardiorespiratory function, although to a lesser extent. The breathing pattern imposed upon participants in the absence of vocal production was sufficient to generate the physiological benefits. The effects of toning are similar to what has been previously described as a result of engaging in formal breathing exercises. Toning and singing may offer an engaging and cost effective tool to trigger beneficial respiratory patterns and the related cardiovascular benefits. PMID- 28808335 TI - Direct electrochemical measurement of metanephrines in spot urine samples for the diagnosis of phaeochromocytomas. AB - Metanephrines (MNs) were suggested as a potential first-line biochemical index for the diagnosis of phaeochromocytomas (PHEO). In this study, we developed a simple electrochemical method for the quantitative measurement of MNs in spot urine samples. As MNs contain a hydroxyphenyl group, they could be oxidized at a certain potential to quinines, which could be further detected by the differential pulse voltammetry (DPV) method using unmodified screen-printed carbon electrode (SPCE). Meanwhile, the solid phase extraction (SPE) technique was used to eliminate the matrix effect in the samples. Consequently, free MNs from the extracted urine sample were screened in a linear range from 0.25 mg/L to 12.5 mg/L. The lowest limit of quantification (LLOQ) for MNs was 0.25 mg/L and the limit of detection (LOD) was 0.05 mg/L. Both the precisions and recoveries were sufficient for clinical applications. The urine samples from 22 patients with PHEO and 63 controls were analyzed by the proposed method. The area under the ROC curve was 0.981 (95% CI, 0.958-1.000) with the sensitivity of 95.5% and the specificity of 92.4% at the cut-off value of 0.404 mg/L in these urine samples. Overall, the proposed method provides a cost-effective, rapid and simple tool for clinical diagnosis of PHEO. PMID- 28808336 TI - Linear and non-linear responses of vegetation and soils to glacial-interglacial climate change in a Mediterranean refuge. AB - The impact of past global climate change on local terrestrial ecosystems and their vegetation and soil organic matter (OM) pools is often non-linear and poorly constrained. To address this, we investigated the response of a temperate habitat influenced by global climate change in a key glacial refuge, Lake Ohrid (Albania, Macedonia). We applied independent geochemical and palynological proxies to a sedimentary archive from the lake over the penultimate glacial interglacial transition (MIS 6-5) and the following interglacial (MIS 5e-c), targeting lake surface temperature as an indicator of regional climatic development and the supply of pollen and biomarkers from the vegetation and soil OM pools to determine local habitat response. Climate fluctuations strongly influenced the ecosystem, however, lake level controls the extent of terrace surfaces between the shoreline and mountain slopes and hence local vegetation, soil development and OM export to the lake sediments. There were two phases of transgressional soil erosion from terrace surfaces during lake-level rise in the MIS 6-5 transition that led to habitat loss for the locally dominant pine vegetation as the terraces drowned. Our observations confirm that catchment morphology plays a key role in providing refuges with low groundwater depth and stable soils during variable climate. PMID- 28808337 TI - MicroRNA-214 modulates neural progenitor cell differentiation by targeting Quaking during cerebral cortex development. AB - The accurate generation of an appropriate number of different neuronal and glial subtypes is fundamental to normal brain functions and requires tightly orchestrated spatial and temporal developmental programmes to maintain the balance between the proliferation and the differentiation of neural progenitor cells. However, the molecular mechanism governing this process has not been fully elucidated. Here, we found that miR-214-3p was highly expressed in neural progenitor cells and dynamically regulated during neocortical development. Moreover, our in vivo and in vitro studies showed that miR-214 inhibited self renewal of neural progenitor cells and promoted neurogenesis. In addition, after target screening, we identified miR-214 targets including Quaking (Qki) by binding the 3'- untranslated region (3'-UTR) of the Qki mRNA, which was specifically expressed in the progenitor cells of the proliferative ventricular zone as 3 Qki isoforms. Furthermore, overexpression and knockdown of Qki showed that the different isoforms of Qki had different functions in the regulation of neural progenitor cells differentiation. Moreover, overexpression of Qki could counteract the function of miR-214 in neurogenesis. Our results revealed that miR 214 maintains the balance between neural progenitor/stem cell proliferation and differentiation together with Quaking, its target gene. PMID- 28808338 TI - A dynamical framework for complex fractional killing. AB - When chemotherapy drugs are applied to tumor cells with the same or similar genotypes, some cells are killed, while others survive. This fractional killing contributes to drug resistance in cancer. Through an incoherent feedforward loop, chemotherapy drugs not only activate p53 to induce cell death, but also promote the expression of apoptosis inhibitors which inhibit cell death. Consequently, cells in which p53 is activated early undergo apoptosis while cells in which p53 is activated late survive. The incoherent feedforward loop and the essential role of p53 activation timing makes fractional killing a complex dynamical challenge, which is hard to understand with intuition alone. To better understand this process, we have constructed a representative model by integrating the control of apoptosis with the relevant signaling pathways. After the model was trained to recapture the observed properties of fractional killing, it was analyzed with nonlinear dynamical tools. The analysis suggested a simple dynamical framework for fractional killing, which predicts that cell fate can be altered in three possible ways: alteration of bifurcation geometry, alteration of cell trajectories, or both. These predicted categories can explain existing strategies known to combat fractional killing and facilitate the design of novel strategies. PMID- 28808339 TI - Direct reprogramming of fibroblasts into skeletal muscle progenitor cells by transcription factors enriched in undifferentiated subpopulation of satellite cells. AB - Satellite cells comprise a functionally heterogeneous population of stem cells in skeletal muscle. Separation of an undifferentiated subpopulation and elucidation of its molecular background are necessary to identify the reprogramming factors to induce skeletal muscle progenitor cells. In this study, we found that intracellular esterase activity distinguishes a subpopulation of cultured satellite cells with high stemness using esterase-sensitive cell staining reagent, calcein-AM. Gene expression analysis of this subpopulation revealed that defined combinations of transcription factors (Pax3, Mef2b, and Pitx1 or Pax7, Mef2b, and Pitx1 in embryonic fibroblasts, and Pax7, Mef2b and MyoD in adult fibroblasts) reprogrammed fibroblasts into skeletal muscle progenitor cells. These reprogrammed cells formed Dystrophin-positive mature muscle fibers when transplanted into a mouse model of Duchenne muscular dystrophy. These results highlight the new marker for heterogenous population of cultured satellite cells, potential therapeutic approaches and cell sources for degenerative muscle diseases. PMID- 28808341 TI - Tuning the Fermi velocity in Dirac materials with an electric field. AB - Dirac materials are characterized by energy-momentum relations that resemble those of relativistic massless particles. Commonly denominated Dirac cones, these dispersion relations are considered to be their essential feature. These materials comprise quite diverse examples, such as graphene and topological insulators. Band-engineering techniques should aim to a full control of the parameter that characterizes the Dirac cones: the Fermi velocity. We propose a general mechanism that enables the fine-tuning of the Fermi velocity in Dirac materials in a readily accessible way for experiments. By embedding the sample in a uniform electric field, the Fermi velocity is substantially modified. We first prove this result analytically, for the surface states of a topological insulator/semiconductor interface, and postulate its universality in other Dirac materials. Then we check its correctness in carbon-based Dirac materials, namely graphene nanoribbons and nanotubes, thus showing the validity of our hypothesis in different Dirac systems by means of continuum, tight-binding and ab-initio calculations. PMID- 28808340 TI - Kruppel-like factor 6 is a transcriptional activator of autophagy in acute liver injury. AB - Kruppel-like factor 6 (KLF6) is a transcription factor and tumor suppressor. We previously identified KLF6 as mediator of hepatocyte glucose and lipid homeostasis. The loss or reduction of KLF6 is linked to the progression of hepatocellular carcinoma, but its contribution to liver regeneration and repair in acute liver injury are lacking so far. Here we explore the role of KLF6 in acute liver injury models in mice, and in patients with acute liver failure (ALF). KLF6 was induced in hepatocytes in ALF, and in both acetaminophen (APAP)- and carbon tetrachloride (CCl4)-treated mice. In mice with hepatocyte-specific Klf6 knockout (DeltaKlf6), cell proliferation following partial hepatectomy (PHx) was increased compared to controls. Interestingly, key autophagic markers and mediators LC3-II, Atg7 and Beclin1 were reduced in DeltaKlf6 mice livers. Using luciferase assay and ChIP, KLF6 was established as a direct transcriptional activator of ATG7 and BECLIN1, but was dependent on the presence of p53. Here we show, that KLF6 expression is induced in ALF and in the regenerating liver, where it activates autophagy by transcriptional induction of ATG7 and BECLIN1 in a p53 dependent manner. These findings couple the activity of an important growth inhibitor in liver to the induction of autophagy in hepatocytes. PMID- 28808342 TI - Effect of Nitric Oxide on Human Corneal Epithelial Cell Viability and Corneal Wound Healing. AB - Although the wound healing effects of nitric oxide (NO) are known, the mechanism by which NO modulates corneal wound healing remains unclear. In this study, we investigated the effect of exogenous NO donor (NaNO2) on corneal wound healing. We found that NaNO2 (0.1 MUM to 100 MUM) increased human corneal epithelial cell (HCEC) viability and migration. It also modulated the phosphorylation of mitogen activated protein kinases (MAPKs) in a time- dependent manner in those HCECs. Further, p38 MAPK phosphorylation increased at 6 h and normalized at 24 h, while the phosphorylation of extracellular signal regulated kinase (ERK) was increased both at 6 h and 24 h. Topical treatment with NaNO2 (10 MUM) enhanced corneal epithelial healing and decreased corneal opacity in murine corneal alkali burn model by modulating inflammatory cytokines. Our findings suggest that NO increased HCEC proliferation and migration via time-dependent MAPK activation and eventually enhanced corneal recovery from the alkali burn. PMID- 28808343 TI - Structure formation during translocon-unassisted co-translational membrane protein folding. AB - Correctly folded membrane proteins underlie a plethora of cellular processes, but little is known about how they fold. Knowledge of folding mechanisms centres on reversible folding of chemically denatured membrane proteins. However, this cannot replicate the unidirectional elongation of the protein chain during co translational folding in the cell, where insertion is assisted by translocase apparatus. We show that a lipid membrane (devoid of translocase components) is sufficient for successful co-translational folding of two bacterial alpha-helical membrane proteins, DsbB and GlpG. Folding is spontaneous, thermodynamically driven, and the yield depends on lipid composition. Time-resolving structure formation during co-translational folding revealed different secondary and tertiary structure folding pathways for GlpG and DsbB that correlated with membrane interfacial and biological transmembrane amino acid hydrophobicity scales. Attempts to refold DsbB and GlpG from chemically denatured states into lipid membranes resulted in extensive aggregation. Co-translational insertion and folding is thus spontaneous and minimises aggregation whilst maximising correct folding. PMID- 28808344 TI - Hypothalamic effects of progesterone on regulation of the pulsatile and surge release of luteinising hormone in female rats. AB - Progesterone can block the oestradiol-induced GnRH/LH surge and inhibit LH pulse frequency. Recent studies reported that progesterone prevented premature LH surges during ovarian hyperstimulation in women. As the most potent stimulator of GnRH/LH release, kisspeptin is believed to mediate the positive and negative feedback effects of oestradiol in the hypothalamic anteroventral periventricular (AVPV) and arcuate (ARC) nuclei, while the region-specific role of progesterone receptors in these nuclei remains unknown. This study examined the hypothesis that progesterone inhibits LH surge and pulsatile secretion via its receptor in the ARC and/or AVPV nuclei. Adult female rats received a single injection of pregnant mare serum gonadotropin followed by progesterone or vehicle. Progesterone administration resulted in a significant prolongation of the oestrous cycle and blockade of LH surge. However, microinjection of the progesterone receptor antagonist, RU486, into the AVPV reversed the prolonged cycle length and rescued the progesterone blockade LH surge, while RU486 into the ARC shortened LH pulse interval in the progesterone treated rats. These results demonstrated that progesterone's inhibitory effect on the GnRH/LH surge and pulsatile secretion is mediated by its receptor in the kisspeptin enriched hypothalamic AVPV and ARC respectively, which are essential for progesterone regulation of oestrous cyclicity in rats. PMID- 28808345 TI - Minimally invasive treatment of both-column acetabular fractures through the Stoppa combined with iliac fossa approach. AB - Both-column fractures are the most complicated group of acetabular fractures. Although great progress of surgical technique has been made, the choice of approach is controversial. All the fragments could be exposed and managed through combined ilioinguinal and Kocher-Langenbeck (IL+KL) approaches, which has been widely used to conduct the both-column fractures. However, the clinical popularization may be restricted for high rate of complication. Most internal area of the hemipelvis could be exposed through Stoppa combined with iliac fossa (S+IF) approach. The majority of both-column fractures were managed through IL+KL approaches or S+IF approach in our institution. The comparison of the two surgical methods was done in this study. The purpose is to examine whether S+IF approach could achieve the satisfactory reduction and fixation for both-column fractures. PMID- 28808346 TI - Evidence that Listeria innocua modulates its membrane's stored curvature elastic stress, but not fluidity, through the cell cycle. AB - This paper reports that the abundances of endogenous cardiolipin and phosphatidylethanolamine halve during elongation of the Gram-positive bacterium Listeria innocua. The lyotropic phase behaviour of model lipid systems that describe these modulations in lipid composition indicate that the average stored curvature elastic stress of the membrane is reduced on elongation of the cell, while the fluidity appears to be maintained. These findings suggest that phospholipid metabolism is linked to the cell cycle and that changes in membrane composition can facilitate passage to the succeding stage of the cell cycle. This therefore suggests a means by which bacteria can manage the physical properties of their membranes through the cell cycle. PMID- 28808347 TI - TaiNi: Maximizing research output whilst improving animals' welfare in neurophysiology experiments. AB - Understanding brain function at the cell and circuit level requires representation of neuronal activity through multiple recording sites and at high sampling rates. Traditional tethered recording systems restrict movement and limit the environments suitable for testing, while existing wireless technology is still too heavy for extended recording in mice. Here we tested TaiNi, a novel ultra-lightweight (<2 g) low power wireless system allowing 72-hours of recording from 16 channels sampled at ~19.5 KHz (9.7 KHz bandwidth). We captured local field potentials and action-potentials while mice engaged in unrestricted behaviour in a variety of environments and while performing tasks. Data was synchronized to behaviour with sub-second precision. Comparisons with a state-of the-art wireless system demonstrated a significant improvement in behaviour owing to reduced weight. Parallel recordings with a tethered system revealed similar spike detection and clustering. TaiNi represents a significant advance in both animal welfare in electrophysiological experiments, and the scope for continuously recording large amounts of data from small animals. PMID- 28808348 TI - Rapid phenotypic stress-based microfluidic antibiotic susceptibility testing of Gram-negative clinical isolates. AB - Bacteremia is a life-threatening condition for which antibiotics must be prescribed within hours of clinical diagnosis. Since the current gold standard for bacteremia diagnosis is based on conventional methods developed in the mid 1800s-growth on agar or in broth-identification and susceptibility profiling for both Gram-positive and Gram-negative bacterial species requires at least 48-72 h. Recent advancements in accelerated phenotypic antibiotic susceptibility testing have centered on the microscopic growth analysis of small bacterial populations. These approaches are still inherently limited by the bacterial growth rate. Our approach is fundamentally different. By applying environmental stress to bacteria in a microfluidic platform, we can correctly assign antibiotic susceptibility profiles of clinically relevant Gram-negative bacteria within two hours of antibiotic introduction rather than 8-24 h. The substantial expansion to include a number of clinical isolates of important Gram-negative species-Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa reported here underscores the broad utility of our approach, complementing the method's proven utility for Gram-positive bacteria. We also demonstrate that the platform is compatible with antibiotics that have varying mechanisms of action meropenem, gentamicin, and ceftazidime-highlighting the versatility of this platform. PMID- 28808349 TI - Dysregulation of photosynthetic genes in oceanic Prochlorococcus populations exposed to organic pollutants. AB - The impact of organic pollutants on oceanic ecosystem functioning is largely unknown. Prochlorococcus, the most abundant known photosynthetic organism on Earth, has been suggested to be especially sensible to exposure to organic pollutants, but the sub-lethal effects of organic pollutants on its photosynthetic function at environmentally relevant concentrations and mixtures remain unexplored. Here we show the modulation of the expression of two photosynthetic genes, rbcL (RuBisCO large subunit) and psbA (PSII D1 protein), of oceanic populations of Prochlorococcus from the Atlantic, Indian and Pacific Oceans when exposed to mixtures of organic pollutants consisting of the non-polar fraction of a seawater extract. This mixture included most persistent organic pollutants, semivolatile aromatic-like compounds, and the unresolved complex mixture of hydrocarbons. Prochlorococcus populations in the controls showed the expected diel cycle variations in expression of photosynthetic genes. However, exposure to a complex mixture at concentrations only 2-fold above the environmental levels resulted in a decrease of expression of both genes, suggesting an effect on the photosynthetic function. While organic pollutant effects on marine phytoplankton have been already demonstrated at the cellular level, this is the first field study showing alterations at the molecular level of the photosynthetic function due to organic pollutants. PMID- 28808350 TI - Fano resonance Rabi splitting of surface plasmons. AB - Rabi splitting and Fano resonance are well-known physical phenomena in conventional quantum systems as atoms and quantum dots, arising from strong interaction between two quantum states. In recent years similar features have been observed in various nanophotonic and nanoplasmonic systems. Yet, realization of strong interaction between two or more Fano resonance states has not been accomplished either in quantum or in optical systems. Here we report the observation of Rabi splitting of two strongly coupled surface plasmon Fano resonance states in a three-dimensional plasmonic nanostructure consisting of vertical asymmetric split-ring resonators. The plasmonic system stably supports triple Fano resonance states and double Rabi splittings can occur between lower and upper pairs of the Fano resonance states. The experimental discovery agrees excellently with rigorous numerical simulations, and is well explained by an analytical three-oscillator model. The discovery of Fano resonance Rabi splitting could provide a stimulating insight to explore new fundamental physics in analogous atomic systems and could be used to significantly enhance light-matter interaction for optical sensing and detecting applications. PMID- 28808351 TI - Inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells. AB - Only 40% of patients with advanced ovarian cancer survive more than 5 years. We have previously shown that pitavastatin induces regression of ovarian cancer xenografts in mice. To evaluate whether the response of ovarian cancer cells to pitavastatin is potentiated by farnesyl diphosphate synthase inhibitors or geranylgeraniol transferase I inhibitors, we evaluated combinations of pitavastatin with zoledronic acid, risedronate and GGTI-2133 in a panel of ovarian cancer cells. Pitavastatin (IC50 = 0.6-14 MUM), zoledronic acid (IC50 = 21-57 MUM), risedronate (IC50 > 100 MUM) or GGTI-2133 (IC50 > 25 MUM) inhibited the growth of ovarian cancer cell cultures. Combinations of pitavastatin with zoledronic acid displayed additive or synergistic effects in cell growth assays in 10 of 11 cell lines evaluated as well as in trypan blue exclusion, cellular ATP or caspase 3/7, 8 and 9 assays. Pitavastatin reduced levels of GGT-IIbeta and the membrane localization of several small GTPases and this was potentiated by zoledronic acid. siRNA to GGT-Ibeta and GGT-IIbeta used in combination, but not when used individually, significantly increased the sensitivity of cells to pitavastatin. These data suggest that zoledronic acid, a drug already in clinical use, may be usefully combined with pitavastatin in the treatment of ovarian cancer. PMID- 28808352 TI - The effect of androgen excess on maternal metabolism, placental function and fetal growth in obese dams. AB - Pregnant women with polycystic ovary syndrome (PCOS) are often overweight or obese. To study the effects of maternal androgen excess in obese dams on metabolism, placental function and fetal growth, female C57Bl6J mice were fed a control (CD) or a high fat/high sucrose (HF/HS) diet for 4-10 weeks, and then mated. On gestational day (GD) 15.5-17.5, dams were injected with dihydrotestosterone (CD-DHT, HF/HS-DHT) or a vehicle (CD-Veh, HF/HS-Veh). HF/HS dams had higher fat content, both before mating and on GD18.5, with no difference in glucose homeostasis, whereas the insulin sensitivity was higher in DHT-exposed dams. Compared to the CD groups, the livers from HF/HS dams weighed more on GD18.5, the triglyceride content was higher, and there was a dysregulation of liver enzymes related to lipogenesis and higher mRNA expression of Fitm1. Fetuses from HF/HS-Veh dams had lower liver triglyceride content and mRNA expression of Srebf1c. Maternal DHT exposure, regardless of diet, decreased fetal liver Pparg mRNA expression and increased placental androgen receptor protein expression. Maternal diet-induced obesity, together with androgen excess, affects maternal and fetal liver function as demonstrated by increased triglyceride content and dysfunctional expression of enzymes and transcription factors involved in de novo lipogenesis and fat storage. PMID- 28808353 TI - Milk microbiome and bacterial load following dry cow therapy without antibiotics in dairy cows with healthy mammary gland. AB - Preventive infusion of antibiotics in the mammary gland of cows consumes 11 tons/year of medically relevant antimicrobials, yet, this practice might not be critical to prevent new infections in the healthy mammary gland of cows. Here, we used next-generation sequencing and quantitative real-time PCR to determine the impact of dry cow therapy without antibiotics on milk microbiome and bacterial load, respectively. Cows diagnosed as negative for mastitis at dry off were randomly allocated to receive antibiotic (intramammary ceftiofur hydrochloride) and teat sealant or just teat sealant. Firmicutes was the most abundant phylum, and Corynebacterium, Acinetobacter, and Staphylococcus, often involved in mastitis cases, were the most abundant genera across treatments and time. However, there were no effects of antimicrobial on milk microbiome and bacterial load. Bacterial load was greater at seven days postpartum than at dry off. Dry cow therapy based on teat sealant without antibiotics can be used with no detrimental impacts on milk microbiome and bacterial load in cows with a healthy mammary gland. PMID- 28808354 TI - The Relationship Between HR Capabilities and Quality of Patient Care: The Mediating Role of Proactive Work Behaviors. AB - Based on theoretical frameworks of resource-based theory, dynamic capabilities, and behavioral perspective on human resource management, we developed a multidimensional construct of human resource (HR) capabilities and tested its relationship with quality of patient care using a national sample of U.S. hospitals. The data on HR capabilities were collected from senior managers (421 individuals nested in 279 hospitals) representing both the administrative and clinical sides of the hospitals. The data on quality of patient care were gathered from two unique sources - patients of 207 hospitals who reported the data via the Hospital Consumer Assessment of Healthcare Providers and Systems Survey and 421 senior managers of 279 hospitals. Our analyses using structural equation modeling suggests that the positive relationship of HR capabilities with quality of patient care is mediated by proactive behaviors of health care workers. Implications of the study findings for research and practice are discussed. PMID- 28808355 TI - New Markers of Inflammation and Tubular Damage in Children with Chronic Kidney Disease. AB - INTRODUCTION AND AIMS: Monocyte chemoattractant protein- (MCP-) 1, macrophage colony-stimulating factor (MCSF), and neopterin are connected with monocyte migration and transition into macrophages, leading to fibrosis and tubular damage in the course of CKD. The aim of the study was to analyze the applicability of urinary fractional excretion (FE) of MCP1, MCSF, and neopterin, as markers of inflammation and tubular damage, in children with CKD. METHODS: The study group consisted of 61 children with CKD stages 1-5 and 23 age-matched controls. The serum and urine concentrations of MCP1, MCSF, and neopterin were assessed by ELISA and then the fractional excretion (FE) was calculated. RESULTS: FE MCSF and neopterin values exceeded 1% already in controls. FE MCSF rose significantly since CKD stages 1-2, FE neopterin since CKD stages 3-5. FE MCP1 was below 1% in healthy controls and in CKD stages 1-2, then increased significantly in CKD stages 3-5. CONCLUSIONS: The FE MCP-1 values show that inflammation precedes the tubular dysfunction. FE MCSF and FE neopterin may be considered new markers of the renal parenchyma progressive damage. Fractional excretion may become a useful tool in the assessment of inflammation and tubular damage in children with CKD. PMID- 28808356 TI - The Gist of Delay of Gratification: Understanding and Predicting Problem Behaviors. AB - Delay of gratification captures elements of temptation and self-denial that characterize real-life problems with money and other problem behaviors such as unhealthy risk taking. According to fuzzy-trace theory, decision makers mentally represent social values such as delay of gratification in a coarse but meaningful form of memory called "gist." Applying this theory, we developed a gist measure of delay of gratification that does not involve quantitative trade-offs (as delay discounting does) and hypothesize that this construct explains unique variance beyond sensation seeking and inhibition in accounting for problem behaviors. Across four studies, we examine this Delay-of-gratification Gist Scale by using principal components analyses and evaluating convergent and divergent validity with other potentially related scales such as Future Orientation, Propensity to Plan, Time Perspectives Inventory, Spendthrift-Tightwad, Sensation Seeking, Cognitive Reflection, Barratt Impulsiveness, and the Monetary Choice Questionnaire (delay discounting). The new 12-item measure captured a single dimension of delay of gratification, correlated as predicted with other scales, but accounted for unique variance in predicting such outcomes as overdrawing bank accounts, substance abuse, and overall subjective well-being. Results support a theoretical distinction between reward-related approach motivation, including sensation seeking, and inhibitory faculties, including cognitive reflection. However, individuals' agreement with the qualitative gist of delay of gratification, as expressed in many cultural traditions, could not be reduced to such dualist distinctions nor to quantitative conceptions of delay discounting, shedding light on mechanisms of self-control and risk taking. PMID- 28808358 TI - MBD2 Regulates Th17 Cell Differentiation and Experimental Severe Asthma by Affecting IRF4 Expression. AB - Th17 cells and IL-17 participate in airway neutrophil infiltration characteristics in the pathogenesis of severe asthma. Methyl-CpG binding domain protein 2 (MBD2) expression increased in CD4+ T cells in peripheral blood samples of asthma patients. However, little is known about that epigenetic regulation of MBD2 in both immunological pathogenesis of experimental severe asthma and CD4+ T cell differentiation. Here, we established a neutrophil-predominant severe asthma model, which was characterized by airway hyperresponsiveness (AHR), BALF neutrophil granulocyte (NEU) increase, higher NEU and IL-17 protein levels, and more Th17 cell differentiation. In the model, MBD2 and IRF4 protein expression increased in the lung and spleen cells. Under overexpression or silencing of the MBD2 and IRF4 gene, the differentiation of Th17 cells and IL-17 secretion showed positive changes. IRF4 protein expression showed a positive change with overexpression or silencing of the MBD2 gene, whereas there was no significant difference in the expression of MBD2 under overexpression or silencing of the IRF4 gene. These data provide novel insights into epigenetic regulation of severe asthma. PMID- 28808359 TI - Electronic Health Records and Improved Patient Care: Opportunities for Applied Psychology. AB - Healthcare is undergoing an unprecedented technology transition from paper medical records to electronic health records (EHRs). While the adoption of EHRs holds tremendous promise for improving efficiency, quality and safety, there have been numerous challenges that have been largely centered on the technology not meeting the cognitive needs of the clinical end-users. Clinicians are experiencing increased stress and frustration, and new safety hazards have been introduced. There is a significant opportunity for applied psychologists to address many of these challenges. I highlight three key areas: studying and modeling clinician needs, applying theoretically grounded design principles, and developing technology to support teamwork and communication. PMID- 28808357 TI - Platelet-Released Growth Factors Induce Differentiation of Primary Keratinocytes. AB - Autologous thrombocyte concentrate lysates, for example, platelet-released growth factors, (PRGFs) or their clinically related formulations (e.g., Vivostat PRF(r)) came recently into the physicians' focus as they revealed promising effects in regenerative and reparative medicine such as the support of healing of chronic wounds. To elucidate the underlying mechanisms, we analyzed the influence of PRGF and Vivostat PRF on human keratinocyte differentiation in vitro and on epidermal differentiation status of skin wounds in vivo. Therefore, we investigated the expression of early (keratin 1 and keratin 10) and late (transglutaminase-1 and involucrin) differentiation markers. PRGF treatment of primary human keratinocytes decreased keratin 1 and keratin 10 gene expression but induced involucrin and transglutaminase-1 gene expression in an epidermal growth factor receptor- (EGFR-) dependent manner. In concordance with these results, microscopic analyses revealed that PRGF-treated human keratinocytes displayed morphological features typical of keratinocytes undergoing terminal differentiation. In vivo treatment of artificial human wounds with Vivostat PRF revealed a significant induction of involucrin and transglutaminase-1 gene expression. Together, our results indicate that PRGF and Vivostat PRF induce terminal differentiation of primary human keratinocytes. This potential mechanism may contribute to the observed beneficial effects in the treatment of hard-to heal wounds with autologous thrombocyte concentrate lysates in vivo. PMID- 28808360 TI - Bemiparin versus Enoxaparin in the Prevention of Venous Thromboembolism among Intensive Care Unit Patients. AB - BACKGROUND: Critically ill patients are considered a high-risk group for developing venous thromboembolism (VTE). Due to their impaired cardiopulmonary reserve, these VTEs may result in significant morbidity and mortality. In this study, we compared two types of low molecular weight heparin, enoxaparin, and bemiparin, as regards to their efficacy and safety in VTE prevention among Intensive Care Unit (ICU) patients. METHODS: This study was a prospective, randomized trial of 100 critically ill patients who are at high risk for developing VTE were included in this study and assigned to receive subcutaneous injections of either 3500 international units (IU) anti-factor Xa of bemiparin sodium or 40 mg of enoxaparin given once a day and patient were followed for 60 days after initiation of anticoagulant therapy for the development of documented deep venous thrombosis (DVT) using bilateral lower limb venous duplex, documented pulmonary embolism using computed tomography pulmonary angiography, and complications related to injectant anticoagulant. RESULTS: Confirmed DVT was observed in two patients (4%) in the bemiparin group compared with 10 patients (20%) in the enoxaparin group with P < 0.05. Confirmed pulmonary embolism (PE) was observed in seven patients (14%) in the enoxaparin group with no recorded cases of confirmed PE in the bemiparin group (P < 0.05). No deaths were recorded in either group. Adverse events such as ecchymosis or hematoma at the injection site were observed in one patient (2%) in the bemiparin group and eight patients (16%) in the enoxaparin group (P < 0.05). There was no significant statistical difference between both groups as regards other adverse effects and complications related to the injectant anticoagulant. CONCLUSION: Bemiparin was superior to enoxaparin as a prophylactic anticoagulant for VTE in critically ill patients with less adverse local complications at the injection site. The study was registered on www.clinicaltrials.gov. Registration ID: NCT02795065. Registered June 8, 2016. PMID- 28808361 TI - Interleukin-6: An Early Predictive Marker for Severity of Acute Pancreatitis. AB - BACKGROUND AND AIMS: Interleukin (IL)-6, IL-8, IL-10, and C-reactive protein (CRP) have been evaluated for predicting outcomes of acute pancreatitis. However, there is considerable variation in their performance among different studies. We evaluate their accuracy in predicting progression to severe pancreatitis. MATERIALS AND METHODS: Serum IL-6, IL-8, IL-10, and CRP levels were measured within 24 h of admission in forty patients of clinically predicted severe acute pancreatitis (SAP). Persistent organ failure (>48 h) defined SAP. The performance of inflammatory markers was evaluated in predicting the progression of pancreatitis. RESULTS: IL-6 >=28.90 pg/mL had a sensitivity of 62.86%, specificity of 80%, positive predictive value (PPV) of 95.65%, LR+ of 3.1429, LR- of 0.4643, and diagnostic odds ratio (DOR) of 6.7692; IL-8 >=88.70 pg/mL had a sensitivity of 60%, specificity of 80%, PPV of 95.45%, LR+ of 3.000, LR- of 0.5000, and DOR of 6.000; IL-10 <=5.70 pg/mL had DOR of 0.2647, sensitivity of 51.43%, specificity of 20%, PPV of 81.82%, LR+ of 0.6429, and LR- of 2.4286. CRP >=110.00 mg/L had DOR of 2.3636, sensitivity of 37.14%, specificity of 80%, PPV of 92.86%, LR+ of 1.8571, and LR of 0.7857. CONCLUSIONS: IL-6 >=28.90 pg/mL, measured within 48 h of onset is the best among the tested biomarkers in this study for predicting the progression to severe pancreatitis. PMID- 28808362 TI - A Study on the Psychometric Properties of Revised-nonverbal Pain Scale and Original-nonverbal Pain Scale in Iranian Nonverbal-ventilated Patients. AB - BACKGROUND AND AIMS: The nonverbal pain scale is one of the instruments which study pain in nonverbal-ventilated patients with regard to the changes of behavioral and physiological indices. The purpose of the study is to survey the psychometric properties of revised-nonverbal pain scale (R-NVPS) and original nonverbal pain scale (O-NVPS) in ventilated patients hospitalized in critical care units. MATERIALS AND METHODS: Four nurses studied pain in sixty patients hospitalized in trauma, medical, neurology, and surgical critical care units using R-NVPS and O-NVPS at six times (before, during, and after nociceptive and nonnociceptive procedures). The test was repeated in 37 patients after 8-12 h. RESULTS: Cronbach's alpha coefficient for R-NVPS and O-NVPS was 0.8 and 0.76, respectively. The inter-rater correlation coefficient during different times was r = 0.89-0.96 for R-NVPS and r = 0.80-0.87 for O-NVPS. Test-retest correlation coefficient for R-NVPS and O-NVPS was r = 0.55-0.86 and r = 0.51-0.75, respectively. The meaningful difference in pain score between nociceptive and nonnociceptive procedures (P < 0.001) and a higher pain score in patients who confirmed pain (P < 0.001) showed a discriminant and criterion validity for both scales of NVPS, respectively. CONCLUSIONS: R-NVPS and O-NVPS can both be used as valid and reliable scales in studying pain in ventilated patient. However, in comparing the items, "respiration" (R-NVPS) had a higher sensitivity than "physiology II" (O-NVPS) in assessing pain. PMID- 28808363 TI - Incidence, Characteristics, and Survival Trend of Cardiopulmonary Resuscitation Following In-hospital Compared to Out-of-hospital Cardiac Arrest in Northern Jordan. AB - BACKGROUND: Cardiac arrest remains a leading cause of mortality worldwide. Early cardiopulmonary resuscitation (CPR) is the cornerstone intervention to optimize the survival rates. OBJECTIVES: The main aim of this study was to determine and compare the incidence, characteristics, risk factors, and outcomes of CPR in a referral university hospital following in-hospital cardiac arrests (IHCAs) and out-of-hospital cardiac arrest (OHCA) in Northern Jordan. PATIENTS AND METHODS: Retrospective observational study of adults referred to King Abdulla University Hospital who received CPR between January 2014 and January 2015. Data were obtained from the medical recorded of included patients. The primary outcome was survival to hospital discharge. Chi-square and logistic regression analyses were performed to identify risk factors associated with survival to discharge. RESULTS: A total of 79 OHCA and 257 IHCA were included in the study. The overall survival rate for OHCA was 2.97%. The survival rate increased to 4.3% if CPR performed before arriving the hospital. Only 22% of the OHCA cases had CPR performed mainly due to lack of knowledge and skills of bystanders. The survival rate for IHCA was 14.88%. In this study, patient survival was not associated with age, smoking habit, diabetes mellitus, cancer status, hypertension, or heart failure. CONCLUSION: This is the first study to describe the incidence and outcome of adult IHCA and OHCA in Jordan. The findings will serve as a benchmark to evaluate future impact of changes in service delivery, organization, and treatment for OHCA and IHCA. Furthermore, findings will urge the regulatory bodies to establish well-structured Emergency Medical Service system. Educational programs at the national level to improve public awareness of CPR intervention are crucial to improve survival rates. PMID- 28808364 TI - The Effect of Furosemide on the Level of Neutrophil Gelatinase-associated Lipocalin in Critically Hospitalized Patients with Acute Kidney Injury. AB - BACKGROUND AND AIMS: Oliguric acute kidney injury (AKI), commonly attributed to a more severe degree of renal injury, is associated with poorer prognosis than nonoliguric form. The aim of this study was to determine the effect of furosemide therapy on kidney function and on the level of neutrophil gelatinase-associated lipocalin (NGAL) in critically hospitalized patients in the Intensive Care Unit (ICU). MATERIALS AND METHODS: In this randomized controlled trial, 106 ICU patients with AKI were assigned into furosemide and control groups. In furosemide group, 40-80 mg of intravenous furosemide was administrated, followed by 1-5 mg/h furosemide infusion. In control group, patients received standard treatment. Serum and urinary NGAL were measured on the 1st, 3rd, and 7th days of the study. RESULTS: The results of this study indicated that during the study, serum blood urea nitrogen levels of patients increased in both groups; this, however, was significant only in the control group (P = 0.009). Both plasma and urine NGAL decreased significantly (P < 0.05) in both groups. The findings of 28-day mortality follow-up revealed that 20% and 28% of patients died in the furosemide and the control groups, respectively. CONCLUSIONS: NGAL was not found to reflect any positive or negative effects of Furosemide in patients with AKI. PMID- 28808365 TI - Intra- and Inter-observer Reliability of Quadriceps Muscle Thickness Measured with Bedside Ultrasonography by Critical Care Physicians. AB - BACKGROUND: Muscle wasting is common among critically ill patients with sepsis and has a significant effect on clinical outcome. However, appropriate tool for measurement of muscle loss is debatable. Ultrasonography (USG) has been used for objective assessment of quadriceps muscle thickness among these patients; however, there is limited data on its reliability. AIMS AND OBJECTIVE: This study was aimed to assess the reliability of quadriceps muscle thickness as measured by critical care physicians. METHODOLOGY: This cross-sectional study included twenty patients with sepsis. Quadriceps muscle thickness was measured on right mid-thigh at a predefined point by two critical care fellows using bedside USG. Intra- and inter-observer reliability of the measurements was assessed by intra-class correlation coefficient (ICC). RESULTS: Hundred and twenty quadriceps muscle thickness measurements, three by each of the two critical care fellows, were done in twenty patients with sepsis. First, second, and third measurements (mean +/- standard deviation) taken by the first observer (RK) were 35.030 +/- 3.546 mm, 35.055 +/- 3.307 mm, and 35.245 +/- 3.027 mm, respectively. The three values recorded by the second observer (AD) were 35.585 +/- 3.746 mm, 35.1 +/- 3.006 mm, and 34.89 +/- 2.556 mm, respectively. ICC for observer 1 and 2 was 0.925 (95% confidence interval [CI]: 0.851-0.967) and 0.835 (95% CI: 0.689-0.925), respectively. The mean difference of measurement between two observers was 0.082 mm (95% CI: -1.194-1.031). The mean ICC (95% CI) for inter-observer reliability was 0.992 (0.979-0.997); P < 0.001. CONCLUSIONS: This study shows that ultrasound is a reliable tool for the measurement of quadriceps muscle thickness by critical care physicians with excellent inter- and intra-class reliability. PMID- 28808366 TI - Clinical Features and Outcomes of Patients with Posterior Reversible Encephalopathy Syndrome. AB - AIMS: The aim of this study was to study the clinical features and outcomes of patients with posterior reversible encephalopathy syndrome (PRES) admitted to the Intensive Care Unit (ICU). SUBJECTS AND METHODS: All adult patients admitted to our ICU with acute onset neurologic symptoms with focal vasogenic edema on magnetic resonance imaging (MRI) were included in the study. Data were collected on demography, coexisting illness, admission severity of illness, neurological symptoms, blood pressure, treatment initiated, and MRI findings. Outcome data collected included mortality, ICU average length of stay (ALOS), number of ventilator days, and neurological disability at discharge assessed by modified Rankin scale (MRS). RESULTS: Fourteen patients were admitted with PRES. Thirteen patients were female, and their mean age was 31.5 +/- 8.3 years. Etiology of PRES included eclampsia (64.2%), lupus nephritis (21.4%), CKD (7.1%), and hypertension (n = 1 [7.1%]). The most common presenting symptom was seizure (92.8%), followed by visual disturbance (42.8%), headache (42.8%), encephalopathy (14.2%), and status epilepticus (14.2%). The Glasgow coma scale on admission was 12.3 +/- 2.9. High blood pressure was seen in 12 patients 85.7%; their mean systolic and diastolic pressures were 173 +/- 10.2 and 110 +/- 8.6 mmHg, respectively. MRI showed that parieto-occipital region was most commonly involved (92.8%), followed by frontal lobe (42.8%). ICU ALOS was 4.35 +/- 2.4 days and mean ventilator days was 1.7 +/- 2.0 days. One patient (1/14 [7.4%]) died of multiorgan failure and 13 patients were discharged with no residual neurological deficit (MRS, 0). CONCLUSIONS: PRES is a potentially reversible disorder with prompt recognition and control of blood pressure. PMID- 28808367 TI - Isolated Renal Mucormycosis in Immunocompetent Children: A Report of Two Cases. AB - Isolated renal mucormycosis is a rare entity in children. It is potentially fatal when not detected and managed early with antifungal therapy, and surgery as and when needed. We present two immunocompetent children who developed this infection and subsequently succumbed to it. The diagnosis was established postmortem on renal biopsy specimens. We also discuss the 9 cases of isolated renal involvement in children published in literature. PMID- 28808368 TI - Uncommon Presentation of an Unusual Foreign Body. AB - Esophageal foreign bodies (FBs) are common and can be the serious cause of morbidity and mortality in children. One-third of FBs, retained in the gastrointestinal tract, are found in the esophagus. Their management depends on the anatomical location, shape, size, and the duration of impaction. In children, unwitnessed esophageal FBs can present with respiratory symptoms such as stridor. Therefore, a high index of suspicion is generally required to avoid significant morbidity and mortality. We are reporting an unusual FB with unusual symptoms in a 2-year-old female child. PMID- 28808369 TI - Ultrasound Guidance for Central Venous Catheterization: A Step Further to Prevent Malposition of Central Venous Catheter before Radiographic Confirmation. AB - Ultrasound (USG) guidance has long been used for guiding central venous catheterization. USG provides direct visualization of needle puncture through the skin into the vein. Most of the time USG guidance is just limited to puncturing of the vein and seeing guidewire entering the vein while malpositioning of catheter occurs after that which is seen later on while checking chest radiograph. Repositioning of catheter after that becomes not only difficult requiring repeated chest radiograph to reconfirm position of catheter but also increases chances of infection with repeated manipulations. USG guidance can be used for tracing both guidewire and catheter during the procedure to prevent malpositioning of catheter, thus when done at the right time can prevent complication related to malpositioning and repeated manipulations. We used linear USG probe to check malposition of guidewire and microconvex probe to confirm position of central venous catheter. PMID- 28808370 TI - A Rare Case of Strongyloides Hyperinfection from Hypogammaglobulinemia. AB - Strongyloides infection can range from asymptomatic eosinophilia to disseminated disease. Common in tropical and subtropical nations, it can lead to hyperinfection, an autoinfection increasing parasitic burden in immunocompromised. Cell-mediated immunity is important in combating parasite infection. We present a case of Strongyloides hyperinfection in hypogammaglobulinemia which was refractory to conventional treatment but responded to immunoglobulin administration with complete resolution indicating role of humoral immunity also. PMID- 28808371 TI - Efficacy of Osteopathic Manipulative Treatment Approach in the Patient with Pulmonary Fibrosis in Critical Care Outpatient Department. AB - The purpose of the present case study was to explore the efficacy of osteopathic manipulative treatment (OMT) in patient with pulmonary fibrosis (PF) in the critical care outpatient department. Here, we present a 48-year-old male case with breathlessness, increased frequency of defecation, and pain in and around the nape of neck with diagnosed pulmonary fibrosis. He scored 3 on a patient reported modified Medical Research Council (mMRC) dyspnea scale. Osteopathic examination reveals multiple somatic findings across the chest and abdominal region and treated by OMT. Pre- and post-intervention changes were assessed by the 13-item shortness of breath with daily activities (13iSOBDA). 27.2, 22, 16.4, and 11.8 were noted at the end of 1st, 2nd, 3rd, and 4th week of intervention, respectively, on 13iSOBDA while mMRC decreased from 3 to 1. OMT may be a feasible option in decreasing the symptoms of the PPF in the critical care outpatient department. PMID- 28808372 TI - Cardiac Herniation with Torsion after Right Pneumonectomy. PMID- 28808373 TI - Is Edaravone the Future of Free Radical Scavenging in Inflammatory States? PMID- 28808374 TI - Hypothermia in Organophosphate Compound Poisoning: Recognizing the Big Chill. PMID- 28808375 TI - Chemopreventive and Antioxidant Effect of Polyphenol Free Spirulina maxima and Its Hydrolyzed Protein Content: Investigation on Azoxymethane Treated Mice. AB - BACKGROUND: Spirulina maxima (Sm) is known to have nutritive value as well as a number of potentially useful biomedical properties. OBJECTIVES: The initial purpose of this report was to evaluate the inhibitory effect of the alga (without its polyphenol content), on the induction of azoxymethane (AOM)-induced colon aberrant crypts (AC) in mouse. Besides, we hydrolyzed the protein content of such mixture. Our second aim was to determine the inhibitory potential of this last plant mixture on the AOM-induced colon AC in mouse. Moreover, we also determined the effect of the two indicated Sm samples on the oxidative damage caused by AOM in the colon and liver of treated mice. MATERIALS AND METHODS: The experiment lasted 5 weeks. At the end, we registered the level of AC, nitric oxide, and the lipid and protein oxidation. RESULTS: Our results showed the following: (1) the carcinogen increased more than 18 times the amount of the AC found in the control group. (2) On the contrary, the two tested mixtures of Sm produced a significant reduction over this damage (about 45%). (3) The two tested Sm mixtures were generally able to reduce the oxidative stress markers although with variable effects which go from 59% to 100% with respect to the control mice. CONCLUSION: Therefore, the present report established that the tested Sm fractions have mouse colon anticarcinogenic potential, partially related with their antioxidant capacity. Our report also suggested the need to further evaluate specific Sm chemicals as chemopreventive agents. PMID- 28808376 TI - Isolation of Abscisic Acid from Korean Acacia Honey with Anti-Helicobacter pylori Activity. AB - BACKGROUND: Helicobacter pylori (H. pylori) is linked to the development of the majority of peptic ulcers and some types of gastric cancers, and its antibiotic resistance is currently found worldwide. OBJECTIVE: This study is aimed at evaluating the anti-H. pylori activity of Korean acacia honey and isolating the related active components using organic solvents. MATERIAL AND METHODS: The crude acacia honey was extracted with n-hexane, dichloromethane, ethyl acetate (EtOAc), and n-butanol. The EtOAc extract was subjected to octadecyl-silica chromatography. The extracts and fractions were then examined for anti-H. pylori activity using the agar well diffusion method. The antimicrobial activity of abscisic acid against H. pylori was investigated by determining the minimum inhibitory concentrations (MICs), minimum bactericidal concentrations (MBCs), and by performing a time-kill assay. RESULTS: Abscisic acid related to the botanical origins of acacia honey from Korea has been analyzed using ultra-performance liquid chromatography. The MICs and MBCs of abscisic acid were 2.7 +/- 1.3 and 6.9 +/- 1.9 MUg/mL, respectively. The bactericidal activity of abscisic acid (at 10.8 MUg/mL corresponding to 4 * MIC) killed the organism within 36-72 h. These results suggest that abscisic acid isolated from Korean acacia honey has antibacterial activity against H. pylori. CONCLUSION: Abscisic acid isolated from Korean acacia honey can be therapeutic and may be further exploited as a potential lead candidate for the development of treatments for H. pylori-induced infections. SUMMARY: The crude acacia honey was extracted with n-hexane, dichloromethane, EtOAc, and n-butanolThe EtOAc extract yielded eight fractions and four subfractions were subsequently obtained chromatographicallyAbscisic acid was isolated from one subfractionAll the solvent extracts and fractions showed antibacterial activity against H. pyloriAbscisic acid exhibited antibacterial activity against H. pylori. Abbreviations used: MeOH: Methanol; EtOAc: Ethyl acetate; TSB: Trypticase soy broth; MIC: Minimum inhibitory concentration; MBC: Minimum bactericidal concentration; CFU: Colony-forming units; UPLC: Ultra performance liquid chromatography; DAD: Diode array detector; UV: Ultraviolet; ODS: Octadecyl-silica; MS: Mass spectrometry; SE: Standard error. PMID- 28808377 TI - Anti-inflammatory Potential of Petiveria alliacea on Activated RAW264.7 Murine Macrophages. AB - BACKGROUND: Defense and protection to multiple harmful stimuli are the inflammation, when is self-amplified and uncontrolled is the basis of the pathogenesis of a wide variety of inflammatory illness. The aim of this study was to evaluate if Petiveria alliacea could attenuate inflammation in a murine model of RAW264 macrophages the involved model and its involved mechanism. MATERIALS AND METHODS: The ethanol extract from P. alliacea was precipitated with water and supernatant was used for this study (PW). The anti-inflammatory effects of PW were investigated through evaluating of the production of several cytokines, chemokines, and expression of nuclear factor-kappa B (NF-kappaB) in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Also was determined the ability to decrease the oxidative stress in RAW264.7 cells with carboxy-2',7' dichloro-dihydro-fluorescein diacetate. RESULTS: PW significantly suppress the secretion of prostaglandin E2, leukotriene C4, interleukin (IL)-1 beta, IL-6, IL 10, interferon gamma nitric oxide (NO), inducible NO synthase, IL-1 beta, IL-4, in RAW264.7 cells in a dose-dependent manner. In addition, PW also markedly inhibited the transcriptional activity of NF-kappaB. PW produced significant anti inflammatory activity through inhibiting the production of inflammatory mediators through the NF-kappaB inactivation in the LPS-stimulated RAW24.7 cells. CONCLUSIONS: PW exerts significant antioxidant and anti-inflammatory activities, and this effect can be attributed in part, to the presence of dibenzyl disulfide, dibenzyl trisulfide pinitol, coumarin, myricetin, glutamyl-S-benzyl cysteine, and petiveriins A and B. SUMMARY: Treatment with ethanol extract from Petiveria alliacea which was previously precipitated with water and supernatant (PE) was tested in LPS-stimulated RAW264.7 cells. PE suppressed the level of oxidative stress and the induction of proinflammatory mediators, as PGE2, LTC4, IL-1 beta, IL-6, IL-10, IFN- NO, iNOS, IL-1 beta, IL-4, in RAW264.7 macrophages through NF-B inactivation. These findings suggest that P. alliacea affords promising therapeutic in inflammatory diseases. Abbreviation used: COX-2: Ciclooxigenasa 2; DCFHDA: Carboxy-2',7'-dichloro-dihydro-fluorescein diacetate; DMEM: Dulbecco's modified eagle's medium; FBS: Fetal bovine serum; HSP70: Heat shock protein; IFN gamma: Interferon gamma; IL-1 beta: Interleukin 1 beta, IL-6: Interleukin 6; IL 10: Interleukin 10; IL-4: Interleukin 4; iNOS: Nitric oxide synthase; KCl: Potassium chloride; LPS: Lipopolysaccharides; LTC4: leukotriene C 4; MgCl2: Magnesium chloride; MTT: 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide; NF-kappaB: Nuclear factor kappa-light-chain-enhancer of activated B cells or transcriptional activity of nuclear factor-kB; NO: Nitric oxide; PBS: Phosphate-buffered saline; PGE2: Prostaglandin E2, PMSF: Phenylmethylsulfonyl fluoride; PTC: Chloroform extract from Petiveria alliacea; PE: Ethanol extract from Petiveria alliacea; PTH: Hexane extract from Petiveria alliacea; PW: Supernatant of PTE precipitated with water; RAW264.7: Cell line murine macrophages; ROS: Reactive oxygen species; TNF-alpha: Tumor necrosis factor. PMID- 28808378 TI - Rutamarin, an Active Constituent from Ruta angustifolia Pers., Induced Apoptotic Cell Death in the HT29 Colon Adenocarcinoma Cell Line. AB - BACKGROUND: Ruta angustifolia Pers. is a perennial herb that is cultivated worldwide, including Southeast Asia, for the treatment of various diseases as traditional medicine. OBJECTIVE: The purpose of the study was to identify an active principle of R. angustifolia and to investigate its effect on the HT29 cell death. MATERIALS AND METHODS: The methanol and fractionated extracts (hexane, chloroform, ethyl acetate, and water) of R. angustifolia Pers. were initially investigated for their cytotoxic activity against two human carcinoma cell lines (MCF7 and HT29) and a normal human colon fibroblast cell line (CCD 18Co) using sulforhodamine B cytotoxicity assay. Eight compounds including rutamarin were isolated from the active chloroform extract and evaluated for their cytotoxic activity against HT29 human colon carcinoma cell line and CCD 18Co noncancer cells. Further studies on the induction of apoptosis such as morphological examinations, biochemical analyses, cell cycle analysis, and caspase activation assay were conducted in rutamarin-treated HT29 cells. RESULTS: Rutamarin exhibited remarkable cytotoxic activity against HT29 cells (IC50 value of 5.6 MUM) but was not toxic to CCD-18Co cells. The morphological and biochemical hallmarks of apoptosis including activation of caspases 3, 8, and 9 were observed in rutamarin-treated HT29 cells. These may be associated with cell cycle arrest at the G0/G1 and G2/M checkpoints, which was also observed in HT29 cells. CONCLUSIONS: The present study describes rutamarin-induced apoptosis in the HT29 cell line for the first time and suggests that rutamarin has the potential to be developed as an anticancer agent. SUMMARY: Rutamarin was cytotoxic to HT29 colon cancer cells but exerted no damage to normal colon cellsRutamarin induced morphological and biochemical hallmarks of apoptosis in HT29 cellsRutamarin induced cell cycle arrest at the G0/G1 and G2/M checkpoints in a dose-dependent manner in HT29 cellsRutamarin activated caspases 3, 8, and 9 in a dose-dependent manner in HT29 cells. Abbreviations used: ACN: Acetonitrile, ANOVA: One-way analysis of variance, BrdU: Bromodeoxyuridine, 13C-NMR: Carbon-13 Nuclear magnetic resonance, CAD: Caspase-activated endonuclease, CCD-18Co: Human colon normal, DLD1: Human Duke's type C colorectal adenocarcinoma, DMRT: Duncan's multiple range test, DMSO: Dimethyl sulfoxide, DNA: Deoxyribonucleic acid, DR4/5: Death receptor 4/5 protein, EMEM: Eagle's minimum essential media, FBS: Fetal bovine serum, FITC Annexin V: Annexin V conjugated with fluorescein isothiocyanate, FITC-DEVD-FMK: Fluorescein isothiocyanate conjugate of caspase inhibitor Asp-Glu-Val-Asp-fluoromethyl ketone, FITC-IETD-FMK: Fluorescein isothiocyanate conjugate of caspase inhibitor Ile-Glu-Thr-Asp-fluoromethyl ketone, FITC-LEHD-FMK: Fluorescein isothiocyanate conjugate of caspase inhibitor Leu-Glu-His-Asp-fluoromethyl ketone, G0: Quiescent phase of cell cycle, G1: Gap 1 phase of cell cycle, G2: Gap 2 phase of cell cycle, GC-MS: Gas chromatography mass spectrometry, HeLa: Human cervical adenocarcinoma, HPLC: High performance liquid chromatography, HT29: Human colon adenocarcinoma, Huh7.5: Human hepatocellular carcinoma, IC50: Half maximal inhibitory concentration, KSHV: Kaposi's sarcoma-associated herpesvirus, M phase: Mitotic phase of cell cycle, MCF7: Human breast adenocarcinoma, NMR: Nuclear magnetic resonance, PBS: Phosphate-buffered saline, PI: Propidium iodide, RNase: Ribonuclease, rt: Retention time, S phase: Synthesis phase of cell cycle, SD: Standard deviation, SRB: Sulforhodamine B, TCA: Trichloroacetic acid, TLC: Thin layer chromatography, TNF-R1: Tumor necrosis factor receptor 1 protein, TUNEL: Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling, UV: Ultraviolet. PMID- 28808379 TI - Screening of Fruits of Seven Plants Indicated for Medicinal Use in Iraq. AB - INTRODUCTION: Coumarins exert many biological effects in humans, animals, and plants, which make the evaluation of their biological activities and study of their role in ethnomedicine highly valued. OBJECTIVES: Here, we selected seven plants which have ethnopharmacological use as antimicrobial in Iraq and the aims were to quantify the two structural isomers bergapten and methoxsalen in their seeds, to evaluate the antibacterial activities against several clinical isolates, and to isolate bergapten and methoxsalen from Ammi majus. MATERIALS AND METHODS: Seven plants were extracted by petroleum ether (PE) and ethanol (EtOH). Bergapten and methoxsalen were separated and purified by preparative thin-layer chromatography. Quantification of the furanocoumarins has been conducted by high performance liquid chromatography, and all the plant extracts and pure compounds were checked for antibacterial activities utilizing alamar blue microplate assay. RESULTS: Cuminum cyminum was deprived of bergapten and methoxsalen and methoxsalen was not detected from Apium graveolens. Bergapten was abundant in PE more than in EtOH; on the other hand, EtOH was rich in methoxsalen. The separation of the two structural isomers was performed using normal phase chromatography and ultraviolet light as an indicator. All extracts showed weak to moderate antibacterial activities against Gram-positive isolates which were more sensitive than the negative ones. C. cyminum extract was least active, uncover the antibacterial role of bergapten and methoxsalen. CONCLUSION: These findings support the medicinal use of seeds of seven plants from Apiaceae family and quantify the two pharmacologically important furanocoumarins (bergapten and methoxsalen). SUMMARY: This study was conducted to evaluate the antibacterial activities of seven plants seeds used in local medicine in Iraq. High-performance liquid chromatography was used to quantify bergapten and xanthotoxin in non-polar and polar extracts of these seeds. This study supports the medicinal use of these plants and clarifies the role of bergapten and xanthotoxin in antibacterial activities of these plants. Abbreviations used: EtOH: Ethanol; MIC: Minimum inhibitory concentration; PE: Petroleum ether; Rf: Retardation factor; Rt: Retention time. PMID- 28808380 TI - Identification and Analysis of Jasmonate Pathway Genes in Coffea canephora (Robusta Coffee) by In Silico Approach. AB - BACKGROUND: Coffea canephora is the commonly cultivated coffee species in the world along with Coffea arabica. Different pests and pathogens affect the production and quality of the coffee. Jasmonic acid (JA) is a plant hormone which plays an important role in plants growth, development, and defense mechanisms, particularly against insect pests. The key enzymes involved in the production of JA are lipoxygenase, allene oxide synthase, allene oxide cyclase, and 12-oxo phytodienoic reductase. There is no report on the genes involved in JA pathway in coffee plants. OBJECTIVE: We made an attempt to identify and analyze the genes coding for these enzymes in C. canephora. MATERIALS AND METHODS: First, protein sequences of jasmonate pathway genes from model plant Arabidopsis thaliana were identified in the National Center for Biotechnology Information (NCBI) database. These protein sequences were used to search the web-based database Coffee Genome Hub to identify homologous protein sequences in C. canephora genome using Basic Local Alignment Search Tool (BLAST). RESULTS: Homologous protein sequences for key genes were identified in the C. canephora genome database. Protein sequences of the top matches were in turn used to search in NCBI database using BLAST tool to confirm the identity of the selected proteins and to identify closely related genes in species. The protein sequences from C. canephora database and the top matches in NCBI were aligned, and phylogenetic trees were constructed using MEGA6 software and identified the genetic distance of the respective genes. The study identified the four key genes of JA pathway in C. canephora, confirming the conserved nature of the pathway in coffee. The study expected to be useful to further explore the defense mechanisms of coffee plants. CONCLUSION: JA is a plant hormone that plays an important role in plant defense against insect pests. Genes coding for the 4 key enzymes involved in the production of JA viz., LOX, AOS, AOC, and OPR are identified in C. canephora (robusta coffee) by bioinformatic approaches confirming the conserved nature of the pathway in coffee. The findings are useful to understand the defense mechanisms of C. canephora and coffee breeding in the long run. SUMMARY: JA is a plant hormone that plays an important role in plant defense against insect pests. Genes coding for the 4 key enzymes involved in the production of JA viz., LOX, AOS, AOC and OPR were identified and analyzed in C. canephora (robusta coffee) by in silico approach. The study has confirmed the conserved nature of JA pathway in coffee; the findings are useful to further explore the defense mechanisms of coffee plants. Abbreviations used:C. canephora: Coffea canephora; C. arabica: Coffea arabica; JA: Jasmonic acid; CGH: Coffee Genome Hub; NCBI: National Centre for Biotechnology Information; BLAST: Basic Local Alignment Search Tool; A. thaliana: Arabidopsis thaliana; LOX: Lipoxygenase, AOS: Allene oxide synthase; AOC: Allene oxide cyclase; OPR: 12 oxo phytodienoic reductase. PMID- 28808381 TI - Characterization, Antibacterial and Antioxidant Properties of Silver Nanoparticles Synthesized from Aqueous Extracts of Allium sativum, Zingiber officinale, and Capsicum frutescens. AB - BACKGROUND: Herbal drug delivery is limited by poor solubility and bioavailability which can be overcome with suitable nanomaterials that will enhance their pharmacokinetics and performance. OBJECTIVE: This study aimed to analyze the synthesis, characterization, and biological activities of silver nanoparticles (AgNPs) from three spices. MATERIALS AND METHODS: AgNPs were prepared using 0.1 M silver nitrate and aqueous extracts of Allium sativum L. (garlic), Zingiber officinale Rosc. (ginger), and Capsicum frutescens L. (cayenne pepper). The AgNPs were characterized using ultraviolet-visible (UV-Vis) spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy dispersive X-ray, X-ray diffraction (XRD), and Fourier transform infrared (FTIR) spectroscopy. RESULTS: The AgNPs were formed within an hour of the reaction and showed maximum UV-Vis absorption in the 375-480 nm range. SEM and TEM revealed well-dispersed spherical particles with little agglomeration, average sizes of 3-6 nm, 3-22 nm, and 3-18 nm for garlic, ginger, and cayenne pepper, respectively. FTIR showed that amine, protein, phenolic, aromatic, and alkynes groups contributed to AgNP synthesis and XRD confirmed their crystalline and face-centered cubic nature. Antibacterial action of the AgNPs was in the following order: ginger (minimum inhibitory concentration [MIC] <25 MUg/mL) > garlic> cayenne pepper (MIC 125 MUg/mL). Antioxidant action showed cayenne pepper > ginger > garlic (inhibitory concentration 50% [IC50]: 40, 240, and 250 MUg/mL, respectively) against 2,2-Azino-bis (3-ethylbenzthiazoline-6 sulfonic acid) and garlic > cayenne pepper > ginger (IC50: <31.25, 40, and 120 MUg/mL, respectively) against 1,1-diphenyl-2-picrylhydrazyl. CONCLUSION: Optimization of this green synthesis would support the production of AgNPs with great therapeutic potentials. SUMMARY: The synthesis, characterization, and biological activities of silver nanoparticles (AgNPs) from garlic, ginger and cayenne pepper were evaluatedThe AgNPs formed were characterized using UV-Vis spectroscopy, SEM and TEM microscopy, as well as EDX, XRD and FTIR spectroscopy AgNPs were well dispersed with spherical shapes and average sizes of 3-6nm, 3 22nm and 3-18 nm for garlic, ginger and cayenne pepper respectivelyAmine, protein, phenolic and alkyne groups were revealed as the capping agents for the nanoparticlesThe silver nanoparticles were confirmed to be crystalline with characteristic face centred cubic natureThe antibacterial and antioxidant activities of the AgNPs confirmed the therapeutic potential of the AgNPs. Abbreviations used: AgNPs: Silver nanoparticles; UV-Vis: ultraviolet-visible; SEM: Scanning electron microscopy; TEM: Transmission electron microscopy; EDX: Energy dispersive X-ray; XRD: X-ray diffraction; FTIR: Fourier transform infrared; GaNPs: Garlic nanoparticles; GiNPs: Ginger nanoparticles; C.PeNPs: Cayenne pepper nanoparticles; FCC: Face centred cubic; SPR: Surface Plasmon resonance; ABTS-2: 2-Azino-bis (3-ethylbenzthiazoline-6-sulfonic acid); DPPH-1: 1 diphenyl-2-picrylhydrazyl. PMID- 28808382 TI - Allium sativum Constituents Exhibit Anti-tubercular Activity In vitro and in RAW 264.7 Mouse Macrophage Cells Infected with Mycobacterium tuberculosis H37Rv. AB - BACKGROUND: Long duration of treatment, side-effects of currently used anti tubercular drugs and emergence of drug-resistant forms of Mycobacterium tuberculosis (MTB) warrants the need to develop new drugs to tackle the scourge of tuberculosis (TB). Garlic is an edible plant reported to have anti-tubercular activity. However, previous researches on anti-tubercular effect of garlic were focused mostly on preliminary in vitro screening. OBJECTIVE: To identify constituents responsible for anti-tubercular activity of thiosulfinate-derivative rich extract of garlic (GE) and to evaluate activity of the most active constituent in RAW 264.7 mouse macrophage cells infected with M. tuberculosis H37Rv (MTBH). MATERIALS AND METHODS: In the present study, we have isolated eight compounds from GE by flash chromatography. The isolated compounds were characterized by 1H nuclear magnetic resonance spectroscopy, liquid chromatography-mass spectrometry and Fourier transform infrared spectroscopy. Individual isolates and GE were screened for activity against MTBH by Resazurin Microtitre Plate Assay (REMA). RESULTS: Anti-tubercular activity of GE was superior to that of isolates when evaluated by REMA, possibly due to synergism amongst the constituents of GE. Cytotoxicity of GE was evaluated in RAW 264.7 mouse macrophage cells and it was observed that GE had a favorable selectivity index (>10). Therefore, anti-tubercular activity of GE was further evaluated by intracellular macrophage infection model. GE demonstrated concentration-dependent activity in macrophages infected with MTBH. CONCLUSION: This is the first report on intracellular anti-tubercular activity of any extract of garlic or its components. Appreciable intracellular anti-tubercular activity of GE in macrophages combined with low cytotoxicity makes it a suitable candidate for further development as an anti-tubercular agent. SUMMARY: Thiosulfinate derivative rich extract of Allium sativum showed better activity than its isolated constituents against Mycobacterium tuberculosis H37Rv.(MTBH) when evaluated by Resazurin Microtitre Plate AssayThe extract showed least cytotoxic potential against RAW 264.7 mouse macrophage cells as compared to rifampicin, isoniazid and ethambutol when evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. The extract had an appreciable selectivity indexExtract showed appreciable activity in RAW 264.7 mouse macrophage cells infected with MTBH, indicating its potential to be developed further as an anti tubercular agent that can be administered as an adjunct to the existing anti tubercular drug regimen. Abbreviations used: TB: Tuberculosis, MTB: Mycobacterium tuberculosis, MTBH: Mycobacterium tuberculosis H37Rv, GE: Thiosulfinate derivative rich extract of garlic, REMA: Resazurin Microtitre Plate Assay, VD: Vinyldithiin, CFU: Colony forming unit, 1H NMR: 1H nuclear magnetic resonance spectroscopy, FT-IR: Fourier transform-infrared spectroscopy, LC-MS: Liquid chromatography-mass spectrometry, IC50: Concentration required to inhibit the cells by 50%, ANOVA: Analysis of variance. PMID- 28808383 TI - Chemopreventive Potential of Major Flavonoid Compound of Methanolic Bark Extract of Saraca asoca (Roxb.) in Benzene-induced Toxicity of Acute Myeloid Leukemia Mice. AB - BACKGROUND: Saraca asoca (SA) (Roxb.) is one of the folk medicinal plants found in India, Bangladesh, and Sri Lanka. Its major biological activity appears due to the presence of flavonoid group of compounds in its bark extract. OBJECTIVE: In this study, our research aims to analyze the chemopreventive effect of flavonoids, especially a natural phenol catechin present in the bark methanolic extract of SA on acute myeloid leukemia (AML) mice. MATERIALS AND METHODS: The total bark extract was partitioned and analyzed on thin-layer chromatography (TLC) plate. The yellow-brown material of spot 4 was analyzed and identified as catechin. The yellowish brown material (YBM) was tested for their chemopreventive potential. An in vivo AML mice model was used to test the efficacy. Hematological parameters (Hb %, red blood cell, and white blood cell count), expression of cell cycle regulatory proteins, and DNA fragmentation analysis were performed. RESULTS: After treatment of benzene-exposed mice with the major flavonoid compound, namely catechin, the above parameters increase significantly (P < 0.05). There was an upregulation of p53 and p21, caspase 11 myeloperoxidase, bcl2, and CYP2EI in catechin-treated group. DNA was less fragmented in flavonoid treated group compared to that of control (P <= 0.05). The present study indicates that the secondary metabolites of SA methanolic bark extract, comprising flavonoid catechin as major constituents, have modulatory effect in cell cycle deregulation and hematological abnormalities induced by benzene in mice. CONCLUSIONS: Our data suggest that catechin from methanolic bark extract of SA effectively attenuates benzene-induced secondary AML in bone marrow, which is likely associated with the anticell cycle deregulation properties of this flavan 3-ol. This study was supported by the observation that catechin (YBM), like doxorubicin, can act as the neutralizer and protector of mortality in cancer cases. SUMMARY: The catechin from methanolic bark extract of Saraca asoca has chemoprotective activity in benzene-induced secondary acute myeloid leukemia.(AML) in bone marrowHematological parameters, structural analysis of DNA showed that the purified catechin attenuates the conditions responsible for the development of AMLThe purified flavonol, catechin has a modulatory effect on different cell cycle deregulations induced by benzene in AML model. PMID- 28808384 TI - Molecular Authentication of the Traditional Medicinal Plant "Lakshman Booti" (Smithia conferta Sm.) and Its Adulterants through DNA Barcoding. AB - BACKGROUND: Smithia conferta Sm. is an annual herb widely used in Indian traditional medical practice and commonly known as "Lakshman booti" in Sanskrit. Morphological resemblance among the species of genus Smithia Aiton. leads to inaccurate identification and adulteration. This causes inconsistent therapeutic effects and also affects the quality of herbal medicine. AIM: This study aimed to generate potential barcode for authentication of S. conferta and its adulterants through DNA barcoding technique. MATERIALS AND METHODS: Genomic DNA extracted from S. conferta and its adulterants was used as templates for polymerase chain reaction amplification of the barcoding regions. The amplicons were directed for sequencing, and species identification was conducted using BLASTn and unweighted pair-group method with arithmetic mean trees. In addition, the secondary structures of internal transcribed spacer (ITS) 2 region were predicted. RESULTS: The nucleotide sequence of ITS provides species-specific single nucleotide polymorphisms and sequence divergence (22%) than psbA-trnH (10.9%) and rbcL (3.1%) sequences. The ITS barcode indicates that S. conferta and Smithia sensitiva are closely related compared to other species. CONCLUSION: ITS is the most applicable barcode for molecular authentication of S. conferta, and further chloroplast barcodes should be tested for phylogenetic analysis of genus Smithia. SUMMARY: The present investigation is the first effort of utilization of DNA barcode for molecular authentication of S. conferta and its adulterants. Also, this study expanded the application of the ITS2 sequence data in the authentication. The ITS has been proved as a potential and reliable candidate barcode for the authentication of S. conferta. Abbreviations used: BLASTn: Basic Local Alignment Search Tool for Nucleotide; MEGA: Molecular Evolutionary Genetic Analysis; EMBL: European Molecular Biology Laboratory; psbA-trnH: Photosystem II protein D1- stuctural RNA: His tRNA gene; rbcL: Ribulose 1,5 bi-phosphate carboxylase/oxygenase large subunit gene. PMID- 28808385 TI - Anti-inflammatory Effect of Etlingera pavieana (Pierre ex Gagnep.) R.M.Sm. Rhizomal Extract and Its Phenolic Compounds in Lipopolysaccharide-Stimulated Macrophages. AB - BACKGROUND: In our continuing search for anti-inflammatory agents from Thai herbs, Etlingera pavieana (Pierre ex Gagnep.) R.M.Sm. showed potent inhibition on nitric oxide (NO) production in lipopolysaccharide (LPS)-induced macrophages. However, the mechanism behind its inhibitory effect has not been yet explored, and little is known regarding its bioactive compounds responsible for the anti inflammatory effect. OBJECTIVE: In the present study, anti-inflammatory effect of hexane, ethyl acetate, and water fractions of rhizomal ethanol extracts of E. pavieana was evaluated for their inhibition on NO production and mechanism in LPS stimulated macrophages. Active compounds responsible for such anti-inflammatory activity were identified. MATERIALS AND METHODS: Inhibitory activities on NO production were performed in LPS-stimulated RAW264.7 macrophage. Cytotoxicity of plant extracts was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay, mRNA and protein expressions by reverse transcription-polymerase chain reaction and Western blotting analysis, respectively. Anti-inflammatory compounds were isolated by activity-guided isolation technique using column chromatography. RESULTS: Ethyl acetate fraction of E. pavieana (EPE) showed the most potent inhibitory effect on NO production in macrophages. EPE significantly decreased NO production and inhibited inducible nitric oxide synthase (iNOS) protein and mRNA expression in a dose-dependent manner. Furthermore, the level of nuclear factor-kappa B p65 subunit was markedly reduced in activated cells treated with EPE. Four phenolic compounds, 4 methoxycinnamyl alcohol (1), trans-4-methoxycinnamaldehyde (2), 4-methoxycinnamyl p-coumarate (3), and p-coumaric acid (4), were obtained from bioactivity-guided isolation technique. CONCLUSIONS: The anti-inflammatory property contained in E. pavieana rhizome extract and conferred through inhibition of iNOS expression, and NO formation provides scientific evidence and support for the development of new anti-inflammatory agents based on extracts from this plant. SUMMARY: Ethyl acetate fraction (EPE) of Etlingera pavieana showed the most potent inhibitory effect on NO production in LPS-induced macrophagesFour phenolic compounds, 4 methoxycinnamyl alcohol (1), trans-4-methoxycinnamaldehyde (2), 4-methoxycinnamyl p-coumarate (3) and p-coumaric acid (4), responsible for the anti-inflammatory effect of EPE were isolated. Abbreviations used: EPE: Ethyl acetate fraction of Etlingera pavieana; EPH: Hexane fraction of Etlingera pavieana; EPW: Water fraction of Etlingera pavieana; NO: Nitric oxide (NO); LPS: Lipopolysaccharide; iNOS: Inducible nitric oxide synthase (iNOS); MTT: 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide; NF-kappaB: Nuclear factor-kappa B; DMSO: Dimethyl sulfoxide; EtOAc: Ethylacetate; MeOH: Methanol; AG: Aminoguanidine; DCM: Dichloromethane; MCA: 4-methoxycinnamyl alcohol; MCD: trans-4 methoxycinnamaldehyde; MCC: 4-methoxycinnamyl p-coumarate; CM: p-coumaric acid. PMID- 28808386 TI - In vitro Inhibitory Effects of Andrographis paniculata, Gynura procumbens, Ficus deltoidea, and Curcuma xanthorrhiza Extracts and Constituents on Human Liver Glucuronidation Activity. AB - BACKGROUND: Andrographis paniculata, Gynura procumbens, Ficus deltoidea and Curcuma xanthorrhiza are commonly consumed as herbal medicines. However their effects on human liver glucuronidation activity are not yet evaluated. OBJECTIVE: In this study, we evaluate the inhibitory Effects of Andrographis paniculata, Gynura procumbens, Ficus deltoidea and Curcuma xanthorrhiza extracts and their constituents on human liver glucuronidation activity. MATERIALS AND METHODS: Herbal extracts (aqueous, methanolic and ethanolic extracts) and their constituents were incubated with human liver microsomes with the addition of UDPGA to initiate the reaction. Working concentrations of herbal extracts and their constituents ranged from 10 MUg/mL to 1000 MUg/mL and 10 MUM to 300 MUM respectively. IC50 was determined by monitoring the decrement of glucuronidation activity with the increment of herbal extracts or phytochemical constituent's concentrations. RESULTS: All herbal extracts inhibited human liver glucuronidation activity in range of 34.69 MUg/mL to 398.10 MUg/mL whereas for the constituents, only xanthorrhizol and curcumin (constituents of Curcuma xanthorrhiza) inhibited human liver glucuronidation activity with IC50 of 538.50 and 32.26 MUM respectively. CONCLUSION: In the present study, we have proved the capabilities of Andrographis paniculata, Gynura procumbens, Ficus deltoidea and Curcuma xanthorrhiza to interfere with in vitro glucuronidation process in human liver microsomes. SUMMARY: This study documented the capabilities of Andrographis paniculata, Gynura procumbens, Ficus deltoidea and Curcuma xanthorrhiza to inhibit human liver glucuronidation activity which may affect the metabolism of therapeutic drugs or hazardous toxicants that follow the same glucuronidation pathway. Abbreviations used: UGT: Uridine 5'-diphospho-glucuronosyltransferase; 4 MU: 4-methylumbelliferone; IC50: Half Maximal Inhibitory Concentration; Km: Michaelis constant; Vmax: Maximum velocity. PMID- 28808387 TI - New Apigenin Glycoside, Polyphenolic Constituents, Anti-inflammatory and Hepatoprotective Activities of Gaillardia grandiflora and Gaillardia pulchella Aerial Parts. AB - BACKGROUND: Gaillardia grandiflora Hort. ex Van Houte and Gaillardia pulchella Foug are flowering plants widely cultivated in Egypt for their ornamental value. Previous reports demonstrated that sesquiterpene derivatives represent the major compounds in both species. Moreover, only few flavones were identified from genus Gaillardia and few studies on the cytotoxicity of G. pulchella were found. AIM OF THE STUDY: Investigation of the phenolic constituents of the aerial parts of both species and evaluation of their anti-inflammatory and hepatoprotective activities. MATERIALS AND METHODS: The 80% aqueous methanol extracts (AME) were prepared for both plants and evaluated for their biological activities. Phytochemical investigation of both extracts resulted in isolation of twelve compounds, which have been identified on the basis of ultraviolet, 1D and 2D nuclear magnetic resonance spectroscopy and negative ESI-MS. RESULTS: The new 8 hydroxyapigenin 6-O-beta-D-apiofuranosyl-(1'''->6'')-C-beta-D-4C1-glucopyranoside was isolated from G. grandiflora for the first time in nature, along with schaftoside, luteolin 6-C-beta-D-4C1-glucopyranoside 8-methyl ether, apigenin 6-C beta-D-4C1-glucopyranoside 8-methyl ether, isoorientin, isovitexin, 6 methoxyluteolin and hispidulin, as well as vicenin-2, vitexin, luteolin and apigenin, which were isolated from G. pulchella together with 6-methoxyluteolin. Furthermore, the AME of both species were found to be nontoxic to mice and exhibited significant anti-inflammatory and hepatoprotective activities in dose dependent manner. CONCLUSION: Current results shed light on the phenolic constituents of G. grandiflora and G. pulchella aerial parts and the safety of the AME of both species, in addition to their significant anti-inflammatory and hepatoprotective activities. Both plant species may be promising candidates for natural anti-inflammatory and hepatoprotective drugs. SUMMARY: Phytochemical investigation of Gaillardia grandiflora and Gaillardia pulchella 80% aqueous methanol extracts of the aerial parts led to the isolation of twelve compoundsThe new compound 8-hydroxyapigenin 6-O-beta-D-apiofuranosyl-(1''''->6'')-C-beta-D-4C1 glucopyranoside was isolated from G. grandiflora for the first time in natureSchaftoside, luteolin 6-C-beta-D-4C1-glucopyranoside 8-methyl ether, apigenin 6-C-beta-D-4C1-glucopyranoside 8-methyl ether, isoorientin, isovitexin, 6-methoxyluteolin and hispidulin were isolated from G. grandifloraVicenin-2, vitexin, luteolin, apigenin and 6-methoxyluteolin were isolated from G. pulchellaThe extracts of both species were nontoxic to mice up to 5 g/kg body weightBoth extracts exhibited significant anti-inflammatory and hepatoprotective activities in dose dependent manner Abbreviations used: ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AME: The 80% aqueous methanol extract of G. grandiflora or G. pulchella aerial parts; AST: Aspartate aminotransferase; br d: Broad doublet; Comp-PC: Comparative paper chromatography; d: Doublet; 2D PC: Two-dimensional paper chromatography; DMSO-d6: Deuterated dimethyl sulfoxide; G.: Gaillardia; GPx: Glutathione peroxidase; GRd: Glutathione reductase; GSH: glutathione; GST: Glutathione-S-transferase; J: Nuclear spin-spin coupling constant; m: Multiplet; [M-H]-: Molecular ion peak; MDA: Malondialdehyde; m/z: Mass/charge ratio; NO: Nitric oxide; p: Probability; PC: Paper chromatography; Rf: Retention flow; rpm: Rotation per minute; s: Singlet; SDE: The ethanol extract of Scoparia dulcis; SE: Standard error; SOD: Superoxide dismutase; TMS: Tetramethylsilane; lambdamax: Maximum fluorescence emission wavelength. PMID- 28808388 TI - Caesalpinia Crista Linn. Induces Protection against DNA and Membrane Damage. AB - BACKGROUND: Caesalpinia crista is a medicinal herb used to cure various ailments in subtropical and tropical regions of Southeast Asia. OBJECTIVE: The objective of this evaluation of C. crista against free radical induced DNA and erythrocyte damage. MATERIALS AND METHODS: The profiles of polyphenol and flavonoid were quantified through reversed-phase high-performance liquid chromatography. Free radical induced DNA and membrane damage were performed using H2O2 as oxidative agent. RESULTS: The total polyphenol content of C. crista leaf ethyl acetate extract (CcEA) was 94.5 +/- 3.8 mg/gGAE, CcME (C. crista leaf methanol extract) was 52.7 +/- 2.8 mg/gGAE, and CcWE (C. crista leaf Water extract) was 31.84 +/- 1.8 mg/gGAE. Total flavonoid content of CcEA was 60.46 +/- 2.3 mg/gQE, CcME was 46.26 +/- 1.8 mg/gQE, and CcWE was 20.47 +/- 1.1 mg/gQE. The extracts also exhibited good antioxidant activity as confirmed by 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid), hydroxyl scavenging, reducing power, and total antioxidant assays. Among the three extracts, CcEA and CcME showed better protection against red blood cell (RBC) hemolysis and DNA damage as confirmed by electrophoretic study. Further, Scanning electron micrograph data showed that CcEA revealed the free radical induced structural alterations in RBC. CONCLUSION: These findings suggest that C. crista contains bioactive molecules and can inhibit oxidative stress and can be source of further study to use this in herbal medicine. SUMMARY: ROS are generated under normal biological systems. These ROS generated can be scavenged by endogenous and exogenous cellular mechanisms. Environmental stress, radiation, smoke etc. elevates ROS dramatically. This leads to significant damage to cellular biomolecules like DNA and cell structures. Plants as a large reservoir of drugs for protecting DNA and cell structures from oxidative stress. Polyphenols present in the C. crista extracts acts through several mechanisms to quench free radicals. Extracts exhibited potent antioxidant properties and also protected DNA and cell membrane from oxidative damage. Hence this can be used in herbal medicine for treating oxidative stress mediated diseases. Abbreviations used: ABTS: 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid); CcEA: C. crista leaf ethyl acetate extract; CcME: C. crista leaf methanol extract; CcWE: C. crista leaf Water extract; DPPH: 2,2-diphenyl-1-picrylhydrazyl; GAE: Gallic acid Equivalent; H2O2: Hydrogen Peroxide; QE: Quercetin Equivalent; RNS: Reactive Nitrogen Spevcies; ROS: Reactive Oxygen Species; SEM: Scanning Electron Microscope. PMID- 28808389 TI - Simultaneous Determination of Four Compounds, Campesterol, Emodin8-O-beta-D Glucopyranoside, Quercetin, and Isoquercitrin in Reynoutria sachalinensis by High performance Liquid Chromatography-Diode Array Detector. AB - BACKGROUND: Reynoutria sachalinensis is a well-known and used herbal medicine to treatment of arthralgia, jaundice, amenorrhea, coughs, carbuncles, and sores. OBJECTIVE: We have developed high-performance liquid chromatography analysis method for simultaneous determination of isolated four compounds, campesterol, emodin8-O-beta-D-glucopyranoside, quercetin, and isoquercitrin from R. sachalinensis is. MATERIALS AND METHODS: The four compounds were separated on Shiseido C18 column (S-5 MUm, 4.6 mm I.D. *250 mm) at a column temperature of 25 degrees C. The mobile phase composed of water and methanol with gradient elution system, and flow rate is 1.0 ml/min. The detection wavelength was set at 205 nm. RESULTS: Validation of this analytical method was evaluated by linearity, precision, and accuracy test. This established method had good linearity (R2 > 0.997). The relative standard deviation values of intra- and inter-day testing were indicated that <2%, and accuracy is 91.66%-103.31% at intraday and 91.69% 103.31% at intraday. The results of recovery test were 92.60%-108.99%. CONCLUSION: In these results, developed method was accurate and reliable to the quality evaluation of campesterol, emodin 8-O-beta-D-glucopyranoside, quercetin, and isoquercitrin isolated from R. sachalinensis. SUMMARY: We have developed high performance liquid analysis method for simultaneous determination of 4 compounds of Reynoutria sachalinensis. Abbreviations used: HPLC: High-performance liquid chromatography, DAD: Diode array detector, LOD: Limit of detection, LOQ: Limit of quantitation, ICH: International Conference on Harmonisation. PMID- 28808390 TI - Immunomodulatory, Cytotoxicity, and Antioxidant Activities of Roots of Ziziphus mauritiana. AB - AIMS: The study is conducted to evaluate the immunomodulatory, cytotoxicity, and antioxidant potential of Ziziphus mauritiana (Rhamnaceae). Phytochemical analysis of Z. mauritiana revealed the presence of alkaloids, anthraquinone glycoside, cardiac glycoside, saponin, tannin, and flavonoids. METHODOLOGY: The cytotoxicity of the plant Z. mauritiana was evaluated by brine shrimp lethality test. Antioxidant parameters such as superoxide dismutase (SOD), total antioxidant capacity (T-AOC), and malondialdehyde (MDA) levels were calculated in the plasma of rats after chronic administration of 400 mg/kg of Z. mauritiana for 6 weeks. RESULTS: The dichloromethane extract of the plant exhibited significant immunomodulatory activity, with inhibitory concentration 50% of 55.43 +/- 7.9. The dichloromethane extracts of the plant showed 70% mortality at concentration 1000 MUg/ml. SOD and T-AOC levels were increased while MDA level in the plasma was reduced in the plasma of rats treated with dichloromethane Z. mauritiana. CONCLUSION: This can be deduced that the root of Z. mauritiana has immunomodulatory, cytotoxic, and antioxidant potential. SUMMARY: Roots of Z. mauritiana was exhibited immunomodulator, cytotoxic and antioxidant activitiesZ. mauritiana showed potential antioxidant activity in rats Abbreviations used: SOD: Superoxide dismutase; T-AOC: Total antioxidant capacity; MDA: Malondialdehyde; ZMRD: Z. mauritiana root extract of dichloromethane fraction; LD50: Z. mauritiana root extract of methanol fraction ZMRM, lethal dose 50. PMID- 28808391 TI - Resolving Identification Issues of Saraca asoca from Its Adulterant and Commercial Samples Using Phytochemical Markers. AB - : Saraca asoca (Roxb.) De Wilde (Ashoka) is a highly valued endangered medicinal tree species from Western Ghats of India. Besides treating cardiac and circulatory problems, S. asoca provides immense relief in gynecological disorders. Higher price and demand, in contrast to the smaller population size of the plant, have motivated adulteration with other plants such as Polyalthia longifolia (Sonnerat) Thwaites. The fundamental concerns in quality control of S. asoca arise due to its part of medicinal value (Bark) and the chemical composition. Phytochemical fingerprinting with proper selection of analytical markers is a promising method in addressing quality control issues. In the present study, high-performance liquid chromatography of phenolic compounds (gallic acid, catechin, and epicatechin) coupled to multivariate analysis was used. Five samples each of S. asoca, P. longifolia from two localities alongside five commercial market samples showed evidence of adulteration. Subsequently, multivariate hierarchical cluster analysis and principal component analysis was established to discriminate the adulterants of S. asoca. The proposed method ascertains identification of S. asoca from its putative adulterant P. longifolia and commercial market samples. The data generated may also serve as baseline data to form a quality standard for pharmacopoeias. SUMMARY: Simultaneous quantification of gallic acid, catechin, epicatechin from Saraca asoca by high performance liquid chromatographyDetection of S. asoca from adulterant and commercial samplesUse of analytical method along with a statistical tool for addressing quality issues. Abbreviations used: HPLC: High Performance Liquid Chromatography; RP-HPLC: Reverse Phase High Performance Liquid Chromatography; CAT: Catechin; EPI: Epicatechin; GA: Gallic acid; PCA: Principal Component Analysis. PMID- 28808392 TI - Antiurolithiatic Effect of Sirupeelai Samoola Kudineer: A Polyherbal Siddha Decoction on Ethylene Glycol-induced Renal Calculus in Experimental Rats. AB - BACKGROUND: Sirupeelai Samoola Kudineer (SK), a polyherbal decoction containing four medicinal plants has been used in Siddha system of medicine, practiced in Southern parts of India for the management of urolithiasis. OBJECTIVE: The present study is carried out to scientifically validate the traditional claim and to study the mechanism of action of the drug. MATERIALS AND METHODS: In the present study, anti-urolithiatic effect of SK was evaluated in Sprague-Dawley rats using ethylene glycol through drinking water and intraperitoneal injection of sodium oxalate. Renal damage was confirmed by the increased production of thiobarbituric acid reactive substance (TBARS). RESULTS: Co-treatment with SK to urolithiatic rats for 21 days significantly prevented the elevation of renal and urinary stone biomarkers in plasma and renal tissue thereby preventing renal damage and the formation of renal calculi. Administration of SK at all doses and cystone restored the antioxidant (glutathione) levels by preventing the elevation of TBARS in the kidney tissue, which was further confirmed by histological sections. CONCLUSIONS: SK treatment promotes diuresis which leads to flushing of the renal stones and maintains the alkaline environment in the urinary system which probably mediates the antilithiatic activity. SK provides structural and functional protection to the kidneys by enhancing its physiological function against stone formation and validates its clinical use. SUMMARY: SK exhibited antilithiatic and diuretic potential in ethylene glycol and sodium oxalate induced urolithiasis in ratsElevated urinary stone markers (Calcium, oxalate, uric acid, magnesium and phosphates) in plasma and renal tubular enzymes (LDH, GGT, ALP, AST ALT) in urolithiatic rats were reversed by SK treatmentSK administration significantly reduced the level of renal stress markers like Urea, Creatinine, LPO and elevated SOD, GPx, GSH levels aiding in nephroprotectionSK also provides structural and functional protection against ethylene glycol- induced renal calculus in rats as evidenced by histopathological studies. Abbreviations used: SK: Sirupeelai Samoola Kudineer; TBARS: ThioBarbituric Acid Reactive Substances; SOD: SuperOxide Dismutase; GPx: Gluthathione peroxidase; GSH Glutathione; LPO: Lipid peroxidation as measured as TBARS; AST: Aspartate AminoTransferase; ALT: Alanine Amino transferase; GGT: Gamma Glutamyl Transferase; LDH: Lactate Dehydrogenase. PMID- 28808393 TI - Evaluation of the Antidiabetic Properties of S-1708 Mulberry Variety. AB - BACKGROUND: Diabetes is a metabolic disease prevalent worldwide in all age group of people. The source of diabetes is due to an oxidation process that can produce free radicals. An increase in oxidative free radicals in the body is reported to be one of the several causes of diabetes. The best remedy to combat oxidative stress is the use of antioxidants, which inhibit and scavenge free radicals. AIM: This study has been undertaken to evaluate the antioxidant activity and antidiabetic effect of mulberry leaf extract in diabetic mice. MATERIALS AND METHODS: Antioxidant activity of mulberry leaves was determined by 2,2-diphenyl-1 picryl-hydrazyl (DPPH) and ferric reducing/antioxidant power (FRAP) assay. Antidiabetic assay of mulberry leaf extract was analyzed by oral administration of leaf extract up to 3 weeks in diabetic mice induced by streptozotocin. RESULTS: In vitro antioxidant activity in both DPPH and FRAP assays showed significantly (P < 0.05) higher inhibition of free radicals than that with ascorbic acid. Diabetic mice fed with mulberry leaf extract showed increment (+25.88%) in body weight and a significant reduction in blood glucose concentration (-71.58%). Further, glucose-6-phosphate dehydrogenase enzyme activity was significantly (P < 0.05) increased, whereas activities of other enzymes particularly catalase, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase were decreased in diabetic mice after oral administration of mulberry leaf extracts. Histology of liver revealed regeneration of hepatocytes, central vein, and nucleus. CONCLUSION: This study demonstrated that S-1708 mulberry variety has a potential therapeutic value in diabetes and related complications. SUMMARY: Diabetes mellitus is a grave metabolic deviations and responsible for many complications affecting various organs in the human body. In spite of the known antidiabetic medicine available in the market, diabetes and the associated impediments sustained to be a major medical crisis. Medicinal plants have been proven to be useful in diabetes due to their rich therapeutic value. In the current study, S-1708 mulberry variety not only authenticated the earlier results obtained from other medicinal plants but also turn out to be known as a potential source for treating diabetes by demonstrating tremendous ant- diabetic properties. Abbreviations used: S-1708, DPPH, FRAP. PMID- 28808394 TI - Antiproliferative activity of Haematoxylum brasiletto H. Karst. AB - BACKGROUND: Haematoxylum brasiletto is a tree that grows in Central America, commonly known as "Palo de Brasil," which is used in the traditional medicine for the treatment of cancer and gastric ulcers. OBJECTIVE: The aim of this study was to isolate the compounds responsible for antiproliferative activity of H. brasiletto. MATERIALS AND METHODS: A bioassay-guided fractionation of ethanol extract of H. brasiletto was performed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide cell proliferation assay to measure the antiproliferative activity on six human cancer cell lines (A549, LS180, HeLa, SiHa, MDA-MB-231, and NCI-H1299) and one human noncancer cell line (ARPE-19). The ethanol extract was partitioned with hexane, dichloromethane, and ethyl acetate. The active dichloromethane fraction was fractioned by silica-column chromatography, and active subfractions were separated using preparative-thin layer chromatography. The chemical structure of an isolated compound was elucidated with different chemical and spectroscopic methods. RESULTS: The flavonoid brazilin (1) was isolated from the heartwood of H. brasiletto. The measurement of antiproliferative activity showed that brazilin can inhibit the growth of SiHa, MDA-MB-231, A549, and NCI-H1299 cell lines by 50% at doses of 44.3, 48.7, 45.4, and 48.7 MUM, respectively. Furthermore, the flavonoid showed a high antiproliferative activity on LS 180 and HeLa with IC50 values of 62.2 and 71.9 MUM, respectively. Brazilin also exhibited a high antiproliferative activity on the human noncancer cell line ARPE-19 with an IC50 value of 37.9 MUM. CONCLUSIONS: Brazilin: (6aS, 11bR)-7,11b-Dihidro-6H-indeno[2,1-c] cromeno-3,6a, 9,10-tetrol was isolated; this compound demonstrated antiproliferative activity against several human cancer cell lines. This work demonstrated that brazilin, a flavonoid isolated and characterized of H. brasiletto, has antiproliferative activity against cancer cell lines. SUMMARY: The flavonoid brazilin was isolated from the heartwood of H. brasilettoBrazilin is able to inhibit the growth of SiHa, MDA-MB-231, A549 and NCI- H1299 cancerous cell linesBrazilin exhibited a moderate antiproliferative activity on the human non-cancer cell line ARPE 19Brazilin demonstrated to have antiproliferative activity against human cancer cell lines and could be a potential source of anticancer agents. Abbreviations used: MTT: [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium]; FBS: Fetal bovine serum; TLC: Thin layer chromatography. PMID- 28808395 TI - Hepatoprotective Effect of Gallotannin-enriched Extract Isolated from Gall on Hydrogen Peroxide-induced Cytotoxicity in HepG2 Cells. AB - BACKGROUND: Gall (Galla Rhois [GR]) is known to have antibacterial, anti inflammatory, antimetastatic, and anti-invasion activities and exert hepatoprotective effects. However, the hepatoprotective effects of gallotannin enriched GR (GEGR) and their mechanisms have not yet been investigated. OBJECTIVE: The potential protective effect of GEGR against hepatotoxicity induced by hydrogen peroxide (H2O2) was investigated. MATERIALS AND METHODS: Changes in cell viability, apoptosis protein expression, and reactive oxygen species (ROS) generation were determined in HepG2 cells that were pretreated with four different concentrations of GEGR (6.25-50 MUg/ml) for 24 h before H2O2 exposure. RESULTS: GEGR consisted of gallotannin (69.2%), gallic acid (26.6%), and methyl gallate (4.2%) and showed remarkable 2,2-diphenyl-1-picrylhydrazyl scavenging activity (inhibitory concentration 50% = 0.212 MUg/ml). The lethal dose 50% and effective dose 50% values for the response of HepG2 cells to GEGR were determined to be 178 and 6.85 MUg/ml, respectively. Significant reductions in the immunofluorescence intensity indicating apoptosis were also detected in the nuclei of HepG2 cells stained with 4',6-diamidino-2-phenylindole and Annexin V after GEGR treatment. The Bax/Bcl-2 ratio and active caspase-3 level were higher in H2O2 + vehicle-treated cells. However, these levels gradually decreased to those of the No-treated group in the GEGR pretreated group even though little or no decrease was observed in response to low GEGR concentrations. Furthermore, the GEGR pretreated group showed a reduced level of 2',7'-dichlorofluorescein diacetate stained cells, indicating ROS generation relative to the H2O2 + vehicle treated group. CONCLUSION: The results of this study provide strong evidence that GEGR can prevent cell death induced by H2O2 in HepG2 cells through the induction of antioxidant conditions. SUMMARY: The gallotannin (69.2%), gallic acid (26.6%), and methyl gallate (4.2%) are the main constituents of water extracts of GRGEGR was more potent in DPPH scavenging, and gallotannin contributes to this extract activityGEGR significantly reduced the increase of apoptosis, Bax/Bcl-2 ratio, and active caspase-3 level after H2O2 treatmentGEGR pretreatment showed protection against H2O2-induced ROS production in DCFH-DA staining analysis. Abbreviations used: COX: Cyclooxygenase; DAPI: 4',6-diamidino-2-phenylindole; DMSO: Dimethyl sulfoxide; DPPH: 2,2-diphenyl-1-picrylhydrazyl; GEGR: Gallotannin enriched Galla Rhois; GR: Galla Rhois; HPLC: High-performance liquid chromatography; H2O2: Hydrogen peroxide; MMP: Metallopeptidase; MTT: 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; ROS: Reactive oxygen species; UV-Vis: Ultraviolet-visible. PMID- 28808396 TI - Catechin Isolated from Garcinia celebica Leaves Inhibit Plasmodium falciparum Growth through the Induction of Oxidative Stress. AB - BACKGROUND: Resistance of antimalarial drugs to Plasmodium falciparum has become a major concern in malaria eradication. Although it is also affected by several socioeconomic factors, a new antiplasmodial agent is needed for a global malaria control program. OBJECTIVE: In this study, we attempted to uncover the antiplasmodial properties of Garcinia celebica, an Indonesian medicinal plant, along with the responsible compound and its possible mechanism. MATERIALS AND METHODS: The G. celebica leaves were ethanol extracted and fractionated based on their polarity using n-hexane, ethyl acetate, and water. The antiplasmodial activity was tested in vitro against chloroquine-resistant P. falciparum at 100 MUg/ml for 72 h. The active compound of the most active ethyl acetate fraction was subsequently isolated using column chromatography and identified by nuclear magnetic resonance. RESULTS: The IC50 of (+)-catechin, the characterized compound, against P. falciparum was 198 MUM in 24 h and experiment. The isolated catechin inhibited P. falciparum growth in both trophozoite and schizont stages. An additional experiment also suggests that the antiplasmodial property of catechin occurs through the induction of the oxidative stress to P. falciparum. CONCLUSION: This result shows that the potential of catechin and its antimalarial properties should be explored further. SUMMARY: Garcinia celebica leaf extract and fractions inhibit Plasmodium falciparum growthCatechin, the active compound of Garcinia celebica leaf extract, inhibits Plasmodium falciparum growth in a time- and dose-dependent manner Abbreviations used: RBC: Red Blood Cells; IC50: Inhibition Concentrattino 50; MeOH: Methanol; RPMI: Roswell Park Memorial Institute; EI: Electron Ionization. PMID- 28808397 TI - Genistein-attenuated Gastric Injury on Indomethacin-induced Gastropathy in Rats. AB - OBJECTIVES: To investigates the mucoprotective effect of genistein on gastric injury in rats with indomethacin (IMN)-induced gastropathy. METHODS: Male Sprague Dawley rats were randomly divided into three groups. Group 1 (control; n = 6) was given distilled water (DW). Group 2 (IMN; n = 6) was given indomethacin (IMN) 150 mg/kg dissolved in 5% sodium bicarbonate (NaHCO3-) 1 mL/rat via intragastric tube at time 0 and 4 h. Group 3 (genistein; n = 6) was given genistein 100 mg/kg dissolved in 0.1% dimethyl sulfoxide (DMSO) plus IMN 150 mg/kg at time described as group 2. Four hours after the second dose, the stomach was removed to examine iNOS western blot expression, malondialdehyde (MDA), and histopathologic examination. Serum was collected to determine TNF-alpha and prostaglandin E2 (PGE2) levels using ELISA technique. RESULTS: Tissue MDA and serum TNF-alpha were significantly increased in the IMN group, as compared to the control group (9.70 +/- 0.40 vs. 1.56 +/- 0.14 nmol/mg protein, P = 0.000; 210.28 +/- 0.98 vs. 126.4 +/- 0.13 pg/mL, P = 0.000, respectively) and decreased in the genistein group when compared to the IMN group (2.87 +/- 0.37 vs. 9.70 +/- 0.40 nmol/mg protein, P = 0.000; 156.59 +/- 0.10 vs. 210.28 +/- 0.98 pg/mL, P = 0.000, respectively). Serum PGE2 level in IMN group was decreased significantly compared with control group (152.83 +/- 0.10 vs. 303.33 +/- 2.16 pg/mL, P = 0.000) and increased in the genistein group compared to the IMN group (247.65 +/- 0.01 vs. 152.83 +/- 0.10 pg/mL, P = 0.000). Expression of tissue iNOS was increased in the IMN group and improved in genistein groups. Most of the rats in the IMN group developed moderate to severe gastric erosion and ulcers. Gastric erosions and neutrophil infiltration score were significantly decreased in the genistein group. CONCLUSIONS: Genistein attenuated IMN-induced gastropathy in rats by reducing inflammation, decreasing oxidative stress, restoring mucoprotective function, and improving gastric histopathology. SUMMARY: This is an experimental study of the effect of NSAIDs in gastropathy. This study demonstrated the efficacy of genistein in treatment of NSAIDs-induced gastropathy. Genistein efficacy is reflected in the attenuation of histological alterations, with improvement in key biological parameters involved in the pathogenesis of NSAIDs gastropathy. Abbreviations used: NSAIDs: Non-steroidal anti-inflammatory drugs; IMN: Indomethacin; COX: Cyclooxygenase; TNF: Tumor necrosis factor; ICAM: Intercellular adhesion molecule; iNOS: Inducible nitric oxide synthase; MDA: Malondialdehyde; CINC: Cytokine-induced neutrophil chemoattractant. PMID- 28808398 TI - Mechanism of Action of Isolated Caffeic Acid and Epicatechin 3-gallate from Euphorbia hirta against Pseudomonas aeruginosa. AB - BACKGROUND: The escalating dominance of resistant Pseudomonas aeruginosa strains as infectious pathogen had urged the researchers to look for alternative and complementary drugs. OBJECTIVE: The objective of this study is to address the biological targets and probable mechanisms of action underlying the potent antibacterial effect of the isolated compounds from Euphorbia hirta (L.) against P. aeruginosa. MATERIALS AND METHODS: The action mechanisms of caffeic acid (CA) and epicatechin 3-gallate (ECG) on P. aeruginosa cells were investigated by several bacterial physiological manifestations involving outer membrane permeabilization, intracellular potassium ion efflux, and nucleotide leakage. RESULTS: The findings revealed that ECG and CA targeted both cell wall and cytoplasmic membrane of P. aeruginosa. The cellular membrane destruction and ensuing membrane permeability perturbation of P. aeruginosa had led to the ascending access of hydrophobic antibiotics, release of potassium ions, and leakages of nucleotides. CONCLUSION: The overall study concludes that ECG and CA isolated from E. hirta possess remarkable anti-infective potentials which can be exploited as drug template for the development of new antibacterial agent against resistant P. aeruginosa pathogen. SUMMARY: Epicatechin 3-gallate (ECG) and caffeic acid (CA) exhibited remarkable bactericidal abilities by increasing the outer membrane and plasma membrane permeability of Pseudomonas aeruginosa pathogenECG and CA had facilitated the entry of hydrophobic antibiotics into P. aeruginosa by disintegrating the lipopolysaccharides layer of the outer membraneECG-induced potassium efflux with efficiency close to that obtained with cefepime suggesting mode of action through membrane disruptionBoth ECG and CA had caused consistent leakage of intracellular nucleotide content with the increase in time. Abbreviations used: ECG: Epicatechin 3-gallate; CA: Caffeic acid; E. hirta: Euphoria hirta. PMID- 28808399 TI - Wound Healing Activity of Azadirachta indica A. Juss Stem Bark in Mice. AB - BACKGROUND: The paste of stem bark of Azadirachta indica (AI) has been traditionally used on wound and scar for rapid healing in Bundelkhand region of India. OBJECTIVE: In the present investigation, wound healing potential of different extracts of stem bark of AI was explored in mice model. MATERIALS AND METHODS: To study the wound healing properties in small animal model, the excision and incision wound models were used and water, ethanol-water (1:1, v/v) and ethanol extracts were applied topically (15% w/w in ointment base). In the excision wound model, wound contraction, hydroxyproline content, DNA content, protein content, and nitric oxide levels were estimated after 14 days of topical treatment along with histopathological examinations. In the incision wound model, wound breaking strength was determined after 10 days of topical application of different extracts of AI. RESULTS: The animals treated with water extract of AI exhibited significant increment in rate of wound contraction (93.39%, P < 0.01), hydroxyproline content (13.31 +/- 6.65 mg/g of dry tissue, P < 0.001), DNA content (20.99 +/- 0.68 MUg/100 mg of tissue, P < 0.01), protein content (100.53 +/- 7.88 mg/g of wet tissue, P < 0.01) and nitric oxide level (3.05 +/- 0.03 mMol/g of tissue, P < 0.001) as well as in wound breaking strength (289.40 +/- 29.45 g, P < 0.01) when compared with vehicle control group which was also supported by histopathological studies. CONCLUSION: The water extract of stem bark of AI possesses significant wound healing property, validating its traditional use. PMID- 28808400 TI - Induction of Apoptosis and Cell Cycle Arrest by Flavokawain C on HT-29 Human Colon Adenocarcinoma via Enhancement of Reactive Oxygen Species Generation, Upregulation of p21, p27, and GADD153, and Inactivation of Inhibitor of Apoptosis Proteins. AB - : Chalcones have been shown to exhibit anti-cancer properties by targeting multiple molecular pathways. It was, therefore, of interest to investigate flavokawain C (FKC), a naturally occurring chalcone, which can be isolated from Kava (Piper methysticum Forst) root extract. The aim of this study was to investigate the inhibitory effect of FKC on the growth of HT-29 cells and its underlying mechanism of action. Cell viability of HT-29 cells was assessed by Sulforhodamine B assay after FKC treatment. Induction of apoptosis was examined by established morphological and biochemical assays. ROS generation was determined by dichlorofluorescein fluorescence staining, and superoxide dismutase activity was measured using the spectrophotometric method. Western blotting was used to examine the changes in the protein levels. FKC markedly decreased the cell viability of HT-29 cells and the cells showed dramatic changes in cellular and nuclear morphologies with typical apoptotic features. The induction of apoptosis correlated well with the externalization of phosphatidylserine, DNA fragmentation, decreased mitochondrial membrane potential, activation of caspases, and PARP cleavage. This was associated with an increase in reactive oxygen species and a decrease in SOD activity. The protein levels of XIAP, c IAP1, and c-IAP2 were downregulated, whereas the GADD153 was upregulated after FKC treatment. FKC induced cell cycle arrest at the G1 and G2/M phases via upregulation of p21 and p27 in a p53-independent manner. Our results provide evidence that FKC has the potential to be developed into chemotherapeutic drug for the treatment of colon adenocarcinoma. SUMMARY: Flavokawain C inhibited the growth of HT-29 human colon adenocarcinoma cellsFlavokawain C induced apoptosis in HT-29 cells, associated with an increase in reactive oxygen species and a decrease in SOD activityFlavokawain C induced cell cycle arrest at the G1 and G2/M phases via upregulation of p21 and p27 in HT-29 cellsHT-29 cells treated with flavokawain C caused downregulation of XIAP, c-IAP1, and c-IAP2, and upregulation of GADD153. Abbreviations used: FKC: Flavokawain C; SRB: Sulforhodamine B; ROS: Reactive oxygen species; SOD: Superoxide dismutase; PARP: Poly(ADP-ribose) polymerase; ER: Endoplasmic reticulum; IAPs: Inhibitor of apoptosis proteins; TUNEL: Transferase dUTP nick end labeling; Annexin V-FITC: Annexin V conjugated with fluorescein isothicyanate. PMID- 28808401 TI - In vitro alpha-amylase and alpha-glucosidase Inhibitory and Cytotoxic Activities of Extracts from Cissus cornifolia Planch Parts. AB - CONTEXT: Hyperglycemia is the hallmark of type 2 diabetes mellitus, and its prevention will go a long way in managing the disease and its associated complications. Reduction of postprandial hyperglycemia through retarding carbohydrates digesting enzymes is one of the major therapeutic approaches used in the management of diabetes. OBJECTIVE: The aim of the present study was to investigate the antidiabetic and cytotoxic effects of Cissus cornifolia extracts in vitro. MATERIALS AND METHODS: The alpha-amylase and alpha-glucosidase inhibitory activities of ethanolic and aqueous extracts of C. cornifolia root and leaves were investigated when the cytotoxic effects of these extracts were analyzed using MTT assay on human embryonic kidney (HEK 293) cell lines. RESULTS: The root ethanolic extract showed a mild alpha-amylase inhibitory activity with IC50 value of 22.75 +/- 1.23 MUg/ml, but strong alpha-glucosidase inhibitory activity with IC50 value 2.81 +/- 0.97 MUg/ml and the aqueous root extract indicated moderate inhibition for both alpha-amylase and alpha-glucosidase with IC50 values of 33.70 +/- 3.75 and 37.48 +/- 2.35 MUg/ml, respectively. The ethanolic root extract was found nontoxic at tested concentrations on HEK 293 cell lines as confirmed by the MTT assay with 93% cell viability at the highest concentration (200 MUg/ml) tested. However, the aqueous extracts (leaf and root) were found cytotoxic at concentrations above 50 MUg/ml. CONCLUSION: Data of this study suggest that the root ethanolic extracts of C. cornifolia possesses moderate alpha-amylase, but strong alpha-glucosidase inhibitory activity in vitro and did not show significant cytotoxicity with the tested concentrations. SUMMARY: Present study was conducted to examine effects of antidiabetic and cyctotoxic effects of Cissus conrnifolia root and leaves extracts in vitro. Data of this study suggest that the root ethanolic extract of C. cornifolia possesses mild to moderated antidiabetic activity via inhibiting carbohydrate digesting enzymes when no significant toxicity was observed with tested concentrations. Abbreviations used: alex: Aqueous leaf extract; arex: Aqueous root extract; CC: Cissus cornifolia; DNS: Dinitrosalicylic acid; DMSO: Dimethylsulfoxide; elex: Ethanolic leaf extract; erex: Ethanolic root extract; IDF: International Diabetes Federation; MEM: Minimum essential medium; NIDDM: Noninsulin-dependent diabetes mellitus; pNPG: Para-nitrophenyl glucopyranoside; SD: Standard deviation; T2D: Type 2 diabetes. PMID- 28808402 TI - Role of Adiantum philippense L. on Glucose Uptake in Isolated Pancreatic Cells and Inhibition of Adipocyte Differentiation in 3T3-L1 Cell Line. AB - BACKGROUND: Adiantum philippense (AP) is a pteridophyte that shows antihyperglycemic activity in vivo diabetic model, but the mechanism of action is unknown. OBJECTIVE: AP was found to play a pivotal role in minimizing the high blood glucose in alloxan-induced diabetic rats. Simultaneously, it was observed that it could maintain the normal lipid profile even in diabetic condition. To investigate its insulin-like activity along with its inhibitory role on adipocyte differentiation became the objective of our present study. MATERIALS AND METHODS: Glucose uptake potential of this fern was done in isolated pancreatic islets and inhibition of adipocyte differentiation was assessed in 3T3-L1 cell line. Before this, the cytotoxic concentration was determined by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide assay on L929 cell line. To determine its role in lipid metabolism, the oil droplets produced in adipocytes were stained with Oil 'O' red staining, and triglyceride levels of various drug treatments were measured spectrophotometrically. RESULTS: This fern extract was found to be actively utilizing glucose in the glucose uptake assay. Moreover, it was also involved in inhibiting differentiation of pro-adipocyte to adipocyte in the 3T3 L1 cell lines. The percentage inhibition as obtained from the absorbance showed that the ethanolic extract at the concentration of 200 MUg/ml showed 32.48% inhibition. CONCLUSION: All the above-mentioned parameters when appraised indicated that this fern could be used as an alternative medicine in managing diabetes associated with obesity. SUMMARY: Adiantum phillippense (AP) is a pteridophyte that can work as antihyperglycemic agent by minimizing some adverse effects produced by diabetes. Diabetes produces oxidative stress, hampers normal glucose uptake in the pancreas, promotes adipocyte differentiation, and leads to obesity, and as a result, it generates catastrophic effect to the normal cells. The present study has shown that ethanolic extract of AP gives better protection rate against H2 O2-induced cytotoxicity, elicits insulinotropic activity in isolated mouse pancreatic glucose uptake assay. It also inhibits the preadipocytes to become mature adipocytes judged by morphology or lipid-specific Oil-Red-O staining of 3T3-L1 cell line. Abbreviations used: AP: Adiantum phillipense; MTT: (3-(4,5- Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide); BSA: Bovine serum albumin; FCS: Fetal calf serum; DMEM: Dulbecco's minimum essential media; RPMI: Roswell park memorial institute medium; DTZ: Dithizone; TG: Triglyceride; PPARgamma: Peroxisome proliferator-activated receptor gamma; IBMX: 3-isobutyl-1-methylxanthine; nm: Nanometer; GI: Growth Inhibition; ELISA: Enzyme linked immunosorbent assay. PMID- 28808403 TI - The Possible Pre- and Post-UVA Radiation Protective Effect of Amaranth Oil on Human Skin Fibroblast Cells. AB - BACKGROUND: The health effects of Amaranth Oil (AO) are attributed to its specific chemical composition. That makes it an outstanding natural product for the prevention and treatment of ultraviolet (UV) irradiation-related pathologies such as sunburn, photoaging, photoimmunosuppression, and photocarcinogenesis. Most of the studies are taken on animal model, and there is a lack of research on the endogenous effect of AO on fibroblast level, where UVA takes it harmful place. OBJECTIVE: The aim of this study was evaluation if AO can protect or abolish UVA exposure effect on human skin fibroblast. MATERIALS AND METHODS: The 0.1% AO, 0.25% AO, and 0.5% AO concentration and irradiation for 15 min under UVA emitting lamp were studied in various condition. In all experiments, the mean values for six assays +/- standard deviations were calculated. RESULTS: Pretreatment with various concentrations of AO was tested. The highest concentration of AO where cell survival was observed was 0.5%. Cytotoxicity assays provided evidence for pre- and post-UVA protective effect of 0.1% AO among three tested concentrations. The results also provide evidence that UVA has inhibitory effect on collagen biosynthesis in confluent skin fibroblast, but presence of 0.1% AO abolishes pre- and post-UVA effect comparing to other used AO concentration. The assessment results on DNA biosynthesis show the significant abolished post-UVA effect when 0.1% and 0.5% of AO were added. CONCLUSION: AO gives pre- and post-UVA protection in low concentration. This provides the evidence for using it not as a main protective factor against UV but as one of the combined components in cosmetic formulation. SUMMARY: The recommended Amaranth Oil (AO) concentration in cosmetic formulation is between 0.1 and 5%Pretreatment with various concentrations of AO suggests to use the highest 0.5% concentration of AO in human skin fibroblast culturesThe 0.1% of AO in fibroblast cultures, protects and abolishes effect of ultraviolet A (UVA) exposureUVA has inhibitory effect on collagen biosynthesis in skin fibroblast, but presence of 0.1% AO abolishes pre- and post-UVA effectThe abolished post-UVA effect occurs when 0.1% and 0.5% of AO were added on DNA biosynthesis. Abbreviations used: AO: Amaranth Oil. PMID- 28808404 TI - In vitro Antioxidant and Antiproliferative Activities of Various Solvent Fractions from Clerodendrum viscosum Leaves. AB - BACKGROUND: Free radicals such as reactive oxygen and nitrogen species, generated in the body, play an important role in the fulfillment of various physiological functions but their imbalance in the body lead to cellular injury and various clinical disorders such as cancer, neurodegenaration, and inflammation. OBJECTIVE: The objective of this study is to fight this problem, natural antioxidant from plants can be considered as possible protective agents against various diseases such as cancer which might also modify the redox microenvironment to reduce the genetic instability. This study was designed to evaluate the antioxidant and antiproliferative potential of Clerodendrum viscosum fractions against various carcinomas. MATERIALS AND METHODS: In this present study, 70% methanolic extract of C. viscosum leaves have been fractionated to obtain hexane, chloroform, ethyl acetate, butanol, and water fractions, which were tested for their antioxidant and anticancer properties. RESULTS: It was observed that chloroform and ethyl acetate fractions showed good free radical scavenging properties as well as inhibited the proliferation of human lung cancer (A459), breast (MCF-7), and brain (U87) cells. Moreover, they arrested the cell cycle at G2/M phase of breast and brain cancer. These inhibitory effects were further confirmed by bromodeoxyuridine uptake imaging. Phytochemical investigations further indicate the presence of tannic acid, quercetin, ellagic caid, gallic acid, reserpine, and methyl gallate which might be the reason for these fractions' antioxidant and antiproliferative activities. CONCLUSION: Clerodendrum viscosum leaf chloroform and Clerodendrum viscosum leaf ethyl acetate fractions from C. viscosum showed good reactive oxygen species and reactive nitrogen species scavenging potential. Both the fractions arrested cell cycle at G2/M phase in MCF-7 and U87 cells which lead to induce apoptosis. SUMMARY: Crude extract of Clerodendrum viscosum leaves was fractionated using different solventsAmong them, chloroform and ethyl acetate fractions exhibited excellent free radical scavenging propertiesThe same fractions inhibited the proliferation of human lung cancer (A459), breast (MCF-7), and brain (U87) cellsChloroform and ethyl acetate fractions arrested the cell cycle at G2/M phase of breast and brain cancerPhytochemical investigations further indicate the presence of several bioactive principles present in them. Abbreviations used: CVLME: Clerodendrum viscosum leaf methanolic extract; CVLH: Clerodendrum viscosum leaf hexane; CVLC: Clerodendrum viscosum leaf chloroform; CVLE: Clerodendrum viscosum leaf ethyl acetate; CVLB: Clerodendrum viscosum leaf butanol; CVLW: Clerodendrum viscosum leaf water; BrdU: Bromodeoxyuridine; WST-1: Water soluble tetrazolium salt. PMID- 28808405 TI - Catha edulis Forsk. (Khat): Evaluation of its Antidepressant-like Activity. AB - BACKGROUND: Catha edulis Forsk. (Khat) is traditionally used for treating various disorders. Nevertheless there are no reports of any scientific assessment of its psychopharmacological properties. OBJECTIVE: Therefore, the current study was designed to evaluate the antidepressant-like activity of Khat ethanolic extract using established animal models of depression and stress. MATERIALS AND METHODS: Ninety healthy male albino mice were used in this study. Forced swim, tail suspension and head poking tests were utilized to evaluate the antidepressant like activity of the ethanolic extract of Khat (100, 200 and 400 mg/kg, i.p.) and escitalopram (standard drug) which were administered 30 min prior to the tests. Phytochemical analysis of the standardized extract was conducted using liquid chromatography-mass spectroscopy (LC-MS). RESULTS: A significant decrease in the head-dipping behavior was noticed after administration of 100, 200 and 400 mg/kg of Khat extract. Moreover, the extract significantly decreased the immobility time in tail suspension and forced swim tests. The presence of cathinone and cathine were detected in the extract using LC-MS. CONCLUSION: The current results suggest that the extract of Khat leaves has acute antidepressant properties and may have sedative effects. SUMMARY: Antidepressant-like activity of Khat established in vivoThe extract decreased the immobility time in tail suspension and forced swim testsLiquid chromatography-mass spectroscopy data revealed the presence of cathinone and cathine in Khat extract. Abbreviations used: LC-MS: Liquid chromatography-mass spectroscopy; NIST: National institute of standard technology; SSRI: Serotonin reuptake inhibitors; FST: Forced swim test; TST: Tail suspension test. PMID- 28808406 TI - Peimine Inhibits the Production of Proinflammatory Cytokines Through Regulation of the Phosphorylation of NF-kappaB and MAPKs in HMC-1 Cells. AB - BACKGROUND: Peimine is a major biologically active component of Fritillaria ussuriensis. Peimine was investigated in chronic inflammation response, but it has not been studied in mast cell-related immediate allergic reaction. The present study aimed to evaluate anti-allergic effect of peimine in human mast cell (HMC-1). MATERIALS AND METHODS: The effect of peimine on cell viability was measured by MTS assay in HMC-1. Histamine release was investigated in rat peritoneal mast cells (RPMCs). Interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha (TNF-alpha) expressions were measured by ELISA assay and reverse transcription-polymerase chain reaction. Mitogen-activated protein kinases (MAPKs) and nuclear factor-kappaB (NF-kappaB) were examined by Western blot. Passive cutaneous anaphylaxis (PCA) reactions were evaluated using Sprague-Dawley (SD) rats. RESULTS: Peimine inhibited the production of pro-inflammatory cytokines, such as IL-6, IL-8, and TNF-alpha. Moreover, peimine reduced MAPKs phosphorylation and the nuclear NF-kappaB expression in PMACI-induced HMC-1. Peimine decreased PCA reactions in rats as well. CONCLUSION: Our study proved that peimine might be suitable for the treatment of mast cell-derived allergic inflammatory reactions. SUMMARY: Peimine inhibited the production of pro inflammatory cytokines, such as IL-6, IL-8, and TNF-alphaPeimine reduced MAPKs phosphorylation and the nuclear NF-kappaB expression in PMACI-induced HMC 1Peimine decreased PCA reactions in ratsPeimine has anti-allergic effect through regulation of pro-inflammatory mechanism on mast cell. Abbreviations used: HMC-1: Human mast cell, MTS: 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2 (4-sulfophenyl)-2H-tetrazolium, RPMCs: Rat peritoneal mast cells. IL-6: Interleukin 6, IL-8: Interleukin 8, TNF-alpha: Tumor necrosis factor-alpha, MAPKs: Mitogen-activated protein kinases; NF-kappaB: Nuclear factor-kappaB, PCA: Passive cutaneous anaphylaxis reactions, SD: Sprague-Dawley. PMID- 28808407 TI - In vitro Cell Viability by CellProfiler(r) Software as Equivalent to MTT Assay. AB - OBJECTIVE: This study evaluated in vitro cell viability by the colorimetric MTT stands for 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (3-(4, 5 dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) (3-(4, 5-dimethylthiazolyl 2)-2, 5-diphenyltetrazolium bromide) assay compared to image analysis by CellProfiler(r) software. MATERIALS AND METHODS: Hepatoma (Hepa-1c1c7) and fibroblast (L929) cells were exposed to isolated substances, camptothecin, lycorine, tazettine, albomaculine, 3-epimacronine, trispheridine, galanthine and Padina gymnospora, Sargassum sp. methanolic extract, and Habranthus itaobinus Ravenna ethyl acetate in different concentrations. After MTT assay, cells were stained with Panotic dye kit. Cell images were obtained with an inverted microscope equipped with a digital camera. The images were analyzed by CellProfiler(r). RESULTS: No cytotoxicity at the highest concentration analyzed for 3-epimacronine, albomaculine, galanthine, trispheridine, P. gymnospora extract and Sargassum sp. extract where detected. Tazettine offered cytotoxicity only against the Hepa1c1c7 cell line. Lycorine, camptothecin, and H. itaobinus extract exhibited cytotoxic effects in both cell lines. The viability methods tested were correlated demonstrated by Bland-Atman test with normal distribution with mean difference between the two methods close to zero, bias value 3.0263. The error was within the limits of the confidence intervals and these values had a narrow difference. The correlation between the two methods was demonstrated by the linear regression plotted as R2. CONCLUSION: CellProfiler(r) image analysis presented similar results to the MTT assay in the identification of viable cells, and image analysis may assist part of biological analysis procedures. The presented methodology is inexpensive and reproducible. SUMMARY: In vitro cell viability assessment with MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5 diphenyltetrazolium bromide) assay may be replaced by image analysis by CellProfiler(r). The viability methods tested were correlated demonstrated by Bland-Atman test with normal distribution with mean difference between the two methods close to zero, bias value 3.0263. The correlation between the two methods was demonstrated by the linear regression plotted as R2. Abbreviations: HPLC: High pressure liquid chromatography MTT: (3-(4, 5-dimethylthiazolyl-2)-2, 5 diphenyltetrazolium bromide) (3-(4, 5-dimethylthiazolyl-2)-2, 5 diphenyltetrazolium bromide). PMID- 28808408 TI - Anti-lipid Potential of Drimys brasiliensis. AB - BACKGROUND: The traditional use of Drimys brasiliensis Miers (Winteraceae) in the south of Brazil to reduce cholesterol has not been described in scientific literature. OBJECTIVE: To verify the hypocholesterolemic effects of D. brasiliensis using rats as animal model. MATERIALS AND METHODS: The bark of D. brasiliensis was extracted with water with further lyophilization and was subjected to phytochemical analysis by high-performance liquid chromatography (HPLC), and free radical scavenging activities by 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay to determine antioxidant potential. The hypocholesterolemic activity was determined in male Wistar rats treated with 100 and 250 mg/kg/day extract concomitantly fed a hypercaloric diet, over 20 days (prevention assay). In the treatment assay, rats were fed a hypercaloric diet for 40 days and received the extract (100 mg/kg/day) from day 20. RESULTS: In this research, we found that the extract of the bark of D. brasiliensis was able to reduce the triglycerides significantly and reduce total cholesterol at doses 100 and 250 mg/kg/day and both administration regimens (prevention and treatment) in rats treated with the extract and hypercaloric diet. The extract showed strong antioxidant properties (DPPH assay), probably responsible by hypocholesterolemic activity of the plant. By HPLC, we detected catechin (1.34%), epicatechin (3.48%), rutin (0.86%), caffeic acid (0.45%), and ferulic acid (0.84%) in D. brasiliensis extract. CONCLUSIONS: We confirm the popular use of the plant to reduce of cholesterol. SUMMARY: The extract of the bark of Drimys brasiliensis was able to reduce the triglycerides significantly and reduced total cholesterol at doses 100 and 250 mg/kg/day and both administration regimens (prevention and treatment) in rats treated with the extract and hypercaloric dietThe extract showed strong antioxidant properties (1,1-diphenyl-2-picrylhydrazyl assay), probably responsible by hypocholesterolemic activity of the plantThe extracts present catechin (1.34%), epicatechin (3.48%), rutin (0.86%), caffeic acid (0.45%), and ferulic acid (0.84%)The plant can be used to cholesterol reduction. Abbreviations used: HPLC: High-performance liquid chromatography; PDA: Photodiode array detector; RS: Reference substances; DPPH: 1,1-diphenyl-2-picrylhydrazyl; VCEAC: Vitamin C equivalent antioxidant capacity. PMID- 28808409 TI - Novel Approaches to Extraction Methods in Recovery of Capsaicin from Habanero Pepper (CNPH 15.192). AB - INTRODUCTION: The objective of this study was to compare three capsaicin extraction methods: Shoxlet, Ultrasound-assisted Extraction (UAE), and Shaker assisted Extraction (SAE) from Habanero pepper, CNPH 15.192. MATERIALS AND METHODS: The different parameters evaluated were alcohol degree, time extraction, and solid-solvent ratio using response surface methodology (RSM). RESULTS: The three parameters found significant (p < 0.05) were for UAE and solvent concentration and extraction time for SAE. The optimum conditions for the capsaicin UAE and SAE were similar 95% alcohol degree, 30 minutes and solid liquid ratio 2 mg/mL. The Soxhlet increased the extraction in 10-25%; however, long extraction times (45 minutes) degraded 2% capsaicin. CONCLUSION: The extraction of capsaicin was influenced by extraction method and by the operating conditions chosen. The optimized conditions provided savings of time, solvent, and herbal material. Prudent choice of the extraction method is essential to ensure optimal yield of extract, thereby making the study relevant and the knowledge gained useful for further exploitation and application of this resource. SUMMARY: Habanero pepper, line CNPH 15.192, possess capsaicin in higher levels when compared with others speciesHigher levels of ethanolic strength are more suitable to obtain a higher levels of capsaicinBox-Behnken design indicates to be useful to explore the best conditions of ultrasound assisted extraction of capsaicin. Abbreviations used: Nomenclature UAE: Ultrasound-assisted Extraction; SAE: Shaker-assisted Extraction. PMID- 28808410 TI - The Effects of Erzincan Grape (Vitis vinifera spp., Cimin) and Benzothiazol on a Caenorhabditis elegans Organism Model. AB - BACKGROUND: Grapes and their products are known to have been used for the treatment of diseases throughout history. OBJECTIVE: It was aimed to investigate the effects of Erzincan Cimin grapes on an organism model of Caenorhabditis elegans N2 wild type and C. elegans BS913 strains with gonad cancer. MATERIALS AND METHODS: The effects of methanol extracts of the skin and seeds of Erzincan Cimin grapes were examined separately on C. elegans N2 wild type and an effect was determined on lifespan. By applying GS-MS analysis, a potential agent substance was determined in the skin and seed methanol extracts. This substance was purchased and the effects of this substance were investigated on lifespan and fertility in C. elegans BS913 strains with gonad cancer. In addition, the effects on young subjects exposed to this agent substance in L1 form were investigated. RESULTS: Grape seed and skin methanol extract was observed to prolong the lifespan most at a dose of 10 mg/100 mL. Lifespan was determined to be at a maximum in a gonad cancer organism model with benzothiazol at a dose of 50 ppm. At the same dose, positive effects were determined on the fertility of strains with cancer. When the effects of benzothiazol were examined on young L1 forms, an evident retardation of growth was determined at doses of 10, 50, and 100 ppm. CONCLUSION: Owing to anti-carcinogenic effects of benzothiazol and benzothiazol derived substances, they can be considered as agent substances in academic studies related to cancer. SUMMARY: The effects of methanol extracts of the skin and seeds of Erzincan Cimin grapes were examined on C. elegans N2 wild type and an effect was determined on lifespanThrough GS-MS analysis, benzothiazol was determined in the skin methanol extractsBenzothiazol was purchased and the effects of this substance were investigated on lifespan and fertility in C. elegans BS913 strains with gonad cancerThe effects on young subjects exposed to benzothiazol in L1 formGrape seed, skin methanol extract, and benzothiazol was observed to prolong the lifespanPositive effects were determined on the fertility of gonad cancer strains. Abbreviations used: GC-MS: gas chromatography and mass spectrometry; C. elegans: Caenorhabditis elegans; NGM: Nematode growth medium; E. coli: Escherichia coli; FUDR: Fluorodeoxyuridine; LDL: Low-density lipoprotein. PMID- 28808411 TI - Preoperative Factors Associated with Infiltrative Histologic Growth Patterns in Extremity Soft Tissue Sarcoma. AB - Soft tissue sarcoma (STS) with an infiltrative histologic growth pattern, when compared to STS with an expansile pattern, may pose difficulties in local control. Preoperative assessment of the presence of infiltrative histologic growth pattern would be helpful in deciding treatment strategies. A review of 144 patients who underwent surgery for extremity STS was performed. Microscopically, the histologic growth pattern was defined as infiltrative if the penetration of the tumor cells into the surrounding tissue was observed. Possible clinicopathologic factors that might be associated with infiltrative histologic growth pattern were investigated with regard to patient demographics, tumor characteristics, and MRI findings. Of the 144 tumors, 71 (49%) showed infiltrative histologic growth pattern. On multivariate analysis, histological subtypes other than liposarcoma (OR = 4.57, p = 0.02) and infiltrative border on MRI (OR = 2.48, p = 0.01) were independent factors associated with infiltrative histologic growth pattern. Predictive index based on these two factors showed a significant improved accuracy (ROC-AUC = 0.647) for predicting infiltrative histologic growth pattern compared to either factor alone. Our data suggests that liposarcoma histology and tumor border on MRI can predict histologic growth pattern in extremity STS. PMID- 28808412 TI - Cross-Cultural Adaptation, Translation, and Validation of the Toronto Extremity Salvage Score for Extremity Bone and Soft Tissue Tumor Patients in Netherlands. AB - PURPOSE: The aim of this study was to translate and culturally adapt the Toronto Extremity Salvage Score (TESS) to Dutch and to validate the translated version. METHODS: The TESS lower and upper extremity versions (LE and UE) were translated to Dutch according to international guidelines. The translated version was validated in 98 patients with surgically treated bone or soft tissue tumors of the LE or UE. To assess test-retest reliability, participants were asked to fill in a second questionnaire after one week. Construct validity was determined by computing Spearman rank correlations with the Short Form- (SF-) 36. RESULTS: The internal consistency (0.957 and 0.938 for LE and UE, resp.) and test-retest reliability (intraclass correlation coefficients 0.963 and 0.969 for LE and UE, resp.) were good for both questionnaires. The Dutch LE and UE TESS versions correlated most strongly with the SF-36 physical function dimension (r = 0.737 for LE, 0.726 for UE) and the physical component summary score (r = 0.811 and 0.797 for LE and UE). INTERPRETATION: The Dutch TESS questionnaire for lower and upper extremities is a consistent, reliable, and valid instrument to measure patient-reported physical function in surgically treated patients with a soft tissue or bone tumor. PMID- 28808413 TI - Diastereoselective Intramolecular Cyanoamidation with Alkenes. AB - Reported herein is a diastereoselective intramolecular alkene cyanoamidation, wherein high d.r. values are imparted by chiral directing groups. Lactams with an alpha-all-carbon quaternary stereocenter are readily synthesized, which may enable access to structures frequently found in biologically active molecules and natural products. PMID- 28808414 TI - Diiron Dithiolate Hydrides Complemented with Proton-Responsive Phosphine-Amine Ligands. AB - The reaction of Fe2(pdt)(CO)6 with two equivalents of Ph2PC6H4NH2 (PNH2) affords the amido hydride HFe2(pdt)(CO)2(PNH2)(PNH) {[H1H]0, pdt2- = CH2(CH2S-)2}. Isolated intermediates in this conversion include Fe2(pdt)(CO)5-(kappa1-PNH2) and Fe2(pdt)(CO)4(kappa2-PNH2). X-ray crystallographic analysis of [H1H]0 shows that the chelating amino/amido-phosphine ligands occupy trans-dibasal positions. The 31P NMR spectrum indicates that [H1H]0 undergoes rapid proton exchange between the amido and amine centers. No exchange was observed for the hydride. Protonation of [H1H]0 gives [HFe2(pdt)(CO)2(PNH2)2]+ ([H21H]+), which contains two equivalent amino-phosphine ligands. Single-crystal X-ray crystallographic analysis of [H21H]+ also reveals hydrogen bonds between the exo amine protons with a THF molecule and BF4. Deprotonation of [H1H]0 with potassium tert-butoxide gave [HFe2(pdt)(CO)2(PNH)2]- ([1H]-), which was characterized spectroscopically. The complex has time-averaged C2 symmetry with two amido-phosphine ligands. FTIR spectroscopic measurements show that upsilonCO shifts by approximately 20 cm-1 in the series [1H]-, [H1H]0, and [H21H]+. These shifts are comparable to those seen for the S-protonation of the (NC)2(CO)Fe-(MU-Scys)2Ni(Scys)2 site in the [NiFe] hydrogenases.[1]. PMID- 28808416 TI - Platelet-derived Extracellular Vesicles: An Emerging Therapeutic Approach. AB - Extracellular vesicles (EVs) are a newly-discovered way by which cells communicate with their neighbors, as well as transporting cargos which once were considered to be limited by membrane barriers, including membrane proteins, cytosolic proteins and RNA. The discovery of platelet-derived EVs (P-EVs), the most abundant EVs in human blood, has been a very tortuous process. At first, P EVs were identified as nothing but 'platelet dust', and subsequent research did not progress smoothly because of the limited research techniques to study EVs. Following leaps and bounds of technical progress in studying EVs, more and more attractive features of P-EVs were revealed and they began to be further researched. The aim of this review is to present the latest knowledge about the role of P-EVs in tissue repair and tumor progression. The potential mechanism of P-EVs is emphasized. Then the limitations of the present study and future research directions are discussed. PMID- 28808415 TI - FOXO Signaling Pathways as Therapeutic Targets in Cancer. AB - Many transcription factors play a key role in cellular differentiation and the delineation of cell phenotype. Transcription factors are regulated by phosphorylation, ubiquitination, acetylation/deacetylation and interactions between two or more proteins controlling multiple signaling pathways. These pathways regulate different physiological processes and pathological events, such as cancer and other diseases. The Forkhead box O (FOXO) is one subfamily of the fork head transcription factor family with important roles in cell fate decisions and this subfamily is also suggested to play a pivotal functional role as a tumor suppressor in a wide range of cancers. During apoptosis, FOXOs are involved in mitochondria-dependent and -independent processes triggering the expression of death receptor ligands like Fas ligand, TNF apoptosis ligand and Bcl-XL, bNIP3, Bim from Bcl-2 family members. Different types of growth factors like insulin play a vital role in the regulation of FOXOs. The most important pathway interacting with FOXO in different types of cancers is the PI3K/AKT pathway. Some other important pathways such as the Ras-MEK-ERK, IKK and AMPK pathways are also associated with FOXOs in tumorigenesis. Therapeutically targeting the FOXO signaling pathway(s) could lead to the discovery and development of efficacious agents against some cancers, but this requires an enhanced understanding and knowledge of FOXO transcription factors and their regulation and functioning. This review focused on the current understanding of cell biology of FOXO transcription factors which relates to their potential role as targets for the treatment and prevention of human cancers. We also discuss drugs which are currently being used for cancer treatment along with their target pathways and also point out some potential drawbacks of those drugs, which further signifies the need for development of new drug strategies in the field of cancer treatment. PMID- 28808417 TI - Down-regulation of aminopeptidase N and ABC transporter subfamily G transcripts in Cry1Ab and Cry1Ac resistant Asian corn borer, Ostrinia furnacalis (Lepidoptera: Crambidae). AB - The Asian corn borer (ACB), Ostrinia furnacalis (Lepidoptera: Crambidae), is a highly destructive pest of cultivated maize throughout East Asia. Bacillus thuringiensis (Bt) crystalline protein (Cry) toxins cause mortality by a mechanism involving pore formation or signal transduction following toxin binding to receptors along the midgut lumen of susceptible insects, but this mechanism and mutations therein that lead to resistance are not fully understood. In the current study, quantitative comparisons were made among midgut expressed transcripts from O. furnacalis susceptible (ACB-BtS) and laboratory selected strains resistant to Cry1Ab (ACB-AbR) and Cry1Ac toxins (ACB-AcR) when feeding on non-Bt diet. From a combined de novo transcriptome assembly of 83,370 transcripts, ORFs of >= 100 amino acids were predicted and annotated for 28,940 unique isoforms derived from 12,288 transcripts. Transcriptome-wide expression estimated from RNA-seq read depths predicted significant down-regulation of transcripts for previously known Bt resistance genes, aminopeptidase N1 (apn1) and apn3, as well as a putative ATP binding cassette transporter group G (abcg) gene in both ACB-AbR and -AcR (log2[fold-change] >= 1.36; P < 0.0001). The transcripts that were most highly differentially regulated in both ACB-AbR and AcR compared to ACB-BtS (log2[fold-change] >= 2.0; P < 0.0001) included up- and down-regulation of serine proteases, storage proteins and cytochrome P450 monooxygenases, as well as up-regulation of genes with predicted transport function. This study predicted the significant down-regulation of transcripts for previously known Bt resistance genes, aminopeptidase N1 (apn1) and apn3, as well as abccg gene in both ACB-AbR and -AcR. These data are important for the understanding of systemic differences between Bt resistant and susceptible genotypes. PMID- 28808419 TI - Exposure to Concentrated Ambient Fine Particulate Matter Induces Vascular Endothelial Dysfunction via miR-21. AB - Vascular endothelial permeability transition does not cause significant lesions, but enhanced permeability may contribute to the development of vascular and other diseases, including atherosclerosis, hypertension, heart failure and cancer. Therefore, elucidating the effect of Particulate Matter 2.5 (PM2.5) on vascular endothelial permeability could help prevent disease that might be caused by PM2.5. Our previous study and the present one revealed that PM2.5 significantly increased the permeability of vascular endothelial cells and disrupted the barrier function of the vascular endothelium in Sprague Dawley (SD) rats. We found that the effect occurred mainly through induction of signal transducer and activator of transcription 3 (STAT3) phosphorylation, further transcriptional regulation of microRNA21 (miR-21) and promotion of miR-21 expression. These changes post-transcriptionally repress tissue inhibitor of metalloproteinases 3 (TIMP3) and promote matrix metalloproteinases 9 (MMP9) expression. This work provides evidence that PM2.5 exerts direct inhibitory action on vascular endothelial barrier function and might give rise to a number of vascular diseases. PMID- 28808418 TI - Emerging roles of SIRT1 in fatty liver diseases. AB - Fatty liver diseases, which are commonly associated with high-fat/calorie diet, heavy alcohol consumption and/or other metabolic disorder causes, lead to serious medical concerns worldwide in recent years. It has been demonstrated that metabolic homeostasis disruption is most likely to be responsible for this global epidemic. Sirtuins are a group of conserved nicotinamide adenine dinucleotide (NAD+) dependent histone and/or protein deacetylases belonging to the silent information regulator 2 (Sir2) family. Among seven mammalian sirtuins, sirtuin 1 (SIRT 1) is the most extensively studied one and is involved in both alcoholic and nonalcoholic fatty liver diseases. SIRT1 plays beneficial roles in regulating hepatic lipid metabolism, controlling hepatic oxidative stress and mediating hepatic inflammation through deacetylating some transcriptional regulators against the progression of fatty liver diseases. Here we summarize the latest advances of the biological roles of SIRT1 in regulating lipid metabolism, oxidative stress and inflammation in the liver, and discuss the potential of SIRT1 as a therapeutic target for treating alcoholic and nonalcoholic fatty liver diseases. PMID- 28808420 TI - Inhibition of mTOR signaling Confers Protection against Cerebral Ischemic Injury in Acute Hyperglycemic Rats. AB - Hyperglycemia is known to exacerbate neuronal death resulted from cerebral ischemia. The mechanisms are not fully understood. The mammalian target of rapamycin (mTOR) pathway regulates cell growth, division and apoptosis. Recent studies suggest that activation of mTOR may mediate ischemic brain damage. The objective of the present experiment is to explore whether mTOR mediates ischemic brain damage in acute hyperglycemic animals. Rats were subjected to 10 min of forebrain ischemia under euglycemic, hyperglycemic and rapamycin-treated hyperglycemic conditions. The rat brain samples were collected from the cortex and hippocampi after 3h and 16h of reperfusion. The results showed that hyperglycemia significantly increased neuronal death in the cortex and hippocampus and the exacerbation effect of hyperglycemia was associated with further activation of mTOR under control and/or ischemic conditions. Inhibition of mTOR with rapamycin ameliorated the damage and suppressed hyperglycemia elevated p-MTOR, p-P70S6K and p-S6. In addition, hyperglycemia per se increased the levels of cytosolic cytochrome c and autophagy marker LC3-II, while rapamycin alleviated these alterations. It is concluded that activation of mTOR signaling may play a detrimental role in mediating the aggravating effect of hyperglycemia on cerebral ischemia. PMID- 28808421 TI - Crosstalk between Mitochondrial Fission and Oxidative Stress in Paraquat-Induced Apoptosis in Mouse Alveolar Type II Cells. AB - Paraquat (PQ), as a highly effective and nonselective herbicide, induces cell apoptosis through generation of superoxide anions which forms reactive oxygen species (ROS). Mitochondria, as regulators for cellular redox signaling, have been proved to play an important role in PQ-induced cell apoptosis. This study aimed to evaluate whether and how mitochondrial fission interacts with oxidative stress in PQ-induced apoptosis in mouse alveolar type II (AT-II) cells. Firstly, we demonstrated that PQ promoted apoptosis and release of cytochrome-c (Cyt-c). Furthermore, we showed that PQ broke down mitochondrial network, enhanced the expression of fission-related proteins, increased Drp1 mitochondrial translocation while decreased the expression of fusion-related proteins in AT-II cells. Besides, inhibiting mitochondrial fission using mdivi-1, a selective inhibitor of Drp1, markedly attenuated PQ-induced apoptosis, release of Cyt-c and the generation of ROS. These results indicate that mitochondrial fission involves in PQ-induced apoptosis. Further study demonstrated that antioxidant ascorbic acid inhibited Drp1 mitochondrial translocation, mitochondrial fission and attenuated PQ-induced apoptosis. Overall, our findings suggest that mitochondrial fission interplays with ROS in PQ-induced apoptosis in mouse AT-II cells and mitochondrial fission could serve as a potential therapeutic target in PQ poisoning. PMID- 28808423 TI - In Search for Pheromone Receptors: Certain Members of the Odorant Receptor Family in the Desert Locust Schistocerca gregaria (Orthoptera: Acrididae) Are Co expressed with SNMP1. AB - Under given environmental conditions, the desert locust (Schistocera gregaria) forms destructive migratory swarms of billions of animals, leading to enormous crop losses in invaded regions. Swarm formation requires massive reproduction as well as aggregation of the animals. Pheromones that are detected via the olfactory system have been reported to control both reproductive and aggregation behavior. However, the molecular basis of pheromone detection in the antennae of Schistocerca gregaria is unknown. As an initial step to disclose pheromone receptors, we sequenced the antennal transcriptome of the desert locust. By subsequent bioinformatical approaches, 119 distinct nucleotide sequences encoding candidate odorant receptors (ORs) were identified. Phylogenetic analyses employing the identified ORs from Schistocerca gregaria (SgreORs) and OR sequences from the related species Locusta migratoria revealed a group of locust ORs positioned close to the root, i.e. at a basal site in a phylogenetic tree. Within this particular OR group (termed basal or b-OR group), the locust OR sequences were strictly orthologous, a trait reminiscent of pheromone receptors from lepidopteran species. In situ hybridization experiments with antennal tissue demonstrated expression of b-OR types from Schistocerca gregaria in olfactory sensory neurons (OSNs) of either sensilla trichodea or sensilla basiconica, both of which have been reported to respond to pheromonal substances. More importantly, two-color fluorescent in situ hybridization experiments showed that most b-OR types were expressed in cells co-expressing the "sensory neuron membrane protein 1" (SNMP1), a marker indicative of pheromone-sensitive OSNs in insects. Analyzing the expression of a larger number of SgreOR types outside the b-OR group revealed that only a few of them were co-expressed with SNMP1. In summary, we have identified several candidate pheromone receptors from Schistocerca gregaria that could mediate responses to pheromones implicated in controlling reproduction and aggregation behavior. PMID- 28808422 TI - Lycium Barbarum Polysaccharides Decrease Hyperglycemia-Aggravated Ischemic Brain Injury through Maintaining Mitochondrial Fission and Fusion Balance. AB - Although it has been reported that polysaccharides found in Lycium barbarum possess neuroprotective effects, little is known of their ability to ameliorate hyperglycemia-aggravated ischemia/reperfusion brain injury. In this study, normoglycemic (NG) and hyperglycemic (HG) rats were compared after 30 minutes of middle cerebral artery occlusion (MCAO), followed by 24 or 27 hours of reperfusion, with HG rats pretreated with lyceum barbarum polysaccharides (LBP) or insulin. In each group, the neurological deficit, infarct volume, pathohistology, and expression of proteins, Opa1 and Drp1, were assessed to determine the efficacy of LBP in alleviating hyperglycemia-aggravated ischemia/reperfusion brain injury. Our results show that, compared to the NG group, the HG group had increases in neurological deficits, infarct volume, and evidence of neuronal pyknosis at 24- and/or 72-h of reperfusion (P<0.05) and that pre-treatment with LBP decreased these effects (P<0.05). In addition, immunohistochemistry revealed an increase of Drp1 and a decrease of Opa1 positive neurons in the HG group after 24 and 72 hours of reperfusion when compared to the NG group. LBP treatment prevented the HG-induced alterations in Drp-1 and Opa1 expression. Western blots further confirmed these findings showing that HG caused an increase in phospho-Drp1 and a decrease in Opa1 which were subsequently reversed by LBP addition. These results suggest that hyperglycemia-aggravated ischemic brain damage is associated with an alteration of mitochondrial dynamics and that pre-treatment with LBP ameliorates the hyperglycemia-enhanced ischemic brain damage through maintaining mitochondrial dynamic balance. PMID- 28808424 TI - Acetylation of hMOF Modulates H4K16ac to Regulate DNA Repair Genes in Response to Oxidative Stress. AB - Oxidative stress is considered to be a key risk state for a variety of human diseases. In response to oxidative stress, the regulation of transcriptional expression of DNA repair genes would be important to DNA repair and genomic stability. However, the overall pattern of transcriptional expression of DNA repair genes and the underlying molecular response mechanism to oxidative stress remain unclear. Here, by employing colorectal cancer cell lines following exposure to hydrogen peroxide, we generated expression profiles of DNA repair genes via RNA-seq and identified gene subsets that are induced or repressed following oxidative stress exposure. RRBS-seq analyses further indicated that transcriptional regulation of most of the DNA repair genes that were induced or repressed is independent of their DNA methylation status. Our analyses also indicate that hydrogen peroxide induces deacetylase SIRT1 which decreases chromatin affinity and the activity of histone acetyltransferase hMOF toward H4K16ac and results in decreased transcriptional expression of DNA repair genes. Taken together, our findings provide a potential mechanism by which oxidative stress suppresses DNA repair genes which is independent of the DNA methylation status of their promoters. PMID- 28808425 TI - Structure elucidation and antitumor activity of a new polysaccharide from Maerkang Tricholoma matsutake. AB - A new heteropolysaccharide was isolated from the fruiting bodies of Tricholoma matsutake which had a molecular weight of 12078 Da. The results of structural features analysis showed that T. matsutake polysaccharide, here named TMP-B, was mainly composed of alpha - D - glucose and alpha - D - galactose which ratios were 7:2 and had a backbone of 1, 4 - linked alpha - D - glucose which branches were mainly composed of two 6 - linked alpha - D - galactose residue, and the alpha - D - galactose was 1, 6 - linked. Antitumor activity results showed that heteropolysaccharide TMP-B could inhibit the growth of S180 tumor in vivo and promote the apoptosis of L929 cells in vitro. Immunoregulatory activity results showed that TMP-B could promote the proliferation of macrophages by affecting G0/G1 phase, S phases and G2/M phases and promote cytokines release and gene expression. The result of this study introduced Maerkang T. matsutake as a possible valuable source which helped to exhibit unique antitumor and immunoregulatory properties. PMID- 28808426 TI - Organisational and environmental characteristics of residential aged care units providing highly person-centred care: a cross sectional study. AB - BACKGROUND: Few studies have empirically investigated factors that define residential aged care units that are perceived as being highly person-centred. The purpose of this study was to explore factors characterising residential aged care units perceived as being highly person-centred, with a focus on organisational and environmental variables, as well as residents' and staff' characteristics. METHODS: A cross-sectional design was used. Residents (n = 1460) and staff (n = 1213) data from 151 residential care units were collected, as well as data relating to characteristics of the organisation and environment, and data measuring degree of person-centred care. Participating staff provided self reported data and conducted proxy ratings on residents. Descriptive and comparative statistics, independent samples t-test, Chi2 test, Eta Squared and Phi coefficient were used to analyse data. RESULTS: Highly person-centred residential aged care units were characterized by having a shared philosophy of care, a satisfactory leadership, interdisciplinary collaboration and social support from colleagues and leaders, a dementia-friendly physical environment, staff having time to spend with residents, and a smaller unit size. Residential aged care units with higher levels of person-centred care had a higher proportion of staff with continuing education in dementia care, and a higher proportion of staff receiving regular supervision, compared to units with lower levels of person-centred care. CONCLUSIONS: It is important to target organisational and environmental factors, such as a shared philosophy of care, staff use of time, the physical environment, interdisciplinary support, and support from leaders and colleagues, to improve person-centred care in residential care units. Managers and leaders seeking to facilitate person-centred care in daily practice need to consider their own role in supporting, encouraging, and supervising staff. PMID- 28808427 TI - Public engagement in setting healthcare priorities: a ranking exercise in Cyprus. AB - BACKGROUND: In countries such as Cyprus the financial crisis and the recession have severely affected the funding and priority setting of the health care system. There is evidence highlighting the importance of population' preferences in designing priorities for health care settings. Although public preferences have been thorough analysed in many countries, there is a research gap in terms of simultaneously investigating the relative importance and the weight of differing and competing criteria for determining healthcare priority settings. The main objective of the study was tomicron investigate public preferences for the relative utility and weight of differing and competing criteria for health care priority setting in Cyprus. METHODS: The 'conjoint analysis' technique was applied to develop a ranking exercise. The aim of the study was to identify the preferences of the participants for alternative options. Participants were asked to grade in a priority order 16 hypothetical case scenarios of patients with different disease and of diverse socio-economic characteristics awaiting treatment. The sample was purposive and consisted of 100 Cypriots, selected from public locations all over the country. RESULTS: It was revealed that the "severity of the disease" and the "age of the patient" were the key prioritization criteria. Participants assigned the smallest relative value to the criterion "healthy lifestyle". More precisely, participants older than 35 years old assigned higher relative importance to "age", while younger participants to the "severity of the disease". The "healthy lifestyle" criterion was assigned to the lowest relative importance to by all participants. CONCLUSION: In Cyprus, public participation in health care priority setting is almost inexistent. Nonetheless, it seems that the public's participation in this process could lead to a wider acceptance of the healthcare system especially as a result of the financial crisis and the upcoming reforms implemented such as the establishment of the General System of Health Insurance. PMID- 28808428 TI - A comparison of concurrent cisplatin versus cetuximab with radiotherapy in locally-advanced head and neck cancer: A bi-institutional analysis. AB - AIM: To present our experience comparing cisplatin- and cetuximab-based radiotherapy for locally-advanced head and neck squamous cell carcinoma. BACKGROUND: The comparative effectiveness of cisplatin-based chemoradiotherapy (CRT) versus cetuximab-based bioradiotherapy (BRT) for locally-advanced head and neck squamous cell carcinoma (LAHNSCC) continues to be explored. MATERIALS AND METHODS: Outcomes of LAHNSCC patients treated with CRT (125) or BRT (34) at two institutions were compared retrospectively, with attention to overall survival (OS), cancer-specific survival (CSS), locoregional control (LRC), and distant control (DC). Univariate analysis (UVA) using Cox regression was performed to explore the association of intervention with survival and disease control, and multivariate (MVA) Cox regression was then performed to assess the association of intervention with survival. RESULTS: There were significant baseline differences between the CRT and BRT groups with respect to age, race, performance status, N classification, tobacco history, and human papillomavirus status. UVA demonstrated inferiority of BRT versus CRT with respect to both OS (hazard ratio [HR] 2.19, 95% confidence interval [95%CI] 1.03-4.63, p = 0.04) and CSS (HR 3.33, 95%CI 1.42-7.78, p < 0.01), but non-significantly different outcomes in LRC (HR 0.99, 95%CI 0.37-2.61, p = 0.98) and DC (HR 2.01, 95%CI 0.78-5.37, p = 0.14). On MVA, there was no significant OS difference between interventions (HR 1.19, 95%CI 0.42-3.35, p = 0.74); there were too few events for the other outcomes to draw meaningful conclusions with MVA. CONCLUSIONS: In our retrospective analysis, patients undergoing CRT experienced improved OS and CSS over those receiving BRT; however, disease control did not significantly differ. These findings may inform management of LAHNSCC patients. PMID- 28808429 TI - Fast, Reliable 3D Amide Proton Transfer Imaging of Brain Tumors at 3T with Variably-accelerated Sensitivity Encoding (vSENSE). AB - The clinical use of amide proton transfer (APT) imaging is hindered by long scan times. Accuracy generally limits the use of conventional sensitivity encoding (SENSE) methods in APT, to an acceleration factor of 2. A novel variably accelerated sensitivity encoding (vSENSE) method can provide more accurate results and therefore substantially higher overall acceleration factors than conventional SENSE. Here, vSENSE is further developed to eliminate the requirement that one fully-sampled APT frame be acquired, and extended to three dimensions (3D). Furthermore, we combine vSENSE with parallel transmit saturation, and apply it proactively to three normal volunteers and eleven patients with brain tumors. PMID- 28808430 TI - Amelogenin Affects Brushite Crystal Morphology and Promotes Its Phase Transformation to Monetite. AB - Amelogenin protein is involved in organized apatite crystallization during enamel formation. Brushite (CaHPO4.2H2O), one of the precursors of hydroxyapatite mineralization in vitro, has been used for fabrication of biomaterials for hard tissue repair. In order to explore its potential application in biomimetic material synthesis, we studied the influence of the enamel protein amelogenin on brushite morphology and phase transformation to monetite. Our results show that amelogenin can adsorb onto the surface of brushite, leading to the formation of layered morphology on the (010) face. Amelogenin promoted the phase transformation of brushite into monetite (CaHPO4) in the dry state, presumably by interacting with crystalline water layers in brushite unit cells. Changes to the crystal morphology mediated by amelogenin continued even after the phase transformation from brushite to monetite, leading to the formation of organized platelets with an interlocked structure. This effect of amelogenin on brushite morphology and the phase transformation to monetite could provide a new approach to developing biomimetic materials. PMID- 28808431 TI - Reconstructing three-dimensional protein crystal intensities from sparse unoriented two-axis X-ray diffraction patterns. AB - Recently, there has been a growing interest in adapting serial microcrystallography (SMX) experiments to existing storage ring (SR) sources. For very small crystals, however, radiation damage occurs before sufficient numbers of photons are diffracted to determine the orientation of the crystal. The challenge is to merge data from a large number of such 'sparse' frames in order to measure the full reciprocal space intensity. To simulate sparse frames, a dataset was collected from a large lysozyme crystal illuminated by a dim X-ray source. The crystal was continuously rotated about two orthogonal axes to sample a subset of the rotation space. With the EMC algorithm [expand-maximize-compress; Loh & Elser (2009). Phys. Rev. E, 80, 026705], it is shown that the diffracted intensity of the crystal can still be reconstructed even without knowledge of the orientation of the crystal in any sparse frame. Moreover, parallel computation implementations were designed to considerably improve the time and memory scaling of the algorithm. The results show that EMC-based SMX experiments should be feasible at SR sources. PMID- 28808432 TI - Grazing-incidence small-angle neutron scattering from structures below an interface. AB - Changes of scattering are observed as the grazing angle of incidence of an incoming beam increases and probes different depths in samples. A model has been developed to describe the observed intensity in grazing-incidence small-angle neutron scattering (GISANS) experiments. This includes the significant effects of instrument resolution, the sample transmission, which depends on both absorption and scattering, and the sample structure. The calculations are tested with self organized structures of two colloidal samples with different size particles that were measured on two different instruments. The model allows calculations for various instruments with defined resolution and can be used to design future improved experiments. The possibilities and limits of GISANS for different studies are discussed using the model calculations. PMID- 28808433 TI - FELIX: an algorithm for indexing multiple crystallites in X-ray free-electron laser snapshot diffraction images. AB - A novel algorithm for indexing multiple crystals in snapshot X-ray diffraction images, especially suited for serial crystallography data, is presented. The algorithm, FELIX, utilizes a generalized parametrization of the Rodrigues-Frank space, in which all crystal systems can be represented without singularities. The new algorithm is shown to be capable of indexing more than ten crystals per image in simulations of cubic, tetragonal and monoclinic crystal diffraction patterns. It is also used to index an experimental serial crystallography dataset from lysozyme microcrystals. The increased number of indexed crystals is shown to result in a better signal-to-noise ratio, and fewer images are needed to achieve the same data quality as when indexing one crystal per image. The relative orientations between the multiple crystals indexed in an image show a slight tendency of the lysozme microcrystals to adhere on ([Formula: see text]10) facets. PMID- 28808434 TI - Continuous diffraction of molecules and disordered molecular crystals. AB - The intensities of far-field diffraction patterns of orientationally aligned molecules obey Wilson statistics, whether those molecules are in isolation (giving rise to a continuous diffraction pattern) or arranged in a crystal (giving rise to Bragg peaks). Ensembles of molecules in several orientations, but uncorrelated in position, give rise to the incoherent sum of the diffraction from those objects, modifying the statistics in a similar way as crystal twinning modifies the distribution of Bragg intensities. This situation arises in the continuous diffraction of laser-aligned molecules or translationally disordered molecular crystals. This paper develops the analysis of the intensity statistics of such continuous diffraction to obtain parameters such as scaling, beam coherence and the number of contributing independent object orientations. When measured, continuous molecular diffraction is generally weak and accompanied by a background that far exceeds the strength of the signal. Instead of just relying upon the smallest measured intensities or their mean value to guide the subtraction of the background, it is shown how all measured values can be utilized to estimate the background, noise and signal, by employing a modified 'noisy Wilson' distribution that explicitly includes the background. Parameters relating to the background and signal quantities can be estimated from the moments of the measured intensities. The analysis method is demonstrated on previously published continuous diffraction data measured from crystals of photosystem II [Ayyer et al. (2016 ?), Nature, 530, 202-206]. PMID- 28808435 TI - Double cone of eigendirections in optically active ethylenediammonium selenate crystals. AB - Circular birefringence (CB) is generally responsible for only a small perturbation to the state of light polarization in crystals that also exhibit linear birefringence (LB). As such, the magnetoelectric tensor of gyration, which gives rise to CB and optical activity, is less well determined than the electric permittivity tensor in optical models of the Mueller matrix. To visualize the effect of the magnetoelectric tensor on polarimetric measurements, reported here are experimental mappings of the Mueller matrix and of the CB in a new chiral crystal with accidental null LB at an accessible optical frequency. Single crystals of ethylenediammonium selenate (EDSeO4) were synthesized and characterized by X-ray diffraction and Mueller matrix measurements in transmission and reflection. The crystals are isomorphous with the corresponding sulfate salt. They are tetragonal, space group P41(3)212. The constitutive relations of EDSeO4 were recovered using a partial wave summation of incoherent reflections. The extraordinary and ordinary refractive indices cross at 364 nm (3.41 eV), a scenario commonly called the 'isotropic point' or 'iso-index point'. At this wavelength, the magnetoelectric tensor fully describes the polarization transformation, giving rise to a double cone of eigendirections. PMID- 28808436 TI - Ewald: an extended wide-angle Laue diffractometer for the second target station of the Spallation Neutron Source. AB - Visualizing hydrogen atoms in biological materials is one of the biggest remaining challenges in biophysical analysis. While X-ray techniques have unrivaled capacity for high-throughput structure determination, neutron diffraction is uniquely sensitive to hydrogen atom positions in crystals of biological materials and can provide a more complete picture of the atomic and electronic structures of biological macromolecules. This information can be essential in providing predictive understanding and engineering control of key biological processes, for example, in catalysis, ligand binding and light harvesting, and to guide bioengineering of enzymes and drug design. One very common and large capability gap for all neutron atomic resolution single-crystal diffractometers is the weak flux of available neutron beams, which results in limited signal-to-noise ratios giving a requirement for sample volumes of at least 0.1 mm3. The ability to operate on crystals an order of magnitude smaller (0.01 mm3) will open up new and more complex systems to studies with neutrons which will help in our understanding of enzyme mechanisms and enable us to improve drugs against multi resistant bacteria. With this is mind, an extended wide-angle Laue diffractometer, 'Ewald', has been designed, which can collect data using crystal volumes below 0.01 mm3. PMID- 28808437 TI - How to assign a (3 + 1)-dimensional superspace group to an incommensurately modulated biological macromolecular crystal. AB - Periodic crystal diffraction is described using a three-dimensional (3D) unit cell and 3D space-group symmetry. Incommensurately modulated crystals are a subset of aperiodic crystals that need four to six dimensions to describe the observed diffraction pattern, and they have characteristic satellite reflections that are offset from the main reflections. These satellites have a non-integral relationship to the primary lattice and require q vectors for processing. Incommensurately modulated biological macromolecular crystals have been frequently observed but so far have not been solved. The authors of this article have been spearheading an initiative to determine this type of crystal structure. The first step toward structure solution is to collect the diffraction data making sure that the satellite reflections are well separated from the main reflections. Once collected they can be integrated and then scaled with appropriate software. Then the assignment of the superspace group is needed. The most common form of modulation is in only one extra direction and can be described with a (3 + 1)D superspace group. The (3 + 1)D superspace groups for chemical crystallographers are fully described in Volume C of International Tables for Crystallography. This text includes all types of crystallographic symmetry elements found in small-molecule crystals and can be difficult for structural biologists to understand and apply to their crystals. This article provides an explanation for structural biologists that includes only the subset of biological symmetry elements and demonstrates the application to a real-life example of an incommensurately modulated protein crystal. PMID- 28808438 TI - ATSAS 2.8: a comprehensive data analysis suite for small-angle scattering from macromolecular solutions. AB - ATSAS is a comprehensive software suite for the analysis of small-angle scattering data from dilute solutions of biological macromolecules or nanoparticles. It contains applications for primary data processing and assessment, ab initio bead modelling, and model validation, as well as methods for the analysis of flexibility and mixtures. In addition, approaches are supported that utilize information from X-ray crystallography, nuclear magnetic resonance spectroscopy or atomistic homology modelling to construct hybrid models based on the scattering data. This article summarizes the progress made during the 2.5-2.8 ATSAS release series and highlights the latest developments. These include AMBIMETER, an assessment of the reconstruction ambiguity of experimental data; DATCLASS, a multiclass shape classification based on experimental data; SASRES, for estimating the resolution of ab initio model reconstructions; CHROMIXS, a convenient interface to analyse in-line size exclusion chromatography data; SHANUM, to evaluate the useful angular range in measured data; SREFLEX, to refine available high-resolution models using normal mode analysis; SUPALM for a rapid superposition of low- and high-resolution models; and SASPy, the ATSAS plugin for interactive modelling in PyMOL. All these features and other improvements are included in the ATSAS release 2.8, freely available for academic users from https://www.embl-hamburg.de/biosaxs/software.html. PMID- 28808439 TI - SAXS4COLL: an integrated software tool for analysing fibrous collagen-based tissues. AB - This article provides an overview of a new integrated software tool for reduction and analysis of small-angle X-ray scattering (SAXS) data from fibrous collagen tissues, with some wider applicability to other cylindrically symmetric scattering systems. SAXS4COLL combines interactive features for data pre processing, bespoke background subtraction, semi-automated peak detection and calibration. Both equatorial and meridional SAXS peak parameters can be measured, and the former can be deconstructed into cylinder and lattice contributions. Finally, the software combines functionality for determination of collagen spatial order parameters with a rudimentary orientation plot capability. PMID- 28808440 TI - Corrigendum: Coupling Developmental Physiology, Photoperiod, and Temperature to Model Phenology and Dynamics of an Invasive Heteropteran, Halyomorpha halys. AB - [This corrects the article on p. 165 in vol. 7, PMID: 27242539.]. PMID- 28808441 TI - An Improved Extrapolation Scheme for Truncated CT Data Using 2D Fourier-Based Helgason-Ludwig Consistency Conditions. AB - We improve data extrapolation for truncated computed tomography (CT) projections by using Helgason-Ludwig (HL) consistency conditions that mathematically describe the overlap of information between projections. First, we theoretically derive a 2D Fourier representation of the HL consistency conditions from their original formulation (projection moment theorem), for both parallel-beam and fan-beam imaging geometry. The derivation result indicates that there is a zero energy region forming a double-wedge shape in 2D Fourier domain. This observation is also referred to as the Fourier property of a sinogram in the previous literature. The major benefit of this representation is that the consistency conditions can be efficiently evaluated via 2D fast Fourier transform (FFT). Then, we suggest a method that extrapolates the truncated projections with data from a uniform ellipse of which the parameters are determined by optimizing these consistency conditions. The forward projection of the optimized ellipse can be used to complete the truncation data. The proposed algorithm is evaluated using simulated data and reprojections of clinical data. Results show that the root mean square error (RMSE) is reduced substantially, compared to a state-of-the-art extrapolation method. PMID- 28808442 TI - Firefly Mating Algorithm for Continuous Optimization Problems. AB - This paper proposes a swarm intelligence algorithm, called firefly mating algorithm (FMA), for solving continuous optimization problems. FMA uses genetic algorithm as the core of the algorithm. The main feature of the algorithm is a novel mating pair selection method which is inspired by the following 2 mating behaviors of fireflies in nature: (i) the mutual attraction between males and females causes them to mate and (ii) fireflies of both sexes are of the multiple mating type, mating with multiple opposite sex partners. A female continues mating until her spermatheca becomes full, and, in the same vein, a male can provide sperms for several females until his sperm reservoir is depleted. This new feature enhances the global convergence capability of the algorithm. The performance of FMA was tested with 20 benchmark functions (sixteen 30-dimensional functions and four 2-dimensional ones) against FA, ALC-PSO, COA, MCPSO, LWGSODE, MPSODDS, DFOA, SHPSOS, LSA, MPDPGA, DE, and GABC algorithms. The experimental results showed that the success rates of our proposed algorithm with these functions were higher than those of other algorithms and the proposed algorithm also required fewer numbers of iterations to reach the global optima. PMID- 28808443 TI - Angiotensin-Converting Enzyme Inhibition and Parathyroid Hormone Secretion. AB - BACKGROUND: Prior studies suggest that renin-angiotensin-aldosterone system (RAAS) inhibitors decrease parathyroid hormone (PTH) secretion. OBJECTIVE: To evaluate the effect of angiotensin-converting enzyme inhibitors (ACEi) on serum PTH in participants with and without primary hyperparathyroidism (P-HPT). METHODS: An open-label, single-arm, pilot study whereby participants with and without P-HPT had PTH were evaluated before and after 1 week of maximally tolerated lisinopril therapy. RESULTS: A total of 12 participants with, and 15 participants without, P-HPT successfully completed the protocol. Following 1 week of lisinopril, participants with P-HPT had a decrease in systolic blood pressure (SBP) (-6.4 mmHg, P < 0.01), an increase in plasma renin activity (PRA) (+1.50 ng/mL/h, P = 0.06), and a decrease in PTH (79.5 (21.6) to 70.9 (19.6) pg/mL, ? = 8.6 pg/mL, P = 0.049); however, serum and urine calcium did not change. In contrast, although 1 week of lisinopril significantly decreased SBP and increased PRA among participants without P-HPT, there were no changes in PTH or calcium. CONCLUSION: In this short pilot investigation, 1 week of maximally titrated ACEi did not impact PTH in participants without P-HPT, but resulted in a modest and marginally significant reduction of PTH but not calcium, among participants with P-HPT. This trial is registered with ClinicalTrials.gov NCT01691781. PMID- 28808444 TI - Association of SUDOSCAN Values with Vibration Perception Threshold in Chinese Patients with Type 2 Diabetes Mellitus. AB - AIMS/INTRODUCTION: SUDOSCAN has been proved to be an efficient method in detecting diabetic microvascular complications. In this study, we determine to detect the possible relationship between vibration perception threshold (VPT) and cardiac autonomic neuropathy (CAN) values produced by SUDOSCAN. MATERIALS AND METHODS: A total of 920 Chinese patients with T2DM were enrolled in the study. Spearman correlation analysis and multivariate regression analysis were performed to determine the relation between CAN and VPT values. Mean VPT values across the CAN value tertiles were analyzed stratified by HbA1c status. RESULTS: In the study, we discovered a relatively high correlation between CAN value and both VPT values from dorsal feet and toes. Multivariate regression analyses also showed a significant relation between VPT and CAN values after adjusting all covariates. The mean value of VPT decreased across the SUDOSCAN-CAN value quartiles in both groups, and it was higher in patients with HbA1C > 9% than in patients with HbA1C < 9% across all quartiles of the SUDOSCAN-CAN except for the VPT mean in the low quartile of the SUDOSCAN-CAN value. CONCLUSIONS: All these results suggested that SUDOSCAN-CAN result was associated with VPT value which indicated a probable link between VPT value and cardiovascular autonomic dysfunction. PMID- 28808445 TI - Targeting Adult Neurogenesis for Poststroke Therapy. AB - Adult neurogenesis mainly occurs at the subventricular zone (SVZ) on the walls of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus (DG). However, the majority of newborn neurons undergo programmed cell death (PCD) during the period of proliferation, migration, and integration. Stroke activates neural stem cells (NSCs) in both SVZ and SGZ. This process is regulated by a wide variety of signaling pathways. However, the newborn neurons derived from adult neurogenesis are insufficient for tissue repair and function recovery. Thus, enhancing the endogenous neurogenesis driven by ischemia and promoting the survival of newborn neurons can be promising therapeutic interventions for stroke. Here, we present an overview of the process of adult neurogenesis and the potential of stroke-induced neurogenesis on brain repair. PMID- 28808446 TI - Neuron-Specific Fluorescence Reporter-Based Live Cell Tracing for Transdifferentiation of Mesenchymal Stem Cells into Neurons by Chemical Compound. AB - Although transdifferentiation of mesenchymal stem cells (MSCs) into neurons increases the possibility of therapeutic use of MSCs for neurodevelopmental disorders, the use of MSCs has the limitation on differentiation efficiency to neuronal lineage and lack of an easy method to monitor the transdifferentiation. In this study, using time-lapse live cell imaging, we assessed the neuronal differentiation of MSCs induced by a small molecule "NHPDQC (N-hydroxy-2-oxo-3-(3 phenylprophyl)-1,2-dihydroquinoxaline-6-carboxamide, C18H17N3O3)." Plasmid vector containing red fluorescence reporter genes under the control of the tubulin alpha1 (Talpha1) promoter (pTalpha1-DsRed2) traced the neuronal differentiation of MSCs. Two days after NHPDQC treatment, MSCs showed neuron-like phenotype with neurite outgrowth and high expression of neuron-specific markers in more than 95% cells. The fluorescence signals increased in the cytoplasm of pTalpha1-DsRed2 transfected MSCs after NHPDQC treatment. In vitro monitoring of MSCs along the time courses showed progressive increase of fluorescence till 30 h after treatment, corresponding with the increase in neurite length. We examined an efficient neuronal differentiation of MSCs by NHPDQC alone and monitored the temporal changes of neuronal differentiation by neuron-specific fluorescence reporter along time. This method would help further our understanding of the differentiation of MSCs to produce neurons by simple treatment of small molecule. PMID- 28808447 TI - Predictors for Mortality among Multidrug-Resistant Tuberculosis Patients in Tanzania. AB - PROBLEM: Factors related to MDRTB mortality in Tanzania have not been adequately explored and reported. OBJECTIVES: To determine demographic, clinical, radiographic, and laboratory factors associated with MDRTB mortality in a Tanzanian TB Referral Hospital. METHODOLOGY: This was a cross-sectional study with 193 participants. Demographic, clinical, laboratory, and radiological data were collected, and their associations with mortality among MDRTB patients were determined. RESULTS AND CONCLUSIONS: Cough was the commonest finding among these MDRTB patients, with 179 (92.75%) of them presenting with cough, followed by chest X-ray consolidation in 156 patients (80.83%) and history of previous TB treatment in 151 patients (78.24%). Cigarette smoking, HIV positivity, and low CD4 counts were significantly associated with MDRTB mortality, p values of 0.034, 0.044, and 0.048, respectively. Fever on the other hand was at the borderline with p value of 0.059. We conclude that cigarette smoking and HIV status are significant risk factors for mortality among MDRTB patients. HIV screening should continually be emphasized among patients and the general community for early ARTs initiation. Based on the results from our study, policy makers and public health personnel should consider addressing tobacco cessation as part of national TB control strategy. PMID- 28808448 TI - Relevance of the NR4A sub-family of nuclear orphan receptors in trophoblastic BeWo cell differentiation. AB - Nur-77, a member of the NR4A sub-family of nuclear orphan receptors, is downregulated in the placentae of pre-eclamptic women. Here, we investigate the relevance of Nor-1, Nurr-1 and Nur-77 in trophoblastic cell differentiation. Their transcript levels were found to be significantly upregulated in BeWo cells treated with forskolin. The maximum increase was observed after 2 h, with a second peak in the expression levels after 48 h. The expression of NR4A sub family members was also found to be upregulated in BeWo cells after treatment with hCG and GnRH. A similar significant increase was observed at the respective protein levels after 2 and 48 h of treatment with forskolin, hCG or GnRH. Silencing Nor-1, Nurr-1 or Nur-77 individually did not show any effect on forskolin-, hCG- and/or GnRH-mediated BeWo cell fusion and/or hCG secretion. After silencing any one member of the NR4A sub-family, an increase in the transcript levels of the other sub-family members was observed, indicating a compensatory effect due to their functional redundancy. Simultaneously silencing all three NR4A sub-family members significantly downregulated forskolin- and hCG mediated BeWo cell fusion and/or hCG secretion. However, a considerable amount of cell death occurred after forskolin or hCG treatment as compared to the control siRNA-transfected cells. These results suggest that the NR4A sub-family of nuclear orphan receptors has a role in trophoblastic cell differentiation. PMID- 28808449 TI - Efficacy of Enamel Matrix Derivative in Vital Pulp Therapy: A Review of Literature. AB - INTRODUCTION: Vital pulp therapy (VPT) aims to preserve the health and maintain life of the tooth pulp which has been compromised by caries, trauma or restorative procedures. Recently, enamel matrix derivative (EMD) has been introduced as a material for vital pulp therapy. The aim of this review is to critically analyze and summarize the available literature on EMD for VPT. METHODS AND MATERIALS: Online databases (PubMED/MEDLINE, Google Scholar, ISI Web of Science, and Wiley-Online) were searched by using the following keywords in various combinations: Enamel Matrix Derivative, Emdogain, 'Vital Pulp Therapy, 'Apexogenisis', Apexification, Pulp Capping, Endodontics, Dentine and Pulpotomy for studies indexed from January 1949 to April 2016. We used an English-limited search in Google.co.uk for the missing grey literature. All studies fulfilling the selection criteria were carefully reviewed for the focused question: "Does using EMD in VPT, compared with other materials, result in better clinical, radiographic and histological outcomes?". RESULTS: The primary search resulted in 18 articles of which, 14 articles (including 6 animal studies and 6 clinical trials and 2 case reports) met the inclusion criteria for this review and hence were included. The number of teeth tested in the animal studies ranged from 8 to 144 including pigs, rats and dogs teeth. A number of studies used EMD in the experimental group in comparison with calcium hydroxide, propylene glycol alginate (PGA) and MTA as a control. The observation period ranged from 1 to 2 months and 4 out of 6 animal trials reported more favorable outcomes with EMD while two studies reported comparable outcomes. CONCLUSION: Although EMD has potential for various applications in endodontics, studies conducted to date have failed to demonstrate any significant advantage of EMD over conventional VPT materials. Additionally, the 5-year and 10-year survival rate of EMD-treated teeth is not yet known. Hence, studies with a longer follow-up periods are required to deduce the long-term viability of teeth treated with EMD. PMID- 28808450 TI - The Efficacy of Buccal Infiltration of 4% Articaine and PSA Injection of 2% Lidocaine on Anesthesia of Maxillary Second Molars. AB - INTRODUCTION: During the early mixed dentition period, the location of the deciduous maxillary second molar results in ineffectiveness of the infiltration technique in this area. In such cases, administration of posterior superior alveolar (PSA) nerve block is recommended; however, such a technique has some complications. The present study was undertaken to compare the effects of buccal infiltration of 4% Articaine and PSA technique with 2% Lidocaine on the success of anesthesia of maxillary deciduous second molars in 6 to 9-year old children. METHODS AND MATERIALS: In the present double-blind randomized clinical trial, 56 children aged 6-9 years requiring vital pulp therapy of deciduous maxillary second molar were included. In group 1, 4% Articaine was injected using a buccal infiltration technique. In group 2, 2% Lidocaine was injected using the PSA nerve block technique. After 10 min, the caries was removed and access cavity preparation was instituted. The patients were asked to report the presence or absence of pain during the procedure. Therefore, the existence of pain was measured by the patient's self-report. Data were analyzed with descriptive statistical methods and the chi-squared test. RESULTS: Pain was reported by 6 (21.4%) and 9 (32.1%) subjects in the Articaine and Lidocaine groups, respectively. Chi-squared test did not reveal any significant differences between the two groups (P=0.54). CONCLUSION: Under the limitations of the present study, there was no significant differences between the results of Articaine buccal infiltration and Lidocaine PSA technique, so Articaine buccal infiltration can be used as a substitute for the PSA technique. PMID- 28808451 TI - Prevalence of Taurodont Molars in a Selected Iranian Adult Population. AB - INTRODUCTION: Taurodontism is an anomaly characterized by elongated crowns and consumedly apical location of the bifurcation area. This study aimed to determine the prevalence of taurodontism in molars based on digital panoramic radiographies in eight cities of Iran. METHODS AND MATERIALS: This descriptive cross-sectional study was conducted on 2360 digital panoramic radiographs taken for different treatment purposes. Demographic information of patients was recorded and radiographs were evaluated for presence of taurodont molars. The prevalence rates were calculated and the data were analyzed using SPSS software version 18 via paired t-test, chi square test and ANOVA. RESULTS: A total of 2360 panoramic radiographs (from 51.4% male and 48.6% female patients) were evaluated and the prevalence of taurodontism was reported 22.9% (22.6% in males and 23.3% in females) (P>0.05). Its prevalence was 51.67% in the right and 48.33% in the left quadrants (P>0.05), 34.1% in the mandible and 65.9% in the maxilla (P=0.000) and 79.52% in the second and 20.48% in the first molar (P=0.000). The prevalence of hypotaurodontism, mesotaurodontism and hypertaurodontism was 84.13%, 11.07% and 4.8%, respectively. CONCLUSION: The prevalence of taurodont molars was high in Iran and it was more common in the second molars and in the maxilla. Hypotaurodontism had the highest prevalence. PMID- 28808452 TI - Root Morphology and Canal Configuration of First and Second Maxillary Molars in a Selected Iranian Population: A Cone-Beam Computed Tomography Evaluation. AB - INTRODUCTION: The aim of this investigation was to evaluate root canal morphology of maxillary first and second molars and also to assess the prevalence and morphology of the second mesiobuccal canal (MB2) in these teeth, using cone-beam computed tomography (CBCT). METHODS AND MATERIALS: In this cross-sectional study, the total of 470 CBCT images from the archive of Radiology Department of Isfahan University of Medical Sciences (IUMS), Iran, was evaluated and 295 images were selected. The number of roots, and canal configuration were determined based on Vertucci's classification system. The data was analyzed using SPSS 20, and P values less than 0.05 were considered significant. RESULTS: A total of 295 images from 295 patients (165 females and 130 males), including 389 maxillary first (197 right and 192 left) and 460 maxillary second (235 right and 225 left) molars were evaluated. The prevalence of MB2 canals were 70.2% and 43.4% in the maxillary first and second molars, respectively. The most common type of Vertucci's classification was type II (53.1%), followed by type I. CONCLUSION: The second mesiobuccal canal was present in almost two thirds of first and less than half of second molars. The morphology and canal configuration of a maxillary molar can almost predict the morphology of contralateral molar. However, it does not relate to the ipsilateral molar. PMID- 28808453 TI - Bond Strength of White Mineral Trioxide Aggregate with and without Disodium Hydrogen Phosphate with Different Liquid-to-Powder Ratios. AB - INTRODUCTION: Mineral trioxide aggregate (MTA) can be used in the treatment of irritated vital pulp and repair of root perforations. However, the initial reaction of inflammatory cells to this material and also its setting time are not ideal. Studies have shown that disodium hydrogen phosphate (DHP), decreases the setting time of MTA, with no effect on its pH. This study was undertaken to evaluate the effect of DHP on push-out bond strength of MTA at different liquid to-powder ratios. METHODS AND MATERIALS: A total of 120 samples were prepared from the middle third of the roots of single-rooted teeth for evaluation of push out bond strength. The push-out bond strength was measured in both groups after 72 h at different liquid-to-powder ratios, including 0.33:1, 0.5:1 and 0.6:1. Factorial ANOVA and Tukey's HSD post-hoc tests were used to compare the differences between the independent groups. Statistical significant was set at P<0.05. RESULTS: The push-out bond strengths of pure MTA and MTA+DHP groups were 10.96+/-5.78 and 13.32+/-5.03, respectively. Tukey's HSD post-hoc test revealed significant differences between the two groups. Furthermore, there were no interactive effect between material and the liquid: powder ratio. CONCLUSION: Incorporation of DHP into MTA resulted in an increase in push-out bond strength of MTA, and an increase in liquid-to-powder ratio resulted in a decrease in push out bond strength. PMID- 28808454 TI - Concurrent Effects of Bleaching Materials and the Size of Root Canal Preparation on Cervical Dentin Microhardness. AB - INTRODUCTION: The aim of the present study was to evaluate the concurrent effect of root canal preparation size and intra coronal bleaching on dentin microhardness. METHODS AND MATERIALS: Seventy-two intact anterior teeth were root canal treated and randomly divided into two groups (n=36) according to the size of coronal root canal preparation. The coronal portions of the canals were then enlarged with #2 and 4 Peeso reamers, respectively. Following root canal obturation, teeth were assigned into three groups (n=12) to be treated with bleaching agents containing 35% hydrogen peroxide (HP), sodium perborate (SP) and distilled water as control group. The teeth were stored at 37oC and 100% humidity for 7 days. Dentinal blocks with 3 mm thickness were obtained from the cervical region and Vickers microhardness number (VHN) were measured for outer and inner dentin in each tooth sample. Data were analyzed using two-way ANOVA and Tukey's HSD tests. RESULTS: In the outer dentin, the mean VHN in the HP and control groups showed statistically significant differences (P=0.047). The mean VHN of inner dentin for the large preparation size was statistically higher in comparison to the small preparation size (P=0.042). There was a statistically significant difference in the mean VHN of inner dentin with small preparation size between HP and SP groups (P=0.029) and HP and control groups (P=0.021). CONCLUSION: Intra coronal bleaching with 35% hydrogen peroxide, affects the inner and outer dentin significantly. Excessive removal of cervical dentin, following root canal preparation, alongside the adverse effect of bleaching materials on dentin could result in the tooth fracture. PMID- 28808455 TI - Effect of Nickel-Chromium and Non-Precious Gold Color Alloy Cast Posts on Fracture Resistance of Endodontically Treated Teeth. AB - INTRODUCTION: Root canal-treated teeth are weaker than vital teeth and are more susceptible to fractures. Therefore, special precautions should be adhered to, such as the use of various types of cast or prefabricated posts. Regarding the effect of post material on fracture resistance of teeth, the aim of this in vitro study was to evaluate the effect of non-precious gold color alloy (NPG) and nickel-chrome (Ni-Cr) cast posts on resistance of endodontically treated teeth. METHODS AND MATERIALS: In this study, 30 freshly extracted single-rooted premolar teeth were randomly divided into two groups. After root canal treatment, post patterns were made with Duralay in group 1 and cast with Ni-Cr alloy; in group 2, the patterns were cast with NPG alloy. Zinc phosphate cement was used for cementation in this study. Shear force was applied at 1 mm/min at 45oC to the buccal cusps until root fracture occurred. Independent sample t test was used for data analysis by using SPSS version 21. The level of significance was set at 0.05. RESULTS: Mean fracture resistance values were 1380+/-454 N for Ni-Cr versus 1964+/-640 N for NPG, with significant differences (P=0.007). CONCLUSION: The fracture resistance of endodontically treated teeth with non-precious gold color alloy cast post was higher than that of endodontically treated teeth with Ni-Cr cast post. PMID- 28808456 TI - An In vitro Comparison of Apically Extruded Debris Using Reciproc, ProTaper Universal, Neolix and Hyflex in Curved Canals. AB - INTRODUCTION: As a consequence of root canal preparation, dentinal chips, irrigants and pulp remnants are extruded into preradicular space. This phenomenon may lead to post endodontic flare-ups. The purpose of this study was to compare the amount of extruded debris with four endodontic NiTi engine-driven systems. METHODS AND MATERIALS: Sixty mesiobuccal roots of maxillary molars with 15-30 curvature were divided randomly into four groups (n=15). Each group was instrumented up to apical size of 25 using Reciproc, ProTaper Universal, Neolix and Hyflex. Bidistilled water was used as irrigant and extruded debris was collected in pre-weighted Eppendorf tubes. Tubes were stored in incubator for drying the debris. Extruded debris were weighted in electronic microbalance with accuracy of 0.0001 g. The raw data was analyzed with one way analysis of variance (ANOVA) and Tukey's HSD post hoc test. Level of significance was set at 0.05. RESULTS: The debris extrusion with Reciproc files was significantly higher than the other groups (P<0.05). Hyflex significantly extruded less debris than other files (P<0.05). There was no significant difference between ProTaper Universal and Neolix regarding the amount of extruded debris (P=0.98). CONCLUSION: All systems extruded debris during the instrumentation. Reciproc system significantly extruded more debris. Caution should be taken when interpreting the results of this study and applying it to the real clinical situation. PMID- 28808457 TI - Physicochemical Properties of MTA and Portland Cement after Addition of Aloe Vera. AB - INTRODUCTION: The aim of this in vitro study was to determine the liquid-powder ratio, setting time, solubility, dimensional change, pH, and radiopacity of white structural and non-structural Portland cement, ProRoot MTA and MTA Bio, associated with a 2% glycolic solution containing Aloe Vera, as vehicle. METHODS AND MATERIALS: Five samples of each material were used for each test, according to the American National Standards Institute/American Dental Association (ANSI/ADA) specification No. 57. Statistical analyses were performed using ANOVA and Tukey's test at 5% significance. When sample distribution was not normal, non parametric analysis of variance and the Kruskal-Wallis test were used (alpha=0.05). RESULTS: No statistical differences were found in liquid-powder ratios among the tested materials. ProRoot MTA showed the longest setting time. Dimensional change values were acceptable in all groups. Also, no significant differences were found in pH values and pH was alkaline in all samples throughout the experiment. Mean radiopacity results obtained for white Portland cements did not meet ANSI/ADA requirements, and were significantly lower than those obtained for MTA-based cements. Finally, Portland cements showed significantly higher mean solubility values compared to the other samples. CONCLUSION: The physicochemical properties of the tested materials in association with Aloe Vera were compatible with ANSI/ADA requirements, except for the white Portland cements, which failed to meet the radiopacity specification. PMID- 28808458 TI - Effect of Propylene Glycol on the Sealing Ability of Mineral Trioxide Aggregate and Calcium-Enriched Mixture Cement Apical Barriers. AB - INTRODUCTION: Propylene glycol (PG) improves the handling, physical, and chemical properties of mineral trioxide aggregate (MTA). This study aimed to evaluate the effect of PG on the sealing ability of MTA and calcium-enriched mixture (CEM) apical barriers. METHODS AND MATERIALS: A total of 70 extracted human maxillary single-rooted teeth were prepared using ProTaper rotary system. The apical 3 mm of the root tips were resected and the root canals were enlarged with Peeso reamers up to #4, to create open apex teeth. The teeth were then randomly divided into four experimental (n=15) and two control (n=5) groups. Group1: MTA+ MTA liquid, group2; MTA+MTA liquid (80%) + PG (20%), group3; CEM+CEM liquid, group4; CEM+ liquid (80%) + PG (20%). Cements were mixed with their respective mixing agents and a 4-mm thick apical plug was fabricated. The microleakage was measured on day 1, 3, 7 and 21 using a fluid filtration technique. The repeated measures ANOVA and Sidak test were used to analyze the data. RESULTS: All experimental groups demonstrated various amounts of microleakage. No significant difference was found between MTA and CEM cement (P=0.193), regardless of time and liquid components. There was no significant difference was observed between liquids (P=0.312) in all time intervals. The rate of microleakage decreased over time and a significant differences was observed between all intervals (P<0.05), except 3-7 and 7-21 (P=0.190) days. CONCLUSION: PG demonstrated neither a positive nor a negative effect on the sealing ability of Angelus MTA and CEM cement. PMID- 28808459 TI - Evaluation of Apically Extruded Debris during Root Canal Retreatment Using ProTaper Next and Reciproc in Severely Curved Canals. AB - INTRODUCTION: To compare the apical extrusion of debris produced during root obturating material removal from severely curved root canals using either Reciproc (REC) or ProTaper Next (PTN) systems. METHODS AND MATERIALS: Twenty-six mesial canals of lower molars were instrumented, filled and allocated into two groups (n=13). Micro-computed tomographic images were performed to determine the root canal configuration (Vertucci's type IV) and initial volume of obturation. One Eppendorf tube was assigned per canal and weighed (10-4g) before and after removal of the obturating material. The difference between the initial and final weights was calculated and statistically evaluated. RESULTS: Apical extrusion of debris was confirmed in all samples, and the mean amount of apical extrusion was similar between both groups (0.061+/-0.014 g in PTN vs. 0.065+/-0.016 g in REC samples) (P<0.05). CONCLUSION: Both systems caused apical extrusion of debris with no differences between PTN and REC systems. PMID- 28808460 TI - The Effect of Intracanal Medicaments on Microleakage of Mineral Trioxide Aggregate Apical Plugs. AB - INTRODUCTION: The purpose of this in vitro study was to evaluate the effect of calcium hydroxide, double and triple antibiotic paste on the sealing ability of mineral trioxide aggregate (MTA) apical plugs. METHODS AND MATERIALS: A total of 90 extracted teeth with single canals were prepared and randomly divided into four experimental groups (n=20). Intra-canal medicaments were applied for 3 weeks. MTA was placed through the access opening and condensed to the apical area and then fluid filtration technique was utilized to evaluate sealing ability after 1, 7, 14 and 30 days. RESULTS: Triple antibiotic paste significantly reduced the sealing ability of MTA plug compared with double antibiotic paste (P=0.024) and normal saline (P=0.04) groups on day 1. The sealing ability was not different on days 14 and 30 between experimental groups (P>0.05). CONCLUSION: All medicaments can be used without any long term effect on microleakage. PMID- 28808461 TI - The Effect of Calcium Chloride on Push-Out Bond Strength of Calcium-Enriched Mixture Cement and Mineral Trioxide Aggregate. AB - INTRODUCTION: This in vitro study investigated the effect of adding 10% calcium chloride (CaCl2) on push out bond strength of calcium-enriched mixture (CEM) cement and mineral trioxide aggregate (MTA) to root canal dentin. METHODS AND MATERIALS: A total of 120 root dentin slices with 2 mm thickness were prepared from sixty single-rooted human teeth. Dentinal discs were enlarged to achieve 1.3 mm diameter. The specimens were randomly allocated into eight groups (n=15). Dentin discs were filled with either CEM cement or MTA with or without CaCl2 and the push out test was performed after 3 and 21 days. Data were analyzed with two way ANOVA test. The level of significance was set at 0.05. RESULTS: There was an interaction effect amongst all groups (P=0.028). After 3 days, CEM cement showed a significantly lower bond strength than other groups (P<0.05) while MTA demonstrated significantly higher bond strength than CEM cement with or without CaCl2 (P=0.001). After 21 days, CEM cement with or without CaCl2 had no significant difference with other groups (P>0.05). However, the bond strength of MTA decreased when CaCl2 was added (P=0.011). CONCLUSION: The addition of 10% CaCl2 increased the push out bond strength of CEM cement and improved it over time; while, this substance aggravated this property for MTA. PMID- 28808462 TI - Temperature Rises in the Pulp Chamber with Different Techniques of Orthodontic Adhesive Removal. AB - INTRODUCTION: The aim of this in vitro study was to compare the temperature rises in the pulp chamber and time spent with different techniques for orthodontic resin adhesive removal. METHODS AND MATERIALS: Adhesive removal was performed in 20 extracted human maxillary second premolars with five techniques: high-speed tungsten carbide burs with water-cooling (BurH-cool) and without cooling (BurH), low-speed carbide burs (BurL), low-speed aluminum-oxide discs (DiscL), and low speed fiberglass burs (BurFGL). Pulp chamber temperature was measured with a thermocouple probe and time spent was recorded with a digital stopwatch. Comparisons of temperature rise and time between the techniques were performed with Analysis of variance and Tukey's Honestly test. Correlation between variables was investigated with Pearson's correlation coefficient. RESULTS: Temperature rise and time were statistically different between techniques and showed a positive correlation between them (r=0.826) (P<0.01). BurH-cool provoked the lowest temperature rise and BurFGL the highest (P<0.01). Temperature rises were higher with DiscL than with BurH and BurL (P<0.01), which showed no statistical differences between them (P>0.05). The fastest technique was BurH cool followed by BurL, BurH, DiscL and BurFGL (P<0.01). CONCLUSION: BurH-cool, BurH and BurL are safe adhesive removal techniques, whereas DiscL and BurFGL may damage pulp tissues. Time spent on adhesive removal has direct effect on temperature rise in the pulp chamber. PMID- 28808463 TI - Micro Push-out Bond Strength and Bioactivity Analysis of a Bioceramic Root Canal Sealer. AB - INTRODUCTION: Bioactive endodontic sealers have been developed to improve the quality of root canal obturation. EndoSequence Bioceramic (BC) Sealer is amongst calcium silicate-based materials recently developed for permanent root canal filling. The objective of this study was to evaluate the bioactivity of BC Sealer and its micro push-out bond strength to dentin compared to AH-Plus (AH) sealer. METHODS AND MATERIALS: To perform the micro push-out test, 24 root canals of mandibular premolars were instrumented and divided into two groups (n=12). Each root was cut into 4 slices and lumens of the canals were filled with the sealers and submitted to micro push-out test. Failure mode was assessed using scanning electron microscopy (SEM). Bioactivity of BC sealer was investigated with scanning electron microscopy/energy-dispersive X-ray (SEM/EDS) and X-ray diffraction (XRD). Bioactivity assessments were reported descriptively. Bond strength data were analyzed by parametric t-test (alpha=5%). RESULTS: In micro push-out test AH had higher bond strength mean values (16.29 MPa) than BC sealer (9.48 MPa) (P<0.05). Both groups had low amount of adhesive failure. SEM showed the presence of a mineral precipitate after 30 days and EDS analysis showed that those precipitates have high proportion of Ca. XRD showed peaks of crystalline phases of calcium carbonate compatible with the bioactivity. CONCLUSION: BC sealer showed indications of bioactivity and lower bond strength to dentine compared to AH. PMID- 28808464 TI - Success Rate and Time for Bypassing the Fractured Segments of Four NiTi Rotary Instruments. AB - INTRODUCTION: The aim of this in vitro study was to compare the success rate and time required for bypassing the fractured segments of four different nickel titanium (NiTi) rotary systems. METHODS AND MATERIALS: This study was conducted on the mesiobuccal canals of 60 mandibular molars with fully-formed apices. Fifteen Flex Master, K3, RaCe and Hero Shaper instruments with 0.04 taper and tip size of #30 and 25 mm in length, were obtained. These instruments were notched at a point 3 mm from the tip of the instrument and were driven into the canals using a handpiece until the instruments fractured and became lodged therein. In the next step, an endodontist tried to bypass the fractured segment using K-files. The number of bypassed samples and the time required for bypassing of each sample were recorded. The Chi-square test was used to compare the bypassing rate among the experimental groups. One-way analysis of variance followed by Tukey's post hoc test was conducted to compare the time taken for bypassing of the fractured fragments. RESULTS: One instrument in Flex Master group and two broken segments in each of the K3 and Hero groups were not bypassed. All of the samples in RaCe group were bypassed. No significant difference was found among four tested groups regarding rate of bypassing (P=0.738). The time taken to bypass fragments in the Hero group was significantly more than in those of K3 (P=0.047) and RaCe (P=0.024). CONCLUSION: Under the limitations of this study, design features of rotary files can influence the time needed to bypass separated fragments. PMID- 28808465 TI - In Vitro Cytotoxicity of GuttaFlow Bioseal, GuttaFlow 2, AH-Plus and MTA Fillapex. AB - INTRODUCTION: The aim of the present in vitro study was to evaluate the cytotoxicity of different sealers including GuttaFlow Bioseal, GuttaFlow 2, AH Plus and MTA Fillapex on L929 murine fibroblasts. METHODS AND MATERIALS: Samples of GuttaFlow Bioseal, GuttaFlow 2, AH-Plus and MTA Fillapex were fabricated in Teflon disks of 5 mm diameter and 3 mm thickness. L929 fibroblasts were exposed to the extracts of these materials for 3, 24, 72 and 168 h at 37 degrees C with 5% CO2. Cell viability was evaluated by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide (MTT) assay. Apoptosis was evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. The data were analysed by ANOVA. RESULTS: GuttaFlow Bioseal was nontoxic at all experimental time points (P>0.05), whereas MTA Fillapex and AH-Plus were toxic (P<0.001). At 7 days, there were more viable cells in the GuttaFlow 2 group than in the control group, and MTA Fillapex was more cytotoxic than AH-Plus. There were more apoptotic cells in the MTA Fillapex and AH-Plus groups than in the other groups at 3 h (P<0.001). CONCLUSION: GuttaFlow sealers are less cytotoxic than MTA Fillapex and AH-Plus. At all experimental time points, there was no significant difference in the cell viability between the GuttaFlow Bioseal group and the control group. PMID- 28808466 TI - Apical Microleakage in Root Canals Containing Broken Rotary Instruments. AB - INTRODUCTION: Broken instruments in root canals complicate routine endodontic treatment. This study aimed to compare apical microleakage in root canals containing broken rotary instruments filled with mineral trioxide aggregate (MTA), calcium-enriched mixture (CEM) cement, laterally compacted gutta-percha and injected gutta-percha. METHODS AND MATERIALS: In this in vitro, experimental study, 80 extracted human premolars were decoronated and then the roots were randomly divided into four groups (n=20). Root canals were instrumented with Mtwo rotary files. The files were scratched 3 mm from the tip by a high speed handpiece and they were intentionally broken in the apical third of the canals. The middle and coronal thirds of the canals were then filled with MTA, CEM cement, gutta-percha with lateral compaction technique and injected gutta-percha. Apical microleakage was measured using dye penetration method. Data were analyzed using ANOVA and Tukey's test. RESULTS: Root canals filled with CEM cement showed the lowest and those filled with injected gutta-percha showed the highest microleakage according to dye penetration depth. No significant difference was noted between the microleakage of CEM cement and MTA or between lateral compaction of gutta-percha and injected gutta-percha (P>0.05). However, CEM cement and MTA groups had significantly lower microleakage than laterally compacted and injected gutta-percha groups (P<0.05). CONCLUSION: Due to their superior sealing ability, MTA and CEM cement are suitable for filling of root canals containing a broken instrument compared to laterally compacted and injected gutta-percha. PMID- 28808467 TI - Comparison of the Penetration Depth of Conventional and Nano-Particle Calcium Hydroxide into Dentinal Tubules. AB - INTRODUCTION: The aim of this in vitro study was to evaluate and compare the penetration depth of conventional (CH) and nano-particle calcium hydroxide (NCH) into dentinal tubules. METHODS AND MATERIALS: Ninety human single-rooted teeth were instrumented by RaCe rotary system and after chemomechanical preparation were randomly divided in two equal groups (n=45). In the first group conventional CH and in the other NCH was used as intracanal medicament. After 2 weeks of incubation all roots were intentionally split at longitudinal axis and prepared for scanning electron microscope (SEM) observation. Three zones of each root, coronal, middle and apical were examined under SEM and the maximum penetration depth of the dressing material into dentinal tubules was recorded for each zone. Data were analyzed using the independent sample t test and the level of significance was set at 0.05. RESULTS: In all of the three zones, NCH group had greater penetration depth than CH (P<0.001). In both groups the penetration depth increased from the apical section to the coronal. CONCLUSION: The depth of penetration of nano-particle calcium hydroxide into the dentinal tubules was significantly higher than that of conventional calcium hydroxide. The lowest penetration depth was observed in apical zone in both groups. PMID- 28808468 TI - Treatment of a Maxillary Second Molar with One Buccal and Two Palatal Roots Confirmed with Cone-Beam Computed Tomography. AB - Root canal configuration is an important subject in endodontic practice and dentists should be familiar with all possible types of root canal configuration. A forty-three year old male was referred for root canal treatment of his maxillary left second molar tooth with symptomatic irreversible pulpitis. Pre operative radiographs showed a three rooted molar. However, after access cavity preparation two palatal and one buccal orifices were detected. The patient was informed of the unusual root canal anatomy and cone-beam computed tomography (CBCT) was ordered for precise evaluation of the anatomy. CBCT image confirmed the presence of one buccal and two palatal root canals; an exceptionally rare condition. PMID- 28808469 TI - Endodontic Surgery of a Symptomatic Overfilled MTA Apical Plug: A Histological and Clinical Case Report. AB - This case report presents the successful surgical treatment of a symptomatic open apex upper central incisor with a failed overfilled mineral trioxide aggregate (MTA) apical plug. Unintentional overextension of the MTA had occurred two years before the initial visit. An apical lesion adjacent to the excess MTA was radiographically detectable. Endodontic surgery was performed using calcium enriched mixture (CEM) cement as a root-end filling material. Curettage of the apical lesion showed a mass of unset MTA particles; histopathological examination revealed fragments of MTA and granulation tissues. Up to 18-month follow-up, the tooth was clinically asymptomatic and fully functional. Periapical radiograph and CBCT images showed a normal periodontal ligament around the root. In conclusion, favorable outcomes in this case study suggested that root-end filling with CEM cement might be an appropriate approach; in addition, however many factors probably related to the initial failure of the case, the extrusion of MTA into the periapical area should be avoided. PMID- 28808470 TI - Non-Surgical Retreatment of Maxillary Lateral Incisor with Unusual Anatomy: A Case Report and Mini Review. AB - Knowledge about internal anatomy plays a crucial role in the success of the root canal treatment. Many studies on internal anatomy have repeatedly reported that maxillary lateral incisors have only one canal. The primary aim of this article was to describe successful non-surgical retreatment of a permanent maxillary lateral incisor with two root canals and open apices. The treatment was carried out using dental operating microscope and the canals were obturated with mineral trioxide aggregate (MTA) as an apical plug. A review of literature was also conducted to evaluate the anatomical variations of maxillary lateral incisors. PMID- 28808471 TI - Management of Invasive Cervical Root Resorption in a Mandibular Canine Using Biodentine as a Restorative Material: A Case Report. AB - Invasive cervical root resorption (ICR) is the reversible/irreversible loss of tooth structure in the connective tissue attachment zone with unclear etiology. In the present case a history of periodontal surgery was presumed to be the predisposing factor. Early diagnosis and proper treatment may lead to long-term retention of the tooth. The tooth is usually asymptomatic and diagnosis is commonly made as a result of a routine radiographic finding. Cone-beam computed tomography (CBCT) is extremely useful in diagnosis and treatment planning of ICR. The treatment should aim toward complete removal of the resorptive defect and reconstruction by placement of a suitable filling material. The present report demonstrates the management of a mandibular canine with invasive cervical root resorption using Biodentine for the defect. PMID- 28808472 TI - Successful Ultra-Conservative Management of a Mandibular Premolar with Dens Invaginatus. AB - Dens invaginatus is one of the most common anomalies of tooth structure. It is caused by the invagination of the crown surface during odontogenesis that enters the pulp chamber of the affected tooth. Depending on the complexity of invagination, the tooth might present with pulp necrosis, open apex and a complicated root canal system. This case report presents an Oehlers' type 2 dens invaginatus in a mandibular premolar with chronic apical abscess. In most cases, dens invaginatus is removed during treatment. However, in this case report, based on cone-beam computed tomography (CBCT) evaluation, non-surgical treatment and maintenance of the invaginated segment was chosen in order to prevent compromising the tooth structure and its susceptibility to future root fracture. This is a new treatment approach and has not been performed in previous reports. Calcium-enriched mixture (CEM) cement was used as an apical plug followed by gutta-percha in warm vertical compaction for root canal obturation. The case was followed up for 36 months after treatment. This report highlights the importance of selecting the appropriate treatment approach based on CBCT evaluation. PMID- 28808473 TI - Failure of Cone-Beam Computed Tomography in Detection of Fiber Post Perforation. AB - Detection of iatrogenic root perforation during post-space preparation especially in labiolingual plane can be challenging due to the two-dimensional nature of conventional radiography; this can be even more challenging if the cemented post is radiolucent. Cone-beam computed tomography (CBCT) scans were shown to be a valuable diagnostic aid in diagnosis of such cases. However, in this case, the application of CBCT did not help in diagnosis of a labial fiber post perforation in a maxillary central incisor which was finally detected through exploratory surgery. PMID- 28808474 TI - Effect of Shin'iseihaito (Xinyiqingfeitang) on Acute Streptococcus pneumoniae Murine Sinusitis via Macrophage Activation. AB - Streptococcus pneumoniae (S. pneumoniae) causes sinusitis. The general treatment of S. pneumonia sinusitis is by using antibiotics; however, one of their serious problems is the attenuation of their effect. Shin'iseihaito (Xinyiqingfeitang), a formula of Japanese traditional Kampo medicine, has been used for the treatment of sinusitis in Japan. In this study, we investigated the efficacy of Shin'iseihaito against S. pneumoniae-caused sinusitis in mice. Oral administration of Shin'iseihaito extract (SSHT) decreased the nasal colonization of S. pneumoniae in both prophylactic and therapeutic treatments, respectively, and the former was more effective than the latter. Histopathological analysis revealed that the epithelial tissue from S. pneumoniae-infected nose under SSHT treatment recovered the tissue destruction in comparison to infected nose. We also confirmed this result by scanning electron microscopic analysis. Murine peritoneal macrophages from SSHT-treated mice had significant phagocytic activity in comparison to those from untreated group. We also found that tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and monocyte chemotactic protein 1 levels and the migration of macrophages from S. pneumoniae-infected mice with the treatment with SSHT were increased compared to those from untreated group. Our data suggest that Shin'iseihaito may be useful for the treatment of S. pneumoniae-induced sinusitis. PMID- 28808475 TI - Yacon (Smallanthus sonchifolius) Leaf Extract Attenuates Hyperglycemia and Skeletal Muscle Oxidative Stress and Inflammation in Diabetic Rats. AB - The effects of hydroethanolic extract of Yacon leaves (HEYL) on antioxidant, glycemic, and inflammatory biomarkers were tested in diabetic rats. Outcome parameters included glucose, insulin, interleukin-6 (IL-6), and hydrophilic antioxidant capacity (HAC) in serum and IL-6, HAC, malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in soleus. The rats (10/group) were divided as follows: C, controls; C + Y, HEYL treated; DM, diabetic controls; and DM + Y, diabetic rats treated with HEYL. Diabetes mellitus was induced by administration of streptozotocin. C + Y and DM + Y groups received 100 mg/kg HEYL daily via gavage for 30 d. Hyperglycemia was improved in the DM + Y versus DM group. Insulin was reduced in DM versus C group. DM rats had higher IL-6 and MDA and lower HAC in the soleus muscle. HEYL treatment decreased IL-6 and MDA and increased HAC in DM rats. DM + Y rats had the highest CAT activity versus the other groups; GPx was higher in C + Y and DM + Y versus their respective controls. The apparent benefit of HEYL may be mediated via improving glucoregulation and ameliorating oxidative stress and inflammation, particularly in diabetic rats. PMID- 28808476 TI - Bark Extracts of Ceylon Cinnamon Possess Antilipidemic Activities and Bind Bile Acids In Vitro. AB - Ethanol (95%) and dichloromethane : methanol (1 : 1) bark extracts of authenticated Ceylon cinnamon were investigated for range of antilipidemic activities (ALA): HMG-CoA reductase, lipase, cholesterol esterase, and cholesterol micellization inhibitory activities and bile acids binding in vitro. Individual compounds in bark extracts were also evaluated. Bark extracts showed ALA in all the assays studied. The IC50 (MUg/mL) values ranged within 153.07 +/- 8.38-277.13 +/- 32.18, 297.57 +/- 11.78-301.09 +/- 4.05, 30.61 +/- 0.79-34.05 +/- 0.41, and 231.96 +/- 9.22-478.89 +/- 9.27, respectively, for HMG-CoA reductase, lipase, cholesterol esterase, and cholesterol micellization inhibitory activities. The bile acids binding (3 mg/mL) for taurocholate, glycodeoxycholate, and chenodeoxycholate ranged within 19.74 +/- 0.31-20.22 +/- 0.31, 21.97 +/- 2.21 26.97 +/- 1.61, and 16.11 +/- 1.42-19.11 +/- 1.52%, respectively. The observed ALA were moderate compared to the reference drugs studied. Individual compounds in bark extracts ranged within 2.14 +/- 0.28-101.91 +/- 3.61 and 0.42 +/- 0.03 49.12 +/- 1.89 mg/g of extract. Cinnamaldehyde and gallic acid were the highest and the lowest among the tested compounds. The ethanol extract had highest quantity of individual compounds and ALA investigated. Properties observed indicate usefulness of Ceylon cinnamon bark in managing hyperlipidemia and obesity worldwide. Further, this study provides scientific evidence for the traditional claim that Ceylon cinnamon has antilipidemic activities. PMID- 28808477 TI - Effect of lamotrigine in the treatment of bipolar depression with psychotic features: a case report. AB - BACKGROUND: Major depressive episodes with psychotic features are more common in bipolar disorder than in major depressive disorder; however, there is little information on the optimal treatment for bipolar depression with psychotic features. CASE PRESENTATION: The patient was a 69-year-old man. At the age of 66, he was admitted to the hospital for the treatment of bipolar depression with psychotic features. He was treated with a combination therapy of antipsychotics and antidepressants during long-term hospitalization. At the age of 69, he relapsed and was admitted to the hospital again. He was initially treated with olanzapine and lithium for the treatment of bipolar depression with psychotic features. He partially responded to the combination therapy, and psychomotor retardation and delusion of guilt disappeared; however, he developed psychomotor agitation and delusion of persecution, which was a mood-incongruent psychotic feature. Finally, he fully recovered with an additional dosage of lamotrigine, and had no experience of relapse after discontinuation of olanzapine. CONCLUSIONS: This case report implicates the utility of lamotrigine for bipolar depression with psychotic features, and further studies are needed to establish the optimal treatment. PMID- 28808478 TI - The Portuguese long version of the Copenhagen Psychosocial Questionnaire II (COPSOQ II) - a validation study. AB - BACKGROUND: Psychosocial risks are now widely recognised as one of the biggest challenges for occupational safety and health (OSH) and a major public health concern. The aim of this paper is to investigate the Portuguese long version of the Copenhagen Psychosocial Questionnaire II (COPSOQ II), in order to analyse the psychometric properties of the instrument and to validate it. METHODS: The Portuguese COPSOQ II was issued to a total of 745 Portuguese employees from both private and public organisations across several economic sectors at a baseline and then 2 weeks later. Methodological quality appraisal was based on COnsensus based Standards for the selection of health Measurement INstruments (COSMIN) recommendations. An analysis of the psychometric properties of the long version of COPSOQ II (internal consistency, intraclass correlation coefficient, floor and ceiling effects, response rate, missing values, mean and standard deviation, exploratory factor analysis) was performed to determine the validity and reliability of the instrument. RESULTS: The COPSOQ II had a response rate of 60.6% (test) and a follow-up response rate of 59.5% (retest). In general, a Cronbach's alpha of the COPSOQ scales (test and retest) was above the conventional threshold of 0.70. The test-retest reliability estimated by the intraclass correlation coefficient (ICC) showed a higher reliability for most of the scales, above the conventional 0.7, except for eight scales. The proportion of the missing values was less than 1.3%, except for two scales. The average scores and standard deviations showed similar results to the original Danish study, except for eight scales. All of the scales had low floor and ceiling effects, with one exception. Overall, the exploratory factor analysis presented good results in 27 scales assuming a reflective measurement model. The hypothesized factor structure under a reflective model was not supported in 14 scales and for some but not all of these scales the explanation may be a formative measurement model. CONCLUSION: The Portuguese long version of COPSOQ II is a reliable and valid instrument for assessing psychosocial risks in the workplace. Although the results are good for most of the scales, there are those that should be evaluated in greater depth in future studies. This instrument may contribute to the promotion of a healthy working environment and workforce, providing clear benefits for companies and employees. PMID- 28808479 TI - A Multiscale Model for the World's First Parasitic Disease Targeted for Eradication: Guinea Worm Disease. AB - Guinea worm disease (GWD) is both a neglected tropical disease and an environmentally driven infectious disease. Environmentally driven infectious diseases remain one of the biggest health threats for human welfare in developing countries and the threat is increased by the looming danger of climate change. In this paper we present a multiscale model of GWD that integrates the within-host scale and the between-host scale. The model is used to concurrently examine the interactions between the three organisms that are implicated in natural cases of GWD transmission, the copepod vector, the human host, and the protozoan worm parasite (Dracunculus medinensis), and identify their epidemiological roles. The results of the study (through sensitivity analysis of R0) show that the most efficient elimination strategy for GWD at between-host scale is to give highest priority to copepod vector control by killing the copepods in drinking water (the intermediate host) by applying chemical treatments (e.g., temephos, an organophosphate). This strategy should be complemented by health education to ensure that greater numbers of individuals and communities adopt behavioural practices such as voluntary reporting of GWD cases, prevention of GWD patients from entering drinking water bodies, regular use of water from safe water sources, and, in the absence of such water sources, filtering or boiling water before drinking. Taking into account the fact that there is no drug or vaccine for GWD (interventions which operate at within-host scale), the results of our study show that the development of a drug that kills female worms at within-host scale would have the highest impact at this scale domain with possible population level benefits that include prevention of morbidity and prevention of transmission. PMID- 28808480 TI - Salvage chemotherapy for adults with relapsed or refractory lymphoma in Malawi. AB - BACKGROUND: Lymphoma is highly associated with HIV in sub-Saharan Africa (SSA), which contributes to worse outcomes relative to resource-rich settings, and frequent failure of first-line chemotherapy. However, there are no second-line treatment descriptions for adults with relapsed or refractory lymphoma (RRL) in SSA. METHODS: We describe HIV+ and HIV- patients with RRL receiving salvage chemotherapy in Malawi. Patients were prospectively treated at a national teaching hospital in Lilongwe, with the modified EPIC regimen (etoposide, prednisolone, ifosfamide, cisplatin) between June 2013 and May 2016, after failing prior first-line chemotherapy. RESULTS: Among 21 patients (18 relapsed, 3 refractory), median age was 40 years (range 16-78), 12 (57%) were male. Thirteen patients (62%) were HIV+, of whom 12 (92%) were on antiretroviral therapy (ART) at initiation of salvage chemotherapy, with median CD4 cell count 139 cells/MUL (range 12-529) and 11 (85%) with suppressed HIV RNA. Median number of EPIC cycles was 3 (range 1-6), and the commonest toxicity was grade 3/4 neutropenia in 19 patients (90%). Fifteen patients responded (3 complete, 12 partial, overall response rate 71%), but durations were brief. Median overall survival was 4.5 months [95% confidence interval (CI) 2.4-5.6]. However, three patients, all HIV+, experienced sustained remissions. Tolerability, response, and survival did not differ by HIV status. CONCLUSIONS: The appropriateness and cost-effectiveness of this approach in severely resource-limited environments is uncertain, and multifaceted efforts to improve first-line lymphoma treatment should be emphasized, to reduce frequency with which patients require salvage chemotherapy. TRIAL REGISTRATION: NCT02835911. Registered 19 January 2016. PMID- 28808481 TI - Cul4B is a novel prognostic marker in cholangiocarcinoma. AB - Cullin 4B (Cul4B), a scaffold protein that assembles the ubiquitin ligase complex, is involved in a wide variety of physiological and developmental processes, such as cell cycle progression, DNA damage response and gene expression regulation. Cul4B is overexpressed in various solid tumors. However, the prognostic value and role of Cul4B in cholangiocarcinoma (CCA) is largely unknown. The present study demonstrated that Cul4B was overexpressed in 21 (26.6%) of 79 patients with intrahepatic CCA, and in 40 (28.6%) of 140 patients with extrahepatic CCA (EHCC). Kaplan-Meier survival analysis suggested that Cul4B expression is an unfavorable prognostic factor in EHCC patients. Notably, Cul4B and epidermal growth factor receptor expression define a subset of CCA patients with poor prognosis. In vitro data indicated that Cul4B promotes the proliferation, migration and invasion of CCA cells. Furthermore, Cul4B expression promotes the epithelial-mesenchymal transition (EMT) process in CCA cells. Finally, Cul4B repressed the expression of the tumor suppressor genes P16 and phosphatase and tensin homolog. Collectively, the results of the present study revealed an important role of Cul4B in CCA with respect to initiating EMT. Cul4B expression may serve as a prognostic marker for patients with EHCC. PMID- 28808482 TI - The Chinese herb Prunella vulgaris promotes apoptosis in human well differentiated thyroid carcinoma cells via the B-cell lymphoma-2/Bcl-2-associated X protein/caspase-3 signaling pathway. AB - Prunella vulgaris (PV), a traditional Chinese herb, has been shown to be rich in bioactive chemicals and possess anti-proliferative and pro-apoptotic effects on tumor cells. The effect of PV on human well-differentiated thyroid carcinoma (WDTC), which accounts for the majority of common endocrine malignancies, remains to be elucidated. The present study aimed to investigate the function of PV on WDTC cell lines and apoptosis-associated signaling pathway activity. Additional studies demonstrated that PV may induce apoptosis in WDTC TPC-1 and FTC-133 cell lines, using the Cell Counting Kit-8 assay. Morphological changes of apoptotic cells were observed by Hoechst 33342 and acridine orange/ethidium bromide staining. In addition, ladder pattern of fragmented DNA was observed by DNA gel electrophoresis. It was also observed that PV significantly increased Bcl-2 associated X protein and caspase-3 expression, and downregulated B-cell lymphoma 2 expression in TPC-1 and FTC-133 by reverse transcription-quantitative polymerase chain reaction (P<0.05). Thus, the present results indicated that PV has the potential to be a future WDTC therapeutic agent. PMID- 28808483 TI - Therapeutic immune monitoring of CD4+CD25+ T cells in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. AB - Tyrosine kinase inhibitors (TKIs), including imatinib, dasatinib and nilotinib, are effective forms of therapy for various types of solid cancers and Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia. A number of TKIs have been known to have strong effects on T cells, particularly cluster of differentiation (CD) 4+CD25+ T cells, also known as regulatory T cells (Tregs). There is currently a deficit in the available clinical data regarding this area of study. In the present study, a total of 108 peripheral blood samples were collected from patients with chronic myeloid leukemia (CML) at diagnosis (n=31), and at 3 and 6 months following treatment with TKI [imatinib (n=12), dasatinib (n=11) and nilotinib groups (n=8)] and healthy controls (n=15). Peripheral blood mononuclear cells were collected from the patients prior to and following TKI treatment. The subtype and number of T lymphocytes in patients and healthy donors were analyzed using flow cytometry. Additionally, flow cytometry and ELISA were used to detect the proliferation and suppression of Tregs. Expression of cytokines and other molecules [forkhead box P3 (FOXP3), glucocorticoid-induced tumor necrosis factor receptor (GITR) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)] were also analyzed at 3 and 6 months following treatment with TKIs. It was indicated that, at diagnosis, a similar number of lymphocytes were detected in patients and control. However, following treatment with a TKI, the number of total T cells, Tregs, CD4+ T and CD8+ T cells decreased to various degrees in patients. Furthermore, the decrease in the number of Tregs was more significant with time. Although treatment with imatinib, dasatinib and nilotinib demonstrated similar inhibitory effects on the quantity of Tregs in vivo, the TKIs exhibited differential effects on the function of Tregs in vitro. Proliferation, suppression and expression of cytokines [interleukin (IL)-4, IL-10 and transforming growth factor (TGF)-beta] and molecules (FOXP3, GITR and CTLA-4) decreased significantly in treatment groups with imatinib and dasatinib. The decrease was not significant in the nilotinib treatment group. Imatinib and dasatinib may exert more marked inhibitory roles compared with nilotinib on regulating the number and function of Tregs. These results suggest that personalized treatment and follow-up of CML patients during TKI treatment, particularly for those who received post-transplant TKI treatment may be beneficial. PMID- 28808484 TI - ERalpha and ERbeta co-expression: An indicator of aggressive tumors and hormonal sensitivity. AB - The estrogen receptors (ERs) ERalpha and ERbeta are important factors in breast cancer progression. Nevertheless, the molecular interplay between ERalpha and ERbeta and its clinical significance in breast cancer is controversial. The establishment of a clear association is required; therefore, the current study analyzed the expression patterns of ERalpha and ERbeta in 32 breast tumor tissues using reverse transcription-quantitative polymerase chain reaction. Furthermore, human epidermal growth factor receptor 2 (HER2) and the Ki-67 status were detected by immunohistochemistry. The results revealed that the ERalpha and ERbeta expression rates recorded were 68 and 65%, respectively. The ERalpha:ERbeta ratio exhibited a decline along with disease progression. ERalpha and ERbeta were found to be negatively correlated with HER2 status but positively correlated with Ki-67. Co-expression of ERalpha and ERbeta was associated with breast cancer aggressiveness, including higher histological grade and positive nodal status, which commonly occur following the menopause. In addition, in cases where ERbeta was coexpressed with ERalpha, HER2 expression was frequently found to be negative, whereas the Ki-67 index was upregulated. These data suggest that ERalpha and ERbeta co-expression may be an indicator of tumor aggressiveness and the sensitivity of hormonal therapy via the downregulation of HER2. PMID- 28808485 TI - Improving the management of people with bronchiectasis in Saudi: A new beginning. PMID- 28808487 TI - Gaining access to the periphery of the lung: Bronchoscopic and transthoracic approaches. AB - Globally, lung cancer remains the leading cause of cancer-related death. Annual low-dose computed tomography has been recommended as a screening test for early detection of lung cancers. Implementing this screening strategy is expected to challenge pulmonologist to confirm the nature of the increasing number of detected pulmonary nodules. Clinicians are obliged to use the less invasive and most efficient and safe means to set diagnoses. Hence, the field of diagnostic modalities, especially the advanced diagnostic bronchoscopy is witnessing rapid evolution to fulfill these unmet needs. This review highlights the available diagnostic modalities, describes their advantages and discusses the limitations of each technique. It also suggests an integrated diagnostic algorithm based on the best available evidence. A search of the PubMed database was conducted using relevant terms described at methodology; only articles in English were reviewed by November 2016. PMID- 28808488 TI - Predictive factors for a successful diagnostic bronchoscopy of ground-glass nodules. AB - INTRODUCTION: Since the National Lung Screening Trial demonstrated the utility of low-dose computed tomography screening for lung cancer, the detection rate of ground-glass nodules (GGNs) has increased. Endobronchial ultrasound with a guide sheath (EBUS-GS) is widely performed to diagnose peripheral pulmonary lesions, but there are not enough reports on the predictive ability of EBUS-GS in diagnosing GGNs. The aim of this study is to investigate the predictive factors for a successful diagnostic bronchoscopy for GGNs. METHODS: Consecutive patients who underwent diagnostic bronchoscopy for GGNs from September 2012 to January 2016 were enrolled in this study. From these, cases who underwent EBUS-GS were selected. They were reviewed and analyzed to examine the association between the diagnostic yield and the following clinical factors: lesion size, lobar position, location, consolidation-to-tumor ratio, visibility on X-ray, use of virtual bronchoscopy, bronchus sign, guide sheath size, and number of biopsies. RESULTS: We enrolled 254 cases, of which 167 were diagnosed using EBUS-GS (65.7% diagnostic yield). Univariate analysis indicated that a positive bronchus sign was a significant factor for higher diagnostic yield (72.9% vs. 34.0%; P < 0.001). The use of virtual bronchoscopy also tended toward a higher yield, but the result was not significant (69.0% vs. 54.4%; P = 0.058). However, multivariate analysis indicated that both were significantly associated with higher diagnostic yield (P < 0.001, odds ratio [OR]: 5.35; P < 0.001, OR: 1.97, respectively). CONCLUSIONS: Our results suggest that a positive bronchus sign and the use of virtual bronchoscopy are positive predictive factors for successful diagnostic bronchoscopy of GGNs. PMID- 28808489 TI - What should be the appropriate minimal duration for patient examination and evaluation in pulmonary outpatient clinics? AB - INTRODUCTION: Patient examinations performed in a limited time period may lead to impairment in patient and physician relationship, defective and erroneous diagnosis, inappropriate prescriptions, less common use of preventive medicine practices, poor patient satisfaction, and increased violent acts against health care staff. OBJECTIVE: This study aimed to determine the appropriate minimal duration of patient examination in the pulmonary practice. METHODS: A total of 49 researchers from ten different study groups of the Turkish Thoracic Society participated in the study. The researchers were asked to examine patients in an almost ideal manner, without time constraint under available conditions. RESULTS: A total of 1680 patient examinations were reviewed. The mean duration of patient examination in ideal conditions was determined to be 20.4 +/- 9.6 min. Among all steps of patient examination, the longest time was spent for "taking medical history." The total time spent for patient examination was statistically significantly longer in the university hospitals than in the governmental hospitals and training and research hospitals (P < 0.001). Among different patient categories, the patients with a chronic disorder presenting for the first time and were referred from primary or secondary to tertiary care for further evaluation have required the longest time for patient examination. CONCLUSION: According to our study, the appropriate minimal duration for patient examination is 20 min. It has been observed that in university hospitals and in patients with chronic pulmonary diseases, this duration has been increased to above 25 min. The durations in clinical practice should be planned accordingly. PMID- 28808490 TI - The influence of intermittent fasting on the circadian pattern of melatonin while controlling for caloric intake, energy expenditure, light exposure, and sleep schedules: A preliminary report. AB - AIMS: We hypothesized that if we control for food composition, caloric intake, light exposure, sleep schedule, and exercise, intermittent fasting would not influence the circadian pattern of melatonin. Therefore, we designed this study to assess the effect of intermittent fasting on the circadian pattern of melatonin. METHODS: Eight healthy volunteers with a mean age of 26.6 +/- 4.9 years and body mass index of 23.7 +/- 3.5 kg/m2 reported to the Sleep Disorders Center (the laboratory) on four occasions: (1) adaptation, (2) 4 weeks before Ramadan while performing Islamic intermittent fasting for 1 week (fasting outside Ramadan [FOR]), (3) 1 week before Ramadan (nonfasting baseline [BL]), and (4) during the 2nd week of Ramadan while fasting (Ramadan). The plasma levels of melatonin were measured using enzyme-linked immunoassays at 22:00, 02:00, 04:00, 06:00, and 11:00 h. The light exposure, meal composition, energy expenditure, and sleep schedules remained the same while the participants stayed at the laboratory. RESULTS: The melatonin levels followed the same circadian pattern during the three monitoring periods (BL, FOR, and Ramadan). The peak melatonin level was at 02:00 h and the trough level was at 11:00 h in all studied periods. Lower melatonin levels at 22:00 h were found during fasting compared to BL. Cosinor analysis revealed no significant changes in the acrophase of melatonin levels. CONCLUSIONS: In this preliminary report, under controlled conditions of light exposure, meal composition, energy expenditure, and sleep-wake schedules, intermittent fasting has no significant influence on the circadian pattern of melatonin. PMID- 28808491 TI - Distribution patterns of the metastases of the lung carcinoma in relation to histological type of the primary tumor: An autopsy study. AB - INTRODUCTION: Lung cancer is among leading causes of death worldwide. Different histological types of the lung carcinoma show significant differences in behavior. OBJECTIVES: The aim of this study is to determine the distribution patterns of metastases of different lung cancer histological types in autopsied individuals. METHODS: Protocols from all autopsies performed at the Institute of Pathology from 2008 till 2014 were reviewed retrospectively, and information on individuals' age, sex, histological type of primary lung cancer, presence and location of metastases, and causes of death were recorded. RESULTS: More than 90% of the individuals with lung cancer metastases were older than 50 years (mean age: 64.5 +/- 10.3), with two-fold male predominance. The most frequent histological type in both sexes was adenocarcinoma (48%). Although, in general, hematogenous metastases were mostly found in the liver and adrenal glands, various histological types of lung cancer show specific dissemination patterns. Metastases in adrenal glands derived mostly from adenocarcinoma and large-cell carcinoma. Metastases in the intestines most frequently originated from large cell carcinoma (P = 0.01). Metastatic complications and bronchopneumonia were the most frequent causes of death. CONCLUSIONS: While, overall, the most frequent hematogenous metastases occur in the liver and adrenal glands, various histological types of lung cancer show specific dissemination patterns. Knowing distribution of metastases is essential for making algorithms of treatment, as well as for improving clinical assessment of the patients with unclear clinical findings and suspicion on occult primary lung cancer. PMID- 28808492 TI - Assessment of anti-factor Xa activity of enoxaparin for venous thromboembolism prophylaxis in morbidly obese surgical patients. AB - BACKGROUND: Venous thromboembolism (VTE) can be encountered by 60% of hospitalized patients. Anticoagulants have been recommended to reduce the risk of VTE in patients with risk factors. However, no specific dosing recommendations for obese patients are provided in the current practice guidelines. The purpose of this study was to determine the efficacy and safety of weight-based dosing of enoxaparin for VTE prophylaxis among morbidly obese patients undergoing surgery. METHODS: Adult patients were enrolled if they have a body mass index (BMI) of >=35 kg/m2 and were scheduled for surgery. These patients were prescribed enoxaparin (0.5 mg/kg subcutaneously [SC] once daily). Peak anti-factor Xa levels were measured 4 h after the third dose of enoxaparin. The primary outcome measure was to determine whether a weight-based dosing of enoxaparin of 0.5 mg/kg produce the anticipated peak anti-Xa levels (0.2-0.6 IU/m) among obese patients undergoing surgery. Secondary outcomes include the incidence of VTE, the incidence of minor or major bleeding, and the incidence of heparin-induced thrombocytopenia (HIT). RESULTS: Fifty patients were enrolled in the study. The mean age was 53 +/- 16 years, 74% of the patients were female. The mean BMI was 40.5 +/- 5, and the average enoxaparin dose was 50 +/- 9.8 SC daily. Nearly 88% of the patients reached the target anti-factor Xa (0.427 +/- 0.17). None of the patients developed HIT or VTE. There was no incidence of major or minor bleeding. CONCLUSIONS: Weight-based enoxaparin dose led to the anticipated peak anti-Xa levels (0.2-0.6 IU/mL) in most of the morbidly obese study patients undergoing surgery without any evidence of major side effects. The weight-based dosing of enoxaparin was also effective in preventing VTE in all patients. Although these results are promising, further comparative trials are needed in the setting of morbidly obese surgical patients. PMID- 28808486 TI - The Saudi Thoracic Society guidelines for diagnosis and management of noncystic fibrosis bronchiectasis. AB - This is the first guideline developed by the Saudi Thoracic Society for the diagnosis and management of noncystic fibrosis bronchiectasis. Local experts including pulmonologists, infectious disease specialists, thoracic surgeons, respiratory therapists, and others from adult and pediatric departments provided the best practice evidence recommendations based on the available international and local literature. The main objective of this guideline is to utilize the current published evidence to develop recommendations about management of bronchiectasis suitable to our local health-care system and available resources. We aim to provide clinicians with tools to standardize the diagnosis and management of bronchiectasis. This guideline targets primary care physicians, family medicine practitioners, practicing internists and respiratory physicians, and all other health-care providers involved in the care of the patients with bronchiectasis. PMID- 28808493 TI - Pulmonary consequences of hypothyroidism. AB - BACKGROUND: Although hypothyroidism has an insidious onset and relatively asymptomatic, exertional dyspnea and fatigue can be the presenting complaints. OBJECTIVES: The aim is to assess functional lung impairment in hypothyroid patients both at rest and during exercise. METHODS: A case-control study was carried out on 42 patients with newly diagnosed hypothyroidism and 12 control subjects. Hypothyroidism was diagnosed based on high value of thyroid stimulating hormone (TSH) >=6 MUIU/ml, and low value of free thyroxin (FT4) <=0.8 ng/dl, both groups had chest X-ray, spirometry, diffusing capacity of the lungs for carbon monoxide (DLCO), arterial blood gases (ABGs) and symptom-limited exercise testing using treadmill. RESULTS: Both groups were comparable as regard age, sex, and body mass index. Although ABG and spirometry were within normal in both groups, forced vital capacity %, and forced expiratory flow (FEF25-75) % were significantly reduced in the hypothyroid group (P = 0.014, 0.000, respectively), DLCO significantly reduced in hypothyroidism (P = 0.005). As regard exercise testing parameters, maximum oxygen consumption %, minute ventilation, tidal volume, and oxygen pulse were significantly reduced in hypothyroidism (0.005, 0.000, 0.000, and 0.02 respectively). TSH significantly negatively correlated with forced expiratory volume in 1 s %, FEF25-75%, and DLCO while they significantly positively correlated with FT4. CONCLUSION: Even with the presence of normal chest X-ray, arterial blood gases, and spirometry in patients with hypothyroidism DLCO and exercise testing parameters can be significantly reduced. PMID- 28808494 TI - Severe fibrosing mediastinitis with atypical presentation: Effective control with novel therapeutic approach. AB - Fibrosing mediastinitis (FM), also known as sclerosing mediastinitis, is an uncommon but serious disease involving the mediastinal structures. A high index of suspicion is essential to establish the diagnosis of FM and starting the appropriate therapy for patients. Here, we report a case of a young female who presented with chest symptoms and subsequently underwent different laboratory and radiologic investigations and an excisional biopsy. The findings of these investigations were consistent with the diagnosis of idiopathic FM. Her disease was associated with complete occlusion of three pulmonary veins and the left main pulmonary artery. The patient was treated with initial high-dose steroids followed by maintenance steroid and methotrexate therapy with very good long-term disease control. Clinical response, high-sensitivity C-reactive protein, and erythrocyte sedimentation rate were used to monitor disease activity and response to therapy. PMID- 28808495 TI - The most frequent ABCA3 nonsense mutation -p.Tyr1515* (Y1515X) causing lethal neonatal respiratory failure in a term neonate. AB - Defects in the surfactant biosynthesis are associated with respiratory distress syndrome, commonly occurring in premature infants due to lung immaturity. However, interstitial lung diseases have also been observed in full-term infants with mutations in the SFTPC, SFTPB, NKX2-1, or ABCA3 genes, involved in the surfactant metabolism. Herein, we report a newborn baby with neonatal respiratory distress and diffuse lung disease caused by ABCA3 mutation. The baby died at 5 weeks of age after developing pulmonary hypertension. Genomic DNA was analyzed for four genes involved in surfactant metabolism out of which the c. 4545C>G (p.Tyr1515*) homozygous mutation in exon 29 of ABCA3 was identified which is one of the most frequent mutation causing lethal neonatal respiratory failure in a term neonate. This case study emphasizes the importance of raising awareness about this diagnosis in the clinical settings for fruitful outcomes in health care delivery. PMID- 28808496 TI - Role of pleural transthoracic ultrasound guidance. PMID- 28808497 TI - Prevalence of antibodies against the Middle East Respiratory Syndrome coronavirus, influenza A and B viruses among blood donors, Saudi Arabia. PMID- 28808498 TI - Functional, Cellular, and Molecular Remodeling of the Heart under Influence of Oxidative Cigarette Tobacco Smoke. AB - Passive and active chronic cigarette smoking (CS) remains an international epidemic and a key risk factor for cardiovascular disease (CVD) development. CS induced cardiac damage is divided into two major and interchangeable mechanisms: (1) direct adverse effects on the myocardium causing smoking cardiomyopathy and (2) indirect effects on the myocardium by fueling comorbidities such as atherosclerotic syndromes and hypertension that eventually damage and remodel the heart. To date, our understanding of cardiac remodeling following acute and chronic smoking exposure is not well elucidated. This manuscript presents for the first time the RIMD (oxidative stress (R), inflammation (I), metabolic impairment (M), and cell death (D)) detrimental cycle concept as a major player in CS induced CVD risks and direct cardiac injury. Breakthroughs and latest findings in the field with respect to structural, functional, cellular, and molecular cardiac remodeling following chronic smoking exposure are summarized. This review also touches the genetics/epigenetics of smoking as well as the smoker's paradox and highlights the most currently prominent pharmacological venues to mitigate CS induced adverse cardiac remodeling. PMID- 28808499 TI - Epigenetics and Oxidative Stress in Aging. AB - Aging is a multifactorial process characterized by the progressive loss of physiological functions, leading to an increased vulnerability to age-associated diseases and finally to death. Several theories have been proposed to explain the nature of aging. One of the most known identifies the free radicals produced by the mitochondrial metabolism as the cause of cellular and DNA damage. However, there are also several evidences supporting that epigenetic modifications, such as DNA methylation, noncoding RNAs, and histone modifications, play a critical role in the molecular mechanism of aging. In this review, we explore the significance of these findings and argue how the interlinked effects of oxidative stress and epigenetics can explain the cause of age-related declines. PMID- 28808500 TI - Emerging molecular targets and therapy for cholangiocarcinoma. AB - Cholangiocarcinoma (CCA) is a rare cancer arising from the biliary tree with a poor prognosis and limited therapeutic options. Recent large scale molecular characterisation studies have identified recurrent genetic alterations in CCA which may be amenable to therapeutic targeting. In this review we explore the genomic landscape of CCA and examine results from trials of molecularly targeted agents and immunotherapy in this disease. Challenges in CCA diagnosis, treatment and trial design are discussed and we reflect on future directions which may lead to improved outcomes for CCA patients. PMID- 28808501 TI - Evolving treatment landscape for early and advanced pancreatic cancer. AB - Pancreatic ductal adenocarcinoma is an infrequent cancer with a high disease related mortality rate, even in the context of early stage disease. Until recently, the rate of death from pancreatic cancer has remained largely similar whereby gemcitabine monotherapy was the mainstay of systemic treatment for most stages of disease. With the discovery of active multi-agent chemotherapy regimens, namely FOLFIRINOX and gemcitabine plus nab-paclitaxel, the treatment landscape of pancreatic cancer is slowly evolving. FOLFIRINOX and gemcitabine plus nab-paclitaxel are now considered standard first line treatment options in metastatic pancreatic cancer. Studies are ongoing to investigate the utility of these same regimens in the adjuvant setting. The potential of these treatments to downstage disease is also being actively examined in the locally advanced context since neoadjuvant approaches may improve resection rates and surgical outcomes. As more emerging data become available, the management of pancreatic cancer is anticipated to change significantly in the coming years. PMID- 28808503 TI - Prognostic efficacy of inflammation-based markers in patients with curative colorectal cancer resection. AB - AIM: To evaluate the prognostic significance of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and prognostic nutritional index (PNI) and other clinicopathological factors in patients undergoing curative resection of colon cancer. METHODS: 183 patients with histologically proven colorectal cancer who had undergone potentially curative resection between 2010 and 2016 at Ankara Numune Training and Research Hospital were retrospectively analyzed and clinicopathological characteristics included age, sex, tumor type, grade, size and localization, the number of metastatic and total number of lymph nodes removed, vascular and perineural invasion of the tumor, TNM stages, tumor marker levels (CEA, CA19-9, AFP, CA-125, CA15-3), complete blood counts, albumin levels, overall survival (months), NLR, PLR, LMR and PNI ratios were retrospectively reviewed and analyzed from the electronic database. The primary outcome measure was overall survival. RESULTS: Regarding overall survival, on univariate analysis the following variables were significantly associated with poor outcome following resection: T-stage (P = 0.037), lymph node invasion (P = 0.037), cancer stage (P = 0.034), CEA (P = 0.042), CA19-9 (P = 0.004), and PNI (P = 0.001). To evaluate the independent prognostic value, multivariate Cox proportional hazard analysis to control for other prognostic factors was used. Using cancer-specific death as an end point for NLR, PLR, LMR, PNI and CA19-9 the optimal cut off values were calculated by ROC analysis. Regarding overall survival, on multivariate analysis high CA19-9 (HR = 1.001, 95%CI: 1.00-1.002, P = 0.012) and low PNI (HR = 0.938, 95%CI: 0.891 0.987, P = 0.014) were the only variables independently associated with shortened overall survival. Patients with a PNI < 35 had a median OS of 52.25 mo. In contrast, patients with an PNI > 35 had a median OS of 66 mo. Patients with a CA 19-9 < 17 had a median OS of 66 mo and in patients with a CA19-9 > 17 had a median OS of 53.76 mo. CONCLUSION: This study shows that decrease in the PNI and increase in CA 19-9 is associated with poor survival in patients with resectable colon cancer. PMID- 28808502 TI - Clinical significance of tumor-infiltrating lymphocytes for gastric cancer in the era of immunology. AB - Immunotherapy has begun to revolutionize cancer treatment, by introducing therapies that target the host immune system instead of the tumor, therapies that possess unique adverse event profiles, and therapies that may cure certain types of cancer. The immune microenvironment of tumors is emerging as the most important means of understanding the relationship between a patient' immune system and their cancer, informing prognosis, and guiding immunotherapy, such as an antibody blockade of immune checkpoints. For some solid tumors, simple quantitation of lymphocyte infiltration would seem to have prognostic significance, suggesting that lymphocyte infiltration is not passive but may actively promote or inhibit tumor growth. For gastric cancers, several studies have provided strong evidence that immune cells contribute to determining prognosis. However, the exact role of immune cells in gastric cancer remains unclear. Therefore, this review focuses on the clinical significance of immune cells, especially tumor-infiltrating lymphocytes, in gastric cancer. PMID- 28808504 TI - Goblet cell carcinoid of the appendix and mixed adenoneuroendocrine carcinoma: Report of three cases. AB - Neuroendocrine neoplasms are the most common epithelial tumors among appendix tumors. Appendix tumors that are completely or partially composed of neuroendocrine cells are divided into two categories: Classic carcinoid tumors and goblet cell carcinoid tumors (GCCT). They are known to progress more aggressively than classic (neuro) endocrine tumors. In this study, three cases with acute appendicitis symptoms are presented, including their clinical and histopathological findings. Microscopic examination detected GCCT in two cases and mixed adenoneuroendocrine carcinoma in one case, in addition to acute appendicitis. PMID- 28808506 TI - The knowledge, concerns and healthcare practices among physicians regarding electronic cigarettes. AB - Background: Electronic cigarettes (e-cigarettes) are battery-powered devices that deliver aerosolized nicotine. With easy access and over-the-counter availability, many patients consider using electronic cigarettes for smoking cessation. Few studies have looked at long-term safety/efficacy and physician knowledge/attitudes toward e-cigarettes. Physicians have insufficient guidelines for advising their patients about e-cigarettes. Objective: 1) To identify knowledge and attitude of health care practitioners toward electronic cigarettes. 2) To identify the effect of level of training, experience and speciality on knowledge and practice of electronic cigarettes. 3) To identify factors influencing electronic cigarettes advise/prescribing practice. Methods: An anonymous online questionnaire was sent to residents, fellows, and faculty in pre selected specialties at Saint Louis University (SLU) Hospital. Results: We received 115 responses. Nine percent reported being 'very familiar' with e cigarettes, while 25% reported no familiarity; 18% of physicians would advise e cigarettes as nicotine-replacement therapy if asked by patients; 91% were aware of the nicotine content of e-cigarettes, but only 20% and 39%, respectively, were aware of the presence of carcinogens and polyethylene glycol. Only 63% of respondents knew what 'vape' meant. Lack of evidence regarding long-term safety (76%), e-cigarettes as starter products for nonsmokers (50%), absence of Food and Drug Administration (FDA) regulations (51%) and marketing to youth (42%) were major concerns. Stricter regulations (54%), warning labels similar to tobacco products (53%), restricting advertising (36%), banning sales to minors (34%), and banning use in public spaces (25%) were favored as regulatory measures. More than 50% of physicians see a role for e-cigarettes as part of 'harm-reduction strategy'. Conclusions: Further research is needed to assess whether e- cigarettes could be an effective smoking-cessation tool. There is an apparent knowledge deficit among physicians and an urgent need for evidence-based guidelines to aid with advising patients enquiring about e-cigarettes. PMID- 28808507 TI - CYP2C19 genetic variation and individualized clopidogrel prescription in a cardiology clinic. AB - Background: Clopidogrel (Plavix) is an antiplatelet medication that is routinely used in patients with cardiovascular disease. Cytochrome P2C19 enzymes play a major role in its metabolism, which determines its varied therapeutic level and its effectiveness. Objectives: To customize clopidogrel therapy and evaluate its efficacy by using CYP2C19 genotypic and phenotypic information to improve clinical outcomes in patients. Methods: A total of 465 patients with underlying cardiovascular disease were selected from our out-patient cardiology clinic. DNA sequences of CYP2C19 were analyzed in 465 patients. Results: Of 465 patients, 183 were wild-type homozygous (*1/*1) and 18.8% gain-of function and 19.8% loss-of function alleles in our patient population The following changes were made: 1) Switching to prasugrel in patients whose genotype noted them to be "Slow metabolizers. This medication adjustment improved clinical outcomes in this patient group. 2) Discontinuing or lowering clopidogrel doses in patients whose genotypes noted them to be "Fast or ultra-fast metabolizes" to decrease bleeding risk. For those who were not on clopidogrel but carried abnormal allele(s), "clopidogrel caution" was documented. These individuals were followed up for 3 years and there has not been any cardiac clinical symptoms, cardiac death or excessive bleeding reported. Conclusions: Given the varied effectiveness of clopidogrel due to its metabolism by CYP2C19 enzyme, and the relatively high frequency of both gain-of-function (18.8%) and loss-of-function (19.8%) alleles in our patient population, we believe that genotyping CYP2C19 is clinically important in order to improve patient outcomes and minimize patient risk. PMID- 28808509 TI - An educational intervention to increase awareness reduces unnecessary laboratory testing in an internal medicine resident-run clinic. AB - At our resident-run clinic in an underserved community, laboratory test costs in 2013 exceeded the government subsidy by $400 000. To optimize limited resources and improve patient care, an education program to reduce testing was implemented. Between November 2014 and January 2015, residents attended lectures on utilization of laboratory testing, focusing on standard practice guidelines, and analyses of unnecessary tests. Multivariate nonparametric statistical methods and subgroup analysis were used to evaluate cost reduction. There were 453 clinic visits during the intervention period and 471 visits during the control period. Lectures were independently associated with a significant laboratory cost reduction. Median laboratory cost per visit decreased from $106.00 to $74.00. Total cost in the study period decreased from $79 403 to $51 463. There were similar reductions of laboratory costs in two subgroups: age groups of <50 years and >=50 years, new encounters, and follow-up visits . In the analysis of individual tests, the cost of TSH and Vitamin D tests had the greatest reduction ($8176 and $5088 respectively). An appropriate physician education program can reduce laboratory tests and costs. Screening tests with inadequate evidence support were reduced most, whereas those with proven benefits did not decrease significantly. PMID- 28808508 TI - New-onset acute thrombocytopenia in hospitalized patients: pathophysiology and diagnostic approach. AB - Thrombocytopenia is a hematological finding commonly encountered in daily clinical practice from asymptomatic clinic patients to critically ill intensive care unit patients. A broad spectrum of etiologies and variation in clinical presentation often present a diagnostic challenge. Furthermore, concomitant presence of thrombosis and thrombocytopenia, as in cases of thrombotic thrombocytopenia, complicates the management. In hospitalized patients, new-onset thrombocytopenia is an important reason for hematology consultation. Therefore, it is of utmost importance that the etiology is diagnosed accurately. In addition, a basic understanding of the pathophysiology and the differential diagnosis avoids delay in the diagnosis and leads to rapid initiation of treatment. This review will address causes of thrombocytopenia that arises in hospitalized patients with an emphasis on the pathophysiological basis of each disorder. PMID- 28808510 TI - Multi-organ failure, weeks after being exposed to murky water - rule out leptospirosis. AB - Leptospirosis is a rare zoonotic disease which occurs in people exposed to contaminated water or/and animal urine. We report two cases of moderate to severe leptospirosis. The first case was a healthy middle-aged biology professor who recently visited his family in Jamaica and presented with multi-organ failure. The second case was a 27-year-old police officer who was admitted for acute liver injury and thrombocytopenia after helping people evacuate during a flood/disaster situation. PMID- 28808511 TI - Large endocardial rheumatoid nodules: a case report and review of the literature. AB - Rheumatoid nodules occur frequently in patients with rheumatoid arthritis and are the most common cutaneous manifestation of the disease. Although uncommon, rheumatoid nodules may also occur on cardiac valves, where they may be large and clinically significant. They may embolize and cause stroke. They may cause regurgitant murmurs, or they may result in valvular destruction. Echocardiographically, they may mimic an atrial myxoma or appear as a vegetation. We present a patient with seronegative rheumatoid arthritis who developed an acute embolic stroke; he had peripheral stigmata of infective endocarditis on physical examination and echocardiography revealed a mitral valve vegetation. We illustrate that these findings were due to a large, highly destructive mitral valve rheumatoid nodule. We review the literature on macroscopic endocardial nodules and emphasize their diverse clinical behavior. PMID- 28808512 TI - A case of hypercalcemia with double pathology. AB - Hypercalcemia has many causes including primary hyperparathyroidism, malignancy, and other rare etiologies. In most of the cases, hypercalcemia is secondary to one etiology. In this case, we are reporting hypercalcemia with two causes. The initial workup showed primary hyperparathyroidism due to parathyroid adenoma. But because all features were not fully explained by primary hyperparathyroidism, further work-up revealed multiple myeloma. This case represents coexistence of two different diseases, which was rarely reported in the literature previously. Usually, the co-diagnosis was made subsequently after failure to correct hypercalcemia. In our case, both diagnoses were established at the same time of the patient's presentation as of high suspicion. Establishing the diagnosis early will aid in the initiation of treatment in a timely fashion. PMID- 28808513 TI - Lance-Adams syndrome associated with cerebellar pathology. AB - Lance-Adams syndrome (LAS) is an uncommon neurological disorder characterized by the development of chronic post-hypoxic myoclonus. There are relatively few cases described following successful cardiopulmonary resuscitation. We report a patient who developed LAS 3 months after successful resuscitation. Cerebral imaging studies indicate that brain pathology in LAS patients is not uniform, suggesting that the pathophysiology of myoclonus may vary from patient to patient. Our patient adds to this etiological heterogeneity by demonstrating the unusual feature of cerebellar pathology by both cerebral magnetic resonance imaging and single-photon emission computed tomography scans. There is also heterogeneity of these patients in their response to therapy. Unlike some patients described in the literature, our patient has not responded to drug treatment. Studies of these rare patients with LAS are important as they provide insight into the pathophysiology of this condition which, it is hopefully, will facilitate the development of more effective therapy. PMID- 28808514 TI - Nodular pulmonary amyloidosis with primary pulmonary MALT lymphoma masquerading as metastatic lung disease. AB - Nodular pulmonary amyloidosis is a very rare form of localized amyloidosis involving the lung, with very little known about its nature. It is usually associated with indolent B cell lymphoproliferative disorder and also connective tissue disorders. No definite treatment guideline exists. Many patients respond to chemotherapy with low risk of progression and a 'wait and watch' strategy is also considered a valid treatment option. In this report the authors present a case of nodular pulmonary amyloidosis with pulmonary mucosa associated lymphoid tissue (MALT) lymphoma that presented with features of metastatic malignant disease and after definitive diagnosis decided not to undergo treatment. PMID- 28808515 TI - Palpitations as a presenting feature of multisystem sarcoidosis. AB - Introduction: Sarcoidosis is described as a systemic condition characterized by non-caseating granulomas in multiple organs. In this report, we present an unusual manifestation of cardiac sarcoidosis and review management strategies. Case presentation: A 29-year-old African-American man presented with weight loss, fatigue, dyspnea, palpitations, night sweats, painless left eye redness and bilateral leg pain over the course of three months. His physical exam revealed left conjunctival congestion and bilateral crackles on auscultation. Computerized tomography of the chest showed severe parenchymal disease with bilateral fibrotic bands. Bronchoscopy and transbronchial biopsy revealed noncaseating granulomas and multinucleated giant cells, confirming sarcoidosis. Non-sustained ventricular tachycardia developed. Cardiac MRI showed myocardial delayed gadolinium enhancement. He responded to methotrexate and steroid therapy. An implantable cardioverter-defibrillator was placed. Discussion: Although cardiac sarcoidosis manifests in only 5% of sarcoidosis, autopsy reports indicate subclinical cardiac involvement in up to 30%. There are no established criteria for diagnosis of cardiac sarcoidosis. Conclusion: Early recognition and diagnosis of cardiac sarcoidosis is challenging but vital due to unpredictability and high risk for malignant cardiac involvement. Newer diagnostic imaging modalities have further aided in earlier identification and prevention of sudden cardiac death. PMID- 28808516 TI - Double whammy- acute splenic sequestration crisis in patient with aplastic crisis due to acute parvovirus infection. AB - Splenic dysfunction is a major feature of sickle cell disease (SCD) and can manifest as acute splenic sequestration crisis (ASSC), which is the earliest life threatening complication seen in patients with SCD. Aplastic crisis is another potentially deadly complication of sickle cell disease that develops when erythrocyte production temporarily drops. Infection with parvovirus B-19 frequently causes aplastic crises. These two complications are known to be mutually exclusive due to their classic presentation signs and symptoms but there have been few cases where a patient can have concomitant presentation of both phenomena, which can result in a fatal outcome. These few cases force us to rethink the etiology and subsequent management guidelines of these complications. We present to you a case of an unfortunate 23-year-old female who had both complications occurring at the same time, resulting in death. PMID- 28808517 TI - The mythos of laudable pus along with an explanation for its origin. AB - The presence of pus is one of the most easily recognizable signs of an infection. However, for several centuries suppuration, known as 'laudable pus,' was believed to be a sign of a healthy, healing wound. This historical misconception can be explained by the difference in the presentation of a necrotizing soft tissue infection versus other more common skin and soft tissue infections. Chronic wound infections, due to pyogenic bacteria, typically produce large amounts of thick, whitish-yellow pus. On the other hand, necrotizing soft tissue infections, despite their severe mortality and morbidity, are devoid of pus in the traditional sense. What the ancient medical observers recognized was the fact that pus is not characteristic of this subset of incredibly severe infections. This is an important distinction to remember when evaluating an infection, even today. PMID- 28808518 TI - Evolocumab to reduce cardiovascular events: results of the (FOURIER) multinational trial. PMID- 28808519 TI - Rectus Sheath Hematoma Associated with Apixaban. AB - Apixaban is an oral anticoagulant that directly inhibits Factor Xa and is indicated for the prophylaxis and treatment of deep venous thrombosis and stroke prevention in non-valvular atrial fibrillation. Rectus sheath hematoma is a rare, life-threatening complication of anticoagulant treatment. We describe a case of an elderly patient on apixaban for the treatment of deep venous thrombosis who developed severe abdominal pain during hospitalization. Computed tomography of the abdomen revealed left rectus sheath hematoma. Apixaban was discontinued and the patient was monitored for extension of the hematoma. After 2 days she was discharged home. Outpatient computed tomography 1 month later showed complete resolution of the rectus sheath hematoma. We recommend that clinicians become aware of the potential for rare and serious bleeding complications of anticoagulants and identify the need for early recognition and prompt management. PMID- 28808520 TI - Gallstone Ileus: Dilemma in the Management. AB - Gallstone ileus is a mechanical intestinal obstruction caused due to impaction of a large gallstone within the bowel. The ideal treatment of gallstone ileus remains controversial, with the main dilemma being between a one-stage and a two stage surgical procedure. A 69-year old male patient presented with gallstone ileus. A one-stage procedure with enterolithotomy and primary closure of duodenal fistula was done. His immediate postoperative recovery was uneventful, but after 3 weeks of surgery, he developed respiratory complications and expired of multi organ failure. In gallstone ileus, patient presents with symptoms of intestinal obstruction. Enterolithotomy alone remains the most common operative method, but the definitive surgical management is still under research. An intraoperative dilemma between a one-stage or two-stage surgery is difficult to resolve in absence of clear guidelines. Hence, more studies are required to come to a consensus in deciding its definitive management. PMID- 28808521 TI - Replicative genetic association study between functional polymorphisms in AVPR1A and social behavior scales of autism spectrum disorder in the Korean population. AB - BACKGROUND: Arginine vasopressin has been shown to affect social and emotional behaviors, which is mediated by the arginine vasopressin receptor (AVPR1A). Genetic polymorphisms in the AVPR1A promoter region have been identified to be associated with susceptibility to social deficits in autism spectrum disorder (ASD). We hypothesize that alleles of polymorphisms in the promoter region of AVPR1A may differentially interact with certain transcriptional factors, which in turn affect quantitative traits, such as sociality, in children with autism. METHODS: We performed an association study between ASD and polymorphisms in the AVPR1A promoter region in the Korean population using a family-based association test (FBAT). We evaluated the correlation between genotypes and the quantitative traits that are related to sociality in children with autism. We also performed a promoter assay in T98G cells and evaluated the binding affinities of transcription factors to alleles of rs7294536. RESULTS: The polymorphisms-RS1, RS3, rs7294536, and rs10877969-were analyzed. Under the dominant model, RS1-310, the shorter allele, was preferentially transmitted. The FBAT showed that the rs7294536 A allele was also preferentially transmitted in an additive and dominant model under the bi-allelic mode. When quantitative traits were used in the FBAT, rs7294536 and rs10877969 were statistically significant in all genotype models and modes. Luciferase and electrophoretic mobility-shift assays suggest that the rs7294536 A/G allele results in a Nf-kappaB binding site that exhibits differential binding affinities depending on the allele. CONCLUSION: These results demonstrate that polymorphisms in the AVPR1A promoter region might be involved in pathophysiology of ASD and in functional regulation of the expression of AVPR1A. PMID- 28808522 TI - Galvanic replacement synthesis of Ag x Au1-x @CeO2 (0 <= x <= 1) core@shell nanospheres with greatly enhanced catalytic performance. AB - A galvanic replacement strategy has been successfully adopted to design Ag x Au1 x @CeO2 core@shell nanospheres derived from Ag@CeO2 ones. After etching using HAuCl4, the Ag core was in situ replaced with Ag x Au1-x alloy nanoframes, and void spaces were left under the CeO2 shell. Among the as-prepared Ag x Au1-x @CeO2 catalysts, Ag0.64Au0.36@CeO2 shows the optimal catalytic performance, whose catalytic efficiency reaches even 2.5 times higher than our previously reported Pt@CeO2 nanospheres in the catalytic reduction of 4-nitrophenol (4-NP) by ammonia borane (AB). Besides, Ag0.64Au0.36@CeO2 also exhibits a much lower 100% conversion temperature of 120 degrees C for catalytic CO oxidation compared with the other samples. PMID- 28808523 TI - Label-free luminescence switch-on detection of hepatitis C virus NS3 helicase activity using a G-quadruplex-selective probe. AB - A series of luminescent Ir(iii) complexes were synthesised and evaluated for their ability to act as luminescent G-quadruplex-selective probes. The Ir(iii) complex 9, [Ir(phq)2(phen)]PF6 (where phq = 2-phenylquinoline; phen = 1,10 phenanthroline), exhibited high luminescence in the presence of G-quadruplex DNA compared to dsDNA and ssDNA, and was employed to construct a label-free G quadruplex-based assay for hepatitis C virus NS3 helicase activity in aqueous solution. Moreover, the application of the assay for screening potential helicase inhibitors was demonstrated. To our knowledge, this is the first G-quadruplex based assay for helicase activity. PMID- 28808524 TI - Computational study of the mechanism and selectivity of ruthenium-catalyzed hydroamidations of terminal alkynes. AB - Density functional theory calculations were performed to elucidate the mechanism of the ruthenium-catalyzed hydroamidation of terminal alkynes, a powerful and sustainable method for the stereoselective synthesis of enamides. The results provide an explanation for the puzzling experimental finding that with tri-n butylphosphine (P(Bu)3) as the ligand, the E-configured enamides are obtained, whereas the stereoselectivity is inverted in favor of the Z-configured enamides with (dicyclohexylphosphino)methane (dcypm) ligands. Using the addition of pyrrolidinone to 1-hexyne as a model reaction, various pathways were investigated, among which a catalytic cycle turned out to be most advantageous for both ligand systems that consists of: (a) oxidative addition, (b) alkyne coordination, (c) alkyne insertion (d) vinyl-vinylidene rearrangement, (e) nucleophilic transfer and finally (f) reductive elimination. The stereoselectivity of the reaction is decided in the nucleophilic transfer step. For the P( n Bu)3 ligand, the butyl moiety is oriented anti to the incoming 2 pyrolidinyl unit during the nucleophilic transfer step, whereas for the dcypm ligand, steric repulsion between the butyl and cyclohexyl groups turns it into a syn orientation. Overall, the formation of E-configured product is favorable by 4.8 kcal mol-1 (Delta?GSDL) for the catalytic cycle computed with P(Bu)3 as ancillary ligand, whereas for the catalytic cycle computed with dcypm ligands, the Z-product is favored by 7.0 kcal mol-1 (Delta?GSDL). These calculations are in excellent agreement with experimental findings. PMID- 28808525 TI - Anticancer metallohelices: nanomolar potency and high selectivity. AB - A range of new helicate-like architectures have been prepared via highly diastereoselective self-assembly using readily accessible starting materials. Six pairs of enantiomers [Fe2L3]Cl4.nH2O (L = various bidentate ditopic ligands NN NN) show very good water solubility and stability. Their activity against a range of cancer cell lines in vitro is structure-dependent and gives IC50 values as low as 40 nM. In an isogenic pair of HCT116 colorectal cancer cells, preferential activity was observed against cell lines that lack functional p53. Selectivity is also excellent, and against healthy human retinal pigment epithelial (ARPE19) and lung fibroblast (WI38) cells IC50 values are nearly three orders of magnitude higher. Cisplatin is unselective in the same tests. The compounds also appear to have low general toxicity in a number of models: there is little if any antimicrobial activity against methicillin-resistant Staphylococcus aureus and Escherichia coli; Acanthamoeba polyphaga is unaffected at 25 MUg mL-1 (12.5 MUM); Manduca sexta larvae showed clear evidence of systemic distribution of the drug, and rather than any observation of adverse effects they exhibited a significant mean weight gain vs. controls. Investigation of the mode of action revealed no significant interaction of the molecules with DNA, and stimulation of substantial cell death by apoptosis. PMID- 28808526 TI - Co-delivery of nitric oxide and antibiotic using polymeric nanoparticles. AB - The rise of hospital-acquired infections, also known as nosocomial infections, is a growing concern in intensive healthcare, causing the death of hundreds of thousands of patients and costing billions of dollars worldwide every year. In addition, a decrease in the effectiveness of antibiotics caused by the emergence of drug resistance in pathogens living in biofilm communities poses a significant threat to our health system. The development of new therapeutic agents is urgently needed to overcome this challenge. We have developed new dual action polymeric nanoparticles capable of storing nitric oxide, which can provoke dispersal of biofilms into an antibiotic susceptible planktonic form, together with the aminoglycoside gentamicin, capable of killing the bacteria. The novelty of this work lies in the attachment of NO-releasing moiety to an existing clinically used drug, gentamicin. The nanoparticles were found to release both agents simultaneously and demonstrated synergistic effects, reducing the viability of Pseudomonas aeruginosa biofilm and planktonic cultures by more than 90% and 95%, respectively, while treatments with antibiotic or nitric oxide alone resulted in less than 20% decrease in biofilm viability. PMID- 28808527 TI - Carborane-based design of a potent vitamin D receptor agonist. AB - The vitamin D nuclear receptor (VDR) is a potential target for cancer therapy. It is expressed in many tumors and its ligand shows anticancer actions. To combine these properties with the application of boron neutron capture therapy (BNCT), we design and synthesize a potent VDR agonist based on the skeleton of the hormone 1alpha,25-dihydroxyvitamin D3 (1,25D) and an o-carborane (dicarba-o-closo-1,2 dodecaborane) at the end of its side chain. The present ligand is the first secosteroidal analog with the carborane unit that efficiently binds to VDR and functions as an agonist with 1,25D-like potency in transcriptional assay on vitamin D target genes. Moreover it exhibits similar antiproliferative and pro differentiating activities but is significantly less hypercalcemic than 1,25D. The crystal structure of its complex with VDR ligand binding domain reveals its binding mechanism involving boron-mediated dihydrogen bonds that mimic vitamin D hydroxyl interactions. In addition to the therapeutic interest, this study establishes the basis for the design of new unconventional vitamin D analogs containing carborane moieties for specific molecular recognition, and drug research and development. PMID- 28808528 TI - A highly selective near-infrared fluorescent probe for imaging H2Se in living cells and in vivo. AB - Hydrogen selenide (H2Se), a highly reactive Se species, is an important selenium metabolism intermediate involved in many physiological and pathological processes. This compound is of scientific interest with regard to the real-time monitoring of H2Se in living cells and in vivo to understand the anti-cancer mechanism of selenium. However, monitoring H2Se in living cells is still challenging due to the lack of straight forward, highly selective and rapid methods. Here, we developed a novel small-molecule fluorescent probe, NIR-H2Se, for imaging endogenous H2Se. NIR-H2Se exhibited high selectivity toward H2Se over selenocysteine (Sec), H2S and small molecule thiols and was successfully used to image the H2Se content in HepG2 cells during Na2SeO3-induced apoptosis. Increased H2Se content and reduced ROS levels were observed under hypoxic conditions compared to normoxic conditions, which indicated that the cell apoptosis induced by Na2SeO3 under a hypoxic environment is via a non-oxidative stress mechanism. Thus, this probe should serve as a powerful tool for exploring the physiological function of H2Se and Se anticancer mechanisms in a variety of physiological and pathological contexts. PMID- 28808529 TI - A highly active nickel electrocatalyst shows excellent selectivity for CO2 reduction in acidic media. AB - The development of selective electrocatalysts for CO2 reduction in water offers a sustainable route to carbon based fuels and feedstocks. However, molecular catalysts are typically studied in non-aqueous solvents, in part to avoid competitive H2 evolution. [Ni(cyclam)]2+ (1) is one of the few known electrocatalysts that operate in water and 30 years after its report its activity remains a rarely surpassed benchmark. Here we report that [Ni(cyclam-CO2H)]2+ (cyclam-CO2H = 1,4,8,11-tetraazacyclotetradecane-6-carboxylic acid (2)) shows greatly enhanced activity versus1 for CO production. At pHs < pKa of the pendant carboxylic acid a large increase in catalytic activity occurs. Remarkably, despite the high proton concentration (pH 2), 2 maintains selectivity for CO2 reduction and is believed to be unique in operating selectively in such acidic aqueous solutions. PMID- 28808530 TI - Length-independent transport rates in biomolecules by quantum mechanical unfurling. AB - Experiments on hole transfer in DNA between donor and acceptor moieties revealed transfer rates which are independent of the molecular bridge length (within experimental error). However, the physical origin of this intriguing observation is still unclear. The hopping model implies that the hole propagates in multiple steps along the bridge from one localized state to another, and therefore the longer the bridge, the slower the transfer. This can explain weak length dependence but not a length-independent transfer rate. We show that the rigid molecular structure of a poly-A bridge supports single step transitions from a localized hole state to delocalized states, spread over the entire bridge. Since propagation to the bridge end is a single step process (termed quantum unfurling) the transfer rate becomes independent of the bridge length. This explanation is consistent with experimental results, and emphasizes the importance of structural order in charge transfer through bio-molecular systems. PMID- 28808531 TI - Many Mg-Mg bonds form the core of the Mg16Cp*8Br4K cluster anion: the key to a reassessment of the Grignard reagent (GR) formation process? AB - It caused a sensation eight years ago, when the first room temperature stable molecular compound with a Mg-Mg bond (LMgMgL, L = chelating ligand) containing magnesium in the oxidation state +1 was prepared. Here, we report the preparation of a [Mg16Cp*8Br4K]- cluster anion (Cp* = pentamethylcyclopentadiene) with 27 Mg Mg bonds. It has been obtained through the reaction of KCp* with a metastable solution of MgBr in toluene. A highly-resolved Fourier transform mass spectrum (FT-MS) of this cluster anion, brought into vacuum by electrospraying its solution in THF, provides the title cluster's stoichiometry. This Mg16 cluster together with experiments on the metastable solution of MgBr show that: during the formation process of GRs (Grignard reagents) which are involved in most of sophisticated syntheses of organic products, not the highly reactive MgBr radical as often presumed, but instead the metalloid Mg16Cp*8Br4 cluster anion and its related cousins that are the operative intermediates along the pathway from Mg metal to GRs (e.g. Cp*MgBr). PMID- 28808532 TI - A cobalt(ii) spin-crossover compound with partially charged TCNQ radicals and an anomalous conducting behavior. AB - The bifunctional salt [Co(terpy)2](TCNQ)3.CH3CN (terpy = 2,2';6',2''-terpyridine, TCNQ = 7,7,8,8-tetracyanoquino-dimethane) exhibits a high room temperature conductivity of 0.13 S cm-1 and an anomaly in conductivity at ~190 K as evidenced by variable temperature structural, magnetic and conductivity studies. The anomaly in the conductivity at 190 K has been correlated with the temperature dependent structural breathing and Jahn-Teller distortion of the low spin state of the SCO units, as well as the charge fluctuations and supramolecular pi stacking interactions of partially charged TCNQ radicals. The modular synthetic approach leads to an accessible source of partially charged TCNQ radicals for the facile preparation of bifunctional molecular materials with high electrical conductivity. PMID- 28808533 TI - Mesoporous Pt nanospheres with designed pore surface as highly active electrocatalyst. AB - A novel strategy for large-scale synthesis of shape- and size-controlled mesoporous Pt nanospheres (MPNs) through a slow reduction reaction in the presence of surfactant is reported here for the first time. The slow reduction reaction exclusively results in well-defined mesoporous architectures distinctly different from the dendritic constructions reported previously. More importantly, abundant catalytically active sites are created on the highly accessible mesoporous surfaces by the selective adsorption of bromide ions. The MPNs prepared by using the new synthetic route not only show superior electrochemical performance toward methanol oxidation reaction and oxygen reduction reaction, but also exhibit extremely high structural thermostability, which makes them promising catalysts for industrial applications. PMID- 28808534 TI - A bioscaffolding strategy for hierarchical zeolites with a nanotube-trimodal network. AB - Hierarchical zeolite monoliths with multimodal porosity are of paramount importance as they open up new horizons for advanced applications. So far, hierarchical zeolites based on nanotube scaffolds have never been reported. Inspired by the organization of biominerals, we have developed a novel precursor scaffolding-solid phase crystallization strategy for hierarchical zeolites with a unique nanotube scaffolding architecture and nanotube-trimodal network, where biomolecular self-assembly (BSA) provides a scaffolding blueprint. By vapor treating Sil-1 seeded precursor scaffolds, zeolite MFI nanotube scaffolds are self-generated, during which evolution phenomena such as segmented voids and solid bridges are observed, in agreement with the Kirkendall effect in a solid phase crystallization system. The nanotube walls are made of intergrown single crystals rendering good mechanical stability. The inner diameter of the nanotube is tunable between 30 and 90 nm by varying the thickness of the precursor layers. Macropores enclosed by cross-linked nanotubes can be modulated by the choice of BSA. Narrow mesopores are formed by intergrown nanocrystals. Hierarchical ZSM-5 monoliths with nanotube (90 nm), micropore (0.55 nm), mesopore (2 nm) and macropore (700 nm) exhibit superior catalytic performance in the methanol-to hydrocarbon (MTH) conversion compared to conventional ZSM-5. BSA remains intact after crystallization, allowing a higher level of organization and functionalization of the zeolite nanotube scaffolds. The current work may afford a versatile strategy for hierarchical zeolite monoliths with nanotube scaffolding architectures and a nanotube-multimodal network leading to self-supporting and active zeolite catalysts, and for applications beyond. PMID- 28808535 TI - Bimetallic iron-iron and iron-zinc complexes of the redox-active ONO pincer ligand. AB - A new bimetallic platform comprising a six-coordinate Fe(ONO)2 unit bound to an (ONO)M (M = Fe, Zn) has been discovered ((ONOcat)H3 = bis(3,5-di-tert-butyl-2 phenol)amine). Reaction of Fe(ONO)2 with either (ONOcat)Fe(py)3 or with (ONOq)FeCl2 under reducing conditions led to the formation of the bimetallic complex Fe2(ONO)3, which includes unique five- and six-coordinate iron centers. Similarly, the reaction of Fe(ONO)2 with the new synthon (ONOsq)Zn(py)2 led to the formation of the heterobimetallic complex FeZn(ONO)3, with a six-coordinate iron center and a five-coordinate zinc center. Both bimetallic complexes were characterized by single-crystal X-ray diffraction studies, solid-state magnetic measurements, and multiple spectroscopic techniques. The magnetic data for FeZn(ONO)3 are consistent with a ground state S = 3/2 spin system, generated from a high-spin iron(ii) center that is antiferromagnetically coupled to a single (ONOsq)2- radical ligand. In the case of Fe2(ONO)3, the magnetic data revealed a ground state S = 7/2 spin system arising from the interactions of one high-spin iron(ii) center, one high-spin iron(iii) center, and two (ONOsq)2- radical ligands. PMID- 28808536 TI - Asymmetric 18F-fluorination for applications in positron emission tomography. AB - Positron emission tomography (PET) is becoming more frequently used by medicinal chemists to facilitate the selection of the most promising lead compounds for further evaluation. For PET, this entails the preparation of 11C- or 18F-labeled drugs or radioligands. With the importance of chirality and fluorine substitution in drug development, chemists can be faced with the challenge of preparing enantiopure molecules featuring the 18F-tag on a stereogenic carbon. Asymmetric 18F-fluorination is an emerging field of research that provides an alternative to resolution or conventional SN2-based radiochemistry. To date, both transition metal complexes and organomediators have been successfully employed for 18F incorporation at a stereogenic carbon. PMID- 28808537 TI - One-pot synthesis of a [c2]daisy-chain-containing hetero[4]rotaxane via a self sorting strategy. AB - The construction and efficient synthesis of hetero[n]rotaxanes with high structural complexity are always attractive challenges. Herein, we demonstrate a facile one-pot preparation of a hetero[4]rotaxane, by employing a self-sorting strategy, which contains an interpenetrated dibenzo-24-crown-8 (DB24C8) based [c2]daisy chain structure and is ended with a benzo-21-crown-7 (B21C7) based rotaxane at each side. The key to the design involved encoding the selective threading using a steric hindrance-related "language", where highly selective self-assemblies occurred in a three-component self-sorting process, which included the threading of a benzylalkylammonium into a B21C7 and interpenetrated dimerized formation of a DB24C8 based [c2]daisy chain simultaneously; the precise pre-assembled system resulted in the efficient synthesis of hetero[4]rotaxane with a high-level of structural complexity under the "CuAAC" reaction. PMID- 28808538 TI - Dual stimuli-induced formation of a MU-hydroxido bridged [Zn9L5(MU-OH)6]12+ half pipe. AB - Low-symmetry metal-organic architectures that feature unusual binding motifs are useful for exploring new modes of guest recognition. Such structures remain difficult to create using current rational design principles. One approach to constructing such architectures is to employ ligands with coordination vectors oriented to preclude the formation of simple, low nuclearity molecular assemblies upon complexation to metal ions. Here we report two new supramolecular assemblies generated from such a ligand: a simple metastable [Zn3L3]6+ assembly, which was observed to convert to a more complex [Zn9L5(MU-OH)6]12+ twisted half-pipe architecture. Two chemically distinct stimuli-an anionic template and a base-must be applied for the conversion to occur. Perchlorate, perrhenate, trifluoromethanesulfonate and 2-naphthalenesulfonate were found to act as competent templates for the [Zn9L5(MU-OH)6]12+ structure. PMID- 28808539 TI - Soil conditioning effects of Phragmites australis on native wetland plant seedling survival. AB - Interactions between introduced plants and soils they colonize are central to invasive species success in many systems. Belowground biotic and abiotic changes can influence the success of introduced species as well as their native competitors. All plants alter soil properties after colonization but, in the case of many invasive plant species, it is unclear whether the strength and direction of these soil conditioning effects are due to plant traits, plant origin, or local population characteristics and site conditions in the invaded range. Phragmites australis in North America exists as a mix of populations of different evolutionary origin. Populations of endemic native Phragmites australis americanus are declining, while introduced European populations are important wetland invaders. We assessed soil conditioning effects of native and non-native P. australis populations on early and late seedling survival of native and introduced wetland plants. We further used a soil biocide treatment to assess the role of soil fungi on seedling survival. Survival of seedlings in soils colonized by P. australis was either unaffected or negatively affected; no species showed improved survival in P. australis-conditioned soils. Population of P. australis was a significant factor explaining the response of seedlings, but origin (native or non-native) was not a significant factor. Synthesis: Our results highlight the importance of phylogenetic control when assessing impacts of invasive species to avoid conflating general plant traits with mechanisms of invasive success. Both native (noninvasive) and non-native (invasive) P. australis populations reduced seedling survival of competing plant species. Because soil legacy effects of native and non-native P. australis are similar, this study suggests that the close phylogenetic relationship between the two populations, and not the invasive status of introduced P. australis, is more relevant to their soil-mediated impact on other plant species. PMID- 28808540 TI - Who's My Daddy? Considerations for the influence of sexual selection on multiple paternity in elasmobranch mating systems. AB - Polyandry resulting in multiply-sired litters has been documented in the majority of elasmobranch species examined to date. Although commonly observed, reasons for this mating system remain relatively obscure, especially in batoids. The round stingray (Urobatis halleri) is an abundant, well-studied elasmobranch distributed throughout the northeastern Pacific that we used to explore hypotheses regarding multiple paternity in elasmobranchs. Twenty mid- to late-term pregnant females were sampled off the coast of southern California and their litters analyzed for the occurrence of multiple paternity using five nuclear microsatellite loci. In addition, embryo sizes and their position within the female reproductive system (i.e., right or left uterus) were recorded and used to make inferences for patterns of ovulation. Multiple paternity was observed in 90% of litters and male reproductive success within litters was relatively even among sires. High variability in testes mass was observed suggesting that sperm competition is high in this species, although male reproductive success per litter appeared to be relatively even. Using embryo size as a proxy for fertilization, females were found to exhibit a variety of ovulation patterns that could function to limit a male's access to eggs and possibly promote high rates of multiple paternity. Our study highlights that elasmobranch mating systems may be more varied and complex than presumed and further investigation is warranted. PMID- 28808541 TI - How can distinct egg polymorphism be maintained in the rufescent prinia (Prinia rufescens)-plaintive cuckoo (Cacomantis merulinus) interaction-a modeling approach. AB - In avian brood parasitism, both the host and the parasite are expected to develop various conflicting adaptations; hosts develop a defense against parasitism, such as an ability to recognize and reject parasitic eggs that look unlike their own, while parasites evolve egg mimicry to counter this host defense. Hosts may further evolve to generate various egg phenotypes that are not mimicked by parasites. Difference in egg phenotype critically affects the successful reproduction of hosts and parasites. Recent studies have shown that clear polymorphism in egg phenotype is observed in several host-parasite interactions, which suggests that egg polymorphism may be a more universal phenomenon than previously thought. We examined the mechanism for maintaining egg polymorphism in the rufescent prinia (Prinia rufescens) that is parasitized by the plaintive cuckoo (Cacomantis merulinus) from a theoretical viewpoint based on a mathematical model. The prinia has four distinct egg phenotypes: immaculate white, immaculate blue, white with spots, and blue with spots. Only two egg phenotypes, white with spots and blue with spots, are found in the cuckoo population. We show that the observed prinia and cuckoo phenotypes cannot be at an equilibrium and that egg polymorphism can be maintained either at stationary equilibrium or with dynamic, frequency oscillations, depending on the mutation rates of the background color and spottiness. Long-term monitoring of the prinia cuckoo interaction over a wide geographic range is needed to test the results of the model analyses. PMID- 28808542 TI - The relationship between male sexual signals, cognitive performance, and mating success in stickleback fish. AB - Cognitive ability varies dramatically among individuals, yet the manner in which this variation correlates with reproduction has rarely been investigated. Here, we ask (1) do male sexual signals reflect their cognitive ability, and (2) is cognitive ability associated with male mating success? Specifically, we presented threespine sticklebacks (Gasterosteus aculeatus) with a detour-reaching task to assess initial inhibitory control. Fish that performed better were those who solved the detour-reaching task, solved it faster, and required fewer attempts to solve. We then reexamined males' performance on this task over several days to assess learning ability in this context. We next measured sexual signals (coloration, nest area, and courtship vigor) and asked whether they reveal information about these male cognitive abilities. Finally, we examined whether success at attracting a female is associated with male cognition. After controlling for the strong effect of neophobia, we found that no measured sexual signals were associated with initial inhibitory control. Sexual signals were also not associated with change in performance on the detour-reaching task over time (learning). However, females preferred mating with males who had better initial inhibitory control. We speculate that inhibitory control is a critical trait for male sticklebacks. In this system, males perform all parental care, but must avoid eating their own fry which closely resemble their prey items. Therefore, males with better inhibitory control may be more likely to successfully raise their offspring to independence. Our research adds to a growing list of mating systems and taxa in which cognition is important for measures related to fitness. PMID- 28808543 TI - Exploiting opportunistic observations to estimate changes in seasonal site use: An example with wetland birds. AB - Nonsystematically collected, a.k.a. opportunistic, species observations are accumulating at a high rate in biodiversity databases. Occupancy models have arisen as the main tool to reduce effects of limited knowledge about effort in analyses of opportunistic data. These models are generally using long closure periods (e.g., breeding season) for the estimation of probability of detection and occurrence. Here, we use the fact that multiple opportunistic observations in biodiversity databases may be available even within days (e.g., at popular birding localities) to reduce the closure period to 1 day in order to estimate daily occupancies within the breeding season. We use a hierarchical dynamic occupancy model for daily visits to analyze opportunistic observations of 71 species from nine wetlands during 10 years. Our model derives measures of seasonal site use within seasons from estimates of daily occupancy. Comparing results from our "seasonal site use model" to results from a traditional annual occupancy model (using a closure criterion of 2 months or more) showed that our model provides more detailed biologically relevant information. For example, when the aim is to analyze occurrences of breeding species, an annual occupancy model will over-estimate site use of species with temporary occurrences (e.g., migrants passing by, single itinerary prospecting individuals) as even a single observation during the closure period will be viewed as an occupancy. Alternatively, our model produces estimates of the extent to which sites are actually used. Model validation based on simulated data confirmed that our model is robust to changes and variability in sampling effort and species detectability. We conclude that more information can be gained from opportunistic data with multiple replicates (e.g., several reports per day almost every day) by reducing the time window of the closure criterion to acquire estimates of occupancies within seasons. PMID- 28808544 TI - Flower power: Floral and resource manipulations reveal how and why reproductive trade-offs occur for lowbush blueberry (Vaccinium angustifolium). AB - Plant reproductive trade-offs are thought to be caused by resource limitations or other constraints, but more empirical support for these hypotheses would be welcome. Additionally, quantitative characterization of these trade-offs, as well as consideration of whether they are linear, could yield additional insights. We expanded our flower removal research on lowbush blueberry (Vaccinium angustifolium) to explore the nature of and causes of its reproductive trade offs. We used fertilization, defoliation, positionally biased flower removal, and multiple flower removal levels to discern why reproductive trade-offs occur in this taxon and to plot these trade-offs along two continuous axes. We found evidence through defoliation that vegetative mass per stem may trade off with reproductive effort in lowbush blueberry because the two traits compete for limited carbon. Also, several traits including ripe fruit production per reproductive node and fruit titratable acidity may be "sink-limited"-they decline with increasing reproductive effort because average reproductive structure quality declines. We found no evidence that reproductive trade-offs were caused by nitrogen limitation. Use of reproductive nodes remaining per stem as a measure of reproductive effort indicated steeper trade-offs than use of the proportion of nodes remaining. For five of six traits, we found evidence that the trade-off could be concave down or up instead of strictly linear. Synthesis. To date, studies have aimed primarily at identifying plant reproductive trade-offs. However, understanding how and why these trade-offs occur represent the exciting and necessary next steps for this line of inquiry. PMID- 28808545 TI - Dioecious plants are more precocious than cosexual plants: A comparative study of relative sizes at the onset of sexual reproduction in woody species. AB - The reproductive capacities of dioecious plant species may be limited by severe pollen limitation and narrow seed shadows for the two reasons. First, they are unable to self-pollinate, and seed production occurs only with pollinator movement from males to females. Second, only 50% of the individuals in populations contribute to seed production. Despite these handicaps, dioecious plants maintain their populations in plant communities with cooccurring cosexual plants, and no substantial difference in population growth rates has been found between dioecious and cosexual plants. Hence, dioecious plants are thought to mitigate these disadvantages by adopting ecological traits, such as insect pollination, animal-dispersed fleshy fruits, and precocious flowering. We studied the relationship between flowering and plant size in 30 woody species with different sex expressions, leaf habits, fruit types, and maximum plant sizes. The study site was located in an evergreen broad-leaved forest on the island of Honshu, Japan. A phylogenetic linear regression model showed that dioecious species tended to mature at smaller sizes than did cosexual taxa. At the population level, given equal plant densities and reproductive efforts, the precocity of dioecious plants could serve as one of the factors that mitigate the limitations of pollen and seed-shadow handicaps by increasing the density of reproductive individuals in the population. At the individual level, smaller size of onset of flowering may play a role in enhancing reproductive success over a lifetime by increasing reproductive opportunities. We discussed the possible effect of the relationship between precocity and some ecological traits of dioecious plants, such as small flowers pollinated by unspecialized insects, fleshy fruit dispersed by animals, and their preferential occurrence in the tropics and in island habitats. The universality of precocity among dioecious plants should be investigated in diverse plant communities. Such studies will increase our understanding of the evolution of plant breeding systems. PMID- 28808546 TI - Characterization of measurement errors using structure-from-motion and photogrammetry to measure marine habitat structural complexity. AB - Habitat structural complexity is one of the most important factors in determining the makeup of biological communities. Recent advances in structure-from-motion and photogrammetry have resulted in a proliferation of 3D digital representations of habitats from which structural complexity can be measured. Little attention has been paid to quantifying the measurement errors associated with these techniques, including the variability of results under different surveying and environmental conditions. Such errors have the potential to confound studies that compare habitat complexity over space and time. This study evaluated the accuracy, precision, and bias in measurements of marine habitat structural complexity derived from structure-from-motion and photogrammetric measurements using repeated surveys of artificial reefs (with known structure) as well as natural coral reefs. We quantified measurement errors as a function of survey image coverage, actual surface rugosity, and the morphological community composition of the habitat-forming organisms (reef corals). Our results indicated that measurements could be biased by up to 7.5% of the total observed ranges of structural complexity based on the environmental conditions present during any particular survey. Positive relationships were found between measurement errors and actual complexity, and the strength of these relationships was increased when coral morphology and abundance were also used as predictors. The numerous advantages of structure-from-motion and photogrammetry techniques for quantifying and investigating marine habitats will mean that they are likely to replace traditional measurement techniques (e.g., chain-and-tape). To this end, our results have important implications for data collection and the interpretation of measurements when examining changes in habitat complexity using structure-from motion and photogrammetry. PMID- 28808547 TI - Patterns of seasonality and group membership characterize the gut microbiota in a longitudinal study of wild Verreaux's sifakas (Propithecus verreauxi). AB - The intestinal microbiota plays a major role in host development, metabolism, and health. To date, few longitudinal studies have investigated the causes and consequences of microbiota variation in wildlife, although such studies provide a comparative context for interpreting the adaptive significance of findings from studies on humans or captive animals. Here, we investigate the impact of seasonality, diet, group membership, sex, age, and reproductive state on gut microbiota composition in a wild population of group-living, frugi-folivorous primates, Verreaux's sifakas (Propithecus verreauxi). We repeatedly sampled 32 individually recognizable animals from eight adjacent groups over the course of two different climatic seasons. We used high-throughput sequencing of the 16S rRNA gene to determine the microbiota composition of 187 fecal samples. We demonstrate a clear pattern of seasonal variation in the intestinal microbiota, especially affecting the Firmicutes-Bacteroidetes ratio, which may be driven by seasonal differences in diet. The relative abundances of certain polysaccharide fermenting taxa, for example, Lachnospiraceae, were correlated with fruit and fiber consumption. Additionally, group membership influenced microbiota composition independent of season, but further studies are needed to determine whether this pattern is driven by group divergences in diet, social contacts, or genetic factors. In accordance with findings in other wild mammals and primates with seasonally fluctuating food availability, we demonstrate seasonal variation in the microbiota of wild Verreaux's sifakas, which may be driven by food availability. This study adds to mounting evidence that variation in the intestinal microbiota may play an important role in the ability of primates to cope with seasonal variation in food availability. PMID- 28808548 TI - Habitat patch size alters the importance of dispersal for species diversity in an experimental freshwater community. AB - Increased dispersal of individuals among discrete habitat patches should increase the average number of species present in each local habitat patch. However, experimental studies have found variable effects of dispersal on local species richness. Priority effects, predators, and habitat heterogeneity have been proposed as mechanisms that limit the effect of dispersal on species richness. However, the size of a habitat patch could affect how dispersal regulates the number of species able to persist. We investigated whether habitat size interacted with dispersal rate to affect the number of species present in local habitats. We hypothesized that increased dispersal rates would positively affect local species richness more in small habitats than in large habitats, because rare species would be protected from demographic extinction. To test the interaction between dispersal rate and habitat size, we factorially manipulated the size of experimental ponds and dispersal rates, using a model community of freshwater zooplankton. We found that high-dispersal rates enhanced local species richness in small experimental ponds, but had no effect in large experimental ponds. Our results suggest that there is a trade-off between patch connectivity (a mediator of dispersal rates) and patch size, providing context for understanding the variability observed in dispersal effects among natural communities, as well as for developing conservation and management plans in an increasingly fragmented world. PMID- 28808549 TI - Characterization of natural variation in North American Atlantic Salmon populations (Salmonidae: Salmo salar) at a locus with a major effect on sea age. AB - Age at maturity is a key life-history trait of most organisms. In anadromous salmonid fishes such as Atlantic Salmon (Salmo salar), age at sexual maturity is associated with sea age, the number of years spent at sea before the spawning migration. For the first time, we investigated the presence of two nonsynonymous vgll3 polymorphisms in North American Atlantic Salmon populations that relate to sea age in European salmon and quantified the natural variation at these and two additional candidate SNPs from two other genes. A targeted resequencing assay was developed and 1,505 returning adult individuals of size-inferred sea age and sex from four populations were genotyped. Across three of four populations sampled in Quebec, Canada, the late-maturing component (MSW) of the population of a given sex exhibited higher proportions of SNP genotypes 54Thr vgll3 and 323Lys vgll3 compared to early-maturing fish (1SW), for example, 85% versus 53% of females from Trinite River carried 323Lys vgll3 (nMSW = 205 vs. n1SW = 30; p < .001). However, the association between vgll3 polymorphism and sea age was more pronounced in females than in males in the rivers we studied. Logistic regression analysis of vgll3 SNP genotypes revealed increased probabilities of exhibiting higher sea age for 54Thr vgll3 and 323Lys vgll3 genotypes compared to alternative genotypes, depending on population and sex. Moreover, individuals carrying the heterozygous vgll3 SNP genotypes were more likely (>66%) to be female. In summary, two nonsynonymous vgll3 polymorphisms were confirmed in North American populations of Atlantic Salmon and our results suggest that variation at those loci correlates with sea age and sex. Our results also suggest that this correlation varies among populations. Future work would benefit from a more balanced sampling and from adding data on juvenile riverine life stages to contrast our data. PMID- 28808550 TI - A novel meta-analytical approach to improve systematic review of rates and patterns of microevolution. AB - A classic topic in ecology and evolution, phenotypic microevolution of quantitative traits has received renewed attention in the face of rapid global environmental change. However, for plants, synthesis has been hampered by the limited use of standard metrics, which makes it difficult to systematize empirical information. Here we demonstrate the advantages of incorporating meta analysis tools to the review of microevolutionary rates. We perform a systematic survey of the plant literature on microevolution of quantitative traits over known periods of time, based on the scopus database. We quantify the amount of change by standard mean difference and develop a set of effect sizes to analyze such data. We show that applying meta-analysis tools to a systematic literature review allows the extraction of a much larger volume of information than directly calculating microevolutionary rates. We also propose derived meta-analysis effect sizes (h, LG and LR) which are appropriate for the study of evolutionary patterns, the first being similar to haldanes, the second and third allowing the application of a preexisting analytical framework for the inference of evolutionary mechanisms. This novel methodological development is applicable to the study of microevolution in any taxa. To pilot test it, we built an open access database of 1,711 microevolutionary rates of 152 angiosperm species from 128 studies documenting population changes in quantitative traits following an environmental novelty with a known elapsed time (<260 years). The performance of the metrics proposed (h, LG and LR) is similar to that of preexisting ones, and at the same time they bring the advantages of lower estimation bias and higher number of usable observations typical of meta-analysis. PMID- 28808551 TI - Evolutionary responses to a changing climate: Implications for reindeer population viability. AB - If we want to understand how climate change affects long-lived organisms, we must know how individuals allocate resources between current reproduction and survival. This trade-off is affected by expected environmental conditions, but the extent to which density independent (DI) and density dependent (DD) processes interact in shaping individual life histories is less clear. Female reindeer (or caribou: Rangifer tarandus) are a monotocous large herbivore with a circumpolar distribution. Individuals that experience unpredictable and potentially harsh winters typically adopt risk averse strategies where they allocate more resources to building own body reserves during summer and less to reproduction. Such a strategy implies that the females do not reproduce or that they produce fewer or smaller offspring. A risk averse strategy thus results in females with large autumn body reserves, which is known to increase their survival probabilities if the coming winter is harsh. In contrast, females experiencing predictable winters may adopt a more risk prone strategy in which they allocate more resources to reproduction as they do not need as many resources to buffer potentially adverse winter conditions. This study uses a seasonal state-dependent model showing that DD and DI processes interact to affect the evolution of reproductive strategies and population dynamics for reindeer. The model was run across a wide range of different winter climatic scenarios: One set of simulations where the average and variability of the environment was manipulated and one set where the frequency of good and poor winters increased. Both reproductive allocation and population dynamics of reindeer were affected by a combination of DI and DD processes even though they were confounded (harsh climates resulted in lowered density). Individual strategies responded, in line with a risk sensitive reproductive allocation, to climatic conditions and in a similar fashion across the two climatic manipulations. PMID- 28808552 TI - Evolution of mammalian migrations for refuge, breeding, and food. AB - Many organisms migrate between distinct habitats, exploiting variable resources while profoundly affecting ecosystem services, disease spread, and human welfare. However, the very characteristics that make migration captivating and significant also make it difficult to study, and we lack a comprehensive understanding of which species migrate and why. Here we show that, among mammals, migration is concentrated within Cetacea and Artiodactyla but also diffusely spread throughout the class (found in 12 of 27 orders). We synthesize the many ecological drivers of round-trip migration into three types of movement-between breeding and foraging sites, between breeding and refuge sites, and continuous tracking of forage/prey-each associated with different traits (body mass, diet, locomotion, and conservation status). Our results provide only partial support for the hypothesis that migration occurs without phylogenetic constraint. Furthermore, our findings suggest that categorizing migration into these three types may aid predictions of migrants' responses to environmental changes. PMID- 28808553 TI - Parasite and host elemental content and parasite effects on host nutrient excretion and metabolic rate. AB - Ecological stoichiometry uses the mass balance of elements to predict energy and elemental fluxes across different levels of ecological organization. A specific prediction of ecological stoichiometry is the growth rate hypothesis (GRH), which states that organisms with faster growth or reproductive rates will require higher phosphorus content for nucleic acid and protein synthesis. Although parasites are found ubiquitously throughout ecosystems, little is understood about how they affect nutrient imbalances in ecosystems. We (1) tested the GRH by determining the carbon (C), nitrogen (N), and phosphorus (P) content of parasitic trematodes and their intermediate host, the freshwater snail Elimia livescens, and (2) used this framework to determine the trematode effects on host nutrient excretion and metabolism. Snail and parasite tissues were analyzed for elemental content using a CHN analyzer and soluble reactive phosphorus (SRP) methods. Ammonium and SRP assays were used to estimate N and P excretion rates. A respirometer was used to calculate individual snail metabolism. Trematode tissues contained lower C:P and N:P (more P per unit C and N) than the snail tissues. Snail gonadal tissues more closely resembled the elemental content of parasite tissues, although P content was 13% higher in the gonad than the trematode tissues. Despite differences in elemental content, N and P excretion rates of snails were not affected by the presence of parasites. Parasitized snails maintained faster metabolic rates than nonparasitized snails. However, the species of parasite did not affect metabolic rate. Together, this elemental imbalance between parasite and host, and the altered metabolic rate of infected snails may lead to broader parasite effects in stream ecosystems. PMID- 28808554 TI - Arthropod communities on hybrid and parental cottonwoods are phylogenetically structured by tree type: Implications for conservation of biodiversity in plant hybrid zones. AB - Although hybridization in plants has been recognized as an important pathway in plant speciation, it may also affect the ecology and evolution of associated communities. Cottonwood species (Populus angustifolia and P. fremontii) and their naturally occurring hybrids are known to support different plant, animal, and microbial communities, but no studies have examined community structure within the context of phylogenetic history. Using a community composed of 199 arthropod species, we tested for differences in arthropod phylogenetic patterns within and among hybrid and parental tree types in a common garden. Three major patterns emerged. (1) Phylogenetic diversity (PD) was significantly different between arthropod communities on hybrids and Fremont cottonwood when pooled by tree type. (2) Mean phylogenetic distance (MPD) and net relatedness index (NRI) indicated that communities on hybrid trees were significantly more phylogenetically overdispersed than communities on either parental tree type. (3) Community distance (Dpw) indicated that communities on hybrids were significantly different than parental species. Our results show that arthropod communities on parental and hybrid cottonwoods exhibit significantly different patterns of phylogenetic structure. This suggests that arthropod community assembly is driven, in part, by plant-arthropod interactions at the level of cottonwood tree type. We discuss potential hypotheses to explain the effect of plant genetic dissimilarity on arthropod phylogenetic community structure, including the role of competition and environmental filtering. Our findings suggest that cottonwood species and their hybrids function as evolutionarily significant units (ESUs) that affect the assembly and composition of associated arthropod communities and deserve high priority for conservation. PMID- 28808555 TI - Phenotypic convergence of artificially reared and wild trout is mediated by shape plasticity. AB - Phenotypic plasticity can be viewed as the first level of defense of organism homeostasis against environmental stress and therefore represents the potential to deal with rapid environmental changes. Transitions between low complexity, artificial environments and complex, natural habitats can promote phenotypic plasticity. Here, we conducted an experimental introduction with juvenile brown trout to evaluate the plasticity of shape in response to a transition between contrasting environments. We released 202 juvenile trout reared under hatchery conditions in a natural stream and analyzed changes in shape and morphological variability after 5 months. A geometric morphometrics approach based on 14 landmarks was used to compare changes in body shape for 37 fish recaptured at the end of the experiment. A similar number of hatchery and wild fish caught at the receptor stream were used as controls for shape in the two environments. After 5 months, fish showed significant change in shape, shifting from elongated to robust shapes, and affecting to the relative position of the caudal peduncle. These new shapes were closer to wild than to the hatchery shapes, suggesting a process of rapid phenotype change. Moreover, these changes were concomitant with a marked increase in morphological variability. Our results support the hypothesis that phenotypic plasticity is a major potential for adjustment to environmental change but not the idea that shape can be constrained by initial shapes. We confirmed the "increased" variance hypothesis and phenotype convergence with wild morphs. This has important implications because stresses the role of phenotypic plasticity as a buffer that allows organisms to cope with important environmental discontinuities at time scales that preclude the onset of adaptive adjustments. We suggest that environmental conditioning and shape plasticity can overcome both reduced morphological diversity and phenotype uncoupling with habitat characteristics resulting from initial rearing in low complexity artificial environments. PMID- 28808556 TI - Seedling tolerance to cotyledon removal varies with seed size: A case of five legume species. AB - It is generally accepted that seedlings from large seeds are more tolerant to defoliation than those from small seeds due to the additional metabolic reserves present in the large seeds. However, information on the effects of amount of seed reserves (cotyledon removal) from seedlings resulting from large vs. small seeds on seedling growth and long-term survival in the field is limited. Five legume species with different sizes of seeds were sown in the field and none, one, or both cotyledons removed 7 days after seedling emergence. Seedling biomass, relative growth rate (RGR) and survival were determined at different time. Cotyledon removal, species, and their interaction had significant effects on seedling growth and survival. During the period between 33 and 70 days, seedlings from large seeds had a significantly lower RGR than those from small seeds. Biomass, RGR, and survival of seedlings from large seeds were significantly reduced by removal one or both cotyledons, whereas those of seedlings from small seeds were not affected. Seed energy reserves are more important for the early growth of seedlings from large seeds than for those from small seeds. The overall effect of cotyledon removal on growth and survival varies with seed size (i.e., energy reserves) with seedlings from small seeds being less sensitive than those from large seeds under field conditions. PMID- 28808557 TI - Timing and pattern of annual silver eel migration in two European watersheds are determined by similar cues. AB - Many animals perform long-distance migrations in order to maximize lifetime reproductive success. The European eel migrates several thousand kilometers between their feeding habitats in continental waters (fresh-, brackish, and sea water) and their spawning area in the Sargasso Sea. Eels residing in freshwaters usually initiate their spawning migration as silver eels during autumn, triggered by diverse environmental cues. We analyzed the time series of silver eel downstream migration in Burrishoole, Ireland (1971-2015), and Imsa, Norway (1975 2015), to examine factors regulating the silver eel migration from freshwater to the sea. The migration season (90% of the run) generally lasted from 1 August to 30 November. Environmental factors acting in the months before migration impacted timing and duration of migration, likely through influencing the internal processes preparing the fish for migration. Once the migration had started, environmental factors impacted the day-to-day variation in number of migrants, apparently stimulating migration among those eels ready for migration. Both the day-to-day variation in the number of migrants and the onset of migration were described by nearly identical models in the two rivers. Variables explaining day to-day variation were all associated with conditions that may minimize predation risk; number of migrants was reduced under a strong moon and short nights and increased during high and increasing water levels. Presence of other migrants stimulated migration, which further indicates that silver eel migration has evolved to minimize predation risk. The onset of migration was explained mainly by water levels in August. The models for duration of the migration season were less similar between the sites. Thus, the overall migration season seems governed by the need to reach the spawning areas in a synchronized manner, while during the actual seaward migration, antipredator behavior seems of overriding importance. PMID- 28808558 TI - The impact of parasitism on resource allocation in a fungal host: the case of Cryphonectria parasitica and its mycovirus, Cryphonectria Hypovirus 1. AB - Parasites are known to profoundly affect resource allocation in their host. In order to investigate the effects of Cryphonectria Hypovirus 1 (CHV1) on the life history traits of its fungal host Cryphonectria parasitica, an infection matrix was completed with the cross-infection of six fungal isolates by six different viruses. Mycelial growth, asexual sporulation, and spore size were measured in the 36 combinations, for which horizontal and vertical transmission of the viruses was also assessed. As expected by life-history theory, a significant negative correlation was found between host somatic growth and asexual reproduction in virus-free isolates. Interestingly this trade-off was found to be positive in infected isolates, illustrating the profound changes in host resource allocation induced by CHV1 infection. A significant and positive relationship was also found in infected isolates between vertical transmission and somatic growth. This last relationship suggests that in this system, high levels of virulence could be detrimental to the vertical transmission of the parasite. Those results underscore the interest of studying host-parasite interaction within the life history theory framework, which might permit a more accurate understanding of the nature of the modifications triggered by parasite infection on host biology. PMID- 28808559 TI - Reproductive cycles in tropical intertidal gastropods are timed around tidal amplitude cycles. AB - Reproduction in iteroparous marine organisms is often timed with abiotic cycles and may follow lunar, tidal amplitude, or daily cycles. Among intertidal marine invertebrates, decapods are well known to time larval release to coincide with large amplitude nighttime tides, which minimizes the risk of predation. Such bimonthly cycles have been reported for few other intertidal invertebrates. We documented the reproduction of 6 gastropod species from Panama to determine whether they demonstrate reproductive cycles, whether these cycles follow a 2 week cycle, and whether cycles are timed so that larval release occurs during large amplitude tides. Two of the species (Crepidula cf. marginalis and Nerita scabricosta) showed nonuniform reproduction, but without clear peaks in timing relative to tidal or lunar cycles. The other 4 species show clear peaks in reproduction occurring every 2 weeks. In 3 of these species (Cerithideopsis carlifornica var. valida, Littoraria variegata, and Natica chemnitzi), hatching occurred within 4 days of the maximum amplitude tides. Siphonaria palmata exhibit strong cycles, but reproduction occurred during the neap tides. Strong differences in the intensity of reproduction of Cerithideopsis carlifornica, and in particular, Littoraria variegata, between the larger and smaller spring tides of a lunar month indicate that these species time reproduction with the tidal amplitude cycle rather than the lunar cycle. For those species that reproduce during both the wet and dry seasons, we found that reproductive timing did not differ between seasons despite strong differences in temperature and precipitation. Overall, we found that most (4/6) species have strong reproductive cycles synchronized with the tidal amplitude cycle and that seasonal differences in abiotic factors do not alter these cycles. PMID- 28808560 TI - Exploring the relationship between tychoparthenogenesis and inbreeding depression in the Desert Locust, Schistocerca gregaria. AB - Tychoparthenogenesis, a form of asexual reproduction in which a small proportion of unfertilized eggs can hatch spontaneously, could be an intermediate evolutionary link in the transition from sexual to parthenogenetic reproduction. The lower fitness of tychoparthenogenetic offspring could be due to either developmental constraints or to inbreeding depression in more homozygous individuals. We tested the hypothesis that in populations where inbreeding depression has been purged, tychoparthenogenesis may be less costly. To assess this hypothesis, we compared the impact of inbreeding and parthenogenetic treatments on eight life-history traits (five measuring inbreeding depression and three measuring inbreeding avoidance) in four laboratory populations of the desert locust, Schistocerca gregaria, with contrasted demographic histories. Overall, we found no clear relationship between the population history (illustrated by the levels of genetic diversity or inbreeding) and inbreeding depression, or between inbreeding depression and parthenogenetic capacity. First, there was a general lack of inbreeding depression in every population, except in two populations for two traits. This pattern could not be explained by the purging of inbreeding load in the studied populations. Second, we observed large differences between populations in their capacity to reproduce through tychoparthenogenesis. Only the oldest laboratory population successfully produced parthenogenetic offspring. However, the level of inbreeding depression did not explain the differences in parthenogenetic success between all studied populations. Differences in development constraints may arise driven by random and selective processes between populations. PMID- 28808561 TI - Quantifying the degree of bias from using county-scale data in species distribution modeling: Can increasing sample size or using county-averaged environmental data reduce distributional overprediction? AB - Citizen-science databases have been used to develop species distribution models (SDMs), although many taxa may be only georeferenced to county. It is tacitly assumed that SDMs built from county-scale data should be less precise than those built with more accurate localities, but the extent of the bias is currently unknown. Our aims in this study were to illustrate the effects of using county scale data on the spatial extent and accuracy of SDMs relative to true locality data and to compare potential compensatory methods (including increased sample size and using overall county environmental averages rather than point locality environmental data). To do so, we developed SDMs in maxent with PRISM-derived BIOCLIM parameters for 283 and 230 species of odonates (dragonflies and damselflies) and butterflies, respectively, for five subsets from the OdonataCentral and Butterflies and Moths of North America citizen-science databases: (1) a true locality dataset, (2) a corresponding sister dataset of county-centroid coordinates, (3) a dataset where the average environmental conditions within each county were assigned to each record, (4) a 50/50% mix of true localities and county-centroid coordinates, and (5) a 50/50% mix of true localities and records assigned the average environmental conditions within each county. These mixtures allowed us to quantify the degree of bias from county scale data. Models developed with county centroids overpredicted the extent of suitable habitat by 15% on average compared to true locality models, although larger sample sizes (>100 locality records) reduced this disparity. Assigning county-averaged environmental conditions did not offer consistent improvement, however. Because county-level data are of limited value for developing SDMs except for species that are widespread and well collected or that inhabit regions where small, climatically uniform counties predominate, three means of encouraging more accurate georeferencing in citizen-science databases are provided. PMID- 28808562 TI - Floral scent and species divergence in a pair of sexually deceptive orchids. AB - Speciation is typically accompanied by the formation of isolation barriers between lineages. Commonly, reproductive barriers are separated into pre- and post-zygotic mechanisms that can evolve with different speed. In this study, we measured the strength of different reproductive barriers in two closely related, sympatric orchids of the Ophrys insectifera group, namely Ophrys insectifera and Ophrys aymoninii to infer possible mechanisms of speciation. We quantified pre- and post-pollination barriers through observation of pollen flow, by performing artificial inter- and intraspecific crosses and analyzing scent bouquets. Additionally, we investigated differences in mycorrhizal fungi as a potential extrinsic factor of post-zygotic isolation. Our results show that floral isolation mediated by the attraction of different pollinators acts apparently as the sole reproductive barrier between the two orchid species, with later-acting intrinsic barriers seemingly absent. Also, the two orchids share most of their fungal mycorrhizal partners in sympatry, suggesting little or no importance of mycorrhizal symbiosis in reproductive isolation. Key traits underlying floral isolation were two alkenes and wax ester, present predominantly in the floral scent of O. aymoninii. These compounds, when applied to flowers of O. insectifera, triggered attraction and a copulation attempt of the bee pollinator of O. aymoninii and thus led to the (partial) breakdown of floral isolation. Based on our results, we suggest that adaptation to different pollinators, mediated by floral scent, underlies species isolation in this plant group. Pollinator switches may be promoted by low pollination success of individuals in dense patches of plants, an assumption that we also confirmed in our study. PMID- 28808563 TI - Conceptualizing ecosystem tipping points within a physiological framework. AB - Connecting the nonlinear and often counterintuitive physiological effects of multiple environmental drivers to the emergent impacts on ecosystems is a fundamental challenge. Unfortunately, the disconnect between the way "stressors" (e.g., warming) is considered in organismal (physiological) and ecological (community) contexts continues to hamper progress. Environmental drivers typically elicit biphasic physiological responses, where performance declines at levels above and below some optimum. It is also well understood that species exhibit highly variable response surfaces to these changes so that the optimum level of any environmental driver can vary among interacting species. Thus, species interactions are unlikely to go unaltered under environmental change. However, while these nonlinear, species-specific physiological relationships between environment and performance appear to be general, rarely are they incorporated into predictions of ecological tipping points. Instead, most ecosystem-level studies focus on varying levels of "stress" and frequently assume that any deviation from "normal" environmental conditions has similar effects, albeit with different magnitudes, on all of the species within a community. We consider a framework that realigns the positive and negative physiological effects of changes in climatic and nonclimatic drivers with indirect ecological responses. Using a series of simple models based on direct physiological responses to temperature and ocean pCO 2, we explore how variation in environment performance relationships among primary producers and consumers translates into community-level effects via trophic interactions. These models show that even in the absence of direct mortality, mismatched responses resulting from often subtle changes in the physical environment can lead to substantial ecosystem-level change. PMID- 28808564 TI - Effects of parasitic infection and reproduction on corticosterone plasma levels in Galapagos land iguanas, Conolophus marthae and C. subcristatus. AB - In vertebrates, one main feature of stress response is the release of glucocorticoids (corticosterone in reptiles), steroid hormones whose synthesis is regulated by the hypothalamic-pituitary-adrenal axis (HPA). In the Galapagos Islands, populations of land iguanas are differentially impacted by a tick transmitted apicomplexan hemoparasite of genus Hepatozoon, which could cause diseases and ultimately reduce fitness. Using competitive enzyme-linked immunosorbent assays (ELISA), we examined baseline plasma corticosterone levels of two syntopic and highly parasitized populations of the land iguana species Conolophus marthae and C. subcristatus in Wolf volcano (Isabela Island). We also used a poorly parasitized population of C. subcristatus from the same island (Bahia Urbina) as a reference. To better interpret the observed glucocorticoids patterns, we simultaneously performed the count of white blood cells (WBCs) in all individuals and investigated the reproductive status of females. We did not find evidence in support of either a positive or negative relationship between the tick load, hemoparasite infection, and glucocorticoid plasma concentration in C. marthae and C. subcristatus at Wolf volcano. The comparison between parasitized and non-parasitized sites (V. Wolf and Bahia Urbina) would instead suggest an inverse relationship between corticosterone and parasites. Our findings support association between corticosterone plasma levels and reproduction. PMID- 28808565 TI - Acute pancreatitis: A 7 year retrospective cohort study of the epidemiology, aetiology and outcome from a tertiary hospital in Jamaica. AB - BACKGROUND: Acute pancreatitis (AP) is a significant cause of acute abdominal pain, morbidity and hospitalisation. There was previously a dearth of studies exploring the incidence, risk factors and outcome of AP in the Caribbean region. MATERIALS AND METHODS: All patients with a diagnosis of AP admitted to the University Hospital of the West Indies (UHWI) between 2006 and 2012 were reviewed. The epidemiological profile, risk factors, clinical presentation and outcomes of patients with AP were retrospectively studied. RESULTS: There were 70 females and 21 males with a median age of 44 years (range 2-86). The median age of males was significantly higher than that of females (p = 0.041). The incidence of AP was 74 per 100,000 admissions per year. Vomiting and abdominal tenderness were noted in the majority of patients. The most common aetiology was biliary disease (71.4%), idiopathic (12%), post-ERCP (6.6%) and alcohol (5.5%). Alcoholic pancreatitis was only seen in males whereas idiopathic and post-ERCP pancreatitis only occurred in females. The mean duration of hospitalisation was 9.51 +/- 8.28 days. Disease severity was mild in 61.1%, moderately severe in 26.7%, and severe in 12.2% of patients. Factors associated with more severe disease included overweight/obesity, idiopathic aetiology and post-ERCP status. The case fatality rate was 2%. CONCLUSION: The incidence of AP was 74/100,000 hospital admissions annually. There was an unusual female preponderance, with biliary pancreatitis being the most common type occurring at an equal frequency among males and females. Only 12.2% of the total cases seen were severe. The case fatality rate was 2%. Local health policy should target timely interventions for biliary pancreatitis and should also address the local factors affecting disease severity. PMID- 28808566 TI - Laparoscopic double-tract reconstruction after total gastrectomy for postoperative duodenal surveillance: Case series. AB - INTRODUCTION: When gastric cancer or carcinoid patients have coexisting diseases such as duodenal adenoma, FAP, or Crohn's disease, periodic observation of the duodenum is necessary. METHODS: Between August 2013 and April 2015, we performed four consecutive laparoscopic total gastrectomies with double tract reconstruction for duodenal surveillance. Three of the patients were diagnosed with gastric cancer, while the remaining patient was diagnosed with gastric carcinoid. RESULTS: No deaths occurred, and three of the patients showed no early complications. One patient with Crohn's disease developed anastomotic leakage, but it was successfully managed conservatively. On endoscopy three to seven months later, we were able to observe the duodenum via jejunal anastomosis in all of the patients. DISCUSSION: Roux-en-Y reconstruction is one of the options after laparoscopic total gastrectomy. However, given that periodical endoscopic examinations of the duodenum are strongly recommended after surgery, double-tract reconstruction may be preferable in these patients. CONCLUSION: Although more detailed data are required, double-tract reconstruction may be the best choice for patients requiring total gastrectomy with regular check-up of the duodenum. PMID- 28808567 TI - Community based saving groups: an innovative approach to overcome the financial and social barriers in health care seeking by the women in the rural remote communities of Pakistan. AB - BACKGROUND: In remote rural areas of Pakistan, access to the maternal, newborn and child health (MNCH) care provided by a skilled health provider is quite difficult. There are many reasons such as women's restricted social mobility, lack of education, disenfranchised in decision making and poverty. To overcome these barriers and impediments in district Chitral, which is the largest territory in terms of geography in province Khyber Pakhtunkhwa, local women of reproductive age, were mobilized to form the Community Based Saving Groups (CBSGs) at the village level. In these CBSGs, they pool-in their money, and then provide soft loans to the expecting mothers to meet the expenses of delivery. Simultaneously, young literate women were identified from the local communities; they were trained as Community Midwives (CMWs), using national MNCH curriculum, and later deployed in their respective villages within the district. This study captured their perceptions about the formation of CBSGs to overcome the financial and social barriers, and subsequent use of CMW services. METHODS: A qualitative enquiry was conducted with the delivered mothers and their husbands through gender specific separate focus group discussions, with CBSG members and with non members in four different sites of District Chitral. RESULTS: CBSG member women were far more aware on health issues. Information sought from these forums brought a noticeable change in the health seeking practices. Seeking care from a trained birth attendant in the community became easier. Women associated with the CBSGs as members, expressed an increased access to money for utilizing the CMW services, better awareness on MNCH issues, and empowerment to decide for seeking care. CBSG have been an instrumental platform for social networking, helping each other in other household matters. CONCLUSION: Women have started using the services of CMW and the CBSGs have actually helped them overcome the financial barriers in health care seeking. Moreover, the CBSGs became a medium to improve the awareness of service availability, understanding the MNCH issues, and timely utilization of MNCH services. PMID- 28808568 TI - Thymosin beta4 in rheumatoid arthritis: Friend or foe. AB - Rheumatoid arthritis (RA) has characteristic pannus tissues, which show tumor like growth of the synovium through chronic joint inflammation. The synovium is highly penetrated by various immune cells, and the synovial lining becomes hyperplastic due to increased numbers of macrophage-like and fibroblast-like synoviocytes. Thus, a resultant hypoxic condition stimulates the expression of inflammation-related genes in various cells, in particular, vascular endothelial growth factor. Thymosin beta4 (Tbeta4), a 5-kDa protein, is known to play a significant role in various biological activities, such as actin sequestering, cell motility, migration, inflammation, and damage repair. Recent studies have provided evidence that Tbeta4 may have a role in RA pathogenesis. The Tbeta4 level has been shown to increase significantly in the joint fluid and serum of RA patients. However, whether Tbeta4 stimulates or inhibits activation of RA immune responses remains to be determined. In the present study, we discuss the logical and clinical justifications for Tbeta4 as a potential target for RA therapeutics. PMID- 28808570 TI - Nitric oxide/cyclic GMP pathway mediates the endothelin-1-upregulation of adiponectin expression in rat cardiomyocytes. AB - Endothelin-1 (ET-1) serves an important role in the development of cardiac dysfunction and heart failure. ET-1 and angiotensin II (AngII) comprise a mutually reciprocal signalling network in the myocardium and serve similar or additive roles in the development of heart failure. Our previous study previously demonstrated that AngII upregulated the expression of APN in cardiomyocytes through an AngII receptor type 2/nitric oxide (NO)/cyclic GMP(cGMP)-dependent pathway. The purpose of the present study was to determine the effects of ET-1 and the additive effects of ET-1 and AngII on the gene expression and secretion of APN, and the underlying mechanisms involved. ELISA was used to determine the secretion of adiponectin (APN) and reverse transcription-quantitative polymerase chain reaction was used to evaluate the gene expression of APN. ET-1 induced APN secretion in a time- and dose-dependent manner, and induced APN secretion with AngII simultaneously, as determined via APN mRNA analyses. ETA and ETB receptors were also involved. The use of a NO synthase inhibitor and an analogue of cGMP antagonist resulted in a diminished ET-1- and/or AngII-mediated APN induction in cardiomyocytes. These results suggested that ET-1, as well as AngII, upregulated the gene expression and secretion of APN via the common NO/cGMP-mediated mechanism. PMID- 28808569 TI - Study and therapeutic progress on spinal cord perimedullary arteriovenous fistulas. AB - Spinal cord perimedullary arteriovenous fistulas (PMAVFs) are rare and belong to type IV spinal cord arteriovenous malformations (AVMs). Little is known regarding the treatment and prognosis of spinal cord PMAVFs. In the present study the relevant literature from PubMed was reviewed, and it was found that these fistulas can occur at all ages but are more common in children. In children, most spinal cord PMAVFs are large and with high flow, begin with bleeding and are frequently associated with hereditary hemorrhagic telangiectasia. However, in adults, most spinal cord PMAVFs are small and with low flow and begin with progressive spinal cord dysfunction. The early diagnosis of spinal cord PMAVFs is generally difficult, and symptoms can be very severe at the time of diagnosis. Digital subtraction angiography remains the gold standard; however, computed tomography angiography and magnetic resonance angiography are also promising. Spinal cord PMAVFs can be treated by endovascular embolization, surgical removal or a combination of the two methods. Most spinal cord PMAVFs show good outcomes after the appropriate treatment, and the prognosis is primarily associated with the blood flow of the PMAVF. For high-flow spinal cord PMAVFs, endovascular embolization is more effective and can lead to a good outcome; however, for low flow spinal cord PMAVFs, surgical removal or the combination with endovascular embolization is the optimal choice. The prognosis for low-flow types is slightly worse than for high-flow spinal cord PMAVFs in children, but the outcome is acceptable. PMID- 28808571 TI - The combination of CRP isoforms with oxLDL decreases TNF-alpha and IL-6 release by U937-derived macrophages. AB - C-reactive protein (CRP) and oxidized low density lipoprotein (oxLDL) serve major roles at both early and advanced stages of atherosclerosis. CRP exists in two isoforms, monomeric (m) and pentameric (p), that bring about pro- or anti inflammatory effects in macrophages. In addition, CRP may form a complex with oxidized low-density lipoprotein (oxLDL) via phosphatidylcholine, thus decreasing its pro-inflammatory effects within macrophages. The aim of the present study was to investigate the single and the combined effects of mCRP, pCRP and oxLDL on U937-derived macrophages. In the current study, U937-derived macrophages were treated in vitro with different combinations of CRP isoforms with or without oxLDL. The levels of major inflammatory cytokines [interleukin (IL)-1beta, IL-6, IL-8 and tumor necrosis factor (TNF)-alpha] along with the production of reactive oxygen species (ROS) were determined. TNF-alpha and IL-6 levels were significantly decreased (P<0.05) by the effect of mCRP and pCRP combined with oxLDL. No significant changes were observed in IL-1beta, IL-8 or ROS levels. PMID- 28808572 TI - A mesenteric solid tumor with unusual features in a young male: A case report. AB - The current study presents a mesenteric mesenchymal tumor case, with unusual features in diagnostic imaging and histology. A 16-year-old male was admitted to the hospital with abdominal pain. Computed tomography (CT) revealed an abdominal mass, 2 cm in diameter. The results of contrast-enhanced CT, magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography indicated no specific features suggestive of its histology. Two arteries branching from the superior mesenteric artery were observed feeding the hypervascular tumor. After endoscopic and other laboratory findings revealed no additional lesions, the lesion was diagnosed as a primary mesenteric tumor. As the possibility of malignancy and future bleeding from this tumor could not be ruled out, a resection of the tumor was performed. During the surgery, the tumor, which was well circumscribed and hypervascular, was located in the mesentery of the jejunum. The resected tumor did not exhibit typical histological characteristics, and was labeled as 'myxoid smooth muscle neoplasm of uncertain biologic potential'. At 2 years after surgery, the patient remained well without evidence of recurrence. As primary mesenteric tumors are rare, particularly in young patients, it is considered important that this type of unusual tumor be included in the differential diagnosis for mesenteric tumors. PMID- 28808573 TI - Osimertinib-induced interstitial lung disease in a patient with non-small cell lung cancer pretreated with nivolumab: A case report. AB - Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for EGFR-T790M-positive non-small cell lung cancer. A high incidence of interstitial lung disease (ILD) during combination treatment with osimertinib and anti-programmed cell death-ligand 1 (PD-L1) inhibitor has been reported. The current study presents a case of ILD development during osimertinib treatment following nivolumab (an anti-PD-1 antibody) treatment. The 59-year-old female was diagnosed with stage IV lung adenocarcinoma harboring a deletion in exon 19 of the EGFR gene. Following nivolumab as a sixth-line treatment, an EGFR-T790M-encoding mutation in EGFR exon 20 was identified by re-biopsy. Osimertinib was therefore initiated as a seventh line treatment. A partial response was subsequently noted; however, 63 days after initiation of the treatment the patient presented with dyspnea with decreased oxygenation in the absence of fever and sputum. A computed tomography scan revealed the emergence of ground-glass opacities with bronchiectasis in both lungs, and a diagnosis of ILD due to osimertinib was made. Following steroid pulse therapy with discontinuation of osimertinib, the patient's chest findings and respiratory condition improved. Therefore, it is considered that anti-PD-1 therapies may be associated with a risk of ILD during subsequent osimertinib treatment. PMID- 28808574 TI - Anastomosing haemangioma of liver: A case report. AB - Anastomosing haemangioma (AH) is a recently described, unusual variant of capillary hemangioma that appears to be unique to the genitourinary system, with a particular proclivity for the kidney. AH is a subtype of capillary haemangioma, which is rarely encountered in clinical practice, particularly in the liver. We herein present the case of a 57-year-old woman with an incidental finding on magnetic resonance imaging of a local lesion in the liver, sized 3.3*3.0 cm. The patient underwent hepatectomy with a good postoperative recovery. The histopathological diagnosis was AH of the liver. To the best of our knowledge, this is the first case report of hepatic AH. PMID- 28808575 TI - Reduced ventilation-perfusion (V/Q) mismatch following endobronchial valve insertion demonstrated by Gallium-68 V/Q photon emission tomography/computed tomography. AB - Endobronchial valves (EBVs) are increasingly deployed in the management of severe emphysema. Initial studies focussed on volume reduction as the mechanism, with subsequent improvement in forced expiratory volume in 1 s (FEV1). More recent studies have emphasized importance of perfusion on predicting outcomes, though findings have been inconsistent. Gallium-68 ventilation-perfusion (V/Q) photon emission tomography (PET)/computed tomography (CT) is a novel imaging modality with advantages in spatial resolution, quantitation, and speed over conventional V/Q scintigraphy. We report a pilot case in which V/Q-PET/CT demonstrated discordant findings compared with quantitative CT analysis, and directed left lower lobe EBV placement. The patient experienced a significant improvement in 6 min walk distance (6MWD) without change in spirometry. Post-EBV V/Q-PET/CT demonstrated a marked decrease in unmatched (detrimental) V/Q areas and improvement in overall V/Q matching on post-EBV V/Q-PET/CT. These preliminary novel findings suggest that EBVs improve V/Q matching and may explain the observed functional improvements. PMID- 28808576 TI - "Awake" ECCO2R superseded intubation in a near-fatal asthma attack. AB - BACKGROUND: Near-fatal asthma attacks are life threatening events that often require mechanical ventilation. Extracorporeal carbon dioxide removal (ECCO2R) is, beside extracorporeal membrane oxygenation (ECMO), a well-established rescue option whenever ventilation gets to its limits. But there seems to be very rare experience with those techniques in avoiding mechanical ventilation in severe asthma attacks. CASE PRESENTATION: A 67-year-old man with a near-fatal asthma attack deteriorated under non-invasive ventilation conditions. Beside pharmacological treatment, the intensivists decided to use an extracorporeal carbon dioxide removal system (ECCO2R) to avoid sedation and intubation. Within only a few hours, there was a breakthrough and the patient's status improved continuously. One and a half days later, weaning from ECCO2R was already completed. CONCLUSIONS: The discussion deals with several advantages of extracorporeal lung support in acute asthma, the potential of avoiding intubation and sedation, as well as the benefits of a conscious and spontaneously breathing patient. Extracorporeal membrane oxygenation (ECMO) in general and ECCO2R in particular is a highly effective method for the treatment of an acute near-fatal asthma attack. Pathophysiological aspects favor the "awake" approach, without sedation, intubation, and mechanical ventilation. Therefore, experienced clinicians might consider "awake" ECCO2R in similar cases. PMID- 28808577 TI - Transition from intravenous to enteral ketamine for treatment of nonconvulsive status epilepticus. AB - BACKGROUND: Nonconvulsive status epilepticus (NCSE) is a diagnosis that is often challenging and one that may progress to refractory NCSE. Ketamine is a noncompetitive N-methyl-d-aspartate antagonist that increasingly has been used to treat refractory status epilepticus. Current Neurocritical Care Society guidelines recommend intravenous (IV) ketamine infusion as an alternative treatment for refractory status epilepticus in adults. On the other hand, enteral ketamine use in NCSE has been reported in only 6 cases (1 adult and 5 pediatric) in the literature to date. CASE PRESENTATION: A 33-year-old woman with a history of poorly controlled epilepsy presented with generalized tonic-clonic seizures, followed by recurrent focal seizures that evolved into NCSE. This immediately recurred within 24 h of a prior episode of NCSE that was treated with IV ketamine. Considering her previous response, she was started again on an IV ketamine infusion, which successfully terminated NCSE. This time, enteral ketamine was gradually introduced while weaning off the IV formulation. Treatment with enteral ketamine was continued for 6 months and then tapered off. There was no recurrence of NCSE or seizures and no adverse events noted during the course of treatment. CONCLUSION: This case supports the use of enteral ketamine as a potential adjunct to IV ketamine in the treatment of NCSE, especially in cases without coma. Introduction of enteral ketamine may reduce seizure recurrence, duration of stay in ICU, and morbidity associated with intubation. PMID- 28808578 TI - Antibiotic use during pregnancy: a retrospective study of prescription patterns and birth outcomes at an antenatal clinic in rural Ghana. AB - BACKGROUND: Babies are increasingly being exposed to antibiotics intrapartum in the bid to reduce neonatal and maternal deaths. Intrapartum antibiotic exposure, including even those considered safe in pregnancy, have been associated with childhood obesity and compromised immunity. Data on the extent of antibiotic use, safety and its impact on birth outcomes and neonatal health in Sub-Saharan Africa is very limited. This study sought to ascertain the extent of antibiotic use in pregnancy and its effects on birth outcomes in a rural hospital in Ghana. METHODS: The study was a retrospective randomized study of mothers who delivered babies in a rural hospital between 2011 and 2015 in Ghana. A total of 412 mother/baby records out of 2100 pre-selected met the inclusion criteria of the study. Indicators of neonatal health used were birthweight, Apgar score, incidence of birth defects. RESULTS: Sixty five percent of pregnant women were administered antibiotics at some stage during pregnancy. Beta Lactam antibiotics accounted for more than 67% of all antibiotics prescribed. There was a statistically significant association between antibiotic exposure and pregnancy factors such as stage of pregnancy, parity and mode of delivery but not with socio-economic status of the mother. Intrapartum antibiotic exposure did not significantly affect the birthweight, incidence of congenital birth defect and mean Apgar scores. After adjusting for method of delivery, however, perinatal antibiotic use (24 h to delivery) was associated with lower mean Apgar scores. Birth weight was affected significantly by maternal socio-economic factors such as age and marital status. CONCLUSION: Sixty five percent of women attending the antenatal clinic received antibiotics. Intrapartum antibiotics did not affect early markers of neonatal health such as birthweight, congenital birth defect and mean Apgar scores. However, antibiotic use less than 24 h to delivery was associated with a decrease in mean APGAR score. PMID- 28808579 TI - A novel BBS10 mutation identified in a patient with Bardet-Biedl syndrome with a violent emotional outbreak. AB - We report a 10-year-old girl with Bardet-Biedl syndrome caused by a novel mutation in the Bardet-Biedl syndrome 10 (BBS10) gene. She had multiple malformations, including a dysmorphic face, postaxial polydactyly, polycystic kidney and amblyopia. She presented with typical BBS features, including intellectual disability with emotional outbursts and mild obesity. Whole-exome sequencing identified compound heterozygous mutations with NM_024685.3:c.1677C>A [p.(Tyr559*)] and c.1974T>G [p.(Tyr658*)]. To our knowledge, the latter mutation has never been reported previously. PMID- 28808580 TI - The detection of influenza virus at the community pharmacy to improve the management of local residents with influenza or influenza-like disease. AB - BACKGROUND: As of 2014, community pharmacies in Japan are approved by the Ministry of Health, Labour and Welfare to measure lipid panel, HbA1c, glucose, ALT, AST and gamma-GTP, but not to screen for influenza virus. We provided influenza virus screening tests at a community pharmacy to triage people with symptoms suggestive of influenza. Participants were given appropriate advice on how to prevent the spread of and safeguard against influenza. We subsequently evaluated the effects of community pharmacy-based influenza virus screening and prevention measures. METHODS: Local residents with symptoms suggestive of influenza participated in this study. Influenza virus screening tests using nasal samples were provided to the pharmacy, and we assessed samples for the presence of influenza virus. The study consisted of a preliminary interview, informed consent, and screening test on Day 1, and mail-in survey on Day 14. RESULTS: A total 52 local residents participated in the study. The number of participants and influenza virus positive results followed the same trend as the influenza epidemic in the study area. Influenza virus was found in 28.8% of samples. There was no significant difference between the appearance ratios of subjective symptoms among influenza-positive and influenza-negative groups. The percentages of participants who were first screened at the pharmacy, and those who were first screened at a clinic and then tested again at the pharmacy, were 71.2% (37/52) and 28.8% (15/52), respectively. In the latter group, 14 of 15 were negative by screening at the clinic, and one was diagnosed with influenza without testing. Subsequently, 46.8% (7/15) of participants tested positive for influenza by pharmacy-based screening. According to the mail-in survey, all influenza-positive (100%, 7/7) and 35.3% (6/17) of influenza-negative participants visited the clinic after being tested at the community pharmacy; test results between the community pharmacy and clinic were consistent. A total 64.7% (11/17) of symptomatic participants who tested negative recovered spontaneously at home. CONCLUSIONS: Implementation of influenza virus screening followed by provision of appropriate advice for both influenza-positive and influenza-negative participants at the community pharmacy showed a significant effect on improving the health of the local community. PMID- 28808582 TI - Ludwig Guttmann's Memorandum: a review on the surgical aspects of spinal cord injuries written in 1944 for the Nerve Injury Committee of the Medical Research Council: with notes and commentary. PMID- 28808581 TI - DECADE-pilot: decision aid, action planning, and follow-up support for patients to reduce the 10-year risk of cardiovascular diseases-a protocol of a randomized controlled pilot trial. AB - BACKGROUND: A healthy lifestyle can reduce cardiovascular risk (CVR) and prevent premature death. Usually most patients at increased CVR have difficulties implementing the necessary health behavior changes, such as smoking cessation, increasing of physical activity, healthy diet, stress reduction, etc. In this pilot study, a new intervention (DECADE) that includes a cardiovascular risk calculation, evidence-based decision aids, action planning, and follow-up support for patients to reduce their 10-year risk of cardiovascular diseases will be tested in primary care. The objectives of this trial are to test (1) the feasibility of the study design in preparation for the main trail including (2) the usability and acceptance of DECADE, and (3) initial data to ascertain that changes can be observed in these patients. METHODS: This randomized controlled pilot trial will generate initial data on the potential effects of DECADE on patients' self-evaluated activity and behavior change as well as on clinical outcomes such as blood pressure, cholesterol, body mass index (BMI), HbA1C, and CVR score. In the qualitative part of the study, we will analyze data collected in semi-structured interviews with participating general practitioners (GP) and in patient questionnaires. DISCUSSION: The outcomes of this pilot study will indicate whether DECADE is a promising intervention in the domain of patient centered prevention of cardiovascular diseases (CVD) and whether a larger multi center randomized controlled trial is feasible. TRIAL REGISTRATION: German Clinical Trials Register (DRKS), DRKS00010584. PMID- 28808583 TI - Successful spinal cord stimulation for neuropathic below-level spinal cord injury pain following complete paraplegia: a case report. AB - INTRODUCTION: Neuropathic pain is common in patients with spinal cord injury (SCI) and often difficult to treat. We report a case where epidural spinal cord stimulation (SCS) below the level of injury has been successfully applied in a patient with a complete spinal cord lesion. CASE PRESENTATION: A 53-year-old female presented with neuropathic below-level SCI pain of both lower legs and feet due to complete SCI below T5. Time and pain duration since injury was 2 years. Pain intensity was reported on numeric rating scale with an average of 7/10 (0 meaning no pain, 10 meaning the worst imaginable pain), but also with about 8-10 pain attacks during the day with an intensity of 9/10, which lasted between some minutes and half an hour. SCS was applied below the level of injury at-level T11-L1. After a successful 2 weeks testing period the pulse generator has been implanted permanently with a burst-stimulation pattern. The average pain was reduced to a bearable intensity of 4/10, in addition attacks could be reduced both in frequency and in intensity. This effects lasted for at least three months of follow-up. DISCUSSION: Even in case of complete SCI, SCS might be effective. Mechanisms of pain relief remain unclear. A modulation of suggested residual spinothalamic tract function may play a role. Further investigation has to be carried out to support this theory. PMID- 28808584 TI - International spinal cord injury male sexual function and female sexual and reproductive function basic data sets-version 2.0. AB - STUDY DESIGN: Data set review and modification. OBJECTIVE: To describe modifications in the International Spinal Cord Injury (SCI) Male Sexual Function Basic Data Set Version 2.0 and the International SCI Female Sexual and Reproductive Function Basic Data Set Version 2.0. SETTING: International expert work group using on line communication. METHODS: An international team of experts was compiled to review and revise the International SCI Male Sexual Function and Female Sexual and Reproductive Function Basic Data Sets Version 1.0. The group adapted Version 1.0 based upon review of published research, suggestions from concerned individuals and on line work group consensus. The revised data sets were then posted on the International Spinal Cord Society (ISCoS) and American Spinal Injury Association (ASIA) websites for 2 months for review. Subsequently, the data sets were approved by the ISCoS Scientific and Executive Committees and ASIA board of directors. RESULTS: The data sets were modified to a self-report format. They were reviewed for appropriateness for the pediatric age group and adapted to include a new variable to address the issue of sexual orientation. A clarification of the difference between the data sets and the autonomic standards was also developed. CONCLUSION: Sexuality is a continuously evolving topic. Modifications were needed to address this topic in a comprehensive fashion. It is recommended that Version 2.0 of these data sets are used for ongoing documentation of sexual status in the medical record and for documentation of sexual concerns during on-going research. PMID- 28808585 TI - Spinal cord injury during the second trimester of pregnancy. AB - INTRODUCTION: Pregnancies in women with spinal cord injury (SCI) are at greater risk of morbidity and mortality. Although pregnancy after SCI is well elaborated in the literature, SCI occurring during pregnancy is rarely reported. Abrupt changes in the body physiology because of SCI and the resulting disability add a risk to maternal and fetal well-being. Not only is the burden of care increased but there is also a higher risk of developing pressure ulcers, urinary tract infections, autonomic instability, intrauterine growth retardation and venous thromboembolism. CASE PRESENTATION: We report a case of a 32-year-old lady who had a traumatic SCI at C6 level during the second trimester of her pregnancy. She was admitted to a tertiary care rehabilitation facility after 2 months of her injury. This case highlights the comprehensive approach toward her management, including rehabilitation, spinal intervention and obstetrical care. To the best of our knowledge, this is the first case report of its kind from the Middle East. DISCUSSION: Multi-system involvement due to SCI during pregnancy results in intense physiological changes that affect the treatment options for anesthesia, surgery, labor and comprehensive rehabilitation. This case report emphasizes the need for well-equipped, specialized centers for similar patients in developing health systems and aims to increase the awareness for management of SCI during pregnancy using a comprehensive approach. PMID- 28808586 TI - Quality of Vision after Deep Anterior Lamellar Keratoplasty (Fluid Dissection) Compared to Penetrating Keratoplasty for the Treatment of Keratoconus. AB - PURPOSE: To compare the visual quality of patients with keratoconus who underwent penetrating keratoplasty (PKP) or deep anterior lamellar keratoplasty (DALK) with fluid dissection. DESIGN: Cross-sectional, observational study. METHODS: Twelve eyes that underwent PKP (PKP group) were compared to 24 eyes that underwent DALK (DALK group) after complete removal of sutures and stability of refraction. Visual, refractive, corneal topographic, corneal aberrometry, and ocular aberrometry parameters were compared for both groups. The chi2 and Mann-Whitney U tests were used for comparisons as appropriate. P < 0.05 was considered statistically significant. RESULTS: Uncorrected and best spectacle-corrected visual acuity (UCVA and BSCVA, resp.), mean refractive spherical equivalent and mean refractive cylinder (MRSE and MRC, resp.), root mean square of the 3 mm and 5 mm OPD Scan (NIDEK Co. Ltd., Gamagori, Japan), steep and flat meridians (SimK1 and SimK2, resp.), and the difference (corneal cylinder) were not statistically significantly different between groups (P > 0.05, all comparisons). All aberrations, point spread functions (PSF), and the modulation transfer function (MTF) were not statistically different between groups (P > 0.05). CONCLUSION: For our small study, the postoperative PKP and DALK with fluid dissection patient groups had vision/optical quality parameters that were not statistically different. This may indicate that DALK with fluid dissection can replace PKP for keratoconus without compromising vision quality. PMID- 28808587 TI - Oral Administration of the Endocannabinoid Anandamide during Lactation: Effects on Hypothalamic Cannabinoid Type 1 Receptor and Food Intake in Adult Mice. AB - We have previously shown that administration of the endocannabinoid anandamide (AEA) during lactation leads to overweight, increased body fat accumulation, and insulin resistance in adult mice. This study was designed to elucidate if these effects are due to increased food intake, stimulated by an augmented abundance and binding ability of the hypothalamic cannabinoid type 1 receptor (CB1R). With this aim, male mice pups were treated with a daily oral dose of AEA during lactation. Adult mice were also treated with a single oral dose of AEA, to evaluate acute food intake during 4 h. At 21 and 160 days, CB1R protein abundance was calculated by western blot analysis. Capacity of hypothalamic membranes to specifically bind the radioligand 3[H]-CP55.940 was also measured. Western blots showed a 72% increase in CB1R abundance in AEA-treated 21-day-old mice, without differences in adult mice. Additionally, specific binding of 3[H]-CP55.940 to hypothalamic membranes from adult mice was significantly lower in those mice treated with AEA during lactation. Moreover, AEA did not stimulate acute food intake in both, AEA-treated and control mice. Results suggest that metabolic alterations found in adult mice because of AEA treatment during lactation are not associated with hypothalamic CB1R. PMID- 28808588 TI - Appropriate Weaning Practice and Associated Factors among Infants and Young Children in Northwest Ethiopia. AB - BACKGROUND: The right nutrition from the start of a pregnancy to the child's second birthday has a profound impact on the future health, wellbeing, and success of a child. This can be achieved through proper maternal nutrition during pregnancy, exclusive breastfeeding, and appropriate weaning practice. OBJECTIVE: This study was aimed at assessing appropriate weaning practice and associated factors among infants and young children aged 6-23 months in Feres Bet Town, Northwest Ethiopia. METHODS: A community based cross-sectional study was conducted among 351 children aged 6-23 months. Simple random sampling technique was used to select study participants. Interviewer administered questionnaires were used. Bivariate and multivariable logistic regression analyses were employed to identify factors associated with appropriate weaning practice. RESULTS: Nearly quarter (23.9%) of mothers have practiced appropriate weaning. Proportion of children who started consumption of weaning food timely and met the recommended dietary diversity was 61.5% and 43.9%, respectively. Child age [AOR (Adjusted Odds Ratio): 7.04], husband's occupation [AOR: 6.85], and maternal weaning advice [AOR: 4.38] were positively associated with appropriate weaning practice, while family size [AOR: 0.28] showed negative association. CONCLUSION: Appropriate weaning practice was found to be low. Health education at community level and one on-one advice for mothers in health institutions are highly recommended to improve appropriate weaning. PMID- 28808591 TI - Immune Thrombocytopenia and JAK2V617F Positive Essential Thrombocythemia: Literature Review and Case Report. AB - We present the case where immune thrombocytopenia (ITP) and essential thrombocythemia (ET) sequentially appeared in the space of twenty-one years of follow-up. Impaired platelet production is present in both diseases, but clinical presentation and treatment are different. On the basis of this case history a possible role of autoimmunity as a predisposing factor to myeloproliferation has been discussed. PMID- 28808592 TI - A Case of Fulminant Meningococcemia: It Is All in the Complement. AB - Eculizumab is a novel monoclonal antibody that inhibits complement-mediated hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH). Complement deficiency is a well-known risk factor for meningococcal infection. We describe a case of a young patient with PNH treated with eculizumab who presented with a life-threatening case of nongroupable meningococcemia. As this new biologic agent becomes more widely prescribed, providers should be aware of the increased risk of meningococcemia. In addition to vaccination, providers may consider the use of oral penicillin for antibiotic prophylaxis against Neisseria meningitidis in these cases of functional complement deficiency. PMID- 28808589 TI - Anti-angiogenic agents for the treatment of solid tumors: Potential pathways, therapy and current strategies - A review. AB - Recent strategies for the treatment of cancer, other than just tumor cell killing have been under intensive development, such as anti-angiogenic therapeutic approach. Angiogenesis inhibition is an important strategy for the treatment of solid tumors, which basically depends on cutting off the blood supply to tumor micro-regions, resulting in pan-hypoxia and pan-necrosis within solid tumor tissues. The differential activation of angiogenesis between normal and tumor tissues makes this process an attractive strategic target for anti-tumor drug discovery. The principles of anti-angiogenic treatment for solid tumors were originally proposed in 1972, and ever since, it has become a putative target for therapies directed against solid tumors. In the early twenty first century, the FDA approved anti-angiogenic drugs, such as bevacizumab and sorafenib for the treatment of several solid tumors. Over the past two decades, researches have continued to improve the performance of anti-angiogenic drugs, describe their drug interaction potential, and uncover possible reasons for potential treatment resistance. Herein, we present an update to the pre-clinical and clinical situations of anti-angiogenic agents and discuss the most recent trends in this field. PMID- 28808593 TI - Combined Bone Transportation and Lengthening Techniques for the Treatment of Septic Nonunion of the Forearm Followed by Tendon Transfer. AB - Infected nonunion of a forearm fracture complicated by a considerable skin-muscle defect poses a great challenge to orthopaedic surgeons. The treatment strategy comprises eradication of the infection, ensuring bony union and soft tissue coverage along with functional restoration. We report a case of a 23-year-old man with an open Gustilo-Anderson IIIb fracture complicated by infected nonunion after internal fixation. After thorough surgical debridement, a considerable soft tissue defect, extensor muscle loss, and posterior interosseous nerve laceration had to be addressed. He was finally treated with bone transportation and bone lengthening followed by tendon transfers. PMID- 28808590 TI - Genesis and Maintenance of Attentional Biases: The Role of the Locus Coeruleus Noradrenaline System. AB - Emotionally arousing events are typically better remembered than mundane ones, in part because emotionally relevant aspects of our environment are prioritized in attention. Such biased attentional tuning is itself the result of associative processes through which we learn affective and motivational relevance of cues. We propose that the locus coeruleus-noradrenaline (LC-NA) system plays an important role in the genesis of attentional biases through associative learning processes as well as their maintenance. We further propose that individual differences in and disruptions of the LC-NA system underlie the development of maladaptive biases linked to psychopathology. We provide support for the proposed role of the LC-NA system by first reviewing work on attentional biases in development and its link to psychopathology in relation to alterations and individual differences in NA availability. We focus on pharmacological manipulations to demonstrate the effect of a disrupted system as well as the ADRA2b polymorphism as a tool to investigate naturally occurring differences in NA availability. We next review associative learning processes that-modulated by the LC-NA system-result in such implicit attentional biases. Further, we demonstrate how NA may influence aversive and appetitive conditioning linked to anxiety disorders as well as addiction and depression. PMID- 28808594 TI - Spontaneous Renal Allograft Rupture Caused by Acute Tubular Necrosis: A Case Report and Review of the Literature. AB - Renal allograft rupture (RAR) is a rare but lethal complication of renal transplantation. It potentially threatens graft and patient survival. RAR is frequently associated with acute rejection, but other causes like renal vein thrombosis and acute tubular necrosis have also been observed. Most commonly a graft nephrectomy is required, but graft repair can also be attempted in selected cases to salvage the graft. Herein, we describe a rare case of spontaneous renal allograft rupture in the early posttransplant period due to acute tubular necrosis. A 42-year-old male, living donor renal allograft recipient, experienced RAR on the sixth posttransplant day. Surgical exploration showed two lacerations of 10 cm and 5 cm length at the upper and mid pole of the kidney. Histologically, the graft demonstrated acute tubular injury; no features of humoral or cellular rejection were identified. The successful management of this complication resulted in the salvage of the patient and the graft. This case demonstrates that early diagnosis and prompt treatment of a life-threatening RAR can salvage the graft. PMID- 28808595 TI - A Case of Superficial Femoral Arteriovenous Fistula and Severe Venous Stasis Ulceration, Managed with an Iliac Extender Prosthesis. AB - Most femoral artery arteriovenous fistulas occur as a result of percutaneous interventions. However, arteriovenous fistulas can occur in the setting of trauma, with resultant consequences such as heart failure, steal syndrome, or venous insufficiency. Indications for endovascular repair in this setting are limited to patients who are at too high risk for anesthesia, have a hostile groin, or would not survive significant bleeding. We report the case of a traumatic femoral arteriovenous fistula, causing severe venous insufficiency and arteriomegaly, in a 58-year-old male, with history of traumatic gunshot wound complicated by popliteal DVT. Surgical options for arteriovenous fistula include open and endovascular repair but this patient's fistula was more suitable for endovascular repair for reasons that will be discussed. PMID- 28808596 TI - The Severity of Intracranial Hemorrhages Measured by Free Hemoglobin in the Brain Depends on the Anticoagulant Class: Experimental Data. AB - Background and Purpose. Anticoagulant therapy is broadly used to prevent thromboembolic events. Intracranial hemorrhages are serious complications of anticoagulation, especially with warfarin. Direct oral anticoagulants reduce but do not eliminate the risk of intracranial hemorrhages. The aim of this study is to determine the degree of intracranial hemorrhage after application of anticoagulants without additional triggers. Methods. Rats were treated with different anticoagulant classes (vitamin K antagonists, heparin, direct thrombin inhibitor, and factor Xa inhibitor). Brain hemorrhages were assessed by the free hemoglobin concentration in the brain parenchyma. Results. Vitamin K antagonists (warfarin and brodifacoum) significantly increased free hemoglobin in the brain. Among direct oral anticoagulants, thrombin inhibitor dabigatran also significantly increased free hemoglobin in the brain, whereas treatment with factor Xa inhibitor rivaroxaban did not have significant effect on the free hemoglobin concentration. Conclusions. Our data indicates that the severity of brain hemorrhages depends on the anticoagulant class and it is more pronounced with vitamin K antagonists. PMID- 28808597 TI - Visual Evoked Potentials in Primary Open Angle Glaucoma. AB - BACKGROUND AND AIMS: Visual evoked potentials (VEPs) assess the integrity of the visual pathways from the optic nerve to the occipital cortex. Optic disc cupping and visual field loss have been associated with prolongation of latency of VEP in primary open angle glaucoma (POAG). METHODS: Pattern reversal and flash VEP tests were done in consenting 20 primary open angle glaucoma eyes and 40 normal control eyes. RESULTS: In POAG cases, the refractive error [3.51 +/- 1.88 versus 1.88 +/- 1.11, D, p = 0.001], cup-disc ratio in percent [66.00 +/- 16.98 versus 28.50 +/- 5.80, p = 0.001], intraocular pressure [19.55 +/- 2.08 versus 11.65 +/- 1.64, mmHg, p = 0.001], and automated visual field pattern standard deviation [4.13 +/- 6.96 versus 1.64 +/- 0.45, dB, p = 0.001] were significantly more than in control. The visual acuity [0.41 +/- 0.29 versus 1.00 +/- 0.00, p = 0.001], foveal visual sensitivity [25.92 +/- 6.88 versus 33.48 +/- 1.75, dB, p = 0.001], and automated visual field mean deviation [-9.63 +/- 10.58 versus 0.07 +/- 1.54, dB, p = 0.001] were significantly less in cases than in control. Among VEP variables, pattern reversal latency N145 [149.00 +/- 15.75 versus 137.52 +/- 15.20, ms, p = 0.011], flash amplitude N75 [2.18 +/- .57 versus 1.47 +/- .38, MUV, p = 0.001], and flash amplitude N145 [1.99 +/- .39 versus 1.43 +/- .38, MUV, p = 0.001] were increased in cases. The pattern reversal amplitude N75 [1.97 +/- .35 versus 2.47 +/- .58, MUV, p = 0.001], amplitude P100 [3.09 +/- .46 versus 6.07 +/- 1.44, MUV, p = 0.001], and amplitude N145 [2.21 +/- .58 versus 4.45 +/- 1.99, MUV, p = 0.001] were decreased in cases. CONCLUSIONS: POAG caused glaucomatous damage to optic pathway. PMID- 28808598 TI - Synthesis, Characterization, and Adsorptive Properties of Fe3O4/GO Nanocomposites for Antimony Removal. AB - A magnetic Fe3O4/GO composite with potential for rapid solid-liquid separation through a magnetic field was synthesized using GO (graphene oxide) and Fe3O4 (ferriferous oxide). Characterization of Fe3O4/GO used scanning electron microscope (SEM), X-ray diffractometer (XRD), Fourier transform infrared spectrometer (FT-IR), and Vibrating Sample Magnetometer (VSM). A number of factors such as pH and coexisting ions on adsorbent dose were tested in a series of batch experiments. The results showed that GO and Fe3O4 are strongly integrated. For pH values in the range of 3.0~9.0, the removal efficiency of Sb(III) using the synthesized Fe3O4/GO remained high (95%). The adsorption showed good fit to a pseudo-second-order and Langmiur model, with the maximum adsorption capacity of 9.59 mg/g maintained across pH 3.0-9.0. Thermodynamic parameters revealed that the adsorption process was spontaneous and endothermic. Analysis by X-ray photoelectron spectroscopy (XPS) showed that the adsorption process is accompanied by a redox reaction. PMID- 28808599 TI - Solidified Floating Organic Drop Microextraction for the Detection of Trace Amount of Lead in Various Samples by Electrothermal Atomic Absorption Spectrometry. AB - A novel method was developed for determination of trace amounts of lead in water and food samples. Solidified floating organic drop microextraction was used to preconcentrate the lead ion. After the analyte was complexed with 1-(2 pyridylazo)-2-naphthol, undecanol and acetonitrile were added as extraction and dispersive solvent, respectively. Variables such as pH, volumes of extraction and dispersive solvents, and concentration of chelating agent were optimized. Under the optimum conditions, the detection limit of Pb (II) was determined as 0.042 ug L-1 with an enrichment factor of 300. The relative standard deviation is <10%. Accuracy of the developed procedure was evaluated by the analysis of certified reference material of human hair (NCS DC 73347) and wastewater (SPS-WW2) with satisfactory results. The developed procedure was then successfully applied to biscuit and water samples for detection of Pb (II) ions. PMID- 28808600 TI - Simultaneous Determination of 11 Compounds in Gualou Guizhi Granule and Pharmacokinetics Study by UPLC-MS/MS. AB - A rapid and sensitive ultrafast performance liquid chromatography-tandem mass spectrometry method (UPLC-MS/MS) was developed for the simultaneous determination of 11 compounds in Gualou Guizhi Granule (GLGZG), including liquiritin, isoliquiritin, liquirtin apioside, isoliquiritin apioside, liquiritigenin, isoliquiritigenin, glycyrrhizic acid, glycyrrhetinic acid, paeoniflorin, albiflorin, and paeoniflorin sulfonate in rat plasma. UPLC-MS/MS assay with negative ion mode was performed on a Waters CORTECS C18 (2.1 * 100 mm, 1.6 MUm) with the mobile phase consisting of 0.1% aqueous formic acid (A) and acetonitrile (B) in gradient elution at a flow rate of 0.25 mL.min-1. The method was linear for all analytes within the detection range (r >= 0.9597). The inter- and intraday precision (RSD) were 2.21-6.41% and 1.67-6.18%; the inter- and intraday accuracy (recover) were 92.48-114.03% and 90.23-112.04%. And the recovery rate ranged from 81.30% to 108.22%. The matrix effect values obtained for analytes ranged from 88.91% to 113.32%. This validated method was successfully applied to a pharmacokinetics study in rats after oral administration of GLGZG. PMID- 28808601 TI - High posterior cervical fusion rates with iliac autograft and Nanoss/bone marrow aspirate. AB - BACKGROUND: Patients with severe cervical multilevel stenosis and an adequate lordotic curvature often undergo multilevel laminectomies with posterior instrumented fusions. Although the "gold standard" for the fusion mass remains iliac crest autograft, many require additional volume provided by bone graft expanders. Here, we studied the fusion rates for 32 patients undergoing multilevel cervical laminectomy and vertex/rod/eyelet/titanium cable fusions utilizing lamina/iliac autograft and the bone graft expander Nanoss (RTI Surgical, Alachua, FL, USA) with autogenous bone marrow aspirate (BMA). METHODS: Thirty-two patients, averaging 63.0 years of age, presented with severe cervical myeloradiculopathy (average Nurick Grade 4.4). Magnetic resonance (MR) studies documented 2-3-level high intrinsic cord signals, whereas computed tomography (CT) scans confirmed marked stenosis and ossification of the posterior longitudinal ligament (OPLL)/ossification of the yellow ligament (OYL). Patients underwent multilevel lamnectomies/instrumented fusions, and were followed up for an average of 2.7 years. RESULTS: Multilevel laminectomies (2.8 levels) and average 7.8-level vertex/rod/eyelet/cable fusions were performed utilizing lamina/iliac crest autograft and Nanoss/BMA. Fusion was confirmed on X-ray/CT studies an average of 4.7 months postoperatively in 31 of 32 patients (97%); there was just one pseudarthrosis requiring secondary surgery. The only other complication was a delayed transient C5 palsy that fully resolved in 6 postoperative months. CONCLUSIONS: Thirty-two severely myelopathic underwent 2.8 level cervical laminectomies/7.8 level fusions utilizing lamina/iliac autograft and Nanoss/BMA. Fusion was documented on both dynamic X-ray and CT studies in 31 of 32 (97%) patients an average of 4.7 months postoperatively. Nanoss/BMA appears to be a safe and effective bone graft expander that can be utilized for posterior cervical fusions. PMID- 28808602 TI - High lumbar noninstrumented fusion rates using lamina autograft and Nanoss/bone marrow aspirate. AB - BACKGROUND: Patients with marked osteoporosis and/or obesity/morbid obesity and severe multilevel lumbar stenosis and other pathology often undergo multilevel laminectomies with non instrumented posterolateral fusions (PLF). The other pathology may include combinations of degenerative spondylolisthesis/lysis, foraminal/far lateral discs, and/or synovial cysts requiring more extensive facet resections. Presently, spine surgeons often use bone graft expanders to supplement the lamina autograft harvested in the course of laminectomy/decompressions for the PLF mass. METHODS: In 59 patients, we prospectively analyzed the fusion rates following multilevel laminectomies/noninstrumented fusions using lamina autograft and the bone graft expander Nanoss (RTI Surgical Alachua, FL, and USA) with autogenous bone marrow aspirate (BMA). Patients averaged 66.1 years of age; many exhibited marked osteoporosis (48 patients) and obesity (13 of 27 morbidly obese). Magnetic resonance (MR) and computed tomography (CT) studies documented stenosis/ossified yellow ligament (OYL) and degenerative spondylolisthesis (51 patients)/lysis (2 patients), synovial cysts (32 patients), and disc herniations (10 of 21 far lateral). Patients were followed remove up for an average of 3.12 years. RESULTS: Average 4.0 level laminectomies/1.2 level noninstrumented fusions utilized lamina autograft and Nanoss/BMA. Both X-ray/CT studies performed an average of 4.9 months postoperatively documented a 97% fusion rate (57 of 59 patients). Two patients with severe osteoporosis, morbid obesity, and smoking histories exhibited pseudarthroses; neither was sufficiently symptomatic to require secondary surgery. CONCLUSIONS: Fifty-nine patients with multilevel lumbar stenosis/OYL and other pathology underwent multilevel lumbar laminectomies/noninstrumented fusions using lamina autograft and Nanoss/BMA. Both dynamic X-ray/CT studies confirmed a 97% fusion rate an average of 4.9 months postoperatively. Nanoss/BMA contributed to a high posterolateral lumbar non instrumented fusion rate without complciations. PMID- 28808603 TI - Aneurysm treatment practice patterns for newly appointed dual-trained cerebrovascular/endovascular neurosurgeons: Comparison of open surgical to neuroendovascular procedures in the first 2 years of academic practice. AB - BACKGROUND: The practice patterns of a hybrid open cerebrovascular/neuroendovascular (CVNV) neurosurgeon in early academic practice is unknown. METHODS: We performed a multi-institutional retrospective cohort study of patients with cerebral aneurysms that were treated within the first 24 months of the neurosurgeon's practice. RESULTS: A total of 533 aneurysms were treated by the three senior authors within the first 24 months of their academic practice. Of these aneurysms, 172 were treated with microsurgical clipping, 191 with coiling, and 170 with flow diversion. Treatment in the setting of acute subarachnoid hemorrhage (SAH) occurred in 23% (122/533) of the aneurysms. Majority of the clipped aneurysms (70%, 121/172) were anterior cerebral artery (ACA), anterior communicating artery (ACOM), or middle cerebral artery (MCA) in location. In comparison, only 23% (82/361) of aneurysms treated with coiling or flow diversion therapy were ACA, ACOM, or MCA in location (P < 0.05). Additionally, majority of the flow diverted aneurysm (65%, 111/170) were cavernous or ophthalmic/paraophthalmic in location. During the second year of practice, there appeared to be a trend towards more aneurysms treated with neuroendovascular techniques (22% increase), particularly in flow diversion. CONCLUSION: Although the CVNV neurosurgeon treats cerebral aneurysms more commonly with neuroendovascular techniques, a third of the cerebral aneurysms are still selected for microsurgical clipping. Aneurysms located along the ACA/ACOM or MCA are the most frequent aneurysms reserved for microsurgical clipping. The CVNV neurosurgeon must be prepared to manage a high percentage of ACA/ACOM or MCA aneurysms microsurgically. PMID- 28808604 TI - Treatment strategies of ruptured posterior inferior cerebellar artery aneurysm according to its segment. AB - BACKGROUND: The aim of this study was to evaluate the clinical outcomes between endovascular treatment (EVT) and surgery of the ruptured posterior inferior cerebellar artery (PICA) aneurysms and suggest proper management strategies according to the PICA segment. METHODS: We retrospectively analyzed clinical and radiological data of patients with ruptured PICA aneurysms who underwent surgery or EVT from three different institutes. Clinical outcomes were evaluated by mRS. RESULTS: We collected 39 consecutive patients with 39 ruptured PICA aneurysms; 26 patients were with proximal segment aneurysm and 13 patients were with distal. Of the 26 proximal PICA aneurysms, 20 aneurysms were treated with EVT and 6 aneurysms were treated with surgery. EVT seemed to have more favorable clinical outcome (mRS 0-2; mean mRS, 1.75 for EVT vs 3.50 for surgery, P = 0.152). Of the 13 distal PICA aneurysms, 7 aneurysms were treated with EVT and 6 were treated with surgery. Surgery showed more favorable clinical outcome (mean mRS, 2.63 for EVT vs 0.33 for surgery, P = 0.023) and lower procedure-related complication rate (42.9% for EVT vs 0% for surgery, P = 0.046) than EVT. CONCLUSIONS: For the treatment of ruptured PICA aneurysms, EVT seemed to have more favorable outcomes for proximal segment, while surgery showed more favorable outcomes for distal segment. Additional experience and follow-up are needed in a larger series to state the efficacy of this strategy. PMID- 28808605 TI - Fatal cerebral swelling immediately after cranioplasty: A case report. AB - BACKGROUND: Cranioplasty is a standard neurosurgical procedure which is performed after decompressive craniotomy. Fatal complications associated with this procedure are not well documented. Here, we report a case of fatal cerebral swelling after cranioplasty and discuss the possible mechanism of this complication. CASE DESCRIPTION: A 64-year-old man was admitted with the diagnosis of cerebral hemorrhage, and emergency surgery for hemorrhage removal and decompressive craniotomy were performed. One month after surgery, cranioplasty was performed using a titanium mesh plate. Sixteen hours after the surgery, the patient became comatose with bilateral dilated pupils followed by blood pressure lowering. Computed tomography of the brain showed bilateral massive cerebral edema. The titanium mesh plate was immediately removed, however, the patient's neurological condition did not recover and he died 7 days after the surgery. We speculated that the negative pressure difference and increase in cerebral blood flow after cranioplasty may have attributed to the fatal cerebral swelling. CONCLUSION: Fatal cerebral swelling after cranioplasty is a rare but devastating complication. Although it is rare, neurosurgeons should keep in mind that this fatal complication can follow cranioplasty. PMID- 28808606 TI - Middle cerebral artery dissection causing subarachnoid hemorrhage and cerebral infarction: Trapping with high-flow bypass preserving the lenticulostriate artery. AB - BACKGROUND: Spontaneous intracranial arterial dissection (IAD) is an increasingly important cause of stroke, such as subarachnoid hemorrhage (SAH) and hemodynamic or thromboembolic cerebral ischemia. IAD usually occurs in the posterior circulation, and is relatively rare in the anterior circulation including the middle cerebral artery (MCA). Various surgical and endovascular methods to reduce blood flow in the dissected lesion have been proposed, but no optimum treatment has been established. CASE DESCRIPTION: An 80-year-old woman with dissection in the M1 portion of the MCA manifesting as SAH presented with repeated hemorrhage and cerebral infarction in the area of the inferior trunk of the MCA. High-flow bypass to the MCA was performed and the dissecting lesion was trapped. Prevention of repeated hemorrhage was achieved, and blood flow was preserved to the lenticulostriate artery as well as the MCA area distal to the lesion. CONCLUSIONS: Treatment strategy for IAD of the MCA should be planned for each patient and condition, and surgery should be performed promptly to prevent critical rebleeding given the high recurrence rate. In addition, preventing re rupture of the IAD, and preserving important perforators around the lesion and blood flow distal to the dissection should be targeted by the treatment strategy. PMID- 28808607 TI - Surgically treated spinal metastases: Do prognostic scores have a role? AB - BACKGROUND: The outcome for patients with metastatic disease in spine is difficult to predict. Multiple scoring systems were utilized in this study to determine their effectiveness in predicting long-term prognoses. METHODS: A retrospective analysis of surgically treated patients of spinal metastasis was performed between 2005 and 2016. Data were collected prospectively during which 8 patients were lost to follow-up. Ultimately, data from 63 patients were reviewed. Treatment and prognoses were analyzed utilizing various scoring systems including the SINS, the Tomita, the modified Tokouhashi and Bauer scores. RESULTS: Records of 63 patients, averaging 54 years of age, were analyzed. The Tomita score was applied in 44 patients, a modified Bauer score was studied in 49 patients, while SINS and modified Tokouhashi scores were calculated in all 63 patients. The hazard ratios for the Tomita score were 1, 0.030, 0.622, and 0.272, respectively. The hazard ratios for the modified Bauer scores were 1, 4.663, and 1.622, respectively. The Tokouhashi ratios were 1, 1.656, and 0.501, respectively. Of interest, the Tomita scores provided the highest statistical significance (P = 0.000) followed by the Bauer (P = 0.002) and Tokuhashi scores (P = 0.003). Notably, the SINS score showed no significant correlation in predicting patient survival. CONCLUSION: For evaluating the metastatic spine disease, this study evaluated the prognostic efficacy of four widely used scores: the Tomita, score, the modified Tokouhashi and Bauer scores, and the SINS scores. The Tomita scores provided the highest statistical significance, followed by the Bauer, and Tokuhashi scores, while the SINS score showed no significant correlation in predicting patient survival. PMID- 28808608 TI - Intrathecal catheter-associated inflammatory mass in a neurofibromatosis type-1 patient receiving fentanyl and bupivacaine. AB - BACKGROUND: Catheter-associated inflammatory masses (CIMs) are a rare but serious complication of intrathecal drug delivery devices. CIM formation is influenced by local medication concentration, which is determined in part by flow dynamics at the catheter tip. Underlying spinal pathologies, such as neoplasms, may alter flow at the catheter tip, thereby contributing to CIM formation. Moreover, they may also complicate the clinical and radiologic diagnosis of a CIM. CASE DESCRIPTION: A 36-year-old man with neurofibromatosis type 1 presented to our emergency department with complaints of increased back pain and leg weakness. To treat pain secondary to his multiple spinal masses, he had previously undergone placement of an implantable drug delivery system, which infused a compounded drug of fentanyl and bupivacaine. Imaging studies depicted numerous masses consistent with neurofibromatosis, including a compressive mass located circumferentially at the porous catheter terminus and proximal to the catheter tip. Surgical removal of this mass was performed; pathologic findings were consistent with a catheter tip granuloma. CONCLUSIONS: In the described case, CIM formation likely resulted from a combination of, 1) an unusually high fentanyl concentration, and, 2) altered infusate flow due to spinal neurofibromas. Consideration of underlying spinal pathologies, particularly mass lesions, is critical to the management of intrathecal drug delivery devices. PMID- 28808609 TI - Optimizing peripheral blood stem cells transplantation outcome through amend relapse and graft failure: a review of current literature. AB - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been considered as a valuable approach in treatment of numerous malignant and none malignant hematologic disorders. However, relapse and poor graft function (PGF) after allo-SCT remain to be controversial issues which may affect the transplantation outcome. Relevant articles were searched in MEDLINE database (2000-2016) using keywords and phrases: donor lymphocyte infusions, allogeneic stem cells transplantation, relapsed hematologic malignancies, booster schedules, cell dose, laboratory monitoring protocols and technical aspects of apheresis. Relapse of disease and PGF could be reduced via noting some main points such as choosing the suitable time and patient for donor lymphocyte infusion (DLI) and also determination of patients who ought to candidate for second allogeneic HSCT or for the use of stem cell boost. DLI and stem cell booster are promising treatment strategies noted in this review. Finally, this paper discusses indications and technical aspects of DLI and stem cell booster in hematological malignancies and emphasizes their therapeutic or pre-emptive potentials. PMID- 28808610 TI - Association between Alcohol Consumption and Diverticulosis and Diverticular Bleeding: A Systematic Review and Meta-analysis. AB - There have been conflicting reports on the association of alcohol use and diverticular disease. We aimed to determine the odds of developing diverticular disease and diverticular bleeding in patients who consumed alcohol on a regular basis compared with those who did not. MEDLINE and PUBMED were searched up until February 2017 on observational trials, which investigated the effect of alcohol use on two outcomes of diverticular disease: diverticulosis and diverticular bleeding. Quantitative estimates (odds ratios [OR] and confidence intervals [CI]) from included studies were pooled by using a random-effects model. Heterogeneity across studies was assessed by the I2 statistic. In 6 studies including 53,644 subjects and 6 studies including 3,404 subjects, alcohol consumption on a regular basis was not associated with either diverticulosis (OR=1.99; 95% CI 0.99-4.03, I2=99%) or diverticular bleeding (OR=1.39; 95% CI 0.84-2.32, I2=45%) compared to subjects who did not consume alcohol on a regular basis, respectively. Increased odds of diverticulosis or diverticular bleeding among individuals who consume alcohol on a regular basis were not observed in these meta-analyses. PMID- 28808611 TI - Red Snappers and Red Herrings: Pelvic Tuberculosis Causing Elevated CA 125 and Mimicking Advanced Ovarian Cancer. A Case Report and Literature Review. AB - Female genital tuberculosis (FGTB) is a form of extra-pulmonary tuberculosis that has been primarily described in developing countries, where it is an important cause of infertility, ectopic pregnancy, and miscarriage. FGTB is rare in the United States and because its clinical presentation is non-specific and often insidious, FGTB may be misdiagnosed as a gynecologic malignancy or endometriosis. The tendency of tuberculosis to dramatically increase serum CA 125 levels contributes to the potential for FGTB to be mistaken for ovarian cancer in particular. We describe the case of a young woman who presented with what was initially thought to be advanced ovarian cancer but who had tuberculosis of the peritoneum, uterus, and ovaries discovered at laparotomy. This case emphasizes the importance of considering tuberculosis in the differential of any patient presenting with an abdomino-pelvic mass and an elevated CA 125 level. PMID- 28808613 TI - Medical School Hotline: Annual Report for John A. Burns School of Medicine - 2017. PMID- 28808614 TI - Insights in Public Health: Screening Brief Intervention and Referral to Treatment (SBIRT): One of the way's the Hawai'i Department of Health is working to "Make Health Hawai'i's Shared Value". PMID- 28808612 TI - Para I Famagu'on-Ta: Fruit and Vegetable Intake, Food Store Environment, and Childhood Overweight/Obesity in the Children's Healthy Living Program on Guam. AB - This cross-sectional study examined the: (1) association between food store environment (FSE), fruit and vegetable (FV) availability and access, and prevalence of early childhood overweight/obesity (COWOB); and (2) influence of young child actual FV intake on the relationship between the FSE and early COWOB prevalence. Anthropometric and socio-demographic data of children (2 to 8 years; N=466) in baseline communities on Guam participating in the Children's Healthy Living (CHL) Program community trial were included. CDC year 2000 growth charts were used to calculate BMI z-scores and categories. FSE factors (fresh FV scores, store type) were assessed using the CX3 Food Availability and Marketing Survey amended for CHL. ArcGIS maps were constructed with geographic coordinates of participant residences and food stores to calculate food store scores within 1 mile of participant's residences. A sub-sample of participants (n = 355) had Food and Activity Log data to calculate FV and energy intakes. Bivariate correlations and logistic regression evaluated associations. Of 111 stores surveyed, 73% were small markets, 16% were convenience stores, and 11% were large grocery/supermarkets. Supermarkets/large grocery stores averaged the highest FV scores. Most participants did not meet FV intake recommendations while nearly half exceeded energy intake recommendations. Living near a small market was negatively correlated with BMI z-score (r = - 0.129, P < .05) while living near a convenience store was positively correlated with BMI z-score (r = 0.092, P < .05). Logistic regression analysis yielded non-significant associations. The high density of small markets may be an opportunity for FSE intervention but further investigation of Guam's FSE influence on health is needed. PMID- 28808616 TI - Periprosthetic hip joint infection with Aspergillus terreus: A clinical case and a review of the literature. AB - Fungal periprosthetic joint infections due to Aspergillus species are rare but are associated with significant cost and morbidity. We present a case of Asperigillus terreus prosthetic joint infection of the hip. The patient was successfully treated with a prolonged course of systemic antifungals along with surgical management. PMID- 28808617 TI - A novel method of quantifying brain atrophy associated with age-related hearing loss. AB - A growing body of evidence has shown that a relationship between age-related hearing loss and structural brain changes exists. However, a method to measure brain atrophy associated with hearing loss from a single MRI study (i.e. without an interval study) that produces an independently interpretable output does not. Such a method would be beneficial for studying patterns of structural brain changes on a large scale. Here, we introduce our method for this. Audiometric evaluations and mini-mental state exams were obtained in 34 subjects over the age of 80 who have had brain MRIs in the past 6 years. CSF and parenchymal brain volumes (whole brain and by lobe) were obtained through a novel, fully automated algorithm. Atrophy was calculated by taking the ratio of CSF to parenchyma. High frequency hearing loss was associated with disproportional temporal lobe atrophy relative to whole brain atrophy independent of age (r = 0.471, p = 0.005). Mental state was associated with frontoparietal atrophy but not to temporal lobe atrophy, which is consistent with known results. Our method demonstrates that hearing loss is associated with temporal lobe atrophy and generalized whole brain atrophy. Our algorithm is efficient, fully automated, and able to detect significant associations in a small cohort. PMID- 28808618 TI - Neuroimaging studies in patients with psychogenic non-epileptic seizures: A systematic meta-review. AB - Psychogenic Non-epileptic Seizures (PNES) are 'medically unexplained' seizure like episodes which superficially resemble epileptic seizures but which are not caused by epileptiform discharges in the brain. While many experts see PNES disorder as a multifactorial biopsychosocial condition, little is known about the neurobiological processes which may predispose, precipitate and/or perpetuate PNES symptomology. This systematic meta-review advances our knowledge and understanding of the neurobiological correlates of PNES by providing an up-to date assessment of neuroimaging studies performed on individuals with PNES. Although the results presented appear inconclusive, they are consistent with an association between structural and functional brain abnormalities and PNES. These findings have implications for the way in which we think about this "medically unexplained" disorder and how we communicate the diagnosis to patients. However, it is also evident that neuroimaging studies in this area suffer from a number of significant limitations and future larger studies will need to better address these if we are to improve our understanding of the neurobiological correlates of predisposition to and/or manifestation of PNES. PMID- 28808620 TI - Lemierre's syndrome: Case report and brief literature review. AB - Lemierre's syndrome has been shown to be increasing in incidence in the past 20 years with one popular suggesting that said rise occurred from less aggressive antibacterial coverage. We report a case of Lemierre's syndrome and also reviewed the 15 most recent case reports. A previously healthy 25 year old male who initially developed sore throat and flu-like symptoms, was prescribed antibacterials as an outpatient but was hospitalized for worsening symptoms. He was later diagnosed with Lemierre's syndrome and improved clinically with IV antimicrobials alone. From our concise literature review, we determined that a decrease in antibiotic prescriptions may not fully explain why the incidence of Lemierre's has been increasing. Thus, future research should be focused in evaluating possible worsening susceptibilities to antibiotics and improvements on detection. We also advise physicians to be aware of the signs and symptoms of this rare but potentially fatal condition as well as the available detection methods and treatment. PMID- 28808619 TI - Gastrointestinal parasites in captive and free-ranging Cebus albifrons in the Western Amazon, Ecuador. AB - Currently, there is a lack of surveys that report the occurrence of gastrointestinal parasites in the white-headed capuchin monkey (Cebus albifrons). We therefore assessed the presence and richness (= number of different parasite genera) of parasites in C. albifrons in wildlife refuges (n = 11) and in a free ranging group near a human village (n = 15) in the Ecuadorian Amazon. In the 78 samples collected (median of 3 samples per animal), we identified a total of 6 genera of gastrointestinal parasites, representing protozoa, nematodes, acanthocephalans and cestodes. We observed a high prevalence (84%) across the 26 individuals, with the most prevalent parasite being Strongyloides sp. (76.9%), followed by Hymenolepis sp. (38.5%) and Prosthenorchis elegans (11.5%). We found Entamoeba histolytica/dispar/moskovskii/nuttalli and Capillaria sp. in only a minority of the animals (3.8%). In addition, we observed unidentified strongyles in approximately one-third of the animals (34.6%). We found a total of 6 parasite genera for the adult age group, which showed higher parasite richness than the subadult age group (5) and the juvenile age group (3). Faecal egg/cyst counts were not significantly different between captive and free-ranging individuals or between sexes or age groups. The free-ranging group had a higher prevalence than the captive group; however, this difference was not significant. The only genus common to captive and free-ranging individuals was Strongyloides sp. The high prevalence of gastrointestinal parasites and the presence of Strongyloides in both populations support results from previous studies in Cebus species. This high prevalence could be related to the high degree of humidity in the region. For the free-ranging group, additional studies are required to gain insights into the differences in parasite prevalence and intensity between age and sex groups. Additionally, our study demonstrated that a serial sampling of each individual increases the test sensitivity. PMID- 28808621 TI - von Brunn's Nests and Follicular Cystitis Following Intradetrusor OnabotulinumtoxinA Injections for Overactive Bladder. AB - A 67-year-old female with refractory OAB was treated with intradetrusor Botox. She subsequently developed multiple papillary bladder lesions with tissue biopsy showing Von Brunn's nests. Von Brunn's nests are benign bladder lesions similar in appearance to a rare urothelial tumor called Nested Variant of Urothelial Carcinoma (NVUC). It is critical that patients with these findings undergo evaluation to rule out the presence of carcinoma. This finding suggests the possibility of a previously unreported adverse reaction in association with intradetrusor Botox. PMID- 28808622 TI - Radiation exposure and reduction in the operating room: Perspectives and future directions in spine surgery. AB - Intraoperative imaging is vital for accurate placement of instrumentation in spine surgery. However, the use of biplanar fluoroscopy and other intraoperative imaging modalities is associated with the risk of significant radiation exposure in the patient, surgeon, and surgical staff. Radiation exposure in the form of ionizing radiation can lead to cellular damage via the induction of DNA lesions and the production of reactive oxygen species. These effects often result in cell death or genomic instability, leading to various radiation-associated pathologies including an increased risk of malignancy. In attempts to reduce radiation associated health risks, radiation safety has become an important topic in the medical field. All practitioners, regardless of practice setting, can practice radiation safety techniques including shielding and distance to reduce radiation exposure. Additionally, optimization of fluoroscopic settings and techniques can be used as an effective method of radiation dose reduction. New imaging modalities and spinal navigation systems have also been developed in an effort to replace conventional fluoroscopy and reduce radiation doses. These modalities include Isocentric Three-Dimensional C-Arms, O-Arms, and intraoperative magnetic resonance imaging. While this influx of new technology has advanced radiation safety within the field of spine surgery, more work is still required to overcome specific limitations involving increased costs and inadequate training. PMID- 28808623 TI - Use of recombinant human bone morphogenetic protein-2 in spine surgery. AB - Bone morphogenetic proteins are osteoinductive factors which have gained popularity in orthopaedic surgery and especially in spine surgery. The use of recombinant human bone morphogenetic protein-2 has been officially approved by the United States Food and Drug Administration only for single level anterior lumbar interbody fusion, nevertheless it is widely used by many surgeons with off label indications. Despite advantages in bone formation, its use still remains a controversial issue and several complications have been described by authors who oppose their wide use. PMID- 28808624 TI - Possibilities for arthroscopic treatment of the ageing sternoclavicular joint. AB - AIM: To investigate if there are typical degenerative changes in the ageing sternoclavicular joint (SCJ), potentially accessible for arthroscopic intervention. METHODS: Both SCJs were obtained from 39 human cadavers (mean age: 79 years, range: 59-96, 13 F/26 M). Each frozen specimen was divided frontally with a band saw, so that both SCJs were opened in the same section through the center of the discs. After thawing of the specimens, the condition of the discs was evaluated by probing and visual inspection. The articular cartilages were graded according to Outerbridge, and disc attachments were probed. Cranio-caudal heights of the joint cartilages were measured. Superior motion of the clavicle with inferior movement of the lateral clavicle was measured. RESULTS: Degenerative changes of the discs were common. Only 22 discs (28%) were fully attached and the discs were thickest superiorly. We found a typical pattern: Detachment of the disc inferiorly in connection with thinning, fraying and fragmentation of the inferior part of the disc, and detachment from the anterior and/or posterior capsule. Severe joint cartilage degeneration >= grade 3 was more common on the clavicular side (73%) than on the sternal side (54%) of the joint. In cadavers < 70 years 75% had <= grade 2 changes while this was the case for only 19% aged 90 years or more. There was no difference in cartilage changes when right and left sides were compared, and no difference between sexes. Only one cadaver - a woman aged 60 years - had normal cartilages. CONCLUSION: Changes in the disc and cartilages can be treated by resection of disc, cartilage, intraarticular osteophytes or medial clavicle end. Reattachment of a degenerated disc is not possible. PMID- 28808625 TI - Epidemiology of open fractures in sport: One centre's 15-year retrospective study. AB - AIM: To describe the epidemiology of sport-related open fractures from one centre's adult patient population over a 15-year period. METHODS: A retrospective review of a prospectively-collected database was performed: The database contained information all sport-related open fractures, sustained from 1995 to 2009 in the Edinburgh, Mid and East Lothian Populations. RESULTS: Over the 15 year period, there were 85 fractures recorded in 84 patients. The annual incidence of open sport-related fractures was 0.01 per 1000 population. The mean age at injury was 29.2 years (range 15-67). There were 70 (83%) males and 14 females (17%). The 6 most common sports were soccer (n = 19, 22%), rugby (n = 9, 11%), cycling (n = 8, 9%), hockey (n = 8, 9%); horse riding (n = 6, 7%) and skiing (n = 6, 7%). The five most common anatomical locations were finger phalanges (n = 30, 35%); tibial diaphysis (n = 19, 23%); forearm (n = 12, 14%); ankle (n = 7, 8%) and metacarpals (n = 5, 6%). The mean injury severity score was 7.02. According to the Gustilo-Anderson classification system, 45 (53%) fractures were grade 1; 28 (33%) fractures were grade 2; 8 (9%) fractures were grade 3a; and 4 (5%) fractures were grade 3b. Out of the total number of fractures, 7 (8%) required plastic surgical intervention as part of management. The types of flaps used were split skin graft (n = 4), fasciocutaneous flaps (n = 2); and adipofascial flap (n = 1). CONCLUSION: We analysed the epidemiology of open fractures secondary to sport in one centre over a 15-year period. Soccer and rugby were the most common causative sports while fractures of the finger phalanx and of the tibial diaphysis were the most common sites. Open fractures are uncommon in sport; however, when they are sustained they usually occur on muddy sport fields or forest tracks and therefore must be treated appropriately. It is important that clinicians and sports therapists have knowledge of these injuries, in order to ensure they are managed optimally. PMID- 28808626 TI - Acetabular revisions using porous tantalum components: A retrospective study with 5-10 years follow-up. AB - AIM: To evaluate the clinical and X-ray results of acetabular components and tantalum augments in prosthetic hip revisions. METHODS: Fifty-eight hip prostheses with primary failure of the acetabular component were reviewed with tantalum implants. The clinical records and X-rays of these cases were retrospectively reviewed. Bone defect evaluations were based on preoperative CT scans and classified according to Paprosky criteria of Radiolucent lines and periprosthetic gaps; implant mobilization and osteolysis were evaluated by X-ray. An ad hoc database was created and statistical analyses were performed with SPSS software (IBM SPSS Statistics for Windows, version 23.0). Statistical analyses were carried out using the Student's t test for independent and paired samples. A P value of < 0.05 was considered statistically significant and cumulative survival was calculated by the Kaplan-Meier method. RESULTS: The mean follow-up was 87.6 +/- 25.6 mo (range 3-120 mo). 25 cases (43.1%) were classified as minor defects, and 33 cases (56.9%) as major defects. The preoperative HHS rating improved significantly from a mean of 40.7 +/- 6.1 (range: 29-53) before revision, to a mean of 85.8 +/- 6.1 (range: 70-94) at the end of the follow-up (Student's t test for paired samples: P < 0.001). Considering HHS only at the end of follow-up, no statistically significant difference was observed between patients with a major or minor defect (Student's t test for independent samples: P > 0.05). Radiolucent lines were found in 4 implants (6.9%). Postoperative acetabular gaps were observed in 5 hips (8.6%). No signs of implant mobilization or areas of periprosthetic osteolysis were found in the x-rays at the final follow-up. Only 3 implants failed: 1 case of infection and 2 cases of instability. Defined as the end-point, cumulative survival at 10 years was 95% (for all reasons) and 100% for aseptic loosening of the acetabular component. CONCLUSION: The medium-term use of prosthetic tantalum components in prosthetic hip revisions is safe and effective in a wide variety of acetabular bone defects. PMID- 28808627 TI - Non-ossifying fibromas: Case series, including in uncommon upper extremity sites. AB - AIM: To investigate non-ossifying fibromas (NOFs) common fibrous bone lesions in children that occur in bones of the lower extremities. METHODS: We analyzed 44 cases of NOF including 47 lesions, which were referred with a working diagnosis of neoplastic lesions. Lesions were located in the upper extremities (1 proximal humerus, 1 distal radius) and the lower extremities (25 distal femurs, 12 proximal and 4 distal tibias, and 4 proximal fibulas). RESULTS: Three cases had NOFs in multiple anatomical locations (femur and fibula in 1 case, femur and tibia in 2 cases). Overall, larger lesions > 4 cm and lesion expansion at the cortex were seen in 21% and 32% of cases, respectively. Multiple lesions with bilateral symmetry in the lower extremities suggest that these NOFs were developmental bone defects. Two patients suffered from fracture and were treated without surgery, one in the radius and one in the femur. Lesions in the upper extremities (i.e., humerus of a 4-year-old female and radius of a 9-year-old male) expanded at the cortex and lesion size increased with slow ossification. CONCLUSION: NOFs in the lower extremity had fewer clinical problems, regardless of their size and expansiveness. In these two upper extremity cases, the NOFs had aggressive biological features. It seems that there is a site specific difference, especially between the upper extremity and the lower extremity. Furthermore, NOFs in the radius are predisposed to fracture because of the slender structure of the radius and the susceptibility to stress. PMID- 28808628 TI - Distal radius volar rim plate: Technical and radiographic considerations. AB - AIM: To determine technical considerations and radiographic outcomes of the Synthes volar rim distal radius plate to treat complex intra-articular fractures. METHODS: This review highlights technical considerations learnt using this implant since it was introduced in a major trauma unit in November 2011, including anatomical reduction and whether this was maintained radiographically. RESULTS: Twenty-six of the 382 internally fixed distal radial fractures at our unit (6.8%) were deemed to require this plate in order to achieve optimal fracture fixation between November 2011 and May 2014. A further dorsal and/or radial plate was necessary in 35% and variable angle screws were used in 54% of cases. Post-operatively, mean radial height, inclination, volar tilt and ulnar variance restored were 11.7 mm, 21o, 4.3o and -1.2 mm respectively. There were no cases of non-union or flexor/extensor tendon rupture; one case of loss of fracture reduction. Overall incidence of plate removal was 15% with one plate removed for flexor and one for extensor tendon irritation. CONCLUSION: The use of a rim plate enables control of challenging far distal fracture patterns. However, additional plates were required to improve and maintain reduction. Variable angle screws were necessary in half the cases to avoid intra-articular screw penetration. If used judiciously, this implant can achieve stable fixation despite the complexity of the fracture pattern. PMID- 28808629 TI - Return to sport following tibial plateau fractures: A systematic review. AB - AIM: To systemically review all studies reporting return to sport following tibial plateau fracture, in order to provide information on return rates and times to sport, and to assess variations in sporting outcome for different treatment methods. METHODS: A systematic search of CINAHAL, Cochrane, EMBASE, Google Scholar, MEDLINE, PEDro, Scopus, SPORTDiscus and Web of Science was performed in January 2017 using the keywords "tibial", "plateau", "fractures", "knee", "athletes", "sports", "non-operative", "conservative", "operative", "return to sport". All studies which recorded return rates and times to sport following tibial plateau fractures were included. RESULTS: Twenty-seven studies were included: 1 was a randomised controlled trial, 7 were prospective cohort studies, 16 were retrospective cohort studies, 3 were case series. One study reported on the outcome of conservative management (n = 3); 27 reported on the outcome of surgical management (n = 917). Nine studies reported on Open Reduction Internal Fixation (ORIF) (n = 193), 11 on Arthroscopic-Assisted Reduction Internal Fixation (ARIF) (n = 253) and 7 on Frame-Assisted Fixation (FRAME) (n = 262). All studies recorded "return to sport" rates. Only one study recorded a "return to sport" time. The return rate to sport for the total cohort was 70%. For the conservatively-managed fractures, the return rate was 100%. For the surgically-managed fractures, the return rate was 70%. For fractures managed with ORIF, the return rate was 60%. For fractures managed with ARIF, the return rate was 83%. For fractures managed with FRAME was 52%. The return rate for ARIF was found to be significantly greater than that for ORIF (OR 3.22, 95%CI: 2.09-4.97, P < 0.001) and for FRAME (OR 4.33, 95%CI: 2.89-6.50, P < 0.001). No difference was found between the return rates for ORIF and FRAME (OR 1.35, 95%CI: 0.92-1.96, P = 0.122). The recorded return time was 6.9 mo (median), from a study reporting on ORIF. CONCLUSION: Return rates to sport for tibial plateau fractures remain limited compared to other fractures. ARIF provides the best return rates. There is limited data regarding return times to sport. Further research is required to determine return times to sport, and to improve return rates to sport, through treatment and rehabilitation optimisation. PMID- 28808630 TI - Systematic review on the use of autologous matrix-induced chondrogenesis for the repair of articular cartilage defects in patients. AB - AIM: To systematically review the results of studies looking at autologous matrix induced chondrogenesis (AMIC) in humans. METHODS: A literature search was performed, adhering to the PRISMA guidelines, to review any studies using such techniques in humans. Our initial search retrieved 297 articles listed on MEDLINE, Google Scholar, CINHal and EMBASE. From these studies, 15 studies meeting the eligibility criteria were selected and formed the basis of our systematic review. RESULTS: The study designs, surgical techniques and outcome measures varied between the studies. Although all studies reported improvements in patient outcome measures, this was not necessarily correlated with magnetic resonance imaging findings. Although there were many additional procedures performed, when AMIC was performed in isolation, the results tended to peak at 24 mo before declining. CONCLUSION: Although short-term studies suggest improved patient reported outcomes with a variety of scaffolds, surgical techniques and rehabilitation regimes, the literature remains equivocal on whether the defect size and location, and patient factors affect the outcome. Patient benefit appears to be maintained in the short-to-medium term but more high level studies with extensive and robust validated outcome measures should be conducted to evaluate the medium- and long-term effect of the AMIC procedure. PMID- 28808631 TI - Painless swollen calf muscles of a 75-year-old patient caused by bilateral venous malformations. AB - A 75-year-old man presented with knee pain due to medial osteoarthritis of the knee in the orthopedic outpatient clinic. Conservative treatment was started with steroid infiltration. Besides his knee complaint reported a bilateral painless swollen calf muscle without traumatic cause, and also without any pain at night, fever or medical illness. On physical examination the soleus muscle had a swollen aspect in both calfs. The skin appeared normal without deformities and the arterial pulsations were intact. An X-ray did not show abnormalities in the tibia. Magnetic resonance imaging of the legs revealed bilateral multiple saccular intramuscular venous malformations involving the soleus muscle. Intramuscular venous malformations in skeletal muscles are rare, especially when the occurrence is bilateral. Bilateral venous malformations have the potential to be missed because of the intramuscular localization. Symptoms of intramuscular venous malformation can be often mild and overlap with non-exercise related compartment syndrome, claudication, lymphedema and post thrombotic syndrome or muscle strains. PMID- 28808632 TI - Survival rates against fracture of endodontically treated posterior teeth restored with full-coverage crowns or resin composite restorations: a systematic review. AB - This systematic review aims to summarize the current clinical studies that investigated survival rates against fracture of endodontically treated posterior teeth restored with crowns or resin composite restorations. Literature search were performed using keywords. Publications from 1980 to 2016 were searched in PubMed, ScienceDirect, Web of Science, MEDLINE, and SCOPUS. Included studies were selected based on inclusion and exclusion criteria. Three clinical studies were included: 1 randomized controlled trial and 1 prospective and 1 retrospective cohort studies. Pooled survival rates ranged from 94%-100% and 91.9%-100% for crowns and resin composite, respectively. The majority of teeth had no more than 3 surface loss of tooth structure. The studies included were heterogeneous, and were not appropriate for further meta-analysis. Current evidence suggested that the survival rates against the fracture of endodontically treated posterior teeth restored with crowns or resin composites were not significantly different in the teeth with minimum to moderate loss of tooth structure. PMID- 28808633 TI - Comparing the effect of a desensitizing material and a self-etch adhesive on dentin sensitivity after periodontal surgery: a randomized clinical trial. AB - OBJECTIVES: This double-blind randomized placebo-controlled clinical trial evaluated the ability of a desensitizing agent and a self-etch adhesive on cervical dentin sensitivity (CDS) after periodontal surgery. MATERIALS AND METHODS: Ninety hypersensitive teeth of 13 subjects were included in the study. After periodontal surgery, the teeth of each posterior sextant treated with one of the following materials: G1: Clearfil S3 Bond (Kuraray Dental), G2: Gluma Desensitizer (Heraeus Kulzer), and G3: placebo (water). The sensitivity was assessed using evaporative stimuli before treatment (baseline, T0), 1 day after treatment (T1), after 1 week (T2), and after 1 month (T3) according to visual analog scale (VAS). RESULTS: Following the treatment, all the 3 groups showed significant reduction of CDS in T1 compared to T0. Reduction of CDS between T1 and T2 was observed only in G1 but there was no significant difference between T2 and T3 in this group. Although we observed a significant difference in T3 compared to T1 and T2 in G2 and G3, comparison of treatment groups in each assessment time showed a significant difference only in T3. According to paired comparison, this was due to the difference between G2 and G3. CONCLUSIONS: Dentin sensitivity following periodontal surgery will decrease spontaneously over time, but treating the sensitive teeth with Gluma Desensitizer and Clearfil S3 Bond can have some benefits. PMID- 28808634 TI - White mineral trioxide aggregate mixed with calcium chloride dihydrate: chemical analysis and biological properties. AB - OBJECTIVES: This study aimed to evaluate the chemical and biological properties of fast-set white mineral trioxide aggregate (FS WMTA), which was WMTA combined with calcium chloride dihydrate (CaCl2.2H2O), compared to that of WMTA. MATERIALS AND METHODS: Surface morphology, elemental, and phase analysis were examined using scanning electron microscope (SEM), energy dispersive X-ray microanalysis (EDX), and X-ray diffraction (XRD), respectively. The cytotoxicity and cell attachment properties were evaluated on human periodontal ligament fibroblasts (HPLFs) using methyl-thiazol-diphenyltetrazolium (MTT) assay and under SEM after 24 and 72 hours, respectively. RESULTS: Results showed that the addition of CaCl2.2H2O to WMTA affected the surface morphology and chemical composition. Although FS WMTA exhibited a non-cytotoxic profile, the cell viability values of this combination were lesser than WMTA, and the difference was significant in 7 out of 10 concentrations at the 2 time intervals (p < 0.05). HPLFs adhered over the surface of WMTA and at the interface, after 24 hours of incubation. After 72 hours, there were increased numbers of HPLFs with prominent cytoplasmic processes. Similar findings were observed with FS WMTA, but the cells were not as confluent as with WMTA. CONCLUSIONS: The addition of CaCl2.2H2O to WMTA affected its chemical properties. The favorable biological profile of FS WMTA towards HPLFs may have a potential impact on its clinical application for repair of perforation defects. PMID- 28808635 TI - Effect of dentin biomodifiers on the immediate and long-term bond strengths of a simplified etch and rinse adhesive to dentin. AB - OBJECTIVES: This in vitro study evaluated the effect of dentin biomodifiers on the immediate and long-term bond strengths of a simplified etch and rinse adhesive to dentin. MATERIALS AND METHODS: Flat coronal dentin surfaces were prepared in 120 extracted human molars. Teeth were randomly divided into 5 groups (n = 24) according to 5 different surface pre-treatments: No pre-treatment (control); 1M carbodiimide (EDC); 0.1% epigallocatechin-3-gallate (EGCG); 2% minocycline (MI); 10% sodium ascorbate (SA). After surface pre-treatment, adhesive (Adper Single Bond 2 [SB], 3M ESPE) was applied. Composite was applied into transparent plastic tubes (2.5 mm in diameter), which was placed over the bonded dentin surface. From each group, 10 samples were subjected to shear bond strength (SBS) evaluation at 24 hours (immediate) and remaining 10 samples were tested after 6 months (delayed). Additionally, 4 samples per group were subjected to scanning electron microscopic analysis for observation of resin-dentin interface. The data were statistically analysed with Shaperio-Wilk W test, 2-way analysis of variance (ANOVA), and post hoc Tukey's test. RESULTS: At 24 hours, SBS of all surface pre-treatment groups were comparable with the control group, with significant differences found between EDC and SA groups only (p = 0.009). After 6 months storage, EDC, EGCG, and MI pre-treatments preserved the resin dentin bond strength with no significant fall. CONCLUSIONS: Dentin pre-treatment with all the dentin biomodifiers except SA resulted in significant preservation of resin-dentin bond over 6 months storage period, without negatively affecting the immediate bond strength of the etch and rinse adhesive tested. PMID- 28808636 TI - In vivo assessment of accuracy of Propex II, Root ZX II, and radiographic measurements for location of the major foramen. AB - OBJECTIVES: The aim of this in vivo study was to assess the accuracy of 2 third generation electronic apex locators (EALs), Propex II (Dentsply Maillefer) and Root ZX II (J. Morita), and radiographic technique for locating the major foramen (MF). MATERIALS AND METHODS: Thirty-two premolars with single canals that required extraction were included. Following anesthesia, access, and initial canal preparation with size 10 and 15 K-flex files and SX and S1 rotary ProTaper files, the canals were irrigated with 2.5% sodium hypochlorite. The length of the root canal was verified 3 times for each tooth using the 2 apex locators and once using the radiographic technique. Teeth were extracted and the actual WL was determined using size 15 K-files under a * 25 magnification. The Biostat 4.0 program (AnalystSoft Inc.) was used for comparing the direct measurements with those obtained using radiographic technique and the apex locators. Pearson's correlation analysis and analysis of variance (ANOVA) were used for statistical analyses. RESULTS: The measurements obtained using the visual method exhibited the strongest correlation with Root ZX II (r = 0.94), followed by Propex II (r = 0.90) and Ingle's technique (r = 0.81; p < 0.001). Descriptive statistics using ANOVA (Tukey's post hoc test) revealed significant differences between the radiographic measurements and both EALs measurements (p < 0.05). CONCLUSIONS: Both EALs presented similar accuracy that was higher than that of the radiographic measurements obtained with Ingle's technique. Our results suggest that the use of these EALs for MF location is more accurate than the use of radiographic measurements. PMID- 28808637 TI - Effects of air-abrasion pressure on the resin bond strength to zirconia: a combined cyclic loading and thermocycling aging study. AB - OBJECTIVES: To determine the combined effect of fatigue cyclic loading and thermocycling (CLTC) on the shear bond strength (SBS) of a resin cement to zirconia surfaces that were previously air-abraded with aluminum oxide (Al2O3) particles at different pressures. MATERIALS AND METHODS: Seventy-two cuboid zirconia specimens were prepared and randomly assigned to 3 groups according to the air-abrasion pressures (1, 2, and 2.8 bar), and each group was further divided into 2 groups depending on aging parameters (n = 12). Panavia F 2.0 was placed on pre-conditioned zirconia surfaces, and SBS testing was performed either after 24 hours or 10,000 fatigue cycles (cyclic loading) and 5,000 thermocycles. Non-contact profilometry was used to measure surface roughness. Failure modes were evaluated under optical and scanning electron microscopy. The data were analyzed using 2-way analysis of variance and chi2 tests (alpha = 0.05). RESULTS: The 2.8 bar group showed significantly higher surface roughness compared to the 1 bar group (p < 0.05). The interaction between pressure and time/cycling was not significant on SBS, and pressure did not have a significant effect either. SBS was significantly higher (p = 0.006) for 24 hours storage compared to CLTC. The 2 bar-CLTC group presented significantly higher percentage of pre-test failure during fatigue compared to the other groups. Mixed-failure mode was more frequent than adhesive failure. CONCLUSIONS: CLTC significantly decreased the SBS values regardless of the air-abrasion pressure used. PMID- 28808638 TI - Effect of surface treatment on the mechanical properties of nickel-titanium files with a similar cross-section. AB - OBJECTIVES: The aim of this study was to compare the mechanical properties of various nickel-titanium (NiTi) files with similar tapers and cross-sectional areas depending on whether they were surface-treated. MATERIALS AND METHODS: Three NiTi file systems with a similar convex triangular cross-section and the same ISO #25 tip size were selected for this study: G6 (G6), ProTaper Universal (PTU), and Dia-PT (DPT). To test torsional resistance, 5 mm of the straightened file's tip was fixed between polycarbonate blocks (n = 15/group) and continuous clockwise rotation until fracture was conducted using a customized device. To evaluate cyclic fatigue resistance, files were rotated in an artificial curved canal until fracture in a dynamic mode (n = 15/group). The torsional data were analyzed using 1-way analysis of variance and the Tukey post-hoc comparison test, while the cyclic fatigue data were analyzed using the Mann-Whitney U test at a significance level of 95%. RESULTS: PTU showed significantly greater toughness, followed by DPT and G6 (p < 0.05). G6 showed the lowest resistance in ultimate torsional strength, while it showed a higher fracture angle than the other files (p < 0.05). In the cyclic fatigue test, DPT showed a significantly higher number of cycles to failure than PTU or G6 (p < 0.05). CONCLUSIONS: Within the limitations of this study, it can be concluded that the torsional resistance of NiTi files was affected by the cross-sectional area, while the cyclic fatigue resistance of NiTi files was influenced by the surface treatment. PMID- 28808639 TI - Comparison of cyclic fatigue life of nickel-titanium files: an examination using high-speed camera. AB - OBJECTIVES: To determine the actual revolutions per minute (rpm) values and compare the cyclic fatigue life of Reciproc (RPC, VDW GmbH), WaveOne (WO, Dentsply Maillefer), and TF Adaptive (TFA, Axis/SybronEndo) nickel-titanium (NiTi) file systems using high-speed camera. MATERIALS AND METHODS: Twenty RPC R25 (25/0.08), 20 WO Primary (25/0.08), and 20 TFA ML 1 (25/0.08) files were employed in the present study. The cyclic fatigue tests were performed using a dynamic cyclic fatigue testing device, which has an artificial stainless steel canal with a 60 degrees angle of curvature and a 5-mm radius of curvature. The files were divided into 3 groups (group 1, RPC R25 [RPC]; group 2, WO Primary [WO]; group 3, TF Adaptive ML 1 [TFA]). All the instruments were rotated until fracture during the cyclic fatigue test and slow-motion videos were captured using high-speed camera. The number of cycles to failure (NCF) was calculated. The data were analyzed statistically using one-way analysis of variance (ANOVA, p < 0.05). RESULTS: The slow-motion videos were indicated that rpm values of the RPC, WO, and TFA groups were 180, 210, and 425, respectively. RPC (3,464.45 +/- 487.58) and WO (3,257.63 +/- 556.39) groups had significantly longer cyclic fatigue life compared with TFA (1,634.46 +/- 300.03) group (p < 0.05). There was no significant difference in the mean length of the fractured fragments. CONCLUSIONS: Within the limitation of the present study, RPC and WO NiTi files showed significantly longer cyclic fatigue life than TFA NiTi file. PMID- 28808640 TI - Light-emitting diode assessment of dentinal defects: the role of presumed extraction forces. AB - OBJECTIVES: The evaluation of iatrogenic dentinal defects in extracted teeth may be influenced by extraction forces and prolonged dry times. The purpose of this study was to compare the presence of dentinal defects in freshly extracted, periodontally compromised teeth with those in a group of teeth with uncontrolled extraction forces and storage time. MATERIALS AND METHODS: The experimental group consisted of eighteen roots obtained from teeth extracted due to periodontal reasons with class II or III mobility. They were kept in saline and sectioned within 1 hour following extraction. The control group consisted of matched root types obtained from an anonymous tooth collection, consistent with previous dentinal defect studies. The slices were obtained at 3, 6, and 9 mm from the apex. The imaging process exposed all specimens to no more than 60 seconds of dry time. The * 12.8 magnification was used for the 9 mm slices and * 19.2 magnification for the 3 mm and 6 mm slices under light-emitting diode (LED) transillumination. The root canal spaces and periodontal tissues were masked to minimize extraneous factors that might influence the evaluators. Chi-square test was used for statistical analysis. RESULTS: Dentinal defects were detected in 17% of the experimental group teeth, compared to 61% of control teeth (p = 0.015). CONCLUSIONS: LED transillumination assessment of freshly extracted roots with class II or III mobility showed smaller number of dentinal defects than roots with uncontrolled storage time and extraction forces. The use of freshly extracted roots with mobility should be considered for future dental defect assessment studies. PMID- 28808641 TI - Management of large class II lesions in molars: how to restore and when to perform surgical crown lengthening? AB - The restoration of endodontic tooth is always a challenge for the clinician, not only due to excessive loss of tooth structure but also invasion of the biological width due to large decayed lesions. In this paper, the 7 most common clinical scenarios in molars with class II lesions ever deeper were examined. This includes both the type of restoration (direct or indirect) and the management of the cavity margin, such as the need for deep margin elevation (DME) or crown lengthening. It is necessary to have the DME when the healthy tooth remnant is in the sulcus or at the epithelium level. For caries that reaches the connective tissue or the bone crest, crown lengthening is required. Endocrowns are a good treatment option in the endodontically treated tooth when the loss of structure is advanced. PMID- 28808642 TI - Burden of disease attributable to vitamin A deficiency in Iranian population aged less than five years: findings from the global burden of disease study 2010. AB - BACKGROUND: Vitamin A deficiency (VAD) is considered as one of the most serious public health concerns in developing countriesand the leading cause of mortality in under-five-year-old children.A large number of young children and pregnant women especially in low-income, non-industrialized communities are more susceptible to VAD. This study aims to report the burden of disease (BOD) attributable to VAD in Iranian population aged less than 5 years by using data of the Global Burden of Disease (GBD) study 2010. METHODS: The GBD 2010 study calculated the proportion of deaths, years of life lost (YLLs), and years lived with disability (YLDs) and disability-adjusted life years (DALYs) attributable to VAD by using the comparative risk assessment (CRA). VAD defined as low serum retinol concentrations (plasma retinol concentration < 0.70 umole/L) among children aged less than five. The VAD outcomes consisted of mortality due to diarrhea, measles, malaria, neglected infectious diseases, morbidity due to malaria (children < 5 years), low birth weight and other perinatal conditions. Uncertainty in the estimates is presented as 95% uncertainty interval (UI). RESULTS: In 1990, there were 371 (95% UI: 166,665) DALYs due to VAD per 100,000 under five-year-old Iranian children in both sexes. The DALYs rate had a downward trend throughout the following years and reached to 76 (95% UI: 33-139)in 2010.The DALYs in children aged under 5 years was 378 (95% UI: 153-747) years for boys and 363 (95% UI: 148-692) years for girls in 1990 which fell to 79 (95% UI: 32-149) and 73 (95% UI: 29-138) in boys and girls in 2010, respectively. The rates of YLDs attributable to VAD changed in both sexes from 87(95% UI: 34-162) in 1990 to 46 (95% UI: 17-69) in 2010. The highest rate of YLDs attributed to VAD was observed in children aged 1-4. On the other hand, the YLLs were mostly in the 0-1-year-oldchildren in all years except 2010. CONCLUSION: It was found that DALYs attributable to VAD in 1990, followed by a considerable reduction rate after a period of two decades, in 2010. Additional studies on the burden of diseases particularly at sub-national level with more accurate data are recommended. PMID- 28808643 TI - Polymorphism (rs16917496) at the miR-502 Binding Site of the Lysine Methyltransferase 5A (SET8) and Its Correlation with Colorectal Cancer in Iranians. AB - BACKGROUND: One of the gene expression regulatory mechanisms is mediated by small noncoding RNAs called microRNA (miRNA). They interact with a recognition sequence located mostly in 3'-untranslated regions (3'-UTRs) of mRNAs. Polymorphisms in miRNAs recognition sequences could affect gene expression which in turn may alter disease susceptibility. SET8, a member of the SET domain-containing methyltransferase, acts in a variety of biological processes such as genomic stability. Here, we report correlation of rs16917496 polymorphism, located in the recognition sequence of miR-502 within 3'-UTR of SET8, with colorectal cancer (CRC) in Iranians. MATERIALS AND METHODS: One hundred and seventy CRC patients and 170 noncancer counterparts were recruited in this case-control study. Genotyping of rs16917496 was performed using polymerase chain reaction restriction fragment length polymorphism method. RESULTS: There was no significant association of rs16917496 with CRC in population under study (P value for genotype and allele distribution were >0.05). However, stratification analysis based on smoking status revealed that TT+TC genotypes of SET8 rs16917496 are strongly associated with increased risk of CRC (odds ratio: 5.8, 95% confidence interval: 1.37-24.34, P - 0.005) in smoker subgroup. CONCLUSION: Correlation of rs16917496 T allele with CRC in smokers is emphasizing the importance of individuals' genotype in the recruitment of adverse health hazards of smoking more profoundly for certain people compared to others. PMID- 28808644 TI - The Comparative Study of Refractive Index Variations between Haigis, Srk/T and Hoffer-Q Formulas Used for Preoperative Biometry Calculation in Patients with the Axial Length >25 mm. AB - BACKGROUND: To compare refractive index variation between Hoffer-Q, Haigis and SRK/T formulas used for preoperative biometry calculation in patients with axial length >25 mm, undergoing cataract surgery. MATERIALS AND METHODS: This is a randomized clinical trial study was performed on 54 eyes of 54 patients with ages of 40-70 years old and axial length >25 mm classified into three groups that their IOL POWER were calculated by Haigis, SRK/T and Hoffer-Q formulas before undergoing cataract surgery. Their refractive index variations were calculated from the difference between predicted refractive error formula and actual post operative refractive error formula. The collected data was entered in SPSS software and was analyzed by ANOVA and Chi-square statistical test. RESULTS: With comparison sphere, astigmatism and spherical equivalent indexes before and after of cataract surgery between Haigis, SRK/T, and Hoffer-Q formulas, statistically significant differences were found between the mean of sphere and SE indexes in patients with use of Haigis and SRK/T formulas that have been more favorable post operative refraction. CONCLUSIONS: Haigis formula and then, with slight difference, SRK/T formula have better and more acceptable post-operative refraction results than Hoffer-Q formula in patients with high axial myopia. Therefore, it is recommended using Haigis and SRK/T formulas for IOL power calculation in patients with high axial myopia undergoing cataract surgery. PMID- 28808645 TI - Effect of Vitamin D Supplementation on the Incidence of Gestational Diabetes. AB - BACKGROUND: The aim of this study was survey of the effect of Vitamin D supplementation on the incidence of gestational diabetes (GDM) in pregnant women. MATERIALS AND METHODS: This randomized clinical trial was conducted at Alzahra and Shahid Beheshti Hospital in Isfahan, Iran, from January, 2013 to January, 2014 on 210 pregnant women referred to gynecology clinics. Serum levels of Vitamin D were measured, and those with lower serum levels of 10 nmol/L randomly divided into two groups of A and B. Pregnant women with normal Vitamin D level assigned as Group C. Group A was given 50,000 IU Vitamin D supplement every 2 weeks for 10 weeks, and Group B were given the omega-3 pearl as placebo. Then, the incidence of GDM was measured in 24-26 weeks of pregnancy with glucose tolerance test and compared in three groups. Data were analyzed using SPSS version 20 by descriptive statistics, Chi-square and Logistic regression. RESULTS: The mean age of participants was 24.76 years (8.02 standard deviation, range 16-36 years). The incidence of GDM at 24-26 weeks gestational age were 8.57% in normal Vitamin D group, 10.00% in Vitamin D deficiency with treatment group, and 11.43% in Vitamin D deficiency without treatment group. The difference between groups in terms of incidence of GDM was not statistically significant (P = 0.112). CONCLUSION: Vitamin D supplementation had not effect on incidence of GDM during pregnancy. PMID- 28808646 TI - Application of Epstein-Barr Virus for Optimization of Immortalized B-lymphocyte Production as a Positive Control in Genetic Studies. AB - BACKGROUND: Infection of B-cells with Epstein-Barr virus (EBV) leads to more and subsequent immortalization. This is considered as the method of choice for generating lymphoblastoid cell lines (LCLs). Producing LCLs, although very useful but is very time consuming and troublesome, drives the requirement for quicker and more reliable methods for EBV-driven B-cell transformation. MATERIALS AND METHODS: After successfully production of LCLs, different parameters including temperature, serum concentration, type of culture medium, and CO2 concentration were evaluated on EBV-transformed B-cells. In this study, we were able to produce LCLs and optimize condition. RESULTS: The best condition for generating LCLs was 37 degrees C, 5% CO2, 20% fasting blood sugar, and RPMI 1640. The study results were to establish a reliable method for producing LCLs that can be used to produce immortalized B-cells from almost any sources. CONCLUSION: This can help with tumorgenecity studies, as well as producing control material for rare genetic disorders and so on. The aim of this study was to determine optimized condition for reliable and reproducible LCLs from different sources. PMID- 28808647 TI - The Relationship between the Time of Endoscopy and Morbidity and Mortality Rates in Patients with Upper Gastrointestinal Bleeding. AB - BACKGROUND: This study was done to evaluate the relationship between the time of endoscopy in patients with upper gastrointestinal bleeding with morbidity and mortality rates of patients at the Al Zahra Hospital emergency room. MATERIALS AND METHODS: In a cohort study, 1152 patients at 2014 and 2015 have been hospitalized due to gastrointestinal bleeding in Al Zahra Hospital, were selected and demographic and clinical information and day and time of endoscopy and hospital mortality and fewer deaths than a month after discharge were studied, and prognosis was analyzed in terms of day and time of endoscopy. RESULTS: Nine hundred and seventy-three cases (84.5%) of endoscopy were performed during the working days and 179 (15.5%) were performed on holidays. Moreover, 801 cases (69.5%) of endoscopy were done in the morning and 351 cases (30.5%) were performed in the evening and night shifts. The day and time of endoscopy had no significant effect on mortality in hospital and less than a month after but hospital death in whom underwent endoscopy by fellowship was significantly higher (P = 0.004). CONCLUSION: Endoscopy in nonholiday and holiday days and the time of endoscopy has no significant effect on hospital mortality 1 month after discharge. However, other factors such as endoscopy by attendant or fellowship, time between admission to endoscopy, age and sex of the patients, etc., were significantly effective on in-hospital mortality and death 1 months after discharge. Also faster and sooner endoscopy cannot reduce rate of blood transfusions or reduce the length of hospital stay but faster endoscopy of patients can reduce the risk of in-hospital death. PMID- 28808648 TI - Traumatic Arteriovenous Malformation of the Superficial Temporal Artery. AB - Most of the vascular lesions on head and neck soft tissue are congenital, but a rare cause can be trauma. A 23-year-old man came to our clinic with a wide pulsatile tortuous mass in the left temporofrontal area. That mass was appeared since 10 years ago. Ten years before his coming to our clinic, he had a blunt trauma in that area. After that, a small wound appeared there and healed gradually. In clinical examination, mass was large and pulsatile, and a fine murmur was detected from it. In paraclinical examination, computed tomography scan with intravenous contrast and sonography revealed a vascular mass with arteriovenous (AV) fistula in soft tissue only in that area. We operated him and vascular mass completely excised without recurrency. Pathologic report was AV malformation (AVM). According to our study, also rare trauma is one of the causes of AVMs, and we able to resection it completely without recurrency. PMID- 28808649 TI - The Effect of a Single dose Dantrolene in Patients with Vasospasm Following Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: Cerebral vasospasm is a prolonged, occasionally severe, but reversible narrowing of the cerebral arteries that begins 3 to 5 days after the hemorrhage becomes maximal at 14 days. This study is designed to evaluate the effect of dantrolene on the reduction of vasospasm following aneurysmal subarachnoid hemorrhage (SAH). MATERIALS AND METHODS: This randomized controlled clinical trial was conducted on 32 patients with proven aneurysms in AL-Zahra hospital during 2011-2013. They were randomly divided into two groups. In all patients, daily transcranial Doppler sonography was performed and as soon as the diagnosis of vasospasm onset in the first group, in addition to conventional treatment of vasospasm 2.5 mg/kg Dantrolene infusion within 60 minutes and while the blood pressure and heart rate of patient monitored, and arterial flow velocity changes such as PSV and MFV were measured by transcranial Doppler sonography in 45, 90 and 135 minutes. Data was analyzed by SPSS 22 and Chi square, Student t, Mann-Whitney and ANOVA tests with repeated observations. RESULTS: There was no significant difference in the site of the aneurysm in the two groups. The mean of PSV index prior to treatment and the 45th minute was not different but at 90th and 135th minutes it was significantly lower in the Dantrolene receiving group (P < 0.05). The mean of MFV index prior to intervention and in the 45th minute was not different between two groups, but at 90th and 135th minutes was significantly lower in the target group. CONCLUSION: Using dantrolene in patients with artery vasospasm significantly reduced artery spasm and increased the patient recovery. PMID- 28808650 TI - Comparison of Two Treatment Methods "One Shot" and "Sequential" on Reduction the Level of Hemoglobin in Patients with Percutaneous Nephrolithotripsy in Al Zahra Hospital in 2012-2013. AB - BACKGROUND: Access dilation is the most important part of percutaneous nephrolithotripsy (PCNL) that is done by different methods, especially metal telescoping and one shot. In this study, two different methods of access dilation one shot and telescoping were compared. MATERIALS AND METHODS: In observational cross-sectional study, 240 patients who were a candidate for PCNL were selected and randomly divided into two groups. The first group was undergone one-shot method and the second group was undergone telescoping method. The decrease in hemoglobin (Hb), duration of hospitalization and the time of radiation exposure during access dilation was compared in two groups by SPSS software version 21, (SPSS Inc., Chicago, IL, USA). RESULTS: The decrease of Hb level after intervention in one-shot group was 1.08 +/- 1.23 g/dl and in telescoping, group was 1.51 +/- 1.08 g/dl with no difference statistically (P = 0.37). The mean duration of hospitalization in one shot and telescoping group were 2.36 +/- 0.67 and 2.28 +/- 0.61 days, respectively. According to t-test, there was no significant difference between the two groups (P = 0.37). Average radiation exposure in one shot group was 7.13 s and in telescoping, group was 35.75 s, and there was a significant difference between the two groups (P < 0.001). CONCLUSION: One-shot method is superior to telescoping method due to less time for radiation exposure and no more blood loss and other complications during PCNL. PMID- 28808651 TI - Evaluation of Acute Aortic Dissection Type a Factors and Comparison the Postoperative Clinical Outcomes between Two Surgical Methods. AB - BACKGROUND: Although aortic dissection is a rare disease, it causes high level of mortality. If ascending aorta gets involved in this disease, it is known as type A. According to small number of studies about this disease in Iran, this study conducted to detect the factors related to acute aortic dissection type A, its surgery consequences and the factors affecting them. MATERIALS AND METHODS: In this historical cohort study, all patients having acute aortic dissection type A referring to Chamran Hospital from 2006 to 2012 were studied. The impact of two surgical methods including antegrade cerebral perfusion (ACP) and retrograde cerebral one (RCP) on surgical and long-term mortality and recurrence of dissection was determined. The relation of mortality rate and hemodynamic instability before surgery, age more than 70 years old, ejection fraction lower than 50%, prolonged cardiopulmonary bypass pump (CPBP) time and excessive blood transfusion, was assessed. RESULTS: Surgery and long-term mortality and recurrence of dissection were 35.3%, 30.8% and 30.4%. Surgical and long-term death in the patients being operated by ACP method was lower than those one being operated by RCP (P < 0.001). Excessive blood transfusion and unstable hemodynamic condition had significant effect on surgical mortality (P = 0.014, 0.030, respectively). CPBP time and unstable hemodynamic condition affected long-term mortality significantly (P = 0.002). CONCLUSION: The result found that ACP is the preferable kind of surgery in comparison with RCP according to the surgical and long-term mortality. PMID- 28808652 TI - Capillary versus Venous Blood Glucose in Patients with Coma. PMID- 28808653 TI - Acyl-CoA Synthetase 5 Promotes the Growth and Invasion of Colorectal Cancer Cells. AB - BACKGROUND AND AIMS: Acyl-CoA synthetase 5 (ACS5) has been reported to be associated with the development of various cancers, but the role of it in colorectal cancer (CRC) is not well understood. The present study aimed to explore the potential role of ACS5 in the development and progression of CRC. METHODS: ACS5 expression in CRC tissues and CRC cell lines was examined, and its clinical significance was analyzed. The role of ACS5 in cell proliferation, apoptosis, and invasion was examined in vitro. RESULTS: We found that ACS5 expression was upregulated in CRC cells and CRC tissues and that high ACS5 expression was more frequent in CRC patients with excess muscular layer and with poor tumor differentiation. Furthermore, knockdown of ACS5 in HT29 and SW480 cells significantly dampened cell proliferation, induced cell apoptosis, and reduced cell migration and invasion. In contrast, the ectopic overexpression of ACS5 in LOVO and SW620 cells remarkably promoted cell proliferation, inhibited cell apoptosis, and enhanced cell migration and invasion. Enhanced cell growth and invasion ability mediated by the gain of ACS5 expression were associated with downregulation of caspase-3 and E-cadherin and upregulation of survivin and CD44. CONCLUSIONS: Our data demonstrate that ACS5 can promote the growth and invasion of CRC cells and provide a potential target for CRC gene therapy. PMID- 28808654 TI - Genome-Wide Identification and Transcriptional Expression Analysis of Cucumber Superoxide Dismutase (SOD) Family in Response to Various Abiotic Stresses. AB - Superoxide dismutase (SOD) proteins are widely present in the plant kingdom and play important roles in different biological processes. However, little is known about the SOD genes in cucumber. In this study, night SOD genes were identified from cucumber (Cucumis sativus) using bioinformatics-based methods, including 5 Cu/ZnSODs, 3 FeSODs, and 1 MnSOD. Gene structure and motif analysis indicated that most of the SOD genes have relatively conserved exon/intron arrangement and motif composition. Phylogenetic analyses with SODs from cucumber and several other species revealed that these SOD proteins can be traced back to two ancestral SODs before the divergence of monocot and dicot plants. Many cis elements related to stress responses and plant hormones were found in the promoter sequence of each CsSOD gene. Gene expression analysis revealed that most of the CsSOD genes are expressed in almost all the tested tissues. qRT-PCR analysis of 8 selected CsSOD genes showed that these genes could respond to heat, cold, osmotic, and salt stresses. Our results provide a basis for further functional research on SOD gene family in cucumber and facilitate their potential applications in the genetic improvement of cucumber. PMID- 28808655 TI - Multirapid Serial Visual Presentation Framework for EEG-Based Target Detection. AB - Target image detection based on a rapid serial visual presentation (RSVP) paradigm is a typical brain-computer interface system with various applications, such as image retrieval. In an RSVP paradigm, a P300 component is detected to determine target images. This strategy requires high-precision single-trial P300 detection methods. However, the performance of single-trial detection methods is relatively lower than that of multitrial P300 detection methods. Image retrieval based on multitrial P300 is a new research direction. In this paper, we propose a triple-RSVP paradigm with three images being presented simultaneously and a target image appearing three times. Thus, multitrial P300 classification methods can be used to improve detection accuracy. In this study, these mechanisms were extended and validated, and the characteristics of the multi-RSVP framework were further explored. Two different P300 detection algorithms were also utilized in multi-RSVP to demonstrate that the scheme is universally applicable. Results revealed that the detection accuracy of the multi-RSVP paradigm was higher than that of the standard RSVP paradigm. The results validate the effectiveness of the proposed method, and this method can provide a whole new idea in the field of EEG based target detection. PMID- 28808656 TI - HOXB9 Expression Correlates with Histological Grade and Prognosis in LSCC. AB - The purpose of this study was to investigate the HOX gene expression profile in laryngeal squamous cell carcinoma (LSCC) and assess whether some genes are associated with the clinicopathological features and prognosis in LSCC patients. The HOX gene levels were tested by microarray and validated by qRT-PCR in paired cancerous and adjacent noncancerous LSCC tissue samples. The microarray testing data of 39 HOX genes revealed 15 HOX genes that were at least 2-fold upregulated and 2 that were downregulated. After qRT-PCR evaluation, the three most upregulated genes (HOXB9, HOXB13, and HOXD13) were selected for tissue microarray (TMA) analysis. The correlations between the HOXB9, HOXB13, and HOXD13 expression levels and both clinicopathological features and prognosis were analyzed. Three HOX gene expression levels were markedly increased in LSCC tissues compared with adjacent noncancerous tissues (P < 0.001). HOXB9 was found to correlate with histological grade (P < 0.01) and prognosis (P < 0.01) in LSCC. In conclusion, this study revealed that HOXB9, HOXB13, and HOXD13 were upregulated and may play important roles in LSCC. Moreover, HOXB9 may serve as a novel marker of poor prognosis and a potential therapeutic target in LSCC patients. PMID- 28808658 TI - Trends and Inequalities in Use of Maternal Health Care Services in Nepal: Strategy in the Search for Improvements. AB - BACKGROUND: Nepal has made significant progress against the Millennium Development Goals for maternal and child health over the past two decades. However, disparities in use of maternal health services persist along geographic, economic, and sociocultural lines. METHODS: Trends and inequalities in the use of maternal health services in Nepal between 1994 and 2011 were examined using four Nepal Demographic and Health Surveys (NDHS), nationally representative cross sectional surveys conducted by interviewing women who gave birth 3-5 years prior to the survey. Sociodemographic disparities in maternal health service utilization were measured. Rate difference, rate ratios, and concentration index were calculated to measure income inequalities. FINDINGS: The percentage of mothers that received four antenatal care (ANC) consultations increased from 9% to 54%, the institutional delivery rate increased from 6% to 47%, and the cesarean section (C-section) rate increased from 1% in 1994 to 6% in 2011. The ratio of the richest and the poorest quintile mothers for use of four ANC, institutional delivery, and C-section delivery were 5.08 (95% CI: 3.82-6.76), 9.00 (95% CI: 6.55-12.37), and 9.37 (95% CI: 4.22-20.83), respectively. However, inequality is reducing over time; for the use of four ANC services, the concentration index fell from 0.60 (95% CI: 0.56-0.64) in 1994-1996 to 0.31 (95% CI: 0.29-0.33) in 2009-2011. For institutional delivery, the concentration index fell from 0.65 (95% CI: 0.62-0.70) to 0.40 (95% CI: 0.38-0.40) between 1994-1996 and 2009-2011. For C-section deliveries, an increase in concentration index was observed, 0.64 (95% CI: 0.51-0.77); 0.76 (95% CI: 0.64-0.88); 0.77 (95% CI: 0.71 0.84); and 0.66 (95% CI: 0.60-0.72) in the periods 1994-1996, 1999-2001, 2004 2006, and 2009-2011, respectively. All sociodemographic variables were significant predictors of use of maternal health services, out of which maternal education was the most powerful. CONCLUSION: To increase equitable use of maternal health services in Nepal there is a need to strengthen the health system to increase access to and utilization of services among poorer women, those with less education, and those living in remote areas. Beyond the health sector stronger efforts are needed to tackle the root causes of health inequality, reduce poverty, increase female education, eradicate caste/ethnicity based social discrimination, and invest in the development of remote areas. PMID- 28808657 TI - Nanoparticulate Tubular Immunostimulating Complexes: Novel Formulation of Effective Adjuvants and Antigen Delivery Systems. AB - New generation vaccines, based on isolated antigens, are safer than traditional ones, comprising the whole pathogen. However, major part of purified antigens has weak immunogenicity. Therefore, elaboration of new adjuvants, more effective and safe, is an urgent problem of vaccinology. Tubular immunostimulating complexes (TI-complexes) are a new type of nanoparticulate antigen delivery systems with adjuvant activity. TI-complexes consist of cholesterol and compounds isolated from marine hydrobionts: cucumarioside A2-2 (CDA) from Cucumaria japonica and monogalactosyldiacylglycerol (MGDG) from marine algae or seagrass. These components were selected due to immunomodulatory and other biological activities. Glycolipid MGDG from marine macrophytes comprises a high level of polyunsaturated fatty acids (PUFAs), which demonstrate immunomodulatory properties. CDA is a well characterized individual compound capable of forming stable complex with cholesterol. Such complexes do not possess hemolytic activity. Ultralow doses of cucumariosides stimulate cell as well as humoral immunity. Therefore, TI complexes comprising biologically active components turned out to be more effective than the strongest adjuvants: immunostimulating complexes (ISCOMs) and complete Freund's adjuvant. In the present review, we discuss results published in series of our articles on elaboration, qualitative and quantitative composition, ultrastructure, and immunostimulating activity of TI-complexes. The review allows immersion in the history of creating TI-complexes. PMID- 28808659 TI - Functional Profile Evaluation of Lactobacillus fermentum TCUESC01: A New Potential Probiotic Strain Isolated during Cocoa Fermentation. AB - The use of intestinal probiotic bacteria is very common in the food industry and has been the focus of the majority of research in this field. Yet in recent years, research on extraintestinal microorganisms has greatly increased due to their well-known potential as probiotics. Thus, we studied a strain of Lactobacillus fermentum (TCUESC01) extracted from fermenting cocoa. First, we examined the impact of pH on the growth of this strain and studied its survival under conditions similar to those of the human gastrointestinal tract. L. fermentum TCUESC01 demonstrated resistance to conditions mimicking the human stomach and intestines and grew well between pH 5 and pH 7. Next, we subjected L. fermentum TCUESC01 to storage at 4 degrees C in a milk solution and found that it survived well for 28 days. Lastly, we measured the susceptibility of this strain to numerous antibiotics and its tendency to autoaggregate. L. fermentum TCUESC01 showed significant autoaggregation, as well as susceptibility to the majority of antibiotics tested. Overall, our findings support the potential use of this extraintestinal bacterium as a dietary probiotic. PMID- 28808660 TI - Corrigendum to "Intraoperative Contrast Enhanced Ultrasound Evaluates the Grade of Glioma". AB - [This corrects the article DOI: 10.1155/2016/2643862.]. PMID- 28808661 TI - The Role of Intereukin-31 in Pathogenesis of Itch and Its Intensity in a Course of Bullous Pemphigoid and Dermatitis Herpetiformis. AB - Itch which is one of the major, subjective symptoms in a course of bullous pemphigoid and dermatitis herpetiformis makes those two diseases totally different than other autoimmune blistering diseases. Its pathogenesis is still not fully known. The aim of this research was to assess the role of IL-31 in development of itch as well as to measure its intensity. Obtained results, as well as literature data, show that lower concentration of IL-31 in patients' serum may be correlated with its role in JAK/STAT signaling pathway which is involved in development of autoimmune blistering disease. Intensity of itch is surprisingly huge problem for the patients and the obtained results are comparable with results presented by atopic patients. PMID- 28808662 TI - The Status of Maculopathy in Diabetes and Prediabetes Patients in a Population Based Study Detected by Optical Coherence Tomography: The 2011 Health Examination Survey in Beijing. AB - OBJECTIVE: The aim of the study was to investigate the prevalence and the risk factors of maculopathy detected by optical coherence tomography (OCT) in a Chinese population with diabetes or prediabetes. Methods. 8,155 people were randomly selected to participate in the 2011 annual Health Examination Survey in Beijing. A 75 g oral glucose tolerance test (OGTT) was tested in 3760 subjects with fasting plasma glucose (FPG) >= 5.6 mmol/L. Of 3,760 subjects, 583 were also randomly selected to take OCT. RESULTS: In this study population, 21 (3.95%) patients had maculopathy. Eight patients had diabetes macular edema (DME) and the prevalence was 6.72% in diabetes patients and 1.51% in all subjects. Eleven patients had age-related macular degeneration (AMD) and the prevalence was 3.36% in diabetes patients and 2.07% in all subjects. Logistic regression model confirmed that elevated HbA1c (p < 0.001) and systolic pressure (p < 0.05) made significant contributions to DME. Stepwise regression analysis revealed that HbA1c and blood creatinine were significantly independent influence factors for central subfield thickness (CST) (p = 0.01, p < 0.001). CONCLUSIONS: High prevalence of maculopathy was found in patients with diabetes in a Chinese population. Maculopathy poses a significant public health problem in China with rapid rising trend of diabetes. PMID- 28808663 TI - Effect of Pregnancy on Quantitative Medication Use and Relation to Exacerbations in Asthma. AB - BACKGROUND: The quantification of asthma medication reduction and its relation to an aggravation of asthma during pregnancy at an individual level are unclear. METHODS: We conducted a nationwide retrospective cohort study of asthmatic pregnant women in South Korea. All of the asthma medications were ranked from 1 to 4 according to the guideline-based stepwise approach. We assessed the daily sums of the ranks of the asthma medications and their association with exacerbations during three phases based on the individual's delivery date: before, during, and after pregnancy. RESULTS: The study cohort included 115,169 asthmatic pregnant women who gave birth between 2011 and 2013. The subjects were clustered into four groups according to the daily rank sums of their asthma medication. Asthma medications were rapidly reduced at the beginning of the pregnancy and then slowly increased after delivery. Exacerbations were more frequent in the group with higher rank-sum values than in the group with lower values. Overall exacerbations were reduced during pregnancy compared to before or after delivery. CONCLUSIONS: Asthmatic pregnant women tended to reduce their asthma medication use during pregnancy. This led to a greater number of exacerbations in a small part of the study population. PMID- 28808664 TI - Expression of Telomere Repeat Binding Factor 1 and TRF2 in Prostate Cancer and Correlation with Clinical Parameters. AB - OBJECTIVE: The objective of this study was to investigate the expression of telomere repeat binding factor 1 (TRF1) and TRF2 in prostate cancer and their relationships with clinicopathological features. METHODS: In total 50 prostate cancer tissues and paired benign prostate hyperplasia tissues were analyzed. The telomere-binding proteins TRF1 and TRF2 were measured using immunohistochemical method. Correlation analyses were used to evaluate the association between immunohistochemical score and clinical parameters. RESULTS: The expression of TRF1 was significantly higher in prostate cancer tissue than in benign prostate hyperplasia tissue (chi2 = 62.69, P < 0.01). Elevated levels of TRF2 were observed in both prostate cancer and benign prostate hyperplasia tissue (chi2 = 1.13, P = 0.76). TRF1 expression was significantly positively correlated with surgical capsular invasion (Spearman's r = 0.43, P = 0.002), seminal vesicle invasion (Spearman's r = 0.35, P = 0.01), lymph nodes metastases (Spearman's r = 0.41, P = 0.003), total prostate specific antigen (r = 0.61, P < 0.05), and Gleason score (r = 0.47, P = 0.01). However, there were no significant statistical differences between prostate volume (r = 0.06, P = 0.75) and age (r = 0.14, P = 0.09). CONCLUSION: Both TRF1 and TRF2 were overexpressed in prostate cancer. There was no specificity of TRF2 in prostate cancer, while TRF1 may be associated with prostate cancer progression. PMID- 28808667 TI - Process Information and Evolution. AB - Universal Semantic Communication (USC) is a theory that models communication among agents without the assumption of a fixed protocol. We demonstrate a connection, via a concept we refer to as process information, between a special case of USC and evolutionary processes. In this context, one agent attempts to interpret a potentially arbitrary signal produced within its environment. Sources of this effective signal can be modeled as a single alternative agent. Given a set of common underlying concepts that may be symbolized differently by different sources in the environment, any given entity must be able to correlate intrinsic information with input it receives from the environment in order to accurately interpret the ambient signal and ultimately coordinate its own actions. This scenario encapsulates a class of USC problems that provides insight into the semantic aspect of a model of evolution proposed by Rivoire and Leibler. Through this connection, we show that evolution corresponds to a means of solving a special class of USC problems, can be viewed as a special case of the Multiplicative Weights Updates algorithm, and that infinite population selection with no mutation and no recombination conforms to the Rivoire-Leibler model. Finally, using process information we show that evolving populations implicitly internalize semantic information about their respective environments. PMID- 28808666 TI - Lipidomic Evaluation of Feline Neurologic Disease after AAV Gene Therapy. AB - GM1 gangliosidosis is a fatal lysosomal disorder, for which there is no effective treatment. Adeno-associated virus (AAV) gene therapy in GM1 cats has resulted in a greater than 6-fold increase in lifespan, with many cats remaining alive at >5.7 years of age, with minimal clinical signs. Glycolipids are the principal storage product in GM1 gangliosidosis whose pathogenic mechanism is not completely understood. Targeted lipidomics analysis was performed to better define disease mechanisms and identify markers of disease progression for upcoming clinical trials in humans. 36 sphingolipids and subspecies associated with ganglioside biosynthesis were tested in the cerebrospinal fluid of untreated GM1 cats at a humane endpoint (~8 months), AAV-treated GM1 cats (~5 years old), and normal adult controls. In untreated GM1 cats, significant alterations were noted in 16 sphingolipid species, including gangliosides (GM1 and GM3), lactosylceramides, ceramides, sphingomyelins, monohexosylceramides, and sulfatides. Variable degrees of correction in many lipid metabolites reflected the efficacy of AAV gene therapy. Sphingolipid levels were highly predictive of neurologic disease progression, with 11 metabolites having a coefficient of determination (R2) > 0.75. Also, a specific detergent additive significantly increased the recovery of certain lipid species in cerebrospinal fluid samples. This report demonstrates the methodology and utility of targeted lipidomics to examine the pathophysiology of lipid storage disorders. PMID- 28808665 TI - HLA Class II Allele, Haplotype, and Genotype Associations with Type 1 Diabetes in Benin: A Pilot Study. AB - BACKGROUND: Several studies have reported the implication of HLA-DR/DQ loci in the susceptibility to type 1 diabetes (T1D). Since no such study has yet been performed in Benin, this pilot one aimed at assessing HLA class II allele, haplotype, and genotype associations with T1D. MATERIAL AND METHODS: Class II HLA genotyping was performed in 51 patients with T1D and 51 healthy unrelated controls by means of the PCR-SSP method. The diagnosis of T1D was set up according to American Diabetes Association criteria. Odds ratio (OR) and its 95% confidence interval (95% CI) were calculated to assess the associations between T1D and HLA alleles, haplotypes, and genotypes. RESULTS: Participants were aged 1 24 years. T1D was significantly associated with DR3, DQA1*05:01, DQB1*02:01, and DR3-DR4. No significant associations were observed with DR4, DQB1*03:02, and DQB1*06:02. CONCLUSION: Certain HLA class II alleles, haplotypes, and genotypes were related to T1D and may be used as genetic susceptibility markers to T1D in Benin. PMID- 28808668 TI - Physician Preferences for Aggressive Treatment at the End of Life and Area-Level Health Care Spending: The Johns Hopkins Precursors Study. AB - Objective: To determine whether physician preferences for end-of-life care were associated with variation in health care spending. Method: We studied 737 physicians who completed the life-sustaining treatment questionnaire in 1999 and were linked to end-of-life care data for the years 1999 to 2009 from Medicare eligible beneficiaries from the Dartmouth Atlas of Health Care (in hospital related regions [HRRs]). Using latent class analysis to group physician preferences for end-of-life treatment into most, intermediate, and least aggressive categories, we examined how physician preferences were associated with health care spending over a 7-year period. Results: When all HRRs in the nation were arrayed in quartiles by spending, the prevalence of study physicians who preferred aggressive end-of-life care was greater in the highest spending HRRs. The mean area-level intensive care unit charges per patient were estimated to be US$1,595 higher in the last 6 months of life and US$657 higher during the hospitalization in which death occurred for physicians who preferred the most aggressive treatment at the end of life, when compared with average spending. Conclusions: Physician preference for aggressive end-of-life care was correlated with area-level spending in the last 6 months of life. Policy measures intended to minimize geographic variation in health care spending should incorporate physician preferences and style. PMID- 28808669 TI - Factors Contributing to Unexpected Retirement and Unemployment in Adults Over 50 Years Old in Ireland. AB - Older adults are increasingly important to maintaining stable workforces. As such, factors contributing to early workforce exit must be identified. This study aimed to identify predictors of unexpected retirement and unemployment at older age, with respect to psychological constructs, resulting adverse behaviors, and health-related factors reflecting functional status. Data were extracted from The Irish Longitudinal Study on Ageing (TILDA) to predict unexpected retirement and unemployment in older adults in Ireland. Increasing age, increasing number of impairments in activities of daily living, and frailty status of "pre frail/frail" (relative to non-frail) increased the likelihood of unexpected retirement; while greater numbers of physical limitations and "pre-frail/frail" status significantly predicted unemployment at older age. Pre-frail/frail status or reduced physical capability for everyday tasks may adversely affect older individuals' ability to obtain and/or maintain employment. These findings advance the current understanding of factors associated with unexpected retirement and unemployment at older ages. Findings may aid in identifying strategies to extend working life and to aid at-risk older adults, and may inform components of care on which to focus to minimize loss of function and mobility, and maintain independence, with aging. PMID- 28808670 TI - Utilization and predictors of expectant management among elderly men with low-and intermediate-risk localized prostate cancer in U.S. urological practice. AB - INTRODUCTION: Expectant management (EM) reduces overtreatment in low-risk but not intermediate-risk localized prostate cancer (PCa). We assessed the use and predictors of EM to understand its uptake in U.S. practice. METHODS: Using the U.S. SEER-Medicare database, we conducted a retrospective cohort study of men 66 years and older diagnosed with low-risk (N=25,506) or intermediate-risk (N=25,597) localized PCa between 2004 - 2011 and followed through December 31, 2012. We defined EM as no definitive therapy (DT) and at least one prostate specific antigen (PSA) test or re-biopsy 4 - 12 months post diagnosis; or receiving DT after PSA testing or re-biopsy 7 - 12 months after diagnosis. We performed separate analyses for low-risk and intermediate-risk groups using multiple logistic regressions. RESULTS: For men diagnosed with PCa in 2004-2011, EM increased from 22% to 43% in the low-risk group and from 15% to 18% in the intermediate-risk group. In the low-risk group, EM increased with patients' age (adjusted odds ratio [aOR] = 1.26 for 71-75 years; 2.21 for 76-80 years; 6.33 for older then 80, p<0.0001, compared to 66-70 years). EM uptake was higher among men with comorbidities (aOR=1.29), and residing in the Pacific region (aOR=0.56, compared to the East Coast). CONCLUSIONS: In U.S. practice, the utilization of EM steadily increased in low-risk PCa and remained low in the intermediate-risk group over time. While patients with advanced age or comorbidities were more likely to receive EM, its use varied substantially by geographic region. Our findings bring attention to the presence of multiple barriers for EM implementation. PMID- 28808672 TI - Data for the physical and mechanical properties of staple fibers cement paste composites. AB - The data presented herein are compiled of the research summary of "Staple-wire reinforced high-volume fly-ash cement paste composites" (Aydin, in preparation) [1]. This data article provides general information about the novel high volume fly ash cement paste composites composed of various volume of staple wires. The dataset here also helps the readers to understand the mechanisms of staple wires on physical and mechanical properties of pure cement paste composites. PMID- 28808671 TI - Survey data of intra-household decision making and smallholder agricultural production in Northern Uganda and Southern Tanzania. AB - This article provides a description of intra-household survey data that were collected in Uganda and Tanzania in 2014 and 2015, respectively. The surveys were implemented using a structured questionnaire administered among 585 households in Uganda and 608 in Tanzania. Information on decision making processes in agricultural production was collected from the principal adult male and female decision-makers in each household. The survey consisted of two parts. Firstly, the decision-makers, both male and female of each household were jointly interviewed. Secondly, individual interviews were carried out, questioning the decision-makers separately. The datasets include both household and individual level data containing numeric, categorical and string variables. The datasets have been shared publicly on the Harvard dataverse. PMID- 28808673 TI - Data on the impact of the blood sample collection methods on blood protein profiling studies. AB - Complete blood protein profiles of 4 different blood sample collection methods (EDTA-, heparin- and citrate plasma and serum) were investigated and the data presented herein is an extension of the research article in Ilies et al. [1]. Specimens were depleted of 6 highly abundant proteins and protein profiling was assessed by nano-LC UDMSE. Exhaustive protein sets and protein abundances before and after depletion are presented in tables and figures. Also, the core protein set and the unique proteins for each sample collection method previously described [1] are disclosed. PMID- 28808674 TI - In-situ Generated Tribomaterial in Metal/Metal Contacts: current understanding and future implications for implants. AB - Artificial hip joints operate in aqueous biofluids that are highly reactive towards metallic surfaces. The reactivity at the metal interface is enhanced by mechanical interaction due to friction, which can change the near-surface structure of the metal and surface chemistry. There are now several reports in the literature about the in-situ generation of reaction films and tribo metallurgical transformations on metal-on-metal hip joints. This paper summarizes current knowledge and provides a mechanistic interpretation of the surface chemical and metallurgical phenomena. Basic concepts of corrosion and wear are illustrated and used to interpret available literature on in-vitro and in-vivo studies of metal-on-metal hip joints. Based on this review, three forms of tribomaterial, characterized by different combinations of oxide films and organic layers, can be determined. It is shown that the generation of these tribofilms can be related to specific electrochemical and mechanical phenomena in the metal interface. It is suggested that the generation of this surface reaction layer constitutes a way to minimize (mechanical) wear of MoM hip implants. PMID- 28808675 TI - Acute Appendicitis in Pregnancy and the Developing World. AB - BACKGROUND: Acute appendicitis is the commonest nonobstetric surgical emergency during pregnancy. The aim of the study was to compare perioperative outcomes of acute appendicitis in pregnant and nonpregnant patients. METHODS: A retrospective review of medical records of 56 pregnant patients between 2011 and 2016 who were compared with 164 nonpregnant women of reproductive age who underwent open appendectomy between 2014 and 2016 for acute appendicitis. The patient's demographics and perioperative data were analyzed. RESULTS: The median age of pregnant and nonpregnant patients observed was 26 years (range 19-37) and 26 years (range 18-43). There were no significant differences between the groups in negative appendectomy (21.4 and 21.3%, P = 0.52), perforated appendicitis (25 and 23.8%, P = 0.85), postoperative complications (28.6 and 26.8%, P = 0.80), and median length of hospital stay (5 and 4.5 days, P = 0.36). There were 3.6% preterm labour, no maternal mortality, and no fetal loss. In multivariate analysis, WBC >18000/mm3 and long patient time to surgery were independent risk factors for appendicular perforation and postoperative complication (P < 0.05). CONCLUSION: Our results of appendectomy in pregnant patients are comparable with nonpregnant patients. Hence the same perioperative treatment protocol can be followed in pregnant and nonpregnant patients even in resource-poor setting. PMID- 28808677 TI - Correction: McMurray et al., Brain Stimulation Reward Supports More Consistent and Accurate Rodent Decision-Making than Food Reward (eNeuro March/April 2017, 4(2) e0015-17.2017 1-13 http://dx.doi.org/10.1523/ENEURO.0015-17.2017). AB - [This corrects the article DOI: 10.1523/ENEURO.0015-17.2017.][This corrects the article DOI: 10.1523/ENEURO.0015-17.2017.]. PMID- 28808676 TI - Efficacy and Safety of Doubly-Regulated Vaccinia Virus in a Mouse Xenograft Model of Multiple Myeloma. AB - Multiple myeloma is a malignancy of plasma cells of the bone marrow. Although the prognosis is variable, no curative therapy has been defined. Vaccinia virus infects cancer cells and kills such cells in a variety of ways. These include direct infection, triggering of immunomediated cell death, and vascular collapse. The potential of the vaccinia virus as an anti-tumor therapy has attracted the attention of oncologists. Interestingly, our preliminary experiments revealed that myeloma cells were particularly susceptible to vaccinia virus. To exploit this susceptibility and to render vaccinia more myeloma specific, we generated thymidine-kinase-deleted microRNA (miRNA)-regulated vaccinia viruses in which the essential viral gene B5R was regulated by miRNAs of normal human cells. Of the miRNAs examined, let-7a was found to be the most reliable in terms of regulating viral transmission. Exposure to unregulated vaccinia virus killed myeloma transplanted severe combined immunodeficiency (SCID) mice; the animals succumbed to viral toxicity. In contrast, the thymidine-kinase-deleted let-7a-regulated virus remained localized within myeloma cells, triggering tumor regression and improving overall survival. In conclusion, a thymidine-kinase-deleted let-7a regulated vaccinia virus was safe and effective for mice, warranting clinical trials in humans. PMID- 28808678 TI - Interest in STEM is contagious for students in biology, chemistry, and physics classes. AB - We report on a study of the effect of peers' interest in high school biology, chemistry, and physics classes on students' STEM (science, technology, engineering, and mathematics)-related career intentions and course achievement. We define an interest quorum as a science class where students perceive a high level of interest for the subject matter from their classmates. We hypothesized that students who experience such an interest quorum are more likely to choose STEM careers. Using data from a national survey study of students' experiences in high school science, we compared the effect of five levels of peer interest reported in biology, chemistry, and physics courses on students' STEM career intentions. The results support our hypothesis, showing a strong, positive effect of an interest quorum even after controlling for differences between students that pose competing hypotheses such as previous STEM career interest, academic achievement, family support for mathematics and science, and gender. Smaller positive effects of interest quorums were observed for course performance in some cases, with no detrimental effects observed across the study. Last, significant effects persisted even after controlling for differences in teaching quality. This work emphasizes the likely importance of interest quorums for creating classroom environments that increase students' intentions toward STEM careers while enhancing or maintaining course performance. PMID- 28808679 TI - A two-billion-year history for the lunar dynamo. AB - Magnetic studies of lunar rocks indicate that the Moon generated a core dynamo with surface field intensities of ~20 to 110 MUT between at least 4.25 and 3.56 billion years ago (Ga). The field subsequently declined to <~4 MUT by 3.19 Ga, but it has been unclear whether the dynamo had terminated by this time or just greatly weakened in intensity. We present analyses that demonstrate that the melt glass matrix of a young regolith breccia was magnetized in a ~5 +/- 2 MUT dynamo field at ~1 to ~2.5 Ga. These data extend the known lifetime of the lunar dynamo by at least 1 billion years. Such a protracted history requires an extraordinarily long-lived power source like core crystallization or precession. No single dynamo mechanism proposed thus far can explain the strong fields inferred for the period before 3.56 Ga while also allowing the dynamo to persist in such a weakened state beyond ~2.5 Ga. Therefore, our results suggest that the dynamo was powered by at least two distinct mechanisms operating during early and late lunar history. PMID- 28808681 TI - Comment on "How will induced seismicity in Oklahoma respond to decreased saltwater injection rates?" by C. Langenbruch and M. D. Zoback. AB - The state of Oklahoma has experienced an unprecedented increase in earthquake activity since 2009, likely driven by large-scale wastewater injection operations. Statewide injection rates peaked in early 2015 and steadily decreased thereafter, approximately coinciding with collapsing oil prices and regulatory action. If seismic activity is primarily driven by fluid injection, a noticeable seismogenic response to the decrease in injection rates is expected. Langenbruch and Zoback suggest that "the probability of potentially damaging larger events, should significantly decrease by the end of 2016 and approach historic levels within a few years." We agree that the rate of small earthquakes has decreased toward the second half of 2016. However, their specific predictions about seismic hazard require reexamination. We test the influence of the model parameters of Langenbruch and Zoback based on fits to observed seismicity distributions. The results suggest that a range of realistic aftershock decay rates and b values can lead to an increase in moderate earthquake probabilities from 37 to 80% in 2017 without any further alteration to the model. In addition, the observation that all four M >= 5 earthquakes to date occurred when injection rates were below the triggering threshold of Langenbruch and Zoback challenges the applicability of the model for the most societally significant events. PMID- 28808680 TI - Early formation of planetary building blocks inferred from Pb isotopic ages of chondrules. AB - The most abundant components of primitive meteorites (chondrites) are millimeter sized glassy spherical chondrules formed by transient melting events in the solar protoplanetary disk. Using Pb-Pb dates of 22 individual chondrules, we show that primary production of chondrules in the early solar system was restricted to the first million years after the formation of the Sun and that these existing chondrules were recycled for the remaining lifetime of the protoplanetary disk. This finding is consistent with a primary chondrule formation episode during the early high-mass accretion phase of the protoplanetary disk that transitions into a longer period of chondrule reworking. An abundance of chondrules at early times provides the precursor material required to drive the efficient and rapid formation of planetary objects via chondrule accretion. PMID- 28808682 TI - Effects of population dispersal on regional signaling networks: An example from northern Iroquoia. AB - The dispersal of Iroquoian groups from St. Lawrence River valley during the 15th and 16th centuries A.D. has been a source of archaeological inquiry for decades. Social network analysis presented here indicates that sites from Jefferson County, New York at the head of the St. Lawrence River controlled interactions within regional social signaling networks during the 15th century A.D. Measures indicate that Jefferson County sites were in brokerage liaison positions between sites in New York and Ontario. In the network for the subsequent century, to which no Jefferson County sites are assigned, no single group took the place of Jefferson County in controlling network flow. The dispersal of Jefferson County populations effectively ended this brokerage function concomitant with the emergence of the nascent Huron-Wendat and Iroquois confederacies and may have contributed to the escalation of conflict between these entities. These results add to a growing literature on the use of network analyses with archaeological data and contribute new insights into processes of population relocation and geopolitical realignment, as well as the role of borderlands and frontiers in nonstate societies. PMID- 28808683 TI - In situ generation of N-unsubstituted imines from alkyl azides and their applications for imine transfer via copper catalysis. AB - Although azides have been widely used in nitrene transfer reactions, in situ generation of N-H imines from azides for downstream transformations has rarely been explored. We report copper-mediated formation of N-unsubstituted aliphatic imines from easily available aliphatic azides using a customized phenanthroline based ligand (L1*). Through trapping in situ-generated N-H imines, multisubstituted pyridines or indoles were readily synthesized. 13C-labeled azide was used as part of an isotope labeling study, which suggests that the construction of pyridine derivatives involves a three-component dehydrogenative condensation. The construction of 2,3,5-triaryl pyridines using this method provided evidence supporting a proposed pathway involving both imine formation and abnormal Chichibabin pyridine synthesis. The generation of N-unsubstituted imine intermediates was also confirmed by formation of indole derivatives from alkyl azides. PMID- 28808684 TI - Constraining the rate of oceanic deoxygenation leading up to a Cretaceous Oceanic Anoxic Event (OAE-2: ~94 Ma). AB - The rates of marine deoxygenation leading to Cretaceous Oceanic Anoxic Events are poorly recognized and constrained. If increases in primary productivity are the primary driver of these episodes, progressive oxygen loss from global waters should predate enhanced carbon burial in underlying sediments-the diagnostic Oceanic Anoxic Event relic. Thallium isotope analysis of organic-rich black shales from Demerara Rise across Oceanic Anoxic Event 2 reveals evidence of expanded sediment-water interface deoxygenation ~43 +/- 11 thousand years before the globally recognized carbon cycle perturbation. This evidence for rapid oxygen loss leading to an extreme ancient climatic event has timely implications for the modern ocean, which is already experiencing large-scale deoxygenation. PMID- 28808685 TI - Structure of a 1.5-MDa adhesin that binds its Antarctic bacterium to diatoms and ice. AB - Bacterial adhesins are modular cell-surface proteins that mediate adherence to other cells, surfaces, and ligands. The Antarctic bacterium Marinomonas primoryensis uses a 1.5-MDa adhesin comprising over 130 domains to position it on ice at the top of the water column for better access to oxygen and nutrients. We have reconstructed this 0.6-MUm-long adhesin using a "dissect and build" structural biology approach and have established complementary roles for its five distinct regions. Domains in region I (RI) tether the adhesin to the type I secretion machinery in the periplasm of the bacterium and pass it through the outer membrane. RII comprises ~120 identical immunoglobulin-like beta-sandwich domains that rigidify on binding Ca2+ to project the adhesion regions RIII and RIV into the medium. RIII contains ligand-binding domains that join diatoms and bacteria together in a mixed-species community on the underside of sea ice where incident light is maximal. RIV is the ice-binding domain, and the terminal RV domain contains several "repeats-in-toxin" motifs and a noncleavable signal sequence that target proteins for export via the type I secretion system. Similar structural architecture is present in the adhesins of many pathogenic bacteria and provides a guide to finding and blocking binding domains to weaken infectivity. PMID- 28808686 TI - A conformational checkpoint between DNA binding and cleavage by CRISPR-Cas9. AB - The Cas9 endonuclease is widely used for genome engineering applications by programming its single-guide RNA, and ongoing work is aimed at improving the accuracy and efficiency of DNA targeting. DNA cleavage of Cas9 is controlled by the conformational state of the HNH nuclease domain, but the mechanism that governs HNH activation at on-target DNA while reducing cleavage activity at off target sites remains poorly understood. Using single-molecule Forster resonance energy transfer, we identified an intermediate state of Streptococcus pyogenes Cas9, representing a conformational checkpoint between DNA binding and cleavage. Upon DNA binding, the HNH domain transitions between multiple conformations before docking into its active state. HNH docking requires divalent cations, but not strand scission, and this docked conformation persists following DNA cleavage. Sequence mismatches between the DNA target and guide RNA prevent transitions from the checkpoint intermediate to the active conformation, providing selective avoidance of DNA cleavage at stably bound off-target sites. PMID- 28808687 TI - Whole-exome sequencing associates novel CSMD1 gene mutations with familial Parkinson disease. AB - OBJECTIVE: Despite the enormous advancements made in deciphering the genetic architecture of Parkinson disease (PD), the majority of PD is idiopathic, with single gene mutations explaining only a small proportion of the cases. METHODS: In this study, we clinically evaluated 2 unrelated Spanish families diagnosed with PD, in which known PD genes were previously excluded, and performed whole exome sequencing analyses in affected individuals for disease gene identification. RESULTS: Patients were diagnosed with typical PD without relevant distinctive symptoms. Two different novel mutations were identified in the CSMD1 gene. The CSMD1 gene, which encodes a complement control protein that is known to participate in the complement activation and inflammation in the developing CNS, was previously shown to be associated with the risk of PD in a genome-wide association study. CONCLUSIONS: We conclude that the CSMD1 mutations identified in this study might be responsible for the PD phenotype observed in our examined patients. This, along with previous reported studies, may suggest the complement pathway as an important therapeutic target for PD and other neurodegenerative diseases. PMID- 28808689 TI - Role of AmpR in the High Expression of the Plasmid-Encoded AmpC beta-Lactamase CFE-1. AB - CFE-1 is a unique plasmid-encoded AmpC beta-lactamase with the regulator gene ampR. It imparts high resistance to most cephalosporins with constitutive high level beta-lactamase activity. Here, the beta-lactamase activities and expression levels of ampC with or without ampR were investigated. Results suggested that the resistance of CFE-1 to cephalosporins is caused by a substitution in AmpR, in which the Asp at position 135 is modified to Ala to allow the constitutive high level expression (derepression) of ampC. PMID- 28808688 TI - Adaptive Mistranslation Accelerates the Evolution of Fluconazole Resistance and Induces Major Genomic and Gene Expression Alterations in Candida albicans. AB - Regulated erroneous protein translation (adaptive mistranslation) increases proteome diversity and produces advantageous phenotypic variability in the human pathogen Candida albicans. It also increases fitness in the presence of fluconazole, but the underlying molecular mechanism is not understood. To address this question, we evolved hypermistranslating and wild-type strains in the absence and presence of fluconazole and compared their fluconazole tolerance and resistance trajectories during evolution. The data show that mistranslation increases tolerance and accelerates the acquisition of resistance to fluconazole. Genome sequencing, array-based comparative genome analysis, and gene expression profiling revealed that during the course of evolution in fluconazole, the range of mutational and gene deregulation differences was distinctively different and broader in the hypermistranslating strain, including multiple chromosome duplications, partial chromosome deletions, and polyploidy. Especially, the increased accumulation of loss-of-heterozygosity events, aneuploidy, translational and cell surface modifications, and differences in drug efflux seem to mediate more rapid drug resistance acquisition under mistranslation. Our observations support a pivotal role for adaptive mistranslation in the evolution of drug resistance in C. albicans. IMPORTANCE Infectious diseases caused by drug resistant fungi are an increasing threat to public health because of the high mortality rates and high costs associated with treatment. Thus, understanding of the molecular mechanisms of drug resistance is of crucial interest for the medical community. Here we investigated the role of regulated protein mistranslation, a characteristic mechanism used by C. albicans to diversify its proteome, in the evolution of fluconazole resistance. Such codon ambiguity is usually considered highly deleterious, yet recent studies found that mistranslation can boost adaptation in stressful environments. Our data reveal that CUG ambiguity diversifies the genome in multiple ways and that the full spectrum of drug resistance mechanisms in C. albicans goes beyond the traditional pathways that either regulate drug efflux or alter the interactions of drugs with their targets. The present work opens new avenues to understand the molecular and genetic basis of microbial drug resistance. PMID- 28808690 TI - The Hemagglutinin-Esterase Fusion Glycoprotein Is a Primary Determinant of the Exceptional Thermal and Acid Stability of Influenza D Virus. AB - Influenza D virus (IDV) is unique among four types of influenza viruses in that it utilizes cattle as a primary reservoir. The thermal and acid stability of IDV were examined and directly compared with those of influenza A virus (IAV), influenza B virus (IBV), and influenza C virus (ICV). The results of our experiments demonstrated that only IDV had a high residual infectivity (~2.5 log units of 50% tissue culture infective dose [TCID50]/ml) after a 60-min exposure to 53 degrees C in solution at a neutral pH, and remarkably, IDV retained this infectivity even after exposure to 53 degrees C for 120 min. Furthermore, the data showed that IDV was extremely resistant to inactivation by low pH. After being treated at pH 3.0 for 30 min, IDV lost only approximately 20% of its original infectiousness, while all other types of influenza viruses were completely inactivated. Finally, replacement of the hemagglutinin (HA) and neuraminidase (NA) proteins of a temperature- and acid-sensitive IAV with the hemagglutinin-esterase fusion (HEF) protein of a stable IDV through a reverse genetic system largely rendered the recombinant IAVs resistant to high temperature and low-pH treatments. Together, these results indicated that the HEF glycoprotein is a primary determinant of the exceptional temperature and acid tolerance of IDV. Further investigation into the viral entry and fusion mechanism mediated by the intrinsically stable HEF protein of IDV may offer novel insights into how the fusion machinery of influenza viruses evolve to achieve acid and thermal stability, which as a result promotes the potential to transmit across mammal species. IMPORTANCE Influenza D virus (IDV) utilizes cattle as a primary reservoir. Increased outbreaks in pigs and serological evidence of human infection have raised a concern about the potential of IDV adapting to humans. Here, we directly compared IDV's stability to that of other influenza types (A, B, and C) following prolonged incubation at high temperatures or in a low-pH environment. We found that IDV is the most stable of the four types of influenza viruses. Importantly, we demonstrated that the hemagglutinin-esterase fusion (HEF) protein, which drives the fusion between viral and host cell membranes, is the primary determinant for the high thermal and acid stability of IDV. Considering that there is a link between the acid stability of the hemagglutinin protein of influenza A virus and its cross-species transmission, further investigation of the mechanism of HEF-directed viral tolerance may offer novel insights into tissue tropism and cross-species transmission of influenza viruses. PMID- 28808691 TI - Fluoride Depletes Acidogenic Taxa in Oral but Not Gut Microbial Communities in Mice. AB - Fluoridation of drinking water and dental products prevents dental caries primarily by inhibiting energy harvest in oral cariogenic bacteria (such as Streptococcus mutans and Streptococcus sanguinis), thus leading to their depletion. However, the extent to which oral and gut microbial communities are affected by host fluoride exposure has been underexplored. In this study, we modeled human fluoride exposures to municipal water and dental products by treating mice with low or high levels of fluoride over a 12-week period. We then used 16S rRNA gene amplicon and shotgun metagenomic sequencing to assess fluoride's effects on oral and gut microbiome composition and function. In both the low- and high-fluoride groups, several operational taxonomic units (OTUs) belonging to acidogenic bacterial genera (such as Parabacteroides, Bacteroides, and Bilophila) were depleted in the oral community. In addition, fluoride associated changes in oral community composition resulted in depletion of gene families involved in central carbon metabolism and energy harvest (2-oxoglutarate ferredoxin oxidoreductase, succinate dehydrogenase, and the glyoxylate cycle). In contrast, fluoride treatment did not induce a significant shift in gut microbial community composition or function in our mouse model, possibly due to absorption in the upper gastrointestinal tract. Fluoride-associated perturbations thus appeared to have a selective effect on the composition of the oral but not gut microbial community in mice. Future studies will be necessary to understand possible implications of fluoride exposure for the human microbiome. IMPORTANCE Fluoride has been added to drinking water and dental products since the 1950s. The beneficial effects of fluoride on oral health are due to its ability to inhibit the growth of bacteria that cause dental caries. Despite widespread human consumption of fluoride, there have been only two studies of humans that considered the effect of fluoride on human-associated microbial communities, which are increasingly understood to play important roles in health and disease. Notably, neither of these studies included a true cross-sectional control lacking fluoride exposure, as study subjects continued baseline fluoride treatment in their daily dental hygiene routines. To our knowledge, this work (in mice) is the first controlled study to assess the independent effects of fluoride exposure on the oral and gut microbial communities. Investigating how fluoride interacts with host-associated microbial communities in this controlled setting represents an effort toward understanding how common environmental exposures may potentially influence health. PMID- 28808693 TI - The simulated air flow pattern around a moving animal transport vehicle as the basis for a prospective biosecurity risk assessment. AB - Research that investigates bioaerosol emissions from animal transport vehicles (ATVs) and their importance in the spread of harmful airborne agents while the ATVs travel on roads is limited. To investigate the dynamical behaviour of theoretically released particles from a moving ATV, the open-source computational fluid dynamics (CFD) software OpenFOAM was used to calculate the external and internal air flow fields with passive and forced ventilated openings of a common ATV moving at a speed of 80 km/h. In addition to a computed flow rate of approximately 40,000 m3/h crossing the interior of the ATV, the visualization of the trajectories has demonstrated distinct patterns of the spatial distribution of potentially released bioaerosols in the vicinity of the ATV. Although the front openings show the highest air flow to the outside, the recirculations of air masses between the interior of the ATV and the atmosphere also occur, which complicate the emission and the dispersion characterizations. To specify the future emission rates of ATVs, a database of bioaerosol concentrations within the ATV is necessary in conjunction with high-performance computing resources to simulate the potential dispersion of bioaerosols in the environment. PMID- 28808692 TI - Treating Nicotine Dependence and Preventing Smoking Relapse in Cancer Patients. AB - INTRODUCTION: Despite the well-documented harmful effects of smoking, many cancer patients continue to smoke. Smoking cessation is critical to address in this population given the associated increase in treatment toxicity, risk of second primary tumors, decrease in treatment response and higher disease-specific and all-cause mortality with continued smoking following a cancer diagnosis. This review seeks to summarize the latest recommendations and guidelines on smoking cessation treatment for patients diagnosed with cancer, and the evidence behind those recommendations. AREAS COVERED: We reviewed the latest evidence for smoking cessation treatments for cancer patients and the clinical guidelines and recommendation available for oncologists and health care providers. The unique aspects of nicotine dependence among patients diagnosed with cancer, and key challenges and barriers that cancer survivors and health care providers experience when considering smoking cessation treatments, and available clinical resources, are also discussed. Lastly, the authors summarize future directions in the field of smoking cessation treatment for cancer patients. EXPERT COMMENTARY: While there are areas of improvement in research of smoking cessation treatment for cancer patients, critical under-explored areas remain. Nonetheless, providers should adhere to the NCCN guidelines and offer a brief counseling intervention to motivate patients to quit smoking when appropriate resources are not available. PMID- 28808694 TI - Human serum albumin and oxidative stress in preeclamptic women and the mechanism of albumin for stress reduction. AB - AIMS: The present study to address one of the mechanisms in preeclampsia, examined whether levels of oxidative stress, human serum albumin, and endothelial function correlate in pregnant women and whether human serum albumin reduces levels of superoxide produced by NADPH oxidase activation in the human vascular smooth muscle cells. MATERIALS AND METHODS: Pregnant women with (Preeclampsia group, n = 33) and without preeclampsia (Normal group, n = 37) were recruited to determine levels of reactive oxygen species (serum diacron-reactive oxygen metabolite [d-ROM]), and the flow-mediated dilation (FMD). Human coronary arterial smooth muscle cells or omental arteries were subjected to evaluate isometric force recordings, levels of superoxide, western immunoblotting, and immunohistochemistry. The superoxide scavenging assay was also performed in a cell-free system. KEY FINDINGS: Women in the preeclampsia group demonstrated lower FMD and higher serum d-ROM values than those in the normal group. There were the inverse correlations between serum levels of d-ROM and the degree of FMD and between serum levels of albumin and those of d-ROM. D-glucose reduced the levcromakalim-induced dilation of human omental arteries, and it increased levels of superoxide and the recruitment of the NADPH oxidase subunit p47phox in human coronary arterial smooth muscle cells. Human serum albumin (0.05 to 0.5 g/dL) prevented these alterations whereas it exerted no superoxide scavenging effect. SIGNIFICANCE: Serum albumin relates to oxidative stress inversely, but to the endothelial function positively, in pregnant women. Human serum albumin appears to reduce oxidative stress via NADPH oxidase inhibition in the human vascular smooth muscle, indicating that the serum level may be a critical determinant of vascular oxidative stress in some human diseases. PMID- 28808695 TI - Resolving multicopy duplications de novo using polyploid phasing. AB - While the rise of single-molecule sequencing systems has enabled an unprecedented rise in the ability to assemble complex regions of the genome, long segmental duplications in the genome still remain a challenging frontier in assembly. Segmental duplications are at the same time both gene rich and prone to large structural rearrangements, making the resolution of their sequences important in medical and evolutionary studies. Duplicated sequences that are collapsed in mammalian de novo assemblies are rarely identical; after a sequence is duplicated, it begins to acquire paralog specific variants. In this paper, we study the problem of resolving the variations in multicopy long-segmental duplications by developing and utilizing algorithms for polyploid phasing. We develop two algorithms: the first one is targeted at maximizing the likelihood of observing the reads given the underlying haplotypes using discrete matrix completion. The second algorithm is based on correlation clustering and exploits an assumption, which is often satisfied in these duplications, that each paralog has a sizable number of paralog-specific variants. We develop a detailed simulation methodology, and demonstrate the superior performance of the proposed algorithms on an array of simulated datasets. We measure the likelihood score as well as reconstruction accuracy, i.e., what fraction of the reads are clustered correctly. In both the performance metrics, we find that our algorithms dominate existing algorithms on more than 93% of the datasets. While the discrete matrix completion performs better on likelihood score, the correlation clustering algorithm performs better on reconstruction accuracy due to the stronger regularization inherent in the algorithm. We also show that our correlation clustering algorithm can reconstruct on an average 7.0 haplotypes in 10-copy duplication data-sets whereas existing algorithms reconstruct less than 1 copy on average. PMID- 28808696 TI - Psychological Stress Alters Extracellular Matrix Metabolism in Mandibular Condylar Cartilage. AB - OBJECTIVE: To explore the effect of long-term stress on the temporomandibular joint (TMJ) condyle and its possible underlying mechanism. METHODS: A 12-week, chronic unpredictable mild stress (CUMS) model was used to induce long-term psychological stress in rats. Rats were randomly divided into control group (CONT), chronic unpredictable mild stress group (CUMS) and chronic unpredictable mild stress with fluoxetine treatment group (CUMS + DT) (n = 30 per group). A 5 mg/kg dose of fluoxetine was intraperitoneally injected daily 0.5 h before stress. A sucrose preference test, plasma corticosterone test and open-field test were performed to verify the feasibility of the CUMS model. Histopathology was used to observe the pathological changes of condyle. The expression levels of inflammatory cytokines, matrix metalloproteases (MMPs) and extracellular matrix (ECM) were measured by real-time polymerase chain reaction, western blotting and immunohistochemistry. RESULTS: At 8 and 12 weeks after exposure to CUMS, the rats showed higher plasma corticosterone than the control rats. Additionally, for the open-field test, the rats exposed to CUMS spent more time in the centre zone and moved a shorter distance than the control and drug treatment rats. In addition, pathological changes in the condylar cartilage occurred in the 8-week CUMS subgroup and were more obvious in the 12-week CUMS subgroup. The CUMS caused an increase in the secretion of inflammatory cytokines, imbalanced expression of MMPs and tissue inhibitor of metalloproteinase-1 and accelerated degradation of ECM in condylar cartilage in a time-dependent manner. CONCLUSION: Osteoarthritis like lesions can be caused by long-term CUMS in the mandibular condyles, which suggests that the imbalance in chondrocyte-secreted regulatory factors within the cartilage of the TMJ may play an important role in cartilage injury induced by psychological stress. PMID- 28808697 TI - Mechanical Properties and Wear of Five Commercial Fibre-Reinforced Filling Materials. AB - OBJECTIVE: To evaluate and compare certain mechanical properties and wear of five commercial short-fibre reinforced composites (Alert, EasyCore, Build-It, TI-Core, and everX Posterior), in relation to their microstructural characteristics. METHODS: Fracture toughness, work of fracture, and flexural strength were determined for each material following ISO standards. The specimens (n = 6) were dry stored (37 degrees C for 2 days) before they were tested. A wear test was conducted with 15,000 chewing cycles using a dual-axis chewing simulator. Wear pattern was analysed by a three-dimensional (3D) noncontact optical profilometer. Scanning electron microscopy (SEM) was used to evaluate the microstructure of each composite material. The results were statistically analysed using ANOVA followed by post hoc Tukey's test. RESULTS: everX Posterior exhibited the highest fracture toughness (2.4 MPa m1/2) among the materials tested (P < 0.05). EasyCore presented the highest flexural strength (125.4 MPa), which was not significantly different (P > 0.05) from Alert (119 MPa) and everX Posterior (120 MPa). Lowest wear values were found for EasyCore and Build-It (19 and 22 um). TI-Core showed significantly higher wear depth (45 um) than all other materials (P < 0.05). CONCLUSION: Significant differences between commercial short-fibre reinforced composites were found for fracture toughness and wear. PMID- 28808698 TI - Subgingival Microbiome of Gingivitis in Chinese Undergraduates. AB - OBJECTIVE: To analyse the microbiome composition of health and gingivitis in Chinese undergraduates with high-throughput sequencing. METHODS: Sequencing of 16S rRNA gene amplicons was performed with the MiSeq system to compare subgingival bacterial communities from 54 subjects with gingivitis and 12 periodontally healthy controls. RESULTS: A total of 1,967,372 sequences representing 14 phyla, 104 genera, and 96 species were detected. Analysis of similarities (Anosim) test and Principal Component Analysis (PCA) showed significantly different community profiles between the health control and the subjects with gingivitis. Alpha-diversity metrics were significantly higher in the subgingival plaque of the subjects with gingivitis compared with that of the healthy control. Overall, the relative abundance of 35 genera and 46 species were significantly different between the two groups, among them 28 genera and 45 species showed higher relative abundance in the subjects with gingivitis, whereas seven genera and one species showed a higher relative abundance in the healthy control. The genera Porphyromonas, Treponema, and Tannerella showed higher relative abundance in the subjects with gingivitis, while the genera Capnocytophaga showed higher proportions in health controls. Porphyromonas gingivalis, Prevotella intermedia and Porphyromonas endodontalis had higher relative abundance in gingivitis. Among them, Porphyromonas gingivalis was most abundant. CONCLUSION: Our results revealed significantly different microbial community composition and structures of subgingival plaque between subjects with gingivitis and healthy controls. Subjects with gingivitis showed greater taxonomic diversity compared with periodontally healthy subjects. The proportion of Porphyromonas, especially Porphyromonas gingivalis, may be associated with gingivitis subjects aged between 18 and 21 years old in China. Adults with gingivitis in this age group may have a higher risk of developing periodontitis. PMID- 28808699 TI - Association between EDAR Polymorphisms and Non-Syndromic Tooth Agenesis in the Chinese Han Population. AB - OBJECTIVE: To explore the relationship between single nuclear polymorphisms (SNPs) in ectodysplasin A receptor (EDAR) and EDAR-associated death domain (EDARADD) genes and non-syndromic tooth agenesis. METHODS: Ten putative SNPs in EDAR and EDARADD were selected, and a case-control study was conducted in 112 subjects with non-syndromic tooth agenesis and 112 normal control subjects. DNA was obtained from peripheral blood samples. Genotyping was performed by Sanger sequencing. RESULTS: Three SNPs (rs3749098, rs3749099, and rs10432616) in EDAR exhibited significant differences in the alleles and/or genotype frequencies between the case group (individuals with non-syndromic tooth agenesis) and control group (normal individuals). The T allele was identified in the SNP rs3749098 in 99.1% of the case group and in 96.0% of the control group (P = 0.0326). Regarding the SNP rs3749099, the C allele was identified in 99.1% of the case group and in 96.0% of the control group (P = 0.0326). Regarding the SNP rs10432616, the C allele was identified in 97.8% of the case group and in 100.0% of the control group (P = 0.0245). CONCLUSION: Our results suggested that SNPs in EDAR could be a pathogenic factor for non-syndromic tooth agenesis. Furthermore, EDAR can be regarded as a marker gene for the risk of tooth agenesis. PMID- 28808700 TI - Effect of Chlorhexidine and Ethanol on Microleakage of Composite Resin Restoration to Dentine. AB - OBJECTIVE: To evaluate the effect of chlorhexidine and ethanol on microleakage of composite resin restoration to dentine. METHODS: Class II cavities with dentinal margin were prepared on 96 premolar teeth. All specimens were acid-etched, rinsed and dried. Then the samples were randomly divided into four groups according to pre-treatment of the dentine: no treatment (control group); treatment with 100% ethanol for 60 s (group 2); treatment with 2% chlorhexidine for 60 s (group 3); 100% ethanol for 60 s and then 2% chlorhexidine for 60 s (group 4). After dentine treatment, each group was bonded and restored with a universal micro hybrid composite resin, according to the manufacturers' recommendation. Microleakage was evaluated by dye extraction method in two subgroups, immediately (24 h) and after 6 months in storage. Scan electronic microscope analyses for two samples of each group were also conducted. Data were analysed by two-way analysis of variance and Tukey test. RESULTS: The lowest and the highest amount of microleakage were observed in the ethanol group and in the control group, respectively. There were significant differences in microleakage among the groups (P = 0.003) and between measurement times (P = 0.001). For each storage time, the control group showed significant differences from the other groups and there were no differences between the other groups. CONCLUSION: Ethanol-wet bonding and chlorhexidine application may have potential benefits in lowering the occurrence of microleakage in the long term. PMID- 28808701 TI - Osteosarcoma of the Mandible: a Case Report with CT, MRI and Scintigraphy. AB - Osteosarcomas are especially rare in the mandible and maxilla, representing 1.6% of all bony malignant tumours. In this article, we described a case of osteosarcoma of the mandible. Computed tomography (CT) image showed a well circumscribed homogeneous mass, with nonhomogeneous contrast enhancement. T1 weighted magnetic resonance imaging (MR) image showed intermediate signal intensity on, and after administration the lesion showed signal intensity lower than muscle. T2-weighted MR image showed heterogeneous high signal intensity. Bone scintigraphy revealed monostatic involvement of the mandible with a homogenous intense uptake pattern. Ga-67 citrate scintigraphy revealed significantly increased uptake. Histopathological examination confirmed the diagnosis of osteosarcoma. PMID- 28808702 TI - Virtual Simulation Teaching Centre in Dental Education: a Report from Fujian Medical University, China. AB - This report gives a brief introduction to the Virtual Simulation Teaching Centre of Fujian Medical University School of Stomatology (VSFMUSS), China. As one of the best dental simulation laboratories in China, the VSFMUSS aims to train dental students and clinicians to be professionals who are able to provide optimal oral health care by giving them the best virtual patient care experience possible in a nonclinical setting. The features, achievements and future directions of the VSFMUSS are addressed. Moreover, the role of the VSFMUSS was evaluated and discussed based on the students' and faculties' perceptions, rate of employment after graduation, and so on. PMID- 28808703 TI - Molecular insights into the effect of graphene packing on mechanical behaviors of graphene reinforced cis-1,4-polybutadiene polymer nanocomposites. AB - Through united-atom molecular dynamics simulations, we build a series of graphene (GP) reinforced cis-1,4-polybutadiene (cis-PB) models with two novel GP structures, intercalated and stacked GP structures, to investigate the effect of different GP packing patterns on the chain structure, chain dynamics, uniaxial tension and visco-elastic behaviors, and correlate the microscopic mechanism with macroscopic mechanical properties. Simulation results show that the interlayer polymer chains in the void of intercalated GPs are strongly confined, leading to higher bond orientation of polymer chains during the stretch process compared with monodisperse systems. And due to this restriction effect, intercalated systems exhibit higher tensile stress under large tensile strain. For stacked systems, the interaction within GP layers and the orientation of the whole stacked GP structure play dominant roles in mechanical and visco-elastic properties. Furthermore, from the results that stacked systems have higher tensile stress and intercalated systems exhibit a higher storage modulus, we can conclude that the GP-GP interaction makes greater contribution than the GP-PB interaction and the chain confinement effect to the tensile behavior, whereas the restriction and orientation of polymer chains become more crucial factors than the GP-GP interaction under shear conditions. This work may provide rational means to tune the mechanical and visco-elastic properties of GP reinforced polymer nanocomposites. PMID- 28808705 TI - Anisotropic carrier mobility in two-dimensional materials with tilted Dirac cones: theory and application. AB - We have theoretically investigated the intrinsic carrier mobility in semimetals with tilted Dirac cones under both longitudinal and transverse acoustic phonon scattering. An analytical formula for the carrier mobility was obtained. It shows that tilting significantly reduces the mobility. The theory was then applied to 8B-Pmmn borophene and borophane (fully hydrogenated borophene), both of which have tilted Dirac cones. The predicted carrier mobilities in 8B-Pmmn borophene at room temperature are 14.8 * 105 and 28.4 * 105 cm2 V-1 s-1 along the x and y directions, respectively, both of which are higher than that in graphene. For borophane, despite its superhigh Fermi velocity, the carrier mobility is lower than that in 8B-Pmmn owing to its smaller elastic constant under shear strain. PMID- 28808704 TI - Enzymatic activity inside a DNA/peptide complex. AB - The mutual interaction between enzymes and their environments plays a key role in various life processes. In this study, using the complexes formed by salmon DNA and a de novo designed peptide, Ac-RRRRRRRRRGALGLPGKGGGLQRLTALDGR-NH2 (abbreviated as RR-30), as a model, we studied the activity of collagenase encapsulated inside the complex. Collagenase is able to cleave RR-30 at a LG/LP site, generating two shorter length peptides, which decreases the stability of the complex. Results show that the complex dissociates with time in the presence of collagenase. The dissociation rate is linearly proportional to the collagenase concentration. On the other hand, the collagenase activity is severely deteriorated inside the complex, where only 1/3 of the enzyme is active. We attribute it to the electrostatic interaction and hydrophobic interaction between collagenase and the components of the complex. Therefore, the mutual interaction determines the structure and kinetics of the DNA/peptide complex. PMID- 28808706 TI - Defined tetranuclear coinage metal chains. AB - To force metal ions in heterometallic coinage metal complexes into preset compartments, we have synthesized a ligand with two N-heterocyclic carbenes (NHCs) separated by a methylene bridge and two bipyridine moieties tethered to each NHC moiety. By using this ligand, tetranuclear heterodimetallic gold/copper and gold/silver complexes were obtained. These complexes show an unprecedented V shape or linear MAu2M (M = Cu, Ag) configuration in the solid state. The photophysical properties of the new compounds are significantly affected by the complexed metal ions. PMID- 28808707 TI - Molecular co-assembly as a strategy for synergistic improvement of the mechanical properties of hydrogels. AB - Molecular self-assembly is a key direction for the fabrication of advanced materials. Yet, the physical properties of the formed assemblies are limited by the inherent characteristics of the specific building blocks. Here, we have applied a co-assembly approach to synergistically modulate the mechanical properties of peptide hydrogels, thereby forming extremely stable and rigid hydrogels. PMID- 28808708 TI - A graphitic edge plane rich meso-porous carbon anode for alkaline water electrolysis. AB - There is growing interest in alkaline water electrolysis as a sustainable approach for producing hydrogen, but developing efficient and inexpensive catalysts for the oxygen evolution reaction, which can limit the operational efficiency of water electrolysis due to its considerable overpotential, is regarded as the most overriding challenge. Therefore, significant progress has been made in developing catalysts with transition metal and carbon materials as alternative catalysts. Here, we prepared cobalt containing carbon nanofibers via a facile route of electrospinning and pyrolysis, and metal leached carbon nanofibers were also prepared by subsequently leaching the metal. Despite metal leaching, the latter ones still show comparable activity and stability with iridium black in alkaline water electrolysis. After detailed physicochemical and electrochemical characterizations, we revealed that graphitic edge plane rich carbon is mainly responsible for the activity of our material rather than embedded metal species. In addition, the metal plays a role in forming the specific carbon structure along with improving graphitization based on the catalytic graphitization. This result indicates the importance of the graphitic edge plane and might be helpful to understand carbon anodes for alkaline water electrolysis. PMID- 28808709 TI - Phase diagram and structural evolution of tin/indium (Sn/In) nanosolder particles: from a non-equilibrium state to an equilibrium state. AB - A binary system of tin/indium (Sn/In) in the form of nanoparticles was investigated for phase transitions and structural evolution at different temperatures and compositions. The Sn/In nanosolder particles in the composition range of 24-72 wt% In were synthesized by a surfactant-assisted chemical reduction method under ambient conditions. The morphology and microstructure of the as-synthesized nanoparticles were analyzed by scanning electron microscopy (SEM), high resolution transmission electron microscopy (HRTEM), selected area electron diffraction (SAED) and X-ray diffraction (XRD). HRTEM and SAED identified InSn4 and In, with some Sn being detected by XRD, but no In3Sn was observed. The differential scanning calorimetry (DSC) thermographs of the as synthesized nanoparticles exhibited an endothermic peak at around 116 degrees C, which is indicative of the metastable eutectic melting of InSn4 and In. When the nanosolders were subjected to heat treatment at 50-225 degrees C, the equilibrium phase In3Sn appeared while Sn disappeared. The equilibrium state was effectively attained at 225 degrees C. A Tammann plot of the DSC data of the as synthesized nanoparticles indicated that the metastable eutectic composition is about 62% In, while that of the DSC data of the 225 degrees C heat-treated nanoparticles yielded a eutectic composition of 54% In, which confirmed the attainment of the equilibrium state at 225 degrees C. The phase boundaries estimated from the DSC data of heat-treated Sn/In nanosolder particles matched well with those in the established Sn-In equilibrium phase diagram. The phase transition behavior of Sn/In nanosolders leads to a new understanding of binary alloy particles at the nanoscale, and provides important information for their low temperature soldering processing and applications. PMID- 28808710 TI - Interface nanoparticle control of a nanometer water pump. AB - Nanoparticles are highly versatile and exhibit broad applications in tuning material properties. Herein, we show through molecular dynamics simulations the possibility of a nanometer water pump, driven by the motion of nanoparticles (NPs) on a membrane surface. Surprisingly, considerable net water flux can be induced through a carbon nanotube (CNT) that is perpendicular to the NP motion. The water transport can occur in a highly controllable fashion, not only by using a single NP with different forces, but also by varying the CNT length or the NP number. Specifically, for a single NP, the water flow and flux are found to increase linearly with an increase in force, following the same behavior of NP velocity. Inversely, the water translocation time exhibits a linear decrease. We further revealed the unique relation between the water flow and occupancy divided by the translocation time. The CNT length can significantly screen the thermal fluctuation of an outside water reservoir, leading to an increase in the water flux and subsequent unidirectional transport. More interestingly, under moderate force, the water flow and flux demonstrate maximum behaviors with an increase in NP number, co-determined by the NP velocity and water occupancy. The maximum location shifts to the lower NP number region for a larger force. We also identify two CNT states that correspond to low water flow. Our results provide a significant new method to pump water molecules through a CNT channel, which is helpful for the design of controllable nanofluidic devices. PMID- 28808711 TI - Orthogonal switching of self-sorting processes in a stimuli-responsive library of cucurbit[8]uril complexes. AB - The self-sorting processes in dynamic libraries of cucurbit[8]uril complexes can be switched in an orthogonal way by external stimuli. Protonated phenylpyridine guests form a 2 : 1 homoternary pi-donor-pi-acceptor complex, while deprotonation makes it a partner for ethylviologen in a 1 : 1 : 1 heteroternary complex. Reduction of the viologen instead generates a 2 : 1 homoternary complex of viologen radical-cations. PMID- 28808712 TI - From aqueous speciation to supramolecular assembly in alkaline earth-uranyl polyoxometalates. AB - The interplay between aqueous alkaline earth (Ca, Sr, Ba) polycationic speciation and uranyl-peroxide polyoxometalate self-assembly and evolution is described here using solution (Raman and X-ray scattering) and solid-state (microscopy, X-ray diffraction) characterization. Supramolecular assembly of Sr-encapsulated and decorated polyanions and polycations yields the fourth largest inorganic unit cell reported from single-crystal X-ray diffraction. PMID- 28808713 TI - A smart organic gel template as metal cation and inorganic anion sensor. AB - A carboxamide based molecule has shown unique gelation property in an aqueous mixture of DMF or DMSO. The gel itself has shown aggregation-induced fluorescence enhanced emission (AIEE), which can be utilized effectively in sensing ferrous and ferric ions as both of them switch off the fluorescence completely. An investigation by IR spectroscopy reveals an enhanced pi interaction of nitrile group with the iron center and this could be the possible reason behind the complete quenching of AIEE. This molecule was further investigated for the formation of metallogels for a wide array of cations, which in turn can act in tandem to behave as a dynamic array to detect several anions by either switching off or switching on the emission property of the metallogels. PMID- 28808715 TI - Constructing heterostructured Li-Fe-Ni-Mn-O cathodes for lithium-ion batteries: effective improvement of ultrafast lithium storage. AB - Surface modification is proved to be an effective strategy to improve the power density of lithium-ion batteries (LIBs) applied in electric vehicles. In this article, a protective modification layer (FeF3/LiF) is successfully deposited onto the surface of a low-cost cathode material, Li6/5[Fe1/10Ni3/20Mn11/20]O2, for realizing the improvement of ultrafast lithium storage. The reversible specific capacity and ultrahigh rate capability are effectively improved. The modified sample can achieve a higher reversible discharge specific capacity of 171.8 mA h g-1 at 0.2C. A discharge specific capacity of 150.4 mA h g-1 is delivered at 1C after 60 cycles. Even at 2C and 5C, the discharge specific capacities are still maintained at 135.7 and 124.5 mA h g-1. Notably, when charged and discharged at 20C, a discharge specific capacity of 73.4 mA h g-1 can be achieved after 200 cycles by the heterostructured Li-Fe-Ni-Mn-O cathode, almost twice that of the bare material. The good fast lithium storage capability can be ascribed to the effective suppression of interfacial side reactions, the conversion reaction from the FeF3 phase, and the harmonious coexistence of layered and spinel phases. The triple benefits from the heterostructured cathode provide a promising route for constructing advanced LIBs. PMID- 28808714 TI - A complicated biocomputing system based on multi-responsive P(NIPAM-co-APBA) copolymer film electrodes and electrocatalysis of NADH. AB - In this paper, poly(N-isopropylacrylamide-co-3-aminophenylboronic acid) (P(NIPAM co-APBA)) copolymer films were successfully electropolymerized on the Au electrode surface. The electroactive probe ferrocene carboxylic acid (FCA) in solution showed reversible thermal-, glucose- and pH-responsive on-off cyclic voltammetric (CV) behaviors at the film electrodes. The comparative experiments demonstrated that the thermo-responsive property of the film electrode was ascribed to the PNIPAM component of the films, whereas the glucose- and pH sensitive behaviors came from the PAPBA constituent. The reduced form of nicotinamide adenine dinucleotide (NADH) could be electrocatalytically oxidized by FCA at the film electrodes, which would greatly amplify the multi-responsive CV signal difference between the on and off states. On the basis of these results, a binary 4-input/4-output logic circuit was fabricated with temperature, glucose, pH and NADH as inputs and the CV responses at 4 different levels as outputs. Moreover, a ternary CONSENSUS logic circuit was established on the same platform, which was the first report on the combination of ternary logic gate and bioelectrocatalysis without using enzymes. This work provided a novel idea for constructing complicated biocomputing systems by increasing the number of inputs/outputs with multi-sensitive interfaces and by designing new types of multi-valued logic gates on the basis of bioelectrocatalysis. PMID- 28808716 TI - Spectroscopic characterization of the on-surface induced (cyclo)dehydrogenation of a N-heteroaromatic compound on noble metal surfaces. AB - New nanoarchitectures can be built from polycyclic aromatic hydrocarbons (PAHs) by exploiting the capability of some metal surfaces for inducing cyclodehydrogenation reactions. This bottom-up approach allows the formation of nanostructures with a different dimensionality from the same precursor as a consequence of the diffusion and coupling of the PAHs adsorbed on the surface. In this work we present a thorough study, by means of a combination of X-ray photoemission spectroscopy, near-edge X-ray absorption fine structure and scanning tunneling microscopy with first principle calculations of the structural and chemical transformations undergone by pyridyl-substituted dibenzo[5]helicene on three coinage surfaces, namely Cu(110), Cu(111) and Au(111). Upon annealing, on-surface chemical reactions are promoted affecting the adsorbate/substrate and the molecule/molecule interactions. This thermally induced process favours the transformation from diffusing isolated molecules to polymeric nanographene chains and finally to N-doped graphene. PMID- 28808717 TI - The opening/closure of the P-loop and hinge of BCR-ABL1 decodes the low/high bioactivities of dasatinib and axitinib. AB - To obtain new insights into the resistance caused by T315I and the differential selectivities of dasatinib and axitinib against BCR-ABL1(WT) and BCR-ABL1(T315), molecular dynamics simulations and free energy calculations were performed. A rule is summarized that the opening/closure of the P-loop and hinge of BCR-ABL1 could reflect the low/high bioactivities of dasatinib and axitinib. This may be because strong interactions of the ligands with key residues induce the P-loop and hinge of BCR-ABL1 to close, being favorable for the retention of the ligand in the binding site. However, weak interactions of the ligands with key residues cause the P-loop and hinge of BCR-ABL1 to open, improving the dissociation of the ligand. These key residues, which predominantly govern the differential selectivities of dasatinib and axitinib against BCR-ABL1(WT) and BCR-ABL1(T315), are highlighted, and the impacts of T315 mutation and the chemical structures of dasatinib and axitinib are also explored. The rule extracted from this study may have potential in screening kinase inhibitors, rationally designing the next generation kinase inhibitors, and guiding the precise treatment of kinase-related cancer. PMID- 28808719 TI - A new strategy for effective distance regulation of the surface plasmon assisted coupling reaction of p-nitrothiophenol to p,p'-dimercaptoazobenzene. AB - Plasmon assisted reactions on a metal surface occur through a different mechanism compared to traditional reaction conditions. Based on a SERS study of the model plasmon assisted reaction of PNTP to DMAB, we present the first regulation strategy for these reactions, enabled here, through the controlled adjustment of acidic properties. PMID- 28808718 TI - Covalent modification of biological targets with natural products through Paal Knorr pyrrole formation. AB - Covering: up to June 2017Natural products and endogenous metabolites engage specific targets within tissues and cells through complex mechanisms. This review examines the extent to which natural systems have adopted the Paal-Knorr reaction to engage nucleophilic amine groups within biological targets. Current understanding of this mode of reactivity is limited by only a few examples of this reaction in a biological context. This highlight is intended to stimulate the scientific community to identify potential research directions and applications of the Paal-Knorr reaction in native and engineered biological systems. PMID- 28808720 TI - External electric field control: driving the reactivity of metal-free azide alkyne click reactions. AB - Recent reports have suggested that an external electric field (EEF) can assist and even control product selectivity. In this work, we have shown that the barrier for the Huisgen reaction between alkyl (aryl) azide and cyclooctyne(biflurocyclooctyne) is reduced by ~3-4 kcal mol-1 when an oriented EEF is applied along the reaction axis. As a consequence of their inherently polar transition-states (TSs), a parallel orientation of the EEF results in enhancement of the charge transfer (CT) between the fragments and concomitant increase in the dipole moment along the reaction axes. This leads to an increase in the reaction rate for moderate EEFs in the range of 0.3-0.5 V A-1. Since highly polar and directional environments are omnipresent in biological environments, metal-free click reactions can be further accelerated for non invasive imaging of live-cells. Conceptually, electric field control appears to be a novel tool (catalyst) to drive, and possibly even tune, the reactivity of organic molecules. PMID- 28808721 TI - Unveiling universal trends for the energy level alignment in organic/oxide interfaces. AB - In this perspective we present a comprehensive analysis of the energy level alignment at the interface between an organic monolayer (organic = perylenetetracarboxylic dianhydride, PTCDA, zinc tetraphenylporphyrin, Zn-TPP, and tetracyanoquinodimethane, TCNQ) and a prototypical oxide surface, TiO2(110), looking for universal behaviours. PTCDA shows a physisorbed interaction with TiO2 and a small interface dipole potential with its highest occupied molecular orbital (HOMO) energy level located in the oxide energy gap and the lowest occupied molecular orbital (LUMO) energy level located above the oxide conduction band minimum, EC. We analyse how the interface barrier depends on an external bias potential between the organic layer and the oxide surface, Delta, and find for this interface that the screening parameter S = d|(EC - HOMO)|dDelta is close to 1. In the second case, the Zn-TPP monolayer shows a moderate chemisorbed interaction with some charge transfer from the molecule to the oxide and a significant interface dipole potential, in such a way that S decreases to around 0.8. In the TCNQ/TiO2(110) case, the TCNQ molecules present a strong chemical interaction with the oxide; the LUMO energy level is located in the oxide energy gap in such a way that one electron is transferred from the oxide to the organic molecule; we also find that in this case S ~ 0.5. All these cases can be integrated within a universal behaviour when (EC - HOMO) is calculated as a function of Delta; that function presents a zig-zag curve with a central part having an S-slope, and two plateaus associated with either the LUMO or the HOMO energy levels crossing the oxide Fermi level. In these plateaus, a Coulomb blockade regime arises and a pace charge layer develops in the oxide surface. PMID- 28808722 TI - Role of carboxylic acid groups in the reduction of nitric oxide by carbon at low temperature, as exemplified by graphene oxide. AB - Graphene oxide (GO) was utilized to investigate the role of carboxylic acid groups in the reduction of nitric oxide (NO) for the first time. As a result, GO with sufficient carboxylic acid groups reduced 45% of NO at 100 degrees C. However, GO without these oxygen-containing groups barely reduced NO (lower than 5%) under the same conditions. After reduction of NO, the carboxylic acid group content on GO decreased from 8.32 to 5.22 mmol g-1. Simultaneously, the anhydride group content increased from 0.14 to 0.28 mmol g-1. FTIR spectroscopy also indicated that the carboxylic acid groups transformed into anhydride and lactone groups. Moreover, both transient kinetics and TG-MS studies demonstrated that reactive intermediates formed during the reaction between NO and GO at 100 degrees C. Based on these results, it was proposed that the carboxylic acid groups participated in NO reduction by consumption and regeneration. This mechanism explains why carbon is usually an effective reductant and catalyst support for NO removal at low temperature. PMID- 28808724 TI - Water and CO (co-)adsorption on pseudomorphic Pt films on Ru(0001) - a low temperature scanning tunneling microscopy study. AB - Coadsorption of CO and water under ultrahigh vacuum (UHV) conditions can be considered as a model system for the interaction of metal surfaces with CO in an aqueous electrochemical environment. Nevertheless, this has rarely been investigated, and in particular for catalytically relevant bimetallic systems, there is hardly any information available. Here we report results of a low temperature scanning tunneling microscopy (STM) study on the adsorption and coadsorption of CO and water on a Ru(0001) surface covered with a pseudomorphic Pt film of 2 or 3 monolayers thickness. The role of kinetic effects introduced by the sequence of adsorption, either pre-adsorption of CO followed by water adsorption or pre-adsorption of water followed by CO adsorption, on the adlayer structure formation will be demonstrated and discussed. Furthermore, the data show a distinct influence of the thickness of the Pt film, reflecting changes in the chemistry of the Pt surface due to electronic interactions with the underlying Ru(0001) substrate ('vertical ligand effects'). Implications of the present findings on the interaction of CO with these bimetallic PtRu surfaces under electrochemical conditions will be discussed. PMID- 28808725 TI - The role of the capping bond effect on pyclen natY3+/90Y3+ chelates: full control of the regiospecific N-functionalization makes the difference. AB - Thanks to a smart regiospecific N-functionalization, a pyclen based ligand bearing one picolinate and two acetate arms organized in a dissymmetric manner was synthesized for Y3+ complexation, and compared to its symmetric analogue. The nature of the capping bonds around the metal coordination environment has a dramatic effect on the properties of the chelate, the natY3+ and 90Y3+ dissymmetric derivatives presenting enhanced thermodynamic stability and kinetic inertness. PMID- 28808723 TI - Plasma metabolite abundances are associated with urinary enterolactone excretion in healthy participants on controlled diets. AB - Enterolignans, products of gut bacterial metabolism of plant lignans, have been associated with reduced risk of chronic diseases, but their association with other plasma metabolites is unknown. We examined plasma metabolite profiles according to urinary enterolignan excretion in a cross-sectional analysis using data from a randomized crossover, controlled feeding study. Eighty healthy adult males and females completed two 28-day feeding periods differing by glycemic load, refined carbohydrate, and fiber content. Lignan intake was calculated from food records using a polyphenol database. Targeted metabolomics was performed by LC-MS on plasma from fasting blood samples collected at the end of each feeding period. Enterolactone (ENL) and enterodiol, were measured in 24 h urine samples collected on the penultimate day of each study period using GC-MS. Linear mixed models were used to test the association between enterolignan excretion and metabolite abundances. Pathway analyses were conducted using the Global Test. Benjamini-Hochberg false discovery rate (FDR) was used to control for multiple testing. Of the metabolites assayed, 121 were detected in all samples. ENL excretion was associated positively with plasma hippuric acid and melatonin, and inversely with epinephrine, creatine, glycochenodeoxycholate, and glyceraldehyde (P < 0.05). Hippuric acid only satisfied the FDR of q < 0.1. END excretion was associated with myristic acid and glycine (q < 0.5). Two of 57 pathways tested were associated significantly with ENL, ubiquinone and terpenoid-quinone biosynthesis, and inositol phosphate metabolism. These results suggest a potential role for ENL or ENL-metabolizing gut bacteria in regulating plasma metabolites. PMID- 28808726 TI - Polarization transfer efficiency in PHIP experiments. AB - Parahydrogen induced polarization (PHIP) is a hyperpolarization method for NMR signal enhancement with applications in spectroscopy and imaging. Although parahydrogen can be easily enriched up to nearly 95%, the polarization detected on the hydrogenated substrate is substantially lower, where numerous loss mechanisms between the start of the hydrogenation reaction and detection affect polarization levels. The quality of PHIP systems is commonly determined by stating either the polarization degree or the enhancement factor of the product at the time of detection. In this study, we present a method that allows the distinction of polarization loss due to both the catalytic cycle and T1 relaxation of the formed product prior to detection. We determine the influence of homogeneous catalysts and define a rigorous measure of the polarization transfer efficiency (PTE). Our results show that the PTE strongly depends on the concentration of all components and the chemical structure of the catalyst as well as on the magnetic field of detection. PMID- 28808727 TI - [25 years of the Association of Middle-German Otorhinolaryngologists (MDHNO)]. PMID- 28808728 TI - [Subpectoral tenodesis of the long head of the biceps tendon with an interference screw and a cortical button : Clinical and cosmetic results after 1 year]. AB - BACKGROUND: Pathologies of the long head of biceps tendon (LHB) can cause anterior shoulder pain. Surgical treatment includes tenotomy and tenodesis (TD), however TD causes fewer cosmetic deformities and less cramping of the biceps muscle. To date, numerous techniques for TD have been described but the "gold standard" has not yet been established. OBJECTIVES: The purpose of this study is to evaluate the functional and cosmetic outcome following subpectoral biceps TD with an interference screw and a cortical-button (STLHB-IC) after 1 year. MATERIALS AND METHODS: 35 patients (10 female, 25 male) with an average age of 57.4 +/- 7 years were examined after STLHB-IC with a follow up of 12.8 +/- 1.2 months. The constant score (CS), the long head of biceps score (LHBS) and the subjective shoulder value (SSV) were assessed. Furthermore, the cosmetic result was evaluated by the patient and the examiner, and the elbow flexion strength (EFS) was measured. RESULTS: The CS (82.5 +/- 17.2), LHBS (90.1 +/- 11.5) and SSV (83.2 +/- 17.7) showed good and excellent results. The SSV increased significantly pre vs. postoperatively (40.6 +/- 19.7 vs. 83.2 +/- 17.7). The CS (82.5 +/- 17.2) and the LHBS (90.1 +/- 11.5), as well as the EFS (17.5 +/- 4.8 kg) of the affected shoulder revealed no significant differences compared with the non-affected shoulder (CS: 91.8 +/- 11.3, LHBS: 99.1 +/- 11.5; EFS: 19.7 +/- 4.8). Severe Popeye deformities (measured by LHBS) were found in 6% of the cases, however if they occurred patients (13.4 +/- 3.8) evaluated them as significantly less disadvantageous than the examiners (11.9 +/- 4.7). There were no neurovascular injuries, infections or fractures. CONCLUSION: STLHB-IC is a safe, reproducible technique with convincing functional and cosmetic results that provides high patient satisfaction. PMID- 28808729 TI - Twig-like Middle Cerebral Artery: a Seldom Vessel Anomaly of Important Relevance. PMID- 28808730 TI - [Spontaneous reposition of a hip prosthesis after atraumatic dislocation]. AB - Traumatic dislocations of a hip prosthesis are not uncommon, and spontaneous repositions are well documented as well. To the best of our knowledge, however, there has been no report of a spontaneous reposition of a dislocated hip prosthesis head on the stem taper. We present such a rare case. PMID- 28808731 TI - Biomacromolecules as tools and objects in nanometrology-current challenges and perspectives. AB - Nucleic acids, proteins, and polysaccharides are the most important classes of biopolymers. The inherent properties of biomacromolecules are contrary to those of well-defined small molecules consequently raising a number of specific challenges which become particularly apparent if biomacromolecules are treated as objects in quantitative analysis. At the same time, their specific functional ability of molecular recognition and self-organization (e.g., enzymes, antibodies, DNA) enables us to make biomacromolecules serving as molecular tools in biochemistry and molecular biology, or as precisely controllable dimensional platforms for nanometrological applications. Given the complexity of biomacromolecules, quantitative analysis is not limited to the measurement of their concentration but also involves the determination of numerous descriptors related to structure, interaction, activity, and function. Among the biomacromolecules, glycans set examples that quantitative characterization is not necessarily directed to the measurement of amount-of-substance concentration but instead involves the determination of relative proportions (molar ratios) of structural features for comparison with theoretical models. This article addresses current activities to combine optical techniques such as Raman spectroscopy with isotope dilution approaches to realize reference measurement procedures for the quantification of protein biomarkers as an alternative to mass spectrometry-based techniques. Furthermore, it is explored how established ID-MS protocols are being modified to make them applicable for quantifying virus proteins to measure the HIV viral load in blood samples. As an example from the class of carbohydrates, the challenges in accurate determination of substitution patterns are outlined and discussed. Finally, it is presented that biomacromolecules can also serve as tools in quantitative measurements of dimensions with an example of DNA origami to generate defined dimensional standards to be used for calibration in super-resolution fluorescence microscopy. Graphical abstract Quantitative analysis of biomacromolecules is accompanied with special challenges different from low molecular weight compounds. In addition, they are not only objects but also tools applicable for quantitative measurements. PMID- 28808733 TI - [Basic principles: signaling pathways and checkpoints]. AB - Immune checkpoint inhibitors have shown significant antitumor activity and good tolerability in a number of cancer types and have entered the everyday oncological practice. This article briefly summarizes the mode of action of immune checkpoint inhibitors to provide a basis for the understanding of their clinical activity, radiological response patterns and adverse event profile. PMID- 28808732 TI - Individualized risk assessment in neuroblastoma: does the tumoral metabolic activity on 123I-MIBG SPECT predict the outcome? AB - PURPOSE: Risk-adapted treatment in children with neuroblastoma (NB) is based on clinical and genetic factors. This study evaluated the metabolic tumour volume (MTV) and its asphericity (ASP) in pretherapeutic 123I-MIBG SPECT for individualized image-based prediction of outcome. METHODS: This retrospective study included 23 children (11 girls, 12 boys; median age 1.8 years, range 0.3 6.8 years) with newly diagnosed NB consecutively examined with pretherapeutic 123I-MIBG SPECT. Primary tumour MTV and ASP were defined using semiautomatic thresholds. Cox regression analysis, receiver operating characteristic analysis (cut-off determination) and Kaplan-Meier analysis with the log-rank test for event-free survival (EFS) were performed for ASP, MTV, laboratory parameters (including urinary homovanillic acid-to-creatinine ratio, HVA/C), and clinical (age, stage) and genetic factors. Predictive accuracy of the optimal multifactorial model was determined in terms of Harrell's C and likelihood ratio chi 2. RESULTS: Median follow-up was 36 months (range 7-107 months; eight patients showed disease progression/relapse, four patients died). The only significant predictors of EFS in the univariate Cox regression analysis were ASP (p = 0.029; hazard ratio, HR, 1.032 for a one unit increase), MTV (p = 0.038; HR 1.012) and MYCN amplification status (p = 0.047; HR 4.67). The mean EFS in patients with high ASP (>32.0%) and low ASP were 21 and 88 months, respectively (p = 0.013), and in those with high MTV (>46.7 ml) and low MTV were 22 and 87 months, respectively (p = 0.023). A combined risk model of either high ASP and high HVA/C or high MTV and high HVA/C best predicted EFS. CONCLUSIONS: In this exploratory study, pretherapeutic image-derived and laboratory markers of tumoral metabolic activity in NB (ASP, MTV, urinary HVA/C) allowed the identification of children with a high and low risk of progression/relapse under current therapy. PMID- 28808734 TI - What is the true catheterization rate after intravesical onabotulinumtoxinA injection? AB - INTRODUCTION AND HYPOTHESIS: A known side effect of intravesical onabotulinumtoxinA (Botox(r)) injection for overactive bladder (OAB) is urinary retention requiring clean intermittent catheterization (CIC), the fear of which deters patients from choosing this therapy. In clinical practice, patients with an elevated postvoid residual (PVR) are often managed by observation only, providing they do not have subjective complaints or contraindications. We sought to determine the true rate of urinary retention requiring CIC in clinical practice. METHODS: A retrospective review was performed over a 3-year period of patients who received 100 units of intravesical onabotulinumtoxinA for the treatment of OAB. Patients were seen 2 weeks after the procedure to measure PVR. CIC was initiated in patients with a PVR >=350 ml and in those with subjective voiding difficulty or acute retention. RESULTS: A total of 187 injections were performed on 99 female patients. CIC was required following three injections (1.6%): for acute retention in two patients and subjective voiding difficulty in one patient with a PVR of 353 ml. Following 12 injections, the patient had a PVR of >=350 ml, and following 29 injections, the patient had a PVR of >200 but <350 ml without symptoms. CIC was not initiated in these 41 patients. None of these patients experienced subsequent retention, and all showed resolution of their elevated PVR within 8 weeks. CONCLUSIONS: In our series of 187 intravesical injections for OAB, the rate of postprocedure urinary retention requiring catheterization was only 1.6%. This low rate can be attributed to less rigorous criteria for CIC initiation than those applied in previous studies. While important to counsel patients on the risk of retention, patients can be reassured that the actual rate of CIC is low. PMID- 28808735 TI - [Diagnostics and endovascular treatment of venous diseases]. AB - In venous disease, acute thromboses and chronic venous insufficiency have the highest health economics relevance. Duplex sonography is the first line diagnostic assessment tool, while cross-sectional imaging is employed as a supplementary method. Due to the availability and examination times computed tomography is preferred in the emergency setting and is supplemented by magnetic resonance imaging (MRI) for specific questions. Endovascular treatment procedures are increasingly becoming available in addition to classical conservative treatment methods. PMID- 28808737 TI - Development of neutron imaging quantitative data treatment to assess conservation products in cultural heritage. AB - Distribution, penetration depth and amount of new mineralogical phases formed after the interaction between an inorganic treatment and a matrix are key factors for the evaluation of the conservation treatment behaviour. Nowadays, the conventional analytical methodologies, such as vibrational spectroscopies, scanning electron microscopy and X-ray diffraction, provide only qualitative and spot information. Here, we report, for the first time, the proof of concept of a methodology based on neutron imaging able to achieve quantitative data useful to assess the formation of calcium oxalate in a porous carbonatic stone treated with ammonium oxalate. Starting from the neutron attenuation coefficient of Noto stone treated specimens, the concentrations of newly formed calcium oxalate and the diffusion coefficient have been calculated for both sound and decayed substrates. These outcomes have been also used for a comparative study between different treatment modalities. Graphical abstract Horizontal slice at 300 mm depth and CaOx molar density profile by NEUTRA output. PMID- 28808736 TI - The role of isolated posterior cruciate ligament reconstruction in knees with combined posterior cruciate ligament and posterolateral complex injury. AB - PURPOSE: This is a meta-analysis comparing biomechanical outcomes to determine whether an isolated posterior cruciate ligament (PCL) reconstruction can restore normal knee kinematics in a combined PCL/posterolateral complex (PLC) injury and whether double-bundle (DB) PCL reconstruction is superior in controlling posterior and rotational laxity compared with single-bundle (SB) PCL reconstruction in a PCL/PLC-deficient knee. METHODS: A number of electronic databases were searched for relevant articles published through August 2016 that compared biomechanical outcomes of PCL reconstruction in patients who underwent reconstruction for combined PCL/PLC deficiencies. Data were searched, extracted, analysed, and assessed for quality according to Cochrane Collaboration guidelines, and biomechanical outcomes were evaluated using various outcome values. The results are presented as relative ratios for binary outcomes and standard mean differences for continuous outcomes with 95% confidence intervals. RESULTS: Five biomechanical studies were included in this meta-analysis. There were significant differences in laxities such as posterior tibial translation (PTT), external rotation, varus rotation, and PTT coupled with external rotation in the isolated PCL reconstruction group compared with the native PCL group. Furthermore, there were no significant differences in laxities such as PTT, external rotation, or varus rotation between the SB and DB PCL reconstruction groups. CONCLUSION: Isolated PCL reconstruction, whether SB or DB, could not restore normal knee kinematics in the PCL/PLC-deficient knee. In such cases, residual laxity after isolated PCL reconstruction can be controlled successfully with PLC reconstruction. Therefore, simultaneous PCL and PLC reconstruction is recommended for patients with combined PCL/PLC injury. PMID- 28808738 TI - Formaldehyde passive sampler using an optical chemical sensor: how to limit the humidity interference. AB - The behaviour of a new formaldehyde diffusive sampler using an optical chemical sensor with respect to high humidity conditions is examined in controlled atmospheres. Five prototypes of the radial diffusion sampler having the same chemical sensor and different designs were tested. In addition, a set of experiments were performed on the chemical sensor to characterise its efficiency of trapping water vapour in the absence and in the presence of the reactants, Fluoral-P and formaldehyde. Differences in humidity interference between the five diffusive sampler prototypes were studied and discussed. From all the results obtained, it was shown that the prototype LDE1.4 combining a small diffusion slot, a reduced internal volume and a sensor shifted upwards from the diffusion slot provided formaldehyde measurements least affected by humidity up to 80% RH at 20 degrees C. This new type of diffusive sampler with on-site direct reading is intended to ultimately replace conventional passive samplers with DNPH requiring offset laboratory analyses. PMID- 28808739 TI - An intracortical chondromyxoid fibroma in the diaphysis of the metatarsal. AB - Chondromyxoid fibromas (CMFs) are rare, benign, primary tumors of bones, and occur in the metaphyses of the medullary canals of the long bones. The occurrence of intracortical CMFs is extremely rare. Very few cases of intracortical CMFs located in the long tubular bones have been reported to date. Moreover, even though the feet are the second most common site for CMF (after the knees), intracortical metatarsal CMF has not been reported previously, to our knowledge. We report an intracortical CMF occurring in the diaphysis of the metatarsal in a 17-year-old man. It showed the same imaging findings as usual intramedullary CMFs, except for its cortical location. The development and serial increase in this tumor over time are also demonstrated in this report. Additionally, we present a review of current literature on intracortical CMFs. PMID- 28808740 TI - Similar views on rehabilitation following hip arthroscopy among physiotherapists and surgeons in Scandinavia: a specialized care survey. AB - PURPOSE: The rising number of hip arthroscopies (HA) is leading to increasing numbers of patients requiring post-surgical rehabilitation; however, evidence regarding post-operative rehabilitation is currently limited. The purpose of the study was to describe and compare current rehabilitation strategies and views among surgeons and physiotherapists in Scandinavia. METHODS: Scandinavian surgeons and physiotherapists experienced with HA and post-surgical rehabilitation were asked to complete an online survey. Ninety clinicians (28 surgeons, 62 physiotherapists) responded. RESULTS: Both professions mostly rated physiotherapy as very or extremely important in the rehabilitation process. The majority advocated criteria-based or combined criteria- and time-based progression. Expected rehabilitation timelines were reported with large intra professional variation but general inter-professional agreement. However, compared with physiotherapists surgeons expected fewer weeks on crutches and faster return to competitive sport. Surgeons more often reported use of evidence based self-reported outcomes while physiotherapists more often evaluated readiness for return to play. CONCLUSIONS: Among surgeons and physiotherapists, physiotherapy is considered very important following HA. Generally, very similar views were held between professions. Surgeons expected reduced time on crutches and to return to competitive sports than physiotherapists. Surgeons also used evidence-based self-reported outcomes to a higher degree than physiotherapists. Being the first study to provide an overview on currently applied rehabilitation strategies following HA, results of this study may guide much needed, future research on the rehabilitation process following HA. LEVEL OF EVIDENCE: IV. PMID- 28808741 TI - Stable-isotope Raman microspectroscopy for the analysis of soil organic matter. AB - We examined the potential of stable-isotope Raman microspectroscopy (SIRM) for the evaluation of differently enriched 13C-labeled humic acids as model substances for soil organic matter (SOM). The SOM itself can be linked to the soil water holding capacity. Therefore, artificial humic acids (HA) with known isotopic compositions were synthesized and analyzed by means of SIRM. By performing a pregraphitization, a suitable analysis method was developed to cope with the high fluorescence background. Results were verified against isotope ratio mass spectrometry (IRMS). The limit of quantification was 2.1 * 10-1 13C/C tot for the total region and 3.2 * 10-2 13C/C tot for a linear correlation up to 0.25 13C/C tot. Complementary nanoscale secondary ion mass spectrometry (NanoSIMS) analysis indicated small-scale heterogeneity within the dry sample material, even though-owing to sample topography and occurring matrix effects obtained values deviated in magnitude from those of IRMS and SIRM. Our study shows that SIRM is well-suited for the analysis of stable isotope-labeled HA. This method requires no specific sample preparation and can provide information with a spatial resolution in the micrometer range. Graphical abstract Analysis of the isotopic composition of humic acids by Raman microspectroscopy in combination with isotope ratio mass spectrometry and nanoscale secondary ion mass spectrometry. PMID- 28808742 TI - A More Comprehensive Community of Ammonia-Oxidizing Archaea (AOA) Revealed by Genomic DNA and RNA Analyses of amoA Gene in Subtropical Acidic Forest Soils. AB - Ammonia-oxidizing bacteria (AOB) and archaea (AOA) are the main nitrifiers which are well studied in natural environments, and AOA frequently outnumber AOB by orders especially in acidic conditions, making AOA the most promising ammonia oxidizers. The phylogeny of AOA revealed in related studies, however, often varied and hardly reach a consensus on functional phylotypes. The objective of this study was to compare ammonia-oxidizing communities by amoA gene and transcript based on both genomic DNA and RNA in extremely acidic forest soils (pH <4.5). Our results support the numerical and functional dominance of AOA over AOB in acidic soils as bacterial amoA gene and transcript were both under detection limits and archaeal amoA, in contrast, were abundant and responded to the fluctuations of environmental factors. Organic matter from tree residues was proposed as the main source of microbial available nitrogen, and the potential co precipitation of dissolved organic matter (DOM) with soluble Al3+ species in acidic soil matrix may further restrict the amount of nitrogen sources required by AOB besides NH3/NH4+ equilibrium. Although AOA were better adapted to oligotrophic environments, they were susceptible to the toxicity of exchangeable Al3+. Phylotypes affiliated to Nitrososphaera, Nitrososphaera sister group, and Nitrosotalea were detected by amoA gene and transcript. Nitrosotalea devantaerra and Nitrososphaera sister group were the major AOA. Compared to the genomic DNA data, higher relative abundances of Nitrososphaera and Nitrososphaera sister group were recognized in amoA transcript inferred AOA communities, where Nitrosotalea relative abundance was found lower, implying the functional activities of Nitrososphaera sister group and Nitrososphaera were easily underestimated and Nitrosotalea did not attribute proportionally to nitrification in extremely acidic soils. Further comparison of the different AOA community compositions and relative abundance of each phylotypes revealed by amoA genes and transcripts make it possible to identify the functional AOA species and assess their ecological role in extremely acidic soils. PMID- 28808743 TI - Saving costs in cancer patient management through molecular imaging. PMID- 28808744 TI - Comment on "Comparison of CT and PET/CT for biopsy guidance in oncological patients". PMID- 28808746 TI - [Erratum to: Compression or expansion of morbidity in outpatient healthcare? : Generation 65plus in 2007 and 2014]. PMID- 28808748 TI - Erratum to: Characterization of three pathway-specific regulators for high production of monensin in Streptomyces cinnamonensis. PMID- 28808745 TI - Parathyroid hormone (1-34) promotes fracture healing in ovariectomized rats with type 2 diabetes mellitus. AB - : Ovariectomized (OVX) rats with type 2 diabetes mellitus (T2DM) with femur fracture received vehicle, insulin, or insulin plus parathyroid hormone (PTH) treatment for 2 and 3 weeks. Radiography, histomorphometry, histology, and immunohistochemistry in callus were evaluated. INTRODUCTION: Reports about effects of PTH plus insulin on callus formation of osteoporotic fracture with T2DM were limited. This study was designed to investigate the effects of the combination of PTH and insulin on fracture healing in OVX rats with T2DM. METHODS: Two-month-old female rats were randomly divided into five groups: normal fracture (F), OVX fracture (OF), T2DM + OVX fracture (DOF), insulin-treated (2-4 u/daylight, 4-6 u/night, DOFI), and treated with insulin and PTH (50 MUg/kg/day, 5 days/week, DOFIP). A closed mid-shaft fracture was established in the right femurs of all rats after 6 weeks of OVX. Rats were euthanized at 2 and 3 weeks post-fracture according to the time schedule, respectively. RESULTS: The administration of insulin alone or insulin combined with PTH significantly increased mineralized bone volume fraction (BV/TV) and connectivity density (Conn.D) compared with those of the DOF group at 3 weeks post-fracture and also increased cartilaginous callus area ratio in the DOFI and DOFIP groups at 2 weeks and bony callus area ratio in the DOFIP groups at both the 2 and 3 weeks post fracture. CONCLUSIONS: OVX rats with T2DM exhibited a marked delay in the fracture healing process; insulin treatment ameliorated these effects, and the healing process was enhanced following treatment with a combination of insulin and PTH. PMID- 28808750 TI - [A main topic to initiate discussion : The new DGUV treatment procedures]. PMID- 28808749 TI - BioXmark for high-precision radiotherapy in an orthotopic pancreatic tumor mouse model : Experiences with a liquid fiducial marker. AB - BACKGROUND AND PURPOSE: High-precision radiotherapy (RT) requires precise positioning, particularly with high single doses. Fiducial markers in combination with onboard imaging are excellent tools to support this. The purpose of this study is to establish a pancreatic cancer mouse model for high-precision image guided RT (IGRT) using the liquid fiducial marker BioXmark (Nanovi, Kongens Lyngby, Denmark). METHODS: In an animal-based cancer model, different volumes of BioXmark (10-50 ul), application forms, and imaging modalities-cone-beam computer tomography (CBCT) incorporated in either the Small Animal Radiation Research Platform (SARRP) or the small-animal micro-CT Scanner (SkyScan; Bruker, Brussels, Belgium)-as well as subsequent RT with the SARRP system were analyzed to derive recommendations for BioXmark. RESULTS: Even small volumes (10 ul) of BioXmark could be detected by CBCT (SARRP and Skyscan). Larger volumes (50 ul) led to hardening artefacts. The position of BioXmark was monitored at least weekly by CBCT and was stable over 4 months. BioXmark was shown to be well tolerated; no changes in physical condition or toxic side effects were observed in comparison to control mice. BioXmark enabled an exact fusion with the original treatment plan with less hardening artefacts, and minimized the application of contrast agent for fractionated RT. CONCLUSION: An orthotopic pancreatic tumor mouse model was established for high-precision IGRT using a fiducial marker. BioXmark was successfully tested and provides the perfect basis for improved imaging in high precision RT. BioXmark enables a unique application method and optimal targeted precision in fractionated RT. Therefore, preclinical trials evaluating novel fractionation regimens and/or combination treatment with high-end RT can be performed. PMID- 28808751 TI - New reduction technique for the treatment of unilateral locked facet joints of the lower cervical spine : A retrospective analysis of 12 cases. AB - BACKGROUND: Closed reduction of bilateral locked facet joints of the lower cervical spine is possible, but reduction of unilateral locked facet joints of the lower cervical spine (ULFJLCS) is challenging. We explored a new, simple, safe, and effective closed reduction method for the treatment of ULFJLCS. METHODS: A retrospective analysis was done on 12 consecutive cases with traumatic ULFJLCS that underwent closed reduction by Z-shape elevating-pulling reduction through a halo-vest. After reduction, only anterior cervical decompression and internal fixation were performed. The success of reduction and nerve function was assessed, and follow-up data analyzed. RESULTS: All patients using our new reduction technique underwent successful closed reduction; the shortest time of reduction was 40 min and the longest 110 (mean, 65) min. No aggravation of neurological damage was observed, nor were other complications. All patients were followed-up from 28 to 72 (mean, 44) months after surgery. The improvement in Frankel's score (on average) was two levels in most patients. CONCLUSION: These data demonstrate that our new reduction technique is a simple, safe, and effective treatment for ULFJLCS. PMID- 28808752 TI - Return to work and work-related disability among AML survivors. AB - Acute myeloid leukemia (AML) is an aggressive, acute-onset hematological malignancy. Greater use of intensive chemotherapy (IC), supportive care, and stem cell transplantation have led to an increasing number of long-term survivors. Few studies have examined employment issues among AML survivors and to our knowledge, no study has examined the long-term effects of treatment on return to work. This study is the first to utilize a validated measure of work-related limitation and productivity (WLQ-16) to assess the long-term effects of AML treatment on employment rates, work-related limitations, and overall productivity. We examined RTW issues in 111 adult AML 1-year survivors after conventional IC. We found that, over time, the number of employed survivors increased (to 54% by 36 months) while the number of unemployed, retired, and sick leave patients decreased. Among those employed, the majority were employed full time. Employed individuals reported few work-related limitations and productivity loss scores were low, ranging from 3.47% at 18 months to 2.34% at 36 months. These data suggest that, over time, over half of AML survivors who underwent IC regain social, emotional, cognitive, and physical function sufficient to RTW with few limitations. PMID- 28808753 TI - Segmental torsion assessment is a reliable method for in-depth analysis of femoral alignment in Computer Tomography. AB - PURPOSE: De-rotational osteotomies are indicated in patients with pathologic femoral torsion. However, there is disagreement whether an osteotomy should be performed proximally or distally. Conventionally only the total torsion is measured, which does not allow differentiation between a torsional deformity located in the proximal or distal metaphysis or the diaphysis. The aim of this study is to validate a new multi-level measurement protocol for evaluation of the magnitude of torsion of the respective femoral segments in CT. PATIENTS AND METHODS: The torsional profile of 30 femora was evaluated in CT scans. For separate measurements of the torsion of the metaphysis and the diaphysis, four axes where determined: one through the femoral neck, a second determined by the midpoint of the femoral shaft and the lesser trochanter, a third determined by a tangent dorsal to the popliteal surface, and a fourth axis posterior to the condyles. The total femoral torsion was measured between the first and the fourth axis, proximal torsion between the first and the second, mid torsion between the second and the third, and distal torsion between the third and the fourth axis. Four investigators performed all measurements independently and intra-class correlation coefficients (ICC) were calculated to evaluate intra- and inter-rater reliability. RESULTS: Average total femoral torsion was 22.6 +/- 8.7 degrees , proximal torsion 47.7 +/- 10.6 degrees , mid torsion -33.4 +/- 9.9 degrees , and distal torsion 8.3 +/- 3.2 degrees . Intra-rater ICC ranged between 0.504 and 0.957 and inter-rater ICC between 0.643 and 0.992. The majority of the ICC were graded as "almost perfect" and some as "substantial" agreement. CONCLUSION: Evaluation of the segmental torsion of the femur allows in-depth analysis of femoral alignment. High reliability was shown for this measuring method in computed tomography, which can be deployed when studying interdependencies between joint pathologies and torsional deformities or when planning the site for an osteotomy. LEVEL OF EVIDENCE: Level III. PMID- 28808754 TI - Three dimensionalCT analysis of femoral tunnel position after ACL reconstruction. A prospective study of one hundred and thirty five cases. AB - BACKGROUND: One of the principal causes for failure of anterior cruciate ligament reconstruction (ACL) is femoral tunnel mal-position. Several studies compare the position of femoral tunnels achieved with various techniques, with small series and using a quadrant assessment method. QUESTIONS: (1) What is the incidence of anatomical positioning of the intra-articular femoral tunnel aperture in primary ACL reconstruction in a university knee surgery? (2) What are the main errors in positioning? METHODS: 3D-CT scans were performed after primary ACL reconstruction in 135 consecutive cases. The intra-articular position of the femoral tunnel aperture was analyzed using the Magnussen classification. RESULTS: The intra articular tunnel position was deemed anatomical in 77%, intermediate in 20.8%, and non-anatomical in 2.2%. Among the mal-positioned tunnels, 54.8% were vertical, 29% were anteriorly positioned, and 16.1% were both. CONCLUSIONS: The intra articular femoral tunnel aperture was well positioned using an outside-in technique. The main error of tunnel positioning was a tunnel too vertical. LEVEL OF EVIDENCE: Level III, prospective study (case series). PMID- 28808755 TI - The Impact of the Location of Esophagogastrostomy on Acid and Duodenogastroesophageal Reflux After Transthoracic Esophagectomy with Gastric Tube Reconstruction and Intrathoracic Esophagogastrostomy. AB - BACKGROUND: The aim of this study was to evaluate the impact of the location of esophagogastrostomy on acid and duodenogastroesophageal reflux (DGER) in patients undergoing gastric tube reconstruction and intrathoracic esophagogastrostomy. METHODS: Thirty patients receiving transthoracic esophagectomy without cervical lymph node dissection and gastric tube reconstruction by intrathoracic anastomosis were enrolled. All patients underwent 24-h pH and bilirubin monitoring and gastrointestinal endoscopy one year after surgery. Patients were divided into three groups according to esophagogastrostomy location: group A (n = 9), above the top of the aortic arch; group B (n = 15), between the top and bottom of the aortic arch; and group C (n = 6), below the bottom of the aortic arch. The relations among the esophagogastrostomy location, 24-h pH and bilirubin monitoring results, endoscopic findings, and reflux symptoms were investigated. RESULTS: No acid reflux into the remnant esophagus was observed in group A, whereas it was observed in three of 15 patients (20%) in group B and in two of six patients (33%) in group C (P = 0.139). No DGER was found in group A, whereas DGER was observed in eight (53%) patients in group B and all patients in group C (P < 0.001). Reflux esophagitis was observed in one patient (11%) in group A, five patients (33%) in group B, and all patients in group C (P = 0.002). CONCLUSION: In gastric tube reconstruction via intrathoracic anastomosis, esophagogastrostomy should be performed above the top of the aortic arch to prevent postoperative DGER and reduce the incidence of reflux esophagitis. PMID- 28808756 TI - Relationship Between 18F-fluorodeoxyglucose Accumulation and the BRAF V600E Mutation in Papillary Thyroid Cancer. AB - BACKGROUND: To determine whether 18F-fluoro-2-deoxyglucose (18F-FDG)-PET/CT is useful for predicting the BRAF V600E mutation status of a primary papillary thyroid carcinoma (PTC). METHODS: A retrospective analysis was performed in 108 patients who underwent 18F-FDG positron emission tomography-computed tomography (PET/CT) for staging before thyroidectomy and BRAF analysis in biopsy-confirmed PTC. The maximum standardized uptake value (SUVmax) of the primary tumor was calculated according to FDG accumulation. Univariate and multivariate analyses were performed to assess the association between the SUVmax and clinicopathological variables. RESULTS: The BRAF V600E mutation was detected in 71 of 108 (65.7%) patients. In all subjects, the tumor size and BRAF V600E mutation were independently related to the SUVmax according to multivariate analyses (P = 0.002 and 0.007, respectively). The SUVmax was significantly higher in tumors with the BRAF V600E mutation than in tumors with wild-type BRAF (10.24 +/- 11.89 versus 4.02 +/- 3.86; P = 0.007). In the tumor size >1 cm subgroup, the BRAF V600E mutation was the only factor significantly associated with the SUVmax (P = 0.016). A SUVmax cutoff level of 4.9 was determined to be significant for predicting the BRAF V600E mutation status (sensitivity 77.4%, specificity 100.0%, area under the curve 0.929; P < 0.0001) according to ROC curve analysis. CONCLUSIONS: The BRAF V600E mutation is independently associated with high 18F FDG uptake in PTC, especially in those with a tumor size >1 cm. PMID- 28808757 TI - CT-Guided Percutaneous Trans-scapular Lung Biopsy in the Diagnosis of Peripheral Pulmonary Lesion Nodules of the Superior Lobes Using Large Needles. AB - PURPOSE: CT-guided percutaneous transthoracic lung needle biopsy (PLB) is an effective procedure for obtaining cyto-histological diagnoses of peripheral lesions. However, upper postero-lateral lung nodules (UPLN) may be difficult to reach using a standard intercostal either anterior or lateral approach or when the nodule is just behind a rib or scapula. We evaluated the feasibility and effectiveness of trans-scapular approach (tPLB) in these patients using large core needles. METHODS: We retrospectively collected the data of 11 consecutive patients (mean age 74.6 years, SD 5.9) among those scheduled to undergo CT-guided PLB over the period February 2015 to February 2017. In these patients, the presence of a UPLN required a tPLB using a co-axial technique and large full-core needles (15G for the scapular piercing and 18-19G for tissue sampling). All patients were assessed by telephone at 24 h, 78 h and at an office visit at 30 days after the procedure to evaluate post-procedural pain (VAS score) and shoulder mobility. RESULTS: Ten of the eleven samples were diagnostic. No major complications were encountered. Three patients developed a pneumothorax, but none required pleural drainage. All the patients confirmed the absence of pain at 24 72 h and 30 days, reporting a VAS score less than 1, without any shoulder mobility limitation. CONCLUSION: tPLB seems to be an effective and feasible procedure, accompanied by a low risk of pneumothorax in UPLN cases. PMID- 28808758 TI - Radical Nephrectomy for Primary Retroperitoneal Liposarcoma Near the Kidney has a Beneficial Effect on Disease-Free Survival. AB - BACKGROUND: The purpose of this study is to analyze the clinical impact of radical nephrectomy on retroperitoneal liposarcoma near the kidney. METHODS: Data of patients who underwent surgery for unilateral primary retroperitoneal liposarcoma near the kidney were retrospectively collected. Patients were divided into four groups according to whether they underwent nephrectomy and combined resection of other organs. Kaplan-Meier survival analysis was used to estimate disease-free survival and overall survival. Multivariable Cox analysis was used to analyze factors related to disease-free survival and overall survival. RESULTS: Nephrectomy (HR = 0.260, CI = 0.078-0.873, p = 0.029) had a beneficial effect on disease-free survival, while interaction model of nephrectomy*other organ resection (HR = 4.655, CI = 1.767-12.263, p = 0.002) showed poor disease free survival. Other organ resection was not related to disease-free survival (HR = 1.543, CI = 0.146-16.251, p = 0.718). Operation method (p = 0.007) and FNCLCC grade (p < 0.001; G2, HR = 1.833, CI = 0.684-4.915, p = 0.228; G3, HR = 9.190, CI = 3.351-25.199, p < 0.001) were significant factors for disease-free survival. While combined organ resection without nephrectomy group (HR = 1.604, CI = 0.167 15.370, p = 0.682) and radical nephrectomy with combined organ resection group (HR = 1.309, CI = 0.448-3.825, p = 0.622) did not show significant difference in disease-free survival from the mass excision only group, radical nephrectomy without combined organ resection group (HR = 0.279, CI = 0.078-0.991, p = 0.048) showed superior disease-free survival. CONCLUSIONS: Radical nephrectomy of unilateral primary retroperitoneal liposarcoma near the kidney has a beneficial effect on disease-free survival. PMID- 28808759 TI - Life-threatening bleeding episodes in primary immune thrombocytopenia: a single center retrospective study of 169 inpatients. AB - Bleeding is the most important clinical outcome in patients with immune thrombocytopenia (ITP), and the goal of therapy in such cases is to treat or prevent bleeding. The frequency of and risk factors for bleeding events in ITP have only recently been identified in several large-scale studies. However, there is little published information about severe life-threatening bleeding in ITP. To clarify the clinical features of life-threatening bleeding in patients with primary ITP, we systematically reviewed the medical records of all ITP patients that were admitted to our hospital between January 1, 1992, and December 31, 2015. Of 169 consecutive inpatients with primary ITP, 8 suffered life-threatening bleeding (10 episodes: gastrointestinal, 4 cases; pulmonary, 1 case; and intracranial, 5 cases). All of these patients were >= 60 years of age and had platelet counts of < 20 * 109/L. The highest incidence of such bleeding was found among elderly patients in their 80s with platelet counts of < 5 * 109/L. Among the patients aged >= 60 years with platelet counts of < 20 * 109/L, the background data of the patients with and without life-threatening bleeding episodes were compared. It was shown that the patients in the bleeding group were older than those in the non-bleeding group (80.13 +/- 2.31 vs. 73.39 +/- 2.51 years, p = 0.0266). Hypertension, diabetes mellitus, anticoagulant use, ITP phase, and sex were not identified as strong risk factors for life-threatening bleeding. Combining age and the platelet count might be a useful way of identifying ITP patients that are at risk of life-threatening bleeding. Most intracranial hemorrhaging (4/5) was spontaneous and multifocal, suggesting that these might be characteristics of ITP-related bleeding in elderly patients. PMID- 28808760 TI - [Orthogeriatrics]. PMID- 28808761 TI - The underappreciated risk of thrombosis and bleeding in patients with myelofibrosis: a review. AB - Bleeding and thrombosis are long recognized complications of myelofibrosis (MF) and contribute significantly to its morbidity and mortality. However, so far, few studies have evaluated the frequency of these events, their characteristics, and their prognostic impact. Based on these studies, thrombotic events in MF are about as common as in essential thrombocytemia (ET) but less common than in polycythemia vera (PV), while bleeding events are relatively more common in MF than in ET or PV. The emergence of the concept of prefibrotic primary MF (PMF), which is associated with a higher frequency of thrombohemorrhagic complications than ET, and the growing evidence that prefibrotic PMF may also have a different thrombotic and bleeding risk profiles than fibrotic (overt) PMF have emphasized the need for a reappraisal of the risk of thrombosis and hemorrhage in patients with MF. In this review, we discuss the frequency of thrombosis and bleeding in patients with MF, including prefibrotic PMF and their established and potential risk factors. PMID- 28808762 TI - Relationships between more than 90% coronary luminal narrowing induced by ergonovine provocation test and ECG ischemic change as well as chest symptoms. AB - In the clinic, patients with >=90% luminal narrowing during ergonovine (ER) testing had variable response. We investigated ischemic findings and chest symptoms in patients with >=90% luminal narrowing when performing ER tests, retrospectively. We performed 1210 ER tests over 26 years (1991-2016). We analyzed chest symptoms and positive ischemic ECG changes during ER tests. More than 90% luminal narrowing was found in 352 patients (29.1%) including 211 patients in the right coronary artery (RCA) and 217 patients in the left coronary artery (LCA). Chest symptom was observed in 290 patients (82.4%) including 162 patients in the RCA and 179 patients in the LCA. ST elevation was found in 154 patients including 98 in the RCA and 73 patients in the LCA, while ST depression was recognized in 81 patients including 38 patients in the RCA and 62 patients in the LCA. Two-third of patients with >=90% luminal narrowing had significant ischemic ECG changes, whereas 60.5% of patients with >=90% luminal narrowing complained usual chest pain accompanied with significant ischemic ECG changes. Unusual chest symptom was complained in 7.1% of patients with >=90% luminal narrowing. Neither chest symptom nor ECG changes was found in 48 patients (13.6%) with >=90% luminal narrowing. We should understand some limitation to diagnose positive coronary spasm during ER tests. PMID- 28808763 TI - Characteristics of gastroesophageal reflux in pediatric patients with neurological impairment. AB - PURPOSE: To clarify the characteristics of gastroesophageal reflux (GER) in pediatric patients with neurological impairment (NI). METHODS: Twenty-six patients with NI, 1-17-year-old, fed via a nasogastric tube were categorized based on the absence (group I) or presence (group II) of abnormal GER, defined with multichannel intraluminal impedance-pH monitoring as %time with an esophageal pH <4.0 being >=5.0% or number of liquid/mixed bolus reflux events(RE) >70 in 24 h. RESULTS: %Time and number of distal and proximal bolus REs were not significantly different between acid and nonacid REs. %Time of acid bolus RE and that of acid and total number of distal and proximal bolus REs were significantly higher in group II than in group I. Mean acid clearance time was significantly longer in group II. Median bolus clearance time was similar between the groups. No bolus RE parameters were significantly different between acid and nonacid REs in group I. Acid bolus RE was significantly higher than nonacid RE in terms of %time and number of proximal bolus RE in group II. CONCLUSION: Acid REs significantly increased in pediatric patients with NI with abnormal GER. The number of acid and nonacid REs was comparable in patients without abnormal GER. PMID- 28808764 TI - High-resolution 3-T MRI of the triangular fibrocartilage complex in the wrist: injury pattern and MR features. AB - OBJECTIVES: To investigate if using high-resolution 3-T MRI can identify additional injuries of the triangular fibrocartilage complex (TFCC) beyond the Palmer classification. MATERIALS AND METHODS: Eighty-six patients with surgically proven TFCC injury were included in this study. All patients underwent high resolution 3-T MRI of the injured wrist. The MR imaging features of TFCC were analyzed according to the Palmer classification. RESULTS: According to the Palmer classification, 69 patients could be classified as having Palmer injuries (52 had traumatic tears and 17 had degenerative tears). There were 17 patients whose injuries could not be classified according to the Palmer classification: 13 had volar or dorsal capsular TFC detachment and 4 had a horizontal tear of the articular disk. CONCLUSION: Using high-resolution 3-T MRI, we have not only found all the TFCC injuries described in the Palmer classification, additional injury types were found in this study, including horizontal tear of the TFC and capsular TFC detachment. We propose the modified Palmer classification and add the injury types that were not included in the original Palmer classification. PMID- 28808765 TI - Presentation and symptom interval in children with central nervous system tumors. A single-center experience. AB - PURPOSE: The aim of this study is to describe the symptoms and signs of central nervous system (CNS) tumors in a pediatric population and to assess the time interval between the onset of the disease and the time of the diagnosis. METHODS: A retrospective observational study was conducted at our Oncology Pediatric Unit between January 2000 and November 2011. We included 75 children between 5 months and 16 years (mean age of 7.8 +/- 4.7 years), with male to female ratio of 3:2. The tumor localization was supratentorial in 51% of cases, and the most frequent histological type was low-grade astrocytoma (48%). RESULTS: Presenting symptoms were headache (31%), vomiting (31%), seizures (21%), and behavioral change (11%). The most common symptoms at diagnosis were headache (51%), vomiting (51%), visual difficulties (37%), seizures (24%), and behavioral change (21%). By the time of diagnosis, neurologic examination was altered in 68% of our patients. Vomiting (44%) and behavioral change (44%) were the most frequent symptoms in children under 4 years of age, headache (61%) and vomiting (54%) in children older than 4 years. The median interval between symptoms' onset and diagnosis was 4 weeks (range 0 to 314 weeks). A longer symptom interval was associated with younger age, infratentorial localization and low-grade tumors. The differences in symptom intervals between the different age, location, and grade groups were not statistically significant. Survival probability was influenced by tumor grade but not by diagnostic delay or age of the child. CONCLUSIONS: Headache and vomiting are the earliest and commonest symptoms in children with brain tumors. Visual symptoms and signs and behavioral change are often present. Abnormalities in neurological examination are reported in most of the children. Intracranial hypertension symptoms suggest the need for a neurological clinical examination and an ophthalmological assessment. PMID- 28808766 TI - Water penetration of grommets: an in vitro study. AB - The insertion of grommets has been one of the most common procedures carried out by ENT surgeons for patients with persistent middle ear fluid. There has always been apprehension at the use of grommets by patients undertaking swimming or other water sports due to concerns of grommet penetration by water into the middle ear. Despite this, no common consensus exists amongst otolaryngologists regarding post-operative advice following grommet insertion. Most studies focus on surface swimming and do not consider other activities such as diving that patients may undertake. This study aimed to determine the hydrostatic head required for water to pass through a grommet using different water-based solutions. These were selected to simulate conditions such as swimming and showering or bathing. An improved model of a grommeted middle ear (based on previous work by Ricks et al.) was constructed using two 5-ml plastic syringes, latex (from a surgical glove), two rubber neoprene membranes and a Shah Ventilation Tube (1.14 mm). Different water solutions were added to the system and the hydrostatic head measured using digital calipers. The results revealed that the hydrostatic head required to penetrate a grommet is lowest using soapy water and highest with distilled water. The differences between chlorinated water and 3% saline were not significant. We hope that this study can be used in conjunction with previous work to better prepare the ENT surgeon in giving suitable post-operative advice following grommet insertion. PMID- 28808768 TI - High-resolution MRI (3T-MRI) in diagnosis of wrist pain: is diagnostic arthroscopy still necessary? AB - INTRODUCTION: 3T MRI has become increasingly available for better imaging of interosseous ligaments, TFCC, and avascular necrosis compared with 1.5T MRI. This study assesses the sensitivity and specificity of 3T MRI compared with arthroscopy as the gold standard. PATIENTS AND METHODS: Eighteen patients were examined with 3T MRI using coronal T1-TSE; PD-FS; and coronal, sagittal, and axial contrast-enhanced T1-FFE-FS sequences. Two musculoskeletal radiologists evaluated the images independently. Patients underwent diagnostic arthroscopy. RESULTS: The classifications of the cartilage lesions showed good correlations with the arthroscopy findings (kappa = 0.8-0.9). In contrast to the arthroscopy, cartilage of the distal carpal row was very good and could be evaluated in all patients on MRI. The sensitivity for the TFCC lesion was 83%, and the specificity was 42% (radiologist 1) and 63% (radiologist 2). For the ligament lesions, the sensitivity and specificity were 75 and 100%, respectively, with a high interobserver agreement (kappa = 0.8-0.9). DISCUSSION: 3T MRI proved to be of good value in diagnosing cartilage lesions, especially in the distal carpal row, whereas wrist arthroscopy provided therapeutic options. When evaluating the surgical therapeutical options, 3T MRI is a good diagnostic tool for pre operatively evaluating the cartilage of the distal carpal row. PMID- 28808767 TI - Identification and expression analysis of microRNAs during ovule development in rice (Oryza sativa) by deep sequencing. AB - KEY MESSAGE: MicroRNA (miRNA) expression profiles during rice ovule development revealed the possible miRNA-mediated regulation between ovule sporophytic tissue and female gametophyte and the involvement of miRNAs in programmed cell death. MiRNAs are 20-24-nucleotide small RNAs that play key roles in the regulation of many growth and developmental processes in plants. Rice ovule development comprises a series of biological events, which are regulated by complex molecular mechanisms. To gain insight into miRNA-mediated regulation of rice ovule development, Illumina sequencing was used to examine the expression of miRNAs from the megaspore mother cell meiosis stage to the fertilized ovule stage. Based on the sequencing data, 486 known and 204 novel miRNAs were identified during rice ovule development. Moreover, 56, 65 and 11 differentially expressed miRNAs between adjacent developmental stages were identified. By analyzing transcriptome and degradome data, we identified 41, 65 and 12 coherent target genes for the differentially expressed miRNAs in ovule development. We found that changes in the expression of plant hormone-related miRNAs may play important roles in embryo sac development, providing evidence for cross-talk communication between sporophytic tissue and the female gametophyte. Additionally, we revealed that miRNAs may be involved in programmed cell death after fertilization. Finally, we constructed miRNA-mediated regulatory networks that are active during rice ovule development. PMID- 28808769 TI - The genetic characteristics in cytology and plant physiology of two wheat (Triticum aestivum) near isogenic lines with different freezing tolerances. AB - KEY MESSAGE: Freezing tolerance in taft plants relied more upon an ABA independent- than an ABA-dependent antifreeze signaling pathway. Two wheat (Triticum aestivum) near isogenic lines (NIL) named tafs (freezing sensitivity) and taft (freezing tolerance) were isolated in the laboratory and their various cytological and physiological characteristics under freezing conditions were studied. Proplastid, cell membrane, and mitochondrial ultrastructure were less damaged by freezing treatment in taft than tafs plants. Chlorophyll, ATP, and thylakoid membrane protein contents were significantly higher, but malondialdehyde content was significantly lower in taft than tafs plants under freezing condition. Antioxidant capacity, as indicated by reactive oxygen species accumulation and antioxidant enzyme activity, and the relative gene expression were significantly greater in taft than tafs plants. Soluble sugars and abscisic acid (ABA) contents were significantly higher in taft plants than in tafs plants under both normal and freezing conditions. The upregulated expression levels of certain freezing tolerance-related genes were greater in taft than tafs plants under freezing treatment. The addition of sodium tungstate, an ABA synthesis inhibitor, led to only partial freezing tolerance inhibition in taft plants and the down-regulated expression of some ABA-dependent genes. Thus, both ABA dependent and ABA-independent signaling pathways are involved in the freezing tolerance of taft plants. At the same time, freezing tolerance in taft plants relied more upon an ABA-independent- than an ABA-dependent antifreeze signaling pathway. PMID- 28808770 TI - Associations between serum calcium, phosphorus and mortality among patients with coronary heart disease. AB - PURPOSE: Serum calcium and phosphorus abnormalities are associated with cardiovascular disorders in general population, but evidence among patients with established coronary heart disease (CHD) is limited and controversial. This study aimed to investigate the associations of baseline serum calcium and phosphorus levels with long-term mortality risk among patients with CHD. METHODS: We conducted a prospective cohort study among 3187 patients with CHD from October 2008 and December 2011 in China. Cox proportional hazards model was used to assess the associations of serum calcium and phosphorus at baseline with the risk of death. RESULTS: During follow-up (mean, 4.9 years), 295 patients died, 193 of which resulted from cardiovascular causes. Multivariable-adjusted hazard ratios (HR) for each 1 mmol/L increase in serum calcium at baseline were 0.27 (95% confidence interval (CI) 0.14-0.51) for all-cause mortality and 0.26 (95% CI 0.12 0.54) for cardiovascular mortality. Patients in the highest compared to the lowest quartile of serum calcium were at lower risk of all-cause mortality (HR, 95% CI 0.57, 0.40-0.82) and cardiovascular mortality (0.50, 0.32-0.79) (both P trend < 0.001). This inverse association between serum calcium and the risk of mortality did not change when participants were stratified by sex, age groups, level of overweight, types of CHD, and history of diabetes. We also observed a graded positive association between baseline serum phosphorus and the risks of mortality. CONCLUSIONS: The present study is the first to report that lower serum calcium at baseline is associated with an increased risk of all-cause and cardiovascular mortality in a Chinese coronary heart disease cohort. Further studies are required to investigate the causal relationship and actual mechanisms. PMID- 28808771 TI - Multicentre, controlled, randomized clinical trial to compare the efficacy and safety of ambulatory treatment of mild acute diverticulitis without antibiotics with the standard treatment with antibiotics. AB - PURPOSE: Acute diverticulitis (AD) is a highly prevalent disease in Spain. Its chronic-recurrent appearance and high rate of relapse mean that it has a major epidemiological and economic impact on our health system. In spite of this, it has not been studied in any great depth. Reassessing its etiopathology, recent studies have observed that it is an inflammatory disease-not, as classic theories had postulated, an infectious one. In the light of these findings, the suitability of antibiotics for its treatment has been reconsidered. At present, however, the evidence for incorporating these findings into clinical practice guidelines remains insufficient. METHODS: This study was designed to analyse the safety and efficacy of a non-antibiotic treatment for mild AD. Patients with mild AD (grade 0 in the modified Neff classification) who meet the inclusion criteria will be randomly assigned to one of two outpatient treatment strategies: (a) classical treatment (antibiotics, anti-inflammatories and low-fibre diet) or (b) experimental treatment (anti-inflammatories and low-fibre diet). Clinical controls will be performed at 2, 7, 30, and 90 days. We will determine whether there are any differences in the clinical outcome between groups. The main objective is to demonstrate that antibiotics neither accelerate the resolution of the disease nor decrease the number of complications and/or recurrences in these patients, suggesting that their use may be unnecessary. CONCLUSIONS: The results of this trial will help to optimize and homogenize the treatment of this highly prevalent disease. However, more studies are required before firm changes can be introduced in international clinical practice guidelines. TRIAL REGISTRATION: The trial has been registered at the ClinicalTrials.gov database (ID: NCT02785549) and the EU Clinical Trials Register database (EudraCT number: 2016-001596-75). PMID- 28808773 TI - [Requirements of clinicians on pathology : A viewpoint from pathology]. PMID- 28808772 TI - Longitudinal strain assessed by cardiac magnetic resonance correlates to hemodynamic findings in patients with severe aortic stenosis and predicts positive remodeling after transcatheter aortic valve replacement. AB - AIMS: To assess left-ventricular strain parameters before and after transcatheter aortic valve replacement (TAVR) by feature tracking cardiac magnetic resonance imaging (FT CMR) and to correlate the findings to hemodynamic state and left ventricular remodeling. METHODS AND RESULTS: Patients with symptomatic AS underwent FT CMR before and after TAVR. Patients were carefully evaluated by a comprehensive work-up including CMR, echocardiography and left and right heart catheterization. Thirty patients formed the study population. High-flow/high gradient (HF/HG) aortic stenosis was diagnosed in 11 patients (36.7%), 6 patients (20.0%) exhibited low-flow/low-gradient AS (LF/LG) and 13 patients (43.3%) were classified to have so-called paradoxical low-flow/low-gradient (PLF/LG) AS. The HF/HG patients had a significantly reduced longitudinal strain which recovered after TAVR (-12.67 +/- 4.60 to -15.46 +/- 5.61%, p = 0.048). In the LF/LG group, an even more pronounced reduction of longitudinal strain and also an impairment of longitudinal velocity could be observed. Both parameters improved after therapy (strain: -5.06 +/- 4.25 to -8.02 +/- 3.28%, p = 0.045; velocity: 25.33 +/ 9.63 to 37.13 +/- 11.64 mm/s, p = 0.042). Patients with PLF/LG showed preserved longitudinal strain but a reduction of longitudinal velocity similar to the LF/LG group. These patients did not show a significant improvement of strain parameters after TAVR. Longitudinal velocity exhibited the highest predictive power for the identification of a low-flow state (sensitivity 75%, specificity 80%). CONCLUSION: Improvement of longitudinal strain parameters after TAVR is dependent on the initial hemodynamically defined AS subgroup. PMID- 28808774 TI - [Refractive lenticule extraction - The ReLEx/SMILE technique : Video article]. AB - Refractive lenticule extraction (ReLEx/SMILE) is a refractive surgical method developed by the authors in stages primarily for correction of myopia and myopic astigmatism, in which a femtosecond laser is exclusively used. In the (ReLEx/SMILE) method a refractive lenticule is generated by the femtosecond laser, which is subsequently extracted through a small incision. Opening of the corneal surface with a flap and use of an excimer laser is no longer necessary. In 2013 the method was newly assessed and classified by the Joint Commisssion for Refractive Surgery (KRC) of the Professional Association of Ophthalmologists (BVA) and the German Ophthalmological Society (DOG). This article presents the individual stages of the technique in a video and possible errors and their avoidance are explained. PMID- 28808776 TI - [Anabolic and molecular interventions on muscle : Meaningful anti-aging strategy?] PMID- 28808775 TI - How novel structures inform understanding of complement function. AB - During the last decade, the complement field has experienced outstanding advancements in the mechanistic understanding of how complement activators are recognized, what C3 activation means, how protein complexes like the C3 convertases and the membrane attack complex are assembled, and how positive and negative complement regulators perform their function. All of this has been made possible mostly because of the contributions of structural biology to the study of the complement components. The wealth of novel structural data has frequently provided support to previously held knowledge, but often has added alternative and unexpected insights into complement function. Here, we will review some of these findings focusing in the alternative and terminal complement pathways. PMID- 28808777 TI - Phase II study of bi-weekly temozolomide plus bevacizumab for adult patients with recurrent glioblastoma. AB - PURPOSE: Bevacizumab is an active anti-angiogenic agent in the treatment of recurrent glioblastoma. Temozolomide can prolong survival in patients with newly diagnosed glioblastoma. At recurrence, alternate dosing of temozolomide has shown to further deplete methyl-guanine-methyltransferase (MGMT) conferring added activity for patients who have progressed on the standard dosing regimen. In this study, bevacizumab plus biweekly temozolomide was evaluated for efficacy in adult patients with recurrent glioblastoma. METHODS: Thirty patients with recurrent glioblastoma were treated with bevacizumab on (10 mg/kg i.v.) days 1 and 15 of a 28-day cycle combined with temozolomide (100 mg/m2) on days 1-5 and 15-19 on a 28 day cycle. Responses were assessed at week 4 and then every 8 weeks. MGMT status and quality of life measures were also assessed. RESULTS: Overall response rate from diagnosis was 51 weeks, the 6-month progression-free survival was 52%, and median time to tumor progression was 5.5 months. CONCLUSION: Bevacizumab plus bi weekly temozolomide was well tolerated and may be a salvage regimen to be considered in a subset of patients with recurrent glioblastoma. PMID- 28808778 TI - Audiogram of the mallard duck (Anas platyrhynchos) from 16 Hz to 9 kHz. AB - The pure-tone thresholds of three mallard ducks were determined from 16 Hz to 9 kHz. The purpose was to determine whether the mallard duck hears infrasound, which then may potentially be used for navigation, similar to how it is proposed that pigeons use it for homing. At a level of 60 dB sound pressure level (re 20 MUN/m2), their hearing range extends 6.85 octaves from 66 Hz to 7.6 kHz, with a best sensitivity of 12.5 dB at 2 kHz. However, at no frequency, including the lowest tested, were the ducks' thresholds lower than those of humans. Therefore, unlike pigeons and chickens, but like budgerigars, mallard ducks do not hear infrasound. Thus, the fact that a bird may fly long distances does not necessarily indicate that it hears infrasound. PMID- 28808779 TI - Optimisation of extraction methods and quantification of benzo[a]pyrene and benz[a]anthracene in yerba mate tea by isotope dilution mass spectrometry. AB - A gas chromatography-isotope dilution mass spectrometry (GC-IDMS) technique was developed for the quantification of two heavy polyaromatic hydrocarbons (PAHs), benz[a]anthracene and benzo[a]pyrene, in yerba mate tea (mate). The optimisation of two extraction methods, namely liquid-liquid extraction and accelerated solvent extraction, was carried out. Both optimised methods were validated using a certified reference material of fine dust and the results were within the expanded uncertainties at 95% confidence level. Recoveries of 99.2-106.7% with RSD of measurements of 1.1-2.3% were achieved for benz[a]anthracene. Recoveries of 95.7-101.9% with RSD of measurements of 0.4-1.4% were achieved for benzo[a]pyrene. The validated methods were applied for the extraction of benz[a]anthracene and benzo[a]pyrene in mate powder from NIST. A metrological approach was undertaken to ensure the traceability of measurement results. The uncertainties associated with the results were rigorously evaluated and also reported herein. Graphical abstract Quantification of benz[a]anthracene and benzo[a]pyrene using IDMS. PMID- 28808781 TI - Spontaneous complete regression of a brain stem glioma pathologically diagnosed as a high-grade glioma. AB - BACKGROUND: Spontaneous regressions of brain stem gliomas are extremely rare. Only six cases have been reported in the literature. CASE PRESENTATION: We describe the case of a patient who was diagnosed with a pontomedullary dorsal brain stem glioma at the age of 15 years. An open biopsy showed the presence of an anaplastic glioma. Because the patient and her parents refused conventional therapies, including radiation and chemotherapy, we followed up the patient by performing magnetic resonance imaging scans on her every 3 months. At 3 months after biopsy, we observed the radiological disappearance of her tumor. One year after biopsy, the tumor retained the spontaneous complete regression observed earlier. CONCLUSION: In this case report, we present the first report of the spontaneous complete regression of a brain stem glioma that was histologically proven to be a high-grade glioma and we believe that this regression was the natural progression of this case, as may be the scenario in a few other cases of brain stem gliomas. PMID- 28808780 TI - Non-CNS pathogenic origin of Parkinson's disease. AB - The gut with its variety of microbiota may serve as an etiological origin of diseases. Gut microbes may also play a role in the pathogenesis of diseases beyond their simple nutritional maintenance and support. For example, gut protein aggregation, possibly aided by microbes as well as nasal influences, might be linked to disease that may move to the brain through the vagus nerve. To this end, Braak has offered a "dual-hit" hypothesis that proposes a novel etiology for Parkinson's disease (PD). The hypothesis places the initial origin of the disease in the nose and the gastrointestinal tract (GI) after infection by an unknown pathogen that could aggregate in the gut and then eventually spread to the brain via the autonomic plexuses. Gut health functioning, therefore, may affect brain status and behavior. A protein known as alpha-synuclein accumulates in brains of people with Parkinson's disease that is also present in the GI before the onset of motor symptoms. Therefore, the stomach, previously thought to be a stable mechanism throughout life, might explain some etiological origins of disease. Finally, the vagus nerve of the autonomic system that extends from the brain to the abdomen and exercises both sympathetic and parasympathetic roles might be associated with PD diagnosis along with Lewy body influences. PMID- 28808782 TI - Thromboembolic Events Following Splenectomy: Risk Factors, Prevention, Management and Outcomes. AB - BACKGROUND: Thromboembolic events following splenectomy are not uncommon. However, the role of thromboprophylaxis and risk factors for thrombosis, as well as the clinical course and outcomes, are not well characterized. METHODS: A retrospective review of individuals who underwent splenectomy between January 2006 and December 2015 in two university hospitals. RESULTS: Overall, 297 patients underwent splenectomy [open splenectomy (n = 199), laparoscopic splenectomy (n = 98)]. Mechanical (thigh-length pneumatic compression stockings) and pharmacologic thromboprophylaxis (40 mg enoxaparin daily, starting 12 h after surgery until discharge) was provided for all patients. One hundred and sixteen patients (39%) also received an extended thromboprophylaxis course of enoxaparin for 2-4 weeks after discharge. Twenty-three patients (7.7%) experienced thrombotic complications following splenectomy, including 16 cases (5.4%) of portal-splenic mesenteric venous thrombosis (PSMVT), 5 (1.7%) pulmonary embolism and 2 (0.7%) deep vein thrombosis. Longer operative time (mean operative time of 405 vs. 273 min, P = 0.03) was independently associated with PSMVT. Post splenectomy thrombocytosis was not associated with thrombosis (P = 0.41). The overall thrombosis rate was significantly lower in patients who received an extended thromboprophylaxis course following splenectomy (3.4 vs. 10.5%, P = 0.02). Complete resolution of thrombosis was observed in most cases (n = 20, 87.0%), with no recurrent thrombosis during a mean follow-up of 38 +/- 25 months. CONCLUSIONS: Thromboembolic complications, mainly PSMVT, are common following splenectomy. Longer operative time was associated with thrombosis. Significantly lower rates of thrombosis were found in patients who received an extended thromboprophylaxis course. PMID- 28808783 TI - Post-stroke seizures are clinically underestimated. AB - Cerebrovascular disease is the leading cause of epilepsy in adults, although post stroke seizures reported frequency is variable and few studies used EEG in their identification. To describe and compare EEG and clinical epileptic manifestations frequency in patients with an anterior circulation ischaemic stroke. Prospective study of acute anterior circulation ischaemic stroke patients, consecutively admitted to a Stroke Unit over 24 months and followed-up for 1 year. All patients underwent standardized clinical and diagnostic assessment. Seizure occurrence was clinically evaluated during hospitalization and by a telephone interview at 6 months and a clinical appointment at 12 months after stroke. Video-EEG was performed in the first 72 h (1st EEG), daily after the 1st EEG for the first 7 days after the stroke, or later if neurological worsening, at discharge, and at 12 months. 151 patients were included (112 men) with a mean age of 67.4 (11.9) years. In the 1st year after stroke, 38 patients (25.2%) had an epileptic seizure. During hospitalization, 27 patients (17.9%) had epileptiform activity (interictal or ictal) in the EEG, 7 (25.9%) of them electrographic seizures. During the first week after stroke, 22 (14.6%) patients had a seizure and 4 (2.6%) non-convulsive status epilepticus criteria. Five (22.7%) acute symptomatic seizures were exclusively electrographic. At least one remote symptomatic seizure occurred in 23 (16%) patients. In the first 7 days after stroke, more than one fifth of patients with seizures had exclusively electrographic seizures. Without a systematic neurophysiological evaluation the frequency of post-stroke seizures are clinically underestimated. PMID- 28808784 TI - The history of optic chiasm from antiquity to the twentieth century. AB - PURPOSE: The optic chiasm is an essential structure located at the skull base that stirred over time the curiosity of anatomists, who became more and more interested in its structure and function. Through centuries, the optic chiasm was viewed as a vessel crossing, a way of transporting tears secreted by the brain to the eye, integrating images, or responsible for coordinated eye movements. The paper aims to overview the history of understanding the optic chiasm from the beginnings of antiquity to the twentieth century. METHODS: We reviewed the literature and studied all the historical sources on optic chiasm and eyes in the works of ancient, medieval, Renaissance authors, and the seventeenth to nineteenth century works. RESULTS: The optic chiasm is a structure that fascinated ancient anatomists and made them develop various theories on its function. In terms of function, the optic chiasm had a history based more on speculation, the seventeenth century bringing its first understanding and reaching the peak in the nineteenth century with the understanding of the anatomical structure of the chiasm and its role in the visual process. CONCLUSION: The history of the optic chiasm is a fascinating time travel displaying the conceptual transformations that have been made in anatomy and medicine by our forerunners. PMID- 28808786 TI - Inhibition of TLR4 alleviates the inflammation and apoptosis of retinal ganglion cells in high glucose. AB - PURPOSE: To investigate the expression profiles of Toll-like receptor 4 (TLR4), the effect of TLR4 on inflammation, and apoptosis of retinal ganglion cells (RGCs) cultured in high glucose and the underlying mechanism. METHODS: A high glucose model was established in RGCs isolated from Sprague-Dawley (SD) rats (2-3 days old) and identified with Brn3a. Primary cultured RGCs were divided into control (0 mM), HG1 (10 mM glucose), HG2 (20 mM glucose), HG3 (30 mM glucose), HG (20 mM glucose) + TAK-242 (1.0 MUM), and HG (20 mM glucose) + vehicle (1% DMSO) groups. The expression levels of TLR4, its downstream signalling molecules, and pro-inflammatory cytokines were measured by real-time PCR, Western blot or ELISA at 24 h and 48 h. The apoptosis rate of RGCs was measured by flow cytometry. RESULTS: The mRNA and protein expression levels of TLR4 were increased in high glucose groups (10 mM, 20 mM, 30 mM). Consistent with these findings, four TLR4 downstream signalling molecules (MyD88, NF-kappaB, TRAF6, NLRP3) and pro inflammatory cytokines (IL-1beta, IL-18) were upregulated in the three high glucose groups. Apoptosis of RGCs was clearly increased in the high-glucose group. The administration of TAK-242, an antagonist of TLR4, inhibited inflammation and apoptosis of RGCs in the high-glucose group. CONCLUSION: Our results demonstrated that TLR4 plays a critical role in the inflammation and apoptosis of RGCs induced by high glucose. TLR4 might become a novel potential pharmacological target for preventing the progression of DR. PMID- 28808785 TI - Conserved DNA methylation combined with differential frontal cortex and cerebellar expression distinguishes C9orf72-associated and sporadic ALS, and implicates SERPINA1 in disease. AB - We previously found C9orf72-associated (c9ALS) and sporadic amyotrophic lateral sclerosis (sALS) brain transcriptomes comprise thousands of defects, among which, some are likely key contributors to ALS pathogenesis. We have now generated complementary methylome data and combine these two data sets to perform a comprehensive "multi-omic" analysis to clarify the molecular mechanisms initiating RNA misregulation in ALS. We found that c9ALS and sALS patients have generally distinct but overlapping methylome profiles, and that the c9ALS- and sALS-affected genes and pathways have similar biological functions, indicating conserved pathobiology in disease. Our results strongly implicate SERPINA1 in both C9orf72 repeat expansion carriers and non-carriers, where expression levels are greatly increased in both patient groups across the frontal cortex and cerebellum. SERPINA1 expression is particularly pronounced in C9orf72 repeat expansion carriers for both brain regions, where SERPINA1 levels are strictly down regulated across most human tissues, including the brain, except liver and blood, and are not measurable in E18 mouse brain. The altered biological networks we identified contain critical molecular players known to contribute to ALS pathology, which also interact with SERPINA1. Our comprehensive combined methylation and transcription study identifies new genes and highlights that direct genetic and epigenetic changes contribute to c9ALS and sALS pathogenesis. PMID- 28808787 TI - Malignant transformation of a conservatively managed incidental childhood cerebral mass lesion: controversy regarding management paradigm. AB - BACKGROUND: Incidental findings on neuroimaging in the pediatric population are an emerging treatment challenge. Treatment options for these incidental childhood brain mass lesions, which radiologically may be assumed to be low-grade gliomas (LGG), vary, ranging from careful conservative "wait and scan" treatment to surgical biopsy, gross total resection, and upfront radiation and/or chemotherapy. As malignant transformation of LGG in children is extremely rare, some series advocate careful conservative management of these lesions; however, universal treatment protocols are not totally agreed upon. ILLUSTRATIVE CASE: We present the case of a 10-year-old boy with a fronto-basal incidental cerebral mass lesion, suspected to be a low-grade glial neoplasm. Initially, magnetic resonance imaging (MRI) was done to rule out a pathology causing his growth to be delayed. A treatment with growth hormone was initiated. After close clinical and radiological follow-up of this asymptomatic lesion for 6 years, a minimal growth of the lesion was seen, which we decided to continue following. After 7 years, a clear growth with new contrast enhancement was seen on routine MRI. At this point, the lesion was surgically resected. The diagnosis was, surprisingly, glioblastoma multiforme (WHO grade IV, BRAF V-600E mutation). DISCUSSION: Malignant transformation of LGGs in children is a very rare phenomenon. This is to our knowledge the first well-documented case describing malignant transformation of a suspected benign pediatric cerebral mass lesion, which did not undergo radiation, in a patient without a cancer predisposition syndrome (e.g., neurofibromatosis), with the transformation occurring after such a long follow-up period. The management of these lesions is still controversial. Unfortunately, radiological risk factors for malignant transformation of such lesions in the pediatric age group are lacking. CONCLUSION: Conservative treatment of incidental cerebral mass lesions in children seems a valid option. These lesions should probably be followed indefinitely, while carefully watching for changes in imaging characteristics. PMID- 28808788 TI - Shocks after implantable cardioverter-defibrillator implantation in idiopathic cardiomyopathy patients: a myocardial biopsy study. AB - Prediction of follow-up shock is crucial to stratify patients with dilated cardiomyopathy (DCM) requiring implantable cardioverter defibrillator (ICD). The objective of the article is to assess the predictive value of endo-myocardial biopsy (EMB) towards ICD shock and follow-up mortality. A series of patients with DCM scheduled for ICD implantation underwent EMB to further determine the genesis of DCM. Presence of fibrosis and inflammation was documented and related to outcomes. A total of 240 patients were referred for ICD as primary (56%) and secondary (44%) prophylaxis. EMB showed myocardial fibrosis in 55.4%, inflammation in 55.7%, and viral genomic material in 60%. Median follow-up was 39 months (1-209). Appropriate and inappropriate shocks occurred in 29.2 and 20.4%. At logistic regression, determinants of appropriate shock were ICD indication for secondary prophylaxis (direct relationship: p = 0.009, OR 3.4, CI 1.3-8.8) and presence of inflammation at EMB (inverse relationship: p = 0.04, OR 0.4, CI 0.1 0.9). Moreover, the sole determinant of inappropriate shock was age at implant (inverse relationship: p = 0.003, OR = 0.9, CI 0.90-0.98). Overall mean estimated survival was 168 months and 5-year survival was 83%. Degree of improvement in LVEF% was the sole determinant of follow-up mortality (inverse relationship p = 0.02; HR = 0.9; CI 0.88-0.99). Present selection criteria for ICDs implant rely mainly on LVEF% that lacks sensitivity and specificity. EMB can identify the substrate of increased or reduced life-threatening arrhythmias. Presence of inflammation is a positive prognostic factor for reduced arrhythmogenic risk, independently by the ICD implantation indication. PMID- 28808789 TI - Palliative care for children with a yet undiagnosed syndrome. AB - : The number of children without a diagnosis in pediatric palliative home care and the process of decision-making in these children are widely unknown. The study was conducted as single-center retrospective cohort study. Between January 2013 and September 2016, 198 children and young adults were cared for; 27 (13.6%) of these were without a clear diagnosis at the start of pediatric palliative home care. A definite diagnosis was ultimately achieved in three children. Median age was 7 years (0-25), duration of care 569 days (2-2638), and number of home visits 7.5 (2-46). Most patients are still alive (19; 70.4%). Median number of drugs administered was eight (range 2-19); antiepileptics were given most frequently. Despite the lack of a clear diagnosis (and thus prognosis), 13 (48.1%) parents faced with their critically ill and clinically deteriorating children decided in favor of a DNAR order. Comparing this with 15 brain-injured children, signs, symptoms, and supportive needs were similar in both groups. CONCLUSION: Children without a clear diagnosis are relatively common in pediatric palliative care and have-like all other patients-the right to receive optimized and symptom-adapted palliative care. Parents are less likely to choose treatment limitation for children who lack a definitive diagnosis. What is Known: * A clear diagnosis is usually considered important for best-practice pediatric palliative care (PPC) including advanced care planning (ACP). * Timely initiation of pediatric palliative care (PPC) is highly recommended in children with life-limiting conditions. What is New: * SWAN (syndrome without a name) children show similar signs and symptoms (mostly neurological) and have similar supportive needs as brain-injured children. * Defining treatment limitations in advance care planning is more difficult for parents of SWAN compared to brain-injured children. PMID- 28808790 TI - Health risks in the cleaning industry: a Belgian census-linked mortality study (1991-2011). AB - PURPOSE: Cleaning work has been associated with a wide range of occupational health hazards. However, little is known about mortality risks in the cleaning industry. This study examines differences in cause-specific mortality between cleaners, manual and non-manual workers. METHODS: Using exhaustive census-linked mortality data, the total Belgian working population aged 30-60 was selected from the 1991 census. Analyses were based on 202,339 male and 58,592 female deaths between 1 March 1991 and 31 December 2011. Standardized Mortality Ratios were calculated and indirectly adjusted for smoking (SMR). In addition, Cox proportional hazards regression models were used to account for age, educational level, part-time employment and marital status. RESULTS: Large mortality differences were observed between cleaners, manual and non-manual workers. In 2001-2011, smoking-adjusted SMRs for all-cause mortality were higher among cleaners than among non-manual workers (Men 1.25 CI 1.22-1.28; women 1.10 CI 1.07 1.13). SMRs also show cleaners had significantly more deaths due to COPD (men 2.13 CI 1.92-2.37; women 2.03 CI 1.77-2.31); lung cancer (men 1.31 CI 1.22-1.39; women 1.21 CI 1.11-1.32); pneumonia (men 1.64 CI 1.35-1.97; women 1.31 CI 1.00 1.68); ischaemic heart diseases (men 1.22 CI 1.13-1.31; women 1.40 CI 1.25-1.57) and cerebrovascular diseases (men 1.19 CI 1.05-1.35; women 1.13 CI 1.00-1.27). Mortality risks among cleaners remained elevated after adjustment for education. CONCLUSIONS: Respiratory and cardiovascular mortality is considerably higher for male and female cleaners than for non-manual workers. PMID- 28808791 TI - Consumption of extra virgin olive oil improves body composition and blood pressure in women with excess body fat: a randomized, double-blinded, placebo controlled clinical trial. AB - PURPOSE: Despite the fact that extra virgin olive oil (EVOO) is widely used in obese individuals to treat cardiovascular diseases, the role of EVOO on weight/fat reduction remains unclear. We investigated the effects of energy restricted diet containing EVOO on body composition and metabolic disruptions related to obesity. METHODS: This is a randomized, double-blinded, placebo controlled clinical trial in which 41 adult women with excess body fat (mean +/- SD 27.0 +/- 0.9 year old, 46.8 +/- 0.6% of total body fat) received daily high fat breakfasts containing 25 mL of soybean oil (control group, n = 20) or EVOO (EVOO group, n = 21) during nine consecutive weeks. Breakfasts were part of an energy-restricted normal-fat diets (-2090 kJ, ~32%E from fat). Anthropometric and dual-energy X-ray absorptiometry were assessed, and fasting blood was collected on the first and last day of the experiment. RESULTS: Fat loss was ~80% higher on EVOO compared to the control group (mean +/- SE: -2.4 +/- 0.3 kg vs. -1.3 +/- 0.4 kg, P = 0.037). EVOO also reduced diastolic blood pressure when compared to control (-5.1 +/- 1.6 mmHg vs. +0.3 +/- 1.2 mmHg, P = 0.011). Within-group differences (P < 0.050) were observed for HDL-c (-2.9 +/- 1.2 mmol/L) and IL-10 (+0.9 +/- 0.1 pg/mL) in control group, and for serum creatinine (+0.04 +/- 0.01 umol/L) and alkaline phosphatase (-3.3 +/- 1.8 IU/L) in the EVOO group. There was also a trend for IL-1beta EVOO reduction (-0.3 +/- 0.1 pg/mL, P = 0.060). CONCLUSION: EVOO consumption reduced body fat and improved blood pressure. Our results indicate that EVOO should be included into energy-restricted programs for obesity treatment. PMID- 28808792 TI - Using Natural Language Processing of Free-Text Radiology Reports to Identify Type 1 Modic Endplate Changes. AB - Electronic medical record (EMR) systems provide easy access to radiology reports and offer great potential to support quality improvement efforts and clinical research. Harnessing the full potential of the EMR requires scalable approaches such as natural language processing (NLP) to convert text into variables used for evaluation or analysis. Our goal was to determine the feasibility of using NLP to identify patients with Type 1 Modic endplate changes using clinical reports of magnetic resonance (MR) imaging examinations of the spine. Identifying patients with Type 1 Modic change who may be eligible for clinical trials is important as these findings may be important targets for intervention. Four annotators identified all reports that contained Type 1 Modic change, using N = 458 randomly selected lumbar spine MR reports. We then implemented a rule-based NLP algorithm in Java using regular expressions. The prevalence of Type 1 Modic change in the annotated dataset was 10%. Results were recall (sensitivity) 35/50 = 0.70 (95% confidence interval (C.I.) 0.52-0.82), specificity 404/408 = 0.99 (0.97-1.0), precision (positive predictive value) 35/39 = 0.90 (0.75-0.97), negative predictive value 404/419 = 0.96 (0.94-0.98), and F1-score 0.79 (0.43-1.0). Our evaluation shows the efficacy of rule-based NLP approach for identifying patients with Type 1 Modic change if the emphasis is on identifying only relevant cases with low concern regarding false negatives. As expected, our results show that specificity is higher than recall. This is due to the inherent difficulty of eliciting all possible keywords given the enormous variability of lumbar spine reporting, which decreases recall, while availability of good negation algorithms improves specificity. PMID- 28808793 TI - Complete genome sequence of a bovine ephemeral fever virus JT02L strain in mainland China. AB - In this study, we report the complete genome sequence of bovine ephemeral fever virus (BEFV) JT02L, which has been used in our laboratory, in mainland China, for more than a decade. The genome is 14941 nucleotide (nt), comprising a leader sequence of 50 nt, nucleoprotein (N) gene of 1328 nt, phosphoprotein (P) gene of 858 nt, matrix protein (M) gene of 691 nt, glycoprotein (G) gene of 1897 nt, non structural glycoprotein (GNS) gene of 1785 nt, alpha1alpha2 gene of 638 nt, beta gene of 460 nt, gamma gene of 400 nt, large multi-functional enzyme (L) gene of 6470 nt and a trailer sequence of 73 nt. Individual genes are separated by intergenic regions (IGRs) of 26, 44, 47, 51, 37, 39, 68 and -21 nt respectively. The overall organization is similar to an Australian BEFV isolate BB7721 but demonstrates some distinctive features including longer alpha3 and beta open reading frames, intact termination/polyadenylation (TTP) sequence downstream of the beta open reading frame and a longer beta-gamma IGR integrated with a 38 nt AT-rich fragment. To our knowledge, this is the first report describing the complete genome of a BEFV strain of East Asian lineage, which may facilitate studies on genomic diversity among geographic strains of BEFV in China and the world. PMID- 28808794 TI - Thiol/disulfide homeostasis as a novel indicator of oxidative stress in children with simple febrile seizures. AB - Simple febrile seizures are generally benign, but during the seizure, elevated levels of glutamate and high levels of oxygen use due to the high metabolic brain activity result in oxidative stress. However, the relationship between febrile seizures and oxidative stress remains unclear. In this study, we investigated thiol/disulfide homeostasis as a new oxidative stress parameter in patients with simple febrile seizures. This study was performed between February 2016 and May 2016 at the Pediatric Emergency Unit. The study population consisted of 40 patients with a diagnosis of simple febrile seizure and 30 control participants aged 8-59 months. Total thiol, native thiol and disulfide levels, disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios were used as thiol/disulfide homeostasis parameters and were quantified in patient and control groups. Furthermore, correlations with seizure duration were investigated. In the patient group, native and total thiol levels and native thiol/total thiol ratios were low, and disulfide levels, disulfide/native thiol, and disulfide/total thiol ratios were significantly higher than in the control group. Negative correlations were observed between seizure duration, total and native thiol levels, and native thiol/total thiol ratio, whereas positive correlations were observed between seizure duration and disulfide/native thiol and disulfide/total thiol ratio. The sensitivities of both disulfide/native thiol and disulfide/total thiol ratios were high for simple febrile seizures. Simple febrile seizures may cause impairment in favor of disulfide bonds in thiol/disulfide homeostasis. Overall, these changes may contribute to neuronal cell damage after simple febrile seizures. PMID- 28808795 TI - Cerebral venous thrombosis: continental disparities. AB - Cerebral venous thrombosis (CVT) usually accounts for < 1% of all strokes. Global disparity and diversity in their demographics, etiology, clinical features, radiological presentation, and mortality have not been previously explored. A systematic search was performed for publications in PubMed using key words "cerebral venous thrombosis," "Cerebral vein thrombosis," and "Cortical vein Thrombosis." A total of 600 relevant studies were abstracted with strict selection criteria, and a total of 7048 patient's data were used for the final analysis. The frequency and relative frequency statistics were used to describe the data. Cases reported were Europe-3152, Asia-2722, North America-852, Africa 122, Australia-121, and South America-79. Overall male to female ratio was 1:2.2; among clinical characteristics, headache was the most common symptom and hematological factors were the most common etiology. Location of the thrombosis was described mostly in the transverse sinus. Intercontinental differences in relation to demographics, etiology, clinical features, radiological presentation, and mortality were identified. CVT can have significant disparity in their demographics, etiology, clinical features, radiological presentation, and mortality when compared from one continent to other. It is important for the worldwide physicians to recognize these differences and to follow the most recent guidelines, diagnostic methods, and treatment to insure the best outcome and prognosis. PMID- 28808796 TI - Structural alteration of the endothelial glycocalyx: contribution of the actin cytoskeleton. AB - The endothelial glycocalyx is a carbohydrate-protein layer that lines the luminal surface of the endothelium. It anchors to the cell membrane via its core proteins that share extended link to the actin cytoskeleton. It is widely accepted that those protein domains and the attached carbohydrates are susceptible to pathological changes. It is unclear, however, to what extent the actin cytoskeleton contributes to the glycocalyx stability. In this study, we investigate the role of the actin cytoskeleton in the maintenance of the glycocalyx under static and laminar flow conditions in vitro. Our results show that in the static culture medium neither rapid actin depolymerisation nor prolonged actin disturbance leads to glycocalyx disruption from the apical surface of human umbilical vein endothelial cells. However, when endothelial cells are exposed to laminar flow for 24 h, the glycocalyx is seen to shift to the downstream peripheral region of the cell surface. The mean fluorescence intensity decreases to [Formula: see text] of the control. When actin depolymerisation is introduced, the intensity decreases significantly to [Formula: see text], indicating a severe disruption of the glycocalyx. Similar changes are observed in human aortic endothelial cells, where the intensity of the glycocalyx is reduced to [Formula: see text] of the control. Collectively, we demonstrate that the actin cytoskeleton contributes to structural stability of the glycocalyx under shear stress. Our results can be used to develop new strategies to prevent shedding of the glycocalyx in cardiovascular diseases. PMID- 28808797 TI - Do carer's levels of unmet needs change over time when caring for patients diagnosed with high-grade glioma and how are these needs correlated with distress? AB - PURPOSE: The aim of the current study was to determine how carer needs changed longitudinally and understand associations between unmet needs and distress. METHODS: Family carers of patients with high-grade glioma (HGG) were recruited. Carers completed questionnaires during patients' chemoradiotherapy (T1), 3 months (T2) and 6 months (T3) including the following: the Distress Thermometer, the General Health Questionnaire-12, the Partner and Carer Supportive Care (PCS) Needs Scale and its supplement the Access to Services Needs Scale and the Brain Tumour Specific Supportive Care Needs Scale. Linear latent growth models were applied. RESULTS: The time 1 questionnaire was completed by 118 carers; 70 carers provided responses at time 3. While the mean numbers of elevated (moderate to high) needs remained stable over time, the specific needs changed. The most frequently reported PCS needs included the impact of caring on the carer's working life or usual activities, finding more accessible parking, making life decisions in the context of uncertainty, reducing stress in the patient's life and understanding the patient's experience. The most frequently reported need unique to carers of a brain tumour patient was for information on adjusting to cognitive changes in the patient. Other prominent needs included managing difficult aspects of the patient's behaviour and adjusting to changes in the patient's personality, both of which increased over time. Higher numbers of unmet needs were associated cross-sectionally with higher distress levels. CONCLUSION: Carers of people with HGG remain highly distressed and their needs evolve over time, indicating a requirement for ongoing evaluation of unmet needs and interventions to address carer psychological morbidities. PMID- 28808798 TI - Genetic engineering approach using early Vinca alkaloid biosynthesis genes led to increased tryptamine and terpenoid indole alkaloids biosynthesis in differentiating cultures of Catharanthus roseus. AB - Catharanthus roseus today occupies the central position in ongoing metabolic engineering efforts in medicinal plants. The entire multi-step biogenetic pathway of its very expensive anticancerous alkaloids vinblastine and vincristine is fairly very well dissected at biochemical and gene levels except the pathway steps leading to biosynthesis of monomeric alkaloid catharanthine and tabersonine. In order to enhance the plant-based productivity of these pharma molecules for the drug industry, cell and tissue cultures of C. roseus are being increasingly tested to provide their alternate production platforms. However, a rigid developmental regulation and involvement of different cell, tissues, and organelles in the synthesis of these alkaloids have restricted the utility of these cultures. Therefore, the present study was carried out with pushing the terpenoid indole alkaloid pathway metabolic flux towards dimeric alkaloids vinblastine and vincristine production by over-expressing the two upstream pathway genes tryptophan decarboxylase and strictosidine synthase at two different levels of cellular organization viz. callus and leaf tissues. The transformation experiments were carried out using Agrobacterium tumefaciens LBA1119 strain having tryptophan decarboxylase and strictosidine synthase gene cassette. The callus transformation reported a maximum of 0.027% dry wt vindoline and 0.053% dry wt catharanthine production, whereas, the transiently transformed leaves reported a maximum of 0.30% dry wt vindoline, 0.10% catharanthine, and 0.0027% dry wt vinblastine content. PMID- 28808799 TI - Transorbital endoscopic approach for exposure of the sylvian fissure, middle cerebral artery and crural cistern: an anatomical study. AB - BACKGROUND: The availability of minimal access instrumentation and endoscopic visualization has revolutionized the field of minimally invasive skull base surgery. The transorbital endoscopic approach using an eyelid incision has been proposed as a new minimally invasive technique for the treatment of skull base pathology, mostly extradural tumors. Our study aims to evaluate the anatomical aspects and potential role of the transorbital endoscopic approach for exposure of the sylvian fissure, middle cerebral artery and crural cistern. METHODS: An anatomical dissection was performed in four freshly injected cadaver heads (8 orbits) using 0- and 30-degree endoscopes. First, an endoscopic endonasal medial orbital decompression was done to facilitate medial retraction of the orbit. An endoscopic transorbital approach through an eyelid incision, with drilling of the posterior wall of the orbit and lesser sphenoidal wing, was then performed to expose the sylvian fissure and crural cisterns. A stepwise anatomical description of the approach and visualized anatomy is detailed. RESULTS: A superior eyelid incision followed by orbital retraction provided a surgical window of approximately 1.2 cm (range 1.0-1.5 cm) for endoscopic transorbital dissection. The superior (SOF) and inferior (IOF) orbital fissures represent the medial limits of the approach and are identified in the initial part of the procedure. Drilling of the orbital roof (lateral and superior to the SOF), greater sphenoidal wing (lateral to the SOF and IOF) and lesser sphenoidal wing exposed the anterior and middle fossa dura. A square-shaped dural opening provided visualization of the posterior orbital gyri, sylvian fissure and temporal pole. Intradural dissection allowed exposure of the sphenoidal portion of the sylvian fissure, M1, MCA bifurcation and M2 branches and lenticulostriate perforators. Dissection of the medial aspect of the sylvian and carotid cisterns with a 30 degree endoscope allowed exposure of the mesial temporal lobe and crural cistern. CONCLUSIONS: The transorbital endoscopic approach allows successful exposure of the sphenoidal portion of the sylvian fissure and M1 and M2 segments of the middle cerebral artery. Angled endoscopes may provide visualization of the mesial temporal lobe and crural cistern. Although our anatomical study demonstrates the feasibility of intradural dissection and closure via an endoscopic transorbital approach, further studies are necessary to evaluate its role in the clinical scenario. PMID- 28808800 TI - Insights into the self-assembly steps of cyanuric acid toward rosette motifs: a DFT study. AB - The nature of non-covalent interactions in self-assembling systems is a topic that has aroused great attention in literature. In this field, the 1,3,5 triazinane-2,4,6-trione or cyanuric acid (CA) is one of the most widely used molecules to formulate self-assembled materials or monolayers. In the present work, a variety of molecular aggregates of CA are examined using three different DFT functionals (B3LYP, B3LYP-D3, and omega-B97XD) in the framework of the quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analysis. Herein, a step by step aggregation path is proposed and the origin of cooperative effects is also examined. It is shown that a greater cooperativity is not always associated with a greater binding energy, and the greatest cooperative effect occurs with highly directional hydrogen bonds. The intramolecular charge transfers play a key role in this effect. Graphical abstract The noncovalent interactions in cyanuric acid supramolecules were analyzed. The calculations provide insights into the self-assembly steps from dimers to rosette-like motif. The complexes with collinear hydrogen bonds show positive cooperativity, while in the arrangement with double hydrogen bonds the cooperative effect is essentially zero. PMID- 28808801 TI - Post-operative seizures after burr hole evacuation of chronic subdural hematomas: is prophylactic anti-epileptic medication needed? AB - INTRODUCTION: There are limited data with regards to the associated risk of post operative seizures in patients with surgically treated chronic subdural hematomas (CSDHs). The use of anti-epileptic drugs (AEDs) is associated with significant side effects. METHODS: A retrospective chart review was performed on patients operated via burr hole for CSDH in our institution from 2004 to 2013. Post operative seizures at 1-year follow-up were identified. Demographic data, medical history, and imaging characteristics were recorded. RESULTS: A total of 220 patients were included in the study. Post-operative seizures occurred in 2.3%. The mean time of onset of seizures was 8.4 days. No difference in age and gender between seizing and non-seizing groups was identified p > 0.05. Mean midline shift was 4.6 mm in seizing group vs. 4.2 mm in non-seizing group, p > 0.05. Mean thickness was 14.6 mm in patients without post-operative seizures and 18.4 mm in patients with post-operative seizures, p > 0.05. There was no significant difference in post-operative seizure incidence related to the side or location of the CSDHs. CONCLUSIONS: The incidence of post-operative seizures in patients with CSDH evacuated via burr holes was low. Prophylactic AEDs should not be routinely administered if no other risk factor for seizure exists. Demographic and clinical factors did not appear to influence post-operative seizures. PMID- 28808802 TI - Interpretation and Diplomacy Aspects of Authority and Care in Imaging Reports. AB - Whereas the creativity and intellectual power of the radiologist are measured against his/her written report, the value of the message will not only be judged by the precision of the medical statement. The same result can be attributed to different words. Numerous common and accidental factors exert influence on the decision on what is said and what is not said, how it is assessed and what is ignored. The less certain a diagnosis is and the less favourable its possible consequences are, the more subtleties and periphrases are to be expected within the report. The decision on the nature and the volume of the written report will not only be taken by the time of recording, but is likewise prepared by the knowledge of the patient's history and symptoms, the personal relationship to him/her as well as by a set of conditions throughout the inspection of the images. The intuition that accompanies the information transfer in imaging diagnostics does not only explain the differences in volume and depth of diagnosis and differential diagnosis, but also the range of diagnostic and therapeutic recommendations. PMID- 28808803 TI - A Prototype Educational Model for Hepatobiliary Interventions: Unveiling the Role of Graphic Designers in Medical 3D Printing. AB - In the context of medical three-dimensional (3D) printing, in addition to 3D reconstruction from cross-sectional imaging, graphic design plays a role in developing and/or enhancing 3D-printed models. A custom prototype modular 3D model of the liver was graphically designed depicting segmental anatomy of the parenchyma containing color-coded hepatic vasculature and biliary tree. Subsequently, 3D printing was performed using transparent resin for the surface of the liver and polyamide material to develop hollow internal structures that allow for passage of catheters and wires. A number of concepts were incorporated into the model. A representative mass with surrounding feeding arterial supply was embedded to demonstrate tumor embolization. A straight narrow hollow tract connecting the mass to the surface of the liver, displaying the path of a biopsy device's needle, and the concept of needle "throw" length was designed. A connection between the middle hepatic and right portal veins was created to demonstrate transjugular intrahepatic portosystemic shunt (TIPS) placement. A hollow amorphous structure representing an abscess was created to allow the demonstration of drainage catheter placement with the formation of pigtail tip. Percutaneous biliary drain and cholecystostomy tube placement were also represented. The skills of graphic designers may be utilized in creating highly customized 3D-printed models. A model was developed for the demonstration and simulation of multiple hepatobiliary interventions, for training purposes, patient counseling and consenting, and as a prototype for future development of a functioning interventional phantom. PMID- 28808804 TI - Identification of a new liver-specific c-type mRNA transcriptional variant for mouse ST3GAL5 (GM3/GM4 synthase). AB - GM3, a major lipid component of the plasma membrane outer leaflet in mammalian cells, is synthesized in the luminal side of Golgi by ST3GAL5 protein (ST3G5), a type II membrane protein. Two strains of St3Gal5 knockout mice have been established for studies of GM3 physiological function: St3Gal5-Ex5-KO (lacking exon 5, which contains the catalytic domain of ST3G5), and St3Gal5-Ex3-KO (lacking exon 3, which contains the initiation codons). Results of the present study demonstrate that GM3 synthesis is still present, at a low level, in liver of St3Gal5-Ex3-KO mice. St3Gal5 has two mRNA transcriptional variants: a-type and b-type. When exon 3 is deleted, ST3G5 is not translated from a-type or b-type, as a result of initiation codon deletion or frame shift. Through NCBI database search and real-time PCR analyses of various mouse tissues, we identified a liver specific St3Gal5 transcriptional variant (c-type) capable of producing artificial ST3G5 (M*-ST3G5) having GM3 synthase activity in the absence of exon 3. St3Gal5 Ex3-KO mice expressed c-type mRNA without exon 3 (c-type-/-) in liver. The transmembrane and catalytic domains of M*-ST3G5 translated from c-type-/- were identical to those from wild-type, although the cytoplasmic regions differed. Expression of M*-ST3G5 in embryonic fibroblasts derived from St3Gal5-Ex3-KO mice led to GM3 synthesis; M*-ST3G5 thus displayed enzyme activity in vivo. Taken together, our findings indicate that expression of liver-specific c-type variant accounts for the residual GM3 synthase activity observed in liver of St3Gal5-Ex3 KO mice. PMID- 28808805 TI - Molecular factors regulating E-cadherin expression in urothelial bladder cancer and their correlations with the clinicopathological features. AB - This study aimed to assess the expression of S100A4, Twist and E-cadherin (mRNA and protein) in urothelial bladder cancer, investigate the correlation between them and evaluate their association with the clinicopathological features of the disease. The study included 54 patients diagnosed as urothelial bladder cancer of different stages and grades. The expression levels of S100A4, Twist and E cadherin (mRNA and protein) in tissue samples were determined by quantitative RT PCR and immunohistochemistry. The expression of S100A4 and Twist was significantly upregulated while E- cadherin was significantly downregulated in urothelial bladder cancer tissues compared to the adjacent surrounding normal bladder tissues at both mRNA and protein levels (p < 0.001). Expression levels of S100A4 and Twist were significantly higher in recurrent tumor than in non recurrent tumors (p < 0.001) while the expression level of E-cadherin was significantly lower in recurrent tumors than in non-recurrent tumors at both mRNA and protein levels (p < 0.001). There was a significant positive correlation between S100A4 and Twist expressions (r = 0.875, p < 0.001) while significant negative correlations were found between E- cadherin and S100A4 expressions(r=- 0.803, p < 0.001) and between E-cadherin and Twist (r = -0.809, p < 0.001). Up regulation of S100A4 and Twist and down-regulation of E-cadherin in urothelial bladder cancer tissues compared to adjacent normal tissues were observed. There was a significant negative correlation between S100A4 and E- cadherin and between E- cadherin and Twist expression. However, there was a significant positive correlation between S100A4 and Twist expressions. Furthermore, the alterations in the gene expression were associated with disease stage and grade. PMID- 28808806 TI - BRCA1-mimetic compound NSC35446.HCl inhibits IKKB expression by reducing estrogen receptor-alpha occupancy in the IKKB promoter and inhibits NF-kappaB activity in antiestrogen-resistant human breast cancer cells. AB - PURPOSE: We previously identified small molecules that fit into a BRCA1-binding pocket within estrogen receptor-alpha (ERalpha), mimic the ability of BRCA1 to inhibit ERalpha activity ("BRCA1-mimetics"), and overcome antiestrogen resistance. One such compound, the hydrochloride salt of NSC35446 ("NSC35446.HCl"), also inhibited the growth of antiestrogen-resistant LCC9 tumor xenografts. The purpose of this study was to investigate the down-stream effects of NSC35446.HCl and its mechanism of action. METHODS: Here, we studied antiestrogen-resistant (LCC9, T47DCO, MCF-7/RR, LY2), ERalpha-negative (MDA-MB 231, HCC1806, MDA-MB-468), and antiestrogen-sensitive (MCF-7) cell lines. Techniques utilized include RNA-seq, qRT-PCR, cell growth analysis, cell-cycle analysis, Western blotting, luciferase reporter assays, TUNEL assays, in silico analysis of the IKKB gene, and ChIP assays. RESULTS: SC35446.HCl inhibited proliferation and induced apoptosis in antiestrogen-resistant LCC9, T47DCO, MCF 7/RR, and LY2 cells but not in ERalpha-negative breast cancer cell lines. IKKB (IKKbeta, IKBKB), an upstream activator of NF-kappaB, was identified as a BRCA1 mimetic-regulated gene based on an RNA-seq analysis. NSC35446.HCl inhibited IKKB, IKKA, and IKKG/NEMO mRNA and protein expression in LCC9 cells. NSC35446.HCl also inhibited NF-kappaB activity and expression of NF-kappaB target genes. In silico analysis of the IKKB promoter identified nine estrogen response element (ERE) half-sites and one ERE-like full-site. ChIP assays revealed that ERalpha was recruited to the ERE-like full-site and five of the nine half-sites and that ERalpha recruitment was inhibited by NSC35446.HCl in LCC9 and T47DCO cells. CONCLUSIONS: These studies identify functional EREs in the IKKB promoter and identify IKKB as an ERalpha and NSC35446.HCl-regulated gene, and they suggest that NF-kappaB and IKKB, which were previously linked to antiestrogen resistance, are targets for NSC35446.HCl in reversing antiestrogen resistance. PMID- 28808807 TI - Sociodemographic and Lifestyle Factors, and Health Conditions of Dominican Adults Living in Puerto Rico. AB - Dominicans are the largest migrant community in Puerto Rico, yet understudied. We compared risk factors and health conditions of Dominicans versus Puerto Ricans (PRs). Cross-sectional survey of Dominicans (n = 55) and PRs (n = 310) aged 30-75 years, assessed with validated questionnaires and standardized anthropometric measurements. Significantly, more Dominicans than PRs had attained <8th grade education (37.7 vs. 8.0%), reported household income <=$10,000 (76.1 vs. 56.9%), lacked health insurance (19.6 vs. 5.5%), and reported food insecurity (24.5 vs. 12.1%). They spent fewer hours/day watching television (2.9 vs. 3.8), and were less likely to smoke (7.6 vs. 19.6%). Medically-diagnosed depression was lower among Dominicans than PRs (9.6 vs. 23.0%); questionnaire-based high depressive symptomatology was similar (47.9 vs. 52.8%). Dominicans living in Puerto Rico had more socioeconomic risk factors but healthier lifestyle behaviors and lower prevalence of medically-diagnosed depression than PRs. Tailored approaches are needed to ameliorate disparities in each ethnic group. PMID- 28808808 TI - Ketogenic diet versus gluten free casein free diet in autistic children: a case control study. AB - : Many diet regimens were studied for patients with autism spectrum disorder (ASD) over the past few years. Ketogenic diet is gaining attention due to its proven effect on neurological conditions like epilepsy in children. Forty-five children aged 3-8 years diagnosed with ASD based on DSM-5 criteria were enrolled in this study. Patients were equally divided into 3 groups, first group received ketogenic diet as modified Atkins diet (MAD), second group received gluten free casein free (GFCF) diet and the third group received balanced nutrition and served as a control group. All patients were assessed in terms of neurological examination, anthropometric measures, as well as Childhood Autism Rating Scale (CARS), Autism Treatment Evaluation Test (ATEC) scales before and 6 months after starting diet. Both diet groups showed significant improvement in ATEC and CARS scores in comparison to control group, yet ketogenic scored better results in cognition and sociability compared to GFCF diet group. Depending on the parameters measured in our study, modified Atkins diet and gluten free casein free diet regimens may safely improve autistic manifestations and could be recommended for children with ASD. At this stage, this study is a single center study with a small number of patients and a great deal of additional wide-scale prospective studies are however needed to confirm these results. TRIAL REGISTRATION NUMBER: UMIN-CTR Study Design: trial Number UMIN000021433. PMID- 28808809 TI - Evidence of dengue virus replication in a non-traumatic spleen rupture case. AB - The present report describes a case of splenic rupture due to dengue, a rare complication of dengue that should be considered in any patient with suspected dengue disease who started with left upper quadrant abdominal pain and hypotension. The pathophysiology of this entity is not yet well elucidated, but one of the theories present in the literature is that it is due to a depletion of coagulation factors and platelets leading to intra-splenic hemorrhage and rupture. The RT-PCR technique detected serotype 1 and histopathological studies of the spleen revealed significant atrophy of lymphoid follicles and extensive hemorrhage areas. Besides histopathological observations, virus replication was investigated by detection of dengue antigens, especially the non-structural 3 protein (NS3) in endothelial cells and splenic macrophages. This important complication has serious clinical repercussions and high mortality, due to the diagnostic difficulty and many factors that usually confuse or delay its diagnosis. Therefore, it is of the utmost importance to recognize their manifestations and their management to try to best minimize their consequences and mortality. PMID- 28808810 TI - Interactions of cisplatin analogues with lysozyme: a comparative analysis. AB - The biophysical characterization of drug binding to proteins plays a key role in structural biology and in the discovery and optimization of drug discovery processes. The search for optimal combinations of biophysical techniques that can correctly and efficiently identify and quantify binding of metal-based drugs to their final target is challenging, due to the physicochemical properties of these agents. Different cisplatin derivatives have shown different citotoxicities in most common cancer lines, suggesting that they exert their biological activity via different mechanisms of action. Here we carried out a comparative analysis, by studying the behaviours of three Pt-compounds under the same experimental conditions and binding assays to properly deepen the determinants of the different MAOs. Indeed we compared the results obtained using surface plasmon resonance, isothermal titration calorimetry, fluorescence spectroscopy and thermal shift assays based on circular dichroism experiments in the characterization of the formation of adducts obtained upon reaction of cisplatin, carboplatin and iodinated analogue of cisplatin, cis-Pt (NH3)2I2, with the model protein hen egg white lysozyme, both at neutral and acid pHs. Further we reasoned on the applicability of employed techniques for the study the thermodynamics and kinetics of the reaction of a metallodrug with a protein and to reveal which information can be obtained using a combination of these analyses. Data were discussed on the light of the existing structural data collected on the platinated protein. PMID- 28808811 TI - Construction and biocompatibility of a thin type I/II collagen composite scaffold. AB - Articular cartilage injury is a common type of damage observed in clinical practice. A matrix-induced autologous chondrocyte implant was developed to repair articular cartilage as an advancement on the autologous chondrocyte implant procedure. Here, we establish a thin double layer of collagen as a novel and effective bioscaffold for the regeneration of cartilaginous lesions. We created a collagen membrane with double layers using a cover slip, a cover slip, and the collagen was then freeze-dried under vacuum. Carbodiimide as a crosslinking agent was used to obtain a relatively stable collagen construction. The thickness of the knee joint cartilage from grown rabbits was measured from a frozen section. Both type I and type II collagens were characterized using Sodium dodecylsulfate/polyacrylamide gel electrophoresis (SDS-PAGE) and ultraviolet absorption peaks. The aperture size of the scaffold was observed using a scanning electron microscope (SEM). The degradation of the scaffolds in vitro was tested through digestion using collagenase solution. The mechanical capacity of the scaffolds was assessed under dynamic compression. The influence of the scaffold on chondrocyte proliferation was assessed using the methyl thiazolyl tetrazolium (MTT) colourimetric assay and scanning electron microscopy. The frozen sections of the rabbit femoral condyle showed that the thickness of the weight-bearing area of the articular cartilage was less than 1 mm. The results of the SDS-PAGE and ultraviolet absorption peaks of the collagens were in agreement with the standard photographs in the references. SEM showed that the aperture size of the cross-linked scaffold was 82.14 +/- 15.70 MUm. The in vitro degradation studies indicated that Carbodiimide cross-linking can effectively enhance the biostability of the scaffolds. The Carbodiimide cross-linking protocol resulted in a mean value for the samples that ranged from 8.72 to 15.95 MPa for the compressive strength. The results of the MTT demonstrated that the scaffold had promoted chondrocyte proliferation and SEM observations showed that the scaffold was a good adhesive and growth material for chondrocytes. Thin type I/II collagen composite scaffold can meet the demands of cartilage tissue engineering and have good biocompatibility. PMID- 28808812 TI - Antioxidant effects of chrysin-loaded electrospun nanofibrous mats on proliferation and stemness preservation of human adipose-derived stem cells. AB - An ideal biomaterial in regenerative medicine should be able to regulate the stem cell proliferation without the loss of its pluripotency. Chrysin (Chr) is a naturally occurring flavone with a wide spectrum of biological functions including anti-inflammatory and anti-oxidant properties. The present study describes the influence of Chr-loaded nanofibrous mats on the regulation of proliferation and stemness preservation of adipose-derived stem cells (ADSCs). For this purpose, Chr-loaded poly (epsilon-caprolactone)/poly (ethylene glycol) (PCL/PEG) nanofibrous mats were produced via electrospinning process and the successful fabrication of these bioactive mats was confirmed by field emission scanning electron microscopy (FE-SEM) and fourier transform infrared spectroscopy. ADSCs were seeded on the nanofibers and their morphology, viability, and stemness expression were analyzed using FE-SEM, MTT, and qPCR assays after 2 weeks of incubation, respectively. The results display that ADSCs exhibit better adhesion and significantly increased viability on the Chr-loaded PCL/PEG nanofibrous mats in relative to the PCL/PEG nanofibers and tissue culture polystyrene. The greater viability of ADSCs on Chr based nanofibers was further confirmed by higher expression levels of stemness markers Sox-2, Nanog, Oct-4, and Rex-1. These findings demonstrate that Chr-loaded PCL/PEG electrospun nanofibrous mats can be applied to improve cell adhesion and proliferation while concurrently preserving the stemness of ADSCs, thus representing a hopeful potential for application in stem cell therapy strategies. PMID- 28808813 TI - Maximized Inter-Class Weighted Mean for Fast and Accurate Mitosis Cells Detection in Breast Cancer Histopathology Images. AB - Based on the Nottingham criteria, the number of mitosis cells in histopathological slides is an important factor in diagnosis and grading of breast cancer. For manual grading of mitosis cells, histopathology slides of the tissue are examined by pathologists at 40* magnification for each patient. This task is very difficult and time-consuming even for experts. In this paper, a fully automated method is presented for accurate detection of mitosis cells in histopathology slide images. First a method based on maximum-likelihood is employed for segmentation and extraction of mitosis cell. Then a novel Maximized Inter-class Weighted Mean (MIWM) method is proposed that aims at reducing the number of extracted non-mitosis candidates that results in reducing the false positive mitosis detection rate. Finally, segmented candidates are classified into mitosis and non-mitosis classes by using a support vector machine (SVM) classifier. Experimental results demonstrate a significant improvement in accuracy of mitosis cells detection in different grades of breast cancer histopathological images. PMID- 28808814 TI - The Impact of Being a Migrant from a Non-English-Speaking Country on Healthcare Outcomes in Frail Older Inpatients: an Australian Study. AB - The purpose of this prospective study of 2180 consecutive index admissions to an acute geriatric service was to compare in-hospital outcomes of frail older inpatients born in non-English-speaking counties, referred to as culturally and linguistically diverse (CALD) countries in Australia, with those born in English speaking countries. Multivariate logistic regression was used to model in hospital mortality and new nursing home placement. Multivariate Cox proportional hazards regression was used to model length of stay. The mean age of all patients was 83 years and 93% were admitted through the emergency department. In multivariate analyses, patients from CALD and non-CALD backgrounds were equally likely to die (CALD odds ratio [OR] 0.69, 95% confidence interval [95% CI] 0.44 1.10) and be newly placed in a nursing home (OR 0.75, 95% CI 0.51-1.12). Patients from CALD backgrounds unable to speak English were more likely to die (11.5% vs. 7.2%, p = 0.02). While patients from CALD backgrounds had significantly shorter lengths of stay in univariate analysis (median 9 days vs. 10 days, p = 0.02), this was not apparent in multivariate analysis (hazard ratio 1.02, 95% CI 0.91 1.14), where the ability to speak English proved to be a strong confounder. While most of the literature shows poorer outcomes of people from minority ethnic groups, our findings indicate that this is not necessarily the case. Developing culturally appropriate services may mitigate some of the adverse outcomes commonly associated with ethnicity. Our findings are particularly relevant to countries populated by multiple ethnic groups. PMID- 28808815 TI - Physiological responses and antioxidant enzyme changes in Sulla coronaria inoculated by cadmium resistant bacteria. AB - Plant growth promoting bacteria (PGPB) may help to reduce the toxicity of heavy metals on plants growing in polluted soils. In this work, Sulla coronaria inoculated with four Cd resistant bacteria (two Pseudomonas spp. and two Rhizobium sullae) were cultivated in hydroponic conditions treated by Cd; long time treatment 50 uM CdCl2 for 30 days and short time treatment; 100 uM CdCl2 for 7 days. Results showed that inoculation with Cd resistant PGPB enhanced plant biomass, thus shoot and root dry weights of control plants were enhanced by 148 and 35% respectively after 7 days. Co-inoculation of plants treated with 50 and 100 uM Cd increased plant biomasses as compared to Cd-treated and uninoculated plants. Cadmium treatment induced lipid peroxidation in plant tissues measured through MDA content in short 7 days 100 uM treatment. Antioxidant enzyme studies showed that inoculation of control plants enhanced APX, SOD and CAT activities after 30 days in shoots and SOD, APX, SOD, GPOX in roots. Application of 50 uM CdCl2 stimulated all enzymes in shoots and decreased SOD and CAT activities in roots. Moreover, 100 uM of CdCl2 increased SOD, APX, CAT and GPOX activities in shoots and increased significantly CAT activity in roots. Metal accumulation depended on Cd concentration, plant organ and time of treatment. Furthermore, the inoculation enhanced Cd uptake in roots by 20% in all treatments. The cultivation of this symbiosis in Cd contaminated soil or in heavy metal hydroponically treated medium, showed that inoculation improved plant biomass and increased Cd uptake especially in roots. Therefore, the present study established that co inoculation of S. coronaria by a specific consortium of heavy metal resistant PGPB formed a symbiotic system useful for soil phytostabilization. PMID- 28808816 TI - A genome-wide association study of cognitive function in Chinese adult twins. AB - Multiple loci or genes have been identified using genome-wide association studies mainly in western countries but with inconsistent results. No similar studies have been conducted in the world's largest and rapidly aging Chinese population. The paper aimed to identify the specific genetic variants associated with cognitive function in middle and old-aged Chinese dizygotic twins (DZ). Cognitive function was measured on 139 pairs of DZ by Montreal Cognitive Assessment. The subjects were genotyped at 1048575 SNP positions. Regression-based mixed-effect kinship model of GWAS was conducted to test the SNPs. Gene-based analysis was performed on VEGAS2. The statistically significant genes were then subject to gene set enrichment analysis to further identify the specific biological pathways associated with cognitive function. No SNPs reached genome-wide significance although there were 13 SNPs of suggestive significance (P < 10-5). Gene-based analysis found 823 significant genes topped by TNRC18P1 (P = 1.00 * 10-6), FGFR1OP2 (P = 6.00 * 10-6), and AKR1D1 (P = 2.30 * 10-5). Enrichment analysis identified 46 biological pathways, mainly involving in signaling transmission, metabolic process and Alzheimer's disease. Analysis of SNPs involved in the regulatory motif detected cell-type specific enhancers involving aorta and colon smooth muscle both have been reported to implicate in cognition. We conclude that genetic variations are significantly involved in functional genes, biological pathways and the regulatory domain that mediate cognitive performances. PMID- 28808817 TI - Electrophysiological Modulation in an Effort to Complete Illusory Figures: Configuration, Illusory Contour and Closure Effects. AB - Figure recognition process: From the coarse configuration standing from the background to the closure of a meaningful shape, was investigated by ERP technique. ERP components at different latencies from stimulus onset allowed to tap into the figure recognition process at discrete time-points when different cognitive operations take place. In this study, we present two experiments where the support-ratio (SR) of illusory figures was manipulated to vary continuously the recognition of geometrical figures. In the first experiment three shapes were used to vary the SR and the P1 component (80-130 ms) was modulated by the configuration-effect explained, in part for the first time, with the unbalanced physical stimulation between upper and lower visual field. In the second experiment, we used one shape and varied systematically the SR in a discrimination task. The N1 (130-180 ms) and the N2 (230-270 ms) were modulated by two effects: The Ic-effect, represented by the N1, and the closure-effect, represented by the N2, being larger when the SR was small and the discrimination more difficult with respect to large SRs and easier discrimination. These results showed that figure recognition proceeded from the coarse parsing of the visual scene (configuration-effect), through the completion of a set of illusory borders (Ic-effect) to the final assembling of a meaningful shape (closure-effect). PMID- 28808819 TI - Separating the Idea from the Action: A sLORETA Study. AB - Simple imaginary movements activate similar cortical and subcortical areas to actual movements, chiefly in the sensory-motor network. However, only a few studies also examined the imagery of more skilful movements such as reaching. Ten volunteers performed reaching movements or imagined the same movements. EEG was simultaneously recorded and analysed with sLORETA, which compared the preparation for actual and imagined reaching with respect to their baseline and between tasks. Major differences between them were found at three time intervals after target presentation, always in favour of the actual reaching condition. The first one was from 160 to 220 msec in the frontal and parietal regions. The second difference was evident from 220 to 320 msec in the premotor cortex. The third difference was evident from 320 msec, mainly in the perirolandic region. Also, the anterior and posterior cingulate cortices were widely involved, in both tasks. We suggest the existence of two separate systems which may work together during actual reaching programming. The first one involves structures such as the premotor cortex, supplementary motor area and primary motor cortex, together with the parietal and occipital cortex. This system may integrate extrinsic target coordinates with proprioceptive information from the reaching arm and pre-stored programs in the associative motor cortex. It is activated strongly and involves more cortical areas in actual than imagined reaching. The second system, common to both tasks, involves anterior and posterior cingulate cortices, with the possible role of contributing awareness and focusing the various components of the process. PMID- 28808818 TI - First-in-human study of the epichaperome inhibitor PU-H71: clinical results and metabolic profile. AB - Background Molecular chaperone targeting has shown promise as a therapeutic approach in human cancers of various histologies and genetic backgrounds. The purine-scaffold inhibitor PU-H71 (NSC 750424), selective for Hsp90 in epichaperome networks, has demonstrated antitumor activity in multiple preclinical cancer models. The present study was a first in-human trial of PU-H71 aimed at establishing its safety and tolerability and characterizing its pharmacokinetic (PK) profile on a weekly administration schedule in human subjects with solid tumors refractory to standard treatments. Methods PU-H71 was administered intravenously over 1 h on days 1 and 8 of 21-day cycles in patients with refractory solid tumors. Dose escalation followed a modified accelerated design. Blood and urine were collected during cycles 1 and 2 for pharmacokinetics analysis. Results Seventeen patients were enrolled in this trial. Grade 2 and 3 adverse events were observed but no dose limiting toxicities occurred, thus the human maximum tolerated dose was not determined. The mean terminal half-life (T1/2) was 8.4 +/- 3.6 h, with no dependency to dose level. A pathway for the metabolic disposal of PU-H71 in humans was derived from microsome studies. Fourteen patients were also evaluable for clinical response; 6 (35%) achieved a best response of stable disease for >2 cycles, with 2 patients remaining on study for 6 cycles. The study closed prematurely due to discontinuation of drug supply. Conclusions PU-H71 was well tolerated at the doses administered during this study (10 to 470 mg/m2/day), with no dose limiting toxicities. PMID- 28808820 TI - Benzene-contaminated groundwater remediation using calcium peroxide nanoparticles: synthesis and process optimization. AB - Nano-size calcium peroxide (nCaO2) is an appropriate oxygen source which can meet the needs of in situ chemical oxidation (ISCO) for contaminant remediation from groundwater. In the present study, an easy to handle procedure for synthesis of CaO2 nanoparticles has been investigated. Modeling and optimization of synthesis process was performed by application of response surface methodology (RSM) and central composite rotatable design (CCRD) method. Synthesized nanoparticles were characterized by XRD and FESEM techniques. The optimal synthesis conditions were found to be 5:1, 570 rpm and 10 degrees C for H2O2:CaSO2 ratio, mixing rate and reaction temperature, respectively. Predicted values showed to be in good agreement with experimental results (R 2 values were 0.915 and 0.965 for CaO2 weight and nanoparticle size, respectively). To study the efficiency of synthesized nanoparticles for benzene removal from groundwater, batch experiments were applied in biotic and abiotic (chemical removal) conditions by 100, 200, 400, and 800 mg/L of nanoparticles within 70 days. Results indicated that application of 400 mg/L of CaO2 in biotic condition was able to remediate benzene completely from groundwater after 60 days. Furthermore, comparison of biotic and abiotic experiments showed a great potential of microbial stimulation using CaO2 nanoparticles in benzene remediation from groundwater. PMID- 28808821 TI - [Airway anatomy : Relevant structures in emergency medicine]. AB - The subject of this article is the anatomy of the respiratory tract with an emphasis on the larynx. A differentiation is made between the upper and lower airways according to topographical and functional aspects, the limits of which are marked by the lower section of the larynx. The focus is on the anatomy of the structures involved, which are relevant for emergency medicine. PMID- 28808822 TI - Is Prey Specificity Constrained by Geography? Semiochemically Mediated Oviposition in Rhizophagus grandis (Coleoptera: Monotomidae) with Its Specific Prey, Dendroctonus micans (Coleoptera: Curculionidae: Scolytinae), and with Exotic Dendroctonus species. AB - Examples of totally specific predators are rare, and the mechanisms underlying this specificity are often poorly understood. In Eurasia, the Monotomid beetle Rhizophagus grandis is found only in the galleries of its prey, the bark beetle Dendroctonus micans. The specificity of R. grandis relies on kairomones which female predators use to adjust their oviposition to the number of prey larvae available in a gallery. Yet these chemical signals are still largely unknown. The North American D. punctatus and D. valens, which are not sympatric with R. grandis but have a similar ecology as D. micans, could also elicit predator oviposition, which would suggest that specificity in this predator-prey system is constrained by geography. In order to further identify these determinants of specificity, we used artificial oviposition boxes to compare the oviposition level of R. grandis in the presence of larvae of each of the three prey species. We jointly used sequential dynamic headspace extractions and gas chromatography coupled with mass spectrometry to investigate oviposition stimuli associated with each prey species and potential oviposition inhibitors emitted by the predator. We further assessed potential stimuli with the analysis of emissions from D. micans larvae reared alone. Overall, we identified and quantified 67 compounds, mostly terpenes. Several robust candidate stimulants or inhibitors of R. grandis' oviposition were identified. The three prey species elicited similar oviposition levels in R. grandis, which suggests that this predator could form new associations outside of its native range. PMID- 28808824 TI - Gasless single-incision laparoscopic inguinal hernia repair: initial experience. AB - PURPOSE: Laparoscopic hernioplasty has been gaining its popularity in the past decade for its rapid recovery. Single-incision surgery, as its possible advancement, has also received more attention. Traditional laparoscopic surgery with carbon dioxide insufflation precluded patients with underlying cardiovascular or pulmonary disease from minimal invasive surgery. We report our early experience with gasless single-incision laparoscopic inguinal hernia repair via totally extraperitoneal (TEP) approach. METHODS: Between 2010 and 2012, 15 consecutive patients underwent gasless laparoscopic inguinal hernia repair by the same surgeon, using abdominal wall lifting technique with a self-tailored device. Patient demographics, hernia characteristics, operative findings and postoperative outcomes were analyzed prospectively. RESULTS: Of the 15 patients, all had unilateral hernia. Two presented with acute incarceration, in which one required bowel resection. There was no conversion to open surgery or insertion of additional ports. The median operating time was 80 min (range 51-130) for elective repair and 178 min (range 135-220) for emergency repair. The median hospital stay was 1 day (range 1-6) with minimal requirement of analgesics. Median time taken to resume normal activity was 2 days (range 1-6). No major medical complications or mesh infection was encountered. One patient developed hematoma and was successfully managed by salvage laparoscopic reoperation. During a median follow-up of 54 months (range 38-60), none experienced recurrence. CONCLUSION: Gasless single-incision TEP is feasible with favorable results, even in high-risk patients with compromised cardiorespiratory status. This technique can also be applied to emergency setting in patients with incarcerated inguinal hernia requiring bowel resection. Future large scale randomized study is needed to verify the effectiveness of this technique. PMID- 28808825 TI - Integrating planning perception and action for informed object search. AB - This paper presents a method to reduce the time spent by a robot with cognitive abilities when looking for objects in unknown locations. It describes how machine learning techniques can be used to decide which places should be inspected first, based on images that the robot acquires passively. The proposal is composed of two concurrent processes. The first one uses the aforementioned images to generate a description of the types of objects found in each object container seen by the robot. This is done passively, regardless of the task being performed. The containers can be tables, boxes, shelves or any other kind of container of known shape whose contents can be seen from a distance. The second process uses the previously computed estimation of the contents of the containers to decide which is the most likely container having the object to be found. This second process is deliberative and takes place only when the robot needs to find an object, whether because it is explicitly asked to locate one or because it is needed as a step to fulfil the mission of the robot. Upon failure to guess the right container, the robot can continue making guesses until the object is found. Guesses are made based on the semantic distance between the object to find and the description of the types of the objects found in each object container. The paper provides quantitative results comparing the efficiency of the proposed method and two base approaches. PMID- 28808826 TI - Use of evidence in a categorization task: analytic and holistic processing modes. AB - Category learning performance can be influenced by many contextual factors, but the effects of these factors are not the same for all learners. The present study suggests that these differences can be due to the different ways evidence is used, according to two main basic modalities of processing information, analytically or holistically. In order to test the impact of the information provided, an inductive rule-based task was designed, in which feature salience and comparison informativeness between examples of two categories were manipulated during the learning phases, by introducing and progressively reducing some perceptual biases. To gather data on processing modalities, we devised the Active Feature Composition task, a production task that does not require classifying new items but reproducing them by combining features. At the end, an explicit rating task was performed, which entailed assessing the accuracy of a set of possible categorization rules. A combined analysis of the data collected with these two different tests enabled profiling participants in regard to the kind of processing modality, the structure of representations and the quality of categorial judgments. Results showed that despite the fact that the information provided was the same for all participants, those who adopted analytic processing better exploited evidence and performed more accurately, whereas with holistic processing categorization is perfectly possible but inaccurate. Finally, the cognitive implications of the proposed procedure, with regard to involved processes and representations, are discussed. PMID- 28808823 TI - Vessel wall characterization using quantitative MRI: what's in a number? AB - The past decade has witnessed the rapid development of new MRI technology for vessel wall imaging. Today, with advances in MRI hardware and pulse sequences, quantitative MRI of the vessel wall represents a real alternative to conventional qualitative imaging, which is hindered by significant intra- and inter-observer variability. Quantitative MRI can measure several important morphological and functional characteristics of the vessel wall. This review provides a detailed introduction to novel quantitative MRI methods for measuring vessel wall dimensions, plaque composition and permeability, endothelial shear stress and wall stiffness. Together, these methods show the versatility of non-invasive quantitative MRI for probing vascular disease at several stages. These quantitative MRI biomarkers can play an important role in the context of both treatment response monitoring and risk prediction. Given the rapid developments in scan acceleration techniques and novel image reconstruction, we foresee the possibility of integrating the acquisition of multiple quantitative vessel wall parameters within a single scan session. PMID- 28808828 TI - Health, interests, and equality. PMID- 28808827 TI - Distinctive localization and MRI features correlate of molecular subgroups in adult medulloblastoma. AB - Medulloblastoma (MB) is recognized as comprising four molecular subgroups with distinct transcriptional profiles, clinical features, and outcomes. Previous studies demonstrate that pediatric MBs present with subgroup-specific MRI manifestations. We hypothesized that combination of anatomical localization and conventional features based on MR imaging can predict these subgroups in adult MBs. MR Imaging manifestations of 125 adult patients with MB were analyzed retrospectively based on pre-operative MRI scans. MB molecular subgroups were evaluated by the expression profiling array and immunohistochemistry. A pediatric MB cohort of 60 patients were analyzed for comparison with data of adult patients. Multiple logistic regression analysis revealed that tumor location (P < 0.0001) and pattern of enhancement (P = 0.0048) were significantly correlated with molecular subgroups in adult MBs. Ninety-two percent of adult MBs were correctly predicted by using logistic regression model based on the anatomical localization patterns and pattern of enhancement. Exclusively intra-cerebellar growth, localization in the rostral cerebellum, and no brainstem contact were specific to adult SHH-MBs. Group 4-MBs in adult were characterized by minimal/no enhancement compared with other two subgroups. Infant SHH-MBs represented significant different localization patterns compared with SHH tumors in children and adults. We identified that molecular subgroups of adult MBs could be well predicted by tumor localization patterns and enhancement pattern. Our study also provided important evidence that MB subgroups in adult possibly derived from different cellular origins. PMID- 28808829 TI - Norwegian reference values for the Short-Form Health Survey 36: development over time. AB - PURPOSE: Reference values for patient-reported outcome measures are useful for interpretation of results from clinical trials. The study aims were to collect Norwegian SF-36 reference values and compare with data from 1996 to 2002. METHODS: In 2015, SF-36 was sent by mail to a representative sample of the population (N = 6165). Time trends and associations between background variables and SF-36 scale scores were compared by linear regression models. RESULTS: The 2015 response rate was 36% (N = 2118) versus 67% (N = 2323) in 1996 and 56% (N = 5241) in 2002. Only 5% of the youngest (18-29 years) and 27% of the oldest (>70 years) responded in 2015. Age and educational level were significantly higher in 2015 relative to 1996/2002 (p < .001). The oldest age group in 2015 reported better scores on five of eight scales (p < 0.01), the exceptions being bodily pain, vitality, and mental health compared to 1996/2002 (NS). Overall, the SF-36 scores were relatively stable across surveys, controlled for background variables. In general, the most pronounced changes in 2015 were better scores on the role limitations emotional scale (7.4 points, p < .001) and lower scores on the bodily pain scale (4.6 points, p < .001) than in the 1996/2002 survey. CONCLUSIONS: The low response rate in 2015 suggests that the results, especially among the youngest, should be interpreted with caution. The high response rate among the oldest indicates good representativity for those >70 years. Despite societal changes in Norway the past two decades, HRQoL has remained relatively stable. PMID- 28808830 TI - Social Workers' Perceptions of the Association Between Role Playing Games and Psychopathology. AB - : Whereas role-playing and table-top role-play games (RPGs) have been proven to have potential as therapeutic tools, playing RPGs is often stereotypically associated with social incompetence and psychiatric disorders. Knowledge regarding the stereotype and its implications is very scarce specifically among mental health practitioners. Therefore the present study aimed to narrow this gap in knowledge by examining the perception of Social Workers that are considered to be the forefront of mental health-care, in regard to the association between playing RPGs and mental health. A convenience sample of 130 Social Workers, recruited through social networks (e.g. Facebook, WhatsApp etc.), responded to an on-line survey dealing with their perception of their own knowledge on RPGs, the importance of such knowledge and the association between playing RPGs and mental illness. Results indicated an association between having higher knowledge of RPGs and lower perception of a link between playing RPGs and psychopathology. The study's findings emphasize the false stigma and its potential harmful implication on professionals' practice, especially in the context of intake process and primary diagnostic. The effect of familiarity is also discussed in light of the study's findings. HIGHLIGHTS: * The perception of mental health professionals toward role playing games such as Dungeons and Dragons is understudied. * Social Workers' perception was measured in regard to the connection between use of RPGs and DSM-IV-TR psychopathology. * Greater knowledge of RPGs was found to be associated with lower perception of the connection between use of RPGs and DSM-IV TR psychopathology. PMID- 28808831 TI - The 2017 ESCAP Research Academy Workshop: bright perspectives for child and adolescent psychiatry. PMID- 28808832 TI - Factor Structure of Teacher Ratings of the ODD Symptoms in Children. AB - This study used confirmatory factor analysis (CFA) to determine the best model for Oppositional Defiant Disorder (ODD) symptoms in children aged 3 to 15 years, as presented in the Disruptive Behavior Rating Scale. Teachers' ratings of the ODD symptoms of 213 children from general community schools in Australia were obtained. The findings provided most support for a bifactor model based on Stringaris and Goodman's [1] three-factor model (primary factors for irritable, hurtful, and headstrong). The general factor, but not the group factors in the model, showed high omega hierarchical and explained common variance. Thus, only the general factor in this model can be meaningfully interpreted. Also, the general factor was supported with regard to external validity. Specifically, this factor, but not the group factors, correlated strongly with ADHD inattention and hyperactivity/impulsivity symptom groups, and other measures of behavioural and emotional problems. The taxonomic, diagnostic, practical, and research implications of the findings are discussed. PMID- 28808833 TI - Long Acting Ionically Paired Embonate Based Nanocrystals of Donepezil for the Treatment of Alzheimer's Disease: a Proof of Concept Study. AB - PURPOSE: The aim of the present study was to prepare a patient friendly long acting donepezil (D) nanocrystals (NCs) formulation, with a high payload for i.m administration. As the native D hydrochloride salt has high aqueous solubility it is necessary to increase its hydrophobicity prior to the NCs formation. METHODS: D was ionically paired with embonic acid (E) in aqueous media and was successfully characterized using techniques like DSC, PXRD, FT-IR, NMR etc. Later, we converted the bulk ion pair into NCs using high pressure homogenization technique to study further in-vitro and in-vivo. RESULTS: The bulk ion pair has a drug content of 66% w/w and an 11,000 reduced solubility in comparison to native D hydrochloride. Also, its crystalline nature was confirmed by DSC and PXRD. The possible interaction sites responsible for the ion pair formation were identified though NMR. The prepared NCs has mean particle size 677.5 +/- 72.5 nm and PDI 0.152 +/- 0.061. In-vitro release showed a slow dissolution of NCs. Further, excellent bio compatibility of NCs were demonstrated in 3T3 cells. Following i.m administration of single dose of NCs, the D plasma level was found to be detectable up to 18 days. In vivo pharmacodynamic studies revealed that the single dose NCs i.m injection improved spatial memory learning and retention in ICV STZ model. CONCLUSION: Our results suggest that the developed formulation has a potential to replace the current daily dosing regimen to a less frequent dosing schedule. Graphical Abstract Improved pharmacokinetic and pharmacodynamic profile after administration of single dose donpezil embonate nanocrystals in Rats. PMID- 28808834 TI - Biochemical and behavioral phenotype of AGAT and GAMT deficient mice following long-term Creatine monohydrate supplementation. AB - The creatine/phosphocreatine system is essential for cellular phosphate coupled energy storage and production. We investigated the utility of creatine monohydrate supplementation in two different creatine deficient knockout mouse models. Following weaning, female Arginine: Glycine Amidinotransferase (AGAT) and Guanidinoacetate: methyltransferase (GAMT) knockouts and wild type mice were studied based on their genotypes and dietary supplementation (creatine free or 2% creatine monohydrate supplemented diet) for 10 weeks, using a series of behavioral tests and biochemical analyzes. An improved Rota rod performance was observed in both AGAT (p = 0.02) and GAMT knockout mice (p < 0.001) supplemented with 2% creatine. During Morris water maze probe trial, creatine supplemented AGAT knockout mice took less time to reach virtual platform (p = 0.03) and more frequently crossed this area (p = 0.001) than mice on creatine free diet. Similar observations were recorded for GAMT knockout mice. Urinary creatinine concentrations for AGAT (p = 0.001) and GAMT (p = 0.05) knockout mice were increased following creatine supplementation. Creatine supplementation has a potential to improve neuro-muscular coordination, spatial learning in both AGAT and GAMT knockout mice. Long term Creatine supplementation results in increased urine creatinine concentrations indicating improved creatine metabolism in knockout mice. PMID- 28808835 TI - Carbazole Substituted BODIPYs: Synthesis, Computational, Electrochemical and DSSC Studies. AB - Carbazole and p-anisyl substituted BODIPY dyes with a cyanoacetic acid anchoring group have been prepared and their spectral, electrochemical properties and photosensitizing potential in DSSC have been evaluated. X-ray structure of N phenylcarbazole substituted BODIPY revealed lower torsion angle between BODIPY plane and carbazole plane, suggesting increased communication between the two units. DFT studies indicated effective electronic interactions between the BODIPY unit and carbazole substituents. The N-butylcarbazole and N-phenylcarbazole substituted BODIPYs showed anodic shifts in their reduction potentials, indicating facile reduction process. The predicted HOMO-LUMO gaps are in agreement with the electrochemical result and the lower band gap was observed for the carbazole substituted BODIPYs. PMID- 28808836 TI - Excitation transfer and trapping kinetics in plant photosystem I probed by two dimensional electronic spectroscopy. AB - Photosystem I is a robust and highly efficient biological solar engine. Its capacity to utilize virtually every absorbed photon's energy in a photochemical reaction generates great interest in the kinetics and mechanisms of excitation energy transfer and charge separation. In this work, we have employed room temperature coherent two-dimensional electronic spectroscopy and time-resolved fluorescence spectroscopy to follow exciton equilibration and excitation trapping in intact Photosystem I complexes as well as core complexes isolated from Pisum sativum. We performed two-dimensional electronic spectroscopy measurements with low excitation pulse energies to record excited-state kinetics free from singlet singlet annihilation. Global lifetime analysis resolved energy transfer and trapping lifetimes closely matches the time-correlated single-photon counting data. Exciton energy equilibration in the core antenna occurred on a timescale of 0.5 ps. We further observed spectral equilibration component in the core complex with a 3-4 ps lifetime between the bulk Chl states and a state absorbing at 700 nm. Trapping in the core complex occurred with a 20 ps lifetime, which in the supercomplex split into two lifetimes, 16 ps and 67-75 ps. The experimental data could be modelled with two alternative models resulting in equally good fits-a transfer-to-trap-limited model and a trap-limited model. However, the former model is only possible if the 3-4 ps component is ascribed to equilibration with a "red" core antenna pool absorbing at 700 nm. Conversely, if these low-energy states are identified with the P700 reaction centre, the transfer-to-trap-model is ruled out in favour of a trap-limited model. PMID- 28808838 TI - Comparison of coronary sinus diameter Z-scores in normal fetuses and fetuses with persistent left superior vena cava (PLSVC). AB - To establish Z-score reference ranges for coronary sinus (CS) diameter in normal fetuses and explore the diagnostic value of CS Z-score in fetuses with persistent left superior vena cava (PLSVC). Study of 235 normal fetuses and 30 fetuses with PLSVC was involved. Noncardiac biometrical parameters included biparietal diameter (BPD), femoral length (FL), heart area (HA), gestation age (GA). The coronary sinus systolic and diastolic diameter (CSDs and CSDd ) were measured at the end of systole and diastole. CSDs and CSDd Z-score models were constructed by using linear regression analysis with Non-cardiac biometrical parameters as independent variables. Z-scores between normal fetuses and fetuses with PLSVC were compared. A simple, linear regression model was the best description and correlations between fetal CSDs and CSDd and four independent variables were excellent. Reference ranges for predicting means and SDs of the fetal CS were established. Equations for Z-score calculation were provided, CSDs and CSDd Z scores were statistically different between normal fetuses and those with PLSVC. Development of CSDs and CSDd Z-score reference ranges in normal fetuses was realized. The CSDs and CSDd Z-scores can provide quantitative evidence in prenatal diagnosis of PLSVC. PMID- 28808837 TI - A Multiparticulate Delivery System for Potential Colonic Targeting Using Bovine Serum Albumin as a Model Protein : Theme: Formulation and Manufacturing of Solid Dosage Forms Guest Editors: Tony Zhou and Tonglei Li. AB - PURPOSE: There are many important diseases whose treatment could be improved by delivering a therapeutic protein to the colon, for example, Clostridium difficile infection, ulcerative colitis and Crohn's Disease. The goal of this project was to investigate the feasibility of colonic delivery of proteins using multiparticulate beads. METHODS: In this work, bovine serum albumin (BSA) was adopted as a model protein. BSA was spray layered onto beads, followed by coating of an enteric polymer EUDRAGIT(r) FS 30 D to develop a colonic delivery system. The secondary and tertiary structure change and aggregation of BSA during spray layering process was examined. The BSA layered beads were then challenged in an accelerated stability study using International Council for Harmonization (ICH) conditions. The in vitro release of BSA from enteric coated beads was examined using United States Pharmacopeia (USP) dissolution apparatus 1. RESULTS: No significant changes in the secondary and tertiary structure or aggregation profile of BSA were observed after the spray layering process. Degradation of BSA to different extents was detected after storing at 25 degrees C and 40 degrees C for 38 days. Enteric coated BSA beads were intact in acidic media while released BSA in pH 7.4 phosphate buffer. CONCLUSION: We showed the feasibility of delivering proteins to colon in vitro using multiparticulate system. PMID- 28808839 TI - Individuals with autism have higher 8-Iso-PGF2alpha levels than controls, but no correlation with quantitative assay of Paraoxonase 1 serum levels. AB - Autism spectrum disorder (ASD) represents a very large set of neurodevelopmental issues with diverse clinical outcomes. Various hypotheses have been put forth for the etiology of autism spectrum disorder, including issues pertaining to oxidative stress. In this study, we conducted measurements of serum 8-Iso Prostaglanding F2 alpha (8-iso-PGF2alpha, which is the results of non enzimatically mediated polyunsaturated fatty acid oxidation) in a population of individuals with autism and a control group of age and sex matched controls. A quantitative assay of Paraoxonase 1 (PON1) was conducted. Data regarding comorbidities, structural MRI scans, medication, intelligence quotient (IQ) and Childhood Autism Rating Scale scores (CARS) were also included in our study. Our results show that patients diagnosed with autism have higher levels of 8-iso PGF2alpha than their neurotypical counterparts. Levels of this particular metabolite, however, do not correlate with quantitative serum levels of Paraoxonase 1, which has been shown to be altered in individuals with autism. Neither 8-iso-PGF2alpha nor quantitative levels of PON1 provide any meaningful correlation with clinical or neuroimaging data in this study group. Future research should focus on providing data regarding PON 1 phenotype, in addition to standard quantitative measurements, in relation to 8-iso-PGF2alpha as well as other clinical and structural brain findings. PMID- 28808840 TI - Comparison of health state values derived from patients and individuals from the general population. AB - PURPOSE: Utility values are critical for cost-utility analyses that guide healthcare decisions. We aimed to compare the utility values of the 5-level EuroQoL-5Dimension (EQ-5D-5L) health states elicited from members of the general public and patients with heart disease or cancer. METHODS: In face-to-face interviews with 157 heart disease patients, 169 cancer patients, and 169 members from the general population, participants valued 10 EQ-5D-5L health states using a composite Time Trade-Off method. RESULTS: Pooling utility values for all health states, heart disease patients and cancer patients had mean utility values lower by 0.11 points (P value = 0.014) and 0.06 points (P value = 0.148), respectively, compared to the general population. Adjusting for sociodemographic characteristics, differences in health state utility values between the patient and the general populations were rendered non-significant, except that heart disease patients gave higher utility values (mean difference = 0.08; P value = 0.007) to mild health states than the general population. Difference in utility values, defined as utility value of a better health state minus that of a poorer health state, was higher among heart disease patients compared to the general population, before and after adjusting for sociodemographic characteristics. CONCLUSIONS: Patients may differ from members of the general population in the strength of their preferences for hypothetical health states. Using utility values derived from the general population may under-estimate the comparative effectiveness of healthcare interventions for certain diseases, such as heart diseases. PMID- 28808841 TI - Prognostic significance of myocardial energy expenditure and myocardial efficiency in patients with heart failure with reduced ejection fraction. AB - In heart failure with reduced ejection fraction (HFrEF) patients, myocardial blood flow (MBF), myocardial energy expenditure (MEE), myocardial efficiency has been poorly evaluated because of the necessity of invasive procedures in the determination of these parameters. Transthoracic echocardiography (TTE) can provide reliable data for MEE, MBF (via coronary sinus (CS) flows). Also, myocardial efficiency can be evaluated by the MEE to MBF ratio. We aim to assess MBF, MEE and energy efficiency and the prognostic value of these parameters in HFrEF. In this prospective study, a total of 80 patients with HFrEF due to either ischemic or non-ischemic etiology and 20 healthy control subjects were included. Median follow-up duration was 901 (27-1004) days. MBF was calculated via coronary sinus blood flow. MEE was measured from circumferential end-systolic stress, stroke volume and left ventricular ejection time. MEE to MBF ratio was determined as MEf. Primary composite end-point (CEP) was cardiovascular mortality, heart transplantation or mechanical circulatory support. MEE and MEf were lower and MBF per minute was higher in HF group compared to control subjects whereas MBF per 100 g left ventricular mass was not different. MEE and MEf have significantly negative correlation with troponin I, BNP, uric acid and positive correlation with epicardial fat thickness. In Cox regression analysis, per one calorie decrease of MEE was associated 4.3 times increased risk [HR 4.396 (95% CI 1.230 15.716)] and per one percent decrease of MEf was associated 3.3 times increased risk of CEP [HR 3.343 (95% CI 1.025-10.905)]. Our study demonstrated that while MEE and MEf diminished in HFrEF, MBF preserved with the symptomatic progression of HF. MEE and MEf were found to be associated with important prognostic markers and independent predictors of CEP in HFrEF. Evaluation of MEE, MBF and MEf with echocardiography may provide an additional data regarding prognostic assessment of HFrEF population. PMID- 28808842 TI - Colonic motor dysfunctions in a mouse model of high-fat diet-induced obesity: an involvement of A2B adenosine receptors. AB - Adenosine A2B receptors (A2BR) regulate several enteric functions. However, their implication in the pathophysiology of intestinal dysmotility associated with high fat diet (HFD)-induced obesity has not been elucidated. We investigated the expression of A2BR in mouse colon and their role in the mechanisms underlying the development of enteric dysmotility associated with obesity. Wild-type C57BL/6J mice were fed with HFD (60% kcal from fat) or normocaloric diet (NCD; 18% kcal from fat) for 8 weeks. Colonic A2BR localization was examined by immunofluorescence. The role of A2BR in the control of colonic motility was examined in functional experiments on longitudinal muscle preparations (LMPs). In NCD mice, A2BR were predominantly located in myenteric neurons; in HFD animals, their expression increased throughout the neuromuscular layer. Functionally, the A2BR antagonist MRS1754 enhanced electrically induced NK1-mediated tachykininergic contractions in LMPs from HFD mice, while it was less effective in tissues from NCD mice. The A2B receptor agonist BAY 60-6583 decreased colonic tachykininergic contractions in LMPs, with higher efficacy in preparations from obese mice. Both A2BR ligands did not affect contractions elicited by exogenous substance P. Obesity is related with a condition of colonic inflammation, leading to an increase of A2BR expression. A2BR, modulating the activity of excitatory tachykininergic nerves, participate to the enteric dysmotility associated with obesity. PMID- 28808843 TI - Feasibility of Preoperative Axillary Lymph Node Marking with a Clip in Breast Cancer Patients Before Neoadjuvant Chemotherapy: A Preliminary Study. AB - BACKGROUND: The aim of this study was to determine the feasibility of image guided marker-clip placement in axillary lymph nodes (ALNs) for breast cancer upon initial presentation and to assess the reliability of this method with sentinel lymph node biopsy (SLNB) for axillary restaging after neoadjuvant chemotherapy (NAC). METHODS: Between June 2015 and August 2016, a marker clip was placed at a clinically positive ALN under ultrasonography (US) guidance before initiation of NAC in 20 patients. Preoperative localization of marker-clipped LNs was performed, and the localized LNs were removed by SLNB. We compared the postoperative results of the marker-clipped LNs, SLNs and ALNs. RESULTS: Image guided marker-clip placements and localization of marker-clipped LNs were performed successfully in 20 patients. A total of 24 marker clips were inserted, and 23 marker-clipped LNs were successfully retrieved during surgery (identification rate, 23/24, 95.8%). In the 11 patients with pathologically confirmed metastatic marker-clipped LNs, four became negative after NAC, and seven maintained metastatic residues on the marker-clipped LNs. Three of the seven patients had metastatic residues on the ALNs, and two of the three patients also had negative SLNs. Marker-clipped nodes accurately predicted the axillary nodal status in these two patients compared with SLNs alone. CONCLUSION: Image guided marker-clip placement on positive ALNs before NAC and removal with SLNB is technically feasible. This technique can improve the accuracy of the residual disease evaluation on the axilla, especially in patients with negative SLNB results, and can identify candidates for limited axillary surgery after NAC. PMID- 28808844 TI - Bialellic Mutations in Tetratricopeptide Repeat Domain 7A (TTC7A) Cause Common Variable Immunodeficiency-Like Phenotype with Enteropathy. PMID- 28808845 TI - Targeted treatment in severe traumatic brain injury in the age of precision medicine. AB - In recent years, much progress has been made in our understanding of traumatic brain injury (TBI). Clinical outcomes have progressively improved, but evidence based guidelines for how we manage patients remain surprisingly weak. The problem is that the many interventions and strategies that have been investigated in randomized controlled trials have all disappointed. These include many concepts that had become standard care in TBI. And that is just for adult TBI; in children, the situation is even worse. Not only is pediatric care more difficult than adult care because physiological norms change with age, but also there is less evidence for clinical practice. In this article, we discuss the heterogeneity inherent in TBI and why so many clinical trials have failed. We submit that a key goal for the future is to appreciate important clinical differences between patients in their pathophysiology and their responses to treatment. The challenge that faces us is how to rationally apply therapies based on the specific needs of an individual patient. In doing so, we may be able to apply the principles of precision medicine approaches to the patients we treat. PMID- 28808846 TI - Age-related changes in morphology of left atrial appendage in patients with atrial fibrillation. AB - The purpose of this study was to evaluate the relationship between age and frequency of left atrial appendage (LAA) morphology in patients with atrial fibrillation (AF) compared with sinus rhythm (SR). We enrolled 145 AF patients, and 199 SR patients for the control group without any cardiovascular disease. LAA volume index (LAAVi) and morphology were assessed by electrocardiogram-gated computed tomography angiography. LAA morphology was classified into "chicken wing" or "non-chicken wing" according to the previously described classification. There was no significant trend in frequency of non-chicken wing morphology among ages in the SR group (p = 0.36 for trend), whereas the frequency was negatively related to age in the AF group (p = 0.002 for trend). In multivariable logistic regression, age > 65 (odds ratio [OR] 0.42, p = 0.002) and duration of AF (OR 0.53, p = 0.010) and LAAVi (OR 0.62, p = 0.017) were independent factors of non chicken wing LAA morphology in the AF group. LAA morphology is affected by age, especially in patients with AF. When we utilize non-chicken wing LAA morphology as a stroke risk factor in patients with AF, we should pay attention to their age. PMID- 28808847 TI - Evaluation of hyoscine N-butyl bromide efficacy on the prevention of catheter related bladder discomfort after transurethral resection of prostate: a randomized, double-blind control trial. AB - BACKGROUND: Transurethral resection of prostate (TURP) is the most common treatment for benign prostatic hyperplasia (BPH). Urinary tract catheter is inserted post-operatively which results in catheter-related bladder discomfort (CRBD) in many patients. The purpose of this study was to assess the preventive effect of hyoscine N-butyl bromide on CRBD caused by a urinary tract catheter after TURP surgery in patients with BPH. METHODS: Twenty-four and twenty-six patients in the treatment and control groups were enrolled, respectively. At the end of the surgery, slow intravenous injection of 20 mg hyoscine N-butyl bromide was administered to the patients of treatment group. The severity of CRBD was followed up at five different time periods and up to 2 h after surgery. RESULTS: On arrival to PACU and after 30 min of injection, statistically significant less CRBD was seen in the treatment group comparing to the control group (P <= 0.05 and P <= 0.007). The total utilized meperidine dose during PACU stay and the time to discharge for the intervention group were significantly lower than those for the control group (P <= 0.0001) with no significant difference in adverse effects (P > 0.05). CONCLUSIONS: Hyoscine N-butyl bromide could reduce the severity of CRBD related to TURP in patients with BPH and their need for analgesic consumption either. It shortened the length of stay in the recovery room. Regarding its availability and low cost, it can be an effective pain relief drug for CRBD discomfort related to TURP in BPH patients. PMID- 28808848 TI - Validation study of accelerometer in measuring some sleep parameters in adults reply. PMID- 28808849 TI - A rapid method for establishment of a reverse genetics system for canine parvovirus. AB - Canine parvovirus (CPV) is an important and highly prevalent pathogen of dogs that causes acute hemorrhagic enteritis disease. Here, we describe a rapid method for the construction and characterization of a full-length infectious clone (rCPV) of CPV. Feline kidney (F81) cells were transfected with rCPV incorporating an engineered EcoR I site that served as a genetic marker. The rescued virus was indistinguishable from that of wild-type virus in its biological properties. PMID- 28808851 TI - Assessing the measurement invariance of the Brief Multidimensional Students' Life Satisfaction Scale in Chinese and American adolescents. AB - PURPOSE: This study evaluated the measurement invariance of the Brief Multidimensional Students' Life Satisfaction Scale (BMSLSS) and latent means across early adolescents from two diverse cultural settings, China and America. METHODS: We sampled 2045 middle school students (960 males) from China and 1747 middle school students (887 males) from America. Confirmatory factor analysis and multi-group confirmatory factor analysis were performed to examine the factor structure and the measurement equivalence across the two cultures and then examined latent mean differences between Chinese early adolescents and American early adolescents. RESULTS: Results of confirmatory factor analyses provided support for the expected one-factor structure. And a series of multi-group confirmatory factor analyses supported full configural invariance, full metric invariance, and partial scalar invariance between the two groups. These findings suggest that the BMSLSS may provide acceptable comparisons and meaningful correlates across the two differing cultures. Subsequent analyses of latent means indicated the suitability of the BMSLSS for conducting mean comparisons and revealed significant differences between Chinese early adolescents and American early adolescents. CONCLUSIONS: The BMSLSS appears to be suitable for cross cultural studies between Chinese and American early adolescents. Chinese early adolescents reported lower life satisfaction than early American adolescents. PMID- 28808850 TI - Non-REM sleep-disordered breathing affects performance on the psychomotor vigilance task. AB - PURPOSE: Although many studies have investigated the clinical importance of sleep apnea on rapid eye movement (REM) and non-REM (NREM) sleep, the relationship between behavioral performance and apneic events during different sleep phases remains unclear. In the present study, we sought to investigate the effect of sleep phase fragmentation due to sleep-disordered breathing (SDB) during REM and NREM on the vigilance and sustainability of attention based on psychomotor vigilance task (PVT) performance. METHODS: From a pool of subjects who underwent consecutive diagnostic polysomnography (PSG) for obstructive sleep apnea, 163 adult subjects with both REM and NREM sleep >= 30 min were enrolled for our study and performed a standardized 10-min PVT. The main outcome variables of the PVT were mean reaction time (RT), PVT Lapse count, and the slope of the reciprocal RT. Subjective sleepiness was measured using the Epworth Sleepiness Scale (ESS). RESULTS: After multivariate linear regression analysis with adjustment for age, sex, body mass index, and the apnea-hypopnea index (AHI) of the counterpart sleep phase, we found that AHI during NREM (AHINREM) compared to AHI during REM (AHIREM) was significantly associated with PVT lapses. CONCLUSIONS: Our results suggest that SDB during NREM has a significant impact on vigilance lapses compared to that of REM. PMID- 28808852 TI - Patient Experience with the Patient-Centered Medical Home in Michigan's Statewide Multi-Payer Demonstration: A Cross-Sectional Study. AB - BACKGROUND: The literature on patient-centered medical homes (PCMHs) and patient experience is somewhat mixed. Government and private payers are promoting multi payer PCMH initiatives to align requirements and resources and to enhance practice transformation outcomes. To this end, the multipayer Michigan Primary Care Transformation (MiPCT) demonstration project was carried out. OBJECTIVE: To examine whether the PCMH is associated with a better patient experience, and whether a mature, multi-payer PCMH demonstration is associated with even further improvement in the patient experience. DESIGN: This is a cross-sectional comparison of adults attributed to MiPCT PCMH, non-participating PCMH, and non PCMH practices, statistically controlling for potential confounders, and conducted among both general and high-risk patient samples. PARTICIPANTS: Responses came from 3893 patients in the general population and 4605 in the high risk population (response rates of 31.8% and 34.1%, respectively). MAIN MEASURES: The Clinician and Group Consumer Assessment of Healthcare Providers and Systems survey, with PCMH supplemental questions, was administered in January and February 2015. KEY RESULTS: MiPCT general and high-risk patients reported a significantly better experience than non-PCMH patients in most domains. Adjusted mean differences were as follows: access (0.35**, 0.36***), communication (0.19*, 0.18*), and coordination (0.33**, 0.35***), respectively (on a 10-point scale, with significance indicated by: *= p<0.05, **= p<0.01, and ***= p<0.001). Adjusted mean differences in overall provider ratings were not significant. Global odds ratios were significant for the domains of self-management support (1.38**, 1.41***) and comprehensiveness (1.67***, 1.61***). Non-participating PCMH ratings fell between MiPCT and non-PCMH across all domains and populations, sometimes attaining statistical significance. CONCLUSIONS: PCMH practices have more positive patient experiences across domains characteristic of advanced primary care. A mature multi-payer model has the strongest, most consistent association with a better patient experience, pointing to the need to provide consistent expectations, resources, and time for practice transformation. Our results held for a general population and a high-risk population which has much more contact with the healthcare system. PMID- 28808853 TI - Physicochemical and adsorptive characteristics of activated carbons from waste polyester textiles utilizing MgO template method. AB - Activated carbons with high specific surface areas were produced, utilizing waste polyester textiles as carbon precursor by magnesium oxide (MgO) template method. Magnesium chloride (MgCl2), magnesium citrate (MgCi), and MgO were employed as MgO precursors to prepare activated carbons (AC-MgCl2, AC-MgCi, and AC-MgO). Thermogravimetry-differential scanning calorimetry was conducted to investigate the pore-forming mechanism, and N2 adsorption/desorption isotherms, XRD, SEM-EDS, TEM, FTIR and pHpzc were achieved to analyze physicochemical characteristics of the samples. The specific surface areas of AC-MgCl2 (1173 m2/g) and AC-MgCi (1336 m2/g) were much higher than that of AC-MgO (450 m2/g), and the pores sizes of which were micro-mesoporous, mesoporous, and macropores, respectively, due to the formation of MgO crystal with different sizes. All activated carbons had abundant acidic oxygen groups. In addition, batch adsorption experiments were carried out to investigate the adsorptive characteristics of the prepared activated carbons toward Cr(VI). The adsorption kinetics fitted well with the pseudo-second order, and the adsorptive capacity of AC-MgCl2 (42.55 mg/g) was higher than those of AC MgCi (40.93 mg/g) and AC-MgO (35.87 mg/g). PMID- 28808854 TI - Assessing landscape and contaminant point-sources as spatial determinants of water quality in the Vermilion River System, Ontario, Canada. AB - The Vermilion River and major tributaries (VRMT) are located in the Vermilion watershed (4272 km2) in north-central Ontario, Canada. This watershed not only is dominated by natural land-cover but also has a legacy of mining and other development activities. The VRMT receive various point (e.g., sewage effluent) and non-point (e.g., mining activity runoff) inputs, in addition to flow regulation features. Further development in the Vermilion watershed has been proposed, raising concerns about cumulative impacts to ecosystem health in the VRMT. Due to the lack of historical assessments on riverine-health in the VRMT, a comprehensive suite of water quality parameters was collected monthly at 28 sites during the ice-free period of 2013 and 2014. Canadian water quality guidelines and objectives were not met by an assortment of water quality parameters, including nutrients and metals. This demonstrates that the VRMT is an impacted system with several pollution hotspots, particularly downstream of wastewater treatment facilities. Water quality throughout the river system appeared to be influenced by three distinct land-cover categories: forest, barren, and agriculture. Three spatial pathway models (geographical, topographical, and river network) were employed to assess the complex interactions between spatial pathways, stressors, and water quality condition. Topographical landscape analyses were performed at five different scales, where the strongest relationships between water quality and land-use occurred at the catchment scale. Sites on the main stem of Junction Creek, a tributary impacted by industrial and urban development, had above average concentrations for the majority of water quality parameters measured, including metals and nitrogen. The river network pathway (i.e., asymmetric eigenvector map (AEM)) and topographical feature (i.e., catchment land-use) models explained most of the variation in water quality (62.2%), indicating that they may be useful tools in assessing the spatial determinants of water quality decline. PMID- 28808855 TI - Incidence of myocardial infarction and stroke in acromegaly patients: results from the German Acromegaly Registry. AB - PURPOSE: Acromegaly is a rare disease generally brought about by a benign tumour in the pituitary and characterized by growth hormone (GH) and insulin-like growth factor 1 (IGF-1) excess. Increased mortality has been related to cardiovascular events that could be linked to these hormones and patients suffer from high rates of diabetes and hypertension. In this study, we examine if the incidence of myocardial infarction (MI) and stroke differ from that of the general population. METHODS: Data from the German Acromegaly Registry in seven specialized endocrine centres were analysed (n = 479, 56% female, 46 years old at diagnosis, 5549 person-years from diagnosis). Standardized incidence ratios (SIR) were calculated as compared to the general population. RESULTS: MI and stroke incidences were very close to those of the general population with an SIR (95% CI) of 0.89 (0.47 1.52, p = 0.80) for MI and 1.17 (0.66-1.93, p = 0.61) for stroke. Acromegaly was uncontrolled in 16% of patients with MI or stroke versus 21% in those without (p = 0.56). Prevalence of hypertension at the initial visit was much higher in those with MI or stroke than those without (94 vs. 43%, p < 0.001). No association was seen between radiation therapy and stroke. CONCLUSIONS: For acromegaly patients being treated at specialized centres, the incidence of MIs and strokes does not seem to differ from the general population. Certainty regarding such statements requires large, prospective studies however. PMID- 28808856 TI - Validation of Veterans Affairs Electronic Medical Record Smoking Data Among Iraq- and Afghanistan-Era Veterans. AB - BACKGROUND: Research using the Veterans Health Administration (VA) electronic medical records (EMR) has been limited by a lack of reliable smoking data. OBJECTIVE: To evaluate the validity of using VA EMR "Health Factors" data to determine smoking status among veterans with recent military service. DESIGN: Sensitivity, specificity, area under the receiver-operating curve (AUC), and kappa statistics were used to evaluate concordance between VA EMR smoking status and criterion smoking status. PARTICIPANTS: Veterans (N = 2025) with service during the wars in Iraq/Afghanistan who participated in the VA Mid-Atlantic Post Deployment Mental Health (PDMH) Study. MAIN MEASURES: Criterion smoking status was based on self-report during a confidential study visit. VA EMR smoking status was measured by coding health factors data entries (populated during automated clinical reminders) in three ways: based on the most common health factor, the most recent health factor, and the health factor within 12 months of the criterion smoking status data collection date. KEY RESULTS: Concordance with PDMH smoking status (current, former, never) was highest when determined by the most commonly observed VA EMR health factor (kappa = 0.69) and was not significantly impacted by psychiatric status. Agreement was higher when smoking status was dichotomized: current vs. not current (kappa = 0.73; sensitivity = 0.84; specificity = 0.91; AUC = 0.87); ever vs. never (kappa = 0.75; sensitivity = 0.85; specificity = 0.90; AUC = 0.87). There were substantial missing Health Factors data when restricting analyses to a 12-month period from the criterion smoking status date. Current smokers had significantly more Health Factors entries compared to never or former smokers. CONCLUSIONS: The use of computerized tobacco screening data to determine smoking status is valid and feasible. Results indicating that smokers have significantly more health factors entries than non smokers suggest that caution is warranted when using the EMR to select cases for cohort studies as the risk for selection bias appears high. PMID- 28808857 TI - The Surgeon's Role in Treating Chronic Pancreatitis and Incidentally Discovered Pancreatic Lesions. AB - Chronic pancreatitis and incidentally discovered pancreatic lesions present significant diagnostic and therapeutic challenges for surgeons. While both decompressive and resection procedures have been described for treatment of chronic pancreatitis, optimal management must be tailored to each patient's individual disease characteristics, parenchymal morphology, and ductal anatomy. Surgeons should strive to achieve long-lasting pain relief while preserving native pancreatic function. For patients with incidentally discovered pancreatic lesions, differentiating benign, pre-malignant, and malignant lesions is critical as earlier treatment is thought to result in improved survival. The purpose of this evidence-based manuscript is to review the presentation, workup, surgical management, and associated outcomes for patients with chronic pancreatitis or incidentally discovered solid and cystic lesions of the pancreas. PMID- 28808859 TI - Best practices in cell culture: an overview. AB - This overview describes a series of articles to provide an unmet need for information on best practices in animal cell culture. The target audience primarily consists of entry-level scientists with minimal experience in cell culture. It also include scientists, journalists, and educators with some experience in cell culture, but in need of a refresher in best practices. The articles will be published in this journal over a six-month period and will emphasize best practices in: (1) media selection; (2) use and evaluation of animal serum as a component of cell culture medium; (3) receipt of new cells into the laboratory; (4) naming cell lines; (5) authenticating cell line identity; (6) detecting and mitigating risk of cell culture contamination; (7) cryopreservation and thawing of cells; and (8) storing and shipping viable cells. PMID- 28808858 TI - Vitamin D and Heart Failure. AB - PURPOSE: Vitamin D is principally known for its role in calcium homeostasis, but preclinical studies implicate multiple pathways through which vitamin D may affect cardiovascular function and influence risk for heart failure. Many adults with cardiovascular disease have low vitamin D status, making it a potential therapeutic target. We review the rationale and potential role of vitamin D supplementation in the prevention and treatment of chronic heart failure. RECENT FINDINGS: Substantial observational evidence has associated low vitamin D status with the risk of heart failure, ventricular remodeling, and clinical outcomes in heart failure, including mortality. However, trials assessing the influence of vitamin D supplementation on surrogate markers and clinical outcomes in heart failure have generally been small and inconclusive. There are insufficient data to recommend routine assessment or supplementation of vitamin D for the prevention or treatment of chronic heart failure. Prospective trials powered for clinical outcomes are warranted. PMID- 28808860 TI - Validation of the AJCC 8th lung cancer staging system among patients with small cell lung cancer. AB - BACKGROUND: The current study tried to validate the prognostic significance of the 8th American Joint Committee on Cancer (AJCC) staging system among small cell lung cancer (SCLC) patients recorded within the surveillance, epidemiology, and end results (SEER) database. PATIENTS AND METHODS: SEER database (2004-2014) has been queried through SEER*Stat program, and both AJCC 7th and 8th edition stages were constructed. Cancer-specific and overall survival analyses according to both editions were performed through Kaplan-Meier analysis. The cause-specific Cox regression hazard for both AJCC editions (adjusted for age, gender, race, and surgery) was calculated and pair-wise comparisons of hazard ratios were conducted. RESULTS: A total of 39,286 patients with SCLC were recruited in the period from 2004 to 2014. For overall and cancer-specific survival assessment, according to the AJCC 7th edition, P values for all pair-wise comparisons among different stages were significant (<0.0001) except for the comparisons between stage IB vs. stage IIA, and stage IIB vs. stage IIIA. For overall survival assessment, according to AJCC 8th, P values for all pair-wise comparisons were significant (<0.05) except for IA2 vs. IA3, IA3 vs. IB, IB vs. IIA, IIA vs. IIB, and IIIB vs. IIIC. For cancer-specific survival, according to AJCC 8th, P values for all pair-wise comparisons among different stages were significant (<0.05) except IA1 vs. IA2, IA2 vs. IA3, and IIA vs. IIB. When conducting pair-wise hazard ratio comparisons among different AJCC stages (for both editions), similar findings to the Kaplan-Meier analyses were reported. CONCLUSION: While there is a clear improvement for both the AJCC 7th and 8th systems compared to the old veterans' administration system, there is a modest improvement for the 8th compared to the 7th system among patients with SCLC. PMID- 28808863 TI - Warm Handoffs: a Novel Strategy to Improve End-of-Rotation Care Transitions. AB - BACKGROUND: Hospitalized medical patients undergoing transition of care by house staff teams at the end of a ward rotation are associated with an increased risk of mortality, yet best practices surrounding this transition are lacking. AIM: To assess the impact of a warm handoff protocol for end-of-rotation care transitions. SETTING: A large, university-based internal medicine residency using three different training sites. PARTICIPANTS: PGY-2 and PGY-3 internal medicine residents. PROGRAM DESCRIPTION: Implementation of a warm handoff protocol whereby the incoming and outgoing residents meet at the hospital to sign out in-person and jointly round at the bedside on sicker patients using a checklist. PROGRAM EVALUATION: An eight-question survey completed by 60 of 99 eligible residents demonstrated that 85% of residents perceived warm handoffs to be safer for patients (p < 0.001), while 98% felt warm handoffs improved their knowledge and comfort level of patients on day 1 of an inpatient rotation (p < 0.001) as compared to prior handoff techniques. Finally, 88% felt warm handoffs were worthwhile despite requiring additional time (p < 0.001). DISCUSSION: A warm handoff protocol represents a novel strategy to potentially mitigate the known risks associated with end-of-rotation care transitions. Additional studies analyzing patient outcomes will be needed to assess the impact of this strategy. PMID- 28808862 TI - A pilot study comparing T-regulatory cell function among healthy children in different areas of Gansu, China. AB - Immune system is critical to protecting human health from toxic substances. Our previously published research had found an important link between polycyclic aromatic hydrocarbons (PAHs) in ambient air and changes at the DNA level in immune cells that led to impaired function of regulatory T (Treg) cells in children living in California, USA. But molecular and cellular pathways of these changes remain unclear. The present study aims to explore whether exposure to PAHs leads to changes in Treg cells functions of children living in Gansu, China, where ambient air pollution levels are much higher than those in California, and to explore potential mechanisms of PAH-induced immunological dysfunctions. Air pollutions in Lanzhou and Lintao, Gansu Province, were measured from December 2015 to June 2016. Healthy children were recruited from both cities and enrolled in this pilot study. Demographic information was collected by questionnaires. Blood samples were collected. Peripheral blood Treg cells were analyzed for Treg cells percentage by flow cytometry. Gene expression of forkhead box transcription factor 3 (Foxp3), transforming growth factor-beta (TGF-beta), and interleukin 35 (IL35) were examined by reverse transcription-polymerase chain reaction (RT-PCR). The results indicated PAH concentration (as sum of 16 PAHs) in Lintao was over two times higher than that was in Lanzhou (707 vs. 326 ng/m3), whereas PM2.5 concentration was comparable in two cities (55.3 in Lintao vs. 65.7 MUg/m3 in Lanzhou). Notably, we observed lower gene expressions for Foxp3 (P < 0.05), IL35 (P < 0.05), and TGF-beta, in children living in Lintao, suggesting an impairment of Treg cells function potentially associated with higher PAH exposure in Lintao. However, no significant difference was observed in Treg cells % among CD4+ T cells between Lanzhou and Lintao groups. PMID- 28808861 TI - Epidemiology of Sleep-Disordered Breathing and Heart Failure: What Drives What. AB - PURPOSE OF REVIEW: The bidirectional relationships that have been demonstrated between heart failure (HF) and central sleep apnea (CSA) demand further exploration with respect to the implications that each condition has for the other. This review discusses the body of literature that has accumulated on these relationships and how CSA and its potential treatment may affect outcomes in patients with CSA. RECENT FINDINGS: Obstructive sleep apnea (OSA) can exacerbate hypertension, type 2 diabetes, obesity, and atherosclerosis, which are known predicates of HF. Conversely, patients with HF more frequently exhibit OSA partly due to respiratory control system instability. These same mechanisms are responsible for the frequent association of HF with CSA with or without a Hunter Cheyne-Stokes breathing (HCSB) pattern. Just as is the case with OSA, patients with HF complicated by CSA exhibit more severe cardiac dysfunction leading to increased mortality; the increase in severity of HF can in turn worsen the degree of sleep disordered breathing (SDB). Thus, a bidirectional relationship exists between HF and both phenotypes of SDB; moreover, an individual patient may exhibit a combination of these phenotypes. Both types of SDB remain significantly underdiagnosed in patients with HF and hence undertreated. Appropriate screening for, and treatment of, OSA is clearly a significant factor in the comprehensive management of HF, while the relevance of CSA remains controversial. Given the unexpected results of the Treatment of Sleep-Disordered Breathing with Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients with Heart Failure trial, it is now of paramount importance that additional analysis of these data be expeditiously reported. It is also critical that ongoing and proposed prospective studies of this issue proceed without delay. PMID- 28808864 TI - Elevated bilirubin levels and risk of developing chronic kidney disease: a dose response meta-analysis and systematic review of cohort studies. AB - AIMS: Previous studies have indicated the link of bilirubin levels and risk of developing chronic kidney disease (CKD); however, the findings were inconsistent. METHODS: We searched for cohort studies examining bilirubin as an exposure and CKD as an outcome in the Medline, EMBASE, and Web of Science databases from inception through November 31, 2016. A generalized least-squares approach was applied to assess the dose-response relationship between them by pooling rate ratios with 95% confidence intervals. Subgroup analyses, sensitivity analysis, meta-regression, and publication bias were also conducted. RESULTS: Seven cohort studies with 1316 cases and 21,076 participants were identified for inclusion in the meta-analysis. The combined RR for the highest versus lowest bilirubin level was 0.36 (95% CI 0.19-0.68; P heterogeneity = 0.001; Power = 0.72; n = 6). In the linear dose-response analysis, each 1-MUmol/L increase in bilirubin was associated with a 5% reduced risk of CKD (RR = 0.95; 95% CI 0.92-0.97; P for trend test = 0.113; P heterogeneity = 0.001; Power = 0.99; n = 7). The subgroup analyses and sensitivity analyses showed consistent results, and publication bias may exist. CONCLUSION: This meta-analysis suggests that elevated bilirubin level may be associated with decreased risk of developing CKD. PMID- 28808865 TI - Glucagon-Like Peptides 1 and 2 Are Involved in Satiety Modulation After Modified Biliopancreatic Diversion: Results of a Pilot Study. AB - BACKGROUND: This paper aimed to evaluate the influence of modified biliopancreatic diversion (BPD) on the levels of GLP-1 and GLP-2 and correlate them with satiety regulation. METHODS: This is a pilot prospective cohort study that evaluated six mildly obese individuals with type 2 diabetes mellitus, which underwent modified BPD and were followed-up for 12 months. Levels of GLP-1 and GLP-2 after a standard meal tolerance test were determined and correlated with satiety scores obtained by means of a visual analogue scale (VAS). RESULTS: There were significant changes in BMI (33 +/- 2.2 versus 26.3 +/- 2.2 kg/m2; p < 0.001), HbA1c (7.9 +/- 1.6 versus 5.8 +/- 1.2%; p = 0.026), total cholesterol (172.3 +/- 11.1 versus 134.7 +/- 16.1 mg/dL; p < 0.001), LDL-c (103.3 +/- 13 versus 64.6 +/- 12.2 mg/dL; p < 0.001), and postprandial GLP-2 (972.7 +/- 326.2 versus 1993.2 +/- 1024.7; p = 0. 044). None of the scores obtained in the VAS significantly changed after surgery. After surgery, there were significant correlations of VAS scores and GLP-1 levels in question 01 ("how hungry do you feel?"; R = -0.928; p = .008) and GLP-2 levels in questions 02 ("how full do you feel?" R = 0.943; p = 0.005) and 04 ("how much do you think you can eat now? R = 0.829; p = 0.042). CONCLUSIONS: Modified BPD does not lead to significant changes in satiety evaluated by the VAS; different aspects of satiety regulation are correlated with the postprandial levels of GLP-1 (hunger feeling) and GLP-2 (satiation feeling and desire to eat) 1 year after modified BPD, signaling a specific postoperative gut hormone-related modulation of appetite. PMID- 28808867 TI - Author Productivity Index: Without Distortions. PMID- 28808866 TI - Activations in gray and white matter are modulated by uni-manual responses during within and inter-hemispheric transfer: effects of response hand and right handedness. AB - Because the visual cortices are contra-laterally organized, inter-hemispheric transfer tasks have been used to behaviorally probe how information briefly presented to one hemisphere of the visual cortex is integrated with responses resulting from the ipsi- or contra-lateral motor cortex. By forcing rapid information exchange across diverse regions, these tasks robustly activate not only gray matter regions, but also white matter tracts. It is likely that the response hand itself (dominant or non-dominant) modulates gray and white matter activations during within and inter-hemispheric transfer. Yet the role of uni manual responses and/or right hand dominance in modulating brain activations during such basic tasks is unclear. Here we investigated how uni-manual responses with either hand modulated activations during a basic visuo-motor task (the established Poffenberger paradigm) alternating between inter- and within hemispheric transfer conditions. In a large sample of strongly right-handed adults (n = 49), we used a factorial combination of transfer condition [Inter vs. Within] and response hand [Dominant(Right) vs. Non-Dominant (Left)] to discover fMRI-based activations in gray matter, and in narrowly defined white matter tracts. These tracts were identified using a priori probabilistic white matter atlases. Uni-manual responses with the right hand strongly modulated activations in gray matter, and notably in white matter. Furthermore, when responding with the left hand, activations during inter-hemispheric transfer were strongly predicted by the degree of right-hand dominance, with increased right-handedness predicting decreased fMRI activation. Finally, increasing age within the middle aged sample was associated with a decrease in activations. These results provide novel evidence of complex relationships between uni-manual responses in right handed subjects, and activations during within- and inter-hemispheric transfer suggest that the organization of the motor system exerts sophisticated functional effects. Moreover, our evidence of activation in white matter tracts is consistent with prior studies, confirming fMRI-detectable white matter activations which are systematically modulated by experimental condition. PMID- 28808868 TI - Effect of Multimodal Analgesia on Opioid Use After Open Ventral Hernia Repair. AB - BACKGROUND: There is limited data on enhanced recovery after surgery (ERAS) protocols after ventral hernia repair (VHR). This study reports the impact of multimodal analgesia on opioid use after open VHR. METHODS: Retrospective review of open VHR treated during the initial 6 months after ERAS implementation. Protocol focused on opioid sparing using intraoperative ketamine and/or lidocaine infusion, selective epidural anesthesia, and postoperative ketamine infusion, ketorolac, and acetaminophen. Four groups were analyzed: 1-ERAS protocol with epidural analgesia, 2-historical controls with epidural analgesia prior to ERAS, 3-ERAS protocol without epidural, and 4-historical controls without epidural analgesia, prior to ERAS. Continuous variables were analyzed using ANOVA or Kruskal-Wallis tests, and subgroup analysis using Student's t test or Mann Whitney U test. Discrete variables were analyzed using Pearson's chi-square test or Fisher's exact test. RESULTS: Patients differed in hernia width, but were similar in comorbidity and operative technique. There was no difference in length of stay or readmission. Use of ERAS nearly eliminated patient-controlled analgesia use (group 1, 2.7%; group 2, 68.4%; group 3, 0%; group 4, 65.7%; p < 0.001). ERAS significantly reduced narcotic requirements on postoperative days 0, 1, and 2 (p < 0.001). To account for the bias of selective epidural analgesia, groups 1 and 2 (epidural) and groups 3 and 4 (no epidural) were compared separately. Opioid requirement and PCA use remained significantly lower in patients in the ERAS pathway. CONCLUSION: Implementation of multimodal analgesia in the perioperative and postoperative setting significantly reduced opioid use after VHR. PMID- 28808869 TI - Hospitalizations and Nursing Facility Stays During the Transition from CKD to ESRD on Dialysis: An Observational Study. AB - BACKGROUND: There is little information on hospital and nursing facility stays during the transition from pre-dialysis kidney disease to end-stage renal disease treated with dialysis. OBJECTIVES: To examine hospital and nursing facility stays in the years pre- and post-dialysis initiation, and to develop a novel method for visualizing these data. DESIGN: Observational study of patients in the US Renal Data System initiating dialysis from October 2011 to October 2012. PARTICIPANTS: Patients aged >=67 years with Medicare Part A/B coverage for 1 year pre-dialysis initiation. MAIN MEASURES: Proportion of patients with >=1 facility day, and among these, the mean number of days and the mean proportion of time spent in a facility in the first year post-dialysis initiation. We created "heat maps" to represent data visually. KEY RESULTS: Among 28,049 patients, > 60% initiated dialysis in the hospital. Patients with at least 1 facility day spent 37-42 days in a facility in the year pre-dialysis initiation and 59-67 facility days in the year post-dialysis initiation. The duration of facility stay varied by age: patients aged 67-70 years spent 60 (95% CI 57-62) days or 25.8% of the first year post-dialysis initiation in a facility, while patients aged >80 years spent 67 (CI 65-69) days or 36.8% of the first year post-dialysis initiation in a facility. Patterns varied depending on the presence or absence of certain comorbid conditions, with dementia having a particularly large effect: patients with dementia spent approximately 50% of the first year post-dialysis initiation in a facility, regardless of age. CONCLUSIONS: Older patients, particularly octogenarians and patients with dementia or other comorbidities, spend a large proportion of time in a facility during the first year after dialysis initiation. Our heat maps provide a novel and concise visual representation of a large amount of quantitative data regarding expected outcomes after initiation of dialysis. PMID- 28808870 TI - Chest circumference and birth weight are good predictors of lung function in preschool children from an e-waste recycling area. AB - The purpose of this study was to investigate the associations between birth weight, chest circumference, and lung function in preschool children from e-waste exposure area. A total of 206 preschool children from Guiyu (an e-waste recycling area) and Haojiang and Xiashan (the reference areas) in China were recruited and required to undergo physical examination, blood tests, and lung function tests during the study period. Birth outcome such as birth weight and birth height were obtained by questionnaire. Children living in the e-waste-exposed area have a lower birth weight, chest circumference, height, and lung function when compare to their peers from the reference areas (all p value <0.05). Both Spearman and partial correlation analyses showed that birth weight and chest circumference were positively correlated with lung function levels including forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). After adjustment for the potential confounders in further linear regression analyses, birth weight, and chest circumference were positively associated with lung function levels, respectively. Taken together, birth weight and chest circumference may be good predictors for lung function levels in preschool children. PMID- 28808871 TI - African-American Prostate Cancer Disparities. AB - PURPOSE OF REVIEW: The purpose of this review is to examine prostate cancer racial disparities specific to the African-American population. RECENT FINDINGS: African-American men are more likely to be diagnosed with prostate cancer, present at an earlier age; are more likely to have locally advanced or metastatic disease at diagnosis; and have suboptimal outcomes to standard treatments. Prostate cancer treatment requires a nuanced approach, particularly when applying screening, counseling, and management of African-American men. Oncological as well as functional outcomes may differ and are potentially due to a combination of genetic, molecular, behavioral, and socioeconomic factors. PMID- 28808872 TI - Analysis of blood markers for early breast cancer diagnosis. AB - PURPOSE: Breast cancer is the most common neoplasm in women and has the highest associated mortality rate. Rapid detection programmes can provide early diagnosis and increase the chances of survival. There are no specific tumor biomarkers for the early phase of the disease. The primary aim of this study was to search a blood biomarker with levels that exceeded the normal range established in the general population that could be used to screen breast cancer. METHODS/PATIENTS: Case-control study. Conventional as well as research (NGAL, EGFR and 8-OHdG) tumor biomarkers were analyzed. RESULTS: A total of 126 women were enrolled (cases: 63 patients with local breast cancer; Controls: 63 healthy women). Significant differences were found in patients with higher levels of the conventional markers, Ca15.3, CEA, Cyfra 21.1 and NSE. However, when commercial cut-off values were used, only Ca 15.13 was significant. In the group of research biomarkers, significantly higher levels of EGFR were found in the control group, and of 8-OHdG in the case group. Using logistic regression analysis and a ROC curve, an equation composed of five markers, Ca 15.3, NSE, NGAL, EGFR and 8-OHdG, which yielded a correct diagnostic probability of breast cancer of 91.8% was obtained. CONCLUSIONS: 8-OHdG has been identified as a new potential marker for screening early stage breast cancer. In addition, a model that combines five blood markers that can be used as a diagnostic test in certain groups of patients has been developed. New studies with a larger sample size are needed to verify the results obtained. PMID- 28808873 TI - Elevated Hu-Antigen Receptor (HuR) Expression is Associated with Tumor Aggressiveness and Poor Prognosis but not with COX-2 Expression in Invasive Breast Carcinoma Patients. AB - Hu-antigen R (HuR), a RNA-binding protein, is considered to play a crucial role in tumor development and progression by stabilizing or regulating a group of cellular mRNAs of cancer-related genes, such as cyclooxygenase-2 (COX-2). The present study aimed to evaluate the clinical significance of HuR and COX-2 expression in invasive breast carcinoma. HuR and COX-2 protein expression was assessed immunohistochemically on paraffin-embedded breast cancer tissue sections obtained from 121 patients and was statistically analyzed with clinicopathological parameters, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), as well as with tumor cells' proliferative capacity and overall and disease-free patients' survival. High HuR expression was positively associated with larger tumor size and advanced disease stage (p = 0.0234 and p = 0.0361, respectively), being more frequently observed in ER negative cases (p = 0.0208). High COX-2 expression was negatively associated with histological (p < 0.0001) and nuclear (p = 0.0033) grade and tumor cells' proliferative rate (p = 0.0015), being more frequently observed in luminal-A compared to other molecular subtypes (p = 0.0221). High HuR expression was associated with poor overall and disease-free patients' survival at both univariate (log-rank test, p = 0.0092 and p = 0.0004, respectively) and multivariate (Cox-regression analysis, p = 0.0223 and p = 0.0004, respectively) level. On the other hand, high COX-2 expression was associated with favorable overall and disease-free patients' survival merely at univariate level (log-rank test, p = 0.0389 and p = 0.0154, respectively). HuR expression was not associated with COX-2 expression (Spearman R = 0.1489, p = 0.1032). The present data support evidence that HuR is associated with tumor aggressiveness and poor prognosis in breast carcinoma, reinforcing its potential as promising therapeutic target in this type of neoplasia. PMID- 28808875 TI - SSAT State-of-the-Art Conference: Current Surgical Management of Gastric Tumors. AB - INTRODUCTION: The current era of gastric surgery is marked by low morbidity and mortality rates, innovative strategies to approach resections with a minimally invasive fashion or hyperthermic intraperitoneal chemotherapy (HIPEC), as well as improved understanding of the biology of sporadic and hereditary stromal, neuroendocrine, and epithelial malignancies. METHODS: In 2017, the Society for Surgery of the Alimentary Tract convened a State-of-the-Art Conference on Current Surgical Management of Gastric Tumors with both international experts and emerging leaders in the field of gastric surgery. RESULTS: Martin D. McCarter, MD of the University of Colorado discussed the current management of gastric gastrointestinal stromal tumors (GIST). Kaitlyn J. Kelly, MD of the University of California, San Diego discussed the management of gastric carcinoid tumors. Jeffrey A. Norton of Stanford University discussed recent advances in the management of gastric adenocarcinoma including a focus on hereditary diffuse gastric cancer (HDGC). Joseph Kim, MD of Stony Brook University discussed a systematic approach to minimally invasive gastrectomy for cancer. Joyce Wong, MD of Pennsylvania State University discussed the role for cytoreductive surgery (CRS) and HIPEC for gastric adenocarcinoma. CONCLUSIONS: This review provides gastrointestinal surgeons with a concise update on the current surgical management of gastric tumors. PMID- 28808874 TI - Postpartum glucose intolerance: an updated overview. AB - The prevalence of type 2 diabetes mellitus has increased worldwide over the past three decades, as a consequence of the more westernized lifestyle, which is responsible for the increasing obesity rate in the modern adult's life. Concomitant with this increase there has been a gradual rise in the overall prevalence of gestational diabetes mellitus, a condition that strongly predisposes to overt diabetes later in life. Many women with previous gestational diabetes mellitus show glucose intolerance in the early postpartum period. Although the best screening strategy for postpartum glucose intolerance is still debated, numerous evidences indicate that identification of these women at this time is of critical importance, as efforts to initiate early intensive lifestyle modification, including hypocaloric diet and physical activity, and to ameliorate the metabolic profile of these high-risk subjects can prevent or delay the onset of type 2 diabetes mellitus. Nevertheless, less than one fifth of women attend the scheduled postpartum screening following gestational diabetes mellitus and they are at increased risk to develop type 2 diabetes mellitus later in their lives. Unsatisfying results have also come from early intervention strategies and tools that have been developed during the last few years to help improving the rate of adherence to postpartum glycemic testing, thereby indicating that more effective strategies are needed to improve women's participation in postpartum screening. PMID- 28808877 TI - Reply to the Letter "Gastric Remnant Dilatation: a Rare Technical Complication Following Laparoscopic One Anastomosis (Mini) Gastric Bypass". PMID- 28808876 TI - Changes of cerebrospinal fluid Abeta42, t-tau, and p-tau in Parkinson's disease patients with cognitive impairment relative to those with normal cognition: a meta-analysis. AB - The cerebrospinal fluid (CSF) signature of reduced amyloid beta 1-42 (Abeta42), elevated total tau (t-tau), and phosphorylated tau181 (p-tau) is important for the early diagnosis of Alzheimer's disease (AD). Abeta42, t-tau, and p-tau have been reported in numerous studies to contribute to predicting cognitive impairment in Parkinson's disease (PDCI). However, no consistent conclusion can be drawn so far. Literatures regarding Abeta42, t-tau, and p-tau in CSF were systematically reviewed, and a meta-analysis was thus performed to evaluate the changes of these biomarkers in PDCI patients, including PD with mild cognitive impairment (PDMCI) and PD dementia (PDD) patients, relative to PD with normal cognition (PDNC) patients. Databases of "PubMed," "EBSCO," and "Springer" were retrieved for articles concerning Abeta42, t-tau, and p-tau in PDCI patients relative to those in PDNC patients published from January 1, 2000 to February 1, 2017. The following keywords were set, namely, "dementia" or "cognitive impairment" or "mild cognitive impairment" and "cerebrospinal fluid" and "Parkinson*." Sixteen articles comprising 590 PDCI patients and 1182 PDNC patients were included. The results showed that CSF Abeta42 level in PDCI cohort was lower than that in PDNC cohort (pooled Std.MD = -0.44, 95% CI [-0.61, -0.26], p < 0.00001). Reduced Abeta42 (pooled Std.MD = -0.60, 95% CI [-0.75, -0.45], p < 0.00001) as well as elevated t-tau (pooled Std.MD = 0.21, 95% CI [0.06, 0.35], p = 0.006) and p-tau (pooled Std.MD = 0.36, 95% CI [0.02, 0.69], p = 0.04) could be observed in PDD cohort compared with PDNC cohort. Therefore, amyloid pathology and tauopathy may participate in the development of PDD, which is similar to AD. PMID- 28808879 TI - Influence of ignited sediments on external phosphorus adsorption and sedimentary phosphorus forms. AB - Phosphorus (P) adsorpted by sediments, when covered by and mixed with ignited sediments from Meiliang Bay in Tai Lake, was analyzed in the laboratory. Potassium dihydrogen phosphate (KH2PO4) was added to the parallel experimental units to simulate periodic external P input. Based on the Langmuir model, the sediments after ignition had a greater Smax (maximum P adsorption), a lower equilibrium phosphorus concentration at zero adsorption (EPC0), and a lower degree of phosphorus saturation in comparison with sediments without ignition. This was confirmed by the variation in the dissolved inorganic phosphorus in the overlying water. When sediments were mixed with or covered by the ignited sediments, 5.985 and 5.978 mg of input P disappeared from the overlying water, respectively. However, when the sediments were mixed with the ignited sediments, 84.18% of the input P was converted to HCl-P, whereas when they were covered by the ignited sediments, sedimentary P was released, mainly from Fe/Al-P (up to 87.50%). This was attributed to differences in the microenvironments where less intense anaerobic conditions were formed in the mixed sediments than in the sediments covered by the ignited sediments. This suggests that the injection of ignited sediments into existing sediments enhances their P adsorption and retention. It is favor of the control of the eutrophication with a simple technology. PMID- 28808878 TI - Role of intestinal microbiome in American ginseng-mediated colon cancer prevention in high fat diet-fed AOM/DSS mice [corrected]. AB - OBJECTIVE: Chronic intestinal inflammation is a risk factor for colorectal cancer (CRC) initiation and development. Diets that are rich in Western style fats have been shown to promote CRC. This study was conducted to investigate the role of intestinal microbiome in American ginseng-mediated CRC chemoprevention in a mouse model. The population and diversity of enteric microbiome were evaluated after the ginseng treatment. METHODS: Using an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced gut inflammation and tumorigenesis mouse model, the effects of oral American ginseng on high fat diet-associated enteric pathology were determined. After establishment of a 16S rRNA illumina library from fecal samples, MiSeq sequencing was carried out to reveal the microbial population. The alpha and beta diversities of microbiome were analyzed. RESULTS: American ginseng significantly attenuated AOM/DSS-induced colon inflammation and tumorigenesis by reducing the colitis score and colon tumor multiplicity. The MiSeq results showed that the majority of sequences fell into three phyla: Firmicutes, Bacteroidetes and Verrucomicrobia. Further, two significant abundance shifts at the family level, Bacteroidaceae and Porphyromonadaceae, were identified to support ginseng's anti-colitis and anti-tumor effects. In addition, alpha and beta diversity data demonstrated that ginseng led to a profound recovery from the AOM/DSS-induced dysbiosis in the microbial community. CONCLUSION: Our results suggest that the CRC chemopreventive effects of American ginseng are mediated through enteric microbiome population-shift recovery and dysbiosis restoration. Ginseng's regulation of the microbiome balance contributes to the maintenance of enteric homeostasis. PMID- 28808881 TI - A Proposal to Detect the Double Submission of a Manuscript Sent for Review. AB - Along with the rapid growth of editorial systems and publishers, the number of research articles is increasing, which creates a need for an effective dissemination strategy. Researchers commonly use editorial systems in a candid manner. However, when researchers concurrently submit the same contribution in more than one editorial system, it is considered unethical. In this paper, we propose a novel approach called DeMSum for detecting such duplicate submissions. DeMSum verifies a manuscript (MS) by processing the MS attributes that are accessed through the editorial system. To the best of our knowledge, DeMSum is the first system to address the double submission issue, thus enabling the use of diverse editorial systems for MS review. We implemented a prototype, and our evaluation of the prototype produced excellent results. PMID- 28808880 TI - Increased miR-338-3p expression correlates with invasiveness of GH-producing pituitary adenomas. PMID- 28808882 TI - 1H, 13C and 15N chemical shift assignments of Saccharomyces cerevisiae type 1 thioredoxin in the oxidized state by solution NMR spectroscopy. AB - Thioredoxins (Trx) are ubiquitous proteins that regulate several biochemical processes inside the cell. Trx is an important player, displaying oxidoreductase activity and helping to keep and regulate the oxidative state of the cellular environment. Trx also participates in the regulation of many cellular functions, such as DNA synthesis, protection against oxidative stress, cell cycle and signal transduction. The oxidized Trx is the target for another set of proteins, such as thioredoxin reductase (TrR), which used the reductive potential of NADPH. The oxidized state of Trx also plays important role in regulation of redox state in the cells. In this regard, the oxidized form of Trx is a putative conformer that contributes to the cellular redox environment. Here we report the chemical shift assignments (1H, 13C and 15N) in solution at 15 degrees C. We also showed the secondary structure analysis of the oxidized form of yeast thioredoxin (yTrx1) as basis for future NMR studies of protein-target interactions and dynamics. The assignment was done at low concentration (200 uM) because it is important to keep intact the water cavity. PMID- 28808883 TI - Removal of Water-Soluble Extractives Improves the Enzymatic Digestibility of Steam-Pretreated Softwood Barks. AB - Softwood bark contains a large amounts of extractives-i.e., soluble lipophilic (such as resin acids) and hydrophilic components (phenolic compounds, stilbenes). The effects of the partial removal of water-soluble extractives before acid catalyzed steam pretreatment on enzymatic digestibility were assessed for two softwood barks-Norway spruce and Scots pine. A simple hot water extraction step removed more than half of the water-soluble extractives from the barks, which improved the enzymatic digestibility of both steam-pretreated materials. This effect was more pronounced for the spruce than the pine bark, as evidenced by the 30 and 11% glucose yield improvement, respectively, in the enzymatic digestibility. Furthermore, analysis of the chemical composition showed that the acid-insoluble lignin content of the pretreated materials decreased when water soluble extractives were removed prior to steam pretreatment. This can be explained by a decreased formation of water-insoluble "pseudo-lignin" from water soluble bark phenolics during the acid-catalyzed pretreatment, which otherwise results in distorted lignin analysis and may also contribute to the impaired enzymatic digestibility of the barks. Thus, this study advocates the removal of extractives as the first step in the processing of bark or bark-rich materials in a sugar platform biorefinery. PMID- 28808884 TI - Outcomes of Laparoscopic Hiatal Hernia Repair in Nine Bariatric Patients with Prior Sleeve Gastrectomy. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) may exacerbate gastroesophageal reflux disease (GERD) in patients with a hiatal hernia (HH). Surgical repair may be needed, however prior LSG precludes standard HH repair with fundoplication. METHODS: We retrospectively reviewed our experience with bariatric patients with prior LSG undergoing laparoscopic HH repair from August 2010 to July 2016. Patient demographics and outcomes including mortality, length of stay (LOS), readmission rates, reoperation, and complications were described. A validated 13 point questionnaire was used to determine symptomatic relief, weight loss, and overall satisfaction. RESULTS: A total of nine consecutive patients with prior LSG underwent HH repair and were included in the analysis. Repair was performed using Bio-A Gore(r) mesh (W.L Gore Inc., Newark, DE) in six (66.7%) cases and posterior cruroplasty in three (33.3%) patients. Heartburn was significantly decreased at 1 year (1.4 +/- 0.9 vs. 2.6 +/- 0.9, p = 0.031), and 78% of patients reported some degree of symptomatic relief after HH repair. CONCLUSIONS: Laparoscopic HH repair offers a safe and feasible approach in the management of persistent GERD after LSG in well-selected bariatric patients. Larger prospective studies are warranted to investigate the effectiveness of HH repair in this population as 22% of our patients did not demonstrate postoperative symptomatic improvement. PMID- 28808885 TI - The association of epicardial fat volume with coronary characteristics and clinical outcome. AB - Recent studies have demonstrated the relationship between epicardial fat volume (EFV) and coronary atherosclerosis, but their association is modest at best. Our purpose is to elucidate the association of epicardial fat with coronary characteristics and clinical outcome. We performed coronary computed tomographic angiography in 651 patients and divided them into three groups according to tertiles of EFV; low-tertile (n = 215), 36-123 ml; middle-tertile (n = 218), 124 165 ml; high-tertile (n = 218), 166-489 ml. The prevalence of coronary calcium score (CCS) >0 (71.6, 73.4, and 83.9% in low-, middle-, and high-tertile group, respectively) and CCS >100 (39.1, 39.9, and 59.2% in each group) was significantly higher in patients with high-tertile EFV compared to the other two groups (p = 0.0047 and p < 0.0001, respectively). The prevalence of CCS >400 was 17.2, 25.7, and 33.1% in each group, which increased stepwise as EFV increased. The significant stenosis (36.2 vs. 27.0%, p = 0.0383), total coronary occlusion (5.5 vs. 0.9%, p = 0.0156), and high-risk plaque (11.0 vs. 5.6%, p = 0.0368) were more prevalent in patients with high-tertile EFV compared to those with low tertile EFV. The combined rate of cardiac death and myocardial infarction was 0.9, 2.3, and 6.4% in each patient group, respectively, which was significantly higher in patients with high-tertile EFV compared to those with low-tertile EFV (p = 0.0004). The prevalence of coronary artery calcium, significant stenosis, and high-risk plaque increased sharply in patients with high EFV, which was associated with higher rate of cardiac death and myocardial infarction. Thus, high EFV was associated with advanced coronary atherosclerosis and poor prognosis. PMID- 28808886 TI - Assessment of Pharmacokinetic Interactions Between Obeticholic Acid and Caffeine, Midazolam, Warfarin, Dextromethorphan, Omeprazole, Rosuvastatin, and Digoxin in Phase 1 Studies in Healthy Subjects. AB - INTRODUCTION: Obeticholic acid (OCA), a potent and selective farnesoid X receptor agonist, is indicated for the treatment of primary biliary cholangitis (PBC). We investigated the potential drug-drug interaction effect of OCA on metabolic CYP450 enzymes and drug transporters. METHODS: Five phase 1 single-center, open label, fixed-sequence, inpatient studies were conducted in healthy adult subjects to evaluate the effect of oral daily doses of 10 or 25 mg OCA on single-dose plasma pharmacokinetics of specific probe substrates for enzymes CYP1A2 (caffeine, R-warfarin), CYP3A (midazolam, R-warfarin), CYP2C9 (S-warfarin), CYP2D6 (dextromethorphan), CYP2C19 (omeprazole), and drug transporters, BCRP/OATP1B1/OATP1B3 (rosuvastatin), and P-gp (digoxin). RESULTS: OCA showed no substantial suppression/inhibition of S-warfarin, digoxin, and dextromethorphan and weak interactions with caffeine, omeprazole, rosuvastatin, and midazolam. The maximal pharmacodynamic responses (E max) to warfarin-based INR, PT, and aPTT were reduced by 11%, 11%, and 1%, respectively, for the 10-mg dose group and by 7%, 7% and 0%, respectively, for the 25-mg dose group. Overall, drugs dosed in combination with OCA were well tolerated, and most adverse events were mild in severity. No clinically important trends were noted in laboratory evaluations, vital signs, or 12-lead ECGs. CONCLUSION: In these studies, OCA showed weak to no suppression/inhibition of metabolic enzymes and drug transporters at the highest recommended therapeutic dose in patients with PBC. On the basis on these analyses, monitoring and maintenance of target INR range are required during coadministration of OCA with drugs that are metabolized by CYP1A2 (R-warfarin). FUNDING: Intercept Pharmaceuticals, Inc. PMID- 28808888 TI - Has time come for the use of direct oral anticoagulants in the extended prophylaxis of venous thromboembolism in acutely ill medical patients? Yes. AB - Betrixaban is a direct factor Xa inhibitor with a renal excretion of only approximately 5-7%. On June 23rd 2017, it became the first direct oral anticoagulant to receive Food and Drug Administration approval for the prevention of venous thromboembolism in acutely ill medical patients, and the first anticoagulant agent to be approved for extended-duration thromboprophylaxis after hospital discharge in this setting. Approval followed the results of the APEX trial, a phase III clinical trial comparing betrixaban (80 mg) administered for 35-42 days with enoxaparin (40 mg) administered for 10 +/- 4 days. This study for the first time applied a risk assessment model, integrating clinical factors and a laboratory marker to identify high risk patients. To improve safety, a dose reduction was used for patients with creatinine clearance between 15 and 30 mL/min (betrixaban 40 mg and enoxaparin 20 mg) and for patients receiving concomitant treatment with potent P-glycoprotein inhibitors (betrixaban 40 mg). The primary prespecified analysis tested the hypothesis that the benefit of extended thromboprophylaxis with betrixaban was greatest in patients with elevated D-dimer, but the 21% relative risk reduction failed to meet the prespecified threshold for statistical significance. However, the analysis of the overall study population showed a favorable net clinical benefit with betrixaban, with a statistically significant reduction in all efficacy outcomes and no increase in major bleeding rates. An ongoing trial, MARINER, is also assessing a combined approach for risk stratification comparing extended-duration rivaroxaban with standard duration low molecular weight heparin. PMID- 28808887 TI - Chronic Silymarin, Quercetin and Naringenin Treatments Increase Monoamines Synthesis and Hippocampal Sirt1 Levels Improving Cognition in Aged Rats. AB - Polyphenols have beneficial neurological effects delaying cognitive and motor decline in aging due to their antioxidant, antiinflammatory and neuroprotective properties. These effects could be related to SIRT1 activation (implicated in synaptic plasticity, memory and inflammation) and monoaminergic synthesis modulation. In this work, we studied in old male rats, the in vivo effects of long-term administration of different polyphenols (silymarin, quercetin and naringenin; 20 mg/kg/day i.p, 4 weeks) (Sprague-Dawley, 18 months) on cognition and motor coordination. We also analyzed in different brain regions: tryptophan hydroxylase (TPH) and tyrosine hydroxylase (TH) activities, which mediate central monoaminergic neurotransmitters synthesis; and immunoreactivities of SIRT1 and NF kappaB (total and acetylated forms). Results indicated that chronic polyphenolic treatments showed restorative effects on cognition and motor coordination consistently with the biochemical and molecular results. Polyphenols reversed the age-induced deficits in monoaminergic neurotransmitters (serotonin, noradrenaline, and dopamine), increasing TPH and TH activity. In addition, polyphenolic treatments increased SIRT1 levels and decreased NF-kappaB levels in hippocampus. These results confirm polyphenolic treatments as a valuable potential therapeutic strategy for attenuating inflamm-aging and brain function decline. PMID- 28808889 TI - Interactions between myocardial sympathetic denervation and left ventricular mechanical dyssynchrony: A CZT analysis. AB - BACKGROUND: A correlation between left ventricular (LV) dyssynchrony (LVD) and impaired myocardial sympathetic tone has been hypothesized. We sought to assess the interactions between regional LV sympathetic innervation, perfusion, and mechanical dyssynchrony. METHODS: Eighty-three patients underwent evaluation of LV perfusion and sympathetic innervation on 99mTc-tetrofosmin/123I metaiodobenzylguanidine (123I-MIBG) imaging. The summed rest score and summed 123I-MIBG score (SS-MIBG) were computed. The extent of "innervation/perfusion" mismatch was defined as the number of denervated LV segments with relatively preserved perfusion. LVD was evaluated on phase analysis and the wall with latest mechanical activation identified. RESULTS: LVD was revealed in 36 (43%) patients. Patients with LVD had more abnormal values of SRS (21 +/- 9 vs 10 +/- 8, P < 0.001) and SS-MIBG (29 +/- 9 vs 17 +/- 11, P < 0.001) than those without LVD. The presence of LVD also clustered with a higher burden of "innervation/perfusion" mismatch (P = 0.019). On per-wall analysis, LV walls with delayed mechanical activation showed a higher burden of "innervation/perfusion" mismatch (2.3 +/- 1.4 segments) than normally contracting walls (1.3 +/- 1.2 segments; P < 0.001). On multivariate analysis, the extent of "innervation/perfusion" mismatch was the only predictor of delayed mechanical activation (P = 0.029). CONCLUSIONS: Patients with LVD show an elevated burden of "innervation/perfusion" mismatch that is concentrated at the level of the most dyssynchronous walls. PMID- 28808891 TI - NMR backbone resonance assignment of New Delhi metallo-beta-lactamase. AB - The emerging of the New Delhi metallo-beta-lactamase (NDM-1) has become one of the greatest threats to the clinical treatment. Although the structure of NDM-1 has been determined by X-ray crystallography, the molecular mechanism and process of catalysis reaction remain elusive. NMR spectroscopy plays a unique role in the characterization of conformational dynamics. Here we report the backbone 1H, 15N and 13C chemical shift assignments of NDM-1 by heteronuclear multidimensional NMR spectroscopy as well as its secondary structure in solution as predicted by TALOS+. PMID- 28808890 TI - Vitamin D Activity and Metabolism in Bone. AB - PURPOSE OF REVIEW: In addition to the actions of the endocrine hormone, 1alpha,25 dihydroxyvitamin D (1,25(OH)2D) in stimulating intestinal calcium absorption, the regulation of bone mineral metabolism by 1,25(OH)2D is also considered an important contributor to calcium homeostasis. However, recent evidence suggest that 1,25(OH)2D acting either via endocrine or autocrine pathways plays varied roles in bone, which suggests that vitamin D contributes to the maintenance of bone mineral in addition to its catabolic roles. This review highlights the contrasting evidence for the direct action for vitamin D metabolism and activity in bone. RECENT FINDINGS: Numerous cells within bone express vitamin D receptor (VDR), synthesise and catabolise 1,25(OH)2D via 25-hydroxyvitamin D 1alpha hydroxylase (CYP27B1), and 25-hydroxyvitamin D 24-hydroxylase (CYP24A1) enzymes, respectively. Recent evidence suggests that all three genes are required to regulate processes of bone resorption, mineralization and fracture repair. The actions of vitamin D in bone appear to negatively or positively regulate bone mineral depending on the physiological and pathological circumstances, suggesting that vitamin D plays pleiotropic roles in bone. PMID- 28808892 TI - Incidence Rates and Predictors of Colectomy for Ulcerative Colitis in the Era of Biologics: Results from a Provincial Database. AB - BACKGROUND: We evaluated long-term incidence and identified risk factors of colectomy in pre-biologics and biologics eras for treatment of ulcerative colitis. METHODS: After IRB approval, using data obtained from the Regie d'assurance maladie du Quebec, we defined two cohorts: pre-biologics (1998-2004) and biologics (2005-2011) eras. Patients with inflammatory bowel disease or colectomy 1 year prior to first diagnosis of ulcerative colitis were excluded. Multivariate logistic regression model compared patient baseline characteristics. Kaplan-Meier curves displayed unadjusted time to event. Cox proportional hazards models were used to compare adjusted colectomy and mortality rates, respectively. RESULTS: In pre-biologics and biologics eras, 335/2829 and 314/3313 patients, respectively, underwent colectomy. Median follow-up (first and third quartiles) was similar (p = 0.206). Incidence rates for colectomy were 36.08/1000 and 29.99/1000 patient years. Unadjusted rate of colectomy was higher in pre biologics era (p = 0.004). Predictors of colectomy included anemia (1.66; 1.38 2.01), gastrointestinal hospitalizations (1.24; 1.04-1.47), congestive heart failure (2.08; 1.27-3.40), and male gender (1.47; 1.26-1.72). Mortality was 8.06 and 3.18% in pre-biologics and biologics eras. After adjusting for potential confounders, age (1.08; 1.05-1.12) and urgent colectomy (5.65; 2.19-14.54) remained associated with increased mortality hazard. CONCLUSION: Incidence of colectomy decreased after introduction of biologics. Risk factors for colectomy were gastrointestinal hospitalizations, anemia, male gender, and congestive heart failure. Emergent surgery and age were predictors of mortality. PMID- 28808894 TI - Breast Density Awareness and Knowledge, and Intentions for Breast Cancer Screening in a Diverse Sample of Women Age Eligible for Mammography. AB - The objectives of this study were to assess breast density knowledge and breast density awareness, and to identify information associated with intention to complete routine and supplemental screening for breast cancer in a diverse sample of women age eligible for mammography. We quantitatively (self-report) assessed breast density awareness and knowledge (N = 264) in black (47.7%), Latina (35.2%), and white (17%) women recruited online and in the community. Most participants reported having heard about breast density (69.2%); less than one third knew their own breast density status (30.4%). Knowing their own breast density, believing that women should be notified of their breast density in their mammogram report, and feeling informed if being provided this information are associated with likelihood of completing mammogram. Intending mammogram completion and knowledge regarding the impact of breast density on mammogram accuracy are associated with likelihood of completing supplemental ultrasound tests of the breast. These findings help inform practitioners and policy makers about information and communication factors that influence breast cancer screening concerns and decisions. Knowing this information should prepare practitioners to better identify women who may have not been exposed to breast density messages. PMID- 28808893 TI - Epigenetics and Bone Remodeling. AB - PURPOSE OF REVIEW: Bone remodeling is a diverse field of study with many direct clinical applications; past studies have implicated epigenetic alterations as key factors of both normal bone tissue development and function and diseases of pathologic bone remodeling. The purpose of this article is to review the most important recent advances that link epigenetic changes to the bone remodeling field. RECENT FINDINGS: Epigenetics describes three major phenomena: DNA modification via methylation, histone side chain modifications, and short non coding RNA sequences which work in concert to regulate gene transcription in a heritable fashion. Recent findings include the role of DNA methylation changes of Wnt, RANK/RANKL, and other key signaling pathways, epigenetic regulation of osteoblast and osteoclast differentiation, and others. Although much work has been done, much is still unknown. Future epigenome-wide studies should focus on extending the tissue coverage, integrating multiple epigenetic analyses with transcriptome data, and working to uncover epigenetic changes linked with early events in aberrant bone remodeling. PMID- 28808895 TI - Comparison of Offender and Non-offender Young Men to Setting Goals for Life and Attributing Meaning to Life. AB - The main goal of the present study is to compare male offenders and non-offenders in terms of how they attribute meaning to life and set life goals. The samples were chosen from among offenders (n = 50) and non-offenders (n = 50) who were between ages 19-26. Mixed method was used in this study. The scale of setting life goals and interview form were used to collect data. To analysis of the data, the content analysis technique and t test and were used. Findings of the present study show that offenders tend to have troubles setting life goals when compared to non-offenders. Furthermore, the results of this study could be used in rehabilitating offenders and preventing those at risk of committing criminal acts from doing so. PMID- 28808896 TI - Regadenoson use for stress myocardial perfusion imaging in advance chronic kidney disease and dialysis: Safe, effective, and efficient. PMID- 28808898 TI - Wilhelm His and mechanistic approaches to development at the time of Entwicklungsmechanik. AB - At the end of the nineteenth century, approaches from experimental physiology made inroads into embryological research. A new generation of embryologists felt urged to study the mechanisms of organ formation. This new program, most prominently defended by Wilhelm Roux (1850-1924), was called Entwicklungsmechanik. Named variously as "causal embryology", "physiological embryology" or "developmental mechanics", it catalyzed the movement of embryology from a descriptive science to one exploring causal mechanisms. This article examines the specific scientific and epistemological meaning of the mechanistic approaches of embryological development by focusing on Wilhelm His' (1831-1904) histogenetic work. Roux was neither the first, nor the only one to argue for an experimental exploration of causes in embryology. At the time of Roux, physiological explanations of the genesis of the anatomical forms were developing in parallel, not only in German-speaking countries, but in France, Switzerland and English-speaking countries as well. The experimental approach and the cellular descriptions of embryogenesis were already omni-present when Roux proposed his Entwicklungsmechanik. However, these approaches remained disjointed. It appears that it was Wilhelm His who first succeeded in combining the question of the causal factors determining epigenesis, which was closely connected with experimentation on, and cellular descriptions of, development, in a coherent and concrete synthesis, making him one of the true initiators of the developmental mechanics. PMID- 28808897 TI - Should Posttraumatic Stress Be a Disorder or a Specifier? Towards Improved Nosology Within the DSM Categorical Classification System. AB - PURPOSE OF REVIEW: Since 1980, posttraumatic stress (PTS) disorder has been controversial because of its origin as a social construct, its discriminating trauma definition, and the Procrustean array of symptoms/clusters chosen for inclusion/exclusion. This review summarizes the history of trauma-related nosology and proposed changes, within current categorical models (trauma definitions, symptoms/clusters, subtypes/specifiers, disorders) and new models. RECENT FINDINGS: Considering that trauma is a risk factor for virtually all mental disorders (particularly depressive, anxiety, dissociative, personality), the multi-finality of trauma (some survivors are resilient, and some develop PTS and/or non-PTS symptoms), and the various symptoms that trauma survivors express (mood, cognitive, perceptual, somatic), it is difficult to classify PTS. Because the human mind best comprehends categories, reliable classification generally necessitates using a categorical nosology but PTS defies categories (internalizing and/or externalizing, fear-based and/or numbing symptoms), the authors conclude that PTS-like DSM-5's panic attacks specifier-is currently best conceptualized as a specifier for other mental disorders. PMID- 28808899 TI - Sudden cardiac death from aortoesophageal fistula: an autopsy case report of a rare complication of thoracic aortic aneurysm. PMID- 28808900 TI - Varying ultrasound power level to distinguish surgical instruments and tissue. AB - We investigate a new framework of surgical instrument detection based on power varying ultrasound images with simple and efficient pixel-wise intensity processing. Without using complicated feature extraction methods, we identified the instrument with an estimated optimal power level and by comparing pixel values of varying transducer power level images. The proposed framework exploits the physics of ultrasound imaging system by varying the transducer power level to effectively distinguish metallic surgical instruments from tissue. This power varying image-guidance is motivated from our observations that ultrasound imaging at different power levels exhibit different contrast enhancement capabilities between tissue and instruments in ultrasound-guided robotic beating-heart surgery. Using lower transducer power levels (ranging from 40 to 75% of the rated lowest ultrasound power levels of the two tested ultrasound scanners) can effectively suppress the strong imaging artifacts from metallic instruments and thus, can be utilized together with the images from normal transducer power levels to enhance the separability between instrument and tissue, improving intraoperative instrument tracking accuracy from the acquired noisy ultrasound volumetric images. We performed experiments in phantoms and ex vivo hearts in water tank environments. The proposed multi-level power-varying ultrasound imaging approach can identify robotic instruments of high acoustic impedance from low-signal-to-noise-ratio ultrasound images by power adjustments. PMID- 28808901 TI - The Utility of Routine Intensive Care Admission for Patients Undergoing Intracranial Neurosurgical Procedures: A Systematic Review. AB - BACKGROUND: Patients who have undergone intracranial neurosurgical procedures have traditionally been admitted to an intensive care unit (ICU) for close postoperative neurological observation. The purpose of this study was to systematically review the evidence for routine ICU admission in patients undergoing intracranial neurosurgical procedures and to evaluate the safety of alternative postoperative pathways. METHODS: We were interested in identifying studies that examined selected patients who presented for elective, non-emergent intracranial surgery whose postoperative outcomes were compared as a function of ICU versus non-ICU admission. A systematic review was performed in July 2016 using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist of the Medline database. The search strategy was created based on the following key words: "craniotomy," "neurosurgical procedure," and "intensive care unit." RESULTS: The nine articles that satisfied the inclusion criteria yielded a total of 2227 patients. Of these patients, 879 were observed in a non-ICU setting. The most frequent diagnoses were supratentorial brain tumors, followed by patients with cerebrovascular diseases and infratentorial brain tumors. Three percent (30/879) of the patients originally assigned to floor or intermediate care status were transferred to the ICU. The most frequently observed neurological complications leading to ICU transfer were delayed postoperative neurological recovery, seizures, worsening of neurological deficits, hemiparesis, and cranial nerves deficits. CONCLUSION: Our systematic review demonstrates that routine postoperative ICU admission may not benefit carefully selected patients who have undergone elective intracranial neurosurgical procedures. In addition, limiting routine ICU admission may result in significant cost savings. PMID- 28808902 TI - Genetic diversity, population structure, and correlations between locally adapted zebu and taurine breeds in Brazil using SNP markers. AB - Genetic diversity is one of the most important issues in studies on conservation of cattle breeds and endangered species. The objective of this study was to estimate the levels of genetic differentiation between locally adapted taurine (Bos taurus taurus) and zebu (Bos taurus indicus) breeds in Brazil, which were genotyped for more than 777,000 SNPs. The fixation index (F ST), principal component analysis (PCA), and Bayesian clustering were estimated. The F ST highlighted genetic differentiation between taurine and zebu breeds. The taurine lines, Caracu and Caracu Caldeano, had significant genetic differentiation (F ST close to 5%) despite their recent selection for different uses (meat and milk). This genetic variability can be used for conservation of locally adapted animals, as well as for breeding programs on zebu breeds. Introgression of zebu in locally adapted breeds was identified, especially in Curraleiro Pe-Duro breed. The Gyr breed, however, had low breed purity at genomic level due to its very heterogeneous mixing pattern. PMID- 28808903 TI - Clinical outcomes of aortic repair in young adult patients with ACTA2 mutations. AB - OBJECTIVES: Actin, alpha-2, smooth muscle, aorta (ACTA2) mutations are one of the major causes of familial thoracic aortic aneurysms and dissections. The aim of this study was to review our clinical results of young adult patients with aortic disease caused by ACTA2 mutations. METHODS: We reviewed the medical records of 251 patients (<50 years old) who underwent surgery for thoracic aortic diseases between 2004 and 2014. Among them, nine patients (3.5%) had ACTA2 mutations. Their average age was 35 years (range 22-47) and two patients (22.2%) were males. No patients fulfilled the diagnostic criteria for Marfan syndrome. Preoperative diagnoses included annulo-aortic ectasia (n = 2), localized dissection of the sinus of Valsalva (n = 2), acute type B aortic dissection (n = 1), and chronic type B (n = 4). Eight patients (88.9%) had hypertension. RESULTS: A thoracoabdominal aortic replacement was required in three patients who had descending replacement for residual chronic type B aortic dissection. A patient who had thoracic endovascular aortic repair for complicated acute type B aortic dissection showed no aortic dilatation for 7 years after TEVAR. Histological results revealed cystic medial necrosis (CMN) in most cases (7/8; 87.5%). CONCLUSION: Surgical outcomes for patients with ACTA2 mutations were satisfactory. CMN was a major histological finding and family history of aortic event was detected in only half of the patients with ACTA2 mutations. Despite no characteristic physical findings besides hypertension, connective tissue disease including ACTA2 mutations should be considered for aortic dissection in young adult patients. PMID- 28808904 TI - Measurement of dose in radionuclide therapy by using Cerenkov radiation. AB - This work aims to determine the relationship between Cerenkov photon emission and radiation dose from internal radionuclide irradiation. Water and thyroid phantoms were used to simulate the distribution of Cerenkov photon emission and dose deposition through Monte Carlo method. The relationship between Cerenkov photon emission and dose deposition was quantitatively analyzed. A neck phantom was also used to verify Cerenkov photon detection for thyroid radionuclide therapy. Results show that Cerenkov photon emission and dose deposition exhibit the same distribution pattern in water phantom, and this relative distribution relationship also existed in the thyroid phantom. Moreover, Cerenkov photon emission exhibits a specific quantitative relation to dose deposition. For thyroid radionuclide therapy, only a part of Cerenkov photon produced by thyroid could penetrate the body for detection; therefore, the use of Cerenkov radiation for measurement of radionuclide therapy dose may be more suitable for superficial tumors. This study demonstrated that Cerenkov radiation has the potential to be used for measuring radiation dose for radionuclide therapy. PMID- 28808906 TI - Racial Disparities in HPV-related Knowledge, Attitudes, and Beliefs Among African American and White Women in the USA. AB - The objective of this study was to assess the differences in HPV-related knowledge, attitudes, and beliefs among African American and non-Hispanic white women and to determine their communication preferences for cancer-related information. Data was obtained from the National Cancer Institute's (NCI) 2014 Health Interview National Trends Survey (HINTS), a cross-sectional survey of US adults 18 years of age or older. Descriptive statistics, bivariate, and multivariate logistic regression were used to identify differences in awareness and knowledge. Data was collected in 2014 and analyzed in 2016. HPV awareness (71 vs. 77%) and knowledge that HPV causes cervical cancer (64 vs. 81%) were significantly lower among blacks. Additionally, there were significant disparities in awareness of the HPV vaccine (66 vs. 79%), with only 25% of Black women indicating that they or a family member was recommended the HPV vaccine by a health care professional. There were also differences in cancer communication preferences. Blacks were more likely than Whites to trust cancer information from family (OR 2.7, confidence interval [CI] 0.725-10.048), television (OR 3.0, 95% [CI] 0.733-12.296), government health agencies (OR 5.8, [CI] 0.639-52.818), and religious organizations (OR 6.4, 95% [CI] 1.718-23.932). Study results indicate that racial/ethnic differences exist in HPV knowledge/awareness and cancer communication preferences. These results highlight the need to increase HPV prevention and education efforts using methods that are tailored to Black women. To address HPV/cervical cancer disparities, future interventions should utilize preferred communication outlets to effectively increase HPV knowledge and vaccine awareness. PMID- 28808905 TI - A Pharmacokinetic Bioequivalence Study Comparing Pirfenidone Tablet and Capsule Dosage Forms in Healthy Adult Volunteers. AB - INTRODUCTION: Pirfenidone film-coated tablets were developed to offer an alternative to the marketed capsule formulation. This study assessed the bioequivalence of the tablet and capsule formulations under fed and fasted states. METHODS: A Phase I, open-label, randomized, four-treatment-period, four sequence, crossover pharmacokinetics study (NCT02525484) was conducted. Each subject received an 801-mg single dose of pirfenidone as three 267-mg capsules or one 801-mg tablet under fasted and fed conditions. Pirfenidone plasma C max, AUC0 t and AUC0-infinity were used to assess bioequivalence. RESULTS: Forty-four subjects were randomized to treatment. The 801-mg tablet in the fasted state met bioequivalence criteria [90% confidence intervals (CI) 80.00-125.00%] for the GLSM ratios of natural log-transformed C max, AUC0-t and AUC0-infinity. Under fed conditions, the 801-mg tablet met the bioequivalence criteria for AUC0-t and AUC0 infinity, but slightly exceeded the bioequivalence criteria for the C max (90% CI of 108.26-125.60%). The tablet C max was approximately 17% higher than that of the capsules. In the fed state, the tablet C max, and both AUC0-t and AUC0 infinity were reduced by 39% and 17%, respectively, relative to the fasted state. The tablet and capsules had acceptable tolerability profiles. CONCLUSIONS: The pirfenidone 801-mg tablet met bioequivalence criteria when compared with three 267-mg capsules in the fasted state. The tablet C max was slightly higher relative to capsules in the fed state, but this is not expected to have a clinically meaningful impact on the benefit-risk profile of pirfenidone. FUNDING: This work was supported by F. Hoffmann-La Roche Ltd. PMID- 28808907 TI - Socio-demographic characteristics and factors associated with hospitalization in psychiatry of old age patients: an international comparison between Ireland and Turkey. AB - BACKGROUND: Taking predictors of hospitalization characteristics into consideration internationally would broaden our understanding of this population on a local basis. AIMS: We aimed to examine and compare socio-demographic profiles along with hospitalization characteristics including length of hospital stay (LOS), reasons for admission and diagnoses among older adult inpatients hospitalized in Ireland and Turkey, and to assess factors predicting these features. METHODS: The admission charts of 356 psychiatric inpatients over 65 years of age who were admitted to two different acute psychiatric hospitals (Sligo/Ireland and Istanbul/Turkey) were analysed by means of descriptive modalities and logistic regression. RESULTS: There were significant differences in several domains of socio-demographics, reasons of admission and diagnoses. LOS was significantly longer in Ireland. Living alone was the only significant predictor for longer LOS in both countries, whereas in addition to living alone, younger age was also a contributor for longer LOS in Turkey. DISCUSSION: Given that the only factor predicting LOS both in Turkey and Ireland was living alone, helping to identify more acceptable ways of providing social support for living arrangements constitutes an important service to shorten LOS in old age psychiatric population. CONCLUSIONS: It is possible to infer that independent from the cultural diversities, living arrangement is a consistent entity to influence length of hospital stay in older adult population. PMID- 28808908 TI - A New Smart Surface-Enhanced Raman Scattering Sensor Based on pH-Responsive Polyacryloyl Hydrazine Capped Ag Nanoparticles. AB - A novel pH-responsive Ag@polyacryloyl hydrazide (Ag@PAH) nanoparticle for the first time as a surface-enhanced Raman scattering (SERS) substrate was prepared without reducing agent and end-capping reagent. Ag@PAH nanoparticles exhibited an excellent tunable detecting performance in the range from pH = 4 to pH = 9. This is explained that the swelling-shrinking behavior of responsive PAH can control the distance between Ag NPs and the target molecules under external pH stimuli, resulting in the tunable LSPR and further controlled SERS. Furthermore, Ag@PAH nanoparticles possessed an ultra-sensitive detecting ability and the detection limit of Rhodamine 6G reduced to 10-12 M. These advantages qualified Ag@PAH NP as a promising smart SERS substrate in the field of trace analysis and sensors. PMID- 28808910 TI - NMR resonance assignments of a hypoallergenic isoform of the major birch pollen allergen Bet v 1. AB - In Northern America and Europe a great number of people are suffering from birch pollen allergy and pollen related food allergies. The trigger for these immunological reactions is the 17.5 kDa major birch pollen allergen Bet v 1, which belongs to the family of PR-10 (pathogenesis-related) proteins. In nature, Bet v 1 occurs as a mixture of various isoforms that possess different immunological properties despite their high sequence identities. Bet v 1.0102 (Bet v 1d), which is investigated here, is a hypoallergenic isoform of Bet v 1 and a potential candidate for allergen-specific immunotherapy. We assigned the backbone and side chain 1H, 13C and 15N resonances of this protein and predicted its secondary structure. The NMR-chemical shift data indicate that Bet v 1.0102 is composed of three alpha-helices and a seven stranded beta-sheet, in agreement with the known structure of the hyperallergenic isoform Bet v 1.0101 (Bet v 1a). Our resonance assignments create the foundation for detailed characterization of the dynamic properties of Bet v 1 isoforms by NMR relaxation measurements. PMID- 28808911 TI - Methicillin-Resistant Staphylococcus aureus Acute Keratitis After Intracorneal Ring Segment Implantation. AB - INTRODUCTION: The purpose of this study was to report the first case of acute bacterial keratitis produced by methicillin-resistant Staphylococcus aureus after the implantation of two intracorneal ring segments during an uneventful procedure for treating keratoconus in a 13-year-old child. CASE REPORT: A patient with grade III keratoconus underwent an implantation of intracorneal ring segments with no complications during the procedure. Three days later, a whitish corneal infiltrate appeared in between the union of both corneal rings. Sample cultures were positive for methicillin-resistant S. aureus (MRSA). Corneal infiltrate did not improve despite intensive topical and systemic antibiotics. Melting appeared even after the explantation of both corneal rings. Keratoplasty a chaud had to be performed to preserve the eye integrity. CONCLUSIONS: MRSA keratitis following intracorneal ring segment implantation is a rare but severe complication that can lead to a therapeutic penetrating keratoplasty to definitely cure the process. PMID- 28808909 TI - Oxytocin and Anxiety Disorders: Translational and Therapeutic Aspects. AB - PURPOSE OF REVIEW: This review aims to evaluate the most recent literature examining the oxytocin (OXT) system's role in human anxiety by surveying various fields of preclinical and clinical research supporting this role, and queries whether the OXT system might be a target for novel anxiolytics. RECENT FINDINGS: Evidence from the diverse body of literature presented here, from translational research, genetic and neuroimaging studies, to clinical trials of intranasal (IN) OXT reveals a positive association. In addition, some moderators (e.g., sex, specificities to cues) of OXT's anxiolytic effects can have an important influence on its outcomes, awaiting further research. Evidence for the role of OXT in regulating anxiety is undeniable. We expect that the diverse particularities of the OXT system will help broaden our understanding of anxiety and stress-related disorders. We conclude that OXT promises an enticing treatment option for human anxiety disorders especially those associated with socio emotional dysfunctions. PMID- 28808913 TI - Modified double-barrelled wet colostomy after total pelvic exenteration. AB - Pelvic exenteration is a radical surgery that can require urinary and faecal diversions. Double-barreled wet colostomy, a viable alternative to the traditional ileal conduit with separate colostomy technique, is not always applicable due to the shortness of an ureter. To overcome this problem, I modified the original technique, replacing the two uretero-colic anastomoses with an ureteroureterostomy and an uretero-colic anastomosis. PMID- 28808912 TI - Molecular Imaging and Updated Diagnostic Criteria in Lewy Body Dementias. AB - PURPOSE OF REVIEW: The aims of the study were to review recent advances in molecular imaging in the Lewy body dementias (LBD) and determine if these may support the clinical but contested temporal profile distinction between Parkinson disease (PD) with dementia (PDD) versus dementia with Lewy bodies (DLB). RECENT FINDINGS: There do not appear to be major regional cerebral metabolic or neurotransmitter distinctions between PDD and DLB. However, recent studies highlight the relative discriminating roles of Alzheimer proteinopathies. PDD patients have lower cortical beta-amyloid deposition than DLB. Preliminary tau PET studies suggest a gradient of increasing tau binding from cognitively normal PD (absent to lowest) to cognitively impaired PD (low) to DLB (intermediate) to Alzheimer disease (AD; highest). However, tau binding in DLB, including the medial temporal lobe, is substantially lower than in AD. Alzheimer-type proteinopathies appear to be more common in DLB compared to PDD with relative but no absolute differences. Given the spectrum of overlapping pathologies, future alpha-synuclein ligands are expected to have the best potential to distinguish the LBD from pure AD. PMID- 28808914 TI - From Pleistocene to Holocene: the prehistory of southwest Asia in evolutionary context. AB - In this paper I seek to show how cultural niche construction theory offers the potential to extend the human evolutionary story beyond the Pleistocene, through the Neolithic, towards the kind of very large-scale societies in which we live today. The study of the human past has been compartmentalised, each compartment using different analytical vocabularies, so that their accounts are written in mutually incompatible languages. In recent years social, cognitive and cultural evolutionary theories, building on a growing body of archaeological evidence, have made substantial sense of the social and cultural evolution of the genus Homo. However, specialists in this field of studies have found it difficult to extend their kind of analysis into the Holocene human world. Within southwest Asia the three or four millennia of the Neolithic period at the beginning of the Holocene represents a pivotal point, which saw the transformation of human society in the emergence of the first large-scale, permanent communities, the domestication of plants and animals, and the establishment of effective farming economies. Following the Neolithic, the pace of human social, economic and cultural evolution continued to increase. By 5000 years ago, in parts of southwest Asia and northeast Africa there were very large-scale urban societies, and the first large-scale states (kingdoms). An extension of cultural niche construction theory enables us to extend the evolutionary narrative of the Pleistocene into the Holocene, opening the way to developing a single, long-term, evolutionary account of human history. PMID- 28808915 TI - Cost-Effectiveness of Posaconazole Tablets for Invasive Fungal Infections Prevention in Acute Myelogenous Leukemia or Myelodysplastic Syndrome Patients in Spain. AB - INTRODUCTION: Posaconazole is superior to fluconazole (FLU) and itraconazole (ITRA) in the prevention of invasive fungal diseases (IFDs) in neutropenic patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). A new tablet formulation of posaconazole with improved pharmacokinetic and pharmacodynamic properties compared to posaconazole oral solution has recently been approved. The objective of this study is to estimate the cost-effectiveness of the newly developed posaconazole tablets versus FLU oral suspension or ITRA oral solution for preventing IFDs in high-risk neutropenic patients with AML or MDS and from the perspective of the Spanish National Health System (NHS). METHODS: A previously validated economic model was used. The probabilities of experiencing an IFD, an IFD-related death or death from other causes over 100 days were based on clinical trial data and input into a decision tree. Surviving patients were entered into a Markov model to calculate total costs, number of IFDs and number of life-years gained per patient over a lifetime horizon in each disease and treatment group. Two health states, alive and dead, were considered. Health effects were discounted using a rate of 3%. Univariate and probabilistic sensitivity analyses were conducted. RESULTS: During the first 100 days, posaconazole tablets were associated with a lower risk of IFDs (0.046 vs. 0.111), longer life expectancy (2.92 vs. 2.69 years) and lower total costs (?5906.06 vs. ?7847.20 per patient) over the patients' lifetimes compared to FLU or ITRA treatments. Thus, posaconazole tablets were more effective and less costly than FLU or ITRA. Probabilistic sensitivity analysis indicated that there was a 79.9% probability of posaconazole tablets being cost-saving compared to FLU or ITRA. CONCLUSION: From the Spanish NHS perspective, posaconazole tablets are cost effective compared to FLU or ITRA in AML or MSD patients with chemotherapy induced neutropenia and at high risk for IFDs. FUNDING: MSD Sharp & Dohme. PMID- 28808916 TI - Uhthoff's phenomenon as the presenting symptom of multiple sclerosis (MS). PMID- 28808917 TI - Development of a Translational Physiologically Based Pharmacokinetic Model for Antibody-Drug Conjugates: a Case Study with T-DM1. AB - Systems pharmacokinetic (PK) models that can characterize and predict whole body disposition of antibody-drug conjugates (ADCs) are needed to support (i) development of reliable exposure-response relationships for ADCs and (ii) selection of ADC targets with optimal tumor and tissue expression profiles. Towards this goal, we have developed a translational physiologically based PK (PBPK) model for ADCs, using T-DM1 as a tool compound. The preclinical PBPK model was developed using rat data. Biodistribution of DM1 in rats was used to develop the small molecule PBPK model, and the PK of conjugated trastuzumab (i.e., T-DM1) in rats was characterized using platform PBPK model for antibody. Both the PBPK models were combined via degradation and deconjugation processes. The degradation of conjugated antibody was assumed to be similar to a normal antibody, and the deconjugation of DM1 from T-DM1 in rats was estimated using plasma PK data. The rat PBPK model was translated to humans to predict clinical PK of T-DM1. The translation involved the use of human antibody PBPK model to characterize the PK of conjugated trastuzumab, use of allometric scaling to predict human clearance of DM1 catabolites, and use of monkey PK data to predict deconjugation of DM1 in the clinic. PBPK model-predicted clinical PK profiles were compared with clinically observed data. The PK of total trastuzumab and T-DM1 were predicted reasonably well, and slight systemic deviations were observed for the PK of DM1 containing catabolites. The ADC PBPK model presented here can serve as a platform to develop models for other ADCs. PMID- 28808918 TI - Idarucizumab in Dabigatran-Treated Patients with Acute Ischemic Stroke Receiving Alteplase: A Systematic Review of the Available Evidence. AB - BACKGROUND AND PURPOSE: Current guidelines do not recommend the use of intravenous recombinant tissue plasminogen activator in patients with acute ischemic stroke who receive direct oral anticoagulants. While the humanized monoclonal antibody idarucizumab can quickly reverse the anticoagulant effects of the thrombin inhibitor dabigatran, safety data for subsequent tissue plasminogen activator treatment are sparse. Here, we review current knowledge about dabigatran reversal prior to systemic reperfusion treatment in acute ischemic stroke. METHODS: We performed a systematic review of all published cases of intravenous tissue plasminogen activator treatment following the administration of a dabigatran antidote up to June 2017 and added five unpublished cases of our own. We analyzed clinical and radiological outcomes, symptomatic post thrombolysis intracranial hemorrhage, and other serious systemic bleeding. Additional endpoints were allergic reaction to idarucizumab, and venous thrombosis in the post-acute phase. RESULTS: We identified a total of 21 patients (71% male) with a median age of 76 years (interquartile range 70-84). The median National Institute of Health Stroke Scale score at baseline was 10 (n = 20, interquartile range 5-11) and 18/20 patients (90%) had mild or moderate stroke severity. The time from symptom onset to start of tissue plasminogen activator was 155 min (n = 18, interquartile range 122-214). The outcome was unfavorable in 3/19 patients (16%). There was one fatality as a result of a symptomatic post thrombolysis intracranial hemorrhage, and two patients experienced an increase in the National Institute of Health Stroke Scale compared with baseline. One patient had a recurrent stroke. No systemic bleeding, venous thrombosis, or allergic reactions were reported. CONCLUSION: Experience with idarucizumab administration prior to tissue plasminogen activator treatment in acute ischemic stroke is limited. Initial clinical experience in less severe stroke syndromes and short time windows seems favorable. Larger cohorts are required to confirm safety, including bleeding complications and the risk of thrombosis. PMID- 28808919 TI - Backbone and side chain assignments of the second RNA-binding domain of Musashi-1 in its free form and in complex with 5-mer RNA. AB - Musashi1 (Msi1) is an RNA-binding protein that is involved in cell fate determination. Here, we report the 1H, 15N, and 13C resonance assignments of Msi1 second RNA-binding domain in free form and in complex with RNA. The assignments can be utilized for NMR structure and dynamics analyses of the Msi1:RNA complex, and moreover, for chemical shift perturbation analyses to evaluate the binding of potential small molecule inhibitors against Msi1:RNA interaction. PMID- 28808920 TI - Prospective Turkish Cohort Study to Investigate the Frequency of Niemann-Pick Disease Type C Mutations in Consanguineous Families with at Least One Homozygous Family Member. AB - BACKGROUND: Niemann-Pick disease Type C (NP-C) is a rare, autosomal recessive lysosomal storage disorder caused by mutations in NPC1 or NPC2 genes. Diagnosis of NP-C can be challenging and is frequently delayed. Identifying mutations in individuals with NP-C and their relatives enables genetic counseling and prenatal diagnosis and may support earlier diagnosis. Here we report findings from a prospective cohort study in Turkey, using targeted genetic screening of the families of NP-C probands with homozygous NPC1 or NPC2 mutations. METHODS: Probands were selected from a Turkish National Registration Database. Probands had confirmed diagnosis based on NPC1 or NPC2 mutations, with clear indication for consanguineous, homozygous inheritance. Family members were identified from interviews and pedigree analysis. Genetic analysis was performed on DNA from peripheral blood samples from all subjects. RESULTS: Four probands and 510 individuals from the four families were included. In these four families, the overall NPC1 or NPC2 heterozygous mutation frequency was 22.7%. A novel mutation was identified in NPC1 (p.T375P; c.1123A>C). A previously described NPC2 mutation (p.E118X; c.352G>T) was also observed in two families from different regions of Turkey. We identified two new patients with NP-C from two families. CONCLUSIONS: This is the largest screening study conducted to date in Turkey in the families of patients with NP-C with homozygous inheritance. We have reported heterozygote frequencies, identified a novel mutation, and detected new patients with NP-C. These findings will aid our understanding of NP-C and may lead to improved recognition and more timely diagnosis. PMID- 28808921 TI - Volumetric abnormalities of thalamic subnuclei in medication-overuse headache. AB - BACKGROUND: The thalamus exerts a pivotal role in pain processing and cortical excitability control and a previous voxel-based morphometry study confirmed increased volume in bilateral thalamus in medication-overuse headache (MOH). The aim of this study is to investigate altered thalamic subnuclei volume in MOH compared with normal controls, and to evaluate the relationship of each thalamic subnuclei volume with the clinical variables. METHODS: High resolution three dimensional T1-weighted fast spoiled gradient recalled echo MR images were obtained from 27 patients with MOH and 27 normal controls (NC). Thalamic subnuclei templates were created based on Talairach template with MNI space transformation, and the individual thalamic subnuclei templates were generated by applying the deformation field from structural image segment to the thalamic subnuclei templates, and then individual thalamci subnuclei volume were calculated. RESULTS: The whole thalamus and each thalamic subnuclei presented increased volume compared with NC (P < 0.05). The correlation analysis demonstrated that the whole thalamus volume and each thalamic subnuclei volume showed a negative relationship with HAMD scores(P < 0.05), and no any correlation with HAMA, VAS score and disease duration (P > 0.05). CONCLUSION: Increased gray matter volume in the whole thalamus and all the thalamus subnuclei may reflect central sensitization and higher-order of pain alteration in MOH. These structural changes in the thalamus may also be influenced by mood disturbances related to the MOH. PMID- 28808922 TI - Backbone resonance assignments for the SET domain of human methyltransferase NSD3 in complex with its cofactor. AB - NSD3 is a histone H3 methyltransferase that plays an important role in chromatin biology. A construct containing the methyltransferase domain encompassing residues Q1049-K1299 of human NSD3 was obtained and biochemical activity was demonstrated using histone as a substrate. Here we report the backbone HN, N, Calpha, C', and side chain Cbeta assignments of the construct in complex with S adenosyl-L-methionine (SAM). Based on these assignments, secondary structures of NSD3/SAM complex in solution were determined. PMID- 28808923 TI - Evidence-Based Precision Medicine is Needed to Move Toward General Internal Precision Medicine. PMID- 28808924 TI - A Critical Evaluation on MOH Current Treatments. AB - OPINION STATEMENT: Migraine is the most frequent neurological disorder observed in clinical practice characterized by moderate to severe pain attacks associated with neurological, gastrointestinal, and dysautonomic symptoms. Each year, 2.5% of patients with episodic migraine develop chronic migraine (CM). CM is characterized by high frequency of the attacks that may result into chronic intake of abortive medications. Nearly, the 70% of CM patients referring to tertiary head centers show acute pain medications overuse that may lead to the development of medication overuse headache (MOH). The management of MOH requires three steps: (1) education, (2) withdrawal of the overuse drug and detoxification, and (3) re-prophylaxis. In the last years, several real-life prospective studies provided further evidence in clinical setting of the onabotulinumtoxinA 155-195 U efficacy for the headache prophylaxis in CM with MOH patients. There is a general agreement on two factors: (1) withdrawal of the overuse drug is condicio sine qua non to reverse the pattern to medium-low frequency migraine, and (2) the focus of management needs to shift from acute treatment of pain to prevention of headache. CM patients close to developing MOH, patients with high-frequency episodic migraine, and those already abusing of drugs require special attention and should refer to tertiary headache centers. For all of them, a solution could be an "early treatment." Early should be their referral to a tertiary headache center, early should be the withdrawal of the overuse drug and a proper detoxification, and perhaps early should be the start of a preventative therapy. PMID- 28808925 TI - Recommendations of the Spanish brachytherapy group (GEB) of Spanish Society of Radiation Oncology (SEOR) and the Spanish Society of Medical Physics (SEFM) for high-dose rate (HDR) non melanoma skin cancer brachytherapy. AB - Clinical indications of brachytherapy in non-melanoma skin cancers, description of applicators and dosimetry recommendations are described based on the literature review, clinical practice and experience of Spanish Group of Brachytherapy and Spanish Society of Medical Physics reported in the XIV Annual Consensus Meeting on Non Melanoma Skin Cancer Brachytherapy held in Benidorm, Alicante (Spain) on October 21st, 2016. All the recommendations for which consensus was achieved are highlighted in blue. Regular and small surfaces may be treated with Leipzig, Valencia, flap applicators or electronic brachytherapy (EBT). For irregular surfaces, customized molds or interstitial implants should be employed. The dose is prescribed at a maximum depth of 3-4 mm of the clinical target volume/planning target volume (CTV/PTV) in all cases except in flaps or molds in which 5 mm is appropriate. Interstitial brachytherapy should be used for CTV/PTV >5 mm. Different total doses and fraction sizes are used with very similar clinical and toxicity results. Hypofractionation is very useful twice or 3 times a week, being comfortable for patients and practical for Radiotherapy Departments. In interstitial brachytherapy 2 fractions twice a day are applied. PMID- 28808926 TI - Foveal Microstructure Analysis in Eyes with Diabetic Macular Edema Treated with Vitrectomy. AB - INTRODUCTION: The purpose of this study was to evaluate baseline and postoperative factors affecting outcomes after vitrectomy for diabetic macular edema (DME) using optical coherence tomography (OCT). METHODS: Vitrectomy combined with inner limiting membrane (ILM) peeling and additional laser photocoagulation therapy was performed on 36 eyes of 30 DME patients. Evaluations included the logarithm of the minimal angle of resolution (logMAR), best corrected visual acuity (BCVA) and OCT parameters at baseline and 1, 3, 6, and 12 months postoperatively. Correlations between OCT parameters and BCVA were assessed at each follow-up visit. Correlations among postoperative BCVA and preoperative BCVA, foveal macular thickness (FMT), outer foveal thickness (OFT), and photoreceptor outer segment (PROS) length were evaluated using multiple regression analysis. RESULTS: BCVA significantly improved from 0.50 +/- 0.25 to 0.34 +/- 0.26 at 12 months postoperatively (P < 0.001). Mean FMT improved significantly from 526.4 +/- 120.4 to 384.6 +/- 120.5 at 1 month, 325.2 +/- 100.3 at 3 months, 304.1 +/- 102.5 at 6 months and 274.2 +/- 86.6 MUm at 12 months postoperatively (P < 0.001, respectively). OFT 1 month after surgery was significantly decreased 46.5 +/- 14.7-40.2 +/- 14.4 MUm (P = 0.017), although at 3, 6, and 12 months it did not differ from the baseline value. PROS length 1 month after surgery significantly decreased from 31.7 +/- 6.9-28.8 +/- 6.8 MUm (P = 0.015) and that at 3 months and 6 months recovered to the baseline value. PROS length 12 months after surgery was significantly increased to 34.3 +/- 7.2 MUm from baseline (P = 0.023). Mean FMT was not correlated with BCVA at any time point. Mean OFT and PROS length at 3, 6, and 12 months were correlated with BCVA. In multiple regression analysis, PROS length had the greatest effect on VA 12 months postoperatively (P = 0.0262, standard regression coefficient = -0.366). CONCLUSION: Current surgery helps DME patients to maintain VA and foveal structures. The results suggest that PROS length predicts visual outcome in DME patients following vitrectomy with ILM peeling and additional laser photocoagulation. PMID- 28808927 TI - Lymphopaenia in cardiac arrest patients. AB - BACKGROUND: A decrease in circulating lymphocytes has been described as a marker of poor prognosis after septic shock; however, scarce data are available after cardiac arrest (CA). The aim of this study was to evaluate the impact of lymphopaenia after successful cardiopulmonary resuscitation. METHODS: This is a retrospective analysis of an institutional database including all adult CA patients admitted to the intensive care unit (ICU) between January 2007 and December 2014 who survived for at least 24 h. Demographic, CA-related data and ICU mortality were recorded as was lymphocyte count on admission and for the first 48 h. A cerebral performance category score of 3-5 at 3 months was considered as an unfavourable neurological outcome. RESULTS: Data from 377 patients were analysed (median age: 62 [IQRs: 52-75] years). Median time to return of spontaneous circulation (ROSC) was 15 [8-25] min and 232 (62%) had a non-shockable initial rhythm. ICU mortality was 58% (n = 217) and 246 (65%) patients had an unfavourable outcome at 3 months. The median lymphocyte count on admission was 1208 [700-2350]/mm3 and 151 (40%) patients had lymphopaenia (lymphocyte count <1000/mm3). Predictors of lymphopaenia on admission were older age, a shorter time to ROSC, prior use of corticosteroid therapy and high C reactive protein levels on admission. ICU non-survivors had lower lymphocyte counts on admission than survivors (1100 [613-2317] vs. 1316 [891-2395]/mm3; p = 0.05) as did patients with unfavourable compared to those with favourable neurological outcomes (1100 [600-2013] vs. 1350 [919-2614]/mm3; p = 0.003). However, lymphopaenia on admission was not an independent predictor of poor outcomes in the entire population, but only among OHCA patients. CONCLUSIONS: A low lymphocyte count is common in CA survivors and is associated with poor outcome after OHCA. PMID- 28808928 TI - Regulation of Survival Motor Neuron Protein by the Nuclear Factor-Kappa B Pathway in Mouse Spinal Cord Motoneurons. AB - Survival motor neuron (SMN) protein deficiency causes the genetic neuromuscular disorder spinal muscular atrophy (SMA), characterized by spinal cord motoneuron degeneration. Since SMN protein level is critical to disease onset and severity, analysis of the mechanisms involved in SMN stability is one of the central goals of SMA research. Here, we describe the role of several members of the NF-kappaB pathway in regulating SMN in motoneurons. NF-kappaB is one of the main regulators of motoneuron survival and pharmacological inhibition of NF-kappaB pathway activity also induces mouse survival motor neuron (Smn) protein decrease. Using a lentiviral-based shRNA approach to reduce the expression of several members of NF kappaB pathway, we observed that IKK and RelA knockdown caused Smn reduction in mouse-cultured motoneurons whereas IKK or RelB knockdown did not. Moreover, isolated motoneurons obtained from the severe SMA mouse model showed reduced protein levels of several NF-kappaB members and RelA phosphorylation. We describe the alteration of NF-kappaB pathway in SMA cells. In the context of recent studies suggesting regulation of altered intracellular pathways as a future pharmacological treatment of SMA, we propose the NF-kappaB pathway as a candidate in this new therapeutic approach. PMID- 28808929 TI - High expression of HO-1 predicts poor prognosis of ovarian cancer patients and promotes proliferation and aggressiveness of ovarian cancer cells. AB - PURPOSE: HO-1 has been proved to be associated with tumor aggressivity and poor prognosis in various cancers. Our study provides the first study to demonstrate the relationship of HO-1 expression and clinical characteristics in ovarian cancer patients. METHODS: Immunohistochemistry and western blotting were used to examine the expression of HO-1 in tissue species and fresh tissues. CCK-8 was used to investigate cell viability. Transwell chamber was performed to estimate migration and invasion capacities in A2780 and Skov-3 cells. RESULTS: Immunohistochemistry and western blotting showed that the expression of HO-1 was higher in ovarian cancer tissues than normal ovarian tissues. High expression of HO-1 was significantly associated with serous ovarian cancer, high FIGO stage, lymph node metastasis, and non-optimal debulking. Patients with high expression of HO-1 exhibited an unfavorable prognosis. In vitro inducing the expression of HO-1 promoted the proliferation and metastasis of A2780 and Skov-3 cells, with the increased expressions of mesenchymal marker (Vimentin), epithelial mesenchymal transition-associated transcript factor (Zeb-1), anti-apoptotic protein (Bcl-2), and the decreased expressions of epithelial marker (Keratin) and pro-apoptotic protein (Bax). Meanwhile, after incubating A2780 and Skov-3 together with HO-1 inhibitor, above results could be reversed. CONCLUSION: HO-1 might be a potential marker for prediction of ovarian cancer prognosis and a target for ovarian cancer treatment. PMID- 28808930 TI - Hospitalization in the Year Preceding Major Oncologic Surgery Increases Risk for Adverse Postoperative Events. AB - BACKGROUND: Hospitalization is associated with negative clinical effects that last beyond discharge. This study aimed to determine whether hospitalization in the year before major oncologic surgery is associated with adverse outcomes. METHODS: Patients 18 years of age or older with stomach, pancreas, colon, or rectal cancer who underwent resection in California and New York (2008-2010) were included in the study. Patients with hospitalization in the year prior to oncologic resection (HYPOR) were identified. Multivariable logistic regression was used to examine the association of prior hospitalization with the following adverse outcomes: inpatient mortality, complications, complex discharge needs, and 90-day readmission. Subset analysis by cancer type was performed. Outcomes based on temporal proximity of hospitalization to month of surgical admission were evaluated. RESULTS: Of 32,292 patients, 16.3% (n = 5276) were HYPOR. Patients with prior hospitalization were older (median age, 72 vs 67 years; p < 0.001) and had more comorbidities (Elixhauser Index >=3, 86.5 vs 75.3%; p < 0.001). In the multivariable analysis, HYPOR was associated with complications (odds ratio [OR], 1.28; 95% confidence interval [CI] 1.18-1.40), complex discharge (OR, 1.44; 95% CI 1.34-1.55), and 90-day readmission (OR, 1.45; 95% CI 1.35-1.56). The interval from HYPOR to resection was not associated with adverse outcomes. CONCLUSIONS: Patients hospitalized in the year before oncologic resection are at increased risk for postoperative adverse events. Recent hospitalization is a risk factor that is easily ascertainable and should be used by clinicians to identify patients who may need additional support around the time of oncologic resection. PMID- 28808931 TI - Robotic Total Pelvic Exenteration: Video-Illustrated Technique. AB - BACKGROUND: Robotic-assisted total pelvic exenteration (TPE) can offer a minimally invasive approach to a major multi-organ operation. METHODS: In this video, we summarize a stepwise approach to robotic TPE in a 70 year-old female Jehovah's witness with a history of cervical cancer post-chemoradiation and radical hysterectomy who experienced local recurrence at the vaginal cuff involving the rectum and bladder. RESULTS: The patient was placed in the lithotomy position. A total of six robotic ports were used and the da Vinci Si robotic system was docked between the legs. We proceeded as follows: (1) the abdomen and pelvis were thoroughly explored for evidence of metastatic disease; (2) the pelvic sidewalls were mobilized and bilateral ureters identified; (3) the mesorectal plane was dissected to the level of the levators; (4) the lateral and anterior pelvic structures were completely mobilized, and parametrial tissues were mobilized to the pelvic wall; (5) the bladder was separated from the pubis symphysis, the space of Retzius entered, and the bladder and proximal urethra freed; (6) a perineal incision was made around the vagina, perineal body, and anus, which were excised; (7) an Alloderm mesh secured the pelvic floor, and an omental J flap was mobilized; and (8) a 6 cm incision was utilized for creation of an ileal conduit and a permanent-end colostomy. Final pathology was consistent with recurrent cervical squamous cell carcinoma invading into the vaginal, bladder, and rectal walls. Surgical margins and seven lymph nodes were negative for carcinoma. CONCLUSION: Robotic-assisted TPE is technically feasible in a Jehovah's witness under a multidisciplinary surgical team, even in the setting of prior radical hysterectomy and irradiated tissue. PMID- 28808934 TI - A drug-coated balloon effectively treated in-stent restenosis due to a stent fracture. PMID- 28808935 TI - Some microeconometric evidence on the relationship between health and income. AB - This paper examines the association between income, income inequalities and health inequalities in Europe. The contribution of this paper is to study different hypotheses linking self-perceived health status and income, allowing for the identification of different mechanisms in income-related health inequalities. Using data from the Survey of Health, Ageing and Retirement in Europe (15 countries), we take the advantage of the cross-sectional and longitudinal nature of this rich database to make robust results. The analyses (coefficient estimates as well as average marginal effects) strongly support two hypotheses by showing that (i) income has a positive and concave effect on health (Absolute Income Hypothesis); (ii) income inequalities in a country affect all members in a society (strong version of the Income Inequality Hypothesis). However, our study suggests that, when considering the position of the individual in the income distribution, as well as the interaction between income inequalities and these rankings, one cannot identify individuals the most affected by income inequalities (which should be the least well-off in a society according to the weak version of the Income Inequality Hypothesis). Finally, the robustness of this study is emphasized when implementing a generalized ordered probit to consider the subjective nature of the self-perceived health status to avoid the traps encountered in previous studies. PMID- 28808933 TI - Cardiovascular Disease in Clozapine-Treated Patients: Evidence, Mechanisms and Management. AB - Myocarditis occurs in about 3% of those initiated on clozapine but monitoring reduces the risk of serious outcome. Cardiomyopathy may develop after myocarditis, or from prolonged tachycardia. Monitoring using echocardiography is not deemed cost effective. Tachycardia, orthostatic hypotension and reduced heart rate variability are a group of clozapine-related adverse effects associated with autonomic dysfunction and may have serious consequences in the long term. Elevated heart rate and poor heart rate variability can be treated with a beta blocker or a non-dihydropyridine calcium channel blocker, while orthostatic hypotension can be alleviated by increased fluid intake and abdominal binding, but may require pharmacological intervention. Adequate correction for heart rate may show that clozapine does not prolong the QT interval. Other cardiovascular effects, pulmonary embolism, metabolic syndrome, sudden cardiac death and particularly the excessive mortality from cardiovascular disease events may be more strongly associated with the combination of mental illness, lifestyle factors and poor treatment of cardiovascular disease and its risk factors than with clozapine treatment. In view of the efficacy of clozapine and the evidence of reduced mortality relative to other antipsychotics, clozapine should be prescribed when indicated and recipients should be enrolled in lifestyle programmes to increase exercise and improve diet, and referred for diagnosis and treatment of cardiovascular disease and its risk factors. PMID- 28808932 TI - Visual attention and action: How cueing, direct mapping, and social interactions drive orienting. AB - Despite considerable interest in both action perception and social attention over the last 2 decades, there has been surprisingly little investigation concerning how the manual actions of other humans orient visual attention. The present review draws together studies that have measured the orienting of attention, following observation of another's goal-directed action. Our review proposes that, in line with the literature on eye gaze, action is a particularly strong orienting cue for the visual system. However, we additionally suggest that action may orient visual attention using mechanisms, which gaze direction does not (i.e., neural direct mapping and corepresentation). Finally, we review the implications of these gaze-independent mechanisms for the study of attention to action. We suggest that our understanding of attention to action may benefit from being studied in the context of joint action paradigms, where the role of higher level action goals and social factors can be investigated. PMID- 28808936 TI - Envenomation by Micrurus psyches in French Guiana. AB - We report here the first known envenomation by Micrurus psyches, the so-called Carib coral snake, which occurred on April 2016 in the surroundings of Saint Laurent-du-Maroni, Western French Guiana. Besides local neurological symptoms, it featured unexpected electrocardiogram changes, which were emergence of a first degree atrioventricular block and biphasic T waves, both transient. NewWorld elapid venoms were not known for being cardiotoxic so far. The possible reasons of this cardiac injury are discussed. PMID- 28808937 TI - High-Performance Biogas Upgrading Using a Biotrickling Filter and Hydrogenotrophic Methanogens. AB - This research reports the development of a biotrickling filter (BTF) to upgrade biogas, which is achieved by adding H2 to reduce CO2. H2 and CO2 (80:20% vol.) were fed to a bench-scale BTF packed with polyurethane foam (PUF) and inoculated with hydrogenotrophic methanogens. Maximum CH4 production rates recorded were as high as 38 m3CH4 m-3reactor day-1, which is 5-30 times faster than earlier reports with other kinds of bioreactors. The high rates were attributed to the efficient mass transfer and high density of methanogens in the BTF. The removal efficiencies for H2 and CO2 were 83 and 96%, respectively. 5-Cyano-2,3-ditolyl tetrazolium chloride/DAPI staining revealed that 67% of cells were alive near the gas entrance port, while only 8.3% were alive at the exit. Furthermore, DNA sequencing showed that only 27% of the biomass was composed of Euryarchaeota, the phylum which includes methanogens. These two observations suggest that optimizing the methanogen density and activity could possibly reach even higher biogas upgrading rates. PMID- 28808939 TI - Comparison of left ventricular shape by gated SPECT imaging in diabetic and nondiabetic patients with normal myocardial perfusion: A propensity score analysis. AB - BACKGROUND: Diabetes mellitus induces structural and functional cardiac alterations that can result in heart failure. Left ventricular (LV) shape is a dynamic component of cardiac geometry influencing its contractile function. However, few data are available comparing LV shape index in diabetic and nondiabetic patients without overt coronary artery disease after balancing for coronary risk factors. METHODS: We studied 1168 patients with normal myocardial perfusion and normal LV ejection fraction on stress gated single-photon emission computed tomography (SPECT) imaging. To account for differences in baseline characteristics between diabetic and nondiabetic patients, we created a propensity score-matched cohort considering clinical variables, coronary risk factors, and stress type. RESULTS: Before matching, diabetic patients were older, had higher prevalence of male gender and coronary risk factors, and higher end diastolic and end-systolic LV shape index. After matching, all clinical characteristics were comparable between diabetic and nondiabetic patients, but diabetic patients still had higher end-diastolic and end-systolic LV shape index (both P < .001). At multivariable linear regression analysis, diabetes was a strong predictor of end-systolic LV shape index in the overall study population and in the propensity-matched cohort. CONCLUSIONS: Diabetic patients have higher values of LV shape index compared to nondiabetic patients also after balancing clinical characteristics by propensity score analysis. Shape indexes assessment by gated SPECT may be useful for identifying early LV remodeling in patients with diabetes. PMID- 28808938 TI - Advances in Vaccines to Prevent Viral Respiratory Illnesses in Children. AB - Childhood vaccination has played a critical role in the reduction of morbidity and mortality from communicable diseases, including specific respiratory pathogens. Acute lower respiratory infection (ALRI) of both bacterial and viral aetiology continues to impact global child health. Key bacterial pathogens including Streptococcus pneumoniae and Haemophilus influenza type b are specifically targeted with current vaccination programmes, while at present there are less effective strategies for the prevention of viral disease. Influenza vaccines, including both live attenuated intranasal vaccines and inactivated influenza vaccines, are limited by seasonal strain variation and unsustained immunity. Research into the development of a universal influenza vaccine is ongoing; potential targets are the conserved regions of the virus such as the M2e antigen and hemagglutinin stalk. Respiratory syncytial virus (RSV) and parainfluenza virus 3 (PIV3) are the viral pathogens most commonly causing ALRI in children, particularly the infant population. Currently, no vaccine exists for either virus. Over the last decade, promising advances have been made. Protection of neonates via maternal RSV immunisation is being assessed in a phase III clinical trial, with many other candidates for RSV and PIV3 at less advanced stages of development. PMID- 28808940 TI - Plasma alpha-L-fucosidase activity in chronic inflammation and autoimmune disorders in a pediatric cohort of hospitalized patients. AB - Human alpha-fucosidase (EC 3.2.1.51) is an enzyme (hydrolase) of particular biological and medical interest, as the inherited deficiency in its activity leads to fucosidosis, a pathology belonging to severe glycoprotein lysosomal storage disorders. Although its importance has increased in latest years, data about its plasma level in children with inflammatory disorders are still lacking. In the present study, plasma activity of alpha-L-fucosidase-1 (FUCA-1) and its potential association with chronic inflammatory pathologies was evaluated in hospitalized individuals, both pediatric and adult ones. A number of 201 Hungarian hospitalized patients, 144 children (1-13 years) and 57 adults (31-88 years), were enrolled in the study and underwent plasma assay of FUCA-1 activity, following the normal routine analytical run in the hospital service. Regression and Pearson tests were evaluated to investigate the relationship between FUCA-1 plasma levels and inflammatory disorders diagnosed with subjects recruited in the study. No correlation of FUCA-1 activity was observed in the pediatric patients with immune (p = 0.9677) or metabolic (p = 0.6974) disorders, but a correlation was reported when comparing clusters of chronic inflammatory and autoimmune disease vs. controls (p < 0.05). Furthermore, a relationship was found between FUCA-1 activity in plasma and inflammatory disorders and autoimmunity both in adults and in the pediatric cohort of patients (Pearson test, p = 0.000148). Alterations in plasma levels of FUCA-1 were significantly associated with chronic inflammatory and autoimmune disorders, both in children and adults. The result of the present study should encourage further research on FUCA-1 as a marker of chronic inflammation and autoimmunity. PMID- 28808941 TI - Review of Electronics Based on Single-Walled Carbon Nanotubes. AB - Single-walled carbon nanotubes (SWNTs) are extremely promising materials for building next-generation electronics due to their unique physical and electronic properties. In this article, we will review the research efforts and achievements of SWNTs in three electronic fields, namely analog radio-frequency electronics, digital electronics, and macroelectronics. In each SWNT-based electronic field, we will present the major challenges, the evolutions of the methods to overcome these challenges, and the state-of-the-art of the achievements. At last, we will discuss future directions which could lead to the broad applications of SWNTs. We hope this review could inspire more research on SWNT-based electronics, and accelerate the applications of SWNTs. PMID- 28808942 TI - Primary Care Providers' Opening of Time-Sensitive Alerts Sent to Commercial Electronic Health Record InBaskets. AB - BACKGROUND: Time-sensitive alerts are among the many types of clinical notifications delivered to physicians' secure InBaskets within commercial electronic health records (EHRs). A delayed alert review can impact patient safety and compromise care. OBJECTIVE: To characterize factors associated with opening of non-interruptive time-sensitive alerts delivered into primary care provider (PCP) InBaskets. DESIGN AND PARTICIPANTS: We analyzed data for 799 automated alerts. Alerts highlighted actionable medication concerns for older patients post-hospital discharge (2010-2011). These were study-generated alerts sent 3 days post-discharge to InBaskets for 75 PCPs across a multisite healthcare system, and represent a subset of all urgent InBasket notifications. MAIN MEASURES: Using EHR access and audit logs to track alert opening, we performed bivariate and multivariate analyses calculating associations between patient characteristics, provider characteristics, contextual factors at the time of alert delivery (number of InBasket notifications, weekday), and alert opening within 24 h. KEY RESULTS: At the time of alert delivery, the PCPs had a median of 69 InBasket notifications and had received a median of 379.8 notifications (IQR 295.0, 492.0) over the prior 7 days. Of the 799 alerts, 47.1% were opened within 24 h. Patients with longer hospital stays (>4 days) were marginally more likely to have alerts opened (OR 1.48 [95% CI 1.00-2.19]). Alerts delivered to PCPs whose InBaskets had a higher number of notifications at the time of alert delivery were significantly less likely to be opened within 24 h (top quartile >157 notifications: OR 0.34 [95% CI 0.18-0.61]; reference bottom quartile <=42). Alerts delivered on Saturdays were also less likely to be opened within 24 h (OR 0.18 [CI 0.08-0.39]). CONCLUSIONS: The number of total InBasket notifications and weekend delivery may impact the opening of time-sensitive EHR alerts. Further study is needed to support safe and effective approaches to care team management of InBasket notifications. PMID- 28808944 TI - Effect of HA330 resin-directed hemoadsorption on a porcine acute respiratory distress syndrome model. AB - BACKGROUND: Blood purification is an emerging approach to dampening the cytokine storm. This study aims to assess the efficacy of HA330 resin-directed hemoadsorption (HA) on endotoxin-induced porcine acute respiratory distress syndrome (ARDS) model. METHODS: Twenty-four Chinese domestic pigs were allocated into saline group receiving intravenous infusion of saline (N = 6) and endotoxin group receiving intravenous infusion of LPS (N = 18). When ALI model was initially diagnosed, six pigs in the LPS and saline group were killed for BALF and histopathological analysis. The remaining 12 pigs in LPS group received 3-h HA (N = 6) or HA-sham (N = 6) treatment, respectively. Following another 5-h observation, animals were killed. Variables on hemodynamics, blood gases and lung mechanics were recorded at a series of time points. Differentially expressed cytokines and proteins were determined by ELISA and proteomics. RESULTS: HA treatment significantly improved injured oxygenation induced by LPS. HA also partially improved the barrier permeability and reduced lung edema and inflammation/injury induced by LPS infusion. Proteomic analysis showed the differentially expressed proteins between HA- and HA-sham-treated groups mostly belonged to the categories of acute inflammation/immune response, and proteolysis. CONCLUSIONS: Hemoadsorption improved ARDS possibly by blunting the cytokine storm and by restoring homeostasis of the disordered proteome milieu in the exudative phase. PMID- 28808945 TI - Erratum to: Vasodilator Therapy: Nitrates and Nicorandil. PMID- 28808943 TI - A logistic regression model predicting high axillary tumour burden in early breast cancer patients. AB - PURPOSE: As elective axillary dissection is loosing ground for early breast cancer (BC) patients both in terms of prognostic and therapeutic power, there is a growing interest in predicting patients with (nodal) high tumour burden (HTB), especially after a positive sentinel node biopsy (SNB) because they would really benefit from further axillary intervention either by complete lymph-node dissection or axillary radiation therapy. METHODS/PATIENTS: Based on an analysis of 1254 BC patients in whom complete axillary clearance was performed, we devised a logistic regression (LR) model to predict those with HTB, as defined by the presence of three or more involved nodes with macrometastasis. This was accomplished through prior selection of every variable associated with HTB at univariate analysis. RESULTS: Only those variables shown as significant at the multivariate analysis were finally considered, namely tumour size, lymphovascular invasion and histological grade. A probability table was then built to calculate the chances of HTB from a cross-correlation of those three variables. As a suggestion, if we were to follow the rationale previously used in the micrometastasis trials, a threshold of about 10% risk of HTB could be considered under which no further axillary treatment is warranted. CONCLUSIONS: Our LR model with its probability table can be used to define a subgroup of early BC patients suitable for axillary conservative procedures, either sparing completion lymph node dissection or even SNB altogether. PMID- 28808946 TI - Perioperative Care of Elderly Surgical Outpatients. AB - The ambulatory setting offers potential advantages for elderly patients undergoing elective surgery due to the advancement in both surgical and anesthetic techniques resulting in quicker recovery times, fewer complications, higher patient satisfaction, and reduced costs of care. This review article aims to provide a practical guide to anesthetic management of elderly outpatients. Important considerations in the preoperative evaluation of elderly outpatients with co-existing diseases, as well as the advantages and disadvantages of different anesthetic techniques on a procedural-specific basis, and recommendations regarding the management of common postoperative complications (e.g., pain, postoperative nausea and vomiting [PONV], delirium and cognitive dysfunction, and gastrointestinal dysfunction) are discussed. The role of anesthesiologists as perioperative physicians is important for optimizing surgical outcomes for elderly patients undergoing ambulatory surgery. The implementation of high-quality, evidence-based perioperative care programs for the elderly on an ambulatory basis has assumed increased importance. Optimal management of perioperative pain using opioid-sparing multimodal analgesic techniques and preventing PONV using prophylactic antiemetics are key elements for achieving enhanced recovery after surgery. PMID- 28808948 TI - Tiotropium Bromide in Children and Adolescents with Asthma. AB - Evidence is emerging on the use of long-acting muscarinic antagonists (LAMAs) in the management of asthma. Tiotropium bromide (Spiriva(r) Respimat(r)) is the only LAMA approved in children and adolescents. As the use of tiotropium becomes more common in clinical practice, it is necessary to review the existing data to identify patients who may benefit from the addition of this medication to their daily asthma regimen. This review discusses recent evidence on the safety and efficacy of tiotropium bromide in the management of asthma in children and adolescents. Current data support that tiotropium bromide has a bronchodilator effect, as evident by improvements in acute lung function compared with placebo; however, data are not yet available to present a stepwise approach or identify phenotypes that would benefit from the addition of tiotropium bromide. Well designed studies are needed to compare the different step-up options to tiotropium bromide and provide an evidence-based stepwise approach for the management of asthma in children. Furthermore, study design should include identification of phenotypes that might experience a better clinical response to tiotropium bromide compared with other adjunct medications. PMID- 28808947 TI - The Sydney Heart Bank: improving translational research while eliminating or reducing the use of animal models of human heart disease. AB - The Sydney Heart Bank (SHB) is one of the largest human heart tissue banks in existence. Its mission is to provide high-quality human heart tissue for research into the molecular basis of human heart failure by working collaboratively with experts in this field. We argue that, by comparing tissues from failing human hearts with age-matched non-failing healthy donor hearts, the results will be more relevant than research using animal models, particularly if their physiology is very different from humans. Tissue from heart surgery must generally be used soon after collection or it significantly deteriorates. Freezing is an option but it raises concerns that freezing causes substantial damage at the cellular and molecular level. The SHB contains failing samples from heart transplant patients and others who provided informed consent for the use of their tissue for research. All samples are cryopreserved in liquid nitrogen within 40 min of their removal from the patient, and in less than 5-10 min in the case of coronary arteries and left ventricle samples. To date, the SHB has collected tissue from about 450 failing hearts (>15,000 samples) from patients with a wide range of etiologies as well as increasing numbers of cardiomyectomy samples from patients with hypertrophic cardiomyopathy. The Bank also has hearts from over 120 healthy organ donors whose hearts, for a variety of reasons (mainly tissue-type incompatibility with waiting heart transplant recipients), could not be used for transplantation. Donor hearts were collected by the St Vincent's Hospital Heart and Lung transplantation team from local hospitals or within a 4-h jet flight from Sydney. They were flushed with chilled cardioplegic solution and transported to Sydney where they were quickly cryopreserved in small samples. Failing and/or donor samples have been used by more than 60 research teams around the world, and have resulted in more than 100 research papers. The tissues most commonly requested are from donor left ventricles, but right ventricles, atria, interventricular system, and coronary arteries vessels have also been reported. All tissues are stored for long-term use in liquid N or vapor (170-180 degrees C), and are shipped under nitrogen vapor to avoid degradation of sensitive molecules such as RNAs and giant proteins. We present evidence that the availability of these human heart samples has contributed to a reduction in the use of animal models of human heart failure. PMID- 28808950 TI - Gastric Volvulus with Segmental Necrosis Treated with Wedge Resection and Gastrogastrostomy. AB - Ischemic necrosis is a feared complication of acute gastric volvulus, occurring in 11% of patients presenting with the condition and responsible for mortality in 30%. In such cases, there are few well-validated options for surgical reconstruction. We present the case of a 77-year-old woman with intraabdominal mesenteroaxial gastric volvulus with segmental ischemic gastric necrosis who underwent wedge gastrectomy and hand-sewn gastrogastrostomy. She did well postoperatively and experienced no significant gastrointestinal complications. Gastric wedge resection with gastrogastrostomy presents a novel surgical intervention for a rare and highly morbid entity. We hope to add it to the repertoire of surgeons facing acute gastric volvulus complicated by segmental necrosis. PMID- 28808949 TI - Practical Management of Respiratory Comorbidities in Patients with Rheumatoid Arthritis. AB - Lung disease is one of the most common causes of extra-articular morbidity and mortality in patients with rheumatoid arthritis (RA). Development of pulmonary manifestations may be due to the systemic disease itself; to serious respiratory adverse events such as pneumonitis and infections secondary to therapy; or to lifestyle habits such as smoking. Rheumatologists often need to make important treatment decisions and plan future care in RA patients with respiratory comorbidities, despite the absence of clear evidence or consensus. In this review we evaluate the clinical assessment and management of RA-associated interstitial lung disease, bronchiectasis, serious (including opportunistic) infection, and smoking-related diseases. We summarize the international recommendations for the management of such conditions where available, refer to published best practice on the basis of scientific literature, and propose practical management suggestions to aid informed decision-making. PMID- 28808951 TI - What Is the Diagnostic Accuracy of the Duck Walk Test in Detecting Meniscal Tears? AB - BACKGROUND: Clinical weightbearing provocation tests, like the duck walk test, may be of value in diagnosing or screening for medial meniscal tears. However, evidence of the diagnostic accuracy of the duck walk test is lacking. QUESTIONS/PURPOSES: (1) To determine the sensitivity and specificity of the duck walk test in diagnosing medial meniscal tears. (2) To determine whether tear location, tear cause (traumatic versus degenerative), and ACL insufficiency were associated with differences in the sensitivity and specificity of the test. METHODS: A convenience sample of 136 patients of all ages was retrospectively analyzed by evaluating the outpatient knee clinic appointment list of one orthopaedic surgeon for patients with a broad range of knee injuries who had a prior MRI before (24%) or after (76%) physical examination and had a duck walk test stated in their patient records. Of 230 patients with MRI requested by one orthopaedic surgeon attributable to knee complaints, 136 (59%) fulfilled the inclusion criteria; 70 (52%) patients were male and 66 (49%) were female, with a mean age of 42 (+/- SD 14) years. The duck walk test was performed in case of suspected meniscal injury, based on mechanism of injury, general joint line pain, and/or mechanical complaints (ie, locking, giving away). The test is performed by squatting and "waddling" before rising and is positive in case of general joint line pain or painful "clicking". Interobserver repeatability was not evaluated, but the test is well defined and leaves little room for difference in interpretation. Diagnostic accuracy measures were evaluated. Since the convenience sample in this study consisted of patients who had a duck walk test and MRI, and a positive result of the duck walk test almost certainly increased the probability that MRI would be ordered in the majority (76%) of the patients, the test properties calculated here-especially sensitivity-should be considered inflated. RESULTS: The calculated sensitivity of the duck walk test was 71% (95% CI, 59%-81%) and there was low specificity of 39% (95% CI, 27%-52%). We found no difference in sensitivity between medial (67%; 95% CI, 51%-80%) and lateral (76%; 95% CI, 50%-92%; p = 0.492) meniscal tears. With the numbers available, we compared these patients with patients without a history of trauma and with an intact ACL. We found no difference among patients with traumatic tears (79%; 95% CI, 59%-91%; p = 0.253) and in patients with ACL tears (77%; 95% CI, 46%-94%; p = 0.742). CONCLUSIONS: Because of the issue of verification bias, the actual sensitivity of this test in practice is likely much lower than the calculated sensitivity we observed. In addition, the test did not seem to perform better in patients with trauma or ACL insufficiency, nor was it more effective in detecting medial than lateral tears, although the numbers on some of those comparisons were rather small. Based on these results, we conclude that used alone, the duck walk test likely has little value in practice as a screening test. However, it is conceivable that it could be used in combination with other provocative tests for screening purposes. Future studies might consider using it as a means to best identify which patients should undergo MRI for the possibility of a meniscal tear. LEVEL OF EVIDENCE: Level III, diagnostic study. PMID- 28808952 TI - Effect of reducing cost sharing for outpatient care on children's inpatient services in Japan. AB - BACKGROUND: Assessing the impact of cost sharing on healthcare utilization is a critical issue in health economics and health policy. It may affect the utilization of different services, but is yet to be well understood. OBJECTIVE: This paper investigates the effects of reducing cost sharing for outpatient services on hospital admissions by exploring a subsidy policy for children's outpatient services in Japan. METHODS: Data were extracted from the Japanese Diagnosis Procedure Combination database for 2012 and 2013. A total of 366,566 inpatients from 1390 municipalities were identified. The impact of expanding outpatient care subsidy on the volume of inpatient care for 1390 Japanese municipalities was investigated using the generalized linear model with fixed effects. RESULTS: A decrease in cost sharing for outpatient care has no significant effect on overall hospital admissions, although this effect varies by region. The subsidy reduces the number of overall admissions in low-income areas, but increases it in high-income areas. In addition, the results for admissions by type show that admissions for diagnosis increase particularly in high-income areas, but emergency admissions and ambulatory-care-sensitive-condition admissions decrease in low-income areas. CONCLUSIONS: These results suggest that outpatient and inpatient services are substitutes in low-income areas but complements in high-income ones. Although the subsidy for children's healthcare would increase medical costs, it would not improve the health status in high income areas. Nevertheless, it could lead to some health improvements in low income areas and, to some extent, offset costs by reducing admissions in these regions. PMID- 28808953 TI - Frailty, comorbidity and critical illness: a trilogy insights for non invasive mechanical ventilation in elderly. PMID- 28808954 TI - Heavy metal pollutants in selected organs of African giant rats from three agro ecological zones of Nigeria: evidence for their role as an environmental specimen bank. AB - An assessment of the concentration of heavy metals in the liver, brain, kidney, bone, and lungs of African giant rats (AGRs) from three agro-ecological zones of Nigeria having different industrial activities was carried out using atomic absorption spectrophotometer. Twenty adult AGRs from cities in mangrove/freshwater swamp, rainforest, and woodland/tall grass savanna agro ecological zones of Nigeria were used for this study. AGRs were euthanized, carefully dissected, and the brains, liver, lungs, bone, and kidneys were harvested, digested, and analyzed for concentrations of vanadium (V), lead (Pb), cadmium (Cd), zinc (Zn), selenium (Se), copper (Cu), and iron (Fe). All data generated were evaluated for statistical significance using one-way ANOVA with Tukey's multiple post-test comparison. Results showed the major environmental heavy metal pollutants of the mangrove/freshwater swamp to be vanadium and selenium while those of woodland/tall grass savanna agro-ecological zones were lead, selenium, and zinc. The vanadium concentration was more than twofold higher in the observed tissues of AGR from the mangrove/freshwater swamp, and this may be related to increased exploitation of minerals and the activities of militants in pipeline vandalization in this zone. Interestingly, the highest concentration of this metal was seen in the lungs suggestive of a respiratory route of exposure. Among the potential adverse effects derived from exposure to metals, developmental toxicity is a serious risk. This type of investigation can assist in knowing the level of animal and human exposure to environmental pollutants both in highly industrialized and non-industrialized areas and is more ideal in environmental monitoring. This study therefore suggests AGR as model for ecotoxicological research and environmental specimen banks (ESBs) in this part of Africa. PMID- 28808956 TI - Erratum to: Nutritional Rickets and Osteomalacia in the Twenty-first Century: Revised Concepts, Public Health, and Prevention Strategies. PMID- 28808958 TI - The impact of frailty on noninvasive mechanical ventilation in elderly medical intensive care unit patients. PMID- 28808955 TI - Exploring the Biological and Mechanical Properties of Abdominal Aortic Aneurysms Using USPIO MRI and Peak Tissue Stress: A Combined Clinical and Finite Element Study. AB - Inflammation detected through the uptake of ultrasmall superparamagnetic particles of iron oxide (USPIO) on magnetic resonance imaging (MRI) and finite element (FE) modelling of tissue stress both hold potential in the assessment of abdominal aortic aneurysm (AAA) rupture risk. This study aimed to examine the spatial relationship between these two biomarkers. Patients (n = 50) > 40 years with AAA maximum diameters > = 40 mm underwent USPIO-enhanced MRI and computed tomography angiogram (CTA). USPIO uptake was compared with wall stress predictions from CTA-based patient-specific FE models of each aneurysm. Elevated stress was commonly observed in areas vulnerable to rupture (e.g. posterior wall and shoulder). Only 16% of aneurysms exhibited co-localisation of elevated stress and mural USPIO enhancement. Globally, no correlation was observed between stress and other measures of USPIO uptake (i.e. mean or peak). It is suggested that cellular inflammation and stress may represent different but complimentary aspects of AAA disease progression. PMID- 28808957 TI - Differential effect of TGFbeta on the proteome of cancer associated fibroblasts and cancer epithelial cells in a co-culture approach - a short report. AB - BACKGROUND: Solid tumors contain various components that together form the tumor microenvironment. Cancer associated fibroblasts (CAFs) are capable of secreting and responding to signaling molecules and growth factors. Due to their role in tumor development, CAFs are considered as potential therapeutic targets. A prominent tumor-associated signaling molecule is transforming growth factor beta (TGFbeta), an inducer of epithelial-to-mesenchymal transition (EMT). The differential action of TGFbeta on CAFs and ETCs (epithelial tumor cells) has recently gained interest. Here, we aimed to investigate the effects of TGFbeta on CAFs and ETCs at the proteomic level. METHODS: We established a 2D co-culture system of differentially fluorescently labeled CAFs and ETCs and stimulated this co-culture system with TGFbeta. The respective cell types were separated using FACS and subjected to quantitative analyses of individual proteomes using mass spectrometry. RESULTS: We found that TGFbeta treatment had a strong impact on the proteome composition of CAFs, whereas ETCs responded only marginally to TGFbeta. Quantitative proteomic analyses of the different cell types revealed up regulation of extracellular matrix (ECM) proteins in TGFbeta treated CAFs. In addition, we found that the TGFbeta treated CAFs exhibited increased N-cadherin levels. CONCLUSIONS: From our data we conclude that CAFs respond to TGFbeta treatment by changing their proteome composition, while ETCs appear to be rather resilient. PMID- 28808959 TI - Deaths from Medicines: A Systematic Analysis of Coroners' Reports to Prevent Future Deaths. AB - INTRODUCTION: Since legislation in 2009, coroners in England and Wales must make reports in cases where they believe it is possible to prevent future deaths. We categorised the reports and examined whether they could reveal preventable medication errors or novel adverse drug reactions. METHODS: We examined 500 coroners' reports by pre-defined criteria to identify those in which medicines played a part, and to collect information on coroners' concerns. RESULTS: We identified 99 reports (100 deaths) in which medicines or a part of the medication process or both were mentioned. Reports mentioned anticoagulants (22 reports), opioids (17), antidepressants (17), drugs of abuse excluding opioids (12 deaths) and other drugs. The most important concerns related to adverse reactions to prescribed medicines (22), omission of necessary treatment (21), failure to monitor treatment (17) and poor systems (17). These were related to defects in education or training, lack of clear guidelines or protocols and failure to implement existing guidelines, among other reasons. Most reports went either to NHS Hospital Trusts or to local trusts. The responses of addressees were rarely published. We identified four safety warnings from the Medicines and Healthcare Products Regulatory Agency that were based on coroners' warnings. CONCLUSION: Coroners' reports to prevent future deaths provide some information on medication errors and adverse reactions. They rarely identify new hazards. At present they are often addressed to local bodies, but this could mean that wider lessons are lost. PMID- 28808960 TI - The Application of Humanized Mouse Models for the Study of Human Exclusive Viruses. AB - The symbiosis between humans and viruses has allowed human tropic pathogens to evolve intricate means of modulating the human immune response to ensure its survival among the human population. In doing so, these viruses have developed profound mechanisms that mesh closely with our human biology. The establishment of this intimate relationship has created a species-specific barrier to infection, restricting the virus-associated pathologies to humans. This specificity diminishes the utility of traditional animal models. Humanized mice offer a model unique to all other means of study, providing an in vivo platform for the careful examination of human tropic viruses and their interaction with human cells and tissues. These types of animal models have provided a reliable medium for the study of human-virus interactions, a relationship that could otherwise not be investigated without questionable relevance to humans. PMID- 28808961 TI - Zebrafish as a Model for the Study of Host-Virus Interactions. AB - Zebrafish (Danio rerio) has become an increasingly important model for in vivo and in vitro studies on host-pathogen interaction, offering scientists with optical accessibility and genetic tractability, and a vertebrate-type immunity that can be separated into innate and adaptive ones. Although it is shown in previous studies that few species of viruses can naturally infect zebrafish, the spring viraemia of carp virus (SVCV), a rhabdovirus that causes contagious acute hemorrhagic viraemia in a variety of cyprinid fishes, can infect zebrafish by both injection and static immersion methods in laboratory conditions. In addition, SVCV can infect zebrafish fibroblast cell line (ZF4 cells), together with the Epithelioma papulosum cyprini (EPC) cell line (EPC cells), a common cell line used widely in fish disease research. The infection and propagation of SVCV in zebrafish and especially in these cell lines can be employed conveniently in laboratory for functional assays of zebrafish genes. The zebrafish, ZF4 and EPC cell, and SVCV can serve as a simple and efficient model system in understanding host-virus interactions. In the present chapter, we provide detailed protocols for the host-virus interaction analysis based on zebrafish embryos, ZF4/EPC cells, and SVCV, including infection methods of zebrafish embryos and cell lines, analyses of immune responses by quantitative PCR (qPCR) and RNA sequencing (RNA Seq), antiviral assays based on ZF4 and EPC cells, and the analysis of host-virus interaction using luciferase assays. These protocols should provide efficient and typical means to address host-virus interactions in a more general biological sense. PMID- 28808962 TI - Northern Blot Detection of Virus-Derived Small Interfering RNAs in Caenorhabditis elegans Using Nonradioactive Oligo Probes. AB - Northern blot analysis has been widely used as a tool for detection and characterization of specific RNA molecules. When coupled with radioactive probe northern blot allows for robust detection and characterization of small RNA molecules of trace amount. Here, we describe the detection and size characterization of virus-derived small interfering RNAs (vsiRNAs) in C. elegans using nonradioactive DNA oligo probes in northern blotting. Our protocol allows for the detection and characterization of not only primary vsiRNAs but also secondary vsiRNAs, a class of single-stranded vsiRNAs that has distinct migration pattern, and can be easily adapted to the detection of vsiRNAs in other organisms. PMID- 28808963 TI - Extraction and qPCR-Based Detection of miRNAs from Cultured PBMCs of Bubaline Origin. AB - MicroRNAs are small noncoding but functionally important RNA molecules that are involved in regulating diverse cellular, metabolic, and immune processes. Their small size necessitates modification in traditional acid phenol-chloroform based RNA isolation procedures to get highly enriched fraction of small RNA that includes miRNAs and siRNAs . Further, of the different methods available, real time PCR is a powerful tool for precise and specific detection and quantification of miRNA. Moreover, real-time PCR is used to validate the screening or expression of miRNAs that are discovered during high-throughput sequencing, or microarray analysis. We demonstrate here the method of extraction of miRNAs from cultured PBMCs of bubaline origin followed by the qPCR-based (both SYBR green and TaqMan based chemistries) identification of miRNAs expressed in response to TLR ligand stimulation. PMID- 28808964 TI - Visualizing Virus-Derived dsRNA Using Antibody-Independent and -Dependent Methods. AB - Long double-stranded (ds) RNA molecules are produced as a byproduct of viral replication. Studying virus-derived dsRNA is important for understanding virus replication, understanding host responses to virus infections, and as a diagnostic tool for virus presence and replication. Here, we describe four different techniques for visualizing dsRNA; two antibody-dependent methods (immunoblotting and immunocytochemistry), as well as two antibody-independent methods (differential digestion and acridine orange staining). The benefits and disadvantages of each technique are also discussed. PMID- 28808965 TI - RNA PAMPs as Molecular Tools for Evaluating RIG-I Function in Innate Immunity. AB - Pathogen recognition receptors (PRR)s and their cognate pathogen-associated molecular pattern (PAMP) represent the basis of innate immune activation and immune response induction driven by the host-pathogen interaction that occurs during microbial infection in humans and other animals. For RNA virus infection such as hepatitis C virus (HCV) and others, specific motifs within viral RNA mark it as nonself and visible to the host as a PAMP through interaction with RIG-I like receptors including retinoic inducible gene-I (RIG-I). Here, we present methods for producing and using HCV PAMP RNA as a molecular tool to study RIG-I and its signaling pathway, both in vitro and in vivo, in innate immune regulation. PMID- 28808966 TI - Methods to Visualize MAVS Subcellular Localization. AB - The mitochondrial antiviral signaling (MAVS) protein is a central adaptor protein required for antiviral innate immune signaling. To facilitate its roles in innate immunity, MAVS localizes to multiple intracellular membranous compartments, including the mitochondria, the mitochondrial-associated ER membrane (MAM), and peroxisomes. Studies of MAVS function therefore often require an analysis of MAVS localization. To detect MAVS protein on intracellular membranes, biochemical fractionation to isolate MAMs, mitochondria, or peroxisomes can be used. Further, immunofluorescence with antibodies against specific membrane markers can be used to visualize MAVS distribution throughout the cell. Here, we describe the biochemical fractionation and immunofluorescence protocols used to detect MAVS subcellular localization. PMID- 28808967 TI - Purification of Cyclic GMP-AMP from Viruses and Measurement of Its Activity in Cell Culture. AB - Sensing of cytoplasmic DNA by cGAS is essential for the initiation of immune responses against several viruses. cGAS also plays important roles in some autoinflammatory and autoimmune diseases and may be involved in immune responses targeting cancer cells. Once activated, cGAS catalyzes the formation of the di nucleotide 2'-3'-cyclic GMP-AMP (cGAMP), which propagates a signaling cascade leading to the production of type I interferons (IFNs). Interestingly, cGAMP is incorporated into enveloped viruses and is transferred to newly infected cells by virions. In this article, we describe a method to purify cGAMP from viral particles and a bioassay to measure its activity. This assay takes advantage of a reporter cell line that expresses the genes encoding green fluorescent protein (GFP) and firefly luciferase under the control of the IFNbeta promoter, allowing the testing of several samples in a single experiment taking not more than 3 days. PMID- 28808968 TI - cGAMP Quantification in Virus-Infected Human Monocyte-Derived Cells by HPLC Coupled Tandem Mass Spectrometry. AB - Upon virus infection, cells of the innate immune system such as dendritic cells and macrophages can mount type I interferon (IFN-I) responses that restrict viral dissemination. To inform host cells of virus infection, detection of cytosolic DNA is one important mechanism. Inappropriate sensing of endogenous DNA and subsequent induction of IFN-I responses can also cause autoimmunity, highlighting the need to tightly regulate DNA sensing. The cyclic GMP-AMP synthase (cGAS) was recently identified to be the major sensor of cytosolic DNA that triggers IFN-I expression. Upon DNA binding, cGAS synthesizes the second messenger cyclic guanosine-adenosine monophosphate (cGAMP) that induces IFN-I expression by the activation of the stimulator of interferon genes (STING). Notably, cGAMP does not only act in infected cells, but can also be relocated to noninfected bystander cells to there trigger IFN-I expression. Thus, direct quantification of cGAMP in cells of the innate immune system is an important approach to study where, when, and how DNA is sensed and IFN-I responses are induced. Here, we describe a method that allows specific quantification of cGAMP from extracts of virus-infected human myeloid cells by HPLC-coupled tandem mass spectrometry. PMID- 28808969 TI - Methods of Assessing STING Activation and Trafficking. AB - The signaling adapter protein STING is crucial for the host immune response to cytosolic DNA and cyclic dinucleotides. Under basal conditions, STING resides on the endoplasmic reticulum (ER ) , but upon activation, it traffics through secretory pathway to cytoplasmic vesicles, where STING activates downstream immune signaling. Classical STING activation and trafficking are triggered by binding of cyclic dinucleotide ligands. STING signaling can also be activated by gain-of-function mutations that lead to constitutive trafficking of STING. These gain-of-function mutations are associated with several human diseases such as STING-associated vasculopathy with onset in infancy (SAVI), systemic lupus erythematosus (SLE), or familial chilblain lupus (FCL). This dynamic activation pathway presents a challenge to study. We describe methods here for measuring ligand-dependent and ligand-independent activation of STING signaling in HEK293T cells. We also describe a retroviral-based reconstitution assay to study STING protein trafficking and activation in immune competent cells such as mouse embryonic fibroblasts (MEF), which avoids the use of plasmid DNA. These methods will expedite research regarding STING trafficking and signaling dynamics in the settings of infection and autoimmune diseases. PMID- 28808970 TI - Genome-Wide CRISPR/Cas9 Screening for High-Throughput Functional Genomics in Human Cells. AB - It is highly desirable to identify gene's function in a high-throughput fashion, and the CRISPR/Cas9 system has been harnessed to meet such a need. Here, we describe a general method to generate genome-scale lentiviral single-guide RNA (sgRNA) library and conduct a pooled function-based screening in human cells. This protocol would be of interest to researchers to rapidly identify genes in a variety of biological processes. PMID- 28808971 TI - High-Throughput Screening for Identification of Novel Innate Immune Activators. AB - Modern drug discovery has embraced in vitro platforms that enable investigation of large numbers of compounds within tractable timeframes and for feasible costs. These endeavors have been greatly aided in recent years by advances in molecular and cell-based methods such as gene delivery and editing technology, advanced imaging, robotics, and quantitative analysis. As such, the examination of phenotypic impacts of novel molecules may only be limited by the size of the compound collection. Innate immune signaling processes in mammalian cells are especially amenable to high-throughput screening platforms since the cellular responses elicited by their activation often result in high level transcription that can be harnessed in the form of bioluminescent or fluorescent signal. In addition, targeted activation of innate immune pathways represents a valuable therapeutic strategy applicable to multiple chronic and acute human diseases. Herein, we describe the optimization and utilization of a high-throughput screening method using human reporter cells reactive to stimulation of the type I interferon response. Importantly, the principles and methods described can be applied to adherent reporter cells of diverse derivation and innate signaling pathway readouts. PMID- 28808972 TI - Chromosome Conformation Capture for Research on Innate Antiviral Immunity. AB - Chromosome conformation capture (3C) technology has revolutionized our knowledge on chromatin folding and nuclear organization. This cis-loop detection approach can be used to identify candidate regulatory elements interacting with target gene of interest. This chapter introduces the application of 3C technique to investigate a dynamic alteration in the chromosome folding structure or genomic architecture resulting from interaction changes between the enhancer and its target gene. Innate antiviral immunity is one of the well-known gene induction systems, involving rapid first-line response to virus or pathogen to trigger gene expression changes in order to protect cells and to limit further infection. Thus, the 3C technique can be a powerful tool for exploring how enhancers control expression of immunity genes during virus infection. 3C assay consists of four major steps: Cross-linking with formaldehyde, restriction enzyme digestion, ligation of cross-linked DNA fragments, and quantitative data analysis. Here, we discuss in detail the design, application, and data analysis of a 3C experiment. PMID- 28808973 TI - Discovery of Variants Underlying Host Susceptibility to Virus Infection Using Whole-Exome Sequencing. AB - The clinical course of any viral infection greatly differs in individuals. This variation results from various viral, host, and environmental factors. The identification of host genetic factors influencing inter-individual variation in susceptibility to several pathogenic viruses has tremendously increased our understanding of the mechanisms and pathways required for immunity. Next generation sequencing of whole exomes represents a powerful tool in biomedical research. In this chapter, we briefly introduce whole-exome sequencing in the context of genetic approaches to identify host susceptibility genes to viral infections. We then describe general aspects of the workflow for whole-exome sequence analysis together with the tools and online resources that can be used to identify and annotate variant calls, and then prioritize them for their potential association to phenotypes of interest. PMID- 28808974 TI - Isolation, Purification, and Culture of Primary Murine Sensory Neurons. AB - Cultured primary neurons have been of extraordinary value for the study of neuronal anatomy, cell biology, and physiology. While use of neuronal cell lines has ease and utility, there are often caveats that arise due to their mitotic nature. This methods article presents detailed methodology for the preparation, purification, and culture of adult murine sensory neurons for the study of herpes simplex virus lytic and latent infections. While virology is the application for our laboratory, these cultures also have broad utility for neurobiologists and cell biologists. While these primary cultures have been highly informative, the methodology is challenging to many investigators. Through publication of this highly detailed protocol, it is our hope that the use of this culture system can spread in the field to allow more rapid progress in furthering our understanding of neurotropic virus infection. PMID- 28808975 TI - Isolation of Group 2 Innate Lymphoid Cells from Mouse Lungs. AB - The recently described group 2 innate lymphoid cells (ILC2) exert critical roles in type 2 immune responses, epithelial repair at mucosal tissues and metabolic homeostasis. ILC2 release large amounts of type 2 cytokines such as interleukin 4 (IL-4), IL-5, and IL-13, driving type 2 immunity such as the defense against helminths. However, if not tightly regulated ILC2 can trigger unwanted type 2 immunopathologies including allergic airway inflammation, airway hyper responsiveness, and atopic dermatitis. Viral respiratory tract infections, archetypal triggers of type 1 immune responses, often give rise to pulmonary type 2 immunopathologies such as asthma and asthma exacerbations. Interestingly, pulmonary viral infections induce the release of IL-33, followed by induction of ILC2-mediated pulmonary type 2 immunopathology independent of the adaptive immune system. Due to their scarcity at steady state but also after infection and inflammation, pulmonary ILC2 are challenging to work with. In this chapter, we describe the detection and isolation procedure of pulmonary mouse ILC2 by flow cytometry and compare four distinct enzymatic mouse lung tissue processing protocols for optimized cell yield. PMID- 28808976 TI - Epidemiological Methods. AB - This chapter provides an overview of the most common epidemiological designs used in clinical studies to better understand innate anti-viral immunity. Studies to assess risk factors as well as interventions are described. PMID- 28808977 TI - Skeletal Dysplasias: What Every Bone Health Clinician Needs to Know. AB - PURPOSE OF REVIEW: This review highlights how skeletal dysplasias are diagnosed and how our understanding of some of these conditions has now translated to treatment options. RECENT FINDINGS: The use of multigene panels, using next generation sequence technology, has improved our ability to quickly identify the genetic etiology, which can impact management. There are successes with the use of growth hormone in individuals with SHOX deficiencies, asfotase alfa in hypophosphatasia, and some promising data for c-type natriuretic peptide for those with achondroplasia. One needs to consider that a patient with short stature has a skeletal dysplasia as options for management may be available. PMID- 28808979 TI - Decellularization of Liver and Organogenesis in Rats. AB - Recently, organ construction has been attempted using decellularized organs. In this study, we used decellularized rat liver to construct liver tissue by recellularization. The right lobe of the rat liver was decellularized with 4% Triton X-100 solution, recellularized with 107 rat hepatocytes, and albumin synthesis in the recellularized right lobe was observed. Therefore, we introduce a method of decellularizing rat liver, which retains its fine vascular structure after removal of all the cells, perform organogenesis using the decellularized liver, and evaluate the structural and functional properties of the products. PMID- 28808978 TI - The role of negative conductances in neuronal subthreshold properties and synaptic integration. AB - Based on passive cable theory, an increase in membrane conductance produces a decrease in the membrane time constant and input resistance. Unlike the classical leak currents, voltage-dependent currents have a nonlinear behavior which can create regions of negative conductance, despite the increase in membrane conductance (permeability). This negative conductance opposes the effects of the passive membrane conductance on the membrane input resistance and time constant, increasing their values and thereby substantially affecting the amplitude and time course of postsynaptic potentials at the voltage range of the negative conductance. This paradoxical effect has been described for three types of voltage-dependent inward currents: persistent sodium currents, L- and T-type calcium currents and ligand-gated glutamatergic N-methyl-D-aspartate currents. In this review, we describe the impact of the creation of a negative conductance region by these currents on neuronal membrane properties and synaptic integration. We also discuss recent contributions of the quasi-active cable approximation, an extension of the passive cable theory that includes voltage dependent currents, and its effects on neuronal subthreshold properties. PMID- 28808980 TI - Non-invasive ventilation in acute respiratory failure: the key "W" questions. PMID- 28808981 TI - Erratum to: Macrophage M1 Plays a Positive Role in Aseptic Inflammation-Related Graft Loosening After Anterior Cruciate Ligament Reconstruction Surgery. PMID- 28808982 TI - Radial head prosthesis: results overview. AB - BACKGROUND/PURPOSE: Radial head replacement is frequently used in treatment of radial head fractures or sequela. Impossibility to restore a correct anatomy, acute elbow traumatic instability and failure of osteosynthesis hardware are the most common indications. The authors describe their case studies and results on the implantation of various radial head prostheses. MATERIALS: Between June 2005 and June 2016, 28 radial head prostheses were implanted in the same number of patients with an average follow-up of 49 months (6-104). Indications for implantation were: Mason type III and IV radial head fractures and post-traumatic arthritis due to failure of previous treatments. Monopolar prostheses were used and were press-fit implanted via Kaplan's lateral access and Kocher's anconeus approach to the humeroradial joint. At the follow-up, assessments were made of the pain, according to the visual analogic scale, range of motion (ROM), stability and functionality according to the Mayo Elbow Performance Score, presence of osteolysis and mobilization during radiography tests, personal satisfaction of the patients, Disabilities of the Arm, Shoulder and Hand and Patient-Rated Wrist Evaluation outcomes measurements. RESULTS: At the follow-up, we recorded an average level of pain of 1.8 in patients under acute treatments for radial head fractures and a marked reduction in the remaining cases from 6.7 to 2.1. ROM was found on average to be 107 degrees of flexion-extension and 159 degrees of pronosupination. Personal satisfaction was good-excellent in 23 cases. There was no case of infection; removal of the implant was necessary in three cases due to mobilization of the stem and oversized implants. In six cases, bone resorption was seen at the level of the prosthetic collar and it was in all cases asymptomatic. CONCLUSIONS: The results of this study suggest that the use of prostheses, if well positioned, is a valid solution in the treatment of secondary arthritis and fractures of the radial head with poor prognosis, with good results in the reduction of pain, recovery of movement and improved quality of life. PMID- 28808983 TI - Ability and sex differences in spatial thinking: What does the mental rotation test really measure? AB - Spatial ability tests are often interpreted as measuring facility with imagined spatial transformations of objects. But some spatial ability tests can be solved by analytic strategies as well as imagery transformation strategies. In the present study, participants gave verbal protocols while completing items on the Vandenberg and Kuse (Perceptual & Motor Skills, 4, 599-604, 1978) mental rotation test, and/or reported the strategies they had used on the test. Most participants used both imagery transformation and analytic strategies (i.e., feature-based, orientation-independent strategies) to solve the test items. Use of one analytic strategy, the global-shape strategy, was positively correlated with accuracy. Specifically, some of the most successful students used this strategy to eliminate answer choices, reducing the need for mental imagery. Men outperformed women, as is typical on this test, and were more likely than women to use the global-shape strategy, in particular, and more holistic strategies, in general. These results argue against the mental rotation test as a measure of spatial imagery alone and suggest that the ability to discover and use more efficient analytic strategies may be an important additional component of what this test measures. PMID- 28808985 TI - Hemostatic Radiotherapy Used Twice for Inoperable Progressive Gastric Cancer with Bleeding. PMID- 28808984 TI - Multiple Gas-Phase Conformations of a Synthetic Linear Poly(acrylamide) Polymer Observed Using Ion Mobility-Mass Spectrometry. AB - Ion mobility-mass spectrometry (IM-MS) has emerged as a powerful separation and identification tool to characterize synthetic polymer mixtures and topologies (linear, cyclic, star-shaped,...). Electrospray coupled to IM-MS already revealed the coexistence of several charge state-dependent conformations for a single charge state of biomolecules with strong intramolecular interactions, even when limited resolving power IM-MS instruments were used. For synthetic polymers, the sample's polydispersity allows the observation of several chain lengths. A unique collision cross-section (CCS) trend is usually observed when increasing the degree of polymerization (DP) at constant charge state, allowing the deciphering of different polymer topologies. In this paper, we report multiple coexisting CCS trends when increasing the DP at constant charge state for linear poly(acrylamide) PAAm in the gas phase. This is similar to observations on peptides and proteins. Biomolecules show in addition population changes when collisionally heating the ions. In the case of synthetic PAAm, fragmentation occurred before reaching the energy for conformation conversion. These observations, which were made on two different IM-MS instruments (SYNAPT G2 HDMS and high resolution multi-pass cyclic T-Wave prototype from Waters), limit the use of ion mobility for synthetic polymer topology interpretations to polymers where unique CCS values are observed for each DP at constant charge state. Graphical Abstract ?. PMID- 28808986 TI - Interaction Effects in Assembly of Magnetic Nanoparticles. AB - A specific absorption rate of a dilute assembly of various random clusters of iron oxide nanoparticles in alternating magnetic field has been calculated using Landau-Lifshitz stochastic equation. This approach simultaneously takes into account both the presence of thermal fluctuations of the nanoparticle magnetic moments and magneto-dipole interaction between the nanoparticles of the clusters. It is shown that for usual 3D clusters, the intensity of the magneto-dipole interaction is determined mainly by the cluster packing density eta = N p V/V cl , where N p is the average number of the particles in the cluster, V is the nanoparticle volume, and V cl is the cluster volume. The area of the low frequency hysteresis loop and the assembly-specific absorption rate have been found to be considerably reduced when the packing density of the clusters increases in the range of 0.005 <= eta < 0.4. The dependence of the specific absorption rate on the mean nanoparticle diameter is retained with an increase of eta, but becomes less pronounced. For fractal clusters of nanoparticles, which arise in biological media, in addition to a considerable reduction of the absorption rate, the absorption maximum is shifted to smaller particle diameters. It is found also that the specific absorption rate of fractal clusters increases appreciably with an increase of the thickness of nonmagnetic shells at the nanoparticle surfaces. PMID- 28808987 TI - Volume expansion of periaqueductal gray in episodic migraine: a pilot MRI structural imaging study. AB - BACKGROUND: The periaqueductal gray (PAG) dysfunction was recognized in migraine, and the nonspecific PAG lesions were also observed in episodic migraine (EM) recently. However, the PAG volume change was not totally detected in EM up to now. Herein, the aim of this study was to investigate altered PAG volume in EM patients based on high resolution brain structural image. METHODS: The brain structural images were obtained from 18 normal controls (NC), 18 EM patients and 16 chronic migraine (CM) on 3.0 T MR system. PAG template was created based on the ICBM152 gray matter template using MRIcron, and the individual PAG was created by applying the deformation field to the PAG template after structural image segment. One-way analysis of covariance, partial correlation analysis and Receiver operating characteristics (ROC) curve were applied. RESULTS: EM had a larger PAG volume (0.35 +/- 0.02 ml) than that (0.32 +/- 0.02 ml) of NC (P = 0.017). The PAG volume of CM (0.33 +/- 0.02 ml) was negatively related to the VAS score (P = 0.03). ROC analysis demonstrated that PAG volume has higher diagnostic efficacy (AUC, 0.731; Sensitivity, 0.556; Specificity, 0.889) for NC vs. EM compared with that NC vs. CM (AUC, 0.634; Sensitivity, 0.438; Specificity, 0.833) and EM vs. CM (AUC, 0.618; Sensitivity, 0.813; Specificity, 0.556). CONCLUSION: PAG volume expansion may be the direct impairment evidence on the brain in EM, and could be considered as a diagnostic and evaluated imaging biomarker in migraine. PMID- 28808988 TI - Transoral Resection of Human Papillomavirus (HPV)-Positive Squamous Cell Carcinoma of the Oropharynx: Outcomes with and Without Adjuvant Therapy. AB - BACKGROUND: With the rise of oropharyngeal squamous cell carcinoma associated with human papillomavirus (HPV), appropriate treatment strategies continue to be tailored toward minimizing treatment while preserving oncologic outcomes. This study aimed to compare the outcomes for those undergoing transoral resection with or without adjuvant therapy for HPV-related oropharyngeal carcinoma. METHODS: A case-match cohort analysis was performed at two institutions on patients with HPV related oropharyngeal squamous cell carcinoma. All the subjects underwent transoral surgery and neck dissection. The patients treated with surgery alone were matched 1:1 to those treated with surgery and adjuvant therapy using two groups identified as confounders: T-stage (T1/2 or T3/4) and number of pathologically positive lymph nodes (<=4 or >4). RESULTS: The study identified 105 matched pairs, with a median follow-up period of 42 months (range 3.1-102.3 months). The patients were staged as T1/T2 (86%) or T3/4 (14%). Each group had five patients with more than four positive lymph nodes. Adjuvant therapy significantly improved disease-free survival (hazard ratio [HR] 0.067; 95% confidence interval [CI] 0.01-0.62) and was associated with a lower risk of local and regional recurrence (risk ratio [RR] 0.096; 95% CI 0.02-0.47). No difference in disease-specific survival (HR 0.22; 95% CI 0.02-2.57) or overall survival (HR 0.18; 95% CI 0.01-2.4) was observed with the addition of adjuvant therapy. The risk of the gastrostomy tube was higher for those receiving adjuvant therapy (RR 7.3; 95% CI 2.6-20.6). CONCLUSIONS: Transoral surgery is an effective approach for the treatment of HPV-related oropharyngeal carcinoma. The addition of adjuvant therapy appears to decrease the risk of recurrence and improve disease free survival but may not significantly improve overall survival. PMID- 28808989 TI - Can we reliably predict the level of anticoagulation after enoxaparin injection in elderly patients with renal failure? AB - OBJECTIVES: The aim of this study was to evaluate the activity of anti-activated factor X (anti-Xa) in patients with different degrees of chronic renal failure (CRF), treated with therapeutic doses of low molecular weight heparin. DESIGN: This prospective study evaluated the effect of age, renal function, BMI, gender, in determining the efficacy and safety of treatment with enoxaparin, evaluated by assessing the anti-Xa. The therapeutic anticoagulant range was set between 0.20 and 0.70 U/mL. SETTING: Two hospital geriatric units. PARTICIPANTS: 98 patients (64 men, 34 women, mean age 82 years) with CRF, treated with enoxaparin at therapeutic dosage, for deep vein thrombosis or acute coronary syndrome. MEASUREMENTS: Anti-Xa was assessed 4 h after the third administration of LMWH using Chromogenix test. Renal function was assessed by calculating creatinine clearance according to Cockcroft formula. RESULTS: The dose of enoxaparin ranged between 53 and 200 U/kg; total 4000-16000 U/day. The mean anti-Xa was 0.41 U/mL (95% CI 0.36-0.45). Multiple regression analysis selected only the dose of enoxaparin, but not age, creatinine clearance, BMI, gender, as a predictor of anti-Xa serum levels. In seven patients anti-Xa was above the range but none of them received more than 150 U/Kg enoxaparin (100 U/kg if creatinine clearance <30 mL/min). Ten patients (eight men, two women) showed suboptimal levels of anti-Xa, regardless enoxaparin dose or creatinine clearance. CONCLUSION: Enoxaparin dose reduction according to renal function decreases the risk of overdosing and potentially the risk of bleeding. The risk of under dosing seems less predictable; therefore, anti-Xa assay may be useful in severe clinical situations that require higher anticoagulant activity. PMID- 28808990 TI - Onychomadesis in a 9-month-old boy with hand-foot-mouth disease. AB - BACKGROUND: Nail abnormalities in childhood are generally uncommon. Recently, onychomadesis is described as a rare, late complication of hand-foot-mouth disease, which is a viral illness commonly seen in the pediatric age group. It is therefore important to elucidate the presentation of this entity, especially in the context of the hand-foot-mouth disease. CASE PRESENTATION: We report a case of onychomadesis in a 9-month old Lebanese boy who presented to the emergency department with rapidly progressing nail changes involving all four extremities. These changes appeared few days after the healing of cutaneous lesions of hand foot-mouth disease. CONCLUSIONS: This case highlights the importance of recognizing the association between onychomadesis and hand-foot-mouth disease in order to avoid unnecessary treatment and to reassure the patient's parents. PMID- 28808991 TI - Light Chain (AL) Amyloidosis: The Journey to Diagnosis. AB - BACKGROUND: Light chain (AL) amyloidosis is a rare, complex disease associated with significant morbidity and mortality. Delays in diagnosis are common and may have detrimental consequences on patients' prognosis. Too little is known regarding the patient journey to diagnosis. OBJECTIVE: The objective of this study was to describe the patient-reported journey to a correct diagnosis for AL amyloidosis. METHODS: Using a mixed-methods approach, data were collected from clinician (n = 4) and patient (n = 10) interviews and a survey of community-based patients with AL amyloidosis (n = 341). Data were used to document the patient experience between the onset of symptoms and the receipt of a diagnosis. RESULTS: Delays in diagnosis were common. Qualitative and quantitative data indicated that initial symptoms were varied and similar to other more prevalent diseases. Two themes regarding the journey to diagnosis emerged: (1) barriers to an early diagnosis; and (2) the emotional toll of the journey. Time to diagnosis was heavily influenced by how patients interpreted their initial symptoms, whether they sought early medical help, and challenges associated with making differential diagnoses. Survey results indicate that patients with primary cardiac involvement were more likely to receive a delayed diagnosis than those with primary kidney involvement. Patients described mixed emotions associated with the eventual diagnosis of AL amyloidosis. CONCLUSIONS: These data support a need for better early identification and support for patients seeking a diagnosis. Increasing clinician awareness may reduce the time to diagnosis. Additional research is needed to identify optimal diagnostic testing to reduce delays in treatment initiation and subsequent severe impacts on health. PMID- 28808992 TI - A Photoaffinity Labeling-Based Chemoproteomics Strategy for Unbiased Target Deconvolution of Small Molecule Drug Candidates. AB - The combination of photoaffinity labeling (PAL) and quantitative chemoproteomics enables the comprehensive, unbiased determination of protein interaction profiles to support target identification of bioactive small molecules. This approach is amenable to cells in culture and compatible with pharmacologically relevant transmembrane target classes like G-protein coupled receptors and ions channels which have been notoriously hard to access by conventional chemoproteomics approaches. Here, we describe a strategy that combines PAL probe titration and competition with excess parental compounds with the goal of enabling the identification of specific interactors as well as assessing the functional relevance of a binding event for the phenotype under investigation. PMID- 28808994 TI - Monitoring Dynamic Changes of the Cell Surface Glycoproteome by Quantitative Proteomics. AB - The analysis of the cell surface accessible proteome provides invaluable information about cellular identity, cellular functions, and interactions. Cell surface labeling in combination with quantitative proteomics enables the unbiased identification and quantification of cell surface proteins. We describe a fast, efficient, and robust protocol for the enrichment of the N-linked plasma membrane glycoproteome and subsequent analysis by mass spectrometry. Precise and multiplexed quantification of relative changes of cell surface protein presentation is enabled by an isobaric labeling strategy. PMID- 28808995 TI - High-Resolution Parallel Reaction Monitoring with Electron Transfer Dissociation for Middle-Down Proteomics: An Application to Study the Quantitative Changes Induced by Histone Modifying Enzyme Inhibitors and Activators. AB - With the advent of new methodologies, proteomics-based assays are increasingly used to study the efficacy of drugs on a molecular level. For these studies to be meaningful, the proteomics assays need to be sensitive, selective, accurate, and reproducible. This is often accomplished through a targeted approach, either using single or multiple reaction monitoring (SRM/MRM) or, more recently, parallel reaction monitoring (PRM). In PRM, the parallel detection of all product ions in a high-resolution mass spectrometer affords higher selectivity than SRM/MRM. PRM is thus better suited to analyze peptides larger than 2 kDa. Similar to SRM/MRM, PRM provides sensitive, accurate, and reproducible quantitative data. Here, we present a specific PRM method to characterize the effects of histone modifying enzyme drugs such as histone deacetylase inhibitors (HDAC) on the posttranslational modifications of histones, in a quantitative manner. More specifically, we characterize the heavily modified N-terminal tail of histone H3 after treatment with the HDAC inhibitor butyric acid, and monitor the acetylation and methylation events after treatment. To take most advantage of the multiply charged N-terminal histone peptides that are generated by an endoproteinase GluC digestion, we use electron transfer dissociation (ETD) as the method of MS/MS fragmentation. This provides high sequence coverage for the modified peptides. The methodology is not limited to HDAC inhibitors, and can be used for any modifying enzyme. In fact, it can even be expanded beyond histone analyses. To give guidance for the development of a PRM assay, we present here HDAC inhibited H3 histone N-terminal tails as an example. PMID- 28808993 TI - Multiplexed Liquid Chromatography-Multiple Reaction Monitoring Mass Spectrometry Quantification of Cancer Signaling Proteins. AB - Quantitative evaluation of protein expression across multiple cancer-related signaling pathways (e.g., Wnt/beta-catenin, TGF-beta, receptor tyrosine kinases (RTK), MAP kinases, NF-kappaB, and apoptosis) in tumor tissues may enable the development of a molecular profile for each individual tumor that can aid in the selection of appropriate targeted cancer therapies. Here, we describe the development of a broadly applicable protocol to develop and implement quantitative mass spectrometry assays using cell line models and frozen tissue specimens from colon cancer patients. Cell lines are used to develop peptide based assays for protein quantification, which are incorporated into a method based on SDS-PAGE protein fractionation, in-gel digestion, and liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MRM/MS). This analytical platform is then applied to frozen tumor tissues. This protocol can be broadly applied to the study of human disease using multiplexed LC-MRM assays. PMID- 28808996 TI - Preparation and Immunoaffinity Depletion of Fresh Frozen Tissue Homogenates for Mass Spectrometry-Based Proteomics in the Context of Drug Target/Biomarker Discovery. AB - The discovery of novel drug targets and biomarkers via mass spectrometry (MS) based proteomic analysis of clinical specimens has proven to be challenging. The wide dynamic range of protein concentration in clinical specimens and the high background/noise originating from highly abundant proteins in tissue homogenates and serum/plasma encompass two major analytical obstacles. Immunoaffinity depletion of highly abundant blood-derived proteins from serum/plasma is a well established approach adopted by numerous researchers; however, the utilization of this technique for immunodepletion of tissue homogenates obtained from fresh frozen clinical specimens is lacking. We first developed immunoaffinity depletion of highly abundant blood-derived proteins from tissue homogenates, using renal cell carcinoma as a model disease, and followed this study by applying it to different tissue types. Tissue homogenate immunoaffinity depletion of highly abundant proteins may be equally important as is the recognized need for depletion of serum/plasma, enabling more sensitive MS-based discovery of novel drug targets, and/or clinical biomarkers from complex clinical samples. Provided is a detailed protocol designed to guide the researcher through the preparation and immunoaffinity depletion of fresh frozen tissue homogenates for two dimensional liquid chromatography, tandem mass spectrometry (2D-LC-MS/MS)-based molecular profiling of tissue specimens in the context of drug target and/or biomarker discovery. PMID- 28808997 TI - Target Identification Using Cell Permeable and Cleavable Chloroalkane Derivatized Small Molecules. AB - An important aspect for gaining functional insight into the activity of small molecules revealed through phenotypic screening is the identification of their interacting proteins. Yet, isolating and validating these interacting proteins remains difficult. Here, we present a new approach utilizing a chloroalkane (CA) moiety capture handle, which can be chemically attached to small molecules to isolate their respective protein targets. Derivatization of small molecules with the CA moiety has been shown to not significantly impact their cell permeability or potency, allowing for phenotypic validation of the derivatized small molecule prior to capture. The retention of cell permeability also allows for treatment of live cells with the derivatized small molecule and the CA moiety enables rapid covalent capture onto HaloTag coated magnetic beads. Additionally, several options are available for the elution of interacting proteins, including chemical cleavage of the CA moiety, competitive elution using excess unmodified small molecule, or sodium dodecyl sulfate (SDS) elution. These features taken together yield a highly robust and efficient process for target identification, including capture of weak or low abundance interactors. PMID- 28808998 TI - Microfluidics-Mass Spectrometry of Protein-Carbohydrate Interactions: Applications to the Development of Therapeutics and Biomarker Discovery. AB - The functional interactions of carbohydrates and their protein receptors are the basis of biological events critical to the evolution of pathological states. Hence, for the past years, such interactions have become the focus of research for the development of therapeutics and discovery of novel glycan biomarkers based on their binding affinity. Due to the high sensitivity, throughput, reproducibility, and capability to ionize minor species in heterogeneous mixtures, microfluidics-mass spectrometry (MS) has recently emerged as a method of choice in protein-glycan interactomics. In this chapter, a straightforward microfluidics-based MS methodology for the assessment of protein-glycan interactions is presented. The general protocol encompasses: (1) submission of the interacting partners to a binding assay under conditions mimicking the in vivo environment; and (2) screening of the reaction products and their structural characterization by fully automated chip-nanoelectrospray (nanoESI) MS and multistage MS. The first section of the chapter is devoted to describing a method that enables the study of protein-oligosaccharide interactions by chip-nanoESI quadrupole time-of-flight (QTOF) MS and top-down complex analysis by collision induced dissociation (CID). This section provides the protocol for the determination of the complex formed by standard beta-lactoglobulin (BLG) with maltohexaose (Glc6) and recommends as a concrete application the study of the interaction between BLG extracted from human milk with Glc6, considered a ligand able to reduce the allergenicity of this protein. The second part is dedicated to presenting the protocols for the binding assay followed by chip-nanoESI ion trap (ITMS) and electron transfer dissociation (ETD) in combination with CID for protein-ganglioside interactions, using as an example the B subunit of cholera toxin (Ctb5) in interaction with comercially available GM1 species. The methodology described may be successfully applied to native ganglioside mixtures from human brain, in particular for discovery of biomarkers on the basis of their binding affinity. PMID- 28808999 TI - Studying Protein-Protein Interactions by Biotin AP-Tagged Pulldown and LTQ Orbitrap Mass Spectrometry. AB - The study of protein-protein interactions represents a key aspect of biological research. Identifying unknown protein binding partners using mass spectrometry (MS)-based proteomics has evolved into an indispensable strategy in drug discovery. The classic approach of immunoprecipitation with specific antibodies against the proteins of interest has limitations, such as the need for immunoprecipitation-qualified antibody. The biotin AP-tag pull-down system has the advantage of high specificity, ease of use, and no requirement for antibody. It is based on the high specificity, high affinity interaction between biotin and streptavidin. After pulldown, in-gel tryptic digestion and tandem mass spectrometry (MS/MS) analysis of sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) protein bands can be performed. In this work, we provide protocols that can be used for the identification of proteins that interact with FOXM1, a protein that has recently emerged as a potential biomarker and drug target in oncotherapy, as an example. We focus on the pull-down procedure and assess the efficacy of the pulldown with known FOXM1 interactors such as beta-catenin. We use a high performance LTQ Orbitrap MSn system that combines rapid LTQ ion trap data acquisition with high mass accuracy Orbitrap analysis to identify the interacting proteins. PMID- 28809000 TI - Post-Translational Modification Profiling-Functional Proteomics for the Analysis of Immune Regulation. AB - Posttranslational modifications (PTMs) of proteins are an integral part of major cellular regulatory mechanisms dictating protein function, localization, and stability. The capacity to screen PTMs using protein microarrays has advanced our ability to identify their targets and regulatory role. This chapter discusses a unique procedure that combines functional extract-based activity assay with large scale screening utilities of protein microarrays. This "PTM-profiling" system offers advantages in quantitatively identifying modifications in an unbiased manner in the context of specific cellular conditions. While the possibilities of studying PTMs in different settings are enormous, the immune system presents an attractive model for studying the effects of perturbations in PTMs, and specifically the ubiquitin system, as these were already implicated in both immune function and dysfunction. This chapter discusses the significance of PTM profiling in addressing basic questions in immunology. We describe detailed protocols for the preparation of functional cell extracts from immune cell cultures, following differentiation or induced signals, and screening PTMs on protein arrays, as well as basic guidelines for data analysis and interpretation. PMID- 28809001 TI - Reverse Phase Protein Arrays and Drug Discovery. AB - Reverse Phase Protein Arrays (RPPA) represent a sensitive antibody-based proteomic approach, which enables simultaneous quantification of the abundance of multiple proteins and posttranslational modifications across multiple samples. Here, we provide protocols for RPPA performed on two distinct protein-binding substrates associated with two most commonly used RPPA platform technologies. We compare and contrast the respective advantages and limitations of each platform within the context of drug discovery applications. PMID- 28809002 TI - Probing Protein Kinase-ATP Interactions Using a Fluorescent ATP Analog. AB - Eukaryotic protein kinases are an intensely investigated class of enzymes which have garnered attention due to their usefulness as drug targets. Determining the regulation of ATP binding to a protein kinase is not only critical for understanding function in a cellular context but also for designing kinase specific molecular inhibitors. Here, we provide a general procedure for characterizing ATP binding to eukaryotic protein kinases. The protocol can be adapted to identify the conditions under which a particular kinase is activated. The approach is simple, requiring only a fluorescent ATP analog such as TNP-ATP or MANT-ATP and an instrument to monitor changes in fluorescence. Although the interaction kinetics between a kinase and a given ATP analog may differ from that of native ATP, this disadvantage is offset by the ease of performing and interpreting this assay. Importantly, it can be optimized to probe a large variety of conditions under which the kinase-nucleotide binding might be affected. PMID- 28809003 TI - Preparation of Disease-Related Protein Assemblies for Single Particle Electron Microscopy. AB - Electron microscopy (EM) is a rapidly growing area of structural biology that permits us to decode biological assemblies at the nanoscale. To examine biological materials for single particle EM analysis, purified assemblies must be obtained using biochemical separation techniques. Here, we describe effective methodologies for isolating histidine (his)-tagged protein assemblies from the nucleus of disease-relevant cell lines. We further demonstrate how isolated assemblies are visualized using single particle EM techniques and provide representative results for each step in the process. PMID- 28809004 TI - Identification of Lipid Binding Modulators Using the Protein-Lipid Overlay Assay. AB - The protein-lipid overlay assay is an inexpensive, easy-to-implement, and high throughput methodology that employs nitrocellulose membranes to immobilize lipids in order to rapid screen and identify protein-lipid interactions. In this chapter, we show how this methodology can identify potential modulators of protein-lipid interactions by screening water-soluble lipid competitors or even the introduction of pH changes during the binding assay to identify pH-dependent lipid binding events. PMID- 28809005 TI - Resazurin Live Cell Assay: Setup and Fine-Tuning for Reliable Cytotoxicity Results. AB - In vitro cytotoxicity tests allow for fast and inexpensive screening of drug efficacy prior to in vivo studies. The resazurin assay (commercialized as Alamar Blue(r)) has been extensively utilized for this purpose in 2D and 3D cell cultures, and high-throughput screening. However, improper or lack of assay validation can generate unreliable results and limit reproducibility. Herein, we report a detailed protocol for the optimization of the resazurin assay to determine relevant analytical (limits of detection, quantification, and linear range) and biological (growth kinetics) parameters, and, thus, provide accurate cytotoxicity results. Fine-tuning of the resazurin assay will allow accurate and fast quantification of cytotoxicity for drug discovery. Unlike more complicated methods (e.g., mass spectrometry), this assay utilizes fluorescence spectroscopy and, thus, provides a less costly alternative to observe changes in the reductase proteome of the cells. PMID- 28809007 TI - Method to Identify Silent Codon Mutations That May Alter Peptide Elongation Kinetics and Co-translational Protein Folding. AB - Due to the redundancy of the protein genetic code, mutational changes in the second or third nucleotide of an existing codon may not change the amino acid specification of the resulting modified codon. When peptide primary sequence is unchanged by mutation, that mutation is assumed to have no functional consequences. However, for one key gene involved in drug transport, MDR-1, several silent, synonymous mutations have been shown to alter protein structure and substrate affinity (Kimchi-Sarfaty et al., Science 315:525-528, 2007). The mechanism of these changes, in the absence of primary amino acid sequence changes, appears to be the change in abundance of the transfer RNA molecules complementary to the mutated, although synonymous, new codon. Transfer RNA abundance is proportional to the frequency of each codon as found in human protein coding DNA (Sharp et al., Nucleic Acids Res 14(13):5125-5143, 1986). These frequencies have been mapped for many thousands of human proteins (Nakamura et al., Nucleic Acids Res 28:292, 2000). This method analyzes silent codon mutations in whole genome data. Where there are large changes in codon frequency resulting from codon sequence mutation, the affected proteins are mapped to potential disease pathways, in the context of clinical phenotypes associated with the patient genome data. PMID- 28809006 TI - Exploring Protein-Protein Interactions as Drug Targets for Anti-cancer Therapy with In Silico Workflows. AB - We describe a computational protocol to aid the design of small molecule and peptide drugs that target protein-protein interactions, particularly for anti cancer therapy. To achieve this goal, we explore multiple strategies, including finding binding hot spots, incorporating chemical similarity and bioactivity data, and sampling similar binding sites from homologous protein complexes. We demonstrate how to combine existing interdisciplinary resources with examples of semi-automated workflows. Finally, we discuss several major problems, including the occurrence of drug-resistant mutations, drug promiscuity, and the design of dual-effect inhibitors. PMID- 28809008 TI - In Silico Design of Anticancer Peptides. AB - In the past few years, small peptides having anticancer properties have emerged as a potential avenue for cancer therapy. Compared to current anti-cancer chemotherapeutic drugs (or small molecules), anticancer peptides (ACPs) have numerous advantageous properties, such as high specificity, low production cost, high tumor penetration, ease of synthesis and modification. However, in wet lab setups, identification and characterization of novel ACPs is a time-consuming and labor-intensive process. Therefore, in silico designing of anticancer peptides is beneficial, prior to their synthesis and characterization. This approach is less time consuming and more cost-effective. In this chapter, we discuss a web-based tool, AntiCP (http://crdd.osdd.net/raghava/anticp/), for designing ACPs. PMID- 28809009 TI - Docking and Virtual Screening in Drug Discovery. AB - Stages in a typical drug discovery organization include target selection, hit identification, lead optimization, preclinical and clinical studies. Hit identification and lead optimization are very much intertwined with computational modeling. Structure-based virtual screening (VS) has been a staple for more than a decade now in drug discovery with its underlying computational technique, docking, extensively studied. Depending on the objective, the parameters for VS may change, but the overall protocol is very straightforward. The idea behind VS is that a library of small compounds are docked into the binding pocket of a protein (e.g., receptor, enzyme), a number of solutions per molecule, among the top-ranked, are being returned, and a choice is made on the fraction of compounds to be moved forward for testing toward hit identification. The underlying principle of VS is that it differentiates between active and inactive compounds, thus reducing the number of molecules moving forward and possibly offering a complementary tool to high-throughput screening (HTS). Best practices in library selection, target preparation and refinement, criteria in selecting the most appropriate docking/scoring scheme, and a step-wise approach in performing Glide VS are discussed. PMID- 28809010 TI - Bioinformatics Resources for Interpreting Proteomics Mass Spectrometry Data. AB - Developments in mass spectrometry (MS) instrumentation have supported the advance of a variety of proteomic technologies that have enabled scientists to assess differences between healthy and diseased states. In particular, the ability to identify altered biological processes in a cell has led to the identification of novel drug targets, the development of more effective therapeutic drugs, and the growth of new diagnostic approaches and tools for personalized medicine applications. Nevertheless, large-scale proteomic data generated by modern mass spectrometers are extremely complex and necessitate equally complex bioinformatics tools and computational algorithms for their interpretation. A vast number of commercial and public resources have been developed for this purpose, often leaving the researcher perplexed at the overwhelming list of choices that exist. To address this challenge, the aim of this chapter is to provide a roadmap to the basic steps that are involved in mass spectrometry data acquisition and processing, and to describe the most common tools that are available for placing the results in biological context. PMID- 28809011 TI - Some Thoughts on Experimental Design. AB - Perhaps even more important than the techniques themselves are the quality of the biological questions asked and the design of the experiments devised to answer them. This chapter summarizes some of the key issues and also touches on how the same principles affect scholarly use of the scientific literature and good peer reviewing practices. PMID- 28809012 TI - Comparative Genomics as a Foundation for Evo-Devo Studies in Birds. AB - Developmental genomics is a rapidly growing field, and high-quality genomes are a useful foundation for comparative developmental studies. A high-quality genome forms an essential reference onto which the data from numerous assays and experiments, including ChIP-seq, ATAC-seq, and RNA-seq, can be mapped. A genome also streamlines and simplifies the development of primers used to amplify putative regulatory regions for enhancer screens, cDNA probes for in situ hybridization, microRNAs (miRNAs) or short hairpin RNAs (shRNA) for RNA interference (RNAi) knockdowns, mRNAs for misexpression studies, and even guide RNAs (gRNAs) for CRISPR knockouts. Finally, much can be gleaned from comparative genomics alone, including the identification of highly conserved putative regulatory regions. This chapter provides an overview of laboratory and bioinformatics protocols for DNA extraction, library preparation, library quantification, and genome assembly, from fresh or frozen tissue to a draft avian genome. Generating a high-quality draft genome can provide a developmental research group with excellent resources for their study organism, opening the doors to many additional assays and experiments. PMID- 28809013 TI - A Step-by-Step Guide to Assemble a Reptilian Genome. AB - Multiple technologies and software are now available facilitating the de novo sequencing and assembly of any vertebrate genome. Yet the quality of most available sequenced genomes is substantially poorer than that of the golden standard in the field: the human genome. Here, we present a step-by-step protocol for the successful sequencing and assembly of a high-quality snake genome that can be applied to any other reptilian or avian species. We combine the great sequencing depth and accuracy of short reads with the use of different insert size libraries for extended scaffolding followed by optical mapping. We show that this procedure improved the corn snake scaffold N50 from 3.7 kbp to 1.4 Mbp, currently making it one of the snake genomes with the longest scaffolds. Short guidelines are also given on the extraction of long DNA molecules from reptilian blood and the necessary modifications in DNA extraction protocols. This chapter is accompanied by a website ( www.reptilomics.org/stepbystep.html ), where we provide links to the suggested software, examples of input and output files, and running parameters. PMID- 28809014 TI - Genomic and Transcriptomic Analyses of Avian Sex Chromosomes and Sex-Linked Genes. AB - Sex chromosomes and sex-linked genes usually show unusual features comparing to the rest of the genome and thus are of particular interests to evolutionary and developmental biologists. Here we describe recently developed bioinformatic methods for identifying sex-linked sequences, in a genome without priori linkage information. Some are developed during our course of studying avian genomes. These methods require sequence data, either assembled draft genome or raw sequences derived from the heterogametic sex (e.g., a female bird or a male mammal). Their application is not restricted to birds but can be used for any species with a sex chromosome pair that has diverged from each other for a substantial degree. PMID- 28809015 TI - Systems Biology Analyses in Chicken: Workflow for Transcriptome and ChIP-Seq Analyses Using the Chicken Skin Paradigm. AB - With advances in molecular biology, various biological phenomena can now be explored at higher resolution using mRNA sequencing (RNA-Seq) and chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq), two powerful high-throughput next-generation sequencing (NGS) technologies. While methods are used widely in mouse, human, etc., less information is available in other animals, such as the chicken. Here we assemble a workflow of the RNA-Seq and ChIP-Seq analyses for the chicken studies using chicken skin appendage tissue as an example. We present guidelines for RNA-Seq quality control, alignment, quantification, normalization, and differentially expressed gene analysis. In the meantime, we outline a bioinformatics pipeline for ChIP-Seq quality control, alignment, peak calling, super-enhancer identification, and differential enrichment analysis. PMID- 28809016 TI - Application of a CAGE Method to an Avian Development Study. AB - Cap analysis of gene expression (CAGE) is a convenient approach for genome-wide identification of promoter regions at single base-pair resolution level and accurate expression estimation of the corresponding transcripts. Depending on the initial biomaterial amount and sequencing technology, different computational pipelines for data processing are available, as well as variations of the CAGE protocol that improve sensitivity and accuracy. Therefore, this chapter elucidates the key steps of sample preparation, sequencing, and data analysis via an example of a promoter expression estimation study in chicken development. We also describe the applicability of this approach for studying other avian and reptilian species. PMID- 28809018 TI - Fluorescent Quail: A Transgenic Model System for the Dynamic Study of Avian Development. AB - Real-time four-dimensional (4D, xyzt) imaging of cultured avian embryos is an ideal method for investigating the complex movements of cells and tissues during early morphogenesis. While methods that transiently label cells, such as electroporation, are highly useful for dynamic imaging, they can also be limiting due to the number and type of cells that can be effectively targeted. In contrast, the heritable, stable, and long-term expression of a fluorescent protein driven by the exogenous promoter of a transgene overcomes these challenges. We have used lentiviral vectors to produce several novel transgenic quail lines that express fluorescent proteins either ubiquitously or in a cell specific manner. These lines have proven to be useful models for dynamic imaging and analysis. Here, we provide detailed protocols for generating transgenic quail with the emphasis on producing high titer lentivirus , effectively introducing it into the early embryo and efficiently screening for G1 founder birds . PMID- 28809017 TI - CRISPR/Cas9 in the Chicken Embryo. AB - Genome editing is driving a revolution in the biomedical sciences that carries the promise for future treatments of genetic diseases. The CRISPR/Cas9 system of RNA-guided genome editing has been successfully applied to modify the genome of a wide spectrum of organisms. We recently showed that this technique can be combined with in vivo electroporation to inhibit the function of genes of interest in somatic cells of the developing chicken embryo. We present here a simplified version of the previously described technique that leads to effective gene loss-of-function. PMID- 28809019 TI - Lentiviral-Mediated Transgenesis in Songbirds. AB - Transgenesis involves the insertion of an exogenous gene into an animal's genome, which allows the identification of the expressed phenotypes in brain function or behavior. Lentiviral-mediated transgenesis offers unique transduction potency making it possible to deliver and stably integrate transgenes into a wide variety of dividing and nondividing cells. The ability to establish long-term expression of such transgenes allows their use for transgenesis which is especially useful in organisms lacking quality pluripotent stem cell lines and which is otherwise difficult to produce via traditional pronuclear microinjection, such as songbirds. Here we describe a protocol to generate the transgenic songbird, the zebra finch, by producing and inserting lentiviral-mediated transgene into the blastoderm of freshly laid eggs. This protocol includes procedures for production of lentiviral vectors, injection of a virus into zebra finch embryos, and postinjection care. The implementation of the songbird transgenic approach provides a leap toward basic and translational neuroscience that uses an animal model for speech and language and their pathologies. Additionally, the highly quantifiable song behavior, combined with a well-characterized song circuitry, offers an exciting opportunity to develop therapeutic strategies for neurological disorders. PMID- 28809020 TI - In Ovo Electroporation Methods in Chick Embryos. AB - To elucidate a gene function, in vivo analysis is indispensable. We can carry out gain and loss of function experiment of a gene of interest by electroporation in ovo and ex ovo culture system on early-stage and advanced-stage chick embryos, respectively. In this section, we introduce in/ex ovo electroporation methods for the development of the chick central nervous system and visual system investigation. PMID- 28809021 TI - Genetic Manipulation of the Avian Urogenital System Using In Ovo Electroporation. AB - One of the advantages of the avian embryo as an experimental model is its in ovo development and hence accessibility for genetic manipulation. Electroporation has been used extensively in the past to study gene function in chicken and quail embryos . Readily accessible tissues such as the neural tube, somites, and limb bud, in particular, have been targeted. However, more inaccessible tissues, such as the embryonic urogenital system , have proven more challenging to study. Here, we describe the use of in ovo electroporation of TOL2 vectors or RCASBP avian viral vectors for the rapid functional analysis of genes involved in avian sex determination and urogenital development . In the context of the developing urogenital system , these vectors have inherent advantages and disadvantages, which will be considered here. Either vector can both be used for mis-expressing a gene and for targeting endogenous gene knockdown via expression of short hairpin RNAs (shRNAs). Both of these vectors integrate into the genome and are hence spread throughout developing tissues. Going forward, electroporation could be combined with CRISPR/Cas9 technology for targeted genome editing in the avian urogenital system . PMID- 28809022 TI - Enhancer Analyses Using Chicken Embryo Electroporation. AB - Chicken embryo electroporation is a powerful tool used to identify and analyze enhancers involved in developmental gene regulation. In this chapter, the basic procedures and underlying principles of enhancer analysis using chicken embryo electroporation are described in the following steps: (1) identification of enhancers in a wide genomic region, (2) determination of the full enhancer region, (3) definition of the core enhancer regions, and (4) analysis of a functional transcription factor binding sequences in the core region. PMID- 28809023 TI - Transgene Introduction into the Chick Limb Bud by Electroporation. AB - Electroporation enables delivering bionanomolecules, such as DNAs, RNAs, siRNAs, and morpholinos, into chick embryos in a spatially and temporally restricted fashion. Recent advances in electroporation techniques allowed us to deliver transgenes into the restricted area of the limb bud and to analyze the function of the enhancers in the limb field. Here, we describe the introduction of transgenes by electroporation in the limb field and its application on enhancer analysis. PMID- 28809024 TI - Chicken Induced Pluripotent Stem Cells: Establishment and Characterization. AB - In mammals, the introduction of the OSKM (Oct4, Sox2, Klf4, and c-Myc) genes into somatic cells has allowed generating induced pluripotent stem (iPS) cells. So far, this process has been only clearly demonstrated in mammals. Here, using chicken as an avian model, we describe a set of protocols allowing the establishment, characterization, maintenance, differentiation, and injection of putative reprogrammed chicken Induced Pluripotent Stem (iPS) cells. PMID- 28809025 TI - Isolation and Characterization of Chicken Primordial Germ Cells and Their Application in Transgenesis. AB - Primordial germ cells (PGCs), precursors of functional gametes, offer great promise for the use of genetic resources and transgenesis in chickens. PGCs can be isolated from the developing embryo at diverse early stages and are subsequently expandable in vitro. In vitro proliferating chicken PGCs can facilitate the production of efficient germline chimeras and transgenic chickens. Here, we describe methods to isolate and characterize PGCs from chicken embryos and their application to transgenesis. PMID- 28809026 TI - Handling of Gametes for In Vitro Insemination in Birds. AB - A characteristic biological property of avian gamete (e.g., extremely large egg and polyspermic fertilization) does not allow the direct observation of sperm-egg interactions in vitro, but recent research advances make it possible to manipulate the gamete in vitro. Here, we describe the techniques for the handling of gametes required for in vitro fertilization assay. In addition, we also introduce the procedures for sperm-perivitelline membrane assay, intracytoplasmic sperm injection, and ex ovo culture. PMID- 28809027 TI - In Vitro and Ex Ovo Culture of Reptilian and Avian Neural Progenitor Cells. AB - Reptiles and birds have been highlighted as excellent experimental models for the study of developmental biology; however, due to technical limitations in cellular analysis, dynamics of neural stem/progenitor cells of these animals remain unclear. In this chapter, we introduce the protocols for neurosphere culture and ex ovo embryonic culture of developing reptilian and avian embryos, which are modified from the method originally established for rodent embryos. Applications of these techniques provide powerful strategies for the study of comparative neural development of amniotes. PMID- 28809028 TI - Lifting the Veil on Reptile Embryology: The Veiled Chameleon (Chamaeleo calyptratus) as a Model System to Study Reptilian Development. AB - Living amniotes comprise three major phylogenetic lineages: mammals, birds, and non-avian reptiles. Mouse and avian embryos continue to be the primary species used in experimental settings to further our knowledge and understanding of the genetics and embryology of amniotes. In comparison, non-avian reptiles, which constitute up to 40% of all living amniotes, have played a comparatively minor role. Studies of non-avian reptiles are, however, paramount for providing insights into the evolutionary changes that occurred in the transition from reptilian-like amniote ancestors to derived mammalian and avian species. Here, we introduce the Veiled Chameleon, a squamate reptile, as a new experimental model for examining fundamental questions in development, evolution, and disease. PMID- 28809029 TI - Model Clades Versus Model Species: Anolis Lizards as an Integrative Model of Anatomical Evolution. AB - Anolis lizards , known for their replicated patterns of morphological diversification, are widely studied in the fields of evolution and ecology. As a textbook example of adaptive radiation, this genus has supported decades of intense study in natural history, behavior, morphological evolution, and systematics. Following the publication of the A. carolinensis genome, research on Anolis lizards has expanded into new areas, toward obtaining an understanding the developmental and genetic bases of anole diversity. Here, we discuss recent progress in these areas and the burgeoning methodological toolkit that has been used to elucidate the genetic mechanisms underlying anatomical variation in this group. We also highlight the growing number of studies that have used A. carolinensis as the representative squamate in large-scale comparison of amniote evolution and development . Finally, we address one of the largest technical challenges biologists are facing in making Anolis a model for integrative studies of ecology, evolution, development , and genetics, the development of ex-ovo culturing techniques that have broad utility. Ultimately, with the power to ask questions across all biological scales in this diverse genus full, anoles are rapidly becoming a uniquely integrative and powerful biological system. PMID- 28809030 TI - The Feather Model for Chemo- and Radiation Therapy-Induced Tissue Damage. AB - Chemo- and radiation therapy are the main modalities for cancer treatment. A major limiting factor is their toxicity to normal tissue, thus reducing the dose and duration of the therapy. The hair follicle, gastrointestinal tract, and hematopoietic system are among the target organs that often show side effects in cancer therapy . Although these organs are highly mitotic in common, the molecular mechanism of the damage remains unclear. The feather follicle is a fast growing mini-organ, which allows observation and manipulation on each follicle individually. As a model system, the feather follicle is advantageous because of the following reasons: (1) its complex structure is regulated by a set of evolutionarily conserved molecular pathways, thus facilitating the effort to dissect the specific signaling events involved; (2) its morphology allows the continuity of normal-perturbed-normal structure in a single feather, thus "recording" the damaging effect of chemo- and radiation therapy; (3) further histological and molecular analysis of the damage response can be performed on each plucked feather; thus, it is not necessary to sacrifice the experimental animal. Here, we describe methods of applying the feather model to study the molecular mechanism of chemo- and radiation therapy-induced tissue damage. PMID- 28809031 TI - An Early Chick Embryo Culture Device for Extended Continuous Observation. AB - Appropriate mechanical tension of the vitelline membrane as the culture substrate for the early chick embryo is frequently reported to be required for successful in vitro development. Here we describe a modified device, made of anodized aluminum, for in vitro culture which we used for studies of left-right symmetry breaking with emphasis on morphology and gene expression as readouts. The technique allows for easy, high-throughput tissue handling and provides a suitable tension in a stable and easily reproducible manner proven to be suitable for correct molecular left-right patterning and heart looping after long-term culture. PMID- 28809032 TI - A Sensitive and Versatile In Situ Hybridization Protocol for Gene Expression Analysis in Developing Amniote Brains. AB - The detection of specific RNA molecules in embryonic tissues has wide research applications including studying gene expression dynamics in brain development and evolution. Recent advances in sequencing technologies have introduced new animal models to explore the molecular principles underlying the assembly and diversification of brain circuits between different amniote species. Here, we provide a step-by-step protocol for a versatile in situ hybridization method that is immediately applicable to a range of amniote embryos including zebra finch and Madagascar ground gecko, two new model organisms that have rapidly emerged for comparative brain studies over recent years. The sensitive detection of transcripts from low to high abundance expression range using the same platform enables direct comparison of gene of interest among different amniotes, providing high-resolution spatiotemporal information of gene expression to dissect the molecular principles underlying brain evolution. PMID- 28809033 TI - Somitogenesis and Axial Development in Reptiles. AB - Among amniote vertebrates, reptiles display the greatest variation in axial skeleton morphology. Only recently have they been used in gene expression studies of somitogenesis , challenging previous assumptions about the segmentation clock and axial patterning. An increasing number of reptile genomes and transcriptomes are becoming available as next-generation sequencing becomes more affordable. Information regarding gene sequence and structure can be used to design and synthesize labeled riboprobes by in vitro transcription for gene expression analysis by in situ hybridization, thus, enabling the characterization of spatial and temporal expression patterns of genes involved in somitogenesis, a topic of great interest within evolutionary developmental studies of vertebrates. PMID- 28809034 TI - MicroCT Imaging on Living Alligator Teeth Reveals Natural Tooth Cycling. AB - To study tooth cycling in polyphyodont animals, we chose to work on alligators. Alligators have teeth in three phases of development at each tooth location. This assembly of three teeth is called a tooth family unit. As part of the study, in order to study tooth cycling in alligators, we wanted to know the configuration of the tooth family unit in every tooth position. From the surface of the mouth, this is difficult to assess. Therefore, we decided to use MicroCT which can image X-ray dense materials providing a three-dimensional view. MicroCT provided us with valuable information for this study. The method described below can be applied to study tooth cycling in other vertebrate species. PMID- 28809035 TI - Nurse Staffing Patterns and Patient Experience of Care: An Empirical Analysis of U.S. Hospitals. AB - OBJECTIVE: To examine the relationship between nurse staffing patterns and patients' experience of care in hospitals with a particular focus on staffing flexibility. DATA SOURCES/STUDY SETTING: The study sample comprised U.S. general hospitals between 2010 and 2012. Nurse staffing data came from the American Hospital Association Annual Survey, and patient experience data came from the Medicare Hospital Consumer Assessment of Healthcare Providers and Systems. STUDY DESIGN: An observational research design was used entailing a pooled, cross sectional data set. Regression models were estimated using generalized estimating equation (GEE) and hospital fixed effects. Nurse staffing patterns were assessed based on both levels (i.e., ratio of full-time equivalent nurses per 1,000 patient days) and composition (i.e., skill mix-percentage of registered nurses; staffing flexibility-percentage of part-time nurses). PRINCIPAL FINDINGS: All three staffing variables were significantly associated with patient experience in the GEE analysis, but only staffing flexibility was significant in the fixed effects analysis. A higher percentage of part-time nurses was positively associated with patient experience. Multiplicative and nonlinear effects for the staffing variables were also observed. CONCLUSIONS: Among three staffing variables, flexibility was found to be the most important relative to patient experience. Unobserved hospital characteristics appear to underlie patient experience as well as certain nurse staffing patterns. PMID- 28809036 TI - Clinical investigation of 38 cases of oral mucosal melanoma: A multicentre retrospective analysis in Japan. AB - BACKGROUND/OBJECTIVES: The aim of the present study was to investigate treatment modalities and outcomes in oral mucosal melanoma. METHODS: The clinical and pathological data of 38 consecutive patients with oral mucosal melanoma were retrospectively analyzed. Patients' characteristics were analyzed and overall survival (OS) rates were calculated. RESULTS: Sixteen patients had stage III (42%), 19 IVA (50%), and three had stage IVC (8%) disease. Among the therapeutic approaches used, 31 patients (82%) received radical therapy (surgery +/- chemotherapy). The 5-year OS rate was 40%. Five-year OS rates according to the clinical stage were 71% for stage III, 24% for stage IVA, and 0% for stage IVC. Five-year OS rates according to therapeutic approaches were 52% in the radical therapy group and 0% in the palliative therapy and best supportive care groups. CONCLUSIONS: The results of this multicentre retrospective analysis of patients with oral mucosal melanoma suggest that radical therapy based on surgical treatments with complete surgical excision with clear margins leads to a better prognosis. PMID- 28809037 TI - Biological notes on the reef stingray, Urobatis concentricus, an endemic species of Mexico. AB - This study found that the reef stingray Urobatis concentricus presents a matrotrophic aplacental viviparous reproduction with yolk sac and trophonemata formation. Growth of ovarian follicles occurs asynchronously and continuously with fecundity of three embryos per female. A maximum size of 58.4 cm total length and 37.6 cm disc width was recorded, corresponding to a mature female of 3 or 4 years of age. PMID- 28809038 TI - The cadmium tolerance in Saccharomyces cerevisiae depends on inorganic polyphosphate. AB - The sensitivity to cadmium (Cd(II)), an important environmental pollutant, was studied in the cells of Saccharomyces cerevisiae strains with genetically altered polyphosphate metabolism. The strains overproducing polyphosphatases PPX1 or PPN1 were more sensitive to Cd(II) than the parent strain. The half maximal inhibitory concentrations were 0.02 and 0.05 mM for the transformants and the parent strain, respectively. Transformant strains cultivated in the presence of Cd(II) show a decrease in the content of short-chained cytosolic acid soluble polyphosphate. The role of this polyphosphate fraction in detoxification of heavy metal ions is discussed. PMID- 28809039 TI - Juvenile melanomas: Western Australian Melanoma Advisory Service experience. AB - BACKGROUND/OBJECTIVES: Juvenile melanoma (before 20 years of age) is a rare condition with poorly defined risk factors. We describe features of juvenile melanoma in Western Australia over the last two decades. METHOD: A retrospective review of juvenile melanomas was conducted from prospectively maintained databases, reviewed for patients' characteristics, clinical information, histology, treatment, recurrence and survival data. RESULTS: Altogether 95 cases of juvenile melanoma were reported to the Western Australian Cancer Registry between 2000 and 2013. Of these, 27 patients were referred to the Western Australian Melanoma Advisory Service. Over 72% were aged between 13 and 19 years. The most common site for primary melanoma was the head and neck (31.8%). Eight patients (36.4%) had a pre-existing naevus, 13.6% reported 1-5 blistering sunburns in the past and 59.1% had a Fitzpatrick skin grade of 3 or less. Most (88%) were diagnosed with a primary invasive lesion at presentation. Superficial spreading melanomas predominated (27.3%). All but one patient had localised disease at presentation, with six patients undergoing further treatment, including chemotherapy and neck dissection for metastases. At the time of review, two patients had died, due to stroke and metastatic disease. CONCLUSIONS: Juvenile melanoma remains a rarity in Western Australia despite a very high incidence of adult melanoma. Unlike in adults, no definitive risk factors have been established. A significant proportion of this cohort had a pre-existing naevus and while most melanomas occurred in sun-exposed areas in light-skinned individuals the association between sunburn and melanoma was not strong. PMID- 28809040 TI - A mobile APP for sharing contacts on your cell: An Editorial Highlight for 'The physiological role of the amyloid precursor protein as an adhesion molecule in the developing nervous system' on page 11. AB - The Review highlighted in this Editorial followed a CAEN Return Home Grant. PMID- 28809041 TI - Complex malformations involving the fetal body wall - definition and classification issues. AB - OBJECTIVE: The objective of the study is to analyse the sonographic features, cytogenetic results and pregnancy outcomes in complex malformations involving the body wall in a large cohort of fetuses with regard to different definitions proposed in the literature. METHOD: A retrospective study on 96 fetuses with complex malformations comprising ventral wall, craniofacial structures, limbs and umbilical cord that were evaluated between 1997 and 2015. RESULTS: The most common sonographic finding was an extensive ventral wall defect (95.8%; 92/96) comprising liver (94.6%; 87/92), intestine (82.6%; 76/92), heart (17.4%; 16/92) and bladder (8.7%; 8/92). Acrania and encephalocoele were observed in 24 and 9 fetuses (25.0%, 24/96; 9.4%, 9/96), respectively. Limb anomalies were present in 54 fetuses (56.3%; 54/96). Rudimentary or absent umbilical cord was observed in 62 fetuses (64.6%; 62/96). In 79 fetuses, there were additional multiple structural anomalies detected prenatally. None of the currently used definitions encompasses all possible phenotypes of body wall defects present in our cohort. Chromosomal aberrations were seen in 8 out of 60 cases with conclusive cytogenetic result (13.3%, 8/60). CONCLUSION: Chromosomal anomalies are common, and karyotyping should be offered. There is a need for a more rigorous classification of complex malformations in order to better understand the underlying pathophysiology. (c) 2017 John Wiley & Sons, Ltd. PMID- 28809042 TI - Notes on the overlap measure as an alternative to the Youden index: How are they related? AB - The receiver operating characteristic (ROC) curve is frequently used to evaluate and compare diagnostic tests. As one of the ROC summary indices, the Youden index measures the effectiveness of a diagnostic marker and enables the selection of an optimal threshold value (cut-off point) for the marker. Recently, the overlap coefficient, which captures the similarity between 2 distributions directly, has been considered as an alternative index for determining the diagnostic performance of markers. In this case, a larger overlap indicates worse diagnostic accuracy, and vice versa. This paper provides a graphical demonstration and mathematical derivation of the relationship between the Youden index and the overlap coefficient and states their advantages over the most popular diagnostic measure, the area under the ROC curve. Furthermore, we outline the differences between the Youden index and overlap coefficient and identify situations in which the overlap coefficient outperforms the Youden index. Numerical examples and real data analysis are provided. PMID- 28809043 TI - Clarifying the role of physical activity in osteoarthritis and rheumatoid arthritis. PMID- 28809044 TI - Shining new light into the workings of photoreceptors and visual interneurons. PMID- 28809045 TI - Reply from Mari Carmen Gomez-Cabrera and Jose Vina. PMID- 28809047 TI - Corrigendum. PMID- 28809046 TI - Platelet transfusion to reverse antiplatelet therapy before decompressive surgery in patients with intracranial haemorrhage. AB - BACKGROUND: Platelet concentrates (PC) are transfused to improve primary haemostasis before urgent neurosurgery in patients with intracranial haemorrhage (ICH) receiving antiplatelet therapy (APT). It is unresolved, whether PCs increase the risk for major cardio- and cerebrovascular adverse events. We evaluated a standardized transfusion regimen to reverse APT in patients with ICH who required decompressive neurosurgery. METHODS: Analysed were consecutive patients between 2012 and 2014. The primary outcome was the frequency of new arterial thrombotic complications. The secondary outcome was the frequency of recurrent ICH. RESULTS: Of 72 patients, 14 received acetylsalicylic acid and a P2Y12 inhibitor, 53 received acetylsalicylic acid and five clopidogrel. No acute coronary syndrome (95% CI: 0-5.07) and one ischaemic stroke occurred (1.4%; 95% CI: 0.25-7.46). In contrast, 26.4% of patients developed recurrent ICH (95% CI: 17.59-37.58). The risk of bleeding was significantly higher compared to the risk of arterial thrombosis (P < 0.00001) and was increased for patients with chronic ICH (OR: 4.78; 95% CI: 1.57-14.55) and those receiving clopidogrel (OR: 2.78; 95% CI: 0.90-8.57). CONCLUSION: Platelet concentrate transfusion before cranial decompressive surgery in patients with ICH complicating APT showed a low risk for cardio-cerebral thrombotic complications. However, the risk of rebleeding remains high, especially in patients with chronic ICH and those pretreated with clopidogrel. PMID- 28809048 TI - A clean self reduces bribery intent. AB - The present research aimed at investigating the effect of physical cleanliness on bribery intent and the moderating role of personal need for structure (PNS) on this relationship. In Study 1, we used questionnaires to establish the correlation between bodily cleanliness and bribery intent. In Study 2, we examined the effect by priming sense of self-cleanliness. Study 3 was conducted outside a public bath to test our finding that physical purity decreases bribery intent again; we further found that individuals with high PNS showed no reduction in bribery intent even after cleaning themselves. We thus connected physical cleanliness with the corruption field and improved our understanding of its underlying moderating mechanism. PMID- 28809049 TI - Evolution of MNC and lymphocyte collection settings employing different Spectra Optia(r) Leukapheresis systems. AB - BACKGROUND AND OBJECTIVES: The Spectra Optia(r) continuous mononuclear cell (CMNC apheresis) system has emerged as the preferred device in peripheral blood stem cell collections over the original two-step Spectra Optia(r) mononuclear cell (MNC apheresis) system. Until now, no comparative data were available for non stimulated MNC collections that are required for immunotherapy. MATERIALS AND METHODS: We compared collection parameters and product composition for Spectra Optia MNC- as well as CMNC-apheresis systems in non-stimulated MNC collections from 35 registry donors intended for donor lymphocyte infusions. In a subsequent analysis, different centrifugation forces (determined as packing factor or PF) were investigated regarding target cell yield and contamination in 61 collections using the CMNC device only. RESULTS: Comparable collection efficiencies as well as target cell yields could be achieved with the Spectra Optia MNC- versus CMNC program. Similar numbers of MNC, T, B and NK cells could be collected with both devices. This led to a more than twofold lymphocyte recruitment from lymphatic tissue into the blood during apheresis. However, significantly more blood had to be processed with longer procedure time using the MNC program resulting in larger product volumes compared to the CMNC setting. Red blood cell and platelet (PLT) contamination were similar. Lowering the centrifugation force from PF4.5 to PF4.0 significantly reduced PLT contamination without affecting target cell yield in the product. CONCLUSION: The Spectra Optia(r) CMNC device using lower centrifugal force (PF4.0) showed similar target cell yield and composition as well as collection efficiencies with superior performance parameters and lower PLT contamination compared to the MNC setting. PMID- 28809050 TI - Versatile chromatographic method for catechin determination in development of topical formulations containing natural extracts. AB - Catechin is found in several natural sources, as Eugenia dysenterica and Syzygium cumini extracts. Its antioxidant and UV-protective properties suggest a potential use in cosmetic and dermatological formulations. A simple analytical method capable of giving support to experiments performed along the development of topical formulations containing this natural substance (i.e. drug assay, skin permeation and stability studies), however, is still needed. Thus, this work aimed to develop and validate a selective HPLC method for catechin determination during the development of topical formulations. Separation was achieved using an RP-C18 column (300 * 3.9 mm; 10 MUm), with a mobile phase of methanol-phosphoric acid 0.01 m (15: 85, v/v), a flow rate of 0.8 mL/min, temperature set at 40 degrees C and UV detection at 230 nm. The method was linear in a range from 0.5 to 10.0 MUg/mL (r = 0.9998), precise with an overall variation coefficient of 5.5% and accurate with catechin recovery from the skin layers >85%. Additionally, the method was sensitive (limit of detection, 0.109 MUg/mL; limit of quantification, 0.342 MUg/mL) and selective against plant extracts, skin matrices and formulation interferents, as well as catechin degradation products. It was also robust regarding both methodology parameters and analytical stability. PMID- 28809051 TI - Mediation analysis for a survival outcome with time-varying exposures, mediators, and confounders. AB - We propose an approach to conduct mediation analysis for survival data with time varying exposures, mediators, and confounders. We identify certain interventional direct and indirect effects through a survival mediational g-formula and describe the required assumptions. We also provide a feasible parametric approach along with an algorithm and software to estimate these effects. We apply this method to analyze the Framingham Heart Study data to investigate the causal mechanism of smoking on mortality through coronary artery disease. The estimated overall 10 year all-cause mortality risk difference comparing "always smoke 30 cigarettes per day" versus "never smoke" was 4.3 (95% CI = (1.37, 6.30)). Of the overall effect, we estimated 7.91% (95% CI: = 1.36%, 19.32%) was mediated by the incidence and timing of coronary artery disease. The survival mediational g formula constitutes a powerful tool for conducting mediation analysis with longitudinal data. PMID- 28809052 TI - Validation of the Resilience Scale for Adolescents in Norwegian adolescents 13-18 years. AB - AIM: Resilience is seen as a vital resource for coping and mental health in adolescents. However, there is no universally accepted theory or definition of resilience, leading to considerable challenges regarding how to operationalise and measure this construct. The study aimed at providing further knowledge of the psychometric properties (dimensionality, construct validity and internal consistency) of the 28-item version of the Resilience Scale for Adolescents (READ) in N = 1183 Norwegian adolescents, 13-18 years old. METHODS: Dimensionality of READ was tested using confirmatory factor analysis (CFA). Convergent validity and reliability were tested using Pearson's correlation analysis, Cronbach's alpha and composite reliability. RESULTS: The CFA supported a modified, 20-item, five-factor structure with high reliability, supporting the dimensionality and internal consistency of the instrument. Convergent validity was confirmed where all factors correlated in expected directions with measures of sense of coherence, self-esteem, stress and depression. CONCLUSION: The psychometric properties of the READ need to be further evaluated in adolescents; however, the results indicate that a modified 20-item version of READ is adequate for assessing resilience in the present sample of Norwegian adolescents. PMID- 28809053 TI - Case of possible multiple system atrophy with a characteristic imaging finding of open bladder neck during storage phase as an initial sign. AB - Multiple system atrophy is a neurodegenerative disease that affects autonomic and motor systems. Patients with multiple system atrophy usually experience lower urinary tract symptoms, which sometimes appear as an initial symptom before the emergence of the generalized symptoms. An open bladder neck during the filling phase on video urodynamic study is one characteristic imaging finding after the diagnosis of multiple system atrophy, but has not previously been reported at an early phase of the disease. We report a case in which an open bladder neck was observed on several imaging modalities before generalized symptoms emerged. Because occult neurogenic bladder might exist in patients whose lower urinary tract symptoms are resistant to pharmacotherapy, we report this case to raise awareness of the importance of sufficient imaging evaluations. An open bladder neck might be an important imaging finding for diagnosing multiple system atrophy, irrespective of the presence of generalized symptoms. This finding could help avoid false diagnosis and unnecessary treatment. PMID- 28809054 TI - Editorial Comment to Case of hydrocele testis caused by vaginalitis, a rare manifestation of immunoglobulin G4-related disease. PMID- 28809055 TI - Apoptotic Effect of Astragalin in Melanoma Skin Cancers via Activation of Caspases and Inhibition of Sry-related HMg-Box Gene 10. AB - Though Astragalin (kaempferol-3-glucoside) contained in Paeonia lactiflora and other plants was known to have anti-oxidant, antiinflammatory, and anti-tumor activity, the anti-tumor mechanism of Astragalin has never been reported in melanomas until now. Thus, in the present study, the underlying apoptotic mechanism of Astragalin isolated from Aceriphyllum rossii was elucidated in A375P and SK-MEL-2 melanoma cells. Astragalin exerted cytotoxicity in A375P and SK-MEL 2 cells in a concentration-dependent manner. Also, Astragalin significantly increased the number of TdT-mediated dUTP nick end labeling positive cells and sub-G1 population as a feature of apoptosis in A375P and SK-MEL-2 cells compared with untreated control. Consistently, western blotting revealed that Astragalin activated caspase 9/3 and Bax, cleaved poly (ADP-ribose) polymerase, and attenuated the expression of cyclin D1, Mcl-1, and Sry-related HMg-Box gene 10 (SOX10) in A375P and SK-MEL-2 cells. Of note, ectopic expression of SOX10 reduced the apoptotic ability of Astragalin to inhibit proliferation, cleave poly (ADP ribose) polymerase, and caspase 3 in A375P and SK-MEL-2 melanoma cells. Overall, our findings provide evidence that Astragalin induces apoptosis in A375P and SK MEL-2 melanoma cells via activation of caspase9/3 and inhibition of SOX10 signaling. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28809056 TI - SpinDynamica: Symbolic and numerical magnetic resonance in a Mathematica environment. AB - SpinDynamica is a set of Mathematica packages for performing numerical and symbolic analysis of a wide range of magnetic resonance experiments and phenomena. An overview of the SpinDynamica architecture and functionality is given, with some simple representative examples. PMID- 28809057 TI - Understanding frames: A UK survey of parents and professionals regarding the use of standing frames for children with cerebral palsy. AB - BACKGROUND: Standing frames are used for children with cerebral palsy (CP). They may improve body structure and function (e.g., reducing risk of hip subluxation, and improving bladder and bowel function), improving activity (e.g., motor abilities) and participation (e.g., interaction with peers), but there is little evidence that they do. We aimed to identify current UK standing frame practice for children with CP and to understand stakeholder views regarding their clinical benefits and challenges to use. METHOD: Three populations were sampled: clinicians prescribing standing frames for children with CP (n = 305), professionals (health and education) working with children with CP who use standing frames (n = 155), and parents of children with CP who have used standing frames (n = 91). Questionnaires were developed by the co-applicant group and piloted with other professionals and parents of children with CP. They were distributed online via clinical and parent networks across the UK. RESULTS: Prescribing practice was consistent, but achieving the prescribed use was not always possible. Respondents in all groups reported the perceived benefits of frames, which include many domains of the International Classification of Functioning Disability and Health for Children and Youth. Challenges of use are related to physical space and child-reported pain. CONCLUSIONS: These survey findings provide information from key stakeholders regarding current UK standing frame practice. PMID- 28809058 TI - Acylated Iridoids and Rhamnopyranoses from Premna odorata (Lamiaceae) as Novel Mesenchymal-Epithelial Transition Factor Receptor Inhibitors for the Control of Breast Cancer. AB - Phytochemical investigation of Premna odorata Blanco, Lamiaceae, leaves afforded three new acylated iridoid glycosides 1-3 and two new acylated rhamnopyranoses 9 and 10, in addition to ten known compounds. The structures of the new compounds were confirmed using extensive 1D and 2D NMR analysis. Molecular modeling study suggested the potential of the acylated rhamnopyranoses to bind at the c-Met kinase domain. Cell-free Z'-LYTETM assay testing revealed the good c-Met phosphorylation inhibitory activity of 9, followed by 8, and 10, with IC50 values of 2.5, 6.9, and 12.7 MUM, respectively. The (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) cell proliferation assay testing against the human c-Met expressing highly invasive MDA-MB-231 suggested compound 9 as the most active with IC50 value of 13.3 MUM. Testing of compound 9 against multiple phenotypic breast cancer cell lines including MCF-7, BT-474 cells, and MDA-MB-468 proved enhanced activity against the highly c-Met expressing triple-negative breast cancer cell lines. Acylated rhamnopyranoses are potential novel c-Met inhibitors appropriate for future optimizations to control c-Met-dependent breast malignancies. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28809059 TI - Knowledge, attitudes, and behaviours of healthcare professionals regarding child maltreatment in China. AB - BACKGROUND: A new, recently issued national law and regulation in China conferred the responsibility of healthcare professionals in child maltreatment intervention. However, few studies have reported on the recognition and reporting of child maltreatment by healthcare professionals in China. The aim of this study was to assess healthcare professionals' knowledge, attitudes, and self-perceived behaviour in terms of identifying, assessing, and reporting child maltreatment cases in China. METHODS: A cross-sectional survey of 877 healthcare professionals from four provinces was conducted using a structured questionnaire. RESULTS: The respondents demonstrated insufficient knowledge on identifying potential child maltreatment cases. Over 30% of them were less than confident in the medical examination, evaluation, and treatment of child maltreatment cases, especially with regard to cases involving sexual abuse. Only 3.19% of respondents had ever received training on child maltreatment intervention, and as a result, lack of knowledge with regard to dealing with child maltreatment cases, referral procedures, and regulations was indicated to be the main cause of underreporting. CONCLUSIONS: Healthcare professionals in China have insufficient knowledge, skills, and confidence when it comes to dealing with all aspects of child maltreatment. Although participants reported a positive attitude towards their role in detecting and reporting child maltreatment cases, there are obstacles that hinder them from doing so. Appropriate training courses should be developed to empower professionals with knowledge and skills, as well as increase their confidence in dealing with suspected child maltreatment cases. PMID- 28809060 TI - The Phytochemistry and Pharmacology of Butia sp.: A Systematic Review and an Overview of the Technological Monitoring Process. AB - The Butia sp. are native South America trees, whose fruits are consumed in natura and have significant biological properties; however, trees of this genus plant are in danger of extinction. A systematic review of the literature and a technological overview were carried out to summarize the available evidence on the therapeutic uses and the phytochemical compounds of Butia sp. The following electronic databases were researched: MedLine (PubMed), Web of Science, Scopus, Scielo, and the gray literature. Furthermore, the online system such as the US Patent and Trademark Office, Espacenet, National Institute of Industrial Property, and Google Patents were accessed to obtain patent data. The inclusion criteria were articles that describe either the therapeutic uses of Butia sp. (antimicrobial activity, antioxidant activity, anti-inflammatory activity, antineoplastic activity) or studies describing phytochemical compounds of Butia sp. A limited amount of manual search was also undertaken. Reference lists were scanned to identify other relevant studies, and requests for unpublished data were conducted to people working in the field. Among 12 papers and 14 patents, 9 complete texts of scientific articles and 1 patent were scrutinised by two reviewers. We concluded that Butia has shown some antioxidant, anti-inflammatory, and antimicrobial activity, and its use could have important implications for future therapeutic uses. Although there is evidence of pharmacological potential from in vitro studies, clinical studies must be conducted to confirm the effectiveness of Butia sp. The evidence of its therapeutic uses has not been extensively studied yet, and the available evidence still needs further confirmation. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28809061 TI - Associations between substance use disorders and suicide mortality risk should be adjusted for tobacco use disorder. PMID- 28809062 TI - Carbon, nitrogen and sulphur isotopic fractionation in captive juvenile hooded seal (Cystophora cristata): Application for diet analysis. AB - RATIONALE: Intrinsic biogeochemical markers, such as stable isotope ratios of carbon, nitrogen and sulphur, are increasingly used to trace the trophic ecology of marine top predators. However, insufficient knowledge of fractionation processes in tissues continues to hamper the use of these markers. METHODS: We performed a controlled feeding experiment with eight juvenile hooded seals (Cystophora cristata) that were held on a herring-based diet (Clupea harengus) for two years. Stable isotope ratios were measured via isotope ratio mass spectrometry in three of their tissues and related to values of these markers in their diet. RESULTS: Diet-tissue isotope enrichment (trophic enrichment factor, TEF) values between dietary herring and seal tissues for carbon (Delta13 C) were +0.7 0/00 for red blood cells, +1.9 0/00 for hair and +1.1 0/00 for muscle. The TEFs for nitrogen trophic (Delta15 N) were +3.3 0/00 for red blood cells, +3.6 0/00 for hair and +4.3 0/00 for muscle. For sulphur, the Delta34 S values were +1.1 0/00 for red blood cells, +1.0 0/00 for hair and +0.9 0/00 for muscle. CONCLUSIONS: These enrichment values were greater than those previously measured in adult seals. This increase may be related to the higher rate of protein synthesis and catabolism in growing animals. This study is the first report on sulphur isotope enrichment values for a marine mammal species. PMID- 28809064 TI - Electrical Textile Valves for Paper Microfluidics. AB - This paper describes electrically-activated fluidic valves that operate based on electrowetting through textiles. The valves are fabricated from electrically conductive, insulated, hydrophobic textiles, but the concept can be extended to other porous materials. When the valve is closed, the liquid cannot pass through the hydrophobic textile. Upon application of a potential (in the range of 100 1000 V) between the textile and the liquid, the valve opens and the liquid penetrates the textile. These valves actuate in less than 1 s, require low energy (~27 uJ per actuation), and work with a variety of aqueous solutions, including those with low surface tension and those containing bioanalytes. They are bistable in function, and are, in a sense, the electrofluidic analog of thyristors. They can be integrated into paper microfluidic devices to make circuits that are capable of controlling liquid, including autonomous fluidic timers and fluidic logic. PMID- 28809065 TI - Case of hydrocele testis caused by vaginalitis, a rare manifestation of immunoglobulin G4-related disease. AB - We report an extremely rare manifestation of immunoglobulin G4-related disease, presented with hydrocele testis. A planned hydrocelectomy was converted to a high orchiectomy because of bloody fluid, suggestive of paratesticular malignancy. The histopathology showed vaginalitis, which was finally diagnosed as immunoglobulin G4-related disease. To the best of our knowledge, this is the first report of immunoglobulin G4-related disease representing hydrocele testis. PMID- 28809063 TI - Color and power Doppler combined with Fetal Intelligent Navigation Echocardiography (FINE) to evaluate the fetal heart. AB - OBJECTIVE: To evaluate the performance of color and bidirectional power Doppler ultrasound combined with Fetal Intelligent Navigation Echocardiography (FINE) in examining the fetal heart. METHODS: A prospective cohort study was conducted of fetuses in the second and third trimesters with a normal heart or with congenital heart disease (CHD). One or more spatiotemporal image correlation (STIC) volume datasets, combined with color or bidirectional power Doppler (S-flow) imaging, were acquired in the apical four-chamber view. Each successfully obtained STIC volume was evaluated by STICLoopTM to determine its appropriateness before applying the FINE method. Visualization rates for standard fetal echocardiography views using diagnostic planes and/or Virtual Intelligent Sonographer Assistance (VIS-Assistance(r)) were calculated for grayscale (removal of Doppler signal), color Doppler and S-flow Doppler. In four cases with CHD (one case each of tetralogy of Fallot, hypoplastic left heart and coarctation of the aorta, interrupted inferior vena cava with azygos vein continuation and asplenia, and coarctation of the aorta with tricuspid regurgitation and hydrops), the diagnostic potential of this new technology was presented. RESULTS: A total of 169 STIC volume datasets of the normal fetal heart (color Doppler, n = 78; S-flow Doppler, n = 91) were obtained from 37 patients. Only a single STIC volume of color Doppler and/or a single volume of S-flow Doppler per patient were analyzed using FINE. Therefore, 60 STIC volumes (color Doppler, n = 27; S-flow Doppler, n = 33) comprised the final study group. Median gestational age at sonographic examination was 23 (interquartile range, 21-27.5) weeks. Color Doppler FINE generated nine fetal echocardiography views (grayscale) using (1) diagnostic planes in 73-100% of cases, (2) VIS-Assistance in 100% of cases, and (3) a combination of diagnostic planes and/or VIS-Assistance in 100% of cases. The rate of generating successfully eight fetal echocardiography views with appropriate color and S-flow Doppler information was 89-100% and 91-100% of cases, respectively, using a combination of diagnostic planes and/or VIS-Assistance. However, the success rate for the ninth echocardiography view (i.e. superior and inferior venae cavae) was 33% and 30% for color and S-flow Doppler, respectively. In all four cases of CHD, color Doppler FINE demonstrated evidence of abnormal fetal cardiac anatomy and/or hemodynamic flow. CONCLUSIONS: The FINE method applied to STIC volumes of normal fetal hearts acquired with color or bidirectional power Doppler information can generate successfully eight to nine standard fetal echocardiography views (via grayscale, color Doppler or power Doppler) in the second and third trimesters. In cases of CHD, color Doppler FINE demonstrates successfully abnormal anatomy and/or Doppler flow characteristics. Published 2017. This article is a U.S. Government work and is in the public domain in the USA. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. PMID- 28809066 TI - Participation in water-exercising long-term after breast cancer surgery: Experiences of significant factors for continuing exercising as a part of cancer rehabilitation. AB - Although physical exercising has great benefits, little is known regarding factors of significance for cancer survivors to continue exercising within their rehabilitation. The objective was to describe factors experienced to be of significance for cancer survivors to continue with water-exercising long-term after breast cancer surgery. Women (n = 29) who had undergone breast cancer surgery (mastectomy 79%, axillary surgery 86%, and radiotherapy 86%) for median (md) 13 (25th-75th percentile 3-21.5) was followed up regarding their rehabilitation, arm function Disabilities of Arm Shoulder and Hand (md 14, IQR 7 32), EQ-5D score (md 0.8, IQR 0.73-1.0) and quality of life EQ health barometer (md 80, IQR 64-95). We performed qualitative focus-group interviews regarding the women's views (n = 24). The women had participated in water-exercising 1-46 semesters, md 8 (25th-75th percentile 3-21.5) semesters. Nearly all, 97%, participated in the water-exercising group every week, and 21 (72%) had participated in the water-exercising group at least half of the time since their breast cancer surgery, without complications. The women experienced that factors of significance to continue with water-exercising were the convenience of easily modified weightless exercising in the water, social interaction, and access to a private dressing room. These factors would be important to consider to encourage continuing in exercising. PMID- 28809067 TI - In-Situ Fabrication of MOF-Derived Co-Co Layered Double Hydroxide Hollow Nanocages/Graphene Composite: A Novel Electrode Material with Superior Electrochemical Performance. AB - Rational design of a transition metal layered double hydroxide (LDH) and graphene composite is vitally important for designing high-performance supercapacitor electrodes. Although various methods are performed, the realization of high performance is still impeded by the agglomeration of graphene and layered double hydroxide. Here, metal-organic framework derived cobalt-cobalt layered double hydroxide (Co-Co LDH) hollow nanocages, uniformly deposited on graphene nanosheets, are fabricated through facile in situ co-deposition and thermal ion exchange reaction. Electrochemical investigation reveals that Co-Co LDH/15 mg graphene is rather outstanding, which delivers high specific capacitance of 1205 F g-1 , excellent rate capability (60.3 % capacitance retention is obtained after the current density increased 6.67 times), and cycling stability. The excellent performance of electrode is also confirmed by assembling an asymmetric supercapacitor, which delivers high energy density of 49.5 Wh kg-1 as well as the maximum power density of 7000 W kg-1 . The Co-Co LDH/graphene composite proves a promising concept for constructing hierarchical structure materials in the future. PMID- 28809068 TI - False belief attribution in children with Williams syndrome: the answer is in the emotion. AB - BACKGROUND: Individuals with Williams syndrome (WS) show difficulties in attributing false beliefs, whereas they are better at attributing emotions. This study examines whether being asked about the emotion linked to a false belief, instead of explicitly about the belief, facilitates performance on theory of mind (ToM) tasks. METHOD: Thirty children with WS and 90 typically developing children, who were individually matched on mental age (50-112 months), were administered six explicit (i.e. questions on belief) and six implicit (i.e. questions on emotion) trials of false belief tasks. RESULTS: Theory of mind competences were related to cognitive development. Children with WS performed comparably to typically developing children on the emotion questions. CONCLUSION: Correct answers to questions on emotion reveal an implicit understanding of false belief. The Representational redescription process could be impaired in the domain of ToM in this population. This finding has relevant implications for the design of supports aiming to optimise the development of ToM competences in individuals with WS. PMID- 28809069 TI - Response to Aubin et al. (2017). PMID- 28809070 TI - Ambivalence and guilt feelings: Two relevant variables for understanding caregivers' depressive symptomatology. AB - Providing care for a relative with dementia is considered to be a chronic stressor that has been linked to negative mental health consequences for caregivers. A theoretical model was developed and tested to assess the degree to which ambivalence and guilt feelings contribute to caregivers' depressive symptomatology. Participants included 212 dementia family caregivers. In addition to ambivalence and guilt feelings, sociodemographic characteristics, behavioural and psychological symptoms of dementia, and depressive symptomatology were assessed. Hypotheses derived from the stress and coping model were tested using path analysis. The analysed model showed an excellent fit to the data. In total, 35% of the variance in depressive symptomatology was explained by the assessed variables. Although significant correlations were obtained between frequency and appraisal of behavioural and psychological symptoms of dementia and depression, the obtained model suggests that this effect was mediated through ambivalence. In addition, ambivalence had an indirect effect on depression. The association of ambivalence with depression was explained through feelings of guilt; that is, respondents who reported ambivalent feelings were more likely to experience guilt, leading in turn to greater depressive symptomatology. The findings suggest that dementia caregivers' ambivalence and guilt feelings are relevant for understanding their depressive symptomatology. These factors should be addressed in psychological interventions with caregivers. PMID- 28809071 TI - Physicians' communication of risks from non-steroidal anti-inflammatory drugs and attitude towards providing adverse drug reaction information to patients. AB - RATIONALE, AIMS, AND OBJECTIVES: Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed for orthopaedic conditions, therefore this study aimed to explore orthopaedic physicians' perceptions of their role in NSAID-risk communication, their attitudes towards the necessity of informing patients about adverse drug reactions (ADR), and factors associated with these. METHODS: Self administered questionnaires were mailed to all 206 orthopaedic physicians working at hospitals in Northeastern Thailand. Attitudes were assessed using 17 statements and total scores classed as poor, moderate and good attitude. RESULTS: Sixty-six questionnaires were returned (32.04%). The responses showed that 75% of physicians claimed to communicate NSAID ADR information, more frequently about gastrointestinal (GI) complications, than about renal and cardiovascular (CVS) complications. ADR management (36%) and monitoring (30%) were not frequently communicated. The time spent with patients was associated with provision of ADR and monitoring advice. Renal function was the risk factor of greatest concern for prescribing any NSAID, followed by history of GI complications, and allergy for non-selective NSAIDs, and history of CVS diseases and age for selective COX-2 NSAIDs. Most physicians (41) had moderate attitude towards providing information and 24 good attitude. Fewer physicians working in tertiary hospitals than general and community hospital physicians considered that time limitations prevented counseling and that patient information leaflets offered easily accessible information. Additionally, more physicians who did not inform patients about ADRs agreed that ADR communication can lead to anxiety and discontinuing treatment. CONCLUSION: The study indicates that, although orthopaedic physicians had positive attitudes towards providing ADR information to patients, improvement is needed in communicating NSAID risk information. PMID- 28809072 TI - Decarbonylative Phosphorylation of Amides by Palladium and Nickel Catalysis: The Hirao Cross-Coupling of Amide Derivatives. AB - Considering the ubiquity of organophosphorus compounds in organic synthesis, pharmaceutical discovery agrochemical crop protection and materials chemistry, new methods for their construction hold particular significance. A conventional method for the synthesis of C-P bonds involves cross-coupling of aryl halides and dialkyl phosphites (the Hirao reaction). We report a catalytic deamidative phosphorylation of a wide range of amides using a palladium or nickel catalyst giving aryl phosphonates in good to excellent yields. The present method tolerates a wide range of functional groups. The reaction constitutes the first example of a transition-metal-catalyzed generation of C-P bonds from amides. This redox-neutral protocol can be combined with site-selective conventional cross coupling for the regioselective synthesis of potential pharmacophores. Mechanistic studies suggest an oxidative addition/transmetallation pathway. In light of the importance of amides and phosphonates as synthetic intermediates, we envision that this Pd and Ni-catalyzed C-P bond forming method will find broad application. PMID- 28809073 TI - Biocatalytic Stimuli-Responsive Asymmetric Triblock Terpolymer Membranes for Localized Permeability Gating. AB - The functionalization with phosphotriesterase of poly(isoprene-b-styrene-b-4 vinylpyridine)-based nanoporous membranes fabricated by self-assembly and nonsolvent induced phase separation (SNIPS) is shown to enable dynamically responsive membranes capable of substrate-specific and localized gating response. Integration of the SNIPS process with macroporous nylon support layers yields mechanically robust textile-type films with high moisture vapor transport rates that display rapid and local order-of-magnitude modulation of permeability. The simplicity of the fabrication process that is compatible with large-area fabrication along with the versatility and efficacy of enzyme reactivity offers intriguing opportunities for engineered biomimetic materials that are tailored to respond to a complex range of external parameters, providing sensing, protection, and remediation capabilities. PMID- 28809075 TI - Allosteric modulation of alpha4beta2* nicotinic acetylcholine receptors: Desformylflustrabromine potentiates antiallodynic response of nicotine in a mouse model of neuropathic pain. AB - BACKGROUND: Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels. The alpha4beta2 subtype of nAChRs plays an important role in the mediation of pain and several nicotine-evoked responses. Agonists and partial agonists of alpha4beta2 nAChRs show efficacy in animal pain models. In addition, the antinociceptive properties of nicotine, a non-selective nAChR agonist with a high affinity for alpha4beta2 nAChRs, is well-known. There is a growing body of evidence pointing to allosteric modulation of nAChRs as an alternative treatment strategy in experimental pain. Desformylflustrabromine (dFBr) is a positive allosteric modulator (PAM) at alpha4beta2 nAChRs that enhances agonist responses without activating receptors. We hypothesized that dFBr may enhance nicotine induced antinociception. METHODS: The present study investigated whether dFBr could attenuate mouse chronic constriction injury (CCI)-induced neuropathic pain by increasing endogenous cholinergic tone or potentiating the nicotine-evoked antiallodynic response. RESULTS: We found that subcutaneous administration of dFBr failed to reduce pain behaviour on its own. However, the combination of dFBr with nicotine significantly reversed neuropathic pain behaviour dose- and time dependently without motor impairment. Our data revealed that this effect was mediated by the alpha4beta2 nAChRs by using competitive alpha4beta2 antagonist dihydro-beta-erythroidine. In addition, dFBr failed to potentiate the antiallodynic effect of morphine, which shows the effect of dFBr is unique to alpha4beta2 nAChRs. CONCLUSIONS: The present results suggest that allosteric modulation of alpha4beta2 nAChR may provide new strategies in chronic neuropathic pain. SIGNIFICANCE: alpha4beta2 nAChRs are involved in pain modulation. dFBr, a PAM at alpha4beta2 nAChRs, potentiates the nicotine response dose-dependently in neuropathic pain. Thus, the present results suggest that allosteric modulation of alpha4beta2* nAChR may provide new strategies in chronic neuropathic pain. PMID- 28809076 TI - Fe-Doped Ni3 C Nanodots in N-Doped Carbon Nanosheets for Efficient Hydrogen Evolution and Oxygen-Evolution Electrocatalysis. AB - Uniform Ni3 C nanodots dispersed in ultrathin N-doped carbon nanosheets were successfully prepared by carburization of the two dimensional (2D) nickel cyanide coordination polymer precursors. The Ni3 C based nanosheets have lateral length of about 200 nm and thickness of 10 nm. When doped with Fe, the Ni3 C based nanosheets exhibited outstanding electrocatalytic properties for both the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). For example, 2 at % Fe (atomic percent) doped Ni3 C nanosheets depict a low overpotential (292 mV) and a small Tafel slope (41.3 mV dec-1 ) for HER in KOH solution. An outstanding OER catalytic property is also achieved with a low overpotential of 275 mV and a small Tafel slope of 62 mV dec-1 in KOH solution. Such nanodot-incorporated 2D hybrid structures can serve as an efficient bifunctional electrocatalyst for overall water splitting. PMID- 28809077 TI - Donor-Acceptor Complex Enables Alkoxyl Radical Generation for Metal-Free C(sp3 ) C(sp3 ) Cleavage and Allylation/Alkenylation. AB - The alkoxyl radical is an essential and prevalent reactive intermediate for chemical and biological studies. Here we report the first donor-acceptor complex enabled alkoxyl radical generation under metal-free reaction conditions induced by visible light. Hantzsch ester forms the key donor-acceptor complex with N alkoxyl derivatives, which is elucidated by a series of spectrometry and mechanistic experiments. Selective C(sp3 )-C(sp3 ) bond cleavage and allylation/alkenylation is demonstrated for the first time using this photocatalyst-free approach with linear primary, secondary, and tertiary alkoxyl radicals. PMID- 28809078 TI - Profiling Protein S-Sulfination with Maleimide-Linked Probes. AB - Cysteine residues are susceptible to oxidation to form S-sulfinyl (R-SO2 H) and S sulfonyl (R-SO3 H) post-translational modifications. Here we present a simple bioconjugation strategy to label S-sulfinated proteins by using reporter-linked maleimides. After alkylation of free thiols with iodoacetamide, S-sulfinated cysteines react with maleimide to form a sulfone Michael adduct that remains stable under acidic conditions. Using this sequential alkylation strategy, we demonstrate differential S-sulfination across mouse tissue homogenates, as well as enhanced S-sulfination following pharmacological induction of endoplasmic reticulum stress, lipopolysaccharide stimulation, and inhibitors of the electron transport chain. Overall, this study reveals a broadened profile of maleimide reactivity across cysteine modifications, and outlines a simple method for profiling the physiological role of cysteine S-sulfination in disease. PMID- 28809079 TI - Changes in the use of erythropoiesis-stimulating agents (ESAs) and red blood cell transfusion in patients with cancer amidst regulatory and reimbursement changes. AB - PURPOSE: Evaluate changes in use of erythropoiesis-stimulating agents (ESAs) and red blood cell transfusion in cancer patients receiving myelosuppressive chemotherapy following regulatory and reimbursement actions. METHODS: Calendar year patient cohorts (2005-2013) with breast, colorectal, lung, multiple myeloma, non-Hodgkin lymphoma, ovarian, or prostate cancer and receiving myelosuppressive chemotherapy were identified within the Marketscan database. Incidence of ESA treatment and transfusion were estimated in each year, as was median number of ESA administrations. Clinical characteristics associated with ESA administration and transfusions were evaluated by using multivariable logistic regression. Additionally, annual new ESA user cohorts within the Oncology Services Comprehensive Electronic Records database (2011-2014) were examined to assess hemoglobin levels at ESA initiation. RESULTS: Across all tumor types, ESA use decreased substantially (breast cancer: 53.7 to 3.2%; lung cancer: 66.0 to 13.3%, non-Hodgkin lymphoma: 39.8 to 3.8%), transfusion use increased (2 to 5.5%, 5.5 to 18.2%, and 4.5 to 9.1%, respectively), and median number of ESA administrations declined. Across all tumor types, proportion of patients initiating an ESA with hemoglobin >10 g/dL was <10% from 2011 onward. In recent years, cancer patients who are older, female, and have chronic kidney disease or moderate or severe liver disease were most likely to receive ESAs. CONCLUSION: Subsequent to important regulatory and reimbursement ESA-related actions, total ESA exposure among cancer patients receiving myelosuppressive chemotherapy declined substantially. Today, fewer patients receive ESA therapy, and among those treated, more are initiated at hemoglobin levels <10 g/dL and are exposed for a shorter duration, consistent with current product labeling. PMID- 28809080 TI - Congenital complete atrioventricular block with pulmonary hypertension. PMID- 28809081 TI - Diagnosing the Internal Architecture of Zeolite Ferrierite. AB - Large crystals of zeolite ferrierite (FER) are important model systems for spatially resolved catalysis and diffusion studies, though there is considerable variation in crystal habit depending on the chemical composition and employed synthesis conditions. A synergistic combination of techniques has been applied, including single crystal X-ray diffraction, high-temperature in situ confocal fluorescence microscopy, fluorescent probe molecules, wide-field microscopy and atomic force microscopy to unravel the internal architecture of three distinct FER zeolites. Pyrolyzed template species can be used as markers for the 8 membered ring direction as they are trapped in the terraced roof of the FER crystals. This happens as the materials grow in a layer-by-layer, defect-free manner normal to the large crystal surface, and leads to a facile method to diagnose the pore system orientation, which avoids tedious single crystal X-ray diffraction experiments. PMID- 28809083 TI - Laser-Induced Focused Ultrasound for Cavitation Treatment: Toward High-Precision Invisible Sonic Scalpel. AB - Beyond the implementation of the photoacoustic effect to photoacoustic imaging and laser ultrasonics, this study demonstrates a novel application of the photoacoustic effect for high-precision cavitation treatment of tissue using laser-induced focused ultrasound. The focused ultrasound is generated by pulsed optical excitation of an efficient photoacoustic film coated on a concave surface, and its amplitude is high enough to produce controllable microcavitation within the focal region (lateral focus <100 um). Such microcavitation is used to cut or ablate soft tissue in a highly precise manner. This work demonstrates precise cutting of tissue-mimicking gels as well as accurate ablation of gels and animal eye tissues. PMID- 28809082 TI - Development of a Dual-Functional Hydrogel Using RGD and Anti-VEGF Aptamer. AB - Synthetic molecular libraries hold great potential to advance the biomaterial development. However, little effort is made to integrate molecules with molecular recognition abilities selected from different libraries into a single biomolecular material. The purpose of this work is to incorporate peptides and nucleic acid aptamers into a porous hydrogel to develop a dual-functional biomaterial. The data show that an anti-integrin peptide can promote the attachment and growth of endothelial cells in a 3D porous poly(ethylene glycol) hydrogel and an antivascular endothelial growth factor aptamer can sequester and release VEGF of high bioactivity. Importantly, the dual-functional porous hydrogel enhances the growth and survival of endothelial cells. This work demonstrates that molecules selected from different synthetic libraries can be integrated into one system for the development of novel biomaterials. PMID- 28809084 TI - Practice characteristics and service provision rates of dental hygienists in Australia. AB - INTRODUCTION: Dental hygienists (DHs) have been practising in Australia since the early 1970s. OBJECTIVE: This study describes the clinical activity of Australian DHs. METHODS: A questionnaire was mailed to members of two professional associations representing DHs. Practitioner characteristics, employment characteristics and clinical activity on a self-reported typical practice day were collected. The proportion of each service item of all services provided was estimated. Associations between practice characteristics and service provision were assessed by log-binomial regression models. RESULTS: Adjusted response rate was 60.6%. Of the DHs included in analysis (n=341), 80% were employed in general practice, and nearly all (96%) worked in the private sector. About half (53.7%) of all service provided were preventive services, and one-fourth (23.9%) were diagnostic. Service provision varied by practice and practitioner characteristics, with the largest variations observed by practice type. Unadjusted analysis showed that general practice DHs provided a higher mean number of periodontal instrumentation and coronal polishing (0.92 vs 0.26), fluoride applications (0.64 vs 0.08), oral examinations (0.51 vs 0.22) and intraoral radiographs (0.33 vs 0.07) per patient visit and a lower mean number of impressions (0.05 vs 0.17) and orthodontic services (0.02 vs 0.59) than specialist practice DHs. In adjusted analysis, rates of periodontal services also significantly varied by practice type; other associations persisted. CONCLUSION: Service provision of DHs varied by practice type. Practice activity was dominated by provision of preventive services while provision of periodontal treatments, fissure sealants and oral examinations was relatively limited indicating areas in which DHs are possibly underutilized. PMID- 28809085 TI - Electric and Mechanical Switching of Ferroelectric and Resistive States in Semiconducting BaTiO3-delta Films on Silicon. AB - Materials that can couple electrical and mechanical properties constitute a key element of smart actuators, energy harvesters, or many sensing devices. Within this class, functional oxides display specific mesoscale responses which often result in great sensitivity to small external stimuli. Here, a novel combination of molecular beam epitaxy and a water-based chemical-solution method is used for the design of mechanically controlled multilevel device integrated on silicon. In particular, the possibility of adding extra functionalities to a ferroelectric oxide heterostructure by n-doping and nanostructuring a BaTiO3 thin film on Si(001) is explored. It is found that the ferroelectric polarization can be reversed, and resistive switching can be measured, upon a mechanical load in epitaxial BaTiO3-delta /La0.7 Sr0.3 MnO3 /SrTiO3 /Si columnar nanostructures. A flexoelectric effect is found, stemming from substantial strain gradients that can be created with moderate loads. Simultaneously, mechanical effects on the local conductivity can be used to modulate a nonvolatile resistive state of the BaTiO3-delta heterostructure. As a result, three different configurations of the system become accessible on top of the usual voltage reversal of polarization and resistive states. PMID- 28809086 TI - Who, where, what and where to now? A snapshot of publishing patterns in Australian orthopaedic surgery. AB - BACKGROUND: Development of core research competency is a principle of orthopaedic surgical training in Australia. This paper aims to provide an objective snapshot of publications by Australian orthopaedic trainees and surgeons, to contribute to the discussion on how to identify and build on research capability in the Australian Orthopaedic Association (AOA). METHODS: By analysing journals with a journal impact factor >1 from 2009 to 2015, data were gathered to explore scientific journal publications by Australian orthopaedic surgeons and trainees in relation to who are the authors, what they are reporting and where they are publishing. RESULTS: One thousand five hundred and thirty-nine articles were identified with 134 orthopaedic trainees and 519 surgeons as authors. The publication rate for both trainees and surgeons was just over two in five. The majority of studies were of level three or four evidence (Oxford's Centre for Evidence-Based Medicine guidelines). Only 5% of trainee papers were published without surgeons' co-authorship. Eighty-six percent of papers published by surgeons did not involve a trainee. The rates of trainees publishing with other trainees were low. CONCLUSION: Only 5% of trainee papers were published without surgeons' co-authorship, highlighting the importance of surgeon mentorship in developing trainee research capability. The 86% of papers published by surgeons without trainee co-authorship raises the question of missed mentoring opportunities. Low rates of trainee co-authorship highlight potential for trainees to work together to support each other's research efforts. There is scope for more studies involving higher levels of evidence. This paper raises discussion points and areas for further exploration in relation to AOA trainee research capability. PMID- 28809088 TI - The analysis of illicit 25X-NBOMe seizures in Western Australia. PMID- 28809087 TI - Spontaneous reporting of suspected narcolepsy after vaccination against pandemic influenza A (H1N1) in Germany. AB - PURPOSE: We aimed at investigating whether, in Germany, the number of individual case safety reports (ICSR) of confirmed narcolepsy following Pandemrix(r) vaccination notified to the Paul-Ehrlich-Institut (PEI, German Federal Institute for Vaccines and Biomedicines) was higher than expected when compared with the prepandemic background incidence rates. METHODS: ICSR of narcolepsy after vaccination with Pandemrix(r) notified to the PEI until September 2016 were reviewed and validated according to the criteria of narcolepsy defined by the Brighton Collaboration (BC). Cases fulfilling the criteria of BC levels of diagnostic certainty 1 to 4a with symptoms onset after vaccination with Pandemrix(r) were eligible. Adjustment for underreporting was performed with cases of narcolepsy recruited within the scope of the German Narcolepsy Study using capture-recapture methods. An observed versus expected (OvE) analysis was conducted based on adjusted case numbers using risk windows for symptoms onset within 4 and 6 months following vaccination. RESULTS: By the end of September 2016, a total of 85 ICSR of narcolepsy after vaccination with Pandemrix(r) had been notified to the PEI 52 of which were eligible. The OvE estimates for the 4 and 6 months risk windows were 3.8 (95% CI: 2.6-5.4) and 2.8 (95% CI: 2.0-3.9), respectively. The number of excess cases was higher in children and adolescents (15-fold and 11.7-fold increased OvE estimate) than in adults (2.1-fold and 1.5 fold increased estimate). CONCLUSIONS: Compared with the prepandemic background incidence rate, the number of incident narcolepsy cases was 3.8-fold and 2.8-fold as high. PMID- 28809090 TI - The association between P selectin glycoprotein ligand 1 gene variable number of tandem repeats polymorphism and risk of thrombosis in Behcet's disease. AB - OBJECTIVES: Behcet's disease (BD) has been recognized as an unclassified type of vasculitis with an accompanying tendency to thrombosis. No disease-specific pathology has been demonstrated so far to explain the prothrombotic state, and this predisposition is considered to be associated with endothelial activation/dysfunction. P-selectin glycoprotein ligand-1 (PSGL-1) variable number of tandem repeat (VNTR) polymorphism has an impact on the protein length, and heterozygosity affect of the PSGL-1 to P-selectin interaction, which has been found to be associated with an increased risk of thrombosis in patients with antiphospholipid syndrome. We aimed to analyze the association of PSGL-1 gene polymorphism, in a group of BD patients with and without thrombosis. METHODS: The study group consisted of 136 BD patients (112 male, 24 female) with thrombosis, 120 BD patients without thrombosis (54 male, 66 female) during at least 5 years disease course, and 190 healthy controls (103 male, 87 female) All patients fulfilled the International Study Group criteria for classification of BD. Genotyping for the PSGL-1 gene exon 2 VNTR polymorphism was carried out with the amplification of genomic DNA and running of the polymerase chain reaction product on agarose gel electrophoresis. RESULTS: The frequency of heterozygous genotypes (AB+AC+BC) was greater in BD patients with thrombosis compared to BD patients without thrombosis (33.1% vs. 20.8%, P = 0.028, odds ratio = 1.85). However, the increased frequency of heterozygous genotypes in BD patients with thrombosis did not reach a statistically significant level compared to healthy controls (33.1% vs. 32.6%). CONCLUSIONS: PSGL-1 VNTR polymorphism may have limited contribution to the thrombotic tendency in patients with BD. PMID- 28809089 TI - Inverted Quasi-Spherical Droplets on Polydopamine-TiO2 Substrates for Enhancing Gene Delivery. AB - Devising efficient gene delivery systems is crucial to enhancing the therapeutic efficacy of gene-cell therapy approaches. Herein, inverted quasi-spherical (iQS) droplet systems, which enhance gene delivery efficiencies by reducing the path lengths of gene vectors, mediating motions of vectors at early stages, and raising the contact frequencies of vectors with cells, are developed by adopting the principle of 3D hanging-drop cell culture. Micrometer-sized polydopamine (pDA) holes are created on superhydrophobic titanium isopropoxide (TiO2 )-coated substrates by physical scraping; droplets are loaded on the pDA holes, and inversion of the substrate generates iQS droplets with large contact angles. Both human neural stem cells (hNSCs) and adeno-associated viral vectors are simultaneously incorporated into the iQS droplets to assess gene delivery efficiencies. The steep angles of iQS droplets and enhanced cell/vector contact frequencies facilitate the viral association with hNSCs and enhancing cell-cell interactions, thereby significantly promoting gene delivery efficiencies. Even with reduced viral quantities/exposure times and cell numbers, the iQS droplet systems elicit sufficient gene expression (i.e., interleukin-10). The ability of the iQS droplet systems to maximize beneficial gene delivery effects with minimal materials (e.g., medium, cells, and vectors) should enable their extensive use as a platform for preparing genetically stimulated cellular therapeutics. PMID- 28809091 TI - Different localizations of drugs simultaneously administered in a strand of hair by micro-segmental analysis. AB - Segmental hair analysis is used to estimate the time of drug intake at monthly precision in drug-related crimes. Previously, we advanced this analytical method to specify the day of drug intake by cutting a strand of hair into 0.4-mm segments, which correspond to daily hair growth. Herein, we investigated the distributions of 7 compounds in a strand of hair using micro-segmental analysis. Several strands of hair were collected 33.1-229.4 days after subjects were administered 4 pharmaceutical products that contained 10 drugs in single doses within 32 hours. The administered drugs and resulting metabolites were extracted from 0.4-mm hair segments and quantified using liquid chromatography-tandem mass spectrometry. Acidic and neutral compounds were detected at low amounts in any of the hair segments analyzed. Epinastine, fexofenadine, dihydrocodeine, chlorpheniramine, and the chlorpheniramine metabolite, desmethylchlorpheniramine each was localized to 2 regions within a strand of hair. By contrast, methylephedrine and its metabolite, ephedrine, each was localized to only a region. Among 20 individual strands of hair associated with different subjects and head regions, few differences in the shapes of drug concentration-hair segment curves for each compound were detected. Our data indicated that 2 mechanisms for drug uptake into hair can operate depending on drug properties and that co-administered drugs can be localized to different regions in a strand of hair. Micro-segmental analysis may aid in the identification of the day of drug intake and help to elucidate the mechanisms of drug uptake into hair. PMID- 28809092 TI - Particle Targeting in Complex Biological Media. AB - Over the past few decades, nanoengineered particles have gained increasing interest for applications in the biomedical realm, including diagnosis, imaging, and therapy. When functionalized with targeting ligands, these particles have the potential to interact with specific cells and tissues, and accumulate at desired target sites, reducing side effects and improve overall efficacy in applications such as vaccination and drug delivery. However, when targeted particles enter a complex biological environment, the adsorption of biomolecules and the formation of a surface coating (e.g., a protein corona) changes the properties of the carriers and can render their behavior unpredictable. For this reason, it is of importance to consider the potential challenges imposed by the biological environment at the early stages of particle design. This review describes parameters that affect the targeting ability of particulate drug carriers, with an emphasis on the effect of the protein corona. We highlight strategies for exploiting the protein corona to improve the targeting ability of particles. Finally, we provide suggestions for complementing current in vitro assays used for the evaluation of targeting and carrier efficacy with new and emerging techniques (e.g., 3D models and flow-based technologies) to advance fundamental understanding in bio-nano science and to accelerate the development of targeted particles for biomedical applications. PMID- 28809093 TI - Caregiving for children with type 1 diabetes and clinical outcomes in central India: The IDREAM study. AB - AIMS: Parental care influences outcomes for children's type 1 diabetes (T1D). There is little evidence about the impact of parental caregiving in developing countries, where fixed dose human insulin (conventional) therapy and limited self monitoring of blood glucose are common. This article investigates whether performance of key T1D management tasks by children or their caregivers impacts hemoglobin A1c (HbA1c). METHODS: We surveyed the caregivers of 179 children with T1D routinely treated in a specialized diabetes clinic in Maharashtra, India to determine who performs key diabetes care tasks: child or parent. We used linear regression to estimate the relationship between parental caregiving and HbA1c, and how this association varies by child age and time since diagnosis. RESULTS: Caregivers of older children were less involved in care tasks, though caregivers of 11- to 18-year olds performed more care for children diagnosed for a longer duration. Parental involvement in key insulin delivery tasks was associated with lower HbA1c levels for all children. These reductions were greatest among children 11 to 14 years old and diagnosed for less than 2 years: mean HbA1c levels were 8.5% (69 mmol/mol) if the caregiver, and 14.4% (134 mmol/mol) if the child, performed the tasks (P < .05). CONCLUSION: Parents of children diagnosed with T1D early in life remain involved in care throughout the child's adolescence. Parents of children diagnosed in late childhood and early adolescence are significantly less involved in care, and this is associated with worse glycemic control. Clinics must know who performs care tasks and tailor diabetes education appropriately. PMID- 28809094 TI - An automated skills assessment framework for laparoscopic training tasks. AB - BACKGROUND: Various sensors and methods are used for evaluating trainees' skills in laparoscopic procedures. These methods are usually task-specific and involve high costs or advanced setups. METHODS: In this paper, we propose a novel manoeuver representation feature space (MRFS) constructed by tracking the vanishing points of the edges of the graspers on the video sequence frames, acquired by the standard box trainer camera. This study aims to provide task agnostic classification of trainees in experts and novices using a single MRFS over two basic laparoscopic tasks. RESULTS: The system achieves an average of 96% correct classification ratio (CCR) when no information on the performed task is available and >98% CCR when the task is known, outperforming a recently proposed video-based technique by >13%. CONCLUSIONS: Robustness, extensibility and accurate task-agnostic classification between novices and experts is achieved by utilizing advanced computer vision techniques and derived features from a novel MRFS. PMID- 28809095 TI - Isocyanate-Free, UV-Crosslinked Poly(Hydroxyurethane) Networks: A Sustainable Approach toward Highly Functional Antibacterial Gels. AB - An increased sustainabile awarness has inspired the development of new polymeric networks in a remarkable way and this strive should be combined with environmentally concerned end-uses. Therefore, a UV-crosslinked polyhydroxyurethane film with antibacterial properties is developed. First, a hydroxyurethane precursor is synthesized using aminolysis condensation, circumventing the use of isocyanates. The films are subsequently crosslinked under solvent-free conditions through a UV-triggered thiol-ene mechanism. The reactions are monitored by 1 H nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, and Raman spectroscopy, and the networks have gel contents above 90%, and are transparent, hydrophilic, and highly flexible. Antibacterial properties are achieved by a controlled quaternization of the network's tertiary-amine and methylation of thiol-ether functionality, resulting in quaternary ammonium compounds (QACs) and sulfonium compounds. The antibacterial properties are evaluated against both Escherichia coli and Staphylococcus aureus using the agar plate diffusion and tube shaking methods. The QAC-loaded films exhibit outstanding bactericide properties (>99.9%) and the antibacterial mechanism is demonstrated to be a dual killing mechanism, i.e., diffusion killing and contact active killing. PMID- 28809096 TI - Pancreatico-jejunostomy decreases post-operative pancreatic fistula incidence and severity after central pancreatectomy. AB - BACKGROUNDS: Central pancreatectomy (CP) is an alternative to pancreaticoduodenectomy and distal pancreatectomy in benign tumours of pancreatic isthmus management. It is known for a high post-operative pancreatic fistula (POPF) rate. The purpose of this study was to compare POPF incidence between pancreatico-jejunostomy (PJ) and pancreatico-gastrostomy (PG). METHODS: Fifty eight patients (mean age 53.9 +/- 1.9 years) who underwent a CP in four French University Hospitals from 1988 to 2011 were analysed. The distal pancreatic remnant was either anastomosed to the stomach (44.8%, n = 25) or to a Roux-en-Y jejunal loop (55.2%, n = 35) with routine external drainage allowing a systematic search for POPF. POPF severity was classified according to the International Study Group on Pancreatic Fistula (ISGPF) and Clavien-Dindo classifications. RESULTS: The groups were similar on sex ratio, mean age, ASA score, pancreas texture, operative time and operative blood loss. Mean follow-up was 36.2 +/- 3.9 months. POPF were significantly more frequent after PG (76.9 versus 37.5%, P = 0.003). PG was associated with significantly higher grade of POPF both when graded with ISGPF classification (P = 0.012) and Clavien-Dindo classification (P = 0.044). There was no significant difference in post-operative bleeding (0.918) and delayed gastric emptying (0.877) between the two groups. Hospital length of stay was increased after PG (23.6 +/- 3.5 days versus 16.5 +/- 1.9 days, P = 0.071). There was no significant difference in incidence of long-term exocrine (3.8 versus 19.2%, P = 0.134) and endocrine (7.7 versus 9.4%, P = 0.575) pancreatic insufficiencies. CONCLUSION: PG was associated with a significantly higher POPF incidence and severity in CP. We recommend performing PJ especially in older patients to improve CP outcomes. PMID- 28809098 TI - Interfacially Engineered Pyridinium Pseudogemini Surfactants as Versatile and Efficient Supramolecular Delivery Systems for DNA, siRNA, and mRNA. AB - This article presents the synthesis, self-assembly, and biological activity as transfection agents for pDNA, siRNA, and mRNA of novel pyridinium pseudogemini surfactants, interfacially engineered from the most efficient gemini surfactants and lipids generated in our amphiphile research program. Formulation of novel amphiphiles in water revealed supramolecular properties very similar to those of gemini surfactants, despite their lipidlike charge/mass ratio. This dual character was found also to enhance endosomal escape and significantly increase the transfection efficiency. We were also successful in identifying the parameters governing the efficient delivery of pDNA, siRNA, and mRNA, drawing valuable structure-activity and structure-property relationships for each nucleic acid type, and establishing DNA/siRNA/mRNA comparisons. Several supramolecular complexes identified in this study proved to be extremely efficient nucleic acid delivery systems, displaying excellent serum stability and tissue penetration in three-dimensional organoids. PMID- 28809099 TI - Assembly of TeO32- Ions Embedded in an Nb/O Cage with Selective Decolorization of Organic Dye. AB - A novel 24-niobic-2-tellurite, [H2Te2Nb24O72]14-, was isolated by incorporating tellurite anions into a polyoxoniobate cage. The synthesized cluster represents the first example of a sandwich-type polyoxoniobate with the largest telluroniobate aggregate. Furthermore, the hybrid material acts as an efficient catalyst for the decolorization of basic fuchsin. PMID- 28809097 TI - Piconewton-Scale Analysis of Ras-BRaf Signal Transduction with Single-Molecule Force Spectroscopy. AB - Intermolecular interactions dominate the behavior of signal transduction in various physiological and pathological cell processes, yet assessing these interactions remains a challenging task. Here, this study reports a single molecule force spectroscopic method that enables functional delineation of two interaction sites (~35 pN and ~90 pN) between signaling effectors Ras and BRaf in the canonical mitogen-activated protein kinase (MAPK) pathway. This analysis reveals mutations on BRaf at Q257 and A246, two sites frequently linked to cardio faciocutaneous syndrome, result in ~10-30 pN alterations in Ras?BRaf intermolecular binding force. The magnitude of changes in Ras?BRaf binding force correlates with the size of alterations in protein affinity and in alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-sensitive glutamate receptor ( R)-mediated synaptic transmission in neurons expressing replacement BRaf mutants, and predicts the extent of learning impairments in animals expressing replacement BRaf mutants. These results establish single-molecule force spectroscopy as an effective platform for evaluating the piconewton-level interaction of signaling molecules and predicting the behavior outcome of signal transduction. PMID- 28809100 TI - Porous Carbon Materials Based on Graphdiyne Basis Units by the Incorporation of the Functional Groups and Li Atoms for Superior CO2 Capture and Sequestration. AB - The graphdiyne family has attracted a high degree of concern because of its intriguing and promising properties. However, graphdiyne materials reported to date represent only a tiny fraction of the possible combinations. In this work, we demonstrate a computational approach to generate a series of conceivable graphdiyne-based frameworks (GDY-Rs and Li@GDY-Rs) by introducing a variety of functional groups (R = -NH2, -OH, -COOH, and -F) and doping metal (Li) in the molecular building blocks of graphdiyne without restriction of experimental conditions and rapidly screen the best candidates for the application of CO2 capture and sequestration (CCS). The pore topology and morphology and CO2 adsorption and separation properties of these frameworks are systematically investigated by combining density functional theory (DFT) and grand canonical Monte Carlo (GCMC) simulations. On the basis of our computer simulations, combining Li-doping and hydroxyl groups strategies offer an unexpected synergistic effect for efficient CO2 capture with an extremely CO2 uptake of 4.83 mmol/g at 298 K and 1 bar. Combined with its superior selectivity (13 at 298 K and 1 bar) for CO2 over CH4, Li@GDY-OH is verified to be one of the most promising materials for CO2 capture and separation. PMID- 28809101 TI - A Microsphere-Supported Lipid Bilayer Platform for DNA Reactions on a Fluid Surface. AB - We report a versatile microsphere-supported lipid bilayer system that can serve as a general-purpose platform for implementing DNA nanotechnologies on a fluid surface. To demonstrate our platform, we implemented both toehold-mediated strand displacement (TMSD) and DNAzyme reactions, which are typically performed in solution and which are the cornerstone of DNA-based molecular logic and dynamic DNA nanotechnology, on the surface. We functionalized microspheres bearing supported lipid bilayers (MUSLBs) with membrane-bound nucleic acid components. Using functionalized MUSLBs, we developed TMSD and DNAzyme reactions by optimizing reaction conditions to reduce nonspecific interactions between DNA and phospholipids and to enhance bilayer stability. Additionally, the physical and optical properties of the bilayer were tuned via lipid composition and addition of fluorescently tagged lipids to create stable and multiplexable MUSLBs that are easily read out by flow cytometry. Multiplexed TMSD reactions on MUSLBs enabled the successful operation of a Dengue serotyping assay that correctly identified all 16 patterns of target sequences to demonstrate detection of DNA strands derived from the sequences of all four Dengue serotypes. The limit of detection for this assay was 3 nM. Furthermore, we demonstrated DNAzyme reactions on a fluid lipid surface, which benefit from free diffusion on the surface. This work provides the basis for expansion of both TMSD and DNAzyme based molecular reactions on supported lipid bilayers for use in molecular logic and DNA nanotechnology. As our system is multiplexable and results in fluid surfaces, it may be of use in compartmentalization and improved kinetics of molecular logic reactions and as a useful building block in a variety of DNA nanotechnology systems. PMID- 28809102 TI - Hyper Open-Shell States: The Lowest Excited Spin States of O Atom, Fe2+ Ion, and FeF2. AB - Excited spin states are important for reactivity, catalysis, and magnetic applications. This work examines the relative energies of the spin states of O atom, Fe2+ ion, and FeF2 and characterizes their excited spin states. Both single configuration and multireference methods are used to establish the character of the lowest singlet excited state of all three systems and the lowest triplet excited state of Fe2+ and FeF2. We find that the conventional representation of the orbital occupancies is incorrect in that the states have more unpaired electrons than the minimum number required by their total electron spin quantum number. In particular, we find that, for a given spin state, an electronic configuration with more than 2S unpaired electrons is more stable than the configuration with 2S unpaired electrons (where S is the spin of the system). For instance, triplet FeF2 with four unpaired electrons is lower in energy than triplet FeF2 with two unpaired electrons. Such highly open-shell configurations are labeled as hyper open-shell electronic configurations in this work and are compared to ordinary open-shell or closed-shell electronic configurations. The hyper open-shell states considered in this work are especially interesting because, unlike typical biradicals and polyradicals, the unpaired electrons are all on the same center. This work shows that the conventional perspective on spin state energetics that usually assumes ordinary open shells for single-centered radicals needs modification to take into account, whenever possible, hyper open shell configurations as well. PMID- 28809103 TI - Chiral PEDOT-Based Enantioselective Electrode Modification Material for Chiral Electrochemical Sensing: Mechanism and Model of Chiral Recognition. AB - The development of electrochemical methods for enantioselective recognition is a focus of research in pharmaceuticals and biotechnology. In this study, a pair of water-soluble chiral 3,4-ethylenedioxythiophene (EDOT) derivatives, (R)-2' hydroxymethyl-3,4-ethylenedioxythiophene ((R)-EDTM) and (S)-2'-hydroxymethyl-3,4 ethylenedioxythiophene ((S)-EDTM), were synthesized and electrodeposited on the surface of a glassy carbon electrode (GCE) via current-time (I-t) polymerization in an aqueous LiClO4 electrolyte. These chiral PEDOT polymers were used to fabricate chiral sensors and to investigate the enantioselective recognition of d /l-3,4-dihydroxyphenylalanine, d-/l-tryptophan, and (R)-/(S)-propranolol enantiomers, respectively. The results indicated that the (R)-PEDTM/GCE sensor showed a higher peak current response toward the levo or (S) forms of the tested enantiomers, while the opposite phenomenon occurred for (S)-PEDTM/GCE. The mechanism of the stereospecific interaction between these enantiomers and the chiral polymers was determined. Therefore, a model of the chiral recognition by the chiral conducting polymer electrodes and an electrochemical method was proposed. The chirality of the enantiomers was confirmed by two parameters: the chirality of the electrode and the peak current response. These findings pave the way for the application of chiral PEDOT as electrode modification material in the electrochemical chiral recognition field. PMID- 28809104 TI - Large-Scale Multifunctional Electrochromic-Energy Storage Device Based on Tungsten Trioxide Monohydrate Nanosheets and Prussian White. AB - A high-performance electrochromic-energy storage device (EESD) is developed, which successfully realizes the multifunctional combination of electrochromism and energy storage by constructing tungsten trioxide monohydrate (WO3.H2O) nanosheets and Prussian white (PW) film as asymmetric electrodes. The EESD presents excellent electrochromic properties of broad optical modulation (61.7%), ultrafast response speed (1.84/1.95 s), and great coloration efficiency (139.4 cm2 C-1). In particular, remarkable cyclic stability (sustaining 82.5% of its initial optical modulation after 2500 cycles as an electrochromic device, almost fully maintaining its capacitance after 1000 cycles as an energy storage device) is achieved. The EESD is also able to visually detect the energy storage level via reversible and fast color changes. Moreover, the EESD can be combined with commercial solar cells to constitute an intelligent operating system in the architectures, which would realize the adjustment of indoor sunlight and the improvement of physical comfort totally by the rational utilization of solar energy without additional electricity. Besides, a scaled-up EESD (10 * 11 cm2) is further fabricated as a prototype. Such promising EESD shows huge potential in practically serving as electrochromic smart windows and energy storage devices. PMID- 28809105 TI - Linear-to-lambda-Shape P-O-P Bond Transmutation in Polyphosphates with Infinite (PO3)infinity Chain. AB - A new metal polyphosphate, alpha-CsBa2(PO3)5, exhibiting the first example of a linear P-O-P bond angle in a one-dimensional (PO3)infinity chain has been reported. Interestingly, alpha -> beta phase transition occurs in CsBa2(PO3)5 along with the P-O-P bonds varying from linear to lambda-shape, suggesting that alpha-CsBa2(PO3)5 with unfavorable linear P-O-P bonds is more stable at ambient temperature. PMID- 28809106 TI - Structural Characteristics and Function of a New Kind of Thermostable Trehalose Synthase from Thermobaculum terrenum. AB - Trehalose has important applications in the food industry and pharmaceutical manufacturing. The thermostable enzyme trehalose synthase from Thermobaculum terrenum (TtTS) catalyzes the reversible interconversion of maltose and trehalose. Here, we investigated the structural characteristics of TtTS in complex with the inhibitor TriS. TtTS exhibits the typical three domain glycoside hydrolase family 13 structure. The catalytic cleft consists of Asp202-Glu244 Asp310 and various conserved substrate-binding residues. However, among trehalose synthases, TtTS demonstrates obvious thermal stability. TtTS has more polar (charged) amino acids distributed on its protein structure surface and more aromatic amino acids buried within than other mesophilic trehalose synthases. Furthermore, TtTS structural analysis revealed four potential metal ion-binding sites rather than the two in a homologous structure. These factors may render TtTS relatively more thermostable among mesophilic trehalose synthases. The detailed thermophilic enzyme structure provided herein may provide guidance for further protein engineering in the design of stabilized enzymes. PMID- 28809108 TI - Dual Regulations of Thermosensitive Heparin-Poloxamer Hydrogel Using epsilon Polylysine: Bioadhesivity and Controlled KGF Release for Enhancing Wound Healing of Endometrial Injury. AB - Hydrogel was not only used as an effective support matrix to prevent intrauterine adhesion after endometrial injury but also served as scaffold to sustain release of some therapeutics, especially growth factor. However, because of the rapid turnover of the endometrial mucus, the poor retention and bad absorption of therapeutic agents in damaged endometrial cavity were two important factors hindering their pharmacologic effect. Herein, a mucoadhesive hydrogel was described by using heparin-modified poloxamer (HP) as the matrix material and epsilon-polylysine (EPL) as functional excipient. Various EPL-HP hydrogels formulations are screened by rheological evaluation and mucoadhesion studies. It was found that the rheological and mucoadhesive properties of EPL-HP hydrogels were easily controlled by changing the amount of EPL in formulation. The storage modulus of EPL-HP hydrogel with 90 MUg/mL of EPL (EPL-HP-90) was elevated to be 1.9 * 105 Pa, in accordance with the adhesion force rising to 3.18 N (10-fold higher than HP hydrogels). Moreover, in vitro release of model drug keratinocyte growth factor (KGF) from EPL-HP hydrogel was significantly accelerated by adding EPL in comparison with HP hydrogel. Both strong mucoadhesive ability and the accelerated drug release behavior for EPL-HP-90 made more of the encapsulated KGF absorbed by the uterus basal layer and endometrial glands after 8 h of administration in uterus cavity. Meanwhile, the morphology of endometrium in the injured uterus was repaired well after 3 d of treatment with KGF-EPL-HP-90 hydrogels. Compared with KGF-HP group, not only proliferation of endometrial epithelial cell and glands but also angiogenesis in the regenerated endometrium was obviously enhanced after treatment with KGF-EPL-HP-90 hydrogels. Alternatively, the cellular apoptosis in the damaged endometrium was significantly inhibited after treatment with KGF-EPL-HP-90 hydrogels. Overall, the mucoadhesive EPL-HP hydrogel with a suitable KGF release profile may be a more promising approach than HP hydrogel alone to repair the injured endometrium. PMID- 28809107 TI - Synthesis and Insecticidal Activity of Enzyme-Triggered Functionalized Hollow Mesoporous Silica for Controlled Release. AB - In the present study, enzymatic responsive controlled release formulations (CRFs) were fabricated. The CRFs were achieved by anchoring mechanically interlocked molecules using alpha-cyclodextrin onto the surface pore rims of hollow mesoporous silica (HMS). The CRFs were characterized using Fourier transform infrared spectroscopy, scanning electron microscopy, transmission electron microscopy, and thermogravimetric analysis. The results showed that the CRFs had extraordinary loading ability for chlorantraniliprole (42% w/w) and could effectively preserve chlorantraniliprole against degradation under thermal conditions and UV radiation. The CRFs have been proven to be enzyme-sensitive. The release ratio of chlorantraniliprole from CRFs can be accelerated observably when external alpha-amylase was introduced. The persistence of CRFs was evaluated by regular sampling feeding experiment using Plutella xylostella as the target insect. The results showed that the larval mortality of P. xylostella was much higher than that of Coragen under all concentrations after 14 days, which proved that CRFs had remarkable persistence. PMID- 28809109 TI - Characterization of Rotational Stacking Layers in Large-Area MoSe2 Film Grown by Molecular Beam Epitaxy and Interaction with Photon. AB - Transition metal dichalcogenides (TMDCs) are promising next-generation materials for optoelectronic devices because, at subnanometer thicknesses, they have a transparency, flexibility, and band gap in the near-infrared to visible light range. In this study, we examined continuous, large-area MoSe2 film, grown by molecular beam epitaxy on an amorphous SiO2/Si substrate, which facilitated direct device fabrication without exfoliation. Spectroscopic measurements were implemented to verify the formation of a homogeneous MoSe2 film by performing mapping on the micrometer scale and measurements at multiple positions. The crystalline structure of the film showed hexagonal (2H) rotationally stacked layers. The local strain at the grain boundaries was mapped using a geometric phase analysis, which showed a higher strain for a 30 degrees twist angle compared to a 13 degrees angle. Furthermore, the photon-matter interaction for the rotational stacking structures was investigated as a function of the number of layers using spectroscopic ellipsometry. The optical band gap for the grown MoSe2 was in the near-infrared range, 1.24-1.39 eV. As the film thickness increased, the band gap energy decreased. The atomically controlled thin MoSe2 showed promise for application to nanoelectronics, photodetectors, light emitting diodes, and valleytronics. PMID- 28809110 TI - Deprotonative Silylation of Aromatic C-H Bonds Mediated by a Combination of Trifluoromethyltrialkylsilane and Fluoride. AB - A method for the deprotonative silylation of aromatic C-H bonds has been developed using trifluoromethyltrimethylsilane (CF3SiMe3, Ruppert-Prakash reagent) and a catalytic amount of fluoride. In this reaction, CF3SiMe3 is considered to act as a base and a silicon electrophile. This process is highly tolerant to various functional groups on heteroarenes and benzenes. Furthermore, this method can be applied to the synthesis of trimethylsilyl group-containing analogs of TAC-101, which is a bioactive synthetic retinoid with selective affinity for retinoic acid receptor alpha (RAR-alpha) binding. We also report further transformations of the silylated products into useful derivatives. PMID- 28809111 TI - Tumor Acidic Microenvironment Targeted Drug Delivery Based on pHLIP-Modified Mesoporous Organosilica Nanoparticles. AB - Enhancing the tumor-targeting delivery of chemotherapeutic drugs is important yet challenging for improving therapeutic efficacy and reducing the side effects. Here, we first construct a drug delivery system for targeting tumor acidic microenvironment by modification of pH (low) insertion peptide (pHLIP) on mesoporous organosilica nanoparticles (MONs). The MONs has thioether-bridged framework, uniform diameter (60 nm), good biocompatibility, and high doxorubicin (DOX) loading capacity (334 mg/g). The DOX loaded in the pHLIP modified MONs can be released responsive to glutathione and low pH circumstance, ensuring the chemotherapeutic drug exerts higher cytotoxic effects to cancer cells than normal cells because of high intracellular GSH of tumor cells and low pH of tumor microenvironment. Moreover, the engineered MONs exhibit higher cellular uptake in pH 6.5 medium by MDA-MB-231 and MCF-7 cells than the particles decorated with polyethylene glycol (PEG). Importantly, the pHLIP-mosaic MONs with DOX displays better cytotoxic effects against the breast cancer cells in pH 6.5 medium than pH 7.4 medium. The in vivo experiments demonstrate that the pHLIP modified MONs are accumulated in the orthotopic breast cancer via targeting to acidic tumor microenvironment while no serious pathogenic effects was observed. After loading DOX, the pHLIP-modified MONs display better therapeutic effects than the control groups on the growth of MCF-7 breast cancers, showing promise for enhancing chemotherapy. PMID- 28809112 TI - MOFs for the Sensitive Detection of Ammonia: Deployment of fcu-MOF Thin Films as Effective Chemical Capacitive Sensors. AB - This work reports on the fabrication and deployment of a select metal-organic framework (MOF) thin film as an advanced chemical capacitive sensor for the sensing/detection of ammonia (NH3) at room temperature. Namely, the MOF thin film sensing layer consists of a rare-earth (RE) MOF (RE-fcu-MOF) deposited on a capacitive interdigitated electrode (IDE). Purposely, the chemically stable naphthalene-based RE-fcu-MOF (NDC-Y-fcu-MOF) was elected and prepared/arranged as a thin film on a prefunctionalized capacitive IDE via the solvothermal growth method. Unlike earlier realizations, the fabricated MOF-based sensor showed a notable detection sensitivity for NH3 at concentrations down to 1 ppm, with a detection limit appraised to be around 100 ppb (at room temperature) even in the presence of humidity and/or CO2. Distinctly, the NDC-Y-fcu-MOF based sensor exhibited the required stability to NH3, in contrast to other reported MOFs, and a remarkable detection selectivity toward NH3 vs CH4, NO2, H2, and C7H8. The NDC Y-fcu-MOF based sensor exhibited excellent performance for sensing ammonia for simulated breathing system in the presence of the mixture of carbon dioxide and/or humidity (water vapor), with no major alteration in the detection signal. PMID- 28809113 TI - Theoretical Investigation of Methane Hydroxylation over Isoelectronic [FeO]2+- and [MnO]+-Exchanged Zeolites Activated by N2O. AB - While the most likely structure of the active site in iron-containing zeolites has been recently identified as [FeO]2+ (Snyder et al. Nature 2016, 536, 317 321), the mechanism for the direct conversion of methane to methanol over this active species is still debatable between the direct-radical-rebound or nonradical (concerted) mechanism. Using density functional theory on periodic systems, we calculated the two reaction mechanisms over two d4 isoelectronic systems, [FeO]2+ and [MnO]+ zeolites. We found that [FeO]2+ zeolites favor the direct-radical-rebound mechanism with low CH4 activation energies, while [MnO]+ zeolites prefer the nonradical mechanism with higher CH4 activation energies. These contrasts, despite their isoelectronic structures, are mainly due to the differences in the metal coordination number and Oalpha (oxo) spin density. Moreover, molecular orbital analyses suggest that the zeolite steric hindrance further degrades the reactivity of [MnO]+ zeolites toward methane. Two types of zeolite frameworks, i.e., medium-pore ZSM-5 (MFI framework) and small-pore SSZ-39 (AEI framework) zeolites, were evaluated, but no significant differences in the reactivity were found. The rate-determining reaction step is found to be methanol desorption instead of methane activation. Careful examination of the most stable sites hosting the active species and calculation for N2O decomposition over [Fe]2+-MFI and -AEI zeolites were also performed. PMID- 28809114 TI - Boolean Logic Tree of Label-Free Dual-Signal Electrochemical Aptasensor System for Biosensing, Three-State Logic Computation, and Keypad Lock Security Operation. AB - The most serious and yet unsolved problems of molecular logic computing consist in how to connect molecular events in complex systems into a usable device with specific functions and how to selectively control branchy logic processes from the cascading logic systems. This report demonstrates that a Boolean logic tree is utilized to organize and connect "plug and play" chemical events DNA, nanomaterials, organic dye, biomolecule, and denaturant for developing the dual signal electrochemical evolution aptasensor system with good resettability for amplification detection of thrombin, controllable and selectable three-state logic computation, and keypad lock security operation. The aptasensor system combines the merits of DNA-functionalized nanoamplification architecture and simple dual-signal electroactive dye brilliant cresyl blue for sensitive and selective detection of thrombin with a wide linear response range of 0.02-100 nM and a detection limit of 1.92 pM. By using these aforementioned chemical events as inputs and the differential pulse voltammetry current changes at different voltages as dual outputs, a resettable three-input biomolecular keypad lock based on sequential logic is established. Moreover, the first example of controllable and selectable three-state molecular logic computation with active-high and active-low logic functions can be implemented and allows the output ports to assume a high impediment or nothing (Z) state in addition to the 0 and 1 logic levels, effectively controlling subsequent branchy logic computation processes. Our approach is helpful in developing the advanced controllable and selectable logic computing and sensing system in large-scale integration circuits for application in biomedical engineering, intelligent sensing, and control. PMID- 28809116 TI - Organoimido-Polyoxometalate Nonlinear Optical Chromophores: A Structural, Spectroscopic, and Computational Study. AB - Ten organoimido polyoxometalate (POM)-based chromophores have been synthesized and studied by hyper-Rayleigh scattering (HRS), Stark and Resonance Raman spectroscopies, and density functional theory (DFT) calculations. HRS beta0 values for chromophores with resonance electron donors are significant (up to 139 * 10-30 esu, ~5 times greater than that of the DAS+ cation), but systems with no donor, or the -NO2 acceptor show no activity, in some cases, despite large DFT predicted beta-values. In active systems with short (phenyl) pi-bridges, beta0 values comfortably exceed that of the purely organic structural analogue N,N dimethyl-4-nitroaniline (DMPNA), and intrinsic beta-values, beta0/N3/2 (where N is the number of bridge pi-electrons) thus appear to break empirical performance limits (beta0/N3/2 vs lambdamax) for planar organic systems. However, beta0 values obtained for extended systems with a diphenylacetylene bridge are comparable to or lower than that of their nitro analogue, N,N-dimethyl-4-[(4 nitrophenyl)ethynyl]-aniline (DMNPEA). Resonance Raman spectroscopy confirms the involvement of the POM in the electronic transitions, whether donor groups are present or not, but Stark spectroscopy indicates that, in their absence, the transitions have little dipolar character (hence, NLO inactive), consistent with DFT-calculated frontier orbitals, which extend over both POM and organic group. Stark and DFT also suggest that beta is enhanced in the short compounds because the extension of charge transfer (CT) onto the POM increases changes in the excited-state dipole moment. With extended pi-systems, this effect does not increase CT distances, relative to a -NO2 acceptor, so beta0 values do not exceed that of DMNPEA. Overall, our results show that (i) the organoimido-POM unit is an efficient acceptor for second-order NLO, but an ineffective donor; (ii) the nature of electronic transitions in arylimido-POMs is strongly influenced by the substituents of the aryl group; and (iii) organoimido-POMs outperform organic acceptors with short pi-bridges, but lose their advantage with extended pi conjugation. PMID- 28809115 TI - An Intuitive Approach for Predicting Potential Human Health Risk with the Tox21 10k Library. AB - In vitro-in vivo extrapolation (IVIVE) analyses translating high-throughput screening (HTS) data to human relevance have been limited. This study represents the first report applying IVIVE approaches and exposure comparisons using the entirety of the Tox21 federal collaboration chemical screening data, incorporating assay response efficacy and quality of concentration-response fits, and providing quantitative anchoring to first address the likelihood of human in vivo interactions with Tox21 compounds. This likelihood was assessed using a maximum blood concentration to in vitro response ratio approach (Cmax/AC50), analogous to decision-making methods for clinical drug-drug interactions. Fraction unbound in plasma (fup) and intrinsic hepatic clearance (CLint) parameters were estimated in silico and incorporated in a three-compartment toxicokinetic (TK) model to first predict Cmax for in vivo corroboration using therapeutic scenarios. Toward lower exposure scenarios, 36 compounds of 3925 unique chemicals with curated activity in the HTS data using high-quality dose response model fits and >=40% efficacy gave "possible" human in vivo interaction likelihoods lower than median human exposures predicted in the United States Environmental Protection Agency's ExpoCast program. A publicly available web application has been designed to provide all Tox21-ToxCast dose-likelihood predictions. Overall, this approach provides an intuitive framework to relate in vitro toxicology data rapidly and quantitatively to exposures using either in vitro or in silico derived TK parameters and can be thought of as an important step toward estimating plausible biological interactions in a high-throughput risk-assessment framework. PMID- 28809117 TI - N5- in Solution: Isotopic Labeling and Further Details of Its Synthesis by Phenyl Pentazole Reduction. AB - The cyclopentazolate anion, N5-, has been researched extensively over the years and detected in the gas phase more than a decade ago, but was only recently measured in solution. The process whereby aryl pentazole reduction leads to the production of N5- is still not fully understood. Here, the production of N5- in solution was investigated using isotopic labeling techniques while implementing changes to the synthesis methodologies. 15N labeled phenyl pentazole produced appropriately labeled phenyl pentazole radical anions and N5- which, upon collision induced dissociation, produced the expected N3- signals. Changing to higher purity solvent and less coated Na metal allowed for a much more rapid pace, with experiments taking less time. However, the best yields were obtained with heavily coated metal and much longer reaction times. Utilization of a vacuum line and ultrapure solvents led to no products being detected, indicating the importance of a sodium passivation layer in this reaction and the possibility that sodium is too strong a reducer. These findings can lead to better production methods of N5- and also explain past failures in implementing aryl pentazole reduction techniques. PMID- 28809119 TI - Diastereoselective Intramolecular Heck Reaction Assisted by an Acetate Group: Synthesis of the Decahydrobenzofluorene Derivative Dasyscyphin E. AB - The first synthesis of antifungal sesquiterpene quinol dasyscyphin E was achieved starting from trans-communic acid. The process described involves the first diastereoselective synthesis of this type of compound by cyclization of an aryl bicyclosesquiterpene. The acid was efficiently transformed into a sesquiterpene synthon, which was converted into the corresponding bromoaryl sesquiterpene. The key step of synthetic sequence was the cyclization of the latter under Heck reaction conditions, which yielded the tetracyclic skeleton of the target compound with complete diastereoselectivity. The participation of an acetate group is decisive, both for the course of the Heck reaction and for the stereoselectivity of the process. PMID- 28809118 TI - Glucose Limitation Alters Glutamine Metabolism in MUC1-Overexpressing Pancreatic Cancer Cells. AB - Pancreatic cancer cells overexpressing Mucin 1 (MUC1) rely on aerobic glycolysis and, correspondingly, are dependent on glucose for survival. Our NMR metabolomics comparative analysis of control (S2-013.Neo) and MUC1-overexpressing (S2 013.MUC1) cells demonstrates that MUC1 reprograms glutamine metabolism upon glucose limitation. The observed alteration in glutamine metabolism under glucose limitation was accompanied by a relative decrease in the proliferation of MUC1 overexpressing cells compared with steady-state conditions. Moreover, glucose limitation induces G1 phase arrest where S2-013.MUC1 cells fail to enter S phase and synthesize DNA because of a significant disruption in pyrimidine nucleotide biosynthesis. Our metabolomics analysis indicates that glutamine is the major source of oxaloacetate in S2-013.Neo and S2-013.MUC1 cells, where oxaloacetate is converted to aspartate, an important metabolite for pyrimidine nucleotide biosynthesis. However, glucose limitation impedes the flow of glutamine carbons into the pyrimidine nucleotide rings and instead leads to a significant accumulation of glutamine-derived aspartate in S2-013.MUC1 cells. PMID- 28809120 TI - Structural Revision of the Hancock Alkaloid (-)-Galipeine. AB - The 1H and 13C NMR data of synthetic samples of (S)-N(1)-methyl-2-[2'-(3"-hydroxy 4"-methoxyphenyl)ethyl]-1,2,3,4-tetrahydroquinoline, the originally proposed structure of the Hancock alkaloid (-)-galipeine, do not match those of the natural product. Herein, the preparation of the regioisomer (S)-N(1)-methyl-2-[2' (3"-methoxy-4"-hydroxyphenyl)ethyl]-1,2,3,4-tetrahydroquinoline is reported, the 1H and 13C NMR data of which are in excellent agreement with those of (-) galipeine. Comparison of specific rotation data enables assignment of the absolute (S)-configuration of the alkaloid, and together, these data engender the structural revision of (-)-galipeine to (S)-N(1)-methyl-2-[2'-(3"-methoxy-4" hydroxyphenyl)ethyl]-1,2,3,4-tetrahydroquinoline. PMID- 28809121 TI - The Synthesis of Trifluoromethyl-sulfonimidamides from Sulfinamides. AB - A general synthesis of CF3-sulfonimidamides from sulfinamides under both batch and continuous flow conditions is described. The reaction proceeds via a sulfonimidoyl fluoride intermediate. A reaction scope showing good group variation on the substituents of both nitrogen atoms is also presented. PMID- 28809122 TI - Practical Li-Ion Battery Assembly with One-Dimensional Active Materials. AB - Research activities on the development of one-dimensional (1D) nanostructures and their successful implementation in the fabrication of high-performance practical Li-ion batteries (LIBs) are described. Although numerous 1D-structured materials have been explored for use in LIBs as anodes, cathodes, and separator-cum electrolytes, only a very limited number of studies report the practical assembly of LIBs using these components. As a result, the salient features of using 1D materials in charge-storage devices have not been realized from an application perspective. Exceptional battery performance is reported when all-1D-based electro-active materials are used to fabricate LIBs. Using all-1D nanostructures not only provides high power capability, energy density, and durability, it also opens up new avenues for developing high-performance next-generation Li-ion power packs. PMID- 28809123 TI - 18FDG PET/CT in Routine Surveillance of Asymptomatic Patients following Treatment of Sinonasal Neoplasms. AB - Objective Sinonasal neoplasms have a high rate of recurrence following treatment, and current guidelines support the use of a variety of surveillance techniques. Recent work demonstrates that performance parameters of surveillance modalities may differ with sinonasal tumors in particular when compared with head and neck tumors overall. This study aims to characterize the value of 18fluorodeoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT) as a screening tool in asymptomatic patients. Study Design Retrospective cohort study. Setting Hospital of the University of Pennsylvania and Pennsylvania hospital. Methods Records of asymptomatic patients without suspicious endoscopy or suspicious imaging other than PET during the first 3 years following definitive treatment for sinonasal malignancy were screened and analyzed for inclusion in the cohort. Disease recurrence was determined by biopsy following suspicious PET evaluation. Results PET/CT scans (n = 111) were performed for 45 disease-free asymptomatic patients with no evidence of disease on endoscopy, and 6.3% were suspicious and prompted biopsy during this period, revealing 3 cases of disease recurrence. Overall specificity for PET/CT alone was 96.3% (95% CI, 90.7%-99.0%), with a negative predictive value of 99% (95% CI, 94.8%-100%). All recurrences were detected between 7 and 12 months, and all patients with true recurrence diagnosed by PET/CT had extrasinonasal involvement of tumor at the time of surgery. Conclusion We examined performance parameters of 18FDG PET/CT in asymptomatic patients with no evidence of disease on endoscopy during the posttreatment period for sinonasal malignancy. The ability of PET/CT to detect recurrences that may be missed by structural imaging or endoscopy makes it a valuable tool for clinicians. PMID- 28809124 TI - Measurement of the normal feline pituitary gland in brachycephalic and mesocephalic cats. AB - Objectives The purpose of this study was to determine differences in normal feline pituitary dimensions in brachycephalic and mesocephalic cats as a basis for establishing cryohypophysectomy in cats. Methods Measurements were performed on sagittal T2-weighted and transverse post-gadolinium T1-weighted or T1 3D fast field echo-weighted MRI images. A total of 32 brachycephalic and 27 mesocephalic cats were examined. Inter-observer reproducibility was assessed by t-test and Bland-Altman analysis. Results The cats were 0.6-15.9 years of age with a body weight range of 1.84-6.60 kg. For brachycephalic cats, the mean pituitary gland sagittal height was 2.15 +/- 0.15 mm, pituitary gland transverse height was 2.42 +/- 0.21 mm, pituitary gland transverse width was 4.44 +/- 0.27 mm and pituitary gland sagittal length was 3.14 +/- 0.30 mm. In mesocephalic cats, the pituitary gland dimensions were 2.94 +/- 0.16 mm, 3.09 +/- 0.26 mm, 4.73 +/- 0.31 mm and 4.88 +/- 0.30 mm for pituitary gland sagittal height, transverse height, transverse width and sagittal length, respectively. There was a highly significant correlation between brachycephalic and mesocephalic cats and pituitary gland height and length ( P <0.0001), respectively. Sex also had an effect on pituitary gland measurements. Neutering status had no significant effect on hypophyseal measurements. Age had a significant influence on pituitary gland height, width and length in the brachycephalic population. Inter-observer reproducibility was good to excellent. Conclusions and relevance The different pituitary measurements in brachycephalic and mesocephalic cats has to be considered if surgery comes into question. There are ranges in pituitary gland sizes, even among the mesocephalic cat population. Thus, exact measuring of the pituitary gland is crucial before any surgical intervention. PMID- 28809125 TI - Post-chemotherapy perforation in cats with discrete intermediate- or large-cell gastrointestinal lymphoma. AB - Objectives Gastrointestinal (GI) perforation is a well described complication of GI lymphoma in people, commonly occurring within days of initiation of chemotherapy. There are no studies documenting the prevalence of GI perforation in cats with intermediate- or large-cell GI lymphoma or whether it is associated with induction of chemotherapy. The objectives of this study were to document the prevalence and timing of post-chemotherapy perforation in cats with discrete GI masses caused by intermediate- or large-cell lymphoma. Methods Cats with a diagnosis of intermediate- or large-cell lymphoma based on cytologic or histopathologic examination of a mass lesion of the GI tract and treated with chemotherapy were identified by searching the patient record database of three large specialty referral hospitals. Cats undergoing surgical resection of a GI mass prior to chemotherapy were excluded from the study. A clinical diagnosis of GI perforation was made using ultrasound findings and analysis of abdominal fluid. Results Twenty-three cats with intermediate- (n = 3) or large-cell (n = 20) lymphoma were included in the study. GI perforation was confirmed in 4/23 cats (17%), and occurred at 23, 56, 59 and 87 days after induction. There was no association between tumor size, the presence of hypoproteinemia or suppurative inflammation within the mass at the time of diagnosis and subsequent perforation. Post-hoc analysis revealed that the magnitude of weight loss within 15-28 days of diagnosis was greater in cats with perforation. Conclusions and relevance In this pilot study, we found that post-chemotherapy GI perforation in cats with intermediate- or large-cell GI lymphoma occurs. Acute perforation after induction of chemotherapy was not documented. Larger prospective studies are needed to determine risk factors associated with perforation and whether surgical excision would reduce the risk of subsequent GI perforation in these patients. PMID- 28809126 TI - Comprehensive epigenetic analysis of the signature genes in lung adenocarcinoma. AB - AIM: This study aimed to explore the epigenetic modifications of signature genes in lung adenocarcinoma. MATERIALS & METHODS: The data of miRNA expression, mRNA expression and DNA methylation were downloaded from The Cancer Genome Atlas. Differential analysis was performed, followed by correlation analysis of miRNA mRNA and DNA methylation-mRNA. RESULTS: A total of 14 significant inverse correlations between gene expression and DNA methylation were identified, the expressions of which were selected for further validation via GSE27262, displaying similar pattern with that of the integrated analysis. In addition, qRT PCR results showed that the expression profiling results of six mRNAs and one miRNA were consistent with the findings of integrated analysis. Five genes showed higher diagnostic value, which was also associated with overall survival of patients. CONCLUSION: Taken together, the epigenetic alterations of signature genes may hold promise for becoming biomarkers for the early detection of lung adenocarcinoma. PMID- 28809128 TI - Real-world adherence and economic outcomes associated with paliperidone palmitate versus oral atypical antipsychotics in schizophrenia patients with substance related disorders using Medicaid benefits. AB - AIM: Compare medication utilization, costs and healthcare resource use in schizophrenia patients with substance-related disorders initiated on once-monthly paliperidone palmitate (PP1M) or an oral atypical antipsychotic (OAA). MATERIALS & METHODS: Data from six Medicaid states (07/2009-03/2015) were used to compare outcomes between PP1M and OAA patients. RESULTS: PP1M patients had higher 12 month antipsychotic adherence and persistence than OAA patients. PP1M patients had lower medical (mean monthly cost difference [MMCD] = US$-191, p = 0.020), higher pharmacy (MMCD = US$250, p < 0.001) and similar total costs (MMCD = US$59, p = 0.517) during the overall follow-up. PP1M patients had lower rates of outpatient visits and inpatient days but higher rates of mental health-related utilization. CONCLUSION: PP1M was associated with higher antipsychotic adherence and persistence, and similar total costs versus OAA. PMID- 28809127 TI - The correlation of methylation levels measured using Illumina 450K and EPIC BeadChips in blood samples. AB - AIM: We examined concordance of methylation levels across the Illumina Infinium HumanMethylation450 BeadChip and the Infinium MethylationEPIC BeadChip. METHODS: We computed the correlation for 145 whole blood DNA samples at each of the 422,524 CpG sites measured by both chips. RESULTS: The correlation at some sites was high (up to r = 0.95), but many sites had low correlation (55% had r < 0.20). The low correspondence between 450K and EPIC measured methylation values at many loci was largely due to the low variability in methylation values for the majority of the CpG sites in blood. CONCLUSION: Filtering out probes based on the observed correlation or low variability may increase reproducibility of BeadChip based epidemiological studies. PMID- 28809129 TI - Effect of methotrexate/vitamin B12 on DNA methylation as a potential factor in leukemia treatment-related neurotoxicity. AB - : Methotrexate (MTX) is administered to treat childhood acute lymphoblastic leukemia (ALL). It acts by inhibiting dihydrofolate reductase which reduces methyltetrahydrofolate, a key component in one carbon metabolism, thus reducing cell proliferation. Further perturbations to one carbon metabolism, such as reduced vitamin B12 levels via the use of nitrous oxide for sedation during childhood ALL treatment, may increase neurotoxicity risk. With B12 as an enzymatic cofactor, methyltetrahydrofolate is essential to produce methionine, which is critical for DNA methylation. We investigated global and gene specific DNA methylation in neuronal cell lines in response to MTX treatment and vitamin B12 concentration individually, and in combination. RESULTS: MTX treatment alone significantly increased LINE-1 methylation in SH-SY5Y (p = 0.040) and DAOY (p < 0.001), and increased FKBP5 methylation in MO3.13 cells (p = 0.009). CONCLUSION: We conclude that altered DNA methylation of brain/central nervous system cells could be one mechanism involved in MTX treatment-related neurotoxicities and neurocognitive late effects in ALL survivors. PMID- 28809130 TI - Long noncoding RNA: a new contributor and potential therapeutic target in fibrosis. AB - Fibrosis is the excess deposition of extracellular matrix components which occur in multiple organs and ultimately leads to organ failure. Long noncoding RNAs (lncRNAs) are a kind of noncoding RNAs longer than approximately 200 nucleotides with no protein-encoding capacity. A growing body of evidence suggests that lncRNAs are also involved in tissues fibrosis in several organs, such as lungs fibrosis, liver fibrosis, renal fibrosis and cardiac fibrosis. In this review, we summarized the current studies of lncRNAs in the process of fibrosis and hopefully aid in better understanding the molecular mechanism of fibrosis and provide a basis to explore new therapeutic targets of fibrosis. PMID- 28809131 TI - Capecitabine after Surgical Salvage in Recurrent Squamous Cell Carcinoma of Head and Neck. AB - Due to the high incidence of recurrent squamous cell carcinoma of the head and neck and the toxicity profile of current salvage regimens, there is a need for tolerable and effective treatment options. We performed a retrospective matched case series to report our experience with recurrent high-risk patients who received capecitabine (CAP) therapy in the adjuvant setting after salvage therapy. The 5-year recurrence-free survival rates for the CAP and control cohorts were 54% (95% CI, 0.27%-0.75%) and 27% (95% CI, 0.09%-0.50%), respectively. Multivariable Cox modeling showed a significant improvement in recurrence-free survival in the CAP cohort (hazard ratio, 0.19; 95% CI, 0.04 0.92; P = .0392). While this was a respective analysis that could not control for all variables, these exploratory findings offer insights that may inform a prospective study to determine CAP efficacy. PMID- 28809132 TI - Impact of Primary Tracheoesophageal Puncture on Outcomes after Total Laryngectomy. AB - Objectives To identify differences in postoperative wound complications associated with a primary tracheoesophageal puncture (TEP) at the time of laryngectomy versus no TEP. Study Design Retrospective review of large national data set. Setting Academic and nonacademic health care facilities in United States, contributing de-identified, risk-adjusted clinical data to the American College of Surgeons National Surgical Quality Improvement Program. Subjects and Methods The National Surgical Quality Improvement Program data set for years 2006 to 2012 identified 430 patients who underwent total laryngectomy with or without a primary TEP. Patients who underwent a TEP at the time of laryngectomy (n = 68) were compared with patients who underwent laryngectomy without a TEP (n = 362). Postoperative wound complications and secondary outcomes, including medical complications and length of hospitalization, were compared between the groups. Results The incidence of "superficial" and "deep or organ space" surgical site infection, medical complications, return to the operating room, and length of hospitalization were similar between the groups. Patients in the TEP group had a higher overall wound complication rate (relative risk, 2.02; 95% CI = 1.06-3.84; attributable risk, 8.17%; number needed to harm, 12). Conclusions Performance of a primary TEP concurrent to total laryngectomy contributed to a small increase in attributable risk for overall wound complications but did not add substantial risk for "superficial" or "deep or organ space" surgical site infection, medical complications, or increased burden for resource utilization. These data may help inform patient choice and physician recommendations for primary alaryngeal speech rehabilitation. PMID- 28809133 TI - Orientation Relationships in Al0.7CoCrFeNi High-Entropy Alloy. AB - A detailed microstructural evaluation was executed on the crystallographic texture as well as the mechanisms for nucleation, phase transformation, and grain growth in a Al0.7CoCrFeNi high-entropy alloy. The microstructure and crystallographic orientations were characterized by electron backscatter diffraction, and the chemical composition variations by energy-dispersive X-ray spectroscopy. The cast Al0.7CoCrFeNi alloy started in the BCC phase and partially transformed into the FCC phase. It was found that the Pitsch orientation relationship (OR) dominates the nucleation mechanism of the FCC phase; however, deviations with respect to the Pitsch OR are observed and are attributed to the differently sized atoms forming an ordered B2 phase in the alloy causing lattice distortions. The dual phase BCC-FCC microstructure contains FCC Widmanstatten plates oriented parallel to the {110}BCC planes of the parent grain. It was found that the crystal orientation distribution after the BCC-FCC phase transformation is confined and is explained as a product of the governing mechanisms. PMID- 28809134 TI - Cancer treatment experiences among survivors of childhood sexual abuse: A qualitative investigation of triggers and reactions to cumulative trauma. AB - OBJECTIVE: Some 25% of women and 8% of men in the United States have experienced childhood sexual abuse (CSA) before the age of 18. For these individuals, healthcare visits and interactions can be retraumatizing due to perceived similarities to past abuse (e.g., pain, undressing, lack of control). However, no prior studies have provided formal qualitative analyses regarding CSA survivors' reactions to cancer treatment. Therefore, our study's objective was to identify key themes pertaining to CSA survivors' cancer treatment experiences. METHOD: Male and female members of the Amazon Mechanical Turk (N = 159, mean age = 44.27 years, SD = 10.02) participated in an anonymous online survey study. The inclusion criteria included reporting: history of CSA; a diagnosis of colorectal, gynecological, breast, or skin cancer; and experience of triggers and/or difficulties during cancer treatment. Participants' responses to open-ended questions were analyzed using inductive thematic analysis. RESULTS: We identified two primary themes describing CSA survivors' experiences: Theme 1: treatment related triggers (key subthemes: procedure-related, provider-related, and emotional triggers); and Theme 2: questioning the meaning of cumulative trauma (e.g., "Why me again?"). SIGNIFICANCE OF RESULTS: For CSA survivors, cancer and its treatment can trigger thoughts and emotions associated with the original abuse as well as negative evaluations of themselves, the world, and their future. Our findings are consistent with past research on CSA survivors' experiences in non-cancer healthcare settings and add to the literature by highlighting their struggles during cancer treatment. The present results can inform further research on trauma survivors' reactions to cancer treatment and give cancer care providers the context they need to understand and sensitively serve a substantial yet often overlooked patient group. PMID- 28809135 TI - Detecting signatures of past pathogen selection on human HLA loci: are there needles in the haystack? AB - Human leucocyte antigens (HLAs) are responsible for the display of peptide fragments for recognition by T-cell receptors. The gene family encoding them is thus integral to human adaptive immunity, and likely to be under strong pathogen selection. Despite this, it has proved difficult to demonstrate specific examples of pathogen-HLA coevolution. Selection from multiple pathogens simultaneously could explain why the evolutionary signatures of particular pathogens on HLAs have proved elusive. Here, we present an individual-based model of HLA evolution in the presence of two mortality-causing pathogens. We demonstrate that it is likely that individual pathogen species causing high mortality have left recognizable signatures on the HLA genomic region, despite more than one pathogen being present. Such signatures are likely to exist at the whole-population level, and involve haplotypic combinations of HLA genes rather than single loci. PMID- 28809136 TI - Transmission Electron Microscopy Studies of Electron-Selective Titanium Oxide Contacts in Silicon Solar Cells. AB - In this study, the cross-section of electron-selective titanium oxide (TiO2) contacts for n-type crystalline silicon solar cells were investigated by transmission electron microscopy. It was revealed that the excellent cell efficiency of 21.6% obtained on n-type cells, featuring SiO2/TiO2/Al rear contacts and after forming gas annealing (FGA) at 350 degrees C, is due to strong surface passivation of SiO2/TiO2 stack as well as low contact resistivity at the Si/SiO2/TiO2 heterojunction. This can be attributed to the transformation of amorphous TiO2 to a conducting TiO2-x phase. Conversely, the low efficiency (9.8%) obtained on cells featuring an a-Si:H/TiO2/Al rear contact is due to severe degradation of passivation of the a-Si:H upon FGA. PMID- 28809138 TI - Daejeonia ginsenosidivorans gen. nov., sp. nov., a ginsenoside-transforming bacterium isolated from lake water. AB - A Gram-stain-negative, oxidase- and catalase-positive, strictly aerobic, non gliding bacterial strain, designated as NPT, was isolated from lake water and subjected to a taxonomic study using a polyphasic approach. Colonies of strain NP5T were light-yellow-coloured, circular with regular margins, and opaque. Cells were rods, 0.2-0.5 um wide and 1.2-3.0 um long. Strain NP5T possessed beta glycosidase activity, which was responsible for its ability to convert ginsenosides Rb1, Rc and Rd (three main active components of ginseng) to ginsenoside F2. Phylogenetic study based on the 16S rRNA gene sequence put strain NP5T in a distinct lineage in the family Flavobacteriaceae, sharing less than 96.0 % sequence similarity with members of the closely related genera Chryseobacterium, Bergeyella, Epilithonimonas and 'Candidatus Amoebinatus'. The novel isolate showed the highest sequence similarity with the genus Chryseobacterium. Strain NP5T contained MK-6 as predominant quinone, and iso-C15 : 0, iso-C17 : 0 3-OH, iso-C16 : 0 3-OH, C18 : 0 3-OH, anteiso-C15 : 0 and C16 : 1omega7c and/or C16 : 1omega6c (summed feature 3) as major fatty acids. The DNA G+C content was 44.8 mol%. The main polar lipids were phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. The physiological, biochemical and taxonomical characteristics allowed the phenotypic differentiation of strain NP5T from its closest phylogenetic neighbours. On the basis of the evidence of this polyphasic study, isolate NP5T represents a novel genus and species in the family Flavobacteriaceae for which the name Daejeonia ginsenosidivorans gen. nov., sp. nov. is proposed. The type strain is NP5T (=KACC 18626T=LMG 29198T). PMID- 28809137 TI - Paracoccus mangrovi sp. nov., isolated from a mangrove. AB - A bacterial strain, designated gyp-1T, was isolated from a mangrove in Taiwan and characterized using the polyphasic taxonomic approach. Cells of gyp-1T were Gram staining-negative, aerobic, poly-beta-hydroxybutyrate-accumulating, non-motile, coccoid or short-rod-shaped and formed cream-coloured colonies. Growth occurred at 15-37 degrees C (optimum, 25-30 degrees C), at pH 5.5-7.0 (optimum, pH 6.0) and with 0-4 % NaCl (optimum, 1-2 %). Phylogenetic analyses based on 16S rRNA gene sequences indicated that gyp-1T represented a member of the genus Paracoccus and showed the highest levels of sequence similarity with respect to Paracoccus lutimaris HDM-25T (97.8 %) and Paracoccus aminovorans DM-82T (97.7 %). The major fatty acids (>10 %) of gyp-1T were C18 : 1omega7c and C16 : 0. The polar lipid profile consisted of phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, diphosphatidylglycerol, an unidentified glycolipid and two unidentified phospholipids. The major isoprenoid quinone was Q-10. The DNA G+C content was 64.6 mol%. The DNA-DNA hybridization value for gyp-1T with P. lutimaris HDM-25T and P. aminovorans DM-82T was less than 50 %. Differential phenotypic properties, together with the phylogenetic inference, demonstrate that gyp-1T should be classified as representing a novel species of the genus Paracoccus, for which the name Paracoccus mangrovi sp. nov. is presented. The type strain is gyp-1T (=BCRC 80920T=LMG 29172T=KCTC 42899T). PMID- 28809139 TI - Paraphaeobacter pallidus gen. nov., sp. nov., isolated from seawater. AB - A Gram-stain-negative, aerobic, rod-shaped bacterium with a single polar flagellum, designated strain DCSW07T, was isolated from the surface water of the Bohai Sea, China. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain DCSW07T shared highest similarity (96.97 %) with Phaeobacter gallaeciensis DSM 26640T, formed a lineage within the family Rhodobacteraceae and was distinct from the most closely related genera Phaeobacter and Pseudooceanicola (96.6-96.8 and 95.8-96.2 % 16S rRNA gene sequence similarity, respectively). Optimal growth occurred in the presence of 6 % (w/v) NaCl, at pH 6.0 and at 28 degrees C. Strain DCSW07T contained phosphatidylcholine, phosphatidylethanolamine, an unidentified phospholipid and two unidentified polar lipids as the major polar lipids, and C18 : 1omega7c as the main fatty acid (>10 % of the total). The DNA G+C content of strain DCSW07T was 64.8 mol%. On the basis of this polyphasic study, strain DCSW07T is considered to represent a novel species of a new genus in the Roseobacter clade of the family Rhodobacteraceae, for which the name Paraphaeobacter pallidus gen. nov., sp. nov. is proposed. The type strain of Paraphaeobacter pallidus is DCSW07T (=KCTC 52369T=MCCC 1K03197T=JCM 31458T=CGMCC 1.15762T). PMID- 28809140 TI - Planococcus ruber sp. nov., isolated from a polluted farmland soil sample. AB - A pale-red-pigmented bacterial strain, designated CW1T, was isolated from a polluted soil sample in China and was characterized by a polyphasic taxonomic approach. Strain CW1T was Gram-stain-positive (or variable), coccoid, motile by a single polar flagellum and non-spore-forming. Growth was observed at 15-37 degrees C, but not at 10 degrees C or 40 degrees C, at pH 5.0-9.0 and with 0-5 % NaCl (w/v). Phylogenetic analysis showed that strain CW1T belongs to the genus Planococcus. The 16S rRNA gene sequence similarities between CW1T and the four most closely related type strains, Planococcus antarcticus DSM 14505T, Planococcus halocryophilus DSM 24743T, Planomicrobium soli XN13T and Planomicrobium okeanokoites NBRC 12536T were 97.96, 97.83, 97.83 and 97.82 %, respectively. The whole-cell sugars contained galactose, ribose and glucose. The major respiratory quinone was MK-7 followed by MK-8, and the major fatty acids were anteiso-C15 : 0 and anteiso-C17 : 0. The polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and phosphoglycolipid. The DNA G+C content was 48.6 mol%. The phylogenetic and chemotaxonomic analyses indicated that strain CW1T belongs unanimously to the genus Planococcus. However, DNA-DNA hybridization showed relatively low relatedness of 21.8 % (DSM 14505T) and 19.6 % (DSM 24743T) with the two most closely related strains of the genus Planococcus. Combined with the genotypic and phenotypic analysis, strain CW1T should represent a novel species in the genus Planococcus, for which the name Planococcus ruber sp. nov. is proposed. The type strain is CW1T (=CCTCC AB 207187T=LMG 24442T). PMID- 28809141 TI - HPV-11 variability, persistence and progression to genital warts in men: the HIM study. AB - HPV-11 and HPV-6 are the etiological agents of about 90 % of genital warts (GWs). The intra-typic variability of HPV-11 and its association with infection persistence and GW development remains undetermined. Here, HPV infection in men (HIM) participants who had an HPV-11 genital swab and/or GW, preceded or not by a normal skin genital swab were analysed. Genomic variants were characterized by PCR-sequencing and classified within lineages (A, B) and sublineages (A1, A2, A3, A4). HPV-11 A2 variants were the most frequently detected in the genital swab samples from controls and in both genital swabs and GW samples from cases. The same HPV-11 variant was detected in the GW sample and its preceding genital swab. There was a lack of association between any particular HPV-11 variant and the increased risk for GW development. PMID- 28809142 TI - Massilia agri sp. nov., isolated from reclaimed grassland soil. AB - A light yellow-coloured, Gram-stain-negative, motile and rod-shaped bacterium, designated strain K-3-1T, was isolated from reclaimed grassland soils of Belbari, Morang, Nepal. It was able to grow at 4-45 degrees C, at pH 5.0-10.0, and at 0-2 % (w/v) NaCl concentrations. This strain was taxonomically characterized by a polyphasic approach. Based on the 16S rRNA gene sequence analysis, strain K-3-1T belongs to the genus Massilia and is closely related to Massilia consociata CCUG 58010T (98.3 % sequence similarity), Massilia tieshanensis TS3T (98.1 % sequence similarity), Massilia kyonggiensis TSA1T (98.1 % sequence similarity), Massilia yuzhufengensisY1243-1T (98.1 % sequence similarity), Massilia haematophila CCUG 38318T (98.0 % sequence similarity), Massilia varians CCUG 35299T (97.9 % sequence similarity), Massilia niastensis 5516 S-1T (97.6 % sequence similarity) and Massilia alkalitolerans YIM 31775T (97.5 % sequence similarity). The predominant respiratory quinone was ubiquinone-8. The polar lipid profile revealed the presence of phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. The predominant fatty acids of strain K-3-1T were summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), C16 : 0, C12 : 0, C10 : 0 3-OH and summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c). The genomic DNA G+C content of this novel strain was 66.8 mol%. The DNA-DNA relatedness between strain K-3-1T and its closest reference strains were significantly lower than the threshold value of 70 %. The morphological, physiological, chemotaxonomic and phylogenetic analyses clearly distinguished this strain from its closest phylogenetic neighbours. Thus, strain K-3-1T represents a novel species of the genus Massilia, for which the name Massilia agri sp. nov. is proposed. The type strain is K-3-1T (=KEMB 9005-446T=KACC 19000T=JCM 31661T). PMID- 28809143 TI - Bacillus swezeyi sp. nov. and Bacillus haynesii sp. nov., isolated from desert soil. AB - Two isolates of Gram-reaction-positive, facultatively anaerobic, motile, rod shaped, endospore-forming bacteria were identified during a survey of the diversity of strains belonging to the genus Bacillus deposited in the Agriculture Research Service Culture Collection. These strains were originally isolated from soil in Evolution Canyon III (Israel) in a survey of ecological diversification. Phylogenetic analysis of the 16S rRNA gene of strains NRRL B-41294T and NRRL B 41327T determined they were closely related to members of the Bacillus licheniformis clade. The genome of each strain was sequenced, and further analysis indicated that the strains represented unique species based on in silico DNA-DNA hybridization analyses. A phylogenomic analysis revealed that NRRL B 41294T and NRRL B-41327T were closely related to the group that includes B. licheniformis. In phenotypic characterization, both NRRL B-41294T and NRRL B 41327T were found to grow at temperatures of between 15 and 60 degrees C and tolerated up to 12 % NaCl (w/v). The predominant cellular fatty acids were anteiso-C15 : 0 and iso-C15 : 0, and peptidoglycan from cell walls contained meso diaminopimelic acid. The DNA G+C content was 45.7 and 44.3 mol% for NRRL B-41327T and NRRL B-41294T, respectively. Furthermore, each strain had a unique carbon utilization pattern that distinguished it from its nearest phylogenetic neighbours. Based upon the consensus of phylogenetic and phenotypic analyses, we conclude that these strains represent two novel species within the genus Bacillus, for which the name Bacillus swezeyi sp. nov. is proposed, with type strain NRRL B-41294T (=CCUG 70177T), and the name Bacillus haynesii sp. nov. is proposed, with type strain NRRL B-41327T (=CCUG 70178T). PMID- 28809145 TI - Moderate sensitivity of mouse mammary tumour virus to inhibition by human APOBEC3G. AB - Infectivity of the mouse mammary tumour virus (MMTV) is inhibited by mouse APOBEC3 (mA3) which is efficiently packaged into virions. As the inhibition is only partial, the virus can replicate in tissues expressing mA3 and complete its replication cycle. Here, we have examined the sensitivity of MMTV to inhibition by a human orthologue of mA3, A3G. We report that the virus containing A3G is only moderately susceptible to inhibition by the human factor. Whereas the vif deficient HIV-1 vector produced in human epithelial cells expressing endogenous levels of A3G was efficiently inhibited, an MMTV vector remained fully infectious. Greater A3G expression levels were necessary to restrict infectivity of MMTV, but only when the factor retained its deaminase activity. Furthermore, the spreading kinetic of a replication competent MMTV was only moderately accelerated in cells with downmodulated A3G expression. These data suggest that MMTV has evolved a mechanism to neutralize antiviral activity of APOBEC3 proteins. PMID- 28809144 TI - Defluviimonas nitratireducens sp. nov., isolated from surface seawater. AB - A bacterial strain, designated DL5-4T, was isolated from the surface seawater of Dalian Bay and characterized using a polyphasic taxonomy approach. Cells of DL5 4T were Gram-staining-negative, non-motile and short-rod-shaped. Growth was observed at 8-40 degrees C (optimum 28-30 degrees C), at pH 6-9 (optimum pH 7) and in 0-7 % NaCl (optimum 1-3 %, w/v). The results of phylogenetic analysis based on 16S rRNA gene sequences indicated that DL5-4T formed an independent branch with members of the genus Defluviimonas, sharing high similarities with five related type strains, Defluviimonas aquaemixtae CDM-7T (96.6 %), Defluviimonas denitrificans DSM 18921T (96.0 %), Defluviimonas indica 20V17T (95.8 %), Defluviimonas aestuarii BS14T (95.8 %) and Defluviimonas alba cai42T (94.5 %). The predominant fatty acid was summed feature 8 (C18 : 1omega6c and/or C18 : 1omega7c). The isoprenoid quinone was identified as Q-10. The polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, four phospholipids, an aminolipid and an unknown lipid. The DNA G+C content was 63.8 mol%. The results of the phenotypic, phylogenetic and chemotaxonomic analyses clearly indicated that DL5-4T represents a novel species of the genus Defluviimonas, for which the name Defluviimonas nitratireducens sp. nov. is proposed, with type strain DL5-4T (=MCCC 1A06955T=LMG 29616T). PMID- 28809147 TI - Flavobacterium flaviflagrans sp. nov., a bacterium of the family Flavobacteriaceae isolated from forest soil. AB - Two strains of bacteria designated CB-3T and CB-31 were isolated from Kyonggi University forest soil. Cells were aerobic, Gram-stain-negative, oxidase positive, non-motile, non-spore-forming, rod-shaped and yellow-pigmented. They were able to grow at 15-42 degrees C, pH 5.5-9.5 and with 0-1.5 % (w/v) NaCl concentration. Flexirubin-type pigments were absent. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strains CB-3T and CB-31 formed a lineage within the family Flavobacteriaceae of the phylum Bacteroidetes that was distinct from various species of the genus Flavobacterium, including Flavobacterium humicola UCM-46T (99.58 % sequence similarity), Flavobacterium suncheonense GH29 5T (98.12 %), Flavobacterium pedocola UCM-R36T (97.57 %), Flavobacterium fulvum UCM-R15T (96.8 %) and Flavobacterium cauense R2A-7T (96.31 %). Both strains contained MK-6 as the sole quinone. The major polar lipid was phosphatidylethanolamine. The major cellular fatty acids were iso-C15 : 0, iso C17 : 0 3-OH, iso-C15 : 0 3-OH, summed feature 9 (iso-C17 : 1omega9c and/or C16 : 0 10-methyl) and iso-C15 : 1 G. The DNA G+C content of the strains was 35.8-36.7 mol%. DNA-DNA relatedness between strain CB-3T and the most closely related members of the genus Flavobacterium ranged from 32 % to 59 %. The morphological, physiological, chemotaxonomic and phylogenetic analyses clearly distinguished strains CB-3T and CB-31 from their closest phylogenetic neighbours. Thus, strains CB-3T and CB-31 represent a novel species of the genus Flavobacterium, for which the name Flavobacterium flaviflagrans sp. nov. is proposed. The type strain is CB 3T (=KEMB 9005-535T=KACC 19112T=NBRC 112704T). PMID- 28809146 TI - Mycobacterium talmoniae sp. nov., a slowly growing mycobacterium isolated from human respiratory samples. AB - A novel slowly growing, non-chromogenic species of the class Actinobacteria was isolated from a human respiratory sample in Nebraska, USA, in 2012. Analysis of the internal transcribed spacer sequence supported placement into the genus Mycobacterium with high sequence similarity to a previously undescribed strain isolated from a patient respiratory sample from Oregon, USA, held in a collection in Colorado, USA, in 2000. The two isolates were subjected to phenotypic testing and whole genome sequencing and found to be indistinguishable. The bacteria were acid-fast stain-positive, rod-shaped and exhibited growth after 7-10 days on solid media at temperatures ranging from 25 to 42 degrees C. Colonies were non pigmented, rough and slightly raised. Analyses of matrix-assisted laser desorption ionization time-of-flight profiles showed no matches against a reference library of 130 mycobacterial species. Full-length 16S rRNA gene sequences were identical for the two isolates, the average nucleotide identity (ANI) between their genomes was 99.7 % and phylogenetic comparisons classified the novel mycobacteria as the basal most species in the slowly growing Mycobacterium clade. Mycobacterium avium is the most closely related species based on rpoB gene sequence similarity (92 %), but the ANI between the genomes was 81.5 %, below the suggested cut-off for differentiating two species (95 %). Mycolic acid profiles were more similar to M. avium than to Mycobacterium simiae or Mycobacterium abscessus. The phenotypic and genomic data support the conclusion that the two related isolates represent a novel Mycobacterium species for which the name Mycobacterium talmoniae sp. nov. is proposed. The type strain is NE-TNMC-100812T (=ATCC BAA-2683T=DSM 46873T). PMID- 28809149 TI - Cumulibacter manganitolerans gen. nov., sp. nov., isolated from sludge of a manganese mine. AB - A Gram-stain-positive actinobacterium, designated as strain 2-36T, was isolated from sludge of a sewage outlet in a manganese mine. Phylogenetic analysis of 16S rRNA genes assigned strain 2-36T in a single lineage in the family Geodermatophilaceae and closely related to Modestobacter roseus KLBMP 1279T (93.8 % similarity), Blastococcus saxobsidens BC444T (93.1 %) and Geodermatophilus aquaeductus BMG801T (92.8 %). It contained iso-C16 : 0, iso-C15 : 0, C17 : 1omega6c, iso-C14 : 0 and summed feature 3 (C16 : 1omega6c and/or C16 : 1omega7c) as the major fatty acids (>5 %), with MK-9(H4), MK-8(H4) and MK-9(H6) as the quinones. The cell wall contained meso-diaminopimelic acid as the diagnostic diamino acid and the DNA G+C content was 70.1 mol%. The polar lipids were diphosphatidylglycerol, phosphatidylmethylethanolamine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol mannoside, an unknown glycolipid, an unknown aminophospholipid and two unknown phospholipids. Compared to closely related strains, strain 2-36T showed distinguishing characteristics, such as the distinct phylogenetic lineage, positive result for phenylacetic acid assimilation and negative result for alpha-glucosidase and having C17 : 1omega6c and iso-C14 : 0 as the major fatty acids. On the basis of the polyphasic analyses, strain 2-36T represents a novel species of a new genus within the family Geodermatophilaceae, for which the name Cumulibacter manganitolerans gen. nov., sp. nov. is proposed. The type strain of 'Cumulibacter manganitolerans' is 2-36T (=CCTCC AA 2016026T=DSM 103787T). PMID- 28809148 TI - Flaviaesturariibacter terrae sp. nov., isolated from mountain soil. AB - A Gram-stain-negative, aerobic, rod-shaped, non-motile and pale yellow-pigmented bacterial strain, designated as HY03T, was isolated from mountain soil. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain HY03T belonged to the family Chitinophagaceae in the phylum Bacteroidetes and was most closely related to Flaviaesturariibacter amylovorans GCR0105T at a similarity of 95.4 %. The genomic DNA G+C content of strain HY03T was 43.2 mol%. The major fatty acids of the isolate were iso-C15 : 0, iso-C15 : 1 G and iso-C17 : 0 3-OH. The polar lipid profile of strain HY03T consisted of the major compound phosphatidylethanolamine and moderate amounts of an unknown aminophospholipid, unknown phospholipids and unknown lipids. The predominant respiratory quinone was menaquinone 7 (MK-7). Phylogenetic, genotypic, phenotypic and chemotaxonomic characteristics indicated that strain HY03T represents a novel species within the genus Flaviaesturariibacter, for which the name Flaviaesturariibacter terrae sp. nov. is proposed. The type strain is HY03T (=KCTC 52511T=JCM 31723T). PMID- 28809150 TI - A Tupaia paramyxovirus vector system for targeting and transgene expression. AB - Viruses from the diverse family of Paramyxoviridae include important pathogens and are applied in gene therapy and for cancer treatment. The Tupaia paramyxovirus (TPMV), isolated from the kidney of a tree shrew, does not infect human cells and neutralizing antibodies against other Paramyxoviridae do not cross-react with TPMV. Here, we present a vector system for de novo generation of infectious TPMV that allows for insertion of additional genes as well as targeting using antibody single-chain variable fragments. We show that the recombinant TPMV specifically infect cells expressing the targeted receptor and replicate in human cells. This vector system provides a valuable tool for both basic research and therapeutic applications. PMID- 28809151 TI - The pentameric complex of human Cytomegalovirus: cell tropism, virus dissemination, immune response and vaccine development. AB - Between the 1980s and 1990s, three assays were developed for diagnosis of human cytomegalovirus (HCMV) infections: leuko (L)-antigenemia, l-viremia and l DNAemia, detecting viral protein pp65, infectious virus and viral DNA, respectively, in circulating leukocytes Repeated initial attempts to reproduce the three assays in vitro using laboratory-adapted strains and infected cell cultures were consistently unsuccessful. Results were totally reversed when wild type HCMV strains were used to infect either fibroblasts or endothelial cells. Careful analysis and sequencing of plaque-purified viruses from recent clinical isolates drew attention to the ULb' region of the HCMV genome. Using bacterial artificial chromosome technology, it was shown by both gain-of-function and loss of-function experiments that UL131-128 genes are indispensable for virus growth in endothelial cells and virus transfer to leukocytes. In addition, a number of clinical isolates passaged in human fibroblasts had lost both properties (leuko tropism and endothelial cell-tropism) when displaying a mutation in the UL131-128 locus (referred to as UL128L). In the following years, it was shown that pUL128L was complexed with gH and gL to form the pentameric complex (PC), which is required to infect endothelial, epithelial and myeloid cells. The immune response to PC was studied extensively, particularly its humoral component, showing that the great majority of the neutralizing antibody response is directed to PC. Although anti-HCMV antibodies may act with other mechanisms than mere neutralizing activity, these findings definitely favour their protective activity, thus paving the way to the development of a potentially protective HCMV vaccine. PMID- 28809152 TI - Whole-genome sequences of Odocoileus hemionus deer adenovirus isolates from deer, moose and elk are highly conserved and support a new species in the genus Atadenovirus. AB - We present the first complete genome sequence of Odocoileus hemionus deer adenovirus 1 (OdAdV-1). This virus can cause sporadic haemorrhagic disease in cervids, although epizootics with high mortality have occurred in California. OdAdV-1 has been placed in the genus Atadenovirus, based on partial hexon, pVIII and fibre genes. Ten field isolates recovered from naturally infected mule deer (Odocoileus hemionus), white-tailed deer (Odocoileus virginiana) and moose (Alces alces) from Wyoming, black-tailed deer (Odocoileus hemionus columbianus) from California, and Rocky Mountain elk (Cervus elaphus nelsoni) from Colorado and Washington state were sequenced. The genome lengths ranged from 30 620 to 30 699 bp, contained the predicted proteins and gene organization typical of members of genus Atadenovirus, and had a high percentage of A/T nucleotides (66.7 %). Phylogenic analysis found that the closest ancestry was with ruminant atadenoviruses, while a divergence of the hexon, polymerase and penton base proteins of more than 15 % supports classification as a new species. Genetic global comparison between the 10 isolates found an overall 99 % identity, but greater divergence was found between those recovered from moose and elk as compared to deer, and a single variable region contained most of these differences. Our findings demonstrate that OdAdV-1 is highly conserved between 10 isolates recovered from multiple related cervid species, but genotypic differences, largely localized to a variable region, define two strains. We propose that the virus type name be changed to cervid adenovirus 1, with the species name Cervid atadenovirus A. Sequence data were used to develop molecular assays for improved detection and genotyping. PMID- 28809153 TI - Lacihabitans lacunae sp. nov., isolated from a lagoon. AB - A non-motile, orange-pigmented bacterium, designated strain HME7103T, was isolated from lagoon water in the Republic of Korea. A phylogenetic tree based on 16S rRNA gene sequences showed that strain HME7103T formed a lineage within the genus Lacihabitans and family Cytophagaceae. Strain HME7103T was closely related to Lacihabitans soyangensis HME6675T (95.7 % 16S rRNA gene sequence similarity). The major fatty acids of strain HME7103T were summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c) and iso-C15 : 0. The major respiratory quinone was MK-7. The major polyamine was spermidine. The major polar lipids were phosphatidylethanolamine, two unidentified aminolipids, one unidentified aminophospholipid and three unidentified polar lipids. The DNA G+C content of strain HME7103T was 40.6 mol%. On the basis of the evidence presented in this study, strain HME7103T represents a novel species within the genus Lacihabitans, for which the name Lacihabitans lacunae sp. nov. is proposed. The type strain is HME7103T (=KCTC 23619T=CECT 7956T). PMID- 28809154 TI - Interaction between herpesvirus entry mediator and HSV-2 glycoproteins mediates HIV-1 entry of HSV-2-infected epithelial cells. AB - Herpes simplex virus type 2 (HSV-2) increases human immunodeficiency virus type 1 (HIV-1) acquisition and transmission via unclear mechanisms. Herpesvirus entry mediator (HVEM), an HSV-2 entry receptor, is highly expressed on HIV-1 target cells (CD4+ T cells) and may be incorporated into HIV-1 virions, while HSV-2 glycoproteins can be present on the infected cell surface. Since HVEM-gD interaction together with gB/gH/gL is essential for HSV-2 entry, HVEM-bearing HIV 1 (HIV-1/HVEM) may enter HSV-2-infected cells through such interactions. To test this hypothesis, we first confirmed the presence of HVEM on HIV-1 virions and glycoproteins on the HSV-2-infected cell surface. Additional studies showed that HIV-1/HVEM bound to the HSV-2-infected cell surface in an HSV-2 infection-time dependent manner via HVEM-gD interaction. HIV-1/HVEM entry of HSV-2-infected cells was dependent on HVEM-gD interaction and the presence of gB/gH/gL, and was inhibited by azidothymidine. Furthermore, peripheral blood mononuclear cell derived HIV-1 infected HSV-2-infected primary foreskin epithelial cells and the infection was inhibited by anti-HVEM/gD antibodies. Together, our results indicate that HIV-1 produced from CD4+ T cells bears HSV-2 receptor HVEM and can bind to and enter HSV-2-infected epithelial cells depending on HVEM-gD interaction and the presence of gB/gH/gL. Our findings provide a potential new mechanism underlying HSV-2 infection-enhanced HIV-1 mucosal transmission and may shed light on HIV-1 prevention. PMID- 28809155 TI - Microbe Profile: Candida albicans: a shape-changing, opportunistic pathogenic fungus of humans. AB - Candida albicans is normally a harmless commensal of human beings, but it can cause superficial infections of the mucosa (oral/vaginal thrush) in healthy individuals and (rarely) infections of the skin or nails. It can also become invasive, causing life-threatening systemic and bloodstream infections in immunocompromised hosts, where the mortality rate can be as high as 50 %. It is the most common cause of serious fungal infection and is a common cause of nosocomial infections in hospitals. Some strains have been recognized that are resistant to azoles or echinocandins, which are the first-line antifungals for treatment of C. albicans infections. PMID- 28809156 TI - The length of poly(C) stretch in the Bordetella pertussis Pfim3 promoter determines the vag or vrg function of the fim3 gene. AB - Bordetella pertussis, a human pathogenic bacterium, produces either one or two types of serologically distinct fimbriae, Fim2 and Fim3, as virulence factors. The expression of fim2 and fim3 is regulated by the BvgAS two-component system and the length of poly(C) stretches in Pfim promoters. In the Bvg+ phase, B. pertussis virulence-activated genes (vags) are up-regulated and virulence repressed genes (vrgs) are down-regulated. Previous studies have shown that fim2 is a vag, but there is no consensus on fim3 regulation. We examined the regulation of fimbrial expression in B. pertussis clinical isolates. Our findings indicate that fim2 is a vag, while fim3 is a vag when Pfim3 poly(C)>13C, and a vrg when poly(C)<=13C. Although increased fim3 expression was observed in the Bvg phase in isolates with Pfim3 poly(C)<=13C, Fim3 production was not detected, suggesting post-transcriptional regulation of fim3 expression. These findings provide an insight into the regulation of fimbrial expression in B. pertussis. PMID- 28809159 TI - Effect of functionalization of boron nitride flakes by main group metal clusters on their optoelectronic properties. AB - The possibility of functionalizing boron nitride flakes (BNFs) with some selected main group metal clusters, viz. OLi4, NLi5, CLi6, BLI7 and Al12Be, has been analyzed with the aid of density functional theory (DFT) based computations. Thermochemical as well as energetic considerations suggest that all the metal clusters interact with the BNF moiety in a favorable fashion. As a result of functionalization, the static (first) hyperpolarizability ([Formula: see text]) values of the metal cluster supported BNF moieties increase quite significantly as compared to that in the case of pristine BNF. Time dependent DFT analysis reveals that the metal clusters can lower the transition energies associated with the dominant electronic transitions quite significantly thereby enabling the metal cluster supported BNF moieties to exhibit significant non-linear optical activity. Moreover, the studied systems demonstrate broad band absorption capability spanning the UV-visible as well as infra-red domains. Energy decomposition analysis reveals that the electrostatic interactions principally stabilize the metal cluster supported BNF moieties. PMID- 28809160 TI - W-N-TiO2 with positive enough level of valence band maximum and narrowing bandgap for selective aerobic oxidation in visible-light irradiation. AB - A kind of surface complex (triethylamine and mesoporous W-N-TiO2 microspheres with large surface area: 117.5 m2g-1) catalysis was achieved via visible-light photoredox catalysis. Triethylamine behaves as a true redox mediator due to its highly favorable donating ability. With a lower bandgap (2.43 eV) and higher valence band maximum (2.905 V), W-N-TiO2 has the ability to play an active catalytic role yielding excellent conversion and selective oxidation of thioanisole (75.16%) within 12 h under visible-light irradiation. In addition, the reaction and the photocatalyst are applicable to other kinds of thioethers, generally producing high conversion rates and selectivities for the product sulfoxides. The reaction paths were elucidated to reveal that these kinds of surface complexes show characteristics that are likely to be applicable to many aerobic oxidation reactions in future. PMID- 28809157 TI - Brain micro-inflammation at specific vessels dysregulates organ-homeostasis via the activation of a new neural circuit. AB - Impact of stress on diseases including gastrointestinal failure is well-known, but molecular mechanism is not understood. Here we show underlying molecular mechanism using EAE mice. Under stress conditions, EAE caused severe gastrointestinal failure with high-mortality. Mechanistically, autoreactive pathogenic CD4+ T cells accumulated at specific vessels of boundary area of third ventricle, thalamus, and dentate-gyrus to establish brain micro-inflammation via stress-gateway reflex. Importantly, induction of brain micro-inflammation at specific vessels by cytokine injection was sufficient to establish fatal gastrointestinal failure. Resulting micro-inflammation activated new neural pathway including neurons in paraventricular-nucleus, dorsomedial-nucleus-of hypothalamus, and also vagal neurons to cause fatal gastrointestinal failure. Suppression of the brain micro-inflammation or blockage of these neural pathways inhibited the gastrointestinal failure. These results demonstrate direct link between brain micro-inflammation and fatal gastrointestinal disease via establishment of a new neural pathway under stress. They further suggest that brain micro-inflammation around specific vessels could be switch to activate new neural pathway(s) to regulate organ homeostasis. PMID- 28809161 TI - Improved electronic structure and magnetic exchange interactions in transition metal oxides. AB - We discuss the application of the Agapito Curtarolo and Buongiorno Nardelli (ACBN0) pseudo-hybrid Hubbard density functional to several transition metal oxides. For simple binary metal oxides, ACBN0 is found to be a fast, reasonably accurate and parameter-free alternative to traditional DFT + U and hybrid exact exchange methods. In ACBN0, the Hubbard energy of DFT + U is calculated via the direct evaluation of the local Coulomb and exchange integrals in which the screening of the bare Coulomb potential is accounted for by a renormalization of the density matrix. We demonstrate the success of the ACBN0 approach for the electronic properties of a series technologically relevant mono-oxides (MnO, CoO, NiO, FeO, both at equilibrium and under pressure). We also present results on two mixed valence compounds, Co3O4 and Mn3O4. Our results for these binary oxides and all the materials we have investigated, obtained at the computational cost of a standard LDA/PBE calculation, are in excellent agreement with hybrid functionals, the GW approximation and experimental measurements. PMID- 28809158 TI - Germ cell connectivity enhances cell death in response to DNA damage in the Drosophila testis. AB - Two broadly known characteristics of germ cells in many organisms are their development as a 'cyst' of interconnected cells and their high sensitivity to DNA damage. Here we provide evidence that in the Drosophila testis, connectivity serves as a mechanism that confers to spermatogonia a high sensitivity to DNA damage. We show that all spermatogonia within a cyst die synchronously even when only a subset of them exhibit detectable DNA damage. Mutants of the fusome, an organelle that is known to facilitate intracyst communication, compromise synchronous spermatogonial death and reduces overall germ cell death. Our data indicate that a death-promoting signal is shared within the cyst, leading to death of the entire cyst. Taken together, we propose that intercellular connectivity supported by the fusome uniquely increases the sensitivity of the germline to DNA damage, thereby protecting the integrity of gamete genomes that are passed on to the next generation. PMID- 28809162 TI - Statistical signatures of a targeted search by bacteria. AB - Chemoattractant gradients are rarely well-controlled in nature and recent attention has turned to bacterial chemotaxis toward typical bacterial food sources such as food patches or even bacterial prey. In environments with localized food sources reminiscent of a bacterium's natural habitat, striking phenomena-such as the volcano effect or banding-have been predicted or expected to emerge from chemotactic models. However, in practice, from limited bacterial trajectory data it is difficult to distinguish targeted searches from an untargeted search strategy for food sources. Here we use a theoretical model to identify statistical signatures of a targeted search toward point food sources, such as prey. Our model is constructed on the basis that bacteria use temporal comparisons to bias their random walk, exhibit finite memory and are subject to random (Brownian) motion as well as signaling noise. The advantage with using a stochastic model-based approach is that a stochastic model may be parametrized from individual stochastic bacterial trajectories but may then be used to generate a very large number of simulated trajectories to explore average behaviors obtained from stochastic search strategies. For example, our model predicts that a bacterium's diffusion coefficient increases as it approaches the point source and that, in the presence of multiple sources, bacteria may take substantially longer to locate their first source giving the impression of an untargeted search strategy. PMID- 28809164 TI - Aggregation-induced emission-fluorophores and applications. AB - Aggregation-induced emission (AIE) is a novel photophysical phenomenon found in a group of luminogens that are not fluorescent in solution but are highly emissive in the aggregate or solid state. Since the first publication of AIE luminogens in 2001, AIE has become a hot research area in which the number of research papers regarding new AIE molecules and their applications has been increasing in an exponential manner. Thomson Reuters Essential Science Indicators ranked AIE no.3 among the Top 100 Research Frontiers in the field of Chemistry and Materials Science in 2013. In this review, I will give a general introduction of the AIE phenomenon, discuss the structure-property relationship of the AIE lumingens and summarize the recent progress in the applications including as light-emitting materials in optoelectronics, as chemosensors and bioprobes, and for bioimaging (total 69 references cited). PMID- 28809163 TI - Fluorescence polarization assays in high-throughput screening and drug discovery: a review. AB - The sensitivity of fluorescence polarization (FP) and fluorescence anisotropy (FA) to molecular weight changes has enabled the interrogation of diverse biological mechanisms, ranging from molecular interactions to enzymatic activity. Assays based on FP/FA technology have been widely utilized in high-throughput screening (HTS) and drug discovery due to the homogenous format, robust performance and relative insensitivity to some types of interferences, such as inner filter effects. Advancements in assay design, fluorescent probes, and technology have enabled the application of FP assays to increasingly complex biological processes. Herein we discuss different types of FP/FA assays developed for HTS, with examples to emphasize the diversity of applicable targets. Furthermore, trends in target and fluorophore selection, as well as assay type and format, are examined using annotated HTS assays within the PubChem database. Finally, practical considerations for the successful development and implementation of FP/FA assays for HTS are provided based on experience at our center and examples from the literature, including strategies for flagging interference compounds among a list of hits. PMID- 28809166 TI - Resolving environmental microheterogeneity and dielectric relaxation in fluorescence kinetics of protein. AB - The fluorescence intensity decay of protein is easily measurable and reports on the intrinsic fluorophore-local environment interactions on the sub-nm spatial and sub-ns temporal scales, which are consistent with protein activity in numerous biomedical and industrial processes. This makes time-resolved fluorescence a perfect tool for understanding, monitoring and controlling these processes at the molecular level, but the complexity of the decay, which has been traditionally fitted to multi-exponential functions, has hampered the development of this technique over the last few decades. Using the example of tryptophan in HSA we present the alternative to the conventional approach to modelling intrinsic florescence intensity decay in protein where the key factors determining fluorescence decay, i.e. the excited-state depopulation and the dielectric relaxation (Toptygin and Brand 2000 Chem. Phys. Lett. 322 496-502), are represented by the individual relaxation functions. This allows quantification of both effects separately by determining their parameters from the global analysis of a series of fluorescence intensity decays measured at different detection wavelengths. Moreover, certain pairs of the recovered parameters of tryptophan were found to be correlated, indicating the influence of the dielectric relaxation on the transient rate of the electronic transitions. In this context the potential for the dual excited state depopulation /dielectric relaxation fluorescence lifetime sensing is discussed. PMID- 28809168 TI - Shape, size and composition dependence of efficiency and dynamics of Forster resonance energy transfer in dye-silica nanoconjugates. AB - The role of relative concentrations of energy donors (fluorescein, D), acceptors (rhodamine, A) and silica on Forster resonance energy transfer (FRET) efficiency and dynamics in dye silica conjugates has been studied, as a part of our initial attempts to ascertain the potential of dye-silica nanoconjugates as light harvesting nanoantennae. Two types of dye-silica nanoconjugates, prepared by the co-condensation method, have been examined. The first is based on silica nanoshells (SNS-dye) while the second is based on silica nanoparticles (SNP-dye). Both these nanostructures have a diameter of approximately 25 nm. Efficient energy transfer (91% and 97%, respectively) has been observed in both, for total fluorophore concentration upto 5-6 mmol, irrespective of the D : A ratio. The lower efficiency at dye concentrations greater than these has been rationalized by the competitive self-quenching of D. A risetime of approximately 500 fs is observed in the A emission in SNS-dye, but there is no such feature in SNP-dye. The shape and size dependence of the FRET efficiency and dynamics has been rationalized as follows: the initial step of dye rich core formation in nanoparticles results in high proximity of dye molecules to each other, leading to highly efficient FRET than in nanoshells. In larger SNP-dye nanoconjugates of 65 nm in diameter, the FRET efficiency decreases to 85%, while a risetime in D emission emerges. This provides support to the proposed correlation between efficiency and packing. Hence, it is inferred that total fluorophore concentration, rather than D : A ratios, governs the FRET dynamics and efficiency in these systems. PMID- 28809167 TI - Investigation of beta-lactam antibacterial drugs, beta-lactamases, and penicillin binding proteins with fluorescence polarization and anisotropy: a review. AB - This review covers the uses of fluorescence polarization and anisotropy for the investigation of bacterial penicillin binding proteins (PBPs), which are the targets of beta-lactam antibacterial drugs (penicillins, cephalosporins, carbapenems, and monobactams), and of the beta-lactamase enzymes that destroy these drugs and help to render bacterial pathogens resistant to them. Fluorescence polarization and anisotropy-based methods for quantitation of beta lactam drugs are also reviewed. A particular emphasis is on methods for quantitative measurement of the interactions of beta-lactams and other inhibitors with PBPs and beta-lactamases. PMID- 28809169 TI - Photoinduced strong acid-weak base reactions in a polar aprotic solvent. AB - The excited-state proton transfer (ESPT) of the strong photoacid, N-methyl-7 hydroxyquinolinium, was studied in the presence of different weak bases such as methanol, ethanol, and dimethyl sulfoxide in an aprotic solvent of acetonitrile. Here, we present chemical kinetics analysis of the ESPT mechanism to explain biphasic fluorescence decay of the parent photoacid and the sign reversal of the rise and decay of the resulting conjugate-base fluorescence. The ESPT of the free photoacid showed a molecularity of 2 with reacting alcohol molecules. In the ground state, it was found that a fraction of the photoacid formed 1 : 2 hydrogen bonded complexes with the residual water present in the aprotic solvent or 1 : 1 complexes with the additive alcohols. In the excited state, these adducts underwent proton transfer when complexed further with diffusing alcohol molecules. PMID- 28809165 TI - From single-molecule spectroscopy to super-resolution imaging of the neuron: a review. AB - For more than 20 years, single-molecule spectroscopy has been providing invaluable insights into nature at the molecular level. The field has received a powerful boost with the development of the technique into super-resolution imaging methods, ca. 10 years ago, which overcome the limitations imposed by optical diffraction. Today, single molecule super-resolution imaging is routinely used in the study of macromolecular function and structure in the cell. Concomitantly, computational methods have been developed that provide information on numbers and positions of molecules at the nanometer-scale. In this overview, we outline the technical developments that have led to the emergence of localization microscopy techniques from single-molecule spectroscopy. We then provide a comprehensive review on the application of the technique in the field of neuroscience research. PMID- 28809170 TI - Analysis of complex anisotropy decays from single-frequency polarized-phasor ellipse plots. AB - The anisotropy decay of a fluorescently-labelled macromolecule provides information on the internal and global dynamics of the macromolecule. Weber was a pioneer of fluorescent probes, polarization and polarized phase-modulation methods and revealed the power of combining or comparing these methods to disentangle complex modes of emission depolarization. In this paper we take a similar course and show that when measurements of dynamic depolarization are combined with steady-state anisotropy, complex anisotropy decays can be deduced from measurements at a single modulation frequency. Specifically, a double exponential anisotropy decay can be resolved by combining one of the polarized emission phasors with the steady-state anisotropy. The key is the polarized phasor ellipse plot which provides a convenient visualisation aid and reduces the dimensionality of the minimisation problem from three variables to one variable. We illustrate these concepts with an experimental measurement of the anisotropy decay of a small cytoplasmic fluorescent probe in live cells. PMID- 28809172 TI - Tracing the conformational changes in BSA using FRET with environmentally sensitive squaraine probes. AB - A new potential method of detecting the conformational changes in hydrophobic proteins such as bovine serum albumin (BSA) is introduced. The method is based on the change in the Forster resonance energy transfer (FRET) efficiency between protein-sensitive fluorescent probes. As compared to conventional FRET based methods, in this new approach the donor and acceptor dyes are not covalently linked to protein molecules. Performance of the new method is demonstrated using the protein-sensitive squaraine probes Square-634 (donor) and Square-685 (acceptor) to detect the urea-induced conformational changes of BSA. The FRET efficiency between these probes can be considered a more sensitive parameter to trace protein unfolding as compared to the changes in fluorescence intensity of each of these probes. Addition of urea followed by BSA unfolding causes a noticeable decrease in the emission intensities of these probes (factor of 5.6 for Square-634 and 3.0 for Square-685), and the FRET efficiency changes by a factor of up to 17. Compared to the conventional method the new approach therefore demonstrates to be a more sensitive way to detect the conformational changes in BSA. PMID- 28809171 TI - When R > 0.8R 0: fluorescence anisotropy, non-additive intensity, and cluster size. AB - Assembly and clustering feature in many biological processes and homo-FRET and fluorescence anisotropy can assist in estimating the aggregation state of a system. The distance dependence of resonance energy transfer is well described and tested. Similarly, assessment of cluster size using steady state anisotropy is well described for non-oriented systems when R < 0.8R 0, however, these methods break down when R > 0.8R 0. Fused trimeric DNA clusters labelled with fluorescein were engineered to provide inter-fluorophore distances from 0.7 to 1.6 R/R 0 and intensity and anisotropy were measured. These constructs cover a range where anisotropy effects depend on distance. Analytical expressions were derived for fully labelled and fractionally labelled clusters and the experimental results analysed. The experimental results showed that: (1) the system underwent distance dependent quenching; (2) when incompletely labelled both doubly and triply labelled forms could be assessed to obtain distance dependent intensity factors; (3) the anisotropy behaviour of a multiply labelled cluster of a particular size depends on the behaviour of the fluorophores and their distance in a cluster. This work establishes that when emission intensity data are available the analytically useful range for investigating clusters does not have to be restricted to R < 0.8R 0 and is applicable to cases where the anisotropy of a cluster of N fluorophores is not well approximated by r 1/N. PMID- 28809173 TI - Context Sensitive Health Informatics: Delivering 21st Century Healthcare - Building a Quality-and-Efficiency Driven System. AB - Health informatics applications will be a cornerstone in the next generation quality-and-efficiency health care system. Health care is delivered from many different specialties, to many different patients with complex diseases and comorbidity. A one size fits all approach is not adequate to reach the Triple Aim of improving the patient experience of care, improving the health of populations, and reducing the per capita cost of health care. Health informatics applications must be built to be adaptable and sensitive to the complex contexts they will be used in. To enhance patient-centeredness in the 21st Century healthcare, research attention should be focused on investigating and designing models contributing to effective health information retrieval process. PMID- 28809175 TI - The Use of Data Analytics to Build an Australian Context-Sensitive Health Informatics Framework for Consumer-Directed Community Aged Care. AB - The challenge of providing services that meet the growing needs of an ageing population is one confronted by communities across Australia and internationally. The aim of this study was to: a) undertake semi-structured interviews and focus groups across a sample of service and technical staff to identify the interconnection between communication, information, work practices and performance; and b) carry out a comprehensive review of existing data sources to identify the data linkages required to identify and monitor performance across different dimensions of the quality of aged care spectrum. The results from this study provided empirical evidence of the interconnection between communication, information, work practices and performance; and highlighted numerous potential data linkages which can be used to monitor performance across different dimensions of aged care. These included: the uptake and utilisation of community care services, community aged care client interactions and transitions (with hospitals and other health care providers), and quality of life measures (e.g., health and safety status, symptoms of depression and anxiety, social integration and mortality rates). PMID- 28809176 TI - Potential of Decision Support in Preventing Pressure Ulcers in Hospitals. AB - The development of hospital-acquired pressure ulcers signals low quality of care. Despite the established guidelines and best practices on pressure ulcer prevention, the incidence of pressure ulcers in hospital remains high. To meet the challenges of consistently translating best practices into effective clinical practices and promote effective teamwork communication and interprofessional collaboration, we consider the failure of consistent care delivery as loss of information and reveal the opportunities of informatics methods to reinforce information delivery, evidenced by typical cases. We, then, explain and summarize information-related issues existing at the initial assessment upon hospital admission, routine treatments, and team communication. Clinical decision support methods are promising in addressing these issues by optimizing care plans, improving adherence to best practices, reinforcing effective team communication, and customizing event report feedback. PMID- 28809177 TI - Health Sciences Library Closings; A Context Sensitive Pilot Study. AB - A significant number of U.S. health sciences libraries have closed since the mid 1990's. A pilot study was conducted with academic physicians to understand the impact of closing the health sciences library in the teaching hospital with which they were affiliated. A brief survey was designed and distributed to fourteen faculty members with thirteen useable responses received. The study elicited a context-sensitive perspective on the closing of the library with the most noteworthy outcome being the additional time required by attending physicians and trainees to perform the work that previously was performed by library staff. The loss of the expert literature search, instructional services, journal request, and interlibrary loan services had the most significant impact on study participants. Further research is needed to understand the long term consequences of closing hospital-based health sciences library on the education of physicians. PMID- 28809178 TI - How Can Health Information Technologies Contribute to Improve Health Care Services for High-Need Patients? AB - This paper discusses how health information technologies like tele-care, tele health and tele-medicine can improve the condition for high-need patients, specifically in relation to access. The paper addresses specifically the values of timeliness and equity and how tele technological solutions can support and enhance these values. The paper introduces to the concept of scaffolding, which constitutes the framework for dynamic, appropriate, caring and embracing approaches for engaging and involving high-need patients that are vulnerable and exposed. A number of specific considerations for designing tele-technologies for high-need patients are derived, and the paper concludes that ethical and epistemological criterions for design are needed in order to meet the needs and requirements of the weak and exposed. PMID- 28809179 TI - Qualitative Research for Patient Safety Using ICTs: Methodological Considerations in the Technological Age. AB - Considerable effort and resources have been dedicated to improving the quality and safety of patient care through health information systems, but there is still significant scope for improvement. One contributing factor to the lack of progress in patient safety improvement especially where technology has been deployed relates to an over-reliance on purely objective, quantitative, positivist research paradigms as the basis for generating and validating evidence of improvement. This paper argues the need for greater recognition and accommodation of evidence of improvement generated through more subjective, qualitative and pragmatic research paradigms to aid patient safety especially where technology is deployed. This paper discusses how acknowledging the role and value of more subjective ontologies and pragmatist epistemologies can support improvement science research. This paper illustrates some challenges and benefits from adopting qualitative research methods in patient safety improvement projects, particularly focusing challenges in the technological era. While adopting methods that can more readily capture, analyse and interpret direct user experiences, attitudes, insights and behaviours in their contextual settings, patient safety can be enhanced 'on the ground' and errors reduced and/or mitigated, challenges of using these methods with the younger "technologically centred" healthcare professionals and patients needs to recognised. PMID- 28809180 TI - Exploring Socio-Technical Insights for Safe Nursing Handover. AB - Current efforts to improve nursing handover frequently use prescriptive approaches based on research evidence of handover issues within a single nursing ward or nursing specialty. Despite reported handover improvement, few studies adequately consider the transferability of results to other nursing handover environments or acknowledge the unique attributes that supported sustained improvement. With the increasing diffusion of electronic tools it has become even more critical to ensure that socio-technical issues that may impact on the quality and safety of nursing handovers are identified. This paper describes a qualitative research project that examined nursing handover in three different wards - General Medicine, General Surgery and Department of Emergency Medicine in a tertiary teaching hospital. Through conduct of a detailed analysis of nursing handover processes, this paper highlights the similarities and differences in the handover among the three different wards and presents five key socio-technical insights to support safe nursing handover. PMID- 28809182 TI - Developing an Assessment Tool for Enhancing Interprofessional Education of Patient Safety. AB - The increasing recognition of the value of effective interprofessional collaboration has promoted interprofessional education (IPE) among healthcare professionals. The IPE pilot program initiative at UTHealth matriculated students from the disciplines of biomedical informatics, biomedical sciences, dentistry, medicine, nursing and public health. There has been a pressing need for developing an assessment tool in reflecting how IPE participants recognize and understand the other disciplines including clinical informatics in nowadays' practice. This paper reports our development process of the assessment tool, which is still under an iterative, in-depth refinement and aiming at greater collaborations. PMID- 28809184 TI - Moving Past Exploration and Adoption: Considering Priorities for Implementing Mobile Learning by Nurses. AB - Successful implementation of mobile technology for informal learning and continuing professional development within healthcare settings cannot be achieved or sustained, until end-users recognise that the benefits of using this innovation, outweigh the issues of non-use. At a systems level there is a need for standards, guidelines and codes of conduct to support deployment of mobile technology at an individual level. The aim of this research was to explore findings of a previous focus group study to elucidate priorities for action, provide evidence and focus impetus for advocating progression of the installation of standards and guidelines at an organisation level. The study confirms nurse supervisors' preparedness and readiness to employ mobile learning at point of care. However, successful implementation requires organisations engaging with, and embracing the evolving digital landscape, and supporting this new andragogy. Organisational level commitment will promote contemporary nursing practice, support the best clinical outcomes for patients, and provide educational support for nurses. Nurse leaders and professional bodies must drive and guide development of robust standards, guidelines, and codes of conduct to prioritise mobile learning as a component of digital professionalism within healthcare organisations. PMID- 28809183 TI - Helping Hands: Using Augmented Reality to Provide Remote Guidance to Health Professionals. AB - Access to expert practitioners or geographic distance can compound the capacity for appropriate supervision of health professionals in the workplace. Guidance and support of clinicians and students to undertake new or infrequent procedures can be resource intensive. The Helping Hands remote augmented reality system is an innovation to support the development of, and oversee the acquisition of procedural skills through remote learning and teaching supervision while in clinical practice. Helping Hands is a wearable, portable, hands-free, low cost system comprised of two networked laptops, a head-mounted display worn by the recipient and a display screen used remotely by the instructor. Hand hygiene was used as the test procedure as it is a foundation skill learned by all health profession students. The technology supports unmediated remote gesture guidance by augmenting the object with the Helping Hands of a health professional. A laboratory-based study and field trial tested usability and feasibility of the remote guidance system. The study found the Helping Hands system did not compromise learning outcomes. This innovation has the potential to transform remote learning and teaching supervision by enabling health professionals and students opportunities to develop and improve their procedural performance at the workplace. PMID- 28809185 TI - A Quality, Benefit, Cost, and Financial Framework for Health Information Technology, E-Prescribing: A Delphi Study. AB - BACKGROUND: Little research has been conducted about the quality, benefits, costs, and financial considerations associated with health information technology (HIT), particularly informatics technologies, such as e-prescribing, from the perspective of all its stakeholders. OBJECTIVES: This research effort sought to identify the stakeholders involved in e-prescribing and to identify and rank order the positives and the negatives from the perspective of the stakeholders to create a framework to assist in the development of incentives and payment mechanisms which result in better managed care. METHODS: The Delphi method was employed by enlisting a panel of experts. They were presented with the results of initial research in an online survey of questions which sought to prioritize the quality, benefit, cost, and financial effects of e-prescribing from the perspective of each stakeholder. From the results of this study, a framework was presented to framework experts. RESULTS: The experts added stakeholders and positives and negatives to the initial lists and rank-ordered the positives and negatives of e-prescribing from the perspective of each stakeholder. The aggregate results were summarized by category of stakeholder. The framework experts evaluated the framework. CONCLUSIONS: Positives and negatives can be rank ordered from the perspective of each stakeholder. A useful framework was created. PMID- 28809186 TI - Bridging the Gap Between the Social and the Technical: The Enrolment of Socio Technical Information Architects to Cope with the Two-Level Model of EPR Systems. AB - This is a project proposal derived from an urge to re-define the governance of ICT in healthcare towards regional and national standardization of the patient pathways. The focus is on a two-levelled approach for governing EPR systems where the clinicians' model structured variables and patient pathways. The overall goal is a patient centric EPR portfolio. This paper define and enlighten the need for establishing the socio- technical architect role necessary to obtain the capabilities of a modern structured EPR system. Clinicians are not capable to moderate between the technical and the clinical. PMID- 28809187 TI - ICT Design for Collaborative and Community Driven Disaster Management. AB - Information and communication technologies (ICT) have the potential to greatly enhance our ability to develop community reliance and sustainability to support disaster management. However, developing community resilience requires the sharing of numerous resources and the development of collaborative capacity, both of which make ICT design a challenge. This paper presents a framework that integrates community based participatory research (CBPR) and participatory design (PD). We discuss how the framework provides bounding to support community driven ICT design and evaluation. PMID- 28809188 TI - Clinical Supervision of Interns: Understanding the View of Interns and the Potential of ICT to Deliver Supervision for Safer Patient Care. AB - Clinical communication and clinical supervision of junior healthcare professionals are identified as the two most common preventable factors to reduce medical errors. While multiple strategies have been implemented to improve clinical communication, clinical supervision has not attracted as much attention. This is in part due to the lack of understanding of clinical supervision. Furthermore, there is a lack of exploration of information communication technology (ICT) in assisting the delivery of clinical supervision from the perspective of users (i.e. junior clinicians). This paper presents a study to understand clinical supervision from the perspective of medical and pharmacy interns. The important elements of good clinical supervisors and good clinical supervision have been presented in this paper based on our study. More importantly, our results suggest a distinction between good supervisors and good supervisions. Both these factors impact on patient safety. Through discussion of user requirements of good supervision by users (interns), this paper then explores and presents a conceptual framework to assist in the discussion and design of ICT by healthcare organisations to improve clinical supervision of interns and therefore improve patient safety. PMID- 28809190 TI - Design Thinking for mHealth Application Co-Design to Support Heart Failure Self Management. AB - Heart failure is a prevalent, progressive chronic disease costing in excess of $1billion per year in Australia alone. Disease self-management has positive implications for the patient and decreases healthcare usage. However, adherence to recommended guidelines is challenging and existing literature reports sub optimal adherence. mHealth applications in chronic disease education have the potential to facilitate patient enablement for disease self-management. To the best of our knowledge no heart failure self-management application is available for safe use by our patients. In this paper, we present the process established to co-design a mHealth application in support of heart-failure self-management. For this development, an interdisciplinary team systematically proceeds through the phases of Stanford University's Design Thinking process; empathise, define, ideate, prototype and test with a user-centred philosophy. Using this clinician led heart failure app research as a case study, we describe a sequence of procedures to engage with local patients, carers, software developers, eHealth experts and clinical colleagues to foster rigorously developed and locally relevant patient-facing mHealth solutions. Importantly, patients are engaged in each stage with ethnographic interviews, a series of workshops and multiple re design iterations. PMID- 28809191 TI - Understanding Through Use: Elderly's Value Identification in a Service Experience. AB - This paper uses a qualitative approach, specifically; narrative analysis, to contextualize user's formulation of an understanding of a personalized meal planning service within the ambient assisted living domain. By focusing on how user's, in this case elderly over 65, formed an understanding of a service, and, what they thought valuable in using the service, based on their understanding. The results indicate how user's compare their initial understanding to their experienced understanding, formed during usage, and how this affects their value formulation of specific service aspects. The paper gives not only provides valuable insight into contextualizing aspects of health and wellness services, but to aspects of importance for implementation, by showing how value aspects of services from a user perspective are important to consider during these processes. PMID- 28809192 TI - Patient Perceptions About Data Sharing & Privacy: Insights from ActionADE. AB - Information communication technologies (ICTs) may improve health delivery by enhancing informational continuity of care and enabling secondary use of health data including public health surveillance and research. ICTs also introduce concerns related to privacy. In this paper, we examine and address this tension in the context of the development and implementation of a novel platform that will enable the documentation and communication of patient-specific ADE information, titled ActionADE. We explored privacy concerns qualitatively from the perspective of patients. Our findings will inform a series of recommendations for system design that seek to balance the need to both share and protect personal health information. PMID- 28809193 TI - Patient at Work - In the Era of PRO. AB - There is a widespread consensus that it is important to involve patient in their own care, both for the reasons of quality and safety in healthcare and for the sake of the patients' individual rights. The appreciation of patient participation and related notions such as patient empowerment, patient centered care, patient involvement, patient as co-producers of health et cetera, indicate that the role of the patient have changed over the last decades. It has changed from being a passive recipient of treatment to becoming an active and responsible agent. In this paper, we examine these new roles of the patients and discuss the challenges in realizing them. We include the notion of Patient Reported Outcome (PRO) and suggest that realizing this concept indicate a shift in the understanding of participation/empowerment. Participation of patients in a PRO paradigm means to provide patient with a highly-structured task both in terms of the kind of information the health care system requests, and in terms of how and when. It means to focus on what patients do. Further we suggest that a more precise term to denote the new role allocated to the patient would be patient work, not participation or empowerment. To recognize that being a patient is work, would imply a direct emphasis on competences required and the the time needed, on the division of labor and on the necessary condition for doing the work. PMID- 28809194 TI - Patient and Healthcare Provider Factors for Communication (PHPFC) Model. AB - eHealth applications can allow patients to view, manage and track their health conditions while also allowing healthcare providers to monitor and update their patients' healthcare information in a timelier manner. There is a need for studies to describe what common ground is needed for eHealth applications to facilitate communication between patients and healthcare providers. This paper proposes the Patient-Healthcare Provider Factors for Communication (PHPFC) model that describes patient and provider eHealth communication factors as well as a set of integrated factors to support development of common ground between the two groups. PMID- 28809195 TI - Pokemon-Go: Why Augmented Reality Games Offer Insights for Enhancing Public Health Interventions on Obesity-Related Diseases. AB - Stimulating widespread interests of the population to participate in behavioural changes through information and technology has been an aim of much health informatics research. The recent widespread participation of the augmented reality game Pokemon Go which encourages exercises, provides significant insights into the potential of information technology to improve healthcare intervention on obesity-related disease. Does Pokemon Go point to another way of achieving health benefits using mobile devices? This paper analyses the features of Pokemon Go in relation to potential health benefits. This paper suggests from the perspective of a user on changes to the game that potentially could help with obesity, mental health cardiovascular health and vitamin D deficiencies. While the impact of augmented reality games on improving exercises might be substantial, the question of sustainability and likely long-term health outcomes remain debatable. The rapid uptake of Pokemon Go by the population around the world, however, should serve as a useful lesson for information and technological design to improve outcomes obesity-related diseases in the future. PMID- 28809196 TI - Health Informatics and Technology for Integrated Elderly Care in the Context of Hong Kong: A Case Study. AB - The aging population creates tremendous pressure to healthcare. To resolve, scholars recognized the solution to this challenge is integrated care. To facilitate integrated care, health information technologies (HIT) is a critical enabler. This paper will first review how technology enhanced integrated care, and review on the existing literatures in system effective use and the three key external factors that enable HIT implementation. Applying Burton-Jones and Volkoff's contextualized theories of effective use of HIT to understand the role of health informatics and technology in the unique context of Hong Kong, we have conducted a case study research to identify the levers for improving HK integration of care through HIT. PMID- 28809198 TI - A Comparison of Danish and Canadian Consumer Medication Information. AB - Many people around the world use prescription medications. Consumers often require information about their medications to support taking them safely and effectively. One source of such information is Consumer Medication Information (CMI). Canadians typically receive printed CMI when a new prescription is filled whereas Danes have the online resource min.medicin.dk. This study compared the content and design of Danish and Canadian CMI. Danish CMI satisfied seven of the 11 content utility criteria (developed in previous work) identified as supporting the safe and effective medication use. However, Danish CMI provided a more information about how frequently possible side effects occur and multimedia (e.g., images, videos) directions for some medications. This study examined some of the similarities and differences between how Canadians and Danes are informed about medications. However, further research is required to determine what content and methods of delivery are most beneficial in supporting safe and effective medication use. PMID- 28809199 TI - The Role of ICT in Home Care. AB - With an ageing population and limited resources, ICT is often mentioned as a solution to support elderly people in maintaining an independent and healthy lifestyle. In this paper, we describe how ICT can support access to information and rationalization of work processes in a home care context. We do this by modelling the workflow and identifying the possible impact of ICT. The results show a complex process and indicate that the available resources are not used in the best possible way. The introduction of ICT could increase patient safety by reducing the risk of misplacing information about the care recipients and at the same time provide real time information about the care recipients' needs and health at the point of care. However, to rationalize the work processes there is a need to combine ICT with a changed procedure for handling keys. PMID- 28809200 TI - Alarm Fatigue vs User Expectations Regarding Context-Aware Alarm Handling in Hospital Environments Using CallMeSmart. AB - Surveys and research show that mobile communication systems in hospital settings are old and cause frequent interruptions. In the quest to remedy this, an Android based communication system called CallMeSmart tries to encapsulate most of the frequent communication into one hand held device focusing on reducing interruptions and at the same time make the workday easier for healthcare workers. The objective of CallMeSmart is to use context-awareness techniques to automatically monitor the availability of physicians' and nurses', and use this information to prevent or route phone calls, text messages, pages and alarms that would otherwise compromise patient care. In this paper, we present the results from interviewing nurses on alarm fatigue and their expectations regarding context-aware alarm handling using CallMeSmart. PMID- 28809201 TI - Secondary Use of EHR: Interpreting Clinician Inter-Rater Reliability Through Qualitative Assessment. AB - In a retrospective secondary-use EHR study identifying a cohort of Non-Valvular Atrial Fibrillation (NVAF) patients, chart abstraction was done by two sets of clinicians to create a gold standard for risk measures CHA2DS2-VASc and HAS-BLED. Inter-rater reliability between each set of clinicians for NVAF and the outcomes of interest were variable, ranging from extremely low agreement to high agreement. To assess the chart abstraction process, a focus group and a survey was conducted. Survey findings revealed patterns of difficulty in assessing certain items dealing with temporality and social data. The focus group raised issues on the quality and completeness of EHR data, including missing encounters, truncated notes, and low granularity. It also raised the issue of the usability of the data system, the Clinical Data Viewer, which did not mirror a live EHR and made it difficult to record outcomes. Finally, the focus group found it was difficult to infer certain outcomes, like severity, from the provided data. These factors produced differences in clinician rated outcomes. PMID- 28809202 TI - Creativity as a Key Driver for Designing Context Sensitive Health Informatics. AB - In order to face the increasing challenges of complexity and uncertainty in practice of health care, this paper aims to discuss how creativity can contribute to design new technologies in health informatics systems. It will firstly introduce the background highlighting creativity as a missing element in recent studies on context sensitive health informatics. Secondly, the concept of creativity and its relationship with activities of technology design will be discussed from a socio-culture perspective. This will be thirdly followed by understanding the roles of creativity in designing new health informatics technologies for meeting needs of high context sensitivity. Finally, a series of potential strategies will be suggested to improve creativity among technology designers working in healthcare industries. Briefly, this paper innovatively bridges two areas studies on creativity and context sensitive health informatics by issues of technology design that also indicates its important significances for future research. PMID- 28809203 TI - Clinical Simulation: A Protocol for Evaluation of Mobile Technology. AB - For mobile technology to be accepted at point of care in healthcare environments there is a need to demonstrate benefits whilst ameliorating the risks and challenges. To provide a standardised approach to evaluation of mobile technology a simulation protocol was developed to provide guidance for its use in healthcare environments. Simulated conditions provide the opportunity to assess intended and unintended consequences and identify potential workarounds when using technology. The protocol can also be used to demonstrate the importance of the development of digital professionalism by end-users prior to students entering the clinical practice setting. The mobile technology protocol was adapted from a health information systems protocol developed and used at the ITX Lab, Denmark for use in other simulation laboratories. Use case scenarios were developed to enable evaluation of mobile technology for mobile learning of nurses, nurse supervisors, students and patients. The scenarios can be used in a range of simulated environments including hospital bedside, outpatient clinic or community settings. A case study exemplar of a nurse and patient is included to demonstrate how the mobile technology protocol can be applied. PMID- 28809206 TI - Synthetic Aspects and Electro-Optical Properties of Fluorinated Arylenevinylenes for Luminescence and Photovoltaics. AB - In this review, the main synthetic aspects and properties of fluorinated arylenevinylene compounds, both oligomers and polymers, are summarized and analyzed. Starting from vinyl organotin derivatives and aryl halides, the Stille cross-coupling reaction has been successfully applied as a versatile synthetic protocol to prepare a wide series of pi-conjugated compounds, selectively fluorinated on the aromatic and/or vinylene units. The impact of fluoro functionalization on properties, the solid state organization and intermolecular interactions of the synthesized compounds are discussed, also in comparison with the non-fluorinated counterparts. Luminescent and photovoltaic applications are also discussed, highlighting the role of fluorine on the performance of devices. PMID- 28809207 TI - Characterization of an Exopolymeric Flocculant Produced by a Brachybacterium sp. AB - We evaluated the bioflocculant production potential of an Actinobacteria, which was isolated from a freshwater environment in the Eastern Cape province of South Africa. 16S rDNA nucleotide sequencing analyses revealed that the actinobacteria belongs to the Brachybacterium genus, and the sequences were deposited in the GenBank as Brachybacterium sp. UFH, with accession number HQ537131. Optimum fermentation conditions for bioflocculant production by the bacteria include an initial medium pH of 7.2, incubation temperature of 30 degrees C, agitation speed of 160 rpm and an inoculum size of 2% (vol/vol) of cell density 3.0 * 108 CFU/mL. The carbon, nitrogen and cation sources for optimum bioflocculant production were maltose (83% flocculating activity), urea (91.17% flocculating activity) and MgCl2 (91.16% flocculating activity). Optimum bioflocculant production coincided with the logarithmic growth phase of the bacteria, and chemical analyses of the bioflocculant showed 39.4% carbohydrate and 43.7% protein (wt/wt). The mass ratio of neutral sugar, amino sugar and uronic acids was 1.3:0.7:2.2. Fourier transform infrared spectroscopy (FTIR) indicated the presence of carboxyl, hydroxyl and amino groups, amongst others, typical for heteropolysaccharide and glycosaminoglycan polysaccharides. Bioflocculant pyrolysis showed thermal stability at over 600 degrees C, while scanning electron microscope (SEM) imaging revealed a maze-like structure of interlaced flakes. Its high flocculation activity suggests its suitability for industrial applicability. PMID- 28809208 TI - An Ultrasensitive Electrochemical Immunosensor for HIV p24 Based on Fe3O4@SiO2 Nanomagnetic Probes and Nanogold Colloid-Labeled Enzyme-Antibody Copolymer as Signal Tag. AB - An ultrasensitive portable electrochemical immunosensor for human immunodeficiency virus p24 (HIV p24) antigen detection has been developed, whereby the detection sensitivity was 1000 times higher than that of the ELISA method. Firstly, a novel HRP enzyme-antibody copolymer (EV-p24 Ab2) was synthesized through an EnVision regent (EV, a dextrin amine skeleton anchoring more than 100 molecules of HRP and 15 molecules of anti IgG), then incubated in the secondary antibody of p24. Secondly, the copolymer was immobilized on the gold nanocolloids (AuNPs) to fabricate a novel signal tag (AuNPs/EV-p24 Ab2). Subsequently, a sandwich-type immunoreaction would take place between the capture probe (silicon dioxide-coated magnetic Fe3O4 nanoparticles (MNPs) labeled with the primary p24 antibody (MNPs-p24 Ab1)), p24 (different concentrations) and the signal tag [AuNPs/EV-p24 Ab2)] to form the immunocomplex. Finally, the immunocomplex was absorbed on the surface of screen printed carbon electrode (SPCE) by a magnet and immersed in the o-hydroxyl phenol (HQ) and H2O2. The large amounts of HRP on the signal tag can catalyze the oxidation of HQ by H2O2, which can induce an amplified reductive current. Moreover, the capture probe could improve the accumulation ability of p24 and facilitate its separation from the substrate through the magnet. Under optimal conditions, the proposed immunoassay exhibited good sensitivity to p24 within a certain concentration range from 0.001 to 10.00 ng/mL, with a detection limit of 0.5 pg/mL (S/N = 3). The proposed method can be used for real-time and early detection of HIV-infected people. PMID- 28809209 TI - Fabrication of Cellulose Film with Enhanced Mechanical Properties in Ionic Liquid 1-Allyl-3-methylimidaxolium Chloride (AmimCl). AB - More and more attention has been paid to environmentally friendly bio-based renewable materials as the substitution of fossil-based materials, due to the increasing environmental concerns. In this study, regenerated cellulose films with enhanced mechanical property were prepared via incorporating different plasticizers using ionic liquid 1-allyl-3-methylimidazolium chloride (AmimCl) as the solvent. The characteristics of the cellulose films were investigated by scanning electron microscopy (SEM), atomic force microscopy (AFM), thermal analysis (TG), X-ray diffraction (XRD), 13C Solid-state cross-polarization/magic angle spinning nuclear magnetic resonance (CP/MAS NMR) and tensile testing. The results showed that the cellulose films exhibited a homogeneous and smooth surface structure. It was noted that the thermal stability of the regenerated cellulose film plasticized with glycerol was increased compared with other regenerated cellulose films. Furthermore, the incorporation of plasticizers dramatically strengthened the tensile strength and improved the hydrophobicity of cellulose films, as compared to the control sample. Therefore, these notable results exhibited the potential utilization in producing environmentally friendly cellulose films with high performance properties. PMID- 28809211 TI - Lithium Ion Battery Anode Aging Mechanisms. AB - Degradation mechanisms such as lithium plating, growth of the passivated surface film layer on the electrodes and loss of both recyclable lithium ions and electrode material adversely affect the longevity of the lithium ion battery. The anode electrode is very vulnerable to these degradation mechanisms. In this paper, the most common aging mechanisms occurring at the anode during the operation of the lithium battery, as well as some approaches for minimizing the degradation are reviewed. PMID- 28809210 TI - Alginate-Based Biomaterials for Regenerative Medicine Applications. AB - Alginate is a natural polysaccharide exhibiting excellent biocompatibility and biodegradability, having many different applications in the field of biomedicine. Alginate is readily processable for applicable three-dimensional scaffolding materials such as hydrogels, microspheres, microcapsules, sponges, foams and fibers. Alginate-based biomaterials can be utilized as drug delivery systems and cell carriers for tissue engineering. Alginate can be easily modified via chemical and physical reactions to obtain derivatives having various structures, properties, functions and applications. Tuning the structure and properties such as biodegradability, mechanical strength, gelation property and cell affinity can be achieved through combination with other biomaterials, immobilization of specific ligands such as peptide and sugar molecules, and physical or chemical crosslinking. This review focuses on recent advances in the use of alginate and its derivatives in the field of biomedical applications, including wound healing, cartilage repair, bone regeneration and drug delivery, which have potential in tissue regeneration applications. PMID- 28809212 TI - Half-Heusler (TiZrHf)NiSn Unileg Module with High Powder Density. AB - (TiZrHf)NiSn half-Heusler compounds were prepared by arc melting and their thermoelectric properties characterized in the temperature range between 325 K and 857 K, resulting in a Figure of Merit ZT ~ 0.45. Furthermore, the prepared samples were used to construct a unileg module. This module was characterized in a homemade thermoelectric module measurement stand and yielded 275 mW/cm2 and a maximum volumetric power density of 700 mW/cm3. This was reached using normal silver paint as a contacting material; from an improved contacting, much higher power yields are to be expected. PMID- 28809214 TI - Magnetic Graphene Oxide: Effect of Preparation Route on Reactive Black 5 Adsorption. AB - In this study, the effect of preparation route of magnetic graphene oxide (mGO) on Reactive Black 5 (RB5) adsorption was investigated. The synthesis of mGO was achieved both with (i) impregnation method (mGOi nanoparticles), and (ii) co precipitation (mGOp nanoparticles). After synthesis, the full characterization with various techniques (SEM, FTIR, XRD, DTA, DTG, VSM) was achieved revealing many possible interactions/forces of dye-composite system. Effects of initial solution pH, effect of temperature, adsorption isotherms and kinetics were investigated in order to conclude about the aforementioned effect of the preparation method on dye adsorption performance of the magnetic nanocomposites. The adsorption evaluation of the magnetic nanoparticles presented higher adsorption capacity of mGOp derivative (188 mg/g) and lower of mGOi (164 mg/g). Equilibrium experiments are also performed studying the effect of contact time (pseudo-first and -second order equations) and temperature (isotherms at 25, 45 and 65 degrees C fitted to Langmuir and Freundlich model). A full thermodynamic evaluation was carried out, calculating the parameters of enthalpy, free energy and entropy (DeltaH0, DeltaG0 and DeltaS0). PMID- 28809215 TI - Cellulose Perversions. AB - Cellulose micro/nano-fibers can be produced by electrospinning from liquid crystalline solutions. Scanning electron microscopy (SEM), as well as atomic force microscopy (AFM) and polarizing optical microscopy (POM) measurements showed that cellulose-based electrospun fibers can curl and twist, due to the presence of an off-core line defect disclination, which was present when the fibers were prepared. This permits the mimicking of the shapes found in many systems in the living world, e.g., the tendrils of climbing plants, three to four orders of magnitude larger. In this work, we address the mechanism that is behind the spirals' and helices' appearance by recording the trajectories of the fibers toward diverse electrospinning targets. The intrinsic curvature of the system occurs via asymmetric contraction of an internal disclination line, which generates different shrinkages of the material along the fiber. The completely different instabilities observed for isotropic and anisotropic electrospun solutions at the exit of the needle seem to corroborate the hypothesis that the intrinsic curvature of the material is acquired during liquid crystalline sample processing inside the needle. The existence of perversions, which joins left and right helices, is also investigated by using suspended, as well as flat, targets. Possible routes of application inspired from the living world are addressed. PMID- 28809216 TI - Chitosonic(r) Acid as a Novel Cosmetic Ingredient: Evaluation of its Antimicrobial, Antioxidant and Hydration Activities. AB - Chitosonic(r) Acid, carboxymethyl hexanoyl chitosan, is a novel chitosan material that has recently been accepted by the Personal Care Products Council as a new cosmetic ingredient with the INCI (International Nomenclature of Cosmetic Ingredients) name Carboxymethyl Caprooyl Chitosan. In this study, we analyze several important cosmetic characteristics of Chitosonic(r) Acid. Our results demonstrate that Chitosonic(r) Acid is a water-soluble chitosan derivative with a high HLB value. Chitosonic(r) Acid can form a nano-network structure when its concentration is higher than 0.5% and can self-assemble into a nanosphere structure when its concentration is lower than 0.2%. Chitosonic(r) Acid has potent antimicrobial activities against gram-positive bacteria, gram-negative bacteria and fungus. Chitosonic(r) Acid also has moderate DPPH radical scavenging activity. Additionally, Chitosonic(r) Acid exhibits good hydration activity for absorbing and retaining water molecules with its hydrophilic groups. From a safety point of view, Chitosonic(r) Acid has no cytotoxicity to L-929 cells if its concentration is less than 0.5%. Moreover, Chitosonic(r) Acid has good compatibilities with various normal cosmetic ingredients. Therefore, we propose that Chitosonic(r) Acid has the potential to be a widely used ingredient in various types of cosmetic products. PMID- 28809213 TI - How Can Nanotechnology Help to Repair the Body? Advances in Cardiac, Skin, Bone, Cartilage and Nerve Tissue Regeneration. AB - Nanotechnologists have become involved in regenerative medicine via creation of biomaterials and nanostructures with potential clinical implications. Their aim is to develop systems that can mimic, reinforce or even create in vivo tissue repair strategies. In fact, in the last decade, important advances in the field of tissue engineering, cell therapy and cell delivery have already been achieved. In this review, we will delve into the latest research advances and discuss whether cell and/or tissue repair devices are a possibility. Focusing on the application of nanotechnology in tissue engineering research, this review highlights recent advances in the application of nano-engineered scaffolds designed to replace or restore the followed tissues: (i) skin; (ii) cartilage; (iii) bone; (iv) nerve; and (v) cardiac. PMID- 28809218 TI - A Novel Hydrazinecarbothioamide as a Potential Corrosion Inhibitor for Mild Steel in HCl. AB - 2-(1-methyl-4-((E)-(2-methylbenzylidene)amino)-2-phenyl-1H-pyrazol-3(2H)-ylidene) hydrazineecarbothioamide (HCB) was synthesized as a corrosion inhibitor from the reaction of 4-aminoantipyrine, thiosemicarbazide and 2-methylbenzaldehyde. The corrosion inhibitory effects of HCB on mild steel in 1.0 M HCl were investigated using potentiodynamic polarization (PDP) and electrochemical impedance spectroscopy (EIS). The results showed that HCB inhibited mild steel corrosion in acidic solution and inhibition efficiency increased with an increase in the concentration of the inhibitor. The inhibition efficiency was up to 96.5% at 5.0 mM. Changes in the impedance parameters suggested that HCB adsorbed on the surface of mild steel, leading to the formation of a protective film. The novel corrosion inhibitor synthesized in the present study was characterized using Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR) spectral data. PMID- 28809217 TI - Extraction of Perchlorate Using Porous Organosilicate Materials. AB - Sorbent materials were developed utilizing two morphological structures, comprising either hexagonally packed pores (HX) or a disordered pore arrangement (CF). The sorbents were functionalized with combinations of two types of alkylammonium groups. When capture of perchlorate by the sorbents was compared, widely varying performance was noted as a result of differing morphology and/or functional group loading. A material providing improved selectivity for perchlorate over perrhenate was synthesized with a CF material using N trimethoxysilylpropyl-N,N,N-trimethylammonium chloride. Materials were applied in batch and column formats. Binding isotherms followed the behavior expected for a system in which univalent ligands of varying affinity compete for immobilized sites. Performance of the sorbents was also compared to that of commercial Purolite materials. PMID- 28809219 TI - Evaluation of Superficial and Dimensional Quality Features in Metallic Micro Channels Manufactured by Micro-End-Milling. AB - Miniaturization encourages the development of new manufacturing processes capable of fabricating features, like micro-channels, in order to use them for different applications, such as in fuel cells, heat exchangers, microfluidic devices and micro-electromechanical systems (MEMS). Many studies have been conducted on heat and fluid transfer in micro-channels, and they appeared significantly deviated from conventional theory, due to measurement errors and fabrication methods. The present research, in order to deal with this opportunity, is focused on a set of experiments in the micro-milling of channels made of aluminum, titanium alloys and stainless steel, varying parameters, such as spindle speed, depth of cut per pass (ap), channel depth (d), feed per tooth (fz) and coolant application. The experimental results were analyzed in terms of dimensional error, channel profile shape deviation from rectangular and surface quality (burr and roughness). The micro-milling process was capable of offering quality features required on the micro-channeled devices. Critical phenomena, like run-out, ploughing, minimum chip thickness and tool wear, were encountered as an explanation for the deviations in shape and for the surface quality of the micro-channels. The application of coolant and a low depth of cut per pass were significant to obtain better superficial quality features and a smaller dimensional error. In conclusion, the integration of superficial and geometrical features on the study of the quality of micro-channeled devices made of different metallic materials contributes to the understanding of the impact of calibrated cutting conditions in MEMS applications. PMID- 28809220 TI - Dehydration Process of Hofmann-Type Layered Solids. AB - In the present work the dehydration process of layered solids with formula unit M(H2O)2[Ni(CN)4].nH2O, M = Ni, Co, Mn; n = 1, 2, 4 is studied using modulated thermogravimetry. The results show that water molecules need to overcome an energetic barrier (activation energy between 63 and 500 kJ/mol) in order to diffuse through the interlayer region. The related kinetic parameters show a dependence on the water partial pressure. On the other hand, X-ray diffraction results provide evidence that the dehydration process is accompanied by framework collapse, limiting the structural reversibility, except for heating below 80 degrees C where the ordered structure remains. Removal of water molecules from the interlayer region disrupts the long-range structural order of the solid. PMID- 28809221 TI - Organized Silica Films Generated by Evaporation-Induced Self-Assembly as Hosts for Iron Oxide Nanoparticles. AB - In this work, we prepared oriented mesoporous thin films of silica on various solid substrates using the pluronic block copolymer P123 as a template. We attempted to insert guest iron oxide (FexOy) nanoparticles into these films by two different methods: (a) by co-precipitation-where iron precursors are introduced in the synthesis sol before deposition of the silica film-and subsequent oxide production during the film calcination step; (b) by preparing and calcining the silica films first then impregnating them with the iron precursor, obtaining the iron oxide nanoparticles by a second calcination step. We have examined the structural effects of the guest nanoparticles on the silica film structures using grazing incidence X-ray scattering (GISAXS), high resolution transmission electron spectroscopy (HRTEM), spectroscopic ellipsometry, X-ray photoelectron spectroscopy (XPS), and Raman microscopy. Formation of nanoparticles by co-precipitation may induce substantial changes in the film structure leading, in our adopted process, to the appearance of lamellar ordering in the calcination stage. On the contrary, impregnation-based approaches perturb the film structures much more weakly, but are also less efficient in filling the pores with nanoparticles. PMID- 28809222 TI - Mechanical Properties and Microstructure of Class C Fly Ash-Based Geopolymer Paste and Mortar. AB - This paper presents workability, compressive strength and microstructure for geopolymer pastes and mortars made of class C fly ash at mass ratios of water-to fly ash from 0.30 to 0.35. Fluidity was in the range of 145-173 mm for pastes and 131-136 mm for mortars. The highest strengths of paste and mortar were 58 MPa and 85 MPa when they were cured at 70 degrees C for 24 h. In XRD patterns, unreacted quartz and some reacted product were observed. SEM examination indicated that reacted product has formed and covered the unreacted particles in the paste and mortar that were consistent with their high strength. PMID- 28809223 TI - Randomness and Statistical Laws of Indentation-Induced Pop-Out in Single Crystal Silicon. AB - Randomness and discreteness for appearance of pop-out of the single crystal silicon with a (100) orientation were studied by a self-made indentation device. For a given maximum penetration load, the load Ppo for appearance of pop-out fluctuates in a relatively large range, which makes it hard to study the effect of the loading/unloading rate on the load Ppo. Experimental results with different maximum penetration loads indicate that the critical penetration load for appearance of pop-out is in the range of 15 mN~20 mN for the current used single crystal silicon. For a given maximum penetration load, the load Ppo for appearance of pop-out seems random and discrete, but in the point of statistics, it has an obviously increasing trend with increase of the maximum penetration load and also the fraction Ppo/Pmax approximately keeps in the range of 0.2~0.5 for different maximum penetration loads changing from 15 mN to 150 mN. PMID- 28809224 TI - Green Synthesis, Molecular Characterization and Associative Behavior of Some Gemini Surfactants without a Spacer Group. AB - A series of new gemini surfactants without a spacer group, disodium 2,3-dialkyl 1,2,3,4-butanetetracarboxylates, were synthesized in a green chemistry context minimizing the use of organic solvents and applying microwaves (MW) when activation energy was required. Once the desired architecture was confirmed by means of the nuclear magnetic resonance technique (1H-NMR, 1H-1H COSY) for all the studied surfactants, the critical micellization concentration was determined by conductance measurements. The diffusion coefficient of micelles formed by the four compounds was characterized using pulsed field gradient (PFG)-NMR. Diffusion coefficients were found to be dependent on the concentration and on the number of carbon atoms in the alkyl chain. The absence of the spacer group, peculiar to this new series of gemini surfactants, may confer relatively low flexibility to the molecules, with potential implications on the interfacial properties, namely on micellization. These gemini surfactants might have interesting applications in the preparation of composite materials, in nanotechnology, in gene transfection and mainly, due to the low CMCs, as new interesting ingredients of cosmetics and toiletries. PMID- 28809225 TI - Enhanced Microwave Absorption Properties of alpha-Fe2O3-Filled Ordered Mesoporous Carbon Nanorods. AB - A novel kind of alpha-Fe2O3-filled ordered mesoporous carbon nanorods has been synthesized by a facial hydrothermal method. Compared with dendritic alpha-Fe2O3 micropines, both a broader effective absorption range-from 10.5 GHz to 16.5 GHz with reflection loss (RL) less than -10 dB-and a thinner matching thickness of 2.0 mm have been achieved in the frequency range 2-18 GHz. The enhanced microwave absorption properties evaluated by the RL are attributed to the enhanced dielectric loss resulting from the intrinsic physical properties and special structures. PMID- 28809226 TI - Degradation of 2,4-Dichlorophenoxyacetic Acid (2,4-D) by Novel Photocatalytic Material of Tourmaline-Coated TiO2 Nanoparticles: Kinetic Study and Model. AB - The novel complex photocatalytic material was prepared by coating TiO2 nanoparticles on tourmaline using the sol-gel method, and used in the degradation of the herbicide 2,4-D. The results indicated that coating TiO2 with tourmaline enhanced the photocatalytic activity significantly. Based on the research of a simplified model for the average light intensity in the photoreactor, the influence of the concentration of photocatalyst, and the initial concentration of 2,4-D, a model for the degradation of 2,4-D by the tourmaline-coated TiO2 nanoparticles was established. Further tests showed that results calculated from this model were close to those obtained in the actual experiments. PMID- 28809227 TI - Growth of Hexagonal Columnar Nanograin Structured SiC Thin Films on Silicon Substrates with Graphene-Graphitic Carbon Nanoflakes Templates from Solid Carbon Sources. AB - We report a new method for growing hexagonal columnar nanograin structured silicon carbide (SiC) thin films on silicon substrates by using graphene graphitic carbon nanoflakes (GGNs) templates from solid carbon sources. The growth was carried out in a conventional low pressure chemical vapor deposition system (LPCVD). The GGNs are small plates with lateral sizes of around 100 nm and overlap each other, and are made up of nanosized multilayer graphene and graphitic carbon matrix (GCM). Long and straight SiC nanograins with hexagonal shapes, and with lateral sizes of around 200-400 nm are synthesized on the GGNs, which form compact SiC thin films. PMID- 28809228 TI - Preparation of Palladium-Supported Periodic Mesoporous Organosilicas and their Use as Catalysts in the Suzuki Cross-Coupling Reaction. AB - Three periodic mesoporous materials, i.e., two organosilicas with either ethylene or phenylene bridges and one silica, have been used as supports for Pd nanoparticles. All Pd-supported samples (1.0 wt%) were prepared by the incipient wetness method and subsequently reduced in an H2 stream at 200 degrees C. Both hydrogen chemisorption and temperature programmed reduction experiments revealed significant differences depending on the support. Pd2+ species were more reducible on the mesoporous organosilicas than on their silica counterpart. Also, remarkable differences on the particle morphology were observed by transmission electron microscopy. All Pd-supported samples were active in the Suzuki cross coupling reaction between bromobenzene and phenylboronic acid. PMID- 28809229 TI - Comparison of Reactive and Non-Reactive Spark Plasma Sintering Routes for the Fabrication of Monolithic and Composite Ultra High Temperature Ceramics (UHTC) Materials. AB - A wider utilization of ultra high temperature ceramics (UHTC) materials strongly depends on the availability of efficient techniques for their fabrication as dense bodies. Based on recent results reported in the literature, it is possible to state that Spark Plasma Sintering (SPS) technology offers a useful contribution in this direction. Along these lines, the use of two different SPS based processing routes for the preparation of massive UHTCs is examined in this work. One method, the so-called reactive SPS (R-SPS), consists of the synthesis and densification of the material in a single step. Alternatively, the ceramic powders are first synthesized by Self-propagating High-temperature Synthesis (SHS) and then sintered by SPS. The obtained results evidenced that R-SPS method is preferable for the preparation of dense monolithic products, while the sintering of SHS powders requires relatively milder conditions when considering binary composites. The different kinetic mechanisms involved during R-SPS of the monolithic and composite systems, i.e., combustion-like or gradual solid diffusion, respectively, provides a possible explanation. An important role is also played by the SHS process, particularly for the preparation of composite powders, since stronger interfaces are established between the ceramic constituents formed in situ, thus favoring diffusion processes during the subsequent SPS step. PMID- 28809230 TI - Electron Beam Irradiation of Cellulosic Materials-Opportunities and Limitations. AB - The irradiation of pulp is of interest from different perspectives. Mainly it is required when a modification of cellulose is needed. Irradiation could bring many advantages, such as chemical savings and, therefore, cost savings and a reduction in environmental pollutants. In this account, pulp and dissociated celluloses were analyzed before and after irradiation by electron beaming. The focus of the analysis was the oxidation of hydroxyl groups to carbonyl and carboxyl groups in pulp and the degradation of cellulose causing a decrease in molar mass. For that purpose, the samples were labeled with a selective fluorescence marker and analyzed by gel permeation chromatography (GPC) coupled with multi-angle laser light scattering (MALLS), refractive index (RI), and fluorescence detectors. Degradation of the analyzed substrates was the predominant result of the irradiation; however, in the microcrystalline samples, oxidized cellulose functionalities were introduced along the cellulose chain, making this substrate suitable for further chemical modification. PMID- 28809231 TI - From Waste to Healing Biopolymers: Biomedical Applications of Bio-Collagenic Materials Extracted from Industrial Leather Residues in Wound Healing. AB - The biomedical properties of a porous bio-collagenic polymer extracted from leather industrial waste residues have been investigated in wound healing and tissue regeneration in induced wounds in rats. Application of the pure undiluted bio-collagen to induced wounds in rats dramatically improved its healing after 7 days in terms of collagen production and wound filling as well as in the migration and differentiation of keratinocytes. The formulation tested was found to be three times more effective than the commercial reference product Catrix(r) (Heal Progress (HP): 8 +/- 1.55 vs. 2.33 +/- 0.52, p < 0.001; Formation of Collagen (FC): 7.5 +/- 1.05 vs. 2.17 +/- 0.75, p < 0.001; Regeneration of Epidermis (RE): 13.33 +/- 5.11 vs. 5 +/- 5.48, p < 0.05). PMID- 28809232 TI - Accelerated Thermal Cycling Test of Microencapsulated Paraffin Wax/Polyaniline Made by Simple Preparation Method for Solar Thermal Energy Storage. AB - Microencapsulated paraffin wax/polyaniline was prepared using a simple in situ polymerization technique, and its performance characteristics were investigated. Weight losses of samples were determined by Thermal Gravimetry Analysis (TGA). The microencapsulated samples with 23% and 49% paraffin showed less decomposition after 330 degrees C than with higher percentage of paraffin. These samples were then subjected to a thermal cycling test. Thermal properties of microencapsulated paraffin wax were evaluated by Differential Scanning Calorimeter (DSC). Structure stability and compatibility of core and coating materials were also tested by Fourier transform infrared spectrophotometer (FTIR), and the surface morphology of the samples are shown by Field Emission Scanning Electron Microscopy (FESEM). It has been found that the microencapsulated paraffin waxes show little change in the latent heat of fusion and melting temperature after one thousand thermal recycles. Besides, the chemical characteristics and structural profile remained constant after one thousand thermal cycling tests. Therefore, microencapsulated paraffin wax/polyaniline is a stable material that can be used for thermal energy storage systems. PMID- 28809233 TI - The Effect of PtRuIr Nanoparticle Crystallinity in Electrocatalytic Methanol Oxidation. AB - Two structural forms of a ternary alloy PtRuIr/C catalyst, one amorphous and one highly crystalline, were synthesized and compared to determine the effect of their respective structures on their activity and stability as anodic catalysts in methanol oxidation. Characterization techniques included TEM, XRD, and EDX. Electrochemical analysis using a glassy carbon disk electrode for cyclic voltammogram and chronoamperometry were tested in a solution of 0.5 mol L-1 CH3OH and 0.5 mol L-1 H2SO4. Amorphous PtRuIr/C catalyst was found to have a larger electrochemical surface area, while the crystalline PtRuIr/C catalyst had both a higher activity in methanol oxidation and increased CO poisoning rate. Crystallinity of the active alloy nanoparticles has a big impact on both methanol oxidation activity and in the CO poisoning rate. PMID- 28809234 TI - Adhesion and Growth of Vascular Smooth Muscle Cells on Nanostructured and Biofunctionalized Polyethylene. AB - Cell colonization of synthetic polymers can be regulated by physical and chemical modifications of the polymer surface. High-density and low-density polyethylene (HDPE and LDPE) were therefore activated with Ar+ plasma and grafted with fibronectin (Fn) or bovine serum albumin (BSA). The water drop contact angle usually decreased on the plasma-treated samples, due to the formation of oxidized groups, and this decrease was inversely related to the plasma exposure time (50 300 s). The presence of nitrogen and sulfur on the polymer surface, revealed by X ray photoelectron spectroscopy (XPS), and also by immunofluorescence staining, showed that Fn and BSA were bound to this surface, particularly to HDPE. Plasma modification and grafting with Fn and BSA increased the nanoscale surface roughness of the polymer. This was mainly manifested on HDPE. Plasma treatment and grafting with Fn or BSA improved the adhesion and growth of vascular smooth muscle cells in a serum-supplemented medium. The final cell population densities on day 6 after seeding were on an average higher on LDPE than on HDPE. In a serum free medium, BSA grafted to the polymer surface hampered cell adhesion. Thus, the cell behavior on polyethylene can be modulated by its type, intensity of plasma modification, grafting with biomolecules, and composition of the culture medium. PMID- 28809235 TI - Structural, Transport and Electrochemical Properties of LiFePO4 Substituted in Lithium and Iron Sublattices (Al, Zr, W, Mn, Co and Ni). AB - LiFePO4 is considered to be one of the most promising cathode materials for lithium ion batteries for electric vehicle (EV) application. However, there are still a number of unsolved issues regarding the influence of Li and Fe-site substitution on the physicochemical properties of LiFePO4. This is a review-type article, presenting results of our group, related to the possibility of the chemical modification of phosphoolivine by introduction of cation dopants in Li and Fe sublattices. Along with a synthetic review of previous papers, a large number of new results are included. The possibility of substitution of Li+ by Al3+, Zr4+, W6+ and its influence on the physicochemical properties of LiFePO4 was investigated by means of XRD, SEM/EDS, electrical conductivity and Seebeck coefficient measurements. The range of solid solution formation in Li1 3xAlxFePO4, Li1-4xZrxFePO4 and Li1-6xWxFePO4 materials was found to be very narrow. Transport properties of the synthesized materials were found to be rather weakly dependent on the chemical composition. The battery performance of selected olivines was tested by cyclic voltammetry (CV). In the case of LiFe1-yMyPO4 (M = Mn, Co and Ni), solid solution formation was observed over a large range of y (0 < y <= 1). An increase of electrical conductivity for the substitution level y = 0.25 was observed. Electrons of 3d metals other than iron do not contribute to the electrical properties of LiFe1-yMyPO4, and substitution level y > 0.25 leads to considerably lower values of sigma. The activated character of electrical conductivity with a rather weak temperature dependence of the Seebeck coefficient suggests a small polaron-type conduction mechanism. The electrochemical properties of LiFe1-yMyPO4 strongly depend on the Fe substitution level. PMID- 28809236 TI - Waste Minimization Protocols for the Process of Synthesizing Zeolites from South African Coal Fly Ash. AB - Production of a high value zeolite from fly ash has been shown to be an avenue for the utilization of South African fly ash which presently constitutes a huge disposal problem. The synthesis of zeolites Na-P1 and analcime on a micro-scale has been successful and preliminary investigation shows that scale-up synthesis is promising. However, the post-synthesis supernatant waste generated contains high levels of NaOH that may constitute a secondary disposal problem. A waste minimization protocol was developed to reduce the volume of waste generated with a view to enhancing the feasibility of the scale synthesis. Series of experiments were conducted in 100 mL jacketed batch reactors. Fly ash was reacted with 5 Mol NaOH on a 1:1 mass basis during the aging step, followed by hydrothermal treatment in which ultrapure water was added to the slurry. This study shows that by re-introducing the supernatant waste into the experiments in such a way that it supplies the required reagent (NaOH) for the zeolite synthesis, zeolite Na-P1 and analcime can be synthesized. It also shows that the synthesis process can be altered to allow up to 100% re-use of the supernatant waste to yield high value zeolitic products. This study effectively constructed two protocols for the minimization of waste generated during the synthesis of zeolites from South African coal fly ash. This result could be used to establish a basis for legal and environmental aspects involved in the commission of a full-scale plant synthesizing zeolites NaP1 and analcime. PMID- 28809237 TI - Fabrication of a Poly(3-octylthiophene-2,5-diyl) Electrochemiluminescence Device Assisted by Perylene. AB - In this study, we report the light-emitting assistance effect of perylene on a polymer electrochemiluminescence (ECL) device using poly(3-octylthiophene-2,5 diyl) (P3OT). An ECL device is a liquid type self-luminous device with a simple structure, and can be fabricated by a relatively easy procedure. Significant improvement in luminescence properties was confirmed when 1.0 wt % perylene was added to the ECL device using 3.0 wt % P3OT. Improvements of about 12 times of the maximum luminescence intensity and about 23 times of the light-emitting time ratio compared with that of a P3OT ECL device were obtained. We conclude that the light-emitting assistance of perylene is achieved by perylene radical ions shuttling electrons to P3OT while they are moving around in the emitting solution. The light-emitting assistance effect of perylene was also confirmed when poly(3-dodecylthiophene-2,5-diyl), which has almost identical electrochemical and photophysical characteristics to those of P3OT, was used instead of P3OT. PMID- 28809238 TI - Butanol Dehydration over V2O5-TiO2/MCM-41 Catalysts Prepared via Liquid Phase Atomic Layer Deposition. AB - MCM-41 was used as a support and, by using atomic layer deposition (ALD) in the liquid phase, a catalyst was prepared by consecutively loading titanium oxide and vanadium oxide to the support. This research analyzes the effect of the loading amount of vanadium oxide on the acidic characteristics and catalytic performance in the dehydration of butanol. The physical and chemical characteristics of the TiO2-V2O5/MCM-41 catalysts were analyzed using XRF, BET, NH3-TPD, XRD, Py-IR, and XPS. The dehydration reaction of butanol was performed in a fixed bed reactor. For the samples with vanadium oxide loaded to TiO2/MCM-41 sample using the liquid phase ALD method, it was possible to increase the loading amount until the amount of vanadium oxide reached 12.1 wt %. It was confirmed that the structural properties of the mesoporous silica were retained well after titanium oxide and vanadium loading. The NH3-TPD and Py-IR results indicated that weak acid sites were produced over the TiO2/MCM-41 samples, which is attributed to the generation of Lewis acid sites. The highest activity of the V2O5(12.1)-TiO2/MCM-41 catalyst in 2-butanol dehydration is ascribed to it having the highest number of Lewis acid sites, as well as the highest vanadium dispersion. PMID- 28809239 TI - Effect of SiC Content on the Ablation and Oxidation Behavior of ZrB2-Based Ultra High Temperature Ceramic Composites. AB - The ablation and oxidation of ZrB2-based ultra high temperature ceramic (UHTC) composites containing 10%, 15% and 30% v/v SiC were tested under different heat fluxes in a high frequency plasma wind tunnel. Performance was significantly affected by the surface temperature, which was strongly dependent on the composition. Composites containing 10% SiC showed the highest surface temperature (>2300 degrees C) and underwent a marked degradation under both conditions. In contrast, composites with 30% SiC exhibited the lowest surface temperature (<2000 degrees C) and demonstrated excellent ablation resistance. The surface temperature of UHTCs in aerothermal testing was closely associated with the dynamic evolution of the surface and bulk oxide properties, especially for the change in chemical composition on the exposed surface, which was strongly dependent on the material composition and testing parameters (i.e., heat flux, enthalpy, pressure and test time), and in turn affected its oxidation performance. PMID- 28809241 TI - Characterization of Zeolite in Zeolite-Geopolymer Hybrid Bulk Materials Derived from Kaolinitic Clays. AB - Zeolite-geopolymer hybrid materials have been formed when kaolin was used as a starting material. Their characteristics are of interest because they can have a wide pore size distribution with micro- and meso-pores due to the zeolite and geopolymer, respectively. In this study, Zeolite-geopolymer hybrid bulk materials were fabricated using four kinds of kaolinitic clays (a halloysite and three kinds of kaolinite). The kaolinitic clays were first calcined at 700 degrees C for 3 h to transform into the amorphous aluminosilicate phases. Alkali-activation treatment of the metakaolin yielded bulk materials with different amounts and types of zeolite and different compressive strength. This study investigated the effects of the initial kaolinitic clays on the amount and types of zeolite in the resultant geopolymers as well as the strength of the bulk materials. The kaolinitic clays and their metakaolin were characterized by XRD analysis, chemical composition, crystallite size, 29Si and 27Al MAS NMR analysis, and specific surface area measurements. The correlation between the amount of zeolite formed and the compressive strength of the resultant hybrid bulk materials, previously reported by other researchers was not positively observed. In the studied systems, the effects of Si/Al and crystalline size were observed. When the atomic ratio of Si/Al in the starting kaolinitic clays increased, the compressive strength of the hybrid bulk materials increased. The crystallite size of the zeolite in the hybrid bulk materials increased with decreasing compressive strength of the hybrid bulk materials. PMID- 28809240 TI - Nanofibrillated Cellulose Surface Modification: A Review. AB - Interest in nanofibrillated cellulose (NFC) has increased notably over recent decades. This bio-based nanomaterial has been used essentially in bionanocomposites or in paper thanks to its high mechanical reinforcement ability or barrier property respectively. Its nano-scale dimensions and its capacity to form a strong entangled nanoporous network have encouraged the emergence of new high-value applications. It is worth noting that chemical surface modification of this material can be a key factor to achieve a better compatibility with matrices. In order to increase the compatibility in different matrices or to add new functions, surface chemical modification of NFC appears to be the prior choice to conserve its intrinsic nanofibre properties. In this review, the authors have proposed for the first time an overview of all chemical grafting strategies used to date on nanofibrillated cellulose with focus on surface modification such as physical adsorption, molecular grafting or polymer grafting. PMID- 28809242 TI - The Development of Novel Near-Infrared (NIR) Tetraarylazadipyrromethene Fluorescent Dyes. AB - Novel structures of an near-infrared (NIR) tetraarylazadipyrromethene (aza BODIPY) series have been prepared. We designed the core structure containing two amido groups at the para-position of the aromatic rings. The amido group was incorporated to secure insensitivity to pH and to ensure a bathochromic shift to the NIR region. Forty members of aza-BODIPY compounds were synthesized by substitution of the acetyl group with commercial amines on the alpha bromide. The physicochemical properties and photostability were investigated and the fluorescence emission maxima (745~755 nm) were found to be in the near infrared (NIR) range of fluorescence. PMID- 28809243 TI - Prediction of Microporosity in Complex Thin-Wall Castings with the Dimensionless Niyama Criterion. AB - The dimensionless Niyama criterion was used to predict the formation of microporosity in nickel-based superalloy casting, which extended the model application from a simple plate casting to complex thin-wall superalloy casting. The physical characteristics of the superalloy were calculated by JMatPro software. The relation between the volume percentage of microporosity and the dimensionless Niyama values were constructed. Quantitative metallographic measurements of the microporosity of the practical thin-wall casting were carried out. The prediction agreed well with the experiment in general, except for some thick-wall sites in the casting. PMID- 28809245 TI - Tensile and Compressive Responses of Ceramic and Metallic Nanoparticle Reinforced Mg Composites. AB - In the present study, room temperature mechanical properties of pure magnesium, Mg/ZrO2 and Mg/(ZrO2 + Cu) composites with various compositions are investigated. Results revealed that the use of hybrid (ZrO2 + Cu) reinforcements in Mg led to enhanced mechanical properties when compared to that of single reinforcement (ZrO2). Marginal reduction in mechanical properties of Mg/ZrO2 composites were observed mainly due to clustering of ZrO2 particles in Mg matrix and lack of matrix grain refinement. Addition of hybrid reinforcements led to grain size reduction and uniform distribution of hybrid reinforcements, globally and locally, in the hybrid composites. Macro- and micro- hardness, tensile strengths and compressive strengths were all significantly increased in the hybrid composites. With respect to unreinforced magnesium, failure strain was almost unchanged under tensile loading while it was reduced under compressive loading for both Mg/ZrO2 and Mg/(ZrO2 + Cu) composites. PMID- 28809244 TI - Engineering Cellular Photocomposite Materials Using Convective Assembly. AB - Fabricating industrial-scale photoreactive composite materials containing living cells, requires a deposition strategy that unifies colloid science and cell biology. Convective assembly can rapidly deposit suspended particles, including whole cells and waterborne latex polymer particles into thin (<10 um thick), organized films with engineered adhesion, composition, thickness, and particle packing. These highly ordered composites can stabilize the diverse functions of photosynthetic cells for use as biophotoabsorbers, as artificial leaves for hydrogen or oxygen evolution, carbon dioxide assimilation, and add self-cleaning capabilities for releasing or digesting surface contaminants. This paper reviews the non-biological convective assembly literature, with an emphasis on how the method can be modified to deposit living cells starting from a batch process to its current state as a continuous process capable of fabricating larger multi layer biocomposite coatings from diverse particle suspensions. Further development of this method will help solve the challenges of engineering multi layered cellular photocomposite materials with high reactivity, stability, and robustness by clarifying how process, substrate, and particle parameters affect coating microstructure. We also describe how these methods can be used to selectively immobilize photosynthetic cells to create biomimetic leaves and compare these biocomposite coatings to other cellular encapsulation systems. PMID- 28809246 TI - Redox Response of Reduced Graphene Oxide-Modified Glassy Carbon Electrodes to Hydrogen Peroxide and Hydrazine. AB - The surface of a glassy carbon (GC) electrode was modified with reduced graphene oxide (rGO) to evaluate the electrochemical response of the modified GC electrodes to hydrogen peroxide (H2O2) and hydrazine. The electrode potential of the GC electrode was repeatedly scanned from -1.5 to 0.6 V in an aqueous dispersion of graphene oxide (GO) to deposit rGO on the surface of the GC electrode. The surface morphology of the modified GC electrode was characterized by scanning electron microscopy (SEM) and atomic force microscopy (AFM). SEM and AFM observations revealed that aggregated rGO was deposited on the GC electrode, forming a rather rough surface. The rGO-modified electrodes exhibited significantly higher responses in redox reactions of H2O2 as compared with the response of an unmodified GC electrode. In addition, the electrocatalytic activity of the rGO-modified electrode to hydrazine oxidation was also higher than that of the unmodified GC electrode. The response of the rGO-modified electrode was rationalized based on the higher catalytic activity of rGO to the redox reactions of H2O2 and hydrazine. The results suggest that rGO-modified electrodes are useful for constructing electrochemical sensors. PMID- 28809247 TI - Effects of Leaching Behavior of Calcium Ions on Compression and Durability of Cement-Based Materials with Mineral Admixtures. AB - Leaching of calcium ions increases the porosity of cement-based materials, consequently resulting in a negative effect on durability since it provides an entry for aggressive harmful ions, causing reinforcing steel corrosion. This study investigates the effects of leaching behavior of calcium ions on the compression and durability of cement-based materials. Since the parameters influencing the leaching behavior of cement-based materials are unclear and diverse, this paper focuses on the influence of added mineral admixtures (fly ash, slag and silica fume) on the leaching behavior of calcium ions regarding compression and durability of cemented-based materials. Ammonium nitrate solution was used to accelerate the leaching process in this study. Scanning electron microscopy, X-ray diffraction analysis, and thermogravimetric analysis were employed to analyze and compare the cement-based material compositions prior to and after calcium ion leaching. The experimental results show that the mineral admixtures reduce calcium hydroxide quantity and refine pore structure through pozzolanic reaction, thus enhancing the compressive strength and durability of cement-based materials. PMID- 28809248 TI - Durability Characteristics Analysis of Plastic Worm Wheel with Glass Fiber Reinforced Polyamide. AB - Plastic worm wheel is widely used in the vehicle manufacturing field because it is favorable for weight lightening, vibration and noise reduction, as well as corrosion resistance. However, it is very difficult for general plastics to secure the mechanical properties that are required for vehicle gears. If the plastic resin is reinforced by glass fiber in the fabrication process of plastic worm wheel, it is possible to achieve the mechanical properties of metallic material levels. In this study, the mechanical characteristic analysis of the glass-reinforced plastic worm wheel, according to the contents of glass fiber, is performed by analytic and experimental methods. In the case of the glass fiber reinforced resin, the orientation and contents of glass fibers can influence the mechanical properties. For the characteristic prediction of plastic worm wheel, computer-aided engineering (CAE) analysis processes such as structural and injection molding analysis were executed with the polyamide resin reinforcement glass fiber (25 wt %, 50 wt %). The injection mold for fabricating the prototype plastic worm wheel was designed and made to reflect the CAE analysis results. Finally, the durability of prototype plastic worm wheel fabricated by the injection molding process was evaluated by the experimental method and the characteristics according to the glass fiber contents. PMID- 28809249 TI - Simple Preparation of Novel Metal-Containing Mesoporous Starches. AB - Metal-containing mesoporous starches have been synthesized using a simple and efficient microwave-assisted methodology followed by metal impregnation in the porous gel network. Final materials exhibited surface areas >60 m2 g-1, being essentially mesoporous with pore sizes in the 10-15 nm range with some developed inter-particular mesoporosity. These materials characterized by several techniques including XRD, SEM, TG/DTA and DRIFTs may find promising catalytic applications due to the presence of (hydr)oxides in their composition. PMID- 28809250 TI - TiB2-Based Composites for Ultra-High-Temperature Devices, Fabricated by SHS, Combining Strong and Weak Exothermic Reactions. AB - TiB2-based ceramic matrix composites (CMCs) were fabricated using elemental powders of Ti, B and C. The self-propagating high temperature synthesis (SHS) was carried out for the highly exothermic "in situ" reaction of TiB2 formation and the "tailing" synthesis of boron carbide characterized by weak exothermicity. Two series of samples were fabricated, one of them being prepared with additional milling of raw materials. The effects of TiB2 vol fraction as well as grain size of reactant were investigated. The results revealed that combustion was not successful for a TiB2:B4C molar ratio of 0.96, which corresponds to 40 vol% of TiB2 in the composite, however the SHS reaction was initiated and self-propagated for the intended TiB2:B4C molar ratio of 2.16 or above. Finally B13C2 was formed as the matrix phase in each composite. Significant importance of the grain size of the C precursor with regard to the reaction completeness, which affected the microstructure homogeneity and hardness of investigated composites, was proved in this study. The grain size of Ti powder did not influence the microstructure of TiB2 grains. The best properties (HV = 25.5 GPa, average grain size of 9 MUm and homogenous microstructure), were obtained for material containing 80 vol% of TiB2, fabricated using a graphite precursor of 2 MUm. PMID- 28809251 TI - Application-Oriented Chemical Optimization of a Metakaolin Based Geopolymer. AB - In this study the development of a metakaolin based geopolymeric mortar to be used as bonding matrix for external strengthening of reinforced concrete beams is reported. Four geopolymer formulations have been obtained by varying the composition of the activating solution in terms of SiO2/Na2O ratio. The obtained samples have been characterized from a structural, microstructural and mechanical point of view. The differences in structure and microstructure have been correlated to the mechanical properties. A major issue of drying shrinkage has been encountered in the high Si/Al ratio samples. In the light of the characterization results, the optimal geopolymer composition was then applied to fasten steel fibers to reinforced concrete beams. The mechanical behavior of the strengthened reinforced beams was evaluated by four-points bending tests, which were performed also on reinforced concrete beams as they are for comparison. The preliminary results of the bending tests point out an excellent behavior of the geopolymeric mixture tested, with the failure load of the reinforced beams roughly twice that of the control beam. PMID- 28809252 TI - Synthesis and Characterization of Nano Boron Nitride Reinforced Magnesium Composites Produced by the Microwave Sintering Method. AB - In this study, magnesium composites with nano-size boron nitride (BN) particulates of varying contents were synthesized using the powder metallurgy (PM) technique incorporating microwave-assisted two-directional sintering followed by hot extrusion. The effect of nano-BN addition on the microstructural and the mechanical behavior of the developed Mg/BN composites were studied in comparison with pure Mg using the structure-property correlation. Microstructural characterization revealed uniform distribution of nano-BN particulates and marginal grain refinement. The coefficient of thermal expansion (CTE) value of the magnesium matrix was improved with the addition of nano-sized BN particulates. The results of XRD studies indicate basal texture weakening with an increase in nano-BN addition. The composites showed improved mechanical properties measured under micro-indentation, tension and compression loading. While the tensile yield strength improvement was marginal, a significant increase in compressive yield strength was observed. This resulted in the reduction of tension-compression yield asymmetry and can be attributed to the weakening of the strong basal texture. PMID- 28809253 TI - Production and Characterization of a New Bacterial Cellulose/Poly(Vinyl Alcohol) Nanocomposite. AB - Bacterial cellulose (BC) is characterized for its high water holding capacity, high crystallinity, an ultrafine fiber network and high tensile strength. This work demonstrates the production of a new interpenetrated polymer network nanocomposite obtained through the incorporation of poly(vinyl alcohol) (PVA) on the BC matrix and evaluates the effect of oven drying on the morphological, mechanical and mass transfer properties of the composite membranes. Both the addition of PVA and oven drying induce the appearance of larger pores (circa 1-3 um in average diameter) in dried BC/PVA membranes. Both types of treatments also affect the permeability of the composite, as assessed by the diffusion coefficients of polyethylene glycol (PEG) molecules (900, 8,000, 35,000 and 100,000 Da) across the membranes. Finally, the Young's modulus of dry pristine BC decreases following PVA incorporation, resulting in a change from 3.5 GPa to 1 GPa and a five-fold loss in tensile strength. PMID- 28809254 TI - Liquid Foam Templates Associated with the Sol-Gel Process for Production of Zirconia Ceramic Foams. AB - The unique properties of ceramic foams enable their use in a variety of applications. This work investigated the effects of different parameters on the production of zirconia ceramic foam using the sol-gel process associated with liquid foam templates. Evaluation was made of the influence of the thermal treatment temperature on the porous and crystalline characteristics of foams manufactured using different amounts of sodium dodecylsulfate (SDS) surfactant. A maximum pore volume, with high porosity (94%) and a bimodal pore size distribution, was observed for the ceramic foam produced with 10% SDS. Macropores, with an average size of around 30 MUm, were obtained irrespective of the SDS amount, while the average size of the supermesopores increased systematically as the SDS amount was increased up to 10%, after which it decreased. X-ray diffraction analyses showed that the sample treated at 500 degrees C was amorphous, while crystallization into a tetragonal metastable phase occurred at 600 degrees C due to the presence of sulfate groups in the zirconia structure. At 800 and 1000 degrees C the monoclinic phase was observed, which is thermodynamically stable at these temperatures. PMID- 28809255 TI - Effect of Milling on the Mechanical Properties of Chopped SiC Fiber-Reinforced ZrB2. AB - This work aims at studying the effect of the milling conditions on the microstructure and mechanical properties of a ZrB2-5 vol% Si3N4 matrix reinforced with chopped Hi-Nicalon SiC fibers. Several composites were obtained using different milling conditions in terms of time, speed and type of milling media. The composites were prepared from commercial powders, ball milled, dried and shaped, and hot pressed at 1720 degrees C. Their relative bulk densities achieved values as high as 99%. For each material the fiber length distribution, the extent of reacted fiber area and matrix mean grain size were evaluated in order to ascertain the effects of milling time, milling speed and type of milling media. While the fracture toughness and hardness were statistically the same independently of the milling conditions, the flexural strength changed. From the results obtained, the best milling conditions for optimized mechanical properties were determined. PMID- 28809256 TI - Effect of Solvents, Their Mixture and Thermal Annealing on the Performance of Solution Processed Polymer Light-Emitting Diodes. AB - In this study, we first investigated changes seen in electrical and optical properties of a polymer light-emitting diode due to using different kinds of solvents and their mixture. Two-layer light emitting diodes with organic small molecules doped in a PVK polymer host were fabricated using (i) non-aromatic solvent chloroform with a high evaporation rate; (ii) aromatic solvent chlorobenzene with a low evaporation rate, and (iii) their mixture with different relative ratios. The effect of nano-scale layer thickness, surface roughness and internal nano-morphology on threshold voltage and the amount of electric current, the luminance and efficiency of a device were assessed. Results indicated the importance of majority charge carriers' type in the selection of solvent and tuning its properties. Then, the effect of thermal annealing on electrical and optical properties of polymer light emitting diodes was investigated. During the device fabrication, pre-annealing in 80 and/or 120 degrees C and post-annealing in 120 degrees C were performed. The nano-scale effect of annealing on polymer metal interface and electric current injection was described thoroughly. A comparison between threshold voltage, luminance and electric current efficiency of luminescence for different annealing processes was undertaken, so that the best electric current efficiency of luminescence achieved at 120 degrees C pre annealing accompanied with 120 degrees C post-annealing. PMID- 28809257 TI - Characterization of Natural Dyes and Traditional Korean Silk Fabric by Surface Analytical Techniques. AB - Time-of-flight secondary ion mass spectrometry (TOF-SIMS) and X-ray photoelectron spectroscopy (XPS) are well established surface techniques that provide both elemental and organic information from several monolayers of a sample surface, while also allowing depth profiling or image mapping to be carried out. The static TOF-SIMS with improved performances has expanded the application of TOF SIMS to the study of a variety of organic, polymeric and biological materials. In this work, TOF-SIMS, XPS and Fourier Transform Infrared (FTIR) measurements were used to characterize commercial natural dyes and traditional silk fabric dyed with plant extracts dyes avoiding the time-consuming and destructive extraction procedures necessary for the spectrophotometric and chromatographic methods previously used. Silk textiles dyed with plant extracts were then analyzed for chemical and functional group identification of their dye components and mordants. TOF-SIMS spectra for the dyed silk fabric showed element ions from metallic mordants, specific fragment ions and molecular ions from plant-extracted dyes. The results of TOF-SIMS, XPS and FTIR are very useful as a reference database for comparison with data about traditional Korean silk fabric and to provide an understanding of traditional dyeing materials. Therefore, this study shows that surface techniques are useful for micro-destructive analysis of plant extracted dyes and Korean dyed silk fabric. PMID- 28809259 TI - Posidonia oceanica as a Renewable Lignocellulosic Biomass for the Synthesis of Cellulose Acetate and Glycidyl Methacrylate Grafted Cellulose. AB - High-grade cellulose (97% alpha-cellulose content) of 48% crystallinity index was extracted from the renewable marine biomass waste Posidonia oceanica using H2O2 and organic peracids following an environmentally friendly and chlorine-free process. This cellulose appeared as a new high-grade cellulose of waste origin quite similar to the high-grade cellulose extracted from more noble starting materials like wood and cotton linters. The benefits of alpha-cellulose recovery from P. oceanica were enhanced by its transformation into cellulose acetate CA and cellulose derivative GMA-C. Fully acetylated CA was prepared by conventional acetylation method and easily transformed into a transparent film. GMA-C with a molar substitution (MS) of 0.72 was produced by quenching Fenton's reagent (H2O2/FeSO4) generated cellulose radicals with GMA. GMA grafting endowed high grade cellulose from Posidonia with adsorption capability. GMA-C removes beta naphthol from water with an efficiency of 47%, as measured by UV-Vis spectroscopy. After hydrolysis of the glycidyl group to glycerol group, the modified GMA-C was able to remove p-nitrophenol from water with an efficiency of 92%, as measured by UV-Vis spectroscopy. alpha-cellulose and GMA-Cs from Posidonia waste can be considered as new materials of potential industrial and environmental interest. PMID- 28809258 TI - Adsorption Properties of Doxorubicin Hydrochloride onto Graphene Oxide: Equilibrium, Kinetic and Thermodynamic Studies. AB - Doxorubicin hydrochloride (DOX) is an effective anticancer agent for leukemia chemotherapy, although its clinical use has been limited because of its side effects such as cardiotoxicity, alopecia, vomiting, and leucopenia. Attention has been focussed on developing new drug carriers with high adsorption capacity and rapid adsorption rate in order to minimize the side effects of DOX. Graphene oxide (GO), a new type of nanomaterial in the carbon family, was prepared by Hummers method and used as adsorbent for DOX from aqueous solution. The physico chemical properties of GO were characterized by transmission electron microscope (TEM), Fourier transform infrared spectroscopy (FTIR), zeta potential, and element analysis. The adsorption properties of DOX on GO were studied as a function of contact time, adsorbent dosage, temperature and pH value. The results showed that GO had a maximum adsorption capacity of 1428.57 mg/g and the adsorption isotherm data fitted the Langmuir model. The kinetics of adsorption fits a pseudo-second-order model. The thermodynamic studies indicate that the adsorption of DOX on GO is spontaneous and endothermic in nature. PMID- 28809260 TI - Evaluation of Biological Pretreatment of Rubberwood with White Rot Fungi for Enzymatic Hydrolysis. AB - e effects of biological pretreatment on the rubberwood (Hevea brasiliensis), was evaluated after cultivation of white rot fungi Ceriporiopsis subvermispora, Trametes versicolor, and a mixed culture of C. subvermispora and T. versicolor. The analysis of chemical compositions indicated that C. subvermispora had greater selectivity for lignin degradation with the highest lignin and hemicellulose loss at 45.06% and 42.08%, respectively, and lowest cellulose loss (9.50%) after 90 days among the tested samples. X-ray analysis showed that pretreated samples had a higher crystallinity than untreated samples. The sample pretreated by C. subvermispora presented the highest crystallinity of all the samples which might be caused by the selective degradation of amorphous components. Fourier transform infrared (FT-IR) spectroscopy demonstrated that the content of lignin and hemicellulose decreased during the biological pretreatment process. A study on hydrolysis of rubberwood treated with C. subvermispora, T. versicolor, and mixed culture for 90 days resulted in an increased sugar yield of about 27.67%, 16.23%, and 14.20%, respectively, as compared with untreated rubberwood (2.88%). The results obtained demonstrate that rubberwood is a potential raw material for industrial applications and white rot fungus C. subevermispora provides an effective method for improving the enzymatic hydrolysis of rubberwood. PMID- 28809261 TI - Synthesis of Zeolites Na-P1 from South African Coal Fly Ash: Effect of Impeller Design and Agitation. AB - South African fly ash has been shown to be a useful feedstock for the synthesis of some zeolites. The present study focuses on the effect of impeller design and agitation rates on the synthesis of zeolite Na-P1 which are critical to the commercialization of this product. The effects of three impeller designs (4-flat blade, Anchor and Archimedes screw impellers) and three agitation speeds (150, 200 and 300 rpm) were investigated using a modified previously reported synthesis conditions; 48 hours of ageing at 47 degrees C and static hydrothermal treatment at 140 degrees C for 48 hours. The experimental results demonstrated that the phase purity of zeolite Na-P1 was strongly affected by the agitation rate and the type of impeller used during the ageing step of the synthesis process. Although zeolite Na-P1 was synthesized with a space time yield (STY) of 15 +/- 0.4 kg d-1m 3and a product yield of 0.98+/-0.05 g zeolites/g fly ash for each impeller at different agitation speeds, zeolite formation was assessed to be fairly unsuccessful in some cases due the occurrence of undissolved mullite and/or the formation of impurities such as hydroxysodalite with the zeolitic product. This study also showed that a high crystalline zeolite Na-P1 can be synthesized from South African coal fly ash using a 4-flat blade impeller at an agitation rate of 200 rpm during the ageing step at 47 degrees C for 48 hours followed by static hydrothermal treatment at 140 degrees C for 48 hours. PMID- 28809262 TI - Elaboration of Alumina-Zirconia Composites: Role of the Zirconia Content on the Microstructure and Mechanical Properties. AB - Alumina-zirconia (AZ) composites are attractive structural materials, which combine the high hardness and Young's modulus of the alumina matrix with additional toughening effects, due to the zirconia dispersion. In this study, AZ composites containing different amounts of zirconia (in the range 5-20 vol %) were prepared by a wet chemical method, consisting on the surface coating of alumina powders by mixing them with zirconium salt aqueous solutions. After spray drying, powders were calcined at 600 degrees C for 1 h. Green bodies were then prepared by two methods: uniaxial pressing of spray-dried granules and slip casting of slurries, obtained by re-dispersing the spray dried granulates. After pressureless sintering at 1500 degrees C for 1 h, the slip cast samples gave rise to fully dense materials, characterized by a quite homogeneous distribution of ZrO2 grains in the alumina matrix. The microstructure, phase composition, tetragonal to monoclinic transformation behavior and mechanical properties were investigated and are here discussed as a function of the ZrO2 content. The material containing 10 vol % ZrO2 presented a relevant hardness and exhibited the maximum value of KI0, mainly imputable to the t -> m transformation at the crack tip. PMID- 28809263 TI - Selective Preparation of trans-Carveol over Ceria Supported Mesoporous Materials MCM-41 and SBA-15. AB - Ce-modified mesoporous silica materials MCM-41 and SBA-15, namely 32 wt % Ce-Si MCM-41, 16 wt % Ce-H-MCM-41 and 20 wt % Ce-Si-SBA-15, were prepared, characterized and studied in the selective preparation of trans-carveol by alpha pinene oxide isomerization. The characterizations of these catalysts were performed using scanning electron microscopy, X-ray photoelectron spectroscopy, nitrogen adsorption and FTIR pyridine adsorption. Selective preparation of trans carveol was carried out in the liquid phase in a batch reactor. The activity and the selectivity of catalyst were observed to be influenced by their acidity, basicity and morphology of the mesoporous materials. The formation of trans carveol is moreover strongly influenced by the basicity of the used solvent and in order to achieve high yields of this desired alcohol it is necessary to use polar basic solvent. PMID- 28809264 TI - Effect of Core-Shell Ceria/Poly(vinylpyrrolidone) (PVP) Nanoparticles Incorporated in Polymer Films and Their Optical Properties. AB - We fabricated hybrid films of pentaerythritol triacrylate (PETA) with core-shell ceria/poly(vinylpyrrolidone) (PVP) nanoparticles, which consist of cerium oxide as the core and PVP as the shell, and investigated the film optical properties. In this study, we used ceria/PVP nanoparticles with average diameters of 37, 49 and 91 nm. We obtained translucent films consisting of PETA with core-shell ceria/PVP nanoparticles. The core-shell ceria/PVP nanoparticles can reduce the transmittance of near-ultraviolet light. The transmittance of visible light and haze values depends not only on the thickness of the films, but also on the average diameter of the nanoparticles. A SEM observation and the optical analyses prove that the core-shell ceria/PVP nanoparticles do not aggregate into the PETA matrix. PMID- 28809265 TI - Full-Field Strain Mapping at a Ge/Si Heterostructure Interface. AB - The misfit dislocations and strain fields at a Ge/Si heterostructure interface were investigated experimentally using a combination of high-resolution transmission electron microscopy and quantitative electron micrograph analysis methods. The type of misfit dislocation at the interface was determined to be 60 degrees dislocation and 90 degrees full-edge dislocation. The full-field strains at the Ge/Si heterostructure interface were mapped by using the geometric phase analysis (GPA) and peak pairs analysis (PPA), respectively. The effect of the mask size on the GPA and PPA results was analyzed in detail. For comparison, the theoretical strain fields of the misfit dislocations were also calculated by the Peierls-Nabarro and Foreman dislocation models. The results showed that the optimal mask sizes in GPA and PPA were approximately three tenths and one-tenth of the reciprocal lattice vector, respectively. The Foreman dislocation model with an alterable factor a = 4 can best describe the strain field of the misfit dislocation at the Ge/Si heterostructure interface. PMID- 28809266 TI - Study of PVD AlCrN Coating for Reducing Carbide Cutting Tool Deterioration in the Machining of Titanium Alloys. AB - The manufacture of medical and aerospace components made of titanium alloys and other difficult-to-cut materials requires the parallel development of high performance cutting tools coated with materials capable of enhanced tribological and resistance properties. In this matter, a thin nanocomposite film made out of AlCrN (aluminum-chromium-nitride) was studied in this research, showing experimental work in the deposition process and its characterization. A heat treated monolayer coating, competitive with other coatings in the machining of titanium alloys, was analyzed. Different analysis and characterizations were performed on the manufactured coating by scanning electron microscopy and energy dispersive X-ray spectroscopy (SEM-EDXS), and X-ray diffraction (XRD). Furthermore, the mechanical behavior of the coating was evaluated through hardness test and tribology with pin-on-disk to quantify friction coefficient and wear rate. Finally, machinability tests using coated tungsten carbide cutting tools were executed in order to determine its performance through wear resistance, which is a key issue of cutting tools in high-end cutting at elevated temperatures. It was demonstrated that the specimen (with lower friction coefficient than previous research) is more efficient in machinability tests in Ti6Al4V alloys. Furthermore, the heat-treated monolayer coating presented better performance in comparison with a conventional monolayer of AlCrN coating. PMID- 28809268 TI - Self-Healing in Cementitious Materials-A Review. AB - Concrete is very sensitive to crack formation. As wide cracks endanger the durability, repair may be required. However, these repair works raise the life cycle cost of concrete as they are labor intensive and because the structure becomes in disuse during repair. In 1994, C. Dry was the first who proposed the intentional introduction of self-healing properties in concrete. In the following years, several researchers started to investigate this topic. The goal of this review is to provide an in-depth comparison of the different self-healing approaches which are available today. Among these approaches, some are aimed at improving the natural mechanism of autogenous crack healing, while others are aimed at modifying concrete by embedding capsules with suitable healing agents so that cracks heal in a completely autonomous way after they appear. In this review, special attention is paid to the types of healing agents and capsules used. In addition, the various methodologies have been evaluated based on the trigger mechanism used and attention has been paid to the properties regained due to self-healing. PMID- 28809269 TI - Synthesis of Isothianaphthene (ITN) and 3,4-Ethylenedioxy-Thiophene (EDOT)-Based Low-Bandgap Liquid Crystalline Conjugated Polymers. AB - Copolymers, consisting of isothianaphthene and phenylene derivatives with liquid crystal groups, were synthesized via Migita-Kosugi-Stille polycondensation reaction. IR absorption, UV-vis optical absorption, and PL spectroscopy measurements were carried out. Thermotropic liquid crystallinity of the polymers with bandgap of ~2.5 eV was confirmed. PMID- 28809267 TI - Films of Carbon Nanomaterials for Transparent Conductors. AB - The demand for transparent conductors is expected to grow rapidly as electronic devices, such as touch screens, displays, solid state lighting and photovoltaics become ubiquitous in our lives. Doped metal oxides, especially indium tin oxide, are the commonly used materials for transparent conductors. As there are some drawbacks to this class of materials, exploration of alternative materials has been conducted. There is an interest in films of carbon nanomaterials such as, carbon nanotubes and graphene as they exhibit outstanding properties. This article reviews the synthesis and assembly of these films and their post treatment. These processes determine the film performance and understanding of this platform will be useful for future work to improve the film performance. PMID- 28809270 TI - Hydrogen Production by Steam Reforming of Ethanol over Nickel Catalysts Supported on Sol Gel Made Alumina: Influence of Calcination Temperature on Supports. AB - Selecting a proper support in the catalyst system plays an important role in hydrogen production via ethanol steam reforming. In this study, sol gel made alumina supports prepared for nickel (Ni) catalysts were calcined at different temperatures. A series of (Ni/AlS.G.) catalysts were synthesized by an impregnation procedure. The influence of varying the calcination temperature of the sol gel made supports on catalyst activity was tested in ethanol reforming reaction. The characteristics of the sol gel alumina supports and Ni catalysts were affected by the calcination temperature of the supports. The structure of the sol gel made alumina supports was transformed in the order of gamma -> (gamma + theta) -> theta-alumina as the calcination temperature of the supports increased from 600 degrees C to 1000 degrees C. Both hydrogen yield and ethanol conversion presented a volcano-shaped behavior with maximum values of 4.3 mol/mol ethanol fed and 99.5%, respectively. The optimum values were exhibited over Ni/AlS.G800 (Ni catalyst supported on sol gel made alumina calcined at 800 degrees C). The high performance of the Ni/AlS.G800 catalyst may be attributed to the strong interaction of Ni species and sol gel made alumina which lead to high nickel dispersion and small particle size. PMID- 28809271 TI - High Pressure Compression-Molding of alpha-Cellulose and Effects of Operating Conditions. AB - Commercial alpha-cellulose was compression-molded to produce 1A dog-bone specimens under various operating conditions without any additive. The resulting agromaterials exhibited a smooth, plastic-like surface, and constituted a suitable target as replacement for plastic materials. Tensile and three-points bending tests were conducted according to ISO standards related to the evaluation of plastic materials. The specimens had strengths comparable to classical petroleum-based thermoplastics. They also exhibited high moduli, which is characteristic of brittle materials. A higher temperature and higher pressure rate produced specimens with higher mechanical properties while low moisture content produced weaker specimens. Generally, the strong specimen had higher specific gravity and lower moisture content. However, some parameters did not follow the general trend e.g., thinner specimen showed much higher Young's Modulus, although their specific gravity and moisture content remained similar to control, revealing a marked skin-effect which was confirmed by SEM observations. PMID- 28809272 TI - Plasma Enhanced Chemical Vapour Deposition of Horizontally Aligned Carbon Nanotubes. AB - A plasma-enhanced chemical vapour deposition reactor has been developed to synthesis horizontally aligned carbon nanotubes. The width of the aligning sheath was modelled based on a collisionless, quasi-neutral, Child's law ion sheath where these estimates were empirically validated by direct Langmuir probe measurements, thereby confirming the proposed reactors ability to extend the existing sheath fields by up to 7 mm. A 7 mbar growth atmosphere combined with a 25 W plasma permitted the concurrent growth and alignment of carbon nanotubes with electric fields of the order of 0.04 V MUm-1 with linear packing densities of up to ~5 * 104 cm-1. These results open up the potential for multi-directional insitu alignment of carbon nanotubes providing one viable route to the fabrication of many novel optoelectronic devices. PMID- 28809273 TI - Dynamic Behavior of Nanocomposites Reinforced with Multi-Walled Carbon Nanotubes (MWCNTs). AB - The influence of multi-walled carbon nanotubes (MWCNT) on the structural dynamic behavior of MWCNT/epoxy nanocomposites was investigated. Two different types of MWCNTs, pristine MWCNT and functionalized MWCNT, were used in this study. Carboxylic acid-functionalized MWCNTs (MWCNT-COOH) were obtained by oxidation pristine MWCNTs via sonication in sulfuric-nitric acid and characterized by Fourier transform infrared spectroscopy (FTIR). Dynamic behaviors of the MWCNT reinforced nanocomposite including the natural frequency and damping ratio were determined using free vibration test. Experimental results showed that the damping ratio of the nanocomposite decreases with the increase of the MWCNT addition, while the natural frequency is increasing with the increase of the MWCNT addition. Functionalized MWCNTs improved the interfacial bonding between the nanotubes and epoxy resin resulting in the reduction of the interfacial energy dissipation ability and enhancement of the stiffness. PMID- 28809274 TI - Synthesis of Li2Ti3O7 Anode Materials by Ultrasonic Spray Pyrolysis and Their Electrochemical Properties. AB - Ramsdellite-type lithium titanate (Li2Ti3O7) powders were synthesized by performing ultrasonic spray pyrolysis, and their chemical and physical properties were characterized by performing Scanning Electron Microscope (SEM), powder X-ray Diffraction (XRD), and Inductively Coupled Plasma (ICP) analyses. The as-prepared Li2Ti3O7 precursor powders had spherical morphologies with hollow microstructures, but an irregularly shaped morphology was obtained after calcination above 900 degrees C. The ramsdellite Li2Ti3O7 crystal phase was obtained after the calcination at 1100 degrees C under an argon/hydrogen atmosphere. The first rechargeable capacity of the Li2Ti3O7 anode material was 168 mAh/g at 0.1 C and 82 mAh/g at 20 C, and the discharge capacity retention ratio was 99% at 1 C after the 500th cycle. The cycle performance of the Li2Ti3O7 anode was also highly stable at 50 degrees C, demonstrating the superiority of Li2Ti3O7 anode materials reported previously. PMID- 28809276 TI - Use of Amphoteric Copolymer Films as Sacrificial Layers for Constructing Free Standing Layer-by-Layer Films. AB - The present paper reports the use of an amphoteric copolymer, poly(diallylamine co-maleic acid) (PDAMA), as a component of precursor layers (or sacrificial layers) for constructing free-standing layer-by-layer (LbL) films. A PDAMA poly(styrenesulfonate) (PSS) film or PDAMA-poly(dimethyldiallylammonium chloride) (PDDA) film was coated on the surface of a quartz slide at pH 4.0 or 8.0, respectively, as a sacrificial layer that can be removed by changing the pH. The surface of the sacrificial layer was further covered with LbL films composed of poly(allylamine hydrochloride) (PAH) and PSS. The PAH-PSS films were released from the substrate upon immersing the film-coated quartz slide in acidic or neutral/basic solution, respectively, as a result of the pH-induced dissolution of the PDAMA-PDDA or PDAMA-PSS sacrificial layer. Thus, PDAMA-based sacrificial layers have been demonstrated to dissolve in both acidic and neutral solutions, depending on the type of counter polymer. The thicknesses of the sacrificial layers and released LbL films are crucial factors for constructing free-standing LbL films. The releasing kinetics also depended on the thickness of the crucial layers. The free-standing PAH-PSS films obtained were stable in water or in air in the dry state. PDAMA-based sacrificial layers may be useful in constructing free-standing LbL films containing biomolecules with limited pH stability. PMID- 28809277 TI - Structural Properties of Chemically Functionalized Carbon Nanotube Thin Films. AB - Buckypapers are thin sheets of randomly entangled carbon nanotubes, which are highly porous networks. They are strong candidates for a number of applications, such as reinforcing materials for composites. In this work, buckypapers were produced from multiwall carbon nanotubes, pre-treated by two different chemical processes, either an oxidation or an epoxidation reaction. Properties, such as porosity, the mechanical and electrical response are investigated. It was found that the chemical pretreatment of carbon nanotubes strongly affects the structural properties of the buckypapers and, consecutively, their mechanical and electrical performance. PMID- 28809275 TI - Mechanisms of Silver Nanoparticle Release, Transformation and Toxicity: A Critical Review of Current Knowledge and Recommendations for Future Studies and Applications. AB - Nanosilver, due to its small particle size and enormous specific surface area, facilitates more rapid dissolution of ions than the equivalent bulk material; potentially leading to increased toxicity of nanosilver. This, coupled with their capacity to adsorb biomolecules and interact with biological receptors can mean that nanoparticles can reach sub-cellular locations leading to potentially higher localized concentrations of ions once those particles start to dissolve or degrade in situ. Further complicating the story is the capacity for nanoparticles to generate reactive oxygen species, and to interact with, and potentially disturb the functioning of biomolecules such as proteins, enzymes and DNA. The fact that the nanoparticle size, shape, surface coating and a host of other factors contribute to these interactions, and that the particles themselves are evolving or ageing leads to further complications in terms of elucidating mechanisms of interaction and modes of action for silver nanoparticles, in contrast to dissolved silver species. This review aims to provide a critical assessment of the current understanding of silver nanoparticle toxicity, as well as to provide a set of pointers and guidelines for experimental design of future studies to assess the environmental and biological impacts of silver nanoparticles. In particular; in future we require a detailed description of the nanoparticles; their synthesis route and stabilisation mechanisms; their coating; and evolution and ageing under the exposure conditions of the assay. This would allow for comparison of data from different particles; different environmental or biological systems; and structure-activity or structure-property relationships to emerge as the basis for predictive toxicology. On the basis of currently available data; such comparisons or predictions are difficult; as the characterisation and time-resolved data is not available; and a full understanding of silver nanoparticle dissolution and ageing under different conditions is observed. Clear concerns are emerging regarding the overuse of nanosilver and the potential for bacterial resistance to develop. A significant conclusion includes the need for a risk-benefit analysis for all applications and eventually restrictions of the uses where a clear benefit cannot be demonstrated. PMID- 28809278 TI - Density Functional Theory (DFT) Study of Coumarin-based Dyes Adsorbed on TiO2 Nanoclusters-Applications to Dye-Sensitized Solar Cells. AB - Coumarin-based dyes have been successfully used in dye-sensitized solar cells, leading to photovoltaic conversion efficiencies of up to about 8%. Given the need to better understand the behavior of the dye adsorbed on the TiO2 nanoparticle, we report results of density functional theory (DFT) and time-dependent DFT (TD DFT) studies of several coumarin-based dyes, as well as complex systems consisting of the dye bound to a TiO2 cluster. We provide the electronic structure and simulated UV-Vis spectra of the dyes alone and adsorbed to the cluster and discuss the matching with the solar spectrum. We display the energy level diagrams and the electron density of the key molecular orbitals and analyze the electron transfer from the dye to the oxide. Finally, we compare our theoretical results with the experimental data available and discuss the key issues that influence the device performance. PMID- 28809279 TI - Terahertz Wave Propagation in a Nanotube Conveying Fluid Taking into Account Surface Effect. AB - In nanoscale structure sizes, the surface-to-bulk energy ratio is high and the surface effects must be taken into account. Surface effect plays a key role in accurately predicting the vibration behavior of nanostructures. In this paper, the wave behaviors of a single-walled carbon nanotube (CNT) conveying fluid are studied. The nonlocal Timoshenko beam theory is used and the surface effect is taken into account. It is found that the fluid can flow at a very high flow velocity and the wave propagates in the terahertz frequency range. The surface effects can significantly enhance the propagating frequency. This finding is different from the classical model where the surface effect is neglected. PMID- 28809280 TI - Cobalt-based Catalysts for Ammonia Decomposition. AB - An effect of promoters such as calcium, aluminium, and potassium oxides and also addition of chromium and manganese on the structure of cobalt catalysts was examined. Studies of the catalytic ammonia decomposition over the cobalt catalysts are presented. The studies of the ammonia decomposition were carried out for various ammonia-hydrogen mixtures in which ammonia concentration varied in the range from 10% to 100%. Co(0) catalyst, promoted by oxides of aluminium, calcium, and potassium, showed the highest activity in the ammonia decomposition reaction. Contrary to expectations, it was found that chromium and manganese addition into the catalysts decreased their activity. PMID- 28809281 TI - Bio-based Films from Linter Cellulose and Its Acetates: Formation and Properties. AB - This paper describes the results obtained on the preparation of films composed of linter cellulose and the corresponding acetates. The acetylation was carried out in the LiCl/DMAc solvent system. Films were prepared from a LiCl/DMAc solution of cellulose acetates (degree of substitution, DS 0.8-2.9) mixed with linter cellulose (5, 10 and 15 wt %). Detailed characterization of the films revealed the following: (i) they exhibited fibrous structures on their surfaces. The strong tendency of the linter cellulose chains to aggregate in LiCl/DMAc suggests that these fibrous elements consist of cellulose chains, as can be deduced from SEM images of the film of cellulose proper; (ii) the cellulose acetate films obtained from samples with DS 2.1 and 2.9 exhibited microspheres on the surface, whose formation seems to be favored for acetates with higher DS; (iii) AFM analysis showed that, in general, the presence of cellulose increased both the asperity thickness and the surface roughness of the analyzed films, indicating that cellulose chains are at least partially organized in domains and not molecularly dispersed between acetate chains; and (iv) the films prepared from cellulose and acetates exhibited lower hygroscopicity than the acetate films, also suggesting that the cellulose chains are organized into domains, probably due to strong intermolecular interactions. The linter and sisal acetates (the latter from a prior study), and their respective films, were prepared using the same processes; however, the two sets of films presented more differences (as in humidity absorption, optical, and tensile properties) than similarities (as in some morphological aspects), most likely due to the different properties of the starting materials. Potential applications of the films prepared in tissue engineering scaffold coatings and/or drug delivery are mentioned. PMID- 28809283 TI - Simple Procedure to Compute the Inductance of a Toroidal Ferrite Core from the Linear to the Saturation Regions. AB - We propose a specific procedure to compute the inductance of a toroidal ferrite core as a function of the excitation current. The study includes the linear, intermediate and saturation regions. The procedure combines the use of Finite Element Analysis in 2D and experimental measurements. Through the two dimensional (2D) procedure we are able to achieve convergence, a reduction of computational cost and equivalent results to those computed by three dimensional (3D) simulations. The validation is carried out by comparing 2D, 3D and experimental results. PMID- 28809282 TI - Kinetics of Corrosion Inhibition of Aluminum in Acidic Media by Water-Soluble Natural Polymeric Pectates as Anionic Polyelectrolyte Inhibitors. AB - Corrosion inhibition of aluminum (Al) in hydrochloric acid by anionic polyeletrolyte pectates (PEC) as a water-soluble natural polymer polysaccharide has been studied using both gasometric and weight loss techniques. The results drawn from these two techniques are comparable and exhibit negligible differences. The inhibition efficiency was found to increase with increasing inhibitor concentration and decrease with increasing temperature. The inhibition action of PEC on Al metal surface was found to obey the Freundlich isotherm. Factors such as the concentration and geometrical structure of the inhibitor, concentration of the corrosive medium, and temperature affecting the corrosion rates were examined. The kinetic parameters were evaluated and a suitable corrosion mechanism consistent with the kinetic results is discussed in the paper. PMID- 28809284 TI - Interactions and Diffusion of Methane and Hydrogen in Microporous Structures: Nuclear Magnetic Resonance (NMR) Studies. AB - Measurements of nuclear spin relaxation times over a wide temperature range have been used to determine the interaction energies and molecular dynamics of light molecular gases trapped in the cages of microporous structures. The experiments are designed so that, in the cases explored, the local excitations and the corresponding heat capacities determine the observed nuclear spin-lattice relaxation times. The results indicate well-defined excitation energies for low densities of methane and hydrogen deuteride in zeolite structures. The values obtained for methane are consistent with Monte Carlo calculations of A.V. Kumar et al. The results also confirm the high mobility and diffusivity of hydrogen deuteride in zeolite structures at low temperatures as observed by neutron scattering. PMID- 28809286 TI - Mechanism of Generation of ZnO Microstructures by Microwave-Assisted Hydrothermal Approach. AB - In this report, a technique for rapid synthesis of ZnO microstructures by microwave-assisted heating of precursors at hydrothermal conditions is demonstrated. Further, the reaction mechanism for the growth of ZnO microstructures is analyzed. An accelerated rate of reaction obtained using microwaves enables a dissolution-recrystallization mechanism for generation of one dimensional (1D) rod-like structures, thereby showing that time of reaction can be used to dictate ZnO microstructure morphology. PMID- 28809285 TI - Enhancement of the Mechanical Properties of Basalt Fiber-Wood-Plastic Composites via Maleic Anhydride Grafted High-Density Polyethylene (MAPE) Addition. AB - This study investigated the mechanisms, using microscopy and strength testing approaches, by which the addition of maleic anhydride grafted high-density polyethylene (MAPE) enhances the mechanical properties of basalt fiber-wood plastic composites (BF-WPCs). The maximum values of the specific tensile and flexural strengths are achieved at a MAPE content of 5%-8%. The elongation increases rapidly at first and then continues slowly. The nearly complete integration of the wood fiber with the high-density polyethylene upon MAPE addition to WPC is examined, and two models of interfacial behavior are proposed. We examined the physical significance of both interfacial models and their ability to accurately describe the effects of MAPE addition. The mechanism of formation of the Model I interface and the integrated matrix is outlined based on the chemical reactions that may occur between the various components as a result of hydrogen bond formation or based on the principle of compatibility, resulting from similar polarity. The Model I fracture occurred on the outer surface of the interfacial layer, visually demonstrating the compatibilization effect of MAPE addition. PMID- 28809287 TI - Study of the Microstructure Evolution of Low-pH Cements Based on Ordinary Portland Cement (OPC) by Mid- and Near-Infrared Spectroscopy, and Their Influence on Corrosion of Steel Reinforcement. AB - Low-pH cements are designed to be used in underground repositories for high level waste. When they are based on Ordinary Portland Cements (OPC), high mineral admixture contents must be used which significantly modify their microstructure properties and performance. This paper evaluates the microstructure evolution of low-pH cement pastes based on OPC plus silica fume and/or fly ashes, using Mid Infrared and Near-Infrared spectroscopy to detect cement pastes mainly composed of high polymerized C-A-S-H gels with low C/S ratios. In addition, the lower pore solution pH of these special cementitious materials have been monitored with embedded metallic sensors. Besides, as the use of reinforced concrete can be required in underground repositories, the influence of low-pH cementitious materials on steel reinforcement corrosion was analysed. Due to their lower pore solution pH and their different pore solution chemical composition a clear influence on steel reinforcement corrosion was detected. PMID- 28809289 TI - Synthesis of Carbon Nanotubes of Few Walls Using Aliphatic Alcohols as a Carbon Source. AB - Carbon nanotubes with single and few walls are highly appreciated for their technological applications, regardless of the limited availability due to their high production cost. In this paper we present an alternative process that can lead to lowering the manufacturing cost of CNTs of only few walls by means of the use of the spray pyrolysis technique. For this purpose, ferrocene is utilized as a catalyst and aliphatic alcohols (methanol, ethanol, propanol or butanol) as the carbon source. The characterization of CNTs was performed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The study of the synthesized carbon nanotubes (CNTs) show important differences in the number of layers that constitute the nanotubes, the diameter length, the quantity and the quality as a function of the number of carbons employed in the alcohol. The main interest of this study is to give the basis of an efficient synthesis process to produce CNTs of few walls for applications where small diameter is required. PMID- 28809288 TI - Dynamic Morphological Changes Induced By GM1 and Protein Interactions on the Surface of Cell-Sized Liposomes. AB - It is important to understand the physicochemical mechanisms that are responsible for the morphological changes in the cell membrane in the presence of various stimuli such as osmotic pressure. Lipid rafts are believed to play a crucial role in various cellular processes. It is well established that Ctb (Cholera toxin B subunit) recognizes and binds to GM1 (monosialotetrahexosylganglioside) on the cell surface with high specificity and affinity. Taking advantage of Ctb-GM1 interaction, we examined how Ctb and GM1 molecules affect the dynamic movement of liposomes. GM1 a natural ligand for cholera toxin, was incorporated into liposome and the interaction between fluorescent Ctb and the liposome was analyzed. The interaction plays an important role in determining the various surface interaction phenomena. Incorporation of GM1 into membrane leads to an increase of the line tension leading to either rupture of liposome membrane or change in the morphology of the membrane. This change in morphology was found to be GM1 concentration specific. The interaction between Ctb-GM1 leads to fast and easy rupture or to morphological changes of the liposome. The interactions of Ctb and the glycosyl chain are believed to affect the surface and the curvature of the membrane. Thus, the results are highly beneficial in the study of signal transduction processes. PMID- 28809291 TI - A Refined Finite Element Formulation for the Microstructure-Dependent Analysis of Two-Dimensional (2D) Lattice Materials. AB - A finite element approximation is proposed for the dynamic analysis of two dimensional (2D) lattice materials. The unit cell is modeled by means of a defined number of shear deformable micro-beams. The main innovative feature concerns the presence of a microstructure-dependent scale length, which allows the consideration of the so called size-effect that can be highly relevant, due to the characteristics of the lattice at the local scale. Some numerical results show the influence of the microstructure parameter on the dynamic behavior of two dimensional lattice materials. PMID- 28809290 TI - Structural Polymer-Based Carbon Nanotube Composite Fibers: Understanding the Processing-Structure-Performance Relationship. AB - Among the many potential applications of carbon nanotubes (CNT), its usage to strengthen polymers has been paid considerable attention due to the exceptional stiffness, excellent strength, and the low density of CNT. This has provided numerous opportunities for the invention of new material systems for applications requiring high strength and high modulus. Precise control over processing factors, including preserving intact CNT structure, uniform dispersion of CNT within the polymer matrix, effective filler-matrix interfacial interactions, and alignment/orientation of polymer chains/CNT, contribute to the composite fibers' superior properties. For this reason, fabrication methods play an important role in determining the composite fibers' microstructure and ultimate mechanical behavior. The current state-of-the-art polymer/CNT high-performance composite fibers, especially in regards to processing-structure-performance, are reviewed in this contribution. Future needs for material by design approaches for processing these nano-composite systems are also discussed. PMID- 28809292 TI - The Surface of Nanoparticle Silicon as Studied by Solid-State NMR. AB - The surface structure and adjacent interior of commercially available silicon nanopowder (np-Si) was studied using multinuclear, solid-state NMR spectroscopy. The results are consistent with an overall picture in which the bulk of the np-Si interior consists of highly ordered ("crystalline") silicon atoms, each bound tetrahedrally to four other silicon atoms. From a combination of 1H, 29Si and 2H magic-angle-spinning (MAS) NMR results and quantum mechanical 29Si chemical shift calculations, silicon atoms on the surface of "as-received" np-Si were found to exist in a variety of chemical structures, with apparent populations in the order (a) (Si-O-)3Si-H > (b) (Si-O-)3SiOH > (c) (HO-)nSi(Si)m(-OSi)4-m-n ~ (d) (Si-O )2Si(H)OH > (e) (Si-O-)2Si(-OH)2 > (f) (Si-O-)4Si, where Si stands for a surface silicon atom and Si represents another silicon atom that is attached to Si by either a Si-Si bond or a Si-O-Si linkage. The relative populations of each of these structures can be modified by chemical treatment, including with O2 gas at elevated temperature. A deliberately oxidized sample displays an increased population of (Si-O-)3Si-H, as well as (Si-O-)3SiOH sites. Considerable heterogeneity of some surface structures was observed. A combination of 1H and 2H MAS experiments provide evidence for a substantial population of silanol (Si-OH) moieties, some of which are not readily H-exchangeable, along with the dominant Si-H sites, on the surface of "as-received" np-Si; the silanol moieties are enhanced by deliberate oxidation. An extension of the DEPTH background suppression method is also demonstrated that permits measurement of the T2 relaxation parameter simultaneously with background suppression. PMID- 28809293 TI - Molecular Dynamics of Poly(Ethylene Glycol) Intercalated in Clay, Studied Using 13C Solid-State NMR. AB - In this study, Cross-Polarization Magic-angle Spinning CP/MAS, 2D Exchange, Centerband-Only Detection of Exchange (CODEX), and Separated-Local-Field (SLF) NMR experiments were used to study the molecular dynamics of poly(ethylene glycol) (PEG) inside Hectorite/PEG intercalation compounds in both single- and double-layer configurations. The results revealed that the overall amplitude of the motions of the PEG chain in the single-layer configuration is considerably smaller than that observed for the double-layer intercalation compound. This result indicates that the effect of having the polymer chain interacting with both clay platelets is to produce a substantial decrease in the motional amplitudes of those chains. The presence of these dynamically restricted segments might be explained by the presence of anchoring points between the clay platelets and the PEG oxygen atoms, which was induced by the Na+ cations. By comparing the PEG motional amplitudes of the double-layered nanocomposites composed of polymers with different molecular weights, a decrease in the motional amplitude for the smaller PEG chain was observed, which might also be understood using the presence of anchoring points. PMID- 28809294 TI - Morphological Change of Heat Treated Bovine Bone: A Comparative Study. AB - In this work, untreated bovine cortical bones (BCBs) were exposed to a range of heat treatments in order to determine at which temperature the apatite develops an optimum morphology comprising porous nano hydroxyapatite (nanoHAp) crystals. Rectangular specimens (10 mm * 10 mm * 3-5 mm) of BCB were prepared, being excised in normal to longitudinal and transverse directions. Specimens were sintered at up to 900 degrees C under ambient pressure in order to produce apatites by two steps sintering. The samples were characterized by thermogravimetric analysis, X-ray diffraction (XRD), and scanning electron microscopy (SEM) attached to an energy-dispersive X-ray spectroscopy detector. For the first time, morphology of the HAp particles was predicted by XRD, and it was verified by SEM. The results show that an equiaxed polycrystalline HAp particle with uniform porosity was produced at 900 degrees C. It indicates that a porous nanoHAp achieved by sintering at 900 degrees C can be an ideal candidate as an in situ scaffold for load-bearing tissue applications. PMID- 28809295 TI - Thermal Annealing Effect on Optical Properties of Binary TiO2-SiO2 Sol-Gel Coatings. AB - TiO2-SiO2 binary coatings were deposited by a sol-gel dip-coating method using tetrabutyl titanate and tetraethyl orthosilicate as precursors. The structure and chemical composition of the coatings annealed at different temperatures were analyzed by Raman spectroscopy and Fourier Transform Infrared (FTIR) spectroscopy. The refractive indices of the coatings were calculated from the measured transmittance and reflectance spectra. An increase in refractive index with the high temperature thermal annealing process was observed. The Raman and FTIR results indicate that the refractive index variation is due to changes in the removal of the organic component, phase separation and the crystal structure of the binary coatings. PMID- 28809296 TI - Hydrazine-Assisted Formation of Indium Phosphide (InP)-Based Nanowires and Core Shell Composites. AB - Indium phosphide nanowires (InP NWs) are accessible at 440 degrees C from a novel vapor phase deposition approach from crystalline InP sources in hydrazine atmospheres containing 3 mol % H2O. Uniform zinc blende (ZB) InP NWs with diameters around 20 nm and lengths up to several tens of micrometers are preferably deposited on Si substrates. InP particle sizes further increase with the deposition temperature. The straightforward protocol was extended on the one step formation of new core-shell InP-Ga NWs from mixed InP/Ga source materials. Composite nanocables with diameters below 20 nm and shells of amorphous gallium oxide are obtained at low deposition temperatures around 350 degrees C. Furthermore, InP/Zn sources afford InP NWs with amorphous Zn/P/O-coatings at slightly higher temperatures (400 degrees C) from analogous setups. At 450 degrees C, the smooth outer layer of InP-Zn NWs is transformed into bead-shaped coatings. The novel combinations of the key semiconductor InP with isotropic insulator shell materials open up interesting application perspectives in nanoelectronics. PMID- 28809297 TI - Ethylene Formation by Catalytic Dehydration of Ethanol with Industrial Considerations. AB - Ethylene is the primary component in most plastics, making it economically valuable. It is produced primarily by steam-cracking of hydrocarbons, but can alternatively be produced by the dehydration of ethanol, which can be produced from fermentation processes using renewable substrates such as glucose, starch and others. Due to rising oil prices, researchers now look at alternative reactions to produce green ethylene, but the process is far from being as economically competitive as using fossil fuels. Many studies have investigated catalysts and new reaction engineering technologies to increase ethylene yield and to lower reaction temperature, in an effort to make the reaction applicable in industry and most cost-efficient. This paper presents various lab synthesized catalysts, reaction conditions, and reactor technologies that achieved high ethylene yield at reasonable reaction temperatures, and evaluates their practicality in industrial application in comparison with steam-cracking plants. The most promising were found to be a nanoscale catalyst HZSM-5 with 99.7% ethylene selectivity at 240 degrees C and 630 h lifespan, using a microreactor technology with mechanical vapor recompression, and algae-produced ethanol to make ethylene. PMID- 28809298 TI - Photo-Responsive Shape-Memory and Shape-Changing Liquid-Crystal Polymer Networks. AB - "Surrounding matters" is a phrase that has become more significant in recent times when discussing polymeric materials. Although regular polymers do respond to external stimuli like softening of material at higher temperatures, that response is gradual and linear in nature. Smart polymers (SPs) or stimuli responsive polymers (SRPs) behave differently to those external stimuli, as their behavior is more rapid and nonlinear in nature and even a small magnitude of external stimulus can cause noticeable changes in their shape, size, color or conductivity. Of these SRPs, two types of SPs with the ability to actively change can be differentiated: shape-memory polymers and shape-changing polymers. The uniqueness of these materials lies not only in the fast macroscopic changes occurring in their structure but also in that some of these shape changes are reversible. This paper presents a brief review of current progress in the area of light activated shape-memory polymers and shape-changing polymers and their possible field of applications. PMID- 28809299 TI - Design of High Impedance Electromagnetic Surfaces for Mutual Coupling Reduction in Patch Antenna Array. AB - A compact planar meander-bridge high impedance electromagnetic structure (MBHIES) was designed and its bandgap characteristics, mutual coupling reduction abilities were studied and compared in detail. Several parametric analyses were performed to obtain optimized design values and the transmission responses were calculated through the suspended microstrip line and waveguide simulation methods. The achieved bandgap is 2.3 GHz (2.55-4.85 GHz) with -61 dB minimum transmission coefficient level at the center frequency of 3.6 GHz. To see the effectiveness, the proposed design was inserted between a microstrip patch antenna array which operates at 3.8 GHz and whose operating bandwidth falls within the MBHIES bandgap. The surface wave suppression phenomenon was analyzed and simulated results are verified by measuring the fabricated prototypes, both are in good agreement. The configuration reduced the mutual coupling by 20.69 dB in simulation and 19.18 dB in measurement, without affecting the radiation characteristics of the array but increasing the gain slightly. PMID- 28809300 TI - Recent Progress in Advanced Materials for Lithium Ion Batteries. AB - The development and commercialization of lithium ion batteries is rooted in material discovery. Promising new materials with high energy density are required for achieving the goal toward alternative forms of transportation. Over the past decade, significant progress and effort has been made in developing the new generation of Li-ion battery materials. In the review, I will focus on the recent advance of tin- and silicon-based anode materials. Additionally, new polyoxyanion cathodes, such as phosphates and silicates as cathode materials, will also be discussed. PMID- 28809301 TI - Nanocrystalline Akaganeite as Adsorbent for Surfactant Removal from Aqueous Solutions. AB - The present study presents the effective use of nanocrystalline akaganeite for the adsorption of an anionic (SDS), a cationic (CTAB), and a nonionic (tween80) surfactant from wastewater. Equilibrium experiments, as well as thermodynamic analysis, were performed. The maximum SDS adsorption occurs at the lowest pH value (5), the opposite is observed for CTAB (pH = 11), while for tween80, the change of pH value did not affect the adsorption. The equilibrium data could be described by Freundlich and Langmuir isotherms. The maximum adsorption capacity at 25 degrees C (pH = 8) was 823.96 mg/g for SDS, 1007.93 mg/g for CTAB, and 699.03 mg/g for tween80. The thermodynamic parameters revealed the exothermic and spontaneity nature of the process. Also, FTIR measurements established that surfactants are adsorbed on the surface of akaganeite, replacing adsorbed water. PMID- 28809302 TI - Hardness and Elastic Modulus on Six-Fold Symmetry Gold Nanoparticles. AB - The chemical synthesis of gold nanoparticles (NP) by using gold (III) chloride trihydrate (HAuCl?3H2O) and sodium citrate as a reducing agent in aqueous conditions at 100 degrees C is presented here. Gold nanoparticles areformed by a galvanic replacement mechanism as described by Lee and Messiel. Morphology of gold-NP was analyzed by way of high-resolution transmission electron microscopy; results indicate a six-fold icosahedral symmetry with an average size distribution of 22 nm. In order to understand the mechanical behaviors, like hardness and elastic moduli, gold-NP were subjected to nanoindentation measurements-obtaining a hardness value of 1.72 GPa and elastic modulus of 100 GPa in a 3-5 nm of displacement at the nanoparticle's surface. PMID- 28809303 TI - Comparative Study of Loading of Anodic Porous Alumina with Silver Nanoparticles Using Different Methods. AB - Three different routes were used to infiltrate the pores of anodic porous alumina templates with silver nanoparticles, selected as an example of a bioactive agent. The three methods present a continuous grading from more physical to more chemical character, starting from ex situ filling of the pores with pre-existing particles, moving on to in situ formation of particles in the pores by bare calcination and ending with in situ calcination following specific chemical reactions. The resulting presence of silver inside the pores was assessed by means of energy dispersive X-ray spectroscopy and X-ray diffraction. The number and the size of nanoparticles were evaluated by scanning electron microscopy of functionalized alumina cross-sections, followed by image analysis. It appears that the best functionalization results are obtained with the in situ chemical procedure, based on the prior formation of silver ion complex by means of ammonia, followed by reduction with an excess amount of acetaldehyde. Elution of the silver content from the chemically functionalized alumina into phosphate buffer saline has also been examined, demonstrating a sustained release of silver over time, up to 15 h. PMID- 28809304 TI - A Review on the Synthesis and Applications of Mesostructured Transition Metal Phosphates. AB - Considerable efforts have been devoted to extending the range of the elemental composition of mesoporous materials since the pioneering work of the M41S family of ordered mesoporous silica by Mobil researchers. The synthesis of transition metal-containing mesostructured materials with large surface area and high porosity has drawn great attention for its potential applications in acid and redox catalysis, photocatalysis, proton conducting devices, environmental restoration and so on. Thus, various transition metals-containing mesoporous materials, including transition metal-substituted mesoporous silicates, mesostructured transition metal oxides and transition metal phosphates (TMP), have been documented in the literature. Among these, mesostructured TMP materials are less studied, but possess some unique features, partly because of the easy and facile functionalization of PO4 and/or P-OH groups, rendering them interesting functional materials. This review first introduced the general synthesis strategies for manufacturing mesostructured TMP materials, as well as advantages and disadvantages of the respective method; then, we surveyed the ongoing developments of fabrication and application of the TMP materials in three groups on the basis of their components and application fields. Future perspectives on existing problems related to the present synthesis routes and further modifying of the functional groups for the purpose of tailoring special physical-chemical properties to meet wide application requirements were also provided in the last part. PMID- 28809305 TI - Modeling the Microstructure Curvature of Boron-Doped Silicon in Bulk Micromachined Accelerometer. AB - Microstructure curvature, or buckling, is observed in the micromachining of silicon sensors because of the doping of impurities for realizing certain electrical and mechanical processes. This behavior can be a key source of error in inertial sensors. Therefore, identifying the factors that influence the buckling value is important in designing MEMS devices. In this study, the curvature in the proof mass of an accelerometer is modeled as a multilayered solid model. Modeling is performed according to the characteristics of the solid diffusion mechanism in the bulk-dissolved wafer process (BDWP) based on the self stopped etch technique. Moreover, the proposed multilayered solid model is established as an equivalent composite structure formed by a group of thin layers that are glued together. Each layer has a different Young's modulus value and each undergoes different volume shrinkage strain owing to boron doping in silicon. Observations of five groups of proof mass blocks of accelerometers suggest that the theoretical model is effective in determining the buckling value of a fabricated structure. PMID- 28809306 TI - Nanomagnetic Gene Transfection for Non-Viral Gene Delivery in NIH 3T3 Mouse Embryonic Fibroblasts. AB - The objective of this work was to examine the potential of oscillating nanomagnetic gene transfection systems (magnefect-nanoTM) for improving the transfection efficiency of NIH3T3 mouse embryonic fibroblasts (MEFs) in comparison to other non-viral transfection techniques-static magnetofectionTM and the cationic lipid agent, Lipofectamine 2000TM. Magnetic nanoparticles (MNPs) associated with the plasmid coding for green fluorescent protein (GFP) were used to transfect NIH3T3 cells. The magnefect-nano system was evaluated for transfection efficiency, and any potential associated effects on cell viability were investigated. MNPs associated with the plasmid coding for GFP were efficiently delivered into NIH3T3 cells, and the magnefect-nano system significantly enhanced overall transfection efficiency in comparison to lipid mediated gene delivery. MNP dosage used in this work was not found to affect the cell viability and/or morphology of the cells. Non-viral transfection using MNPs and the magnefect-nano system can be used to transfect NIH3T3 cells and direct reporter gene delivery, highlighting the wide potential of nanomagnetic gene transfection in gene therapy. PMID- 28809307 TI - Photocatalytic Oxidation of Low-Level Airborne 2-Propanol and Trichloroethylene over Titania Irradiated with Bulb-Type Light-Emitting Diodes. AB - This study examined the photocatalytic oxidation of gas-phase trichloroethylene (TCE) and 2-propanol, at indoor levels, over titanium dioxide (TiO2) irradiated with light-emitting diodes (LED) under different operational conditions. TiO2 powder baked at 450 degrees C exhibited the highest photocatalytic decomposition efficiency (PDE) for TCE, while all photocatalysts baked at different temperatures showed similar PDEs for 2-propanol. The average PDEs of TCE over a three hour period were four, four, five, and 51% for TiO2 powders baked at 150, 250, 350, and 450 degrees C, respectively. The average PDEs of 2-propanol were 95, 97, 98, and 96% for TiO2 powders baked at 150, 250, 350, and 450 degrees C, respectively. The ratio of anatase at 2theta = 25.2 degrees to rutile at 2theta = 27.4 degrees was lowest for the TiO2 powder baked at 450 degrees C. Although the LED-irradiated TiO2 system revealed lower PDEs of TCE and 2-propanol when compared to those of the eight watt, black-light lamp-irradiated TiO2 system, the results for the PDEs normalized to the energy consumption were reversed. Other operational parameters, such as relative humidity, input concentrations, flow rate, and feeding type were also found to influence the photocatalytic performance of the UV LED-irradiated TiO2 system when applied to the cleaning of TCE and 2-propanol at indoor air levels. PMID- 28809308 TI - "Property Phase Diagrams" for Compound Semiconductors through Data Mining. AB - This paper highlights the capability of materials informatics to recreate "property phase diagrams" from an elemental level using electronic and crystal structure properties. A judicious selection of existing data mining techniques, such as Principal Component Analysis, Partial Least Squares Regression, and Correlated Function Expansion, are linked synergistically to predict bandgap and lattice parameters for different stoichiometries of GaxIn1-xAsySb1-y, starting from fundamental elemental descriptors. In particular, five such elemental descriptors, extracted from within a database of highly correlated descriptors, are shown to collectively capture the widely studied "bowing" of energy bandgaps seen in compound semiconductors. This is the first such demonstration, to our knowledge, of establishing relationship between discrete elemental descriptors and bandgap bowing, whose underpinning lies in the fundamentals of solid solution thermodyanamics. PMID- 28809309 TI - Single Grain Boundary Modeling and Design of Microcrystalline Si Solar Cells. AB - For photovoltaic applications, microcrystalline silicon has a lot of advantages, such as the ability to absorb the near-infrared part of the solar spectrum. However, there are many dangling bonds at the grain boundary in microcrystalline Si. These dangling bonds would lead to the recombination of photo-generated carriers and decrease the conversion efficiency. Therefore, we included the grain boundary in the numerical study in order to simulate a microcrystalline Si solar cell accurately, designing new three-terminal microcrystalline Si solar cells. The 3-MUm-thick three-terminal cell achieved a conversion efficiency of 10.8%, while the efficiency of a typical two-terminal cell is 9.7%. The three-terminal structure increased the JSC but decreased the VOC, and such phenomena are discussed. High-efficiency and low-cost Si-based thin film solar cells can now be designed based on the information provided in this paper. PMID- 28809310 TI - Recent Progress in Fourier Transform Infrared (FTIR) Spectroscopy Study of Compositional, Structural and Physical Attributes of Developmental Cotton Fibers. AB - Cotton fibers are natural plant products, and their end-use qualities depend on their stages of development. In general, the quantity of cellulose in cotton fibers increases rapidly, thus it leads to compositional, structural and physical attribute variations among the fibers with shorter and longer growth periods. This article discusses recent progress in applying the Fourier transform infrared (FTIR) spectroscopic technique to characterize these differences, to discriminate immature fibers from mature fibers, to assess fiber maturity and crystallinity and also to unravel the band assignments in crystalline and amorphous celluloses. The results were achieved through the use of various strategies, including wet chemical analysis, principal component analysis (PCA), simple algorithm development, two-dimensional correlation analysis and other independent fiber tests. Of particular interest is that, in general, immature fibers might have the characteristics of less than 21-28 dpa, MIR < 0.58 (in the maturity range of 0 to 1.0) and CIIR < 42% (in the crystallinity range of 0 to 100%). PMID- 28809311 TI - Low Stress Mechanical Properties of Plasma-Treated Cotton Fabric Subjected to Zinc Oxide-Anti-Microbial Treatment. AB - Cotton fabrics are highly popular because of their excellent properties such as regeneration, bio-degradation, softness, affinity to skin and hygroscopic properties. When in contact with the human body, cotton fabrics offer an ideal environment for microbial growth due to their ability to retain oxygen, moisture and warmth, as well as nutrients from spillages and body sweat. Therefore, an anti-microbial coating formulation (Microfresh and Microban together with zinc oxide as catalyst) was developed for cotton fabrics to improve treatment effectiveness. In addition, plasma technology was employed in the study which roughened the surface of the materials, improving the loading of zinc oxides on the surface. In this study, the low stress mechanical properties of plasma pre treated and/or anti-microbial-treated cotton fabric were studied. The overall results show that the specimens had improved bending properties when zinc oxides were added in the anti-microbial coating recipe. Also, without plasma pre treatment, anti-microbial-treatment of cotton fabric had a positive effect only on tensile resilience, shear stress at 0.5 degrees and compressional energy, while plasma-treated specimens had better overall tensile properties even after anti-microbial treatment. PMID- 28809312 TI - Holographic Spectroscopy: Wavelength-Dependent Analysis of Photosensitive Materials by Means of Holographic Techniques. AB - Holographic spectroscopy is highlighted as a powerful tool for the analysis of photosensitive materials with pronounced alterations of the complex permittivity over a broad range in the visible spectrum, due to the advances made both in the fields of advanced holographic media and highly tunable lasers systems. To analytically discuss consequences for in- and off-Bragg reconstruction, we revised Kogelnik's coupled wave theory strictly on the basis of complex permittivities. We extended it to comply with modern experimental parameters such as out-of-phase mixed holograms and highly modulated gratings. A spatially modulated, wavelength-dependent permittivity that superimposes a spatially homogeneous wavelength-dependent ground state spectrum is taken into account for signal wave reconstruction with bulky elementary mixed gratings as an example. The dispersion characteristics of the respective diffraction efficiency is modelled for color-center-absorption and absorption of strongly localized carriers. As an example for the theoretical possibilities of our newly derived set of equations, we present a quantitative analysis of the Borrmann effect connected to out-of-phase gratings, providing easier and more intuitive methods for the derivation of their grating parameters. PMID- 28809313 TI - Recent Advances in Characterization of Lignin Polymer by Solution-State Nuclear Magnetic Resonance (NMR) Methodology. AB - The demand for efficient utilization of biomass induces a detailed analysis of the fundamental chemical structures of biomass, especially the complex structures of lignin polymers, which have long been recognized for their negative impact on biorefinery. Traditionally, it has been attempted to reveal the complicated and heterogeneous structure of lignin by a series of chemical analyses, such as thioacidolysis (TA), nitrobenzene oxidation (NBO), and derivatization followed by reductive cleavage (DFRC). Recent advances in nuclear magnetic resonance (NMR) technology undoubtedly have made solution-state NMR become the most widely used technique in structural characterization of lignin due to its versatility in illustrating structural features and structural transformations of lignin polymers. As one of the most promising diagnostic tools, NMR provides unambiguous evidence for specific structures as well as quantitative structural information. The recent advances in two-dimensional solution-state NMR techniques for structural analysis of lignin in isolated and whole cell wall states (insitu), as well as their applications are reviewed. PMID- 28809314 TI - Mechanism of Catalytic Water Oxidation by the Ruthenium Blue Dimer Catalyst: Comparative Study in D2O versus H2O. AB - Water oxidation is critically important for the development of energy solutions based on the concept of artificial photosynthesis. In order to gain deeper insight into the mechanism of water oxidation, the catalytic cycle for the first designed water oxidation catalyst, cis,cis-[(bpy)2(H2O)RuIIIORuIII(OH2)(bpy)2]4+ (bpy is 2,2-bipyridine) known as the blue dimer (BD), is monitored in D2O by combined application of stopped flow UV-Vis, electron paramagnetic resonance (EPR) and resonance Raman spectroscopy on freeze quenched samples. The results of these studies show that the rate of formation of BD[4,5] by Ce(IV) oxidation of BD[3,4] (numbers in square bracket denote oxidation states of the ruthenium (Ru) centers) in 0.1 M HNO3, as well as further oxidation of BD[4,5] are slower in D2O by 2.1-2.5. Ce(IV) oxidation of BD[4,5] and reaction with H2O result in formation of an intermediate, BD[3,4]', which builds up in reaction mixtures on the minute time scale. Combined results under the conditions of these experiments at pH 1 indicate that oxidation of BD[3,4]' is a rate limiting step in water oxidation with the BD catalyst. PMID- 28809315 TI - Effect of Thermal Treatment of Veneer on Formaldehyde Emission of Poplar Plywood. AB - A large amount of poplar plywood is now being imported into Japan from China, and as a result, formaldehyde emitted from this plywood represents an undesirable chemical that must be controlled using a chemical catching agent. The aim of this study is to find an approach to reduce the formaldehyde emission of poplar plywood using thermal treatment without employing any chemicals. The experimental results obtained show that heating veneer sheets in the temperature range of 150 degrees C to 170 degrees C effectively reduced the formaldehyde emission of plywood, without diminishing the mechanical properties of the veneer. By applying Langmuir's theory and Hailwood-Horrobin theory to the adsorption isotherm obtained in this study, the relationship between the formaldehyde emission of plywood and the adsorption properties of veneer as a material is discussed. When veneer sheets were heated in the temperature range of 150 degrees C to 170 degrees C, the amount of hydrated water (monomolecular layer) decreased slightly and that of dissolved water (polymolecular layer) did not change. It is hypothesized that the formaldehyde emission of plywood is related to the condition of the adsorption site of the wood. PMID- 28809316 TI - Material Analysis of Coated Siliconized Silicon Carbide (SiSiC) Honeycomb Structures for Thermochemical Hydrogen Production. AB - In the present work, thermochemical water splitting with siliconized silicon carbide (SiSiC) honeycombs coated with a zinc ferrite redox material was investigated. The small scale coated monoliths were tested in a laboratory test rig and characterized by X-ray diffractometry (XRD) and Scanning Electron Microscopy (SEM) with corresponding micro analysis after testing in order to characterize the changes in morphology and composition. Comparison of several treated monoliths revealed the formation of various reaction products such as SiO2, zircon (ZrSiO4), iron silicide (FeSi) and hercynite (FeAl2O4) indicating the occurrence of various side reactions between the different phases of the coating as well as between the coating and the SiSiC substrate. The investigations showed that the ferrite is mainly reduced through reaction with silicon (Si), which is present in the SiSiC matrix, and silicon carbide (SiC). These results led to the formulation of a new redox mechanism for this system in which Zn-ferrite is reduced through Si forming silicon dioxide (SiO2) and through SiC forming SiO2 and carbon monoxide. A decline of hydrogen production within the first 20 cycles is suggested to be due to the growth of a silicon dioxide and zircon layer which acts as a diffusion barrier for the reacting specie. PMID- 28809317 TI - Crystallographic Orientation Influence on the Serrated Yielding Behavior of a Single-Crystal Superalloy. AB - Since Ni-based single-crystal superalloys are anisotropic materials, their behavior in different crystal orientations is of great interest. In this study, the yielding behavior in both tension and compression for , and oriented materials at 500 degrees C has been investigated. The direction showed a serrated yielding behavior, a great tension/compression asymmetry in yield strength and visible deformation bands. However, the and directions showed a more homogeneous yielding, less tension/compression asymmetry in yield strength and no deformation bands. Microstructure investigations showed that the serrated yielding behavior of the direction can be attributed to the appearance of dynamic strain aging (DSA) and that only one slip system is active in this direction during plastic deformation. PMID- 28809318 TI - Semiconductor Nanocrystals as Light Harvesters in Solar Cells. AB - Photovoltaic cells use semiconductors to convert sunlight into electrical current and are regarded as a key technology for a sustainable energy supply. Quantum dot based solar cells have shown great potential as next generation, high performance, low-cost photovoltaics due to the outstanding optoelectronic properties of quantum dots and their multiple exciton generation (MEG) capability. This review focuses on QDs as light harvesters in solar cells, including different structures of QD-based solar cells, such as QD heterojunction solar cells, QD-Schottky solar cells, QD-sensitized solar cells and the recent development in organic-inorganic perovskite heterojunction solar cells. Mechanisms, procedures, advantages, disadvantages and the latest results obtained in the field are described. To summarize, a future perspective is offered. PMID- 28809319 TI - Advances in Fabrication Materials of Honeycomb Structure Films by the Breath Figure Method. AB - Creatures in nature possess almost perfect structures and properties, and exhibit harmonization and unification between structure and function. Biomimetics, mimicking nature for engineering solutions, provides a model for the development of functional surfaces with special properties. Recently, honeycomb structure materials have attracted wide attention for both fundamental research and practical applications and have become an increasingly hot research topic. Though progress in the field of breath-figure formation has been reviewed, the advance in the fabrication materials of bio-inspired honeycomb structure films has not been discussed. Here we review the recent progress of honeycomb structure fabrication materials which were prepared by the breath-figure method. The application of breath figures for the generation of all kinds of honeycomb is discussed. PMID- 28809320 TI - Quantum Dots as Multifunctional Materials for Tumor Imaging and Therapy. AB - The rapidly developing field of quantum dots (QDs) provides researchers with more options for imaging modalities and therapeutic strategies. In recent years, QDs were widely used as multifunctional materials for tumor imaging and therapy due to their characteristic properties such as semiconductive, zero-dimension and strong fluorescence. Nevertheless, there still exist the challenges of employing these properties of QDs for clinical diagnosis and therapy. Herein, we briefly review the development, properties and applications of QDs in tumor imaging and therapy. Future perspectives in these areas are also proposed as well. PMID- 28809321 TI - Extraordinary Magnetoresistance in Semiconductor/Metal Hybrids: A Review. AB - The Extraordinary Magnetoresistance (EMR) effect is a change in the resistance of a device upon the application of a magnetic field in hybrid structures, consisting of a semiconductor and a metal. The underlying principle of this phenomenon is a change of the current path in the hybrid structure upon application of a magnetic field, due to the Lorentz force. Specifically, the ratio of current, flowing through the highly conducting metal and the poorly conducting semiconductor, changes. The main factors for the device's performance are: the device geometry, the conductivity of the metal and semiconductor, and the mobility of carriers in the semiconductor. Since the discovery of the EMR effect, much effort has been devoted to utilize its promising potential. In this review, a comprehensive overview of the research on the EMR effect and EMR devices is provided. Different geometries of EMR devices are compared with respect to MR ratio and output sensitivity, and the criteria of material selection for high-performance devices are discussed. PMID- 28809322 TI - A Review of Aspects of Oxidative Hair Dye Chemistry with Special Reference to N Nitrosamine Formation. AB - This review discusses a new aspect to the safety profile of oxidative hair dyes using data already in the public domain. These dyes contain secondary amines that are capable of forming potentially carcinogenic nitrosamine derivatives when exposed to atmospheric pollution. Numerous scientific articles confirm the existence of secondary amines in hair dyes (and their intermediates), the possibility of nitrosation by atmospheric NOx of secondary amines to give the N nitrosamines, and the significant safety risks on N-nitrosamines. It is believed that such nitrosamine derivatives should be investigated more fully in the interests of consumer safety. PMID- 28809323 TI - Electron Density Modification of Single Wall Carbon Nanotubes (SWCNT) by Liquid Phase Molecular Adsorption of Hexaiodobenzene. AB - Electron density of single wall carbon nanotubes (SWCNT) is effectively modified by hexaiodobenzene (HIB) molecules using liquid-phase adsorption. UV-Vis-NIR absorption spectra of the HIB-adsorbed SWCNT, especially in the NIR region, showed a disappearance of S11 transitions between the V1 valance band and the C1 conduction band of van Hove singularities which can be attributed to the effective charge transfer between HIB and the SWCNT. The adsorption of HIB also caused significant peak-shifts (lower frequency shift around 170 cm-1 and higher shift around 186 cm-1) and an intensity change (around 100-150 cm-1 and 270-290 cm-1) in the radial breathing mode of Raman spectra. The charge transfer from SWCNT to HIB was further confirmed by the change in the C1s peak of X-ray photoelectron spectrum, revealing the oxidation of carbon in SWCNT upon HIB adsorption. PMID- 28809324 TI - Absorption and Tensility of Bioactive Sutures Prepared for Cell Transplantation. AB - Biodegradable scaffolds are widely used to transplant stem cells into various tissues. Recent studies showed that living stem cells can be attached to the surface of absorbable sutures in vitro. Soaking the absorbable material polyglactin in a cell culture medium and thereby creating a stem cell biofilm on its surface may initiate the absorption process even before implantation; therefore, the physicochemical properties of the suture may be compromised in vivo. We found that pre-incubation of sutures in cell culture media in vitro results in tensile strength reduction and faster suture absorption in a rat model of muscle injury. Shorter incubation times of up to 48 h do not influence absorption or tensility; therefore, it is advisable to limit incubation times to two days for polyglactin-based cell delivery protocols. PMID- 28809325 TI - Theoretical Research on Thermal Shock Resistance of Ultra-High Temperature Ceramics Focusing on the Adjustment of Stress Reduction Factor. AB - The thermal shock resistance of ceramics depends on not only the mechanical and thermal properties of materials, but also the external constraint and thermal condition. So, in order to study the actual situation in its service process, a temperature-dependent thermal shock resistance model for ultra-high temperature ceramics considering the effects of the thermal environment and external constraint was established based on the existing theory. The present work mainly focused on the adjustment of the stress reduction factor according to different thermal shock situations. The influences of external constraint on both critical rupture temperature difference and the second thermal shock resistance parameter in either case of rapid heating or cooling conditions had been studied based on this model. The results show the necessity of adjustment of the stress reduction factor in different thermal shock situations and the limitations of the applicable range of the second thermal shock resistance parameter. Furthermore, the model was validated by the finite element method. PMID- 28809327 TI - Pore Narrowing of Mesoporous Silica Materials. AB - To use mesoporous silicas as low-k materials, the pore entrances must be really small to avoid diffusion of metals that can increase the dielectric constant of the low-k dielectric. In this paper we present a new method to narrow the pores of mesoporous materials through grafting of a cyclic-bridged organosilane precursor. As mesoporous material, the well-studied MCM-41 powder was selected to allow an easy characterization of the grafting reactions. Firstly, the successful grafting of the cyclic-bridged organosilane precursor on MCM-41 is presented. Secondly, it is demonstrated that pore narrowing can be obtained without losing porosity by removing the porogen template after grafting. The remaining silanols in the pores can then be end-capped with hexamethyl disilazane (HMDS) to make the material completely hydrophobic. Finally, we applied the pore narrowing method on organosilica films to prove that this method is also successful on existing low-k materials. PMID- 28809328 TI - Solubilization of Hydrophobic Dyes in Surfactant Solutions. AB - In this paper, the use of surfactants for solubilization of hydrophobic organic dyes (mainly solvent and disperse dyes) has been reviewed. The effect of parameters such as the chemical structures of the surfactant and the dye, addition of salt and of polyelectrolytes, pH, and temperature on dye solubilization has been discussed. Surfactant self-assemble into micelles in aqueous solution and below the concentration where this occurs-the critical micelle concentration (CMC)-there is no solubilization. Above the CMC, the amount of solubilized dye increases linearly with the increase in surfactant concentration. It is demonstrated that different surfactants work best for different dyes. In general, nonionic surfactants have higher solubilization power than anionic and cationic surfactants. It is likely that the reason for the good performance of nonionic surfactants is that they allow dyes to be accommodated not only in the inner, hydrocarbon part of the micelle but also in the headgroup shell. It is demonstrated that the location of a dye in a surfactant micelle can be assessed from the absorption spectrum of the dye-containing micellar solution. PMID- 28809329 TI - Materials Best Paper Award 2013. AB - Materials is instituting an annual award to recognize the outstanding papers in the area of materials science and engineering published in Materials. We are pleased to announce the first "Materials Best Paper Award" for 2013. Nominations were selected by the Section Editor-in-Chiefs and Editorial Board members of Materials from all papers published in 2009. [...]. PMID- 28809330 TI - Room Temperature Ferromagnetic, Anisotropic, Germanium Rich FeGe(001) Alloys. AB - Ferromagnetic FexGe1-x with x = 2%-9% are obtained by Fe deposition onto Ge(001) at high temperatures (500 degrees C). Low energy electron diffraction (LEED) investigation evidenced the preservation of the (1 * 1) surface structure of Ge(001) with Fe deposition. X-ray photoelectron spectroscopy (XPS) at Ge 3d and Fe 2p core levels evidenced strong Fe diffusion into the Ge substrate and formation of Ge-rich compounds, from FeGe3 to approximately FeGe2, depending on the amount of Fe deposited. Room temperature magneto-optical Kerr effect (MOKE) evidenced ferromagnetic ordering at room temperature, with about 0.1 Bohr magnetons per Fe atom, and also a clear uniaxial magnetic anisotropy with the in plane easy magnetization axis. This compound is a good candidate for promising applications in the field of semiconductor spintronics. PMID- 28809331 TI - Structural and Electrochemical Investigation during the First Charging Cycles of Silicon Microwire Array Anodes for High Capacity Lithium Ion Batteries. AB - Silicon microwire arrays embedded in Cu present exceptional performance as anode material in Li ion batteries. The processes occurring during the first charging cycles of batteries with this anode are essential for good performance. This paper sheds light on the electrochemical and structural properties of the anodes during the first charging cycles. Scanning Electron Microscopy, X-ray diffractommetry, and fast Fourier transformation impedance spectroscopy are used for the characterization. It was found that crystalline phases with high Li content are obtained after the first lithiation cycle, while for the second lithiation just crystalline phases with less Li are observable, indicating that the lithiated wires become amorphous upon cycling. The formation of a solid electrolyte interface of around 250 nm during the first lithiation cycle is evidenced, and is considered a necessary component for the good cycling performance of the wires. Analog to voltammetric techniques, impedance spectroscopy is confirmed as a powerful tool to identify the formation of the different Si-Li phases. PMID- 28809333 TI - Supported Membranes Meet Flat Fluidics: Monitoring Dynamic Cell Adhesion on Pump Free Microfluidics Chips Functionalized with Supported Membranes Displaying Mannose Domains. AB - In this paper we demonstrate the combination of supported membranes and so-called flat microfluidics, which enables one to manipulate liquids on flat chip surfaces via "inverse piezoelectric effect". Here, an alternating external electric field applied to the inter-digital transducers excites a surface acoustic wave on a piezoelectric substrate. Employing lithographic patterning of self-assembled monolayers of alkoxysilanes, we successfully confine a free-standing, hemi cylindrical channel with the volume of merely 7 uL . The experimentally determined maximum flow velocity scales linearly with the acoustic power, suggesting that our current setup can drive liquids at the speed of up to 7 cm/s (corresponding to a shear rate of 280 s-1) without applying high pressures using a fluidic pump. After the establishment of the functionalization of fluidic chip surfaces with supported membranes, we deposited asymmetric supported membranes displaying well-defined mannose domains and monitored the dynamic adhesion of E.Coli HB101 expressing mannose-binding receptors. Despite of the further technical optimization required for the quantitative analysis, the obtained results demonstrate that the combination of supported membranes and flat fluidics opens a large potential to investigate dynamic adhesion of cells on biofunctional membrane surfaces with the minimum amount of samples, without any fluidic pump. PMID- 28809334 TI - Utilization of an Ionic Liquid/Urea Mixture as a Physical Coupling Agent for Agarose/Talc Composite Films. AB - An ionic liquid, 1-n-butyl-3-methylimidazolium chloride (BmimCl) was blended with urea at 1:1 mole ratio to create a BmimCl/Urea mixture. The agarose/talc composite films containing the BmimCl/Urea mixture were then acquired through a gelation method. The weight ratio of agarose and talc was fixed at 4:1, while the content of BmimCl/Urea was varied from 0 to 10 wt % relative to the overall weight of the composite films. The tensile stress and modulus results showed the optimum BmimCl/Urea content in the composite film lies at 8 wt %. The talc particles are embedded in the agarose matrix and there are no pullouts for the composite films containing BmimCl/Urea as demonstrated by SEM micrographs. The addition of BmimCl/Urea increased the glass transition temperature of the composite films, however, the thermal decomposition temperature decreased drastically. FTIR and FT-Raman spectra indicated the existence of interaction between agarose and talc, which improves their interfacial adhesion. As a conclusion, a BmimCl/Urea mixture can be utilized as a coupling agent for agarose/talc composite films. PMID- 28809335 TI - Hierarchical Fibers with a Negative Poisson's Ratio for Tougher Composites. AB - In this paper, a new kind of hierarchical tube with a negative Poisson's ratio (NPR) is proposed. The first level tube is constructed by rolling up an auxetic hexagonal honeycomb. Then, the second level tube is produced by substituting the arm of the auxetic sheet with the first level tube and rolling it up. The Nth ( ) level tube can be built recursively. Based on the Euler beam theory, the equivalent elastic parameters of the NPR hierarchical tubes under small deformations are derived. Under longitudinal axial tension, instead of shrinking, all levels of the NPR hierarchical tubes expand in the transverse direction. Using these kinds of auxetic tubes as reinforced fibers in composite materials would result in a higher resistance to fiber pullout. Thus, this paper provides a new strategy for the design of fiber reinforced hierarchical bio-inspired composites with a superior pull-out mechanism, strength and toughness. An application with super carbon nanotubes concludes the paper. PMID- 28809332 TI - Advanced Strategies for Articular Cartilage Defect Repair. AB - Articular cartilage is a unique tissue owing to its ability to withstand repetitive compressive stress throughout an individual's lifetime. However, its major limitation is the inability to heal even the most minor injuries. There still remains an inherent lack of strategies that stimulate hyaline-like articular cartilage growth with appropriate functional properties. Recent scientific advances in tissue engineering have made significant steps towards development of constructs for articular cartilage repair. In particular, research has shown the potential of biomaterial physico-chemical properties significantly influencing the proliferation, differentiation and matrix deposition by progenitor cells. Accordingly, this highlights the potential of using such properties to direct the lineage towards which such cells follow. Moreover, the use of soluble growth factors to enhance the bioactivity and regenerative capacity of biomaterials has recently been adopted by researchers in the field of tissue engineering. In addition, gene therapy is a growing area that has found noteworthy use in tissue engineering partly due to the potential to overcome some drawbacks associated with current growth factor delivery systems. In this context, such advanced strategies in biomaterial science, cell-based and growth factor-based therapies that have been employed in the restoration and repair of damaged articular cartilage will be the focus of this review article. PMID- 28809336 TI - Structural and Luminescence Properties of Lu2O3:Eu3+ F127 Tri-Block Copolymer Modified Thin Films Prepared by Sol-Gel Method. AB - Lu2O3:Eu3+ transparent, high density, and optical quality thin films were prepared using the sol-gel dip-coating technique, starting with lutetium and europium nitrates as precursors and followed by hydrolysis in an ethanol-ethylene glycol solution. Acetic acid and acetylacetonate were incorporated in order to adjust pH and as a sol stabilizer. In order to increment the thickness of the films and orient the structure, F127 Pluronic acid was incorporated during the sol formation. Structural, morphological, and optical properties of the films were investigated for different F127/Lu molar ratios (0-5) in order to obtain high optical quality films with enhanced thickness compared with the traditional method. X-ray diffraction (XRD) shows that the films present a highly oriented cubic structure <111> beyond 1073 K for a 3-layer film, on silica glass substrates. The thickness, density, porosity, and refractive index evolution of the films were investigated by means of m-lines microscopy along with the morphology by scanning electron microscope (SEM) and luminescent properties. PMID- 28809337 TI - Behavior of Elastoplastic Auxetic Microstructural Arrays. AB - A continuum-based micromechanical model is employed for the prediction of the elasto-plastic behavior of periodic microstructural arrays that can generate negative values of Poisson's ratios. The combined effects of the negative Poisson's ratio generated by the array microstructure and the elastoplastic behavior of the constituents are studied. A design methodology for the determination of the constituents' properties of two-phase arrays that generate required values of negative Poisson's ratio is considered. PMID- 28809339 TI - Biosynthesis and Characterization of Nanocellulose-Gelatin Films. AB - A nanocellulose-gelatin (bacterial cellulose gelatin (BCG)) film was developed by a supplement of gelatin, at a concentration of 1%-10% w/v, in a coconut-water medium under the static cultivation of Acetobacter xylinum. The two polymers exhibited a certain degree of miscibility. The BCG film displayed dense and uniform homogeneous structures. The Fourier transform infrared spectroscopy (FTIR) results demonstrated interactions between the cellulose and gelatin. Incorporation of gelatin into a cellulose nanofiber network resulted in significantly improved optical transparency and water absorption capacity of the films. A significant drop in the mechanical strengths and a decrease in the porosity of the film were observed when the supplement of gelatin was more than 3% (w/v). The BCG films showed no cytotoxicity against Vero cells. PMID- 28809340 TI - Influence of N2 Partial Pressure on Structure and Mechanical Properties of TiAlN/Al2O3 Multilayers. AB - TiAlN/Al2O3 multilayers with different Ar/N2 ratios were deposited on Si substrates in different N2 partial pressure by magnetron sputtering. The crystalline and multilayer structures of the multilayers were determined by a glancing angle X-ray diffractometer (XRD). A nanoindenter was used to evaluate the hardness, the elastic modulus and scratch scan of the multilayers. The chemical bonding was investigated by a X-ray Photoelectron Spectroscopy (XPS). The maximum hardness (36.3 GPa) and elastic modulus (466 GPa) of the multilayers was obtained when Ar/N2 ratio was 18:1. The TiAlN/Al2O3 multilayers were crystallized with orientation in the (111) and (311) crystallographic planes. The multilayers displayed stably plastic recovery in different Ar/N2 ratios. The scratch scan and post scan surface profiles of TiAlN/Al2O3 multilayers showed the highest critical fracture load (Lc) of 53 mN for the multilayer of Ar/N2 = 18:1. It indicated that the multilayer had better practical adhesion strength and fracture resistance. PMID- 28809338 TI - "Smart" Materials Based on Cellulose: A Review of the Preparations, Properties, and Applications. AB - Cellulose is the most abundant biomass material in nature, and possesses some promising properties, such as mechanical robustness, hydrophilicity, biocompatibility, and biodegradability. Thus, cellulose has been widely applied in many fields. "Smart" materials based on cellulose have great advantages especially their intelligent behaviors in reaction to environmental stimuli-and they can be applied to many circumstances, especially as biomaterials. This review aims to present the developments of "smart" materials based on cellulose in the last decade, including the preparations, properties, and applications of these materials. The preparations of "smart" materials based on cellulose by chemical modifications and physical incorporating/blending were reviewed. The responsiveness to pH, temperature, light, electricity, magnetic fields, and mechanical forces, etc. of these "smart" materials in their different forms such as copolymers, nanoparticles, gels, and membranes were also reviewed, and the applications as drug delivery systems, hydrogels, electronic active papers, sensors, shape memory materials and smart membranes, etc. were also described in this review. PMID- 28809341 TI - Characterization and Stability of Tanshinone IIA Solid Dispersions with Hydroxyapatite. AB - Solid dispersions of tanshinone IIA (TanIIA) using hydroxyapatite (HAp) as the dispersing carrier (TanIIA-HAp SDs) were prepared by the solvent evaporation method. The formed solid dispersions were characterized by scanning electron microscopy (SEM), differential scanning calorimetry analysis (DSC), X-ray powder diffraction (XRPD) and Fourier transforms infrared (FTIR) spectroscopy. The in vitro dissolution rate and the stability of TanIIA-HAp SDs were also evaluated. DSC and XRPD showed that TanIIA was changed from a crystalline to an amorphous form. FTIR suggested the presence of interactions between TanIIA and HAp in solid dispersions. The result of an in vitro dissolution study showed that the dissolution rate of TanIIA-HAp SDs was nearly 7.11-folds faster than free TanIIA. Data from stability studies for over one year of TanIIA-HAp SDs performed under room temperature revealed no significant differences in drug content and dissolution behavior. All these results indicated that HAp may be a promising carrier for improving the oral absorption of TanIIA. PMID- 28809343 TI - Multifunctional Cement Composites Strain and Damage Sensors Applied on Reinforced Concrete (RC) Structural Elements. AB - In this research, strain-sensing and damage-sensing functional properties of cement composites have been studied on a conventional reinforced concrete (RC) beam. Carbon nanofiber (CNFCC) and fiber (CFCC) cement composites were used as sensors on a 4 m long RC beam. Different casting conditions (in situ or attached), service location (under tension or compression) and electrical contacts (embedded or superficial) were compared. Both CNFCC and CFCC were suitable as strain sensors in reversible (elastic) sensing condition testing. CNFCC showed higher sensitivities (gage factor up to 191.8), while CFCC only reached gage factors values of 178.9 (tension) or 49.5 (compression). Furthermore, damage-sensing tests were run, increasing the applied load progressively up to the RC beam failure. In these conditions, CNFCC sensors were also strain sensitive, but no damage sensing mechanism was detected for the strain levels achieved during the tests. Hence, these cement composites could act as strain sensors, even for severe damaged structures near to their collapse. PMID- 28809342 TI - Dye Sensitizers for Photodynamic Therapy. AB - Photofrin(r) was first approved in the 1990s as a sensitizer for use in treating cancer via photodynamic therapy (PDT). Since then a wide variety of dye sensitizers have been developed and a few have been approved for PDT treatment of skin and organ cancers and skin diseases such as acne vulgaris. Porphyrinoid derivatives and precursors have been the most successful in producing requisite singlet oxygen, with Photofrin(r) still remaining the most efficient sensitizer (quantum yield = 0.89) and having broad food and drug administration (FDA) approval for treatment of multiple cancer types. Other porphyrinoid compounds that have received approval from US FDA and regulatory authorities in other countries include benzoporphyrin derivative monoacid ring A (BPD-MA), meta tetra(hydroxyphenyl)chlorin (m-THPC), N-aspartyl chlorin e6 (NPe6), and precursors to endogenous protoporphyrin IX (PpIX): 1,5-aminolevulinic acid (ALA), methyl aminolevulinate (MAL), hexaminolevulinate (HAL). Although no non-porphyrin sensitizer has been approved for PDT applications, a small number of anthraquinone, phenothiazine, xanthene, cyanine, and curcuminoid sensitizers are under consideration and some are being evaluated in clinical trials. This review focuses on the nature of PDT, dye sensitizers that have been approved for use in PDT, and compounds that have entered or completed clinical trials as PDT sensitizers. PMID- 28809344 TI - From Powders to Dense Metal Parts: Characterization of a Commercial AlSiMg Alloy Processed through Direct Metal Laser Sintering. AB - In this paper, a characterization of an AlSiMg alloy processed by direct metal laser sintering (DMLS) is presented, from the analysis of the starting powders, in terms of size, morphology and chemical composition, through to the evaluation of mechanical and microstructural properties of specimens built along different orientations parallel and perpendicular to the powder deposition plane. With respect to a similar aluminum alloy as-fabricated, a higher yield strength of about 40% due to the very fine microstructure, closely related to the mechanisms involved in this additive process is observed. PMID- 28809345 TI - An Efficient Local Molecular Dynamics Polymerization Simulation Combined with an Ab Initio MO Method. AB - A new local ab initio molecular dynamics method, namely elongation molecular dynamics (ELG-MD) is proposed for highly efficient simulations of aperiodic polymer systems. ELG-MD combines the elongation method (ELG) with the Gear predictor corrector (GPC) algorithm of molecular dynamics simulation. In this method, the local gradients acting on the atom's nucleus in the active region are calculated by the ELG method while the equations of the nucleus's motion are solved by the GPC algorithm. In this work, the first application of this ELG-MD method is described to investigate the stable conformation of polyglycine with surrounding water molecules. The water effects on the structure of polyglycine are examined. The ELG-MD simulations show that the formation of the polyglycine helix is strongly induced by the hydrogen bonds observed in two types of H-bond rings. PMID- 28809346 TI - Electronic Two-Transition-Induced Enhancement of Emission Efficiency in Polymer Light-Emitting Diodes. AB - With the development of experimental techniques, effective injection and transportation of electrons is proven as a way to obtain polymer light-emitting diodes (PLEDs) with high quantum efficiency. This paper reveals a valid mechanism for the enhancement of quantum efficiency in PLEDs. When an external electric field is applied, the interaction between a negative polaron and triplet exciton leads to an electronic two-transition process, which induces the exciton to emit light and thus improve the emission efficiency of PLEDs. PMID- 28809347 TI - Ultrafast Transient Spectroscopy of Polymer/Fullerene Blends for Organic Photovoltaic Applications. AB - We measured the picoseconds (ps) transient dynamics of photoexcitations in blends of regio-regular poly(3-hexyl-thiophene) (RR-P3HT) (donors-D) and fullerene (PCBM) (acceptor-A) in an unprecedented broad spectral range of 0.25 to 2.5 eV. In D-A blends with maximum domain separation, such as RR-P3HT/PCBM, with (1.2:1) weight ratio having solar cell power conversion efficiency of ~4%, we found that although the intrachain excitons in the polymer domains decay within ~10 ps, no charge polarons are generated at their expense up to ~1 ns. Instead, there is a build-up of charge-transfer (CT) excitons at the D-A interfaces having the same kinetics as the exciton decay. The CT excitons dissociate into separate polarons in the D and A domains at a later time (>1 ns). This "two-step" charge photogeneration process may be typical in organic bulk heterojunction cells. We also report the effect of adding spin 1/2 radicals, Galvinoxyl on the ultrafast photoexcitation dynamics in annealed films of RR-P3HT/PCBM blend. The addition of Galvinoxyl radicals to the blend reduces the geminate recombination rate of photogenerated CT excitons. In addition, the photoexcitation dynamics in a new D A blend of RR-P3HT/Indene C60 trisadduct (ICTA) has been studied and compared with the dynamics in RR-P3HT/PCBM. PMID- 28809349 TI - Effects of Hydrolysed Whey Proteins on the Techno-Functional Characteristics of Whey Protein-Based Films. AB - Pure whey protein isolate (WPI)-based cast films are very brittle due to its strong formation of protein cross-linking of disulphide bonding, hydrogen bonding as well as hydrophobic and electrostatic interactions. However, this strong cross linking is the reason for its final barrier performance. To overcome film brittleness of whey protein layers, plasticisers like glycerol are used. It reduces intermolecular interactions, increases the mobility of polymer chains and thus film flexibility can be achieved. The objective of this study was to investigate the influence of hydrolysed whey protein isolate (WPI) in whey protein isolate-based cast films on their techno-functional properties. Due to the fact, that the addition of glycerol is necessary but at the same time increases the free volume in the film leading to higher oxygen and water vapour permeability, the glycerol concentration was kept constant. Cast films with different ratios of hydrolysed and not hydrolysed WPI were produced. They were characterised in order to determine the influence of the lower molecular weight caused by the addition of hydrolysed WPI on the techno-functional properties. This study showed that increasing hydrolysed WPI concentrations significantly change the mechanical properties while maintaining the oxygen and water vapour permeability. The tensile and elastic film properties decreased significantly by reducing the average molecular weight whereas the yellowish coloration and the surface tension considerably increased. This study provided new data which put researchers and material developers in a position to tailor the characteristics of whey protein based films according to their intended application and further processing. PMID- 28809348 TI - Covalently Bonded Chitosan on Graphene Oxide via Redox Reaction. AB - Carbon nanostructures have played an important role in creating a new field of materials based on carbon. Chemical modification of carbon nanostructures through grafting has been a successful step to improve dispersion and compatibility in solvents, with biomolecules and polymers to form nanocomposites. In this sense carbohydrates such as chitosan are extremely valuable because their functional groups play an important role in diversifying the applications of carbon nanomaterials. This paper reports the covalent attachment of chitosan onto graphene oxide, taking advantage of this carbohydrate at the nanometric level. Grafting is an innovative route to modify properties of graphene, a two dimensional nanometric arrangement, which is one of the most novel and promising nanostructures. Chitosan grafting was achieved by redox reaction using different temperature conditions that impact on the morphology and features of graphene oxide sheets. Transmission Electron Microscopy, Fourier Transform Infrared, Raman and Energy Dispersive spectroscopies were used to study the surface of chitosan grafted-graphene oxide. Results show a successful modification indicated by the functional groups found in the grafted material. Dispersions of chitosan-grafted graphene oxide samples in water and hexane revealed different behavior due to the chemical groups attached to the graphene oxide sheet. PMID- 28809350 TI - A Special Material or a New State of Matter: A Review and Reconsideration of the Aerogel. AB - The ultrahighly nanoporous aerogel is recognized as a state of matter rather than as a functional material, because of its qualitative differences in bulk properties, transitional density and enthalpy between liquid and gas, and diverse chemical compositions. In this review, the characteristics, classification, history and preparation of the aerogel were introduced. More attention was paid to the sol-gel method for preparing different kinds of aerogels, given its important role on bridging the synthetic parameters with the properties. At last, preparation of a novel single-component aerogel, design of a composite aerogel and industrial application of the aerogel were regarded as the research tendency of the aerogel state in the near future. PMID- 28809351 TI - Preparation of Amidoxime Polyacrylonitrile Chelating Nanofibers and Their Application for Adsorption of Metal Ions. AB - Polyacrylonitrile (PAN) nanofibers were prepared by electrospinning and they were modified with hydroxylamine to synthesize amidoxime polyacrylonitrile (AOPAN) chelating nanofibers, which were applied to adsorb copper and iron ions. The conversion of the nitrile group in PAN was calculated by the gravimetric method. The structure and surface morphology of the AOPAN nanofiber were characterized by a Fourier transform infrared spectrometer (FT-IR) and a scanning electron microscope (SEM), respectively. The adsorption abilities of Cu2+ and Fe3+ ions onto the AOPAN nanofiber mats were evaluated. FT-IR spectra showed nitrile groups in the PAN were partly converted into amidoxime groups. SEM examination demonstrated that there were no serious cracks or sign of degradation on the surface of the PAN nanofibers after chemical modification. The adsorption capacities of both copper and iron ions onto the AOPAN nanofiber mats were higher than those into the raw PAN nanofiber mats. The adsorption data of Cu2+ and Fe3+ ions fitted particularly well with the Langmuir isotherm. The maximal adsorption capacities of Cu2+ and Fe3+ ions were 215.18 and 221.37 mg/g, respectively. PMID- 28809352 TI - Grafting of Amines on Ethanol-Extracted SBA-15 for CO2 Adsorption. AB - SBA-15 prepared via ethanol extraction for template removing was grafted with three kinds of amine precursors (mono-, di-, tri-aminosilanes) to synthesis new CO2 adsorbents. The SBA-15 support and the obtained adsorbents were characterized by X-ray diffraction (XRD), small-angle X-ray scattering (SAXS), N2 adsorption/desorption, thermogravimetry (TG), elemental analysis, Fourier transform infrared (FTIR) spectrometry, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). It was found that, except higher silanol density, the ethanol-extracted SBA-15 support possessed a more regular mesophase and thicker walls than traditionally calcined samples, leading to a good stability of the adsorbent under steam treatment. The adsorption capacity of different amine-grafted samples was found to be influenced by not only the surface amine density, but also their physiochemical properties. These observations provide important support for further studies of applying amine grafted adsorbents in practical CO2 capture process. PMID- 28809353 TI - Cosmetic Analysis Using Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MALDI-MSI). AB - A new "omic" platform-Cosmetomics-that proves to be extremely simple and effective in terms of sample preparation and readiness for data acquisition/interpretation is presented. This novel approach employing Matrix Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MALDI-MSI) for cosmetic analysis has proven to readily identify and quantify compounds of interest. It also allows full control of all the production phases, as well as of the final product, by integration of both analytical and statistical data. This work has focused on products of daily use, namely nail polish, lipsticks and eyeliners of multiple brands sold in the worldwide market. PMID- 28809354 TI - Graphene versus Multi-Walled Carbon Nanotubes for Electrochemical Glucose Biosensing. AB - : A simple procedure was developed for the fabrication of electrochemical glucose biosensors using glucose oxidase (GOx), with graphene or multi-walled carbon nanotubes (MWCNTs). Graphene and MWCNTs were dispersed in 0.25% 3 aminopropyltriethoxysilane (APTES) and drop cast on 1% KOH-pre-treated glassy carbon electrodes (GCEs). The EDC (1-ethyl-(3-dimethylaminopropyl) carbodiimide) activated GOx was then bound covalently on the graphene- or MWCNT-modified GCE. Both the graphene- and MWCNT-based biosensors detected the entire pathophysiological range of blood glucose in humans, 1.4-27.9 mM. However, the direct electron transfer (DET) between GOx and the modified GCE's surface was only observed for the MWCNT-based biosensor. The MWCNT-based glucose biosensor also provided over a four-fold higher current signal than its graphene counterpart. Several interfering substances, including drug metabolites, provoked negligible interference at pathological levels for both the MWCNT- and graphene based biosensors. However, the former was more prone to interfering substances and drug metabolites at extremely pathological concentrations than its graphene counterpart. PMID- 28809355 TI - Advanced Electrodes for High Power Li-ion Batteries. AB - While little success has been obtained over the past few years in attempts to increase the capacity of Li-ion batteries, significant improvement in the power density has been achieved, opening the route to new applications, from hybrid electric vehicles to high-power electronics and regulation of the intermittency problem of electric energy supply on smart grids. This success has been achieved not only by decreasing the size of the active particles of the electrodes to few tens of nanometers, but also by surface modification and the synthesis of new multi-composite particles. It is the aim of this work to review the different approaches that have been successful to obtain Li-ion batteries with improved high-rate performance and to discuss how these results prefigure further improvement in the near future. PMID- 28809356 TI - Photoluminescence Study of Gallium Nitride Thin Films Obtained by Infrared Close Space Vapor Transport. AB - Photoluminescence (PL) studies in GaN thin films grown by infrared close space vapor transport (CSVT-IR) in vacuum are presented in this work. The growth of GaN thin films was done on a variety of substrates like silicon, sapphire and fused silica. Room temperature PL spectra of all the GaN films show near band-edge emission (NBE) and a broad blue and green luminescence (BL, GL), which can be seen with the naked eye in a bright room. The sample grown by infrared CSVT on the silicon substrate shows several emission peaks from 2.4 to 3.22 eV with a pronounced red shift with respect to the band gap energy. The sample grown on sapphire shows strong and broad ultraviolet emission peaks (UVL) centered at 3.19 eV and it exhibits a red shift of NBE. The PL spectrum of GaN films deposited on fused silica exhibited a unique and strong blue-green emission peak centered at 2.38 eV. The presence of yellow and green luminescence in all samples is related to native defects in the structure such as dislocations in GaN and/or the presence of amorphous phases. We analyze the material quality that can be obtained by CSVT-IR in vacuum, which is a high yield technique with simple equipment set-up, in terms of the PL results obtained in each case. PMID- 28809357 TI - Quinacridone-Diketopyrrolopyrrole-Based Polymers for Organic Field-Effect Transistors. AB - Incorporation of pigment or dye molecules as building units is of great interest in the development of semiconducting polymers, due to their strong intermolecular interactions arising from the strong local dipoles in the unit structure, which would facilitate the charge transport property. In this paper, semiconducting polymers based on well-known pigments, namely, quinacridone and diketopyrrolopyrrole, are synthesized and characterized. The pi-stacking distances are found to be 3.5-3.8 A, which is fairly narrow for semiconducting polymers, indicating that they possess strong intermolecular interactions. Interestingly, polymer orientation is influenced by the composition of alkyl side chains. While the edge-on orientation is observed when the linear alkyl groups are introduced for all the side chains, the face-on orientation is observed when the branched alkyl groups are introduced either in the quinacridone or diketopyrrolopyrrole unit. It is found that the electronic structure of the present polymers is mostly affected by that of the diketopyrrolopyrrole unit, as evidenced by the absorption spectra and computation. Although the field-effect mobility of the polymers is modest, i.e., in the order of 10-4-10-3 cm2/Vs, these findings could be important information for the development of semiconducting polymers. PMID- 28809358 TI - Thermo-Mechanical Behavior of Textile Heating Fabric Based on Silver Coated Polymeric Yarn. AB - This paper presents a study conducted on the thermo-mechanical properties of knitted structures, the methods of manufacture, effect of contact pressure at the structural binding points, on the degree of heating. The test results also present the level of heating produced as a function of the separation between the supply terminals. The study further investigates the rate of heating and cooling of the knitted structures. The work also presents the decay of heating properties of the yarn due to overheating. Thermal images were taken to study the heat distribution over the surface of the knitted fabric. A tensile tester having constant rate of extension was used to stretch the fabric. The behavior of temperature profile of stretched fabric was observed. A comparison of heat generation by plain, rib and interlock structures was studied. It was observed from the series of experiments that there is a minimum threshold force of contact at binding points of a knitted structure is required to pass the electricity. Once this force is achieved, stretching the fabric does not affect the amount of heat produced. PMID- 28809360 TI - Recent Advances in Creep Modelling of the Nickel Base Superalloy, Alloy 720Li. AB - Recent work in the creep field has indicated that the traditional methodologies involving power law equations are not sufficient to describe wide ranging creep behaviour. More recent approaches such as the Wilshire equations however, have shown promise in a wide range of materials, particularly in extrapolation of short term results to long term predictions. In the aerospace industry however, long term creep behaviour is not critical and more focus is required on the prediction of times to specific creep strains. The current paper illustrates the capability of the Wilshire equations to recreate full creep curves in a modern nickel superalloy. Furthermore, a finite-element model based on this method has been shown to accurately predict stress relaxation behaviour allowing more accurate component lifing. PMID- 28809359 TI - Towards a Consensus View on Understanding Nanomaterials Hazards and Managing Exposure: Knowledge Gaps and Recommendations. AB - The aim of this article is to present an overview of salient issues of exposure, characterisation and hazard assessment of nanomaterials as they emerged from the consensus-building of experts undertaken within the four year European Commission coordination project NanoImpactNet. The approach adopted is to consolidate and condense the findings and problem-identification in such a way as to identify knowledge-gaps and generate a set of interim recommendations of use to industry, regulators, research bodies and funders. The categories of recommendation arising from the consensual view address: significant gaps in vital factual knowledge of exposure, characterisation and hazards; the development, dissemination and standardisation of appropriate laboratory protocols; address a wide range of technical issues in establishing an adequate risk assessment platform; the more efficient and coordinated gathering of basic data; greater inter-organisational cooperation; regulatory harmonization; the wider use of the life-cycle approaches; and the wider involvement of all stakeholders in the discussion and solution-finding efforts for nanosafety. PMID- 28809361 TI - Applications of Carbon Nanotubes for Lithium Ion Battery Anodes. AB - Carbon nanotubes (CNTs) have displayed great potential as anode materials for lithium ion batteries (LIBs) due to their unique structural, mechanical, and electrical properties. The measured reversible lithium ion capacities of CNT based anodes are considerably improved compared to the conventional graphite based anodes. Additionally, the opened structure and enriched chirality of CNTs can help to improve the capacity and electrical transport in CNT-based LIBs. Therefore, the modification of CNTs and design of CNT structure provide strategies for improving the performance of CNT-based anodes. CNTs could also be assembled into free-standing electrodes without any binder or current collector, which will lead to increased specific energy density for the overall battery design. In this review, we discuss the mechanism of lithium ion intercalation and diffusion in CNTs, and the influence of different structures and morphologies on their performance as anode materials for LIBs. PMID- 28809363 TI - Factors Affecting the Effectiveness of Inorganic Silicate Sealer Material through Multi-Quality Characteristics. AB - This study investigates the effectiveness of concrete protection with two inorganic silicate sealer materials (ISSMs). The Taguchi method and grey relational analysis (GRA) have been used to identify the key factors influencing concrete protection provided by the surface treatment. Seven control factors with two levels were selected. By using the orthogonal array L12 (27), 12 experiments are chosen and four tests-the compressive strength test, resistivity test, absorption test and permeability test-were performed. Results have shown that the major factors affecting the protection effectiveness of ISSM are the water-binder ratio of mortar substrate, age of substrate for sealer application, addition of pozzolanic material and sealer type. PMID- 28809362 TI - Polymeric Thin Films for Organic Electronics: Properties and Adaptive Structures. AB - This review deals with the correlation between morphology, structure and performance of organic electronic devices including thin film transistors and solar cells. In particular, we report on solution processed devices going into the role of the 3D supramolecular organization in determining their electronic properties. A selection of case studies from recent literature are reviewed, relying on solution methods for organic thin-film deposition which allow fine control of the supramolecular aggregation of polymers confined at surfaces in nanoscopic layers. A special focus is given to issues exploiting morphological structures stemming from the intrinsic polymeric dynamic adaptation under non equilibrium conditions. PMID- 28809364 TI - Clinician-related factors behind the decision to extract an asymptomatic lower third molar. A cross-sectional study based on Spanish and Portuguese dentists. AB - BACKGROUND: Scientific literature estimates that around 18 to 40 % of asymptomatic third molars are extracted. The aims of the present study were to determine the indications for extraction of asymptomatic lower third molars in a sample of Spanish and Portuguese dentists, and to relate these indications to the clinicians' training and professional experience. MATERIAL AND METHODS: A survey consisting of 15 cases of asymptomatic lower third molars was emailed to Portuguese and Spanish dentists. The clinicians were asked to assess the level of difficulty of the extractions and to make a reasoned recommendation based on the panoramic radiographs, gender and age of the patients. RESULTS: 381 clinicians filled in the questionnaires. Most of the professionals had over 13 years of clinical experience. The number of Spanish clinicians with postgraduate degrees in Oral Surgery was significantly higher. On average, 42% of respondents recommended extraction of asymptomatic third molars. The indication for extraction was significantly higher among Portuguese dentists. Clinical experience was negatively correlated with the perceived extraction difficulty (p<0.05). The main reason given for extracting was the prevention of pericoronitis, whereas that for not extracting was the absence of a clear indication and the risk of injuring the inferior alveolar nerve. CONCLUSIONS: The Portuguese dentists were more in favour of removing asymptomatic lower third molars than the Spanish dentists, although the latter had a higher proportion of professionals with postgraduate studies in Oral Surgery. PMID- 28809365 TI - Type of surgical treatment and recurrence of oral leukoplakia: A retrospective clinical study. AB - BACKGROUND: Oral leukoplakia (OL) is the most typical potentially malignant disorder of the oral mucosa. We aimed to evaluate the clinical outcome of oral leukoplakia treated with several types of lasers and with the use of quantic molecular resonance (QMR) lancet, in terms of recurrence rate. MATERIAL AND METHODS: Eighty-seven previously untreated OL (52 occurring in females and 35 in males, mean age of 59.4 +/- 13.9 years) were consecutively submitted to surgical treatment at University Hospital of Parma, Italy, and Hospital de Valongo, Portugal, (1999 to 2012). Interventions were subclassified into 5 groups according to the instrument used for the surgical removal of OL (cold blade - 17; Nd:YAG 1064nm laser - 14; Er:YAG 2940nm laser - 33; CO2 10600nm laser - 15; and QMR scalpel - 8). The mean follow-up period after treatment was 21.6 months (range 1-151 months). The outcome of treatment was scored through the same clinical protocol in the two participating units. Statistical analysis were carried by univariate analysis using chi-square test (or Pearson's test when appropriate). RESULTS: Recurrences were observed in 24 cases of OL (27.6%). Malignant transformation occurred in one patient (1.1%) after a period of 35 months. Statistical comparison of the 5 surgical treatment modalities showed no differences in clinical outcomes nor in the recurrence rate of OL. However, when Er:YAG laser group was compared with traditional scalpel, a significantly better outcome in cases treated with Er:YAG laser (P = 0.015) was highlighted. CONCLUSIONS: Our results suggests that Er:YAG laser could be a promising option for the treatment of OL. PMID- 28809366 TI - Oral manifestations of Diabetes Mellitus. A systematic review. AB - BACKGROUND: Diabetes Mellitus has become a global epidemic and presents many complications, usually proportional to the degree and duration of hyperglycemia. The aim of this systematic review was to investigate the different oral manifestations associated with Diabetes Mellitus. MATERIAL AND METHODS: A MEDLINE search for "Diabetes Mellitus and oral manifestations" was performed. A further search was conducted for "diabetes" and its individual oral manifestation. Inclusion criteria were as follows: human clinical studies with a minimum of 30 patients; studies published in relevant scientific journals between January 1998 and January 2016. Nineteen studies fulfilled the inclusion criteria and were analyzed, assessing the strength of scientific evidence according to recommendations made by the Centre for Evidence-Based Medicine, Oxford (OCEBM), which permits adequate assessment of prevalence studies. RESULTS: A total 3,712 patients (2,084 diabetics) were included in the studies reviewed. Of the 19 studies analyzed, 4 were longitudinal studies and 15 cross-sectional studies. Periodontal disease, periapical lesions, xerostomia and taste disturbance were more prevalent among diabetic patients. An association between diabetes and caries and mucosal lesions proved positive in 5 out of 10 studies. CONCLUSIONS: Despite multiple oral manifestations associated with DM, awareness of the associations between diabetes, oral health, and general health is inadequate. It is necessary for doctors and dentists to be aware of the various oral manifestations of diabetes in order to make an early diagnosis. PMID- 28809367 TI - Root caries analysis in working population of 35-44 years of age (Spain). AB - BACKGROUND: The aim of this study was to analyse the influence of socio demographic variables, toothbrushing frequency, frequency of snacking between meals, and tobacco and alcohol consumption, in root caries in the Spanish working population of Valencia and Murcia regions. MATERIAL AND METHODS: Cross sectional study of 458 workers 35-44 years of age, who underwent a routine work-related check-up, from June 2009 to April 2010, and were also examined, following the WHO methodology, by a calibrated dentist. Stratified random sampling. Participants fulfilled a questionnaire comprising demographic data, toothbrushing frequency, snacking frequency and tobacco and alcohol consumption. RESULTS: The DFS index (root caries) in the employed population of 35-44 years was 0.45 +/- 1.3, with a root caries prevalence of 18.6% and an active root caries prevalence of 13.5%. Higher root caries prevalence and active root caries prevalence were associated with male gender, manual occupations, foreign country of origin, lower levels of education and income, lower brushing frequency and higher frequency of snacking between meals. The DFS index was associated with all studied socio-demographic variables, but gender, and it was also associated with brushing frequency. The mean number of root decayed teeth was associated with all socio-demographic variables, but country of origin, and it was also associated with brushing frequency. CONCLUSIONS: Adult workers 35-44 years of age showed worse root condition in regard to caries than general population of this age cohort. In this study, the frequency of toothbrushing and snacking between meals were the variables that influenced more in root caries. PMID- 28809368 TI - Deep neck infections: A single-center analysis of 63 cases. AB - BACKGROUND AND PURPOSE: With the use of antibiotic therapy, the incidence of deep neck infections has decreased in recent decades. The aim of this investigation was to review the clinical course and the management of deep neck infections in our department, compare them to the experiences of the common literature and identify predisposing factors for lethal complications. MATERIAL AND METHODS: In this single-center analysis, 63 patients with deep neck infections were treated surgically. The following clinical data were analyzed and compared: age, gender, laboratory data, spatial manifestation, therapeutic modalities, comorbidities, length of hospitalization and complications. RESULTS: There was a predominance of male patients (58.7%) and a mean age of 57.9 years. The most common symptoms at diagnosis were sore throat (96.8%) and neck swelling (92.0%). Cardio/pulmonary diseases and diabetes mellitus were the most common comorbidities. There was a significantly longer hospital stay for patients with diabetes mellitus. The most common manifestation was a parapharyngeal abscess in 24 patients (38.1%), followed by peri-/retrotonsillar infections in 19 patients (30.2%). In 29 patients, a multiple space infection was observed, with a significantly longer duration of hospitalization and a higher rate of complications. The main life threatening complication was the development of airway obstruction in 20 patients (31.7%), who all received a tracheostomy. The duration of hospitalization for patients with complications was significantly longer. CONCLUSION: Close attention must be paid to the management of patients with deep neck infections, especially patients with diabetes mellitus and cardio/pulmonary diseases or patients with multiple space infections. PMID- 28809370 TI - Marsupialization facilitates movement of the cystic lesion-associated deeply impacted mandibular third molar in spite of its mature roots. AB - BACKGROUND: The odontogenic cystic lesions happened in the angle and ramus region are frequently associated with impacted mandibular third molars. The treatment plan was difficult to work out for the huge cystic lesions with deeply impacted third molars, since the enucleation with simultaneously removing the deeply impacted teeth may cause serious complications. Therefore, the marsupialization of the cystic lesions followed by enucleation with tooth removal has also been advocated. The aim of this study was to explore the movement of cystic lesion associated deeply impacted mandibular third molars (IMTM) after marsupialization. MATERIALS AND METHODS: Between July 2009 and December 2015, patients who had mandibular cystic lesion associated with IMTM and underwent marsupialization followed by enucleation with tooth extraction were included in our retrospective study. The clinical and pathological data was collected. The distance and direction of movement of the IMTM after marsupialization was measured on panoramic radiograph and computed tomography. RESULTS: Four male and six female patients whose ages ranged from 14 years to 67 years were enrolled in this study. Among the all impacted molars, there were 3 cases with mature roots. After marsupialization, all the cystic lesions shrunk and all impacted teeth moved toward the bony windows, and the distance of tooth movement were from 8.3mm to 12.1mm. The complications included swelling and pain, while no numbness of the ipsilateral lower lip was happened. CONCLUSIONS: Marsupialization can promote the movement of impacted teeth with or without mature roots, and may be an optimal treatment approach for the huge posterior mandibular cystic lesions with deeply impacted third molar. PMID- 28809369 TI - Maxillofacial fracture epidemiology and treatment plans in the Northeast of Iran: A retrospective study. AB - BACKGROUND: The epidemiology of facial injuries varies based on lifestyle, cultural background and socioeconomic status in different countries and geographic zones. This study evaluated the epidemiology of maxillofacial fractures and treatment plans in hospitalized patients in Northeast of Iran (2015 2016). MATERIAL AND METHODS: In this retrospective study, the medical records of 502 hospitalized patients were evaluated in the Department of Maxillofacial Surgery in Kamyab Hospital in Mashhad, Iran. The type and cause of fractures and treatment plans were recorded in a checklist. Data were analyzed with Mann Whitney test, chi-squared test and Fisher's exact test, using SPSS 21. RESULTS: The majority of patients were male (80.3%). Most subjects were in 20-30-year age range (43.2%). The fractures were mostly caused by accidents, particularly motorcycle accidents (MCAs), and the most common site of involvement was the body of the mandible. There was a significant association between the type of treatment and age. In fact, the age range of 16-59 years underwent open reduction internal fixation (ORIF) more than other age ranges (P=0.001). Also, there was a significant association between gender and fractures (P=0.002). CONCLUSIONS: It was concluded that patient age and gender and trauma significantly affected the prevalence of maxillofacial traumas, fracture types and treatment plans. This information would be useful for making better health policy strategies. PMID- 28809371 TI - The role of microRNAs in oral lichenoid disorders. Systematic review. AB - BACKGROUND: Certain changes in the microRNA expression are considered to be associated with chronic inflammatory processes and with the malignant transformation of oral potentially malignant disorders. The purpose of this systematic review is to update the existing data on the aberrant microRNA expression profiles identified in oral lichenoid disease (OLD). MATERIAL AND METHODS: A search in PubMed-Medline and Scopus was performed on the English literature published between 2010 and August 2016 using the following keywords: oral lichenoid disease, oral lichen planus and microRNA. RESULTS: Originally, 25 articles were considered, of which 12 case-control articles were selected according to the inclusion/exclusion criteria. CONCLUSIONS: OLD seems to have altered microRNA expression profile. Certain altered microRNAs (146a, 155) may be useful as biomarkers for this disorder. More studies including larger number of cases are needed in order to study further on the biological processes and on the regulation pathways of these altered microRNAs. PMID- 28809372 TI - Coffee is protective against oral and pharyngeal cancer: A systematic review and meta-analysis. AB - OBJECTIVES: Coffee is one of the most popular and consumable drinks worldwide. However, there are conflicting results on the influence of this drink in oral and pharyngeal cancer risk. To clarify this, we aimed to systemically review and carry out a meta-analysis of the relevant literature on the association between coffee and oral and pharyngeal cancer. STUDY DESIGN: We carried out an electronic search of publications up to August 2016 from PubMed, National Library of Medicines Medline, Embase, Science Direct and the Cochrane Central Register. The Newcastle-Ottawa scale was used to address the quality of the studies a meta analysis was carried out using random-effects models. RESULTS: From the 22,515 entries identified in the search, 13 case-control and 4 cohort studies were selected. With regards to quality on the Newcastle-Ottawa scale, an overall value of 6.06 was obtained. The analysis for oral and pharyngeal cancer grouped together indicated a pooled OR of .69 (95% CI of .57-.84; p<.001) for high versus low coffee consumption with a moderate heterogeneity (I2: 50.3%; p=.009). Regarding studies on oral cavity cancers we observed a pooled OR of 0.82; 95% CI =.58-1.16; p=.257) and for pharyngeal cancers a pooled OR of .72 (95% CI of 0.54 .95; p=.019). There was no significant publication bias. CONCLUSION: The results show an inverse association between high coffee consumption and the risk of oral and pharyngeal cancers, which indicates that coffee may have a protective role against these cancers. Further larger prospective observational cohort studies are needed to address any effect of other possible co-factors. PMID- 28809373 TI - Scoring systems for Oral Lichen Planus used by differently experienced raters. AB - BACKGROUND: Scoring systems have been widely used to evaluate the severity and activity of oral lichen planus (OLP). The aim of the present study was to compare two existing (one modified) scoring systems in the evaluation of OLP severity and correlation with pain. Three differently experienced raters were involved. MATERIALS AND METHODS: Consecutive patients with OLP were assessed for pain using the Visual Analogue Scale and examined at 10 intraoral sites before starting (T0) and three weeks after (T1) steroid therapy (Clobetasol). Three differently experienced raters evaluated photographs using two scoring systems designated White-Erosive-Atrophic (WEA) modified from an older WEA system (WEA-MOD) and Reticular-erythematous-Ulcerative (REU) systems. WEA-MOD Kendall's W and interclass correlation coefficient were calculated and correlation between REU/WEA-MOD and pain was calculated using Spearman coefficient. RESULTS: Most patients showed lesions on buccal mucosa (85-93,5%) and maxillary/mandibular gingivae (31,8-31,2%), predominantly reticular. At T0, Kendall-W coefficients of 0.89 and 0.74 were obtained for the REU and WEA respectively. At T1, Kendall-W coefficients of 0.83 and 0.58 were obtained for the REU and WEA respectively. Interclass correlation coefficient ranged from 0.87 to 0.90 for REU and from 0.58 to 0.87 for WEA. REU and WEA scores significantly decreased after therapy (p<0.000) as well as VAS (p<0.05). REU score showed correlation with VAS. CONCLUSION: All the raters achieved comparable measures using REU whereas WEA and WEA-MOD seem less reproducible. REU seems to correlate to disease activity and pain. PMID- 28809374 TI - New horizons in anticoagulation: Direct oral anticoagulants and their implications in oral surgery. AB - BACKGROUND: Thrombotic disorders remain a leading cause of death in the Western World. For decades, vitamin K antagonists used in the prevention of this pathology, such as warfarin or sintrom, were the only oral agents available for long-term anticoagulation, in spite of their disadvantages. MATERIAL AND METHODS: An electronic database search was carried out on MedLine and The Cochrane Library Plus, without restrictions on the type of study nor dates, in English and Spanish. Abstracts were reviewed, and complete articles if necessary, considering all articles that included recommendations on DOACs and oral surgery. RESULTS: In recent years, the so-called "new oral anticoagulants" have been introduced in clinical practice to treat those patients whose medical conditions require long term anticoagulant treatment, replacing traditional oral anticoagulants. CONCLUSIONS: The new oral anticoagulants represent new therapeutic options, with a number of advantages such as poor interaction with food, minor drug interactions, and do not require periodic dose adjustments or routine controls. The purpose of this review is to establish an update on the new oral anticoagulants: Dabigatran, Rivarozaban, Apixaban and Edoxaban. PMID- 28809375 TI - Clinical parameters of implants placed in healed sites using flapped and flapless techniques: A systematic review. AB - BACKGROUND: Dental implant placement using flapless surgery is a minimally invasive technique that improves blood supply compared with flapped surgery. However, the flapless technique does not provide access to allow bone regeneration. OBJECTIVE: The aim of this systematic review was to evaluate the clinical parameters following implant surgery in healed sites, using two procedures: flapped vs. flapless surgery. MATERIALS AND METHODS: A detailed electronic search was carried out in the PubMed/Medline, Embase and Cochrane Library databases. The focused question was, "How do flapped and flapless surgical techniques affect the clinical parameters of dental implants placed in healed sites?". All the studies included with a prospective controlled design were considered separately, depending on whether they had been conducted on animals or humans. The following data were recorded in all the included studies: number of implants, failures, location (maxilla, mandible), type of rehabilitation (partial or single), follow-up and flap design. The variables selected for comparison in the animal studies were the following: flap design, gingival index, mucosal height, recession and probing pocket depth. In humans studies the variables were as follows: flap design, plaque index, gingival index, recession, probing pocket depth, papilla index and keratinized gingiva. RESULTS: Ten studies were included, six were experimental studies and four were clinical studies. Studies in animals showed better results using the flapless technique in the parameters analyzed. There is no consensus in the clinical parameters analyzed in human studies, but there is a trend to better results using flapless approach. CONCLUSION: The animal studies included in the present review show that implants placed in healed sites with a flapless approach have better clinical parameters than the flapped procedure in a short-term follow-up. In human studies, there is no consensus about which technique offer better results in terms of clinical parameters. Therefore, more research in humans is required in order to overcome the limitations and contrast these results. PMID- 28809377 TI - Health-related quality of life of patients with zygomatic fracture. AB - BACKGROUND: The objective was to evaluate health-related quality of life (HRQoL) before and after surgical treatment of zygomatic complex fracture and assess patients' perceptions of the aesthetic and functional outcomes of surgery. MATERIAL AND METHODS: A prospective study of 79 adult patients before and after surgery for zygomatic complex fracture was conducted. HRQoL was measured using the generic 15-dimensional (15D) instrument, and patient satisfaction was assessed by an additional questionnaire. RESULTS: The mean preoperative 15D score for patients was lower than for general population that was matched for age and gender (p=0.011). The mean 15D score was lowest on the first postoperative day (p<0.001) when patients were worse off for 6 of the 15 dimensions of the HRQoL instrument and better off for three dimensions. However, patients achieved, and even exceeded, the mean 15D score of the general population during the first month following surgery. Infraorbital sensory loss at the end of the six-month follow-up appeared to be the single most important factor that plagued the patients. CONCLUSIONS: HRQoL is significantly reduced after trauma but improves a few weeks after surgery. Infraorbital nerve sensory loss is a notable long-term factor that affects patients after zygomatic complex fracture. PMID- 28809376 TI - Inferior alveolar nerve trajectory, mental foramen location and incidence of mental nerve anterior loop. AB - OBJECTIVES: Injury of the inferior alveolar nerve (IAN) is a serious intraoperative complication that may occur during routine surgical procedures, such as dental implant placement or extraction of impacted teeth. Thus, the purpose of this study was to analyze the trajectory of the mandibular canal (MC), the location of the mental foramen (MF) and the presence and extension of an anterior loop of the mental nerve (AL). STUDY DESIGN: In this cross-sectional study, a total of 348 CBCTs were analyzed. Distances from MC to the surface of the basal, medial and lateral cortical of the mandible were measured at the level of the second molar, first molar and second premolar. Location of the MF relative to the apices of the premolars, as well as incidence and anterior extent of the AL were also determined. RESULTS: Significant and clinically relevant correlations were found between the position of the MC in women, which was located more caudal (r=-0.219, p=0.007; r=-0.276, p<0.001; right and left, respectively) and lateral (r=-0.274, p=0.001; r=-0.285, p<0.001; right and left, respectively), particularly at the level of the premolars. Additionally, the presence (r=-0.181, p=0.001; r=-0.163, p=0.002; right and left, respectively) and anterior extension (r=-0.180, p=0.009; r=-0.285, p=0.05; right and left, respectively) of the AL was found to be inversely correlated with the age of the patient. CONCLUSIONS: This analysis of a Caucasian population has found that the older the patient, the lower the incidence of the loop and the shorter its anterior extension. PMID- 28809378 TI - Reduction rate by decompression as a treatment of odontogenic cysts. AB - BACKGROUND: Odontogenic cysts are defined as those cysts that arise from odontogenic epithelium and occur in the tooth-bearing regions of the jaws. Cystectomy, marsupialization or decompression of odontogenic cyst are treatment approach to this pathology. The aim of this study was to evaluate the effectiveness of the decompression as the primary treatment of the cystic lesions of the jaws and them reduction rates involving different factors. MATERIAL AND METHODS: 23 patients with odontogenic cysts of the jaws, previously diagnosed by anatomical histopathology (follicular cysts (7) and radicular cysts (16)) underwent decompression as an initial treatment. Clinical examination and pre and post panoramic radiograph were measured and analyzed. In addition, data as gender, age, time reduction and location of the lesion were collected. RESULTS: Significant results were obtained in relation to the location of lesions and the reduction rate (p<0.01). In a higher initial lesion, a greater reduction rate was observed (p<0.05). CONCLUSIONS: Decompression as an initial treatment of cystic lesions of the jaws was effective; it reduces the size of the lesions avoiding a possible damage to adjacent structures. Cystic lesions in the mandible, regardless of the area where they occur will have a higher reduction rate if it is compared with the maxilla. Similar behavior was identified in large lesions compared to smaller. PMID- 28809379 TI - Periodontal, salivary and IL-6 status in rheumatoid arthritis patients. A cross sectional study. AB - BACKGROUND: The aim of this study was to determine whether saliva interleukin-6 (IL-6) levels are elevated in patients with rheumatoid arthritis versus a control group and examine the possible relationship between the oral condition and the risk of RA. MATERIAL AND METHODS: In 30 patients with RA and 30 healthy controls, different periodontal indices were recorded; sialometric measurements were taken to determine resting whole saliva, stimulated whole saliva and stimulated parotid saliva flow; and the saliva IL-6 levels were measured. Logistic regression analysis was performed, with the presence or absence of RA as dependent variable. RESULTS: The patients with RA had a greater presence of bacterial plaque, a greater periodontal pocket depth, a larger percentage of medium-sized pockets, and greater periodontal attachment loss compared with the controls. Likewise, a decrease in resting and stimulated saliva flow was observed, together with an increase in saliva IL-6 levels. Logistic regression analysis reported that the plaque index is the principal differentiating factor of patients with RA. Stimulated parotid saliva flow was also significantly correlated to the presence of RA. CONCLUSIONS: The patients with RA showed a greater tendency to develop periodontal disease than the controls, with lower salivary flow and higher levels of IL-6 in saliva. PMID- 28809380 TI - Production of bone mineral material and BMP-2 in osteoblasts cultured on double acid-etched titanium. AB - BACKGROUND: The study of osteoblasts and their osteogenic functions is essential in order to understand them and their applications in implantology. In this sense, this study try to study BMP-2 production and bone matrix deposition, in addition to other biological variables, in osteoblasts cultured on a rough double acid-etched titanium surface (Osseotite(r), Biomet 3i, Palm Beach Garden, Florida, USA) in comparison to a smooth titanium surface (machined) and a control Petri dish. MATERIALS AND METHODS: An in vitro prospective study. NHOst human osteoblasts from the femur were cultured on three different surfaces: Control group: 25-mm methacrylate dish (n = 6); Machined group: titanium discs with machined surface (n = 6) and Experimental group: titanium discs with a double acid-etched nitric and hydrofluoric Osseotite(r) acid surface (n = 6). A quantification of the mitochondrial membrane potential, and studies of apoptosis, mobility and adhesion, bone productivity (BMP-2) and cellular bone synthesis were carried out after culturing the three groups for forty-eight hours. RESULTS: A statistically significant difference was observed in the production of BMP-2 between the experimental group and the other two groups (22.33% +/- 11.06 vs. 13.10% +/- 5.51 in the machined group and 3.88% +/- 3.43 in the control group). Differences in cellular bone synthesis were also observed between the groups (28.34% +/- 14.4% in the experimental group vs. 20.03% +/- 6.79 in the machined group and 19.34% +/- 15.93% in the control group). CONCLUSIONS: In comparison with machined surfaces, Osseotite(r) surfaces favor BMP-2 production and bone synthesis as a result of the osteoblasts in contact with it. PMID- 28809382 TI - Exposed necrotic bone in 183 patients with bisphosphonate-related osteonecrosis of the jaw: Associated clinical characteristics. AB - BACKGROUND: The main objective of our study was to identify oral symptoms and signs most likely to be associated with the exposure of necrotic bone in bisphosphonate-related osteonecrosis of the jaw (BRONJ). MATERIAL AND METHODS: The study group consisted of 183 patients with BRONJ. We recorded data on the underlying disease, bisphosphonate used, location of osteonecrosis, symptoms, pain, fistula development, suppuration, infection, exposed necrotic bone, and BRONJ stage. RESULTS: The mean age of the patients was 68.22 +/- 12.19 years. The sample included 118 (64.5%) women. Breast cancer and multiple myeloma were the most common underlying diseases, and 50 patients received oral bisphosphonates for osteoporosis. Dental extractions (69.4%) and mandibular location (74.3%) predominated. The only two variables influencing the possibility of necrotic bone exposure were intravenous bisphosphonate administration and the presence of an intraoral fistula (p < 0.05). CONCLUSIONS: Intravenous bisphosphonate use and intraoral fistula presence were associated with a major predisposition to bone exposure in patients with BRONJ. PMID- 28809381 TI - Serum levels of RANKL and OPG, and the RANKL/OPG ratio in bisphosphonate-related osteonecrosis of the jaw: Are they useful biomarkers for the advanced stages of osteonecrosis? AB - BACKGROUND: We determined whether serum levels of Receptor Activator for Nuclear Factor kappa B Ligand (RANKL), Osteoprotegerin (OPG), and the RANKL/OPG ratio could be useful biomarkers for the severity of oral lesions in bisphosphonate related osteonecrosis of the jaw (BRONJ). MATERIAL AND METHODS: A case-control study in which Group 1 consisted of 41 patients with BRONJ due to intravenous bisphosphonates, and Group 2 consisted of 44 healthy control cases. The plasma levels of RANKL and OPG were analyzed by an ELISA assay. The OPG/RANKL ratio was also calculated. We determined if the mean serum values differed among the different stages of BRONJ. RESULTS: Serum levels of RANKL were lower in Group 1 than in Group 2 (p =0.01), and serum levels of OPG were higher in patients with BRONJ than in the controls (p =0.006). The ratio of RANKL/OPG was greater in the controls than in Group 1 (p >0.01). There were no significant differences in the serum levels of RANKL and OPG among the different stages of osteonecrosis (p >0.05). CONCLUSIONS: Serum levels of RANKL and OPG, and the RANKL/OPG ratio were not valuable biomarkers for determining the severity of oral lesions in patients with BRONJ. PMID- 28809383 TI - Increasing Symptoms in Irritable Bowel Symptoms With Ingestion of Galacto Oligosaccharides Are Mitigated by alpha-Galactosidase Treatment. AB - OBJECTIVES: Galacto-oligosaccharides (GOS) are dietary FODMAPs (fermentable carbohydrates) associated with triggering gastrointestinal symptoms in patients with irritable bowel syndrome (IBS). This randomized, double-blind, placebo controlled, cross-over trial aimed to assess whether oral alpha-galactosidase co ingestion with foods high in GOS and low in other FODMAPs would reduce symptoms. METHODS: Patients meeting the Rome III criteria for IBS who were hydrogen producers on breath testing were recruited. Participants were treated with full dose (300 GALU (galactosidic units) alpha-galactosidase) and half-dose enzyme (150 GALU alpha-galactosidase), and placebo (glucose) in a random order with <=14 days washout between arms. Following a 3-day low FODMAP run-in period, participants consumed provided diets high in GOS for a further 3-days. Gastrointestinal symptoms were measured daily using a 100 mm visual-analogue scale, and breath samples taken hourly on the second last day with hydrogen content analysed as area-under-the-curve. RESULTS: Thirty-one patients with IBS (20 IBS-D, 4 IBS-C, 7 IBS-M) completed the study. The addition of high GOS foods resulted in a significant increase in overall symptoms with 21 patients exhibiting GOS-sensitivity (>10 mm increase for overall symptoms). Of those, full dose enzyme reduced overall symptoms (median 24. 5(IQR 17.5-35.8) vs. 5.5(1.5 15.0) mm; P=0.006) and bloating (20.5(9.5-42.0) vs. 6.5(2.0-15.8); P=0.017). Breath hydrogen production was minimal with no differences seen between placebo and full-dose (P=0.597). CONCLUSIONS: Oral alpha-galactosidase taken with high GOS foods provides a clinically significant reduction in symptoms in GOS sensitive individuals with IBS. This strategy can be translated into practice to improve tolerance to high GOS foods as an adjunct therapy to the low FODMAP diet. PMID- 28809384 TI - The Impact of Cholecystectomy After Endoscopic Sphincterotomy for Complicated Gallstone Disease. AB - OBJECTIVES: Cholecystectomy after endoscopic sphincterotomy (ES) is associated with improved outcomes compared to ES alone, however randomized trials have included mainly fit surgical candidates. Our objective was to assess the impact of cholecystectomy after ES among elderly patients, in whom the perceived risks of surgery may be increased and the prevailing bias may be to defer cholecystectomy. METHODS: We performed adjusted analyses comparing clinical outcomes in patients >=65 years of age who did and did not undergo follow-up cholecystectomy after endoscopic sphincterotomy for choledocholithiasis, ascending cholangitis, or gallstone pancreatitis. We also compared adverse events between the two groups. RESULTS: In the ES alone group, 39.3% of patients experienced a recurrent complication compared with 18.0% in the ES and cholecystectomy group. After adjusting for comorbidities using multivariable regression, cholecystectomy in addition to ES was associated with a reduced risk of recurrent choledocholithiasis (OR 0.38, 95%CI 0.34-0.42, P<0.001), ascending cholangitis (OR 0.28, 95%CI 0.23-0.34, P<0.001), and gallstone pancreatitis (OR 0.35, 95%CI 0.24-0.49, P<0.001) compared to ES alone. This benefit was preserved after propensity score adjustment, in patients >=75 years of age, and in those with major comorbidities including cancer, heart failure, and liver disease. Serious post-operative complications such as myocardial infarction, pulmonary embolism, and pneumonia were not more common in the cholecystectomy group. CONCLUSIONS: Among older patients, including those with serious comorbidities, cholecystectomy after endoscopic sphincterotomy was associated with a significant and clinically important reduction in recurrent complications compared to sphincterotomy alone. This benefit did not appear to be outweighed by surgical complications, highlighting the importance of cholecystectomy, even in elderly patients whose lifespans may be limited by unrelated conditions. PMID- 28809385 TI - Society Leadership and Diversity: Hail to the Women! PMID- 28809386 TI - Complications of Bariatric Surgery: What You Can Expect to See in Your GI Practice. AB - Obesity is one of the most significant health problems worldwide. Bariatric surgery has become one of the fastest growing operative procedures and has gained acceptance as the leading option for weight-loss. Despite improvement in the performance of bariatric surgical procedures, complications are not uncommon. There are a number of unique complications that arise in this patient population and require specific knowledge for proper management. Furthermore, conditions unrelated to the altered anatomy typically require a different management strategy. As such, a basic understanding of surgical anatomy, potential complications, and endoscopic tools and techniques for optimal management is essential for the practicing gastroenterologist. Gastroenterologists should be familiar with these procedures and complication management strategies. This review will cover these topics and focus on major complications that gastroenterologists will be most likely to see in their practice. PMID- 28809387 TI - Accuracy and Safety of the Cytosponge for Assessing Histologic Activity in Eosinophilic Esophagitis: A Two-Center Study. AB - OBJECTIVES: Management of eosinophilic esophagitis (EoE) requires repeated endoscopic mucosal sampling to assess disease activity. A less invasive and expensive means of monitoring of EoE is required. The objective of this study was to assess the accuracy, safety, and tolerability of the cytosponge compared to endoscopy and biopsy for histologic assessment of EoE. METHODS: In this prospective two-center cross-sectional study, patients with known EoE underwent cytosponge sampling followed by endoscopy and biopsy. Sample adequacy and eosinophil counts (eos/HPF) were determined for both cytosponge and endoscopic samples. The cytosponge was assessed for diagnostic accuracy, safety, and patient preference as compared to endoscopy. RESULTS: Six patients (7%) failed to swallow the sponge. One hundred and five procedures were successfully performed in 80 patients (66% male, 100% white, 19% stricture). The cytosponge sample was adequate in 102 and the biopsy in 104; 101 procedures had adequate samples by both techniques. Fifty-seven biopsies were graded as active EoE with >=15 eos/HPF as the gold standard. Eosinophil counts highly correlated between the biopsy and cytosponge (r=0.78, P<0.0001). Using a cutoff of <=15 eos/HPF for inactive disease, the sensitivity and specificity of the cytosponge was 75% and 86%, respectively. Six patients had active EoE on cytosponge not found on biopsy. For biopsies with inactive EoE, the cytosponge identified 38/44. No complications occurred, and cytosponge endoscopic abrasion scores were low (0.34/4). Patients preferred cytosponge to endoscopy with higher rating scores (7.27 vs. 6.11, P=0.002). CONCLUSIONS: Compared to endoscopy with biopsy, cytosponge provided a minimally invasive, safe, well tolerated, and accurate method to assess EoE histologic activity. (ClinicalTrial.gov number NCT01585103). PMID- 28809389 TI - Cost-effectiveness analysis of telephone-based support for the management of pressure ulcers in people with spinal cord injury in India and Bangladesh. AB - OBJECTIVE: To determine from a societal perspective the cost-effectiveness and cost-utility of telephone-based support for management of pressure ulcers. STUDY DESIGN: Cost-effectiveness and cost-utility analysis of a randomised clinical trial. SETTING: Tertiary centre in India and Bangladesh. METHODS: An economic evaluation was conducted alongside a randomised clinical trial comparing 12 weeks of telephone-based support (intervention group) with usual care (control group). The analyses evaluated costs and health outcomes in terms of cm2 reduction of pressure ulcers size and quality-adjusted life years (QALYs) gained. All costs were in Indian Rupees (INR) and then converted to US dollars (USD). RESULTS: The mean (95% confidence interval) between-group difference for the reduction in size of pressure ulcers was 0.53 (-3.12 to 4.32) cm2, favouring the intervention group. The corresponding QALYs were 0.027 (0.004-0.051), favouring the intervention group. The mean total cost per participant in the intervention group was INR 43 781 (USD 2460) compared to INR 42 561 (USD 2391) for the control group. The per participant cost of delivering the intervention was INR 2110 (USD 119). The incremental cost-effectiveness ratio was INR 2306 (USD 130) per additional cm2 reduction in the size of the pressure ulcer and INR 44 915 (USD 2523) per QALY gained. CONCLUSION: In terms of QALYs, telephone-based support to help people manage pressure ulcers at home provides good value for money and has an 87% probability of being cost-effective, based on 3 times gross domestic product. Sensitivity analyses were performed using the overall cost data with and without productivity costs, and did not alter this conclusion. PMID- 28809390 TI - Clinical features and surgical outcomes of cervical spondylotic myelopathy in patients of different ages: a retrospective study. AB - STUDY DESIGN: Retrospective chart audit. OBJECTIVES: This study aims to compare the clinical features and surgical outcomes in patients with cervical spondylotic myelopathy (CSM) among different age groups. SETTING: The first Affiliated Hospital of Anhui Medical University, China. METHODS: A total of 460 patients with CSM who were surgically treated over the period of 1995-2009 were investigated. Considering the peak age (40-60 years old) for the onset of symptoms, we divided the patients into three groups by age: young (<40), middle aged (40-60), and old (>60). The differences in symptoms, symptom durations, involved levels, surgical approaches and outcomes were evaluated. RESULTS: The number of symptoms and involved levels, symptom duration and posterior approach significantly increased with increasing age, whereas preoperative Japanese Orthopedic Association score decreased among the three groups. Spinal cord function improved after surgery in all groups. The highest degree of recovery occurred during the first 6 months after surgery, especially within the first week, and then reached a plateau. After 6 months, however, recovery continuously improved, stabilized and declined in the young, middle-aged, old groups, respectively. The recovery rate was not significantly different at an immediate period (1 week) after operation among the three groups, but was significantly different at later periods (3 or more months postoperatively). Three groups showed no difference in postoperative complication rates. CONCLUSION: The severity of CSM increased with increasing age. Age was inversely correlated with recovery, and recovery decreased as age increased. Six months post operation was the prime time for the recovery of spinal cord function. PMID- 28809391 TI - Determinants of resilience among people who sustained spinal cord injury from the 2015 earthquake in Nepal. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVES: To assess the level of resilience, compare resilience by demographic and injury-related characteristics, and identify significant determinants of resilience in Nepalese people who sustained spinal cord injury (SCI) from the 2015 earthquake. SETTING: Spinal Injury Rehabilitation Center, Kavre and 14 communities in Nepal. METHODS: Eighty two participants were included using a convenience sampling technique. A demographic and injury-related questionnaire was used to identify the characteristics of the participants. The Connor-Davidson Resilience Scale was used to measure resilience. Linear regression analysis was performed to determine the demographic and injury-related factors that contribute to resilience. RESULTS: Almost 54% of the participants had low level of resilience. Independent samples t-tests and ANOVA showed that participants with higher resilience outcome were more likely to be male, employed, paraplegic level of injury and pain free. The regression analysis revealed that only gender was a unique determinant of resilience (beta=0.38, t=3.40, P=0.001) in Nepalese with earthquake-related SCI. CONCLUSION: More than half of Nepalese who sustained SCI from the 2015 earthquake in Nepal had not achieved a high level of resilience 2 years later. Gender was a significant determinant of resilience. The results highlighted the importance of providing appropriate intervention and allocating continuing support to the Nepalese people with SCI. A further longitudinal study is recommended to determine predictive factors of the dynamic nature of resilience. PMID- 28809392 TI - Mettl3-mediated m6A regulates spermatogonial differentiation and meiosis initiation. AB - METTL3 catalyzes the formation of N6-methyl-adenosine (m6A) which has important roles in regulating various biological processes. However, the in vivo function of Mettl3 remains largely unknown in mammals. Here we generated germ cell specific Mettl3 knockout mice and demonstrated that Mettl3 was essential for male fertility and spermatogenesis. The ablation of Mettl3 in germ cells severely inhibited spermatogonial differentiation and blocked the initiation of meiosis. Transcriptome and m6A profiling analysis revealed that genes functioning in spermatogenesis had altered profiles of expression and alternative splicing. Our findings provide novel insights into the function and regulatory mechanisms of Mettl3-mediated m6A modification in spermatogenesis and reproduction in mammals. PMID- 28809394 TI - SMAD5 signaling: more than meets the nuclei. AB - SMADs are essential transcriptional effectors of transforming growth factor-beta (TGFbeta)/TGFbeta-related signaling that underlies embryonic development and adult homeostasis. A recent study by Fang et al. in Cell Research adds to this biological complexity by demonstrating an atypical cytoplasmic role for SMAD5 in modulating the bioenergetic homeostasis (i.e., glycolysis and mitochondrial respiration) of cells in response to fluctuations in intracellular pH that is independent of receptor signaling. PMID- 28809393 TI - Ythdc2 is an N6-methyladenosine binding protein that regulates mammalian spermatogenesis. AB - N6-methyladenosine (m6A) is the most common internal modification in eukaryotic mRNA. It is dynamically installed and removed, and acts as a new layer of mRNA metabolism, regulating biological processes including stem cell pluripotency, cell differentiation, and energy homeostasis. m6A is recognized by selective binding proteins; YTHDF1 and YTHDF3 work in concert to affect the translation of m6A-containing mRNAs, YTHDF2 expedites mRNA decay, and YTHDC1 affects the nuclear processing of its targets. The biological function of YTHDC2, the final member of the YTH protein family, remains unknown. We report that YTHDC2 selectively binds m6A at its consensus motif. YTHDC2 enhances the translation efficiency of its targets and also decreases their mRNA abundance. Ythdc2 knockout mice are infertile; males have significantly smaller testes and females have significantly smaller ovaries compared to those of littermates. The germ cells of Ythdc2 knockout mice do not develop past the zygotene stage and accordingly, Ythdc2 is upregulated in the testes as meiosis begins. Thus, YTHDC2 is an m6A-binding protein that plays critical roles during spermatogenesis. PMID- 28809388 TI - Dramatic Increase in Incidence of Ulcerative Colitis and Crohn's Disease (1988 2011): A Population-Based Study of French Adolescents. AB - OBJECTIVES: Few data are available to describe the changes in incidence of pediatric-onset inflammatory bowel disease (IBD). The aim of this study was to describe changes in incidence and phenotypic presentation of pediatric-onset IBD in northern France during a 24-year period. METHODS: Pediatric-onset IBD (<17 years) was issued from a population-based IBD study in France between 1988 and 2011. Age groups and digestive location were defined according to the Paris classification. RESULTS: 1,350 incident cases were recorded (8.3% of all IBD) including 990 Crohn's disease (CD), 326 ulcerative colitis (UC) and 34 IBD unclassified (IBDU). Median age at diagnosis was similar in CD (14.4 years (Q1=11.8-Q3=16.0)) and UC (14.0 years (11.0-16.0)) and did not change over time. There were significantly more males with CD (females/males=0.82) than UC (females/males=1.25) (P=0.0042). Median time between onset of symptoms and IBD diagnosis was consistently 3 months (1-6). Mean incidence was 4.4/105 for IBD overall (3.2 for CD, 1.1 for UC and 0.1 for IBDU). From 1988-1990 to 2009-2011, a dramatic increase in incidences of both CD and UC were observed in adolescents (10-16 years): for CD from 4.2 to 9.5/105 (+126%; P<0.001) and for UC, from 1.6 to 4.1/105 (+156%; P<0.001). No modification in age or location at diagnosis was observed in either CD or UC. CONCLUSIONS: In this population-based study, CD and UC incidences increased dramatically in adolescents across a 24-year span, suggesting that one or more strong environmental factors may predispose this population to IBD. PMID- 28809395 TI - Cryo-EM structures of the 80S ribosomes from human parasites Trichomonas vaginalis and Toxoplasma gondii. AB - As an indispensable molecular machine universal in all living organisms, the ribosome has been selected by evolution to be the natural target of many antibiotics and small-molecule inhibitors. High-resolution structures of pathogen ribosomes are crucial for understanding the general and unique aspects of translation control in disease-causing microbes. With cryo-electron microscopy technique, we have determined structures of the cytosolic ribosomes from two human parasites, Trichomonas vaginalis and Toxoplasma gondii, at resolution of 3.2-3.4 A. Although the ribosomal proteins from both pathogens are typical members of eukaryotic families, with a co-evolution pattern between certain species-specific insertions/extensions and neighboring ribosomal RNA (rRNA) expansion segments, the sizes of their rRNAs are sharply different. Very interestingly, rRNAs of T. vaginalis are in size comparable to prokaryotic counterparts, with nearly all the eukaryote-specific rRNA expansion segments missing. These structures facilitate the dissection of evolution path for ribosomal proteins and RNAs, and may aid in design of novel translation inhibitors. PMID- 28809396 TI - IPA1 functions as a downstream transcription factor repressed by D53 in strigolactone signaling in rice. AB - Strigolactones (SLs), a group of carotenoid derived terpenoid lactones, are root to-shoot phytohormones suppressing shoot branching by inhibiting the outgrowth of axillary buds. DWARF 53 (D53), the key repressor of the SL signaling pathway, is speculated to regulate the downstream transcriptional network of the SL response. However, no downstream transcription factor targeted by D53 has yet been reported. Here we report that Ideal Plant Architecture 1 (IPA1), a key regulator of the plant architecture in rice, functions as a direct downstream component of D53 in regulating tiller number and SL-induced gene expression. We showed that D53 interacts with IPA1 in vivo and in vitro and suppresses the transcriptional activation activity of IPA1. We further showed that IPA1 could directly bind to the D53 promoter and plays a critical role in the feedback regulation of SL induced D53 expression. These findings reveal that IPA1 is likely one of the long speculated transcription factors that act with D53 to mediate the SL-regulated tiller development in rice. PMID- 28809397 TI - Fibroblasts in an endocardial fibroelastosis disease model mainly originate from mesenchymal derivatives of epicardium. AB - Endocardial fibroelastosis (EFE) refers to the thickening of the ventricular endocardium as a result of de novo deposition of subendocardial fibrous tissue layers during neonatal heart development. The origin of EFE fibroblasts is proposed to be postnatal endocardial cells that undergo an aberrant endothelial to-mesenchymal transition (EndMT). Genetic lineage tracing of endocardial cells with the inducible endocardial Cre line Npr3-CreER and the endothelial cell tracing line Cdh5-CreER on an EFE-like model did not reveal any contribution of neonatal endocardial cells to fibroblasts in the EFE-like tissues. Instead, lineage tracing of embryonic epicardium by Wt1-CreER suggested that epicardium derived mesenchymal cells (MCs) served as the major source of EFE fibroblasts. By labeling MCs using Sox9-CreER, we confirmed that MCs of the embryonic heart expand and contribute to the majority of neonatal EFE fibroblasts. During this pathological process, TGFbeta signaling, the key mediator of fibroblasts activation, was highly upregulated in the EFE-like tissues. Targeting TGFbeta signaling by administration of its antagonist bone morphogenetic protein 7 effectively reduced fibroblast accumulation and tissue fibrosis in the EFE-like model. Our study provides genetic evidence that excessive fibroblasts in the EFE like tissues mainly originate from the epicardium-derived MCs through epicardial to mesenchymal transition (EpiMT). These EpiMT-derived fibroblasts within the EFE like tissues could serve as a potential therapeutic target. PMID- 28809398 TI - Precision medicine for suicidality: from universality to subtypes and personalization. AB - Suicide remains a clear, present and increasing public health problem, despite being a potentially preventable tragedy. Its incidence is particularly high in people with overt or un(der)diagnosed psychiatric disorders. Objective and precise identification of individuals at risk, ways of monitoring response to treatments and novel preventive therapeutics need to be discovered, employed and widely deployed. We sought to investigate whether blood gene expression biomarkers for suicide (that is, a 'liquid biopsy' approach) can be identified that are more universal in nature, working across psychiatric diagnoses and genders, using larger cohorts than in previous studies. Such markers may reflect and/or be a proxy for the core biology of suicide. We were successful in this endeavor, using a comprehensive stepwise approach, leading to a wealth of findings. Steps 1, 2 and 3 were discovery, prioritization and validation for tracking suicidality, resulting in a Top Dozen list of candidate biomarkers comprising the top biomarkers from each step, as well as a larger list of 148 candidate biomarkers that survived Bonferroni correction in the validation step. Step 4 was testing the Top Dozen list and Bonferroni biomarker list for predictive ability for suicidal ideation (SI) and for future hospitalizations for suicidality in independent cohorts, leading to the identification of completely novel predictive biomarkers (such as CLN5 and AK2), as well as reinforcement of ours and others previous findings in the field (such as SLC4A4 and SKA2). Additionally, we examined whether subtypes of suicidality can be identified based on mental state at the time of high SI and identified four potential subtypes: high anxiety, low mood, combined and non-affective (psychotic). Such subtypes may delineate groups of individuals that are more homogenous in terms of suicidality biology and behavior. We also studied a more personalized approach, by psychiatric diagnosis and gender, with a focus on bipolar males, the highest risk group. Such a personalized approach may be more sensitive to gender differences and to the impact of psychiatric co-morbidities and medications. We compared testing the universal biomarkers in everybody versus testing by subtypes versus personalized by gender and diagnosis, and show that the subtype and personalized approaches permit enhanced precision of predictions for different universal biomarkers. In particular, LHFP appears to be a strong predictor for suicidality in males with depression. We also directly examined whether biomarkers discovered using male bipolars only are better predictors in a male bipolar independent cohort than universal biomarkers and show evidence for a possible advantage of personalization. We identified completely novel biomarkers (such as SPTBN1 and C7orf73), and reinforced previously known biomarkers (such as PTEN and SAT1). For diagnostic ability testing purposes, we also examined as predictors phenotypic measures as apps (for suicide risk (CFI-S, Convergent Functional Information for Suicidality) and for anxiety and mood (SASS, Simplified Affective State Scale)) by themselves, as well as in combination with the top biomarkers (the combination being our a priori primary endpoint), to provide context and enhance precision of predictions. We obtained area under the curves of 90% for SI and 77% for future hospitalizations in independent cohorts. Step 5 was to look for mechanistic understanding, starting with examining evidence for the Top Dozen and Bonferroni biomarkers for involvement in other psychiatric and non-psychiatric disorders, as a mechanism for biological predisposition and vulnerability. The biomarkers we identified also provide a window towards understanding the biology of suicide, implicating biological pathways related to neurogenesis, programmed cell death and insulin signaling from the universal biomarkers, as well as mTOR signaling from the male bipolar biomarkers. In particular, HTR2A increase coupled with ARRB1 and GSK3B decreases in expression in suicidality may provide a synergistic mechanistical corrective target, as do SLC4A4 increase coupled with AHCYL1 and AHCYL2 decrease. Step 6 was to move beyond diagnostics and mechanistical risk assessment, towards providing a foundation for personalized therapeutics. Items scored positive in the CFI-S and subtypes identified by SASS in different individuals provide targets for personalized (psycho)therapy. Some individual biomarkers are targets of existing drugs used to treat mood disorders and suicidality (lithium, clozapine and omega-3 fatty acids), providing a means toward pharmacogenomics stratification of patients and monitoring of response to treatment. Such biomarkers merit evaluation in clinical trials. Bioinformatics drug repurposing analyses with the gene expression biosignatures of the Top Dozen and Bonferroni-validated universal biomarkers identified novel potential therapeutics for suicidality, such as ebselen (a lithium mimetic), piracetam (a nootropic), chlorogenic acid (a polyphenol) and metformin (an antidiabetic and possible longevity promoting drug). Finally, based on the totality of our data and of the evidence in the field to date, a convergent functional evidence score prioritizing biomarkers that have all around evidence (track suicidality, predict it, are reflective of biological predisposition and are potential drug targets) brought to the fore APOE and IL6 from among the universal biomarkers, suggesting an inflammatory/accelerated aging component that may be a targetable common denominator. PMID- 28809399 TI - Evidence for newly generated interneurons in the basolateral amygdala of adult mice. AB - New neurons are continually generated from the resident populations of precursor cells in selective niches of the adult mammalian brain such as the hippocampal dentate gyrus and the olfactory bulb. However, whether such cells are present in the adult amygdala, and their neurogenic capacity, is not known. Using the neurosphere assay, we demonstrate that a small number of precursor cells, the majority of which express Achaete-scute complex homolog 1 (Ascl1), are present in the basolateral amygdala (BLA) of the adult mouse. Using neuron-specific Thy1-YFP transgenic mice, we show that YFP+ cells in BLA-derived neurospheres have a neuronal morphology, co-express the neuronal marker betaIII-tubulin, and generate action potentials, confirming their neuronal phenotype. In vivo, we demonstrate the presence of newly generated BrdU-labeled cells in the adult BLA, and show that a proportion of these cells co-express the immature neuronal marker doublecortin (DCX). Furthermore, we reveal that a significant proportion of GFP+ neurons (~23%) in the BLA are newly generated (BrdU+) in DCX-GFP mice, and using whole-cell recordings in acute slices we demonstrate that the GFP+ cells display electrophysiological properties that are characteristic of interneurons. Using retrovirus-GFP labeling as well as the Ascl1CreERT2 mouse line, we further confirm that the precursor cells within the BLA give rise to mature and functional interneurons that persist in the BLA for at least 8 weeks after their birth. Contextual fear conditioning has no effect on the number of neurospheres or BrdU-labeled cells in the BLA, but produces an increase in hippocampal cell proliferation. These results demonstrate that neurogenic precursor cells are present in the adult BLA, and generate functional interneurons, but also show that their activity is not regulated by an amygdala-dependent learning paradigm. PMID- 28809401 TI - Erratum to: Long-term and short-term predictors of worries about getting Alzheimer's disease. AB - [This corrects the article DOI: 10.1007/s10433-015-0350-3.]. PMID- 28809400 TI - Prenatal one-carbon metabolism dysregulation programs schizophrenia-like deficits. AB - The methionine-folate cycle-dependent one-carbon metabolism is implicated in the pathophysiology of schizophrenia. Since schizophrenia is a developmental disorder, we examined the effects that perturbation of the one-carbon metabolism during gestation has on mice progeny. Pregnant mice were administered methionine equivalent to double their daily intake during the last week of gestation. Their progeny (MET mice) exhibited schizophrenia-like social deficits, cognitive impairments and elevated stereotypy, decreased neurogenesis and synaptic plasticity, and abnormally reduced local excitatory synaptic connections in CA1 neurons. Neural transcript expression of only one gene, encoding the Npas4 transcription factor, was >twofold altered (downregulated) in MET mice; strikingly, similar Npas4 downregulation occurred in the prefrontal cortex of human patients with schizophrenia. Finally, therapeutic actions of typical (haloperidol) and atypical (clozapine) antipsychotics in MET mice mimicked effects in human schizophrenia patients. Our data support the validity of MET mice as a model for schizophrenia, and uncover methionine metabolism as a potential preventive and/or therapeutic target. PMID- 28809402 TI - Erratum to: Dual sensory loss and social participation in older Europeans. AB - [This corrects the article DOI: 10.1007/s10433-013-0291-7.]. PMID- 28809403 TI - Erratum to: Gendered support to older parents: do welfare states matter? AB - [This corrects the article DOI: 10.1007/s10433-011-0197-1.]. PMID- 28809405 TI - Benzotrifuran (BTFuran): a building block for pi-conjugated systems. AB - Reported here is the first synthesis, X-ray crystal structure, and derivatization of benzotrifuran (BTFuran). Single crystal X-ray analysis of BTFuran shows a tight hexagonal packing stabilized by pi-stacking interactions and C-H...O contacts. alpha-Lithiation of BTFuran enables the preparation of reactive intermediates suitable for cross-coupling reactions, allowing access to representative BTFuran-containing pi-conjugated systems. PMID- 28809404 TI - Erratum to: Variations in preventive care utilisation in Europe. AB - [This corrects the article DOI: 10.1007/s10433-011-0201-9.]. PMID- 28809406 TI - Clot-entrapped blood cells in synergy with human mesenchymal stem cells create a pro-angiogenic healing response. AB - Blood clots stop bleeding and provide cell-instructive microenvironments. Still, in vitro models used to study implant performance typically neglect any possible interactions of recruited cells with surface-adhering blood clots. Here we study the interaction and synergies of bone marrow derived human mesenchymal stem cells (hMSCs) with surface-induced blood clots in an in vitro model by fluorescence microscopy, scanning and correlative light and electron microscopy, ELISA assays and zymography. The clinically used alkali-treated rough titanium (Ti) surfaces investigated here are known to enhance blood clotting compared to native Ti and to improve the healing response, but the underlying mechanisms remain elusive. Here we show that the presence of blood clots synergistically increased hMSC proliferation, extracellular matrix (ECM) remodelling and the release of matrix fragments and angiogenic VEGF, but did not increase the osteogenic differentiation of hMSCs. While many biomaterials are nowadays engineered to release pro-angiogenic factors, we show here that clot-entrapped blood cells on conventional materials in synergy with hMSCs are potent producers of pro angiogenic factors. Our data might thus not only explain why alkali-treatment is beneficial for Ti implant integration, but they suggest that the physiological importance of blood clots to create pro-angiogenic environments on implants has been greatly underestimated. The importance of blood clots might have been missed because the pro-angiogenic functions get activated only upon stimulation by synergistic interactions with the invading cells. PMID- 28809411 TI - A monomeric bowl-like pyrogallol[4]arene Ti12 coordination complex. AB - Herein, an unprecedented monomeric bowl-like coordination complex, Ti12PgC3 (PgC3 = C-propylpyrogallol[4]arene), has been successfully synthesized. To the best of our knowledge, Ti12PgC3 not only presents the first pyrogallol[4]arene-based titanium coordination complex, but also the highest nuclearity titanium coordination complex in the metal-calixarene system. In addition, this titanium coordination complex can effectively degrade the methylene blue (MB) dye under sunlight. PMID- 28809412 TI - Charging assisted structural phase transitions in monolayer InSe. AB - A recently synthesized InSe monolayer exhibits highly promising electronic and transport properties; it also possesses intricate intralayer atomic bonding configurations that are conducive to modulations of crystal and electronic structures. Here we identify by first-principles calculations two new structural phases of monolayer InSe distinct from the experimentally synthesized beta phase. The first, alpha phase, has the Se atom positions displaced relative to those in the beta phase, and exhibits outstanding electronic properties similar to those of the beta phase. The second, gamma phase, has the In atom positions displaced, and displays exotic quantum spin Hall states in its electronic structure. Charging plays a crucial role in facilitating the transitions from the beta phase to the alpha or gamma phase, and it is also essential for stabilizing the two new phases. Electron injection, alkali metal adsorption, and coupling to the Ag(111) substrate all provide the charging effect that considerably lowers the energies of the new phases and the kinetic barriers of the transition pathways. The charging effect is particularly pronounced in lowering the kinetic barrier for the beta-to-gamma transition with a concomitant energy reduction stabilizing the gamma phase that hosts Dirac cones in the electronic structure. The present results pave the way for further exploration and development of monolayer InSe as a versatile two-dimensional material for innovative device applications. PMID- 28809413 TI - Tumor-targeted nanoprobes for enhanced multimodal imaging and synergistic photothermal therapy: core-shell and dumbbell Gd-tailored gold nanorods. AB - Multifunctional nanoprobes, due to their unique nanocomposite structures, have prominent advantages that combine multimodal imaging of a tumor with photothermal therapy. However, they remain a challenge for constructing nanostructures via conventional approaches due to the peculiar environmental sensitivity of each component. Here, we report the design and synthesis of Gd-based nanoparticle tailored gold nanorods with distinctive core-shell and dumbbell nanoarchitectures (NAs) by a specific synthesis technology. The prepared NAs possess a tunable particle size of 80-120 nm in length and 50-90 nm in diameter, which are suitable for cellular uptake and passive targeting of a tumor. The formation of two distinct heterostructures and their underlying mechanism were studied through systematic investigations on the controllable synthesis process. The as-prepared nanoprobes possess an ultrahigh longitudinal relaxivity (r1) of 22.69 s-1 mM-1 and thus a significant magnetic resonance imaging signal enhancement has been observed in mice tumors. The NAs, especially the dumbbell type, show a vivid two photon cell imaging and a remarkable photothermal conversion efficiency owing to their superior longitudinal surface plasmon resonance. Both in vitro cytotoxicity and in vivo immunotoxicity assays give substantial evidence of excellent biocompatibility attained in the NAs. The development of multifunctional targeting nanoprobes in this study could provide guidance for tailored design and controllable synthesis of heterostructured nanocomposites utilized for multimodal imaging and photothermal therapy of cancer. PMID- 28809414 TI - Carrier photogeneration, drift and recombination in a semiconducting carbon nanotube network. AB - Charge carrier photogeneration, drift and recombination in thin film networks of polymer-wrapped (6,5)-single-wall carbon nanotubes (SWNTs) blended with phenyl C61-butyric acid methyl ester (PCBM) have been investigated by using transient photocurrent and time-delayed collection field (TDCF) techniques. Three distinct transient photocurrent components on the nano- and microsecond timescales have been identified. We attribute the dominant (>50% of total extracted charge) ultrashort photocurrent component with a decay time below our experimental time resolution of 2 ns to the intratube hole motion. The second component on the few microsecond timescale is attributed to the intertube hole transfer, while the slowest component is assigned to the electron drift within the PCBM phase. The hole drift distance appears to be limited by gaps in the nanotube percolation network rather than by hole trapping or recombination. Photocurrent saturation was observed when excitation densities reached more than one charge pair per nanotube; we attribute this to the local electric field screening. PMID- 28809415 TI - Stimuli-responsive emissive behavior of 1- and 1,3-connectivities in azulene based imine ligands: cycloplatination and Pt-Tl dative bond formation. AB - The preparation of two new azulene-based imine ligands N-(2,6-diisopropylphenyl) 6-tBu-1-azulenylmethaneimine, 3, and N-(2,6-diisopropylphenyl)-6-tBu-3-(2,6 diisopropylphenyliminomethyl)-1-azulenylmethaneimine, 4, is described. These imine ligands display stimuli responsive emissive behavior and their fluorescence can be switched on and off by protonation and neutralization with trifluoroacetic acid and trimethylamine, respectively. The cyclometalation of the monoimine ligand by platinum gave the cyclometalated complex [PtMe(SMe2)(3')], 5, (where the prime denotes the cyclometalated ligand 3). The reaction of 5 with TlPF6 yields the trinuclear bent Pt2Tl complex {[PtMe(SMe2)(3')]2(MU-Tl)}PF6, 6, via Pt Tl dative bonds. The compounds 3-6 were characterized using NMR spectroscopy and the solid-state structures of 5 and 6 were further determined by X-ray crystallography. The electronic absorption spectra of the species 3-H+, 4-H+, 5 and 6 were obtained and compared with those observed for the parent species 3 and 4. DFT and TD-DFT calculations are used to elucidate the origin of the electronic transitions in monoimine ligand 3 and its protonated form 3-H+. PMID- 28809416 TI - Heteroleptic nickel(ii)-diNHC complexes and an unusual 'reverse' carbene-transfer reaction to silver(i). AB - A series of rare [NiX2(MeCCprop)] complexes bearing the cis-chelating benzimidazole-derived dicarbene ligand MeCCprop and varying anionic coligands (2, X = N3; 3, X = NCS; 4, X = I; 5, X = O2CCF3) have been prepared and coligand dependent structural and spectroscopic features have been evaluated. This study also revealed an unusual 'reverse' carbene transfer reaction from nickel to silver giving the disilver species [Ag2X2(MU-kappa2-MeCCprop)] (6, X = OAc; 7, X = O2CCF3). A preliminary catalytic study of two representative NiII diNHC complexes in the aqueous and phosphine-free Suzuki-Miyaura coupling reaction of aryl halides is reported as well. These reactions provide good yields of coupling products, but do not require inert conditions. PMID- 28809417 TI - Co9S8 nanoparticles anchored on nitrogen and sulfur dual-doped carbon nanosheets as highly efficient bifunctional electrocatalyst for oxygen evolution and reduction reactions. AB - To promote the practical application of electrochemical energy storage and conversion systems, nonprecious electrocatalysts of low cost and with highly efficient performance in oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) are highly desired. In this work, a cubic sodium chloride (NaCl) crystal-templated strategy is proposed for coupling Co9S8 nanoparticles to nitrogen- and sulfur-doped carbon nanosheets (Co9S8/N,S-CNS) by facile pyrolysis. The nitrogen and sulfur dual-doped carbon nanosheets can effectively prevent the aggregation of Co9S8 nanoparticles and greatly improve the conductivity of the hybrid structure. The well-dispersed Co9S8 nanoparticles could provide more active sites. When evaluated as a bifunctional electrocatalyst, an overpotential of 350 mV could yield 10 mA cm-2 current density for OER and a high onset potential around 0.90 V vs. RHE was obtained with a four-electron pathway for ORR, which is comparable to that of a Pt/C catalyst. The remarkable electrochemical performance can be attributed to the synergistic catalytic effect of Co9S8 nanoparticles and the N,S-doped carbon nanosheets. Considering the simplicity, low cost and scalability of the approach, the strategy presented here can be extendable to the preparation of other nanoparticles/carbon hybrid nanosheets, which may potentially be applied in the fields of high-performance supercapacitors, lithium-ion batteries, catalysts, sensors, adsorbents and so on. PMID- 28809419 TI - Environmental stability of 2D anisotropic tellurium containing nanomaterials: anisotropic to isotropic transition. AB - We report on the vibrational (Raman) spectrum and structural transformation of semiconducting pseudo-1D GaTe and ZrTe3 nanomaterials driven by ambient molecular interactions at the nanoscale by angle-resolved Raman spectroscopy, atomic force microscopy (AFM), and environmental X-ray photoelectron (XPS) measurements. The results show that tellurium containing pseudo-1D materials undergo drastic structural and physical changes within a week. During this process, new Raman peaks start to emerge and surface roughness increases substantially. Surprisingly, aged Raman spectra of GaTe, ZrTe3, and alpha-TeOx show striking similarities suggesting that oxidation of tellurium takes place. Careful, environmental tests reveal that the interaction between GaTe and H2O molecules forms Te-O bonds at the outermost layers of GaTe which leads to newly emerging Raman peaks, a much reduced Schottky junction current density, and an anisotropic to isotropic structural transition. These findings offer fresh interpretation of the aging mechanisms for these material systems, provide new interpretation of the Raman spectrum of aged GaTe which was previously presumed to be of the hexagonal phase, and introduce an anisotropic to isotropic transformation effect induced by molecular interactions on the surface. PMID- 28809418 TI - Native extracellular matrix-derived semipermeable, optically transparent, and inexpensive membrane inserts for microfluidic cell culture. AB - Semipermeable cell culture membranes are commonly used in multilayered microfluidic devices to mimic the basement membrane in vivo and to create compartmentalized microenvironments for physiological cell growth and differentiation. However, existing membranes are predominantly made up of synthetic polymers, providing limited capacity to replicate cellular interactions with native extracellular matrices that play a crucial role in the induction of physiological phenotypes. Here we describe a new type of cell culture membranes engineered from native extracellular matrix (ECM) materials that are thin, semipermeable, optically transparent, and amenable to integration into microfluidic cell culture devices. Facile and cost-effective fabrication of these membranes was achieved by controlled sequential steps of vitrification that transformed three-dimensional (3D) ECM hydrogels into structurally stable thin films. By modulating the composition of the ECM, our technique provided a means to tune key membrane properties such as optical transparency, stiffness, and porosity. For microfluidic cell culture, we constructed a multilayered microdevice consisting of two parallel chambers separated by a thin membrane insert derived from different types of ECM. This study showed that our ECM membranes supported attachment and growth of various types of cells (epithelial, endothelial, and mesenchymal cells) under perfusion culture conditions. Our data also revealed the promotive effects of the membranes on adhesion-associated intracellular signaling that mediates cell-ECM interactions. Moreover, we demonstrated the use of these membranes for constructing compartmentalized microfluidic cell culture systems to induce physiological tissue differentiation or to replicate interfaces between different tissue types. Our approach provides a robust platform to produce and engineer biologically active cell culture substrates that serve as promising alternatives to conventional synthetic membrane inserts. This strategy may contribute to the development of physiologically relevant in vitro cell culture models for a wide range of applications. PMID- 28809421 TI - 'Reactive' nano-complex coated medical cotton: a facile avenue for tailored release of small molecules. AB - Controlled and sustained release of drug-like small molecules in an aqueous medium still remains a challenging problem due to rapid infiltration of liquid water in most reported drug release systems. However, internal superhydrophobicity with an antifouling property extending beyond the surface of a material recently has been recognized as a potential avenue for sustained and extended release of drug-like small molecules. Sluggish removal of metastable trapped air in a superhyrophobic material provides a basis to achieve extended release of encapsulated small molecules. In this article, naturally abundant medical-cotton-extensively used in wound management including control of bleeding, absorbance of secretions and protecting wounds from contamination-is strategically exploited in tailoring (from rapid to extended) the release of small molecules by appropriate modulation of liquid water wettability. Modulation included bio-mimicked adhesive and non-adhesive superhydrophobicity of the medical cotton without erosion of any polymeric material. In this process, amine 'reactive' nano-complexes (RNC) were prepared by just mixing branched poly(ethylenimine) (BPEI) with dipentaerythritol pentaacrylate (5Acl) in ethanol with appropriate compositions. Then they were covalently immobilized on fibrous medical-cotton through a facile and robust 1,4-conjugated addition reaction. Residual acrylate moieties in the immobilized RNC provide an opportunity to tailor water wettability through strategic and appropriate post-chemical modification of RNC-coated medical cotton with a primary amine containing various small molecules. This medical-cotton with tunable wettability was exploited further to control the release rate of small molecules from rapid (<24 h) to sustained (>100 days) times. A volatile solvent induced transient and reversible switching of anti-fouling properties which allowed further varying the amount of post-loading small molecules into the medical cotton up to 2.36 wt% without compromising the embedded anti-wetting property. Thus, our current approach has immense potential to develop appropriate materials for a sustained and controlled release of small molecules from a clinically relevant substrate (i.e., medical cotton) and may be useful in various bio-medical applications including improving wound management, preventing bacterial infections, better pain management, etc. PMID- 28809420 TI - Rapid identification of alpha-glucosidase inhibitors from Dioscorea opposita Thunb peel extract by enzyme functionalized Fe3O4 magnetic nanoparticles coupled with HPLC-MS/MS. AB - Dioscorea opposita Thunb, commonly known as "yam" that has a long dietary therapy history for diabetes, is widely consumed as a botanical dietary supplement and widely cultivated in China. In this work, a method for rapid screening of alpha glucosidase inhibitors from Dioscorea opposita Thunb peel extract was developed using alpha-glucosidase functionalized magnetic nanoparticles (alphaG-MNPs) as a solid phase extraction absorbent in combination with high performance liquid chromatography-mass spectrometry (HPLC-MS). Two alpha-glucosidase inhibitors were selectively extracted and identified as batatasin I and 2,4-dimethoxy-6,7 dihydroxyphenanthrene. Their alpha-glucosidase inhibitory activities (IC50 = 2.55 mM and 0.40 mM, respectively) were significantly higher than that of acarbose (as control). Taking advantage of the specificity in enzyme binding and the convenience of magnetic separation, this method has great potential for rapid and fast screening of alpha-glucosidase inhibitors from complex natural resources. PMID- 28809422 TI - Light-harvesting synthetic nano- and micromotors: a review. AB - Nano- and micromotors are machines that can be made to perform specialized tasks as they propel themselves in response to certain stimuli. While the design of these self-propelling nano- and micromotors remains challenging, they have nevertheless attracted considerable research due to their many promising applications. Most self-propelled nano- and micromotors are based on the conversion of chemical energy into mechanical movement. Recently, however, the development of motors that can be propelled by light as an external stimulus has received much attention. The reason being that light is a renewable energy source that does not require any physical connection to the motor, does not usually lead to any waste products, and is easy to control. This review highlights recent progress in the development of light-harvesting synthetic motors that can be efficiently propelled and accurately controlled by exposure to light, and gives an overview of their fabrication methods, propulsion mechanisms, and practical applications. PMID- 28809423 TI - Methylthionated benzo[1,2-b:4,5-b']dithiophenes: a model study to control packing structures and molecular orientation in thienoacene-based organic semiconductors. AB - Methylthionation on benzo[1,2-b:4,5-b']dithiophene (BDT) was examined as a promising molecular functionalization strategy to tune the packing structure and molecular orientation on the substrates. beta-Methylthionated BDT with a rubrene like "pitched" pi-stacking showed higher mobility than its alpha-counterpart with a herringbone packing in single-crystal organic field-effect transistors (SC OFETs). PMID- 28809424 TI - Correction: Broadband ultrafast photovoltaic detectors based on large-scale topological insulator Sb2Te3/STO heterostructures. AB - Correction for 'Broadband ultrafast photovoltaic detectors based on large-scale topological insulator Sb2Te3/STO heterostructures' by Honghui Sun, et al., Nanoscale, 2017, 9, 9325-9332. PMID- 28809425 TI - pH-Responsive quencher-free molecular beacon systems containing 2'-deoxyuridine units labeled with fluorene derivatives. AB - Three fluorescent nucleosides-UFL, UAF, and UDAF, containing fluorene, 2 aminofluorene, and 2-dimethylaminofluorene units, respectively, covalently attached to 2'-deoxyuridine-have been incorporated into the central positions of oligodeoxynucleotides (ODNs) to examine the effects of their flanking bases (FBs) and pH on the emission properties upon hybridization with fully matched and single-base-mismatched targets. The ODN containing UFL and cytosine-FBs in the pH range from 5.5 to 8.0 and the ODN containing UDAF and cytosine-FBs under slightly acidic conditions (pH 6.0-6.5) exhibited dramatic increases in fluorescence only upon duplex formation with their fully matched target DNAs. PMID- 28809426 TI - Polarization-sensitive and broadband germanium sulfide photodetectors with excellent high-temperature performance. AB - Layered materials, such as graphene, transition metal dichalcogenides and black phosphorene, have been established rapidly as intriguing building blocks for optoelectronic devices. Here, we introduce highly polarization sensitive, broadband, and high-temperature-operation photodetectors based on multilayer germanium sulfide (GeS). The GeS photodetector shows a high photoresponsivity of about 6.8 * 103 A W-1, an extremely high specific detectivity of 5.6 * 1014 Jones, and broad spectral response in the wavelength range of 300-800 nm. More importantly, the GeS photodetector has high polarization sensitivity to incident linearly polarized light, which provides another degree of freedom for photodetectors. Tremendously enhanced photoresponsivity is observed with a temperature increase, and high responsivity is achievable at least up to 423 K. The establishment of larger photoinduced reduction of the Schottky barrier height will be significant for the investigation of the photoresponse mechanism of 2D layered material-based photodetectors. These attributes of high photocurrent generation in a wide temperature range, broad spectral response, and polarization sensitivity coupled with environmental stability indicate that the proposed GeS photodetector is very suitable for optoelectronic applications. PMID- 28809427 TI - Advances in chemoselective intermolecular cross-benzoin-type condensation reactions. AB - The intermolecular cross-benzoin and acyloin condensation reactions are powerful approaches to alpha-hydroxy carbonyls in a single step. However, their potentiality suffers from the occurrence of side reactions including self condensation and the formation of the undesired cross-acyloin. The broad range of azolium salt precatalysts available confers high tunability to NHC mediated benzoin condensation, assuring a good level of selectivity to the direct coupling between two non-equivalent aldehydes. Many efforts have also been devoted to the design of strategies that expand the range of suitable reaction partners beyond the traditional aldehydes and to the discovery of novel umpolung catalytic systems. The synthesis of both racemic and enantiomerically enriched acyloins is reviewed. PMID- 28809428 TI - A critical role of catalyst morphology in low-temperature synthesis of carbon nanotube-transition metal oxide nanocomposite. AB - The effect of the catalyst morphology on the growth of carbon nanotubes (CNT) on nanostructured transition metal oxides was investigated to study a novel low temperature synthetic route to functional CNT-transition metal oxide nanocomposites. Among several nanostructured manganese oxides with various morphologies and structures, only exfoliated 2D nanosheets of layered MnO2 acted as an effective catalyst for the chemical vapor deposition of CNT at low temperatures of 400-500 degrees C, which emphasizes the critical role of the catalyst morphology in CNT growth. Heat treatment of the MnO2 nanosheets under a C2H2 flow induced the deposition of CNT, as well as a phase transition to a 2D ordered assembly of MnO nanoparticles. The resulting CNT-MnO nanocomposites displayed excellent functionalities in Li-ion electrodes with huge discharge capacities and good rate characteristics, which highlights the usefulness of the present method for studying functional CNT-metal oxide nanocomposites. Electron microscopy and density functional theory calculations propose a formation mechanism via the efficient adsorption of carbon on the MnO2 nanosheets followed by the surface diffusion of carbon. It is of prime importance that the substitution of Fe for layered MnO2 nanosheets remarkably improved the efficiency of the formation of CNT by enhancing the surface adsorption of carbon species. This is the first report of the efficient growth of CNT at a very low temperature of 400 degrees C. The universal merit of the 2D nanosheet morphology was confirmed by the successful synthesis of a CNT-TiO2 nanocomposite with exfoliated titanate nanosheets. The present study demonstrates that employing exfoliated transition metal oxide nanosheets as catalysts provides an efficient low temperature synthetic route to functional CNT-transition metal oxide nanocomposites. PMID- 28809429 TI - Dissection of the module network implementation "LemonTree": enhancements towards applications in metagenomics and translation in autoimmune maladies. AB - Under the current deluge of omics, module networks distinctively emerge as methods capable of not only identifying inherently coherent groups (modules), thus reducing dimensionality, but also hypothesizing cause-effect relationships between modules and their regulators. Module networks were first designed in the transcriptomic era and further exploited in the multi-omic context to assess (for example) miRNA regulation of gene expression. Despite a number of available implementations, expansion of module networks to other omics is constrained by a limited characterization of the solutions' (modules plus regulators) accuracy and stability - an immediate need for the better characterization of molecular biology complexity in silico. We hence carefully assessed for LemonTree - a popular and open source module network implementation - the dependency of the software performances (sensitivity, specificity, false discovery rate, solutions' stability) on the input parameters and on the data quality (sample size, expression noise) based on synthetic and real data. In the process, we uncovered and fixed an issue in the code for the regulator assignment procedure. We concluded this evaluation with a table of recommended parameter settings. Finally, we applied these recommended settings to gut-intestinal metagenomic data from rheumatoid arthritis patients, to characterize the evolution of the gut intestinal microbiome under different pharmaceutical regimens (methotrexate and prednisone) and we inferred innovative clinical recommendations with therapeutic potential, based on the computed module network. PMID- 28809430 TI - A one step method for the functional and property modification of DOPA based nanocoatings. AB - Biomimetic poly(catecholamine) coatings have gained much attention in recent years due to their versatility as functional materials. Despite this, only limited methods are available to modify the function and property of poly(catecholamine) coatings, primarily through post-modification methods. Our approach reported herein provides a simple approach to the fabrication of novel functionalized poly(catecholamine) coatings. The strategy employs the copolymerization of N-Ac-3,4-dihydroxyphenylalanine methyl ester (NADOPAMe) with nucleophilic additives, giving rise to nano-coatings on various surfaces including plastic, metal, glass and polymers. With the appropriate choice of nucleophilic additives, coatings with desired properties can be achieved. This is demonstrated through the fabrication of a redox responsive coating based on NADOPAMe with cysteamine as additive, which shows a concentration-dependent glutathione (GSH) responsive behavior. The ability to utilize this as a controlled release system is also demonstrated. PMID- 28809431 TI - Transdifferentiation of myoblasts into osteoblasts - possible use for bone therapy. AB - OBJECTIVES: Transdifferentiation is defined as the conversion of one cell type to another and is an ever-expanding field with a growing number of cells found to be capable of such a process. To date, the fact remains that there are limited treatment options for fracture healing, osteoporosis and bone repair post destruction by bone tumours. Hence, this review focuses on the transdifferentiation of myoblast to osteoblast as a means to further understand the transdifferentiation process and to investigate a potential therapeutic option if successful. KEY FINDINGS: The potent osteoinductive effects of the bone morphogenetic protein-2 are largely implicated in the transdifferentiation of myoblast to osteoblast. Bone morphogenetic protein-2-induced activation of the Smad1 protein ultimately results in JunB synthesis, the first transcriptional step in myoblast dedifferentiation. The upregulation of the activating protein-1 binding activity triggers the transcription of the runt-related transcription factor 2 gene, a transcription factor that plays a major role in osteoblast differentiation. SUMMARY: This potential transdifferentiation treatment may be utilised for dental implants, fracture healing, osteoporosis and bone repair post destruction by bone tumours. PMID- 28809432 TI - Intranasal administration of brain-targeted HP-beta-CD/chitosan nanoparticles for delivery of scutellarin, a compound with protective effect in cerebral ischaemia. AB - OBJECTIVES: Scutellarin (SCU) is a traditional Chinese medicine used for the treatment of ischaemic cerebrovascular disease, but its clinic applications have been limited due to its poor water solubility, poor bioavailability and short half-life. In comparison with the conventional oral and intravenous administration, nasal administration may help targeting the drug more directly to brain. Thus, we proposed to employ a novel SCU-loaded HP-beta-CD/chitosan nanoparticles (CD/CS-SCU-NPs) to deliver SCU to brain through the nasal route. METHODS: CD/CS-SCU-NPs were prepared by an ionic cross-linking method. The NPs formulation was tested in vivo in C57BL mice. The concentrations of SCU in brain and plasma after intranasal and oral administration of the CD/CS-SCU-NPs and after intranasal administration of SCU solution (SCU-SL) were determined and brain targeting parameters were calculated. KEY FINDINGS: Compared to the intranasal administration of SCU-SL, intranasal and oral administration of the CD/CS-SCU-NPs increased accumulation of SCU in brain, indicating that CD/CS-SCU NPs have obvious brain targeting advantage, although the advantage is more evident after intranasal administration. CONCLUSIONS: Findings from in-vivo study indicated that much higher SCU brain exposure was observed after intranasal administration of the CD/CS-SCU-NPs. Administration of CD/CS-SCU-NPs through the nasal route would have potential to treat ischemic cerebrovascular disease. PMID- 28809433 TI - Pharmacokinetic and ocular microdialysis study of oral ginkgo biloba extract in rabbits by UPLC-MS/MS determination. AB - OBJECTIVES: The purpose of this work was to determine and investigate the absorption of ginkgo terpenoids (GT) in plasma and aqueous humour after oral administration of ginkgo biloba extract (GBE) by UPLC-MS/MS method. METHODS: The UPLC-MS/MS determination of GT employed the multiple reaction monitoring mode using an electrospray negative ionization. The rabbits were orally administered the suspension of GBE at a dose of 500 mg/kg. Serial plasma and dialysate samples were collected at the corresponding time and then analysed by UPLC-MS/MS. KEY FINDINGS: In plasma, the mean AUC from 0 to 48 h was 14.12, 12.59, 23.75, 1.51 h MUg/ml for GLJ and 5.34 h MUg/ml for GLA, GLB, GLC, GLJ and BLL, respectively. In aqueous humour, the five ginkgo terpenoids have been detected. Compared with the other four GT, BLL has better absorption in the eyes. CONCLUSIONS: A selective and reproducible UPLC-MS/MS method was developed and validated to determine and investigate the absorption of ginkgo terpenoids in plasma and aqueous humour of rabbits after oral administration of GBE. The main five ginkgo terpenoids could be absorbed into eyes. PMID- 28809434 TI - Pneumatosis intestinalis in an SIV-infected rhesus macaque (Macaca mulatta). AB - Pneumatosis intestinalis (PI) has been described as an incidental finding in domestic animals and humans where it is associated with human immunodeficiency virus infection among other comorbidities. This report describes emphysematous changes consistent with PI in a simian immunodeficiency virus (SIV)-infected rhesus macaque (Macaca mulatta). PMID- 28809435 TI - First case report of non-human primates (Alouatta clamitans) with the hypervirulent Klebsiella pneumoniae serotype K1 strain ST 23: A possible emerging wildlife pathogen. AB - BACKGROUND: Hypervirulent strain of Klebsiella pneumoniae genotype K1 isolates have recently emerged, causing severe pyogenic liver abscess complicated by devastating metastatic infections in humans. METHODS: We describe a short outbreak of the non-human primate (NHP) research center, associated with a hypervirulent K. pneumoniae. The genetic similarity of the strains was evaluated by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) techniques, and virulence encoding genes were detected by polymerase chain reaction (PCR). RESULTS: The isolates were phenotypically like strains causing community-acquired invasive liver abscess syndrome in humans. All strains exhibited identical PFGE patterns and were found to belong to ST23 and presented a hypermucovisity phenotype and possessed magA and rmpA gene. CONCLUSION: This is the first case report of NHPs caused by K. pneumoniae displaying a hypermucoviscosity phenotype and belonging to capsular serotypes K1 and ST23. PMID- 28809436 TI - Anatomical description of the main vessels for venipuncture in the black-striped capuchin monkey (Sapajus libidinosus, Silva Junior, 2002). AB - BACKGROUND: The scarcity of data on the anatomy of Sapajus libidinosus has impeded the execution for appropriate veterinary treatment. The objective of this study was to describe the main peripheral veins of the capuchin monkey, used in venipuncture and indicate the best access route for venipuncture procedures. METHODS: Ten S. libidinosus corpses were used. The face, neck, chest, and pelvic limb were dissected using surgical instruments to identify and locate surface vessels. RESULTS: The main superficial veins identified could be used for venipuncture in capuchin monkey where the external jugular, brachial, cephalic, saphenous, and femoral veins. The veins in the pelvic limb were the most suitable for this purpose, with an un anesthetized subject. CONCLUSIONS: The femoral vein was shown to be the most suitable for blood sampling and drug administration and the saphenous vein for serum therapy protocols. PMID- 28809437 TI - The conditional stimulation of rat organic cation transporter 2, but not its human ortholog, by mesoridazine: the possibility of the involvement of the high affinity binding site of the transporter in the stimulation. AB - OBJECTIVES: To study the functional consequences of the human and rat forms of OCT2 in the presence of phenothiazines. METHODS: MDCK cells expressing human or rat OCT2 were established, and MPP+ transport was determined by uptake assays. Concentration dependency was studied for the stimulatory/inhibitory effects of phenothiazines on MPP+ transport. KEY FINDINGS: Among the 11 phenothiazines examined, the majority were found to have comparable effects on transporter function between the orthologous forms, while three phenothiazines, particularly mesoridazine, had complex impacts on transporter function. For rOCT2, mesoridazine stimulated transport at 0.1 and 1 MUmMPP+ with the mesoridazine concentration-uptake curve becoming bell-shaped. This conditional effect became less pronounced at 30 MUmMPP+, resulting in an inhibition curve with a typical profile. For hOCT2, mesoridazine behaved as a typical inhibitor of transporter function at all MPP+ concentrations, although the kinetics of inhibition were still affected by the substrate concentration. CONCLUSIONS: The conditional stimulation by mesoridazine in rOCT2, and the lack thereof in hOCT2, may be a manifestation of the interaction of phenothiazine with substrate binding at the high-affinity site of the OCT2. As OCT2 was previously indicated in some drug drug interactions, the conditional stimulation of OCT2 and its potential species differences may be of practical relevance. PMID- 28809438 TI - Stimulation of human osteoblast cells (MG63) proliferation using decanoic acid and isopropyl amine fractions of Wattakaka volubilis leaves. AB - OBJECTIVES: This study was carried out to investigate the impact of various isolated phytochemical components present in the Wattakaka volubilis leaves for the growth and proliferation of human osteoblast like cells (MG63). KEY FINDINGS: Ethyl acetate was found to be the best solvent for potential extraction of phytocompounds. Further, the MTT assay was carried out to deduce the viability of 44 isolated phytochemicals. Ten phytochemical fractions found to increase the cell growth were subjected to statistical tool namely Plackett-Burman and Central composite design to screen the optimum phytochemical fraction and its dosage. The active phytochemical constituents were analysed and identified as hexadeconoic acid, octadeconoic acid, N,N-diisopropyl(2,2,3,3,3-pentafluoropropyl)amine using GC-MS and HPLC techniques. The impact of optimized concentration was assessed on osteoblast cells. The maximum % cell viability, % DNA and collagen content were found to be 164.44, 159.32 and 3.81, respectively. CONCLUSIONS: The results confirmed that the optimized fraction containing decanoic acid and isopropyl amine at particular concentration stimulated the proliferation of human osteoblast (MG63) cells. Hence, the optimized concentration of this compound from W. volubilis may used for treatment of bone related injuries externally. PMID- 28809439 TI - In-silico profiling of the biological activities of Amaryllidaceae alkaloids. AB - OBJECTIVES: The large number of publications about Amaryllidaceae alkaloids reflects the abundance and variety in biological activity of these alkaloids. An in-silico approach was implemented in this work to rationalize the individual alkaloids to molecular biological activity. METHODS: A database was generated containing 313 Amaryllidaceae alkaloids which were then subjected to in-silico validated structure-based virtual screening using extra precision (XP) approach of Glide docking program. Further pharmacophore detection of the high scorers resulted in a hybrid model considering the structural and spatial characteristics of the molecules. The focus was laid on representative targets against viral infections, acetylcholinesterase and cancer. BEDROC studies were used for validation of the accuracy of docking methods. KEY FINDINGS: As expected, galanthamine-type alkaloids were the most active against hACHE; yet, lycorenine- and tazettine-type alkaloids contributed significantly, while lycorine-type alkaloids dominated the hit list against HIV-1 PR target protein and were significantly active against HIV-1 RT and influenza NA. Surprisingly, belladine type alkaloids showed the highest number of hits against HDAC2, while lycorine- and narciclasine-type alkaloids dominated the hit lists against Aurora kinase A and VEGFR2. CONCLUSIONS: This report provides useful information on Amaryllidaceae alkaloids and serves as a starting point to access their undiscovered biological activity. PMID- 28809440 TI - Floating solid cellulose nanofibre nanofoams for sustained release of the poorly soluble model drug furosemide. AB - OBJECTIVES: This study aimed to prepare a furosemide-loaded sustained release cellulose nanofibre (CNF)-based nanofoams with buoyancy. METHODS: Dry foams consisting of CNF and the model drug furosemide at concentrations of 21% and 50% (w/w) have been prepared by simply foaming a CNF-drug suspension followed by drying. The resulting foams were characterized towards their morphology, solid state properties and dissolution kinetics. KEY FINDINGS: Solid state analysis of the resulting drug-loaded foams revealed that the drug was present as an amorphous sodium furosemide salt and in form of furosemide form I crystals embedded in the CNF foam cell walls. The foams could easily be shaped and were flexible, and during the drug release study, the foam pieces remained intact and were floating on the surface due to their positive buoyancy. Both foams showed a sustained furosemide release compared to a marketed tablet. It was found that the extent of sustained release from both foams was dependent on the drug loading, the dimension of the foam piece, as well as the solid state of the drug. CONCLUSIONS: Furosemide-loaded CNF-based foams with sustained release and buoyancy have been successfully prepared in a simple casting and drying procedure. PMID- 28809441 TI - Design and Fabrication of Temperature-Sensitive Nanogels with Controlled Drug Release Properties for Enhanced Photothermal Sterilization. AB - For better removal of excessive free radicals and harmful bacteria from the human body, the development of synergistic antioxidant and antibacterial agents is urgently required. Herein, we designed novel temperature-sensitive, curcumin (Cur)-loaded nanogels for the application of scavenging reactive oxygen species and killing pathogenic bacteria. Photothermal sterilization, different from traditional antibiotics, is a promising and effective treatment for pathogenic bacterial infection. The nanogels were fabricated by using poly(N isopropylacrylamide) (a temperature-sensitive hydrogel) to encapsulate poly(3,4 ethylenedioxythiophene) nanoparticles (photothermal agents) and Cur through a reformative precipitation polymerization. When triggered by near-IR light, the Cur-loaded nanogels exhibited high (56.8 %), and excellent temperature-sensitive effects. Moreover, the light-induced temperature increase can also weaken the interaction between the networks of PNIPAAm and Cur, to show excellent antioxidant and antibacterial performance (90 % cell death) of the nanogels. PMID- 28809442 TI - Simultaneous Degradation and Removal of CrVI from Aqueous Solution with Zr-Based Metal-Organic Frameworks Bearing Inherent Reductive Sites. AB - Given the serious harm of CrVI to human health, development of efficient techniques for its degradation and subsequent in situ adsorptive removal is highly desirable. Herein, UiO-66 type metal-organic frameworks (MOFs) integrated with various hydroxyl groups (UiO-66, UiO-66-OH, and UiO-66-(OH)2 ) were successfully explored for the efficient decontamination of CrVI from aqueous solution. The abundant hydroxyl groups in organic ligands not only served as reductive sites for the degradation of CrVI to less toxic CrIII but also acted as inherent anchorages for the efficient capture of CrIII . Thanks to their inherent hydroxyl groups and high porosity, UiO-66-(OH)2 presented almost complete removal of Cr species in simulated industrial wastewater. The total Cr content could be reduced from 5 ppm to 48 ppb under optimized adsorption conditions, which is much lower than the limits of total Cr in drinking water established by the US Environmental Protection Agency (EPA). These outstanding CrVI decontamination features, combined with the exceptional chemical stability as well as high porosity prefigured the great potentials of the current adsorbents for the remediation of real-world CrVI -containing industrial wastewater. PMID- 28809443 TI - Characterisation, in-vitro and in-vivo evaluation of valproic acid-loaded nanoemulsion for improved brain bioavailability. AB - OBJECTIVE: This study was aimed to investigate the potential of formulated valproic acid-encapsulated nanoemulsion (VANE) to improve the brain bioavailability of valproic acid (VPA). METHODS: Valproic acid-encapsulated nanoemulsions were formulated and physically characterised (osmolarity, viscosity, drug content, drug encapsulation efficiency). Further investigations were also conducted to estimate the drug release, cytotoxic profile, in-vitro blood-brain barrier (BBB) permeability, pharmacokinetic parameter and the concentration of VPA and VANE in blood and brain. KEY FINDINGS: Physical characterisation confirmed that VANE was suitable for parenteral administration. Formulating VPA into nanoemulsion significantly reduced the cytotoxicity of VPA. In-vitro drug permeation suggested that VANEs crossed the BBB as freely as VPA. Pharmacokinetic parameters of VANE-treated rats in plasma and brain showed F3 VANE had a remarkable improvement in AUC, prolongation of half-life and reduction in clearance compared to VPA. Given the same extent of in-vitro BBB permeation of VPA and VANE, the higher bioavailability of VANE in brain was believed to have due to higher concentration of VANE in blood. The brain bioavailability of VPA was improved by prolonging the half-life of VPA by encapsulating it within the nanoemulsion-T80. CONCLUSIONS: Nanoemulsion containing VPA has alleviated the cytotoxic effect of VPA and improved the plasma and brain bioavailability for parenteral delivery of VPA. PMID- 28809444 TI - Circannual variation of mitotane and its metabolites plasma levels in patients with adrenocortical carcinoma. AB - OBJECTIVES: Mitotane is the reference drug for the adrenocortical carcinoma treatment; its pharmacological activity seems to depend on drug transformation in two active metabolites: o,p'-DDE (dichlorodiphenylethene) and o,p'-DDA (dichlorodiphenylacetate). Mitotane and metabolites are lipophilic agents; thus, they tend to accumulate into adipose tissues (white and brown), which change their prevalence seasonally. Aim of the work was to evaluate mitotane and metabolites plasma levels variation over the year, in adrenocortical cancer patients treated with Lysodren(r) for at least 6 months. METHODS: We enrolled a group of 86 adrenocortical carcinoma diagnosed patients, who underwent radical surgery and started mitotane as adjuvant treatment. For drug and metabolites plasma level (from samples collected ~12 h after the dose administration of mitotane, just before the subsequent administration) determination, a validated chromatographic method was used. KEY FINDINGS: Results showed an evidence of a seasonal trend for the three substance (o,p'-DDD, o,p'-DDE and o,p'-DDA) plasma levels, in terms of acrophases and lower values. Furthermore, it came out that male patients need a higher significant mitotane drug dose than female patients to reach mitotane therapeutic window. CONCLUSIONS: In conclusion, this is the first study assessing a mitotane plasma level variation over the year, but further studies in larger cohorts are required. PMID- 28809445 TI - A quantitative evaluation of physical and digital approaches to centre of mass estimation. AB - Centre of mass is a fundamental anatomical and biomechanical parameter. Knowledge of centre of mass is essential to inform studies investigating locomotion and other behaviours, through its implications for segment movements, and on whole body factors such as posture. Previous studies have estimated centre of mass position for a range of organisms, using various methodologies. However, few studies assess the accuracy of the methods that they employ, and often provide only brief details on their methodologies. As such, no rigorous, detailed comparisons of accuracy and repeatability within and between methods currently exist. This paper therefore seeks to apply three methods common in the literature (suspension, scales and digital modelling) to three 'calibration objects' in the form of bricks, as well as three birds to determine centre of mass position. Application to bricks enables conclusions to be drawn on the absolute accuracy of each method, in addition to comparing these results to assess the relative value of these methodologies. Application to birds provided insights into the logistical challenges of applying these methods to biological specimens. For bricks, we found that, provided appropriate repeats were conducted, the scales method yielded the most accurate predictions of centre of mass (within 1.49 mm), closely followed by digital modelling (within 2.39 mm), with results from suspension being the most distant (within 38.5 mm). Scales and digital methods both also displayed low variability between centre of mass estimates, suggesting they can accurately and consistently predict centre of mass position. Our suspension method resulted not only in high margins of error, but also substantial variability, highlighting problems with this method. PMID- 28809446 TI - Deferasirox for managing iron overload in people with thalassaemia. AB - BACKGROUND: Thalassaemia is a hereditary anaemia due to ineffective erythropoiesis. In particular, people with thalassaemia major develop secondary iron overload resulting from regular red blood cell transfusions. Iron chelation therapy is needed to prevent long-term complications.Both deferoxamine and deferiprone are effective; however, a review of the effectiveness and safety of the newer oral chelator deferasirox in people with thalassaemia is needed. OBJECTIVES: To assess the effectiveness and safety of oral deferasirox in people with thalassaemia and iron overload. SEARCH METHODS: We searched the Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 12 August 2016.We also searched MEDLINE, Embase, the Cochrane Library, Biosis Previews, Web of Science Core Collection and three trial registries: ClinicalTrials.gov; the WHO International Clinical Trials Registry Platform; and the Internet Portal of the German Clinical Trials Register: 06 and 07 August 2015. SELECTION CRITERIA: Randomised controlled studies comparing deferasirox with no therapy or placebo or with another iron-chelating treatment. DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias and extracted data. We contacted study authors for additional information. MAIN RESULTS: Sixteen studies involving 1807 randomised participants (range 23 to 586 participants) were included. Twelve two-arm studies compared deferasirox to placebo (two studies) or deferoxamine (seven studies) or deferiprone (one study) or the combination of deferasirox and deferoxamine to deferoxamine alone (one study). One study compared the combination of deferasirox and deferiprone to deferiprone in combination with deferoxamine. Three three-arm studies compared deferasirox to deferoxamine and deferiprone (two studies) or the combination of deferasirox and deferiprone to deferiprone and deferasirox monotherapy respectively (one study). One four-arm study compared two different doses of deferasirox to matching placebo groups.The two studies (a pharmacokinetic and a dose-escalation study) comparing deferasirox to placebo (n = 47) in people with transfusion-dependent thalassaemia showed that deferasirox leads to net iron excretion. In these studies, safety was acceptable and further investigation in phase II and phase III studies was warranted.Nine studies (1251 participants) provided data for deferasirox versus standard treatment with deferoxamine. Data suggest that a similar efficacy can be achieved depending on the ratio of doses of deferoxamine and deferasirox being compared. In the phase III study, similar or superior efficacy for the intermediate markers ferritin and liver iron concentration (LIC) could only be achieved in the highly iron-overloaded subgroup at a mean ratio of 1 mg of deferasirox to 1.8 mg of deferoxamine corresponding to a mean dose of 28.2 mg per day and 51.6 mg per day respectively. The pooled effects across the different dosing ratios are: serum ferritin, mean difference (MD) 454.42 ng/mL (95% confidence interval (CI) 337.13 to 571.71) (moderate quality evidence); LIC evaluated by biopsy or SQUID, MD 2.37 mg Fe/g dry weight (95% CI 1.68 to 3.07) (moderate quality evidence) and responder analysis, LIC 1 to < 7 mg Fe/g dry weight, risk ratio (RR) 0.80 (95% CI 0.69 to 0.92) (moderate quality evidence). The substantial heterogeneity observed could be explained by the different dosing ratios. Data on mortality (low quality evidence) and on safety at the presumably required doses for effective chelation therapy are limited. Patient satisfaction was better with deferasirox among those who had previously received deferoxamine treatment, RR 2.20 (95% CI 1.89 to 2.57) (moderate quality evidence). The rate of discontinuations was similar for both drugs (low quality evidence).For the remaining comparisons in people with transfusion-dependent thalassaemia, the quality of the evidence for outcomes assessed was low to very low, mainly due to the very small number of participants included. Four studies (205 participants) compared deferasirox to deferiprone; one of which (41 participants) revealed a higher number of participants experiencing arthralgia in the deferiprone group, but due to the large number of different types of adverse events reported and compared this result is uncertain. One study (96 participants) compared deferasirox combined with deferiprone to deferiprone with deferoxamine. Participants treated with the combination of the oral iron chelators had a higher adherence compared to those treated with deferiprone and deferoxamine, but no participants discontinued the study. In the comparisons of deferasirox versus combined deferasirox and deferiprone and that of deferiprone versus combined deferasirox and deferiprone (one study, 40 participants), and deferasirox and deferoxamine versus deferoxamine alone (one study, 94 participants), only a few patient-relevant outcomes were reported and no significant differences were observed.One study (166 participants) included people with non-transfusion dependent thalassaemia and compared two different doses of deferasirox to placebo. Deferasirox treatment reduced serum ferritin, MD -306.74 ng/mL (95% CI -398.23 to -215.24) (moderate quality evidence) and LIC, MD -3.27 mg Fe/g dry weight (95% CI -4.44 to -2.09) (moderate quality evidence), while the number of participants experiencing adverse events and rate of discontinuations (low quality evidence) was similar in both groups. No participant died, but data on mortality were limited due to a follow-up period of only one year (moderate quality evidence). AUTHORS' CONCLUSIONS: Deferasirox offers an important treatment option for people with thalassaemia and secondary iron overload. Based on the available data, deferasirox does not seem to be superior to deferoxamine at the usually recommended ratio of 1 mg of deferasirox to 2 mg of deferoxamine. However, similar efficacy seems to be achievable depending on the dose and ratio of deferasirox compared to deferoxamine. Whether this will result in similar efficacy and will translate to similar benefits in the long term, as has been shown for deferoxamine, needs to be confirmed. Data from randomised controlled trials on rare toxicities and long-term safety are still limited. However, after a detailed discussion of the potential benefits and risks, deferasirox could be offered as the first-line option to individuals who show a strong preference for deferasirox, and may be a reasonable treatment option for people showing an intolerance or poor adherence to deferoxamine. PMID- 28809447 TI - Pulmonary delivery of tea tree oil-beta-cyclodextrin inclusion complexes for the treatment of fungal and bacterial pneumonia. AB - OBJECTIVES: Bacterial pneumonia is a common cause of death worldwide. Tea tree oil (TTO) is a potent antimicrobial natural product, which is formulated in dry powder inhalers (DPIs) for the treatment of fungal and bacterial pneumonia. METHODS: Tea tree oil-beta-cyclodextrin inclusion complexes (TTO-beta-CD) were prepared and characterized. Aerodynamic properties of TTO-beta-CD powders were measured. The rat models of fungal (Candida albicans) and bacterial (Acinetobacter baumannii) pneumonia were prepared. Saline, TTO, TTO-beta-CD and the positive drug (fluconazole or penicillin) were directly delivered to the rat lungs. Pathological and biological assays were conducted. KEY FINDINGS: Tea tree oil-beta-CD powders had an appropriate aerodynamic diameter of 5.59 MUm and the fine particle fraction of 51.22%, suitable for pulmonary delivery. TTO-beta-CD showed higher and similar antipneumonic effects on the rat models than fluconazole and penicillin, respectively. The effects of TTO-beta-CD were higher than TTO alone. The antipneumonic mechanisms involved blocking the recruitment of leucocytes and neutrophils, eliminating the microbes, downregulating pro inflammatory cytokines (including tumour necrosis factor-alpha, interleukin-1beta and interleukin-6), suppressing cyclooxygenase 2 expression, and further reducing lung injury. CONCLUSIONS: Inhaled TTO-beta-CD powders have the advantages of portability, high stability, self-administration, high lung deposition and good antipneumonic effect. It is a promising DPI for the treatment of fungal and bacterial pneumonia. PMID- 28809448 TI - Improved pharmacokinetic and pharmacodynamic attributes of artemether lumefantrine-loaded solid SMEDDS for oral administration. AB - OBJECTIVES: To evaluate the in-vivo efficacy of solid SMEDDS containing combination of artemether and lumefantrine. METHODS: Formulation development of solid SMEDDS containing combination of artemether and lumefantrine was carried out using spray drying technique. These S-SMEDDS were evaluated for reduction in parasitemia and mortality as well as subacute toxicity in mice. Haematology, biochemical parameters and histopathology were performed for evaluating safety of formulation. Pharmacokinetic characterization of both drugs was performed after oral administration in rats. KEY FINDINGS: Optimized solid SMEDDS containing low, medium and high dose were more effective in reducing parasitemia and mortality of mice as compared to marketed tablets containing high dose of these drugs. Single oral administration of solid SMEDDS containing high-dose combination could maintain plasma concentration of lumefantrine above the minimum effective concentration for ~4 days. CONCLUSIONS: Solid SMEDDS containing low-, medium- and high-dose combination of artemether and lumefantrine are more effective than marketed tablets. PMID- 28809449 TI - Microbial communities as biosensors for monitoring urban environments. AB - The BE microbiome is a naturally embedded biosensor in urban infrastructure that can be used to monitor environmental quality and human activity. There are many potential opportunities for leveraging BE microbial communities to guide urban design and public health policy. PMID- 28809450 TI - Microalgae, old sustainable food and fashion nutraceuticals. AB - Microalgae have been used for centuries to provide nourishment to humans and animals, only very recently they have become much more widely cultured and harvested at large industrial scale. This paper reviews the potential health benefits and nutrition provided by microalgae whose benefits are contributing to expand their market. We also point out several key challenges that remain to be addressed in this field. PMID- 28809452 TI - Neurotoxin synthesis is positively regulated by the sporulation transcription factor Spo0A in Clostridium botulinum type E. AB - Clostridium botulinum produces the most potent natural toxin, the botulinum neurotoxin (BoNT), probably to create anaerobiosis and nutrients by killing the host, and forms endospores that facilitate survival in harsh conditions and transmission. Peak BoNT production coincides with initiation of sporulation in C. botulinum cultures, which suggests common regulation. Here, we show that Spo0A, the master regulator of sporulation, positively regulates BoNT production. Insertional inactivation of spo0A in C. botulinum type E strain Beluga resulted in significantly reduced BoNT production and in abolished or highly reduced sporulation in relation to wild-type controls. Complementation with spo0A restored BoNT production and sporulation. Recombinant DNA-binding domain of Spo0A directly bound to a putative Spo0A-binding box (CTTCGAA) within the BoNT/E operon promoter, demonstrating direct regulation. Spo0A is the first neurotoxin regulator reported in C. botulinum type E. Unlike other C. botulinum strains that are terrestrial and employ the alternative sigma factor BotR in directing BoNT expression, C. botulinum type E strains are adapted to aquatic ecosystems, possess distinct epidemiology and lack BotR. Our results provide fundamental new knowledge on the genetic control of BoNT production and demonstrate common regulation of BoNT production and sporulation, providing a key intervention point for control. PMID- 28809451 TI - Roads to advanced vaccines: influenza case study. AB - Vaccines represent a cornerstone to ensure healthy lives and promote well-being for all at all ages. However, there are many diseases for which vaccines are not available, are relatively ineffective or need to be adapted periodically. Advances in microbial biotechnology will contribute to overcoming these roadblocks by laying the groundwork for improving and creating new approaches for developing better vaccines, as illustrated here in the case of influenza. PMID- 28809454 TI - Palladium-Catalyzed Carbon-Fluorine and Carbon-Hydrogen Bond Alumination of Fluoroarenes and Heteroarenes. AB - Through serendipitous discovery, a palladium bis(phosphine) complex was identified as a catalyst for the selective transformation of sp2 C-F and sp2 C-H bonds of fluoroarenes and heteroarenes to sp2 C-Al bonds (19 examples, 1 mol % Pd loading). The carbon-fluorine bond functionalization reaction is highly selective for the formation of organoaluminium products in preference to hydrodefluorination products (selectivity=4.4:1 to 27:1). Evidence is presented for a tandem catalytic process in which hydrodefluorination is followed by sp2 C H alumination. PMID- 28809453 TI - A meta-analysis: microRNAs' prognostic function in patients with nonsmall cell lung cancer. AB - Accumulating papers have demonstrated that microRNAs play an important role in the progression of lung cancer, mainly as oncogenic and tumor suppressive. Therefore, microRNAs may influence the survival of lung cancer patients. In this meta-analysis, we evaluated the role of microRNAs in affecting the overall survival in nonsmall cell lung cancer (NSCLC) patients, which may provide valuable information for the treatment of nonsmall cell lung cancer. We used keywords to retrieve literatures from online databases PUBMED, EMBASE and Web of Science and included 12 studies into our investigation according to pre-set criteria. Then, we analyzed the data with stata13.1 to evaluate the microRNAs role on the prognosis of NSCLC patients. NSCLC patients with higher microRNAs expression levels tend to show lower overall survival. HR (hazard ratio): 2.49, 95% CI (confidence interval): 1.84-3.37. Besides, both oncogenic and tumor suppressive microRNAs have an evident influence on prognosis with HR values of 2.60 (95% CI: 2.12-3.19) and 0.41 (95% CI: 0.05-0.34), respectively. microRNAs, especially from tissue, have an influence on overall survival of NSCLC patients, which indicates that microRNAs could serve as potential prognostic markers for NSCLC and may provide a treatment strategy for advanced NSCLC patients. PMID- 28809455 TI - A Nanophotonic Structure Containing Living Photosynthetic Bacteria. AB - Photosynthetic organisms rely on a series of self-assembled nanostructures with tuned electronic energy levels in order to transport energy from where it is collected by photon absorption, to reaction centers where the energy is used to drive chemical reactions. In the photosynthetic bacteria Chlorobaculum tepidum, a member of the green sulfur bacteria family, light is absorbed by large antenna complexes called chlorosomes to create an exciton. The exciton is transferred to a protein baseplate attached to the chlorosome, before migrating through the Fenna-Matthews-Olson complex to the reaction center. Here, it is shown that by placing living Chlorobaculum tepidum bacteria within a photonic microcavity, the strong exciton-photon coupling regime between a confined cavity mode and exciton states of the chlorosome can be accessed, whereby a coherent exchange of energy between the bacteria and cavity mode results in the formation of polariton states. The polaritons have energy distinct from that of the exciton which can be tuned by modifying the energy of the optical modes of the microcavity. It is believed that this is the first demonstration of the modification of energy levels within living biological systems using a photonic structure. PMID- 28809456 TI - Real-Time Intracellular Measurements of ROS and RNS in Living Cells with Single Core-Shell Nanowire Electrodes. AB - Nanoelectrodes allow precise and quantitative measurements of important biological processes at the single living-cell level in real time. Cylindrical nanowire electrodes (NWEs) required for intracellular measurements create a great challenge for achieving excellent electrochemical and mechanical performances. Herein, we present a facile and robust solution to this problem based on a unique SiC-core-shell design to produce cylindrical NWEs with superior mechanical toughness provided by the SiC nano-core and an excellent electrochemical performance provided by the ultrathin carbon shell that can be used as such or platinized. The use of such NWEs for biological applications is illustrated by the first quantitative measurements of ROS/RNS in individual phagolysosomes of living macrophages. As the shell material can be varied to meet any specific detection purpose, this work opens up new opportunities to monitor quantitatively biological functions occurring inside cells and their organelles. PMID- 28809457 TI - Inherently Chiral Calixarenes: Synthesis and Applications. AB - This article looks at the chemistry surrounding the concept of inherently chiral calixarenes (ICCs), whose synthesis and application have only recently being realised. One challenge in the area of ICC chemistry is the sheer breadth and scope for installing different aspects of inherent chirality. The aim of this article is not to cover every known method, but rather to give the reader an overview of the main themes that have emerged in this area, including more recent additions to the literature. This overview will also touch on the very limited reports on the applications of ICCs which give a glimpse into the potential these compounds may have in future studies. PMID- 28809458 TI - Redox-Neutral Manganese(I)-Catalyzed C-H Activation: Traceless Directing Group Enabled Regioselective Annulation. AB - A strategy is reported in which traceless directing groups (TDGs) are used to promote the redox-neutral MnI -catalyzed regioselective synthesis of N heterocycles. Alkyne coupling partners bearing a traceless directing group, which serves as both the chelator and internal oxidant, were used to control the regioselectivity of the annulation reactions. This operationally simple approach is highly effective with previously challenging unsymmetrical alkyne systems, including unbiased dialkyl alkynes, with perfect regioselectivity. The simple conditions and the ability to carry out synthesis on a gram scale underscore the usefulness of this method. The application of this strategy in the concise synthesis of the bioactive compound PK11209 and the pharmaceutical moxaverine is also described. PMID- 28809459 TI - Intensity of integrated cancer palliative care plans and end-of-life acute medical hospitalisation among cancer patient in Northern Italy. AB - A high hospital utilisation at the end of life (EOL) is an indicator of suboptimal quality of health care. We evaluated the impact of the intensity of different Integrated Cancer Palliative Care (ICPC) plans on EOL acute medical hospitalisation among cancer decedents. Decedents of cancer aged 18-84 years, who were residents in two Italian regions, were investigated through integrated administrative data. Outcomes considered were prolonged hospital stay for medical reasons, 2+ hospitalisations during the last month of life and hospital death. The ICPC plans instituted 90 to 31 days before death represented the main exposure of interest. Other variables considered were gender, age class at death, marital status, recent hospitalisation and primary cancer site. Among 6,698 patients included in ICPC plans, 44.3% presented at least one critical outcome indicator; among these, 76.5% died in hospital, 60.3% had a prolonged (12+ days) medical hospitalisation, 19.1% had 2+ hospitalisations at the EOL. These outcomes showed a strong dose-response effect with the intensity of the ICPC plans, which is already evident at levels of moderate intensity. A well-ICPC approach can be very effective-beginning at low levels of intensity of care-in reducing the percentage of patients spending many days or dying in hospital. PMID- 28809460 TI - Quasi-Dual-Packed-Kerneled Au49 (2,4-DMBT)27 Nanoclusters and the Influence of Kernel Packing on the Electrochemical Gap. AB - Although face-centered cubic (fcc), body-centered cubic (bcc), hexagonal close packed (hcp), and other structured gold nanoclusters have been reported, it was unclear whether gold nanoclusters with mix-packed (fcc and non-fcc) kernels exist, and the correlation between kernel packing and the properties of gold nanoclusters is unknown. A Au49 (2,4-DMBT)27 nanocluster with a shell electron count of 22 has now been been synthesized and structurally resolved by single crystal X-ray crystallography, which revealed that Au49 (2,4-DMBT)27 contains a unique Au34 kernel consisting of one quasi-fcc-structured Au21 and one non-fcc structured Au13 unit (where 2,4-DMBTH=2,4-dimethylbenzenethiol). Further experiments revealed that the kernel packing greatly influences the electrochemical gap (EG) and the fcc structure has a larger EG than the investigated non-fcc structure. PMID- 28809461 TI - Cancer, comorbidity and workplace discrimination: The US experience. AB - Cancer survivors with comorbidities have more work-related challenges than cancer survivors without these other health problems. This study evaluated how these cancer survivors with comorbidities are faring under a newly revised workplace discrimination policy, which better accounts for the episodic nature of chronic illnesses. The sample included 18-64 year olds with a history of cancer who filed allegations of workplace discrimination in 2009-2011 (N = 1.291) in the US. Multivariable logistic regressions were used. Cancer survivors with comorbidities were more likely to file discrimination claims related to the terms of their employment (OR = 1.37, 95% CI = 1.04-1.80) than cancer survivors without comorbidities. Terms of employment-related claims were more likely to be ruled in favour of cancer survivors (versus employers), regardless of comorbidity status (OR = 1.44, 95% CI = 1.06-1.96). Despite this policy reform, alleged discrimination related to terms of employment existed at higher rates in cancer survivors with concurrent health problems. If employment is a goal in this high risk group, replication of findings in other countries, studies on potential mechanisms and development of innovative interventions in these higher risk cases are warranted. Efforts should be made to mitigate the impact of these comorbid health problems on work-related function. PMID- 28809462 TI - Multiple Electronic and Structural Factors Control Cyclobutane Pyrimidine Dimer and 6-4 Thymine-Thymine Photodimerization in a DNA Duplex. AB - The T-T photodimerization paths leading to the formation of cyclobutane pyrimidine dimer (CPD) and 6-4 pyrimidine pyrimidone (64-PP), the two main DNA photolesions, have been resolved for a T-T step in a DNA duplex by two complementary state-of-the-art quantum mechanical approaches: QM(CASPT2//CASSCF)/MM and TD-DFT/PCM. Based on the analysis of several different representative structures, we define a new-ensemble of cooperating geometrical and electronic factors (besides the distance between the reacting bonds) ruling T T photodimerization in DNA. CPD is formed by a barrierless path on an exciton state delocalized over the two bases. Large interbase stacking and shift values, together with a small pseudorotation phase angle for T at the 3'-end, favor this reaction. The oxetane intermediate, leading to a 64-PP adduct, is formed on a singlet T->T charge-transfer state and is favored by a large interbase angle and slide values. A small energy barrier (<0.3 eV) is associated to this path, likely contributing to the smaller quantum yield observed for this process. Eventually, a clear directionality is always shown by the electronic excitation characterizing the singlet photoactive state driving the photodimerization process: an exciton that is more localized on T3 and a 5'-T->3'-T charge transfer for CPD and oxetane formation, respectively, thus calling for specific electronic constraints. PMID- 28809464 TI - High Sensitivity Tuning of Work Function of Self-Assembled Monolayers Modified Electrodes Using Vacuum Ultraviolet Treatment. AB - We demonstrate systematic work function tuning of thiol-based SAM-modified gold electrodes with high controllability and sensitivity as high as 0.05 eV using vacuum ultraviolet technique (VUV). Under different irradiation times, both work function and wettability of the metal surface is modified. Fine tuning of the electrode work function is demonstrated by observable changes in the reverse current of a polymer Schottky diode. Additionally, the change in SAM chemical functionality validates the work function changes of VUV-irradiated electrodes. Our selective work function patterning on a single Au electrode via VUV could also reduce the required fabrication steps for more complex circuits. PMID- 28809463 TI - Dose-escalated radiation therapy is associated with better overall survival in patients with bone metastases from solid tumors: a propensity score-matched study. AB - We aimed to compare the overall survival (OS) of patients with bone metastases (BM) from solid tumors after standard-dose radiotherapy ([RT]; 30 Gy administered in 10 fractions; EQD2Gy = 32.5 Gy) and dose-escalated RT (EQD2Gy > 32.5 Gy). We retrospectively reviewed the clinical charts of 1795 patients (median age, 62.3 years; age range, 18-96 years) with BM from solid tumors who were referred for RT to our institute between 2000 and 2013. These patients were assigned to the standard-dose (n = 1125; 63%) and dose-escalated (n = 670; 37%) RT groups. OS, estimated as the duration between the first RT session and death, served as the main outcome measure. The dose-escalated RT group had a significantly better OS than the standard-dose RT group (P = 0.000). After allowing potential confounders in multivariate analysis, the RT dose retained its independent association with OS (hazard ratio [HR], 0.837; 95% confidence interval [CI], 0.753-0.929, P = 0.001). After propensity score matching of the baseline characteristics of both groups, RT dose retained its independent association with OS (HR, 0.887; 95% CI, 0.737-0.951; P = 0.011) on multivariate analysis. Dose-escalated RT exerted more favorable effects on OS in patients with non-lung cancer, those without multiple metastases, those without symptoms, and those with favorable prognosis. Dose escalated RT was significantly associated with better OS in patients with BM from solid malignancies, particularly among those with non-lung cancer, those without multiple metastases, those without symptoms, and those with favorable prognosis. PMID- 28809465 TI - Recoverable Self-Polarization in Lead-Free Bismuth Sodium Titanate Piezoelectric Thin Films. AB - Bismuth sodium titanate, Bi0.5Na0.5TiO3 (BNT), is a promising lead-free ferroelectric material. However, its potential applications have not been fully explored, mainly because of the complex domain structure arising from its intricate phase transitions. A deep and thorough study of its domain structure and polarization switching behavior will greatly help with understanding the polarization nature and with promoting future applications. In this work, we demonstrate that BNT polycrystalline films possess a highly ordered out-of-plane polarization (self-polarization) and randomly oriented in-plane polarizations. Interestingly, the inherent nature of polarization in the BNT films does not allow for the nonvolatile domain writing, as the switched polarization spontaneously and rapidly reverses to the initial orientation state once the external poling electric field is removed, making the self-polarization recoverable. Such a stable self-polarization vanishes gradually with temperature increasing over 150 degrees C but starts to recover to its initial state upon cooling down to 250 degrees C, and entirely recovers once the temperature is reduced to below 200 degrees C. Such interesting properties of BNT films are attributed to the combined effects of the free charges at the Pt electrode, (detected) cation vacancies at the oxide/Pt interface and the defects in oxide lattices. Our results make a step closer to fully understand the nature of polarization and related piezoelectricity in BNT. Such films with recoverable self-polarization are of great interest for applications as sensors, actuators, and transducers that can operate particularly under high temperatures and high electric field conditions. PMID- 28809466 TI - Tuning Phase Composition of Polymer Nanocomposites toward High Energy Density and High Discharge Efficiency by Nonequilibrium Processing. AB - Polymer nanocomposite dielectrics with high energy density and low loss are major enablers for a number of applications in modern electronic and electrical industry. Conventional fabrication of nanocomposites by solution routes involves equilibrium process, which is slow and results in structural imperfections, hence high leakage current and compromised reliability of the nanocomposites. We propose and demonstrate that a nonequilibrium process, which synergistically integrates electrospinning, hot-pressing and thermal quenching, is capable of yielding nanocomposites of very high quality. In the nonequilibrium nanocomposites of poly(vinylidene fluoride-co-hexafluoropropylene) (P(VDF-HFP)) and BaTiO3 nanoparticles (BTO_nps), an ultrahigh Weibull modulus beta of ~30 is achieved, which is comparable to the quality of the bench-mark biaxially oriented polypropylene (BOPP) fabricated with melt-extrusion process by much more sophisticated and expensive industrial apparatus. Favorable phase composition and small crystalline size are also induced by the nonequilibrium process, which leads to concomitant enhancement of electric displacement and breakdown strength of the nanocomposite hence a high energy density of ~21 J/cm3. Study on the polarization behavior and phase transformation at high electric field indicates that BTO_nps could facilitate the phase transformation from alpha- to beta polymorph at low electric field. PMID- 28809467 TI - Multidimensional Control of Cas9 by Evolved RNA Polymerase-Based Biosensors. AB - Systems to control Cas9 with spatial and temporal precision offer opportunities to decrease side effects, protect sensitive tissues, and create gene therapies that are only activated at defined times and places. Here, we present the design of new Cas9 controllers based on RNA polymerase (RNAP)-based biosensors that produce gRNAs, thereby regulating target knockout. After development and validation of a new abscisic acid-inducible biosensor to control Cas9, we lowered the background of the system using continuous evolution. To showcase the versatility of the approach, we designed biosensors that measure medically relevant protein-protein interactions to drive knockout. Finally, to test whether orthogonal RNAP biosensors could integrate multiple input signals to drive multiple gRNA-based outputs with a single Cas9 protein, we designed an "on switch/off switch" controller. The addition of one input activates the "on switch" and induces knockout, while the addition of a second input activates the "off switch" and produces a gRNA that directs the Cas9 protein to degrade the "on switch" gRNA vector, thereby deactivating it. This combined activation and deactivation system displayed very low background and inducible target knockout using different combinations of small-molecule treatment. Our results establish engineered RNAP biosensors as deployable Cas9 control elements and open up new opportunities for driving genetic editing technologies by diverse input signals. PMID- 28809468 TI - Construction of a Supramolecular Drug-Drug Delivery System for Non-Small-Cell Lung Cancer Therapy. AB - Nanoscale drug delivery systems (DDSs) are generally considered to be an effective alternative to small molecular chemotherapeutics due to improved accumulation in the tumor site and enhanced retention in blood. Nevertheless, most DDSs have low loading efficiency or even pose a high threat to normal organs from severe side effects. Ideally, a supramolecular drug-drug delivery system (SDDDS) composed of pure drugs via supramolecular interaction provides a hopeful approach for cancer treatment. Herein we propose a facile method to construct SDDDS via coassembly of gefitinib (GEF) and tripeptide tyroservatide (YSV), two kinds of chemotherapeutic pharmaceuticals for non-small-cell lung cancer (NSCLC) via multiple intermolecular interactions, including hydrogen bonding and pi-pi stacking. As shown through transmission electron microscopy (TEM) and dynamic light scattering (DLS), GEF and YSV self-assemble into nanoparticles with regular morphology and uniform size, which facilitates the delivery of both drugs. In vitro studies demonstrate that the SDDDS is much more efficient in entering cancer cells and inhibiting the proliferation of cancer cells compared with single GEF, YSV, or GEF/YSV drug mixture. In vivo experiments show that the SDDDS can selectively accumulate in tumor tissue, resulting in much better drug efficacy without evident side effects. Considering the advantages of the SDDDS, we believe this strategy provides a promising route for enhanced anticancer therapy in nanomedicine. PMID- 28809469 TI - Electrostatic Polysulfides Confinement to Inhibit Redox Shuttle Process in the Lithium Sulfur Batteries. AB - Cationic polymer can capture polysulfide ions and inhibit polysulfide shuttle effect in lithium sulfur (Li-S) rechargeable batteries, enhancing the Li-S battery cycling performance. The cationic poly[bis(2-chloroethyl) ether-alt-1,3 bis[3-(dimethylamino) propyl]urea] quaternized (PQ) with a high density quaternary ammonium cations can trap the lithium polysulfide through the electrostatic attraction between positively charged quaternary ammonium (R4N+) and negatively charged polysulfide (Sx2-). PQ binder based sulfur electrodes deliver much higher capacity and provide better stability than traditional polyvinylidene fluoride (PVDF) binder based electrodes in Li-S cells. A high sulfur loading of 7.5 mg/cm2 is achieved, which delivers a high initial areal capacity of 9.0 mAh/cm2 and stable cycling capacity at around 7.0 mAh/cm2 in the following cycles. PMID- 28809470 TI - Chelation-Controlled Additions to Chiral alpha- and beta-Silyloxy, alpha-Halo, and beta-Vinyl Carbonyl Compounds. AB - The science and art of preventing and managing disease and prolonging life is dependent on advances in medicine, biology, and biochemistry. Many of these advances will involve interactions of small molecules with biological entities. As such, they will rely on the efficient synthesis of active compounds with very high stereochemical purity. Although enantioselective reactions are important in this regard, most stereocenters in complex molecule synthesis are installed in diastereoselective reactions. Perhaps the most well-known diastereoselective C-C bond-forming reaction is the addition of nucleophiles to carbonyl groups with alpha- or beta-stereogenic centers. Diastereoselective additions of organometallic reagents to protected chiral alpha- and beta-hydroxy aldehydes and ketones are described by either Cram chelation or Felkin-Anh models, which are protecting group (PG)-dependent. Small PGs (X = OMOM, OBn, etc.) favor Cram chelation, wherein both the carbonyl group and the O-PG bind to the Lewis acidic metal, providing syn diol motifs. In contrast, silyl PGs, with the OSiR3 moiety being both bulky and weakly coordinating, provide anti diols (Felkin addition). It is well-known that exceptions to this paradigm are scarce. Therefore, the choice of PG is based on the desired stereochemical outcome in the addition step and is often inappropriate for the global protection strategy. Thus, it is critical to develop general methods for chelation-controlled additions of organometallics to chiral silyloxy aldehydes and ketones. Once the challenge of developing chelation-controlled additions to silyloxy carbonyl compounds can be met, the next question is what other pendant functional groups can chelate? Herein we introduce the first general methods for the chelation-controlled addition of organometallics to chiral silyloxy aldehydes and ketones. A wide variety of organozinc reagents have been used in these addition reactions, including dialkylzinc reagents that are commercially available or generated using Knochel's methods. Existing protocols for the generation of (E)-di- and trisubstituted vinylzinc reagents have been employed, and new methods for the generation of (Z)-di- and -trisubstituted vinylzinc reagents have been developed. The generation of 1,1-heterobimetallic reagents based on boron and zinc has been advanced, and the addition of these reagents to silyloxy aldehydes via chelation control is included. We will first describe the initial discovery and a model to explain the observed diastereoselectivities. A wide array of chelation-controlled additions to chiral alpha- and beta-silyloxy aldehydes and ketones will then be presented. We next describe other functional groups that undergo chelation controlled additions. alpha-Halo aldehyde derivatives are well-known to favor Felkin addition (via the Cornforth-Evans model). We introduce a general method for chelation-controlled additions to alpha-halo aldimines that provides useful precursors to aziridines. Finally, we provide preliminary evidence that even C?C bonds can play the role of chelating groups in additions to beta,gamma unsaturated ketones. The results outlined in this Account redefine the commonly held idea that chiral silyloxy- and halo-substituted carbonyl compounds only give Felkin addition products. The key to achieving chelation control in these reactions is the use of weakly coordinating solvents (dichloromethane and toluene) that do not readily bind to the zinc Lewis acids RZnX. PMID- 28809471 TI - 3D Analysis of Fuel Cell Electrocatalyst Degradation on Alternate Carbon Supports. AB - Understanding the mechanisms associated with Pt/C electrocatalyst degradation in proton exchange membrane fuel cell (PEMFC) cathodes is critical for the future development of higher-performing materials; however, there is a lack of information regarding Pt coarsening under PEMFC operating conditions within the cathode catalyst layer. We report a direct and quantitative 3D study of Pt dispersions on carbon supports (high surface area carbon (HSAC), Vulcan XC-72, and graphitized carbon) with varied surface areas, graphitic character, and Pt loadings ranging from 5 to 40 wt %. This is accomplished both before and after catalyst-cycling accelerated stress tests (ASTs) through observations of the cathode catalyst layer of membrane electrode assemblies. Electron tomography results show Pt nanoparticle agglomeration occurs predominantly at junctions and edges of aggregated graphitized carbon particles, leading to poor Pt dispersion in the as-prepared catalysts and increased coalescence during ASTs. Tomographic reconstructions of Pt/HSAC show much better initial Pt dispersions, less agglomeration, and less coarsening during ASTs in the cathode. However, a large loss of the electrochemically active surface area (ECSA) is still observed and is attributed to accelerated Pt dissolution and nanoparticle coalescence. Furthermore, a strong correlation between Pt particle/agglomerate size and measured ECSA is established and is proposed as a more useful metric than average crystallite size in predicting degradation behavior across different catalyst systems. PMID- 28809472 TI - Real-Time Tracking the Synthesis and Degradation of Albumin in Complex Biological Systems with a near-Infrared Fluorescent Probe. AB - In this study, a novel fluorescent detection system for biological sensing of human albumin (HA) was developed on the basis of the pseudoesterase activity and substrate preference of HA. The designed near-infrared (NIR) fluorescent probe (DDAP) could be effectively hydrolyzed by HA, accompanied by significant changes in both color and fluorescence spectrum. The sensing mechanism was fully investigated by fluorescence spectroscopy, NMR, and mass spectra. DDAP exhibited excellent selectivity and sensitivity toward HA over a variety of human plasma proteins, hydrolases, and abundant biomolecules found in human body. The probe has been successfully applied to measure native HA in diluted plasma samples and the secreted HA in the hepatocyte culture supernatant. DDAP has also been used for fluorescence imaging of HA reabsorption in living renal cells, and the results show that the probe exhibits good cell permeability, low cytotoxicity and high imaging resolution. Furthermore, DDAP has been successfully used for real time tracking the uptaking and degradation of albumin in ex vivo mouse kidney models for the first time. All these results clearly demonstrated that DDAP-based assay held great promise for real-time sensing and tracking HA in complex biological systems, which would be very useful for basic researches and clinical diagnosis of HA-associated diseases. PMID- 28809473 TI - Aggregation-Induced-Emission Materials with Different Electric Charges as an Artificial Tongue: Design, Construction, and Assembly with Various Pathogenic Bacteria for Effective Bacterial Imaging and Discrimination. AB - Imaging-based total bacterial count and type identification of bacteria play crucial roles in clinical diagnostics, public health, biological and medical science, and environmental protection. Herein, we designed and synthesized a series of tetraphenylethenes (TPEs) functionalized with one or two aldehyde, carboxylic acid, and quaternary ammonium groups, which were successfully used as fluorescent materials for rapid and efficient staining of eight kinds of representative bacterial species, including pathogenic bacteria Vibrio cholera, Klebsiella pneumoniae, and Listeria monocytogenes and potential bioterrorism agent Yersinia pestis. By comparing the fluorescence intensity changes of the aggregation-induced-emission (AIE) materials before and after bacteria incubation, the sensing mechanisms (electrostatic versus hydrophobic interactions) were simply discussed. Moreover, the designed AIE materials were successfully used as an efficient artificial tongue for bacteria discrimination, and all of the bacteria tested were identified via linear discriminant analysis. Our current work provided a general method for simultaneous broad-spectrum bacterial imaging and species discrimination, which is helpful for bacteria surveillance in many fields. PMID- 28809474 TI - Nano-in-Nano Approach for Enzyme Immobilization Based on Block Copolymers. AB - We set up a facile approach for fabrication of supports with tailored nanoporosity for immobilization of enzymes. To this aim block copolymers (BCPs) self-assembly has been used to prepare nanostructured thin films with well defined architecture containing pores of tailorable size delimited by walls with tailorable degree of hydrophilicity. In particular, we employed a mixture of polystyrene-block-poly(l-lactide) (PS-PLLA) and polystyrene-block-poly(ethylene oxide) (PS-PEO) diblock copolymers to generate thin films with a lamellar morphology consisting of PS lamellar domains alternating with mixed PEO/PLLA blocks lamellar domains. Selective basic hydrolysis of the PLLA blocks generates thin films, patterned with nanometric channels containing hydrophilic PEO chains pending from PS walls. The shape and size of the channels and the degree of hydrophilicity of the pores depend on the relative length of the blocks, the molecular mass of the BCPs, and the composition of the mixture. The strength of our approach is demonstrated in the case of physical adsorption of the hemoprotein peroxidase from horseradish (HRP) using 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulfonic acid) (ABTS) with H2O2 as substrate. The large surface area, the tailored pore sizes, and the functionalization with hydrophilic PEO blocks make the designed nanostructured materials suitable supports for the nanoconfinement of HRP biomolecules endowed with high catalytic performance, no mass-transfer limitations, and long-term stability. PMID- 28809475 TI - A DNA-Fueled and Catalytic Molecule Machine Lights Up Trace Under-Expressed MicroRNAs in Living Cells. AB - The detection of specific intracellular microRNAs (miRNAs) in living cells can potentially provide insight into the causal mechanism of cancer metastasis and invasion. However, because of the characteristic nature of miRNAs in terms of small sizes, low abundance, and similarity among family members, it is a great challenge to monitor miRNAs in living cells, especially those with much lower expression levels. In this work, we describe the establishment of a DNA-fueled and catalytic molecule machinery in cell signal amplification approach for monitoring trace and under-expressed miRNAs in living cells. The presence of the target miRNA releases the hairpin sequences from the dsDNA (containing the fluorescence resonance energy transfer (FRET) pair-labeled and unfolded hairpin sequences)-conjugated gold nanoparticles (dsDNA-AuNPs), and the DNA fuel strands assist the recycling of the target miRNA sequences via two cascaded strand displacement reactions, leading to the operation of the molecular machine in a catalytic fashion and the release of many hairpin sequences. As a result, the liberated hairpin sequences restore the folded hairpin structures and bring the FRET pair into close proximity to generate significantly amplified signals for detecting trace miRNA targets. Besides, the dsDNA-AuNP nanoprobes have good nuclease stability and show low cytotoxicity to cells, and the application of such a molecular system for monitoring trace and under-expressed miRNAs in living cells has also been demonstrated. With the advantages of in cell signal amplification and reduced background noise, the developed method thus offers new opportunities for detecting various trace intracellular miRNA species. PMID- 28809476 TI - Reactivity and Diffusivity of Li Polysulfides: A Fundamental Study Using Impedance Spectroscopy. AB - Polysulfides are central compounds in lithium-sulfur battery cells. However, the fundamental redox and diffusion properties of polysulfides are still poorly understood. We try to fill this gap by performing an accurate impedance spectroscopy investigation using symmetrical cells consisting of two planar glassy carbon electrodes separated with catholyte-soaked separator. The catholyte contains a mixture of selected polysulfides with predetermined nominal concentrations. Impedance measurements reveal textbook shapes of spectra for most polysulfide compounds or their mixtures. This allows reliable and accurate determination of the rate constant (exchange current density) for a given redox reaction as well as the diffusion coefficient and diffusion length for the rate determining polysulfide species. Further, it is confirmed that polysulfides tend to disproportionate with time, which significantly changes the chemistry and electrochemistry of the system. Two approaches are proposed for identification of the prevailing redox mechanism in the resulting mixtures. The values of kinetic and transport parameters obtained for different cases of interest are commented on in significant detail. The study provides a solid basis for better understanding of the complex processes in polysulfide mixtures. PMID- 28809477 TI - Reversible Reaction-Based Fluorescent Probe for Real-Time Imaging of Glutathione Dynamics in Mitochondria. AB - We report a mitochondria-specific glutathione (GSH) probe-designated as Mito RealThiol (MitoRT)-that can monitor in vivo real-time mitochondrial glutathione dynamics, and apply this probe to follow mitochondrial GSH dynamic changes in living cells for the first time. MitoRT can be utilized in confocal microscopy, super-resolution fluorescence imaging, and flow cytometry systems. Using MitoRT, we demonstrate that cells have a high priority to maintain the GSH level in mitochondria compared to the cytosol not only under normal growing conditions but also upon oxidative stress. PMID- 28809478 TI - Ruthenium(II) and Ruthenium(III) Complexes of p-Benziporphyrin: Merging Equatorial and Axial Organometallic Coordination. AB - A diamagnetic ruthenium(II) complex of 5,10,15,20-tetraphenyl-p-benziporphyrin [RuII(p-BzP)(CO)Cl] was obtained via the insertion of ruthenium into p benziporphyrin using triruthenium(0) dodecacarbonyl [Ru3(CO)12] as the metal source. The procedure applying dichloro(cycloocta-1,5-diene)ruthenium(II) (polymer, [Ru(COD)Cl2]n) afforded the paramagnetic six-coordinate ruthenium(III) p-benziporphyrin [RuIII(p-BzP)Cl2]. As shown by X-ray crystallography, the p phenylene ring in both complexes is sharply tilted out of the N3 plane, as reflected by the respective N3 (pyrrole)-C6 (p-phenylene) dihedral angle [RuII(p BzP)(CO)Cl, 52.5 degrees ; RuIII(p-BzP)Cl2, 53.7 degrees ]. p-Phenylene is bound to the ruthenium cation in an eta2 fashion, revealing the shortest ever Ru-C distance in the series of p-benziporphyrin complexes [RuII(p-BzP)(CO)Cl, 2.275(2) A; RuIII(p-BzP)Cl2, 2.324(5) A]. The reaction of RuII(p-BzP)(CO)Cl with ArMgCl or AlkMgCl results in the formation of diamagnetic six-coordinate ruthenium(II) p benziporphyrin complexes containing the apically coordinated sigma-alkyl or sigma aryl ligands, where the metal ion simultaneously coordinates to three carbon centers respectively accommodating eta2 (phenylene) and sigma (aryl and alkyl) modes. Reactions of sigma-aryl (alkyl) carbanions with paramagnetic RuIII(p BzP)Cl2 have been followed by 1H NMR spectroscopy. The procedure afforded the six coordinate paramagnetic ruthenium(III) p-benziporphyrin [RuIII(p-BzP)(Ph)Cl], which binds one sigma-aryl ligand, as reflected by the characteristic 1H NMR spectra spread within the +120 to -120 ppm range. Both paramagnetic complexes RuIII(p-BzP)(Ph)Cl and RuIII(p-BzP)(p-Tol)Cl are formed as a mixture of two stereoisomers differentiated by two nonequivalent locations of sigma-aryl with respect to the puckered macrocyclic ring. The paramagnetic shifts of sigma-aryls are indicative of pi-spin delocalization patterns. Analysis of the contact shifts and parallel density functional theory calculations of the spin density distribution in RuIII(p-BzP)Cl2, RuIII(p-BzP)(Ar)Cl, and RuIII(p-BzP)(Alk)Cl reflect the features of the dxy2(dxzdyz)3 electronic ground state. PMID- 28809479 TI - Natural Seminal Amyloids as Targets for Development of Synthetic Inhibitors of HIV Transmission. AB - Amyloids refer to a class of protein or peptide aggregates that are heterogeneous in size, morphology, and composition, and are implicated to play a central role in many neurodegenerative and systemic diseases. The strong correlation between biological activity and extent of aggregation of amyloidogenic proteins and peptides has led to an explosion of research efforts to target these materials with synthetic molecules or engineered antibodies to try to attenuate their function in disease pathology. Although many of these efforts to attenuate amyloid function have shown great promise in laboratory settings, the vast majority of work has been focused on targeting amyloids associated with neurologic diseases, which has been met with significant additional challenges that preclude clinical evaluation. Only recently have researchers started applying their efforts toward neutralizing the activity of amyloids associated with non-neurologic diseases. For instance, small peptides present in high abundance in human semen have been found to aggregate into amyloid-like fibrils, with in vitro experiments indicating that these amyloid fibrils could potentially increase the rate of infection of pathogens such as HIV by over 400 000-fold during sexual contact. Mechanistic investigations of naturally occurring seminal amyloid species such as Semen-derived Enhancer of Virus Infection (SEVI) and related natural peptide aggregates suggest that these materials interact strongly with virus particles and cell surfaces, facilitating viral attachment and internalization into cells and, thus, possibly promoting sexual transmission of disease. Such amyloid mediators in HIV transmission represent an attractive target for development of chemical approaches to attenuate their biological activity. For instance, the activity of seminal amyloids in genital fluids potentially allows for topical delivery of amyloid-targeting molecules, which could minimize common problems with systemic toxicity or permeability across biological barriers. In addition, molecules that target these amyloid mediators in viral attachment could potentially work synergistically with current antiviral agents to reduce the rate of HIV transmission. This Account will briefly summarize some of the key evidence in support of the capability of SEVI to enhance viral infection, and will highlight examples, many from our group, of recent efforts aimed at inhibiting its activity using synthetic small molecules, oligomeric peptides, and polymeric materials. We present various chemical strategies that have shown promise for neutralizing the role of SEVI in HIV transmission including the development of aggregation inhibitors of SEVI fibril formation, small molecule amyloid binders that modulate the charge or structure of SEVI, and synthetic molecules that form bioresistive coatings on SEVI and inhibit its interaction with the virus or cell surface. We discuss some unique challenges that hamper translation of these molecular strategies toward clinical evaluation, and propose several opportunities for researchers to address these challenges. PMID- 28809480 TI - Rapid Life-Cycle Impact Screening Using Artificial Neural Networks. AB - The number of chemicals in the market is rapidly increasing, while our understanding of the life-cycle impacts of these chemicals lags considerably. To address this, we developed deep artificial neural network (ANN) models to estimate life-cycle impacts of chemicals. Using molecular structure information, we trained multilayer ANNs for life-cycle impacts of chemicals using six impact categories, including cumulative energy demand, global warming (IPCC 2007), acidification (TRACI), human health (Impact2000+), ecosystem quality (Impact2000+), and eco-indicator 99 (I,I, total). The application domain (AD) of the model was estimated for each impact category within which the model exhibits higher reliability. We also tested three approaches for selecting molecular descriptors and identified the principal component analysis (PCA) as the best approach. The predictions for acidification, human health, and the eco-indicator 99 model showed relatively higher performance with R2 values of 0.73, 0.71, and 0.87, respectively, while the global warming model had a lower R2 of 0.48. This study indicates that ANN models can serve as an initial screening tool for estimating life-cycle impacts of chemicals for certain impact categories in the absence of more reliable information. Our analysis also highlights the importance of understanding ADs for interpreting the ANN results. PMID- 28809481 TI - Spectral Mining for Discriminating Blood Origins in the Presence of Substrate Interference via Attenuated Total Reflection Fourier Transform Infrared Spectroscopy: Postmortem or Antemortem Blood? AB - Often in criminal investigations, discrimination of types of body fluid evidence is crucially important to ascertain how a crime was committed. Compared to current methods using biochemical techniques, vibrational spectroscopic approaches can provide versatile applicability to identify various body fluid types without sample invasion. However, their applicability is limited to pure body fluid samples because important signals from body fluids incorporated in a substrate are affected strongly by interference from substrate signals. Herein, we describe a novel approach to recover body fluid signals that are embedded in strong substrate interferences using attenuated total reflection Fourier transform infrared (ATR FT-IR) spectroscopy and an innovative multivariate spectral processing. This technique supported detection of covert features of body fluid signals, and then identified origins of body fluid stains on substrates. We discriminated between ATR FT-IR spectra of postmortem blood (PB) and those of antemortem blood (AB) by creating a multivariate statistics model. From ATR FT-IR spectra of PB and AB stains on interfering substrates (polyester, cotton, and denim), blood-originated signals were extracted by a weighted linear regression approach we developed originally using principal components of both blood and substrate spectra. The blood-originated signals were finally classified by the discriminant model, demonstrating high discriminant accuracy. The present method can identify body fluid evidence independently of the substrate type, which is expected to promote the application of vibrational spectroscopic techniques in forensic body fluid analysis. PMID- 28809482 TI - Structural Dynamics of 15-Lipoxygenase-2 via Hydrogen-Deuterium Exchange. AB - Eicosanoids are inflammatory signaling lipids that are biosynthesized in response to cellular injury or threat. They were originally thought to be pro-inflammatory molecules, but members of at least one subclass, the lipoxins, are able to resolve inflammation. One step in lipoxin synthesis is the oxygenation of arachidonic acid by 15-lipoxygenase (15-LOX). 15-LOX contains two domains: a Ca2+ binding PLAT domain and a catalytic domain. 15-LOX is a soluble cytosolic protein until binding of Ca2+ to the PLAT domain promotes translocation to the membrane surface. The role of 15-LOX structural dynamics in this translocation has remained unclear. We investigated the dynamics of 15-LOX isoform B (15-LOX-2) upon binding of Ca2+ and ligands, as well as upon membrane association using hydrogen-deuterium exchange mass spectrometry (HDX-MS). We used HDX-MS to probe the solvent accessibility and backbone flexibility of 15-LOX-2, revealing significant differences in deuterium incorporation between the PLAT and catalytic domains, with the PLAT domain demonstrating higher flexibility. Comparison of HDX for 15-LOX-2 in the presence and absence of Ca2+ indicates there are few differences in structural dynamics. Furthermore, our HDX results involving nanodisc-associated 15-LOX-2 suggest that significant structural and dynamic changes in 15-LOX-2 are not required for membrane association. Our results also show that a substrate lipid binding to the active site in the catalytic domain does induce changes in incorporation of deuterium into the PLAT domain. Overall, our results challenge the previous hypothesis that Ca2+ binding induces major structural changes in the PLAT domain and support the hypothesis that is interdomain communication in 15-LOX-2. PMID- 28809483 TI - Discrimination and Enantiomeric Excess Determination of Chiral Primary Amines Based on a Chiral-at-Metal Ir(III) Complex Using NMR Spectroscopy. AB - A three-component protocol involving enantiopure Delta-[Ir(ppy)2(MeCN)2](PF6) (ppy is 2-phenylpyridine) and salicylaldehyde as chiral auxiliaries was successfully applied to discriminate the absolute configuration and determine the enantiopurity of primary amines and amine alcohols via 1H NMR spectroscopy. The assembly reaction is rapid and quantitative, generating a pair of diastereomers that can be determined directly without physical separation. Single crystal structural analyses indicate that the shielding effects on the ligands imposed by a pair of diastereomers are different and generate sufficient resolution NMR signals for identification. The enhancement of stability via chelating coordination to Ir(III) ion and more than one pair of diastereotopic resonances in different detection regions of the three-component protocol ensure a high degree of accuracy in quantifying the ee value of chiral amines. The absolute errors in the ee determinations by 1H NMR spectroscopy in different detection windows are within 2.0%. The linear relationship between the experimentally measured ee values and the gravimetrically prepared samples is found to be excellent. This finding would provide a complementary method for the discrimination and determination of the enantiopurity of chiral primary amines and amine alcohols in the screening of asymmetric reactions. PMID- 28809484 TI - Total Synthesis of beta-d-ido-Heptopyranosides Related to Capsular Polysaccharides of Campylobacter jejuni HS:4. AB - The 6-deoxy-beta-d-ido-heptopyranoside related to the capsular polysaccharides of C. jejuni HS:4 is very remarkable, owing to the unique, multifaceted structural features that have been combined into one molecule, which include (1) the rare ido-configuration, (2) the unusual 7-carbon backbone, and (3) the challenging beta-(1->2)-cis-anomeric configuration. Two distinct strategies toward the total synthesis of this interesting target are reported. The first involved establishment of the beta-d-idopyranosyl configuration from beta-d galactopyranosides, prior to a C-6-homologation extending the d-hexose to the desired 6-deoxy-d-heptose. However, this approach encountered difficulties due to the significantly reduced reactivity of the 6-position of the beta-d idopyranosides, so instead a second strategy was employed, which involved first carrying out a 6-homologation on the less flexible d-galactopyranose, followed by a very successful conversion to the desired beta-d-ido-configuration found in the target heptopyranoside (2). This report is the first successful synthesis of the 6-deoxy-beta-d-ido-heptopyranoside, which could possess interesting immunological properties. PMID- 28809485 TI - Dispersion and Halogen-Bonding Interactions: Binding of the Axial Conformers of Monohalo- and (+/-)-trans-1,2-Dihalocyclohexanes in Enantiopure Alleno-Acetylenic Cages. AB - Enantiopure alleno-acetylenic cage (AAC) receptors with a resorcin[4]arene scaffold, from which four homochiral alleno-acetylenes converge to shape a cavity closed by a four-fold OH-hydrogen-bonding array, form a highly ordered porous network in the solid state. They enable the complexation and co-crystallization of otherwise non-crystalline small molecules. This paper analyzes the axial conformers of monohalo- and (+/-)-trans-1,2-dihalocyclohexanes, bound in the interior cavity of the AACs, on the atomic level in the solid state and in solution, accompanied by accurate calculations. The dihedral angles thetaa,a (X C(1)-C(2)-X/H) of the axial/diaxial conformers deviate substantially from 180 degrees , down to 144 degrees , accompanied by strong flattening of the ring dihedral angles. Structure optimization of the isolated guest molecules demonstrates that the non-covalent interactions with the host hardly affect the dihedral angles, validating that the host is an ideal means to study the elusive axial/diaxial conformers. X-ray co-crystal structures of AACs further allowed for a detailed investigation, both experimentally and theoretically, on the interplay between space occupancy, guest conformation, and chiral recognition based purely on dispersion forces and weak C-X...pi (X = Cl, Br, I) and C-X...||| (acetylene) contacts (X = Cl, Br). The theoretical analysis of the non-covalent interactions between host and guest confirmed the high shape complementarity with fully enveloping dispersive interactions between the binding partners, rationalizing the high degree of enantioselectivity in the previously communicated complexation of (+/-)-trans-1,2-dimethylcyclohexane. This study also showed that (+/-)-trans 1,2-dihalocyclohexanes (X = Cl, Br) engage in significant halogen bonding (XB) interactions C-X...||| with the hosts. Slow host-guest exchange on the NMR time scale enabled the characterization of the encapsulated guests in solution, demonstrating that the complexes have identical geometries to those seen in the solid state, with the guests bound in axial/diaxial conformations. PMID- 28809486 TI - Assembling Glycan-Charged Dolichol Phosphates: Chemoenzymatic Synthesis of a Haloferax volcanii N-Glycosylation Pathway Intermediate. AB - N-glycosylation, the covalent attachment of glycans to select protein target Asn residues, is a post-translational modification performed by all three domains of life. In the halophilic archaea Haloferax volcanii, in which understanding of this universal protein-processing event is relatively well-advanced, genes encoding the components of the archaeal glycosylation (Agl) pathway responsible for the assembly and attachment of an N-linked pentasaccharide have been identified. As elsewhere, the N-linked glycan is assembled on phosphodolichol carriers before transfer to target Asn residues. However, as little is presently known of the Hfx. volcanii Agl pathway at the protein level, the seemingly unique ability of Archaea to use dolichol phosphate (DolP) as the glycan lipid carrier, rather than dolichol pyrophosphate used by eukaryotes, remains poorly understood. With this in mind, a chemoenzymatic approach was taken to biochemically study AglG, one of the five glycosyltransferases of the pathway. Accordingly, a novel regio- and stereoselective reduction of naturally isolated polyprenol gave facile access to S-dolichol via asymmetric transfer hydrogenation under very mild conditions. This compound was used to generate glucose-charged DolP, a precursor of the N-linked pentasaccharide, as well as DolP-glucose-glucuronic acid and DolP glucuronic acid. AglG, purified from Hfx. volcanii membranes in hypersaline conditions, like those encountered in situ, was subsequently combined with uridine diphosphate (UDP)-glucuronic acid and DolP-glucose to yield DolP-glucose glucuronic acid. The in vitro system for the study of AglG activity developed here represents the first such tool for studying halophilic glycosyltransferases and will allow for a detailed understanding of archaeal N-glycosylation. PMID- 28809487 TI - Maximum Likelihood Calibration of the UNRES Force Field for Simulation of Protein Structure and Dynamics. AB - By using the maximum likelihood method for force-field calibration recently developed in our laboratory, which is aimed at achieving the agreement between the simulated conformational ensembles of selected training proteins and the corresponding ensembles determined experimentally at various temperatures, the physics-based coarse-grained UNRES force field for simulations of protein structure and dynamics was optimized with seven small training proteins exhibiting a variety of secondary and tertiary structures. Four runs of optimization, in which the number of optimized force-field parameters was gradually increased, were carried out, and the resulting force fields were subsequently tested with a set of 22 alpha-, 12 beta-, and 12 alpha + beta proteins not used in optimization. The variant in which energy-term weights, local, and correlation potentials, side-chain radii, and anisotropies were optimized turned out to be the most transferable and outperformed all previous versions of UNRES on the test set. PMID- 28809488 TI - Text-Displaying Colorimetric Paper-Based Analytical Device. AB - This paper describes a paper-based analytical device allowing the direct semiquantitative interpretation of the result of a chemical assay in the form of "text". The combined use of a classical colorimetric indicator system and an additional inert colorant enables a versatile text-displaying detection mechanism on a paper device. For proof-of-concept, urinary protein has been selected as a model analytical target. The whole text-displaying paper device has been developed based on printing techniques including wax printing, inkjet printing, and 3D printing. The results of user tests performed with protein (human serum albumin) samples in aqueous standard solutions and human urine demonstrated that the accuracy was comparable for the elaborated paper device (74.7% for standard samples and 66.7% for urine) and a conventional colorimetric urine dipstick (67.2% for standard samples and 65.3% for urine). Storage stability as long as at least 117 days has been confirmed based on software-assisted quantitative color analysis. The developed text-displaying approach is proposed as an alternative simple detection motif for paper-based analytical devices. PMID- 28809489 TI - [FeFe]-Hydrogenase H-Cluster Mimics with Various -S(CH2)nS- Linker Lengths (n = 2 8): A Systematic Study. AB - The effect of the nature of the dithiolato ligand on the physical and electrochemical properties of synthetic H-cluster mimics of the [FeFe] hydrogenase is still of significant concern. In this report we describe the cyclization of various alkanedithiols to afford cyclic disulfide, tetrasulfide, and hexasulfide compounds. The latter compounds were used as proligands for the synthesis of a series of [FeFe]-hydrogenase H-cluster mimics having the general formulas [Fe2(CO)6{MU-S(CH2)nS}] (n = 4-8), [Fe2(CO)6{MU-S(CH2)nS}]2 (n = 6-8), and [Fe2(CO)6{(MU-S(CH2)nS)2}] (n = 6-8). The resulting complexes were characterized by 1H and 13C{1H} NMR and IR spectroscopic techniques, mass spectrometry, and elemental analysis as well as X-ray analysis. The purpose of this research was to study the influence of the systematic increase of n from 2 to 7 on the redox potentials of the models and the catalytic ability in the presence of acetic acid (AcOH) by applying cyclic voltammetry. PMID- 28809490 TI - Electrophilic Zinc Homoenolates: Synthesis of Cyclopropylamines from Cyclopropanols and Amines. AB - Metal homoenolates, produced via C-C bond cleavage of cyclopropanols, have been extensively investigated as nucleophiles for the synthesis of beta-substituted carbonyl derivatives. Herein, we demonstrate that zinc homoenolates can react as carbonyl-electrophiles in the presence of nucleophilic amines to yield highly valuable trans-cyclopropylamines in good yields and high diastereoselectivities. GSK2879552, a lysine demethylase 1 inhibitor currently in clinical trials for the treatment of small cell lung carcinoma, was synthesized using this strategy. PMID- 28809491 TI - A Total Synthesis of the Marine Alkaloid Discoipyrrole D. AB - A total synthesis of the diastereoisomeric pair of compounds, 4, assigned to the marine alkaloid discoipyrrole D is reported. A series of palladium-catalyzed cross-coupling and other reactions was employed to assemble the relevant 1,2,3,4 tetrasubstituted pyrrole (16) that was engaged in MoOPH-mediated oxidative cyclization, then conjugate addition, and redox processes to complete the synthesis. This work serves to confirm the structure (4) originally assigned to discoipyrrole D. PMID- 28809492 TI - A Mild, Functional Group Tolerant Addition of Organozinc Nucleophiles to N Activated Quinolines and Isoquinolines. AB - An addition of organozinc nucleophiles to N-acyl activated quinolines and isoquinolines is described. Simple transmetalation with the corresponding Grignard reagents using ZnCl2 forms organozinc compounds which are functional group tolerant and stable to reactive acyl chloride reagents for extended periods. A wide variety of substrates which include reactive electron-withdrawing groups are well tolerated to form 2-substituted dihydroquinolines and dihydroisoquinolines. This methodology has been applied toward an improved synthetic route of uncialamycin and its analogs. PMID- 28809493 TI - Macroscopic Structural Compositions of pi-Conjugated Polymers: Combined Insights from Solid-State NMR and Molecular Dynamics Simulations. AB - Molecular dynamics simulations are combined with solid-state NMR measurements to gain insight into the macroscopic structural composition of the pi-conjugated polymer poly(2,5-bis(3-tetradecyl-thiophen-2-yl)thieno[3,2-b]thiophene) (PBTTT). The structural and dynamical properties, as established by the NMR analyses, were used to test the local structure of three constitutient mesophases with (i) crystalline backbones and side chains, (ii) lamellar backbones and disordered side chains, or (iii) amorphous backbones and side chains. The relative compositions of these mesophases were then determined from the deconvolution of the 1H and 13C solid-state NMR spectra and dynamic order parameters. Surprisingly, on the basis of molecular dynamics simulations, the powder composition consisted of only 28% of the completely crystalline mesophase, while 23% was lamellar with disordered side chains and 49% amorphous. The protocol presented in this work is a general approach and can be used for elucidating the relative compositions of mesophases in pi-conjugated polymers. PMID- 28809494 TI - Protein Assembly and Building Blocks: Beyond the Limits of the LEGO Brick Metaphor. AB - Proteins, like other biomolecules, have a modular and hierarchical structure. Various building blocks are used to construct proteins of high structural complexity and diverse functionality. In multidomain proteins, for example, domains are fused to each other in different combinations to achieve different functions. Although the LEGO brick metaphor is justified as a means of simplifying the complexity of three-dimensional protein structures, several fundamental properties (such as allostery or the induced-fit mechanism) make deviation from it necessary to respect the plasticity, softness, and cross-talk that are essential to protein function. In this work, we illustrate recently reported protein behavior in multidomain proteins that deviates from the LEGO brick analogy. While earlier studies showed that a protein domain is often unaffected by being fused to another domain or becomes more stable following the formation of a new interface between the tethered domains, destabilization due to tethering has been reported for several systems. We illustrate that tethering may sometimes result in a multidomain protein behaving as "less than the sum of its parts". We survey these cases for which structure additivity does not guarantee thermodynamic additivity. Protein destabilization due to fusion to other domains may be linked in some cases to biological function and should be taken into account when designing large assemblies. PMID- 28809495 TI - A Copper(I)-Catalyzed Addition/Annulation Sequence for the Two-Component Synthesis of gamma-Ylidenebutenolides. AB - A highly efficient Cu(I)-catalyzed addition/annulation sequence has been developed for the synthesis of (Z)-ylidenebutenolides employing readily available alpha-ketoacids and alkynes as substrates. The reactions employ a simple commercially available Cu(I)-catalyst, display good substrate scope, and deliver products with high stereoselectivity. The synthetic utility of the method is demonstrated by the straightforward derivatization of the ylidenebutenolides into a diverse range of heterocycles, and also by the preparation of the natural product bovolide, and analogs thereof. PMID- 28809496 TI - Time-Resolved Coherent Anti-Stokes Raman Scattering of Graphene: Dephasing Dynamics of Optical Phonon. AB - We report dynamics of the G-mode in graphene probed with time-resolved coherent anti-Stokes Raman scattering measurements. By applying BOXCARS excitation geometry with three different excitation wavelengths, various nonlinear processes can be selectively detected due to energy and momentum conservation and temporal sequence of the pulses. The Raman signal due to resonant coherent excitation of the G-mode shows exponential decay with lifetime of ~325 +/- 50 fs. This decay time is shorter than expected based on the line width of the G-mode in the Raman spectrum. We propose that the unexpectedly short dephasing time is a result of dynamic variation of nonadiabatic coupling of the photoexcited electron distribution and the G-mode. PMID- 28809498 TI - Bodipy-Anthracene Dyads as Triplet Photosensitizers: Effect of Chromophore Orientation on Triplet-State Formation Efficiency and Application in Triplet Triplet Annihilation Upconversion. AB - Bodipy-anthracene dyads with two chromophores assuming orthogonal geometry to enhance the spin-orbital charge-transfer intersystem crossing (SOCT-ISC) were prepared. The photosensitizers show strong absorption of visible light, efficient triplet-state formation (quantum yield 90%), and a long-lived triplet state (85 MUs). The dipole moment orientation exerts significant effect on the ISC efficiency. It is also the first time that photosensitizers based on SOCT-ISC were used for triplet-triplet annihilation upconversion. The upconversion quantum yield is up to 15.8%. PMID- 28809497 TI - A Chlorinating Reagent Yields Vinyl Chlorides with High Regioselectivity under Heterogeneous Gold Catalysis. AB - A novel chlorinating reagent with a high concentration of HCl has enabled the highly regioselective hydrochlorination of unactivated alkynes using a commercial nanogold catalyst. No overchlorination or hydration products were formed, and various functional groups were tolerated. This hydrochlorination method could be conducted under open air. PMID- 28809499 TI - Copper-Assisted Oxidative Trifluoromethylthiolation of 2,3-Allenoic Acids with AgSCF3. AB - The oxidative trifluoromethylthiolation of 2,3-allenoic acids with AgSCF3 in the presence of (NH4)2S2O8 and catalytic copper salt was investigated. A series of 4 aryl-2,3-allenoic acids underwent radical trifluoromethylthiolation/intramolecular cyclization to afford beta trifluoromethylthiolated butenolides, which were conveniently transformed into trifluoromethylthiolated furan derivatives. In contrast, 2-monosubstituted 2,3 allenoic acids were converted into the corresponding 3,4 bis(trifluoromethylthio)but-2-enoic-acids under similar reaction conditions. PMID- 28809500 TI - Mechanisms and Rates of U(VI) Reduction by Fe(II) in Homogeneous Aqueous Solution and the Role of U(V) Disproportionation. AB - Molecular-level pathways in the aqueous redox transformation of uranium by iron remain unclear, despite the importance of this knowledge for predicting uranium transport and distribution in natural and engineered environments. As the relative importance of homogeneous versus heterogeneous pathways is difficult to probe experimentally, here we apply computational molecular simulation to isolate rates of key one electron transfer reactions in the homogeneous pathway. By comparison to experimental observations the role of the heterogeneous pathway also becomes clear. Density functional theory (DFT) and Marcus theory calculations for all primary monomeric species at pH values <=7 show for UO22+ and its hydrolysis species UO2OH+ and UO2(OH)20 that reduction by Fe2+ is thermodynamically favorable, though kinetically limited for UO22+. An inner sphere encounter complex between UO2OH+ and Fe2+ was the most stable for the first hydrolysis species and displayed an electron transfer rate constant ket = 4.3 * 103 s-1. Three stable inner- and outer-sphere encounter complexes between UO2(OH)20 and Fe2+ were found, with electron transfer rate constants ranging from ket = 7.6 * 102 to 7.2 * 104 s-1. Homogeneous reduction of these U(VI) hydrolysis species to U(V) is, therefore, predicted to be facile. In contrast, homogeneous reduction of UO2+ by Fe2+ was found to be thermodynamically unfavorable, suggesting the possible importance of U(V)-U(V) disproportionation as a route to U(IV). Calculations on homogeneous disproportionation, however, while yielding a stable outer-sphere U(V)-U(V) encounter complex, indicate that this electron transfer reaction is not feasible at circumneutral pH. Protonation of both axial O atoms of acceptor U(V) (i.e., by H3O+) was found to be a prerequisite to stabilize U(IV), consistent with the experimental observation that the rate of this reaction is inversely correlated with pH. Thus, despite prevailing notions that U(V) is rapidly eliminated by homogeneous disproportionation, this pathway is irrelevant at environmental conditions. PMID- 28809501 TI - Microencapsulated Solid Lipid Nanoparticles as a Hybrid Platform for Pulmonary Antibiotic Delivery. AB - Solid lipid nanoparticles (SLN) containing rifabutin (RFB), with pulmonary administration purposes, were developed through a technique that avoids the use of organic solvents or sonication. To facilitate their pulmonary delivery, the RFB-loaded SLN were included in microspheres of appropriate size using suitable excipients (mannitol and trehalose) through a spray-drying technique. Confocal analysis microscopy showed that microspheres are spherical and that SLN are efficiently microencapsulated and homogeneously distributed throughout the microsphere matrices. The aerodynamic diameters observed an optimal distribution for reaching the alveolar region. The dry powder's performance during aerosolization and the in vitro drug deposition were tested using a twin-impinger approach, which confirmed that the microspheres can reach the deep lung. Isothermal titration calorimetry revealed that SLN have higher affinity for mannitol than for trehalose. Upon microsphere dissolution in aqueous media, SLN were readily recovered, maintaining their physicochemical properties. When these dry powders reach the deep lung, microspheres are expected to readily dissolve, delivering the SLN which, in turn, will release RFB. The in vivo biodistribution of microencapsulated RFB-SLN demonstrated that the antibiotic achieved the tested organs 15 and 30 min post pulmonary administration. Their antimycobacterial activity was also evaluated in a murine model of infection with a Mycobacterium tuberculosis strain H37Rv resulting in an enhancement of activity against M. tuberculosis infection compared to nontreated animals. These results suggest that RFB-SLN microencapsulation is a promising approach for the treatment of tuberculosis. PMID- 28809502 TI - Thiophene-Alkyne-Based CMPs as Highly Selective Regulators for Oxidative Heck Reaction. AB - Thiophenes containing an adjacent C=C group as ligands for PdII-promoted organic reactions are reported for the first time. These ligands were utilized as catalytic sites and integrated into the skeleton of conjugated microporous polymers. By employing these CMP materials as selective regulators, oxidative Heck reactions between arylboronic esters and electronically unbiased alkenes provide highly selective linear products. PMID- 28809503 TI - Synthesis of Denser Energetic Metal-Organic Frameworks via a Tandem Anion-Ligand Exchange Strategy. AB - High-density materials have attracted extensive attention because of their broad applications. However, strategies for improving the densities of MOFs and preparing denser MOFs remain almost unexplored. Herein, we propose a tandem anion ligand exchange strategy for synthesizing denser MOFs by using three-dimensional cationic MOFs (3D CMOFs) with pillared layered structures as precursors and high density anions and small monotopic ligands as exogenous guests. By means of this strategy, we choose the high-density nitroformate ion [C(NO2)3-] as an exogenous anion and water as an exogenous ligand to successfully synthesize two layered CMOFs. Single-crystal X-ray diffraction showed that after this transformation, the extra-framework anions are replaced with the C(NO2)3- anions, and the distances between adjacent layers in the two-dimensional (2D) networks are more than 3.70 A shorter than those of their 3D precursors. The resultant materials exhibit higher densities, higher heats of detonation, higher nitrogen and oxygen contents, and lower metal contents. In particular, the density of {Cu(atrz)2[C(NO2)3]2(H2O)2.atrz.2H2O}n (2b, rho = 1.76 g cm-3, atrz = 4,4'-azo 1,2,4-triazole) is increased by 0.12 g cm-3 compared to its 3D precursor {2a, [Cu(atrz)3(NO3)2.2H2O]n, rho = 1.64 g cm-3}, and its heat of detonation is also enhanced to more than 1900 kJ kg-1. The resultant 2D layered CMOFs are also new potential high-energy density materials. This work may provide new insights into the design and synthesis of high-density MOFs. Moreover, we anticipate that the approach reported here would be useful for the preparation of new MOFs, in particular, which are otherwise difficult or unfeasible through traditional synthetic routes. PMID- 28809504 TI - Influence of Particle Size and Loading on Particle Accessibility in Electrospun Poly(ethylene oxide) and ZIF-8 Composite Fibers: Experiments and Theory. AB - Developing electrospun nanofiber/nanoparticle composites (ENNCs) is an emerging strategy for immobilizing functional particles for a variety of applications. The radial location of the particle along the fiber, either at the surface or in the bulk, has implication into the resulting properties. To explore particle location along fibers, ZIF-8 impregnated poly(ethylene oxide) (PEO) nanofibers are formed by electrospinning particle suspensions. Fibers impregnated with two different ZIF-8 particle sizes (200 nm and 12.5 MUm) were electrospun and shown by nitrogen porosimetry to be nearly completely wrapped by PEO in each case at loadings near 10 wt %. This was favorably compared to developed theory of polymeric membrane encapsulated particles and extended to other electrospun fiber/particle composites through a brief literature review. ENNCs with varying loadings of nanosized ZIF-8 particles were then fabricated and tested with nitrogen porosimetry to find that the particles became available for adsorption at the surface of the fibers starting from 25 wt % (28 vol %) loading. This suggests that the particles are kinetically trapped at this loading level since, if allowed to exhibit random close-packing, the ZIF-8 would be expected to fully imbedded inside the fibers up to 56 vol % loading. PMID- 28809505 TI - Relay Catalysis: Manganese(III) Phosphate Catalyzed Asymmetric Addition of beta Dicarbonyls to ortho-Quinone Methides Generated by Catalytic Aerobic Oxidation. AB - The combination of an in situ formed MnL3 complex (HL = Hacac or R(C?O)CH2CO2R) and a chiral phosphoric acid HX* allows for a fully catalytic, asymmetric synthesis of 4H-chromenes starting from 2-alkyl-substituted phenols. The aerobic oxidation toward a transient ortho-quinone methide was efficiently catalyzed by a manganese(III) species MnL3 while the ensuing Michael addition of beta-dicarbonyl compounds proved to be catalyzed by a chiral manganese phosphate MnL2X*. PMID- 28809506 TI - Stereospecific Palladium-Catalyzed C-H Arylation of Pyroglutamic Acid Derivatives at the C3 Position Enabled by 8-Aminoquinoline as a Directing Group. AB - An efficient and stereospecific Pd-catalyzed protocol for the C-H arylation of pyroglutamic acid derivatives that uses 8-aminoquinoline as a directing group is described. The reaction was shown to proceed efficiently with a variety of aryl and heteroaryl iodides bearing different functional groups, giving C3-arylated cis products in good to high yields. Removal of the 8-aminoquinoline unit from these C-H arylation products enables access to synthetically useful cis and trans pyroglutamic acid-based building blocks. PMID- 28809507 TI - Persistence of Indigenous Escherichia coli in Raw Bovine Manure-Amended Soil. AB - The Food Safety Modernization Act attempts to reduce produce-related foodborne illness by using preventive rather than reactive measures. The goal of this research was to determine the persistence of manure-borne generic Escherichia coli under laboratory and field conditions. The population density of naturally occurring E. coli was ~7.2 and 5.4 log CFU/10 g in pre- and postscreened manures, respectively. Postscreened (i.e. after the liquid manure has passed through a screen) manure was applied at light, medium, and heavy rates to fields in Live Oak and Citra, FL, during the fall and summer. Laboratory microcosms of the manure-amended soils (comparable to the field's heavy application rate of manure) from both locations were maintained at 20 and 30 degrees C. Persistence of E. coli, moisture content, and pH were monitored until E. coli became unrecoverable. The longest E. coli persistence seen in field trails was during the summer and fall trials from Citra (heavy application) that terminated on day 112 and day 280, respectively. The rate of E. coli decay ranged from 0.02 to 0.04 log CFU per day across all manure application rates, seasons, and locations. In the microcosm studies, the E. coli became extinct on day 210 in the 30 degrees C, whereas they became unrecoverable on day 420 in the 20 degrees C microcosms. The relatively prolonged persistence of E. coli in the microcosms suggests that survival under laboratory conditions does not mimic real-world survival rates and may not be adequate for predicting E. coli persistence in the field. The persistence data also suggest that the risk from E. coli associated with new contamination events, such as wild life intrusion, runoff, or other vectors, may be greater than the risk associated with the long-term survival of manure-borne E. coli, although more work is needed to confirm this hypothesis. PMID- 28809508 TI - Effects of High Temperatures on the Mortality of Stegobium paniceum (L.) (Coleoptera: Anobiidae). AB - As an alternative to chemical fumigants, heat treatment has been a widely used physical method to successfully control stored-product insects in empty grain storage and food processing facilities. The drugstore beetle, Stegobium paniceum (L.) (Coleoptera: Anobiidae) is one of the most destructive stored-product insects in the world. The mortality of the eggs, larvae, pupae, and adults of S. paniceum was investigated when exposed to 43, 47, 51, and 55 degrees C for different time intervals. The mortality rate of the S. paniceum eggs, larvae, pupae, and adults was found to significantly increase with increased exposure time and temperature, and the pupae were the most heat-tolerant stage. The mortality rate of the S. paniceum pupae was <43.3%, while the mortality rate of the S. paniceum eggs, larvae, and adults achieved nearly 100.0% when they were exposed to 43, 47, 51, and 55 degrees C for 6 h, 17.5 min, 120 s, and 30 s, respectively. The current results favor designing a heat treatment protocol to successfully disinfest S. paniceum in practice. PMID- 28809509 TI - Tailoring Parent-Child Interaction Therapy (PCIT) for Older Children: A Case Study. AB - Parent-Child Interaction Therapy (PCIT) is an evidence-based intervention designed for families of 2- to 6-year-old children with disruptive behavior disorders. This article illustrates the application of PCIT in a 10-year-old boy with attention deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD). Both parents and the patient attended PCIT sessions. The course of therapy included minor changes to the PCIT protocol. After 13 PCIT sessions, the patient displayed disruptive behaviors within normal limits, and 12 months later he no longer met diagnostic criteria for ODD. Results remained stable at a 17-month follow-up assessment. This case study suggests that the use of PCIT in families of children with ODD markedly older than the recommended age range might be a promising approach for improving family functioning and reducing behavior problems. Further research with larger samples of older children with ODD is needed to replicate and elaborate the findings of this case study. PMID- 28809510 TI - Why Do I Smoke and Why Do I Keep Smoking? PMID- 28809511 TI - Vascular Stiffness and Mechanotransduction: Back in the Limelight. PMID- 28809512 TI - Triple Therapy for Chronic Obstructive Pulmonary Disease Management. Are Our Expectations Fulfilled? PMID- 28809513 TI - Vascular Endothelial Growth Factor in Idiopathic Pulmonary Fibrosis. An Imbalancing Act. PMID- 28809514 TI - Individualization of Positive End-Expiratory Pressure Setting in Patients with Acute Respiratory Distress Syndrome under Extracorporeal Membrane Oxygenation. Inputs from Electrical Impedance Tomography. PMID- 28809515 TI - A Biosignature Predicting Complicated Course in Children Presenting with Septic Shock. Why PERSEVERE? PMID- 28809516 TI - Simultaneously Mounted Pro- and Anti-inflammatory Host Response Relates to the Development of Secondary Infections in Patients with Sepsis. PMID- 28809517 TI - Oesophagogastric invagination. AB - Oesophagogastric invagination is a relatively rare disease that is primarily caused by a sliding hiatal hernia. We report a successfully treated case of oesophagogastric invagination caused by achalasia. Oesophagogastric invagination should be considered in patients complaining of upper abdominal discomfort. PMID- 28809519 TI - Practical Suggestions for Implementing Caries Control and Recall Protocols for Children and Young Adults. AB - Caries is a ubiquitous, natural process occurring in the biofilm. Lesion formation can be controlled by plaque control, fluoride and a sensible diet. Diagnosis is a mental resting place for a treatment decision. Active lesions require active management, including non-operative measures to arrest the lesion, supplemented with operative dentistry to facilitate cleaning of cavities. The diagnosis of active lesions is the best measure of caries risk and should determine recall intervals. The paper describes a clinical sequence of oral hygiene instruction, followed by a clinical examination of clean, dry teeth and then fluoride varnish application . PMID- 28809520 TI - Full-Mouth Disinfection. AB - Full-mouth disinfection is a relatively new technique for the management of patients, especially those with moderate to severe chronic periodontitis. In this paper, the technique is reviewed and efficacy evaluated. The methodology and possible outcomes are illustrated with a case report. PMID- 28809521 TI - Gerodontology in Context. AB - The impact of ageing on society, the patient and his/her oral state is summarized, with one case being outlined as an example. PMID- 28809524 TI - Gerodontology: Now and the Future. AB - In this the first article in a series, the discipline of Gerodontology is placed in context and the issues of what constitutes ageing, the demography of the older population, and changes in oral health are considered. Future clinical challenges to the profession and in the delivery of oral healthcare are also outlined. PMID- 28809518 TI - MicroRNA-542 Promotes Mitochondrial Dysfunction and SMAD Activity and Is Elevated in Intensive Care Unit-acquired Weakness. AB - RATIONALE: Loss of skeletal muscle mass and function is a common consequence of critical illness and a range of chronic diseases, but the mechanisms by which this occurs are unclear. OBJECTIVES: To identify microRNAs (miRNAs) that were increased in the quadriceps of patients with muscle wasting and to determine the molecular pathways by which they contributed to muscle dysfunction. METHODS: miRNA-542-3p/5p (miR-542-3p/5p) were quantified in the quadriceps of patients with chronic obstructive pulmonary disease and intensive care unit-acquired weakness (ICUAW). The effect of miR-542-3p/5p was determined on mitochondrial function and transforming growth factor-beta signaling in vitro and in vivo. MEASUREMENTS AND MAIN RESULTS: miR-542-3p/5p were elevated in patients with chronic obstructive pulmonary disease but more markedly in patients with ICUAW. In vitro, miR-542-3p suppressed the expression of the mitochondrial ribosomal protein MRPS10 and reduced 12S ribosomal RNA (rRNA) expression, suggesting mitochondrial ribosomal stress. miR-542-5p increased nuclear phospho-SMAD2/3 and suppressed expression of SMAD7, SMURF1, and PPP2CA, proteins that inhibit or reduce SMAD2/3 phosphorylation, suggesting that miR-542-5p increased transforming growth factor-beta signaling. In mice, miR-542 overexpression caused muscle wasting, and reduced mitochondrial function, 12S rRNA expression, and SMAD7 expression, consistent with the effects of the miRNAs in vitro. Similarly, in patients with ICUAW, the expression of 12S rRNA and of the inhibitors of SMAD2/3 phosphorylation were reduced, indicative of mitochondrial ribosomal stress and increased transforming growth factor-beta signaling. In patients undergoing aortic surgery, preoperative levels of miR-542-3p/5p were positively correlated with muscle loss after surgery. CONCLUSIONS: Elevated miR-542-3p/5p may cause muscle atrophy in intensive care unit patients through the promotion of mitochondrial dysfunction and activation of SMAD2/3 phosphorylation. PMID- 28809525 TI - Implementing NICE Guidelines on Recall Intervals into General Practice. AB - The NICE guidelines require practitioners to ensure that each patient has a specific recall interval based on an oral health needs assessment. There appears to be a hesitancy in the profession to move away from the 'six-month recall'. In England and Wales, Primary Care Organizations (PCOs) monitor activity using quantitative data. One particular metric measures how many patients are seen by the practice within 3 months and also between 3 and 9 months from their last course of treatment. The purpose of this paper is to introduce a quick reference chart based on the NICE guidelines which, when used in combination with clinical judgement, can aid the clinician in selecting a tailored recall interval. This paper discusses the purpose and benefits for using the guidelines in relation to NHS contractual obligations. PMID- 28809526 TI - Antimicrobial Irrigants in Endodontic Therapy. 2: Clinical Tips for Isolation and Irrigant Use. AB - This second article will concentrate on the clinical use of root canal irrigants, highlighting why commonly used techniques may be suboptimal and result in ineffective disinfection during endodontic therapy. PMID- 28809527 TI - Foetal Anticonvulsant Syndrome: Implications on Dento-facial Development in General Dental Practice. AB - Epilepsy affects around 1% of the population and approximately 1 in 250 pregnancies are exposed to antiepileptic drugs (AEDs). Epilepsy is the most common neurological disorder to occur in this group. Exposure to these drugs can result in teratogenic effects, referred to as foetal anticonvulsant syndrome (FACS). The older generation anticonvulsants, such as phenytoin, valproate and carbamazepine, have been shown to be teratogenic and it is hoped that the 'newer' drugs (eg gabapentin and lamotrigine) will be different. We present two siblings born to an epileptic mother and the literature is reviewed. PMID- 28809528 TI - Good Infection Prevention: Hand Hygiene. AB - Hand hygiene is crucial in preventing the spread of infection and is considered to be the single most important infection prevention activity in healthcare. Hand hygiene is part of Standard Infection Control Precautions. Several guidance documents have recently been published that emphasize the importance of carrying out excellent hand hygiene in dental practice. The three levels of hand hygiene are social hand hygiene, hygienic hand decontamination and surgical scrub, the choice depending on the procedure undertaken. The following article summarizes the basic principles of hand hygiene for the General Dental Practitioner and his/her dental team. PMID- 28809529 TI - Multiphoton Fabrication of Fibronectin-Functionalized Protein Micropatterns: Stiffness-Induced Maturation of Cell-Matrix Adhesions in Human Mesenchymal Stem Cells. AB - Cell-matrix adhesions are important structures governing the interactions between cells and their microenvironment at the cell-matrix interface. The focal complex (FC) and focal adhesion (FA) have been substantially investigated in conventional planar culture systems using fibroblasts as an in vitro model. However, the formation of more mature types of cell-matrix adhesion in human mesenchymal stem cells (hMSCs), including fibrillar adhesion (FBA) and 3D matrix adhesion (3DMA), have not been fully elucidated. Here we investigate the niche factor(s) that influence(s) the maturation of FBA and 3DMA by using multiphoton fabrication based micropatterning. First, the bovine serum albumin (BSA)-made protein micropatterns were functionalized by incorporating various concentrations of fibronectin (FN) in fabrication solution. The amount of cross-linked FN is positively correlated with the initial concentration of FN in the reaction liquid, as verified by immunofluorescence staining. On the other hand, the anisotropic FN-functionalized micropatterns were fabricated by varying the length (i.e., in-plane stiffness) and height (i.e., bending stiffness) of micropatterns, respectively. Finally, hMSCs were cultured on these micropatterns for 2 h and 1 day to determine the formation of FBA and 3DMA, respectively, using immunofluorescence staining. Results demonstrated that FN-functionalized micropatterns with high anisotropy in x-y dimension benefit FBA maturation. Furthermore, niche factors such as higher bending and in-plane stiffness and the presence of abundant fibronectin have a positive effect on the maturation of FN based cell-matrix adhesion. These findings could provide some new perspectives on designing platforms for further cell niche study and rationalizing scaffold design for tissue engineering. PMID- 28809530 TI - Steering Surface Reaction at Specific Sites with Self-Assembly Strategy. AB - To discern the catalytic activity of different active sites, a self-assembly strategy is applied to confine the involved species that are "attached" to specific surface sites. The employed probe reaction system is the Ullmann coupling of 4-bromobiphenyl, C6H5C6H4Br, on an atomically flat Ag(111) surface, which is explored by combined scanning tunneling microscopy, synchrotron X-ray photoelectron spectroscopy, and density functional theory calculations. The catalytic cycle involves the detachment of the Br atom from the initial reactant to form an organometallic intermediate, C6H5C6H4AgC6H4C6H5, which subsequently self-assembles with its central Ag atom residing either on 2-fold bridge or 3 fold hollow sites at full coverage. The hollow site turns out to be catalytically more active than the bridge one, allowing us to achieve site-steered reaction control from the intermediate to the final coupling product, p-quaterphenyl, at 390 and 410 K, respectively. PMID- 28809531 TI - Highly Efficient Method for the Synthesis of Activated Mesoporous Biocarbons with Extremely High Surface Area for High-Pressure CO2 Adsorption. AB - A simple and efficient way to synthesize activated mesoporous biocarbons (AMBs) with extremely high BET surface area and large pore volume has been achieved for the first time through a simple solid state activation of freely available biomass, Arundo donax, with zinc chloride. The textural parameters of the AMB can easily be controlled by varying the activation temperature. It is demonstrated that the mesoporosity of AMB can be finely tuned with a simple adjustment of the amount of activating agent. AMB with almost 100% mesoporosity can be achieved using the activating agent and the biomass ratio of 5 and carbonization at 500 degrees C. Under the optimized conditions, AMB with a BET surface area of 3298 m2 g-1 and a pore volume of 1.9 cm3 g-1 can be prepared. While being used as an adsorbent for CO2 capture, AMB registers an impressively high pressure CO2 adsorption capacity of 30.2 mmol g-1 at 30 bar which is much higher than that of activated carbon (AC), multiwalled carbon nanotubes (MWCNTs), highly ordered mesoporous carbons, and mesoporous carbon nitrides. AMB also shows high stability with excellent regeneration properties under vacuum and temperatures of up to 250 degrees C. These impressive textural parameters and high CO2 adsorption capacity of AMB clearly reveal its potential as a promising adsorbent for high-pressure CO2 capture and storage application. Also, the simple one-step synthesis strategy outlined in this work would provide a pathway to generate a series of novel mesoporous activated biocarbons from different biomasses. PMID- 28809533 TI - In Situ Atomic Force Microscopic Studies of Single Tin Nanoparticle: Sodiation and Desodiation in Liquid Electrolyte. AB - Probing electrodes at a nanometer scale is challenging but desirable to reveal the structural evolution of materials in electrochemical reactions. Herein, we present an atomic force microscopic method for an in situ analysis of a single Sn nanoparticle during sodiation and desodiation, which is conducted in an aprotic liquid electrolyte akin to a real electrochemical environment of the Na-ion cells. The morphological evolution of different-sized single Sn nanoparticle is visualized during the charge/discharge cycles by using a homemade planar electrode. All of the Sn nanoparticles exhibit a dramatic initial volume expansion of about 420% after sodiation to Na15Sn4. Interestingly, we find that the smaller Sn nanoparticles show a lower rate of irreversible volume change and a better shape maintenance than the larger ones after desodiation. This finding suggests the importance of downsizing in improving the mechanical stability and the cycling performance of the Sn-based anodes in sodium-ion batteries. PMID- 28809532 TI - Transient and Local Expression of Chemokine and Immune Checkpoint Traps To Treat Pancreatic Cancer. AB - Pancreatic tumors are known to be resistant to immunotherapy due to the extensive immune suppressive tumor microenvironment (TME). We hypothesized that CXCL12 and PD-L1 are two key molecules controlling the immunosuppressive TME. Fusion proteins, called traps, designed to bind with these two molecules with high affinity (Kd = 4.1 and 0.22 nM, respectively) were manufactured and tested for specific binding with the targets. Plasmid DNA encoding for each trap was formulated in nanoparticles and intravenously injected to mice bearing orthotopic pancreatic cancer. Expression of traps was mainly seen in the tumor, and secondarily, accumulations were primarily in the liver. Combination trap therapy shrunk the tumor and significantly prolonged the host survival. Either trap alone only brought in a partial therapeutic effect. We also found that CXCL12 trap allowed T-cell penetration into the tumor, and PD-L1 trap allowed the infiltrated T-cells to kill the tumor cells. Combo trap therapy also significantly reduced metastasis of the tumor cells to other organs. We conclude that the trap therapy significantly modified the immunosuppressive TME to allow the host immune system to kill the tumor cells. This can be an effective therapy in clinical settings. PMID- 28809534 TI - Ordered and Atomically Perfect Fragmentation of Layered Transition Metal Dichalcogenides via Mechanical Instabilities. AB - Thermoplastic polymers subjected to a continuous tensile stress experience a state of mechanical instabilities, resulting in neck formation and propagation. The necking process with strong localized strain enables the transformation of initially brittle polymeric materials into robust, flexible, and oriented forms. Here we harness the polymer-based mechanical instabilities to control the fragmentation of atomically thin transition metal dichalcogenides (TMDs). We develop a simple and versatile nanofabrication tool to precisely fragment atom thin TMDs sandwiched between thermoplastic polymers into ordered and atomically perfect TMD nanoribbons in arbitrary directions regardless of the crystal structures, defect content, and original geometries. This method works for a very broad spectrum of semiconducting TMDs with thicknesses ranging from monolayers to bulk crystals. We also explore the electrical properties of the fabricated monolayer nanoribbon arrays, obtaining an on/off ratio of ~106 for such MoS2 arrays based field-effect transistors. Furthermore, we demonstrate an improved hydrogen evolution reaction with the resulting monolayer MoS2 nanoribbons, thanks to the largely increased catalytic edge sites formed by this physical fragmentation method. This capability not only enriches the fundamental study of TMD extreme and fragmentation mechanics, but also impacts on future developments of TMD-based devices. PMID- 28809535 TI - Ternary Organic Solar Cells with Coumarin7 as the Donor Exhibiting Greater Than 10% Power Conversion Efficiency and a High Fill Factor of 75. AB - Ternary bulk heterojunction (BHJ) is a brilliant photovoltaic technology for improving the performance of organic solar cells (OSCs), because the light absorption range can be significantly extended by using multiple donors or acceptor materials. In this paper, coumarin7 (C7), a small organic molecule typical led used in organic light-emitting diodes, was initially exploited as second electron-donor component in ternary bulk heterojunction OSCs along with conventional blend system spolythieno[3,4-b]-thiophene/benzodithiophene(PTB7) and [6,6]-phenyl-C71 -butyric acid methyl(PC71 BM). A champion PCE value of 10.28% was realized in the ternary OSCs when incorporated with 10 wt % C7 doping ratio in the donors, corresponding to about 35% enhancement compared with the PTB7:PC71BM-based OSCs, a high fill factor (FF) of 75.03%, a short-circuit currentdensity (Jsc) of 18.72 mA cm-2 and an open-circuit voltage (Voc) of 0.73 V. The enhanced performance of the ternary OSCs can be attributed to the simultaneous improvement of the FF and the Jsc. In addition to extended light absorption, a perfect nanofiber filament active layer morphology is obtained due to the good compatibility between C7 and PTB7, which facilitates the balance of charge transportation and the suppression of charge recombination. This investigation suggests that coumarin derivatives, which have completely different structure with polymer donors, can also be used to fabricate ternary solar cells and have the potential applications to obtain amazing performance after further device engineering and optimization. PMID- 28809536 TI - Ternary Solar Cells Based on Two Small Molecule Donors with Same Conjugated Backbone: The Role of Good Miscibility and Hole Relay Process. AB - Ternary organic solar cells (OSCs) are very attractive for further enhancing the power conversion efficiencies (PCEs) of binary ones but still with a single active layer. However, improving the PCEs is still challenging because a ternary cell with one more component is more complicated on phase separation behavior. If the two donors or two acceptors have similar chemical structures, good miscibility can be expected to reduce the try-and-error work. Herein, we report ternary devices based on two small molecule donors with the same backbone but different substituents. Whereas both binary devices show PCEs about 9%, the PCE of the ternary cells is enhanced to 10.17% with improved fill factor and short circuit current values and external quantum efficiencies almost in the whole absorption wavelength region from 440 to 850 nm. The same backbone enables the donors miscible at molecular level, and the donor with a higher HOMO level plays hole relay process to facilitate the charge transportation in the ternary devices. Since side-chain engineering has been well performed to tune the active materials' energy levels in OSCs, our results suggest that their ternary systems are promising for further improving the binary cells' performance although their absorptions are not complementary. PMID- 28809537 TI - Confined Water: Structure, Dynamics, and Thermodynamics. AB - Understanding the properties of strongly confined water is important for a variety of applications such as fast flow and desalination devices, voltage generation, flow sensing, and nanofluidics. Confined water also plays an important role in many biological processes such as flow through ion channels. Water in the bulk exhibits many unusual properties that arise primarily from the presence of a network of hydrogen bonds. Strong confinement in structures such as carbon nanotubes (CNTs) substantially modifies the structural, thermodynamic, and dynamic (both translational and orientational) properties of water by changing the structure of the hydrogen bond network. In this Account, we provide an overview of the behavior of water molecules confined inside CNTs and slit pores between graphene and graphene oxide (GO) sheets. Water molecules confined in narrow CNTs are arranged in a single file and exhibit solidlike ordering at room temperature due to strong hydrogen bonding between nearest-neighbor molecules. Although molecules constrained to move along a line are expected to exhibit single-file diffusion in contrast to normal Fickian diffusion, we show, from a combination of molecular dynamics simulations and analytic calculations, that water molecules confined in short and narrow CNTs with open ends exhibit Fickian diffusion because of their collective motion as a single unit due to strong hydrogen bonding. Confinement leads to strong anisotropy in the orientational relaxation of water molecules. The time scale of relaxation of the dipolar correlations of water molecules arranged in a single file becomes ultraslow, of the order of several nanoseconds, compared with the value of 2.5 ps for bulk water. In contrast, the relaxation of the vector that joins the two hydrogens in a water molecule is much faster, with a time scale of about 150 fs, which is about 10 times shorter than the corresponding time scale for bulk water. This is a rare example of confinement leading to a speedup of orientational dynamics. The orientational relaxation of confined water molecules proceeds by angular jumps between two locally stable states, making the relaxation qualitatively different from that expected in the diffusive limit. The spontaneous entry of water inside the hydrophobic cavity of CNTs is primarily driven by an increase in the rotational entropy of water molecules inside the cavity, arising from a reduction in the average number of hydrogen bonds attached to a water molecule. From simulations using a variety of water models, we demonstrate that the relatively simple SPC/E water model yields results in close agreement with those obtained from polarizable water models. Finally, we provide an account of the structure and thermodynamics of water confined in the slit pore between two GO sheets with both oxidized and reduced parts. We show that the potential of mean force for the oxidized part of GO sheets in the presence of water exhibits two local minima, one corresponding to a dry cavity and the other corresponding to a fully hydrated cavity. The coexistence of these two regimes provides permeation pathways for water in GO membranes. PMID- 28809538 TI - Dynamic Covalent Hydrogels for Triggered Cell Capture and Release. AB - A dual-responsive, cell capture and release surface was prepared through the incorporation of phenylboronic acid (PBA) groups into an oxime-based polyethylene glycol (PEG) hydrogel. Owing to its PEG-like properties, the unfunctionalized hydrogel was nonfouling. The use of highly efficient oxime chemistry allows the incorporation of commercially available 3,5-diformylphenyl boronic acid into the hydrogel matrix. Thus, the surface properties of the hydrogel were modified to enable reversible cell capture and release. Boronic ester formation between PBA groups and cell surface carbohydrates enabled efficient cell capture at pH 6.8. An increase to pH 7.8 resulted in cell detachment. This capture-and-release procedure was performed on MCF-7 human breast cancer cells, NIH-3T3 fibroblast cells, and primary human umbilical vein endothelial cells (HUVECs) and could be cycled with negligible loss in activity. The facile preparation of PBA functionalized surfaces presented here has applications in biomedical fields such as cell diagnostics and cell culture. PMID- 28809540 TI - Simplified Modeling of Organic Contaminant Adsorption by Activated Carbon and Biochar in the Presence of Dissolved Organic Matter and Other Competing Adsorbates. AB - Cyclohexanol, phenol, benzoic acid, and phenanthrene fractional removal (italicized words are defined within the main text) by pulverized granular activated carbon and biochar adsorption in deionized water and stormwater was independent of target-adsorbate initial concentrations (C0) when C0s were below concentration thresholds. This permits a simple-modeling approach. C0-independent removal in deionized water at low-target-adsorbate concentrations potentially suggests that DOM in the deionized water induce a competitive effect that causes deviations from the Freundlich model. The Ideal Adsorbed Solution Theory Equivalent Background Compound model was used to determine the magnitude of concentration thresholds and the competitive effect of stormwater DOM and possibly deionized water DOM. These competing substances' competitive effects were influenced by target-compound adsorbability and structure. Concentration thresholds positively correlate with competing substances' competitive effect and negatively correlate with target-adsorbate-Freundlich 1/n values. In deionized water, concentration thresholds increase as target-compound adsorbability decreases. In stormwater, concentration thresholds do not correlate with adsorbability, potentially because stormwater DOM is better suited to compete for aromatic-compound-adsorption sites. The extent known-competitor adsorbates decrease target-adsorbate removal in the presence of DOM is investigated, which depends on the competing adsorbates' relative adsorbabilities and if they adsorb to a different subpopulation of adsorption sites. PMID- 28809539 TI - Polymersomes with Endosomal pH-Induced Vesicle-to-Micelle Morphology Transition and a Potential Application for Controlled Doxorubicin Delivery. AB - In order to obtain a novel, pH responsive polymersome system, a series of pH responsive block copolymers were synthesized via the reversible addition fragmentation chain transfer (RAFT) polymerization of 3,4-dihydro-2H-pyran (DHP) protected 2-hydroxyethyl methacrylate (HEMA) (2-((tetrahydro-2H-pyran-2 yl)oxy)ethyl methacrylate (THP-HEMA)) and 2-(dimethylamino) ethyl methacrylate (DMAEMA) using p(THP-HEMA) as a macro chain transfer agent (mCTA). The degree of polymerization (DP) of the p(THP-HEMA) block was fixed to 35, whereas the DP of the p(DMAEMA) block was systematically varied from 21 to 50. In aqueous solution, the block copolymer with the shortest p(DMAEMA) block (DP = 21) self-assembled into vesicles, while the polymer with 30 units of p(DMAEMA) formed a mixture of micelles and vesicles. The polymer with the longest p(DMAEMA) block (DP = 50) formed exclusively micelles. The corresponding polymersomes exhibited a morphology transition from vesicles at neutral pH values to micelles upon lowering the pH value down to endosomal pH value as investigated by DLS and cryo TEM. The capability of polymersomes to encapsulate both hydrophobic (e.g., Nile Red) and hydrophilic (e.g., doxorubicin hydrochloride (DOX.HCl)) cargos was verified by in vitro studies. Drug release studies demonstrated that the DOX.HCl release is significantly accelerated under acidic pH values compared to physiological conditions. Cytotoxicity studies revealed that DOX.HCl loaded polymersomes exhibited an efficient cell death comparable to free DOX.HCl. CLSM and flow cytometry studies showed that DOX.HCl loaded vesicles were easily taken up by L929 cells and were mainly located in the cytoplasm and cell nuclei. PMID- 28809542 TI - From the Great to the Scam, Carefully Select Your Scientific Conferences. PMID- 28809541 TI - Ubiquitin Chains Modified by the Bacterial Ligase SdeA Are Protected from Deubiquitinase Hydrolysis. AB - The SidE family of Legionella pneumophila effectors is a unique group of ubiquitin-modifying enzymes. Along with catalyzing NAD+-dependent ubiquitination of certain host proteins independent of the canonical E1/E2/E3 pathway, they have also been shown to produce phosphoribosylated free ubiquitin. This modified ubiquitin product is incompatible with conventional E1/E2/E3 ubiquitination processes, with the potential to lock down various cellular functions that are dependent on ubiquitin signaling. Here, we show that in addition to free ubiquitin, Lys63-, Lys48-, Lys11-, and Met1-linked diubiquitin chains are also modified by SdeA in a similar fashion. Both the proximal and distal ubiquitin moieties are targeted in the phosphoribosylation reaction. Furthermore, this renders the ubiquitin chains unable to be processed by a variety of deubiquitinating enzymes. These observations broaden the scope of SdeA's modulatory functions during Legionella infection. PMID- 28809543 TI - Infrared Spectroscopy Coupled with a Dispersion Model for Quantifying the Real Time Dynamics of Kanamycin Resistance in Artificial Microbiota. AB - Overusage of antibiotics leads to the widespread induction of antibiotic resistance genes (ARGs). Developing an approach to allow real-time monitoring and fast prediction of ARGs dynamics in clinical or environmental samples has become an urgent matter. Vibrational spectroscopy is potentially an ideal technique toward the characterization of the microbial composition of microbiota as it is nondestructive, high-throughput, and label-free. Herein, we employed attenuated total reflection Fourier transform infrared (ATR-FT-IR) spectroscopy and developed a spectrochemical tool to quantify the static and dynamic composition of kanamycin resistance in artificial microbiota to evaluate microbial antibiotic resistance. Second-order differentiation was introduced in identifying the spectral biomarkers, and principal component analysis followed by linear discriminant analysis (PCA-LDA) was used for the multivariate analysis of the entire spectral features employed. The calculated results of the mathematical dispersion model coupled with PCA-LDA showed high similarity to the designed microbiota structure, with no significant difference (P > 0.05) in the static treatments. Moreover, our model successfully predicted the dynamics of kanamycin resistance within artificial microbiota under kanamycin pressures. This work lends new insights into the potential role of spectrochemical analyses in investigating the existence and trends of antibiotic resistance in microbiota. PMID- 28809544 TI - Mechanistic Insights into Alkane Metathesis Catalyzed by Silica-Supported Tantalum Hydrides: A DFT Study. AB - Alkane metathesis transforms small alkanes into their higher and lower homologues. The reaction is catalyzed by either supported d0 metal hydrides (M = Ta, W) or d0 alkyl alkylidene complexes (M = Ta, Mo, W, Re). For the silica supported tantalum hydrides, several reaction mechanisms have been proposed. We performed DFT-D3 calculations to analyze the viability of the proposed pathways and compare them with alkane hydrogenolysis, which is a competitive process observed at the early stages of the reaction. The results show that the reaction mechanisms for alkane metathesis and for alkane hydrogenolysis present similar energetics, and this is consistent with the fact that the process taking place depends on the concentrations of the initial reactants. Overall, a modified version of the so-called one-site mechanism that involves alkyl alkylidene intermediates appears to be more likely and consistent with experiments. According to this proposal, tantalum hydrides are precursors of the alkyl alkylidene active species. During precursor activation, H2 is released and this allows alkane hydrogenolysis to occur. In contrast, the catalytic cycle implies only the reaction with alkane molecules in excess and does not form H2. Thus, the activity for alkane hydrogenolysis decreases. The catalytic cycle proposed here implies three stages: (i) beta-H elimination from the alkyl ligand, liberating ethene, (ii) alkene cross-metathesis, allowing olefin substituent exchange, and (iii) formation of the final products and alkyl alkylidene regeneration by olefin insertion and three successive 1,2-CH insertions to the alkylidene followed by alpha abstraction. These results relate the reactivity of silica-supported hydrides with that of the alkyl alkylidene complexes, the other common catalyst for alkane metathesis. PMID- 28809545 TI - Plasmonic Nanoprobe of (Gold Triangular Nanoprism Core)/(Polyaniline Shell) for Real-Time Three-Dimensional pH Imaging of Anterior Chamber. AB - Three-dimensional (3D) molecular imaging enables the study of biological processes in both living and nonviable systems at the molecular level and has a high potential on early diagnosis. In conjunction with specific molecular probes, optical coherent tomography (OCT) is a promising imaging modality to provide 3D molecular features at the tissue level. In this study, we introduced (gold triangular nanoprism core)/(polyaniline shell) nanoparticles (GTNPs@PANI) as an OCT contrast agent and pH-responsive nanoprobe for 3D imaging of pH distribution. These core/shell nanoparticles possessed significantly different extinction and scattering properties in acidic and basic microenvironments. The switch of the optical features of the nanoparticles upon pH change was reversible, and the response time was less than 1.0 s. The nanoprobe successfully indicated the acid regions of a mimic tumor from the basic region in a gelatin-based phantom under OCT imaging. As a demonstration of practical applications, real-time 3D OCT imaging of pH and lactic acid in the anterior chamber of a fish eye was realized by GTNPs@PANI nanoparticles. Using GTNPs@PANI nanoparticles as the contrast probes for OCT imaging, noninvasive and real-time molecular imaging in both living and nonviable systems at the microscale can be achieved. PMID- 28809546 TI - Staphylococcus aureus CidC Is a Pyruvate:Menaquinone Oxidoreductase. AB - Recent studies have revealed an important role for the Staphylococcus aureus CidC enzyme in cell death during the stationary phase and in biofilm development and have contributed to our understanding of the metabolic processes that are important in the induction of bacterial programmed cell death (PCD). To gain more insight into the characteristics of this enzyme, we performed an in-depth biochemical and biophysical analysis of its catalytic properties. In vitro experiments show that this flavoprotein catalyzes the oxidative decarboxylation of pyruvate to acetate and carbon dioxide. CidC efficiently reduces menadione, but not CoenzymeQ0, suggesting a specific role in the S. aureus respiratory chain. CidC exists as a monomer under neutral-pH conditions but tends to aggregate and bind to artificial lipid membranes at acidic pH, resulting in enhanced enzymatic activity. Unlike its Escherichia coli counterpart, PoxB, CidC does not appear to be activated by other amphiphiles like Triton X-100 or octyl beta-d-glucopyranoside. In addition, only reduced CidC is protected from proteolytic cleavage by chymotrypsin, and unlike its homologues in other bacteria, protease treatment does not increase CidC enzymatic activity. Finally, CidC exhibits maximal activity at pH 5.5-5.8 and negligible activity at pH 7-8. The results of this study are consistent with a model in which CidC functions as a pyruvate:menaquinone oxidoreductase whose activity is induced at the cellular membrane during cytoplasmic acidification, a process previously shown to be important for the induction of bacterial PCD. PMID- 28809547 TI - Quantitative Evaluation of Viral Protein Binding to Phosphoinositide Receptors and Pharmacological Inhibition. AB - There is significant interest in developing analytical methods to characterize molecular recognition events between proteins and phosphoinositides, which are a medically important class of carbohydrate-functionalized lipids. Within this scope, one area of high priority involves quantitatively evaluating drug candidates that pharmacologically inhibit protein-phosphoinositide interactions. As full-length proteins are often difficult to produce, establishing methods to study these interactions with shorter, bioactive peptides would be advantageous. Herein, we report an atomic force microscopy (AFM)-based force spectroscopic approach to detect the specific interaction between an amphipathic, alpha-helical (AH) peptide derived from the hepatitis C virus NS5A protein and its biological target, the phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2] phosphoinositide receptor. After optimization of the peptide tethering strategy and measurement parameters, the binding specificity of AH peptide for PI(4,5)P2 receptors was comparatively evaluated across a panel of phosphoinositides and the influence of ionic strength on AH-PI(4,5)P2 binding strength was tested. Importantly, these capabilities were translated into the development of a novel experimental methodology to determine the inhibitory activity of a small-molecule drug candidate acting against the AH-PI(4,5)P2 interaction, and extracted kinetic parameters agree well with literature values obtained by conventional biochemical methods. Taken together, our findings provide a nanomechanical basis for explaining the high binding specificity of the NS5A AH to PI(4,5)P2 receptors, in turn establishing an analytical framework to study phosphoinositide-binding viral peptides and proteins as well as a broadly applicable approach to evaluate candidate inhibitors of protein-phosphoinositide interactions. PMID- 28809548 TI - Reaction of Dimethyl Trisulfide with Hemoglobin. AB - Dimethyl trisulfide (DMTS) is a promising antidotal candidate for cyanide intoxication. DMTS acts as a sulfur donor in the conversion of cyanide to the less-toxic thiocyanate. The alternate reaction pathways of DMTS in the blood are not well understood. We report changes in the hemoglobin absorption spectrum upon reaction with DMTS. These changes closely match those induced by the known methemoglobin former, sodium nitrite. The kinetics of methemoglobin formation with DMTS is slower than with sodium nitrite. These results support the hypothesis that a potentially significant side-reaction of the therapeutically administered DMTS is the oxidization of hemoglobin to methemoglobin. PMID- 28809549 TI - Mesocosm Studies on the Efficacy of Bioamended Activated Carbon for Treating PCB Impacted Sediment. AB - This report describes results of a bench-scale treatability study to evaluate the efficacy of bioaugmentation with bioamended activated carbon (AC) for in situ treatment of polychlorinated biphenyl (PCB) impacted sediments. To this end, the ability of PCB transforming microorganisms to degrade and reduce the overall concentration of PCBs in sediment was determined in 2 L recirculating mesocosms designed to simulate conditions in Abraham's Creek in Quantico, Virginia. Ten sediment mesocosms were tested for the effects of AC alone, AC with slow release electron donor (cellulose) and different concentrations and combinations of PCB dehalogenating and degrading microorganisms added as bioamendments. A 78% reduction of total PCBs was observed using a cell titer of 5 * 105 Dehalobium chlorocoercia and Paraburkholderia xenovorans cells g-1 sediment with 1.5% AC as a delivery system. Levels of both higher and lower chlorinated congeners were reduced throughout the sediment column indicating that both anaerobic reductive dechlorination and aerobic degradation occurred concurrently. Porewater concentrations of all PCB homologues were reduced 94-97% for bioaugmented treatments. Toxicity associated with coplanar PCBs was reduced by 90% after treatment based on toxic equivalency of dioxin-like congeners. These results suggest that an in situ treatment employing the simultaneous application of anaerobic and aerobic microorganisms on AC could be an effective, environmentally sustainable strategy to reduce PCB levels in contaminated sediment. PMID- 28809551 TI - Direct Speciation Analysis of Arsenic in Whole Blood and Blood Plasma at Low Exposure Levels by Hydride Generation-Cryotrapping-Inductively Coupled Plasma Mass Spectrometry. AB - A method for analysis of toxicologically important arsenic species in blood plasma and whole blood by selective hydride generation with cryotrapping (HG-CT) coupled either to atomic absorption spectrometry (AAS) with a quartz multiatomizer or to inductively coupled plasma mass spectrometry (ICPMS) has been validated. Sample preparation, which involved only 5 times dilution with addition of Triton X-100, Antifoam B, and l-cysteine, suppressed excessive foaming in a hydride generator. Calibration slopes for whole blood and blood plasma spiked with arsenate, monomethylarsonate, and dimethylarsinate at 0.25-1 MUg L-1 As and 0.025-0.1 MUg L-1 As for AAS and ICPMS detection, respectively, did not differ from slopes in aqueous solutions. HG-CT-AAS was used to analyze samples with elevated levels of arsenic species-blood plasma from patients treated with arsenic trioxide for acute promyelocytic leukemia and whole blood from mice fed an arsenic-containing diet. A good agreement between results of the direct analysis and analysis after mild digestion in phosphoric acid proved the good efficiency of the direct HG-CT procedure for the arsenic species in these types of biological samples. In the next step, plasma and whole blood from healthy donors that were spiked with the plasma from leukemia patients at levels of 0.15 0.4 MUg L-1 As were analyzed by direct HG-CT-ICPMS. Good recoveries for all species even at these low levels (88-104%) were obtained. Limits of detection in blood and plasma were 0.014 MUg L-1 for inorganic arsenic and below 0.002 MUg L-1 As for methylated arsenic species. Thus, the ultrasensitive direct HG-CT-ICPMS method is uniquely suited for analyses of blood plasma and whole blood from individuals at low exposure levels. PMID- 28809550 TI - Increase in the Magnetic Ordering Temperature (Tc) as a Function of the Applied Pressure for A2Mn[Mn(CN)6] (A = K, Rb, Cs) Prussian Blue Analogues. AB - Magnetization measurements under pressure reveal that the external hydrostatic pressure significantly increases in the ferrimagnetic transition temperature, Tc, for A2Mn[Mn(CN)6] (A = K, Rb, Cs). In the case of monoclinic A = K and Rb, dTc/dp values are 21.2 and 14.6 K GPa-1, respectively, and Tc increases by 53 and 39%, respectively, from ambient pressure to 1.0 GPa. The cubic A = Cs compound also shows a monotonous increase with an initial rate of 4.22 K GPa-1 and about 11.4 K GPa-1 above 0.6 GPa, and an overall Tc increase by 26% at 1.0 GPa. The increase in Tc is attributed to deformation of the structure such that the MnII-N=C angle decreases with increasing pressure. The smaller the alkali cation, the greater the decrease in the MnII-N=C angle induced by pressure and the larger the increase of dTc/dp. This is in accordance with the ambient-pressure structures for A2Mn[Mn(CN)6] (A = K, Rb, Cs), which have decreasing MnII-N=C angles that correlate to the observed increasing Tcs as K > Rb > Cs. The large increase in Tc for the A = K compound is the highest class among several cyano-bridged metal complexes. The tuning of the transition temperature by such a weak pressure may lead to additional applications such as switching devices. PMID- 28809552 TI - Characterization of 2-Oxindole Forming Heme Enzyme MarE, Expanding the Functional Diversity of the Tryptophan Dioxygenase Superfamily. AB - 3-Substituted 2-oxindoles are important structural motifs found in many biologically active natural products and pharmaceutical lead compounds. Here, we report an enzymatic formation of the 3-substituted 2-oxindoles catalyzed by MarE in the maremycin biosynthetic pathway in Streptomyces sp. B9173. MarE is a homologue of FeII/heme-dependent tryptophan 2,3-dioxygenases (TDOs). Typical TDOs usually catalyze the insertion of two oxygen atoms from O2 into an indole ring to generate N-formylkynurenine (NFK)-like products. In contrast, MarE catalyzes the insertion of a single oxygen atom from O2 into an indole ring, to probably generate an epoxyindole intermediate that undergoes an unprecedented 2,3-hydride migration to form 2-oxindole structure. MarE shows substrate robustness to catalyze the conversion of a series of 3-substituted indoles into their corresponding 3-substituted 2-oxindoles. Although containing most key amino acid residues conserved in well-known TDO homologues, MarE falls into a separate new subgroup in the phylogenetic tree. The characterization of MarE and its homologue enriches the functional diversities of TDO superfamily and provides a new strategy for discovering novel natural products containing 3-substituted 2 oxindole pharmacophores by genome mining. PMID- 28809553 TI - Structure-Directing Role of Phosphonate in the Synthesis of High-Nuclearity Silver(I) Sulfide-Ethynide-Thiolate Clusters. AB - Phosphonate ligands as structure-directing components have been employed to construct four new high-nuclearity silver(I) sulfide-ethynide-thiolate clusters, in which silver(I) aggregates tBuC=C?Ag3, tBuC=C?Ag4, and 2tBuC=C?Ag7 are bridged by tBuS- ligands to engender respective silver(I) ethynide-thiolate clusters functioning as integral shell components, which are supported by phosphonate ligands. In each silver(I) sulfide-ethynide-thiolate cluster, a different encapsulated silver sulfide cluster serves as a core template. PMID- 28809554 TI - A Dual Photochemically Active Molecule Showing Distributable Reactivity Based on Anion-Assisted Coordination Assembly. AB - Distributable reactivity of a dual photochemically active molecule functionalized by a carboxyl coordination unit has been achieved based on anion-assisted coordination assembly. The anions induce the photoactive ligand to align at different orientations in three-dimensional metal-organic frameworks, thus allowing the supramolecular systems to show photocycloaddition with simultaneous luminescence transformation or undergo photoinduced electron transfer accompanied by coloration-decoloration under alternating light and thermal stimuli. PMID- 28809555 TI - Electronic, Magnetic, and Redox Properties and O2 Reactivity of Iron(II) and Nickel(II) o-Semiquinonate Complexes of a Tris(thioether) Ligand: Uncovering the Intradiol Cleaving Reactivity of an Iron(II) o-Semiquinonate Complex. AB - The iron(II) semiquinonate character within the iron(III) catecholate species has been proposed by numerous studies to account for the O2 reactivity of intradiol catechol dioxygenases, but a well-characterized iron(II) semiquinonate species that exhibits intradiol cleaving reactivity has not yet been reported. In this study, a detailed electronic structure description of the first iron(II) o semiquinonate complex, [PhTttBu]Fe(phenSQ) [PhTttBu = phenyltris(tert butylthiomethyl)borate; phenSQ = 9,10-phenanthrenesemiquinonate; Wang et al. Chem. Commun. 2014, 50, 5871-5873], was generated through a combination of electronic and Mossbauer spectroscopies, SQUID magnetometry, and density functional theory (DFT) calculations. [PhTttBu]Fe(phenSQ) reacts with O2 to generate an intradiol cleavage product, diphenic anhydride, in 16% yield. To assess the dependence of the intradiol reactivity on the identity of the metal ion, the nickel analogue, [PhTttBu]Ni(phenSQ), and its derivative, [PhTttBu]Ni(3,5-DBSQ) (3,5-DBSQ = 3,5-di-tert-butyl-1,2-semiquinonate), were prepared and characterized by X-ray crystallography, mass spectrometry, 1H NMR and electronic spectroscopies, and SQUID magnetometry. DFT calculations, evaluated on the basis of the experimental data, support the electronic structure descriptions of [PhTttBu]Ni(phenSQ) and [PhTttBu]Ni(3,5-DBSQ) as high-spin nickel(II) complexes with antiferromagnetically coupled semiquinonate ligands. Unlike its iron counterpart, [PhTttBu]Ni(phenSQ) decomposes slowly in an O2 atmosphere to generate 14% phenanthrenequinone with a negligible amount of diphenic anhydride. [PhTttBu]Ni(3,5-DBSQ) does not react with O2. This dramatic effect of the metal-ion identity supports the hypothesis that a metal(III) alkylperoxo species serves as an intermediate in the intradiol cleaving reactions. The redox properties of all three complexes were probed using cyclic voltammetry and differential pulse voltammetry, which indicate an inner-sphere electron-transfer mechanism for the formation of phenanthrenequinone. The lack of O2 reactivity of [PhTttBu]Ni(3,5-DBSQ) can be rationalized by the high redox potential of the metal-ligated 3,5-DBSQ/3,5-DBQ couple. PMID- 28809557 TI - In Silico and in Vitro Interactions between Short Chain Fatty Acids and Human Histone Deacetylases. AB - Short chain fatty acids (SCFAs) are postulated to modulate the immune development of neonates via epigenetic regulations such as histone deacetylase (HDAC) inhibition. In the context of atopic diseases, the inhibition of HDAC maintains T cell homeostasis and induces naive T-cell differentiation into adaptive Treg, which regulates the production of anti-inflammatory cytokines and suppression of Th2 immune responses. We investigated the structure-inhibition relationships of SCFAs with class I HDAC3 and class IIa HDAC7 using in silico docking simulation and the in vitro human recombinant HDAC inhibition assay. In silico docking simulation demonstrated that the lower binding energy of SCFAs toward HDACs was associated with the longer aliphatic chain length of SCFAs. Conversely, branching of SCFAs increased their binding energies toward both HDAC3 and HDAC7. The in vitro HDAC inhibition assay revealed that SCFAs more potently inhibit HDAC3 than HDAC7, with butyric acid being the most potent HDAC3 inhibitor among SCFAs (IC50 = 0.318 mM). In conclusion, our findings inform novel structural relationships between SCFAs and HDAC3 versus HDAC7. Future investigation of human disposition of SCFAs is important to establish their effects on innate versus adaptive immunity. PMID- 28809556 TI - Radical Chemistry and Structural Relationships of PPCP Degradation by UV/Chlorine Treatment in Simulated Drinking Water. AB - The UV/chlorine process is an emerging advanced oxidation process (AOP) used for the degradation of micropollutants. However, the radical chemistry of this AOP is largely unknown for the degradation of numerous structurally diverse micropollutants in water matrices of varying quality. These issues were addressed by grouping 34 pharmaceuticals and personal care products (PPCPs) according to the radical chemistry of their degradation in the UV/chlorine process at practical PPCP concentrations (1 MUg L-1) and in different water matrices. The contributions of HO* and reactive chlorine species (RCS), including Cl*, Cl2*-, and ClO*, to the degradation of different PPCPs were compound specific. RCS showed considerable reactivity with olefins and benzene derivatives, such as phenols, anilines, and alkyl-/alkoxybenzenes. A good linear relationship was found between the RCS reactivity and negative values of the Hammett ?sigmap+ constant for aromatic PPCPs, indicating that electron-donating groups promote the attack of benzene derivatives by RCS. The contribution of HO*, but not necessarily RCS, to PPCP removal decreased with increasing pH. ClO* showed high reactivity with some PPCPs, such as carbamazepine, caffeine, and gemfibrozil, with second-order rate constants of 9.2 * 107, 1.03 * 108, and 4.16 * 108 M-1 s 1, respectively, which contributed to their degradation. Natural organic matter (NOM) induced significant scavenging of ClO* and greatly decreased the degradation of PPCPs that was attributable to ClO*, with a second-order rate constant of 4.5 * 104 (mg L-1)-1 s-1. Alkalinity inhibited the degradation of PPCPs that was primarily attacked by HO* and Cl* but had negligible effects on the degradation of PPCPs by ClO*. This is the first study on the reactivity of RCS, particularly ClO*, with structurally diverse PPCPs under simulated drinking water condition. PMID- 28809558 TI - Aliphatic C(sp3)-H Bond Activation Using Nickel Catalysis: Mechanistic Insights on Regioselective Arylation. AB - Transition-metal-catalyzed C(sp3)-H bond activation in aliphatic compounds are of current interest. Lack of mechanistic insights on Ni-catalyzed C(sp3)-H activation using 8-aminoquinoline as a directing group motivated us to examine an interesting direct arylation of an aliphatic tertiary amide by using density functional theory. The catalysis employed Ni(II) precatalyst, 4-iodoanisole as an arylating agent, sodium carbonate, and mesitylenic acid as additives in DMF solvent. Examination of a comprehensive set of mechanistic pathways helped us learn that the most preferred route begins with a bidentate chelate binding of deprotonated substrate to the Ni. The C-H activation in the catalyst-substrate complex via a cyclometalation deprotonation provides a five-membered nickelacycle intermediate, which upon the rate-limiting oxidative insertion to aryl iodide forms a Ni(IV)-aryl intermediate. The ensuing reductive elimination furnishes the desired arylated product. We note that the explicit inclusion of sodium carbonate, mesitylenic acid, and solvent molecules on sodium ion all are critical in identifying the most favorable pathway. Of the two types of C(sp3)-H bonds in the substrate [2-methyl-2-phenyl-N-(quinolin-8-yl)heptanamide], the energies for the regiocontrolling reductive elimination is predicted to be more in favor of the methyl group than the methylene of the pentyl chain, in excellent agreement with the previous experimental observation. PMID- 28809559 TI - On the Influence of the Bridge on Triplet State Delocalization in Linear Porphyrin Oligomers. AB - The extent of triplet state delocalization is investigated in rigid linear zinc porphyrin oligomers as a function of interporphyrin bonding characteristics, specifically in meso-meso singly linked and beta,meso,beta fused structures, using electron paramagnetic resonance techniques. The results are compared with those of earlier measurements on porphyrin oligomers with alkyne linkers exhibiting different preferred conformations. It is shown that dihedral angles near 90 degrees between the porphyrin planes in directly meso-to-meso linked porphyrin oligomers lead to localization of the photoexcited triplet state on a single porphyrin unit, whereas previous work demonstrated even delocalization over two units in meso-to-meso ethyne or butadiyne-bridged oligomers, where the preferred dihedral angles amount to roughly 30 degrees and 0 degrees , respectively. The triplet states of fused porphyrin oligomers (i.e., porphyrin tapes) exhibit extended conjugation and even delocalization over more than two porphyrin macrocycles, in contrast to meso-to-meso ethyne or butadiyne-bridged oligomers, where the spin density distribution in molecules composed of more than two porphyrin units is not evenly spread across the oligomer chain. PMID- 28809560 TI - Recombinant Macrocyclic Lanthipeptides Incorporating Non-Canonical Amino Acids. AB - Nisin is a complex lanthipeptide that has broad spectrum antibacterial activity. In efforts to broaden the structural diversity of this ribosomally synthesized lantibiotic, we now report the recombinant expression of Nisin variants that incorporate noncanonical amino acids (ncAAs) at discrete positions. This is achieved by expressing the nisA structural gene, cyclase (nisC) and dehydratase (nisB), together with an orthogonal nonsense suppressor tRNA/aminoacyl-tRNA synthetase pair in Escherichia coli. A number of ncAAs with novel chemical reactivity were genetically incorporated into NisA, including an alpha chloroacetamide-containing ncAA that allowed for the expression of Nisin variants with novel macrocyclic topologies. This methodology should allow for the exploration of lanthipeptide variants with new or enhanced activities. PMID- 28809561 TI - Transition-Metal-Free Direct Trifluoromethylthiolation and Trifluoromethylsulfoxidation of Electron-Rich Aromatics with CF3SO2Na in the Presence of PCl3. AB - A new transition-metal-free route for the direct trifluoromethylthiolation and trifluoromethylsulfoxidation of electron-rich aromatics with CF3SO2Na in the presence of PCl3 was developed. Notably, PCl3 was used as a reducing and chlorination reagent. The transition-metal-free protocol utilized cheap and readily available reagents and exhibited good atom economy; therefore, it will serve as an alternative and practical strategy for the trifluoromethylthiolation and trifluoromethylsulfoxidation of electron-rich aromatics. PMID- 28809562 TI - One-Pot Synthesis of Unsymmetric Diaryliodonium Salts from Iodine and Arenes. AB - The first synthesis of unsymmetric diaryliodonium salts directly from iodine and arenes is presented. The methodology provides diaryliodonium salts with the trimethoxyphenyl (TMP) moiety as dummy group. The protocol avoids the customary use of iodoarenes, which can be both expensive and toxic. Excess reagents are not required, and the reactions are performed under mild conditions. O-Arylations with these TMP salts were demonstrated to be highly chemoselective. PMID- 28809563 TI - Domino-Fluorination-Protodefluorination Enables Decarboxylative Cross-Coupling of alpha-Oxocarboxylic Acids with Styrene via Photoredox Catalysis. AB - Domino-fluorination-protodefluorination decarboxylative cross-coupling of alpha keto acids with styrene has been developed via photoredox catalysis. The critical part of this strategy is the formation of the carbon-fluorine (C-F) bond by the capture of a carbon-centered radical intermediate, which will overcome side reactions during the styrene radical functionalization process. Experimental studies have provided evidence indicating a domino-fluorination protodefluorination pathway with alpha-keto acid initiating the photoredox cycle. The present catalytic protocol also affords a novel approach for the construction of alpha,beta-unsaturated ketones under mild conditions. PMID- 28809564 TI - A Chemoselective N-Arylation Reaction of 2-Aminopyridine Derivatives with Arynes. AB - A chemoselective N-arylation reaction of 2-aminopyridine derivatives with arynes in good to excellent yields has been described. The N-arylation products could be further applied to the facile construction of benzoisoquinuclidines and isoquinuclidines as well as pyrido[1,2-a]benzimidazoles. PMID- 28809566 TI - Carbon-Phosphorus Bond Formation on Anilines Mediated by a Hypervalent Iodine Reagent. AB - Substituted anilines containing a sulfonyl group may be oxidized in situ in the presence of methanol and a hypervalent iodine reagent to form an active iminium species. Subsequent addition of phosphines or phosphites in the same pot produces meta-substituted anilines in good yields. This formal C-H bond functionalization is a direct and efficient means of selectively substituting the meta-position of anilines to produce aromatic phosphonium ions or phosphonates. PMID- 28809567 TI - Palladium(II)-Catalyzed Deacylative Allylic C-H Alkylation. AB - The first deacylative allylic C-H alkylation has been established by employing the palladium-catalyzed allylic C-H activation and decarboxylative nucleophile generation. A wide scope of nucleophiles are tolerated and densely functionalized alkylation products turn out to be furnished in moderate to good yield. More importantly, this strategy provides an alternative method for the allylic C-H alkylation with less stabilized carbon nucleophiles, and can be further expanded to the synthesis of unconjugated enynes. PMID- 28809568 TI - Combinatorial Nickel-Catalyzed Monofluoroalkylation of Aryl Boronic Acids with Unactivated Fluoroalkyl Iodides. AB - A combinatorial nickel-catalyzed cross-coupling between arylboronic acids and unactived 1-fluoro-1-iodoalkanes has been developed, which demonstrated high efficiency, mild conditions, and excellent functional-group compatibility. Readily available nitrogen and phosphine ligands were combined with a nitrogen source, which in situ generated a variety of easily tunable catalysts to promote the fluoroalkylation for broad scopes of both coupling partners. This new strategy on combinatorial catalysis offers new solutions for nickel-catalyzed cross-coupling reactions. PMID- 28809565 TI - Dipicolinic Acid Derivatives as Inhibitors of New Delhi Metallo-beta-lactamase-1. AB - The efficacy of beta-lactam antibiotics is threatened by the emergence and global spread of metallo-beta-lactamase (MBL) mediated resistance, specifically New Delhi metallo-beta-lactamase-1 (NDM-1). By utilization of fragment-based drug discovery (FBDD), a new class of inhibitors for NDM-1 and two related beta lactamases, IMP-1 and VIM-2, was identified. On the basis of 2,6-dipicolinic acid (DPA), several libraries were synthesized for structure-activity relationship (SAR) analysis. Inhibitor 36 (IC50 = 80 nM) was identified to be highly selective for MBLs when compared to other Zn(II) metalloenzymes. While DPA displayed a propensity to chelate metal ions from NDM-1, 36 formed a stable NDM 1:Zn(II):inhibitor ternary complex, as demonstrated by 1H NMR, electron paramagnetic resonance (EPR) spectroscopy, equilibrium dialysis, intrinsic tryptophan fluorescence emission, and UV-vis spectroscopy. When coadministered with 36 (at concentrations nontoxic to mammalian cells), the minimum inhibitory concentrations (MICs) of imipenem against clinical isolates of Eschericia coli and Klebsiella pneumoniae harboring NDM-1 were reduced to susceptible levels. PMID- 28809570 TI - Multiple Hydrogen-Bonding Bifunctional Thiourea-Catalyzed Asymmetric Dearomative [4 + 2] Annulation of 3-Nitroindoles: Highly Enantioselective Access to Hydrocarbazole Skeletons. AB - A method for the enantioselective construction of hydrocarbazole skeletons through dearomative [4 + 2] annulation of 3-nitroindoles with Nazarov reagents is reported. The reactions use multiple hydrogen-bonding bifunctional thiourea as catalyst and are highly diastereo- and enantioselective (up to >20:1 dr and >99% ee). The protocol was demonstrated by preparative-scale experiment and the versatile conversion of the products. The multiple hydrogen-bonding in the catalyst plays a pivotal role in the reactivity and stereoselectivity. PMID- 28809569 TI - Rh-Catalyzed Conjugate Addition of Aryl and Alkenyl Boronic Acids to alpha Methylene-beta-lactones: Stereoselective Synthesis of trans-3,4-Disubstituted beta-Lactones. AB - A one-step preparation of 3,4-disubstituted beta-lactones through Rh-catalyzed conjugate addition of aryl or alkenyl boronic acids to alpha-methylene-beta lactones is described. The operationally simple, stereoselective transformation provides a broad range of beta-lactones from individual alpha-methylene-beta lactone templates. This methodology allowed for a direct, final-step C-3 diversification of nocardiolactone, an antimicrobial natural product. PMID- 28809571 TI - 3-Methylene-4-amido-1,2-diazetidine as a Formal 1,4-Dipole Precursor: Lewis Acid Catalyzed Nucleophilic Addition with Silylated Nucleophiles. AB - 3-Methylene-4-amido-1,2-diazetidine (MADA) was prepared for the first time via formal [2 + 2] cycloaddition of an allenamide and an azodicarboxylate. MADA worked as a formal 1,4-dipole precursor toward nucleophilic addition with various silyl enol ethers and allyltrimethylsilanes. PMID- 28809574 TI - Selectivity Control in Ruthenium(II)-Catalyzed C-H/N-O Activation with Alkynyl Bromides. AB - C-H/N-O activation with 1-bromoalkynes was accomplished within a chemoselective ruthenium(II) catalysis manifold by means of carboxylate assistance. The exceedingly mild reaction conditions set the stage for the positional selective annulations of bromoalkynes at an ambient reaction temperature of 25 degrees C, placing the organic substituent distal to nitrogen in isoquinolones with a regioselectivity that is complementary to all previous protocols. PMID- 28809573 TI - Intrinsic Plasmon-Phonon Interactions in Highly Doped Graphene: A Near-Field Imaging Study. AB - As a two-dimensional semimetal, graphene offers clear advantages for plasmonic applications over conventional metals, such as stronger optical field confinement, in situ tunability, and relatively low intrinsic losses. However, the operational frequencies at which plasmons can be excited in graphene are limited by the Fermi energy EF, which in practice can be controlled electrostatically only up to a few tenths of an electronvolt. Higher Fermi energies open the door to novel plasmonic devices with unprecedented capabilities, particularly at mid-infrared and shorter-wave infrared frequencies. In addition, this grants us a better understanding of the interaction physics of intrinsic graphene phonons with graphene plasmons. Here, we present FeCl3 intercalated graphene as a new plasmonic material with high stability under environmental conditions and carrier concentrations corresponding to EF > 1 eV. Near-field imaging of this highly doped form of graphene allows us to characterize plasmons, including their corresponding lifetimes, over a broad frequency range. For bilayer graphene, in contrast to the monolayer system, a phonon-induced dipole moment results in increased plasmon damping around the intrinsic phonon frequency. Strong coupling between intrinsic graphene phonons and plasmons is found, supported by ab initio calculations of the coupling strength, which are in good agreement with the experimental data. PMID- 28809572 TI - Antigen-Specific Gut Inflammation and Systemic Immune Responses Induced by Prolonging Wheat Gluten Sensitization in BALB/c Murine Model. AB - Gluten-related diseases such as wheat allergy, celiac disease, and gluten intolerance are widespread around the globe to genetically predisposed individuals. The present study aims to develop a wheat-gluten induced BALB/c murine model for addressing wheat-gluten related disorders by sensitizing the wheat gluten through the route of intraperitoneal and oral challenge in prolonged days. During the sensitization, the sera were collected for specific antigliadin antibodies response and proinflammatory markers quantification. Ex vivo primary cells and organs were collected for subsequent analysis of inflammatory profile. Prolonging sensitization of gluten can moderate the antigen-specific inflammatory markers such as IL-1beta, IL-4, IL-15, IL-6, IFN-gamma and TNF-alpha levels in mice sera. However, ex vivo primary cells of splenocytes (SPLs) and intestinal epithelial lymphocytes (IELs) significantly increased the IL-6, IL-15, IL-1beta, and IL-4 levels in G+ (gliadin and gluten) treated cells. Histopathology staining of jejunum sections indicates enterocyte degeneration in the apical part of villi and damage of tight junctions in G+ (gliadin and gluten) sensitized murine model. Immunohistochemistry of embedded jejunum sections showed significant expression of positive cells of IL-15, tTG and IL-4 in G+ sensitized murine model. In contrast, all markers of gluten-related disorders are expressed exclusively such as tTG, ZO-1, IL-15, IL-6, IL-4, and intestinal inflammation was mediated by iNOS, COX-2, TLR-4 and NF-kBp50 signaling mechanism in G+ sensitized mice. PMID- 28809575 TI - Pentavalent Bismuth as a Universal Promoter for S-Containing Glycosyl Donors with a Thiol Additive. AB - S-Propyl glycosides of less activated sugars, such as peracetylated carbohydrates and uronic acid esters that could not previously be activated with triphenylbismuth ditriflate alone, were found to be glycosylated in the presence of propanethiol as an additive in under 3 h. This newly developed protocol was also found to be effective in promoting glycosylation of neutral and uronic acid esters of S-phenyl, S-thiazolinyl, S-benzoxazolyl, and S-adamantyl glycosides as well as sialic acid. PMID- 28809576 TI - N-Radical Initiated Aminosulfonylation of Unactivated C(sp3)-H Bond through Insertion of Sulfur Dioxide. AB - N-Radical initiated aminosulfonylation of unactivated C(sp3)-H bond through insertion of sulfur dioxide in the presence of visible light is reported. O-Aryl oximes react with DABCO.(SO2)2 smoothly at room temperature under blue LED irradiation without any metals or photoredox catalysts, generating diverse 5,6 dihydro-4H-1,2-thiazine 1,1-dioxides in good yield. Additionally, this approach can be extended to the synthesis of 1H-benzo[d][1,2]thiazine 2,2-dioxides. During the reaction process, an N-radical is initiated by the treatment of O-aryl oximes with DABCO.(SO2)2 under visible-light irradiation. It is followed by aminosulfonylation of a nearby C(sp3)-H bond through 1,5-hydrogen atom transfer with accompanying insertion of sulfur dioxide to provide 1,2-thiazine 1,1-dioxide derivatives. PMID- 28809577 TI - Regioselective C-H Sulfanylation of Aryl Sulfoxides by Means of Pummerer-Type Activation. AB - A regioselective C-H sulfanylation of aryl sulfoxides with alkyl aryl sulfides in the presence of acid anhydride was developed, which resulted in the formation of 1,4-disulfanylarenes after dealkylation of initially formed sulfonium salts. The reaction began with Pummerer-type activation of aryl sulfoxides followed by nucleophilic attack of alkyl aryl sulfides. The nucleophilic attack occurred exclusively at the para positions, or at specific positions in case the para position was not available, under perfect control by the dominating sulfoxide directors regardless of any other substituents. The initially formed aryl sulfonium salts were isolable and usefully served as aryl halide surrogates for palladium-catalyzed arylation with sodium tetraarylborates. PMID- 28809578 TI - UV-Vis Action Spectroscopy Reveals a Conformational Collapse in Hydrogen-Rich Dinucleotide Cation Radicals. AB - We report the generation of deoxyriboadenosine dinucleotide cation radicals by gas-phase electron transfer to dinucleotide dications and their noncovalent complexes with crown ether ligands. Stable dinucleotide cation radicals of a novel hydrogen-rich type were generated and characterized by tandem mass spectrometry and UV-vis photodissociation (UVPD) action spectroscopy. Electron structure theory analysis indicated that upon electron attachment the dinucleotide dications underwent a conformational collapse followed by intramolecular proton migrations between the nucleobases to give species whose calculated UV-vis absorption spectra matched the UVPD action spectra. Hydrogen rich cation radicals generated from chimeric riboadenosine 5'-diesters gave UVPD action spectra that pointed to novel zwitterionic structures consisting of aromatic pi-electron anion radicals intercalated between stacked positively charged adenine rings. Analogies with DNA ionization are discussed. PMID- 28809579 TI - Total Synthesis of Nannocystin Ax. AB - The total synthesis of nannocystin Ax in an overall yield of 11% with 14 steps as the longest linear sequence is reported. Nannocystin Ax is a cytotoxic 21 membered depsipeptide and was isolated from the myxobacterial genus Nannocystis sp. The synthesis uses a vinylogous Horner-Wadsworth-Emmons reaction (HWE) and a vinylogous Mukaiyama aldol reaction (VMAR) as the key steps for the construction of the polyketide fragment. The macrocycle was closed via a macrolactamization reaction using COMU. PMID- 28809580 TI - Temperature-Dependent Enantio- and Diastereodivergent Synthesis of Amino Acids with One or Multiple Chiral Centers. AB - A general and facile methodology for temperature-dependent enantiodivergent and diastereodivergent synthesis of amino acids with one or multiple chiral centers was developed. Camphor-based tricyclic iminolactones attack electrophiles from the endo face at low temperature (-78 to -40 degrees C) and from the exo face at high temperature (-10 to 25 degrees C). PMID- 28809581 TI - [Mental health of preschool foster care children: How do foster families influence the way children cope with trauma?] AB - Mental health of preschool foster care children: How do foster families influence the way children cope with trauma? Abstract. Parents and other significant persons have an important role when preschool children develop or cope with psychological symptoms following traumatic experiences. The underlying mechanisms of the interaction between traumatic experiences and influences of the foster family are still unclear. This study investigates foster parents' stress levels and parenting styles as moderators or mediators in the context of trau- matic experiences. Foster parents of 286 children between three and seven years participated in an online or paper-and-pencil survey. The results suggest a connection between the traumatic experiences of foster children and the stress levels as well as the parenting styles of their foster parents. While verbosity and laxness as parenting styles moderated the impact of traumatic experiences on externalising symptoms, stress levels mediated the impact of traumatic experiences on children's internalising and externalising symptoms. The results underscore the necessity of standardized preparation of and support for foster parents in order to avoid deterioration of psychological symptoms following traumatic events. PMID- 28809582 TI - Iodixanol versus Iopromide at Coronary CT Angiography: Lumen Opacification and Effect on Heart Rhythm-the Randomized IsoCOR Trial. AB - Purpose To show that equal coronary lumen opacification can be achieved with iso- and low-osmolar contrast media when it is injected at the same iodine delivery rate with contemporary cardiac computed tomographic (CT) protocols and to investigate the cardiovascular effect of iso-osmolar contrast media and the image quality achieved. Materials and Methods Institutional review board approval and written informed consent were obtained for the Effect of Iso-osmolar Contrast Medium on Coronary Opacification and Heart Rhythm in Coronary CT Angiography, or IsoCOR, trial. Between November 2015 and August 2016, 306 patients (167 [55%] women) at least 18 years old (weight range, 50-125 kg), were prospectively randomized to receive iso-osmolar iodixanol 270 or low-osmolar iopromide 300 contrast media. All coronary segments were assessed for intraluminal opacification and image quality and were compared by using the Student t test. Heart rate, arrhythmia, patient discomfort, and adverse events also were monitored. Results Mean measured coronary attenuation values +/- standard deviation were comparable between the iodixanol 270 and iopromide 300 contrast media groups (469 HU +/- 167 vs 447 HU +/- 166, respectively [P = .241]; 95% confidence interval: -15.1, 60.0), including those from subanalyses. Adjusted for the lower iodine concentration, the mean iodixanol 270 bolus was larger compared with that of iopromide 300 (76.8 mL +/- 11.6 vs 69.7 mL +/- 10.8, respectively; P < .001). The higher injection rate was associated with higher pressure (777 kPa +/- 308 vs 630 kPa +/- 252, respectively; P < .001). Although in the iodixanol 270 group patients experienced less heat discomfort (72% vs 86%, respectively; P < .001), no differences in heart rate or rhythm were observed. Conclusion If injected at comparable iodine delivery rates, the iso-osmolar contrast medium iodixanol 270 is not inferior to low-osmolar contrast medium iopromide 300 for assessment of coronary opacification. Iodixanol 270 was associated with less heat discomfort, but did not affect heart rate differently compared with iopromide 300. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28809583 TI - Meetings & Symposia. PMID- 28809584 TI - Risk of Meningioma after CT of the Head. AB - Purpose To investigate the association between exposure to head computed tomography (CT) and subsequent risk of meningioma. Materials and Methods The study was approved by the local ethics committee. A cohort of 26 370 subjects was retrospectively collected from a radiology archive of CT examinations of the head performed from 1973 through 1992. For comparison, an age- and sex-matched cohort of 96 940 subjects who were not exposed to CT (unexposed cohort) was gathered. The risk of meningioma was assessed by using data from the Swedish Cancer Registry; however, one-third of patients with meningioma had to be excluded because they either had a prevalent meningioma or other brain tumor at the first CT examination or had undergone radiation treatment to the head. Hazard ratios (HRs) were calculated from time of exposure to the occurrence of meningioma or death or until December 31, 2010, with logistic regression. Results Comparison of exposed and unexposed cohorts showed that there was no statistically significant increase in the risk of meningioma after exposure to CT of the head (HR: 1.49; 95% confidence interval: 0.97, 2.30; P = .07). If incident cases at the time of the first CT examination were not excluded, the risk of meningioma would have been falsely increased (HR: 2.28; 95% confidence interval: 1.56, 3.33; P = .0001). Conclusion When prevalent cases of meningioma at first exposure to CT of the head are excluded, no statistically significant increase in risk of meningioma was found among exposed subjects compared with unexposed control subjects. (c) RSNA, 2017. PMID- 28809585 TI - Patient autonomy and doctor's concern - a case of intravenous drug abuser. AB - Intravenous substance abuse is often associated with physical and psychological harm, and often requires urgent medical attention. We report a case of a young male who presented with life-threatening complications of intravenous drug abuse, but refused to give details or agree to the proposed treatment, raising concerns for the team of doctors. A compos mentis patient has a right to decide what should be done to his body. Medical management or surgical interventions cannot be initiated without the patient's consent even if these are lifesaving procedures, or a procedure meant to benefit the patient. Medical practitioner can be liable for assault (criminal law), medical negligence (law of tort), damages (civil action) and even human rights issues may be raised if a patient's autonomy is not respected. PMID- 28809586 TI - The nursing quality indicator framework tool. AB - Purpose The purpose of this paper is to develop a nursing quality indicator (NQI) framework and provide a comprehensive reporting mechanism for nursing care. Design/methodology/approach Mixed method, including patient records audit, patient experience questionnaire, nurse self-report questionnaire and collecting ward-level information. The sample was 53 patients and 22 nurses. Findings Outputs from the NQI framework domains offer a more comprehensive understanding of nursing quality compared to when domains are analysed separately. The NQI framework also provides a more inclusive mechanism for assuring nursing care. Research limitations/implications Sample size was limited to 53 English-speaking patients who consented to participating in the study. Originality/value One design strength was the ability to describe individual patient care across the four domains and subsequently show relationships between nursing knowledge, nursing interventions and patient outcomes/experiences. Additionally, corroborated information from three sources (documentation review, patient and nurse responses) strengthened the conclusion that the NQI framework could provide more comprehensive assurances on nursing quality and identify care improvements. PMID- 28809587 TI - Severe asthma: emergency care patient driven solutions. AB - Purpose Patients with severe asthma were choosing not to use the emergency department (ED) in extremis and were self-medicating when experiencing severe asthma, putting their lives at risk. This local issue reflected a nationwide situation. The purpose of this paper is to better understand the reasons behind patients' reluctance to attend ED and to consider practical solutions in a structured way. Design/methodology/approach Systems thinking (soft systems methodology) was used to examine the issues resulting in this reluctance to attend the ED. Once this tame (well-defined) problem was revealed, a potential solution was developed in co-production with patients. Findings Patients feared attending the ED and felt vulnerable while in the ED for several reasons. This appeared to be a well-defined and solvable problem. The solution proposed was an asthma patient passport (APP), which increased patient's confidence in their ability to communicate their needs while in severe distress. The APP decreases (from 12 to 5 steps) the work patients had to do to achieve care. The APP project is currently being evaluated. Practical implications The APP should be offered to all people with severe asthma. Originality/value By revisiting systems thinking and identifying problems, a solution was identified. Although methods such as soft systems methodology have limitations when used in wicked (difficult or impossible to resolve) problems, such methods still have merit in tame problems and were applicable in this case to fully understand the issues, and to design practical solutions. PMID- 28809588 TI - Applying adult development theories to improvement science. AB - Purpose The purpose of this paper is to address how adult development (AD) theories can contribute to quality improvement (QI). Design/methodology/approach A theoretical analysis and discussion on how personal development empirical findings can relate to QI and Deming's four improvement knowledge domains. Findings AD research shows that professionals have qualitatively diverse ways of meaning-making and ways to approach possibilities in improvement efforts. Therefore, professionals with more complex meaning-making capacities are needed to create successful transformational changes and learning, with the recognition that system knowledge is a developmental capacity. Practical implications In QI and improvement science there is an assumption that professionals have the skills and competence needed for improvement efforts, but AD theories show that this is not always the case, which suggests a need for facilitating improvement initiatives, so that everyone can contribute based on their capacity. Originality/value This study illustrates that some competences in QI efforts are a developmental challenge to professionals, and should be considered in practice and research. PMID- 28809589 TI - Editorial. PMID- 28809590 TI - Brand trust and image: effects on customer satisfaction. AB - Purpose The purpose of this paper is to investigate brand trust and brand image effects on healthcare service users. Nowadays, managers and health activists are showing increased tendency to marketing and branding to attract and satisfy customers. Design/methodology/approach The current study's design is based on a conceptual model examining brand trust and brand image effects on customer satisfaction. Data obtained from 240 questionnaires (310 respondents) were analyzed using path analysis. Findings Results revealed that the most effective items bearing the highest influence on customer satisfaction and on benefiting from healthcare services include brand image, staff sincerity to its patients, interactions with physicians and rapport. Research limitations/implications This study needs to be conducted in different hospitals and with different patients, which would lead to the model's expansion and its influence on the patient satisfaction. Originality/value Being the first study that simultaneously addresses brand trust and brand image effects on customer satisfaction, this research provides in-depth insights into healthcare marketing. Moreover, identifying significant components associated with healthcare branding helps managers and healthcare activists to create and protect their brands and, consequently, leading to an increased profitability resulting from the enhanced consumer satisfaction. Additionally, it would probably facilitate purchasing processes during the service selection. PMID- 28809591 TI - Reducing inappropriate non-steroidal anti-inflammatory prescription in primary care patients with chronic kidney disease. AB - Purpose The purpose of this paper is to reduce inappropriate non-steroidal anti inflammatory prescribing in primary care patients with chronic kidney disease (CKD). Once diagnosed, CKD management involves delaying progression to end stage renal failure and preventing complications. It is well established that non steroidal anti-inflammatories have a negative effect on kidney function and consequently, all nephrology consensus groups suggest avoiding this drug class in CKD. Design/methodology/approach The sampling criteria included all practice patients with a known CKD risk factor. This group was refined to include those with an estimated glomerular filtration rate (eGFR)<60 ml/min per 1.73m2 (stage 3 CKD or greater). Phase one analysed how many prescriptions had occurred in this group over the preceding three months. The intervention involved creating an automated alert on at risk patient records if non-steroidal anti-inflammatories were prescribed and discussing the rationale with practice staff. The re-audit phase occurred three months' post intervention. Findings The study revealed 728/7,500 (9.7 per cent) patients at risk from CKD and 158 (2.1 per cent) who were subsequently found to have an eGFR<60 ml/min, indicating=stage 3 CKD. In phase one, 10.2 per cent of at risk patients had received a non-steroidal anti inflammatory prescription in the preceding three months. Additionally, 6.2 per cent had received non-steroidal anti-inflammatories on repeat prescription. Phase two post intervention revealed a significant 75 per cent reduction in the total non-steroidal anti-inflammatories prescribed and a 90 per cent reduction in repeat non-steroidal anti-inflammatory prescriptions in those with CKD. Originality/value The study significantly reduced non-steroidal anti-inflammatory prescription in those with CKD in primary care settings. It also created a CKD register within the practice and an enduring medication alert system for individuals that risk nephrotoxic non-steroidal anti-inflammatory prescription. It established a safe, reliable and efficient process for reducing morbidity and mortality, improving quality of life and limiting the CKD associated health burden. PMID- 28809592 TI - Survey process quality: a question of healthcare manager approach. AB - Purpose The purpose of this paper is to explore how healthcare first-line managers think about and act regarding workplace survey processes. Design/methodology/approach This interview study was performed at a hospital in south Sweden. First-line healthcare managers ( n=24) volunteered. The analysis was inspired by phenomenography, which aims to describe the ways in which different people experience a phenomenon. The phenomenon was a workplace health promotion (WHP) survey processes. Findings Four main WHP survey process approaches were identified among the managers: as a possibility, as a competition, as a work task among others and as an imposition. For each, three common subcategories emerged; how managers: stated challenges and support from hospital management; described their own work group and collaboration with other managers; and expressed themselves and their situation in their roles as first line managers. Practical implications Insights into how hospital management can understand their first-line managers' motivation for survey processes and practical suggestions and how managers can work proactively at organizational, group and individual level are presented. Originality/value Usually these studies focus on those who should respond to a survey; not those who should run the survey process. Focusing on managers and not co-workers can lead to more committed and empowered managers and thereby success in survey processes. PMID- 28809593 TI - Water, sanitation and hygiene in Jordan's healthcare facilities. AB - Purpose The purpose of this paper is to determine water availability, sanitation and hygiene (WSH) services, and healthcare waste management in Jordan healthcare facilities. Design/methodology/approach In total, 19 hospitals (15 public and four private) were selected. The WSH services were assessed in hospitals using the WSH in health facilities assessment tool developed for this purpose. Findings All hospitals (100 percent) had a safe water source and most (84.2 percent) had functional water sources to provide enough water for users' needs. All hospitals had appropriate and sufficient gender separated toilets in the wards and 84.2 percent had the same in outpatient settings. Overall, 84.2 percent had sufficient and functioning handwashing basins with soap and water, and 79.0 percent had sufficient showers. Healthcare waste management was appropriately practiced in all hospitals. Practical implications Jordan hospital managers achieved major achievements providing access to drinking water and improved sanitation. However, there are still areas that need improvements, such as providing toilets for patients with special needs, establishing handwashing basins with water and soap near toilets, toilet maintenance and providing sufficient trolleys for collecting hazardous waste. Efforts are needed to integrate WSH service policies with existing national policies on environmental health in health facilities, establish national standards and targets for the various healthcare facilities to increase access and improve services. Originality/value There are limited WSH data on healthcare facilities and targets for basic coverage in healthcare facilities are also lacking. A new assessment tool was developed to generate core WSH indicators and to assess WSH services in Jordan's healthcare facilities. This tool can be used by a non-WSH specialist to quickly assess healthcare facility related WSH services and sanitary hazards in other countries. This tool identified some areas that need improvements. PMID- 28809594 TI - Evaluating health service quality: using importance performance analysis. AB - Purpose Measuring healthcare service quality provides an objective guide for managers and policy makers to improve their services and patient satisfaction. Consequently, the purpose of this paper is to measure service quality provided to surgical and medical inpatients at Kerman Medical Sciences University (KUMS) in 2015. Design/methodology/approach A descriptive-analytic study, using a cross sectional method in the KUMS training hospitals, was implemented between October 2 and March 15, 2015. Using stratified random sampling, 268 patients were selected. Data were collected using an importance-performance analysis (IPA) questionnaire, which measures current performance and determines each item's importance from the patients' perspectives. These data indicate overall satisfaction and appropriate practical strategies for managers to plan accordingly. Findings Findings revealed a significant gap between service importance and performance. From the patients' viewpoint, tangibility was the highest priority (mean=3.54), while reliability was given the highest performance (mean=3.02). The least important and lowest performance level was social accountability (mean=1.91 and 1.98, respectively). Practical implications Healthcare managers should focus on patient viewpoints and apply patient comments to solve problems, improve service quality and patient satisfaction. Originality/value The authors applied an IPA questionnaire to measure service quality provided to surgical and medical ward patients. This method identifies and corrects service quality shortcomings and improving service recipient perceptions. PMID- 28809597 TI - Meetings & Symposia. PMID- 28809595 TI - Immobilization of alpha-Glucosidase in Chitosan Coated Polygalacturonic Acid. AB - Crude alpha-glucosidase from Baker's yeast was immobilized in polygalacturonic acid beads and coated with chitosan. Chemical and physical characterization were performed by using p-nitrophenyl-alpha-D-glucopyranoside (pNPG) as an artificial substrate. Operation, thermal, pH, and strorage stabilities of the free and immobilized enzyme were also examined. The stabilities of immobilized enzyme were found to be better than that of the free enzyme. Furthermore, the hydrolysis rate of the chitosan coated alpha-glucosidase polygalacturonic acid beads were studied. In conclusion, the enzyme beads appear to have good characteristics and offer the prospect that this system may find application in enzyme immobilization, in addition to controlled drug release studies. PMID- 28809598 TI - Importance of Reproductive Care in Survivors of Childhood Cancer. PMID- 28809599 TI - Preservation of Fertility and Ovarian Function: A Time-Sensitive Survivorship Need. PMID- 28809600 TI - Linitis Plastica of Muscle Fascia Presenting as Tiptoeing Gait. PMID- 28809601 TI - Detection and Treatment of Monoclonal Gammopathy of Renal Significance With Progression to Light Chain Deposition Disease. PMID- 28809602 TI - Fertility Preservation and Sexual Health After Cancer Therapy. AB - Recent developments in cancer diagnostics and treatments have considerably improved long-term survival rates. Despite improvements in chemotherapy regimens, more focused radiotherapy and diverse surgical options, cancer treatments often have gonadotoxic side-effects that can manifest as loss of fertility or sexual dysfunction, particularly in young cancer survivors. In this review, we focus on two pertinent quality-of-life issues in female cancer survivors of reproductive age-fertility preservation and sexual function. Fertility preservation encompasses all clinical and laboratory efforts to preserve a woman's chance to achieve future genetic motherhood. These efforts range from well-established protocols such as ovarian stimulation with cryopreservation of embryos or oocytes, to nascent clinical trials involving cryopreservation and re implantation of ovarian tissue. Therefore, fertility preservation strategies are individualized to the cancer diagnosis, time interval until initiation of treatments must begin, prognosis, pubertal status, and maturity level of patient. Some patients choose not to pursue fertility preservation, and the conversation then centers around other quality of life issues. Not all cancer treatments cause loss of fertility; however, most treatments can directly impact the physical and psychosocial aspects of sexual function. Cancer treatment is also associated with fear, anxiety, and depression, which can further decrease sexual desire, function, and frequency. Sexual dysfunction after cancer treatment is generally ascertained by compassionate inquiry. Strategies to promote sexual function after cancer treatment include pelvic floor exercises, clitoral therapy devices, pharmacologic agents, as well as couples-based psychotherapeutic and psycho educational interventions. Quality-of-life issues in young cancer survivors are often best addressed by utilizing a multidisciplinary team consisting of physicians, nurses, social workers, psychiatrists, sex educators, counselors, or therapists. PMID- 28809603 TI - Paraneoplastic Thrombocytopenia Cured With Nephrectomy and Vena Cava Thrombectomy: Concurrent Hematology and Oncology Management Conundrums. PMID- 28809604 TI - Prevention Research at the National Institutes of Health. PMID- 28809605 TI - Age Modifies the Effect of 2-MeV Fast Neutrons on Rat Mammary Carcinogenesis. AB - The relative biological effectiveness (RBE) of neutrons depends on their physical nature (e.g., energy) and the biological context (e.g., end points, materials). From the perspective of radiological protection, age is an important biological context that influences radiation-related cancer risk, but very few studies have addressed its potential impact on neutron effects. We therefore investigated the influence of age on the effect of accelerator-generated fast neutrons (mean energy, ~2 MeV) in an animal model of breast carcinogenesis. Female Sprague Dawley rats at 1, 3 and 7 weeks of age were irradiated with fast neutrons at absorbed doses of 0.0485-0.97 Gy. All animals were kept under specific pathogen free conditions and screened weekly for mammary tumors by palpation until they were 90 weeks old. Tumors were diagnosed based on histology. Mathematical modeling was used to analyze mammary cancer incidence, collectively using data from this study and a previously reported experiment on 137Cs gamma rays. The results indicate that neutron irradiation elevated the risk of palpable mammary carcinoma with a linear dose response, the slope of which depended on age at time of irradiation. The RBE of neutron radiation was 7.5 +/- 3.4, 9.3 +/- 3.5 and 26.1 +/- 8.9 (mean +/- SE) for animals exposed at 1, 3 and 7 weeks of age, respectively. Our results indicate that age of the animal is an important factor influencing the effect of fast neutrons on breast cancer risk. PMID- 28809606 TI - A Comparative Meta-Analysis of the Effects of Concussion on a Computerized Neurocognitive Test and Self-Reported Symptoms. AB - CONTEXT: Meta-analyses examining construct-specific cognitive impairment concurrently with self-reported symptoms postconcussion are sparse. OBJECTIVE: To review the literature on the effects of concussion on construct-specific neurocognitive declines and to compare them with self-reported symptoms before 1 week and between 1 and 3 weeks postconcussion. DATA SOURCES: Relevant studies in PubMed, CINAHL, and PsycINFO published from January 1, 1999 through November 30, 2015. STUDY SELECTION: Studies were included if participants completed the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) before and after concussion and if test performance and Postconcussion Symptom Scale (PCSS) scores were reported at both times. DATA EXTRACTION: After reviewing the full texts, we extracted data from 17 studies consisting of 29 independent samples; therefore, this meta-analysis consisted of 1777 unique participants. DATA SYNTHESIS: The Hedges g effect size (ES) was estimated. A random-effects or fixed-effects model was used based on heterogeneity findings. When heterogeneity was present, we used meta-regression to assess unexplained between-studies variance. Within the first week of injury, the ESs were small to moderate for cognitive declines, ranging from -0.43 (95% confidence interval [CI] = -0.52, 0.35) to -0.67 (95% CI = -0.77, -0.58), and large for the PCSS score (Hedges g = 0.81; 95% CI = -0.91, -0.71). After 1 week, the ESs for cognitive declines (Hedges g range = -0.25 [95% CI = -0.35, -0.15] to -0.37 [95% CI = -0.55, -0.19]) and PCSS score (Hedges g = -0.38; 95% CI = -0.53, -0.22) were also small. Within 2 weeks of injury, PCSS score and time since injury weakly moderated the cognitive ES. CONCLUSIONS: When a neurocognitive test was administered within 1 week of injury, the ES was larger for self-reported symptoms than for ImPACT scores generated at the same session. After 1 week of injury, the ESs for ImPACT and PCSS scores were comparable. If the athlete reports symptoms within 1 week of injury, administering a cognitive test does not appear to offer additional information to the clinician. However, if the athlete does not report symptoms postconcussion, cognitive testing may inform the clinical management of the injury. PMID- 28809607 TI - Amoxapine Demonstrates Incomplete Inhibition of beta-Glucuronidase Activity from Human Gut Microbiota. AB - Amoxapine has been demonstrated to be a potent inhibitor of Escherichia coli beta glucuronidase. This study aims to explore the factors causing unsatisfactory efficacy of amoxapine in alleviating CPT-11-induced gastrointestinal toxicity in mice and to predict the outcomes in humans. Amoxapine (100 uM) exhibited poor and varied inhibition on beta-glucuronidase activity in gut microbiota from 10 healthy individuals and their pool (pool, 11.9%; individuals, 3.6%-54.4%) with IC50 >100 uM and potent inhibition toward E. coli beta-glucuronidase (IC50 = 0.34 uM). p-Nitrophenol formation from p-nitrophenyl-beta-D-glucuronide by pooled and individual gut microbiota fitted classical Michaelis-Menten kinetics, showing similar affinity (Km = 113-189 uM) but varied catalytic capability (Vmax = 53-556 nmol/h/mg). Interestingly, amoxapine showed distinct inhibitory effects (8.7% 100%) toward beta-glucuronidases of 13 bacterial isolates (including four Enterococcus, three Streptococcus, two Escherichia, and two Staphylococcus strains; gus genes belonging to OTU1, 2 or 21) regardless of their genetic similarity or bacterial origin. In addition, amoxapine inhibited the growth of pooled and individual gut microbiota at a high concentration (6.3%-30.8%, 200 uM). Taken together, these findings partly explain the unsatisfactory efficacy of amoxapine in alleviating CPT-11-induced toxicity and predict a poor outcome of beta-glucuronidase inhibition in humans, highlighting the necessity of using a human gut microbiota community for drug screening. PMID- 28809609 TI - The Who, What, and How of Cabazitaxel Treatment in Metastatic Castration Resistant Prostate Cancer. PMID- 28809611 TI - Short-course adjuvant trastuzumab will increase cure rates in patients with human epidermal growth factor receptor 2-positive breast cancer. PMID- 28809608 TI - Treatment of Patients With Metastatic Cancer Using a Major Histocompatibility Complex Class II-Restricted T-Cell Receptor Targeting the Cancer Germline Antigen MAGE-A3. AB - Purpose Adoptive transfer of genetically modified T cells is being explored as a treatment for patients with metastatic cancer. Most current strategies use genes that encode major histocompatibility complex (MHC) class I-restricted T-cell receptors (TCRs) or chimeric antigen receptors to genetically modify CD8+ T cells or bulk T cells for treatment. Here, we evaluated the safety and efficacy of an adoptive CD4+ T-cell therapy using an MHC class II-restricted, HLA-DPB1*0401 restricted TCR that recognized the cancer germline antigen, MAGE-A3 (melanoma associated antigen-A3). Patients and Methods Patients received a lymphodepleting preparative regimen, followed by adoptive transfer of purified CD4+ T cells, retrovirally transduced with MAGE-A3 TCR plus systemic high-dose IL-2. A cell dose escalation was conducted, starting at 107 total cells and escalating at half log increments to approximately 1011 cells. Nine patients were treated at the highest dose level (0.78 to 1.23 * 1011 cells). Results Seventeen patients were treated. During the cell dose-escalation phase, an objective complete response was observed in a patient with metastatic cervical cancer who received 2.7 * 109 cells (ongoing at >= 29 months). Among nine patients who were treated at the highest dose level, objective partial responses were observed in a patient with esophageal cancer (duration, 4 months), a patient with urothelial cancer (ongoing at >= 19 months), and a patient with osteosarcoma (duration, 4 months). Most patients experienced transient fevers and the expected hematologic toxicities from lymphodepletion pretreatment. Two patients experienced transient grade 3 and 4 transaminase elevations. There were no treatment-related deaths. Conclusion These results demonstrate the safety and efficacy of administering autologous CD4+ T cells that are genetically engineered to express an MHC class II restricted antitumor TCR that targets MAGE-A3. This clinical trial extends the reach of TCR gene therapy for patients with metastatic cancer. PMID- 28809610 TI - Phase III Study Comparing a Reduced Dose of Cabazitaxel (20 mg/m2) and the Currently Approved Dose (25 mg/m2) in Postdocetaxel Patients With Metastatic Castration-Resistant Prostate Cancer-PROSELICA. AB - Purpose Cabazitaxel 25 mg/m2 (C25) significantly improved overall survival (OS) versus mitoxantrone ( P < .001) in postdocetaxel patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase III TROPIC study. The phase III PROSELICA study ( ClinicalTrials.gov identifier: NCT01308580) assessed the noninferiority of cabazitaxel 20 mg/m2 (C20) versus C25 in postdocetaxel patients with mCRPC. Methods Patients were stratified by Eastern Cooperative Oncology Group performance status, measurability of disease per Response Evaluation Criteria in Solid Tumors (RECIST), and region, and randomly assigned to receive C20 or C25. To claim noninferiority of C20 (maintenance of >= 50% of the OS benefit of C25 v mitoxantrone in TROPIC) with 95% confidence level, the upper boundary of the CI of the hazard ratio (HR) for C20 versus C25 could not exceed 1.214 under a one-sided 98.89% CI after interim analyses. Secondary end points included progression-free survival, prostate-specific antigen (PSA), tumor and pain responses and progression, health-related quality of life, and safety. Results Overall, 1,200 patients were randomly assigned (C20, n = 598; C25, n = 602). Baseline characteristics were similar in both arms. Median OS was 13.4 months for C20 and 14.5 months for C25 (HR, 1.024). The upper boundary of the HR CI was 1.184 (less than the 1.214 noninferiority margin). Significant differences were observed in favor of C25 for PSA response (C20, 29.5%; C25, 42.9%; nominal P < .001) and time to PSA progression (median: C20, 5.7 months; C25, 6.8 months; HR for C20 v C25, 1.195; 95% CI, 1.025 to 1.393). Health-related quality of life did not differ between cohorts. Rates of grade 3 or 4 treatment-emergent adverse events were 39.7% for C20 and 54.5% for C25. Conclusion The efficacy of cabazitaxel in postdocetaxel patients with mCRPC was confirmed. The noninferiority end point was met; C20 maintained >= 50% of the OS benefit of C25 versus mitoxantrone in TROPIC. Secondary efficacy end points favored C25. Fewer adverse events were observed with C20. PMID- 28809612 TI - A retrospective study evaluating the efficacy of identification and management of sepsis at a district-level hospital internal medicine department in the Western Cape Province, South Africa, in comparison with the guidelines stipulated in the 2012 Survivi. AB - BACKGROUND: Currently there is little information on the identification, management and outcomes of patients with sepsis in developing countries. Simple cost-effective measures such as accurate identification of patients with sepsis and early antibiotic administration are achievable targets, within reach without having to make use of unsustainable protocols constructed in developed countries. OBJECTIVES: To assess the ability of clinicians at a district-level hospital to identify and manage sepsis, and to assess patient outcome in terms of in-hospital mortality and length of hospital stay given the above management. METHODS: A retrospective descriptive study design was used, analysing data from the routine burden of disease audit done on a 3-monthly basis at Karl Bremer Hospital (KBH) in the Western Cape Province, South Africa. RESULTS: The total sample size obtained was 70 patients, of whom 18 (25.7%) had an initial triage blood pressure indicative of sepsis-induced hypotension. However, only 1 (5.5%) of these 18 patients received an initial crystalloid fluid bolus of at least 30 mL/kg. The median time that elapsed before administration of antibiotics in septic shock was 4.25 hours. Furthermore, a positive delay in antibiotic administration (p=0.0039) was demonstrated. The data also showed that 8/12 patients (66.7%) with septic shock received inappropriate amounts of fluids. The in-hospital mortality rate for sepsis was 4/24 (16.7%), for severe sepsis 11/34 (32.3%) and for septic shock a staggering 9/12 (75.0%). CONCLUSIONS: The initial classification process and management of sepsis by clinicians at KBH is flawed. This inevitably leads to an increase in in-hospital mortality. PMID- 28809613 TI - Enrolling HIV-positive adolescents in mental health research: A case study reflecting on legal and ethical complexities. AB - BACKGROUND: Adolescents living with HIV are an emerging group in the global HIV/AIDS epidemic. Mental health in this population affects HIV care, treatment, consequential morbidity and secondary transmission. There is a paucity of research regarding these youth in South Africa (SA), partly because section 71 of the National Health Act of 2003 (NHA) requires parental or guardian's consent. OBJECTIVE: To explore legal and ethical issues related to conducting adolescent mental health research in SA. METHODS: After obtaining a High Court order permitting research on minors aged <18 years without prior parental or guardian's consent, we used qualitative and quantitative methods to interview adolescents in five clinics serving HIV-positive adolescents in Johannesburg. RESULTS: Our study enrolled 343 participants; 74% were orphaned and did not have legal guardians, 27% were symptomatic for depression, anxiety or post-traumatic stress disorder, 24% were suicidal, and almost 90% did not feel that they belonged in the family with which they lived. Without court intervention, most of the participants could not have participated in this research because parental consent was impossible to obtain. This case study argues for exceptions to the parental consent requirement, which excludes orphaned and vulnerable children and youth from research. CONCLUSIONS: Recommendations are made to promote ethical integrity in conducting mental health research with adolescents. A balance is needed between protecting adolescents from exploitation and permitting access to benefits of research. Requiring parental consent for all research does not necessarily give effect to policy. For the vast majority of SA HIV-positive adolescents, parental consent is not possible. Section 71 of the NHA ought to be amended to facilitate valuable and necessary research concerning HIV-positive orphan children and adolescents. PMID- 28809614 TI - Confidentiality and fitness to drive: Professional, ethical, and legal duties in the case of the diabetic bus driver. AB - Patients who pose a risk of serious accidents present a difficult ethical problem for medical practitioners. The duty to maintain confidentiality is an ancient and weighty obligation and has many beneficial consequences for patients and society generally. Similarly, the duty of care towards a patient militates against disclosing details that could remove his or her source of income and imperil physical and mental wellbeing. However, in cases where maintaining confidentiality can result in severe harm to the patient and the public, the benefits of confidential practice may be outweighed. While many publications on this topic provide clinical criteria for determining the unfitness of a diabetic patient to drive, the focus in this article is on ethical, professional, and legal responsibilities after a practitioner has decided that a driver poses a significant danger. PMID- 28809615 TI - Does access to private healthcare influence potential lung cancer cure rates? AB - BACKGROUND: Numerous studies show a link between poor socioeconomic status (SES) and late-stage cancer diagnosis. However, this has not been consistently shown looking at non-small-cell lung cancer (NSCLC) in isolation. Despite the extremely high prevalence of lung cancer and disparities in access to healthcare based on health insurance in South Africa, there is a paucity of data on the influence of health insurance (as a surrogate for SES) on stage at presentation of NSCLC. OBJECTIVE: To assess the relationship between health insurance status (and invariably SES) and staging (and therefore resectability) of patients with primary NCSLC at the time of initial presentation. METHODS: Health-insured patients with NSCLC (n=51) were retrospectively compared with NSCLC patients with no health insurance (n=532) with regard to demographics, tumour node metastasis (TNM) staging, and cell type at initial presentation. RESULTS: Patients with no health insurance were younger (mean (standard deviation (SD)) 59.9 (10.1) years) than those with private health insurance (64.2 (9.6) years) (p=0.03). Poorly differentiated NSCLC was significantly more common in the privately health insured group (23.6%) than among those with no health insurance (4.6%) (p<0.01). Six of 51 NSCLC patients (11.8%) with private health insurance presented with early-stage, potentially curable disease (up to stage IIIA), compared with 55 patients (10.3%) in the uninsured group (p=0.75). CONCLUSIONS: Access to private health insurance did not have a significant impact on stage at initial presentation. The only significant differences were the relatively advanced age at presentation and relatively higher percentage of poorly differentiated NSCLC seen in patients with health insurance. PMID- 28809616 TI - A method for determining when the superficial scalp arteries are the source of migraine pain. AB - In some patients the pain of migraine originates in the extracranial cranial arteries. This article describes the location and a logical examination sequence of the vessels most frequently involved in migraine pain. PMID- 28809617 TI - Ocular metastasis as initial presentation in breast cancer. AB - Two patients presented to their ophthalmologists with vision disturbances. On ocular examination, retinopathic lesions were observed. On subsequent examination, these lesions were diagnosed as metastases of breast cancer. Neither patient had a history of breast cancer. In patients with breast cancer and multiple metastases, ocular metastases are well described. However, the latter is uncommon as a presenting complaint. PMID- 28809618 TI - Corneal donations in South Africa: A 15-year review. AB - BACKGROUND: Corneal pathology is one of the leading causes of preventable blindness in South Africa (SA). A corneal transplant can restore or significantly improve vision in most cases. However, in SA there is a gross shortage of corneal tissue available to ophthalmologists. Little has been published describing the magnitude of the problem. OBJECTIVES: To describe trends in the number of corneal donors per year in SA, the number of corneal transplants performed each year, the origin of donors, the allocation of corneas to the public or private sector, and the demographics of donors. METHODS: This was a retrospective review of all corneal donations to SA eye banks over the 15-year period 1 January 2002 - 31 December 2016. RESULTS: There was a progressive year-on-year decline in corneal donors over the study period, from 565 per year in 2002 to 89 in 2016. As a direct result, there has been an 85.5% decrease in the number of corneal transplants performed per year using locally donated corneas, from 1 049 in 2002 to 152 in 2016. Of the donors, 48.8% originated from mortuaries, 39.0% from private hospitals and 12.2% from government hospitals; donors from mortuaries showed the most significant decline over the 15-year period, decreasing by 94.8%. Of donated corneas, 79.3% were allocated to the private sector and 21.7% to the public sector. Males comprised 69.1% of donors, while 77.2% were white, 14.0% coloured, 6.3% black and 2.5% Indian/Asian. Donor age demonstrated a bimodal peak at 25 and 55 years. CONCLUSIONS: The number of corneal donations in SA has declined markedly, causing the burden of corneal disease requiring transplantation to rise steadily. Population groups with a low donor rate may have cultural and other objections to corneal donation, which should be a major focus of future research and initiatives aimed at reversing the current trends. PMID- 28809619 TI - The effect of HIV status on clinical outcomes of surgical sepsis in KwaZulu-Natal Province, South Africa. AB - BACKGROUND: KwaZulu-Natal Province, South Africa (SA), has long been the epicentre of the HIV epidemic, but the impact of HIV co-infection on the clinical outcomes of emergency surgical patients with sepsis remains largely unknown. OBJECTIVE: To review our experience with the management of patients with HIV co infection and to compare the disease spectrum and outcome with those without HIV infection. METHODS: A retrospective study was undertaken at the Pietermaritzburg Metropolitan Surgical Service (PMSS), SA over a 5-year period from January 2010 to December 2014. RESULTS: A total of 675 patients with a documented surgical source of sepsis were reviewed. Of these, 332 (49%) were male, and the mean age was 46 (standard deviation 19) years. HIV status was known in 237 (35%) patients, 146 (62%) were HIV-positive and the remaining 91 (38%) were HIV-negative. Other than tuberculosis of the abdomen being significantly more common in HIV-positive than HIV-negative patients (10% v. 2%, p=0.033), there were no differences in the spectrum of diseases between the two groups. There were no significant differences in overall morbidity or mortality. When adjusted for CD4 counts, the mortality in HIV-positive patients with a CD4 count <200 cells/MUL was 60% (15/25) and in those with a CD4 count >200 cells/MUL it was 2% (2/101) (p<0.001). CONCLUSION: The clinical presentation and the spectrum of surgical sepsis in patients with HIV co-infection were not markedly different to those in patients who were not HIV-infected. HIV-infected patients with a CD4 count <200 cells/MUL had a significantly higher mortality. Management approaches should not differ based solely on the HIV status of patients with surgical sepsis. PMID- 28809620 TI - Pancreatitis in a high HIV prevalence environment. AB - BACKGROUND: Acute pancreatitis is common in HIV-positive individuals in reports from regions with a low incidence of HIV infection. This association has not been reported in areas with a high incidence of HIV infection. OBJECTIVE: To examine the prevalence and outcomes of HIV-associated acute pancreatitis in a high HIV prevalence environment, and trends over the period May 2001 - November 2010. METHODS: The records of patients admitted with acute pancreatitis from 2001 to 2010 were reviewed, looking for HIV status, CD4 counts and medications at presentation. The Glasgow criteria, organ failure, local complications and mortality were assessed. RESULTS: One hundred and six (16.9%) of 627 patients admitted with acute pancreatitis during the study period were infected with HIV. Most were female (65.1%) and black African (91.5%). The serum amylase level was used to confirm acute pancreatitis in 50 patients, with a mean of 1 569 IU/L (range 375 - 5 769), and urinary amylase in 56 patients, with a mean of 4 083 IU/L (range 934 - 36 856). Alcohol was a less frequent cause of pancreatitis in the HIV-positive group than in patients who were HIV-negative (24.5% v. 68.3%), and the prevalence of gallstones as a cause was similar (23.6% v. 17.9%). Antiretroviral therapy was associated with pancreatitis in 35.8%, and 6 (5.7%) had abdominal malignancies. Sixteen (15.1%) had pancreatic necrosis, 20 (18.9%) had septic complications, and 6 (5.7%) died. CONCLUSIONS: HIV-associated acute pancreatitis was most frequent in females and black Africans and was associated with malignancy. Mortality was similar in HIV and non-HIV pancreatitis. PMID- 28809621 TI - Cardiovascular risk factors and mortality in children with chronic kidney disease. AB - BACKGROUND: Cardiovascular disease (CVD) begins early in children with chronic kidney disease (CKD), and its progression is determined by the presence of single or multiple cardiovascular risk factors (CVRFs). OBJECTIVE: To determine the prevalence of CVRFs in children with CKD and their association with mortality in children on chronic dialysis. METHODS: This comparative cross-sectional study recruited children aged 5 - 18 years with all stages of CKD. All patients had a short history taken along with a physical examination, and their blood samples were assessed for serum creatinine, urea, albumin, calcium, phosphorus, parathyroid hormone, alkaline phosphatase, total cholesterol (TC), haemoglobin and C-reactive protein. Urine samples were also assessed for proteinuria. RESULTS: One hundred and six children who met the study criteria were recruited, 34 with CKD I, 36 with CKD II - IV and 36 with CKD V (dialysis). The overall median age was 11 years (range 8 - 14), and the male/female ratio was 2.1:1. The most common CVRF was anaemia (39.6%). The rate of anaemia was higher in the dialysis group than in the CKD II - IV and CKD I groups (77.8%, 33.3% and 5.9%, respectively). Other CVRFs detected were hypertension, proteinuria, hypercholesterolaemia and dysregulated mineral bone metabolism. Seven deaths were recorded in the dialysis group during the study period. Severe hypertension and intracranial bleeding were the most common causes of death. Modifiable risk factors such as increased TC and decreased albumin levels were more common than other CVRFs in the dialysis patients who died. CONCLUSIONS: CVRFs may be present in early CKD, even before the decline in GFR. Routine screening for CVRFs, along with timely intervention, may prevent the progression of CVD and mortality later in life. PMID- 28809622 TI - Suicide in Pretoria: A retrospective review, 2007 - 2010. AB - BACKGROUND: The World Health Organization has declared suicide a global ealth crisis, predicting that ~1.53 million people will commit suicide annually by 2020. OBJECTIVE: A study from South Africa reviewed 1 018 suicide cases in Pretoria over 4 years (1997 - 2000). Our study was undertaken to establish whether there have been substantial changes in the profile of suicide victims who died in Pretoria a decade later. METHODS: Case records at the Pretoria Medico Legal Laboratory were reviewed retrospectively from 2007 to 2010. RESULTS: A total of 957 suicide cases were identified. Hanging was the most common method of suicide, followed by self-inflicted firearm injury. The true incidence of suicidal intake of prescription drugs/medication was difficult to determine, because of a backlog at the state toxicology laboratories. White males and females appeared to be over-represented among suicide victims, but there has been an increase in suicide among blacks. There seems to have been a substantial decrease in the use of firearms to commit suicide - possibly reflecting a positive outcome of gun control legislation that has been introduced in the interim. CONCLUSION: Suicide continues to constitute almost 10% of all fatalities admitted to the Pretoria Medico-Legal Laboratory, confirming suicide as a major cause of mortality in our society. Further research is needed to clarify the profile of suicidal deaths, with a view to informing resource allocation and to improve preventive strategies. PMID- 28809623 TI - How to Choose between the Implant Materials Steel and Titanium in Orthopedic Trauma Surgery: Part 2 - Biological Aspects. AB - BIOLOGICAL ASPECTS OF STEEL AND TITANIUM AS IMPLANT MATERIAL IN ORTHOPEDIC TRAUMA SURGERY The following case from the ICUC database, where a titanium plate was implanted into a flourishing infection, represents the clinical experience leading to preferring titanium over steel. (Fig. 1) (6). Current opinions regarding biological aspects of implant function. The "street" opinions regarding the biological aspects of the use of steel versus titanium as a surgical trauma implant material differ widely. Statements of opinion leaders range from "I do not see any difference in the biological behavior between steel and titanium in clinical application" to "I successfully use titanium implants in infected areas in a situation where steel would act as foreign body "sustaining" infection." Furthermore, some comments imply that clinical proof for the superiority of titanium in human application is lacking. The following tries to clarify the issues addressing the different aspects more through a practical clinical approach than a purely scientific one, this includes simplifications. Today's overall biocompatibility of implant materials is acceptable but: As the vast majority of secondary surgeries are elective procedures this allows the selection of implant materials with optimal infection resistance. The different biological reactions of stainless steel and titanium are important for this segment of clinical pathologies. Biological tole - rance (18) depends on the toxicity and on the amount of soluble implant material released. Release, diffusion and washout through blood circulation determine the local concentration of the corrosion products. Alloying components of steel, especially nickel and chromium, are less than optimal in respect to tissue tolerance and allergenicity. Titanium as a pure metal provides excellent biological tolerance (3, 4, 16). Better strength was obtained by titanium alloys like TiAl6V4. The latter found limited application as surgical implants. It contains Vanadium (9). Today's high strength titanium alloys contain well tolerated alloying components1 like Zr, Nb, Mo and Ta (ISO 5832-14) (7, 15). The corrosion rate of surgical implants is kept low by the passive layer formed when immerged in body fluids (13, 14). The passive layer may be locally destroyed, for instance, by mechanical fretting or by local corrosion conditions like in pitting; it is renewed by an electrochemical corrosion process which releases alloying components like Ni and Cr (Fig. 2) (10). The amount of soluble component may vary markedly depending on the local electrochemical conditions (see below). PMID- 28809624 TI - Spinal Orthoses: The Crucial Role of Comfort on Compliance of Wearing - Monocentric Prospective Pilot Study of Randomized Cross-Over Design. AB - PURPOSE OF THE STUDY Various spine disorders are regularly treated by orthoses, and success of treatment depends on wearing these devices. In this study we examined the compliance, wear comfort, subjective stabilization and side effects associated with spinal orthoses using an individualized questionnaire and the Compact Short Form-12 Health Survey (SF-12). MATERIAL AND METHODS In this prospective pilot study of randomized cross-over design, twelve healthy volunteers with a mean age of 31.2 years wore three different types of orthoses, each for one week: A hyperextension brace (HB), a custom-made semirigid orthosis (SO) and a custom-made rigid orthosis (RO). The daily duration of wearing the orthosis was defined as primary endpoint; contentment was measured using an individualized questionnaire and the standardized SF-12. RESULTS In the study population calculated probability of wearing the HB and RO was between 0.2 und 38.5% (95% confidence interval). No volunteer wore the SO orthosis for the predefined time. The SO and RO each displayed high subjective stabilization, while the RO was more often associated with side effects like skin pressure marks than the SO. The need for rework due to discomfort was mainly necessary with the RO. We observed no substantial differences in feeling compression and sweating. Noteworthy, eight of 12 subjects complained of uncomfortable sternal pressure due to the upper pad of the HB. The SF-12: scores ranged from 52.1 to 48.6 on the physical (PCS), and from 53.7 to 50.8 on the mental component score (MCS), demonstrating an influence on QoL. DISCUSSION AND CONCLUSIONS The design as well as the orthosis itself influence the compliance of wearing and exert a moderate negative, but acceptable impact on QoL. The SO appeared to correlate with the best overall compromise between comfort and subjective stabilization. Further investigations are necessary in patients with spinal diseases, for whom the effect of orthosis wearing may surpass the potential discomfort. Key words: thoracolumbar spine, orthoses, SF-12 - Quality of Life - QoL, comfort, compliance. PMID- 28809625 TI - Microstructural Changes of Tensor Fasciae Latae and Gluteus Medius Muscles Following Total Hip Arthroplasty: A Prospective Trial. AB - PURPOSE OF THE STUDY Although total hip arthroplasty (THA) is one of the most successful orthopedic operations, the soft tissue trauma towards the periarticular musculature during surgical approaches remains a critical concern. However, the actual microstructural proof of muscle trauma on the level of the myofiber due to the surgical approach has never been claimed. MATERIAL AND METHODS Patients undergoing THA were prospectively enrolled and either operated by a direct lateral (DL) or a anterolateral minimally invasive approach (ALMI). Intraoperatively and at 6 months follow-up a needle biopsy was taken from the gluteus medius muscle and the tensor fasciae latae. Pre- and post-operative fiber diameter and composition, of gluteal medius muscle (GMM) and the tensor fasciae latae muscle (TFLM) were compared in both surgical approaches. RESULTS A total of 19 patients (12 F; 7 M) were included in this study. The average pre-operative fiber diameter or fiber type composition did not differ significantly in the GMM and TFLM, nor did it vary among patients with different approaches. The muscle fiber diameter significantly increased post-operatively in the TFLM, in both, the DL (p = 0.043) and the ALMI (p = 0.043) approach. There was a trend towards more pronounced muscle fiber changes in the DL (TFLM: p = 0.077; GMM: p = 0.150), compared to the ALMI. DISCUSSION AND CONCLUSIONS Our results show microstructural changes to the periarticular musculature following THA by a compensatory hypertrophy of the TFLM and GMM. These adaptions directly next to the surgical trauma were observed in DL and AMLI. Key words: total hip arthroplasty, skeletal muscle, muscle biopsy, iatrogenic trauma, muscle scar. PMID- 28809626 TI - [Structural Damage to the Hamstring Graft due to Interaction with Fixation Material and its Effect on Biomechanical Properties of ACL Reconstruction]. AB - PURPOSE OF THE STUDY Hamstring grafts are commonly used for ACL reconstruction. The purpose of our study is to determine the effects of the suspension fixation compared to graft cross-pinning transfixation, and the effect(s) of structural damage during the preparation of the graft on biomechanical properties of the graft. MATERIAL AND METHODS The design of the study is a cadaveric biomechanical laboratory study. 38 fresh-frozen human hamstring specimens from 19 cadaveric donors were used. The grafts were tested for their loading properties. One half of each specimen was suspended over a 3.3mm pin, the other half was cross-pinned by a 3.3mm pin to simulate the graft cross-pinning technique. Single impact testing was performed and the failure force, elongation and acceleration/deceleration of each graft was recorded and the loading force vs. elongation of the graft specimens was calculated. Results for suspended and cross pinned grafts were analysed using ANOVA method, comparing the grafts from each donor. RESULTS The ultimate strength of a double-strand gracilis graft was 1287 +/- 134 N when suspended over a pin, the strength of a cross-pinned graft was 833 +/- 111 N. For double-strand semitendinosus grafts the strengths were 1883 +/- 198 and 997 +/- 234 N, respectively. Thus, the failure load for the cross-pinning method is only 64.7% or 52.9% for the suspension method. DISCUSSION Structural damage to the graft significantly reduces the graft strength. Also, extensive suturing during preparation of the graft reduces its strength. CONCLUSIONS Fixation methods that do not interfere with the graft's structure should be used to reduce the risk of graft failure. Key words: ACL reconstruction, hamstring graft, biomechanical testing. PMID- 28809627 TI - [The Use of BTB Allograft in Revision Reconstruction of the Anterior Cruciate Ligament and Its Success Rate in Terms of Subjective Patient Satisfaction]. AB - PURPOSE OF THE STUDY A retrospective evaluation of the success rate of revision ACL reconstruction performed using BTB allograft in terms of the life expectancy of the procedure up to and over five years from surgery. MATERIAL AND METHODS Over a ten-year period, from 2003 to 2013, we performed 47 revision ACL reconstruction surgeries. The majority of the primary ACL reconstructions using BTB autografts were not performed at our site. The group observed included 16 women (34%) and 31 men (66%). The women were aged between 25 and 48 years, the median age being 32.5, and the men were aged between 25 and 46 years with the median age of 35. We were able to make a full pre- and post-operative evaluation of 22 out of 47 patients who underwent secondary ACL reconstruction surgery using a cadaverous BTB graft. This evaluation included an objective clinical testing and a subjective evaluation of the function and stability of the knee joint using the Tegner activity score, Lysholm score, and a modified Cincinatti score. The set of 22 patients was split into two groups: up to five years from revision surgery and over five years from the procedure. RESULTS In the group of patients who were fully evaluated within five years of revision reconstruction there was an average improvement of 16.4 points on the Cincinatti score, 19.9 points on the Lysholm score, and an upward movement averaging 1.5 levels on the Tegner activity score. In the over five years from surgery category the average improvement was 15.5, 15.9, and 1.2 levels upward movement, respectively. We were unable to prove a significantly increased level of failure in BTB allografts after five and more years from revision ACL reconstruction. DISCUSSION The two strongest factors affecting the life expectancy of ACL replacements are the age of the patient and the type of the graft used, allograft or autograft. The most at risk, in terms of how long the graft will last, is the age group of 10 - 19 years old. With each ten-year increase in age the risk of rupture is reduced more-or-less by half. Patients with ACL allograft replacement show a fourfold increased risk of the graft rupturing. The younger and more active the patient requiring revision ACL reconstruction is, the greater the need for an autograft. If an allograft has been used in revision reconstruction on an athlete, a great emphasis must be placed on the necessity of delaying the return to previous sporting activities for at least nine months. CONCLUSIONS The mid-term results of revision ACL reconstruction show that, subject to reasonable levels of stress, a correctly performed procedure using cadaverous BTB grafts is a good option to restore the stability of the knee joint over a period of five years and more from surgery. An increased incidence of reruptures or greater insufficiency of the cadaverous graft were not evident in our group after five and more years. The risk of cadaverous grafts failure is just like in the autologous replacement directly linked to the return to sport interval, frequency and intensity of stress to which the graft is subjected over a long period of time. The risk of rerupture is always higher in allograft reconstructions that have already stood in need of restructuring for a longer period of time. For this reason, a delay in returning to sports activity must be emphasized. As a rule, we recommend a return to full athletic training only after nine months to a year after surgery. Key words: anterior cruciate ligament, revision ACL reconstruction, tendon graft insufficiency, BTB autograft insufficiency, BTB allograft of the ACL, cadaverous BTB graft, ACL graft rerupture. PMID- 28809628 TI - [The Effect of Activation of the Shoulder Girdle Muscles on Functional Outcomes of Rehabilitation in Patients with Surgically Treated Distal Radius Fractures]. AB - PURPOSE OF THE STUDY The aim of the study was to assess the functional outcomes of rehabilitation in patients with surgically treated distal radius fractures in the early postoperative period. We compared the functional outcomes of patients undergoing standard rehabilitation with the group of patients whose postoperative rehabilitation was extended with shoulder girdle exercises of the affected upper limb while the wrist was immobilized. Several indices and variables were used for the assessment of the functional therapeutic outcomes of the affected wrist. MATERIAL AND METHODS Forty patients (32 females and 8 males, the mean age 60.5 years) with distal radius fractures treated by internal fixation using volar surgical approach were involved in the study between 2013-2016. The tested subjects were randomized and split into two groups according to the selected method of rehabilitation. The tested subjects with standard rehabilitation extended with shoulder girdle muscles activation were labelled as group I. It included patients (n = 20) of the mean age 59.8 (age range 42-73 years) with immobilized wrist (i.e. for 3-4 weeks) performing shoulder girdle muscles exercises at the same time. Furthermore, standard kinesiotherapy continued after their fixation was removed. The other tested group, labelled as group II (n = 20), the mean age 61.3 (variation 40-74 years of age) involved patients with distal radius fractures. Only standard rehabilitation was performed in this group as late as their forearm fixation was removed. The following indices and parameters were assessed in the early postoperative period (i.e. by 8 weeks after the fixation removal): wrist and fingers range of motion (ROM), hand grip strength (dynamometry), local swelling, pain, scores of a nine hole peg test (NHPT), and a DASH score. RESULTS After the fixation had been removed, the group I reported statistically significantly higher values of movement compared to the values of the contralateral limb in the following directions: dorsal flexion, palmar flexion, MP joints flexion, flexion of PIP joints (proximal interphalangeal), and flexion of DIP joints (distal interphalangeal). After eight weeks, the group I manifested significantly higher values in dorsal flexion, palmar flexion and ulnar deviation in the wrist. There were no significant differences in other movement directions. The hand grip strength mean value examined with a dynamometer was significantly higher in the group I in the sixth and eighth week of testing (group I - 58.9% strength of a healthy limb after six weeks, or 66.5% after eight weeks). The results in the group II were 49.9% strength of a healthy limb after six weeks, or 56.6% after eight weeks. The group I showed statistically significantly lower values of wrist swelling and higher finger dexterity in the NHPT in all measured weeks. Lower pain intensity in the group I during the measurements was observed. At the same time, this group showed significantly better results in the DASH score. DISCUSSION The results of this study are useful for clinical practice. They confirm a functional relation between the activity of hand muscles and the shoulder muscle activity. The differences in the functional ability of the hand and the functional state of the injured wrist were detected as early as in the early postoperative period. It could be stated that the tested subjects in the group I showed a greater and faster improvement in the physical function of the injured hand. This was also accompanied by a positive psychological effect. We had not found a study of a similar type in the available literature that we could have compared our submitted results to. CONCLUSIONS Shoulder girdle muscles exercises after a distal radius fracture, while wrist is immobilized, can evidently enhance functional capability and accelerate the hand-function restitution. Early functional outcomes of the injured wrist after the rehabilitation with shoulder girdle muscles exercises support the efficiency of this broadened rehabilitation protocol. Key words: distal radius frac,ture, hand, shoulder, functional treatment, rehabilitation. PMID- 28809629 TI - [Talar Neck Fractures Treated Using Percutaneous Screw Fixation]. AB - PURPOSE OF THE STUDY Closed reduction and percutaneous fixation of nondisplaced talar neck fractures have been applied by some authors. The aim of this paper is to assess the results and complications of this minimally invasive technique. MATERIAL AND METHODS In the period from 2009 to 2014, twenty-one patients with a talar neck fracture were observed after closed reduction and percutaneous screw fixation in the Traumatological Hospital in Brno. The mean age of the patients was 38 years (range 18-56 years). The mechanism of injury was a motor vehicle accident in 11 cases, a fall from height in six cases, a sports injury in 3 cases, and a fall from stairs in one case. Injuries were classified according to the Hawkins classification. Conventional preoperative 3-dimensional CT scans of the fractures were analysed. Under the guidance of C-arm fluoroscopy, Kirscher wires were used for closed reduction and temporary percutaneous fixation. Subsequently, 3.5 and 4.5 mm diameter cannulated screws were inserted. The outcome was evaluated on the American Orthopaedic Foot and Ankle Society (AOFAS) scoring scale. RESULTS The average follow-up was 32 months (21-42 months). The average healing time was 15.5 weeks (13-19 weeks). The average AOFAS score was 82.3 points (69-96 points). 75% of patients with type I injury achieved excellent results and 72% of patients with type II injury achieved excellent or good results. None of the patients developed wound complications. Two patients developed partial avascular necrosis and three patients subtalar traumatic arthritis after surgery. DISCUSSION Talar neck fractures are relatively uncommon fractures. Most of the published studies are small. Tenuous blood supply and displaced talar neck fracture predispose to avascular necrosis of the talus. Closed reduction and percutaneous fixation can reduce the soft tissue damage and disturbance to the blood supply. CONCLUSIONS Preoperative 3D CT scans, early surgery, anatomic articular surface reduction and percutaneous screw fixation increase the fracture healing rate and reduce the incidence of talar avascular necrosis. Key word: talus, closed reduction, percutaneous fixation, screw. PMID- 28809630 TI - ? AB - PURPOSE OF THE STUDY The aim of the study was to evaluate the safety and efficacy of the application of platelet- and leukocyte-rich plasma (L-PRP) in the treatment of lateral humeral epicondyle (ERH) as compared to the administration of corticosteroid therapy. MATERIAL AND METHODS It was a prospective, double blind and randomized clinical trial. It included a total of 25 cases of ERH in 23 patients aged 18 to 60 years. They were divided into two arms: L-PRP arm with 10 cases and corticosteroid arm with 15 cases. The therapy of L-PRP group: first application: 3 ml of native L-PRP without activation, second application: after 6 weeks, 3 ml of thawed L-PRP. Therapy of the corticosteroid arm patients: first and second application (both after 6 weeks) of 3.5 mg of Betamethasonum. The follow-up period was 12 months. The safety evaluation was carried out based on the number of adverse events. The efficacy was evaluated using the DASH score and the Visual Analogue Scale (VAS). The time series outcomes were analysed statistically by percentile graphs and repeated measures ANOVA. RESULTS The ascertained values of blood elements in the received L-PRP as against the original blood were the following: platelets around 400%, white blood cells around 200%, red blood cells around 30%. The differences in individual subpopulations of white blood cells: neutrophils 74%, lymphocytes 424%, monocytes 385%, eosinophils 43%, basophils 337%. The product was classified as L-PRP group based on the POSEIDO classification. Safety evaluation: both the groups reported no adverse and also no serious adverse events. One patient withdrew from the corticosteroid group on the grounds of a subjective feeling of treatment failure. Efficacy evaluation: for both the general DASH score and Work Module a statistically better effect of L-PRP was proven in the first 6 months at p < 0.05. For the general DASH score, the L-PRP group reported a decrease of difficulties from approximately 50% to 20% on DASH score and in the corticosteroid group the difficulties returned to more or less the initial value. In the Work Module, the L-PRP group showed a decline in difficulties from approximately 46% to 18% and the corticosteroid group from approximately 43% only to 38%. The Sports and Music Module was evaluated by percentile graphs only. The VAS assessment proved that an effect was achieved only after the administration of the first dose of L-PRP and corticosteroid, with a more significant effect reported in L-PRP. The overall statistical evaluation using the VAS showed no difference between these two therapies at the level of significance of p<0.05 (p = 0.08). DISCUSSION The product used by us was classified as a L-PRP subcategory. The application of the native and subsequently frozen L-PRP is rare as compared to the corticosteroid therapy. CONCLUSIONS According to our results, the application of L-PRP is suitable to treat lateral humeral epicondyle. The benefits can be foreseen in the form of a better functional score, whereas the analgesic effect equals the effect of corticosteroid. A slightly additive effect was seen in the thawed second dose. Key words: platelet- and leucocyte-rich plasma, epicondylitis radialis humeri. PMID- 28809631 TI - [Comparison between the Range of Movement Canine Real Cervical Spine and Numerical Simulation - Computer Model Validation]. AB - PURPOSE OF THE STUDY In developing new or modifying the existing surgical treatment methods of spine conditions an integral part of ex vivo experiments is the assessment of mechanical, kinematic and dynamic properties of created constructions. The aim of the study is to create an appropriately validated numerical model of canine cervical spine in order to obtain a tool for basic research to be applied in cervical spine surgeries. For this purpose, canine is a suitable model due to the occurrence of similar cervical spine conditions in some breeds of dogs and in humans. The obtained model can also be used in research and in clinical veterinary practice. MATERIAL AND METHODS In order to create a 3D spine model, the LightSpeed 16 (GE, Milwaukee, USA) multidetector computed tomography was used to scan the cervical spine of Doberman Pinscher. The data were transmitted to Mimics 12 software (Materialise HQ, Belgium), in which the individual vertebrae were segmented on CT scans by thresholding. The vertebral geometry was exported to Rhinoceros software (McNeel North America, USA) for modelling, and subsequently the specialised software Abaqus (Dassault Systemes, France) was used to analyse the response of the physiological spine model to external load by the finite element method (FEM). All the FEM based numerical simulations were considered as nonlinear contact statistic tasks. In FEM analyses, angles between individual spinal segments were monitored in dependence on ventroflexion/ /dorziflexion. The data were validated using the latero-lateral radiographs of cervical spine of large breed dogs with no evident clinical signs of cervical spine conditions. The radiographs within the cervical spine range of motion were taken at three different positions: in neutral position, in maximal ventroflexion and in maximal dorziflexion. On X-rays, vertebral inclination angles in monitored spine positions were measured and compared with the results obtain0ed from FEM analyses of the numerical model. RESULTS It is obvious from the results that the physiological spine model tested by the finite element method shows a very similar mechanical behaviour as the physiological canine spine. The biggest difference identified between the resulting values was reported in C6-C7 segment in dorsiflexion (Deltaphi = 5.95%), or in C4-C5 segment in ventroflexion (Deltaphi = -3.09%). CONCLUSIONS The comparisons between the mobility of cervical spine in ventroflexion/dorsiflexion on radiographs of the real models and the simulated numerical model by finite element method showed a high degree of results conformity with a minimal difference. Therefore, for future experiments the validated numerical model can be used as a tool of basic research on condition that the results of analyses carried out by finite element method will be affected only by an insignificant error. The computer model, on the other hand, is merely a simplified system and in comparison with the real situation cannot fully evaluate the dynamics of the action of forces in time, their variability, and also the individual effects of supportive skeletal tissues. Based on what has been said above, it is obvious that there is a need to exercise restraint in interpreting the obtained results. Key words: cervical spine, kinematics, numerical modelling, finite element method, canine. PMID- 28809632 TI - Cerclage Breakage in Trochanteric Revision - High Risk for Hip Endoprosthesis? AB - We report a 72-year-old man who underwent fixation with a multifilament cerclage system after a peri-prosthetic trochanteric fracture (Vancouver A1). Failure of cerclage occurred after 23 month and revision of trochanteric attachment was performed due to non-union. Intraoperatively fragments of the cable were found between prosthesis head and liner. Cup and head were changed and the greater trochanter was re-attached after allograft-impaction. Based on the present case report multifilament cerclage cables should be used with precaution and might require a close and frequent follow-up given the possibility of cerclage breakage and consecutive catastrophic wear by migration of cerclage particles. Key words: cerclage, cerclage breakage, greater trochanter, revision. PMID- 28809633 TI - The Potential of the ICUC(r) Documentation Concept to Improve Trauma Surgery. AB - Conventional documentation of surgical procedures using only pre- and postoperative X-ray images and possibly a few intra-operative pictures does not allow secondary analysis of the technical performance in detail. In particular, the quality of the handling of tissues and surgical tools cannot be judged "post hoc", i.e. after the end of the surgical procedure. The invasiveness of the surgical act cannot yet be quantified. Surrogate invasiveness indices have therefore been developed. Furthermore, conventional documentation does not allow evaluation of the proper use of the C-arm both technically and with regard to fluoroscopy time. Documentation that follows the ICUC(r) documentation concept includes all fluoroscopy shots and images covering all key portions of the entire surgical procedure by multiple still images or videos. In certain cases, such documentation can help to explain post-operative courses that might be difficult to understand based only on X-rays and written operation reports. Finally, the data included in ICUC(r) documentation are a valuable source for knowledge extraction. In addition, time saving is conceivable if operation reports can include images of the key stages of the procedure with a few additional comments dictated during the surgery. Key words: trauma surgery, ICUC(r) documentation concept. PMID- 28809634 TI - [Wear and Roughness of Bearing Surface in Retrieved Polyethylene Bicon-Plus Cups]. AB - PURPOSE OF THE STUDY By 7th December 2016, 4,755 Bicon-Plus cups in total were implanted in the Czech Republic. Some of them have been continuously re-operated, while the most frequent reason of failure is polyethylene wear and aseptic loosening. The present study is focused on surface analysis of retrieved polyethylene Bicon-Plus cups and the determination of the roughness of their bearing surfaces. MATERIAL AND METHODS In this study, we had 13 high molecular weight polyethylene cups with the average time in situ of 8.11 years (3.6-13.7, SD 3.2) before the retrieval. The study population was composed of 3 men, 10 women, with the mean age of 53.31 years. An optical scanning method, based on the principle of active triangulation, was used to determine wear rate. The rate of wear was identified by means of an obtained scan subsequently processed with the use of the GOM Inspect software. The roughness of surfaces was analysed with the application of Contour GT-X8 profiler using the principle of phase shifting interferometry. Measurements of surface topography of the retrieved cups were performed on the entire bearing surfaces. For the individual surface changes, a typical range of surface roughness, describing the particular wear character, was determined. By means of morphology analysis of the tested implants, three areas were identified: unworn area; area representing the worn part of the cup; and the area roughened by parallel grooving. The total surface roughness was evaluated as an arithmetic mean of the measured values. Subsequently, the values were sorted based on frequency and were classified into categories defining the particular wear mechanisms. RESULTS Wear rate of the retrieved acetabular cups was evaluated based on the wear direction vector and the size of linear wear. The average linear wear was equal to 0.13 mm/year (ranging from 0.26 to 2.29 mm/year), and the mean value of total volumetric material loss was 44.37 mm3/year (the range being from 51.80 to 1,119.7 mm3/year). Using the optical profilometer, a map of roughness distribution of the individual cups was obtained. For each implant, 76 values of roughness were evaluated. With the respect to average roughness, the samples were sorted to various categories describing: surface polishing; abrasiveadhesive wear; surfaces with preserved grooving; substantial plastic deformation. DISCUSSION The results clearly showed an increase of wear depending on implant survival; however, the tendency is not linear. This fact can be attributed to a larger amount of abrasive particles, causing an increase of wear or occurrence of surface wear in terms of micro cracks and oxidation degradation of polyethylene. This study indicates that geometry, positioning, and cup alignment during the implantation have a fundamental impact on the cup durability. Further correlation, which was observed in the case of the cup with prevailing roughness in the range from 0.1 to 0.3 MUm, is a relatively wide wear vector angle determined with the use of the optical method. Considering the implants with the longest survival time with no loosening of the acetabular cup, the mean angle of direction vector was 56.8 degrees (SD 2.1 degrees ). CONCLUSIONS The present study provides the results of morphology analysis of the retrieved Bicon-Plus cups. In general, relatively high wear rate, mainly of abrasive-adhesive character was identified. The dependence between wear and implant in situ longevity was not clearly linear, which suggests the influence of other parameters on the polyethylene wear rate. An important role of implant positioning on survival was also revealed. Moreover, it seems that it can be a more important parameter than the characteristics of the patient. Key words: total hip arthroplasty, Bicon-Plus cup, retrieval analysis, surface analysis, wear measurement, roughness, deformation, survivorship. PMID- 28809635 TI - [Clinical Results of Endoscopic Treatment of Greater Trochanteric Pain Syndrome]. AB - PURPOSE OF THE STUDY This retrospective study aims to present short-term clinical outcomes of endoscopic treatment of patients with greater trochanteric pain syndrome (GTPS). MATERIAL AND METHODS The evaluated study population was composed of a total of 19 patients (16 women, 3 men) with the mean age of 47 years (19-63 years). In twelve cases the right hip joint was affected, in the remaining seven cases it was the left side. The retrospective evaluation was carried out only in patients with greater trochanteric pain syndrome caused by independent chronic trochanteric bursitis without the presence of m. gluteus medius tear not responding to at least 3 months of conservative treatment. In patients from the followed-up study population, endoscopic trochanteric bursectomy was performed alone or in combination with iliotibial band release. The clinical results were evaluated preoperatively and with a minimum follow-up period of 1 year after the surgery (mean 16 months). The Visual Analogue Scale (VAS) for assessment of pain and WOMAC (Western Ontario MacMaster) score were used. In both the evaluated criteria (VAS and WOMAC score) preoperative and postoperative results were compared. Moreover, duration of surgery and presence of postoperative complications were assessed. Statistical evaluation of clinical results was carried out by an independent statistician. In order to compare the parameter of WOMAC score and VAS pre- and post-operatively the Mann-Whitney Exact Test was used. The statistical significance was set at 0.05. RESULTS The preoperative VAS score ranged 5-9 (mean 7.6) and the postoperative VAS ranged 0-5 (mean 2.3). The WOMAC score ranged 56.3-69.7 (mean 64.2) preoperatively and 79.8-98.3 (mean 89.7) postoperatively. When both the evaluated parameters of VAS and WOMAC score were compared in time, a statistically significant improvement (p<0.05) was achieved postoperatively. The mean duration of surgical procedure was 68 minutes. Moreover, in peritrochanteric space apart from chronic bursitis also another pathology was found in a total of 14 cases (74%). In six cases (32%) it was a mild degeneration of m. gluteus medius (treated only with debridement) and in eight patients who underwent surgery (42%) the dorsal third of tractus iliotibialis was hypertrophic and protruding into bursa (treated with an incision of the hypertrophied part of the band). No serious neurovascular or thromboembolic complications were recorded. Only minor postoperative complications in a total of 7 patients who underwent surgery (37%) occurred. DISCUSSION There are lots of studies in literature presenting the results of endoscopic treatment of GTPS either using an independent trochanteric bursectomy or its combination with iliotibial band release. In our study we succeeded in achieving similar clinical results as those achieved by the other authors engaged in this area. CONCLUSIONS It has been proven in this retrospective study that the technique of endoscopic trochanteric bursectomy in patients with greater trochanteric pain syndrome yields statistically significant improvement of clinical results with the concurrent minimum incidence of postoperative complications. Key words: greater trochanteric pain syndrome, peritrochanteric space, recalcitrant trochanteric bursitis, hip arthroscopy, endoscopic trochanteric bursectomy, iliotibial band release. PMID- 28809636 TI - [Arthroscopic Finding of Knee Joint in Relation to Age and Its Comparison with Pre-Operative Clinical Finding - a Retrospective Study]. AB - PURPOSE OF THE STUDY In the retrospective study of two South Bohemian centres we present the comparison of pre-operative anamnestic clinical signs in relation to the arthroscopic intraoperative finding. The obtained data is used also to evaluate the arthroscopic finding in relation to age and sex. MATERIAL AND METHODS The arthroscopic findings of patients who underwent surgery in 2013-2014 period (1.1.2013-31.12.2014) at the Department of Trauma Surgery of Ceske Budejovice Hospital, a.s. and in 2014 (1.1.-31.12.2014) at the Department of Orthopaedics and Traumatology of Pisek Hospital, a.s. were evaluated. In total, 1 021 patients underwent surgery, with the mean age of 44 years. The patients were not selected. The group includes all the patients who underwent surgery, including those in whom repeat arthroscopy was performed, in the respective period of time, regardless of the mechanism of difficulties. A preoperative MRI scan was carried out in 470 patients. The referring physician was present during the examination. In all the patients undergoing surgery, the main clinical preoperative sign was examined based on the documentation, namely in the following order - hemarthros, locked knee, hydrops or merely a pain. In the arthroscopic finding, the medial meniscal lesion - anterior and posterior horn, and complete tear was assessed. The same was done for lateral meniscus. In anterior cruciate ligament - ACL - partial or complete tear was assessed. We identified the frequency of findings in relation to age and evaluated the correlations between the clinical signs and the arthroscopic finding. We calculated the sensitivity and specificity of hemarthros as a sign of ACL tear. The analysis was conducted based on the medical history in medical record documentation and the surgical protocol. The cartilage was not assessed. RESULTS Analysis of clinical and anamnestic signs in relation to arthroscopic findings 1. Negative arthroscopic findings (potential cartilage damage with no damage to other soft structures and normal arthroscopic findings) are in 83% accompanied by a mere knee pain. 2. High percentage of isolated locked joint (15%) in negative findings 3. Complete ACL tears are most frequently reported in the under-35 age category - 43% of 191 men who underwent surgery and 33% of 102 women. 4. Isolated injuries to ACL without the meniscus tear are frequent in younger patients - 30% 40% of the total number of patients with injured ACL. 5. In patients older than 56 years of age the ACL damage is accompanied by concurrent meniscus tear (96% in men, 100% in women). 6. Sensitivity of hemarthros (68%) for complete ACL tear. Specificity of the presence of hemarthros in complete ACL lesions (91%) indicates that there are also complete ACL tears with no hemarthros whatsoever in the medical history. For partial tears the values of sensitivity and specificity are 27% and 67%, respectively. In partial tear, the presence of hemarthros is not a diagnostic lead. 7. In 15% of negative findings a "locked knee" was present. It was not a genuinely locked knee, but rather an antalgic position. Not every locked knee must necessarily mean a meniscus lesion or ACL tear. 8. Isolated meniscus tear is in 75% accompanied only by pain. 9. In our group of patients, isolated osteoarthrosis or malacic cartilage without any damage to ligaments or menisci was rare - only in 22 cases (2% of the entire group). DISCUSSION There are lots of studies which focus on comparing the clinical findings with perioperative pathology of knee joint and the importance of pre-operative clinical examination. Our extensive retrospective study proved that in 56-plus age category virtually each ACL injury is accompanied by a meniscal lesion, which can be explained by a possible ACL damage at a young age and subsequent instability resulting in meniscus tear or frequent presence of degenerative meniscal changes at an older age. A small number of isolated degenerative cartilage damage was established (2%). We fully agree with the authors who prove that the degenerative cartilage changes are ever since the very beginning accompanied by changes of the other soft structure of the knee. We revealed a high percentage of locked knee joint in negative arthroscopic findings. According to the clinical pre-operative examination, the locked knee does not automatically mean the meniscal lesion or ACL tear. In agreement with the others we prove a close association between hemarthros and ACL injury. CONCLUSIONS 1. A clinical examination, a detailed medical history is necessary 2. With hemarthros in medical history, there is a likelihood of complete ACL tear. Conversely, even a seemingly trivial knee sprain without hemarthros or locked knee can mean the ACL tear. 3. Where a mere pain is present, it mostly indicates an isolated meniscal damage or a negative finding. 4. Degenerative cartilage changes are accompanied by degeneration of menisci and ligaments. 5. Our group of patients did not include any case of hemarthros in the medical history with a negative arthroscopic finding. Hemarthros always indicated a more serious damage to knee soft structures. Key words: knee joint injuries, knee arthroscopy, sensitivity, specificity, hemarthros. PMID- 28809637 TI - [Comparison of Short-Therm Results of Conservative versus Operative Treatment of Distal Ulna Fractures Associated with Distal Radius Fracture Treated by Plate Osteosynthesis]. AB - PURPOSE OF THE STUDY The study aims to evaluate and compare the results of conservative and operative treatment of individual types of distal ulna fractures associated with distal radius fracture treated by plate osteosynthesis and to verify the conclusions of the other authors regarding the recommended therapeutic procedures in these fractures. MATERIAL AND METHODS In the period from 08/2013 to 09/2015, a total of 81 patients participated in the prospective randomised study, with the mean follow-up period of 24 months (6-36). All the fractures of distal two thirds of ulnar styloid process were treated conservatively. The patients with the other types of ulnar fractures (fractures of the proximal third of ulnar styloid process, ulnar head fractures, subcapital fractures) were systematically divided into two cohorts, based on which the subsequent (conservative vs. operative) treatment of distal ulna fractures was indicated. The operative treatment of all the types of distal ulna fractures was performed by plate osteosynthesis using LCP Distal Ulna Plate implant so that a uniform method is applied. RESULTS In the post-operative follow-up not a single patient with tip fracture of ulnar styloid process in the cohort showed a posttraumatic instability or disorder of distal radioulnar joint (DRUJ) biomechanics (ROM 96.6% (91-100), MWS 61.3 points (75-100), QDASH 2.9 points (0-6.8)). The patients with a fracture of the proximal third of ulnar styloid process, a fracture of ulnar head and a subcapital fracture, treated operatively, achieved better early radiographic and functional outcome (ROM 95.7% (60-100), MWS 91.2 points (75 100), QDASH 3.5 points (0-11.4)) than patients treated conservatively (ROM 89.6% (64-100), MWS 70.4 points (35-85), QDASH 18.4 points (0-52.3)). DISCUSSION The study confirms the conclusions drawn by the other authors that tip fractures of ulna do not cause posttraumatic DRUJ instability and do not require operative treatment. Conservative treatment of ulnar base fractures led to non-union in 60% of cases and to malunion in 25% of cases, altogether in 15 patients (75%) the clinical examination revealed a conclusive posttraumatic DRUJ instability of various severity and these patients showed healing in malunion ad latus greater than 2 mm and non-union of the fracture. By performing anatomical reduction and osteosynthesis of ulnar "base fractures", the stability and DRUJ function were restored in all the patients, thus also a better functional outcome was attained. Conservative treatment of ulnar head fractures brought worse outcomes due to malunion of fractures resulting in a noncongruent articular surface of DRUJ or a change in axial position of the distal end of the bone. The change in DRUJ biomechanics resulted in a limited rotation of radius and a limited range of forearm mobility. The operative treatment of subcapital ulna fracture had a very good early outcome as compared to conservative treatment of the fracture which healed in malunion, the change of axial position of the distal end of the bone resulted in a limited range of forearm mobility. CONCLUSIONS Based on the early functional and radiographic outcomes of RCT study it can be stated, in agreement with the other authors, that the operative treatment of distal ulna fractures associated with the distal radius fracture treated by ORIF should be indicated for base fractures of ulnar styloid process associated with DRUJ instability following the osteosynthesis of distal radius fracture and peripheral fragment dislocation ad axim or ad latus in radial direction by 2 mm and more, and also in case of displaced ulnar head fractures and instable and displaced subcapital fractures of the ulna. Key words: distal ulna fracture, plate osteosynthesis, LCP distal ulna plate. PMID- 28809638 TI - [Four-Corner Arthrodesis of the Wrist with Dorsal Circular Plate - a Retrospective Monocentric Study]. AB - PURPOSE OF THE STUDY Our study aimed to evaluate a group of patients who in the period from 2005 to 2014 underwent a four-corner arthrodesis of the wrist in our department. We also wanted to verify the hypothesis as to whether the use of conventional dorsal plate without the application of bone grafts leads to comparable results as the use of dorsal locking plates and routine application of bone grafts. MATERIAL AND METHODS Throughout the years 2005 to 2014 the four corner arthrodesis of the wrist was performed in our department in a total of 62 patients, in two cases bilaterally. The indication was the diagnosis of SLAC/SNAC grade III. Normed RondoFix implant was used in all the cases. Following the surgery, the wrist was immobilized by a volar plaster splint for the period of 2 weeks and subsequently orthosis was applied for additional 4 weeks. The wrist mobilisation started in week seven when the orthosis was removed, the patients were allowed full load on the wrist 3 months after the surgery. Our group of patients was evaluated retrospectively, a total of 53 operated wrists in 51 patients were assessed. The assessment was carried out based on a radiograph of the wrist, range of motion, Mayo Modified Wrist Score, DASH Score and grip strength test. RESULTS The mean range of motion in sagittal plane was 63.7 degrees , in frontal plane the mean value was 32.1 degrees . According to the Mayo Modified Wrist Score 37 patients were rated "excellent" or "good". Due to the presence of moderate pain, the result in other 10 patients was assessed as "satisfactory". In a total of 4 patients the result was assessed as "weak", in two of them for a presence of non-union and in other two for severe pain under load. One of these patients underwent bilateral surgery and reported severe pain in both the wrists. Regarding DASH score, the best result equalled 0, the worst 65.83, with the mean of 20.5. The grip strength ranged from 8 to 54 kg, with the mean value of 27.5 kg. In two patients, a non-union occurred. In the first case the extraction of implant and re-arthrodesis was performed due to severe pain and screw migration. The patient is now 22 months after the surgery and the radiographs show that the arthrodesis has healed and the patient has no clinical difficulties. The second patient did not report any difficulties, therefore he is only subject to follow-up. No cases of screw or plate breakage were reported. In one case, the patient reported pain in the region of radial styloid process. A revision was indicated with radial styloidectomy and decompression of tendons of m. extensor pollicis brevis and m. abductor pollicis longus. As a result the patient had no clinical difficulty. One case of wrist radial deviation was recorded. It was managed by corrective wedge osteotomy and reosteosynthesis using a circular dorsal plate. In one patient dorsal impingement occurred, accompanied by limited range of motion and pain. Extraction of OS material was indicated and the patient was relieved of any difficulties. We have recorded aseptic necrosis of lunate bone in one case. DISCUSSION When comparing the functional results such as the range of motion and grip strength, our results are fully comparable to previously published papers. In papers where DASH was referred to, its value ranges from 13 to 29.82, which is fully consistent with our observations with the final value of 20.5. The incidence of non-union and the degree of complications is not deviating from the values included in other publications either. In all the mentioned publications the authors refer to routine use of bone grafts. The publications evaluating the use of locking plates do not report different results either. CONCLUSIONS In case of correct indication, the four-corner arthrodesis of the wrist represents a very good solution. In our group of patients, we confirmed the hypothesis that equally good results as with the use of locking plates can be achieved when using a non-locking plate system. Essential is the proper correction of DISI and primary good congruence between fused carpal bones instead of the use of bone grafts. Key words: SLAC wrist, SNAC wrist, four-corner arthrodesis, partial wrist fusion. PMID- 28809640 TI - [Treatment of Displaced Patellar Fractures with Multiple Circular Cerclage]. AB - PURPOSE OF THE STUDY The study aims to conduct a mid-term evaluation of results of the treatment of patellar fractures with multiple circular cerclage. MATERIAL AND METHODS The retrospective clinical study with its own group of patients who underwent surgery in our centre in the period from 2008 to 2014. The study included a total of 29 patients with displaced patellar fractures treated with multiple circular cerclage. The available radiographic documentation was assessed and the quality of perioperative reposition, fracture healing, loss of reposition and potential failure of osteosynthesis material was considered. During the clinical examination, the range of motion (ROM) of the operated knee was measured. The current pain was evaluated on the Visual Analogue Scale for Pain (VAS). For evaluation of functional outcomes, the KOOS and LEFS scoring systems were used. RESULTS A total of 27 fractures (93.1%) healed after a mean period of 10.3 weeks after the primary surgery. In 23 cases two circular loops and in six cases 3 loops were used. The mean follow-up period was 66.6 months (range 22 100). The mean duration of the surgery was 59.6 minutes with the mean length of the incision of 11.8 cm (range 9-15). The quality of reposition was evaluated as exact in 23 patients, as adequate in six patients. The mean extension and flexion was 0.2 degrees and 135 degrees , respectively. The individual mean KOOS scores were the following: pain 75.0, symptom 74.5, knee function in daily living 76.7, knee function in sports and recreational activities 48.1, quality of life 57.8. The mean LEFS score was 68.7. The mean VAS score was 2.4. Extraction of osteosynthesis material was done in a total of seventeen cases (58.6%) at a mean of 10 months after osteosynthesis (range 5-14). In altogether five cases (17.2%) the loss of reposition occurred. In two patients pseudoarthrosis developed. Osteosynthesis material failure was reported in two cases (6.9%). DISCUSSION In our study population, by using the technique of multiple circular cerclage 27 fractures (93.1%) healed. In two cases the fractures failed to heal and pseudoarthrosis developed. In one case it was due to non-adherence to the postoperative regimen by the patient. According to the literature, 15-30% of patients suffer from functional limitations. In our study population the mean values of extension and flexion were 0.2 degrees and 135 degrees , respectively. Compared to the group of 17 patellar fractures managed with the modified Pyrford technique where the mean extension and flexion was 0.5 degrees and 131.1 degrees , respectively. According to the data referred to in literature, in up to 80 % cases post-operative pain of anterior knee is reported. In our population the current pain was assessed on the VAS and the mean value of 2.4 was ascertained in comparison to the set of different ORIF surgical procedures and a partial patellectomy, when the final mean VAS score was 2.8. In our population the values of LEFS and KOOS scores are comparable to the values of populations where different surgical techniques were assessed. The post-operative loss of reposition in up to 20% cases is reported by the literature, compared to our population, where it was recorded in a total of 5 cases (17.2%). CONCLUSIONS Multiple circular cerclage is a simple and inexpensive surgical method for treating displaced patellar fractures. It can be used for majority of types of fracture, including comminuted fractures, in which, however, there is a slightly higher risk of loss of reposition. The functional outcomes and the number of complications are comparable to other surgical techniques used. Key words: displaced patellar fracture, multiple circular cerclage, functional outcomes. PMID- 28809639 TI - The Effect of Incorrect Foot Placement on the Accuracy of Radiographic Measurements of the Hallux Valgus and Inter-Metatarsal Angles for Treating Hallux Valgus. AB - PURPOSE OF THE STUDY Accurate radiographic measurements are crucial in treating hallux valgus (HV). This three-dimensional deformity should not be evaluated from one joint on one plane. However, in practice, surgeons measure the deformity only on transverse dorsoplantar radiographs. We determined the amount of error associated with positioning the foot incorrectly on radiographs. MATERIAL AND METHODS To simulate incorrect positions of the foot in radiographic evaluation, we designed an angled device that can move in transverse and frontal plane. In four patients with symptomatic HV, we took weight-bearing radiographs of the involved foot in seven different positions. These 28 radiographs were given identifying but meaningless labels. On each radiograph, six surgeons blinded to the position of the radiograph measured the HV angle (HVA) and the inter metatarsal angle (IMA) and state the treatment plan according to five treatment options were given to participants. RESULTS Inter-observer agreement was high for measurements of HVA and IMA in all positions (interclass correlation coefficients, 0.96 and 0.88, respectively). However, intra-observer agreement was poor for HVA (intra-observer agreement, 0.17) but good for IMA (intra-observer agreement, 0.64). According to the measurements in different positions, intra observer treatment choices revealed moderate results (ICC: 0.524). Clinical Relevance Radiographic measurements are very important on the treatment decisions of hallux valgus. The foot position can influence the measurement accuracy and can cause incorrect decisions. In this study, we evaluated the impact of foot positions on measurements of hallux valgus angle and inter-metatarsal angle. Additionally, we evaluated the incorrect foot positioning on treatment decisions. Moreover, we analyzed intra-observer and inter-observer agreements of these angles in various positions. CONCLUSIONS We recommend that measurements of IMA are more reliable than those of HVA for managing hallux valgus in terms of false weight bearing radiographs taken in different positions. Positional changes during foot radiographs could lead clinicians to perform incorrect HVA and IMA measurements. This could change the treatment option. HVA measurements were more affected with foot positioning. It is important to take full weight bearing foot radiographs in correct technique. Key words: hallux valgus, radiology, data accuracy. PMID- 28809641 TI - Cementless Total Hip Arthroplasty in Primary Myelofibrosis - a Case Report. AB - There is a great deal of data available, in part contradictory, on the best fixation technique to use for total hip arthroplasty (THA) in hip osteoarthritis. Both the cementless and the cemented versions offer excellent long-term outcomes if the respective technique is applied correctly. However, as far as we know, no recommendation has been made regarding cemented vs. cementless THA in primary myelofibrosis. The case described here concerns a very active 76-year-old patient with primary myelofibrosis. This is a rare hematological disease. It develops from clonal hematopoiesis with impaired blood formation and progressive bone marrow fibrosis. An MRI scan of the patients pelvis showed a marked spotted change over all of the imaged bone. Ultimately, in preoperative planning we decided in favor of a proven cementless implant (Allofit Alloclassic cup and the CLS Spotorno stem from Zimmer). Complication-free osseous integration of the cementless implants was observed. Histologic analysis of the bone showed a focally sclerotically altered bone structure. Neither osteoporosis nor osteopenia were found. In our opinion, taking into account all other indication criteria, there is no reason not to perform a cementless THA implantation in the presence of primary myelofibrosis. Key words: hip, primary myelofibrosis, cementless, THA, total hip replacement. PMID- 28809642 TI - Fibular Strut Graft for Posterior Pelvic Ring Nonunion - a Case Report. AB - Posttraumatic pelvic nonunions in combination with malposition are uncommon in the present-day era of modern pelvic surgery. The case describes a new surgical technique for treatment of the nonunion localized to iliosacral joint. A 42-year old polytraumatized male presented with a pelvic fracture (type 61-C2.3) associated with a complex acetabular fracture. The patient was treated and the pelvis stabilized according to damage control principles (external fixation and pelvic C-clamp) and subsequently definitively treated according to principles of current pelvic surgery. The posterior pelvis was stabilized by bilateral S1 iliosacral screws, however the posterior pelvic ring injury on the left side was not well reduced. The result was a nonunion formation in the left sacroiliacal joit with screw loosening. Two attemps at bone grafting and repeat stabilization were done, but the nonunion did not heal. The end result was a nonunion through left sacroiliacal joint with destruction of the lateral part of sacral bone. The nonunion was treated with nonvascularised autologous fibular strut graft in combination with allogenic corticocancellous grafting. The fibular graft was placed into the bone void after the removal of the iliosacral screw. Radiographically the nonunion healed completely six months after the fibular grafting and the patient had improved clinical outcome. The described technique solves both instability and bone defect in posterior pelvic ring even in the case with low contact areas. The nonvascularised autologous fibular grafting is an effective technique for sacroiliac joint nonunion treatment even in case with large bone defect. Key words: pelvis; nonunion; fibular graft. PMID- 28809643 TI - [Rare Dorsal Traumatic Sternoclavicular Joint Dislocation in a 14-Year-Old Patient - a Case Report]. AB - We report a case of a 14-year-old patient with rare dorsal sternoclavicular dislocation caused by a sports injury. The patient was admitted to our department for further investigation and treatment. After a series of examinations, an open reduction and fixation using K-wires was used as a treatment modality. A satisfactory outcome was achieved, the patient returned to full sports activity 3 months after the surgery, with no limitations of movement. The necessity of early diagnosis and treatment options of this rare injury has been discussed. Key words: sternoclavicular joint, dorsal dislocation, open reduction. PMID- 28809644 TI - [Endoprosthesis Infections - Guidelines for Antibiotic Therapy Common Guidelines of the Czech Society for Orthopaedics and Traumatology and the Society for Infectious Diseases of the Czech Medical Association of J. E. Purkyne]. AB - PURPOSE OF THE STUDY This study aims to articulate regional guidelines for curative and suppressive antibiotic therapy of total joint replacement infections. MATERIAL AND METHODS When developing the standard, used as source materials were the published foreign guidelines for antibiotic therapy of prosthetic joint infections, the analysis of resistance of bacterial strains conducted in the Hospital in Ceske Budejovice, a.s. and the assessment of strain resistance for the Czech Republic published by the European Antimicrobial Resistance Surveillance Network (EARS-Net). Considered was also the availability of individual antibiotics in the Czech Republic and restricted prescription according to the Summary of Product Characteristics as specified in the State Institute for Drug Control marketing authorisation. The expert group composed of orthopaedists, microbiologists and infectious disease specialists elaborated the basic antibiotic guideline for choosing an appropriate antibiotic/antifungal drug based on the usual susceptibility, its dose and dosage interval for initial and continuation therapy. The comments of individual specialists were gradually incorporated therein and in case of doubts majority rule was applied. The drafted document was sent for peer reviews to clinical orthopaedic, infectious disease and microbiological centres, whose comments were also incorporated and the finalised document was submitted for evaluation to specialised medical societies. RESULTS The outcome is the submitted guideline for antibiotic curative and suppressive therapy suitable for managing the prosthetic joint infections, which was approved by the committee of the Czech Society for Orthopaedics and Traumatology andthe Society for Infectious Diseases of the Czech Medical Association of J. E. Purkyne. DISCUSION Curative therapy of total joint replacement infections consists primarily in surgical treatment and has to be accompanied by adequate antibiotic therapy administered initially intravenously and later orally over a sufficient period of time. Bearing in mind the wide spectrum of pathogens that can cause infections of a joint replacement and their capacity to form a biofilm on foreign materials, the correct choice of an antibiotic, its dose and dosage interval are essential for successful treatment. Such standard should respect regional availability of antibiotics, regional pathogen resistance/susceptibility and ensure the achievement of sufficiently high concentrations at the requested location including anti-biofilm activity. CONCLUSIONS The submitted guideline is not the only treatment option for joint total replacement infections, but it makes the decisionmaking easier when treating these complications in the form of infections. The final choice of an antibiotic, its dose and duration of therapy shall be based on a critical assessment of results of microbiological (blood culture and molecular genetic) tests and reflect the patient s clinical condition. Since these are multidisciplinary issues, we consider useful for this guideline to be commented upon and approved by the committee of both the Society for Orthopaedics and Infectious Diseases so that it can become the starting point for treatment. Key words: total joint replacement infection, TEP, ATB, antibiotic therapy, consensus meeting, guideline. PMID- 28809645 TI - Screening for Functional Cognition in Postacute Care and the Improving Medicare Post-Acute Care Transformation (IMPACT) Act of 2014. AB - Occupational therapists have a long history of assessing functional cognition, defined as the ability to use and integrate thinking and performance skills to accomplish complex everyday activities. In response to passage of the Improving Medicare Post-Acute Care Transformation (IMPACT) Act of 2014 (Pub. L. 113-185), the American Occupational Therapy Association has been advocating that the Centers for Medicare and Medicaid Services consider functional cognition for inclusion in routine patient assessment in postacute care settings, with important implications for occupational therapy. These efforts have the potential to increase referrals to occupational therapy, emphasize the importance of addressing functional cognition in occupational therapy practice, and support the value of occupational therapy in achieving optimal postacute care outcomes. PMID- 28809646 TI - Occupational Therapy and Veteran Suicide: A Call to Action. AB - Suicide in the U.S. military veteran population is an epidemic with a wide ranging impact on individuals, families, and society. Death by suicide is preventable. The purpose of this article is to ignite a professional discussion about veteran suicide, a serious mental health issue that is underrepresented in the occupational therapy research literature. Occupational therapy practitioners respond to the changing needs of populations and promote preventive measures to improve health. Actively exploring occupational therapy's role in suicide prevention is a professional responsibility aligned with tenets of the Centennial Vision and Vision 2025. Applying the concept of the scholarship of integration, the authors present a case for the inclusion of suicide prevention training as a professional competency and explore opportunities to address suicide risk through the use of evidence-based interventions for posttraumatic stress disorder, combat stress, and depression. Professional implications include the need to advance professional knowledge through education, advocacy, and intervention research targeting the veteran population. PMID- 28809647 TI - Clinical Effectiveness of Occupational Therapy in Mental Health: A Meta-Analysis. AB - OBJECTIVE: The purpose of this study was to estimate the effectiveness of theory based occupational therapy interventions in improving occupational performance and well-being among people with a mental health diagnosis. METHOD: The meta analysis included 11 randomized controlled trials with a total of 520 adult participants with a mental health diagnosis. Outcomes were occupational performance, well-being, or both. We conducted meta-analyses using Comprehensive Meta-Analysis software (Version 3.0) with occupational performance and well-being as the dependent variables. RESULTS: Results indicated a medium effect of intervention on improving occupational performance (mean Hedge's g = 0.50, Z = 4.05, p < .001) and a small effect on well-being (mean Hedge's g = 0.46, Z = 4.96, p < .001). CONCLUSION: Theory-based occupational therapy interventions may be effective in improving occupational performance and well-being among people with a mental health diagnosis and should be an integral part of rehabilitation services in mental health. PMID- 28809648 TI - Systematic Review of Occupational Therapy in the Treatment of Addiction: Models, Practice, and Qualitative and Quantitative Research. AB - OBJECTIVE: The authors conducted a systematic review of theoretical models, professional practice, and research findings to understand occupational therapy's role in the treatment of addiction. METHOD: PubMed, Academic Search Premier, CINAHL, ERIC, OTseeker, and Google Scholar were searched to identify scientific journal articles, book chapters, or any other similar literature published from 1970 through July 2015 that addressed theoretical approaches, intervention models, and professional roles or were qualitative or quantitative studies in which occupational therapy had a central role. RESULTS: The literature search yielded 16 theoretical and professional role studies, 8 qualitative studies, and 14 quantitative studies. All studies had low levels of evidence, and all were case series, sometimes with very small samples. CONCLUSION: Although occupational therapy has been involved in the treatment of people with substance addiction and, more recently, with behavioral addictions for more than half a century, the research that has been published is poor. PMID- 28809649 TI - Linking Neuroscience, Function, and Intervention: A Scoping Review of Sensory Processing and Mental Illness. AB - PURPOSE: Sensory approaches to mental illness are increasingly prominent in occupational therapy. Despite indicators of efficacy, a paucity of literature supports these approaches. This article provides a scoping review of research on the relationship between sensory processing and mental illness. METHOD: Using Arksey and O'Malley's (2005) framework, we mapped this area of research and identified gaps in the knowledge base. We searched PubMed, CINAHL Plus, PsycINFO, OTseeker, and the Cochrane Library using the terms sensory and mental health. RESULTS: We found a growing body of neuroscientific research, primarily using electroencephalography and functional MRI, that links atypical neurosensory activity to mental illness. The occupational therapy literature has primarily focused on the efficacy of sensory rooms in psychiatric inpatient settings. CONCLUSION: Research on the efficacy of sensory approaches needs to be expanded, including on how atypical sensory processing in adults with mental illness affects meaningful occupational participation. PMID- 28809650 TI - Supporting Adults With Alzheimer's Disease and Related Major Neurocognitive Disorders and Their Caregivers: Effective Occupational Therapy Interventions. AB - Occupational therapy practitioners play a significant role in supporting adults with Alzheimer's disease and related major neurocognitive disorders, as well as their caregivers, through all phases of the disease process. This editorial highlights the systematic reviews completed in collaboration with the American Occupational Therapy Association's Evidence-Based Practice Project that summarize the evidence for the effectiveness of interventions within the scope of occupational therapy practice for this population. Readers are encouraged to translate and integrate this updated knowledge into everyday practice. PMID- 28809651 TI - Effectiveness of Occupational Therapy Interventions to Enhance Occupational Performance for Adults With Alzheimer's Disease and Related Major Neurocognitive Disorders: A Systematic Review. AB - OBJECTIVE: The purpose of this systematic review was to describe the evidence for the effectiveness of interventions designed to establish, modify, and maintain occupations for adults with Alzheimer's disease (AD) and related neurocognitive disorders. METHOD: Titles and abstracts of 2,597 articles were reviewed, of which 256 were retrieved for full review and 52 met inclusion criteria. U.S. Preventive Services Task Force levels of certainty and grade definitions were used to describe the strength of evidence. RESULTS: Articles were categorized into five themes: occupation-based, sleep, cognitive, physical exercise, and multicomponent interventions. Strong evidence supports the benefits of occupation-based interventions, physical exercise, and error-reduction learning. CONCLUSION: Occupational therapy practitioners should integrate daily occupations, physical exercise, and error-reduction techniques into the daily routine of adults with AD to enhance occupational performance and delay functional decline. Future research should focus on establishing consensus on types and dosage of exercise and cognitive interventions. PMID- 28809652 TI - Effectiveness of Interventions for Caregivers of People With Alzheimer's Disease and Related Major Neurocognitive Disorders: A Systematic Review. AB - OBJECTIVE: The goal of the evidence review was to evaluate the effectiveness of interventions for caregivers of people with Alzheimer's disease and related major neurocognitive disorders that facilitate the ability to maintain participation in the caregiver role. METHOD: Scientific literature published in English between January 2006 and April 2014 was reviewed. Databases included MEDLINE, PsycINFO, CINAHL, OTseeker, and the Cochrane Database of Systematic Reviews. RESULTS: Of 2,476 records screened, 43 studies met inclusion criteria. Strong evidence shows that multicomponent psychoeducational interventions improve caregiver quality of life (QOL), confidence, and self-efficacy and reduce burden; cognitive reframing reduces caregiver anxiety, depression, and stress; communication skills training improves caregiver skill and QOL in persons with dementia; mindfulness-based training improves caregiver mental health and reduces stress and burden; and professionally led support groups enhance caregiver QOL. CONCLUSION: Strong evidence exists for a spectrum of caregiver interventions. Translation of effective interventions into practice and evaluation of sustainability is necessary. PMID- 28809653 TI - Effectiveness of Environment-Based Interventions That Address Behavior, Perception, and Falls in People With Alzheimer's Disease and Related Major Neurocognitive Disorders: A Systematic Review. AB - OBJECTIVE: This systematic review evaluated the effectiveness of environment based interventions that address behavior, perception, and falls in the home and other settings for people with Alzheimer's disease (AD) and related major neurocognitive disorders (NCDs). METHOD: Database searches were limited to outcomes studies published in English in peer-reviewed journals between January 2006 and April 2014. RESULTS: A total of 1,854 articles were initially identified, of which 42 met inclusion criteria. CONCLUSION: Strong evidence indicates that person-centered approaches can improve behavior. Moderate evidence supports noise regulation, environmental design, unobtrusive visual barriers, and environmental relocation strategies to reduce problematic behaviors. Evidence is insufficient for the effectiveness of mealtime ambient music, bright light, proprioceptive input, wander gardens, optical strategies, and sensory devices in improving behavior or reducing wandering and falls. Although evidence supports many environment-based interventions used by occupational therapy practitioners to address behavior, perception, and falls in people with AD and related major NCDs, more studies are needed. PMID- 28809654 TI - Family Caregiver Training Program (FCTP): A Randomized Controlled Trial. AB - OBJECTIVE: The purpose of this study was to examine the effectiveness of the Family Caregiver Training Program (FCTP) for caregivers of people with dementia. METHOD: A random assignment control group research design with a 3-mo follow-up was implemented. RESULTS: Thirty-six family caregivers of people with dementia demonstrated an increase in activity of daily living (ADL) knowledge (p < .001) and maintenance of that knowledge 3 mo posttest. Caregiver confidence, regardless of group assignment, improved; however, it was not maintained. Burden, depression, and occupational performance and satisfaction remained unchanged for the intervention group; however, physical health as it pertained to quality of life improved 3 mo posttest (p < .001). CONCLUSION: Findings demonstrate that the FCTP can effectively provide knowledge to family caregivers on how to assist people with dementia with ADLs. Even when standard care was provided, there was limited information on ADLs that family caregivers faced daily. PMID- 28809655 TI - Assistive Technology Addressing Safety Issues in Dementia: A Scoping Review. AB - Safety is an issue for older adults with dementia because they are at risk for various incidents. Intelligent assistive technology (IAT) may mitigate risks while promoting independence and reducing the impact on the caregiver of supporting a relative with dementia. The aim of this scoping review was to describe IATs and to identify factors to consider when selecting one. A systematic search was performed of the scientific and gray literature published between 2000 and 2015. A total of 31 sources were included. Four types of IATs were identified as addressing safety issues in dementia: monitoring technologies, tracking and tagging technologies, smart homes, and cognitive orthoses. Characteristics of the device and ethical considerations emerged as key factors to consider when selecting one. IATs yield promising results but pose various challenges, such as adapting to the evolution of dementia. Further research on their actual impact is needed. PMID- 28809656 TI - Animal-Assisted Therapies and Dementia: A Systematic Mapping Review Using the Lived Environment Life Quality (LELQ) Model. AB - OBJECTIVE: The authors mapped the literature on animal-assisted therapies (AATs) and institutionalized adults with dementia onto the Lived Environment Life Quality (LELQ) Model as a guide for future services and research. METHOD: Refereed literature addressing AATs and institutionalized people with dementia was comprehensively gathered, described, categorized, and synthesized in this systematic mapping review. RESULTS: From 1,342 screened records, the authors included 10 research articles that incorporated dogs in therapy for institutionalized adults with dementia. These canine-assisted therapies offered occupational opportunities and environmental supports conducive to experiences of relative well-being, occupational engagement, and optimal functioning. CONCLUSION: The findings offer proof of the concept that canine-assisted therapies are feasible and can elicit positive quality-of-life experiences in institutionalized people with dementia. Researchers and practitioners need to elucidate the theoretical foundations of AATs. The LELQ Model may serve as a guide for client-centered, occupation-focused, and ecologically valid approaches to animal-assisted occupational therapy. PMID- 28809657 TI - Everyday Technology Use Related to Activity Involvement Among People in Cognitive Decline. AB - OBJECTIVE: We investigated how everyday technology use related to activity involvement over 5 yr in people with mild cognitive impairment. METHOD: Thirty seven older adults with mild cognitive impairment were evaluated regarding everyday technology use and involvement in activities over time. Information on diagnostic changes was collected from medical files. Linear mixed-effects models were used in data analysis. RESULTS: Ability to use everyday technology showed a significant effect on activity involvement (p = .007) beyond the effects of time, diagnostic change, and age. Decreases in number of everyday technologies used (p < .001) and share of accessible and relevant everyday technologies used (p = .04) were associated with decreasing activity involvement. However, these two aspects did not reinforce each other. CONCLUSION: When monitoring activity involvement in clients with cognitive decline, health care professionals should take into account clients' ability to use everyday technologies and the amount of everyday technologies they use. PMID- 28809658 TI - Impact of the Cognitive-Functional (Cog-Fun) Intervention on Executive Functions and Participation Among Children With Attention Deficit Hyperactivity Disorder: A Randomized Controlled Trial. AB - OBJECTIVE: We examined the effect of the Cognitive-Functional (Cog-Fun) occupational therapy intervention on executive functions and participation among children with attention deficit hyperactivity disorder (ADHD). METHOD: We used a randomized, controlled study with a crossover design. One hundred and seven children age 7-10 yr diagnosed with ADHD were allocated to treatment or wait-list control group. The control group received treatment after a 3-mo wait. Outcome measures included the Behavior Rating Inventory of Executive Function (BRIEF) and the Canadian Occupational Performance Measure (COPM). RESULTS: Significant improvements were found on both the BRIEF and COPM after intervention with large treatment effects. Before crossover, significant Time * Group interactions were found on the BRIEF. CONCLUSION: This study supports the effectiveness of the Cog Fun intervention in improving executive functions and participation among children with ADHD. PMID- 28809659 TI - Examining Sensory Overresponsiveness in Preschool Children With Retentive Fecal Incontinence. AB - The development of bowel control is an important activity of daily living in early childhood, and challenges in this area can limit participation in key occupations. Retentive fecal incontinence (RFI) is a common disorder in children. Up to 50% of children do not respond adequately to initial medical intervention, and behaviors around toileting, some related to sensory overresponsivity (SOR), may be partly responsible. Therefore, this study investigated the relationship between RFI and SOR and also examined the discriminative validity of the Toileting Habit Profile Questionnaire (THPQ). Per parent report, children with RFI (n = 16) showed significantly more behaviors related to SOR compared with typically developing children (n = 27). In addition, results indicated that the THPQ effectively discriminates between children with RFI and typically developing children. Results are discussed regarding RFI and SOR, the impact of RFI on childhood occupational engagement, and the role of occupational therapy with this population. PMID- 28809660 TI - Longitudinal Study of Changes in Occupational Therapy Students' Perspectives on Frames of Reference. AB - We explored students' views of the value of frames of reference (FoR) as they progressed through the didactic portion of an occupational therapy program. Thirty-four occupational therapy students were provided with a definition of FoR and asked to provide overall thoughts and impressions about FoR and their value 4 times over a period of 15 mo. Data were analyzed using phenomenological traditions, including open coding and analysis of themes. Throughout the program, students' understanding of how to use FoR evolved as they learned to implement them in practice. Opinions of the use of FoR seemed to be influenced by the students' perceptions of the use of FoR by their Level I fieldwork supervisors. Themes from the narrative data are described and their implications discussed. PMID- 28809661 TI - International Educational Interactions and Students' Critical Consciousness: A Pilot Study. AB - Online technologies facilitate connections between students around the world, but their impact on occupational science and occupational therapy students' critical consciousness about culture is underexplored. In this article we present research on five groups of occupational science and occupational therapy students across two cohorts at one Midwestern university. We used a pretest-posttest group design and the Multicultural Experiences Questionnaire to investigate the potential influence of students' exposure to international educational interactions on their multicultural experiences and desires. Of 157 students surveyed, those who experienced the greatest number of international educational interactions demonstrated statistically significant increases in their desire to become acquainted with other people of different backgrounds and to explore their own prejudices and biases. Given the transformative potential of international educational interactions, future research must assess the ways in which such interactions affect critical cultural consciousness apart from other educational content and design. PMID- 28809662 TI - Adult Age and Cultural Differences in Performance on the Weekly Calendar Planning Activity (WCPA). AB - OBJECTIVE: We compared performance on a cognitively demanding task, the Weekly Calendar Planning Activity, of participants in three age groups and two countries (United States and Israel). METHOD: A sample of 375 U.S. and 433 Israeli healthy adults participated. During the activity, participants were observed for speed, accuracy, strategy use, and efficiency. RESULTS: Accuracy scores were similar in both countries; however, Israeli participants were slower and less efficient (p < .05). The younger and middle-aged Israeli groups were more strategic and the older Israeli group followed fewer rules than the corresponding U.S. groups (p < .05). Older participants in both countries were less accurate, efficient, and strategic than younger participants (p < .05). CONCLUSION: Limited strategy use and poor time allocation may contribute to difficulty managing cognitively demanding activities for older adults and may also be influenced by culture. Practitioners should consider these factors when screening people for occupational performance difficulties. PMID- 28809663 TI - Promoting Physical Activity and Nutrition in People With Stroke. AB - The prevalence of cardiovascular disease, diabetes, and obesity is high in people with stroke. Risk factors for these conditions include hypertension, high cholesterol, and physical inactivity. These risk factors are common in people with stroke and often go unmanaged. Engagement in healthy behaviors is important for managing and preventing these risk factors and comorbid conditions. More specifically, physical activity and nutrition are key health behaviors for the management and maintenance of health in people with stroke. These health behaviors, by their very nature, are also occupations; thus, they are influenced by client factors, performance skills and patterns, and environments and contexts. This article discusses physical activity and nutrition within the context of the Occupational Therapy Practice Framework: Domain and Process and proposes potential roles for occupational therapy practitioners and researchers in developing, testing, and providing physical activity and nutrition interventions for people with stroke. PMID- 28809664 TI - Occupational Therapy Interventions for Adults With Cancer. AB - This Evidence Connection describes a case report of a man with non-Hodgkin's lymphoma who underwent an allogenic stem cell transplant. The occupational therapy assessment and treatment processes for an outpatient rehabilitation setting are described. Evidence Connection articles provide a clinical application of systematic reviews developed in conjunction with the American Occupational Therapy Association's Evidence-Based Practice Project. PMID- 28809666 TI - Biomolecular Network Controllability With Drug Binding Information. AB - Complex networks are ubiquitous in nature. In biological systems, biomolecules interact with each other to form so-called biomolecular networks, which determine the cellular behaviors of living organisms. Controlling the cellular behaviors by regulating certain biomolecules in the network is one of the most concerned problems in systems biology. Recently, the connections between biological networks and structural control theory have been explored, uncovering some interesting biological phenomena. Some researchers have paid attentions to the structural controllability of networks in notion of the minimum steering sets (MSSs). However, because the MSSs for complex networks are not unique and the importance of different MSSs is diverse in real applications, MSSs with certain meanings should be studied. In this paper, we investigated the MSSs of biomolecular networks by considering the drug binding information. The biomolecules in the MSSs with binding preference are enriched with known drug targets and are likely to have more chemical-binding opportunities with existing drugs compared with randomly chosen MSSs, suggesting novel applications for drug target identification and drug repositioning. PMID- 28809667 TI - Nonlinear Dynamic Complexity and Sources of Resting-state EEG in Abstinent Heroin Addicts. AB - It has been reported that chronic heroin intake induces both structural and functional changes in human brain; however, few studies have investigated the carry-over adverse effects on brain after heroin withdrawal. In this paper, we examined the neurophysiological differences between the abstinent heroin addicts (AHAs) and healthy controls (HCs) using nonlinear dynamic analysis and source localization analysis in resting-state electroencephalogram (EEG) data; 5 min resting EEG data from 20 AHAs and twenty age-, education-, and gender-matched HCs were recorded using 64 electrodes. The results of nonlinear characteristics (e.g., the correlation dimension, Kolmogorov entropy, and Lempel-Ziv complexity) showed that the EEG signals in alpha band from AHAs were significantly more irregular. Moreover, the source localization results confirmed the neuronal activities in alpha band in AHAs were significantly weaker in parietal lobe (BA3 and BA7), frontal lobe (BA4 and BA6), and limbic lobe (BA24). Together, our analysis at both the sensor level and source level suggested the functional abnormalities in the brain during heroin abstinence, in particular for the neuronal oscillations in alpha band. PMID- 28809668 TI - Tractography-Based Score for Learning Effective Connectivity From Multimodal Imaging Data Using Dynamic Bayesian Networks. AB - OBJECTIVE: Effective connectivity (EC) is the methodology for determining functional-integration among the functionally active segregated regions of the brain. By definition EC is "the causal influence exerted by one neuronal group on another" which is constrained by anatomical connectivity (AC) (axonal connections). AC is necessary for EC but does not fully determine it, because synaptic communication occurs dynamically in a context-dependent fashion. Although there is a vast emerging evidence of structure-function relationship using multimodal imaging studies, till date only a few studies have done joint modeling of the two modalities: functional MRI (fMRI) and diffusion tensor imaging (DTI). We aim to propose a unified probabilistic framework that combines information from both sources to learn EC using dynamic Bayesian networks (DBNs). METHOD: DBNs are probabilistic graphical temporal models that learn EC in an exploratory fashion. Specifically, we propose a novel anatomically informed (AI) score that evaluates fitness of a given connectivity structure to both DTI and fMRI data simultaneously. The AI score is employed in structure learning of DBN given the data. RESULTS: Experiments with synthetic-data demonstrate the face validity of structure learning with our AI score over anatomically uninformed counterpart. Moreover, real-data results are cross-validated by performing classification-experiments. CONCLUSION: EC inferred on real fMRI-DTI datasets is found to be consistent with previous literature and show promising results in light of the AC present as compared to other classically used techniques such as Granger-causality. SIGNIFICANCE: Multimodal analyses provide a more reliable basis for differentiating brain under abnormal/diseased conditions than the single modality analysis. PMID- 28809669 TI - Muscle Activation and Inertial Motion Data for Noninvasive Classification of Activities of Daily Living. AB - OBJECTIVE: Remote monitoring of physical activity using body-worn sensors provides an objective alternative to current functional assessment tools. The purpose of this study was to assess the feasibility of classifying categories of activities of daily living from the functional arm activity behavioral observation system (FAABOS) using muscle activation and motion data. METHODS: Ten nondisabled, healthy adults were fitted with a Myo armband on the upper forearm. This multimodal commercial sensor device features surface electromyography (sEMG) sensors, an accelerometer, and a rate gyroscope. Participants performed 17 different activities of daily living, which belonged to one of four functional groups according to the FAABOS. Signal magnitude area (SMA) and mean values were extracted from the acceleration and angular rate of change data; root mean square (RMS) was computed for the sEMG data. A nearest neighbors machine learning algorithm was then applied to predict the FAABOS task category using these raw data as inputs. RESULTS: Mean acceleration, SMA of acceleration, mean angular rate of change, and RMS of sEMG were significantly different across the four FAABOS categories ( in all cases). A classifier using mean acceleration, mean angular rate of change, and sEMG data was able to predict task category with 89.2% accuracy. CONCLUSION: The results demonstrate the feasibility of using a combination of sEMG and motion data to noninvasively classify types of activities of daily living. SIGNIFICANCE: This approach may be useful for quantifying daily activity performance in ambient settings as a more ecologically valid measure of function in healthy and disease-affected individuals. PMID- 28809670 TI - Cardio-Pulmonary Stethoscope: Clinical Validation With Heart Failure and Hemodialysis Patients. AB - OBJECTIVE: The purpose of this study is to evaluate the accuracy of a noninvasive radiofrequency-based device, the Cardio-Pulmonary Stethoscope (CPS), to monitor heart and respiration rates, and detect changes in lung water content in human experiments and clinical trials. METHODS: Three human populations (healthy subjects ( ), heart failure (), and hemodialysis () patients) were enrolled in this study. The study was conducted at the University of Hawaii and the Queen's Medical Center in Honolulu, HI, USA. Measurement of heart and respiration rates for all patients was compared with standard FDA - approved monitoring methods. For lung water measurements, CPS data were compared with simultaneous pulmonary capillary wedge pressure (PCWP) measurements for heart failure patients, and with change in weight of extracted fluid for hemodialysis patients. RESULTS: Statistical correlation methods (Pearson, mixed, and intraclass) were used to compare the data and examine accuracy of CPS results. Results show that heart and respiration rates of all patients have excellent correlation factors, r>=0.9. Comparisons with fluid removed during hemodialysis treatment showed correlation factor of to 1, while PCWP measurements of heart failure patients had correlation factor of to 0.97. CONCLUSION: These results suggest that CPS technology accurately quantifies heart and respiration rates and measure fluid changes in the lungs. SIGNIFICANCE: The CPS has the potential to accurately monitor lung fluid status noninvasively and continuously in a clinical and outpatient setting. Early and efficient management of lung fluid status is key in managing chronic conditions such heart failure, pulmonary hypertension, and acute respiration distress syndrome. PMID- 28809671 TI - Transduction on Directed Graphs via Absorbing Random Walks. AB - In this paper we consider the problem of graph-based transductive classification, and we are particularly interested in the directed graph scenario which is a natural form for many real world applications. Different from existing research efforts that either only deal with undirected graphs or circumvent directionality by means of symmetrization, we propose a novel random walk approach on directed graphs using absorbing Markov chains, which can be regarded as maximizing the accumulated expected number of visits from the unlabeled transient states. Our algorithm is simple, easy to implement, and works with large-scale graphs on binary, multiclass, and multi-label prediction problems. Moreover, it is capable of preserving the graph structure even when the input graph is sparse and changes over time, as well as retaining weak signals presented in the directed edges. We present its intimate connections to a number of existing methods, including graph kernels, graph Laplacian based methods, and spanning forest of graphs. Its computational complexity and the generalization error are also studied. Empirically, our algorithm is evaluated on a wide range of applications, where it has shown to perform competitively comparing to a suite of state-of-the-art methods. In particular, our algorithm is shown to work exceptionally well with large sparse directed graphs with e.g., millions of nodes and tens of millions of edges, where it significantly outperforms other state-of-the-art methods. In the dynamic graph setting involving insertion or deletion of nodes and edge-weight changes over time, it also allows efficient online updates that produce the same results as of the batch update counterparts. PMID- 28809672 TI - Photorealistic Monocular Gaze Redirection Using Machine Learning. AB - We propose a general approach to the gaze redirection problem in images that utilizes machine learning. The idea is to learn to re-synthesize images by training on pairs of images with known disparities between gaze directions. We show that such learning-based re-synthesis can achieve convincing gaze redirection based on monocular input, and that the learned systems generalize well to people and imaging conditions unseen during training. We describe and compare three instantiations of our idea. The first system is based on efficient decision forest predictors and redirects the gaze by a fixed angle in real-time (on a single CPU), being particularly suitable for the videoconferencing gaze correction. The second system is based on a deep architecture and allows gaze redirection by a range of angles. The second system achieves higher photorealism, while being several times slower. The third system is based on real-time decision forests at test time, while using the supervision from a "teacher" deep network during training. The third system approaches the quality of a teacher network in our experiments, and thus provides a highly realistic real-time monocular solution to the gaze correction problem. We present in-depth assessment and comparisons of the proposed systems based on quantitative measurements and a user study. PMID- 28809673 TI - Heterogeneous Face Attribute Estimation: A Deep Multi-Task Learning Approach. AB - Face attribute estimation has many potential applications in video surveillance, face retrieval, and social media. While a number of methods have been proposed for face attribute estimation, most of them did not explicitly consider the attribute correlation and heterogeneity (e.g., ordinal versus nominal and holistic versus local) during feature representation learning. In this paper, we present a Deep Multi-Task Learning (DMTL) approach to jointly estimate multiple heterogeneous attributes from a single face image. In DMTL, we tackle attribute correlation and heterogeneity with convolutional neural networks (CNNs) consisting of shared feature learning for all the attributes, and category specific feature learning for heterogeneous attributes. We also introduce an unconstrained face database (LFW+), an extension of public-domain LFW, with heterogeneous demographic attributes (age, gender, and race) obtained via crowdsourcing. Experimental results on benchmarks with multiple face attributes (MORPH II, LFW+, CelebA, LFWA, and FotW) show that the proposed approach has superior performance compared to state of the art. Finally, evaluations on a public-domain face database (LAP) with a single attribute show that the proposed approach has excellent generalization ability. PMID- 28809674 TI - Faceness-Net: Face Detection through Deep Facial Part Responses. AB - We propose a deep convolutional neural network (CNN) for face detection leveraging on facial attributes based supervision. We observe a phenomenon that part detectors emerge within CNN trained to classify attributes from uncropped face images, without any explicit part supervision. The observation motivates a new method for finding faces through scoring facial parts responses by their spatial structure and arrangement. The scoring mechanism is data-driven, and carefully formulated considering challenging cases where faces are only partially visible. This consideration allows our network to detect faces under severe occlusion and unconstrained pose variations. Our method achieves promising performance on popular benchmarks including FDDB, PASCAL Faces, AFW, and WIDER FACE. PMID- 28809675 TI - Jointly Learning Deep Features, Deformable Parts, Occlusion and Classification for Pedestrian Detection. AB - Feature extraction, deformation handling, occlusion handling, and classification are four important components in pedestrian detection. Existing methods learn or design these components either individually or sequentially. The interaction among these components is not yet well explored. This paper proposes that they should be jointly learned in order to maximize their strengths through cooperation. We formulate these four components into a joint deep learning framework and propose a new deep network architecture (Code available on www.ee.cuhk.edu.hk/wlouyang/projects/ouyangWiccv13Joint/index.html). By establishing automatic, mutual interaction among components, the deep model has average miss rate 8.57 percent/11.71 percent on the Caltech benchmark dataset with new/original annotations. PMID- 28809676 TI - Simultaneous Clustering and Model Selection: Algorithm, Theory and Applications. AB - While clustering has been well studied in the past decade, model selection has drawn much less attention due to the difficulty of the problem. In this paper, we address both problems in a joint manner by recovering an ideal affinity tensor from an imperfect input. By taking into account the relationship of the affinities induced by the cluster structures, we are able to significantly improve the affinity input, such as repairing those entries corrupted by gross outliers. More importantly, the recovered ideal affinity tensor also directly indicates the number of clusters and their membership, thus solving the model selection and clustering jointly. To enforce the requisite global consistency in the affinities demanded by the cluster structure, we impose a number of constraints, specifically, among others, the tensor should be low rank and sparse, and it should obey what we call the rank-1 sum constraint. To solve this highly non-smooth and non-convex problem, we exploit the mathematical structures, and express the original problem in an equivalent form amenable for numerical optimization and convergence analysis. To scale to large problem sizes, we also propose an alternative formulation, so that those problems can be efficiently solved via stochastic optimization in an online fashion. We evaluate our algorithm with different applications to demonstrate its superiority, and show it can adapt to a large variety of settings. PMID- 28809678 TI - Ultrasound Aided Vertebral Level Localization for Lumbar Surgery. AB - Localization of the correct vertebral level for surgical entry during lumbar hernia surgery is not straightforward. In this paper, we develop and evaluate a solution using free-hand 2-D ultrasound (US) imaging in the operation room (OR). Our system exploits the difference in spinous process shapes of the vertebrae. The spinous processes are pre-operatively outlined and labeled in a lateral lumbar X-ray of the patient. Then, in the OR the spinous processes are imaged with 2-D sagittal US, and are automatically segmented and registered with the X ray shapes. After a small number of scanned vertebrae, the system robustly matches the shapes, and propagates the X-ray label to the US images. The main contributions of our work are: we propose a deep convolutional neural network based bone segmentation algorithm from US imaging that outperforms state of the art methods in both performance and speed. We present a matching strategy that determines the levels of the spinal processes being imaged. And lastly, we evaluate the complete procedure on 19 clinical data sets from two hospitals, and two observers. The final labeling was correct in 92% of the cases, demonstrating the feasibility of US-based surgical entry point detection for spinal surgeries. PMID- 28809677 TI - Application of the 4-D XCAT Phantoms in Biomedical Imaging and Beyond. AB - The four-dimensional (4-D) eXtended CArdiac-Torso (XCAT) series of phantoms was developed to provide accurate computerized models of the human anatomy and physiology. The XCAT series encompasses a vast population of phantoms of varying ages from newborn to adult, each including parameterized models for the cardiac and respiratory motions. With great flexibility in the XCAT's design, any number of body sizes, different anatomies, cardiac or respiratory motions or patterns, patient positions and orientations, and spatial resolutions can be simulated. As such, the XCAT phantoms are gaining a wide use in biomedical imaging research. There they can provide a virtual patient base from which to quantitatively evaluate and improve imaging instrumentation, data acquisition, techniques, and image reconstruction and processing methods which can lead to improved image quality and more accurate clinical diagnoses. The phantoms have also found great use in radiation dosimetry, radiation therapy, medical device design, and even the security and defense industry. This review paper highlights some specific areas in which the XCAT phantoms have found use within biomedical imaging and other fields. From these examples, we illustrate the increasingly important role that computerized phantoms and computer simulation are playing in the research community. PMID- 28809679 TI - Automatic Localization of the Needle Target for Ultrasound-Guided Epidural Injections. AB - Accurate identification of the needle target is crucial for effective epidural anesthesia. Currently, epidural needle placement is administered by a manual technique, relying on the sense of feel, which has a significant failure rate. Moreover, misleading the needle may lead to inadequate anesthesia, post dural puncture headaches, and other potential complications. Ultrasound offers guidance to the physician for identification of the needle target, but accurate interpretation and localization remain challenges. A hybrid machine learning system is proposed to automatically localize the needle target for epidural needle placement in ultrasound images of the spine. In particular, a deep network architecture along with a feature augmentation technique is proposed for automatic identification of the anatomical landmarks of the epidural space in ultrasound images. Experimental results of the target localization on planes of 3 D as well as 2-D images have been compared against an expert sonographer. When compared with the expert annotations, the average lateral and vertical errors on the planes of 3-D test data were 1 and 0.4 mm, respectively. On 2-D test data set, an average lateral error of 1.7 mm and vertical error of 0.8 mm were acquired. PMID- 28809680 TI - High-Performance SAW Resonator on New Multilayered Substrate Using LiTaO3 Crystal. AB - To develop the high-performance filters and duplexers required for recent long term evolution frequency bands in mobile handsets, a surface acoustic wave (SAW) resonator is needed that has a higher quality (Q) and a lower temperature coefficient of frequency (TCF). To achieve this, the authors focused on acoustic energy confinement in the depth direction for a rotated Y-X LiTaO3 (LT) substrate. Characteristics of multilayered substrates with low-impedance and high impedance layers under LT layer were studied numerically in terms of acoustic energy distribution, phase velocity, coupling coefficient, and temperature characteristics employing a finite-element method simulation. After several calculations, a novel multilayered structure was developed that uses SiO2 for a low-impedance layer and AlN for a high-impedance layer under the thin LT layer. A one-port resonator using the new substrate was fabricated, and its experimental results showed that the developed resonator had a Bode-Q over 4000 and TCF of -8 ppm/ degrees C, which are four times higher than and one-fifth as small as those of a conventional 4 degrees YX-LT SAW resonator, respectively. By applying this technology, a band 25 duplexer with very narrow duplex gap was successfully developed, which shows extremely low insertion loss, steep cutoff characteristics, and stable temperature characteristics. PMID- 28809682 TI - An Optimization and Comparative Study of Air-Coupled CMUT Cells With Circular and Annular Geometries. AB - Air-coupled capacitive micromachined ultrasonic transducers (CMUTs) with annular cell geometry have recently been reported to have a promising transmit sensitivity. This paper reports three optimization schemes, which further improve the transmit sensitivity and also help achieve a reasonable comparison between the novel annular and conventional circular cells. Lumped element models of both cell types with laminate plate structures are presented. Based on these models, a design optimization flowchart was constructed to facilitate analytical optimization on the three schemes. Circular and annular CMUTs with a common 97 kHz natural resonance frequency were fabricated and characterized to verify the efficacy of the optimization principle. Using the optimization flowchart, annular and circular cells with frequencies ranging from 100 to 300 kHz were analytically optimized and then compared. The comparison results demonstrate that, given the same dc bias and ac excitation voltage, the output power density at the plate surface of the optimized annular cell is double that of the optimized circular cell. Additionally, when generating the same surface power density, an optimized annular cell requires either half the dc bias or half the ac excitation voltage of an optimized circular cell. This paper provides a practical optimization framework for CMUT cell design and demonstrates the superiority of annular cells for air-coupled applications. PMID- 28809683 TI - Low-Rank Latent Pattern Approximation With Applications to Robust Image Classification. AB - This paper develops a novel method to address the structural noise in samples for image classification. Recently, regression-related classification methods have shown promising results when facing the pixelwise noise. However, they become weak in coping with the structural noise due to ignoring of relationships between pixels of noise image. Meanwhile, most of them need to implement the iterative process for computing representation coefficients, which leads to the high time consumption. To overcome these problems, we exploit a latent pattern model called low-rank latent pattern approximation (LLPA) to reconstruct the test image having structural noise. The rank function is applied to characterize the structure of the reconstruction residual between test image and the corresponding latent pattern. Simultaneously, the error between the latent pattern and the reference image is constrained by Frobenius norm to prevent overfitting. LLPA involves a closed-form solution by the virtue of a singular value thresholding operator. The provided theoretic analysis demonstrates that LLPA indeed removes the structural noise during classification task. Additionally, LLPA is further extended to the form of matrix regression by connecting multiple training samples, and alternating direction of multipliers method with Gaussian back substitution algorithm is used to solve the extended LLPA. Experimental results on several popular data sets validate that the proposed methods are more robust to image classification with occlusion and illumination changes, as compared to some existing state-of-the-art reconstruction-based methods and one deep neural network-based method. PMID- 28809681 TI - A Prototype Therapy System for Transcutaneous Application of Boiling Histotripsy. AB - Boiling histotripsy (BH) is a method of focused ultrasound surgery that noninvasively applies millisecond-length pulses with high-amplitude shock fronts to generate liquefied lesions in tissue. Such a technique requires unique outputs compared to a focused ultrasound thermal therapy apparatus, particularly to achieve high in situ pressure levels through intervening tissue. This paper describes the design and characterization of a system capable of producing the necessary pressure to transcutaneously administer BH therapy through clinically relevant overlying tissue paths using pulses with duration up to 10 ms. A high voltage electronic pulser was constructed to drive a 1-MHz focused ultrasound transducer to produce shock waves with amplitude capable of generating boiling within the pulse duration in tissue. The system output was characterized by numerical modeling with the 3-D Westervelt equation using boundary conditions established by acoustic holography measurements of the source field. Such simulations were found to be in agreement with directly measured focal waveforms. An existing derating method for nonlinear therapeutic fields was used to estimate in situ pressure levels at different tissue depths. The system was tested in ex vivo bovine liver samples to create BH lesions at depths up to 7 cm. Lesions were also created through excised porcine body wall (skin, adipose, and muscle) with 3 5 cm thickness. These results indicate that the system is capable of producing the necessary output for transcutaneous ablation with BH. PMID- 28809684 TI - Combination of Sharing Matrix and Image Encryption for Lossless $(k,n)$ -Secret Image Sharing. AB - This paper first introduces a (k,n) -sharing matrix S(k, n) and its generation algorithm. Mathematical analysis is provided to show its potential for secret image sharing. Combining sharing matrix with image encryption, we further propose a lossless (k,n) -secret image sharing scheme (SMIE-SIS). Only with no less than k shares, all the ciphertext information and security key can be reconstructed, which results in a lossless recovery of original information. This can be proved by the correctness and security analysis. Performance evaluation and security analysis demonstrate that the proposed SMIE-SIS with arbitrary settings of k and n has at least five advantages: 1) it is able to fully recover the original image without any distortion; 2) it has much lower pixel expansion than many existing methods; 3) its computation cost is much lower than the polynomial-based secret image sharing methods; 4) it is able to verify and detect a fake share; and 5) even using the same original image with the same initial settings of parameters, every execution of SMIE-SIS is able to generate completely different secret shares that are unpredictable and non-repetitive. This property offers SMIE-SIS a high level of security to withstand many different attacks. PMID- 28809685 TI - Human Motion Segmentation via Robust Kernel Sparse Subspace Clustering. AB - Studies on human motion have attracted a lot of attentions. Human motion capture data, which much more precisely records human motion than videos do, has been widely used in many areas. Motion segmentation is an indispensable step for many related applications, but current segmentation methods for motion capture data do not effectively model some important characteristics of motion capture data, such as Riemannian manifold structure and containing non-Gaussian noise. In this paper, we convert the segmentation of motion capture data into a temporal subspace clustering problem. Under the framework of sparse subspace clustering, we propose to use the geodesic exponential kernel to model the Riemannian manifold structure, use correntropy to measure the reconstruction error, use the triangle constraint to guarantee temporal continuity in each cluster and use multi-view reconstruction to extract the relations between different joints. Therefore, exploiting some special characteristics of motion capture data, we propose a new segmentation method, which is robust to non-Gaussian noise, since correntropy is a localized similarity measure. We also develop an efficient optimization algorithm based on block coordinate descent method to solve the proposed model. Our optimization algorithm has a linear complexity while sparse subspace clustering is originally a quadratic problem. Extensive experiment results both on simulated noisy data set and real noisy data set demonstrate the advantage of the proposed method.Studies on human motion have attracted a lot of attentions. Human motion capture data, which much more precisely records human motion than videos do, has been widely used in many areas. Motion segmentation is an indispensable step for many related applications, but current segmentation methods for motion capture data do not effectively model some important characteristics of motion capture data, such as Riemannian manifold structure and containing non-Gaussian noise. In this paper, we convert the segmentation of motion capture data into a temporal subspace clustering problem. Under the framework of sparse subspace clustering, we propose to use the geodesic exponential kernel to model the Riemannian manifold structure, use correntropy to measure the reconstruction error, use the triangle constraint to guarantee temporal continuity in each cluster and use multi-view reconstruction to extract the relations between different joints. Therefore, exploiting some special characteristics of motion capture data, we propose a new segmentation method, which is robust to non-Gaussian noise, since correntropy is a localized similarity measure. We also develop an efficient optimization algorithm based on block coordinate descent method to solve the proposed model. Our optimization algorithm has a linear complexity while sparse subspace clustering is originally a quadratic problem. Extensive experiment results both on simulated noisy data set and real noisy data set demonstrate the advantage of the proposed method. PMID- 28809686 TI - Salient Region Detection Using Diffusion Process on a Two-Layer Sparse Graph. AB - Diffusion-based salient region detection has recently received intense research attention. In this paper, we present some effective improvements concerning two important aspects of diffusion-based methods: the construction of the diffusion matrix and the seed vector. First, we construct a two-layer sparse graph, which is generated by connecting each node to its neighboring nodes and the most similar node that shares common boundaries with its neighboring nodes. Compared with the most frequently used two-layer neighborhood graph, our graph not only effectively uses local spatial relationships, but also removes dissimilar redundant nodes. Second, we use the spatial variance of superpixel clusters to obtain the seed vector and, compared with the previously most-used boundary prior, our approach can better distinguish saliency seeds from the background seeds, especially when salient objects appear near the image boundaries. Finally, we calculate two preliminary saliency maps using the saliency and background seed vectors, and more accurate results are obtained using the manifold ranking diffusion method. Integrating these two diffusion-based saliency maps, we obtain the final saliency map. Extensive experiments in which we compare our method with 20 existing state-of-the-art methods on five benchmark data sets: ASD, DUT-OMRON, ECSSD, MSRA5K, and MSRA10K, show that the proposed method performs better in terms of various evaluation metrics. PMID- 28809687 TI - SonifEye: Sonification of Visual Information Using Physical Modeling Sound Synthesis. AB - Sonic interaction as a technique for conveying information has advantages over conventional visual augmented reality methods specially when augmenting the visual field with extra information brings distraction. Sonification of knowledge extracted by applying computational methods to sensory data is a well-established concept. However, some aspects of sonic interaction design such as aesthetics, the cognitive effort required for perceiving information, and avoiding alarm fatigue are not well studied in literature. In this work, we present a sonification scheme based on employment of physical modeling sound synthesis which targets focus demanding tasks requiring extreme precision. Proposed mapping techniques are designed to require minimum training for users to adapt to and minimum mental effort to interpret the conveyed information. Two experiments are conducted to assess the feasibility of the proposed method and compare it against visual augmented reality in high precision tasks. The observed quantitative results suggest that utilizing sound patches generated by physical modeling achieve the desired goal of improving the user experience and general task performance with minimal training. PMID- 28809688 TI - Live User-Guided Intrinsic Video for Static Scenes. AB - We present a novel real-time approach for user-guided intrinsic decomposition of static scenes captured by an RGB-D sensor. In the first step, we acquire a three dimensional representation of the scene using a dense volumetric reconstruction framework. The obtained reconstruction serves as a proxy to densely fuse reflectance estimates and to store user-provided constraints in three-dimensional space. User constraints, in the form of constant shading and reflectance strokes, can be placed directly on the real-world geometry using an intuitive touch-based interaction metaphor, or using interactive mouse strokes. Fusing the decomposition results and constraints in three-dimensional space allows for robust propagation of this information to novel views by re-projection. We leverage this information to improve on the decomposition quality of existing intrinsic video decomposition techniques by further constraining the ill-posed decomposition problem. In addition to improved decomposition quality, we show a variety of live augmented reality applications such as recoloring of objects, relighting of scenes and editing of material appearance. PMID- 28809689 TI - Natural Environment Illumination: Coherent Interactive Augmented Reality for Mobile and Non-Mobile Devices. AB - Augmented Reality offers many applications today, especially on mobile devices. Due to the lack of mobile hardware for illumination measurements, photorealistic rendering with consistent appearance of virtual objects is still an area of active research. In this paper, we present a full two-stage pipeline for environment acquisition and augmentation of live camera images using a mobile device with a depth sensor. We show how to directly work on a recorded 3D point cloud of the real environment containing high dynamic range color values. For unknown and automatically changing camera settings, a color compensation method is introduced. Based on this, we show photorealistic augmentations using variants of differential light simulation techniques. The presented methods are tailored for mobile devices and run at interactive frame rates. However, our methods are scalable to trade performance for quality and can produce quality renderings on desktop hardware. PMID- 28809690 TI - Occlusion Leak Compensation for Optical See-Through Displays Using a Single-Layer Transmissive Spatial Light Modulator. AB - We propose an occlusion compensation method for optical see-through head-mounted displays (OST-HMDs) equipped with a singlelayer transmissive spatial light modulator (SLM), in particular, a liquid crystal display (LCD). Occlusion is an important depth cue for 3D perception, yet realizing it on OST-HMDs is particularly difficult due to the displays' semitransparent nature. A key component for the occlusion support is the SLM-a device that can selectively interfere with light rays passing through it. For example, an LCD is a transmissive SLM that can block or pass incoming light rays by turning pixels black or transparent. A straightforward solution places an LCD in front of an OST HMD and drives the LCD to block light rays that could pass through rendered virtual objects at the viewpoint. This simple approach is, however, defective due to the depth mismatch between the LCD panel and the virtual objects, leading to blurred occlusion. This led existing OST-HMDs to employ dedicated hardware such as focus optics and multi-stacked SLMs. Contrary to these viable, yet complex and/or computationally expensive solutions, we return to the single-layer LCD approach for the hardware simplicity while maintaining fine occlusion-we compensate for a degraded occlusion area by overlaying a compensation image. We compute the image based on the HMD parameters and the background scene captured by a scene camera. The evaluation demonstrates that the proposed method reduced the occlusion leak error by 61.4% and the occlusion error by 85.7%. PMID- 28809691 TI - FaceForge: Markerless Non-Rigid Face Multi-Projection Mapping. AB - Recent publications and art performances demonstrate amazing results using projection mapping. To our knowledge, there exists no multi-projection system that can project onto non-rigid target geometries. This constrains the applicability and quality for live performances with multiple spectators. Given the cost and complexity of current systems, we present a low-cost easy-to-use markerless non-rigid face multi-projection system. It is based on a non-rigid, dense face tracker and a real-time multi-projection solver adapted to imprecise tracking, geometry and calibration. Using this novel system we produce compelling results with only consumer-grade hardware. PMID- 28809692 TI - Dense Visual SLAM with Probabilistic Surfel Map. AB - Visual SLAM is one of the key technologies to align the virtual and real world together in Augmented Reality applications. RGBD dense Visual SLAM approaches have shown their advantages in robustness and accuracy in recent years. However, there are still several challenges such as the inconsistencies in RGBD measurements across multiple frames that could jeopardize the accuracy of both camera trajectory and scene reconstruction. In this paper, we propose a novel map representation called Probabilistic Surfel Map (PSM) for dense visual SLAM. The main idea is to maintain a globally consistent map with both photometric and geometric uncertainties encoded in order to address the inconsistency issue. The key of our PSM is proper modeling and updating of sensor measurement uncertainties, as well as the strategies to apply them for improving both the front-end pose estimation and the back-end optimization. Experimental results on publicly available datasets demonstrate major improvements with our approach over the state-of-the-art methods. Specifically, comparing with sigma-DVO, we achieve a 40% reduction in absolute trajectory error and an 18% reduction in relative pose error in visual odometry, as well as an 8.5% reduction in absolute trajectory error in complete SLAM. Moreover, our PSM enables generation of a high quality dense point cloud with comparable accuracy as the state-of-the-art approach. PMID- 28809693 TI - Simultaneous Projection and Positioning of Laser Projector Pixels. AB - This paper presents a novel projected pixel localization principle for online geometric registration in dynamic projection mapping applications. We propose applying a time measurement of a laser projector raster-scanning beam using a photosensor to estimate its position while the projector displays meaningful visual information to human observers. Based on this principle, we develop two types of position estimation techniques. One estimates the position of a projected beam when it directly illuminates a photosensor. The other localizes a beam by measuring the reflection from a retro-reflective marker with the photosensor placed in the optical path of the projector. We conduct system evaluations using prototypes to validate this method as well as to confirm the applicability of our principle. In addition, we discuss the technical limitations of the prototypes based on the evaluation results. Finally, we build several dynamic projection mapping applications to demonstrate the feasibility of our principle. PMID- 28809694 TI - A Multiple-View Geometric Model of Specularities on Non-Planar Shapes with Application to Dynamic Retexturing. AB - Predicting specularities in images, given the camera pose and scene geometry from SLAM, forms a challenging and open problem. It is nonetheless essential in several applications such as retexturing. A recent geometric model called JOLIMAS partially answers this problem, under the assumptions that the specularities are elliptical and the scene is planar. JOLIMAS models a moving specularity as the image of a fixed 3D quadric. We propose dual JOLIMAS, a new model which raises the planarity assumption. It uses the fact that specularities remain elliptical on convex surfaces and that every surface can be divided in convex parts. The geometry of dual JOLIMAS then uses a 3D quadric per convex surface part and light source, and predicts the specularities by a means of virtual cameras, allowing it to cope with surface's unflatness. We assessed the efficiency and precision of dual JOLIMAS on multiple synthetic and real videos with various objects and lighting conditions. We give results of a retexturing application. Further results are presented as supplementary video material. PMID- 28809695 TI - Looking Beyond the Simple Scenarios: Combining Learners and Optimizers in 3D Temporal Tracking. AB - 3D object temporal trackers estimate the 3D rotation and 3D translation of a rigid object by propagating the transformation from one frame to the next. To confront this task, algorithms either learn the transformation between two consecutive frames or optimize an energy function to align the object to the scene. The motivation behind our approach stems from a consideration on the nature of learners and optimizers. Throughout the evaluation of different types of objects and working conditions, we observe their complementary nature - on one hand, learners are more robust when undergoing challenging scenarios, while optimizers are prone to tracking failures due to the entrapment at local minima; on the other, optimizers can converge to a better accuracy and minimize jitter. Therefore, we propose to bridge the gap between learners and optimizers to attain a robust and accurate RGB-D temporal tracker that runs at approximately 2 ms per frame using one CPU core. Our work is highly suitable for Augmented Reality (AR), Mixed Reality (MR) and Virtual Reality (VR) applications due to its robustness, accuracy, efficiency and low latency. Aiming at stepping beyond the simple scenarios used by current systems, often constrained by having a single object in the absence of clutter, averting to touch the object to prevent close-range partial occlusion or selecting brightly colored objects to easily segment them individually, we demonstrate the capacity to handle challenging cases under clutter, partial occlusion and varying lighting conditions. PMID- 28809696 TI - Real-Time View Correction for Mobile Devices. AB - We present a real-time method for rendering novel virtual camera views from given RGB-D (color and depth) data of a different viewpoint. Missing color and depth information due to incomplete input or disocclusions is efficiently inpainted in a temporally consistent way. The inpainting takes the location of strong image gradients into account as likely depth discontinuities. We present our method in the context of a view correction system for mobile devices, and discuss how to obtain a screen-camera calibration and options for acquiring depth input. Our method has use cases in both augmented and virtual reality applications. We demonstrate the speed of our system and the visual quality of its results in multiple experiments in the paper as well as in the supplementary video. PMID- 28809697 TI - Geometric and Photometric Consistency in a Mixed Video and Galvanoscopic Scanning Laser Projection Mapping System. AB - We present a geometric calibration method to accurately register a galvanoscopic scanning laser projection system (GLP) based on 2D vector input data onto an arbitrarily complex 3D-shaped projection surface. This method allows for accurate merging of 3D vertex data displayed on the laser projector with geometrically calibrated standard rasterization-based video projectors that are registered to the same geometry. Because laser projectors send out a laser light beam via galvanoscopic mirrors, a standard pinhole model calibration procedure that is normally used for pixel raster displays projecting structured light patterns, such as Gray codes, cannot be carried out directly with sufficient accuracy as the rays do not converge into a single point. To overcome the complications of accurately registering the GLP while still enabling a treatment equivalent to a standard pinhole device, an adapted version is applied to enable straightforward content generation. Besides the geometrical calibration, we also present a photometric calibration to unify the color appearance of GLPs and standard video projectors maximizing the advantages of the large color gamut of the GLP and optimizing its color appearance to smoothly fade into the significantly smaller gamut of the video projector. The proposed algorithms were evaluated on a prototypical mixed video projector and GLP projection mapping setup. PMID- 28809698 TI - Deep 6-DOF Tracking. AB - We present a temporal 6-DOF tracking method which leverages deep learning to achieve state-of-the-art performance on challenging datasets of real world capture. Our method is both more accurate and more robust to occlusions than the existing best performing approaches while maintaining real-time performance. To assess its efficacy, we evaluate our approach on several challenging RGBD sequences of real objects in a variety of conditions. Notably, we systematically evaluate robustness to occlusions through a series of sequences where the object to be tracked is increasingly occluded. Finally, our approach is purely data driven and does not require any hand-designed features: robust tracking is automatically learned from data. PMID- 28809699 TI - AR Feels "Softer" than VR: Haptic Perception of Stiffness in Augmented versus Virtual Reality. AB - Does it feel the same when you touch an object in Augmented Reality (AR) or in Virtual Reality (VR)? In this paper we study and compare the haptic perception of stiffness of a virtual object in two situations: (1) a purely virtual environment versus (2) a real and augmented environment. We have designed an experimental setup based on a Microsoft HoloLens and a haptic force-feedback device, enabling to press a virtual piston, and compare its stiffness successively in either Augmented Reality (the virtual piston is surrounded by several real objects all located inside a cardboard box) or in Virtual Reality (the same virtual piston is displayed in a fully virtual scene composed of the same other objects). We have conducted a psychophysical experiment with 12 participants. Our results show a surprising bias in perception between the two conditions. The virtual piston is on average perceived stiffer in the VR condition compared to the AR condition. For instance, when the piston had the same stiffness in AR and VR, participants would select the VR piston as the stiffer one in 60% of cases. This suggests a psychological effect as if objects in AR would feel "softer" than in pure VR. Taken together, our results open new perspectives on perception in AR versus VR, and pave the way to future studies aiming at characterizing potential perceptual biases. PMID- 28809700 TI - Cognitive Cost of Using Augmented Reality Displays. AB - This paper presents the results of two cognitive load studies comparing three augmented reality display technologies: spatial augmented reality, the optical see-through Microsoft HoloLens, and the video see-through Samsung Gear VR. In particular, the two experiments focused on isolating the cognitive load cost of receiving instructions for a button-pressing procedural task. The studies employed a self-assessment cognitive load methodology, as well as an additional dual-task cognitive load methodology. The results showed that spatial augmented reality led to increased performance and reduced cognitive load. Additionally, it was discovered that a limited field of view can introduce increased cognitive load requirements. The findings suggest that some of the inherent restrictions of head-mounted displays materialize as increased user cognitive load. PMID- 28809701 TI - Fuzzy Object Skeletonization: Theory, Algorithms, and Applications. AB - Skeletonization offers a compact representation of an object while preserving important topological and geometrical features. Literature on skeletonization of binary objects is quite mature. However, challenges involved with skeletonization of fuzzy objects are mostly unanswered. This paper presents a new theory and algorithm of skeletonization for fuzzy objects, evaluates its performance, and demonstrates its applications. A formulation of fuzzy grassfire propagation is introduced; its relationships with fuzzy distance functions, level sets, and geodesics are discussed; and several new theoretical results are presented in the continuous space. A notion of collision-impact of fire-fronts at skeletal points is introduced, and its role in filtering noisy skeletal points is demonstrated. A fuzzy object skeletonization algorithm is developed using new notions of surface- and curve-skeletal voxels, digital collision-impact, filtering of noisy skeletal voxels, and continuity of skeletal surfaces. A skeletal noise pruning algorithm is presented using branch-level significance. Accuracy and robustness of the new algorithm are examined on computer-generated phantoms and micro- and conventional CT imaging of trabecular bone specimens. An application of fuzzy object skeletonization to compute structure-width at a low image resolution is demonstrated, and its ability to predict bone strength is examined. Finally, the performance of the new fuzzy object skeletonization algorithm is compared with two binary object skeletonization methods. PMID- 28809702 TI - Improved Alpha Testing Using Hashed Sampling. AB - We further describe and analyze the idea of hashed alpha testing from Wyman and McGuire [1], which builds on stochastic alpha testing and simplifies stochastic transparency. Typically, alpha testing provides a simple mechanism to mask out complex silhouettes using simple proxy geometry with applied alpha textures. While widely used, alpha testing has a long-standing problem: geometry can disappear entirely as alpha mapped polygons recede with distance. As foveated rendering for virtual reality spreads, this problem worsens as peripheral minification and prefiltering introduce this problem on nearby objects. PMID- 28809703 TI - Motion-Based Rapid Serial Visual Presentation for Gaze-Independent Brain-Computer Interfaces. AB - Most event-related potential (ERP)-based brain-computer interface (BCI) spellers primarily use matrix layouts and generally require moderate eye movement for successful operation. The fundamental objective of this paper is to enhance the perceptibility of target characters by introducing motion stimuli to classical rapid serial visual presentation (RSVP) spellers that do not require any eye movement, thereby applying them to paralyzed patients with oculomotor dysfunctions. To test the feasibility of the proposed motion-based RSVP paradigm, we implemented three RSVP spellers: 1) fixed-direction motion (FM-RSVP); 2) random-direction motion (RM-RSVP); and 3) (the conventional) non-motion stimulation (NM-RSVP), and evaluated the effect of the three different stimulation methods on spelling performance. The two motion-based stimulation methods, FM- and RM-RSVP, showed shorter P300 latency and higher P300 amplitudes (i.e., 360.4-379.6 ms; 5.5867- ) than the NM-RSVP (i.e., 480.4 ms; ). This led to higher and more stable performances for FM- and RM-RSVP spellers than NM-RSVP speller (i.e., 79.06+/-6.45% for NM-RSVP, 90.60+/-2.98% for RM-RSVP, and 92.74+/ 2.55% for FM-RSVP). In particular, the proposed motion-based RSVP paradigm was significantly beneficial for about half of the subjects who might not accurately perceive rapidly presented static stimuli. These results indicate that the use of proposed motion-based RSVP paradigm is more beneficial for target recognition when developing BCI applications for severely paralyzed patients with complex ocular dysfunctions. PMID- 28809704 TI - Kilohertz Electrical Stimulation Nerve Conduction Block: Effects of Electrode Material. AB - Kilohertz electrical stimulation (KES) has enabled a novel new paradigm for spinal cord and peripheral nerve stimulation to treat a variety of neurological diseases. KES can excite or inhibit nerve activity and is used in many clinical devices today. However, the impact of different electrode materials on the efficacy of KES is unknown. We investigated the effect of different electrode materials and their respective charge injection mechanisms on KES nerve block thresholds using 20- and 40-kHz current-controlled sinusoidal KES waveforms. We evaluated the nerve block threshold and the power requirements for achieving an effective KES nerve block. In addition, we evaluated potential effects on the onset duration and recovery of normal conduction after delivery of KES. We found that thresholds and the onset and recovery of KES nerve block are not a function of the electrode material. In contrast, the power dissipation varies among electrode materials and is a function of the materials' properties at high frequencies. We conclude that materials with a proven track record of chronic stability, both for the tissue and electrode, are suitable for developing KES nerve block therapies. PMID- 28809705 TI - Effects of Continuous Kinaesthetic Feedback Based on Tendon Vibration on Motor Imagery BCI Performance. AB - BACKGROUND AND OBJECTIVES: Feedback plays a crucial role for using brain computer interface systems. This paper proposes the use of vibration-evoked kinaesthetic illusions as part of a novel multisensory feedback for a motor imagery (MI)-based BCI and investigates its contributions in terms of BCI performance and electroencephalographic (EEG) correlates. METHODS: sixteen subjects performed two different right arm MI-BCI sessions: with the visual feedback only and with both visual and vibration-evoked kinaesthetic feedback, conveyed by the stimulation of the biceps brachi tendon. In both conditions, the sensory feedback was driven by the MI-BCI. The rich and more natural multisensory feedback was expected to facilitate the execution of MI, and thus to improve the performance of the BCI. The EEG correlates of the proposed feedback were also investigated with and without the performing of MI. RESULTS AND CONCLUSIONS: the contribution of vibration-evoked kinaesthetic feedback led to statistically higher BCI performance (Anova, F(1,14) = 18.1, p < .01) and more stable EEG event-related desynchronization. Obtained results suggest promising application of the proposed method in neuro-rehabilitation scenarios: the advantage of an improved usability could make the MI-BCIs more applicable for those patients having difficulties in performing kinaesthetic imagery. PMID- 28809706 TI - Cluster Synchronization of Coupled Genetic Regulatory Networks With Delays via Aperiodically Adaptive Intermittent Control. AB - In this paper, we study the cluster synchronization of coupled genetic regulatory networks with time-varying delays via aperiodically adaptive intermittent control on some nodes. The network is intermittently coupled and the intra-cluster coupling strength is adaptively adjusted. The graph of the coupling topology of each cluster is only required to have a directed spanning tree. Two cases of delays are considered. In the first case, by using the switching Lyapunov-based function and Razumikhin-type technique, the cluster synchronization criterion is presented which indicates that the cluster synchronization is realized via the aperiodically adaptive intermittent control. The second case is investigated by using the switching Lyapunov functional. Both the cluster synchronization criteria are established by the Linear Matrix Inequalities (LMIs), the lower bound of the aperiodical time span, and the maximum uncontrolled ratio. It is shown that the results are applicable to both the situations that the upper bound of the delay is larger and smaller than the lower bound of the aperiodical coupling and control width. Numerical simulations are carried out to illustrate the theoretical results. PMID- 28809707 TI - A Streaming PCA VLSI Chip for Neural Data Compression. AB - Neural recording system miniaturization and integration with low-power wireless technologies require compressing neural data before transmission. Feature extraction is a procedure to represent data in a low-dimensional space; its integration into a recording chip can be an efficient approach to compress neural data. In this paper, we propose a streaming principal component analysis algorithm and its microchip implementation to compress multichannel local field potential (LFP) and spike data. The circuits have been designed in a 65-nm CMOS technology and occupy a silicon area of 0.06 mm. Throughout the experiments, the chip compresses LFPs by 10 at the expense of as low as 1% reconstruction errors and 144-nW/channel power consumption; for spikes, the achieved compression ratio is 25 with 8% reconstruction errors and 3.05-W/channel power consumption. In addition, the algorithm and its hardware architecture can swiftly adapt to nonstationary spiking activities, which enables efficient hardware sharing among multiple channels to support a high-channel count recorder. PMID- 28809708 TI - On Multiple AER Handshaking Channels Over High-Speed Bit-Serial Bidirectional LVDS Links With Flow-Control and Clock-Correction on Commercial FPGAs for Scalable Neuromorphic Systems. AB - Address event representation (AER) is a widely employed asynchronous technique for interchanging "neural spikes" between different hardware elements in neuromorphic systems. Each neuron or cell in a chip or a system is assigned an address (or ID), which is typically communicated through a high-speed digital bus, thus time-multiplexing a high number of neural connections. Conventional AER links use parallel physical wires together with a pair of handshaking signals (request and acknowledge). In this paper, we present a fully serial implementation using bidirectional SATA connectors with a pair of low-voltage differential signaling (LVDS) wires for each direction. The proposed implementation can multiplex a number of conventional parallel AER links for each physical LVDS connection. It uses flow control, clock correction, and byte alignment techniques to transmit 32-bit address events reliably over multiplexed serial connections. The setup has been tested using commercial Spartan6 FPGAs attaining a maximum event transmission speed of 75 Meps (Mega events per second) for 32-bit events at a line rate of 3.0 Gbps. Full HDL codes (vhdl/verilog) and example demonstration codes for the SpiNNaker platform will be made available. PMID- 28809709 TI - A New Method for Automatic Sleep Stage Classification. AB - Traditionally, automatic sleep stage classification is quite a challenging task because of the difficulty in translating open-textured standards to mathematical models and the limitations of handcrafted features. In this paper, a new system for automatic sleep stage classification is presented. Compared with existing sleep stage methods, our method can capture the sleep information hidden inside electroencephalography (EEG) signals and automatically extract features from raw data. To translate open sleep stage standards into machine rules recognized by computers, a new model named fast discriminative complex-valued convolutional neural network (FDCCNN) is proposed to extract features from raw EEG data and classify sleep stages. The new model combines complex-valued backpropagation and the Fisher criterion. It can learn discriminative features and overcome the negative effect of imbalance dataset. More importantly, the orthogonal decision boundaries for the real and imaginary parts of a complex-valued convolutional neuron are proven. A speed-up algorithm is proposed to reduce computational workload and yield improvements of over an order of magnitude compared to the normal convolution algorithm. The classification performances of handcrafted features and different convolutional neural networks are compared with that of the FDCCNN. The total accuracy and kappa coefficient of the proposed method are 92% and 0.84, respectively. Experiment results demonstrated that the performance of our system is comparable to those of human experts. PMID- 28809710 TI - Double-Mode Microparticle Manipulation by Tunable Secondary Flow in Microchannel With Arc-Shaped Groove Arrays. AB - In this paper, we proposed a microparticle manipulation approach, by which particles are able to be guided to different equilibrium positions through modulating the Reynolds number. In the microchannel with arc-shaped groove arrays, secondary flow vortex arisen due to the pressure gradient varies in the aspects of both magnitude and shape with the increase of Reynolds number. And the variation of secondary flow vortex brings about different focusing modes of microparticles in the microchannel. We investigated the focusing phenomenon experimentally and analyzed the mechanism through numerical simulations. At a high Reynolds number (Re = 127.27), the geometry-induced secondary flow rotates constantly along a direction, and most particles are guided to the equilibrium position near one side of the microchannel. However, at a low Reynolds number (Re = 2.39), the shapes of geometry-induced secondary flow vortices are obviously different, forming a variant Dean-like vortex that consists of two asymmetric counter-rotating streams in cross sections of the straight channel. Because of the periodical effects, suspended particles are concentrated at another equilibrium position on the opposite side of the microchannel. Meanwhile, the effects of particle size influence both the focusing position and quality in regimes. PMID- 28809711 TI - Distinct Motion of GFP-Tagged Histone Expressing Cells Under AC Electrokinetics in Electrode-Multilayered Microfluidic Device. AB - The distinct motion of GFP-tagged histone expressing cells (Histone-GFP type cells) has been investigated under ac electrokinetics in an electrode multilayered microfluidic device as compared with Wild type cells and GFP type cells in terms of different intracellular components. The Histone-GFP type cells were modified by the transfection of green fluorescent protein-fused histone from the human lung fibroblast cell line. The velocity of the Histone-GFP type cells obtained by particle tracking velocimetry technique is faster than Wild type cells by 24.9% and GFP type cells by 57.1%. This phenomenon is caused by the more amount of proteins in the intracellular of single Histone-GFP type cell than that of the Wild type and GFP type cells. The more amount of proteins in the Histone GFP type cells corresponds to a lower electric permittivity epsilonc of the cells, which generates a lower dielectrophoretic force exerting on the cells. The velocity of Histone-GFP type cells is well agreed with Eulerian-Lagrangian two phase flow simulation by 4.2% mean error, which proves that the fluid motion driven by thermal buoyancy and electrothermal force dominates the direction of cells motion, while the distinct motion of Histone-GFP type cells is caused by dielectrophoretic force. The fluid motion does not generate a distinct drag motion for Histone-GFP type cells because the Histone-GFP type cells have the same size to the Wild type and GFP type cells. These results clarified the mechanism of cells motion in terms of intracellular components, which helps to improve the cell manipulation efficiency with electrokinetics. PMID- 28809712 TI - A Novel Intracranial Pressure Readout Circuit for Passive Wireless LC Sensor. AB - We present a wide frequency range, low cost, wireless intracranial pressure monitoring system, which includes an implantable passive sensor and an external reader. The passive sensor consists of two spiral coils and transduces the pressure change to a resonant frequency shift. The external portable reader reads out the sensor's resonant frequency over a wide frequency range (35 MHz-2.7 GHz). We propose a novel circuit topology, which tracks the system's impedance and phase change at a high frequency with low-cost components. This circuit is very simple and reliable. A prototype has been developed, and measurement results demonstrate that the device achieves a suitable measurement distance (>2 cm), sufficient sample frequency (>6 Hz), fine resolution, and good measurement accuracy for medical practice. Responsivity of this prototype is 0.92 MHz/mmHg and resolution is 0.028 mmHg. COMSOL specific absorption rate simulation proves that this system is safe. Considerations to improve the device performance have been discussed, which include the size of antenna, the power radiation, the Analog-to-digital converter (ADC) choice, and the signal processing algorithm. PMID- 28809713 TI - A Survey on Biofeedback and Actuation in Wireless Body Area Networks (WBANs). AB - Wireless body area networks (WBANs) have attained increasing popularity as the next generation framework of wearable technologies for human monitoring. Invasive or noninvasive wearable sensors designed in a WBAN are worn to gather vital information. Biofeedback is a recent concept where collected data are used to generate actuation signals in WBANs. Applications can be seen in various areas such as sports (e.g., locomotor velocity) or medicine (e.g., blood pressure measurement). However, since the body is closely regulated, the next generation WBAN technology must be smart enough to react to monitored data. The main aim of this paper is to review the current state of biofeedback and actuation technology on WBANs in terms of its structure, applications, benefits, and control approaches. The emphasis on the specific requirements when applying biofeedback to humans will be highlighted and discussed. Challenges and open research issues will be concluded at the end. PMID- 28809714 TI - Avoiding Congestion in Cluster Consensus of the Second-Order Nonlinear Multiagent Systems. AB - In order to avoid congestion in the second-order nonlinear leader-following multiagent systems over capacity-limited paths, an approach called cluster lag consensus is proposed, which means that the agents in different clusters will pass through the same positions with the same velocities but lag behind the leader at different times. Lyapunov functionals and matrix theory are applied to analyze such cluster lag consensus. It is shown that when the graphic roots of clusters are influenced by the leader and the intracoupling of cluster agents is larger than a threshold, the cluster lag consensus can be achieved. Furthermore, the cluster lag consensus with a time-varying communication topology is investigated. Finally, an illustrative example is presented to demonstrate the effectiveness of the theoretical results. In particular, when the physical sizes of the agents are taken into consideration, it is shown that with a rearrangement and a position transformation, the multiagent system will reach cluster lag consensus in the new coordinate system. This means that all agents in the same cluster will reach consensus on the velocity, but their positions may be different and yet their relative positions converge to a constant asymptotically. PMID- 28809715 TI - Prescribed Performance Control of Uncertain Euler-Lagrange Systems Subject to Full-State Constraints. AB - This paper studies the zero-error tracking control problem of Euler-Lagrange systems subject to full-state constraints and nonparametric uncertainties. By blending an error transformation with barrier Lyapunov function, a neural adaptive tracking control scheme is developed, resulting in a solution with several salient features: 1) the control action is continuous and smooth; 2) the full-state tracking error converges to a prescribed compact set around origin within a given finite time at a controllable rate of convergence that can be uniformly prespecified; 3) with Nussbaum gain in the loop, the tracking error further shrinks to zero as ; and 4) the neural network (NN) unit can be safely included in the loop during the entire system operational envelope without the danger of violating the compact set precondition imposed on the NN training inputs. Furthermore, by using the Lyapunov analysis, it is proven that all the signals of the closed-loop systems are semiglobally uniformly ultimately bounded. The effectiveness and benefits of the proposed control method are validated via computer simulation. PMID- 28809716 TI - Structured Weak Semantic Space Construction for Visual Categorization. AB - Visual features have been widely used for image representation and categorization. However, visual features are often inconsistent with human perception. Besides, constructing explicit semantic space is still an open problem. To alleviate these two problems, in this paper, we propose to construct structured weak semantic space for image representation. Exemplar classifier is first trained to separate each training image from other images for weak semantic space construction. However, each exemplar classifier separates one training image from other images, and it only has limited semantic separability. Besides, the outputs of exemplar classifiers are inconsistent with each other. We jointly construct the weak semantic space using structured constraint. This is achieved by imposing low-rank constraint on the outputs of exemplar classifiers with sparsity constraint. An alternative optimization procedure is used to learn the exemplar classifiers. Since the proposed method does not dependent on the initial image representation strategy, we can make use of various visual features for efficient exemplar classifier training (e.g., fisher vector-based methods and convolutional neural networks-based methods). We apply the proposed structured weak semantic space-based image representation method for categorization. The experimental results on several public image data sets prove the effectiveness of the proposed method. PMID- 28809717 TI - Multiview Privileged Support Vector Machines. AB - Multiview learning (MVL), by exploiting the complementary information among multiple feature sets, can improve the performance of many existing learning tasks. Support vector machine (SVM)-based models have been frequently used for MVL. A typical SVM-based MVL model is SVM-2K, which extends SVM for MVL by using the distance minimization version of kernel canonical correlation analysis. However, SVM-2K cannot fully unleash the power of the complementary information among different feature views. Recently, a framework of learning using privileged information (LUPI) has been proposed to model data with complementary information. Motivated by LUPI, we propose a new multiview privileged SVM model, multi-view privileged SVM model (PSVM-2V), for MVL. This brings a new perspective that extends LUPI to MVL. The optimization of PSVM-2V can be solved by the classical quadratic programming solver. We theoretically analyze the performance of PSVM-2V from the viewpoints of the consensus principle, the generalization error bound, and the SVM-2K learning model. Experimental results on 95 binary data sets demonstrate the effectiveness of the proposed method. PMID- 28809718 TI - Integration of Semantic and Episodic Memories. AB - This paper describes the integration of semantic and episodic memory (EM) models and the benefits of such integration. Semantic memory (SM) is used as a foundation of knowledge and concept learning, and is needed for the operation of any cognitive system. EM retains personal experiences stored based on their significance-it is supported by the SM, and in return, it supports SM operations. Integrated declarative memories are critical for cognitive system development, yet very little research has been done to develop their computational models. We considered structural self-organization of both semantic and episodic memories with a symbolic representation of input events. Sequences of events are stored in EM and are used to build associations in SM. We demonstrated that integration of semantic and episodic memories improves the native operation of both types of memories. Experimental results are presented to illustrate how the two memories complement each other by improving recognition, prediction, and context-based generalization of individual memories. PMID- 28809719 TI - Hybrid Fuzzy Wavelet Neural Networks Architecture Based on Polynomial Neural Networks and Fuzzy Set/Relation Inference-Based Wavelet Neurons. AB - This paper presents a hybrid fuzzy wavelet neural network (HFWNN) realized with the aid of polynomial neural networks (PNNs) and fuzzy inference-based wavelet neurons (FIWNs). Two types of FIWNs including fuzzy set inference-based wavelet neurons (FSIWNs) and fuzzy relation inference-based wavelet neurons (FRIWNs) are proposed. In particular, a FIWN without any fuzzy set component (viz., a premise part of fuzzy rule) becomes a wavelet neuron (WN). To alleviate the limitations of the conventional wavelet neural networks or fuzzy wavelet neural networks whose parameters are determined based on a purely random basis, the parameters of wavelet functions standing in FIWNs or WNs are initialized by using the C-Means clustering method. The overall architecture of the HFWNN is similar to the one of the typical PNNs. The main strategies in the design of HFWNN are developed as follows. First, the first layer of the network consists of FIWNs (e.g., FSIWN or FRIWN) that are used to reflect the uncertainty of data, while the second and higher layers consist of WNs, which exhibit a high level of flexibility and realize a linear combination of wavelet functions. Second, the parameters used in the design of the HFWNN are adjusted through genetic optimization. To evaluate the performance of the proposed HFWNN, several publicly available data are considered. Furthermore a thorough comparative analysis is covered. PMID- 28809720 TI - Aperiodic Robust Model Predictive Control for Constrained Continuous-Time Nonlinear Systems: An Event-Triggered Approach. AB - The event-triggered control is a promising solution to cyber-physical systems, such as networked control systems, multiagent systems, and large-scale intelligent systems. In this paper, we propose an event-triggered model predictive control (MPC) scheme for constrained continuous-time nonlinear systems with bounded disturbances. First, a time-varying tightened state constraint is computed to achieve robust constraint satisfaction, and an event-triggered scheduling strategy is designed in the framework of dual-mode MPC. Second, the sufficient conditions for ensuring feasibility and closed-loop robust stability are developed, respectively. We show that robust stability can be ensured and communication load can be reduced with the proposed MPC algorithm. Finally, numerical simulations and comparison studies are performed to verify the theoretical results. PMID- 28809721 TI - POSE: Prediction-Based Opportunistic Sensing for Energy Efficiency in Sensor Networks Using Distributed Supervisors. AB - This paper presents a distributed supervisory control algorithm that enables opportunistic sensing for energy-efficient target tracking in a sensor network. The algorithm called Prediction-based Opportunistic Sensing (POSE), is a distributed node-level energy management approach for minimizing energy usage. Distributed sensor nodes in the POSE network self-adapt to target trajectories by enabling high power consuming devices when they predict that a target is arriving in their coverage area, while enabling low power consuming devices when the target is absent. Each node has a Probabilistic Finite State Automaton which acts as a supervisor to dynamically control its various sensing and communication devices based on target's predicted position. The POSE algorithm is validated by extensive Monte Carlo simulations and compared with random scheduling schemes. The results show that the POSE algorithm provides significant energy savings while also improving track estimation via fusion-driven state initialization. PMID- 28809722 TI - Classification for Assessing the Quality of Diagnostic Coronary Angiography. AB - Coronary angiography remains the gold standard for diagnosing obstructive coronary artery disease. However, no standardized, objective, and quantitative classification to assess the quality of coronary angiography exists. In the present report, we sought to establish a novel standardized quantitative classification for the quality of coronary angiography, taking into consideration two main parameters: coronary contrast filling and coronary sinus contrast reflux. Intraobserver and interobserver reproducibility performed among 70 angiograms and 9 readers demonstrated excellent and substantial reproducibility, respectively. The proposed classification may be useful in daily practice, clinician training, and clinical trials. PMID- 28809723 TI - Nitroglycerin-Derived Pd/Pa for the Assessment of Intermediate Coronary Lesions. AB - OBJECTIVES: To assess the predictive value of Pd/Pa after nitroglycerin administration (Pd/Pa[N]) as compared with standard fractional flow reserve (FFR). METHODS: Consecutive patients with intermediate coronary lesions assessed by FFR between January 2014 and October 2015 were included. We measured Pd/Pa at baseline, Pd/Pa(N), and Pd/Pa after incremental doses of intracoronary adenosine. RESULTS: A total of 134 patients (27% females; mean age, 65 years) were included. The diagnostic performance of Pd/Pa(N) and identification of cut-off value for Pd/Pa(N) compared with FFR threshold of 0.8 using receiver-operating characteristic (ROC) area under the curve analysis was between 0.98 (95% confidence interval, 0.95-1.00; P<.05) for 48 MUg and 0.86 (95% confidence interval, 0.79-0.94; P<.05) for 240 MUg adenosine. Pd/Pa(N) <=0.8 had 100% positive predictive value. Pd/Pa(N) >=0.94 provided 100% negative predictive value with a high sensitivity (>92%). Optimal diagnostic accuracy of Pd/Pa(N) was achieved for values <=0.84. The Pearson's correlation between Pd/Pa(N) and FFR varied between 0.89 for 24 MUg adenosine and 0.77 for 240 MUg (P<.01). CONCLUSION: Pd/Pa(N) values can be used for diagnosis of hemodynamically significant lesions. Pd/Pa(N) correlates well with standard FFR. Pd/Pa(N) cut-off of <=0.8 can be considered significant without need for adenosine injection. The value of using adenosine whenever Pd/Pa(N) is >=0.94 is limited. PMID- 28809724 TI - Comparison of Hemostasis Times With a Kaolin-Based Hemostatic Pad (QuikClot Radial) vs Mechanical Compression (TR Band) Following Transradial Access: A Pilot Prospective Study. AB - BACKGROUND: Hemostasis following transradial access (TRA) is usually achieved by mechanical compression. We investigated use of the QuikClot Radial hemostasis pad (Z-Medica) compared with the TR Band (Terumo Medical) to shorten hemostasis after TRA. METHODS: Thirty patients undergoing TRA coronary angiography and/or percutaneous coronary intervention were randomized into three cohorts post TRA: 10 patients received mechanical compression with the TR Band, 10 patients received 30 min of compression with the QuikClot Radial pad, and 10 patients received 60 min of compression with the QuikClot Radial pad. Times to hemostasis and access-site complications were recorded. Radial artery patency was evaluated 1 hour after hemostasis by the reverse Barbeau's test. RESULTS: There were no differences in patient characteristics, mean dose of heparin (7117 +/- 1054 IU), or mean activated clotting time value (210 +/- 50 sec) at the end of procedure among the three groups. Successful hemostasis was achieved in 100% of patients with both the 30-min and 60-min compression groups using the QuikClot pad. Hemostasis failure occurred in 50% of patients when the TR Band was initially weaned at the protocol-driven time (40 min after sheath removal). Mean compression time for hemostasis with the TR Band was 149.4 min compared with 30.7 min and 60.9 min for the 30-min and 60-min QuikClot groups, respectively. No radial artery occlusion occurred in any subject at the end of the study. CONCLUSIONS: Use of the QuikClot Radial pad following TRA in this pilot trial significantly shortened hemostasis times when compared with the TR Band, with no increased complications noted. PMID- 28809725 TI - Clinical Characteristics and Complications of Pediatric Liver Biopsy: A Single Centre Experience. AB - INTRODUCTION: Percutaneous liver biopsy (LB) is the gold standard method for evaluation and management of patients with liver disease. The purpose of this study was to characterize pediatric patients undergoing LB at British Columbia Children's Hospital, and to determine the rate and timing of complications following the procedure. MATERIAL AND METHODS: The medical records of all pediatric patients who underwent LB during a six-year retrospective study were reviewed to collect demographic and procedure-related data. RESULTS: 223 LBs were performed, and 179 of these biopsies were percutaneous or transjugular. Elevated liver enzymes and cholestasis together accounted for almost 70% of the indications for LB, and the histological analysis of liver tissue yielded a specific diagnosis in 89 % of the cases. There were no deaths and no major complications related to LB. The most frequent minor complication was pain (59% of LBs) and the other complications were bleeding-related and classified as minor. The vast majority of complications (88%) were recognized within 8 h of the LB. CONCLUSIONS: LB is a valuable and safe procedure in pediatric patients with a low rate of complications. Pediatric patients can be discharged home safely should no complications occur within the first 8-12 h after the procedure. PMID- 28809726 TI - Clinical and Laboratory Associations with Persistent Hyperferritinemia in 373 Black Hemochromatosis and Iron Overload Screening Study Participants. AB - BACKGROUND: 373 black participants had elevated screening and post-screening serum ferritin (SF) (> 300 MUg/L men; > 200 MUg/L women). MATERIAL AND METHODS: We retrospectively studied SF and post-screening age; sex; body mass index; transferrin saturation (TS); ALT; AST; GGT; elevated C-reactive protein; beta thalassemia; neutrophils; lymphocytes; monocytes; platelets; metacarpophalangeal joint hypertrophy; hepatomegaly; splenomegaly; diabetes; HFE H63D positivity; iron/alcohol intakes; and blood/erythrocyte transfusion units. Liver disease was defined as elevated ALT or AST. We computed correlations of SF and TS with: age; body mass index; ALT; AST; GGT; C-reactive protein; blood cell counts; and iron/alcohol. We compared participants with SF > 1,000 and <= 1,000 MUg/L and performed regressions on SF. RESULTS: There were 237 men (63.5%). Mean age was 55 +/- 13 (SD) y. 143 participants had liver disease (62 hepatitis B or C). There were significant correlations of SF: TS, ALT, AST, GGT, and monocytes (positive); and SF and TS with platelets (negative). 22 participants with SF > 1,000 MUg/L had significantly higher median TS, ALT, and AST, and prevalences of anemia and transfusion > 10 units; and lower median platelets. Regression on SF revealed significant associations: TS; male sex; age; GGT; transfusion units (positive); and splenomegaly (negative) (p < 0.0001, 0.0016, 0.0281, 0.0025, 0.0001, and 0.0096, respectively). Five men with SF > 1,000 MUg/L and elevated TS had presumed primary iron overload (hemochromatosis). Four participants had transfusion iron overload. CONCLUSION: Persistent hyperferritinemia in 373 black adults was associated with male sex, age, TS, GGT, and transfusion. 2.4% had primary iron overload (hemochromatosis) or transfusion iron overload. PMID- 28809727 TI - Models of non-Alcoholic Fatty Liver Disease and Potential Translational Value: the Effects of 3,5-L-diiodothyronine. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in industrialized countries and is associated with increased risk of cardiovascular, hepatic and metabolic diseases. Molecular mechanisms on the root of the disrupted lipid homeostasis in NAFLD and potential therapeutic strategies can benefit of in vivo and in vitro experimental models of fatty liver. Here, we describe the high fat diet (HFD)-fed rat in vivo model, and two in vitro models, the primary cultured rat fatty hepatocytes or the FaO rat hepatoma fatty cells, mimicking human NAFLD. Liver steatosis was invariably associated with increased number/size of lipid droplets (LDs) and modulation of expression of genes coding for key genes of lipid metabolism such as peroxisome proliferator-activated receptors (Ppars) and perilipins (Plins). In these models, we tested the anti-steatotic effects of 3,5-L-diiodothyronine (T2), a metabolite of thyroid hormones. T2 markedly reduced triglyceride content and LD size acting on mRNA expression of both Ppars and Plins. T2 also stimulated mitochondrial oxidative metabolism of fatty acids. We conclude that in vivo and especially in vitro models of NAFLD are valuable tools to screen a large number of compounds counteracting the deleterious effect of liver steatosis. Because of the high and negative impact of liver steatosis on human health, ongoing experimental studies from our group are unravelling the ultimate translational value of such cellular models of NAFLD. PMID- 28809728 TI - Multiple Biliary Hamartomas, The ''Von Meyenburg Complexes''. PMID- 28809729 TI - Fibrates for Primary Biliary Cholangitis: What's All the Hype? AB - Ursodeoxycholic acid is the first-line therapy for primary biliary cholangitis. However, a subset of patients fail to show biochemical response. For these patients, adjuvant therapies are warranted. Obeticholic acid was conditionally approved as a second-line drug. Evidence is building up in favor of fibrates, which are available for off-label use. PMID- 28809730 TI - Transplanting Kidney Allografts from Hepatitis C Infected Donors into Hepatitis C Uninfected Recipients: Re-Thinking the Thinker Trial. AB - In the not so distant past, organs from hepatitis C infected donors were either discarded or rarely transplanted into HCV viremic recipients - but never allocated to non-infected patients. However, the simplicity, ease and unprecedented success rates of HCV direct acting antiviral regimens has raised the possibility of utilizing such organs in an attempt to expand the donor pool. The thinker trial reports the first of such attempts. However, caution must be exercised prior to the widespread adoption of such strategy. PMID- 28809731 TI - The Histopathological Features and CT/MRI Imaging Performances in Hepatic Angiomyolipoma Patients. AB - AIM: To evaluate the diagnostic value of dynamic contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) in the differential diagnosis of hepatic angiomyolipoma (HAML) and hepatocellular carcinoma (HCC) and to clarify the relationship between histopathological features and CT or MRI imaging performances in HAML. MATERIAL AND METHODS: Six HAML and 33 non-cirrhotic HCC patients confirmed by histopathology were retrospectively analyzed. The serum biomarkers, CT and MRI examinations were conventionally performed before the confirmatory histological diagnosis. The clinical data from their medical records was also analyzed. RESULTS: Six HAML patients were annotated as two types according to CT and MRI imaging characteristics, including hypovascular type (n = 1) and hypervascular type (n = 5). The imaging performances of the 33 HCC patients were hypervascular type. Moreover, all the 5 hypervascular type HAML patients were misdiagnosed as HCC by CT or MRI. We also found that the hypervascular type of HAML patients contained more vessels and less fatty tissues in histopathology than hypovascular type of HAML patients. However, the clinical features included HCC high risk factors (hepatitis B or C), non-specific symptoms, male and increased serum alpha fetoprotein (AFP) were more common in HCC patients than HAML patients (P < 0.05, respectively). CONCLUSIONS: The CT or MRI imaging performances of HAML patients containing more vessels and less fatty tissues in histopathology resemble the imaging performance of HCC patients. These clinical features may be of great help in the differential diagnosis in the current clinical practices. PMID- 28809732 TI - Validation of the Simplified Criteria for the Diagnosis of Autoimmune Hepatitis in Chilean-Hispanic Patients. AB - INTRODUCTION AND AIM: In 2008 the International autoimmune hepatitis (AIH) Group proposed the simplified diagnostic criteria for this disease. The original cohort study was performed in 11 international centers, but validation studies are scarce in Latin-America. The aim of this study is validate these criteria in Hispanic patients. MATERIAL AND METHODS: A retrospective cohort of patients undergoing percutaneous liver biopsy and follow-up of at least 12 months was recruited from a Chilean University hospital. Patients with previous immunosuppressive therapy and liver transplant recipients were excluded. The diagnostic accuracy was analyzed using as gold standard the clinical course during long-term follow-up. Sensitivity, specificity, positive and negative predictive values (PPV and NPV) and area under the ROC curve (AUROC) were calculated. RESULTS: Four hundred eighty one patients were evaluated, 294 were included. 218 (74.15%) were female, mean age 48.5 (+/- 12.3) years, mean follow up 34 (+/- 18) months. 66 patients had AIH or overlap syndrome (22.45%), 96 (32.65%) non-alcoholic steatohepatitis, 40 (13.61%) primary biliary cholangitis, 31 (10.54%) hepatitis C, 8 (2.72%) hepatitis B, 53 (18.02%) other etiologies. The AUROC for AIH simplified criteria was 0.976. Using a cutoff >= 6 and >= 7 points, the sensitivity was 86.4% and 54.6%; specificity, 98.7% and 99.6%; PPV, 95% and 97.3%; and NPV, 96.2% and 88.6%, respectively. CONCLUSION: Simplified criteria for the diagnosis of AIH have a high accuracy in our Chilean-Hispanic cohort. The female gender is strongly associated to AIH and could help in difficult cases. Further studies with a prospective design are necessary to confirm these observations. PMID- 28809733 TI - Circulating levels of pentraxin-3 (PTX3) in patients with liver cirrhosis. AB - BACKGROUND: Despite the circulating levels of PTX3 were related to the severity of various diseases, there are no studies investigating its role in patients with liver cirrhosis. We aimed to study PTX3 levels in patients with liver cirrhosis. MATERIAL AND METHODS: A prospective cohort study included 130 patients hospitalized for acute decompensation of liver cirrhosis, 29 stable cirrhotic outpatients and 32 healthy controls evaluated in a tertiary hospital in Southern Brasil. RESULTS: The median PTX3 level was significantly higher in stable cirrhotic patients compared to controls (2.6 vs. 1.1 ng/mL; p < 0.001), hospitalized cirrhotic patients compared to controls (3.8 vs. 1.1 ng/mL; p < 0.001), and hospitalized cirrhotic patients compared to stable cirrhotic patients (3.8 vs. 2.6 ng/mL; p = 0.001). A positive correlation was found between PTX3 and serum creatinine (r = 0.220; p = 0.012), Chronic Liver Failure - Sequential Organ Failure Assessment score (CLIF-SOFA) (r = 0.220; p = 0.010), MELD (r = 0.279; p = 0.001) and Child-Pugh score (r = 0.224; p = 0.010). Significantly higher levels of PTX3 were observed in patients on admission with ACLF (8.9 vs. 3.1 ng/mL; p < 0.001) and MELD score >= 20 (6.6 vs. 3.4 ng/mL; p = 0.002). Death within 90 days occurred in 30.8% of patients and was associated with higher levels of PTX3 (5.3 vs. 3.4 ng/mL; p = 0.009). The probability of Kaplan-Meier survival was 77.0% in patients with PTX-3 < 5.3 ng mL (upper tercile) and 53.5% in those with PTX3 >= 5.3 ng/mL (p = 0.002). CONCLUSION: These results indicate the potential for use of PTX3 as an inflammatory biomarker for the prognosis of patients with hepatic cirrhosis. PMID- 28809734 TI - Wait Time for Curative Intent Radio Frequency Ablation is Associated with Increased Mortality in Patients with Early Stage Hepatocellular Carcinoma. AB - INTRODUCTION: Radiofrequency ablation (RFA) is a recommended curative intent treatment option for patients with early stage hepatocellular carcinoma (HCC). We investigated if wait times for RFA were associated with residual tumor, tumor recurrence, need for liver transplantation, or death. MATERIAL AND METHODS: We conducted a retrospective study of patients diagnosed with HCC between January 2010 and December 2013 presenting to University Health Network (UHN) in Toronto, Canada. All patients receiving curative intent RFA for HCC were included. Multivariable Cox regression was used to determine if wait times were associated with clinical outcomes. RESULTS: 219 patients were included in the study. 72.6% were male and the median age was 62.7 years (IQR 55.6-71). Median tumor size at diagnosis was 21.5 mm (IQR 17-26); median MELD was 8.7 (IQR 7.2-11.4) and 57.1% were Barcelona stage 0. The cause of liver disease was viral hepatitis in 73.5% (Hepatitis B and C). The median time from HCC diagnosis to RFA treatment was 96 days (IQR 75-139). In multivariate analysis, wait time was not associated with requiring liver transplant or tumor recurrence, however, each incremental 30-day wait time was associated with an increased risk of residual tumor (HR = 1.09; 95% CI 1.01-1.19; p = 0.033) as well as death (HR = 1.23; 95% CI 1.11-1.36; p <= 0.001). CONCLUSION: Incremental 30-day wait times are associated with a 9% increased risk of residual tumor and a 23% increased risk of death. We have identified system gaps where quality improvement measures can be implemented to reduce wait times and allocate resources for future RFA treatment, which may improve both quality and efficiency of HCC care. PMID- 28809735 TI - Algorithm for Screening of Adrenal Function in Stable Patients with Cirrhosis. AB - INTRODUCTION AND AIMS: Adrenal insufficiency (AI) is common in patients with cirrhosis. We aimed to assess the presence of AI in stable patients with cirrhosis using the gold-standard insulin tolerance test (ITT) and to propose an algorithm for screening AI in these patients. MATERIAL AND METHODS: We studied 40 stable patients with cirrhosis. We determined the basal total (BTC) and peak cortisol (PTC) levels. Using the ITT, we defined AI as a serum PTC < 18 MUg/dL at 30 min after insulin-induced hypoglycemia. We assessed the diagnostic accuracy of BTC in different stages of liver disease to discriminate between those with NAF and AI. RESULTS: Of the 40 patients, 24 (60%) presented with AI. Child-Pugh and MELD scores differed between the NAF and AI groups (Child-Pugh: NAF 7.2 +/- 1.7 vs. AI 8.8 +/- 2.4, p = 0.024 and MELD: NAF 9.9 +/- 2.5 vs. AI 14.9 +/- 6.3, p = 0.001). The BTC level was lower in patients with AI than in those with NAF (7.2 +/- 2.4 vs. 12.5 +/- 5.2, p < 0.001). A BTC value <= 10.0 MUg/dL had a 96% sensitivity (negative predictive value: 90%) for identifying AI. This cutoff value (BTC <= 10.0 MUg/dL) provided 100% specificity (positive predictive value: 100%) in patients with advanced liver disease (Child-Pugh >= 9 or MELD >= 12). CONCLUSION: An algorithm including the use of BTC and the severity of liver disease may be a useful and simple method for assessing adrenal function in stable patients with cirrhosis. PMID- 28809736 TI - Monosegmental ALPPS after Bilateral Hepatectomy. AB - Associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) has emerged as an alternative for patients with bilobar colorectal liver metastasis and a small future liver remnant (FLR). In cases of extensive disease, ALPPS can be performed, leaving only one segment of the liver as FLR. We describe a case of monosegmental ALPPS using segment 4 as FLR. In conclusion, ALPPS should be reserved for a selected group of patients. Monosegmental ALPPS is feasible, but should be performed by hepatobiliary surgeons in specialized centers. PMID- 28809738 TI - Blue-Print for Elimination of Hepatitis C Viral Infection: One Step Closer. PMID- 28809737 TI - Acute Liver Failure Due to Etodolac, a Selective Cycloxygenase- 2 (COX -2) Inhibitor Non-Steroidal Anti-Inflammatory Drug Established by RUCAM-Based Causality Assessment. AB - Drug induced liver injury is a common cause of acute liver failure (ALF). While most of these cases are due to dose dependent hepatotoxicity with acetaminophen, idiosyncratic drug-induced liver injury (DILI) is responsible for about 15% cases of ALF. Antibiotics are the most common cause of idiosyncratic DILI as well as DILI induced ALF. Etodolac is a selective cycloxygenase- 2 (COX -2) inhibitor non steroidal anti-inflammatory drug used as an analgesic and anti-inflammatory in musculoskeletal diseases. Severe liver impairment is extremely rare. Till date, only 3 cases of ALF related to etodolac have been reported in the literature. Here we report two cases with a unique presentation of ALF occurring due to DILI caused by etodolac, as diagnosed by Roussel Uclaf Causality Assessment Method (RUCAM). PMID- 28809739 TI - Waiting-time and quality of care deserved to patients with early stage hepatocellular carcinoma undergoing RFA treatment PMID- 28809740 TI - Early Successes in an Open Access, Provincially Funded Hepatitis C Treatment Program in Prince Edward Island. AB - INTRODUCTION: The availability of curative hepatitis C therapies has created an opportunity to improve delivery and access. Local providers, government, industry, and community groups in Prince Edward Island developed an innovative province-wide care model. Our goal was to describe the first year of program implementation. MATERIAL AND METHODS: Using a community based prospective observational study design, all chronic hepatitis C referrals received from April 2015 to April 2016 were recorded in a database. Primary analysis assessed the time from referral to assessment/treatment, as well as the number of referrals, assessments, and treatment initiations. Secondary objectives included: 1) Treatment effectiveness using intention-to-treat analysis; and 2) Patient treatment experience assessed using demographics, adverse events, and medication adherence. RESULTS: During the study period 242 referrals were received, 123 patients were seen for intake assessments, and 93 initiated direct-acting antiviral therapy based on medical need. This is compared to 4 treatment initiations in the previous 2 years. The median time from assessment to treatment initiation was 3 weeks. Eighty-two of 84 (97.6%, 95% CI 91.7 - 99.7%) patients for whom outcome data were available achieved sustained virologic response at 12 weeks post-treatment; 1 was lost to follow-up and 1 died from an unrelated event. In the voluntary registry, 39.7% of patients reported missed treatment doses. CONCLUSION: In conclusion, results from the first 12 months of this multi-phase hepatitis C elimination strategy demonstrate improved access to treatment, and high rates of safe engagement and cure for patients living with chronic hepatitis C genotype 1 infections. PMID- 28809741 TI - Hepatitis C Virus Infection Outcomes Among Immigrants to Canada: A Retrospective Cohort Analysis. AB - INTRODUCTION AND AIM: HCV-infected immigrants contribute to the total prevalence in Canada and other developed nations. Little is known about engagement in care, access to service, and treatment outcomes in recipients of Direct Acting Antiviral (DAA) HCV therapies among immigrants living with HCV. MATERIAL AND METHODS: HCV patients assessed at The Ottawa Hospital Viral Hepatitis Clinic between 2000-2016 were identified. Immigration history, race, socioeconomic status, HCV work-up, treatment and outcome data were evaluated. HCV fibrosis assessment, treatment and sustained virologic response (SVR) were compared using logistic regression. RESULTS: 2,335 HCV-infected patients were analyzed with 91% (2114) having data on immigration (23% immigrants). A median 16 years (Quartiles: 5, 29) passed from immigration to referral. Access to diagnostic procedures (Fibroscan/liver biopsy) was greater among immigrants compared to Canadian-born (78% vs. 68%, p = 0.001) and immigrants had an odds ratio of 1.72 (95% CI: 1.18 2.51) of receiving a FibroScan compared to Canadians after adjustment for demographic characteristics, HCV risk factors, and socioeconomic status. No differences in SVR were found between immigrants for IFN recipients. Among DAA recipients, rates of SVR were > 94% among all patients, 93% in Canadian-born and 98% among immigrants (p = 0.14). CONCLUSION: Nearly 80% of immigrants in this setting had access to fibrosis assessment which was higher than Canadian-born patients. Under half of both groups had initiated HCV therapy. Delays in accessing HCV care represent a missed opportunity to engage, treat and cure HCV patients. HCV screening and health care engagement at the time of immigration would optimize HCV care and therapeutic outcomes. PMID- 28809742 TI - Treatment of Chronic HCV Infection with the New Direct Acting Antivirals (DAA): First Report of a Real World Experience in Southern Brazil. AB - INTRODUCTION AND AIM: There is almost no data regarding the efficacy of direct acting antivirals (DAAs) therapy in Brazil. The aim of this historical cohort study is to describe the sustained virologic response (SVR) rate among real-world compensated chronic hepatitis C patients in three hepatology centers from Southern Brazil. MATERIALS AND METHODS: Patients were included if they had at least 12 weeks follow-up after the end of therapy. Patients that were lost to follow-up or had treatment prematurely interrupted for any reason were considered treatment failure in this intention to treat analysis. RESULTS: 219 patients were analyzed. Mean age was 57.4 +/- 10.9 years and 142/219 (64.8%) were male. Genotype 1 was present in 166 patients (75.8%; 1a 29.2%, 1b 46.6%); Genotypes 2, 3 and 4 in 8 (3.7%), 43 (19.6%) and 2 (0.9%), respectively. 96 (43.8%) were cirrhotic. 134 (59.5%) were treatment experienced. DAA therapies were: sofosbuvir (SOF) + ribavirin (RBV) in 10 patients; SOF + simeprevir (SMV) +/- RBV in 73; SOF + pegylated interferon (PEG-IFN) + RBV in 6; SOF + daclatasvir (DCV) +/- RBV in 51, SOF + ledipasvir (LDV) +/- RBV in 61, and paritaprevir/ ritonavir + ombitasvir + dasabuvir (PTVr/OBV/DSV) +/- RBV in 18 patients. SVR-12 was achieved in 208/219 (95%). Ten patients had virologic failure: 6 cirrhotic, 7 treatment experienced, and 6 either genotype 3 or 1a. No adverse event was attributed to the DAA therapy. CONCLUSIONS: Real world experience with DAA therapy in Southern Brazil showed a high rate of SVR and excellent tolerability. Failure to achieve SVR was mainly observed among patients with at least one negative predictor of response: cirrhosis and/or genotypes 1a or 3. PMID- 28809743 TI - Outcomes for Cirrhotic Patients with Hepatitis C Virus 1b Treated with Asunaprevir and Daclatasvir Combination. AB - BACKGROUND: The efficacy and safety of asunaprevir + daclatasvir combination therapy for treatment of hepatitis C virus (HCV) in compensated cirrhotic patients was not fully evaluated in real-world. Outcomes were assessed in cirrhotic patients with sustained viral response (SVR). MATERIAL AND METHODS: A total of 145 patients without resistance-associated substitutions (RASs) at L31 and Y93 in the nonstructural protein 5A of HCV genotype 1b, consisting of 49 hepatic cirrhotic and 96 non-cirrhotic patients, were enrolled to the therapy. The patients were treated with 100 mg asunaprevir twice daily plus 60 mg daclatasvir once daily for 24 weeks. The primary endpoint was SVR 24 weeks after completing treatment. In addition, we evaluated the improvement of liver function and development of HCC for 1 year from the end of treatment (EOT). RESULTS: The SVR24 rate was 96% (47/49) in the cirrhotic group and 96% (91/95) in the non cirrhotic group (p = 0.69). During treatment, grade III/IV adverse events occurred more frequently in cirrhotic patients (10/49; 20.4%) than in non cirrhotic patients (10/96; 10.4%) (p = 0.099). After EOT, alanine aminotransferase and AFP levels were significantly decreased in cirrhotic patients with SVR. In addition, serum levels of albumin and platelet counts were significantly increased. On the other hand, the rates of HCC recurrence (43%) and development (7.4%) were higher in cirrhotic patients than in the non-cirrhotic patients (12.5% and 1.1%, respectively). CONCLUSION: RAS-oriented asunaprevir/daclatasvir therapy has a strong anti-HCV effect in patients with HCV genotype 1b. However, careful management is necessary in patients with cirrhosis. PMID- 28809744 TI - Effect of Vitamin D Serum Levels and GC Gene Polymorphisms in Liver Fibrosis Due to Chronic Hepatitis C. AB - INTRODUCTION AND AIM: Vitamin D has been associated with chronic liver diseases and low vitamin levels may contribute to progression of chronic hepatitis C. The aim of this study was to evaluate the influence of vitamin D serum levels and GC gene polymorphisms in the severity of liver fibrosis in patients with chronic hepatitis C genotype 1. MATERIAL AND METHODS: Cross-sectional study that enrolled 132 adult patients with chronic hepatitis C genotype 1 attended at the outpatient Clinic of Gastroenterology Division at Hospital de Clinicas de Porto Alegre. At the time of enrollment patients had a blood withdraw for serum 25(OH)D determination and genotypic analysis of rs7041 and rs4588 polymorphisms in GC gene. None/mild fibrosis was considered as METAVIR F0, F1 and F2 and severe fibrosis as METAVIR F3 and F4. RESULTS: Median 25(OH)D levels in the sample were 19.9 ng/mL (P25-P75: 14.0-29.4). Fifty percent of patients presented vitamin D deficiency (< 20 ng/mL). In stepwise multiple linear regression the variables associated with 25(OH)D levels were blood withdrawn in Winter/spring season, the haplotypes AT/AT + AG/AT of rs7041 and rs4588 and female sex. For evaluation of severe fibrosis, variables associated in logistic regression were age, vitamin D severe deficiency (< 10 ng/mL), glucose levels, BMI and platelets count. CONCLUSIONS: Vitamin D levels are associated with severity of liver fibrosis in chronic hepatitis C genotype 1 patients. Although the rs7041 and rs4588 GC polymorphisms are strong predictors of vitamin D levels, they do not play a direct role in liver fibrosis. PMID- 28809745 TI - A hybrid active force control of a lower limb exoskeleton for gait rehabilitation. AB - Owing to the increasing demand for rehabilitation services, robotics have been engaged in addressing the drawbacks of conventional rehabilitation therapy. This paper focuses on the modelling and control of a three-link lower limb exoskeleton for gait rehabilitation that is restricted to the sagittal plane. The exoskeleton that is modelled together with a human lower limb model is subjected to a number of excitations at its joints while performing a joint space trajectory tracking, to investigate the effectiveness of the proposed controller in compensating disturbances. A particle swarm optimised active force control strategy is proposed to facilitate disturbance rejection of a conventional proportional derivative (PD) control algorithm. The simulation study provides considerable insight into the robustness of the proposed method in attenuating the disturbance effect as compared to the conventional PD counterpart without compromising its tracking performance. The findings from the study further suggest its potential employment on a lower limb exoskeleton. PMID- 28809746 TI - Analytical evaluation of the performances of Diazyme and BRAHMS procalcitonin applied to Roche Cobas in comparison with BRAHMS PCT-sensitive Kryptor. AB - BACKGROUND: Procalcitonin (PCT) is a recognized marker of sepsis, and its use is expanding to antibiotic stewardship. The aim of this study was the evaluation of two methods: Diazyme PCT on Roche Cobas c702 (PCT-D) and BRAHMS PCT on Roche Cobas e602 analyzers (PCT-BR) in comparison with BRAHMS PCT-sensitive Kryptor (PCT-BK). METHODS: Imprecision was assessed at six critical concentrations following the CLSI EP5-A3; limits of detection (LoDs) were checked according to CLSI EP17-A2; linearity was tested, and method comparison was performed on 239 serum samples. RESULTS: Overall CVs ranged from 12.58% to 5.97% for PCT-D, from 3.94% to 1.70% for PCT-BR and from 6.57% to 1.90% for PCT-BK. LoDs were 0.143 MUg/L, 0.014 MUg/L, 0.040 MUg/L for PCT-D, PCT-BR and PCT-BK, respectively. The functional assay sensitivity was 0.24 MUg/L for PCT-D, 0.045 MUg/L for PCT-BK and <0.035 MUg/L for PCT-BR. PCT-BR was linear up to 68.7 MUg/L, PCT-BK up to 43 MUg/L and PCT-D up to 27.2 MUg/L. Method comparison: PCT-D=0.6543 PCT-BK+0.014, r=0.8463 (but 0.44 if calculated on 0-5 MUg/L range); PCT-BR=0.9125 PCT-BK+0.021, r=0.9917. Cohen's kappa ranged from 45.2% at 0.25 MUg/L to 57.0% at 2.00 MUg/L between PCT-D and PCT-BK, whereas it ranged from 89% to 81.3% between PCT-BR and PCT-BK. CONCLUSIONS: The PCT-D performances were significantly different from those of PCT-BR and PCT-BK regarding sensitivity, precision, linearity and agreement at clinical cutoffs. For some patients with serial testing, significantly deviating results were obtained compared to reference. In contrast to Roche PCT assay, it does not seem feasible to use BRAHMS PCT cutoffs for the Diazyme test. PMID- 28809747 TI - Oxidation of PTH: in vivo feature or effect of preanalytical conditions? AB - BACKGROUND: Posttranslational oxidation of parathyroid hormone (PTH) modifies its biological activity. Measurement of non-oxidized PTH (n-oxPTH) could be an improvement in assessing PTH status, as intact PTH may rather reflect oxidative stress. However, it is debated whether oxidation of PTH occurs in vivo, or whether it is mainly an in vitro artifact. The aim of this study was to investigate the influence of different preanalytical conditions on the oxidation of PTH within a wide range of plasma PTH concentrations and oxidation propensity. METHODS: n-oxPTH was separated from its oxidized form using an affinity column capturing the oxidized PTH. n-oxPTH was measured in eluate using commercially available PTH assays. The study included ethylenediaminetetraacetic acid plasma samples from 17 patients undergoing hemodialysis and 32 healthy subjects. We determined effects of storage temperature, time until centrifugation and freeze thaw cycles. PTH and n-oxPTH concentrations were measured in each sample using six different immunoassays. RESULTS: n-oxPTH concentrations remained unchanged up to 180 min until centrifugation, two freeze-thaw cycles or after storage at -20 degrees C or -80 degrees C up to 79 days. Various methods for n-oxPTH and PTH measurements yielded highly comparable results, apart from standardization differences between various PTH and n-oxPTH assays. CONCLUSIONS: n-oxPTH concentrations were stable under our study conditions, indicating negligible ex vivo oxidation of PTH. In addition, PTH immunoassays have a different sensitivity for n-oxPTH than for total PTH. For this reason, the n-oxPTH/total PTH ratio cannot be used in absence of a n-oxPTH standard. Clinical implications of determining n-oxPTH require additional study. PMID- 28809748 TI - New issues on measurement of B-type natriuretic peptides. AB - The measurement of the active hormone of B-type natriuretic peptide (BNP) system actually has several analytical limitations and difficulties in clinical interpretations compared to that of inactive peptide N-terminal proBNP (NT proBNP) because of the different biochemical and pathophysiological characteristics of two peptides and quality specifications of commercial immunoassay methods used for their measurement. Because of the better analytical characteristics of NT-proBNP immunoassays and the easier pathophysiological and clinical interpretations of variations of NT-proBNP levels in patients with heart failure (HF), some authors claimed to measure the inactive peptide NT-proBNP instead of the active hormone BNP for management of HF patients. The measurement of the active peptide hormone BNP gives different, but complementary, pathophysiological and clinical information compared to inactive NT-proBNP. In particular, the setup of new more sensitive and specific assays for the biologically active peptide BNP1-32 should give better accurate information on circulating natriuretic activity. In conclusion, at present time, clinicians should accurately consider both the clinical setting of patients and the analytical characteristics of BNP and NT-proBNP immunoassays in order to correctly interpret the variations of natriuretic peptides measured by commercially available laboratory methods, especially in patients treated with the new drug class of angiotensin receptor-neprilysin inhibitors. PMID- 28809749 TI - Measurement uncertainty of gamma-glutamyltransferase (GGT) in human serum by four approaches using different quality assessment data. AB - BACKGROUND: Measurement uncertainty (MU) characterizes the dispersion of the quantity values attributed to a measurand. Although this concept was introduced to medical laboratories some years ago, not all medical researchers are familiar with it. Therefore, the evaluation and expression of MU must be highlighted. In this paper, the evaluation of MU is described by using four different approaches from different quality assessment data. METHODS: In accordance with Guide to the Expression of Uncertainty of Measurement (GUM) principles, human serum gamma glutamyltransferase (GGT) level was defined as the measurand. Main sources of MU were analyzed; individual components of MU were evaluated, followed by calculation of standard uncertainty, the combined standard uncertainty and the expanded uncertainty. RESULTS: In method 1, the median of expanded uncertainty (k=2) of GGT in lower level (65+/-1 U/L) was 5 U/L (9%, 95% confidence interval) and in higher level (116+/-2 U/L) was 8% (95% confidence interval), respectively. The results of method 2 were lower than that of method 1. There were no significant differences between the two other methods compared with the method 1. CONCLUSIONS: Three out of the four different approaches based on different quality assessment data yielded similar results. Proficiency testing or external quality assessment data used for MU evaluation can be regarded as a supplementary method in clinical laboratory. PMID- 28809750 TI - Need for better PTH assays for clinical research and patient treatment. PMID- 28809751 TI - Influence of topical iodine-containing antiseptics used during delivery on recall rate of congenital hypothyroidism screening program. AB - BACKGROUND: The proportion of newborns recalled during neonatal screening programs for congenital hypothyroidism (CH) varies substantially by country and may be higher in settings where povodine iodine (PVP-I) is used during delivery. We assessed this hypothesis by substituting PVP-I for chlorhexidine (CHL) and evaluated the reduction in the recall rate of the Irainian newborn screening program. METHODS: This study investigated 2282 neonates of mothers admitted to a local hospital for delivery between December 2012 and October 2013. We measured thyorid stimulating hormone (TSH) levels in heel-prick blood specimens of infants, aged between 3 and 5 days, born to mothers who received PVP-I (phase I) and those who received CHL after withdrawal of PVP-I from obstetric procedures (phase II). Then we compared the median TSH levels and the recall rate based on a TSH level >=5 mU/L. RESULTS: Of 2282 cases, 1094 infants were born to mothers exposed to PVP-I during phase I (PVP-I group) and 1188 ones were born to mothers exposed to chlorhexidine in phase II (CHL group); 6.56% of the PVP-I group and 1.91% of the CHL group were recalled later during screening (p<0.001). The median TSH level was significantly higher in the PVP-I group compared to the CHL group (1.35 vs. 1.00, p<0.001). CONCLUSIONS: Replacement of iodine-containing antiseptics by iodine-free ones, during delivery resulted in a significant reduction in the recall rate of the Iranian screening program for CH. PMID- 28809752 TI - Association of obesity and health related quality of life in Iranian children and adolescents: the Weight Disorders Survey of the CASPIAN-IV study. AB - BACKGROUND: Considering the role of different ethnical, cultural and geographical factors in health related quality of life (HRQOL) as well as the perception of different populations regarding various weight disorders, we aimed to evaluate the association between body mass index (BMI) and HRQOL in Iranian children and adolescents. METHODS: This cross-sectional study was part of the Weight Disorders Survey of the CASPIAN-IV study. During this study, students aged 6-18 years from urban and rural areas of 30 provinces of Iran were selected. HRQOL of the students was evaluated by using the Persian version of the Pediatric Quality of Life inventory (PedsQLTM 4.0TM 4.0) Generic Core Scales. The mean of total HRQOL and its subscales were compared in underweight, normal weight, overweight and obese students. RESULTS: The mean of total HRQOL, physical functioning and psychological functioning scores in the total population were 83.31, 84.25 and 82.79, respectively. The mean of the total HRQOL score and the psychosocial score were significantly lower in underweight students aged 6-12 years than in other groups (p<0.05). The mean of the total HRQOL score and psychosocial score were significantly lower in obese students aged 13-18 years than in other groups (p<0.05). Overweight and obesity was negatively associated with total HRQOL, psychosocial and school functioning subscales (p<0.05). There was a significant negative association between emotional functioning and obesity (p<0.05). CONCLUSIONS: The findings or this study support the importance of personal perception and cultural norm roles in HRQOL. Given the association between weight disorders and psychosocial health, it is suggested that social and cultural factors have a more crucial role in the HRQOL of children and adolescents. PMID- 28809753 TI - An occult ectopic parathyroid adenoma in a pediatric patient: a case report and management algorithm. AB - BACKGROUND: Hyperparathyroidism (HPT) is a rare disease in the pediatric population, and optimal management may be unclear if it is due to an occult parathyroid adenoma. We present a case report of a pediatric patient with an occult, ectopic, supernumerary, parathyroid adenoma. CASE PRESENTATION: A 13-year old female who initially presented with anxiety was diagnosed with HPT. Preoperative imaging and bilateral neck exploration with four-gland biopsy were negative for any parathyroid adenoma. Postoperative MRI identified a thymic mass. She subsequently underwent video-assisted thoracoscopic thymectomy with resection of an intrathymic parathyroid adenoma. CONCLUSIONS: The diagnosis of pediatric HPT is increasing. Supernumerary or occult parathyroid adenomas are rare and add complexity to presurgical planning and management. Our case represents the rare occurrence of a pediatric ectopic supernumerary occult parathyroid adenoma treated with a two-stage approach utilizing multiple imaging studies. We provide a review of the pathology and propose an algorithmic approach to manage these complex patients. PMID- 28809754 TI - Associations of built environment and children's physical activity: a narrative review. AB - PROBLEM: Childhood obesity has been an epidemic particularly in high-income countries. There is a considerable volume of data and studies depicting the rising number of obese children and adolescents in different countries. As suggested by the literature, physical inactivity is one the main drivers of childhood obesity. This paper addresses the associations of the built environment with physical activity of children in order to find to theoretically facilitate intervention and prevention measures. Literature: There is a large body of literature describing the overall determinants of children's physical activity. The built environment is one of the influential factors that have been partially examined. Among the physical environment indicators, distance to school has been repeatedly reported to be negatively associated with active travels to school; thus, it indirectly affects physical activity of children. Apart from distance to school, some other built environment indicators have also been less researched, such as population and construction densities, distance to the city center, land use mix, and type of urban fabric (urban, suburban, etc.). OBJECTIVE: The purpose of this review was to shed light on some of the less-studied areas of the existing literature related to the relationship between the built environment and physical activity of children aged between 3 and 12 years. METHOD: The English language publications, majority of which were peer-reviewed journal papers published in recent years, were collected and descriptively analyzed. Two large categories were the backbone of this narrative review: (1) non-school outdoor activities of children that take place in the residential neighborhood and (2) commuting to school and the related interventions such as safe routes to school. RESULTS: Seven areas were synthesized by this review of the literature. Differences in associations of the built environment and physical activity in (1) different types of urban forms and land uses such as urban, suburban, high density, etc.; (2) different city sizes such as small towns, mid-sized cities, large cities and megacities; (3) different cultures, subcultures and ethnicities in the same city of country, e.g. the Asian minority of London or the Turkish minority of Germany; (4) between perceptions of parents and children and associations with children's physical activity, e.g. how they perceive safety and security of the neighborhood; (5) associations of the built environment with children's physical activity in less-studied contexts, e.g. many developing and under-developed countries or eastern European countries; (6) differences in built environment - physical activity associations in different regions of the world, e.g. continents; and finally (7) associations between mobility patterns of parents and their children's physical activity, for instance, the frequencies of taking public transport or walk as a commute mode. CONCLUSION: Researchers are recommended to focus their less-researched subtopics mentioned under the Results section in accordance with local conditions observed in less-researched contexts so that measures and interventions are accordingly planned. PMID- 28809755 TI - Multiple timescales in the photoswitching kinetics of crystalline thin films of azobenzene-trimers. AB - Functional materials that exhibit photoinduced structural phase transitions are highly interesting for applications in optomechanics and mechanochemistry. It is, however, still not fully understood how photochemical reactions, which are often accompanied by molecular motion, proceed in confined and crystalline environments. Here we show that thin films of azobenzene trimers exhibit high structural order and determine the crystallographic unit cell. We demonstrate that thin film can be switched partially reversibly between a crystalline and an amorphous phase. The time constant of the photoinduced amorphisation as measured with real-time x-ray diffraction ([Formula: see text]220 s) lies between the two time constants (120 s and 2870 s) of the ensemble photoisomerisation processes that are measured via optical spectroscopy. Our observation of a photoinduced shrinking of the crystalline domains indicates a cascading process, in which photoisomerisation starts at the surface of the thin film and propagates deeper into the crystalline layer by introducing disorder and generating free volume. This finding is important for the rapidly evolving research field of photoresponsive thin films and smart crystalline materials in general. PMID- 28809756 TI - Hidden symmetries in N-layer dielectric stacks. AB - The optical properties of a multilayer system with arbitrary N layers of dielectric media are investigated. Each layer is one of two dielectric media, with a thickness one-quarter the wavelength of light in that medium, corresponding to a central frequency f 0. Using the transfer matrix method, the transmittance T is calculated for all possible 2 N sequences for small N. Unexpectedly, it is found that instead of 2 N different values of T at f 0 (T 0), there are only [Formula: see text] discrete values of T 0, for even N, and (N + 1) for odd N. We explain this high degeneracy in T 0 values by finding symmetry operations on the sequences that do not change T 0. Analytical formulae were derived for the T 0 values and their degeneracies as functions of N and an integer parameter for each sequence we call 'charge'. Additionally, the bandwidth at f 0 and filter response of the transmission spectra are investigated, revealing asymptotic behavior at large N. PMID- 28809757 TI - Flexible ZnO nanorod-based piezoelectric nanogenerators on carbon papers. AB - We report on the fabrication of ZnO nanorod (NR)-based flexible piezoelectric nanogenerators (PENGs) on carbon paper (CP). Structural investigations indicate that the ZnO NRs grew well along the porous CP surface. Optical investigation shows that the crystal quality of the ZnO NRs on the CP was comparable to that of NRs grown on Si substrate. As the molar concentration increased from 10-70 mM, the output voltage and current increased consistently from 3.6-6.8 V and 0.79 1.45 MUA, respectively. The enhancements of the voltage and current were attributed to the enhanced accumulation of the potentials generated by the increased number of ZnO NRs in the PENG devices. Therefore, the porous CP enhanced the PENG performance due to the higher surface area, and provided a super-flexible self-powering platform. PMID- 28809758 TI - Optimizing timing performance of CdTe detectors for PET. AB - Despite several attractive properties, the poor timing performance of compound semiconductor detectors such as CdTe and CdZnTe has hindered their use in commercial PET imaging systems. The standard method of pulse timing with such detectors is to employ a constant-fraction discriminator at the output of a timing filter which is fed by the pulses from a charge-sensitive preamplifier. The method has led to a time resolution of about 10 ns at full-width at half maximum (FWHM) with 1 mm thick CdTe detectors. This paper presents a detailed investigation on the parameters limiting the timing performance of Ohmic contact planar CdTe detectors with the standard pulse timing method. The jitter and time walk errors are studied through simulation and experimental measurements and it is revealed that the best timing results obtained with the standard timing method suffer from a significant loss of coincidence events (~50%). In order to improve the performance of the detectors with full detection efficiency, a new digital pulse timing method based on a simple pattern recognition technique was developed. A time resolution of 3.29 +/- 0.10 ns (FWHM) in the energy range of 300-650 keV was achieved with an Ohmic contact planar CdTe detector (5 * 5 * 1 mm3). The digital pulse processing method was also used to correct for the charge-trapping effect and an improvement in the energy resolution from 4.83 +/- 0.66% to 2.780 +/- 0.002% (FWHM) at 511 keV was achieved. Further improvement of time resolution through a moderate cooling of the detector and the application of the method to other detector structures are also discussed. PMID- 28809759 TI - Independent dose verification system with Monte Carlo simulations using TOPAS for passive scattering proton therapy at the National Cancer Center in Korea. AB - For the independent validation of treatment plans, we developed a fully automated Monte Carlo (MC)-based patient dose calculation system with the tool for particle simulation (TOPAS) and proton therapy machine installed at the National Cancer Center in Korea to enable routine and automatic dose recalculation for each patient. The proton beam nozzle was modeled with TOPAS to simulate the therapeutic beam, and MC commissioning was performed by comparing percent depth dose with the measurement. The beam set-up based on the prescribed beam range and modulation width was automated by modifying the vendor-specific method. The CT phantom was modeled based on the DICOM CT files with TOPAS-built-in function, and an in-house-developed C++ code directly imports the CT files for positioning the CT phantom, RT-plan file for simulating the treatment plan, and RT-structure file for applying the Hounsfield unit (HU) assignment, respectively. The developed system was validated by comparing the dose distributions with those calculated by the treatment planning system (TPS) for a lung phantom and two patient cases of abdomen and internal mammary node. The results of the beam commissioning were in good agreement of up to 0.8 mm2 [Formula: see text] for B8 option in both of the beam range and the modulation width of the spread-out Bragg peaks. The beam set up technique can predict the range and modulation width with an accuracy of 0.06% and 0.51%, respectively, with respect to the prescribed range and modulation in arbitrary points of B5 option (128.3, 132.0, and 141.2 mm2 [Formula: see text] of range). The dose distributions showed higher than 99% passing rate for the 3D gamma index (3 mm distance to agreement and 3% dose difference) between the MC simulations and the clinical TPS in the target volume. However, in the normal tissues, less favorable agreements were obtained for the radiation treatment planning with the lung phantom and internal mammary node cases. The discrepancies might come from the limitations of the clinical TPS, which is the inaccurate dose calculation algorithm for the scattering effect, in the range compensator and inhomogeneous material. Moreover, the steep slope of the compensator, conversion of the HU values to the human phantom, and the dose calculation algorithm for the HU assignment also could be reasons of the discrepancies. The current study could be used for the independent dose validation of treatment plans including high inhomogeneities, the steep compensator, and riskiness such as lung, head & neck cases. According to the treatment policy, the dose discrepancies predicted with MC could be used for the acceptance decision of the original treatment plan. PMID- 28809760 TI - The Milestone of Non-invasive Prenatal Identification of Chromosomal Abnormalities in Fetal Trophoblasts Recovered from Maternal Blood. AB - Two recent studies demonstrated that array CGH and NGS allow identification of chromosomal abnormalities in fetal trophoblasts circulating in maternal blood. This remarkable breakthrough paves the way for an improved assay that supersedes the performance of non-invasive prenatal testing (NIPT) in cell-free fetal DNA. Furthermore, it is foreseeable to expand the use of this new genomic analysis in trophoblasts to uncover single gene mutations of clinical significance prenatally. PMID- 28809761 TI - The t(12;21)(p13;q22) in Pediatric B-Acute Lymphoblastic Leukemia: An Update. AB - Pediatric B-cell acute lymphoblastic leukemia (B-ALL) is the most common hematological malignancy in children, and the t(12;21)(p13;q22) occurs in approximately 25% of these cases, making it is the most prevalent chromosomal abnormality. The t(12;21) which disrupts hematopoietic differentiation and proliferation, and can be present as a sole abnormality or within the context of a complex karyotype characterized by three or more chromosomal abnormalities. The prognosis of t(12;21) within a complex karyotype is extensively debated. In this review, we discuss the literature regarding t(12;21) and summarize the cytogenetic features found in 363 pediatric cases compiled from the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer. Cytogenetically, most of the cases had secondary chromosomal abnormalities, about half of which were in the context of a complex karyotype. Trisomy 21 was found to be the most common numerical abnormality in almost one-fifth of the cases, and deletions on chromosome 12 and 6 occurred in 16.9% and 12.5% of cases, respectively. In general, t(12;21) in B-ALL is associated with a favorable prognosis. Herein, we found no significant difference in survival outcome of t(12;21) with a on-complex or complex karyotype. PMID- 28809762 TI - Elucidation of Novel Chromosomal Abnormalities in Pancreatic Cancer: Conventional and Molecular Cytogenetic Characterization of 16 Pancreatic Cell Lines. AB - Pancreatic carcinoma is a major cause of cancer-related death in the United States, with a five-year survival rate of approximately 5%. Cytogenetic analysis has identified clinically significant chromosomal abnormalities in numerous malignancies, but it is not utilized in the clinical management of pancreatic carcinoma. We performed conventional and molecular cytogenetic analysis of 16 pancreatic carcinoma cell lines using Giemsa banding and DNA-based fluorescence in situ hybridization (FISH). Conventional cytogenetic analysis revealed a diversity of recurrent and clonal numerical and structural abnormalities in all cell lines analyzed, many of which occurred at loci of genes implicated in pancreatic or related cancers. FISH analysis revealed significant decreases in copy number of numerous tumor-suppressor genes including TP53, CDKN2A, and SMAD4. In some cell lines, amplification of oncogenes HER2 and MYC was also observed. Finally, novel rearrangements involving ARID1A and TGFBR2 were identified in a small subset of cell lines by means of molecular cytogenetic analysis. All in all, these data provide additional insight into recurrent chromosomal abnormalities in pancreatic carcinoma that can potentially be utilized as biomarkers in the clinical management of the disease. Investigation of other aberrations as well as correlation of recurrent ones with clinicopathologic features is warranted in order to assess the utility of cytogenetic analysis of pancreatic carcinoma. PMID- 28809763 TI - Persistent Placoid Maculopathy Complicated by Cerebral Vasculitis. AB - Persistent placoid maculopathy (PPM) is a bilateral inflammatory chorioretinopathy characterized by long-standing plaque-like macular lesions. No systemic manifestations have been reported to date. We describe a case of PPM complicated by cerebral vasculitis, suggesting that neurological symptoms, including headache, should be enquired about in all PPM subjects. PMID- 28809764 TI - The 43rd Annual Meeting of the North American Neuro-Ophthalmology Society in Washington, DC. PMID- 28809766 TI - CRISPR/Cas9 editing of Nf1 gene identifies CRMP2 as a therapeutic target in neurofibromatosis type 1-related pain that is reversed by (S)-Lacosamide. AB - Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disease linked to mutations of the Nf1 gene. Patients with NF1 commonly experience severe pain. Studies on mice with Nf1 haploinsufficiency have been instructive in identifying sensitization of ion channels as a possible cause underlying the heightened pain suffered by patients with NF1. However, behavioral assessments of Nf1 mice have led to uncertain conclusions about the potential causal role of Nf1 in pain. We used the clustered regularly interspaced short palindromic repeats (CRISPR) associated 9 (CRISPR/Cas9) genome editing system to create and mechanistically characterize a novel rat model of NF1-related pain. Targeted intrathecal delivery of guide RNA/Cas9 nuclease plasmid in combination with a cationic polymer was used to generate allele-specific C-terminal truncation of neurofibromin, the protein encoded by the Nf1 gene. Rats with truncation of neurofibromin, showed increases in voltage-gated calcium (specifically N-type or CaV2.2) and voltage gated sodium (particularly tetrodotoxin-sensitive) currents in dorsal root ganglion neurons. These gains-of-function resulted in increased nociceptor excitability and behavioral hyperalgesia. The cytosolic regulatory protein collapsin response mediator protein 2 (CRMP2) regulates activity of these channels, and also binds to the targeted C-terminus of neurofibromin in a tripartite complex, suggesting a possible mechanism underlying NF1 pain. Prevention of CRMP2 phosphorylation with (S)-lacosamide resulted in normalization of channel current densities, excitability, as well as of hyperalgesia following CRISPR/Cas9 truncation of neurofibromin. These studies reveal the protein partners that drive NF1 pain and suggest that CRMP2 is a key target for therapeutic intervention. PMID- 28809765 TI - Cyclin-dependent kinase 5 modulates the P2X2a receptor channel gating through phosphorylation of C-terminal threonine 372. AB - The purinergic P2X2 receptor (P2X2R) is an adenosine triphosphate-gated ion channel widely expressed in the nervous system. Here, we identified a putative cyclin-dependent kinase 5 (Cdk5) phosphorylation site in the full-size variant P2X2aR (TPKH), which is absent in the splice variant P2X2bR. We therefore investigated the effects of Cdk5 and its neuronal activator, p35, on P2X2aR function. We found an interaction between P2X2aR and Cdk5/p35 by co immunofluorescence and co-immunoprecipitation in HEK293 cells. We also found that threonine phosphorylation was significantly increased in HEK293 cells co expressing P2X2aR and p35 as compared to cells expressing only P2X2aR. Moreover, P2X2aR-derived peptides encompassing the Cdk5 consensus motif were phosphorylated by Cdk5/p35. Whole-cell patch-clamp recordings indicated a delay in development of use-dependent desensitization (UDD) of P2X2aR but not of P2X2bR in HEK293 cells co-expressing P2X2aR and p35. In Xenopus oocytes, P2X2aRs showed a slower UDD than in HEK293 cells and Cdk5 activation prevented this effect. A similar effect was found in P2X2a/3R heteromeric currents in HEK293 cells. The P2X2aR T372A mutant was resistant to UDD. In endogenous cells, we observed similar distribution between P2X2R and Cdk5/p35 by co-localization using immunofluorescence in primary culture of nociceptive neurons. Moreover, co immunoprecipitation experiments showed an interaction between Cdk5 and P2X2R in mouse trigeminal ganglia. Finally, endogenous P2X2aR-mediated currents in PC12 cells and P2X2/3R mediated increases of intracellular Ca in trigeminal neurons were Cdk5 dependent, since inhibition with roscovitine accelerated the desensitization kinetics of these responses. These results indicate that the P2X2aR is a novel target for Cdk5-mediated phosphorylation, which might play important physiological roles including pain signaling. PMID- 28809767 TI - Using Reported Rates of Sexually Transmitted Diseases to Illustrate Potential Methodological Issues in the Measurement of Racial and Ethnic Disparities. AB - BACKGROUND: Racial disparities in the burden of sexually transmitted diseases (STDs) have been documented and described for decades. Similarly, methodological issues and limitations in the use of disparity measures to quantify disparities in health have also been well documented. The purpose of this study was to use historic STD surveillance data to illustrate four of the most well-known methodological issues associated with the use of disparity measures. METHODS: We manually searched STD surveillance reports to find examples of racial/ethnic distributions of reported STDs that illustrate key methodological issues in the use of disparity measures. The disparity measures we calculated included the black-white rate ratio, the Index of Disparity (weighted and unweighted by subgroup population), and the Gini coefficient. RESULTS: The 4 examples we developed included illustrations of potential differences in relative and absolute disparity measures, potential differences in weighted and nonweighted disparity measures, the importance of the reference point when calculating disparities, and differences in disparity measures in the assessment of trends in disparities over time. For example, the gonorrhea rate increased for all minority groups (relative to whites) from 1992 to 1993, yet the Index of Disparity suggested that racial/ethnic disparities had decreased. CONCLUSIONS: Although imperfect, disparity measures can be useful to quantify racial/ethnic disparities in STDs, to assess trends in these disparities, and to inform interventions to reduce these disparities. Our study uses reported STD rates to illustrate potential methodological issues with these disparity measures and highlights key considerations when selecting disparity measures for quantifying disparities in STDs. PMID- 28809768 TI - Missed Opportunities for Chlamydia Screening in Title X Family Planning Clinics. AB - BACKGROUND: Annual chlamydia (CT) screening is recommended for women younger than 25 years, yet less than half of young women seeking health care are screened annually. We analyzed Title X family planning service data from the Northwest United States to assess factors associated with missed opportunities for CT screening. Our primary hypothesis was screening coverage is higher during annual preventive health visits compared to other visit types. Study objectives were: (1) identify gaps in screening coverage by patient demographics, visit characteristics, and clinic measures; and (2) examine the association between visit type and CT screening by controlling for other covariates and stratifying by state. METHODS: Calendar year 2011 Title X visit records (n = 180,856) were aggregated to the patient level (n = 112,926) to assess CT screening coverage by all characteristics. Screening variation was explored by bivariate and multivariate Poisson regression. Adjusted models for each state estimated association between comprehensive examination and screening controlling for confounders. RESULTS: Clinic and visit characteristics were associated with CT screening. Coverage ranged from 45% in Washington to 80% in Alaska. Only 34% of patients visited for a routine comprehensive examination. Visit type was associated with screening; 75% of patients who had a comprehensive examination were screened versus 34% of those without a comprehensive examination (unadjusted PR, 2.18; 95% confidence interval, 2.16-2.21). The association between comprehensive examination and CT screening varied significantly by state (interaction term, P < 0.001). CONCLUSIONS: Missed screening opportunities are common among women who access brief appointments for specific needs but do not seek routine preventive care, particularly in some states. Structural interventions may help address these systematically missed opportunities. PMID- 28809769 TI - Adverse Experiences in Childhood and Sexually Transmitted Infection Risk From Adolescence Into Adulthood. AB - BACKGROUND: Childhood maltreatment, particularly sexual abuse, has been found to be associated with sexual risk behaviors later in life. We aimed to evaluate associations between a broad range of childhood traumas and sexual risk behaviors from adolescence into adulthood. METHODS: Using data from Waves I, III and IV of the National Longitudinal Study of Adolescent to Adult Health (Add Health), we used logistic regression to estimate the unadjusted odds ratio (OR) and adjusted OR (AOR) for associations between 9 childhood traumas and a cumulative trauma score and three sexual risk outcomes (multiple partnerships, sex trade involvement, and sexually transmitted infection [STI]) in adolescence, young adulthood, and adulthood. We also examined modification of these associations by gender. RESULTS: Associations between cumulative trauma score and sexual risk outcomes existed at all waves, though were strongest during adolescence. Dose response-like relationships were observed during at least 1 wave of the study for each outcome. Violence exposures were strong independent correlates of adolescent sexual risk outcomes. Parental binge drinking was the only trauma associated with biologically confirmed infection in young adulthood (AOR, 1.46; 95% confidence interval [CI], 1.01-2.11), whereas parental incarceration was the trauma most strongly associated with self-reported STI in adulthood (AOR, 1.70; 95% CI, 1.11 2.58). A strong connection was also found between sexual abuse and sex trade in the young adulthood period (AOR, 2.17; 95% CI, 1.43-2.49). CONCLUSIONS: A broad range of traumas are independent correlates of sex risk behavior and STI, with increasing trauma level linked to increasing odds of sexual risk outcomes. The results underscore the need to consider trauma history in STI screening and prevention strategies. PMID- 28809771 TI - Efficacy of Human Immunodeficiency Virus/Sexually Transmitted Infection Trial on Condom Use Among Heterosexual Men Patronizing Entertainment Establishments Who Engaged in Casual or Paid Sex in Singapore. AB - BACKGROUND: We assessed the efficacy of a multi-component sexual health promotion program on condom use and human immunodeficiency virus (HIV)/sexually transmitted infection (STI) testing among heterosexual men (HSM) patronizing entertainment establishments who engaged in casual or paid sex in Singapore. METHODS: This was a quasi-experimental trial with a comparison group using cross-sectional surveys at baseline and 6 months postintervention. A locality patronized by local HSM was assigned the intervention, a comparable and distant area served as the comparison site. Using time location sampling, cross-sectional samples of these men were assessed on sexual behaviors using an anonymous questionnaire at baseline (n = 604) and 6 months postintervention (n = 360) in both groups. The coprimary outcomes were condom use at last vaginal and oral sex with casual partner respectively. Mixed effects Poisson regression model accounting for clustering by establishment was used to compute the adjusted prevalence ratio (aPR) of the outcomes postintervention. RESULTS: At postintervention, the intervention group was more likely than the comparison group to report condom use at last vaginal (aPR, 1.41; 95% confidence interval [CI], 1.05-1.89) and oral (aPR, 1.70; 95% CI. 1.11-2.61) sex, respectively, with casual partner. Similar findings were found for consistent condom use in the last 6 months for vaginal (aPR, 1.67; 95% CI, 1.13-2.48) and oral (aPR, 1.97; 95% CI, 1.16-3.32) sex, respectively, with casual partner. The HIV/STI testing was not significantly higher in the intervention than the comparison group (aPR, 1.43; 95% CI, 0.98-2.09). CONCLUSIONS: This trial was effective in promoting condom use with casual partners but not HIV/STI testing among HSM in Singapore. PMID- 28809772 TI - Low Prevalence of Urethral Lymphogranuloma Venereum Infections Among Men Who Have Sex With Men: A Prospective Observational Study, Sexually Transmitted Infection Clinic in Amsterdam, the Netherlands. AB - In contrast to anorectal lymphogranuloma venereum (LGV), few urogenital LGV cases are reported in men who have sex with men. Lymphogranuloma venereum was diagnosed in 0.06% (7/12,174) urine samples, and 0.9% (109/12,174) anorectal samples. Genital-anal transmission seems unlikely the only mode of transmission. Other modes like oral-anal transmission should be considered. PMID- 28809770 TI - Uptake of Home-Based Syphilis and Human Immunodeficiency Virus Testing Among Male Partners of Pregnant Women in Western Kenya. AB - BACKGROUND: Few men are tested for syphilis or human immunodeficiency virus (HIV) during their partner's pregnancy, a high-risk period for HIV and syphilis transmission. Offering home-based rapid testing of syphilis to couples during pregnancy can support prevention efforts to reduce transmission of sexually transmitted diseases and adverse pregnancy outcomes. METHODS: We assessed men's uptake of paired (separate tests, single blood draw) point-of-care syphilis and HIV tests within a randomized controlled trial of pregnant women who received clinic or home partner HIV testing. We evaluated acceptance of paired HIV syphilis testing during pregnancy or at 6 months postpartum, and evaluated whether addition of syphilis testing affected the uptake of HIV testing among men. RESULTS: Of 601 women, we were unable to meet 101 male partners, and 180 tested before syphilis tests were available. Paired syphilis and HIV testing was offered at home to 80 men during pregnancy and to 230 men postpartum. For syphilis, 93% of men agreed to test during pregnancy and 98% agreed postpartum. For paired syphilis and HIV testing, 91% of men tested for both during pregnancy and 96% tested postpartum. Before syphilis test introduction, 96% of men accepted HIV testing, compared with 95% of men who accepted HIV testing when paired testing was offered. CONCLUSIONS: Uptake of syphilis and HIV testing was high among male partners offered couple testing at home. Introducing syphilis testing did not adversely affect HIV testing among men. Point-of-care diagnostics outside facilities can increase testing of male partners who rarely accompany women to antenatal clinics. PMID- 28809773 TI - A Macaque Model for Rectal Lymphogranuloma Venereum and Non-Lymphogranuloma Venereum Chlamydia trachomatis: Impact on Rectal Simian/Human Immunodeficiency Virus Acquisition. AB - BACKGROUND: Sustained genital tract inflammation caused by sexually transmitted infections (STIs) is known to increase risk of vaginal human immunodeficiency virus (HIV) infections but, to our knowledge, there are no nonhuman primate studies that have evaluated its link to rectal HIV acquisition. METHODS: Rhesus macaques inoculated with Chlamydia trachomatis (CT) (serovars LGV-L2 and CT-E; n = 7) or saline (n = 7) received up to 20 rectal challenges twice a week of simian/HIV immunodeficiency virus (SHIVSF162p3). SHIV viremia was determined by real-time PCR and Chlamydia infection by APTIMA Combo 2 testing. The rectal cytokine-chemokine levels were evaluated by multiplex bead assays. RESULTS: Rectal Chlamydia infection was maintained throughout the study. We did not observe significant differences (P = 1.0) in frequency of SHIV acquisition between the STI and control arms. It took fewer SHIV challenges to infect the STI animals although the difference was not significant (P = 0.59). There were no significant differences in peak plasma viremia between STI and control arms (P = 0.63). The association of plasma viremia with rectal shedding was significantly different by arm (P = 0.038). CONCLUSIONS: In the first such study in a macaque model, we did not observe an increased risk of SHIV acquisition due to rectal Chlamydia coinfection. This macaque model can be further developed and expanded to better investigate the impact of different rectal STIs on HIV acquisition. PMID- 28809774 TI - High Prevalence of Concurrent Male-Male Partnerships in the Context of Low Human Immunodeficiency Virus Testing Among Men Who Have Sex With Men in Bamako, Mali. AB - BACKGROUND: Concurrent male-male sexual partnerships have been understudied in sub-Saharan Africa and are especially important because human immunodeficiency virus (HIV) prevalence and acquisition probability are higher among men who have sex with men (MSM) than among heterosexual men and women. METHODS: We conducted a respondent-driven sampling survey of 552 men who have sex with men in Bamako, Mali from October 2014 to February 2015. Eligibility criteria included 18 years or older, history of oral or anal sex with another man in the last 6 months, residence in or around Bamako in the last 6 months, ability to communicate in French. RESULTS: HIV prevalence was 13.7%, with 86.7% of MSM with HIV unaware of their infection. Concurrent male-male sexual partnerships were common, with 60.6% of MSM having a concurrent male sexual partnerships or believing their sex partner did in the last 6 months, and 27.3% having a concurrent male sexual partnerships and believing their sex partner did in the last 6 months. Over half (52.5%) of MSM had sex with women, and 30.8% had concurrent male partnerships and sex with a woman in the last 6 months. Concurrency was more likely among MSM with limited education, telling only MSM of same-sex behaviors, high social cohesion, and not knowing anyone with HIV. CONCLUSIONS: The high proportion of HIV-infected MSM in Bamako who are unaware of their HIV infection and the high prevalence of concurrent partnerships could further the spread of HIV in Bamako. Increasing testing through peer educators conducting mobile testing could improve awareness of HIV status and limit the spread of HIV in concurrent partnerships. PMID- 28809775 TI - Evaluation of an Automated Express Care Triage Model to Identify Clinically Relevant Cases in a Sexually Transmitted Disease Clinic. AB - BACKGROUND: Many sexually transmitted disease (STD) clinics offer testing-only "express" visits. We evaluated the express care triage algorithm that is based on a computer-assisted self-interview (CASI) used in the Public Health-Seattle and King County STD Clinic. METHODS: During the analysis period, patients received a clinician evaluation irrespective of triage status. In this cross-sectional study, we compared the algorithm triage status to a disease-focused outcome determined by medical record review. We defined a patient as "needing a standard visit" if they reported key symptoms, received empiric treatment, or were diagnosed with an infection or syndrome at the same visit. We estimated the sensitivity of the algorithm for identifying patients who needed a standard visit and identified the characteristics of patients who could have received express care but were excluded from it by the algorithm. RESULTS: Between October 2010 and June 2015, patients completed a CASI at 32,113 visits; 23% were triaged by the algorithm to express care. The triage status was appropriate for 21,337 (87%) men and 6259 (82%) women. The algorithm had 95% and 98% sensitivity for identifying men and women, respectively, needing standard visits. The most common reason for mistriage to express care was patient report of symptoms to clinicians that they did not disclose to the CASI. Of women who could have received express care, only 33% were triaged to it by the algorithm; the remainder was triaged to standard visits, primarily for health service indications. CONCLUSIONS: The CASI based algorithm accurately identified patients who were eligible for express care based on a disease-focused outcome. PMID- 28809776 TI - Keeping an Eye on Chlamydia and Gonorrhea Conjunctivitis in Infants in the United States, 2010-2015. PMID- 28809777 TI - Pigmented Epithelioid Melanocytoma (PEM)/Animal Type Melanoma (ATM): Quest for an Origin. Report of One Unusual Case Indicating Follicular Origin and Another Arising in an Intradermal Nevus. AB - Pigmented epithelioid melanocytoma (PEM) is a tumor encompassing epithelioid blue nevus of Carney complex (EBN of CNC) and was previously termed animal-type melanoma. Histologically PEMs are heavily pigmented spindled and epithelioid dermal melanocytic tumors with infiltrative borders, however, their origin remains unclear. Stem cells for the epidermis and hair follicle are located in the bulge area of the hair follicle with the potential to differentiate into multiple lineages. Multiple cutaneous carcinomas, including follicular cutaneous squamous cell carcinoma (FSCC), are thought to arise from stem cells in the follicular bulge. We present two cases of PEM/ATM in a 63 year-old male on the scalp with follicular origin and a 72 year-old female on the upper back arising in an intradermal nevus. Biopsy of both cases revealed a proliferation of heavily pigmented dermal nests of melanocytes with atypia. The Case 1 tumor was in continuation with the outer root sheath of the hair follicle in the bulge region. Case 2 arose in an intradermal melanocytic nevus. Rare mitotic figures, including atypical mitotic figures, were identified in both cases. We present two cases of PEM, with histologic evidence suggesting two origins: one from the follicular bulb and one from an intradermal nevus. PMID- 28809778 TI - Reprimo, a Potential p53-Dependent Tumor Suppressor Gene, Is Frequently Hypermethylated in Estrogen Receptor alpha-Positive Breast Cancer. AB - Aberrant DNA methylation is a hallmark of many cancers. Currently, there are four intrinsic molecular subtypes in breast cancer (BC): Luminal A, B, Her2-positive, and triple negative (TNBC). Recently, The Cancer Genome Atlas (TCGA) project has revealed that Luminal subtypes have higher levels of genome-wide methylation that may be a result of Estrogen/Estrogen receptor alpha (E2/ERalpha) signaling pathway activation. In this study, we analyze promoter CpG-island (CGIs) of the Reprimo (RPRM) gene in breast cancers (n = 77), cell lines (n = 38), and normal breast tissue (n = 10) using a MBDCap-seq database. Then, a validation cohort (n = 26) was used to confirm the results found in the MBDCap-seq platform. A differential methylation pattern was found between BC and cell lines compared to normal breast tissue. In BC, a higher DNA methylation was observed in tissues that were ERalpha-positive than in ERalpha-negative ones; more precisely, subtypes Luminal A compared to TNBC. Also, significant reverse correlation was observed between DNA methylation and RPRM mRNA expression in BC. Our data suggest that ERalpha expression in BC may affect the DNA methylation of CGIs in the RPRM gene. This approach suggests that DNA methylation status in CGIs of some tumor suppressor genes could be driven by E2 availability, subsequently inducing the activation of the ERalpha pathway. PMID- 28809780 TI - Fenton Discoloration of Ultrasonicated Purple Cactus Pear Juice. AB - The aim of this study was to evaluate the stability of color, betaxanthin, and betacyanin pigments in the presence of Cu(II)-dependent hydroxyl radicals (HO*) from ultrasonicated purple cactus pear juice at amplitudes of 40%, 60%, and 80%, in comparison to untreated sample. L* parameter of juice treated at 40% and 80% amplitude for 25 and 15 min, respectively (11.3 and 9.3, respectively), were significantly higher compared to the control; b* and hue parameters of juice treated at 80%, 25 min showed values of 1.7 and 0.1, respectively. Color differences (DeltaE) were lower (<3) for juices treated at high amplitude (80%) and short times (3-5 min). Juice treated at 40% 15 min, 60% 25 min, 80% 15 and 25 min presented high values of betacyanins (281.7 mg.L-1, 255.9 mg.L-1, 294.4 mg.L 1, and 276.7 mg.L-1, respectively). Betaxanthin values were higher in the juices treated at 40% 5 min and 80% 15 and 25 min (154.2 mg.L-1, 135.2 mg.L-1, and 128.5 mg.L-1, respectively). Purple cactus pear juice exhibited significant chelating activity of copper ions and great stability when exposed to HO*. PMID- 28809781 TI - Ac2-26, an Annexin A1 Peptide, Attenuates Ischemia-Reperfusion-Induced Acute Lung Injury. AB - Annexin A1 (AnxA1) is an endogenous protein that modulates anti-inflammatory processes, and its therapeutic potential has been reported in a range of inflammatory diseases. The effect of AnxA1 on ischemia-reperfusion (IR)-induced lung injury has not been examined. In this study, isolated, perfused rat lungs were subjected to IR lung injury induced by ischemia for 40 min, followed by reperfusion for 60 min. The rat lungs were randomly treated with vehicle (phosphate-buffered saline), and Ac2-26 (an active N-terminal peptide of AnxA1) with or without an N-formyl peptide receptor (FPR) antagonist N-Boc-Phe-Leu-Phe Leu-Phe (Boc2). An in vitro study of the effects of Ac2-26 on human alveolar epithelial cells subjected to hypoxia-reoxygenation was also investigated. Administration of Ac2-26 in IR lung injury produced a significant attenuation of lung edema, pro-inflammatory cytokine production recovered in bronchoalveolar lavage fluid, oxidative stress, apoptosis, neutrophil infiltration, and lung tissue injury. Ac2-26 also decreased AnxA1 protein expression, inhibited the activation of nuclear factor-kappaB and mitogen-activated protein kinase pathways in the injured lung tissue. Finally, treatment with Boc2 abolished the protective action of Ac2-26. The results indicated that Ac2-26 had a protective effect against acute lung injury induced by IR, which may be via the activation of the FPR. PMID- 28809779 TI - Application of Solution NMR to Structural Studies on alpha-Helical Integral Membrane Proteins. AB - A large portion of proteins in living organisms are membrane proteins which play critical roles in the biology of the cell, from maintenance of the biological membrane integrity to communication of cells with their surroundings. To understand their mechanism of action, structural information is essential. Nevertheless, structure determination of transmembrane proteins is still a challenging area, even though recently the number of deposited structures of membrane proteins in the PDB has rapidly increased thanks to the efforts using X ray crystallography, electron microscopy, and solid and solution nuclear magnetic resonance (NMR) technology. Among these technologies, solution NMR is a powerful tool for studying protein-protein, protein-ligand interactions and protein dynamics at a wide range of time scales as well as structure determination of membrane proteins. This review provides general and useful guideline for membrane protein sample preparation and the choice of membrane-mimetic media, which are the key step for successful structural analysis. Furthermore, this review provides an opportunity to look at recent applications of solution NMR to structural studies on alpha-helical membrane proteins through some success stories. PMID- 28809782 TI - Dietary Supplementation of Honey Bee Larvae with Arginine and Abscisic Acid Enhances Nitric Oxide and Granulocyte Immune Responses after Trauma. AB - Many biotic and abiotic stressors impact bees' health, acting as immunosupressors and contribute to colony losses. Thus, the importance of studying the immune response of honey bees is central to develop new strategies aiming to enhance bees' fitness to confront the threats affecting them. If a pathogen breaches the physical and chemical barriers, honey bees can protect themselves from infection with cellular and humoral immune responses which represent a second line of defense. Through a series of correlative studies we have previously reported that abscisic acid (ABA) and nitric oxide (NO) share roles in the same immune defenses of Apis mellifera (A. mellifera). Here we show results supporting that the supplementation of bee larvae's diet reared in vitro with l-Arginine (precursor of NO) or ABA enhanced the immune activation of the granulocytes in response to wounding and lipopolysaccharide (LPS) injection. PMID- 28809785 TI - Path Planning for Non-Circular, Non-Holonomic Robots in Highly Cluttered Environments. AB - This paper presents an algorithm for finding a solution to the problem of planning a feasible path for a slender autonomous mobile robot in a large and cluttered environment. The presented approach is based on performing a graph search on a kinodynamic-feasible lattice state space of high resolution; however, the technique is applicable to many search algorithms. With the purpose of allowing the algorithm to consider paths that take the robot through narrow passes and close to obstacles, high resolutions are used for the lattice space and the control set. This introduces new challenges because one of the most computationally expensive parts of path search based planning algorithms is calculating the cost of each one of the actions or steps that could potentially be part of the trajectory. The reason for this is that the evaluation of each one of these actions involves convolving the robot's footprint with a portion of a local map to evaluate the possibility of a collision, an operation that grows exponentially as the resolution is increased. The novel approach presented here reduces the need for these convolutions by using a set of offline precomputed maps that are updated, by means of a partial convolution, as new information arrives from sensors or other sources. Not only does this improve run-time performance, but it also provides support for dynamic search in changing environments. A set of alternative fast convolution methods are also proposed, depending on whether the environment is cluttered with obstacles or not. Finally, we provide both theoretical and experimental results from different experiments and applications. PMID- 28809784 TI - Folate Receptor-Positive Gynecological Cancer Cells: In Vitro and In Vivo Characterization. AB - The folate receptor (FR) is expressed in a variety of gynecological cancer types. It has been widely used for tumor targeting with folic acid conjugates of diagnostic and therapeutic probes. The cervical KB tumor cells have evolved as the standard model for preclinical investigations of folate-based (radio) conjugates. In this study, a panel of FR-expressing human cancer cell lines including cervical (HeLa, KB, KB-V1), ovarian (IGROV-1, SKOV-3, SKOV-3.ip), choriocarcinoma (JAR, BeWo) and endometrial (EFE-184) tumor cells-was investigated in vitro and for their ability to grow as xenografts in mice. FR expression levels were compared in vitro and in vivo and the cell lines were characterized by determination of the sensitivity towards commonly-used chemotherapeutics and the expression of two additional, relevant tumor markers, HER2 and L1-CAM. It was found that, besides KB cells, its multiresistant KB-V1 subclone as well as the ovarian cancer cell lines, IGROV-1 and SKOV-3.ip, could be used as potentially more relevant preclinical models. They would allow addressing specific questions such as the therapeutic efficacy of FR-targeting agents in tumor (mouse) models of multi-resistance and in mouse models of metastases formation. PMID- 28809786 TI - Octopus: A Design Methodology for Motion Capture Wearables. AB - Human motion capture (MoCap) is widely recognised for its usefulness and application in different fields, such as health, sports, and leisure; therefore, its inclusion in current wearables (MoCap-wearables) is increasing, and it may be very useful in a context of intelligent objects interconnected with each other and to the cloud in the Internet of Things (IoT). However, capturing human movement adequately requires addressing difficult-to-satisfy requirements, which means that the applications that are possible with this technology are held back by a series of accessibility barriers, some technological and some regarding usability. To overcome these barriers and generate products with greater wearability that are more efficient and accessible, factors are compiled through a review of publications and market research. The result of this analysis is a design methodology called Octopus, which ranks these factors and schematises them. Octopus provides a tool that can help define design requirements for multidisciplinary teams, generating a common framework and offering a new method of communication between them. PMID- 28809787 TI - Indoor Scene Point Cloud Registration Algorithm Based on RGB-D Camera Calibration. AB - With the increasing popularity of RGB-depth (RGB-D) sensor, research on the use of RGB-D sensors to reconstruct three-dimensional (3D) indoor scenes has gained more and more attention. In this paper, an automatic point cloud registration algorithm is proposed to efficiently handle the task of 3D indoor scene reconstruction using pan-tilt platforms on a fixed position. The proposed algorithm aims to align multiple point clouds using extrinsic parameters of the RGB-D camera obtained from every preset pan-tilt control point. A computationally efficient global registration method is proposed based on transformation matrices formed by the offline calibrated extrinsic parameters. Then, a local registration method, which is an optional operation in the proposed algorithm, is employed to refine the preliminary alignment result. Experimental results validate the quality and computational efficiency of the proposed point cloud alignment algorithm by comparing it with two state-of-the-art methods. PMID- 28809783 TI - Role of Omentin, Vaspin, Cardiotrophin-1, TWEAK and NOV/CCN3 in Obesity and Diabetes Development. AB - Adipose tissue releases bioactive mediators called adipokines. This review focuses on the effects of omentin, vaspin, cardiotrophin-1, Tumor necrosis factor like Weak Inducer of Apoptosis (TWEAK) and nephroblastoma overexpressed (NOV/CCN3) on obesity and diabetes. Omentin is produced by the stromal-vascular fraction of visceral adipose tissue. Obesity reduces omentin serum concentrations and adipose tissue secretion in adults and adolescents. This adipokine regulates insulin sensitivity, but its clinical relevance has to be confirmed. Vaspin is produced by visceral and subcutaneous adipose tissues. Vaspin levels are higher in obese subjects, as well as in subjects showing insulin resistance or type 2 diabetes. Cardiotrophin-1 is an adipokine with a similar structure as cytokines from interleukin-6 family. There is some controversy regarding the regulation of cardiotrophin-1 levels in obese -subjects, but gene expression levels of cardiotrophin-1 are down-regulated in white adipose tissue from diet-induced obese mice. It also shows anti-obesity and hypoglycemic properties. TWEAK is a potential regulator of the low-grade chronic inflammation characteristic of obesity. TWEAK levels seem not to be directly related to adiposity, and metabolic factors play a critical role in its regulation. Finally, a strong correlation has been found between plasma NOV/CCN3 concentration and fat mass. This adipokine improves insulin actions. PMID- 28809788 TI - Correction: Gupta, P.M.; et al. Iron, Anemia, and Iron Deficiency Anemia among Young Children in the United States Nutrients 2016, 8, 330. AB - We would like to submit the following correction to our recently published paper [1] due to the error in classification of children as anemic [...]. PMID- 28809789 TI - Comparison of the Effects of Goat Dairy and Cow Dairy Based Breakfasts on Satiety, Appetite Hormones, and Metabolic Profile. AB - The satiating effects of cow dairy have been thoroughly investigated; however, the effects of goat dairy on appetite have not been reported so far. Our study investigates the satiating effect of two breakfasts based on goat or cow dairy and their association with appetite related hormones and metabolic profile. Healthy adults consumed two breakfasts based on goat (G-Breakfast) or cow (C Breakfast) dairy products. Blood samples were taken and VAS tests were performed at different time points. Blood metabolites were measured and Combined Satiety Index (CSI) and areas under the curves (AUC) were calculated. Desire to eat rating was significantly lower (breakfast & time interaction p < 0.01) and hunger rating tended to be lower (breakfast & time interaction p = 0.06) after the G breakfast. None of the blood parameters studied were different between breakfasts; however, AUCGLP-1 was inversely associated with the AUChunger and AUCdesire-to-eat after the G-Breakfast, whereas triglyceride levels were directly associated with AUCCSI after the C-Breakfast. Our results suggest a slightly higher satiating effect of goat dairy when compared to cow dairy products, and pointed to a potential association of GLP-1 and triglyceride levels with the mechanisms by which dairy products might affect satiety after the G-Breakfast and C-Breakfast, respectively. PMID- 28809790 TI - Genome-Wide Organization and Expression Profiling of the SBP-Box Gene Family in Chinese Jujube (Ziziphus jujuba Mill.). AB - Transcription factors play vital roles in the developmental processes of plants. The SQUAMOSA promoter binding protein (SBP) genes encode a family of plant specific transcription factors and plays many crucial roles in plant development. In this study, 16 SBP-box gene family members were identified in Ziziphus jujuba Mill. Dongzao (Dongzao), which were distributed over 8 chromosomes. They were classified into seven groups according to their phylogenetic relationships with other SBP-box gene families. Within each group, genes shared similar exon-intron structures and motif locations. The number of exons varied among the groups. We identified 12 homologous gene pairs between Dongzao and Arabidopsis. Expression profiling revealed that ZjSBP02 and ZjSBP14 expressed highly in mature fruits, ZjSBP01 expressed higher in mature leaves than other tissues and the expression level of ZjSBP12 was much higher in the flowers. The transcriptome analysis indicated that ZjSBPs had different expression patterns in various tissues. This study represents the first systematic analysis of the SBP-box gene family in Z. jujuba. The data presented here provides a foundation for understanding the crucial roles of ZjSBP genes in plant growth and development. PMID- 28809793 TI - The Degree of Temporal Synchronization of the Pulse Oscillations from a Gain Switched Multimode Semiconductor Laser. AB - Langevin noise leads to inhibition of the temporal synchronization of the pulse oscillations from a gain-switched multimode semiconductor laser, resulting in the power reduction in optical beat detection. In this paper, the degree of the temporal synchronization of the pulse oscillations was examined by numerically estimating the output energy in THz time-domain spectroscopy (THz-TDS) using multimode semiconductor laser rate equations that include Langevin noise. The degree was estimated to be 95.5% from the ratio of the averaged THz-TDS output energy for the case where Langevin noise was included to that for when Langevin noise was excluded. Therefore, a gain-switched multimode semiconductor laser can be regarded as equivalent to optical pulses oscillating simultaneously in all modes in actual applications including optical beat detection. PMID- 28809791 TI - Imaging Collagen in Scar Tissue: Developments in Second Harmonic Generation Microscopy for Biomedical Applications. AB - The ability to respond to injury with tissue repair is a fundamental property of all multicellular organisms. The extracellular matrix (ECM), composed of fibrillar collagens as well as a number of other components is dis-regulated during repair in many organs. In many tissues, scaring results when the balance is lost between ECM synthesis and degradation. Investigating what disrupts this balance and what effect this can have on tissue function remains an active area of research. Recent advances in the imaging of fibrillar collagen using second harmonic generation (SHG) imaging have proven useful in enhancing our understanding of the supramolecular changes that occur during scar formation and disease progression. Here, we review the physical properties of SHG, and the current nonlinear optical microscopy imaging (NLOM) systems that are used for SHG imaging. We provide an extensive review of studies that have used SHG in skin, lung, cardiovascular, tendon and ligaments, and eye tissue to understand alterations in fibrillar collagens in scar tissue. Lastly, we review the current methods of image analysis that are used to extract important information about the role of fibrillar collagens in scar formation. PMID- 28809792 TI - Fat Sensation: Fatty Acid Taste and Olfaction Sensitivity and the Link with Disinhibited Eating Behaviour. AB - Perception of fat taste, aroma, and texture are proposed to influence food preferences, thus shaping dietary intake and eating behaviour and consequently long-term health. In this study, we investigated associations between fatty acid taste, olfaction, mouthfeel of fat, dietary intake, eating behaviour, and body mass index (BMI). Fifty women attended three sessions to assess oleic acid taste and olfaction thresholds, the olfactory threshold for n-butanol and subjective mouthfeel ratings of custard samples. Dietary intake and eating behaviour were evaluated using a Food Frequency and Three-Factor Eating Questionnaire, respectively. Binomial regression analysis was used to model fat taste and olfaction data. Taste and olfactory detection for oleic acid were positively correlated (r = 0.325; p < 0.02). Oleic acid taste hypersensitive women had significantly increased n-butanol olfactory sensitivity (p < 0.03). The eating behaviour disinhibition and BMI were higher in women who were hyposensitive to oleic acid taste (p < 0.05). Dietary intake of nuts, nut spreads, and seeds were significantly correlated with high olfactory sensitivity to oleic acid (p < 0.01). These findings demonstrate a clear link between fatty acid taste sensitivity and olfaction and suggest that fat taste perception is associated with specific characteristics of eating behaviour and body composition. PMID- 28809794 TI - Exploration of the Structural, Electronic and Tunable Magnetic Properties of Cu4M (M = Sc-Ni) Clusters. AB - The structural, electronic and magnetic properties of Cu4M (M = Sc-Ni) clusters have been studied by using density functional theory, together with an unbiased CALYPSO structure searching method. Geometry optimizations indicate that M atoms in the ground state Cu4M clusters favor the most highly coordinated position. The geometry of Cu4M clusters is similar to that of the Cu5 cluster. The infrared spectra, Raman spectra and photoelectron spectra are predicted and can be used to identify the ground state in the future. The relative stability and chemical activity are investigated by means of the averaged binding energy, dissociation energy and energy level gap. It is found that the dopant atoms except for Cr and Mn can enhance the stability of the host cluster. The chemical activity of all Cu4M clusters is lower than that of Cu5 cluster whose energy level gap is in agreement with available experimental finding. The magnetism calculations show that the total magnetic moment of Cu4M cluster mainly come from M atom and vary from 1 to 5 MUB by substituting a Cu atom in Cu5 cluster with different transition-metal atoms. PMID- 28809795 TI - Pricing of Staple Foods at Supermarkets versus Small Food Stores. AB - Prices affect food purchase decisions, particularly in lower-income communities, where access to a range of food retailers (including supermarkets) is limited. The aim of this study was to examine differences in staple food pricing between small urban food stores and the closest supermarkets, as well as whether pricing differentials varied based on proximity between small stores and larger retailers. In 2014, prices were measured for 15 staple foods during store visits in 140 smaller stores (corner stores, gas-marts, dollar stores, and pharmacies) in Minneapolis/St. Paul, MN and their closest supermarket. Mixed models controlling for store type were used to estimate the average price differential between: (a) smaller stores and supermarkets; (b) isolated smaller stores (>1 mile to closest supermarket) and non-isolated smaller stores; and (c) isolated smaller stores inside versus outside USDA-identified food deserts. On average, all items except white bread were 10-54% more expensive in smaller stores than in supermarkets (p < 0.001). Prices were generally not significantly different in isolated stores compared with non-isolated stores for most items. Among isolated stores, there were no price differences inside versus outside food deserts. We conclude that smaller food stores have higher prices for most staple foods compared to their closest supermarket, regardless of proximity. More research is needed to examine staple food prices in different retail spaces. PMID- 28809796 TI - Polymeric and Lipid Membranes-From Spheres to Flat Membranes and vice versa. AB - Membranes are important components in a number of systems, where separation and control of the flow of molecules is desirable. Controllable membranes represent an even more coveted and desirable entity and their development is considered to be the next step of development. Typically, membranes are considered on flat surfaces, but spherical capsules possess a perfect "infinite" or fully suspended membranes. Similarities and transitions between spherical and flat membranes are discussed, while applications of membranes are also emphasized. PMID- 28809798 TI - Socioeconomic Inequalities in Green Space Quality and Accessibility-Evidence from a Southern European City. AB - Background: The provision of green spaces is an important health promotion strategy to encourage physical activity and to improve population health. Green space provision has to be based on the principle of equity. This study investigated the presence of socioeconomic inequalities in geographic accessibility and quality of green spaces across Porto neighbourhoods (Portugal). Methods: Accessibility was evaluated using a Geographic Information System and all the green spaces were audited using the Public Open Space Tool. Kendall's tau b correlation coefficients and ordinal regression were used to test whether socioeconomic differences in green space quality and accessibility were statistically significant. Results: Although the majority of the neighbourhoods had an accessible green space, mean distance to green space increased with neighbourhood deprivation. Additionally, green spaces in the more deprived neighbourhoods presented significantly more safety concerns, signs of damage, lack of equipment to engage in active leisure activities, and had significantly less amenities such as seating, toilets, cafes, etc. Conclusions: Residents from low socioeconomic positions seem to suffer from a double jeopardy; they lack both individual and community resources. Our results have important planning implications and might contribute to understanding why deprived communities have lower physical activity levels and poorer health. PMID- 28809797 TI - Optogenetic Investigation of Arousal Circuits. AB - Modulation between sleep and wake states is controlled by a number of heterogeneous neuron populations. Due to the topological proximity and genetic co localization of the neurons underlying sleep-wake state modulation optogenetic methods offer a significant improvement in the ability to benefit from both the precision of genetic targeting and millisecond temporal control. Beginning with an overview of the neuron populations mediating arousal, this review outlines the progress that has been made in the investigation of arousal circuits since the incorporation of optogenetic techniques and the first in vivo application of optogenetic stimulation in hypocretin neurons in the lateral hypothalamus. This overview is followed by a discussion of the future progress that can be made by incorporating more recent technological developments into the research of neural circuits. PMID- 28809799 TI - Update on Monoterpenes as Antimicrobial Agents: A Particular Focus on p-Cymene. AB - p-Cymene [1-methyl-4-(1-methylethyl)-benzene] is a monoterpene found in over 100 plant species used for medicine and food purposes. It shows a range of biological activity including antioxidant, anti-inflammatory, antinociceptive, anxiolytic, anticancer and antimicrobial effects. This last property has been widely investigated due to the urgent need for new substances with antimicrobial properties, to be used to treat communicable diseases whose diffusion in developed countries has been facilitated by globalization and the evolution of antimicrobial resistance. This review summarizes available scientific data, as reported by the most recent studies describing the antimicrobial activity of p cymene either alone, or as the main component of plant extracts, as well as addressing the mechanisms of action of cymenes as antimicrobial agents. While p cymene is one of the major constituents of extracts and essential oils used in traditional medicines as antimicrobial agents, but considering the limited data on its in vivo efficacy and safety, further studies are required to reach a definitive recommendation on the use and beneficial effects of p-cymene in human healthcare and in biomedical applications as a promising candidate to functionalize biomaterials and nanomaterials. PMID- 28809800 TI - Effect of 2,6-Bis-(1-hydroxy-1,1-diphenyl-methyl) Pyridine as Organic Additive in Sulfide NiMoP/gamma-Al2O3 Catalyst for Hydrodesulfurization of Straight-Run Gas Oil. AB - The effect of 2,6-bis-(1-hydroxy-1,1-diphenyl-methyl) pyridine (BDPHP) in the preparation of NiMoP/gamma-Al2O3 catalysts have been investigated in the hydrodesulfurization (HDS) of straight-run gas oil. The gamma-Al2O3 support was modified by surface impregnation of a solution of BDPHP to afford BDPHP/Ni molar ratios (0.5 and 1.0) in the final composition. The highest activity for NiMoP materials was found when the molar ratio of BDPHP/Ni was of 0.5. X-ray diffraction (XRD) results revealed that NiMoP (0.5) showed better dispersion of MoO3 than the NiMoP (1.0). Fourier transform infrared spectroscopy (FT-IR) results indicated that the organic additive interacts with the gamma-Al2O3 surface and therefore discards the presence of Mo or Ni complexes. Raman spectroscopy suggested a high Raman ratio for the NiMoP (0.5) sample. The increment of the Mo=O species is related to a major availability of Mo species in the formation of MoS2. The temperature programmed reduction (TPR) results showed that the NiMoP (0.5) displayed moderate metal-support interaction. Likewise, X ray photoelectron spectroscopy (XPS) exhibited higher sulfurization degree for NiMoP (0.5) compared with NiMoP (1.0). The increment of the MoO3 dispersion, the moderate metal-support interaction, the increase of sulfurization degree and the increment of Mo=O species provoked by the BDPHP incorporation resulted in a higher gas oil HDS activity. PMID- 28809801 TI - A Unique and Simple Approach to Improve Sensitivity in 15N-NMR Relaxation Measurements for NH3+ Groups: Application to a Protein-DNA Complex. AB - NMR spectroscopy is a powerful tool for research on protein dynamics. In the past decade, there has been significant progress in the development of NMR methods for studying charged side chains. In particular, NMR methods for lysine side-chain NH3+ groups have been proven to be powerful for investigating the dynamics of hydrogen bonds or ion pairs that play important roles in biological processes. However, relatively low sensitivity has been a major practical issue in NMR experiments on NH3+ groups. In this paper, we present a unique and simple approach to improve sensitivity in 15N relaxation measurements for NH3+ groups. In this approach, the efficiency of coherence transfers for the desired components are maximized, whereas undesired anti-phase or multi-spin order components are purged through pulse schemes and rapid relaxation. For lysine side chain NH3+ groups of a protein-DNA complex, we compared the data obtained with the previous and new pulse sequences under the same conditions and confirmed that the 15N relaxation parameters were consistent for these datasets. While retaining accuracy in measuring 15N relaxation, our new pulse sequences for NH3+ groups allowed an 82% increase in detection sensitivity of 15N longitudinal and transverse relaxation measurements. PMID- 28809803 TI - Hitchhiking Robots: A Collaborative Approach for Efficient Multi-Robot Navigation in Indoor Environments. AB - Hitchhiking is a means of transportation gained by asking other people for a (free) ride. We developed a multi-robot system which is the first of its kind to incorporate hitchhiking in robotics, and discuss its advantages. Our method allows the hitchhiker robot to skip redundant computations in navigation like path planning, localization, obstacle avoidance, and map update by completely relying on the driver robot. This allows the hitchhiker robot, which performs only visual servoing, to save computation while navigating on the common path with the driver robot. The driver robot, in the proposed system performs all the heavy computations in navigation and updates the hitchhiker about the current localized positions and new obstacle positions in the map. The proposed system is robust to recover from 'driver-lost' scenario which occurs due to visual servoing failure. We demonstrate robot hitchhiking in real environments considering factors like service-time and task priority with different start and goal configurations of the driver and hitchhiker robots. We also discuss the admissible characteristics of the hitchhiker, when hitchhiking should be allowed and when not, through experimental results. PMID- 28809802 TI - Effects of the HN Antigenic Difference between the Vaccine Strain and the Challenge Strain of Newcastle Disease Virus on Virus Shedding and Transmission. AB - Newcastle disease (ND) leading to heavy economic losses to the poultry industry worldwide is caused by Newcastle disease virus (NDV). Even though intensive vaccination programs have been implemented in many countries, virulent NDV can still be frequently isolated in well-vaccinated flocks. We compared the protection efficiency of LaSota and two sub-genotype VIId vaccines, NDV/AI4 and NDV O/AI4, in which NDV O/AI4 was constructed by replacing the hemagglutinin neuraminidase (HN) gene of the vaccine strain NDV/AI4 with that from the variant NDV strain JS-14-12-Ch by the cross hemagglutination inhibition test and immune protection test. The number of birds shedding the virus and the titer of the shedding virus from the challenged birds were tested to evaluate the protection efficiency in the immune protection test. The cross hemagglutination inhibition and neutralization tests between JS-14-12-Ch and the three vaccines displayed a significant antigenic difference between JS-14-12-Ch and LaSota or NDV/AI4, but not between JS-14-12-Ch and NDV O/AI4. The results of the immune protection test showed that NDV O/AI4 could provide improved protection as determined by a significant decrease in both the number of birds shedding the virus and the titer of the shedding virus from the challenged birds. The results in this study indicated that the antigenic similarity between the vaccine strain and the challenge strain is important in reducing the shedding of virulent virus in which the congruence of the NDV HN protein may play a critical role. PMID- 28809806 TI - A Continuum Damage Mechanics Model for the Static and Cyclic Fatigue of Cellular Composites. AB - The fatigue behavior of a cellular composite with an epoxy matrix and glass foam granules is analyzed and modeled by means of continuum damage mechanics. The investigated cellular composite is a particular type of composite foam, and is very similar to syntactic foams. In contrast to conventional syntactic foams constituted by hollow spherical particles (balloons), cellular glass, mineral, or metal place holders are combined with the matrix material (metal or polymer) in the case of cellular composites. A microstructural investigation of the damage behavior is performed using scanning electron microscopy. For the modeling of the fatigue behavior, the damage is separated into pure static and pure cyclic damage and described in terms of the stiffness loss of the material using damage models for cyclic and creep damage. Both models incorporate nonlinear accumulation and interaction of damage. A cycle jumping procedure is developed, which allows for a fast and accurate calculation of the damage evolution for constant load frequencies. The damage model is applied to examine the mean stress effect for cyclic fatigue and to investigate the frequency effect and the influence of the signal form in the case of static and cyclic damage interaction. The calculated lifetimes are in very good agreement with experimental results. PMID- 28809805 TI - Diet Quality Scores of Australian Adults Who Have Completed the Healthy Eating Quiz. AB - Higher scores obtained using diet quality and variety indices are indicators of more optimal food and nutrient intakes and lower chronic disease risk. The aim of this paper is to describe the overall diet quality and variety in a sample of Australian adults who completed an online diet quality self-assessment tool, the Healthy Eating Quiz. The Healthy Eating Quiz takes approximately five minutes to complete online and computes user responses into a total diet quality score (out of a maximum of 73 points) and then categorizes them into the following groups: 'needs work' (<33), 'getting there' (33-38), 'excellent' (39-46), or 'outstanding' (47+). There was a total of 93,252 first-time respondents, of which 76% were female. Over 80% of respondents were between 16-44 years of age. The mean total score was 34.1 +/- 9.7 points. Females had a higher total score than males (p < 0.001) and vegetarians had higher total scores than non-vegetarians (p < 0.001). Healthy eating quiz scores were higher in those aged 45-75 years compared to 16-44 years (p < 0.001). When comparing Socioeconomic Indices for Areas deciles, those most disadvantaged had a lower total score than those least disadvantaged (p < 0.001). Repeat measures showed that those who scored lowest (needs work) in their first completion increased their total score by 3.2 +/- 7.4 at their second completion (p < 0.001). While the Healthy Eating Quiz data indicates that individuals receiving feedback on how to improve their score can improve their diet quality, there is a need for further nutrition promotion interventions in Australian adults. PMID- 28809804 TI - Type 1 Diabetes and Non-Alcoholic Fatty Liver Disease: When Should We Be Concerned? A Nationwide Study in Brazil. AB - Obesity is increasing worldwide, affecting even patients with type 1 diabetes (T1D). A higher prevalence of associated comorbidities is expected, such as non alcoholic fatty liver disease (NAFLD). This paper reports a cross-sectional multicenter study on a population with T1D (n = 1662), which aimed to evaluate the prevalence of metabolic syndrome (MS), a known risk factor for NAFLD, and to investigate predisposing factors associated with MS, as well as factors associated with elevated alanine aminotransferase (ALT), as it correlates to liver fat content. Patients were from 14 public clinics of 10 cities from all geographical regions of Brazil. A high prevalence of MS was found, especially among adults (32.3%), and this was related to age, female gender, acid uric levels, and the presence of acanthosis nigricans. ALT above the normal range was associated with triglyceride levels (especially above 129.5 mg/dL), serum uric acid, age, male gender, HbA1c, and non-Caucasian ethnicity. Patients with T1D, metabolic syndrome, and the aforementioned factors may be at a higher risk of NAFLD and should be referred to ultrasound for NAFLD evaluation. Further studies are necessary to establish the prevalence of NAFLD in individuals with T1D and to determine the disease's progression in these patients. PMID- 28809807 TI - Dynamics of Implementation and Maintenance of Organizational Health Interventions. AB - In this study, we present case studies to explore the dynamics of implementation and maintenance of health interventions. We analyze how specific interventions are built and eroded, how the building and erosion mechanisms are interconnected, and why we can see significantly different erosion rates across otherwise similar organizations. We use multiple comparative obesity prevention case studies to provide empirical information on the mechanisms of interest, and use qualitative systems modeling to integrate our evolving understanding into an internally consistent and transparent theory of the phenomenon. Our preliminary results identify reinforcing feedback mechanisms, including design of organizational processes, motivation of stakeholders, and communication among stakeholders, which influence implementation and maintenance of intervention components. Over time, these feedback mechanisms may drive a wedge between otherwise similar organizations, leading to distinct configurations of implementation and maintenance processes. PMID- 28809808 TI - Combination of Poly(lactic) Acid and Starch for Biodegradable Food Packaging. AB - The massive use of synthetic plastics, in particular in the food packaging area, has a great environmental impact, and alternative more ecologic materials are being required. Poly(lactic) acid (PLA) and starch have been extensively studied as potential replacements for non-degradable petrochemical polymers on the basis of their availability, adequate food contact properties and competitive cost. Nevertheless, both polymers exhibit some drawbacks for packaging uses and need to be adapted to the food packaging requirements. Starch, in particular, is very water sensitive and its film properties are heavily dependent on the moisture content, exhibiting relatively low mechanical resistance. PLA films are very brittle and offer low resistance to oxygen permeation. Their combination as blend or multilayer films could provide properties that are more adequate for packaging purposes on the basis of their complementary characteristics. The main characteristics of PLA and starch in terms of not only the barrier and mechanical properties of their films but also of their combinations, by using blending or multilayer strategies, have been analyzed, identifying components or processes that favor the polymer compatibility and the good performance of the combined materials. The properties of some blends/combinations have been discussed in comparison with those of pure polymer films. PMID- 28809809 TI - Study of CeO2 Modified AlNi Mixed Pillared Clays Supported Palladium Catalysts for Benzene Adsorption/Desorption-Catalytic Combustion. AB - A new functional AlNi-pillared clays (AlNi-PILC) with a large surface area and pore volume was synthesized. The performance of adsorption/desorption-catalytic combustion over CeO2-modified Pd/AlNi-PILC catalysts was also studied. The results showed that the d001-value and specific surface area (SBET) of AlNi-PILC reached 2.11 nm and 374.8 m2/g, respectively. The large SBET and the d001-value improved the high capacity for benzene adsorption. Also, the strong interaction between PdCe mixed oxides and AlNi-PILC led to the high dispersion of PdO and CeO2 on the support, which was responsible for the high catalytic performance. Especially, 0.2% Pd/12.5% Ce/AlNi-PILC presented high performance for benzene combustion at 240 degrees C and high CO2 selectivity. Also, the combustion temperatures were lower compared to the desorption temperatures, which demonstrated that it could accomplish benzene combustion during the desorption process. Furthermore, its activity did not decrease after continuous reaction for 1000 h in dry air, and it also displayed good resistance to water and the chlorinated compound, making it a promising catalytic material for the elimination of volatile organic compounds. PMID- 28809810 TI - Veterinary and Equine Science Students' Interpretation of Horse Behaviour. AB - Many veterinary and undergraduate equine science students have little previous horse handling experience and a poor understanding of horse behaviour; yet horses are one of the most unsafe animals with which veterinary students must work. It is essential for veterinary and equine students to learn how to interpret horse behaviour in order to understand demeanour and levels of arousal, and to optimise their own safety and the horses' welfare. The study utilised a qualitative research approach to investigate veterinary science and veterinary technology and undergraduate equine science students' interpretation of expressive behaviours shown by horses. The students (N = 127) were shown six short video clips and asked to select the most applicable terms, from a pre-determined list, to describe the behavioural expression of each individual horse. A wide variation of terms were selected by students and in some situations of distress, or situations that may be dangerous or lead to compromised welfare, apparently contradictory terms were also selected (happy or playful) by students with less experience with horses. Future studies should consider the use of Qualitative Behavioural Analysis (QBA) and free-choice profiling to investigate the range of terms used by students to describe the expressive demeanour and arousal levels of horses. PMID- 28809811 TI - Mutation Clusters from Cancer Exome. AB - We apply our statistically deterministic machine learning/clustering algorithm *K means (recently developed in https://ssrn.com/abstract=2908286) to 10,656 published exome samples for 32 cancer types. A majority of cancer types exhibit a mutation clustering structure. Our results are in-sample stable. They are also out-of-sample stable when applied to 1389 published genome samples across 14 cancer types. In contrast, we find in- and out-of-sample instabilities in cancer signatures extracted from exome samples via nonnegative matrix factorization (NMF), a computationally-costly and non-deterministic method. Extracting stable mutation structures from exome data could have important implications for speed and cost, which are critical for early-stage cancer diagnostics, such as novel blood-test methods currently in development. PMID- 28809812 TI - The Healthy Eating Agenda in Australia. Is Salt a Priority for Manufacturers? AB - Many nation states have endorsed and acted on the World Health Organization's target of a 30% reduction in global salt consumption by 2025. In Australia, new government-led voluntary measures were initiated in 2009, consisting of public private partnerships, front-of-pack labelling, and food reformulation targets (which include reduced salt). How Australia's private sector has responded to this healthy eating agenda has been investigated in a limited way, particularly with regards to manufacturers which produce processed foods considered significant sources of sodium. In this study we asked: have Australia's largest food manufacturers made "...positive (nutrition) changes to their product portfolios" as disclosed in their public policies, priorities, and communications? And, is salt reduction a priority for processed food manufacturers? A systematic search and critical content-analysis of grey literature published by food manufacturers was conducted. The results suggest half of the sample publically describe some salt reduction activities but the scale and efficacy of these changes is unclear from the available literature. The Australian Government's Healthy Food Partnership could capitalise on current documented activities in salt reduction, and implement a more comprehensive healthy eating agenda moving forward. In light of the increasing rates of hypertension, population salt consumption and diet-related disease, more could be done. PMID- 28809815 TI - Determination of Amineptine and Amprolium Hydrochlorides through Ion Associates with Cobalt (II) Thiocyanate. AB - Two new methods for the determination of amineptine (AMN) and amprolium (AMP) have been developed. The methods consist of extractin the ion - pairs between the drug and the inorganic complex [Co (SCN)4]-2. The optimal experimental conditions of both methods including pH, concentration of Co (II) and tlxocyanate ions, and the organic solvents were studied. The optimum pH was found to be 3.9, nitrobenzene proved to be the most suitable solvent, giving quantitative extraction for the two drugs. The two drugs can be determined in the organic phase spectrophotometrically at 625 nm showing Sandell sensitivities of 0.19 and 0.12 ug cm-2 with relative standard deviation of 0.46 and 0.87 % for amineptine and amprolium, respectively.The indirect method was also applied to measure cobalt in the organic phase by atomic absorption spectrometry at 240.7 nm, and the relative standard deviation of the method is approximately 0.35 and 0.29 % for amineptine and amprolium, respectively. The proposed methods were found to be suitable for the accurate, simple and rapid analysis of amineptine and amprolium hydrochlorides in the bulk drugs and in pharmaceutical forms. PMID- 28809814 TI - Yerba Mate (Ilex paraguariensis) Metabolic, Satiety, and Mood State Effects at Rest and during Prolonged Exercise. AB - Yerba Mate (YM), has become a popular herb ingested for enhancing metabolic health and weight-loss outcomes. No studies have tested the combined metabolic, satiety, and psychomotor effects of YM during exercise. We tested whether YM ingestion affects fatty acid oxidation (FAO), profile of mood state score (POMS), and subjective appetite scale (VAS), during prolonged moderate exercise. Twelve healthy active females were randomized to ingest either 2 g of YM or placebo (PLC) in a repeated-measures design. Participants rested for 120 min before performing a 30-min cycling exercise corresponding to individuals' crossover point intensity (COP). FAO, determined using indirect calorimetry, was significantly higher during the 30-min exercise in YM vs. PLC (0.21 +/- 0.07 vs. 0.17 +/- 0.06 g/min, p < 0.05). VAS scores for hunger, prospective eating, and desire to eat were all reduced (p < 0.05). Whereas, POMS measures of focus, energy, and concentration were all increased (p < 0.05). There was no significant time-effect for any of the measured variables, nor was there any interaction effects between YM treatment and time. Combining YM intake with prolonged exercise at targeted "fat-loss"' intensities augments FAO and improves measures of satiety and mood state. Such positive combined metabolic, satiety, and psychomotor effects may provide an important role for designing future fat and weight-loss lifestyle interventions. PMID- 28809813 TI - Molecular Mechanisms Underlying Inhibitory Binding of Alkylimidazolium Ionic Liquids to Laccase. AB - Water-miscible alkylimidazolium ionic liquids (ILs) are "green" co-solvents for laccase catalysis, but generally inhibit enzyme activity. Here, we present novel insights into inhibition mechanisms by a combination of enzyme kinetics analysis and molecular simulation. Alkylimidazolium cations competitively bound to the TI Cu active pocket in the laccase through hydrophobic interactions. Cations with shorter alkyl chains (C2~C6) entered the channel inside the pocket, exhibiting a high compatibility with laccase (competitive inhibition constant Kic = 3.36~3.83 mM). Under the same conditions, [Omim]Cl (Kic = 2.15 mM) and [Dmim]Cl (Kic = 0.18 mM) with longer alkyl chains bound with Leu296 or Leu297 near the pocket edge and Leu429 around TI Cu, which resulted in stronger inhibition. Complexation with alkylimidazolium cations shifted the pH optima of laccase to the right by 0.5 unit, and might, thereby, lead to invalidation of the Hofmeister series of anions. EtSO4- showed higher biocompatibility than did Ac- or Cl-, probably due to its binding near the TI Cu and its hindering the entry of alkylimidazolium cations. In addition, all tested ILs accelerated the scavenging of 2, 2'-azino bis-(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radicals, which, however, did not play a determining role in the inhibition of laccase. PMID- 28809816 TI - Modeling the Non-Equilibrium Process of the Chemical Adsorption of Ammonia on GaN(0001) Reconstructed Surfaces Based on Steepest-Entropy-Ascent Quantum Thermodynamics. AB - Clearly understanding elementary growth processes that depend on surface reconstruction is essential to controlling vapor-phase epitaxy more precisely. In this study, ammonia chemical adsorption on GaN(0001) reconstructed surfaces under metalorganic vapor phase epitaxy (MOVPE) conditions (3Ga-H and Nad-H + Ga-H on a 2 * 2 unit cell) is investigated using steepest-entropy-ascent quantum thermodynamics (SEAQT). SEAQT is a thermodynamic-ensemble based, first-principles framework that can predict the behavior of non-equilibrium processes, even those far from equilibrium where the state evolution is a combination of reversible and irreversible dynamics. SEAQT is an ideal choice to handle this problem on a first principles basis since the chemical adsorption process starts from a highly non equilibrium state. A result of the analysis shows that the probability of adsorption on 3Ga-H is significantly higher than that on Nad-H + Ga-H. Additionally, the growth temperature dependence of these adsorption probabilities and the temperature increase due to the heat of reaction is determined. The non equilibrium thermodynamic modeling applied can lead to better control of the MOVPE process through the selection of preferable reconstructed surfaces. The modeling also demonstrates the efficacy of DFT-SEAQT coupling for determining detailed non-equilibrium process characteristics with a much smaller computational burden than would be entailed with mechanics-based, microscopic mesoscopic approaches. PMID- 28809817 TI - Synthesis and Physicochemical Characterization of the Process-Related Impurities of Eplerenone, an Antihypertensive Drug. AB - Two unknown impurities were observed during the process development for multigram scale synthesis of eplerenone (Inspra(r)). The new process-related impurities were identified and fully characterized as the corresponding (7beta,11alpha,17alpha)-11-hydroxy- and (7alpha,11beta,17alpha)-9,11 dichloroeplerenone derivatives 12a and 13. Seven other known but poorly described in the literature eplerenone impurities, including four impurities A, B, C and E listed in the European Pharmacopoeia 8.4 were also detected, identified and fully characterized. All these contaminants result from side reactions taking place on the steroid ring C of the starting 11alpha-hydroxy-7alpha-(methoxycarbonyl)-3-oxo 17alpha-pregn-4-ene-21,17-carbolactone (12) and the key intermediate (7alpha,17alpha)-9(11)-enester 7, including epimerization of the C-7 asymmetric center, oxidation, dehydration, chlorination and lactonization. The impurities were isolated and/or synthesized and fully characterized by infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectrometry/electrospray ionization (HRMS/ESI). Their 1H- and 13C-NMR signals were fully assigned. The molecular structures of the eight impurities, including the new (7beta,11alpha,17alpha)-11-hydroxy- and (7alpha,11beta,17alpha)-9,11 dichloroeplerenone related substances 12a and 13, were solved and refined using single-crystal X-ray diffraction (SCXRD). The full identification and characterization of these impurities should be useful for the quality control and the validation of the analytical methods in the manufacture of eplerenone. PMID- 28809818 TI - Synthesis of 5'-GalNAc-Conjugated Oligonucleotides: A Comparison of Solid and Solution-Phase Conjugation Strategies. AB - Antisense oligonucleotides (ASOs) conjugated to triantennary N-acetyl galactosamine (GalNAc) ligands represent an emerging approach to antisense therapy. Our current generation of GalNAc-ASO conjugates link the GalNAc to the 5'-terminus of the ASO. The conjugation reaction can be accomplished using solution-phase or solid-phase techniques. Here we show a direct comparison of a solution-phase and a solid-phase conjugation strategy. The solution-phase approach, using amine-pentafluorophenyl (PFP) ester coupling, is higher yielding and gives material of slightly higher purity, but requires several additional unit operations and longer production time. The solid-phase approach, using a protected GalNAc ligand phosphoramidite, is more expedient, but results in lower yield and purity. Both strategies efficiently deliver conjugated material in excellent purity. PMID- 28809819 TI - TAMRA/TAMRA Fluorescence Quenching Systems for the Activity Assay of Alkaline Phosphatase. AB - We introduce two types of fluorescence-quenching assay for alkaline phosphatases (APs) by using a carboxytetramethyl-rhodamine (TAMRA)-labeled phosphate-binding tag molecule (TAMRA-Phos-tag). In the first assay, TAMRA-labeled O phosphorylethanolamine (TAMRA-PEA) was used as an artificial AP-substrate. TAMRA Phos-tag specifically captured TAMRA-PEA to form a 1:1 complex at pH 7.4; the intensity of the fluorescence peak of the complex at 580 nm (lambdaex = 523 nm) was significantly reduced to 32% of the average value for the two individual components as a result of the mutual approach of the TAMRA moieties. As TAMRA-PEA was dephosphorylated by AP, the resulting TAMRA-labeled ethanolamine dissociated and the fluorescence increased in a manner dependent on the AP dose and the time. In the second assay, pyrophosphate (PP), a natural AP-substrate, was used as a bridging ligand to form a dimeric TAMRA-Phos-tag complex. The dimerization reduced the fluorescence intensity to 49% of that in the absence of PP. As pyrophosphate was hydrolyzed to two orthophosphate moieties by AP, the 580-nm fluorescence recovered in a time-dependent manner. By examining the initial slope of this time-dependent fluorescence recovery, we succeeded in evaluating the 50% inhibitory concentrations of orthovanadate toward two AP isozymes under near physiological conditions. PMID- 28809820 TI - Certain Dietary Habits Contribute to the Functional Dyspepsia in South China Rural Area. AB - BACKGROUND Functional dyspepsia (FD) refers to a group of upper gastrointestinal syndromes, subdivided into two types: postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). The etiology of FD remains unclear; however, unhealthy dietary habit is one potential underlying cause. We aim to explore the association of poor dietary habits with FD and its subtypes. MATERIAL AND METHODS A validated epidemiological questionnaire was designed to investigate dietary habits and gastrointestinal syndromes. Citizens in the Baotun community of Dongguan were invited to complete the study questionnaire. All participants were asked to undergo a physical examination and a blinded physician interview. The study was conducted from June 2015 to June 2016. FD was diagnosed using ROME III criteria. The association between investigated dietary habits and dyspeptic symptoms were explored. RESULTS There were 1,304 adult residents recruited for the study survey; 165 residents had existing organic dyspepsia (OD), 203 residents were diagnosed with FD, and the other 936 participants, who were without dyspeptic symptoms or functional gastrointestinal diseases, were regarded as the control group. Subtype diagnosis indicated 61 participants had EPS, 66 participants had PDS, and 76 participants had coexisting EPS and PDS. Unhealthy dietary habits were more prevalent in the FD group than in the control groups (75.86% versus 37.50%; p<0.001). FD was found to be associated with irregular mealtime, dining out, fatty food, sweet food, and coffee (p<0.05). The impact of each dietary factor varied with FD subtypes. CONCLUSIONS Certain types of dietary habits were positively correlated with the prevalence of FD. FD subtypes showed relatively different associations with dietary factors. PMID- 28809821 TI - Gradient Strain Chip for Stimulating Cellular Behaviors in Cell-laden Hydrogel. AB - Artificial guidance for cellular alignment is a hot topic in the field of tissue engineering. Most of the previous research has investigated single strain-induced cellular alignment on a cell-laden hydrogel by using complex experimental processes and mass controlling systems, which are usually associated with contamination issues. Thus, in this article, we propose a simple approach to building a gradient static strain using a fluidic chip with a plastic PDMS cover and a UV transparent glass substrate for the stimulation of cellular behavior in a 3D hydrogel. Overloading photo-patternable cell prepolymer in the fluidic chamber can generate a convex curved PDMS membrane on the cover. After UV crosslinking, through a concentric circular micropattern under the curved PDMS membrane, and buffer washing, a microenvironment for investigating cell behaviors under a variety of gradient strains is self-established in a single fluidic chip, without external instruments. NIH3T3 cells were demonstrated after observing the change in the cellular alignment trend under geometry guidance, in cooperation with strain stimulation, which varied from 15 - 65% on hydrogels. After a 3-day incubation, the hydrogel geometry dominated the cell alignment under low compressive strain, where cells aligned along the hydrogel elongation direction under high compressive strain. Between these, the cells showed random alignment due to the dissipation of the radical guidance of hydrogel elongation and the geometry guidance of the patterned hydrogel. PMID- 28809822 TI - Assessment and Communication for People with Disorders of Consciousness. AB - In this experiment, we demonstrate a suite of hybrid Brain-Computer Interface (BCI)-based paradigms that are designed for two applications: assessing the level of consciousness of people unable to provide motor response and, in a second stage, establishing a communication channel for these people that enables them to answer questions with either 'yes' or 'no'. The suite of paradigms is designed to test basic responses in the first step and to continue to more comprehensive tasks if the first tests are successful. The latter tasks require more cognitive functions, but they could provide communication, which is not possible with the basic tests. All assessment tests produce accuracy plots that show whether the algorithms were able to detect the patient's brain's response to the given tasks. If the accuracy level is beyond the significance level, we assume that the subject understood the task and was able to follow the sequence of commands presented via earphones to the subject. The tasks require users to concentrate on certain stimuli or to imagine moving either the left or right hand. All tasks are designed around the assumption that the user is unable to use the visual modality, and thus, all stimuli presented to the user (including instructions, cues, and feedback) are auditory or tactile. PMID- 28809823 TI - Non-equilibrium Microwave Plasma for Efficient High Temperature Chemistry. AB - A flowing microwave plasma based methodology for converting electric energy into internal and/or translational modes of stable molecules with the purpose of efficiently driving non-equilibrium chemistry is discussed. The advantage of a flowing plasma reactor is that continuous chemical processes can be driven with the flexibility of startup times in the seconds timescale. The plasma approach is generically suitable for conversion/activation of stable molecules such as CO2, N2 and CH4. Here the reduction of CO2 to CO is used as a model system: the complementary diagnostics illustrate how a baseline thermodynamic equilibrium conversion can be exceeded by the intrinsic non-equilibrium from high vibrational excitation. Laser (Rayleigh) scattering is used to measure the reactor temperature and Fourier Transform Infrared Spectroscopy (FTIR) to characterize in situ internal (vibrational) excitation as well as the effluent composition to monitor conversion and selectivity. PMID- 28809824 TI - Creation and Transplantation of an Adipose-derived Stem Cell (ASC) Sheet in a Diabetic Wound-healing Model. AB - Artificial skin has achieved considerable therapeutic results in clinical practice. However, artificial skin treatments for wounds in diabetic patients with impeded blood flow or with large wounds might be prolonged. Cell-based therapies have appeared as a new technique for the treatment of diabetic ulcers, and cell-sheet engineering has improved the efficacy of cell transplantation. A number of reports have suggested that adipose-derived stem cells (ASCs), a type of mesenchymal stromal cell (MSC), exhibit therapeutic potential due to their relative abundance in adipose tissue and their accessibility for collection when compared to MSCs from other tissues. Therefore, ASCs appear to be a good source of stem cells for therapeutic use. In this study, ASC sheets from the epididymal adipose fat of normal Lewis rats were successfully created using temperature responsive culture dishes and normal culture medium containing ascorbic acid. The ASC sheets were transplanted into Zucker diabetic fatty (ZDF) rats, a rat model of type 2 diabetes and obesity, that exhibit diminished wound healing. A wound was created on the posterior cranial surface, ASC sheets were transplanted into the wound, and a bilayer artificial skin was used to cover the sheets. ZDF rats that received ASC sheets had better wound healing than ZDF rats without the transplantation of ASC sheets. This approach was limited because ASC sheets are sensitive to dry conditions, requiring the maintenance of a moist wound environment. Therefore, artificial skin was used to cover the ASC sheet to prevent drying. The allogenic transplantation of ASC sheets in combination with artificial skin might also be applicable to other intractable ulcers or burns, such as those observed with peripheral arterial disease and collagen disease, and might be administered to patients who are undernourished or are using steroids. Thus, this treatment might be the first step towards improving the therapeutic options for diabetic wound healing. PMID- 28809825 TI - Analysis of Histone Antibody Specificity with Peptide Microarrays. AB - Post-translational modifications (PTMs) on histone proteins are widely studied for their roles in regulating chromatin structure and gene expression. The mass production and distribution of antibodies specific to histone PTMs has greatly facilitated research on these marks. As histone PTM antibodies are key reagents for many chromatin biochemistry applications, rigorous analysis of antibody specificity is necessary for accurate data interpretation and continued progress in the field. This protocol describes an integrated pipeline for the design, fabrication and use of peptide microarrays for profiling the specificity of histone antibodies. The design and analysis aspects of this procedure are facilitated by ArrayNinja, an open-source and interactive software package we recently developed to streamline the customization of microarray print formats. This pipeline has been used to screen a large number of commercially available and widely used histone PTM antibodies, and data generated from these experiments are freely available through an online and expanding Histone Antibody Specificity Database. Beyond histones, the general methodology described herein can be applied broadly to the analysis of PTM-specific antibodies. PMID- 28809826 TI - High-throughput Screening for Protein-based Inheritance in S. cerevisiae. AB - The encoding of biological information that is accessible to future generations is generally achieved via changes to the DNA sequence. Long-lived inheritance encoded in protein conformation (rather than sequence) has long been viewed as paradigm-shifting but rare. The best characterized examples of such epigenetic elements are prions, which possess a self-assembling behavior that can drive the heritable manifestation of new phenotypes. Many archetypal prions display a striking N/Q-rich sequence bias and assemble into an amyloid fold. These unusual features have informed most screening efforts to identify new prion proteins. However, at least three known prions (including the founding prion, PrPSc) do not harbor these biochemical characteristics. We therefore developed an alternative method to probe the scope of protein-based inheritance based on a property of mass action: the transient overexpression of prion proteins increases the frequency at which they acquire a self-templating conformation. This paper describes a method for analyzing the capacity of the yeast ORFeome to elicit protein-based inheritance. Using this strategy, we previously found that >1% of yeast proteins could fuel the emergence of biological traits that were long lived, stable, and arose more frequently than genetic mutation. This approach can be employed in high throughput across entire ORFeomes or as a targeted screening paradigm for specific genetic networks or environmental stimuli. Just as forward genetic screens define numerous developmental and signaling pathways, these techniques provide a methodology to investigate the influence of protein-based inheritance in biological processes. PMID- 28809827 TI - A Method for Characterizing Embryogenesis in Arabidopsis. AB - Given the highly predictable nature of their development, Arabidopsis embryos have been used as a model for studies of morphogenesis in plants. However, early stage plant embryos are small and contain few cells, making them difficult to observe and analyze. A method is described here for characterizing pattern formation in plant embryos under a microscope using the model organism Arabidopsis. Following the clearance of fresh ovules using Hoyer's solution, the cell number in and morphology of embryos could be observed, and their developmental stage could be determined by differential interference contrast microscopy using a 100X oil immersion lens. In addition, the expression of specific marker proteins tagged with Green Fluorescent Protein (GFP) was monitored to annotate cell identity specification during embryo patterning by confocal laser scanning microscopy. Thus, this method can be used to observe pattern formation in wild-type plant embryos at the cellular and molecular levels, and to characterize the role of specific genes in embryo patterning by comparing pattern formation in embryos from wild-type plants and embryo-lethal mutants. Therefore, the method can be used to characterize embryogenesis in Arabidopsis. PMID- 28809829 TI - Horizontal Whole Mount: A Novel Processing and Imaging Protocol for Thick, Three dimensional Tissue Cross-sections of Skin. AB - Processing a tissue of interest to generate a microscopic image that supports a scientific argument can be challenging. The acquisition of high-quality microscopic images is not entirely dependent upon the quality of the microscope, but also upon the methods of tissue processing, which often involve multiple critical actions or steps. Furthermore, mesenchymal cell types in the skin and other tissues represent a new challenge for tissue preparation and imaging. Here, we present a complete process, from tissue harvest to microscopy. Our technique, called "horizontal whole mount," is one that novices can quickly become proficient in and that allows for antigen preservation and detection in 60-300 um thick sections cut with a cryostat. Sections of this thickness provide enhanced visualization of tissue microarchitecture in a three-dimensional environment. In addition, the protocol preserves mesenchymal cells in a manner that enhances image quality when compared to standard cryostat or paraffin sections, thereby increasing the efficacy and reliability of immunostaining. We believe that this protocol will benefit all laboratories that visualize skin, and possibly other tissues and organs. PMID- 28809828 TI - Bioengineering of Humanized Bone Marrow Microenvironments in Mouse and Their Visualization by Live Imaging. AB - Human hematopoietic stem cells (HSCs) reside in the bone marrow (BM) niche, an intricate, multifactorial network of components producing cytokines, growth factors, and extracellular matrix. The ability of HSCs to remain quiescent, self renew or differentiate, and acquire mutations and become malignant depends upon the complex interactions they establish with different stromal components. To observe the crosstalk between human HSCs and the human BM niche in physiological and pathological conditions, we designed a protocol to ectopically model and image a humanized BM niche in immunodeficient mice. We show that the use of different cellular components allows for the formation of humanized structures and the opportunity to sustain long-term human hematopoietic engraftment. Using two-photon microscopy, we can live-image these structures in situ at the single cell resolution, providing a powerful new tool for the functional characterization of the human BM microenvironment and its role in regulating normal and malignant hematopoiesis. PMID- 28809830 TI - Overexpression and Purification of Human Cis-prenyltransferase in Escherichia coli. AB - Prenyltransferases (PT) are a group of enzymes that catalyze chain elongation of allylic diphosphate using isopentenyl diphosphate (IPP) via multiple condensation reactions. DHDDS (dehydrodolichyl diphosphate synthase) is a eukaryotic long chain cis-PT (forming cis double bonds from the condensation reaction) that catalyzes chain elongation of farnesyl diphosphate (FPP, an allylic diphosphate) via multiple condensations with isopentenyl diphosphate (IPP). DHDDS is of biomedical importance, as a non-conservative mutation (K42E) in the enzyme results in retinitis pigmentosa, ultimately leading to blindness. Therefore, the present protocol was developed in order to acquire large quantities of purified DHDDS, suitable for mechanistic studies. Here, the usage of protein fusion, optimized culture conditions and codon-optimization were used to allow the overexpression and purification of functionally active human DHDDS in E. coli. The described protocol is simple, cost-effective and time sparing. The homology of cis-PT among different species suggests that this protocol may be applied for other eukaryotic cis-PT as well, such as those involved in natural rubber synthesis. PMID- 28809831 TI - Data Processing Methods for 3D Seismic Imaging of Subsurface Volcanoes: Applications to the Tarim Flood Basalt. AB - The morphology and structure of plumbing systems can provide key information on the eruption rate and style of basalt lava fields. The most powerful way to study subsurface geo-bodies is to use industrial 3D reflection seismological imaging. However, strategies to image subsurface volcanoes are very different from that of oil and gas reservoirs. In this study, we process seismic data cubes from the Northern Tarim Basin, China, to illustrate how to visualize sills through opacity rendering techniques and how to image the conduits by time-slicing. In the first case, we isolated probes by the seismic horizons marking the contacts between sills and encasing strata, applying opacity rendering techniques to extract sills from the seismic cube. The resulting detailed sill morphology shows that the flow direction is from the dome center to the rim. In the second seismic cube, we use time-slices to image the conduits, which corresponds to marked discontinuities within the encasing rocks. A set of time-slices obtained at different depths show that the Tarim flood basalts erupted from central volcanoes, fed by separate pipe like conduits. PMID- 28809832 TI - Phagocytosis Assay for Apoptotic Cells in Drosophila Embryos. AB - The molecular mechanisms underlying the phagocytosis of apoptotic cells need to be elucidated in more detail because of its role in immune and inflammatory intractable diseases. We herein developed an experimental method to investigate phagocytosis quantitatively using the fruit fly Drosophila, in which the gene network controlling engulfment reactions is evolutionally conserved from mammals. In order to accurately detect and count engulfing and un-engulfing phagocytes using whole animals, Drosophila embryos were homogenized to obtain dispersed cells including phagocytes and apoptotic cells. The use of dispersed embryonic cells enables us to measure in vivo phagocytosis levels as if we performed an in vitro phagocytosis assay in which it is possible to observe all phagocytes and apoptotic cells in whole embryos and precisely quantify the level of phagocytosis. We confirmed that this method reproduces those of previous studies that identified the genes required for the phagocytosis of apoptotic cells. This method allows the engulfment of dead cells to be analyzed, and when combined with the powerful genetics of Drosophila, will reveal the complex phagocytic reactions comprised of the migration, recognition, engulfment, and degradation of apoptotic cells by phagocytes. PMID- 28809833 TI - Application of Granger Causality Analysis of the Directed Functional Connection in Alzheimer's Disease and Mild Cognitive Impairment. AB - Impaired functional connectivity in the Default Mode Network (DMN) may be involved in the progression of Alzheimer's Disease (AD). The Posterior Cingulate Cortex (PCC) is a potential imaging marker for monitoring the progression of AD. Previous studies did not focus on the functional connectivity between the PCC and nodes in regions outside the DMN, but our study is an effort to explore these overlooked functional connections. For collecting data, we used functional Magnetic Resonance Imaging (fMRI) and Granger Causality Analysis (GCA). fMRI provides a non-invasive method for studying the dynamic interactions between the different brain regions. GCA is a statistical hypothesis test for determining whether one-time series is useful in forecasting another. In simple terms, it is judged by comparing the "Known all the information on the last moment, the distribution of the probability of X at this time" and the "Known all the information on the last moment except Y, the distribution of the probability of X at this time", to determine whether there is a causal relationship between Y and X. This definition is based on the complete information source and stationary chronological sequence. The main step of this analysis is to use X and Y to establish the regression equation and draw a causal relationship by a hypothetical test. Since GCA can measure causal effects, we used it to investigate the anisotropy of the functional connectivity and explore the hub function of the PCC. Here, we screened 116 participants for MRI scanning, and after preprocessing the data obtained from neuroimaging, we used GCA to derive the causal relationship of each node. Finally, we concluded that the directed connection is significantly different between the Mild Cognitive Impairment (MCI) and AD groups, both from the PCC to the whole brain and from the whole brain to the PCC. PMID- 28809834 TI - Quantifying Infra-slow Dynamics of Spectral Power and Heart Rate in Sleeping Mice. AB - Three vigilance states dominate mammalian life: wakefulness, non-rapid eye movement (non-REM) sleep, and REM sleep. As more neural correlates of behavior are identified in freely moving animals, this three-fold subdivision becomes too simplistic. During wakefulness, ensembles of global and local cortical activities, together with peripheral parameters such as pupillary diameter and sympathovagal balance, define various degrees of arousal. It remains unclear the extent to which sleep also forms a continuum of brain states-within which the degree of resilience to sensory stimuli and arousability, and perhaps other sleep functions, vary gradually-and how peripheral physiological states co-vary. Research advancing the methods to monitor multiple parameters during sleep, as well as attributing to constellations of these functional attributes, is central to refining our understanding of sleep as a multifunctional process during which many beneficial effects must be executed. Identifying novel parameters characterizing sleep states will open opportunities for novel diagnostic avenues in sleep disorders. We present a procedure to describe dynamic variations of mouse non-REM sleep states via the combined monitoring and analysis of electroencephalogram (EEG)/electrocorticogram (ECoG), electromyogram (EMG), and electrocardiogram (ECG) signals using standard polysomnographic recording techniques. Using this approach, we found that mouse non-REM sleep is organized into cycles of coordinated neural and cardiac oscillations that generate successive 25-s intervals of high and low fragility to external stimuli. Therefore, central and autonomic nervous systems are coordinated to form behaviorally distinct sleep states during consolidated non-REM sleep. We present surgical manipulations for polysomnographic (i.e., EEG/EMG combined with ECG) monitoring to track these cycles in the freely sleeping mouse, the analysis to quantify their dynamics, and the acoustic stimulation protocols to assess their role in the likelihood of waking up. Our approach has already been extended to human sleep and promises to unravel common organizing principles of non-REM sleep states in mammals. PMID- 28809835 TI - RGB and Spectral Root Imaging for Plant Phenotyping and Physiological Research: Experimental Setup and Imaging Protocols. AB - Better understanding of plant root dynamics is essential to improve resource use efficiency of agricultural systems and increase the resistance of crop cultivars against environmental stresses. An experimental protocol is presented for RGB and hyperspectral imaging of root systems. The approach uses rhizoboxes where plants grow in natural soil over a longer time to observe fully developed root systems. Experimental settings are exemplified for assessing rhizobox plants under water stress and studying the role of roots. An RGB imaging setup is described for cheap and quick quantification of root development over time. Hyperspectral imaging improves root segmentation from the soil background compared to RGB color based thresholding. The particular strength of hyperspectral imaging is the acquisition of chemometric information on the root-soil system for functional understanding. This is demonstrated with high resolution water content mapping. Spectral imaging however is more complex in image acquisition, processing and analysis compared to the RGB approach. A combination of both methods can optimize a comprehensive assessment of the root system. Application examples integrating root and aboveground traits are given for the context of plant phenotyping and plant physiological research. Further improvement of root imaging can be obtained by optimizing RGB image quality with better illumination using different light sources and by extension of image analysis methods to infer on root zone properties from spectral data. PMID- 28809836 TI - Nanosponge Tunability in Size and Crosslinking Density. AB - We describe a protocol for the synthesis of linear polyesters containing pendant epoxide functionality and their incorporation into a nanosponge with controlled dimensions. This approach begins with synthesis of a functionalized lactone which is key to the pendant functionalization of the resulting polymer. Valerolactone (VL) and allyl-valerolactone (AVL) are then copolymerized using ring-opening polymerization. Post-polymerization modification is then used to install an epoxide moiety on some or all of the pendant allyl groups. Epoxy-amine chemistry is employed to form nanoparticles in a dilute solution of both polymer and small molecule diamine crosslinker based on the desired nanosponge size and crosslinking density. Nanosponge sizes can be characterized by transmission electron microscopy (TEM) imaging to determine the dimension and distribution. This method provides a pathway by which highly tunable polyesters can create tunable nanoparticles, which can be used for small molecule drug encapsulation. Due to the nature of the backbone, these particles are hydrolytically and enzymatically degradable for a controlled release of a wide range of hydrophobic small molecules. PMID- 28809837 TI - Protocol for Assessing the Relative Effects of Environment and Genetics on Antler and Body Growth for a Long-lived Cervid. AB - Cervid phenotype can be placed into one of two categories: efficiency, which promotes survival over extravagant morphometric growth, and luxury, which promotes growth of large weaponry and body size. Populations of the same species display each phenotype depending on environmental conditions. Although antler and body size of male white-tailed deer (Odocoileus virginianus) varies by physiographic region in Mississippi, USA and is strongly correlated with regional variation in nutritional quality, the effects of population-level genetics from native stocks and previous re-stocking efforts cannot be disregarded. This protocol describes how we designed a controlled study, where other factors that influence phenotype, such as age and nutrition, are controlled. We brought wild caught pregnant females and six-month-old fawns from three distinct physiographic regions in Mississippi, USA to the Mississippi State University Rusty Dawkins Memorial Deer Unit. Deer from the same region were bred to produce a second generation of offspring, allowing us to assess generational responses and maternal effects. All deer ate the same high-quality (20% crude protein deer pellet) diet ad libitum. We uniquely marked each neonate and recorded body mass, hind foot, and total body length. Each subsequent fall, we sedated individuals via remote injection and sampled the same morphometrics plus antlers of adults. We found that all morphometrics increased in size from first to second generation, with full compensation of antler size (regional variation no longer present) and partial compensation of body mass (some evidence of regional variation) evident in the second generation. Second generation males that originated from our poorest quality soil region displayed about a 40% increase in antler size and about a 25% increase in body mass when compared to their wild harvested counterparts. Our results suggest phenotypic variation of wild male white-tailed deer in Mississippi are more related to differences in nutritional quality than population-level genetics. PMID- 28809838 TI - Easy Manipulation of Architectures in Protein-based Hydrogels for Cell Culture Applications. AB - Hydrogels are recognized as promising materials for cell culture applications due to their ability to provide highly hydrated cell environments. The field of 3D templates is rising due to the potential resemblance of those materials to the natural extracellular matrix. Protein-based hydrogels are particularly promising because they can easily be functionalized and can achieve defined structures with adjustable physicochemical properties. However, the production of macroporous 3D templates for cell culture applications using natural materials is often limited by their weaker mechanical properties compared to those of synthetic materials. Here, different methods were evaluated to produce macroporous bovine serum albumin (BSA)-based hydrogel systems, with adjustable pore sizes in the range of 10 to 70 um in radius. Furthermore, a method to generate channels in this protein based material that are several hundred microns long was established. The different methods to produce pores, as well as the influence of pore size on material properties such as swelling ratio, pH, temperature stability, and enzymatic degradation behavior, were analyzed. Pore sizes were investigated in the native, swollen state of the hydrogels using confocal laser scanning microscopy. The feasibility for cell culture applications was evaluated using a cell-adhesive RGD peptide modification of the protein system and two model cell lines: human breast cancer cells (A549) and adenocarcinomic human alveolar basal epithelial cells (MCF7). PMID- 28809839 TI - A Novel Mammary Fat Pad Transplantation Technique to Visualize the Vessel Generation of Vascular Endothelial Stem Cells. AB - Endothelial cells (ECs) are the fundamental building blocks of the vascular architecture and mediate vascular growth and remodeling to ensure proper vessel development and homeostasis. However, studies on endothelial lineage hierarchy remain elusive due to the lack of tools to gain access as well as to directly evaluate their behavior in vivo. To address this shortcoming, a new tissue model to study angiogenesis using the mammary fat pad has been developed. The mammary gland develops mostly in the postnatal stages, including puberty and pregnancy, during which robust epithelium proliferation is accompanied by extensive vascular remodeling. Mammary fat pads provide space, matrix, and rich angiogenic stimuli from the growing mammary epithelium. Furthermore, mammary fat pads are located outside the peritoneal cavity, making them an easily accessible grafting site for assessing the angiogenic potential of exogenous cells. This work also describes an efficient tracing approach using fluorescent reporter mice to specifically label the targeted population of vascular endothelial stem cells (VESCs) in vivo. This lineage tracing method, coupled with subsequent tissue whole-mount microscopy, enable the direct visualization of targeted cells and their descendants, through which the proliferation capability can be quantified and the differentiation commitment can be fate-mapped. Using these methods, a population of bipotent protein C receptor (Procr) expressing VESCs has recently been identified in multiple vascular systems. Procr+ VESCs, giving rise to both new ECs and pericytes, actively contribute to angiogenesis during development, homeostasis, and injury repair. Overall, this manuscript describes a new mammary fat pad transplantation and in vivo lineage tracing techniques that can be used to evaluate the stem cell properties of VESCs. PMID- 28809840 TI - A Novel Clinical Grade Isolation Method for Human Kidney Perivascular Stromal Cells. AB - Mesenchymal Stromal Cells (MSCs) are tissue homeostatic and immune modulatory cells that have shown beneficial effects in kidney diseases and transplantation. Perivascular Stromal Cells (PSCs) share characteristics with bone marrow MSCs (bmMSCs). However, they also possess, most likely due to local imprinting, tissue specific properties and play a role in local tissue homeostasis. This tissue specificity may result in tissue specific repair, also within the human kidney. We previously showed that human kidney PSCs (kPSCs) have enhanced kidney epithelial wound healing whereas bmMSCs did not have this potential. Moreover, kPSCs can ameliorate kidney injury in vivo. Therefore, kPSCs constitute an interesting source for cell therapy, particularly for kidney diseases and renal transplantation. Here we show the detailed isolation and culture method for kPSCs from transplant-grade human kidneys based on whole-organ perfusion of digestive enzymes via the renal artery and enrichment for the perivascular marker NG2. In this way, large cell quantities can be obtained that are suitable for cellular therapy. PMID- 28809841 TI - Measuring Neuromuscular Junction Functionality. AB - Neuromuscular junction (NMJ) functionality plays a pivotal role when studying diseases in which the communication between motor neuron and muscle is impaired, such as aging and amyotrophic lateral sclerosis (ALS). Here we describe an experimental protocol that can be used to measure NMJ functionality by combining two types of electrical stimulation: direct muscle membrane stimulation and the stimulation through the nerve. The comparison of the muscle response to these two different stimulations can help to define, at the functional level, potential alterations in the NMJ that lead to functional decline in muscle. Ex vivo preparations are suited to well-controlled studies. Here we describe an intensive protocol to measure several parameters of muscle and NMJ functionality for the soleus-sciatic nerve preparation and for the diaphragm-phrenic nerve preparation. The protocol lasts approximately 60 min and is conducted uninterruptedly by means of a custom-made software that measures the twitch kinetics properties, the force frequency relationship for both muscle and nerve stimulations, and two parameters specific to NMJ functionality, i.e. neurotransmission failure and intratetanic fatigue. This methodology was used to detect damages in soleus and diaphragm muscle-nerve preparations by using SOD1G93A transgenic mouse, an experimental model of ALS that ubiquitously overexpresses the mutant antioxidant enzyme superoxide dismutase 1 (SOD1). PMID- 28809842 TI - Noninvasive Sampling of Mucosal Lining Fluid for the Quantification of In Vivo Upper Airway Immune-mediator Levels. AB - This protocol describes noninvasive sampling of undisturbed upper airway mucosal lining fluid. It also details the extraction procedure used prior to the analysis of immune mediators in fluid eluates for the study of the airway topical immune signature, without the need for stimulation procedures (often used by other techniques). The mucosal lining fluid is sampled on a strip of filter paper placed at the anterior part of the inferior turbinate and left for 2 min of absorption. Analytes are eluted from the filter papers, and the extracted protein based eluates are analyzed by an electrochemiluminescence-based immunoassay, allowing for the high-sensitivity quantification of low- and high-level analytes in the same sample. We measured the in vivo levels of 20 preselected immune mediators related to specific immune signaling pathways in the upper airway mucosa, but the technique is not limited to that specific panel or sampling site. The technique was first implemented in 7-year-old children from the Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) cohort with allergic rhinitis. It was thereafter used in the longitudinal COPSAC2010 birth cohort, sampled at 1 month, 2 years, and 6 years of age and at instances of acute respiratory symptoms. We successfully obtained and analyzed samples from 620 (89%) of 700 1-month-old children; a few samples were below the assay detection limit (reported as the median (Inter-Quartile Range (IQR)). The number of samples below the detection limit (i.e. from 0 to the set point for the lower limit of detection) for each mediator was 29 (7.25 - 119.5). This technique enables the quantification of the in vivo airway mucosal immune profile from birth, can be applied longitudinally, and can be applied to studies on the effect of genetics and early-life environmental exposures, pathophysiology, endotyping, and monitoring of respiratory diseases, and development and evaluation of novel therapeutics. PMID- 28809843 TI - Tuning in the Hippocampal Theta Band In Vitro: Methodologies for Recording from the Isolated Rodent Septohippocampal Circuit. AB - This protocol outlines the procedures for preparing and recording from the isolated whole hippocampus, of WT and transgenic mice, along with recent improvements in methodologies and applications for the study of theta oscillations. A simple characterization of the isolated hippocampal preparation is presented whereby the relationship between internal hippocampal theta oscillators is examined together with the activity of pyramidal cells, and GABAergic interneurons, of the cornu ammonis-1 (CA1) and subiculum (SUB) areas. Overall, we show that the isolated hippocampus is capable of generating intrinsic theta oscillations in vitro and that rhythmicity generated within the hippocampus can be precisely manipulated by optogenetic stimulation of parvalbumin-positive (PV) interneurons. The in vitro isolated hippocampal preparation offers a unique opportunity to use simultaneous field and intracellular patch-clamp recordings from visually-identified neurons to better understand the mechanisms underlying theta rhythm generation. PMID- 28809844 TI - The 4-vessel Sampling Approach to Integrative Studies of Human Placental Physiology In Vivo. AB - The human placenta is highly inaccessible for research while still in utero. The current understanding of human placental physiology in vivo is therefore largely based on animal studies, despite the high diversity among species in placental anatomy, hemodynamics and duration of the pregnancy. The vast majority of human placenta studies are ex vivo perfusion studies or in vitro trophoblast studies. Although in vitro studies and animal models are essential, extrapolation of the results from such studies to the human placenta in vivo is uncertain. We aimed to study human placenta physiology in vivo at term, and present a detailed protocol of the method. Exploiting the intraabdominal access to the uterine vein just before the uterine incision during planned cesarean section, we collect blood samples from the incoming and outgoing vessels on the maternal and fetal sides of the placenta. When combining concentration measurements from blood samples with volume blood flow measurements, we are able to quantify placental and fetal uptake and release of any compound. Furthermore, placental tissue samples from the same mother-fetus pairs can provide measurements of transporter density and activity and other aspects of placental functions in vivo. Through this integrative use of the 4-vessel sampling method we are able to test some of the current concepts of placental nutrient transfer and metabolism in vivo, both in normal and pathological pregnancies. Furthermore, this method enables the identification of substances secreted by the placenta to the maternal circulation, which could be an important contribution to the search for biomarkers of placenta dysfunction. PMID- 28809845 TI - Whole-cell Patch-clamp Recordings of Isolated Primary Epithelial Cells from the Epididymis. AB - The epididymis is an essential organ for sperm maturation and reproductive health. The epididymal epithelium consists of intricately connected cell types that are distinct not only in molecular and morphological features but also in physiological properties. These differences reflect their diverse functions, which together establish the necessary microenvironment for the post-testicular sperm development in the epididymal lumen. The understanding of the biophysical properties of the epididymal epithelial cells is critical for revealing their functions in sperm and reproductive health, under both physiological and pathophysiological conditions. While their functional properties have yet to be fully elucidated, the epididymal epithelial cells can be studied using the patch clamp technique, a tool for measuring the cellular events and the membrane properties of single cells. Here, we describe the methods of cell isolation and whole-cell patch-clamp recording to measure the electrical properties of primary dissociated epithelial cells from the rat cauda epididymides. PMID- 28809846 TI - The Use of Trace Eyeblink Classical Conditioning to Assess Hippocampal Dysfunction in a Rat Model of Fetal Alcohol Spectrum Disorders. AB - Neonatal rats were administered a relatively high concentration of ethyl alcohol (11.9% v/v) during postnatal days 4-9, a time when the fetal brain undergoes rapid organizational change and is similar to accelerated brain changes that occur during the third trimester in humans. This model of fetal alcohol spectrum disorders (FASDs) produces severe brain damage, mimicking the amount and pattern of binge-drinking that occurs in some pregnant alcoholic mothers. We describe the use of trace eyeblink classical conditioning (ECC), a higher-order variant of associative learning, to assess long-term hippocampal dysfunction that is typically seen in alcohol-exposed adult offspring. At 90 days of age, rodents were surgically prepared with recording and stimulating electrodes, which measured electromyographic (EMG) blink activity from the left eyelid muscle and delivered mild shock posterior to the left eye, respectively. After a 5 day recovery period, they underwent 6 sessions of trace ECC to determine associative learning differences between alcohol-exposed and control rats. Trace ECC is one of many possible ECC procedures that can be easily modified using the same equipment and software, so that different neural systems can be assessed. ECC procedures in general, can be used as diagnostic tools for detecting neural pathology in different brain systems and different conditions that insult the brain. PMID- 28809848 TI - A multimodal dataset for various forms of distracted driving. AB - We describe a multimodal dataset acquired in a controlled experiment on a driving simulator. The set includes data for n=68 volunteers that drove the same highway under four different conditions: No distraction, cognitive distraction, emotional distraction, and sensorimotor distraction. The experiment closed with a special driving session, where all subjects experienced a startle stimulus in the form of unintended acceleration-half of them under a mixed distraction, and the other half in the absence of a distraction. During the experimental drives key response variables and several explanatory variables were continuously recorded. The response variables included speed, acceleration, brake force, steering, and lane position signals, while the explanatory variables included perinasal electrodermal activity (EDA), palm EDA, heart rate, breathing rate, and facial expression signals; biographical and psychometric covariates as well as eye tracking data were also obtained. This dataset enables research into driving behaviors under neatly abstracted distracting stressors, which account for many car crashes. The set can also be used in physiological channel benchmarking and multispectral face recognition. PMID- 28809849 TI - Spatiotemporal database of US congressional elections, 1896-2014. AB - High-quality historical data about US Congressional elections has long provided common ground for electoral studies. However, advances in geographic information science have recently made it efficient to compile, distribute, and analyze large spatio-temporal data sets on the structure of US Congressional districts. A single spatio-temporal data set that relates US Congressional election results to the spatial extent of the constituencies has not yet been developed. To address this, existing high-quality data sets of elections returns were combined with a spatiotemporal data set on Congressional district boundaries to generate a new spatio-temporal database of US Congressional election results that are explicitly linked to the geospatial data about the districts themselves. PMID- 28809847 TI - Genome-wide expression datasets of anti-VEGF and dexamethasone treatment of angiogenesis in the rat cornea. AB - Therapeutics against pathologic new blood vessel growth, particularly those targeting vascular endothelial growth factor (VEGF) are of enormous clinical interest. In the eye, where anti-VEGF agents are in widespread clinical use for treating retinal and corneal blindness, only partial or transient efficacy and resistance to anti-VEGF agents are among the major drawbacks. Conversely, corticosteroids have long been used in ophthalmology for their potency in suppressing inflammation and angiogenesis, but their broad biological activity can give rise to side effects such as glaucoma and cataract. To aid in the search for more targeted and effective anti-angiogenic therapies in the eye, we present here a dataset comparing gene expression changes in dexamethasone versus anti Vegfa treatment of inflammation leading to angiogenesis in the rat cornea. Global gene expression analysis with GeneChip Rat 230 2.0 microarrays was conducted and the metadata submitted to Expression Omnibus repository. Here, we present a high quality validated dataset enabling genome-wide comparison of genes differentially targeted by dexamethasone and anti-Vegf treatments, to identify potential alternative therapeutic targets for evaluation. PMID- 28809850 TI - Function-related replacement of bacterial siderophore pathways. AB - Bacterial genomes are rife with orphan biosynthetic gene clusters (BGCs) associated with secondary metabolism of unrealized natural product molecules. Often up to a tenth of the genome is predicted to code for the biosynthesis of diverse metabolites with mostly unknown structures and functions. This phenomenal diversity of BGCs coupled with their high rates of horizontal transfer raise questions about whether they are really active and beneficial, whether they are neutral and confer no advantage, or whether they are carried in genomes because they are parasitic or addictive. We previously reported that Salinispora bacteria broadly use the desferrioxamine family of siderophores for iron acquisition. Herein we describe a new and unrelated group of peptidic siderophores called salinichelins from a restricted number of Salinispora strains in which the desferrioxamine biosynthesis genes have been lost. We have reconstructed the evolutionary history of these two different siderophore families and show that the acquisition and retention of the new salinichelin siderophores co-occurs with the loss of the more ancient desferrioxamine pathway. This identical event occurred at least three times independently during the evolution of the genus. We surmise that certain BGCs may be extraneous because of their functional redundancy and demonstrate that the relative evolutionary pace of natural pathway replacement shows high selective pressure against retention of functionally superfluous gene clusters. PMID- 28809851 TI - Grape pomace compost harbors organohalide-respiring Dehalogenimonas species with novel reductive dehalogenase genes. AB - Organohalide-respiring bacteria have key roles in the natural chlorine cycle; however, most of the current knowledge is based on cultures from contaminated environments. We demonstrate that grape pomace compost without prior exposure to chlorinated solvents harbors a Dehalogenimonas (Dhgm) species capable of using chlorinated ethenes, including the human carcinogen and common groundwater pollutant vinyl chloride (VC) as electron acceptors. Grape pomace microcosms and derived solid-free enrichment cultures were able to dechlorinate trichloroethene (TCE) to less chlorinated daughter products including ethene. 16S rRNA gene amplicon and qPCR analyses revealed a predominance of Dhgm sequences, but Dehalococcoides mccartyi (Dhc) biomarker genes were not detected. The enumeration of Dhgm 16S rRNA genes demonstrated VC-dependent growth, and 6.55+/-0.64 * 108 cells were measured per MUmole of chloride released. Metagenome sequencing enabled the assembly of a Dhgm draft genome, and 52 putative reductive dehalogenase (RDase) genes were identified. Proteomic workflows identified a putative VC RDase with 49 and 56.1% amino acid similarity to the known VC RDases VcrA and BvcA, respectively. A survey of 1,173 groundwater samples collected from 111 chlorinated solvent-contaminated sites in the United States and Australia revealed that Dhgm 16S rRNA genes were frequently detected and outnumbered Dhc in 65% of the samples. Dhgm are likely greater contributors to reductive dechlorination of chlorinated solvents in contaminated aquifers than is currently recognized, and non-polluted environments represent sources of organohalide respiring bacteria with novel RDase genes. PMID- 28809852 TI - The SNP-set based association study identifies ITGA1 as a susceptibility gene of attention-deficit/hyperactivity disorder in Han Chinese. AB - Genome-wide association studies, which detect the association between single nucleotide polymorphisms (SNPs) and disease susceptibility, have been extensively applied to study attention-deficit/hyperactivity disorder (ADHD), but genome-wide significant associations have not been found yet. Genetic heterogeneity and insufficient genomic coverage may account for the missing heritability. We performed a two-stage association study for ADHD in the Han Chinese population. In the discovery stage, 1033 ADHD patients and 950 healthy controls were genotyped using both the Affymetrix Genome-Wide Human SNP Array 6.0 and the Illumina Infinium HumanExome BeadChip. The genotyped SNPs were combined to generate a powerful SNP set with better genomic coverage especially for the nonsynonymous variants. In addition to the association of single SNPs, we collected adjacent SNPs as SNP sets, which were determined by either genes or successive sliding windows, to evaluate their synergetic effect. The candidate susceptibility SNPs were further replicated in an independent cohort of 1441 ADHD patients and 1447 healthy controls. No genome-wide significant SNPs or gene-based SNP sets were found to be associated with ADHD. However, two continuous sliding windows located in ITGA1 (P-value=8.33E-7 and P-value=8.43E-7) were genome-wide significant. The quantitative trait analyses also demonstrated their association with ADHD core symptoms and executive functions. The association was further validated by follow-up replications for four selected SNPs: rs1979398 (P value=2.64E-6), rs16880453 (P-value=3.58E-4), rs1531545 (P-value=7.62E-4) and rs4074793 (P-value=2.03E-4). Our results suggest that genetic variants in ITGA1 may be involved in the etiology of ADHD and the SNP-set based analysis is a promising strategy for the detection of underlying genetic risk factors. PMID- 28809853 TI - RNA-seq analysis of amygdala tissue reveals characteristic expression profiles in schizophrenia. AB - The amygdala brain region has been implicated in the pathophysiology of schizophrenia through emotion processing. However, transcriptome messages in the amygdala of schizophrenia patients have not been well studied. We used RNA sequencing to investigate gene-expression profiling in the amygdala tissues, and identified 569 upregulated and 192 downregulated genes from 22 schizophrenia patients and 24 non-psychiatric controls. Gene functional enrichment analysis demonstrated that the downregulated genes were enriched in pathways such as 'synaptic transmission' and 'behavior', whereas the upregulated genes were significantly over-represented in gene ontology pathways such as 'immune response' and 'blood vessel development'. Co-expression-based gene network analysis identified seven modules including four modules significantly associated with 'synaptic transmission', 'blood vessel development' or 'immune responses'. Taken together, our study provides novel insights into the molecular mechanism of schizophrenia, suggesting that precision-tailored therapeutic approaches aimed at normalizing the expression/function of specific gene networks could be a promising option in schizophrenia. PMID- 28809855 TI - Brain connectivity changes occurring following cognitive behavioural therapy for psychosis predict long-term recovery. AB - This corrects the article DOI: 10.1038/tp.2016.263. PMID- 28809854 TI - In the grip of worry: cerebral blood flow changes during worry induction and reappraisal in late-life generalized anxiety disorder. AB - Severe worry includes a complex blend of maladaptive affective and cognitive processes. Contrary to other forms of anxiety, there is no consensus in the field regarding the neural basis of worry. To date, no study has looked at neural patterns associated specifically with in-scanner induction and reappraisal of worry. In this study, we attempt to describe distinct components of the 'neural phenomenology' of worry: induction, maintenance, severity and reappraisal, by using a personalized, in-scanner worry script. Twenty older, non-anxious participants and twenty late-life generalized anxiety disorder (GAD) participants were included. Whole-brain axial pseudo-continuous arterial spin-labeling scans were collected. We used a voxel-wise two-way ANOVA to test the group-by-block interaction. Worry induction was associated with greater cerebral blood flow (CBF) in the visual cortex, thalamus, caudate and medial frontal cortex compared with the rest. Reappraisal was associated with greater CBF in similar regions, whereas the orbital frontal gyrus showed lower CBF relative to rest. Relative to non-anxious participants, GAD had greater CBF in multiple regions during worry induction (visual and parietal cortex, middle and superior frontal) and lower CBF during reappraisal in the supplemental motor area, middle cingulate gyrus, insula and putamen. Except for the thalamus, there was no change in CBF throughout the five blocks of worry induction and reappraisal. Severe worry is distinctly associated with increased CBF in several neocortical regulatory regions. We present new data supporting the view of worry as a complex process, engaging multiple regions in the initiation, maintenance and reappraisal of worry. PMID- 28809856 TI - Decreased NOX2 expression in the brain of patients with bipolar disorder: association with valproic acid prescription and substance abuse. AB - Neuroinflammation and increased oxidative stress are believed to contribute to the development of psychiatric diseases. Animal studies have implicated NADPH oxidases (NOX) as relevant sources of reactive oxygen species in the brain. We have analyzed the expression of NOX isoforms in post-mortem brain samples from patients with psychiatric disorders (schizophrenia, bipolar disorder) and non psychiatric subjects. Two collections from the Stanley Medical Research Institute were studied: the Array Collection (RNA, 35 individuals per group), and a neuropathology consortium collection (paraffin-embedded sections, 15 individuals per group). Quantitative PCR analysis revealed expression of NOX2 and NOX4 in prefrontal cortex. No impact of psychiatric disease on NOX4 levels was detected. Remarkably, the expression of NOX2 was specifically decreased in prefrontal and cingulate cortices of bipolar patients, as compared with controls and schizophrenic patients. NOX2 expression was not statistically associated with demographic parameters and post-mortem interval, but correlated with brain pH. Immunostaining demonstrated that NOX2 was predominantly expressed in microglia, which was corroborated by a decrease in the microglial markers CD68 and CD11b in the cingulate cortex of bipolar disorder patients. The analysis of potentially confounding parameters showed association of valproic acid prescription and heavy substance abuse with lower levels of NOX2. Taken together, we did not observe changes of NOX2 in schizophrenic patients, but a marked decrease of microglial markers and NOX2 in the brain of bipolar patients. This might be an underlying feature of bipolar disorder and/or a consequence of valproic acid treatment and substance abuse. PMID- 28809858 TI - Brain connectivity changes occurring following cognitive behavioural therapy for psychosis predict long-term recovery. PMID- 28809857 TI - Grandmaternal stress during pregnancy and DNA methylation of the third generation: an epigenome-wide association study. AB - Stress during pregnancy may impact subsequent generations, which is demonstrated by an increased susceptibility to childhood and adulthood health problems in the children and grandchildren. Although the importance of the prenatal environment is well reported with regards to future physical and emotional outcomes, little is known about the molecular mechanisms that mediate the long-term consequences of early stress across generations. Recent studies have identified DNA methylation as a possible mediator of the impact of prenatal stress in the offspring. Whether psychosocial stress during pregnancy also affects DNA methylation of the grandchildren is still not known. In the present study we examined the multigenerational hypothesis, that is, grandmaternal exposure to psychosocial stress during pregnancy affecting DNA methylation of the grandchildren. We determined the genome-wide DNA methylation profile in 121 children (65 females and 56 males) and tested for associations with exposure to grandmaternal interpersonal violence during pregnancy. We observed methylation variations of five CpG sites significantly (FDR<0.05) associated with the grandmother's report of exposure to violence while pregnant with the mothers of the children. The results revealed differential methylation of genes previously shown to be involved in circulatory system processes (FDR<0.05). This study provides support for DNA methylation as a biological mechanism involved in the transmission of stress across generations and motivates further investigations to examine prenatal-dependent DNA methylation as a potential biomarker for health problems. PMID- 28809859 TI - Do regional brain volumes and major depressive disorder share genetic architecture? A study of Generation Scotland (n=19 762), UK Biobank (n=24 048) and the English Longitudinal Study of Ageing (n=5766). AB - Major depressive disorder (MDD) is a heritable and highly debilitating condition. It is commonly associated with subcortical volumetric abnormalities, the most replicated of these being reduced hippocampal volume. Using the most recent published data from Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium's genome-wide association study of regional brain volume, we sought to test whether there is shared genetic architecture between seven subcortical brain volumes and intracranial volume (ICV) and MDD. We explored this using linkage disequilibrium score regression, polygenic risk scoring (PRS) techniques, Mendelian randomisation (MR) analysis and BUHMBOX. Utilising summary statistics from ENIGMA and Psychiatric Genomics Consortium, we demonstrated that hippocampal volume was positively genetically correlated with MDD (rG=0.46, P=0.02), although this did not survive multiple comparison testing. None of the other six brain regions studied were genetically correlated and amygdala volume heritability was too low for analysis. Using PRS analysis, no regional volumetric PRS demonstrated a significant association with MDD or recurrent MDD. MR analysis in hippocampal volume and MDD identified no causal association, however, BUHMBOX analysis identified genetic subgrouping in GS:SFHS MDD cases only (P=0.00281). In this study, we provide some evidence that hippocampal volume and MDD may share genetic architecture in a subgroup of individuals, albeit the genetic correlation did not survive multiple testing correction and genetic subgroup heterogeneity was not replicated. In contrast, we found no evidence to support a shared genetic architecture between MDD and other regional subcortical volumes or ICV. PMID- 28809861 TI - High-frequency measurement of depressive severity in a patient treated for severe treatment-resistant depression with deep-brain stimulation. AB - Although there have been previous studies of deep-brain stimulation (DBS), we present, to our knowledge, the first example of high-frequency depressive severity measurement-based DBS treatment in particular and psychiatric treatment in general. Daily post-surgical e-mail prompts for a period of 6 months resulted in 93 administrations of a computerized adaptive test (CAT) of depression severity (CAT-Depression Inventory or CAT-DI) via the internet. There was an average of 3.37 weekly measurements with an average separation of 2.12 days. No additional incentive was provided to the patient for completing the adaptive tests. The patient is a 55-year-old female with six psychiatric hospitalizations for depression, two suicide attempts, marginal response to eight electroconvulsive therapy (ECT) treatments and 35 psychotropic medications. We report results after high-frequency stimulation of the superolateral branch of the medial forebrain bundle. The CAT-DI was used for daily assessments before, during and after (remotely in response to an e-mail prompt) the DBS procedure. Two follow-up Hamilton Depression Scales (HAM-Ds) were also collected. Response to treatment varied markedly, with a decrease from severe (>75) to mild (60), which is three times the size of the uncertainty level. Although the HAM-D scores decreased, they missed the more complete temporal pattern identified by CAT-DI daily monitoring. We demonstrated feasibility of daily depressive severity measurement at high levels of precision and compliance. Clinician ratings confirm the general pattern of treatment benefit, but mask the marked variability in mood and more marked periods of benefit and decline. PMID- 28809860 TI - Repeated exposure to systemic inflammation and risk of new depressive symptoms among older adults. AB - Evidence on systemic inflammation as a risk factor for future depression is inconsistent, possibly due to a lack of regard for persistency of exposure. We examined whether being inflamed on multiple occasions increases risk of new depressive symptoms using prospective data from a population-based sample of adults aged 50 years or older (the English Longitudinal Study of Ageing). Participants with less than four of eight depressive symptoms in 2004/05 and 2008/09 based on the Eight-item Centre for Epidemiologic Studies Depression scale were analysed. The number of occasions with C-reactive protein ?3 mg l-1 over the same initial assessments (1 vs 0 occasion, and 2 vs 0 occasions) was examined in relation to change in depressive symptoms between 2008/09 and 2012/13 and odds of developing depressive symptomology (having more than or equal to four of eight symptoms) in 2012/13. In multivariable-adjusted regression models (n=2068), participants who were inflamed on 1 vs 0 occasion showed no increase in depressive symptoms nor raised odds of developing depressive symptomology; those inflamed on 2 vs 0 occasions showed a 0.10 (95% confidence intervals (CIs)=-0.07, 0.28) symptom increase and 1.60 (95% CI=1.00, 2.55) times higher odds. In further analyses, 2 vs 0 occasions of inflammation were associated with increased odds of developing depressive symptoms among women (odds ratio (OR)=2.75, 95% CI=1.53, 4.95), but not among men (OR=0.70, 95% CI=0.29, 1.68); P-for-sex interaction=0.035. In this cohort study of older adults, repeated but not transient exposure to systemic inflammation was associated with increased risk of future depressive symptoms among women; this subgroup finding requires confirmation of validity. PMID- 28809862 TI - GNAQ and GNA11 mutations and downstream YAP activation in choroidal nevi. AB - BACKGROUND: Mutations in GNAQ/11 genes are considered an early event in the development of uveal melanoma that may derive from a pre-existing nevus. The Hippo pathway, by way of YAP activation, rather than MAP kinase, has a role in the oncogenic capacity of GNAQ/11 mutations. METHODS: We investigated 16 nevi from 13 human eyes for driver GNAQ/11 mutations using droplet digital PCR and determined whether nevi are clonal by quantifying mutant nevus cell fractions. Immunohistochemistry was performed on 15 nevi to analyse YAP activation. RESULTS: For 15 out of 16 nevi, a GNAQ/11 mutation was detected in the nevus cells albeit at a low frequency with a median of 13%. Nuclear YAP, a transcriptional co activator in the Hippo tumour-suppressor pathway, was detected in 14/15 nevi. CONCLUSIONS: Our analysis suggests that a mutation in GNAQ/11 occurs in a subset of choroidal nevus cells. We hypothesise that GNAQ/11 mutant-driven extracellular mitogenic signalling involving YAP activation leads to accumulation of wild-type nevus cells. PMID- 28809864 TI - Predicting response to radical (chemo)radiotherapy with circulating HPV DNA in locally advanced head and neck squamous carcinoma. AB - BACKGROUND: Following chemo-radiotherapy (CCRT) for human papilloma virus positive (HPV+) locally advanced head and neck cancer, patients frequently undergo unnecessary neck dissection (ND) and/or repeated biopsies for abnormal PET-CT, which causes significant morbidity. We assessed the role of circulating HPV DNA in identifying 'true' residual disease. METHODS: We prospectively recruited test (n=55) and validation (n=33) cohorts. HPV status was confirmed by E7 RT-PCR. We developed a novel amplicon-based next generation sequencing assay (HPV16-detect) to detect circulating HPV DNA. Circulating HPV DNA levels post CCRT were correlated to disease response (PET-CT). RESULTS: In pre-CCRT plasma, HPV-detect demonstrated 100% sensitivity and 93% specificity, and 90% sensitivity and 100% specificity for the test (27 HPV+) and validation (20 HPV+) cohorts, respectively. Thirty-six out of 37 patients (test and validation cohort) with complete samples-set had negative HPV-detect at end of treatment. Six patients underwent ND (3) and repeat primary site biopsies (3) for positive PET-CT but had no viable tumour. One patient had positive HPV-detect and positive PET-CT and liver biopsy, indicating 100% agreement for HPV-detect and residual cancer. CONCLUSIONS: We demonstrate that HPV16-detect is a highly sensitive and specific test for identification of HPV DNA in plasma at diagnosis. HPV DNA post-treatment correlates with clinical response. PMID- 28809865 TI - ? PMID- 28809863 TI - Dynamic plasma microRNAs are biomarkers for prognosis and early detection of recurrence in colorectal cancer. AB - BACKGROUND: Plasma microRNAs (miRNAs) are promising non-invasive biomarkers for colorectal cancer (CRC) prognosis. However, the published studies to date have yielded conflicting and inconsistent results for specific plasma miRNAs. METHODS: We have conducted a study using robust assays to assess a panel of nine miRNAs for CRC prognosis and early detection of recurrence. Plasma samples from 144 patients in a prospective CRC cohort study were collected at diagnosis, 6, 12, and 24 months after diagnosis. miRNAs were assayed by Taqman qRT-PCR to generate miRNA normalised copy numbers. RESULTS: Preoperative high plasma miRNA levels were associated with increased recurrence risk for miR-200b (HR [95% CI]=2.04 [1.00, 4.16], P=0.05), miR-203 (HR=4.2 [1.48, 11.93], P=0.007), miR-29a (HR=2.61 [1.34,5.07], P=0.005), and miR-31 (HR=4.03 [1.76, 9.24], P=0.001). Both plasma miR-31 (AUC: 0.717) and miR-29a (AUC: 0.703) could discriminate recurrence from these patients without recurrence. In addition, high levels of miR-31 during surveillance was associated with a three-fold increased risk of recurrence across all time points. Dynamic postoperative plasma miR-141 and 16 levels correlated with recurrence in the surveillance samples. CONCLUSIONS: Pre-operative plasma miR-29a, 200b, 203, and 31 are potential CRC prognosis biomarkers. In addition, dynamic postoperative miR-31, 141 and 16 levels are potential biomarkers for the early detection of recurrence during CRC surveillance. PMID- 28809866 TI - [Employee Wellbeing in a University Department, Italy]. AB - A serene workplace environment can provide significant benefits to employees. The aim of the present study was to assess wellbeing of employees in a university department, by administering validated questionnaires (Karasek and INAIL) and to determine any similarities and / or differences. The sample consisted of 48 employees (22.9 % male and 77.1% female) in various job categories including doctors, biologists, nurses, and technical and administrative staff. Results obtained from the Karasek questionnaire allowed us to calculate the values of Decision latidude and Job demand. The intersection of the medians of the two components, respectively 56 and 30, allowed us to divide participants into four quadrants consisting of high "strain" workers, active and passive and low "strain" workers. Thirty seven percent of the sample was found to be at high risk of stress. Significant differences in responses were identified in relation to gender, age, job seniority and educational level. Responses to the two questionnaires compared favorably. Seventeen questions were compared, and for eleven of these there was sufficient agreement, with kappa test values comprised between 0.194 and 0.408 (p<0.05). Results confirm that work-related stress is a relevant issue. Karasek and INAIL questionnaires, while investigating similar issues, should not be used alternatively but rather administered simultaneously. PMID- 28809867 TI - [Risk perception and biological parameters related to obesity in a sample population of the city of Rome, Italy: nurses' contribution to supporting health related decisions]. AB - INTRODUCTION: Obesity is a major public health problem because it is a risk factor for various chronic diseases and its incidence is constantly increasing due to changes in diet and lifestyle. In Italy, studies show that 32% of the population aged between 18 and 69 years is overweight and 10% is obese. The aim of this study was to measure the anthropometric characteristics of a sample population of the city of Rome (Italy) and correlate these with dietary habits and socio-demographic characteristics of participants in order to evaluate their specific health and educational needs. METHODS: A cross-sectional study was conducted in February 2015 by administering an ad-hoc questionnaire to subjects over 18 years of age attending a General Practitioner's practice in Rome (Italy). The questionnaire collected demographic, clinical and anthropometric data, and information regarding dietary habits. RESULTS: The sample consisted of 150 individuals with a mean age of 47,8 years. Fifty nine percent were women. The mean Body Mass Index (BMI) was 26.7. The average blood pressure was 131/80 mmHg. BMI values were higher in respondents with a lower educational level and BMI was significantly associated with the quality of the source of nutrition information used. CONCLUSIONS: Poor and unreliable information regarding proper nutrition can correlate with the risk of overweight and the consequent development of chronic diseases. The family or community nurse could play a critical role in prevention, by helping to provide correct information for specific populations and by planning training and prevention activities with the GP. PMID- 28809868 TI - [Criminal liability in case of medical acts considered to be incompetent: article 6 of the new Italian Law 8 March 2017, n.24]. AB - In Italy, Law n. 24 of 8 March 2017, Article 6, introduces in the current criminal code, Article 590 sexies entitled "Medical liability in case of death and personal lesions", which follows article 590 quinquies. The new article states that a healthcare professional who has acted in accordance with guidelines approved by the National Health Institute or, if no such guidelines exist, in accordance with good clinical practices, is not criminally liable in case of death or personal lesions due to actions that could be considered to be incompetent. We discuss criminal liability of health professionals in Italy in light of this new law, and decriminalization in case of adverse event due to incompetence, also in the context of medical care provided by different health professionals. PMID- 28809869 TI - [Some considerations on revision of legislation Hygiene-sanitary for the management of swimming pools for swimming-pool use and the National Consultation of the Ministry of Health]. AB - After over a decade the Italian regulation on hygiene and surveillance in swimming pools is under revision based on WHO guidelines and current laws from other European countries. The Ministry of Health is proposing an update of the Annex 1 that contains physical, chemical and microbiological indicators for monitoring swimming pool hygiene. The authors review current regulations and the new proposal for updating surveillance. A comparison of Annex 1 as approved in 2003 and the new version as proposed in 2016 allowed to enlighten innovative improvements. The suggested updates underwent a public consultation through an online questionnaire involving citizens and stakeholders, following the required procedure for accessing the final approval of a new regulation. The updates include new requirements and changes involving several controls and microbiological parameters. Safety of recreational waters is presently under revision in different European countries. This updating process is a valuable opportunity to implement critical control points and improve monitoring. The final aim is an optimization of surveillance in terms of efficacy and costs, with an advantage for both the National Health Service as the swimming pool management. PMID- 28809871 TI - [Recall system for vaccinations in preschool children in a Local Health Unit in Rome, Italy]. AB - In Italy, in this period, much attention is dedicated to reach adequate vaccination coverage in children and adolescents. In this study, Vaccination Registry was checked in a Local Health Unit in Rome, Italy, to identify children born in 2007 and 2008 who had not completed the vaccination schedule. Coverage for booster doses of measles, mumps, rubella and for diphtheria, tetanus, pertussis and polio vaccines in the 2213 children was around 70%. A reminder letter was send to parents of the 661 incompletely immunized children and, if they did not reply, a phone call was made when the phone number was available. With this recall system, 12% of the children were correctly immunized, reaching about 82% coverage. PMID- 28809870 TI - [Case report: Iatrogenic shoulder pain syndrome following spinal accessory nerve injury during lateral cervical neck dissection for tongue cancer: the role of rehabilitation and ethical-deontological issues]. AB - The shoulder pain syndrome is the most frequent complication of lateral cervical neck dissection and may be caused by iatrogenic injury to the spinal accessory nerve, causing pain and functional limitation of the upper limb and of the cervical spine. Interdisciplinary collaboration and early rehabilitation can reduce the consequences of disability and the possible issues that can arise due to inadequate management of the problem. PMID- 28809872 TI - Surface nanoscale axial photonics at a capillary fiber. AB - We present the theory and first experimental demonstration, to the best of our knowledge, of a sensing platform based on surface nanoscale axial photonics (SNAP) at a capillary fiber. The platform explores optical whispering gallery modes, which circulate inside the wall of a capillary and slowly propagate along its axis. Due to the small thickness of the capillary wall, these modes are sensitive to spatial and temporal variations of the refractive index of the media adjacent to the internal capillary surface. In particular, the developed theory allows us to determine the internal effective radius variation of the capillary from the measured mode spectra. Experimentally, a SNAP resonator is created by local annealing of the capillary with a focused CO2 laser followed by internal etching with hydrofluoric acid. The comparison of the spectra of this resonator in the cases when it is empty and filled with water allows us to determine the internal surface nonuniformity introduced by etching. The results obtained pave the way for a novel advanced approach in sensing of media adjacent to the internal capillary surface and, in particular, in microfluidic sensing. PMID- 28809873 TI - Generating broadband vortex modes in ring-core fiber by using a plasmonic q plate. AB - A mode convertor was proposed and investigated for generating vortex modes in a ring-core fiber based on a plasmonic q-plate (PQP), which is composed of specially organized L-shaped resonator (LSR) arrays. A multicore fiber was used to transmit fundamental modes, and the LSR arrays were used to modulate phases of these fundamental modes. Behind the PQP, the transmitted fundamental modes with gradient phase distribution can be considered as the incident lights for generating broadband vortex modes in the ring-core fiber filter. The topological charges of generated vortex modes can be various by using an optical PQP with different q, and the chirality of the generated vortex mode can be controlled by the sign of q and handedness of the incident circularly polarized light. The operation bandwidth is 800 nm in the range of 1200-2000 nm, which covers six communication bands from the O band to the U band. The separation of vortex modes also was addressed by using a dual ring-core fiber. The mode convertor is of potential interest for connecting a traditional network and vortex communication network. PMID- 28809874 TI - Three-dimensional object visualization and detection in low light illumination using integral imaging. AB - Conventional two-dimensional (2D) imaging systems that operate in the visible spectrum may perform poorly in environments under low light illumination. In this work, we present the potential of passive three-dimensional (3D) integral imaging (II) to perform 3D imaging of a scene under low light conditions in the visible spectrum and without the need for a photon counting or cooled CCD camera. Using dedicated algorithms, we demonstrate that the reconstructed 3D integral image is naturally optimum in a maximum likelihood sense in low light levels and in the presence of detector noise enabling object visualization in the scene. The conventional 2D imaging fails due to the limited number of photons. Using 3D imaging, we demonstrate the potential for 3D detection of objects behind occlusion in a photon-starved scene. To the best of our knowledge, this is the first report of experimentally using II sensing under low illumination conditions for 3D visualization and 3D object detection in the presence of obscurations with a conventional image sensor. PMID- 28809875 TI - Bi-directional top-hat D-Scan: single beam accurate characterization of nonlinear waveguides. AB - The characterization of a third-order nonlinear integrated waveguide is reported for the first time by means of a top-hat dispersive-scan (D-Scan) technique, a temporal analog of the top-hat Z-Scan. With a single laser beam, and by carrying two counterdirectional nonlinear transmissions to assess the input and output coupling efficiencies, a novel procedure is described leading to accurate measurement of the TPA figure of merit, the effective two-photon absorption (TPA), and optical Kerr (including the sign) coefficients. The technique is validated in a silicon strip waveguide for which the effective nonlinear coefficients are measured with an accuracy of +/-10%. PMID- 28809876 TI - Sub-100 fs Tm:MgWO4 laser at 2017 nm mode locked by a graphene saturable absorber. AB - We present the first sub-100 fs bulk solid-state laser in the 2-MUm spectral range employing the monoclinic Tm3+-dopedMgWO4 crystal as an active medium. By applying a graphene-based saturable absorber and chirped mirrors for dispersion management, stable self-starting mode-locked operation at 2017 nm was achieved. Nearly Fourier-limited pulses as short as 86 fs featuring a bandwidth of 53 nm were generated at a repetition rate of 76 MHz. A pulse energy of 1.1 nJ was achieved at 87 MHz for a pulse duration of 96 fs. The mode-locked Tm3+:MgWO4 laser exhibits excellent stability with a fundamental beat note extinction ratio of 80 dBc above noise level. PMID- 28809877 TI - Photoinduced terahertz radiation and negative conductivity dynamics in Heusler alloy Co2MnSn film. AB - We report the broadband terahertz (THz) radiation in ferromagnetic half-metallic Heusler alloy Co2MnSn thin film upon the irradiation of a femtosecond laser pulse at room temperature. The magnetic-, sample symmetry-, and pump fluence-dependent THz emission reveals that the THz radiation is originated from the magnetic dipole radiation, i.e., the light-induced subpicosecond demagnetization. In addition, by optical pump-THz probe spectroscopy, we found that the photoexcited increase of the scattering rate of hot carriers thereby leads to the photoinduced negative THz conductivity in Co2MnSn thin film. PMID- 28809878 TI - Partially coherent sources with circular coherence: comment. AB - In [Opt. Lett.42, 1512 (2017)OPLEDP0146-959210.1364/OL.42.001512], the authors present a new class of non-uniformly correlated sources with circular coherence. They also describe a basic experimental setup for synthesizing this class of sources, which uses the Van Cittert-Zernike theorem. Here, we present an alternative way to analyze these sources and a different way to generate them. PMID- 28809879 TI - Zak phase induced multiband waveguide by two-dimensional photonic crystals. AB - Interface states in photonic crystals provide efficient approaches to control the flow of light. Photonic Zak phase determines the bulk band properties of photonic crystals, and, by assembling two photonic crystals with different bulk band properties together, deterministic interface states can be realized. By translating each unit cell of a photonic crystal by half the lattice constant, another photonic crystal with identical common gaps but a different Zak phase at each photonic band can be created. By assembling these two photonic crystals together, multiband waveguide can thus be easily created and then experimentally characterized. Our experimental results have good agreement with numerical simulations, and the propagation properties of these measured interface states indicate that this new type of interface state will be a good candidate for future applications of optical communications. PMID- 28809880 TI - Incoherent lensless imaging via coherency back-propagation. AB - The two-point complex coherence function constitutes a complete representation for scalar quasi-monochromatic optical fields. Exploiting dynamically reconfigurable slits implemented with a digital micromirror device, we report on measurements of the complex two-point coherence function for partially coherent light scattering from a "scene" composing one or two objects at different transverse and axial positions with respect to the source. Although the intensity shows no discernible shadows in the absence of a lens, numerically back propagating the measured complex coherence function allows estimating the objects' sizes and locations and, thus, the reconstruction of the scene subject to the effects of occlusion and shadowing. PMID- 28809881 TI - Genetic-algorithm-optimized wideband on-chip polarization rotator with an ultrasmall footprint. AB - Polarization control of light waves is an important technique in optical communication and signal processing. On-chip polarization rotation from the fundamental transverse-electric (TE00) mode to the fundamental transverse magnetic (TM00) mode is usually difficult because of their large effective refractive index difference. Here, we demonstrate an on-chip wideband polarization rotator designed with a genetic algorithm to convert the TE00 mode into the TM00 mode within a footprint of 0.96 MUm *4.2 MUm. In simulation, the optimized structure achieves polarization rotation with a minimum conversion loss of 0.7 dB and the 1-dB bandwidth of 157 nm. Experimentally, our fabricated devices have demonstrated the expected polarization rotation with a conversion loss of ~2.5 dB in the measured wavelength range of 1440-1580 nm, where the smallest value reaches ~2 dB. The devices can serve as a generic approach and standard module for controlling light polarization in integrated photonic circuitry. PMID- 28809882 TI - Modulated vortex six-wave mixing. AB - We have experimentally generated a vortex six-wave mixing (SWM) signal via a photonic band gap structure in a hot atomic ensemble. The output SWM carrying orbital angular momentum, transferred from a probe beam, has the interaction with the nonlinear effect in the multilevel atomic system. Our results show that a spatial SWM image can be modulated by the detunings and intensities of the related generating fields. Also, the nonreciprocal feature of the SWM signal is demonstrated. Such characteristics can potentially be used in information processing. PMID- 28809884 TI - Whispering-gallery-mode laser-based noise-immune cavity-enhanced optical heterodyne molecular spectrometry. AB - The whispering-gallery-mode (WGM) laser is a type of laser that has an exceptionally narrow linewidth. Noise-immune cavity-enhanced optical heterodyne molecular spectrometry, which is a detection technique with extraordinary properties that benefit from narrow linewidth lasers, has been realized with a WGM laser. By locking to a cavity with a finesse of 55 000, acetylene and carbon dioxide could be simultaneously detected down to an unprecedented noise equivalent absorption per unit length of 6.6*10-14 cm-1 over 150 s, corresponding to 5 ppt of C2H2. PMID- 28809883 TI - Noninvasive measurement of tissue blood oxygenation with Cerenkov imaging during therapeutic radiation delivery. AB - Tumor tissue oxygenation significantly affects the outcome of radiotherapy. Real time monitoring of tumor hypoxia is highly desirable for effective radiotherapy, and is the basis for improved treatment because hypoxic tumor cells are more resistant to radiation damage than fully oxygenated cells. We propose to use Cerenkov imaging to monitor tumor hypoxia by means of tissue blood oxygenation without the need for any exogenous contrast agent. Using a rodent hypoxia model, we demonstrate that Cerenkov imaging can be used as a noninvasive and noncontact method to measure tissue blood oxygenation level during radiation delivery. The data from Cerenkov imaging were validated using near infrared spectrometry methods. The results demonstrate the feasibility of using Cerenkov imaging to monitor tumor hypoxia during therapeutic radiation delivery. PMID- 28809885 TI - Two-photon absorption and subband photodetection in monolayer MoS2. AB - We develop a theoretical model to quantify the two-photon absorption (2 PA) coefficients of monolayer MoS2. Based on two-dimensional excitons, our model reveals the 2 PA coefficient spectrum on the order of 0.01-0.1 cm/MW in the near infrared for monolayer MoS2. As compared to the band theory for bulk semiconductors, these coefficients are enhanced by at least one order of magnitude. Our model is in agreement with light-intensity-dependent photocurrent measurements on a monolayer MoS2, subband photodetector with femtosecond laser pulses. PMID- 28809886 TI - Nano/micro dual-textured antireflective subwavelength structures in anisotropically etched GaAs. AB - Light trapping by surface texturing is widely used to improve the performance of optoelectronic devices. In this Letter, we demonstrate nano/micro dual-scale textured GaAs by integrating triangular GaAs by orientation-dependent wet etching and subwavelength nanoholes by metal-assisted chemical etching (MacEtch). This is the first report on nano/micro dual-scale textured GaAs. The reflectance was adjusted by controlling the aspect ratio of the nanoholes by varying the MacEtch duration. The combination of the microstructure and subwavelength structures significantly reduced the solar-weighted reflectance of a bare GaAs substrate by 72%. PMID- 28809887 TI - Fano-resonance-based mode-matching hybrid metasurface for enhanced second harmonic generation. AB - Plasmonic nanostructures have been considered as potential candidates for enhancing the nonlinear upconversion rate at nanoscale levels due to their strong near-field enhancement. Here, we propose a Fano-resonance-based mode-matching hybrid metasurface that combines the advantages of Fano resonances and mode matching for boosting second-harmonic conversion. A confined and strong near field intensity is generated by gold nanoantennas within the volume of polycrystalline zinc sulfide nanoparticles, thus resulting in a larger effective second-harmonic coefficient. The combination of the abovementioned features allows for the realization of a second-harmonic generation (SHG) conversion efficiency of 5.55*10-8, and the SHG signal is twice that obtained with dipole hybrid metasurfaces. Our designed metasurface may pave the way for optimizing nonlinear light-matter interactions at the nanoscale. PMID- 28809888 TI - Quantum temporal imaging by four-wave mixing. AB - We investigate temporal imaging of broadband squeezed light by four-wave-mixing. We consider two possible imaging configurations: phase-conjugating (PC) and phase preserving (PP). Both of these configurations have been successfully used for temporal imaging of classical temporal waveforms. We demonstrate that for quantum temporal imaging, precisely, temporal imaging of broadband squeezed light, these two schemes have very different behavior: the PC configuration deteriorates squeezing, while the PP configuration leaves it intact. These results are very important for the applications of temporal imaging for quantum communications and quantum information processing. PMID- 28809889 TI - Two-stage cross-talk mitigation in an orbital-angular-momentum-based free-space optical communication system. AB - We propose and experimentally demonstrate a two-stage cross-talk mitigation method in an orbital-angular-momentum (OAM)-based free-space optical communication system, which is enabled by combining spatial offset and low density parity-check (LDPC) coded nonuniform signaling. Different from traditional OAM multiplexing, where the OAM modes are centrally aligned for copropagation, the adjacent OAM modes (OAM states 2 and -6 and OAM states -2 and 6) in our proposed scheme are spatially offset to mitigate the mode cross talk. Different from traditional rectangular modulation formats, which transmit equidistant signal points with uniform probability, the 5-quadrature amplitude modulation (5-QAM) and 9-QAM are introduced to relieve cross-talk-induced performance degradation. The 5-QAM and 9-QAM formats are based on the Huffman coding technique, which can potentially achieve great cross-talk tolerance by combining them with corresponding nonbinary LDPC codes. We demonstrate that cross talk can be reduced by 1.6 dB and 1 dB via spatial offset for OAM states +/-2 and +/-6, respectively. Compared to quadrature phase shift keying and 8-QAM formats, the LDPC-coded 5-QAM and 9-QAM are able to bring 1.1 dB and 5.4 dB performance improvements in the presence of atmospheric turbulence, respectively. PMID- 28809890 TI - Tunable photonic radiofrequency filter with complementary bandpass and bandstop responses. AB - A photonic radiofrequency (RF) filter with two complementary bandpass and bandstop responses that is capable of simultaneously providing a single transmission channel at one port and a notch rejection channel at the other port is proposed. An integrated polarization division-multiplexing Mach-Zehnder modulator and the in-fiber stimulated Brillouin scattering effect are used to control the amplitudes and phases of the RF modulation sidebands along two orthogonal states of polarization to generate two complementary bandpass and bandstop responses at two output ports, respectively. Experiments are then performed. Two complementary responses are simultaneously generated in a high frequency resolution of ~20 MHz, with a rejection over 35 or 51 dB being achieved for the passband or stopband. A tunable central frequency to the bandpass and bandstop responses is also demonstrated within the range from 3 to 15 GHz. PMID- 28809891 TI - High-power and high-conversion efficiency deep ultraviolet (DUV) laser at 258 nm generation in the CsLiB6O10 (CLBO) crystal with a beam quality of M2<1.5. AB - We report a 10 kHz, 10.5 W deep ultraviolet (DUV) laser at 258 nm with a pulse duration of 3 ns by fourth-harmonic generation (FHG) in a CsLiB6O10 crystal with high-conversion efficiency. The fundamental laser is at 1030 nm with 35 W output power consisting of a Yb:YAG ceramics thin rod amplifier. The M2 of the DUV laser was confirmed to be <1.5. To the best of our knowledge, this is the best beam quality for DUV laser power higher than 10 W generated by FHG of a solid-state laser, as well as the highest conversion efficiency of 31% from infrared to DUV so far. PMID- 28809892 TI - Beam folding analysis and optimization of mask-enhanced toroidal multipass cells. AB - We present computational and experimental investigations of the beam folding properties and fringe suppression capabilities in monolithic toroidal multipass cells (MPCs) when combined with absorption masks. Coherent field simulations based on the Fresnel-Huygens theory were performed to understand the effect of multiple field truncations in such an optically semi-unstable mirror arrangement. The explicit numerical calculation of the radiation field at each reflection allows detailed optimization and performance analysis. We experimentally verified the evolving irradiance distributions and identified optimal initial field configurations. Furthermore, we suggest a proxy to estimate the noise level for specific initial conditions. These insights pave the way to a better optical performance and, thus, to even more lightweight and compact designs of this MPC type. PMID- 28809893 TI - Distributed feedback lasers with alternating laterally coupled ridge-waveguide surface gratings. AB - Distributed feedback lasers with laterally coupled ridge-waveguide surface gratings having the protrusions placed alternately on the lateral sides of the ridge are demonstrated. This configuration enables easier-to-fabricate wider trenches than in the gratings with protrusions placed symmetrically on both sides of the ridge. The design strategy and coupling coefficient calculations are discussed. The output characteristics of fabricated lasers show lower threshold currents and higher slope efficiencies for devices with first-order alternating gratings than for those with third-order symmetric gratings having comparable grating trench widths and similar coupling coefficients. PMID- 28809894 TI - High-sensitivity and large-dynamic-range refractive index sensors employing weak composite Fabry-Perot cavities. AB - Most sensors face a common trade-off between high sensitivity and a large dynamic range. We demonstrate here an all-fiber refractometer based on a dual-cavity Fabry-Perot interferometer (FPI) that possesses the advantage of both high sensitivity and a large dynamic range. Since the two composite cavities have a large cavity length difference, one can observe both fine and coarse fringes, which correspond to the long cavity and the short cavity, respectively. The short cavity FPI and the use of an intensity demodulation method mean that the individual fine fringe dips correspond to a series of quasi-continuous highly sensitive zones for refractive index measurement. By calculating the parameters of the composite FPI, we find that the range of the ultra-sensitive zones can be considerably adjusted to suit the end requirements. The experimental trends are in good agreement with the theoretical predictions. The co-existence of high sensitivity and a large dynamic range in a composite FPI is of great significance to practical RI measurements. PMID- 28809895 TI - 1.5 kW efficient CW Nd:YAG planar waveguide MOPA laser. AB - In this Letter, we report a 1064 nm continuous wave Nd:YAG planar waveguide laser with an output power of 1544 W based on the structure of the master oscillator power amplification. A fiber laser is used as the master oscillator, and diode laser arrays are used as the pump source of the waveguide laser amplifier. The dimension of the waveguide is 1 mm (T)*10 mm (W)*60 mm (L), and the dual end oblique pumping is adopted with different angles. After a single-pass amplification, the power is scaled from 323 to 1544 W with the pump power of 2480 W, leading to an optical-to-optical efficiency of 49%. At the maximum output, the beam quality M2 are measured to be 2.8 and 7.0 in the guided direction and the unguided direction, respectively. To the best of our knowledge, this is the highest output power of a Nd:YAG planar waveguide laser to date. PMID- 28809896 TI - Multifrequency excitation and detection scheme in apertureless scattering near field scanning optical microscopy. AB - Near-field scanning optical microscopy has revolutionized the study of fundamental physics, as it is one of very few label-free optical noninvasive nanoscale-resolved imaging techniques. However, its resolution remains strongly limited by the poor discrimination of weak near-field optical signals from a far field background. Here, we theoretically and experimentally demonstrate a multifrequency excitation and detection scheme in apertureless near-field optical microscopy that exceeds current state-of-the-art sensitivity and background suppression. We achieved a twofold enhancement in sensitivity and deep subwavelength resolution in optical measurements. This method offers rich control over experimental degrees of freedom, breaking the ground for noninterferometric complete retrieval of the near-field signal. PMID- 28809897 TI - Topology-optimized metasurfaces: impact of initial geometric layout. AB - Topology optimization is a powerful iterative inverse design technique in metasurface engineering and can transform an initial layout into a high performance device. With this method, devices are optimized within a local design phase space, making the identification of suitable initial geometries essential. In this Letter, we examine the impact of initial geometric layout on the performance of large-angle (75 deg) topology-optimized metagrating deflectors. We find that when conventional metasurface designs based on dielectric nanoposts are used as initial layouts for topology optimization, the final devices have efficiencies around 65%. In contrast, when random initial layouts are used, the final devices have ultra-high efficiencies that can reach 94%. Our numerical experiments suggest that device topologies based on conventional metasurface designs may not be suitable to produce ultra-high-efficiency, large-angle metasurfaces. Rather, initial geometric layouts with non-trivial topologies and shapes are required. PMID- 28809898 TI - Analog receiver for coherent optical analog radio-over-fiber transmission. AB - A receiver for low-cost coherent optical applications is presented. Conceptual simplicity is guaranteed through the use of a monolithic integrated externally modulated laser. Local oscillators and fast photodetectors are provided by the distributed feedback section and electro-absorption modulator of the monolithic laser. The injection-locking feature, which is obtained by virtue of the inline configuration of the receiver, guarantees exact frequency translation during coherent reception and obviates the need for digital signal processing typically employed for the purpose of signal recovery. The proposed receiver is experimentally demonstrated for wired multi-carrier and analog transmission of wireless radio signals. Nyquist-shaped frequency division multiplexing with data rates up to 10 Gb/s and real-time transmission of 64-ary quadrature amplitude modulated narrowband orthogonal frequency division multiplexed radio signals is shown for an optical loss budget of 31 dB. PMID- 28809899 TI - Direct coupling of tomography and ptychography. AB - A generalization of the ptychographic phase problem is presented for recovering refractive properties of a three-dimensional object in a tomography setting. This approach, which ignores the lateral overlapping probe requirements in existing ptychography algorithms, can enable the reconstruction of objects using highly flexible acquisition patterns and pave the way for sparse and rapid data collection with lower radiation exposure. PMID- 28809900 TI - Modulation bandwidth enhancement for coupled twin-square microcavity lasers. AB - Modulation bandwidth enhancements are investigated for coupled twin-square microcavity lasers due to photon-photon resonance effect. For a coupled twin square microcavity laser with the square side length of 20 MUm, we demonstrate the increase of 3-dB modulation bandwidth from 9.6 GHz to 19.5 GHz, by adjusting the resonance mode wavelength interval between two square microcavities. The enhanced modulation bandwidth is explained by rate equation analysis, and numerical simulations are conducted for large signal modulation with improved eye diagrams at 40 Gbit/s. PMID- 28809901 TI - Pump-linewidth-tolerant wavelength multicasting using soliton Kerr frequency combs. AB - We experimentally demonstrate pump-linewidth-tolerant wavelength multicasting using microresonator-based soliton Kerr frequency combs. When Kerr comb lines serve as coherent pumps in a periodically poled lithium niobate waveguide, the linewidth of the multicast signal almost remains that of the original signal at different linewidths of Kerr combs, ranging from 100 kHz to 1 MHz. However, in conventional multicasting where free-running (FR) pumps are used, the linewidth of the converted signal significantly increases. Furthermore, the error vector magnitude (EVM) performance demonstrates eight-fold error-free multicasting of 10 Gbaud 16-quadrature amplitude modulation signals, even when the linewidths of the Kerr combs are as broad as 1 MHz (no Kalman filtering algorithm in the receiver). In contrast, the EVM performance of the signal copy is degraded with an FR laser as a dummy pump. PMID- 28809902 TI - Tunable, low-phase-noise microwave signals from an optically injected semiconductor laser with opto-electronic feedback. AB - We experimentally demonstrate the generation of microwave signals with linewidths below 3 Hz and a tuning range over 35 GHz from a semiconductor laser subject to optical injection and opto-electronic feedback. The feedback loop uses neither a microwave spectral filter nor an amplifier to achieve a reduction in the microwave linewidth of six orders of magnitude. Two microwave frequencies, 25.4 and 45.9 GHz, are chosen to highlight single-sideband phase measurements of -105 and -95 dBc/Hz at a 10-kHz offset, respectively. Finally, we demonstrate that longer-term stability can be further improved via asymmetric mutual injection. PMID- 28809903 TI - Kerr-lens mode-locked Tm3+:Sc2O3 single-crystal laser in-band pumped by an Er:Yb fiber MOPA at 1611 nm. AB - We demonstrate a Kerr-lens mode-locked Tm3+:Sc2O3 single-crystal laser in-band pumped by an Er3+:Yb3+ fiber master oscillator power amplifier at 1611 nm. Pulses as short as 166 fs with an average output power of 440 mW are obtained. The spectral bandwidth and center wavelength are 29.3 and 2124 nm, respectively. At a longer pulse duration of 298 fs, we obtain 1 W of average output power. The repetition rate is 95 MHz, and the conversion efficiency against the absorbed pump power is as high as 47%. To the best of our knowledge, this is the first Kerr-lens mode-locked Tm3+-doped solid state laser. PMID- 28809904 TI - SPARSE (spatially phase-retarded spectroscopic ellipsometry) for real-time film analysis. AB - In this Letter, we propose a novel type of spectroscopic ellipsometer, named spatially phase-retarded spectroscopic ellipsometry (SPARSE), based on the spatial polarization distribution opposed to the temporal polarization changes. SPARSE can collect all information necessary to characterize film structures with a single image acquisition, and it has the benefit of real-time measurements. For the verification, feasible experiments with single film-layered certificated reference materials and multi-layered film specimens were carried out. PMID- 28809905 TI - Endoscopic forward-viewing optical coherence tomography and angiography with MHz swept source. AB - Endoscopic optical coherence tomography (OCT) instruments are mostly side viewing and rely on at least one proximal scan, thus limiting accuracy of volumetric imaging and en face visualization. Previous forward-viewing OCT devices had limited axial scan speeds. We report a forward-viewing fiber scanning 3D-OCT probe with 900 MUm field of view and 5 MUm transverse resolution, imaging at 1 MHz axial scan rate in the human gastrointestinal tract. The probe is 3.3 mm diameter and 20 mm rigid length, thus enabling passage through the endoscopic channel. The scanner has 1.8 kHz resonant frequency, and each volumetric acquisition takes 0.17 s with 2 volumes/s display. 3D-OCT and angiography imaging of the colon was performed during surveillance colonoscopy. PMID- 28809906 TI - Efficient method for the measurement of lifetime optical damage performance of thin film coatings from laser damage size analysis. AB - A laser damage test method based on damage size analysis (DSA) is described that simplifies the derivation of the lifetime optical damage threshold of film materials critical in the design of devices used in high-repetition-rate, high power laser systems. The DSA method presented here is solely based on imaging to measure the damage site size produced from exposure to a known Gaussian-shaped beam with a fixed, systematically selected fluence well above the ablation threshold. The method locates the damage boundary produced from repeated exposures, using images with a high contrast, and maps it to the beam profile to extract a lifetime laser damage fluence threshold value. We validate the DSA approach using a few relevant transparent film material systems and by comparing it to the standard S/1 laser damage test method. The DSA method can be more efficient and accelerate materials development and validation necessary to support the design of high-power repetition-rated lasers and optoelectronic devices. PMID- 28809907 TI - Optical frequency combs generated mechanically. AB - An elongated bottle microresonator with nanoscale parabolic effective radius variation can possess a series of dense equally spaced optical eigenfrequencies whose separation can match the eigenfrequency of its axially symmetric acoustic mode. It is shown that this acoustic mode can parametrically excite optical modes and give rise to a highly equidistant and moderately broadband optical frequency comb with the teeth spacing independent of the input laser power and the amplitude of mechanical vibrations. PMID- 28809908 TI - Coherent combining of second-harmonic generators by active phase control of the fundamental waves. AB - Coherent beam combining by active phase control could be useful for power scaling fiber-laser-pumped optical frequency converters. However, a fast phase modulator operating at the frequency-converted wavelength, a non-standard component, would be necessary. Fortunately, nonlinear conversion processes rely on a phase matching condition allowing for indirect phase control using standard phase modulators. In this Letter, coherent combining of second-harmonic generators is demonstrated in both birefringent and quasi-phase-matching schemes in CW regime. Phase control operates at the fundamental wavelength, using all-fiber electro optic modulators. An excellent beam combination is achieved with a residual phase error of lambda/30 on the second-harmonic wave. PMID- 28809909 TI - Axial sub-Fourier focusing of an optical beam. AB - We demonstrate experimentally the generation of an optical beam having an axial focusing that is narrower than the Fourier limit. The beam is constructed from a superposition of Bessel beams with different longitudinal wave vectors, realizing a super-oscillatory axial intensity distribution. Such beams can be useful for microscopy and for optical particle manipulation. PMID- 28809910 TI - Enhanced depth-of-field of an integral imaging microscope using a bifocal holographic optical element-micro lens array. AB - We propose and implement an integral imaging microscope with extended depth-of field (DoF) using a bifocal holographic micro lens array (MLA). The properties of the two MLAs are switched via peristrophic multiplexing, where different properties of the MLA are recorded onto the single holographic optical element (HOE). The recorded MLA properties are perpendicular to each other: after the first mode is recorded, the HOE is rotated by 90 degrees clockwise, and the second mode is recorded. The experimental results confirm that the DoF of the integral imaging microscopy system is extended successfully by using the bifocal MLA. PMID- 28809911 TI - Precision wander model of beam wave in the weak to strong turbulence of atmosphere. AB - We present a new beam wander model valid in all irradiance fluctuation regions by using extended Rytov theory with large-scale and small-scale filters. Comparing the calculated results of our wander model and commonly used models with the experimental data obtained in the case of different propagation distances, the waist radius of a beam wave, the outer scale of turbulence and turbulence strength, our new theory gives better agreement with the experimental results than others do. PMID- 28809912 TI - Accurate analysis of mechanical stress in dielectric multilayers. AB - We present a systematic study of a stress coefficient of dielectric materials (SiO2, Nb2O5, and HfO2). In particular, we show a thickness dependence of the stress coefficient on layer thickness, which shows that the determination of this coefficient is complex and requires careful analysis. We then apply the different models of the stress coefficient to multilayer structures and show that stress induced deformation can be precisely predicted in final components with a few percent accuracy. PMID- 28809913 TI - All-fiber highly chirped dissipative soliton generation in the telecom range. AB - A high-energy (0.93 nJ) all-fiber erbium femtosecond oscillator operating in the telecom spectral range is proposed and realized. The laser cavity, built of commercially available fibers and components, combines polarization maintaining (PM) and non-PM parts providing stable generation of highly chirped (chirp parameter 40) pulses compressed in an output piece of standard PM fiber to 165 fs. The results of the numerical simulation agree well with the experiment. The analyzed intracavity pulse dynamics enables the classification of the generated pulses as dissipative solitons. PMID- 28809914 TI - Beyond the perturbative description of the nonlinear optical response of low index materials. AB - We show that standard approximations in nonlinear optics are violated for situations involving a small value of the linear refractive index. Consequently, the conventional equation for the intensity-dependent refractive index, n(I)=n0+n2I, becomes inapplicable in epsilon-near-zero and low-index media, even in the presence of only third-order effects. For the particular case of indium tin oxide, we find that the chi(3), chi(5), and chi(7) contributions to refraction eclipse the linear term; thus, the nonlinear response can no longer be interpreted as a perturbation in these materials. Although the response is non perturbative, we find no evidence that the power series expansion of the material polarization diverges. PMID- 28809915 TI - Reflectionless and invisible potentials in photonic lattices. AB - An arbitrarily shaped optical potential on a discrete photonic lattice, which transversely drifts at a speed greater than the maximum speed allowed by the light cone of the lattice band, becomes reflectionless. Such an intriguing result, which arises from the discrete translational symmetry of the lattice, is peculiar to discretized light and does not have any counterpart for light scattering in continuous optical media. A drifting non-Hermitian optical potential of the Kramers-Kronig type also is an invisible potential, i.e., a discrete optical beam crosses the drifting potential without being distorted, delayed, nor advanced. PMID- 28809916 TI - Binary zero-order diffractive and anti-reflective optical elements in silicon for the mid-infrared. AB - We propose a novel method for the design of binary two-level diffractive optical elements that provide an efficient diffractive function while reducing the reflectivity of a high-index interface. The structure can be fabricated with a single patterning step and is particularly useful for the mid-infrared spectral range. The concept is based on zero-order transmission gratings using subwavelength microstructures. To demonstrate the concept a Dammann grating has been realized in silicon and characterized in the mid-infrared by scanning the far-field intensity distribution. PMID- 28809917 TI - Negative illumination thermoradiative solar cell. AB - The negative illumination thermoradiative solar cell (NITSC) consisting of a concentrator, an absorber, and a thermoradiative cell (TRC) is established, where the radiation and reflection losses from the absorber to the environment and the radiation loss from the TRC to the environment are taken into consideration. The power output and overall efficiency of the NITSC are analytically derived. The operating temperature of the TRC is determined through the thermal equilibrium equations, and the efficiency of the NITSC is calculated through the optimization of the output voltage of the TRC and the concentrating factor for a given value of the bandgap. Moreover, the maximum efficiencies of the NITSC at different conditions and the optimal values of the bandgap are determined, and consequently, the corresponding optimum operating conditions are obtained. The results obtained here will be helpful for the optimum design and operation of TRCs. PMID- 28809918 TI - Freestanding optical negative-index metamaterials of green light. AB - A freestanding, multilayered fishnet metamaterial is reported to experimentally exhibit a negative refractive index in the green-light spectral range. The realization of a negative refractive index at such a high frequency range mainly originates from low-loss magnetic resonance and interactions between the neighboring functional layers. Based on a good agreement between the numerically simulated and experimentally measured transmittance and reflectance spectra, a single negative refractive index of -0.76 with a figure-of-merit of 0.5 is achieved for the metamaterial at the wavelength of 532 nm. PMID- 28809919 TI - Photonic crystal slow light waveguides in a kagome lattice. AB - Slow light photonic crystal waveguides tightly compress propagating light and increase interaction times, showing immense potential for all-optical delay and enhanced light-matter interactions. Yet, their practical application has largely been limited to moderate group index values (<100), due to a lack of waveguides that reliably demonstrate slower light. This limitation persists because nearly all such research has focused on a single photonic crystal lattice type: the triangular lattice. Here, we present waveguides based on the kagome lattice that demonstrate an intrinsically high group index and exhibit slow and stopped light. We experimentally demonstrate group index values of >150, limited by our measurement resolution. The kagome-lattice waveguides are an excellent starting point for further slow light engineering in photonic crystal waveguides. PMID- 28809920 TI - Single-longitudinal-mode broadband tunable random laser. AB - In this work, we demonstrate a broadband tunable single-longitudinal-mode (SLM) random laser based on Rayleigh backscattering in a standard single-mode fiber. The wide tuning range of this SLM fiber laser over 1500-1570 nm is demonstrated with a linewidth of 4.5-30 kHz. The tuning is achieved using a tunable bandpass Fabry-Perot filter, and a semiconductor optical amplifier is used as the wide bandwidth gain medium. The laser is able to operate in the S + C + L band. PMID- 28809921 TI - First choice of treatment place in the pathways to epileptic care at the outpatient department of University of Gondar Hospital, Northwest Ethiopia: Cross sectional institutional based study. AB - BACKGROUND: Epilepsy treatment gap range from 87% to 98%. In spite of this, there is a gross inadequacy of the availability, accessibility and affordability of Anti-Epileptic Drugs. In countries like Ethiopia, where most populations are less aware about mental health problems, most people seek help for their illness from traditional healers. Thus, the main purpose of this study was to assess the pathways to epilepsy care and associated factors. METHODS: Cross-sectional study design utilized among 409 participants selected by systematic random sampling technique. Pathways to epilepsy care were assessed by using the WHO Pathway Study tool. Multivariable logistic regression was done to identify factors associated with pathways to epileptic care. RESULTS: Overall, 162 (39.6%) of participants first contacted with modern treatment. Two hundred and forty seven (60.4%) of participants counted traditional healers and religious healers were the most common (47.2%). Being men, attending higher education, urban residence, short duration of illness, social support and age at the onset of illness were factors associated with first contact with modern treatment. CONCLUSION: Modern treatment was not the first place of choice for the majority of the respondents. Strengthening awareness creation program about epilepsy and its treatment is highly recommended with special emphases to urban dwellers and less educated people. PMID- 28809922 TI - Increased signaling by the autism-related Engrailed-2 protein enhances dendritic branching and spine density, alters synaptic structural matching, and exaggerates protein synthesis. AB - Engrailed 1 (En1) and 2 (En2) code for closely related homeoproteins acting as transcription factors and as signaling molecules that contribute to midbrain and hindbrain patterning, to development and maintenance of monoaminergic pathways, and to retinotectal wiring. En2 has been suggested to be an autism susceptibility gene and individuals with autism display an overexpression of this homeogene but the mechanisms remain unclear. We addressed in the present study the effect of exogenously added En2 on the morphology of hippocampal cells that normally express only low levels of Engrailed proteins. By means of RT-qPCR, we confirmed that En1 and En2 were expressed at low levels in hippocampus and hippocampal neurons, and observed a pronounced decrease in En2 expression at birth and during the first postnatal week, a period characterized by intense synaptogenesis. To address a putative effect of Engrailed in dendritogenesis or synaptogenesis, we added recombinant En1 or En2 proteins to hippocampal cell cultures. Both En1 and En2 treatment increased the complexity of the dendritic tree of glutamatergic neurons, but only En2 increased that of GABAergic cells. En1 increased the density of dendritic spines both in vitro and in vivo. En2 had similar but less pronounced effect on spine density. The number of mature synapses remained unchanged upon En1 treatment but was reduced by En2 treatment, as well as the area of post-synaptic densities. Finally, both En1 and En2 elevated mTORC1 activity and protein synthesis in hippocampal cells, suggesting that some effects of Engrailed proteins may require mRNA translation. Our results indicate that Engrailed proteins can play, even at low concentrations, an active role in the morphogenesis of hippocampal cells. Further, they emphasize the over-regulation of GABA cell morphology and the vulnerability of excitatory synapses in a pathological context of En2 overexpression. PMID- 28809923 TI - Generalized structural equations improve sexual-selection analyses. AB - Sexual selection is an intense evolutionary force, which operates through competition for the access to breeding resources. There are many cases where male copulatory success is highly asymmetric, and few males are able to sire most females. Two main hypotheses were proposed to explain this asymmetry: "female choice" and "male dominance". The literature reports contrasting results. This variability may reflect actual differences among studied populations, but it may also be generated by methodological differences and statistical shortcomings in data analysis. A review of the statistical methods used so far in lek studies, shows a prevalence of Linear Models (LM) and Generalized Linear Models (GLM) which may be affected by problems in inferring cause-effect relationships; multi collinearity among explanatory variables and erroneous handling of non-normal and non-continuous distributions of the response variable. In lek breeding, selective pressure is maximal, because large numbers of males and females congregate in small arenas. We used a dataset on lekking fallow deer (Dama dama), to contrast the methods and procedures employed so far, and we propose a novel approach based on Generalized Structural Equations Models (GSEMs). GSEMs combine the power and flexibility of both SEM and GLM in a unified modeling framework. We showed that LMs fail to identify several important predictors of male copulatory success and yields very imprecise parameter estimates. Minor variations in data transformation yield wide changes in results and the method appears unreliable. GLMs improved the analysis, but GSEMs provided better results, because the use of latent variables decreases the impact of measurement errors. Using GSEMs, we were able to test contrasting hypotheses and calculate both direct and indirect effects, and we reached a high precision of the estimates, which implies a high predictive ability. In synthesis, we recommend the use of GSEMs in studies on lekking behaviour, and we provide guidelines to implement these models. PMID- 28809924 TI - Species delimitation in frogs from South American temperate forests: The case of Eupsophus, a taxonomically complex genus with high phenotypic variation. AB - One of the most characteristic and abundant amphibian taxa of South American temperate forests is Eupsophus. The ten currently recognized species of the genus have been divided in two species groups, roseus and vertebralis, but most of them, eight, belong to the roseus group. Recent phylogeographic and phylogenetic studies have suggested that species diversity of the roseus group could be underestimated. An examination of the literature shows that species of the roseus group exhibit high levels of variation in their external characteristics, particularly those used as diagnostic characters, which compromises their taxonomy and hinders their field recognition. High levels of variation were also observed in several new populations of the roseus group discovered in southern Chile (36 degrees -40 degrees S), which could not be identified to the species level by their external characteristics. On the other hand, the literature reveals a scarse karyotype differentiation and a high bioacoustic uniformity among the species of the roseus group. We performed a Bayesian phylogenetic analysis using mitochondrial and nuclear genes to reevaluate the species diversity of the roseus group, including all the nominal species of Eupsophus and new populations. This analysis was complemented with three species delimitation approaches, General Mixed Yule Coalescent, multi-rate Poisson Tree Process and Automatic Barcode Gap Discovery. We favored a conservative delimitation of only four species for the roseus group, a result more consistent with the distribution of pairwise genetic distances, and the available chromosome and bioacoustic evidence. The four recognized lineages, which have nearly completely allopatric distributions, are named after the earliest nominal species that they include, but because high levels of phenotypic variation, they are not diagnosable by consistent differences in external morphology. We discuss the implications of this new proposal for the taxonomy and conservation of the genus, and the possible causes of the difficulty to estimate its species diversity. PMID- 28809925 TI - Salivary peptidome profiling analysis for occurrence of new carious lesions in patients with severe early childhood caries. AB - This study aimed to identify differences of peptide profiles in stimulated whole saliva among children with and without occurrence of new carious lesions, and to provide a simple way for early diagnosis and prevention of the relapse of severe early childhood caries (s-ECC). Overall, 26 children aged 3-4 years were selected out from all the children in the kindergarten to be involved in the present study, among them 13 were diagnosed as s-ECC and underwent dental treatment, whilst the other 13 were matched by age and sex as control. Stimulated whole saliva samples were collected before treatment, and at 10 days and 4 months after treatment. During follow-up, 7 of the 13 children with s-ECC showed a relapse, and the new carious lesions were then treated. Salivary peptides were detected using the technique of magnetic beads combined with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Fifteen peptides showed significant differences in the group without occurrence of new carious lesions (CH group). On comparing the CH group and the other group with occurrence of new carious lesions (CR group), no significant differences were observed before treatment, whereas certain peptides showed significant differences at both 10 days and 4 months after treatment. Two peptides (experimental m/z values: 3162.0 Da and 3290.4 Da) exhibited a consistent tendency in cross-sectional and longitudinal comparisons among these groups; these may be associated with recurrence of s-ECC. Based on our findings, it is concluded that different saliva peptide peaks can be detected in s-ECC using MALDI-TOF MS combined with magnetic beads. Moreover, 2 specific peptides with m/z values 3162.0 Da and 3290.4 Da could be promising salivary protein biomarkers for diagnosis of recurrence of s-ECC. PMID- 28809926 TI - Impact of fortified versus unfortified lipid-based supplements on morbidity and nutritional status: A randomised double-blind placebo-controlled trial in ill Gambian children. AB - BACKGROUND: Multiple micronutrients (MMN) are commonly prescribed in pediatric primary healthcare in sub-Saharan Africa to improve nutritional status and appetite without evidence for their effectiveness or international clinical guidelines. Community-wide MMN supplementation has shown limited and heterogeneous impact on growth and morbidity. Short-term ready-to-use therapeutic foods in acutely sick children in a hospital setting also had limited efficacy regarding subsequent growth. The effectiveness of MMN in improving morbidity or growth in sick children presenting for primary care has not been assessed. METHODS AND FINDINGS: We undertook a double-blind randomised controlled trial of small-quantity lipid-based nutrient supplements (SQ-LNS) fortified with 23 micronutrients in children aged 6 months (mo) to 5 years (y) presenting with an illness at a rural primary healthcare centre in The Gambia. Primary outcomes were repeat clinic presentations and growth over 24 wk. Participants were randomly assigned to receive 1 of 3 interventions: (1) supplementation with micronutrient fortified SQ-LNS for 12 wk (MMN-12), (2) supplementation with micronutrient fortified SQ-LNS for 6 wk followed by unfortified SQ-LNS for 6 wk (MMN-6), or (3) supplementation with unfortified SQ-LNS for 12 wk (MMN-0) to be consumed in daily portions. Treatment masking used 16 letters per 6-wk block in the randomisation process. Blinded intention-to-treat analysis based on a prespecified statistical analysis plan included all participants eligible and correctly enrolled. Between December 2009 and June 2011, 1,101 children (age 6-60 mo, mean 25.5 mo) were enrolled, and 1,085 were assessed (MMN-0 = 361, MMN-6 = 362, MMN-12 = 362). MMN supplementation was associated with a small increase in height-for-age z-scores 24 wk after recruitment (effect size for MMN groups combined: 0.084 SD/24 wk, 95% CI: 0.005, 0.168; p = 0.037; equivalent to 2-5 mm depending on age). No significant difference in frequency of morbidity measured by the number of visits to the clinic within 24 wk follow-up was detected with 0.09 presentations per wk for all groups (MMN-0 versus MMN-6: adjusted incidence rate ratio [IRR] 1.03, 95% CI: 0.92, 1.16; MMN-0 versus MMN-12: 1.05, 95% CI: 0.93, 1.18). In post hoc analysis, clinic visits significantly increased by 43% over the first 3 wk of fortified versus unfortified SQ-LNS (adjusted IRR 1.43; 95% CI: 1.07, 1.92; p = 0.016), with respiratory presentations increasing by 52% with fortified SQ-LNS (adjusted IRR 1.52; 95% CI: 1.01, 2.30; p = 0.046). The number of severe adverse events during supplementation were similar between groups (MMN-0 = 20 [1 death]; MMN-6 = 21 [1 death]; MMN-12 = 20 [0 death]). No participant withdrew due to adverse effects. Study limitations included the lack of supervision of daily supplementation. CONCLUSION: Prescribing micronutrient-fortified SQ-LNS to ill children presenting for primary care in rural Gambia had a very small effect on linear growth and did not reduce morbidity compared to unfortified SQ-LNS. An early increase in repeat visits indicates a need for the establishment of evidence-based guidelines and caution with systematic prescribing of MMN. Future research should be directed at understanding the mechanisms behind the lack of effect of MMN supplementation on morbidity measures and limited effect on growth. TRIAL REGISTRATION: ISRCTN 73571031. PMID- 28809927 TI - In middle-aged and old obese patients, training intervention reduces leptin level: A meta-analysis. AB - BACKGROUND: Leptin is one of the major adipokines in obesity that indicates the severity of fat accumulation. It is also an important etiological factor of consequent cardiometabolic and autoimmune disorders. Aging has been demonstrated to aggravate obesity and to induce leptin resistance and hyperleptinemia. Hyperleptinemia, on the other hand, may promote the development of age-related abnormalities. While major weight loss has been demonstrated to ameliorate hyperleptinemia, obese people show a poor tendency to achieve lasting success in this field. The question arises whether training intervention per se is able to reduce the level of this adipokine. OBJECTIVES: We aimed to review the literature on the effects of training intervention on peripheral leptin level in obesity during aging, in order to evaluate the independent efficacy of this method. In the studies that were included in our analysis, changes of adiponectin levels (when present) were also evaluated. DATA SOURCES: 3481 records were identified through searching of PubMed, Embase and Cochrane Library Database. Altogether 19 articles were suitable for analyses. STUDY ELIGIBILITY CRITERIA: Empirical research papers were eligible provided that they reported data of middle-aged or older (above 45 years of age) overweight or obese (body mass index above 25) individuals and included physical training intervention or at least fitness status of groups together with corresponding blood leptin values. STATISTICAL METHODS: We used random effect models in each of the meta-analyses calculating with the DerSimonian and Laird weighting methods. I-squared indicator and Q test were performed to assess heterogeneity. To assess publication bias Egger's test was applied. In case of significant publication bias, the Duval and Tweedie's trim and fill algorithm was used. RESULTS: Training intervention leads to a decrease in leptin level of middle-aged or older, overweight or obese male and female groups, even without major weight loss, indicated by unchanged serum adiponectin levels. Resistance training appears to be more efficient in reducing blood leptin level than aerobic training alone. CONCLUSIONS: Physical training, especially resistance training successfully reduces hyperleptinemia even without diet or major weight loss. PMID- 28809928 TI - Lay worker-administered behavioral treatments for psychological distress in resource-limited settings: Time to move from evidence to practice? AB - In this Perspective on the study by Bryant and colleagues, Alex Tsai discusses the evidence supporting lay worker-administered, behavioral interventions for women survivors of interpersonal violence. PMID- 28809929 TI - Pregnant and breastfeeding women: A priority population for HIV viral load monitoring. AB - Landon Myer and colleagues discuss viral load monitoring for pregnant HIV positive women and those breastfeeding; ART treatments can suppress viral load and are key to preventing transmission to the child. PMID- 28809930 TI - Declining survival across invasion history for Microstegium vimineum. AB - Many alien species become invasive because they lack coevolutionary history with the native community; for instance, they may lack specialized enemies. These evolutionary advantages may allow the invader to establish and persist when rare within a community and lead to its monodominance through positive frequency dependence, i.e. increasing per capita population growth rate with increasing frequency of conspecifics. However, this advantage could degrade through time due to evolutionary and ecological changes in the invasive and native plant and microbial communities. We investigated survival rates and individual biomass as proxies for per capita population growth rates for the invasive grass, Microstegium vimineum, across a gradient of conspecific frequencies (10-100% relative cover of M. vimineum) within 12 sites that varied in time since invasion. We expected M. vimineum frequency dependence to become more negative and its proxies for population growth at low conspecific frequency to decline across invasion history. We also explored the belowground fungal community associated with M. vimineum, since we hypothesized that changes in M. vimineum population dynamics may result from shifting microbial interactions over time. Microstegium vimineum frequency dependence changed from negative to neutral across invasion history and the shift was driven by a decline in survival at low frequency. Changes in M. vimineum root fungal community were associated with time since invasion. Our results do not support a shift in frequency dependence from positive to negative across invasion history. However, our results suggest M. vimineum populations may be less prone to persist at older invaded sites and thus more vulnerable to management intervention. PMID- 28809931 TI - The cost of entry: An analysis of pharmaceutical registration fees in low-, middle-, and high-income countries. AB - BACKGROUND: Advances in pharmaceuticals offer improved health outcomes for a wide range of illnesses, yet medicines are often inaccessible for many patients worldwide. One potential barrier to making medicines available to all is the cost of product registration, the fees for regulatory review and licensing for the sale of medicines beyond the cost of clinical trials, if needed. METHODS AND FINDINGS: We performed a cross-sectional analysis of pharmaceutical registration fees in low-, middle-, and high-income countries. We collected data on market authorization fees for new chemical entities and for generic drugs in 95 countries. We calculated measures of registration fee size relative to population, gross domestic product (GDP), and total health spending in each country. Each of the 95 countries had a fee for registering new chemical entities. On average, the ratio of registration fees to GDP was highest in Europe and North America and lowest in South and Central America. Across individual countries, the level of registration fees was positively correlated with GDP and total health spending, with relatively few outliers. DISCUSSION: We find that, generally speaking, the regulatory fees charged by medicines regulatory authorities are roughly proportional to the market size in their jurisdictions. The data therefore do not support the hypothesis that regulatory fees are a barrier to market entry in most countries. PMID- 28809932 TI - REM sleep deprivation induces endothelial dysfunction and hypertension in middle aged rats: Roles of the eNOS/NO/cGMP pathway and supplementation with L-arginine. AB - Sleep loss can induce or aggravate the development of cardiovascular and cerebrovascular diseases. However, the molecular mechanism underlying this phenomenon is poorly understood. The present study was designed to investigate the effects of REM sleep deprivation on blood pressure in rats and the underlying mechanisms of these effects. After Sprague-Dawley rats were subjected to REM sleep deprivation for 5 days, their blood pressures and endothelial function were measured. In addition, one group of rats was given continuous access to L arginine supplementation (2% in distilled water) for the 5 days before and the 5 days of REM sleep deprivation to reverse sleep deprivation-induced pathological changes. The results showed that REM sleep deprivation decreased body weight, increased blood pressure, and impaired endothelial function of the aortas in middle-aged rats but not young rats. Moreover, nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) concentrations as well as endothelial NO synthase (eNOS) phosphorylation in the aorta were decreased by REM sleep deprivation. Supplementation with L-arginine could protect against REM sleep deprivation induced hypertension, endothelial dysfunction, and damage to the eNOS/NO/cGMP signaling pathway. The results of the present study suggested that REM sleep deprivation caused endothelial dysfunction and hypertension in middle-aged rats via the eNOS/NO/cGMP pathway and that these pathological changes could be inhibited via L-arginine supplementation. The present study provides a new strategy to inhibit the signaling pathways involved in insomnia-induced or insomnia-enhanced cardiovascular diseases. PMID- 28809933 TI - Using light-dependent scleractinia to define the upper boundary of mesophotic coral ecosystems on the reefs of Utila, Honduras. AB - Shallow water zooxanthellate coral reefs grade into ecologically distinct mesophotic coral ecosystems (MCEs) deeper in the euphotic zone. MCEs are widely considered to start at an absolute depth limit of 30m deep, possibly failing to recognise that these are distinct ecological communities that may shift shallower or deeper depending on local environmental conditions. This study aimed to explore whether MCEs represent distinct biological communities, the upper boundary of which can be defined and whether the depth at which they occur may vary above or below 30m. Mixed-gas diving and closed-circuit rebreathers were used to quantitatively survey benthic communities across shallow to mesophotic reef gradients around the island of Utila, Honduras. Depths of up to 85m were sampled, covering the vertical range of the zooxanthellate corals around Utila. We investigate vertical reef zonation using a variety of ecological metrics to identify community shifts with depth, and the appropriateness of different metrics to define the upper MCE boundary. Patterns observed in scleractinian community composition varied between ordination analyses and approaches utilising biodiversity indices. Indices and richness approaches revealed vertical community transition was a gradation. Ordination approaches suggest the possibility of recognising two scleractinian assemblages. We could detect a mesophotic and shallow community while illustrating that belief in a static depth limit is biologically unjustified. The switch between these two communities occurred across bathymetric gradients as small as 10m and as large as 50m in depth. The difference between communities appears to be a loss of shallow specialists and increase in depth-generalist taxa. Therefore, it may be possible to define MCEs by a loss of shallow specialist species. To support a biological definition of mesophotic reefs, we advocate this analytical framework should be applied around the Caribbean and extended into other ocean basins where MCEs are present. PMID- 28809934 TI - Long-term exposure to air pollution and the incidence of Parkinson's disease: A nested case-control study. AB - BACKGROUND: Previous studies revealed that chronic exposure to air pollution can significantly increase the risk of the development of Parkinson's disease (PD), but this relationship is inconclusive as large-scale prospective studies are limited and the results are inconsistent. Therefore, the purpose of this study was to ascertain the adverse health effects of air pollution exposure in a nationwide population using a longitudinal approach. MATERIALS AND METHODS: We conducted a nested case-control study using the National Health Insurance Research Dataset (NHIRD), which consisted of 1,000,000 beneficiaries in the National Health Insurance Program (NHI) in the year 2000 and their medical records from 1995 to 2013 and using public data on air pollution concentrations from monitoring stations across Taiwan released from the Environmental Protection Administration to identify people with ages >= 40 years living in areas with monitoring stations during 1995-1999 as study subjects. Then, we excluded subjects with PD, dementia, stroke and diabetes diagnosed before Jan. 1, 2000 and obtained 54,524 subjects to follow until Dec. 31, 2013. In this observational period, 1060 newly diagnosed PD cases were identified. 4240 controls were randomly selected from those without PD using a matching strategy for age, sex, the year of PD diagnosis and the year of entering the NHI program at a ratio of 1:4. Ten elements of air pollution were examined, and multiple logistic regression models were used to measure their risks in subsequent PD development. RESULTS: The incidence of PD in adults aged >= 40 years was 1.9%, and the median duration for disease onset was 8.45 years. None of the chemical compounds (SO2, O3, CO, NOx, NO, NO2, THC, CH4, or NMHC) significantly affected the incidence of PD except for particulate matter. PM10 exposure showed significant effects on the likelihood of PD development (T3 level: > 65MUg/m3 versus T1 level: <= 54MUg/m3; OR = 1.35, 95% CI = 1.12-1.62, 0.001 <= P < 0.01). In addition, comorbid conditions such as dementia (ORs = 3.53-3.93, Ps < 0.001), stroke (ORs = 2.99 3.01, Ps < 0.001), depression (ORs = 2.51-2.64, Ps < 0.001), head injury (ORs = 1.24-1.29, 0.001 <= Ps < 0.01 or 0.01 <= Ps < 0.05), sleep disorder (OR = 1.23 1.26, 0.001 <= Ps < 0.01), and hypertension (ORs = 1.18-1.19, 0.01 <= Ps < 0.05) also significantly increased the risk for PD development. CONCLUSIONS: Although PM10 plays a significant role in PD development, the associated chemical/metal compounds that are capable of inducing adverse biological mechanisms still warrant further exploration. Because of a link between comorbid conditions and PM exposure, research on the causal relationship between long-term exposure to PM and the development of PD should be considered with caution because other possible modifiers or mediators, comorbid diseases in particular, may be involved. PMID- 28809935 TI - Effectiveness of a brief behavioural intervention on psychological distress among women with a history of gender-based violence in urban Kenya: A randomised clinical trial. AB - BACKGROUND: Gender-based violence (GBV) represents a major cause of psychological morbidity worldwide, and particularly in low- and middle-income countries (LMICs). Although there are effective treatments for common mental disorders associated with GBV, they typically require lengthy treatment programs that may limit scaling up in LMICs. The aim of this study was to test the effectiveness of a new 5-session behavioural treatment called Problem Management Plus (PM+) that lay community workers can be taught to deliver. METHODS AND FINDINGS: In this single-blind, parallel, randomised controlled trial, adult women who had experienced GBV were identified through community screening for psychological distress and impaired functioning in Nairobi, Kenya. Participants were randomly allocated in a 1:1 ratio either to PM+ delivered in the community by lay community health workers provided with 8 days of training or to facility-based enhanced usual care (EUC) provided by community nurses. Participants were aware of treatment allocation, but research assessors were blinded. The primary outcome was psychological distress as measured by the total score on the 12-item General Health Questionnaire (GHQ-12) assessed at 3 months after treatment. Secondary outcomes were impaired functioning (measured by the WHO Disability Adjustment Schedule [WHODAS]), symptoms of posttraumatic stress (measured by the Posttraumatic Stress Disorder Checklist [PCL]), personally identified problems (measured by Psychological Outcome Profiles [PSYCHLOPS]), stressful life events (measured by the Life Events Checklist [LEC]), and health service utilisation. Between 15 April 2015 and 20 August 2015, 1,393 women were screened for eligibility on the basis of psychological distress and impaired functioning. Of these, 518 women (37%) screened positive, of whom 421 (81%) were women who had experienced GBV. Of these 421 women, 209 were assigned to PM+ and 212 to EUC. Follow-up assessments were completed on 16 January 2016. The primary analysis was intention to treat and included 53 women in PM+ (25%) and 49 women in EUC (23%) lost to follow-up. The difference between PM+ and EUC in the change from baseline to 3 months on the GHQ-12 was 3.33 (95% CI 1.86-4.79, P = 0.001) in favour of PM+. In terms of secondary outcomes, for WHODAS the difference between PM+ and EUC in the change from baseline to 3-month follow-up was 1.96 (95% CI 0.21-3.71, P = 0.03), for PCL it was 3.95 (95% CI 0.06-7.83, P = 0.05), and for PSYCHLOPS it was 2.15 (95% CI 0.98-3.32, P = 0.001), all in favour of PM+. These estimated differences correspond to moderate effect sizes in favour of PM+ for GHQ-12 score (0.57, 95% CI 0.32-0.83) and PSYCHLOPS (0.67, 95% CI 0.31-1.03), and small effect sizes for WHODAS (0.26, 95% CI 0.02-0.50) and PCL (0.21, 95% CI 0.00-0.41). Twelve adverse events were reported, all of which were suicidal risks detected during screening. No adverse events were attributable to the interventions or the trial. Limitations of the study include no long-term follow-up, reliance on self report rather than structured interview data, and lack of an attention control condition. CONCLUSIONS: Among a community sample of women in urban Kenya with a history of GBV, a brief, lay-administered behavioural intervention, compared with EUC, resulted in moderate reductions in psychological distress at 3-month follow up. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12614001291673. PMID- 28809937 TI - Understanding large-scale, long-term larval connectivity patterns: The case of the Northern Line Islands in the Central Pacific Ocean. AB - Protecting key hotspots of marine biodiversity is essential to maintain ecosystem services at large spatial scales. Protected areas serve not only as sources of propagules colonizing other habitats, but also as receptors, thus acting as protected nurseries. To quantify the geographical extent and the temporal persistence of ecological benefits resulting from protection, we investigate larval connectivity within a remote archipelago, characterized by a strong spatial gradient of human impact from pristine to heavily exploited: the Northern Line Islands (NLIs), including part of the Pacific Remote Islands Marine National Monument (PRI-MNM). Larvae are described as passive Lagrangian particles transported by oceanic currents obtained from a oceanographic reanalysis. We compare different simulation schemes and compute connectivity measures (larval exchange probabilities and minimum/average larval dispersal distances from target islands). To explore the role of PRI-MNM in protecting marine organisms with pelagic larval stages, we drive millions of individual-based simulations for various Pelagic Larval Durations (PLDs), in all release seasons, and over a two decades time horizon (1991-2010). We find that connectivity in the NLIs is spatially asymmetric and displays significant intra- and inter-annual variations. The islands belonging to PRI-MNM act more as sinks than sources of larvae, and connectivity is higher during the winter-spring period. In multi-annual analyses, yearly averaged southward connectivity significantly and negatively correlates with climatological anomalies (El Nino). This points out a possible system fragility and susceptibility to global warming. Quantitative assessments of large scale, long-term marine connectivity patterns help understand region-specific, ecologically relevant interactions between islands. This is fundamental for devising scientifically-based protection strategies, which must be space- and time-varying to cope with the challenges posed by the concurrent pressures of human exploitation and global climate change. PMID- 28809936 TI - Benefits and safety of gabapentinoids in chronic low back pain: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND AND OBJECTIVE: Chronic Low Back Pain (CLBP) is very common, with a lifetime prevalence between 51% and 80%. In majority, it is nonspecific in nature and multifactorial in etiology. Pregabalin (PG) and Gabapentin (GB) are gabapentinoids that have demonstrated benefit in neuropathic pain conditions. Despite no clear rationale, they are increasingly used for nonspecific CLBP. They necessitate prolonged use and are associated with adverse effects and increased cost. Recent guidelines from the National Health Service (NHS), England, expressed concerns on their off-label use, in addition to the risk of misuse. We aimed to assess the effectiveness and safety of gabapentinoids in adult CLBP patients. METHODS: Electronic databases of MEDLINE, EMBASE, and Cochrane were searched from their inception until December 20th, 2016. We included randomized control trials reporting the use of gabapentinoids for the treatment of CLBP of >3 months duration, in adult patients. Study selection and data extraction was performed independently by paired reviewers. Outcomes were guided by Initiative on Methods, Measurement and Pain Assessment in Clinical Trials guidelines, with pain relief and safety as the primary outcomes. Meta-analyses were performed for outcomes reported in 3 or more studies. Outcomes were reported as mean differences (MDs) or risk ratios (RRs) with their corresponding 95% confidence intervals (CIs), and I2 in percentage representing the percentage variability in effect estimates that could be explained by heterogeneity. GRADE (Grading of Recommendations Assessment, Development, and Evaluation) was used to assess the quality of evidence. RESULTS: Out of 1,385 citations, eight studies were included. Based on the interventions and comparators, studies were analyzed in 3 different groups. GB compared with placebo (3 studies, n = 185) showed minimal improvement of pain (MD = 0.22 units, 95% CI [-0.5 to 0.07] I2 = 0%; GRADE: very low). Three studies compared PG with other types of analgesic medication (n = 332) and showed greater improvement in the other analgesic group (MD = 0.42 units, 95% CI [0.20 to 0.64] I2 = 0; GRADE: very low). Studies using PG as an adjuvant (n = 423) were not pooled due to heterogeneity, but the largest of them showed no benefit of adding PG to tapentadol. There were no deaths or hospitalizations reported. Compared with placebo, the following adverse events were more commonly reported with GB: dizziness-(RR = 1.99, 95% CI [1.17 to 3.37], I2 = 49); fatigue (RR = 1.85, 95% CI [1.12 to 3.05], I2 = 0); difficulties with mentation (RR = 3.34, 95% CI [1.54 to 7.25], I2 = 0); and visual disturbances (RR = 5.72, 95% CI [1.94 to 16.91], I2 = 0). The number needed to harm with 95% CI for dizziness, fatigue, difficulties with mentation, and visual disturbances were 7 (4 to 30), 8 (4 to 44), 6 (4 to 15), and 6 (4 to 13) respectively. The GRADE evidence quality was noted to be very low for dizziness and fatigue, low for difficulties with mentation, and moderate for visual disturbances. Functional and emotional improvements were reported by few studies and showed no significant improvements. CONCLUSIONS AND RELEVANCE: Existing evidence on the use of gabapentinoids in CLBP is limited and demonstrates significant risk of adverse effects without any demonstrated benefit. Given the lack of efficacy, risks, and costs associated, the use of gabapentinoids for CLBP merits caution. There is need for large high-quality trials to more definitively inform this issue. TRIAL REGISTRATION: PROSPERO CRD42016034040. PMID- 28809938 TI - Perinatal testosterone exposure potentiates vascular dysfunction by ERbeta suppression in endothelial progenitor cells. AB - Recent clinical cohort study shows that testosterone therapy increases cardiovascular diseases in men with low testosterone levels, excessive circulating androgen levels may play a detrimental role in the vascular system, while the potential mechanism and effect of testosterone exposure on the vascular function in offspring is still unknown. Our preliminary results showed that perinatal testosterone exposure in mice induces estrogen receptor beta (ERbeta) suppression in endothelial progenitor cells (EPCs) in offspring but not mothers, while estradiol (E2) had no effect. Further investigation showed that ERbeta suppression is due to perinatal testosterone exposure-induced epigenetic changes with altered DNA methylation on the ERbeta promoter. During aging, EPCs with ERbeta suppression mobilize to the vascular wall, differentiate into ERbeta suppressed mouse endothelial cells (MECs) with downregulated expression of SOD2 (mitochondrial superoxide dismutase) and ERRalpha (estrogen-related receptor alpha). This results in reactive oxygen species (ROS) generation and DNA damage, and the dysfunction of mitochondria and fatty acid metabolism, subsequently potentiating vascular dysfunction. Bone marrow transplantation of EPCs that overexpressed with either ERbeta or a SIRT1 single mutant SIRT1-C152(D) that could modulate SIRT1 phosphorylation significantly ameliorated vascular dysfunction, while ERbeta knockdown worsened the problem. We conclude that perinatal testosterone exposure potentiates vascular dysfunction through ERbeta suppression in EPCs. PMID- 28809940 TI - Provably secure identity-based identification and signature schemes from code assumptions. AB - Code-based cryptography is one of few alternatives supposed to be secure in a post-quantum world. Meanwhile, identity-based identification and signature (IBI/IBS) schemes are two of the most fundamental cryptographic primitives, so several code-based IBI/IBS schemes have been proposed. However, with increasingly profound researches on coding theory, the security reduction and efficiency of such schemes have been invalidated and challenged. In this paper, we construct provably secure IBI/IBS schemes from code assumptions against impersonation under active and concurrent attacks through a provably secure code-based signature technique proposed by Preetha, Vasant and Rangan (PVR signature), and a security enhancement Or-proof technique. We also present the parallel-PVR technique to decrease parameter values while maintaining the standard security level. Compared to other code-based IBI/IBS schemes, our schemes achieve not only preferable public parameter size, private key size, communication cost and signature length due to better parameter choices, but also provably secure. PMID- 28809939 TI - A cross-sectional study comparing lateral and diagonal maximum weight shift in people with stroke and healthy controls and the correlation with balance, gait and fear of falling. AB - Impaired balance is common post stroke and can be assessed by means of force platforms measuring center of pressure (COP) displacements during static standing, or more dynamically during lateral maximum weight shift (MWS). However, activities of daily life also include diagonal MWS and since force platforms are nowadays commercially available, investigating lateral and diagonal MWS in a clinical setting might be feasible and clinically relevant. We investigated lateral and diagonal MWS while standing in patients with stroke (PwS) and healthy controls (HC), evaluated MWS towards the affected and the non-affected side for PwS and correlated MWS with measures of balance, gait and fear of falling. In a cross-sectional observational study including 36 ambulatory sub-acute inpatients and 32 age-matched HC, a force platform (BioRescue, RM Ingenierie, France) was used to measure lateral and diagonal MWS in standing. Clinical outcome measures collected were Berg Balance Scale and Community Balance and Mobility Scale (CBMS) for balance, 10-meter walk test (10MWT) for gait speed and Falls Efficacy Scale international version for fear of falling. MWS for PwS towards the affected side was significantly smaller compared to HC (lateral: p = 0.029; diagonal-forward: p = 0.000). MWS for PwS was also significantly reduced towards the affected side in the diagonal-forward direction (p = 0.019) compared to the non-affected side of PwS. Strong correlations were found for MWS for PwS in the diagonal-forward direction towards the affected side, and clinical measures of balance (CBMS: r = 0.66) and gait speed (10MWT: r = 0.66). Our study showed that ambulatory sub acute PwS, in comparison to HC, have decreased ability to shift their body weight diagonally forward in standing towards their affected side. This reduced ability is strongly related to clinical measures of balance and gait speed. Our results suggest that MWS in a diagonal-forward direction should receive attention in rehabilitation of ambulatory sub-acute PwS in an inpatient setting. PMID- 28809941 TI - Analysis of AgoshRNA maturation and loading into Ago2. AB - The RNA interference (RNAi) pathway was recently expanded by the discovery of multiple alternative pathways for processing of natural microRNA (miRNA) and man made short hairpin RNA (shRNA) molecules. One non-canonical pathway bypasses Dicer cleavage and requires instead processing by Argonaute2 (Ago2), which also executes the subsequent silencing step. We named these molecules AgoshRNA, which generate only a single active RNA strand and thus avoid off-target effects that can be induced by the passenger strand of a regular shRNA. Previously, we characterized AgoshRNA processing by deep sequencing and demonstrated that-after Ago2 cleavage-AgoshRNAs acquire a short 3' tail of 1-3 A-nucleotides and are subsequently trimmed, likely by the poly(A)-specific ribonuclease (PARN). As a result, the mature single-stranded AgoshRNA may dock more stably into Ago2. Here we set out to analyze the activity of different synthetic AgoshRNA processing intermediates. Ago2 was found to bind preferentially to partially single-stranded AgoshRNA in vitro. In contrast, only the double-stranded AgoshRNA precursor associated with Ago2 in cells, correlating with efficient intracellular processing and reporter knockdown activity. These results suggest the presence of a cellular co-factor involved in AgoshRNA loading into Ago2 in vivo. We also demonstrate specific AgoshRNA loading in Ago2, but not Ago1/3/4, thus further reducing unwanted side effects. PMID- 28809942 TI - Correction: Effect of caffeine ingestion on anaerobic capacity quantified by different methods. AB - [This corrects the article DOI: 10.1371/journal.pone.0179457.]. PMID- 28809943 TI - Genetic evidence for subspecies differentiation of the Himalayan marmot, Marmota himalayana, in the Qinghai-Tibet Plateau. AB - The primary host of plague in the Qinghai-Tibet Plateau (QTP), China, is Marmota himalayana, which plays an essential role in the maintenance, transmission, and prevalence of plague. To achieve a more clear insight into the differentiation of M. himalayana, complete cytochrome b (cyt b) gene and 11 microsatellite loci were analyzed for a total of 423 individuals from 43 localities in the northeast of the QTP. Phylogenetic analyses with maximum likelihood and Bayesian inference methods showed that all derived haplotypes diverged into two primary well supported monophyletic lineages, I and II, which corresponded to the referential sequences of two recognized subspecies, M. h. himalayana and M. h. robusta, respectively. The divergence between the two lineages was estimated to be at about 1.03 million years ago, nearly synchronously with the divergence between M. baibacina and M. kastschenkoi and much earlier than that between M. vancouverensis and M. caligata. Genetic structure analyses based on the microsatellite dataset detected significant admixture between the two lineages in the mixed region, which verified the intraspecies level of the differentiation between the two lineages. Our results for the first time demonstrated the coexistence of M. h. himalayana and M. h. robusta, and also, determined the distribution range of the two subspecies in the northeast of QTP. We provided fundamental information for more effective plague control in the QTP. PMID- 28809944 TI - Correction: The microbial community characteristics of ancient painted sculptures in Maijishan Grottoes, China. AB - [This corrects the article DOI: 10.1371/journal.pone.0179718.]. PMID- 28809945 TI - Correction: Asymptomatic aortic stenosis: An assessment of patients' and of their general practitioners' knowledge, after an indexed specialized assessment in community practice. AB - [This corrects the article DOI: 10.1371/journal.pone.0179988.]. PMID- 28809946 TI - Structure-function analyses of metal-binding sites of HypA reveal residues important for hydrogenase maturation in Helicobacter pylori. AB - The nickel-containing enzymes of Helicobacter pylori, urease and hydrogenase, are essential for efficient colonization in the human stomach. The insertion of nickel into urease and hydrogenase is mediated by the accessory protein HypA. HypA contains an N-terminal nickel-binding site and a dynamic structural zinc binding site. The coordination of nickel and zinc within HypA is known to be critical for urease maturation and activity. Herein, we test the hydrogenase activity of a panel of H. pylori mutant strains containing point mutations within the nickel- and zinc-binding sites. We found that the residues that are important for hydrogenase activity are those that were similarly vital for urease activity. Thus, the zinc and metal coordination sites of HypA play similar roles in urease and hydrogenase maturation. In other pathogenic bacteria, deletion of hydrogenase leads to a loss in acid resistance. Thus, the acid resistance of two strains of H. pylori containing a hydrogenase deletion was also tested. These mutant strains demonstrated wild-type levels of acid resistance, suggesting that in H. pylori, hydrogenase does not play a role in acid resistance. PMID- 28809947 TI - High-density genetic linkage map construction by F2 populations and QTL analysis of early-maturity traits in upland cotton (Gossypium hirsutum L.). AB - Due to China's rapidly increasing population, the total arable land area has dramatically decreased; as a consequence, the competition for farming land allocated for grain and cotton production has become fierce. Therefore, to overcome the existing contradiction between cotton grain and fiber production and the limited farming land, development of early-maturing cultivars is necessary. In this research, a high-density linkage map of upland cotton was constructed using genotyping by sequencing (GBS) to discover single nucleotide polymorphism (SNP) markers associated with early maturity in 170 F2 individuals derived from a cross between LU28 and ZHONG213. The high-density genetic map, which was composed of 3978 SNP markers across the 26 cotton chromosomes, spanned 2480 cM with an average genetic distance of 0.62 cM. Collinearity analysis showed that the genetic map was of high quality and accurate and agreed well with the Gossypium hirsutum reference genome. Based on this high-density linkage map, QTL analysis was performed on cotton early-maturity traits, including FT, FBP, WGP, NFFB, HNFFB and PH. A total 47 QTLs for the six traits were detected; each of these QTLs explained between 2.61% and 32.57% of the observed phenotypic variation. A major region controlling early-maturity traits in Gossypium hirsutum was identified for FT, FBP, WGP, NFFB and HNFFB on chromosome D03. QTL analyses revealed that phenotypic variation explained (PVE) ranged from 10.42% to 32.57%. Two potential candidate genes, Gh_D03G0885 and Gh_D03G0922, were predicted in a stable QTL region and had higher expression levels in the early-maturity variety ZHONG213 than in the late-maturity variety LU28. However, further evidence is required for functional validation. This study could provide useful information for the dissection of early-maturity traits and guide valuable genetic loci for molecular-assisted selection (MAS) in cotton breeding. PMID- 28809948 TI - "When I first saw a condom, I was frightened": A qualitative study of sexual behavior, love and life of young cross-border migrants in urban Chiang Mai, Thailand. AB - BACKGROUND: Many young migrant workers move across the border to Chiang Mai, a major city in Northern Thailand, in search of work opportunities. This study describes their sexual behavior, lifestyles, relationships and experiences with youth-friendly sexual and reproductive health (SRH) services. METHODS: This is the qualitative arm of a mixed methods study using focus group discussions (FGDs) among young MWs aged 15-24 years in urban Chiang Mai. We conducted 6 FGDs with 84 participants (43 males, 41 females) organized in groups of 10-15 people, including 3 groups of males, 2 groups of females, and 1 group of both males and females. RESULTS: We found that the lack of parental control, pressure to assimilate into Thai society, access to social media and modern communication technologies, and limited knowledge and access to sexual and reproductive health (SRH) services interplayed to shape lifestyle and sexual behaviors, including low condom use among young migrants. CONCLUSION: The present study helped discern the vulnerability of young migrants to adverse SRH outcomes. This particular group of youth needs urgent intervention to improve their knowledge on SRH and access to a youth-friendly clinic to help them personalize risk of HIV and other adverse SRH outcomes. PMID- 28809949 TI - Maturation-dependent expression of AIM2 in human B-cells. AB - Intracellular DNA- and RNA-sensing receptors, such as the IFN-inducible protein Absent in Melanoma 2 (AIM2), serve as host sensors against a wide range of infections. Immune sensing and inflammasome activation by AIM2 has been implicated in innate antiviral recognition in many experimental systems using cell-lines and animal models. However, little is known about the expression and function of AIM2 in freshly isolated human cells. In this study we investigated the expression of AIM2 in different cell types derived from human cord and adult peripheral blood, in steady state and following in vitro-activation. Adult but not cord blood B-cells expressed high levels of AIM2 mRNA at steady state. In adults, AIM2 was primarily expressed in mature memory CD27+ B-cells. Both adult and cord blood derived B-cells could induce their transcription of AIM2 mRNA in response to type II IFN but not type I IFN or the AIM2 ligand poly dA:dT. Upon B cell receptor stimulation, B-cells from adult blood expressed reduced levels of AIM2 mRNA. In addition, we show that adult B-cells were able to release IL-1beta upon stimulation with synthetic DNA. We conclude that functional AIM2 is preferentially expressed in adult human CD27+ B-cells, but is absent in cord blood mononuclear cells. PMID- 28809950 TI - Characterization of the complete chloroplast genome of Arabis stellari and comparisons with related species. AB - Arabis stellari var. japonica is an ornamental plant of the Brassicaceae family, and is widely distributed in South Korea. However, no information is available about its molecular biology and no genomic study has been performed on A. stellari. In this paper, the authors report the complete chloroplast genome sequence of A. stellari. The plastome of A. stellari was 153,683 bp in length with 36.4% GC and included a pair of inverted repeats (IRs) of 26,423 bp that separated a large single-copy (LSC) region of 82,807 bp and a small single-copy (SSC) region of 18,030 bp. It was also found to contain 113 unique genes, of which 79 were protein-coding genes, 30 were transfer RNAs, and four were ribosomal RNAs. The gene content and organization of the A. stellari chloroplast genome were similar to those of other Brassicaceae genomes except for the absence of the rps16 protein-coding gene. A total of 991 SSRs were identified in the genome. The chloroplast genome of A. stellari was compared with closely related species of the Brassicaceae family. Comparative analysis showed a minor divergence occurred in the protein-coding matK, ycf1, ccsA, accD and rpl22 genes and that the KA/KS nucleotide substitution ratio of the ndhA genes of A. stellari and A. hirsuta was 1.35135. The genes infA and rps16 were absent in the Arabis genus and phylogenetic evolutionary studies revealed that these genes evolved independently. However, phylogenetic analysis showed that the positions of Brassicaceae species are highly conserved. The present study provides A. stellari genomic information that may be found useful in conservation and molecular phylogenetic studies on Brassicaceae. PMID- 28809951 TI - Stronger selection can slow down evolution driven by recombination on a smooth fitness landscape. AB - Stronger selection implies faster evolution-that is, the greater the force, the faster the change. This apparently self-evident proposition, however, is derived under the assumption that genetic variation within a population is primarily supplied by mutation (i.e. mutation-driven evolution). Here, we show that this proposition does not actually hold for recombination-driven evolution, i.e. evolution in which genetic variation is primarily created by recombination rather than mutation. By numerically investigating population genetics models of recombination, migration and selection, we demonstrate that stronger selection can slow down evolution on a perfectly smooth fitness landscape. Through simple analytical calculation, this apparently counter-intuitive result is shown to stem from two opposing effects of natural selection on the rate of evolution. On the one hand, natural selection tends to increase the rate of evolution by increasing the fixation probability of fitter genotypes. On the other hand, natural selection tends to decrease the rate of evolution by decreasing the chance of recombination between immigrants and resident individuals. As a consequence of these opposing effects, there is a finite selection pressure maximizing the rate of evolution. Hence, stronger selection can imply slower evolution if genetic variation is primarily supplied by recombination. PMID- 28809952 TI - Computational and experimental analysis of short peptide motifs for enzyme inhibition. AB - The metabolism of living systems involves many enzymes that play key roles as catalysts and are essential to biological function. Searching ligands with the ability to modulate enzyme activities is central to diagnosis and therapeutics. Peptides represent a promising class of potential enzyme modulators due to the large chemical diversity, and well-established methods for library synthesis. Peptides and their derivatives are found to play critical roles in modulating enzymes and mediating cellular uptakes, which are increasingly valuable in therapeutics. We present a methodology that uses molecular dynamics (MD) and point-variant screening to identify short peptide motifs that are critical for inhibiting beta-galactosidase (beta-Gal). MD was used to simulate the conformations of peptides and to suggest short motifs that were most populated in simulated conformations. The function of the simulated motifs was further validated by the experimental point-variant screening as critical segments for inhibiting the enzyme. Based on the validated motifs, we eventually identified a 7-mer short peptide for inhibiting an enzyme with low MUM IC50. The advantage of our methodology is the relatively simplified simulation that is informative enough to identify the critical sequence of a peptide inhibitor, with a precision comparable to truncation and alanine scanning experiments. Our combined experimental and computational approach does not rely on a detailed understanding of mechanistic and structural details. The MD simulation suggests the populated motifs that are consistent with the results of the experimental alanine and truncation scanning. This approach appears to be applicable to both natural and artificial peptides. With more discovered short motifs in the future, they could be exploited for modulating biocatalysis, and developing new medicine. PMID- 28809953 TI - Monitoring health and reproductive status of olms (Proteus anguinus) by ultrasound. AB - The olm (Proteus anguinus) is a troglomorphic, neotenous amphibian with extraordinary life expectancy and unique adaptations that deserve further investigation. A low reproductive rate and habitat decline render it threatened by extinction. Establishing captive populations for maintenance and artificial breeding may one day become crucial to the species. Longitudinal, in-vivo assessment of inner organs is invaluable to our understanding of reproductive physiology, health, and behavior. Using ultrasound, we measured heart rate and assessed health and reproductive status of 13 captive olms at Zagreb Zoo. Heart rate averaged 42.9 +/- 4.6 bpm (32-55 bpm), as determined via pulsed-wave Doppler at 4-12 MHz. By using frequencies of up to 70 MHz (ultrasound biomicroscopy), inner organs were visualized in detail. Assessment of the gastrointestinal tract provided insights into feeding status and digestive processes. Several subclinical pathologies were detected, including biliary sludge, subcutaneous edema, ascites, and skin lesions. Detection of skin lesions by ultrasound was more sensitive than visual adspection. Olms with ultrasonographically detected skin lesions tested positive for Saprolegnia and were treated. Three of the four affected individuals survived and subsequently tested negative for Saprolegnia. Sex was reliably determined; only one individual proved male. The reason for this extreme female-biased sex-ratio remains unknown. However, as most of the individuals were flushed from the caves by strong currents in spring, the sample may not be representative of natural populations. In female olms, different stages of ovarian follicular development were observed with diameters ranging between 0.1 and 1.1 mm. Results were confirmed by comparing ultrasound, necropsy, and histological findings of one dead specimen. In summary, ultrasound proved a valuable tool to support conservation and captive breeding programs by allowing non-invasive assessment of physiological parameters, clinical condition, and reproductive status in olms. PMID- 28809954 TI - The burden of septic arthritis on the U.S. inpatient care: A national study. AB - OBJECTIVE: To assess the health care burden of septic arthritis in the U.S. and examine the associated factors. METHODS: We used the U.S. Nationwide Emergency Department Sample (NEDS) data of patients hospitalized with septic arthritis as the primary diagnosis from 2009-12 to assess time-trends. Multivariable-adjusted models assessed demographics, comorbidity and hospital characteristics as potential predictors of duration of hospitalization, total hospital (inpatient and ED) charges and discharge to home. RESULTS: In 2009, 2010 and 2012 in the U.S., respectively, there were 13,087, 13,662 and 13,714 hospitalizations with septic arthritis as the primary diagnosis. Respective average hospital stay was 7.4 vs. 7.4 vs. 7.2 days; total hospital charges were $601 vs. $674 vs. $759 million; and proportion discharged home were 43% vs. 43% vs. 44%. Almost 25% each were discharged to a skilled facility or with home health. Age >50 years, Medicaid and self-pay as primary payer, Northeast U.S. hospital location, teaching hospital status, heart failure and diabetes were associated with longer hospitalization; hyperlipidemia, hypertension or gout were associated with a shorter hospital stay. Similar associations were noted for higher hospital charges. Age >50 years, higher income, Medicare insurance, heart failure, diabetes and longer hospital stay were associated with lower odds, and Western U.S. hospital location and gout with higher odds, of discharge to home. CONCLUSIONS: We noted an increase in hospital charges from 2009-12, but no time trends in duration or outcomes of hospitalization for septic arthritis. Comorbidity associations with outcomes indicate the potential for developing interventions to improve outcomes. PMID- 28809955 TI - Biodegradation of diuron by an endophytic fungus Neurospora intermedia DP8-1 isolated from sugarcane and its potential for remediating diuron-contaminated soils. AB - A diuron-degrading endophyte DP8-1 was isolated from sugarcane root grown in diuron-treated soil in the present study. The endophyte was identified as Neurospora intermedia based on the morphological characteristics and sequence analysis. The fermentation parameters including temperature, pH, inoculation size, carbon source, and initial diuron concentration were also investigated for the optimization of degradation efficiency. The results indicated that strain DP8 1 was capable of degrading up to 99% diuron within 3 days under the optimal degrading condition. The study of degradation spectrum indicated that strain DP8 1 could also degrade and utilize fenuron, monuron, metobromuron, isoproturon, chlorbromuron, linuron, and chlortoluron as substrate for strain growth. On basis of liquid chromatography-mass spectrometry analysis for the products of the degradation of diuron, strain DP8-1 metabolized diuron to produce N-(3,4 dichlorophenyl)-urea and N-(3,4-dichlorophenyl)-N-methylurea through sequential N dealkylations. In a soil bioaugmentation experiment, the inoculation of strain DP8-1 into diuron-treated soil effectively enhanced the disappearance rate of diuron. PMID- 28809956 TI - Natural reversal of pulmonary vascular remodeling and right ventricular remodeling in SU5416/hypoxia-treated Sprague-Dawley rats. AB - AIMS: Pulmonary arterial hypertension (PAH) is a lethal disease and improved therapeutic strategies are needed. Increased pulmonary arterial pressure, due to vasoconstriction and vascular remodeling, causes right ventricle (RV) failure and death in patients. The treatment of Sprague-Dawley rats with SU5416 injection and exposure to chronic hypoxia for three weeks followed by maintenance in normoxia promote progressive and severe PAH with pathologic features that resemble human PAH. At 5-17 weeks after the SU5416 injection, PAH is developed with pulmonary vascular remodeling as well as RV hypertrophy and fibrosis. The present study investigated subsequent events that occur in these PAH animals. METHODS & RESULTS: At 35 weeks after the SU5416 injection, rats still maintained high RV pressure, but pulmonary vascular remodeling was significantly reduced. Metabolomics analysis revealed that lungs of normal rats and rats from the 35 week time point had different metabolomics profiles. Despite the maintenance of high RV pressure, fibrosis was resolved at 35-weeks. Masson's trichrome stain and Western blotting monitoring collagen 1 determined 12% fibrosis in the RV at 17 weeks, and this was decreased to 5% at 35-weeks. The level of myofibroblasts was elevated at 17-weeks and normalized at 35-weeks. CONCLUSIONS: These results suggest that biological systems possess natural ways to resolve pulmonary and RV remodeling. The resolution of RV fibrosis appears to involve the reduction of myofibroblast-dependent collagen synthesis. Understanding these endogenous mechanisms should help improve therapeutic strategies to treat PAH and RV failure. PMID- 28809957 TI - Social adaptation in multi-agent model of linguistic categorization is affected by network information flow. AB - This paper explores how information flow properties of a network affect the formation of categories shared between individuals, who are communicating through that network. Our work is based on the established multi-agent model of the emergence of linguistic categories grounded in external environment. We study how network information propagation efficiency and the direction of information flow affect categorization by performing simulations with idealized network topologies optimizing certain network centrality measures. We measure dynamic social adaptation when either network topology or environment is subject to change during the experiment, and the system has to adapt to new conditions. We find that both decentralized network topology efficient in information propagation and the presence of central authority (information flow from the center to peripheries) are beneficial for the formation of global agreement between agents. Systems with central authority cope well with network topology change, but are less robust in the case of environment change. These findings help to understand which network properties affect processes of social adaptation. They are important to inform the debate on the advantages and disadvantages of centralized systems. PMID- 28809958 TI - A CRE1- regulated cluster is responsible for light dependent production of dihydrotrichotetronin in Trichoderma reesei. AB - Changing light conditions, caused by the rotation of earth resulting in day and night or growth on the surface or within a substrate, result in considerably altered physiological processes in fungi. For the biotechnological workhorse Trichoderma reesei, regulation of glycoside hydrolase gene expression, especially cellulase expression was shown to be a target of light dependent gene regulation. Analysis of regulatory targets of the carbon catabolite repressor CRE1 under cellulase inducing conditions revealed a secondary metabolite cluster to be differentially regulated in light and darkness and by photoreceptors. We found that this cluster is involved in production of trichodimerol and that the two polyketide synthases of the cluster are essential for biosynthesis of dihydrotrichotetronine (syn. bislongiquinolide or bisorbibutenolide). Additionally, an indirect influence on production of the peptaibol antibiotic paracelsin was observed. The two polyketide synthetase genes as well as the monooxygenase gene of the cluster were found to be connected at the level of transcription in a positive feedback cycle in darkness, but negative feedback in light, indicating a cellular sensing and response mechanism for the products of these enzymes. The transcription factor TR_102497/YPR2 residing within the cluster regulates the cluster genes in a light dependent manner. Additionally, an interrelationship of this cluster with regulation of cellulase gene expression was detected. Hence the regulatory connection between primary and secondary metabolism appears more widespread than previously assumed, indicating a sophisticated distribution of resources either to degradation of substrate (feed) or to antagonism of competitors (fight), which is influenced by light. PMID- 28809960 TI - Metrics for comparing neuronal tree shapes based on persistent homology. AB - As more and more neuroanatomical data are made available through efforts such as NeuroMorpho.Org and FlyCircuit.org, the need to develop computational tools to facilitate automatic knowledge discovery from such large datasets becomes more urgent. One fundamental question is how best to compare neuron structures, for instance to organize and classify large collection of neurons. We aim to develop a flexible yet powerful framework to support comparison and classification of large collection of neuron structures efficiently. Specifically we propose to use a topological persistence-based feature vectorization framework. Existing methods to vectorize a neuron (i.e, convert a neuron to a feature vector so as to support efficient comparison and/or searching) typically rely on statistics or summaries of morphometric information, such as the average or maximum local torque angle or partition asymmetry. These simple summaries have limited power in encoding global tree structures. Based on the concept of topological persistence recently developed in the field of computational topology, we vectorize each neuron structure into a simple yet informative summary. In particular, each type of information of interest can be represented as a descriptor function defined on the neuron tree, which is then mapped to a simple persistence-signature. Our framework can encode both local and global tree structure, as well as other information of interest (electrophysiological or dynamical measures), by considering multiple descriptor functions on the neuron. The resulting persistence-based signature is potentially more informative than simple statistical summaries (such as average/mean/max) of morphometric quantities Indeed, we show that using a certain descriptor function will give a persistence based signature containing strictly more information than the classical Sholl analysis. At the same time, our framework retains the efficiency associated with treating neurons as points in a simple Euclidean feature space, which would be important for constructing efficient searching or indexing structures over them. We present preliminary experimental results to demonstrate the effectiveness of our persistence-based neuronal feature vectorization framework. PMID- 28809959 TI - Expression and activity of angiotensin-regulating enzymes is associated with prognostic outcome in clear cell renal cell carcinoma patients. AB - The discovery of the intrarenal renin-angiotensin system (iRAS), which regulates angiogenesis, cell differentiation and proliferation, has opened new perspectives in the knowledge of kidney carcinogenesis. In this study we analyzed the immunohistochemical expression and fluorimetric activity of four key peptidases of iRAS in tumor tissue (n = 144) and serum samples (n = 128) from patients with renal neoplasms. Neutral endopeptidase (NEP/CD10), Angiotensin-converting enzyme 2 (ACE2), and aminopeptidase A (APA) were expressed in tumor cells whilst Angiotensin-converting enzyme (ACE) was expressed in the endothelial cells of intratumor blood vessels. The expression of ACE, ACE2 and NEP/CD10 was highest in clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma (PRCC). The expression of these enzymes correlated with CCRCC aggressiveness. In addition, NEP/CD10 correlated with 15-year overall survival. On the other hand, APA expression was decreased in CCRCC with higher grade and stage. The loss of expression of APA independently correlated with a worse 15-year overall survival. Serum activity of ACE2, NEP/CD10 and APA was significantly higher in renal tumor patients than in healthy subjects. Serum ACE activity was lower in high grade and metastatic CCRCC patients, and NEP/CD10 activity was negatively correlated with UISS (UCLA Integrated Staging System) and SSIGN (Mayo Clinic stage, size, grade and necrosis model) scores and with overall survival of CCRCC patients. These results suggest a metabolic imbalance of iRAS in renal tumors. This finding should be taken into account in the search of new diagnostic, prognostic and therapeutic tools for this disease. PMID- 28809962 TI - Nonlinear behavior and fluctuation-induced dynamics in the photosensitive Belousov-Zhabotinsky reaction. AB - The photosensitive Belousov-Zhabotinsky (pBZ) reaction has been used extensively to study the properties of chemical oscillators. In particular, recent experiments revealed the existence of complex spatiotemporal dynamics for systems consisting of coupled micelles (V < 10-21 L) or droplets (V ~ [10-8-10-11] L) in which the pBZ reaction takes place. These results have been mostly understood in terms of reaction-diffusion models. However, in view of the small size of the droplets and micelles, large fluctuations of concentrations are to be expected. In this work, we investigate the role of fluctuations on the dynamics of a single droplet with stochastic simulations of an extension of the Field-Koros-Noyes (FKN) model taking into account the photosensitivity. The birhythmicity and chaotic behaviors predicted by the FKN model in the absence of fluctuations become transient or intermittent regimes whose lifetime decreases with the size of the droplet. Simple oscillations are more robust and can be observed even in small systems (V > 10-12 L), which justifies the use of deterministic models in microfluidic systems of coupled oscillators. The simulations also reveal that fluctuations strongly affect the efficiency of inhibition by light, which is often used to control the kinetics of these systems: oscillations are found for parameter values for which they are supposed to be quenched according to deterministic predictions. PMID- 28809961 TI - Biochemical characterization of recombinant influenza A polymerase heterotrimer complex: Endonuclease activity and evaluation of inhibitors. AB - Influenza polymerase is a heterotrimer composed of polymerase acidic protein A (PA) and basic proteins 1 (PB1) and 2 (PB2). The endonuclease active site, located in the PA subunit, cleaves host mRNA to prime viral mRNA transcription, and is essential for viral replication. To date, the human influenza A endonuclease activity has only been studied on the truncated active-site containing N-terminal domain of PA (PAN) or full-length PA in the absence of PB1 or PB2. In this study, we characterized the endonuclease activity of recombinant proteins of influenza A/PR8 containing full length PA, PA/PB1 dimer, and PA/PB1/PB2 trimer, observing 8.3-, 265-, and 142-fold higher activity than PAN, respectively. Using the PA/PB1/PB2 trimer, we developed a robust endonuclease assay with a synthetic fluorogenic RNA substrate. The observed Km (150 +/- 11 nM) and kcat [(1.4 +/- 0.2) x 10-3s-1] values were consistent with previous reports using virion-derived replication complex. Two known influenza endonuclease phenylbutanoic acid inhibitors showed IC50 values of 10-20 nM, demonstrating the utility of this system for future high throughput screening. PMID- 28809963 TI - Deciphering environment effects in peptide bond solvation dynamics by experiment and theory. AB - Most proteins work in aqueous solution and the interaction with water strongly affects their structure and function. However, experimentally the motion of a specific single water molecule is difficult to trace by conventional methods, because they average over the heterogeneous solvation structure of bulk water surrounding the protein. Here, we provide a detailed atomistic picture of the water rearrangement dynamics around the -CONH- peptide linkage in the two model systems formanilide and acetanilide, which simply differ by the presence of a methyl group at the peptide linkage. The combination of picosecond pump-probe time-resolved infrared spectroscopy and molecular dynamics simulations demonstrates that the solvation dynamics at the molecular level is strongly influenced by this small structural difference. The effective timescales for solvent migration triggered by ionization are mainly controlled by the efficiency of the kinetic energy redistribution rather than the shape of the potential energy surface. This approach provides a fundamental understanding of protein hydration and may help to design functional molecules in solution with tailored properties. PMID- 28809964 TI - Self-assembly of M7L2 metal-organic nanocapsules using mixed macrocycles. AB - The solvothermal synthesis of two M7L2 metal-organic nanocapsules from C-alkyl pyrogallol[3]resorcin[1]arene is reported. Using mixed macrocycles as building blocks shows great potential in the discovery of new metal-organic nanocapsules with novel properties. PMID- 28809966 TI - Template-assisted photodimerization of N-unprotected uracil derivatives: selective formation of the cis-syn photodimer. AB - A UV light-induced photodimerization of 5-[(imidazol-1-yl)methyl]uracil using glutamate- and aspartate-derived cyclic dipeptides (2,5-diketopiperazines - DKPs) as templates was investigated. Dual salt bridge formation between imidazole side chains and carboxylic acids resulted in the preorganization of the uracil monomers and the preferential formation of the cis-syn photodimer. PMID- 28809965 TI - Hill kinetics as a noise filter: the role of transcription factor autoregulation in gene cascades. AB - An intuition based on deterministic models of chemical kinetics is that population heterogeneity of transcription factor levels in cells is transmitted unchanged downstream to the target genes. We use a stochastic model of a two-gene cascade with a self-regulating upstream gene to show that, counter to the intuition, there is no simple mapping (bimodal to bimodal, unimodal to unimodal) between the shapes of the distributions of transcription factor numbers and target protein numbers in cells. Due to the presence of the two regulations, the system contains two nonlinear transfer functions, defined by the Hill kinetics of transcription factor binding. The transfer function of the regulator can "interfere" with the transfer function of the target, converting the bimodal input into a unimodal output or vice versa. We show that this effect can be predicted by a geometric construction. As an example application of the method, we present a case study of a system of several downstream genes of different sensitivities, controlled by a common transcription factor which also regulates its own transcription. We show that a single regulator can induce qualitatively different patterns (binary or graded) of responses to a signal in different downstream genes, depending on whether the sensitivity regions of the transfer functions of the upstream and downstream genes overlap or not. Alternatively, the same model can be interpreted as describing a single downstream gene that has different sensitivities in different cell lines due to mutations. Our model shows, therefore, a possible kinetic mechanism by which different genes can interpret the same biological signal in a different manner. PMID- 28809967 TI - Stability of dye-sensitized solar cells under extended thermal stress. AB - In the last few decades, dye-sensitized solar cell (DSC) technology has been demonstrated to be a promising candidate for low cost energy production due to cost-effective materials and fabrication processes. Arguably, DSC stability is the biggest challenge for making this technology appealing for industrial exploitation. This work provides further insight into the stability of DSCs by considering specific dye-electrolyte systems characterized by Raman and impedance spectroscopy analysis. In particular, two ruthenium-based dyes, Z907 and Ru505, and two commercially available electrolytes, namely, the high stability electrolyte (HSE) and solvent-free Livion 12 (L-12), were tested. After 4700 h of thermal stress at 85 degrees C, the least stable device composed of Z907/HSE showed an efficiency degradation rate of ~14%/1000 h, while the Ru505/L-12 system retained 96% of its initial efficiency by losing ~1% each 1000 h. The present results show a viable route to stabilize the DSC technology under prolonged annealing conditions complying with the IEC standard requirements. PMID- 28809968 TI - Spectroscopic characterization of (diiodomethyl)zinc iodide: application to the stereoselective synthesis and functionalization of iodocyclopropanes. AB - Herein is described an improved synthetic route to enantio- and diastereoenriched iodocyclopropylmethanols using (diiodomethyl)zinc iodide etherate as the active species. The products obtained by this methodology were successfully functionalized by Suzuki-Miyaura cross-coupling reactions. A Buchwald-type palladium precatalyst allowed access to highly substituted and stereo-enriched cyclopropanes without requiring a protecting group. PMID- 28809969 TI - Solvent-controlled selective synthesis of biphenols and quinones via oxidative coupling of phenols. AB - A regioselective synthesis of unsymmetrical and symmetrical biphenols and binaphthols via oxidative coupling of phenols or naphthols in the presence of K2S2O8 in CF3COOH under ambient conditions is described. Interestingly, the 1 : 1 ratio of H2O and CH3CN solvent mixtures at 80 degrees C instead of CF3COOH provided substituted unsymmetrical quinones. A gram-scale synthesis of biphenols and binaphthols was demonstrated. PMID- 28809970 TI - pH-Sensitive metal-free carbon monoxide prodrugs with tunable and predictable release rates. AB - Carbon monoxide prodrugs with triggered release profiles are highly desirable for targeted CO delivery to minimize their untoward side-effects. Herein, we describe a series of pH-sensitive metal-free CO prodrugs which are stable under acidic conditions and yet begin to release CO in response to increases in pH with tunable and predictable release rates. PMID- 28809971 TI - Construction of a superior visible-light-driven photocatalyst based on a C3N4 active centre-photoelectron shift platform-electron withdrawing unit triadic structure covalent organic framework. AB - Herein, three functional factors inducing photocatalytic ability were artfully integrated into a covalent organic framework (COF), where triazine units served as photoactive centers, cyclic ketone units served as electron-withdrawing moieties, and the conjugated structure served as a photoelectron shift platform. This COF with segregated donor-acceptor alignments exhibits an excellent visible light photocatalytic capacity for the decomposition of organic pollutants. PMID- 28809972 TI - Ab initio study of Li, Mg and Al insertion into rutile VO2: fast diffusion and enhanced voltages for multivalent batteries. AB - Vanadium oxides are among the most promising materials that can be used as electrodes in rechargeable metal-ion batteries. In this work, we systematically investigate thermodynamic, electronic, and kinetic properties associated with the insertion of Li, Mg and Al atoms into rutile VO2. Using first-principles calculations, we systematically study the structural evolution and voltage curves of LixVO2, MgxVO2 and AlxVO2 (0 < x < 1) compounds. The calculated lithium intercalation voltage starts at 3.50 V for single-atom insertion and decreases to 2.23 V for full lithiation, to the LiVO2 compound, which agrees well with the experimental results. The Mg insertion features a plateau about 1.6 V up to Mg0.5VO2 and then another plateau-like region at around 0.5 V up to Mg1VO2. The predicted voltage curve for Al insertion starts at 1.98 V, followed by two plateaus at 1.48 V and 1.17 V. The diffusion barrier of Li, Mg and Al in the tunnel structure of VO2 is 0.06, 0.33 and 0.50 eV, respectively. The demonstrated excellent Li, Mg and Al mobility, high structural stability and high specific capacity suggest promising potential of rutile VO2 electrodes especially for multivalent batteries. PMID- 28809973 TI - Competitive affinity-based proteome profiling and imaging to reveal potential cellular targets of betulinic acid. AB - Betulinic acid (BA), a pentacyclic triterpenoid natural product, has received considerable attention owing to the broad spectrum of biological activities such as anti-HIV, anti-inflammatory, and especially, antitumor. Despite numerous studies on the antitumor mechanisms over the past decade, the cellular targets in cancer cells remain obscure. Here, we developed two photoprobes, BA-1/BA-2, by attaching terminal alkyne-containing "minimalist" tetrazole/diazirine photo crosslinkers (L3 and L7) at the C-3 and C-28 positions of BA, respectively, based on well-established structure-activity relationships. The potential cellular targets were identified via competitive proteome profiling and bioimaging approaches. PMID- 28809974 TI - In situ generation of electrochemiluminescent DNA nanoflowers as a signal tag for mucin 1 detection based on a strategy of target and mimic target synchronous cycling amplification. AB - A sensitive electrochemiluminescent (ECL) aptasensor consisting of a novel ECL signal tag of DNA nanoflowers (DNA NFs) and a highly efficient target conversion strategy for the MUC1 assay was developed, which not only increased the stability for luminophore loading, but also greatly improved the detection sensitivity. PMID- 28809975 TI - Discovery of synthetic small molecules that enhance the number of stomata: C-H functionalization chemistry for plant biology. AB - The increasing climate changes and global warming are leading to colossal agricultural problems such as abatement of food production and quality. As stomatal development is considered to play a key role in crop plant productivity and water-use efficiency, studying stomatal development is useful for understanding the productivity of plant systems for both natural and agricultural systems. Herein, we report the first-in-class synthetic small molecules enhancing the number of stomata in Arabidopsis thaliana that have been discovered by screening of the chemical library and further optimized by the Pd-catalyzed C-H arylation reaction. The present study shows not only huge potential of small molecules to control the cellular and developmental processes of stomata without using genetically modified plants, but also the power of C-H functionalization chemistry to rapidly identify the optimized compounds. PMID- 28809976 TI - 2,2-Diiododimedone: a mild electrophilic iodinating agent for the selective synthesis of alpha-iodoketones from allylic alcohols. AB - 2,2-Diiodo-5,5-dimethylcyclohexane-1,3-dione is reported as a new electrophilic iodinating agent that selectively iodinates electron-rich aromatics. In contrast to other common electrophilic iodinating reagents, its mild nature allows it to be used for the selective synthesis of alpha-iodinated carbonyl compounds from allylic alcohols through a 1,3-hydrogen shift/iodination process catalyzed by iridium(iii) complexes. PMID- 28809977 TI - Correlation between collective and molecular dynamics in pH-responsive cyclodextrin-based hydrogels. AB - UV Raman and Brillouin light scattering (BLS) experiments have been used in this study to explore the complex phase change behavior occurring in pH-responsive polysaccharide hydrogels as a function of temperature. Due to the different physical quantities measured by the two techniques, the joint analysis of Raman and BLS spectra has provided an unprecedented large-scale characterization of the molecular rearrangements and of the different kinds of hydrophilic and hydrophobic interactions that cooperate to determine the phase transformation observed in these hydrogels during the heating of the gel. As the main result, the analysis of the Raman and BLS spectra showed the existence of a correlation between the local (molecular) and collective properties of the gels during the phase transformation undergone by the system, which is markedly triggered by pH. The joint set of experimental results suggests a model according to which the mechanism of pH dependence in the hydrogels under investigation is dominated by the interactions involving the hydrophobic parts of the polymer skeleton, whereas the solvation process observed under heating of the gels is driven by the progressive distancing of the polymer domains among them, as monitored by the Brillouin sound velocity. PMID- 28809978 TI - Phase separation dynamics of polydisperse colloids: a mean-field lattice-gas theory. AB - New insights into phase separation in colloidal suspensions are provided via a dynamical theory based on the polydisperse lattice-gas model. The model gives a simplified description of polydisperse colloids, incorporating a hard-core repulsion combined with polydispersity in the strength of the attraction between neighbouring particles. Our mean-field equations describe the local concentration evolution for each of an arbitrary number of species, and for an arbitrary overall composition of the system. We focus on the predictions for the dynamics of colloidal gas-liquid phase separation after a quench into the coexistence region. The critical point and the relevant spinodal curves are determined analytically, with the latter depending only on three moments of the overall composition. The results for the early-time spinodal dynamics show qualitative changes as one crosses a 'quenched' spinodal that excludes fractionation and so allows only density fluctuations at fixed composition. This effect occurs for dense systems, in agreement with a conjecture by Warren that, at high density, fractionation should be generically slow because it requires inter-diffusion of particles. We verify this conclusion by showing that the observed qualitative changes disappear when direct particle-particle swaps are allowed in the dynamics. Finally, the rich behaviour beyond the spinodal regime is examined, where we find that the evaporation of gas bubbles with strongly fractionated interfaces causes long-lived composition heterogeneities in the liquid phase; we introduce a two-dimensional density histogram method that allows such effects to be easily visualized for an arbitrary number of particle species. PMID- 28809979 TI - Raman and infrared spectroscopy differentiate senescent from proliferating cells in a human dermal fibroblast 3D skin model. AB - Senescent cells contribute to tissue aging and dysfunction. Therefore, detecting senescent cells in skin is of interest for skin tumor diagnostics and therapy. Here, we studied the transition into senescence of human dermal fibroblasts (HDFs) in a three-dimensional (3D) human fibroblast-derived matrix (FDM). Senescent and proliferating cells were imaged by Raman spectroscopy (RS) and Fourier transform infrared (FTIR) spectroscopy. The obtained averaged spectra were analyzed using PLS-LDA. For these 3D cultured cells, RS and FTIR could clearly distinguish senescent from proliferating cells. For both techniques, we detected senescence-associated alterations in almost all cellular macromolecules. Furthermore, we identified different biochemical properties of 3D compared to two dimensional (2D) cultured cells, indicating that cells in their natural, skin like 3D environment act differently than in (2D) cell cultivations in vitro. Compared to 2D cultured cells, cells grown in 3D models displayed a sharper contrast between the proliferating and senescent state, also affecting the abundance of biomolecules including nucleic acids. The training accuracies of both vibrational spectroscopic techniques were >96%, demonstrating the suitability of these label-free measurements for detecting these cellular states in 3D skin models. PMID- 28809980 TI - Stimuli-responsive NLO properties of tetrathiafulvalene-fused donor-acceptor chromophores. AB - The second-order nonlinear optical (NLO) properties of two tetrathiafulvalene (TTF)-fused electron donor-acceptor dyads have been determined using the Electric Field Induced Second Harmonic generation (EFISH) technique and theoretically rationalized. Dyads TTF-dppz (1) and TTF-BTD (2) were obtained by direct fusion of a TTF electron donor unit either with a dipyrido[3,2-a:2',3'-c]phenazine (dppz) or a benzothiadiazole (BTD) electron acceptor moiety. Dyad 1 acts as a reversible acido-triggered NLO switch by protonation/deprotonation at two nitrogen atoms of the dppz acceptor moiety induced by sequential exposure to HCl and ammonia vapors. Dyad 2, on the other hand, displays redox-tunable NLO properties upon two consecutive oxidations to its radical cation 2+ and dication 22+ species. The resulting final dication 22+ exhibits an inversion of the sign of beta0, due to a completely inverted distribution of the frontier molecular orbitals with respect to those of its neutral species, leading to a scarcely polar species in the excited state, as indicated by the theoretical calculations. PMID- 28809981 TI - Leucine zipper motif inspiration: a two-dimensional leucine Velcro-like array in peptide coordination polymers generates hydrophobicity. AB - Here, we show that the well-known hydrophobic leucine (Leu) zipper motif (also known as the coiled-coil or Leu scissors motif), typically found in proteins, can be used as a source of inspiration in coordination polymers built from Leu containing dipeptides or tripeptides. We demonstrate that this motif can be extended to form Velcro-like layers of Leu, and that the hydrophobicity of these layers is transferred to coordination polymers, thereby enabling the development of a new type of hydrophobic materials. PMID- 28809982 TI - Coordination polymer-derived nano-sized zinc ferrite with excellent performance in nitro-explosive detection. AB - Herein, a mixed metal coordination polymer, {(H2pip)[Zn1/3Fe2/3(pydc 2,5)2(H2O)].2H2O} 1 {where H2pip = piperazinediium and pydc-2,5 = pyridine-2,5 dicarboxylate}, was successfully synthesized using a hydrothermal technique. To confirm the structure and phase purity of 1, single crystals of an isomorphous pure Fe compound, {(H2pip)[Fe(pydc-2,5)2(H2O)].2H2O} 1a, were synthesized based on similar synthetic conditions. Single crystal X-ray data of 1a confirmed the one-dimensional anionic metal-organic coordination polymer hydrogen bonded with protonated piprazine (piperazinediium) and lattice water molecules. The phase purity of 1 and 1a were confirmed via powder X-ray diffraction. Compound 1 was systematically characterized using IR, TGA, SEM, and EDX elemental mapping analysis. Compound 1 was used as a single source precursor for the preparation of nano-sized ZnFe2O4via thermal decomposition. The as-obtained ZnFe2O4 was fully characterized using PXRD, SEM, TEM, and EDX elemental mapping analysis. It was found that ZnFe2O4 was formed in its pure form with particle size in the nano dimension. The aqueous dispersion of nano-sized ZnFe2O4 exhibits a strong emission at 402 nm upon excitation at 310 nm. This emissive property was employed for luminescence-based detection of nitroaromatic explosives in an aqueous medium through luminescence quenching for the first time. Importantly, selective detections have been observed for phenolic nitroaromatics based on differential luminescence quenching behaviour along with a detection limit of 57 ppb for 2,4,6 trinitrophenol (TNP) in water. PMID- 28809983 TI - Controllable synthesis of inorganic-organic Zn1-xCdxS-DETA solid solution nanoflowers and their enhanced visible-light photocatalytic hydrogen-production performance. AB - Sustainable photocatalytic hydrogen evolution (PHE) of water splitting has been utilized to solve the serious environmental pollution and energy shortage problems over the last decade. Inorganic-organic hybrid materials could combine the organic molecules and functional inorganic blocks into unique materials through complicated physical and chemical interactions. In this paper, diethylenetriamine (DETA) was used as an organic molecule template for the synthesis of inorganic-organic Zn1-xCdxS-DETA solid solution nanoflowers (NFs) at very low temperature. The obtained Zn0.2Cd0.8S-DETA NFs exhibited the highest H2 production rate (12 718 MUmol g-1 h-1), which is 1.75 times as high as that of CdS-DETA. The suitable conduction band potential and excellent visible-light absorption of Zn0.2Cd0.8S-DETA solid solution NFs are closely related to the excellent PHE activity. Furthermore, the calculation on the electronic structure provides a new understanding of the band-gap shifts of the Zn1-xCdxS-DETA solid solution hybrids and the design of novel structural photocatalysts. PMID- 28809984 TI - In situ synthesis of electroactive conjugated microporous fullerene films capable of supercapacitive energy storage. AB - We describe a general strategy for synthesizing conjugated microporous fullerene thin films via a high-throughput, efficient and controllable thiophene-based electropolymerization. By virtue of the ambipolar redox charge/discharge of the films, we showed the microporous fullerene films as outstanding pseudocapacitor materials with high capacity and wide potential windows. PMID- 28809986 TI - Static and dynamic hidden symmetries of icosahedral viral capsids. AB - Viral shells self-assemble from identical proteins, which tend to form equivalent environments in the resulting assembly. However, in icosahedral capsids containing more than 60 proteins, they are enforced to occupy not only the symmetrically equivalent locations but also the quasi-equivalent ones. Due to this important fact, static and dynamic symmetries of viral shells can include additional hidden components. Here, developing the Caspar and Klug ideas concerning the quasi-equivalence of protein environments, we derive the simplest hexagonal tilings, that in principle could correspond to the local protein order in viral shells, and apply the resulting theory to nucleocytoplasmic large dsDNA viruses. In addition, analyzing the dynamic symmetry of the P22 viral shell, we demonstrate that the collective critical modes responsible for the protein reorganization during the procapsid maturation are approximately equivalent to the normal modes of the isotropic spherical membrane with O(3) symmetry. Furthermore, we establish the relationship between the dynamic symmetry of the P22 procapsid and the protein arrangement regularities that appear only in the mature capsid. PMID- 28809985 TI - A magnetic micropore chip for rapid (<1 hour) unbiased circulating tumor cell isolation and in situ RNA analysis. AB - The use of microtechnology for the highly selective isolation and sensitive detection of circulating tumor cells has shown enormous promise. One challenge for this technology is that the small feature sizes - which are the key to this technology's performance - can result in low sample throughput and susceptibility to clogging. Additionally, conventional molecular analysis of CTCs often requires cells to be taken off-chip for sample preparation and purification before analysis, leading to the loss of rare cells. To address these challenges, we have developed a microchip platform that combines fast, magnetic micropore based negative immunomagnetic selection (>10 mL h-1) with rapid on-chip in situ RNA profiling (>100* faster than conventional RNA labeling). This integrated chip can isolate both rare circulating cells and cell clusters directly from whole blood and allow individual cells to be profiled for multiple RNA cancer biomarkers, achieving sample-to-answer in less than 1 hour for 10 mL of whole blood. To demonstrate the power of this approach, we applied our device to the circulating tumor cell based diagnosis of pancreatic cancer. We used a genetically engineered lineage-labeled mouse model of pancreatic cancer (KPCY) to validate the performance of our chip. We show that in a cohort of patient samples (N = 25) that this device can detect and perform in situ RNA analysis on circulating tumor cells in patients with pancreatic cancer, even in those with extremely sparse CTCs (<1 CTC mL-1 of whole blood). PMID- 28809988 TI - Methods for Imputing Missing Efficacy Data in Clinical Trials of Biologic Psoriasis Therapies: Implications for Interpretations of Trial Results. AB -

BACKGROUND: An issue in long-term clinical trials of biologics in psoriasis is how to handle missing efficacy data. This methodological challenge may not be understood by clinicians, yet can have a significant effect on the interpretation of clinical trials.

OBJECTIVE Evaluate the effects of different data imputation methods on apparent secukinumab response rates.

METHODS: Post hoc analyses were conducted on efficacy data from 2 phase III, multicenter, randomized, double-blind trials (FIXTURE and ERASURE) of secukinumab in moderate to severe plaque psoriasis. Per study protocols, missing data were imputed using strict non-response imputation (NRI), a highly conservative method that assumes non-response for all missing data. Alternative imputation methods (observed data, last observation carried forward [LOCF], modified NRI, and multiple imputation [MI]) were applied in this analysis and the resultant response rates compared.

RESULTS: Response rates obtained with each imputation method diverged increasingly over 52-weeks of follow-up. Strict NRI response estimates were consistently lower than those using the other methods. At week 52, Psoriasis Area and Severity Index (PASI) 90 rates for secukinumab 300 mg based on strict NRI were 9.2% (FIXTURE) and 8.7% (ERASURE) lower than estimates obtained using the least conservative method (observed data). Estimates obtained through LOCF and modified NRI were closest to those produced by MI, currently regarded as the most methodologically sophisticated approach available.

CONCLUSION: Awareness of differences in assumptions and limitations among imputation methods is necessary for well-informed interpretation of trial data.

J Drugs Dermatol. 2017;16(8):734-742.

. PMID- 28809989 TI - A Comparative Study to Evaluate Epidermal Barrier Integrity of Psoriasis Patients Treated With Calcipotriene/Betamethasone Topical Suspension Versus Betamethasone Dipropionate 0.05% Lotion. AB - BACKGROUND: Topical corticosteroids are known to impair the epidermal barrier, even after short-term use, whereas topical vitamin D analogues can have a reparative effect. Combination products using corticosteroids and vitamin D analogues have gained popularity in recent years and may provide a means to minimize skin atrophy in patients treated with topical corticosteroids.OBJECTIVE: To compare epidermal barrier function and cutaneous atrophy after 4 weeks of calcipotriene 0.005% and betamethasone dipropionate 0.064% topical suspension (Taclonex(r) TS) versus betamethasone dipropionate 0.05% lotion (Diprosone(r)).METHODS: Ten subjects with moderate plaque psoriasis were enrolled. Patients were randomized to apply calcipotriene 0.005%/betamethasone dipropionate 0.064% once daily to psoriasis plaques on one side of the body and betamethasone dipropionate 0.05% lotion twice daily to plaques on the other side. Biopsies were performed at baseline and after four weeks of treatment to evaluate for epidermal and dermal changes.RESULTS: Treatment with betamethasone lotion resulted in significant decreases in epidermal thickness and dermal thickness. In contrast, treatment with calcipotriene/betamethasone did not lead to significant decreases in epidermal thickness or dermal thickness. Comparing betamethasone and calcipotriene/betamethasone, there was a significantly greater reduction in epidermal thickness with betamethasone lotion versus calcipotriene/betamethasone (P less than .0001). Relative differences in dermal thickness and transepidermal water loss (TEWL) did not reach statistical significance.CONCLUSION: This study is the first to demonstrate that treatment of plaque psoriasis with a combination topical corticosteriod and calcipotriene product results in greater preservation of the skin layers relative to topical corticosteroid use alone. These results hold important ramifications for minimizing cutaneous atrophy in patients receiving treatment with topical corticosteroid . PMID- 28809990 TI - Topical Desoximetasone 0.25% Spray and Its Vehicle Have Little Potential for Irritation or Sensitization. AB - :

BACKGROUND: Topical corticosteroids are the most common dermatologic medications and are available in numerous different vehicles. Adherence is limited by traditional vehicles because they are messy and time consuming to apply. The preferred spray formulations have the advantage of being applied with ease, resulting in improved adherence and subsequently improved psoriasis. One limitation of topical treatments, especially spray vehicles, is the potential for irritation and sensitization.

OBJECTIVE: To evaluate the irritation and sensitization potential of topical desoximetasone spray formulation.

METHODS: A multicenter, double-blinded, randomized, controlled study assessed the irritancy and sensitization of 0.25% and 0.05% topical desoximetasone spray. Controls included vehicle, a positive control (0.1% sodium lauryl sulfate), negative control (0.9% saline), and an active comparator control (clobetasol spray). The primary outcome of the study was to evaluate the difference in mean cumulative irritation and potential sensitization response of desoximetasone 0.25% and 0.05% topical sprays.

RESULTS: Of the 297 enrolled, 269 completed the study per protocol for the irritation phase and 250 completed the protocol for the sensitization phase. At 22 days, desoximetasone 0.25 and 0.5% spray were less irritating than clobetasol 0.05% spray; mean irritation score difference of -0.46 and -0.57, respectively. Median total irritation score over the 22 days was 0 for all products. No subjects demonstrated any sensitization reaction to any of the six products. No serious adverse reactions were reported.

LIMITATIONS: Selection bias, use of a healthy population, limits the external validity. In addition, the duration of the study was short lived, unlike numerous inflammatory skin diseases. CONCLUSIONS: Desoximetasone spray has little potential for irritation or sensitization. The availability of another spray option for patients desiring less messy treatment may facilitate better adherence and treatment outcomes.

J Drugs Dermatol. 2017;16(8):755 758.

. PMID- 28809987 TI - Label-free ferrohydrodynamic cell separation of circulating tumor cells. AB - Circulating tumor cells (CTCs) have significant implications in both basic cancer research and clinical applications. To address the limited availability of viable CTCs for fundamental and clinical investigations, effective separation of extremely rare CTCs from blood is critical. Ferrohydrodynamic cell separation (FCS), a label-free method that conducted cell sorting based on cell size difference in biocompatible ferrofluids, has thus far not been able to enrich low concentration CTCs from cancer patients' blood because of technical challenges associated with processing clinical samples. In this study, we demonstrated the development of a laminar-flow microfluidic FCS device that was capable of enriching rare CTCs from patients' blood in a biocompatible manner with a high throughput (6 mL h-1) and a high rate of recovery (92.9%). Systematic optimization of the FCS devices through a validated analytical model was performed to determine optimal magnetic field and its gradient, ferrofluid properties, and cell throughput that could process clinically relevant amount of blood. We first validated the capability of the FCS devices by successfully separating low-concentration (~100 cells per mL) cancer cells using six cultured cell lines from undiluted white blood cells (WBCs), with an average 92.9% cancer cell recovery rate and an average 11.7% purity of separated cancer cells, at a throughput of 6 mL per hour. Specifically, at ~100 cancer cells per mL spike ratio, the recovery rates of cancer cells were 92.3 +/- 3.6% (H1299 lung cancer), 88.3 +/- 5.5% (A549 lung cancer), 93.7 +/- 5.5% (H3122 lung cancer), 95.3 +/- 6.0% (PC-3 prostate cancer), 94.7 +/- 4.0% (MCF-7 breast cancer), and 93.0 +/- 5.3% (HCC1806 breast cancer), and the corresponding purities of separated cancer cells were 11.1 +/- 1.2% (H1299 lung cancer), 10.1 +/- 1.7% (A549 lung cancer), 12.1 +/- 2.1% (H3122 lung cancer), 12.8 +/- 1.6% (PC-3 prostate cancer), 11.9 +/- 1.8% (MCF-7 breast cancer), and 12.2 +/- 1.6% (HCC1806 breast cancer). Biocompatibility study on H1299 cell line and HCC1806 cell line showed that separated cancer cells had excellent short-term viability, normal proliferation and unaffected key biomarker expressions. We then demonstrated the enrichment of CTCs in blood samples obtained from two patients with newly diagnosed advanced non-small cell lung cancer (NSCLC). While still at its early stage of development, FCS could become a complementary tool for CTC separation for its high recovery rate and excellent biocompatibility, as well as its potential for further optimization and integration with other separation methods. PMID- 28809991 TI - Treatment of Inverse/Intertriginous Psoriasis: Updated Guidelines from the Medical Board of the National Psoriasis Foundation. AB -

Inverse or intertriginous psoriasis commonly involves skin fold areas including the axillae, perianal skin, intergluteal cleft, inframammary, genital/inguinal, abdominal, and retroauricular folds. After reviewing the literature for new treatments, a task force was convened to update a consensus on inverse psoriasis therapy. Short-term treatment continues to be low-potency topical steroids. In order to avoid steroid-induced adverse effects, long-term therapy includes topical immunomodulators, calcitriol, and calcipotriene. Second and third-line therapies include antimicrobials, emollients, and tar-based products. Inverse psoriasis resistant to topical therapy has been shown to respond to botulinum toxin injections, excimer laser therapy, and certain systemic agents (such as anti-TNF and anti-IL12/IL23 therapy). Based on promising results from case reports and prior clinical experience, these systemic agents should be strongly considered in inverse psoriasis resistant to topical therapy. However, they need further evidence-based evaluation. The use of randomized trials and objective severity indices may allow for more robust therapeutic data.

J Drugs Dermatol. 2017;16(8):760-766.

. PMID- 28809992 TI - International Dermatology Outcome Measures (IDEOM) Group 2016 New York Meeting: Meeting Summary and Data from the Psoriasis Working Group. AB -

The International Dermatology Outcome Measures (IDEOM) Group was established to develop validated and standardized patient-centered outcome measures in dermatology that meet the needs of stakeholders and can be used in clinical practice as well as clinical research. At this meeting, we aimed to define the final core domain set to be assessed in psoriasis clinical research and to identify which of the current psoriasis assessment instruments appropriately address those domains. Specifically, we sought to ascertain stakeholder input on domain match and feasibility of multiple psoriasis instruments. We presented 19 physician-reported and 23 patient-reported outcome measures at the meeting. Stakeholders anonymously voted on the validity and feasibility of each instrument. Validity was rated as: green (good), amber (fair), red (poor), and white (not enough information). Feasibility was rated as: green (feasible), amber (concerns about some aspects of feasibility), red (not feasible), and white (not enough information). Eighteen physician-reported and 20 patient-reported instruments received a favorable green or amber rating for validity from the majority of voters. Seventeen physician-reported and 19 patient-reported instruments received a green or amber rating for feasibility from the majority of voters. A significant proportion of the psoriasis instruments received a good or fair vote for measuring their intended psoriasis domains in a feasible manner. We will continue to refine our voting methodology and incorporate patient input into our process of defining psoriasis domains and developing validated instruments.

J Drugs Dermatol. 2017;16(8):770-777.

. PMID- 28809993 TI - Adalimumab in Chronic Plaque Psoriasis: A Clinical Guide. AB -

Psoriasis is a common, inflammatory disease that manifests itself as lesions on the skin, which greatly impacts the physical and psychological wellbeing of those affected. The current goal of treatment in psoriasis is to improve the signs and symptoms of disease, whilst minimizing the burden of disease on patient health-related quality of life. Psoriasis can also be associated with other comorbidities such as joint disease, cardiovascular disease, and depression, which can add to the complexity of treatment.

Adalimumab is a recombinant, fully human, monoclonal antibody against tumor necrosis factor alpha (TNF-alpha), which blocks the interaction of TNF with both of its cell-surface receptors, with high affinity and specificity. Adalimumab is well established for the treatment of moderate-severe chronic plaque psoriasis in adults, and has more recently been approved in the European Union for use in pediatric patients with severe chronic plaque psoriasis.

Here we provide a clinical guide for adalimumab and review existing data on the efficacy and safety of originator adalimumab in moderate-severe chronic plaque psoriasis in adult and pediatric patients. We discuss short- and long-term treatment with adalimumab, and efficacy in hard-to treat psoriasis of the scalp, hands, feet, and nails, in addition to the impact on associated pain and pruritus. We also discuss treatment optimization with adalimumab in the context of relevant clinical scenarios, and treatment of complex patients with underlying comorbidities. Finally, we examine available real-world clinical data for adalimumab in psoriasis.

J Drugs Dermatol. 2017;16(8):779-790.

. PMID- 28809994 TI - The Static Physician's Global Assessment of Genitalia: A Clinical Outcome Measure for the Severity of Genital Psoriasis. AB -

Introduction: Genital psoriasis is a common but frequently overlooked manifestation of psoriasis with a considerable impact on patients' quality of life. Currently no validated clinical trial outcome measures exist to assess genital psoriasis severity that meet regulatory agency requirements.

Methods: This study describes the development of the static Physician's Global Assessment of Genitalia (sPGA-G) scale, a clinical outcome measure for the assessment of genital psoriasis severity that accounts for the erythematous clinical presentation of genital psoriasis. The reliability of the sPGA-G was evaluated using scores collected from clinician assessments of photographs of genital psoriasis cases. Scores were collected from 10 academic and clinical experts in genital psoriasis and 95 clinician assessors who participated in either in-person (n=28) or online (n=67) sPGA-G training modules.

Results: The sPGA-G had a high inter-rater reliability (IRR, measured by Kendall's W) for expert raters (W=0.856, P less than 0.0001), in-person assessors (W=0.822, P less than 0.0001), and online assessors (W=0.678, P less than 0.0001). IRR was also high for all clinical assessors combined, (W=0.714, P less than 0.0001).

Discussion: This study demonstrates that the sPGA-G is an intuitive and reliable clinical outcome measure that specifically measures the severity of genital psoriasis.

J Drugs Dermatol. 2017;16(8):793-799.

. PMID- 28809995 TI - Efficacy and Safety of Apremilast in Patients With Moderate Plaque Psoriasis With Lower BSA: Week 16 Results from the UNVEIL Study. AB -

INTRODUCTION: Many options are available for patients with moderate to severe plaque psoriasis. Patients with moderate disease, however, are often undertreated and do not achieve satisfactory clearance. UNVEIL (NCT02425826) assessed efficacy and safety of apremilast in patients with chronic moderate plaque psoriasis.

METHODS: Patients with psoriasis body surface area (BSA) 5% to 10% and static Physician's Global Assessment (sPGA) score of 3 (moderate) without prior exposure to systemics were randomized (2:1) to apremilast 30 mg twice daily or placebo for 16 weeks. The primary efficacy endpoint was mean percentage change in the product of sPGA and BSA scores (PGAxBSA).

RESULTS: Of 221 patients (placebo, n=73; apremilast, n=148), >80% had received prior topical therapy. At week 16, apremilast yielded a significantly greater percentage change from baseline in PGAxBSA (-48.1%) vs placebo (-10.2^; P less than 0.0001). Dermatology Life Quality Index scores were significantly improved with apremilast (-4.8) vs placebo (-2.4; P=0.0008). Mean improvements in the Treatment Satisfaction Questionnaire for Medication, version II, were greater with apremilast vs placebo for global satisfaction (63.2 vs 48.7; P less than 0.0001) and treatment effectiveness (57.3 vs 38.8; P less than 0.0001). Most adverse events were mild or moderate; most common were diarrhea, headache, nausea, upper respiratory tract infection, decreased appetite, and vomiting.

CONCLUSION: Apremilast was effective and well tolerated, significantly improved quality of life, and was associated with high patient satisfaction in systemic-naive, post-topical patients with moderate plaque psoriasis.

ClinicalTrials.gov: NCT02425826

J Drugs Dermatol. 2017;16(8):801-808.

. PMID- 28809996 TI - Submammary Granular Parakeratosis Treated With Mastopexy. AB -

Granular parakeratosis, originally named axillary granular parakeratosis, is an uncommon disease with an unclear etiology. It is thought to result from defective processing of profillagrin to fillagrin, causing retention of keratohyaline granules in the epidermis. A myriad of causative factors has been proposed, including friction, moisture, heat, and contact irritants such as deodorants. We present a case in the inframammary area that resolved with mastopexy, further supporting the role of friction, moisture, and heat. Furthermore, we present electron microscopic evidence demonstrating non-degraded keratohyaline granules upon epidermal maturation. This entity, we believe, is reactive and represents a protective response of the body to moisture and heat.

J Drugs Dermatol. 2017;16(8):810-812.

. PMID- 28809997 TI - Twenty-Nail Transverse Melanonychia Induced by Hydroxyurea: Case Report and Review of the Literature. AB -

Twenty-nail transverse melanonychia from hydroxyurea is a rare phenomenon, only reported four times previously. Here we describe a 51-year-old female who presented with 20-nail transverse melanonychia 3 months after initiating hydroxyurea therapy. Transverse melanonychia is a benign process but can cause patients significant distress, and thus is an entity with which dermatologists should recognize. We then review the cutaneous manifestations, differential diagnosis, and clinical considerations when evaluating patients with transverse melanonychia from hydroxyurea or other causes.

J Drugs Dermatol. 2017;16(8):814-815.

. PMID- 28809999 TI - Psoriasis Is a Chronic Disease: Long Term Efficacy and Safety of New Biologics Is Important. AB -

Increased understanding of psoriasis has led to a shift in treatments from non specific immunosuppressants to targeted biologics. Studies in psoriasis have demonstrated minimal risk and substantial benefit. As a result, dermatologists and patients are more frequently choosing biologics as first-line treatments for moderate-to-severe disease as our biologics options have recently increased.

. PMID- 28809998 TI - Temporal Association of Herpes Zoster Eruption Post-Aminolevulinic Acid Hydrochloride Photodynamic Therapy for Actinic Keratoses. AB -

Herpes zoster is a common and painful disease caused by the reactivation of the varicella-zoster virus with a higher incidence and severity associated with increasing age as well as compromised immune status. Acute inciting events for this eruption are not always known, but can include illness, stress, and mechanical injury. Photodynamic therapy (PDT) is a widely used treatment modality for precancerous skin lesions that has not been previously associated with provoking a herpes zoster outbreak. We present a case of herpes zoster eruption occurring after PDT for actinic keratoses in a patient with Non-Hodgkin Lymphoma (NHL).

J Drugs Dermatol. 2017;16(8):817-818.

. PMID- 28810000 TI - Effect of a Blueberry-Derived Antioxidant Matrix on Infrared-A Induced Gene Expression in Human Dermal Fibroblasts. AB -

There is compelling evidence that Infrared A (IRA) from natural sunlight contributes to photoaging of human skin by inducing the expression of matrix metalloproteinase-1 (MMP-1) expression in human dermal fibroblasts. Corresponding mechanistic studies have shown that IRA does so by increasing the production of reactive oxygen species in irradiated cells. In the present study, we therefore asked if treatment of primary human skin fibroblasts with a blueberry-derived antioxidant matrix (BerrimatrixTM), which is employed as an active ingredient in commercially available skin care products that are topically applied, can prevent IRA-induced MMP-1 expression in these cells. In this in vitro study, we have found that this antioxidant containing matrix is well tolerated by fibroblast over a broad concentration range and that it efficiently prevents IRA-induced MMP 1 mRNA expression. It may thus be speculated that topical application of this antioxidant containing matrix may be efficient in protecting human skin against IRA-induced wrinkle formation.

J Drugs Dermatol. 2017;16(8 Suppl 2):s125-128.

. PMID- 28810001 TI - Deferoxamine synergizes with transforming growth factor-beta signaling in chondrogenesis. AB - Osteoarthritis, also known as degenerative arthritis or degenerative joint disease, is an epidemic disease that affects millions of people worldwide. Despite extensive recent work on the cellular biology of osteoarthritis, the precise mechanisms involved are still poorly understood and there is no effective treatment for this disease. The role of transforming growth factor-beta (TGF beta) in promoting chondrogenesis and inducing the expression of cartilage specific extracellular matrix molecules to form cartilage is well-established. Historically, TGF-beta has been considered to prevent osteoarthritis, but recent work suggests that TGF-beta overexpression accelerates the progression of osteoarthritis in vivo. Clinically, it is therefore important to limit TGF-beta expression while still providing effective treatment of osteoarthritis. One possible approach to achieve this effect would be to use a combination of TGF beta with other small molecular chemical compounds. Hypoxia promotes chondrogenesis and the usefulness of deferoxamine, a chelating agent that mimics hypoxia, in stimulating chondrogenesis has been investigated in clinical trials. In this study, we investigated the role of deferoxamine in TGF-beta-induced chondrogenesis in pre-chondrogenic cells and examined whether deferoxamine synergizes with the TGF-beta signaling pathway to promote chondrocyte differentiation. PMID- 28810002 TI - Retinal Oximetry Discovers Novel Biomarkers in Retinal and Brain Diseases. AB - Purpose: Biomarkers for several eye and brain diseases are reviewed, where retinal oximetry may help confirm diagnosis or measure severity of disease. These include diabetic retinopathy, central retinal vein occlusion (CRVO), retinitis pigmentosa, glaucoma, and Alzheimer's disease. Methods: Retinal oximetry is based on spectrophotometric fundus imaging and measures oxygen saturation in retinal arterioles and venules in a noninvasive, quick, safe manner. Retinal oximetry detects changes in oxygen metabolism, including those that result from ischemia or atrophy. Results: In diabetic retinopathy, venous oxygen saturation increases and arteriovenous difference decreases. Both correlate with diabetic retinopathy severity as conventionally classified on fundus photographs. In CRVO, vein occlusion causes hypoxia, which is measured directly by retinal oximetry to confirm the diagnosis and measure severity. In both diseases, the change in oxygen levels is a consequence of disturbed blood flow with resulting tissue hypoxia and vascular endothelial growth factor (VEGF) production. In atrophic diseases, such as retinitis pigmentosa and glaucoma, retinal oxygen consumption is reduced and this is detected by retinal oximetry. Retinal oximetry correlates with visual field damage and retinal atrophy. It is an objective metabolic measure of the degree of retinal atrophy. Finally, the retina is part of the central nervous system tissue and reflects central nervous system diseases. In Alzheimer's disease, a change in retinal oxygen metabolism has been discovered. Conclusions: Retinal oximetry is a novel, noninvasive technology that opens the field of metabolic imaging of the retina. Biomarkers in metabolic, ischemic, and atrophic diseases of the retina and central nervous system have been discovered. PMID- 28810003 TI - Incomplete Financial Disclosure. PMID- 28810004 TI - Balancing the Need for Access With the Imperative for Empirical Evidence of Benefit and Risk. PMID- 28810005 TI - Shared Decision Making and Improving Health Care: The Answer Is Not In. PMID- 28810006 TI - Patient Decision Aids to Engage Adults in Treatment or Screening Decisions. AB - Clinical Question: Are patient decision aids (PtDAs) associated with (1) improved decision quality defined as a decision informed by the evidence and a value-based decision; (2) improved decision-making processes defined as feeling informed, defining clear values related to the decision, and active participation in making the decision; and (3) better patient and health system outcomes compared with either usual care or a non-PtDA intervention? Bottom Line: Patient decision aids are associated with improved decision quality and decision-making processes without worse patient or health system outcomes. PMID- 28810007 TI - Faster Orphan Drug Decisions. PMID- 28810009 TI - New Leukemia, Lymphoma Diagnostic. PMID- 28810008 TI - Sickle Cell Therapy Drought Ends. PMID- 28810011 TI - Reforming Medicaid. PMID- 28810012 TI - Politics and the Medical Profession. PMID- 28810013 TI - Public Response to a Proposed Field Trial of Genetically Engineered Mosquitoes in the United States. PMID- 28810014 TI - Prenatal Antidepressant Use and Autism Spectrum Disorder. PMID- 28810015 TI - Alveolar Recruitment Strategies After Cardiac Surgery. PMID- 28810016 TI - Alveolar Recruitment Strategies After Cardiac Surgery. PMID- 28810017 TI - Maternal Antidepressant Use and Pregnancy Outcomes. PMID- 28810018 TI - Prenatal Antidepressant Use and Autism Spectrum Disorder-Reply. PMID- 28810019 TI - Alveolar Recruitment Strategies After Cardiac Surgery-Reply. PMID- 28810020 TI - Maternal Antidepressant Use and Pregnancy Outcomes. PMID- 28810021 TI - Bezlotoxumab (Zinplava) for Prevention of Recurrent Clostridium Difficile Infection. PMID- 28810022 TI - Characteristics of Clinical Studies Used for US Food and Drug Administration Approval of High-Risk Medical Device Supplements. AB - Importance: High-risk medical devices often undergo modifications, which are approved by the US Food and Drug Administration (FDA) through various kinds of premarket approval (PMA) supplements. There have been multiple high-profile recalls of devices approved as PMA supplements. Objective: To characterize the quality of the clinical studies and data (strength of evidence) used to support FDA approval of panel-track supplements (a type of PMA supplement pathway that is used for significant changes in a device or indication for use and always requires clinical data). Design and Setting: Descriptive study of clinical studies supporting panel-track supplements approved by the FDA between April 19, 2006, and October 9, 2015. Exposure: Panel-track supplement approval. Main Outcomes and Measures: Methodological quality of studies including randomization, blinding, type of controls, clinical vs surrogate primary end points, use of post hoc analyses, and reporting of age and sex. Results: Eighty-three clinical studies supported the approval of 78 panel-track supplements, with 71 panel-track supplements (91%) supported by a single study. Of the 83 studies, 37 (45%) were randomized clinical trials and 25 (30%) were blinded. The median number of patients per study was 185 (interquartile range, 75-305), and the median follow up duration was 180 days (interquartile range, 84-270 days). There were a total of 150 primary end points (mean [SD], 1.8 [1.2] per study), and 57 primary end points (38%) were compared with controls. Of primary end points with controls, 6 (11%) were retrospective controls and 51 (89%) were active controls. One hundred twenty-one primary end points (81%) were surrogate end points. Thirty-three studies (40%) did not report age and 25 (30%) did not report sex for all enrolled patients. The FDA required postapproval studies for 29 of 78 (37%) panel-track supplements. Conclusions and Relevance: Among clinical studies used to support FDA approval of high-risk medical device modifications, fewer than half were randomized, blinded, or controlled, and most primary outcomes were based on surrogate end points. These findings suggest that the quality of studies and data evaluated to support approval by the FDA of modifications of high-risk devices should be improved. PMID- 28810023 TI - Characteristics of Preapproval and Postapproval Studies for Drugs Granted Accelerated Approval by the US Food and Drug Administration. AB - Importance: Drugs treating serious or life-threatening conditions can receive US Food and Drug Administration (FDA) accelerated approval based on showing an effect in surrogate measures that are only reasonably likely to predict clinical benefit. Confirmatory trials are then required to determine whether these effects translate to clinical improvements. Objective: To characterize preapproval and confirmatory clinical trials of drugs granted accelerated approval. Design and Setting: Publicly available FDA documents were reviewed to identify the preapproval trials leading to accelerated approval between 2009 and 2013. Information on the status and findings of required confirmatory studies was extracted from the FDA's database of postmarketing requirements and commitments, ClinicalTrials.gov, and matched peer-reviewed publications. Follow-up ended on April 7, 2017. Exposures: Granting of accelerated approval. Main Outcomes and Measures: Characteristics of preapproval and confirmatory studies were compared in terms of study design features (randomization, blinding, comparator, primary end point). Subsequent regulatory decisions and estimated time between accelerated approval and fulfillment of regulatory requirements were summarized. Results: The FDA granted accelerated approval to 22 drugs for 24 indications (19 for indications involving cancer treatment) between 2009 and 2013. A total of 30 preapproval studies supported the 24 indications. The median number of participants enrolled in the preapproval studies was 132 (interquartile range, 89 224). Eight studies (27%) included fewer than 100 participants and 20 (67%) included fewer than 200. At a minimum 3 years of follow-up, 19 of 38 (50%) required confirmatory studies were completed, including 18 published reports. Twenty-five of the 38 (66%) examined clinical efficacy, 7 (18%) evaluated longer follow-up, and 6 (16%) focused on safety The proportion of studies with randomized designs did not differ before and after accelerated approval (12/30 [40%] vs 10/18 [56%]; difference, 16%; 95% CI, -15% to 46%; P = .31). Postapproval requirements were completed and demonstrated efficacy in 10 of 24 indications (42%) on the basis of trials that evaluated surrogate measures. Among the 14 of 24 indications (58%) that had not yet completed all requirements, at least 1 of the confirmatory studies failed to demonstrate clinical benefit in 2 (8%), were terminated in 2 (8%), and were delayed by more than 1 year in 3 (13%). Studies were progressing according to target timelines for the remaining 7 indications (29%). Clinical benefit had not yet been confirmed for 8 indications that had been initially approved 5 or more years prior. Conclusions and Relevance: Among 22 drugs with 24 indications granted accelerated approval by the FDA in 2009-2013, efficacy was often confirmed in postapproval trials a minimum of 3 years after approval, although confirmatory trials and preapproval trials had similar design elements, including reliance on surrogate measures as outcomes. PMID- 28810025 TI - Eye Emergencies. PMID- 28810028 TI - Trials and Tribulations. PMID- 28810027 TI - Climate Change: What Would Lincoln Do? PMID- 28810024 TI - Effect of an Intensive Lifestyle Intervention on Glycemic Control in Patients With Type 2 Diabetes: A Randomized Clinical Trial. AB - Importance: It is unclear whether a lifestyle intervention can maintain glycemic control in patients with type 2 diabetes. Objective: To test whether an intensive lifestyle intervention results in equivalent glycemic control compared with standard care and, secondarily, leads to a reduction in glucose-lowering medication in participants with type 2 diabetes. Design, Setting, and Participants: Randomized, assessor-blinded, single-center study within Region Zealand and the Capital Region of Denmark (April 2015-August 2016). Ninety-eight adult participants with non-insulin-dependent type 2 diabetes who were diagnosed for less than 10 years were included. Participants were randomly assigned (2:1; stratified by sex) to the lifestyle group (n = 64) or the standard care group (n = 34). Interventions: All participants received standard care with individual counseling and standardized, blinded, target-driven medical therapy. Additionally, the lifestyle intervention included 5 to 6 weekly aerobic training sessions (duration 30-60 minutes), of which 2 to 3 sessions were combined with resistance training. The lifestyle participants received dietary plans aiming for a body mass index of 25 or less. Participants were followed up for 12 months. Main Outcomes and Measures: Primary outcome was change in hemoglobin A1c (HbA1c) from baseline to 12-month follow-up, and equivalence was prespecified by a CI margin of +/-0.4% based on the intention-to-treat population. Superiority analysis was performed on the secondary outcome reductions in glucose-lowering medication. Results: Among 98 randomized participants (mean age, 54.6 years [SD, 8.9]; women, 47 [48%]; mean baseline HbA1c, 6.7%), 93 participants completed the trial. From baseline to 12-month follow-up, the mean HbA1c level changed from 6.65% to 6.34% in the lifestyle group and from 6.74% to 6.66% in the standard care group (mean between-group difference in change of -0.26% [95% CI, -0.52% to 0.01%]), not meeting the criteria for equivalence (P = .15). Reduction in glucose lowering medications occurred in 47 participants (73.5%) in the lifestyle group and 9 participants (26.4%) in the standard care group (difference, 47.1 percentage points [95% CI, 28.6-65.3]). There were 32 adverse events (most commonly musculoskeletal pain or discomfort and mild hypoglycemia) in the lifestyle group and 5 in the standard care group. Conclusions and Relevance: Among adults with type 2 diabetes diagnosed for less than 10 years, a lifestyle intervention compared with standard care resulted in a change in glycemic control that did not reach the criterion for equivalence, but was in a direction consistent with benefit. Further research is needed to assess superiority, as well as generalizability and durability of findings. Trial Registration: clinicaltrials.gov Identifier: NCT02417012. PMID- 28810029 TI - Celiac Disease and Nonceliac Gluten Sensitivity: A Review. AB - Importance: The prevalence of gluten-related disorders is rising, and increasing numbers of individuals are empirically trying a gluten-free diet for a variety of signs and symptoms. This review aims to present current evidence regarding screening, diagnosis, and treatment for celiac disease and nonceliac gluten sensitivity. Observations: Celiac disease is a gluten-induced immune-mediated enteropathy characterized by a specific genetic genotype (HLA-DQ2 and HLA-DQ8 genes) and autoantibodies (antitissue transglutaminase and antiendomysial). Although the inflammatory process specifically targets the intestinal mucosa, patients may present with gastrointestinal signs or symptoms, extraintestinal signs or symptoms, or both, suggesting that celiac disease is a systemic disease. Nonceliac gluten sensitivity is diagnosed in individuals who do not have celiac disease or wheat allergy but who have intestinal symptoms, extraintestinal symptoms, or both, related to ingestion of gluten-containing grains, with symptomatic improvement on their withdrawal. The clinical variability and the lack of validated biomarkers for nonceliac gluten sensitivity make establishing the prevalence, reaching a diagnosis, and further study of this condition difficult. Nevertheless, it is possible to differentiate specific gluten-related disorders from other conditions, based on currently available investigations and algorithms. Clinicians cannot distinguish between celiac disease and nonceliac gluten sensitivity by symptoms, as they are similar in both. Therefore, screening for celiac disease must occur before a gluten-free diet is implemented, since once a patient initiates a gluten-free diet, testing for celiac disease is no longer accurate. Conclusions and Relevance: Celiac disease and nonceliac gluten sensitivity are common. Although both conditions are treated with a gluten-free diet, distinguishing between celiac disease and nonceliac gluten sensitivity is important for long-term therapy. Patients with celiac disease should be followed up closely for dietary adherence, nutritional deficiencies, and the development of possible comorbidities. PMID- 28810031 TI - Lethal Heat Waves Expected to Increase. PMID- 28810032 TI - Effect of Malaria Initiative. PMID- 28810033 TI - Global Obesity Epidemic Worsening. PMID- 28810034 TI - Letter to the Editor: A Modified Perfluoro-n-Octane-Assisted Autologous Internal Limiting Membrane Transplant for Failed Macular Hole Reintervention. PMID- 28810035 TI - The Role of Pneumatic Retinopexy: Lessons Learned and Keys to Successful Outcomes. PMID- 28810036 TI - Evaluation of Macular Perfusion in Healthy Smokers by Using Optical Coherence Tomography Angiography. AB - BACKGROUND AND OBJECTIVE: To investigate the macular perfusion changes in healthy smokers by using optical coherence tomography angiography (OCTA). PATIENTS AND METHODS: OCTA measurements were taken for the right eyes of 40 smokers (Group 1) and age- and sex-matched control cases (Group 2). Group 1 underwent OCTA scanning with the XR Avanti AngioVue OCTA (Optovue, Fremont, CA) at baseline and at 5 minutes, 30 minutes, and 60 minutes after one standard cigarette smoking. The same scanning protocol was applied without smoking in Group 2. Macular vessel area density, flow index of the choriocapillaris, foveal avascular zone (FAZ), and central macular thickness were evaluated in both groups. RESULTS: Group 1 consisted of 28 men and 12 women with a mean age of 41.2 years +/- 9.1 years (range: 24 years to 63 years). The mean age of Group 2 was 42.6 years +/- 8.4 years (range: 21 years to 65 years), which consisted of 28 men and 12 women. The mean baseline vessel area density, flow index of the choriocapillaris, FAZ, and central macular thickness showed no statistically significant differences between Groups 1 and 2. Although the flow index of choriocapillaris values were similar at the repetitive OCTA measurements in the control group (P > .05), it was decreased from 1.94 +/- 0.06 to 1.89 +/- 0.08, 1.90 +/- 0.08, and 1.91 +/- 0.07 at 5 minutes, 30 minutes, and 60 minutes following smoking, respectively, in Group 1 (P < .001). CONCLUSION: Smoking causes a significant decrease in the blood flow index of the choriocapillary area by the acute effects of nicotine and other chemical substances in cigarettes on peripheral vascular structure, as evaluated by OCTA. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:617-622.]. PMID- 28810037 TI - Quantitative Features of the Choriocapillaris in Healthy Individuals Using Swept Source Optical Coherence Tomography Angiography. AB - BACKGROUND AND OBJECTIVE: To quantify vessel density (VD) and grey value (GV) as a measure of flow in the choriocapillaris (CC) in healthy subjects with optical coherence tomography angiography (OCTA). PATIENTS AND METHODS: In this prospective, noncomparative case series, 3 mm * 3 mm OCTA images of 36 eyes of 22 healthy individuals were obtained using a swept-source instrument. VD and GV levels were calculated on CC en face slabs in the central 1-mm (subfoveal field) and surrounding 2.5-mm parafoveal ring. VD was calculated as a ratio of vessel area over nonvessel area following image binarization. GV was computed as the mean, un-normalized greyscale intensity value for all pixels in the region of interest. For each eye, the procedure was repeated 1 minute to 2 minutes later and intersession repeatability was analyzed. The choroidal thickness (CT) was automatically measured in the subfoveal and parafoveal regions and compared to VD and GV values. RESULTS: The VD ratio and GV was lower in the subfoveal field than in the parafoveal four sectors. The intersession intraclass correlation coefficients were high for both VD and GV measurements. There was no correlation observed between CT and VD or GV. CONCLUSIONS: Quantitative metrics can be obtained from CC OCTA en face images. These values show moderate to good intersession repeatability. These normative data may be of value as a reference of comparison in future studies of eyes with disease. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:623-631.]. PMID- 28810038 TI - Culture-Positive Endophthalmitis After Open Globe Injuries With and Without Retained Intraocular Foreign Bodies. AB - BACKGROUND AND OBJECTIVE: To report the visual and anatomical outcomes and microbiologic spectrum of culture-positive endophthalmitis in open globe injuries (OGIs) with or without intraocular foreign bodies (IOFBs). PATIENTS AND METHODS: A retrospective, interventional case series of OGIs (n = 718) treated between 2004 and 2015. Patients underwent a management protocol for OGI, including systemic broad-spectrum antibiotics, on presentation. RESULTS: Culture-positive cases of endophthalmitis after open globe repair occurred in 2.1% of eyes (n = 15 of 718 eyes); two eyes had evidence of endophthalmitis on presentation. The most common organism was Staphylococcus species (five of 17 eyes). An IOFB was present in 6.8% of eyes (n = 49 of 718 eyes). All of these eyes received prophylactic intravitreal antimicrobials. In eyes with IOFB, the rate of culture-positive endophthalmitis after initial globe repair was 8.1% (n = 4 of 49 eyes) versus 1.6% (n = 11 of 669 eyes) in eyes without IOFB (P < .01). CONCLUSION: Culture positive endophthalmitis was identified after OGIs more often in eyes with a concurrent IOFB. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:632-637.]. PMID- 28810039 TI - Distinguishing White Dot Syndromes With Patterns of Choroidal Hypoperfusion on Optical Coherence Tomography Angiography. AB - BACKGROUND AND OBJECTIVE: To compare patterns of choroidal hypoperfusion in white dot syndromes (WDS) using optical coherence tomography angiography (OCTA). PATIENTS AND METHODS: Consecutive patients with WDS were imaged with either the Zeiss AngioPlex OCT Angiography (Carl Zeiss AG, Oberkochen, Germany) or the AngioVue OCT Angiography (Optovue, Fremont, CA) from February to November 2016. Four patients with acute posterior multifocal placoid pigment epitheliopathy (APMPPE), birdshot chorioretinopathy (BCR), presumed ocular histoplasmosis syndrome (POHS), and multiple evanescent white dot syndrome (MEWDS) were selected. This study was approved by the institutional review board at Massachusetts Eye and Ear. RESULTS: Unique patterns of choroidal hypoperfusion were observed. In POHS and MEWDS, areas of choroidal hypoperfusion correlated well with clinically observed pathology, but in APMPPE and BCR, they were more widespread. CONCLUSION: OCTA can identify different patterns of choroidal hypoperfusion in APMPPE, BCR, POHS, and MEWDS, which appears to be a shared feature of WDS. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:638-646.]. PMID- 28810040 TI - Vascular Density of Retinal Capillary Plexuses in Different Subtypes of Macular Hole. AB - BACKGROUND AND OBJECTIVE: To compare vessel density and the foveal avascular zone (FAZ) area among eyes with full-thickness macular hole (FTMH), lamellar macular hole (LMH), and macular pseudohole (MPH) using optical coherence tomography angiography (OCTA). PATIENTS AND METHODS: Cross-sectional study involving 10 eyes with idiopathic FTMH, 10 eyes with LMH, 10 eyes with MPH, 17 unaffected fellow eyes, and 10 healthy controls. All patients underwent 3 mm * 3 mm OCTA centered on the macula. Vessel density and FAZ area were calculated. RESULTS: In the deep capillary plexus, FTMHs disclosed the highest vessel density (82.7% +/- 16.8%), superior to LMHs (63.7% +/- 5.9%; P = .0092), MPHs (37.8% +/- 2.5%; P = .0011), and controls (53.0% +/- 12.2%; P < .0001). In the superficial capillary plexus (SCP), MPHs had the lowest vascular density. Fellow eyes had reduced vascular density at SCP compared to control eyes. CONCLUSIONS: Microvascular changes are evident in different subtypes of macular holes. Unaffected fellow eyes exhibit early involvement of SCP. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:648 654.]. PMID- 28810041 TI - Morphologic and Postoperative Fixation Characteristics of the Macular Epiretinal Membrane in Young Patients Undergoing Surgery. AB - BACKGROUND AND OBJECTIVE: To describe morphologic characteristics, surgical outcomes, postoperative preferred retinal loci (PRL), and fixation stability of epiretinal membranes (ERMs) in young patients. PATIENTS AND METHODS: This retrospective study analyzed 43 eyes of 41 young patients (age range: 0.8 years to 28 years) with ERMs, which were divided into two groups: secondary ERMs (SERMs; n = 28) and idiopathic ERMs (IERMs; n = 13). All 43 eyes underwent 25 gauge vitrectomy and membrane peeling. Spectral-domain optical coherence tomography scans and microperimetry were used to analyze morphologic and fixation characteristics, respectively. RESULTS: Premacular fibrosis was more common in SERMs group (P = .006). SERMs were also associated with less external limiting membrane (ELM) (P = .008) and ellipsoid zone visibility (P = .008) compared with IERMs. Best-corrected visual acuity (BCVA) improved in 20 eyes (69%) with SERMs (P = .005) and in 12 eyes (86%) with IERMs (P = .13). From the analysis of the postoperative fixation characteristics, there was a linear correlation between visual acuity and fixation stability (R2 = 0.495). CONCLUSION: BCVA improved significantly in young patients with ERM, even in cases with a severely disrupted ELM and ellipsoid zone. More attention should be paid to the postoperative fixation location and stability. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:655-662.]. PMID- 28810042 TI - OCT Angiographic Findings in Glucose-6-Phosphate Dehydrogenase Deficiency. AB - Fovea plana (FP) describes the abnormal absence of the foveal pit in the retina. It is a sign that is associated with prematurity, albinism, and other ophthalmic disorders. The authors present the optical coherence tomography angiographic findings in a case of a 19-year-old male with FP and glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD deficiency is a very common condition that typically presents with hemolytic anemia and jaundice. G6PD deficiency is also known to affect vision, but these pathologies have been less well-characterized. To the authors' knowledge, this is the first report of G6PD deficiency in FP. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:664-667.]. PMID- 28810043 TI - Amalric Triangular Syndrome Associated With Outer Nuclear Layer Infarction. AB - An 85-year-old man presented with temporal headache and bilateral paracentral scotomas. Clinical examination, laboratory testing, and temporal artery biopsy confirmed the diagnosis of giant cell arteritis. Fluorescein angiography illustrated Amalric triangular choroidal infarction of the left eye. Spectral domain optical coherence tomography of the left eye demonstrated outer nuclear layer abnormalities adjacent to the choroidal infarct. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:668-670.]. PMID- 28810045 TI - Scleral Buckle Infection With Pseudallescheria boydii. AB - Pseudallescheria boydii is a ubiquitous fungus that infects soft tissues and is known to cause ocular disease, including keratitis and endophthalmitis, in rare cases. In immunocompromised hosts, P. boydii can disseminate to or from the eye and other organs with lethal consequences. Postoperative P. boydii infections have, in rare cases, complicated several types of ocular surgeries in immunocompetent patients, but never for a scleral buckle. The authors present the first case of an infected scleral buckle from P. boydii. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:676-678.]. PMID- 28810044 TI - Swept-Source Optical Coherence Tomography Angiography in West Nile Virus Chorioretinitis and Associated Occlusive Retinal Vasculitis. AB - A 65-year-old man with diabetes and a history of fever of unknown origin 2 weeks earlier complained of sudden decreased vision in the left eye. The patient was diagnosed with bilateral West Nile virus (WNV) chorioretinitis associated with occlusive retinal vasculitis in the left eye. Swept-source optical coherence tomography angiography (SS-OCTA) of the left eye showed extensive, well delineated, hypointense non-perfusion areas and perifoveal capillary arcade disruption in the superficial capillary plexus, as well as larger non-perfusion areas, capillary rarefaction, and diffuse capillary network attenuation and disorganization in the deep capillary plexus. OCTA may be a valuable tool for noninvasively assessing occlusive retinal vasculitis associated with WNV infection. It allows an accurate detection and precise delineation of areas of retinal capillary nonperfusion in both the superficial and deep capillary plexuses. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:672-675.]. PMID- 28810046 TI - Aspergillus Endophthalmitis Resulting in Development of Retinal Aspergilloma. AB - A 78-year-old immunocompetent man presented with a 3-month history of painless decreased vision and panuveitis with a macular lesion presumed to be due to endogenous endophthalmitis. He had been treated with systemic, intravenous, and intravitreal antibiotics and antifungal agents as well as intravitreal steroids. A culture from a prior vitrectomy had grown a single colony of Aspergillus thought to be a contaminant. The macular lesion enlarged and caused a tractional retinal detachment. The patient underwent surgery including resection of what appeared to be an invasive retinal aspergilloma, from which polymerase chain reaction and histopathology confirmed Aspergillus fumigatus. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:680-683.]. PMID- 28810048 TI - 8 Questions with Darius Moshfeghi. PMID- 28810047 TI - Optical Coherence Tomography Angiography of Retinal Cavernous Hemangioma. AB - Retinal cavernous hemangioma is a rare, benign, retinal tumor characterized by angiomatous proliferation of vessels within the inner retina or the optic disc.1 Here we report a case of retinal cavernous hemangioma on the margin of the optic disc in the right eye of a 61-year-old asymptomatic female. The lesion was studied with multimodal imaging which included structural optical coherence tomography, fluorescein angiography, blue fundus auto-fluorescence, optical coherence tomography angiography (OCTA) (DRI OCT Triton; Topcon, Tokyo, Japan) and visual field examination. Blood circulation inside retinal cavernous hemangioma lesion is typically low-stagnant.2 However, OCTA demonstrated blood flow inside the lesion, illustrating its vascular circulation.3 Visual field was within the normal limits, except from a slight enlargement of the blind spot. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:684-685.]. PMID- 28810049 TI - ? PMID- 28810050 TI - ? PMID- 28810052 TI - ? PMID- 28810051 TI - ? PMID- 28810053 TI - ? PMID- 28810054 TI - Dynamic Self-Assembly of Gold/Polymer Nanocomposites: pH-Encoded Switching between 1D Nanowires and 3D Nanosponges. AB - The design of tunable dynamic self-assembly of nanoparticles with switchable assembled dimensions and morphologies is a challenging goal whose realization is vital for the evolution of smart nanomaterials. Herein, we report on chitosan polymer as an effective supramolecular "glue" for aldehyde-modified Au nanoparticles to reversibly modulate the states of self-assembled nanocomposites. By simultaneous integration of dynamic covalent Schiff base interactions and noncovalent hydrogen bonds, the chitosan/Au nanocomposites could reversibly transform their assembled morphologies from one-dimensional nanowires to three dimensional nanosponges in response to the variation of pH value. Moreover, the obtained nanosponges could be used as an efficient pH-controlled cargo release system. PMID- 28810055 TI - Impact of miR-26b on cardiomyocyte differentiation in P19 cells through regulating canonical/non-canonical Wnt signalling. AB - BACKGROUND AND OBJECTIVES: The control of cardiomyocyte differentiation is tightly linked to microRNAs (miRNAs), which have been emerging as important players in heart development. However, the regulation mechanisms mediated by miRNAs in early heart development remains speculative. Here, we evaluated the impact of miR-26b during the progression of cardiomyocyte differentiation from the P19 cell line. MATERIALS AND METHODS: The overexpression of miR-26b in P19 cells was performed by transduction with lentivirus vector. The levels of cardiac related genes during P19 cell differentiation were detected using quantitative real-time PCR for mRNA abundance and Western blots for protein expression. ICG 001 was applied to elucidate the role of beta-catenin on P19 cells differentiation. The Cell Counting kit-8 (CCK-8) was used to monitor the cell proliferation. The target genes of miR-26b were validated using the dual luciferase reporter system. RESULTS: Overexpression of miR-26b upregulates the expression level of cardiomyocyte-related genes such as Gata4, cTNT, alpha-MHC and alpha-Actinin that comprehensively represent cardiomyocyte differentiation by effecting Wnt5a signalling and Gsk3beta activity. However, ICG-001 blocks the differentiation along with inhibition of the cell proliferation. In addition, miR 26b also regulates CyclinD1 to promote P19 cell proliferation, thereby, demonstrating the rapid aggregation and differentiation programming of these cells into cardiomyocytic types. CONCLUSIONS: Our results indicated that miR-26b exerts a role on promoting cardiomyocyte differentiation of P19 cells by controlling the canonical and non-canonical Wnt signalling. PMID- 28810056 TI - Crosstalk between transcription and metabolism: how much enzyme is enough for a cell? AB - Cells employ various mechanisms for dynamic control of enzyme expression. An important mechanism is mutual feedback-or crosstalk-between transcription and metabolism. As recently suggested, enzyme levels are often much higher than absolutely needed to maintain metabolic flux. However, given the potential burden of high enzyme levels it seems likely that cells control enzyme expression to meet other cellular objectives. In this review, we discuss whether crosstalk between metabolism and transcription could inform cells about how much enzyme is optimal for various fitness aspects. Two major problems should be addressed in order to understand optimization of enzyme levels by crosstalk. First, mapping of metabolite-protein interactions will be crucial to obtain a better mechanistic understanding of crosstalk. Second, investigating cellular objectives that define optimal enzyme levels can reveal the functional relevance of crosstalk. We present recent studies that approach these problems, drawing from experimental transcript and metabolite data, and from theoretical network analyses. WIREs Syst Biol Med 2018, 10:e1396. doi: 10.1002/wsbm.1396 This article is categorized under: Biological Mechanisms > Metabolism Laboratory Methods and Technologies > Metabolomics Biological Mechanisms > Regulatory Biology. PMID- 28810057 TI - Crowders and Cosolvents-Major Contributors to the Cellular Milieu and Efficient Means to Counteract Environmental Stresses. AB - The free energy and conformational landscape of biomolecular systems as well as biochemical reactions depend not only on temperature and pressure, but also on the particular solution conditions. Such conditions include the effects of cosolvents (for example osmolytes) and macromolecular crowding, which are crucial components to understand the energetics and kinetics of biological processes in living system. Such conditions are also important for the understanding of many debilitating diseases, such as those where misfolding and amyloid formation of proteins are involved. Moreover, understanding their effects on biomolecular processes is prerequisite for designing industrially relevant enzymatic reactions, which seldom take place under neat conditions. Here, we review and discuss experimental and theoretical studies on the characterization of cosolvent and crowding induced effects in biologically relevant systems, approaching even the complexity of living organisms. In particular, we focus on cosolvent and crowding effects on the conformational equilibrium and folding kinetics of proteins and nucleic acids as well as on enzymatic reactions, including their effects on the temperature and pressure dependence of these processes. By presenting a few representative examples, we show how such effects are unveiled and described in thermodynamic and kinetic terms. PMID- 28810058 TI - Estimation of optical rotation of gamma-alkylidenebutenolide, cyclopropylamine, cyclopropyl-methanol and cyclopropenone based compounds by a Density Functional Theory (DFT) approach. AB - Computing the optical rotation of organic molecules can be a real challenge, and various theoretical approaches have been developed in this regard. A benchmark study of optical rotation of various classes of compounds was carried out by Density Functional Theory (DFT) methods. The aim of the present research study was to find out the best-suited functional and basis set to estimate the optical rotations of selected compounds with respect to experimental literature values. Six DFT functional LSDA, BVP86, CAM-B3LYP, B3PW91, and PBE were applied on 22 different compounds. Furthermore, six different basis sets, i.e., 3-21G, 6-31G, aug-cc-pVDZ, aug-cc-pVTZ, DGDZVP, and DGDZVP2 were also applied with the best suited functional B3LYP. After rigorous effort, it can be safely said that the best combination of functional and basis set is B3LYP/aug-cc-pVTZ for the estimation of optical rotation for selected compounds. PMID- 28810059 TI - Targeted genome editing in Caenorhabditis elegans using CRISPR/Cas9. AB - Utilization of programmable nucleases to generate DNA lesions at precise endogenous sequences has transformed the ability to edit genomes from microbes to plants and animals. This is especially true in organisms that previously lacked the means to engineer precise genomic changes, like Caenorhabditis elegans. C. elegans is a 1 mm long free-living, nonparasitic, nematode worm, which is easily cultivated in a laboratory. Its detailed genetic map and relatively compact genome (~100 megabases) helped make it the first metazoan to have its entire genome sequenced. With detailed sequence information came development of numerous molecular tools to dissect gene function. Initially absent from this toolbox, however, were methods to make precise edits at chosen endogenous loci. Adapting site-specific nucleases for use in C. elegans, revolutionized studies of C. elegans biology. Zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and then CRISPR-associated protein 9 (Cas9) were used to target specific endogenous DNA sequences to make double-strand DNA breaks (DSBs). Precise changes could be engineered by providing repair templates targeting the DSB in trans. The ease of programming Cas9 to bind and cleave DNA sequences with few limitations has led to its widespread use in C. elegans research and sped the development of strategies to facilitate mutant recovery. Numerous innovative CRISPR/Cas9 methodologies are now primed for use in C. elegans. WIREs Dev Biol 2017, 6:e287. doi: 10.1002/wdev.287 For further resources related to this article, please visit the WIREs website. PMID- 28810060 TI - Society Leadership and Diversity: Hail to the Women! PMID- 28810061 TI - Single-dose pharmacokinetics of co-crystal of tramadol-celecoxib: Results of a four-way randomized open-label phase I clinical trial in healthy subjects. AB - AIMS: Co-crystal of tramadol-celecoxib (CTC) is a novel co-crystal molecule containing two active pharmaceutical ingredients under development by Esteve (E 58425) and Mundipharma Research (MR308). This Phase I study compared single-dose pharmacokinetics (PK) of CTC with those of the individual reference products [immediate-release (IR) tramadol and celecoxib] alone and in open combination. METHODS: Healthy adults aged 18-55 years were orally administered four treatments under fasted conditions (separated by 7-day wash-out period): 200 mg IR CTC (equivalent to 88 mg tramadol and 112 mg celecoxib; Treatment 1); 100 mg IR tramadol (Treatment 2); 100 mg celecoxib (Treatment 3); and 100 mg IR tramadol and 100 mg celecoxib (Treatment 4). Treatment sequence was assigned using computer-generated randomization. PK parameters were calculated using noncompartmental analysis with parameters for CTC adjusted according to reference product dose (100 mg). RESULTS: Thirty-six subjects (28 male, mean age 36 years) participated. Tramadol PK parameters for Treatments-1, -2 and -4, respectively, were 263, 346 and 349 ng ml-1 (mean maximum plasma concentration); 3039, 2979 and 3119 ng h ml-1 (mean cumulative area under the plasma concentration-time curve); and 2.7, 1.8 and 1.8 h (median time to maximum plasma concentration). For Treatments 1, 3 and 4, the respective celecoxib PK parameters were 313, 449 and 284 ng ml-1 ; 2183, 3093 and 2856 ng h ml-1 ; and 1.5, 2.3 and 3.0 h. No unexpected adverse events were reported. CONCLUSION: PK parameters of each API in CTC were modified by co-crystallization compared with marketed formulations of tramadol, celecoxib, and their open combination. PMID- 28810063 TI - The health of older people in Australia: 85 is the new 65. PMID- 28810062 TI - The association between patient attitudes and values and the strength of consideration for contralateral prophylactic mastectomy in a population-based sample of breast cancer patients. AB - BACKGROUND: Little is known about how the individual decision styles and values of breast cancer patients at the time of treatment decision making are associated with the consideration of different treatment options and specifically with the consideration of contralateral prophylactic mastectomy (CPM). METHODS: Newly diagnosed patients with early-stage breast cancer who were treated in 2013-2014 were identified through the Surveillance, Epidemiology, and End Results registries of Los Angeles and Georgia and were surveyed approximately 7 months after surgery (n = 2578; response rate, 71%). The primary outcome was the consideration of CPM (strong vs less strong). The association between patients' values and decision styles and strong consideration was assessed with multivariate logistic regression. RESULTS: Approximately one-quarter of women (25%) reported strong/very strong consideration of CPM, and another 29% considered it moderately/weakly. Decision styles, including a rational-intuitive approach to decision making, varied. The factors most valued by women at the time of treatment decision making were as follows: avoiding worry about recurrence (82%) and reducing the need for more surgery (73%). In a multivariate analysis, patients who preferred to make their own decisions, those who valued avoiding worry about recurrence, and those who valued avoiding radiation significantly more often strongly considered CPM (P < .05), whereas those who reported being more logical and those who valued keeping their breast did so less often. CONCLUSIONS: Many patients considered CPM, and the consideration was associated with both decision styles and values. The variability in decision styles and values observed in this study suggests that formally evaluating these characteristics at or before the initial treatment encounter could provide an opportunity for improving patient clinician discussions. Cancer 2017;123:4547 4555. (c) 2017 American Cancer Society. PMID- 28810064 TI - The rural and remote health workforce of the future. PMID- 28810066 TI - "Oh, the Places You'll Go" by Bringing Developmental Science Into the World! AB - Urie Bronfenbrenner and Ernest Boyer argued for leaving the laboratory to conduct rigorous developmental research in the real world where children are found-in the places they go. Contributions to this special issue meet Bronfenbrenner and Boyer's call while at the same time recognizing the continued importance of laboratory research. These articles range from a review of research on the arts to a language intervention in Senegal to large-scale dissemination and intervention projects designed to communicate the best developmental science to families, public agencies, and schools. Together these articles illustrate how we can study development in the world and enrich our work on the factors that promote development. Taking this path presents us with a set of additional hurdles to be addressed, such as how to communicate with the public and how to scale up our interventions in the face of diversity along many dimensions. PMID- 28810065 TI - Olodaterol shows anti-fibrotic efficacy in in vitro and in vivo models of pulmonary fibrosis. AB - BACKGROUND AND PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a fatal respiratory disease characterized by excessive fibroblast activation ultimately leading to scarring of the lungs. Although, the activation of beta2 adrenoceptors (beta2 -AR) has been shown to inhibit pro-fibrotic events primarily in cell lines, the role of beta2 -adrenoceptor agonists has not yet been fully characterized. The aim of our study was to explore the anti-fibrotic activity of the long-acting beta2 -adrenoceptor agonist olodaterol in primary human lung fibroblasts (HLF) and in murine models of pulmonary fibrosis. EXPERIMENTAL APPROACH: We assessed the activity of olodaterol to inhibit various pro-fibrotic mechanisms, induced by different pro-fibrotic mediators, in primary HLF from control donors and patients with IPF (IPF-LF). The in vivo anti-fibrotic activity of olodaterol, given once daily by inhalation in either a preventive or therapeutic treatment regimen, was explored in murine models of lung fibrosis induced by either bleomycin or the overexpression of TGF-beta1. KEY RESULTS: In both HLF and IPF-LF, olodaterol attenuated TGF-beta-induced expression of alpha smooth muscle actin, fibronectin and endothelin-1 (ET-1), FGF- and PDGF-induced motility and proliferation and TGF-beta/ET-1-induced contraction. In vivo olodaterol significantly attenuated the bleomycin-induced increase in lung weight, reduced bronchoalveolar lavage cell counts and inhibited release of pro fibrotic mediators (TGF-beta, MMP-9 and tissue inhibitor of metalloproteinase-1). Forced vital capacity was increased only with the preventive treatment regimen. In the TGF-beta-overexpressing model, olodaterol additionally reduced the Col3A1 mRNA expression. CONCLUSION AND IMPLICATIONS: Olodaterol showed anti-fibrotic properties in primary HLF from control and IPF patients and in murine models of lung fibrosis. PMID- 28810068 TI - Putrefaction: An Additional Complicating Factor in the Assessment of Freshwater Drownings in Rivers. AB - : Background hypothesis: That bodies immersed in freshwater (rivers) may show greater changes of decomposition than bodies immersed in saltwater (sea). Fifty de-identified river drownings and 50 sea drownings were randomly selected from autopsy files at Forensic Science SA, Adelaide, Australia and assessed for decomposition. RESULTS: The river cases consisted of 43 males and seven females (M:F 6:1); age range of 2-92 years (mean 46.8 years); decomposition-16/50 (32%); postmortem interval 1-14 days, average 3.8. The sea cases consisted of 36 males and 14 females (M:F 2.6:1); age range of 9-81 years (mean 50.7 years); decomposition-2/50 (4%) (p < 0.001%); postmortem interval 1-6 days, average 2.8. As decomposition reduces information obtained at autopsy, postmortem examination of deaths in rivers may be less informative than deaths that have occurred in the sea. The reasons for less decomposition in the sea include cooler temperatures, exposure to salt and shorter postmortem intervals. PMID- 28810069 TI - Homicide Rates in Lithuania. AB - Homicide rate in Lithuania between 2004 and 2013 decreased and reached an average of 6.7 per 100,000 people in 2013. The data regarding forensic autopsies of intentional homicide victims were obtained from the State Forensic Medicine Service. Spearman's correlation test was used to assess trends in the homicide rates. A significant correlation was observed between homicide distribution and the following variables: Lithuania's gross domestic product (r = -0.85, p = 0.003), the number of alcohol intoxication cases of victims (r = 0.97, p < 0.05). After regression model adjustments, these variables remained significantly associated with the homicide distribution (p < 0.05). 73% of victims were men, with a mean age of 45.5 +/- 15. Alcohol intoxication was present in 58% of victims. 66% of homicides were carried out indoors, 57% in urban area. The presented findings help decide which prevention programs may be the most effective in homicide rate reduction. PMID- 28810070 TI - The Appearance, Taste, and Concentrations of Zolpidem Dissolved in Still Water and Carbonated Beverages. AB - Zolpidem is a sedative that could be used to drug victims, but its suitability to dissolve in drinks is unknown. In this small study, we added either crushed or whole tablets of zolpidem hemitartrate to carbonated beverages or still water to observe how this affected the taste and appearance. Also, concentrations were measured by ultra-high performance liquid chromatography tandem mass spectrometry at different time intervals. Two crushed tablets (20 mg) in cider (250 mL) lead to a maximum concentration of 84 mg/L zolpidem base after 30 min, while the corresponding concentration after adding fifteen tablets (150 mg) was 467 mg/L. There was little change in taste, but froth and turbidity were observed when adding high doses to carbonated beverages. Carbonated beverages spiked with 20 mg of crushed zolpidem hemitartrate tablets reached concentrations that could cause impairment. Spiking with 150 mg could possibly be lethal if several mouthfuls were ingested. PMID- 28810071 TI - Understanding the Geometry of Connected Fracture Flow with Multiperiod Oscillatory Hydraulic Tests. AB - An understanding of the spatial and hydraulic properties of fast preferential flow pathways in the subsurface is necessary in applications ranging from contaminant fate and transport modeling to design of energy extraction systems. One method for the characterization of fracture properties over interwellbore scales is Multiperiod Oscillatory Hydraulic (MOH) testing, in which the aquifer response to oscillatory pressure stimulations is observed. MOH tests were conducted on isolated intervals of wells in siliciclastic and carbonate aquifers in southern Wisconsin. The goal was to characterize the spatial properties of discrete fractures over interwellbore scales. MOH tests were conducted on two discrete fractured intervals intersecting two boreholes at one field site, and a nest of three piezometers at another field site. Fracture diffusivity estimates were obtained using analytical solutions that relate diffusivity to observed phase lag and amplitude decay. In addition, MOH tests were used to investigate the spatial extent of flow using different conceptual models of fracture geometry. Results indicated that fracture geometry at both field sites can be approximated by permeable two-dimensional fracture planes, oriented near horizontally at one site, and near-vertically at the other. The technique used on MOH field data to characterize fracture geometry shows promise in revealing fracture network characteristics important to groundwater flow and transport. PMID- 28810072 TI - Dreamless: the silent epidemic of REM sleep loss. AB - We are at least as dream deprived as we are sleep deprived. Many of the health concerns attributed to sleep loss result from a silent epidemic of REM sleep deprivation. REM/dream loss is an unrecognized public health hazard that silently wreaks havoc with our lives, contributing to illness, depression, and an erosion of consciousness. This paper compiles data about the causes and extent of REM/dream loss associated with commonly used medications, endemic substance use disorders, rampant sleep disorders, and behavioral and lifestyle factors. It examines the consequences of REM/dream loss and concludes with recommendations for restoring healthy REM/dreaming. PMID- 28810073 TI - Implications of Pseudologia Fantastica in Criminal Forensic Evaluations: A Review and Case Report. AB - Pseudologia fantastica, a psychological phenomenon that has been described in the literature for at least a century, is an understudied and poorly understood entity. Sometimes referred to as pathological lying, pseudologia fantastica involves disproportionate fabrication that may be present for many years or a lifetime. In a forensic context, it can significantly complicate the evaluation of capacity to stand trial and, in certain jurisdictions, criminal responsibility. We review the current literature regarding pseudologia fantastica and present a case to highlight the clinical and forensic challenges it may create. We specifically discuss the complications that pseudologia fantastica may have on the assessment of a defendant's rational ability to consult with an attorney, a required element of capacity to stand trial. In addition, we discuss the implications of pseudologia fantastica in the evaluation of criminal responsibility. PMID- 28810074 TI - Preliminary Data on the Role of Emotional Intelligence in Moderating the Link between Psychopathy and Aggression in a Nonforensic Sample. AB - This short report presents preliminary data on the role of emotional intelligence (EI) in moderating the relationship between psychopathy and aggression in a nonforensic sample. A sample of 109 volunteer men was administered the Psychopathic Personality Inventory-Revised (PPI-R), the Reactive-Proactive Aggression Questionnaire, and the Mayer-Salovey-Caruso emotional intelligence Test in individual sessions. Correlation and moderation analyzes showed that, at low levels of EI (in terms of strategic ability to understand and manage one's own and others' emotions), people scoring high on the total PPI-R and impulsivity dimension seemed to be both reactively and proactively aggressive. By contrast, at high levels of strategic ability, the relationships between psychopathy and aggression were no longer significant. These preliminary results encourage further investigation into the role of EI ability in mitigating aggressive outcomes in psychopathic subjects. PMID- 28810075 TI - A B-Spline Framework for Smooth Derivative Computation in Well Test Analysis Using Diagnostic Plots. AB - In the oil and gas industry, well test analysis using derivative plots, has been the core technique in examining reservoir and well behavior over the last three decades. Recently, diagnostics plots have gained recognition in the field of hydrogeology; however, this tool is still underused by groundwater professionals. The foremost drawback is that the derivative function must be computed from noisy field measurements, usually based on finite-difference schemes, which complicates the analysis. We propose a B-spline framework for smooth derivative computation, referred to as Constrained Quartic B-Splines with Free Knots. The approach presents the following novelties in relation to methodological precedents: (1) the use of automatic equality derivative constraints, (2) a knot removal strategy and (3) the introduction of a Boolean shape parameter that defines the number of initial knots to choose. These can lead to evaluate both simple (manually recorded drawdown measurements) and complex (transducer measured records) datasets. Furthermore, we propose an additional shape preserving smoothing preprocess procedure, as a simple, fast and robust method to deal with extremely noisy signals. Our framework was tested in four pumping tests by comparing the spline derivative with regards to the Bourdet algorithm, and we found that the latter is rather noisy (even for large differentiation intervals) and the second derivative response is basically unreadable. In contrast, the spline first and second derivative led to smoother responses, which are more suitable for interpretation. We concluded that the proposed framework is a welcome contribution to evaluate reliable aquifer tests using derivative-diagnostic plots. PMID- 28810076 TI - Groundwater Development Stress: Global-Scale Indices Compared to Regional Modeling. AB - The increased availability of global datasets and technologies such as global hydrologic models and the Gravity Recovery and Climate Experiment (GRACE) satellites have resulted in a growing number of global-scale assessments of water availability using simple indices of water stress. Developed initially for surface water, such indices are increasingly used to evaluate global groundwater resources. We compare indices of groundwater development stress for three major agricultural areas of the United States to information available from regional water budgets developed from detailed groundwater modeling. These comparisons illustrate the potential value of regional-scale analyses to supplement global hydrological models and GRACE analyses of groundwater depletion. Regional-scale analyses allow assessments of water stress that better account for scale effects, the dynamics of groundwater flow systems, the complexities of irrigated agricultural systems, and the laws, regulations, engineering, and socioeconomic factors that govern groundwater use. Strategic use of regional-scale models with global-scale analyses would greatly enhance knowledge of the global groundwater depletion problem. PMID- 28810077 TI - Synthesis of Ladder Polymers: Developments, Challenges, and Opportunities. AB - Ladder polymers are unique in that their backbones consist of fused rings with adjacent rings having two or more atoms in common. The restriction of bond rotations in rigid ladder polymers greatly limits their conformational freedom, leading to many intriguing and unique properties. As a non-traditional type of polymers, rigid ladder polymers are of great fundamental interest and technical importance as advanced materials for applications such as membrane gas separation and organic electronics. Ladder polymers can be divided into non-conjugated (with kinked conformations) and conjugated (with planar conformations) structures. Their synthesis can be broadly classified into two general strategies: direct ladder polymerization, and zipping of a linear precursor polymer. This Concept article outlines the historical development of ladder polymers and the chemical strategies used for their synthesis; highlights the challenges associated with their synthesis and characterization, and presents opportunities and outlooks for this unique and intriguing type of polymers. PMID- 28810079 TI - LC-ESI-MS/MS determination of 4-methylpyrazole in dog plasma and its application to a pharmacokinetic study in dogs. AB - A simple, specific, sensitive and rapid LC-ESI-MS/MS method has been developed and validated for the quantification of 4-methylpyrazole in dog plasma using N methylnicotinamide-d4 as an internal standard (IS) as per regulatory guidelines. Sample preparation was accomplished through a simple protein precipitation. Chromatographic separation of 4-methylpyrazole and the IS was performed on a monolithic (Chromolith RP18e ) column using an isocratic mobile phase comprising 0.2% formic acid in water and acetonitrile (20:80, v/v) at a flow rate of 1.0 mL/min. Elution of 4-methylpyrazole and the IS occurred at ~1.60 and 1.56 min, respectively. The total chromatographic run time was 3.2 min. A linear response function was established in the concentration range of 4.96-4955 ng/mL. The intra and inter-day accuracy and precision were in the ranges 1.81-12.9 and 3.80 11.1%, respectively. This novel method has been applied to a pharmacokinetic study in dogs. PMID- 28810078 TI - Discovery of Key Physicochemical, Structural, and Spatial Properties of RNA Targeted Bioactive Ligands. AB - While a myriad non-coding RNAs are known to be essential in cellular processes and misregulated in diseases, the development of RNA-targeted small molecule probes has met with limited success. To elucidate the guiding principles for selective small molecule/RNA recognition, we analyzed cheminformatic and shape based descriptors for 104 RNA-targeted ligands with demonstrated biological activity (RNA-targeted BIoactive ligaNd Database, R-BIND). We then compared R BIND to both FDA-approved small molecule drugs and RNA ligands without reported bioactivity. Several striking trends emerged for bioactive RNA ligands, including: 1) Compliance to medicinal chemistry rules, 2) distinctive structural features, and 3) enrichment in rod-like shapes over others. This work provides unique insights that directly facilitate the selection and synthesis of RNA targeted libraries with the goal of efficiently identifying selective small molecule ligands for therapeutically relevant RNAs. PMID- 28810080 TI - In Response to 'The role of circulating T follicular helper cells and regulatory cells in non-small cell lung cancer patients'. PMID- 28810081 TI - A Risk Analysis Approach to Prioritizing Epidemics: Ebola Virus Disease in West Africa as a Case Study. AB - The 2014 Ebola virus disease (EVD) outbreak affected several countries worldwide, including six West African countries. It was the largest Ebola epidemic in the history and the first to affect multiple countries simultaneously. Significant national and international delay in response to the epidemic resulted in 28,652 cases and 11,325 deaths. The aim of this study was to develop a risk analysis framework to prioritize rapid response for situations of high risk. Based on findings from the literature, sociodemographic features of the affected countries, and documented epidemic data, a risk scoring framework using 18 criteria was developed. The framework includes measures of socioeconomics, health systems, geographical factors, cultural beliefs, and traditional practices. The three worst affected West African countries (Guinea, Sierra Leone, and Liberia) had the highest risk scores. The scores were much lower in developed countries that experienced Ebola compared to West African countries. A more complex risk analysis framework using 18 measures was compared with a simpler one with 10 measures, and both predicted risk equally well. A simple risk scoring system can incorporate measures of hazard and impact that may otherwise be neglected in prioritizing outbreak response. This framework can be used by public health personnel as a tool to prioritize outbreak investigation and flag outbreaks with potentially catastrophic outcomes for urgent response. Such a tool could mitigate costly delays in epidemic response. PMID- 28810082 TI - Therapeutic monoclonal antibodies and clinical laboratory tests: When, why, and what is expected? AB - BACKGROUND: We herein provide an overview of the clinical laboratory tests that should be performed before, during and after using therapeutic monoclonal antibodies (mAbs) and the clinical laboratory tests that may be affected by mAbs. METHODS: The labels of FDA-approved therapeutic mAbs were downloaded from DailyMed (the official website for drug labels) and were used as the sources of data for this review. RESULTS: It was found that most of the labels provided information relevant to the clinical laboratory tests, including the tests needed before mAbs treatment to check the patients' background status and to identify potentially sensitive patients, the tests needed during or after the treatment to evaluate the patients' response, and the mAbs that may lead to false positive or negative results for clinical laboratory tests. CONCLUSIONS: The present findings will be of interest to physicians, laboratory scientists, those involved in drug development and surveillance and individuals making health care policy. PMID- 28810083 TI - Self-Cyclizing Antioxidants to Prevent DNA Damage Caused by Hydroxyl Radical. AB - Antioxidant therapy is a promising treatment strategy for protecting DNA from the damage caused by reactive oxygen species (ROS). Here, we report new self cyclizing antioxidant reagents that are selective for the hydroxyl radical. Our mechanistic investigation revealed that the reagents react with three equivalents of oxidant in a cascade reaction to form a bicyclic final product. Among the reagents synthesized, 1 c showed favorable properties in vitro and in cellular studies. Using As2 O3 , which triggers ROS production, we showed that 1 c prevents formation of the guanine oxidation product 2,2,4-triamino-2H-oxazol-5 one-2'-deoxyribonucleoside and lowers cellular levels of reactive oxygen. The described self-cyclizing antioxidants are efficient, flexible, and tunable reagents with the potential to limit toxic oxidative stress. PMID- 28810084 TI - Contemporaneous reproduction of preclinical science: a case study of FSH and fat. PMID- 28810085 TI - Secondary Intention. PMID- 28810086 TI - Point-Counterpoint: Genotype-Guided Warfarin Therapy. PMID- 28810087 TI - Multiple Pulmonary Arteriovenous Malformations: An Unusual Cause of Shortness of Breath and Recurrent Strokes. AB - OBJECTIVE: To discuss an uncommon case of a patient with multiple pulmonary arteriovenous malformations (PAVMs) presenting with dyspnea on exertion and recurrent strokes. BACKGROUND: A 79-year-old woman with recent onset recurrent cerebrovascular accidents (CVAs) was referred to cardiology for evaluation of dyspnea on exertion. Clinical examination was unrevealing. METHODS: A transthoracic echocardiogram (TTE) with agitated saline was suggestive of an extra-cardiac shunt. Subsequent chest computed tomographic angiography (CTA) demonstrated five large PAVMs. RESULTS: The patient underwent transcatheter coil embolization of the five PAVMs, resulting in marked improvement in dyspnea and resolution of the shunt on bubble study echocardiography. CONCLUSIONS: Although PAVMs are rare, they remain an important entity to consider when evaluating patients with extracardiac shunts. They may present with nonspecific features such as dyspnea on exertion and recurrent CVAs. All patients with multiple PAVMs should undergo thorough skin screening for telangiectasia as well as radiologic imaging to screen for additional AVMs in the liver and brain in order to exclude hereditary hemorrhagic telangiectasia (HHT). PMID- 28810088 TI - The Impact of Maternal Diabetes, Obesity and Race on Infant Birth Weights in South Dakota. AB - INTRODUCTION: Maternal obesity, high gestational weight gain and diabetes mellitus during pregnancy are known risk factors that correlate with high infant birth weight and the mother's race. Previous studies have focused on low birth weight, prematurity and infant mortality. This study examined the interaction between race, maternal risk factors and high infant birth weights at the population level in South Dakota to identify factors contributing to the high Native American infant birth weights. We hypothesized that high infant birth weights were associated with maternal diabetes, obesity and high gestational weight gain, and that Native American infants' higher birth weights were related to the prevalence of diabetes and obesity. MATERIALS AND METHODS: De-identified birth certificate data was provided by the South Dakota Department of Health. We used data for live infant births to South Dakota resident mothers from 2006 through 2011. The mothers were categorized as Native American or white by the mother's self-reported primary race. Infants were excluded from the study population for missing data, birth weight less than 350 g or gestational age less than 24 weeks or greater than 45 weeks. The study population included 11,416 Native American infants and 59,263 white infants for a total study population of 70,679 infants. Maternal variables (race, pre-pregnancy weight and body mass index [BMI], gestational weight gain, pre-pregnancy diabetes mellitus [DM], gestational diabetes [GDM] and delivery BMI) and infant variables (gestational age and birth weight) were analyzed using SPSS software. RESULTS: The mean birth weight (BW) of Native American (NA) infants (3377 g) was significantly greater than the mean BW of white (W) infants (3315 g) even though NA infants had a younger mean gestational age (p = 0.006). More NA infants were categorized as high birth weight (HBW) (11.8 percent) than W infants (8.5 percent). Both DM and GDM were significantly more common among NA mothers. Infants of NA mothers with GDM had a higher mean BW than infants of W mothers with GDM. There were more overweight and obese NA mothers (p = 0.006). In each maternal BMI category, NA infants had a higher mean BW. Mean BW was even higher for infants born to mothers with excessive gestational weight gain (GWG) for their BMI. The infants with the highest mean BW were born to obese NA mothers with GDM and excessive GWG (3680 g). Multivariable linear regression showed that race was the most significant variable affecting infant BW (R2 = 0.57, F = 692). Pre-pregnancy BMI, GWG and excessive GWG were also significant. The most significant interaction variables were race and GDM and race and BMI. CONCLUSIONS: Native American race, gestational diabetes mellitus, overweight and obese BMI, and excessive gestational weight gain for BMI were the most significant maternal factors associated with high infant birth weight. Mothers with any one risk factor gave birth to heavier infants. Mothers with all risk factors had infants with the highest mean birth weights in South Dakota. This large population-based study provides evidence that Native American mothers in South Dakota with GDM, overweight or obese BMI and excessive GWG are more likely to give birth to high birth weight infants. At-risk mothers should be educated regarding the risks and potential complications of high birth weight infants. PMID- 28810089 TI - The Healing Arts Through Poetry A Rush to Undertake a Fool's Errand. PMID- 28810090 TI - Evaluating for Intimate Partner Violence in the Healthcare Setting. PMID- 28810091 TI - Preoperative Chest Radiography in Elective Surgery: Review and Update. AB - INTRODUCTION: The preoperative evaluation is designed to identify factors that may predispose a patient to perioperative complications in an effort to ensure patient safety. The use of chest radiography in the preoperative evaluation has progressed from routine testing to a more selective approach based on evidence that routine testing is low yield. However, preoperative chest radiography (POCR) may still be utilized more frequently than necessary as guidelines provide varying recommendations and providers continue to order the test by convention. The literature is reviewed to update providers on the indications for POCR and encourage more selective use. METHODS: Articles related to POCR were retrieved via PubMed search and subsequent cited reference search. Effort was made to analyze primarily meta-analysis, systematic reviews and current guidelines and secondarily larger observational studies. No randomized controlled trials related to use of POCR were identified. FINDINGS: POCR frequently detects abnormalities; however, a majority of abnormalities detected are in patients with a history of cardiopulmonary disease or signs and symptoms indicative of cardiopulmonary disease. The frequency with which detected abnormalities influence perioperative management is low and evidence suggests that the clinical examination alone provides sufficient information to dictate any necessary changes in management in a majority of cases. Current evidence does not support the ability of POCR to reliably predict postoperative pulmonary complications. CONCLUSIONS: Selective use of POCR is recommended. Emphasis on a thorough preoperative clinical examination is usually sufficient to make decisions on perioperative management as POCR rarely provides significant additional information. POCR is generally indicated in patients with signs or symptoms of acute or unstable cardiopulmonary disease. The relationship between POCR and patient outcomes, morbidity and mortality is not known. PMID- 28810092 TI - How Healthy is Student Interest in Health Care Professions? PMID- 28810094 TI - Medication Assistance Fund: A Novel Template for Community Health. PMID- 28810093 TI - Quality Focus: Improving Cardiac Care and Reducing Cardiac Healthcare Disparities. PMID- 28810095 TI - State of South Dakota's Child: 2016. AB - In 2015, there was an increase in the number of births in South Dakota compared to the previous year. Further, the state's 2014 birth rate (14.4) exceeded the 12.5 rate observed nationally for this year. Similar to national trends, one quarter of South Dakota newborns represent minority populations. The infant mortality rate of 7.3 for the state in 2015 was 24 percent higher than the 2014 rate. Analyses of factors that contributed to this increase show that twice as many infants died of sudden unexpected infant death (SUID) in 2015 as has been observed in previous years. SUID was the cause of 30 percent of the state's infant deaths in 2015 versus 19 percent in 2014. Between 2011 and 2015, the SUID rate has been four times higher for minority than white infants. A discussion of strategies for the prevention of these deaths is presented. PMID- 28810096 TI - Point-Counterpoint: CYP2C19 Genotyping for Clopidogrel. PMID- 28810097 TI - Early Hearing Loss Detection and Intervention in South Dakota. PMID- 28810098 TI - A Rare Case of Pulmonary Lymphomatoid Granulomatosis. AB - In this report, we discuss an unusual case of pulmonary lymphomatoid granulomatosis (LYG), a rare form of angiocentric and angiodestructive lymphoproliferative disorder. This disease is thought to be caused by Epstein Barr virus-induced lymphoproliferation. A 39-year-old male with no signi ficant past medical history presented with flu-like symptoms. Upon further evaluation, laboratory studies noted pancytopenia, and a chest X-ray showed bilateral nodular densities. A computerized tomography (CT) scan demonstrated bilateral pulmonary nodules and splenomegaly. A biopsy of the pulmonary nodules revealed polymorphous, CD3-positive, lymphohistiocytic, inflammatory in filtrate within the walls of the arterioles and venules with associated necrosis. This histopathology is consistent with LYG. The patient was started on a regimen of rituximab, and he signi ficantly improved within a few weeks after the initiation of therapy, including resolution of the pancytopenia. A repeat CT scan showed the decreased size of the lung nodules. This case was histopathologically consistent with LYG but negative for Epstein-Barr virus ribonucleic acid. This demonstrates the potential for diagnostic difficulty in a case presentation of multiple pulmonary nodules. Extensive work-up for neoplastic, infectious, inflammatory, and autoimmune etiologies needs to be done in such cases. A prompt diagnosis of LYG is necessary for optimal management and improved patient outcomes. PMID- 28810099 TI - Childhood Vision Screening in Western South Dakota: Examining Barriers to Post Vision Screening Follow-up Referral. AB - BACKGROUND: Poor follow-up after post-screening referral is a challenge faced by vision screening organizations. This study examines barriers to follow-up eye care in children who were referred for a comprehensive eye exam following a vision screening event in western South Dakota. METHODS: Children referred for a comprehensive eye exam following a screening event by Northern Plains Eye Foundation Western South Dakota Lions Children's Vision Screening Initiative (CVSI) from September 2014 to February 2015 were identified for a telephone survey. Parents/guardians of these children were contacted and asked a series of questions aimed at assessing the barriers to obtaining eye care. RESULTS: Of the 282 children identified, parents/guardians of 63 were successfully surveyed (22.3 percent), 38 had attended an appointment (60.3 percent), and 19 (30.2 percent) brought the CVSI referral form when they attended the appointment. When parents/guardians of the 25 children who had not attended an appointment were surveyed, 12 (19 percent) were not aware the screening results indicated a full eye exam was recommended, 10 (15.9 percent) identified barriers to scheduling an appointment, and three (4.8 percent) had an appointment scheduled in the future or forgot a scheduled appointment. CONCLUSION: The majority of surveyed parents/guardians reported their children having seen an eye care provider. Appropriate documentation has been limited due to reliance on parents/guardians to give referral forms to eye care providers and subsequent dependence on providers to forward completed referral forms to CVSI. Improved documentation is needed to assess the accuracy of the screening, support screening prevalence data, and evaluate the impact of CVSI. PMID- 28810100 TI - Ascending Colon Schwannoma an Unusual Cause of Acute Lower Gastrointestinal Bleeding. AB - This is a case report of a 61-year-old female who presented with acute lower gastrointestinal bleeding resulting from a schwannoma involving the ascending colon. The patient was successfully treated with laparoscopic hemicolectomy. Schwannoma involving the large bowel is a rare entity; only around 90 cases of colonic schwannomas are reported in world literature. Although the vast majority of these tumors demonstrate a slow growing and benign profile, recurrence and malignant transformation can occur. Given the exceptional rarity of this pathological process, much of what is currently understood about this disease comes from case studies. Continued reporting of this pathology will be essential for further development and understanding its clinical and pathologic presentation. PMID- 28810101 TI - You Abused What? Getting High with Unique Medications. PMID- 28810102 TI - Quality Focus: Physician Reimbursement Changes: An Update. PMID- 28810103 TI - Safe and Effective Vaccinations: Great Results. PMID- 28810104 TI - Strategies for Prevention of Methicillin Resistant Staphylococcus aureus (MRSA) Infections and Decolonization. AB - Methicillin resistant Staphylococcus aureus (MRSA) invasive infections can be severe in the pediatric population with high morbidity and mortality. MRSA colonization can predispose to recurrent skin and soft tissue infections and invasive MRSA disease and is a frequent challenge faced by clinicians. This article reviews the importance of MRSA as a pathogen, MRSA colonization and various MRSA decolonization strategies. PMID- 28810105 TI - Increased Activity in Unstructured Versus Structured Gym Time in an After-School Program. AB - BACKGROUND: More than 10 million American youth engage in after-school programs that provide an opportunity to increase physical activity. The purpose of this study was to test the hypothesis that children in unstructured gym time (free) would have greater activity than both structured gym time (structured) and when increased screen time was available. METHODS: Three interventions were compared in a nested design, with each two-week intervention preceded and followed by a two-week control period. Seventy-four children aged 6 to 12 years were enrolled and wore pedometers during the interventions. RESULTS: Mean pedometer counts were higher during free than structured gym time (p=0.01), which was more apparent in boys (p=0.02) than girls (p=0.24). Neither age nor habitual activity was associated with pedometer counts. Body mass index (BMI) was inversely correlated with counts during free gym time (r=-0.314) in boys and girls combined. Accident rates did not differ among interventions. CONCLUSIONS: After-school programs may be appropriate environments to increase activity levels, but greatest increases were observed in children with the lowest BMIs and may not be as effective in girls as boys. Future research should focus on identifying where children at risk of overweight spend their time and how to implement a program designed at increasing activity levels within those spaces. PMID- 28810106 TI - A Case of Silent Q Fever Endocarditis. AB - Q fever endocarditis is a rare, culture negative endocarditis caused by Coxiella burnetii, a spore-forming gram negative coccobacillus. Presenting symptoms can be very non-specific; thus, diagnosis may be delayed. We present a case of a 65-year old male patient with history of aortic aneurysm who complained of chronic fatigue. He was found to have aortic valve vegetation on routine echocardiography. Q fever endocarditis was diagnosed based on elevated Q fever serology; there was absence of fever. This case illustrated a rare, under recognized and atypical manifestation of Q fever endocarditis. We would like to encourage physicians of rural states like South Dakota to remain vigilant when it comes to screening for the suspected cases of Q fever, specifically in cases of unexplained fatigue and valvulopathy. PMID- 28810107 TI - A Case of Acute Compartment Syndrome of the Thigh Associated with Repetitive Athletic Trauma. AB - We present a case of acute compartment syndrome (ACS) in an athlete who sustained minimal but repetitive trauma to the thigh during a sporting event. During his evaluation, concern was raised regarding the diagnosis of ACS as a cause of his symptoms. This was confirmed by measuring the intra-compartmental pressures and he subsequently underwent successful emergent fasciotomy, eventually making a complete recovery. ACS is a potential complication of muscular-skeletal injuries from various causes, and our case is unusual as the cause was mild but repetitive trauma in an otherwise healthy athlete. It is important to recognize the signs and symptoms of ACS to avoid the potentially significant complications should the diagnosis be missed. PMID- 28810108 TI - Immunization Update - Adolescents. PMID- 28810110 TI - Quality Focus: First, Do No Harm: Adverse Drug Events. PMID- 28810109 TI - Shit. PMID- 28810111 TI - Update on the USD Sanford School of Medicine: National Boards. PMID- 28810112 TI - Patient and Physician Perceptions of Genetic Testing in Primary Care. AB - INTRODUCTION: The convergence of biomedical informatics and translational genomics is changing the way we practice. Primary care will play a pivotal role in this transformation. We therefore sought to assess general knowledge about genetic testing among outpatient internal medicine providers, and the patients that they serve across a five state region in the Midwest. METHODS: One thousand take-home paper surveys were created and distributed to internal medicine patients at 13 Midwestern clinics. Sixty-two electronic surveys were also created and distributed to internal medicine providers at these same clinics. Questions assessed knowledge, interest, and comfort with genetic testing as well as the role of genetic counselors. Differences in response based on physician characteristics were compared using a Chi-squared analysis. RESULTS: In general, patients cared for in internal medicine clinics expressed an understanding of both content (75 percent) and rationale (81 percent) for genetic testing. Patients are open to hearing about genetic risks that could affect their health (88 percent) even if their visit was scheduled for a different reason. In these same clinics, providers expressed a strong understanding of the purpose of genetic testing (88 percent). However, providers were not confident in responding to questions about the impact of genetic testing on disease susceptibility (25 percent). Providers were more confident answering questions about genetic variability in drug response (46 percent). In general, outpatient internal medicine providers feel comfortable referring patients to genetic counselors to assess disease risk (88 percent) and they believe genetic testing is relevant to their practice (75 percent). CONCLUSIONS: In our Midwestern sample, we found that both patients and providers express interest in learning more about genetic testing in the context of primary care. Patient and physician responses indicate a role for genetic counselors in helping our patients understand and interpret genetic test results. PMID- 28810113 TI - An Unusual Presentation of an Unusual Disease: Spontaneous Pneumomediastinum. AB - We report a case of spontaneous pneumomediastinum with unusual clinical presentation. The most common symptoms of spontaneous mediastinum are chest pain and shortness of breath. Our patient presented with neck swelling and change in voice, an unusual presentation for spontaneous pneumothorax. A 30-year-old previously healthy man presented with complaints of neck swelling and hoarseness of voice beginning after an intense coughing spell. He had no other complaints. He denied any trauma to the chest, nausea, vomiting, recent air travel, scuba diving or recreational drug use. His vital signs were stable with an O2 saturation of 97 percent on room air. Chest examination was remarkable for palpable crepitus over lower neck as well as bilateral upper and mid anterior chest. Chest radiograph as well as chest computed tomography (CT) demonstarted a massive pneumomediastinum with free air dissecting throughout the soft tissues of the neck. The patient was admitted for observation. Neck swelling and hoarseness of voice resolved in less than 24 hours with conservative management of cough. He was discharged without incident. Spontaneous pneumomediastinum is an uncommon, self-limiting condition in which air is present in the mediastinum with no obvious precipitating factor. Cough, inhaled drugs, physical exercise, labor, and diabetic ketoacidosis have been reported to trigger spontaneous pneumomediastinum. Our patient developed the condition after an intense coughing spell following smoking cessation. CT scan is considered gold standard for the diagnosis. Spontaneous pneumomediastinum is characterized by spontaneous recovery and can be treated with short period of observation and symptomatic management. PMID- 28810114 TI - Embracing a Deep Peace in My Soul: The Father of Autism and Treatment of the Insane in South Dakota. PMID- 28810115 TI - Current Guidelines on Syncope. AB - Syncope is a very commonly encountered clinical problem in general practice and in the emergency department. In the evaluation of syncope, it is important to identify the specific cause to determine the treatment, to estimate the precise risk to a patient, and to reduce recurrence. Sometimes, making a diagnosis of syncope is difficult, as different mechanisms may often coexist. Syncope causes a significant impact on quality of life due to associated risk of physical injury. In particular, syncope can be a precursor to sudden cardiac death in patients with underlying cardiac disease. It is crucial to identify patients at increased risk of death, such as those with myocardial ischemia and/or potentially life threatening genetic diseases (e.g., Long-QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and arrhythmogenic right ventricular dysplasia). After these conditions have been excluded, other benign conditions that cause syncope must be identified, and efforts should be made to improve quality of life. The lack of a gold-standard clinical tool to aid in diagnosing syncope as well as improper use of various diagnostic tests, are leading to high economic burdens in this area. PMID- 28810116 TI - Stop the Bleeding! Reversing the Effects of Direct-acting Oral Anticoagulants. PMID- 28810117 TI - Quality Focus: Diabetes: A Challenge for Patient and Provider. PMID- 28810118 TI - Capacitive Detection of Low-Enthalpy, Higher-Order Phase Transitions in Synthetic and Natural Composition Lipid Membranes. AB - In-plane lipid organization and phase separation in natural membranes play key roles in regulating many cellular processes. Highly cooperative, first-order phase transitions in model membranes consisting of few lipid components are well understood and readily detectable via calorimetry, densitometry, and fluorescence. However, far less is known about natural membranes containing numerous lipid species and high concentrations of cholesterol, for which thermotropic transitions are undetectable by the above-mentioned techniques. We demonstrate that membrane capacitance is highly sensitive to low-enthalpy thermotropic transitions taking place in complex lipid membranes. Specifically, we measured the electrical capacitance as a function of temperature for droplet interface bilayer model membranes of increasing compositional complexity, namely, (a) a single lipid species, (b) domain-forming ternary mixtures, and (c) natural brain total lipid extract (bTLE). We observed that, for single-species lipid bilayers and some ternary compositions, capacitance exhibited an abrupt, temperature-dependent change that coincided with the transition detected by other techniques. In addition, capacitance measurements revealed transitions in mixed lipid membranes that were not detected by the other techniques. Most notably, capacitance measurements of bTLE bilayers indicated a transition at ~38 degrees C not seen with any other method. Likewise, capacitance measurements detected transitions in some well-studied ternary mixtures that, while known to yield coexisting lipid phases, are not detected with calorimetry or densitometry. These results indicate that capacitance is exquisitely sensitive to low-enthalpy membrane transitions because of its sensitivity to changes in bilayer thickness that occur when lipids and excess solvent undergo subtle rearrangements near a phase transition. Our findings also suggest that heterogeneity confers stability to natural membranes that function near transition temperatures by preventing unwanted defects and macroscopic demixing associated with high-enthalpy transitions commonly found in simpler mixtures. PMID- 28810119 TI - Conformational Flexibility of the Benzyl-Guanine Adduct in a Bypass Polymerase Active Site Permits Replication: Insights from Molecular Dynamics Simulations. AB - Although translesion synthesis (TLS) polymerases play key roles in replicating DNA that contains nucleobase addition products (adducts), there are many unknowns about their function. The present work gains indispensable structural insights from molecular dynamics simulations on the replication of O6-benzyl-guanine (Bz dG) prior to bond formation during dCTP insertion opposite the adduct by Dpo4. When combined with previous X-ray crystal structures of the Bz-dG extension complex, molecular details are now available for each stage during a single TLS replication cycle for this carcinogenic lesion. Our calculations illustrate that Bz-dG preferentially adopts an intercalated bulky moiety orientation in the Dpo4 preinsertion complex, which stabilizes the complex through Bz-dG interactions with the previously replicated 3'-base pair and positions the carcinogenic group in the dNTP binding site. Nevertheless, the maintained inherent flexibility of Bz dG due to a stark lack of interactions with the polymerase or template DNA allows the bulky moiety to adopt a major groove position opposite an incoming dCTP in an orientation that is conducive for the experimentally observed nonmutagenic bypass. Comparison of Bz-dG and canonical dG replication clarifies that the experimentally observed decrease in dCTP binding affinity and replication efficiency upon adduct formation is likely caused by a combination of factors, including the required template nucleotide conformational change and destabilized template-dCTP hydrogen bonding. Although additional aspects of the replication process, such as the impact of the adduct on the nucleotidyl-transfer reaction, may also be important for fully rationalizing experimental replication data and must be considered in future work, the present contribution emphasizes the importance of considering the effect of DNA damage on the early stages of the TLS process. PMID- 28810120 TI - Aqueous Solvation of Ammonia and Ammonium: Probing Hydrogen Bond Motifs with FT IR and Soft X-ray Spectroscopy. AB - In a multifaceted investigation combining local soft X-ray and vibrational spectroscopic probes with ab initio molecular dynamics simulations, hydrogen bonding interactions of two key principal amine compounds in aqueous solution, ammonia (NH3) and ammonium ion (NH4+), are quantitatively assessed in terms of electronic structure, solvation structure, and dynamics. From the X-ray measurements and complementary determination of the IR-active hydrogen stretching and bending modes of NH3 and NH4+ in aqueous solution, the picture emerges of a comparatively strongly hydrogen-bonded NH4+ ion via N-H donating interactions, whereas NH3 has a strongly accepting hydrogen bond with one water molecule at the nitrogen lone pair but only weakly N-H donating hydrogen bonds. In contrast to the case of hydrogen bonding among solvent water molecules, we find that energy mismatch between occupied orbitals of both the solutes NH3 and NH4+ and the surrounding water prevents strong mixing between orbitals upon hydrogen bonding and, thus, inhibits substantial charge transfer between solute and solvent. A close inspection of the calculated unoccupied molecular orbitals, in conjunction with experimentally measured N K-edge absorption spectra, reveals the different nature of the electronic structural effects of these two key principal amine compounds imposed by hydrogen bonding to water, where a pH-dependent excitation energy appears to be an intrinsic property. These results provide a benchmark for hydrogen bonding of other nitrogen-containing acids and bases. PMID- 28810121 TI - Comparative Proteomic and Transcriptomic Analysis of Follistatin-Induced Skeletal Muscle Hypertrophy. AB - Skeletal muscle, the most abundant body tissue, plays vital roles in locomotion and metabolism. Myostatin is a negative regulator of skeletal muscle mass. In addition to increasing muscle mass, Myostatin inhibition impacts muscle contractility and energy metabolism. To decipher the mechanisms of action of the Myostatin inhibitors, we used proteomic and transcriptomic approaches to investigate the changes induced in skeletal muscles of transgenic mice overexpressing Follistatin, a physiological Myostatin inhibitor. Our proteomic workflow included a fractionation step to identify weakly expressed proteins and a comparison of fast versus slow muscles. Functional annotation of altered proteins supports the phenotypic changes induced by Myostatin inhibition, including modifications in energy metabolism, fiber type, insulin and calcium signaling, as well as membrane repair and regeneration. Less than 10% of the differentially expressed proteins were found to be also regulated at the mRNA level but the Biological Process annotation, and the KEGG pathways analysis of transcriptomic results shows a great concordance with the proteomic data. Thus this study describes the most extensive omics analysis of muscle overexpressing Follistatin, providing molecular-level insights to explain the observed muscle phenotypic changes. PMID- 28810122 TI - Crystal Face Distributions and Surface Site Densities of Two Synthetic Goethites: Implications for Adsorption Capacities as a Function of Particle Size. AB - Two synthetic goethites of varying crystal size distributions were analyzed by BET, conventional TEM, cryo-TEM, atomic resolution STEM and HRTEM, and electron tomography in order to determine the effects of crystal size, shape, and atomic scale surface roughness on their adsorption capacities. The two samples were determined by BET to have very different site densities based on CrVI adsorption experiments. Model specific surface areas generated from TEM observations showed that, based on size and shape, there should be little difference in their adsorption capacities. Electron tomography revealed that both samples crystallized with an asymmetric {101} tablet habit. STEM and HRTEM images showed a significant increase in atomic-scale surface roughness of the larger goethite. This difference in roughness was quantified based on measurements of relative abundances of crystal faces {101} and {201} for the two goethites, and a reactive surface site density was calculated for each goethite. Singly coordinated sites on face {210} are 2.5 more dense than on face {101}, and the larger goethite showed an average total of 36% {210} as compared to 14% for the smaller goethite. This difference explains the considerably larger adsorption capacitiy of the larger goethite vs the smaller sample and points toward the necessity of knowing the atomic scale surface structure in predicting mineral adsorption processes. PMID- 28810123 TI - Electrochemical Dissolution of Iridium and Iridium Oxide Particles in Acidic Media: Transmission Electron Microscopy, Electrochemical Flow Cell Coupled to Inductively Coupled Plasma Mass Spectrometry, and X-ray Absorption Spectroscopy Study. AB - Iridium-based particles, regarded as the most promising proton exchange membrane electrolyzer electrocatalysts, were investigated by transmission electron microscopy and by coupling of an electrochemical flow cell (EFC) with online inductively coupled plasma mass spectrometry. Additionally, studies using a thin film rotating disc electrode, identical location transmission and scanning electron microscopy, as well as X-ray absorption spectroscopy have been performed. Extremely sensitive online time-and potential-resolved electrochemical dissolution profiles revealed that Ir particles dissolve well below oxygen evolution reaction (OER) potentials, presumably induced by Ir surface oxidation and reduction processes, also referred to as transient dissolution. Overall, thermally prepared rutile-type IrO2 particles are substantially more stable and less active in comparison to as-prepared metallic and electrochemically pretreated (E-Ir) analogues. Interestingly, under OER-relevant conditions, E-Ir particles exhibit superior stability and activity owing to the altered corrosion mechanism, where the formation of unstable Ir(>IV) species is hindered. Due to the enhanced and lasting OER performance, electrochemically pre-oxidized E-Ir particles may be considered as the electrocatalyst of choice for an improved low temperature electrochemical hydrogen production device, namely a proton exchange membrane electrolyzer. PMID- 28810124 TI - Ferroelectric Phase Transition Induced a Large FMR Tuning in Self-Assembled BaTiO3:Y3Fe5O12 Multiferroic Composites. AB - Yttrium iron garnet (YIG) is of great importance in RF/microwave devices for its low loss, low intrinsic damping, and high permeability. Nevertheless, tuning of YIG-based multiferroics is still a challenge due to its near-zero magnetostriction and the difficulty of building epitaxial interface between ferromagnetic garnet and ferroelectric perovskite phases. In this work, the vertically aligned heterostructure of YIG:BTO/STO(001) with local epitaxial interface between BTO and YIG is well-constructed, where the single crystal BTO pillars are embedded in YIG matrix. A large magnetoelectric coupling effect that drives YIG's FMR shift up to 512 and 333 Oe (1-2 order greater than those of all state-of-the-art progresses) is obtained through BTO ferroelectric phase changes induced by temperature variation at 295 and 193 K, correspondingly. This record high magnetoelectric tunability of YIG paves a way toward thermal/electrical tunable YIG devices. PMID- 28810125 TI - Cheminformatic Analysis of Antimalarial Chemical Space Illuminates Therapeutic Mechanisms and Offers Strategies for Therapy Development. AB - The clear and present danger of malaria, which has been amplified in recent years by climate change, and the progressive thinning of our drug arsenal over the past two decades raise uncomfortable questions about the current state and future of antimalarial drug development. Besides suffering from many of the same technical challenges that affect drug development in other disease areas, the quest for new antimalarial therapies is also hindered by the complex, dynamic life cycle of the malaria parasite, P. falciparum, in its mosquito and human hosts, and its role thereof in the elicitation of drug resistance. New strategies are needed in order to ensure economical and expeditious development of new, more efficacious treatments. In the present study, we employ open-source cheminformatics tools to analyze the chemical space traversed by approved antimalarial drugs and promising candidates at various stages of development to uncover insights that could shape future endeavors in the field. Our scaffold-centric analysis reveals that the antimalarial chemical space is disjointed and segregated into a few dominant structural groups. In fact, the structures of antimalarial drugs and drug candidates are distributed according to Pareto's principle. This structural convergence can potentially be exploited for future drug discovery by incorporating it into bioinformatics workflows that are typically employed for solving problems in structural biology. Significantly, we demonstrate how molecular scaffold hunting can be applied to unearth putative mechanisms of action of drugs whose activities remain a mystery, and how scaffold-centric analysis of drug space can also provide a recipe for combination therapies that minimize the likelihood of emergence of drug resistance, as well as identify areas on which to focus efforts. Finally, we also observe that over half of the molecules in the antimalarial space bear no resemblance to other molecules in the collection, which suggests that the pharmacobiology of antimalarial drugs has not been entirely surveyed. PMID- 28810126 TI - Combined Virtual Screening and Substructure Search for Discovery of Novel FABP4 Inhibitors. AB - Fatty acid-binding protein 4 (FABP4, AFABP) is a potential drug target for diabetes and atherosclerosis. In this study, a series of novel FABP4 inhibitors were discovered through combining virtual screening and substructure search. Seventeen compounds exhibited FABP4 inhibitory activities with IC50 < 10 MUM, among which 11 compounds showed high selectivity against FABP3. The best compound 36b displayed an IC50 value of 1.5 MUM. Molecular docking and point mutation studies revealed that Gln95, Arg126, and Tyr128 play key roles for these compounds binding with FABP4. Interestingly, Gln95 seems to be essential for conformation stability of FABP4. The new scaffolds of these compounds and their interaction mechanisms binding with FABP4 should provide an important clue for the further development of novel FABP4 inhibitors. PMID- 28810127 TI - Medicaid prior authorization and opioid medication abuse and overdose. AB - OBJECTIVES: The US opioid medication epidemic has resulted in serious health consequences for patients. Formulary management tools adopted by payers, specifically prior authorization (PA) policies, may lower the rates of opioid medication abuse and overdose. We compared rates of opioid abuse and overdose among enrollees in plans that varied in their use of PA from "High PA" (ie, required PA for 17 to 74 opioids), with "Low PA" (ie, required PA for 1 opioid), and "No PA" policies for opioid medications. STUDY DESIGN: Retrospective cohort study of patients initiating opioid treatment in Pennsylvania Medicaid from 2010 to 2012. METHODS: Generalized linear models with generalized estimating equations were employed to assess the relationships between the presence of PA policies and opioid medication abuse and overdose, as measured in Medicaid claims data, adjusting for demographics, comorbid health conditions, benzodiazepine/muscle relaxant use, and emergency department use. RESULTS: The study cohort included 297,634 enrollees with a total of 382,828 opioid treatment episodes. Compared with plans with No PA, enrollees in High PA (adjusted rate ratio [ARR], 0.89; 95% confidence interval [CI], 0.85-0.93; P <.001) and Low PA plans (ARR, 0.93; 95% CI, 0.87-1.00; P = .04) had lower rates of abuse. Enrollees in the Low PA plan had a lower rate of overdose than those within plans with No PA (ARR, 0.75; 95% CI, 0.59-0.95; P = .02). High PA plan enrollees were also less likely than No PA enrollees to experience an overdose, but this association was not statistically significant (ARR, 0.88; 95% CI, 0.76-1.02; P = .08). CONCLUSIONS: Enrollees within Medicaid plans that utilize PA policies appear to have lower rates of abuse and overdose following initiation of opioid medication treatment. PMID- 28810128 TI - The association of mental health program characteristics and patient satisfaction. AB - OBJECTIVES: Satisfaction with care is an important patient-centered domain of health system quality. However, satisfaction measures are costly to collect and not directly modifiable. Therefore, we assessed the relationships between veterans' satisfaction and measures of modifiable aspects of Veterans Health Administration (VHA) mental health care programs. STUDY DESIGN: For a sample of 6990 patients who received mental health care from the VHA in 2013, we used survey and administrative data to investigate the association of a suite of access and encounter satisfaction measures with a large collection of measures of program characteristics. METHODS: We estimated risk-adjusted correlations between 6 satisfaction measures (across 2 domains: access and encounter satisfaction) and 28 mental health care program characteristics (across 4 domains: program reach, psychosocial service access, program intensity, and treatment continuity). RESULTS: We found that satisfaction with access to care was higher than experiences with care encounters, but that broad measures of mental health care program reach and intensity were positively associated with both kinds of satisfaction. No measures of psychosocial service access were positively associated with access and encounter satisfaction. Most measures of treatment continuity were consistently and positively associated with both kinds of satisfaction. CONCLUSIONS: As the VHA strives to increase access to, and provision of, mental health care, policy makers and program managers should be aware that satisfaction with care, as it is currently measured, may not rise as more patients initiate treatment, unless continuity of care is maintained or enhanced. PMID- 28810129 TI - Opioid prescribing for chronic pain in a community-based healthcare system. AB - OBJECTIVES: We sought to evaluate opioid prescribing in an ambulatory setting among patients with noncancer chronic pain (CP). STUDY DESIGN: Cross-sectional analysis. METHODS: We identified patients with at least 2 CP encounters at least 30 days apart in 2012 in the electronic health records of a community-based healthcare delivery system in northern California. We used logistic regression models to assess associations of receiving an opioid prescription with respect to number and type of CP conditions and patient demographics and characteristics. Odds ratios (ORs) with 95% confidence intervals (CIs) and the adjusted prevalence of receiving an opioid prescription were generated after controlling for important covariates. RESULTS: A total of 120,481 patients with CP met eligibility criteria, with 58% receiving an opioid in 2012. The adjusted prevalence of receiving an opioid was highest for back/cervical pain (71%). The odds of receiving an opioid increased linearly with the number of CP conditions per patient (OR, 1.29; 95% CI, 1.25-1.33; P <.001). Men were generally more likely to receive an opioid than women, as were patients with noncommercial insurance, especially Medicaid (OR, 2.77; 95% CI, 2.56-3.01; P <.001) versus commercial. CONCLUSIONS: In an ambulatory healthcare setting, opioid prescribing to patients with CP varied by type and number of pain conditions. Opioid prescriptions to men, those with back/cervical pain, and Medicaid beneficiaries were particularly prevalent. The identification of populations more likely to receive an opioid in the treatment of CP should be of interest to healthcare systems to ensure these drugs are being used appropriately and safely. PMID- 28810130 TI - The cost of adherence mismeasurement in serious mental illness: a claims-based analysis. AB - OBJECTIVES: To quantify how adherence mismeasurement affects the estimated impact of adherence on inpatient costs among patients with serious mental illness (SMI). STUDY DESIGN: Proportion of days covered (PDC) is a common claims-based measure of medication adherence. Because PDC does not measure medication ingestion, however, it may inaccurately measure adherence. We derived a formula to correct the bias that occurs in adherence-utilization studies resulting from errors in claims-based measures of adherence. METHODS: We conducted a literature review to identify the correlation between gold-standard and claims-based adherence measures. We derived a bias-correction methodology to address claims-based medication adherence measurement error. We then applied this methodology to a case study of patients with SMI who initiated atypical antipsychotics in 2 large claims databases. RESULTS: Our literature review identified 6 studies of interest. The 4 most relevant ones measured correlations between 0.38 and 0.91. Our preferred estimate implies that the effect of adherence on inpatient spending estimated from claims data would understate the true effect by a factor of 5.3, if there were no other sources of bias. Although our procedure corrects for measurement error, such error also may amplify or mitigate other potential biases. For instance, if adherent patients are healthier than nonadherent ones, measurement error makes the resulting bias worse. On the other hand, if adherent patients are sicker, measurement error mitigates the other bias. CONCLUSIONS: Measurement error due to claims-based adherence measures is worth addressing, alongside other more widely emphasized sources of bias in inference. PMID- 28810131 TI - Prescription opioid registry protocol in an integrated health system. AB - OBJECTIVES: To establish a prescription opioid registry protocol in a large health system and to describe algorithms to characterize individuals using prescription opioids, opioid use episodes, and concurrent use of sedative/hypnotics. STUDY DESIGN: Protocol development and retrospective cohort study. METHODS: Using Kaiser Permanente Northern California (KPNC) electronic health record data, we selected patients using prescription opioids in 2011. Opioid and sedative/hypnotic fills, and physical and psychiatric comorbidity diagnoses, were extracted for years 2008 to 2014. Algorithms were developed to identify each patient's daily opioid and sedative/hypnotic use, and morphine daily-dose equivalent. Opioid episodes were classified as long-term, episodic, or acute. Logistic regression was used to predict characteristics associated with becoming a long-term opioid user. RESULTS: In 2011, 18% of KPNC adult members filled at least 1 opioid prescription. Among those patients, 25% used opioids long term and their average duration of use was more than 4 years. Sedative/hypnotics were used by 76% of long-term users. Being older, white, living in a more deprived neighborhood, having a chronic pain diagnosis, and use of sedative/hypnotics were predictors of initiating long-term opioid use. CONCLUSIONS: This study established a population-based opioid registry that is flexible and can be used to address important questions of prescription opioid use. It will be used in future studies to answer a broad range of other critical public health issues relating to prescription opioid use. PMID- 28810132 TI - Short communication: Alteration in blood parameters by enrofloxacin in juvenile lesser spotted dogfish (Scyliorhinus canicula, Linnaeus, 1758) after intramuscular injection. AB - Enrofloxacin (EF) is a veterinary drug for respiratory, gastrointestinal and urinary tract infections. Parenteral administration at doses higher than the manufacturer recommended dosage has induced cartilage lesions in juvenile mammals and poultry. In elasmobranchs EF is commonly used for the treatment of infectious diseases, however only one study has been performed previously to evaluate pharmacokinetics and the potential chondrotoxicity of a fluoroquinolone in adult skates. In present study juvenile lesser spotted dogfish (Scyliorhinus canicula, Linnaeus, 1758) were treated with low (LD, 5mg/kg) and high dose (HD, 10mg/kg) of EF daily via intramuscular injection for 15 consecutive days, as indicated in a recognized treatment. Hematological parameters, oxidative stress and histology of vertebral cartilage were evaluated. No cartilage damage was observed. Hematological parameters evaluation underlined a significant (p=0.035), dose dependent reduction in red blood cell count and in hematocrit (40% and 6%, respectively). Anyway, the biological significance of this reduction is doubtful, due to limited decrease observed. The evaluation of oxidative stress parameters underlined that glutathione levels, as well as glutathione S-transferase and catalase activities, were significantly increased in HD group animals, with respect to untreated and solvent control groups. Obtained data do not support a toxic effect of EF on dogfish cartilage, while concern arises from hematological and oxidative stress data. PMID- 28810133 TI - Floor-of-Mouth Hematoma Following Dental Implant Placement: Literature Review and Case Presentation. AB - PURPOSE: The authors provide a structured review of reported cases of floor-of mouth hematoma during or after dental implantation and frequent causes and management and present a related case. MATERIALS AND METHODS: An online search of the medical literature was conducted from 1990 through 2016. The following search terms were used: floor of mouth hematoma, sublingual hematoma, dental implant hematoma, implant in mandible, and complication of dental implant. Abstracts were screened for relevance to the aims of the review. Relevant reports in the English language were included and referenced. The articles were reviewed for patient demographics, implant location, coagulopathy, pre- or postoperative imaging, airway management, treatment of the hematoma, and management of the offending implant. RESULTS: The literature search identified 25 reported cases. Hemorrhage was caused by perforation of the lingual cortex in 84% of cases (n = 21). Airway obstruction resulted in emergency intubation or tracheostomy in 68% of patients (n = 17). Most cases (n = 18; 72%) required surgical management in the hospital setting. Management of the offending implant was reported inconsistently. Of 17 reported cases, 5 implants had to be removed, 9 remained in situ, and in 3 cases implant placement was abandoned. Only 1 case involved preoperative 3-dimensional (3D) imaging before implant insertion. The authors report on an additional case with a serious floor-of-mouth hematoma that required immediate surgical evacuation and hemostasis. CONCLUSION: Serious complications, such as floor-of mouth hematoma after dental implant insertion, can occur, which could be life threatening. Preoperative 3D imaging helps to visualize the individual mandibular shape, which could decrease the incidence of serious complications. If injury to vessels of the floor of the mouth cannot be confidently excluded, then further assessment and treatment are recommended before the patient is discharged. PMID- 28810134 TI - Improvements in reading accuracy as a result of increased interletter spacing are not specific to children with dyslexia. AB - Recently, increased interletter spacing (LS) has been studied as a way to enhance reading fluency. It is suggested that increased LS improves reading performance, especially in poor readers. Theoretically, these findings are well substantiated as a result of diminished crowding effects. Empirically, however, findings on LS are inconclusive. In two experiments, we examined whether effects of increased LS are specific to children with dyslexia and whether increased LS affects word or sentence processing. In the first experiment, 30 children with dyslexia and 30 controls (mean age=9years 11months) read sentences in standard and increased LS conditions. In the second experiment, these sentences were read by an unselected sample of 189 readers (mean age=9years 3months) in either a sentence or word-by word reading condition. The first experiment showed that increased LS affected children with dyslexia and controls in similar ways. Participants made fewer errors in the increased LS condition than in the standard LS condition. Reading rates were not affected. There were no indications that the effect of LS was related to reading ability, not even for a subgroup of readers. Findings of the second experiment were similar. Increased LS resulted in fewer errors, not faster reading rates. This was found only when complete sentences were presented, not when sentences were read word by word. Three main conclusions can be drawn. First, increased LS appears to affect reading accuracy only. Second, the findings do not support claims that increased LS specifically affects poor readers. And third, the effect of LS seems to occur at the interword level. Theoretical and practical implications of these findings are discussed. PMID- 28810135 TI - Is processing of symbols and words influenced by writing system? Evidence from Chinese, Korean, English, and Greek. AB - We examined cross-linguistic effects in the relationship between serial and discrete versions of digit naming and word reading. In total, 113 Mandarin speaking Chinese children, 100 Korean children, 112 English-speaking Canadian children, and 108 Greek children in Grade 3 were administered tasks of serial and discrete naming of words and digits. Interrelations among tasks indicated that the link between rapid naming and reading is largely determined by the format of the tasks across orthographies. Multigroup path analyses with discrete and serial word reading as dependent variables revealed commonalities as well as significant differences between writing systems. The path coefficient from discrete digits to discrete words was greater for the more transparent orthographies, consistent with more efficient sight-word processing. The effect of discrete word reading on serial word reading was stronger in alphabetic languages, where there was also a suppressive effect of discrete digit naming. However, the effect of serial digit naming on serial word reading did not differ among the four language groups. This pattern of relationships challenges a universal account of reading fluency acquisition while upholding a universal role of rapid serial naming, further distinguishing between multi-element interword and intraword processing. PMID- 28810136 TI - Dysfunctional posttraumatic cognitions as a mediator of symptom reduction in Trauma-Focused Cognitive Behavioral Therapy with children and adolescents: Results of a randomized controlled trial. AB - OBJECTIVE: To investigate whether the change in dysfunctional posttraumatic cognitions (PTC) during Trauma-Focused Cognitive Behavioral Therapy (TF-CBT) is a mediator of posttraumatic stress symptom (PTSS) reduction in a sample of children and adolescents. METHOD: A bootstrap mediation analysis was performed to investigate the indirect effect of dysfunctional PTC on treatment outcome in a recently completed RCT study with children and adolescents (n = 123; 7-17 years old) that investigated the effectiveness of TF-CBT. RESULTS: The mediation model revealed that changes in dysfunctional PTC mediated the relationship between the group (TF-CBT vs. waitlist) and PTSS at the end of treatment. CONCLUSION: Change in dysfunctional PTC is an important mechanism mediating the reduction of PTSS in TF-CBT. Monitoring dysfunctional PTC throughout treatment might, therefore, be an important factor in optimizing treatment outcome. PMID- 28810137 TI - Time-gated luminescence imaging of singlet oxygen photoinduced by fluoroquinolones and functionalized graphenes in Daphnia magna. AB - Singlet oxygen (1O2) can be photogenerated by photoactive xenobiotics and is capable of causing adverse effects due to its electrophilicity and its high reactivity with biological molecules. Detection of the production and distribution of 1O2 in living organisms is therefore of great importance. In this study, a luminescent probe ATTA-Eu3+ combined with time-gated luminescence imaging was adopted to detect the distribution and temporal variation of 1O2 photoinduced by fluoroquinolone antibiotics and carboxylated/aminated graphenes in Daphnia magna. Results show that the xenobiotics generate 1O2 in living daphnids under simulated sunlight irradiation (SSR). The photogeneration of 1O2 by carboxylated/aminated graphenes was also confirmed by electron paramagnetic resonance spectroscopy. The strongest luminescence signals of 1O2 were observed in the hindgut of daphnids, and the signals in different areas of the daphnids (gut, thoracic legs and post-abdominal claw) displayed a similar trend of enhancement over irradiation time. Mean 1O2 concentrations at different regions of daphnids within one hour of SSR irradiation were estimated to be in the range of 0.5~4.8MUM. This study presented an efficient method for visualizing and quantifying the temporal and spatial distribution of 1O2 photogenerated by xenobiotics in living organisms, which can be employed for phototoxicity evaluation of xenobiotics. PMID- 28810138 TI - Corrigendum to "A comprehensive review on the colourless carotenoids phytoene and phytofluene" [Arch. Biochem. Biophys. 572 (2015) 188-200]. PMID- 28810139 TI - Cliques and Schisms of Cancer Genes. AB - With a few exceptions, cancers typically carry more than one driver mutation, sometimes five, ten, or more, and these driver mutations do not necessarily assort randomly. In this issue of Cancer Cell, Mina et al. systematically characterize patterns of co-mutation and mutual exclusivity in 6,456 cancers across 23 tumor types. PMID- 28810140 TI - New Views into the Genetic Landscape of Metastatic Breast Cancer. AB - Whether metastasis-specific genetic alterations exist remains controversial. The study by Yates et al. in this issue of Cancer Cell provides evidence that metastases emerge late during primary breast cancer progression and that additional driver mutations are often acquired, posing both challenges and opportunities for precision treatment of metastatic breast cancer. PMID- 28810141 TI - A Viro-Immunotherapy Triple Play for the Treatment of Glioblastoma. AB - In this issue of Cancer Cell, Saha et al. systematically test and optimize combination therapy strategies in a challenging model of glioblastoma. Durable complete responses were seen only when an oncolytic virus expressing IL12 was coupled with anti-CTLA-4 and anti-PD-1 therapeutics. PMID- 28810142 TI - Control of Metastasis by NK Cells. AB - The metastatic spread of malignant cells to distant anatomical locations is a prominent cause of cancer-related death. Metastasis is governed by cancer-cell intrinsic mechanisms that enable neoplastic cells to invade the local microenvironment, reach the circulation, and colonize distant sites, including the so-called epithelial-to-mesenchymal transition. Moreover, metastasis is regulated by microenvironmental and systemic processes, such as immunosurveillance. Here, we outline the cancer-cell-intrinsic and -extrinsic factors that regulate metastasis, discuss the key role of natural killer (NK) cells in the control of metastatic dissemination, and present potential therapeutic approaches to prevent or target metastatic disease by harnessing NK cells. PMID- 28810143 TI - Genomic Evolution of Breast Cancer Metastasis and Relapse. AB - Patterns of genomic evolution between primary and metastatic breast cancer have not been studied in large numbers, despite patients with metastatic breast cancer having dismal survival. We sequenced whole genomes or a panel of 365 genes on 299 samples from 170 patients with locally relapsed or metastatic breast cancer. Several lines of analysis indicate that clones seeding metastasis or relapse disseminate late from primary tumors, but continue to acquire mutations, mostly accessing the same mutational processes active in the primary tumor. Most distant metastases acquired driver mutations not seen in the primary tumor, drawing from a wider repertoire of cancer genes than early drivers. These include a number of clinically actionable alterations and mutations inactivating SWI-SNF and JAK2 STAT3 pathways. PMID- 28810148 TI - Choose and Use Your Chemical Probe Wisely to Explore Cancer Biology. PMID- 28810146 TI - Swarm Intelligence-Enhanced Detection of Non-Small-Cell Lung Cancer Using Tumor Educated Platelets. AB - Blood-based liquid biopsies, including tumor-educated blood platelets (TEPs), have emerged as promising biomarker sources for non-invasive detection of cancer. Here we demonstrate that particle-swarm optimization (PSO)-enhanced algorithms enable efficient selection of RNA biomarker panels from platelet RNA-sequencing libraries (n = 779). This resulted in accurate TEP-based detection of early- and late-stage non-small-cell lung cancer (n = 518 late-stage validation cohort, accuracy, 88%; AUC, 0.94; 95% CI, 0.92-0.96; p < 0.001; n = 106 early-stage validation cohort, accuracy, 81%; AUC, 0.89; 95% CI, 0.83-0.95; p < 0.001), independent of age of the individuals, smoking habits, whole-blood storage time, and various inflammatory conditions. PSO enabled selection of gene panels to diagnose cancer from TEPs, suggesting that swarm intelligence may also benefit the optimization of diagnostics readout of other liquid biopsy biosources. PMID- 28810147 TI - Macrophage Polarization Contributes to Glioblastoma Eradication by Combination Immunovirotherapy and Immune Checkpoint Blockade. AB - Glioblastoma is an immunosuppressive, fatal brain cancer that contains glioblastoma stem-like cells (GSCs). Oncolytic herpes simplex virus (oHSV) selectively replicates in cancer cells while inducing anti-tumor immunity. oHSV G47Delta expressing murine IL-12 (G47Delta-mIL12), antibodies to immune checkpoints (CTLA-4, PD-1, PD-L1), or dual combinations modestly extended survival of a mouse glioma model. However, the triple combination of anti-CTLA-4, anti-PD-1, and G47Delta-mIL12 cured most mice in two glioma models. This treatment was associated with macrophage influx and M1-like polarization, along with increased T effector to T regulatory cell ratios. Immune cell depletion studies demonstrated that CD4+ and CD8+ T cells as well as macrophages are required for synergistic curative activity. This combination should be translatable to the clinic and other immunosuppressive cancers. PMID- 28810149 TI - O2?- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. PMID- 28810150 TI - Occurrence of carbazoles in dust and air samples from different locations in Germany. AB - 9H-carbazole is generated from incomplete combustion of diverse fossil fuels and biomass, in tobacco smoke and from industrial processes, while halogenated carbazoles have natural and anthropogenic sources. We analyzed 9H-carbazole and 14 halogenated carbazoles in dust samples from 14 schools, 13 daycare centers, and 13 residences, as well as 5 indoor air samples from residences in Munich, Germany. Overall, we present first data of various carbazoles in different indoor environments without visible combustion sources. The median (95th percentile) values of the halogenated analytes mainly detected in the entire study group were 10.3ng/g (308ng/g) for 9H-carbazole, 13.3ng/g (735ng/g) for 3,6-dichloro-9H carbazole, 6.2ng/g (159ng/g) for 1,3,6-tribromo-9H-carbazole, and 1.2ng/g (21.1ng/g) for 2,7-dibromo-9H-carbazole. For most of the target analytes, the highest concentrations were observed in dust samples from schools, and the lowest were found in residences. In the air samples, all analytes were found only at low levels, with median values of 7.7pg/m3 for 9H-carbazole and 6.1pg/m3 for 2,3,6,7 tetrachloro-9H-carbazole. For 9H-carbazole, "typical" and "high" non-dietary intake of children through dust ingestion using median and 95th percentile values were calculated to be 0.03ng/kg b.w. and 1.1ng/kg b.w. daily, respectively. Due to limited toxicological information and exposure data for other relevant pathways (e.g., dietary intake), the risk assessment is inconclusive. Nevertheless, there are indications that 9H-carbazole has carcinogenic properties and that halogenated carbazoles have dioxin-like toxicities. Therefore, further research is essential. PMID- 28810151 TI - "Heavy metal" - What to do now: To use or not to use? PMID- 28810152 TI - Driving forces and impacts of food system nitrogen flows in China, 1990 to 2012. AB - Food nitrogen (N), which includes animal-food (AN) and plant-food N (PN), has been driven by population growth (PG), dietary changes associated with income growth (DC) and rural-urban migration (M) over the past three decades, and these changes combined with their N cost, have caused some effect on N use in China's food system. Although there is an increasing literature on food N and its environmental impacts in China, the relative magnitude of these driving forces are not well understood. Here we first quantify the differences in per capita AN and PN consumption in urban and rural areas and their impacts on N input to the food system during 1990-2012, and then quantify the relative contributions of DC, PG and M in the overall N change during this period. Our results show that a resident registered as living in city required 0.5kg more ANyr-1 and 0.5kg less PNyr-1 than one living in a rural area, in 2012. DC, PG and M accounted for 52%, 31% and 17% of the total AN increase, respectively. These three factors caused 46% of the increased N use for food production over the past two decades. Another 54% was mainly caused by the declining in N use efficiencies of the food system. Food-sourced N loss intensity in urban and rural areas were 502 and 162kgNhm-2 in 2012, a three-fold difference due to the increasing amount and a linear rural urban flow of N input, and inadequate N recovery via solid waste and wastewater treatment in cities. Our study highlights China is facing higher risks of environmental N pollution with urbanization, because of the high demand for AN and higher food-sourced N loss intensity in urban than in rural areas. PMID- 28810144 TI - Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. AB - We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFbetaR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine. PMID- 28810145 TI - Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma. AB - Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1-mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low- versus intermediate-risk clinical mutation subtypes. PMID- 28810153 TI - Evaluation of affibody molecule-based PNA-mediated radionuclide pretargeting: Development of an optimized conjugation protocol and 177Lu labeling. AB - INTRODUCTION: We have previously developed a pretargeting approach for affibody mediated cancer therapy based on PNA-PNA hybridization. In this article we have further developed this approach by optimizing the production of the primary agent, ZHER2:342-SR-HP1, and labeling the secondary agent, HP2, with the therapeutic radionuclide 177Lu. We also studied the biodistribution profile of 177Lu-HP2 in mice, and evaluated pretargeting with 177Lu-HP2 in vitro and in vivo. METHODS: The biodistribution profile of 177Lu-HP2 was evaluated in NMRI mice and compared to the previously studied 111In-HP2. Pretargeting using 177Lu HP2 was studied in vitro using the HER2-expressing cell lines BT-474 and SKOV-3, and in vivo in mice bearing SKOV-3 xenografts. RESULTS AND CONCLUSION: Using an optimized production protocol for ZHER2:342-SR-HP1 the ligation time was reduced from 15h to 30min, and the yield increased from 45% to 70%. 177Lu-labeled HP2 binds specifically in vitro to BT474 and SKOV-3 cells pre-treated with ZHER2:342 SR-HP1. 177Lu-HP2 was shown to have a more rapid blood clearance compared to 111In-HP2 in NMRI mice, and the measured radioactivity in blood was 0.22+/-0.1 and 0.68+/-0.07%ID/g for 177Lu- and 111In-HP2, respectively, at 1h p.i. In contrast, no significant difference in kidney uptake was observed (4.47+/-1.17 and 3.94+/-0.58%ID/g for 177Lu- and 111In-HP2, respectively, at 1h p.i.). Co injection with either Gelofusine or lysine significantly reduced the kidney uptake for 177Lu-HP2 (1.0+/-0.1 and 1.6+/-0.2, respectively, vs. 2.97+/-0.87%ID/g in controls at 4h p.i.). 177Lu-HP2 accumulated in SKOV-3 xenografts in BALB/C nu/nu mice when administered after injection of ZHER2:342-SR-HP1. Without pre injection of ZHER2:342-SR-HP1, the uptake of 177Lu-HP2 was about 90-fold lower in tumor (0.23+/-0.08 vs. 20.7+/-3.5%ID/g). The tumor-to-kidney radioactivity accumulation ratio was almost 5-fold higher in the group of mice pre-injected with ZHER2:342-SR-HP1. In conclusion, 177Lu-HP2 was shown to be a promising secondary agent for affibody-mediated tumor pretargeting in vivo. PMID- 28810154 TI - Synthesis and evaluation of a 99mTc-labeled chemokine receptor antagonist peptide for imaging of chemokine receptor expressing tumors. AB - OBJECTIVE: The chemokine receptor CXCR4 is highly expressed in tumor cells and plays an important role in tumor metastasis. In the present study, we report on the evaluation of a new radiopharmaceutical peptide for its potential to visualization for CXCR4-expressing tumors in vivo. METHODS: A CXCR4 antagonist analogue was synthesized using a standard Fmoc solid phase strategy and labeled with 99mTc via HYNIC and EDDA/tricine as coligands. In addition, stability in human serum, receptor binding internalization, in vivo tumor uptake, and tissue biodistribution were evaluated. Labeling procedure has been accomplished at 100 degrees C. RTLC and HPLC analysis methods have been used to confirm the procedure. The receptor binding internalization rate studied using B16-F10 melanoma tumor cells. C57BL/6 mice bearing B16-F10 tumor were used for radiopeptide biodistribution studies. RESULTS: Labeling yield of >95% (n=3) was obtained corresponding to a specific activity of 123+/-60GBq/MUmol. Efficient stability in the presence of human serum was observed. The radioligand showed specific internalization (of total add) into B16-F10 cells (1.57+/-0.27% at 2h). In animal biodistribution study, the uptake in mouse tumor was 2.74+/-0.47%ID/g after 15min (percentage of injected dose per gram of tissue). CONCLUSION: Results of this study show that labeled peptide conjugate could be a potential candidate for diagnosis of malignant tumors. PMID- 28810155 TI - Gas bremsstrahlung shielding calculation for first optic enclosure of ILSF XPD beamline. AB - Gas bremsstrahlung is generated in high energy electron storage ring and accompanies the synchrotron radiation into the beamlines, where both strike the various components of the beamline. In this paper, radiation shielding calculations for secondary gas bremsstrahlung are performed for the First Optics Enclosure (FOE) of X-ray powder diffraction (XPD) beamline of the Iranian Light Source Facility. Dose equivalent rate (DER) calculations are accomplished using FLUKA Monte Carlo code. A comprehensive study of DER distribution at the back wall, sides and roof are given. PMID- 28810156 TI - More inflammation but less brain-derived neurotrophic factor in antisocial personality disorder. AB - Antisocial personality disorder (ASPD) is highly comorbid with substance use disorders (SUDs). We hypothesize that chronic neuroinflammation and the loss of neurotrophic factors prompts the pathogenesis of both disorders. We used ELISA to measure plasma levels of proinflammatory (tumor necrosis factor-alpha [TNF alpha], C-reactive protein [CRP]) and anti-inflammatory factors (transforming growth factor-beta1 [TGF-beta1] and interleukin-10 [IL-10]), and brain-derived neurotrophic factor (BDNF) in male patients with ASPD (n=74), SUDs (n=168), ASPD comorbid with SUDs (ASPD+SUDs) (n=438), and Healthy Controls (HCs) (n=81). A multivariate analysis of covariance (MANCOVA) controlled for possible confounders was used to compare cytokines and BDNF levels between groups. The results of MANCOVA adjusted for age showed a significant (p<0.001) main effect of diagnosis on inflammatory factors and BDNF expression in these groups. ASPD, SUDs, and ASPD+SUDs patients had significantly (p<0.001) higher TNF-alpha levels but lower TGF-beta1 and BDNF levels. SUDs and ASPD+SUDs patients had higher IL-10 levels than did ASPD patients and HCs. There was no difference in IL-10 levels between HCs and ASPD. Moreover, subgrouping SUDs and ASPD+/-SUDs into opioid use disorder (OUD) and other SUDs groups showed that the IL-10 levels were specifically higher in OUD and ASPD+/-OUD groups than other SUDs (P<=0.001). We conclude that uncontrolled inflammation and losing neurotrophic factors, with or without comorbid SUDs, underlies ASPD. IL-10 expression might be more specifically associated with OUD. PMID- 28810157 TI - Propagating the Haze? Community and professional perceptions of cannabis cultivation and the impacts of prohibition. AB - BACKGROUND: Recent decades have seen substantial changes in the UK cannabis landscape, including increased domestic production, the ascendancy of stronger strains (namely 'skunk') and the drug's reclassification under the 1971 Misuse of Drugs Act. Resultantly, cannabis retains significance in the consciousness, priorities and policy agendas of communities, drug services and criminal justice agencies. METHODS: This paper presents an empirical study, which examined both perceptions and impacts of cannabis cultivation and its control within a North West English borough. It draws on qualitative research with samples of professionals, practitioners, resident groups, cannabis users, cannabis users' families and cannabis cultivators themselves. FINDINGS: The findings suggest that cannabis cultivation was not a uniformly familiar concept to respondents, who had limited knowledge and experience of its production. Across all participant groups, the transmission of accurate information was lacking, with individuals instead drawing on the reductionist drug discourse (Taylor, 2016) to fill knowledge deficits. Consequently, some participants conflated cannabis cultivation with wider prohibitionist constructions of drug markets, resulting in the diffusion of misinformation and an amplification of anxieties. In contrast, other participants construed cultivation as making economic sense during austerity, justifying such tolerance through inverse adherence to the same narrow socio-cultural construction of drugs i.e. that cultivation carried comparatively less harms than real drug markets. Enforcement mechanisms also drew on generic prohibitionist conceptions, assuming cultivators to be unconstrained, autonomous actors in need of punishment; a belief which lacked nuanced understanding of the local terrain where vulnerable individuals cultivating under duress played a key role in the supply chain. CONCLUSION: The paper concludes with a call for the provision of accessible information/education; the need to challenge and reconceptualise the assumed autonomy and resultant punity directed at all cannabis cultivators; and a subsequent need to reassess established forms of legal (and increasingly social) enforcement. PMID- 28810158 TI - A typology of vaping: Identifying differing beliefs, motivations for use, identity and political interest amongst e-cigarette users. AB - BACKGROUND: The aim of this study was to identify and differentiate socially shared accounts of e-cigarette use (vaping) using Q-methodology, combining factor analysis with qualitative comments. METHODS: Seventy statements on e-cigarettes, drawn from media, academic and online discussions, were sorted by participants along a continuum of agreement/disagreement, commenting on strongly ranked items. Each participant thus created their own 'account' of their vaping. A by-person correlation matrix of the sorts was conducted, then factor analysed, to identify similar accounts (p<0.01). Fifty-five UK vapers participated by post, 55% male, mean age of 46, 84% only vaping/16% vaping and smoking, 95% vaping daily. RESULTS: Three accounts of e-cigarettes were identified. The first two were associated with having quit smoking; the third with ongoing tobacco smoking and vaping. In Factor One, 'Vaping as Pleasure', vaping was characterized as enjoyable, with long-term use envisaged and a medical model of vaping rejected. Factor One participants also held a strong vaping identity and were politically motivated to maintain the rights of adults to vape. In Factor Two, 'Vaping as Medical Treatment', vaping was understood as a pragmatic choice about how to medicate one's smoking addiction, with the aim being to treat and ultimately reduce nicotine dependence. In Factor Three, 'Ambivalent E-Cigarette Use', participants reported fewer benefits and harboured more negative beliefs about e cigarettes; they also strongly rejected a vaper identity, having no interest in online forums or being labelled a 'vaper' themselves. CONCLUSION: The UK e cigarette users in this sample were not a homogeneous group; differing in their beliefs, motivations for use, identity and political interest. In particular they diverged on whether they accepted a medicalized account of vaping and identified as a vaper. Public health messages targeted to one group of e-cigarette users may not resonate with others. PMID- 28810159 TI - Hair testing to assess both known and unknown use of drugs amongst ecstasy users in the electronic dance music scene. AB - BACKGROUND: Data on both known and unknown drug use in the electronic dance music (EDM) scene is important to inform prevention and harm reduction. While surveys are the most common method of querying drug use, additional biological data can help validate use and detect unknown/unintentional use of drugs such as new psychoactive substances (NPS). We sought to determine the extent of both known and unknown use of various substances in this high-risk scene. METHODS: We hair tested 90 self-reported past-year ecstasy/MDMA/Molly users attending EDM parties in New York City during the summer of 2016 using UHPLC-MS/MS. Results were compared to self-reported past-year use. RESULTS: Three quarters (74.4%) tested positive for MDMA, a third (33.3%) tested positive for an NPS, and 27.8% tested positive specifically for one or more synthetic cathinones (e.g., butylone, ethylone, pentylone, methylone, alpha-PVP). Half (51.1%) of participants tested positive for a drug not self-reported, with most testing positive for synthetic cathinones (72.0%), methamphetamine (69.0%), other NPS stimulants (e.g., 4-FA, 5/6-APB; 66.7%), or new dissociatives (e.g., methoxetamine, diphenidine; 60.0%). Attending parties every other week or more often, reporting higher-frequency ecstasy pill use, having tested one's ecstasy, and having found out one's ecstasy was adulterated, were risk factors for testing positive for synthetic cathinones and NPS in general. CONCLUSION: Hair testing appears to be a valuable addition to drug epidemiology studies. Many EDM party attendees-even those who test their ecstasy-are unknowingly using NPS and/or other drugs. Prevention information and harm reduction may help reduce unknown/unintentional use. PMID- 28810161 TI - Ethical considerations for forensic scientists participating in humanitarian action: A personal reflection. AB - Humanitarian Forensic Action is aimed at relieving suffering by comforting and informing the relatives of disaster victims. It is not a priority to report human rights abuses to the authorities. It is thereby different from forensic human rights work with an inquisitive way of demonstrating culpability. The following tasks are relevant. The forensic scientist as an interviewer of the next of kin and witnesses. Emphasizing independency in armed conflicts. Assisting in man-made and natural disasters Assisting in the prevention and of the spread of epidemics. PMID- 28810160 TI - Differences in prevalence, socio-behavioral correlates, and psychosocial distress between club drug and hard drug use in Taiwan: Results from the 2014 National Survey of Substance Use. AB - BACKGROUND: This study examined variation between users of 'club' and 'hard' drugs in Taiwan in terms of prevalence of use and demographics and psychosocial characteristics. METHODS: Data were derived from a survey of 17,837 Taiwanese civilians, aged 12-64 years, using stratified, multi-stage, random sampling. Participants completed a computer-assisted self-interview on tablet computers which covered use of legal substances, sedatives/hypnotics and prescription analgesics; use of illicit drugs/inhalants, risky sexual experiences; expectations of drugs; and psychological distress. FINDINGS: Approximately 1.29% of respondents reported ever using an illicit drug in their lifetime; prevalence estimates of club drugs (mainly ketamine, marijuana, and ecstasy) were slightly higher than hard drugs (mainly methamphetamine and heroin). Concurrent use of legal substances, particularly problematic use of alcohol and tobacco, as well as non-medical use of prescription drugs, were strong correlates of illicit drug use in general, with club drug use exhibiting an extremely strong association with alcohol use. Club drug users were demographically different from hard drug users, including in terms of their gender, age, and level of educational attainment. They were also more likely to be divorced or widowed, to report risky sexual partnerships and more depressive symptoms than hard drug users. CONCLUSIONS: Our findings indicate drug type specific distinct psychosocial characteristics, which may warrant further attention in the design of treatment and intervention programs. PMID- 28810163 TI - Decoding the architecture and origins of mechanisms for developmental polyphenism. AB - Developmental polyphenism affords a single genotype multiple solutions to match an organism to its environment. Because polyphenism is the extreme example of how development deviates from a linear genetic blueprint, it demands a genetic explanation for how environmental cues shunt development to hypothetically alternative modules. We highlight several recent advances that have begun to illuminate genetic mechanisms for polyphenism and how this recurring developmental novelty may arise. An emerging genetic knowledge of polyphenism is providing precise targets for testing hypotheses of how switch mechanisms are built-out of olfactory, nutrient-sensing, hormone-reception, and developmental and genetic buffering systems-to accommodate plasticity. Moreover, classic and new model systems are testing the genetic basis of polyphenism's proposed causal roles in evolutionary change. PMID- 28810162 TI - Standardized anthropological measurement of postcranial bones using three dimensional models in CAD software. AB - This study introduces a standardized protocol for conducting linear measurements of postcranial skeletal elements using three-dimensional (3D) models constructed from post-mortem computed tomography (PMCT) scans. Using femoral DICOM datasets, reference planes were generated and plane-to-plane measurements were conducted on 3D surface rendered models. Bicondylar length, epicondylar breadth, anterior posterior (AP) diameter, medial-lateral (ML) diameter and cortical area at the midshaft were measured by four observers to test the measurement error variance and observer agreement of the protocol (n=6). Intra-observer error resulted in a mean relative technical error of measurement (%TEM) of 0.11 and an intraclass correlation coefficient (ICC) of 0.999 (CI=0.998-1.000); inter-observer error resulted in a mean %TEM of 0.54 and ICC of 0.996 (CI=0.979-1.000) for bicondylar length. Epicondylar breadth, AP diameter, ML diameter and cortical area also yielded minimal error. Precision testing demonstrated that the approach is highly repeatable and is recommended for implementation in anthropological investigation and research. This study exploits the benefits of virtual anthropology, introducing an innovative, standardized alternative to dry bone osteometric measurements. PMID- 28810164 TI - Catalytic oxidation of soot on mesoporous ceria-based mixed oxides with cetyltrimethyl ammonium bromide (CTAB)-assisted synthesis. AB - Mesoporous ceria and transition metal-doped ceria (M0.1Ce0.9O2 (M=Mn, Fe, Co, Cu)) catalysts were synthesized via CTAB-assisted method. The physicochemical properties of the prepared catalysts were characterized by XRD, DLS analysis, SEM, BET, Raman, H2-TPR and in situ DRIFT techniques. The catalytic activity tests for soot oxidation were performed under tight contact of soot/catalyst mixtures in the presence of O2 and NO+O2, respectively. The obtained results show that mesoporous ceria-based solid solutions can be formed with large surface areas and small crystallite size. Transition metals doping enhances the oxygen vacancies and improves redox properties of the solids, resulting in the increased NO oxidation capacity and NOx adsorption capacity. The soot oxidation activity in the presence of O2 is enhanced by doping transition metal, which may be related to their high surface area, increased oxygen vacancies and improved redox properties. The soot combustion is accelerated by the NO2-assisted mechanism under NO+O2 atmosphere, facilitating an intimate contact between the soot and the catalyst. PMID- 28810166 TI - Humanized mouse models of latent HIV infection. AB - Antiretroviral therapy can efficiently control HIV viral replication, resulting in low viral loads and sustained CD4+ T cell counts in HIV-infected persons. However, fast viral rebound occurs in most infected persons when therapy is interrupted. The principal component of persistent infection is a latent but replication-competent HIV reservoir. The long half-life of this reservoir is a major barrier to cure, and its elimination is the target of important research efforts. Animal models that can recapitulate this aspect of human infection are needed to examine the HIV reservoir in tissues in vivo, and to test eradication strategies. In this review, we will summarize recent studies using humanized mouse models to examine different aspects of the viral reservoir. PMID- 28810165 TI - Human immune system mouse models of Ebola virus infection. AB - Human immune system (HIS) mice, immunodeficient mice engrafted with human cells (with or without donor-matched tissue), offer a unique opportunity to study pathogens that cause disease predominantly or exclusively in humans. Several HIS mouse models have recently been used to study Ebola virus (EBOV) infection and disease. The results of these studies are encouraging and support further development and use of these models in Ebola research. HIS mice provide a small animal model to study EBOV isolates, investigate early viral interactions with human immune cells, screen vaccines and therapeutics that modulate the immune system, and investigate sequelae in survivors. Here we review existing models, discuss their use in pathogenesis studies and therapeutic screening, and highlight considerations for study design and analysis. Finally, we point out caveats to current models, and recommend future efforts for modeling EBOV infection in HIS mice. PMID- 28810167 TI - Intimate partner violence as a subject of study during the training of nurses and midwives in Catalonia (Spain): A qualitative study. AB - While nurses and midwives are in a unique position to identify and help victims of IPV, since they are often their first point of contact in the healthcare system, they need appropriate training. This study sought to examine the presence of IPV-related contents and the depth to which they are addressed in the bachelor's degree in Nursing and in the Midwifery specialisation programme. The study also explored lecturers' motivations for including IPV in their subjects. The methodology employed was qualitative. In-depth interviews were conducted with 16 university lecturers who teach IPV contents in the Nursing degree and Midwifery specialisation programme. The study took place in Catalonia (Spain). The research shows that lecturers feel personally committed in the training for prevention and detection of IPV. The main teaching methodology is active, experiential and requires student activity. In all cases, the lecturers call for more time and spaces to be made available to carry out this training. It would be desirable for more time to be dedicated to nurses and midwives' university training in IPV. The topic should be approached with a more cross-disciplinary, systematised focus from all perspectives: health, psychological, social, ethical and legal. It is important that the training of teaching staff in IPV should be fostered and methodised. PMID- 28810168 TI - Plagiarism governance in nurse education; dispositions, dimensions and tensions. AB - The reality of managing plagiarism in nurse education is indicative of multilayered and cumulative governance processes, which exist to fit with the needs of both the higher education institution and that of the Professional Statutory and Regulatory Body. However, the relationship between these entities is diffuse, particularly when this involves major plagiarism by post-qualified learners. This study sought to explore the strategic governance of plagiarism in Scottish higher education institutions offering nurse education and its articulation with the professional requirements of nurse education. The design involved a retrospective quantitative documentary analysis of plagiarism policies within 11 Scottish higher education institutions and a national on-line survey involving nurse educators with an active teaching role (n = 187). The documentary analysis demonstrated deficits and variations in how Scottish higher education institutions communicated the dimensions of plagiarism, and its subsequent management. Statistically significant findings from the on-line survey provided a clear mandate for educational providers to make visible the connectivity between organisational and professional governance processes to support responsive and proportional approaches to managing plagiarism by nurse learners. Significant findings also confirmed role implications and responsibilities, which nurse educators in this study, viewed as primarily pedagogical but crucially remain professionally centric. PMID- 28810169 TI - Association of genetic polymorphisms with plasma TFPI level: Boon or curse for DVT patients - Study from India. AB - Low plasma TFPI levels have been associated with an increased risk of DVT; however its association with TFPI gene polymorphisms is controversial and not yet studied in India. The aim of our study was to analyze prevalence of TFPI gene polymorphisms, evaluate their effects on its plasma levels and determine its association with DVT. Plasma level and genetic polymorphisms (33T>C, 399C>T and 536C>T) of TFPI were screened in subjects (100 DVT patients and 100 controls). Mean TFPI level in patients was significantly lower than controls (Patients: 33.55+/-11.72ng/ml, Controls: 48.05+/-13.68ng/ml, p<0.001). DVT patients had significantly higher prevalence of 399C>T (p=0.001, ORa: 5.69, CI: 1.14-28.46) and lower prevalence of 33T>C polymorphism (p<0.001, ORa: 0.239, CI: 0.065 0.871). The wild type (TT genotype) of 33T>C and variant form (CT and TT genotype) of 399C>T polymorphism was significantly associated with low TFPI levels. TFPI 536C>T polymorphism was absent in all subjects. In conclusion, dual nature of TFPI gene polymorphisms were established in our association study; 33T>C being protective and 399C>T as an important risk factor in Indian DVT patients, probably mediated by alteration in TFPI levels. These findings may prove a vital role in risk stratification and treatment of DVT. PMID- 28810170 TI - The role of speed and incline in the spontaneous choice of technique in classical roller-skiing. AB - Cross-country skiers change technique depending on terrain (incline) and effort (work rate; speed at a particular incline or resistance). The literature is not unequivocal about the influence of incline or speed on the choice of technique, i.e., which of these act as a 'control parameter'. Identifying task related control parameters for spontaneous technique shifts assists elucidating which mechanisms are active for triggering technique transitions. The aim of this study was to investigate whether speed or incline acted as such control parameter for technique shifts during classic style roller skiing. In this study, we kept the exercise intensity constant while changing two potential control parameters (speed and incline). Thus, any effect of work rate was excluded. Eight male competitive cross-country skiers performed roller skiing on a treadmill while incline was altered from 3 to 11% and back to 3% each minute by 1% and speed changed accordingly to obtain a constant work rate. This protocol was performed at three submaximal work rates (170, 200, and 230W) to obtain various combinations of speed and incline. The athletes were free to choose their technique (double poling, double poling with kick and diagonal stride), which was identified using continuous phase analysis on the motion of the skis. Physiological response (heart rate, oxygen uptake) was recorded continuously. The incline seemed to affect choice of technique shift more than speed: the ANOVA for repeated measures on all work rates showed no significant effect of incline (p>0.2) and an effect for speed (p<0.001). No effect of protocol order (increasing versus decreasing incline) was found for transitions. The physiological response was lowest for conditions of steep incline-low speed and was affected by protocol order. Cycle rate was affected by incline only in the double poling technique. Possible mechanisms related to the triggering of technique transitions are discussed. PMID- 28810171 TI - Properties of intermodal transfer after dual visuo- and auditory-motor adaptation. AB - Previous work documented that sensorimotor adaptation transfers between sensory modalities: When subjects adapt with one arm to a visuomotor distortion while responding to visual targets, they also appear to be adapted when they are subsequently tested with auditory targets. Vice versa, when they adapt to an auditory-motor distortion while pointing to auditory targets, they appear to be adapted when they are subsequently tested with visual targets. Therefore, it was concluded that visuomotor as well as auditory-motor adaptation use the same adaptation mechanism. Furthermore, it has been proposed that sensory information from the trained modality is weighted larger than sensory information from an untrained one, because transfer between sensory modalities is incomplete. The present study tested these hypotheses for dual arm adaptation. One arm adapted to an auditory-motor distortion and the other either to an opposite directed auditory-motor or visuomotor distortion. We found that both arms adapted significantly. However, compared to reference data on single arm adaptation, adaptation in the dominant arm was reduced indicating interference from the non dominant to the dominant arm. We further found that arm-specific aftereffects of adaptation, which reflect recalibration of sensorimotor transformation rules, were stronger or equally strong when targets were presented in the previously adapted compared to the non-adapted sensory modality, even when one arm adapted visually and the other auditorily. The findings are discussed with respect to a recently published schematic model on sensorimotor adaptation. PMID- 28810172 TI - Changes in interlimb coordination during walking and grasping task in older adult fallers and non-fallers. AB - The aim of this study was to investigate interlimb coordination in young and older adults with and without a history of falls during the combined task of walking and prehension with different levels of manual task difficulty. Participants walked on a pathway and grasped a dowel. A vector coding technique evaluated coordination patterns. The coordination pattern was not affected by the difficulty level of the manual task. Older adults seemed to prioritize the movement of the right shoulder to grasp the dowel and then 'froze' the movement of the other joint (left shoulder) not directly involved in the grasping task. The preference to pick up the dowel in the double support phase and the increase in right shoulder phase made by older adults with a history of falls suggests an even greater decoupling between walking and prehension. PMID- 28810173 TI - Effect of haptic sensory input through a fluttering cloth on tandem gait performance. AB - This study investigated the effects of haptic sensory input through a fluttering cloth on balance control during locomotion. Twenty-one healthy men performed a tandem gait test for 4m with their eyes closed under two different conditions: (1) wearing only half or short tights (HT-condition), or (2) wearing a fluttering cloth that was wrapped around the waist and extended to the lower leg (CLOTH condition). Participants performed two trials with a 3-min rest period. The first trial involved the HT-condition, whereas the second trial involved either the CLOTH-condition (n=11), or the HT-condition again (n=10). The gait time and double support phase were significantly lower in the CLOTH-condition than in the HT-condition, and the relationship between the change in these two parameters was significant (r=0.74, P<0.01). Further, the relationship between the change in gait time and subjective walking sensation (evaluated through a visual-analogue scale) was significant in the CLOTH-condition (r=0.82, P<0.01). Therefore, if the participant demonstrated improved gait performance while wearing a fluttering cloth, it was accompanied by an improvement in subjective walking sensation. These results suggest that wearing a fluttering cloth can provide a haptic sensory cue to enhance the individuals' perception of their body orientation, which contributes to better balance control during locomotion. Therefore, locomotive ability may improve depending on the shape of the garment. PMID- 28810174 TI - para-Sulfonatocalix[4]arene and polyamidoamine dendrimer nanocomplexes as delivery vehicles for a novel platinum anticancer agent. AB - Novel para-sulfonatocalix[4]arene (sCX[4]) and polyamidoamine (PAMAM) dendrimer nanocomplexes were evaluated as delivery vehicles for the platinum anticancer agent [(1,10-phenanthroline)(1S,2S-diaminocyclohexane)platinum(II)] chloride (PHENSS). Different ratios of sCX[4] to PHENSS were tested for their compatibility, with a ratio of 6:1 sCX[4]:PHENSS having the best solubility. The loading of sCX[4], and sCX[4]-bound PHENSS, onto three different generations of PAMAM dendrimers (G3.0-5.0) was examined using UV-visible spectrophotometry. The quantity of sCX[4] bound was found to increase exponentially with dendrimer size: G3, 15 sCX[4] molecules per dendrimer; G4, 37; and G5, 78. Similarly, the loading of sCX[4]-bound PHENSS also increased with increasing dendrimer size: G3, 7 PHENSS molecules per dendrimer; G4, 14; and G5, 28.5. The loading of sCX[4]-bound PHENSS molecules is significantly lower when compared with that of sCX[4], which indicates that less than half of the binding sites were occupied (45, 44, and 44%, respectively). By 1H NMR and UV-vis analysis, the nanocomplex was found to be stable in NaCl solutions at concentrations up to 150mM. While PHENSS is more active in vitro than cisplatin against the human breast cancer cell line, MCF-7, delivery of PHENSS using the sCX[4]-dendrimer nanocomplexes, regardless of dendrimer generation, had little effect on PHENSS cytotoxicity. The results of this study may have application in the delivery of a variety of small molecule metal-based drugs for which chemical conjugation to a nanoparticle is undesired or not feasible. PMID- 28810175 TI - Time trends for prostate cancer mortality in Brazil and its geographic regions: An age-period-cohort analysis. AB - BACKGROUND: In the 1980s, an increase in mortality rates for prostate cancer was observed in North America and developed European countries. In the 1990s, however, mortality rates decreased for these countries, an outcome related to early detection of the disease. Conversely, an upward trend in mortality rates was observed in Brazil. This study describe the trends in mortality for prostate cancer in Brazil and geographic regions (North, Northeast, South, Southeast, and Central-West) between 1980 until 2014 and analyze the influence of age, period, and cohort effects on mortality rates. METHODS: This time-series study used data from the Mortality Information System (SIM) and population data from Brazilian Institute for Geography and Statistics (IBGE). The effects on mortality rates were examined using age-period-cohort (APC) models. RESULTS: Crude and standardized mortality rates showed an upward trend for Brazil and its regions more than 2-fold the last 30 years. Age effects showed an increased risk of death in all regions. Period effects showed a higher risk of death in the finals periods for the North and Northeast. Cohort effects showed risk of death was higher for younger than older generations in Brazil and regions, mainly Northeast (RRAdjusted=3.12, 95% CI 1.29-1.41; RRAdjusted=0.28, 95% CI 0.26-0.30, respectively). CONCLUSION: The increase in prostate cancer mortality rates in Brazil and its regions was mainly due to population aging. The differences in mortality rates and APC effects between regions are related to demographic differences and access of health services across the country. PMID- 28810176 TI - Influence of gender on inpatient treatment for bipolar disorder: An analysis of 60,607 hospitalisations. AB - BACKGROUND: The influence of gender on inpatient treatment patterns in bipolar patients is unclear. The aim of this study is to examine whether differences in length of stay and frequency of inpatient episodes, according to ICD-10 bipolar disorder (BD)-subgroups, exist between men and women. METHODS: All episodes of a manic (F31.0-2), depressive (F31.3-5) or mixed (F31.6) subtype of BD during an inpatient stay in an Austrian hospital in the period of 2001-2014 were included in this study. Data on episodes was provided by the national statistics agency. Weekly admission rates per 100,000 people were calculated by directly age standardized rates. RESULTS: The database comprised 60,607 admissions (35.8% men). The number of inpatient episodes was significantly higher (p < 0.001) in women in all BD subgroups. Average length of stay in manic (p < 0.001) and depressive (p < 0.001) episodes was shorter in women compared to men. No difference could be found for mixed episodes. LIMITATIONS: Only aggregated patient data and no single case histories were available for this study. CONCLUSIONS: The current study reveals relevant gender differences regarding inpatient treatment patterns, as women were overrepresented in all BD-subgroups. Despite equal life time prevalence, severe mood episodes lead more often to hospitalisations in women. There is a high necessity to further research the underlying causes of these findings. PMID- 28810178 TI - Distance dependent fluorescence quenching and enhancement of gold nanoclusters by gold nanoparticles. AB - The interaction between fluorescent gold nanoclusters (AuNCs) and gold nanoparticles (AuNPs) has been investigated. It was observed that the fluorescence of AuNCs was remarkably quenched when direct contact with AuNPs. The fluorescence quenching of AuNCs by AuNPs was dynamic quenching and exhibited size dependent property. A larger size of AuNPs displayed a stronger quenching effect and gave a larger quenching constant. When a silica spacer shell was introduced between AuNPs and AuNCs, a fluorescence enhancement of AuNCs by Au@SiO2 NPs was observed. The fluorescence enhancement was strongly dependent on the separation distance between the AuNPs and the AuNCs. A maximal enhancement of 3.72 times was observed when Au@SiO2 NPs have a silica shell thickness of 12nm. This nanocomposite consisting of relatively nontoxic AuNPs and AuNCs may have a potential application in developing novel fluorescent sensor. PMID- 28810177 TI - Use of atypical antipsychotics in pregnancy and maternal gestational diabetes. AB - BACKGROUND: Second generation antipsychotic medications (SGAs) are widely used by reproductive-age women to treat a number of psychiatric illnesses. Some SGAs have been associated with an increased risk of developing diabetes, although information regarding their diabetogenic effect in pregnant women is scarce. OBJECTIVE: To evaluate the risk of gestational diabetes (GDM) among women treated with SGA. METHOD: The Massachusetts General Hospital (MGH) National Pregnancy Registry for Atypical Antipsychotics (NPRAA) collects data on drug use, pregnancy outcomes, and other characteristics from pregnant women, ages 18-45 years, using 3 phone interviews conducted at (1) enrollment during pregnancy, (2) 7 months' gestation, and (3) 2-3 months postpartum. Information on GDM was abstracted from obstetric and delivery medical records. The study population was restricted to women without pre-gestational diabetes. Pregnancies exposed to SGAs during the first trimester were compared with a reference group of women with psychiatric conditions but not treated with SGAs during pregnancy. Generalized linear models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for GDM. RESULTS: Of 303 women exposed to SGAs, 33 (10.9%) had GDM compared to 16 (10.7%) in the 149 non-exposed women. The crude OR of GDM for SGA was 1.02 (95% CI, 0.54-1.91). After adjustment for maternal age, race, marital status, employment status, level of education, smoking, and primary psychiatric diagnosis, the OR moved to 0.79 (0.40-1.56). CONCLUSIONS: Findings did not suggest an increased risk of GDM associated with exposure to SGAs during pregnancy in women who had used SGA before pregnancy without developing diabetes, compared to psychiatrically ill women who were not exposed to SGA. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01246765. PMID- 28810179 TI - Utility of ultrasound assisted-cloud point extraction and spectophotometry as a preconcentration and determination tool for the sensitive quantification of mercury species in fish samples. AB - The current study reports, for the first time, the development of a new analytical method employing ultrasound assisted-cloud point extraction (UA-CPE) for the extraction of CH3Hg+ and Hg2+ species from fish samples. Detection and quantification of mercury species were performed at 550nm by spectrophotometry. The analytical variables affecting complex formation and extraction efficiency were extensively evaluated and optimized by univariate method. Due to behave 14 fold more sensitive and selective of thiophene 2,5-dicarboxylic acid (H2TDC) to Hg2+ ions than CH3Hg+ in presence of mixed surfactant, Tween 20 and SDS at pH5.0, the amounts of free Hg2+ and total Hg were spectrophotometrically established at 550nm by monitoring Hg2+ in the pretreated- and extracted-fish samples in ultrasonic bath to speed up extraction using diluted acid mixture (1:1:1, v/v, 4molL-1 HNO3, 4molL-1 HCl, and 0.5molL-1 H2O2), before and after pre-oxidation with permanganate in acidic media. The amount of CH3Hg+ was calculated from difference between total Hg and Hg2+ amounts. The UA-CPE method showed to be suitable for the extraction and determination of mercury species in certified reference materials. The results were in a good agreement (with Student's t-test at 95% confidence limit) with the certified values, and the relative standard deviation was lower than 3.2%. The limits of detection have been 0.27 and 1.20MUgL-1, for Hg2+ from aqueous calibration solutions and matrix-matched calibration solutions spiked before digestion, respectively, while it is 2.43MUgL 1 for CH3Hg+ from matrix-matched calibration solutions. A significant matrix effect was not observed from comparison of slopes of both calibration curves, so as to represent the sample matrix. The method was applied to fish samples for speciation analysis of Hg2+ and CH3Hg+. In terms of speciation, while total Hg is detected in range of 2.42-32.08MUgkg-1, the distribution of mercury in fish were in range of 0.7-11.06MUgkg-1 for CH3Hg+ and in range of 1.72-24.56MUgkg-1 for Hg2+. PMID- 28810180 TI - Classification and quantitation of milk powder by near-infrared spectroscopy and mutual information-based variable selection and partial least squares. AB - Milk is among the most popular nutrient source worldwide, which is of great interest due to its beneficial medicinal properties. The feasibility of the classification of milk powder samples with respect to their brands and the determination of protein concentration is investigated by NIR spectroscopy along with chemometrics. Two datasets were prepared for experiment. One contains 179 samples of four brands for classification and the other contains 30 samples for quantitative analysis. Principal component analysis (PCA) was used for exploratory analysis. Based on an effective model-independent variable selection method, i.e., minimal-redundancy maximal-relevance (MRMR), only 18 variables were selected to construct a partial least-square discriminant analysis (PLS-DA) model. On the test set, the PLS-DA model based on the selected variable set was compared with the full-spectrum PLS-DA model, both of which achieved 100% accuracy. In quantitative analysis, the partial least-square regression (PLSR) model constructed by the selected subset of 260 variables outperforms significantly the full-spectrum model. It seems that the combination of NIR spectroscopy, MRMR and PLS-DA or PLSR is a powerful tool for classifying different brands of milk and determining the protein content. PMID- 28810181 TI - Screening performance for callosal agenesis in prenatal life. Single center study. AB - OBJECTIVES: 1) To analyze screening performance of second trimester scan for ACC, 2) to evaluate the agreement between ultrasound and MRI and 3) to compare prenatal and postnatal diagnosis. METHODS: It was a prospective observational study. All patients with fetuses suspected of ACC were referred to prenatal MRI (pMRI). RESULTS: One subject was not confirmed by pMRI with the diagnosis of ACC. This case demonstrated partial ACC in neonatal MRI (nMRI). CONCLUSION: Sensitivity of second trimester scan for callosal agenesis of 73% and specificity of 99%. Prenatal MRI and US has similar amount of misdiagnoses. PMID- 28810182 TI - Selenium increases hepatic DNA methylation and modulates one-carbon metabolism in the liver of mice. AB - The average intake of the essential trace element selenium (Se) is below the recommendation in most European countries, possibly causing sub-optimal expression of selenoproteins. It is still unclear how a suboptimal Se status may affect health. To mimic this situation, mice were fed one of three physiologically relevant amounts of Se. We focused on the liver, the organ most sensitive to changes in the Se supply indicated by hepatic glutathione peroxidase activity. In addition, liver is the main organ for synthesis of methyl groups and glutathione via one-carbon metabolism. Accordingly, the impact of Se on global DNA methylation, methylation capacity, and gene expression was assessed. We observed higher global DNA methylation indicated by LINE1 methylation, and an increase of the methylation potential as indicated by higher S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) ratio and by elevated mRNA expression of serine hydroxymethyltransferase in both or either of the Se groups. Furthermore, increasing the Se supply resulted in higher plasma concentrations of triglycerides. Hepatic expression of glycolytic and lipogenic genes revealed consistent Se-dependent up-regulation of glucokinase. The sterol regulatory element-binding transcription factor 1 (Srebf1) was also up-regulated by Se. Both effects were confirmed in primary hepatocytes. In contrast to the overall Se dependent increase of methylation capacity, the up-regulation of Srebf1 expression was paralleled by reduced local methylation of a specific CpG site within the Srebf1 gene. Thus, we provided evidence that Se-dependent effects on lipogenesis involve epigenetic mechanisms. PMID- 28810183 TI - Computer modeling of drug delivery in the anterior human eye after subconjunctival and episcleral implantation. AB - Recently, subconjunctival and episcleral implants have been proposed in the treatment of anterior eye diseases. In order to improve the delivery efficacy, it is important to understand the transport process of the implanted drugs. A 3D computational model, which includes heat transfer, aqueous humor (AH) flow, as well as diffusive and convective transport of the drug concentration, is developed to study the temporal and spatial evolution of the drug in the anterior segment of a human eye after subconjunctival and episcleral implantation, with a focus on drug delivery to three targets: iris, lens, and trabecular meshwork (TM). The release rate of the implanted drug is based on experimental data and effects of implantation location, eye orientation, and AH flow are investigated. Our numerical results indicate that subconjunctival implantation is more effective than episcleral implantation for drug delivery to all the three targets, and the accumulative amount of drug delivered to the three targets is larger in the horizontally-facing eye than in the up-facing eye. Implantation at the 12 o'clock circumferential position is the most effective for drug delivery to iris and lens, and the 3 o'clock position is the most effective for drug delivery to TM. This study may help to better understand the delivery process of implanted drugs in the anterior human eye, and improve delivery efficacy for clinical treatment of anterior eye diseases. PMID- 28810184 TI - Design and evaluation of a parametric model for cardiac sounds. AB - Heart sound analysis plays an important role in the auscultative diagnosis process to detect the presence of cardiovascular diseases. In this paper we propose a novel parametric heart sound model that accurately represents normal and pathological cardiac audio signals, also known as phonocardiograms (PCG). The proposed model considers that the PCG signal is formed by the sum of two parts: one of them is deterministic and the other one is stochastic. The first part contains most of the acoustic energy. This part is modeled by the Matching Pursuit (MP) algorithm, which performs an analysis-synthesis procedure to represent the PCG signal as a linear combination of elementary waveforms. The second part, also called residual, is obtained after subtracting the deterministic signal from the original heart sound recording and can be accurately represented as an autoregressive process using the Linear Predictive Coding (LPC) technique. We evaluate the proposed heart sound model by performing subjective and objective tests using signals corresponding to different pathological cardiac sounds. The results of the objective evaluation show an average Percentage of Root-Mean-Square Difference of approximately 5% between the original heart sound and the reconstructed signal. For the subjective test we conducted a formal methodology for perceptual evaluation of audio quality with the assistance of medical experts. Statistical results of the subjective evaluation show that our model provides a highly accurate approximation of real heart sound signals. We are not aware of any previous heart sound model rigorously evaluated as our proposal. PMID- 28810185 TI - Outcome of treatment changes in patients with drug-resistant chronic epilepsy: A tertiary center experience. AB - BACKGROUND: Previous studies suggest that changing patients' anti-epileptic drug regimen can reduce the frequency of seizures. The approval of new anti-epileptic drugs with different modes of action during the last decades has provided multiple options for the treatment of epilepsy, although the efficacy of these new drugs is controversial. We aimed to determine the effects of adding or changing to a previously untried anti-epileptic drug, including recently approved drugs, on the frequency of seizures in patients with drug-resistant epilepsy. METHODS: We analyzed treatment changes in drug-resistant patients at our outpatient clinic between 2010 and 2015. We classified patients' frequency of seizures after changes as freedom from seizures, >=50% reduction, <50% reduction, no change, increase in seizures <50% or increase in seizures >=50%. RESULTS: We analyzed 189 drug changes in 144 consecutive drug-resistant patients followed up for at least 6 months after the change; 138 changes involved administering newly marketed drugs: lacosamide (n=65), perampanel (n=30), eslicarbazepine (n=29), and retigabine (n=14). Changes resulted in freedom from seizures in 20 (13.9%) patients and in >=50% decrease in frequency in 55 (38.2%). The drugs most commonly associated with significant improvement (freedom from seizures or >=50% reduction) were lacosamide (39.3%), clobazam (11.2%), and levetiracetam (11.2%). CONCLUSIONS: In patients with drug-resistant epilepsy, sequential changes increase the possibility of seizure control, and newer anti-epileptic drugs offer additional options for effective changes. Best combinations must be chosen taking into account drug, epilepsy and patient features. PMID- 28810186 TI - The efficacy of lapatinib and capecitabine in HER-2 positive breast cancer with brain metastases: A systematic review and pooled analysis. AB - INTRODUCTION: Breast cancer (BC) with HER-2/neu overexpression or amplification (HER-2+) is associated with a higher prevalence of brain metastases (BMs) when compared to other subtypes. Among approved drugs for HER-2+ BC, lapatinib (L) is associated with single agent activity toward BMs. We conducted a systematic review to determine the efficacy of L, singly or in combination with capecitabine (C), as a treatment for HER-2+ BMs. MATERIAL AND METHODS: We searched PubMed, EMBASE, The Cochrane Library, SCOPUS, Web of Science, ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform (ICTRP), and the European Union Clinical Trials Register for studies reporting data on L, singly or in combination with C, for the treatment of HER-2+ BC with BMs. Primary end-points were overall response rate (ORR) and disease control rate (DCR); these were pooled to provide an aggregate value. Progression-free survival (PFS) and overall survival (OS) were secondary end-points. Data were pooled using number of events/number of evaluable patients, according to a fixed or random effect model. RESULTS: Overall, 12 studies were included in the present meta-analysis, for a total of 799 patients with BMs. The pooled overall response rate (ORR) was 21.4% (95% CI 11.7-35.9). After exclusion of patients that received L alone, ORR reached 29.2% (95% CI 18.5-42.7). The pooled median PFS and OS were 4.1 (95% CI 3.1-6.7) and 11.2 (95% CI 8.9-14.1) months, respectively. CONCLUSIONS: Due to its activity on BMs, the L + C combination may be considered for HER-2+ BC that has progressed in the brain, when local therapy has been performed or failed and re irradiation is not feasible. PMID- 28810187 TI - Histochemical and immunohistochemical examination of odontoblasts (petroblasts) in petrodentine formation of lungfish. AB - OBJECTIVE: Petrodentine, the core of the lungfish tooth plate, is a well mineralized tissue similar to mammalian enamel and analogous to enameloid in fish teeth. Petrodentine is formed solely by petroblasts, which are specialized odontoblasts, whereas enameloid is a composite tissue produced by both odontoblasts and dental epithelial cells. To clarify the details of petrodentine formation, petroblasts were investigated using histochemical and immunohistochemical techniques. METHODS: Extant lungfish (Lepidosiren paradoxa) were used in this study. Tooth plates during the stage of petrodentine formation were observed by means of histochemistry and immunohistochemistry. Commercial kits were used to detect enzyme activity. Correlative sections were immunostained using antibodies against selected peptides. Routine staining such as periodic acid-Schiff (PAS) reaction to identify glycogen and Elastica van Gieson staining for the detection of elastic fibers in histological sections were performed. In addition, conventional transmission electron microscopy was used for observing the fine structure. RESULTS: Petroblasts showed marked acid and alkaline phosphatase activities, and positive immunoreactivities against anti-nestin, anti V-ATPase, and anti-Ca2+-ATPase, during the maturation stage, but in the matrix formation stage, reactions were much weaker than that of the maturation stage. During the maturation stage, petroblasts showed intense PAS reactivity, and glycogen particles were observed in petroblasts by transmission electron microscopy. Glucose transporter 1-immunoreactivity was observed in petroblasts in the matrix formation stage and the initial to mid part of the maturation stage. CONCLUSIONS: The results in this study suggested that petroblasts have two functional stages, matrix formation and maturation, and glycogen plays an important role in the modulation of petroblasts. PMID- 28810188 TI - Novel tacrine derivatives exhibiting improved acetylcholinesterase inhibition: Design, synthesis and biological evaluation. AB - A novel series of twenty four tacrine derivatives were designed and synthesised. Among these, thirteen were taken for the acetylcholinesterase (AChE) inhibition studies. Three compounds such as 4c, 6c and 6f were found to possess significant AChE inhibitory properties with IC50 values 12.97 +/- 0.47 nM, 5.17 +/- 0.24 nM and 7.14 +/- 0.78 nM respectively. In silico docking studies revealed that these compounds can bind strongly in the active site of the enzyme and prevent enzyme substrate interactions. On binding, the substituted groups were oriented either towards the peripheral anionic site (PAS) (Pocket A) or towards a hydrophobic cavity (pocket B) located near the active site. The cytotoxicity and hepatotoxicity of the compounds were tested using HEK-293 and HepG2 cell lines respectively. The compound 4c did not show any significant decrease in the cell viability even at a concentration of 300 MUM indicating that its cytotoxicity and hepatotoxicity are significantly lesser compared to tacrine, due to the chemical modification. Based on the available results, it can be suggested that the compound 4c might be a potential drug lead compound with AChE inhibitory activity. However, further pharmacokinetic studies are necessary to comment on the efficacy of the compound as a drug for AD. PMID- 28810189 TI - Hydroxy-substituted trans-cinnamoyl derivatives as multifunctional tools in the context of Alzheimer's disease. AB - Alzheimer's disease (AD) is a multifactorial pathology that requires multifaceted agents able to address its peculiar nature. In recent years, a plethora of proteins and biochemical pathways has been proposed as possible targets to counteract neurotoxicity. Although the complex scenario is not completely elucidated, close relationships are emerging among some of these actors. In particular, increasing evidence has shown that aggregation of amyloid beta (Abeta), glycogen synthase kinase 3beta (GSK-3beta) and oxidative stress are strictly interconnected and their concomitant modulation may have a positive and synergic effect in contrasting AD-related impairments. We designed compound 3 which demonstrated the ability to inhibit both GSK-3beta (IC50 = 24.36 +/- 0.01 MUM) and Abeta42 self-aggregation (IC50 = 9.0 +/- 1.4 MUM), to chelate copper (II) and to act as exceptionally strong radical scavenger (kinh = 6.8 +/- 0.5 . 105 M-1s-1) even in phosphate buffer at pH 7.4 (kinh = 3.2 +/- 0.5 . 105 M-1s-1). Importantly, compound 3 showed high-predicted blood-brain barrier permeability, did not exert any significant cytotoxic effects in immature cortical neurons up to 50 MUM and showed neuroprotective properties at micromolar concentration against toxic insult induced by glutamate. PMID- 28810190 TI - Design, synthesis and biological evaluation of novel 2-methoxyestradiol analogs as dual selective estrogen receptor modulators (SERMs) and antiangiogenic agents. AB - 2-methoxyestradiol is a novel agent showing both anti-angiogenic and vascular disrupting properties. In this study, a series of 11alpha-substituted 2 methoxyestradiol analogs have been designed and synthesized targeting dual ERalpha and microtubulin. Biological evaluation was performed on their anti proliferative activities against 5 different cell lines. The results indicated that most compounds exhibited good activities, in which compound 24c and 30c showed the best activity with low micromolar IC50 (2.73 MUM -7.75 MUM) in all cell lines. The investigation of ER affinity showed that the majority of the compounds displayed good activity at the concentration of 50 MUM. In further mechanism study, it was observed that 24c and 30c could induce G2/M cell cycle arrest as well as significant anti-estrogenic activity. In CAM assay, compound 24c and 30c presented significantly anti-angiogenesis activity comparable with 2 methoxyestradiol. Overall, based on biological activities data, 24c and 30c can be identified as a potential lead molecule which might be of therapeutic importance for cancer treatment. PMID- 28810191 TI - Structure-function studies of BPP-BrachyNH2 and synthetic analogues thereof with Angiotensin I-Converting Enzyme. AB - The vasoactive proline-rich oligopeptide termed BPP-BrachyNH2 (H-WPPPKVSP-NH2) induces in vitro inhibitory activity of angiotensin I-converting enzyme (ACE) in rat blood serum. In the present study, the removal of N-terminal tryptophan or C terminal proline from BPP-BrachyNH2 was investigated in order to predict which structural components are important or required for interaction with ACE. Furthermore, the toxicological profile was assessed by in silico prediction and in vitro MTT assay. Two BPP-BrachyNH2 analogues (des-Trp1-BPP-BrachyNH2 and des Pro8-BPP-BrachyNH2) were synthesized, and in vitro and in silico ACE inhibitory activity and toxicological profile were assessed. The des-Trp1-BPP-BrachyNH2 and des-Pro8-BPP-BrachyNH2 were respectively 3.2- and 29.5-fold less active than the BPP-BrachyNH2-induced ACE inhibitory activity. Molecular Dynamic and Molecular Mechanics Poisson-Boltzmann Surface Area simulations (MM-PBSA) demonstrated that the ACE/BBP-BrachyNH2 complex showed lower binding and van der Wall energies than the ACE/des-Pro8-BPP-BrachyNH2 complex, therefore having better stability. The removal of the N-terminal tryptophan increased the in silico predicted toxicological effects and cytotoxicity when compared with BPP-BrachyNH2 or des Pro8-BPP-BrachyNH2. Otherwise, des-Pro8-BPP-BrachyNH2 was 190-fold less cytotoxic than BPP-BrachyNH2. Thus, the removal of C-terminal proline residue was able to markedly decrease both the BPP-BrachyNH2-induced ACE inhibitory and cytotoxic effects assessed by in vitro and in silico approaches. In conclusion, the aminoacid sequence of BPP-BrachyNH2 is essential for its ACE inhibitory activity and associated with an acceptable toxicological profile. The perspective of the interactions of BPP-BrachyNH2 with ACE found in the present study can be used for development of drugs with differential therapeutic profile than current ACE inhibitors. PMID- 28810192 TI - Vaginal and Laparoscopic hysterectomy as an outpatient procedure: A systematic review. AB - OBJECTIVES: Laparoscopic and vaginal hysterectomies are common gynaecological procedures. Same-day discharge is usual care in various gynaecological procedures like laparoscopic sterilisation and laparoscopic oophorectomies. In major procedures like vaginal or laparoscopic hysterectomy patients are usually admitted overnight. We systematically reviewed the literature to identify complications, risk factors for (re)admittance, financial consequences and patient satisfaction of same-day discharge after a vaginal or laparoscopic hysterectomy. METHODS: We systematically searched PubMed, UptoDate, Embase, Cochrane and CINAHL database from inception until July 16th 2016. We selected randomized controlled trials, prospective and retrospective cohort studies assessing the safety and feasibility of same-day discharge after vaginal or laparoscopic hysterectomy. The outcome parameters that were assessed were admission rate, re-admission rate, minor and major complications, patient satisfaction and financial consequences. RESULTS: 27 articles were included in the systematic review. All studies provided data about the admission rate and therefore failure of same-day discharge. Eleven prospective studies were included which compromised a total of 2391 hysterectomies. The percentage of overnight admissions was median 9.3% [0-25%]. Eight retrospective studies, which screened their patients before undergoing an outpatient hysterectomy, showed in 1500 subjects a mean admission rate of 10% [4,4-64%]. Four retrospective studies, which considered a large total cohort of 142,799 hysterectomies had a mean admission rate of 59,7% [48-79%]. The overall re-admission rate was low, varying from 0.73-4.0%. Minor complications were reported in respectively 4,3% and 7,3% in prospective respectively retrospective trials. Major complications were described in 0.7%-3.6% of all cases. Generally high satisfaction rates were reported in the observational trials. CONCLUSIONS: Same-day discharge after laparoscopic and vaginal hysterectomy seems feasible in a pre-selected, healthy population. It is associated with a low (re)admission rate, low complication rate and a reduction in hospital costs. Patient satisfaction seems generally high. PMID- 28810193 TI - Kinetics and mechanism of antibacterial activity and cytotoxicity of Ag-RGO nanocomposite. AB - Nowadays, nanomaterials with remarkable antibacterial activity and low cytotoxicity attract much interest in research. By considering the antibacterial activity of Ag and graphene oxide (GO), the Ag-RGO nanocomposite was prepared by a one-pot and facile technique and it was used to evaluate its antibacterial activity and cytotoxicity against Escherichia coli and glioblastoma cancer cells (U87MG), respectively. The antibacterial activity was studied by micro-dilution and colony counting methods to investigate cell viability. The viability of glioblastoma cells was determined using MTT assay. Since MIC and MBC values of the nanocomposite are 20 and 40MUg/mL, respectively, it acts as a bactericidal agent. The antibacterial properties of nanocomposite are time and concentration dependent. The kinetics and mechanism of the antibacterial activity of the nanocomposite were investigated. The antibacterial activity for Ag-RGO nanocomposite is induced by capturing-killing process. From the results, we concluded that Ag-RGO nanocomposite can simultaneously induce apoptosis. Our results bring up a new plan for the use of silver nanoparticles in the form of nanocomposite with reduced graphene oxide in antibacterial applications. Also, Ag RGO nanocomposite can reduce the viability of U87MG in a dose dependent manner which may show its anticancer potential. PMID- 28810194 TI - Towards detecting regulatory protein-metabolite interactions. AB - New mapping approaches have greatly expanded our view on the cellular landscape of protein-metabolite interactions. These methods either identify proteins interacting with a selected metabolite or vice versa. By reviewing recent developments, we found that comprehensive mapping of the protein-metabolite interaction space can be achieved eventually using existing methods, amongst which proteomics techniques to assess cell wide protein property changes in response to metabolite treatment currently offer the highest potential. Since we expect major advances in mapping protein-metabolite interactions in the near future, the challenge shifts to the identification of interaction functionality, for which currently only few specialized methods are available. PMID- 28810195 TI - Alcohol use and receipt of alcohol screening and brief intervention in a representative sample of sexual minority and heterosexual adults receiving health care. AB - BACKGROUND: Despite evidence of alcohol disparities between sexual minority and heterosexual individuals in the general population, research has not examined whether there are disparities in receipt of alcohol screening and brief intervention - together considered one of the highest prevention priorities for US adults. This study examined differences in alcohol use and receipt of alcohol screening and brief intervention across sexual minority status. METHODS: Behavioral Risk Factor Surveillance System 2014 data from eight US states were used to estimate patterns of alcohol use and receipt of alcohol screening and brief intervention among persons reporting sexual orientation and a checkup in the last two years (N=47,800). Analyses were conducted in 2016-2017. RESULTS: Gay men and bisexual women reported higher rates of alcohol use on some measures compared to heterosexual men and women, respectively. There were some differences in screening and brief intervention by sexual orientation. Lesbian women were more likely to report being asked about heavy episodic drinking than heterosexual women, and among those reporting unhealthy alcohol use, gay men were less likely, and bisexual men were more likely, to report receiving brief intervention compared to heterosexual men. CONCLUSIONS: Overall similarities between sexual minorities and heterosexuals in alcohol use and receipt of screening and brief intervention are encouraging. Nonetheless, research is needed to confirm findings and understand mechanisms underlying disparities in receipt of brief intervention between gay and heterosexual men. PMID- 28810197 TI - Photochemical formation of chitosan-stabilized near-infrared-absorbing silver Nanoworms: A "Green" synthetic strategy and activity on Gram-negative pathogenic bacteria. AB - A facile, single-step, non-seeded photochemical protocol for producing a new type of anisotropic silver nanostructure, "nanoworms", with curved longer dimensions and smooth, rounded edges. The nanoworms exhibit surface plasmon resonance (SPR) absorption in the near-infrared window (NIRW) region and are stabilized using biocompatible polymer chitosan, rendering biocompatibility and amplified safety for biological utility of the composition. Both NIRW-absorbing nanoworms and visible-absorbing nanospheres herein are attained exclusively by employing green chemistry principles. Contrary to seed-mediated or polyol techniques, the protocol demonstrates the feasibility to selectively synthesize NIRW-absorbing silver nanostructures in a single step and in complete absence of any known reducing agent. The effect of irradiation, pH, and concentration of starting materials on the formation of nanoworms vs nanospheres is investigated in detail and analyzed by optical spectroscopy and electron microscopy. The dominant SPR obtained in the NIRW region of the nanoworms results from anisotropic AgNPs, as opposed to agglomeration. From TEM images, it is also very clear that a strong correlation exists between the SPR peak maximum and the size distribution of the anisotropic nanoworm structures, with SPR peak maximum exhibiting red shift with the increase in the size of the nanoworm population. Although there is significant size variation of different nanoworms of a given population, all samples exhibit remarkable stability. The nanoworms retained their NIRW-absorbing features even at physiological pH and at a constant ionic strength. The nanodispersions also retained their SPR features in King's B medium. Antipathogenic assays reveal that the anisotropic NIRW-absorbing nanoworms exhibit the highest growth inhibition compared to other spherical nanosilver and molecular silver forms on Gram-negative pathogenic bacteria, Pseudomonas syringae pv. maculicola ES4326 and P. syringae pv. tomato DC3000. These results underscore shape effects of AgNPs and suggest that nanoworms favor the adhesion to (curved) rod-shaped Gram-negative bacteria, resulting in the highest inhibition compared to isotropic AgNPs (smaller spheres), sulfa antibiotics (silver sulfadiazine), and silver ions (AgNO3). PMID- 28810198 TI - Phthalate metabolites related to infertile biomarkers and infertility in Chinese men. AB - Although in vitro and in vivo laboratory studies have demonstrated androgen and anti-androgen effects on male reproduction from phthalate exposures, human studies still remain inconsistent. Therefore, a case-control study (n = 289) was conducted to evaluate the associations between phthalate exposures, male infertility risks, and changes in metabolomic biomarkers. Regional participants consisted of fertile (n = 150) and infertile (n = 139) males were recruited from Nanjing Medical University' affiliated hospitals. Seven urinary phthalate metabolites were measured using HPLC-MS/MS. Associations between levels of phthalate metabolites, infertility risks, and infertility-related biomarkers were statistically evaluated. MEHHP, one of the most abundant DEHP oxidative metabolites was significantly lower in cases than in controls (p = 0.039). When using the 1st quartile range as a reference, although statistically insignificant for odds ratios (ORs) of the 2nd, 3rd, and 4th quartiles (OR (95% CI) = 1.50 (0.34-6.48), 0.70 (0.14-3.52) and 0.42 (0.09-2.00), respectively), the MEHHP dose dependent trend of infertility risk expressed as OR decreased significantly (p = 0.034). More interestingly, most of the phthalate metabolites, including MEHHP, were either positively associated with fertile prevention metabolic biomarkers or negatively associated with fertile hazard ones. Phthalate metabolism, along with their activated infertility-related biomarkers, may contribute to a decreased risk of male infertility at the subjects' ongoing exposure levels. Our results may be illustrated by the low-dose related androgen effect of phthalates and can improve our understanding of the controversial epidemiological results on this issue. PMID- 28810196 TI - Tobacco demand, delay discounting, and smoking topography among smokers with and without psychopathology. AB - INTRODUCTION: Tobacco demand (i.e., relative value attributed to a given reinforcer) and delay discounting (i.e., relative preference for smaller immediate rewards over larger delayed rewards) are two behavioral economic processes that are linked to the progression of problematic substance use. These processes have not been studied among those with psychopathology, a vulnerable group of smokers. The current study examined differences in tobacco demand and delay discounting, and their association with smoking topography among smokers with (n=43) and without (n=64) past-year psychopathology. METHOD: Adult daily smokers (n=107,Mage=43.5; SD=9.7) participated in a study on "smoking behavior." Past-year psychological disorders were assessed via a clinician-administered diagnostic assessment. All subjects participated in an ad libitum smoking trial and then completed an assessment of delay discounting (Monetary Choice Questionnaire) and tobacco demand (Cigarette Purchase Task) approximately 45 60min post-smoking. RESULTS: Smokers with psychopathology, compared to those without, had significantly higher demand intensity and maximum expenditure on tobacco (Omax), but did not differ on other demand indices or delay discounting. Smokers with psychopathology had shorter average inter-puff intervals and shorter time to cigarette completion than smokers without psychopathology. Tobacco demand and delay discounting measures were significantly intercorrelated among smokers with psychopathology, but not those without. Both behavioral economic measures were associated with specific aspects of smoking topography in smokers with psychopathology. DISCUSSION: The association between tobacco demand and delay discounting is evident among smokers with psychopathology and both measures were most consistently related to smoking behavior. PMID- 28810199 TI - Diallyl trisulfide (DATS) suppresses benzene-induced cytopenia by modulating haematopoietic cell apoptosis. AB - Benzene is a well-known occupational and environmental toxicant associated with cytopenia, which is characterized by a disorder in the peripheral blood cell counts. However, no effective preventive strategy has been developed yet to tackle the exposure to benzene in daily life. The aim of this study was to evaluate the protective effects of diallyl trisulfide (DATS) on benzene-induced haematopoietic damage and to reveal its potential mechanisms of action. In our study, male Sprague-Dawley rats were divided into six groups. Rats were administered with benzene (1.3 g/kg BW by gavage) to establish the benzene poisoning model, while the DATS treatment groups were treated with benzene plus DATS (15 mg/kg, 30 mg/kg, 45 mg/kg, respectively, by gavage) for 28 days. Our results demonstrated that the counts of peripheral blood WBC and RBC decreased to 31.0% and 79.2%, respectively, in the benzene poisoning model group compared to the control. However, blood cell counts were restored by DATS treatment (30 mg/kg, 45 mg/kg). The apoptosis rates of peripheral blood mononuclear cells (PBMCs) and bone marrow cells (BMCs) were increased to 274% and 284%, respectively, following benzene exposure. Furthermore, expression levels of Bcl 2, PI3K and p-Akt were downregulated and those of Bax were upregulated in both cell types. Moreover, the oxidative parameters (oxygen species, malonaldehyde) were significantly increased, while the non-enzymatic GSH/GSSG ratios and the activities of enzymatic antioxidants (superoxide dismutase, glutathione peroxidase and catalase) were decreased. Interestingly, DATS treatment can restore the WBC number by 267.1% and 304.8% while RBC number by 108.6% and 117.7% in 30,45 mg/k DATS treated groups. In summary, we demonstrated that benzene induced cytopenia was related to the apoptosis of PBMCs and BMCs, and DATS treatment could prevent benzene-induced cytopenia by suppressing oxidative stress mediated cell apoptosis via the PI3K/Akt pathway. PMID- 28810200 TI - Influences of TiO2 nanoparticles on dietary metal uptake in Daphnia magna. AB - Increasing applications of titanium dioxide nanoparticles (nano-TiO2) have intensified the risk of environmental contamination. Since nano-TiO2 can absorb metals and be consumed as 'food' by zooplankton but also can interact with phytoplankton, they could significantly disturb the existing metal assimilation patterns. In the present study, we quantified the dietary assimilation of Cd and Zn from nano-TiO2 and algae (Chlamydomonas reinhardtii) at comparable particle concentrations as well as in complex food environment (variable food quality and quantity) in a freshwater zooplankton Daphnia magna using the radiotracer technique. For both nano-TiO2 and algae as food, the feeding food quality and depuration food quantity significantly affected the assimilation efficiencies (AEs) of Cd and Zn. At feeding food quantity of 1 mg/L to 10 mg/L without food in depuration, the AEs of Cd and Zn from nano-TiO2 were lower than those from algae. When food was added during depuration, the influences of nano-TiO2 on metal AEs were variable due to the differential effects of food quantity on the gut passage of nano-TiO2 and algae. Furthermore, mixed nano-TiO2 and algae had the lowest metal AEs compared to sole nano-TiO2 or algae as a result of interaction between nano-TiO2 and algae during feeding. Overall, this study showed the distinguishing metal AEs between nano-TiO2 and algae, and that nano-TiO2 could significantly reduce the existing metal AEs from algae. More attention should be paid to the potential roles of nano-TiO2 in disturbing metal assimilation in the environmental risk assessments of nanoparticles. PMID- 28810201 TI - The association between non-Hodgkin lymphoma and organophosphate pesticides exposure: A meta-analysis. AB - Several epidemiological studies show the association between organophosphate pesticides (OPs) and the risk of non-Hodgkin lymphoma (NHL), yet various research results remain controversial. To explore the hazard of OPs exposure to human health, three kinds of OPs (Terbufos, Malathion, and Diazinon) that are non halogenated aliphatic compounds were included in the meta-analysis. We searched PubMed and Web of Science Databases for articles published from 1985 to February 2017. The databases were also searched for eligible studies through a manual references search. The random-effect model was utilized to compute the odds ratios (ORs) and 95% confident intervals (CIs). A total of ten observational studies (five cohort, four case-control, and one nested case-control) were included in our meta-analysis, with a pooled OR of 1.22 (95% CI 1.04 to 1.43) of Malathion, Terbufos and Diazinion. The general heterogeneity for OR was moderate (Ph = 0.032, I2 = 41.2%). The OR estimates in the subset analyses were utilized to compare the association between the three kinds of OPs and NHL; Terbufos (OR = 1.07, 95% CI 0.85 to 1.36) and Malathion (OR = 1.17, 95% CI 0.82 to 1.67) had a statistically non-significant relationship, whereas Diazinon (OR = 1.39, 95% CI 1.11 to 1.73) was significantly associated with an increased NHL risk. Because immune dysfunction was thought to increase NHL risk, the toxicity levels in the immune system of the three types of OPs were compared. Malathion attacked immune cells via a direct effect and Diazinon disrupted the neuro-immune system, which involves the cholinergic system of lymphocytes via indirect immune damage, whereas an immunotoxic effect involving Terbufos was not reported. Overall, the present meta-analysis indicated a statistically significant association between Diazinon exposure and NHL risk. PMID- 28810202 TI - Seasonal variation and potential source regions of PM2.5-bound PAHs in the megacity Beijing, China: Impact of regional transport. AB - Based on the 12-hour PM2.5 samples collected in an urban site of Beijing, sixteen PM2.5-bound Polycyclic Aromatic Hydrocarbons (PAHs) were measured to investigate the characteristics and potential source regions of particulate PAHs in Beijing. The study period included the summer period in July-August 2014, the APEC source control period during the Asia-Pacific Economic Cooperation (APEC) meeting in the first half of November 2014, and the heating period in the second half of November 2014. Compared to PM2.5, sum of 16 PM2.5-bound PAHs exhibited more significant seasonal variation with the winter concentration largely exceeding the summer concentration. Temperature appeared to be the most crucial meteorological factor during the summer and heating periods, while PM2.5-bound PAHs showed stronger correlation with relative humidity and wind speed during the APEC source control period. Residential heating significantly increased the concentrations of higher-ring-number (>=4) PAHs measured in PM2.5 fraction. Potential source contribution function (PSCF) and concentration weighted trajectory (CWT) analysis as well as the (3 + 4) ring/(5 + 6) ring PAH ratio analysis revealed the seasonal difference in the potential source area of PM2.5 bound PAHs in Beijing. Southern Hebei was the most likely potential source area in the cold season. Using black carbon (BC) and carbon monoxide (CO) as the PAH tracers, regional residential, transportation and industry emissions all contributed to the PAH pollution in Beijing. PMID- 28810203 TI - Chemical activity and distribution of emerging pollutants: Insights from a multi compartment analysis of a freshwater system. AB - Emerging pollutants are ubiquitous in the aquatic system and may pose risks to aquatic ecosystems. The quantification and prediction of environmental partitioning of these chemicals in aquatic systems between water, sediment and biota is an important step in the comprehensive assessment of their sources and final fates in the environment. In this multi-compartment field study, we applied equilibrium partitioning theory and chemical activity estimates to investigate the predictability of concentrations in Gammarus pulex as a model invertebrate from water and sediment in a typical small central European river. Furthermore, KOW-based and LSER approaches were assessed for the calculation of sediment organic carbon-, lipid-, and protein-water partitioning coefficients and activity ratios between the different compartments. Gammarid-water activity ratios close to unity have been observed for many chemicals, while sediment-water and sediment biota chemical activity ratios exceeded unity by up to six orders of magnitudes. Causes may be: disequilibrium due to slow desorption kinetics and/or an underestimation of partition coefficients due to the presence of strongly adsorbing phases in the sediments. Water concentrations, particularly when using LSER for prediction of partition coefficients were good predictors of internal concentrations in gammarids for most emerging pollutants. Some hydrophilic chemicals such as the neonicotinoid imidacloprid tend to accumulate more in G. pulex than expected from equilibrium partitioning. This conclusion holds both for KOW as well as for LSER-based predictions and suggests previously unidentified mechanisms of bio-accumulation which may include binding to specific protein structures. PMID- 28810204 TI - Characteristics of black carbon emissions from in-use light-duty passenger vehicles. AB - Mitigating black carbon (BC) emissions from various combustion sources has been considered an urgent policy issue to address the challenges of climate change, air pollution and health risks. Vehicles contribute considerably to total anthropogenic BC emissions and urban BC concentrations. Compared with heavy-duty diesel vehicles, there is much larger uncertainty in BC emission factors for light-duty passenger vehicles (LDPVs), in particular for gasoline LDPVs, which warrants further studies. In this study, we employed the dynamometer and the Aethalometer (AE-51) to measure second-by-second BC emissions from eight LDPVs by engine technology and driving cycle. The average BC emission factors under transient cycles (e.g., ECE-15, New European Driving Cycle, NEDC, Worldwide Harmonized Light Vehicles Test Cycle, WLTC) are 3.6-91.5 mg/km, 7.6 mg/km and 0.13-0.58 mg/km, respectively, for diesel (N = 3), gasoline direct injection (GDI) (N = 1) and gasoline port-fuel injection (PFI) engine categories (N = 4). For gasoline PFI LDPVs, the instantaneous emission profiles show a strong association of peak BC emissions with cold-start and high-speed aggressive driving. Such impacts lead to considerable BC emission contributions in cold start periods (e.g., the first 47 s-94 s) over the entire cycle (e.g., 18-76% of the NEDC and 13-36% of the WLTC) and increased BC emission factors by 80-440% under the WLTC compared to the NEDC. For diesel BC emissions, the size distribution exhibits a typical unimodal pattern with one single peak appearing approximately from 120 to 150 nm, which is largely consistent with previous studies. Nevertheless, the average mass ratios of BC to particle mass (PM) range from 0.38 to 0.54 for three diesel samples, representing substantial impacts from both driving and engine conditions. The significant discrepancy between gasoline BC emission factors obtained from tailpipe exhaust versus ambient conditions suggest that more comparative measurements and fine-grained simulations should be designed and implemented to address this discrepancy. PMID- 28810205 TI - Chemical composition, source, and process of urban aerosols during winter haze formation in Northeast China. AB - The characteristics of aerosol particles have been poorly evaluated even though haze episodes frequently occur in winter in Northeast China. OC/EC analysis, ion chromatography, and transmission electron microscopy (TEM) were used to investigate the organic carbon (OC) and elemental carbon (EC), and soluble ions in PM2.5 and the mixing state of individual particles during a severe wintertime haze episode in Northeast China. The organic matter (OM), NH4+, SO42-, and NO3- concentrations in PM2.5 were 89.5 MUg/m3, 24.2 MUg/m3, 28.1 MUg/m3, and 32.8 MUg/m3 on the haze days, respectively. TEM observations further showed that over 80% of the haze particles contained primary organic aerosols (POAs). Based on a comparison of the data obtained during the haze formation, we generate the following synthetic model of the process: (1) Stable synoptic meteorological conditions drove the haze formation. (2) The early stage of haze formation (light or moderate haze) was mainly caused by the enrichment of POAs from coal burning for household heating and cooking. (3) High levels of secondary organic aerosols (SOAs), sulfates, and nitrates formation via heterogeneous reactions together with POAs accumulation promoted to the evolution from light or moderate to severe haze. Compared to the severe haze episodes over the North China Plain, the PM2.5 in Northeast China analyzed in the present study contained similar sulfate, higher SOA, and lower nitrate contents. Our results suggest that most of the POAs and secondary particles were likely related to emissions from coal-burning residential stoves in rural outskirts and small boilers in urban areas. The inefficient burning of coal for household heating and cooking should be monitored during wintertime in Northeast China. PMID- 28810206 TI - Selection of anesthesia technique: Not always the right reasons or the right outcomes.... PMID- 28810208 TI - Tungsten-doped TiO2/reduced Graphene Oxide nano-composite photocatalyst for degradation of phenol: A system to reduce surface and bulk electron-hole recombination. AB - Recombination of photogenerated charges is the main factor affecting the photocatalytic activity of TiO2. Here, we report a combined strategy of suppressing both the bulk as well as the surface recombination processes by doping TiO2 with tungsten and forming a nanocomposite with reduced graphene oxide (rGO), respectively. Sol-gel method was used to dope and optimize the concentration of W in TiO2 powder. UV-Vis, XPS, PL and time resolved PL spectra along with DFT calculations indicate that W6+ in TiO2 lattice creates an impurity level just below the conduction band of TiO2 to act as a trapping site of electrons, which causes to improve the lifetime of the photo-generated charges. Maximum reduction in the PL intensity and the improvement in charge carrier lifetime was observed for TiO2 doped with 1 at.% W (1W-TiO2), which also displayed the highest photo-activity for the degradation of p-nitro phenol pollutant in water. Tuning of rGO/TiO2 ratio (weight) disclosed that the highest activity can be achieved with the composite formed by taking equal amounts of TiO2 and rGO (1:1), in which the strong interaction between TiO2 and rGO causes an effective charge transfer via bonds formed near the interface as indicated by XPS. Both these optimized concentrations were utilized to form the composite rGO/1W-TiO2, which showed the highest activity in photo-degradation of p-nitro phenol (87%) as compared to rGO/TiO2 (42%), 1W-TiO2 (62%) and pure TiO2 (29%) in 180 min. XPS and PL results revealed that in the present nanocomposite, tungsten species traps the excited electron to reduce the interband recombination in the bulk, while the interaction between TiO2 and rGO creates a channel for fast transfer of excited electrons towards the latter before being recombined on the surface defect sites. PMID- 28810209 TI - Benefits of the fire mitigation ecosystem service in The Great Dismal Swamp National Wildlife Refuge, Virginia, USA. AB - The Great Dismal Swamp (GDS) National Wildlife Refuge delivers multiple ecosystem services, including air quality and human health via fire mitigation. Our analysis estimates benefits of this service through its potential to reduce catastrophic wildfire related impacts on the health of nearby human populations. We used a combination of high-frequency satellite data, ground sensors, and air quality indices to determine periods of public exposure to dense emissions from a wildfire within the GDS. We examined emergency department (ED) visitation in seven Virginia counties during these periods, applied measures of cumulative Relative Risk to derive the effects of wildfire smoke exposure on ED visitation rates, and estimated economic losses using regional Cost of Illness values established within the US Environmental Protection Agency BenMAP framework. Our results estimated the value of one avoided catastrophic wildfire in the refuge to be $3.69 million (2015 USD), or $306 per hectare of burn. Reducing the frequency or severity of extensive, deep burning peatland wildfire events has additional benefits not included in this estimate, including avoided costs related to fire suppression during a burn, carbon dioxide emissions, impacts to wildlife, and negative outcomes associated with recreation and regional tourism. We suggest the societal value of the public health benefits alone provides a significant incentive for refuge mangers to implement strategies that will reduce the severity of catastrophic wildfires. PMID- 28810210 TI - Biomechanical and histologic evaluation of two application forms of surgical glue for mesh fixation to the abdominal wall. AB - The use of an adhesive for mesh fixation in hernia repair reduces chronic pain and minimizes tissue damage in the patient. This study was designed to assess the adhesive properties of a medium-chain (n-butyl) cyanoacrylate glue applied as drops or as a spray in a biomechanical and histologic study. Both forms of glue application were compared to the use of simple-loose or continuous-running polypropylene sutures for mesh fixation. Eighteen adult New Zealand White rabbits were used. For mechanical tests in an ex vivo and in vivo study, patches of polypropylene mesh were fixed to an excised fragment of healthy abdominal tissue or used to repair a partial abdominal wall defect in the rabbit respectively. Depending on the fixation method used, four groups of 12 implants each or 10 implants each respectively for the ex vivo and in vivo studies were established: Glue-Drops, Glue-Spray, Suture-Simple and Suture-Continuous. Biomechanical resistance in the ex vivo implants was tested five minutes after mesh fixation. In vivo implants for biomechanical and histologic assessment were collected at 14 days postimplant. In the ex vivo study, the continuous suture implants showed the highest failure sample tension, while the implants fixed with glue showed lower failure sample tension values. However, the simple and continuous suture implants returned the highest stretch values. In the in vivo implants, failure sample tension values were similar among groups while the implants fixed with a continuous running suture had the higher stretch values, and the glue-fixed implants the lower stretch values. All meshes showed good tissue integration within the host tissue regardless of the fixation method used. Our histologic study revealed the generation of a denser, more mature repair tissue when the cyanoacrylate glue was applied as a spray rather than as drops. PMID- 28810207 TI - Intermediate care to intensive care triage: A quality improvement project to reduce mortality. AB - PURPOSE: Medical patients whose care needs exceed what is feasible on a general ward, but who do not clearly require critical care, may be admitted to an intermediate care unit (IMCU). Some IMCU patients deteriorate and require medical intensive care unit (MICU) admission. In 2012, staff in the Johns Hopkins IMCU expressed concern that patient acuity and the threshold for MICU admission were too high. Further, shared triage decision-making between residents and supervising physicians did not consistently occur. METHODS: To improve our triage process, we used a 4Es quality improvement framework (engage, educate, execute, evaluate) to (1) educate residents and fellows regarding principles of triage and (2) facilitate real-time communication between MICU residents conducting triage and supervising physicians. RESULTS: Among patients transferred from the IMCU to the MICU during baseline (n=83;July-December 2012) and intervention phases (n=94;July-December 2013), unadjusted mortality decreased from 34% to 21% (p=0.06). After adjusting for severity of illness, admitting diagnosis, and bed availability, the odds of death were lower during the intervention vs. baseline phase (OR 0.33; 95%CI 0.11-0.98). CONCLUSIONS: Using a structured quality improvement process targeting triage education and increased resident/supervisor communication, we demonstrated reduced mortality among patients transferred from the IMCU to the MICU. PMID- 28810211 TI - How local health departments work towards health equity. AB - BACKGROUND: Health inequities are exacerbated when health promotion programs and resources do not reach selected populations. Local health departments (LHDs)1 have the potential to address health equity via engaging priority populations in their work. However, we do not have an understanding of what local agencies are doing on this front. METHODS: In the summer of 2016, we collaborated with informants from thirteen LHDs across North Carolina. Via semi-structured interviews, the research team asked informants about their LHD's understanding of health equity and engaging priority populations in program planning, implementation, and evaluation. FINDINGS: All informants discussed that a key function of their LHD was to improve the health of all residents. LHDs with a more comprehensive understanding of health equity engaged members of priority populations in their organizations' efforts to a greater extent than LHDs with a more limited understanding. Additionally, while all LHDs identified similar barriers to engaging priority populations, LHDs that identified facilitators more comprehensively engaged members of the priority population in program planning, implementation, and evaluation. CONCLUSIONS: LHDs are ideally situated between the research and practice worlds to address health equity locally. To promote this work, we should ensure LHDs hold an understanding of health equity, have the means to realize facilitators of health equity work, and recognize the complex context in which health equity work exists. PMID- 28810212 TI - Evaluation of Bikers Against Child Abuse (BACA) program: A community intervention for child abuse victims. AB - Children who have experienced physical abuse benefit from a multitude of community interventions including support programs to address emotional and behavioral stability. This pilot study evaluated the services of Bikers Against Child Abuse (BACA), a community of bikers lending intervention to abused children, using a pre/post exploratory design. Participants (N=154) were children who had been referred by parents/guardians for current or past physical and/or sexual abuse. Parents/guardians of children were interviewed four times over a course of one year. Results indicated children demonstrated substantial improvements in their overall levels of emotional distress, conduct concerns, hyperactivity, and behavioral and emotional functioning. Overall, results support the premise that services provided by BACA may serve as a unique intervention for children who have experienced abuse. PMID- 28810213 TI - The effect of circulating progesterone on magnitude of the GnRH-induced LH surge: Are there any differences between Bos indicus and Bos taurus heifers? AB - This study evaluated the effects of differing circulating progesterone (P4) levels on the luteinizing hormone (LH) surge profile following treatment with gonadotropin releasing hormone (GnRH) in B. indicus (Nelore, n = 13) and B. taurus (Holstein, n = 16) heifers. All heifers were synchronized with a hormonal protocol to induce either a Low or High circulating P4 environment at the time of GnRH treatment. Heifers were randomly assigned to a 2 * 2 factorial design composed by two genetic groups (B. indicus and B. taurus) and two levels of circulating P4 concentrations (Low or High). Blood samples were collected every 30 min from -30 to 210 min and at 270 min after GnRH treatment. As expected, mean P4 concentration was greater for cows in the High than in the Low P4 group (P = 0.0008) and in Bos indicus than in Bos taurus heifers (P = 0.06). Despite genetic group, the area under the curve of LH release was greater in the Low-P4 than in High-P4 concentration group (P < 0.0001). Interestingly, it appears that High P4 concentrations had a more pronounced effect on LH peak in B. indicus than in B. taurus heifers, as indicated by the interaction (P = 0.01) between genetic group and P4 levels. In conclusion, circulating P4 concentration have a great impact on the GnRH-induced LH surge of both B. indicus and B. taurus heifers, but it does not explain the much lower LH peak in B. indicus with low circulating P4. Thus, more studies are essential to uncover some of the underlying physiological factors other than circulating P4 that are limiting LH release following a GnRH treatment in B. indicus cattle. PMID- 28810214 TI - Evaluation of chemical, thermobaric and thermochemical pre-treatment on anaerobic digestion of high-fat cattle slaughterhouse waste. AB - This work aimed to enhance the anaerobic digestion of fat-rich dissolved air flotation (DAF) sludge through chemical, thermobaric, and thermochemical pre treatment methods. Soluble chemical oxygen demand was enhanced from 16.3% in the control to 20.84% (thermobaric), 40.82% (chemical), and 50.7% (thermochemical). Pre-treatment altered volatile fatty acid concentration by -64% (thermobaric), 127% (chemical) and 228% (thermochemical). Early inhibition was reduced by 20% in the thermochemical group, and 100% in the thermobaric group. Specific methane production was enhanced by 3.28% (chemical), 8.32% (thermobaric), and 8.49% (thermochemical) as a result of pre-treatment. Under batch digestion, thermobaric pre-treatment demonstrated the greatest improvement in methane yield with respect to degree of pre-treatment applied. Thermobaric pre-treatment was also the most viable for implementation at slaughterhouses, with potential for heat-exchange to reduce pre-treatment cost. Further investigation into long-term impact of pre treatments in semi-continuous digestion experiments will provide additional evaluation of appropriate pre-treatment options for high-fat slaughterhouse wastewater. PMID- 28810215 TI - Continuous operation of thermophilic food waste digestion with side-stream ammonia stripping. AB - Digesters fed on food waste (high nitrogen content) were operated successfully over an extended period using sidestream biogas stripping to control total ammonia nitrogen (TAN) below inhibitory concentrations. This is the first time biogas stripping has been used to achieve stable thermophilic operation with undiluted substrate of this type. Stripping columns operated batch-wise treated the equivalent of 1.7-4.1% of digester contents daily at pH >10 and 70 degrees C, with no detrimental effect on digestion. TKN removal was 54%, with potential to recover 3.5kgNtonne-1 substrate. When stripping was stopped in one digester TAN increased, accompanied by rising propionic acid concentrations with progressive instability observed from 2.5gNL-1. Eventual failure as TAN approached 5gNL-1 was due to rapid acetic acid accumulation, resulting in a fall in pH to below 6.5. The pattern of VFA accumulation indicated failure of both acetoclastic methanogenesis and acetate oxidation. PMID- 28810216 TI - Light intensity as major factor to maximize biomass and lipid productivity of Ettlia sp. in CO2-controlled photoautotrophic chemostat. AB - The optimal culture conditions are critical factors for high microalgal biomass and lipid productivity. To optimize the photoautotrophic culture conditions, combination of the pH (regulated by CO2 supply), dilution rate, and light intensity was systematically investigated for Ettlia sp. YC001 cultivation in a chemostat during 143days. The biomass productivity increased with the increase in dilution rate and light intensity, but decreased with increasing pH. The average lipid content was 19.8% and statistically non-variable among the tested conditions. The highest biomass and lipid productivities were 1.48gL-1d-1 and 291.4mgL-1d-1 with a pH of 6.5, dilution rate of 0.78d-1, and light intensity of 1500MUmolphotonsm-2s-1. With a sufficient supply of CO2 and nutrients, the light intensity was the main determinant of the photosynthetic rate. Therefore, the surface-to-volume ratio of a photobioreactor should enable efficient light distribution to enhance microalgal growth. PMID- 28810217 TI - Porous cellulose as promoter of oil production by the oleaginous yeast Lipomyces starkeyi using mixed agroindustrial wastes. AB - Enhanced single cell oil (SCO) production by the oleaginous yeast Lipomyces starkeyi DSM 70296, immobilised on delignified porous cellulose, is reported. Pure glucose media were initially used. The effects of substrate pH and treatment temperature were evaluated, showing that 30 degrees C and pH 5.0 were the optimum conditions for SCO production by the immobilised yeast. The immobilisation technique led to increased lipid accumulation and cell growth by 44% and 8%, respectively, in the glucose media, compared to free cells in suspension. This positive effect was also shown when low concentration mixed agro-industrial waste suspensions were used as substrates, leading to 85% enhanced SCO production in comparison with free cells. Higher fatty acid (HFA) analysis showed that yeast immobilisation led to increased formation of unsaturated HFAs (6%) and reduced saturated HFAs (5%) compared to free cells. PMID- 28810218 TI - Effect of cold-adapted microbial agent inoculation on enzyme activities during composting start-up at low temperature. AB - In order to put forward a method to promote composting start-up at low ambient temperature, the cold-adapted microbial agent (CAMA) was inoculated in chicken manure (CM), and compared the enzymes activities, including urease, proteases, beta-glucosidase and invertase, with no CAMA group (CK). In this study, the temperature of CM reached 50 degrees C in 53h, but it in CK was only around 30 degrees C during the composting process. Moreover, the enzymes exhibited higher activity in CM than CK, indicating the effectiveness of CAMA. Furthermore, redundancy analysis was conducted to study the relationships of CAMA, with enzymes activities and temperature. Results showed that the positive effect of CAMA on the enzyme activities were achieved by affecting the bacterial community structure. Accordingly, we provide a method to guide CAMA inoculation for promoting compost start-up in cold area. PMID- 28810219 TI - Industrial hemp as a potential bioenergy crop in comparison with kenaf, switchgrass and biomass sorghum. AB - This study takes combined field trial, lab experiment, and economic analysis approaches to evaluate the potential of industrial hemp in comparison with kenaf, switchgrass and biomass sorghum. Agronomy data suggest that the per hectare yield (5437kg) of industrial hemp stem alone was at a similar level with switchgrass and sorghum; while the hemp plants require reduced inputs. Field trial also showed that ~1230kg/ha hemp grain can be harvested in addition to stems. Results show a predicted ethanol yield of ~82gallons/dry ton hemp stems, which is comparable to the other three tested feedstocks. A comparative cost analysis indicates that industrial hemp could generate higher per hectare gross profit than the other crops if both hemp grains and biofuels from hemp stem were counted. These combined evaluation results demonstrate that industrial hemp has great potential to become a promising regional commodity crop for producing both biofuels and value-added products. PMID- 28810220 TI - Effectiveness of piggery waste treatment using microbial fuel cells coupled with elutriated-phased acid fermentation. AB - The present study evaluates the feasibility of increased power generation in microbial fuel cells (MFCs) coupled with acid elutriation fermentation. Raw piggery waste (RPW) and acid elutriation effluents (AEE) of piggery waste were used to generate bioelectricity in single-chambered air-cathode MFCs. RPW-fed MFCs exhibited stable performance after 12-days of operation, generating 540mV of open circuit voltage (OCV). RPW fed-MFCs displayed peak potential and maximal power density (PDmax) of 0.364V and 192mW/m2 with 980Omega external resistance (Rext), respectively. AEE-fed MFCs documented 818mV of maximum OCV. Furthermore, the peak potential and PDmax of 0.329V and 1553mW/m2 were generated with 100Omega Rext, respectively. RPW and AEE-fed MFCs exhibited 84% and 93% substrate removal efficiency, respectively. These findings suggest that a two-stage process including acid elutriation reactor asa pre-fermentation and MFCs greatly enhances substrate removal and electricity generation from piggery waste. PMID- 28810221 TI - New naphthalene whole-cell bioreporter for measuring and assessing naphthalene in polycyclic aromatic hydrocarbons contaminated site. AB - A new naphthalene bioreporter was designed and constructed in this work. A new vector, pWH1274_Nah, was constructed by the Gibson isothermal assembly fused with a 9 kb naphthalene-degrading gene nahAD (nahAa nahAb nahAc nahAd nahB nahF nahC nahQ nahE nahD) and cloned into Acinetobacter ADPWH_lux as the host, capable of responding to salicylate (the central metabolite of naphthalene). The ADPWH_Nah bioreporter could effectively metabolize naphthalene and evaluate the naphthalene in natural water and soil samples. This whole-cell bioreporter did not respond to other polycyclic aromatic hydrocarbons (PAHs; pyrene, anthracene, and phenanthrene) and demonstrated a positive response in the presence of 0.01 MUM naphthalene, showing high specificity and sensitivity. The bioluminescent response was quantitatively measured after a 4 h exposure to naphthalene, and the model simulation further proved the naphthalene metabolism dynamics and the salicylate-activation mechanisms. The ADPWH_Nah bioreporter also achieved a rapid evaluation of the naphthalene in the PAH-contaminated site after chemical spill accidents, showing high consistency with chemical analysis. The engineered Acinetobacter variant had significant advantages in rapid naphthalene detection in the laboratory and potential in situ detection. The state-of-the-art concept of cloning PAHs-degrading pathway in salicylate bioreporter hosts led to the construction and assembly of high-throughput PAH bioreporter array, capable of crude oil contamination assessment and risk management. PMID- 28810223 TI - Effects of an allelochemical in Phaeodactylum tricornutum filtrate on Heterosigma akashiwo: Morphological, physiological and growth effects. AB - The effects of an allelochemical extracted from the culture filtrate of diatom Phaeodactylum tricornutum on the raphidophyte Heterosigma akashiwo were investigated using a series of morphological, physiological and biochemical characters. Growth experiments showed that H. akashiwo was significantly inhibited immediately after exposure to the allelochemical, with many cells rapidly dying and lysing based on microscopic observation. The effects of the allelochemical on the surviving cells were explored using Scanning Electron Microscopy (SEM) and Flow cytometry (FCM), the latter by examination of a suite of physiological parameters (membrane integrity, esterase activity, chlorophyll-a content, membrane potential). The results demonstrate that the membrane of H. akashiwo was attacked by the allelochemical directly, causing cell membrane breakage and loss of integrity. Esterase activity was the most sensitive indicator of the impacts of the allelochemical. Membrane potential and chlorophyll-a content both showed significant decreases following exposure of the Heterosigma cells to high concentrations of the allelochemical for 5 and 6 days. Both were affected, but the membrane potential response was more gradual compared to other effects. The cell size of H. akashiwo did not change compared with the control group. The surviving cells were able to continue to grow and in a few days, re-establish a successful culture, even in the presence of residual allelochemical, suggesting either development of cellular resistance, or the degradation of the chemical. PMID- 28810222 TI - Bio-electro oxidation of indigo carmine by using microporous activated carbon fiber felt as anode and bioreactor support. AB - The bioremediation and electro-oxidation (EO) processes are included among the most promising cleaning and decontamination mechanisms of water. The efficiency of bioremediation is dictated by the biological actuator for a specific substrate, its suitable immobilization and all involved biochemical concepts. The EO performance is defined by the anode efficiency to perform the complete mineralization of target compounds and is highlighted by the low or null use of reagent. Recently, the combination of both technologies has been proposed. Thus, the development of high efficient, low cost and eco-friendly anodes for sustainable EO, as well as, supporting devices for immobilization of biological systems applied in bioremediation is an open field of research. Therefore, the aim of this work was to promote the bio-electrochemical remediation of indigo carmine dye (widely common in textile industry), using new anode based on a microporous activated carbon fiber felt (ACFF) and ACFF with immobilized Laccase (Lcc) from Pycnoporus sanguineus. The results were discolorations of 62.7% with ACFF anode and 83.60% with ACFF-MANAE-Lcc anode, both for 60 min in tap water. This remediation rates show that this new anode has low cost and efficiency in the degradation of indigo dye and can be applied for other organic pollutant. PMID- 28810224 TI - Simultaneous leaching of arsenite, arsenate, selenite and selenate, and their migration in tunnel-excavated sedimentary rocks: I. Column experiments under intermittent and unsaturated flow. AB - Rocks excavated in tunnel construction projects for roads and railways throughout Japan often leached out hazardous trace elements like arsenic (As) and selenium (Se) upon their exposure to the environment. In nature, the various oxyanionic species of As and Se not only coexist but also exhibit contrasting adsorption desorption behaviors, so speciation is a crucial factor in their migration through natural geologic media. In this study, the leaching and transport of arsenite (AsIII), arsenate (AsV), selenite (SeIV) and selenate (SeVI) in four tunnel-excavated rocks from the Cretaceous-Paleocene Yezo forearc basin were investigated using laboratory column experiments supplemented by batch leaching experiments. The single- and consecutive-batch leaching results revealed that AsIII, AsV, SeIV and SeVI were released simultaneously, which could be attributed to the rapid dissolution of trace evaporite salts found in the rocks. Arsenic in the leachates was also predominated by AsV while SeIV and SeVI concentrations were nearly equal, which are both consistent with predictions of equilibrium Eh pH diagrams. Under intermittent and unsaturated flow, however, periods when AsIII and SeVI predominated in the effluents were observed. Spatial distributions of As and Se species with depth at the end of the column experiments suggest that migrations of AsIII, AsV and SeIV were delayed, the extent of which depended on the rock. These results indicate that migration and speciation of As and Se in the rocks are controlled by preferential adsorption-desorption reactions, the effects of which were most probably magnified by changes in the pH and concentrations of coexisting ions due to intermittent and unsaturated flow. PMID- 28810225 TI - Critical evaluation of distillation procedure for the determination of methylmercury in soil samples. AB - In the present work, the efficiency of distillation process for extracting monomethylmercury (MMHg) from soil samples was studied and optimized using an experimental design methodology. The influence of soil composition on MMHg extraction was evaluated by testing of four soil samples with different geochemical characteristics. Optimization suggested that the acid concentration and the duration of the distillation process were most significant and the most favorable conditions, established as a compromise for the studied soils, were determined to be a 70 min distillation using an 0.2 M acid. Corresponding limits of detection (LOD) and quantification (LOQ) were 0.21 and 0.7 pg absolute, respectively. The optimized methodology was applied with satisfactory results to soil samples and was compared to a reference methodology based on isotopic dilution analysis followed by gas chromatography-inductively coupled plasma mass spectrometry (IDA-GC-ICP-MS). Using the optimized conditions, recoveries ranged from 82 to 98%, which is an increase of 9-34% relative to the previously used standard operating procedure. Finally, the validated methodology was applied to quantify MMHg in soils collected from different sites impacted by coal fired power plants in the north-central zone of Chile, measuring MMHg concentrations ranging from 0.091 to 2.8 ng g-1. These data are to the best of our knowledge the first MMHg measurements reported for Chile. PMID- 28810226 TI - Rapid removal of organic pollutants by activation sulfite with ferrate. AB - With the addition of sulfite, almost complete removal of seven out of eight tested contaminants, i.e. benzotriazole, phenol, ciprofloxacin, methyl blue, rhodamine B, methyl orange and sulfamethoxazole, was observed in 30 s except for sulfamethoxazole at pH 9.0, while Fe(VI) alone only resulted in less than 6% removal. In this study, the mechanism of sulfite/Fe(VI) process was explored for the first time. Firstly, sulfite attacks Fe(VI) via a 1-e- transfer forming the primary sulfite radical (SO3-), then SO3- reacts rapidly with oxygen in a diffusion controlled rate to form a much more reactive peroxyl radical SO5-, which further reacts with HSO3- and produces SO4-. All the signals of sulfite, sulfate and hydroxyl radicals were observed in the electron spin resonance (ESR) analysis. The DMPO and alcohol quenching experiments confirmed that sulfite/Fe(VI) process involves radicals as the plausible reactive species for decomposition of organic pollutants, and SO4.-/.OH instead of SO3-/SO5- are the major reactive oxygen species. Since oxygen participates in the formation of the secondary radicals, i.e. SO5-, SO4- and .OH, the sulfite/Fe(VI) process open to air displayed better performance than that purged with nitrogen. Compared with previous sulfite/Cr(VI) and sulfite/Mn(VII) processes, which are only effective under acidic conditions, sulfite/Fe(VI) process provides an alternative under neutral and alkaline conditions. The extraordinarily fast oxidation of pollutants in sulfite/Fe(VI) process suggests that activation of sulfite by Fe(VI) might lead to a new class of advanced oxidation processes (AOPs) in water treatment. PMID- 28810227 TI - Determining the zone of impact of norovirus contamination in shellfish production areas through microbiological monitoring and hydrographic analysis. AB - Norovirus (NoV) contamination of filter feeding bivalve shellfish is a well recognised human health threat when shellfish are grown in sewage polluted waters. To date, the identification of high risk zones around sewage discharges in shellfish production areas (SPAs) has not been based on NoV data. This study utilised molecular methods for NoV analysis, combined with hydrographic studies, to determine the relationship between NoV concentrations in shellfish and sewage effluent dilution. Cages with mussels and oysters were placed at different distances downstream of sewage discharges in two coastal sites in England. The shellfish were tested for concentrations of NoV (genogroups I and II) and E. coli. Drogue tracking and dye tracing studies were conducted to quantify the dispersion and dilution of sewage effluent in the SPAs. Significant negative associations were found between both total concentrations of NoV (GI + GII) and E. coli and sewage effluent dilution in the SPAs. The total NoV concentrations predicted by the model at 300:1, 1000:1 and 5000:1 ratios of estuarine water to sewage effluent were 1200; 600; and 200 copies/g, respectively. The estimated area of NoV contamination varied according with local pollution source impacts and hydrographic characteristics. The results help to inform the derivation of sewage discharge buffer zones as a control measure for mitigating risk from human NoV contamination in SPAs. PMID- 28810228 TI - Evolution of molecular weight and fluorescence of effluent organic matter (EfOM) during oxidation processes revealed by advanced spectrographic and chromatographic tools. AB - Effluent organic matter (EfOM) is an emerging concern to receiving aquatic environment due to its refractory property. The degradation of EfOM in ozonation and other two advanced oxidation processes (AOPs), UV/H2O2 and UV/persulfate (PS), was investigated in this study. Fluorescence spectra coupled with parallel factor analysis (PARAFAC) and two-dimensional correlation gel permeation chromatography (2D-GPC) were used to track the evolution of EfOM during each oxidation process. Results showed that the degradation of EfOM indicated by dissolved organic carbon (DOC), UV254 and fluorescence components, fitted well with pseudo-first-order kinetic model during the oxidation processes. Ozonation showed higher degradation efficiency than AOPs, while UV/PS was more effective than UV/H2O2 with equimolar oxidants dosage. Ozone and SO.4- were more reactive with terrestrial humic-like substances, while hydroxyl radical preferentially reacted with protein-like substances. Organic molecules with higher molecular weight (MW) were susceptible to ozone or radicals. Ozonation could transform higher MW (MW of 3510 and 575) organic matters into lower MW organic matters (MW of 294), while reductions of all the organics were observed in both AOPs. Due to the higher reaction rates between ozone and EfOM, ozonation maybe serve as a pre treatment for AOPs to reduce the radical and energy consumption and improve mineralization of EfOM by AOPs. The decline in DOC, UV254, fluorescence and reduction in oxidants increased with the increase of oxidants dosage, and linear correlations among them were found during the ozonation and AOPs. PMID- 28810229 TI - Photodegradation of sulfathiazole under simulated sunlight: Kinetics, photo induced structural rearrangement, and antimicrobial activities of photoproducts. AB - Photolysis is a core natural process impacting the fate of some sulfonamide antibiotics in sunlit waters. In this study, sunlight-induced phototransformation of sulfathiazole was investigated. A photolytic quantum yield of 0.079 was obtained in buffered water (pH = 8.0). Different natural organic matter isolates inhibited the photolysis of sulfathiazole by light screening effect. A kinetic model was developed to predict the photodegradation rate of sulfathiazole using the light screening correction factor of the water matrix in the wavelength range of 300-350 nm. An isomeric photoproduct of sulfathiazole with a longer retention time was observed on liquid chromatography. Based on its MS/MS spectra and absorption characteristics, the isomer was postulated as 2-imino-3-(p aminobenzenesulfinyl-oxy)-thiazole. A reaction mechanism for the photo-cleavage and photo-induced structural rearrangement was proposed. The formation mechanism of the isomer was supported by photochemical experiments spiking synthetic 2 aminothiazole; while the formation kinetics were treated with a partly-diffusion controlled model. The three identified products showed significantly enhanced photo-stability. Antimicrobial assay of irradiated sulfathiazole solutions with Escherichia coli indicated little antimicrobial potency ascribed to photoproducts. This study demonstrates the efficacy of sunlight in rapidly degrading sulfathiazole at a predictable rate, leading to photoproducts of low antimicrobial potency. The mass spectrometry and mechanistic work described here are new insights into the photochemistry of sulfonamides. PMID- 28810230 TI - A novel hydrophilic interaction liquid chromatography method for the determination of underivatized amino acids in alimentary supplements. AB - Amino acids playing important roles in metabolic processes are often included in dietary supplements whose use has largely expanded over the last 20 years not only in patients with particular deficiencies, but also in athletes and even common people that want to enrich their regular daily diet. In the present study, a bare silica Kinetex core-shell 2.6MUm HILIC column was used for separation of some important hydrophilic amino acids and amino acids-like molecules i.e., aspartic acid, creatine, carnitine, arginine and the tripeptide glutathione (GSH), by optimizing the chromatographic conditions for their determination in complex alimentary supplements. The contribution of partition, adsorption and ion exchange on the retention mechanism was studied by varying parameters such as water content and the counter-ion concentration in the mobile phase. Optimum conditions employed a Phenomenex Kinetex core-shell 2.6MUm HILIC (100*4.6mm i.d.) column and a mobile phase of acetonitrile/potassium phosphate buffer (12.5mM; pH=2.8) 85:15, v/v, at the flow rate of 1.4mL/min, using UV detection at 200nm. A reference HPLC method for the selective determination of GSH by using 1,4 naphthoquinone as derivatization reagent was also introduced for comparative purposes. The developed HILIC method was validated and applied to the analysis of the considered compounds in dietary supplements. Interestingly, in some of the real samples, oxidized glutathione which is an inactive impurity of GSH, was found at the level of about 20%. The proposed study confirms the importance of simple analytical methods for a rigorous quality control of dietary supplements containing unstable active ingredients. PMID- 28810231 TI - Cr-induced cellular injury and necrosis in Glycine max L.: Biochemical mechanism of oxidative damage in chloroplast. AB - Chromium-induced toxicity and mechanisms of cell death involved in plants are yet to be fully elucidated. To understand the events of these processes, the stress response of the soybean plant using trivalent and hexavalent chromium compounds, namely, basic chromium sulphate (BCS) and potassium dichromate (K2Cr2O7) was investigated. The leaf surface morphology for stomatal aperture, wax deposition and presence of trichomes for chromium accumulation was examined by SEM-EDAX and light microscopy. The leaf mesophyll cell integrity was identified by trypan blue staining; chlorophyll autofluorescence, ROS generation and mitochondrial function were studied by fluorescence microscopy using different dyes. Isolated chloroplasts were analysed for micronutrients and total chromium content by AAS. Elevated Cr level and decreased Fe, Cu and Zn content in chloroplast revealed the active transportation of highly soluble Cr6+ species resulting in poor absorption of micronutrients. Cr accumulation as Cr(V) in chloroplast was noticed at g = 1.98 of electron paramagnetic resonance signal. Plants grown in Cr(VI) amended soil showed chemical modification of biological macromolecules in the chloroplast as observed from fourier transform infra-red (FTIR) spectra; the chloroplast DNA damage was confirmed by DAPI staining. Cr(VI)-treated plants showed significant reduction in the levels of various biochemical parameters. The results altogether clearly indicate that Cr(VI)-induced reactive oxygen species (ROS) production leads to oxidative stress-associated changes in the organelles, particularly in chloroplast, resulting in cell death. PMID- 28810232 TI - Microfluidic dielectrophoresis device for trapping, counting and detecting Shewanella oneidensis at the cell level. AB - Shewanella oneidensis, a model organism for electrochemical activity bacteria, has been widely studied at the biofilm level. However, to obtain more information regarding this species, it is essential to develop an approach to trap and detect S. oneidensis at the cell level. In this study, we report a rapid and label-free microfluidic platform for trapping, counting and detecting S. oneidensis cells. A microfluidic chip was integrated with a modified dielectrophoresis (DEP) trapping technique and hole arrays of different hole sizes. By numerical simulation and an elaborate electric field distribution design, S. oneidensis cells were successfully trapped and positioned in the hole arrays. Real time fluorescence imaging was also used to observe the trapping process. With the aid of a homemade image program, the trapped bacteria were accurately counted, and the results demonstrated that the amount of bacteria correlated with the hole sizes. As one of the significant applications of the device, Raman identification and detection of countable S. oneidensis cells was accomplished in two kinds of holes. The microfluidic platform provides a quantitative sample preparation and analysis method at the cell level that could be widely applied in the environmental and energy fields. PMID- 28810233 TI - An ultrasensitive electrochemical biosensor for the detection of mecA gene in methicillin-resistant Staphylococcus aureus. AB - Electrochemical DNA biosensor has unique advantages for on-site pathogenic microorganism detection, yet the detection of long DNA towards genome DNA (gDNA) analysis remains challenge. In this work, we report a novel electrochemical biosensor for the ultrasensitive analysis of mecA DNA on methicillin-resistant Staphylococcus aureus (MRSA) genome, using a multi-signal probes (MSP) system. The MSP consists of 7 biotin-labelled signal probes that will combine to the target DNA in a prehybridization step, and then the complex will be captured by a DNA tetrahedron structure probe (TSP) on the electrode surface. Then, after the introduction of the streptavidin-labelled HRP enzyme, a catalysis current signal is detected that is found to be corresponding to the concentration of the target DNA. MSP in this work plays a critical role not only for the signal amplification through bringing 7 biotins, but also dramatically improves the accessibility of the target sequence embedded in the double-strand DNA molecules and complex second structures. The 3-D DNA TSP here provides steady support and optimized surface density for the very "large" complex of MSP system and gDNA, as a base of the capture probe. Finally, as low as 10fM synthetic target DNA was successfully detected, which is at least 3 magnitudes lower than that using single signal probe. Most importantly, we demonstrated the practicability of our analysis method by analyzing a 57fM MRSA gDNA sample showing excellent selectivity, and the reliability of the analysis was also demonstrated by digital PCR. PMID- 28810234 TI - Electrochemical aptamer-based nanosensor fabricated on single Au nanowire electrodes for adenosine triphosphate assay. AB - In this work, single Au nanowire electrodes (AuNWEs) were fabricated by laser assisted pulling/hydrofluoric acid (HF) etching process, which then were characterized by transmission electron microscopy (TEM), electrochemical method and finite-element simulation. The as-prepared single AuNWEs were used to construct electrochemical aptamer-based nanosensors (E-AB nanosensors) based on the formation of Au-S bond that duplex DNA tagged with methylene blue (MB) was modified on the surface of electrode. In the presence of adenosine triphosphate (ATP), the MB-labeled aptamer dissociated from the duplex DNA due to the strong specific affinity between aptamer and target, which lead to the reduction of MB electrochemical signals. Moreover, BSA was employed to further passivate electrode surface bonding sites for the stable of the sensor. The as-prepared E AB nanosensor has been used for ATP assay with excellent sensitivity and selectivity, even in a complex system like cerebrospinal fluid of rat brain. Considering the unique properties of good stability, larger surface area and smaller overall dimensions, this E-AB nanosensor should be an ideal platform for widely sensing applications in living bio-system. PMID- 28810235 TI - Obesity as a Conditioning Factor for High-Altitude Diseases. AB - Obesity, a worldwide epidemic, has become a major health burden because it is usually accompanied by an increased risk for insulin resistance, diabetes, hypertension, cardiovascular diseases, and even some kinds of cancer. It also results in associated increases in healthcare expenditures and labor and economic consequences. There are also other fields of medicine and biology where obesity or being overweight play a major role, such as high-altitude illnesses (acute mountain sickness, hypoxic pulmonary hypertension, and chronic mountain sickness), where an increasing relationship among these two morbid statuses has been demonstrated. This association could be rooted in the interactions between obesity-related metabolic alterations and critical ventilation impairments due to obesity, which would aggravate hypobaric hypoxia at high altitudes, leading to hypoxemia, which is a trigger for developing high-altitude diseases. This review examines the current literature to support the idea that obesity or overweight could be major conditioning factors at high altitude. PMID- 28810236 TI - MicroRNA-375 Inhibits Growth and Enhances Radiosensitivity in Oral Squamous Cell Carcinoma by Targeting Insulin Like Growth Factor 1 Receptor. AB - BACKGROUND: MicroRNAs (miRNAs) have emerged as key players in various human biological processes, including tumorigenesis. Here, we investigated the roles of miR-375 in the pathogenesis of oral squamous cell carcinoma (OSCC). METHODS: We performed quantitative real-time PCR (qRT-PCR) to detect miR-375 expression in OSCC tissues and corresponding normal oral epithelial tissues and analyze the correlation of miR-375 expression with OSCC metastasis and patient's survival. Then, the effects of miR-375 expression on proliferation, cell cycle, apoptosis and radiosensitivity in OSCC cells were determined by using MTT, flow cytometry and clonogenic survival assays. A dual-luciferase reporter assay was performed to test whether miR-375 binds to the 3'-untranslated region (3'-UTR) of target mRNA. RESULTS: The expression level of miR-375 in OSCC tissues was significantly lower than that in normal oral epithelial tissues, and low miR-375 expression was correlated with higher incidence of lymph node metastasis and poor survival of OSCC patients. Upregulation of miR-375 significantly inhibits growth, induces cell cycle arrest in G0/G1 phase, increases apoptosis and enhances radiosensitivity in OSCC cells. Analysis of luciferase activity demonstrated that miR-375 binds to the 3'-UTR of insulin like growth factor 1 receptor (IGF-1R). Small interfering RNA (shRNA)-mediated IGF-1R knockdown mimics the effects of miR 375 upregulation, while overexpression of IGF-1R partially reverses those effects in OSCC cells. CONCLUSION: It was obviously demonstrated that miRNA-375 inhibits growth and enhances radiosensitivity in OSCC cells by targeting IGF-1R, suggesting that miR-375 may be a potential therapeutic target for OSCC patients. PMID- 28810237 TI - Tooth Wear Inclination in Great Ape Molars. AB - Primate dietary diversity is reflected in their dental morphology, with differences in size and shape of teeth. In particular, the tooth wear angle can provide insight into a species' ability to break down certain foods. To examine dietary and masticatory information, digitized polygon models of dental casts provide a basis for quantitative analysis of wear associated with tooth attrition. In this study, we analyze and compare the wear patterns of Pongo pygmaeus, Gorilla gorillagorilla and Pan troglodytes schweinfurthii lower molars, focusing on the degree of inclination of specific wear facets. The variation in wear angles appears to be indicative of jaw movements and the specific stresses imposed on food during mastication, reflecting thus the ecology of these species. Orangutans exhibit flatter wear angles, more typical of a diet consisting of hard and brittle foods, while gorillas show a wear pattern with a high degree of inclination, reflecting thus their more leafy diet. Chimpanzees, on the other hand, show intermediate inclinations, a pattern that could be related to their highly variable diet. This method is demonstrated to be a powerful tool for better understanding the relationship between food, mastication and tooth wear processes in living primates, and can be potentially used to reconstruct the diet of fossil species. PMID- 28810240 TI - Efficient Statistical Method for Association Analysis of X-Linked Variants. AB - BACKGROUND/AIMS: Unlike the gene-poor Y chromosome, the X chromosome contains over 1,000 genes that are essential for viability of cells. Females have 2 X chromosomes, and thus female X-linked gene expression would be expected to be twice that of males. To adjust this imbalance, one of the 2 X-linked genes is often inactivated, and this is known as X-chromosome inactivation (XCI). However, recent studies described that a gene can be nonrandomly selected for inactivation from 2 X-linked genes and that XCI is not observed in some X-linked genes. Since this complex biological process has prevented efficient statistical association analyses, we propose a new statistical method against this uncertain biological process. METHODS: The proposed method consists of 2 steps. First, p values for various biological processes are calculated and then combined into a single p value with the modified Fisher method and a minimum p value. RESULTS: Our simulation results show that the proposed method is generally the most statistically efficient and is not sensitive to the unknown biological model. CONCLUSION: Therefore, we can conclude that the proposed approaches are robust against the various XCI processes for testing the association of X-linked single nucleotide polymorphisms with the disease of interest and the proposed method is a practical solution. PMID- 28810239 TI - The Prevalence of and Factors Related to Vascular Hyperintensity on T1-Weighted Imaging in Acute Ischemic Stroke. AB - BACKGROUND: Thrombus visualization in patients with acute ischemic stroke has been detected and reported using various imaging modalities. T1-weighted imaging (T1-WI) can depict thrombi as hyperintense signals within vessels. Moreover, in addition to thrombi, T1-WI hyperintensities in arteries may suggest arterial dissection. However, the frequency of and factors related to the T1-hyperintense vessel sign (T1-HVS) are not fully known. The aim of this study was to clarify the prevalence of and related factors for the T1-HVS in patients with acute ischemic stroke. METHODS: From September 2014 through December 2015, consecutive acute ischemic stroke patients who were admitted to our stroke unit within 7 days from symptom onset were retrospectively recruited from the prospective registry. A T1-HVS was defined as the presence of a hyperintense signal, with intensity higher than surrounding brain, within the vessel lumen. Moreover, T1-HVSs were separated into filled T1-HVSs (hyperintensity fills whole vessel lumen) and non filled T1-HVSs. The frequency of the T1-HVS and the timing of emersion and the relationship between the presence of the T1-HVS and arterial occlusion were assessed. RESULTS: A total of 399 patients (139 women; median age 73 years; National Institutes of Health Stroke Scale score 3) were enrolled in the present study. Of these, 327 (82%) patients had T1-WI on admission. Two hundred and sixty seven (67%) subjects had at least one follow-up T1-WI (median 6 days after admission), and 134 (34%) cases had >=2 follow-up T1-WI examinations. The T1-HVS was observed in 18 patients during admission; therefore, the frequency of the T1 HVS in acute ischemic stroke patients was 4.5% (95% CI 2.5-6.5%). All but one (94%) of the T1-HVSs were first observed on follow-up imaging, and the median number of days from onset to T1-HVS appearance was 9. For patients having initial major artery occlusion and follow-up MRI (n = 95), sensitivity and specificity of the T1-HVS for persistent arterial occlusion on follow-up MR angiography were 22 and 100%, respectively. T1-HVS persisted for a few months and then normalized. Although there were no significant differences between filled and non-filled T1 HVS, more patients with non-filled T1-HVS had arterial dissection (43%) than those with filled T1-HVS (9%, p = 0.245). CONCLUSION: The T1-HVS was observed in 4.5% of acute ischemic stroke patients. T1-HVSs appeared in the subacute phase in arteries with persistent occlusion and remained for a few months. PMID- 28810238 TI - Long-Term Weight Maintenance Strategies Are Experienced as a Burden by Persons Who Have Lost Weight Compared to Persons with a lifetime Normal, Stable Weight. AB - OBJECTIVE: To assess dietary intake, eating patterns, physical activity and eating behaviors, and to explore strategies and perceptions of the experience of weight maintenance in weight loss maintainers (weight loss maintenance (WLM) >= 10% weight loss maintained for >=1 year) and in matched controls with a lifetime stable normal weight. METHODS: Volunteers (32) were recruited by a snowball procedure in this cross-sectional, mixed-methods study. Diet, physical activity, and eating behaviors were assessed with validated questionnaires. Strategies and experiences were investigated during interviews. Descriptive coding, thematic analysis (qualitative data) as well as descriptive analysis and t-tests (quantitative data) were performed. RESULTS: Both groups had similar energy and macronutrient consumption. Those in the WLM group reported higher levels of exercise and scored higher on several dimensions of eating disorders. Four themes - 'food choices,' 'quantities and portion control,' 'physical activity', and 'burden' - emerged from the qualitative data. Both groups used similar weight maintenance strategies, but those in the WLM group experienced a higher burden, expressing effortful control which contrasted with the control group's confidence in their internal cues. CONCLUSION: Our results show an additional burden related with maintaining weight loss compared to keeping a stable normal weight. They provide evidence to devise interventions that will address the difficulty of regulating intake. PMID- 28810241 TI - Molecular Epidemiology of Charcot-Marie-Tooth Disease in Northern Ostrobothnia, Finland: A Population-Based Study. AB - BACKGROUND: Charcot-Marie-Tooth (CMT) disease is the most common hereditary neuromuscular disorder with a population prevalence of 9.7-82.3/100,000. In this study, we have estimated the prevalence of CMT and its subtypes in Finland and examined the frequency of molecular etiologies. METHODS: A population-based survey included adult patients with peripheral neuropathy from the province of Northern Ostrobothnia, Finland. Secondary causes of peripheral polyneuropathy were excluded and patients with clinical and neurophysiological features pertinent with CMT were included. Molecular diagnostics was carried out when DNA was available. RESULTS: We found 107 subjects with CMT yielding a prevalence 34.6/100,000 in Northern Ostrobothnia. The heterozygous point mutation p.His123Arg in ganglioside induced differentiation associated protein 1 (GDAP1) was found in 31.5% and peripheral myelin protein 22 (PMP22) duplication in 16.9% of the affected. Point mutations in myelin protein zero, mitofusin 2, and gap junction protein beta 1 accounted for 6.7% of the cases. In addition, 18 persons had hereditary neuropathy with liability to pressure palsies and 15 of them carried the PMP22 deletion. CONCLUSIONS: The prevalence of CMT in Northern Ostrobothnia, Finland, seems to be slightly higher than those in previous studies in European populations. Founder mutation in the GDAP1 gene accounts for a large part of the genetically defined CMT2 in Finland. PMID- 28810243 TI - Evaluating Critical Brain Radiation Doses in the Treatment of Multiple Brain Lesions with Gamma Knife Radiosurgery. AB - BACKGROUND: Treatment of patients with multiple brain metastases has shifted to stereotactic radiosurgery, withholding whole-brain (WB) radiation therapy. However, radiation toxicity to the brain is a concern when treating multiple brain lesions with single-fraction stereotactic radiosurgery. OBJECTIVE: The purpose of this study was to determine the changes in brain radiation doses when treating various numbers of targets and lesion volumes. METHODS: We simulated different treatment plans with different combinations of varying tumor volumes including 0.1, 0.5, 1, 2, and 5 cm3, and tumor numbers including 1, 3, 5, 10, 15, 20, and 25. Treatment planning was performed for all combinations in a computerized tomography of the head of a patient, using Leksell GammaPlan version 10.1.1 (Elekta AB, Stockholm, Sweden). Two different dosing strategies were used. In the lower-prescription dosing schedule, a marginal dose was given to the 50% isodose line, and 20 Gy were used when the number of lesions was less than 15 and 18 Gy were applied when the number of lesions was equal to or more than 15. In the higher-prescription dosing schedule, a marginal dose of 24 Gy was used for lesions of less than 5 cm3 and 20 Gy were applied for lesions equal to 5cm3. The mean WB dose, the WB integral dose, and the volume of brain receiving 12 Gy (V12 Gy) were calculated for each scenario. Also, the beam-on time of the Gamma Knife 4C unit was reported for all treatment scenarios. RESULTS: Regression analysis showed that the total tumor volume was a more significant predictor of V12 Gy than the number of lesions, and a linear correlation between the total tumor volume and V12 Gy was found. We also found that the total tumor volume was a more significant predictor of the mean WB dose and the WB integral dose compared to the number of lesions. CONCLUSION: Our results suggest that multiple small to mid sized lesions could be safely treated with a single-fraction gamma knife. PMID- 28810242 TI - MiR-490-5p Suppresses Cell Proliferation and Invasion by Targeting BUB1 in Hepatocellular Carcinoma Cells. AB - OBJECTIVE: To verify that miR-490-5p could influence hepatocellular carcinoma (HCC) cells' proliferation, invasion, cycle, and apoptosis by targeting BUB1. METHODS: Quantitative real time-PCR (QRT-PCR) was used to determine the miR-490 5p expression. Immunohistochemistry, qRT-PCR, and Western blot were employed to detect BUB1 and transforming growth factor-beta (TGFbeta/Smad) signaling-related proteins expression in hepatic tissues and cells. The luciferase assay was used to confirm the targeting relationship between miR-490-5p and BUB1. The Cell Counting Kit-8, colony formation, Transwell invasion, scratch healing assays, and flow cytometry analysis were conducted to evaluate HCC cells proliferation, invasion, migration, and apoptosis alteration after transfection. RESULTS: In HCC tissues and cells, lower expression of miR-490-5p was detected, while BUB1 was overexpressed than controls. The upregulation of miR-490-5p inhibited BUB1 expression and the overexpression of miR-490-5p or the under-expression of BUB1 inhibited HCC cells proliferation, migration, invasion, and increased the apoptosis rate. CONCLUSION: MiR-490-5p could regulate TGFbeta/Smad signaling pathways by inhibiting BUB1, which could then inhibit HCC cells proliferation, invasion, and migration as well as decrease cell viability and increase apoptosis. PMID- 28810244 TI - Increasing Haemodialytic Clearances as Residual Renal Function Declines: An Incremental Approach. AB - Many patients with chronic kidney disease start undergoing thrice-weekly haemodialysis (HD), aiming for an HD sessional dialyzer urea clearance target, irrespective of whether they have residual renal function (RRF). While increasing sessional dialyzer urea clearance above a target of 1.2 has not been shown to improve patient survival, it has been shown that the preservation of RRF improves patient self-reported outcomes and survival. Observational studies have suggested that initiating twice-weekly HD schedules leads to greater preservation of RRF. This has led to the concept of following an incremental approach to initiating HD, steadily increasing the amount of weekly dialyzer clearance as RRF decreases. Incremental dialysis practice requires the regular assessment of RRF to prevent inadequate delivery of dialysis treatment. Once RRF is lost, then the dialysis schedule and modality need to be adjusted to try to increase the middle-sized solute clearance and protein-bound toxins. PMID- 28810245 TI - The Etiology of Hoarding Disorder: A Review. AB - This article will review the evidence of various proposed factors that contribute to the onset and maintenance of hoarding disorder (HD). Data suggests that hoarding is a chronic condition that starts early in life and does not remit if left untreated. There is emerging evidence that a number of factors contribute to the expression of HD symptoms, including genetics, neurocognitive functioning, attachments to possessions, beliefs, avoidance, personality factors, and life events. The extent to which each etiological factor uniquely contributes to hoarding is still unknown. Other demographic factors, such as socioeconomic status, age, and gender, may impact hoarding severity. Research on the causes and characteristics of hoarding has recently started making progress into understanding this newly recognized disorder, yet we still have a ways to go in understanding the biological and environmental causes. This paper will synthesize available literature on the etiology of HD. PMID- 28810246 TI - GPER Agonist G1 Attenuates Neuroinflammation and Dopaminergic Neurodegeneration in Parkinson Disease. AB - OBJECTIVE: Epidemiological studies have shown that women of reproductive age have much less possibility of developing Parkinson disease (PD) than men. The beneficial effect of estrogen also has been well-described in both culture and animal models of PD. G protein-coupled estrogen receptor (GPER) is a membrane associated estrogen receptor, and displayed a neuroprotective role in a mouse model of PD. Since GPER is highly expressed in microglia, we speculate that GPER mediates the neuroprotective function of estradiol through suppressing the neuroinflammation of PD. METHODS: We investigated the effects of GPER agonist G1 and GPER antagonist G15 on the neurodegeneration of dopaminergic neuron, the activation of microglia, and the production of IL-1beta, TNF-alpha, and IL-6 in 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced animal model of parkinsonism. Furthermore, we confirmed the effects of GPER activation on the production of IL-1beta, TNF-alpha, and IL-6 in an in vitro MPP+ model in BV2 microglial cells. RESULTS: After 12-day treatment with G1, mice showed an increase in the number of tyrosine hydroxylase-immunoreactive cells, reduced activation of microglia, and the abatement of proinflammatory cytokines, and the anti-inflammatory effect of G1 was abolished by G15. Meanwhile, in vitro studies demonstrated that GPER activation also reduced the release of proinflammatory cytokines from BV2 microglial cells after MPP+ stimulation. CONCLUSION: Our data suggest that GPER mediates the anti-neuroinflammatory effect of estrogen in experimental PD progression. PMID- 28810247 TI - Physical Inactivity Predicts Slow Gait Speed in an Elderly Multi-Ethnic Cohort Study: The Northern Manhattan Study. AB - INTRODUCTION: Gait speed is associated with multiple adverse outcomes of aging. We hypothesized that physical inactivity would be prospectively inversely associated with gait speed independently of white matter hyperintensity volume and silent brain infarcts on MRI. METHODS: Participants in the Northern Manhattan Study MRI sub-study had physical activity assessed when they were enrolled into the study. A mean of 5 years after the MRI, participants had gait speed measured via a timed 5-meter walk test. Physical inactivity was defined as reporting no leisure-time physical activity. Multi-variable logistic and quantile regression was performed to examine the associations between physical inactivity and future gait speed adjusted for confounders. RESULTS: Among 711 participants with MRI and gait speed measures (62% women, 71% Hispanic, mean age 74.1 +/- 8.4), the mean gait speed was 1.02 +/- 0.26 m/s. Physical inactivity was associated with a greater odds of gait speed in the lowest quartile (<0.85 m/s, adjusted OR 1.90, 95% CI 1.17-3.08), and in quantile regression with 0.06 m/s slower gait speed at the lowest 20 percentile (p = 0.005). CONCLUSIONS: Physical inactivity is associated with slower gait speed independently of osteoarthritis, grip strength, and subclinical ischemic brain injury. Modifying sedentary behavior poses a target for interventions aimed at reducing decline in mobility. PMID- 28810248 TI - Antibiotic Susceptibility and Molecular Characterization of Escherichia coli O157 Isolates from Urinary Tract Infections. AB - BACKGROUND: Escherichia coli O157 is an important food-borne pathogen that can cause diarrhoea, hemorrhagic colitis, and hemolytic uraemic syndrome. Enterobacterial repetitive intergenic consensus sequence PCR (ERIC-PCR) and multilocus sequence typing (MLST) are good methods for molecular typing and the extensive use of antibiotics is a contributing factor to the increasing incidence of antimicrobial-resistant for these strains. OBJECTIVES: The aim of this study was to determine the prevalence, antimicrobial resistance, and genetic diversity of E. coli O157 based on the prevalence of urinary tract infection (UTI) in Hubei, China. RESULTS: We obtained 23 (8.07%) E. coli O157 isolates from 285 UTI patients in Hubei, China. All isolates were subjected to antibiotic susceptibility analysis, and molecular typing was performed using ERIC-PCR and MLST. Antimicrobial susceptibility results indicated that most strains were resistant to penicillin (95.65%), chloramphenicol (73.91%), and ampicillin (69.57%). All isolates were discovered to be multiresistant (resistance to more than 3 antibiotics). Genetic variability analysis showed that all of the isolates were grouped into 4 clusters both by ERIC-PCR and MLST. CONCLUSION: Our findings demonstrated the presence of E. coli O157 in UTIs, provided insights into the dissemination of antibiotic-resistant strains, and improved our knowledge of E. coli O157 risk assessment in UTIs. PMID- 28810249 TI - Knockdown of Cxcl10 Inhibits Mesangial Cell Proliferation in Murine Habu Nephritis Via ERK Signaling. AB - BACKGROUND/AIMS: IFN-gamma-inducible protein 10 (IP-10, CXCL10) has been widely demonstrated to be involved in chemotaxis, cell growth regulation and angiogenesis inhibition. It has been reported that CXCL10 expression is significantly increased in patients with MesPGN (Mesangial proliferative glomerulonephritis). However, the underlying mechanism of CXCL10 in MesPGN reminds unclear. METHODS: Wildtype (Cxcl10+/+) mice and Cxcl10-deficient (Cxcl10 /-) mice were used to generate a murine model of MesPGN. The histological changes in glomeruli were examined by PAS staining (Periodic Acid-Schiff staining), and cell proliferation was detected by PCNA immunohistochemistry staining. The expression of cell cycle regulatory proteins was analyzed by Western blotting and the effects of CXCL10 on primary mouse renal mesangial cells (MRMC) proliferation were detected using the EDU assay. Furthermore, the specific mechanisms by which CXCL10 affected mesangial cells were investigated in vitro using a specific inhibitor. RESULTS: Typical pathological phenotypes were observed in both mouse types, while the Cxcl10-/- mice had lighter accumulation of extracellular matrix, less cell proliferation and diminished up-regulation of cell cycle regulatory proteins compared to Cxcl10+/+ mice at day 7. Furthermore, we observed that CXCL10 inhibition resulted in less activation of ERK phosphorylation, and ERK pathway inhibition by a specific inhibitor, U0126, prevented CXCL10 induced MRMC proliferation and the activation of phosphorylated ERK. CONCLUSIONS: CXCL10 may aggravate mesangial proliferation in MesPGN by activating the ERK signaling pathway. These results provide a novel insight into the mechanism and potential therapy target of MesPGN. PMID- 28810250 TI - Cerebral Small Vessel Disease Is Associated with Dysregulation in the Ubiquitin Proteasome System and Other Major Cellular Pathways in Specific Brain Regions. AB - BACKGROUND/AIMS: Cerebral small vessel disease (SVD) is characterized by periventricular white matter (WM) changes and can lead to vascular dementia, the second most common form of age-dependent dementia. The pathogenesis of the disease remains poorly understood, and studies of its molecular basis are limited. By profiling gene expression of dissected postmortem brain tissue in SVD patients and comparisons with tissue of nonneurological controls, we aimed to identify genes and processes that are involved in the pathogenesis of SVD to gain new pathogenetic insights. METHODS: We performed genome-wide expression analyses in postmortem brain tissue samples dissected from frontal, temporal, and occipital lobes as well as basal nuclei comprising thalamus, basal ganglia, and hippocampus from 5 SVD cases and 5 nonaffected control cases. Cellular pathways associated with differently expressed genes were identified in each brain region individually. RESULTS: This analysis disclosed regional differences, with frontal lobe and thalamus showing the highest numbers of genes with significantly altered expression. Biological functions and pathways associated with changed gene expression depicted brain area-specific defective pathways. Vessel-associated functions, such as increased extracellular matrix-receptor interactions and cell adhesion molecules, were enhanced in all regions. Inflammation and apoptosis were induced particularly in basal nuclei and temporal and occipital regions. Interestingly, genes associated with the ubiquitin-dependent proteolysis (ubiquitin proteasome system) pathway were downregulated in the frontal lobe and in the thalamus, leading to the formation of protein aggregates. CONCLUSION: This analysis deciphers brain region-specific molecular processes to increase the present knowledge of SVD pathology and determine new potential therapeutic targets. PMID- 28810251 TI - A Prospective, Randomized, Open-Label, Blinded, Endpoint Study Exploring Platelet Response to Half-Dose Prasugrel and Ticagrelor in Patients with the Acute Coronary Syndrome: HOPE-TAILOR Study. AB - BACKGROUND: The optimal dosing of novel oral P2Y12 receptor platelet inhibitors such as prasugrel or ticagrelor is unclear and especially challenging in East Asians. We hypothesize that half-dose prasugrel and ticagrelor may be sufficient for long-term maintenance management in Korean patients with the acute coronary syndrome (ACS) compared with conventional dosages. DESIGN: HOPE-TAILOR (Half Dose of Prasugrel and Ticagrelor in Platelet Response after Acute Coronary Syndromes) is a prospective, randomized, open-label, blinded, endpoint (PROBE) single center, clinical trial. A total of 100 patients with ACS undergoing drug-eluting stent implantation will be randomly assigned to prasugrel, ticagrelor, or clopidogrel, and the patients in each treatment group will receive 1-month therapy with 100 mg q.d. aspirin plus prasugrel 10 mg q.d., ticagrelor 90 mg b.i.d., or clopidogrel 75 mg q.d., followed by half-dose prasugrel 5 mg q.d. or ticagrelor 45 mg b.i.d. for maintenance treatment but without clopidogrel dose reduction. The primary endpoint will be optimal platelet reactivity 3 months after coronary intervention, defined by VerifyNow Analyzer (PRU: 85-208) and vasodilator-stimulated phosphoprotein P2Y12 flow cytometry assay (platelet reactivity indices: 16-50%). Clinical outcomes will also be assessed, including major efficacy (composite of cardiac death, nonfatal myocardial infarction, repeat revascularization, or stroke) and safety (bleeding >=2 according to the Bleeding Academic Research Consortium). CONCLUSION: HOPE-TAILOR is a prospective, randomized, open-label, blinded, endpoint study to explore the efficacy and safety of novel P2Y12 receptor inhibitors administered orally at half the dose in Korean patients with ACS. The results will be available late in 2017. PMID- 28810252 TI - The Impact of the Hepatitis B Core Antibody Status on Recurrence in Patients with Non-B Non-C Hepatocellular Carcinoma after Curative Surgery. AB - BACKGROUND: The serum antibody to hepatitis B core antigen (HBcAb) is considered a risk factor of liver carcinogenesis. This study aimed to reveal whether HBcAb status is a prognostic factor after hepatectomy is performed for treating hepatocellular carcinoma (HCC). METHODS: This retrospective study enrolled 272 patients who underwent hepatectomy as the initial treatment for HCC and who were followed up over 5 years after surgery. The types of HCC were classified into the following 3 types according to the hepatitis virus infection status and the patients without hepatitis virus infection non-B non-C HCC (NBNC-HCC) were further classified into 2 groups. RESULTS: There is no novel finding as a result of the comparison made among hepatitis virus status. Of 90 patients (33.1%) with NBNC-HCC, 10 patients were excluded because the preoperative HBcAb status was not measured. There were 51 patients (63.8%) who were HBcAb-positive and 29 patients (36.2%) who were HBcAb-negative. In multivariate analysis, the presence of HBcAb negative (hazard ratio 2.10, 95% CI 1.09-4.03, p = 0.026) remained as significant independent risk factors for recurrence in NBNC-HCC. CONCLUSIONS: This study shows that the HBcAb-positive is rather a favorable predictor for recurrence after curative resection in NBNC-HCC. PMID- 28810253 TI - Outcomes of Self-Expanding Metal Stents in Malignant Colonic Obstruction are Independent of Location or Length of the Stenosis: Results of a Retrospective, Single-Center Series. AB - AIM: To evaluate the length and location of stenosis in the colon as predictors of technical and clinical outcomes of stent placement in patients presenting with obstructive colorectal cancer. METHODS: A prospective single-center cohort study of patients treated with a colonic stent for malignant obstruction, regardless of stenosis length or location. Stenosis length was assessed globally on the appropriate CT slice as well as by 3D CT reconstruction. We analyzed whether outcomes were different in patients with a right sided-tumor and/or a stenosis >4 cm long. RESULTS: One hundred forty-one patients were evaluated, 63 with a stenosis >4 cm, 48 with a stenosis proximal to the splenic flexure. Technical failure (n = 9) was mainly caused because of looping or due to the difficulty in engaging the stenosis precluding analysis of the relation between the stenosis length and technical success. Both measurement methods showed good agreement. Clinical outcomes were not associated with stenosis length or location. CONCLUSION: Clinical outcomes of stenting did not differ between groups regardless of stenosis length or location. Measuring stenosis length more precisely using 3D CT reconstructions is not of help. PMID- 28810254 TI - Insulin Influences LPS-Induced TNF-alpha and IL-6 Release Through Distinct Pathways in Mouse Macrophages from Different Compartments. AB - BACKGROUND/AIMS: Diabetic subjects are more susceptible to infections, which is partially due to insulin deficiency and hyperglycemia. We hypothesized that insulin influences cytokine release by macrophages from diabetic C57BL/6 mice stimulated with lipopolysaccharides (LPS). METHODS: Bone marrow-derived macrophages (BMDM) and tissue-specific macrophages from diabetic (alloxan 60 mg/kg, i.v.) male C57BL/6 mice were stimulated by LPS (100 ng/mL) and/or treated by insulin (1 mU/mL). RESULTS: Using BMDM from diabetic mice, we showed that LPS induced an increase in TNF-alpha and IL-6 release and p38, SAPK/JNK, ERK 1/2, and Akt (308-Thr and 473-Ser) phosphorylation but not in PKCalpha/beta II and delta. Insulin increased TNF-alpha and IL-6 secretion in LPS-stimulated macrophages as well as p-p38, p-SAPK/JNK, p-ERK 1/2, p-PI3K (p55) and p-Akt (473-Ser) expression. Furthermore, PI3-kinase inhibition by wortmannin decreased TNF-alpha release, and inhibition by LY294002 decreased both TNF-alpha and IL-6 levels after LPS-insulin treatment. PD98059, which inhibits the ERK upstream activators MAPK kinase (MKK) 1 and MKK2, reduced the effect promoted by insulin in BMDM stimulated by LPS In tissue-specific macrophages, insulin reduced LPS-induced TNF alpha, IL-6 and IL-1beta secretion in alveolar and peritoneal macrophages. CONCLUSION: These data suggest that insulin through the modulation of PI3-kinase and ERK 1/2 pathways drive different responses in macrophages, thereby enhancing our understanding of the plasticity of these cells. PMID- 28810256 TI - Dose-Response Relationship between the Risk of Vasovagal Syncope and Body Mass Index or Systolic Blood Pressure in Young Adults Undergoing Blood Tests. PMID- 28810255 TI - Ponatinib-Induced Graft-versus-Host Disease/Graft-versus-Leukemia Effect in a Patient with Philadelphia-Positive Acute Lymphoblastic Leukemia without the T315I Mutation Relapsing after Allogeneic Transplant. AB - We describe the case of a patient with Philadelphia-positive acute lymphoblastic leukemia treated with dasatinib plus steroids as first-line therapy, who achieved a major molecular response (MMR) before undergoing matched, unrelated donor allogeneic stem cell transplant. Eleven months after the transplant, she experienced molecular relapse. Mutational screening showed negativity for the T315I mutation, The patient underwent a salvage chemotherapy regimen with clofarabine + cyclophosphamide + steroids and ponatinib (clofarabine 70 mg i.v., days 1-5, cyclophosphamide 700 mg i.v., days 1-5, and ponatinib 45 mg p.o., daily starting at day 15). We observed a rapid decrease in minimal residual disease on molecular assessment with an MMR of P190-BCR-ABL/ABL = 0.01% confirmed by bone marrow revaluations at days +23, +59, +108, and +191 after the first day of salvage chemotherapy. After starting ponatinib, the patient experienced skin graft-versus-host disease, suggesting that the efficacy of ponatinib could be related not only to the direct antileukemic effect but also to its ability to promote an indirect graft-versus-leukemia effect. Ponatinib treatment was well tolerated and considered safe with easily manageable side effects. PMID- 28810257 TI - Karyotypes and Distribution of Tandem Repeat Sequences in Brassica nigra Determined by Fluorescence in situ Hybridization. AB - Whole-genome shotgun reads were analyzed to determine the repeat sequence composition in the genome of black mustard, Brassica nigra (L.) Koch. The analysis showed that satellite DNA sequences are very abundant in the black mustard genome. The distribution pattern of 7 new tandem repeats (BnSAT13, BnSAT28, BnSAT68, BnSAT76, BnSAT114, BnSAT180, and BnSAT200) on black mustard chromosomes was visualized using fluorescence in situ hybridization (FISH). The FISH signals of BnSAT13 and BnSAT76 provided useful cytogenetic markers; their position and fluorescence intensity allowed for unambiguous identification of all 8 somatic metaphase chromosomes. A karyotype showing the location and fluorescence intensity of these tandem repeat sequences together with the position of rDNAs and centromeric retrotransposons of Brassica (CRB) was constructed. The establishment of the FISH-based karyotype in B. nigra provides valuable information that can be used in detailed analyses of B. nigra accessions and derived allopolyploid Brassica species containing the B genome. PMID- 28810258 TI - Prevalence of Hyponatremia in Elderly Patients with Hip Fractures: A Two-Year Study. AB - OBJECTIVE: This study investigated the prevalence of hyponatremia in elderly patients (>=65 years old) with hip fractures. SUBJECTS AND METHODS: All records containing clinical and laboratory data on the 334 elderly patients admitted to the San Giovanni di Dio e Ruggi d'Aragona Hospital of Salerno, Italy, with hip fractures during 2014 and 2015, were retrieved from the hospital database. Patients were divided into 4 groups, according to their sex and the type of hip fracture. Sodium serum concentrations were retrieved from the medical records. Hyponatremia was defined as the presence of at least 1 episode of hyponatremia during the hospital stay. RESULTS: Of 334 elderly patients, hyponatremia was found in 64 (19%). The prevalence of hyponatremia was 18% (28/157) for female patients with extracapsular proximal femoral fracture, 22% (17/79) for female patients with intracapsular proximal femoral fracture, 20% (12/60) for male patients with extracapsular proximal femoral fracture, and 18% (7/38) for male patients with intracapsular proximal femoral fracture. CONCLUSION: There was a high prevalence of hyponatremia in the elderly patients with hip fractures. Hence, serum sodium concentrations should be regularly assessed to prevent occurrence of hyponatremia. PMID- 28810259 TI - Reliability, Reproducibility and Prognostic Accuracy of the Alberta Stroke Program Early CT Score on CT Perfusion and Non-Contrast CT in Hyperacute Stroke. AB - BACKGROUND: Alberta Stroke Program Early CT Score (ASPECTS) assesses early ischemic change on non-contrast CT (NCCT). We hypothesised that assessing ASPECTS regions on CT Perfusion (CTP) rather than NCCT would improve inter-rater agreement and prognostic accuracy, particularly in patients presenting early after stroke onset. METHODS: Ischemic stroke patients treated with intravenous alteplase from 2009 to 2014 at our institution were included in this study. Inter rater agreement and prognostic accuracy of ASPECTS across modalities were analysed by the time between stroke onset and initial NCCT, dichotomized 1st quartile versus quartiles 2-4, referred to as epochs. ASPECTS was assessed by 2 independent raters, blinded to stroke onset time, with agreement determined by weighted kappa (kappaw). Prognostic accuracy for favourable outcome (modified Rankin Scale 0-2) was assessed using the receiver-operating characteristic analysis. RESULTS: A total of 227 participants were included. There was significant time-by-CT modality interaction for ASPECTS, p < 0.0001. The inter rater agreement of ASPECTS on NCCT significantly increased as onset to CT time increased (kappaw epoch 1 = 0.76 vs. kappaw epoch 2-4 = 0.89, p = 0.04), whereas agreement using CTP parameters was stable across epochs. Inter-rater agreement for CTP-ASPECTS was significantly higher than NCCT in early epoch: Tmax kappaw = 0.96, p = 0.002; cerebral blood volume (CBV) kappaw = 0.95, p = 0.003; cerebral blood flow (CBF) kappaw = 0.94, p = 0.006, with no differences in the later epochs. Prognostic accuracy of ASPECTS on NCCT in epoch 1 were (area under the ROC curves [AUC] = 0.52, 95% CI 0.48-0.56), CBV (AUC = 0.55, 95% CI 0.42-0.69, CBF (AUC = 0.58, 95% CI 0.46-0.71) and Tmax (AUC = 0.62, 95% CI 0.49-0.75), p = 0.46 between modalities. CONCLUSIONS: CTP can improve reliability when assessing the extent of ischemic changes, particularly in patients imaged early after stroke onset. PMID- 28810260 TI - Cytoplasmic Lipid Accumulation Characteristic of the Cribriform Variant of Papillary Thyroid Carcinoma. AB - OBJECTIVE: The purpose of this study was to clarify the diagnostic significance of cytoplasmic lipid accumulation (CLIA) in the cribriform variant of papillary thyroid carcinoma (CV-PTC). METHODS: We performed a histological, immunohistochemical, and cytological examination of 35 CV-PTC cases at the Kuma Hospital. CLIA was defined as bubble-like multivacuolation in cytoplasm with distinct cell border. We also examined 100 conventional PTC (con-PTC) cases as controls. RESULTS: Histological analysis showed the presence of carcinoma cells with CLIA in 60.0% of CV-PTC and 5.0% of con-PTC cases. The vacuoles tended to distribute in the subnuclear portion of carcinoma cells showing papillary growth. They were positive for oil red O staining and adipophilin. The carcinoma cells without the vacuoles showed a subnuclear dot-like expression for adipophilin in CV-PTC cases, but not in the con-PTC cases. Cytological analysis showed CLIA in 17 (54.8%) of the 31 CV-PTC cases, but not in the con-PTC cases. CONCLUSION: This is the first study to report the presence of carcinoma cells with CLIA in CV-PTC. The subnuclear dot-like expression of adipophilin may be characteristic of CV PTC. These findings might be related to degenerative changes occurring in CV-PTC. PMID- 28810261 TI - Comparative Evaluation of Magnetic Resonance-Guided Focused Ultrasound Surgery for Essential Tremor. AB - BACKGROUND: Treatment options for patients with drug-resistant essential tremor (ET) are limited. Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is an emerging technique to treat refractory ET. OBJECTIVES: To present MRgFUS as an alternative to radiofrequency (RF) thalamotomy or deep brain stimulation (DBS) for ET treatment. METHODS: We retrospectively analyzed 59 patients who underwent unilateral surgery for drug-resistant ET. Treatments included RF thalamotomy (n = 17), DBS (n = 19), and MRgFUS (n = 23). The outcomes measured were tremor severity and treatment-related complications. RESULTS: At 1 month postoperatively, 100% of RF thalamotomy patients, 89.5% of DBS patients, and 91.3% of MRgFUS patients exhibited absent/mild tremor (successful treatment); other patients exhibited partial relief. At 12 months postoperatively, treatment success for each procedure was observed in 70.6, 84.2, and 78.3% of patients, respectively. At 1 month postoperatively, treatment-related complications had occurred in 58.8, 5.3, and 13.0% of patients, respectively. At 12 months postoperatively, side effects persisted in 11.8, 21.1, and 4.4% of patients, respectively. No statistical differences in treatment success were observed between treatments or over time. Complication rates differed between treatment modalities (p < 0.01) and were lowest in the MRgFUS group. CONCLUSIONS: Patients with drug-resistant ET received equivalent results from RF thalamotomy, DBS, and MRgFUS. DBS and MRgFUS resulted in fewer treatment-related complications. PMID- 28810262 TI - Fetal Sheep Mesenteric Resistance Arteries: Functional and Structural Maturation. AB - BACKGROUND: Fetal blood pressure increases during late gestation; however, the underlying vascular mechanisms are unclear. Knowledge of the maturation of resistance arteries is important to identify the mechanisms and vulnerable periods for the development of vascular dysfunction in adulthood. METHODS: We determined the functional and structural development of fetal sheep mesenteric resistance arteries using wire myography and immunohistochemistry. RESULTS: Media mass and distribution of myosin heavy-chain isoforms showed no changes between 0.7 (100 +/- 3 days) and 0.9 (130 +/- 3 days) gestation. However, from 0.7 to 0.9 gestation, the resting wall tension increased accompanied by non-receptor dependent (potassium) and receptor-dependent (noradrenaline; endothelin-1) increases in vasocontraction. Angiotensin II had no contractile effect at both ages. Endothelium-dependent relaxation to acetylcholine and prostaglandin E2 was absent at 0.7 but present at 0.9 gestation. Augmented vascular responsiveness was paralleled by the maturation of sympathetic and sensory vascular innervation. Non endothelium-dependent relaxation to nitric oxide showed no maturational changes. The expression of vasoregulator receptors/enzymes did not increase between 0.7 and 0.9 gestation. CONCLUSION: Vascular maturation during late ovine gestation involves an increase in resting wall tension and the vasoconstrictor and vasodilator capacity of the mesenteric resistance arteries. Absence of structural changes in the tunica media and the lack of an increase in vasoregulator receptor/enzyme expression suggest that vasoactive responses are due to the maturation of intracellular pathways at this gestational age. PMID- 28810263 TI - Association Between C1q/TNF-Related Protein-1 Levels in Human Plasma and Epicardial Adipose Tissues and Congestive Heart Failure. AB - BACKGROUND/AIMS: C1q and tumour necrosis factor-related protein 1 (CTRP1) possesses anti-atherogenic and anti-inflammatory effects. This study investigated whether the CTRP1 levels in the plasma and epicardial adipose tissue (EAT) were associated with congestive heart failure (CHF) and to disclose possible molecular mechanisms. METHODS: Plasma and tissue samples were obtained from subjects with or without CHF. Plasma levels of CTRP1 were measured by ELISA. The mRNA levels of CTRP1 and inflammatory cytokines were detected by RT-PCR. The protein levels of CTRP1, aldosterone synthase (CYP11B2) and mitogen-activated protein kinase were examined by Western blotting. RESULTS: The levels of CTRP1 in the plasma and EAT were higher in the CHF patients than those in the controls. There were no differences in the CTRP1 levels in cardiomyocytes between the CHF group and the non-CHF group. An exploratory survival analysis showed that higher CTRP1 values at admission were associated with a worse prognosis after discharge. CTRP1 increased the IL-6 mRNA level in H295R cells. CTRP1 recruited ERK1/2 and Jak-2 for aldosterone release by modulating the CYP11B2 protein level, and brain natriuretic peptide repressed the CTRP1-induced aldosterone release through the JAK2-STAT3 signalling pathways. CONCLUSION: The CTRP1 levels in the plasma and EAT were increased in the CHF patients. CTRP1 is involved in the pathogenesis of CHF by modulating IL-6 levels and aldosterone release. PMID- 28810264 TI - Mesenchymal Stem Cells Promote Diabetic Corneal Epithelial Wound Healing Through TSG-6-Dependent Stem Cell Activation and Macrophage Switch. AB - Purpose: To explore the role and mechanism of bone marrow-derived mesenchymal stem cells (BM-MSCs) in corneal epithelial wound healing in type 1 diabetic mice. Methods: Diabetic mice were treated with subconjunctival injections of BM-MSCs or recombinant tumor necrosis factor-alpha-stimulated gene/protein-6 (TSG-6). The corneal epithelial wound healing rate was examined by fluorescein staining. The mRNA and protein expression levels of TSG-6 were measured by quantitative RT-PCR and Western blot. The infiltrations of leukocytes and macrophages were analyzed by flow cytometry and immunofluoresence staining. The effect of TSG-6 was further evaluated in cultured limbal epithelial stem/progenitor cells, macrophages, and diabetic mice by short hairpin RNA (shRNA) knockdown. Results: Local MSC transplantation significantly promoted diabetic corneal epithelial wound healing, accompanied by elevated corneal TSG-6 expression, increased corneal epithelial cell proliferation, and attenuated inflammatory response. Moreover, in cultured human limbal epithelial stem/progenitor cells, TSG-6 enhanced the colony-forming efficiency, stimulated mitogenic proliferation, and upregulated the expression level of DeltaNp63. Furthermore, in diabetic mouse cornea and in vitro macrophage culture, TSG-6 alleviated leukocyte infiltration and promoted the polarization of recruited macrophages to anti-inflammatory M2 phenotypes with increased phagocytotic capacity. In addition, the promotion of epithelial stem/progenitor cell activation and macrophage polarization by MSC transplantation was largely abrogated by shRNA knockdown of TSG-6. Conclusions: This study provided the first evidence of TSG-6 secreted by MSCs promoting corneal epithelial wound healing in diabetic mice through activating corneal epithelial stem/progenitor cells and accelerating M2 macrophage polarization. PMID- 28810265 TI - Viral Retinopathy in Experimental Models of Zika Infection. AB - Purpose: Emerging evidence has shown that both congenital and adult Zika virus (ZIKV) infection can cause eye diseases. The goals of the current study were to explore mechanisms and pathophysiology of ZIKV-induced eye defects. Methods: Wild type or A129 interferon type I receptor-deficient mice were infected by either FSS13025 or Mex1-7 strain of ZIKV. Retinal histopathology was measured at different time points after infection. The presence of viral RNA and protein in the retina was determined by in situ hybridization and immunofluorescence staining, respectively. Growth curves of ZIKV in permissive retinal cells were assessed in cultured retinal pigment epithelial (RPE) and Muller glial cells. Results: ZIKV-infected mice developed a spectrum of ocular pathologies that affected multiple layers of the retina. A primary target of ZIKV in the eye was Muller glial cells, which displayed decreased neurotrophic function and increased expression of proinflammatory cytokines after infection. ZIKV also infected RPE; and both the RPE and Muller cells expressed viral entry receptors TYRO3 and AXL. Retinitis, focal retinal degeneration, and ganglion cell loss were observed after the clearance of viral particles. Conclusions: Our data suggest that ZIKV can infect infant eyes with immature blood-retinal barrier and cause structural damages to the retina. The ocular findings in microcephalic infants may not be solely caused by ZIKV-induced impairment of neurodevelopment. PMID- 28810267 TI - Incidence of Discomfort During Pure-Tone Audiometry and Measurement of Uncomfortable Loudness Levels Among People Seeking Help for Tinnitus and/or Hyperacusis. AB - Purpose: The aim of this study was to assess the proportion of patients seen in a tinnitus and hyperacusis therapy clinic for whom presentation levels based on the British Society of Audiology (BSA)-recommended procedures for pure-tone audiometry and determination of uncomfortable loudness levels (ULLs) exceed ULLs, leading to discomfort during administration of these procedures. Method: This was a retrospective cross-sectional study of 362 consecutive patients who attended a National Health Service audiology clinic for tinnitus and/or hyperacusis rehabilitation. Results: For 21% of the patients, presentation levels based on the BSA procedure for pure-tone audiometry exceeded the ULL for at least 1 of the measured frequencies (excluding the first frequency tested, 1 kHz): 0.25, 0.5, 2, 3, 4, 6, and 8 kHz. For 24% of patients, the starting presentation level of 60 dB hearing level recommended for determination of ULLs exceeded the ULL for at least 1 frequency. Conclusion: The starting presentation levels used for pure-tone audiometry and measurement of ULLs should be lower than those recommended by the BSA for people with tinnitus and hyperacusis. PMID- 28810266 TI - Physiological and Optical Alterations Precede the Appearance of Cataracts in Cx46fs380 Mice. AB - Purpose: Cx46fs380 mice model a human autosomal-dominant cataract caused by a mutant lens connexin46, Cx46. Lenses from Cx46fs380 mice develop cataracts that are first observed at ~2 months in homozygotes and at >=4 months in heterozygotes. The present studies were conducted to determine whether Cx46fs380 mouse lenses exhibited abnormalities before there are detectable cataracts. Methods: Lenses from wild-type and Cx46fs380 mice were studied at 1 to 3 months of age. Connexin levels were determined by immunoblotting. Gap junctional coupling was calculated from intracellular impedance studies of intact lenses. Optical quality and refractive properties were assessed by laser scanning and by photographing a 200-mesh electron microscopy grid through wild-type and Cx46fs380 mouse lenses. Results: Connexin46 and connexin50 levels were severely reduced in mutant lenses. Gap junctional coupling was decreased in differentiating and mature fibers from Cx46fs380 lenses; in homozygotes, the mature fibers had no detectable coupling. Homozygous lenses were slightly smaller and had reduced focal lengths. Heterozygous and homozygous lenses significantly distorted the electron microscopy grid pattern as compared with wild-type lenses. Conclusions: Before cataract appearance, Cx46fs380 lenses have decreased gap junctional conductance (at least in heterozygotes) and alterations in refractive properties (heterozygotes and homozygotes). The decreased focal distance of Cx46fs380 homozygous lenses is consistent with an increase in refractive index due to changes in cellular composition. These data suggest that Cx46fs380 lenses undergo a sequence of changes before the appearance of cataracts: low levels of connexins, decreased gap junction coupling, alterations in lens cell homeostasis, and changes in refractive index. PMID- 28810268 TI - Swallowing Mechanics Associated With Artificial Airways, Bolus Properties, and Penetration-Aspiration Status in Trauma Patients. AB - Purpose: Artificial airway procedures such as intubation and tracheotomy are common in the treatment of traumatic injuries, and bolus modifications may be implemented to help manage swallowing disorders. This study assessed artificial airway status, bolus properties (volume and viscosity), and the occurrence of laryngeal penetration and/or aspiration in relation to mechanical features of swallowing. Method: Coordinates of anatomical landmarks were extracted at minimum and maximum hyolaryngeal excursion from 228 videofluoroscopic swallowing studies representing 69 traumatically injured U.S. military service members with dysphagia. Morphometric canonical variate and regression analyses examined associations between swallowing mechanics and bolus properties based on artificial airway and penetration-aspiration status. Results: Significant differences in swallowing mechanics were detected between extubated versus tracheotomized (D = 1.32, p < .0001), extubated versus decannulated (D = 1.74, p < .0001), and decannulated versus tracheotomized (D = 1.24, p < .0001) groups per post hoc discriminant function analysis. Tracheotomy-in-situ and decannulated subgroups exhibited increased head/neck extension and posterior relocation of the larynx. Swallowing mechanics associated with (a) penetration-aspiration status and (b) bolus properties were moderately related for extubated and decannulated subgroups, but not the tracheotomized subgroup, per morphometric regression analysis. Conclusion: Specific differences in swallowing mechanics associated with artificial airway status and certain bolus properties may guide therapeutic intervention in trauma-based dysphagia. PMID- 28810270 TI - The Personal Antipsychotic Choice Index. AB - INTRODUCTION: We present an online decision aid to involve patients with a psychotic disorder in shared decision-making concerning the selection of antipsychotic medication. METHOD: Patients selected effectiveness and adverse effects criteria from the Subject's Response to Antipsychotics-34 questionnaire. Numerical data from meta-analyses, clinical trial data, receptor affinities and expert opinions were used to rank antipsychotics on each criterion. When using the the tool, patients indicate on a 5-point Likert scale how they value each (adverse) effect. The Likert scale values are combined in an algorithm with the rank orders of antipsychotics to create a personalized ranking. RESULTS: Criteria used were: effectiveness concerning psychotic, depressive and cognitive symptoms, weight gain, sexual dysfunction, drowsiness, hypersomnia, extrapyramidal symptoms, anticholinergic adverse effects, hypersalivation, nausea, dizziness, energy loss, blunted affect/less need for companionship. High-level evidence was available for ranking weight gain, sexual dysfunction, menstrual disorders, extrapyramidal symptoms and effectiveness on psychotic symptoms. We used lower level evidence ranking the remaining criteria. DISCUSSION: A transparent procedure has resulted in an updateable tool to produce individual ranking of antipsychotics based on the patients' input. PMID- 28810271 TI - Outcomes of Patients with Behcet's Syndrome after Pulmonary Endarterectomy. AB - BACKGROUND: Behcet's syndrome (BS) is a multisystem disorder and is not known as a risk factor for chronic thromboembolic pulmonary hypertension (CTEPH), for which the treatment of choice is pulmonary endarterectomy (PEA). The aim of this study was to review our experience in the surgical treatment of CTEPH in patients with BS. METHODS: Data were collected prospectively for consecutive patients with BS who underwent PEA over a 6-year period. RESULTS: We identified nine patients (seven males, two females, mean age: 34.7 +/- 9.9 years) with BS. The mean disease duration before PEA was 88.0 +/- 70.2 months. All patients but one received immunosuppressive therapy before the surgery. Exercise-induced dyspnea presented symptoms in six patients. One patient had associated intracardiac thrombosis. PEA was bilateral in five patients, unilateral in three, and lobar in one. No perioperative mortality was observed; however, one patient died four weeks after PEA due to massive hemoptysis. Morbidity was observed in two patients. The systolic pulmonary artery pressure fell significantly from 59.0 +/- 22.7 mm Hg to 30.0 +/- 6.5 mm Hg after surgery (p = 0.031). Pulmonary vascular resistance also improved significantly from 611.8 +/- 300.2 to 234.7 +/- 94.9 dyn/s/cm5 (p = 0.031). After a median follow-up of 29.4 months, all patients improved to the New York Heart Association (NYHA) functional class I and II. CONCLUSION: Patients with BS may suffer recurrent pulmonary embolism and develop CTEPH. In patients who do not respond to anticoagulation or immunosuppressive therapy, PEA may be a therapeutic option when thrombotic lesions are surgically accessible. Due to the high risk of perioperative mortality, the procedure should be undertaken in centers with experience. PMID- 28810272 TI - Tricuspid Valve Repair after Previous Mitral Valve Surgery. AB - Tricuspid valve (TV) regurgitation in patients after previous mitral valve surgery isusually a secondary failure and conditioned by a long-lasting left sided valve failure. TVsurgery in these patients represents a high-risk procedure regarding the operativestrategy and perioperative management. This article will discuss the indication for TVsurgery in patients with secondary TV regurgitation and previous mitral valve surgery,the choice of surgical access, as well as TV repair techniques and their postoperativeresults. PMID- 28810274 TI - [Extraclinical Ventilation: An Increasing Challenge]. PMID- 28810273 TI - [Nursing Internship Internal Medicine: Evaluation and Influences on the Attitude towards the Specialization]. AB - Background German medical students have to perform a nursery internship of three month duration. While this internship is widely discussed, there is a lack of student evaluation data. Objectives Here, for the first time, student evaluation of a nursery internship in internal medicine (IM) is investigated. Moreover, the question was raised, whether the early experience during this internship may influence students' attitude towards the specialty. Methods In a nation-wide online-survey, 767 German medical students (mean age 22.8 years; 58 % female) evaluated a nursery internship on an IM ward concerning integration in medical teams, teachers, structure and quality of teaching, and satisfaction. Multivariate comparisons were conducted following the question, whether students could imagine choosing IM for a clinical elective after this nursery internship. Results 71 % of the students felt well integrated in the medical team, most was learned from the nurses, and most students indicated having acquired nursing skills. Only 19 % evaluated the structure of the internship as good, and 40 % indicated that they reached the learning goals. Students who could imagine performing an IM clinical elective (52 %) gave best evaluations on all items. Conclusions A successful nursery internship can promote students' interest in the specialty of internal medicine. But, there is a strong need for improvement in structure and content, including the, to date missing, definition of learning targets, regarding this first practical experience in medical studies. PMID- 28810275 TI - [59-Year-Old Man with Infarction-Related Cardiogenic Shock]. PMID- 28810277 TI - [Concepts to Optimize Home Care of Patients with Mechanical Ventilation]. AB - The care of patients with extraclinical mechanical ventilation has to be improved particularly with regard to their specialist care. One care option is the empowering of clinicians at the respiratory centers to enable ambulant care of patients and home visits. An intersectoral linkage in the form of transfer management is the basis for competent coordination. Aim is to ensure the necessary multidisciplinary collaboration in the outpatient care of multimorbid chronically ill patients. For the optimal care of chronically ill patients, sectoral limits should become more permeable. PMID- 28810276 TI - [Home mechanical Ventilation - Concepts and Therapy Recommendations]. AB - The prognosis of patients receiving home mechanical ventilation is very heterogeneous and depends on the underlying disease, the degree of respiratory dependency and the comorbidities. Due to the severe chronic diseases, the initiation of a long-term NIV must be done during an inpatient treatment. Two recently published randomized controlled trials using more aggressive forms of NPPV targeted at normalizing hypercapnic PaCO2 values, showed improved long term survival also in patients with an underlying diagnosis of COPD. Consequently, the number of patients receiving home mechanical ventilation has dramatically increased in recent years and more and more outpatient settings has been established without scientific evidence. Nevertheless, beside reliable care structures, ethical aspects and health related quality of life are of great importance in the context of home mechanical ventilation. PMID- 28810278 TI - [Infections in Patients with Home Ventilation]. AB - In patients with home ventilation, there is a markedly higher probability for lower respiratory infections or pneumonia and severe courses due to comorbidity. Tracheobronchitis and pneumonia are often difficult to distinguish. Tracheobronchitis with pronounced secretion which can't be controlled otherwise can be an indication for antimicrobial therapy.There are no data available in order to establish a recommendation for the initial empiric calculated antimicrobial therapy in patients with home ventilation. However, risk factors for multi drug resistance (MDR) are mostly present and should be considered in the selection of antimicrobial therapy.The principles of antimicrobial therapy are also essential for infections in home ventilation: judicious indication, dosage, microbiological investigation, de-escalation and duration of therapy. In individual cases, inhaled antimicrobials are an option.In order to avoid lower airway infections, adherence to hygienic standards is essential. In addition, invasive ventilation should be avoided wherever possible. If possible, weaning attempts are to be repeated given that invasive ventilation is a risk factor for pneumonia caused by aspiration. PMID- 28810279 TI - [Severe Yellow fever vaccine-associated disease: a case report and current overview]. AB - History and physical examination A 56-year-old man developed high fever with severe headaches, fatigue, impaired concentration skills, and an exanthema 5 days after a yellow fever (YF) vaccination. Laboratory tests Liver enzymes and YF antibody titers were remarkably elevated. YF vaccine virus was detected in urine by PCR. Diagnosis and therapy Initially, severe YF vaccine-associated visceral disease was suspected and treated symptomatically. Clinical Course His fever ceased after 10 days in total, no organ failure developed. However, postencephalitic symptoms persisted with fatigue and impaired concentration, memory, and reading skills and partly incapability to work for over 3 months. A diagnosis was made of suspected YF vaccine-associated neurotropic disease. Conclusion Severe vaccine-derived adverse effects need to be considered in the indication process for YF vaccination. PMID- 28810280 TI - [Dual Antiplatelet Therapy in the Perioperative Period - To Continue or Discontinue Treatment?] AB - Background For secondary prevention of acute coronary syndrome, guidelines recommend dual antiplatelet therapy (DAPT) with acetylsalicylic acid and a P2Y12 receptor antagonist such as clopidogrel, prasugrel or ticagrelor for a period of 12 months. Often, uncertainty exists with respect to surgical or diagnostic procedures in these high-risk patients: can the DAPT be continued without interruption? If not, what is the recommended withdrawal strategy? What should be considered for the perioperative management? Methods An interdisciplinary group of experienced experts in the fields of cardiology, cardiac surgery, gastroenterology, anaesthesiology, intensive care and haemostaseology developed recommendations relevant to daily clinical practice based on the current scientific evidence. Results These recommendations include instructions for evaluating the patient- and procedure-specific risks of bleeding and ischaemia, general recommendations regarding the DAPT withdrawal strategy, and specific guidance for frequent surgical or diagnostic procedures. Discussion This article aims to facilitate the management of patients with DAPT for all medical disciplines involved, thereby ensuring optimal care of patients during the perioperative period. PMID- 28810281 TI - [Hyponatremia: Differential Diagnosis and Treatment]. AB - Hyponatremia is the most common electrolyte abnormality seen in hospitalized patients, with up to 30 % having a plasma sodium concentration below 135 mmol/l. It is now clear that the clinical problem extends beyond the neurological symptoms, which can be explained by intracerebral osmotic fluid shifts and brain edema. Instead, chronic hyponatremia is associated with impaired gait stability and an increased risk of bone fragility fractures. Moreover, hyponatremia has been demonstrated to be an indicator of poor prognosis in a variety of conditions.Hyponatremia can be a life-threatening disorder due to increased intracranial pressure, thus requiring prompt and efficacious treatment. However, overly rapid correction may be complicated by osmotic demyelination syndrome with catastrophic clinical sequelae, i. e., spastic quadriparesis, or even coma or death.To avoid inappropriate treatment, the underlying pathophysiology in each case as well as the time course (acute vs. chronic) and the clinical and biochemical severity must be considered.The purpose of this review is to provide the reader with a systematic approach to the correct diagnosis and management of hyponatremia based on available European and international guidelines. PMID- 28810282 TI - [Late Complications After Retinal Surgery Using Hydrogel (MIRAgel(r)) Sponges]. PMID- 28810283 TI - [Comparison of Discriminant Analysis and Decision Trees for the Detection of Subclinical Keratoconus]. AB - Background Iatrogenic keratectasia is one of the most dreaded complications of refractive surgery. In most cases, keratectasia develops after refractive surgery of eyes suffering from subclinical stages of keratoconus with few or no signs. Unfortunately, there has been no reliable procedure for the early detection of keratoconus. In this study, we used binary decision trees (recursive partitioning) to assess their suitability for discrimination between normal eyes and eyes with subclinical keratoconus. Patients and Methods The method of decision tree analysis was compared with discriminant analysis which has shown good results in previous studies. Input data were 32 eyes of 32 patients with newly diagnosed keratoconus in the contralateral eye and preoperative data of 10 eyes of 5 patients with keratectasia after laser in-situ keratomileusis (LASIK). The control group was made up of 245 normal eyes after LASIK and 12-month follow up without any signs of iatrogenic keratectasia. Results Decision trees gave better accuracy and specificity than did discriminant analysis. The sensitivity of decision trees was lower than the sensitivity of discriminant analysis. Conclusion On the basis of the patient population of this study, decision trees did not prove to be superior to linear discriminant analysis for the detection of subclinical keratoconus. PMID- 28810284 TI - [Development of Non-Arteritic Anterior Ischaemic Optic Neuropathy in the Initially Unaffected Fellow Eye in Patients Treated with Systemic Corticosteroids]. AB - Background The objective of this prospective pilot study was to evaluate the results of systemic corticosteroid therapy in patient with non-arteritic anterior ischaemic neuropathy of the optical nerve (NAION) for an observation period of one year and to measure the NAION incidence in the initially healthy contralateral eye of these patients. Patients and Methods All patients diagnosed with acute NAION who were admitted to our ward during 2014 and who fulfilled all inclusion criteria for systemic corticosteroid therapy were included in the study. The inclusion criteria were corrected visual acuity of 0.3 or less and duration of illness of less than 2 weeks. All patients were examined by a rheumatologist and given a complete ophthalmological examination, including fluorescein angiography and examination of the visual field. Only 3 of the 23 patients fulfilled our inclusion criteria for corticoid treatment and were then treated. 10 patients served as controls. The treatment plan started with an initial dose of 80 mg prednisolone during the first two weeks. The dose was then tapered over 3 to 4 months. Results The mean best corrected visual acuity on admission was 0.12 and 0.35 after one year. The mean duration of treatment was 3.3 months. Treatment was discontinued after 5 to 6 months or 8 to 9 months after the initial examination. All patients then developed NAION on the contralateral eye. The mean visual acuity on the contralateral eye was 0.73. After 4 month follow-up, the visual acuity in two patients had decreased to 1.0 and in one patient was reduced from 0.8 to 0.4. No steroid treatment was initiated for the contralateral eye. No NAION was found in the contralateral eye in the control group. Conclusion Corticosteroid treatment improved vision in all patients with NAION in comparison with the untreated contralateral eye. In a single patient, visual acuity decreased in the contralateral eye. Our study confirmed that corticosteroid treatment may be a predisposing factor for the development of NAION am in the contralateral eye. Additional studies with more patients are needed to confirm our results. PMID- 28810285 TI - Correction: Intraductal tubulopapillary neoplasm of the pancreas diagnosed by endoscopic ultrasonography-guided fine needle aspiration. PMID- 28810286 TI - [Driving ability in Parkinson's disease]. AB - About 60 % of all patients with Parkinson's disease (PD) and about 50 % of PD patients with deep brain stimulation (DBS) in possession of a driving license are active car-drivers. Parkinson patients, however, often display physical and/or psychological weaknesses that can lead to loss of or reduced driving ability. Driving capability can also be affected by Parkinson medication. The attending physician is therefore obliged to advise his patients regarding their ability to be in command of a vehicle. This however can prove difficult in practice. On the one hand, there is no standardised predictive test battery to evaluate driving capability and on the other, levels of motor impairment do not correlate sufficiently with driving skills. This article will provide an overview of motor and non-motor symptoms that affect general and/or Parkinson's disease-related driving capability and which criteria demonstrate a temporary or permanent inability to drive. Furthermore, we will highlight which neuropsychological investigations are beneficial and how PD patients with DBS should be evaluated and subsequently advised regarding their driving fitness. PMID- 28810287 TI - Seeding density is a crucial determinant for the in vivo vascularisation capacity of adipose tissue-derived microvascular fragments. AB - Adipose tissue-derived microvascular fragments (ad-MVF) represent effective vascularisation units for the seeding of dermal substitutes. However, particularly in case of extensive skin defects, the required amounts of donor fat tissue for the harvesting of ad-MVF may not always be available. Therefore, we herein determined the lowest ad-MVF density needed to induce a sufficient vascularisation and incorporation of seeded implants. Collagen-glycosaminoglycan matrices (Integra(r); diameter: 4 mm) were seeded with 15,000 (HD), 10,000 (MD) and 5,000 (LD) ad-MVF and implanted into full-thickness skin defects within mouse dorsal skinfold chambers, to analyse their in vivo vascularisation and incorporation. Intravital fluorescence microscopy showed a comparable vascularisation of HD and MD ad-MVF-seeded Integra(r), which was significantly higher when compared to LD ad-MVF-seeded Integra(r). As assessed by photoacoustic imaging, this was associated with an increased oxygenation of the implants. Additional histological and immunohistochemical analyses revealed an enhanced cellular infiltration, collagen content, microvessel density and epithelialisation of HD and MD ad-MVF-seeded Integra(r), indicating a better incorporation compared to LD ad-MVF-seeded implants. These findings demonstrate that 80,000 ad-MVF/cm2 is the least required density to guarantee an effective vascularisation of the dermal substitute. PMID- 28810288 TI - Overexpression of DEMETER, a DNA demethylase, promotes early apical bud maturation in poplar. AB - The transition from active growth to dormancy is critical for the survival of perennial plants. We identified a DEMETER-like (CsDML) cDNA from a winter enriched cDNA subtractive library in chestnut (Castanea sativa Mill.), an economically and ecologically important species. Next, we characterized this DNA demethylase and its putative ortholog in the more experimentally tractable hybrid poplar (Populus tremula * alba), under the signals that trigger bud dormancy in trees. We performed phylogenetic and protein sequence analysis, gene expression profiling, and 5-methyl-cytosine methylation immunodetection studies to evaluate the role of CsDML and its homolog in poplar, PtaDML6. Transgenic hybrid poplars overexpressing CsDML were produced and analysed. Short days and cold temperatures induced CsDML and PtaDML6. Overexpression of CsDML accelerated short-day-induced bud formation, specifically from Stages 1 to 0. Buds acquired a red-brown coloration earlier than wild-type plants, alongside with the up-regulation of flavonoid biosynthesis enzymes and accumulation of flavonoids in the shoot apical meristem and bud scales. Our data show that the CsDML gene induces bud formation needed for the survival of the apical meristem under the harsh conditions of winter. PMID- 28810290 TI - [Practical approach to macroscopic examination of breast specimens: experiences in M.D.Anderson Cancer Center]. PMID- 28810289 TI - Targeted gene replacement at the URA3 locus of the basidiomycetous yeast Pseudozyma antarctica and its transformation using lithium acetate treatment. AB - The basidiomycetous yeast Pseudozyma antarctica is a remarkable producer of industrially valuable enzymes and extracellular glycolipids. In this study, we developed a method for targeted gene replacement in P. antarctica. In addition, transformation conditions were optimized using lithium acetate, single-stranded carrier DNA and polyethylene glycol (lithium acetate treatment), generally used for ascomycetous yeast transformation. In the rice-derived P. antarctica strain GB-4(0), PaURA3, a homologue of the Saccharomyces cerevisiae orotidine-5' phosphate decarboxylase gene (URA3), was selected as the target locus. A disruption cassette was constructed by linking the nouseothricine resistance gene (natMX4) to homologous DNA fragments of PaURA3, then electroporated into the strain GB-4(0). We obtained strain PGB015 as one of the PaURA3 disruptants (Paura3Delta::natMX4). Then the PCR-amplified PaURA3 fragment was introduced into PGB015, and growth of transformant colonies but not background colonies was observed on selective media lacking uracil. The complementation of uracil auxotrophy in PGB015 by introduction of PaURA3 was also performed using lithium acetate treatment, which resulted in a transformation efficiency of 985 CFU/6.8 MUg DNA and a gene-targeting ratio of two among 30 transformants. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28810291 TI - [Correlation between extranodal invasion in axillary lymph node metastasis and prognosis of breast cancer patients]. AB - Objective: To investigate the significance of extranodal extension of axillary lymph nodes (ALN-ENE) metastases in post-operative primary invasive breast carcinoma of non-specific type. Methods: Six hundred and thirty-eight invasive breast cancer cases confirmed by postoperative pathological examination were collected from January 2006 to December 2008. The relationship of lymph node metastases and ALN-ENE with other lymph node parameters and patient outcome was analyzed. Results: Among 638 cases, 263 (41.2%) showed axillary lymph node metastases. ALN-ENE was present in 91 cases (36.4%). The rate of ALN-ENE increased with pT stage and tumor size. Five-year recurrence-free survival rate (RFS) and 5-year overall survival rate (OS) was 86.6% and 91.2% respectively for ALN-ENE positive group, and both were lower than ALN-ENE negative group (P<0.01). One hundred and forty-nine patients with 1 to 3 positive lymph nodes had a 5-year RFS of 91.9%, and 5-year OS of 92.3%, less than ALN-ENE negative group (P<0.01). Univariate analysis showed ALN-ENE positively correlated with lymph node metastasis. Multivariate analysis suggested that ENE was associated with increased recurrence risk and shortened recurrence-free and overall survival, especially in patients with 1 to 3 positive lymph nodes; and it was an independent prognostic factor (P<0.01). Conclusions: The number of lymph nodes metastases is an important predictor of survival in breast cancer patients. ALN ENE is an independent risk indicator for recurrence and overall survival. For patients with 1 to 3 metastatic axillary lymph nodes, ALN-ENE could alter the patient's clinical pathologic staging, and therefore it is an independent prognostic factor. PMID- 28810292 TI - [Clinicopathologic features of mammary microglandular adenosis with carcinoma: a study of 5 cases]. AB - Objective: To study the clinicopathologic, immunohistochemical features, differential diagnoses and prognosis of mammary microglandular adenosis with carcinoma (MGACA) with micropapillary pattern. Methods: Five cases of MGACA were collected from 2010 to 2016 and reviewed for their clinical, histologic features and outcome.EnVision method were done for S-100 protein, cytokeratin (CK), p63, Calponin, smooth muscle myosin heavy chain (SMMHC), PR, ER and HER2. Results: Histologically, microglandular adenosis(MGA), atypical MGA (AMGA) and invasive carcinoma were seen in all five cases of MGACA. The invasive component was metaplastic carcinoma in one case and ductal in four cases. All epithelial cells were S-100 and CK positive in MGA, AMGA and invasive carcinoma. p63, Calponin and SMMHC negativity confirmed the lack of a myoepithelial cell layer in MGA, AMGA and MGACA. PR was weakly focally positive in one case, but ER and HER2 were negative in all cases (four cases were triple negative). Ki-67 index was 20% to 40%. Laminin and collagen IV staining showed the presence of basement membrane in MGA and AMGA, except MGACA. The follow-up time ranged from 3 months to 6 years, and all patients were alive without recurrence or distant metastasis. Conclusions: MGACA is a rare tumor with distinct morphological and IHC features. Compared to most triple-negative breast cancers, MGACA seems to have a relatively favorable outcome. PMID- 28810293 TI - [Comparative study of three different decalcifying solutions in bone metastasis specimens with breast cancer]. AB - Objective: To investigate the optimal strategy for immunohistochemical (IHC) staining in bone metastasis specimens from breast cancer. Methods: Twenty-eight bone metastases specimens from breast cancers were divided into three groups and subjected to different decalcifying agents (group A-10% nitrate, group B-EDTA decalcification, and group C-imported decalcifying solution RapidCal). The effects of those on HE and IHC staining for Ki-67, ER, PR, GATA3, RANK, RANKL, HER2 and HER2 FISH results were assessed. Results: There were no significant differences among three groups in HE morphology and IHC staining. Antigen content in the RapidCal group were all intact; the EDTA group showed a similar staining rate, which was better than the nitrate group (P<0.05). Nitrate group showed marked reduction in nuclear Ki-67 staining, but the loss of cytoplasmic antigens (RANK, RANKL) was less than cell membrane antigen (HER2). For FISH, the RapidCal group and EDTA group showed same results, concordant with IHC staining results. The expression of HER2 protein in the nitric acid group was significantly decreased and chromosome 17 labelling was lost (P<0.05). Conclusions: RapidCal treated bone metastases specimens from breast cancer show excellent sample quality in morphological, IHC and FISH results compared with traditional decalcifying agents. Owing to the longer time of EDTA decalcification, the new decalcifying agent RapidCal plays an important role in quality control and clinical application. PMID- 28810294 TI - [Morphologic features of fallopian tubal epithelium in pelvic high-grade serous carcinoma]. AB - Objective: To study the pathologic features of fallopian tubal epithelium in patients with pelvic high-grade serous carcinoma (HGSC), to investigate its role in pelvic serous carcinogenesis and to reclassify the primary site of HGSC based on recently proposed criteria. Methods: The fallopian tubes in 58 cases of pelvic HGSC (54 cases of ovarian primary, 3 cases of tubal primary, 1 case of peritoneum) and 25 cases of pelvic non-HGSC (5 cases of ovarian low-grade serous cancer, 9 cases of endometrioid cancer, and 11 cases of clear cell ovary carcinoma) were collected from June 2015 to December 2016, and serially examined under light microscope (SEE-FIM protocol). Immunostaining for p53 and Ki-67 was performed to evaluate the presence of p53 signature, serous tubal intraepithelial lesion (STIL), serous tubal intraepithelial carcinoma (STIC) and invasive carcinoma in these fallopian tubes. Meanwhile, primary site of HGSC based on the recently proposed diagnostic criteria were also reclassified. Results: Among the study group, the frequencies of p53 signature, STIL, STIC and invasive HGSC were 27.6% (16/58), 43.1% (25/58), 36.2% (21/58) and 67.2% (39/58), respectively, while in control group, the proportions were 24.0% (6/25), 0, 0 and 8.0% (2/25), respectively. The continuum of epithelial changes in the process of serous neoplasia including p53 signature, STIL, STIC and invasive carcinoma was identified in 8 cases of pelvic HGSC. The proportions of STIL, STIC and invasive carcinomas in HGSC group were higher than that in non-HGSC group (P<0.01). About 80.0% (20/25) of STIL and 85.7% (18/21) of STIC were present unilaterally. Diagnostically, the study group contained the 17 cases of ovarian HGSC, 40 cases of tubal HGSC, and 1 case of peritoneal HGSC after reclassification of the cancer primary. Conclusions: Continuous changes of tubal epithelium including p53 signature, STIL, STIC and invasive carcinomas are identified in patients with HGSC, supporting the current understanding that the fallopian tube is likely the cellular source of the majority HGSC. STIL and STIC may be specific to pelvic HGSC and may act as a target for future research on the early detection and prevention of this disease. The newly proposed diagnostic criteria for pelvic HGSC will lead us to more accurate classification of cancer primary sites. Correct classification of HGSC may have potential impacts for cancer prevention and improve our understanding of ovarian serous carcinogenesis. PMID- 28810295 TI - [Utility and evaluation of immunohistochemical detection of BRAF V600E mutation in melanoma]. AB - Objective: To evaluate the sensitivity, specificity and clinical value of anti BRAF V600E antibody (clone VE1) in detection of the BRAF V600E mutant in formalin fixed and paraffin-embedded (FFPE) melanoma specimens by immunohistochemical (IHC) methods. Methods: A total of 50 melanoma samples collected between 2008 and 2016 from 40 patients were analyzed for BRAF mutation (exon 15) by DNA sequencing using FFPE. These tissues were immunostained with VE1 antibody, and the results were analyzed and compared with those by DNA sequencing. Results: By DNA sequencing, 36 cases showed BRAF mutation while others were BRAF wild type. Among the 36 cases with BRAF mutation, 32 harbored BRAF V600E, two harbored BRAF V600K, one had BRAF K601E and one had BRAF D594N, respectively. IHC staining showed 30 specimens were VE1 positive, while 19 were negative. The determination of IHC result for one case was obscured by heavy pigments. Of the BRAF-mutated specimens, four specimens with BRAF mutation other than V600E were all negative for VE1. The sensitivity and specificity of the VE1 immunostaining was 96.8% and 100.0% respectively.Concordance of BRAF V600E detection between immunostaining and DNA sequencing was 98.0%(48/49). Conclusions: High sensitivity and specificity for VE1 immunostaining in detecting BRAF V600E in melanomas are demonstrated. It is a rapid and cost-effective method for detecting BRAF V600E mutations in melanoma patients. Hence, VE1 immunostaining can be used as an important screening method for BRAF mutation in laboratories. PMID- 28810296 TI - [Prognostic study of visceral pleural invasion by pulmonary adenocarcinoma with tumor size <=3 cm]. AB - Objective: To evaluate the relationship between visceral pleural invasion (VPI) and other clinicopathological features in lung adenocarcinoma with tumor size <=3 cm, and to investigate the impact of VPI on the patients' prognosis. Methods: The clinical and pathological features were retrospectively reviewed in 231 cases of lung adenocarcinoma with the largest diameter of tumor <=3 cm, following complete resection and systemic lymphadenectomy. VPI was divided into three grades, PL0, PL1 and PL2 according to modified Hammar classification for lung cancer upon elastic fiber staining. Survival analysis was performed by Kaplan-Meier method, and the risk factors for prognosis were explored by Cox proportional hazards model. Patient prognosis was evaluated by progression-free survival (PFS) and overall survival (OS). Results: In all 231 cases, the number of patients with VPI was 70 (30.3%), of which 61 cases were PL1 and 9 cases were PL2. The remaining 161 cases (69.7%) had no VPI (PL0). The tumor size (P=0.003), histological grade (P<0.01), the presence of solid component (P=0.001) and micropapillary component (P=0.009), N stage (P<0.01) and TNM stage (P<0.01) were significantly correlated with VPI. Patients with VPI had significantly shorter PFS and OS than those without VPI (P<0.01). There were significant differences in PFS and OS between patients with different VPI levels (P<0.01). Cox multivariate regression analysis showed that VPI was not an independent prognostic factor, whereas PL2 was an independent prognostic factor for PFS (P=0.007), but not an independent prognostic factor for OS (P=0.052). Conclusions: For patients with lung adenocarcinoma of tumor size <=3 cm, VPI is related to poor prognosis; However, only PL2 is an independent prognostic factor for PFS. It may be not necessary to separate PL0 and PL1 status in smaller lung adenocarcinomas. Therefore, the definition of VPI may need further modification through large cohort studies. PMID- 28810297 TI - [Clinical and pathologic features of extrapleural sarcomatoid mesothelioma]. AB - Objective: To investigate the morphological features, diagnosis and differential diagnosis of extrapleural sarcomatoid malignant mesothelioma (SMM). Methods: Six cases of extrapleural SMM were evaluated for their clinical, histological, immunohistochemical features, and prognosis. Results: Patients included 3 men and 3 women, with a median age of 60 years (range 41-75 years). All patients had no asbestos exposure in history and no pleural lesions. The tumors involved peritoneum (3 cases), bone (2 cases), and neck soft tissue (1 case). Histologically, the tumors were mainly composed of slender to plump spindle cells with occasional polymorphic cells, arranged in fascicular to storiform pattern or haphazardly organized, closely resembling those of fibromatosis, fibrosarcoma or malignant fibrous histiocytoma. The tumor cells were imunohistochemically positive for cytokeratin (pan, 6/6), calretinin (5/6), podoplanin (6/6), D2-40 (4/6), vimentin (6/6), WT1 (4/6), CD10 (3/6), SMA (4/6), and variably positive for CK7, and CK8/18, but were negative for other linage-specific markers. The Ki 67 proliferation indexes ranged from 25% to 55%, consistent with the diagnosis of malignant mesothelioma of the sarcomatous type. Ultrastructurally, the tumor cells possessed discontinuous external lamina, cytoplasmic processes, microfilaments and desmosomal intercellular junctions. Local recurrence or metastasis was seen in 1 case and 4 cases, respectively, after surgery, and all the patients died of the disease within 9 months. Conclusions: Extrapleural SMM, although rare, should be considered as a differential diagnosis among other benign or malignant sarcomatoid tumors and sarcomas. Along with clinical and radiological presentation, the combination of broad-spectrum cytokeratin, vimentin, and a series of mesothelial markers are useful for diagnosis of SMM. PMID- 28810298 TI - [Blastic plasmacytoid dendritic cell neoplasm: a clinicopathologic analysis of 6 cases]. PMID- 28810299 TI - [Nodular lesions of lung]. PMID- 28810300 TI - [Computer-assisted evaluation of HER2 heterogeneity in breast cancer]. PMID- 28810301 TI - [Clinicopathologic characteristics of primary gastric choriocarcinoma: report of a case]. PMID- 28810302 TI - [Primary basaloid thymic carcinoma: report of a case]. PMID- 28810303 TI - [Advance on microRNA and renal cell carcinoma]. PMID- 28810304 TI - [Research on circRNA in regulatory mechanism of diseases]. PMID- 28810305 TI - [Application of whole slide imaging in diagnostic cytology]. PMID- 28810306 TI - [Alternative splicing and tumor]. PMID- 28810307 TI - [Research progress of inhaled antibiotics in pulmonary infectious disease]. PMID- 28810308 TI - [The management of infections with multidrug-resistant gram-negative bacilli in lower respiratory tract]. PMID- 28810310 TI - [Current situation and mechanism of drug resistance of gram-negative bacteria in China]. PMID- 28810309 TI - [The clinical value of genotypic diagnosis and current state of community acquired Methicillin-resistant Staphylococcus aureus pneumonia]. PMID- 28810311 TI - [Retrospective analysis of 13 cases of nocardiosis]. AB - Objective: To evaluate the clinical features, chest radiological manifestations, microbiological examination and treatments of nocardial disease. Methods: A retrospective study was conducted to analyze the data of patients with nocardial infection admitted to Beijing Chaoyang Hospital from January 2010 to January 2016. Results: The 13 patients, 6 males and 7 females, aged (51+/-17) years. Twelve cases were diagnosed with pulmonary nocardiosis, and 1 with disseminated nocardial infection. Most of these patients had complications: autoimmune diseases in 3 (2 with autoimmune hemolytic anemia and 1 with systemic lupus erythematosus), and bronchiectasis in 6 patients. The most common symptoms were cough, expectoration and fever. The main manifestations of CT scans included nodules or masses, bronchiectasis, ground glass opacity, cavity and pleural thickening. Six cases were confirmed by sputum smear microscopy, 4 by bronchoalveolar lavage, 2 by percutaneous lung biopsy and 1 by renal abscess puncture. After diagnosis, antibiotics such as Co-trimoxazole, amikacin, cephalosporins, imipenem, minomycin, or linezolid were used, and the 13 patients were all cured and discharged. Conclusions: Pulmonary nocardiosis was the most common clinical presentation of nocardial infection. Cough, expectoration and fever were the most common symptoms. The main findings of CT scans were nodules or masses, bronchiectasis, ground glass opacity, cavity and pleural thickening. The diagnosis of nocardiosis was not easy because of the non-specific clinical presentations and difficult culture of nocardia spp. Thus, high clinical suspicion of nocardiosis is necessary for earlier diagnosis and treatment. PMID- 28810312 TI - [Analysis of infection and drug-resistance in 6 107 cases of extrapulmonary tuberculosis in Chengdu area]. AB - Objective: To analyze the infection and drug resistance of extrapulmonary tuberculosis, in order to provide useful references for prevention and treatment of tuberculosis (TB). Methods: A total of 6 107 suspected cases of extrapulmonary tuberculosis, including lymph node, pleural, peritoneal, meningeal, urinary tract, and bone tuberculosis, were collected retrospectively from January 2013 to December 2015 in Public Health Clinical Center of Chengdu. There were 4 033 male and 2 074 female patients, and the average age was 37 years.The epidemiological data, infection and drug resistance were analyzed statistically. Results: There were 21 036 cases of mycobacterial culture from January 2013 to December 2015, of which 7 119 were positive(33.8%). Extrapulmonary tuberculosis was found in 6 107 cases, of which 896 were positive, accounting for 12.6% of the positive cases(896/7 119). Culture-positive cases of extra-pulmonary tuberculosis showed a rising trend from 2013 to 2015 (n=174, 310, 421, respectively), and the annual average increasing rate was over 50%.Cases were distributed at younger ages (21 40 years), with an average age of 34 years.There were more male patients, with a male to female ratio of 2.1?1. The most common site of extrapulmonary tuberculosis was the bone(62/243, 25.5%), followed by lymph node(283/1 297, 21.8%), pleural(289/1 840, 15.7%), urinary tract(63/452, 13.9%), peritoneum(41/303, 13.5%), meningeal(156/1 915, 8.1%)and other types of tuberculosis(2/57, 3.5%). Drug sensitivity test of 896 extrapulmonary tuberculosis strains showed that the resistance rate (from high to low) was in the order of isoniazid, rifampicin, streptomycin, ofloxacin, ciprofloxacin, amikacin, capreomycin and ethambutol. Multidrug-resistant(MDR)and extremely-drug resistant (XDR) rate was 9.7 %(87/896)and 2.0%(17/896)respectively. Conclusions: Cases of extrapulmonary tuberculosis sent for bacterial culture and the positive rate showed a rising trend by years in Chengdu area.The drug resistance level was higher than that reported both in China and abroad.The prevention and treatment of extrapulmonary tuberculosis should be strengthened in this area. PMID- 28810313 TI - [Efficacy and safety of tiotropium Respimat in the treatment of chronic obstructive pulmonary disease: systematic review]. AB - Objective: To evaluate the efficacy and safety of tiotropium Respimat in the treatment of chronic obstructive pulmonary disease (COPD) according to the Cochrane systematic evaluation. Methods: The Cochrane Library, PubMed, EMbase, CNKI, VIP and CBM, Wanfang Data were searched(from the foundation date to Jan. 2016) for the randomized controlled trials (RCTs) of tiotropium Respimat in the treatment of patients with COPD. Two reviewers independently retrieved the RCTs according to the inclusion and exclusion criteria, assessed the methodological quality of the included trials.and performed statistical analysis on the data using RevMan 5.3 software. Results: Totally 11 RCTs on efficacy were finally included.The results of the combined analysis showed that FEV(1) was significantly improved in the tiotropium Respimat group than that in the placebo group[MD=0.12, 95%CI(0.10-0.14), P<0.000 01], while FEV(1) was similar between the tiotropium Respimat group and the tiotropium HandiHaler group[5 MUg: MD=0.00, 95%CI(-0.04-0.04), P=0.94; 2.5 MUg: MD=-0.04, 95%CI(-0.10-0.01), P=0.12; 10 MUg: MD=0.02, 95%CI(-0.06-0.09), P=0.66]. FVC was significantly improved in the tiotropium Respimat group than that in the placebo group[MD=0.18, 95%CI(0.09 0.28), P=0.0002], while FVC was similar between the tiotropium Respimat group and the HandiHaler group[2.5 MUg: MD=-0.06, 95%CI(-0.16-0.04), P=0.24; 5 MUg: MD= 0.00, 95%CI(-0.08-0.08), P=1.00; 10 MUg: MD=0.02, 95%CI(-0.14-0.19), P=0.78]. The risk of acute exacerbations was lower in the tiotropium Respimat group (5 MUg / kg) than in the placebo group [OR=0.72, 95%CI(0.60-0.86), P=0.000 3]. It was similar in the tiotropium Respimat group (5 MUg) and the HandiHaler group[OR=1.01, 95%CI(0.94-1.09), P=0.71]. The SGRQ total score of the tiotropium Respimat group (5 MUg) was significantly different from that of the placebo group[MD=-3.6, 95%CI(-3.88--3.32), P<0.000 01]. C(max, ss) and AUC(0-6 h, ss) were also similar between the tiotropium Respimat group and the HandiHaler group[MD=0.2, 95%CI(-5.1-5.5), P=0.94]; MD=-1.01, 95%CI(-11.78-9.77), P=0.85]. Nine RCTs were included in the evaluation of the incident rates of adverse drug reactions(ADR). There was no significant difference between the tiotropium Respimat group HandiHaler group and the placebo group[RR=0.95, 95%CI(0.89-1.00), P=0.05], [OR=1.07, 95%CI(1.00-1.16), P=0.06]. Conclusions: The efficacy and safety of tiotropium Respimat was similar to tiotropium HandiHaler in the treatment of COPD. They can effectively improve the pulmonary function and clinical symptoms of patients. But the long-term efficacy and safety of tiotropium Respimat still need to be confirmed by higher quality and larger RCTs with long-term follow-up. PMID- 28810314 TI - [Clinical and pathological characteristics of Erdheim-Chester disease involving the lungs]. AB - Objective: To explore the clinical manifestations, pathological features, differential diagnosis and gene mutation status in patients with pulmonary involvement of Erdheim-Chester disease (ECD). Methods: The clinical data of 4 cases of Erdheim-Chester disease admitted to Peking Union Medical College Hospital from October 2014 to August 2016 were examined for imaging, microscopic and immunohistochemitry findings, and BRAFV600E mutation. The related literatures were reviewed. Results: Among the 4 cases, there were 3 males and 1 female, aging from 7 to 47 years, and the average age was 34.5 years. They complained of chest tightness, shortness of breath and bone pain. They all had multiple bone lesions, involving the long bones, skulls and vertebrae, and imaging showed increased bone uptake and bone sclerosis. CT scan showed pleural thickening or pleural effusion(4/4), widened lobular septa(3/4), bronchial vascular bundle thickening(3/4), multiple patchy ground glass and solid shadows(4/4), and cystic shadows(1/4). Multiple bone lesions were the main extrapulmonary manifestations. All the cases had multiple bone lesions, involving the long bones, skulls and vertebrae, and showed increased bone uptake and bone sclerosis. Surgical biopsy of the thoracic tissue was performed in all 4 cases (pleural in 1 case, lung in 2, anterior mediastinal mass in 1). Microscopically, the lesion was composed of spindle-shaped fibroblasts and foamy histiocytes enmeshed in reactive fibrous tissue. Lymphocytes and plasma cells were also found. Immunohistochemically, all the histiocytes were positive for CD(68), and none of them expressed CD1a. All cases were detected by real-time quantitative PCR for BRAFV600E gene mutation. Conclusions: The pulmonary involvement of Erdheim-Chester disease is rare, with clinical manifestations of chest tightness, shortness of breath, and some have no obvious respiratory symptoms. Pulmonary involvement in Erdheim-Chester disease has important manifestations, in which foam-like tissue cells with diffuse distribution along the lymphatic enmeshed in reactive fibrous tissue. It should be differentiated from diffuse interstitial lung diseases and metastatic tumors. The clinical features are often manifested as pleural thickening and pleural effusion, with multiple bone sclerosis lesions.BRAFV600E mutation detection is helpful for the diagnosis. PMID- 28810315 TI - [Adult peripheral primary neuroectodermal tumor: a case report and literature review]. AB - Objective: To analyze the clinical features, diagnosis and differential diagnosis of peripheral primary neuroectodermal tumor(pPNET). Methods: The clinical data and diagnosis of a patient with rapid progressive pPNET in Shandong Provincial Hospital affiliated to Shandong University in January 2016 was reported and the related literatures were reviewed.The literature reviews were carried out respectively in CNKI, Wanfang and PubMed by July 2016 with "primitive neurotodermal tumour" and "PNET" being the search term from March 1994 to July 2016, including 13 articles. Results: A 41 year-old male patient was admitted to the hospital because of shortness of breath and occasional chest tightness, accompanied by general asthenia of about 15 d. Positron emission and transmission CT of total trunk showed a mass in the right femoral osteoperiosteal mass, and multiple nodules in the left lung, lumps and nodules in the right lung, and right pleural thickening and effusion. Thoracoscopy was performed and pathology study confirmed the diagnosis of peripheral primary neuroectodermal tumor. The patient was given 2 courses of chemotherapy, but had rapid progressive worsening and died 1 month after PNET diagnosis. A total of 13 literatures of PNET were retrieved, all of which were case reports, and a total of 15 cases were reported.There were 9 male and 7 female patients, with a median age of 26 years.The symptoms had no specificity and most of them were solid masses in chest images, with or without pleural effusion. Eight cases were diagnosed by imaging guided percutaneous biopsy, 7 by operation and pathology, and 1 by medical thoracoscopy. Four cases underwent chemotherapy, and the survival time was less than 6 months. Twelve cases got surgical resection: 2 with surgical treatment, 7 with postoperative chemotherapy, 2 with postoperative radiotherapy and chemotherapy, 1 with postoperative chemotherapy and autologous bone marrow transplantation treatment, among which 11 patients completed follow-up. During follow-up, 3 cases died, and the survival time was 10 months, 3 years and 7 years, respectively. Conclusions: PNET is rare.Due to the lack of specificity of clinical manifestations, clinical diagnosis depends on biopsy. Early diagnosis and surgical resection are especially important for prognosis and quality of life. PMID- 28810316 TI - [Advances in the pathogenesis of asthma in the elderly]. PMID- 28810317 TI - [Advance in transbronchial cryobiopsy]. PMID- 28810318 TI - [Application of bronchoscopy navigation in peripheral pulmonary lesions]. PMID- 28810319 TI - [Update of idiopathic inflammatory myopathy associated interstitial lung disease]. PMID- 28810320 TI - [Chinese expert consensus on the diagnosis and treatment of eosinophilia (2017)]. PMID- 28810321 TI - [Agranulocytosis as the major clinical manifestation of nonsecretory multiple myeloma: a rare case report]. PMID- 28810322 TI - [Comparison of generic and original imatinib in the treatment of newly diagnosed patients with chronic myelogenous leukemia in chronic phase: a multicenter retrospective clinical study]. AB - Objective: To evaluate the efficacy and safety of generic imatinib (Genike, Chiatai Tianqing Pharmaceutical Group Co., Ltd.) and imatinib (Glevic, Novartis, Switzerland) in newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-CP) . Methods: A retrospective study of 323 CML-CP patients (205 in Glivec treatment group and 118 in Genike group) who were >= 18 years old receiving imatinib monotherapy over the period of June 2013 to March 2016 was done to compare the differences of cytogenetics, molecular curative effect, survival, and adverse reactions between the two groups. The beginning dosage of imatinib was 400mg per day. There was no statistically difference between the two groups of patients on baseline. Results: 1The median duration of imatinib treatment was 13 (0.5-36) months in Glevic group and 11 (1-31) months in Genike group. 2The rate of complete hematological remission (CHR) had no statistically difference between Glivec and Genike treatment groups[98% (201/205) vs 97.5% (115/118) , chi(2)=0.123, P=0.725]. 3Cumulative rates of major cytogenetic responses (MCyR) at 3, 6 and 12 months after imatinib treatment in Gleevec and Genike groups were (59.7+/-3.5) % vs (79.8+/-3.1) %, (89.2+/-2.6) % vs (59.1+/ 4.7) %, (80.3+/-4.1) % vs (87.1+/-4.3) %, respectively, the difference was not statistically significant (chi(2)=0.084, P=0.772) . Cumulative rates of complete cytogenetic response (CCyR) at 3, 6 and 12 months after imatinib treatment in Gleevec and Genike groups were (32.9+/-3.4) % vs (58.3+/-3.7) %, (87.4+/-3.0) % vs (35.2+/-4.5) %, (64.8+/-4.8) % vs (87.3+/-4.7) %, respectively, the difference was not statistically significant (chi(2)=0.660, P=0.417) . 4Cumulative rates of major molecular responses at 6, 12 months after imatinib treatment in Glevic and Genike groups were (24.9+/-3.3) % vs (57.0+/-4.1) %, (16.3+/-4.0) % vs (55.3+/ 7.7) %, respectively, there was no statistical significance (chi(2)=1.617, P=0.204) . Cumulative rates of molecular response 4.5 (MR4.5) at 12 months after imatinib treatment in Glevic and Genike groups were (14.9+/-3.2) % vs (8.1+/-2.1) % (chi(2)=3.628, P=0.057) , respectively. 5At a median follow-up of 12 months, the difference of progression-free survival (PFS) in Glevic and Genike groups had no statistical significance[ (96.6+/-1.4) % vs (93.3+/-2.5) %, chi(2)=2.293, P=0.130]. The difference of event-free survival (EFS) had no statistical significance, either[ (95.6+/-1.5) % vs (93.3+/-2.4) %, chi(2)=2.124, P=0.145]. 6Genike was well tolerated in patients with CML-CP and had no statistically significant difference in adverse events compared with Glevic group. Conclusion: There were no statistically significant differences in efficacy and safety between Glevic and Genike treatment in newly diagnosed patients with CML-CP. PMID- 28810323 TI - [The efficacy and safety of the patients of myelodysplastic syndromes-refractory anemia with excess blasts treated with decitabine alone or CAG/HAG regimen]. AB - Objective: To observe the clinical efficacy and safety of the patients of myelodysplastic syndromes-refractory anemia with excess blasts (MDS-REAB) treated with decitabine alone or based on low dose cytarabine (Ara-C) regimen CAG/HAG [aclarubrci (ACR) /homoharring-tonine (HHT) +cytarabine+granulocyte colony stimulating factor (G-CSF) ]. Methods: Totally 121 patients with MDS-REAB were retrospectively analyzed, including 59 patients treated with decitabine alone (20 mg.m(-2).d(-1) for 5 days) , the rest 62 ones treated with low-dose Ara-C-based regimen CAG/HAG. Overall response rate (ORR) , overall survival (OS) and adverse events of the two groups were analyzed and compared retrospectively. Results: The ORR of decitabine alone or CAG/HAG were 66.2% and 56.4% respectively, with no statistically significant differences (chi(2)=1.185, P=0.276) . Initial response rate detected by the end of first cycle of CAG/HAG was higher than that of decitabine alone (94.3% vs 69.2%) , there was statistically significant difference in the overall comparison of two groups (chi(2)=7.612, P=0.009) . The median OS of decitabine alone was 19.5 (95% CI 10.5-28.4) months, the median OS of CAG/HAG was 20.3 (95% CI 10.7-29.9) months, with no statistically significant differences (chi(2)=0.004, P=0.947) . Grade 3-4 cytopenia and infection were the most prevalent adverses of two group patients. Grade 3-4 cytopenia rate of CAG/HAG was higher than that of decitabine alone (100.0% vs 64.4%, P<0.001) . The infection rate detected at third cycle of CAG/HAG was higher than that of decitabine alone (52.9% vs 15.2%, P=0.008) . Conclusion: The efficacy of treating MDS-RAEB with decitabine alone or CAG/HAG was equivalent. CAG/HAG treatment came into effect faster, but decitabine alone treatment was safer. PMID- 28810324 TI - [Minimal residual disease level predicts outcomes in the non-favorable risk patients with acute myeloid leukemia]. AB - Objective: To explore impact of minimal residual leukemia (MRD) on outcomes in the non-favorable risk adults with de novo acute myeloid leukemia (AML) . Methods: From January 2008 to February 2016, data of consecutive newly-diagnosed non-favorable risk adults with AML (non-APL) according to SWOG criteria who achieved morphologic leukemia-free state (MLFS) and received continuous chemotherapy were assessed retrospectively. Results: 292 AML patients were enrolled, 150 (51.4%) were male. Median age was 46 years (range, 18-65 years) . Using the SWOG cytogenetic classification, 186 (63.7%) , 49 (16.8%) and 57 (19.5%) patients belonged to intermediate, unfavorable and unknown categories, respectively. With a median follow-up period of 15 months (range, 1 to 94 months) in survivors, the probabilities of cumulative rates of relapse (CIR) , disease free survival (DFS) and overall survival (OS) at 2-years were 51.6%, 42.6% and 60.0%, respectively. Multivariate analyses showed that MRD positive (defined as Q PCR WT1 mRNA >=0.6% or any level of abnormal blast population detected by flow cytometry) after achieving MLFS and PLT<100*10(9)/L were common adverse factors affecting CIR and DFS. In addition, positive FLT3-ITD mutation and CRp/CRi had negatively impact on CIR, DFS and OS. Monosomal karyotype was adverse factors affecting CIR and OS. Age >=44 years and unfavorable-risk of SWOG criteria were associated with shorter DFS. Conclusions: MRD level after achieving MLFS had prognostic significance on outcomes in non-favorable adults with AML who received continuous chemotherapy after achieving MLFS. PMID- 28810325 TI - [Heterogeneity and clonal evolution in pediatric ETV6-RUNX1(+) acute lymphoblastic leukemia by quantitative multigene fluorescence in situ hybridization]. AB - Objective: To evaluate heterogeneity and clonal evolution in pediatric ETV6 RUNX1(+) acute lymphoblastic leukemia (ALL) in China. Methods: Totally 48 children (<14 years) with newly diagnosed ETV6-RUNX1(+) ALL in Institute of Hematology and Blood Disease Hospital, CAMS and PUMC, from February 2006 to June 2011 were included. The copy number variations were analyzed by quantitative multigene fluorescence in situ hybridization (QM-FISH) in 48 patients. Non-normal distribution of measurement data were shown with Median (range) , count data were shown with percent (%) . Overall survival and event-free survival were estimated by the Kaplan-Meier method and compared with the log-rank test. Results: Forty eight patients were tested by QM-FISH. Of 48 patients, 70.8% harbored one clone, 18.8% two subclones, and 10.4% three or more subclones. The clone heterogeneity was detected by two different models: the linear succession model and the branching evolution model. ETV6-RUNX1(+) ALL relapse evolved from an ancestral clone or a new clone. The patients relapsed from a new clone got the worse outcome. Conclusion: The clone evolution was detected in pediatric ETV6-RUNX1(+) ALL in China. QM-FISH might be helpful to evaluate the outcome of relapsed patients. A new clone was associated with a poorer outcome. PMID- 28810327 TI - [Acute myeloid leukemia with increased eosinophils and PDGFRbeta mutation in one case]. PMID- 28810326 TI - [The analysis of prognosis-associated factors in adults with acute promyelocytic leukemia]. AB - Objective: To explore the prognostic value of CD34, CD2, CD56 expressions and FLT3-ITD mutation in adults with acute promyelocytic leukemia (APL) . Methods: The immuno-phenotypic and molecular characteristics of 137 adult patients with APL (from January 2010 to March 2016, in Henan Provincial People's Hospital) were investigated. And the relationships between CD34, CD2, CD56 expressions, FLT3-ITD mutation and the outcomes of high WBC counts at onset, complete remission (CR) rate, early mortality, relapse rate (RR) , overall survival (OS) , disease free survival (DFS) were explored. Results: 1Among the 137 patients, the positive ratios of CD34, CD2, CD56 expressions and mutation rate of FLT3-ITD were 26.3%, 25.5%, 10.2% and 17.5%, respectively. The morbidities of positive CD34, CD2, CD56 expressions and FLT3-ITD mutation in the high-risk group were 43.2%, 47.7%, 18.2% and 27.3% respectively, while those in the low-/intermediate-risk groups were 18.3%, 15.1%, 6.5% and 12.9%, respectively (P<0.05) . 2At a median follow-up of 41 months, the total CR rate of the 137 adults APL patients was 96.9%, early mortality 6.6% and relapse rate 7.3% respectively. And RR of positive CD34 or CD2 expression patients was higher than negative CD34/CD2 expression ones (18.8% vs 3.3%, chi(2)=8.462, P=0.004; 16.1% vs 4.3%, chi(2)=4.382, P=0.028, respectively) . In addition, the early mortality of patients with positive CD56 expression or FLT3-ITD mutation was extremely higher than in negative ones (21.4% vs 4.9%, chi(2)=5.610, P=0.018; 16.7% vs 4.4%, chi(2)=4.833, P=0.028, respectively) . 3The whole OS and DFS were 88.3% and 84.7%, respectively. Wherein, OS and DFS in patients with CD34(+), CD56(+) or FLT3-ITD mutation were worse (P<0.05) . Conclusions: Positive CD34, CD2, CD56 expression and FLT3-ITD mutation were latent poor prognostic factors in adults with APL. PMID- 28810328 TI - [Clinical features of 11 cases of primary bone lymphoma]. AB - Objective: To analyze the clinical features, treatment and outcomes of primary lymphoma of bone (PLB) . Methods: The clinical data of 11 PLB patients were retrospectively analyzed. Results: 11 patients were enrolled in our study including 7 females and 4 males. The median age of the patients was 45 years old. The main histologic type was diffuse large B cell lymphoma and anaplastic large cell lymphoma. Of the 11 PLB cases, 3 cases were at stage IE, 2 at stage IIE, 6 at stage IVE respectively. 6 cases were treated with chemotherapy and radiotherapy, 2 cases with total joint arthroplasty and chemotherapy, and 3 cases chemotherapy alone respectively. 5 cases got complete remission, 4 cases partial remission and 2 cases stable disease respectively. The median progression free survival was 17 (5-58) months after a median follow up of 21 (6-58) months. Conclusions: Most of PLB patients were clinically in late stage lacking of clinical and imagine features. The optimal treatment for PLB was radiotherapy combined with chemotherapy, and its prognosis was relatively good. PMID- 28810329 TI - [Distribution and drug resistance of pathogens at hematology department of Jiangsu Province from 2014 to 2015: results from a multicenter, retrospective study]. AB - Objective: To describe the distribution and drug resistance of pathogens at hematology department of Jiangsu Province from 2014 to 2015 to provide reference for empirical anti-infection treatment. Methods: Pathogens were from hematology department of 26 tertiary hospitals in Jiangsu Province from 2014 to 2015. Antimicrobial susceptibility testing was carried out according to a unified protocol using Kirby-Bauer method or agar dilution method. Collection of drug susceptibility results and corresponding patient data were analyzed. Results: The separated pathogens amounted to 4 306. Gram-negative bacteria accounted for 64.26%, while the proportions of gram-positive bacteria and funguses were 26.99% and 8.75% respectively. Common gram-negative bacteria were Escherichia coli (20.48%) , Klebsiella pneumonia (15.40%) , Pseudomonas aeruginosa (8.50%) , Acinetobacter baumannii (5.04%) and Stenotropho-monas maltophilia (3.41%) respectively. CRE amounted to 123 (6.68%) . Common gram-positive bacteria were Staphylococcus aureus (4.92%) , Staphylococcus hominis (4.88%) and Staphylococcus epidermidis (4.71%) respectively. Candida albicans were the main fungus which accounted for 5.43%. The rates of Escherichia coli and Klebsiella pneumonia resistant to carbapenems were 3.5%-6.1% and 5.0%-6.3% respectively. The rates of Pseudomonas aeruginosa resistant to tobramycin and amikacin were 3.2% and 3.3% respectively. The resistant rates of Acinetobacter baumannii towards tobramycin and cefoperazone/sulbactam were both 19.2%. The rates of Stenotrophomonas maltophilia resistant to minocycline and sulfamethoxazole were 3.5% and 9.3% respectively. The rates of Staphylococcus aureus, Enterococcus faecium and Enterococcus faecalis resistant wards vancomycin were 0, 6.4% and 1.4% respectively; also, the rates of them resistant to linezolid were 1.2%, 0 and 1.6% respectively; in addition, the rates of them resistant to teicoplanin were 2.8%, 14.3% and 8.0% respectively. Furthermore, MRSA accounted for 39.15% (83/212) . Conclusions: Pathogens were mainly gram-negative bacteria. CRE accounted for 6.68%. The rates of Escherichia coli and Klebsiella pneumonia resistant to carbapenems were lower compared with other antibacterial agents. The rates of gram-positive bacteria resistant to vancomycin, linezolid and teicoplanin were still low. MRSA accounted for 39.15%. PMID- 28810330 TI - [The function of NLRP1 in noninfectious pulmonary injury following allogeneic hematopoietic stem cell transplantation]. AB - Objective: To explore the function of NLRP1 in noninfectious pulmonary injury (nonIPI) after allogeneic stem cell transplantation (allo-HSCT) . Methods: In this study, we established the model of allo-HSCT with C57BL/6 and NLRP(-/-) mouse as recipients. Chimera rate was measured by flow cytometry. The HE staining was used to observe the pathology changes in the lungs. NLRP1 and relevant inflammatory proteins were measured by Western Blot. Results: On the day 14 after allo-HSCT, the chimera rate was more than 96%, HSCs of donors had been successfully transplanted into recipients. HE staining showed that nonIPI occurred after allo-HSCT. The degrees of injuries reached the peak on day 21. In addition, the expressions of MPO, NLRP1, p20, Mature-IL-1beta and Mature-IL-18 had same tends with the degrees of nonIPI. When we knocked out NLRP1 gene of recipients, the degrees of nonIPI reduced and the expressions of MPO, p20, Mature IL-1beta and Mature-IL-18 were less than in non-knockout group. Conclusion: allo HSCT could cause nonIPI and high expressions of MPO, p20, IL-1beta, IL-18, NLRP1. Knocking out NLRP1 gene could alleviate the degrees of nonIPI and reduce the expressions of relevant inflammatory proteins, indicating that NLRP1 might be one of factors contributed to nonIPI after allo-HSCT. PMID- 28810331 TI - [Effect of TSC2 gene expression downregulation by lentivirus induced RNA interference on U937 cell line and its mechanism]. AB - Objective: To investigate the effect of biology and mTOR pathway activity of down regulated TSC2 gene expression on U937 leukemia cells. Methods: Gene expression was down-regulated by lentivirus induced RNA interference on TSC2 high expressed U937 cell line; the proliferation, apoptosis and differentiation were detected by CCK-8 assay, colony formation assay and flow cytometry; the gene expression level and protein kinase activity were detected by qRT-PCR and Western blot. Results: Down-regulated expression of TSC2 gene promoted U937 cell proliferation and colony formation ability (P<0.05) . The proportion in G(0)/G(1) phase of TSC2 down-regulated U937 cell was much lower than that of the control cells [ (52.53+/ 3.75) % vs (75.10+/-4.33) %, t=6.829, P=0.002], the S phase [ (22.43+/-1.00) % vs (15.47+/-1.20) %, t=-5.581, P=0.019] and G(2)/M phase [ (25.03+/-4.34) % vs (14.33+/-0.91) %, t=-5.413, P=0.013] was remarkably higher than that of the control cells (P<0.05) . There were no statistically significant differences in cell apoptosis and differentiation (P>0.05) . Down-regulation of TSC2 led to the increased activity of mTOR, 4EBP1 and S6K1, but did not influence the activity of AKT. The expressions of proliferation related cyclinD1, c-myc and PTEN were also up-regulated after TSC2 silenced, but the expressions of P27KIP and BCL-XL were not changed. Conclusion: Downregulation of TSC2 could promote the proliferation of U937 cells through up-regulation of mTOR activity. PMID- 28810332 TI - [Study on the expression of TRIP13 mRNA in chronic lymphocytic leukemia B lymphocyte and the molecular mechanism of TRIP13 mediated JVM-2 cell proliferation and apoptosis]. AB - Objective: To investigate the clinical significance of expression level of thyroid hormone receptor interactors 13 (TRIP13) gene to probe its function and downstream molecular mechanism in chronic lymphocytic leukemia (CLL) . Methods: Real-time quantitative PCR method was used to detect the expression levels of TRIP13 mRNA of CD19(+) B lymphocytes in 30 cases of patients with CLL and 12 cases of peripheral blood hematopoietic stem cell donors (normal control group) . Lentivirus mediated shRNA was used to interference the mRNA and TRIP13 protein in CLL cells JVM-2. Scramble sequence was used as control. Methyl thiazolyl tetrazolium colorimetric assay (MTT) and flow cytometry was used to detect the cell proliferation and apoptosis in TRIP13 knocked-down and negative control JVM 2 cells. Results: TRIP13 mRNA level was significantly higher in 30 cases of CLL patients (2(-?Ct)= 0.014 89) compared with 12 healthy donors (2(-?Ct)= 0.000 19) (P<0.001) . Validated TRIP13 shRNA target was achieved in JVM2 cell. Compared with the control group, down-regulation of TRIP13 expression could significantly inhibit the proliferation of JVM-2 cells and induce apoptosis. The expressions of Myc and Bcl-2 protein in JVM-2 cells decreased significantly after interference with TRIP13 (P<0.001) , and the expressions of Bax, caspase 3 and Bad protein increased significantly (P<0.001) . Conclusion: TRIP13 mRNA significantly over expressed in CLL patients CD19(+) B lymphocytes. TRIP13 could influence JVM2 cell proliferation and apoptosis through proliferation- and apoptosis-related proteins. PMID- 28810333 TI - [Clinical features and risk factors of vein thrombosis in 259 patients with chronic myelofiberation neoplasms]. PMID- 28810334 TI - [Bortezomib-based treatment of 26 cases multiple myeloma complicating with intestinal obstruction]. PMID- 28810335 TI - [Expression of IL-37 in peripheral blood of adults with primary immune thrombocytopenia]. PMID- 28810336 TI - [Identification and characterization of PKLR gene mutation in two patients with erythrocyte pyruvate kinase deficiency]. PMID- 28810337 TI - [The clinical efficacy and safety of lenalidomide plus rituximab regimen in the treatment of elderly or relapsed/refractory B-non-Hodgkin's lymphoma patients]. PMID- 28810338 TI - [Clinical features of hereditary stomatocytosis: 12 cases report and literatures review]. PMID- 28810339 TI - [Clinical characterization and outcome of non-Hodgkin lymphoma presenting with initial spinal cord compression: a retrospective study of 25 patients]. PMID- 28810341 TI - [Research progress of bone marrow microenvironment abnormalities in myelodysplastic syndrome]. PMID- 28810340 TI - [Interstitial pneumonia induced by imatinib in patients with Ph(+) acute lymphoblastic leukemia: a case report]. PMID- 28810342 TI - [Study on the excavated wooden carved acupuncture statue of the Western Han Dynasty in Laoguanshan]. AB - The painted red lines on the wooden carved acupuncture statue of Western Han Dynasty in Laoguanshan, illustrate the running courses of the"eleven meridians"on the body surface in the early meridian doctrine. The carved white lines show the body surface running courses of the"twelve meridians"in the meridian doctrine and the Sanjiao images in Sanjiao doctrine. The dots on the wooden carved acupuncture statue are of two categories, one of them is of regulatory, round and concave spots, which are carved before the process of lacquer undercoat. The other category is of different sizes and in irregular forms, which are carved simultaneously with those white lines. Altogether there are over one hundred dots in these two categories, representing the mai shu (transport point of vessels). The wooden carved acupuncture statue reflects the distinct characteristics on the running courses of meridians, Sanjiao doctrine, the nomenclature and localization of"mai shu"in Bianque medicine, which provides the most powerful evidence for the confirmation of the correlation between Laoguanshan excavated documents and Bianque medicine. PMID- 28810343 TI - [Textual criticism and discrimination on the naming of"Five-abstention Soup of Medical Professional"from the Han-tomb of the Marquis of Haihun]. AB - A lacquer vessel with the inscription of Yi gong wu jin tang (Five-abstention Soup of Medical Profession) has been unearthed from the Han-tomb of Marquis of Haihun, in which"Five abstentions"is related to the incantations and abstention therapies prevalent in the Qin and Han Dynasties. The"Five-abstention Law"is the five rituals and methods during the process of practicing incantations and abstentions therapies including"keeping one's thinking (cun si)","holding the breath(bi qi)","twirling eyes (nian mu)","stepping after Yu's sample (yu bu)"and"incanting and blessing (zhou zhu)". The"Five-abstention Law"uses the medium"soup"to achieve the purpose of treatment."Soup"refers either to"decoction"or to"magic water". The lacquer vessel with the inscription"Five abstention Soup of Medical professional"could be an instrument for implementing the process of practising the"Five-abstention Law", reflecting the historical facts that Liu He, the Marquis Haihun did accept the incantations and abstention therapies. PMID- 28810344 TI - [Discussion on medicinal history and germplasm resource of Clinopodium Herba]. AB - By sorting out the literature on materiamedica, it is found that medicinal history of ClinopodiumHerba is rather long which can be traced back to caoxuejiein Luchan yan ben cao (Mountainous Materia Medica) with definite efficacy and usage; it is generally believed that the original plant of ClinopodiumHerba is Clinopodiumpolycephalum (Vaniot) C. Y. Wu et Hsuan and C. chinensis (Benth.) O. Kuntze are two separate species, also some scholarsclaim that C. polycephalum and C. chinensisare the same plant. But I think C. polycephalum is the main origin of ClinopodiumHerba, and the relationship of C. polycephalum and C. chinensis maybe a species and its variety. PMID- 28810345 TI - [Commentary on self-compiled teaching materialsby Singapore Chinese Physician Training College]. AB - The Singapore Chinese Physician Training College has been playing a role in the development of traditional Chinese medicine (TCM) and the training of TCM talents in modern and contemporary Singapore not to be ignored. Due to the limitations of the objective condition, the College had to creatively compile by themselves 115 volumes of teaching materials with rather complete subjects, which did pay attention to applying theory to practice, ran through the thought of Chinese integrating with western medicine, and is of literature and cultural significance.As a carrier of educational contents and methods, these teaching materials not only embodied the educational idea of the editor, but also reflected the status of TCM development in modern Singapore. PMID- 28810346 TI - [Brief survey of some foreign currents of classical acupuncture]. AB - This paper reviews the history of acupuncture's dissemination to Japan, France, and England in the modern period. In particular, it examines how Chinese acupuncture methods were modified in each of these countries and how these modifications were theoretically justified based on new readings of classical texts. In each country, these currents of acupuncture practice all claimed to be transmitting true traditional acupuncture, even as they developed along different trajectories and created new and different theories and practices of acupuncture. Some of these foreign methods were re-exported back to China, where they, in turn, have influenced the development of Chinese acupuncture. PMID- 28810347 TI - [History of world neurosurgery]. AB - In 5000 BC, South American tribes digged the bones in the living head to seek ways to communicate with the gods, which was primitive trephination and may be the first neurosurgical behavior. In 2600 BC, Imhotep in ancient Egypt took the brain out of the head from the nose, for a better preserve of the mummy, which was a prototype of modern transsphenoidal surgery. And the development of anatomy in ancient Greek laid a solid foundation for neurosurgery. From 500 to 1500 AD, the rise of religion and the occurrence of war, prompted a large number of craniocerebral trauma, which contributed greatly to the early development of neurosurgery as a distinct specialty. In 1861, Brocca astutely localized the language function to the third left frontal convolution in a series of studies, which was considered to be of landmark importance in the understanding of cerebral localization. In 1878, William Macewen performed a successful surgery to remove an en plaque meningioma with intrathecal anesthesia, representing the first modern neurosurgical operation. However, the contributions of the Americans, starting with Harvey Cushing, exerted a definitive force. Portuguese Moritz performed the first cerebral angiogram on a living schizophrenia patient in 1926. And he established the Moniz-Lima prefrontal leucotomy for the treatment of schizophrenia, for which he won the Nobel Prize in Physiology and Medicine in 1949. In 1968, the Swiss scholar Yassagir firstly carried out neurosurgical surgeries under the microscope. China's neurosurgery was founded by Zhao Yicheng in 1952 in Tianjin, and the gap in neurosurgery between China and the world gradually narrowed after 60 years of development. PMID- 28810348 TI - [A preliminary discussion on the contents and value of All Diseases(1), the medical bamboo slips unearthed from Han tomb in Laoguanshan of Chengdu]. AB - Among the medical bamboo slips unearthed from Han tomb in Laoguanshan of Chengdu, the Zhu bing (All Diseases) is a monograph to discuss the characteristics of signs and symptoms. Based on the differences of writing styles, diseases involved, expounding methods and writing rules, the book is divided, by the research team, into 2 parts: All Diseases(1) and All Diseases(2). All Diseases(1) includes over 130 slips, 2 000 characters with totally more than 100 disease names, containing multiple clinical disciplines. The elaborated classification, varied naming methods, grasping the symptom characteristics guided by the four diagnostic approaches, paying attention to the comparison of similar diseases, and dealing with the prognosis and healthcare in this part reflect the holism of correspondence between human body and natural environment, and syndrome differentiation thought of combining disease with symptoms and signs, revealing its academic significance. PMID- 28810349 TI - [Decipherment and annotation of some terms in the remnant scrolls of Hui hui yao fang (Huihui Formularies)]. AB - The etymology of the terms in Hui hui yao fang (Huihui Formularies) is complicated. Their origin might be Arabian, Persian, or Sanskrit, or even the northern dialects of Han language during the Yuan and Ming Dynasties. There are obvious mistakes or indefinite decipherments and interpretations of the terms in Song Xian's Investigated Annotations of Huihui Formularies. There are also missing annotations for those transliterated terms. To tackle such defects, 12 such terms are deciphered and annotated here. PMID- 28810350 TI - [Analysis of compiling date of Huang di nei jing (Huangdi's Internal Classic)]. AB - There are Seven Medical Classics recorded in the Han shu Yi wen zhi(Bibliography in Annals of the Han Dynasty), among which the 18-volume Huang di nei jing (Huangdi's Internal Classic) is not the current edition of Ling shu (Miraculous Pivot) and Su wen(Plain Questions). The present edition of Huang di nei jing containing these two works might be merged in the Eastern Han Dynasty, benefited from the invention of Cai Lun's papermaking technique and the development of Nine needles, especially filiform needle manufacturing. Huang di nei jing was compiled on the basis of two major integrations: The first was joined by some medical experts such as Bian Que and tai yi ling (minister of imperial physicians) of the Qin State by using the language in the Warring States, contributing mainly to the theoretical system and forming its basic academic framework; The second was the second Royal book-collating activity in the Eastern Han Dynasty (100-110), which had revised the seven volumes of Chinese Medical Classics and incorporated them into two parts, Ling Shu and Su Wen, together with Bian Que's medical works and the new contents from the introductory Chapter on Nine Needles and Twelve Yuan(origin) Acupoints. PMID- 28810351 TI - [Schofield and the first spread of western medicine in Shanxi]. AB - After the Second Opium War, the signing of the Tientsin Treaty and the Peking Treaty legitimized the missionary activities and authorized the missionary the rights to enter inland China for propagating their religious doctrines. In the late 1870s, the"The extraordinary famine of the Ding Wu year"and the subsequent epidemic provided the opportunity for missionaries to enter Shanxi. Dr. Schofield, sent by the China Inland Mission, arrived in Taiyuan in 1880, set up clinics and practised there. He died of typhus after treating a typhus patient in the summer of 1883. Schofield stayed and practised in Taiyuan for 2 years and 8 months. Later, the China Inland Mission and other missionaries donated to establish a Shanxi's first western medicine Hospital to commemorate Schofield. The medical activities of Dr. Schofield enlightened and promoted the Shanxi people's understanding of western medicine. PMID- 28810352 TI - Maternal responses to difficult food request scenarios: Relationships with feeding style and child unhealthy snack intake. AB - This study sought to identify parent-feeding behaviours in real-life difficult feeding situations through the use of a set of scenarios. These were then used to examine links between parent feeding and child snack intake. Mothers of children aged 2-7 years ( n = 611) completed an online survey containing five snack food request scenarios, two commonly used parent-feeding scales (Restriction and Covert Control), and reported on their child's snack intake. Results showed that parent-feeding styles (restrictive or covert) translated into specific behaviours in response to the scenarios. These parent behaviours predicted children's intake of unhealthy snack food over and above the feeding style. PMID- 28810353 TI - Living as a couple with anorexia nervosa: A dyadic interpretative phenomenological analysis. AB - This study examined the difficulties couples face in relation to anorexia nervosa. Using interpretative phenomenological analysis, five couples in which one of the partners lives with anorexia nervosa were interviewed separately. The findings are conceptualized into three areas: first, the encounter 'at the crossroads between remission and relapse'; second, the way that 'anorexia reveals itself'; and finally, the way the 'menage a trois' works, including the illness fully as part of the couple. Psychotherapists should take into account the context of the couple and the complex interaction between the couple and the illness to support both partners' development of appropriate responses. PMID- 28810354 TI - Validation of the Intuitive Eating Scale in pregnancy. AB - The objective of this study was to examine the content validity and test-retest reliability of the Intuitive Eating Scale among pregnant women. A qualitative think-aloud study of the Intuitive Eating Scale analysed the content validity. Overall, the Intuitive Eating Scale made sense to pregnant women, but food safety affected the interpretation of some items. A version with instructions modified accounting for food safety, the Intuitive Eating Scale-Pregnancy, was subsequently shown to have stable scores over 5 weeks during the second trimester, mean change = -0.08 (95% limits of agreement: -0.61 to 0.45), r = 0.79, n = 240. The Intuitive Eating Scale-Pregnancy was acceptable for use in this New Zealand pregnant population. PMID- 28810355 TI - Effects of a randomized trial comparing standard and enhanced counseling for men at high risk of prostate cancer as a function of race and monitoring style. AB - Despite conflicting guidelines, a significant subset of high-risk men decide to undergo routine prostate cancer screening. Yet, there is a scarcity of available programs, and no studies evaluating interventions to support men in dealing with the psychosocial impact of screening. In this study, one of the first to explore the responses of high-risk men enrolling in a Prostate Cancer Risk Assessment Program ( N = 128), patients underwent a prostate cancer risk counseling visit immediately followed by either a cognitive-affective preparation session designed to help them process the information they received or a general health education session. All men in this self-selected sample chose to participate in prostate cancer screening. Men were assessed 3 weeks and 6 months post-counseling. The impact of the enhanced counseling condition on knowledge, perceived risk, expectancies, and intrusive ideation was a function of racial and coping style group. Implications for tailored interventions to maximize preparedness for risk and screening counseling are discussed. PMID- 28810357 TI - A graduated food addiction classification approach significantly differentiates obesity among people with type 2 diabetes. AB - This study examined a graduated severity level approach to food addiction classification against associations with World Health Organization obesity classifications (body mass index, kg/m2) among 408 people with type 2 diabetes. A survey including the Yale Food Addiction Scale and several demographic questions demonstrated four distinct Yale Food Addiction Scale symptom severity groups (in line with Diagnostic and Statistical Manual of Mental Disorders (5th ed.) severity indicators): non-food addiction, mild food addiction, moderate food addiction and severe food addiction. Analysis of variance with post hoc tests demonstrated each severity classification group was significantly different in body mass index, with each grouping being associated with increased World Health Organization obesity classifications. These findings have implications for diagnosing food addiction and implementing treatment and prevention methodologies of obesity among people with type 2 diabetes. PMID- 28810356 TI - Relationship cognitions and longitudinal trajectories of sexual risk behavior among young gay and bisexual men: The P18 cohort study. AB - This study examines how romantic relationship cognitions are associated with changes of condomless anal sex among emerging adult gay and bisexual men. The sample was drawn from four waves of a prospective cohort study ( N = 598; Mage = 18.2). Results suggest that condomless anal sex increased over the emerging adulthood period. Romantic relationship fear was associated with increased receptive condomless anal sex. Perceptions of greater romantic relationship control increased the likelihood of having insertive and receptive condomless anal sex. Findings suggest that romantic relationship cognitions are important to consider when understanding longitudinal changes in condomless anal sex in this population. PMID- 28810358 TI - Human papillomavirus vaccine information, motivation, and behavioral skills among young adult US women. AB - This study elicited the information needs, motivations, and behavioral skills related to human papillomavirus vaccine decision-making among young adult women. Interviews were conducted with college women, aged 18-26 years, and stratified by recently vaccinated ( N = 25) and unvaccinated ( N = 25). Comparative thematic analysis using the Information, Motivation, and Behavioral Skills Model was conducted. Healthcare providers were identified as the most trusted sources for information. While unvaccinated women did not have experience receiving the vaccine, they reported the same procedural knowledge for vaccination. These findings suggest that young adult women have the information and procedural knowledge for human papillomavirus vaccination, but motivations may influence their decision-making. PMID- 28810359 TI - The role of motivation in predicting antiretroviral therapy adherence in China. AB - Patient motivation is important in managing medication regimens such as antiretroviral treatment for HIV/AIDS. We tested whether self-determination theory could predict adherence behavior among 115 HIV-positive patients in the China Adherence through Technology Study, a randomized controlled trial of an intervention using text reminders and supportive counseling to increase adherence. Being in the treatment group had a significant effect on improving adherence; however, we did not find evidence that self-determination theory predicts adherence in this population of HIV-positive patients. Autonomous motivation was strongly associated with perceived competence; among low adherers, external regulation was negatively correlated with adherence. PMID- 28810360 TI - Habit strength as a moderator of the association between symptoms of poor mental health and unintentional non-adherence to oral hypoglycemic medication in adults with type 2 diabetes. AB - This study tested if habit strength for taking oral hypoglycemic medication moderated the association between poor mental health symptoms (i.e. depressive symptoms, diabetes distress) and unintentional non-adherence in 790 adults with type 2 diabetes. Data were cross-sectional. A habit strength * depressive symptom interaction was observed. Depressive symptoms were negatively associated with adherence if habit was weak or of average strength; no association was observed if habit was strong. A similar interaction emerged when diabetes distress was examined. Results suggest that habit strength might operate as a buffer in the association between poor mental health symptoms and medication adherence. PMID- 28810361 TI - Body dissatisfaction predicts inflammatory status in asymptomatic healthy individuals. AB - Body dissatisfaction may play some role in the pathophysiology of chronic diseases. This study examined relations between body dissatisfaction and circulating levels of inflammatory biomarkers C-reactive protein, tumour necrosis factor-alpha, interleukin-6 and anti-inflammatory adiponectin, and to explore positive changes in relevant lifestyle behaviour after these associations. A total of 33 asymptomatic overweight men and women were evaluated at the baseline and after a 6-month lifestyle behaviour intervention. Body dissatisfaction emerged as an important predictor of pro- and anti-inflammatory biomarkers and may promote the production of inflammatory cytokines by reducing the level of anti-inflammatory and increasing the level of pro-inflammatory cytokine production. PMID- 28810362 TI - Effect of exercise training in heart rate variability, anxiety, depression, and sleep quality in kidney recipients: A preliminary study. AB - The aim of this study was to compare the sleep quality, depression, anxiety, and autonomic function of a group of kidney-transplanted recipients who joined a combined exercise program (KTRt) or remained sedentary (KTRs). A total of 20 kidney-transplanted recipients, split into two groups (10 KTRt and 10 KTRs), joined the study. Heart rate variability, cardiorespiratory capacity, depression, and sleep questionnaires were evaluated. KTRt presented lower Pittsburgh Sleep Quality Index and greater entropy, and increased parasympathetic and decreased sympathetic modulation than KTRs. Anxiety level was minimal and depression was absent in both groups. KTRt group presented better sleep quality and better autonomic modulation than KTRs. PMID- 28810363 TI - Depression among left-behind children in China. AB - By retrieving literature published from 2005 to 2015 from Chinese National Knowledge Infrastructure, Wanfang, Vip, PubMed, and Web of Science, we filtered out studies using the Children's Depression Inventory only and compared left behind children and non-left-behind children. The methodological quality of the papers was evaluated using the Newcastle-Ottawa Scale. Finally, we included six studies to carry out a meta-analysis. The results showed that the Children's Depression Inventory scores of left-behind children are significantly higher than those of non-left-behind children (standardized mean difference: -0.233, 95% confidence interval: -0.036 to -0.430, p < 0.05). PMID- 28810364 TI - Identifying barriers to help-seeking for non-motor symptoms in people with Parkinson's disease. AB - Non-motor symptoms of Parkinson's disease have a significant impact on quality of life. Despite this, many non-motor symptoms remain unreported by patients and consequently untreated. This study explored barriers to help-seeking using two theoretical frameworks, the Common Sense Model of illness perception and Theoretical Domains Framework. A total of 20 participants completed semi structured interviews to explore symptom beliefs and help-seeking behaviour. Uncertainty about the relationship of non-motor symptoms to Parkinson's disease and lack of clarity around treatments were common. Embarrassment and communication difficulties were common for potentially sensitive symptoms such as sexual dysfunction. Symptom perceptions and beliefs about help-seeking acted as barriers to reporting non-motor symptoms. PMID- 28810365 TI - Will personal values predict the development of smoking and drinking behaviors? A prospective cohort study of children and adolescents in Taiwan. AB - This study examined how personal values predict the development of smoking and drinking behaviors in adolescence. The longitudinal data of 1545 adolescents over a 6-year period were analyzed. The results showed that adolescents who valued health and academics had similarly lower odds of reporting cigarette and alcohol use and those who valued friends had significantly higher odds. While the odds increased over time, the trend on alcohol use lessened for adolescents who valued academics, while the trend accelerated for those who valued friends. The finding suggests the important role that personal values play in adolescent risk behavioral development. PMID- 28810366 TI - "Broken windows": Relationship between neighborhood conditions and behavioral health among low-income African American adolescents. AB - This study explored the association between neighborhood conditions and behavioral health among African American youth. Cross-sectional data were collected from 683 African American youth from low-income communities. Measures for demographics, neighborhood conditions (i.e. broken windows index), mental health, delinquency, substance use, and sexual risk behaviors were assessed. Major findings indicated that participants who reported poorer neighborhood conditions compared to those who lived in better living conditions were more likely to report higher rates of mental health problems, delinquency, substance use, and unsafe sexual behaviors. Environmental factors need to be considered when addressing the behavioral health of low-income African American youth. PMID- 28810367 TI - Culturally based health assumptions in Sub-Saharan African immigrants: Body mass index predicting self-reported health status. AB - This study examined whether Sub-Saharan African adult immigrants maintained cultural preferences for curvier/higher body size post-migration to the United States. Linear and multiple regression analyses were utilized to discern the predicting effects of Sub-Saharan African immigrants' body mass index score on their self-reported health status at two post-migration data collection points. The initial assessment reveals that Sub-Saharan African immigrants' overweight body mass index score predicted better self-reported health status. Four to six years later, higher body mass index score predicted a better self-reported health status and lower dietary acculturation moderated the predicting effect of body mass index on self-reported health status. Limitations of the study and implications for research and practice are explored. PMID- 28810368 TI - Public health messages about antibiotic treatment for respiratory tract infection may increase perceived symptom severity reporting. AB - Public health campaigns to reduce expectations for antibiotic treatment for respiratory tract infections have shown little or no effect on antibiotic prescribing and consumption. We examined whether such messages can increase respiratory tract infection symptom reporting. Participants ( N = 318) received one of four campaign messages, a combination of all four messages, or no message. Respiratory tract infection symptoms increased for those who received information that emphasized the ineffectiveness of antibiotic treatment for respiratory tract infections. As symptom severity is associated with greater contact with primary healthcare and receiving antibiotic prescriptions, campaigns to encourage antimicrobial stewardship should consider the side effects of antibiotic ineffectiveness messages. PMID- 28810369 TI - A closer look at the relationships between panic attacks, emergency department visits and non-cardiac chest pain. AB - This study examined the prevalence of emergency department visits prompted by panic attacks in patients with non-cardiac chest pain. A validated structured telephone interview was used to assess panic attacks and their association with the emergency department consultation in 1327 emergency department patients with non-cardiac chest pain. Patients reported at least one panic attack in the past 6 months in 34.5 per cent (95% confidence interval: 32.0%-37.1%) of cases, and 77.1 per cent (95% confidence interval: 73.0%-80.7%) of patients who reported panic attacks had visited the emergency department with non-cardiac chest pain following a panic attack. These results indicate that panic attacks may explain a significant proportion of emergency department visits for non-cardiac chest pain. PMID- 28810370 TI - 'Chronic cough, cause unknown': A qualitative study of patient perspectives of chronic refractory cough. AB - Chronic refractory cough patients have persistent, unexplained, treatment resistant symptoms. Very little is known about non-physiological processes underlying chronic refractory cough or patients' experience of the condition. In all, 14 patients participated in semi-structured interviews. Interviews were based on the comprehensive cognitive behavioural model and analysed thematically. Eight key themes emerged illustrating that the experience of the onset and persistence of chronic refractory cough is complex, often involving multiple interlinking factors. Themes highlighted the involvement of biological and psychological factors, and the prominent role of the social dimension in how the cough is experienced, perceived and managed. Implications for intervention development are discussed. PMID- 28810371 TI - Physical activity and perceptions of stress during the menopause transition: A longitudinal study. AB - The transition to menopause is a critical period of significant biopsychosocial change. The purpose of this study was to examine the influence of the transition to menopause and volume of physical activity on levels of perceived stress over five years in 102 healthy middle-aged women. Questionnaire and accelerometer data were analyzed using linear mixed models. Adjusting for age and body mass index, there were no significant effects of menopause status or time on perceived stress. Independent of menopause status, minutes per week of vigorous activity was associated with lower perceived stress in years 1 and 2 of the study. PMID- 28810373 TI - Museum object handling: A health-promoting community-based activity for dementia care. AB - In a quasi-experimental design ( N = 80), this study examined the wellbeing impact of handling museum artefacts, by testing for differences across domain, time, gender and stages of dementia. The results indicated that people with early and moderate impairment showed positive increases in wellbeing, regardless of the type of dementia but those with early stage dementia showed larger positive increases in wellbeing. We can feel confident that for most people with early- to middle-stage dementia, handling museum objects in a supportive group environment increases subjective wellbeing and should be considered part of a health promotion strategy in dementia care. PMID- 28810372 TI - Support and conflict in relationships and psychological health in adolescents and young adults with cancer. AB - Perceived support and conflict between adolescents and young adults with cancer and their primary caregivers, other family, close friends, and medical staff were examined in relation to adolescents and young adults' psychological health. Adolescents and young adults ( n = 115, 51% male, ages 12-24 years, M (standard deviation) = 16.07 (2.29)) in outpatient cancer treatment perceived more support and conflict within familial relationships than other relationships. Among familial relationships, perceived support and conflict were associated with psychological health; within other relationships, only support was associated with psychological health. Interactions among family were most strongly correlated with psychological distress; interactions with friends were stronger correlates of posttraumatic stress symptoms, positive affect, and posttraumatic growth. PMID- 28810374 TI - The relationship between cyberbullying and friendship dynamics on adolescent body dissatisfaction: A cross-sectional study. AB - The relationship between cyberbullying and friendship dynamics on adolescent body dissatisfaction was examined. Data from the Irish contribution to the international cross-sectional 2013/2014 Health Behaviour in School-aged Children study were used. Results showed that girls were three times more likely than boys to report that their body is too fat, and adolescents who were cyberbullied were almost twice as likely as adolescents who were not cyberbullied to consider themselves too fat. Stronger friendship dynamics were associated with decreased levels of body dissatisfaction, and friendship dynamics were found to partially mediate the relationship between cyberbullying and body dissatisfaction. PMID- 28810375 TI - Processes of change in quality of life, weight self-stigma, body mass index and emotional eating after an acceptance-, mindfulness- and compassion-based group intervention (Kg-Free) for women with overweight and obesity. AB - This study examined the effectiveness of Kg-Free: an acceptance-, mindfulness- and compassion-based group intervention for women with overweight and obesity at post-treatment and 3-month follow-up and explored the psychological processes that underlie changes in quality of life, weight self-stigma, body mass index and emotional eating at post-treatment. Overall, 53 women completed Kg-Free. At post treatment and 3-month follow-up, participants reported increased quality of life, mindfulness and self-compassion abilities and decreased weight self-stigma, emotional eating, shame, weight-related experiential avoidance, self-criticism and body mass index. Shame and self-criticism reductions were important mediators of changes in health-related outcomes, whereas weight-related experiential avoidance, mindfulness and self-compassion mediated changes in weight and eating related outcomes. PMID- 28810376 TI - The reliability and validity of the Spanish version of the Fear of Pain Questionnaire. AB - The purpose of this study was to evaluate the psychometric properties of the Spanish version of the Fear of Pain Questionnaire-III. The original three-factor structure of the Fear of Pain Questionnaire-III was confirmed and indicated a good to excellent level of internal consistency. Criterion validity was supported by positive significant correlations between the Fear of Pain Questionnaire-III scores and measures of pain catastrophizing and anxiety sensitivity; discriminant validity was supported by non-significant correlations between the Fear of Pain Questionnaire-III scores and measures of pain intensity and depressive symptomatology. The findings support the reliability and validity of the scores obtained by the Spanish version of the Fear of Pain Questionnaire-III. PMID- 28810377 TI - Self-esteem moderates the associations between body-related self-conscious emotions and depressive symptoms. AB - The objectives of this study were to describe the cross-sectional associations between body-related self-conscious emotions and depressive symptoms in young adults and examine self-esteem as a moderator of these associations. Data from a population-based sample of 811 young adults were analyzed using hierarchical multivariate linear regression analysis. Body-related shame ( beta = .26) and guilt ( beta = .25) were positively related to frequency of depressive symptoms. Self-esteem was negatively related to frequency of depressive symptoms ( beta = .46). Self-esteem moderated the association between body-related guilt and frequency of depressive symptoms. These findings suggest promoting self-esteem may help to reduce the negative effects of body-related guilt on depressive symptoms. PMID- 28810378 TI - The Health Behavior Checklist: Factor structure in community samples and validity of a revised good health practices scale. AB - This study examined the factor structure and predictive validity of the commonly used multidimensional Health Behavior Checklist. A three-factor structure was found in two community samples that included men and women. The new 16-item Good Health Practices scale and the original Wellness Maintenance scale were the only Health Behavior Checklist scales to be related to cardiovascular and metabolic risk factors. While the other Health Behavior Checklist scales require further validation, the Good Health Practices scale could be used where more objective or longer measures are not feasible. PMID- 28810380 TI - When food becomes an obsession: Overweight is related to food-related obsessive compulsive behavior. AB - In this study, it was examined whether overweight is associated with food-related obsessions and compulsions. Participants with a healthy weight ( n = 27) and participants who were overweight ( n = 33) filled out the Yale-Brown-Cornell Eating Disorder Scale, the Eating Obsessive-Compulsive Scale, and the Emotional and Behavioral Reactions to Intrusions Questionnaire to assess frequency, distress, control, and reactance associated with food-related preoccupations and compulsions. Overweight participants showed increased food-related preoccupations, compulsive eating, and heightened emotional and behavioral reactance compared to participants with a healthy weight. Increased food-related obsessive-compulsiveness was also associated with unhealthy eating patterns. PMID- 28810379 TI - Preliminary support for the role of alcohol cues in food cravings and attentional biases. AB - This study examined whether alcohol odors, in isolation or when combined with pictures, would influence food attentional biases and cravings. Participants' cravings and attentional biases to food and alcohol pictures were assessed after exposure to alcohol or water odors ( n = 77; mean age = 30.84 years, 51.9% female, 83.1% Caucasian). Food attentional biases were increased by alcohol odors, but food cravings were increased only by a combination of alcohol odors and food pictures. These effects were related with self-reported problematic food consumption. These findings support a research program for further examining the effect of alcohol cues on problematic food consumption. PMID- 28810381 TI - The prevalence and the predictors of insomnia among refugees. AB - This study aimed to investigate the prevalence of insomnia and associated sociodemographic factors among refugees in Jordan. A cross-sectional survey was undertaken with a representative sample of 373 refugees. The majority of refugees had moderate to severe insomnia ( n = 196, 52.2%). Older age, living in the city of Mafraq, having secondary education or below, unemployed, and lacking easy access to medication were the predictors of higher insomnia. More attention by health care providers including nurses should be given to older refugees and those with a lower level of education, as these groups tend to be more liable to suffer from insomnia. PMID- 28810382 TI - Age moderates the relationship between source of social support and mental health in racial minority lesbian, gay, and bisexual youth. AB - We examined the relationship between source of social support and mental health (and the moderating impact of age) in 64 low socioeconomic status, racial minority lesbian, gay, and bisexual adolescents/young adults. Social support from family ( beta = -.302, p = .03; beta = -.364, p = .008), but not friends or significant others, was independently related to posttraumatic stress disorder and depression symptoms, respectively. Family social support was associated with lower posttraumatic stress disorder and depression symptoms in participants aged 16-19 years, while friend social support was associated with lower symptoms for participants aged over 20 years. Friend social support was also associated with lower posttraumatic stress disorder symptoms in participants aged 16-17 years. Interventions should target age-appropriate sources of social support. PMID- 28810383 TI - The association between stress, resilience, and emotional symptoms in Norwegian adolescents from 13 to 18 years old. AB - This study investigated associations between stress, resilience factors, and symptoms of depression and anxiety in a cross-sectional sample of 1183 adolescents 13-18 years old. The results showed a positive significant association between stress and symptoms of depression and anxiety. Personal competence was significantly negatively associated with depression and anxiety, whereas social support was significantly negatively associated with anxiety. Significant interaction effects were found between gender by personal competence and gender by structured style in relation to anxiety, with stronger associations for girls. A compensatory role of resilience was found on the relation between stress and emotional symptoms. PMID- 28810384 TI - Prototypes of drinkers and accessibility of injunctive norms predict college drinking. AB - A self-report survey of first-year college students ( n = 421; 46% female) included measures of perceived prototype, attitude and injunctive norm accessibility, past drinking behavior, and future drinking intention. Both norm accessibility and prototype perception were significant predictors of intention to drink in the future among first-year college students. The effect of prototypes on drinking diminished as pro-drinking norms became more accessible, indicating greater automaticity of drinking decision-making. Theoretical models of drinking intention should include both normative constructs and prototypes. Implications for interventions to reduce college student drinking are discussed. PMID- 28810385 TI - Is a general or specific exercise recommendation more effective for promoting physical activity among postpartum mothers? AB - This comparative effectiveness trial examined the effects of a behavior change intervention supplemented by a general or specific exercise recommendation on physical activity among postpartum mothers. Participants ( N = 49) attended three workshop sessions that provided the exercise recommendation and taught self regulatory skills. Physical activity, self-efficacy, planning, and barriers were assessed at baseline, post-intervention, and 6-month follow-up. Self-reported physical activity increased significantly in both groups ( p < .001), but the increase was larger in the general condition ( p = .03). Both groups reported increased planning and decreased barriers. Postpartum mothers may benefit from interventions that teach strategies for overcoming barriers while allowing them to choose preferred activities. PMID- 28810386 TI - "Free butterflies will come out of these deep wounds": A grounded theory of how endometriosis affects women's psychological health. AB - This study aimed to develop a grounded theory of how endometriosis affects psychological health. Open interviews were conducted with 74 patients. The Hospital Anxiety and Depression Scale was administered to all women, who were divided into distressed versus non-distressed. At the core of our grounded theory was the notion of disruption due to the common features of living with endometriosis. Experiencing disruption (vs restoring continuity) involved higher distress and was associated with a long pathway to diagnosis, bad doctor-patient relationships, poor physical health, lack of support, negative sense of female identity, and identification of life with endometriosis. PMID- 28810387 TI - The mediating role of resilience in the relationship between personality and adjustment to disease in patients with a drainage enterostomy. AB - An understanding of what variables are involved in a better adjustment to chronic disease makes it possible to implement more suitable community healthcare interventions. It also allows the design of educational programmes aimed at increasing the independence of these patients, thereby enabling them to achieve a better health status. Both the personality and the resilience of the patient have been shown to play an important role in the process of adjusting to the new living conditions that result from having a chronic disease. Yet, to date, little research has been conducted in this area. This study uses structural equation modelling to explore the relationships among the personality factors, resilience and the variables of adjustment to disease (i.e. quality of life and level of self-care). The sample consists of 125 patients with a drainage enterostomy. Results show that the relationship model with the best fit is the one that considers resilience as a mediating variable in the relation between personality and disease adjustment variables. The implications of the findings and the limitations of the study are also discussed. PMID- 28810388 TI - Perceived consequences of a successful weight loss: A pluralist qualitative study. AB - Weight loss improves health but little is known regarding how those who achieve feel about it. Aiming to identify positive and negative consequences of a successful weight loss, 30 men and women who achieved a successful weight loss were interviewed. Interviews were analysed (content and thematic analysis). Inter rater agreement was assessed. With multiple correspondence analysis, a three factor model explained the associations between categories: (1) personal growth/social adversities, (2) body image/social benefits and (3) physical/emotional well-being. Successful weight loss has positive and negative consequences that need to be addressed; positive aspects (e.g. personal growth) and negative consequences (e.g. relational problems) need to be tackled. PMID- 28810389 TI - Preoperative sense of coherence associated with the 10-year outcomes of lumbar spinal stenosis surgery. AB - A prospective 10-year follow-up study was conducted to determine the significance of the preoperative sense of coherence, with respect to the preoperative and 10 year clinical characteristics, among lumbar spinal stenosis patients ( N = 99). In addition, the predictive value of the preoperative sense of coherence regarding the 10-year surgery outcome was also evaluated. In a logistic regression analysis, a weak preoperative sense of coherence and low functional ability predicted the patients' functional ability 10 years after the surgery. Moreover, those patients with weak sense of coherence before surgery showed poorer functional ability 10 years after the surgery, but not preoperatively. A weak preoperative sense of coherence seems to associate with poorer long-term outcome after surgery; therefore, various rehabilitation strategies are discussed. PMID- 28810390 TI - Shared decision-making - Rhetoric and reality: Women's experiences and perceptions of adjuvant treatment decision-making for breast cancer. AB - This interview-based study uses phenomenology as a theoretical framework and thematic analysis to challenge existing explanatory frameworks of shared decision making, in an exploration of women's experiences and perceptions of shared decision-making for adjuvant treatment in breast cancer. Three themes emerged are as follows: (1) women's desire to participate in shared decision-making, (2) the degree to which shared decision-making is perceived to be shared and (3) to what extent are women empowered within shared decision-making. Studying breast cancer patients' subjective experiences of adjuvant treatment decision-making provides a broader perspective on patient participatory role preferences and doctor-patient power dynamics within shared decision-making for breast cancer. PMID- 28810391 TI - Predictors of diet failure: A multifactorial cognitive and behavioural model. AB - Obesity is recognised as a multidetermined issue. However, research aimed at addressing diet failure has typically examined factors in isolation. Furthermore, previous research has included limited input from dieters themselves. A qualitative study identified a number of themes contributing to diet failure. This study aimed to test these themes with a larger sample ( n = 426) while also determining their fit within a multifactorial model. The results of this study supported the conceptualisation of diet failure using a multifactorial model while also illustrating correlational pathways to be more complex than currently understood in the literature. PMID- 28810392 TI - First-time fathers' perception of their childbirth experiences. AB - Birth satisfaction impacts on a man's adjustment to his new role as father. Fathers have been found to have needs similar to those of mothers during pregnancy and childbirth. Research suggests that these needs may not be being met for first-time fathers. In a quantitative survey, fathers' birth satisfaction was similar to mothers. This study then used a phenomenological form of thematic analysis to gain an insight into the birth experiences of 155 first-time New Zealand fathers. Core themes included safety of mother and baby, understanding support role, mother in control and managing pain and care and communication after birth. Fathers commented on what impacted on their childbirth experiences and in so doing outlined their needs for a positive experience. Fathers experienced a high level of satisfaction along with a need to be involved and included. PMID- 28810393 TI - Can disclaimer labels or Dove Evolution commercial mitigate negative effects of thin-ideal exposure? AB - We examined the comparative effectiveness of the Dove Evolution commercial and disclaimer labels as media literacy interventions. Women ( N = 287) viewed thin ideal images by themselves, preceded by the Dove Evolution commercial, or containing specific or generic disclaimer labels. Participants completed pre- and post-test measures of body satisfaction, post-test social comparison, and media literacy. Interventions were not effective in mitigating drops in body satisfaction, reducing social comparison, or increasing media literacy, despite women understanding their purpose. A 2-week follow-up showed no delayed effects on media literacy. None of these interventions were effective in counteracting the negative effects of media exposure in women. PMID- 28810395 TI - Rasch analysis of the Perceived Stress Scale: Transformation from an ordinal to a linear measure. AB - Rasch analysis was conducted to enhance the precision of the widely used 10-item Perceived Stress Scale using two datasets ( n = 450 each) randomly selected from samples of the New Zealand general population ( n = 1102), New Zealand university students ( n = 479) and US university students ( n = 396). The best Rasch model fit ( chi2(27) = 29.92, p = .36), good person separation reliability (.80) and coverage (98%) of the sample by the scale items were achieved when locally dependent items were combined into subtests. These findings support reliability and internal structural validity of the 10-item Perceived Stress Scale. The instrument precision can be further improved using the ordinal-to-linear conversion tables published here. PMID- 28810394 TI - Adapting evidence-based behavioral weight loss programs for emerging adults: A pilot randomized controlled trial. AB - Emerging adults are at high risk of obesity but behavioral weight loss programs do not meet their needs. Emerging adults ( N = 52, age = 22.3 +/- 2 years, body mass index = 34.2 +/- 5.5 kg/m2, 46.2% non-Hispanic White) were randomly assigned to one of three behavioral weight loss programs adapted based on formative work: face-to-face behavioral weight loss, web-based behavioral weight loss, or web plus optional community sessions (Hybrid). Assessments occurred at 0 and 3 months. Engagement and self-monitoring were highest in Hybrid. Intent-to-treat weight losses were -2.8 +/- 2.9 percent in face-to-face behavioral weight loss, 2.2 +/- 4.5 percent in web-based behavioral weight loss, and 4.8 +/- 4.9 percent in Hybrid. Percent achieving ?5 percent weight loss was highest in Hybrid (63%). Findings suggest potential for adapted behavioral weight loss to promote engagement and weight loss in emerging adults. PMID- 28810396 TI - Body image satisfaction among male military veterans with cancer. AB - Impaired body satisfaction is commonly reported among cancer patients. This study prospectively evaluated body image disturbance among male military veterans with head and neck or colorectal cancer. Patients ( N = 109) completed measures at three points post-diagnosis. Results showed about one-third of participants reporting body-related concerns. Endorsement did not change significantly during the study period. Predictors of worse body satisfaction included younger age, lower education, less social support, and weight loss. Results indicate a substantial minority of men with cancer endorsing body image disturbance, and highlight psychosocial circumstances and weight change as key considerations. PMID- 28810397 TI - Healthcare experiences of a Black lesbian in the United States. AB - Little is known about the healthcare experiences of Black lesbian and bisexual women. This exploratory study examined the healthcare experiences of a 24-year old Black lesbian and the interconnection between race, ethnicity, gender, and sexual identity in her lived experiences. Data were gathered through an in-depth audio-recorded interview. Findings revealed the risks of and barriers to self disclosure in healthcare settings, factors that influence the quality of the patient-provider relationship, and the positive and negative healthcare experiences of this Black American lesbian. This study is an important first step in exploring the healthcare experiences of Black lesbian and bisexual women. The findings of this case study highlight themes and avenues for future research. Clinical implications and suggestions for future research are discussed. PMID- 28810398 TI - Lay theories of health, self-rated health, and health behavior intentions. AB - We used an experimental design to examine young adults' ( N = 247; M age = 19.71; 86% female) intentions to engage in health-promoting behaviors in relation to beliefs concerning whether health is malleable or fixed, and how their health is unfolding over time. Individuals in the incremental (health is malleable) and control conditions viewed their health as improving over time; those in the entity (health is fixed) condition viewed their health as relatively stable. Individuals with more incremental theories of health and those who viewed their health as improving over time (particularly past to present) reported stronger health-promoting behavior intentions. PMID- 28810399 TI - Identification and regulation of emotions in adults of varying weight statuses. AB - Comparing individuals of varying weight statuses on their identification and regulation of emotions may increase our understanding of mechanisms that drive excess weight gain and highlight more precise weight regulation targets. In Study I ( N = 1333), adults with obesity had reduced self-reported attention to and repair of emotions compared to adults with overweight or normal weight. In Study II ( N = 85), adults with obesity had deficits in assessor-administrated tasks of strategic emotional intelligence (i.e. understanding and using emotional information for self-management). Problems identifying and regulating emotions could impact emotion regulation processes that lead to problematic behaviors associated with eating and weight gain. PMID- 28810401 TI - A dual-process view on medication adherence: The role of affect. AB - Medication non-adherence has been recognised as one of the major problems in health care that leads to preventable costs and hospitalisations. This study aimed to assess the role of affect in medication adherence. We propose a dual process framework of medication adherence based on the reflective-impulsive model, which includes both cognitive and affective processes. We tested this framework in a cross-sectional study ( N = 525). The results supported this framework by illustrating the clear role of both cognitive and affective processes. PMID- 28810400 TI - An event-level examination of successful condom negotiation strategies among young women. AB - This study examines the effect of condom negotiation strategies on condom use and partner type and substance use before sex as moderators of strategy effectiveness. Women reported their daily sexual behavior during the last month. Withholding sex was more strongly associated with condom use when utilized with a non-casual sex partner. Directly requesting condom use was more strongly and using deceptive reasons to influence condom use was less strongly related to condom use during substance use. Results underscore the importance of understanding the contexts in which condom negotiation strategies are successful in order to improve HIV/sexually transmitted infection prevention efforts among women. PMID- 28810402 TI - Physical activity intensity and subjective well-being in healthy adults. AB - The effect of physical activity intensity on subjective well-being has not been well established. We examined this relationship among 419 healthy adults using objective and subjective physical activity measurements (sample size varied among well-being assessments). For accelerometers, light-intensity physical activity positively associated with psychological well-being ( n = 150) and negatively associated with depression ( n = 99); moderate intensity negatively associated with pain severity ( n = 419) and positively associated with psychological well being; sedentary behavior negatively associated with psychological well-being and positively associated with depression ( ps < .05). These findings were generally consistent with subjective measurements of physical activity (Question 8, Paffenbarger Questionnaire). Higher levels of sedentary behavior are associated with lower subjective well-being. PMID- 28810403 TI - Information support, illness perceptions, and distress in survivors of differentiated thyroid cancer. AB - Survivors of differentiated thyroid cancer report significant distress. This study examines illness perceptions as mediating the relationship between information support and distress among survivors of differentiated thyroid cancer. Data were obtained from the Patient Reported Outcomes Following Initial Treatment and Long-term Evaluation of Survivorship registry. Model results revealed that greater information support was associated with better illness perceptions, and that better illness perceptions were associated with less distress. Information support and distress were indirectly related via illness perceptions. Results highlight the importance of addressing illness perceptions in this population and suggest that informational interventions may help serve this function. PMID- 28810404 TI - Sexual orientation, bullying for being labeled gay or bisexual, and steroid use among US adolescent boys. AB - Use of anabolic-androgenic steroids is a public health concern for adolescent boys. This study examined bullying based on being labeled gay/bisexual and steroid use among US adolescent boys, including sexual orientation disparities. Data from 2660 boys from the 2015 Youth Behavior Risk Survey were used. Among heterosexual boys, steroid use was higher among those who reported being bullied due to being labeled gay or bisexual. No such relationship existed among non heterosexual boys. The results speak to the need to address issues of masculinity in clinical work with boys and young men. PMID- 28810405 TI - A case-control study of psychosocial factors and their relationship to impairment and functionality in multiple sclerosis. AB - The stress effect on multiple sclerosis remains unclear. Moderating psychosocial factors may be involved. This study compares some of them in people with multiple sclerosis and healthy controls, and their association with disease parameters. Coping style, social support, anxiety, alexithymia and early-life stress were measured, along with impairment and functionality. People with multiple sclerosis scored significantly higher on anxiety, alexithymia, and avoidance and instinctive coping but lower in social support. No differences were found in early-life stress. Impairment was related to avoidance, and functionality to avoidance and anxiety. Psychotherapeutic approaches focused on these psychosocial factors may improve functionality, impairment and quality of life in people with multiple sclerosis. PMID- 28810406 TI - An ecological momentary assessment of weight stigma among weight loss participants. AB - This investigation explored experiences of weight stigma using momentary, real time diary assessments among adults seeking weight loss treatment. In total, 51 participants completed diary assessments of weight stigmatizing events and reported how they felt and coped with each incident. Experiencing stigma was significantly associated with fewer positive and greater negative emotions. There was a significant inverse relationship between using positive self-talk and feeling numb and a positive relationship between using isolation/avoidance coping and feeling depressed, ashamed, and less happy. The significant negative momentary impacts of weight stigma likely contribute to the long-term negative consequences of experiencing weight stigma. PMID- 28810407 TI - Intrasexual competition as a potential influence on anabolic-androgenic steroid use initiation. AB - An estimated 293,000 people living in the United Kingdom have used anabolic androgenic steroids. However, there is currently no intervention to reduce usage available in practice or academic circulation throughout the United Kingdom. This study aimed to test a novel hypothesis that increased levels of intrasexual competition may play an important influential role in the use of anabolic androgenic steroids. Significantly higher levels of intrasexual competition were evident in users compared to non-users but only in the novice group (0-2 years of experience). The research provides evidence for intrasexual competition potentially influencing anabolic-androgenic steroid use but only during the initial stages of usage. PMID- 28810408 TI - Emotional responses to disfigured faces and Disgust Sensitivity: An eye-tracking study. AB - Facial disfigurement attracts attention and evokes negative emotion, but evidence is lacking for a link between these two reactions. The present experiment ( n = 29) investigated emotional and attentional reactions to photographs of people with disfigured faces. An eye-tracker was used to measure fixation on internal expressive features and on the forehead. Disfigurement to the internal expressive features invoked a stronger emotional reaction than disfigurement to the forehead. Attention in the area of disfigurement was associated with negative emotion (embarrassment, sympathy, disgust, repulsion) as well as surprise. Attention to the disfigurement, and negative emotion, was related to the trait of Disgust Sensitivity. PMID- 28810409 TI - Celebrity-endorsed e-cigarette brand Instagram advertisements: Effects on young adults' attitudes towards e-cigarettes and smoking intentions. AB - Celebrities endorsing e-cigarette brands on social media may exert a strong influence on e-cigarette uptake. Using a between-subject experiment, this study examines the effects of endorser type (celebrities, non-celebrities and products only) in e-cigarette brand Instagram advertisements on e-cigarette attitudes and smoking intentions. Results showed that celebrity endorsers significantly increased positive attitudes towards e-cigarettes and smoking intentions, compared to non-celebrities or products only. Celebrity endorsers also rated significantly higher on trustworthiness, expertise, goodwill and attractiveness, compared to non-celebrities. Additionally, identification, social comparison, health consciousness and social networking site use moderated between endorser type and key dependent measures. Implications for e-cigarette marketing regulation are discussed. PMID- 28810410 TI - Perfectionism and adolescent sleep quality: The mediating role of repetitive negative thinking. AB - This study explores the mediating effects of repetitive negative thinking in the relationship between perfectionism and adolescent sleep quality. A sample of 1664 Chinese adolescents with a mean age of 15.0 years was recruited, and they completed four measures relating to perfectionism, sleep quality, worry, and rumination. The results showed that maladaptive perfectionism was positively correlated with poor sleep quality in adolescents, which was mediated by both worry and rumination. However, adaptive perfectionism was not significantly associated with adolescent sleep quality, and this relationship was suppressed by rumination (but not worry). The implications of these results are also discussed. PMID- 28810412 TI - Retraction notice. AB - At the request of the Journal Editor and the Publisher, the following article has been retracted: Khani Jeihooni A, Hidarnia A, Hossein Kaveh M, Hajizadeh E and Askari A (2015) The effect of an education program based on health belief model and social cognitive theory in prevention of osteoporosis in women. Journal of Health Psychology. Epub ahead of print 8 September. DOI: 10.1177/1359105315603696. PMID- 28810411 TI - Wellness among African-American and Caucasian students attending a predominantly White institution. AB - The wellness movement is growing on college campuses; however, the examination of race is lacking. We examined aspects of physical and emotional well-being as a function of race in 197 college students at a predominantly White institution. Results revealed racial differences on diet, F(1, 196) = 7.537, p = 0.007 and resilient coping, F(1, 196) = 8.614, p = 0.004. Furthermore, regression analyses revealed that the association between stress and coping was moderated by race ( F(1, 196) = 8.196, p = 0.005), demonstrating that Whites and Blacks experience and cope with stressors in differing ways. Findings of this study suggest that race is an influential factor of wellness and subsequent well-being in college students. PMID- 28810413 TI - Negotiations between health and social goals over the lifespan: The role of future time perspective. AB - The interplay between health and social goals in relation to age and future time perspective was examined among 131 older and 131 younger adults via surveys and future time manipulations (limited, unchanged, and expansive). Being older was associated with weaker physical activity intentions and social activity intentions as mediated by a limited future time perspective. Physical activity intentions decreased in the limited condition and increased in the expansive condition, social activity intentions increased in all conditions, and preference toward health (over social) goals decreased in both the limited and expansive conditions. The results suggest that anticipated endings may become salient in all conditions and favor social goals, which are emotionally relevant. PMID- 28810414 TI - Body image and sexual orientation: The experiences of lesbian and bisexual women. AB - Western cultures promote a thin and curvaceous ideal body size that most women find difficult to achieve by healthy measures, resulting in poor body image and increased risk for eating pathology. Research focusing on body image in lesbian and bisexual women has yielded inconsistent results. In total, 11 lesbian and bisexual women were interviewed regarding their experiences with body image. Interpretative phenomenological analysis revealed that these women experienced similar mainstream pressures to conform to a thin body ideal. Furthermore, participants perceived additional pressure to conform to heteronormative standards of beauty since the normalisation of homosexuality and the increase in Lesbian, Gay, Bisexual and Transgender representation in mainstream media. PMID- 28810415 TI - The digital divide: Examining socio-demographic factors associated with health literacy, access and use of internet to seek health information. AB - This article aims to examine the socio-demographic characteristics associated with access and use of Internet for health-related purposes and its relationship with health literacy. Data were drawn from a health literacy survey ( N = 1046) and analysed using logistic regression. Results show a strong association between health literacy, internet access and use. Socio-demographic characteristics particularly age, education, income, perceived health and social isolation also predict internet access. Thus, in addition to widening access, the movement towards digitisation of health information and services should also consider digital skills development to enable people to utilise digital technology more effectively, especially among traditionally hard-to-reach communities. PMID- 28810416 TI - Is disclosure a privilege? Race and disclosure patterns of hepatitis C. AB - Research suggests that decisions to disclose hepatitis C status are affected by individual and interpersonal factors. However, no existing studies have examined the role of race in disclosure, despite the potential implications of being doubly marginalized on the basis of both race and hepatitis C status. Drawing on qualitative research with 53 persons with hepatitis C in the Southeastern United States, findings indicate that participants practiced four patterns of disclosure: activist disclosure, open disclosure, limited disclosure, and reluctant disclosure. The majority of African Americans in this research practiced limited and reluctant disclosure, while Whites' disclosure patterns were more varied. These findings suggest that race shapes patterns of disclosure of hepatitis C, which has important implications for prevention, help seeking, social support, exposure to discrimination, and addressing racial disparities in health. PMID- 28810417 TI - Outdoor group activity, depression, and subjective well-being among retirees of China: The mediating role of meaning in life. AB - This study examined the effect of outdoor group activity on mental health and the potential mediating effect of meaning in life. Participants were 559 retired people. A self-developed questionnaire measured outdoor group activity; the Meaning in Life Scale, the Philadelphia Geriatric Center Morale Scale, and the Center for Epidemiological Studies-Depression assessed meaning in life, subjective well-being, and depression, respectively. Results indicated outdoor group activity significantly predicted subjective well-being and depression; meaning in life fully mediated the relationship between outdoor group activity and subjective well-being and partially mediated the relationship between outdoor group activity and depression. The implications and limitations were also discussed. PMID- 28810418 TI - Preventing cardiovascular disease: Participant perspectives of the FAITH! Program. AB - Striking cardiovascular health disparities exist among African-Americans in Minnesota compared to Whites; however, community-based interventions to address cardiovascular disease risk are lacking. This study explored participant perceptions of a culturally tailored, cardiovascular disease prevention program developed using a community-based participatory research process. Research participation perceptions, program benefits, and program satisfaction/acceptability were analyzed using a mixed-methods approach. Overall, acceptability was high. Findings highlight the favorable inclusion of African Americans (research perception), knowledge gained about healthy lifestyle practices (benefits), and quality of the curriculum/speakers (satisfaction). Community-based participatory research may be useful in fostering the acceptability of behavior change interventions among marginalized African American communities. PMID- 28810419 TI - Body image and dissatisfaction among rural Deep South African American women in a weight loss intervention. AB - Body image perception may impact health-promoting behaviors as well as knowledge regarding health risks associated with obesity. Our cross-sectional analysis evaluated body image and its association with body mass index among overweight and obese treatment-seeking African American women ( N = 409). Differences between current and desired body image were captured using the Pulvers scale. Results indicated the presence of body image dissatisfaction among participants (median = 2.00, interquartile range: 2.00-3.00), with greater dissatisfaction observed at higher categories of body mass index. Additionally, receiver operating curves demonstrated the ability of the Pulvers scale to correctly identify participants classified by body mass index. Further research is needed to identify factors that influence body image perception. PMID- 28810420 TI - The effects of power and stretch yoga on affect and salivary cortisol in women. AB - Yoga practice is known to improve well-being and decrease stress. However, acute yoga is understudied. This study investigated the effects of two different types of yoga on affect and salivary cortisol levels in college women. Thirty-three women aged 18-30 years each completed 1-hour sessions of power yoga and stretch yoga. Measures of affect and salivary cortisol were assessed before, during, and after each session. Participants perceived power yoga to be more pleasurable and energizing. Salivary cortisol significantly decreased after both yoga sessions. Thus, even one session of yoga may be effective in improving affect and decreasing stress in college women. PMID- 28810421 TI - Predictors of perceived vulnerability to cancer diagnoses among adult Black males. AB - As much as the significance of age, education, masculinity, illness attitude, and self-esteem to preventive health have been reported, much less is known on how these factors predict perceived vulnerability to cancer diagnosis. This study aimed to determine the association between identified demographic, health, and social factors and perceived vulnerability to cancer diagnosis among adult Black males. Data reveal that incidences of cancer among Black men are contingent upon a myriad of psychological, social, and behavioral factors that are not exclusive but rather coexisting determinants of health. PMID- 28810422 TI - Measurement invariance of intuitive cancer risk perceptions across diverse populations: The Cognitive Causation and Negative Affect in Risk scales. AB - Intuitive cancer risk perceptions may inform strategies to motivate cancer prevention behaviors. This study evaluated factor structure and measurement invariance of two new measures of intuitive cancer risk, the Cognitive Causation and Negative Affect in Risk scales. Single- and multiple-group confirmatory factor analysis models were fit to responses from three diverse samples. The confirmatory factor analysis models fit the data well, with all comparative fit indices (CFI) >= 0.94. Items flagged by chi-square difference tests as potentially non-invariant were largely invariant between samples according to practical fit indices (e.g. DeltaCFI). These novel scales may be particularly relevant in diverse, underserved populations. PMID- 28810423 TI - Psychological factors addressed in cognitive behaviour therapy for paediatric functional abdominal pain: Which are most important to target? AB - The effectiveness of cognitive behaviour therapy for paediatric functional abdominal pain leaves room for improvement. We studied which factors addressed in cognitive behaviour therapy relate most strongly to the physical and psychological functioning of children with functional abdominal pain and are thus most important to target. Questionnaires were filled out by 117 children with functional abdominal pain and their parents. Multiple regression analyses showed that children's passive coping and parental and children's positive cognitions relate to child functioning. Negative cognitions and parental solicitous behaviour were unrelated to child functioning. Cognitive behaviour therapy for functional abdominal pain may benefit most from changing children's passive coping and promoting positive cognitions. PMID- 28810424 TI - The psychological costs of social support imbalance: Variation across relationship context and age. AB - Psychological well-being benefits of receiving social support are well established. Growing evidence also suggests parallel benefits of giving support. However, much less attention has been given to understanding the psychological correlates of imbalance in giving and receiving social support. We examined associations between social support (given, received, and imbalance) and psychological well-being in multiple relationship types (friends, family, and spouse). Greater levels of both receiving and giving social support were independently associated with more favorable psychological well-being, while imbalance in the ratio of support given and received was associated with poorer psychological well-being. Findings varied between relationship types and across age. PMID- 28810425 TI - Psychological and behavioral effects of obesity prevention campaigns. AB - Public health campaigns are often used to prevent or reduce obesity. However, social psychological theory suggests these efforts might not be universally helpful and could potentially have detrimental consequences. This investigation explored the effects of obesity prevention campaigns. Participants were randomized to view either weight-focused or weight-neutral campaigns. Assessments at three time points (pre, post, and follow-up) examined the differences between groups in reactions to campaigns and changes in health behaviors and psychological outcomes. Compared with weight-neutral campaigns, weight-focused campaigns were associated with increases in negative perceptions of obesity and decreases in self-efficacy for health behavior change. PMID- 28810426 TI - Body dissatisfaction and eating disorder symptomatology: Which factors interfere with sexuality in women with eating disorders? AB - Body dissatisfaction is a relevant aspect in both eating disorders and sexuality. Using Stice's model, this study aimed to evaluate the relationship between these variables in eating disorder patients compared with healthy controls. Statistically significant correlations between body dissatisfaction and sexuality were found in the whole sample. The clinical group had higher rates of body dissatisfaction and sexual impairment. Within the clinical group, the participants with a greater drive for thinness showed higher sexual dysfunctions. These results suggest that sexuality should be systematically explored in eating disorders. Higher rates of drive for thinness may be associated with greater sexual impairment. PMID- 28810427 TI - The partner's perspective of the impact of pituitary disease: Looking beyond the patient. AB - People with pituitary disease report impairments in quality of life. The aim of this study was to elucidate the impact of the pituitary condition on the lives of partners. Four focus groups of partners of people with pituitary disease (Cushing's disease, non-functioning adenoma, acromegaly, prolactinoma) were conducted. Partners mentioned worries related to the pituitary disease and negative beliefs about medication, coping challenges, relationship issues, social issues and unmet needs regarding care. This study emphasizes the importance of not only paying attention to psychosocial well-being of people with pituitary disease but also to their partners. PMID- 28810428 TI - How have selection bias and disease misclassification undermined the validity of myalgic encephalomyelitis/chronic fatigue syndrome studies? AB - Myalgic encephalomyelitis/chronic fatigue syndrome has been a controversial diagnosis, resulting in tensions between patients and professionals providing them with care. A major constraint limiting progress has been the lack of a 'gold standard' for diagnosis; with a number of imperfect clinical and research criteria used, each defining different, though overlapping, groups of people with myalgic encephalomyelitis or chronic fatigue syndrome. We review basic epidemiological concepts to illustrate how the use of more specific and restrictive case definitions could improve research validity and drive progress in the field by reducing selection bias caused by diagnostic misclassification. PMID- 28810429 TI - Individual differences in pain sensitivity predict the experience of unfairness. AB - Pain has shaped our evolutionary history, and pain-free experiences are critical for our health. There are, however, enormous individual differences in pain sensitivity, and the psychological consequences of this heterogeneity are only poorly understood. Here, we investigated whether individual differences in pain sensitivity predicted the experience of unfairness. We found that the magnitude of pain sensitivity correlated with the extent to which participants experienced unfairness. This association was due to the shared human alarm system of unfairness and pain sensitivity. This finding may elucidate mechanisms for producing a new and positive cycle of a healthy experience between fairness and feeling pain-free. PMID- 28810430 TI - Exploring changes in distress among individuals with bleeding disorders: What is linked to improvements in distress? AB - Adults with chronic bleeding disorders report high distress, but it is unclear how distress varies over time. Patients rated their distress on a 10-point scale at two clinic visits. Of 83 patients, roughly one-quarter reported consistent no/low distress (29%), one-quarter reported consistent distress (22%), and half (49%) reported a change in distress of at least two points. Overall activity levels, depressive symptoms, and non-White race were significantly associated with worsening and consistent distress in adjusted analyses while improvements in activity levels and depressive symptoms during the study period were associated with distress improvement. Our results suggest that distress is modifiable. PMID- 28810431 TI - 'When it comes to HIV, that's when you find out the genuinity of that love': The experience of disclosing a HIV+ status to an intimate partner. AB - Despite a medical discourse of the 'normalisation' of HIV, it remains a highly stigmatising condition and makes the issue of disclosing one's HIV status particularly complex. This article reports on the experience of 18 people living with HIV in the United Kingdom of disclosing their HIV+ status in arguably their most important relationship, their intimate partnership. Five main themes arose: disclosure as the battlefield, preparing psychologically to disclose, disclosure as a test of the partner's love, disclosure as an opportunity for the partner to know them more deeply and the renegotiation of the relationship narrative. PMID- 28810432 TI - Reliability and validity of the Perceived Stress Scale-10 in Hispanic Americans with English or Spanish language preference. AB - This study examined the psychometric properties of the Perceived Stress Scale-10 among 436 community-dwelling Hispanic Americans with English or Spanish language preference. Multigroup confirmatory factor analysis examined the factorial invariance of the Perceived Stress Scale-10 across language groups. Results supported a two-factor model (negative, positive) with equivalent response patterns and item intercepts but different factor covariances across languages. Internal consistency reliability of the Perceived Stress Scale-10 total and subscale scores was good in both language groups. Convergent validity was supported by expected relationships of Perceived Stress Scale-10 scores to measures of anxiety and depression. These results support the use of the Perceived Stress Scale-10 among Hispanic Americans. PMID- 28810433 TI - Ultra-brief non-expert-delivered defusion and acceptance exercises for food cravings: A partial replication study. AB - Food cravings are a common barrier to losing weight. This article presents a randomised comparison of non-expert group-delivered ultra-brief defusion and acceptance interventions against a distraction control. A total of 63 participants were asked to carry a bag of chocolates for a week while trying to resist the temptation to eat them. A behavioural rebound measure was administered. Each intervention out-performed control in respect of consumption, but not cravings. These techniques may have a place in the clinical management of food cravings. We provide tentative evidence that the mechanism of action is through decreased reactivity to cravings, not through reduced frequency of cravings. PMID- 28810435 TI - The impact of breast cancer awareness interventions on breast screening uptake among women in the United Kingdom: A systematic review. AB - The impact of breast screening awareness campaigns on mammography attendance among British women was explored. British Nursing Index, Medline, PsycINFO, Embase and Cumulative Index to Nursing and Allied Health were searched between October 2012 and February 2013. Searches identified research on breast cancer awareness interventions and breast self-examination. In total, 867 articles were identified and 14 met criteria for review. Breast cancer awareness interventions were found to increase the uptake of breast self-examination behaviours and increase the likelihood of breast cancer screening attendance. Predicting the impact of these interventions on survivability and general morbidity/mortality outcomes remains a challenge due to a shortage of suitably evaluated campaigns. PMID- 28810434 TI - Unhealthy weight control strategies: An outcome of body image and eating tensions in women of Mexican origin living in rural farming communities. AB - Unhealthy eating and weight control behaviors are important but modifiable factors that contribute to obesity in majority and minority populations. Studies suggest that these behaviors are common in Mexican American women, but most studies completed to date have focused on college enrolled Mexican American women. Little is known about body weight concerns, eating and weight control behaviors in low acculturated immigrant Mexican women. This qualitative descriptive study utilized two focus groups with 15 women to identify and describe body weight and shape perceptions, and thoughts and behaviors related to eating and weight control of low acculturated Mexican American living in disadvantaged economic situations. Conventional content analysis was used to analyze data and three main themes were identified: (1) body weight values and concerns, (2) eating and food, and (3) weight loss strategies and consequences. The first two themes shared five subthemes including emotion, health, age, family, and culture. Results suggest Mexican American women experience weight concerns that are in conflict with food/eating values and experiences. This conflict is influenced by cultural, family, and inter/intrapersonal factors and contributes to unhealthy eating and weight control behavior. The transition and assimilation to the United States is complex and dynamic. Thus understanding how the conflict regarding body weight and food influence Mexican American women's health behaviors is important and provides valuable knowledge essential to guide further research and intervention development. PMID- 28810436 TI - Employment and multiple sclerosis: A meta-analytic review of psychological correlates. AB - The association between employment and psychological health in adults with multiple sclerosis was examined ( N = 33 studies). Standardised mean differences (Hedges' g) between those employed and those not in the workforce were calculated. Employed peers reported significantly greater quality of life and mood, cited fewer work and multiple sclerosis-related difficulties and were more likely to adopt problem-focused coping strategies, considered to be more effective in managing specific stressors. These data are consistent with the positive by-products of maintaining work with multiple sclerosis. Further research is needed to determine the longitudinal course of coping for those who remain employed. PMID- 28810437 TI - A systematic review of the association between emotions and eating behaviour in normal and overweight adult populations. AB - A systematic review was completed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search of four electronic databases (2004-2015) yielded 60,017 articles, of which 29 met inclusion criteria. Included studies performed poorly on data quality analysis in terms of randomisation and controlling for confounding factors. Participant's body mass index scores range from 19.73 (standard deviation = 1.54) to 28.4 (standard deviation = 1.4) kg/m2. Where positive and negative affects were compared, food was more likely to be consumed in response to positive affect. With regard to discrete emotions; stress, depression and sadness consistently elicited eating behaviours that fall outside of nutritional recommendations (e.g. increased food intake or poor nutritional food choices). The role of moderators including individual differences in dietary restraint and emotional eating, as well as methodological considerations, such as means of eliciting and measuring emotions, may account for equivocality with regard to some emotion and eating associations. This article concludes with recommendations for future research and implications for practice. PMID- 28810438 TI - Patients with limited communication in end-of-life situations: Initial psychometric properties of a discomfort observation scale. AB - This work presents an observational scale which takes into account different observable indicators of discomfort of patients in end-of-life situations with difficulties in communicating due to cognitive impairment, fatigue or sedation and provides details of its validation. In all, 71 adults participated. Model fit was adequate ( chi2(27) = 43.28, p = .024, comparative fit index = .975, root mean square error of approximation = .092 and confidence interval 90% (.033 .140)). Alpha coefficient was .70 and composite reliability index was .90. Our study provides data regarding the properties of a discomfort assessment scale. Such a scale is needed and could be very useful for the evaluation of such patients and thus to attend to their needs. PMID- 28810440 TI - Nature relatedness is connected with modern health worries and electromagnetic hypersensitivity. AB - Although nature relatedness is considered a positive characteristic, its relationship to constructs involving worries about the negative effects of artificial environmental factors is also feasible. A questionnaire assessing modern health worries, electrosensitivity, somatosensory amplification, spirituality, and nature relatedness was completed by 510 individuals. Nature relatedness was related to electrosensitivity, modern health worries, and spirituality. In a binary logistic regression analysis, somatosensory amplification, modern health worries, and nature relatedness were associated with electrosensitivity, and nature relatedness moderated the connection between modern health worries and electrosensitivity. In naive representations, "natural" might be associated with health, whereas "modern" and "artificial" evoke negative associations. PMID- 28810439 TI - The impact of both spousal caregivers' and care recipients' health on relationship satisfaction in the Caregiver Health Effects Study. AB - This study examined, with a sample of older adult, caregiving couples, whether each spouse's health was associated with their own and their partner's relationship satisfaction. Dyads ( n = 233; age = 64-99 years) in the Caregiver Health Effects Study, ancillary to the Cardiovascular Health Study, reported relationship satisfaction, depressive symptoms, disability, and self-reported health. The cross-sectional Actor-Partner Interdependence Model showed that for both caregivers and care recipients, greater depressive symptoms and lower self reported health related to lower relationship satisfaction (actor effects). Caregivers had lower relationship satisfaction when they were more disabled (actor effect) and when care recipients were more depressed (partner effect). PMID- 28810441 TI - The Berlin Social Support Scales: Validation of the Received Support Scale in a Canadian sample of patients affected by melanoma. AB - The purpose of this study was to examine the reliability and validity of the Received Support Scale of the Berlin Social Support Scales in a Canadian sample of English and French language melanoma patients ( N = 137). Participants received a skin self-examination education and completed self-report questionnaires. Exploratory factor analyses, reliability analyses, and independent samples t-tests were conducted. Findings support the unidimensionality of the Received Support Scale of the Berlin Social Support Scales. The psychometric similarities of the French and English versions of the scale, its strong internal consistency, as well as its convergent and discriminant validity support the use of the Received Support Scale of the Berlin Social Support Scales in patients with melanoma. PMID- 28810442 TI - Evaluation of a web-based cognitive behavioral smoking cessation treatment for overweight/obese smokers. AB - This pilot study tested the efficacy of an Internet-administered smoking cessation treatment for overweight/obese smokers. Participants were 54 community volunteers with overweight/obesity who were regular smokers. Treatment consisted of 12 weeks of nicotine replacement therapy and randomization to Internet administered cognitive behavioral treatment or health education. In-person assessments of key outcomes occurred at baseline, post-treatment, and at 24-week follow-up. Cessation rates did not differ across the two treatments (25.9% vs 18.5%). Participants receiving cognitive behavioral treatment gained less weight when abstinent than those receiving the standard treatment. Larger studies are needed to replicate these findings. PMID- 28810443 TI - Disgust, shame and the psychosocial impact of skin picking: Evidence from an online support forum. AB - This article examines the accounts of individuals who problematically pick their skin and explores their subjective experiences. In total, 100 problem disclosure statements were taken from posts made to a publicly accessible online skin picking support forum. These posts were systematically analysed using thematic analysis. Themes of disgust, shame and psychosocial avoidance dominated the analysis and appeared central to the experience of skin picking. Skin picking was shown to be a heterogeneous experience with a complex emotional profile. We argue that disgust, shame and related avoidance behaviour should be considered when conceptualising skin picking and considering treatment interventions. PMID- 28810444 TI - The role of self-disgust in eating psychopathology in overweight and obesity: Can self-compassion be useful? AB - This study explores the relationship between self-disgust and eating psychopathology and whether self-compassion plays a mediator role on this relationship. Participants were 203 adults, from both genders, with overweight and obesity ( MBMI = 31.17, standard deviation = 5.43). Women reported higher levels of self-disgust and eating psychopathology and lower levels of self compassion than men. Path analysis results suggested that the effect of self disgust on eating psychopathology occurred partially through one's inability to be self-compassionate. The results highlight the damaging role of self-disgust on eating psychopathology and the importance of developing a more compassionate attitude towards the self to promote healthy eating behaviors. PMID- 28810446 TI - Physical recovery, mental detachment and sleep as predictors of injury and mental energy. AB - Although sports activities are generally considered beneficial to people's health and well-being, they can cause injuries and increased fatigue. Guided by the Demand-Induced Strain Compensation Recovery Model, this study hypothesized that physical recovery and mental detachment from sport-related activities would prevent injury and enhance mental energy. A cross-sectional survey study was conducted among 161 recreational athletes. Structural equation modelling analyses showed that mental detachment was negatively associated with injury and positively associated with mental energy. Sleep deprivation partially mediated the relation between mental detachment and mental energy. These findings imply an important role for mental detachment in maintaining people's health and well being. PMID- 28810445 TI - Enduring somatic threat perceptions and post-traumatic stress disorder symptoms in survivors of cardiac events. AB - Post-traumatic stress disorder due to acute cardiovascular events may be uniquely defined by enduring perceptions of somatic threat. We tested whether post traumatic stress disorder at 1 month post-acute coronary syndrome indeed required both high peritraumatic threat during the acute coronary syndrome and ongoing cardiac threat perceptions. We assessed peritraumatic threat during emergency department enrollment of 284 patients with a provisional acute coronary syndrome diagnosis and cardiac threat perceptions and post-traumatic stress disorder symptoms 1 month post-discharge. In a multiple regression model with adjustment for important covariates, emergency department threat perceptions were associated with higher 1 month post-traumatic stress disorder symptoms only among those with high levels of ongoing cardiac threat. PMID- 28810447 TI - Healthcare professionals' experiences of perinatal loss: A systematic review. AB - Healthcare professionals' psychological involvement in perinatal loss is a largely overlooked subject by healthcare systems, scientific research and prevention policies. A systematic scientific review has been carried out about emotional experiences, attributed meanings and needs conveyed by healthcare professionals in relation to perinatal loss. We identified 213 studies between 1985 and 2015, 20 of which were included in the present study for qualitative analysis. Our results point out the need for a targeted vocational training in perinatal loss, enabling healthcare professionals to achieve a proper management of their own internal states. PMID- 28810448 TI - Traumatic exposure and posttraumatic stress disorder among flood victims: Testing a multiple mediating model. AB - A total of 187 flood victims from Wuhu, a Chinese city affected most severely by a flood during July 2016, were selected to complete self-report measures of traumatic exposure, feelings of safety, fear, posttraumatic negative cognition, and posttraumatic stress disorder. The results found that traumatic exposure could directly predict posttraumatic stress disorder. Besides, traumatic exposure had indirect prediction on posttraumatic stress disorder through three ways, including a one-step path of negative self-cognition, a two-step path from feelings of safety to fear, and a three-step path from feelings of safety to negative self-cognition via fear. Implications and future directions are correspondingly discussed. PMID- 28810449 TI - The importance of relationships in treatment for chronic leg ulceration. AB - Leg ulcers are a hard-to-heal wound that can have a profound impact on the lives of those that they affect. While a significant body of evidence has explored the efficacy of various treatments for leg ulcers, little research has addressed the patient experience of such treatment. A total of 21 participants were recruited for this qualitative interview study, exploring patient's experiences of non surgical treatment for leg ulcers. Thematic analysis identified two major themes, 'Failure' and 'Powerlessness', as well as the overarching theme of 'Relationships'. These findings are discussed in relation to concepts of acceptance and in the broader context of patient-centred care. PMID- 28810450 TI - Perceived somatic and affective barriers for self-efficacy and physical activity. AB - According to Bandura's social-cognitive theory, perceptions of somatic and affective barriers are sources of self-efficacy. This longitudinal study compares general indicators of health barriers with measures of perceived somatic and affective barriers to predict self-efficacy and accelerometer-assessed physical activity in a subsample of n = 153 (selected at random from N = 310) community dwelling German older adults. Perceived somatic and affective barriers longitudinally predicted physical activity mediated by self-efficacy, whereas general health barriers did not. Perceived health barriers to physical activity might be more important than more objective health barriers for older adults' physical activity levels. PMID- 28810451 TI - The pre-history of health psychology in the United Kingdom: From natural science and psychoanalysis to social science, social cognition and beyond. AB - Health psychology formally came of age in the United Kingdom in the 1980s, but it was prefigured by much discussion about challenges to the dominance of biomedicine in healthcare and debates. This articles focuses on what could be termed the pre-history of health psychology in the UK. This was the period in the earlier 20th century when psychological approaches were dominated by psychoanalysis which was followed by behaviourism and then cognitivism. Review of this pre-history provides the backdrop for the rise of health psychology in the UK and also reveals the tensions between the different theoretical perspectives. PMID- 28810452 TI - Structure, coercive control, and autonomy promotion: A comparison of fathers' and mothers' food parenting strategies. AB - This study explored differences in mothers' and fathers' food parenting strategies, specifically coercive control, structure, and autonomy promotion, and whether parenting style and parental responsibility for food parenting related to the use of these strategies. Parents of children aged 2.5-7.5 years ( N = 497) reported about their parenting practices and food parenting strategies. Parenting style accounted for the majority of the variance in food parenting. Fathers were more authoritarian than mothers. Authoritarian and permissive parenting practices were related to more coercive strategies. Mothers reported more food parenting responsibility. Responsibility was related to less coercive practices and more autonomy promotion and structure. PMID- 28810453 TI - 'Health psychology' or 'psychology for health'? A history of psychologists' engagement with health in South Africa. AB - In contrast to the institutionalization of health psychology in North America and Europe, much psychological work on health issues in South Africa emerged as part of a critical revitalization of South African psychology as a whole, coinciding with the dismantling of Apartheid and global shifts in health discourse. The field's development reflects attempts to engage with urgent health problems in the context of rapid sociopolitical changes that followed democratic transition in the 1990s, and under new conditions of knowledge production. We provide an account of these issues, as well as reflections on the field's future, as inflected through the experiences of 12 South African psychologists whose careers span the emergence of health-related psychology to the present day. PMID- 28810454 TI - Ineffectiveness of commercial weight-loss programs for achieving modest but meaningful weight loss: Systematic review and meta-analysis. AB - This study collates existing evidence regarding weight loss among overweight but otherwise healthy adults who use commercial weight-loss programs. Systematic search of 3 databases identified 11 randomized controlled trials and 14 observational studies of commercial meal-replacement, calorie-counting, or pre packaged meal programs which met inclusion criteria. In meta-analysis using intention-to-treat data, 57 percent of individuals who commenced a commercial weight program lost less than 5 percent of their initial body weight. One in two (49%) studies reported attrition >=30 percent. A second meta-analysis found that 37 percent of program completers lost less than 5 percent of initial body weight. We conclude that commercial weight-loss programs frequently fail to produce modest but clinically meaningful weight loss with high rates of attrition suggesting that many consumers find dietary changes required by these programs unsustainable. PMID- 28810455 TI - Comparison group matters for chronic stress effects of subjective social status. AB - Inconsistent associations between health and measures of subjective social status compared to one's community suggest that how people define community may matter. This study broke down community into status among neighborhood and friends/family to assess the impact of each domain on chronic stress in individuals differing in socioeconomic status (18 employed and 18 unemployed individuals). The findings suggest that for ratings of subjective social status, the social and physical proximity of the reference group matters. Specifically, neighborhood status was affected by unemployment, while friends/family status was associated with perceived stress, emphasizing the importance of the comparison group in assessing subjective status. PMID- 28810456 TI - Components of preoperative anxiety: A qualitative study. AB - Limited research has explored preoperative anxiety through qualitative methodologies. This study aimed to identify specific factors that contribute to preoperative anxiety. A total of 17 patients awaiting general, plastic reconstructive and hand, orthopaedic, or ear, nose, and throat/otorhinolaryngology surgery were interviewed about their concerns in a public hospital. Thematic analysis identified five main sources of anxiety: surgical procedures, surgical complications, symptoms, recovery process, and organisation and delivery of care. These themes support current knowledge and identify wider concerns around the hospital environment and recovery. This study may inform the development of future interventions aimed at reducing preoperative anxiety. PMID- 28810457 TI - Measures of psychosocial factors that may influence help-seeking behaviour in cancer: A systematic review of psychometric properties. AB - Advanced stage cancer is frequently attributed to delays in presentation to a healthcare professional. To reduce undue delay, it is imperative to understand the reasons underlying help-seeking behaviour and to measure those using valid and reliable tools. This systematic review aimed to identify how studies have measured psychosocial factors affecting time to presentation for (potential) cancer symptoms. A total of 35 studies were included. Most studies failed to use valid and reliable tools, and predominantly provided inconclusive results regarding psychosocial factors and time to presentation when no or minimal psychometric evidence was present. Consequently, measure selection and future measure development should be guided by psychometric principles. PMID- 28810458 TI - Cognitive and behavioral coping in people with Chronic fatigue syndrome: An exploratory study searching for intervention targets for depressive symptoms. AB - The aim of the study was to find relevant coping factors for the development of psychological interventions for people with chronic fatigue syndrome who suffer from depressive symptoms. A total of 30 adults with chronic fatigue syndrome filled in the Cognitive Emotion Regulation Questionnaire, the COPE and the Hospital Anxiety and Depression Scale. The findings suggested that cognitive coping strategies have a stronger influence than behavioral coping strategies on depressive symptoms. Especially, the cognitive coping strategies refocusing positive, positive reappraisal and catastrophizing were of importance. These findings suggest that these coping strategies should be part of psychological programs for people with chronic fatigue syndrome. PMID- 28810459 TI - A purposeful lifestyle is a healthful lifestyle: Linking sense of purpose to self rated health through multiple health behaviors. AB - Having a purpose in life has been consistently linked to subjective and objective health markers. Using data from the Hawaii Study of Personality and Health ( n = 749, Mage = 60.1 years), we tested multiple health behaviors as unique mediators of the correlation between sense of purpose and self-rated health ( r = .29). Correlational analyses found that participants' sense of purpose was positively associated with their reports of vigorous and moderate activity, vegetable intake, flossing, and sleep quality. Combined in a multiple-mediator model, bootstrapping analyses suggested that sleep quality and vigorous activity proved significant unique mediators. PMID- 28810461 TI - A journey to HIV prevention research: From social psychology to social health via multidisciplinarity. AB - This is a personal account of my research in HIV prevention from 1984 to the present day. It demonstrates my disquiet with the individualism of psychology as a way of thinking about what was needed to prevent HIV transmission. HIV prevention requires social transformation which is produced via changes in social practices and norms of communities and networks rather than by changes in behaviours of individuals. My colleagues and I developed a 'social health' model of social transformation that involves enabling communities to modify their social practices by building on emergent community responses, responses that were identified by the use of a reflexive research methodology. PMID- 28810460 TI - Exploring our understanding of fatigue among adolescents living with HIV: Highlighting the unknown. AB - Due to antiretroviral therapies, HIV is now a chronic illness rather than a terminal disease. Chronic symptoms, including fatigue, should be identified and managed to prevent or minimise their potential negative consequences. We apply a Symptom Management Model to conceptualise fatigue among adolescents with HIV. In the context of minimal research, we seek to identify a research agenda for resource-constrained contexts, where HIV prevalence remains high and treatment adherence is a significant problem. By better understanding and addressing the symptom of fatigue, treatment adherence, occupational, social and emotional functioning could be improved. We highlight conceptual, methodological and measurement-related caveats. PMID- 28810462 TI - Association between socio-demographic factors, coping style, illness perceptions and preference for disclosure/nondisclosure of diagnosis in Chinese patients with hepatocellular carcinoma. AB - We explored the association between socio-demographic factors, coping style, illness perceptions and preferences for disclosure/nondisclosure of cancer diagnosis in 384 Chinese patients with hepatocellular carcinoma. We found that (1) 69.3 percent of the patients preferred disclosure and (2) multivariate analysis showed that four variables were significantly positively associated with preference for disclosure, including active emotional-focused coping style, illness perceptions of personal control, chronic infection of hepatitis B virus, and educational level, whereas perceived emotional impact of illness and objective social support (mainly family support) were significantly associated with preference for nondisclosure. The findings provide useful information for understanding patients' preferences for disclosure/nondisclosure of cancer diagnosis from a psychosocial perspective. PMID- 28810463 TI - Body image in adult women: Associations with health behaviors, quality of life, and functional impairment. AB - This study examined body image in adult women along with probable correlates including health behaviors, negative affect, quality of life, and functional impairment. Adult women ( N = 738, age = 25-86 years) completed an online survey assessing these domains. Women across all ages reported similar body image concerns. Negative body image significantly correlated with poorer wellness behaviors, negative affect, quality of life, and functional impairment. The inverse held for positive body image. The majority of correlations remained even when controlling for negative affect. Further research is warranted to investigate nature of the correlational relationships identified in this study. PMID- 28810464 TI - The buddy system: A randomized controlled experiment of the benefits and costs of dieting in pairs. AB - A total of 67 pairs of female roommates were randomized into a diet condition: (1) both ate normally; (2) one dieted, the other ate normally; and (3) both dieted. Adherence, weight loss, anxiety, depression, disordered eating symptoms, and stress were measured. Dieters lost more weight than non-dieters, but average loss was <1 pound. Pairs where both dieted reported higher anxiety, depression, and disordered eating than one-dieter pairs. Structural equation models revealed an interrelated network of stress, anxiety, depression, and disordered eating. This was weakest when one roommate dieted. The "buddy system" may not promote weight loss, but living with a non-dieting partner may buffer consequences. PMID- 28810465 TI - Valuing health for oneself versus one's child or elderly parent. AB - The aim of this study was to determine if adults value health states or are willing to accept risk differently for themselves than for their children or elderly parents. Participants (701) were asked to rate four hypothetical health states for themselves using both the standard gamble and time trade-off methodologies. They then did the same assessments for a real or hypothetical child as well as an elderly parent. Participants were willing to take more risk or trade more years of life to avoid bilateral vision loss and mental impairment for themselves than they were for their children and elderly parents. PMID- 28810466 TI - Mediation of an efficacious HIV risk reduction intervention for adolescents: A cluster-randomised controlled trial. AB - The 'Cuidate' programme for adolescents in Spain has proven to be effective for promoting healthy sexuality ( N = 626), but the mechanisms underlying its effects are unknown. This study aimed to identify mediators of the intervention's effects compared to a control group. Participants were students from five areas of Spain, who completed baseline, immediate-posttest, 12-month and 24-month follow-up assessments. Mediation analyses revealed that 'Cuidate' positively affected consistent condom use indirectly through knowledge in serial with the intention to use condoms. The findings underscore the importance of targeting knowledge on HIV and sexually transmitted infections to promote condom use intention and consistent condom use. PMID- 28810467 TI - Binge eating and binge drinking among adolescents: The role of drinking and eating motives. AB - This study aimed to investigate the motivations underlying binge eating and binge drinking in a sample of 302 adolescents. Our findings showed that binge eating was significantly correlated with gender, environmental, emotional, and social eating. Hierarchical multiple regression analysis indicated that emotional and environmental eating were significant positive predictors of binge eating, whereas binge drinking was significantly correlated with enhancement, social, and coping motives. Only enhancement motives were significant predictors of binge drinking. Our results support the argument that the reasons underlying binge eating and binge drinking in adolescents may be similar and may perform the same function. PMID- 28810468 TI - Investigating the function spiral in later life: Aging attitudes, physical activity, and gait. AB - This study tests the Function Spiral Model, which proposes that functional decline often occurs prematurely: negative aging attitudes reduce activity engagement, which then advances functional decline via physical deconditioning. A total of 89 adults aged 61-96 ( M = 77) years completed a questionnaire assessing aging attitudes and physical activity and participated in a follow-up assessment of gait/balance and function. Results supported the process model: physical activity mediated the impact of negative aging attitudes on gait/balance, and gait/balance mediated the impact of physical activity on function. Findings highlight multiple points of intervention that could mitigate the acceleration of functional decline in later life. PMID- 28810469 TI - Psychological factors and self-rated health: An observative study on cardiological patients. AB - This study investigated the association of illness representations, awareness of bodily states and health complaints to self-rated health in N = 150 consecutive patients with heart disease (ischaemic disease, heart failure and heart valve disease) and explored differences between 'health optimist' and 'health pessimist' patients. After controlling for medical variables, health complaints accounted for 14.2 per cent of patients' self-rated health, and illness representations contributed for another 16.2 per cent; body awareness was not associated with self-rated health. Also, 'optimists' tended to see less negative consequences from their illness and perceived greater control over illness treatment compared to 'pessimists'. Targeting symptoms and illness representations may optimize rehabilitation outcomes. PMID- 28810471 TI - Gay men's experiences with prostate cancer: Implications for future research. AB - Gay men's experiences with prostate cancer and its impact on health-related quality of life are poorly understood. This qualitative study explored gay men's experience with prostate cancer with a focus on the emotional, physical, and sexual impact of cancer; support needs; and healthcare interactions. Three semi structured focus groups of gay men with prostate cancer were conducted. A conventional content analytic approach was used to identify six primary content areas that described poignant aspects of the men's experience with prostate cancer: minority stress, intimacy and sexuality concerns, impact on life outlook, healthcare experiences, social support and the gay community, and intersectional identities. PMID- 28810470 TI - Representations and experiences of well-being among diabetic adolescents: Relational, normative, and identity tensions in diabetes self-management. AB - We explore representations of well-being in adolescents with Type 1 diabetes in order to better understand their expectations and needs in therapeutic patient education. In total, 28 interviews were performed and then submitted to thematic content analysis and lexicometric analysis. Results show the intervention of psychosocial processes in the relationship that adolescents maintain with well being and self-management. More specifically, we observed that well-being is impacted by areas of tension between the expectations of adolescents and the therapeutic objectives expressed by health professionals. These tensions should be taken into account in the conception, implementation, and evaluation of therapeutic education programs. PMID- 28810472 TI - The rapid expansion of (mainstream) health psychology in France: Historical foundations. AB - This article traces the historical evolution of ongoing theoretical debates in psychology in France from the 1940s until today. Its aim is to show how the conjunction of certain conditions led to a rapid expansion of American-derived mainstream health psychology during the 1980s. The authors describe the French context in the post-World War II period and outline the implementation of 'clinical psychology in health settings' in the 1950s, under the influence of Daniel Lagache. The strong critiques of the new psychology profession in the 1950s, 1960s and 1970s are examined. Our conclusion reflects upon future implications of ongoing rivalries between different approaches to psychology. PMID- 28810473 TI - The effect of self-compassion on the self-regulation of health behaviors: A systematic review. AB - The purpose of this review was to systematically review the published research on the effect of self-compassion interventions on health behaviors. A self regulation intervention was defined as participants engaged in goal-setting behavior, goal-directed behavior, monitoring, and/or adjusting health behavior. Seven studies met the inclusion criteria and were analyzed in this review. Self compassion interventions were just as effective as other behavior change techniques at improving self-regulation of health behavior. The review discusses sample characteristics, study design, health behavior measures, self-compassion intervention implementation, and the theoretical frameworks of the studies, along with limitations of the research and suggestions for future researchers. PMID- 28810474 TI - Racial centrality may be linked to mistrust in healthcare institutions for African Americans. AB - Evidence suggests that racial identity is an important component to African Americans' self-concepts and therefore may be relevant to patients' trust in healthcare, yet little is known as to how racial identity may influence trust or mistrust. African American adults ( N = 220) in the greater Portland, Oregon, area provided survey reports of healthcare-related attitudes and experiences. Those who reported higher racial centrality had lower trust in healthcare institutions. Based on these findings, clinicians employing patient-centered care approaches should recognize racial identity as an important component to patients' experiences when they seek to deliver equitable care to African American patients. PMID- 28810475 TI - HIV symptom management self-efficacy mediates the relationship of internalized stigma and quality of life among people living with HIV in China. AB - HIV-related stigma negatively influences quality of life among people living with HIV. Little is known about psychological protective factors that mitigate negative impacts. This study aims to examine the role of self-efficacy in reducing effects of stigma on quality of life. A total of 2987 people living with HIV (age: M = 42.46 years, SD = 12.83; time since diagnosis: M = 3.23 years, SD = 2.39) provided data on internalized stigma, HIV symptom management self-efficacy, and health-related quality of life, as well as covariates. Using structural equation modeling, we found that self-efficacy mediated the relationship of stigma and quality of life. Future interventions to promote quality of life in people living with HIV need to focus on increasing HIV symptom management self efficacy. PMID- 28810476 TI - Experiences of stigma over the lifetime of people with xeroderma pigmentosum: A qualitative interview study in the United Kingdom. AB - This study explored experiences of stigma in 25 adults with xeroderma pigmentosum. Analysis of semi-structured interviews revealed the changing nature of stigma over the lifetime. Bullying occurred in childhood, whereas adults were questioned about both their photoprotection and skin damage, often resulting in internalised feelings of stigma. Resilience and rejection of feelings of stigma increased with age and experiences of stigma differed across cultures. Findings indicate a need to develop social skills training to help people reject feelings of stigma. Future research should explore perspectives of families, friends and formal institutions and their potential to cause or reduce feelings of stigma. PMID- 28810477 TI - Feasibility randomised controlled trial of a self-help acceptance and commitment therapy intervention for grief and psychological distress in carers of palliative care patients. AB - We tested the feasibility and preliminary effectiveness of an acceptance and commitment therapy self-help intervention for grief and psychological distress in carers of patients in palliative care. Carers were randomised to the control group, which received treatment as usual, or the intervention group, which received treatment as usual plus an acceptance and commitment therapy-based self help booklet and telephone support call. Questionnaires were completed at baseline, 1-month post-allocation and 6 months post-loss. Results indicated that the intervention was generally feasible and viewed as acceptable to carers. Preliminary effectiveness analyses showed at least a small effect in acceptance, valued-living, grief and psychological distress. PMID- 28810478 TI - Brief report: Contemplate your symptoms and re-evaluate your health. A study on working adults. AB - We investigated whether self-ratings of health are affected by a symptom rating. A diary including a one-item self-rating of health ("pre-self-rated health"; 1 = excellent, 7 = very poor), a subsequent 26-item rating of symptoms, and thereafter a second (identical) health rating ("post-self-rated health") was completed by 820 persons 21 times. Self-rated health worsened significantly ( p < .0001) after the symptom rating, from 2.72 pre-self-rated health (95% confidence interval: 2.70-2.74) to 2.77 post-self-rated health (95% confidence interval: 2.75-2.79) and more so in persons who reported more symptoms ( b = .058, p < .05). The results support the notion that subjective health perception is influenced by attending to symptoms, especially so in persons with a high symptom burden. PMID- 28810479 TI - Revenge is sour, but is forgiveness sweet? Psychological health and cortisol reactivity among women with experiences of abuse. AB - This study examined the relations among women's experiences of abuse, forgiveness, revenge, psychological health, and physiological stress reactivity. Both dispositional (Study 1; N = 103) and state (Study 2; N = 258) forgiveness and vengeance were associated with psychological symptoms. However, the relation between revenge and greater depression was magnified among psychologically abused women, whereas-unexpectedly-the positive link between forgiveness and psychological health was strengthened among physically abused women. Moreover, while revenge coincided with increased cortisol reactivity following any relationship conflict, this was only evident for forgiveness following physical abuse. The complex interactions among these variables are discussed within a stress and coping framework. PMID- 28810480 TI - Nonverbal intelligence and scholastic performance in children with type 1 diabetes. AB - This study examined nonverbal intelligence and scholastic achievement in children with type 1 diabetes. In a retrospective case-control study, 69 children (35 males) ages 5-10 years with type 1 diabetes and 69 healthy controls matched to patients by age, gender and socioeconomic status were compared according to their performance on Raven's Coloured Progressive Matrices and their scholastic grades. No differences in nonverbal intelligence and grades were observed between children with type 1 diabetes and healthy control subjects. Raven's Coloured Progressive Matrices scores inversely correlated with duration of illness both in children with early onset of type 1 diabetes and poor metabolic control. Possible explanations of the results and implications are discussed. PMID- 28810481 TI - The effectiveness of cognitive behavioural therapy for depressed patients with diabetes: A systematic review. AB - Depression is common among patients with diabetes, who have a higher risk of diabetes-related complications such as diabetic retinopathy, nephropathy, neuropathy and macrovascular complications. The aim of the systematic review is to determine whether cognitive behavioural therapy is effective in reducing depressive symptoms and improving glycaemic control among depressed diabetic patients. The results reveal diversified application of cognitive behavioural therapy. All studies reported that cognitive behavioural therapy had a positive impact on depressive symptoms; three found an improvement in glycated haemoglobin, and one demonstrated improved self-efficacy and self-concept related to successful diabetes management. There is a need for controlled studies with larger sample sizes and long-term follow-up. PMID- 28810482 TI - A journey in the field of health: From social psychology to multi-disciplinarity. AB - "Health psychology" is a newer sub-discipline whose research methodologies, theories, and practices were borrowed from diverse areas of psychology. It appeared later in France than in the United States or United Kingdom. In 1966, I adopted a perspective between anthropology and psycho-sociology of medicine. I never have self-identified as a "Health Psychologist", continuing to work outside of disciplinary boundary constraints, but studied health questions moving first from psychology (and anthropology), through social psychology to sociology. By the 1980s, I adopted an even broader multi-disciplinary approach to health, as the HIV/AIDS epidemic urgently challenged health researchers/practitioners, in France and worldwide. PMID- 28810483 TI - The experience of fatherhood following childhood cancer survival. AB - This study explored the experience of becoming a father following childhood cancer survival. Semi-structured interviews were conducted with five fathers and analysed using interpretative phenomenological analysis. Three superordinate themes emerged: 'moving away from and revisiting the experience of cancer', 'making sense of fortune and loss following a life-threatening illness' and 'valuing the opportunity to be a father'. The transition to fatherhood brought unique and specific challenges to fathers. Nevertheless, all appeared to have positively adjusted to this transition. Findings recommended providing information and support to childhood survivors who wish to or who are about to become fathers. PMID- 28810484 TI - Comparison of food recommendations varying in sustainability: Impact on dietary intake and motivation to follow recommendations. AB - Food recommendations increasingly focus on sustainability in addition to nutritional value. By providing participants with standard versus sustainable (plant-based) dietary recommendations for 3 weeks, the present research tested the impact of recommendations on dietary compliance. Furthermore, predictors of food intake were tested across food categories. Participants in the sustainable diet condition complied less with recommendations as compared to those in the standard diet condition and were less motivated to continue complying after the intervention. Taste was the main predictor of intake across food categories. Together, this stresses the importance of considering factors stimulating consumers' compliance when formulating food recommendations. PMID- 28810486 TI - Effects of multidimensional child poverty on children's mental health in Mainland China. AB - This study aimed to investigate the effects of multidimensional child poverty on children's mental health in Mainland China. The data were based on a survey of children in 2015 conducted by multi-stage cluster random sampling method in Xiushui, where levels of poverty are very high. Structural equation model was adopted to analyze the data and test the hypothesized model. Results showed that multidimensional child poverty had a significant effect on both negative mental health and positive mental health of children, and the seven indicators of multidimensional child poverty all had slightly different effects on children's mental health. PMID- 28810485 TI - Risk perception, self-efficacy, trust for physician, depression, and behavior modification in diabetic patients. AB - We evaluated the associations of risk perception, self-efficacy, and trust with two health promotion behaviors (food habits and exercise) and depressive mood. Diabetic patients aged between 40 and 64 ( n = 1195) were included in the analyses. Risk perception worsened behavioral changes in terms of food habits and depression, whereas self-efficacy and trust improved food habits, exercise, and depression; trust improved exercise and depression. In conclusion, self-efficacy and trust appear to be more beneficial than risk perception for positive behavioral changes and for improving depression in diabetic patients. However, their influence on behavioral changes may be different according to the types of behaviors. PMID- 28810487 TI - The aging population in China: Subjective well-being of empty nesters in rural eastern China. AB - In this article, we explore the subjective well-being of empty nesters who lived in rural eastern China ( N = 967). The Memorial University of Newfoundland Scale of Happiness is used to measure subjective well-being. The results indicate that Memorial University of Newfoundland Scale of Happiness is appropriate for empty nesters in rural China due to its reliability and validity. Generally, male empty nesters report greater subjective well-being scores than females. Negative factors include low levels of education, being a widow or widower, or being unmarried. It is argued that the empty nesters' incapability to access adequate social service and home care leads to their poor subjective well-being. PMID- 28810488 TI - The effect of socioeconomic status and social inclusion on the mental health of Chinese migrants: A comparison between interprovincial and intra-provincial migrants. AB - This article sought to explore the impacts of socioeconomic status and social inclusion on intra-provincial and interprovincial migrants' mental health by constructing the Bayesian structural equation model. A total of 14,584 migrants aged 15-59 years living in eight cities of China were selected. It was found that the impacts of socioeconomic status and social inclusion on mental health were converse for these two groups. And the manifest variables coefficients of socioeconomic status and social inclusion were also converse. Therefore, governments should make some policies to further improve the mental health of migrants, including strengthening the community cohesion, social atmosphere, and governmental support. PMID- 28810489 TI - Social inhibition and emotional distress in patients with coronary artery disease: The Type D personality construct. AB - We examined the validity of the social inhibition component of Type D, its distinctiveness from negative affectivity, and value regarding emotional distress as measured with the DS14 in 173 coronary artery disease patients. In dimensional analysis, social inhibition and negative affectivity emerged as distinct traits. Analysis of continuous negative affectivity and social inhibition measures showed main effects for several emotional and inhibition markers and an interaction effect for social anxiety. Categorical analysis indicated that Type D patients reported more depression, negative mood, social anxiety, and less positive mood. Social inhibition is not a redundant trait, but has additional conceptual value. PMID- 28810490 TI - Trust in hybrid closed loop among people with diabetes: Perspectives of experienced system users. AB - Automated closed loop systems will greatly change type 1 diabetes management; user trust will be essential for acceptance of this new technology. This qualitative study explored trust in 32 individuals following a hybrid closed loop trial. Participants described how context-, system-, and person-level factors influenced their trust in the system. Participants attempted to override the system when they lacked trust, while trusting the system decreased self management burdens and decreased stress. Findings highlight considerations for fostering trust in closed loop systems. Systems may be able to engage users by offering varying levels of controls to match trust preferences. PMID- 28810491 TI - The body compassion scale: Development and initial validation. AB - As the newer mindfulness and acceptance-based cognitive behavioral therapies continue to grow, it is important that corresponding valid and reliable assessment tools are developed and evaluated. This article describes the initial development and validation of the body compassion scale. The body compassion scale is a theoretically derived measure designed to bridge the constructs of body image and self-compassion to provide a targeted measure of underlying mindfulness and acceptance-based constructs. Herein, two studies using exploratory and confirmatory factor analysis and examining subsequent relationships among other health-related constructs in college-age samples are presented. PMID- 28810492 TI - Perceived haze, stress, and negative emotions: An ecological momentary assessment study of the affective responses to haze. AB - The aim of this study was to examine the mediating role of stress in the association between people's perceived haze and negative emotions in daily life. Using ecological momentary assessment, 95 college students reported their perceived haze, stress, and negative emotions twice a day over the course of 2 weeks. The results showed a positive relationship between perceived haze and negative emotions. More importantly, this association was significantly mediated by levels of stress. Findings suggested that people who perceived more severe haze may report higher stress levels, which in turn may lead to increases in negative emotions. PMID- 28810493 TI - People with a body mass index ?30 under-report their dietary intake: A systematic review. AB - Under-reporting of total energy intake is a common and well-known source of measurement error in dietary assessment, and evidence suggests that this bias is particularly significant in obese individuals. After a multi-stage selection process of eligible papers, this literature review appraised 34 papers detailing the accuracy of self-reported dietary intake in people with an obese body mass index (BMI ? 30). The available literature to date shows that having a body mass index ?30 is associated with significant under-reporting of food intake. Future research should look into identifying effective techniques to reduce this bias in clinical practice. PMID- 28810494 TI - Development and validation of a smoking rationalization scale for male smokers in China. AB - The purpose of this study is to develop a smoking rationalization scale for Chinese male smokers. A total of 35 focus groups and 19 one-on-one interviews were conducted to collect items of the scale. Exploratory factor analyses and confirmatory factor analyses were conducted to identify the underlying structure of the scale. Results found a 26-item scale within six dimensions (smoking functional beliefs, risk generalization beliefs, social acceptability beliefs, safe smoking beliefs, self-exempting beliefs, and quitting is harmful beliefs). The scale showed acceptable validity and reliability. Results highlight that smoking rationalization is common among Chinese male smokers, and some beliefs of smoking rationalization seem to be peculiar to China. PMID- 28810495 TI - Perceptions of stigma among people affected by early- and late-onset Alzheimer's disease. AB - The aim of this research was to explore perceptions of stigma among people with early- and late-onset Alzheimer's disease and those who support them, using questionnaires ( n = 44) and semi-structured interviews ( n = 14). Perceived stigma reporting was low in the questionnaires, whereas interviews revealed higher levels of perceived stigma in the form of unpredictable reactions to diagnosis, feeling stupid and ignorance of the condition among the public. Perceived stigma was managed in similar ways across age groups, focusing on 'being the lucky ones'. Results support the need to further tackle stigma and challenge expectations, particularly given the drive to diagnose people and thereby expose them to stigma. PMID- 28810496 TI - Life satisfaction and trauma in clinical and non-clinical children living in a war-torn environment: A discriminant analysis. AB - The aim of this work was to discriminate between healthy children and children at risk of developing mental impairments by evaluating the impact on contextual and individual factors of a context characterized by war. We tested the hypothesis that a linear discriminant function composed of trauma, life satisfaction, and affect balance has the power to classify the children as community or clinical referred. Membership of the clinical-referred group was associated with poorer life satisfaction and higher levels of trauma. Community-referred profiles were associated with lesser trauma. Perceived life satisfaction regarding family and school was the main contributor to the discriminant function. PMID- 28810497 TI - Shame and emotion regulation in inflammatory bowel disease: Effects on psychosocial functioning. AB - Although patients with inflammatory bowel disease seem to be prone to high levels of shame, the mechanisms behind the impact of chronic illness-related shame on patients' functioning have not been explored yet. This study aims to address these gaps using a sample of 161 patients with inflammatory bowel disease who completed self-report measures on an online survey. The results from path analyses showed that chronic illness-related shame presented direct and indirect effects on psychological health ( R2 = .66) and social relationships ( R2 = .46). The indirect effects were mediated by experiential avoidance and uncommitted living. Possible explanations to these findings and clinical implications are discussed. PMID- 28810498 TI - Late emotional effects of rehabilitation during childhood and their impact on coping with deafness in adulthood. AB - This study examined potential influences of childhood rehabilitation and over normalization on coping with disability in adulthood. A total of 88 deaf and hard of-hearing students were interviewed retrospectively about their childhood and completed self-report questionnaires assessing psychological environment directedness and present emotional and behavioral coping with deafness. It was partially supported that over-normative parental attitude negatively affected coping with deafness through the mediation of elevated environment-directedness. Intensity of childhood rehabilitation was not found to affect adulthood coping with deafness. However, post-hoc analyses supported this mediation path when rehabilitation had been intensive yet not prolonged. Alleviating changes in the perception and practice of rehabilitation are suggested. PMID- 28810499 TI - The relationship between negative responses to HIV status disclosure and psychosocial outcomes among people living with HIV. AB - This report examines rates of HIV status disclosure and negative responses to disclosure among people living with HIV in Australia. Among 697 people living with HIV, most (>90%) had disclosed their status to friends, sexual partners and health providers. Almost a third had not disclosed to family, and half had not told any work colleagues. Negative responses to disclosure (e.g. blame, rejection) by all groups were associated with increased HIV-related stigma, psychological distress and diminished social support and health satisfaction. These results shed light on rates of disclosure among people living with HIV in Australia and the adverse health impacts of negative responses to disclosure. PMID- 28810500 TI - Anxiety effects on disaster precautionary behaviors: A multi-path cognitive model. AB - Previous studies have revealed a negative relationship between anxiety and health promoting behavior. This study identified three cognitive pathways through which anxiety operates on preparedness behaviors for terrorist attacks. Preparedness was regressed on trait anxiety, perceived threat, and self-efficacy based on data from 306 adults. Mediating paths through perceived threat (positive) and self efficacy (negative) and an independent negative path were identified. Results suggest that the anxiety/precautionary behavior relationship is more complex than previously thought, involving multiple pathways of competing directionality. Interventions to improve disaster preparedness and thus reduce disaster-related morbidity/mortality would benefit by capitalizing on this multidimensionality. PMID- 28810501 TI - Relational resilience as a potential mediator between adverse childhood experiences and prenatal depression. AB - This study examined the indirect effects of individual, relational, and contextual resilience in the relationship between adverse childhood experiences and prenatal depression. Participants included 101 pregnant women. Adverse childhood experiences had a direct effect on depression, B = 1.11, standard error = .44, p = .01, and relational resilience, B = -1.15, standard error = .19, p < .001, but not individual or contextual resilience. With resilience as a mediator, the effect of adverse childhood experiences on depression was no longer significant. Specifically, relational resilience had a significant indirect effect (IE) on the association between adverse childhood experiences and depression, IE = 1.04, boot standard error = .28 (95% confidence interval = .58, 1.68). Results emphasize the associated role of relational qualities, such as sense of security and belongingness, with childhood adversity and mental health. PMID- 28810502 TI - Brief report: How short is too short? An ultra-brief measure of the big-five personality domains implicates "agreeableness" as a risk for all-cause mortality. AB - Controversy exists over the use of brief Big Five scales in health studies. We investigated links between an ultra-brief measure, the Big Five Inventory-10, and mortality in the General Social Survey. The Agreeableness scale was associated with elevated mortality risk (hazard ratio = 1.26, p = .017). This effect was attributable to the reversed-scored item "Tends to find fault with others," so that greater fault-finding predicted lower mortality risk. The Conscientiousness scale approached meta-analytic estimates, which were not precise enough for significance. Those seeking Big Five measurement in health studies should be aware that the Big Five Inventory-10 may yield unusual results. PMID- 28810503 TI - Two is a perfect number: Patient-doctor relationship and patient attachment style in palliative care. AB - We tested the association between the palliative patient's attachment style and the patient-doctor relationship, by means of Revised Adult Attachment Scale and a self-designed, patient-doctor relationship questionnaire. The study included 110 (52 M, 58 F) cancer, hospice patients, aged 36-80 years. We observed 54 percent of secure, 18 percent of dismissive, 9 percent of preoccupied, and 19 percent of fearful styles. Securely attached patients developed significantly ( p < .05) better relationships with doctors than insecure patients. There was no difference in the quality of the patient-doctor relationship among dismissive versus preoccupied versus fearful patients. We argue that attachment theory should be applied in palliative care to improve patients' quality of life and dying. PMID- 28810504 TI - Torrefaction of empty fruit bunches under biomass combustion gas atmosphere. AB - Torrefaction of oil palm empty fruit bunches (EFB) under combustion gas atmosphere was conducted in a batch reactor at 473, 523 and 573K in order to investigate the effect of real combustion gas on torrefaction behavior. The solid mass yield of torrefaction in combustion gas was smaller than that of torrefaction in nitrogen. This may be attributed to the decomposition enhancement effect by oxygen and carbon dioxide in combustion gas. Under combustion gas atmosphere, the solid yield for torrefaction of EFB became smaller as the temperature increased. The representative products of combustion gas torrefaction were carbon dioxide and carbon monoxide (gas phase) and water, phenol and acetic acid (liquid phase). By comparing torrefaction in combustion gas with torrefaction in nitrogen gas, it was found that combustion gas can be utilized as torrefaction gas to save energy and inert gas. PMID- 28810505 TI - Denitrification of the anaerobic membrane bioreactor (AnMBR) effluent with alternative electron donors in domestic wastewater treatment. AB - A fixed film bioreactor for the denitrification of the effluent from an anaerobic membrane bioreactor (AnMBR) treating domestic wastewater was designed, built and investigated. After anaerobic treatment, the wastewater usually has a low C/N ratio (~1.3), and a remaining chemical oxygen demand of around 117mg O2/L, which is not enough to make conventional heterotrophic denitrification possible. That effluent also holds methane and sulfide dissolved and oversaturated after leaving the AnMBR. This paper demonstrates the feasibility of using these reduced compounds as electron donors in order to remove 80mg NOx--N/L at 18 degrees C and 2h of hydraulic retention time. In addition, the influence of the NO2-/NO3- ratios in the feed was studied. Total nitrogen removal was achieved in all the cases studied, except for a feed with 100% NO3-. Methane was the main electron donor used to remove the nitrites and nitrates, with a participation rate of over 70%. PMID- 28810506 TI - Controls on anastomosis in lowland river systems: Towards process-based solutions to habitat conservation. AB - Anastomosing rivers were historically common around the world before extensive agricultural and industrial development in river valleys. Few lowland anastomosing rivers remain in temperate zones, and the protection of these river floodplain systems is an international conservation priority. However, the mechanisms that drive the creation and maintenance of multiple channels, i.e. anabranches, are not well understood, particularly for lowland rivers, making it challenging to identify effective management strategies. This study uses a novel multi-scale, process-based hydro-geomorphological approach to investigate the natural and anthropogenic controls on anastomosis in lowland river reaches. Using a wide range of data (hydrologic, cartographic, remote-sensing, historical), the study (i) quantifies changes in the planform of the River Narew, Poland over the last 100years, (ii) documents changes in the natural and anthropogenic factors that could be driving the geomorphic change, and (iii) develops a conceptual model of the controls of anastomosis. The results show that 110km of anabranches have been lost from the Narew National Park (6810ha), a 42% reduction in total anabranch length since 1900. The rates of anabranch loss have increased as the number of pressures inhibiting anabranch creation and maintenance has multiplied. The cessation of localized water level and channel management (fishing dams, water mills and timber rafting), the loss of traditional floodplain activities (seasonal mowing) and infrastructure construction (embanked roads and an upstream dam) are contributing to low water levels and flows, the deposition of sediment at anabranch inlets, the encroachment of common reed (Phragmites australis), and the eventual loss of anabranches. By identifying the processes driving the loss of anabranches, this study provides transferable insights into the controls of anastomosis in lowland rivers and the management solutions needed to preserve the unique anastomosing river pattern and diverse wet grasslands that are central to the conservation value of lowland floodplains. PMID- 28810507 TI - Landscape determinants of spatio-temporal patterns of aerosol optical depth in the two most polluted metropolitans in the United States. AB - Elevated concentration of atmospheric aerosols during severe urban air pollution episodes necessitates a deep understanding of the underlying determinants for a sustainable urban environment. The 15-year (2001-2015) Moderate Resolution Imaging Spectroradiometer (MODIS) aerosol optical depth (AOD) data for the Phoenix and Los Angeles Metropolitan Areas were applied to examine the spatio temporal patterns and dynamics of urban aerosols. The strongly correlated temporal trends of AOD were observed due to the similar seasonal pattern of aerosol emissions and potential synoptic connections between two areas. Relatively higher mean value and lower decreasing trend of AOD were found in the PMA. Correlations reveal that topography is the predominant factor affecting the spatial pattern of AOD, as compared to the urban land use and vegetation. The effect of urbanization on air pollution varies with preexisting landscape, which apparently alleviates aerosol concentration in the PMA. Vegetation mitigates air pollution despite its emission of fine mode aerosols. As a cross-validation, the ground-measured concentrations of particulate matters (PM2.5 and PM10) were compared against AOD. The abnormal weak positive or strong negative AOD-PM2.5 associations result from the relatively small portion of anthropogenic aerosols and the changing atmospheric boundary layer height. PMID- 28810508 TI - Anticipating (the) nature: The future in environmental science, introduction to the virtual special issue. PMID- 28810509 TI - Spatiotemporal assessment and trade-offs of multiple ecosystem services based on land use changes in Zengcheng, China. AB - Driven by rapid urbanization, land use change has become a significant factor influencing ecosystem services (ESs). To support the decision-making process of city planners and policy makers, assessing the spatiotemporal changes associated with multiple ESs is vital. In this study, we developed a general structure to assess the changes of multiple ESs in Zengcheng, China. A new index also was developed to measure the comprehensive ecosystem service (CES). Trade-offs of various ESs were analyzed by using correlation analysis. We then designed four alternate scenarios to explore the optimal land use strategies to increase the CES value and minimize trade-offs among various ESs. Results demonstrated that rapid expansion of built-up land and traffic land resulted in a decrease of CES in Zengcheng from 2003 to 2013. Although the water supply, water purification, and vegetable and fruit production services increased, the climate regulation, soil conservation, biodiversity protection, recreation opportunity and grain production services decreased during the ten-year period. Government should implement land use policies and ecological engineering measures to improve soil conservation in the northern region; recreation opportunity in the central region; and carbon storage, water purification, biodiversity protection and recreation opportunity in the southern region. Among all alternative scenarios, woodland buffer and soil conservation scenarios exhibit the highest CES values, indicating that policies such as the "Ecological corridor construction" project and the "Grain for Green" project should be implemented. However, a caveat is that these policies improve the ESs at the expense of food production due to significant trade-off relationships. To minimize the trade-offs, a more sustainable intensification of agriculture should be adopted to increase food production without decreasing other ESs or occupying additional land. The land use strategies and ecological engineering measures in this study can provide a reliable reference for sustainable development of other urbanized regions in China. PMID- 28810511 TI - Estimation of the proximity of private domestic wells to underground storage tanks: Oklahoma pilot study. AB - For protecting drinking water supplies, the locations of areas with reliance on private domestic wells (hereafter referred to as "wells") and their relationship to contaminant sources need to be determined. A key resource in the U.S. was the 1990 Census where the source of domestic drinking water was a survey question. Two methods are developed to update estimates of the areal density of well use using readily accessible data. The first uses well logs reported to the states and the addition of housing units reported to the Census Bureau at the county, census tract and census block group scales. The second uses housing units reported to the Census and an estimated well use fraction. To limit the scope and because of abundant data, Oklahoma was used for a pilot project. The resulting well density estimates were consistent among spatial scales, and were statistically similar. High rates of well use were identified to the north and east of Oklahoma City, primarily in expanding cities located over a productive aquifer. In contrast, low rates of well use were identified in rural areas without public water systems and in Oklahoma's second largest city, Tulsa, each attributable to lack of suitable ground water. High densities of well use may be expected in rural areas without public water systems, expanding cities and suburbs, and legacy areas of well usage. The completeness of reported well logs was tested by counts from neighborhoods with known reliance on wells which showed reporting rates of 20% to 98%. Well densities in these neighborhoods were higher than the larger-scale estimates indicating that locally high densities typically exist within analysis units. A Monte Carlo procedure was used to determine that 27% of underground storage tanks that had at least one well within a typical distance of concern of 300m (1000ft). PMID- 28810510 TI - Estimation of caffeine intake from analysis of caffeine metabolites in wastewater. AB - Caffeine metabolites in wastewater were investigated as potential biomarkers for assessing caffeine intake in a population. The main human urinary metabolites of caffeine were measured in the urban wastewater of ten European cities and the metabolic profiles in wastewater were compared with the human urinary excretion profile. A good match was found for 1,7-dimethyluric acid, an exclusive caffeine metabolite, suggesting that might be a suitable biomarker in wastewater for assessing population-level caffeine consumption. A correction factor was developed considering the percentage of excretion of this metabolite in humans, according to published pharmacokinetic studies. Daily caffeine intake estimated from wastewater analysis was compared with the average daily intake calculated from the average amount of coffee consumed by country per capita. Good agreement was found in some cities but further information is needed to standardize this approach. Wastewater analysis proved useful to providing additional local information on caffeine use. PMID- 28810512 TI - Co-digestion of rice straw and cow dung to supply cooking fuel and fertilizers in rural India: Impact on human health, resource flows and climate change. AB - Anaerobic digestion of cow dung with new feedstock such as crop residues to increase the biogas potential is an option to help overcoming several issues faced by India. Anaerobic digestion provides biogas that can replace biomass cooking fuels and reduce indoor air pollution. It also provides digestate, a fertilizer that can contribute to compensate nutrient shortage on agricultural land. Moreover, it avoids the burning of rice straw in the fields which contributes to air pollution in India and climate change globally. Not only the technical and economical feasibility but also the environmental sustainability of such systems needs to be assessed. The potential effects of implementing community digesters co-digesting cow dung and rice straw on carbon and nutrients flows, human health, resource efficiency and climate change are analyzed by conducting a Substance Flow Analysis and a Life Cycle Assessment. The implementation of the technology is considered at the level of the state of Chhattisgarh. Implementing this scenario reduces the dependency of the rural community to nitrogen and phosphorus from synthetic fertilizers only by 0.1 and 1.6%, respectively, but the dependency of farmers to potassium from synthetic fertilizers by 31%. The prospective scenario returns more organic carbon to agricultural land and thus has a potential positive effect on soil quality. The implementation of the prospective scenario can reduce the health impact of the local population by 48%, increase the resource efficiency of the system by 60% and lower the impact on climate change by 13%. This study highlights the large potential of anaerobic digestion to overcome the aforementioned issues faced by India. It demonstrates the need to couple local and global assessments and to conduct analyses at the substance level to assess the sustainability of such systems. PMID- 28810513 TI - Effects of source and seasonal variations of natural organic matters on the fate and transport of CeO2 nanoparticles in the environment. AB - Natural organic matter (NOM) affects the stability and transport of nanoparticles (NPs) in natural waters by modifying their physiochemical properties. Source location, and seasonal variations, influence their molecular, physical and electrical charge properties. To understand the variations of NOM on the mobilization of NPs, large volumes of water were collected from the Ohio River (OR) over winter and summer seasons and dissolved NOMs were concentrated. The chemical and structural differences of these NOMs were compared with the Suwannee River humic acid (SRHA) SRHA using 1H and 13C nuclear magnetic resonance spectroscopy, and Fourier transforms infrared (FTIR) spectroscopy. Thermal analysis and FTIR confirmed that differences in composition, structure, and functional groups are a result of SRHA fractionation compared to whole molecule OR-NOM. The influence of OR-NOMs on the surface charge of CeO2 NPs and the effects on the transport and retention in a three-phase (deposition-rinse-re entrainment) sand-packed columns were investigated at CeO2 NPs initial concertation of 10ppm, pH6.8, increasing ionic strength (3, 5, and 10mM), retention time of 1min, and increasing NOM concentration (1, 5, and 10ppm). The summer OR-NOM showed higher stabilization and mobilization effect on the CeO2 than the winter NOM; while their effect was very different form the SRHA. The stabilization of NPs is attributed to both electrostatic and steric effects. The differences in the chemical structure of the complex and heterogeneous NOMs showed disparate reactivity and direct impact on CeO2-NPs stability. Using SRHA to study the effect of NOM for drinking water related assessment does not sufficiently represent the natural conditions of the environment. PMID- 28810514 TI - Multi-objective spatial tools to inform maritime spatial planning in the Adriatic Sea. AB - This research presents a set of multi-objective spatial tools for sea planning and environmental management in the Adriatic Sea Basin. The tools address four objectives: 1) assessment of cumulative impacts from anthropogenic sea uses on environmental components of marine areas; 2) analysis of sea use conflicts; 3) 3 D hydrodynamic modelling of nutrient dispersion (nitrogen and phosphorus) from riverine sources in the Adriatic Sea Basin and 4) marine ecosystem services capacity assessment from seabed habitats based on an ES matrix approach. Geospatial modelling results were illustrated, analysed and compared on country level and for three biogeographic subdivisions, Northern-Central-Southern Adriatic Sea. The paper discusses model results for their spatial implications, relevance for sea planning, limitations and concludes with an outlook towards the need for more integrated, multi-functional tools development for sea planning. PMID- 28810515 TI - Physcion blocks cell cycle and induces apoptosis in human B cell precursor acute lymphoblastic leukemia cells by downregulating HOXA5. AB - Acute lymphoblastic leukemia (ALL) presents the most common type of malignancy in children and ranks the third most common cancer in adults. This study is aimed to investigate the anti-leukemia activity of physcion in ALL. Our results have showed that physcion could significantly suppress cell growth, induce apoptosis and blocked cell cycle progression in vitro. Mechanistically, we found that physcion downregulated the expression of HOXA5, which is responsible for the anti leukemia activity of physcion. To verify this finding, siRNA targeting HOXA5 and overexpressing plasmid were used to repress HOXA5 expression and introduce ectopic overexpression of HOXA5 in ALL cell lines, respectively. Our results showed that overexpression of HOXA5 significantly abrogated the inducing effect of physcion on apoptosis and cell cycle blockasde. In contrast, knockdown of HOXA5 by siRNA enhanced the anti-tumor effect of physcion on ALL cell lines. Our results provided experimental base for the use of physcion in the treatment of ALL. PMID- 28810516 TI - Lectin from inflorescences of ornamental crop Alpinia purpurata acts on immune cells to promote Th1 and Th17 responses, nitric oxide release, and lymphocyte activation. AB - Alpinia purpurata is an ornamental crop known as a source of bioactive molecules. This is the first study to report isolation of a lectin (carbohydrate-binding protein) from A. purpurata inflorescences (ApuL). The immunomodulatory potential of ApuL was evaluated by investigating its effects on the production of cytokines and release of nitric oxide by human peripheral blood mononuclear cells (PBMCs). In addition, the differentiation and activation of lymphocytes treated with ApuL was evaluated by immunophenotyping assays. ApuL is an acidic and oligomeric protein with native molecular mass of 34kDa. The hemagglutinating activity (HA) of ApuL was inhibited by the glycoproteins fetuin and ovalbumin, was resistant to heating at 100 degrees C and stimulated in the presence of calcium and magnesium ions. ApuL showed highest HA at pH 7.5 but failed to agglutinate erythrocytes at pH 8.0 and 9.0. ApuL induced the release of cytokines belonging to Th1 (IFN gamma, TNF-alpha, and IL-6) and Th17 (IL-17A) profiles as well as of nitric oxide, stimulating a pro-inflammatory environment. Moreover, ApuL also stimulated the production of IL-10, an anti-inflammatory cytokine with regulatory role. Incubation with lectin resulted in differentiation and activation of both T CD8+ and CD4+ subsets of lymphocytes, as evident from the expression of the CD28 costimulatory molecule. In conclusion, A. purpurata inflorescence is a source of an immunomodulatory lectin with potential immunoregulatory application, thereby adding biotechnological value to this ornamental crop. PMID- 28810517 TI - Argan oil reduces oxidative stress, genetic damage and emperipolesis in rats treated with acrylamide. AB - Acrylamide (AA), a well-known toxicant, is present in high-temperature-processed foods in heated foods. Argan oil (AO), a natural vegetable oil, is receiving increasing attention due to its powerful biological properties. However, limited information is available about its effects in lymphoid organs and bone marrow. The aim of this study is to investigate the effects of AO on hematological parameters, 8-hydroxydeoxyguanosine (8-OHdG), thiobarbituric acid reactive substances (TBARs), protein carbonyl (PCO), glutathione (GSH), myeloperoxidase (MPO) levels, the formation of micronucleus (MN) and megakaryocytic emperipolesis (ME) against AA-induced toxicity in rats. The animals were treated with AA (50mg/kg/day), AO (6ml/kg/day per day) and AA+AO (50mg+6ml/kg/day) for 30days. Treatment of rats with AA significantly decreased the hematological parameters, GSH and MPO activity and PCEs ratio while it increased TBARs, PCOs and 8-OHdG levels and formation of MN and ME. No significant differences were observed in the animals received the AO alone. Co-treatment with AA+AO ameliorated almost all of the alterations caused by AA and exhibited protective effect in rats. Based on the obtained results, we suggest that integration of AO in diet or using its supplements may be a good strategy for improving tissue injury in many diseases. PMID- 28810519 TI - The beneficial role of Naringin- a citrus bioflavonoid, against oxidative stress induced neurobehavioral disorders and cognitive dysfunction in rodents: A systematic review and meta-analysis. AB - OBJECTIVES: Naringin is a bioflavonoid, very abundantly found in citrus species. In literature, naringin has been scientifically well documented for its beneficial effects in various neurological disorders. In this systematic review and meta-analysis, we have made an attempt to correlate the protective role of naringin against oxidative stress-induced neurological disorders in rodents. METHODS: The systematic search was performed using electronic databases; the search was mainly focused on the role of naringin in oxidative stress-induced neuropathological conditions in rodents. While, the meta-analysis was performed on the effect of naringin on oxidative stress markers [superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), reduced glutathione (GSH), lipid peroxidation (LPO)], nitrite, mitochondrial complexes (I to IV) and enzymes (acetylcholinesterase, Na+-K+-ATPase, Ca2+-ATPase, and Mg2+-ATPase) in the rodent brain. The data was analyzed using Review Manager Software. THE RESULTS: Based on the inclusion and exclusion criteria, twenty studies were selected. The meta-analysis revealed that, naringin could significantly inhibit various physical and chemical stimuli- induced neurological perturbances in the rodent brain, mediated through oxidative stress. Further, naringin also significantly restored the levels of all the oxidative stress markers (oxidative, nitrosative, enzymes, and mitochondrial complexes) in different parts of the rodent brain. SUMMARY: This systematic review and meta-analysis supports the available scientific evidence on the beneficial role of naringin in the management of various neurological ailments. However, further studies involving human subjects is recommended to establish the safety and therapeutic efficacy in humans. PMID- 28810518 TI - Ameliorative effects of Artemisia pallens in a murine model of ovalbumin-induced allergic asthma via modulation of biochemical perturbations. AB - INTRODUCTION: Asthma is a chronic, heterogeneous airway disorder characterized by airway inflammatory and remodeling. Artemisia pallens has been reported to possess antioxidant, anti-inflammatory and Anti-allergic potential. OBJECTIVE: To evaluate the anti-asthmatic effects of methanolic extract of Artemisia pallens (APME) against ovalbumin (OVA)-induced airway hyperresponsiveness (AHR) in rats. MATERIALS AND METHOD: AHR was induced in male Sprague-Dawley rats (180-200g) by intraperitoneal (i.p.) injection of OVA and boosted with an identical OVA solution (s.c.) on day 7. Rats were either treated orally with vehicle (10mg/kg), montelukast (10mg/kg) or APME (100, 200 and 400mg/kg) for next 28days. At the end treatments, various biochemical, molecular (RT-PCR and ELISA analysis) and histological parameters were evaluated. RESULTS: APME (200 and 400mg/kg) significantly attenuated (p<0.05) OVA-induced alteration in lung functions measured by Whole-body plethysmography. Increased Bronchoalveolar Lavage (BAL) fluid differential cell count, as well as total protein and albumin in BAL fluid and lungs, was significantly decreased (p<0.05) by APME. It also significantly attenuated (p<0.05) elevated lung oxido-nitrosative stress, myeloperoxidase, and serum IgE levels. OVA-induced down-regulation in lung Nrf2 and upregulation in TNF-alpha, IL-1beta, IL-4, IL-6, TGF-beta mRNA expression was significantly attenuated (p<0.05) by APME (200 and 400mg/kg) treatment. Histopathological analysis of lung tissue showed that APME treatment reduced OVA-induced inflammatory influx and fibrosis. CONCLUSION: Artemisia pallens simultaneously orchestrate plethora of mechanisms viz. modulations of IgE, TGF-beta, TNF-alpha, IL's and Nrf-2 levels to exhibit its anti-asthmatic potential in OVA-induced AHR in rats. PMID- 28810520 TI - Studies on the regulation of lipid metabolism and the mechanism of the aqueous and ethanol extracts of Usnea. AB - OBJECTIVES: Usnea is a lichen of Usnea diffracta Vain and Usnea longissima Ach, which belongs to the genus Usnea Adans of Usneaceae. Usnea exerts numerous pharmacological activities, while its lipid regulatory activities remain unreported. This study aims to evaluate the effects of aqueous and ethanol extracts of Usnea on the regulation of lipid metabolism and to explore the possible mechanism. METHODS: Hyperlipidemia rat model was established by feeding with high-fat diet for 45days. Therapy rats were intragastrically administered with simvastatin (0.004g/kg/d), Usnea aqueous extract (2.766g/kg/d), or Usnea ethanol extract (2.766g/kg/d) for 20days. Pharmacodynamic effects, including body weight, serum and liver lipid levels, total bile acid (TBA), aspartate aminotransferase (AST), alanine aminotransferase (ALT), liver index, and hepatic morphological changes were evaluated. To explore the mechanisms, the lipase activities and protein expressions related to lipid metabolism were detected. RESULTS: Compared with the model group, aqueous and ethanol extracts of Usnea can slow down the weight gain of rats, significantly reduce the serum levels of total cholesterol, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and the liver contents of TG, LDL-C, as well as significantly increase the contents of high-density lipoprotein cholesterol in serum. In addition, aqueous and ethanol extracts of Usnea can significantly reduce the serum contents of AST and ALT. Furthermore, ethanol extract of Usnea can also significantly reduce the TBA content in serum and liver index. Liver tissue pathological observation showed that aqueous and ethanol extracts of Usnea can improve cell degeneration to a certain extent. Aqueous and ethanol extracts of Usnea can significantly reduce sterol regulatory element-binding proteins-1c, and liver X receptor alpha (LXR alpha) protein expressions. Furthermore, aqueous extract of Usnea can significantly increase hepatic lipase activity and promote apoprotein A5 (ApoA5) protein expression. CONCLUSIONS: These findings strongly suggest that the aqueous and ethanol extracts of Usnea play significant roles in regulating lipid metabolism, and the ethanol extract exhibits higher activity than the aqueous extract. The mechanism of the regulation of lipid metabolism by Usnea aqueous extract may involve the increased ApoA5 protein expression via inhibition of the LXR-alpha signal pathway; however, the mechanism of the regulation of lipid metabolism by Usnea ethanol extract remains to be further studied. PMID- 28810521 TI - Cropping systems affect paddy soil organic carbon and total nitrogen stocks (in rice-garlic and rice-fava systems) in temperate region of southern China. AB - The accumulation of soil organic carbon (SOC) in agricultural soils is critical to food security and climate change. However, there is still limited information on the dynamic trend of SOC sequestration following changes in cropping systems. Paddy soils, typical of temperate region of southern China, have a large potential for carbon (C) sequestration and nitrogen (N) fixation. It is of great importance to study the impacts of changes in cropping systems on stocks of SOC and total nitrogen (TN) in paddy soils. A six-year field experiment was conducted to clarify the dynamics of SOC and TN stocks in the paddy topsoil (0-20cm) when crop rotation of rice (Oryza sativa L.) -garlic (Allium sativum) (RG) was changed to rice-fava (Vicia faba L.) (RF), and to examine how the dynamics were affected by two N management strategies. The results showed that SOC stocks increased by 24.9% in the no N (control) treatment and by 18.9% in the treatment applied with conventional rate of N (CON), when RG was changed to RF. Correspondingly, TN stocks increased by 8.5% in the control but decreased by 2.6% in the CON. Compared with RG, RF was more conducive to increase the contents of soil microbial biomass C and N. Moreover, changing the cropping system from RG to RF increased the year-round N use efficiency from 21.6% to 34.4% and reduced soil N surplus in the CON treatment from 547kg/ha to 93kg/ha. In conclusion, changes in the cropping system from RG to RF could markedly increase SOC stocks, improve N utilization, reduce soil N surplus, and thus reduce the risk of N loss in the paddy soil. Overall, this study showed the potential of paddy agro-ecological systems to store C and maintain N stocks in the temperate regions. PMID- 28810522 TI - Unrepresented community odour impact: Improving engagement strategies. AB - Complaints for odour causing industry continue to increase in numeracy and severity. One assessment approach using Gas Chromatography-Mass Spectrometry/Olfactometry (GC-MS/O), has been used primarily to identify priority odourants within a standardised panel. We investigated the variation of response between participants of average and high olfactory sensitivity, and discovered that current GC-MS/O methodologies do not represent the entirety of community odour impact. Based on these results we constructed a Biosolids Processing Odour Wheel followed by a Community Odour Wheel for use by untrained community members and site operators. By using the information gathered from this research, as well as odour testing workshops for a wastewater treatment plant's staff and community surrounding the facility, we established a communicative system, which was subsequently incorporated into an online dynamic odour observation platform. This platform provides the WWTP with meaningful information from the community, as well as a common language for which to discuss environmental malodour with all stakeholders. PMID- 28810523 TI - Reactive oxygen species mediated NF-kappaB/p38 feedback loop implicated in proliferation inhibition of HFLS-RA cells induced by 1,7-dihydroxy-3,4 dimethoxyxanthone. AB - 1,7-Dihydroxy-3,4-dimethoxyxanthone (XAN) is a bioactive compound isolated from Securidaca inappendiculata Hassk. and exerts the inhibitory effects on fibroblast like synoviocytes by targeting NF-kappaB and p38. This study was designed to elucidate mechanisms underlying the divergent regulation on the two pathways in HFLS-RA cells by XAN. Expressions of hallmark proteins and transcription of GADD45alpha mRNA were determined by Western-blot and RT-qPCR methods, respectively. Fluorescence staining was employed to evaluate intracellular oxidative stress. Effects of XAN and N-acetyl-l-cysteine (NAC) on the proliferation of cells were investigated by MTT assay, and pro-apoptotic effects of XAN were assessed by Annexin V-FITC/PI method. It was found XAN blocked NF kappaB signaling in HFLS-RA cells shortly after treatment. Moreover, it up regulated both transcription and expression of GADD45alpha, and subsequently activated p38 pathway. As time went on, XAN significantly promoted the generation of reactive oxygen species (ROS), which accompanied with sustained up-regulation of p-p38 and increased apoptosis. 48H later, dual-effects of XAN on NF-kappaB and p38 were reversed. As activation of p38 and increased apoptosis induced by XAN were antagonized by NAC, they were deemed as ROS mediated effects. Furthermore, the accumulated ROS should also account for the activation of NF-kappaB in the late stage of treatments via interfering in p38/MSK1/NF-kappaB feedback. Altogether, these findings suggested XAN-induced ROS contributed great importance to the proliferation inhibition of HFLS-RA cells by mediating NF-kappaB/p38 feedback loop and apoptosis, which provided us a panoramic view of potential target in the therapy of RA by XAN. PMID- 28810524 TI - Pioglitazone-induced bone loss in diabetic rats and its amelioration by berberine: A portrait of molecular crosstalk. AB - Diabetes mellitus and osteoporosis both are high prevalence disorders, especially in the elderly population. Pioglitazone, a PPAR-gamma agonist associated with bone loss and risk of fracture in type 2 diabetes mellitus patients. In this study, ameliorative effect of berberine against pioglitazone-induced bone loss in diabetic rats and possible mechanisms has been explored. Diabetes was induced in male Wistar albino rats by streptozotocin (65 mg/kg, i.v.) after 15min of nicotinamide (230mg/kg, i.p.) administration. Diabetic rats were treated orally with pioglitazone (10mg/kg) and berberine (100mg/kg) alone and in combination of both for 12 weeks. Femur of each rat was isolated and evaluated for the bone micro-architecture, BMD, histology and mRNA expression of PPAR-gamma, AMPK, and bone turnover markers (RANKL, OPG, Runx2, and osteocalcin). Urinary calcium and serum TRAP was also measured. Treatment of pioglitazone and berberine alone and in combination significantly ameliorate abnormal blood glucose, serum insulin, and HbA1c levels in streptozotocin-induced diabetic rats. Pioglitazone treatment significantly increased urinary calcium, serum TRAP, mRNA expression of RANKL, PPAR-gamma as well as significantly decreased Runx2, OPG, osteocalcin and AMPK levels in diabetic rats. Pioglitazone administration also shows detrimental effect on femur epiphysis micro-architecture, BMD and histology. Whereas, berberine treatment alone and in combination with pioglitazone remarkably ameliorates the abnormal urinary calcium, mRNA expression of AMPK, bone turnover markers, femur epiphysis micro-architecture, histology and also increases BMD in diabetic rats. In conclusion, berberine shows protective effect against pioglitazone-induced bone loss in diabetic rats possibly through AMPK activation pathway. PMID- 28810525 TI - In vitro anticancer activities of osthole against renal cell carcinoma cells. AB - Renal cell carcinoma (RCC) is a common urinary malignancy that is resistant to chemotherapy and radiotherapy. Osthole, a monomer compound extracted from a traditional Chinese herb, has potent anti-tumor effects on various types of cancer cells. However, the therapeutic effects of osthole on RCC remain unclear. In our study, osthole could suppress the proliferation and colony formation of two RCC cell lines, ACHN and 786-O cells, in a dose-dependent manner. Treatment with osthole resulted in a significant, dose-dependent increase in the expression of pro-apoptotic proteins (cleaved caspase-3 and Bax) and decreased expression of anti-apoptotic proteins (Bcl-2 and survivin), which were consistent with evidence of apoptotic nuclear morphology revealed by DAPI staining. Pre-treatment with osthole attenuated the migratory and invasive abilities of RCC cells in a dose dependent manner, as evidenced by a reduction in migrating cells in a Transwell assay and a decreased wound closure ratio in a scratch assay as compared with the control. Additionally, osthole down-regulated the expression of migration/invasion-related proteins matrix metalloproteinase (MMP)-2 and MMP-9. Osthole significantly up-regulated epithelial biomarkers (E-cadherin and beta catenin) and down-regulated mesenchymal biomarkers (N-cadherin and vimentin). Furthermore, our results suggest that osthole suppressed the expression of epithelial-mesenchymal transition transcriptional factors Smad-3, Snail-1, and Twist-1. Taken together, the results of this study suggest that osthole might be a potential novel herbal agent against RCC. PMID- 28810526 TI - MicroRNA-374c-5p regulates the invasion and migration of cervical cancer by acting on the Foxc1/snail pathway. AB - Some microRNAs (miRNAs) have been implicated in cervical cancer development and progression. However, the roles and mechanisms of several miRNAs in epithelial mesenchymal transition (EMT) in cervical cancer remain poorly understood. Here, we conducted a microarray analysis and found that miR-374c-5p was most down regulated miRNA in TGFbeta1-treated cervical cancer cells compared to the expression in parental cell lines. Ectopic overexpression of miR-374c-5p inhibited cervical cancerl invasion and migration in TGFbeta1- treated cervical cancer cells. Conversely, miR-374c-5p knockdown increased the migration and invasion abilities of parental cell lines. Moreover, miR-374c-5p exerted its function by directly targeting the FOXC1 3/-UTR and repressing FOXC1 expression, thus leading to suppression of snail. In clinical cervical cancer samples, lower miR-374c-5p expression predicted poor patient survival and highe lymph node metastasis in cervical cancers. miR-374c-5p was negatively correlated with FOXC1, which was upregulated in cervical cancers with lymph node metastasis. Taken together, our findings highlight the important role of miR-374c-5p in regulating cervical cancers metastasis by targeting FOXC1, suggesting that miR-374c-5p may represent a novel potential therapeutic target and prognostic marker in cervical cancers. PMID- 28810527 TI - Icariin combined with snailase shows improved intestinal hydrolysis and absorption in osteoporosis rats. AB - Icariin has a significant anti-osteoporotic activity, but its clinical application is limited due to a poor oral bioavailability especially under pathological conditions like osteoporosis. Based on the intestinal absorption and metabolism characteristics of icariin in the osteoporosis rats, a kind of simple enteric capsules containing icariin and snailase was designed to overcome this issue in this study. Snailase was secleted as the most efficient exogenous hydrolase of icariin and the related hydrolysis reaction parameters were optimized in the artificial intestinal liquid. Moreover, the hydrolysates of icariin were proved more effective in promoting the rat calvarial osteoblast proliferation than icariin by the MTT assay. Therefore, snailase and icariin were packed into the enteric-coated capsules at an appropriate mass ratio of 1:1 to prepare the icariin loaded enteric-coated capsules (IECs), and then the in vitro release and in vivo pharmacokinetic behavior of IECs was evaluated. Icariin was almost completely hydrolyzed within 4h and approximately 89% of the total flavonoid had been released from IECs at 0.75h in the release medium, which met the requirement of the Chinese Pharmacopoeia on enteric preparations and the Weibull function model. The pharmacokinetic data showed IECs could significantly improved the integrated oral bioavailability of icariin by 50% compared to the IP (icariin without the snailase) in the ovariectomized rats, but no obvious difference was observed in the sham rats. The aforementioned results suggested that such a strategy of icariin combined with the snailase held a great potential in promoting the intestinal hydrolysis and absorption of icariin in the osteoporosis status, providing new research ideas for the active ingredients of traditional Chinese medicine with similar properties. PMID- 28810528 TI - Neuroprotection of bradykinin/bradykinin B2 receptor system in cerebral ischemia. AB - Bradykinin B2 receptor (B2R) activated by its endogenous ligand bradykinin participates in various physiological processes including neurogenesis, neuronal differentiation, and control of inflammation and blood pressure. Besides these effects, B2R has been demonstrated to protect neurons from ischemia/reperfusion (I/R) injury. Here, we highlight the mechanisms of BK/B2R-mediated neuroprotective effects in the peripheral and central nervous systems. Moreover, this review article summarizes some of the signaling pathways of B2R in cerebral ischemia, leading to a better understanding of its neuroprotection. PMID- 28810529 TI - Silymarin induces a multi-targeted cell death process in the human colon cancer cell line HT-29. AB - This study investigated the Silymarin (SM) effects on growth of HT-29 human colon cancer cell line and its cellular death mechanism. HT-29 cells were treated by 25MUM/ml of SM for 48h. HT-29 cells were also pretreated with 10mmol zVAD (apoptosis inhibitor), 10mmol 3-MA (autophagy inhibitor) and 3mmol Nec (necroptosis inhibitor) for evaluation cell death induced by apoptosis, outophagy and necroptosis. MTT and clonogenicity assays revealed that the SM without inhibitors induced a significant decrease in cell viability and proliferation of HT-29 cells (p<0.05). SM in presence of Nec and 3-MA significantly decreased viability and proliferation of HT-29 cells. Apoptotic indexes were significantly increased compare to other groups. SM in presence of zVAD and 3-MA significantly decreased viability and proliferation of HT-29 cells, and expression of RIPK1 and RIPK3 in compare to absence the inhibitors. Necroptotic index was also increased. zVAD could not completely blocked apoptosis. This indicate that SM may stimulate both caspase-dependent and caspase-independent apoptotic pathways. SM in presence of zVAD and Nec significantly decreased cell viability and proliferation of HT-29 cells in compare to control and other experimental groups. LC3-II positive cells were significantly increased in this group in compare to the control and SM without inhibitors treatment. Our results revealed that the high SM toxicity to HT-29 cells depends on multiple cell death pathways, which involved mainly autophagy. PMID- 28810530 TI - Caspase-dependent and caspase-independent induction of apoptosis in breast cancer by fucoidan via the PI3K/AKT/GSK3beta pathway in vivo and in vitro. AB - : Purpose Fucoidan, a complex, sulfated polysaccharide obtained from brown seaweed, exerted anticancer activity through the down-regulation of beta-catenin signaling in mouse breast cancer cells in our previous study. This study examines the anti-cancer effects of fucoidan as well as its underlying molecular mechanisms in the human triple negative breast cancer (TNBC) cell line and in 7,12-dimethylbenz[a]anthracene (DMBA)-induced experimental mammary carcinogenesis in rats. Methods in vitro studies, fluorescent staining, flow cytometry and Western blotting were performed to analyze apoptosis and protein expression in human breast cancer MDA-MB-231 cells. In vivo intervention experiments were conducted with Sprague Dawley (SD) rats with DMBA-induced breast cancer. Tumor volumes and weights were measured. Results in vitro fucoidan treatment inhibited proliferation and induced apoptosis in MDA-MB-231 cells. Western blotting detected that Cyt C and Smac were released into the cell cytoplasm and that caspase-3 and caspase-9 were activated in MDA-MB-231 cells. The levels of AIF and EndoG were significantly increased in the cytoplasm and in the nuclei by fucoidan. These data show that fucoidan induced caspase-dependent and caspase independent apoptosis. Moreover, fucoidan treatment down-regulated the expression of Bid, Bcl-2 and Bcl-xl and up-regulated the level of Bax. In vivo, fucoidan supplementation decreased the mean tumor weight. DISCUSSION: Results from the in vivo and in vitro experiments both showed that fucoidan decreased the levels of p PI3K, p-AKT and p-GSK-3beta (Ser9) in breast cancer. The level of beta-catenin was also decreased. These results suggest that fucoidan can inhibit MDA-MB-231 human breast cancer cells and DMBA-induced tumors in rats by down-regulating the PI3 K/AKT/GSK3beta pathway. This study provides experimental evidence that elucidates the mechanism of antitumor effect of fucoidan and clarifies the mechanism of the effect of fucoidan on the regulation of beta-catenin. PMID- 28810531 TI - MiR-146a overexpression effectively improves experimental allergic conjunctivitis through regulating CD4+CD25-T cells. AB - OBJECTIVE: To study the mechanism of miR-146a in the regulation of allergic conjunctivitis (AC) through CD4+CD25-T cells. METHODS: BALB/c mice were sensitized with ragweed pollen (RW) and alum, and then challenged with RW. Eosinophil infiltration was determined using Giemsa assay. ELISA assay was performed to examine the level of antigen-specific IgE in the serum and cytokine levels in splenocytes. The expression of miR-146a was measured by qRT-PCR. Flow cytometric analysis was used to analyze the percentage of CD4+CD25-T cells and Tregs. RESULTS: In this study, we found that miR-146a overexpression could effectively improve the symptoms of AC in mouse models. Moreover, in vitro experiments, the proliferation of splenocytes was controlled and the expression of IL-5 and IL-13 was also decreased after transfected with miR-146a mimic. In addition, the inhibitory effect of Tregs on Tcons was affected by the change of miR-146a content in Tcons and had a positive correlation effect. When the content of miR-146a in Tregs changed, the inhibition was not affected. In addition, when inhibited miR-146a, NF-kappaB signaling pathway was activated, and the expression of IL-5 and IL-13 in Tcons increased. While after added Bay (NF-kappaB blocker), the NF-kappaB activity was decreased, and the expression of IL-5 and IL-13 in Tcons also reduced. CONCLUSION: MiR-146a decreased in Tcons was contributed to the development of AC through regulating the inhibitory effect of Tregs on Tcons and NF-kappaB signaling pathway. PMID- 28810532 TI - PLGA-CTAB curcumin nanoparticles: Fabrication, characterization and molecular basis of anticancer activity in triple negative breast cancer cell lines (MDA-MB 231 cells). AB - Triple-negative breast cancers (TNBC) are aggressive cancers, which do not control by hormonal therapy or therapies that target HER-2 receptors. Curcumin (Cur) has shown cytotoxic effects in multiple cancer cell lines. However, its medical uses remain limited due to low aqueous solubility and poor bioavailability. Therefore, present study was aimed to fabricate the small positive charge curcumin nanoparticles (CN) by nanoprecipitation methods using PLGA and CTAB, and to evaluate its anticancer efficacy and underlying the mechanism in triple negative breast cancer cell lines (MDA-MB-231 cells). In in vitro drug release assay, Cur was released from CN by flicking diffusion and anomalous transport process. CN showed a higher cellular incorporation than free Cur resulted in higher cytotoxicity. Checking the anticancer activity at the molecular level, Cur has shown to induce the reactive oxygen species production that subsequently causes the DNA damage and resulting in p38-MAPK activation. The p38-MAPK induce the expression of p16/INKK4a, p21/waf1/cip1 and p53 resulting in a reduction in the level of CDK2, CDK4, cyclin D1 and cyclin E and subsequently cell cycle arrest at G1/S and G2/M phase. It also reduces the expression of DNA repair gene, i.e. BRCA1, BRCA2, Rad51, Rad50, Mre11 and NBS1 resulting in apoptosis induction due to persistent DNA damage. This study presents an effective delivery of curcumin in TNBC cancer cells and it could open the new frontiers in clinical cancer chemotherapy. PMID- 28810533 TI - Deltamethrin induced oxidative stress in kidney and brain of rats: Protective effect of Artemisia campestris essential oil. AB - Artemisia campestris (Asteraceae) is widely used in traditional medicine in Southern Tunisia as a decoction for its antivenom, anti-inflammatory, antirheumatic, and antimicrobial activities. A. campestris essential oil (ACEO) was obtained by hydrodistillation from the aerial parts, since it has beneficial and therapeutic effects. Deltamethrin is a synthetic pyrethroid with broad spectrum activities against acaricides and insects and widely used for veterinary and agricultural purposes. Exposure to deltamethrin leads to nephrotoxic and neurotoxic side effects for human and many species including birds and fish. The present study was conducted to investigate the potential nephroprotective, neuroprotective and antioxidant effects of ACEO against sub-acute deltamethrin toxicity in male rats. Deltamethrin intoxicated rats revealed a significant increase in serum kidney and brain indicators as well as creatinin, urea and uric acid levels, and AChE activity as compared to control rats. In addition, kidney and brain lipid peroxidation and antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were altered significantly in deltamethrin treated rats. These biochemical disturbances were confirmed by histological and histomorphometric changes in brain and kidney tissues. However, ACEO normalized the altered serum levels of creatinin, urea, uric acid, and AChE. Moreover, ACEO reduced deltamethrin-induced lipid peroxidation and oxidative stress profile. Furtheremore, it reduced deltamethrin-induced histopathology and histomorphometric degeneration. It can be concluded that the protective effect of ACEO may be attributed to its antioxidant properties. PMID- 28810534 TI - Thymoquinone prevents endoplasmic reticulum stress and mitochondria-induced apoptosis in a rat model of partial hepatic warm ischemia reperfusion. AB - This study was undertaken to evaluate the protective effect of thymoquinone (TQ), the bioactive compound of Nigella sativa seeds, against warm ischemia-reperfusion (I/R) injury in liver. Rats were given an oral administration of a vehicle solution (sham group) or TQ at the appropriate dose (10, 20, 30 and 40mg/kg) for ten days consecutively. Following, they were subjected to 60min of partial hepatic ischemia followed by 24h of reperfusion. .Transaminase activities, histopathological changes, TNFalpha and antioxidant parameters were evaluated. Also, endoplasmic reticulum (ER) stress, mitochondrial damage and apoptosis were studied. In addition, ERK and P38 phosphorylation was determined by Western blot technique. We found that TQ at 30mg/kg is the effective dose to protect rat liver against I/R injury. Moreover, 30mg/kg of TQ prevented histological damages, inflammation and oxidative stress. Interestingly, it decreased the expression of ER stress parameters including GRP78, CHOP and caspase-12. In parallel, it improved mitochondrial function and attenuated the expression of apoptotic parameters. Furthermore, TQ significantly enhanced ERK and P38 phosphorylation. In conclusion, we demonstrated the potential of TQ to protect the rat liver against I/R injury through the prevention of ER stress and mitochondrial dysfunction. These effects implicate the prevention of oxidative stress. PMID- 28810536 TI - Drug-resistant gram-negative uropathogens: A review. AB - Urinary tract infection(UTI) caused by Gram-negative bacteria is the second most common infectious presentation in community medical practice. Approximately 150 million people are diagnosed with UTI each year worldwide. Drug resistance in Gram-negative uropathogens is a major global concern which can lead to poor clinical outcomes including treatment failure, development of bacteremia, requirement for intravenous therapy, hospitalization, and extended length of hospital stay. The mechanisms of drug resistance in these bacteria are important due to they are often not identified by routine susceptibility tests and have an exceptional potential for outbreaks. Treatment of UTIs depends on the access to effective drugs, which is now threatened by antibiotic resistant Gram-negative uropathogens. Although several effective antibiotics with activity against highly resistant Gram-negatives are available, there is not a unique antibiotic with activity against the high variety of resistance. Therefore, antimicrobial susceptibility tests, correlation between clinicians and laboratories, development of more rapid diagnostic methods, and continuous monitoring of drug resistance are urgent priorities. In this review, we will discuss about the current global status of drug-resistant Gram-negative uropathogens and their mechanisms of drug resistance to provide new insights into their treatment options. PMID- 28810535 TI - Curcumin enhances the radiosensitivity of renal cancer cells by suppressing NF kappaB signaling pathway. AB - The radiation resistance of renal cell carcinoma (RCC) remains the primary obstacle to improve patient survival. This study aimed to investigate the effects of curcumin on the radiosensitivity of RCC cells. Human RCC cell (ACHN) was exposed to irradiation (IR) and/or curcumin treatment. Cell viability, DNA repair, cell cycle, and apoptosis, were evaluated by MTT, immunofluoresence staining and flow cytometry. Moreover, ACHN cells were xenografted into nude mice and subjected to IR and/or curcumin treatment. The expression of NF-kappaB signaling related proteins in ACHN cells and xenografts was detected by western blot analysis. The results showed that curcumin significantly increased radiosensitivity of ACHN cells by inhibiting the cell proliferation and DNA damage repair, causing cell cycle arrest at G2/M phase, inducing apoptosis in vitro, and suppressing the growth of xenografts in vivo. In addition, curcumin enhanced radiosensitivity was through markedly inhibiting IR-induced NF-kappaB signaling by modulating the related protein expressions including NF-kappaBP65, I kappaB, VEGF, COX2, and Bcl-2 in ACHN cells, which was further strengthened by NF kappaB inhibitor PDTC treatment. Thus, curcumin may confer radiosensitivity on RCC via inhibition of NF-kappaB activation and its downstream regulars, suggesting the potential application of curcumin as an adjuvant in radiotherapy of RCC. PMID- 28810538 TI - Corrigendum to "Development of an effective and efficient DNA isolation method for Cinnamomum species" [Food Chem. 188 (2015) 264-270]. PMID- 28810537 TI - Cilostazol protects mice against myocardium ischemic/reperfusion injury by activating a PPARgamma/JAK2/STAT3 pathway. AB - Myocardial ischemia/reperfusion (MIR) injury causes severe arrhythmias and a high lethality. The present study is designed to investigate the effect of cilostazol on MIR injury and the underlying mechaism. We measured the effects of cilostazol on heart function parameters in a mouse model of MIR. Proinflammatory cytokines and apoptosis proteins in the myocardium were examined to investigate the anti inflammatory and anti-apoptosis ability of cilostazol. The participation of PPARgamma/JAK2/STAT3 pathway was investigated. Results showed that the impairment of hemodynamic parameters caused by MIR was attenuated by cilostazol. The IL-6, IL-1beta and TNF-a levels were all decreased by cilostazol. Cilostazol also significantly inhibited Bax and cleaved caspase-3 levels and restored the Bcl-2 levels. PPARgamma, JAK2 and STAT3 were all activated by cilostazol. Treatment of inhibitors of them abolished the protective effects of cilostazol on cardiac function, myocardial inflammation and apoptosis. In summary, cilostazol alleviated the cardiac function impairment, myocardial inflammation and apoptosis induced by MIR. The results present a novel signaling mechanism that cilostazol protects MIR injury by activating a PPARgamma/JAK2/STAT3 pathway. PMID- 28810539 TI - Corrigendum to "Antioxidant activity and enzyme inhibition of phenolic acids from fermented rice bran with fungus Rizhopus oryzae" [Food Chem. 146 (2014) 371-377]. PMID- 28810540 TI - Erratum to "Immobilization of Cd in a paddy soil using moisture management and amendment" [Chemosphere, 122 March 2015, 131-136]. PMID- 28810541 TI - MicroRNA-130a is highly expressed in the esophageal mucosa of achalasia patients. AB - Esophageal achalasia is considered as a risk factor of esophageal cancer. The etiologies of esophageal achalasia remain unknown. Peroral endoscopic myotomy (POEM) has recently been established as a minimally invasive method with high curability. The aims of the present study were to identify the microRNAs (miRs) specific to esophageal achalasia, to determine their potential target genes and to assess their alteration following POEM. RNA was extracted from biopsy samples from middle esophageal mucosa and analyzed using a microarray. Differentially expressed miRs in achalasia patients compared with control samples were identified and analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Correlations between specific miR expression levels and the patients' clinical background were also investigated. In addition, alterations of selected miR expression levels before and after POEM were analyzed. The results of RT-qPCR analysis demonstrated that the miR-130a expression levels were significantly higher in patients with achalasia (P<0.0001). In addition, miR-130a expression was significantly correlated with male sex and smoking history in patients with achalasia. However, no significant change in miR-130a expression was observed between before and after POEM. In conclusion, miR-130a is highly expressed in the esophageal mucosa of patients with achalasia and may be a biomarker of esophageal achalasia. PMID- 28810542 TI - Electroacupuncture promotes axonal regeneration in rats with focal cerebral ischemia through the downregulation of Nogo-A/NgR/RhoA/ROCK signaling. AB - The purpose of the present study was to evaluate the effect of electroacupuncture (EA) on the axonal regeneration environment following cerebral ischemia injury and to investigate whether it was associated with Nogo-A/Nogo receptor (NgR)/RhoA/Rho-associated protein kinase (ROCK) signaling. Using a rat model of focal cerebral ischemia, the effects of EA at the Quchi (LI11) and Zusanli (ST36) acupoints on axonal growth inhibitory protein and axonal growth factors were assessed and the underlying molecular mechanisms were investigated. It was found that EA at the Quchi and Zusanli acupoints significantly improved neurological deficit scores following ischemia (P<0.05), and reduced the cerebral infarct volume. Moreover, it was demonstrated that crucial signaling molecules in the Nogo-A signaling pathway were regulated by EA. These results suggest that EA provides a less inhibitory environment for axonal regeneration following cerebral ischemia through inhibition of Nogo-A/NgR/RhoA/ROCK signaling. PMID- 28810543 TI - Atorvastatin has a protective effect in a mouse model of bronchial asthma through regulating tissue transglutaminase and triggering receptor expressed on myeloid cells-1 expression. AB - Airway remodeling in asthma contributes to airway hyperreactivity, loss of lung function and persistent symptoms. Current therapies do not adequately treat the structural airway changes associated with asthma. Statin drugs have improved respiratory health and their therapeutic potential in asthma has been tested in clinical trials. However, the mechanism of action of statins in this context has remained elusive. The present study hypothesized that atorvastatin treatment of ovalbumin-exposed mice attenuates early features of airway remodeling via a mevalonate-dependent mechanism. BALB/c mice were sensitized with ovalbumin and atorvastatin was delivered via oral gavage prior to each ovalbumin exposure. Reverse transcription-semi-quantitative polymerase chain reaction (RT-semi-qPCR), ELISA and western blot analysis were used to assess the expression of a number of relevant genes, including tissue transglutaminase (tTG), triggering receptor expressed on myeloid cells (TREM)-1, nuclear factor erythroid 2-related factor (Nrf) 2, hypoxia-inducible factor (HIF)-1alpha, transforming growth factor (TGF) beta1, matrix metalloproteinase (MMP)-9 and tissue inhibitors of metalloproteinases (TIMP)-1 in lung tissue. alpha-Smooth muscle actin (alpha-SMA) activity was measured by immunohistochemistry. Airway hyperresponsiveness, lung collagen deposition, airway wall area, airway smooth muscle thickness and lung pathology were also assessed. Atorvastatin treatment led to downregulation of tTG and TREM-1 expression in lung tissue after ovalbumin sensitization, blocked the activity of MMP-9, vascular endothelial growth factor, nuclear factor-kappaB p65, alpha-SMA, HIF-alpha and TGF-beta1 and up-regulated Nrf2 expression. Furthermore, the number of lymphocytes and eosinophils in the atorvastatin group was significantly lower than that in the control group. In addition, airway hyperresponsiveness, lung collagen deposition, airway wall area, airway smooth muscle thickness and pathological changes in the lung were significantly decreased in the atorvastatin group, and tumor necrosis factor-alpha, interleukin (IL)-8, IL-13 and IL-17 in serum were significantly decreased. Histological results demonstrated the attenuating effect of atorvastatin on ovalbumin-induced airway remodeling in asthma. In conclusion, the present study indicated that atorvastatin significantly alleviated ovalbumin-induced airway remodeling in asthma by downregulating tTG and TREM-1 expression. The marked protective effects of atorvastatin suggest its therapeutic potential in ovalbumin-induced airway remodeling in asthma treatment. PMID- 28810544 TI - MicroRNA-9 inhibits the proliferation and migration of malignant melanoma cells via targeting sirituin 1. AB - MicroRNA (miR) are a class of small non-coding RNA that are able to inhibit gene expression by directly binding to the 3' untranslated region (UTR) of their target mRNA and thus promote translational repression or mRNA degradation. Recently, miR-9 was reported to have a suppressive role in malignant melanoma; however, the underlying mechanism remains largely unclear. In the present study, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to examine the mRNA and protein expression levels in malignant melanoma tissues and cell lines. The MTT assay and wound healing assay were used to examine the cell viability, proliferation and migratory capacities. Bioinformatics prediction and luciferase reporter assay were performed to investigate the relationship between miR-9 and its potential target gene. The present data revealed that miR-9 expression was significantly downregulated in malignant melanoma tissues when compared with their matched adjacent non-tumor tissues. Furthermore, the expression levels of miR-9 were reduced in malignant melanoma cell lines when compared with human normal skin HACAT cells. Moreover, the ectopic expression of miR-9 significantly suppressed the proliferation and migration of malignant melanoma cells, accompanied with a remarkable decrease in the protein expression levels of sirtuin 1 (SIRT1), which were markedly upregulated in malignant melanoma tissues and cell lines. Additionally, restoration of SIRT1 reversed the suppressive effects of miR-9 on the proliferation and migration of malignant melanoma cells. Luciferase reporter assay data further identified SIRT1 as a direct target gene of miR-9. To conclude, the present findings indicate that miR-9 has a suppressive role in malignant melanoma cell viability and migration, at least in part, via directly inhibiting the protein expression of its target gene, SIRT1. Therefore, miR-9 may serve as a potential candidate for the treatment of malignant melanoma. PMID- 28810545 TI - Electroacupuncture attenuates learning and memory impairment via activation of alpha7nAChR-mediated anti-inflammatory activity in focal cerebral ischemia/reperfusion injured rats. AB - Studies have reported that electroacupuncture (EA) may reduce learning and memory impairment following cerebral ischemic injury. However, the precise mechanism of action remains unclear. In the present study, the attenuation of focal cerebral ischemia/reperfusion injury by EA in rats was investigated. EA at the Baihui (DU 20) and Shenting (DU 24) acupoints was demonstrated to significantly improve performance in the Morris water maze task, with shortened latency time and increased frequency of passing the platform. Molecular analysis revealed that EA activated the expression of alpha7 nicotinic acetylcholine receptors (alpha7nAChR) in the hippocampus. In addition, EA led to a decreased expression of the microglia/macrophage marker Iba1 and the astrocyte marker glial fibrillary acidic protein in the hippocampus. EA treatment also led to decreased production of the inflammatory cytokines tumor necrosis factor-alpha and interleukin-1beta. Treatment with methyllycaconitine, an alpha7nAChR antagonist, attenuated the improvement of learning and memory following EA treatment and the inhibitory effects of EA on glial cell activation and inflammatory cytokine production. In conclusion, the findings of the present study demonstrate that EA is able to improve learning and memory function following cerebral ischemic injury via activation of alpha7nAChR, which significantly decreases the neuroinflammatory response. PMID- 28810546 TI - Changes in cell junctions induced by inhibition of epidermal growth factor receptor in oral squamous cell carcinoma cells. AB - The benefits of epidermal growth factor receptor (EGFR) targeting in the treatment of head and neck cancer, have been documented. However, a minority of patients with head and neck cancer are unresponsive to EGFR targeting therapies. The present study evaluated the effects and limitations of an EGFR inhibitor on oral squamous cell carcinoma cells, particularly on cell-cell junctions mediated by epithelial (E)-cadherin. HSC-3 oral squamous cell carcinoma cells were treated with the EGFR inhibitor, AG1478 (0, 0.5, 2, 10 and 50 uM), and the effects of EGFR inhibition in HSC-3 cells were evaluated by wound healing assays, E-cadherin immunostaining and measurement of transepithelial electrical resistance in vitro. It was observed that treatment of oral squamous cell carcinoma cells with AG1478 suppressed cell motility, altered cell morphology and increased the number of cell-cell junctions compared with untreated control cells. Knockdown of EGFR induced a similar phenotype to that observed by the inhibition of EGFR. Furthermore, in oral squamous cell carcinoma cells treated with high-dose EGFR inhibitor (50 uM), the small number of cells that survived formed cell-cell junctions that were positive for E-cadherin expression. In cells treated with low concentrations of EGFR inhibitor (2 uM), recovery of epithelial properties was observed. The retention of E-cadherin expression in cells that survived high-dose EGFR inhibitor treatment may be a survival mechanism of cancer cells. PMID- 28810547 TI - Salvianolic acid A protects against myocardial ischemia/reperfusion injury by reducing platelet activation and inflammation. AB - The aim of the present study was to investigate the protective effect of salvianolic acid A (SAA) on myocardial ischemia/reperfusion injury in rats. SAA (10 mg/kg) or Tirofiban (60 ug/kg) was administered to rats by jugular vein injection 10 min before the initiation of reperfusion. After 3 h of reperfusion, platelet aggregation was measured using an aggregometer and levels of nitric oxide (NO) were detected using an ultraviolet spectrophotometer. Serum levels of cardiac troponin T (cTnT), creatine kinase isoenzyme MB (CK-MB), p-selectin, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) were also measured 3 and 24 h after reperfusion. Furthermore, morphology of the ischemic myocardium was histopathologically analyzed by hematoxylin and eosin staining, and the infarct area was evaluated by Evans blue and triphenyltetrazolium chloride staining. In rats subjected to reperfusion, it was observed that pretreatment with SAA significantly increased the survival rate (P<0.05), and that increased survival rate was due to a significant decrease in infarct size, as evidenced by significantly reduced serum levels of cTnT and CK MB (P<0.05). In addition, decreases in infarct size occurred through the inhibition of platelet aggregation and inflammation associated with reperfusion induced myocardial cell damage, as indicated by reduced serum levels of p selectin, TNF-alpha, IL-1beta and NO. In conclusion, SAA was protective against myocardial ischemia/reperfusion injury in rats by serving antiplatelet and anti inflammation roles. PMID- 28810548 TI - Effect of follicular helper T cells on the pathogenesis of asthma. AB - Follicular helper T (TFH) cells are considered to be a separate T helper cell subset, specifically to help memory B cell participate in humoral immunity. It has been reported that there is an association between the imbalance of TFH function and certain autoimmune diseases. However, to the best of our knowledge, the effect of TFH cells on the process of bronchial asthma has not been investigated. The aim of the present study was to investigate the associated markers of TFH cells in bronchial asthma-induced mice. In the current study, sensitized and long-term challenges induced a mouse asthmatic model and were used to investigate the associated markers of TFH cells in the pathogenesis of asthma. The results demonstrated that B cell lymphoma 6, inducible T-cell costimulator (ICOS), ICOS ligand, C-X-C chemokine receptor type 5 (CXCR5) and interleukin (IL) 21 protein and mRNA expression levels were higher in the asthma group, as compared with the control group. Furthermore, the ratio of cluster of differentiation (CD) 4+CXCR5+/CD4+ and CD4+CXCR5+ICOS+/CD4+CXCR5+ was significantly increased in the asthma group. The results of the current study suggest that TFH cells and associated markers may have a role in the pathogenesis of chronic bronchial asthma. PMID- 28810549 TI - Dexmedetomidine preconditioning protects against lung injury induced by ischemia reperfusion through inhibition of autophagy. AB - The present study aimed to evaluate the role of autophagy in the protective effect of dexmedetomidine in lung injury caused by ischemia-reperfusion (IR) in rats. In total 48 adult male Sprague-Dawley rats were randomly divided into 6 groups (n=8) as follows: i) Sham group; ii) the IR group; iii) IR + 1 ug/kg dexmedetomidine preconditioning group (pre-LD); iv) IR + 10 ug/kg dexmedetomidine preconditioning group (pre-HD); v) IR + 1 ug/kg dexmedetomidine postconditioning group (post-LD); and vi) IR + 10 ug/kg dexmedetomidine postconditioning group (post-HD). After the rats were anesthetized, the hilum of the left lung was occluded with a non-invasive microvascular clip for 30 min to induce ischemia. The clip was then removed and the left lung was allowed to regain ventilation and blood for 2 h. The rats were then sacrificed, the left lung removed and the wet/dry (W/D) lung weight ratio was determined. Pathological changes to the lungs were evaluated by light and transmission electron microscopy. Furthermore, the rate of lung cell apoptosis was determined by the TUNEL assay. The expression of hypoxia-inducible factor 1alpha (HIF-1alpha), Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3), BNIP3 like (BNIP3 L) and microtubule-associated protein 1A/1B light chain 3B (LC3II) was determined by western blotting. Compared with the sham group, a significant increase in the W/D lung weight ratio, and malondialdehyde (MDA), BNIP3, BNIP3 L and LC3II levels were observed in the IR group, and HIF-1alpha levels and superoxide dismutase (SOD) activity were decreased. Furthermore, the W/D ratio was lower in the pre-LD and pre-HD groups than in the IR group. Additionally, SOD activity was significantly higher and MDA expression was significantly lower in the pre-LD and pre-HD groups compared with the IR group. BNIP3, BNIP3 L and LC3II protein levels were significantly lower in the pre-LD and pre-HD groups compared with the IR group, while HIF-1alpha was notably upregulated in the pre-LD and pre-HD groups compared with the IR group. In conclusion, the results of the present study indicate that dexmedetomidine preconditioning protects against lung injury induced by IR through inhibition of autophagy and apoptosis. PMID- 28810550 TI - 2D-STI combined with gated 99Tcm-MIBI MPI for the diagnosis of myocardial ischemia in hypercholesterolemia patients. AB - This study aimed to investigate the reliability of ultrasound two-dimensional speckle tracking imaging (2D-STI) for the evaluation of myocardial ischemia in familial hypercholesterolemia (FH) patients. We recruited 28 patients clinically diagnosed with homozygous familial hypercholesterolemia (HoFH) and subjected them to 2D-STI, gated transthoracic Doppler echocardiography (TTDE), and 99Tcm methoxyisobutylisonitrile myocardial perfusion imaging (99Tcm-MIBI MPI). The sensitivity, specificity and diagnostic accordance rate of TTDE and 2D-STI for myocardial ischemia in HoFH patients were compared with the 99Tcm-MIBI scores. According to the diagnosis of ischemia in the three main coronary arteries (LAD, LCX, and RCA) by MPI, patients were further divided into different groups for comparing segmental strain by 2D-STI. The total correlation between TTDE and 99Tcm-MIBI MPI for evaluation of myocardial ischemia was r=0.483 and between 2D STI and 99Tcm-MIBI MPI was 0.786. The total correlation index for ejection fraction (EF) between TTDE and 99Tcm-MIBI MPI was r=0.606 and for 2D-STI and 99Tcm-MIBI MPI was r=0.919. TTDE indicated that differences among LVDd, LVDs, IVS, LVPW, AO Vmax, PG, E/e', and DT were statistically significant. STI indicated that the total strain of the ischemia group was lower than that of the non-ischemia group. The total systolic strain and total early diastolic strain of the ischemia group were lower than that of the non-ischemia group. TTDE can be used for primary observation and evaluation of ventricular wall ischemia for HoFH patients. Ultrasound 2D-STI is better than TTDE in the evaluation of myocardial ischemia in HoFH patients. Ultrasound 2D-STI shows the same effectiveness as 99Tcm-MIBI MPI for the detection of myocardial ischemia, serving as good tool for prognosis and treatment evaluation in HoFH patients. PMID- 28810551 TI - Alterations in biomechanical properties and microstructure of colon wall in early stage experimental colitis. AB - The aim of the current study was to investigate the effects of early-stage dextran sodium sulfate (DSS)-induced mouse colitis on the biomechanical properties and microstructure of colon walls. In the present study, colitis was induced in 8-week-old mice by the oral administration of DSS, and then 10 control and 10 experimental colitis samples were harvested. Uniaxial tensile tests were performed to measure the ultimate tensile strength and ultimate stretches of colon tissues. In addition, histological investigations were performed to characterize changes in the microstructure of the colon wall following treatment. The results revealed that the ultimate tensile stresses were 232+/-33 and 183+/ 25 kPa for the control and DSS groups, respectively (P=0.001). Ultimate stretches at rupture for the control and DSS groups were 1.43+/-0.04 and 1.51+/-0.06, respectively (P=0.006). However, there was no statistically significant difference in tissue stiffness between the two groups. Histological analysis demonstrated high numbers of inflammatory cells infiltrated into the stroma in the DSS group, leading to significant submucosa edema. Hyperplasia was also identified in the DSS-treated submucosa, causing a disorganized microstructure within the colon wall. Furthermore, a large number of collagen fibers in the DSS treated muscular layer were disrupted, and fiber bundles were thinner when compared with the control group. In conclusion, early-stage experimental colitis alters the mechanical properties and microstructural characteristics of the colon walls, further contributing to tissue remodeling in the pathological process. PMID- 28810552 TI - Anti-CXCL4 monoclonal antibody accelerates telogen to anagen transition and attenuates apoptosis of the hair follicle in mice. AB - Although hair loss or alopecia is a common disease, its exact mechanisms are not yet well understood. The present study investigated the hypothesis that the homeostatic regulation of genes during hair regeneration may participate in hair loss, based on the cyclicity of hair growth. A cluster of such genes was identified by an expression gene-array from the dorsal skin in a depilated mouse model, and CXCL4 was identified as a significantly regulated gene during the hair regeneration process. To elucidate the function of CXCL4 in hair growth, CXCL4 activity was blocked by the administration of an anti-CXCL4 monoclonal antibody (mAb). Histomorphometric analysis indicated that anti-CXCL4 mAb induced an earlier anagen phase and delayed hair follicle regression, in contrast with that in the control group. Moreover, CXCL4 mAb upregulated the transcription levels of several hair growth-related genes, including Lef1, Wnt10b, Bmp4 and Bmp2. In addition, CXCL4 mAb increased the levels of the proliferation-related protein PCNA and Bcl-2 during the anagen phase, while it reduced the expression of pro apoptotic protein Bax and cleaved caspase-3 during the catagen phase. These findings reveal that CXCL4 plays an important role in hair growth, and that blockade of CXCL4 activity promotes hair growth. PMID- 28810553 TI - Evaluation of the C-domain of heparanase during AGE-induced macrophage inflammatory response. AB - Diabetic vasculopathy is intensified by macrophage inflammation caused by advanced glycation end products (AGEs). Heparanase (HPA) is a unique endoglycosidase, which cleaves heparan sulfate proteoglycans (HSPGs) including syndecan-1 (Syn-1) to further stimulate macrophage cell migration and inflammation. The present study was planned to evaluated the role of C-domain (if any) of HPA in AGE inflammatory response in macrophages. Cell viability was assessed using MTT assay, migration assay, ELISA for tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) levels, mRNA expression by RT-PCR and heparan degrading enzyme assay for HPA activity. In the present study, we found that pretreatment with anti-HPA antibody, which recognizes the C-domain of HPA inhibited macrophage migration, secretion of IL-1beta and TNF-alpha as well as decreased HPA enzymatic activity and increased Syn-1 protein expression in AGE induced macrophages. Compared with anti-HPA antibody pretreatment, co pretreatment with anti-HPA plus Syn-1 antibodies promoted macrophage migration, and secretion of IL-1beta and TNF-alpha significantly in AGE-induced macrophages. In addition, pretreatment with anti-HPA or anti-HPA plus Syn-1 antibodies did not markedly change the mRNA levels of IL-1beta and TNF-alpha concentration AGE treated macrophages. The results showed that C-domain of HPA mediates AGE-induced macrophage migration and inflammatory cytokine release via Syn-1 protein expression. Furthermore, C-domain of HPA may have a key role in diabetic vascular complication-associated inflammatory response. PMID- 28810555 TI - Evaluation of rat C6 malignant glioma using spectral computed tomography. AB - To investigate the use of multi-parameter spectral computed tomography (CT) for the evaluation of rat C6 glioma, 15 male Wistar rats were seeded with C6 glioma cells into the right basal ganglia and scanned 12 days later using spectral CT. Brain sections corresponding to scanned regions were immunostained for proliferation marker protein Ki67 (Ki67). Pearson's correlation coefficients between spectral CT parameters and Ki67 expression were determined. Thirteen rats survived 12 days and developed tumors. Optimal contrast-to-noise ratio achieved was 65 keV. Brain regions containing liquefactive necrosis, solid tumor, peripheral tumor and normal tissue differed significantly with regard to the spectral curve slope (0.24+/-0.46, 1.81+/-1.09, 0.8+/-0.43 and 0.11+/-0.27, respectively; P<0.01), CT value (27.2+/-4.51, 103.18+/-35.48, 65.19+/-13.72 and 38.07+/-7.36, respectively; P<0.01) and iodine concentration (2.41+/-3.86, 16.05+/-9.75, 6.76+/-3.66 and 1.06+/-2.35, respectively; P<0.0001). The percentage of Ki67-positive cells correlated with the CT value (r=0.903; P<0.001), spectral curve slope (r=0.821; P<0.001) and iodine concentration (r=0.813; P<0.001). Spectral CT can detect microstructural changes within malignant gliomas and potentially provide important information regarding tumor proliferation and the extent of the invasion. PMID- 28810554 TI - Beneficial effects of dried pomegranate juice concentrated powder on ultraviolet B-induced skin photoaging in hairless mice. AB - The present study investigated the anti-aging effects of pomegranate juice concentrated powder (PCP) in hairless mice following 15 weeks of UVB irradiation (three times a week; 0.18 J/cm2). Skin moisturizing effects were evaluated through skin water, collagen type I and hyaluronan contents, as well as collagen type I and hyaluronan synthesis-related transcript levels. Wrinkle formation and edema scores (skin weights) were also assessed, along with skin matrix metalloproteinase (MMP)-1, MMP-9 and MMP-13 transcript levels. To determine the anti-inflammatory effects of PCP, myeloperoxidase (MPO) activity, interleukin (IL)-1beta and IL-10 contents were observed. Caspase-3 and cleaved poly(ADP ribose) polymerase (PARP) were used as an apoptotic index in epidermal keratinocytes. To determine the anti-oxidative effects of PCP, nitrotyrosine and 4-hydroxynonenal immunoreactive cells were detected and glutathione (GSH) content, malondialdehyde levels, superoxide anion production, Nox2, and GSH reductase mRNA expression were all measured. The results indicated that skin wrinkles induced by photoaging were significantly reduced by PCP, whereas skin water contents, collagen type I and hyaluronan contents all increased. Furthermore, IL-1beta levels in the PCP-treated groups were lower than those in the UVB-exposed control group. UVB-induced GSH depletion was also inhibited by PCP. Taken together, the results of the current study suggest that PCP has favorable protective effects against UVB-induced photoaging through anti apoptotic effects, MMP activity inhibition and ECM (COL1 and hyaluronan) synthesis-related moisturizing, anti-inflammatory and anti-oxidative effects. PMID- 28810556 TI - miR-187 inhibits tumor growth and invasion by directly targeting MAPK12 in osteosarcoma. AB - MicroRNAs (miRNAs/miRs) play crucial roles in cancer development and progression. The purposes of this study were to investigate the role of miR-187 in osteosarcoma and clarify the regulation of MAPK12 by miR-187. Quantitative polymerase chain reaction was used to examine miR-187 expression in osteosarcoma tissues and cell lines. The clinicopathological significance of miR-187 downregulation was further analyzed. Transwell migration and invasion assays were performed. A luciferase reporter assay was conducted to confirm the target gene of miR-187, and the results were validated in cervical cancer tissues and cell lines. MiR-187 was significantly decreased in clinical tissues and osteosarcoma cell lines. The low miR-187 level was significantly correlated with stage, node metastasis, and deep stromal invasion. Upregulation of miR-187 suppressed cell migration and invasion in vitro. MAPK12 was verified as a direct target of miR 187, which was further confirmed by the inverse expression of miR-187 and MAPK12 in patients' specimens. The newly identified miR-187/MAPK12 pathway provides an insight into osteosarcoma metastasis and may represent a novel therapeutic target. PMID- 28810557 TI - Role of mammalian target of rapamycin signaling in autophagy and the neurodegenerative process using a senescence accelerated mouse-prone 8 model. AB - The mammalian target of rapamycin (mTOR) kinase is an inhibitor of autophagy, which is an intracellular system involved in the degradation of long-lived proteins and organelles in lysosomes. Recent evidence suggests that the steady incline in mTOR function during aging may be associated with the cognitive decline related to aging and may also promote development of Tau pathology. At present, the senescence accelerated mouse prone 8 (SAMP8) is an experimental model that has been proposed for the study of age-related neurodegenerative changes associated with aging. In the present study, mTOR signaling in the hippocampus of SAMP8 newborn mice and in the control-strain SAMR1 mice was investigated. Consequently, hyper phosphorylated Tau (pS199 or pS396) and upregulated mTOR activity were observed in SAMP8 when compared with SAMR1; however, 0.5 uM rapamycin administration significantly reduced the levels of phosphorylated Tau and p70S6K (pT389) in SAMP8 mice. Related to these findings, SAMP8 exhibited an increase in the neuronal loss of hippocampus that was associated with lower levels of anti-apoptotic proteins. These results indicate that mTOR signaling participates in the neurodegenerative process and rapamycin administration may protect neurons of SAMP8 mice and may have a potential role in curing cognitive decline. PMID- 28810558 TI - Functional assessment of prefrontal lobes in patients with major depression disorder using a dual-mode technique of 3D-arterial spin labeling and 18F fluorodeoxyglucose positron emission tomography/computed tomography. AB - The aim of this study was to explore the functions of cerebral blood perfusion and glucose metabolism in the prefrontal lobe of patients with major depression disorder (MDD), and to analyze the correlations between these functional changes and depressive symptoms. 3D-arterial spin labeling (ASL) and 18F fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) were successfully performed in 17 patients with MDD and 16 healthy controls in a resting state. The depressive symptoms of the patients were classified into seven factors and scored with the Hamilton Depression Rating Scale. Regional cerebral blood flow (CBF) values and standardized uptake values (SUV) of 18F-FDG in the whole brain were respectively compared between the patients and healthy controls using a two-sample t-test, and the correlations between the CBF and SUV in the prefrontal cerebral regions with the patients' Hamilton scores were evaluated using Pearson correlation analysis. Decreased regional CBF was indicated in the bilateral middle and the right superior frontal gyri, and decreased regional SUV was indicated in the bilateral superior, middle and inferior frontal gyri in the MDD patients compared with the controls. Positive correlations were observed between CBF values and aggregate Hamilton scores in the left middle and right middle frontal gyri of the patients. Positive correlations were also observed between SUVs and aggregate Hamilton scores in the left middle and right middle frontal gyri. 18F-FDG PET/CT was indicated to be more sensitive than 3D-ASL in identifying the functional abnormalities in the prefrontal lobe. Decreased CBF and SUV in the prefrontal lobe were closely correlated with Hamilton score. The left middle frontal gyrus may be a key functional region in MDD. PMID- 28810559 TI - Identification of key genes and pathways associated with obesity in children. AB - The present study aimed to identify potential key genes and pathways in obese children in order to explore possible molecular mechanisms associated with child obesity. The array dataset GSE29718 was downloaded from the Gene Expression Omnibus database. Subcutaneous adipose tissue samples derived from 7 obese children and 8 lean children were selected for the analysis. Differentially expressed genes (DEGs) in samples from obese children compared with those from lean children were analyzed by the limma package. Gene ontology (GO) annotation, Kyoto Encyclopedia of Genes and Genomes and Reactome pathway enrichment analyses for up and downregulated genes were performed. A protein-protein interaction (PPI) network was constructed with Cytoscape software and important genes associated with obesity were determined using IRegulon. A total of 199 DEGs (79 up and 120 downregulated genes) were identified in the samples of obese children compared with those from lean children. The PPI network was established with 103 nodes and 147 protein pairs. Matrix metalloproteinase 9 (MMP9) and acetyl-CoA carboxylase beta (ACACB) were identified as hub genes in the PPI network and may therefore be marker genes for child obesity. In addition, upregulated DEGs were enriched in Reactome pathways associated with the immune system. Besides, MMP9 was upregulated in immune system processes as a GO term in the category Biological Processes. The results of the present study indicated that MMP9, ACACB and immune system pathways may have a significant role in child obesity. PMID- 28810560 TI - Effects of Taohongsiwu decoction on the expression of alpha-SMA and TGF-beta1 mRNA in the liver tissues of a rat model of hepatic cirrhosis. AB - The present study aimed to explore the treatment effects of Taohongsiwu decoction on the liver fibrosis in a rat model, as few prior studies have investigated the anti-fibrotic effects of Taohongsiwu decoction. High-performance liquid chromatography was used to measure the concentration of ferulic acid and hydrosafflower flavin A in the decoction. Male Sprague-Dawley rats were randomly divided into control, model, colchicine (positive group), Taohongsiwu-high, Taohongsiwu-moderate and Taohongsiwu-low groups; 50% carbon tetrachloride (CCl4) of peanut oil solution was subcutaneously injected to the rats except for the control group, and the drugs were intragastrically administered (10 ml/kg) starting at week 7 for 6 continuous weeks. The rats were deprived of food but not water for 12 h following the final administration, then blood was collected from the abdominal aorta. The liver tissues were obtained, fixed with 10% neutral formaldehyde, and embedded with paraffin. The concentrations of ferulic acid and hydroxysafflor flavin A in Taohongsiwu decoction were 0.12 and 0.57 mg/ml, respectively. The three groups treated with Taohongsiwu decoction were found with significantly lower serum levels of aspartate aminotransferase, alanine amino transferase, collagen IV and hyaluronic acid, as well as higher level of albumin (ALB); in addition, the expression levels of alpha-smooth muscle actin (alpha SMA) and transforming growth factor-beta1 (TGF-beta1) mRNA and collagen I were significantly downregulated. Taohongsiwu decoction improved the liver function, reduced the collagen deposition in the serum and liver tissues, and inhibited the expression of alpha-SMA and TGF-beta1. PMID- 28810561 TI - Cytotoxic T lymphocytes promote cytarabine-induced acute myeloid leukemia cell apoptosis via inhibiting Bcl-2 expression. AB - Acute myeloid leukemia (AML) remains difficult to cure due to its drug tolerance and refractoriness. Immunotherapy is a growing area of cancer research, which has been applied for the treatment of numerous types of cancer, including leukemia. The present study generated AML cell-specific cytotoxic T lymphocytes (CTLs) in vitro and investigated the effect of combining CTL treatment with one of the most commonly used drugs for the treatment of hematological malignancies, cytarabine, on AML cell apoptosis. Firstly, it was observed that monocyte-depleted peripheral blood lymphocytes from healthy donors could be used to generate large numbers of CD3+CD8+ CTLs through immune stimulation. These CD3+CD8+ CTLs could effectively recognize and induce the apoptosis of human Kasumi-3 AML cells. In addition, cytarabine-induced AML cell apoptosis was enhanced by CTL treatment. Western blotting revealed that Bcl-2 expression was downregulated in AML cells following cytarabine and CTL treatment, indicating that the synergistic effect of this treatment on AML cell apoptosis is due to the downregulation of Bcl-2. These results highlight the potential application of CTL immunotherapy for the treatment of AML. Further studies optimizing the specificity and potency of CTLs, and identifying favorable combinations with other chemotherapeutic drug are required. PMID- 28810562 TI - Anti-depressant-like effects of Jieyu chufan capsules in a mouse model of unpredictable chronic mild stress. AB - Jieyu chufan (JYCF) is a well-known Chinese traditional medicine used for depression; however, the molecular mechanism underlying its anti-depressant action has remained elusive. In the present study, the anti-depressant effects of JYCF and the potential mechanisms were investigated in a mouse model. Five groups of 12 C57BL/6 mice each were used in the study, including a normal control group (NC group), a model control group (MC group) and three groups, which received different doses of JYCF (1.25, 2.5 and 5 g/kg) orally for 21 days (JYCF groups). The MC group and the three JYCF groups were subjected to 3 weeks of unpredictable chronic mild stress (UCMS) to induce depression-like behavior. All groups were subjected to a sucrose consumption test along with a forced swimming test to confirm depression-like behavior, an open-field test and an elevated plus maze test to confirm anxiety-like behavior, and a Morris water maze test to evaluate spatial learning and memory. In addition, synaptic density in the hippocampus was evaluated and western blot and immunostaining were used to analyze hippocampal expression of postsynaptic density protein-95 (PSD95), synaptophysin (Syn), cyclic adenosine monophosphate response element binding protein (CREB), brain derived neurotrophic factor (BDNF), Akt and glycogen synthase kinase (GSK)-3beta as well as their phosphorylated (p) versions. The results showed that JYCF (2.5 and 5 g/kg) alleviated depressive-like behaviors and increased synaptic density in UCMS mice. Moreover, JYCF upregulated the expression of PSD95, Syn and BDNF and increased phosphorylated Akt, CREB and GSK-3beta in the hippocampus. These results suggested that JYCF exerts an anti-depressant-like activity in UCMS induced mice, which is likely to be mediated by reversing the stress-induced disruption of BDNF and GSK-3beta activity. PMID- 28810563 TI - Dystrophia myotonica type 1 presenting with dysarthria: A case report and literature review. AB - Dystrophia myotonica (DM) type 1 is an autosomal dominant disorder, caused by a trinucleotide CTG repeat expansion in the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene (chromosome 19q13.3). The disorder affects different organ systems, including the skeletal muscles, ocular lens, lungs, heart and gastrointestinal tract, as well as the endocrine and central nervous systems. The skeletal muscles are most frequently involved, whereby the disorder manifests as myotonia, muscle weakness and amyotrophy. However, DM type 1 presenting with dysarthria is rare. The current study presents a case of a 28-year-old male with DM type 1 presenting with dysarthria and associated multifocal hyperintense lesions in the white matter. Although electromyogram measurements identified myotonic discharges in all extremities, a muscle biopsy failed to detect the characteristic pathological features of DM type 1. A lack of a positive family history for DM type 1 also obscured diagnosis. However, genetic analysis detected a single allele in the P12 segment of the DMPK gene that included a CTG expansion of 13 repeats and a three-base gradient fragment in the P134 segment that included a CTG expansion of >600 repeats. According to the characteristics of dysarthria, multifocal hyperintense lesions in the white matter, electromyogram measurement results and genetic testing results, a diagnosis of DM type 1 was confirmed. PMID- 28810564 TI - Clinical efficacy of conjunctival flap surgery in the treatment of refractory fungal keratitis. AB - The aim of the present study was to investigate the use and effectiveness of a selective, partial, pedunculated (tongue-shaped) conjunctival flap (CF) for the treatment of refractory fungal keratitis (FK) with or without perforation. A total of 31 cases of corneal diseases treated by CF surgery between April 2014 and October 2015 were evaluated. Among the 31 cases, 16 cases (male:female, 11:5) with FK were selected. Logistic regression analysis was used to investigate factors associated with complications of CF surgery. A higher prevalence of FK was identified among male farmers compared with female farmers, in which plant trauma was the most prevalent cause of the disease. Only 4 patients had experienced corneal perforation prior to CF surgery. Patients aged 61-80 years had a higher prevalence of FK (50%) compared with other age groups; however, there was no statistically significant correlation between the prevalence of FK and sex or age. It was also demonstrated that age, sex, combined surgery and surgery duration were not significantly associated with post-surgical complications. All CF surgeries were performed following corneal ulcer scraping; however, 4 patients (12.5%) required additional surgery. The visual acuity of participants post-surgery decreased in 4 cases and remained unchanged in 12 cases. A total of 3 study patients experienced post-surgical complications of corneal perforation (1 patient) and purulent exudate spreading (2 patients). The post-surgical outcome was good for all study participants as the surgeries were able to control infection and preserve the eyeball, with the potential of future corneal transplant. These results suggest that CF surgery may be a useful alternative treatment for refractory FK in countries such as China where there is lack of cornea donors. PMID- 28810565 TI - Alteration of Th17 and Foxp3+ regulatory T cells in patients with unexplained recurrent spontaneous abortion before and after the therapy of hCG combined with immunoglobulin. AB - We conducted this study to investigate the effects of the combination therapy of human chorionic gonadotropin (hCG) plus immunoglobulin (IG) on the levels of T helper 17 (Th17) cells and Foxp3+ regulatory T cells (Treg) in patients with unexplained recurrent spontaneous abortion (URSA). Twenty pregnant women with URSA underwent combination therapy of hCG plus IG. Flow cytometry was performed to measure the proportions of Th17 and Treg cells before and after treatment. RT PCR and ELISA were applied to detect the concentrations of interleukin (IL)-17, IL-6, IL-10, and transforming growth factor (TGF)-beta1 in the peripheral blood. The therapy of hCG combined with IG may induce a decrease in the Th17/Treg ratio and the Treg bias, which may be beneficial for the maintenance of pregnancy. The levels of Th17 cells and related cytokines IL-17 and IL-6 decreased after the treatment (P<0.05). At the same time, levels of Treg cells and the related cytokines IL-10 and TGF-beta1 increased (P<0.05). The Th17/Treg ratio decreased significantly after treatment. In conclusion, the occurrence of URSA may be associated with the Th17/Treg balance disorder, and correcting the disorder may be one of the mechanisms behind the efficacy of combination therapy for URSA. PMID- 28810566 TI - Correlation analysis between the LDL-C in serum and the onset of transient ischemic attack caused by CSVD. AB - The aim of this study was to investigate the correlation between the low-density lipoprotein cholesterol (LDL-C) in serum and the onset of transient ischemic attack caused by cerebral small vascular disease (CSVD). Between September 2012 and September 2015, 249 patients who were diagnosed as CSVD were randomly enrolled in this study. According to MRI results, patients were divided into the patient and control groups. In the patient group, the patients were further subdivided into the white matter lesion (WML) group (n=86) and lacunar infarction (LI) group (n=53). Head MRI and/or CT were conducted on all the patients. This included T1 and T2 phases, diffusion weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR). Additionally, mini-mental status examination (MMSE) test and Montreal cognitive assessment (MoCA) test were carried out on all the patients. As a result, the age, total cholesterol (TC) level and low-density lipoprotein (LDL) levels in the patient group were higher than those in the control group (p<0.05). The MMSE and MoCA scores in the patient group were significantly lower than those in the control group (p<0.05). With all the risk factors being set as independent variables and small vessel disease (SVD) as the dependent variable, we performed the logistic regression analysis and correlation analysis for paired data, and found that the increase in LDL was correlated to the onset of SVD, OR=1,321. After adjustment of other risk factors, we enrolled the level of triglyceride (TG) into the multivariable analysis and obtained a statistically significant difference (p<0.05). In conclusion, LDL is a major risk factor affecting the onset of transient ischemic attack (TIA) induced by CSVD. Patients with hyperlipidemia should receive head MRI or CT examination to eliminate the probability of the existence of CSVD. To reduce the occurrence of adverse events in clinical practice, we can perform early intervention in SVD by decreasing the level of LDL, improving the endothelial function of small vessels and applying the anti-inflammation and nerve-protection methods. PMID- 28810567 TI - Factors related to infection after fixation in the process of late healed bone fracture. AB - We studied the factors related to infection after fixation in the process of bone late healed fracture and explored the factors that could predict the risk of postoperative infection. A total of 100 patients with open fractures of the tibia and fibula diagnosed in Zhengzhou No. 7 People's Hospital from 2007 to 2016 were enrolled in this study. Patients were subjected to staging surgery treatment. We divided them into the infection group (n=52) and the non-infection group (n=48) according to whether or not infection occurred after operation. Pearson correlation was used to analyze the relationship between postoperative infection and preoperative factors, and ROC curve was used to explore the factors which could predict the risk of postoperative infection. As a result, surgical timing and C-reactive protein were correlated with postoperative infection (P<0.05), and surgical timing was negatively correlated with postoperative infection. C reactive protein was positively correlated with postoperative infection. Using 7 days as the cut-off point of surgical timing, false positive and false negative rates were 0 and 27.7%, respectively. Youden index value was 72.3%, and positive predictive and negative predictive values were 42.5 and 100%, respectively. With 54.55 mg/l as the cut-off point of C-reactive protein, the sensitivity and specificity of prediction were 88.2 and 94.1%, while the false negative and false positive rates were 11.8 and 5.9%, respectively. The Youden index value was 82.3%, and the positive predictive and negative predictive values were 75 and 96.7%, respectively. With 7 days as the cut-off point of surgical timing and 54.55 mg/l as the cutoff point of C-reactive protein at the same time, the positive predictive and negative predictive values were 88.2 and 97.6%, respectively. The false negative and false positive rates were 11.8 and 2.4%, respectively. The Youden index value was 85.8%. The positive predictive and negative predictive values were 88.2 and 97.6%, respectively. In conclusion, surgical timing and C-reactive protein were strongly correlated with postoperative infection and this correlation was not affected by age, sex or other inflammatory indexes. The incidence of postoperative infection was reduced when both factors were applied for the determination of surgery. In addition, incidence of complications will be reduced and the cure rate improved. PMID- 28810569 TI - Ultrasound guided injections of botulinum toxin type A into stellate ganglion to treat insomnia. AB - The aim of the study was to investigate the curative effect of botulinum toxin type A (BTX-A) injection into stellate ganglion under ultrasound guidance in patients suffering from insomnia. From October 2015 to April 2016, 48 patients suffering from insomnia were enrolled in this study. Patients were divided into 2 groups using a random digital grouping method: i) Control group (24 cases), and ii) treatment group (24 cases). Patients in the control group received 1 mg oral estazolam 30 min before sleep every night, while patients in the treatment group received BTX-A injection in bilateral stellate ganglions under ultrasound guidance. Curative effect evaluation was carried out after treatment. The international Pittsburgh Sleep Quality Index (PSQI) and polysomnogram (PSG) were evaluated in the two groups before and after treatment. The total effective rate was obviously higher in the treatment group. The PSQI score and the results of the PSG indicated that the insomnia situation improved in both groups. However, compared with the control group, the treatment group had a more significant improvement. In conclusion, BTX-A injection in stellate ganglion was a relatively easy and effective way to treat insomnia without any notable adverse reactions. PMID- 28810568 TI - Mechanism of microRNA-146a-mediated IL-6/STAT3 signaling in lumbar intervertebral disc degeneration. AB - The aim of the study was to investigate the mechanism of microRNA (miR)-146a mediated activation of interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) in lumbar intervertebral disc degeneration. To obtain intervertebral tissue, we recruited 5 patients with lumbar intervertebral disc herniation (experimental group) and 5 patients with lumbar burst fracture (control group). Nucleus pulposus tissue was extracted by surgery and cultured. miR-146a empty vector, mimic, and inhibitor were transfected into the two groups of cells for 24 h and the levels of IL-6, type II collagen (Col II), aggrecan, STAT3, matrix metalloproteinase (MMP)-3, and a disintegrin and metalloproteinase with thrombospondin type I motifs (ADAMTS) were detected. We found no differences in the levels of IL-6, Col II, aggrecan, STAT3, MMP-3, and ADAMTS before and after treatment in the control group. However, the levels of miR-146a, IL-6, STAT3, MMP-3, and ADAMTS were significantly elevated, whereas Col II and aggrecan levels were lower in the experimental group before treatment. The levels of IL-6, STAT3, MMP-3, and ADAMTS were elevated after treatment with miR-146a mimic when compared with the miR-146a empty vector in the experimental group, and Col II and aggrecan levels were decreased. However, the cells treated with miR-146a inhibitor had the opposite result. Thus, the IL-6/STAT3 signaling pathway can be mediated by a high expression of miR-146a to regulate the occurrence of lumbar intervertebral disc degeneration. PMID- 28810570 TI - Research on the function and related mechanism of P27 gene in the intervertebral disc degeneration of mice. AB - This study aims to investigate the function and related mechanism of P27 gene in intervertebral disc (IVD) degeneration of mice. X-ray, immunohistochemical staining, and alkaline phosphatase (ALP) histochemical staining were used to analyze the phenotypic difference of the intervertebral discs of 4-week-old mice with P27 gene knockout (P27-/-) and wild-type (WT) mice in the same brood. Protein in the intervertebral disc was extracted and western blot analysis was employed to detect the changes in the expression of related molecules in the Shh signal pathways, including Shh, Patched, Smoothened and Gli2. As a result, the ALP histochemical staining revealed that the ALP-positive area of mice in the P27 /- group was obviously increased compared to the 4-week-old mice of the same brood in the WT group. In addition, the Col-I immunohistochemical staining showed that the Col-I-positive area of mice in the P27-/- group was significantly increased compared to mice in the WT group. Furthermore, Smo-positive cell rate of mice in the P27-/- group was apparently increased compared to mice in the WT group. Western blot analysis revealed that in terms of changes of protein expression levels of Shh, Patched, Smoothened and Gli2 in the intervertebral disc, protein expression levels of Shh, Patched, Smoothened and Gli2 of mice in the P27-/- group were significantly increased compared to those of mice in the WT group. The results show that P27 deficiency activates the expression of Shh signal pathway and promotes the proliferation of osteoblast, thus, playing a role in promoting IVD degeneration, which provides a scientific and reliable experimental basis for the treatment of the IVD degeneration-related diseases in clinical practice. PMID- 28810571 TI - Docosahexaenoic acid inhibits the phosphorylation of STAT3 and the growth and invasion of renal cancer cells. AB - Docosahexaenoic acid (DHA) has a variety of anti-tumor activities. The present study examined the anti-tumor activity of DHA in renal cancer cells and its underlying mechanisms of action. The effects of DHA on the viability and proliferation of the human renal cancer cell lines Caki-1 and 786-O were examined by an MTS assay and cell counting. In addition, cell cycle distribution and cell apoptosis were analyzed by flow cytometry and Annexin V staining, and modulation of cell mobility and invasiveness was assessed by wound healing and Matrigel invasion assays. Effects of DHA on intracellular signaling pathways were also analyzed by western blotting. It was observed that DHA significantly reduced the viability and proliferation of Caki-1 and 786-O cells (P<0.01). Specifically, there were increases in the sub-G1 and G2/M cell populations, as well as the percentages of cells exhibiting Annexin-positive and propidium-iodide-negative staining. In addition, the covered area in a wound and the number of cells invading through a Matrigel chamber decreased when Caki-1 or 786-O cells were treated with DHA. Phosphorylation of epidermal growth factor receptor was also upregulated following DHA treatment, while phosphorylation of signal transducer and activator of transcription 3 and Akt was downregulated. Collectively, these data suggest that DHA may be useful in the treatment of renal cell carcinoma. PMID- 28810572 TI - Diffusion-weighted imaging of injuries to the visual centers of the brain in patients with type 2 diabetes and retinopathy. AB - The present study aimed to investigate the ability of diffusion-weighted imaging (DWI) to identify injury to the visual centers of the brain in patients with type 2 diabetes with retinopathy. The study included 84 cases (63 patients with type 2 diabetic retinopathy and 21 healthy individuals) that were assessed using DWI. Diabetic patients were equally divided into three groups: Proliferative diabetic retinopathy (PDR), non-proliferative diabetic retinopathy (NPDR) and diabetic without retinopathy. The results demonstrated that individuals in the PDR group had significantly higher disease duration and glycated hemoglobin levels than the diabetic without retinopathy group (P<0.05). Apparent diffusion coefficient (ADC) values were significantly higher in functional brain areas of the PDR group compared with the NPDR group (P<0.001), whose values were significantly higher compared with the diabetic without retinopathy and control groups (P<0.001). In addition, glycated hemoglobin levels and disease duration were positively correlated with mean ADC values in the same functional areas of the brain. In conclusion, DWI-measured ADC values may be an effective indicator of brain dysfunction in individuals with type 2 diabetic retinopathy. DWI is able to assess brain injury in individuals with early diabetic retinopathy, which may make the diagnostic technique a useful predictor of early ocular disease. PMID- 28810573 TI - Warfarin-induced life-threatening bleeding associated with a CYP3A4 loss-of function mutation in an acute limb ischemia patient: Case report and review of the literature. AB - Patients with acute limb ischemia, deep venous thrombosis and pulmonary artery embolism may be treated with warfarin. The dose-response interaction of warfarin is associated with numerous factors, depending on which an uncommon life threatening bleeding may occur. The present case study reported on a patient with acute limb ischemia and a history of warfarin-induced bleeding ten years previously and who again developed life threatening bleeding associated with warfarin treatment and received vascular surgery. In this patient, a cytochrome P450 3A4 loss-of-function mutation decreased the effective dose of warfarin. Although this was a rare case, clinicians should be alert to the bleeding risk associated with such rare genetic mutations. PMID- 28810574 TI - Tissue kallikrein protects against ischemic stroke by suppressing TLR4/NF-kappaB and activating Nrf2 signaling pathway in rats. AB - Brain damage following cerebral ischemia-reperfusion (I/R) is a complicated pathophysiological course, in which inflammation and oxidative stress have been suggested to serve an important role. Toll-like receptor 4 (TLR4) has been suggested to be involved in secondary inflammatory process in cerebral ischemia. Nuclear factor erythroid 2-related factor 2 (Nrf2), an important regulator of the antioxidant host defense, maintains the cellular redox homeostasis. Tissue kallikrein (TK) has been proven to elicit a variety of biological effects in ischemic stroke through its anti-inflammatory and anti-oxidant properties. However, the mechanisms underlying its beneficial effects remain poorly defined. The present study examined the hypothesis that TK attenuates ischemic cerebral injury via the TLR4/nuclear factor-kappaB (NF-kappaB) and Nrf2 signaling pathways. Using a transient rat middle cerebral artery occlusion (MCAO) model, the effects of immediate and delayed TK treatment subsequent to reperfusion were investigated. The neurological deficits, infarct size, and the expression of TLR4/NF-kappaB and Nrf2 pathway in ischemic brain tissues were measured at 24 following MCAO. The results indicated that TK immediate treatment significantly improved neurological deficits and reduced the infarct size, accompanied by the inhibition of TLR4 and NF-kappaB levels, and the activation of Nrf2 pathway. Furthermore, TK delayed treatment also exerted neuroprotection against I/R injury. However, the neuroprotective effect of TK immediate treatment was better compared with that of TK delayed treatment. In conclusion, the results indicated that TK protected the brain against ischemic injury in rats after MCAO through its anti-oxidative and anti-inflammatory effects. Suppression of TLR4/NF-kappaB and activation of the Nrf2 pathway contributed to the neuroprotective effects induced by TK in cerebral ischemia. Therefore, TK may provide an effective intervention with a wider therapeutic window for ischemic stroke. PMID- 28810575 TI - Increased bone morphogenetic protein-6 in follicular fluid and granulosa cells may correlate with fertilization and embryo quality in humans. AB - Bone morphogenetic protein-6 (BMP-6), which is a member of the transforming growth factor-beta superfamily, is associated with the regulation of bone development and various physiological processes. In the present study, the expression of BMP-6 in follicular fluid and granulosa cells (GCs) from pregnant and non-pregnant patients was explored. A total of 44 pregnant patients (pregnant group) and 36 non-pregnant patients (non-pregnant group) were recruited for the present study. The expression of BMP-6 was detected using western blotting and reverse transcription-quantitative polymerase chain reaction. The expression of BMP-6 was significantly higher at the protein level (P<0.01) in follicular fluid obtained from the pregnant group compared with that from the non-pregnant group. The mRNA and protein expression of BMP-6 in GCs were significantly upregulated in the pregnant group compared with the non-pregnant group (both P<0.01). These results suggest that high expression of BMP-6 in pregnant women may be a novel biomarker for the fertility process. PMID- 28810576 TI - Application of low-dose dual-source computed tomography angiography in children with complex congenital heart disease. AB - The objective of the present study was to evaluate image quality and radiation dosage using a low-dose prospectively electrocardiogram (ECG)-gated computed tomography (CT) protocol for dual-source angiography in children with complex congenital heart disease. A total of 206 patients with complex congenital heart disease were equally assigned into two groups at random. The children in group A underwent low-dose retrospective ECG-gated CT scanning with an ECG-pulsing technique, and group B underwent prospective ECG-gated scanning with an ECG pulsing technique. Radiation dose volume computed tomography dose index (CTDI vol), dose length product (DLP) and effective dose (ED) were recorded after scanning. Raw data were transferred to workstations for post-processing, diagnosis, grading, comparison with intra-operation findings or cardiac catheterisation, and the coincidence, false negative rate and misdiagnosis rates of groups A and B, respectively, were subsequently recorded. The results of the present study indicated that the height, age and weight of the children in the two groups exhibited no significant differences. The image quality of group A was graded as 3.94+/-0.08, whereas the grade for the image quality in group B was 4.05+/-0.08; no significant difference was detected. The coincidence rates of groups A and B were 89.37 and 88.48%, respectively; the false negative rates of groups A and B were 9.66 and 10.60%, respectively; the misdiagnosis rates of groups A and B were 0.97 and 0.92%. No significant differences between the two groups were detected. The CTDI value of group A was 3.24+/-1.62 mGy, the DLP value was 47.53+/-33.28 mGy.cm2, the ED value was 0.93+/-0.42 mSv. By contrast, the CTDI value of group B was 2.27+/-0.94 mGy, the DLP value was (27.03+/-17.64) mGy.cm2, and the ED value was 0.53+/-0.23 mSv. Significant differences were detected between the two groups (CTDI t=5.287, P<0.05; DLP t=5.523, P<0.05; ED t=8.497, P<0.05), and the radiation dose of group B was markedly decreased, compared with group A. In conclusion, the present study demonstrated that prospectively ECG-gated scanning of dual-source CT is an effective method of examination for dose reduction in children with congenital heart disease without impairment of image quality, which suggests that this protocol may be suitable for future application and dissemination. PMID- 28810577 TI - Patchouli oil ameliorates acute colitis: A targeted metabolite analysis of 2,4,6 trinitrobenzenesulfonic acid-induced rats. AB - The incidence of inflammatory bowel disease (IBD), characterized by chronic, relapsing intestinal inflammation, has continually increased in recent years. A previous study by our group identified five potential metabolic markers possibly associated with the pathology of 2,4,6-trinitrobenzenesulfonic acid (TNBS) induced IBD in rats. The present study aimed to examine the potential therapeutic effects of the essential oil of Pogostemon cablin (also known as patchouli; PO) on TNBS-induced rats and investigate the concomitant metabolic changes by targeting the previously identified potential markers. Pogostemon cablin is widely used to treat gastrointestinal diseases, including IBD, in China. The results of the present study showed that PO (270 mg/kg, rectal instillation) significantly alleviated colonic damage and reduced disease activity indicators and colonic myeloperoxidase in TNBS-induced rats. In addition, a targeted metabolic profiling study identified that four metabolites were elevated in the urine of the animals in the TNBS group, which were significantly inhibited by treatment with PO: Two tryptophan metabolites [4-(2-aminophenyl)-2,4 dioxobutanoic acid and 4,6-cihydroxyquinoline] and two gut microbial metabolites (phenylacetylglycine and p-cresol glucuronide). Taken together, these findings suggested that PO ameliorated the symptoms of TNBS-induced IBD and reversed the metabolic changes potentially associated with TNBS-induced IBD in rats. PMID- 28810578 TI - 25G compared with 20G vitrectomy under Resight non-contact wide-angle lenses for Terson syndrome. AB - The aim of the present study was to compare the effectiveness of 25G vitrectomy to standard 20G vitrectomy for treatment of Terson syndrome under Resight non contact wide-angle lenses. This was a case-control study of 20 patients with Terson syndrome (study group) that underwent 25G vitrectomy under Resight non contact wide-angle lenses, with those of 20 matched patients that underwent 20G vitrectomy (control group). Medical records were reviewed from between July 2011 and October 2013. Data included results of the Early Treatment Diabetic Retinopathy Study examination, ophthalmology B-scan ultrasonography and fundus photography. The mean age, follow-up time, the preoperative visual acuity of LogMAR and the preoperative intraocular pressure (IOP) were all comparable in the two groups (all P>0.05). There were statistically significant differences in postoperative visual acuity of LogMAR compared with preoperative visual acuity (P<0.001) in both groups, but no difference between the groups (P=0.845). However, the operative times (13.5 min in study group vs. 42 min in control group) and post-operative IOP at day 1 (13.5 vs. 20 mmHg) were significantly reduced in the study group compared to the control group (P<0.001). Therefore, the present findings suggest that 25G Vitrectomy for Terson syndrome under Resight non-contact wide-angle lenses can achieve a significantly shorter operative time and lower post-operative IOP compared with 20G Vitrectomy. PMID- 28810579 TI - MicroRNA-375 targets PAX6 and inhibits the viability, migration and invasion of human breast cancer MCF-7 cells. AB - MicroRNAs (miRs) are a type of small non-coding RNA that serve crucial roles in the development and progression of breast cancer. However, the exact role and underlying molecular mechanism of miR-375 in mediating the growth and metastasis of breast cancer remains unknown. In the present study, reverse transcription quantitative polymerase chain reaction and western blot analysis were conducted to examine RNA and protein expression. A luciferase reporter assay was performed to determine the association between miR-375 and paired box 6 (PAX6). The results of the current study indicate that the expression of miR-375 was reduced in breast cancer tissues compared with matched adjacent normal tissues. Transfection with miR-375 mimics led to a significant increase in levels of miR-375 in human breast cancer Michigan Cancer Foundation (MCF)-7 cells (P<0.05). The increase in miR-375 expression caused a significant decrease in the viability, migration and invasion of MCF-7 cells (P<0.05), accompanied by a reduced expression of matrix metalloproteinase (MMP) 2 and MMP9 proteins. Luciferase reporter assay identified PAX6 as a novel target of miR-375 and miR-375 in turn, negatively regulated the protein expression of PAX6 in MCF-7 cells. By contrast, overexpression of PAX6 led to a significant increase in MCF-7 cell viability (P<0.01) but did not affect the migration and invasion of MCF-7 cells, suggesting that the inhibitory effect of miR-375 on MCF-7 cell viability may be occurring, in part, via the direct targeting of PAX6. PMID- 28810580 TI - Connexin 43 enhances paclitaxel cytotoxicity in colorectal cancer cell lines. AB - Colorectal cancer has a relatively low sensitivity to paclitaxel. The purpose of this study was to investigate the role of connexin 43 (Cx43), which is a structural component of gap junctional communication (GJC), in paclitaxel cytotoxicity in colorectal cancer cells. Three colorectal cancer cell lines (HCT106, HCT116 and LoVo) were transfected with Cx43 and used to examine paclitaxel cytotoxicity. A western blot assay was used to confirm Cx43 expression in transfected cell lines as well as the expression of several proteins that are associated with paclitaxel cytotoxicity. A parachute dye-coupling assay was used to measure GJC function. An MTT assay was used to analyze the viability of paclitaxel-treated cells. Cx43 expression level and GJC function were significantly upregulated by the transfection (P<0.05). The viability of transfected cells was significantly inhibited compared with that of untransfected cells when treated with paclitaxel (20 or 80 nM) at high culture density but not at low culture density (P<0.05). Cx43 transfection significantly increased the mitotic arrest, tubulin polymerization and apoptosis effects of paclitaxel (P<0.05). It was also found that paclitaxel had an inhibitory effect on GJC function after 12 h of treatment in LoVo cells (P<0.05). These results indicate that Cx43 may serve as a target of paclitaxel chemotherapy for colorectal cancer. PMID- 28810581 TI - Protective effect of glycyrrhizin on myocardial ischemia/reperfusion injury induced oxidative stress, inducible nitric oxide synthase and inflammatory reactions through high-mobility group box 1 and mitogen-activated protein kinase expression. AB - Glycyrrhizin, which is a type of perennial leguminous caudex, has been used in various Asian countries, including P.R. China, India and Japan, for thousands of years. The present study was designed to investigate the protective effect of glycyrrhizin on myocardial ischemia/reperfusion (I/R) injury through oxidative stress, inducible nitric oxide synthase (iNOS), and inflammatory reactions via high-mobility group box 1 (HMGB1) and mitogen-activated protein kinase (MAPK) expression. Sprague-Dawley rats were divided into five groups: Sham; myocardial I/R injury + non-treated; myocardial I/R injury + 2 mg/kg glycyrrhizin; myocardial I/R injury + 4 mg/kg glycyrrhizin; and myocardial I/R injury + 10 mg/kg glycyrrhizin. Pre-treatment with glycyrrhizin significantly reduced infarct size and inhibited creatine kinase, creatine kinase-MB, lactate dehydrogenase and cardiac troponin T activities in rats with myocardial I/R injury. Furthermore, glycyrrhizin treatment significantly suppressed oxidative stress, iNOS protein expression and inflammatory reactions in rats with myocardial I/R injury. Additionally, treatment with glycyrrhizin significantly decreased the release of HMGB1 from the cerebral cortex into the serum in rats with myocardial I/R injury. Notably, glycyrrhizin significantly suppressed p-ERK, p-p38 MAPK and p-c-Jun N terminal kinase protein expressions, and promoted extracellular signal-regulated kinase protein expression in rats with myocardial I/R injury. Collectively, the present study indicates that the protective effect of glycyrrhizin may reduce myocardial I/R injury through oxidative stress, iNOS and inflammatory reactions, via HMGB1 and MAPK expression. PMID- 28810582 TI - MicroRNA-92a promotes cell viability and invasion in cervical cancer via directly targeting Dickkopf-related protein 3. AB - MicroRNA-92a (miR-92a) was recently reported to have an oncogenic role in cervical cancer; however, the underlying mechanism remains largely unclear. The present study aimed to investigate the expression, clinical significance and regulatory mechanism of miR-92a in cervical cancer. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) data indicated that miR-92a was significantly upregulated in cervical cancer tissues compared with matched adjacent non-tumor tissues (P<0.01). High expression of miR-92a was significantly associated with poor differentiation (P=0.031), advanced clinical stage (P=0.011) and lymph node metastasis (P=0.014), but not associated with age, tumor size and distant metastasis. Knockdown of miR-92a significantly inhibited the viability and invasion of cervical cancer HeLa cells, while overexpression of miR-92a significantly enhanced HeLa cell viability and invasion (P<0.01). Luciferase reporter assay identified Dickkopf-related protein 3 (DKK3) as a target gene of miR-92a, and the protein expression of DKK3 was negatively regulated by miR-92a in HeLa cells. Furthermore, overexpression of DKK3 significantly eliminated the stimulative effects of miR-92a on HeLa cell viability and invasion (P<0.01). Additionally, DKK3 was significantly downregulated in cervical cancer tissues compared with adjacent non-tumor tissues (P<0.01), inversely correlated to the miR-92a levels in cervical cancer tissues (P<0.01). In summary, the present study indicated that miR-92a promotes cell viability and invasion in cervical cancer, partly at least, via inhibiting the protein expression of DKK3. Therefore, the present study highlights the clinical significance of the miR-92a/DKK3 axis in cervical cancer. PMID- 28810583 TI - Kidney dysfunction following adrenalectomy in autosomal dominant polycystic kidney disease complicated with primary aldosteronism: A case report. AB - The present study reported a case of autosomal dominant polycystic kidney disease complicated with primary aldosteronism in a 49-year-old woman. The patient was referred for refractory hypertension. Laboratory examinations revealed low potassium and renin levels. Computed tomography indicated a right adrenal tumor and multiple renal cysts. Adrenal vein sampling revealed a high aldosterone level on the side of the tumor. The patient was diagnosed with autosomal dominant polycystic kidney disease complicated by primary aldosteronism and adrenalectomy was performed. Over the following 7 months, the estimated glomerular filtration rate decreased from 76 to 48 ml/min/1.73 m2, which was attributed to glomerular hyperfiltration correction induced by hyperaldosteronism remission, indicating kidney dysfunction. Clinicians must therefore monitor for the unmasking of kidney dysfunction following adrenalectomy in such cases. PMID- 28810584 TI - Evaluation of two-dimensional strain echocardiography for quantifying right ventricular function in patients with pulmonary arterial hypertension. AB - The aim of the current study was to evaluate the use of two-dimensional strain echocardiography (2DS) in quantifying right ventricular (RV) function in patients with pulmonary arterial hypertension (PAH). A total of 41 patients with PAH and 40 healthy control patients were recruited to the study. 2DS was used to determine the strain (epsilon) and strain rate (SR) of basal, middle and apical segments of the RV free wall. The aforementioned indicators were compared with measurements of RV function taken by conventional ultrasound and right heart catheterization. The epsilon and SR of all segments of the right ventricular free wall were significantly lower in the PAH group, as compared with the control group (P<0.05). In the PAH group, the epsilon and SR of the middle and apical segments were significantly lower compared with basal segments (P<0.01). The SR of the apical segments were positively correlated with the area and diameter of the right ventricular. The epsilon of the apical segments were positively correlated with RV area, diameter and systolic function. The epsilon and SR of apical segments were positively correlated with pulmonary artery pressure and pulmonary vascular resistance measured by right heart catheterization. These findings indicated that 2DS can accurately evaluate RV longitudinal systolic function. PMID- 28810585 TI - Glutamine promotes Hsp70 and inhibits alpha-Synuclein accumulation in pheochromocytoma PC12 cells. AB - Hsp70 regulates alpha-Synuclein (alpha-Syn) degeneration in Parkinson's disease (PD), indicating that Hsp70 promotion may be able to prevent or reverse alpha-Syn induced toxicity in PD. Additionally, it has been demonstrated that glutamine (Gln) enhances Hsp70 expression. In the present study, Gln-induced Hsp70 promotion in pheochromocytoma was investigated with reverse transcription- quantitative polymerase chain reaction and western blotting methods. Then it was observed whether heat shock factor (HSF)-1 was required for this phenomenon with an RNA interference strategy. The regulatory role of Gln on alpha-Syn degeneration was also determined in the alpha-Syn-overexpressed PC12 [PC12 (alpha Syn+)] cells, which were treated with or without the proteasomal inhibitor lactacystin (Lac). The results demonstrated that treatment with >=10 mM Gln significantly increased Hsp70 mRNA and protein levels (P<0.05) and that this promotion was HSF-1-dependent, as HSF-1 knockout with HSF-1-specific small interfering RNA abrogated Hsp70 promotion in PC12 (alpha-Syn+) cells. Furthermore, Gln treatment markedly upregulated alpha-Syn degeneration in PC12 (alpha-Syn+) cells, which was significantly reduced (P<0.05) in the presence of Lac. Therefore, the present study suggests that Gln is able to induce the promotion of Hsp70 expression in PC12 cells in an HSF-1-dependent manner and that Gln-mediated Hsp70 promotion may increase alpha-Syn degradation even in the presence of proteasomal inhibitor. Thus, glutamine may be a potential therapeutic agent to prevent alpha-Syn aggregation in PD. PMID- 28810586 TI - Worldwide research productivity in fracture surgery: A 10-year survey of publication activity. AB - Worldwide research contributions have allowed the field of fracture surgery to progress. However, to the best of our knowledge, no studies have documented the main characteristics of publications from different countries. The present study aimed to determine the quantity and quality of worldwide research in fracture surgery. The Web of Science database was searched to identify fracture articles published between 2005 and 2014. The contributions of countries were evaluated based on paper and citation numbers, and the research output of each country was adjusted according to population size. A total of 19,423 papers on the topic of fracture surgery were identified worldwide, and the total number of publications from 2005 to 2014 had significantly increased by 1.82-fold (P<0.001). The majority of papers (86.64%) were published by high-income countries (gross national income per capita >=$12,736), 13.25% by middle-income countries ($1,046 12,735) and 0.11% by low-income countries (<=$1,045). The United States contributed the highest number of publications (33.34%), followed by the United Kingdom (9.03%), Germany (8.42%), China (5.58%) and Japan (4.18%). Furthermore, the United States ranked first according to total citations (72,640). Articles from Sweden achieved the highest average citations per paper (15.63), followed by Australia (12.84) and Canada (12.44). When the number of publications were adjusted for population size, Switzerland was the first (56.39), followed by Austria (35.43) and the Netherlands (30.68). In conclusion, the number of publications in fracture surgery increased from 2005 to 2014, and the majority of fracture papers were published by high-income countries, while few papers were published by low-income countries. The United States was the most prolific country, but based on population size, a number of smaller countries in Europe may be relatively more prolific. PMID- 28810587 TI - Association of polycystic ovary syndrome with metabolic syndrome and gestational diabetes: Aggravated complication of pregnancy. AB - Polycystic ovary syndrome (PCOS) affects 5-20% of the reproductive age women globally. PCOS is diagnosed by the presence of hyperandrogenism, oligo anovulation, and polycystic morphology of at least one ovary. Insulin resistance (IR), hyperinsulinemia and associated metabolic abnormalities including metabolic syndrome play a significant role in the development of PCOS. The chances of developing MS in PCOS women was shown to increase by almost 14-fold in patients with increasing body mass index. Even in the absence of overt obesity, a preferential deposition of intra-abdominal fat is noted in PCOS women and this intra-abdominal fat leads to impaired insulin action and functional IR and hyperandrogenism. Functional ovarian hyperandrogenism of ovaries was suggested to be a consequence of IR, which activates androgen synthesizing enzyme, cytochrome p450-c17alpha-hydroxylase, in ovarian theca cells and causes elevated oxidative stress accompanied by lower antioxidant status in ovaries, which contribute to PCOS pathogenesis. The elevated levels of luteinizing hormone that accompany the early stages of hyperandrogenemia, accelerate ovarian functional deterioration, which is further aggravated by hyperinsulinemia, in PCOS women. The risk of developing gestational diabetes in PCOS women is approximately three times greater, as compared to non-PCOS women, due to IR and hyperinsulinemia. Typical insulin-sensitizing drugs such as metformin, have been used to curtail IR and hyperinsulinemia in pregnant PCOS women, with varying results indicating the complexity of the disease and the need for better controlled studies and additional efforts for PCOS-specific drug discovery. PMID- 28810588 TI - Chronic disorders of consciousness. AB - Over the last 20 years, studies have provided greater insight into disorders of consciousness (DOC), also known as altered state of consciousness. Increased brain residual functions have been identified in patients with DOC due to the successful application of novel next-generation imaging technologies. Many unconscious patients have now been confirmed to retain considerable cognitive functions. It is hoped that greater insight regarding the psychological state of patients may be achieved through the use of functional magnetic resonance imaging and brain-computer interfaces. However, issues surrounding the research and treatment of DOC remain problematic. These include differing opinions on the definition of consciousness, difficulties in diagnosis, assessment, prognosis and/or treatment, and newly emerging ethical, legal and social issues. To overcome these, appropriate care must be offered to patients with DOC by clinicians and families, as DOC patients may now be considered to live in more than just a vegetative state. The present article reviews the controversy surrounding the definition of consciousness and the reliability of novel technologies, prognostic prediction, communication with DOC patients and treatment methods. The ethical and social issues surrounding the treatment of DOC and future perspectives are also considered. PMID- 28810589 TI - Phenotypic switch in lung interstitial macrophage polarization in an ovalbumin induced mouse model of asthma. AB - Macrophage phenotype and function varies according to their polarized state, which in turn is dependent on microenvironmental stimuli. Under normal physiological conditions, lung interstitial macrophages that express interleukin (IL)-10 are considered to serve regulatory roles in the prevention of allergic reactions in the airways. However, the phenotypic profile of lung interstitial macrophages during the pathophysiology of asthma remains unknown. In the current study, the phenotypic characteristics of lung interstitial macrophages were investigated in an ovalbumin (OVA)-induced mouse model of asthma. The patterns of surface markers chemokine ligand and interleukin, and the metabolic enzyme activity of lung interstitial macrophages were investigated using flow cytometry analysis, reverse transcription-quantitative polymerase chain reaction, western blot analysis, and ELISA. It was observed that lung interstitial macrophages derived from OVA-induced asthmatic mice expressed phenotypic markers associated with alternatively activated macrophages (M2), including cluster of differentiation-206, transglutaminase 2, arginase (Arg) 1 and chemokine ligand (CCL)17/CCL22/CCL24 secretion. The M2 macrophages also exhibited increased levels of Arg1 activity and reduced levels of IL-10 expression, relative to macrophages derived from control mice. However, when evaluating the expression of markers associated with classically activated (M1) macrophages, namely inducible nitric oxide synthase and IL-12, it was observed that levels of M1 markers in the interstitial macrophages from asthmatic mice did not differ significantly to those in controls. Collectively, these data suggest that lung interstitial macrophages undergo a phenotypic switch from a regulatory macrophage phenotype under normal conditions to an alternative activation state in OVA-induced asthmatic mice. PMID- 28810590 TI - Diagnosis and surgical treatment of cervical macrocystic lymphatic malformations in infants. AB - The treatment of lymphatic malformations (LMs) represents a great clinical challenge. The present study reported on the treatment of 68 infants with cervical macrocystic LMs using surgical resection. The cases were retrospectively analyzed. All patients underwent pre-operative ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI) examinations. The surgery was performed under general anesthesia with endotracheal intubation. Ultrasonograms showed that 24 cases were monolocular, 44 were multilocular, 16 had no echo, 20 had a uniform low-level echo and 32 had a non-uniform low-level echo. CT showed non-enhancing low-attenuating cystic lesions and attenuation values of 10-45 HU. The magnetic resonance images of the LMs showed a low signal intensity on T1-weighted imaging (WI) and a high signal intensity on T2-WI. Complete resection was achieved in 56 patients, subtotal resection in eight and partial resection in four. Two complications were noted, including reversible paresis of the marginal mandibular branch of the facial nerve and a surgical-site infection. One patient in whom partial resection was achieved had recurrence at ~2 months after the surgery. Ultrasonography, CT and MRI clearly demonstrated the size, shape, extent and adjacent structures of LMs, which aided in surgical planning and assessment of potential risks. Surgical excision increased the chances of cure and was relatively safe for infants aged <1 year. Location and extent, rather than age, were determined to be the most important factors for successful surgical treatment. PMID- 28810591 TI - Dual character of flavonoids in attenuating and aggravating ischemia-reperfusion induced myocardial injury. AB - The concept that flavonoids exert cardioprotection against myocardial ischemia reperfusion (I/R) injury has been acknowledged by a large body of evidence. However, recent studies reported cardiotoxic effects of certain flavonoids, while the underlying mechanisms have remained largely elusive. Flavonoids have been demonstrated to activate aryl hydrocarbon receptor (Ahr), which is implicated in an array of cell signaling processes. The present study examined the cardioprotective roles of quercetin (Qu) and beta-naphthoflavone (beta-NF) against I/R injury and explored whether the underlying mechanism proceeds via molecular signaling downstream of Ahr. An oxygen glucose deprivation/reoxygenation (OGD/R) model of I/R was established in myocardial H9c2 cells in the absence or presence of Qu or beta-NF. Qu as well as beta-NF reversed OGD/R-induced overproduction of reactive oxygen species by increasing the anti oxidative capacity of the cells and protected them from lethal injury, as demonstrated by a decreased cell death rate, lactate hydrogenase leakage and caspase-3 activity as determined by flow cytometry, colorimetric assay and western blot analysis, respectively. Immunocytochemistry, co-immunoprecipitation and western blot assays collectively revealed that Qu and beta-NF engendered the translocation of Ahr from the cytoplasm into the cell nucleus, where binding of Ahr with the Ahr nuclear translocator (ARNT) blocked its binding to hypoxia inducible factor (HIF)-1alpha, which inhibited the cardioprotection of HIF 1alpha, including the induction of nitric oxide (NO) and inhibition of vascular endothelial growth factor (VEGF) production. Ahr knockdown recovered the binding of ARNT to HIF-1alpha and the generation of NO and VEGF. The results of the present study suggested a dual character of Qu and beta-NF in the process of myocardial I/R. PMID- 28810592 TI - Protective effect and mechanism of estrogen receptor beta on myocardial infarction in mice. AB - The protective effect and the mechanism of estrogen receptor beta (ERbeta) on myocardial infarction (MI) in mice were explored. A total of 12 female Tg-ERbeta transgenic mice and 12 non-transgenic littermate control (NLC) wild-type C57 mice were used for the present study. Both transgenic and wild-type mice had similar baseline data such as age, sex, and weight. The mouse model of MI was established by coronary artery ligation method, and the cardiac structure and function changes of the mouse were observed by ultrasonic echocardiography on days 1, 3 and 7 after the operation. RT-PCR method was used to detect the expression of collagen I, alpha-SMA, TGF-beta mRNA in the mouse heart, and Masson staining was used to detect cardiac fibrosis. At 3 days after operation, echocardiographic posterior wall thickness at end diastole (PWTD) and end systolic PWTS of Tg ERbeta mice were significantly reduced, and left ventricular systolic diameter and left ventricular diastolic diameter significantly increased (P<0.05) compared with NLC mice. The levels of expression of Tg-ERbeta cardiac tissue collagen I, alpha-SMA, TGF-beta mRNA were significantly lower than those in the NLC mice (P<0.05). In conclusion, Tg-ERbeta exerts a protective effect on MI. PMID- 28810593 TI - Carotid atherosclerosis promotes the progression of Alzheimer's disease: A three year prospective study. AB - Although cerebrovascular diseases have been considered as risk factors for cognitive decline and dementia, the associations between atherosclerosis and Alzheimer's disease (AD) have not been fully examined and remain controversial. The aim of this three-year prospective study was to investigate whether arotid artery atherosclerosis accelerates cognitive impairment in AD patients. The association of carotid intimal medial thickness (IMT) with prospective trajectories of cognitive function was assessed among 521 patients with light to moderate AD, and 437 AD patients were followed up annually for 3 years. Participants underwent initial carotid ultrasonography and repeated neuropsychological testing every year. Mixed-effects regression analyses were adjusted to estimate the effect of carotid IMT and other adjusting variables. The results of the present study indicated that carotid IMT was significantly associated with various measures of cognitive function. Furthermore, AD patients with higher carotid IMT values had a faster decline in cognitive scores in a variety of neuropsychological tests, particularly in verbal and non-verbal memory, semantic fluency and executive function. The present prospective study showed that carotid atherosclerosis is a predictive factor regarding the progression of cognitive impairment in AD patients, suggesting that early detection and treatment of vascular risk factors may prevent or at least postpone the evolution of the disease. PMID- 28810594 TI - Tissue-engineered sling with adipose-derived stem cells under static mechanical strain. AB - The implantation of a suburethral sling is an important treatment for stress urinary incontinence (SUI). However, the slings used current have a number of inherent limitations, such as tissue rejection and infection. The present study investigated the potential of engineering sling tissue in vitro using adipose derived stem cells (ADSCs). The ADSCs were obtained from Sprague-Dawley rats and were characterized in vitro. The ADSCs were seeded on polyglycolic acid (PGA) fibers that formed a scaffold with a shape mimicking a sling complex. The results demonstrated that following in vitro culture for 12 weeks under static strain, neo-sling tissue could be generated using ADSCs. With increasing culture time, the engineered neo-sling tissue exhibited a significant improvement in biomechanical properties, including maximal load and Young's modulus (P<0.05), and the tissue and collagen structures matured. Furthermore, differentiated ADSCs cultured under static strain were maintained their myoblast phenotype within the PGA scaffolds. These results indicate that ADSCs may serve as a novel cell source for tissue sling engineering and could improve treatment for patients with SUI. PMID- 28810596 TI - Expression of Kruppel-like factor 8 and Ki67 in lung adenocarcinoma and prognosis. AB - Kruppel-like factor 8 (KLF8) belongs to the KLF family and has various roles in the regulation of the cell cycle, proliferation and tumor genesis. KLF8 is overexpressed in gastric, ovarian, breast and renal cancer. Additionally, KLF8 may affect invasion and metastasis of tumors. However, whether KLF8 also acts as an ontogeny in lung adenocarcinoma (LAC) remains unknown. The aim of the present study was to determine the association between KLF8 expression and various clinical and pathological parameters. Western blot assays and immune histochemistry analyses revealed that KLF8 level in LAC tissues was higher than that in the normal lung tissues and KLF8 expression was significantly associated with clinical variables (P<0.05). Kaplan-Meier curves revealed that high expression of KLF8 was related to poor prognosis in patients with LAC. The present study also demonstrated that KLF8 was involved in the progression of lung adenocarcinoma. This data suggested that KLF8 may act as a prognostic factor in lung adenocarcinoma progression. PMID- 28810595 TI - SUDOSCAN, an effective tool for screening chronic kidney disease in patients with type 2 diabetes. AB - SUDOSCAN is a non-invasive method of measuring peripheral small fiber and autonomic nerve activity by detection of abnormal sweat gland function through electrochemical skin conductance. It has been reported to be an effective screening tool in early detection of microvascular type 2 diabetes mellitus (T2DM) complications including diabetic neuropathy and nephropathy in recent studies. However, previous studies used estimated glomerular filtration rate (eGFR) as the golden standard, which has a 90% chance of being within 30% of the measured GFR at best. No relevant study has been performed in the Chinese population concerning SUDOSCAN in the screening of diabetic nephropathy (DN) in comparison with GFR. In this cross-sectional study, SUDOSCAN was performed in 176 Chinese patients with T2DM between September 2014 and September 2015. It was found that the SUDOSCAN test had a sensitivity of 57.8% and a specificity of 100% to detect chronic kidney disease at a cut-off SUDOSCAN-DN score of 59.5. The area under receiver operating characteristic curve for DN was 0.85 [95% confidence interval (CI), 0.76-0.93] compared with 0.84 for eGFRMDRD (MDRD, modification of diet in renal disease; 95% CI, 0.71-0.98) and 0.77 for eGFREPI (EPI, epidemiology collaboration; 95% CI, 0.68-0.87). Patients with DN score <59.5 had a significantly lower GFR level (P<0.001) and significantly older age (P<0.001), longer duration of T2DM (P<0.001) and higher risk of diabetic complications, including diabetic neuropathy (P<0.001) and peripheral vascular disease (P<0.05). These results suggested that SUDOSCAN may be useful for detecting patients at risk of impaired renal function as part of a screening program in the Chinese population with T2DM. PMID- 28810597 TI - Dual inhibition of MET and SRC kinase activity as a combined targeting strategy for colon cancer. AB - Hepatocyte growth factor (HGF)/MET signaling is implicated in the development of colorectal cancer (CRC) and possesses therapeutic value for various types of cancer. However, inhibition of MET alone has been demonstrated to have limited efficacy. The present study examined the combined inhibition of MET and SRC kinase activity in colon cancer cells. Furthermore, the role of the HGF/MET pathway in ligand-dependent and -independent activation was demonstrated. The single inhibition of MET by knockdown small interfering RNA or inhibitor indicated a limited anti-viability effects without inhibiting the basal phosphorylation levels of SRC, protein kinase B (AKT) or extracellular signal regulated kinase (ERK). In view of the strong association between MET and SRC identified by direct regulation, growth factor-induced MET activation was suppressed by pretreatment with the SRC inhibitor, dasatinib, and downstream phosphorylation of AKT and ERK partially decreased, which suggested that SRC activation was essential for ligand-dependent and -independent activation of MET. Considering that both the activation of MET and SRC was required in ligand dependent and -independent MET activation, the antitumor effect of concurrent inhibition of MET and SRC was examined, and it was demonstrated that combination treatment exerted increased viability inhibition and apoptosis enhancement in mutant and wild type RAS colon cancer cells. Therefore, combinational inhibition of MET and SRC may be a promising strategy for the treatment of CRC. PMID- 28810598 TI - Differentially methylated regions in patients with rheumatic heart disease and secondary pulmonary arterial hypertension. AB - The aim of the present study was to identify differentially methylated regions (DMRs) in patients with rheumatic heart disease and secondary pulmonary arterial hypertension (RHD-PAH). A genome-wide DNA methylation assay was performed between 6 patients with RHD-PAH and 6 healthy controls using an Illumina Infinium HumanMethylation450 BeadChip kit. The Limma software package was subsequently used to identify significant DMRs. A total of 40 hypome-thylated and 64 hypermethylated CpG sites were identified between the RHD-PAH group and the control group. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes term and signaling pathway enrichment analyses revealed that the DMRs, mapped to the genes including protein kinase C alpha, protein kinase AMP-activated non-catalytic subunit gamma2, sprouty related EVH1 domain containing 2 and LIF interleukin 6 family cytokine, were significantly enriched in the negative regulation of protein kinase/transferase activity and the positive regulation of protein amino acid phosphorylation/phosphate metabolic process. The identified DMRs may provide novel insights into the pathogenesis of RHD-PAH. PMID- 28810599 TI - Effects of niflumic acid on gamma-aminobutyric acid-induced currents in isolated dorsal root ganglion neurons of neuropathic pain rats. AB - Niflumic acid (NFA) is a type of non-steroidal anti-inflammatory drug. Neuropathic pain is caused by a decrease in presynaptic inhibition mediated by gamma-aminobutyric acid (GABA). In the present study, a whole-cell patch-clamp technique and intracellular recording were used to assess the effect of NFA on GABA-induced inward current in dorsal root ganglion (DRG) neurons of a chronic constriction injury (CCI) model. It was observed that 1-1,000 umol/l GABA induced a concentration-dependent inward current in DRG neurons. Compared with pseudo operated rats, the thermal withdrawal latency (TWL) of CCI rats significantly decreased (P<0.01); however, the TWLs of each NFA group (50 and 300 umol/l) were significantly longer than that of the CCI group (P<0.01). In the CCI group, the response evoked by GABA (10-6-10-3 mol/l) was reduced in a concentration dependent manner compared with a normal control group (P<0.01), and the current amplitudes of CCI rats activated by the same concentrations of GABA (10-6-10-3 mol/l) were significantly decreased compared with the control group (P<0.05). The inward currents activated by 100 umol/l GABA were suppressed by treatment with 1, 10 and 100 umol/l NFA (5.32+/-3.51, 33.8+/-5.20, and 52.2+/-6.32%, respectively; P<0.05). The inverse potentials of GABA-induced currents were 9.87+/-1.32 and 9.64+/-1.24 mV with and without NFA, respectively (P<0.05). Pre-treatment with NFA exerted a strong inhibitory effect on the peak value of GABA-induced current, and the GABA-induced response was inhibited by the same concentrations of NFA (1, 10 and 100 umol/l) in the control and CCI groups (P<0.05). The results suggest that NFA reduced the primary afferent depolarization (PAD) associated with neuropathic pain and mediated by the GABAA receptor. NFA may regulate neuropathic pain by inhibiting dorsal root reflexes, which are triggered PAD. PMID- 28810600 TI - Ethanol extract of gardenia fruit alleviates renal interstitial fibrosis induced by unilateral ureteral obstruction in rats. AB - Gardenia fruit has been used in traditional Chinese medicine for thousands of years. A previous study by the present authors indicated that the ethanol extract of gardenia fruits (EEG) primarily contains eight constituents. In the present study, the potential effects of EEG on unilateral ureteral obstruction (UUO) induced renal interstitial fibrosis were observed in rats. A total of 30 rats were randomly divided into three groups (n=10 each): Sham group, UUO group, and EEG group, which were administered with EEG (200 mg/kg/day) or the same volume of distilled water as a vehicle. UUO were established by ligating left ureter at two points and cut between the ligatures. All rats were sacrificed at 14 days after UUO operation. the present results demonstrated that EEG significantly elevated the expressions of vascular endothelial growth factor and E-cadherin induced by UUO (both P<0.05), and reduced levels of hypoxia-inducible factor-1alpha, transforming growth factor-beta1, connective tissue growth factor and alpha smooth muscle actin (all P<0.05). The present findings suggest that EEG is a potential novel renoprotective compound for renal fibrosis through inhibiting epithelial-to-mesenchymal transition. PMID- 28810602 TI - Hepatitis C virus-associated cryoglobulinemia with membrano-proliferative glomerulonephritis treated with prednisolone and interferon: A case report. AB - Hepatitis C virus (HCV) is a major cause of liver-associated morbidity and has an increasing prevalence worldwide. Hepatitis C virus infection may lead to chronic hepatitis, cirrhosis and liver failure. However, it is also associated with a wide range of extra-hepatic complications, such as cryoglobulinemia, an immune complex disease associated with cryoglobulin leading to multiple organ damage and, while the major symptom is vasculitis. The present study reported on a-58 year-old woman who was diagnosed with HCV-associated cryoglobulinemia with skin, kidney and blood system damage and biopsy-proven cryoglobulinemia membrano proliferative glomerulonephritis. HCV RNA clearance occurred within a few weeks of interferon treatment and the patient was then treated by prednisolone and sustained interferon. While the therapeutic effect was obvious at first, the disease reappeared in combination with refractory infection and multiple organ failure, and the patient finally died. HCV-associated cryoglobulinemia is uncommon in developing countries such as China, while treatment guidelines remain to be established, particularly if complex complications are present. PMID- 28810601 TI - Comparative study of dendritic cells matured by using IL-1beta, IL-6, TNF-alpha and prostaglandins E2 for different time span. AB - Interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha and prostaglandins E2 is considered as the standard cocktail for maturing dendritic cells (DCs). However, the appropriate time span for DC maturation with the standard cocktail remains unclear. The present study aimed to compare the differences between DCs matured with the standard cocktail for 24 and 48 h, respectively, and determine whether 24-h stimulation was sufficient for DC maturation. The findings demonstrated that, compared with DCs matured for 48 h, the levels of cluster of differentiation (CD)80, CD83, CD86 and programmed death ligand 1 expression in DCs matured for 24 h were relatively lower. However, with the exception of CD80 whose mean fluorescence intensity (MFI) was higher in DCs matured for 48 h, the MFI values of other surface markers were comparable. Notably, the MFI of CD40 was higher in DCs matured for 24 h. In addition, the viability, T cell stimulatory capacity in allogeneic mixed lymphocyte reaction and cytokine production, including IL-12p40, IL-12p70 and IL-10, were all comparable between DCs matured for 24 and 48 h, respectively. These results indicated that 24-h stimulation may be sufficient for DC maturation when using the standard cocktail. PMID- 28810603 TI - Intratracheal administration of isosorbide dinitrate improves pulmonary artery pressure and ventricular remodeling in a rat model of heart failure following myocardial infarction. AB - Pulmonary hypertension due to left heart disease is associated with poor outcomes. This study investigated the beneficial effects of isosorbide dinitrate (ISDN) inhalation on pulmonary pressure and ventricular remodeling in a rat model of heart failure (HF) following myocardial infarction (MI). To assess the effect of ISDN on pulmonary pressure, 20 male Sprague-Dawley (SD) rats were randomized to four groups: Normal saline (NS) 1 ml/kg, ISDN 1 mg/kg, NS 3 ml/kg or ISDN 3 mg/kg following coronary ligation. Assessments included pulmonary and systemic artery pressure alterations, lung weight/body weight and plasma nitric oxide (NO) concentration. To assess the effect of ISDN on ventricular remodeling, 30 SD rats were randomized to three groups: Sham surgery, MI-NS (intratracheal NS 3 ml/kg for 13 days following coronary ligation), and MI-ISDN (intratracheal ISDN 3 mg/kg for 13 days following coronary ligation). On day 15, all rats underwent echocardiogram and hemodynamic assessments. The area affected by MI was evaluated using microscopy and vascular endothelial growth factor (VEGF) expression was examined using immunohistochemistry. Plasma epinephrine, norepinephrine and brain natriuretic peptide (BNP) levels were assessed by ELISA. Intratracheal ISDN reduced pulmonary and systematic artery pressure without pulmonary edema when compared with NS. The reduction was associated with increased plasma NO levels. ISDN inhalation for 14 days reduced MI size and alleviated left and right ventricular remodeling following MI. These hemodynamic and morphological improvements were associated with decreased plasma epinephrine, norepinephrine and BNP levels, and an increased VEGF positive area at the border of MI region. In conclusion, intratracheal administration of ISDN was effective in improving ventricular remodeling and cardiac function in a rat model of HF following MI. PMID- 28810604 TI - Hard clam extracts induce atypical apoptosis in human gastric cancer cells. AB - Hard clams (HCs) are a nutritionally high-quality and popular seafood, and are established to be a potent antitumor food. The aim of the present study was to determine whether HC extracts induce apoptosis in the human gastric cancer cell line, AGS. In contrast with previously reported methods of extraction, crude extracts of HC were obtained by freezing and thawing and by a method free of hot water or organic solvents. The composition, quality and properties of the HC extracts were demonstrated to be stable since the extracts that were evaluated by capillary electrophoresis and HPLC analysis at different timepoints were similar. HC extracts also have an inhibitory effect against the survival of AGS cells. Treatment with HC extracts induced a marked sub-G1 DNA peak and reduced the expression of the anti-apoptotic genes BIRC5 and KPNA2. However, hallmarks of classical apoptosis such as DNA fragmentation and apoptotic body formation were not observed, indicating atypical apoptosis. Furthermore, it was revealed that HC extracts interrupted cell cycle progression in AGS cells through altered expression of six cell cycle-associated genes: CDC20, KPNA2, BIRC5, ANAPC2, CDKN1A and RB1. The present findings suggest that HC may contribute to a novel future anticancer agent. PMID- 28810605 TI - MicroRNA-19a promotes nasopharyngeal carcinoma by targeting transforming growth factor beta receptor 2. AB - MicroRNA (miR), a class of small non-coding RNA, function as key regulators in gene expression through directly binding to the 3' untranslated region of their target mRNA, which further leads to translational repression or mRNA degradation. miR-19a, a member of miR-17-92 cluster, has an oncogenic role in a variety of malignant tumors. However, the exact role of miR-19a in nasopharyngeal carcinoma (NPC) has not previously been studied. The present study aimed to investigate the function and mechanism of miR-19a in regulating the viability and invasion of NPC cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) data indicated that the expression levels of miR-17-92 cluster members (miR-17, miR-18a, miR-19a and miR-20a) were frequently increased in NPC tissues compared to the normal tissues. It was also demonstrated that miR-19a was significantly upregulated in NPC C666-1 cells compared to NP69 cells (P<0.01). Knockdown of miR 19a led to a significant decrease in the viability and invasion of NPC C666-1 cells (P<0.01), and induced increased protein expression levels of transforming growth factor beta receptor 2 (TGFbetaR2), which was further identified as a direct target gene of miR-19a by using a luciferase reporter assay. Overexpression of TGFbetaR2 also suppressed the viability and invasion of C666-1 cells, similar to the effects of miR-19a inhibition. Furthermore, knockdown of TGFbetaR2 reversed the suppressive effects of miR-19a inhibition on C666-1 cell viability and invasion, suggesting that the role of miR-19a in mediating cell viability and invasion is through directly targeting TGFbetaR2 in NPC cells. In addition, RT-qPCR data demonstrated that the mRNA expression level of TGFbetaR2 was markedly reduced in NPC tissues and C666-1 cells. In summary, the present study demonstrated an oncogenic role of miR-19a in NPC via mediation of TGFbetaR2. Therefore, miR-19a may be a potential therapeutic target for NPC. PMID- 28810606 TI - Aspergillus niger bloodstream infection in gastric cancer after common hepatic artery embolization: A case report. AB - The present case study reported on a 62-year-old male patient with gastric cancer associated Aspergillus (A.) niger bloodstream infection. The patient presented with massive hemorrhage in the gastrointestinal tract 3 months after total gastrectomy for gastric cancer. Conservative treatment consisting of blood transfusion to supplement blood volume loss was ineffective. Digital subtraction angiography indicated gastroduodenal artery bleeding. The first attempt of performing arterial embolization using gelatin sponges failed, while the second attempt of performing common hepatic artery embolization using gelatin sponges and micro-coil springs stopped the bleeding. Four weeks after angiography, the patient presented with the complication of A. niger bloodstream infection, which was cured using intravenous and oral voriconazole. Clinicians should be aware of the possibility of A. niger bloodstream infection after invasive operations in immunocompromised patients and apply timely antifungal treatment. PMID- 28810607 TI - Effects of low dose of ethanol on the senescence score, brain function and gene expression in senescence-accelerated mice 8 (SAMP8). AB - Accumulating epidemiological evidence suggests light to moderate alcohol intake reduces risk of several chronic diseases. However, there is limited information regarding the effects of low alcohol intake in animal studies. This study investigated the effect of low ethanol dosage on senescence-accelerated mouse (SAMP8), an animal model of aging and neurodegenaration. Male SAMP8 mice (11 weeks old) had free access to a commercial stock diet with drinking water containing 0, 1 or 2% (v/v) ethanol for 15 weeks. The total grading score of senescence in the 1%-ethanol group was, in large part, the lowest among the three groups. Analysis using the open-field test revealed a significant elevation (+77%, P<0.05) in the rearing activity (index of seeking behavior) in the 1% ethanol group, but not in the 2%-ethanol group. In addition, 2% ethanol elevated spontaneous locomotor activity (+75%, P<0.05), whereas 1% ethanol did not. Scrutiny of serum parameters indicated intake of 1% ethanol significantly decreased serum insulin levels (-13%, P<0.05), whereas 2% did not. Intake of 2% ethanol significantly elevated (2.5-fold, P<0.05) S100a8 mRNA (an inflammatory signal) in the brain, but that of 1% ethanol did not. Intriguingly, 1% ethanol intake remarkably elevated (10-fold, P<0.05) mRNA of brain alcohol dehydrogenase 1 (Adh1), which metabolizes lipid-peroxidation products and is involved in the synthesis of retinoic acid, a neuroprotective factor. Of note, 2%-ethanol intake did not exert this effect. Taken together, intake of 1% ethanol is likely to be beneficial for SAMP8 mice. PMID- 28810608 TI - Mechanism of microRNA-21 regulating IL-6 inflammatory response and cell autophagy in intervertebral disc degeneration. AB - This study investigated the mechanism of microRNA-21 in regulating IL-6 inflammatory response and cell autophagy in intervertebral disc degeneration. A total of 10 patients with lumbar disc herniation accompanied by nerve root pain (observation group) and 10 patients with lumbar burst fractures (control group) were selected. The nucleus pulposus tissues of the lesion were obtained during operation for cell culture. Real-time quantitative polymerase chain reaction (PCR) was used to detect the expression of microRNA-21. The ELISA method was used to detect the levels of IL-6, and type II collagen (Col II). Aggrecan and western blotting was used to detect autophagy-related gene 7 (ATG7) and microtubule associated protein 1 light chain 3 (LC3)-II/-I. As a result, the levels of microRNA-21 and IL-6 in the observation group were significantly higher than those in the control group, but the levels of Col II and aggrecan were significantly lower than those in the control group. The differences were statistically significant (P<0.05). The levels of ATG7 and LC3-II/-I in the observation group were significantly decreased (P<0.05). In conclusion, the expression of microRNA-21 is abnormally high in the nerve root pain of the lumbar intervertebral disc, which can increase the IL-6 inflammatory response and reduce the capacity of cell autophagy. PMID- 28810609 TI - Value of serum Mycoplasma pneumoniae immunoglobulin in the diagnosis of mycoplasma-related pneumonia in newborns. AB - Mycoplasma pneumoniae (M. pneumoniae) is an important pathogen of neonatal acquired pneumonia in newborns. Rapid and accurate diagnosis of M. pneumoniae infection is critical because timely antibiotic therapy can reduce drug overuse and prevent the development of bacterial resistance. Anti-M. pneumoniae immunoglobulin M (IgM) is an indicator of early infection that can persist for several months. Studies have shown that anti-M. pneumoniae IgA in adults is a reliable indicator of early M. pneumoniae infection. The aim of this study was to assess the association between M. pneumoniae IgA, IgM and IgG in mycoplasma associated pneumonia. We recruited 80 newborns with pneumonia with potency of serum M. pneumoniae IgM positive or two sera anti-M. pneumoniae IgG increased by 4-fold. The potency of serum M. pneumoniae IgA, IgM and IgG were detected. The initial positive rates of IgM and IgA in M. pneumoniae were 63.6 and 33.8%, respectively, after infection. The positive rate of IgM and IgA in M. pneumoniae increased to 97.5 and 56.3%, respectively, at one week after infection. Compared with anti-M. pneumoniae IgA, anti-M. pneumoniae IgM has higher sensitivity in the diagnosis of neonatal mycoplasma-associated pneumonia. Detection of two sera can more effectively improve the diagnostic accuracy. PMID- 28810610 TI - Microbial investigations in throat swab and tracheal aspirate specimens are beneficial to predict the corresponding endotracheal tube biofilm flora among intubated neonates with ventilator-associated pneumonia. AB - Ventilator-associated pneumonia (VAP) is a common nosocomial infection in neonatal intensive care units with high morbidity and mortality. Bacterial biofilm in the endotracheal tube (ET) provides a notable and persistent source of pathogens that may cause VAP, and thus is important for VAP detection. However, during intubation microbial investigations in ET, samples are unavailable due to the infeasibility of collecting ET samples during intubation of neonates. It is therefore of great importance to find alternative sources of samples that can help identify the ET biofilm flora. In the present study, the microbial signatures of throat swabs and tracheal aspirates were compared with ET biofilm samples from VAP neonates using 16S ribosomal RNA gene polymerase chain reaction, denaturing gradient gel electrophoresis (DGGE), cloning and sequencing. Sequences were assigned to phylogenetic species using BLAST. Microbial diversity and richness among the three types of specimens were compared based on their DGGE fingerprints, and taxonomic characteristics based on the BLAST results. The microbial richness and diversity of ET biofilms were similar to tracheal aspirate yet significantly different from throat swab samples (P<0.05). Compared with ET biofilms, the overall constituent ratio of microflora was significantly different in throat swab and tracheal aspirate samples (P<0.05). However tracheal aspirate samples were useful for predicting Staphylococcus sp. in ET biofilms with a sensitivity of 85.7% and a specificity of 83.3%. The sensitivity for the combination of tracheal aspirate and throat swab samples to detect Staphylococcus sp. in ET biofilms was 100%. The detection of Pseudomonas sp. in throat swabs assisted its identification in ET biofilms (sensitivity 33.3% and specificity 100%). The results of the present study suggest that microbial investigations in throat swab and tracheal aspirate samples are beneficial for identifying the ET biofilm flora. There may therefore be clinical applications of using substituent samples to identify pathogens in ET biofilms for VAP surveillance among intubated neonates. PMID- 28810611 TI - Three-dimensional spiral CT measurement of atlantal pedicle and its clinical application. AB - The study aimed to establish the safe placement area and corresponding entry angle of atlantal pedicle screw using axial computed tomography (CT) measurement of atlas, in order to guide the clinical operation. Spiral thin-slice CT scan of atlas and three-dimensional reconstruction of 38 patients were randomly selected. Screw placement space was defined as the distance between the tangent lines of entry channel on the atlantal cross section and inner edge of transverse foramen and outer edge of spinal canal. Before operation, spiral CT measurement was used to determine the safe placement area, and the pipeline dredge method was used to conduct the internal fixation of atlantal pedicle screw for 7 patients. In CT measurements, the width of pedicle was 9.15+/-2.57 mm, which could safely accommodate screws with the diameter of 3.5 mm. The safe placement area was located in posterior arch of atlas (18.35+/-2.86 to 25.26+/-1.76 mm) away from the posterior tubercle, the entry angle ranged from 9.09+/-7.45 degrees outward to 18.72+/-17.42 degrees inward, and the length of screw channel ranged from 26.20+/-2.69 to 27.04+/-2.51 mm. The width of the safe placement area was up to 6.91+/-7.66 mm, and the angle of inclination on cross section was up to 27.81+/ 10.32 degrees . In conclusion, we identified a safe placement area for atlantal pedicle screw, where the screw was implanted inwards and outwards according to different entry points within the safe placement area. The detailed preoperative image measurement, determination of safe placement area and individual screw placement were found to be the key to a successful surgery. PMID- 28810612 TI - Effect of OPG gene mutation on protein expression and biological activity in osteoporosis. AB - The effect of an osteoprotegerin (OPG) gene mutation was investigated on its protein expression and biological activity in osteoporosis. The pcDNA3.0-OPG plasmid or wild-type plasmid were transfected into HEK293 cells. Osteoclast tartrate-resistant acid phosphatase (TRAP) staining and counting were then performed, and the expression of genes related to osteoclast differentiation and activation were measured by RT-PCR. The wild-type or mutant-type OPG at concentrations of 0, 10, 20, 50 and 100 ng/ml were added respectively to RAW264.7 cells and incubated for 24 h. The viability of cells treated with the wild-type and mutant-type OPG at a concentration of 100 ng/ml was still over 99%, which indicated that the wild-type and mutant-type OPG at this concentration had no cytotoxic effect on RAW264.7 cells. The number of TRAP-positive cells decreased with increasing concentration of wild-type or mutant-type OPG. At the concentrations of 20, 50 and 100 ng/ml, the inhibitory effect of wild-type OPG was significantly higher than that of mutant-type OPG (p<0.05). Both mutant-type and wild-type OPG inhibited the bone resorption activity of osteoclasts, and the inhibitory effect of wild-type OPG was significantly higher than that of mutant type OPG at the concentrations of 20, 50 and 100 ng/ml (p<0.05). The levels of TRAP and RANK mRNA in the wild-type OPG treatment group were significantly lower than those in the control group, while the levels of TRAP and RANK mRNA in the mutant-type OPG treatment group were significantly lower than those in the wild type group (p<0.05). The genetic mutation did not affect the protein expression levels of OPG, but inhibited the normal activity of OPG. PMID- 28810613 TI - miR-127-5p promotes chondrogenic differentiation in rat bone marrow mesenchymal stem cells. AB - The effect and related mechanisms of miR-127-5p on the cartilage differentiation of rat bone marrow mesenchymal stem cells (BMSCs) was investigated. Rat BMSCs were generated and transfected with miR-127-5p, RT-PCR and Safranin O staining were used to detect the effect of miR-127-5p on the cartilage differentiation of rat BMSCs. Western blot analysis was used to detect the related mechanisms of miR 127-5p on the cartilage differentiation of rat BMSCs. Genes related to cartilage differentiation such as Sox9, collagen II and aggrecan were significantly increased in the group which were transfected with miR-127-5p, while collagen X, which was related to cartilage hypertrophy, was decreased in the miR-127-5p transfected group. Safranin O staining revealed that the expression of chondroitin sulfate was significantly increased in the group of miR-127-5p, than the miRNA control group. Western blot analysis showed that miR-127-5p transfection promoted the expression of Sox9, while decreased the expression of Runx2 of rat BMSCs. In conclusion, via increasing the expression of Sox9 and decreasing the expression of Runx2, miR-127-5p could promote cartilage differentiation and decrease cartilage hypertrophy of rat BMSCs. PMID- 28810614 TI - Evolution of correlation between Helicobacter pylori infection and autoimmune liver disease. AB - The present study was planned to evaluate correlation between Helicobacter pylori (HP) infection and autoimmune liver disease (AILD). A total of 60 patients diagnosed with AILD in Affiliated Hospital of Binzhou Medical College were continuously enrolled in the present study. HP infection was detected by 13C-urea breath test. The levels of anti-myeloperoxidase were tested by ELISA. The positive rate of anti-nuclear antibody (ANA), anti-mitochondrial antibody (AMA), anti-smooth muscle antibody (SMA) and anti-neutrophil cytoplasm antibody (ANCA) were tested by indirect immunofluorescence. The positive rates of anti mitochondrial antibody (AMA-M2), anti-liver-kidney microsomal antibody (LKM-1), anti-liver cytoplasm antibody I (LC-1) and anti-soluble liver antigen/liver pancreas antigen (SLA/LP) were tested by immunoblotting. Liver function indexes including alanine transaminase, aspartate transaminase, alkaline phosphatase and glutamyltransferase, were analyzed with a fully automatic biochemical analyzer. The levels of serum cytokine IFN-gamma, interleukin-6 (IL-6), IL-10 and tumor necrosis factor-alpha (TNF-alpha) were tested by ELISA. A total of 37 patients (61.67%) were observed to be HP-positive. MPO-positive rate, positive rate of ANA, AMA, SMA and ANCA and positive rate of AMA-M2, LKM-1, LC-1 and SLA/LP in patients with positive HP infection were significantly higher than those of patients with negative HP infection. On the other hand, the levels of liver function indices did not showed any significant differences among HP-positive cases or HP-negative cases. However, the levels of IFN-gamma, IL-6, IL-10 and TNF alpha in patients with positive HP infection were significantly higher than those of patients with negative HP infection. In conclusion, the positive infection rate of HP infection in patients with AILD is high and is closely associated with various positive immune antibodies as well as cytokine levels. PMID- 28810616 TI - Single-blinded, randomized, and controlled clinical trial evaluating the effects of Omega-3 fatty acids among septic patients with intestinal dysfunction: A pilot study. AB - Sepsis is a systemic inflammatory reaction, which is aggravated by aspects of the immune response that are thought to be inhibited by Omega-3 fatty acids. The aim of the present study was to determine if Omega-3 fatty acid could modulate immunological function and improve survival rate among septic patients with intestinal dysfunction. A total of 48 mechanically ventilated patients with intestinal dysfunction were included in this prospective, randomized and single blind clinical study. Patients were randomly divided into control (group A) and treatment groups (group B). The treatment protocol for all the participants followed the Sepsis Survival Campaign guidelines, and group B received total parenteral nutrition containing 100 ml of Omega-3 fatty acids (containing 10 g refined fish oil) per day in addition to the standard treatment applied in group A. Group B had a significantly lower mortality rate compared with group A (12.5 vs. 41.7%, P<0.05) during the 28-day follow-up. Group B also had lower Acute Physiology and Chronic Health Evaluation II scores (P<0.05) and lower Marshall scores (P<0.05) at day 7. In addition, group B had a higher ratio of T helper to inducer lymphocytes as well as a higher ratio of CD4 to CD8 lymphocytes (P<0.01 for both) than group A. It was concluded that Omega-3 fatty acids improved T helper/inducer and CD4/CD8 ratios, and may have reduced mortality, among septic patients with intestinal dysfunction. PMID- 28810617 TI - Multicomponent quantification of Astragalus residue fermentation liquor using ion chromatography-integrated pulsed amperometric detection. AB - Chinese medicine residues contain abundant cellulose and hemicellulose, which are potential renewable carbon sources for ethanol production. The aim of the present study was to develop a rapid and reliable method to evaluate the cellulose and hemicellulose utilization in Chinese medicine residues. In the present study, key hydrolysates (arabinose, galactose, glucose, xylose, and cellobiose) of the cellulose and hemicellulose in fermentation liquor of Astragalus residues were simultaneously quantified by ion chromatography using an integrated pulsed amperometric detector (IPAD). HPLC analysis was performed on a Dionex ICS-2500 equipped with GP50 gradient pump and ED50 IPAD. The working and reference electrodes were gold electrode and Ag/AgCl electrode, respectively. Separation was achieved on serial no. 002627 Dionex Analytical column (2*250 mm). Sodium hydroxide of 250 mM and water were used as the mobile phase with a flow rate of 0.2 ml/min. The temperature of column was kept at 30 degrees C. This method was validated for accuracy and precision. The regression equation revealed a good linear relationship (R2=0.9959-0.9984) within the test ranges. The limits of detection and quantification for five standard analytes (arabinose, galactose, glucose, xylose and cellobiose) were in the range of 0.067-0.091 and 0.08-0.23 mg/l, respectively. The method showed good reproducibility for the quantification of five analytes in fermentation liquor of Astragalus residue with intra-and inter-day variations less than 3.843%. PMID- 28810615 TI - Detecting serum and urine metabolic profile changes of CCl4-liver fibrosis in rats at 12 weeks based on gas chromatography-mass spectrometry. AB - Liver fibrosis is caused by liver injury induced by a number of chronic liver diseases, including schistosome infection, hepatitis infection, metabolic disease, alcoholism and cholestasis. The tissue damage occurring after injury or inflammation of the liver is a reversible lesion; however, liver fibrosis has become a worldwide problem and poses a threat to human health. The development of an effective drug for the prevention and treatment of liver fibrosis is ongoing and uses information from different occurrences of liver fibrosis. In the present study, carbon tetrachloride (CCl4)-induced metabonomic changes in serum and urine at 12 weeks were analyzed using gas chromatography-mass spectrometry (GC/MS) to investigate potential biomarkers. Liver fibrosis was induced in rats by subcutaneous injections of CCl4 twice a week for 12 consecutive weeks. Histopathological changes were used to assess the successful production of a CCl4 induced liver fibrosis model. Serum and urine samples from the two groups were collected at 12 weeks. The metabolic profile changes were analyzed by GC/MS alongside principal component analysis and orthogonal projections to latent structures. Metabolic profile studies indicated that the clustering of the two groups could be separated and seven metabolites in serum and five metabolites in urine were identified. In serum, the metabolites identified included isoleucine, L-malic acid, alpha-copper, carnitine, hippuric acid, glutaric acid and glucose. In urine 2-hydroxy butyric acid, isoleucine, N-acetyl-beta-alanine, cytidine and corticoid were identified. The present study demonstrated that the pathogenesis of liver fibrosis may be associated with the dysfunction of a number of metabolic pathways, including glucose, amino acid, P450, fatty acid, nucleic acid, water electrolyte and glutathione biosynthesis. Assessing potential biomarkers may therefore provide novel targets and theories for the innovation of novel drugs to prevent and cure liver fibrosis. PMID- 28810618 TI - Sivelestat sodium hydrate improves post-traumatic knee osteoarthritis through nuclear factor-kappaB in a rat model. AB - As a specific inhibitor of neutrophil elastase, sivelestat sodium hydrate has primarily been used in the treatment of acute lung injury caused by various factors since its approval in 2002. Sivelestat sodium hydrate also improves post traumatic knee osteoarthritis (KOA), although its underlying mechanisms of action have yet to be elucidated. The aim of the current study was to determine if sivelestat sodium hydrate improves post-traumatic KOA through nuclear factor (NF) kappaB in a rat model. Treatment with sivelestat sodium hydrate significantly inhibited the induction of structural changes and significantly increased the vertical episode count and ipsilateral static weight bearing of the joint in KOA rats (all P<0.01). Sivelestat sodium hydrate significantly inhibited tumor necrosis factor-alpha and interleukin-6 production, serum nitrite levels, inducible nitric oxide synthase protein expression and high mobility group box 1 (HMGB1) secretion in KOA rats compared with the model group (all P<0.01). Sivelestat sodium hydrate also significantly suppressed p50/p65 DNA binding activity and NF-kappaB and phosphorylated inhibitor of kappaB protein expression in the joints of KOA rats compared with the model group (all P<0.01). These results suggest that sivelestat sodium hydrate improves post-traumatic KOA through HMGB1 and NF-kappaB in rats. PMID- 28810620 TI - CCAAT enhancer binding protein beta has a crucial role in regulating breast cancer cell growth via activating the TGF-beta-Smad3 signaling pathway. AB - The aim of the present study was to examine the effect of CCAAT enhancer binding protein beta (C/EBPbeta) on human breast cancer cells. The plasmids pCDH C/EBPbeta and pLKO.1-shC/EBPbeta were constructed and were infected into MDA-MB 468 cells, to provide C/EBPbeta overexpressing and C/EBPbeta knockdown cells, respectively. Cell viability, cell cycle and apoptosis were observed by MTT assay and flow cytometry analysis. Protein expression levels of C/EBPbeta, TGF-beta1, P Smad3 and Smad3 were detected by western blotting. MTT assay showed that the absorbance of MDA-MB-468 cells in the pCDH-C/EBPbeta group was increased, whereas that in the pLKO.1-shC/EBPbeta group was decreased, compared with the respective control at 48 and 72 h. Flow cytometric analysis indicated that the percentage of cells in the G2 phase was significantly increased in the pCDH-C/EBPbeta group (P<0.05) and decreased in the pLKO.1-shC/EBPbeta group compared with the respective control group. The proportion of apoptotic cells was decreased in the pCDH-C/EBPbeta group and increased in the pLKO.1-shC/EBPbeta group compared with the controls. The scratch-wound assay revealed that MDA-MB-468 cells depleted of C/EBPbeta exhibited reduced motility compared with the control cells. Moreover, western blotting demonstrated that pCDH-C/EBPbeta increased transforming growth factor (TGF)beta1 and P-Smad3 protein expression and decreased Smad3 protein expression, whereas pLKO.1-shC/EBPbeta decreased TGFbeta1 and P-Smad3 protein expression and increased Smad3 protein expression levels. The present study demonstrated that C/EBPbeta has a crucial role in regulating breast cancer cell growth through activating TGF-beta-Smad3 signaling. These findings suggest that C/EBPbeta may be a potential therapeutic target for breast cancer; however, in vivo studies are required to confirm this. PMID- 28810619 TI - MicroRNA-503 suppresses cell proliferation and invasion in osteosarcoma via targeting insulin-like growth factor 1 receptor. AB - MicroRNAs (miRs) are a class of small non-coding RNAs and have key roles in various cancer types. Recently, miR-503 has been reported to act as a tumor suppressor in osteosarcoma. However, the detailed mechanism of the regulatory role of miR-503 in osteosarcoma cell proliferation and invasion has largely remained elusive. The present study found that miR-503 was significantly downregulated in osteosarcoma tissues compared to that in matched adjacent non tumorous tissues. In addition, the expression of miR-503 in osteosarcoma of T3-T4 stage was significantly lower when compared with that in T1-T2 stage samples. miR 503 was also downregulated in osteosarcoma cell lines (Saos-2, MG63, U2OS and SW1353), when compared with that in the normal osteoblast cell line hFOB. Overexpression of miR-503 significantly inhibited the proliferation and invasion of U2OS cells and decreased the protein levels of insulin-like growth factor 1 receptor (IGF-1R), which was further identified as a novel target of miR-503 by a luciferase reporter assay. Moreover, overexpression of IGF-1R eliminated the suppressive effects of miR-503 on the proliferation and invasion of U2OS cells, suggesting that miR-503 inhibits osteosarcoma cell proliferation and invasion by directly targeting IGF-1R. Furthermore, IGF-1R was significantly upregulated in osteosarcoma tissues compared with that in adjacent non-tumor tissues, as well as in osteosarcoma cell lines compared with that in hFOB cells. In addition, the expression levels of IGF-1R were inversely correlated to the miR-503 levels in osteosarcoma tissues, suggesting that the increased IGF-1R expression may be caused by the reduced expression of miR-503. In conclusion, the present study demonstrated that miR-503 suppresses cell proliferation and invasion in osteosarcoma via targeting IGF-1R and thus highlights the importance of miR 503/IGF-1R signaling in the malignant progression of osteosarcoma. PMID- 28810621 TI - Effect of isopsoralen on Smad7 in osteoblastic MC3T3-E1 cells. AB - The primary pathological change in postmenopausal osteoporosis (PM-OP) is bone collagen loss caused by estrogen depletion. Osteoblasts synthesize type I collagen, which composes the organic matrix of bone. Although isopsoralen stimulates osteoblastic cell proliferation and differentiation, transforming growth factor (TGF)-beta1 is an important cell signaling factor for stimulating collagen synthesis. To explore the association between isopsoralen and the synthesis of collagen in vitro, the molecular and biological association between isopsoralen and TGF-beta signaling was examined. (CAGA) 12-luciferase-reporter gene was used to measure TGF-beta1 signaling activity. Type I collagen was detected by semiquantitative reverse transcription polymerase chain reaction, and mothers against decapentaplegic homolog 7 (Smad7) protein expression levels were analyzed by western blotting. The expression of collagen in MC3T3-E1 cells stimulated with isopsoralen was significantly upregulated compared with the control groups (P<0.05). Conversely, isopsoralen significantly decreased Smad7 protein expression compared with the control groups (P<0.05). Moreover, it was observed that isopsoralen activates the TGF-beta1 signaling pathway and ultimately promotes collagen synthesis through inhibition of Smad7 protein expression. Therefore, isopsoralen is a potential target for the treatment of PM OP. PMID- 28810623 TI - Evaluation of heat shock protein (HSP-72) expression in retinal ganglion cells of rats with glaucoma. AB - The present study was planned to observe the expression of heat shock protein 72 (HSP72) in retina of rats in a glaucoma model. A total of 50 Wistar rats were randomly divided into the high intraocular tension group (glaucoma model) and the sham control (sham operation) group. Glaucoma rat models were created by application of electrocoagulation on at least three groups of veins, reduction of venous return of aqueous humor and by enhancement of intraocular tension at the same time; 1, 2, 3, 4 and 8 weeks after operation, the intraocular tension of rats was observed respectively, and the expression/distribution of HSP72 in retina was assessed by immunohistochemical detection. As a result, the high intraocular tension group was found with obviously increased intraocular tension of the right eyes after operation (P<0.05), which was stable after one week. It was observed that the positive expression of HSP72 in retina gradually increased significantly with increase in intraocular tension in the rat model of glaucoma in comparison to controls. Furthermore, retinal ganglion cells (RGCs) of rats from both groups were cultured respectively, for confirmation. It was observed that the expression levels of HSP72 in the high intraocular tension group were higher in comparison to the sham control group. In conclusion, the enhanced expression of endogenous HSP72 may play an important role in glaucomatous optic neuro-protection. PMID- 28810622 TI - Oral N-acetylcysteine for prophylaxis of contrast-induced nephropathy in patients following coronary angioplasty: A meta-analysis. AB - It is acknowledged that contrast-induced nephropathy (CIN) is a common cause of acute renal insufficiency after cardiac catheterization and affects mortality and morbidity. To date, it is unknown whether oral N-acetylcysteine (NAC) is able to prevent contrast-induced nephropathy (CIN) in patients undergoing coronary angioplasty. A meta-analysis of randomized controlled trials was performed to assess the effects of NAC in the prevention of CIN in patients following coronary angioplasty. A total of 19 studies published prior to January 2015 that investigated the efficacy of oral NAC for the prevention of CIN were collected from Medline, Cochrane and Embase databases and conference proceedings from cardiology and nephrology meetings. The primary point of investigation was CIN, and the secondary points were renal failure requiring dialysis, mortality and length of hospitalization. The meta-analysis was performed using fixed- or random effect models according to heterogeneity. Up to January 2015, 19 randomized placebo-controlled clinical trials met the inclusion criteria for the meta analysis, including 4,514 patients. The pooled data showed that oral NAC did not reduce the CIN incidence [relative risk 0.84, 95% confidence interval (CI) 0.65 1.10; P=0.20], without heterogeneity among trials (I2=29%). Thus, the present meta-analysis suggests that oral NAC therapy is not effective as an alternative treatment to prevent CIN in patients following angioplasty. Further high quality randomized clinical controlled trials are required to confirm the usage and availability of this treatment. PMID- 28810624 TI - High mobility group box 1 protein attenuates myocardial ischemia reperfusion injury via inhibition of the p38 mitogen-activated protein kinase signaling pathway. AB - The present study aimed to determine the effects of high mobility group box 1 protein (HMGB1) on myocardial ischemia reperfusion (I/R) injury in rats following acute myocardial ischemia and investigate the underlying molecular mechanisms of these effects. Male Wistar rats were randomly divided into the following groups (n=10/group): Sham operation; I/R; HMGB50 (50 ng/kg HMGB1 before I/R); HMGB100 (100 ng/kg HMGB1 before I/R); and HMGB200 (200 ng/kg HMGB1 before I/R). Serum cardiac troponin I (cTnI), interleukin (IL)-6 and tumor necrosis factor (TNF) alpha levels were subsequently measured. Myocardial levels of malondialdehyde (MDA) and superoxide dismutase (SOD) were also determined. Myocardial infarction size (IS) was determined by 2,3,5-triphenyltetrazolium chloride staining. Myocardial expression of hypoxia inducible factor (HIF)-1alpha and phosphorylated p38 mitogen-activated protein kinase (P-p38 MAPK) protein was measured using western blotting. The results demonstrated that HMGB1 significantly decreased serum levels of cTnI, IL-6 and TNF-alpha and myocardial IS in I/R rats compared with the sham group (all P<0.05). HMGB1 also significantly decreased and increased myocardial levels of MDA and SOD, respectively (both P<0.05). HMGB1 significantly increased myocardial expression of HIF-1alpha and decreased expression of P-p38 MAPK following I/R (both P<0.05). These effects of HMGB1 occurred in a dose-dependent manner. The results of the current study indicate that the cardioprotective effects of intravenous HMGB1 are associated with increased myocardial expression of HIF-1alpha via inhibition of P-p38 MAPK expression, leading to inhibition of the P-p38 MAPK signaling pathway. PMID- 28810625 TI - Inhaled corticosteroids improve lung function, airway hyper-responsiveness and airway inflammation but not symptom control in patients with mild intermittent asthma: A meta-analysis. AB - It remains controversial whether inhaled corticosteroid (ICS) should be used in patients with intermittent asthma. The present study aimed to assess the effect of ICS compared with placebo or other therapies in patients with intermittent asthma. Medline, Embase and CNKI databases were searched up to June 2016 and a meta-analysis was conducted. The findings demonstrated that in adult patients, when compared with placebo, ICS increased forced expiratory volume in 1 sec FEV1 [standardized mean difference (SMD), 0.51; 95% confidence interval (CI), 0.22 0.80] and alleviated airway hyper-responsiveness, which was indicated as log transformed PC20FEV1 (concentrations of methacholine when there was a fall in FEV1 >=20%; SMD, 0.87; 95% CI, 0.60 to 1.14). ICS also reduced fractional exhaled nitric oxide (FeNO) levels [weighted mean difference (WMD), -12.57 parts per billion (ppb; a unit of NO concentration in exhaled air); 95% CI -15.88 to -9.25 ppb]. However, symptom scores did not change after ICS treatment (SMD, -0.26; 95% CI, -0.52 to 0). When compared with leukotriene receptor antagonists (LTRA), ICS had no advantage in increasing FEV1 (WMD, 0.04 l; 95% CI, -0.06 to 0.13 l), reducing sputum eosinophil percentage (WMD, -6%; 95% CI, -12.38 to 0.38%) or symptom scores (SMD, 0.44; 95% CI, -0.02 to 0.9). However, in child patients, ICS significantly (P<0.05) increased the possibility of symptom control when compared with placebo [relative risk (RR), 8; 95% CI, 1.04 to 61.52] or LTRA (RR, 2.67; 95% CI, 0.39 to 18.42). In conclusion, ICS improves lung function and alleviates airway hyper-responsiveness and airway inflammation but cannot influence symptom scores, and has no advantage over LTRA in terms of lung function improvement and airway inflammation control in adult patients with mild intermittent asthma. However, in children, the benefit of ICS in symptom control is more significant than with LTRA. PMID- 28810626 TI - Expression of synovial fluid biomarkers in patients with knee osteoarthritis and meniscus injury. AB - In the present study, the levels of synovial fluid biomarkers of patients with knee osteoarthritis (OA) and those with meniscus injury (MI) were compared to associate the levels of synovial fluid biomarkers with the degree of OA and MI. Synovial fluid samples were obtained from 51 cases with OA and 40 patients with MI. Severity of OA and MI were evaluated using the Kellgren-Lawrence (K-L) classification and Magnetic Resonance Imaging Osteoarthritis Knee Score, respectively. A comparative analysis of the levels of matrix metalloproteinase-13 (MMP-13), vascular endothelial growth factor (VEGF), interleukin (IL)-10, IL-8, IL-6, IL-1, tumor necrosis factor-alpha (TNF-alpha), as well as collagenase 2 in synovial fluid was made between patients with OA and MI. We found that synovial fluid levels of VEGF and IL-6 were significantly higher in patients with OA than in patients with MI, and IL-10 was lower in patients with OA compared to MI patients (p<0.05). After adjusting for sex, course of disease, and surgical history, no significant associations between K-L scores and biomarker levels were found for patients with OA. In the MI patients, TNF-alpha was significantly associated with magnetic resonance imaging (MRI) score. In conclusion, patients with knee OA and MI have different patterns of biomarker expression in their synovial fluid. PMID- 28810627 TI - Carthamin yellow inhibits matrix degradation and inflammation induced by LPS in the intervertebral disc via suppression of MAPK pathway activation. AB - Carthamin yellow (CY), which is a flavonoid compound isolated from safflower, has various pharmacological effects including promoting blood circulation to remove blood stasis and alleviating pain. CY is a herb used in Chinese traditional medicines. Intervertebral disc degeneration (IDD) is a common spinal disorder and degeneration of nucleus pulposus (NP) cells and inflammation are significant parts of the pathological cascade. The curative effect of CY on NP cells in association with degeneration and inflammation remains to be elucidated. In the present study, rat NP cells were isolated, cultured and used to detect the suppressive effects of CY on lipopolysaccharide (LPS)-induced genetic expression variation and the expression of matrix degradation enzymes, including matrix metallopeptidase-3, ADAM metallopeptidase with thrombospondin type 1 motif (ADAMTS)-4 and ADAMTS-5. A protective effect of CY on NP cells was observed against LPS-induced matrix degradation and inflammation. Western blotting results demonstrated that pretreatment with CY significantly suppressed the LPS-induced activation of the mitogen activated protein kinase (MAPK) pathway. The results of the present study suggested that CY exerted anti-degenerative and anti inflammatory effects on NP cells via inhibition of MAPK pathway activation. Therefore, CY may be a potential therapeutic drug for the treatment of IDD in the future. PMID- 28810628 TI - Use of aerosol inhalation treatment with budesonide and terbutaline sulfate on acute pediatric asthmatic bronchitis. AB - The use of oxygen-driven aerosol inhalation therapy with budesonide (suspension) and terbutaline sulfate for the treatment of pediatric asthmatic bronchitis was studied. Sixty pediatric patients diagnosed with asthmatic bronchitis in Xuzhou Children's Hospital during the period comprising April 2013 to December 2015 were enrolled in the study. After randomly dividing the patients into a control (conventional dexamethasone drip) and a treatment group (inhalation of budesonide with terbutaline sulfate) of 30 patients each, the symptoms were treated using antibiotics when necessary. The results of our evaluation showed the overall effective rate of treatment in the control group was 73.33% (40% with marked improvement, 33.33% with some improvement and 26.67% with no improvement) and that in the treatment group was 96.67% (73.73% with marked improvement, 23.33% with some improvement and only 3.33% with no improvement) with a statistically significant difference (p<0.05). The pulmonary functions of all pediatric patients showed no statistically significant differences in the pulmonary function indexes between the two groups before treatment (p>0.05). However, the differences in FEV1, FVC, FEV1/FVC and PEF between control and treatment groups before and after treatment were statistically significant (p<0.05), with overall improvement being higher in the treatment group. Finally, the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level in patients of the two groups improved significantly after treatment (p<0.05). The ESR and CRP level in the treatment group were improved to a higher degree than those in the control group (p<0.05). There were only minor adverse reactions in two patients in the treatment group, and the overall rate of adverse reactions was not significantly different between the two groups (p>0.05). Based on our evaluation the aerosol inhalation therapy of budesonide (suspension) with terbutaline sulfate has definite curative effects and is safe to use on pediatric asthmatic bronchitis patients. The approach is superior to the conventional dexamethasone treatment and is worth studying in larger populations for recommending it widely. PMID- 28810629 TI - Inhibition of microRNA-34a ameliorates murine collagen-induced arthritis. AB - Rheumatoid arthritis (RA) is one of the most frequently occurring autoimmne diseases, with symptoms including synovium hyperplasia, immune disorder, cartilage damage and bone resorption. It has previously been demonstrated that microRNA-34a (miR-34a) may participate in cell apoptosis, immune activation and bone metabolism, therefore the present study investigated the effects of miR-34a on RA. Collagen-induced arthritic (CIA) mice were employed as a murine model of experimental arthritis, and it was demonstrated that the level of miR-34a in the spleens, lymph nodes and synovium was increased in the CIA mice compared with normal DBA/1j mice. Administration of miR-34a antagomir, the chemically modified inhibitor, ameliorated CIA and delayed the onset of symptoms. Arthritis scores decreased and joint swelling was alleviated with the miR-34a antagomir treatment and the expression of inflammatory cytokines was decreased. miR-34a antagomir delivery significantly decreased the percentage of T cells present including T helper (Th) 1, Th2, Th17 and regulatory T cells. Furthermore miR-34a antagomir treated CIA mice demonstrated decreased inflammatory-induced bone loss. Overall, it was observed that inhibition of miR-34a ameliorated murine arthritis, downregulated T cell percentage and cytokine expression, and suppressed bone loss. The experimental results suggest that inhibition of miR-34a may offer a novel alternative for the treatment of RA. PMID- 28810630 TI - Selective depletion of cultured macrophages by magnetite nanoparticles modified with gelatin. AB - Previous studies have indicated pro-tumor functions of macrophages in tumor progression in different types of malignant tumors. The detailed mechanisms of cell-cell interaction between macrophages and tumor cells have been investigated by means of in vitro co-culture experiments. The present study developed magnetite nanoparticles modified with gelatin that are specifically engulfed by macrophages and investigated methods to deplete these macrophages in co-culture experiments using a magnet. T98G glioma cell line and human monocyte-derived macrophages were mixed and co-cultured for 2 days. The T98G cells were isolated by depletion of the macrophages using the magnetite nanoparticles. mRNA expression of a number of pro-tumor molecules in the isolated T98G cells, with or without co-culture with macrophages, was then evaluated. The mRNA expression levels of chemokine (CC motif) ligand 2, interleukin-6 and macrophage-colony stimulating factor receptor (M-CSFR) were significantly upregulated in T98G cells by co-culture with macrophages (P<0.01). M-CSFR protein expression was also increased by co-culture with macrophages. The conditioned medium of co-cultured cells increased M-CSFR expression in T98G cells. Magnetite nanoparticles may be a novel tool not only for investigating the unique activation status of tumor cells in co-culture conditions, but also for targeting pro-tumor macrophages in tumor tissues. PMID- 28810631 TI - Hyperoside inhibits biofilm formation of Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa (P. aeruginosa) is a common pathogen in hospital-acquired infection and is readily able to form biofilms. Due to its high antibiotic resistance, traditional antibacterial treatments exert a limited effect on P. aeruginosa biofilm infections. It has been indicated that hyperoside inhibits P. aeruginosa PAO1 (PAO1) biofilm formation without affecting growth. Therefore, the current study examined the biofilm formation and quorum sensing (QS) system of PAO1 in the presence of hyperoside. Confocal laser scanning microscopy analysis demonstrated that hyperoside significantly inhibited biofilm formation. It was also observed that hyperoside inhibited twitching motility in addition to adhesion. Data from reverse transcription-quantitative polymerase chain reaction indicated that hyperoside inhibited the expression of lasR, lasI, rhlR and rhlI genes. These results suggest that the QS-inhibiting effect of hyperoside may lead to a reduction in biofilm formation. However, the precise mechanism of hyperoside on P. aeruginosa pathogenicity remains unclear and requires elucidation in additional studies. PMID- 28810632 TI - A novel antitumor compound nobiliside D isolated from sea cucumber (Holothuria nobilis Selenka). AB - An anticancer compound, triterpene glycoside, was isolated from Holothuria nobilis Selenka. Its chemical structure and configuration were determined by two dimensional nuclear magnetic resonance spectroscopy and electrospray ionization mass spectrometry. The novel active compound was identified as nobiliside D, with the molecular formula C40H61O17SNa and chemical name 3-O-[-beta-D-pyranosyl (1-2) 4'-O-sulfon-ate-beta-D-xylopyranosyl]-alkoxy-9-ene-3beta, 12alpha, 17alpha, 25beta-4 alcohol. An antitumor test was performed using xCELLigence Real-Time Cell Analysis. Nobiliside D exhibited inhibitory effects on human leukemic cell line K562, human leukemia cell line U937, human lung cancer cell line A-549, human cervix carcinoma cell line HeLa, human breast cancer cell line MCF-7 and human liver carcinoma cell line HepG2. Nobiliside exhibited the greatest inhibitory effect on K562 and MCF-7 cells with an IC50 of 0.83+/-0.14 and 0.82+/ 0.11 ug/ml, respectively. When human tumor cell lines K562 and MCF-7 were treated by nobiliside D (0.5 ug/ml) for 24 h, 45.8% of K562 cells and 58.7% of MCF-7 cells were apoptotic, whereas only 0.5% of un-treated control cells were apoptotic. These data indicate the compound should offer potential as a novel drug for the treatment of a range of cancers. PMID- 28810633 TI - Clinical significance of 5-(and 6)-carboxyfluorescein diacetate succinimidyl ester-labeled microspheres for detecting endothelial progenitor cells in human peripheral blood. AB - The aims of the present study were to establish a single-platform flow cytometry method using 5-(and 6)-carboxyfluorescein diacetate succinimidyl ester (CFSE) labeled microspheres as the reference for determining endothelial progenitor cell (EPC) number and to evaluate the efficacy of this detection method. Single platform flow cytometry was used to count cell numbers using CFSE-stained fluorescent microspheres as the internal reference and the EPC numbers in specimens using this novel method were compared with an in vitro clonogenic counting assay. The results of the two counting methods were consistent and compared with the in vitro clonogenic counting assay, the time and cost of the novel method was markedly reduced, as were the corresponding technical requirements. The present findings indicated that single-platform flow cytometry, with CFSE-labeled microspheres as the reference, provides faster and improved detection of EPCs in human peripheral blood specimens, with reduced time and cost, making it more suitable for routine clinical application. PMID- 28810634 TI - Misdiagnosis of a cloacal exstrophy variant as urorectal septum malformation in a fetus by ultrasound: A case report. AB - Cloacal exstrophy variants are comprised of a wide range of characteristics, of which there are four primary features, including omphalocele, bladder exstrophy, an imperforate anus and spina bifida. The existing literature regarding the differential diagnosis from alternative urinary diseases prenatally are limited. If the bladder is present, defects in the ventral wall may not be visualized with prenatal ultrasound in certain conditions, including oligohydramnios, and differential diagnosis from urorectal septum malformation sequence is a challenge. In order to improve the diagnosis of cloacal exstrophy variants, the present study investigated the misdiagnosis of a cloacal exstrophy variant as a urorectal septum malformation in a fetus by ultrasound and analyzed the reasoning of diagnosis in detail. PMID- 28810635 TI - Curcumin protects against acute renal injury by suppressing JAK2/STAT3 pathway in severe acute pancreatitis in rats. AB - The aim of the present study was to investigate the effect of curcumin on acute renal injury in a rat model of severe acute pancreatitis (SAP). A SAP model with acute kidney injury was established in rats by retrograde injection of 5% sodium taurocholate into the pancreatic duct. The serum amylase, creatinine (Cr) and blood urea nitrogen (BUN) levels in rats were measured. Hematoxylin and eosin staining was used to assess pancreatic and renal histological changes. Serum tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 levels were measured using ELISA kits. Renal protein levels of Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3 pathway components were determined by western blot assay. The results showed that curcumin significantly decreased serum amylase, Cr and BUN levels, and alleviated pancreatic and renal histological changes in SAP rats. Furthermore, curcumin markedly decreased serum TNF-alpha and IL-6 levels and downregulated renal protein levels of JAK2/STAT3 pathway components. These results proved that curcumin ameliorates acute renal injury in a rat model of SAP. The molecular mechanism of its effect may be associated with the suppression of the JAK2/STAT3 pathway to reduce TNF-alpha and IL-6 levels in SAP-induced acute renal injury. Therefore, the findings of the present study revealed the potential use of curcumin for the prevention and treatment of SAP and the associated renal injury. PMID- 28810636 TI - Necessity of heparin for maintaining peripheral venous catheters: A systematic review and meta-analysis. AB - Heparin has typically been used as a flushing or infusion solution for vascular lines in daily practice. However, several clinical trials have yielded controversial results about the benefits of heparin in maintaining peripheral venous catheters. The present meta-analysis was conducted to evaluate the efficacy of heparin on the patency profiles and complications in peripheral intravenous catheters. PubMed, Embase and Cochrane Central Register of Controlled Trials were searched up to February 2016 for randomized controlled trials comparing heparin with placebo in maintaining peripheral intravenous catheters. Additional studies were retrieved from the reference lists of identified articles. In total 32 eligible studies were included, from which the pooled standard mean difference (SMD), relative risk (RR) and corresponding 95% confidence interval (CI) were calculated. The use of heparin as a continuous infusion significantly prolonged the duration of patency (SMD, 0.90; 95% CI, 0.48 1.32; P<0.001), reduced rates of infusion failure (RR, 0.83; 95% CI, 0.76-0.92; P<0.001) and occlusion (RR, 0.82; 95% CI, 0.69-0.98; P<0.05) in a peripheral intravenous catheter. However, there were no significant changes in the duration of patency and infusion failure when heparin was used intermittently as a flushing solution, although a significantly decreased risk of occlusion was observed in this setting (RR, 0.80; 95% CI, 0.66-0.98; P<0.05). Furthermore, the risk of phlebitis was significantly decreased by both continuous infusion (RR, 0.66; 95% CI, 0.58-0.75; P<0.01) and intermittent flushing (RR, 0.70; 95% CI, 0.56-0.86; P<0.01) of heparin in peripheral venous catheters. In conclusion, the use of heparin as continuous infusion in peripheral intravenous catheters improved the duration of patency, reduced infusion failure and phlebitis, whereas heparin as intermittent flushing showed more benefits in ameliorating phlebitis rather than in patency profiles. PMID- 28810637 TI - Binding of LINE-1 RNA to PSF transcriptionally promotes GAGE6 and regulates cell proliferation and tumor formation in vitro. AB - Hepatocellular carcinoma (HCC) has one of the highest mortality rates among numerous types of cancer. It has been demonstrated that in hepatitis B (HBV) associated HCC, the expression of chimeric fusion transcript HBx-long interspersed nuclear element-1 (LINE-1) initiated by HBV integration is correlated with hepatocarcinogenesis and poor patient survival rates. Furthermore, increased rates of LINE-1 hypomethylation have been detected in HCC tissues compared with adjacent tissues. This suggests that individual LINE-1 RNA (L1 RNA) serves an important role in the processes of hepatocarcinogenesis. The present study assessed the epigenic interaction between L1 RNA and polypyrimidine tract-binding protein-associated splicing factor (PSF) in the A549 human alveolar epithelial and 16HBE human bronchial epithelial cell lines. In addition, changes in the transcriptional regulatory activity of PSF on its target gene, proto oncogene G antigen 6 (GAGE6), were investigated following overexpression of L1 RNA, as well as its impact on cell-proliferative capacity, carried out by plotting cell growth curves and 5-ethynyl-2'-deoxyuridine assay. It was observed that L1 RNA specifically bound to the RNA binding domain of PSF and released the GAGE6 promoter region from the DNA-binding domain of PSF. This increased the transcription of GAGE6 and led to the promotion of cell proliferation as well as colony formation. Furthermore, at least two binding sites specific for PSF were identified on L1 RNA. In conclusion, the transcriptional regulatory activity of L1 RNA may partially result in cell transformation, and endogenous L1 RNA may function as an important regulatory factor in the process of tumorigenesis. PMID- 28810638 TI - MicroRNA differential expression spectrum and microRNA-125a-5p inhibition of laryngeal cancer cell proliferation. AB - The present study aimed to screen and analyze the differential expression spectrum of microRNA (miRNA) between laryngeal cancer tissue and surrounding normal laryngeal mucosa in order to provide an indication for further study to determine the role of miRNA in the initiation and development of laryngeal cancer. A total of 42 pairs of specimens of laryngeal carcinoma tissues and adjacent normal laryngeal mucosa were collected. A total of 10 pairs of specimens were randomly selected for miRNA microarray gene chip analysis, and the remaining 32 pairs of specimens were used for reverse transcription-quantitative polymerase chain reaction (RT-qPCR) verification to identify miRNA that were differentially expressed in laryngeal cancer tissues. Methylthiazolyldiphenyl-tetrazolium bromide and clone formation assays were utilized to elucidate the physiological relevance of the miRNA miR-125a-5p on the proliferation of laryngeal cancer human epithelial type 2 (Hep2) cells. Results demonstrated that the expression levels of six miRNA were significantly downregulated in laryngeal carcinoma tissue, as identified by gene chip analysis and RT-qPCR (P<0.05). The six miRNA included let 7f-5p, miR-10a-5p, miR-125a-5p, miR-144-3p, miR-195-5p and miR-203. Compared with the control group, the proliferative ability of laryngeal cancer Hep2 cells was inhibited in a transfected miR-125a-mimics group. In contrast, proliferation was promoted in a transfected miR-125a-inhibitor group. In conclusion, the results of gene chip analysis were consistent with that of RT-qPCR. Results demonstrated that miRNA in laryngeal cancer and normal laryngeal mucosa exhibited evident differential expression, which may contribute to the laryngeal cancer incidence and invasion. miR-125a was able to inhibit the proliferation of Hep2 laryngeal cancer cells and, therefore, may serve as a novel target for laryngeal cancer biological therapy. PMID- 28810640 TI - In-hospital and long-term outcomes of congestive heart failure: Predictive value of B-type and amino-terminal pro-B-type natriuretic peptides and their ratio. AB - Relative changes in B-type natriuretic peptide (BNP) and amino terminal pro-BNP (NT-proBNP) levels may help to assess the risk of congestive heart failure (CHF). However, whether these levels at the time of admission enable the prediction of outcomes with acute exacerbation remains unknown. The current study determined the abilities of BNP, NT-proBNP and their ratio to predict in-hospital and long term outcomes of patients with CHF. Patients who were admitted to the cardiac care unit of Juntendo University Hospital (Tokyo, Japan) with acute CHF onset were consecutively enrolled into the present observational study. Serum levels of BNP and NT-proBNP were immediately measured on admission, and other biomarkers and clinical data were also investigated. Of 195 enrolled patients, 16 (8.2%) succumbed to CHF in hospital and 124 (69.3%) reached the endpoint of mortality or readmission following a median follow-up of 14 months. Multiple linear regression analysis revealed body mass index, low density lipoprotein cholesterol, hemoglobin, estimated glomerular filtration rate and C-reactive protein as independent predictors of the NT-proBNP/BNP ratio. BNP, NT-proBNP and their ratio were significantly higher among those who succumbed to CHF than in those who remained alive in hospital (P<0.05). Logistic regression analysis indicated that the ratio was an independent predictor for in-hospital mortality and long-term outcomes. In conclusion, the ratio of NT-proBNP to BNP more effectively predicts in-hospital outcomes than either factor alone and it may also help to predict outcomes among patients with acute exacerbation of HF. PMID- 28810639 TI - MicroRNA-200b inhibits pituitary tumor cell proliferation and invasion by targeting PKCalpha. AB - The present study aimed to investigate the expression of miR-200b and protein kinase Calpha (PKCalpha) in pituitary tumors and to determine whether miR-200b may inhibit proliferation and invasion of pituitary tumor cells. The regulation of PKCalpha expression was targeted in order to find novel targets for the treatment of pituitary tumors. In total, 53 pituitary tumor tissue samples were collected; these included 28 cases of invasive pituitary tumors and 25 cases of non-invasive tumors, in addition to 5 normal pituitaries. The expression level of miR-200b in the pituitary tumor tissue was detected by quantitative polymerase chain reaction (qPCR) and the expression of PKCalpha protein was detected by immunohistochemistry. A PKCalpha 3'untranslated region (UTR) luciferase vector was constructed and a dual luciferase reporter gene assay was employed in order to examine the effect of miR-200b on the PKCalpha 3'UTR luciferase activity. AtT 20 cells were transfected with miR-200b mimics, PKCalpha siRNA and miR-200b mimics + PKCalpha, and the changes in cellular proliferation, invasion and apoptosis were observed via MTT, Transwell assay and flow cytometric analysis. Furthermore, PKCalpha mRNA expression was determined by qPCR, and Western blotting was performed to detect the expression of PKCalpha protein. miR-200b revealed downregulation in invasive pituitary tumor tissue, and the expression level was significantly down-regulated compared with normal and non-invasive pituitary tumor tissue (P<0.01). In addition, the positive rate of PKCalpha protein expression in invasive pituitary tumor tissues was significantly higher than in normal and non-invasive tissues (P<0.01). PKCalpha protein levels are inversely correlated with miR-200b levels in invasive pituitary tumor tissues (r= 0.436, P=0.021). The dual luciferase reporter gene assay revealed that miR-200b could specifically bind to the 3'UTR of PKCalpha and significantly inhibit the luciferase activity by 39% (P<0.01). Upregulation of miR-200b or downregulation of PKCalpha could suppress cell proliferation and invasion, and increase apoptosis of AtT-20 cells. It was revealed that PKCalpha siRNA could suppress both proliferation and invasion of AtT-20 cells and partially simulate the function of miR-200b. Expression of PKCalpha mRNA and protein decreased significantly in AtT-20 cells overexpressing miR-200b. Additionally, miR-200b was significantly down-regulated in invasive pituitary tumor tissue and inversely correlated with PKCalpha protein levels. In conclusion, miR-200b inhibited proliferation and invasiveness and promoted the apoptosis of pituitary tumor cells by targeting PKCalpha. The observations of the present study indicate that miR-200b and PKCalpha may serve as promising therapeutic targets for invasive pituitary tumors. PMID- 28810641 TI - Allicin improves carotid artery intima-media thickness in coronary artery disease patients with hyperhomocysteinemia. AB - Homocysteine (Hcy) is an important and independent risk factor for atherosclerotic diseases, such as coronary artery disease and ischemic cerebrovascular disease. Increased carotid artery intima-media thickness (IMT) is a non-invasive marker of systemic atherosclerosis. Allicin treatment may decrease serum Hcy levels and improve impaired endothelial function in rats with hyperhomocysteinemia (HHcy). The present study hypothesized that allicin has an anti-atherosclerotic effect in coronary heart disease and tested the effects of allicin treatment on carotid artery IMT and plasma Hcy levels in coronary heart disease patients with HHcy. Sixty-two coronary heart disease patients with HHcy were randomly divided into an allicin group and a control group. All patients underwent diagnostic assessment, plasma Hcy assay, blood lipid measurement and B mode ultrasound of the carotid artery prior to and after treatment. Plasma Hcy levels were determined by high-performance liquid chromatography and fluorescence detection. Carotid artery IMT was calculated using an automated algorithm based on a validated edge-detection technique. After 12 weeks, significant decreases in carotid artery IMT, plasma Hcy levels, total cholesterol and triglycerides were observed in the allicin group (all P<0.05), and the decreases in the allicin group were significantly greater than those in the control group (all P<0.01). These findings suggested that reducing plasma Hcy levels may be useful for preventing the generation and development of atherosclerosis in patients with coronary heart disease. Allicin was able to decrease Hcy levels, total cholesterol and triglycerides as well as carotid artery IMT. PMID- 28810642 TI - Overexpressed eNOS upregulates SIRT1 expression and protects mouse pancreatic beta cells from apoptosis. AB - Loss of sirtuin 1 (SIRT1) activity may be associated with metabolic diseases, including diabetes. The aim of the present study was to investigate the potential effects of overexpressed endothelial nitric oxide synthase (eNOS) on cell proliferation and apoptosis with SIRT1 activation in the Min6 mouse pancreatic beta cell line. A pcDNA3.0-eNOS plasmid was constructed and transfected into Min6 cells for 24 h prior to harvesting. eNOS expression was validated and SIRT1 expression was detected following plasmid transfection using reverse transcription-quantitative polymerase chain reaction and western blot analysis, which demonstrated that the expression levels of eNOS and SIRT1 were significantly upregulated. Furthermore, the cell proliferation and cell apoptosis of the Min6 cells were evaluated, using a cell counting kit-8 assay and flow cytometry, respectively. The results suggested that overexpressed eNOS promoted cell proliferation and inhibited cell apoptosis in Min6 cells. The interaction between eNOS and SIRT1 was explored through co-immunoprecipitation, and it found that there was a strong interaction between eNOS and SIRT1. In conclusion, overexpressed eNOS may induce SIRT1 activation, which is implied to play a protective role in Min6 cells, and eNOS may be a new therapeutic target for diseases such as type 2 diabetes. PMID- 28810643 TI - Occludin downregulation in high glucose is regulated by SSTR2 via the VEGF/NRP1/Akt signaling pathway in RF/6A cells. AB - Occludin is a tight junction protein that forms the permeability barrier, which is typically disturbed in ischemic associated diseases. The aim of the present study was to determine whether somatostatin receptor 2 (SSTR2) in RF/6A cells is involved in the modulation of the downregulation of occludin induced by high glucose, and to evaluate the implicated molecules. RF/6A cells were maintained in Dulbecco's modified Eagle medium and treated with 0 or 30 mM D-glucose. SSTR2 agonist octreotide (OCT), OCT with SSTR2 antagonist cycle-somatostatin (c-SOM) and neuropilin 1 (NRP1) inhibitor ATWLPPR, respectively, were administered to RF/6A cells under high glucose conditions. Cell apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labeling. Western blot analysis was used to detect the protein expression level of SSTR2, occludin, vascular endothelial growth factor (VEGF), protein kinase B (Akt), phosphorylated Akt (p-Akt), extracellular signal-related kinases (ERK) and p-ERK proteins. The amount of VEGF released was determined by ELISA. Notably, the level of occludin reduced significantly under high glucose conditions. The results indicated that the administration of OCT prevented the reduction of occludin induced by high glucose, and co-administration with c-SOM reversed the effect of OCT. Increased VEGF secretion and expression of VEGF, p-Akt and p-ERK in RF/6A cells induced by high glucose were inhibited by OCT. ATWLPPR also prevented the downregulation of occludin, but did not inhibit p-Akt and p-ERK levels under high glucose conditions. The current study concluded that the activation of SSTR2 prevents high glucose-induced occludin downregulation in RF/6A cells, and VEGF, NRP1, p Akt and p-ERK were implicated in this process. The pharmacological effects of SSTR2 targeting to endothelium may be used to assess the role of resistance of permeability and anti-inflammation. PMID- 28810644 TI - Feasibility of a novel low-volume and sodium phosphate-free bowel preparation regimen for colon capsule endoscopy. AB - Bowel preparation regimens for colon capsule endoscopy are not yet standardized since they are not well optimized. The aim of the present study was to evaluate the feasibility of a novel low-volume and sodium phosphate-free bowel preparation regimen for colon capsule endoscopy. A total of 31 patients were prospectively enrolled. In the novel regimen, on the day prior to examination, a low-fiber diet was permitted, 5 mg mosapride citrate was administered twice (1 h prior to lunch and supper) and 1 l polyethylene glycol was administered in the evening. On the day of the examination, an additional 1 l polyethylene glycol, 5 mg mosapride citrate and 200 mg simethicone were administered before capsule ingestion. Polyethylene glycol booster (0.5 l) was administered twice, at 1 and 4 h following capsule ingestion. Colon cleansing levels, ileocecal valve transit time and completion rate were evaluated. A total of 29 patients were included in the final analysis, 90% of whom achieved adequate preparation of the overall colon. Ileocecal valve transit time was 2.35+/-0.82 h and completion rate was 79.3%. The results revealed that the novel low-volume and sodium phosphate-free bowel preparation regimen for colon capsule endoscopy was feasible, with adequate colon cleansing and completion rates, and has the potential to be used as an alternative regimen. PMID- 28810645 TI - Influence of the shape of the micro-finite element model on the mechanical properties calculated from micro-finite element analysis. AB - Assessing the biomechanical properties of trabecular bone is of major biological and clinical significance for the research of bone diseases, fractures and their treatments. Micro-finite element (uFE) models are becoming increasingly popular for investigating the biomechanical properties of trabecular bone. The shapes of uFE models typically include cube and cylinder. Whether there are differences between cubic and cylindrical uFE models has not yet been studied. In the present study, cubic and cylindrical uFE models of human vertebral trabecular bone were constructed. A 1% strain was prescribed to the model along the superior-inferior direction. E values were calculated from these models, and paired t-tests were performed to determine whether these were any differences between E values obtained from cubic and cylindrical models. The results demonstrated that there were no statistically significant differences in the E values between cubic and cylindrical models, and there were no significant differences in Von Mises stress distributions between the two models. These findings indicated that, to construct uFE models of vertebral trabecular bone, cubic or cylindrical models were both feasible. Choosing between the cubic or cylindrical uFE model is dependent upon the specific study design. PMID- 28810646 TI - Sex comb on midleg like-2 is a novel specific marker for the diagnosis of gastroenteropancreatic neuroendocrine tumors. AB - Sex comb on midleg like-2 (SCML2) is a polycomb-group protein that encodes transcriptional repressors essential for appropriate development in the fly and in mammals. On the basis of previous findings, the present study aimed to explore the possibility of developing SCML2 into a new diagnostic marker for gastroenteropancreatic neuroendocrine tumors (GEP-NETs). A total of 64 paired GEP NET tissues and adjacent non-tumorous tissues were obtained from patients who had undergone surgical resection between January 2009 and January 2014, and the expression of SCML2 and two neuroendocrine markers, namely synaptophysin (Syn) and chromogranin A (CgA), in the tissues was assessed by immunohistochemistry. Strong SCML2 staining was observed predominantly in the cell nuclei of GEP-NET tissues, and the overall expression rate and staining intensity of SCML2 were higher than those of Syn or CgA, respectively. Spearman rank correlation analysis demonstrated that SCML2 was not correlated with either Syn or CgA, while the combined detection of SCML2 with Syn or with CgA increased the diagnostic sensitivity to 100%. SCML2 expression in GEP-NETs was associated with several clinicopathological parameters, such as histological type, tumor grade, depth of invasion and clinical stage. Kaplan-Meier survival curves revealed that patients with higher SCML2 expression had lower survival rates than those with lower expression levels, while Cox proportional hazards regression analysis revealed that SCML2 was not an independent prognostic factor for GEP-NET patients. Therefore, SCML2 may have potential as a specific marker for joint use with other markers to improve the diagnostic efficiency of GEP-NETs. PMID- 28810647 TI - Limb graft occlusion following endovascular aortic repair: Incidence, causes, treatment and prevention in a study cohort. AB - The present study investigated the incidence, causes, treatment and prevention of limb graft occlusion following endovascular aortic repair (EVAR). A total of 66 cases of abdominal aortic aneurysm receiving EVAR at our department from January 2005 to December 2013 were enrolled. After EVAR, patients received routine antiplatelet therapy of 75 mg PLAVIX for 6 months and then 100 mg Aspirin for another 6 months by oral administration. According to previous clinical experiences, antiplatelet therapy is able to effectively reduce the incidence of iliac occlusion after EVAR. A total of 61 bifurcated grafts and 5 aortauniilac grafts (127 limbs in total) were used. Physical examination, ankle-brachial-index and computer tomographic angiography were performed at 10 days, at 3, 6 and 12 months and annually thereafter. It was found that 7 limbs in 7 patients (10.6% of patients, 5.5% of limbs) were occluded between 20 days and 12 months (average, 7.8+/-5.3 months) after EVAR. Acute and severe ischemia was found in 2 cases, claudication was in found 3 cases, asthenia in both legs was found in 1 case and 1 case was asymptomatic. Femoral-femoral bypass, femoral-femoral bypass and stenting, aorto-iliac/femoral bypass, thrombectomy and conservative treatment were performed in 1 patient each and thrombectomy together with stenting was performed in 2 cases. Limb graft occlusion was not rare after EVAR. Treatment of this complication included surgery and endovascular therapy such as bypass, thrombectomy and thrombolysis. In conclusion, aggressive pre-emptive treatment including angioplasty and stenting prevented occlusion in certain cases. PMID- 28810648 TI - Combination of alendronate and genistein synergistically suppresses osteoclastic differentiation of RAW267.4 cells in vitro. AB - Bone is a dynamic tissue that undergoes constant remodeling, with removal by osteoclastic bone resorption and replacement via osteoblastic bone formation and mineralization. Deterioration of bone mass with aging leads to osteoporosis. Bisphosphonates are potent inhibitors of osteoclastic bone resorption. Genistein, an isoflavone, exerts a bone anabolic effect by suppressing osteoclastic bone resorption and stimulating osteoblastic bone formation. The present study was undertaken to investigate the anabolic effects of a combination of alendronate and genistein on osteoclastic differentiation. Preosteoclastic RAW267.4 cells were cultured with alendronate (0.1-100 uM) and/or genistein (0.1-100 uM) in vitro. Alendronate or genistein alone had no significant effect on the proliferation and death of RAW267.4 cells. Notably, the combination of the two agents was found to potently and synergistically repress the proliferation and death of RAW267.4 cells. Moreover, alendronate or genistein used separately at higher concentrations suppressed the osteoclastic differentiation of RAW267.4 cells induced by receptor activator of nuclear factor-kappaB ligand (RANKL) in vitro. However, combinations of the two agents (0.1-100 uM) synergistically suppressed the RANKL-induced osteoclastic differentiation. In conclusion, bisphosphonate and genistein combination therapy may provide a novel strategy for the prevention and treatment of osteoclastic bone resorption. PMID- 28810649 TI - Effect of dexmedetomidine combined with sufentanil on preventing emergence agitation in children receiving sevoflurane anesthesia for cleft palate repair surgery. AB - The aim of the present study was to observe whether dexmedetomidine (DEX) combined with sufentanil decreased emergence agitation (EA) in children receiving sevoflurane anesthesia for cleft palate repair surgery. Children undergoing elective cleft palate repair surgery were randomly allocated into the DEX + sufentanil group (group DS; n=50) and the normal saline + fentanyl group (group SF; n=50). Patients in group DS were treated with 0.5 ug/kg DEX prior to induction of anesthesia, whereas patients in group SF received an equal volume of normal saline. Sufentanil (0.2 ug/kg) was administered to induce anesthesia, and 30 min before the end of surgery for patients in group DS. Fentanyl (2 ug/kg) was administered at the same time point for patients in group SF. Mean arterial pressure (MAP), heart rate (HR), duration of surgery and anesthesia, and the dosage of remifentanil were assessed. EA score, Pediatric Anesthesia Emergence Delirium (PAED) score and the Children and Infants Postoperative Pain Scale (CHIPPS) score were documented every 15 min in the post-anesthesia care unit (PACU). The number of cases requiring fentanyl (1 ug/kg) and the recovery profile data were analyzed. Compared with group DS (P<0.05) and the baseline (P<0.05), HR and MAP were significantly increased in group SF immediately following tracheal intubation and extubation. Mean values of maximum EA, PAED and CHIPPS scores were significantly reduced in group DS compared with group SF at 0 (P<0.01), 15 (P<0.05), and 30 min (P<0.05) after arrival at PACU. The incidence of EA in group SF was significantly increased compared with group DS (P<0.05). The dosage of remifentanil during the surgery and the number of cases requiring fentanyl (1 ug/kg) in group DS were significantly decreased compared with group SF (P<0.05). The findings of the present study suggested that DEX combined with sufentanil was able to effectively decrease the incidence of EA in children receiving sevoflurane anesthesia for cleft palate repair surgery. PMID- 28810650 TI - Glutathione S-transferase A1 mediates nicotine-induced lung cancer cell metastasis by promoting epithelial-mesenchymal transition. AB - The present study aimed to investigate the effect of glutathione S-transferase A1 (GSTA1) on lung cancer cell viability, invasion and adhesion in the presence of nicotine in vitro. Furthermore, the effect of GSTA1 on the epithelial-mesenchymal transition (EMT), a process strongly associated with lung cancer metastasis, was examined. Human lung carcinoma A549 cells were treated with various concentrations of nicotine (0.01, 0.1, 1 and 10 uM) and levels of GSTA1 mRNA and protein were measured by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. To knock down GSTA1 expression, GSTA1-small interfering RNA was transfected into A549 cells. Cell viability, invasion and adhesion abilities were determined by MTT, Transwell-Matrigel invasion and cell adhesion assays, respectively. The expression of the epithelial cell markers E-cadherin and keratin, and the mesenchymal cell markers vimentin and N-cadherin in A549 cells were examined by western blot analysis. The current study indicated that the expression of GSTA1 was increased in A549 cells following nicotine treatment. GSTA1 suppression inhibited the viability, invasion and adhesion of lung cancer cells. In addition, the increase in lung cancer cell viability, invasion and adhesion by nicotine was suppressed following GSTA1 knockdown. Furthermore, GSTA1 affected the expression of EMT markers in nicotine treated or untreated lung cancer cells. Thus the present study demonstrates that GSTA1 promotes lung cancer cell invasion and adhesion and mediates the effect of nicotine on lung cancer cell metastasis in vitro. Furthermore, the results demonstrated that GSTA1 exerts its effect on lung cancer cell metastasis by promoting the EMT. PMID- 28810651 TI - Kanglaite inhibits the expression of drug resistance genes through suppressing PVT1 in cisplatin-resistant gastric cancer cells. AB - Kanglaite (KLT) was shown to alleviate the development of multidrug resistance (MDR) clinically. The purpose of this study is to examine the mechanism of KLT for chemotherapy resistance in gastric cancer cells involving the regulation of MDR-related proteins. The cisplatin-resistant BGC823/DPP and SGC7901/DDP cells were treated with 1, 2.5 and 5 ul/ml of KLT for 24, 36 and 48 h. Cell Counting Kit-8 (CCK-8) assay and flow cytometry were performed to detect the cell viability and cell apoptosis, respectively. The expression of MDR1 and multidrug resistance associated protein 1 (MRP1) were examined by quantitative PCR and western blotting in BGC823/DPP cells and SGC7901/DDP cells treated with KLT. The effect of KLT on the expression of PVT1 was investigated. PVT1-overexpression vector was constructed and transfected into BGC823/DPP cells and SGC7901/DDP cells which were treated with KLT. KLT inhibited the cell viability and promoted the cell apoptosis of BGC823/DPP cells and SGC7901/DDP cells in a concentration dependent manner. KLT suppressed the expression of MDR1 and MRP1 and the level of PVT1. PVT1 overexpression reversed the increased percentage of apoptotic cells induced by KLT. Finally, we found that PVT1 overexpression also abrogated the effect of KLT on the mRNA level and protein level of MDR1 and MRP1 in BGC823/DPP and SGC7901/DDP cells. KLT inhibited the expression of MDR1 and MRP1 via suppressing the expression of PVT1, which suggested the potential mechanism of KLT involving in MDR in gastric cancer. PMID- 28810653 TI - Surgical trauma and low-dose methylprednisolone modulate the severity of the acute-phase response induced by zoledronic acid infusion. AB - The aim of the present study was to investigate risk factors for the development of an acute-phase response (APR) associated with the initial zoledronic acid (ZA) infusion in patients undergoing surgery, and to assess whether its onset may be reduced by post-dose administration of low-dose methylprednisolone (MP) or acetaminophen. A retrospective study of patients with osteoporosis who attended the departments of orthopedics and endocrinology of a single hospital and received 5 mg ZA was conducted; the patients included surgical and non-surgical cases. A total of 450 ZA-naive patients who were treated with acetaminophen following ZA infusion were stratified based on whether they suffered APR (APR+) or not (APR-). In addition, 155 of the aforementioned acetaminophen-treated patients (acetaminophen group) were compared with another 32 patients from the orthopedic department who were treated with MP immediately following ZA infusion (MP group). Inflammatory marker levels were significantly higher in APR+ patients than in APR- patients, and the odds ratios of experiencing APR following minimally invasive or open surgery were found to be 3.54 (P<0.001) and 5.71 (P<0.001), respectively, compared with non-surgical intervention after multiple adjustments. C-reactive protein levels prior to dosing were positively correlated with body temperature (r=0.023; P<0.001). The severity of APR also exhibited a negative correlation with 23-hydroxyvitamin D3 levels (r=-0.006; P<0.05). Patients treated with MP following surgery and ZA infusion had a significantly lower incidence of APR compared with those treated with acetaminophen (6.3 vs. 62.6%; P<0.05). However, no significant differences were observed in bone mineral density between the MP and acetaminophen groups at 12 months post-surgery. The results of the present study suggest that surgical trauma serves a key role in ZA associated APR, and low-dose MP may a suitable post-dose treatment to manage the symptoms of APR in patients undergoing surgery. PMID- 28810652 TI - Expression of prostate stem cell antigen is downregulated during flavonoid induced cytotoxicity in prostate cancer cells. AB - Prostate stem cell antigen (PSCA) is expressed in the majority of prostate cancer cases and may be a potential therapeutic target in the treatment of prostate cancer. The present study evaluated the cytotoxicity of three flavonoids (genistein, luteolin and quercetin) towards DU145 prostate cancer cells, and investigated the effect of these flavonoids on PSCA expression. The results demonstrated that genistein, luteolin and quercetin inhibited the growth of DU145 cells in a dose-dependent manner (P<0.05) and induced morphological changes characteristic of apoptosis in DU145 cells. Flow cytometry analysis also indicated that the flavonoids induced S phase cycle arrest in DU145 cells. Notably, it was observed that expression of PSCA was inhibited at the mRNA (P<0.05) and protein levels in DU145 cells following flavonoid treatment compared with the control. These results suggest that flavonoids may be potential therapeutic agents in the treatment and prevention of prostate cancer. PMID- 28810654 TI - Roles of p38 and JNK protein kinase pathways activated by compound cantharidin capsules containing serum on proliferation inhibition and apoptosis of human gastric cancer cell line. AB - The aim of the present study was to investigate the inhibitory effect of compound cantharides capsules (CCCs) on the viability and apoptosis of human gastric cancer cell lines, BGC-823 and SGC-7901, and to detect its regulation of gene expression levels, as well as its inhibition mechanisms. Each cell line was grouped into a control group, CCC serum group, 5-fluorouracil (5-FU) group, combination therapy group (CCC serum + 5-FU) and serum control group. Growth curves were measured and flow cytometry was used to detect cell apoptosis and cell viability. The mRNA expression level of proliferation-related C-MYC and p53 genes were assayed by reverse transcription-quantitative polymerase chain reaction. Protein phosphorylation levels of proliferating cell nuclear antigen, p38 mitogen-activated protein kinase, extracellular signal-related kinase 1/2, c Jun N-terminal kinase (JNK) and IkappaB were assayed by western blotting. The combined CCC serum and 5-FU group exhibited a higher inhibition rate in both cell lines and CCC serum therapy demonstrated a similar effect to 5-FU treatment, as demonstrated in the MTT and cell growth assay. Combined therapy significantly decreased the C-MYC mRNA expression levels and increased p53 mRNA expression levels (P<0.05). Combined therapy of 5-FU and CCC was more significant compared with CCC serum or 5-FU only (P<0.05). P38 and JNK-related protein phosphorylation are involved in apoptosis initiated by CCC combined 5-FU therapy. Combined therapy was able to significantly inhibit human gastric cancer cell growth (P<0.05), and advance cell apoptosis compared with CCC serum only. CCC serum resulted in downregulation of the c-Myc gene and upregulation of the p53 gene. p38 and JNK-related protein phosphorylation is involved in the inhibition of cell viability and apoptosis of human gastric cancer cell lines. PMID- 28810655 TI - MicroRNA-590-3p enhances the radioresistance in glioblastoma cells by targeting LRIG1. AB - microRNA (miR)-590 has been found to serve potential roles in cancer development; however, the expression and function of miR-590 in human gliomas remains to be elucidated. The present study aimed to investigate the expression of miR-590 in human glioma tissues and radioresistant human glioblastoma cells (U251R), and to determine the effect and related molecular mechanism of miR-590-3p on the radiosensitivity of U251R cells in vitro. The results from reverse transcription quantitative polymerase chain reaction indicated that miR-590-3p was upregulated in human glioma tissues and radioresistant human glioblastoma cells, and that miR 590-3p expression was higher in high grade than in low grade gliomas. In vitro experiments revealed that the miR-590-3p inhibitor enhanced the radiosensitivity of U251R cells by suppressing cell viability, decreasing colony formation capacity and increasing cell apoptosis rate, as demonstrated by MTT, colony formation and flow cytometry analyses. A luciferase reporter assay demonstrated that leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) was a direct target of miR-590-3p. Furthermore, it was demonstrated that the effect of miR-590-3p suppression on cell viability, colony formation capacity and cell apoptosis rate was attenuated by the knockdown of LRIG1 in the U251R cells. In conclusion, the present study revealed that miR-590-3p was upregulated in human glioma tissues and radioresistant human glioblastoma cells, and miR-590-3p contributes to the radioresistance of human glioblastoma cells by directly targeting LRIG1. These findings may provide potential therapeutic strategies to prevent radioresistance in human gliomas. PMID- 28810656 TI - Hypoxia-inducible factor 1alpha participates in hypoxia-induced epithelial mesenchymal transition via response gene to complement 32. AB - The aim of the present study was to explore the function of response gene to complement 32 (RGC-32) in hypoxia-induced epithelial-mesenchymal transition (EMT) in pancreatic cancer. Three kinds of hypoxia-inducible factor 1alpha (HIF-1alpha) small interfering (si)RNA were synthesized and the different effects on the expression of HIF-1alpha were detected by western blotting. In human pancreatic cancer BxPC-3 cells, HIF-1alpha levels were diminished using siRNA transfection or HIF-1alpha inhibitor pretreatment, and the expression levels of RGC-32 and EMT associated proteins were analyzed using reverse transcription-quantitative polymerase chain reaction and western blotting. Subsequently, the protein levels of epithelial marker, E-cadherin, and mesenchymal marker, vimentin, were determined by western blotting. Results demonstrated that HIF-1alpha-Homo-488 siRNA and HIF-1alpha-Homo-1216 siRNA diminished the protein level of HIF-1alpha. Compared with normoxia, hypoxia induced the levels of HIF-1alpha, RGC-32, N cadherin and vimentin, but suppressed the expression of E-cadherin and cytokeratins. The inhibition of HIF-1alpha by HIF-1alpha-Homo-1216 siRNA transfection or HIF-1alpha inhibitor repressed hypoxia-induced HIF-1alpha, RGC 32, N-cadherin and vimentin, but increased the expression of E-cadherin and cytokeratins. When RGC-32 was knocked down, hypoxia-induced vimentin was suppressed; however, hypoxia-suppressed N-cadherin was released. In conclusion, the present results demonstrated that hypoxia induced the expression of HIF 1alpha to activate the levels of RGC-32, in turn to regulate the expression EMT associated proteins for EMT. These findings revealed the function of RGC-32 in hypoxia-induced EMT and may have identified a novel link between HIF-1alpha and EMT for pancreatic cancer therapy. PMID- 28810657 TI - Anti-exudation effects of sodium ferulate and oxymatrine combination via modulation of aquaporin 1. AB - The present study aimed to investigate the anti-exudative effects of sodium ferulate combined with oxymatrine in a mouse model of acetic acid-induced peritonitis. Furthermore, the underlying mechanisms were explored by determining the effects of these drugs on the volume and aquaporin 1 (AQP1) expression in vascular endothelial cells on omentum majus and human umbilical vein endothelial cells (HUVEC). Treatment with sodium ferulate combined with oxymatrine was shown to significantly inhibit acetic acid-induced vascular permeability in the peritonitis model mice and furthermore to significantly decrease the optical density of Evans blue, the leukocyte number and the levels of interleukin-6, C reactive protein and interferon-gamma in peritoneal lavage fluid. Pathological analysis of the omentum majus revealed that sodium ferulate and oxymatrine combination treatment significantly alleviated vascular endothelial cell edema and capillary loss. In vitro, flow cytometry revealed that the volume of HUVECs was significantly reduced in the drug treatment groups, as reflected in the forward scatter value. The optical density of AQP1 on the membrane of the vascular endothelial cells on omentum majus and HUVECs were significantly increased in the drug treatment groups compared with the model group. These results indicated that sodium ferulate and oxymatrine combination treatment possessed prominent anti-exudative effects and that the underlying mechanisms are likely to include the improvement of vascular endothelial cellular edema, possibly by upregulation of AQP1 expression on their membrane, which requires further exploration. PMID- 28810658 TI - Abnormal phenotypic features of IgM+B cell subsets in patients with chronic hepatitis C virus infection. AB - Hepatitis C virus (HCV) infection is associated with B cell abnormality; however the phenotypic profiles of immunoglobulin (Ig)M+B cell subsets in patients with HCV infection remain unclear. In the current study, the effect of HCV infection on IgM+B cell subsets was evaluated. The percentages, as well as the differentiation and activation features of peripheral IgM+B naive subsets [cluster of differentiation (CD)27-IgM+B cells] and IgM+B memory subsets (CD27+IgM+B cells) were assessed using flow cytometry in 27 patients with chronic hepatitis C (CHC) and 20 healthy controls (HCs). The frequency of CD27+IgM+B memory subsets detected in patients with CHC was significantly higher than that in HCs (P<0.05). Although the frequency of CD27-IgM+B naive subsets was similar in both groups, there was a significantly higher proportion of CD5+B cells detected in the CD27-IgM+B subsets of patients with CHC compared with HCs (P<0.05). Among CD27-IgM+B subsets, abnormal differentiation was associated with HCV infection, with significantly increased percentages of IgD+B cells and CD38+B cells in patients with CHC compared with HCs (P<0.05). In CD27+IgM+B memory subsets, the abnormality of cell differentiation was associated with a significantly increased percentage of CD38+B cells in patients with CHC compared with HCs (P<0.05). In addition, the percentage of activated CD27+IgM+B subsets in patients with CHC were significantly higher than those observed in HCs (P<0.05). The number of CD27-IgD+IgM+B, CD27-CD38+IgM+B and CD27+CD38+IgM+B cells were negatively correlated with HCV RNA in patients with CHC. These results suggest that HCV infection contributes to abnormalities in the percentage, differentiation and activation of IgM+B cell subsets and may disrupt the immune response mediated by IgM+B cells. PMID- 28810659 TI - Hyaluronic acid conjugation facilitates clearance of intracellular bacterial infections by streptomycin with neglectable nephrotoxicity. AB - Antibiotics such as beta-lactams and aminoglycosides are often subtherapeutic to intracellular infections due to their high hydrophilicity, resulting in low effectiveness against intracellular pathogens and the emergence of antibiotic resistance. Here we reported that an endogenous aminoglycan, hyaluronic acid could be an effective carbohydrate carrier of the aminoglycoside antibiotic, streptomycin against intracellular pathogens. This conjugation could enhance phagocytic activity, and facilitated the entry of streptomycin into host cells via a CD44-mediated pathway. It appeared that this conjugate could clear intracellular bacteria in phagocytic or nonphagocytic cells in a short-term therapy (4 h) at a lower effective dose. In addition, this conjugate was more efficient in reducing bacteria burden in an in vivo acute infection model than streptomycin did. Interestingly, subcutaneous injection of this conjugate at an excess amount had undetectable side effects such as nephrotoxicity. These results suggested that hyaluronic acid might be an efficient Trojan horse for the delivery of hydrophilic antibiotics to deal with intracellular infections. PMID- 28810661 TI - Identification of lectin counter-receptors on cell membranes by proximity labeling. AB - Lectin-glycan interactions play important roles in many biological systems, but the nature of glycoprotein counter-receptors expressed on cell membranes is often poorly understood. To help overcome this problem, we developed a method based on proximity labeling technology. Using a peroxidase-coupled lectin, addition of H2O2 and tyramide-biotin substrates leads to generation of short-range biotin radicals that biotinylate proteins in the immediate vicinity of the bound lectin, which can subsequently be identified. As a proof-of-principle, sialoadhesin horseradish peroxidase-human IgG1 Fc recombinant protein constructs were precomplexed with anti-Fc antibodies, bound to human erythrocytes and reacted with H2O2 and tyramide-SS-biotin. The erythrocyte membrane protein with strongest biotinylation was identified as glycophorin A, in agreement with early studies using lectin overlay and reglycosylation approaches. As a further test of the method, the plant lectin MAL II was conjugated with horseradish peroxidase and used in proximity labeling of human erythrocytes. Glycophorin A was again selectively labeled, which is consistent with previous reports that MAL II has high affinity for glycophorin. This method could be applied to other lectins to identify their membrane counter-receptors. PMID- 28810662 TI - Galectin-9 binds to O-glycans on protein disulfide isomerase. AB - Changes in the T cell surface redox environment regulate critical cell functions, such as cell migration, viral entry and cytokine production. Cell surface protein disulfide isomerase (PDI) contributes to the regulation of T cell surface redox status. Cell surface PDI can be released into the extracellular milieu or can be internalized by T cells. We have found that galectin-9, a soluble lectin expressed by T cells, endothelial cells and dendritic cells, binds to and retains PDI on the cell surface. While endogenous galectin-9 is not required for basal cell surface PDI expression, exogenous galectin-9 mediated retention of cell surface PDI shifted the disulfide/thiol equilibrium on the T cell surface. O glycans on PDI are required for galectin-9 binding, and PDI recognition appears to be specific for galectin-9, as galectin-1 and galectin-3 do not bind PDI. Galectin-9 is widely expressed by immune and endothelial cells in inflamed tissues, suggesting that T cells would be exposed to abundant galectin-9, in cis and in trans, in infectious or autoimmune conditions. PMID- 28810663 TI - Different properties of polysialic acids synthesized by the polysialyltransferases ST8SIA2 and ST8SIA4. AB - Polysialic acid (polySia) is mainly found as a modification of neural cell adhesion molecule (NCAM) in whole embryonic brains, as well as restricted areas of adult vertebrate brains, including the hippocampus. PolySia shows not only repulsive effects on NCAM-involved cell-cell interactions due to its bulky and hydrated properties, but also attractive effects on the interaction with neurologically active molecules, which exerts a reservoir function. Two different polysialyltransferases, ST8SIA2 and ST8SIA4, are involved in the synthesis of polySia chains; however, to date, the differences of the properties between polySia chains synthesized by these two enzymes remain unknown. In this study, to clarify this point, we first prepared polySia-NCAMs from HEK293 cells stably expressing ST8SIA4 and ST8SIA2, or ST8SIA2 (SNP-7), a mutant ST8SIA2 derived from a schizophrenia patient. The conventional sensitive chemical and immunological characterizations showed that the quantity and quality (structural features) of polySia are not so much different between ST8SIA4- and ST8SIA2-synthesized ones, apart from those of ST8SIA2 (SNP-7). Then, we assessed the homophilic and heterophilic interactions mediated by polySia-NCAM by adopting a surface plasmon resonance measurement as an in vitro analytical method. Our novel findings are as follows: (i) the ST8SIA2- and ST8SIA4-synthesized polySia-NCAMs exhibited different attractive and repulsive effects than each other; (ii) both polySia- and oligoSia-NCAMs synthesized by ST8SIA2 were able to bind polySia-NCAMs; (iii) the polySia-NCAM synthesized by a ST8SIA2 (SNP-7) showed markedly altered attractive and repulsive properties. Collectively, polySia-NCAM is suggested to simultaneously possess both attractive and repulsive properties that are highly regulated by the two polysialyltransferases. PMID- 28810660 TI - Recent advancements in understanding mammalian O-mannosylation. AB - The post-translational glycosylation of select proteins by O-linked mannose (O mannose or O-man) is a conserved modification from yeast to humans and has been shown to be necessary for proper development and growth. The most well studied O mannosylated mammalian protein is alpha-dystroglycan (alpha-DG). Hypoglycosylation of alpha-DG results in varying severities of congenital muscular dystrophies, cancer progression and metastasis, and inhibited entry and infection of certain arenaviruses. Defects in the gene products responsible for post-translational modification of alpha-DG, primarily glycosyltransferases, are the basis for these diseases. The multitude of clinical phenotypes resulting from defective O-mannosylation highlights the biomedical significance of this unique modification. Elucidation of the various O-mannose biosynthetic pathways is imperative to understanding a broad range of human diseases and for the development of novel therapeutics. In this review, we will focus on recent discoveries delineating the various enzymes, structures and functions associated with O-mannose-initiated glycoproteins. Additionally, we discuss current gaps in our knowledge of mammalian O-mannosylation, discuss the evolution of this pathway, and illustrate the utility and limitations of model systems to study functions of O-mannosylation. PMID- 28810664 TI - Bacterial phosphoglycosyl transferases: initiators of glycan biosynthesis at the membrane interface. AB - Phosphoglycosyl transferases (PGTs) initiate the biosynthesis of both essential and virulence-associated bacterial glycoconjugates including lipopolysaccharide, peptidoglycan and glycoproteins. PGTs catalyze the transfer of a phosphosugar moiety from a nucleoside diphosphate sugar to a polyprenol phosphate, to form a membrane-bound polyprenol diphosphosugar product. PGTs are integral membrane proteins, which include between 1 and 11 predicted transmembrane domains. Despite this variation, common motifs have been identified in PGT families through bioinformatics and mutagenesis studies. Bacterial PGTs represent important antibacterial and virulence targets due to their significant role in initiating the biosynthesis of key bacterial glycoconjugates. Considerable effort has gone into mechanistic and inhibition studies for this class of enzymes, both of which depend on reliable, high-throughput assays for easy quantification of activity. This review summarizes recent advances made in the characterization of this challenging but important class of enzymes. PMID- 28810665 TI - Determinants of full vaccination status in children aged 12-23 months in Gurue and Milange districts, Mozambique: results of a population-based cross-sectional survey. AB - Background: In 2011, 64% of children in Mozambique, ages 12-23 months, were fully immunized. Large provincial differences in vaccine uptake exist. Methods: We conducted a survey of 1650 females with children aged 12-23 months in the districts of Gurue and Milange. Implementation occurred from November to December 2014. Descriptive statistics and logistic regression using R-software 3.0.2 were used to examine factors associated with full vaccination status. ArcGIS version 10.3.1 (ESRI, Redlands, CA, USA) was used to map spatial patterns of vaccine uptake. Results: Full vaccination was roughly 48%. Identifying 'hospital' as a location to get vaccinated was associated with having a fully vaccinated child (OR=1.87, 95% CI=1.02, 3.41, p=0.043). Households where health decisions are made solely by the male or the female had 38% (95% CI=0.32, 1.21) and 55% (95% CI=0.29, 0.69) lower odds, respectively, of their child being fully immunized. For every 10 km increase from the nearest health facility there was a 36% lower odds of the child being fully immunized (OR=0.64, 95% CI=0.44, 0.93, p<0.001). Conclusion: Zambezia Province, as a whole and the districts of Gurue and Milange specifically, is falling short of vaccination targets. Intensified efforts focused on the least educated, most distant and which take a more family-centered approach are needed to improve vaccine uptake. PMID- 28810667 TI - Understanding data sources to measure patient retention in HIV care in sub Saharan Africa. AB - Antiretroviral therapy (ART) programs in sub-Saharan Africa are moving towards universal treatment, yet the success of these programs is threatened by gaps within the continuum of HIV care. In this commentary, we seek to draw attention to the advantages and limitations of different data sources currently used for measuring retention in HIV care. Within the context of a piecemeal combination of imperfect data sources, selecting a gold standard of collecting retention data is difficult. Currently, our data systems for measuring retention provide an incomplete picture of the health of our national ART systems and, thus, the health of our patients. PMID- 28810666 TI - Monitoring and discharging children being treated for severe acute malnutrition using mid-upper arm circumference: secondary data analysis from rural Gambia. AB - Background: Severe acute malnutrition (SAM) is a major public health problem. Mid upper arm circumference (MUAC) is widely used to admit children to treatment programmes. However, insufficient data supporting MUAC discharge criterion limits its use as a stand-alone tool. Our aim was to evaluate MUAC for monitoring nutritional recovery and discharge. Methods: This was a secondary analysis of clinical data from children 6-59 months-old treated for SAM from January 2003 to December 2013 at the Nutritional Rehabilitation Unit in rural Gambia. Weight, weight-for-height z-score (WHZ) and MUAC response to treatment were assessed. Treatment indicators and regression models controlled for admission measurement and age were compared by discharge MUAC and WHZ. Results: Four hundred and sixty three children with marasmus were included. MUAC, WHZ and weight showed parallel responses to treatment. MUAC>=125 mm as a discharge criterion performed well, showing good prediction of default and referral to hospital, acceptable duration of stay, and a higher absolute MUAC measure compared to WHZ>=-2.00, closely related to lower risk of mortality. Conclusions: MUAC can be used as a standalone tool for monitoring nutritional recovery. MUAC>=125 mm performs well as a discharge criterion; however, follow-up data is needed to assess its safety. Further research is needed on children meeting MUAC discharge criterion but with WHZ<=2.0. PMID- 28810668 TI - Mass drug administration in Central Equatoria, South Sudan: results and suggestions for future distributions. AB - Background: South Sudan has rolled out a neglected tropical disease programme, which envisaged deworming campaigns in states endemic for soil transmitted helminth infections and schistosomiasis. Methods: In 2016, two deworming campaigns targeting school-age children were performed in Central Equatoria. Distribution sites were set up in primary schools, Boma Health Initiative headquarters, health centres and markets. Training, radio adverts and community meetings were performed before the campaigns. Results and Conclusions: Central Equatoria implemented the first helminth infections and schistosomiasis treatment campaign, achieving a satisfactory programme coverage (>90%). Setting up drug distribution sites and engaging the Boma Health Initiative are recommended approaches for future campaigns. PMID- 28810669 TI - HIV status disclosure, facility-based delivery and postpartum retention of mothers in a prevention clinical trial in rural Nigeria. AB - Background: Within the context of a cluster randomized prevention of mother-to child HIV transmission (PMTCT) trial, we evaluated the impact of disclosure on selected PMTCT continuum of care measures. Methods: In 12 rural matched-pair clinics randomly assigned to an intervention package versus standard-of-care, we enrolled 372 HIV-infected pregnant women from April 2013 to March 2014. This secondary analysis included 327 (87.9%) women with unknown HIV status or who were treatment naive at presentation to antenatal care. We employed mixed effects logistic regression to estimate impact of disclosure on facility delivery and postpartum retention in HIV care at 6 and 12 weeks. Results: Fully 86.5% (283/327) of women disclosed their HIV status to their partner, more in the trial intervention arm (OR 3.17, 95% CI 1.39-7.23). Adjusting for intervention arm, maternal age, education and employment, women who disclosed were more likely to deliver at a health facility (OR 2.73, 95%CI 1.11-6.72). Participants who disclosed also had a trend towards being retained in care at 6 and 12 weeks' postpartum (OR 2.72, 95% CI 0.79-9.41 and 2.46, 95% CI 0.70-8.63, respectively). Conclusions: HIV status disclosure at 6 weeks' postpartum was positively associated with facility-based delivery, but not with early postpartum retention. Facilitating HIV status disclosure to partners can increase utilization of facility obstetric services. PMID- 28810671 TI - Beyond the P-value and the sound bite: learning from 'negative' clinical trials. PMID- 28810670 TI - Journey towards universal viral load monitoring in Maputo, Mozambique: many gaps, but encouraging signs. AB - Introduction: Viral load (VL) monitoring for people on antiretroviral therapy (ART) is extremely challenging in resource-limited settings. We assessed the VL testing scale-up in six Medecins Sans Frontieres supported health centres in Maputo, Mozambique, during 2014-15. Methods: In a retrospective cohort study, routine programme data were used to describe VL testing uptake and results, and multi-variate logistical regression to estimate predictors of VL testing uptake and suppression. Results: Uptake of a first VL test was 40% (17 236/43 579). Uptake of a follow-up VL test for patients with a high first VL result was 35% (1095/3100). Factors associated with a higher uptake included: age below 15 years, longer time on ART and attending tailored service delivery platforms. Virological suppression was higher in pregnant/breastfeeding women and in community ART Group members. Patients with a high first VL result (18%; 3100/17 236) were mostly younger, had been on ART longer or had tuberculosis. Out of 1095 attending for a follow-up VL test, 678 (62%) had virological failure. Of those, less than one-third had started second line ART. Conclusion: This was the first study describing the uptake and results of VL testing scale-up in Mozambique. Identified gaps show patient and programmatic challenges. Where service delivery was customized to patient needs, VL monitoring was more successful. PMID- 28810673 TI - The EAPC EXPERT tool. PMID- 28810675 TI - EuroHeartCare 2017. PMID- 28810674 TI - Carina Blomstrom-Lundqvist. PMID- 28810672 TI - Cardiomyocyte renewal in the human heart: insights from the fall-out. AB - The capacity of the mammalian heart to regenerate cardiomyocytes has been debated over the last decades. However, limitations in existing techniques to track and identify nascent cardiomyocytes have often led to inconsistent results. Radiocarbon (14C) birth dating, in combination with other quantitative strategies, allows to establish the number and age of human cardiomyocytes, making it possible to describe their age distribution and turnover dynamics. Accurate estimates of cardiomyocyte generation in the adult heart can provide the foundation for novel regenerative strategies that aim to stimulate cardiomyocyte renewal in various cardiac pathologies. PMID- 28810676 TI - Leadership in cardiology. PMID- 28810677 TI - Exercise and case fatality in myocardial infarction. PMID- 28810678 TI - Update on heart failure: biomarkers, intensive therapy, remote monitoring, and cardiomyocyte renewal. PMID- 28810680 TI - A Bayesian Approach for Summarizing and Modeling Time-Series Exposure Data with Left Censoring. AB - Objective: Direct reading instruments are valuable tools for measuring exposure as they provide real-time measurements for rapid decision making. However, their use is limited to general survey applications in part due to issues related to their performance. Moreover, statistical analysis of real-time data is complicated by autocorrelation among successive measurements, non-stationary time series, and the presence of left-censoring due to limit-of-detection (LOD). A Bayesian framework is proposed that accounts for non-stationary autocorrelation and LOD issues in exposure time-series data in order to model workplace factors that affect exposure and estimate summary statistics for tasks or other covariates of interest. Method: A spline-based approach is used to model non stationary autocorrelation with relatively few assumptions about autocorrelation structure. Left-censoring is addressed by integrating over the left tail of the distribution. The model is fit using Markov-Chain Monte Carlo within a Bayesian paradigm. The method can flexibly account for hierarchical relationships, random effects and fixed effects of covariates. The method is implemented using the rjags package in R, and is illustrated by applying it to real-time exposure data. Estimates for task means and covariates from the Bayesian model are compared to those from conventional frequentist models including linear regression, mixed effects, and time-series models with different autocorrelation structures. Simulations studies are also conducted to evaluate method performance. Results: Simulation studies with percent of measurements below the LOD ranging from 0 to 50% showed lowest root mean squared errors for task means and the least biased standard deviations from the Bayesian model compared to the frequentist models across all levels of LOD. In the application, task means from the Bayesian model were similar to means from the frequentist models, while the standard deviations were different. Parameter estimates for covariates were significant in some frequentist models, but in the Bayesian model their credible intervals contained zero; such discrepancies were observed in multiple datasets. Variance components from the Bayesian model reflected substantial autocorrelation, consistent with the frequentist models, except for the auto-regressive moving average model. Plots of means from the Bayesian model showed good fit to the observed data. Conclusion: The proposed Bayesian model provides an approach for modeling non stationary autocorrelation in a hierarchical modeling framework to estimate task means, standard deviations, quantiles, and parameter estimates for covariates that are less biased and have better performance characteristics than some of the contemporary methods. PMID- 28810679 TI - Association of Endotoxin and Allergens with Respiratory and Skin Symptoms: A Descriptive Study in Laboratory Animal Workers. AB - Background: In laboratory animal work, allergens are classically considered to play a prominent role in generation of respiratory and skin symptoms. However, recent development may have changed working conditions and require an updating of preventive measures. Objective: In workers exposed to a range of animals besides laboratory mice and rats the relative role of endotoxin, irritants, and allergens in symptom generation was assessed for updating preventative measures and health surveillance. Methods: Eligible workers were recruited from university units in which exposure to rats and/or mice, occurrence of respiratory and/or skin symptoms, and/or a history of animal bites had been reported. Exposure to endotoxin and rat and mouse allergen was assessed (71 half-day personal samples). 'Symptomatic' was defined by work-related ocular, nasal, respiratory, or skin symptoms. A concentration of specific IgE against rat or mouse (e87 and e88) >=0.35 kU/l defined sensitization. Sensitivity analyses examined the effect of alternative exposure indicators and definitions of 'sensitized' and 'symptomatic'. Results: From 302 eligible workers, 177 participated. There were 121 and 41 workers in the asymptomatic and non-sensitized and symptomatic but non sensitized group, respectively. Eight subjects were symptomatic and sensitized. Six sensitized subjects were asymptomatic. One participant could not be assigned to a subgroup. Airborne endotoxin and allergen concentrations were mostly below 20 EU m-3 or the detection limit, respectively. Clinical history showed that irritants and sensitizers other than mouse/rat allergen or endotoxin were a major cause of symptoms. Results were sensitive to the selected exposure indicator and the definition of 'symptomatic'. Conclusions: Health surveillance programs need to be adapted to include a larger range of allergens and pay more attention to irritants. PMID- 28810681 TI - Workplace Measurements of Ultrafine Particles-A Literature Review. AB - Workers are exposed to ultrafine particles (UFP) in a number of occupations. In order to summarize the current knowledge regarding occupational exposure to UFP (excluding engineered nanoparticles), we gathered information on UFP concentrations from published research articles. The aim of our study was to create a basis for future epidemiological studies that treat UFP as an exposure factor. The literature search found 72 publications regarding UFP measurements in work environments. These articles covered 314 measurement results and tabled concentrations. Mean concentrations were compared to typical urban UFP concentration level, which was considered non-occupational background concentration. Mean concentrations higher than the typical urban UFP concentration were reported in 240 workplace measurements. The results showed that workers' exposure to UFP may be significantly higher than their non occupational exposure to background concentration alone. Mean concentrations of over 100 times the typical urban UFP concentration were reported in welding and metal industry. However, according to the results of the review, measurements of the UFP in work environments are, to date, too limited and reported too heterogeneous to allow us to draw general conclusions about workers' exposure. Harmonization of measurement strategies is essential if we are to generate more reliable and comparable data in the future. PMID- 28810682 TI - Effects of Known Determinants on Methylene Bisphenyl Isocyanate (MDI) Concentration During Spray-On Truck Bed-Lining Processes. AB - Background: Occupational exposure to methylene bisphenyl isocyanate (MDI) presents serious worker health concerns as it may lead to short- and long-term health effects such as asthma, airway irritation, hypersensitivity pneumonitis, and irritation of skin and mucous membranes. While studies of worker isocyanate exposures during vehicle painting activities are widespread, few studies have investigated the spray-on truck bed-liner (STBL) industry. The purpose of this study was to determine the effectiveness of several ventilation system variables and process characteristics in controlling MDI concentrations in the STBL industry. Methods: A total of 47 personal air samples were collected for MDI during 18 site visits at nine STBL companies in Colorado and Wyoming. Ventilation system and process characteristics that were assessed included: ventilation system face velocity, airflow, air changes per minute (AC/M), capture velocity, percent of MDI in bed-liner product, application temperature, application pressure, paint booth temperature, paint booth relative humidity, paint booth volume, and quantity of bed-liner product applied. Results: Pearson correlation revealed percentage of MDI in bed-liner product (r = 0.557, n = 14, P < 0.05) and process temperature (r = 0.677, n = 14, P < 0.05) had high positive correlation with MDI concentration. Ventilation system face velocity (r = -0.578, n = 14, P < 0.05) and AC/M (r = -0.657, n = 14, P < 0.05) had high negative correlation with MDI concentration while airflow (r = -0.475, n = 14, P < 0.05) and capture velocity (r = -0.415, n = 14, P = 0.07) had moderate negative correlation with MDI concentration. Multiple linear regression revealed process temperature and capture velocity made a statistically significant and unique contribution in estimating MDI concentration (F (2, 11) = 10.99, P < 0.05) with an adjusted R2 of 0.61, explaining 61% of the variability in MDI concentration. Conclusions: This investigation contributed to an understudied STBL industry by targeting determinants germane to MDI exposures during STBL application processes. Increasing ventilation performance for AC/M, airflow, face velocity, and capture velocity while also decreasing bed-liner application temperature and bed-liner product MDI content may have the greatest effect on reducing worker MDI exposures during STBL activities. PMID- 28810683 TI - Evaluating the Physiological and Perceptual Responses of Wearing a Newly Designed Cooling Vest for Construction Workers. AB - Construction workers are subjected to heat stress because of the hot environment, physically demanding tasks, and/or personal protective equipment. A tailor-made cooling vest that protects construction workers from heat-related injuries was developed. The purpose of the study is to examine a newly designed cooling vest's effectiveness in alleviating physiological and perceptual strain in a hot and humid environment. Twelve male participants performed two trials, i.e., cooling vest (VEST) and control (CON) in a climatic chamber controlled at 37 degrees C temperature, 60% relative humidity, 0.3 m/s air velocity, and 450 W/m2 solar radiation to simulate the summer working environment of construction sites. Two bouts of treadmill exercise intermitted with 30-minute passive recovery were designed to simulate the practical work-rest schedule of the construction industry. The cooling vest was used during the passive recovery period in the VEST condition, and the results were compared with that of no cooling vest in the CON condition. The results revealed that the newly designed cooling vest can significantly alleviate heat strain and improve thermal comfort, based on the decrease in body temperature, heart rate, and subjective perceptions (including perceived exertion, thermal, wetness, and comfort sensation) of the participants. It can also prolong work duration in the subsequent exercise. The cooling countermeasures proposed in this study will be able to provide an effective solution in situations that involve repeated bouts of outdoor construction work. PMID- 28810684 TI - A New Approach Combining Analytical Methods for Workplace Exposure Assessment of Inhalable Multi-Walled Carbon Nanotubes. AB - To date there is no consensus about the most appropriate analytical method for measuring carbon nanotubes (CNTs), hampering the assessment and limiting the comparison of data. The goal of this study is to develop an approach for the assessment of the level and nature of inhalable multi-wall CNTs (MWCNTs) in an actual workplace setting by optimizing and evaluating existing analytical methods. In a company commercially producing MWCNTs, personal breathing zone samples were collected for the inhalable size fraction with IOM samplers; which were analyzed with carbon analysis, inductively coupled plasma mass spectrometry (ICP-MS) and scanning electron microscopy/energy dispersive X-ray spectroscopy (SEM/EDX). Analytical methods were optimized for carbon analysis and SEM/EDX. More specifically, methods were applied and evaluated for background correction using carbon analyses and SEM/EDX, CNT structure count with SEM/EDX and subsequent mass conversion based on both carbon analyses and SEM/EDX. A moderate to-high concordance correlation coefficient (RC) between carbon analyses and SEM/EDX was observed [RC = 0.81, 95% confidence interval (CI): 0.59-0.92] with an absolute mean difference of 59 ug m-3. A low RC between carbon analyses and ICP MS (RC = 0.41, 95% CI: 0.07-0.67) with an absolute mean difference of 570 ug m-3 was observed. The large absolute difference between EC and metals is due to the presence of non-embedded inhalable catalyst particles, as a result of which MWCNT concentrations were overestimated. Combining carbon analysis and SEM/EDX is the most suitable for quantitative exposure assessment of MWCNTs in an actual workplace situation. PMID- 28810686 TI - Sampling Efficiency and Performance of Selected Thoracic Aerosol Samplers. AB - Measurement of worker exposure to a thoracic health-related aerosol fraction is necessary in a number of occupational situations. This is the case of workplaces with atmospheres polluted by fibrous particles, such as cotton dust or asbestos, and by particles inducing irritation or bronchoconstriction such as acid mists or flour dust. Three personal and two static thoracic aerosol samplers were tested under laboratory conditions. Sampling efficiency with respect to particle aerodynamic diameter was measured in a horizontal low wind tunnel and in a vertical calm air chamber. Sampling performance was evaluated against conventional thoracic penetration. Three of the tested samplers performed well, when sampling the thoracic aerosol at nominal flow rate and two others performed well at optimized flow rate. The limit of flow rate optimization was found when using cyclone samplers. PMID- 28810685 TI - Characterising the Exposure of Prison Staff to Second-Hand Tobacco Smoke. AB - Second-hand tobacco smoke (SHS) is an avoidable and harmful exposure in the workplace but >25000 prison staff continue to be exposed on a daily basis in the UK and many more worldwide. SHS exposures in prisons are incompletely understood but may be considerable given the large proportion of smoking prisoners and limited ventilation. This study characterized the exposure of prison staff to SHS in all 15 prisons in Scotland using multiple methods. Exposure assessment strategies included 6-day area measurement of fine Particulate Matter (PM2.5) and airborne nicotine in each prison together with short (30-minute) measurements of PM2.5 covering a range of locations/activities. Pre- and post-shift saliva samples were also gathered from non-smoking staff and analysed for cotinine to estimate exposure. There was evidence of exposure to SHS in all prisons from the results of PM2.5 and nicotine measurements. The salivary cotinine results from a sub-sample of non-smoking workers indicated SHS exposures of similar magnitude to those provided by the 6-day area measurements of PM2.5. There was a high degree of exposure variability with some locations/activities involving exposure to SHS concentrations that were comparable to those measured in bars in Scotland prior to smoke-free legislation in 2006. The median shift exposure to SHS-PM2.5 was ~20 to 30 ug m-3 and is broadly similar to that experienced by someone living in a typical smoking home in Scotland. This is the most comprehensive assessment of prison workers' exposure to SHS in the world. The results are highly relevant to the development of smoke-free policies in prisons and should be considered when deciding on the best approach to provide prison staff with a safe and healthy working environment. PMID- 28810687 TI - The Characterization of Polycyclic Aromatic Hydrocarbons in Northeastern US Trucking Terminals. AB - In recent years, significant attention has been given to polycyclic aromatic hydrocarbons (PAHs) exposures given their mutagenic and carcinogenic properties. However, levels of exposure and the key determinants of exposure are not well defined for the trucking industry. We measured ultrafine particle characteristics at 10 trucking terminals of varying operating size and location in the Northeast region of the United States using particle concentration counter and a surface area analyzer. Multivariate mixed-effects linear regression models were used to assess determinants of the concentration of total bound PAHs (tPAH), the total aerosol active surface area (AS), and the ratio tPAH/AS overall and individually within docks, trucking cabs, and administrative offices. Associations between PAH measures with integrated measures of elemental carbon (EC), organic carbon (OC), and particulate matter (PM)2.5 were assessed by Spearman rank correlation. In adjusted models, tPAH, AS, and tPAH/AS average concentrations (95% confidence interval) were significantly higher in truck cabs compared to office locations (1.26 (ng m-3) (1.18, 1.35); 0.99 (mm2 mm-3) (0.91, 1.08); 0.26 (ng mm-2) (0.18, 0.33), respectively). In the loading dock, AS concentrations were significantly higher than in the office (0.67 (0.61, 0.71), while the tPAH/AS was not (-0.63 ( 0.67, -0.58). In each location, average tPAH concentrations were moderately but significantly correlated with EC (r = 0.47-0.63) and with tPAH/AS (r = 0.34-0.40) in the truck cabs and loading docks. In conclusion, key predictors of tPAH, AS, and tPAH/AS within the trucking industry are work location (in particular truck cabs and terminal docks) and terminal characteristics (size). The association of tPAH and tPAH/AS with EC concentrations in dockworkers and pick-up and delivery drivers is consistent with occupational exposure attributable to vehicle exhaust. Therefore, measurement of tPAH, AS, and tPAH/AS to characterize ultrafine particles and bound PAH concentrations provide additional information regarding exposures in the trucking industry not captured by integrated measures by EC, OC, and PM2.5. PMID- 28810688 TI - Exhaled Breath Condensate: A Novel Matrix for Biological Monitoring to Assess Occupational Exposure to Respirable Crystalline Silica. AB - Biological monitoring (BM) is a useful way of determining overall exposures to chemical substances; however, in the case of respirable crystalline silica (RCS), this has not been analytically feasible in conventional biological matrices. The aim of this study was to investigate the utility of exhaled breath condensate (EBC) as a potential biological matrix in which to determine exposure to RCS. A small pilot study was undertaken collecting EBC from six quarry workers and six occupationally unexposed persons; the samples were analysed using both single particle inductively coupled plasma mass spectrometry (spICP-MS) and transmission electron microscopy (TEM). The results showed that EBC obtained from the occupationally unexposed persons exhibited low background levels of dissolved silica whilst silica particles of various sizes were present in samples from quarry workers. This is the first study to report EBC as a potential biological matrix that allows differentiation of RCS concentrations between samples from workers and occupationally unexposed controls. The results shown here confirm the presence of RCS in EBC by both spICP-MS and TEM. However, there are difficult analytical challenges still to be overcome before this can be used as a BM method to determine workplace exposure, these are currently being investigated. PMID- 28810689 TI - Temporal Trends in Airborne Dust Concentrations at a Large Chrysotile Mine and its Asbestos-enrichment Factories in the Russian Federation During 1951-2001. AB - Objectives: Mining and processing of chrysotile, an established carcinogen, has been undertaken in Asbest, Russian Federation since the late 1800s. Dust concentrations were routinely recorded at the open-pit mine and its asbestos enrichment factories. We examined the temporal trends in these dust concentrations from 1951 to 2001. Methods: Analyses included 89290 monthly averaged gravimetric dust concentrations in six factories (1951-2001) and 1457 monthly averaged concentrations in the mine (1964-2001). Annual percent changes (APC) in geometric mean dust concentrations were estimated for each factory and the mine separately from linear mixed models of the logarithmic-transformed monthly averaged concentrations. Results: Dust concentrations declined significantly in the mine [APC: -1.6%; 95% confidence interval (CI): -3.0 to 0.2] and Factories 1-5 but not 6. Overall factory APCs ranged from -30.4% (95% CI: -51.9 to -8.9; Factory 1: 1951-1955) to -0.6% (95% CI: -1.5 to 0.2; Factory 6: 1969-2001). Factory trends varied across decades, with the steepest declines observed before 1960 [APCs: -21.5% (Factory 2) and -17.4% (Factory 3)], more moderate declines in the 1960s and 1970s [APCs from -10% in Factory 2 (1960s) to 0.3% (not statistically significant) in Factory 4 (1970s)], and little change thereafter. Mine dust concentrations increased in the 1960s (APC: +9.7%; 95% CI: 3.6 to 15.9), decreased in the 1990s (APC: -5.8%; 95% CI: -8.1 to -3.5) and were stable in between. Conclusions: In this analysis of >90000 dust concentrations, factory dust concentrations declined between 1951 and 1979 and then stabilized. In the mine, dust levels increased in the 1960s, declined in the 1990s and were unchanged in the interim. PMID- 28810690 TI - Validation of the dermal exposure model in ECETOC TRA. AB - The ECETOC TRA model (presently version 3.1) is often used to estimate worker inhalation and dermal exposure in regulatory risk assessment. The dermal model in ECETOC TRA has not yet been validated by comparison with independent measured exposure levels. This was the goal of the present study. Measured exposure levels and relevant contextual information were gathered via literature search, websites of relevant occupational health institutes and direct requests for data to industry. Exposure data were clustered in so-called exposure cases, which are sets of data from one data source that are expected to have the same values for input parameters in the ECETOC TRA dermal exposure model. For each exposure case, the 75th percentile of measured values was calculated, because the model intends to estimate these values. The input values for the parameters in ECETOC TRA were assigned by an expert elicitation and consensus building process, based on descriptions of relevant contextual information.From more than 35 data sources, 106 useful exposure cases were derived, that were used for direct comparison with the model estimates. The exposure cases covered a large part of the ECETOC TRA dermal exposure model. The model explained 37% of the variance in the 75th percentiles of measured values. In around 80% of the exposure cases, the model estimate was higher than the 75th percentile of measured values. In the remaining exposure cases, the model estimate may not be sufficiently conservative.The model was shown to have a clear bias towards (severe) overestimation of dermal exposure at low measured exposure values, while all cases of apparent underestimation by the ECETOC TRA dermal exposure model occurred at high measured exposure values. This can be partly explained by a built-in bias in the effect of concentration of substance in product used, duration of exposure and the use of protective gloves in the model. The effect of protective gloves was calculated to be on average a factor of 34 in this data set, while factors of five to ten were used in the model estimations. There was also an effect of the sampling method in the measured data on the exposure levels. Exposure cases where sampling was done via an interception method, such as gloves, on average showed a factor of six higher 75th percentiles of measured values than exposure cases where sampling was done via a removal method, such as hand washing. This may partly be responsible for the apparent underestimation of dermal exposure by the model at high exposure values. However, there also appeared to be a relation between expected exposure level (as indicated by the model estimate) and the choice of sampling method.In this study, solid substances used in liquid products were treated as liquids with negligible volatility. The results indicate that the ECETOC TRA dermal exposure model performs equally well for these substances as for liquids. There were suggestions of a difference in performance of the model between solids and liquids.For several parts of the ECETOC TRA dermal model, no or hardly any measured dermal exposure data were available. Therefore, gathering of more dermal exposure levels is recommended, specifically for situations not yet sufficiently covered in the present data set. PMID- 28810691 TI - Improvement of implantation potential in mouse blastocysts derived from IVF by combined treatment with prolactin, epidermal growth factor and 4 hydroxyestradiol. AB - STUDY QUESTION: Can supplementation of medium with prolactin (PRL), epidermal growth factor (EGF) and 4-hydroxyestradiol (4-OH-E2) prior to embryo transfer improve implantation potential in mouse blastocysts derived from IVF? SUMMARY ANSWER: Combined treatment with PRL, EGF and 4-OH-E2 improves mouse blastocyst implantation rates, while alone, each factor is ineffective. WHAT IS KNOWN ALREADY: Blastocyst dormancy during delayed implantation caused by ovariectomy is maintained by continued progesterone treatment in mice, and estrogen injection rapidly activates blastocysts to implantation-induced status in vivo. While the expression of many proteins is upregulated in implantation-induced blastocysts, selective proteolysis by proteasomes, such as estrogen receptor alpha (ESR1), occurs in implantation-induced blastocysts to achieve implantation-competent status. It is worth evaluating the proteins expressed during these periods to identify humoral factors that might improve the implantation potential of IVF derived blastocysts because the poor quality of embryos obtained by IVF is one of the major causes of implantation failure. STUDY DESIGN, SIZE, DURATION: Superovulated oocytes from ICR mice were fertilized with spermatozoa and then cultured in vitro in potassium simplex optimized medium (KSOM) without phenol red (KSOM-P) for 90-96 h. Blastocysts were treated with PRL (10 or 20 mIU/mL), EGF (5 or 10 ng/mL) or 4-OH-E2 (1 or 10 nM) in KSOM-P for 24 h. PARTICIPANTS/MATERIALS, SETTING, METHODS: Levels of breast cancer 1 (BRCA1), EGF receptor (EGFR, also known as ERBB1), ERBB4, tubulointerstitial nephritis antigen-like 1 (TINAGL1) and ESR1 protein were examined with immunohistochemical analysis using immunofluorescence methods and confocal laser scanning microscopy. For embryo transfer, six blastocysts were suspended in HEPES-buffered KSOM-P medium and transferred into the uteri of recipient mice on the morning of Day 4 (0900-1000 h) of pseudopregnancy (Day 1 = vaginal plug). The number of implantation sites was then recorded on Day 6 using the blue dye method. MAIN RESULTS AND THE ROLE OF CHANCE: PRL, EGF and 4-OH-E2 each promoted BRCA1 protein level in the trophectoderm (TE). While PRL treatment resulted in an increase in EGFR, EGF increased both EGFR and ERBB4 in the blastocyst TE. TINAGL1 in the TE was enhanced by 4-OH-E2, which also increased localization of this protein to the basement membrane. Treatment with PRL, EGF or 4-OH-E2 alone did not improve blastocyst implantation rates. Combined treatment with PRL, EGF and 4-OH-E2 resulted in increased levels of EGFR, ERBB4, TINAGL1 and BRCA1 in the TE, whereas ESR1 was not upregulated in the treated blastocysts. Furthermore, combined treatment with PRL, EGF and 4-OH-E2 improved blastocyst implantation rates versus control (P = 0.009). LARGE SCALE DATA: Not applicable. LIMITATIONS, REASONS FOR CAUTION: Our studies were carried out in a mouse model, and the conclusions were drawn from limited results obtained from one species. Whether the increase in EGFR, ERBB4 and TINAGL1 protein in the TE improves implantation potential of blastocysts needs to be further studied experimentally by assessing other expressed proteins. The influence of combined supplementation in vitro of PRL, EGF and 4-OH-E2 on implantation also requires further examination and optimization in human blastocysts before it can be considered for clinical use in ART. WIDER IMPLICATIONS OF THE FINDINGS: Enhanced implantation potential by combined treatment with PRL, EGF and 4-OH-E2 appears to result in the upregulation of at least two distinct mechanisms, namely signaling via EGF receptors and basement membrane formation during the peri-implantation period in mice. While PRL, EGF and 4-OH-E2 each promoted BRCA1 protein level in the TE, treatment with each alone did not improve blastocyst implantation. Therefore, BRCA1 protein appears to be unnecessary for the attachment reaction in blastocysts in mice Combined supplementation of PRL, EGF and 4-OH-E2 might also be of relevance for embryo transfer of human IVF-derived blastocysts for ART. STUDY FUNDING/COMPETING INTEREST(S): This work was supported in part by the JSPS KAKENHI [Grant numbers 22580316 and 25450390 (to H.M.)] and the Joint Research Project of Japan-U.S. Cooperative Science Program (to H.M.). The authors have no conflict of interest to declare. PMID- 28810693 TI - Deregulation of the endometrial stromal cell secretome precedes embryo implantation failure. PMID- 28810694 TI - The AMA and AAPM. A Historical Partnership Now Advocating for the "Future of Pain Medicine". PMID- 28810692 TI - Resveratrol protects from lipopolysaccharide-induced inflammation in the uterus and prevents experimental preterm birth. AB - STUDY QUESTION: Is resveratrol able to prevent the lipopolysaccharide (LPS) induced preterm labor in 15-day pregnant BALB/c mice? SUMMARY ANSWER: Resveratrol prevented the LPS-induced onset of preterm labor in 64% of the cases and showed anti-inflammatory and tocolytic effects by downregulating COX-2 and iNOS expression and NOS activity, and by changing the uterine prostaglandin and endocannabinoid profiling. WHAT IS KNOWN ALREADY: Genital tract infections by Gram-negative bacteria are a common complication in human pregnancy and have been shown to increase risk of preterm delivery. Bacterial LPS elicits a strong maternal inflammatory response that results in preterm delivery and fetal death in a murine model endotoxin-induced preterm labor. STUDY DESIGN, SIZE, DURATION: An in vivo animal study was conducted. On Day 15 of pregnancy, mice received at 8:00 h a dose of vehicle (40% ethanol in saline solution) or resveratrol (3 mg/kg in vehicle) via oral gavage followed by two doses of LPS or vehicle administered intraperitoneally (i.p.), the first one at 10:00 h (0.17 mg/kg in 0.1 ml of sterile saline solution) and the second at 13:00 h (0.5 mg/kg in 0.1 ml of sterile saline solution). The mice were closely observed for any signs of morbidity (piloerection, decreased movement, and diarrhea), vaginal bleeding or preterm delivery. The beginning of preterm delivery was defined by early delivery of the first pup. Normal term labor occurs on Day 19 of gestation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Time of labor, pregnancy outcome and morphological features were evaluated after LPS and/or resveratrol administration. Uterine stripes were collected 5 h after the last LPS injection and prostaglandin and endocannabinoid profiling was analyzed by mass spectrometry. Nitric oxide synthase (NOS) activity was measured by radioconversion assay. Cyclooxygenase-2 (Cox-2) and 15-hydroxyprostaglandin dehydrogenase (15-Pgdh) mRNA levels were analyzed by RT-PCR whilst the protein expression of inducible nitric oxide synthase (iNOS), COX-1 and COX-2 were studied by western blot. MAIN RESULTS AND THE ROLE OF CHANCE: In vivo treatment of 15-day pregnant BALB/c mice with resveratrol prevented the LPS-induced preterm birth in 64% of the cases, whereas only 15% of mice with LPS alone escaped preterm birth. Treatment with resveratrol resulted in a reduced NOS activity (P < 0.05) in the uterus of LPS-treated mice. Similarly, resveratrol reduced the expression of LPS-induced pro-inflammatory agents such as iNOS (P < 0.05), COX-2 (P < 0.05), prostaglandin E2 (PGE2) (P < 0.05) and anandamide (AEA) (P < 0.05). Moreover, resveratrol administration resulted in changes in the uterine endocannabinoid profiling altered by LPS. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Since our experimental design involves the use of mice, the extrapolation of the results presented here to humans is limited. WIDER IMPLICATIONS OF THE FINDINGS: Our findings provide evidence for the tocolytic effects of resveratrol. STUDY FUNDING AND COMPETING INTEREST(S): Dr Ana Maria Franchi was funded by Agencia Nacional para la Promocion Cientifica y Tecnologica (PICT 2013/0097) and by Consejo Nacional de Investigaciones Cientificas y Tecnicas (PIP 2012/0061). Dr Heather B. Bradshaw was funded by NIH (DA006668). The authors have no competing interests. PMID- 28810696 TI - iATC-mISF: a multi-label classifier for predicting the classes of anatomical therapeutic chemicals. PMID- 28810695 TI - Long-Term Safety and Efficacy of Subcutaneous Methylnaltrexone in Patients with Opioid-Induced Constipation and Chronic Noncancer Pain: A Phase 3, Open-Label Trial. AB - Objective: Methylnaltrexone, a peripherally acting u-opioid receptor antagonist, alleviates opioid-induced constipation. Understanding its long-term safety and efficacy profile in patients with chronic noncancer pain is warranted given the persistence of opioid-induced constipation. Methods. : In this phase 3, multicenter, open-label trial, adults with chronic noncancer pain (N = 1034) received subcutaneous methylnaltrexone 12 mg once daily for 48 weeks. Results: The most common adverse events were gastrointestinal related (e.g., abdominal pain, diarrhea, nausea) and were mild to moderate in intensity. Only 15.2% of patients discontinued because of an adverse event. Serious cardiac-related adverse events occurred in nine patients. Of the seven instances of major adverse coronary events reported, three were adjudicated after external review; all instances occurred in patients with cardiovascular risk factors. Methylnaltrexone elicited a bowel movement within four hours in 34.1% of the injections throughout the 48-week treatment period. Conclusions: Change from baseline in mean weekly bowel movement rate, Bowel Movement Straining Scale score, Bristol Stool Scale score, and mean percentage of patients with complete evacuation from baseline to week 48 were significantly improved ( P < 0.001 for all). Long-term subcutaneous methylnaltrexone was well tolerated, with no new safety concerns, and provided consistent opioid-induced constipation relief in patients with chronic noncancer pain. PMID- 28810697 TI - Shanghai Consensus on Healthy Cities 2016. AB - More than hundred mayors leading cities and towns from around the world met at the Ninth Global Conference on Health Promotion, held in Shanghai (People's Republic of China), 21-24 November 2016. They reaffirmed the vision of Healthy Cities and the Ottawa Charter for Health Promotion and committed politically to growing the global Healthy Cities movement. They invite every city to join. PMID- 28810698 TI - Healthy Cities are back! (They were never gone). PMID- 28810699 TI - Promoting health in a post-truth world. PMID- 28810700 TI - A single mini-barcode test to screen for Australian mammalian predators from environmental samples. AB - Identification of species from trace samples is now possible through the comparison of diagnostic DNA fragments against reference DNA sequence databases. DNA detection of animals from non-invasive samples, such as predator faeces (scats) that contain traces of DNA from their species of origin, has proved to be a valuable tool for the management of elusive wildlife. However, application of this approach can be limited by the availability of appropriate genetic markers. Scat DNA is often degraded, meaning that longer DNA sequences, including standard DNA barcoding markers, are difficult to recover. Instead, targeted short diagnostic markers are required to serve as diagnostic mini-barcodes. The mitochondrial genome is a useful source of such trace DNA markers because it provides good resolution at the species level and occurs in high copy numbers per cell. We developed a mini-barcode based on a short (178 bp) fragment of the conserved 12S ribosomal ribonucleic acid mitochondrial gene sequence, with the goal of discriminating amongst the scats of large mammalian predators of Australia. We tested the sensitivity and specificity of our primers and can accurately detect and discriminate amongst quolls, cats, dogs, foxes, and devils from trace DNA samples. Our approach provides a cost-effective, time-efficient, and non-invasive tool that enables identification of all 8 medium-large mammal predators in Australia, including native and introduced species, using a single test. With modification, this approach is likely to be of broad applicability elsewhere. PMID- 28810701 TI - Yeast genes involved in regulating cysteine uptake affect production of hydrogen sulfide from cysteine during fermentation. AB - An early burst of hydrogen sulfide (H2S) produced by Saccharomyces cerevisiae during fermentation could increase varietal thiols and therefore enhance desirable tropical aromas in varieties such as Sauvignon Blanc. Here we attempted to identify genes affecting H2S formation from cysteine by screening yeast deletion libraries via a colony colour assay on media resembling grape juice. Both Deltalst4 and Deltalst7 formed lighter coloured colonies and produced significantly less H2S than the wild type on high concentrations of cysteine, likely because they are unable to take up cysteine efficiently. We then examined the nine known cysteine permeases and found that deletion of AGP1, GNP1 and MUP1 led to reduced production of H2S from cysteine. We further showed that deleting genes involved in the SPS-sensing pathway such as STP1 and DAL81 also reduced H2S from cysteine. Together, this study indirectly confirms that Agp1p, Gnp1p and Mup1p are the major cysteine permeases and that they are regulated by the SPS sensing and target of rapamycin pathways under the grape juice-like, cysteine supplemented, fermentation conditions. The findings highlight that cysteine transportation could be a limiting factor for yeast to generate H2S from cysteine, and therefore selecting wine yeasts without defects in cysteine uptake could maximise thiol production potential. PMID- 28810703 TI - Exploring the potential of Saccharomyces eubayanus as a parent for new interspecies hybrid strains in winemaking. AB - Yeast cryotolerance brings some advantages for wine fermentations, including the improved aromatic complexity of white wines. Naturally cold-tolerant strains are generally less adept at wine fermentation but fermentative fitness can potentially be improved through hybridization. Here we studied the potential of using hybrids involving Saccharomyces eubayanus and a S. cerevisiae wine strain for low-temperature winemaking. Through screening the performance in response to variable concentrations of sugar, nitrogen and temperature, we isolated one hybrid strain that exhibited the superior performance. This hybrid strain was propagated and dried in pilot scale and tested for the fermentation of Macabeu and Sauvignon blanc grape musts. We obtained highly viable active dry yeast, which was able to efficiently ferment the grape musts with superior production of aroma active volatiles, in particular, 2-phenylethanol. The genome sequences of the hybrid strains revealed variable chromosome inheritance among hybrids, particularly within the S. cerevisiae subgenome. With the present paper, we expand the knowledge on the potentialities of using S. eubayanus hybrids in industrial fermentation at beverages other than lager beer. PMID- 28810702 TI - The nutrient transceptor/PKA pathway functions independently of TOR and responds to leucine and Gcn2 in a TOR-independent manner. AB - Two nutrient-controlled signalling pathways, the PKA and TOR pathway, play a major role in nutrient regulation of growth as well as growth-correlated properties in yeast. The relationship between the two pathways is not well understood. We have used Gap1 and Pho84 transceptor-mediated activation of trehalase and phosphorylation of fragmented Sch9 as a read-out for rapid nutrient activation of PKA or TORC1, respectively. We have identified conditions in which L-citrulline-induced activation of Sch9 phosphorylation is compromised, but not activation of trehalase: addition of the TORC1 inhibitor, rapamycin and low levels of L-citrulline. The same disconnection was observed for phosphate activation in phosphate-starved cells. The leu2 auxotrophic mutation reduces amino acid activation of trehalase, which is counteracted by deletion of GCN2. Both effects were also independent of TORC1. Our results show that rapid activation of the TOR pathway by amino acids is not involved in rapid activation of the PKA pathway and that effects of Gcn2 inactivation as well as leu2 auxotrophy all act independently of the TOR pathway. Hence, rapid nutrient signalling to PKA and TOR in cells arrested by nutrient starvation acts through parallel pathways. PMID- 28810704 TI - Yeast Kch1 and Kch2 membrane proteins play a pleiotropic role in membrane potential establishment and monovalent cation homeostasis regulation. AB - The Kch1 and Kch2 plasma-membrane proteins were identified in Saccharomyces cerevisiae as being essential for the activation of a high-affinity Ca2+ influx system. We searched for Kch proteins roles in the maintenance of cation homeostasis and tested the effect of kch1 and/or kch2 deletions on various physiological parameters. Compared to wild-type, kch1 kch2 mutant cells were smaller, relatively hyperpolarised, grew better under limited K+ conditions and exhibited altered growth in the presence of monovalent cations. The absence of Kch1 and Kch2 did not change the intracellular pH in cells growing at low potassium or the tolerance of cells to divalent cations, high concentration of sorbitol or extreme external pH. The overexpression of KCH1 only increased the intracellular pH in the presence of elevated K+ in media. None of the phenotypes associated with the deletion of KCH1 and KCH2 in wild type were observed in a strain lacking KCH genes and main K+ uptake systems Trk1 and Trk2. The role of the Kch homologue in cation homeostasis was also tested in Candida albicans cells. Our data demonstrate that Kch proteins significantly contribute to the maintenance of optimal cation homeostasis and membrane potential in S. cerevisiae but not in C. albicans. PMID- 28810705 TI - Flowers as a reservoir of yeast diversity: description of Wickerhamiella nectarea f.a. sp. nov., and Wickerhamiella natalensis f.a. sp. nov. from South African flowers and pollinators, and transfer of related Candida species to the genus Wickerhamiella as new combinations. AB - Flowers offer favourable microenvironments for yeast growth, and are increasingly recognised as a rich source of novel yeast species. Independent surveys of yeasts associated with flowers and pollinators in South Africa led to the discovery of 38 strains of two new species. Physiological profiles and analysis of the internal transcribed spacer and the D1/D2 domains of the large subunit rRNA gene showed that they represent two novel species that belong to the Wickerhamiella clade. We describe the species as Wickerhamiella nectarea f.a. sp. nov. (type strain EBDCdVSA11-1T, CBS 14162T, NRRL Y-63791T) and W. natalensis f.a. sp. nov. (type strain EBDCdVSA7-1T, CBS 14161T, NRRL Y-63790T). We extend the known range of flower-associated Wickerhamiella species to South Africa and discuss the ecology and phylogenetic relationships of the clade in relation to its host species and biogeography. Examination of growth characteristics supports that the Wickerhamiella clade exhibits a high degree of evolutionary lability, and that specialisation to different niches may occur rapidly. We review the current status of floral yeast biodiversity and nectar as a reservoir of species diversity, and the importance of pollinators and biogeography. In addition, 18 species formerly assigned to the genus Candida are reassigned formally to the genus Wickerhamiella. PMID- 28810706 TI - Effects of trigonelline inhibition of the Nrf2 transcription factor in vitro on Echinococcus granulosus. AB - The aim of this study was to investigate the impact of trigonelline (TRG) on Echinococcus granulosus, and to explore the inhibition impact of nuclear factor erythroid-2-related factor 2 (Nrf2) signaling pathway on E. granulosus protoscoleces. Echinococcus granulosus protoscoleces were incubated with various concentrations of TRG, and then Nrf2 protein expression and its localization in protoscoleces were detected by western blot analysis and immunofluorescence assay, respectively. Reactive oxygen species (ROS) level in protoscoleces was measured using ROS detection kit. Caspase-3 activity was measured using a caspase 3 activity assay kit, and NAD(P)H quinone oxidoreductase (NQO)-1 and heme oxygenase (HO)-1 activities in protoscoleces were measured by ELISA. The effect of TRG on protoscoleces viability was investigated using 0.1% eosin staining, and ultrastructural alterations in protoscoleces were examined by scanning electron microscopy (SEM). Immunolocalization experiment clearly showed that Nrf2 protein was predominantly present in cells of protoscoleces. TRG treatment reduced NQO-1 and HO-1 activities in protoscoleces, but could increase ROS level at early time. Protoscoleces could not survive when treated with 250 MUM TRG for 12 days. SEM results showed that TRG-treated protoscoleces presented damage in the protoscoleces region, including hook deformation, lesions, and digitiform protuberance. Nrf2 protein expression was significantly decreased and caspase-3 activity was clearly increased in protoscoleces treated with TRG for 24 and 48 h, respectively, when compared with that in controls (P < 0.05). Our results demonstrated that TRG had scolicidal activity against E. granulosus protoscoleces. Nrf2 protein was mainly expressed in the cells and TRG could efficiently inhibit the Nrf2 signaling pathway in E. granulosus. PMID- 28810707 TI - Seasonal and spatial variations of prokaryoplankton communities in a salinity influenced watershed, China. AB - Prokaryotes represent the largest biodiversity pool and drive the biogeochemical cycles in fluvial environments. However, the mechanisms underlying the assembly of prokaryotic communities are largely unexplored at taxonomic and functional levels, simultaneously. Here, we investigated the spatio-seasonal distribution of prokaryoplankton communities in a salinity-influenced watershed, China using 16S rRNA gene amplicon sequencing. The OTUs were divided into core and satellite, based on a statistical approach. Our results indicated that the core taxa accounted for 87.4% of all the communities, predominantly including Betaproteobacteria, Actinobacteria and Thaumarchaeota. Whereas 10 of 22 metabolic phenotypes annotated using METAGENassist had significantly higher relative abundances in the core than satellite communities. Temporal variations in the composition of ammonia-oxidizing prokaryotes could be attributed to the seasonal nutrient concentrations. Multivariate statistical analysis indicated that environmental filtering rather than dispersal limitation is the primary mechanism driving the assembly of the whole, core and satellite communities at both taxonomic and functional levels. Network analysis revealed that the mutualistic interactions might also have certain roles in the assembly of the core taxonomic community. However, taxonomic community fluctuations can only partially reflect the functional community variations. Collectively, this study significantly advanced our understanding of the biogeographic pattern of the fluvial prokaryotic communities. PMID- 28810708 TI - Bacteria-induced morphogenesis of Ulva intestinalis and Ulva mutabilis (Chlorophyta): a contribution to the lottery theory. AB - The green marine macroalgae of the class Ulvophyceae (Ulvophytes) are common algae distributed worldwide particularly in intertidal areas, which play a key role in aquatic ecosystems. They are potentially valuable resources for food, animal feed and fuel but can also cause massive nuisance blooms. Members of Ulvaceae, like many other seaweeds, harbour a rich diversity of epiphytic bacteria with functions related to host growth and morphological development. In the absence of appropriate bacterially derived signals, germ cells of the genus Ulva develop into 'atypical' colonies consisting of undifferentiated cells with abnormal cell walls. This paper examines the specificity of bacteria-induced morphogenesis in Ulva, by cross-testing bacteria isolated from several Ulva species on two Ulva species, the emerging model system Ulva mutabilis and the prominent biofouler species Ulva intestinalis. We show that pairs of bacterial strains isolated from species other than U. mutabilis and U. intestinalis can fully rescue axenic plantlets generated either from U. mutabilis or U. intestinalis gametes. This laboratory-based study demonstrates that different compositions of microbial communities with similar functional characteristics can enable complete algal morphogenesis and thus supports the 'competitive lottery' theory for how symbiotic bacteria drive algal development. PMID- 28810709 TI - Parallel Evolution of Sperm Hyper-Activation Ca2+ Channels. AB - Sperm hyper-activation is a dramatic change in sperm behavior where mature sperm burst into a final sprint in the race to the egg. The mechanism of sperm hyper activation in many metazoans, including humans, consists of a jolt of Ca2+ into the sperm flagellum via CatSper ion channels. Surprisingly, all nine CatSper genes have been independently lost in several animal lineages. In Drosophila, sperm hyper-activation is performed through the cooption of the polycystic kidney disease 2 (pkd2) Ca2+ channel. The parallels between CatSpers in primates and pkd2 in Drosophila provide a unique opportunity to examine the molecular evolution of the sperm hyper-activation machinery in two independent, nonhomologous calcium channels separated by > 500 million years of divergence. Here, we use a comprehensive phylogenomic approach to investigate the selective pressures on these sperm hyper-activation channels. First, we find that the entire CatSper complex evolves rapidly under recurrent positive selection in primates. Second, we find that pkd2 has parallel patterns of adaptive evolution in Drosophila. Third, we show that this adaptive evolution of pkd2 is driven by its role in sperm hyper-activation. These patterns of selection suggest that the evolution of the sperm hyper-activation machinery is driven by sexual conflict with antagonistic ligands that modulate channel activity. Together, our results add sperm hyper-activation channels to the class of fast evolving reproductive proteins and provide insights into the mechanisms used by the sexes to manipulate sperm behavior. PMID- 28810710 TI - Testing Convergent Evolution in Auditory Processing Genes between Echolocating Mammals and the Aye-Aye, a Percussive-Foraging Primate. AB - Several taxonomically distinct mammalian groups-certain microbats and cetaceans (e.g., dolphins)-share both morphological adaptations related to echolocation behavior and strong signatures of convergent evolution at the amino acid level across seven genes related to auditory processing. Aye-ayes (Daubentonia madagascariensis) are nocturnal lemurs with a specialized auditory processing system. Aye-ayes tap rapidly along the surfaces of trees, listening to reverberations to identify the mines of wood-boring insect larvae; this behavior has been hypothesized to functionally mimic echolocation. Here we investigated whether there are signals of convergence in auditory processing genes between aye ayes and known mammalian echolocators. We developed a computational pipeline (Basic Exon Assembly Tool) that produces consensus sequences for regions of interest from shotgun genomic sequencing data for nonmodel organisms without requiring de novo genome assembly. We reconstructed complete coding region sequences for the seven convergent echolocating bat-dolphin genes for aye-ayes and another lemur. We compared sequences from these two lemurs in a phylogenetic framework with those of bat and dolphin echolocators and appropriate nonecholocating outgroups. Our analysis reaffirms the existence of amino acid convergence at these loci among echolocating bats and dolphins; some methods also detected signals of convergence between echolocating bats and both mice and elephants. However, we observed no significant signal of amino acid convergence between aye-ayes and echolocating bats and dolphins, suggesting that aye-aye tap foraging auditory adaptations represent distinct evolutionary innovations. These results are also consistent with a developing consensus that convergent behavioral ecology does not reliably predict convergent molecular evolution. PMID- 28810711 TI - Whole RNA-Sequencing and Transcriptome Assembly of Candida albicans and Candida africana under Chlamydospore-Inducing Conditions. AB - Candida albicans is the most common cause of life-threatening fungal infections in humans, especially in immunocompromised individuals. Crucial to its success as an opportunistic pathogen is the considerable dynamism of its genome, which readily undergoes genetic changes generating new phenotypes and shaping the evolution of new strains. Candida africana is an intriguing C. albicans biovariant strain that exhibits remarkable genetic and phenotypic differences when compared with standard C. albicans isolates. Candida africana is well-known for its low degree of virulence compared with C. albicans and for its inability to produce chlamydospores that C. albicans, characteristically, produces under certain environmental conditions. Chlamydospores are large, spherical structures, whose biological function is still unknown. For this reason, we have sequenced, assembled, and annotated the whole transcriptomes obtained from an efficient C. albicans chlamydospore-producing clinical strain (GE1), compared with the natural chlamydospore-negative C. africana clinical strain (CBS 11016). The transcriptomes of both C. albicans (GE1) and C. africana (CBS 11016) clinical strains, grown under chlamydospore-inducing conditions, were sequenced and assembled into 7,442 (GE1 strain) and 8,370 (CBS 11016 strain) high quality transcripts, respectively. The release of the first assembly of the C. africana transcriptome will allow future comparative studies to better understand the biology and evolution of this important human fungal pathogen. PMID- 28810714 TI - Vitamin D supplementation in heart failure: case closed? PMID- 28810712 TI - Genomic Analysis of the Evolution of Phototrophy among Haloalkaliphilic Rhodobacterales. AB - A characteristic feature of the order Rhodobacterales is the presence of a large number of photoautotrophic and photoheterotrophic species containing bacteriochlorophyll. Interestingly, these phototrophic species are phylogenetically mixed with chemotrophs. To better understand the origin of such variability, we sequenced the genomes of three closely related haloalkaliphilic species, differing in their phototrophic capacity and oxygen preference: the photoheterotrophic and facultatively anaerobic bacterium Rhodobaca barguzinensis, aerobic photoheterotroph Roseinatronobacter thiooxidans, and aerobic heterotrophic bacterium Natronohydrobacter thiooxidans. These three haloalcaliphilic species are phylogenetically related and share many common characteristics with the Rhodobacter species, forming together the Rhodobacter Rhodobaca (RR) group. A comparative genomic analysis showed close homology of photosynthetic proteins and similarity in photosynthesis gene organization among the investigated phototrophic RR species. On the other hand, Rhodobaca barguzinensis and Roseinatronobacter thiooxidans lack an inorganic carbon fixation pathway and outer light-harvesting genes. This documents the reduction of their photosynthetic machinery towards a mostly photoheterotrophic lifestyle. Moreover, both phototrophic species contain 5-aminolevulinate synthase (encoded by the hemA gene) incorporated into their photosynthesis gene clusters, which seems to be a common feature of all aerobic anoxygenic phototrophic Alphaproteobacteria. Interestingly, the chrR-rpoE (sigma24) operon, which is part of singlet oxygen defense in phototrophic species, was found in the heterotrophic strain Natronohydrobacter thiooxidans. This suggests that this organism evolved from a photoheterotrophic ancestor through the loss of its photosynthesis genes. The overall evolution of phototrophy among the haloalkaliphilic members of the RR group is discussed. PMID- 28810713 TI - Co-Opted Megasatellite DNA Drives Evolution of Secondary Night Vision in Azara's Owl Monkey. AB - Owl monkeys (genus Aotus) are the only taxon in simian primates that consists of nocturnal or otherwise cathemeral species. Their night vision is superior to that of other monkeys, apes, and humans but not as good as that of typical nocturnal mammals. This incomplete night vision has been used to conclude that these monkeys only secondarily adapted to a nocturnal lifestyle, or to their cathemeral lifestyle that involves high night-time activity. It is known that the rod cells of many nocturnal mammals possess a unique nuclear architecture in which heterochromatin is centrally located. This "inverted nuclear architecture", in contrast with "conventional nuclear architecture", provides elevated night vision by passing light efficiently to the outer segments of photoreceptors. Owl monkey rod cells exhibit an intermediate chromatin distribution, which may provide them with less efficient night vision than other nocturnal mammals. Recently, we identified three megasatellite DNAs in the genome of Azara's owl monkey (Aotus azarae). In the present study, we show that one of the three megasatellite DNAs, OwlRep, serves as the primary component of the heterochromatin block located in the central space of the rod nucleus in A. azarae. This satellite DNA is likely to have emerged in the Aotus lineage after its divergence from those of other platyrrhini taxa and underwent a rapid expansion in the genome. Our results indicate that the heterochromatin core in the A. azarae rod nucleus was newly formed in A. azarae or its recent ancestor, and supports the hypothesis that A. azarae, and with all probability other Aotus species, secondarily acquired night vision. PMID- 28810715 TI - Basic Science and Cardiology I: Basics. PMID- 28810716 TI - Basic Science and Cardiology II: Funding. PMID- 28810717 TI - Andreas Baumbach MD FESC FRCP. PMID- 28810718 TI - My 10th TAVI Anniversary. PMID- 28810720 TI - Risk assessement and its management: from SCORE to statins, ezetimibe to PCSK inhibitors. PMID- 28810719 TI - Delirium in cardiac patients. PMID- 28810722 TI - The clinical epidemiology of young adults starting renal replacement therapy in the UK: presentation, management and survival using 15 years of UK Renal Registry data. PMID- 28810721 TI - De novo low-dose sirolimus versus mycophenolate mofetil in combination with extended-release tacrolimus in kidney transplant recipients: a multicentre, open label, randomized, controlled, non-inferiority trial. AB - Background: Most of the previous studies reported that tacrolimus (TAC) with sirolimus (SRL) was associated with worse post-transplant outcomes in kidney transplantation, compared with TAC with mycophenolate mofetil (MMF). These might be attributable to high-dose SRL. However, outcomes using low-dose SRL with TAC for kidney transplantation are uncertain. The aim of this study was to assess the efficacy and safety of low-dose SRL with extended-release tacrolimus (ER-TAC) versus MMF with ER-TAC. Methods: We randomly assigned 158 renal transplant patients to receive low-dose SRL or MMF in combination with ER-TAC and corticosteroid. The primary endpoint was the composite efficacy failure rate, including biopsy-proven acute rejection (BPAR), graft loss, death or loss to follow-up, within 12 months post-transplantation. This trial is registered with ClinicalTrial.gov (number NCT01680952). Results: The efficacy failure rate was 6.6% in the low-dose SRL group and 13.3% in the MMF group in the intention-to treat population (absolute difference, 6.8%; 95% confidence interval, -2.8% to 16.3%). The incidence of BPAR within 12 months post-transplantation was 5.3% in the low-dose SRL group and 13.3% in the MMF group (P = 0.09). The mean estimated glomerular filtration rate at 12 months post-transplantation was 53.2 mL/min/1.73 m2 in the low-dose SRL group and 52.4 mL/min/1.73 m2 in the MMF group (P = 0.76). The incidences of adverse events and serious adverse events were similar between groups. Conclusion: Low-dose SRL with ER-TAC was not inferior to MMF with ER-TAC with respect to efficacy and safety. When used for immunosuppression in kidney transplantation, low-dose SRL with ER-TAC can effectively prevent acute rejection and preserve renal function. PMID- 28810724 TI - Sympathetic nerve traffic and blood pressure changes after bilateral renal denervation in resistant hypertension: a time-integrated analysis. AB - Background: Renal denervation reduces blood pressure (BP) and sympathetic drive in experimental animal models, but the effect of this intervention on sympathetic activity in patients with treatment-resistant hypertension is still unclear. Methods: In an incident series of 29 patients with treatment-resistant hypertension, we performed serial measurements (n = 123) of muscle sympathetic nerve activity (MSNA, microneurography) and standardized BP measurements. Data were analysed by mixed linear modelling (MLM) and by regression analysis of time integrated changes of both MSNA and synchronous, standardized (in-lab) BP measurements. Results: Bilateral renal denervation was accompanied by a marked reduction in MSNA (P = 0.01 by MLM), which was parallelled by a reduction in systolic (from 175 +/- 14 to 156 +/- 16 mmHg) and, to a lesser extent, in diastolic (from 96 +/- 12 to 87 +/- 6 mmHg) BP over time. Neither systolic nor diastolic BP associated to a significant extent with corrected MSNA (MSNAC) in the MLM analysis (systolic BP versus MSNAC: beta = -0.08, P = 0.08; diastolic BP versus MSNAC: beta = -0.007, P = 0.75). However, the study of time-integrated changes in MSNA and BP showed a robust association between proportional changes in MSNA over time and simultaneous changes in systolic and diastolic BP (beta = 0.61, P < 0.001 and beta = 0.37 P < 0.05). Conclusions: Time-integrated changes in MSNAC and BP after bilateral renal denervation document a close link between the sympathetic activity and BP responses to this procedure. These findings further strengthen the relevance of the sympathetic nervous system both in the pathophysiology of resistant hypertension and in the BP-lowering effect of the procedure. PMID- 28810723 TI - Graft survival of pediatric kidney transplant recipients selected for de novo steroid avoidance-a propensity score-matched study. AB - Background: Steroid-avoidance protocols have gained popularity in pediatric kidney transplant recipients at low immunologic risk. The long-term safety of steroid avoidance in children with immunologic risk factors remains unknown. Methods: Pediatric kidney transplant recipients from 2004 to 2014 in the Organ Procurement and Transplantation Network database who received tacrolimus and mycophenolate immunosuppression were investigated. Propensity score matching was used to compare graft survival in 1624 children who received steroid avoidance with 1624 children who received steroid-based immunosuppression. The effect of steroid avoidance on graft failure among immunologic risk strata was estimated using Cox proportional hazards regression in this propensity score-matched cohort. Results: It was observed that 5-year graft survival was mildly improved in children receiving steroid avoidance (84.8% versus 81.2%, P = 0.03). This improvement in graft survival occurred in the first 2 years following transplant, when the hazard ratio (HR) for allograft failure in children receiving steroid avoidance was 0.62 [95% confidence interval (CI) 0.45-0.86]. In contrast, steroid avoidance was not associated with improved allograft survival during Years 2-10 following transplant (HR = 0.93; 95% CI 0.75-1.15). During this time period, HRs (95% CIs) for allograft failure within immunologic risk strata were not significantly different from the null value of 1: repeat kidney transplants, 1.84 (0.84-4.05); African-Americans, 1.02 (0.67-1.56); sensitized recipients, 1.24 (0.63-2.43); recipients of deceased donor kidneys, 1.02 (0.79-1.32); recipients of completely human leukocyte antigen-mismatched kidneys, 0.80 (0.47-1.37); and recipients with pretransplant glomerular disease, 0.94 (0.71-1.23). Conclusions: In pediatric kidney transplant recipients receiving tacrolimus- and mycophenolate based immunosuppression, steroid avoidance can be safely practiced in children with immunologic risk factors. PMID- 28810725 TI - Does renal denervation lower sympathetic activity? PMID- 28810726 TI - Diagnostic and therapeutic approach to peritonitis. PMID- 28810727 TI - NDT Digest: rapid revelations in renal disease. PMID- 28810728 TI - Is There a Link between Clinical Manifestation of Gastric Anisakiasis and Helicobacter pylori Infection? PMID- 28810729 TI - Thermal Stability of Organic Monolayers Grafted to Si(111): Insights from ReaxFF Reactive Molecular Dynamics Simulations. AB - We used the ReaxFF reactive molecular dynamics simulations to investigate the chemical mechanisms and kinetics of thermal decomposition processes of silicon surfaces grafted with different organic molecules via Si-C bonds at atomistic level. In this work, we considered the Si(111) surface grafted with n-alkyl (ethyl, propyl, pentyl, and decyl) layers in 50% coverage and, Si-CH3, Si-CCCH3 and Si-CHCHCH3 layers in full coverage. Si radicals primarily formed by the homolytic cleavage of Si-C bonds play a key role in the dehydrogenation processes that lead to the decomposition of the monolayers. Contrary to commonly proposed mechanisms that only involve a single Si atom center, we found that the main decomposition pathways require two Si lattice atoms to proceed. The ability of surface silyl radicals to dehydrogenate the organic molecules depends on the flexibility of the carbon backbones of the organic molecules as well as on the C H bond strength. The dehydrogenation of n-alkyl chains mainly involves the H atoms of the beta-carbon (leading to 1-alkene desorption). However, as the surface coverage decreases, the flexibility of the alkyl chains allows for the dehydrogenation of any methylene group and even the terminal methyl group of the long decyl layer. On the contrary, the rigid carbon backbone of the Si-CCCH3 and Si-CHCHCH3 moieties hinders the dehydrogenation of the terminal methyl group, which confers these layers a higher thermal stability. For all layers, the surface ends up mostly hydrogenated as Si-C bonds break and new Si-H bonds are formed during the dehydrogenation reactions. PMID- 28810730 TI - Hydrogen Isotope Fractionation during the Biodegradation of 1,2-Dichloroethane: Potential for Pathway Identification Using a Multi-element (C, Cl, and H) Isotope Approach. AB - Even though multi-element isotope fractionation patterns provide crucial information with which to identify contaminant degradation pathways in the field, those involving hydrogen are still lacking for many halogenated groundwater contaminants and degradation pathways. This study investigates for the first time hydrogen isotope fractionation during both aerobic and anaerobic biodegradation of 1,2-dichloroethane (1,2-DCA) using five microbial cultures. Transformation associated isotope fractionation values (epsilonbulkH) were -115 +/- 180/00 (aerobic C-H bond oxidation), -34 +/- 40/00 and -38 +/- 40/00 (aerobic C-Cl bond cleavage via hydrolytic dehalogenation), and -57 +/- 30/00 and -77 +/- 90/00 (anaerobic C-Cl bond cleavage via reductive dihaloelimination). The dual-element C-H isotope approach (LambdaC-H = Deltadelta2H/Deltadelta13C ~ epsilonbulkH/epsilonbulkC, where Deltadelta2H and Deltadelta13C are changes in isotope ratios during degradation) resulted in clearly different LambdaC-H values: 28 +/- 4 (oxidation), 0.7 +/- 0.1 and 0.9 +/- 0.1 (hydrolytic dehalogenation), and 1.76 +/- 0.05 and 3.5 +/- 0.1 (dihaloelimination). This result highlights the potential of this approach to identify 1,2-DCA degradation pathways in the field. In addition, distinct trends were also observed in a multi (i.e., Deltadelta2H versus Deltadelta37Cl versus Deltadelta13C) isotope plot, which opens further possibilities for pathway identification in future field studies. This is crucial information to understand the mechanisms controlling natural attenuation of 1,2-DCA and to design appropriate strategies to enhance biodegradation. PMID- 28810732 TI - Tracking Radionuclide Fractionation in the First Atomic Explosion Using Stable Elements. AB - Compositional analysis of postdetonation fallout is a tool for forensic identification of nuclear devices. However, the relationship between device composition and fallout composition is difficult to interpret because of the complex combination of physical mixing, nuclear reactions, and chemical fractionations that occur in the chaotic nuclear fireball. Using a combination of in situ microanalytical techniques (electron microprobe analysis and secondary ion mass spectrometry), we show that some heavy stable elements (Rb, Sr, Zr, Ba, Cs, Ba, La, Ce, Nd, Sm, Dy, Lu, U, Th) in glassy fallout from the first nuclear test, Trinity, are reliable chemical proxies for radionuclides generated during the explosion. Stable-element proxies show that radionuclides from the Trinity device were chemically, but not isotopically, fractionated by condensation. Furthermore, stable-element proxies delineate chemical fractionation trends that can be used to connect present-day fallout composition to past fireball composition. Stable-element proxies therefore offer a novel approach for elucidating the phenomenology of the nuclear fireball as it relates to the formation of debris and the fixation of device materials within debris. PMID- 28810731 TI - Impact of Hydrogen Bonding on the Dynamics and Structure of Protic Ionic Liquid/Water Binary Mixtures. AB - The orientational dynamics and microscopic liquid structure of a protic ionic liquid, 1-ethylimidazolium bis(trifluoromethylsulfonyl)imide (EhimNTf2), and its aprotic analogue, 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide (EmimNTf2), were studied at various water concentrations using optical heterodyne detected optical Kerr effect (OHD-OKE) spectroscopy, linear infrared spectroscopy, and atomistic simulations. The OHD-OKE experiments essentially measure the orientational relaxation of the Ehim+ and Emim+ cations. The experiments and simulations show a significant dynamical and structural change in EhimNTf2 between the 2:1 ion pair:water and the 1:1 ion pair:water concentrations. The OHD-OKE data show that EmimNTf2/water mixtures exhibit hydrodynamic behavior at all water concentrations up to saturation. In contrast, EhimNTf2/water mixtures deviate from hydrodynamic behavior at water concentrations above 2:1. At the 1:1 concentration, the orientational randomization of the Ehim+ cation is slower than that predicted using viscosity data. Atomistic simulation results reveal the microscopic ionic structures of dry liquids and the preferential hydrogen bonding of water to the H atom of the N-H of Ehim+ over other sites on the Ehim+ and Emim+ cations. Atomistic simulation results demonstrate that in EhimNTf2 RTIL/water mixtures there is a substantial jump in the formation of water-water hydrogen bonds in addition to N-H-water hydrogen bonds upon increasing the water concentration from 2:1 to 1:1. Water water hydrogen bonding strengthens the spatial coordination of the H atom of the N-H moiety of Ehim+ to neighboring water molecules through preferential hydrogen bonding. The jump in the concentration of water-water hydrogen bonds occurs at the Ehim+/water concentration at which the orientational relaxation deviates from hydrodynamic behavior. This structural observation is confirmed with FT-IR spectra that show asymmetry in the peak for the O-D stretch that is indicative of water clusters. The formation of water clusters and the strengthening of the N H...OH2 hydrogen bonds slow the orientational relaxation of Ehim+ cations as observed by the OHD-OKE experiments. PMID- 28810733 TI - Doxorubicin and Indocyanine Green Loaded Hybrid Bicelles for Fluorescence Imaging Guided Synergetic Chemo/Photothermal Therapy. AB - Hybrid bicelles have been demonstrated to have great potential for hydrophobic drug delivery. Herein, we report a near-infrared light-driven, temperature sensitive hybrid bicelles co-encapsulating hydrophobic doxorubicin (DOX) and indocyanine green (ICG) (DOX/ICG@HBs). Encapsulation of ICG into the lipid bilayer membrane of DOX/ICG@HBs results in higher photostability than free ICG. DOX/ICG@HBs exhibited temperature-regulated drug release behavior and significant photothermal cytotoxicity. After tail vein injection, such discotic nanoparticles of DOX/ICG@HBs were found to accumulate selectively at the tumor site and act as an efficient probe to enhance fluorescence imaging greatly. The in vivo experiments showed that the DOX/ICG@HBs-mediated chemo- and photothermal combination therapy was more cytotoxic to tumor cells than the photothermal treatment or the chemotherapy alone due to the synergistic effect, reducing the occurrence of tumor metastasis. Therefore, DOX/ICG@HBs can act as a powerful nanotheranostic agent for chemo/photothermal therapy of cancer under the guidance of near-infrared fluorescence imaging. PMID- 28810734 TI - Adsorption and Depletion Regimes of a Nonionic Surfactant in Hydrophilic Mesopores: An Experimental and Simulation Study. AB - Adsorption and aggregation of nonionic surfactants at oxide surfaces has been studied extensively in the past, but only for concentrations below and near the critical micelle concentration. Here we report an adsorption study of a short chain surfactant (C6E3) in porous silica glass of different pore sizes (7.5 to 50 nm), covering a wide composition range up to 50 wt % in a temperature range from 20 degrees C to the LCST. Aggregative adsorption is observed at low concentrations, but the excess concentration of C6E3 in the pores decreases and approaches zero at higher bulk concentrations. Strong depletion of surfactant (corresponding to enrichment of water in the pores) is observed in materials with wide pores at high bulk concentrations. We propose an explanation for the observed pore-size dependence of the azeotropic point. Mesoscale simulations based on dissipative particle dynamics (DPD) were performed to reveal the structural origin of this transition from the adsorption to the depletion regime. The simulated adsorption isotherms reproduce the behavior found in the 7.5 nm pores. The calculated bead density profiles indicate that the repulsive interaction of surfactant head groups causes a depletion of surfactant in the region around the corona of the surface micelles. PMID- 28810735 TI - Accurate Electrochemistry Analysis of Circulating Methylated DNA from Clinical Plasma Based on Paired-End Tagging and Amplifications. AB - Circulating methylated DNA has been a new kind of cancer biomarker, yet its small fraction of trace total DNA from clinical samples impairs the accurate analysis. Though fluorescence methods based on quantitative methylation specific PCR (qMSP) have been adopted routinely, yet alternative electrochemistry assay of such DNA from clinical samples remains a great challenge. Herein, we report accurate electrochemistry analysis of circulating methylated DNA from clinical plasma samples based on a paired-end tagging and amplifications strategy. Two DNA primers each labeled with digoxigenin (Dig) and biotin are designed for the recognition and amplification of methylated DNA. Paired-end tagging amplicons and avidin-HRP molecules are successively captured on the electrode modified with Anti-Dig. Then HRP executes catalytic reaction to generate amplified signal. The design of paired-end tagging can readily integrate downstream electrochemical amplified reaction, and two heterogeneous amplifications enable high assay sensitivity. As little as 40 pg of methylated genomic DNA (~10 genomic equivalents) is well identified, and our strategy can even distinguish as low as 1% methylation level. Tumor-specific methylated DNA is clearly detected in the plasma of 10 of 11 NSCLC patients. The high clinical sensitivity of 91% (10/11) indicates the good consistency with clinical diagnosis. Excellent spatial control of electrochemistry allows simpler detection of more methylation patterns compared to fluorescence methods. The developed electrochemical assay is a promising liquid biopsy tool for the analysis of tumor-specific circulating DNA. PMID- 28810736 TI - Microstructure of Flow-Driven Suspension of Hardspheres in Cylindrical Confinement: A Dynamical Density Functional Theory and Monte Carlo Study. AB - We have studied the microstructure of a flow-driven hardsphere suspension inside a cylinder using dynamical density functional theory and Monte Carlo simulations. In order to be representative of various physical conditions that may prevail in experiments, we investigate the problem using both the grand canonical (MUVT) ensemble and the canonical (NVT) ensemble. In both ensembles, the hydrodynamic effect on the suspension mediated by the presence of the confining wall is implemented in a mean-field fashion by incorporating the thermodynamic work done by the inertial lift force on the particle given the average flow field. The predicted particle distribution in the MUVT ensemble displays strong structural ordering at increasing flow rates due to the correspondingly higher particle concentrations inside the cylinder. In the NVT ensemble, for dilute suspensions we observe a peak in the distribution of density at a location similar to that of the Segre-Silberberg annulus, while for dense suspensions the competing effects of the inertial lift and the hardsphere interaction lead to the formation of several annuli. PMID- 28810737 TI - Identification of the Colicin V Bacteriocin Gene Cluster by Functional Screening of a Human Microbiome Metagenomic Library. AB - The forces that shape human microbial ecology are complex. It is likely that human microbiota, similarly to other microbiomes, use antibiotics as one way to establish an ecological niche. In this study, we use functional metagenomics to identify human microbial gene clusters that encode for antibiotic functions. Screening of a metagenomic library prepared from a healthy patient stool sample led to the identification of a family of clones with inserts that are 99% identical to a region of a virulence plasmid found in avian pathogenic Escherichia coli. Characterization of the metagenomic DNA sequence identified a colicin V biosynthetic cluster as being responsible for the observed antibiotic effect of the metagenomic clone against E. coli. This study presents a scalable method to recover antibiotic gene clusters from humans using functional metagenomics and highlights a strategy to study bacteriocins in the human microbiome which can provide a resource for therapeutic discovery. PMID- 28810738 TI - Nature of the Active Sites for CO Reduction on Copper Nanoparticles; Suggestions for Optimizing Performance. AB - Recent experiments show that the grain boundaries (GBs) of copper nanoparticles (NPs) lead to an outstanding performance in reducing CO2 and CO to alcohol products. We report here multiscale simulations that simulate experimental synthesis conditions to predict the structure of a 10 nm Cu NP (158 555 atoms). To identify active sites, we first predict the CO binding at a large number of sites and select four exhibiting CO binding stronger than the (211) step surface. Then, we predict the formation energy of the *OCCOH intermediate as a descriptor for C-C coupling, identifying two active sites, both of which have an under coordinated surface square site adjacent to a subsurface stacking fault. We then propose a periodic Cu surface (4 by 4 supercell) with a similar site that substantially decreases the formation energy of *OCCOH, by 0.14 eV. PMID- 28810739 TI - A Hexa-rhodium Metallopeptide Catalyst for Site-Specific Functionalization of Natural Antibodies. AB - Preparation of antibody-drug conjugates (ADCs), an emerging novel class of highly targeted biological hybrid agents, necessitates precise control of conjugation reactivity. Antibodies have complex multistranded architectures, and specific modification of natural antibodies has proven quite challenging. Here, we demonstrate that cooperative activity of a multimetallic metallopeptide enables efficient site-specific antibody functionalization, based on molecular recognition of the constant Fc region. This interplay of multiple metal centers enables introduction of an orthogonal alkyne handle into monoclonal or polyclonal antibodies from different species in an Fc-specific fashion. Elaboration of this simple functionalization allows preparation of conjugates with fluorophore, affinity handle, and pharmacological agents. This method opens a new opportunity for quick and easy production of well-defined antibody conjugates from a variety of antibody sequence and species of origin. PMID- 28810740 TI - Cis/Trans Isomerization in Secondary Amides: Reaction Paths, Nitrogen Inversion, and Relevance to Peptidic Systems. AB - Cis/trans isomerization of 2 degrees -amide bonds is a key step in a wide range of important processes. Here we present a theoretical assessment of cis/trans isomerization of 2 degrees -amide bonds using B3LYP density functional methods, describing two reaction paths and corresponding geometry changes during isomerization of N-methylacetamide (NMA) and glycylglycine methyl ester (GGMe). The isomerization begins via a common path, as the extended pi-bonding of the amide bond maintains approximate planarity of the O-C-N-H dihedral angle, with only gradually increasing pyramidalization of the nitrogen atom, until a bifurcation point is reached. Both subsequent paths comprise two phases, an "omega phase" (characterized by a major change in C-C-N-C dihedral) and a "theta phase" (characterized by major change in O-C-N-H dihedral), with two distinct transition states. The theta phase involves inversion of the pyramidal amide nitrogen geometry. Both reaction paths converge at another bifurcation point near the opposite geometry. Studies on the larger GGMe show in addition that the multiple additional rotamers do not change the qualitative properties of the isomerization, but do affect the energies of the differing transition states. These detailed results provide significant new insights into cis/trans isomerization paths in 2 degrees -amides, and serve as a basis for theoretical studies on larger peptidic systems. PMID- 28810741 TI - Photochemical Synthesis of 3-Azabicyclo[3.2.0]heptanes: Advanced Building Blocks for Drug Discovery. AB - We have developed a rapid two-step synthesis of substituted 3 azabicyclo[3.2.0]heptanes which are attractive building blocks for drug discovery. This new method utilizes very common chemicals, benzaldehyde, allylamine, and cinnamic acid, via intramolectular [2+2]-photochemical cyclization. PMID- 28810742 TI - Determination of Rate-Limiting Factor for Formation of Beta-Catenin Destruction Complexes Using Absolute Protein Quantification. AB - Wnt/beta-catenin signaling plays important roles in both ontogenesis and development. In the absence of a Wnt stimulus, beta-catenin is degraded by a multiprotein "destruction complex" that includes Axin, APC, GSK3B, and FBXW11. Although the key molecules required for transducing Wnt signals have been identified, a quantitative understanding of this pathway has been lacking. Here, we calculated the absolute number of beta-catenin destruction complexes by absolute protein quantification using LC-MS/MS. Similar amounts of destruction complex-constituting proteins and beta-catenin interacted, and the number of destruction complexes was calculated to be about 1468 molecules/cell. We demonstrated that the calculated number of destruction complexes was valid for control of the beta-catenin destruction rate under steady-state conditions. Interestingly, APC had the minimum expression level among the destruction complex components at about 2233 molecules/cell, and this number approximately corresponded to the calculated number of destruction complexes. Decreased APC expression by siRNA transfection decreased the number of destruction complexes, resulting in beta-catenin accumulation and stimulation of the transcriptional activity of T-cell factor. Taken together, our results suggest that the amount of APC expression is the rate-limiting factor for the constitution of beta-catenin destruction complexes. PMID- 28810743 TI - Layer-by-Layer Molecular Assemblies for Dye-Sensitized Photoelectrosynthesis Cells Prepared by Atomic Layer Deposition. AB - In a dye sensitized photoelectrosynthesis cell (DSPEC), the relative orientation of the catalyst and chromophore plays an important role in determining the device efficiency. Here we introduce a new, robust atomic layer deposition (ALD) procedure for the preparation of molecular chromophore-catalyst assemblies on wide bandgap semiconductors. In this procedure, solution deposited, phosphonate derivatized metal complexes on metal oxide surfaces are treated with reactive metal reagents in the gas phase by ALD to form an outer metal ion bridging group, which can bind a second phosphonate containing species from solution to establish a R1-PO2-O-M-O-PO2-R2 type surface assembly. With the ALD procedure, assemblies bridged by Al(III), Sn(IV), Ti(IV), or Zr(IV) metal oxide units have been prepared. To evaluate the performance of this new type of surface assembly, intra assembly electron transfer was investigated by transient absorption spectroscopy, and light-driven water splitting experiments under steady-state illumination were conducted. A SnO2 bridged assembly on SnO2/TiO2 core/shell electrodes undergoes light-driven water oxidation with an incident photon to current efficiency (IPCE) of 17.1% at 440 nm. Light-driven water reduction with a ruthenium trisbipyridine chromophore and molecular Ni(II) catalyst on NiO films was also used to produce H2. Compared to conventional solution-based procedures, the ALD approach offers significant advantages in scope and flexibility for the preparation of stable surface structures. PMID- 28810744 TI - ACS Chemical Neuroscience: Most Cited Papers from 2015. PMID- 28810745 TI - Torn from the Headlines: Angiostrongylus cantonensis (Rat Lungworm) Is Established in Florida. PMID- 28810746 TI - New 2016 Data and Statistics for Global Pharmaceutical Products and Projections through 2017. PMID- 28810748 TI - Chronic Traumatic Encephalopathy (CTE): A Brief Historical Overview and Recent Focus on NFL Players. PMID- 28810750 TI - The metal-insulator transition in the organic conductor beta"-(BEDT TTF)2Hg(SCN)2Cl. AB - We explore the nature of the metal-insulator transition in the two-dimensional organic compound beta"-(BEDT-TTF)2Hg(SCN)2Cl by x-ray, electrical transport, ESR, Raman, and infrared investigations. Magnetic and vibrational spectroscopy concurrently reveal a gradual dimerization along the stacking direction (a-b), setting in already at the crossover temperature of 150 K from the metallic to the insulating state. A spin gap of Deltasigma=47 meV is extracted. From the activated resistivity behavior below T = 55 K, a charge gap of Deltarho=60 meV is derived. At TCO = 72 K, the C=C vibrational modes reveal the development of a charge-ordered state with a charge disproportionation of 2deltarho=0.34e. In addition to a slight structural dimerization, charge-order causes stripes most likely perpendicular to the stacks. PMID- 28810751 TI - Communication: On the diffusion tensor in macroscopic theory of cavitation. AB - The classical description of nucleation of cavities in a stretched fluid relies on a one-dimensional Fokker-Planck equation (FPE) in the space of their sizes r, with the diffusion coefficient D(r) constructed for all r from macroscopic hydrodynamics and thermodynamics, as shown by Zeldovich. When additional variables (e.g., vapor pressure) are required to describe the state of a bubble, a similar approach to construct a diffusion tensor D^ generally works only in the direct vicinity of the thermodynamic saddle point corresponding to the critical nucleus. It is shown, nevertheless, that "proper" kinetic variables to describe a cavity can be selected, allowing to introduce D^ in the entire domain of parameters. In this way, for the first time, complete FPE's are constructed for viscous volatile and inertial fluids. In the former case, the FPE with symmetric D^ is solved numerically. Alternatively, in the case of an inertial fluid, an equivalent Langevin equation is considered; results are compared with analytics. The suggested approach is quite general and can be applied beyond the cavitation problem. PMID- 28810752 TI - Rupturing the hemi-fission intermediate in membrane fission under tension: Reaction coordinates, kinetic pathways, and free-energy barriers. AB - Membrane fission is a fundamental process in cells, involved inter alia in endocytosis, intracellular trafficking, and virus infection. Its underlying molecular mechanism, however, is only incompletely understood. Recently, experiments and computer simulation studies have revealed that dynamin-mediated membrane fission is a two-step process that proceeds via a metastable hemi fission intermediate (or wormlike micelle) formed by dynamin's constriction. Importantly, this hemi-fission intermediate is remarkably metastable, i.e., its subsequent rupture that completes the fission process does not occur spontaneously but requires additional, external effects, e.g., dynamin's (unknown) conformational changes or membrane tension. Using simulations of a coarse-grained, implicit-solvent model of lipid membranes, we investigate the molecular mechanism of rupturing the hemi-fission intermediate, such as its pathway, the concomitant transition states, and barriers, as well as the role of membrane tension. The membrane tension is controlled by the chemical potential of the lipids, and the free-energy landscape as a function of two reaction coordinates is obtained by grand canonical Wang-Landau sampling. Our results show that, in the course of rupturing, the hemi-fission intermediate undergoes a "thinning -> local pinching -> rupture/fission" pathway, with a bottle-neck shaped cylindrical micelle as a transition state. Although an increase of membrane tension facilitates the fission process by reducing the corresponding free-energy barrier, for biologically relevant tensions, the free-energy barriers still significantly exceed the thermal energy scale kBT. PMID- 28810753 TI - Dynamical transition in molecular glasses and proteins observed by spin relaxation of nitroxide spin probes and labels. AB - In glassy substances and biological media, dynamical transitions are observed in neutron scattering that manifests itself as deviations of the translational mean squared displacement, , of hydrogen atoms from harmonic dynamics. In biological media, the deviation occurs at two temperature intervals, at ~100-150 K and at ~170-230 K, and it is attributed to the motion of methyl groups in the former case and to the transition from harmonic to anharmonic or diffusive motions in the latter case. In this work, electron spin echo (ESE) spectroscopy-a pulsed version of electron paramagnetic resonance-is applied to study the spin relaxation of nitroxide spin probes and labels introduced in molecular glass former o-terphenyl and in protein lysozyme. The anisotropic contribution to the rate of the two-pulse ESE decay, DeltaW, is induced by spin relaxation appearing because of restricted orientational stochastic molecular motion; it is proportional to tauc, where is the mean-squared angle of reorientation of the nitroxide molecule around the equilibrium position and tauc is the correlation time of reorientation. The ESE time window allows us to study motions with tauc < 10-7 s. For glassy o-terphenyl, the tauc temperature dependence shows a transition near 240 K, which is in agreement with the literature data on . For spin probes of essentially different size, the obtained data were found to be close, which evidences that motion is cooperative, involving a nanocluster of several neighboring molecules. For the dry lysozyme, the tauc values below 260 K were found to linearly depend on the temperature in the same way as it was observed in neutron scattering for . As spin relaxation is influenced only by stochastic motion, the harmonic motions seen in ESE must be overdamped. In the hydrated lysozyme, ESE data show transitions near 130 K for all nitroxides, near 160 K for the probe located in the hydration layer, and near 180 K for the label in the protein interior. For this system, the two latter transitions are not observed in neutron scattering. The ESE-detected transitions are suggested to be related with water dynamics in the nearest hydration shell: with water glass transition near 130 K and with the onset of overall water molecular reorientations near 180 K; the disagreement with neutron scattering is ascribed to the larger time window for ESE-detected motions. PMID- 28810754 TI - On the adiabatic representation of Meyer-Miller electronic-nuclear dynamics. AB - The Meyer-Miller (MM) classical vibronic (electronic + nuclear) Hamiltonian for electronically non-adiabatic dynamics-as used, for example, with the recently developed symmetrical quasiclassical (SQC) windowing model-can be written in either a diabatic or an adiabatic representation of the electronic degrees of freedom, the two being a canonical transformation of each other, thus giving the same dynamics. Although most recent applications of this SQC/MM approach have been carried out in the diabatic representation-because most of the benchmark model problems that have exact quantum results available for comparison are typically defined in a diabatic representation-it will typically be much more convenient to work in the adiabatic representation, e.g., when using Born Oppenheimer potential energy surfaces (PESs) and derivative couplings that come from electronic structure calculations. The canonical equations of motion (EOMs) (i.e., Hamilton's equations) that come from the adiabatic MM Hamiltonian, however, in addition to the common first-derivative couplings, also involve second-derivative non-adiabatic coupling terms (as does the quantum Schrodinger equation), and the latter are considerably more difficult to calculate. This paper thus revisits the adiabatic version of the MM Hamiltonian and describes a modification of the classical adiabatic EOMs that are entirely equivalent to Hamilton's equations but that do not involve the second-derivative couplings. The second-derivative coupling terms have not been neglected; they simply do not appear in these modified adiabatic EOMs. This means that SQC/MM calculations can be carried out in the adiabatic representation, without approximation, needing only the PESs and the first-derivative coupling elements. The results of example SQC/MM calculations are presented, which illustrate this point, and also the fact that simply neglecting the second-derivative couplings in Hamilton's equations (and presumably also in the Schrodinger equation) can cause very significant errors. PMID- 28810755 TI - Anomalous critical slowdown at a first order phase transition in single polymer chains. AB - Using Brownian dynamics, we study the dynamical behavior of a polymer grafted onto an adhesive surface close to the mechanically induced adsorption-stretching transition. Even though the transition is first order (in the infinite chain length limit, the stretching degree of the chain jumps discontinuously), the characteristic relaxation time is found to grow according to a power law as the transition point is approached. We present a dynamic effective interface model which reproduces these observations and provides an excellent quantitative description of the simulation data. The generic nature of the theoretical model suggests that the unconventional mixing of features that are characteristic for first-order transitions (a jump in an order parameter) and features that are characteristic of critical points (an anomalous slowdown) may be a common phenomenon in force-driven phase transitions of macromolecules. PMID- 28810756 TI - Precision measurement of electron affinity of Zr and fine structures of its negative ions. AB - The high-resolution photoelectron spectra of Zr- were obtained via the slow electron velocity-map imaging method. The electron affinity of Zr was measured to be 3494.67(72) cm-1 or 0.433 283(89) eV. The accuracy has been improved by a factor of 160 compared with the previous result. The fine structures of Zr- were also well resolved: 251.0(37) (4F5/2), 579.6(8) (4F7/2), and 971.7(12) cm-1 (4F9/2) above the ground state 4F3/2. PMID- 28810757 TI - Encapsulation of epitaxial silicene on ZrB2 with NaCl. AB - Silicene and other two-dimensional materials, such as germanene and stanene, have chemically reactive surfaces and are prone to oxidation in air, and thus require an encapsulation layer for ex situ studies or integration in an electronic device. In this work, we investigated NaCl as an encapsulation material for silicene. NaCl was deposited on the surface of epitaxial silicene on ZrB2(0001) thin films near room temperature and studied using synchrotron-based high resolution photoelectron spectroscopy. The deposition of NaCl resulted in dissociative chemisorption, where the majority of epitaxial silicene reacted to form Si-Clx species. PMID- 28810758 TI - Molecular conformation of linear alkane molecules: From gas phase to bulk water through the interface. AB - We studied the behavior of long chain alkanes (LCAs) as they were transferred from gas to bulk water, through the liquid-vapor interface. These systems were studied using umbrella sampling molecular dynamics simulation and we have calculated properties like free energy profiles, molecular orientation, and radius of gyration of the LCA molecules. The results show changes in conformation of the solutes along the path. LCAs adopt pronounced molecular orientations and the larger ones extend appreciably when partially immersed in the interface. In bulk water, their conformations up to dodecane are mainly extended. However, larger alkanes like eicosane present a more stable collapsed conformation as they approach bulk water. We have characterized the more probable configurations in all interface and bulk regions. The results obtained are of interest for the study of biomatter processes requiring the transfer of hydrophobic matter, especially chain-like molecules like LCAs, from gas to bulk aqueous systems through the interface. PMID- 28810759 TI - Lanthanum-mediated dehydrogenation of 1- and 2-butynes: Spectroscopy and formation of La(C4H4) isomers. AB - La atom reactions with 1-butyne and 2-butyne are carried out in a laser vaporization molecular beam source. Both reactions yield the same La-hydrocarbon products from the dehydrogenation and carbon-carbon bond cleavage and coupling of the butynes. The dehydrogenated species La(C4H4) is characterized with mass analyzed threshold ionization (MATI) spectroscopy and quantum chemical computations. The MATI spectra of La(C4H4) produced from the two reactions exhibit two identical transitions, each consisting of a strong origin band and several vibrational intervals. The two transitions are assigned to the ionization of two isomers: La(eta4-CH2CCCH2) (Iso A) and La(eta4-CH2CHCCH) (Iso B). The ground electronic states are 2A1 (C2v) for Iso A and 2A (C1) for Iso B. The ionization of the doublet state of each isomer removes a La 6s-based electron and results in a 1A1 ion of Iso A and a 1A ion of Iso B. The formation of Iso A from 2-butyne and Iso B from 1-butyne involves the addition of La to the C=C triple bond, the activation of two C(sp3)-H bonds, and concerted elimination of a H2 molecule. The formation of Iso A from 1-butyne and Iso B from 2-butyne involves the isomerization of the two butynes to 1,2-butadiene in addition to the concerted H2 elimination. PMID- 28810760 TI - A thermodynamic model of contact angle hysteresis. AB - When a three-phase contact line moves along a solid surface, the contact angle no longer corresponds to the static equilibrium angle but is larger when the liquid is advancing and smaller when the liquid is receding. The difference between the advancing and receding contact angles, i.e., the contact angle hysteresis, is of paramount importance in wetting and capillarity. For example, it determines the magnitude of the external force that is required to make a drop slide on a solid surface. Until now, fundamental origin of the contact angle hysteresis has been controversial. Here, this origin is revealed and a quantitative theory is derived. The theory is corroborated by the available experimental data for a large number of solid-liquid combinations. The theory is applied in modelling the contact angle hysteresis on a textured surface, and these results are also in quantitative agreement with the experimental data. PMID- 28810761 TI - Closures of the functional expansion hierarchy in the non-Markovian quantum state diffusion approach. AB - To find a practical scheme to numerically solve the non-Markovian Quantum State Diffusion equation (NMQSD), one often uses a functional expansion of the functional derivative that appears in the general NMQSD equation. This expansion leads to a hierarchy of coupled operators. It turned out that if one takes only the zeroth order term into account, one has a very efficient method that agrees remarkably well with the exact results for many cases of interest. We denote this approach as zeroth order functional expansion (ZOFE). In the present work, we investigate two extensions of ZOFE. Firstly, we investigate how the hierarchy converges when taking higher orders into account (which, however, leads to a fast increase in numerical size). Secondly, we demonstrate that by using a terminator that approximates the higher order contributions, one can obtain significant improvement, at hardly any additional computational cost. We carry out our investigations for the case of absorption spectra of molecular aggregates. PMID- 28810762 TI - Phase diagram of Janus particles: The missing dimension of pressure anisotropy. AB - Brownian dynamics simulations of single-patch Janus particles under sedimentation equilibrium reveal that the phases found at fixed temperature and volume fraction are extremely sensitive to small changes in lateral box dimension. We trace this sensitivity to an uncontrolled parameter, namely, the pressure component parallel to the hexagonally ordered layers formed through sedimentation. We employ a flexible-cell constant-pressure scheme to achieve explicit control over this usually overlooked parameter, enabling the estimation of phase behavior under given pressure anisotropy. Our results show an increase in the stability range of an orientationally ordered lamellar phase with lateral layer compression and suggest a novel mechanism to control solid-solid phase transitions with negligible change in system volume, thus showing prospect for design of novel structures and switchable crystals from anisotropic building blocks. PMID- 28810763 TI - The collision-free photochemistry of methyl azide at 157 nm: Mechanism and energy release. AB - Synchrotron radiation VUV-photoionization based photofragment translational spectroscopy was used to identify the primary and secondary photodissociation reactions of methyl azide (CH3N3) at 157 nm under collision-free conditions. Two primary dissociation channels are identified, leading to CH3 + N3 (the radical channel) and CH3N + N2 (the molecular elimination channel). The last channel is the major dissociation pathway, but unlike work at longer photolysis wavelengths, here, the radical channel exclusively produces the higher energy isomer cyclic N3. Product time-of-flight data for both channels were obtained and compared with earlier work on methyl azide photochemistry at 193 nm based on electron impact ionization, allowing us to estimate a product branching ratio PhiCH3-N3 PhiCH3N N2 =2.3%+/-0.6%97.7%+/-0.6%. PMID- 28810764 TI - Many-body dynamics of chemically propelled nanomotors. AB - The collective behavior of chemically propelled sphere-dimer motors made from linked catalytic and noncatalytic spheres in a quasi-two-dimensional confined geometry is studied using a coarse-grained microscopic dynamical model. Chemical reactions at the catalytic spheres that convert fuel to product generate forces that couple to solvent degrees of freedom as a consequence of momentum conservation in the microscopic dynamics. The collective behavior of the many body system is influenced by direct intermolecular interactions among the motors, chemotactic effects due to chemical gradients, hydrodynamic coupling, and thermal noise. Segregation into high and low density phases and globally homogeneous states with strong fluctuations are investigated as functions of the motor characteristics. Factors contributing to this behavior are discussed in the context of active Brownian models. PMID- 28810765 TI - High pressure studies on structural and secondary relaxation dynamics in silyl derivative of D-glucose. AB - In this paper, broadband dielectric spectroscopy was applied to investigate molecular dynamics of 1,2,3,4,6-penta-O-(trimethylsilyl)-D-glucopyranose (S-GLU) at ambient and elevated pressures. Our studies showed that apart from the structural relaxation, one well resolved asymmetric secondary process (initially labeled as beta) is observed in the spectra measured at p = 0.1 MPa. Analysis with the use of the coupling model and criterion proposed by Ngai and Capaccioli indicated that the beta-process in S-GLU is probably a Johari-Goldstein relaxation of intermolecular origin. Further high pressure experiments demonstrated that there are in fact two secondary processes contributing to the beta-relaxation. Therefore, one can postulate that the coupling model is a necessary, but not sufficient criterion to identify the true nature of the given secondary relaxation process. The role of pressure experiments in better understanding of the molecular origin of local mobility seems to be much more important. Interestingly, our research also revealed that the structural relaxation in S-GLU is very sensitive to compression. It was reflected in an extremely high pressure coefficient of the glass transition temperature (dTg/dp = 412 K/GPa). According to the literature data, such a high value of dTg/dp has not been obtained so far for any H-bonded, van der Waals, or polymeric glass-formers. PMID- 28810767 TI - Non-hydrodynamic transverse collective excitations in hard-sphere fluids. AB - Collective excitations in hard-sphere fluids were studied in a wide range of wave numbers and packing fractions eta by means of molecular dynamics simulations. We report the observation of non-hydrodynamic transverse excitations for packing fractions eta>=0.395 in the shape of transverse current spectral functions. Dispersion of longitudinal excitations in the whole range of packing fractions shows a negative deviation from the linear hydrodynamic law with increasing wave numbers even for dense hard-sphere fluids where the transverse excitations were observed. These results do not support a recent proposal within the "Frenkel line" approach that the positive sound dispersion in liquids is defined by transverse excitations. We report calculations of the cutoff "Frenkel frequencies" for transverse excitations in hard-sphere fluids and discuss their consistency with the estimated dispersions of shear waves. PMID- 28810768 TI - Massively parallel GPU-accelerated minimization of classical density functional theory. AB - In this paper, we discuss the ability to numerically minimize the grand potential of hard disks in two-dimensional and of hard spheres in three-dimensional space within the framework of classical density functional and fundamental measure theory on modern graphics cards. Our main finding is that a massively parallel minimization leads to an enormous performance gain in comparison to standard sequential minimization schemes. Furthermore, the results indicate that in complex multi-dimensional situations, a heavy parallel minimization of the grand potential seems to be mandatory in order to reach a reasonable balance between accuracy and computational cost. PMID- 28810766 TI - Mixtures of two self- and mutually-associating liquids: Phase behavior, second virial coefficients, and entropy-enthalpy compensation in the free energy of mixing. AB - The theoretical description of the phase behavior of polymers dissolved in binary mixtures of water and other miscible solvents is greatly complicated by the self- and mutual-association of the solvent molecules. As a first step in treating these complex and widely encountered solutions, we have developed an extension of Flory-Huggins theory to describe mixtures of two self- and mutually-associating fluids comprised of small molecules. Analytic expressions are derived here for basic thermodynamic properties of these fluid mixtures, including the spinodal phase boundaries, the second osmotic virial coefficients, and the enthalpy and entropy of mixing these associating solvents. Mixtures of this kind are found to exhibit characteristic closed loop phase boundaries and entropy-enthalpy compensation for the free energy of mixing in the low temperature regime where the liquid components are miscible. As discussed by Widom et al. [Phys. Chem. Chem. Phys. 5, 3085 (2003)], these basic miscibility trends, quite distinct from those observed in non-associating solvents, are defining phenomenological characteristics of the "hydrophobic effect." We find that our theory of mixtures of associating fluids captures at least some of the thermodynamic features of real aqueous mixtures. PMID- 28810769 TI - Simulation of photo-excited adenine in water with a hierarchy of equations of motion approach. AB - We present a theoretical method to simulate the electronic dynamics and two dimensional ultraviolet spectra of the nucleobase adenine in water. The method is an extension of the hierarchy of equations of motion approach to treat a model with one or more conical intersections. The application to adenine shows that a two-level model with a direct conical intersection between the optically bright state and the ground state, generating a hot ground state, is not consistent with experimental observations. This supports a three-level model for the decay of electronically excited adenine in water as was previously proposed in the work of V. I. Prokhorenko et al. [J. Phys. Chem. Lett. 7, 4445 (2016)]. PMID- 28810770 TI - Electronic structures at the interface between CuPc and black phosphorus. AB - The electronic structure at the organic-inorganic semiconductor interface of pi conjugated copper phthalocyanine (CuPc) on a black phosphorus (BP) crystal surface is studied with photoemission spectroscopy and density functional theory calculations. From the photoemission spectra, we observe a shift of about 0.7 eV for the highest occupied molecular orbital, which originates from the transition of phase in the organic molecular thin film (from the interface phase to the bulk phase). On the other hand, we find 0.2 eV band bending at the CuPc/BP interface while the formation of an interface dipole is very small. According to our photoemission spectrum and theoretical simulation, we also define that the interaction between CuPc and BP is physisorption via van der Waals forces, rather than chemisorption. Our results provide a fundamental understanding of CuPc/BP interfacial interactions that could be important for future two-dimensional organic/inorganic heterostructure devices. PMID- 28810771 TI - Switching dynamics in cholesteric liquid crystal emulsions. AB - In this work we numerically study the switching dynamics of a 2D cholesteric emulsion droplet immersed in an isotropic fluid under an electric field, which is either uniform or rotating with constant speed. The overall dynamics depend strongly on the magnitude and on the direction (with respect to the cholesteric axis) of the applied field, on the anchoring of the director at the droplet surface and on the elasticity. If the surface anchoring is homeotropic and a uniform field is parallel to the cholesteric axis, the director undergoes deep elastic deformations and the droplet typically gets stuck into metastable states which are rich in topological defects. When the surface anchoring is tangential, the effects due to the electric field are overall less dramatic, as a small number of topological defects form at equilibrium. The application of the field perpendicular to the cholesteric axis usually has negligible effects on the defect dynamics. The presence of a rotating electric field of varying frequency fosters the rotation of the defects and of the droplet as well, typically at a lower speed than that of the field, due to the inertia of the liquid crystal. If the surface anchoring is homeotropic, a periodic motion is found. Our results represent a first step to understand the dynamical response of a cholesteric droplet under an electric field and its possible application in designing novel liquid crystal-based devices. PMID- 28810772 TI - Computational prediction of a simple cubic carbon allotrope consisting of C12 clusters. AB - We identify by ab initio calculations a new simple cubic carbon phase in Pa3- symmetry, which has a 48-atom unit cell in all-sp3 bonding networks, thus termed SC48 carbon. It can be viewed as a crystalline form of C12 clusters or a combined structure of SC24 and BC12 carbon, but it is energetically more stable than the recently reported cubic carbon phases such as BC8, SC24, BC12, and fcc-C12. The structural stability is verified by phonon mode analysis. Electronic band and density of state calculations reveal that SC48 carbon is an insulator with a large direct band gap of 4.40 eV. Moreover, simulated x-ray diffraction patterns provide an excellent match to the distinct diffraction peaks found in milled fullerene soot. These results provide a solid foundation for further exploration of this new carbon allotrope. PMID- 28810773 TI - Geometric phase effects in excited state dynamics through a conical intersection in large molecules: N-dimensional linear vibronic coupling model study. AB - We investigate geometric phase (GP) effects in nonadiabatic transitions through a conical intersection (CI) in an N-dimensional linear vibronic coupling (ND-LVC) model. This model allows for the coordinate transformation encompassing all nonadiabatic effects within a two-dimensional (2D) subsystem, while the other N - 2 dimensions form a system of uncoupled harmonic oscillators identical for both electronic states and coupled bi-linearly with the subsystem coordinates. The 2D subsystem governs ultra-fast nonadiabatic dynamics through the CI and provides a convenient model for studying GP effects. Parameters of the original ND-LVC model define the Hamiltonian of the transformed 2D subsystem and thus influence GP effects directly. Our analysis reveals what values of ND-LVC parameters can introduce symmetry breaking in the 2D subsystem that diminishes GP effects. PMID- 28810774 TI - Effect of solute nature on the polyamorphic transition in glassy polyol aqueous solutions. AB - I examined the polyamorphic behavior of glassy dilute aqueous solutions of polyols (ethylene glycol, glycerol, meso-erythritol, xylitol, and D-sorbitol) under pressure at low temperatures. Although the volume change of the glassy aqueous solution varied continuously against pressure, the rate of the volume change appeared to vary discontinuously at the onset pressure of the gradual polyamorphic transition. It is thought that low-density liquid-like solvent water and high-density liquid-like solvent water coexist during the transition. Moreover, the existence of a solute induces the shift of polyamorphic transition to the lower-pressure side. The effect of a solute on the polyamorphic transition becomes larger in the order ethylene glycol, glycerol, meso-erythritol, xylitol, and D-sorbitol. Therefore, the solute can become a variable controlling the polyamorphic state of liquid water. This experimental result suggests that the metastable-equilibrium phase boundary between the low-density and the high density amorphs for pure water is likely to be located at 0.22-0.23 GPa at about 150 K, which is slightly larger than the previously estimated pressure. Moreover, the solute-nature dependence on the polyamorphic transition seems to connect to that on the homogeneous nucleation temperature of polyol aqueous solution at ambient pressure. The region in which a low-density liquid appears coincides with the region in which the nucleus of ice Ih appears, suggesting that the formation of a low-density liquid is a precursory phenomenon of the nucleation of ice Ih. PMID- 28810775 TI - Chemical dynamics between wells across a time-dependent barrier: Self-similarity in the Lagrangian descriptor and reactive basins. AB - In chemical or physical reaction dynamics, it is essential to distinguish precisely between reactants and products for all times. This task is especially demanding in time-dependent or driven systems because therein the dividing surface (DS) between these states often exhibits a nontrivial time-dependence. The so-called transition state (TS) trajectory has been seen to define a DS which is free of recrossings in a large number of one-dimensional reactions across time dependent barriers and thus, allows one to determine exact reaction rates. A fundamental challenge to applying this method is the construction of the TS trajectory itself. The minimization of Lagrangian descriptors (LDs) provides a general and powerful scheme to obtain that trajectory even when perturbation theory fails. Both approaches encounter possible breakdowns when the overall potential is bounded, admitting the possibility of returns to the barrier long after the trajectories have reached the product or reactant wells. Such global dynamics cannot be captured by perturbation theory. Meanwhile, in the LD-DS approach, it leads to the emergence of additional local minima which make it difficult to extract the optimal branch associated with the desired TS trajectory. In this work, we illustrate this behavior for a time-dependent double well potential revealing a self-similar structure of the LD, and we demonstrate how the reflections and side-minima can be addressed by an appropriate modification of the LD associated with the direct rate across the barrier. PMID- 28810776 TI - Perspective: Surface freezing in water: A nexus of experiments and simulations. AB - Surface freezing is a phenomenon in which crystallization is enhanced at a vapor liquid interface. In some systems, such as n-alkanes, this enhancement is dramatic and results in the formation of a crystalline layer at the free interface even at temperatures slightly above the equilibrium bulk freezing temperature. There are, however, systems in which the enhancement is purely kinetic and only involves faster nucleation at or near the interface. The first, thermodynamic, type of surface freezing is easier to confirm in experiments, requiring only the verification of the existence of crystalline order at the interface. The second, kinetic, type of surface freezing is far more difficult to prove experimentally. One material that is suspected of undergoing the second type of surface freezing is liquid water. Despite strong indications that the freezing of liquid water is kinetically enhanced at vapor-liquid interfaces, the findings are far from conclusive, and the topic remains controversial. In this perspective, we present a simple thermodynamic framework to understand conceptually and distinguish these two types of surface freezing. We then briefly survey fifteen years of experimental and computational work aimed at elucidating the surface freezing conundrum in water. PMID- 28810777 TI - Description of ground and excited electronic states by ensemble density functional method with extended active space. AB - An extended variant of the spin-restricted ensemble-referenced Kohn-Sham (REKS) method, the REKS(4,4) method, designed to describe the ground electronic states of strongly multireference systems is modified to enable calculation of excited states within the time-independent variational formalism. The new method, the state-interaction state-averaged REKS(4,4), i.e., SI-SA-REKS(4,4), is capable of describing several excited states of a molecule involving double bond cleavage, polyradical character, or multiple chromophoric units. We demonstrate that the new method correctly describes the ground and the lowest singlet excited states of a molecule (ethylene) undergoing double bond cleavage. The applicability of the new method for excitonic states is illustrated with pi stacked ethylene and tetracene dimers. We conclude that the new method can describe a wide range of multireference phenomena. PMID- 28810778 TI - Hydrogen bond network rearrangement dynamics in water clusters: Effects of intermolecular vibrational excitation on tunneling rates. AB - Theoretical studies of hydrogen bond network rearrangement (HBNR) dynamics in liquid water have indicated that librational motions initiate the hydrogen bond breaking/formation processes. We present the results of using a simple time evolution method to extract and compare the tunneling lifetimes for motions that break and reform the hydrogen bond for the water dimer, trimer, and pentamer from the experimentally measured tunneling splittings in the ground and excited intermolecular vibrational states. We find that the specific nature of the intermolecular vibrational excitation does not significantly influence the tunneling lifetime of the dimer, but that only excitations to a librational vibration affect the water trimer and pentamer lifetimes. The specific enhancement of bifurcation tunneling in larger clusters relative to the dimer also indicates that hydrogen bond cooperativity is a vital element of these dynamics. PMID- 28810779 TI - Sequence transferable coarse-grained model of amphiphilic copolymers. AB - Polymer properties are inherently multi-scale in nature, where delicate local interaction details play a key role in describing their global conformational behavior. In this context, deriving coarse-grained (CG) multi-scale models for polymeric liquids is a non-trivial task. Further complexities arise when dealing with copolymer systems with varying microscopic sequences, especially when they are of amphiphilic nature. In this work, we derive a segment-based generic CG model for amphiphilic copolymers consisting of repeat units of hydrophobic (methylene) and hydrophilic (ethylene oxide) monomers. The system is a simulation analogue of polyacetal copolymers [S. Samanta et al., Macromolecules 49, 1858 (2016)]. The CG model is found to be transferable over a wide range of copolymer sequences and also to be consistent with existing experimental data. PMID- 28810780 TI - A surprisingly simple correlation between the classical and quantum structural networks in liquid water. AB - Nuclear quantum effects in liquid water have profound implications for several of its macroscopic properties related to the structure, dynamics, spectroscopy, and transport. Although several of water's macroscopic properties can be reproduced by classical descriptions of the nuclei using interaction potentials effectively parameterized for a narrow range of its phase diagram, a proper account of the nuclear quantum effects is required to ensure that the underlying molecular interactions are transferable across a wide temperature range covering different regions of that diagram. When performing an analysis of the hydrogen-bonded structural networks in liquid water resulting from the classical (class) and quantum (qm) descriptions of the nuclei with two interaction potentials that are at the two opposite ends of the range in describing quantum effects, namely the flexible, pair-wise additive q-TIP4P/F, and the flexible, polarizable TTM3-F, we found that the (class) and (qm) results can be superimposed over the temperature range T = 250-350 K using a surprisingly simple, linear scaling of the two temperatures according to T(qm) = alpha T(class) + DeltaT, where alpha = 0.99 and DeltaT = -6 K for q-TIP4P/F and alpha = 1.24 and DeltaT = -64 K for TTM3-F. This simple relationship suggests that the structural networks resulting from the quantum and classical treatment of the nuclei with those two very different interaction potentials are essentially similar to each other over this extended temperature range once a model-dependent linear temperature scaling law is applied. PMID- 28810781 TI - Projected coupled cluster theory. AB - Coupled cluster theory is the method of choice for weakly correlated systems. But in the strongly correlated regime, it faces a symmetry dilemma, where it either completely fails to describe the system or has to artificially break certain symmetries. On the other hand, projected Hartree-Fock theory captures the essential physics of many kinds of strong correlations via symmetry breaking and restoration. In this work, we combine and try to retain the merits of these two methods by applying symmetry projection to broken symmetry coupled cluster wave functions. The non-orthogonal nature of states resulting from the application of symmetry projection operators furnishes particle-hole excitations to all orders, thus creating an obstacle for the exact evaluation of overlaps. Here we provide a solution via a disentanglement framework theory that can be approximated rigorously and systematically. Results of projected coupled cluster theory are presented for molecules and the Hubbard model, showing that spin projection significantly improves unrestricted coupled cluster theory while restoring good quantum numbers. The energy of projected coupled cluster theory reduces to the unprojected one in the thermodynamic limit, albeit at a much slower rate than projected Hartree-Fock. PMID- 28810782 TI - First-principles molecular dynamics study of deuterium diffusion in liquid tin. AB - Understanding the retention of hydrogen isotopes in liquid metals, such as lithium and tin, is of great importance in designing a liquid plasma-facing component in fusion reactors. However, experimental diffusivity data of hydrogen isotopes in liquid metals are still limited or controversial. We employ first principles molecular dynamics simulations to predict diffusion coefficients of deuterium in liquid tin at temperatures ranging from 573 to 1673 K. Our simulations indicate faster diffusion of deuterium in liquid tin than the self diffusivity of tin. In addition, we find that the structural and dynamic properties of tin are insensitive to the inserted deuterium at temperatures and concentrations considered. We also observe that tin and deuterium do not form stable solid compounds. These predicted results from simulations enable us to have a better understanding of the retention of hydrogen isotopes in liquid tin. PMID- 28810783 TI - Self-consistent calculation of protein folding pathways. AB - We introduce an iterative algorithm to efficiently simulate protein folding and other conformational transitions, using state-of-the-art all-atom force fields. Starting from the Langevin equation, we obtain a self-consistent stochastic equation of motion, which directly yields the reaction pathways. From the solution of this set of equations we derive a stochastic estimate of the reaction coordinate. We validate this approach against the results of plain MD simulations of the folding of a small protein, which were performed on the Anton supercomputer. In order to explore the computational efficiency of this algorithm, we apply it to generate a folding pathway of a protein that consists of 130 amino acids and has a folding rate of the order of s-1. PMID- 28810784 TI - Molecular simulation of homogeneous crystal nucleation of AB2 solid phase from a binary hard sphere mixture. AB - Co-crystal formation from fluid-mixtures is quite common in a large number of systems. The simplest systems that show co-crystal (also called substitutionally ordered solids) formation are binary hard sphere mixtures. In this work, we study the nucleation of AB2 type solid compounds using Monte Carlo molecular simulations in binary hard sphere mixtures with the size ratio of 0.55. The conditions chosen for the study lie in the region where nucleation of an AB2 type solid competes with that of a pure A solid with a face-centered-cubic structure. The fluid phase composition is kept equal to that of the AB2 type solid. The nucleation free-energy barriers are computed using the seeding technique of Sanz et al. [J. Am. Chem. Soc. 135, 15008 (2013)]. Our simulation results show that the nucleation of the AB2 type solid is favored even under conditions where the pure A solid is more stable. This is primarily due to the similarity in the composition of the fluid phase and the AB2 type solid which in turn leads to much lower interfacial tension between the crystal nucleus and the fluid phase. This system is an example of how the fluid phase composition affects the structure of the nucleating solid phase during crystallization and has relevance to crystal polymorphism during crystallization processes. PMID- 28810785 TI - Explicitly correlated N-electron valence state perturbation theory (NEVPT2-F12). AB - In this work, explicitly correlated second order N-electron valence state perturbation theory (NEVPT2-F12) has been derived and implemented for the first time. The NEVPT2-F12 algorithm presented here is based on a fully internally contracted wave function and includes the correction of semi-internal excitation subspaces. The algorithm exploits the resolution of identity (RI) approximation to improve the computational efficiency. The overall O(N5) scaling of the computational effort is documented. In Sec. III, the dissociation processes of diatomic molecules and the singlet-triplet gap of several systems are studied. For all relative energies studied in this work, the errors with respect to the complete basis set (CBS) limit for the NEVPT2-F12 method are within 1 kcal/mol. For moderately sized active spaces, the computational cost of a RI-NEVPT2-F12 correlation energy calculation for each root is comparable to a closed-shell RI MP2-F12 calculation on the same system. PMID- 28810786 TI - Reducing the cost of using collocation to compute vibrational energy levels: Results for CH2NH. AB - In this paper, we improve the collocation method for computing vibrational spectra that was presented in the work of Avila and Carrington, Jr. [J. Chem. Phys. 143, 214108 (2015)]. Known quadrature and collocation methods using a Smolyak grid require storing intermediate vectors with more elements than points on the Smolyak grid. This is due to the fact that grid labels are constrained among themselves and basis labels are constrained among themselves. We show that by using the so-called hierarchical basis functions, one can significantly reduce the memory required. In this paper, the intermediate vectors have only as many elements as the Smolyak grid. The ideas are tested by computing energy levels of CH2NH. PMID- 28810787 TI - Transforming high-dimensional potential energy surfaces into sum-of-products form using Monte Carlo methods. AB - We propose a Monte Carlo method, "Monte Carlo Potfit," for transforming high dimensional potential energy surfaces evaluated on discrete grid points into a sum-of-products form, more precisely into a Tucker form. To this end we use a variational ansatz in which we replace numerically exact integrals with Monte Carlo integrals. This largely reduces the numerical cost by avoiding the evaluation of the potential on all grid points and allows a treatment of surfaces up to 15-18 degrees of freedom. We furthermore show that the error made with this ansatz can be controlled and vanishes in certain limits. We present calculations on the potential of HFCO to demonstrate the features of the algorithm. To demonstrate the power of the method, we transformed a 15D potential of the protonated water dimer (Zundel cation) in a sum-of-products form and calculated the ground and lowest 26 vibrationally excited states of the Zundel cation with the multi-configuration time-dependent Hartree method. PMID- 28810788 TI - Direct measurement of site-specific rates of reactions of H with C3H8, i-C4H10, and n-C4H10. AB - We measured the rates of abstraction of a hydrogen atom from specific sites in propane C3H8, 2-methyl propane (i-C4H10), and butane (n-C4H10); the sites are a primary hydrogen of C3H8 and i-C4H10 and a secondary hydrogen of n-C4H10. The excellent reproducibility of conditions of a diaphragm-less shock tube enabled us to conduct comparative measurements of the evolution of H atoms in three mixtures (i) 0.5 ppm C2H5I + Ar, (ii) 0.5 ppm C2H5I + 50-100 ppm alkane as C3H8 or i-C4H10 or n-C4H10 + Ar, and (iii) the same concentrations of alkane + Ar without C2H5I in the temperature range 1000-1200 K and at a pressure of 2.0 bars. The net profile of rise and decay of H atoms in the C2H5I + alkane mixture was derived on subtracting the absorbance of (iii) from that of (ii). Measurements of the mixture (iii) are important because the absorption of alkanes at 121.6 nm is not negligible. In the temperature range 1000-1100 K, the rate of decomposition of C2H5I was evaluated directly on analyzing the exponential growth of H atoms in the mixture (i). The rate of decomposition of C2H5I is summarized as ln(k/s-1) = (33.12 +/- 1.4) - (25.23 +/- 1.5) 103/T (T = 1000-1100 K, P = 2.0 bars); the broadening factor F(T) in the Lindemann-Hinshelwood formula was evaluated in the fall-off region. The site-specific rates of H + (C3-C4) alkanes are summarized as follows: H + C3H8 -> H2 + 1-C3H7, ln(k1a) = -(21.34 +/- 0.86) - (5.39 +/- 0.93)103/T, H + i-C4H10 -> H2 + i-C4H9, ln(k2a) = -(20.50 +/- 1.36) - (6.14 +/- 0.13)103/T, H + n-C4H10 -> H2 + 2-C4H9, ln(k3b) = -(21.37 +/- 1.15) - (4.83 +/- 1.26)103/T. The present experimental results are compared with published results from quantum-chemical calculations of potential-energy surfaces and transition state theory. The present experiments are consistent with those calculations for the reaction rates for the attack at the primary site for H + C3H8 and H + i C4H10, but for the attack at the secondary site of n-C4H10, our results are substantially smaller than the computational prediction, which might indicate a hindrance by the C-H bonds of the primary sites that serves to decrease the rate of abstraction from the secondary site of n-C4H10. The influence on the total rates of reactions H + alkane and the group additivity rule are discussed. PMID- 28810789 TI - Tunneling lifetimes of electrons escaping from atoms under a static electric field. AB - The tunneling lifetime of an electron escaping from an atom is calculated using a projected Green's function method, combining with the radial potential of the atom which is obtained from density functional theory. Results of the calculated electron tunneling lifetimes in model systems such as a quantum dot are shown to be comparable with other theoretical studies. For the first time, we have obtained the tunneling lifetimes of electrons escaping from a series of atoms (He, Ne, Ar, Kr, H, Li, Na, K) under a static electric field. Dependent on both the barrier width/height and the bound strength of the ground state electron, the calculated tunneling lifetime under a static electric field spans from femtosecond level to picosecond level, consistent with the attosecond-level results in experiments using a time-dependent external field. PMID- 28810790 TI - Nonlinear interferometer: Design, implementation, and phase-sensitive sum frequency measurement. AB - Sum frequency generation (SFG) spectroscopy is a unique tool for probing the vibrational structure of numerous interfaces. Since SFG is a nonlinear spectroscopy, it has long been recognized that measuring only the intensity-the absolute square of the surface response-limits the potential of SFG for examining interfacial interactions and dynamics. The potential is unlocked by measuring the phase-sensitive or imaginary response. As with any phase, the phase-sensitive SFG response is measured relative to a reference; the spatial relationship between the phase reference and the sample modulates the observed interference intensity and impacts sensitivity and accuracy. We have designed and implemented a nonlinear interferometer to directly measure the phase-sensitive response. If the phase of the reference is known, then the interferometer produces an absolute phase of the surface. Compared to current configurations, phase accuracy and stability are greatly improved due to active stabilization of the sample reference position. The design is versatile and thus can be used for any system that can be probed with SFG including buried interfaces and those with high vapor pressure. Feasibility and advantages of the interferometer are demonstrated using an octadecyltrichlorosilane film on fused silica. PMID- 28810791 TI - A general, rotating, hard sphere model applied to the transport properties of a low density gas. AB - A general, spherical, rigid model is introduced for describing rotating and translating particles. The model contains a parameter, which we label gamma, that smoothly interpolates between the smooth hard sphere (gamma = 0) and rough hard sphere (gamma = 1) limits. Analytic expressions for transport coefficients are determined for the general model in the low density limit and compared with those for the smooth and rough hard sphere cases. While the diffusion constant decreases monotonically on moving from the smooth to the rough sphere limits, both the viscosity and thermal conductivity first decrease and then increase, thereby producing a minimum between the two limits. This qualitative change in behaviour is new and suggests translational-rotational coupling acts to decrease the values of the transport coefficients (in contrast to the prediction from the rough sphere model). Although the model still has the (known) deficiencies of rigid models, it is more flexible than either the smooth or rough sphere model and should find use in better representing molecular behaviour. The general model provides a consistent representation of the transport coefficients because it has proper, microscopic collision dynamics obeying conservation laws for total momentum, total angular momentum, and total energy. PMID- 28810792 TI - Coupled electron-nuclear quantum dynamics through and around a conical intersection. AB - In solving the time-dependent Schrodinger equation for a coupled electron-nuclear system, we study the motion of wave packets in a model which exhibits a conical intersection (CoIn) of adiabatic potential energy surfaces. Three different situations are studied. In the first case, an efficient non-adiabatic transition takes place while the wave packet passes the region of the CoIn. It is demonstrated that during these times, the nuclear probability density retains its Gaussian shape and the electronic density remains approximately constant. Second, dynamics are regarded where non-adiabatic transitions do not take place, and the nuclear dynamics follows a circle around the location of the CoIn. During this motion, the electronic density is shown to rotate. The comparison with the Born Oppenheimer nuclear dynamics reveals the geometrical phase being associated with the circular motion. This phase is clearly revealed by an analysis of time dependent autocorrelation functions and spectra obtained from the numerically exact and the Born-Oppenheimer calculation. The intermediate situation with a small non-adiabatic transition probability is characterized by wave-packet splitting into several fractions. PMID- 28810793 TI - Image method for electrostatic energy of polarizable dipolar spheres. AB - The multiple-scattering theory for the electrostatics of many-body systems of monopolar spherical particles, embedded in a dielectric medium, is generalized to describe the electrostatics of these particles with embedded dipoles and multipoles. The Neumann image line construction for the electrostatic polarization produced by one particle is generalized to compute the energy, forces, and torques for the many-body system as functions of the positions of the particles. The approach is validated by comparison with direct numerical calculation, and the convergence rate is analyzed and expressed in terms of the discontinuity in dielectric contrast and particle density. As an illustration of this formalism, the stability of small particle clusters is analyzed. The theory is developed in a form that can readily be adapted to Monte Carlo and molecular dynamics simulations for polarizable particles and, more generally, to study the interactions among polarizable molecules. PMID- 28810794 TI - Communication: Stiff and soft nano-environments and the "Octopus Effect" are the crux of ionic liquid structural and dynamical heterogeneity. AB - In a recent set of articles [J. C. Araque et al., J. Phys. Chem. B 119(23), 7015 7029 (2015) and J. C. Araque et al., J. Chem. Phys. 144, 204504 (2016)], we proposed the idea that for small neutral and charged solutes dissolved in ionic liquids, deviation from simple hydrodynamic predictions in translational and rotational dynamics can be explained in terms of diffusion through nano environments that are stiff (high electrostriction, charge density, and number density) and others that are soft (charge depleted). The current article takes a purely solvent-centric approach in trying to provide molecular detail and intuitive visual understanding of time-dependent local mobility focusing on the most common case of an ionic liquid with well defined polar and apolar nano domains. We find that at intermediate time scales, apolar regions are fluid, whereas the charge network is much less mobile. Because apolar domains and cationic heads must diffuse as single species, at long time the difference in mobility also necessarily dissipates. PMID- 28810795 TI - The effects of slit-like confinement on flow-induced polymer deformation. AB - This paper is broadly concerned with the dynamics of a polymer confined to a rectangular slit of width D and deformed by a planar elongational flow of strength gamma. It is interested, more specifically, in the nature of the coil stretch transition that such polymers undergo when the flow strength gamma is varied, and in the degree to which this transition is affected by the presence of restrictive boundaries. These issues are explored within the framework of a finitely extensible Rouse model that includes pre-averaged surface-mediated hydrodynamic interactions. Calculations of the chain's steady-state fractional extension x using this model suggest that different modes of relaxation (which are characterized by an integer p) exert different levels of control on the coil stretch transition. In particular, the location of the transition (as identified from the graph of x versus the Weissenberg number Wi, a dimensionless parameter defined by the product of gamma and the time constant taup of a relaxation mode p) is found to vary with the choice of taup. In particular, when tau1 is used in the definition of Wi, the x vs. Wi data for different D lie on a single curve, but when tau3 is used instead (with tau3 > tau1) the corresponding data lie on distinct curves. These findings are in close qualitative agreement with a number of experimental results on confinement effects on DNA stretching in electric fields. Similar D-dependent trends are seen in our calculated force vs. Wi data, but force vs. x data are essentially D-independent and lie on a single curve. PMID- 28810796 TI - Molecular dynamics simulations of fluid cyclopropane with MP2/CBS-fitted intermolecular interaction potentials. AB - Modeling fluid cycloalkanes with molecular dynamics simulations has proven to be a very challenging task partly because of lacking a reliable force field based on quantum chemistry calculations. In this paper, we construct an ab initio force field for fluid cyclopropane using the second-order Moller-Plesset perturbation theory. We consider 15 conformers of the cyclopropane dimer for the orientation sampling. Single-point energies at important geometries are calibrated by the coupled cluster with single, double, and perturbative triple excitation method. Dunning's correlation consistent basis sets (up to aug-cc-pVTZ) are used in extrapolating the interaction energies at the complete basis set limit. The force field parameters in a 9-site Lennard-Jones model are regressed by the calculated interaction energies without using empirical data. With this ab initio force field, we perform molecular dynamics simulations of fluid cyclopropane and calculate both the structural and dynamical properties. We compare the simulation results with those using an empirical force field and obtain a quantitative agreement for the detailed atom-wise radial distribution functions. The experimentally observed gross radial distribution function (extracted from the neutron scattering measurements) is well reproduced in our simulation. Moreover, the calculated self-diffusion coefficients and shear viscosities are in good agreement with the experimental data over a wide range of thermodynamic conditions. To the best of our knowledge, this is the first ab initio force field which is capable of competing with empirical force fields for simulating fluid cyclopropane. PMID- 28810797 TI - Asymmetric breathing motions of nucleosomal DNA and the role of histone tails. AB - The most important packing unit of DNA in the eukaryotic cell is the nucleosome. It undergoes large-scale structural re-arrangements during different cell cycles. For example, the disassembly of the nucleosome is one of the key steps for DNA replication, whereas reassembly occurs after replication. Thus, conformational dynamics of the nucleosome is crucial for different DNA metabolic processes. We perform three different sets of atomistic molecular dynamics simulations of the nucleosome core particle at varying degrees of salt conditions for a total of 0.7 MUs simulation time. We find that the conformational dynamics of the nucleosomal DNA tails are oppositely correlated from each other during the initial breathing motions. Furthermore, the strength of the interaction of the nucleosomal DNA tail with the neighboring H2A histone tail modulates the conformational state of the nucleosomal DNA tail. With increasing salt concentration, the degree of asymmetry in the conformation of the nucleosomal DNA tails decreases as both tails tend to unwrap. This direct correlation between the asymmetric breathing motions of the DNA tails and the H2A histone tails, and its decrease at higher salt concentrations, may play a significant role in the molecular pathway of unwrapping. PMID- 28810798 TI - Binding energies of hydrated cobalt hydroxide ion complexes: A guided ion beam and theoretical investigation. AB - The sequential bond energies of CoOH+(H2O)x complexes, where x = 1-4, are measured by threshold collision-induced dissociation using a guided ion beam tandem mass spectrometer. The primary dissociation pathway for all reactants consists of loss of a single water molecule. This is followed by the sequential loss of additional water molecules at higher collision energies for the x = 2-4 complexes, whereas the x = 1 reactant loses the OH ligand competitively with the H2O ligand. The kinetic energy dependent cross sections for dissociation of CoOH+(H2O)x complexes are modeled to obtain 0 and 298 K binding energies. Our experimental results agree well with theoretically determined bond dissociation energies (BDEs) at the B3LYP, B3LYP-GD3BJ, B3P86, and MP2(full) levels of theory with a 6-311+G(2d,2p) basis set using geometries and vibrational frequencies determined at the B3LYP/6-311+G(d,p) level. Thermochemical information for the loss of OH from CoOH+(H2O)x where x = 0-4 is also derived by combining the present experimental HO-Co+(H2O) and water loss BDEs from CoOH+(H2O)x with those for Co+(H2O)y from the literature. These BDEs are also compared to theory with mixed results. PMID- 28810799 TI - Spin-dependent charge recombination along para-phenylene molecular wires. AB - We have used an efficient new quantum mechanical method for radical pair recombination reactions to study the spin-dependent charge recombination along PTZ*+-Phn-PDI*- molecular wires. By comparing our results with the experimental data of Weiss et al. [J. Am. Chem. Soc. 126, 5577 (2004)], we are able to extract the spin-dependent (singlet and triplet) charge recombination rate constants for wires with n = 2-5. These spin-dependent rate constants have not been extracted previously from the experimental data because they require fitting its magnetic field-dependence to the results of quantum spin dynamics simulations. We find that the triplet recombination rate constant decreases exponentially with the length of the wire, consistent with the superexchange mechanism of charge recombination. However, the singlet recombination rate constant is nearly independent of the length of the wire, suggesting that the singlet pathway is dominated by an incoherent hopping mechanism. A simple qualitative explanation for the different behaviours of the two spin-selective charge recombination pathways is provided in terms of Marcus theory. We also find evidence for a magnetic field-independent background contribution to the triplet yield of the charge recombination reaction and suggest several possible explanations for it. Since none of these explanations is especially compelling given the available experimental evidence, and since the result appears to apply more generally to other molecular wires, we hope that this aspect of our study will stimulate further experimental work. PMID- 28810800 TI - Confinement, curvature, and attractive interaction effects on polymer surface adsorption. AB - We investigate the conformation and dynamics of a semi-flexible polymer near an attractive plane or a cylindrical post using Langevin dynamics. We characterize the transition from the desorbed to absorbed state and quantify how absorption depends on the attraction interaction, polymer molecular weight, polymer flexibility, intra-polymer interaction, and micro-confinement. We find that the critical point of adsorption for ideal flexible polymers only weakly depends on confinement. However, the critical point of adsorption increases significantly for self-avoiding flexible polymers and under confinement, deviating from scaling theory predictions. These findings provide insights into DNA surface adsorption in nanoslits and nanochannels. PMID- 28810802 TI - The importance of aberrant beliefs in obsessive-compulsive disorder and related conditions. PMID- 28810801 TI - May Dietary Supplementation Augment Respiratory Burst in Wound-Site Inflammatory Cells? AB - Persistent infection contributes to wound chronicity. At the wound site, NADPH oxidase (NOX) activity in immune cells fights infection to enable the healing process. Fermented papaya preparation (FPP) is a carbohydrate-rich nutritional supplement that has demonstrated ability to bolster respiratory burst in experimental rodent systems. In FPP, glucose coexists with fructose and maltose in addition to multiple other sugar alcohols such as inositol. We have previously reported that FPP supplementation augments wound healing in diabetic mice via improvement of respiratory burst activity of wound innate immune cells. In this clinical study ( clinicaltrials.gov : NCT02332993), chronic wound patients were orally supplemented with FPP daily. Inducible production of reactive oxygen species was significantly higher in wound-site immune cells from patients supplemented with FPP and on standard of care (SoC) for wound management compared with those patients receiving SoC alone. Wound closure in FPP-supplemented patients showed improvement. Importantly, the consumption of this mixture of carbohydrates, including significant amounts of glucose, did not increase HbA1c. These observations warrant a full-length clinical trial testing the hypothesis that FPP improves wound closure by augmenting NOX activity in immune cells at the wound site. Antioxid. Redox Signal. 28, 401-405. PMID- 28810803 TI - Driving CARs on the Highway to Solid Cancer: Some Considerations on the Adoptive Therapy with CAR T Cells. AB - Adoptive therapy with chimeric antigen receptor (CAR) redirected T cells achieved lasting remissions in hematologic malignancies, even in terminal stages of the disease. Exploring CAR T cell therapy in the treatment of solid tumors has just begun, balancing efficacy versus toxicity in early phase trials. In contrast to leukemia/lymphoma, solid tumors display a tremendously variable biology demanding different strategies to make a T cell attack successful in the long term. This article summarizes current developments, discusses the hurdles, and considers some modifications to improve the CAR T cell therapy in the treatment of solid tumors. PMID- 28810804 TI - Clinically relevant changes in clozapine serum concentrations after breast reduction surgery. PMID- 28810805 TI - Hindfoot Arthritis Progression and Arthrodesis Risk After Total Ankle Replacement. AB - BACKGROUND: The purpose of this study was to assess the radiographic progression of subtalar and talonavicular degenerative joint disease in a series of patients who had undergone TAA (total ankle arthroplasty) with minimum follow-up of 5 years. METHODS: TAA patient radiographs from a single institution were analyzed for peritalar arthritic changes by extrapolating the modified Kellgren Lawrence (KL) grades of the knee to the subtalar and talonavicular joints. Patients were included if they had a minimum of 5 years of follow-up. Patients who had undergone prior arthrodesis of the talonavicular or subtalar joints were excluded. A total of 140 patients with average follow-up of 6.5 years (range, 5.0 8.9 years) were included. RESULTS: Overall, 27% of patients advanced 1 KL grade at the subtalar joint and 31% of patients increased 1 KL grade at the talonavicular joint. Furthermore, 60% and 66% of patients showed no progression in the subtalar and talonavicular joints, respectively. Two patients progressed greater than 2 KL subtalar arthritis grades and only 2 patients with talonavicular arthritis progressed to the same extent. Sixteen patients went on to require a subtalar arthrodesis compared to 2 requiring a talonavicular fusion ( P < .05). CONCLUSION: This study suggests a moderate but nominal radiographic increase in adjacent subtalar and talonavicular arthritis over a minimum of 5 years after TAA. Future studies require a comparative control group of ankle fusion, but these data may suggest the motion preserved with an arthroplasty diminishes the stresses and compensatory motion incurred during tibiotalar arthrodesis. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 28810806 TI - Evaluating Structural Change Approaches to Health Promotion: An Exploratory Scoping Review of a Decade of U.S. Progress. AB - Structural change approaches-also known as policy and environmental changes-are becoming increasingly common in health promotion, yet our understanding of how to evaluate them is still limited. An exploratory scoping review of the literature was conducted to understand approaches and methods used to evaluate structural change interventions in health promotion and public health literature. Two analysts-along with health sciences librarian consultation-searched PubMed, Web of Science, and EMBASE for peer-reviewed U.S.-based, English language studies published between 2005 and 2016. Data were extracted on the use of evaluation frameworks, study designs, duration of evaluations, measurement levels, and measurement types. Forty-five articles were included for the review. Notably, the majority (73%) of studies did not report application of a specific evaluation framework. Studies used a wide range of designs, including process evaluations, quasi- or nonexperimental designs, and purely descriptive approaches. In addition, 15.6% of studies only measured outcomes at the individual level. Last, 60% of studies combined more than one measurement type (e.g., site observation + focus groups) to evaluate interventions. Future directions for evaluating structural change approaches to health promotion include more widespread use and reporting of evaluation frameworks, developing validated tools that measure structural change, and shifting the focus to health-directed approaches, including an expanded consideration for evaluation designs that address health inequities. PMID- 28810807 TI - Exploratory Analyses of Risk Behaviors Among GLBT Youth Attending a Drop-In Center. AB - This exploratory study examines measures of one drop-in center's efforts to improve health outcomes of gay, lesbian, bisexual, and transgender (GLBT) youth by facilitating out-group secondary social ties. Hatch Youth, located in Houston, Texas, aims to increase self-esteem and decrease negative health outcomes by encouraging GLBT youth to be part of Houston's greater GLBT community. Survey data ( N = 614) collected between October 2003 and April 2013 were entered into logistic regression models. Attending Hatch Youth for 6 or more months was associated with having a social group outside of school (adjusted odds ratio [aOR] = 2.07; 95% confidence interval [CI] = [1.33, 3.20]), being out to that social group (aOR = 2.34; 95% CI = [1.35, 4.03]), and interacting with the GLBT community outside of Hatch Youth (aOR = 2.33; 95% CI = [1.50, 3.54]), when referenced against youth attending less than 1 month. Having a good family relationship in the last 90 days (aOR = 2.48; 95% CI = [1.67, 3.70]) and having a social group outside of school (aOR = 2.57; 95% CI = [1.67, 3.97]) were associated with higher self-esteem. Higher self-esteem was associated with practicing safe sex (aOR = 1.86; 95% CI = [1.25, 2.75]) and not using street drugs (aOR = 0.45; 95% CI = [0.24, 0.83]). Interacting with the GLBT community outside of Hatch Youth was associated with practicing safe sex (aOR = 1.64; 95% CI = [1.12, 2.42]). Drop-in centers can strengthen secondary social ties among youth. Because questions remain about how drop-in centers can assist youth aging out of their programs to find other supportive secondary social ties, additional studies examining similar drop-in centers are needed. PMID- 28810808 TI - Advances and Challenges in Cardiovascular Gene Therapy. AB - Many promising cardiovascular gene therapy approaches have failed to fulfill expectations in clinical trials. However, 20 years of research and method development has laid a solid groundwork for future therapies, and the need for new treatment options still exists. The safety of gene therapy has been established with various viral vectors, transgenes and delivery methods. Improving success in clinical settings requires careful consideration of the translational process. This requires both improving animal models and preclinical end points, and new approach in patient recruitment and selection of clinical end points. This review focuses on bidirectional translationality from bench to bedside and back and proposes ways to improve the process. Developing a highly complex new therapy has taken an enormous amount of work and resources, but perhaps now after the hard lessons cardiovascular gene therapy is ready become a clinical reality. PMID- 28810809 TI - Optimization of Human NK Cell Manufacturing: Fully Automated Separation, Improved Ex Vivo Expansion Using IL-21 with Autologous Feeder Cells, and Generation of Anti-CD123-CAR-Expressing Effector Cells. AB - The administration of ex vivo expanded natural killer (NK) cells as potential antitumor effector cells appears to be suitable for effector cell-based immunotherapies in high-risk cancer patients. However, good manufacturing practice (GMP)-compliant manufacturing of clinical-grade NK cells at sufficiently high numbers represents a great challenge. Therefore, previous expansion protocols for those effector cells were improved and optimized by using newly developed culture medium, interleukin (IL)-21, and autologous feeder cells (FCs). Separation of primary human NK cells (CD56+CD3-) was carried out with the CliniMACS Prodigy(r) in a single process, starting with approximately 1.2 * 109 leukocytes collected by small-scale lymphapheresis or from buffy coats. Enriched NK cells were adjusted to starting cell concentrations within approximately 1 * 106 effector cells/mL and cultured in comparative expansion experiments for 14 days with IL-2 (1,000 IU/mL) in different GMP-compliant media (X-VIVOTM10, CellGro(r), TexMACSTM, and NK MACS(r)). After medium optimization, beneficial effects for functionality and phenotype were investigated at the beginning of cell expansion with irradiated (25 Gy) autologous FCs at a ratio of 20:1 (feeder: NK) in the presence or absence of IL-21 (100 ng/mL). Additionally, expanded NK cells were gene modified to express chimeric antigen receptors (CARs) against CD123, a common marker for acute myeloid leukemia (AML). Cytotoxicity, degranulation, and cytokine release of transduced NK cells were determined against KG1a cells in flow cytometric analysis and fluorescent imaging. The Prodigy manufacturing process revealed high target cell viabilities (median 95.4%), adequate NK cell recovery (median 60.4%), and purity of 95.4% in regard to CD56+CD3- target cells. The process in its early phase of development led to a median T-cell depletion of log 3.5 after CD3 depletion and log 3.6 after the whole process, including CD3 depletion and CD56 enrichment steps. Manually performed experiments to test different culture media demonstrated significantly higher NK cell expansion rates and an approximately equal distribution of CD56dimCD16pos and CD56brightCD16dim&neg NK subsets on day 14 with cells cultivated in NK MACS(r) media. Moreover, effector cell expansion in manually performed experiments with NK MACS(r) containing IL-2 and irradiated autologous FCs and IL-21, both added at the initiation of the culture, induced an 85-fold NK cell expansion. Compared to freshly isolated NK cells, expanded NK cells expressed significantly higher levels of NKp30, NKp44, NKG2D, TRAIL, FasL, CD69, and CD137, and showed comparable cell viabilities and killing/degranulation activities against tumor and leukemic cell lines in vitro. NK cells used for CAR transduction showed the highest anti-CD123 CAR expression on day 3 after gene modification. These anti-CD123 CAR-engineered NK cells demonstrated improved cytotoxicity against the CD123pos AML cell line KG1a and primary AML blasts. In addition, CAR NK cells showed higher degranulation and enhanced secretion of tumor necrosis factor alpha, interferon gamma, and granzyme A and B. In fluorescence imaging, specific interactions that initiated apoptotic processes in the AML target cells were detected between CAR NK cells and KG1a. After the fully automated NK cell separation process on Prodigy, a new NK cell expansion protocol was generated that resulted in high numbers of NK cells with potent antitumor activity, which could be modified efficiently by novel third-generation, alpha retroviral SIN vector constructs. Next steps are the integration of the manual expansion procedure in the fully integrated platform for a standardized GMP compliant overall process in this closed system that also may include gene modification of NK cells to optimize target-specific antitumor activity. PMID- 28810810 TI - Reduced Expression of Siglec-7, NKG2A, and CD57 on Terminally Differentiated CD56 CD16+ Natural Killer Cell Subset Is Associated with Natural Killer Cell Dysfunction in Chronic HIV-1 Clade C Infection. AB - HIV-1 viremia has been shown to induce several phenotypic and functional abnormalities in natural killer (NK) cells. To assess immune defects associated with HIV viremia, we examined NK cell function, differentiation status, and phenotypic alterations based on expression of inhibitory and activating receptors on NK cells in HIV-1 subtype C chronically infected participants from Durban, South Africa. NK cell phenotypic profiles were characterized by assessing sialic acid-binding immunoglobulin-like lectin-7 (Siglec-7), NKG2A, and NKG2C markers on frozen peripheral blood mononuclear cells from viremic, antiretroviral therapy (ART)-naive HIV-1 chronically infected participants (n = 23), HIV-1 chronically infected participants who had been on combination antiretroviral therapy (cART) for at least 12 months (n = 23) compared with healthy donors (n = 23). NK cell differentiation was assessed by measurement of killer immunoglobulin receptor (KIR) and NKG2A expression; CD57 and CD107a measurements were carried out in HIV viremic and healthy donors. All phenotypic and functional assessments were analyzed by using multicolor flow cytometry. HIV-1-infected participants displayed greater frequencies of the CD56-CD16+ (CD56negative) NK cell subset compared with healthy donors (p < .0001). Downregulation of Siglec-7 and NKG2A and upregulation of NKG2C were more pronounced in the CD56negative NK cell subset of viremic participants. The CD56negative subset demonstrated a differentiated (KIR+NKG2A-) phenotype with reduced CD57 expression and lower degranulation capacity in HIV-1-infected participants compared with healthy donors. HIV-1 infection induces the expansion of the CD56negative NK cell subset marked by altered receptor expression profiles that are indicative of impaired function and may explain the overall NK cell dysfunction observed in chronic HIV-1 infection. PMID- 28810811 TI - [Dialectical-behavioral outpatient therapy for adolescents with impulsive and self-harming behavior]. AB - A slightly modified version of the Dialectical-Behavioral Therapy for Adolescents (DBT-A) for impulsive and self-injurious adolescents has been implemented in the Child and Adolescent Psychiatric Service in Zurich, Switzerland, since 2005. This DBT-A comprises individual therapy, skills training, and a single parent meeting over a 6-month period. This article reports on the translation of this approach into clinical practice and presents an evaluation based on the clinical quality of control assessments. Participants of the treatment program were 43 female adolescents aged 14 to 19 living in the Zurich area and showing impulsive and self-injurious behavior and problems regulating their emotions and relationships. Each skill group contained 4-6 adolescents. Our mostly positive experiences with this approach were supplemented by evaluation data from a quality control group based on self- and parent-report of a total of 19 participants. There is convincing evidence that DBT-A leads to reductions in both general and specific psychopathology. PMID- 28810812 TI - Are perceptions of social norms regarding peer alcohol and other drug use associated with personal use in Danish adolescents? AB - AIMS: This study aims to describe norm perceptions among Danish pupils aged 13-17 years related to the prevalence of personal lifetime use of alcohol and other drugs (AODs). Further we examined if norm perceptions were associated with personal lifetime AOD use. METHOD: The data were collected as baseline data in the trial The GOOD Life. A total of 2601 pupils from 42 public schools in the Region of Southern Denmark completed an online questionnaire measuring personal lifetime AOD use and personal approval of use. Additionally the perceived frequency of AOD use and approval of use among peers of their own grade were measured. Lifetime AOD outcome variables were alcohol consumption (at least one drink, being drunk and had five or more drinks on one occasion), smoking, and cannabis use. RESULTS: Pupils' perceptions of peer approval were significantly higher than pupils' personal approval of AOD use among adolescents for all outcomes. With the exception of cannabis use the estimated AOD prevalence among peers (median) were higher than the actual prevalence of personal lifetime use. Multilevel logistic regression models showed a significantly increased risk of personal AOD use for pupils that overestimated their peers' AOD use and also for pupils that perceived peers to approve of AOD use. CONCLUSIONS: The findings highlight that pupils' exaggerated perceptions regarding their peers' use and approval of AOD use are related to personal experience with AODs. PMID- 28810813 TI - Newborn Thyroid Screening: Influence of Pre-Analytic Variables on Dried Blood Spot Thyrotropin Measurement. AB - BACKGROUND: Measuring thyrotropin (TSH) eluted from a dried blood spot (DBS) is used to screen an estimated 30 million newborns annually for congenital hypothyroidism (CH). Newborn thyroid screening has eliminated cretinism from the industrialized world and decreased the adverse effects of unrecognized CH on neurocognitive development. Hematocrit, a pre-analytic variable that affects the measurement of TSH from a DBS, contributes to the imprecision of DBS TSH measurement and could account for false-negative and false-positive DBS newborn screening test results. To assess whether variations in hematocrit found in newborns have a clinical effect in DBS-based newborn thyroid screening, the effects of hematocrit variability on the measurement of DBS TSH were studied. METHODS: U.S. Centers for Disease Control and Prevention procedures for manufacturing DBS performance testing standards were used to generate DBSs from blood samples, with hematocrits of 35%, 40%, 45%, 50%, 55%, 60%, and 65% and serum TSH concentrations of 6.3 +/- 0.4 and 26.6 +/- 8.0 mIU/L. TSH was measured in the eluates of four replicate DBS 3 mm punches at each hematocrit using the Thailand Ministry of Public Health Newborn Screening Operation Center enzyme linked immunosorbent assay. Data were analyzed using a linear mixed-effects model. RESULTS: Based on the mixed-effects model, hematocrit significantly affected DBS TSH measurement (p < 0.001). A 1% increase in hematocrit resulted in a 0.06 mIU/L decrease in eluate TSH when TSH was 6.3 + 0.4 mIU/L, and a 0.21 mIU/L decrease in eluate TSH when TSH was 26.6 + 8.0 mIU/L. CONCLUSIONS: DBS TSH is significantly affected by the blood sample hematocrit. The pre-analytic variability due to hematocrit is independent of TSH assay sensitivity, specificity, precision, repeatability, and reference intervals. The effect of hematocrit on DBS TSH measurement is clinically relevant, could account for geographic and ethnic variation in the incidence of CH, and may result in both false-positive and false-negative CH screening results. Individual newborn and population-specific hematocrit correction factors may improve the precision of DBS TSH measurement. PMID- 28810814 TI - Acceptability of a vocational advice service for patients consulting in primary care with musculoskeletal pain: A qualitative exploration of the experiences of general practitioners, vocational advisers and patients. AB - AIMS: Using qualitative interviews, this study explored the experiences of GPs, vocational advisers and patients towards a new vocational advice (VA) service in primary care. METHODS: This study was nested within the Study of Work and Pain (SWAP) cluster randomised controlled trial. The SWAP trial located a VA service within three general practices in Staffordshire. Interviews took place with 10 GPs 12 months after the introduction of the VA service, four vocational advisers whilst the VA service was running and 20 patients on discharge from the VA service. The data were analysed using the constant comparative method, which is a variation of grounded theory. RESULTS: The key factors determining the acceptability and perceived effectiveness of the VA service from the perspective of the three groups of stakeholders were (1) the timing of referrals to the VA, (2) the perceived lack of patient demand for the service and (3) role uncertainty experienced by VAs. CONCLUSIONS: Early vocational intervention may not be appropriate for all musculoskeletal patients with work difficulties. Indeed, many patients felt they did not require the support of a VA, either because they had self-limiting work difficulties and/or already had support mechanisms in place to return to work. Future VA interventions may be better implemented in a targeted way so that appropriate patients are identified with characteristics which can best be addressed by the VA service. PMID- 28810815 TI - Social selection in cohort studies and later representation of childhood psychiatric diagnoses: The Danish National Birth Cohort. AB - AIM: This study aimed to estimate the relative representation of childhood psychiatric diagnoses and use of psychotropic medication in the Danish National Birth Cohort (DNBC) compared to the general population. METHODS: The general population was identified as all childbirths in Denmark during 1998-2002 ( N=344,160). Linking the DNBC ( N=91,442) and the general population to the Danish national health registries, all children were followed until they received an ICD 10 psychiatric diagnosis, had a prescription of psychotropic medication or to the end of follow-up in 2013. The prevalence ratios (PRs) with corresponding 95% confidence intervals (CI) were estimated for each psychiatric diagnosis and by sex. Age at first diagnosis presented as means were compared using the one-sample t-test. RESULTS: In the DNBC, the selected childhood psychiatric diagnoses were underrepresented by 3% (PR=0.97, 95% CI 0.94-0.99), ranging from a 20% underrepresentation for schizophrenia (PR=0.80, 95% CI 0.59-1.09) to a 6% over representation for anxiety disorder or obsessive-compulsive disorder (PR=1.06, 95% CI 0.97-1.17). The majority of the specific diagnoses were modestly underrepresented in the DNBC compared to the general population, while use of psychotropic medication had similar representation. Girls were generally more underrepresented than boys. Depression was on average diagnosed 0.4 years earlier in the DNBC than in the general population ( p=0.023). CONCLUSIONS: These findings suggest that the social selection may influence the prevalence of diagnosed childhood psychiatric disorders in the DNBC. PMID- 28810816 TI - Prosody of Dual-focus in German: Interaction between Focus and Phrasing. AB - This paper studies the prosodic realization of dual-focus in German, that is, two foci in a single sentence, with special consideration of the interaction between focus assignment and phrasing. In a production experiment, dual-focus was compared with its initial, final, and all-new counterparts in sentences with subject NPs and VPs of different lengths. The results showed that there were three different patterns of dual-focus realization: (1) The most frequent one was the two-peak pattern (57.8%), that is, a falling tone on both focused words and compressed and lowered pitch in-between; (2) the second most frequent was the two phrase realization (23.5%), in which both foci were also realized as a falling tone, but in this case, a high boundary tone was inserted after the subject NP; (3) the least frequent pattern was the hat-pattern (18.7%), consisting of a rising tone on the first focus and a falling tone on the second one while the pitch in-between is kept as a high plateau. This was applied mostly in utterances containing a short subject NP. We interpret these results in terms of optional prosodic phrasing. A sentence with two foci can be realized in one or two intonation phrases, but in both cases, the focus is assigned within the prosodic domain derived from syntax. These results show that Culminativity, the principle requiring a one-to-one correspondence between prosodic domains and their heads, is violable in German. Two equally prominent pitch accents are allowed to co exist in one intonation phrase. Finally, the metrical structure of dual-focus speaks for a recursive structure of German prosody. PMID- 28810817 TI - Struggles Over Antibiotics: Physicians' Stance-Taking Toward a Nonconforming Policy in an Intensive Care Unit. AB - One of the most pressing contemporary health care challenges consists in rethinking antibiotic use to contrast the increase of multidrug resistant bacteria. Drawing on an ethnographic fieldwork in an Intensive Care Unit that adopts a nonconforming policy of antibiotic stewardship, this article analyzes doctor-doctor interaction concerning infectious disease diagnosis and antibiotic treatment. By analyzing examples of medical decision-making from a corpus of video-recorded morning briefings, we focus on physicians' stance-taking toward the ward's nonconforming policy and illustrate how it is contingently situated along a continuum from strong commitment to overt resistance. We suggest that physicians' oscillating stance-taking is favored by the moral load of following an extreme and "off-label" policy and, in turn, impacts on the way this policy is practically accomplished as a highly reflective interactional achievement by the team members. PMID- 28810818 TI - [Nonsuicidal self-injury in adolescence: a clinical guideline for diagnostics and therapy]. AB - Objective: Nonsuicidal self-injury (NSSI) is a frequent, clinically relevant phenomenon occurring in adolescence, which can be observed parallel to various mental disorders. Within Europe, Germany has one of the highest prevalence rates in youths, with the lifetime prevalence ranging between 25-35 %. To date a guideline on the treatment of self-injury and stereotypic motoric disorders has been available, the last having been updated in 2006 and expired in 2011. Methods: The guideline development group consisted of members of 11 medical, psychological, or psychotherapeutic professional associations and two members from patient and prevention groups. The guideline was developed in two meetings followed up by consecutive literature searches; it was adopted in a final consensus conference. The algorithm on the treatment of NSSI was approved in three rounds of a Delphi process. Results: Although there is solid evidence of NSSI from the fields of epidemiology and diagnostics, few studies report data on the longitudinal course as well as on the psychotherapeutic and adjuvant psychopharmacological treatment of NSSI in adolescence. The stepped care regimens in cases demanding somatic treatment were addressed interdisciplinarily. Conclusions: In accordance with the heterogeneous evidence, important points for the treatment of NSSI in adolescence were determined in a consensus conference. There is still a lack of knowledge on prevention as well as clinical interventions, both of which need to be addressed by further research. PMID- 28810819 TI - Low CLL-1 Expression Is a Novel Adverse Predictor in 123 Patients with De Novo CD34+ Acute Myeloid Leukemia. AB - Recent reports state that C-type lectin-like molecule-1 (CLL-1) in acute myeloid leukemia (AML) is expressed primarily on myeloid cells, but there is still no investigation about its prognostic significance on leukemic blast compartment. Hence, this study aimed to evaluate the prognostic value of CLL-1 in 123 patients with de novo CD34+ Non-M3 AML. Multiparameter flow cytometry was used to assess the expression of CLL-1 on immature compartment in AML and control groups. We found that CLL-1 expression level on blast compartment was closely linked to clinical characteristics, treatment response, and survival outcome of patients. Decreased expression of CLL-1 was observed on immature compartment from AML patients as compared with controls (62.6% vs. 86.5%, P < 0.05). Logistic model exhibited that CLL-1low independently predicted low complete remission rate with an odds ratio of 4.57 (2.53-6.61, P < 0.05). Additionally, CLL-1 expression level at diagnosis was inversely correlated to the residual blast cells (residual leukemia cell) after induction chemotherapy (r = -0.423, P < 0.05). Furthermore, multivariate Cox regression model demonstrated that CLL-1low was still an independent adverse predictor (P < 0.05 for event-free survival, P < 0.05 for overall survival). Notably, CLL-1low was able to discriminate poor survival patients from intermediate- and favorable-risk groups. Taken together, CLL-1 is a novel prognostic predictor that could be exploited to supplement the current AML prognostic risk stratification system, and potentially optimize the clinical management of AML. PMID- 28810820 TI - Quantitative, Label-Free Evaluation of Tissue-Engineered Skeletal Muscle Through Multiphoton Microscopy. AB - The lack of tools for assessing engineered tissue viability and function in a noninvasive manner is a major regulatory and translational challenge facing tissue engineers. Label-free, nonlinear optical molecular imaging (OMI) has utilized endogenous nicotinamide adenine dinucleotide and flavin adenine dinucleotide fluorescence to indicate metabolic activity. Similarly, second harmonic generation (SHG) signals from myosin and collagen can measure overall muscle structural integrity and function. The purpose of this study was to demonstrate these OMI techniques for the first time in engineered skeletal muscle and to develop a novel method for evaluating our engineered skeletal muscle units (SMUs) before implantation. Three experimental groups were studied: Control, Steroid Supplemented, and Metabolically Stressed SMUs. After imaging and analysis in ImageJ, a redox ratio (RR) metric was calculated to indicate metabolic activity, and a structure ratio metric was calculated to reflect structural composition. In addition, function was evaluated as tetanic force production in response to electrical stimulation. In living tissues, the RRs successfully distinguished control and metabolically stressed SMUs in both monolayer and 3D form. OMI of myosin and collagen SHG similarly differentiated control SMUs from the steroid supplemented group. With respect to function, steroid supplementation significantly increased active force generation. When comparing functional and OMI measures, a significant correlation was present between overall myosin density and active force generation. This work demonstrates the potential for using label-free OMI to evaluate tissue-engineered skeletal muscle constructs. The positive correlation between structural OMI measures and force production suggests that OMI could potentially serve as an accurate predictor of functional behaviors, such as integration and tissue regeneration, after implantation. This noninvasive OMI methodology, demonstrated for the first time in engineered skeletal muscle, could prove invaluable for assessing our tissue engineering technology and confirming release criteria for validation. PMID- 28810821 TI - Idiopathic Low Ovarian Reserve Is Associated with More Frequent Positive Thyroid Peroxidase Antibodies. AB - BACKGROUND: While screening of thyroid peroxidase antibody (TPOAb) has been recommended in women with primary ovarian insufficiency, the relationship between thyroid autoimmunity (TAI) and ovarian reserve remains undetermined. Because the TAI prevalence was reported to be different between different ethnic/racial groups, this study aimed to investigate the TAI prevalence in Chinese women with variable ovarian reserve. METHODS: This is a cross-sectional study conducted in a university infertility clinic between October 2013 and March 2016. Among patients at their first entry to the infertility clinic, a total of 1044 patients with available results of anti-Mullerian hormone (AMH), thyrotropin (TSH), TPOAb, and thyroglobulin antibody (TgAb) were enrolled. The TSH levels and the prevalence of positive TPOAb and positive TgAb were compared between patients with low, normal, and high ovarian reserve categorized with age-specific AMH levels. RESULTS: For the whole study population, the TSH levels, TPOAb positivity, and TgAb positivity were comparable between patients with variable ovarian reserve. However, after patients with known causes compromising ovarian reserve (iatrogenic or genetic) were excluded, only TPOAb positivity became significantly different between patients with low (22.7%), normal (14.0%), and high ovarian reserve (10.3%; p = 0.012). The TPOAb levels were not significantly correlated to AMH levels (Spearman's rho = -0.027; p = 0.413). For the infertile subgroup, TPOAb positivity was significantly associated with idiopathic low ovarian reserve in unexplained infertility (low ovarian reserve: 28.6%; normal: 15.7%; high: 9.5%; p = 0.020). CONCLUSIONS: Idiopathic low ovarian reserve was associated with more frequent positive TPOAb rather than thyroid function or TgAb positivity in Chinese women. PMID- 28810822 TI - Gamma-irradiated beta-glucan modulates signaling molecular targets of hepatocellular carcinoma in rats. AB - beta-glucans are one of the most abundant forms of polysaccharides known as biological response modifiers which influence host's biological response and stimulate immune system. Accordingly, this study was initiated to evaluate irradiated beta-glucan as a modulator for cellular signaling growth factors involved in the pathogenesis of hepatocellular carcinoma in rats. Hepatocellular carcinoma was induced with 20 mg diethylnitrosamine/kg BW. Rats received daily by gastric gavage 65 mg irradiated beta-glucan/kg BW. It was found that treatment of rats with diethylnitrosamine induced hepatic injury and caused significant increase in liver injury markers with a concomitant significant increase in both hepatic oxidative and inflammatory indices: alpha-fetoprotein, interferon gamma, and interleukin 6 in comparison with normal and irradiated beta-glucan-treated groups. Western immunoblotting showed a significant increase in the signaling growth factors: extracellular signal-regulated kinase 1 and phosphoinositide 3 kinase proteins in a diethylnitrosamine-treated group while both preventive and therapeutic irradiated beta-glucan treatments recorded significant improvement versus diethylnitrosamine group via the modulation of growth factors that encounters hepatic toxicity. The transcript levels of vascular endothelial growth factor A and inducible nitric oxide synthase genes were significantly higher in the diethylnitrosamine-treated group in comparison with controls. Preventive and therapeutic treatments with irradiated beta-glucan demonstrated that the transcript level of these genes was significantly decreased which demonstrates the protective effect of beta-glucan. Histological investigations revealed that diethylnitrosamine treatment affects the hepatic architecture throughout the significant severe appearance of inflammatory cell infiltration in the portal area and congestion in the portal vein in association with severe degeneration and dysplasia in hepatocytes all over hepatic parenchyma. The severity of hepatic architecture changes was significantly decreased with both beta-glucan therapeutic and preventive treatments. In conclusion, irradiated beta-glucan modulated signal growth factors, vascular endothelial growth factor A, extracellular signal-regulated kinase 1, and phosphatidylinositol-3-kinase, which contributed to experimental hepatocarcinogenesis. PMID- 28810823 TI - Validation of Ultrasonographic Kidney Volume Measurements: A Reliable Imaging Modality. AB - OBJECTIVES: To investigate the kidney selection procedure before donation to maximize donor safety, we investigated whether ultrasonographic measurements of kidney volume are comparable with computed tomography measurements. Predonation volume and increases in kidney size may be important indicators of renal function after donation and subsequent loss of function. MATERIALS AND METHODS: Consecutive donors with predonation computed tomography scans were approached preoperatively for additional ultrasonographic examinations. Measurements were independently performed by 2 ultrasonographers and considered accurate when the mean differences between both examiners for length, width, and thickness of the kidneys were < 5 mm. Ultrasonographic volumes were calculated with the ellipsoid equation (length * width * thickness * pi/6) and an adjusted equation (length * width * thickness * 0.674), and computed tomography volumes were calculated with the voxel count method, which is considered the criterion standard. RESULTS: For this study (Dutch Trial Register NTR3795), 100 kidneys were measured. The mean differences between examiner 1 and 2 for similar ultrasonography measurements were < 5 mm. The ellipsoid equation underestimated the volume for examiner 1 by 16.9% and for examiner 2 by 14.8%, whereas the adjusted equation overestimated the volume by 6.8% and 9.5% respectively. The correlation between computed tomography and ultrasonographic volume with the adjusted equation was strong for both examiner 1 (r = 0.76; P < .001) and examiner 2 (r = 0.80; P < .001). CONCLUSIONS: Ultrasonographic measurements of kidney volume are comparable with computed tomography measurements. Therefore, ultrasonography is a reliable modality for living kidney donor follow-up monitoring of kidney size adaption after donation. PMID- 28810824 TI - Laparoscopic Donor Nephrectomy: Early Experience at a Single Center in Pakistan. AB - OBJECTIVES: Laparoscopic donor nephrectomy has become the criterion standard for kidney retrieval from living donors. There is no information on the experience and outcomes of laparoscopic donor nephrectomy in Pakistan. The objective of the study was to identify benefits and harms of using laparoscopic compared with open nephrectomy techniques for renal allograft retrieval. MATERIALS AND METHODS: In this a retrospective study, patient files from May 2014 to September 2015 were analyzed. Patients were divided into 2 groups: those with open donor nephrectomy and those with laparoscopic donor nephrectomy. Donor case files and operative notes were analyzed for age, sex, laterality, body mass index, warm ischemia time, perioperative and postoperative complications, surgery time, and length of hospital stay. Finally, serum creatinine patterns of both donors and recipients were analyzed. Data were analyzed using SPSS version 10 (SPSS: An IBM Company, IBM Corporation, Armonk, NY, USA). RESULTS: Of 388 total donors, 190 (49%) had open donor nephrectomy and 198 (51%) had laparoscopic donor nephrectomy. For both groups, most donors were older than 25 years with male preponderance. Left-to right kidney donation ratio was markedly higher in the laparoscopic group than in the open donor nephrectomy group, with 6 cases of double renal artery also included in this study. There were no significant differences in surgery times between the 2 groups, whereas the laparoscopic donor nephrectomy group had shorter hospital stay. Analgesic requirements were markedly shorter in the laparoscopic donor nephrectomy group. The 1-year graft function was not significantly different between the 2 groups. CONCLUSIONS: The results for laparoscopic donor nephrectomy were comparable to those for open donor nephrectomy, and its acceptability was high. Laparoscopic donor nephrectomy should be the preferred approach for procuring the kidney graft. PMID- 28810825 TI - Regulatory T-Cell Levels in the Longest Surviving Asian Patient After Heart-Lung Transplant. AB - Heart-lung transplant is the most effective therapy for patients with end-stage cardiopulmonary disease. Here, we report an initial assessment of a 31-year-old man who had survived more than 11 years after heart-lung transplant, which represents the longest survival time in this procedure in Asian studies. At his 11th anniversary after transplant, extensive tests were carried out, especially to detect regulatory T-cell levels for the first time in a surviving heart-lung transplant recipient. Preliminarily data revealed the status of his immunologic function in relation to chronic allograft rejection. All data indicated that the patient was in good condition. This is the first study detecting regulatory T cell levels in a heart-lung transplant patient. PMID- 28810826 TI - Improving fold resistance prediction of HIV-1 against protease and reverse transcriptase inhibitors using artificial neural networks. AB - BACKGROUND: Drug resistance in HIV treatment is still a worldwide problem. Predicting resistance to antiretrovirals (ARVs) before starting any treatment is important. Prediction accuracy is essential, as low-accuracy predictions increase the risk of prescribing sub-optimal drug regimens leading to patients developing resistance sooner. Artificial Neural Networks (ANNs) are a powerful tool that would be able to assist in drug resistance prediction. In this study, we constrained the dataset to subtype B, sacrificing generalizability for a higher predictive performance, and demonstrated that the predictive quality of the ANN regression models have definite improvement for most ARVs. RESULTS: Trained regression ANNs were optimized for eight protease inhibitors, six nucleoside reverse transcriptase (RT) inhibitors and four non-nucleoside RT inhibitors by experimenting combinations of rare variant filtering (none versus 1 residue occurrence) and ANN topologies (1-3 hidden layers with 2, 4, 6, 8 and 10 nodes per layer). Single hidden layers (5-20 nodes) were used for training where overfitting was detected. 5-fold cross-validation produced mean R2 values over 0.95 and standard deviations lower than 0.04 for all but two antiretrovirals. CONCLUSIONS: Overall, higher accuracies and lower variances (compared to results published in 2016) were obtained by experimenting with various preprocessing methods, while focusing on the most prevalent subtype in the raw dataset (subtype B).We thus highlight the need to develop and make available subtype-specific datasets for developing higher accuracy in drug-resistance prediction methods. PMID- 28810827 TI - Validation of beta-lactam minimum inhibitory concentration predictions for pneumococcal isolates with newly encountered penicillin binding protein (PBP) sequences. AB - BACKGROUND: Genomic sequence-based deduction of antibiotic minimum inhibitory concentration (MIC) has great potential to enhance the speed and sensitivity of antimicrobial susceptibility testing. We previously developed a penicillin binding protein (PBP) typing system and two methods (Random Forest (RF) and Mode MIC (MM)) that accurately predicted beta-lactam MICs for pneumococcal isolates carrying a characterized PBP sequence type (phenotypic beta-lactam MICs known for at least one isolate of this PBP type). This study evaluates the prediction performance for previously uncharacterized (new) PBP types and the probability of encountering new PBP types, both of which impact the overall prediction accuracy. RESULTS: The MM and RF methods were used to predict MICs of 4309 previously reported pneumococcal isolates in 2 datasets and the results were compared to the known broth microdilution MICs to 6 beta-lactams. Based on a method that specifically evaluated predictions for new PBP types, the RF results were more accurate than MM results for new PBP types and showed percent essential agreement (MICs agree within +/-1 dilution) >97%, percent category agreement (interpretive results agree) >93%, major discrepancy (sensitive isolate predicted as resistant) rate < 1.2%, and very major discrepancy (resistant isolate predicted as sensitive) rate < 1.4% for all 6 beta-lactams. The identification of new PBP types over time was well approximated by a diminishingly increasing curve (Pearson's r = 0.99) and minimally impacted overall MIC prediction performance. CONCLUSIONS: MIC prediction using the RF method could be an accurate alternative of phenotypic susceptibility testing even in the presence of previously uncharacterized PBP types. PMID- 28810828 TI - Suitable reference gene for quantitative real-time PCR analysis of gene expression in gonadal tissues of minnow Puntius sophore under high-temperature stress. AB - BACKGROUND: High ambient temperature is known to affect fish gonadal development and physiology in a variety of ways depending on the severity and duration of exposure; however, the underlying molecular mechanisms are poorly understood. Gonadal gene expression influence the gonadal development, physiology and the quality of egg/sperm produced in teleosts and the mechanistic understanding of spatio-temporal changes in the gonadal gene expression could be instrumental in controlling the fate of egg/sperm and the quality of seed produced. Real time quantititative polymerase chain reaction (RT-qCR), is a high throughput, sensitive and reproducible methodology used for understanding gene expression patterns by measuring the relative abundance of mRNA transcripts. However, its accuracy relies upon a suitable reference gene whose expression levels remain stable across various experimental conditions. In the present study, we evaluated the suitability of ten potential reference genes to be used as internal controls in RT-qPCR analysis in gonadal tissues (ovary and testis) of minnow Puntius sophore exposed to high temperature stress for different time periods (7 days, 60 days). Expression analysis of ten different constitutively expressed genes viz. 18S ribosomal RNA (18S rRNA), beta actin (betaactin), beta-2 microglobulin (b2mg), eukaryotic elongation factor-1 (eef1), glyceraldehyde-3phosphate dehydrogenase (gapdh), glucose-6-phosphate dehydrogenase (g6pd), ribosomal binding protein L13 (rpl13), tubulin (tub), tata box binding protein (tbp), ubiquitin (ubi) was carried out by using RT-qPCR and the stability in their expressions were evaluated by using four different algorithms; namely, delta Ct, BestKeeper, geNorm and NormFinder. RESULTS: In ovary, eef1 was found to be the most suitable reference gene in all the algorithms used. In testis, b2mg was found to be the most suitable reference gene in delta Ct, BestKeeper, NormFinder analysis while tbp and eef1 were found to be the most suitable reference genes in geNorm analysis. CONCLUSIONS: In conclusion, eef1 and b2mg were found to be the most suitable reference genes in ovary and testis, respectively, of Puntius sophore exposed to high temperature stress, and could be used as internal controls for gene expression analysis in gonadal tissues of Puntius sophore. PMID- 28810829 TI - Blocking IL-10 signalling at the time of immunization does not increase unwanted side effects in mice. AB - BACKGROUND: Cancer therapeutic vaccine induced cytotoxic T cell (CTL) responses are pivotal for the killing of tumour cells. Blocking interleukin 10 (IL-10) signalling at the time of immunization increases vaccine induced CTL responses and improves prevention of tumour growth in animal models compared to immunization without an IL-10 signalling blockade. Therefore, this immunization strategy may have potential to curtail cancer in a clinical setting. However, IL 10 deficiency leads to autoimmune disease in the gut. Blocking IL-10 at the time of immunization may result in unwanted side effects, especially immune pathological diseases in the intestine. METHODS: We investigated whether blocking IL-10 at the time of immunization results in intestinal inflammation responses in a mouse TC-1 tumour model and in a NOD autoimmune disease prone mouse model. RESULTS: We now show that blocking IL-10 at the time of immunization increases IL 10 production by CD4+ T cells in the spleen and draining lymph nodes, and does not result in blood cell infiltration to the intestines leading to intestinal pathological changes. Moreover, immunization with papillomavirus like particles combined with simultaneously blocking IL-10 signalling does not increase the incidence of autoimmune disease in Non-obese diabetic (NOD) mice. CONCLUSIONS: Our results indicate that immunization with an IL-10 inhibitor may facilitate the generation of safe, effective therapeutic vaccines against chronic viral infection and cancer. PMID- 28810830 TI - Annotating long intergenic non-coding RNAs under artificial selection during chicken domestication. AB - BACKGROUND: Numerous biological functions of long intergenic non-coding RNAs (lincRNAs) have been identified. However, the contribution of lincRNAs to the domestication process has remained elusive. Following domestication from their wild ancestors, animals display substantial changes in many phenotypic traits. Therefore, it is possible that diverse molecular drivers play important roles in this process. RESULTS: We analyzed 821 transcriptomes in this study and annotated 4754 lincRNA genes in the chicken genome. Our population genomic analysis indicates that 419 lincRNAs potentially evolved during artificial selection related to the domestication of chicken, while a comparative transcriptomic analysis identified 68 lincRNAs that were differentially expressed under different conditions. We also found 47 lincRNAs linked to special phenotypes. CONCLUSIONS: Our study provides a comprehensive view of the genome-wide landscape of lincRNAs in chicken. This will promote a better understanding of the roles of lincRNAs in domestication, and the genetic mechanisms associated with the artificial selection of domestic animals. PMID- 28810831 TI - Application of a Bayesian non-linear model hybrid scheme to sequence data for genomic prediction and QTL mapping. AB - BACKGROUND: Using whole genome sequence data might improve genomic prediction accuracy, when compared with high-density SNP arrays, and could lead to identification of casual mutations affecting complex traits. For some traits, the most accurate genomic predictions are achieved with non-linear Bayesian methods. However, as the number of variants and the size of the reference population increase, the computational time required to implement these Bayesian methods (typically with Monte Carlo Markov Chain sampling) becomes unfeasibly long. RESULTS: Here, we applied a new method, HyB_BR (for Hybrid BayesR), which implements a mixture model of normal distributions and hybridizes an Expectation Maximization (EM) algorithm followed by Markov Chain Monte Carlo (MCMC) sampling, to genomic prediction in a large dairy cattle population with imputed whole genome sequence data. The imputed whole genome sequence data included 994,019 variant genotypes of 16,214 Holstein and Jersey bulls and cows. Traits included fat yield, milk volume, protein kg, fat% and protein% in milk, as well as fertility and heat tolerance. HyB_BR achieved genomic prediction accuracies as high as the full MCMC implementation of BayesR, both for predicting a validation set of Holstein and Jersey bulls (multi-breed prediction) and a validation set of Australian Red bulls (across-breed prediction). HyB_BR had a ten fold reduction in compute time, compared with the MCMC implementation of BayesR (48 hours versus 594 hours). We also demonstrate that in many cases HyB_BR identified sequence variants with a high posterior probability of affecting the milk production or fertility traits that were similar to those identified in BayesR. For heat tolerance, both HyB_BR and BayesR found variants in or close to promising candidate genes associated with this trait and not detected by previous studies. CONCLUSIONS: The results demonstrate that HyB_BR is a feasible method for simultaneous genomic prediction and QTL mapping with whole genome sequence in large reference populations. PMID- 28810833 TI - Population effectiveness of the pentavalent and monovalent rotavirus vaccines: a systematic review and meta-analysis of observational studies. AB - BACKGROUND: Rotavirus was the leading cause of acute gastroenteritis (AGE) in infants and young children prior to the introduction of routine vaccination. Since 2006 there have been two licensed vaccines available; with successful clinical trials leading the World Health Organization to recommend rotavirus vaccination for all children worldwide. In order to inform immunisation policy we have conducted a systematic review and meta-analysis of observation studies to assess population effectiveness against acute gastroenteritis. METHODS: We systematically searched PubMed, Medline, Web of Science, Cinhal and Academic Search Premier and grey literature sources for studies published between January 2006 and April 2014. Studies were eligible for inclusion if they were observational measuring population effectiveness of rotavirus vaccination against health care attendances for rotavirus gastroenteritis or AGE. To evaluate study quality we use used the Newcastle-Ottawa Scale for non-randomised studies, categorising studies by risk of bias. Publication bias was assessed using funnel plots. If two or more studies reported a measure of vaccine effectiveness (VE), we conducted a random effects meta-analysis. We stratified analyses by World Bank country income level and used study quality in sensitivity analyses. RESULTS: We identified 30 studies, 19 were from high-income countries and 11 from middle income countries. Vaccine effectiveness against hospitalization for laboratory confirmed rotavirus gastroenteritis was highest in high-income countries (89% VE; 95% CI 84-92%) compared to middle-income countries (74% VE; 95% CI 67-80%). Vaccine effectiveness was higher for those receiving the complete vaccine schedule (81% VE; 95% CI 75-86%) compared to partial schedule (62% VE; 95% CI 55 69%). Two studies from high-income countries measured VE against community consultations for AGE with a pooled estimate of 40% (95% CI 13-58%; 2 studies). CONCLUSIONS: We found strong evidence to further support the continued use of rotavirus vaccines. Vaccine effectiveness was similar to that reported in clinical trials for both high and middle-income countries. There is limited data from Low income settings at present. There was lower effectiveness against milder disease. Further studies, should continue to report effectiveness against AGE and less-severe rotavirus disease because as evidenced by pre-vaccine introduction studies this is likely to contribute the greatest burden on healthcare resources, particularly in high-income countries. PMID- 28810834 TI - Multiple-trait QTL mapping and genomic prediction for wool traits in sheep. AB - BACKGROUND: The application of genomic selection to sheep breeding could lead to substantial increases in profitability of wool production due to the availability of accurate breeding values from single nucleotide polymorphism (SNP) data. Several key traits determine the value of wool and influence a sheep's susceptibility to fleece rot and fly strike. Our aim was to predict genomic estimated breeding values (GEBV) and to compare three methods of combining information across traits to map polymorphisms that affect these traits. METHODS: GEBV for 5726 Merino and Merino crossbred sheep were calculated using BayesR and genomic best linear unbiased prediction (GBLUP) with real and imputed 510,174 SNPs for 22 traits (at yearling and adult ages) including wool production and quality, and breech conformation traits that are associated with susceptibility to fly strike. Accuracies of these GEBV were assessed using fivefold cross validation. We also devised and compared three approximate multi-trait analyses to map pleiotropic quantitative trait loci (QTL): a multi-trait genome-wide association study and two multi-trait methods that use the output from BayesR analyses. One BayesR method used local GEBV for each trait, while the other used the posterior probabilities that a SNP had an effect on each trait. RESULTS: BayesR and GBLUP resulted in similar average GEBV accuracies across traits (~0.22). BayesR accuracies were highest for wool yield and fibre diameter (>0.40) and lowest for skin quality and dag score (<0.10). Generally, accuracy was higher for traits with larger reference populations and higher heritability. In total, the three multi-trait analyses identified 206 putative QTL, of which 20 were common to the three analyses. The two BayesR multi-trait approaches mapped QTL in a more defined manner than the multi-trait GWAS. We identified genes with known effects on hair growth (i.e. FGF5, STAT3, KRT86, and ALX4) near SNPs with pleiotropic effects on wool traits. CONCLUSIONS: The mean accuracy of genomic prediction across wool traits was around 0.22. The three multi-trait analyses identified 206 putative QTL across the ovine genome. Detailed phenotypic information helped to identify likely candidate genes. PMID- 28810835 TI - Secondary organizing pneumonia following viral pneumonia caused by severe influenza B: a case report and literature reviews. AB - BACKGROUND: Some reported that organizing pneumonia (OP) may occur after influenza A infections including swine-origin influenza A (H1N1). However, OP associated with influenza B infection has never been reported. We report the first case of secondary OP associated with viral pneumonia caused by influenza B. CASE PRESENTATION: A 23-year old woman was diagnosed as viral pneumonia caused by type B influenza. Despite of antiviral therapy, abnormal chest shadows were not improved. Bronchoscopy and transbronchial lung biopsy showed organizing pneumonia due to viral pneumonia caused by influenza B. Corticosteroid therapy was started at 30 mg daily (0.5 mg/kg), and the dose was reduced to 25, 20, 15 or 10 mg per day every month with symptomatic and radiological resolution. Even after corticosteroid therapy was discontinued, we did not confirm disease recurrence. CONCLUSIONS: Physicians should be aware of the possibility for SOP and severe viral pneumonia even in case of type B as well as type A influenza infections. PMID- 28810836 TI - Suppression of AGR2 in a TGF-beta-induced Smad regulatory pathway mediates epithelial-mesenchymal transition. AB - BACKGROUND: During cancer progression, epithelial cancer cells can be reprogrammed into mesenchymal-like cells with increased migratory potential through the process of epithelial-mesenchymal transition (EMT), representing an essential step of tumor progression towards metastatic state. AGR2 protein was shown to regulate several cancer-associated processes including cellular proliferation, survival and drug resistance. METHODS: The expression of AGR2 was analyzed in cancer cell lines exposed to TGF-beta alone or to combined treatment with TGF-beta and the Erk1/2 inhibitor PD98059 or the TGF-beta receptor specific inhibitor SB431542. The impact of AGR2 silencing by specific siRNAs or CRISPR/Cas9 technology on EMT was investigated by western blot analysis, quantitative PCR, immunofluorescence analysis, real-time invasion assay and adhesion assay. RESULTS: Induction of EMT was associated with decreased AGR2 along with changes in cellular morphology, actin reorganization, inhibition of E cadherin and induction of the mesenchymal markers vimentin and N-cadherin in various cancer cell lines. Conversely, induction of AGR2 caused reversion of the mesenchymal phenotype back to the epithelial phenotype and re-acquisition of epithelial markers. Activated Smad and Erk signaling cascades were identified as mutually complementary pathways responsible for TGF-beta-mediated inhibition of AGR2. CONCLUSION: Taken together our results highlight a crucial role for AGR2 in maintaining the epithelial phenotype by preventing the activation of key factors involved in the process of EMT. PMID- 28810832 TI - Genome-wide analysis of basic helix-loop-helix (bHLH) transcription factors in Brachypodium distachyon. AB - BACKGROUND: As a superfamily of transcription factors (TFs), the basic helix-loop helix (bHLH) proteins have been characterized functionally in many plants with a vital role in the regulation of diverse biological processes including growth, development, response to various stresses, and so on. However, no systemic analysis of the bHLH TFs has been reported in Brachypodium distachyon, an emerging model plant in Poaceae. RESULTS: A total of 146 bHLH TFs were identified in the Brachypodium distachyon genome and classified into 24 subfamilies. BdbHLHs in the same subfamily share similar protein motifs and gene structures. Gene duplication events showed a close relationship to rice, maize and sorghum, and segment duplications might play a key role in the expansion of this gene family. The amino acid sequence of the bHLH domains were quite conservative, especially Leu-27 and Leu-54. Based on the predicted binding activities, the BdbHLHs were divided into DNA binding and non-DNA binding types. According to the gene ontology (GO) analysis, BdbHLHs were speculated to function in homodimer or heterodimer manner. By integrating the available high throughput data in public database and results of quantitative RT-PCR, we found the expression profiles of BdbHLHs were different, implying their differentiated functions. CONCLUSION: One hundred fourty-six BdbHLHs were identified and their conserved domains, sequence features, phylogenetic relationship, chromosomal distribution, GO annotations, gene structures, gene duplication and expression profiles were investigated. Our findings lay a foundation for further evolutionary and functional elucidation of BdbHLH genes. PMID- 28810838 TI - Violence and depression among men who have sex with men in Tanzania. AB - BACKGROUND: Men who have sex with men (MSM) continue to be at an increased risk of Violence, HIV transmission and Mental Disorders such as depression on top of many other bio-psycho-socio challenges they face as a result of their sexual orientation. METHODS: We recruited 345 MSM using a respondent driven sampling technique. Revised Conflict Tactic Scale, PHQ-9 and questions adapted from the TDHS 2010 were used to assess for violence, depression and HIV-risk behaviors respectively. Continuous and categorical variables were analyzed with student's t test and chi-square test respectively. Logistic regression analyses were performed to assess for predictors of depression and HIV-risk behaviors. All tests were two sided and p < 0.05 was taken as significance level. RESULTS: Overall, 325 (94.2%) of participants experienced any form of violence, with emotional violence constituting the majority (90.1%), while physical and sexual violence were reported by 254 (73.6%) and 250 (72.5%) of participants respectively. Depressive symptoms were present in 245 (70.0%) and participants who experienced violence had a 3 times increased risk of depressive symptoms compared to their violence-free counterparts, p < 0.001. On the other hand, participants who experienced any form of violence displayed an over 11 times increased rate of depressive symptoms compared to their counterparts who were violence free, p < 0.001. Violence experience was found to be the strongest associated factor for depressive symptoms. CONCLUSIONS: The rates of violence, depressive symptoms and HIV risk behaviors amongst MSM are astoundingly high thus necessitating extensive interventions. In view of this, deliberate measures to deal with the reported high rates necessitate joint intervention efforts from the policy makers, health providers and community at large. PMID- 28810837 TI - Phase I dose-escalation study of pazopanib combined with bevacizumab in patients with metastatic renal cell carcinoma or other advanced tumors. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) directed therapies are being used in a large number of advanced tumors. Metastatic renal cell carcinoma (mRCC) is highly dependent on the VEGF pathway; VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKI) and humanized VEGF monoclonal antibody have been registered for clinical use in advanced renal cell carcinoma. The VEGFR TKI, pazopanib, with a rather manageable toxicity profile, was preferred to sunitinib by mRCC patients. We investigate the combination of pazopanib and bevacizumab to determine the maximum tolerated dose (MTD) in mRCC and other advanced solid tumors. METHODS: In this bicentric phase I trial with a 3 + 3 + 3 dose-escalation design, patients received oral pazopanib once daily plus intravenous infusion of bevacizumab every 2 weeks from D15, at one of the four dose levels (DL) planned according to the occurrence of dose limiting toxicities (DLT). 400 and 600 mg pazopanib were respectively combined with 7.5 mg/kg bevacizumab in DL1 and DL2, and 600 and 800 mg pazopanib with 10 mg/kg bevacizumab in DL3 and DL4. Tumor response was evaluated every 8 weeks. Blood samples were assayed to investigate pazopanib pharmacokinetics. RESULTS: Twenty five patients including seven mRCC were enrolled. Nine patients received the DL1, ten received the DL2. No DLT were observed at DL1, five DLT at DL2, and 3 DLT in the six additional patients who received the DL1. A grade 3 microangiopathic hemolytic anemia syndrome was observed in four (16%) patients. Five (22%) patients achieved a partial response. The mean (range) plasmatic concentrations of 400 and 600 pazopanib were respectively 283 (139-427) and 494 (227-761) MUg.h/mL at Day 1, and 738 (487-989) and 1071 (678-1464) MUg.h/mL at Day 15 i.e. higher than those previously reported with pazopanib, and were not directly influenced by bevacizumab infusion. CONCLUSIONS: The combination of pazopanib and bevacizumab induces angiogenic toxicity in patients without any pre-existing renal or vascular damage. Even if a marginal efficacy was reported with five (22%) patients in partial response in different tumor types, the toxicity profile compromises the development of this combination. TRIAL REGISTRATION: The study was retrospectively registered on ClinicalTrials.gov (number NCT01202032 ) on 2010, Sept 14th. PMID- 28810839 TI - Relationships between sickle cell trait, malaria, and educational outcomes in Tanzania. AB - BACKGROUND: Sickle Cell Trait (SCT) has been shown to be protective against malaria. A growing literature suggests that malaria exposure can reduce educational attainment. This study assessed the relationship and interactions between malaria, SCT and educational attainment in north-eastern Tanzania. METHODS: Seven hundred sixty seven children were selected from a list of individuals screened for SCT. Febrile illness and malaria incidence were monitored from January 2006 to December 2013 by community health workers. Education outcomes were extracted from the Korogwe Health and Demographic Surveillance system in 2015. The primary independent variables were malaria and SCT. The association between SCT and the number of fever and malaria episodes from 2006 to 2013 was analyzed. Main outcomes of interest were school enrolment and educational attainment in 2015. RESULTS: SCT was not associated with school enrolment (adjusted OR 1.42, 95% CI [0.593,3.412]) or highest grade attained (adjusted grade difference 0.0597, 95% CI [-0.567, 0.686]). SCT was associated with a 29% reduction in malaria incidence (adjusted IRR 0.71, 95% CI [0.526, 0.959]) but not with fever incidence (adjusted IRR 0.905, 95% CI [0.709-1.154]). In subgroup analysis of individuals with SCT, malaria exposure was associated with reduced school enrollment (adjusted OR 0.431, 95% CI [0.212, 0.877]). CONCLUSIONS: SCT appears to reduce incidence of malaria. Overall, children with SCT do not appear to attend more years of school; however children who get malaria despite SCT appear to have lower levels of enrolment in education than their peers. PMID- 28810840 TI - The association between tuberculosis and the development of insulin resistance in adults with pulmonary tuberculosis in the Western sub-district of the Cape Metropole region, South Africa: a combined cross-sectional, cohort study. AB - BACKGROUND: The existence of a bi-directional relationship between tuberculosis (TB) and insulin resistance (IR)/diabetes has been alluded to in literature. Although diabetes has been linked to increased tuberculosis risk, the relationship between tuberculosis as a causative factor for IR remains unclear. The study aimed to determine if an association existed between tuberculosis and IR development in adults with newly diagnosed pulmonary tuberculosis at baseline. It was additionally aimed to document changes in IR status during TB follow-up periods. METHODS: This cross-sectional study evaluated ambulatory participants at baseline for IR prevalence via anthropometry, biochemistry and diagnostic IR tests [homeostasis model assessment-IR (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI)]. A prospective cohort sub-section study was additionally performed on approximately half of the baseline study population, who were followed-up at two and five months whilst on tuberculosis treatment. Summary statistics, correlation co-efficients and appropriate analysis of variance were used to describe and analyse data. Participants were excluded if they presented with other forms of tuberculosis, were HIV-positive, obese or had any pre-disposing IR conditions such as diabetes or metabolic syndrome. RESULTS: Fifty-nine participants were included from August 2013 until December 2014 (33.95 +/- 12.02 years old; 81.4% male). IR prevalence was 25.4% at baseline, determined by a calculated HOMA-IR cut-off point of 2.477. Patients with IR were younger (p = 0.04). Although the difference between IR levels in participants between baseline and follow-up was not significant, a decrease was observed over time. The majority of participants (61.0%) presented with a normal BMI at baseline. Mean baseline values of fasting glucose were within normal ranges (4.82 +/- 0.80 mmol/L), whereas increased mean CRP levels (60.18 +/- 50.92 mg/L) and decreased mean HDL-cholesterol levels (males: 0.94 +/- 0.88 mmol/L; females: 1.14 +/- 0.88 mmol/L) were found. CONCLUSIONS: The study found an association between tuberculosis and IR development in newly diagnosed pulmonary tuberculosis patients. Although not significant, IR levels decreased over time, which could be indicative of a clinical improvement. A high prevalence of IR amongst young tuberculosis patients therefore highlights the need for early identification in order to facilitate a reversal of IR and prevent possible IR-related complications. PMID- 28810842 TI - Erratum to: short-term efficacy of intravitreal Aflibercept injections for retinal angiomatous proliferation. PMID- 28810841 TI - Effectiveness of online and mobile telephone applications ('apps') for the self management of suicidal ideation and self-harm: a systematic review and meta analysis. AB - BACKGROUND: Online and mobile telephone applications ('apps') have the potential to improve the scalability of effective interventions for suicidal ideation and self-harm. The aim of this review was therefore to investigate the effectiveness of digital interventions for the self-management of suicidal ideation or self harm. METHODS: Seven databases (Applied Science & Technology; CENTRAL; CRESP; Embase; Global Health; PsycARTICLES; PsycINFO; Medline) were searched to 31 March, 2017. Studies that examined the effectiveness of digital interventions for suicidal ideation and/or self-harm, or which reported outcome data for suicidal ideation and/or self-harm, within a randomised controlled trial (RCT), pseudo RCT, or observational pre-test/post-test design were included in the review. RESULTS: Fourteen non-overlapping studies were included, reporting data from a total of 3,356 participants. Overall, digital interventions were associated with reductions for suicidal ideation scores at post-intervention. There was no evidence of a treatment effect for self-harm or attempted suicide. CONCLUSIONS: Most studies were biased in relation to at least one aspect of study design, and particularly the domains of participant, clinical personnel, and outcome assessor blinding. Performance and detection bias therefore cannot be ruled out. Digital interventions for suicidal ideation and self-harm may be more effective than waitlist control. It is unclear whether these reductions would be clinically meaningful at present. Further evidence, particularly with regards to the potential mechanisms of action of these interventions, as well as safety, is required before these interventions could recommended. PMID- 28810843 TI - Trial of labour or elective repeat caesarean delivery:are women making an informed decision at Kenyatta national hospital? AB - BACKGROUND: Trial of labour is a safe option for most women after one previous caesarean delivery. However, the proportion of women attempting trial of labour after previous caesarean delivery (TOLAC) has been declining in many countries. In addition, women with prior caesarean delivery appear to know little regarding their mode of delivery and healthcare providers' recommendations. The doctors' preferences exert a strong influence on patient's decision whether or not to pursue TOLAC. In Kenya, it is unclear whether women who opt for trial of labour after caesarean delivery (TOLAC) or elective repeat caesarean delivery (ERCD) do that based on clear understanding of risks and benefits of both modes of delivery. This study aimed at determining whether patients with one previous caesarean delivery make an informed decision on preferred mode of delivery following their interactions with doctors. METHODS: A cross-sectional descriptive study was carried out on 202 pregnant women with one previous caesarean delivery at Kenyatta National Hospital (KNH) antenatal clinic. Data was collected from both the patients' records and women were interviewed using a structured questionnaire. RESULTS: Out of 202 women with mean age of 30.2 years 136 (67.2%) chose Elective Repeat Caesarean Delivery (ERCD), while 66 (32.8%) opted for TOLAC. Only 61/202 (30.6%; 95% C.I: 24.4 to 37.6%) made informed decisions. Few women (65: 32.2%) knew that the chance of successful TOLAC was high (60-80%) and 97 (48%) were not aware of the chances for a successful TOLAC. More than half of the women (109: 53.9%) were unaware of the risk of uterine rupture after one previous delivery and only few patients (64: 31.7%) knew that the risk of uterine rupture in TOLAC is low (< 1%). The majority of the women (112: 55.4%) did not know that the indications for previous caesarean delivery are an important factor in determining the chance of a successful Vaginal Birth after Caesarean Delivery (VBAC). For 47(23.3%) of the women, there was no documented indication for the previous caesarean delivery. The women's mode of delivery was significantly associated with the preference of the counseling doctor (p < 0.001) and their qualification (p = 0.020). Only 23 (11.4%) women signed the consent form for ERCD while none of the women for TOLAC signed any consent form. CONCLUSIONS: There was an overall lack of information on both modes of delivery while doctor's preferences affected women's decisions. Only just under one third of the women made an informed decision. There is a need to develop clear standard protocols and checklists for information to be disseminated to doctors and all patients with previous caesarean deliveries in subsequent pregnancies in Kenya. PMID- 28810844 TI - Effect of tolvaptan on renal handling of water and sodium, GFR and central hemodynamics in autosomal dominant polycystic kidney disease during inhibition of the nitric oxide system: a randomized, placebo-controlled, double blind, crossover study. AB - BACKGROUND: Tolvaptan slows progression of autosomal dominant polycystic kidney disease (ADPKD) by antagonizing the vasopressin-cAMP axis. Nitric oxide (NO) stimulates natriuresis and diuresis, but its role is unknown during tolvaptan treatment in ADPKD. METHODS: Eighteen patients with ADPKD received tolvaptan 60 mg or placebo in a randomized, placebo-controlled, double blind, crossover study. L-NMMA (L-NG-monomethyl-arginine) was given as a bolus followed by continuous infusion during 60 min. We measured: GFR, urine output (UO), free water clearance (CH2O), fractional excretion of sodium (FENa), urinary excretion of aquaporin-2 channels (u-AQP2) and epithelial sodium channels (u-ENaCgamma), plasma concentrations of vasopressin (p-AVP), renin (PRC), angiotensinII (p-AngII), aldosterone (p-Aldo), and central blood pressure (cBP). RESULTS: During tolvaptan with NO-inhibition, a more pronounced decrease was measured in UO, CH2O (61% vs 43%) and FENa (46% vs 41%) after placebo than after tolvaptan; GFR and u-AQP2 decreased to the same extent; p-AVP increased three fold, whereas u-ENaCgamma, PRC, p-AngII, and p-Aldo remained unchanged. After NO-inhibition, GFR increased after placebo and remained unchanged after tolvaptan (5% vs -6%). Central diastolic BP (CDBP) increased to a higher level after placebo than tolvaptan. Body weight fell during tolvaptan treatment. CONCLUSIONS: During NO inhibition, tolvaptan antagonized both the antidiuretic and the antinatriuretic effect of L NMMA, partly via an AVP-dependent mechanism. U-AQP2 was not changed by tolvaptan, presumeably due to a counteracting effect of elevated p-AVP. The reduced GFR during tolvaptan most likely is caused by the reduction in extracellular fluid volume and blood pressure. TRIAL REGISTRATION: Clinical Trial no: NCT02527863 . Registered 18 February 2015. PMID- 28810845 TI - A bioinformatics approach for identifying transgene insertion sites using whole genome sequencing data. AB - BACKGROUND: Genetically modified crops (GM crops) have been developed to improve the agricultural traits of modern crop cultivars. Safety assessments of GM crops are of paramount importance in research at developmental stages and before releasing transgenic plants into the marketplace. Sequencing technology is developing rapidly, with higher output and labor efficiencies, and will eventually replace existing methods for the molecular characterization of genetically modified organisms. METHODS: To detect the transgenic insertion locations in the three GM rice gnomes, Illumina sequencing reads are mapped and classified to the rice genome and plasmid sequence. The both mapped reads are classified to characterize the junction site between plant and transgene sequence by sequence alignment. RESULTS: Herein, we present a next generation sequencing (NGS)-based molecular characterization method, using transgenic rice plants SNU Bt9-5, SNU-Bt9-30, and SNU-Bt9-109. Specifically, using bioinformatics tools, we detected the precise insertion locations and copy numbers of transfer DNA, genetic rearrangements, and the absence of backbone sequences, which were equivalent to results obtained from Southern blot analyses. CONCLUSION: NGS methods have been suggested as an effective means of characterizing and detecting transgenic insertion locations in genomes. Our results demonstrate the use of a combination of NGS technology and bioinformatics approaches that offers cost- and time-effective methods for assessing the safety of transgenic plants. PMID- 28810846 TI - Personality traits and suicide attempts with and without psychiatric disorders: analysis of impulsivity and neuroticism. AB - BACKGROUND: There is a critical need for empirical data concerning the association of personality traits and attempted suicide with and without psychiatric disorders in mainland China. The objective of the present study is to provide such data by determining the prevalence of psychiatric disorders and analyzing the levels of impulsivity and neuroticism among people who have attempted suicide, and to examine the association between these personality traits and suicide attempt in people with or without psychiatric disorders. METHODS: We administered self-reported tests and clinical interviews to 196 people who have attempted suicide who were admitted to a hospital emergency room or our psychiatric settings after a suicide attempt. RESULTS: One hundred and fifty-six subjects (79.6%) met the criteria for Axis I disorders and eleven (6.6%) met the criteria Axis II personality disorders. Those who have attempted suicide who did not have psychiatric disorders exhibited a greater degree of background characteristics (e.g., high lethality, more interpersonal conflicts and more alcohol use), lower levels of suicidality (suicide risk, depressive symptoms) and differences of personality traits (e.g., more impulsive and less neuroticism) as compared to those who do have psychiatric disorders. Profile differences existed even after control for the stressful life event. CONCLUSION: Our findings suggest that some personality traits differ between people who have attempted suicide depending on whether or not they have psychiatric disorders. Based on these findings, investigating the impact of personality traits on suicidal behavior in therapeutic settings would provide critical data to improve patient treatment and outcomes. PMID- 28810847 TI - FEV1 and FVC and systemic inflammation in a spinal cord injury cohort. AB - BACKGROUND: Systemic inflammation has been associated with reduced pulmonary function in individuals with and without chronic medical conditions. Individuals with chronic spinal cord injury (SCI) have clinical characteristics that promote systemic inflammation and also have reduced pulmonary function. We sought to assess the associations between biomarkers of systemic inflammation with pulmonary function in a chronic SCI cohort, adjusting for other potential confounding factors. METHODS: Participants (n = 311) provided a blood sample, completed a respiratory health questionnaire, and underwent spirometry. Linear regression methods were used to assess cross-sectional associations between plasma C-reactive protein (CRP) and interleukin-6 (IL-6) with forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC. RESULTS: There were statistically significant inverse relationships between plasma CRP and IL-6 assessed in quartiles or continuously with FEV1 and FVC. In fully adjusted models, each interquartile range (5.91 mg/L) increase in CRP was associated with a significant decrease in FEV1 (-55.85 ml; 95% CI: -89.21, -22.49) and decrease in FVC (-65.50 ml; 95% CI: -106.61, -24.60). There were similar significant findings for IL-6. There were no statistically significant associations observed with FEV1/FVC. CONCLUSION: Plasma CRP and IL-6 in individuals with chronic SCI are inversely associated with FEV1 and FVC, independent of SCI level and severity of injury, BMI, and other covariates. This finding suggests that systemic inflammation associated with chronic SCI may contribute to reduced pulmonary function. PMID- 28810848 TI - Erratum to: Safety and tolerability of Bifidobacterium longum subspecies infantis EVC001 supplementation in healthy term breastfed infants: a phase I clinical trial. PMID- 28810849 TI - In vitro antiplasmodial activity and prophylactic potentials of extract and fractions of Trema orientalis (Linn.) stem bark. AB - BACKGROUND: Trema orientalis (T. orientalis Linn) has been used in the management of malaria in the western part of Nigeria and despite its application in ethnomedicine, there is dearth of scientific evidence to justify the acclaimed prophylactic antimalarial usage of the plant. The aim of this study is to assess the in vitro antiplasmodial cell-free assay and chemopreventive efficacy of the methanol extract of the stem bark of T. orientalis and its fractions as a prophylactic regimen for malaria prevention. Also, the antimicrobial activities of the extract and the fractions were investigated. METHOD: Vacuum liquid chromatography was used to obtain dichloromethane, ethylacetate and methanol fractions from the methanol extract of T. orientalis. The fractions were tested for their prophylactic and cell-free antimalarial activity using murine models and beta-hematin formation assay respectively. Disc diffusion method was used to determine the antibacterial activity of the extract and its fractions against both Gram-positive and Gram-negative bacteria. RESULTS: In the prophylactic experiment, dichloromethane (DCMF), methanol fraction (MF) and extract (ME) (in this order) showed significant chemopreventive effects against P. berghei invasion of the red blood cells when compared with both Sulfadoxine-Pyrimethamine (SP) and untreated controls. Results of the in vitro study showed that the DCMF had the highest effect in preventing the formation of beta-hematin when compared with other fractions. The DCMF also had the highest percentage inhibition of beta hematin formation when compared with chloroquine. The extract and fractions showed a concentration dependent antibacterial activity. Methanol extract had a pronounced inhibitory effect on Enterobacter cloaca ATCC 13047 and Enterococcus faecalis ATCC 29212. Serratia mercescens ATCC 9986 and Pseudomonas aeruginosa ATCC 19582 were the most susceptible bacteria. CONCLUSION: The results obtained showed that both extract and fractions of T. orientalis possessed antiplasmodial and antimicrobial activity. PMID- 28810850 TI - Variations in diabetes remission rates after bariatric surgery in Spanish adults according to the use of different diagnostic criteria for diabetes. AB - BACKGROUND: There are multiple criteria to define remission of type 2 diabetes (DM2) after bariatric surgery but there is not a specific one widely accepted. Our objectives were to compare diagnostic criteria for DM2 remission after bariatric surgery: Criteria from Spanish scientific associations (SEEN/SEEDO/SED) and from the American Diabetes Association (ADA). We also aim to analyse the degree of correlation between these sets of criteria. METHODS: Retrospective observational study in 127 patients undergoing bariatric surgery in a single centre (Hospital Universitario Reina Sofia, Cordoba, Spain) between January 2001 and December 2009. We analysed DM2 remission following bariatric surgery comparing DM2 diagnostic criteria approved by Spanish scientific associations and ADA criteria. RESULTS: In total, 62.2% of patients were women; mean age was 47.1 years. Following surgery, 52% achieved complete remission according to ADA criteria, and 63.8% following the criteria approved by Spanish associations (p = 0.001);18.9 and 8.7%, respectively, showed partial remission (p = 0.007), and 29.1 and 27.6% no remission, according to the criteria approved by each association (p = 0.003). There was good correlation between both sets of criteria (Rho 0.781; p < 0.001). CONCLUSIONS: In our series, using more stringent criteria for defining DM2 remission (ADA criteria) results in a lower rate of remission, although we found a a high degree of correlation between both sets of criteria. PMID- 28810851 TI - Chitosan in viscosupplementation: in vivo effect on rabbit subchondral bone. AB - BACKGROUND: To investigate the effect of intra-articular injection of Chitosan (Cs) added to hyaluronic acid (HA) on subchondral bone during osteoarthritis (OA), microarchitectural parameters and mineral density were measured in a rabbit model of early OA. A novel hybrid hydrogel adding reacetylated Cs of fungal origin to HA was compared to high molecular weight HA commercial formulation. METHOD: Eighteen rabbits underwent unilateral anterior cruciate ligament transection (ACLT) and were divided into three groups (Saline-group, HA-group and Hybrid-group) depending on the intra-articular injection compound. Eight contralateral knees were used as non-operated controls (Contralateral-group). Micro-computed tomography was performed six weeks post-ACLT to study subchondral bone microarchitectural parameters and mineral density at an early stage of OA development. RESULTS: Cartilage thickness mean value was reduced only in Saline group compared to Contralateral-group. When the Hybrid-group was compared to Saline-group, subchondral bone microarchitectural parameters (trabecular thickness and trabecular bone volume fraction) were significantly changed; subchondral bone plate and trabecular bone mineral densities (bone mineral density and tissue mineral density) were reduced. When the Hybrid-group was compared to HA-group, subchondral bone microarchitectural parameters (subchondral plate thickness and trabecular thickness) and trabecular bone mineral densities (bone mineral density and tissue mineral density) were significantly decreased. CONCLUSION: Conclusion: Compared to HA alone, the novel hybrid hydrogel, constituted of Cs added to HA, enhanced microarchitectural parameters and mineral density changes, leading to subchondral bone loss in a rabbit model of early experimental OA. PMID- 28810852 TI - Implementation of a guideline for local health policy making by regional health services: exploring determinants of use by a web survey. AB - BACKGROUND: Previous evaluation showed insufficient use of a national guideline for integrated local health policy by Regional Health Services (RHS) in the Netherlands. The guideline focuses on five health topics and includes five checklists to support integrated municipal health policies. This study explores the determinants of guideline use by regional Dutch health professionals. METHODS: A web survey was send to 304 RHS health professionals. The questionnaire was based on a theory- and research-based framework of determinants of public health innovations. Main outcomes were guideline use and completeness of use, defined as the number of health topics and checklists used. Associations between determinants and (completeness of) guideline use were explored by multivariate regression models. RESULTS: The survey was started by 120 professionals (39%). Finally, results from 73 respondents (24%) were eligible for analyses. All 28 Dutch RHS organizations were represented in the final dataset. About half of the respondents (48%) used the guideline. The average score for completeness of use (potential range 1-10) was 2.37 (sd = 1.78; range 1-7). Knowledge, perceived task responsibility and usability were significantly related to guideline use in univariate analyses. Only usability remained significant in the multivariate model on guideline use. Only self-efficacy accounted for significant proportions of variance in completeness of use. CONCLUSIONS: The results imply that strategies to improve guideline use by RHSs should primarily target perceived usability. Self-efficacy appeared the primary target for improving completeness of guideline use. Methods for targeting these determinants in RHSs are discussed. PMID- 28810854 TI - Relationship satisfaction and interpartner agreement about acts of physical and psychological aggression: a multilevel analysis. AB - BACKGROUND: To analyze, in a multilevel context, the impact of individual-level relationship satisfaction on couples' mean reports of aggression and agreement about acts of physical and psychological aggression. METHODS: We conducted a quota sampling method to recruit a community sample of 2.988 heterosexual adult couples from the Region of Madrid (Spain). RESULTS: The percentages of intimate partner aggression considering the highest report of aggression in the couple were around 60% of psychological aggression and 15% of physical aggression. Couples that used aggressive tactics showed low to moderate levels of agreement about physical and psychological aggression. Multilevel models confirm that women's relationship satisfaction had a significant influence on the level of agreement about acts of psychological aggression, but the same pattern of results was not observed for men. On the other hand, men and women's relationship satisfaction had no significant influence on the level of agreement about physical aggression. CONCLUSIONS: Psychological aggression plays a more relevant role in women's relationship satisfaction than physical aggression. PMID- 28810853 TI - Acute effects of reducing sitting time in adolescents: a randomized cross-over study. AB - BACKGROUND: Levels of sitting among adolescents are high, especially during the school day. The acute cognitive and health consequences associated with prolonged sitting are poorly understood in adolescents. This randomized crossover design study examined the acute effects of a simulated school day with reduced sitting or usual sitting on adolescents' cognitive function and cardiometabolic biomarkers. METHODS: Eighteen healthy school aged adolescents were recruited from the community to the study (11 males; 7 females; mean age [SD] = 13.5 +/- 0.9 years). Two protocols were developed to simulate an adolescent school day, the amount of time spent sitting was manipulated reflecting: a 'typical' day (65% of the time spent sitting with two sitting bouts sitting >20 min) and a 'reduced sitting' day (adolescents sat for 50% less time with no bouts of sitting >20 mins). The order that participants were exposed to each condition was randomized (via random number generator). Participants were not fully blinded as they could observe the difference between conditions. Energy intake and moderate to vigorous physical activity (MVPA) were standardized for both conditions and monitored for 48 h post-condition for compensatory effects. Cognitive (working memory) and cardiometabolic outcomes (lipids, glucose, insulin, IL-6, apo-A1, apo-B, blood pressure,) were assessed pre and post for both conditions, BMI and body fat were assessed on the morning of the intervention. Data were analyzed using linear mixed models. Standardised effect sizes were calculated. RESULTS: Compared with the typical school day, the reduced sitting day demonstrated significant positive effects for apoB/apoA-1 ratio (adjusted difference +/- SD) -0.02 +/- 0.03; P = 0.03; effect size [Cohen's d] = -0.67. Findings for total cholesterol -0.19 +/- 0.27; P = 0.28; d = -0.71; HDL cholesterol -0.23 +/- 0.50; P = 0.12 d = -0.66; and total cholesterol/HDL ratio 0.25 +/- 0.53; P = 0.25; d = 0.51 and for cognition 0.64 +/- 0.15; P = 0.15; d = 0.54 were non-significant. There were no compensatory changes in participant energy expenditure or energy intake for 48 h post intervention. CONCLUSION: Reducing school day sitting time in adolescents' resulted in significant improvements in apoB/apoA-1 ratio with medium effect sizes for total cholesterol, HDL cholesterol and total cholesterol/HDL ratio. Cognitive function results showed the equivalent of a 6 month improvement in effective mental-attentional capacity. TRIAL REGISTRATION: The trial was registered as a clinical trial with the Australian and New Zealand Clinical Trials Registry ( ACTRN12614001064695 ) on the 3rd of October 2014 - registered retrospectively. PMID- 28810855 TI - The influence of family accommodation on pediatric hospital experience in Canada. AB - BACKGROUND: The goals of our study were to describe the types of family accommodation for parents of hospitalized children and to examine their influence on the pediatric hospital experience. METHODS: This multi-site cohort survey included 10 hospitals in Ontario Province, Canada. Participants were parents of inpatient children (n = 1240). Main outcome measures included ratings of three parent-reported measures of hospital experience: overall hospital experience; willingness to recommend the hospital to family or friends; and how much the accommodation type helped parent stay involved in their child's hospital care. RESULTS: Parents most often stayed in the child's room (74.7%), their own home (12.3%), hotel (4.0%) or a Ronald McDonald House (3.0%). Accommodation varied based on hospital, parent and child factors. Length of stay and the child's health status were significant predictors for overall hospital experience and recommending the hospital to family or friends, but accommodation type was not. Families who stayed at a Ronald McDonald House reported greater involvement in their child's care compared with other accommodation types (odds ratio: 1.54 20.73 for contrasted accommodation types). CONCLUSION: Use of different overnight accommodations for families of hospitalized pediatric patients in Canada is similar to a previous report of U.S. family hospital accommodations. In contrast to the previous U.S. findings, Canadian hospital experience scores were lower and accommodation type was not a significant predictor of overall hospital experience or willingness to recommend the hospital. In Canada, as in the U.S., families who stayed at a Ronald McDonald House reported that this accommodation type significantly improved their ability to be involved in their child's care. PMID- 28810856 TI - Ibrutinib continues to influence the therapeutic landscape of chronic lymphocytic leukemia: new data presented at ASCO 2017. AB - According to data presented at the 2017 American Society of Oncology (ASCO) Annual Meeting, with more than 4 years of follow-up, ibrutinib continues to provide clinical utility in chronic lymphocytic leukemia (CLL). However, treatment of CLL patients with high-risk cytogenetics features remains a challenge and the outcome of these hard-to-treat patients is dismal. At the 2017 ASCO Meeting, results of the GENUINE phase III trial showed that, by adding ublituximab, a glycoengineered, anti-CD20 type 1 monoclonal antibody, to ibrutinib, the overall response rate (ORR), complete response rate (CRR), and minimal residual disease (MRD) negativity may be improved in high-risk CLL patients. A further way to improve the results obtained with Bruton's tyrosine kinase (BTK) inhibitors is the parallel use of ibrutinib with chimeric antigen receptor (CAR) T-cell therapy. Through this investigational approach, the rate of MRD negativity was shown to be higher, implying potential eradication of CLL. These novel data indicate that ibrutinib continues to have a positive effect in CLL. PMID- 28810857 TI - New onset diabetes in adulthood is associated with a substantial risk for mortality at all ages: a population based historical cohort study with a decade long follow-up. AB - BACKGROUND: Diabetes has been reported to be associated with an increased relative risk for mortality, with estimates ranging from 1.1 to 2.1. Findings are inconsistent regarding modification of the risk by gender and by age. The aim of this study was to estimate the mortality risk associated with new-onset diabetes in adulthood, by age group and gender. METHODS: From the database of a large health care provider, we identified 31,987 individuals diagnosed with diabetes during 2003-2005; and 162,656 individuals without diabetes, group-matched by age. We used Cox regression to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for overall mortality adjusted for age, gender, socioeconomic (SE) level, obesity, smoking and comorbidities at baseline. RESULTS: During a median follow-up of 9.5 years, 4464 (14%) of persons with diabetes and 13,327 (8.2%) of those without died. Among persons with incident diabetes, the proportion of men, smokers, obese and patients of low SE level was higher, as was the prevalence of cardiovascular disease and renal impairment at baseline. Incident diabetes was associated with an adjusted HR for mortality of 1.38 (95% CI 1.32-1.43). Mortality HR for DM was comparable with hypertension (1.42; 1.37 1.46), smoking (1.65; 1.58-1.71) and atherosclerosis (1.40; 1.35-1.46). Diabetes associated mortality HR was somewhat higher among women 1.78 (95% CI 1.58-2.08) as compared with men 1.51 (95% CI 1.41-1.62). CONCLUSIONS: Incident diabetes in adults is associated with a substantial risk for mortality, especially in younger adults. Further efforts should be allocated to diabetes primary prevention. PMID- 28810858 TI - Rapid and sensitive detection of canine distemper virus by real-time reverse transcription recombinase polymerase amplification. AB - BACKGROUND: Canine distemper, caused by Canine distemper virus (CDV), is a highly contagious and fatal systemic disease in free-living and captive carnivores worldwide. Recombinase polymerase amplification (RPA), as an isothermal gene amplification technique, has been explored for the molecular detection of diverse pathogens. METHODS: A real-time reverse transcription RPA (RT-RPA) assay for the detection of canine distemper virus (CDV) using primers and exo probe targeting the CDV nucleocapsid protein gene was developed. A series of other viruses were tested by the RT-RPA.Thirty-two field samples were further tested by RT-RPA, and the resuts were compared with those obtained by the real-time RT-PCR. RESULTS: The RT-RPA assay was performed successfully at 40 degrees C, and the results were obtained within 3 min-12 min. The assay could detect CDV, but did not show cross-detection of canine parvovirus-2 (CPV-2), canine coronavirus (CCoV), canine parainfluenza virus (CPIV), pseudorabies virus (PRV) or Newcastle disease virus (NDV), demonstrating high specificity. The analytical sensitivity of RT-RPA was 31.8 copies in vitro transcribed CDV RNA, which is 10 times lower than the real time RT-PCR. The assay performance was validated by testing 32 field samples and compared to real-time RT-PCR. The results indicated an excellent correlation between RT-RPA and a reference real-time RT-PCR method. Both assays provided the same results, and R2 value of the positive results was 0.947. CONCLUSIONS: The results demonstrated that the RT-RPA assay offers an alternative tool for simple, rapid, and reliable detection of CDV both in the laboratory and point-of-care facility, especially in the resource-limited settings. PMID- 28810859 TI - The presence of ovarian cysts in a captive Antillean manatee (Trichechus manatus manatus L. 1758). AB - BACKGROUND: Several pathological changes associated with reproductive systems of marine mammals have been reported in primary literature. However, no such records exist regarding ovarian cysts in the Antillean manatee (Trichechus manatus manatus L. 1758). CASE PRESENTATION: A nulliparous female Antillean manatee, held in captivity at the Wroclaw Zoological Garden, died in April 2015. The animal was 370 cm long from nose to tail and weighed 670 kg. The width of manatee's fluke was 80 cm. The post-mortem examination of the reproductive system showed the numerous pathological cysts on the external surface of the left and the right ovaries. Morphologically, the cysts had varying diameters and were attached to the ovaries by stalks. Some of the cysts were thin-walled and contained fluid, while several others were solid or contained a semi-solid mass. The structure of the ovaries displayed features of the polycystic ovary syndrome (PCOS). The cysts also exhibited positivity with cytokeratin and vimentin. There were no pathological changes within the uterus, uterine tube and vagina. CONCLUSION: Although we were unable to definitively determine the exact source of the ovarian cysts in the studied manatee, we found that one of the causes may be age-related. Our study also revealed that ovarian cysts in the Antillean manatee form both types of corpora lutea (CL). PMID- 28810860 TI - Tartrate-resistant acid phosphate as biomarker of bone turnover over the lifespan and different physiologic stages in sheep. AB - BACKGROUND: Currently, the best resources for assessment of bone tissue using imaging techniques are expensive and available in few medical facilities, thus serum or urinary bone turnover biomarkers could be useful as early indicators of prognosis. However, there is a wide range of variability in bone turnover markers due to several factors, such as different ages and metabolic stages, thus it is important to have as much data published on the subject as possible. The aim of this study was therefore to generate a reference range for alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) and validate the already published data. RESULTS: Serum alkaline phosphatase decreased with age, with statistical difference between the 1 month old and the other groups and between the over 8 years and the 6 months old groups. There was also a statistical difference in the ALP levels between the 3 to 5 years old gestation and lactation groups. For serum tartrate-resistant acid phosphatase, there was a statistical difference mainly between the 1 month old and the 6 months old, 6-8 years old, and above 8 years old groups. CONCLUSIONS: The results obtained could represent a useful tool for future studies using sheep as an animal model for orthopedic research. The different groups presented a wide variation of serum ALP and TRAP levels, however, these variations are entirely explained by known physiology. Therefore, this detailed study confirms the prediction that unexplained changes in these bone turnover markers do not occur during the lifespan of sheep. PMID- 28810862 TI - The cytotoxic mechanism of epigallocatechin gallate on proliferative HaCaT keratinocytes. AB - BACKGROUND: Epigallocatechin gallate (EGCG) is the major ingredient of sinecatechins ointment, approved for the treatment of external genital and perianal warts. However, the molecular mechanism for EGCG's effect on warts resulting from the human papillomavirus (HPV) infection of keratinocytes is not well understood. HPV may survive in proliferative keratinocytes and may be involved in cell cycle regulation and progression. The objective of this study was to investigate the mechanism underlying EGCG's treatment on external genital warts of HPV infection through the cultured keratinocyte cells from the HaCaT cell line. METHODS: MTT and flow cytometry assays were used to measure cell viability and the cell cycle profile, with and without EGCG treatment, for HaCaT keratinocyte cells cultured in a calcium-free medium and 1.8 mM calcium which induced proliferative and differentiated keratinocytes, respectively, for 24 h. The expression levels of cytotoxic proteins and factors were evaluated with the RT-PCR and western blotting analysis. RESULTS: EGCG influenced the proliferation stage but not the differentiation stage of keratinocytes. We suggest that apoptosis and autophagy might be the possible mechanism for the EGCG's effect on the proliferative HaCaT cells. Furthermore, we found that EGCG reduced the protein levels of cyclin D1 and Zac1 (a zinc-finger protein which regulates apoptosis and cell cycle arrest 1) dose-dependently in proliferative as compared to differentiated keratinocytes. It also induced the expression of p21 and DEC1 (differentiated embryo-chondrocyte expressed gene 1), and promoted G1 arrest of cell cycle in proliferative keratinocytes. CONCLUSIONS: These results help clarify the mechanisms of EGCG treatment of HPV-infected keratinocytes and may contribute to new targets, such as Zac1 and DEC1 for external genital and perianal warts. PMID- 28810861 TI - The implementation of long-lasting insecticidal bed nets has differential effects on the genetic structure of the African malaria vectors in the Anopheles gambiae complex in Dielmo, Senegal. AB - BACKGROUND: Mosquitoes belonging to the Anopheles gambiae complex are the main vectors of malaria in sub-Saharan Africa. Among these, An. gambiae, Anopheles coluzzii and Anopheles arabiensis are the most efficient vectors and are largely distributed in sympatric locations. However, these species present ecological and behavioural differences that impact their vectorial capacity and complicate vector-control efforts, mainly based on long-lasting insecticidal bed nets (LLINs) and indoor residual spraying (IRS). In this study, the genetic structure of these three species in a Senegalese village (Dielmo) was investigated using microsatellite data in samples collected in 2006 before implementation of LLINs, in 2008, when they were introduced, and in 2010, 2 years after the use of LLINs. RESULTS: In this study 611 individuals were included, namely 136 An. coluzzii, 101 An. gambiae, 6 An. coluzzii/An. gambiae hybrids and 368 An. arabiensis. According to the species, the effect of the implementation of LLINs in Dielmo is differentiated. Populations of the sister species An. coluzzii and An. gambiae regularly experienced bottleneck events, but without significant inbreeding. The Fst values suggested in 2006 a breakdown of assortative mating resulting in hybrids, but the introduction of LLINs was followed by a decrease in the number of hybrids. This suggests a decrease in mating success of hybrids, ecological maladaptation, or a lesser probability of mating between species due to a decrease in An. coluzzii population size. By contrast, the introduction of LLINs has favoured the sibling species An. arabiensis. In this study, some spatial and temporal structuration between An. arabiensis populations were detected, especially in 2008, and the higher genetic diversity observed could result from a diversifying selection. CONCLUSIONS: This work demonstrates the complexity of the malaria context and shows the need to study the genetic structure of Anopheles populations to evaluate the effectiveness of vector-control tools and successful management of malaria vector control. PMID- 28810863 TI - Multiple essential functions of Plasmodium falciparum actin-1 during malaria blood-stage development. AB - BACKGROUND: The phylum Apicomplexa includes intracellular parasites causing immense global disease burden, the deadliest of them being the human malaria parasite Plasmodium falciparum, which invades and replicates within erythrocytes. The cytoskeletal protein actin is well conserved within apicomplexans but divergent from mammalian actins, and was primarily reported to function during host cell invasion. However, novel invasion mechanisms have been described for several apicomplexans, and specific functions of the acto-myosin system are being reinvestigated. Of the two actin genes in P. falciparum, actin-1 (pfact1) is ubiquitously expressed in all life-cycle stages and is thought to be required for erythrocyte invasion, although its functions during parasite development are unknown, and definitive in vivo characterisation during invasion is lacking. RESULTS: Here we have used a conditional Cre-lox system to investigate the functions of PfACT1 during P. falciparum blood-stage development and host cell invasion. We demonstrate that PfACT1 is crucially required for segregation of the plastid-like organelle, the apicoplast, and for efficient daughter cell separation during the final stages of cytokinesis. Surprisingly, we observe that egress from the host cell is not an actin-dependent process. Finally, we show that parasites lacking PfACT1 are capable of microneme secretion, attachment and formation of a junction with the erythrocyte, but are incapable of host cell invasion. CONCLUSIONS: This study provides important mechanistic insights into the definitive essential functions of PfACT1 in P. falciparum, which are not only of biological interest, but owing to functional divergence from mammalian actins, could also form the basis for the development of novel therapeutics against apicomplexans. PMID- 28810864 TI - Molecular determination of antimicrobial resistance in Escherichia coli isolated from raw meat in Addis Ababa and Bishoftu, Ethiopia. AB - BACKGROUND: Consumption of meat contaminated by E. coli causes a serious illness and even death to affected individuals. Recently the emerging of antibiotic resistant foodborne E. coli poses serious public health risks worldwide. However, little is known about the antibiotic resistance profile of E. coli in Ethiopia. This study aimed to determine the prevalence and Antimicrobial resistance (AMR) status of E. coli isolated from different type of meat. METHODS: Overall 292 samples were collected from December 2015 to April 2016 from slaughterhouses to determine the prevalence and AMR of E. coli isolated from raw beef, mutton, chevon and chicken meat from Addis Ababa and Bishoftu, Ethiopia. The isolates were screened for AMR against commonly used antibiotics circulating in the Ethiopian market. Both phenotypic and genotypic approach were employed for AMR detection using disc diffusion test and PCR respectively. RESULTS: The prevalence of E. coli was 63 (21.6%), indicating one sample in every five samples harbors E. coli. Among these, the highest E. coli isolates was observed in chicken meat samples (37.0%; 27), followed by mutton (23.3%; 17), chevon (20.6%; 15) and beef (5.5%; 4). Results of disk diffusion test on the 63 isolates showed that only 4.8% of them were not resistance to all antimicrobials tested. Multiple drug resistance (resistance to >=3 drugs) was 46.0%. Significantly high resistance to ampicillin (71.4%) and tetracycline (47.6%) was observed. Identification of genes associated with AMR was also done using PCR. The prevalence of E. coli isolates harboring resistance gene responsible for tetracycline (tet(A)), beta lactams (blaCMY) and sulphanamide (sulI) antibiotics were found 65.1, 65.1 and 54.0%, respectively. Twenty-five out of the 63 (39.7% %) E. coli isolates have got antimicrobial resistance gene to three or more classes of drugs. The associations of antimicrobial resistance phenotypes and resistance genes was also determined. The detection of resistance trait against tetracycline, sulphametazole and chloramphenicol measured either phenotypically or genotypically were high. CONCLUSIONS: The rising levels of resistance E. coli to multiple antimicrobial dictate the urgent need to regulate and monitor antimicrobial use in both animals and humans. PMID- 28810865 TI - Cryptic Plasmodium ovale concurrent with mixed Plasmodium falciparum and Plasmodium malariae infection in two children from Central African Republic. AB - BACKGROUND: Since several malaria parasite species are usually present in a particular area, co-infections with more than one species of Plasmodium are more likely to occur in humans infected in these areas. In many mixed infections, parasite densities of the cryptic species may be low and often not recognized in clinical practice. CASE PRESENTATION: Two children (3 and 6 years old) adopted recently from Central African Republic were admitted to hospital because of intermittent fever. Thin blood smears stained with Giemsa showed Plasmodium falciparum and Plasmodium malariae co-infection for both children at admission. They were both treated with atovaquone-proguanil combination for 3 days. At day 7, both thin blood smears examination remained negative but at day 28, thin blood smear was positive for P. malariae trophozoites and for Plasmodium ovale for the girl and her brother, respectively. Samples collected at day 1 and day 28 were submitted to real-time PCR showing the presence of the three parasite species (P. falciparum, P malariae and P. ovale) in admission blood samples from the two children and only P. ovale at day 28. CONCLUSIONS: Twenty-eight days follow-up after treatment led to detection of a third parasite species in the blood of these two patients suggesting covert co-infection and a delayed appearance of one cryptic species following treatment. Concurrently infecting malaria species could be mutually suppressive, with P. falciparum tending to dominate other species. These observations provide more evidence that recommendations for treatment of imported malaria should take into account the risk of concurrent or cryptic infection with Plasmodium species. Clinicians and biologists should be aware of the underestimated frequency of mixed infections with cryptic species and of the importance of patient follow-up at day 28. Future guidelines should shed more light on the treatment of mixed infection and on the interest of using artemisinin-based combinations for falciparum and non-falciparum species. PMID- 28810866 TI - The development of an ivermectin-based attractive toxic sugar bait (ATSB) to target Anopheles arabiensis. AB - BACKGROUND: An increasing number of countries in sub-Saharan Africa are moving towards malaria-elimination, mostly thanks to successful vector control campaigns. However, elimination has proven challenging, resulting in the persistence of malaria transmission. It is now accepted that in order to eliminate malaria, new complementary vector control approaches must be developed. This study describes the development of a sugar-baited resting place containing a toxic dose of ivermectin for the control of Anopheles arabiensis. RESULTS: Dose response experiments were performed in insectary conditions to determine the LD90 of ivermectin against An. arabiensis. Over 95% of An. arabiensis were knocked down 48 h post-sugar feeding on 10% sucrose solutions containing 0.01% ivermectin. When investigating different juices as attractants, it was observed that An. arabiensis preferred orange, watermelon and commercial guava juice over pawpaw, tomato, mango or banana, but were most likely to feed on simple 10% sugar solution. Using recycled materials, different bait prototypes were tested to determine the best design to maximize sugar feeding. Baits that offered a resting place for the mosquito rather than just a surface to sugar feed were more likely to attract An. arabiensis to sugar feed. The optimized prototype was then placed in different locations within a screen-house, colour-coded with different food dyes, containing competing vegetation (Ricinus communis) and experimental huts where humans slept under bed nets. Around half of all the released An. arabiensis sugar fed on the sugar baits, and approximately 50% of all sugar fed mosquitoes chose the baits close to outdoor vegetation before entering the huts. CONCLUSIONS: Ivermectin is an effective insecticide for use in sugar baits. The design of the sugar bait can influence feeding rates and, therefore, efficacy. Sugar baits that offer a resting surface are more efficient and sugar feeding on the baits is maximized when these are placed close to peri-domestic vegetation. Attractive toxic sugar baited resting places may provide an additional vector control method to complement with existing strategies. PMID- 28810867 TI - New inducible promoter for gene expression and synthetic biology in Yarrowia lipolytica. AB - BACKGROUND: The oleaginous yeast Yarrowia lipolytica is increasingly used as alternative cell factory for the production of recombinant proteins. At present, several promoters with different strengths have been developed based either on the constitutive pTEF promoter or on oleic acid inducible promoters such as pPOX2 and pLIP2. Although these promoters are highly efficient, there is still a lack of versatile inducible promoters for gene expression in Y. lipolytica. RESULTS: We have isolated and characterized the promoter of the EYK1 gene coding for an erythrulose kinase. pEYK1 induction was found to be impaired in media supplemented with glucose and glycerol, while the presence of erythritol and erythrulose strongly increased the promoter induction level. Promoter characterization and mutagenesis allowed the identification of the upstream activating sequence UAS1EYK1. New hybrid promoters containing tandem repeats of either UAS1XPR2 or UAS1EYK1 were developed showing higher expression levels than the native pEYK1 promoter. Furthermore, promoter strength was improved in a strain carrying a deletion in the EYK1 gene, allowing thus the utilization of erythritol and erythrulose as free inducer. CONCLUSIONS: Novel tunable and regulated promoters with applications in the field of heterologous protein production, metabolic engineering, and synthetic biology have been developed, thus filling the gap of the absence of versatile inducible promoter in the yeast Y. lipolytica. PMID- 28810868 TI - Nontuberculosis mycobacteria are the major causes of tuberculosis like lesions in cattle slaughtered at Bahir Dar Abattoir, northwestern Ethiopia. AB - BACKGROUND: The main cause of bovine tuberculosis (bTB) is believed to be Mycobacterium bovis (M. bovis). Nontuberculosis mycobacteria (NTM) are neglected but opportunistic pathogens and obstacles for bTB diagnosis. This study aimed to isolate and characterize the mycobacteria organisms involved in causing TB-like lesions in cattle in northwestern Ethiopia. RESULTS: A total of 2846 carcasses of cattle were inspected for TB lesions. Ninety six tissues (including lymph nodes such as submandibular, retropharyngeal, tonsilar, mediatinal, bronchial and mesenteric, and organs such as lung, liver and kidney) with suspicious TB lesion(s) were collected and cultured on Lowenstein-Jensen medium. Twenty one showed culture growth, of which only 17 were identified containing acid fast bacilli (AFB) by Ziehl-Neelsen staining. Among the 17 AFB isolates 15 generated a polymerase chain reaction product of 1030 bp by gel electrophoresis based on the 16S ribosomal RNA gene amplification. No M. tuberculosis complex species were isolated. Further characterization by Genotype Mycobacterium CM assay showed 6 isolates identified as M. peregrinum. Eight isolates represented by mixed species, which includes M. fortuitum-peregrinum (3 isolates), M. gordonae peregrinum (3 isolates) and M. fortuitum-gordonae-peregrinum (2 isolates). One NTM could not be interpreted. CONCLUSION: A significant number of NTM species were isolated from TB-like lesions of grazing cattle slaughtered at Bahir Dar Abattoir. Such finding could suggest the role of NTM in causing lesions in cattle. Further investigations are recommended on the pathogenesis of the reported NTM species in cattle, and if they have public health significance. PMID- 28810869 TI - "Evolution and financial cost of socioeconomic inequalities in ambulatory care sensitive conditions: an ecological study for Portugal, 2000-2014". AB - BACKGROUND: Hospitalizations for Ambulatory Care Sensitive Conditions (ACSC) are specific conditions for which hospitalization is thought to be avoidable through patient education, health promotion initiatives, early diagnosis and by appropriate chronic disease management, and have been shown to be greatly influenced by socioeconomic (SE) characteristics. We examined the SE inequalities in hospitalization rates for ACSC in Portugal, their evolution over time (2000 2014), and their associated financial burden. METHODS: We modeled municipality level ACSC hospitalization rates per 1000 inhabitants and ACSC hospitalization related costs per inhabitant, for the 2000-2014 period (n = 4170), as a function of SE indicators (illiteracy and purchasing power, in quintiles), controlling for the proportion of elderly, sex, disease specific mortality rate, population density, PC supply, and time trend. The evolution of inequalities was measured interacting SE indicators with a time trend. Costs attributable to ACSC related hospitalization inequalities were measured by the predicted values for each quintile of the SE indicators. RESULTS: Hospitalization rate for ACSC was significantly higher in the 4th quintile of illiteracy compared with the 1st quintile (beta = 1.97; p < 0.01), and significantly lower in the 5th quintile of purchasing power, compared with the 1st quintile (beta = - 1.19; p < 0.05). ACSC hospitalization-related costs were also significantly higher in the 4th quintile of illiteracy compared with the 1st quintile (beta = 4.04?; p < 0.05), and significantly lower in the 5th quintile of purchasing power, compared with the 1st quintile (beta = - 4,69?; p < 0.01). The SE gradient significantly increased over the 2000-2014 period, and the annual cost of inequalities were estimated at more than 15 million euros for the Portuguese NHS. CONCLUSION: There was an increasing SE patterning in ACSC related hospitalizations, possibly reflecting increasing SE inequalities in early and preventive high-quality care, imposing a substantial financial burden to the Portuguese NHS. PMID- 28810871 TI - Effect of different inner core diameters on structural strength of cannulated pedicle screws under various lumbar spine movements. AB - BACKGROUND: Currently, cannulated pedicle screws have been widely used in minimal invasive or navigation techniques. However, the stress distribution and the strength of different core diameters of cannulated screw are not clear. This study aimed to investigate the mechanical strength of cannulated screws with different inner core diameter under various lumbar spine movements using finite element analysis. RESULTS: The results showed that the von-Mises stress of a cannulated screw was larger than that of a solid screw in all loading conditions, especially above 2 mm in cannulated core diameter. In lateral bending, extension, and flexion, the maximum von-Mises stress was found approximate to the proximal thread for all types of screws. In rotation condition, the maximum von-Mises stress was located at the middle of the screw. Additionally, the difference in stiffness of instrumented levels was not significant among four screws under the same loading condition. CONCLUSION: Cannulated screws could provide enough stability for the vertebral body fusion comparing to solid screws. The diameter of cannulated core is suggested not to exceed 2.0 mm. PMID- 28810870 TI - Vector-borne and zoonotic diseases of dogs in North-west New South Wales and the Northern Territory, Australia. AB - BACKGROUND: Vector-borne diseases of dogs in Australian Aboriginal communities are relatively unexplored. These dogs represent a unique group with variable ecto and endo-parasitic burdens, nutritional stresses and a general lack of veterinary intervention. We investigated haemoprotozoal and bacterial pathogen prevalences in relation to erythrocyte and platelet numbers in dogs from North West New South Wales (N-W NSW) and the Northern Territory (NT; Central Australia). METHODS: Real-time PCR (qPCR) amplification of Anaplasma platys, Babesia vogeli, Mycoplasma haemocanis, Candidatus Mycoplasma haematoparvum and Bartonella spp., serological screening for Coxiella burnetii, and Bartonella spp. and haematological analyses were performed on dogs from the two cohorts (96 dogs in total). Brucella suis serology was determined additionally for the N-W NSW cohort. RESULTS: Anaplasma platys (n = 26 dogs), Babesia vogeli (n = 7), Candidatus Mycoplasma haematoparvum (n = 10 dogs), and Mycoplasma haemocanis (n = 14) were detected in the sample population (n = 96) using qPCR. There were significant associations between (i) A. platys and anaemia (OR 8.7, CI 2.4-31.7; P < 0.001), thrombocytopenia (OR 12.1, CI 3.4-43.2; P < 0.001) and breed (OR 16.1, CI 2.1-121.5; P = 0.007), and (ii) between B. vogeli and anaemia (OR 11.8, CI 2.3-61.6; P = 0.003). Neither protozoal nor bacterial DNA loads, estimated using qPCR, were positively correlated with anaemia or thrombocytopenia. Haemotropic mycoplasmas were not associated with any haematologic abnormality. Four dogs from the NT were seropositive for Coxiella burnetii, while no dogs were seropositive for Brucella suis or to a panel of Bartonella spp. antigens. Despite directed efforts, Bartonella DNA was not detected in blood from any of the cohorts studied. A sample of dogs from the NT recruited specifically for Bartonella alpha-proteobacteria growth medium enrichment blood culture were also Bartonella PCR negative. CONCLUSIONS: Vector-borne pathogens occur in dogs free ranging near Aboriginal communities, with higher detection rates in NT than N-W NSW. The preponderant haematologic abnormalities were anaemia and thrombocytopenia, likely attributable to A. platys and B. vogeli infections, but also probably affected by nutritional, parasitic, lactational and environmental stressors. The absence of Bartonella spp. is of importance to the Australian setting, and work needs to be extended to tropical coastal communities where fleas are present as well as ticks. Dogs living in and around Aboriginal communities may provide valuable sentinel information on disease infection status of human public health significance. PMID- 28810872 TI - 'Repel all biters': an enhanced collection of endophilic Anopheles gambiae and Anopheles arabiensis in CDC light-traps, from the Kagera Region of Tanzania, in the presence of a combination mosquito net impregnated with piperonyl butoxide and permethrin. AB - BACKGROUND: Mosquito nets containing synergists designed to overcome metabolic resistance mechanisms in vectors have been developed. These may enhance excitability in the mosquitoes and affect how they respond to CDC light-traps. Investigating the behaviour of vectors of disease in relation to novel mosquito nets is, therefore, essential for the design of sampling and surveillance systems. METHODS: In an initial experiment in Muleba, Tanzania, nine bedrooms from three housing clusters were sampled. CDC light-traps were operated indoors next to occupied untreated nets (UTN), Olyset(r) long lasting insecticidal net (LLIN) and Olyset Plus(r) LLIN containing piperonyl butoxide (PBO) synergist. Nets were rotated daily between the nine rooms over nine nights. A further series of experiments using the nets on alternate nights in a single room was undertaken during the short rains. Anopheles gambiae s.l. were collected in CDC light-traps, a window-trap and Furvela tent-trap. Anopheles gambiae s.l. were identified to species by polymerase chain reaction (PCR). RESULTS: In the initial experiment 97.7% of the 310 An. gambiae s.l. were An. gambiae s.s., the remainder being Anopheles arabiensis. The number of mosquitoes collected from 81 light-trap collections was greater in the presence of an Olyset [density rate ratio 1.81, 95% CI (1.22-2.67), p = 0.003] relative to an UTN. In a second experiment, in the wet season 84% of the 180 An. gambiae s.l. identified were An. arabiensis. The number of An. gambiae s.l. collected from a light-trap compared to a tent-trap was significantly higher when an Olyset Plus net was used compared to an UTN. Survival of the mosquitoes in the window trap was not reduced by the use of an Olyset Plus net in the bedroom relative to an Olyset net. CONCLUSION: Mosquitoes entering bedrooms, even those susceptible to pyrethroids, were not killed by contact with an Olyset Plus LLIN. The enhanced numbers of An. gambiae or An. arabiensis collected in light-traps when a treated net is used requires further experimentation and may be because of a heightened escape reaction on the part of the mosquito. PMID- 28810873 TI - Six-month adherence to Statin use and subsequent risk of major adverse cardiovascular events (MACE) in patients discharged with acute coronary syndromes. AB - BACKGROUND: The evidence of adherence to statin decreasing risk of major adverse cardiovascular events (MACEs) is still lack among patients discharged with acute coronary syndrome (ACS). Our objective is to determine the relationship between six-month adherence to statins and subsequent risk of MACEs in patients discharged with ACS. METHODS: Using two prospective registry cohorts (CPACS-1 and -2), we analyzed data from 12,516 consecutive patients with ACS who were prescribed statin at hospital discharge and survived beyond 6 months without recurrent myocardial infarction (MI) or stroke. Adherence to statin was defined as good (using statin at discharge and 6 months without declined dosage) and poor adherence groups (using statin at discharge but declining dosage or stopping at 6 months). We compared the hazard ratios of all-cause mortality and MACE in subsequent 6 months between groups, using Cox-regression models, adjusting for multiple potential confounders. RESULTS: Seventy two percent of patients adhered to statin therapy at 6 months. The incident MACE in the poor adherence group was significantly higher than in good adherence group (2.7% vs. 1.8%, p = 0.002). Compared with poor adherence group, the good adherence group showed a 27% lower relative risk of MACE during the 6 month follow up (fully-adjusted hazard ratio (HR) = 0.73; 95%CI: 0.56-0.97). The protective effects of good adherence were similar in groups with different statin dose as well as groups by other baseline clinical characteristics and treatments (p > 0.05 for interaction). CONCLUSION: Our study highlights the importance of adherence to statin therapy in prevention of MACE and clinicians should aim to achieve higher dosage if tolerable. CLINICAL TRIAL REGISTRATION: CPACS2 was registered on URL: http://www.anzctr.org.au/default.aspx and unique identifier is ACTRN12609000491268 . CPACS1 was not a clinical trial and thus not registered. PMID- 28810875 TI - Role of IQGAP3 in metastasis and epithelial-mesenchymal transition in human hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide owing to its high rates of metastasis and recurrence. The oncogene IQ motif-containing GTPase activating protein 3 (IQGAP3) is ubiquitously overexpressed in several human cancers, including liver, ovary, lung, large intestine, gastric, bone marrow, and breast malignancies and is involved in the invasion and metastasis of cancer cells. Therefore, we aimed to determine the biological role and molecular mechanism of IQGAP3 in HCC. METHODS: We used 120 archived clinical HCC samples, 9 snap-frozen HCC tumor tissues, and 4 normal liver tissues. Expression of IQGAP3 mRNA and protein in HCC cell lines (Hep3B, SMMC-7721, HCCC-9810, HepG2, BEL-7404, HCCLM3, QGY-7701, Huh7, and MHCC97H) and normal liver epithelial cells LO2 was examined by western blot, quantitative polymerase chain reaction, and immunohistochemistry. In addition, wound-healing and transwell matrix penetration assays were used to assess the migratory and invasive abilities of HCC cells, respectively. RESULTS: Expression of the IQGAP3 was robustly upregulated in HCC cells and tissues. High expression of IQGAP3 in HCC correlated with aggressive clinicopathological features and was an independent poor prognostic factor for overall survival. Furthermore, ectopic expression of IQGAP3 markedly enhanced HCC cell migration, invasion, and epithelial-to-mesenchymal transition (EMT) in vitro and promoted metastasis of orthotopic hepatic tumors in nude mice. Conversely, silencing endogenous IQGAP3 showed an opposite effect. Mechanistically, IQGAP3 promoted EMT and metastasis by activating TGF-beta signaling. CONCLUSIONS: IQGAP3 functions as an important regulator of metastasis and EMT by constitutively activating the TGF-beta signaling pathway in HCC. Our findings present new evidence of the role of IQGAP3 in EMT and metastasis, indicating its potential as a prognostic biomarker candidate and a therapeutic target against HCC. PMID- 28810874 TI - Sudden cardiac death: focus on the genetics of channelopathies and cardiomyopathies. AB - Sudden cardiac death (SCD) describes a natural and unexpected death from cardiac causes occurring within a short period of time (generally within 1 h of symptom onset) in the absence of any other potentially lethal condition. Most SCD-related diseases have a genetic basis; in particular congenital cardiac channelopathies and cardiomyopathies have been described as leading causes of SCD. Congenital cardiac channelopathies are primary electric disorders caused by mutations affecting genes encoding cardiac ion channels or associated proteins, whereas cardiomyopathies are related to mutations in genes encoding several categories of proteins, including those of sarcomeres, desmosomes, the cytoskeleton, and the nuclear envelope. The purpose of this review is to provide a general overview of the main genetic variants that have been linked to the major congenital cardiac channelopathies and cardiomyopathies. Functional alterations of the related proteins are also described. PMID- 28810876 TI - Prenatal caloric restriction alters lipid metabolism but not hepatic Fasn gene expression and methylation profiles in rats. AB - BACKGROUND: Undernutrition is an increasingly common problem. Insufficient calorie intake and nutrient deficiencies during pregnancy may have an impact not only on the mother, but may also alter metabolism in the infant. In this study, we have applied a calorie-restricted diet during gestation and examined its effect on hepatic Fasn mRNA and DNA methylation profiles in rats and their female progeny. The body composition and blood lipid profiles were also evaluated in both generations. RESULTS: The results showed that the investigated diet regimen exerted a greater effect on the dams than on the offspring. We found that, in the calorie-restricted group, the transcript level of the Fasn gene in the liver increased in the mothers, while in the progeny it was only slightly enhanced. The implemented diet altered lipid profile in the dams by decreasing total cholesterol, HDL, and TG levels. An increase in LDL was noted in the offspring. No change in DNA methylation profile was observed in response to the calorie restricted diet. CONCLUSIONS: Calorie restriction during pregnancy modified the hepatic Fasn mRNA transcript level and altered the blood cholesterol concentrations in dams, but there were no such effects in their four-week-old offspring. The examined dietary regimen had no effect on DNA methylation of the Fasn 5'-flanking region in the rat liver. PMID- 28810877 TI - Neutrophils in cancer: prognostic role and therapeutic strategies. AB - Expression of high levels of immune cells including neutrophils has been associated with detrimental outcome in several solid tumors and new strategies to decrease their presence and activity are currently under clinical development. Here, we review some of the relevant literature of the role of neutrophils in different stages of the oncogenic process including tumor initiation, growth, proliferation or metastatic spreading and also focus on how neutrophil counts or the neutrophil-to-lymphocyte ratio may be used as a prognostic and predictive biomarker. Strategies to avoid the deleterious effects of neutrophils in cancer and to reduce their activity are discussed. Examples for such strategies include inhibition of CXCR1 and CXCR2 to decrease migration of neutrophils to tumoral areas or the inhibition of granulocyte colony stimulating factor to decrease the amount of neutrophils which has shown efficacy in preclinical models. PMID- 28810878 TI - Classification of chronic radiation-induced ulcers in the chest wall after surgery in breast cancers. AB - BACKGROUND AND PURPOSE: To explore the methods of clinical classification in chronic radiation-induced ulcers in the chest wall (CRUCWs). MATERIALS AND METHODS: A total of 64 patients with CRUCWs were treated. We divided the cases into 3 types (mild, moderate, or severe) according to their clinical manifestations. Conservative treatments, axial-pattern myocutaneous or local flaps, or filleted flaps were applied correspondingly. RESULTS: The cases were divided as follows: mild (n = 11), moderate (n = 45), and severe (n = 8). Eight cases were cured by conservative surgical therapy. One case had a recurrence 6 months after conservative therapy and was cured by a latissimus dorsi myocutaneous flap. The transferred flaps all survived, including 26 transverse rectus abdominis myocutaneous flaps, 8 longitudinal rectus abdominis myocutaneous flaps, 6 latissimus dorsi myocutaneous flaps, 3 contralateral breast flaps, 5 lateral thoracic rotation flaps, and 7 filleted flaps. In 2 transverse rectus abdominis myocutaneous flaps and 2 latissimus dorsi myocutaneous flaps, distal necrosis appeared in small areas. The resulting wounds were salvaged with skin graft and full healing was achieved. CONCLUSION: CRUCWs can be divided into three types. Surgical methods should vary with distinguished classifications. The effective classification of CRUCWs has definite instructive significance on the selection of surgical approaches. PMID- 28810879 TI - Quantification of mutant SPOP proteins in prostate cancer using mass spectrometry based targeted proteomics. AB - BACKGROUND: Speckle-type POZ protein (SPOP) is an E3 ubiquitin ligase adaptor protein that functions as a potential tumor suppressor, and SPOP mutations have been identified in ~10% of human prostate cancers. However, it remains unclear if mutant SPOP proteins can be utilized as biomarkers for early detection, diagnosis, prognosis or targeted therapy of prostate cancer. Moreover, the SPOP mutation sites are distributed in a relatively short region with multiple lysine residues, posing significant challenges for bottom-up proteomics analysis of the SPOP mutations. METHODS: To address this issue, PRISM (high-pressure, high resolution separations coupled with intelligent selection and multiplexing)-SRM (selected reaction monitoring) mass spectrometry assays have been developed for quantifying wild-type SPOP protein and 11 prostate cancer-derived SPOP mutations. RESULTS: Despite inherent limitations due to amino acid sequence constraints, all the PRISM-SRM assays developed using Arg-C digestion showed a linear dynamic range of at least two orders of magnitude, with limits of quantification ranged from 0.1 to 1 fmol/MUg of total protein in the cell lysate. Applying these SRM assays to analyze HEK293T cells with and without expression of the three most frequent SPOP mutations in prostate cancer (Y87N, F102C or F133V) led to confident detection of all three SPOP mutations in corresponding positive cell lines but not in the negative cell lines. Expression of the F133V mutation and wild-type SPOP was at much lower levels compared to that of F102C and Y87N mutations; however, at present, it is unknown if this also affects the biological activity of the SPOP protein. CONCLUSIONS: In summary, PRISM-SRM enables multiplexed, isoform-specific detection of mutant SPOP proteins in cell lysates, providing significant potential in biomarker development for prostate cancer. PMID- 28810880 TI - NLRP7 contributes to in vitro decidualization of endometrial stromal cells. AB - BACKGROUND: Nucleotide-binding oligomerization domain (NACHT), leucine rich repeat (LRR) and pyrin domain (PYD) 7 containing protein, NLRP7, is a member of the NLR family which serves as innate immune sensors. Mutations and genetic variants of NLRP7 have been found in women with infertility associated conditions, such as recurrent hydatidiform mole, recurrent miscarriage, and preeclampsia. Decidualization of endometrial stromal cells is a hallmark of tissue remodeling to support embryo implantation and proper placental development. Given defective decidualization has been implicated in miscarriage as well as preeclampsia, we aimed to explore the link between the NLRP7 gene and decidualization. METHODS: Endometrial samples obtained from pregnant women in the first trimester and non-pregnant women were used to study NLRP7 expression pattern. The human telomerase reverse transcriptase (hTERT)-immortalized human endometrial stromal cells (T-HESCs) were used to study the effect of NLRP7 on decidualization. Decidualization of T-HESCs was induced with 1 MUM medroxyprogesterone acetate (MPA) and 0.5 mM 8-bromoadenosine 3':5'-cyclic monophosphate (8-Br-cAMP). siRNA was used to knock down NLRP7 while lentiviral vectors were used to overexpress NLRP7 in cells. NLRP7 expression was detected by immunofluorescence, qRT-PCR, and Western blotting. Decidualization markers, Insulin-like growth factor-binding protein 1 (IGFBP-1) and prolactin (PRL), were detected by qRT-PCR and ELISA. Nuclear translocation of NLRP7 was detected by the subcellular fractionation and confocal microscopy. The effect of NLRP7 on progesterone receptor (PR) activity was evaluated by a reporter system. RESULTS: NLRP7 was up-regulated in the decidual stromal cells of human first-trimester endometrium. After in vitro decidualization, T-HESCs presented with the swollen phenotype and increased expressions of IGFBP-1 and PRL. Knockdown or over expression of NLRP7 reduced or enhanced the decidualization, respectively, according to the expression level of IGFBP-1. NLRP7 was found to translocate in the nucleus of decidualized T-HESCs and able to promote PR activity. CONCLUSIONS: NLRP7 was upregulated and translocated to the nucleus of the endometrial stromal cells in an in vitro decidualization model. Overexpressed NLRP7 promoted the IGFBP-1 expression and PR reporter activation. IGFBP-1 expression decreased with the knockdown of NLRP7. Therefore, we suggest that NLRP7 contributes to in vitro decidualization of endometrial stromal cells. PMID- 28810882 TI - Bioinformatics analysis of glial inflammatory responses to air pollution. PMID- 28810881 TI - Comparison of photon volumetric modulated arc therapy, intensity-modulated proton therapy, and intensity-modulated carbon ion therapy for delivery of hypo fractionated thoracic radiotherapy. AB - PURPOSE: The aim of the present study was to compare the dose distribution generated from photon volumetric modulated arc therapy (VMAT), intensity modulated proton therapy (IMPT), and intensity modulated carbon ion therapy (IMCIT) in the delivery of hypo-fractionated thoracic radiotherapy. METHODS AND MATERIALS: Ten selected patients who underwent thoracic particle therapy between 2015 and 2016 were re-planned to receive a relative biological effectiveness (RBE) weighted dose of 60 Gy (i.e., GyE) in 15 fractions delivered with VMAT, IMPT, or IMCIT with the same optimization criteria. Treatment plans were then compared. RESULTS: There were no significant differences in target volume dose coverage or dose conformity, except improved D95 was found with IMCIT compared with VMAT (p = 0.01), and IMCIT was significantly better than IMPT in all target volume dose parameters. Particle therapy led to more prominent lung sparing at low doses, and this result was most prominent with IMCIT (p < 0.05). Improved sparing of other thoracic organs at risk (OARs) was observed with particle therapy, and IMCIT further lowered the D1cc and D5cc for major blood vessels, as compared with IMPT (p = 0.01). CONCLUSION: Although it was comparable to VMAT, IMCIT led to significantly better tumor target dose coverage and conformity than did IMPT. Particle therapy, compared with VMAT, improved thoracic OAR sparing. IMCIT, compared with IMPT, may further improve normal lung and major blood vessel sparing under limited respiratory motion. PMID- 28810883 TI - Treatment of localized gastric and gastroesophageal adenocarcinoma: the role of accurate staging and preoperative therapy. AB - Gastric cancer is the third most common cause of cancer death worldwide, although it is not in the top 10 causes of cancer death in Northern America. Due to clear differences in incidence, screening, risk factors, tumor biology, and treatment between gastric cancers from Eastern and Western countries, our treatment is primarily guided by trials from Western countries. Patients undergo an extensive staging evaluation including high-quality CT imaging, endoscopic ultrasound, and diagnostic laparoscopy with peritoneal washings for cytology. Patients are presented in multidisciplinary conference with input from medical, radiation, and surgical oncology, in addition to further evaluation of existing studies and biopsy results by diagnostic radiology and pathology colleagues. Due to the well documented difficulty in tolerating postoperative therapy, patients are frequently treated with preoperative chemotherapy and chemoradiotherapy. Extended lymph node (D2) dissection is routinely performed during subtotal or total gastrectomy. Ongoing trials in Western populations comparing preoperative chemotherapy to chemoradiotherapy will help inform the decision regarding the optimal treatment for patients with resectable gastric cancer. Additional studies are needed to identify predictors of treatment response to identify the optimal preoperative or perioperative approach. As peritoneal disease is the most common site of recurrence, studies are also urgently needed for more accurate methods of detecting peritoneal disease at diagnosis, and also investigating potential treatment modalities such as hyperthermic intraperitoneal chemotherapy. PMID- 28810884 TI - A novel method for transmitting southern rice black-streaked dwarf virus to rice without insect vector. AB - BACKGROUND: Southern rice black-streaked dwarf virus (SRBSDV) has spread from the south of China to the north of Vietnam in the past few years, and has severely influenced rice production. However, previous study of traditional SRBSDV transmission method by the natural virus vector, the white-backed planthopper (WBPH, Sogatella furcifera), in the laboratory, researchers are frequently confronted with lack of enough viral samples due to the limited life span of infected vectors and rice plants and low virus acquisition and inoculation efficiency by the vector. Meanwhile, traditional mechanical inoculation of virus only apply to dicotyledon because of the higher content of lignin in the leaves of the monocot. Therefore, establishing an efficient and persistent-transmitting model, with a shorter virus transmission time and a higher virus transmission efficiency, for screening novel anti-SRBSDV drugs is an urgent need. METHODS: In this study, we firstly reported a novel method for transmitting SRBSDV in rice using the bud-cutting method. The transmission efficiency of SRBSDV in rice was investigated via the polymerase chain reaction (PCR) method and the replication of SRBSDV in rice was also investigated via the proteomics analysis. RESULTS: Rice infected with SRBSDV using the bud-cutting method exhibited similar symptoms to those infected by the WBPH, and the transmission efficiency (>80.00%), which was determined using the PCR method, and the virus transmission time (30 min) were superior to those achieved that transmitted by the WBPH. Proteomics analysis confirmed that SRBSDV P1, P2, P3, P4, P5-1, P5-2, P6, P8, P9-1, P9-2, and P10 proteins were present in infected rice seedlings infected via the bud-cutting method. CONCLUSION: The results showed that SRBSDV could be successfully transmitted via the bud-cutting method and plants infected SRBSDV exhibited the symptoms were similar to those transmitted by the WBPH. Therefore, the use of the bud-cutting method to generate a cheap, efficient, reliable supply of SRBSDV infected rice seedlings should aid the development of disease control strategies. Meanwhile, this method also could provide a new idea for the other virus transmission in monocot. PMID- 28810885 TI - Intensity-modulated versus 3-dimensional conformal radiotherapy in the definitive treatment of esophageal cancer: comparison of outcomes and acute toxicity. AB - BACKGROUND: Though the vast majority of seminal trials for locally advanced esophageal cancer (EC) utilized three-dimensional conformal radiotherapy (3DCRT), the advanced and highly conformal technology known as intensity-modulated radiotherapy (IMRT) can decrease doses to critical cardiopulmonary organs. To date, there have been no studies comparing both modalities as part of definitive chemoradiation (dCRT) for EC. Herein, we investigated local control and survival and evaluated clinical factors associated with these endpoints between cohorts. METHODS: We retrospectively analyzed 93 patients (3DCRT n = 49, IMRT n = 44) who received dCRT at our institution between 2000 and 2012 with the histologic diagnosis of nonmetastatic EC, a Karnofsky performance status of >=70, curative treatment intent, and receipt of concomitant CRT. Patients were excluded if receiving <50 Gy. Kaplan-Meier analysis was used to evaluate the endpoints of local relapse rate (LR), progression-free survival (PFS), and overall survival (OS). Cox proportional hazards modeling addressed factors associated with outcomes with univariate and multivariate approaches. Rates of acute toxicities and basic dosimetric parameters were compared between 3DCRT and IMRT patients. RESULTS: Mean follow-up was 34.7 months. The 3-year LR was 28.6% in the 3DCRT group and 22.7% in the IMRT group (p = 0.620). Median PFS were 13.8 and 16.6 months, respectively (p = 0.448). Median OS were 18.4 and 42.0 months, respectively (p = 0.198). On univariate analysis, only cumulative radiation dose was associated with superior LR (hazard ratio (HR) 0.736; 95% confidence interval (CI) 0.635 - 0.916, p = 0.004). Factors clearly affecting survival were not observed. CONCLUSIONS: When comparing 3DCRT- versus IMRT-based dCRT, no survival benefits were observed. However, we found a lower local recurrence rate in the IMRT group potentially owing to dose-escalation. Prospective data are needed to verify the presented results herein. PMID- 28810886 TI - Factors affecting survival after concurrent chemoradiation therapy for advanced hepatocellular carcinoma: a retrospective study. AB - BACKGROUND: Concurrent chemoradiation therapy (CCRT) followed by hepatic arterial infusional chemotherapy (HAIC) was reported to be effective for advanced hepatocellular carcinoma (HCC) with portal vein thrombosis. However, transarterial chemoembolization (TACE) is not preferred in this setting. The aim of this study was to assess the factors affecting survival after CCRT, including additional TACE during repeated HAIC. METHODS: Thirty-eight patients who underwent CCRT as the initial treatment for Barcelona Clinic Liver Cancer stage C HCC with vascular invasion between 2009 and 2016 were reviewed retrospectively. During CCRT, 5-fluorouracil (5-FU) was infused via chemoport during the first and last five days of five weeks of external beam radiation therapy. After CCRT, repeated HAIC with cisplatin and 5-FU was performed monthly. Nineteen patients (50%) underwent additional TACE between repeated HAICs. Factors related to overall survival and progression free survival (PFS) were analyzed. RESULTS: The mean age of patients was 55 years (male:female, 33:5). Underlying liver diseases were hepatitis B, hepatitis C and non-B/C in 29, 1 and 8 patients, respectively. The median radiation dose was 4500 cGy. The objective response (OR) rate at one months after CCRT was 36.8%. The median PFS was 7.4 (range, 1.8 - 32.1) months. The median overall survival was 11.6 (range 2.8-65.7) months. Achieving an OR after CCRT (hazard ratio [HR], 0.028; P < 0.001), additional TACE (HR, 0.134, P < 0.001), and further rounds of HAIC (HR, 0.742, P = 0.001) were independent significant factors related to overall survival. The overall survival duration of patients with an OR after CCRT (median 44.2 vs. 6.6 months, P < 0.001) and additional TACE (median 19.8 vs. 9.1 months, P = 0.001) were significantly greater than those without an OR after CCRT or additional TACE. CONCLUSION: Patients who achieved an OR after CCRT, underwent additional TACE, and were subjected to repeated rounds of HAIC following CCRT showed better survival after CCRT for advanced stage of HCC with vascular invasion. A further prospective study is needed to confirm the positive effect of additional TACE after CCRT. PMID- 28810887 TI - Dietary diversity and meal frequency among infant and young children: a community based study. AB - BACKGROUND: Insufficient quantities, frequencies, and inadequate quality of complementary feedings have a negative effect on child health and growth, especially in the first two years of life. Therefore, the aim of this study was to assess the minimum dietary diversity, meal frequency and its associated factors among infants and young children aged 6-23 months at Dabat District, northwest, Ethiopia. METHODS: A community- based cross-sectional study was conducted from February 15 to March 10, 2016. The simple random sampling method was used to select study participants. An interviewer- administered structured questionnaire was used to collect data. Both Crude and Adjusted Odds Ratio with the corresponding 95% confidence interval were calculated to show the strength of association. In the multivariable analysis, variables with less than 0.05 P-value were considered statistically significant. RESULTS: The proportion of children who met the minimum dietary diversity and meal frequency were 17% (95% CI: 14.9, 19.4%) and 72.2% (95% CL: 69.3, 75%), respectively. Satisfactory media exposure (AOR = 2.79; 95% CI: 1.74, 4.47), postnatal care visits (AOR = 1.96; 95% CI: 1.32, 2.88), participation in child growth and monitoring follow ups (AOR = 1.65; 95% CI: 1.14, 2.39), age of children (AOR = 2.34; 95% CI: 1.33, 4.11) and age of mothers (AOR = 1.89; 95% CI: 1.09, 3.27) were positively associated with dietary diversity. Similarly, age of children (AOR = 2.38; 95% CI: 1.56, 3.65), household wealth status (AOR = 1.84; 95% CI: 1.27, 2.68), residence (AOR = 3.02; 95% CI: 1.41, 6.48), sources of information (AOR = 1.72; 95% CI:1.14, 2.59) and participation in child growth monitoring folow ups (AOR = 1.57; 95% CI: 1.13, 2.19) were significantly associated with meal frequency. CONCLUSION: In this study, the proportion of children who received the minimum dietary diversity and meal frequency were low. Media exposure, age of children, postnatal care visits, and participation in child growth and monitoring follow-ups were significantly associated with dietary diversity. Likewise, wealth status and residence had a significant association with meal frequency. Thus, encouraging all mothers to participate in child monthly growth monitoring programs, intensive media advertising and strengthening counseling of mothers, and postnatal care visit are highly recommended for achieving the recommended dietary practices. PMID- 28810888 TI - Hospitalisation in an emergency department short-stay unit compared to an internal medicine department is associated with fewer complications in older patients - an observational study. AB - BACKGROUND: Older patients are at particular risk of experiencing adverse events during hospitalisation. OBJECTIVE: To compare the frequencies and types of adverse events during hospitalisation in older persons acutely admitted to either an Emergency Department Short-stay Unit (SSU) or an Internal Medicine Department (IMD). METHODS: Observational study evaluating adverse events during hospitalisation in non-emergent, age-matched, internal medicine patients >=75 years, acutely admitted to either the SSU or the IMD at Holbaek Hospital, Denmark, from January to August, 2014. Medical records were reviewed by independent assessors to detect adverse events according to predefined criteria. The primary outcome was the proportion of patients with an adverse event during and within 30 days after hospitalisation. Secondary outcomes included 90-day mortality, subtypes of adverse events, and timing of adverse events. Adjusted analyses were conducted to correct for potential confounders. RESULTS: Four hundred-fifty patients, 225 patients in each group, were included. Adverse events were found in 67 (30%) patients in the SSU-group and 90 (40%) patients in the IMD group (Odds Ratio (OR) 0.64 (95% Confidence Interval (95% CI) 0.43-0.94, p = 0.02). The result was unchanged in an analysis adjusted for age, Charlson Comorbidity score, and sex. We found no significant difference in 90-day mortality (OR 0.75, 95% CI 0.41-1.38, p = 0.36). The most common adverse events were transfer during hospitalisation, unplanned readmission, and nosocomial infection. CONCLUSIONS: Adverse events of hospitalisation were significantly less common in older patients acutely admitted to an Emergency Department Short-stay Unit as compared to admission to an Internal Medicine Department. PMID- 28810889 TI - Dehydroepiandrosterone sulfate and dehydroepiandrosterone sulfate/cortisol ratio in cirrhotic patients with septic shock: another sign of hepatoadrenal syndrome? AB - BACKGROUND: Cirrhotic patients are susceptible to sepsis and critical illness related corticosteroid insufficiency (CIRCI). Dehydroepiandrosterone sulfate (DHEAS) is a corticotropin-dependent adrenal androgen, which has immunostimulating and antiglucocorticoid effects. Considering the synchronized synthesis of cortisol and DHEAS and their opposing effects to each other, investigators have proposed measuring these two hormones as a ratio. Severe sepsis has been associated with low DHEAS, especially relative to high cortisol. Despite growing interest in the role of adrenal androgen replacement in critical illness, there have been no data about DHEAS and the DHEAS/cortisol ratio in patients with liver cirrhosis. We studied whether low concentrations of DHEAS and decreased DHEAS/cortisol ratio are associated with poor outcome in patients with liver cirrhosis and septic shock. METHODS: We recruited 46 cirrhotic patients with septic shock, and 46 noncirrhotic counterparts matched by age and sex. We evaluated adrenal function using the short corticotropin stimulation test and analyzed the relation between DHEAS and cortisol. RESULTS: While the nonsurvivors in the cirrhotic group had significantly lower baseline DHEAS, lower baseline DHEAS/cortisol ratio, and reduced increments of both DHEAS and cortisol upon corticotropin stimulation, the survivors had lower baseline cortisol. Cirrhotic patients with lower DHEAS/cortisol ratio (<1.50) had higher levels of interleukin 6 and tumor necrosis factor alpha, higher Sequential Organ Failure Assessment scores, and higher rates of CIRCI and hospital mortality. Using the area under the receiver operating characteristic (AUROC) curve, both DHEAS and the DHEAS/cortisol ratio demonstrated a good discriminative power for predicting hospital survival (AUROC 0.807 and 0.925 respectively). The cirrhotic group had lower DHEAS and DHEAS/cortisol ratio but higher rates of CIRCI and hospital mortality, compared to the noncirrhotic group. CONCLUSIONS: There is dissociation between cortisol (increased) and DHEAS (decreased) in those cirrhotic patients who succumb to septic shock. Low DHEAS/cortisol ratios are associated with more severe diseases, inflammation, and CIRCI and can serve as a prognostic marker. More investigations are needed to evaluate the role of adrenal androgen in this clinical setting. PMID- 28810890 TI - Outcome of hearing preservation related to tumor morphologic analysis in acoustic neuromas treated by gamma knife radiosurgery. AB - BACKGROUND: Gamma Knife radiosurgery (GKRS) is an important part of the neurosurgical armamentarium in the treatment of acoustic neuromas. However, the treatment outcome related to the morphology of the tumor has not been rigorously studied. In this cohort, we evaluated the morphological features of the tumor in the tumor response and neurological outcomes after GKRS. MATERIAL AND METHODS: From July 2003 to December 2008, there were 93 cases of acoustic neuromas treated upfront with GKRS with 64 cases with serviceable hearing and 29 cases without serviceable hearing to fulfill the margin dose of 12Gy with at least follow up 5 years. RESULTS: The duration of symptom before GKRS in serviceable /no serviceable hearing was 7.9 +/- 1.2 and 15.3 +/- 3.1 months (p < 0.001) and associated no-hearing symptom was 70% and 35%, respectively (p < 0.001). There was 81.2% of hearing preservation after GKRS in serviceable hearing group including 27 cases of pear type (84%), 14 of linear type (70%), and 9 cases of sphere type (90%) (p < 0.01); however, there was no case of hearing improvement in the no-serviceable hearing group (0 of 29). There were 85% of patients with decreased tinnitus in serviceable hearing groups as compared to 61.5% of patients in no serviceable hearing group (p < 0.05). In multivariate analysis, the tumor morphology was highly correlated to hearing preservation rate (p < 0.01). CONCLUSION: In the limited case of this cohort, we found that the tumor morphology and timing of treatment was highly correlated to the rate of hearing preservation. The sphere type of tumor morphology was associated with the best chance of hearing preservation. PMID- 28810891 TI - The variation in urinary calcium levels in adult patients with fracture and surgical intervention. AB - BACKGROUND: Generally, a higher calcium diet is fed to fracture patients after surgery. However, recent studies have indicated that higher dietary calcium intakes increase the risk of urinary stones for fracture patients. Therefore, this study aimed to observe the variation in urinary calcium levels among fracture patients who underwent surgery, based on fracture type, fracture location, age and gender. METHODS: A total of 768 subjects were enrolled in this study from 2012 to 2015 and were divided into 2 groups: group A (fracture patients who underwent surgery) and group B (normal patients without fracture). Urine samples were collected for a 24-h period (24-h urine), at multiple specific time points before and after surgery for group A, or after hospitalisation for group B. Subsequently, urine calcium was detected and the changes were evaluated according to fracture location, fracture type, age and gender, as well as the distribution of hypercalciuria. RESULTS: Compared with group B, the level of urine calcium in group A significantly increased at different time points during the study period (P < 0.05). There were significant differences in the changes in urine calcium levels according to fracture location, fracture type and age, but not gender. Further, there were more patients with hypercalciuria in group A at the different time points, compared with group B. CONCLUSION: Variation in urinary calcium among fracture patients that underwent surgery was of a regular pattern and hypercalciuria was also found in these patients. Therefore, a high calcium diet and calcium supplements should be used with caution in this patient population. PMID- 28810892 TI - Absence of CX3CR1 impairs the internalization of Tau by microglia. AB - BACKGROUND: Extracellular Tau is toxic for neighboring cells, and it contributes to the progression of AD. The CX3CL1/CX3CR1 axis is an important neuron/microglia communication mechanism. METHODS: We studied Tau clearance by microglia both in vitro (microglia primary cultures treated with Cy5-Tau, affinity chromatography to study the binding of Tau to CX3CR1, and Tau-CX3CL1 competition assays) and in vivo (stereotaxic injection of Cy5-Tau into WT and CX3CR1-/- mice). The expression of CX3CR1, CX3CL1 and the microglial phagocytic phenotype were studied in brain tissue samples from AD patients. RESULTS: Tau binding to CX3CR1 triggers the internalization of the former by microglia, whereas S396 Tau phosphorylation decreases the binding affinity of this protein to CX3CR1. Of note, the progressive increase in the levels of phosho-Tau occurred in parallel with an increase in CX3CR1. In addition, our studies suggest that the phagocytic capacity of microglia in brain tissue samples from AD patients is decreased. Furthermore, the CX3CR1/CX3CL1 axis may be impaired in late stages of the disease. CONCLUSIONS: Our data suggest that the CX3CR1/CX3CL1 axis plays a key role in the phagocytosis of Tau by microglia in vitro and in vivo and that it is affected as AD progresses. Taken together, our results reveal CX3CR1 as a novel target for the clearance of extracellular Tau. PMID- 28810893 TI - Subcutaneous emphysema of the leg after hardware removal and bone allografting for infected non-union of the distal femur. AB - BACKGROUND: Infected non-unions of the supracondylar region of the femur are uncommon. Even though hardware removal is a common procedure, it may lead to complications, including neurovascular injury, refracture, worsening pain or recurrence of deformity. CASE PRESENTATION: We report on a male who developed subcutaneous emphysema of the leg after hardware removal and bone allografting for an infected non-union of the distal femur. He was managed by debridement of the surgical wound, antibiotic therapy, multiple fasciotomies, and application of a VAC (vacuum-assisted closure) system. CONCLUSIONS: Although subcutaneous emphysema of the leg after hardware removal and bone allografting for infected non-union of the distal femur is extremely rare, the potential life treating complications and their potential impact on the functional status of the patient have to be taken into consideration when counseling patients about this procedure. Even when it is not possible to identify a bacterial pathogen responsible for the subcutaneous emphysema of the leg, prompt intervention may save the limb of the patient. PMID- 28810894 TI - Chikungunya: an emerging viral infection with varied clinical presentations in Bangladesh: Reports of seven cases. AB - BACKGROUND: Chikungunya is an emerging and rapidly spreading viral infection in many parts of the world including Bangladesh. It shares many epidemiological and clinical characteristics with dengue. So, a sound knowledge is required for its detection and differentiation from dengue, specially in endemic regions. CASE PRESENTATION: We present seven confirmed cases of chikungunya having different clinical presentations occurring among middle aged males and females from different socio-economic background in Dhaka city, the capital of Bangladesh. All patients had fever and aches and pains. Less common features were rash, diarrhea, vomiting and altered liver biochemistry. Dengue was excluded in six patients. Paracetamol remained the mainstay of treatment during febrile periods, but over 50% of the patients had prolonged joint symptoms requiring non-steroidal anti inflammatory drugs. CONCLUSIONS: In spite of being a self-limiting disease, chikungunya may have different presentations and a protracted clinical course. During the febrile episode, exclusion of dengue is equally important. Physicians should be aware of the condition and public health initiatives are necessary to break the disease transmission. PMID- 28810895 TI - Understanding the cluster randomised crossover design: a graphical illustraton of the components of variation and a sample size tutorial. AB - BACKGROUND: In a cluster randomised crossover (CRXO) design, a sequence of interventions is assigned to a group, or 'cluster' of individuals. Each cluster receives each intervention in a separate period of time, forming 'cluster periods'. Sample size calculations for CRXO trials need to account for both the cluster randomisation and crossover aspects of the design. Formulae are available for the two-period, two-intervention, cross-sectional CRXO design, however implementation of these formulae is known to be suboptimal. The aims of this tutorial are to illustrate the intuition behind the design; and provide guidance on performing sample size calculations. METHODS: Graphical illustrations are used to describe the effect of the cluster randomisation and crossover aspects of the design on the correlation between individual responses in a CRXO trial. Sample size calculations for binary and continuous outcomes are illustrated using parameters estimated from the Australia and New Zealand Intensive Care Society - Adult Patient Database (ANZICS-APD) for patient mortality and length(s) of stay (LOS). RESULTS: The similarity between individual responses in a CRXO trial can be understood in terms of three components of variation: variation in cluster mean response; variation in the cluster-period mean response; and variation between individual responses within a cluster-period; or equivalently in terms of the correlation between individual responses in the same cluster-period (within cluster within-period correlation, WPC), and between individual responses in the same cluster, but in different periods (within-cluster between-period correlation, BPC). The BPC lies between zero and the WPC. When the WPC and BPC are equal the precision gained by crossover aspect of the CRXO design equals the precision lost by cluster randomisation. When the BPC is zero there is no advantage in a CRXO over a parallel-group cluster randomised trial. Sample size calculations illustrate that small changes in the specification of the WPC or BPC can increase the required number of clusters. CONCLUSIONS: By illustrating how the parameters required for sample size calculations arise from the CRXO design and by providing guidance on both how to choose values for the parameters and perform the sample size calculations, the implementation of the sample size formulae for CRXO trials may improve. PMID- 28810896 TI - Silencing the Girdin gene enhances radio-sensitivity of hepatocellular carcinoma via suppression of glycolytic metabolism. AB - BACKGROUND: Radiotherapy has been used increasingly to treat primary hepatocellular carcinoma. Clinically, the main cause of radiotherapy failure is cellular radioresistance, conferred via glycolytic metabolism. Our previous study demonstrated that Girdin is upregulated in primary hepatocellular carcinoma and promotes the invasion and metastasis of tumor cells. However, whether Girdin underlies the radio-sensitivity of hepatocellular carcinoma remains unclear. METHODS: A short hairpin RNA (shRNA) was used to silence CCDC88A (encoding Girdin), and real-time PCR was performed to determine CCDC88A mRNA expression. Then, cell proliferation, colony formation, flow cytometric, scratch, and transwell assays were to examine the influence of Girdin silencing on cellular radiosensitivity. Glycolysis assays were conducted to exam cell glycolysis process. Western blotting was performed to explore the signaling pathway downstream of Girdin. Finally, animal experiments were performed to demonstrate the effect of CCDC88A silencing on the radiosensitivity of hepatoma in vivo. RESULTS: shRNA-induced Girdin silencing suppressed glycolysis and enhanced the radio-sensitivity of hepatic cell lines, HepG2 and Huh-7. Furthermore, silencing of Girdin inhibited the PI3K/AKT/HIF-1alpha signaling pathway, which is a central regulator of glycolysis. CONCLUSION: Girdin can regulate glycolysis in hepatocellular carcinoma cells through the PI3K/AKT/HIF-1alpha signaling pathway, which decreases the sensitivity of tumor cells to radiotherapy. PMID- 28810897 TI - Cost of hospitalization for childbirth in India: how equitable it is in the post NRHM era? AB - BACKGROUND AND OBJECTIVE: Information on out-of-pocket (OOP) expenditure during childbirth in public and private health facilities in India is needed to make rational decisions for improving affordability to maternal care services. We undertook this study to evaluate the OOP expenditure due to hospitalization from childbirth and its impact on households. METHODS: This is a secondary data analysis of a nationwide household survey by the National Sample Survey Organization in 2014. The survey reported health service utilization and health care related expenditure by income quintiles and type of health facility. The recall period for hospitalization expenditure was 365 days. OOP expenditure amounting to more than 10% of annual consumption expenditure was termed as catastrophic. RESULTS: Median expenditure per episode of hospitalisation due to childbirth was US$54. The expenditure incurred was about six times higher among the richest quintile compared to the poorest quintile. Median private sector OOP hospitalization expenditure was nearly nine times higher than in the public sector. Hospitalization in a private sector facility leads to a significantly higher prevalence of catastrophic expenditure than hospitalization in a public sector (60% vs. 7%). Indirect cost (43%) constituted the largest share in the total expenditure in public sector hospitalizations. Urban residence, poor wealth quintile, residing in eastern and southern regions of India and delivery in private hospital were significantly associated with catastrophic expenditure. CONCLUSIONS: We strongly recommend cash transfer schemes with effective pro-poor targeting to reduce the impact of catastrophic expenditure. Strengthening of public health facilities is required along with private sector regulation. PMID- 28810898 TI - Erratum to: Insights into the design and interpretation of iCLIP experiments. PMID- 28810899 TI - Chronic pain and opioid misuse: a review of reviews. AB - OBJECTIVE: The crisis of prescription opioid (PO) related harms has focused attention toward identifying and treating high-risk populations. This review aims to synthesize systematic reviews on the epidemiology and clinical management of comorbid chronic pain and PO or other substance misuse. METHODS: A systematic database search was conducted to identify systematic reviews published between 2000 and 2016. Eligible studies were systematic reviews related to chronic non cancer pain and PO or other substance misuse. Evidence from the included reviews was synthesized according to epidemiology and clinical management themes. RESULTS: Of 1908 identified articles, 18 systematic reviews were eligible for final inclusion. Two meta-analyses estimated the prevalence of chronic non-cancer pain in individuals using POs non-medically to be approximately 48% to 60%, which is substantially higher than the prevalence of chronic non-cancer pain in general population samples (11% to 19%). Five systematic reviews estimated the rates of PO or other opioid use in chronic pain populations with substantial variation in results (0.05% to 81%), likely due to widely varying definitions of dependence, substance use disorder, misuse, addiction, and abuse. Several clinical assessment and treatment approaches were identified, including: standardized assessment instruments; urine drug testing; medication counts; prescription drug monitoring programs; blood level monitoring; treatment agreements; opioid selection; dosing and dispensing strategies; and opioid agonist treatment. However, the reviews commonly noted serious limitations, inconsistencies, and imprecision of studies, and a lack of evidence on effectiveness or clinical utility for the majority of these strategies. CONCLUSION: Overall, current systematic reviews have found a lack of high-quality evidence or consistent findings on the prevalence, risk factors, and optimal clinical assessment and treatment approaches related to concurrent chronic pain and substance misuse. Given the role of systematic reviews in guiding evidence-based medicine and health policy, there is an urgent need for high-quality primary research to guide future systematic reviews to address the escalating epidemic of harms related to chronic pain and substance misuse. PMID- 28810900 TI - Polymer-free dual drug-eluting stents evaluated in a porcine model. AB - BACKGROUND: Although drug-eluting stents have dramatically reduced the rates of restenosis and target lesion revascularization, they are associated with stent thrombosis (ST), a catastrophic event likely due to delayed endothelialization and chronic inflammation caused by the polymer and the metal scaffolds. To increase the safety and efficacy of stents, polymer-free dual drug-eluting stents (DDES) have been developed. METHODS: A total 160 stents (Bare-metal stents (BMS), polymer-free probucol stents (PrES), sirolimus-eluting stents (SES) and DDES) were randomly implanted in the coronary arteries of 80 pigs. 14, 28, 90 and 191 days after implantation, QCA and OCT evaluations were performed in 20 pigs respectively, and the arteries were harvested for scanning electron microscope (SEM), histomorphology, histopathology analyses and for the relative expression of CD31, CD34 and CD133 on mRNA and protein levels. RESULTS: At the 14-day time point, there were significant differences in the strut rate coverage (p = 0.011), with greater coverage in the PrES than in the SES group (53.2%vs. 20.3%, p = 0.002). As well, there were no significant differences in the expression of CD31, CD34 and CD133 between groups in mRNA and protein level. CONCLUSIONS: DDES were as safe as BMS and SES, but they did not further improve the endothelialization of the stented coronary arteries in the porcine model. PMID- 28810901 TI - Immediate versus delayed surgery for hip fractures in the elderly patients: a protocol for a systematic review and meta-analysis. AB - BACKGROUND: Hip fractures are a major public health problem in elderly populations and are accompanied by high-mortality rates. Whether timing of surgery has an impact on morbidity and mortality has been discussed controversially, numerous studies suggest that the delay of surgery can significantly increase the risk of morbidity and mortality; others report that achieving a stable medical condition is more important than early surgery. The goal of our systematic review is to assess the impact of timing of surgery on health outcomes in patients aged 60 years or older with acute hip fracture. In addition, we will investigate differences in beneficial or harmful effects of timing of surgery in subgroups of patients based on demographic characteristics, physical status, and the use of anticoagulant medications. METHODS: We will systematically search MEDLINE via Ovid, the Cochrane Library, Embase, PubMed, and clinical trial registries (from 1997 to 2017). In addition, we will search reference lists of pertinent reviews, archives of annual meetings of orthopaedic societies, and contact experts. We will include randomized controlled trials and non-randomized studies assessing the impact of timing of surgery after hip fracture in patients 60 years or older, published in English or German. Our outcomes of interest include health outcomes such as mortality, perioperative complications, functional capacity, and quality of life. We plan to perform meta analyses if we have at least three sufficiently similar studies. If data are sufficient, we will conduct subgroup-analyses testing for differences between age groups, sex, patients' physical status as assessed with ASA (American Society of Anesthesiologists) scores, and the use of anticoagulation. DISCUSSION: Since this is the first systematic review on this topic since 2010, our findings will help to inform clinical practice guidelines concerning timing of surgery in hip fractures. Furthermore, our findings could contribute to define an optimal time period for surgery for different groups of patients with acute hip fracture. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2017 CRD42017058216. PMID- 28810902 TI - The isotype and IgG subclass distribution of anti-carbamylated protein antibodies in rheumatoid arthritis patients. AB - BACKGROUND: Anti-carbamylated protein (anti-CarP) antibodies have recently been reported to occur in around 45% of rheumatoid arthritis (RA) patients and to have prognostic and diagnostic properties. At present, the breadth and molecular make up of the anti-CarP antibody response is ill defined. To understand the anti-CarP antibody immune response and potential immune effector mechanisms it can recruit, we determined the anti-CarP antibody isotype and IgG-subclass usage in RA patients. METHODS: Anti-CarP antibody IgM, IgA, and IgG or IgG subclasses were detected by enzyme-linked immunosorbent assay (ELISA) in sera from 373 unselected RA patients and 196 healthy controls. An additional 114 anti-citrullinated protein antibody (ACPA) and anti-CarP IgG double-positive patients were selected to study the concomitant presence of both antibody systems. RESULTS: Anti-CarP IgG was present in around 45% of the patients and comprised all anti-CarP IgG subclasses. The presence of anti-CarP IgG1 particularly associates with radiological damage. Anti-CarP IgM was detected in 16% of RA patients, even in anti-CarP IgG-positive individuals, and is indicative of an actively ongoing immune response. Around 45% of the patients were positive for IgA which included ACPA-positive cases but also 24% of the ACPA-negative cases. In ACPA and anti CarP double-positive patients, the distribution and number of isotypes and IgG subclasses was similar for both autoantibodies at the group level, but substantial variation was observed within individual patient samples. CONCLUSIONS: In RA, the anti-CarP antibody response uses a broad spectrum of isotypes and seems to be an actively ongoing immune reaction. Furthermore, the anti-CarP and ACPA autoantibody responses seems to be differentially regulated. PMID- 28810903 TI - A neural network multi-task learning approach to biomedical named entity recognition. AB - BACKGROUND: Named Entity Recognition (NER) is a key task in biomedical text mining. Accurate NER systems require task-specific, manually-annotated datasets, which are expensive to develop and thus limited in size. Since such datasets contain related but different information, an interesting question is whether it might be possible to use them together to improve NER performance. To investigate this, we develop supervised, multi-task, convolutional neural network models and apply them to a large number of varied existing biomedical named entity datasets. Additionally, we investigated the effect of dataset size on performance in both single- and multi-task settings. RESULTS: We present a single-task model for NER, a Multi-output multi-task model and a Dependent multi-task model. We apply the three models to 15 biomedical datasets containing multiple named entities including Anatomy, Chemical, Disease, Gene/Protein and Species. Each dataset represent a task. The results from the single-task model and the multi-task models are then compared for evidence of benefits from Multi-task Learning. With the Multi-output multi-task model we observed an average F-score improvement of 0.8% when compared to the single-task model from an average baseline of 78.4%. Although there was a significant drop in performance on one dataset, performance improves significantly for five datasets by up to 6.3%. For the Dependent multi task model we observed an average improvement of 0.4% when compared to the single task model. There were no significant drops in performance on any dataset, and performance improves significantly for six datasets by up to 1.1%. The dataset size experiments found that as dataset size decreased, the multi-output model's performance increased compared to the single-task model's. Using 50, 25 and 10% of the training data resulted in an average drop of approximately 3.4, 8 and 16.7% respectively for the single-task model but approximately 0.2, 3.0 and 9.8% for the multi-task model. CONCLUSIONS: Our results show that, on average, the multi-task models produced better NER results than the single-task models trained on a single NER dataset. We also found that Multi-task Learning is beneficial for small datasets. Across the various settings the improvements are significant, demonstrating the benefit of Multi-task Learning for this task. PMID- 28810904 TI - Antiarrhythmic drug therapy among patients presenting to emergency department with symptomatic atrial fibrillation - a prospective nationwide cohort. AB - BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia that causes numerous visits to emergency departments (ED). The aim of the FinFib2 study was to evaluate whether treatment of patients with AF in ED is consistent with the contemporary European Society of Cardiology (ESC) management guidelines. Here we report the results of antiarrhythmic drug therapy (AAD) in ED. METHODS: All patients within the two-week study period whose primary reason for the ED visit was symptomatic AF were included into this prospective multicentre study. Comprehensive data on factors contributing to the treatment of AF were collected, including a data of previous use of ADDs, and changes made for them during a visit in ED. RESULTS: The study population consisted of 1013 consecutive patients (mean age 70 +/- 13 years, 47.6% female). The mean European Heart Rhythm Association (EHRA) symptom score was 2.2 +/- 0.8. Rhythm control strategy was opt for 498 (63.8%) and 140 (64.5%) patients with previously and newly diagnosed AF, respectively. In patients with previously diagnosed AF the most frequently used AAD was a beta blocker (80.9%). Prior use of class I (11.4%) and III (9.1%) AADs as well as start or adjustment of their dosage (7.4%) were uncommon. Most of the patients with newly diagnosed AF were prescribed a beta blocker (71.0%) or a calcium channel antagonist (24.0%), and only two of them received class I or class III AADs. CONCLUSIONS: Our data demonstrated that in patients presenting to the ED with recurrent symptomatic AF and aimed for rhythm control strategy, the use of class I and class III AADs was rare despite ESC guideline recommendations. It is possible that early adaptation of a more aggressive rhythm control strategy might improve a quality of life for symptomatic patients and alleviate the ED burden associated with AF. Beta blockers were used by majority of patients as rate control therapy both in rate and rhythm control groups. TRIAL REGISTRATION: NCT01990105 . Registered 15 November 2013. PMID- 28810905 TI - Omni-PolyA: a method and tool for accurate recognition of Poly(A) signals in human genomic DNA. AB - BACKGROUND: Polyadenylation is a critical stage of RNA processing during the formation of mature mRNA, and is present in most of the known eukaryote protein coding transcripts and many long non-coding RNAs. The correct identification of poly(A) signals (PAS) not only helps to elucidate the 3'-end genomic boundaries of a transcribed DNA region and gene regulatory mechanisms but also gives insight into the multiple transcript isoforms resulting from alternative PAS. Although progress has been made in the in-silico prediction of genomic signals, the recognition of PAS in DNA genomic sequences remains a challenge. RESULTS: In this study, we analyzed human genomic DNA sequences for the 12 most common PAS variants. Our analysis has identified a set of features that helps in the recognition of true PAS, which may be involved in the regulation of the polyadenylation process. The proposed features, in combination with a recognition model, resulted in a novel method and tool, Omni-PolyA. Omni-PolyA combines several machine learning techniques such as different classifiers in a tree-like decision structure and genetic algorithms for deriving a robust classification model. We performed a comparison between results obtained by state-of-the-art methods, deep neural networks, and Omni-PolyA. Results show that Omni-PolyA significantly reduced the average classification error rate by 35.37% in the prediction of the 12 considered PAS variants relative to the state-of-the-art results. CONCLUSIONS: The results of our study demonstrate that Omni-PolyA is currently the most accurate model for the prediction of PAS in human and can serve as a useful complement to other PAS recognition methods. Omni-PolyA is publicly available as an online tool accessible at www.cbrc.kaust.edu.sa/omnipolya/ . PMID- 28810906 TI - Atypical presentation of anti-N-methyl-D-aspartate receptor encephalitis: two case reports. AB - BACKGROUND: Anti-N-methyl-D-aspartate receptor encephalitis is a rare autoimmune disease characterized by severe neurological and psychiatric symptoms and a difficult diagnosis. The disease is often secondary to a neoplastic lesion, seldom diagnosed years later. Psychiatric symptoms are prevalent in adults; neurologic symptoms are more evident in children, who typically present primarily with neurological symptoms. To the best of our knowledge, the association with juvenile idiopathic arthritis has not been described. CASE PRESENTATION: We report the cases of two caucasian girls with an atypical presentation. The first patient was an 8-year-old girl with normal psychomotor development. Over a 4 month period she developed behavioral problems, speech impairment, and deterioration in academic skills. Within 8 months from the onset of symptoms, choreic movements gradually appeared. Hematological, neuroradiological, and neurophysiological examinations were negative; however, her symptoms worsened and treatment with prednisone was started. Although her choreic movements improved within 1 month, her neuropsychological and behavioral symptoms continued. Anti-N methyl-D-aspartate receptor antibodies in cerebrospinal fluid and in blood were detected. Therapy with intravenously administered immunoglobulins was administered, without improvement of symptoms. After 2 months of steroid treatment, she suddenly started to pronounce some words with a progressive improvement in language and behavior. The second patient was a 14-year-old girl with classic anti-N-methyl-D-aspartate receptor encephalitis, treated successfully with intravenously administered immunoglobulins and methylprednisolone, followed by orally administered prednisone, who developed chronic arthritis of the hip. The arthritis was confirmed by magnetic resonance imaging and associated to antinuclear antigen antibody positivity. One year after the encephalitis presentation, an ovarian cystic mass was identified as a teratoma. The surgical resection of the mass was followed by the resolution of the psychotic spectrum and arthritis. CONCLUSIONS: Anti-N-methyl-D-aspartate receptor encephalitis in pediatric patients can present initially with neuropsychological and behavioral symptoms. In the literature, the association of anti-N-methyl-D-aspartate receptor encephalitis with juvenile idiopathic arthritis is not yet described: to the best of our knowledge, this is the first case reported. The link to a neoplastic lesion can explain the favorable course of encephalitis and arthritis, after the surgical resection of the mass. Early diagnosis and treatment can improve the patient's outcome. PMID- 28810908 TI - Relative risk estimation of dengue disease at small spatial scale. AB - BACKGROUND: Dengue is a high incidence arboviral disease in tropical countries around the world. Colombia is an endemic country due to the favourable environmental conditions for vector survival and spread. Dengue surveillance in Colombia is based in passive notification of cases, supporting monitoring, prediction, risk factor identification and intervention measures. Even though the surveillance network works adequately, disease mapping techniques currently developed and employed for many health problems are not widely applied. We select the Colombian city of Bucaramanga to apply Bayesian areal disease mapping models, testing the challenges and difficulties of the approach. METHODS: We estimated the relative risk of dengue disease by census section (a geographical unit composed approximately by 1-20 city blocks) for the period January 2008 to December 2015. We included the covariates normalized difference vegetation index (NDVI) and land surface temperature (LST), obtained by satellite images. We fitted Bayesian areal models at the complete period and annual aggregation time scales for 2008-2015, with fixed and space-varying coefficients for the covariates, using Markov Chain Monte Carlo simulations. In addition, we used Cohen's Kappa agreement measures to compare the risk from year to year, and from every year to the complete period aggregation. RESULTS: We found the NDVI providing more information than LST for estimating relative risk of dengue, although their effects were small. NDVI was directly associated to high relative risk of dengue. Risk maps of dengue were produced from the estimates obtained by the modeling process. The year to year risk agreement by census section was sligth to fair. CONCLUSION: The study provides an example of implementation of relative risk estimation using Bayesian models for disease mapping at small spatial scale with covariates. We relate satellite data to dengue disease, using an areal data approach, which is not commonly found in the literature. The main difficulty of the study was to find quality data for generating expected values as input for the models. We remark the importance of creating population registry at small spatial scale, which is not only relevant for the risk estimation of dengue but also important to the surveillance of all notifiable diseases. PMID- 28810907 TI - Schrodinger's microbes: Tools for distinguishing the living from the dead in microbial ecosystems. AB - While often obvious for macroscopic organisms, determining whether a microbe is dead or alive is fraught with complications. Fields such as microbial ecology, environmental health, and medical microbiology each determine how best to assess which members of the microbial community are alive, according to their respective scientific and/or regulatory needs. Many of these fields have gone from studying communities on a bulk level to the fine-scale resolution of microbial populations within consortia. For example, advances in nucleic acid sequencing technologies and downstream bioinformatic analyses have allowed for high-resolution insight into microbial community composition and metabolic potential, yet we know very little about whether such community DNA sequences represent viable microorganisms. In this review, we describe a number of techniques, from microscopy- to molecular-based, that have been used to test for viability (live/dead determination) and/or activity in various contexts, including newer techniques that are compatible with or complementary to downstream nucleic acid sequencing. We describe the compatibility of these viability assessments with high-throughput quantification techniques, including flow cytometry and quantitative PCR (qPCR). Although bacterial viability-linked community characterizations are now feasible in many environments and thus are the focus of this critical review, further methods development is needed for complex environmental samples and to more fully capture the diversity of microbes (e.g., eukaryotic microbes and viruses) and metabolic states (e.g., spores) of microbes in natural environments. PMID- 28810909 TI - A multi-center randomized, controlled, open-label trial evaluating the effects of eosinophil-guided corticosteroid-sparing therapy in hospitalised patients with COPD exacerbations - The CORTICO steroid reduction in COPD (CORTICO-COP) study protocol. AB - BACKGROUND: The most commonly applied treatment for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) is a 5-day course of high-dose systemic corticosteroids. However, this treatment has not been shown to reduce mortality and can potentially have serious side effects. Recent research has shown that, presumably, only a subgroup of COPD patients identifieable by blood eosinophil count benefit from a rescue course of prednisolone. By applying a biomarker-guided strategy, the aim of this study is to determine whether it is possible to reduce the use of systemic corticosteroids in AECOPD without influencing the outcome. METHODS: This is an ongoing prospective multicenter randomized controlled open label trial comprising 320 patients with AECOPD recruited from four hospitals in Denmark. The patients are randomized 1:1 to either standard care or eosinophil-guided corticosteroid-sparing therapy where prednisolone is not administered if the daily blood sampling reveals an eosinophil level below 0.3 * 109 cells/L. The primary endpoint is length of hospital stay within 14 days after recruitment. The secondary endpoints are treatment failure, 30-day mortality rate, COPD related re-admission rate, change in FEV1, and a number of adverse effect measures obtained within 3 months after the index hospitalisation date related to corticosteroid usage. DISCUSSION: This will be a very large RCT providing knowledge about the effectiveness of individualized biomarker-guided corticosteroid therapy in hospitalised patients with AECOPD. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02857842 , 02-august 2016. Clinicaltrialregister.eu: Classification Code: 10,010,953, 02-marts-2016. PMID- 28810910 TI - Comprehensive evaluation of gene expression signatures in response to electroacupuncture stimulation at Zusanli (ST36) acupoint by transcriptomic analysis. AB - BACKGROUND: Electroacupuncture (EA) has been applied to treat and prevent diseases for years. However, molecular events happened in both the acupunctured site and the internal organs after EA stimulation have not been clarified. METHODS: Here we applied transcriptomic analysis to explore the gene expression signatures after EA stimulation. Mice were applied EA stimulation at ST36 for 15 min and nine tissues were collected three hours later for microarray analysis. RESULTS: We found that EA affected the expression of genes not only in the acupunctured site but also in the internal organs. EA commonly affected biological networks involved in cytoskeleton and cell adhesion, and also regulated unique process networks in specific organs, such as gamma-aminobutyric acid-ergic neurotransmission in brain and inflammation process in lung. In addition, EA affected the expression of genes related to various diseases, such as neurodegenerative diseases in brain and obstructive pulmonary diseases in lung. CONCLUSIONS: This report applied, for the first time, a global comprehensive genome-wide approach to analyze the gene expression profiling of acupunctured site and internal organs after EA stimulation. The connection between gene expression signatures, biological processes, and diseases might provide a basis for prediction and explanation on the therapeutic potentials of acupuncture in organs. PMID- 28810911 TI - Outcomes from patients with presumed drug resistant tuberculosis in five reference centers in Brazil. AB - BACKGROUND: The implementation of rapid drug susceptibility testing (DST) is a current global priority for TB control. However, data are scarce on patient relevant outcomes for presumptive diagnosis of drug-resistant tuberculosis (pDR TB) evaluated under field conditions in high burden countries. METHODS: Observational study of pDR-TB patients referred by primary and secondary health units. TB reference centers addressing DR-TB in five cities in Brazil. Patients age 18 years and older were eligible if pDR-TB, culture positive results for Mycobacterium tuberculosis and, if no prior DST results from another laboratory were used by a physician to start anti-TB treatment. The outcome measures were median time from triage to initiating appropriate anti-TB treatment, empirical treatment and, the treatment outcomes. RESULTS: Between February,16th, 2011 and February, 15th, 2012, among 175 pDR TB cases, 110 (63.0%) confirmed TB cases with DST results were enrolled. Among study participants, 72 (65.5%) were male and 62 (56.4%) aged 26 to 45 years. At triage, empirical treatment was given to 106 (96.0%) subjects. Among those, 85 were treated with first line drugs and 21 with second line. Median time for DST results was 69.5 [interquartile - IQR: 35.7 111.0] days and, for initiating appropriate anti-TB treatment, the median time was 1.0 (IQR: 0-41.2) days. Among 95 patients that were followed-up during the first 6 month period, 24 (25.3%; IC: 17.5%-34.9%) changed or initiated the treatment after DST results: 16/29 MDRTB, 5/21 DR-TB and 3/45 DS-TB cases. Comparing the treatment outcome to DS-TB cases, MDRTB had higher proportions changing or initiating treatment after DST results (p = 0.01) and favorable outcomes (p = 0.07). CONCLUSIONS: This study shows a high rate of empirical treatment and long delay for DST results. Strategies to speed up the detection and early treatment of drug resistant TB should be prioritized. PMID- 28810912 TI - Inhibition of TRPM7 suppresses cell proliferation of colon adenocarcinoma in vitro and induces hypomagnesemia in vivo without affecting azoxymethane-induced early colon cancer in mice. AB - BACKGROUND: Magnesium (Mg2+) is an essential cation implicated in carcinogenesis, solid tumor progression and metastatic potential. The Transient Receptor Potential Melastatin Member 7 (TRPM7) is a divalent ion channel involved in cellular and systemic Mg2+ homeostasis. Abnormal expression of TRPM7 is found in numerous cancers, including colon, implicating TRPM7 in this process. METHODS: To establish a possible link between systemic magnesium (Mg2+) status, the Mg2+ conducting channel TRPM7 in colon epithelial cells, and colon carcinogenesis, in vitro whole-cell patch clamp electrophysiology, qPCR, and pharmacological tools were used probing human colorectal adenocarcinoma HT-29 as well as normal primary mouse colon epithelial cells. This was extended to and combined with aberrant crypt foci development in an azoxymethane-induced colorectal cancer mouse model under hypomagnesemia induced by diet or pharmacologic intervention. RESULTS: We find that TRPM7 drives colon cancer cell proliferation in human HT-29 and expresses in normal primary mouse colon epithelia. This is linked to TRPM7's dominant role as Mg2+ transporter, since high extracellular Mg2+ supplementation cannot rescue inhibition of cell proliferation caused by suppressing TRPM7 either genetically or pharmacologically. In vivo experiments in mice provide evidence that the specific TRPM7 inhibitor waixenicin A, given as a single bolus injection, induces transient hypomagnesemia and increases intestinal absorption of calcium. Repeated injections of waixenicin A over 3 weeks cause hypomagnesemia via insufficient Mg2+ absorption by the colon. However, neither waixenicin A, nor a diet low in Mg2+, affect aberrant crypt foci development in an azoxymethane induced colorectal cancer mouse model. CONCLUSION: Early stage colon cancer proceeds independent of systemic Mg2+ status and TRPM7, and waixenicin A is a useful pharmacological tool to study of TRPM7 in vitro and in vivo. PMID- 28810914 TI - Eliciting meta consent for future secondary research use of health data using a smartphone application - a proof of concept study in the Danish population. AB - BACKGROUND: The increased use of information technology in every day health care creates vast amounts of stored health data that can be used for research. The secondary research use of routinely collected data raises questions about appropriate consent mechanisms for such use. One option is meta consent where individuals state their own consent preferences in relation to future use of their data, e.g. whether they want the data to be accessible to researchers under conditions of specific consent, broad consent, blanket consent or not at all. This study investigates whether meta consent preferences can be successfully elicited by a smartphone application in the adult Danish population. METHODS: A smartphone app was developed for the elicitation of meta consent preferences. An invitation to use the app was distributed to a stratified, representative sample of the Danish adult population. The meta consent choices, the use of the app, user experience data, and demographic data were logged and analysed statistically using IBM SPSS version 20. RESULTS: Of 1000 potential respondents 221 used the app. One hundred eighty-eight of the respondents were female and 103 male. The age range was 19 to 79 years with an average of 51 years (SD 16). Most users indicate 1) that they find the choices they are asked to make easy to understand (>75% find it 'Easy' or 'Very easy'), 2) that the application is easy to use (>75% find it 'Easy' or 'Very easy'), and 3) that this kind of choice should be offered to people (89% find it 'Absolutely' or 'Somewhat' important). CONCLUSIONS: It is possible to collect meta consent preferences in the general, adult population using a smartphone app. PMID- 28810913 TI - Selinexor (KPT-330) demonstrates anti-tumor efficacy in preclinical models of triple-negative breast cancer. AB - BACKGROUND: Selinexor (KPT-330) is an oral agent that has been shown to inhibit the nuclear exporter XPO1. Given the pressing need for novel therapies for triple negative breast cancer (TNBC), we sought to determine the antitumor effects of selinexor in vitro and in vivo. METHODS: Twenty-six breast cancer cell lines of different breast cancer subtypes were treated with selinexor in vitro. Cell proliferation assays were used to measure the half-maximal inhibitory concentration (IC50) and to test the effects in combination with chemotherapy. In vivo efficacy was tested both as a single agent and in combination therapy in TNBC patient-derived xenografts (PDXs). RESULTS: Selinexor demonstrated growth inhibition in all 14 TNBC cell lines tested; TNBC cell lines were more sensitive to selinexor (median IC50 44 nM, range 11 to 550 nM) than were estrogen receptor (ER)-positive breast cancer cell lines (median IC50 > 1000 nM, range 40 to >1000 nM; P = 0.017). In multiple TNBC cell lines, selinexor was synergistic with paclitaxel, carboplatin, eribulin, and doxorubicin in vitro. Selinexor as a single agent reduced tumor growth in vivo in four of five different TNBC PDX models, with a median tumor growth inhibition ratio (T/C: treatment/control) of 42% (range 31 to 73%) and demonstrated greater antitumor efficacy in combination with paclitaxel or eribulin (average T/C ratios of 27% and 12%, respectively). CONCLUSIONS: Collectively, these findings strongly suggest that selinexor is a promising therapeutic agent for TNBC as a single agent and in combination with standard chemotherapy. PMID- 28810915 TI - Quality of life and correlation with clinical and radiographic variables in patients with ankylosing spondylitis: a retrospective case series study. AB - BACKGROUND: Previously, many studies have evaluated quality of life (QoL) in patients with ankylosing spondylitis (AS), however, none of them specifically investigated the correlation between pain-related disability measured by Oswestry Disability Index (ODI) and QoL in AS patients. In addition, the correlation between global kyphosis (GK) in lateral plain radiographs and QoL in AS patients remains unclear up to now. Therefore, this study aimed to evaluate QoL and correlation with clinical and radiographic variables in AS patients, especially to figure out the relationship about the pain-specific disability measured by ODI, GK and QoL. METHODS: From January 2008 to November 2015, two hundred and forty-five consecutive patients with an average age of 36.2 +/- 10.9 years (range, 17-66 years) satisfying the Modified New York Criteria for AS from a single institution were enrolled. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Metrology Index (BASMI) and Bath Ankylosing Spondylitis Global score (BAS-G) were applied to assess the disease activity, functional status, spinal mobility and overall feeling of AS patients, respectively. ODI was recorded to evaluate low back pain-related disability. QoL was evaluated by the Short Form-36 (SF-36). According to global kyphosis (GK) measured on standing lateral full-spine radiographs, the patients were divided into two groups: mild kyphotic group (GK < 70 degrees ,n = 176) and severe kyphotic group (GK >= 70 degrees ,n = 69). RESULTS: The scores of BASDAI, BASFI, BASMI and ODI had significant negative correlations with all SF-36 subscale scores (P < 0.01). BASFI and BASMI scores of severe kyphotic group were much higher than those of mild kyphotic group, respectively (P = 0.005 and P = 0.001, respectively) and the score of physical function (PF) subscale in severe kyphotic group was significantly higher than that in mild kyphotic group (P = 0.046) as well. Notably, the scores of ODI, BASFI and BASMI were the major predictors of PF subscale score of SF-36. CONCLUSIONS: Poor QoL is significantly correlated with high disease activity, poor functional status and decreased spinal mobility in AS. GK is significantly associated with functional status, spinal mobility and QoL in AS patients. ODI, BASFI and BASMI are the major predictors of PF subscale of SF-36. PMID- 28810917 TI - Erratum to: Multifactorial discrimination as a fundamental cause of mental health inequities. PMID- 28810916 TI - The Catsper channel and its roles in male fertility: a systematic review. AB - The Catsper channel is a sperm-specific, Ca2+-permeable, pH-dependent, and low voltage-dependent channel that is essential for the hyperactivity of sperm flagellum, chemotaxis towards the egg, capacitation and acrosome reaction. All of these physiological events require calcium entry into sperm cells. Remarkably, Catsper genes are exclusively expressed in the testis during spermatogenesis, and are sensitive to ion channel-induced pH change, such as NHEs, Ca2+ATPase, K+ channel, Hv1 channel and HCO3- transporters. Furthermore, the Catsper channel is regulated by some physiological stimulants, such as progesterone, cyclic nucleotides (e.g., cAMP, cGMP), zona pellucida (ZP) glycoproteins and bovine serum albumin (BSA). All of these factors normally stimulate Ca2+ entry into sperm through the Catsper channel. In addition, the Catsper channel may be a potential target for male infertility treatment or contraception. This review will focus on the structure, functions, regulation mechanisms and medicinal targets of the Catsper channel. PMID- 28810918 TI - Tranexamic acid reduces hidden blood loss in the treatment of intertrochanteric fractures with PFNA: a single-center randomized controlled trial. AB - BACKGROUND: Hidden blood loss is a major concern for patients undergoing hip surgery for intertrochanteric fracture. The objective of this study was to investigate whether tranexamic acid (TXA) could reduce postoperative hidden blood loss in patients undergoing hip surgery for intertrochanteric fracture. METHODS: A total of 77 patients with intertrochanteric fracture were enrolled in this randomized controlled study. Patients received either 200 mL (1 g) of TXA (n = 37) or normal-saline (NS) (n = 40) i.v. before hip surgery using proximal femoral nail anti-rotation (PFNA). Hemoglobin and hematocrit levels were measured preoperatively and postoperatively at day 1 and 3. Visible and hidden blood loss volumes were calculated at postoperative day 3. RESULTS: On postoperative day 3, the transfusion rate was significantly lower in the TXA group compared to the NS group, although mean hemoglobin and hematocrit levels were not significantly different between the two groups. However, the estimated hidden blood loss volume (210.09 +/- 202.14 mL vs. 359.35 +/- 290.12 mL; P < 0.05) and total blood loss volume (279.35 +/- 209.11 mL vs. 417.89 +/- 289.56 mL; P < 0.05) were significantly less in the TXA group compared to the NS group, respectively. CONCLUSION: TXA significantly reduced postoperative hidden blood loss in patients with intertrochanteric fracture who underwent PFNA. (Registration number: ChiCTR INR-16008134). PMID- 28810919 TI - Patterns of resident health workforce turnover and retention in remote communities of the Northern Territory of Australia, 2013-2015. AB - BACKGROUND: The geographical maldistribution of the health workforce is a persisting global issue linked to inequitable access to health services and poorer health outcomes for rural and remote populations. In the Northern Territory (NT), anecdotal reports suggest that the primary care workforce in remote Aboriginal communities is characterised by high turnover, low stability and high use of temporary staffing; however, there is a lack of reliable information to guide workforce policy improvements. This study quantifies current turnover and retention in remote NT communities and investigates correlations between turnover and retention metrics and health service/community characteristics. METHODS: This study used the NT Department of Health 2013-2015 payroll and financial datasets for resident health workforce in 53 remote primary care clinics. Main outcome measures include annual turnover rates, annual stability rates, 12-month survival probabilities and median survival. RESULTS: At any time point, the clinics had a median of 2.0 nurses, 0.6 Aboriginal health practitioners (AHPs), 2.2 other employees and 0.4 additional agency-employed nurses. Mean annual turnover rates for nurses and AHPs combined were extremely high, irrespective of whether turnover was defined as no longer working in any remote clinic (66%) or no longer working at a specific remote clinic (128%). Stability rates were low, and only 20% of nurses and AHPs remain working at a specific remote clinic 12 months after commencing. Half left within 4 months. Nurse and AHP turnover correlated with other workforce measures. However, there was little correlation between most workforce metrics and health service characteristics. CONCLUSIONS: NT Government-funded remote clinics are small, experience very high staff turnover and make considerable use of agency nurses. These staffing patterns, also found in remote settings elsewhere in Australia and globally, not only incur higher direct costs for service provision-and therefore may compromise long-term sustainability-but also are almost certainly contributing to sub-optimal continuity of care, compromised health outcomes and poorer levels of staff safety. To address these deficiencies, it is imperative that investments in implementing, adequately resourcing and evaluating staffing models which stabilise the remote primary care workforce occur as a matter of priority. PMID- 28810920 TI - Erratum to: Genomic innovations, transcriptional plasticity and gene loss underlying the evolution and divergence of two highly polyphagous and invasive Helicoverpa pest species. PMID- 28810921 TI - The role of whole-body computed tomography in the diagnosis of thoracic injuries in severely injured patients - a retrospective multi-centre study based on the trauma registry of the German trauma society (TraumaRegister DGU(r)). AB - BACKGROUND: Thoracic injuries are a leading cause of death in polytrauma patients. Early diagnosis and treatment are of paramount importance. Whole-body computed tomography (WBCT) has largely replaced traditional imaging techniques such as conventional radiographs and focused computed tomography (CT) as diagnostic tools in severely injured patients. It is still unclear whether WBCT has led to higher rates of diagnosis of thoracic injuries and thus to a change in outcomes. METHODS: In a retrospective study based on the trauma registry of the German Trauma Society (TraumaRegister DGU(r)), we analysed data from 16,545 patients who underwent treatment in 59 hospitals between 2002 and 2012 (ISS >= 9). The 3 years preceding and the 3 years following the introduction of WBCT as a standard imaging modality for the investigation of severely injured patients were assessed for every hospital. Accordingly, patients were assigned to either the pre-WBCT or the WBCT group. We compared the numbers of thoracic injuries and the outcomes of patients before and after the routine use of WBCT. RESULTS: A total of 13,564 patients (pre-WBCT: n = 5005, WBCT: n = 8559) were included. Relevant thoracic injuries were detected in 47.8%. There were no major differences between the patient groups in injury severity (pre-WBCT: median ISS 21; WBCT: median ISS 22), injury patterns and demographics. After the introduction of WBCT, only minor changes were observed regarding the rates of most thoracic injuries. Clinically relevant injuries were pulmonary contusions (pre-WBCT: 18.5%; WBCT: 28.7%), injuries to the lung parenchyma (pre-WBCT: 12.6%; WBCT: 5.9%), multiple rib fractures (pre-WBCT: 10.6%; WBCT: 21.6%), and pneumothoraces (pre-WBCT: 17.3%; WBCT: 21.6%). The length of stay in the intensive care unit (pre-WBCT: 10.8 days; WBCT: 9.7 days) and in hospital (pre-WBCT: 26.2 days; WBCT: 23.3 days) decreased. There was no difference in overall mortality (pre-WBCT: 15.5%; WBCT: 15.6%). CONCLUSIONS: The routine use of WBCT in the trauma room setting has led to changes in patient management that are not reflected in the rates of diagnosis of severe thoracic injuries (e.g. tension pneumothoraces, cardiac injuries, arterial injuries). By contrast, there was a relevant increase in the rates of diagnosis of minor thoracic injuries, which, however, did not result in an improvement in survival prognosis. PMID- 28810922 TI - Pleural epithelioid angiosarcoma with lymphatic differentiation arisen after radiometabolic therapy for thyroid carcinoma: immunohistochemical findings and review of the literature. AB - BACKGROUND: Pleural angiosarcoma is a rare tumor that causes diffuse pleural thickening and effusion, mimicking mesothelioma. Immunohistochemistry is needed to highlight endothelial differentiation. We describe the first case of pleural angiosarcoma with lymphatic differentiation following radiometabolic therapy for thyroid carcinoma. CASE PRESENTATION: A 50-year-old man showed diffuse pleural thickening and effusion. Nine years earlier, he underwent thyroidectomy and radiometabolic therapy for thyroid carcinoma with lymph node metastases. Histologically, the tumor consisted of a solid proliferation of atypical epithelioid cells and anastomosed vascular spaces, lacking of red blood cells and containing Alcian blue positive material. The tumor showed positive immunostaining for Vimentin, CD31, CK7, D2-40, c-MYC, Ki67, focal positivity for PanCK, and negative immunostaining for Factor VIII, CD34, WT1, CK5/6, Calretinin, EMA, HBME-1, CEA, p63, EpCAM, Bcl-2, TTF1 and Thyroglobulin. CD99 showed a granular/paranuclear pattern of positivity. The histological and immunohistochemical features were consistent with "pleural angiosarcoma with lymphatic differentiation, epithelioid variant". DISCUSSION AND CONCLUSIONS: Epithelioid angiosarcoma with lymphatic differentiation is very rare and aggressive. Moreover, the positivity for c-MYC suggests the relationship with radiometabolic therapy. To our knowledge, this is the first case of pleural c-MYC positive angiosarcoma with lymphatic differentiation reported in the literature and the first one arisen after radiometabolic therapy for thyroid carcinoma. PMID- 28810923 TI - The chemokine fractalkine (CX3CL1) attenuates H2O2-induced demyelination in cerebellar slices. AB - BACKGROUND: Fractalkine/CX3CR1 signalling has been implicated in many neurodegenerative and neurological diseases of the central nervous system (CNS). This signalling pathway plays an important role in regulating reactive oxygen species (ROS), as well as itself being altered in conditions of oxidative stress. Here, we investigated the effects of recombinant fractalkine (rCX3CL1) in models of hydrogen peroxide (H2O2)-induced demyelination and astrocyte toxicity, within organotypic cerebellar slice cultures. METHODS: Organotypic cerebellar slice cultures were generated from postnatal day 10 C57BL/6J mice to assess myelination. Immunohistochemistry was used to measure the degree of myelination. Fluorescent images were obtained using a leica SP8 confocal microscope and data analysed using ImageJ software. RESULTS: We show here, for the first time, that rCX3CL1 significantly attenuated bolus H2O2-induced demyelination as measured by expression of myelin basic protein (MBP) and attenuated reduced vimentin expression. Using the GOX-CAT system to continuously generate low levels of H2O2 and induce demyelination, we observed similar protective effects of rCX3CL1 on MBP and MOG fluorescence, although in this model, the decrease in vimentin expression was not altered. CONCLUSIONS: This data indicates possible protective effects of fractalkine signalling in oxidative stress-induced demyelination in the central nervous system. This opens up the possibility of fractalkine receptor (CX3CR1) modulation as a potential new target for protecting against oxidative stress-induced demyelination in both inflammatory and non-inflammatory nervous system disorders. PMID- 28810924 TI - Mutational analysis of COL1A1 and COL1A2 genes among Estonian osteogenesis imperfecta patients. AB - BACKGROUND: Osteogenesis imperfecta (OI) is a rare bone disorder. In 90% of cases, OI is caused by mutations in the COL1A1/2 genes, which code procollagen alpha1 and alpha2 chains. The main aim of the current research was to identify the mutational spectrum of COL1A1/2 genes in Estonian patients. The small population size of Estonia provides a unique chance to explore the collagen I mutational profile of 100% of OI families in the country. METHODS: We performed mutational analysis of peripheral blood gDNA of 30 unrelated Estonian OI patients using Sanger sequencing of COL1A1 and COL1A2 genes, including all intron-exon junctions and 5'UTR and 3'UTR regions, to identify causative OI mutations. RESULTS: We identified COL1A1/2 mutations in 86.67% of patients (26/30). 76.92% of discovered mutations were located in the COL1A1 (n = 20) and 23.08% in the COL1A2 (n = 6) gene. Half of the COL1A1/2 mutations appeared to be novel. The percentage of quantitative COL1A1/2 mutations was 69.23%. Glycine substitution with serine was the most prevalent among missense mutations. All qualitative mutations were situated in the chain domain of pro-alpha1/2 chains. CONCLUSION: Our study shows that among the Estonian OI population, the range of collagen I mutations is quite high, which agrees with other described OI cohorts of Northern Europe. The Estonian OI cohort differs due to the high number of quantitative variants and simple missense variants, which are mostly Gly to Ser substitutions and do not extend the chain domain of COL1A1/2 products. PMID- 28810925 TI - Surgical versus percutaneous isolated pelvic perfusion (IPP) for advanced melanoma: comparison in terms of melphalan pharmacokinetic pelvic bio availability. AB - BACKGROUND: Isolated pelvic perfusion (IPP) can be used to treat unresectable melanoma metastases of the pelvis. IPP can be performed either by surgical or percutaneous approaches, using different balloon catheters. The aim of this study was to examine whether the surgical and percutaneous approaches were comparable with respect to tumor drug exposure in the pelvis. METHODS: A pharmacokinetic study was performed in 5 melanoma patients treated with surgical IPP and five with percutaneous IPP. Both groups received melphalan at the dose of 30 mg/m2. Melphalan pharmacokinetic analyses were performed and the main parameter used to evaluate pelvic tumor drug-exposure was the ratio of areas under the melphalan plasma concentration curves in the pelvis and the systemic compartment, during the perfusion time (AUC0 to 20). Non-parametric Mann-Whitney tests were employed for statistical comparisons. RESULTS: The median and interquartile range (IQR) values of the ratios between melphalan AUC0 to 20 in pelvic and systemic compartments were 7.9 (IQR 7.2 to 9.9) and 5 (IQR 4 to 7.9) for surgical and percutaneous IPPs, respectively (p = 0.209). CONCLUSIONS: Tumor exposure to drug using these two methods did not statistically differ and both methods, therefore, can be adopted interchangeably, utilizing a perfusion blood flow rate of approximately 120 ml/min. The small sample size is a limitation of this study but our preliminary results can be used to calculate the effect size of a larger trial. Trial Registration Clinical Trials.gov Identifier NCT01920516; date of trial registration: August 6, 2013. PMID- 28810926 TI - The association between sonographic enthesitis and radiographic damage in psoriatic arthritis. AB - BACKGROUND: To examine the association between sonographic enthesitis and the severity of radiographic features of damage in the peripheral and axial joints in psoriatic arthritis (PsA). METHODS: A cross-sectional analysis was conducted in patients with PsA. The MAdrid Sonography Enthesitis Index (MASEI) scoring system was used to quantify the extent of sonographic entheseal abnormalities. Radiographic damage in the peripheral joints and spine was assessed by the modified Steinbrocker score (mSS), Modified New York Criteria for sacroiliitis, and the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). The association between MASEI and the extent of radiographic damage was assessed using negative binomial and logistic regression. The results were expressed in terms of the regression coefficient estimates and their exponentiated values (ebeta) or odds ratios (OR), and 95% confidence intervals (CI). RESULTS: Two hundred and twenty three patients were analyzed; 58% were males, with mean +/- SD age of 55.9 +/- 12.9 years and PsA duration of 16.7 +/- 12.4 years. Regression analyses yielded an association between higher MASEI scores (10 units increase) and peripheral joint damage including mSS (ebeta = 1.42, 95% CI: 1.15, 1.72), joint ankylosis (OR = 1.93, 95% CI: 1.37, 2.72), arthritis mutilans (OR = 1.77, 95% CI: 1.23, 2.54), and periostitis (OR = 1.41, 95% CI: 1.08, 1.84). Similarly, an association was found between higher MASEI scores and axial damage as measured by mSASSS (ebeta = 2.18, 95% CI: 1.16, 4.09) and sacroiliitis (OR = 1.33, 95% CI: 1.03, 1.72). CONCLUSIONS: The severity of sonographic enthesitis is a potential marker of radiographic peripheral and axial joint damage in PsA. PMID- 28810927 TI - STAT3-mediated upregulation of lncRNA HOXD-AS1 as a ceRNA facilitates liver cancer metastasis by regulating SOX4. AB - BACKGROUND: Several of the thousands of human long noncoding RNAs (lncRNAs) have been functionally characterized, yet their potential involvement in hepatocellular carcinoma (HCC) remains poorly understood. METHODS: LncRNA-HOXD AS1 was identified by microarray and validated by real-time PCR. The clinicopathological significance of HOXD-AS1 was analyzed by Kaplan-Meier method. Chromatin immunoprecipitation was conducted to examine the mechanism of HOXD-AS1 upregulation. The role of HOXD-AS1 in HCC cells was assessed both in vitro and in vivo. ceRNA function of HOXD-AS1 was evaluated by RNA immunoprecipitation and biotin-coupled miRNA pull down assays. RESULTS: In this study, we found that HOXD AS1 was significantly upregulated in HCC tissues. Clinical investigation demonstrated high expression level of HOXD-AS1 was associated with poor prognosis and high tumor node metastasis stage of HCC patients, and was an independent risk factor for survival. Moreover, our results revealed that STAT3 could specifically interact with the promoter of HOXD-AS1 and activate HOXD-AS1 transcription. Knockdown of HOXD-AS1 significantly inhibited migration and invasion of HCC cells in vitro and distant lung metastasis in vivo. Additionally, HOXD-AS1 was enriched in the cytoplasm, and shared miRNA response elements with SOX4. Overexpression of HOXD-AS1 competitively bound to miR-130a-3p that prevented SOX4 from miRNA mediated degradation, thus activated the expression of EZH2 and MMP2 and facilitated HCC metastasis. CONCLUSIONS: In summary, HOXD-AS1 is a prognostic marker for HCC patients and it may play a pro-metastatic role in hepatocarcinogenesis. PMID- 28810928 TI - Gait characteristics and their discriminative power in geriatric patients with and without cognitive impairment. AB - BACKGROUND: A detailed gait analysis (e.g., measures related to speed, self affinity, stability, and variability) can help to unravel the underlying causes of gait dysfunction, and identify cognitive impairment. However, because geriatric patients present with multiple conditions that also affect gait, results from healthy old adults cannot easily be extrapolated to geriatric patients. Hence, we (1) quantified gait outcomes based on dynamical systems theory, and (2) determined their discriminative power in three groups: healthy old adults, geriatric patients with- and geriatric patients without cognitive impairment. METHODS: For the present cross-sectional study, 25 healthy old adults recruited from community (65 +/- 5.5 years), and 70 geriatric patients with (n = 39) and without (n = 31) cognitive impairment from the geriatric dayclinic of the MC Slotervaart hospital in Amsterdam (80 +/- 6.6 years) were included. Participants walked for 3 min during single- and dual-tasking at self-selected speed while 3D trunk accelerations were registered with an IPod touch G4. We quantified 23 gait outcomes that reflect multiple gait aspects. A multivariate model was built using Partial Least Square- Discriminant Analysis (PLS-DA) that best modelled participant group from gait outcomes. RESULTS: For single-task walking, the PLS-DA model consisted of 4 Latent Variables that explained 63 and 41% of the variance in gait outcomes and group, respectively. Outcomes related to speed, regularity, predictability, and stability of trunk accelerations revealed with the highest discriminative power (VIP > 1). A high proportion of healthy old adults (96 and 93% for single- and dual-task, respectively) was correctly classified based on the gait outcomes. The discrimination of geriatric patients with and without cognitive impairment was poor, with 57% (single-task) and 64% (dual-task) of the patients misclassified. CONCLUSIONS: While geriatric patients vs. healthy old adults walked slower, and less regular, predictable, and stable, we found no differences in gait between geriatric patients with and without cognitive impairment. The effects of multiple comorbidities on geriatric patients' gait possibly causes a 'floor-effect', with no room for further deterioration when patients develop cognitive impairment. An accurate identification of cognitive status thus necessitates a multifactorial approach. PMID- 28810929 TI - The impact of age and gut microbiota on Th17 and Tfh cells in K/BxN autoimmune arthritis. AB - BACKGROUND: Age is an important risk factor for rheumatoid arthritis (RA), which often develops in middle age. However, how age-associated changes in immunity impact RA is poorly understood. Gut microbiota are known to be involved in the pathogenesis of RA, but the effects of microbiota in older subjects remain mostly unknown. METHODS: We used segmented filamentous bacteria (SFB), a gut commensal species with immunomodulatory effects, and K/BxN mice, a T cell receptor (TCR) transgenic model, to study the effect of age and microbiota on autoimmune arthritis. Comparing young and middle-aged K/BxN T cells of the same TCR specificity allows us to study T cells with an age focus eliminating a key variable: TCR repertoire alteration with age. In addition to joints, we also studied pathological changes in the lung, an important extra-articular RA manifestation. We used flow cytometry to evaluate T follicular helper (Tfh) and T helper 17 (Th17) cells, as they both contribute to autoantibody production, a key disease index in both RA and K/BxN arthritis. RESULTS: Middle-aged K/BxN mice had aggravated arthritis and pathological changes in the lung compared to young mice. Middle-aged mice displayed a strong accumulation of Tfh but not Th17 cells, and had defective Th17 differentiation and low expression of interleukin-23, a critical cytokine for Th17 maintenance. Although a soaring Tfh cell population accompanied by robust germinal center B cell responses were found in middle-aged mice, there was decreased cycling of Tfh cells, and SFB only induced the non-Tfh cells to upregulate Bcl-6, the Tfh master transcription factor, in the young but not the middle-aged group. Finally, the accumulated Tfh cells in middle-aged mice had an effector phenotype (CD62LloCD44hi). CONCLUSION: Age-dependent Tfh cell accumulation may play a crucial role in the increased autoimmune disease phenotype in middle-age. SFB, a potent stimulus for inducing Tfh differentiation, fails to promote Tfh differentiation in middle-aged K/BxN mice, suggesting that most of the middle-aged Tfh cells with an effector phenotype are Tfh effector memory cells induced at an earlier age. Our results also indicate that exposure to immunomodulatory commensals may allow the young host to develop an overactive immune system reminiscent of that found in the middle-aged host. PMID- 28810931 TI - A comprehensive regional clinical and educational ECPR protocol decreases time to ECMO in patients with refractory out-of-hospital cardiac arrest. AB - OBJECTIVE: Extracorporeal membrane oxygenation within CPR (ECPR) may improve survival for refractory out-of-hospital cardiac arrest (OHCA). We developed a prehospital, emergency department (ED), and hospital-based clinical and educational protocol to improve the key variable of time-to-ECPR (TTE). METHODS: In a single urban health region we involved key prehospital, clinical, and administrative stakeholders over a 2-year period, to develop a regional ECPR program with destination to a single urban tertiary care hospital. We developed clear and reproducible inclusion criteria and processes, including measures of program efficiency. We conducted seminars and teaching modules to paramedics and hospital-based clinicians including monthly simulator sessions, and performed detailed reviews of each treated case in the form of report cards. In this before and-after study we compared patients with ECPR attempted prior to, and after, protocol implementation. The primary outcome was TTE, defined as the time of initial professional CPR to establishment of extracorporeal circulation. We compared the median TTE for patients in the two groups using the Wilcoxon signed rank test. RESULTS: Four patients were identified prior to the protocol and managed in an ad hoc basis; for nine patients the protocol was utilized. Overall favourable neurological outcomes among ECPR-treated patients were 27%. The median TTE was 136 minutes (IQR 98 - 196) in the pre-protocol group, and 60 minutes (IQR 49 - 81) minutes in the protocol group (p=0.0165). CONCLUSION: An organized clinical and educational protocol to initiate ECPR for patients with OHCA is feasible and significantly reduces the key benchmark of time-to-ECPR flows. PMID- 28810930 TI - Sex differences in microRNA-mRNA networks: examination of novel epigenetic programming mechanisms in the sexually dimorphic neonatal hypothalamus. AB - BACKGROUND: Sexual differentiation of the male brain, and specifically the stress circuitry in the hypothalamus, is primarily driven by estrogen exposure during the perinatal period. Surprisingly, this single hormone promotes diverse programs of sex-specific development that vary widely between different cell types and across the developing male brain. The complexity of this phenomenon suggests that additional layers of gene regulation, including microRNAs (miRNAs), must act downstream of estrogen to mediate this specificity. METHODS: To identify noncanonical mediators of estrogen-dependent sex-specific neural development, we assayed the miRNA complement of the mouse PN2 hypothalamus by microarray following an injection of vehicle or the aromatase inhibitor, formestane. Initially, multivariate analyses were used to test the influence of sex and experimental group on the miRNA environment as a whole. Then, we utilized traditional hypothesis testing to identify individual miRNA with significantly sex-biased expression. Finally, we performed a transcriptome-wide mapping of Argonaute footprints by high-throughput sequencing of RNA isolated by cross linking immunoprecipitation (Ago HITS-CLIP) to empirically characterize targeting relationship between estrogen-responsive miRNAs and their messenger RNA (mRNA) targets. RESULTS: In this study, we demonstrated that the neonatal hypothalamic miRNA environment has robust sex differences and is dynamically responsive to estrogen. Analyses identified 162 individual miRNAs with sex-biased expression, 92 of which were estrogen-responsive. Examining the genomic distribution of these miRNAs, we found three miRNA clusters encoded within a 175-kb region of chromosome 12 that appears to be co-regulated by estrogen, likely acting broadly to alter the epigenetic programming of this locus. Ago HITS-CLIP analysis uncovered novel miRNA-target interactions within prototypical mediators of estrogen-driven sexual differentiation of the brain, including Esr1 and Cyp19a1. Finally, using Gene Ontology annotations and empirically identified miRNA-mRNA connections, we identified a gene network regulated by estrogen-responsive miRNAs that converge on biological processes relevant to sexual differentiation of the brain. CONCLUSIONS: Sexual differentiation of the perinatal brain, and that of stress circuitry in the hypothalamus specifically, seems to be particularly susceptible to environmental programming effects. Integrating miRNA into our conceptualization of factors, directing differentiation of this circuitry could be an informative next step in efforts to understand the complexities behind these processes. PMID- 28810932 TI - Long Noncoding RNA NEAT1 Promotes Growth and Metastasis of Cholangiocarcinoma Cells. AB - Long noncoding RNAs (lncRNAs) are known to play important roles in cancers. However, little is known about lncRNAs in cholangiocarcinoma (CCA), a cholangiocyte malignancy with poor prognosis. We investigated the role of nuclear paraspeckle assembly transcript 1 (NEAT1) lncRNA in promoting CCA. qRT-PCR analysis of patient samples showed that NEAT1 expression was higher in CCA tumors than in matched adjacent nontumor tissue. NEAT1 levels were also higher in CCA cell lines than in a normal biliary epithelium cell line (HIBEpic). NEAT1 knockdown in CCA cell lines using shNEAT1 reduced cell proliferation and colony formation in CCK-8 and colony formation assays, respectively. CCA cells transfected with shNEAT1 also exhibited reduced metastasis and invasiveness in Transwell assays. NEAT1 knockdown cells produced smaller tumors, demonstrating that NEAT1 promotes tumor growth in vivo. Silencing of NEAT1 increased E-cadherin expression in vitro, and E-cadherin expression was inversely correlated with NEAT1 expression in CCA tissue samples. RIP and ChIP assays suggest that NEAT1 is recruited to the E-cadherin promoter by EZH2 (enhancer of zeste homolog 2), where it represses E-cadherin expression. These findings indicate that NEAT1 exerts oncogenic effects in CCA. We postulate that NEAT1 is a potentially useful diagnostic and therapeutic target for CCA. PMID- 28810933 TI - MicroRNA-152 Suppresses Human Osteosarcoma Cell Proliferation and Invasion by Targeting E2F Transcription Factor 3. AB - MicroRNA-152 (miR-152) expression has been reported to be downregulated in osteosarcoma (OS). However, the role of miR-152 in OS is not well documented. In the present study, we aimed to explore the function and underlying mechanism of miR-152 in OS. We found that miR-152 was underexpressed in OS tissues and cell lines. Decreased miR-152 was inversely correlated with lymph node metastasis and advanced clinical stage. Overexpression of miR-152 significantly inhibited cell proliferation, colony formation, migration, and invasion of OS cells. Bioinformatics analyses showed that miR-152 directly targeted E2F transcription factor 3 (E2F3), as further confirmed by a dual-luciferase reporter assay. E2F3 expression was upregulated and inversely correlated with miR-152 expression level in human OS tissues. Moreover, the inhibitory effects of miR-152 on OS growth and invasion were attenuated by E2F3 overexpression. Taken together, our findings indicated that miR-152 reduced OS growth and invasion by targeting E2F3 and provided new evidence of miR-152 as a potential therapeutic target for OS. PMID- 28810934 TI - Does Cyberbullying Prevalence Among Adolescents Relate With Country Socioeconomic and Development Indicators? An Ecological Study of 31 Countries. AB - BACKGROUND: In addition to individual characteristics, it is also important to evaluate how the environment may influence the dynamics of cyberbullying. We aim to study the correlation between cyberbullying prevalence among adolescents and selected country-level indicators. METHODS: We used two different data sources: data from a previously published literature review, to identify information on cyberbullying prevalence across countries, and data from the World Bank databases, to extract information on country-level indicators. A correlation matrix was used to present the association between the selected country-level indicators and the prevalence of cyberbullying. RESULTS: We observed a statistically significant negative correlation between cyberbullying victimization (cybervictims and cyberbully-victims, respectively) and gross domestic product (r = -.474 and -.842), gross national income (r = -.485 and .758), enrollment in secondary (r = -.446 and -.898) and tertiary education (r = .222 and -.881), the number of secure Internet servers (r = -.118 and -.794), and the number of Internet users (r = -.190 and -.818). CONCLUSIONS: A country's educational level seems to be an important contributor to the occurrence of cyberbullying. PMID- 28810935 TI - Men's Sexual Coerciveness, Perceptions of Women's Attachment, and Dating Preferences. AB - This study examined whether sexually coercive men are uniquely drawn to certain attachment styles in women. Specifically, it employed an experimental design to investigate what sorts of inferences men draw about women based on women's attachment styles and whether a woman's attachment style may serve as an indicator of vulnerability, rendering sexually coercive men more attracted to some women than to others. One-hundred thirty-six college men completed a measure of sexual coerciveness and answered questions about personal ads experimentally manipulated for portrayed attachment style. Findings suggest that sexually coercive men may be more attracted to women with characteristics associated with sexual vulnerability. Additionally, men perceive women differently based on their attachment styles, and sexually coercive men may perceive women differently than do other men. PMID- 28810936 TI - lncRNA C2dat1 Promotes Cell Proliferation, Migration, and Invasion by Targeting miR-34a-5p in Osteosarcoma Cells. AB - Osteosarcoma is a highly aggressive malignant bone tumor with poor prognosis. Evidence has suggested that lncRNAs are deregulated in multiple cancers. In this study, we investigated the role of the lncRNA C2dat1 on the biological functions of osteosarcoma cells. The expressions of C2dat1, miR-34a-5p, and Sirt1 in human osteosarcoma cells were altered by transfection with their specific vectors/shRNA or mimic/inhibitor. Cell viability, migration, invasion, and apoptosis were assessed posttransfection. The mRNA and protein levels of C2dat1, miR-34a-5p, and Sirt1 were detected by qRT-PCR and Western blot. The results showed that C2dat1 suppression reduced cell viability, invasion, and migration, whereas it increased cell apoptosis in OS-732 cells. The expression of miR-34a-5p was downregulated when C2dat1 was overexpressed, whereas it negatively regulated Sirt1 expression. miR-34a-5p overexpression inhibited cell viability, migration, and invasion and promoted cell apoptosis in osteosarcoma cells by downregulation of Sirt1. Furthermore, miR-34a-5p overexpression deactivated the p38/ERK/AKT and Wnt/beta catenin signaling pathways by inhibition of Sirt1. PMID- 28810938 TI - Social Norms for Intimate Partner Violence: A Replication With College Students. AB - This study replicated prior research on college students' perceived descriptive norms (i.e., prevalence estimates) for intimate partner violence (IPV). In this study, male and female college students were instructed to estimate the prevalence of physical forms of IPV for "typical students" of their same gender on campus. Perpetrators of IPV-both male and female-made higher estimates than nonperpetrators. When compared to actual prevalence rates, both perpetrators and nonperpetrators overestimated the prevalence of IPV on campus. Findings have implications for prevention programs that address social norms. PMID- 28810937 TI - Tweets, Gangs, and Guns: A Snapshot of Gang Communications in Detroit. AB - The aim of this study is to determine the frequency of violent and criminal Twitter communications among gang-affiliated individuals in Detroit, Michigan. We analyzed 8.5 million Detroit gang members' tweets from January 2013 to March 2014 to assess whether they contained Internet banging-related keywords. We found that 4.7% of gang-affiliated user tweets consisted of terms related to violence and crime. Violence and crime-related communications fell into 4 main categories: (a) beefing (267,221 tweets), (b) grief (79,971 tweets), (c) guns (3,551 tweets), and (d) substance use and distribution (47,638 tweets). Patterns in violent and criminal communication that may be helpful in predicting future gang activities were identified, which has implications for violence prevention research, practice, and policy. PMID- 28810939 TI - Roadway Aggression Among Drivers and Passengers With or Without a History of Traumatic Brain Injury. AB - OBJECTIVE: This study examined the association between roadway aggression and traumatic brain injury (TBI) among drivers and passengers who reside in the province of Ontario, Canada. METHODS: Data were based on a 3-year cumulated cross sectional sample of 6,048 adults aged 18 years and older who were surveyed by telephone. The outcome in this study was road rage in the form of verbal/gestural or physical aggression toward other road users and/or their vehicle. RESULTS: Driving status, history of TBI, age, gender, education, and the interaction between history of TBI and education significantly predicted roadway aggression. Odds ratios (ORs) for roadway aggression were significantly higher among drivers ( OR= 2.65) compared to passengers, between 2 and 4.5 times higher among individuals aged 18-64 years old compared to those older than 65 years, higher among adults with TBI (OR = 2.05) than without, and men (OR = 1.54) than women. Among respondents with lowest, but not highest, levels of education, roadway aggression was predicted by a history of TBI. CONCLUSION: This is the first population-based study to compare rates of roadway aggression between drivers and passengers with and without TBI. Research to understand these differences will be important for roadway aggression prevention efforts and policy. PMID- 28810940 TI - Unique Associations Among Emotion Dysregulation Dimensions and Aggressive Tendencies: A Multisite Study. AB - Although problems with emotion regulation (ER) have long been associated with internalizing symptoms, only recently has an ER framework been applied to the study of aggression. Therefore, little is known about the unique and independent associations between specific domains of the ER construct and different kinds of aggressive tendencies. We sought to explore these associations in two independent samples of young adults. Furthermore, we tested whether gender moderated the proposed emotion dysregulation-aggression link. Our results corroborated the association between emotion dysregulation and aggression in both samples. Specifically, the inability to control impulsive behavior when upset (i.e., negative urgency) was uniquely related to physical aggression, verbal aggression, anger, and hostility. Limited access to ER strategies was also significantly associated with overall aggression and hostility. The effect of negative urgency on physical and verbal aggression was stronger among males than females, although only in one sample. PMID- 28810941 TI - Coercive Control and the Stay-Leave Decision: The Role of Latent Tactics Among a Sample of Abused Pregnant Women. AB - Prior research on intimate partner violence (IPV) and a survivor's decision whether to remain in or leave a violent relationship has often been framed by the question "why do they stay?" This study looks reframe the discussion and examine one facet of this stay-leave decision: abusers' use of coercive control tactics. Using a qualitative approach with a sample of pregnant women exposed to IPV, we sought to expand on the current knowledge by looking at coercive control more broadly via an open-ended assessment. Interview responses show that (a) coercive control was experienced by most of the women in this sample and (b) coercion most often took the form of "latent" or hidden control, including such tactics as providing incentives, showing remorse, and making promises. However, such latent coercive tactics are rarely assessed in IPV survivors and represent an important factor deserving of further research and recognition. PMID- 28810942 TI - Psychosocial Maladjustment at Student and Classroom Level as Indicators of Peer Victimization. AB - The purpose of this study was to examine the role of aggressive behavior, anxiety, and peer rejection as multilevel indicators of peer victimization. A cross-sectional sample of 1,115 Finnish 9th grade students nested in 76 classrooms (mean age 15 years) were used to conduct multilevel models. All forms of psychosocial maladjustment, as well as student family economy, were found to predict peer victimization within classrooms. In addition, classrooms with more aggressive behavior and a higher proportion of rejected students suffered more peer victimization, beyond compositional effects of aggressive and rejected students being victimized. PMID- 28810943 TI - Language Barrier as a Risk Factor for Injuries From Patient Violence Among Direct Care Workers in Home Settings: Findings From a U.S. National Sample. AB - This study explored potential risk factors for injuries from patient violence among direct care workers in U.S. homes (DCWHs). A national probability sample of 3,377 DCWHs including home health and personal care aides was analyzed using complex sample analysis and generalized estimating equation. Injury from violence was defined as a workrelated injury sustained by aggression, violence, or abuse that was reported to the agency, required medical attention or resulted in absenteeism from work. An association between suffering an injury from patient violence and having a language barrier with patients was noted (OR = 4.44; 95% CI = 1.57, 12.56; p = .005). Findings illuminate the importance of homecare providers to match language between DCWHs and patients to reduce patient violence and improve quality of care in the home setting. PMID- 28810944 TI - A Mixed Method Study of Intimate Partner Violence: How Sex and Severity Impact Perpetrator Prior Involvement, Abnormality, and Responsibility. AB - This study employed a mixed method approach to examine the effects of participant sex, perpetrator sex, and severity of violence on perceptions of intimate partner violence (IPV) perpetrators. Quantitative participants (n = 449) completed a survey and qualitative participants (n = 31) participated in a focus group or an interview. Participants believed that it was more likely male perpetrators had prior involvement in IPV. Participants rated stories of female perpetrators as more abnormal than stories of male perpetrators. Participants in the weak severity of violence condition had lower evaluations of responsibility than the strong or fatal severity of violence conditions and only women were discerning about perpetrator sex in their ratings of responsibility. Theoretical implications extend intimate terrorism and defensive attribution theory. PMID- 28810945 TI - Teen Dating Violence: Predicting Physical and Sexual Violence and Mental Health Symptoms Among Heterosexual Adolescent Males. AB - This study investigated the prevalence of female-to-male intimate partner violence (IPV) and mental health symptoms among 589 male high school students. Participants completed questionnaires asking if they had experienced dating violence victimization, mental health symptoms, and violent attitudes. Correlations revealed strong positive associations between sexual, physical, and psychological IPV among male victims. Multiple regression found significant predictors of negative mental health consequences were experiencing psychological violence, experiencing physical violence, and having attitudes that accept violence. Further analysis revealed that participants who experience three types of dating violence (physical, sexual, and psychological) were significantly more likely to perpetrate physical and sexual violence. These findings suggest that violent attitudes and experiencing dating violence are significantly predictive of future negative mental health and perpetration among adolescent boys. PMID- 28810946 TI - Safety and Efficacy of Rotigotine for Treating Parkinson's Disease: A Meta Analysis of Randomised Controlled Trials. AB - We aimed to comprehensively analyse the safety and efficiency of rotigotine for treating Parkinson's disease (PD). We conducted systematic literature searches of Cochrane library, PubMed and Embase databases up to April 2016, with 'Rotigotine', 'Parkinson Disease ' and 'Parkinson's disease' as key searching terms. Outcomes, including Unified Parkinson's Disease Rating Scale (UPDRS) Part III and Part II scores, 'off' time, adverse events (AEs), serious AEs and discontinuation because of AEs, were compared between rotigotine and placebo groups under a fixed or random effect model. For dichotomous and continuous data, risk ratio (RR) and weighted mean difference with their corresponding 95% confidence intervals (95% CIs) were taken as the effect sizes to calculate merged results. Twelve eligible studies were included. For patients with early or advanced PD, rotigotine could significantly improve UPDRS Part III and Part II scores (p < 0.001) and it had significantly higher incidence of AEs than the placebo (p < 0.001). Regarding discontinuation because of AEs, rotigotine showed a significant advantage over placebo in patients with early PD, whereas the overall result demonstrated no statistically significant difference between the groups. Rotigotine can improve daily living and motor ability of patients with PD, although it has higher incidence of AEs. Rotigotine might be more appropriate for patients with advanced PD than for those with early PD. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 28810947 TI - Intravaginal Delivery Approaches for Contraception: An Overview with Emphasis on Gels. AB - The rising population with grave ramifications for the future is a fundamental issue, demanding for newer and better contraceptive modalities. Also, in order to achieve the contraceptive purpose, the choice of the most suitable delivery system is of unquestionable importance. Out of all dosage forms, vaginal gel formulations present indubitable benefits for contraceptive administration. Therefore, this review summarizes the history of research in the field of vaginal delivery systems with special emphasis on the development of vaginal gels containing safer and more effective contraceptive agents. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 28810948 TI - Development and Validation of a Robust and Efficient HPLC Method for the Simultaneous Quantification of Levodopa, Carbidopa, Benserazide and Entacapone in Complex Matrices. AB - PURPOSE: A variety of fixed-dose combination products is used in the therapy of Parkinson Disease. However, to date a proper analytical method applicable for comparative screening of different antiparkinson products was not available. The objective of the present work was thus to develop and validate an analytical method for the simultaneous quantification of levodopa, carbidopa, benserazide and entacapone. The method should be applicable for quantifying samples from drug release experiments with marketed products and prototype formulations performed under compendial and biorelevant test conditions. METHODS: A fast and robust method applicable for separation and quantification of the four compounds was developed and validated according to International Conference on Harmonization guidelines. Method validation covered applicability to a wide concentration range of all compounds and peak separation in complex sample matrices such as biorelevant dissolution media. RESULTS: The compounds were successfully separated by using a gradient elution method on an endcapped LiChrospher 100 RP-18 (250 x 4.6 mm, 5 um) column coupled with a LiChrospher 100 RP-18 precolumn (4 x 4 mm, 5 um) at a column temperature of 35.0 degrees C and a flow rate of 1.50 mL/min. The injection volume was 30 uL and the detection wavelengths were 280 and 210 nm, respectively. For all drug/media combinations the method was linear (r2 > 0.999) for a concentration range corresponding to 1.25 - 125 % label claim (i.e. 200 mg levodopa/entacapone and 50 mg carbidopa/benserazide) released. All other validation parameters were in the specified limits over the same concentration range. CONCLUSION: The new method allows for robust and fast separation of levodopa, carbidopa, benserazide and entacapone without any interference caused by excipients or ingredients of compendial and biorelevant dissolution media and thus presents a valuable tool in both formulation development and in vitro drug release screening of numerous fixed-dose combinations of antiparkinson drugs. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 28810949 TI - Analysis of Non-Pivotal Bioequivalence Studies Submitted in Abbreviated New Drug Submissions for Delayed-Release Drug Products. AB - The US FDA's rule on "Requirements for Submission of Bioequivalence Data" requiring submission of all bioequivalence (BE) studies conducted on the same formulation of the drug product submitted for approval was published in Federal Register in January 2009. With the publication of this rule, we evaluated the impact of data from non-pivotal BE studies in assessing BE and identified the reasons for failed in vivo BE studies for generic oral delayed-release (DR) drug products only. We searched the Agency databases from January 2009 toDecember 2016 to identify Abbreviated New Drug Applications (ANDAs) submitted for DR drug products containing non-pivotal BE studies. Out of 202 ANDAs, 43 ANDAs contained 102 non-pivotal BE studies. Forty-nine non-pivotal BE studies were conducted on the to-be-marketed (TBM) formulation and 53 were conducted on formulations different from the TBM formulation. These experimental formulations primarily differed in the ratio of components of the enteric coating layer and/or amount (i.e., %w/w) of enteric coating layer. Of the 49 non-pivotal BE studies conducted on the TBM formulation, 41 failed to meet the BE acceptance criteria. The majority of failed non-pivotal BE studies on the TBM DR generic products had insufficient power, which was expected as these studies are exploratory in nature and not designed to have adequate power to pass the BE statistical criteria. In addition, among the failed non-pivotal BE studies on the TBM DR generic products, the most commonly failing pharmacokinetic parameter was Cmax. The data from these non-pivotal BE studies indicate that inadequate BE study design can lead to failure of the BE on the same formulation. Also, the non-pivotal BE studies on formulations different from the TBM formulation help us link the formulation design to the product performance in vivo. This article is open to POST PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 28810950 TI - Clofibrate Attenuates ROS Production by Lipid Overload in Cultured Rat Hepatoma Cells. AB - PURPOSE: To investigate the effect of clofibrate on inducing liver fatty acid binding protein (FABP1) following a high-fat load in a hepatocyte cell culture model. METHODS: Rat hepatoma cells (CRL-1548) were treated with a fatty acid (FA) mixture consisting of oleate:palmitate (2:1) in the presence of 3% albumin. Cells were treated with 0, 0.5, 1, 2, or 3 mM FA for 24 and 48 hr, or further treated with 500 uM clofibrate (CLO) to induce FABP1 levels. Cytotoxicity was determined using the WST-1 assay. Intracellular lipid droplets were quantitated following staining with Nile Red. Dichlorofluorescein (DCF) was used to assess the extent of intracellular reactive oxygen species (ROS). RESULTS: Cell viability decreased (p < 0.01) with an increase in lipid concentration. Intracellular lipid droplets accumulated significantly (p < 0.001) with an increase in long-chain fatty acid load, which was associated with a statistical increase (p < 0.05) in ROS levels. Early clofibrate treatment showed significant increases in intracellular FABP1 levels with significant decreases in ROS levels (p < 0.05). Silencing FABP1 expression using siRNA revealed that FABP1 was the main contributor for the observed intracellular ROS clearance. CONCLUSIONS: Characteristic cellular damage resulted from released ROS following a high fat load to hepatoma cells. The damage was attenuated through early treatment with clofibrate, which may act as a hepatoprotectant by inducing FABP1 expression and in this manner, suppress intracellular ROS levels. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 28810951 TI - Veterans and Agent Orange: Update 2014. PMID- 28810952 TI - Operation Babylift: Delivering a Nameless Cargo to Freedom, Part I. PMID- 28810953 TI - Continuous Leadership Education and Development at the San Antonio Uniformed Services Health Education Consortium. PMID- 28810954 TI - The Use of Apremilast to Treat Psoriasis During Deployment. AB - Psoriasis is a chronic immune-mediated dermatologic disorder affecting approximately 2% of the general population. Under current U.S. Army regulation, the diagnosis of psoriasis is a bar to enlistment or appointment and, if poorly controlled, is grounds for referral to a Medical Evaluation Board and potential discharge from military service, according to Army Regulation 40-501. However, between 2008 and 2015, over 3,600 soldiers sought care for psoriasis while deployed to combat theaters, indicating that psoriasis remains a significant medical concern in the U.S. military. Although mild psoriasis is treatable with topical agents, moderate to severe psoriasis may require systemic treatment. Prior to Food and Drug Administration approval of apremilast (Otezla) in 2014, the standard systemic treatment options were methotrexate and biologic agents such as anti-Tumor Necrosis Factor-alpha medications. Active use of methotrexate or biologic immunomodulatory medications automatically disqualifies soldiers from deployment due to monitoring requirements, the need for refrigeration, and the risk for immune compromise. Apremilast offers treatment efficacy similar to that of methotrexate, and it may be taken while deployed because it does not require monitoring or refrigeration. However, efficacy must be evaluated in the context of its much higher unit cost. Nonetheless, we argue that apremilast may be a useful treatment option for psoriasis in a select group of soldiers who must deploy despite suffering from moderate to severe psoriasis. PMID- 28810955 TI - Embedded Mental Health: Promotion of Psychological Hygiene Within a Submarine Squadron. AB - INTRODUCTION: Psychological fitness is an important component to operational unit readiness and success. Embedding behavioral health providers can reduce unplanned personnel losses (UPL) as a result of psychological stress. The U.S. Submarine Forces implemented the Submarine Squadron 6 (CSS-6) Embedded Mental Health Pilot (EMHP) Program to address this type of UPL, which is classified as a Code 2 loss. The aim of the study is to evaluate the effectiveness of the EMHP Program at reducing UPL by improving psychological readiness through expedited access to care. MATERIALS AND METHODS: Using data from the CSS-6 EMHP Program, we identified the cohort of patients who were evaluated and received a full course of treatment from August 1, 2013, to April 30, 2015, and examined their final dispositions. A comparative review of Code 2 losses between 2012 and 2014 was performed to assess for any reduction in the annual incidence of Code 2 losses with EMHP. The Outcome Questionnaire (OQ-45) survey was used to determine the quantitative impact of EMHP on patient psychological readiness. We performed multiple regression analysis to identify any significant correlation between all independent variables and improvement in final OQ-45 scores. We performed logistic regression analysis to assess the logistic score as a function of predicting patient probability of returning vice not returning to duty. The logistic score is a by-product of the end results data and was not an original metric when the program was started. The Clinical Investigations Department at Naval Medical Center, Portsmouth waived this study from institutional review board review. Authorization was obtained from the U.S. Submarine Forces Command Public Affairs Office to publish the contents of this study. RESULTS: EMHP providers conducted a total of 878 patient sessions for 183 sailors over a 21 month period. There were eight fewer Code 2 losses after 2014, the first full calendar year with EMHP. This decrease in the number of Code 2 losses was in fact statistically significant, given p < 0.001. EMHP providers saw a 200% increase in patient volume and contributed to a 12% decrease in the annual incidence of Code 2 losses in 2014. Seventy patients returning to duty demonstrated clinically and statistically significant improvements in OQ-45 scores at the end of treatment. Only the initial symptomatic distress score on the OQ-45 survey demonstrated any statistical significance of predicting an improvement in OQ-45 composite scores by the end of treatment, given p < 0.01. A negative logistic score was significantly associated with not returning to duty (odds ratio, 16.0; 95% confidence interval, 5.22-49.02; chi2 = 30.63; p < 0.001). CONCLUSION: The EMHP Program reduced Code 2 losses and positively promoted psychological hygiene for submariners. With the establishment of embedded programs at other squadrons, we can develop a longitudinal study that provides a more inclusive assessment of this model. A future study may be warranted to evaluate the validity of the logistic score as a metric to determine further fitness for submarine duty. PMID- 28810956 TI - The Reasons for Living Scale-Military Version: Assessing Protective Factors Against Suicide in a Military Sample. AB - INTRODUCTION: Military suicide rates have been rising over the past decade and continue to challenge military treatment facilities. Assessing suicide risk and improving treatments are a large part of the mission for clinicians who work with uniformed service members. This study attempts to expand the toolkit of military suicide prevention by focusing on protective factors over risk factors. In 1983, Marsha Linehan published a checklist called the Reasons for Living Scale, which asked subjects to check the reasons they choose to continue living, rather than choosing suicide. The authors of this article hypothesized that military service members may have different or additional reasons to live which may relate to their military service. They created a new version of Linehan's inventory by adding protective factors related to military life. The purpose of these additions was to make the inventory more acceptable and relevant to the military population, as well as to identify whether these items constitute a separate subscale as distinguished from previously identified factors. MATERIALS AND METHODS: A commonly used assessment tool, the Reasons for Living Inventory (RFL) designed by Marsha Linehan, was expanded to offer items geared to the military population. The RFL presents users with a list of items which may be reasons to not commit suicide (e.g., "I have a responsibility and commitment to my family"). The authors used focus groups of staff and patients in a military psychiatric partial hospitalization program to identify military-centric reasons to live. This process yielded 20 distinct items which were added to Linehan's original list of 48. This expanded list became the Reasons for Living-Military Version. A sample of 200 patients in the military partial hospitalization program completed the inventory at time of or close to admission. This study was approved by the Institutional Review Board at Walter Reed National Military Center for adhering to ethical principles related to pursuing research with human subjects. RESULTS: The rotated factor matrix revealed six factors that have been labeled as follows: Survival and Coping Beliefs, Military Values, Responsibility to Family, Fear of Suicide/Disability/Unknown, Moral Objections and Child-Related Concerns. The subscale of Military Values is a new factor reflecting the addition of military items to the original RFL. CONCLUSIONS: Results suggest that formally assessing protective factors in a military psychiatric population has potential as a useful tool in the prevention of military suicide and therefore warrants further research. The latent factor we have entitled "Military Values" may help identify those service members for whom military training or "esprit de corps" is a reason for living. Further research can focus on further validation, pre/post-treatment effects on scores, expanded clinical use to stimulate increased will to live, or evaluation of whether scores on this scale, or the subscale of Military Values, can predict future suicidal behavior by service members. Finally, a larger sample size may produce more robust results to support these findings. PMID- 28810957 TI - Treatment-Seeking Beliefs and Behaviors in Air Force Nursing Personnel. AB - INTRODUCTION: Perceptions of stigma and barriers associated with seeking mental health services have been described in past research with military service members who reported or screened positively for mental health concerns or who reported an intention to seek care. The reported influence of stronger perceptions of stigma on treatment seeking has varied. MATERIALS AND METHODS: An anonymous, online survey was administered to Air Force nursing personnel (N = 250) at three locations to describe beliefs associated with seeking mental health treatment and to investigate the extent to which stigma and barriers, stress, and resilience were related to mental health treatment seeking. RESULTS: Over 40% reported having accessed mental health services in their lifetime. A majority who accessed mental health services did so during their service, but there was no significant relationship with a deployment. Approximately 44% reported experiencing a current stress or emotional problem, and 28% accessed mental health services within the past 6 months. Levels of stress were significantly higher among individuals who accessed mental health care in the previous 6 months. There were no significant differences in stigma, barriers to care, or resilience on the basis of having accessed mental health care. Military resources were preferred to address a mental health concern, and respondents preferred to seek care from a mental health professional rather than other providers. CONCLUSION: Additional resources may be needed to address military personnel's nondeployment-related mental health concerns. Improved screening for increased levels of stress may aid in identifying service members who could benefit from referral to a mental health professional. PMID- 28810958 TI - Multispecialty Synchronous Telehealth Utilization and Patient Satisfaction Within Regional Health Command Europe: A Readiness and Recapture System for Health. AB - BACKGROUND: Telehealth implementation within the Military Healthcare System continues to advance toward the goal of a mature regional health platform; however, specialty-specific usage or patient satisfaction regarding synchronous or "real-time" telehealth at the regional military hospital level has not been described. METHODS: A retrospective review of synchronous telehealth encounters and patient satisfaction surveys from Landstuhl Regional Medical Center (LRMC) specialty clinics engaging in synchronous telehealth to regional Army Health Clinics (AHCs) during 2015 was conducted. RESULTS: 2,354 synchronous telehealth encounters were conducted for 1,886 unique patients. The majority of patients were adults (88.4%), male (71.1%), and active duty (75%). Twelve distinct distant locations were engaged in synchronous telehealth with 31 distinct specialties. 1,552 (62.5%) patients had a single telehealth visit with a median (range) of 1 (1-7) visit. Median (range) visits per specialty was 25 (1-582) with sleep medicine (24.7%), general surgery (13.1%), nutrition (9.7%), orthopedics (9.0%), and ENT (6.0%) representing 62.5% of all encounters. Median (range) number of encounters per location was 146 (13-685). Surgical specialties preferentially evaluated patients at locations with a specialty-trained presenter (p < 0.001), whereas nonsurgical specialties did not (p > 0.05). Fifteen percent (372/2,354) of patients completed an anonymous survey at the time of their telehealth visit. Mean responses on a 5-point Likert scale ranging from "strongly disagree" (1) to "strongly agree" (5) was 4.8 +/- 0.5 for both recommending and being satisfied with their telehealth visit. The 2,354 telehealth visits represented 2.4% (2,354/100,094) of all visits to LRMC during 2015 for 25 of 31 specialties whose total outpatient visits could be determined. CONCLUSION: Clinic utilization varied between specialties as well as whether a specialty-trained patient presenter was preferred. This robust multispecialty synchronous telehealth experience provides insight into both specialty-specific utilization and patient satisfaction which may aid regional medical centers recognizing avenues for specialty-specific telehealth initiatives. PMID- 28810959 TI - A Retrospective Review of Clinical Admissions to Afghan National Security Forces Health Care Institutions. AB - BACKGROUND: Few published reports have examined the numbers of civilian injuries treated at Military Treatment Facilities in the Afghan Theater of Operations. However, review of Department of Defense Trauma Registry revealed a persistent percentage of civilians treated by NATO, and this study compares the proportion of civilians served by Afghan and Coalition military hospitals between 2009 and 2013. METHODS: A retrospective review of records from Department of Defense trauma Registry for Coalition data, and Afghan data from the Office of the Inspector General. We assessed changes in the proportion of civilians served between 2009 and 2013 at Afghan and Coalition hospitals. RESULTS: There was a significant percentage (>=21.55%) of civilians served at both Afghan and Coalition hospitals. Although the total population of Afghan Nationals treated remained steady, the number of total civilians decreased over this time period. To account for this, the percentage of military personnel increased at Afghan military hospitals. In Coalition hospitals, the civilian population increased between 2009 and 2011 and then decreased between 2011 and 2013. CONCLUSIONS: For all hospitals, whether Afghan or Coalition hospitals, there was a persistent level of civilian admissions. A downward trend for civilian patients in the Coalition hospitals and a similar increase in Afghan hospitals was expected. However, the numbers for Afghan hospitals instead showed a downward trend, potentially from the loss of logistical assistance provided by Coalition forces in transferring patients to Afghan hospitals. As evidenced by our data, future missions should plan to provide care for this civilian population, by allocating funding and appropriately training personnel. Additionally, logistical concerns of transferring to host-nation facilities and training host-nation providers will require foresight, planning, and diplomatic overtures, not always included in tactical decision-making. PMID- 28810960 TI - Talk to the Hand: U.S. Army Biophysical Testing. AB - BACKGROUND: Many people are unaware of the science underlying the biophysical properties of Soldier clothing and personal protective equipment, yet there is a well-refined biomedical methodology initiated by Army physiologists in World War II. This involves a methodical progression of systematic material testing technologies, computer modeling, and human testing that enables more efficient development and rapid evaluation of new concepts for Soldier health and performance. Sophisticated manikins that sweat and move are a central part of this testing continuum. This report briefly summarizes the evolution and use of one specialized form of the manikin technologies, the thermal hand model, and its use in research on Soldier hand-wear items that sustain dexterity and protect the hand in extreme environments. METHODS: Thermal manikin testing methodologies were developed to provide an efficient and consistent analytical tool for the rapid evaluation of new clothing concepts. These methods have been upgraded since the original World War II and Korean War eras to include articulation and sweating capabilities, as characterized and illustrated in this article. The earlier "retired" versions of thermal hand models have now been transferred to the National Museum of Health and Science. FINDINGS: The biophysical values from manikin testing are critical inputs to the U.S. Army Research Institute of Environmental Medicine mathematical models that provide predictions of soldier comfort, duration of exposure before loss of manual dexterity, and time to significant risk of freezing (skin temperature <-1 degrees C) and nonfreezing cold injuries (skin temperature <5 degrees C). The greater thickness of better insulated handwear reduces dexterity and also increases surface area which makes added insulation increasingly less effective in retaining heat. Measurements of both thermal resistance (insulation) and evaporative resistance (permeability) collectively characterize the biophysical properties and enable mathematical modeling of the human thermophysiological responses. This information can help guide the hand-wear development and selection process which often requires trade offs between factors such as material, cost, and sizing. IMPACT: Soldier hands provide fine motor dexterity in tactical functions, ranging from pulling a trigger to pulling a parachute ripcord; thus, protecting hand function is critical to soldier readiness. Also, the importance of protection against nonbattle cold injuries was highlighted during World War II in northern Europe, in the Aleutian Islands, and later in Korea. The U.S. Army has been on the forefront of the biophysical analysis of clothing including gloves since environmental research was established at the Armored Medical Research Laboratory and Climatic Research Laboratory during World War II. U.S. Army Research Institute of Environmental Medicine does not make the equipment but works with their Natick Soldier Research, Development, and Engineering Center partners to make the equipment better. PMID- 28810961 TI - Resuscitation of Hypotensive Traumatic Brain Injured Animals With Spray-Dried Plasma Does Not Adversely Alter Physiology and Improves Blood-Brain Barrier Function. AB - INTRODUCTION: According to the Defense and Veterans Brain Injury Center and the Armed Forces Health Surveillance Center, the number of soldiers who have sustained a traumatic brain injury (TBI) has risen dramatically over the past decade. Studies have shown that brain damage can be exacerbated if blood loss occurs (often occurring in polytrauma). As blood supply is critical for brain function and survival, TBI patients must be properly resuscitated to maintain blood volume, blood pressure, and cerebral perfusion. Recent studies have suggested that blood loss can damage the vascular endothelium and enhance blood brain barrier (BBB) permeability. Brain endothelial cells and the tight junctions between them are key structural components of the BBB. As the BBB is critical for isolating the brain from potential pathogens and for regulating the influx of molecules into the brain, evaluation of resuscitation fluids for their efficacy to improve BBB function has clinical relevance. Although whole blood and fresh frozen plasma (FFP) contain the essential coagulation factors, ions, and other factors, the transport and storage of these products in remote, austere environments can be challenging. The use of spray-dried plasma (SDP) has several advantages including storage at ambient temperature, can be readily reconstituted before use, and infectious materials can be inactivated during the drying process. In this study, we compared FFP and SDP for their effects on blood pressure, cerebral blood flow, BBB integrity, and markers of endothelial cells and tight junction proteins, in TBI animals with blood loss. MATERIALS AND METHODS: All procedures were reviewed and approved by the UTHealth animal welfare committee. Sprague Dawley rats received controlled cortical impact brain injury followed by removal of 25% blood volume. Animals were resuscitated 40 minutes later with either FFP or concentrated SDP (Resusix) Heart rate and blood pressure were monitored continuously using catheters implanted into the femoral artery. Cerebral perfusion was assessed using a scanning laser Doppler device. Twenty four hours after the injury and resuscitation with either FFP or SDP, BBB integrity were monitored by measuring the amount of Evans Blue dye in the injured brain following its intravenous administration. As this dye is excluded from the uninjured brain, its presence in the injured brain is an indicator of BBB breakdown. In addition, von Willebrand Factor immunohistochemistry was used to examine endothelial cell loss, whereas claudin-5 immunohistochemistry was used to assess the loss of tight junctions, in FFP- and SDP-resuscitated TBI animals. RESULTS: Our results show that post-TBI resuscitation with FFP and SDP had similar influences on cardiovascular physiology and cerebral perfusion. Resuscitation with SDP after TBI was found to decrease BBB permeability as indicated by reduced Evans Blue dye extravasation, and increased levels of von Willebrand Factor and claudin-5, as compared to resuscitation with FFP. CONCLUSIONS: These preclinical results show that resuscitation with SDP may be superior to FFP, and support the further evaluation of this product as a resuscitation fluid for polytrauma patients with TBI. PMID- 28810962 TI - Association Between Alcohol Craving and Health-Related Quality of Life Among Veterans With Co-occurring Conditions. AB - BACKGROUND: Probable alcohol use disorder (AUD), mental health disorders (MHDs), and mild traumatic brain injury (mTBI) are endemic among U.S. Veterans of the recent conflicts in Iraq and Afghanistan. Previous research demonstrates that recent Veterans with AUD and MHD both with and without mTBI (MHD +/- mTBI) self report higher alcohol craving levels relative to Veterans with AUD only. Since it is unknown if alcohol craving negatively impacts health-related quality of life (HRQOL), the purpose of this study is to identify and describe the relationship between alcohol craving and HRQOL for recent Veterans with AUD alone and those with AUD and co-occurring conditions. METHODS: This cross-sectional study included Penn Alcohol Craving Scale (PACS) and Veterans RAND 36 Item Health Survey mental and physical component score data collected among recent Veterans with AUD (N = 29, n = 27 males): 14 combat controls, 15 MHD +/- mTBI. The Alcohol Use Disorder Identification Test, consumption questions determined AUD classification. That is only Veterans scoring a 4 or above for males and a 3 or above for females on the Alcohol Use Disorder Identification Test, consumption questions were included in this study. Associations between alcohol craving and HRQOL were examined using correlations and regression models. RESULTS: There was a significant negative linear relationship between PACS and mental component score (p < 0.05) that did not significantly differ between groups. There was a significant negative curvilinear relationship between PACS and physical component score with a significant group effect. DISCUSSION: Greater alcohol craving was associated with poorer mental HRQOL. Physical HRQOL was also significantly associated with alcohol craving. These relationships have important implications for clinical assessment and treatment among people with AUD. These findings suggest that alcohol craving is an important symptom of AUD for clinicians to assess and focus their treatment upon because it may negatively impact HRQOL. PMID- 28810963 TI - Treating Decompression Sickness: Military Flight Simulation Site-Community Hospital Partnership. AB - BACKGROUND: High-altitude flight simulation familiarizes military trainees with the symptoms of hypoxia to prepare them for emergency situations. Decompression sickness (DCS) can occur as a result of these simulations. In cases when ground level supplemental oxygen does not resolve symptoms, hyperbaric oxygen (HBO) therapy is indicated. Many military hyperbaric chambers have been closed because of cost reductions, necessitating partnerships with community hospitals to ensure access to treatment. MATERIALS AND METHODS: This article describes the unique arrangement between a community hospital in Colorado and a military training site to treat DCS cases emergently. We gathered cost data from the community hospital to estimate and compare the cost of providing HBO therapy in the hospital versus a standalone chamber similar to the former military hyperbaric chamber. RESULTS: Since the closure of the military hyperbaric chamber, the community hospital treated an estimated 50 patients with DCS requiring HBO therapy attributed to high-altitude flight simulation between October 2003 and April 2015. Cost to the institution providing HBO treatment varies widely on the basis of patient volume. Assuming a volume of five treatments, per-treatment cost at a standalone center is $95,380. In contrast, per-treatment cost at the hospital assuming a volume of 1,000 treatments commensurate with the hospital's ability to bill for other services is $698 per treatment. CONCLUSION: The cost analysis demonstrates that the per-treatment cost of operating a standalone HBO therapy center may be greater than 100 times that of operating a center at a community hospital, suggesting the arrangement is beneficial to the military. PMID- 28810964 TI - A Study on the Tactical Safety of Endotracheal Intubation Under Darkness. AB - OBJECTIVE: Strict blackout discipline is extremely important for all military units. To be able to effectively determine wound characteristics and perform the necessary interventions at nighttime, vision and light restrictions can be mitigated through the use of tactical night vision goggles (NVGs). The lamp of the classical laryngoscope (CL) can be seen with the naked eye; infrared light, on the other hand, cannot be perceived without the use of NVGs. The aim of the study is to evaluate the safety of endotracheal intubation (ETI) procedures in the dark under tactically safe conditions with modified laryngoscope (ML) model. METHODS: We developed an ML model by changing the standard lamp on a CL with an infrared light-emitting diode lamp to obtain a tool which can be used to perform ETI under night conditions in combination with NVGs. We first evaluated the safety of ETI procedures in prehospital conditions under darkness by using both the CL and the ML for the study, and then researched the procedures and methods by which ETI procedure could be performed in the dark under tactically safe conditions. In addition, to better ensure light discipline in the field of combat, we also researched the benefits, from a light discipline standpoint, of using the poncho liner (PL) and of taking advantage of the oropharyngeal region during ETIs performed by opening the laryngoscope blades directly in the mouth and using a cover. During the ETI procedures performed on the field, two experienced combatant staff simulated the enemy by determining whether the light from the two different types of laryngoscope could be seen at 100-m intervals up to 1,500 m. RESULTS: In all scenarios, performing observations with an NVG was more advantageous for the enemy than with the naked eye. The best measure that can be taken against this threat by the paramedic is to ensure tactical safety by having an ML and by opening the ML inside the mouth with the aid of a PL. The findings of the study are likely to shed light on the tactical safety of ETI performed with NVGs under darkness. CONCLUSION: Considering this finding, we still strongly recommend that it would be relatively safer to open the ML blade inside the mouth and to perform the procedures under a PL. In chaotic environments where it might become necessary to provide civilian health services for humanitarian aid purposes (Red Crescent, Red Cross, etc.) without NVGs, we believe that it would be relatively safer to open the CL blade inside the mouth and to perform the procedures under a PL. PMID- 28810965 TI - The Benefits and Risks of Energy Drinks in Young Adults and Military Service Members. AB - INTRODUCTION: Energy drinks (EDs) have become an integral part of the young adult, athletic, and military culture. Many athletes are convinced that EDs enhance performance, and service members as well as college students frequently use EDs as stimulants to counter sleep deprivation, or to improve academic performance. However, concerns have been raised by some military leaders about potential adverse effects of EDs. MATERIALS AND METHODS: A needs assessment survey of a convenience sample of military health care providers was conducted and identified EDs as a top knowledge need for those providers working in the area of traumatic brain injury (TBI). The instrument demonstrated high interitem consistency (Cronbach's alpha > .80). To further explore the state of knowledge on EDs, and to prompt further discussion of ED use and how it may related to military treatment protocols and supporting educational products, we conducted a literature review of English language publications listed in the National Library of Medicine using the search term "energy drinks" and published during the last 5 years to determine what is known about EDs in terms of their potential benefits and health risks. RESULTS: The active ingredients in most EDs are caffeine, and to a lesser extent taurine and sugars. Several reports suggest that the combination of these ingredients is more active than the caffeine alone. Despite the positive attributes of EDs, there are increasing reports of serious and potentially life-threatening side effects. Most recently there also has been a dramatic increase in the use of ED/alcohol combination drinks, and there are preliminary studies that suggest important adverse effects with this combination. A 2013 National Institutes of Health expert workshop concluded that more clinical studies are needed to clearly define the health risks associated with ED use. CONCLUSION: The needs assessment points to a desire for more ED knowledge of health providers working with TBI patients. A few key themes emerged from the exploratory literature review that can be taken into consideration when educating health providers and delivering knowledge-based resources. Adverse effects of EDs are most closely associated with the dose of caffeine consumed. In general, the combination of ED with alcohol should be avoided because the ED can mask the level of intoxication, and the combination may be associated with increased risk taking behavior. Overall, the risks and benefits of EDs remain controversial and good-quality long-term clinical trials are needed to inform policymaking, regulation, and the development of prevention and treatment resources. PMID- 28810966 TI - The Importance of Medical Readiness Training Exercises: Maintaining Medical Readiness in a Low-Volume Combat Casualty Flow Era. AB - INTRODUCTION: Ringed external fixation has demonstrated promising results in the management of severe combat-related extremity injuries. The purpose of this study was to identify and compare rates of wartime-related surgical cases at times of high and low casualty time periods, and then compare these case numbers with those performed during a 2-week Medical Readiness Training Exercise (MEDRETE) in Honduras. MATERIALS AND METHODS: A retrospective review was performed of patients treated at a single Military Treatment Facility with definitive ringed external fixators during a 2-year period of high-volume combat casualty flow (January 2009 December 2010) and a subsequent 2-year period of low-volume combat casualty flow (January 2013-December 2014). These data were then compared with cases performed over a 2-week period during a MEDRETE in 2011 to Honduras. RESULTS: Sixty-one cases were identified as having definitive treatment using ringed external fixation at the Military Treatment Facility during the high- and low-volume eras. During the high-volume era, 47 ringed external fixators were used as a definitive treatment. During the low-volume era, only 14 of the definitive ringed external fixation were identified. Of the 32 total cases performed during the 2-week MEDRETE to Honduras, 11 cases of definitive ringed external fixator placement were performed. This accounted for 34.4% of all cases performed during this 2 week period. CONCLUSION: Appropriately planned MEDRETEs can provide a concentrated case volume to allow maintenance of complex surgical skills related to the management of severe combat-related extremity injuries. These training exercises will be vital to maintain surgical skills during a low-volume combat casualty flow era. PMID- 28810967 TI - Improving Awareness of Behavioral Health Readiness. AB - INTRODUCTION: Readiness for worldwide deployments as force structure decreases is of vital importance to our military. Advances in access and efforts to decrease stigma for behavioral health (BH) treatment has impacted unit readiness levels. However, concern exists that there are still a significant number of service members with behavioral health conditions who are unable to deploy. This article outlines the current state of behavioral health readiness in one U.S. Army Division and provides a programmatic review of a systems based initiative, the Behavioral Health Readiness Tool (BHRT), designed to enhance awareness of current levels. METHODS: BHRT was constructed in August 2015 and implemented in September 2015 by Unit Behavioral Health Officers. Current duty limitation profiles were reconciled with behavioral health utilization and pharmacy prescription data. Results were recorded for four enduring brigade combat teams over 7 months and reported to senior leadership on a monthly basis. A program review was conducted in April 2016 to determine whether the desired effect was occurring. RESULTS: An approximate 1% of the Division's population (100 per 10,000 soldiers) with a nondeployable behavioral health condition was found to be lacking documentation (profile) of the condition. If substance abuse was included, the total increased to a conservative estimate of 1.5%. On the basis of a limited pharmacologic review alone, an additional 2% to 3% of Division soldiers with minor behavioral conditions were also lacking a profile. CONCLUSIONS: The BHRT initiative was successful at improving behavioral health readiness by improving the documentation of nondeployable behavioral health conditions, fostering communication between parallel behavioral health services, increasing the visibility of Commanders to at-risk soldiers, and enhancing Commanders' abilities to provide for the health and welfare of their soldiers. PMID- 28810968 TI - Self-Management Strategies for Stress and Anxiety Used by Nontreatment Seeking Veteran Primary Care Patients. AB - INTRODUCTION: One of the most common reasons individuals do not seek mental health treatment is a preference to manage emotional concerns on their own. Self management refers to the strategies that individuals use on their own (i.e., without professional guidance) to manage symptoms. Little research has examined self-management for anxiety despite its potential utility as the first step in a stepped care approach to primary care. The objectives of this study were to describe patients' anxiety self-management strategies, identify which types were perceived to be effective, and explore potential correlates. MATERIALS AND METHODS: This was an exploratory descriptive study (N = 182) of nontreatment seeking Veterans Health Administration primary care patients (M = 58.3 years of age, SD = 14.9) who reported current anxiety symptoms (>=8 on Generalized Anxiety Disorder-7). The Institutional Review Board approved the study, and all participants provided informed consent. We assessed self-management strategies, anxiety and depression symptoms, and past-year treatment via telephone. Two independent raters coded strategies into 1 of 7 categories (kappa = 0.85) and 23 subcategories (kappa M = 0.82, SD = 0.16). RESULTS: Participants reported nearly universal (98%) use of self-management, with an average of 2.96 (SD = 1.2) strategies used in the past 3 months, and 91% of all strategies perceived as effective. Self-care (37.0%), cognitive (15.8%), and avoidance (15.1%) strategies were reported most commonly; the most prevalent subcategories were exercise (11.0% of all strategies), redirecting thoughts (9.1%), and family/friends (8.1%). Age and depression screen status were associated with self-management strategy use. CONCLUSION: Our results demonstrate the ubiquity and high perceived effectiveness of self-management for anxiety among Veteran primary care patients. Although avoidance strategies were fairly common, self-care strategies, particularly exercising, and cognitive strategies, such as redirecting thoughts, were most prevalent in this sample. Strengths of the study include its novelty, our sample of non-treatment seeking Veteran primary care patients with current symptoms, and the open-ended format of the strategies questions. Limitations include reliance on self-report data, dichotomous response options for the perceived effectiveness item, limited number of potential correlates, and sampling from a single medical center. Overall, this research highlights the opportunity that health care providers have to engage primary care patients around self-management to determine what strategies they are using and how effective those strategies may be. Future directions include identification of the most effective and feasible self-management strategies for anxiety to facilitate promotion of evidence-based self-management among primary care patients. PMID- 28810969 TI - A Review of the Effectiveness of a Combat and Operational Stress Control Restoration Center in Afghanistan. AB - BACKGROUND: The management of Combat and Operational Stress Reactions (COSR) within an operational environment is a multidimensional process. The aim is to help prevent behavioral health problems, preserve combat power, and increase return to duty rates for combat stress related casualties. In some COSR cases, enhanced services are required and the Combat and Operational Stress Control (COSC) Clinic refers Service Members (SMs) to the Freedom Restoration Clinic (FRC). The purpose was to describe a deployed restoration center in Afghanistan and examine the long-term effectiveness of those services. METHODS: The data analyzed were obtained by a retrospective clinical records review from the participants' responses to the Outcome Questionnaire-45.2 (OQ-45.2) and a 30-Day Post-Restoration Program Survey created by the occupational therapist. The OQ 45.2 was administered pretreatment and immediately post-treatment. In addition, the OQ-45.2 and 30-Day Post-Restoration Program Survey was sent electronically by secure e-mail to each participant 30 days after treatment. These outcome measures were part of the standard operating procedures and were ongoing for the duration of the FRC restoration program. Descriptive statistics and frequencies were computed to describe participant characteristics. Paired t-tests were used to compare the means of the OQ45.2 total and subscale scores at pretreatment versus post-treatment and post-treatment versus 30-day follow-up. FINDINGS: There were 37 participants with an average age of 29 years, primarily Army (81.1%), served in combat-support roles (75.6%), and reported no exposure to combat (89.2%). The results showed a statistically significant decrease (p < 0.001) in OQ-45.2 scores from pre to post for the total score and for each subscale. There was no significant difference in means when comparing post versus 30 days. Lastly, the top five utilized classes were anger management (78%), goal setting (76%), resiliency (76%), stress management (76%), and positive thinking (76%); 81% of SMs reported that they are almost always or sometimes using the lessons learned from the FRC. DISCUSSION: This performance improvement project described an occupational therapist's role within a COSC restoration center and examined the effectiveness of the FRC program. There were several limitations: no control/comparison groups, use of only one clinical assessment tool, and a short follow-up. This performance improvement evaluation provides some empirical support for the utility of the COSC FRC program in reducing psychological distress in SM in a deployed environment. PMID- 28810970 TI - Completion of a Veteran-Focused Civic Service Program Improves Health and Psychosocial Outcomes in Iraq and Afghanistan Veterans With a History of Traumatic Brain Injury. AB - INTRODUCTION: Volunteering as a health promotion intervention is positively related to improved health and well-being in civilians and older adults. Yet, the impacts of participating in a community-based volunteering program on returning military veterans have not been studied, nor have the outcomes for veterans who have experienced a traumatic brain injury (TBI). MATERIALS AND METHODS: This observational, pre-post survey examines health, psychological, and social outcomes from a cohort of post-9/11/01 veterans with (N = 67) and without a reported TBI history (N = 273) who completed a 6-month, 20-hour per week veteran focused civic service program. This study was approved by the Saint Louis University Institutional Review Board. RESULTS: Veterans with a TBI history who completed the 6-month civic service program conducted by a veteran-focused national nonprofit organization showed significant pre-post improvement (p < 0.05) in overall health, decreased post-traumatic stress disorder (PTSD) symptoms, increased perceived self-efficacy, decreased feelings of isolation and loneliness, and increased perceived availability of social support. These significant findings were not due to participants seeking external help for emotional problems. Out of four aspects of PTSD symptomatology assessed, "feeling numb or detached from others, activities, or surroundings" most accounted for the decrease in PTSD scores. Given this and taken together with the significant decrease in social isolation and loneliness and the social nature of the program, we posit that decreased social isolation and loneliness is the primary driver of the improved psychological and social outcomes documented here. Finally, pre-post change scores did not differ significantly between veterans with and without a TBI, indicating that TBI history did not hinder the ability to benefit from this program. CONCLUSION: Completion of this civic service program positively impacted veterans with TBI, especially on psychological and social outcomes important to recovery and life satisfaction after TBI. Civic service may provide an innovative approach to promoting wellness in returning veterans with a TBI. Results of this study provide preliminary evidence that civic service decreases social isolation and loneliness in veterans with a reported TBI history. Given our findings, volunteering may prevent against social isolation and be promotional of perceived social support in veterans with TBI. PMID- 28810971 TI - Effect of Mixed Basic Military Training on the Physical Fitness of Male and Female Soldiers. AB - INTRODUCTION: Mixed gender basic military training (BMT) is adopted to integrate the female South African soldier into the military. This study aimed to assess gender differences before, during (12 weeks), and after a 20-week mixed BMT course and determine if BMT significantly reduced these differences. METHODS: A total of 186 soldiers (114 male: mean age = 21.0 +/- 1.1 year; 72 female: mean age = 20.5 +/- 1.2 year) completed the BMT course and all anthropometric, physical fitness, explosive power, and hand grip strength measurements. Repeated measures analysis of variance was used to model BMT data with main effects for gender comparison between males and females, and time main effect for evaluation of differences between weeks 1, 12, and 20 of BMT, as well as an interaction effect for differences in changes over time for males and females. Alpha was set at alpha <=0.05. RESULTS: Male soldiers were significantly taller (p < 0.001) and scored better in all measurements at the start of BMT, differences ranged from 1.6% to 50% between genders. Differences narrowed by up to 18.5% in aerobic, push up, abdominal measurements, and to 4.6% in the South African National Defense Force fitness test. Differences in power output and hand grip strength remained unchanged. CONCLUSION: Large initial anthropometrical and physical fitness differences decreased but were still obvious at the end of BMT. BMT should bridge the physical gap between male and female soldiers to ensure they can all perform the same duties. The enforcing of equal minimum physical fitness requirements for acceptance into BMT; conditional acceptance into the military subject to the successful completion of a bridging course aimed at improving physical fitness in individuals who do not meet the minimum physical fitness requirements for acceptance; and developing a cyclic physical training program with different entry points, dependent on initial physical performance at the start of BMT, ensuring adequate progression and overload for all soldiers are possible avenues to explore to achieve this goal. PMID- 28810972 TI - When Military Fitness Standards No Longer Apply: The High Prevalence of Metabolic Syndrome in Recent Air Force Retirees. AB - BACKGROUND: Metabolic syndrome (MetS) is strongly associated with cardiovascular disease. With MetS prevalence rates increasing in the U.S. population, prevention efforts have largely focused on diet and exercise interventions. Before retirement, military service members have met fitness requirements for at least 20 years, and have lower MetS rates compared to age-matched U.S. population controls (23.4% vs. 39.0%), which suggests a protective effect of the lifestyle associated with military service. However, MetS rates in military retirees have not been previously reported, so it is unknown whether this protective effect extends beyond military service. The purpose of this study was to examine the prevalence of MetS and individual diagnostic criteria in a population of recent U.S. Air Force (USAF) retirees. METHODS: We obtained institutional review board approval for all participating sites at Wilford Hall Ambulatory Surgical Center. From December 2011 to May 2013, USAF retirees within 8 years of their date of retirement were recruited at five USAF bases. Consenting subjects underwent examination and laboratory studies to assess the five diagnostic criteria measures for MetS. We used binary logistic regression to examine the relationship between various factors and the presence of MetS. RESULTS: The study population (n = 381) was primarily male (81.9%), enlisted (71.1%) and had a mean age of 48.2 years. When applying the American Heart Association MetS diagnostic criteria to this population, the MetS prevalence was 37.2%. When using alternative diagnostic criteria found in other published studies that did not include the use of cholesterol medications, the MetS prevalence was 33.6%. Per American Heart Association criteria, the prevalence of each of the MetS diagnostic criteria was as follows: central obesity, 39.8%; elevated fasting glucose, 32.4%; high blood pressure, 56.8%; low-high-density lipoproteins cholesterol, 33.3%; and elevated triglycerides, 42.7%. MetS was more common among males (odds ratio [OR] = 4.05; confidence interval [CI] = 1.94, 8.48) and enlisted (OR = 2.23; CI = 1.24, 4.01). It was also strongly associated with a history of participating in the Air Force Weight Management Program (OR = 2.82; CI = 1.41, 5.63) and increased weight since retirement (OR = 4.00; CI = 1.84, 8.70). However, the study did not find an association between the presence of MetS and time since retirement or self reported diet and exercise changes since retirement. CONCLUSIONS: The MetS prevalence among recent USAF retirees represents a shift from age-matched active duty rates toward higher rates described in the overall U.S. POPULATION: This finding suggests the protective health effects of fitness standards may be reduced shortly after retirement. This is true despite activities such as screening before and during military service and exposure to USAF health promotion efforts and fitness standards throughout a period of active duty service lasting at least 20 years. In general, military members should be counseled that on retirement, efforts to maintain a healthy weight have continued benefit and should not be forgotten. The risk of MetS after retirement is particularly increased for those identified as being overweight during their active duty careers. Interventions that prevent and reduce unhealthy weight gain may be an appropriate investment of resources and should be studied further. PMID- 28810973 TI - The Influence of Combat Experience on Psychologically Healthy Soldiers' Attentiveness to Environmental Threats. AB - INTRODUCTION: In contrast to previous research that has primarily examined how psychological disorders (e.g., post-traumatic stress disorder [PTSD], anxiety) are affected by and affect individuals' threat perceptions, this study examines the relationship between combat experience and threat-monitoring in psychologically healthy Soldiers. Existing research has established how prolonged or intense experiences with war-related stressors can lead individuals to undergo an unconscious fear-conditioning process that affects the circuitry of the prefrontal cortex, hippocampus, amygdala, and anterior cingulate cortex regions of the brain. We predict that the intensity of one's combat experience positively influences Soldiers' attention to environmental threats. MATERIALS AND METHODS: Participants included U. S. Army Soldiers with a score of 50 or below on the PTSD Checklist-Military Version. Participants completed the Combat Exposure Scale and the State-Trait Anxiety Inventory. The experimental prediction task we employed assesses the expectation of an intrusively loud white noise sound that occurred on three variable patterns in a pseudorandomized order. Each tone pattern was used 20 times over a total of 60 trials. The experimental prediction task included two neutral tones (700 and 1,300 Hz) that were presented in a repeated pattern along with a 100-dB burst of white noise (0.5-second duration). In each trial, one of three possible tone combinations was presented. To assess their attentiveness to threats, participants were asked to continuously rate their expectancy of the burst of white noise using a visual analogue scale (VAS) ranging from 0 to 100. VAS ratings were collected at controlled points throughout the task. RESULTS: None of the participants reported scores on any of the diagnostic surveys that met standards for clinical significance. A repeated measures analysis of variance was conducted to assess the overall effect of the three prediction conditions on participants' VAS ratings. There was a significant main effect for Combat Exposure Scale scores on VAS ratings [F(1, 27) = 5.19, p = 0.031], with high scorers demonstrating a generally higher expectancy of the white noise burst throughout the entire experimental sequence. Results suggest that within subclinical populations of Soldiers, the intensity of one's combat experience is positively associated with their attention to threats. CONCLUSION: These findings suggest that Soldiers who experience combat should be observed for signs of increased threat-attention bias, as this may indicate that their capacities for information processing, decision-making, and emotion regulation could be compromised. The positive relationship we observe between a level of combat experience and attentional biases toward threatening stimuli may also help to explain why these veterans engage in "externalizing" behaviors that are risky, aggressive, or violent as well as relational problems and antisocial behaviors that are reported in higher-than-average rates among these populations of Soldiers. Acknowledging that increased threat attention may be a preclinical indication of developing PTSD or other related psychological conditions (e.g., depression, anxiety) should motivate clinicians to more actively diagnose and treat this condition. PMID- 28810974 TI - Factors Affecting Organizational Commitment in Navy Corpsmen. AB - BACKGROUND: Organizational commitment is a psychological state that has a strong impact on the likelihood that employees will remain with an organization. Among military personnel, organizational commitment is predictive of a number of important outcomes, including reenlistment intentions, job performance, morale, and perceived readiness. Because of the unique challenges and experiences associated with military service, it may be that organizational commitment is even more critical in the military than in civilian populations. Despite the essential role that they play in protecting the health of other service members, little is known about the factors that influence Navy Corpsmen's organizational commitment. This study investigated demographic and psychosocial factors that may be associated with organizational commitment among Corpsmen. METHODS: Surveys of organizational commitment and possible demographic and psychosocial correlates of organizational commitment were completed by 1,597 male, active duty Navy Corpsmen attending Field Medical Training Battalion-West, Camp Pendleton, California. Bivariate correlations and hierarchical multiple regression analyses were used to determine significant predictors of organizational commitment. FINDINGS: Of the 12 demographic and psychosocial factors examined, 6 factors emerged as significant predictors of organizational commitment in the final model: preservice motivation to be a Corpsman, positive perceptions of Corpsman training, confidence regarding promotions, occupational self-efficacy, social support for a Corpsman career, and lower depression. DISCUSSION/IMPACT/RECOMMENDATIONS: Importantly, a number of the factors that emerged as significant correlates of organizational commitment in this study are potentially modifiable. These factors include confidence regarding promotions, positive perceptions of Corpsman training, and occupational self-efficacy. It is recommended that military leaders and policy-makers take concrete steps to address these factors, thereby strengthening organizational commitment among Corpsmen. Further research is needed to identify ways in which organizational commitment could be strengthened among Corpsmen. PMID- 28810975 TI - Adaptation of Screening, Brief Intervention, Referral to Treatment to Active Duty Military Personnel in an Emergency Department: Findings From a Formative Research Study. AB - BACKGROUND: The transient nature of military life coupled with environmental and psychosocial stressors increase the risk for alcohol misuse and abuse among active duty (AD) military service members and recent epidemiological studies demonstrate high rates of heavy drinking among AD personnel. Over the past decade, Department of Defense health care systems have observed increases in the utilization of substance use services among military personnel demobilizing from Operation Enduring Freedom and Operation Iraqi Freedom. Given the high rates of heavy drinking and increased use of substance use services in this population of AD personnel, the purpose of this study was to investigate how to best translate and implement an effective alcohol abuse prevention intervention tool (screening, brief intervention, and referral to treatment [SBIRT]) used in civilian populations to a military emergency department (ED) setting. METHODS: We conducted focus groups with ED staff as well as short interviews with AD personnel at a Naval Medical Center in the southwestern United States to determine the suitability of SBIRT with military populations as well as how to best translate SBIRT to a military hospital setting. FINDINGS: Participants expressed support for utilizing civilian health educators to conduct the SBIRT intervention; however, many were concerned with issues of confidentiality and were skeptical of whether AD would speak truthfully about alcohol consumption. CONCLUSIONS: Results of this formative research study clearly indicate the implementation and translation of SBIRT into a military medical setting require attention to issues related to confidentiality, the veracity of alcohol reporting, as well as use of civilians over AD military personnel to deliver the SBIRT intervention. Furthermore, most participants expressed support for the SBIRT model and felt it could be implemented, with caveats, into a military health care setting such as an ED. PMID- 28810976 TI - Women's Health Knowledge and Skills Among Transitional Year Internship-Trained Military Medical Officers Serving as Independent Health Care Providers. AB - BACKGROUND: Women comprise 14.5% of active duty service members. Delivery of women's health services is a critical component to personal, medical, and mission readiness. Our objective was to evaluate the knowledge, skills, and practices pertaining to basic elements of women's/reproductive health issues among transitional internship-trained general medical officers in the Army, Navy, and Air Force. MATERIALS AND METHODS: This is a cross-sectional survey study of transitional internship-trained graduates from 2012 to 2015 who transitioned to an operational assignment as an independent provider after internship graduation. The study involved an anonymous 21-question survey evaluating aspects of knowledge and practice related to basic reproductive health care services (contraceptive provision, cervical cancer, and chlamydia screening). RESULTS: Thirty-four of 62 (55%) eligible physicians completed the survey. The majority (85%) of respondents were male; 71% practiced at troop or unit-based clinic outside a hospital setting. Among the respondents, 97% cared for female service members within their patient population; one respondent (3%) reported no female service members in their patient population. Most respondents (82%) reported provision of contraceptive services to female patients of reproductive age. The copper intrauterine device (IUD) was least comfortably discussed. Less than half of the respondents were trained to place either the copper or levonorgestrel IUD or the etonogestrel contraceptive implant. Seventy-six percent of respondents performed cervical cancer screening and 79% performed chlamydia screening in their female patient population. Among the respondents, 15% did not offer cervical cancer and 12% did not offer chlamydia screening in their practice. Eighty-eight percent of the respondents correctly identified the recommended age at which to begin cervical cancer screening and 64% correctly identified the aged based recommendation and interval to screen for chlamydia. CONCLUSION: Our survey conveyed that the majority of respondents were comfortable discussing self administered methods (combined contraceptives); fewer were comfortable discussing or had training to place the more efficacious, longer-acting methods. Although screening services specific to female health are offered, the uniform provision of these basic services appears to be inconsistent among our surveyed population of first-line health care providers. Our study identifies potential areas for refinement in transitional year medical training that could translate to enhanced female medical and mission readiness. PMID- 28810977 TI - Moving Beyond Accidental Leadership: A Graduate Medical Education Leadership Curriculum Needs Assessment. AB - BACKGROUND: Despite calls for greater physician leadership, few medical schools, and graduate medical education programs provide explicit training on the knowledge, skills, and attitudes necessary to be an effective physician leader. Rather, most leaders develop through what has been labeled "accidental leadership." A survey was conducted at Walter Reed to define the current status of leadership development and determine what learners and faculty perceived as key components of a leadership curriculum. METHODS: A branching survey was developed for residents and faculty to assess the perceived need for a graduate medical education leadership curriculum. The questionnaire was designed using survey best practices and established validity through subject matter expert reviews and cognitive interviewing. The survey instrument assessed the presence of a current leadership curriculum being conducted by each department, the perceived need for a leadership curriculum for physician leaders, the topics that needed to be included, and the format and timing of the curriculum. Administered using an online/web-based survey format, all 2,041 house staff and educators at Walter Reed were invited to participate in the survey. Descriptive statistics were conducted using SPSS (version 22). RESULTS: The survey response rate was 20.6% (421/2,041). Only 17% (63/266) of respondents stated that their program had a formal leadership curriculum. Trainees ranked their current leadership abilities as slightly better than moderately effective (3.22 on a 5-point effectiveness scale). Trainee and faculty availability were ranked as the most likely barrier to implementation. Topics considered significantly important (on a 5-point effectiveness scale) were conflict resolution (4.1), how to motivate a subordinate (4.0), and how to implement change (4.0). Respondents ranked the following strategies highest in perceived effectiveness on a 5-point scale (with 3 representing moderate effectiveness): leadership case studies (3.3) and small group exercises (3.2). Online power points were reported as only slightly effective (1.9). Free text comments suggest that incorporating current duties, a mentoring and coaching component, and project based would be valuable to the curriculum. DISCUSSION: Few training programs at Walter Reed have a dedicated leadership curriculum. The survey data provide important information for programs considering implementing a leadership development curriculum in terms of content and delivery. PMID- 28810978 TI - Factors Associated With Medical School Entrants' Interest in Military Financial Assistance in Exchange for a Service Obligation: The Michigan State University College of Human Medicine Cohort. AB - INTRODUCTION: The U.S. military offers comprehensive scholarships to medical students to help offset costs in exchange for either reserve or active duty service commitments. Our goal was to describe to what degree newly admitted students to Michigan State University's College of Human Medicine were aware of and interested in these opportunities. MATERIALS AND METHODS: We surveyed 176 newly admitted students at the beginning and immediately following a presentation on military medicine opportunities. We collected anonymous paper surveys from program attendees and entered the data into Stata v13.1. The project was submitted for institutional review board review and deemed to not involve human subjects. Tests of association were performed using Chi-square test of independence and Fisher's exact test where needed. RESULTS: Our cohort was 49% female, 51% male, and over 90% were less than 30 years of age. Only 14% reported having family involved in the military. Our results indicated that over 90% of students were aware of these programs but less than 3% took advantage of the offerings. Despite 65% reporting somewhat or significant concerns over debt, financial concerns were not statistically associated with scholarship interest level. Instead, having a family member in the military was the most significant positive predictor of interest (47% compared with 17%, p < 0.01). Among those expressing disinterest, 66% cited apprehension over control of their lives as their primary concern. CONCLUSION: Recruiters may wish to emphasize benefits of military service aside from financial support. Career vignettes and summaries may offer better insight into the service experience for those lacking familiarity thereby potentially increasing interest and applications. Focus groups with current scholarship awardees may inform recruitment strategies. PMID- 28810979 TI - Women Veterans, a Population at Risk for Fibromyalgia: The Associations Between Fibromyalgia, Symptoms, and Quality of Life. AB - BACKGROUND: The Institute of Federal Health Care recently published an executive summary from a round table discussion indicating that active duty and retired female military personnel are at high risk for adverse health outcomes unique to military service including complications related to post-traumatic stress disorder (PTSD), unreported sexual trauma, and musculoskeletal problems. In 2008, the Institute of Medicine began to review, evaluate, and summarize the literature on health outcomes in Gulf War-deployed and found sufficient evidence of a causal relationship with PTSD and suggestive evidence of an association with fibromyalgia (FM). This study examines the prevalence and impact of FM in women veterans and to explore the association between other comorbidities to improve risk differentiation for treatment and improve outcomes. METHODS: This study is designed as a nested, cross-sectional study within a larger project funded by the U.S. Army at the University of South Florida, College of Nursing entitled "Nursing Health Initiative for Empowering Women Veterans." A sample of 76 participants completed a battery of study instruments related to physical and psychological stressors. FINDINGS: Over half of the sample had a positive FM screening score (56.68%) although only 14.42% were deployed to the Middle East. More than 70% of participants reported harassment in life in the military and 32.9% reported sexual assault while in the military. Results of the 1-way analysis of variances find that there was a significant association of FM with the psychological symptoms of stress, depression, and PTSD. There was a significant association of FM with quality of life and sleep difficulty. DISCUSSION, IMPACT, AND RECOMMENDATIONS: The results from this pilot study suggest there is a significant relationship between FM and the psychological symptoms of depression and PTSD. Nearly two-thirds of these women screened positive for depressive symptoms and just over one-quarter of participants had symptoms indicative of PTSD. Only a small proportion of women veterans in this study were deployed (14.42%) and this suggests that a trigger or risk factor other than deployment or combat may contribute to the development of FM and mental health symptomology. To focus on the complex interrelationships between pain, fatigue, sleep, and depression, a follow-up study with a larger sample powered for more complex statistical analyses is warranted. Additional analyses in this study reveal that over half of women veterans who reported military sexual trauma (MST) while in the military, screened positive for FM. Although our analyses did not reveal there to be a significant effect between FM and MST, it should be considered as a potential risk factor for FM as MST can be a precursor for PTSD. Women veterans who present with FM should be screened for MST as sexual trauma may not be disclosed. Understanding how many women veterans are affected with FM and the relationship with PTSD, MST, stress, depression, and sleep can improve screening and treatment to improve quality of life. This will also inform decision-making about how best to design and implement interventions, programs, and policies. PMID- 28810980 TI - Risk Factors for Rhabdomyolysis in the U.S. Army. AB - : The standardized mortality rate of rhabdomyolysis (RM) in Active Duty U.S. Army Soldiers is considerably higher than in the civilian population. RM occurs when large amounts of intracellular contents from damaged skeletal muscle escape into circulation, leading to serious sequelae (e.g., acute renal failure, hyperkalemia, compartment syndrome). Extended physical exertion, especially in hot environments, and trauma can precipitate RM. The aim of this study was to identify RM risk factors among U.S. Active Duty Army (ADA) Soldiers. METHODS: This nested case-control study used data from the Total Army Injury and Health Outcomes Database (years 2004-2006) to examine RM among ADA male Soldiers. Demographic and occupational variables were identified as potential risk factors. Each RM case was age and date-matched to 4 controls. Adjusted odds ratios (OR) were computed using conditional logistic regression analyses. RESULTS: From years 2004 to 2006, 1,086 Soldiers (0.19%) met the study criteria for clinically diagnosed RM. Three variables were found to increase the odds of acquiring RM: (1) prior heat stroke, OR 4.95 (95% confidence interval [CI] 1.1-21.7); (2) self reported Black race, OR 2.56 (95% CI 2.2-3.0); and (3) length of service (0-90 days), OR 2.05 (95% CI 1.6-2.7). CONCLUSION: There is a substantially greater likelihood for male U.S. Army Soldiers to develop RM who: (1) have had a prior heat injury, (2) self-report in the Black racial category, and (3) who are within the initial 90 days of service. Greater awareness of the risk factors associated with RM may improve force health protection and readiness through targeted mitigation strategies. PMID- 28810981 TI - Thermoregulatory Response to Exercise After Exertional Heat Stroke. AB - BACKGROUND: After one episode of exertional heat stroke (EHS), risk factors must be identified to determine the potential for subsequent episodes. One of these risk factors, core body temperature (Tco) kinetics during strenuous exercise, may be a surrogate marker suggestive of impaired thermoregulation. This study aimed to determine the kinetics of increases in Tco among military subjects who had a history of EHS. METHODS: Forty subjects (38 males, mean age 28.4 +/- 4.9 years, mean body mass index 24.9 +/- 2.4) who had a history of EHS ran 8 km in full combat gear with continuous monitoring of Tco and heart rate. The run was a qualifying event for military service. Tco was assessed using an ingestible sensor (Cortemp HQ Inc., Palmetto, Florida). Maximum oxygen uptake (VO2max) was measured on the day before the run. FINDINGS: The mean performance time for the run was 44.6 +/- 6.6 minutes achieved under mild climatic conditions. No neurological impairment was observed. The mean maximum Tco was 39.9 +/- 0.5 degrees C. On the basis of Tco during the last 10 minutes of running, two Tco profiles were identified: increased Tco (Tco increase > 0.5 degrees C) and plateaued Tco. Neither profile depended on initial, mid-run, or maximal Tco, VO2max, speed running, body surface area or body fat mass. DISCUSSION: Subjects who had a history of EHS exhibited different Tco profiles at the end of an 8-km run. Laboratory studies will be necessary to identify the mechanisms underlying these profiles; future longitudinal studies can determine whether a Tco increase >0.5 degrees C during the last 10 minutes is a risk factor for EHS recurrence. PMID- 28810982 TI - Evaluation of the Validity and Response Burden of Patient Self-Report Measures of the Pain Assessment Screening Tool and Outcomes Registry (PASTOR). AB - BACKGROUND: In 2009, the Army Pain Management Task Force was chartered. On the basis of their findings, the Department of Defense recommended a comprehensive pain management strategy that included development of a standardized pain assessment system that would collect patient-reported outcomes data to inform the patient-provider clinical encounter. The result was the Pain Assessment Screening Tool and Outcomes Registry (PASTOR). The purpose of this study was to assess the validity and response burden of the patient-reported outcome measures in PASTOR. METHODS: Data for analyses were collected from 681 individuals who completed PASTOR at baseline and follow-up as part of their routine clinical care. The survey tool included self-report measures of pain severity and pain interference (measured using the National Institutes of Health Patient-Reported Outcome Measurement Information System [PROMIS] and the Defense and Veterans Pain Rating scale). PROMIS measures of pain correlates also were administered. Validation analyses included estimation of score associations among measures, comparison of scores of known groups, responsiveness, ceiling and floor effects, and response burden. RESULTS: Results of psychometric testing provided substantial evidence for the validity of PASTOR self-report measures in this population. Expected associations among scores largely supported the concurrent validity of the measures. Scores effectively distinguished among respondents on the basis of their self-reported impressions of general health. PROMIS measures were administered using computer adaptive testing and each, on average, required less than 1 minute to administer. Statistical and graphical analyses demonstrated the responsiveness of PASTOR measures over time. PMID- 28810983 TI - Evaluation of a Novel Field Expedient Musculoskeletal Readiness Screening Tool in an Army Basic Training Population. AB - BACKGROUND: Musculoskeletal injuries present a significant challenge to military readiness accounting for over 29% of ambulatory medical visits and 25 million limited duty days across the U.S. Army. Although U.S. Military Health Systems perform periodic general health and deployment assessments, there is no validated tool to determine when a service member is at increased risk of sustaining a musculoskeletal injury. METHOD: 292 U.S. Army basic training recruits completed a novel injury screening test called the Musculoskeletal Readiness Screening Tool (MRST). It consisted of six separate physical movements and asked one question regarding perceived risk of personal injury. The injury surveillance period covered the duration of the basic training program lasting from 9 to 20 weeks. An independent t test was performed to assess for differences in composite MRST scores between those who sustained an injury and those who did not. A Receiver Operator Characteristic curve analysis was completed to determine if an appropriate cutoff score existed to predict increased likelihood for sustaining an injury within this cohort. RESULTS: Our results indicate that the difference in mean composite score between injured (n = 143) and noninjured subjects fell just short of being significantly different (p = 0.053). The MRST is most specific with a cutoff score of 6 (out of a maximum score of 12) at 0.89 (95% confidence interval: 0.82, 0.93). Those scoring less than or equal to 6 on the screening tool were 2.05 times (95% confidence interval: 1.07, 3.9) as likely to sustain an injury as those scoring greater than 6. Additionally, the results indicate that the test can be applied to both male and female trainees, as scores were not significantly different between the sexes. CONCLUSION: The MRST shows potential as a tool for identifying service members at higher risk for sustaining a musculoskeletal injury. Further research is needed to assess the validity, reliability, and responsiveness of this novel screening tool. PMID- 28810984 TI - Impact of a 7-Day Field Training on Oral Health Condition in Japan Ground Self Defense Force Personnel. AB - INTRODUCTION: In the Japan Ground Self-Defense Force (JGSDF), personnel periodically perform intensive training that mimics the conditions seen in battle and during natural disasters. Military training involves intensive, stressful conditions, and changes in immune responses have been found in personnel following training. Good oral condition is important for military personnel to fulfill their duties; however, they have difficulty performing daily oral care under training conditions. In this study, we investigated the impact of a 7-day field training on the oral health status of JGSDF personnel by comparing their oral condition before and just after training. MATERIALS AND METHODS: The participants were 59 male and 3 female JGSDF personnel undergoing a 7-day field training. All personnel provided informed written consent to participate, and this study was approved by the ethics committee of the Kagoshima University Graduate School of Medical and Dental Sciences. Oral health behaviors before and during the training period were surveyed using a self-administered questionnaire. Dental caries was assessed before training in terms of decayed, missing and filled teeth (DMFT), and periodontal condition was examined before and immediately after training using the community periodontal index (CPI). The presence of eight species of bacteria in dental plaque, including commensal streptococci that are early colonizers on the tooth surface, cariogenic bacteria, and periodontopathic bacteria, was determined using real-time polymerase chain reaction. We also assessed antibacterial factors and a stress marker in saliva samples. Sample collection was performed before and just after training. In addition to difference analysis between groups, logistic regression analysis was performed to examine the association between each health behavior and periodontal deterioration. RESULTS: The frequency of toothbrushing decreased, and snacking increased during the training period. Thirty-five personnel (56.5%) showed an increase in individual CPI code, and 57 personnel (91.9%) showed deterioration in the CPI code in 1 or more sextants after training (Figure 1). Toothbrushing frequency was significantly associated with CPI deterioration; the odds ratio in subjects who did not brush their teeth was 7.51 compared to those who brushed at least once during the training period. Severe periodontal deterioration was observed in the high-DMFT group (Figure 2), and toothbrushing frequency during the training period decreased more in this group compared to the low-DMFT group. The percentages of Streptococcus sanguinis and Streptococcus gordonii increased significantly after the training period suggesting dental plaque maturation, and an increase in S. sanguinis was associated with toothbrushing frequency. The lactoferrin concentration in saliva increased significantly after training. CONCLUSIONS: We demonstrated periodontal deterioration in JGSDF personnel after a 7-day training. Behavioral changes, especially discontinuation of regular toothbrushing, fostered dental plaque maturation, resulting in inflammatory changes in participants' periodontal condition. The results indicate the importance of performing toothbrushing at least once over a 7-day training period for prevention of periodontal deterioration. The regimen could be applicable to evacuees from disasters because they are under conditions of stress that may limit oral hygiene activity. PMID- 28810985 TI - Multimedia Campaign Enhances Orthopaedic Patient Perceptions of Health Care Quality: A Prospective Analysis of Effect at a Military Treatment Facility. AB - BACKGROUND: The importance of patient satisfaction as a measure of quality has grown with initiatives intended to enhance demand for services, refocus reimbursement paradigms, encourage health care efficiencies, and ultimately improve clinical outcomes. The purpose of our performance improvement project was to (1) characterize the effect of a two-pronged multimedia initiative on patient perceptions of health care quality and satisfaction as assessed by the Army Provider Level Satisfaction Survey (APLSS) and (2) assess for differences in APLSS scores between the surgeons that did and did not participate in the program. METHODS: Baseline APLSS data for our Department of Orthopaedic Surgery were collected and subsequently compared to APLSS results 3 months after the implementation of a department-wide multimedia campaign. The multimedia initiative consisted of two concurrently implemented interventions to the orthopaedic surgery outpatient clinics. One intervention involved placing large framed posters about the orthopaedic clinic waiting areas on which were written, "We helped write the book," and included pictures of various orthopaedic textbooks of which attending surgeons and/or residents had contributed to as authors. The other intervention provided patients with surgeon "face sheets" upon arrival to their clinic appointments. These sheets included a picture of their attending surgeon, contact information for the surgeon's nurse care coordinator, and a brief biographical sketch of the surgeon's training, clinical interests and expertise, and other information at each surgeon's discretion. FINDINGS: Among APLSS survey results for the orthopaedic surgery clinic including all surgeons, significant increases were observed between baseline data and 3-month data for Top 1 and Top 2 responses to the questions, "How satisfied do you feel about your visit?" and "Did your surgeon listen to you carefully about your concerns and questions?" (p = 0.003 and p = 0.004, respectively). IMPACT: The implementation of a multimedia campaign resulted in significant improvements among indices of orthopaedic patient satisfaction. We believe this model could be used at other military or nonmilitary treatment facilities as a means to engender patients' familiarity with their surgeon and prompt an appreciation for his/her expertise and enhance overall patient perceptions of department-wide health care quality. PMID- 28810986 TI - Cancer Incidence Among Patients of the U.S. Veterans Affairs Health Care System: 2010 Update. AB - INTRODUCTION: Nearly 50,000 incident cancer cases are reported in Veterans Affairs (VA) Central Cancer Registry (VACCR) annually. This article provides an updated report of cancer incidence recorded in VACCR. MATERIALS AND METHODS: Data were obtained from VACCR for incident cancers diagnosed in the VA health care system, focusing on 2010 data. Cancer incidence among VA patients is described by anatomical site, sex, race, stage, and geographic location, and was compared to the general U.S. cancer population. RESULTS: In 2010, among 46,170 invasive cancers, 97% were diagnosed among men. Approximately 80% of newly diagnosed patients were white, 19% black, and less than 2% were other minority races. Median age at diagnosis was 65 years. The three most frequently diagnosed cancers among VA were prostate (29%), lung/bronchus (18%), and colon/rectum (8%). Melanoma and kidney/renal pelvis tied for fourth (4%), and urinary bladder tied for sixth with liver and intrahepatic bile duct (3.4%). Approximately 23% of prostate, 21% of lung/bronchus, and 31% of colon/rectum cancers were diagnosed with Stage I disease. The overall invasive cancer incidence rate among VA users was 505.8 per 100,000 person-years. CONCLUSIONS: Although the composition of the VA population is shifting and includes a larger number of women, registry data indicate that incident cancers in VA in 2010 were most similar to those observed among U.S. men. Consistent reporting of VACCR data is important to provide accurate estimates of VA cancer incidence. This information can be used to plan efforts to improve quality of cancer care and access to services. PMID- 28810987 TI - Deployment Length, Inflammatory Markers, and Ambulatory Blood Pressure in Military Couples. AB - INTRODUCTION: Changes in the frequency, duration, and nature of military deployments over the past 14 years have spurred efforts to understand the effects of deployment on the health of military service members and their spouses. However, few studies have examined the impact of deployments on health outcomes in both veterans and their partners. This study aims to examine the association between deployment length and health, including ambulatory blood pressure (BP) and stress-related markers of inflammation, in military veterans and their spouses. MATERIALS AND METHODS: This study includes 32 male veterans and 29 female civilian partners. Veterans reported about their deployment and military experiences, including deployment length, combat exposure, and post-traumatic stress disorder (PTSD) symptoms. Plasma measures of inflammatory markers, C reactive protein (CRP) and interleukin 6 (IL-6), were collected from veterans and spouses. Participants also completed 48 hours of BP monitoring for calculation of mean arterial pressure (MAP) during wakefulness and sleep, and sleep/wake MAP ratio, as an indicator BP nondipping. Regression models examined the association between deployment length and each outcome in the combined sample of veterans and their spouses, including tests of interactions between gender and deployment length, controlling for age, gender, waist circumference, current PTSD, and combat exposure. RESULTS: Longer deployment length was associated with higher CRP levels in veterans and their spouses, although this effect became nonsignificant when limiting analyses to individuals with CRP <=10 mg/L. There was a significant gender by deployment length interaction effect on MAP ratio, such that longer deployments were associated with higher MAP ratios in female spouses. There was no significant effect of combat exposure in these models. CONCLUSION: Longer deployments are associated with health-related markers in military veterans as well as their spouses. These results suggest the importance of monitoring health during and postdeployment, and of finding ways to mitigate the adverse impact of deployment on health in both members of military couples. PMID- 28810988 TI - Association Between Personal Protective Equipment Use and Injury Occurrence Among the Republic of Korea Armed Forces. AB - INTRODUCTION: Soldiers are at a higher risk of injury than people of other occupations. To date, no studies have examined the association between injury and personal protective equipment (PPE) use in the Republic of Korea (ROK) military. Thus, this study aimed to investigate possible associations between injury and PPE use in military personnel. In addition, we aimed to identify the possible interactions between injury and PPE use according to military personnel characteristics. MATERIALS AND METHODS: We used secondary data from the 2014-2015 Military Health Survey. To compare the average number of injuries according to the independent variables, we performed a t-test and analyses of variance. Additionally, statistical methods were used to compare injury incidence among PPE users and non-PPE users and, while controlling for variables including age, sex, education level, military service, and health-related characteristics were controlled. Additionally, subgroup analysis was performed for occupational variables. RESULTS: Among the 9,407 military personnel included in our study, 1,091 (11.6%) individuals had been injured in the past 12 months. For the 9,407 personnel, the average number of injuries was 0.17 +/- 0.64; among the participants with injuries, the average number of injuries was 1.49 +/- 1.25. Regression analysis revealed that personnel who did not routinely wear PPE were significantly associated with the number of injuries (relative risk [RR] = 1.13, p = 0.0138). A higher number of injuries occurred among individuals who were not wearing PPE, with a high possibility of an injury occurring because of their job characteristics (RR = 1.34, p <= 0.0001); however, participants in units with a high level of injury prevention efforts had a significantly lower number of injuries than those in units with moderate/low injury-prevention efforts (RR = 0.91, p = 0.0269). In addition, the practice of PPE use had a greater impact on officers than on personnel of other ranks (RR = 4.22, p <= 0.0001). CONCLUSION: The practice of PPE use is significantly and negatively associated with the number of injuries in soldiers. PMID- 28810989 TI - Comparison of Circumference Body Composition Measurements and Eight-Point Bioelectrical Impedance Analysis to Dual Energy X-Ray Absorptiometry to Measure Body Fat Percentage. AB - BACKGROUND: To compare the circumference measurement (CM) body composition method and 8-point segmental bioelectrical impedance analysis (DSM-BIA) to dual energy X ray absorptiometry (DEXA) in military members. OBJECTIVE: The objective was to compare three body composition methods. Our hypothesis was the CM is as accurate as DSM-BIA and DEXA in assessing body fat percentage (%BF). DESIGN: Cross sectional, observational study. PARTICIPANTS/SETTING: Healthy active duty military males and nonpregnant females. Seventy-six participants (mean age 35.0 +/- 9.7 years, mean body mass index 28.9 +/- 4.7 kg/m2), outpatient clinic setting was used. STATISTICAL ANALYSES: Agreement between DEXA and the other two methods was examined using an intraclass correlation coefficient (ICC) using the two-way random method with absolute agreement. Repeated measures analysis of covariance was used to examine the effect of gender and waist circumference on differences in %BF. RESULTS: The agreement of DSM-BIA with DEXA for females was ICC = 0.93 (95% confidence interval [CI]: 0.87-0.96) and for males, ICC = 0.89 (95% CI: 0.78-0.94). For the agreement of CM with DEXA, the ICC for females was 0.83 (95% CI: 0.71-0.91) and for males the ICC = 0.72 (95% CI: 0.49-0.85). For females with smaller waists (<81.3 cm), the DSM-BIA underestimated the DEXA measurement by a mean of 1.6% (95% CI: 0.5-2.6%). For males with larger waists (>=95.3 cm), the DSM-BIA overestimated the DEXA measurement by a mean of 2.6% (95% CI: 0.9-4.3%). For females with larger waists (>=81.3 cm), the CM overestimated the DEXA %BF by an average of 2.4% (95% CI: 0.7-4.1%). CONCLUSION: There was good agreement between the three methods assessed in this study. Both waist circumference and gender had an effect on the accuracy of the DSM-BIA and CM measurements. PMID- 28810990 TI - Gait and Functional Outcomes for Young, Active Males With Traumatic Unilateral Transfemoral Limb Loss. AB - OBJECTIVE: Altered body structures that occur with the loss of a lower limb can impact mobility and quality of life. Specifically, biomechanical changes that result from wearing a prosthesis have been associated with an increased risk of falls or joint degeneration, as well as increased energy demands. While previous studies describing these outcomes are typically limited by number of outcome measures and/or small, diverse patient groups, recent military conflicts present a unique opportunity to collect outcomes from a relatively homogenous, active patient population with limb loss. Thus, the objective of this study is to provide reference outcome measures on the basis of a large, relatively homogenous cohort of military personnel with transfemoral limb loss. METHODS: A retrospective review of biomechanical, physiological, functional, and subjective measures was completed for 67 male servicemembers who sustained an injury resulting in traumatic, transfemoral limb loss during recent conflicts. These individuals represent a defined cohort, capable of exhibiting improved clinical outcomes resulting from demographic characteristics and extensive rehabilitation. Biomechanical and physiological outcome measures for 76 uninjured male servicemembers are also provided to serve as normative reference for full return to function. Select biomechanical and physiological outcomes related to stability, overuse, and efficiency are discussed in the text, on the basis of relevance to clinical gait assessment, in addition to functional and subjective measures. RESULTS: In general, individuals with transfemoral limb loss exhibit decreased stability relative to uninjured individuals, noted by larger peak trunk velocity and step width variability; increased risk of low back and knee joint pain and/or degeneration, noted by larger trunk lateral flexion and bending moments, as well as larger vertical ground reaction force (vGRF) loading rates and impulses, respectively; and decreased efficiency during gait, noted by larger oxygen costs and leading limb mechanical work. CONCLUSION: Although the comprehensive set of measures presented here indicates overall reductions in biomechanical and functional performance with transfemoral limb loss compared to uninjured individuals, these reductions were relatively smaller than existing evidence among populations that are more diverse in age and activity level. Therefore, this data set may be used as benchmarks for young, active individuals with transfemoral limb loss, to assist with setting clinical goals, and to aid in the evaluation of new treatment techniques or interventions. These measures will also be particularly important for subsequent evaluations and longitudinal follow ups to determine the longer-term impact of transfemoral limb loss on this cohort. PMID- 28810991 TI - Posterior Cruciate Ligament Injuries Associated With Military Survival Swim Training. AB - OBJECTIVES: Posterior cruciate ligament (PCL) injuries are relatively common injuries associated with athletic activities and high-energy trauma. Posterolateral corner (PLC) injuries frequently accompany injury to the PCL. Diagnosis can be challenging and requires a comprehensive history and physical examination. Patients frequently report vague, nonspecific symptoms and the mechanism of injury is often useful in localizing injured structures. Two of the more common mechanisms for PCL injury include a direct blow to the proximal anterior tibia with the knee flexed, as well as a significant knee hyperextension injury. With a PCL tear, patients rarely describe an audible "pop" that is commonly reported in ACL injuries. On physical exam, a frequent finding in PCL tears is a loss of 10 to 20 degrees of knee flexion. Although the most common clinical tests for PCL tears include the posterior drawer test, the posterior sag sign, and the quadriceps active test, there is a lack of high-quality diagnostic accuracy studies. MATERIALS AND METHODS: Two cases of U.S. Military Academy Cadets who sustained PCL injuries while removing combat boots during military survival swim training are presented. The results of the clinical examination are accompanied by magnetic resonance imaging results and intraoperative arthroscopic images to highlight key findings. RESULTS: Both patients were evaluated and diagnosed with PCL injures within 10 days of their injuries. Each reported feeling/hearing a "pop," which is atypical in PCL tears. Both patients demonstrated a lack of active and passive knee flexion, which is a commonly reported impairment. One patient was managed nonsurgically with physical therapy and eventually returned to full duty without limitations 9 months after his injury. The other patient, who sustained a combined PCL-PLC injury, underwent a PCL reconstruction and PLC repair and reconstruction 8 weeks after his injury. He returned all training, with the exception of contact/collision sports, 9 months after surgery. Both patient's rehabilitation programs consisted of a progression of exercises to improve range of motion, muscle strength/endurance, motor control, and muscular power. CONCLUSION: Military and sports medicine professionals should be aware of the potential for PCL injury with this unusual, and previously unreported, mechanism of injury during survival swim training. Prompt diagnosis and appropriate treatment is essential to prevent long-term disability. PMID- 28810992 TI - Two New Effective Tourniquets for Potential Use in the Military Environment: A Serving Soldier Study. AB - BACKGROUND: Limb tourniquets have been used extensively during modern Middle Eastern conflicts. Despite its undeniable successes, the combat applied tourniquet (C-A-T) has some shortfalls, principally its inability to reliably control lower limb bleeding when applied to the mid-thigh. We tested two tourniquets which may represent an improvement to the combat applied tourniquet; the tactical mechanical tourniquet and the tactical pneumatic tourniquet. METHODS: We recruited 12 healthy service personnel and applied the tactical mechanical tourniquet and tactical pneumatic tourniquet to both lower limbs in a randomly generated sequence. Tourniquets were tightened until popliteal artery occlusion. This was measured via a SonoSite portable ultrasound machine by a single consultant vascular radiologist familiar with its use. A longitudinal view of the popliteal artery was obtained, and Doppler waveform monitored. The tourniquets were tightened around volunteers' mid-thigh by a second researcher accustomed with their use. Time to complete occlusion, number of windlass revolutions, and pain scores were collected by a third researcher. Non-normally distributed data are present as median (interquartile range). Ordinal nonparametric data are analysed by Mann-Whitney U testing. RESULTS: Participants had a median age of 32.5 (28-35). Both tourniquets demonstrated complete occlusion of the popliteal artery in all limbs (n = 24). The mechanical tourniquet achieved arterial occlusion after a median of 3.8 (3-4) turns, and 16 (12-20) seconds. No participants dropped out of the study because of intolerable pain, or any cause. Median pain scores for the mechanical tourniquets were 4.5 (3 7) (maximum pain) and 4.0 (2-7) (pain when locked). Median pain scores for the pneumatic tourniquet were 5 (2-6) (maximum pain) and 5 (2-6) (pain when fully applied). There was no statistical difference in maximum pain scores between the tactical mechanical tourniquet and the tactical pneumatic tourniquet (p = 0.75). No participant had any tourniquet applied for longer than 80 seconds. CONCLUSION: Both tourniquets completely occluded the popliteal artery in all participants within an acceptable pain threshold. Further testing is required before the presented tourniquets can be taken to the battlefield; particularly measures of self-application, and use on other anatomical areas. PMID- 28810993 TI - Prevalence and Trends of Cigarette Smoking Among Military Personnel in Taiwan: Results of 10-Year Anti-Smoking Health Promotion Programs in Military. AB - OBJECTIVES: The purpose of this study is to evaluate the prevalence and trends of cigarette smoking among young military conscripts, military officers, and military university students during recently 10 years in Taiwan. METHODS: Repeated cross-sectional surveys were conducted annually among young military conscripts and military university students from 2006 to 2014. All the young conscripts were reviewed within 1 month at the military training center and before retiring after 1 year of military services. The military officers were included using purposive sampling from 2004 to 2008 and 2013 to 2014 in different military services. Military university students were included in this study. Freshman and senior students were random sampled as the study subjects. Participants completed a structured questionnaire that included questions on general demographics and health-related behaviors. Current smokers is defined as subjects who smoked >=1 cigarette/day during the past 30 days or had smoked >=100 cigarettes in their lifetime or still have the habit of smoking during study. We used a chi2 test to examine the difference between the prevalence of cigarette smoking among different groups. The Cochran-Armitage test for trend was applied to examine the change of prevalence of smoking after repeated cross-sectional surveys among populations. RESULTS: The prevalence of cigarette smoking within military training center and after 1-year military services was 48.6% and 48.1% on 2006, which became 39.2% and 38.6% on 2010, and then further declined to 31.0% and 30.1% on 2014. For military officers, the trends of prevalence of smoking among different military services showed slight decline from 2004 to 2008, but decreased significantly between 2013 and 2014. The prevalence of smoking in 2014 was 32.1%, 32.8%, and 32.4% for the Army, Navy, and Air Force, respectively. More interestingly, the prevalence of smoking of freshman and senior students increased during the first 5 years (2007-2011) of survey and then decreased after 2012. Furthermore, in 2014, the prevalence of smoking decreased as the difference became smaller, 4.5% and 6.1% for freshman and senior, respectively. CONCLUSION: During this 10-year period, the smoking cessation programs include in-class education course, out-door physical training, antismoking clinic, and group therapy. After these military health promoting programs, there are some beneficial effects to decline the prevalence of cigarette smoking for military personnel in Taiwan. However, more active intervention and health promoting programs in prevention and cessation of smoking are needed for the military. The military also have to develop specific approaches and programs to prevent cigarette smoking among conscripts and officers. PMID- 28810994 TI - Comparison of Point-of-Care Versus Laboratory Troponin Testing in an Emergency Department Setting. AB - BACKGROUND: There have been concerns regarding troponin results accuracy between point-of-care (POC) testing preformed in an emergency department (ED) setting and laboratory testing. The purpose of this study was to compare the results of cardiac troponin I testing as concerns POC testing and laboratory analysis as a way to show that these results are interchangeable. METHODS: A retrospective chart review was performed from October 2012 through September 2013 to identify all patients who presented to the ED that received both a POC and laboratory troponin associated with the same blood draw. FINDINGS: A total of 189 patients met inclusion criteria. Three laboratory samples were hemolyzed and not available for comparison. Of the remaining 186 samples, when a positive cutoff value of 0.034 ng/mL was used: 37 POC tests were positive and 149 POC tests were negative, sensitivity 0.85 (95% confidence interval [CI] = 0.69-0.94), specificity 0.98 (95% CI = 0.94-0.99), positive predictive value 91.9% (95% CI = 77-97.9%), and negative predictive value 96% (95% CI = 91.1-98.4%). When a POC troponin positive cutoff value of 0.12 ng/mL was used: 20 POC tests were positive and 164 were negative: sensitivity 1.0 (95% CI = 0.8-1.0), specificity 0.99 (95% CI = 0.95 1.0), positive predictive value 91% (95% CI = 69-98.4%), and negative predictive value 100% (95% CI = 97.1-100%). DISCUSSION: In an ED setting; POC testing is accurate and correlates well with laboratory testing. Considering that the POC analysis takes a fraction of time to yield results, the validity of its data is important. The results of this study show that the POC system is a suitable test for rapid evaluation of patients presenting to the ED. This correlation increased with a higher testing positive cutoff value (0.12 versus 0.034 ng/mL). These data can assist the emergency physician with rapid identification of evidence of cardiac injury and be assured that the results are accurate. RECOMMENDATIONS: POC lab testing should be considered whenever possible to provide the fastest troponin results. PMID- 28810995 TI - Chondrocyte Viability After a Simulated Blast Exposure. AB - OBJECTIVES: The effects of blast exposure have gained increasing interest in the military medical community with their continued occurrence on the battlefield. The impact of the direct and indirect energy imparted from blasts to hollow viscera, as well as closed head injuries, have been well studied. However, the injury to articular cartilage has not been investigated, despite previous correlations regarding the development of osteoarthritis. The purpose of this study was to assess the degree of injury to articular chondrocytes after exposure to a simulated blast overpressure wave. METHODS: Fresh juvenile porcine stifle joints were subjected to a simulated blast overpressure wave utilizing a custom fabricated blast simulator with compressed gases, within the reported range of observed battlefield blasts. Chondrocyte viability was assessed with live/dead staining using ethidium homodimer-2 and calcien acetoxymethylester stain and confocal laser scanning microscopy, calculated as a ratio of dead chondrocytes to live chondrocytes. Testing was performed at time points of 2, 4, and 8 hours after blast exposure and was compared with unblasted control samples. RESULTS: Chondrocyte viability decreased after exposure to a blast overpressure wave when compared with control samples. The amount of death was greater closer to the articular surface and dissipated with increasing tissue depth. Chondrocyte death increased with time after exposure. CONCLUSIONS: Chondrocyte death is present after exposure to a simulated blast wave. There is an inverse relationship between chondrocyte viability and the depth from the articular surface. Additional studies are needed to further characterize dose and time effects of blast exposure. PMID- 28810996 TI - Rhabdomyolysis After Crawling Military Training. AB - INTRODUCTION: Rhabdomyolysis is a syndrome characterized by muscle necrosis followed by release of intracellular muscle contents into the circulation. Exertional rhabdomyolysis (ER) occurs in response to nonfamiliar and/or excessive, prolonged, or repetitive exercises, with eccentric characteristics. In military populations, due to the type of intense, all out physical loads, ER is a significant threat, particularly when training under heat stress. However, many other etiologies exist, and clinical presentations vary greatly. This heterogeneity may result in difficulty in prevention, diagnosis, and return-to duty decision. The purpose of this report is to point to a new potential risk factor to an extreme muscle breakdown and ER. CASES DESCRIPTION: In this article, we describe three cases of ER in army recruits after strenuous acts of crawling over hard surfaces during an intense military selection process. The soldiers' creatine phosphokinase levels were markedly raised (44,000, 123,500, and 176,599 IU/L), but none of them developed any significant medical complication. DISCUSSION: There are two major mechanisms leading to ER: the mechanical pathway which is associated with muscle tension, and the metabolic pathway which is associated with cellular energy depletion. During this military selection process, the intensity of the exercises, and cycles of work and rest are highly controlled, and so are the timings of meals and fluids consumption. Moreover, the soldiers were all at least moderately fit and had participated in strenuous exercise events before. According to years of experience with this military selection process, under similar conditions (exercise volumes and loads) we have experienced along the years minimal medical events. At the same time, and this was the unique part in these case, all patients suffered significantly from mechanical injuries caused by crawling on hard surface which were not a part of the planned selection program. Thus, we suggest that the significant muscle breakdown in the presented cases occurred mostly due to crush injury and was not solely a result of the metabolic strain. CONCLUSION: Thus, we suggest that the extreme creatine phosphokinase levels may be attributed to a synergistic interaction between low-energy trauma, caused by crawling on hard soil and stones, and exertion. We also emphasize the fact that proper physiological support such as proper hydration may assist in prevention of ER complication such as acute renal failure. PMID- 28810997 TI - Cutaneous Leishmaniasis in a Saudi Arabian Soldier Stationed in the United States. AB - BACKGROUND: Leishmaniasis is a common parasitic disease seen in many parts of the world, especially in areas where current U.S. and international forces are deployed. Approximately 350 million people are thought to be at risk of cutaneous leishmaniasis (CL) with an annual incidence of 1.5 million cases. Over 90% of cutaneous infections with Leishmania occur in the Middle East, Brazil, and Peru. Outbreaks of CL may occur in military personnel deployed to endemic areas. Since the incubation period for symptomatic CL ranges from weeks to months, symptoms may not appear until well after returning to the United States. As operations continue to expand globally, the exposure and concern for leishmaniasis persists for military physicians. We describe localized CL in a previously healthy male in an effort to help medical personnel identify leishmaniasis on the basis of cutaneous lesions alone, as well as increase diagnostic suspicion when treating patients in nonendemic areas. RESULTS: A previously healthy 30-year-old Saudi Arabian male presented to the emergency department with a 1-month history of four well-demarcated nonhealing, painless ulcers on his left ear, hand, and foot. Symptoms began shortly after arriving in the United States. He had been treated with trimethoprim/sulfamethoxazole, oral clindamycin, mupirocin ointment, and vancomycin for suspected infection without improvement of lesions. Upon presentation to dermatology, physical examination revealed a firm erythematous plaque with central ulceration on his left ear. Two shallow indurated ulcers were also found on his left fourth dorsal finger and left dorsal foot. Biopsy of the foot revealed granulomatous inflammation with predominantly lymphoplasmacytic infiltrate and multinucleated giant cells. Parasitized histiocytes were identified on hematoxylin and eosin stain and focally on Giemsa stain. Polymerase chain was consistent with a diagnosis of leishmaniasis and outpatient treatment was initiated with fluconazole 200 mg daily for 6 weeks. At 2-week follow-up, lesions were noted to be stabilized. DISCUSSION: CL has a wide variety of presentations. The classic lesion appears as a papule that will enlarge, often developing into a nodule or plaque-like lesion with central ulceration. The lesion may be covered with an eschar or by fibrinous material. This presentation can mimic many disease processes resulting in an extensive differential diagnosis that includes bacterial, fungal, and viral infections, cutaneous malignancy, and insect bites. The clinical course, treatment options, response to therapy, and prognosis are all highly variable and dependent on the causative species. Local therapy options, oral systemic agents, and parenteral agents have all shown varying results in the treatment of leishmaniasis. The difficulty with standardizing treatment options for CL stems from the lack of well-controlled studies and the lack of standardized outcome measures. This deficiency in comparative studies of treatment hinders consensual recommendations. However, the choice of the correct therapy often depends on the experience of the clinician, burden of disease, preferences of patients, and cost-effectiveness considerations for the patient and/or the health care system. PMID- 28810998 TI - Delayed Diagnosis of Acromegaly in the Context of Post-Traumatic Stress Disorder due to Symptoms Mimicking Known Psychotropic Medication Side Effects. AB - BACKGROUND: Acromegaly is caused by elevated secretion of human growth hormone, which is frequently because of intracranial tumors. This diagnosis is fairly uncommon with an incidence of 3 to 4 cases per million patients per year. We are presenting a case of acromegaly diagnosed in an active duty Chief Petty Officer. MATERIALS AND METHODS: A 38-year-old male Chief Petty Officer with no previous mental health diagnosis experienced post-traumatic stress disorder (PTSD)-like symptoms in early 2012 after deploying to Iraq and Afghanistan from 2010 to 2011. Initially he self-managed his symptoms, but in July 2012 he required a reduction mammoplasty because of gynecomastia. The metabolic workup revealed elevated prolactin, but this was not further investigated. His recovery from anesthesia was complicated by intensified PTSD-like symptoms, which continued to worsen after the surgery. On self-referral to mental health, he was diagnosed with PTSD and managed for 6 months with cognitive behavioral therapy. Because of persistent and worsening symptoms, his therapy was augmented to include continued cognitive behavioral therapy, alpha-blockers, antidepressants, antihistamines, and sleep aids. Because of night sweats, the selective serotonin reuptake inhibitors doses were modified. Night sweats persisted, and the patient was re-evaluated for other potential etiologies. On evaluation, the patient endorsed a history of obstructive sleep apnea, cervicalgia, visual changes, depressed mood, as well as multiple physical symptoms including coarsened facial features, large hands/feet, and increased interdental distance. On laboratory analysis, insulin-like growth factor 1 was noted to be 3 times the upper limit of normal, and a prolactin level was five times the upper limit of normal. A brain magnetic resonance imaging revealed a cystic pituitary lesion with suprasellar extension, compression of the infundibulum without invasion of the cavernous sinus, or displacement of the optic chiasm. Based on clinical history, physical examination, laboratory data, and the pituitary lesion, this patient was diagnosed with acromegaly. He was referred to neurosurgery for further evaluation and management. RESULTS AND CONCLUSION: This case shows that side effects of medications can easily mimic some medical conditions. The possibility of unrecognized disease should not be overlooked simply because a patient's symptoms that develop after starting a medication correspond well the side effect profile of the prescribed medications. This is especially true if side effects do not stop with alteration of medication dose, cessation of the medication, or changing to another medication. Pituitary adenomas are rare in patients treated for PTSD. However, attribution of PTSD patient's symptoms to the side effects of selective serotonin reuptake inhibitors therapy without considering a broader differential may lead to a missed diagnosis of an endocrine disease. In this case, the presence of an undiagnosed pituitary lesion resulted in ineffective medical management of PTSD in the patient. Mental health providers should remain allied with their primary care counterparts and consider directing patients to primary care for periodic physical re-evaluation to provide the most effective approach to symptom evaluation and management. PMID- 28810999 TI - Case Report on the Use of a Custom Myoelectric Elbow-Wrist-Hand Orthosis for the Remediation of Upper Extremity Paresis and Loss of Function in Chronic Stroke. AB - INTRODUCTION: This case study describes the application of a commercially available, custom myoelectric elbow-wrist-hand orthosis (MEWHO), on a veteran diagnosed with chronic stroke with residual left hemiparesis. The MEWHO provides powered active assistance for elbow flexion/extension and 3 jaw chuck grip. It is a noninvasive orthosis that is driven by the user's electromyographic signal. Experience with the MEWHO and associated outcomes are reported. MATERIALS AND METHODS: The participant completed 21 outpatient occupational therapy sessions that incorporated the use of a custom MEWHO without grasp capability into traditional occupational therapy interventions. He then upgraded to an advanced version of that MEWHO that incorporated grasp capability and completed an additional 14 sessions. Range of motion, strength, spasticity (Modified Ashworth Scale [MAS]), the Box and Blocks test, the Fugl-Meyer assessment and observation of functional tasks were used to track progress. The participant also completed a home log and a manufacturers' survey to track usage and user satisfaction over a 6-month period. RESULTS: Active left upper extremity range of motion and strength increased significantly (both with and without the MEWHO) and tone decreased, demonstrating both a training and an assistive effect. The participant also demonstrated an improved ability to incorporate his affected extremity (with the MEWHO) into a wide variety of bilateral, gross motor activities of daily living such as carrying a laundry basket, lifting heavy objects (e.g. a chair), using a tape measure, meal preparation, and opening doors. CONCLUSION: Custom myoelectric orthoses offer an exciting opportunity for individuals diagnosed with a variety of neurological conditions to make advancements toward their recovery and independence, and warrant further research into their training effects as well as their use as assistive devices. PMID- 28811000 TI - A Case of Cutaneous Leishmaniasis guyanensis Mimicking Otitis Externa. AB - Cutaneous leishmaniasis typically presents as a painless papule progressing to an ulcer or plaque. In this case study of the ear, the disease manifested as a small painful bump progressing into redness and swelling about the ear with purulent drainage. After multiple oral/intravenous antipseudomonal, antistaphylococcal, and antifungal treatments, there was no improvement. The skin progressed to an erythematous plaque and hemorrhagic ulcer; punch biopsy and speciation revealed Leishmaniasis guyanensis. The patient was switched to a seven-dose course of intravenous L-amphotericin B (visceral leishmaniasis protocol). Within 21 days, pain and edema resolved and the ulcers healed. Three-month follow-up demonstrated no recurrence. Further studies are needed to evaluate the use of L-amphotericin B in Leishmaniasis guyanensis. PMID- 28811001 TI - Topical Rapamycin: An Additional Therapeutic Option for Tufted Angioma in Adults. PMID- 28811002 TI - In DeBakey Type I Aortic Dissection, Bovine Aortic Arch Is Associated With Arch Tears and Stroke. AB - BACKGROUND: The study sought to evaluate if a bovine aortic arch (BAA) influences the location of the entry site in acute aortic dissection type A (AADA) and to identify the impact of BAA on postoperative outcome, especially stroke. METHODS: A total of 315 patients underwent surgery due to AADA DeBakey type I (72.1% men, mean age 59.5 +/- 13.4 years) between 2002 and 2015. Imaging studies and operative reports were screened for presence of BAA and location of the entry site. Patients were divided into 2 groups based on presence (BAA+) and absence (BAA-) of BAA (BAA+ n = 49, BAA- n = 264). Dissection patterns, surgical treatment, risk factors for postoperative complications, and long-term outcome were analyzed. RESULTS: Prevalence of BAA in patients with AADA was 15.6%. Location of the entry site was more commonly in the aortic arch in patients with BAA (BAA+ 46.8% versus BAA- 14.3%; p < 0.001). Multivariable analysis identified BAA (odds ratio [OR], 5.9; 95% confidence interval [CI], 2.89 to 12.04; p < 0.001) and preoperative competent aortic valve (OR, 2.26; 95% CI, 1.19 to 4.31; p = 0.013) as independent predictors for an arch tear. Thirty-nine patients (12.4%) suffered from stroke. Patients with BAA had higher stroke rates (BAA+ 24.5% versus BAA- 10.2%; p = 0.009). BAA emerged as one risk factor for stroke in the setting of AADA (OR, 2.69; 95% CI, 1.2 to 6.0; p = 0.016). Long-term survival was comparable for patients with BAA and patients without congenital arch anomalies. CONCLUSIONS: BAA is an independent predictor for the distinctive location of the entry site in the aortic arch and risk factor for stroke. PMID- 28811003 TI - The Impact of Thoracic Endovascular Aortic Repair on Long-Term Survival in Type B Aortic Dissection. AB - BACKGROUND: Currently, optimal medical therapy is first-line therapy for uncomplicated acute type B aortic dissection (aTBAD) despite poor long-term outcomes. This study examines the impact of thoracic endovascular aortic repair (TEVAR) in the acute and chronic phases on short-term and long-term survival of patients presenting with aTBAD. METHODS: A review of the Emory aortic database from 2000 to 2016 identified 398 patients diagnosed with aTBAD. At index hospitalization, complicated patients underwent TEVAR (aTEVAR [thoracic endovascular aortic repair in the acute phase], n = 80) and uncomplicated patients received optimal medical therapy (n = 318). Uncomplicated patients were divided into subgroups based on final treatment: (1) TEVAR (cTEVAR [thoracic endovascular aortic repair in the chronic phase], n = 87); (2) open aortic replacement (n = 59); and (3) optimal medical therapy (n = 172). Kaplan-Meier curves assessed long-term mortality. RESULTS: The mean age of patients was 57 +/- 12 years. In the uncomplicated group, 146 patients (45.9%) patients failed optimal medical therapy and underwent open repair (n = 59) or endovascular repair (cTEVAR, n = 87) repair in the chronic phase. Inhospital mortality was 5% and equivalent between complicated and uncomplicated aTBAD groups at index hospitalization. For patients requiring intervention, mortality and renal failure were highest for open patients (16.9%, p < 0.01, and 10.2%, p = 0.05, respectively), and stroke was highest among aTEVAR patients (7.5%, p < 0.01). The incidence of paraparesis and paraplegia was low and equivalent among the three groups. Despite a higher mortality risk at presentation, there was a trend toward improved long-term survival among complicated aTBAD patients (complicated 84.1% versus uncomplicated 58.9%, p = 0.17). Intervention-free survival at 5 and 10 years for all uncomplicated patients was 50.4% and 32.9%, respectively. CONCLUSIONS: The treatment of uncomplicated aTBAD with optimal medical therapy results in a high incidence of surgical intervention and poor long-term survival. At the index hospitalization, TEVAR may confer a survival advantage and serve as optimal therapy for complicated and uncomplicated aTBAD patients. PMID- 28811004 TI - Component separation technique for giant incisional hernia: A systematic review. AB - The component separation technique (CST) has gained popularity among general surgeons in the management of giant abdominal hernia. A systematic review of the MedLine and EMBASE databases was performed. 36 observational cohort studies were included for data-analysis and divided in 4 main groups: Open Anterior Approach (OAA), Transversus Abdominis Release (TAR), Laparoscopic Anterior Approach (LAA) and Perforator Preserving Approach (PPA). Surgical Site Occurrences (SSO) occurred in 21.4%, 23.7%, 20.3% and 16.0% respectively. Incidence of recurrence was 11.9% (OAA), 5.25% (TAR), 7.02% (LAA) and 6.47% (PPA) with a significant difference in the advantage of TAR over OAA (p < 0.001). Limitations in this systematic review were a lack of randomized trials, a heterogenous population and non-standardized methods for measuring outcomes, all making it difficult to postulate conclusions about CST and its modifications. Based on pooled results of 36 studies, the prevalence of SSO is comparable between the techniques with an average of one in five and the prevalence of recurrences is highest when using the Open Anterior Approach at 11.9%. PMID- 28811005 TI - Regulatory effects of miR-146a/b on the function of endothelial progenitor cells in acute ischemic stroke in mice. AB - The study aims to explore how microRNA-146a/b (miR-146a/b) regulates the function of endothelial progenitor cells (EPCs) in acute ischemic stroke in mice. Eighty male SPF C57BL/6J mice were evenly divided into the model-6 h, model-12 h, model 24 h (mice suffered from middle cerebral artery occlusion [MCAO] for 6 h, 12 h and model-24 h) and normal groups. EPCs were transfected and assigned into the control, MCAO, MCAO-miR-146a, MCAO-miR-146b and MCAO-miR-146a/b groups. The qRT PCR was used to detect miR-146a/b expression in EPCs. Expressions of tumor necrosis factor receptor-associated factor 6 (TRAF6) and interleukin-1 receptor associated kinase 1 (IRAK1) were detected using western blotting. Cell proliferation and migration of EPCs were testified using CCK-8 assay and scratch test, respectively. Angiogenesis ability of EPCs was observed under microscope. MiR-146a and miR-146b expressions were lower in the model groups than the normal group. There were up-regulated TRAF6 and IRAK1 expressions in the model-6 h, model-12 h and model-24 h groups compared with the normal group. And there were down-regulated TRAF6 and IRAK1 expressions in the MCAO-miR-146a, MCAO-miR-146b and MCAO-miR-146a/b groups than in the MCAO group. Compared with the control group, the proliferation, migration and angiogenesis ability of EPCs were significantly lower in the MCAO group, but higher in the MCAO-miR-146a, MCAO-miR 146b and MCAO-miR-146a/b groups. Besides, the miR-146a/b group showed more enhancement than the MCAO-miR-146a and MCAO-miR-146b groups. MiR-146a/b could down-regulate the TRAF6 and IRAK1 expressions and promote proliferation, migration and angiogenesis ability of EPCs, which was important for recovery of patients with hyperacute ischemic stroke. PMID- 28811006 TI - Improved fat transplantation survival by using the conditioned medium of vascular endothelial growth factor transfected human adipose-derived stem cells. AB - Autologous fat transplantation has been applied widely in clinic. However, the low survival rate is still a problem to be solved. Studies shows that the human adipose-derived stem cells (ADSCs) transfected by vascular endothelial growth factor (VEGF) can improve the survival rate of autologous fat transplantation. Our study is to evaluate the effects of the conditioned medium of VEGF transfected human adipose-derived stem cells (VEGF-ADSCs-CM) on fat transplantation. ADSCs were isolated and transfected with MOI = 40. The study was divided into three groups, VEGF-ADSCs-CM group, normal-ADSCs-CM group and control group. The conditioned media for VEGF-ADSCs-CM group and normal-ADSCs-CM group were collected, and then mixed with fat, with the mixtures being injected into the back of nude mice. On 4, 7, 15, 30, 60 days after transplantation, the grafts were evaluated on the wet weight, histology, ELISA and western blot. As the results revealed, the survival rate of VEGF-ADSCs-CM group was highest with the best fat cell morphology, and the VEGF secretion of VEGF-ADSCs-CM group was also highest. Therefore, our study demonstrates that VEGF-ADSCs-CM can improve the survival rate of fat transplantation effectively, and VEGF-ADSCs-CM can be regarded as an effective assisted method for fat transplantation. PMID- 28811007 TI - Acceleration of skin wound healing by low-dose indirect ionizing radiation in male rats. AB - A recent hypothesis has revealed that low-dose irradiation (LDI) with ionizing radiation might have a promoting effect on fracture healing. The aim of this study was to investigate the influence of direct (electron beam) and indirect (gamma-ray) low-dose ionizing irradiations on the wound healing process in male rats. In 72 male rats, a full-thickness wound was incised. The animals were randomly assigned to three groups, each with 24 rats. The first two groups were named IG-I and IG-II and respectively exposed to electron and gamma-radiations (75 cGy) immediately after the surgical procedure. The third group was considered as the control (CG) and remained untreated. Skin biopsies from the subgroups were collected on days 3, 7, 15, and 21 after the operation and evaluated using histological and biomechanical methods. Data were analyzed by one-way ANOVA, followed by Tukey's post hoc test using SPSS 20 software. Histological studies of tissues showed that the mean number of fibroblasts, macrophages, blood vessel sections, and neutrophils on the third and seventh days after the surgery in the gamma-treated group was higher than that in both other groups. In contrast, on day 21, the mean number of mentioned cells in the gamma-treated group was lower than in the other two groups. In addition, the mean maximum stress value was significantly greater in the gamma-treated group. Results of this study showed that gamma-ray irradiation is effective in the acceleration of wound healing. PMID- 28811008 TI - Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein expression predicts disease severity in chronic hepatitis C patients. AB - Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+-M2BP) has recently been developed as a promising liver fibrosis glyco biomarker. We assessed its efficacy in evaluating liver disease severity in chronic hepatitis C (CHC) in Taiwan. The association between WFA+-M2BP and histological features was evaluated among those CHC patients underwent liver biopsy. We also aimed to clarify the factors determining the performance of WFA+-M2BP in CHC. A total of 229 CHC patients were consecutively recruited. The mean value of WFA+-M2BP in patients from F0 to F4 was 1.68, 2.23, 3.45, 3.48, 3.77 respectively (linear trend P = 0.008). Linear regression analysis revealed that alanine aminotransferase (odds ratio [OR]: 0.03, 95% confidence intervals [CI]: 0.02 0.05, P < 0.001), AST (OR: -0.1, 95% CI: -0.02 to -0.01, P < 0.001), and liver fibrosis (OR: 0.30, 95% CI: 0.01-0.59, P = 0.043) were the independent factors correlated to serum WFA+-M2BP level. The optimal cutoff values of WFA+-M2BP for fibrosis stages F1, F2, F3, and F4 were 1.42, 1.61, 1.42, and 2.67, respectively. Multivariate analysis revealed that the platelet count (OR/CI: -0.009/0.986 0.996, P = <0.001), r-glutamyl transferase (OR/CI: 0.007/1.000-1.013, P = 0.036), and WFA+-M2BP (OR/CI: 0.187/1.057-1.374, P = 0.005). We concluded that WFA+-M2BP is a competent noninvasive marker for liver fibrosis assessment in CHC patients. PMID- 28811009 TI - The feasibility of sugammadex for general anesthesia and facial nerve monitoring in patients undergoing parotid surgery. AB - The use of neuromuscular blocking agent (NMBA) during anesthesia may interfere with facial nerve monitoring (FNM) during parotid surgery. Sugammadex has been reported to be an effective and safe reversal of rocuronium-induced neuromuscular block (NMB) during surgery. This study investigated the feasibility and clinical effectiveness of sugammadex for NMB reversal during FNM in Parotid surgery. Fifty patients undergoing parotid surgery were randomized allocated into conventional anesthesia group (Group C, n = 25) and sugammadex group (Group S, n = 25). Group C did not receive any NMBA. Group S received rocuronium 0.6 mg/kg at anesthesia induction and sugammadex 2 mg/kg at skin incision. The intubating condition and influence on FNM evoked EMG results were compared between groups. The intubation condition showed significantly better in group S patients than C group patients (excellent in 96% v.s. 24%). In group S, rapid reverse of NMB was found and the twitch (%) recovered from 0 to >90% within 10 min. Positive and high EMG signals were obtained in all patients at the time point of initial facial nerve stimulation in both groups. There was no significant difference as comparing the EMG amplitudes detected at the time point of initial and final facial nerve stimulation in both groups. Implementation of sugammadex in anesthesia protocol is feasible and reliable for successful FNM during parotid surgery. PMID- 28811010 TI - Distinct clinical characteristics of paroxysmal nocturnal hemoglobinuria in patients in Southern Taiwan: A multicenter investigation. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is an extremely rare acquired disorder. The aim of this study was to investigate the demographics, clinical manifestations, and outcomes of PNH patients in southern Taiwan. Data on PNH patients diagnosed over a 30-year period (1985-2015) were retrospectively collected from four tertiary medical centers in southern Taiwan. Blood samples were collected for hematologic panel testing and flow cytometry detection of PNH clones. Radiologic studies were performed to assess the frequency of complications. Twenty-four patients were enrolled in this study. The median duration of disease in the study participants was 10.8 years. The median granulocyte PNH clone size was 92.5% (range, 1.3%-99.8%), and the median lactate dehydrogenase (LDH) level was 2920.2 +/- 1462.0 IU/L. The incidence of thromboembolism and impaired renal function was 16.7% and 29.2%, respectively. The primary treatment strategies included steroids (79.2%), androgens (42.0%), eculizumab (33.3%), immunosuppressants (16.7%), and anticoagulants (4.2%). In eight patients treated with eculizumab, there was a marked reduction in the LDH levels of 14.89-fold-1.63-fold that of the upper limit of normal; seven patients exhibited decreased transfusion requirements. Twenty-one patients were alive with regular follow-up at the time of publication. Our study demonstrates that PNH patients in southern Taiwan may exhibit different clinical characteristics and outcomes relative to patients in other countries. There was a trend toward a greater PNH granulocyte clone size, which may lead to more hemolysis. In our study, the percentage of patients with impaired renal function, but not the percentage of patients with thrombotic events, was higher than values reported worldwide and in the observational cross-sectional International PNH Registry. More large-scale studies with comprehensive data on the clinical response to different treatments are needed. PMID- 28811011 TI - Educational intervention on physical restraint use in long-term care facilities - Systematic review and meta-analysis. AB - : "Physical restraint" formerly used as a measure of protection for psychiatric patients is now widely used. However, existing studies showed that physical restraint not only has inadequate effect of protection but also has negative effects on residents. To analyzes the impact of educational program on the physical restraint use in long-term care facilities. DESIGN: A systematic review with meta-analysis and meta-regression. Eight databases, including Cochrane Library, ProQuest, PubMed, EMBASE, EBSCO, Web of Science, Ovid Medline and Physiotherapy Evidence Database (PEDro), were searched up to January 2017. Eligible studies were classified by intervention and accessed for quality using the Quality Assessment Tool for quantitative studies. Sixteen research articles were eligible in the final review; 10 randomize control trail studies were included in the analysis. The meta-analysis revealed that the use of physical restraint was significantly less often in the experimental (education) group (OR = 0.55, 95% CI: 0.39 to 0.78, p < 0.001) compared to the control group. Meta regression revealed the period of post education would have decreased the effect of the restraint educational program (beta: 0.08, p = 0.002); instead, the longer education period and more times of education would have a stronger effect of reducing the use of physical restraint (beta: -0.07, p < 0.001; beta: -0.04, p = 0.056). The educational program had an effect on the reduced use of physical restraint. The results of meta-regression suggest that long-term care facilities should provide a continuous education program of physical restraint for caregivers. PMID- 28811012 TI - Cholesterol granuloma of the orbit. PMID- 28811013 TI - Treat penile Mondor's disease with corticosteroid cream. PMID- 28811014 TI - Assessing need for pharmacist involvement to improve care coordination for patients on LAI antipsychotics transitioning from hospital to home: A work system approach. AB - BACKGROUND: The use of Long-Acting Injectable (LAI) antipsychotic medications has increased for patients with Serious Mental Illness (SMI). Care coordination for this population is complex, and pharmacist involvement may improve and support long-term medication adherence and patient outcomes. OBJECTIVES: (1) Examine pharmacists' role in addressing care coordination and adherence challenges for patients taking Long-Acting Injectable (LAI) antipsychotics; and (2) explore patients' medication use experiences with LAI antipsychotics and educational needs. METHODS: This project utilized a holistic work systems approach to assess the usefulness of implementing a pharmacist-led intervention to improve care coordination for patients taking LAI antipsychotics. Data collection and analyses were guided by the Systems Engineering Initiative for Patient Safety (SEIPS) model. Data were collected using interviews with healthcare team members and patients taking LAI antipsychotics and retrospective chart reviews at a psychiatric hospital in Southwestern Pennsylvania. Data collection elicited information about LAI care coordination, the pharmacist's role, and patients' experiences. Content and thematic analyses were conducted to identify opportunities to improve quality of care and patient outcomes. RESULTS: Sixteen healthcare team members and six patients were interviewed. Twenty patient charts were reviewed to examine the care coordination process. Four themes of the workflow process emerged: pharmacist consultation, in-hospital LAI administration, discharge planning, and outpatient treatment. Key challenges identified included inadequate communication, limited knowledge, and the need for standardized roles. Most patients did not know the name of their LAI antipsychotic and did not recall receiving medication counseling, but were interested in discussing medication concerns with pharmacists. CONCLUSIONS: There is a need for improved communication during LAI care coordination, targeted education for healthcare team members, and standardization of roles. Many patients did not have adequate LAI antipsychotic knowledge or receive appropriate medication counseling. Increased pharmacist involvement in the care coordination process may promote adherence and optimal management of SMI. PMID- 28811015 TI - Multiple-targeted graphene-based nanocarrier for intracellular imaging of mRNAs. AB - Simultaneous detection and imaging of multiple intracellular messenger RNA (mRNAs) hold great significant for early cancer diagnostics and preventive medicine development. Herein, we propose a multiple-targeted graphene oxide (GO) nanocarrier that can simultaneously detect and image different type mRNAs in living cells. First of all, in vitro detection of multiple targets have been realized successfully based on the multiple-targeted GO nanocarrier with linear relationship ranging from 3 nM to 200 nM, as well as sensitive detection limit of 1.84 nM for manganese superoxide dismutase (Mn-SOD) mRNA and 2.45 nM for beta actin mRNA. Additionally, this nanosensing platform composed of fluorescent labelled single strand DNA probes and GO nanocarrier can identify Mn-SOD mRNA and endogenous mRNA of beta-actin in living cancer cells, showing rapid response, high specificity, nuclease stability, and good biocompatibility during the cell imaging. Thirdly, changes of the expression levels of mRNA in living cells before or after the drug treatment can be monitored successfully. By using multiple ssDNA as probes and GO nanocarrier as the cellular delivery cargo, the proposed simultaneous multiple-targeted sensing platform will be of great potential as a powerful tool for intracellular trafficking process from basic research to clinical diagnosis. PMID- 28811016 TI - Activated biochar: Preparation, characterization and electroanalytical application in an alternative strategy of nickel determination. AB - This work reports for the first time the use of chemically activated biochar as electrode modifier for nickel determination. The biochar activation was performed by refluxing with HNO3, which promoted a higher nickel preconcentration compared to unmodified and modified biochar precursor electrodes. Morphological and structural characterization revealed the increase of surface acid groups, surface area and porosity of biochar after activation. Nickel determination was investigated adopting an alternative voltammetric methodology based on monitoring the Ni(II)/Ni(III) redox couple. In the proposed method, it was not necessary to use a complexing agent and the biochar itself was responsible for the analyte preconcentration. A linear response for Ni(II) concentration range from 1.0 to 30 MUmol L-1 and a limit of detection of 0.25 MUmol L-1 were obtained. The method was successfully applied for Ni(II) determination in spiked samples of bioethanol fuel and discharge water, with recoveries values between 103 and 109%. PMID- 28811017 TI - Improved methodology for analysis of multiple phytohormones using sequential magnetic solid-phase extraction coupled with liquid chromatography-tandem mass spectrometry. AB - Phytohormones are special small molecules that play important role in plant growth and development at trace levels. Quantification of multiple phytohormones will be great helpful for researches about cross-talks that plant hormones regulate the responses of plants against both biotic and abiotic stresses by means of synergistic or antagonistic interactions. In the current study, we developed a method for profiling of phytohormones in one small sample, including indole-3-acetic acid, abscisic acid, jasmonic acid, gibberellins, cytokinins and brassinosteroids. These phytohormones mentioned above were firstly purified and separated by sequential magnetic solid-phase extraction (MSPE) and then analyzed by ultra-high performance liquid chromatography-electrospray tandem mass spectrometry (UHPLC-MS/MS). Under the optimized extraction conditions, good linearity was obtained with correlation coefficients (r) ranging from 0.9961 to 0.9998. The limits of detection (LODs, S/N = 3) were ranged from 0.45 to 126.1 pg mL-1. The recoveries were between 85.0% and 116.2%. The relative standard deviations (RSDs) were ranged from 2.7% to 16.1%. With the proposed strategy, 23 phytohormones could be purified and analyzed from a single plant extract. Finally, 16 phytohormones could be detected in 100 mg (fresh weight) flower of Brassica napus L., including IAA, ABA, JA, 4 GAs, 3 BRs and 6 CKs with the concentration ranged from 0.09 to 305.23 ng g-1. PMID- 28811018 TI - Direct coupling of electromembrane extraction to mass spectrometry - Advancing the probe functionality toward measurements of zwitterionic drug metabolites. AB - A triple-flow electromembrane extraction (EME) probe was developed and coupled directly to electrospray-ionization mass spectrometry (ESI-MS). Metabolic reaction mixtures (pH 7.4) containing drug substances and related metabolites were continuously drawn (20 MUL/min) into the EME probe in one flow channel, and mixed inside the probe with 7.5 MUL min-1 of 1 M formic acid as make-up flow from a second flow channel. Following this acidification, the drug substances and their related metabolites were continuously extracted by EME at 400 V, across a supported liquid membrane (SLM) comprising 2-nitrophenyl octyl ether (and for some experiments containing 30% triphenyl phosphate (TPP)), and into 20 MUL min-1 of formic acid as acceptor phase, which was introduced through a third flow channel. The acceptor phase was pumped directly to the MS system, and the ion intensity of extracted analytes was followed continuously as function of time. The triple-flow EME probe was used for co-extraction of positively charged parent drugs and their zwitterionic drug metabolites (hydroxyzine and its carboxylic acid metabolite cetirizine; and vortioxetine and its carboxylic acid metabolite Lu AA34443). While the zwitterionic metabolites could not be extracted at pH 7.4, it was shown that by acidifying the sample solution the zwitterionic metabolites could be extracted effectively. Various extraction parameters like make-up flow, extraction voltage and SLM composition were optimized for simultaneous extraction of parent drugs and metabolites. It was found that TPP added to the SLM improved extraction efficiencies of certain drug metabolites. Finally the optimized and characterized triple-flow EME probe was used for online studying the in-vitro metabolism of hydroxyzine and vortioxetine by rat liver microsomes. Due to the automated pre-extraction acidification of the rat liver microsomal solutions, it was possible to continuously monitor formation of the zwitterionic drug metabolites. As the triple-flow EME probe allowed modification of the pH of the sample without changing the pH in the bulk sample, the system can potentially be used for direct analysis of various kinds of chemical reactions that have to be run at pH conditions unfavorable for direct analyte extractions. PMID- 28811019 TI - Introducing a new and rapid microextraction approach based on magnetic ionic liquids: Stir bar dispersive liquid microextraction. AB - With the aim of contributing to the development and improvement of microextraction techniques, a novel approach combining the principles and advantages of stir bar sorptive extraction (SBSE) and dispersive liquid-liquid microextraction (DLLME) is presented. This new approach, termed stir bar dispersive liquid microextraction (SBDLME), involves the addition of a magnetic ionic liquid (MIL) and a neodymium-core magnetic stir bar into the sample allowing the MIL coat the stir bar due to physical forces (i.e., magnetism). As long as the stirring rate is maintained at low speed, the MIL resists rotational (centrifugal) forces and remains on the stir bar surface in a manner closely resembling SBSE. By increasing the stirring rate, the rotational forces surpass the magnetic field and the MIL disperses into the sample solution in a similar manner to DLLME. After extraction, the stirring is stopped and the MIL returns to the stir bar without the requirement of an additional external magnetic field. The MIL-coated stir bar containing the preconcentrated analytes is thermally desorbed directly into a gas chromatographic system coupled to a mass spectrometric detector (TD-GC-MS). This novel approach opens new insights into the microextraction field, by using the benefits provided by SBSE and DLLME simultaneously, such as automated thermal desorption and high surface contact area, respectively, but most importantly, it enables the use of tailor-made solvents (i.e., MILs). To prove its utility, SBDLME has been used in the extraction of lipophilic organic UV filters from environmental water samples as model analytical application with excellent analytical features in terms of linearity, enrichment factors (67-791), limits of detection (low ng L-1), intra- and inter-day repeatability (RSD<15%) and relative recoveries (87-113%, 91-117% and 89-115% for river, sea and swimming pool water samples, respectively). PMID- 28811020 TI - Peanut agglutinin and beta-cyclodextrin functionalized polymer monolith: Microextraction of IgG galactosylation coupled with online MS detection. AB - A facile online method coupling polymer monolithic microextraction (PMME) with mass spectrometry (MS) was developed for the detection of Immunoglobulin G (IgG) galactosylation glycopeptides. A peanut agglutinin-beta-cyclodextrin (PNA-beta CD) functionalized poly(hydroxyethyl methylacrylate-ethyleneglycol dimethacrylate) monolith was designed via a click reaction. Thanking to the specificity of PNA-beta-CD for the targets, the material exhibited enhanced enrichment selectivity and extraction efficiency for IgG galactosylation glycopeptides. Under optimal conditions, the developed method gave a linear range of 0.005-5 pmol for IgG glycopeptides with the regression coefficient greater than 0.9990, and the detection limit of IgG galactosylation glycopeptides as low as 0.5 fmol was achieved. The PMME-MS method was applied to IgG galactosylation glycopeptides in real samples including human serum and acute myelogenous leukemia (AML) cell lysate. A series of unique IgG galactosylation glycopeptides were captured by the monolith in the complex samples, indicating satisfactory enrichment ability for IgG galactosylation glycopeptides. The quick and integrated online PMME-MS method exhibited high selectivity for IgG galactosylation, demonstrating its perspectives on the development and broad applications of MS in studying galactosylation proteins regulated biological processes. PMID- 28811021 TI - Quantitative analysis of major and trace elements in NH4HF2-modified silicate rock powders by laser ablation - inductively coupled plasma mass spectrometry. AB - In this paper, we described a NH4HF2 digestion method as sample preparation for the rapid determination of major and trace elements in silicate rocks using laser ablation-inductively coupled plasma mass spectrometry (LA-ICP-MS). Sample powders digested by NH4HF2 at 230 degrees C for 3 h form ultrafine powders with a typical grain size d80 < 8.5 MUm, and various silicate rocks have a consistent grain morphology and size, allowing us to produce pressed powder pellets that have excellent cohesion and homogeneity suitable for laser ablation micro analysis without the addition of binder. The influences of the digestion parameters were investigated and optimized, including the evaporation stage of removing residual NH4HF2, sample homogenization, selection of the digestion vessel and calibration strategy of quantitative analysis. The optimized NH4HF2 digestion method was applied to dissolve six silicate rock reference materials (BCR-2, BHVO-2, AGV-2, RGM-2, GSP-2, GSR-1) covering a wide range of rock types. Ten major elements and thirty-five trace elements were simultaneously analyzed by LA-ICP-MS. The analytical results of the six reference materials generally agreed with the recommended values, with discrepancies of less than 10% for most elements. The analytical precision is within 5% for most major elements and within 10% for most trace elements. Compared with previous methods of LA-ICP-MS bulk analysis, our method enables the complete dissolution of refractory minerals, such as zircon, in intermediate-acidic intrusive rocks and limits contamination as well as the loss of volatile elements. Moreover, there are many advantages for the new technique, including reducing matrix effects between reference materials and samples, spiking the internal standard simply and feasibly and sample batch processing. The applicability filed of the new technique in this study was focused on the whole-rock analysis of igneous rock samples, which are from basic rocks to acid rocks (45% < SiO2 < 73%). However, we thought that the NH4HF2 digestion method can be used as a new alternative in LA ICP-MS for a wider range of geological samples, and will significantly accelerate the application of LA-ICP-MS for the whole-rock analysis. PMID- 28811022 TI - Intact metabolite profiling of mouse brain by probe electrospray ionization/triple quadrupole tandem mass spectrometry (PESI/MS/MS) and its potential use for local distribution analysis of the brain. AB - Probe electrospray ionization (PESI), which is an ambient ionization technique, enables us to analyze intact endogenous metabolites without sample preparation. In this study, we applied the newly developed method of PESI coupled to tandem mass spectrometry (PESI/MS/MS) to analyze metabolites in mouse brain, where its lipid composition often interfere with MS-based metabolome analysis. As a result, PESI/MS/MS directly detected 25 metabolites in a mouse frontal cortex, and clearly discriminated the metabolic profiles of mice model with energy metabolism disruption from control mice. PESI/MS/MS also allowed us to perform local distribution analysis of the hippocampus as well as the frontal cortex in each mouse (n = 5), discriminating their subtle metabolic differences. These results showed high potential of PESI/MS/MS for direct metabolome profiling of mouse brain. PMID- 28811023 TI - AgNPs-3D nanostructure enhanced electrochemiluminescence of CdSe quantum dot coupled with strand displacement amplification for sensitive biosensing of DNA. AB - A novel strategy using Ag nanoparticles-3D (AgNPs-3D) nanostructure enhanced electrochemiluminescence (ECL) of CdSe quantum dots (QDs) coupled with strand displacement amplification (SDA) for sensitive biosensing of DNA was successfully designed. The prepared CdSe QDs with intense ECL were assembled on the poly (diallyldimethylammonium chloride) (PDDA) graphene oxide (GO) nanocomposites modified electrode, then gold nanoparticles (NPs) as the quenching probe was conjugated to the QDs, ECL signal was efficiently quenched. The target DNA induced cycling SDA and generated a large number of DNA s1. The released DNA s1 could open the hairpin DNA with quenching probe. So the presence of low levels of target DNA can potentially result in a significant enhancement of ECL signal. Furthermore, large number of AgNPs were then in situ reduced in the 3D DNA skeleton on the electrode, which dramaticlly enhanced ECL signal of QDs owing to the excellent electrical conductivity, and the much amplified ECL signal change has a quantitative relation with the target DNA. So by combining the AgNPs-3D nanostructure and cycling SDA to achieve greatly amplified detection of DNA, the promising ECL strategy could provide a highly sensitive platform for various biomolecules and has a good prospect for clinical diagnosis in the future. PMID- 28811024 TI - Aptamer induced multicoloured Au NCs-MoS2 "switch on" fluorescence resonance energy transfer biosensor for dual color simultaneous detection of multiple tumor markers by single wavelength excitation. AB - An aptamer induced "switch on" fluorescence resonance energy transfer (FRET) biosensor for the simultaneous detection of multiple tumor markers (e.g., AFP and CEA) combining molybdenum disulfide (MoS2) nanosheets with multicolored Au NCs by a single excitation was developed for the first time. Here, AFP aptamer functionalized green colored Au NCs (510 nm) and CEA aptamer functionalized red colored Au NCs (650 nm) are used as energy donors, while MoS2 is used as energy receptor. On the basis of recording the change of the recovered fluorescence intensity at 510 nm and 650 nm upon the addition of targets CEA and AFP, these two tumor markers can be simultaneously quantitatively detected, with detection limits of 0.16 and 0.21 ng mL-1 (3sigma) for AFP and CEA, respectively. In addition, it is noteworthy that the developed biosensor can not only realize accurate quantitative determination of multiple tumor markers by fluorescent intensity, but also be applied in semi-quantitative determination through photo visualization. More importantly, confocal microscope experiments prove that serums from normal and hepatoma patients can also be visually and qualitatively discriminated by this FRET-based biosensor with a single excitation wavelength, indicating promising potential of this assay for clinical diagnosis. PMID- 28811025 TI - Simultaneous detection of two hepatocellar carcinoma-related microRNAs using a clever single-labeled fluorescent probe. AB - The simultaneous detection of two important microRNAs (miRNAs) can potentially evaluate pathological states. The simultaneous detection of miRNA-26a and miRNA 122 is proposed in this study using a cleverly designed single-labeled, dual functional fluorescent probe with a 2-aminopurine as a fluorophore, which is a G quadruplex single-stranded DNA. The probe can partly complement cDNA-1 and cDNA 2. cDNA-1 and cDNA-2 are complementary strands of miRNA-26a and miRNA-122, respectively. When the target miRNAs are added simultaneously, these cDNA (cDNA-1 and cDNA-2) can be competed off from the cDNA?probe duplex to form a cDNA?RNA heteroduplex. The probe is released and the fluorescent signal is increased. The detection limits of miRNA-26a and miRNA-122 are both 2.5 nM, and their wide linear which ranges from 2.5 to 500 nM are achieved using the assay. This method has potential practical applications. PMID- 28811026 TI - Multiple epitope presentation and surface density control enabled by chemoselective immobilization lead to enhanced performance in IgE-binding fingerprinting on peptide microarrays. AB - Multiple ligand presentation is a powerful strategy to enhance the affinity of a probe for its corresponding target. A promising application of this concept lies in the analytical field, where surface immobilized probes interact with their corresponding targets in the context of complex biological samples. Here we investigate the effect of multiple epitope presentation (MEP) in the challenging context of IgE-detection in serum samples using peptide microarrays, and evaluate the influence of probes surface density on the assay results. Using the milk allergen alpha-lactalbumin as a model, we have synthesized three immunoreactive epitope sequences in a linear, branched and tandem form and exploited a chemoselective click strategy (CuAAC) for their immobilization on the surface of two biosensors, a microarray and an SPR chip both modified with the same clickable polymeric coating. We first demonstrated that a fine tuning of the surface peptide density plays a crucial role to fully exploit the potential of oriented and multiple peptide display. We then compared the three multiple epitope presentations in a microarray assay using sera samples from milk allergic patients, confirming that a multiple presentation, in particular that of the tandem construct, allows for a more efficient characterization of IgE-binding fingerprints at a statistically significant level. To gain insights on the binding parameters that characterize antibody/epitopes affinity, we selected the most reactive epitope of the series (LAC1) and performed a Surface Plasmon Resonance Imaging (SPRi) analysis comparing different epitope architectures (linear versus branched versus tandem). We demonstrated that the tandem peptide provides an approximately twofold increased binding capacity with respect to the linear and branched peptides, that could be attributed to a lower rate of dissociation (Kd). PMID- 28811027 TI - Design of carbohydrate/electron-transfer peptides for human histocytic lymphoma cell sensing. AB - A carbohydrate/electro-transfer peptide probe was fabricated to perform cell sensing. The probe consisted of a cello-oligosaccharide that was created by the conjugation of an electron-transfer peptide (Y5C) and a carbohydrate via a Schiff base. An oxidation wave due to a phenolic hydroxyl group was obtained by scanning with a glassy carbon electrode. This cell-sensing system was based on a competitive reaction between carbohydrates on a cell surface and the probe as each reacted to a protein that recognized the carbohydrate. When amounts of the protein and probe were constant, the peak current of the probe was changed as the number of cells increased. A human histocytic lymphoma cell (U937 cell) with carbohydrates such as glucose and N-acetylglucosamine on its surface was selected as the target cell. Wheat germ agglutinin (WGA) binded to both the probe and the carbohydrates on U937 cells, which resulted in a linear peak current of the cellobiose/electron-transfer peptide at concentrations that ranged from 100 to 3500 cells/ml. The values of the cell sensing using this electrochemical method were consistent with those established via ELSIA. The sensitivity of this procedure, however, was two-fold superior to that of ELISA. Consequently, this carbohydrate/electron-transfer peptide could be a powerful tool for cell sensing and searching for carbohydrate chains on a cell surface. PMID- 28811028 TI - Advanced nanotechnologies in avian influenza: Current status and future trends - A review. AB - In the last decade, the control of avian influenza virus has experienced many difficulties, which have caused major global agricultural problems that have also led to public health consequences. Conventional biochemical methods are not sufficient to detect and control agricultural pathogens in the field due to the growing demand for food and subsidiary products; thus, studies aiming to develop potent alternatives to conventional biochemical methods are urgently needed. In this review, emerging detection systems, their applicability to diagnostics, and their therapeutic possibilities in view of nanotechnology are discussed. Nanotechnology-based sensors are used for rapid, sensitive and cost-effective diagnostics of agricultural pathogens. The application of different nanomaterials promotes interactions between these materials and the virus, which enables researchers to construct portable electroanalytical biosensing analyser that should effectively detect the influenza virus. The present review will provide insights into the guidelines for future experiments to develop better techniques to detect and control influenza viruses. PMID- 28811029 TI - Use of diffusive gradient in thin films for in situ measurements: A review on the progress in chemical fractionation, speciation and bioavailability of metals in waters. AB - Chemical fractionation, speciation analysis and bioavailability of metals and metalloids in waters have received increased attention in recent years. However, this interest is not matched by progress in improving species integrity during standard 'grab' sample collection, processing and storage. Time-averaged, low disturbance sampling, in situ, of trace element species, in particular, is a more reliable approach for environmental chemical surveillance and methods based on the diffusive gradients in thin films (DGT) technique stand out as one of the most widely used of the passive sampler classes, and hence will be the primary focus of this review. The DGT technique was initially developed to sample metals and semi-metals in freshwaters, and later was extended to include marine settings as well as the measurement of metal fluxes in sediments/soils. Nowadays, DGT based technologies are used extensively in a variety of geochemical and environmental health research disciplines. This review specifically surveys the application of the DGT measurement for fractionation and speciation analysis (as defined by IUPAC) of metal or metalloids in aqua. Use of DGT in fresh, estuarine and marine waters, as well as effluents has improved the knowledge base of in situ data related to fractionation processes (e.g. labile and inert species; organic and inorganic species; dissolved and nanoparticles), and speciation analysis. This supports not only the calculations underpinning numerous software speciation models for cation and anion behavior, but also our understanding of the bioavailability and toxicity of these species. The measurement of metals by DGT are easy to obtain, which is core to its popular use, but often the results require sophisticated interpretation and a wide spectrum of chemical knowledge to really explain in full, which is why the method has and continues to capture the interest of researchers. PMID- 28811030 TI - Targeted analyte deconvolution and identification by four-way parallel factor analysis using three-dimensional gas chromatography with mass spectrometry data. AB - Comprehensive three-dimensional gas chromatography with time-of-flight mass spectrometry (GC3-TOFMS) creates an opportunity to explore a new paradigm in chemometric analysis. Using this newly described instrument and the well understood Parallel Factor Analysis (PARAFAC) model we present one option for utilization of the novel GC3-TOFMS data structure. We present a method which builds upon previous work in both GC3 and targeted analysis using PARAFAC to simplify some of the implementation challenges previously discovered. Conceptualizing the GC3-TOFMS instead as a one-dimensional gas chromatograph with GC * GC-TOFMS detection we allow the instrument to create the PARAFAC target window natively. Each first dimension modulation thus creates a full GC * GC TOFMS chromatogram fully amenable to PARAFAC. A simple mixture of 115 compounds and a diesel sample are interrogated through this methodology. All test analyte targets are successfully identified in both mixtures. In addition, mass spectral matching of the PARAFAC loadings to library spectra yielded results greater than 900 in 40 of 42 test analyte cases. Twenty-nine of these cases produced match values greater than 950. PMID- 28811031 TI - Bayesian approach to peak deconvolution and library search for high resolution gas chromatography - Mass spectrometry. AB - A novel probabilistic Bayesian strategy is proposed to resolve highly coeluting peaks in high-resolution GC-MS (Orbitrap) data. Opposed to a deterministic approach, we propose to solve the problem probabilistically, using a complete pipeline. First, the retention time(s) for a (probabilistic) number of compounds for each mass channel are estimated. The statistical dependency between m/z channels was implied by including penalties in the model objective function. Second, Bayesian Information Criterion (BIC) is used as Occam's razor for the probabilistic assessment of the number of components. Third, a probabilistic set of resolved spectra, and their associated retention times are estimated. Finally, a probabilistic library search is proposed, computing the spectral match with a high resolution library. More specifically, a correlative measure was used that included the uncertainties in the least square fitting, as well as the probability for different proposals for the number of compounds in the mixture. The method was tested on simulated high resolution data, as well as on a set of pesticides injected in a GC-Orbitrap with high coelution. The proposed pipeline was able to detect accurately the retention times and the spectra of the peaks. For our case, with extremely high coelution situation, 5 out of the 7 existing compounds under the selected region of interest, were correctly assessed. Finally, the comparison with the classical methods of deconvolution (i.e., MCR and AMDIS) indicates a better performance of the proposed algorithm in terms of the number of correctly resolved compounds. PMID- 28811032 TI - Recent advancements and future trends in environmental analysis: Sample preparation, liquid chromatography and mass spectrometry. AB - Among the thousands of chemicals having potential to enter the environment, the NORMAN network has identified at least 700 substances categorized into 20 classes in the European surface waters. Pesticides, pharmaceuticals, disinfection by products, wood preservation and industrial chemicals are the prominent classes. Since the impact of these substances on aquatic life and human health might be dramatic, action is urgently required at multiple levels; one of them is just related to the development of more and more sensible and selective analytical methods. This review highlights the latest advancements and trends in liquid chromatography-mass spectrometry based environmental analysis. Specific sections are dedicated to novelties in sample preparation, chromatographic separation and mass spectrometry detection of emerging pollutants. The review also offers insights on last generation chromatographic and extraction materials, technological progresses and innovative methodological approaches for target and non-target analysis. As numerous papers have been published in this field, this overview covers the most representative and original works published in the 2011 2016 period. PMID- 28811033 TI - Strong magnetoelectrolysis effect during electrochemical reaction monitored in situ by high-resolution NMR spectroscopy. AB - The strong effect of magnetic field on the electrochemical (EC) reduction of a diamagnetic species was monitored in situ in a 600 MHz (14 T) NMR spectrometer. Throughout EC-NMR experiments, the diamagnetic species is influenced by the Lorentz force (cross product of current density and magnetic field), which in turn acts on analyte transport and, as a result, enhances reaction rates. This phenomenon, known as magnetoelectrolysis, has not been considered in several in situ EC-NMR studies in solution, electron paramagnetic resonance (EC-EPR) spectroscopy, and magnetic resonance imaging (EC-MRI) involving the oxidation and reduction of organic compounds and lithium ion batteries. Recently, we have demonstrated the presence of this effect in the electroplating of a paramagnetic ion species by monitoring it in situ in a low-field (0.23 T) NMR spectrometer. In this report, a ca. five-fold enhancement in the electroreduction rate of benzoquinone was observed when the analyses were performed in situ in the NMR spectrometer. Therefore, this work has the objective of informing the scientific community that before every electrochemical reaction carried out in situ in NMR, EPR and MRI apparatuses, the influence of the magnetic field on the reactions must be evaluated, since it can alter the mechanism and kinetics of the reaction which, if not taken into account may lead to wrong interpretations of the data. PMID- 28811034 TI - A simple microdroplet chip consisting of silica nanochannel-assisted electrode and paper cover for highly sensitive electrochemiluminescent detection of drugs in human serum. AB - This paper describes a simple and miniaturized microdroplet chip (MUchip) that is constructed with a silica nanochannel (SNC)-assisted electrode array and a hydrophobic paper cover (SNC&P-MUchip). Vertically aligned SNCs with uniform pore size of 2-3 nm in diameter and negatively charged surface can significantly accelerate the mass transport of the positively charged tris(2,2'-bipyridyl) ruthenium (II), resulting in a remarkably enhanced electrochemiluminescence (ECL) signal. The SNC-assisted electrode array was coupled to a low cost paper cover to achieve simultaneous detection of six samples in 1 min. The feasibility and universality of the SNC&P-MUchip was evaluated by detecting a series of alkaloidal drugs both in buffers and in human serum. The performance of the SNC&P MUchip was fully validated with respect to linearity (0.9999 > R > 0.9939), sensitivity (limits of detection from 1.799 nM to 11.43 nM), and accuracy (recovery rate between 94.38% and 109.12%). The facile and economic SNC&P-MUchip shows promising potential for rapid drug detection in complex biofluids. PMID- 28811035 TI - Corrigendum to "Anaplasma phagocytophilum and Rickettsia spp. infections in hard ticks (Ixodes ricinus) in the city of Hanover (Germany): Revisited" [Ticks Tick Borne Dis. 4 (2013) 432-438]. PMID- 28811036 TI - Corrigendum to "Heritability and genome-wide association mapping for supernumerary teats in French Alpine and Saanen dairy goats" (J. Dairy Sci. 99:8891-8900). PMID- 28811037 TI - Effects of metal contamination on the gene expression profile of two benthic species: Cerastoderma edule and Ruditapes philippinarum. AB - This study aimed to identify new biomarkers for metal exposure in two bivalve species. Suppressive Subtractive Hybridization (SSH) was employed to evaluate the transcriptomic response of Cerastoderma edule and Ruditapes philippinarum to metal pollution. Protein synthesis and catalytic activity were the most affected metabolic processes in C. edule and R. philippinarum, respectively. Also, different genes responded to the effect of contamination in each species. The different response observed in both species reinforces the importance of including more than one bioindicator species in risk assessment studies. These results provide the basis for new studies, which are necessary for further validation of the use of the identified genes as molecular biomarkers for metal exposure. PMID- 28811038 TI - Fast and robust online adaptive planning in stereotactic MR-guided adaptive radiation therapy (SMART) for pancreatic cancer. AB - BACKGROUND AND PURPOSE: To implement a robust and fast stereotactic MR-guided adaptive radiation therapy (SMART) online strategy in locally advanced pancreatic cancer (LAPC). MATERIAL AND METHODS: SMART strategy for plan adaptation was implemented with the MRIdian system (ViewRay Inc.). At each fraction, OAR (re )contouring is done within a distance of 3cm from the PTV surface. Online plan re optimization is based on robust prediction of OAR dose and optimization objectives, obtained by building an artificial neural network (ANN). Proposed limited re-contouring strategy for plan adaptation (SMART3CM) is evaluated by comparing 50 previously delivered fractions against a standard (re-)planning method using full-scale OAR (re-)contouring (FULLOAR). Plan quality was assessed using PTV coverage (V95%, Dmean, D1cc) and institutional OAR constraints (e.g. V33Gy). RESULTS: SMART3CM required a significant lower number of optimizations than FULLOAR (4 vs 18 on average) to generate a plan meeting all objectives and institutional OAR constraints. PTV coverage with both strategies was identical (mean V95%=89%). Adaptive plans with SMART3CM exhibited significant lower intermediate and high doses to all OARs than FULLOAR, which also failed in 36% of the cases to adhere to the V33Gy dose constraint. CONCLUSIONS: SMART3CM approach for LAPC allows good OAR sparing and adequate target coverage while requiring only limited online (re-)contouring from clinicians. PMID- 28811039 TI - Twenty years of staffing, practice environment, and outcomes research in military nursing. AB - BACKGROUND: Two decades ago, findings from an Institute of Medicine (IOM) report sparked the urgent need for evidence supporting relationships between nurse staffing and patient outcomes. PURPOSE: This article provides an overview of nurse staffing, practice environment, and patient outcomes research, with an emphasis on findings from military studies. Lessons learned also are enumerated. METHOD: This study is a review of the entire Military Nursing Outcomes Database (MilNOD) program of research. DISCUSSION: The MilNOD, in combination with evidence from other health care studies, provides nurses and leaders with information about the associations between staffing, patient outcomes, and the professional practice environment of nursing in the military. Leaders, therefore, have useful empirical evidence to make data-driven decisions. The MilNOD studies are the basis for the current Army nursing dashboard, and care delivery framework, called the Patent CaringTouch System. CONCLUSION: Future research is needed to identify ideal staffing based on workload demands, and provide leaders with factors to consider when operationalizing staffing recommendations. PMID- 28811040 TI - Implant-specific follow-up imaging of treated intracranial aneurysms: TOF-MRA vs. metal artifact reduced intravenous flat panel computed tomography angiography (FPCTA). AB - AIM: To compare the diagnostic quality of time-of-flight magnetic resonance angiography (TOF-MRA) and metal-artefact-reduction (MAR) flat-panel-detector computed tomography angiography (FPCTA) and to determine the imaging technique best suited for evaluation endovascular and surgically treated aneurysms. METHODS: The image quality of TOF-MRA and MAR-FPCTA of 44 intracranial implants (coiling: n=20; clipping: n=15; coiling + stenting: n=9) in a patient cohort of 25 was evaluated by two independent readers. Images obtained using MAR-FPCTA (20 second scan time, 496 projections, intravenous contrast medium administration; Artis Zee, Siemens Healthcare, Forchheim) were compared with TOF-MRA-images (1.5 or 3 T). Nominal data were analysed using McNemar's chi-square test and ordinal variables using the Wilcoxon rank test. RESULTS: Compared to TOF-MRA, MAR-FPCTA was significantly better suited to detect aneurysm remnants and to evaluate parent vessels after clipping (p<0.01). For coil packages >160 mm3, TOF-MRA provided significantly better assessment than MAR-FPCTA (p<0.01). For small coil packages (<160 mm3), no significant difference between TOF-MRA and MAR-FPCTA (p=0.232) was observed. For different clip sizes (cut-off 492 mm3) likewise no significant differences were found. The interobserver comparison showed high interrater agreement. CONCLUSION: MAR-FPCTA is significantly better suited for follow-up examinations of clipped aneurysms, whereas for larger coil packages TOF MRA is preferable. Smaller coil packages can be analysed using MAR-FPCTA or TOF MRA. PMID- 28811041 TI - Post-thrombotic syndrome in children. AB - The post-thrombotic syndrome (PTS) is the most common long-term complication of pediatric deep venous thrombosis (DVT). It is a burdensome condition that can lead to severe disability and poor quality-of-life of affected children. Although its pathophysiology remains poorly understood, it is thought to be the result of chronic venous hypertension. Recent studies have shown that the inflammatory response associated with an acute DVT likely plays a key role in the development of PTS. The Manco-Johnson Instrument and the modified Villalta Scale are the most widely used instruments for the diagnosis of pediatric PTS. To date, few prognostic indicators for the development of PTS following pediatric-onset DVT have been identified and substantiated in published research, limiting our ability to identify those patients at high-risk for the development of this complication. There is also limited evidence on therapeutic strategies and long term outcomes of pediatric PTS. Further research aimed at improving our understanding of the pathophysiology and prognostic indicators of PTS is needed to enhance the currently limited risk prediction models for pediatric PTS. Early identification of pediatric patients at risk for PTS is essential to investigate preventive and therapeutic interventions aimed at decreasing the risk and severity of this complication in children. This review aims to summarize the current available evidence on the pathophysiology, risk factors, diagnosis, and management of pediatric PTS. PMID- 28811042 TI - Understanding readmissions in children undergoing surgery: A pediatric NSQIP analysis. AB - BACKGROUND: Readmission is increasingly being utilized as an important clinical outcome and measure of hospital quality. Our aim was to delineate rates, risk factors, and reasons for unplanned readmission in pediatric surgery. MATERIALS AND METHODS: Retrospective review of pediatric patients (n=130,274) undergoing surgery (2013-2014) at hospitals enrolled in the Pediatric National Surgical Quality Improvement Program (NSQIP-P) was performed. Logistic regression was used to model factors associated with unplanned 30-day readmission. Reasons for readmission were reviewed to determine the most common causes of readmission. RESULTS: There were 6059 (n=4.7%) readmitted children within 30days of the index operation. Of these, 5041 (n=3.9%) were unplanned, with readmission rates ranging from 1.3% in plastic surgery to 5.2% in general pediatric surgery, and 10.8% in neurosurgery. Unplanned readmissions were associated with emergent status, comorbidities, and the occurrence of pre- or postdischarge postoperative complications. Overall, the most common causes for readmission were surgical site infections (23.9%), ileus/obstruction/gastrointestinal (16.8%), respiratory (8.6%), graft/implant/device-related (8.1%), neurologic (7.0%), or pain (5.8%). Median time from discharge to readmission was 8days (IQR: 3-14days). Reasons for readmission, time until readmission, and need for reoperative procedure (overall 28%, n=1414) varied between surgical specialties. CONCLUSION: The reasons for readmission in children undergoing surgery are complex, varied, and influenced by patient characteristics and postoperative complications. These data inform risk stratification for readmission in pediatric surgical populations, and help to identify potential areas for targeted interventions to improve quality. They also highlight the importance of accounting for case-mix in the interpretation of hospital readmission rates. LEVEL OF EVIDENCE: 3. PMID- 28811043 TI - Treatment of the Fixation Surface Improves Glenoid Prosthesis Longevity in vitro. AB - : Many commercial cemented glenoid components claim superior fixation designs and increased survivability. However, both research and clinical studies have shown conflicting results and it is unclear whether these design variations do improve loosening rates. Part of the difficulty in investigating fixation failure is the inability to directly observe the fixation interface, a problem addressed in this study by using a novel experimental set-up. Cyclic loading-displacement tests were carried out on 60 custom-made glenoid prostheses implanted into a bone substitute. Design parameters investigated included treatment of the fixation surface of the component resulting in different levels of back-surface roughness, flat-back versus curved-back, keel versus peg and more versus less conforming implants. Visually-observed failure and ASTM-recommended rim-displacements were recorded throughout testing to investigate fixation failure and if rim displacement is an appropriate measure of loosening. Roughening the implant back (Ra>3um) improved resistance to failure (P<0.005) by an order of magnitude with the rough and smooth groups failing at 8712+/-5584 cycles (mean+/-SD) and 1080+/ 1197 cycles, respectively. All other design parameters had no statistically significant effect on the number of cycles to failure. All implants failed inferiorly and 95% (57/60) at the implant/cement interface. Rim-displacement correlated with visually observed failure. The most important effect was that of roughening the implant, which strengthened the polyethylene-cement interface. Rim displacement can be used as an indicator of fixation failure, but the sensitivity was insufficient to capture subtle effects. LEVEL OF EVIDENCE: Basic Science Study, Biomechanical Analysis. PMID- 28811044 TI - Learning how to "teach one": A needs assessment of the state of faculty development within the Consortium of the American College of Surgeons Accredited Education Institutes. AB - BACKGROUND: Developing faculty competencies in curriculum development, teaching, and assessment using simulation is critical for the success of the Consortium of the American College of Surgeons Accredited Education Institutes program. The state of and needs for faculty development in the Accredited Education Institute community are unknown currently. The Faculty Development Committee of the Consortium of the Accredited Education Institutes conducted a survey of Accredited Education Institutes to ascertain what types of practices are used currently, with what frequency, and what needs are perceived for further programs and courses to guide the plan of action for the Faculty Development Committee. METHODS: The Faculty Development Committee created a 20-question survey with quantitative and qualitative items aimed at gathering data about practices of faculty development and needs within the Consortium of Accredited Education Institutes. The survey was sent to all 83 Accredited Education Institutes program leaders via Survey Monkey in January 2015 with 2 follow-up reminders. Quantitative data were compiled and analyzed using descriptive statistics, and qualitative data were interpreted for common themes. RESULTS: Fifty-four out of the 83 programs (65%) responded to the survey. Two-thirds of the programs had from 1 to 30 faculty teaching at their Accredited Education Institutes. More than three-quarters of the programs taught general surgery, emergency medicine, or obstetrics/gynecology. More than 60% of programs had some form of faculty development, but 91% reported a need to expand their offerings for faculty development with "extreme value" for debriefing skills (70%), assessment (47%), feedback (40%), and curriculum development (40%). Accredited Education Institutes felt that the Consortium could assist with faculty development through such activities as the provision of online resources, sharing of best practices, provision of a blueprint for development of a faculty curriculum and information related to available, credible master programs of faculty development and health professions education. CONCLUSION: Many Accredited Education Institutes programs are engaged in faculty development activities, but almost all see great needs in faculty development related to debriefing, assessment, and curricular development. These results should help to guide the action and decision-making of the Consortium Faculty Development Committee to improve teaching within the American College of Surgeons Accredited Education Institutes. PMID- 28811045 TI - Laparoscopic dissection of female pelvis in 10 steps. PMID- 28811046 TI - Effect of real-time biofeedback on peak knee adduction moment in patients with medial knee osteoarthritis: Is direct feedback effective? AB - BACKGROUND: Gait modifications can reduce the knee adduction moment, a representation of knee loading. Reduced loading may help to slow progression of medial knee osteoarthritis. We aimed to investigate the response of patients with medial knee osteoarthritis to direct feedback on the knee adduction moment as a method for modifying the gait pattern, before and after training with specific gait modifications. METHODS: Forty patients with medial knee osteoarthritis underwent 3D gait analysis on an instrumented-treadmill, while receiving real time feedback on the peak knee adduction moment. Patients were trained with three different modifications; toe-in, wider steps and medial thrust gait. The response to real-time feedback on the knee adduction moment was measured before and after training. To evaluate the short term retention effect, we measured the changes without feedback. We also evaluated the effects on the knee flexion moment and at the hip and ankle joints. FINDINGS: With direct feedback on the knee adduction moment, patients were initially unable to reduce the knee adduction moment. After training with specific modifications, peak knee adduction moment was reduced by 14% in response to direct feedback. Without feedback a 9% reduction in peak knee adduction moment was maintained. Hip moments were not increased with modified gait, but small increases in ankle adduction moment and knee flexion moment were observed. INTERPRETATION: Real-time biofeedback directly on the knee adduction moment is a promising option for encouraging gait modifications to reduce knee loading, however only when combined with specific instructions on how to modify the gait. PMID- 28811047 TI - Development of an item bank to measure factual disease and treatment related knowledge of rheumatoid arthritis patients in the treat to target era. AB - OBJECTIVE: To develop a Disease and treatment associated Knowledge in RA item bank (DataK-RA) based on item response theory. METHODS: Initial items were developed from a systematic review. Rheumatology professionals identified relevant content trough a RAND modified Delphi scoring procedure and consensus meeting. RA patients provided additional content trough a focus group. Patients and professionals rated readability, feasibility and comprehensiveness of resulting items. Cross-sectional data were collected to evaluate psychometric properties of the items. RESULTS: Data of 473 patients were used for item reduction and calibration. Twenty items were discarded based on corrected item total point biserial correlation <0.30. Confirmatory factor analysis with weighted least squares estimation on the polychoric correlation matrix suggested good fit for a unidimensional model for the remaining 42 items (CFI 0.97 TLI=0.97, RMSEA=0.02, WRMR=0.97), supporting the proposed scoring procedure. Scores were highly reliable and normally distributed with minimal ceiling (1.8%) and no floor effects. 75% of tested hypotheses about the association of DataK-RA scores with related constructs were supported, indicating good construct validity. CONCLUSION: DataK-RA is a psychometrically sound item bank. PRACTICE IMPLICATIONS: DataK-RA provides health professionals and researchers with a tool to identify and target patients' information needs or to assess effects of educational efforts. PMID- 28811049 TI - Marijuana and Cannabinoids in ESRD and Earlier Stages of CKD. AB - Marijuana is the most commonly used recreational drug in the United States, and legal recreational and medicinal use has gained public acceptance during the last decade. Twenty-nine US states have established medical marijuana programs, 8 of which have also legalized recreational marijuana, and Canada is expected to legalize recreational marijuana in 2018. Advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) are chronic conditions with significant associated morbidity and mortality. Patients experience substantial symptom burden that is frequently undertreated due to adverse medication side effects. This article reviews the available evidence for the use of medical marijuana to manage chronic pain, nausea/vomiting, anorexia/cachexia, and pruritus, all of which are frequently reported by patients with advanced CKD or ESRD. Potential adverse health effects of medical and recreational marijuana use are also discussed. Regardless of personal, social, and political beliefs, marijuana use is becoming mainstream, and nephrologists should be aware of the potential impact on our patient population. Further research is warranted to investigate the renal endocannabinoid system, the impact of marijuana use on kidney disease outcomes, and the risks and benefits of medical marijuana use on symptoms of advanced CKD and ESRD. PMID- 28811048 TI - Receipt of Nephrology Care and Clinical Outcomes Among Veterans With Advanced CKD. AB - BACKGROUND: Clinical practice guidelines recommend referral to nephrology when estimated glomerular filtration rate (eGFR) decreases to <30mL/min/1.73m2; however, evidence for benefits of nephrology care are mixed. STUDY DESIGN: Observational cohort using landmark analysis. SETTINGS & PARTICIPANTS: A national cohort of veterans with advanced chronic kidney disease, defined as an outpatient eGFR<=30mL/min/1.73m2 for January 1, 2010, through December 31, 2010, and a prior eGFR<60mL/min/1.73m2, using administrative and laboratory data from the Department of Veterans Affairs and the US Renal Data System. PREDICTOR: Receipt and frequency of outpatient nephrology care over 12 months. OUTCOMES: Survival and progression to end-stage renal disease (ESRD; receipt of dialysis or kidney transplantation) were the primary outcomes. In addition, control of associated clinical parameters over 12 months were intermediate outcomes. RESULTS: Of 39,669 patients included in the cohort, 14,983 (37.8%) received nephrology care. Older age, heart failure, dementia, depression, and rapidly declining kidney function were independently associated with the absence of nephrology care. During a mean follow-up of 2.9 years, 14,719 (37.1%) patients died and 4,310 (10.9%) progressed to ESRD. In models adjusting for demographics, comorbid conditions, and trajectory of kidney function, nephrology care was associated with lower risk for death (HR, 0.88; 95% CI, 0.85-0.91), but higher risk for ESRD (HR, 1.48; 95% CI, 1.38-1.58). Among patients with clinical parameters outside guideline recommendations at cohort entry, a significantly higher adjusted proportion of patients who received nephrology care had improvement in control of hemoglobin, potassium, albumin, calcium, and phosphorus concentrations compared with those who did not receive nephrology care. LIMITATIONS: May not be generalizable to nonveterans. CONCLUSIONS: Among patients with advanced chronic kidney disease, nephrology care was associated with lower mortality, but was not associated with lower risk for progression to ESRD. PMID- 28811050 TI - Vaccine decision-making begins in pregnancy: Correlation between vaccine concerns, intentions and maternal vaccination with subsequent childhood vaccine uptake. AB - INTRODUCTION: Maternal and childhood vaccine decision-making begins prenatally. Amongst pregnant Australian women we aimed to ascertain vaccine information received, maternal immunisation uptake and attitudes and concerns regarding childhood vaccination. We also aimed to determine any correlation between a) intentions and concerns regarding childhood vaccination, (b) concerns about pregnancy vaccination, (c) socioeconomic status (SES) and (d) uptake of influenza and pertussis vaccines during pregnancy and routine vaccines during childhood. METHODS: Women attending public antenatal clinics were recruited in three Australian states. Surveys were completed on iPads. Follow-up phone surveys were done three to six months post delivery, and infant vaccination status obtained via the Australian Childhood Immunisation Register (ACIR). RESULTS: Between October 2015 and March 2016, 975 (82%) of 1184 mothers consented and 406 (42%) agreed to a follow up survey, post delivery. First-time mothers (445; 49%) had significantly more vaccine concerns in pregnancy and only 73% had made a decision about childhood vaccination compared to 89% of mothers with existing children (p value<0.001). 66% of mothers reported receiving enough information during pregnancy on childhood vaccination. In the post delivery survey, 46% and 82% of mothers reported receiving pregnancy influenza and pertussis vaccines respectively. The mother's degree of vaccine hesitancy and two attitudinal factors were correlated with vaccine uptake post delivery. There was no association between reported maternal vaccine uptake or SES and childhood vaccine uptake. CONCLUSION: First time mothers are more vaccine hesitant and undecided about childhood vaccination, and only two thirds of all mothers believed they received enough information during pregnancy. New interventions to improve both education and communication on childhood and maternal vaccines, delivered by midwives and obstetricians in the Australian public hospital system, may reduce vaccine hesitancy for all mothers in pregnancy and post delivery, particularly first-time mothers. PMID- 28811051 TI - Patient Blood Management in the Intensive Care Unit. AB - Patient Blood Management underscores a fundamental shift from a product-centered approach to a patient-centric approach through timely application of evidence based medical and surgical concepts designed to maintain hemoglobin concentration, optimize hemostasis, and minimize blood loss in an effort to improve patient outcome. In this concept, allogeneic blood transfusion is not viewed as the treatment of default for anemic patients, but one among many treatment modalities that should be weighed based on its merits-potentials risks and benefits-for the individual patient in the context of other alternatives. Patient blood management provides a multidisciplinary framework for patient centered decision making with strategies focusing on the management of anemia, optimization of coagulation and hemostasis, and utilization of blood conservation modalities. Among the critically ill patients, Patient Blood Management can be particularly effective given the extremely high prevalence of anemia, variable and unjustified transfusion practices, high frequency of coagulation disorders, and avoidable sources of blood loss such as unnecessary diagnostic blood draws. Proper management of anemia-prevention, screening/monitoring, diagnostic workup, and treatment including hematinic agents-is the key to effective implementation of patient blood management. Blood transfusions should be used in accordance of current guidelines, which are supportive of more restrictive transfusion strategies in most critically ill patients. Emerging studies report on the success of Patient Blood Management programs in reducing transfusion utilization, reducing the burden of anemia in patients, and improving patient outcomes including shortened length of hospital stays, less frequency of complications and lower risk of mortality. PMID- 28811052 TI - Current and future perspectives on the evaluation, prevention and conservative management of breast cancer related lymphoedema: A best practice guideline. PMID- 28811053 TI - Burns first aid treatment in remote Northern Australia. AB - BACKGROUND AND OBJECTIVE: It is well demonstrated that adequate burns first aid treatment (BFAT) improves clinical outcomes for the injured but adequacy remains low in many studies. This study presents a twelve month assessment of the adequacy of burns first aid treatment for patients managed by the Burns Service, Royal Darwin Hospital (RDH). METHODS: Prospective study design of all patients managed by the Burns Service, Royal Darwin Hospital. Data were collated from two sources; RDH Burns Registry, and the Burns Registry of Australia and New Zealand (BRANZ). Inclusion criterion was all patients managed by the Burns Service, Royal Darwin Hospital for the period 1 January 2014-31 December 2014. Variables collected and analysed include: demographics, burn mechanism, burn wound depth and adequacy of and circumstances around first aid. RESULTS: Overall 310 cases were analysed. Most injuries involved adults (68%), 19% Indigenous persons and 70% of all patients had their burn injury occur in the urban region. Adequate BFAT occurred in 41% of cases. Adults, contact burns and those where the burn injury occurred in the remote regions were less likely to receive adequate BFAT. Indigenous persons were less likely to attempt any BFAT at all and when they did receive BFAT it was more likely applied by an emergency responder or health professional. CONCLUSION: Overall adequacy of BFAT is low in the Top End of the Northern Territory. Remote dwellers and Indigenous persons are at increased risk of not applying or receiving adequate BFAT. The poor level of adequate BFAT demonstrated in this study suggests that the Top End community particularly remote and Indigenous persons would benefit from targeted BFAT education programs that are delivered in a culturally and linguistically appropriate fashion. PMID- 28811054 TI - Geographic modeling for children at risk for home fires and burns. AB - This study developed a predictive model for fires and burns among parents and children in Jefferson County, Kentucky. Eight risk factors for pediatric burns with census tract level data available were identified. Risk factors were synthesized to develop a cartographic model with risk levels low, medium, high, and severe. Validation was performed with fire dispatch data. At-risk areas were concentrated in the county's northwest. Risk was correlated with fire incidence rate (rho=0.67, p<0.001). Significant risk factors were race (beta=0.54, p<0.001), education (beta=0.38, p<0.001), and year home built (beta=-0.17, p=0.005). Cartographic modeling is a underutilized tool to identify at-risk areas. PMID- 28811055 TI - [Tutor and resident in rural rotation]. PMID- 28811056 TI - Measurements of ionic concentrations along with endocochlear potential in wild type and claudin 14 knockout mice. AB - OBJECTIVE: To examine whether the changes in endolymphatic ion concentrations were involved in hair cells degeneration in claudin-14 knockout (KO) mice (Cldn14 /-), we measured the endocochlear potential (EP) along with concentrations of K+, Na+, H+, or Ca2+ ([K]e, [Na]e, pHe, [Ca]e) in Cldn14-/-, in which hair cells were selectively damaged, and compared with measurements in wild type mice (Wt). METHODS: We used the Cldn14-/- from 3 weeks of age, in which the auditory brain responses (ABR) was severely diminished. Using double-barreled ion-selective microelectrodes, we measured [K]e, [Na]e, pHe, and [Ca]e in both Wt and Cldn14-/- at 8-10 weeks of age. RESULTS: (1) In Wt, the EP was +92mV. [K]e, [Na]e, pHe, and [Ca]e were 169mM, ~1.0mM, 7.50, and 395nM, respectively. In the Cldn14-/-, the EP was +96mV. [K]e, [Na]e, pHe, and [Ca]e were 167mM, ~1.0mM, 7.73, and 179nM, respectively. No significant differences in the above values were observed between Wt and Cldn14-/-. (2) A significant linear correlation between EP and [Ca]e (R=0.93) was observed for both Wt and Cldn14-/-, but no correlation was observed between EP and K+, Na+, or H+. CONCLUSION: These findings suggest that (1) the changes in endolymphatic ion concentrations might not be involved in hair cells degeneration in Cldn14-/-, (2) [Ca]e might be regulated by EP in both Wt and Cldn14-/-. PMID- 28811057 TI - An Integrative Review of Social Determinants of Health Assessment and Screening Tools Used in Pediatrics. AB - PROBLEM: Social and physical contexts which make up social determinants of health (SDOH) have tremendous impacts on youth development, health and well-being. Despite knowledge and evidence of these impacts, few pediatric SDOH screening tools are known. The purpose of this review was to identify and evaluate available pediatric SDOH screening tools. ELIGIBILITY CRITERIA: Articles were limited to studies in the English language, with pediatric populations, conducted in the United States, and were peer-reviewed, primary studies. SAMPLE: Search of 3 databases (PsychInfo, CINAHL and PubMed) yielded 499 articles, 486 were excluded. Total of 13 articles were appraised and synthesized using the SDOH framework outlined by Healthy People 2020. RESULTS: Thirteen articles relevant to the assessment of SDOH domains were evaluated. Majority of studies were limited in both the number of SDOH domains screened and the depth of screening. Tools were heterogeneous in methods used to assess SDOH risks and few were validated. Limited number of studies included youth or families in the initial development of tools. CONCLUSIONS: Despite growing recognition across healthcare that SDOH greatly influence pediatric health risks, management and outcomes, there is a dearth of available high quality, multidimensional, comprehensive screening tools for pediatric care professionals. IMPLICATIONS: This review emphasizes the need for the continued development of effective, comprehensive and practical tools for assessing pediatric SDOH risk factors. Pediatric nursing care includes the assessment of the youth and family context to effectively evaluate resource needs. Pediatric nurses are well poised to address this knowledge and resource gap. PMID- 28811058 TI - Early Detection of Tuberous Sclerosis Complex: An Opportunity for Improved Neurodevelopmental Outcome. AB - BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant condition associated with epilepsy, benign tumors, and variable neurodevelopmental outcomes. The diagnosis is most commonly made after epilepsy onset, although a proportion are diagnosed prenatally. Presymptomatic or early treatment with agents such as vigabatrin offers the hope of improved neurodevelopmental outcome. Therefore early diagnosis, before the onset of seizures, is important. In a cohort of children with TSC, we evaluated the age and mode of initial presentation, assessed the neurocognitive and epilepsy outcome, and analyzed whether those diagnosed before the onset of seizures have a different outcome compared with those diagnosed postseizures. METHODS: We reviewed patients at the TSC clinic at Sydney Children's Hospital who were born between 2001 and 2015. RESULTS: A total of 74 patients were identified: 34 (46%) diagnosed preseizure (21 prenatally) and 40 (54%) postseizure. In the preseizure cohort, 77% presented with cardiac rhabdomyoma(s) and 72% developed seizures. The postseizure cohort had more severe epilepsy, requiring more antiepileptic drugs for seizure control (median five, compared with three in the preseizure cohort [P = 0.01]). Developmental disability occurred in 65% of the preseizure cohort compared with 72% of the postseizure cohort. Severe developmental disability most often occurred in children who had their first seizure before age 12 months. CONCLUSION: Children who are diagnosed with TSC before the onset of seizures have less severe epilepsy and better developmental outcome. PMID- 28811059 TI - An Infant With Epilepsy and Recurrent Hemiplegia due to Compound Heterozygous Variants in ATP1A2. AB - BACKGROUND: Pathogenic heterozygous variants in the ATP1A2 gene have most commonly been associated with familial hemiplegic migraine. However, a wide spectrum of phenotypes that include alternating hemiplegia of childhood and epilepsy have been described. PATIENT DESCRIPTION: We describe a boy who presented at age three months with a complex phenotype that included epilepsy, nonepileptic paroxysmal events, and recurrent hemiplegia. Magnetic resonance imaging demonstrated unilateral cortical edema during a severe episode of hemiplegia that was followed by a persistent mild hemiparesis. RESULTS: Whole exome sequencing identified a previously reported ATP1A2 missense variant (p.Arg548Cys) classified as pathogenic and a novel missense variant (p.Arg1008Trp) classified as a variant of uncertain significance. After this genetic diagnosis, treatment with flunarizine was initiated and no further episodes of hemiplegia have occurred. CONCLUSIONS: This is only the second report of compound heterozygosity of the ATP1A2 gene. It demonstrates the spectrum of paroxysmal neurological events that can arise as a result of ATP1A2 variants, with unique features overlapping alternating hemiplegia of childhood, hemiplegic migraine, and epilepsy. This child illustrates the diagnostic challenges that these disorders can present and the importance of genetic diagnosis in guiding management. PMID- 28811060 TI - Isolated Osteochondral Fracture of the Trochlea in the Coronal Plane in a Child Before Ossification of the Trochlea: A Case Report and Literature Review. AB - Isolated coronal shear fracture of the trochlea is a rare injury. Isolated fractures of the humeral trochlea have all been reported in adults. We present the case of a 7-year-old boy with pain and swelling of the elbow joint. Magnetic resonance imaging and arthrogram revealed an isolated osteochondral fracture of the trochlea in the coronal plane. Ossification of the trochlea had not yet occurred. An anterior approach was used for reduction and fixation of the fragment. A good clinical outcome was achieved with no signs of bony or chondral necrosis of the fragment 1 year after surgery. PMID- 28811061 TI - Surgical Demographics of Carpal Tunnel Syndrome and Cubital Tunnel Syndrome Over 5 Years at a Single Institution. AB - PURPOSE: Carpal tunnel and cubital tunnel syndrome are the 2 most common upper limb compressive neuropathies. However, whether the characteristics of patient populations undergoing surgery for these conditions are similar is unclear in terms of demographics and concomitant pathologies. Our null hypothesis was that there are no identifiable differences between these patient populations. METHODS: A retrospective cohort study was performed by billing system query using Common Procedural Terminology (CPT) codes for all patients who underwent open carpal tunnel release (CTR) (CPT code 64721) and/or open cubital tunnel surgery (CPT code 64718) by 1 of 4 hand surgeons from August 2008 to July 2013. Application of exclusion criteria of acute trauma, revision surgery, neoplasm, age less than 18 years, and inaccurate or insufficient records resulted in identification of 1,114 patients who underwent CTR, 264 patients who underwent cubital tunnel surgery, and 76 patients who underwent both. Computerized medical records were analyzed for demographic variables, medical comorbidities, and other procedures performed under the same anesthetic. RESULTS: In the multivariable analysis, older age, female sex, higher body mass index, trigger finger, and de Quervain tenosynovitis were associated with CTR. Prior trauma to the anatomic site was more common in the cubital tunnel group. Diabetes mellitus was associated with patients who had both procedures. CONCLUSIONS: The populations of patients who undergo surgery for different upper-extremity compressive neuropathies are not homogenous: CTR is associated with older age, female sex, higher body mass index, and hand tendinopathies. Cubital tunnel decompression is associated with prior trauma to the anatomic site. Diabetic patients are more likely to have both procedures. Diabetic patients undergoing either procedure should be evaluated for other peripheral nerve compression pathologies. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic IV. PMID- 28811062 TI - Validation of the prostate health index in a predictive model of prostate cancer. AB - OBJECTIVES: To validate and analyse the clinical usefulness of a predictive model of prostate cancer that incorporates the biomarker "[-2] pro prostate-specific antigen" using the prostate health index (PHI) in decision making for performing prostate biopsies. MATERIAL AND METHODS: We isolated serum from 197 men with an indication for prostate biopsy to determine the total prostate-specific antigen (tPSA), the free PSA fraction (fPSA) and the [-2] proPSA (p2PSA). The PHI was calculated as p2PSA/fPSA*?tPSA. We created 2 predictive models that incorporated clinical variables along with tPSA or PHI. The performance of PHI was assessed with a discriminant analysis using receiver operating characteristic curves, internal calibration and decision curves. RESULTS: The areas under the curve for the tPSA and PHI models were 0.71 and 0.85, respectively. The PHI model showed a better ability to discriminate and better calibration for predicting prostate cancer but not for predicting a Gleason score in the biopsy >=7. The decision curves showed a greater net benefit with the PHI model for diagnosing prostate cancer when the probability threshold was 15-35% and greater savings (20%) in the number of biopsies. CONCLUSIONS: The incorporation of p2PSA through PHI in predictive models of prostate cancer improves the accuracy of the risk stratification and helps in the decision-making process for performing prostate biopsies. PMID- 28811063 TI - Sperm quality variables as indicators of bull fertility may be breed dependent. AB - A means of discriminating among bulls of high fertility based on sperm quality is needed by breeding centers. The objective of the study was to examine parameters of sperm quality in bulls of known fertility to identify useful indicators of fertility. Frozen semen was available from bulls of known fertility (Viking Genetics, Skara, Sweden): Swedish Red (n=31), Holstein (n=25) and Others (one each of Charolais, Limousin, Blonde, SKB). After thawing, the sperm samples were analyzed for motility (computer assisted sperm analysis), plasma membrane integrity, chromatin integrity, acrosome status, mitochondrial activity and reactive oxygen species. A fertility index score based on the adjusted 56-day non return rate for >1000 inseminations was available for each bull. Multivariate data analysis (Partial Least Squares Regression and Orthogonal Partial Least Squares Regression) was performed to identify variables related to fertility; Pearson univariate correlations were made on the parameters of interest. Breed of bull affected the relationship of sperm quality variables and fertility index score, as follows: Swedish Red: %DNA Fragmentation Index, r=-0.56, P<0.01; intact plasma membrane, r=0.40, P<0.05; membrane damaged, not acrosome reacted, r=-0.6, P<0.01; Linearity, r=0.37, P<0.05; there was a trend towards significance for Wobble, r=0.34, P=0.08. Holstein: Linearity was significant r=0.46, P<0.05; there was a trend towards significance for Wobble, r=0.45, P=0.08. In conclusion, breed has a greater effect on sperm quality than previously realized; different parameters of sperm quality are needed to indicate potential fertility in different breeds. PMID- 28811065 TI - Erratum to 'Could Linear Hysteresis Contribute to Shear Wave Losses in Tissues? [Ultrasound Med Biol 41 (2015) 1100-1104]. PMID- 28811064 TI - Evaluation of Non-alcoholic Fatty Liver Disease Using Acoustic Radiation Force Impulse Imaging Elastography in Rat Models. AB - The aim of this study is to evaluate the utility of acoustic radiation force impulse (ARFI) elastography for assessing hepatic fibrosis stage and non alcoholic fatty liver disease (NAFLD) severity, as well as the relationship among hepatic histologic changes using shear wave velocity (SWV). Animal models with various degrees of NAFLD were established in 110 rats. The right liver lobe was processed and embedded in a fabricated gelatin solution (porcine skin). Liver mechanics were measured using SWV induced by acoustic radiation force. Among the histologic findings, liver elasticity could be used to differentiate normal rats from rats with simple steatosis (SS) as well as distinguish SS from non-alcoholic steatohepatitis (NASH), with areas under the receiver operating characteristic curves (AUROC) of 0.963 (95% confidence interval = 0.871-0.973) and 0.882 (95% confidence interval = 0.807-0.956), respectively. For NAFLD rats, the diagnostic performance of ARFI elastography in predicting significant fibrosis (F >= 2) had an AUROC of 0.963. For evaluating steatosis severity, we found a progressive increase in ARFI velocity proportional to steatotic severity in NAFLD rat models, but we observed no significant differences for steatotic severity after excluding the rats with fibrosis. ARFI elastography may be used to differentiate among degrees of severity of NAFLD and hepatic fibrotic stages in NAFLD rat models. PMID- 28811066 TI - PhD by Prior Publication: An New Approach to the Doctoral Thesis. PMID- 28811067 TI - Aspergilloma in Honeycomb Cysts and Paraseptal Emphysema: An Unusual Association. PMID- 28811069 TI - Prevalence of primate and interdental spaces for primary dentition in 3- to 6 year-old children in Taiwan. AB - BACKGROUND/PURPOSE: Spaced primary dentition plays a critical role in the eruption of permanent teeth and the establishment of ideal occlusion. A lack of these spaces in deciduous dentition may result in disproportionate jaw and tooth sizes. Additionally, spaced primary dentition is significantly affected by ethnic factors. However, few of these studies have been conducted in Asia. The purpose of this study was to investigate the prevalence of spaced primary dentition in Taiwan. METHODS: One hundred and forty-seven 3- to 6-year-old Taiwanese children (58 girls and 89 boys) were recruited for a cross-sectional study. Primate and interdental spaces were recorded by intraoral photos. The prevalence of spaced dentition was evaluated. The interpersonal agreement of spaced dentition between the upper and lower arches was also assessed. RESULTS: Most of the subjects had spaced primary dentition. The prevalence of primate space was 83.7% in the upper arch and 61.2% in the lower arch, whereas the prevalence of interdental space was 44.2% in the upper arch and 53.1% in the lower arch. The prevalence rates of interdental space and upper primate space were significantly higher in boys than in girls. Interdental spaces of the lower arch increased with age. CONCLUSION: Ethnic factors can affect the ratio of spaced dentition. Most of the 3- to 6-year old Taiwanese children have spaced dentition. The boys have higher incidence of spaced dentition than the girls. Furthermore, primate space is more frequently found in the upper arch than in the lower arch, whereas interdental space is reversed. PMID- 28811068 TI - A positron emission tomography study of the serotonergic system in relation to anxiety in depression. AB - Symptoms of anxiety are highly comorbid with major depressive disorder (MDD) and are known to alter the course of the disease. To help elucidate the biological underpinnings of these prevalent disorders, we previously examined the relationship between components of anxiety (somatic, psychic and motoric) and serotonin 1A receptor (5-HT1A) binding in MDD and found that higher psychic and lower somatic anxiety was associated with greater 5-HT1A binding. In this work, we sought to examine the correlation between these anxiety symptom dimensions and 5-HTT binding. Positron emission tomography with [11C]-3-amino-4-(3-dimethylamino methylphenylsulfanyl)-benzonitrile ([11C]DASB) and a metabolite-corrected arterial input function were used to estimate regional 5-HTT binding in 55 subjects with MDD and anxiety symptoms. Somatic anxiety was negatively correlated with 5-HTT binding in the thalamus (beta=-.33, p=.025), amygdala (beta=-.31, p=.007) and midbrain (beta=-.72, p<.001). Psychic anxiety was positively correlated with 5-HTT binding in midbrain only (beta=.46, p=.0025). To relate to our previous study, correlation between 5-HT1A and 5-HTT binding was examined, and none was found. We also examined how much of the variance in anxiety symptom dimensions could be explained by both 5-HTT and 5-HT1A binding. The developed model was able to explain 68% (p<.001), 38% (p=.012) and 32% (p=.038) of the total variance in somatic, psychic, and motoric anxiety, respectively. Results indicate the tight coupling between the serotonergic system and anxiety components, which may be confounded when using aggregate anxiety measures. Uncovering serotonin's role in anxiety and depression in this way may give way to a new generation of therapeutics and treatment strategies. PMID- 28811070 TI - Evaluation of sequence variability in HIV-1 gp41 C-peptide helix-grafted proteins. AB - Many therapeutically-relevant protein-protein interactions (PPIs) have been reported that feature a helix and helix-binding cleft at the interface. Given this, different approaches to disrupting such PPIs have been developed. While short peptides (<15 amino acids) typically do not fold into a stable helix, researchers have reported chemical approaches to constraining helix structure. However, these approaches rely on laborious, and often expensive, chemical synthesis and purification. Our premise is that protein-based solutions that stabilize a therapeutically-relevant helix offer a number of advantages. In contrast to chemically constrained helical peptides, or minimal/miniature proteins, which must be synthesized (at great expense and labor), a protein can be expressed in a cellular system (like all current protein therapeutics). If selected properly, the protein scaffold can stabilize the therapeutically relevant helix. We recently reported a protein engineering strategy, which we call "helix-grafted display", and applied it to the challenge of suppressing HIV entry. We have reported helix-grafted display proteins that inhibit formation of an intramolecular PPI involving HIV gp41 C-peptide helix, and HIV gp41 N-peptide trimer, which contain C-peptide helix-binding clefts. Here, we used yeast display to screen a library of grafted C-peptide helices for N-peptide trimer recognition. Using 'hits' from yeast display library screening, we evaluated the effect helix mutations have on structure, expression, stability, function (target recognition), and suppression of HIV entry. PMID- 28811071 TI - Biological evaluation of 2-pyrazolinyl-1-carbothioamide derivatives against HCT116 human colorectal cancer cell lines and elucidation on QSAR and molecular binding modes. AB - In the search of compounds exhibiting anticancer activity, 37 derivatives of 2 pyrazolinyl-1-carbothioamide were designed and synthesized. Clonogenic cell survival assays were adapted to measure the cytotoxicities of the synthetic derivatives against HCT116 human colon cancer cell lines. Half-maximal cell growth inhibitory concentrations (GI50) ranged from 0.49 to 41.22uM. The compound with the lowest GI50 value, 3-(2-hydroxy-4,5-dimethoxyphenyl)-5-(naphthalen-1-yl) N-(3,4,5-trimethoxyphenyl)-pyrazolinyl-1-carbothioamide, was subjected to further biological studies, including cell viability and apoptosis assays to examine levels of annexin-V in the outer plasma membrane layer and poly ADP-ribose polymerase cleavage. Additionally, in vitro kinase assays were performed, and Abelson murine leukemia viral oncogene homolog 1 (Abl 1) tyrosine kinase demonstrated good inhibitory activity. The binding mode between the compound of interest and Abl 1 was elucidated using in silico docking. The pharmacophores derived for 2-pyrazolinyl-1-carbothioamides based on their quantitative structure activity relationships will help us design novel chemotherapeutic agents. PMID- 28811073 TI - Quality of life of people living with HIV compared with that of the general population in Japan. AB - OBJECTIVE: To evaluate the health-related quality of life (HRQOL) of people living with HIV (PLWH) in Japan. METHODS: A cross-sectional comparative study was conducted between June and December 2016 on PLWH. HRQOL was assessed using the Japanese version of the Short Form-36 Health Survey questionnaire (SF-36), and the three-component model of SF-36 scores was used. The values from the present study were compared with the published general Japanese values. Multivariate analysis was performed to identify the independent factors associated with the HRQOL of PLWH. RESULTS: A total of 151 PLWH were enrolled in the present study. Six out of the eight subscales were significantly lower than the normative data. With respect to the summary scores, compared with those in the general population, the physical component summary score (PCS) was significantly higher in PLWH, although the mental and social/role component summary scores (MCS and RCS, respectively) were lower. Older Age was independently related to lower PCS; formal employment and higher CD4 counts were independently related to higher PCS. The factor associated with lower MCS was taking psychoactive drug(s). Formal employment was independently associated with higher RCS; taking psychoactive drug(s) was independently associated with lower RCS. CONCLUSIONS: The physical HRQOL of PLWH was slightly higher; however, the mental and social/role HRQOL were slightly lower than in the general population in Japan. PMID- 28811072 TI - Evolution of hemoglobin loci and their regulatory elements. AB - Across the expanse of vertebrate evolution, each species produces multiple forms of hemoglobin in erythroid cells at appropriate times and in the proper amounts. The multiple hemoglobins are encoded in two globin gene clusters in almost all species. One globin gene cluster, linked to the gene NPRL3, is preserved in all vertebrates, including a gene cluster encoding the highly divergent globins from jawless vertebrates. This preservation of synteny may reflect the presence of a powerful enhancer of globin gene expression in the NPRL3 gene. Despite substantial divergence in noncoding DNA sequences among mammals, several epigenetic features of the globin gene regulatory regions are preserved across vertebrates. The preserved features include multiple DNase hypersensitive sites, at least one of which is an enhancer, and binding by key lineage-restricted transcription factors such as GATA1 and TAL1, which in turn recruit coactivators such as P300 that catalyze acetylation of histones. The maps of epigenetic features are strongly correlated with activity in gene regulation, and resources for accessing and visualizing such maps are readily available to the community of researchers and students. PMID- 28811075 TI - Regulatory T cell deficient scurfy mice exhibit a Th2/M2-like inflammatory response in the skin. AB - BACKGROUND: Scurfy mice have a functional defect in regulatory T cells (Treg), which leads to lethal multi-organ inflammation. The missing Treg function results in uncontrolled autoimmune cellular and humoral inflammatory responses. We and others have previously shown that during the course of disease scurfy mice develop severe skin inflammation and autoantibodies including anti-nuclear autoantibodies (ANA). OBJECTIVE: Autoimmune skin inflammation and ANA are hallmarks for the diagnosis of autoimmune connective tissue diseases; therefore we analyzed scurfy mice for typical signs of these diseases. METHODS: Indirect immunofluorescence was used to specify the ANA pattern in scurfy mice. Skin fibrosis was assessed by cutaneous collagen accumulation (Goldeners trichrome staining), collagen crosslinking/disorganization (Sirus red polarimetry) and quantitative PCR for fibrosis-related transcripts. The cellular components of the inflammatory infiltrates in scurfy skin were analyzed by flow cytometry and intracellular cytokine staining. RESULTS: The majority of scurfy mice developed ANA with a predominant AC-5 pattern typical for mixed connective tissue disease, especially scleroderma. Scurfy mice showed higher skin collagen content compared to WT controls with a significant tendency in upregulation of TIMP-1. CD3+CD4+ T cells in scurfy skin exhibited a strong Th2 deviation with a significant increase of IL-4, IL-5 and IL-13, and M2-polarized CD11b+MHCII+ macrophages compared to WT mice. CONCLUSION: We show that Scurfy mice show a predominant AC-5 ANA pattern typical for mixed connective tissue disease as in scleroderma. The autoimmune inflammation in scurfy skin mainly consists of CD4+ T cells with Th2 differentiation and alternatively-activated (M2) macrophages as it is found in scleroderma with advanced fibrosis. PMID- 28811076 TI - Submucosal injection of dexamethasone and methylprednisolone for the control of postoperative sequelae after third molar surgery: randomized controlled trial. AB - Pain, swelling, and trismus are known sequelae of third molar surgery that can significantly affect the individual's quality of life (QOL). These should be minimized to improve QOL. The purpose of this study was to compare the effects of the preoperative submucosal administration of equivalent doses of two commonly used steroids on these postoperative sequelae. A randomized controlled clinical trial was conducted involving 60 subjects requiring the removal of impacted mandibular third molars. Extraction cases with a similar difficulty index were included. The participants were allocated randomly to three groups: the placebo group received normal saline injection (control), while the 8mg dexamethasone group and 40mg methylprednisolone group received submucosal injections of these steroids preoperatively. Each participant was assessed for postoperative pain, swelling, and trismus, along with a subjective assessment of QOL through a structured questionnaire. The participants administered dexamethasone showed significant reductions in pain and trismus compared to the control group (P<0.05). Submucosal injection of dexamethasone was found to be superior to methylprednisolone only in terms of the reduction in swelling. QOL was minimally affected in patients administered dexamethasone as compared to methylprednisolone and control subjects. The preoperative submucosal use of steroids can be considered an effective, safe, and simple therapeutic strategy to reduce swelling, pain, and trismus after the surgical removal of impacted mandibular third molars. PMID- 28811074 TI - Management of multidrug resistant Gram-negative bacilli infections in solid organ transplant recipients: SET/GESITRA-SEIMC/REIPI recommendations. AB - Solid organ transplant (SOT) recipients are especially at risk of developing infections by multidrug resistant (MDR) Gram-negative bacilli (GNB), as they are frequently exposed to antibiotics and the healthcare setting, and are regulary subject to invasive procedures. Nevertheless, no recommendations concerning prevention and treatment are available. A panel of experts revised the available evidence; this document summarizes their recommendations: (1) it is important to characterize the isolate's phenotypic and genotypic resistance profile; (2) overall, donor colonization should not constitute a contraindication to transplantation, although active infected kidney and lung grafts should be avoided; (3) recipient colonization is associated with an increased risk of infection, but is not a contraindication to transplantation; (4) different surgical prophylaxis regimens are not recommended for patients colonized with carbapenem-resistant GNB; (5) timely detection of carriers, contact isolation precautions, hand hygiene compliance and antibiotic control policies are important preventive measures; (6) there is not sufficient data to recommend intestinal decolonization; (7) colonized lung transplant recipients could benefit from prophylactic inhaled antibiotics, specially for Pseudomonas aeruginosa; (8) colonized SOT recipients should receive an empirical treatment which includes active antibiotics, and directed therapy should be adjusted according to susceptibility study results and the severity of the infection. PMID- 28811077 TI - The receptor for advanced glycation end products: A fuel to pancreatic cancer. AB - The receptor for advanced glycation end products (RAGEs) was first illustrated in the year 1992. RAGE is a single-transmembrane and multi-ligand component of the immunoglobulin protein super family. The engagement of RAGE turns out to an establishment of numerous intracellular signalling mechanisms resulting in the progression and perpetuation of many types of cancer including, the pancreatic cancer. The present review primarily focuses on the multi-ligand activation of RAGEs leading to the downstream signalling cascade activation. The kick start of the RAGEs activation leads to the several anomalies and includes multiple types of cancers. The RAGE expression correlates well with the survival of pancreatic cancer cells leading to the myeloid response. RAGEs assist in the tumourogenesis which enhance and thrive to its fullest in the stressed tumour microenvironment. An improved perceptive of its involvement in pancreatic cancer may offer novel targets for tumour supervision and risk measurement. PMID- 28811078 TI - Mentoring models in neurosurgical training: Review of literature. AB - BACKGROUND: Effective mentoring is an invaluable element in the development of next generation of neurosurgeons. A mentor helps to develop professional core values, technical and non-technical skills, attitudes and disposition required to be qualified and competent neurosurgeon. Giving the invaluable significance of mentoring in neurosurgery, we undertook this literature review to identify mentoring models evaluating its success and relative benefit. METHODS: Literature search identified using MeSH word 'mentor', mentoring, mentorship, mentoring model, neurosurgery' in MEDLINE, EMBASE and Scopus databases from 1990 to 2016. Literature reviewed to identify status of mentoring in neurosurgery, potential barriers, pitfalls and future framework for mentoring in neurosurgery. Additional articles identified through manual search of reference lists. RESULTS: A total of 247 studies were obtained from electronic databases, after removing duplicates, abstracts, letters to the editor and non-neurosurgery papers. Sixteen full text articles retrieved out of which five met the inclusion criteria. Generally, there is paucity of articles regarding mentoring in neurosurgery, all included papers were written in English Language, all of them described mentoring model used including simulation, distance, collaborative, facilitative tele-mentoring and peer mentoring. CONCLUSION: Mentoring in Neurosurgery is an important aspect of personal and professional development of neurosurgical trainees, currently there is decline in traditional apprenticeship due to increase demand for modern use of specialised technology, simulation and tele-medicine in neurosurgery practice. Effective and efficient mentoring will be an interplay of six mentoring models (collaborative, facilitative, distance, simulation, tele mentoring and peer mentoring) identified. PMID- 28811079 TI - Neuroleptic-free youth at ultrahigh risk for psychosis evidence diminished emotion reactivity that is predicted by depression and anxiety. AB - Although abnormalities in emotional response have long been considered a core feature of the chronic phase of schizophrenia, few investigations have examined emotional response in individuals at ultrahigh-risk (UHR) for psychosis. We investigated whether neuroleptic-free UHR (n=29) and healthy control (n=32) participants differed in emotional reactivity and emotion regulation on a laboratory-based task that required reporting levels of positive and negative affect to pleasant, unpleasant, and neutral stimuli. Results indicated that the UHR group evidenced reduced emotional reactivity, including decreased positive emotion to pleasant stimuli and decreased negative emotion to unpleasant stimuli. Furthermore, within the UHR group, attenuated positive emotion to pleasant stimuli was associated with greater severity of depression and anxiety. There were no group differences in self-reported emotion regulation effectiveness to unpleasant or pleasant stimuli. Findings suggest that UHR youth display a profile of emotional experience abnormalities that differs from the chronic phase of illness, which can be characterized as reduced positive emotion reactivity to pleasant stimuli (i.e., anhedonia) that may be driven by mood and anxiety symptoms. PMID- 28811080 TI - Mechanochemical Ablation for Treatment of Truncal Venous Insufficiency: A Review of the Current Literature. AB - Mechanochemical ablation (MOCA) is a nonthermal nontumescent technique used in the treatment of superficial venous disease. This review analyzed the available data on the efficacy and safety of MOCA. A systematic literature search was performed. Of 101 studies identified, 14 were suitable for inclusion. The studies were found to be heterogeneous in design, and the quality of evidence was found to be low or very low. MOCA was demonstrated to be effective in the short-term with minimal complications. Consensus guidelines and definitions of reporting outcome measures must be standardized to allow comparison with other techniques. PMID- 28811081 TI - Prognostic value of WHO grade in pancreatic neuro-endocrine tumors in Multiple Endocrine Neoplasia type 1: Results from the DutchMEN1 Study Group. AB - BACKGROUND: The prognostic value of WHO grade in pancreatic neuroendocrine tumors (PanNETs) in patients with Multiple Endocrine Neoplasia Type 1 (MEN1) is unknown. METHODS: We performed a cohort study using the Dutch National MEN1 database, which includes >90% of the Dutch MEN1 population with data collected between 1990 and 2014. Formalin-fixed paraffin embedded tissue blocks from the largest resected PanNET per patient were collected. MIB1 staining was performed and KI67 labeling index (LI) was determined by manual eye-counting under a microscope and by digital image analysis. Mitotic count was evaluated from hematoxylin & eosin stains. Association between WHO grade and (time until) development of liver metastases was calculated. RESULTS: Sixty-nine MEN1 patients who underwent pancreatic surgery were included. Ten patients (14%) developed liver metastases and all had PanNETs >=3 cm. WHO G1, G2 and G3 PanNETs were seen in 83% (n = 57), 16% (n = 11) and 1% (n = 1) respectively. In non-functioning PanNETs >2 cm, liver metastases occurred in 80% of WHO G2 PanNETs (4/5) compared to 23% (5/22) in WHO G1 PanNETs (p = 0.03) when WHO grade was based on mitotic count only. This significant association was not seen for WHO grade based on Ki67 LI. After five years, liver metastases in non-functioning PanNETs were not seen in tumors <=2 cm, in 10% of the large WHO G1 (according to mitotic count only) tumors and in 60% of large WHO G2 tumors (p-value 0.000). CONCLUSION: High mitotic count is correlated with poor prognosis in MEN1 patients with large non-functioning PanNETs. PMID- 28811082 TI - Correlation between molecular analysis, diagnosis according to the 2015 WHO classification of unresected lung tumours and TTF1 expression in small biopsies and cytology specimens from 344 non-small cell lung carcinoma patients. AB - We investigated correlations between diagnosis according to the 2015 World Health Organization (WHO) classification of unresected lung tumours, molecular analysis and TTF1 expression in small biopsy and cytology specimens from 344 non-small cell lung carcinoma (NSCLC) patients. One case failed testing for EGFR, KRAS and ALK abnormalities and six had insufficient tumour for ALK testing. Overall mutation rate in 343 cases was 48% for the genes tested, with 19% EGFR, 33% KRAS and 4% BRAF mutations, and 5% ALK rearrangements detected. More EGFR-mutant (78%) and ALK-rearranged (75%) tumours had morphologic adenocarcinoma than KRAS-mutant (56%) tumours. Despite no significant difference in the overall rate of any molecular abnormality between morphologic adenocarcinoma (52%) and NSCLC, favour adenocarcinoma (47%) (p = 0.18), KRAS mutations were detected more frequently in the latter group. No significant difference in the overall rate of any molecular abnormality between TTF1 positive (49%) and TTF1 negative tumours (44%) (p = 0.92) was detected, but more EGFR-mutant (97%) and ALK-rearranged tumours (92%) were TTF1 positive than KRAS-mutant tumours (68%). Rates of EGFR, KRAS and BRAF mutations and ALK rearrangements in this Australian NSCLC patient population are consistent with the published international literature. Our findings suggest that 2015 WHO classification of unresected tumours may assist in identifying molecular subsets of advanced NSCLC. PMID- 28811083 TI - Phenotypic chlorhexidine and triclosan susceptibility in clinical Staphylococcus aureus isolates in Australia. AB - Antiseptics such as chlorhexidine gluconate and triclosan are widely used in healthcare settings for both skin antisepsis and decolonisation of Staphylococcus aureus. We determined the minimum inhibitory concentration (MIC) of 198 methicillin susceptible and resistant Staphylococcus aureus clinical isolates to both chlorhexidine and triclosan using an agar dilution method. Of these, 10% (19/198) showed a raised MIC to chlorhexidine and 3% (6/198) showed an elevated MIC to triclosan. The multilocus sequence type (MLST) of each isolate was predicted using a binary method, and although ST93-MRSA-IV was the most common, ST22-MRSA-IV was shown to have statistically higher chlorhexidine MIC values compared with non ST22-MRSA-IV isolates (z = -8.7, p < 0.01). Additionally, isolates from patients known to have failed decolonisation were included and did not demonstrate elevated MIC to the decolonisation antiseptic. Monitoring for non susceptibility of clinical isolates to biocides is important to determine trends, and may have clinical implications in terms of sub-lethal concentration in residues and concomitant antibiotic resistance. PMID- 28811084 TI - Low tumour cell content in a lung tumour bank: implications for molecular characterisation. AB - Lung cancer encompasses multiple malignant epithelial tumour types, each with specific targetable, potentially actionable mutations, such that precision management mandates accurate tumour typing. Molecular characterisation studies require high tumour cell content and low necrosis content, yet lung cancers are frequently a heterogeneous mixture of tumour and stromal cells. We hypothesised that there may be systematic differences in tumour cell content according to histological subtype, and that this may have implications for tumour banks as a resource for comprehensive molecular characterisation studies in lung cancer. To investigate this, we estimated tumour cell and necrosis content of 4267 samples resected from 752 primary lung tumour specimens contributed to a lung tissue bank. We found that banked lung cancer samples had low tumour cell content (33%) generally, although it was higher in carcinoids (77.5%) than other lung cancer subtypes. Tumour cells comprise a variable and often small component of banked resected tumour samples, and are accompanied by stromal reaction, inflammation, fibrosis, and normal structures. This has implications for the adequacy of unselected tumour bank samples for diagnostic and molecular investigations, and further research is needed to determine whether tumour cell content has a significant impact on analytical results in studies using tissue from tumour bank resources. PMID- 28811085 TI - The use of phenobarbital and other anti-seizure drugs in newborns. AB - Neonatal seizures constitute the most frequent presenting neurologic sign encountered in the neonatal intensive care unit. Despite limited efficacy and safety data, phenobarbital continues to be used near-universally as the first line anti-seizure drug (ASD) in neonates. The choice of second-line ASDs varies by provider and institution, and is still not supported by sufficient scientific evidence. In this review, we discuss the available evidence supporting the efficacy, mechanism of action, potential adverse effects, key pharmacokinetic characteristics such as interaction with therapeutic hypothermia, logistical issues, and rationale for use of neonatal ASDs. We describe the widely used neonatal ASDs, namely phenobarbital, phenytoin, midazolam, and levetiracetam, in addition to potential ASDs, including lidocaine, topiramate, and bumetanide. PMID- 28811086 TI - Proteomic profiling of the antifungal drug response of Aspergillus fumigatus to voriconazole. AB - Antifungal resistance is an emerging problem and one of the reasons for treatment failure of invasive aspergillosis (IA). Voriconazole has become a standard therapeutic for the treatment of this often fatal infection. We studied the differentially expressed proteins as a response of Aspergillus fumigatus to voriconazole by employing the two-dimensional difference gel electrophoresis (DIGE) technique. Due to addition of drug, a total of 135 differentially synthesized proteins were identified by MALDI-TOF/TOF-mass spectrometry. In particular, the level of proteins involved in the general stress response and cell detoxification increased prominently. In contrast, cell metabolism and energy proteins were down-regulated, which suggests the cellular effort to maintain balance in energy utilization while trying to combat the cellular stress exerted by the drug. We detected several so-far uncharacterized proteins which may play a role in stress response and drug metabolism and which could be future targets for antifungal treatment. A mutant strain, which is deleted in the cross pathway control gene cpcA, was treated with voriconazole to investigate the contribution of the general control of amino acid biosynthesis to drug resistance. We compared the mutant strain's protein expression profile with the wild-type strain. The absence of CpcA led to an increased resistance to voriconazole and a reduced activation of some general stress response proteins, while the transcript level of the triazole target gene erg11A (cyp51A) remained unchanged. In contrast, the sensitivity of strain DeltacpcA to terbinafine and amphotericin B was slightly increased. These findings imply a role of CpcA in the cellular stress response to azole drugs at the post transcriptional level. PMID- 28811087 TI - Real-time qRT-PCR assay for the detection of miRNAs using bi-directional extension sequences. AB - Highly specific detection of miRNAs was performed using a novel bi-directional extension (BDE) assay. After reverse transcription, the cDNA was hybridized to a uniquely designed specific BDE sequence; this cDNA-BDE hybrid forms the PCR template. The PCR template was amplified in a SYBR Green-based quantitative real time PCR. The miR-145 in human brain total RNA could be detected quantitatively in the range of seven orders of magnitude with high linearity and reproducibility. This innovative BDE assay has several performance advantages over the poly(A) tailing method that include lower CT values, clear gel electrophoresis images, and distinct nucleotide peaks in sequencing chromatograms. PMID- 28811088 TI - Primary prevention aspirin use in high-risk patients: A pharmacist intervention and comparison of risk stratification tools. AB - OBJECTIVES: The objectives of this project are 1) to describe aspirin use for primary prevention in an underserved, minority population; 2) to determine the impact of a pharmacist-led intervention on the prevalence of aspirin use for primary prevention; and 3) to compare aspirin indications based on Framingham Risk Score (FRS) and atherosclerotic cardiovascular disease (ASCVD) risk score. METHODS: Men and women age 45-79 and 55-79 years, respectively, without ASCVD were screened for aspirin use. An FRS of 10% or greater and low risk for a serious bleed were considered indications for primary prevention aspirin on the basis of guideline-directed medical therapy recommendations. When treatment with aspirin was indicated, providers were notified with patient-specific messages. Patients' FRS and ASCVD risk score distributions were plotted and compared. Primary prevention aspirin indications were identified using both risk stratification tools. RESULTS: One hundred sixteen patients were evaluated for aspirin use in a predominantly black (80%), middle-aged (mean age, 58 years), and indigent population. Thirty-one patients (27%) had an FRS of 10% or greater and low risk for bleeding, and 10 patients (9%) were taking aspirin at baseline. Providers approved recommendations to start administering aspirin in 19 of 31 patients (61%), which significantly increased the overall proportion receiving aspirin compared to baseline (9%-25%; P < 0.01). Patients were more than twice as likely to meet the minimum risk score threshold (>=10%) for a primary prevention aspirin indication using ASCVD risk scores versus FRS (70% vs. 30%; P < 0.01). CONCLUSIONS: Baseline utilization of primary prevention aspirin was low in an indigent, minority population. A provider-focused pharmacist intervention improved the prevalence of aspirin use for primary prevention, while minimizing risk for serious bleeding events. Among our cohort, more patients had indications for primary prevention aspirin using ASCVD risk scores versus FRS. PMID- 28811089 TI - Physician experiences with clinical pharmacists in primary care teams. AB - BACKGROUND: Improving medication management is an important component of comprehensive care coordination for health systems. The Managing Your Medication for Education and Daily Support (MyMeds) medication management program at the University of California Los Angeles addresses medication management issues by embedding trained clinical pharmacists in primary care practice teams. OBJECTIVES: The aim of this work was to examine and explore physician opinions about the clinical pharmacist program and identify common themes among physician experiences as well as barriers to integration of clinical pharmacists into primary care practice teams. METHODS: We conducted a mixed quantitative qualitative methods study consisting of a cross-sectional physician survey (n = 69) as well as semistructured one-on-one physician interviews (n = 13). Descriptive statistics were used to summarize survey responses, and standard qualitative content-analysis methods were used to identify major themes from the interviews. RESULTS: The survey response rate was 61%; 13 interviews were conducted. Ninety percent of survey respondents agreed or strongly agreed that having the pharmacist in the office makes management of the patient's medication more efficient, 93% agreed or strongly agreed that pharmacist recommendations are clinically helpful, 71% agreed or strongly agreed that having access to a pharmacist has increased their knowledge about medications they prescribe, and 75% agreed or strongly agreed that having a pharmacist as part of the primary care team has made their job easier. Qualitative interviews corroborated survey findings, and physicians highlighted the value of the clinical pharmacist's communication, team care and expanded roles, and medication management. CONCLUSION: Primary care physicians valued the integrated pharmacy program highly, particularly its features of strong communication, expanded roles, and medication management. Pharmacists were viewed as integral members of the health care team. PMID- 28811090 TI - Guanosine exerts antiplatelet and antithrombotic properties through an adenosine related cAMP-PKA signaling. AB - BACKGROUND: Guanosine is a natural product and an endogenous nucleoside that has shown to increase during myocardial ischemia. Platelets are critically involved in ischemic coronary events. It remains unknown, however, whether guanosine may affect platelet activation and function. We sought to investigate the potential antiplatelet and antithrombotic properties of guanosine and decipher the mechanisms behind. METHODS: We firstly assessed the effects of guanosine on platelet activation/aggregation upon stimulation with several platelet agonists including adenosine diphosphate (ADP), collagen, arachidonic acid (AA), and TRAP 6. Guanosine antithrombotic potential was also evaluated both in vitro (Badimon perfusion chamber) and in vivo (murine model). In addition we assessed any potential effect on bleeding. At a mechanistic level we determined the release of thromboxane B2, intraplatelet cAMP levels, the binding affinity on platelet membrane, and the activation/phosphorylation of protein kinase A (PKA), phospholipase C (PLC) and PKC. RESULTS: Guanosine markedly inhibited platelet activation/aggregation-challenged by ADP and, although to a lesser extent, also reduced platelet aggregation challenged by collagen, AA and TRAP-6. Guanosine significantly reduced thrombus formation both in vitro and in vivo without significantly affects bleeding. Guanosine antiplatelet effects were associated with the activation of the cAMP/PKA signaling pathway, and a reduction in thromboxane B2 levels and PLC and PKC phosphorylation. The platelet aggregation and binding affinity assays revealed that guanosine effects on platelets were mediated by adenosine. CONCLUSION: Guanosine effectively reduces ADP-induced platelet aggregation and limits thrombotic risk. These antithrombotic properties are associated with the activation of the cAMP/PKA signaling pathway. PMID- 28811091 TI - Pregravid hypertension may have different secondary sex ratio effects in different races in the United States. AB - BACKGROUND: Males are born in excess of females and the ratio is expressed as M/F (male/female births=secondary sex ratio, also known as secondary sex ratio). This is expected to approximate 1.048. Racial M/F disparities are known. A recent study in China showed that pregravid systolic hypertension is higher in women who delivered a boy than in those who had a girl. This study was carried out in order to identify the effect of pregravid hypertension in the United States on M/F by race. METHODS: Monthly male and female live births by race for the entire US along with the presence/absence of hypertension were obtained from the website of the Centers for Disease Control and Prevention for 2007-2015 for the four racial groups: American Indian or Alaska Native, Asian or Pacific Islander, Black or African American and White. RESULTS: This study analysed 36,364,253 live births. For White births, mothers who had chronic hypertension were likelier to have male than female offspring when compared to non-hypertensives (p=0.003). Conversely, Black or African American mothers who had hypertension were less likely to have male than female offspring when compared to non-hypertensives (p=0.022). There were F differences for/F differences for the presence or absence of hypertension for the other two races or for the total. CONCLUSIONS: It is possible that hypothesised innate interracial periconceptual hormonal differences may modulate M/F responses to hypertension in different races. PMID- 28811092 TI - Direct oral anticoagulants in patients with hypertrophic cardiomyopathy and atrial fibrillation. AB - BACKGROUND: Chronic anticoagulation with vitamin K antagonists (VKAs) is recommended in patients with hypertrophic cardiomyopathy (HCM) and atrial fibrillation (AF). Direct oral anticoagulants (NOACs) are an alternative to VKAs but there are limited data to support their use in HCM. We sought to describe the pattern of use, thromboembolic events, bleeding and quality of life in patients with HCM and AF treated with NOACs. METHODS: Data from patients treated with NOACs (n=99) and VKA (n=433) at 9 inherited cardiac diseases units were retrospectively collected. Annual rates of embolic events, serious bleeding and death were analysed and compared. Quality of life and treatment satisfaction were evaluated with SF-36 and SAFUCA questionnaires in 80 NOAC-treated and 57 VKA treated patients. RESULTS: After median follow-up of 63 months (IQR: 26-109), thromboembolic events (TIA/stroke and peripheral embolism) occurred in 10% of patients on oral anticoagulation. Major/clinically relevant bleeding occurred in 3.8% and the global mortality rate was 23.3%. Thromboembolic event rate was 0.62 per 100patient-years in the NOAC group vs. 1.59 in the VKA group [subhazard ratio (SHR) 0.32;95%CI:0.04-2.45; p=0.27]. Major/clinically relevant bleeding occurred in 0.62 per 100person-years in the NOAC group vs. 0.60 in the VKA group (SHR 1.28;95%CI 0.18-9.30; p=0.85). Quality of life scores were similar in both groups; however, NOAC-treated patients achieved higher scores in the SAFUCA. CONCLUSIONS: HCM patients with AF on NOACs showed similar embolic and bleeding rates to those on VKA. Although quality of life was similar in both groups, the NOAC group reported higher treatment satisfaction. PMID- 28811093 TI - Risk factors for infective endocarditis in children with congenital heart diseases - A nationwide population-based case control study. AB - BACKGROUND: Infective endocarditis (IE) is uncommon in childhood. Its associated epidemiological characteristics in patients with congenital heart disease (CHD) remain unclear. METHODS: The study population included children born in Taiwan during the years 1997 to 2005 who were diagnosed as having CHD before 3years of age. All children were followed up until the end year of 2010, the diagnosis of infective endocarditis, or death. The demographic characteristics of patients with and without IE, the invasive procedures performed during 6months before the index date, the prophylactic antibiotics related to dental procedures, and in hospital mortality were collected. RESULTS: Information of 24,729 children with CHD were retrieved for our analysis and 237 patients with newly diagnosed IE were identified. The incidence rate of IE in all CHD lesions was 11.13 per 10,000person-years. Taking ASD for reference, the following CHD lesions were at risk for IE: cyanotic CHD (adjusted OR, 9.58; 95% confidence interval, 5.38 17.05), endocardial cushion defect (ECD) (8.01; 2.73-23.50), Left-sided lesions (4.36; 1.90-10.01) and VSD (2.93; 1.64-5.23). Patients who underwent procedures have a higher risk of acquiring IE which include central venous catheter (CVC) insertion (3.17; 2.36-4.27), cardiac catheterization (3.74; 2.67-5.22), open heart surgery (2.47; 1.61-3.77), valve surgery (3.20; 1.70-6.02), and shunt surgery (7.43; 2.36-23.41). However, dental procedures did not increase the risk of IE, irrespective of antibiotic usage. CONCLUSIONS: The risk of IE varies markedly among CHD lesions in our study. Invasive heart procedures but not dental procedures, are more significantly associated with IE among children with CHD. PMID- 28811094 TI - [Adaptation and validation of the SMP-T2D questionnaire in Spanish for evaluating self-management of high blood pressure and type 2 diabetes: PAG-DT2+HTA]. AB - BACKGROUND: High blood pressure is one of the most common chronic conditions worldwide. It affects one in every 3 adults over 40, while one in 10 suffers from diabetes. For both diseases, adherence to pharmacological treatment is over 30%, and self-management, which takes into account diet and physical activity, is still unknown, as there is no tool available to measure self-management. Therefore, the object of this study was to adapt and validate the Spanish version of the self-management profile for type 2 diabetes (SMP-T2D) questionnaire in patients with type 2 diabetes and high blood pressure among users of first level care in the social security institution of Mexico. METHODS: The SMP-T2D was adapted to Spanish by translation into Spanish, and being used only in patients with high blood pressure and type 2 diabetes-hypertension. A convergent and discriminatory validation was performed. Patients over 50 years old with high blood pressure were include. Those that did not complete the questionnaire or give informed consent were rejected. RESULTS: The Spanish version of the SMP-T2D was called PAG-DT2+HTA, and was applied to 145 people with hypertension: 54.4% with hypertension only, and 43.6% with hypertension and type 2 diabetes. Mean age was 66.14 years (SD=10.78), with 34.7% women and 65.3% men. Internal consistency by alpha-Cronbach for the questionnaire was 0.561 (P=.000). The correlation between the PAG-DT2+HTA and Morisky-Green was significant. The ability to discriminate between people with and without education and with and without economic means was obtained. CONCLUSION: The Spanish version of SMP-T2D (PAG DT2+HTA) that measures self-management in type 2 diabetes, can be used to measure self-management in people with type 2 diabetes-hypertension. PMID- 28811095 TI - Can the optimum artificial tear treatment for dry eye disease be predicted from presenting signs and symptoms? AB - PURPOSE: To assess dry eye treatment with four preservative-free dry eye artificial tear treatments to facilitate evidence-based prescribing. METHODS: A randomised, single masked crossover trial of Clinitas Soothe, Hyabak, Tears Again and TheraTears artificial tears was conducted on 50 symptomatic dry eye patients, aged 60.8+/-14.2years. At baseline and after trialling each treatment for 4 weeks, signs and symptoms were assessed using the Ocular Surface Disease Index (OSDI), non-invasive tear break-up time, fluorescein tear break-up time, tear meniscus height (TMH), Phenol Red test, lid-parallel conjunctival folds (LIPCOF), ocular surface staining, and lipid layer grading and osmolarity (baseline visit only). RESULTS: OSDI (p=0.002), LIPCOF (p=0.014) and conjunctival staining (p<0.001) significantly improved from baseline, however, the impact of each dry eye treatment on ocular symptoms and signs was similar. Clinitas Soothe and Hyabak were preferred by 34%/30% of participants, but only subjective comparison with the other drops influenced this choice. TheraTears was preferred (by 24%) by those with a lower baseline tear volume (p=0.01) and Tears Again (by 12%) by those with a thinner baseline lipid layer (p=0.04). The treatment that afforded the greatest improvement in clinical signs did not consistently match each individual's preferred treatment. CONCLUSIONS: If prescribed to a general dry eye population, the artificial tears performed similarly, improving symptoms and conjunctival signs. However, osmolarity balanced artificial tears were the preferred treatment in individuals with low baseline tear volume and lipisomal spray for individuals with a baseline lipid layer deficiency. PMID- 28811096 TI - Topical anaesthetic use prior to rigid gas permeable contact lens fitting. AB - PURPOSE: To investigate effect of topical anaesthetic (TA) during gas permeable (GP) contact lens (CL) fitting on subjective and objective measures of patient anxiety. METHODS: 47 subjects (mean+/-sd age=26.9+/-4.9years; soft CL wearers, 18, neophytes, 29). Each subject randomly assigned to Group A or B, and attended on two occasions, one week apart. First visit: subject received bilaterally either a single drop of TA (0.5% proxymetacaine) (Group A) or placebo (0.9% saline) (Group B) prior to GP CL application. No drops were instilled at second visit. Each visit mimicked a GP CL fitting. At each visit, patient anxiety was assessed either subjectively (visual analogue scale (VAS)) or objectively (skin conductance (SC)), as well as anterior ocular health. RESULTS: Visit 1: GP CL trial produced small increases in hyperaemia and corneal staining, but no difference associated with TA use. Visit 2: increases in staining and hyperaemia were observed, but hyperaemic responses significantly less than at Visit 1, for both groups. Corneal staining also less, but not statistically significant. VAS scores indicated subjects who received TA during Visit 1 were significantly less anxious at Visit 2. Visit 2: comfort slightly reduced for subjects who received TA at Visit 1, and significantly increased for subjects who received placebo. Use of TA reduced anxiety during lens adaptation period compared with subjects receiving placebo. CONCLUSIONS: TA use during GP CL fitting has potential patient benefits: improved first-time GP CL wear comfort, reduced anxiety during adaptation, reduced anxiety prior to subsequent GP CL wear. PMID- 28811097 TI - Type I collagen promotes primary cilia growth through down-regulating HDAC6 mediated autophagy in confluent mouse embryo fibroblast 3T3-L1 cells. AB - Primary cilia are microtubule-based organelles that extend from nearly all vertebrate cells. Abnormal ciliogenesis and cilia length are suggested to be associated with hypertension and obesity as well as diseases such as Meckel Gruber syndrome. Extracellular matrix (ECM), comprising cellular microenvironment, influences cell shape and proliferation. However, influence of ECM on cilia biogenesis has not been well studied. In this study we examined the effects of type I collagen (col I), the major component of ECM, on primary cilia growth. When cultured on collagen-coated dishes, confluent 3T3-L1 cells were found to exhibit fibroblast-like morphology, which was different from the cobblestone-like shape on non-coated dishes. The level of autophagy in the cells cultured on col I-coated dishes was attenuated compared with the cells cultured on non-coated dishes. The cilia of the cells cultured on col I-coated dishes became longer, accompanying increased expression of essential proteins for cilia assembly. Transfection of the siRNA targeting microtubule-associated protein light chain 3 (LC3) further enhanced the length of primary cilia, suggesting that col I positively regulated cilia growth through inhibition of autophagy. Histone deacetylase 6 (HDAC6), which was suggested as a mediator of autophagy in our previous study on primary cilia, was down-regulated with col I. 3T3-L1 cells treated with the siRNA against HDAC6 reduced the autophagy level and enhanced collagen-induced cilia elongation, implying that HDAC6 was involved in mediating autophagy. In conclusion, col I promotes cilia growth through repressing the HDAC autophagy pathway that can be involved in the interaction between primary cilia and col I. PMID- 28811098 TI - The governance of integrated health and social care in England since 2010: great expectations not met once again? AB - Integrating health and social care has long been a goal of policy-makers and practitioners. Yet, this aim has remained elusive, partly due to conflicting definitions and a weak evidence base. As part of a special edition exploring the use of the TAPIC (transparency, accountability, participation, integrity and capability) framework in different national contexts and inter-agency settings, this article examines the governance of integrated care in England since 2010, focusing on the extent to which thesefive governance attributes are applicable to integrated care in England. The plethora of English policy initiatives on integrated care (such as the 'Better Care Fund', personal health budgets, and 'Sustainability and Transformation Plans') mostly shows signs of continuity over time although the barriers to integrated care often persist. The article concludes that the contribution of integrated care to improved outcomes remains unclear and yet it remains a popular policy goal. Whilst some elements of the TAPIC framework fit less well than others to the case of integrated care, the case of integrated care can be better understood and explained through this lens. PMID- 28811099 TI - Understanding operational system differences for transfer of miniaturized chromatography column data using simulations. AB - In this paper, a simulation tool was employed to identify and appropriately incorporate differences between MiniColumns and benchtop column systems. It was first demonstrated that including multi-step gradients and fraction collection into the simulations resulted in improved agreement between simulated and experimental linear gradient profiles as well as calculated first moments in the MiniColumn experiments. Step elution experiments of binary mixtures (a monoclonal antibody and one of three model proteins) were then carried out to examine comparability of the MiniColumns to the benchtop system. Although the peak shapes were qualitatively similar, peak elution began earlier in the MiniColumn system while improved separation was observed between overlapping peaks using the benchtop format. Simulations were then carried out to demonstrate that increased dispersion of the eluent breakthrough in the benchtop system could readily explain these observed differences. Importantly, by incorporating these system differences into the simulations, we were able to predict benchtop step elution performance using the parameters solely obtained from the MiniColumns. The findings presented in this paper illustrate that the appropriate consideration of system differences can facilitate the implementation of miniature chromatography columns as scale-down models for bioprocess development. PMID- 28811100 TI - Is supercritical fluid chromatography hyphenated to mass spectrometry suitable for the quality control of vitamin D3 oily formulations? AB - Nowadays, many efforts are devoted to improve analytical methods regarding efficiency, analysis time and greenness. In this context, Supercritical Fluid Chromatography (SFC) is often regarded as a good alternative over Normal Phase Liquid Chromatography (NPLC). Indeed, modern SFC separations are fast, efficient with suitable quantitative performances. Moreover, the hyphenation of SFC to mass spectrometry (MS) provides additional gains in specificity and sensitivity. The present work aims at the determination of vitamin D3 by SFC-MS for routine Quality Control (QC) of medicines specifically. Based on the chromatographic parameters previously defined in SFC-UV by Design of Experiments (DoE) and Design Space methodology, the method was adapted to work under isopycnic conditions ensuring a baseline separation of the compounds. Afterwards, the response provided by the MS detector was optimized by means of DoE methodology associated to desirability functions. Using these optimal MS parameters, quantitative performances of the SFC-MS method were challenged by means of total error approach method validation. The resulting accuracy profile demonstrated the full validity of the SFC-MS method. It was indeed possible to meet the specification established by the European Medicines Agency (EMA) (i.e. 95.0 - 105.0% of the API content) for a dosing range corresponding to at least 70.0-130.0% of the API content. These results highlight the possibility to use SFC-MS for the QC of medicine and obviously support the switch to greener analytical methods. PMID- 28811101 TI - Chiral stationary phase optimized selectivity liquid chromatography: A strategy for the separation of chiral isomers. AB - Chiral Stationary-Phase Optimized Selectivity Liquid Chromatography (SOSLC) is proposed as a tool to optimally separate mixtures of enantiomers on a set of commercially available coupled chiral columns. This approach allows for the prediction of the separation profiles on any possible combination of the chiral stationary phases based on a limited number of preliminary analyses, followed by automated selection of the optimal column combination. Both the isocratic and gradient SOSLC approach were implemented for prediction of the retention times for a mixture of 4 chiral pairs on all possible combinations of the 5 commercial chiral columns. Predictions in isocratic and gradient mode were performed with a commercially available and with an in-house developed Microsoft visual basic algorithm, respectively. Optimal predictions in the isocratic mode required the coupling of 4 columns whereby relative deviations between the predicted and experimental retention times ranged between 2 and 7%. Gradient predictions led to the coupling of 3 chiral columns allowing baseline separation of all solutes, whereby differences between predictions and experiments ranged between 0 and 12%. The methodology is a novel tool allowing optimizing the separation of mixtures of optical isomers. PMID- 28811102 TI - High resolution separations of charge variants and disulfide isomers of monoclonal antibodies and antibody drug conjugates using ultra-high voltage capillary electrophoresis with high electric field strength. AB - Ultra-high voltage capillary electrophoresis with high electric field strength has been applied to the separation of the charge variants, drug conjugates, and disulfide isomers of monoclonal antibodies. Samples composed of many closely related species are difficult to resolve and quantify using traditional analytical instrumentation. High performance instrumentation can often save considerable time and effort otherwise spent on extensive method development. Ideally, the resolution obtained for a given CE buffer system scales with the square root of the applied voltage. Currently available commercial CE instrumentation is limited to an applied voltage of approximately 30kV and a maximum electric field strength of 1kV/cm due to design limitations. The instrumentation described here is capable of safely applying potentials of at least 120kV with electric field strengths over 2000V/cm, potentially doubling the resolution of the best conventional CE buffer/capillary systems while decreasing analysis time in some applications. Separations of these complex mixtures using this new instrumentation demonstrate the potential of ultra-high voltage CE to identify the presence of previously unresolved components and to reduce analysis time for complex mixtures of antibody variants and drug conjugates. PMID- 28811103 TI - Identification and phylogenetic position of Naegleria spp. from geothermal springs in Italy. AB - Naegleria spp. are free-living amoebae belonging to the family Vahlkampfiidae, in the class Heterolobosea. Among the recognized species, Naegleria fowleri causes primary amoebic meningoencephalitis (PAM), while two other species, Naegleria australiensis and Naegleria italica, have been reported as pathogenic in experimental animals. Due to the thermotolerance properties of some species, geothermal water sources including hot springs represent suitable habitats for their proliferation. The main aim of this study was a year-round sampling in two geothermal springs in Central Italy, to investigate the presence of Naegleria spp. using PCR/DNA sequencing based methods. The affinities between the sequences generated here and others reported in the literature were explored by using POY, which implements the concept of dynamic homology. Naegleria australiensis, Naegleria italica, and Naegleria lovaniensis, plus an unassigned Naegleria spp. were detected. Indels in the rDNA ITS1 and ITS2 turned out to be critical to distinguish the three species and confirmed their phylogenetic relationships. This is the first molecular report on the Naegleria spp. occurrence in geothermal waters in Central Italy, coupled with a fine genetic characterization. PMID- 28811104 TI - A double determination of central motor conduction time in the assessment of Hirayama disease. AB - OBJECTIVE: To investigate central motor conduction time (CMCT) in patients with Hirayama disease (HD) and to analyse the role of motor nerve root lesions in the pathogenesis of HD. METHODS: CMCT measured by F-wave (CMCT-F) and by paravertebral magnetic stimulation (CMCT-M) was performed on both abductor pollicis brevis (APB) and abductor digiti minimi (ADM) in 41 HD patients and 22 controls. All patients underwent neck-flexion magnetic resonance imaging evaluation. RESULTS: Prolonged CMCT (CMCT-F and/or CMCT-M) was recorded in at least one tested muscle from 7/41 (17.1%) HD patients, and 4 cases presented significant prolonged CMCT-M with normal CMCT-F on the side with significant cervical cord forward-shifting. This asymmetric forward-shifting was identified in 13 HD patients, and forward-shifting on the symptomatic side was more obvious. Compared to the controls (ADM: 0.9+/-0.3ms; APB: 0.8+/-0.3ms) and the other 28 HD patients (symptomatic side: ADM: 0.8+/-0.2ms, APB: 0.8+/-0.3ms), increased nerve root conduction times were demonstrated in these symptomatic sides (ADM: 1.5+/ 0.7ms; APB: 1.2+/-0.6ms) (P<0.05). CONCLUSIONS: Motor nerve root may be main lesion site in some HD patients, especially on the symptomatic side of patients with asymmetric neck-flexion cervical cord forward-shifting. SIGNIFICANCE: Compared to spinal motor neuron lesions, damage to motor nerve root (intra- and/or extra-medullary motor roots) may play an equally important role in the pathogenesis of HD. Abnormally increased forward traction in shorter nerve roots may be the cause for the main damage in motor nerve root. PMID- 28811105 TI - Axonal hyperexcitability due to Schwann cell involvement in chronic progressive external ophthalmoplegia. PMID- 28811106 TI - Questiomycin A stimulates sorafenib-induced cell death via suppression of glucose regulated protein 78. AB - Hepatocellular carcinoma (HCC) is one of the most difficult cancers to treat owing to the lack of effective chemotherapeutic methods. Sorafenib, the first line and only available treatment for HCC, extends patient overall survival by several months, with a response rate below 10%. Thus, the identification of an agent that enhances the anticancer effect of sorafenib is critical for the development of therapeutic options for HCC. Endoplasmic reticulum (ER) stress response is one of the methods of sorafenib-induced cell death. Here we report that questiomycin A suppresses expression of GRP78, a cell-protective ER chaperone protein. Analysis of the molecular mechanisms of questiomycin A revealed that this compound stimulated GRP78 protein degradation in an ER stress response-independent manner. Cotreatment with sorafenib and questiomycin A suppressed GRP78 protein expression, which is essential for the stimulation of sorafenib-induced cell death. Moreover, our in vivo study demonstrated that the coadministration of sorafenib and questiomycin A suppressed tumor formation in HCC-induced xenograft models. These results suggest that cotreatment with sorafenib and questiomycin A is a novel therapeutic strategy for HCC by enhancing sorafenib-dependent ER stress-induced cell death, and downregulation of GRP78 is a new target for the stimulation of the therapeutic effects of sorafenib in HCC. PMID- 28811107 TI - Local Efficacy of Periarticular Morphine Injection in Simultaneous Bilateral Total Knee Arthroplasty: A Prospective, Randomized, Double-Blind Trial. AB - BACKGROUND: The periarticular multimodal cocktail injection including morphine is currently commonly used to reduce postoperative pain following total knee arthroplasty (TKA). Despite its analgesic effect, it frequently causes nausea, which is an adverse effect of opioids. It is inconclusive whether the intraoperative injection of periarticular morphine is effective peripherally. The aim of this study was to assess whether the addition of morphine to unilateral periarticular knee injections improves postoperative pain, range of motion, and swelling in patients undergoing simultaneous bilateral TKA. METHODS: A prospective, single-center, double-blinded, randomized, controlled trial was conducted to assess the local efficacy of adding morphine to intraoperative periarticular anesthesia in patients undergoing simultaneous bilateral TKA. Fifty three patients undergoing 106 TKAs received an intraoperative periarticular injection in randomly selected one knee with added morphine (0.1 mg/kg) and the other knee without added morphine. The periarticular injection was composed of ropivacaine (a local anesthetic), epinephrine, ketoprofen, and methylprednisolone sodium. Visual analog scale pain scores at rest and on motion, range of motion (ROM), thigh swelling, the Western Ontario and McMaster Universities Osteoarthritis Index score, and adverse outcomes were compared between the 2 knees. RESULTS: There were no statistically significant differences in the visual analog scale score, ROM, thigh girth, Western Ontario and McMaster Universities Osteoarthritis Index score, and adverse events between the 2 sides. CONCLUSION: Adding morphine to periarticular injections is ineffective locally for relieving pain, reducing swelling, and improving the postoperative ROM. PMID- 28811108 TI - Methylene Blue-Guided Debridement as an Intraoperative Adjunct for the Surgical Treatment of Periprosthetic Joint Infection. AB - BACKGROUND: Current methods to identify infected tissue in periprosthetic joint infection (PJI) are inadequate. The purpose of this study was (1) to assess methylene blue-guided surgical debridement as a novel technique in PJI using quantitative microbiology and (2) to evaluate clinical success based on eradication of infection and infection-free survival. METHODS: Sixteen total knee arthroplasty patients meeting Musculoskeletal Infection Society criteria for PJI undergoing the first stage of 2-stage exchange arthroplasty were included in this prospective study. Dilute methylene blue (0.1%) was instilled in the knee before debridement, residual dye was removed, and stained tissue was debrided. Paired tissue samples, stained and unstained, were collected from the femur, tibia, and capsule during debridement. Samples were analyzed by neutrophil count, semiquantitative culture, and quantitative polymerase chain reaction (PCR). Clinical success was a secondary outcome. RESULTS: The mean age was 64.0 +/- 6.0 years, and follow-up was 24.4 +/- 3.5 months. More bacteria were found in methylene blue-stained vs unstained tissue-based on semiquantitative culture (P = .001). PCR for staphylococcal species showed 9-fold greater bioburden in methylene blue-stained vs unstained tissue (P = .02). Tissue pathology found 53 +/- 46 polymorphonuclear leukocytes per high-power field in methylene blue stained vs 4 +/- 13 in unstained tissue (P = .0001). All subjects cleared their primary infection and underwent reimplantation. At mean 2-year follow-up, 25% of patients failed secondary to new infection with a different organism. CONCLUSION: These results suggest a role for methylene blue in providing a visual index of surgical debridement in the treatment of PJI. PMID- 28811109 TI - The Risk of Acute Infection Following Intra-articular Corticosteroid Injection Into a Pre-existing Total Knee Arthroplasty. AB - BACKGROUND: No previous studies have investigated the risk of infection following intra-articular corticosteroid injection (IACI) into a pre-existing total knee arthroplasty (TKA). The aim of this study is to determine the risk of acute infection following IACI into a pre-existing TKA. METHODS: A retrospective chart review identified all patients at a single institution between October 2009 and May 2015 that had an ipsilateral knee injection subsequent to a TKA. The risk of acute infection, as defined by development of an infection within 3 months of IACI, was determined via review of clinic notes, operative reports, laboratory records, and telephone interviews. RESULTS: A total of 1845 injections in 736 patients met the inclusion criteria. In total, 101 (4.8%) patients were lost to follow-up. Three infections in 3 patients occurred within 3 months of IACI, yielding an infection rate of 0.16% per injection, or 1 infection in every 625 IACIs following TKA. CONCLUSION: This study is the first to investigate the risk of acute infection following injection of corticosteroid into a pre-existing TKA. Given the dire consequences of infection following TKA, the routine use of IACI into a pre-existing TKA should be avoided, and a thorough workup should be performed in any patient with a painful TKA prior to consideration of IACI. PMID- 28811110 TI - Characterizing the Diagnosis and Treatment of Allergic Contact Dermatitis to 2 Octyl Cyanoacrylate Used for Skin Closure in Elective Orthopedic Surgery. AB - BACKGROUND: While studies have shown that postoperative wound complications can predispose to deep infection following orthopedic surgery, the best form of skin closure has not been elucidated. Furthermore, the unique risks and benefits of each type of wound closure have not been studied. The goal of this study is to present the diagnosis and treatment of patients with allergic contact dermatitis (ACD) from 2-octyl cyanoacrylate, a skin adhesive commonly used in wound closure. METHODS: Twenty-nine patients with ACD to 2-octyl cyanoacrylate (Prineo, Ethicon, NJ) following elective orthopedic surgeries from 2013 to 2016 were retrospectively reviewed; this occurred in 29 of 6088 units of Prineo used at our institution, for an estimated incidence of 0.5%. Nineteen patients (66%) had knee operations. Mean age was 55 years (range, 15-92 years). We classified patients by symptom severity and treatment requirements into mild, moderate, and severe reactions. RESULTS: Most reactions were moderate (48%) or severe (38%) reactions. Mean time from surgery to diagnosis was 11.8 days (range, 2-42 days). All patients underwent removal of the Prineo dressing and daily dressing changes with a specific protocol. Twenty patients (69%) received oral antihistamines, 16 patients (55%) required topical corticosteroids, and 5 patients (17%) required oral corticosteroids. All cases of ACD ultimately resolved at a mean of 22 days (range, 13-56 days) postoperatively. CONCLUSION: 2-Octyl cyanoacrylate skin adhesive occurs in an estimated 0.5% of cases and can lead to severe postoperative ACD when used following orthopedic operations. However, with early recognition and appropriate treatment, patients' symptoms resolve without a significant impact on wound healing. PMID- 28811111 TI - Cell cultures in drug discovery and development: The need of reliable in vitro-in vivo extrapolation for pharmacodynamics and pharmacokinetics assessment. AB - For ethical and cost-related reasons, use of animals for the assessment of mode of action, metabolism and/or toxicity of new drug candidates has been increasingly scrutinized in research and industrial applications. Implementation of the 3 "Rs"1; rule (Reduction, Replacement, Refinement) through development of in silico or in vitro assays has become an essential element of risk assessment. Physiologically based pharmacokinetic (PBPK2) modeling is the most potent in silico tool used for extrapolation of pharmacokinetic parameters to animal or human models from results obtained in vitro. Although, many types of in vitro assays are conducted during drug development, use of cell cultures is the most reliable one. Two-dimensional (2D) cell cultures have been a part of drug development for many years. Nowadays, their role is decreasing in favor of three dimensional (3D) cell cultures and co-cultures. 3D cultures exhibit protein expression patterns and intercellular junctions that are closer to in vivo states in comparison to classical monolayer cultures. Co-cultures allow for examinations of the mutual influence of different cell lines. However, the complexity and high costs of co-cultures and 3D equipment exclude such methods from high-throughput screening (HTS).3In vitro absorption, distribution, metabolism, and excretion assessment, as well as drug-drug interaction (DDI), are usually performed with the use of various cell culture based assays. Progress in in silico and in vitro methods can lead to better in vitro-in vivo extrapolation (IVIVE4) outcomes and have a potential to contribute towards a significant reduction in the number of laboratory animals needed for drug research. As such, concentrated efforts need to be spent towards the development of an HTS in vitro platform with satisfactory IVIVE features. PMID- 28811112 TI - Exogenous testosterone affects early threat processing in socially anxious and healthy women. AB - Testosterone plays an important role in social threat processing. Recent evidence suggests that testosterone administration has socially anxiolytic effects, but it remains unknown whether this involves early vigilance or later, more sustained, processing-stages. We investigated the acute effects of testosterone administration on social threat processing in 19 female patients with Social Anxiety Disorder (SAD) and 19 healthy controls. Event-related potentials (ERPs) were recorded during an emotional Stroop task with subliminally presented faces. Testosterone induced qualitative changes in early ERPs (<200ms after stimulus onset) in both groups. An initial testosterone-induced spatial shift reflected a change in the basic processing (N170/VPP) of neutral faces, which was followed by a shift for angry faces suggesting a decrease in early threat bias. These findings suggest that testosterone specifically affects early automatic social information processing. The decreased attentional bias for angry faces explains how testosterone can decrease threat avoidance, which is particularly relevant for SAD. PMID- 28811113 TI - Acrylamide-forming potential of cereals, legumes and roots and tubers analyzed by UPLC-UV. AB - For directing scientists, consumers, industry and stakeholders on mitigation strategies, there is a need to understand the acrylamide-forming potential of important Indian foods. Flour obtained from total 16 varieties of 9 Indian cereals, legumes and roots and tubers was heated at 160 degrees C for 20 min, acrylamide was extracted and quantified by UPLC-UV. Acrylamide level was above the European Commission indicative value in potato- and cereal-based food products, it ranged from 3436.13 to 5562.56 MUg/kg in roots and tubers (potato and sweet potato). Among the cereals, maize (2195.31 MUg/kg) and wheat (161.12 MUg/kg) had the highest and lowest contents, respectively, whereas rice, sorghum and pearl millet showed intermediate values. Among the 2 legumes, soybean contained higher acrylamide (337.08-717.52 MUg/kg) than chickpea (377.83-480.49 MUg/kg). Analysis of variance revealed that roots and tubers acrylamide was highly significantly greater than the content in cereals (p < 0.0001) and in legumes (p < 0.0001) while there was no significant difference between cereals and legumes (p = 0.443). These results support the combination of pulses and minor cereals (chickpea, soybean, millets and sorghum) in cereal-based foods for improving the nutritional value and reducing acrylamide formation. PMID- 28811114 TI - Determination of acrylamide levels in potato crisps and other snacks and exposure risk assessment through a Margin of Exposure approach. AB - Potato crisps, corn-based extruded snacks and other savoury snacks are very popular products especially among younger generations. These products could be a potential source of acrylamide (AA), a toxic compound which could develop during frying and baking processes. The purpose of this study was the assessment of the dietary intake to AA across six groups of consumers divided according to age through the consumption of potato crisps and other snacks, in order to eventually evaluate the margin of exposure (MOE) related to neurotoxic and carcinogenic critical endpoints. Different brands of potato crisps and other popular snacks were analyzed through a matrix solid-phase dispersion method followed by a bromination step and GC-MS quantification. The concentration of detected AA ranged from 21 to 3444 ng g-1 and the highest level occurred in potato crisps samples which showed a median value of 968 ng g-1. The risk characterization through MOE assessment revealed that five out of six consumers groups showed higher exposure values associated with an augmented carcinogenic risk. PMID- 28811115 TI - Recurrence of cutaneous coccidioidomycosis 6 years after valley fever: A case presentation and literature review. AB - Coccidioidomycosis is usually acquired by inhalation of spores of Coccidioides immitis and C. posadasii. The disease ranges from a self-limited acute pneumonia (Valley Fever) to a disseminated disease. We present a 44-year-old healthy male who had patchy hair loss of several months duration resembling discoid lupus. He developed a firm non-scaly red plaque on the right forehead. Initial biopsy showed spongiotic dermatitis, and he was treated with systemic steroids. He then developed forehead and periorbital cellulitis and was treated with systemic antibiotics. A second biopsy showed fungal hyphae, and he was treated with itraconazole 200mg bid for 4months beyond clinical resolution. A year later, he presented with intermittent swelling of the right forehead lesion and worsening of the scalp lesions. A forehead biopsy showed interface dermatitis and negative PAS stain for fungi. Scalp biopsy was highly suggestive of discoid lupus and he was started on plaquenil. Many months later, a third biopsy showed fungal infection, and the culture grew C. immitis. He was treated with itraconazole. Retrospectively, the patient gave a history of Valley fever 6 years back when he was in Arizona, USA. PMID- 28811116 TI - Identification of Nocardia, Streptomyces, and Tsukamurella using MALDI-TOF MS with the Bruker Biotyper. AB - Nocardia species are the most commonly isolated aerobic actinomycetes from human clinical specimens. Our objective was to assess the identification of clinically relevant actinomycetes using the Bruker Biotyper MALDI-TOF system, including comparison of extraction methods, Biotyper library versions, score cutoffs, and media. Banked Streptomyces (n=10), Tsukamurella (n=2), and Nocardia isolates (n=60) were cultured and extracted using three methods: mycobacterial extraction, ethanol formic acid extraction, or direct on-target extraction. Following MALDI TOF analysis, spectra were analyzed using versions 5 and 6 of the BDAL Biotyper library. Optimal species-level identifications for Nocardia were achieved using BDAL v6 at a score cutoff of >=1.8 after direct extraction (49/60, 82%). Overall, the Biotyper platform with BDAL v6 accurately identified 12/16 species of Nocardia, demonstrating the utility of MALDI-TOF for identification of clinically relevant actinomycetes without the need for supplementation of the database. PMID- 28811117 TI - Bilayered buccal films as child-appropriate dosage form for systemic administration of propranolol. AB - Buccal mucosa has emerged as an attractive site for systemic administration of drug in paediatric patients. This route is simple and non-invasive, even if the saliva wash-out effect and the relative permeability of the mucosa can reduce drug absorption. Mucoadhesive polymers represent a common employed strategy to increase the contact time of the formulation at the application site and to improve drug absorption. Among the different mucoadhesive dosage forms, buccal films are particularly addressed for paediatric population since they are thin, adaptable to the mucosal surface and able to offer an exact and flexible dose. The objective of the present study was to develop bilayered buccal films for the release of propranolol hydrochloride. A primary polymeric layer was prepared by casting and drying of solutions of film-forming polymers, such as polyvinylpyrrolidone (PVP) or polyvinylalcohol (PVA), added with different weight ratios of gelatin (GEL) or chitosan (CH). In order to achieve unidirectional drug delivery towards buccal mucosa, a secondary ethylcellulose layer was applied onto the primary layer. Bilayered films were characterized for their physico-chemical (morphology, thickness, drug content and solid state) and functional (water uptake, mucoadhesion, drug release and permeation) properties. The inclusion of CH into PVP and PVA primary layer provided the best mucoadhesion ability. Films containing CH provided a lower drug release with respect to films containing GEL and increased the amount of permeated drug through buccal mucosa, thanks to its ability of interfering with the lipid organization. The secondary ethylcellulose layer did not interfere with drug permeation, but it could limit drug release in the buccal cavity. PMID- 28811118 TI - Prediction and characterization of the stability enhancing effect of the Cherry TagTM in highly concentrated protein solutions by complex rheological measurements and MD simulations. AB - Solution stability attributes are one of the key parameters within the production and launching phase of new biopharmaceuticals. Instabilities of active biological compounds can reduce the yield of biopharmaceutical productions, and may induce undesired reactions in patients, such as immunogenic rejections. Protein solution stability thus needs to be engineered and monitored throughout production and storage. In contrast to the gold standard of long-term storage experiments applied in industry, novel experimental and in silico molecular dynamics tools for predicting protein solution stability can be applied within several minutes or hours. Here, a rheological approach in combination with molecular dynamics simulations are presented, for determining and predicting long-term phase behavior of highly concentrated protein solutions. A diversity of liquid phase conditions, including salt type, ionic strength, pH and protein concentration are tested in a Glutathione-S-Transferase (GST) case study, in combination with the enzyme with and without solubility-enhancing Cherry-TagTM. The rheological characterization of GST and Cherry-GST solutions enabled a fast and efficient prediction of protein instabilities without the need of long-term protein phase diagrams. Finally, the strong solubility enhancing properties of the Cherry-TagTM were revealed by investigating protein surface properties in MD simulations. The tag highly altered the overall surface charge and hydrophobicity of GST, making it less accessible to alteration by the chemical surrounding. PMID- 28811119 TI - Family planning funding cuts and teen childbearing. AB - Publicly funded family planning clinics provide low-cost and free contraception to nearly 1.5 million teens each year. In recent years, several states have considered legislation to defund family planning services, although little is known about how these cuts affect teen pregnancy. This paper fills this knowledge gap by exploiting a policy change in Texas that reduced funding for family planning services by 67% and resulted in over 80 clinic closures. I estimate the effects of the funding cuts on teen health outcomes using a difference-in differences approach that compares the changes in teen birth rates in Texas counties that lost family planning funding to changes in counties outside of Texas with publicly funded clinics. I find that reducing funding for family planning services in Texas increased teen birth rates by approximately 3.4% over four years with effects concentrated 2-3 years after the initial cuts. PMID- 28811120 TI - Impact of caregiver incentives on child health: Evidence from an experiment with Anganwadi workers in India. AB - This paper tests the effectiveness of performance pay and bonuses among government childcare workers in India. In a controlled study of 160 ICDS centers serving over 4000 children, we randomly assign workers to either fixed bonuses or payments based on the nutritional status of children in their care, and also collect data from a control group receiving only standard salaries. In all three study arms mothers receive nutrition information. We find that performance pay reduces underweight prevalence by about 5 percentage points over 3 months, and height improves by about one centimeter. Impacts on weight continue when incentives are renewed and return to parallel trends thereafter. Fixed bonuses are less expensive but lead to smaller and less precisely estimated effects than performance pay, especially for children near malnutrition thresholds. Both treatments improve worker effort and communication with mothers, who in turn feed a more calorific diet to children at home. PMID- 28811121 TI - Emergency Department Use in the Perinatal Period: An Opportunity for Early Intervention. AB - STUDY OBJECTIVE: We characterize emergency department (ED) utilization among perinatal women and identify differences in risk factors and outcomes between women who use versus do not use the ED during the perinatal period. METHODS: This is a retrospective cross-sectional study comparing patients who used the ED versus did not use the ED during the perinatal period. Patient data were collected from medical chart review and postpartum interviews. RESULTS: Of the 678 participants, 218 (33%) had at least 1 perinatal ED visit. Women who used the ED were more likely than those who did not to be adolescent (relative risk [RR] 2.23; 95% confidence interval [CI] 1.38 to 3.63), of minority race (RR 1.94; 95% CI 1.46 to 2.57), and Medicaid insured (RR 2.14; 95% CI 1.71 to 2.67). They were more likely to smoke prenatally (RR 3.42; 95% CI 2.34 to 4.99), to use recreational drugs prenatally (RR 3.53; 95% CI 1.78 to 7.03), and to have experienced domestic abuse (RR 1.78; 95% CI 1.12 to 2.83). They were more likely to have delayed entry to prenatal care (RR 2.01; 95% CI 1.46 to 2.77) and to experience postpartum depression (RR 2.97; 95% CI 1.90 to 4.64). Their infants were nearly twice as likely to be born prematurely (RR 1.92; 95% CI 1.07 to 3.47). CONCLUSION: Results highlight that pregnant patients using the ED are a high-risk, vulnerable population. Routine ED screening and linkage of this vulnerable population to early prenatal care and psychosocial interventions should be considered as a public health strategy worth investigating. PMID- 28811123 TI - Emergency Department Involvement in Accountable Care Organizations in Massachusetts: A Survey Study. AB - STUDY OBJECTIVE: We assess Massachusetts emergency department (ED) involvement and internal ED constructs within accountable care organization contracts. METHODS: An online survey was distributed to 70 Massachusetts ED directors. Questions attempted to assess involvement of EDs in accountable care organizations and the structures in place in EDs-from departmental resources to physician incentives-to help achieve accountable care organization goals of decreasing spending and improving quality. RESULTS: Of responding ED directors, 79% reported alignment between the ED and an accountable care organization. Almost all ED groups (88%) reported bearing no financial risk as a result of the accountable care organization contracts in which their organizations participated. Major obstacles to meeting accountable care organization objectives included care coordination challenges (62%) and lack of familiarity with accountable care organization goals (58%). The most common cost-reduction strategies included ED case management (85%) and information technology (61%). Limitations of this study include that information was self-reported by ED directors, a focus limited to Massachusetts, and a survey response rate of 47%. CONCLUSION: The ED directors perceived that the majority of physicians were not familiar with accountable care organization goals, many challenges remain in coordinating care for patients in the ED, and most EDs have no financial incentives tied to accountable care organizations. EDs in Massachusetts have begun to implement strategies aimed at reducing admissions, utilization, and overall cost, but these strategies are not widespread apart from case management, even in a state with heavy accountable care organization penetration. Our results suggest that Massachusetts EDs still lack clear directives and direct involvement in meeting accountable care organization goals. PMID- 28811122 TI - Acute Kidney Injury After Computed Tomography: A Meta-analysis. AB - STUDY OBJECTIVE: Computed tomography (CT) is an important imaging modality used in the diagnosis of a variety of disorders. Imaging quality may be improved if intravenous contrast is added, but there is a concern for potential renal injury. Our goal is to perform a meta-analysis to compare the risk of acute kidney injury, need for renal replacement, and total mortality after contrast-enhanced CT versus noncontrast CT. METHODS: We searched MEDLINE (PubMed), the Cochrane Library, CINAHL, Web of Science, ProQuest, and Academic Search Premier for relevant articles. Included articles specifically compared rates of renal insufficiency, need for renal replacement therapy, or mortality in patients who received intravenous contrast versus those who received no contrast. RESULTS: The database search returned 14,691 articles, inclusive of duplicates. Twenty-six unique articles met our inclusion criteria, with an additional 2 articles found through hand searching. In total, 28 studies involving 107,335 participants were included in the final analysis, all of which were observational. Meta-analysis demonstrated that, compared with noncontrast CT, contrast-enhanced CT was not significantly associated with either acute kidney injury (odds ratio [OR] 0.94; 95% confidence interval [CI] 0.83 to 1.07), need for renal replacement therapy (OR 0.83; 95% CI 0.59 to 1.16), or all-cause mortality (OR 1.0; 95% CI 0.73 to 1.36). CONCLUSION: We found no significant differences in our principal study outcomes between patients receiving contrast-enhanced CT versus those receiving noncontrast CT. Given similar frequencies of acute kidney injury in patients receiving noncontrast CT, other patient- and illness-level factors, rather than the use of contrast material, likely contribute to the development of acute kidney injury. PMID- 28811124 TI - Two cap residues in the S1 subsite of a Plasmodium falciparum M1-family aminopeptidase promote broad specificity and enhance catalysis. AB - The aminopeptidase PfA-M1 is a key contributor to peptide catabolism in the human malaria parasite Plasmodium falciparum. PfA-M1 substrate specificity is shaped by the cylindrical S1 subsite, which accommodates the sidechain of the substrate P1 residue. At the top of the S1 subsite are two "cap" residues, E572 and M1034, that are positioned to influence S1 subsite specificity. In this study, we have mutated the cap residues, individually and together, and have evaluated the effects on PfA-M1 specificity and catalytic efficiency. When the P1 residue was too small to engage the cap residues, the mutations had no effect on catalysis. Hydrolysis of dipeptide substrates with a basic P1 residue was significantly impaired in the E572A mutant, most likely due to the loss of a stabilizing salt bridge between E572 and the P1 sidechain. With M1034A, a substantial reduction in catalytic efficiency was observed when the P1 sidechain was large and non-polar. The double E572A/M1034A exhibited significant decreases in catalytic efficiency for most substrates. This effect was not reversed with the polar substitutions E572N/M1034Q, which replaced the PfA-M1 cap residues with those of Escherichia coli aminopeptidase N. Both E572 and M1034 contributed to the binding of the competitive aminopeptidase inhibitor bestatin. PMID- 28811125 TI - Pharmacokinetics and pharmacodynamics of thiopurines in an in vitro model of human hepatocytes: Insights from an innovative mass spectrometry assay. AB - AIM: To apply an innovative LC-MS/MS method to quantify thiopurine metabolites in human hepatocytes and to associate them to cytotoxicity. METHODS: Immortalized human hepatocytes (IHH cells) were treated for 48 and 96 h, with 1.4 * 10-4 M azathioprine and 1.1 * 10-3 M mercaptopurine, concentrations corresponding to the IC50 values calculated after 96 h exposure in previous cytotoxicity analysis. After treatments, cells were collected for LC-MS/MS analysis to quantify 11 thiopurine metabolites with different level of phosphorylation and viable cells were counted by trypan blue exclusion assay to determine thiopurines in vitro effect on cell growth and survival. Statistical significance was determined by analysis of variance (ANOVA). RESULTS: Azathioprine and mercaptopurine had a significant time-dependent cytotoxic effect (p-value ANOVA = 0.012), with a viable cell count compared to controls of 55.5% and 67.5% respectively after 48 h and 23.7% and 36.1% after 96 h; no significant difference could be observed between the two drugs. Quantification of thiopurine metabolites evidenced that the most abundant metabolite was TIMP, representing 57.1% and 40.3% of total metabolites after 48 and 96 h. Total thiopurine metabolites absolute concentrations decreased over time: total mean content decreased from 469.9 pmol/million cells to 83.6 pmol/million cells (p-value ANOVA = 0.0070). However, considering the relative amount of thiopurine metabolites, TGMP content significantly increased from 11.4% cells to 26.4% (p-value ANOVA = 0.017). A significant association between thiopurine effects and viable cell counts could be detected only for MeTIMP: lower MeTIMP concentrations were associated with lower cell survival (p-value ANOVA = 0.011). Moreover, the ratio between MeTIMP and TGMP metabolites directly correlated with cell survival (p-value ANOVA = 0.037). CONCLUSION: Detailed quantification of thiopurine metabolites in a human hepatocytes model provided useful insights on the association between thioguanine and methyl-thioinosine nucleotides with cell viability. PMID- 28811126 TI - Flavonoids from persimmon (Diospyros kaki L.) leaves inhibit proliferation and induce apoptosis in PC-3 cells by activation of oxidative stress and mitochondrial apoptosis. AB - Persimmon (Diospyros kaki L.) leaves are extensively used in Chinese medicine and are also excellent source of dietary polyphenols. Here we investigated the antiproliferative and pro-apoptotic activity of the total flavonoids extracted from persimmon leaves (FPL) in PC-3 cells. After treating cells with different concentration of FPL, Quercetin or Rutin for 24 h, MTT and flow cytometry were used to measure the cytotoxicity, apoptotic rate and cell cycle arrest. Compared with Quercetin and Rutin, FPL showed higher cytotoxicity at 12.5 and 25 MUg/ml concentrations and also presented lower IC50 in PC-3 cells. In addition, FPL induced PC-3 cells apoptosis by activation of oxidative stress, as detected by ROS, MDA, nitrite and iNOS activity, and increased mitochondrial membrane permeability. Morphological changes, inactivation of Bcl-2, upregulation of BAX, release of cytochrome c and activation of downstream apoptotic signaling in FPL treated PC-3 cells also suggested apoptotic death. Meanwhile, FPL significantly inhibited migration of PC-3 cells. Therefore, FPL inhibited proliferation, migration and induced apoptosis of PC-3 cells by activation of oxidative stress and mitochondrial-related apoptosis. PMID- 28811127 TI - Attenuation of Sunitinib-induced cardiotoxicity through the A3 adenosine receptor activation. AB - Sunitinib is an anti-cancer tyrosine kinase inhibitor associated with severe cardiotoxic adverse effects. Using rat Langendorff heart model and human acute myeloid leukaemia 60 (HL60) cell line we detected the involvement of protein kinase C (PKC) alpha during Sunitinib-induced cardiotoxicity and the effect of Sunitinib on cancer progression. The cardioprotective and anti-cancer properties of the A3 adenosine receptor agonist 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N methyluronamide (IB-MECA) were investigated. The cardiac effect of Sunitinib (1uM) and IB-MECA (1nM) treatment was measured through haemodynamic and infarct size assessment. The cytotoxic effect of Sunitinib (0.1 - 10MUM) and IB-MECA (10nM - 10MUM) on HL60 cells was assessed using the methylthiazolyldiphenyl tetrazolium bromide (MTT) assay technique. Myocardial injury associated microRNAs (miR-1, miR-27a, miR-133a and miR-133b) and cancer associated microRNAs (miR-15a, miR-16-1 and miR-155) were profiled by qRT-PCR in the cardiac tissue and HL60 cells, while phosphorylated PKCalpha levels were measured by Western Blot analysis. Sunitinib treatment increased infarct size and decreased left ventricular developed pressure and heart rate. Co-treatment of IB-MECA reversed the myocardial injury produced by Sunitinib administration. IB-MECA did not jeopardize the anti-cancer effect of Sunitinib in HL60 cells. The expression signature of the specific microRNAs in cardiac tissue and HL60 cells showed an altered expression profile when treated with Sunitinib and IB-MECA. pPKCalpha levels were increased by Sunitinib treatment in cardiac tissue and HL60 cells and co-administration of IB-MECA attenuated this increase in the cardiac tissue. This study reveals that A3 adenosine receptor activation by IB-MECA attenuates Sunitinib-induced cardiotoxicity through the involvement of PKCalpha. PMID- 28811128 TI - A newly synthesized Ligustrazine stilbene derivative inhibits PDGF-BB induced vascular smooth muscle cell phenotypic switch and proliferation via delaying cell cycle progression. AB - Vascular Smooth muscle cells (VSMCs) possess remarkable phenotype plasticity that allows it to rapidly adapt to fluctuating environmental cues, including the period of development and progression of vascular diseases such as atherosclerosis and restenosis subsequent to vein grafting or coronary intervention. Although VSMC phenotypic switch is an attractive target, there is no effective drug so far. Using rat aortic VSMCs, we investigate the effects of Ligustrazine and its synthetic derivatives on platelet-derived growth factor-BB (PDGF-BB) induced proliferation and phenotypic switch by a cell image-based screening of 60 Ligustrazine stilbene derivatives. We showed that one of the Ligustrazine stilbene derivatives TMP-C4a markedly inhibited PDGF-BB-induced VSMCs proliferation in a time and dose-dependent manner, which is more potent than Ligustrazine. Stimulation of contractile VSMCs with PDGF-BB significantly reduced the contractile marker protein alpha-smooth muscle actin expression and increased the synthetic marker proteins osteopontin expression. However, TMP-C4a effectively reversed this phenotypic switch, which was accompanied by a decreased expression of Matrix metalloproteinase 2 and 9 (MMP2 and MMP9) and cell cycle related proteins, including cyclin D1 and CDK4. In conclusion, the present study showed that a new Ligustrazine stilbene derivative TMP-C4a suppressed PDGF induced VSMC proliferation and phenotypic switch, indicating that it has a potential to become a promising therapeutic agent for treating VSMC-related atherosclerosis and restenosis. PMID- 28811129 TI - MicroRNA-29a regulates lipopolysaccharide (LPS)-induced inflammatory responses in murine macrophages through the Akt1/ NF-kappaB pathway. AB - Akt activation in macrophages enhances lipopolysaccharide (LPS)-induced inflammatory responses through upregulation of the NF-kappaB signal pathway. Akt phosphorylation via microRNA (miR) caused the downregulation of Akt1. Here, we evaluated the role of miR-29a in LPS-triggered inflammatory responses. LPS stimulation of primary macrophages and RAW264.7 cells gradually increased the levels of miR-29a and was dependent on the LPS concentration. Overexpression of miR-29a in macrophages enhanced the expression of proinflammatory cytokines including IL-1beta and IL-6, but not TNF-alpha. Conversely, knockdown of miR-29a diminished cytokine expression. Bioinformatics analyses indicated that Akt1 was a potential target of miR-29a through its interaction with the CDS region of Akt1. The miR-29a also enhanced LPS-induced NF-kappaB signaling through increased NF kappaB transcriptional activity and phosphorylation of p65, and through binding to Akt1. Moreover, Akt1 silencing promoted the LPS-induced expression of IL-1beta and IL-6, and upregulated the NF-kappaB pathway. Taken together, our results suggested that miR-29a participates in the regulation of inflammatory responses in LPS-stimulated macrophages by promoting NF-kappaB activation through targeting Akt1. PMID- 28811130 TI - Comparative study on stabilizing ability of food protein, non-ionic surfactant and anionic surfactant on BCS type II drug carvedilol loaded nanosuspension: Physicochemical and pharmacokinetic investigation. AB - Carvedilol (CAR) in its pure state has low aqueous solubility and extremely poor bioavailability which largely limit its clinical application. The aim of the study is to improve the dissolution rate and the bioavailability of CAR via preparing nanosuspensions with different stabilizers. Antisolvent precipitation ultrasonication technique was used here. Attempts have been made to use food protein- Whey protein isolate (WPI) as a stabilizer in CAR loaded nanosuspension and also to compare its stabilizing potential with conventional nanosuspension stabilizers such as non-ionic linear copolymer-poloxamer 188 (PLX188) and anionic surfactant-sodium dodecyl sulfate (SDS). Optimized nanosuspensions showed narrow size distribution with particle size ranging from 275 to 640nm. Amorphous state of CAR nanocrystals which also improved the solubility by 16-, 25-, 55-fold accordingly was confirmed by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). From scanning electron microscopy (SEM), flaky shape of PLX188 and SDS nanosuspensions could be revealed but WPI nanosuspension was sphere-shaped. Up to 70% dissolution of loaded drug was observed within 15min in phosphate buffer (pH6.8). A pharmacokinetic study in rats indicated that both Cmax and AUC0-36 values of nanosuspensions were estimated to be 2-fold higher than those of reference, suggesting a significant increase in CAR bioavailability. PMID- 28811131 TI - Assessment of translational risk in drug research: Role of biomarker classification and mechanism-based PKPD concepts. AB - In 2005, Danhof and coauthors proposed a new biomarker classification in the context of the application of mechanism-based PKPD modeling. They defined the term 'biomarker' as a measure that characterizes a drug-induced response, which is on the causal path between drug administration and clinical outcome. The biomarker classification identified seven categories that provide different insights into the kinetics of drug action, such as target site distribution, target engagement, or into the impact of the drug on physiology or disease. The original biomarker classification has been further modified into a translational biomarker scheme that is used as a communication tool for drug hunting teams to guide designing translational and early clinical development plans as part of an integrated model-informed drug discovery and development strategy. It promotes a dedicated discussion on the topic of the translational relevance of biomarkers and enables efficient identification of translational gaps and opportunities. Based on the elucidated PKPD characteristics exhibited by a novel drug and the kinetics of the investigated biomarker, prospective predictions can be made for the drug response under new conditions; translating from the preclinical arena to the clinical setting, from the healthy volunteer to the patient, or from an adult to an elderly or a child. These drug response predictions provide support to decisions on appropriate next steps in the development of the drug, while keeping clear line of sight on the potential to address unmet medical need. Moreover, this framework enables a transparent translational risk assessment for drug hunting projects, and as such can underpin decisions at program and portfolio level. PMID- 28811132 TI - Relative changes in earned income five years after diagnosis with diabetes: A register based study 1996-2012. AB - OBJECTIVE: With previous studies indicating that diabetes affects employment status and lifetime earnings, the aim of this study was to determine the impact on earnings in the immediate period after diagnosis. Recognising that earnings and employment status are dynamic over the life course, we matched people with diabetes to counterparts in the general population and compared nominal growth in earned income five calendar years after diagnosis. RESEARCH DESIGN AND METHODS: The study draws upon Danish population registers. Residents aged 25-62years between 1996 and 2007 were included in the study. We identified an individually matched control group from approximately 2,800,000 'diabetes-free' Danish adults using propensity score matching. Matching was based on age, gender, residence, earned income, growth in earned income, and unemployment in the calendar year before diagnosis. RESULTS: 91,090 people with diabetes were included in the study and matched to 91,090 controls in the general population. The analysis revealed highly significant loss of earnings for people with diabetes when compared with people without diabetes, with an overall relative loss of US $ 3694 (8.01%) among men and US $ 924 (3.03%) among women. The effect was generally largest in the youngest age-group, in lower earners and among men. CONCLUSIONS: The results clearly indicate that a diagnosis of diabetes has a significant impact on earnings. Age and earnings at the time of diagnosis appear to play a moderating role. PMID- 28811133 TI - Arylamidonaphtalene sulfonate compounds as a novel class of heparanase inhibitors. AB - The search for antimetastatic agents for cancer therapy may involve the ability of new compounds to maintain the tissue extracellular matrix integrity. Among known factors, heparanase, an endoglucuronidase responsible for heparan sulfate cleavage, is a promising target whose inhibition could represent a strong obstacle for metastatic cancerous mechanisms. The antimetastatic activity of some suramin derivatives reported in literature suggests a possible involvement of the heparanase enzyme. To confirm such hypothesis, we have investigated FCE27266, a molecule known for its antiangiogenic and antimetastatic properties. Other new derivatives were also synthesized and investigated. Our findings revealed that FCE27266 as well as some derivatives have a strong heparanase inhibition activity, together with no cytotoxic power. Moreover, a FCE27266 analogue (SST0546NA1; 17a) resulted also positive to lower gene expression of some proangiogenic factors. PMID- 28811134 TI - A new chemotype inhibitor for the human organic cation transporter 3 (hOCT3). AB - Human organic cation transporters (OCTs) represent an understudied neurotransmitter uptake mechanism for which no selective agents have yet been identified. Several neurotransmitters (e.g. serotonin, norepinephrine) are low affinity substrates for these transporters, but possess higher affinity for other transporters (e.g. the serotonin or norepinephrine transporters; SERT and NET, respectively). We have identified a new class of OCT inhibitors with a phenylguanidine structural scaffold. Here, we examine the actions of a series of such compounds and report preliminary structure-activity relationships (SARs) - the first dedicated SAR study of OCT3 action. Initial results showed that the presence of a substituent on the phenyl ring, as well as its position, contributes to the phenylguanidines' inhibitory potency (IC50 values ranging from 2.2 to >450MUM) at hOCT3. There is a trend towards enhanced inhibitory potency of phenylguanidines with increased lipophilic character and the size of the substituent at the phenyl 4-position, with the latter reaching a ceiling effect. The first PiPT-based hOCT3 homology models were generated and are in agreement with our biological data. PMID- 28811135 TI - Code ICU - A great opportunity for patients and critical care management. PMID- 28811136 TI - Determination of GHB and GHB-beta-O-glucuronide in hair of three narcoleptic patients-Comparison between single and chronic GHB exposure. AB - Gamma-hydroxybutyric acid (GHB) can be used as a knock-out drug in drug facilitated crime (DFC). Due to its rapid metabolism and resulting narrow detection window, uncovering GHB use in DFC still constitutes a problem. In this experiment we determined the GHB and GHB-beta-O-glucuronide (GHB-Gluc) concentrations in hair samples after single and chronic GHB exposures. Hair samples of three narcoleptic patients therapeutically taking sodium oxybate (GHB sodium-salt) were collected. Patients 1 (P1) and 2 (P2) took the medication for nine and six years, respectively. P1 took daily the pharmaceutical Xyrem(r) in a total dose of 5.78g GHB at bed time (2.89g) and four hours (2.89g) later. P2 took a dose of 3.10g GHB at bed time and an additional dose of 2.68g GHB four hours later. Patient 3 (P3) was newly diagnosed with narcolepsy and started his therapy with oral dose of 6g (divided in three portions of 2g GHB) within 24h. The hair samples were extracted both with and without forerunning washing steps. GHB and GHB-Gluc were determined by a published ultra-high performance liquid chromatography-tandem mass spectrometry method using GHB-d6 and GHB-Gluc-d4 as internal standards. GHB and GHB-Gluc concentrations in unwashed hair samples of P1 and P2 were determined in a range of 0.56-1.30ng/mg and <0.48-0.85ng/mg, respectively. In washed hair samples of P1 and P2 the concentrations were in a range of <0.32-0.68ng/mg and <0.48-1.20ng/mg for GHB and GHB-Gluc, respectively. The determined concentrations were within the published endogenous range. The confirmed results showed that the washing procedure before extraction causes a minor decrease of GHB concentrations in hair (difference: <1ng/mg). The investigations showed that a single GHB exposure might not be determined by hair analysis of GHB and GHB-Gluc. The chronical intake of therapeutic sodium oxybate with doses up to 7g per night was also not confirmed by hair analysis maybe due to hair treatments. Therefore, GHB hair analysis should be assessed critically and determined negative results could not exclude GHB exposures. PMID- 28811137 TI - Influence of guidelines on management of paediatric mild traumatic brain injury: CT-assessment and admission policy. AB - BACKGROUND: The annual number of paediatric injury-related emergency visits and application of computed tomography (CT) has substantially increased, with associated higher risk of malignancies. In 2010, a guideline for CT-assessment based on risk factors for patients with mild traumatic brain injury (mTBI) became effective in all Emergency Departments (ED) in the Netherlands. This study evaluated the influence of this guideline on the frequency of CT-assessments, hospital admissions and factors that are related to guideline adherence. METHODS: Retrospective cohort study of paediatric mTBI (<18 years), defined by Glasgow Coma Scale score of 13-15 admitted to the ED of the University Medical Center Groningen from 2008 to 2014. Data before (pre-GL) and after (post-GL) introduction of the guideline were evaluated. Primary outcome parameters were frequency of CT-assessments and hospital admissions after ED. RESULTS: In total 633 patients were enrolled and data from pre-GL (n = 216) and post-GL (n = 315) were compared. Mean age was 7.9 years (SD 5.9), 59% were male. CT-assessments increased from 32% to 46% (p = .001), mostly in children aged 6-18 years. Hospital admissions increased from 38% to 54% (p < .001), mostly in children <6 years. No significant increase in CT-abnormalities is seen. Guideline adherence was 57%, although CT-assessments varied from 44 to 100% depending on presence of specific major risk factors. CONCLUSIONS: Introduction of a new guideline on management of paediatric mTBI showed significant increase in CT-assessments and more hospital admissions. In clinical practice, despite increase of guideline adherence the applications of cranial CT-scan varies within age groups and depends on the weighing of risk factors. PMID- 28811139 TI - Metabonomics approach to assessing the metabolism variation and gender gap of Drosophila melanogaster in aging process. AB - Drosophila melanogaster is increasingly used for study aging mechanism and evaluating anti-aging drugs, but the changes of metabolites and differences of metabolites change between male and female during the aging process are not well known. Metabolomics technology, a massive information provider, has promoted the understanding of metabolic profile and overall changes of metabolites in organism. In this study, 1H NMR based metabonomics was employed to investigate the dynamic changes of metabolites in whole bodies of male and female Drosophila melanogaster at 3, 15, 30, 45days and to research the gender gap of metabolites changes in aging process. The results showed that the metabolic profile at different ages in both male and female Drosophila melanogaster were separated obviously by multivariate analysis. Besides, the variety track of metabolites between male and female Drosophila melanogaster were different, the change speed in female was significantly slow than that in male. In addition, the results showed 14 metabolites (including leucine, valine, alanine, methionine, cysteine, phenylalanine, glycine, glutamine, tyrosine, tryptophan and histidine, succinate, xanthine and DMA) were associated with aging and 7 metabolites (including leucine, valine, methionine, cysteine phenylalanine, succinate and DMA) were associated with gender gap in the aging process of Drosophila melanogaster. Corresponding metabolic mechanisms referenced to the KEGG database and literatures were discussed. This study demonstrate that metabolomics is promising as a valuable method not only to reveal metabolites that related to senescence, but also to help us understand differences between male and female flies in aging process. PMID- 28811140 TI - Divergent effects of resistance training and anabolic steroid on the postsynaptic region of different skeletal muscles of aged rats. AB - This study aimed to analyze the effects of resistance training associated with testosterone administration in the neuromuscular junction (NMJ) postsynaptic region of different skeletal muscle types of aged rats. Wistar rats were divided into: SEI - 20-months-old control, SEF - 24-months-old control, T - 20-months-old with testosterone, S - 20-months-old resistance trained and ST - 20-months-old with resistance training associated with testosterone propionate. All groups were submitted to familiarization and maximum load carrying testing (MLCT). The MLCT was applied before and after the resistance training (RT) period. RT (6 8*/session with progressive loads of 50 to 100%, 3*/week and 120s interval) was performed in ladder climbing for 15weeks. The administration of testosterone propionate was performed 2*/week (10mg/kg/body weight). After euthanize, soleus and plantaris muscles were removed and prepared for histochemistry and cytofluorescence. T, S and ST significantly increased their maximum carrying load capacity compared to SEI and SEF (p<0.05). For soleus postsynaptic region, ST had lower total and stained area than SEF (p<0.05). For plantaris, the postsynaptic component of T was statistically larger than SEI (p<0.05). For soleus histochemistry, T, S and ST groups showed the same magnitude of type I myofibers hypertrophy, thus statistically different from SEI and SEF (p<0.05). The cross sectional area of the type IIa myofibers of the ST was larger than SEF (p<0.05). The volume density of type I myofibers show to be lower in ST than SEI (p<0.05). As for type IIa myofibers, ST increased Vv [type IIa] compared to SEI and SEF (p<0.05). For plantaris, T significantly hypertrophied type I myofibers compared to SEI and SEF (p<0.05). S and ST demonstrated significant increases of type I myofibers compared to SEI and SEF (p<0.05). As for type IIx myofibers, both S and ST showed myofibers larger than SEI (p<0.05). However, only the ST had significant difference compared to SEF (p<0.05). In conclusion, both therapies, alone or combined, have little effect on the morphology of the NMJ postsynaptic region of distinct muscles. Moreover, the three therapies are potentially stimulating for strength gains and muscle hypertrophy. PMID- 28811141 TI - The pharmacokinetic profile of synthetic cathinones in a pregnancy model. AB - In recent years, the abuse of synthetic cathinones or 'bath salts' has become a major public health concern. Although these compounds were initially sold legally and labeled "not for human consumption", the 'bath salts' are psychostimulants, with similar structures and pharmacologic mechanisms to cocaine, the amphetamines, and 3,4 methylendioxymethamphetamine (MDMA, Molly, or Ecstasy). The reported use of these substances by women of child-bearing age highlights the necessity of studies seeking to delineate risks of prenatal exposure. Three popular drugs of this type are methylone, mephedrone, and 3, 4 methylenedioxypyrovalerone (MDPV). Unfortunately, there is currently no information available on the teratogenicity of these compounds, or of the extent to which they cross the placenta. As such, the purpose of this study was to examine the pharmacokinetic profile of the 'bath salts' in a pregnancy model. Pregnant mice (E17.5 gestation) were injected intraperitoneally with a cocktail of 5mg/kg methylone, 10mg/kg mephedrone, and 3mg/kg (MDPV) dissolved in sterile saline. Maternal brain, maternal plasma, placenta, and fetal brain were collected at 30s, 1min, 5min, 10min, 15min, 30min, 1h, 2h, 4h, and 8h following injection. Methylone, mephedrone, and MDPV were extracted from tissue by solid phase extraction, and concentrations were determined using a previously validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Interestingly, all 3 cathinones reached measurable concentrations in the placenta, as well as the fetal brain; in fact, for MDPV, the maximal concentration (Cmax) was highest in fetal brain, while mephedrone's highest Cmax value was achieved in placenta. Additionally, the total drug exposure for all 3 compounds (as represented by area under the curve, AUC) was higher in fetal matrices (placenta and fetal brain) than in maternal matrices (maternal brain and plasma), and the half-lives for the drugs were longer. Given the extensive presence of methylone, mephedrone, and MDPV in the fetal brain following prenatal exposure, fetal risk is definitely a concern. As there are currently no prenatal studies available on the teratogenicity of these agents, pregnant patients should be informed about the potential risks that these substances may have. PMID- 28811142 TI - Anatomical analysis of human ligamentum flavum in the cervical spine: Special consideration to the attachments, coverage, and lateral extent. AB - BACKGROUND: Posterior decompression surgeries of cervical spine such as laminoplasty and laminoforaminotomy are well established and increasing in aging population. The anatomical knowledge of cervical ligamentum flavum (LF) is critical to perform posterior spinal surgeries, however, few studies have evaluated it, especially the relation of LF and neural foramen. METHODS: The whole spine was removed en bloc from 15 formalin-embalmed human cadavers and then divided into two segments along the pedicle bases. A total of 90 LFs from C2-C3 to C7-T1 were measured manually from the ventral side before being painted with iron powder containing contrast agent and scanned by computed tomography. We recorded dimensions, coverage of adjacent laminae, and the relationships between LF and neural foramen or facet joints. Three-dimensional CT data was used to evaluate manually limited areas and make reconstructed images. RESULTS: LF height gradually increased from C2-C3 to C7-T1, and gradually decreased from medial to lateral within each level. LF width and thickness were relatively constant from cranial to caudal. The laminar surface covered by LF gradually increased from 33% in para midline and 30% laterally at C2, and increased to 70% in para midline and 47% laterally at C6, this trend was not completed at C7. The empty zone of the laminar surface (without LF coverage) was located at the upper half of each lamina; this zone gradually decreased from cranial to caudal. The craniomedial side of the cervical facet joint was covered by a mean 4.6 +/- 0.7 mm of LF, however, LF did not enter the cervical neural foramen. CONCLUSIONS: LF did not enter the neural foramen in cervical spine unlike lumbar spine. This information might be critical to avoid neurological deterioration after cervical laminoplasty or laminoforaminotomy. Surgeons would imagine the attachments and coverage of LF and its relation to posterior bony structures to perform safe posterior cervical surgeries. PMID- 28811138 TI - Intermittent hypoxia training: Powerful, non-invasive cerebroprotection against ethanol withdrawal excitotoxicity. AB - Ethanol intoxication and withdrawal exact a devastating toll on the central nervous system. Abrupt ethanol withdrawal provokes massive release of the excitatory neurotransmitter glutamate, which over-activates its postsynaptic receptors, causing intense Ca2+ loading, p38 mitogen activated protein kinase activation and oxidative stress, culminating in ATP depletion, mitochondrial injury, amyloid beta deposition and neuronal death. Collectively, these mechanisms produce neurocognitive and sensorimotor dysfunction that discourages continued abstinence. Although the brain is heavily dependent on blood-borne O2 to sustain its aerobic ATP production, brief, cyclic episodes of moderate hypoxia and reoxygenation, when judiciously applied over the course of days or weeks, evoke adaptations that protect the brain from ethanol withdrawal-induced glutamate excitotoxicity, mitochondrial damage, oxidative stress and amyloid beta accumulation. This review summarizes evidence from ongoing preclinical research that demonstrates intermittent hypoxia training to be a potentially powerful yet non-invasive intervention capable of affording robust, sustained neuroprotection during ethanol withdrawal. PMID- 28811144 TI - Microwave induced plasma for solid fuels and waste processing: A review on affecting factors and performance criteria. AB - High temperature thermal plasma has a major drawback which consumes high energy. Therefore, non-thermal plasma which uses comparatively lower energy, for instance, microwave plasma is more attractive to be applied in gasification process. Microwave-induced plasma gasification also carries the advantages in terms of simplicity, compactness, lightweight, uniform heating and the ability to operate under atmospheric pressure that gains attention from researchers. The present paper synthesizes the current knowledge available for microwave plasma gasification on solid fuels and waste, specifically on affecting parameters and their performance. The review starts with a brief outline on microwave plasma setup in general, and followed by the effect of various operating parameters on resulting output. Operating parameters including fuel characteristics, fuel injection position, microwave power, addition of steam, oxygen/fuel ratio and plasma working gas flow rate are discussed along with several performance criteria such as resulting syngas composition, efficiency, carbon conversion, and hydrogen production rate. Based on the present review, fuel retention time is found to be the key parameter that influences the gasification performance. Therefore, emphasis on retention time is necessary in order to improve the performance of microwave plasma gasification of solid fuels and wastes. PMID- 28811143 TI - NADPH oxidases as drug targets and biomarkers in neurodegenerative diseases: What is the evidence? AB - Neurodegenerative disease are frequently characterized by microglia activation and/or leukocyte infiltration in the parenchyma of the central nervous system and at the molecular level by increased oxidative modifications of proteins, lipids and nucleic acids. NADPH oxidases (NOX) emerged as a novel promising class of pharmacological targets for the treatment of neurodegeneration due to their role in oxidant generation and presumably in regulating microglia activation. The unique function of NOX is the generation of superoxide anion (O2*-) and hydrogen peroxide (H2O2). However in the context of neuroinflammation, they present paradoxical features since O2*-/H2O2 generated by NOX and/or secondary reactive oxygen species (ROS) derived from O2*-/H2O2 can either lead to neuronal oxidative damage or resolution of inflammation. The role of NOX enzymes has been investigated in many models of neurodegenerative diseases by using either genetic or pharmacological approaches. In the present review we provide a critical assessment of recent findings related to the role of NOX in the CNS as well as how the field has advanced over the last 5 years. In particular, we focus on the data derived from the work of a consortium (Neurinox) funded by the European Commission's Programme 7 (FP7). We discuss the evidence gathered from animal models and human samples linking NOX expression/activity with neuroinflammation in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Creutzfeldt-Jakob disease as well as autoimmune demyelinating diseases like multiple sclerosis (MS) and chronic inflammatory demyelinating polyneuropathy (CIDP). We address the possibility to use measurement of the activity of the NOX2 isoform in blood samples as biomarker of disease severity and treatment efficacy in neurodegenerative disease. Finally we clarify key controversial aspects in the field of NOX, such as NOX cellular expression in the brain, measurement of NOX activity, impact of genetic deletion of NOX in animal models of neurodegeneration and specificity of NOX inhibitors. PMID- 28811145 TI - Characterization of methane oxidation in a simulated landfill cover system by comparing molecular and stable isotope mass balances. AB - Biological methane oxidation may be regarded as a method of aftercare treatment for landfills to reduce climate relevant methane emissions. It is of social and economic interest to estimate the behavior of bacterial methane oxidation in aged landfill covers due to an adequate long-term treatment of the gas emissions. Different approaches assessing methane oxidation in laboratory column studies have been investigated by other authors recently. However, this work represents the first study in which three independent approaches, ((i) mass balance, (ii) stable isotope analysis, and (iii) stoichiometric balance of product (CO2) and reactant (CH4) by CO2/CH4-ratio) have been compared for the estimation of the biodegradation by a robust statistical validation on a rectangular, wide soil column. Additionally, an evaluation by thermal imaging as a potential technique for the localization of the active zone of bacterial methane oxidation has been addressed in connection with stable isotope analysis and CO2/CH4-ratios. Although landfills can be considered as open systems the results for stable isotope analysis based on a closed system correlated better with the mass balance than calculations based on an open system. CO2/CH4-ratios were also in good agreement with mass balance. In general, highest values for biodegradation were determined from mass balance, followed by CO2/CH4-ratio, and stable isotope analysis. The investigated topsoil proved to be very suitable as a potential cover layer by removing up to 99% of methane for CH4 loads of 35-65gm-2d-1 that are typical in the aftercare phase of landfills. Finally, data from stable isotope analysis and the CO2/CH4-ratios were used to trace microbial activity within the reactor system. It was shown that methane consumption and temperature increase, as a cause of high microbial activity, correlated very well. PMID- 28811146 TI - N2O emissions from an intermittently aerated semi-aerobic aged refuse bioreactor: Combined effect of COD and NH4+-N in influent leachate. AB - The carbon-nitrogen ratio (COD/NH4+-N) is an important factor affecting nitrification and denitrification in wastewater treatment; this factor also influences nitrous oxide (N2O) emissions. This study investigated two simulated intermittently aerated semi-aerobic aged refuse bioreactors (SAARB) filled with 8 year old aged refuse (AR). The research analyzed how differences in and the combination of influent COD and NH4+-N impact N2O emissions in leachate treatment. Experimental results showed that N2O emissions increased as the influent COD/NH4+-N decreased. The influent COD had a greater effect on N2O emissions than NH4+-N at the same influent ratios of COD/NH4+-N (2.7 and 8.0, respectively). The maximum N2O emission accounted for 8.82+/-2.65% of the total nitrogen removed from the influent leachate; the maximum level occurred when the COD was 2000mg/L. An analysis of differences in influent carbon sources at the same COD/NH4+-N ratios concluded that the availability of biodegradable carbon substrates (i.e. glucose) is an important factor affecting N2O emissions. At a low influent COD/NH4+-N ratio (2.7), the N2O conversion rate was greater when there were more biodegradable carbon substrates. Although the SAARB included the N2O generation and reduction processes, N2O reduction mainly occurred later in the process, after leachate recirculation. The maximum N2O emission rate occurred in the first hour of single-period (24h) experiments, as leachate contacted the surface AR. In practical SAARB applications, N2O emissions may be reduced by measures such as reducing the initial recirculation loading of NH4+-N substrates, adding a later supplement of biodegradable carbon substrates, and/or prolonging hydraulic retention time (HRT) of influent leachate. PMID- 28811147 TI - Neutralization of cement-asbestos waste by melting in an arc-resistance furnace. AB - The paper presents the results of research on asbestos waste disposal by the melting process. The tests were carried out in a laboratory arc-resistance electric furnace. The obtained results showed that the fibrous structure of asbestos contained in cement-asbestos waste was completely destroyed. This led to the formation of new mineral phases without dangerous properties. The melting test was conducted on raw cement-asbestos samples without any additives and with a content of mineral compounds, the aim of which was to support the melting process. The additives were selected among others on the basis of the computer simulation results carried out using FactSage database computing system. The research results indicate that the melting process of asbestos wastes is a potential and interesting method of neutralizing hazardous asbestos waste, which allows for further treatment and material recycling. PMID- 28811148 TI - Metagenomes from deep Baltic Sea sediments reveal how past and present environmental conditions determine microbial community composition. AB - Microbial communities that lived near the sediment surface in the past become slowly buried and are the source of deep subsurface communities thousands of years later. We used metagenomes to analyse how the composition of buried microbial communities may change to conform to altered environmental conditions at depth. Sediment samples were collected from down to 85m below sea floor during the Integrated Ocean Drilling Program Expedition 347, "Baltic Sea Paleoenvironment". The sediments vary in age, organic carbon content, porewater salinity, and other parameters that reflect the changing Baltic environment from the last ice age and throughout the Holocene. We found microorganisms capable of energy conservation by fermentation, acetogenesis, methanogenesis, anaerobic oxidation of methane, and reductive dehalogenation. Glacial sediments showed a greater relative abundance of genes encoding enzymes in the Wood-Ljungdahl pathway and pyruvate:ferredoxin oxidoreductase than Holocene sediments. Relative abundance of genes conferring salinity tolerance was found to correlate with the present salinity, even in deep late-glacial sediment layers where salinity has increased since the sediment was deposited in a freshwater lake >9000years ago. This suggests that deeply buried and isolated sediment communities can slowly change in composition in response to geochemical changes that happen long after deposition. PMID- 28811149 TI - Three-center feasibility of lung clearance index in infants and preschool children with cystic fibrosis and other lung diseases. AB - BACKGROUND: Lung clearance index (LCI) detects early ventilation inhomogeneity and has been suggested as sensitive endpoint in multicenter intervention trials in infants and preschoolers with cystic fibrosis (CF). However, the feasibility of multicenter LCI in this age group has not been determined. We, therefore, investigated the feasibility of LCI in infants and preschoolers with and without CF in a three-center setting. METHODS: Following central training, standardized SF6-MBW measurements were performed in 73 sedated children (10 controls, 49 with CF and 14 with other lung diseases), mean age 2.3+/-1.2years across three centers, and data were analyzed centrally. RESULTS: Overall success rate of LCI measurements was 91.8% ranging from 78.9% to 100% across study sites. LCI was increased in patients with CF (P<0.05) and with other lung diseases (P<0.05) compared to controls. CONCLUSION: Our results support feasibility of LCI as multicenter endpoint in clinical trials in infants and preschoolers with CF. PMID- 28811150 TI - Best Practice Recommendations for the Retention of Radiotherapy Records. AB - This paper offers best practice recommendations for the maintenance and retention of radiotherapy health records and technical information for cancer programmes. The recommendations are based on a review of the published and grey literature, feedback from key informants from seven countries and expert consensus. Ideally, complete health records should be retained for 5 years beyond the patient's lifetime, regardless of where they are created and maintained. Technical information constituting the radiotherapy plan should also be retained beyond the patient's lifetime for 5 years, including the primary images, contours of delineated targets and critical organs, dose distributions and other radiotherapy plan objects. There have been increased data storage and access requirements to support modern image-guided radiotherapy. Therefore, the proposed recommendations represent an ideal state of radiotherapy record retention to facilitate ongoing safe and effective care for patients as well as meaningful and informed retrospective research and policy development. PMID- 28811151 TI - Proposed model for translational research at a teaching-intensive college of pharmacy. AB - BACKGROUND: Many American colleges of pharmacy are small, private, teaching institutions. Faculty are required to maintain a research agenda, although the publication quota is less compared with their publicly funded college of pharmacy peers. Faculty at these smaller schools conduct research with very little internal or external funding. This tends to lead to smaller, less impactful research findings. Translational research is becoming popular for research faculty as it bridges theory to practice. The Knowledge-to-Action (KTA) framework presents the steps to conduct translational research. PURPOSE: To apply and determine if the KTA framework would be able to produce practice-impactful research at an institution that does not depend on grant funding as part of faculty research agendas. PROCEDURES: An interdisciplinary team was formed with providers at the clinical faculty's practice site. As the team moved through the KTA steps, authors documented the roles of each team member. It was clear that many different types of teams were formed throughout the KTA process. These teams were then categorized according to the Interdisciplinary Teamwork System. The final result is a proposed model of types of teams and required member roles that are necessary within each KTA step for faculty to conduct practice-impactful research at a small, private, teaching institution without substantial grant funding awards. MAIN FINDINGS: Applying the KTA framework, two impactful original research manuscripts were developed over two academic years. Furthermore, the practitioners at the clinical faculty member's site were very pleased with the ease of conducting research, as they were never required to take a lead role. In addition, both faculty members alternated lead and support role allowing for a decreased burden of workload while producing theory-driven research. CONCLUSION: The KTA framework can create a model for translational research and may be particularly beneficial to small teaching institutions to conduct impactful research. PMID- 28811152 TI - How does media coverage effect the consumption of antidepressants? A study of the media coverage of antidepressants in Danish online newspapers 2010-2011. AB - BACKGROUND: The news media has become a major source of health information for the public, and hence vital in the individuals' opinions and decisions about health topics. The first decrease in the usage of antidepressants in Denmark in over a decade happened alongside an intensive period of media coverage about antidepressants. OBJECTIVES: The aim of this study was to examine the Danish media's coverage of antidepressants during 2010-2011 in order to explore what influence it could have had on the change in the use of antidepressants. METHODS: Three media theoretical concepts, agenda-setting, priming and framing, were used to explain the media influence with regard to which subject the public should think about, which criteria the public should judge the subject by, and how the public should think about the subject. All articles about antidepressants in the main Danish Internet newspapers from 2010-2011 were analyzed via quantitative and qualitative content analyses. The quantitative analysis was used to determine agenda-setting (number of articles) and, by coding articles, how priming was used in the descriptions of antidepressants. In the qualitative analysis, all articles were analyzed and condensed to determine which frames were used. RESULTS: Quantitative results: 271 articles were included. Agenda-setting was shown by a marked increase in the number of articles about antidepressants. Eight main codes were identified, with the negatively-associated side effects being the major one, thereby priming the public to use side effects as a criterion when judging antidepressants. Qualitative results: Two main frames were identified: 1) economic profits vs. medicine safety, and 2) the necessity of antidepressants. Both frames presented a critical view on antidepressants. CONCLUSION: It is believed that the media's agenda-setting, priming and framing of antidepressants led the public to have a more skeptical view on antidepressants, which may have probably contributed to a decrease in the usage of antidepressants. PMID- 28811153 TI - The design of target specific antibodies (scFv) by applying de novo workflow: Case study on BmR1 antigen from Brugia malayi. AB - De novo approach was applied to design single chain fragment variable (scFv) for BmR1, a recombinant antigen from Bm17DIII gene which is the primary antigen used for the detection of anti-BmR1 IgG4 antibodies in the diagnostic of lymphatic filariasis. Three epitopes of the BmR1 was previously predicted form an ab initio derived three-dimensional structure. A collection of energetically favourable conformations was generated via hot-spot-centric approach. This resulted in a set of three different scFv scaffolds used to compute the high shape complementary conformations via dock-and-design approach with the predicted epitopes of BmR1. A total of 4227 scFv designs were generated where 200 scFv designs produced binding energies of less than -20 R.E.U with shape complementarity higher than 0.5. We further selected the design with at least one hydrogen bond and one salt bridge with the epitope, thus resulted in a total of 10, 1 and 19 sFv designs for epitope 1, 2 and 3, respectively. The results thus showed that de novo design can be an alternative approach to yield high affinity in silico scFv designs as a starting point for antibody or specific binder discovery processes. PMID- 28811154 TI - Theoretical study on electron structure and charge transport properties of tetraazapentacene derivatives. AB - By Means of Marcus electron transfer theory, the charge transport properties of tetraazapentacene (4N-PEN) derivatives were systematically explored. The reorganization energies were studied by both adiabatic potential-energy surfaces and normal mode analysis. The charge diffusion constants were evaluated from the random walk simulation. From the perspective of homology modeling, a selected 4N PEN derivative without experimental crystal structure was built into three kinds of possible packing modes with reference to its relative analogues and then fully optimized. The calculated results show that the charge transport property for the same kind of systems strongly depends on the packing mode, and the pi...stacking is more beneficial for electron transport of 4N-PEN derivatives. Meanwhile, the 4N-PEN derivatives have larger electron transfer integrals and lower energy levels of the lowest unoccupied molecular orbitals as well as smaller electron reorganization energies, which provides a three-in-one advantage for electron transport. Fascinatingly, the data obtained from the hopping and band models both suggest that the 4N-PEN derivatives have the intrinsic property of electron transport. Thus, the 4N-PEN derivatives have the potential for preparing n-type organic semiconductors. PMID- 28811155 TI - Assessing changes in quality of life and independent living and working levels among AgrAbility farmers and ranchers with disabilities. AB - BACKGROUND: While emerging research has focused on quality of life (QOL) levels among farmers and ranchers with disabilities, much work is still needed on this largely understudied population. The AgrAbility Project, a USDA initiative, offers pragmatic solutions to increase farmers and ranchers with disabilities' QOL and ability to work and live independently (ILW). OBJECTIVES: To assess pretest-posttest changes in farmers and ranchers with disabilities' ILW and QOL levels after participating in AgrAbility, to identify demographic predictors of ILW and QOL (e.g. with whom AgrAbility works best), and to determine how much variance in QOL is accounted for by change in ILW levels. METHODS: Participants (N = 191) included farmers and ranchers from 10 states with various disabilities who participated in AgrAbility. They completed ILW and McGill QOL measures before and after AgrAbility. RESULTS: Paired samples t-tests highlighted that participants' ILW and QOL levels improved (p < 0.001) with large or larger than typical effect sizes. Repeated measures ANOVA indicated that change in ILW over time was qualified by age and origin of disability. Regression results revealed that change in ILW predicted 13% of the variance in QOL change. CONCLUSIONS: These results suggest that participation in the AgrAbility Project was positively associated with increased ILW and QOL levels. AgrAbility participants reported increases in their QOL levels and their ability to continue their work and live in their homes. Further research is needed to compare results with a no-treatment comparison group of similar ranchers and farmers with disabilities. PMID- 28811156 TI - Screening of congenital hypothyroidism in preterm, low birth weight and very low birth weight neonates: A systematic review. AB - Evidence from different screening programs indicated that the rate of congenital hypothyroidism (CH) was higher in pre-term and low-birth-weight (LBW) newborns than normal ones. Incomplete development of hypothalamic-pituitary axis in this group of neonates results in the delayed rise of TSH and missing cases with CH. Hence, there is a great need for a practicable systematic screening method for proper diagnosis of CH in this group of neonates. In this review, we systematically reviewed papers with the following key words ([Congenital Hypothyroidism AND Screening AND Thyroxine AND Thyroid Stimulating Hormone AND Low Birth Weight AND Premature]) in international electronic databases including PubMed, Scopus, and Google Scholar. After quality assessment of selected documents, data of finally included papers were extracted. In this review, 1452 papers (PubMed: 617; Scopus: 714; Google scholar: 121) were identified through electronic database search. One hundred and ninety four articles were assessed for eligibility, from which 36 qualified articles were selected for final evaluation. From the reviewed articles, 38.9%, 11.11% and 8.3% recommended rescreening in this group of neonates, lowering the screening cutoff of TSH and using cutoffs according to the gestational age, respectively. Some of them (13.9%) recommended using both TSH and T4 for screening of preterm infants. After reviewing available data, we recommend repeating the screening test in pre-term, LBW and very-low- birth-weight (VLBW) infants at age of two, six and ten weeks by measuring TSH and FT4 levels simultaneously and considering TSH = 10 mU/L as the cutoff level for positive and suspicious cases. PMID- 28811157 TI - An electronic smart watch monitors heart rate of an extremely preterm baby. PMID- 28811158 TI - High HCV cure rates for people who use drugs treated with direct acting antiviral therapy at an urban primary care clinic. AB - BACKGROUND: Though direct acting antivirals (DAAs) promise high cure rates, many providers and payers remain concerned about successful treatment for people who use drugs (PWUD), even among those engaged in opioid agonist treatment (OAT). The efficacy of DAAs among PWUD in real-world settings is unclear. METHODS: We conducted a cohort study of patients initiating HCV treatment between January 2014 and August 2015 (n=89) at a primary care clinic in the Bronx, NY. Onsite HCV treatment with DAAs was performed by an HCV specialist, with support from a care coordinator funded by the NYC Department of Health. We identified four categories of drug use and drug treatment: (1) no active drug use/not receiving OAT (defined as non-PWUD); (2) no active drug use/receiving OAT; (3) active drug use/not receiving OAT; and (4) active drug use/receiving OAT. The primary outcome was SVR at 12 weeks post-treatment. RESULTS: Overall SVR rates were 95% (n=41/43) for non PWUD and 96% (n=44/46) for patients actively using drugs and/or receiving OAT [p=0.95]. There were no differences in SVR rates by drug use or drug treatment category. Compared to non-PWUD, those with no active drug use/receiving OAT had 100% SVR (n=15/15; p=1.0), those actively using drugs/not receiving OAT had 90% SVR (n=9/10; p=0.47), and those actively using drugs/receiving OAT had 95% SVR (20/21; p=1.0). CONCLUSION: Regardless of active drug use or OAT, patients who received DAA therapy at an urban primary care clinic achieved high HCV cure rates. We found no clinical evidence to justify restricting access to HCV treatment for patients actively using drugs and/or receiving OAT. PMID- 28811160 TI - High-efficiency removal of lead from wastewater by biochar derived from anaerobic digestion sludge. AB - The properties of biochar derived from waste activated sludge and anaerobic digestion sludge under pyrolysis temperature varying from 400 degrees C to 800 degrees C were investigated. The heavy metals adsorption efficiency of the sludge derived biochar was also examined. Among the biochar samples tested, ADSBC600 possessing highly porous structure, special surface chemical behaviors and high thermal stability was found to remove Pb2+ from aqueous solutions efficiently with an adsorption capacity of 51.20mg/g. The Pb2+ adsorption kinetics and isotherm for ADSBC600 can be described using the pseudo second-order model and Langmuir isotherm, respectively. Analysis of the characteristics of biochar before and after metal treatment suggests that electrostatic attraction, precipitation, surface complexation and ion exchange are the possible Pb2+ removal mechanisms. This study demonstrates a successful example of waste refinery by converting anaerobic digestion sludge to feasible heavy metal adsorbents to implement the concept of circular economy. PMID- 28811159 TI - Implementing and scaling up HCV treatment services for people who inject drugs and other high risk groups in Ukraine: An evaluation of programmatic and treatment outcomes. AB - BACKGROUND: HCV prevalence estimates among people who inject drugs (PWID) in Ukraine is high (60-90%), yet barriers to HCV treatment and care remain substantial including limited access to direct acting antiviral (DAA) medications. A feasibility scale-up project implemented HCV treatment in community-based settings to improve access to DAA treatment for key populations in this context. METHODS: Using program-level data and verified medical records, we describe the development, implementation processes and outcomes for HCV treatment for PWID and other risks groups. Most participants (76%) received a combination of sofosbuvir, pegylated interferon, and ribavirin for 12 weeks. Treatment enrollment started in June 2015; the first two waves are reported. Data on demographics, HIV characteristics, HCV genotype and RNA levels, including sustained virologic response (SVR) were obtained from verified medical records. We used logistic regression to examine the independent correlates of achieving a SVR. RESULTS: The project was implemented in 19 healthcare institutions from 16 regions of Ukraine, mainly within AIDS specialty centers. Our analytical sample included 1126 participants who were mostly men (73%) and the majority were HIV co infected (79%). Treatment retention was 97.7%; the proportions of participants who achieved SVR for the overall sample and for those with complete data (N=1029) were 86.2% (95% CI 84.08-88.19%) and 94.3% (95% CI 92.8-95.7%) respectively. The analysis of data restricted to only those with SVR data available showed that PWID who were currently injecting had comparable SVR rates (89.2%, 95% CI 81.5 94.5%) to PWID not injecting (94.4%, 95% CI 92.4-96.1), PWID on methadone (94.4%, 95%CI 92.4-96.1), and 'other' risk groups (95.2%, 95% CI 91.3-97.7). Independent factors associated with achieving a SVR were female sex (AOR: 3.44, 95% CI 1.45 8.14), HCV genotype 3 (AOR: 4.57, 95% CI 1.97-10.59) compared to genotype 1. SVR rates in PWID actively injecting did not differ significantly from any other group. CONCLUSION: Both patient-level and structural factors influence HCV treatment scale-up in Ukraine, but patient-level outcomes confirm high levels of achieving SVR in PWID, irrespective of injection and treatment status. PMID- 28811161 TI - Acceleration of electroactive anammox (electroammox) start-up by switching acetate pre-acclimated biofilms to electroammox biofilms. AB - In this study, an operational method of switching acetate media to ammonium media after the formation of stable acetate-oxidizing biofilms (ACAM mode), was developed. The results showed that the start-up time was shortened to 48days in the ACAM mode compared to the AM (always ammonium media) mode (>120days), and an ammonia removal rate of 82+/-3% was achieved successfully and sustainably in the ACAM mode during the following long-term operation of more than 2months. Moreover, the ACAM mode was more efficient in enriching both electroammox bacteria and electricigens with Ignavibacteriaceae, Geobacteraceae and Nitrosomonadaceae as dominant families, which could favour the formation of high performance electroammox biofilms. Thus, the ACAM mode might promote the widespread implementation of the electroammox process. PMID- 28811162 TI - Engineering peptidoglycan degradation related genes of Bacillus subtilis for better fermentation processes. AB - In this study, Bacillus subtilis 168 Deltaupp was engineered to change the bacterial shapes. Namely, some peptidoglycan hydrolase related genes were inactivated individually or in different combinations, including sigD, lytE, lytF, lytC, lytD and lytG. Inactivations of these genes resulted in various intensities of blockages on cell division, leading to elongation of bacterial cells. The resulted fiber phenotypes showed different lengths ranging from tens of microns to several millimeters. Mutants with multiple gene inactivations such as DeltasigDDeltalytEDeltalytD showed more easily precipitated phenomenon, obviously increased growth rate, more sensitive to antibiotics and improved alpha amylase production compared with that of B. subtilis 168 Deltaupp. Mutants DeltasigDDeltalytEDeltalytD and DeltasigDDeltalytEDeltalytCDeltalytD also showed an increased tolerance to high osmotic pressure of sodium chloride, allowing unsterile fermentation, all of which contributes to reduced processing cost. PMID- 28811163 TI - Climate Change, CO2, and Defense: The Metabolic, Redox, and Signaling Perspectives. AB - Ongoing human-induced changes in the composition of the atmosphere continue to stimulate interest in the effects of high CO2 on plants, but its potential impact on inducible plant defense pathways remains poorly defined. Recently, several studies have reported that growth at elevated CO2 is sufficient to induce defenses such as the salicylic acid pathway, thereby increasing plant resistance to pathogens. These reports contrast with evidence that defense pathways can be promoted by photorespiration, which is inhibited at high CO2. Here, we review signaling, metabolic, and redox processes modulated by CO2 levels and discuss issues to be resolved in elucidating the relationships between primary metabolism, inducible defense, and biotic stress resistance. PMID- 28811164 TI - Corrigendum to "Functional quantum dot-siRNA nanoplexes to regulate chondrogenic differentiation of mesenchymal stem cells" [Acta Biomater. 46 (2016) 165-176]. PMID- 28811165 TI - Dicyanomethylene Substituted Benzothiazole Squaraines: The Efficiency of Photodynamic Therapy In Vitro and In Vivo. AB - The lack of ideal photosensitizers limits the clinicalapplication of photodynamic therapy (PDT). Here we report the PDT efficiency of dicyanomethylene substituted benzothiazole squaraine derivatives. This class of squaraine derivatives possess strong absorption and long excitation and emission wavelengths (ex/em, 685/720nm). They show negligible dark toxicity, but can generate singlet oxygen under irradiation resulting in the apoptosis and necrosis of cells (phototoxicity). Changing the side chains of these compounds greatly influences their albumin-binding rate, cellular uptake and their phototoxicity. One of the squaraine derivatives with two methyl butyrate side chains shows high PDT efficiency in a mouse subcutaneous xenograft model under the irradiation of a 690nm laser. These results show the great potential of dicyanomethylene substituted benzothiazole squaraines to be the leading compound of near-infrared photosensitizers in PDT. PMID- 28811166 TI - Biomechanical implications of cortical elastic properties of the macaque mandible. AB - Knowledge of the variation in the elastic properties of mandibular cortical bone is essential for modeling bone function. Our aim was to characterize the elastic properties of rhesus macaque mandibular cortical bone and compare these to the elastic properties from mandibles of dentate humans and baboons. Thirty cylindrical samples were harvested from each of six adult female rhesus monkey mandibles. Assuming orthotropy, axes of maximum stiffness in the plane of the cortical plate were derived from ultrasound velocity measurements. Further velocity measurements with longitudinal and transverse ultrasonic transducers along with measurements of bone density were used to compute three-dimensional cortical elastic properties using equations based on Hooke's law. Results showed regional variations in the elastic properties of macaque mandibular cortical bone that have both similarities and differences with that of humans and baboons. So far, the biological and structural basis of these differences is poorly understood. PMID- 28811167 TI - Differences in mating behavior between two allopatric populations of a Neotropical scorpion. AB - Courtship and mating behavior generally evolve rapidly in diverging populations and species. The adaptation to different environments may cause behavioral divergence in characteristics involved in mate choice. Our objective in this study was to compare the sexual behavior of two distant populations of the scorpion Bothriurus bonariensis. This species has a broad distribution in South America, inhabiting Central Argentina, Uruguay and south-eastern Brazil. It is known that in this species there is a divergence in morphological patterns (body size, coloration, allometry and fluctuating asymmetry indexes) among distant populations. Considering the differences in environmental conditions between localities, we compare the sexual behavior in intra-population and inter population matings from Central Argentina and southern Uruguay populations. We found significant differences in mating patterns, including differences in the frequency and duration of important stimulatory courtship behaviors. In addition, most inter-population matings were unsuccessful. In this framework, the differences in reproductive behavior could indicate reproductive isolation between these populations, which coincides with their already known morphological differences. This is the first study comparing the sexual behavior of allopatric populations of scorpions; it provides new data about the degree of intraspecific geographical divergence in the sexual behavior of B. bonariensis. PMID- 28811168 TI - An ontogenetic perspective on symphyseal fusion, occlusion and mandibular loading in alpacas (Vicugna pacos). AB - A primary hypothesis for the evolution of mandibular symphyseal fusion in some mammals is that it functions to resist loads incurred during routine mastication. Anecdotal support for this hypothesis is based on the fact that when the symphysis fuses, it typically does so early during postnatal ontogeny prior to or around the time of weaning. However, little is known about the process of fusion, particularly relative to feeding behaviors and the dynamics of mastication, including occlusion and masticatory loading. In the present study, we investigate the timing and process of symphyseal fusion in alpacas (Vicugna pacos) in the context of maturation of the oral apparatus and oral behavior. We also report on in vivo strains from the symphysis and corpus in young alpacas prior to and following full fusion and M1 occlusion. Results show that fusion begins rostrally by 1 month and is complete by 6-7 months whereas all deciduous premolars and M1 come into occlusion by 6 months. Although symphyseal loading patterns are maintained throughout ontogeny, in young alpacas symphyseal strain magnitudes are low compared with adults but corpus strain magnitudes are comparable to those found in adults. Reduced symphyseal loading in young individuals is contrary to what might be predicted given that the symphysis is still fusing. When considered in light of the development of occlusion and rumination, strain magnitudes may be necessarily low and reflect an overall delay in the maturation of masticatory dynamics. PMID- 28811169 TI - Tissue engineered extracellular matrices (ECMs) in urology: Evolution and future directions. AB - Autologous gastrointestinal tissue has remained the gold-standard reconstructive biomaterial in urology for >100 years. Mucus-secreting epithelium is associated with lifelong metabolic and neuromechanical complications when implanted into the urinary tract. Therefore, the availability of biocompatible tissue-engineered biomaterials such as extracellular matrix (ECM) scaffolds may provide an attractive alternative for urologists. ECMs are decellularised, biodegradable membranes that have shown promise for repairing defective urinary tract segments in vitro and in vivo by inducing a host-derived tissue remodelling response after implantation. In urology, porcine small intestinal submucosa (SIS) and porcine urinary bladder matrix (UBM) are commonly selected as ECMs for tissue regeneration. Both ECMs support ingrowth of native tissue and differentiation of multi-layered urothelial and smooth muscle cells layers while providing mechanical support in vivo. In their native acellular state, ECM scaffolds can repair small urinary tract defects. Larger urinary tract segments can be repaired when ECMs are manipulated by seeding them with various cell types prior to in vivo implantation. In the present review, we evaluate and summarise the clinical potential of tissue engineered ECMs in reconstructive urology with emphasis on their long-term outcomes in urological clinical trials. PMID- 28811171 TI - Molecular Sensors of Blood Flow in Endothelial Cells. AB - Mechanical stress from blood flow has a significant effect on endothelial physiology, with a key role in initiating vasoregulatory signals. Disturbances in blood flow, such as in regions of disease-associated stenosis, arterial branch points, and sharp turns, can induce proatherogenic phenotypes in endothelial cells. The disruption of vascular homeostasis as a result of endothelial dysfunction may contribute to early and late stages of atherosclerosis, the underlying cause of coronary artery disease. In-depth knowledge of the mechanobiology of endothelial cells is essential to identifying mechanosensory complexes involved in the pathogenesis of atherosclerosis. In this review, we describe different blood flow patterns and summarize current knowledge on mechanosensory molecules regulating endothelial vasoregulatory functions, with clinical implications. Such information may help in the search for novel therapeutic approaches. PMID- 28811170 TI - Zika virus research models. AB - The 2015 Brazilian Zika virus outbreak sparked a rapid response to control the spread of the virus. What was first understood to be a mild self-resolving infection is now linked to significant neurological defects in both neonates and adults. The WHO declared the 2016 Zika epidemic a public health emergency and issued an unprecedented recommendation to women in affected regions to delay pregnancy until the risks surrounding Zika virus could be understood, or the epidemic contained. Since that time, considerable effort has been dedicated to understanding Zika transmission and pathogenesis to aid the development of drugs and vaccines. Several models have emerged to study numerous facets of Zika biology; this review details the various model systems. PMID- 28811172 TI - Current Options for Cell Therapy in Spinal Cord Injury. AB - Spinal cord injury (SCI) is a complex pathology that evolves after primary acute mechanical injury, causing further damage to the spinal cord tissue that exacerbates clinical outcomes. Based on encouraging results from preclinical experiments, some cell treatments being translated into clinical practice demonstrate promising and effective improvement in sensory/motor function. Combinatorial treatments of cell and drug/biological factors have been demonstrated to be more effective than cell treatments alone. Recent advances have led to the development of biomaterials aiming to promote in situ cell delivery for SCI, together with combinatorial strategies using drugs/biomolecules to achieve a maximized multitarget approach. This review provides an overview of single and combinatorial regenerative cell treatments as well as potential delivery options to treat SCI. PMID- 28811173 TI - Prenatal exposure to pyrethroid pesticides and childhood behavior and executive functioning. AB - Several previous studies of pyrethroid biomarkers and behavior have reported associations between concurrent pyrethroid levels and adverse behavioral problems in children. One geospatial study reported associations between prenatal exposure to pyrethroids and autism. However, the association between prenatal pyrethroid biomarkers and childhood behavior is unknown. The Mount Sinai Children's Environmental Health Center is a prospective birth cohort with urinary pyrethroid biomarkers during pregnancy and behavioral measurements at 4, 6, and 7-9 years of age. Primiparous women were enrolled between 1998 and 2002. 162 mother/child pairs with complete exposure and behavioral outcomes data were used to investigate associations between detectable levels of prenatal pyrethroid metabolites and scores on the Behavioral Assessment System for Children and the Behavior Rating Inventory of Executive Function. Overall, detection frequencies of pyrethroid metabolites were low (<30%). In longitudinal mixed models, detectable levels of 3-PBA during pregnancy were associated with worse Internalizing (beta -4.50, 95% CI -8.05, -0.95), Depression (beta -3.21, 95% CI 6.38, -0.05), Somatization (beta -3.22, 95% CI -6.38, -0.06), Behavioral Regulation (beta -3.59, 95% CI -6.97, -0.21), Emotional Control (beta -3.35, 95% CI -6.58, -0.12), Shifting (beta -3.42, 95% CI -6.73, -0.11), and Monitoring (beta -4.08, 95% CI -7.07, -1.08) scales. Detectable levels of cis-DCCA were associated with worse Externalizing (beta -4.74, 95% CI -9.37, -0.10), Conduct Problems (beta -5.35, 95% CI -9.90, -0.81), Behavioral Regulation (beta -6.42, 95% CI -11.39, -1.45), and Inhibitory Control (beta -7.20, 95% CI -12.00, -2.39). Although detection frequencies of pyrethroid metabolites were low, we found suggestive evidence that prenatal exposure to 3-PBA and cis-DCCA may be associated with a variety of behavioral and executive functioning deficits. PMID- 28811174 TI - Subchronic exposure to sublethal dose of imidacloprid changes electrophysiological properties and expression pattern of nicotinic acetylcholine receptor subtypes in insect neurosecretory cells. AB - Neonicotinoids are the most important class of insecticides used in agriculture over the last decade. They act as selective agonists of insect nicotinic acetylcholine receptors (nAChRs). The emergence of insect resistance to these insecticides is one of the major problems, which limit the use of neonicotinoids. The aim of our study is to better understand physiological changes appearing after subchronic exposure to sublethal doses of insecticide using complementary approaches that include toxicology, electrophysiology, molecular biology and calcium imaging. We used cockroach neurosecretory cells identified as dorsal unpaired median (DUM) neurons, known to express two alpha-bungarotoxin insensitive (alpha-bgt-insensitive) nAChR subtypes, nAChR1 and nAChR2, which differ in their sensitivity to imidacloprid. Although nAChR1 is sensitive to imidacloprid, nAChR2 is insensitive to this insecticide. In this study, we demonstrate that subchronic exposure to sublethal dose of imidacloprid differentially changes physiological and molecular properties of nAChR1 and nAChR2. Our findings reported that this treatment decreased the sensitivity of nAChR1 to imidacloprid, reduced current density flowing through this nAChR subtype but did not affect its subunit composition (alpha3, alpha8 and beta1). Subchronic exposure to sublethal dose of imidacloprid also affected nAChR2 functions. However, these effects were different from those reported on nAChR1. We observed changes in nAChR2 conformational state, which could be related to modification of the subunit composition (alpha1, alpha2 and beta1). Finally, the subchronic exposure affecting both nAChR1 and nAChR2 seemed to be linked to the elevation of the steady-state resting intracellular calcium level. In conclusion, under subchronic exposure to sublethal dose of imidacloprid, cockroaches are capable of triggering adaptive mechanisms by reducing the participation of imidacloprid-sensitive nAChR1 and by optimizing functional properties of nAChR2, which is insensitive to this insecticide. PMID- 28811175 TI - Clinical tolerance in eosinophilic esophagitis. PMID- 28811176 TI - Bullous Fixed Drug Eruption Secondary to Chlorthalidone. PMID- 28811177 TI - Prospective associations between peer teasing in childhood and young men's obesity. AB - OBJECTIVE: Being teased and otherwise victimised by peers during childhood increases risk for obesity. However, few prospective studies have considered whether risk extends to adulthood. We tested whether being teased in childhood predicted higher body mass index (BMI) and increased odds of obesity in early adulthood in a community sample of American males. METHOD: Boys (n=206) were classified as victims of peer teasing or non-victims (n=55 and 151, respectively) based on mother, father, and teacher reports at ages 10-12 years. BMI was assessed at ages 24 or 32 years for 203 of the participants. Family income, parent and child depressive symptoms, child antisocial behaviour, and childhood BMI were assessed at ages 10-13 years and served as control variables. RESULTS: In unadjusted comparisons, childhood victims did not differ significantly from non-victims on BMI (mean [SD]=27.49 [4.53] and 26.97 [4.60], respectively) or rates of obesity (42% and 31%, respectively) in early adulthood. In adjusted models, no group differences emerged for BMI (beta [95% confidence interval (CI)]=.02 [-.09 to .13], p=.77) or obesity (odds ratio [95% CI]=1.58 [.67-3.71], p=.30). CONCLUSIONS: Peer victimization has been associated with immediate and long-term maladjustment outcomes that are in some cases life threatening. However, our null results do not support that peer victimization significantly increases long-term risk for obesity, and findings are consistent with two other long-term prospective studies of this issue. PMID- 28811178 TI - Acute Delta-9-tetrahydrocannabinol administration in female rats attenuates immediate responses following losses but not multi-trial reinforcement learning from wins. AB - Delta-9-Tetrahydrocannabinol (THC) is the main psychoactive component of marijuana and has potent effects on decision-making, including a proposed reduction in cognitive flexibility. We demonstrate here that acute THC administration differentially affects some of the processes that contribute to cognitive flexibility. Specifically, THC reduces lose-shift responding in which female rats tend to immediately shift choice responses away from options that result in reward omission on the previous trial. THC, however, did not impair the ability of rats to flexibly bias responses toward feeders with higher probability of reward in a reversal task. This response adaptation developed over several trials, suggesting that THC did not impair slower forms of reinforcement learning needed to choose among options with unequal utility. This dissociation of THC's effects on innate/rapid and learned/gradual decision-making processes was unexpected, but is supported by emerging evidence that lose-shift responding is mediated by neural mechanisms distinct from those involved in other forms of reinforcement learning. The present data suggest that, at least in some tasks, the apparent reductions in cognitive flexibility by THC may be explained by the immediate effects on loss sensitivity, rather than impairments of all processes used for choice adaptation. PMID- 28811179 TI - Lateral frontal pole and relational processing: Activation patterns and connectivity profile. AB - The functional contribution of the lateral frontal cortex to behavior has been discussed with reference to several higher-order cognitive domains. In a separate line of research, recent studies have focused on the anatomical organization of this part of the brain. These different approaches are rarely combined. Here, we combine previous work using anatomical connectivity that identified a lateral subdivision of the human frontal pole and work that suggested a general role for rostrolateral prefrontal cortex in processing higher-order relations, irrespective of the type of information. We asked healthy human volunteers to judge the relationship between pairs of stimuli, a task previously suggested to engage the lateral frontal pole. Presenting both shape and face stimuli, we indeed observed overlapping activation of the lateral prefrontal cortex when subjects judged relations between pairs. Using resting state functional MRI, we confirmed that the activated region's whole-brain connectivity most strongly resembles that of the lateral frontal pole. Using diffusion MRI, we showed that the pattern of connections of this region with the main association fibers again is most similar to that of the lateral frontal pole, consistent with the observation that it is this anatomical region that is involved in relational processing. PMID- 28811180 TI - Development of an opioid self-administration assay to study drug seeking in zebrafish. AB - The zebrafish (Danio rerio) has become an excellent tool to study mental health disorders, due to its physiological and genetic similarity to humans, ease of genetic manipulation, and feasibility of small molecule screening. Zebrafish have been shown to exhibit characteristics of addiction to drugs of abuse in non contingent assays, including conditioned place preference, but contingent assays have been limited to a single assay for alcohol consumption. Using inexpensive electronic, mechanical, and optical components, we developed an automated opioid self-administration assay for zebrafish, enabling us to measure drug seeking and gain insight into the underlying biological pathways. Zebrafish trained in the assay for five days exhibited robust self-administration, which was dependent on the function of the MU-opioid receptor. In addition, a progressive ratio protocol was used to test conditioned animals for motivation. Furthermore, conditioned fish continued to seek the drug despite an adverse consequence and showed signs of stress and anxiety upon withdrawal of the drug. Finally, we validated our assay by confirming that self-administration in zebrafish is dependent on several of the same molecular pathways as in other animal models. Given the ease and throughput of this assay, it will enable identification of important biological pathways regulating drug seeking and could lead to the development of new therapeutic molecules to treat addiction. PMID- 28811181 TI - Beneficial effects of postnatal choline supplementation on long-Term neurocognitive deficit resulting from fetal-Neonatal iron deficiency. AB - Early-life iron deficiency is a common nutrient condition worldwide and can result in cognitive impairment in adulthood despite iron treatment. In rodents, prenatal choline supplementation can diminish long-term hippocampal gene dysregulation and neurocognitive deficits caused by iron deficiency. Since fetal iron status is generally unknown in humans, we determined whether postnatal choline supplementation exerts similar beneficial effects. Male rat pups were made iron deficient (ID) by providing pregnant and nursing dams an ID diet (3 6ppm Fe) from gestational day (G) 3 through postnatal day (P) 7, and an iron sufficient (IS) diet (200ppm Fe) thereafter. Control pups were provided IS diet throughout. Choline (5ppm) was given to half the nursing dams and weanlings in each group from P11-P30. P65 rat cognitive performance was assessed by novel object recognition (NOR). Real-time PCR was performed to validate expression levels of synaptic plasticity genes known to be dysregulated by early-life iron deficiency. Postnatal choline supplementation prevented impairment of NOR memory in formerly iron-deficient (FID) adult rats but impaired NOR memory in IS controls. Gene expression analysis revealed a recovery of 4 out of 10 dysregulated genes compared to 8 of the same 10 genes that we previously demonstrated to recover following prenatal choline supplementation. Recognition memory deficits induced by early-life iron deficiency can be prevented by postnatal choline supplementation and disrupted expression of a subset of synaptic plasticity genes can be ameliorated. The positive response to postnatal choline represents a potential adjunctive therapeutic supplement to treat iron deficient anemic children in order to spare long-term neurodevelopmental deficits. PMID- 28811182 TI - Implementing Sustainable Data Collection for a Cardiac Outcomes Registry in an Australian Public Hospital. AB - BACKGROUND: Clinical outcome registries are an increasingly vital component of ensuring quality and safety of patient care. However, Australian hospitals rarely have additional resources or the capacity to fund the additional staff time to complete the task of data collection and entry. At the same time, registry funding models do not support staff for the collection of data at the site but are directed towards the central registry tasks of data reporting, managing and quality monitoring. The sustainability of a registry is contingent on building efficiencies into data management and collection. METHODS: We describe the methods used in a large Victorian public hospital to develop a sustainable data collection system for the Victorian Cardiac Outcomes Registry (VCOR), using existing staff and resources common to many public hospitals. We describe the features of the registry and the hospital specific strategies that allowed us to do this as part of our routine business of providing good quality cardiac care. RESULTS: All clinical staff involved in patient care were given some data collection task with the entry of these data embedded into the staff's daily workflow. A senior cardiology registrar was empowered to allocate data entry tasks to colleagues when data were found to be incomplete. The task of 30-day follow-up proved the most onerous part of data collection. Cath-lab nursing staff were allocated this role. CONCLUSION: With hospital accreditation and funding models moving towards performance based quality indicators, collection of accurate and reliable information is crucial. Our experience demonstrates the successful implementation of clinical outcome registry data collection in a financially constrained public hospital environment utilising existing resources. PMID- 28811183 TI - Deletion of protein kinase D1 in osteoprogenitor cells results in decreased osteogenesis in vitro and reduced bone mineral density in vivo. AB - Protein kinase D1 (PRKD1) is thought to play a role in a number of cellular functions, including proliferation and differentiation. We hypothesized that PRKD1 in bone marrow-derived mesenchymal stem cells (BMMSC) could modulate osteogenesis. In BMMSCs from floxed PRKD1 mice, PRKD1 ablation with adenovirus mediated Cre-recombinase expression inhibited BMMSC differentiation in vitro. In 3- and 6-month-old conditional knockout mice (cKO), in which PRKD1 was ablated in osteoprogenitor cells by osterix promoter-driven Cre-recombinase, bone mineral density (BMD) was significantly reduced compared with floxed control littermates. Microcomputed tomography analysis also demonstrated a decrease in trabecular thickness and bone volume fraction in cKO mice at these ages. Dynamic bone histomorphometry suggested a mineralization defect in the cKO mice. However, by 9 months of age, the bone appeared to compensate for the lack of PRKD1, and BMD was not different. Taken together, these results suggest a potentially important role for PRKD1 in bone formation. PMID- 28811184 TI - Experimental cocrystal screening and solution based scale-up cocrystallization methods. AB - Cocrystals are crystalline single phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts. If one of the components is an active pharmaceutical ingredient (API), the term pharmaceutical cocrystal is often used. There is a growing interest among drug development scientists in exploring cocrystals, as means to address physicochemical, biopharmaceutical and mechanical properties and expand solid form diversity of the API. Conventionally, coformers are selected based on crystal engineering principles, and the equimolar mixtures of API and coformers are subjected to solution-based crystallization that are commonly employed in polymorph and salt screening. However, the availability of new knowledge on cocrystal phase behaviour in solid state and solutions has spurred the development and implementation of more rational experimental cocrystal screening as well as scale-up methods. This review aims to provide overview of commonly employed solid form screening techniques in drug development with an emphasis on cocrystal screening methodologies. The latest developments in understanding and the use of cocrystal phase diagrams in both screening and solution based scale-up methods are also presented. Final section is devoted to reviewing the state of the art research covering solution based scale-up cocrystallization process for different cocrystals besides more recent continuous crystallization methods. PMID- 28811185 TI - The Effect of Receptor Status on Mastectomy and Contralateral Prophylactic Mastectomy Rates in Early Stage Invasive Breast Carcinoma. AB - BACKGROUND: There is an established relationship between hormone receptor (HR; estrogen and/or progesterone receptors) status, HER2 status, and locoregional recurrence. The purpose of this study was to analyze how HR and HER2 receptor status have influenced the surgical management trends among patients with early stage breast cancer. PATIENTS AND METHODS: The National Cancer Database was queried for patients with cT1 to cT3, cN0, and cM0 breast carcinoma from 2004 to 2012. Patients were grouped on the basis of receptor status and surgical management (mastectomy or breast-conserving surgery [BCS]). Multivariable analyses were performed to investigate factors associated with increased odds of receiving mastectomy over BCS. Among a subgroup of patients who underwent ipsilateral mastectomy, analyses were performed to determine any association between contralateral prophylactic mastectomy (CPM) and receptor status. RESULTS: We found 280,241 patients who met inclusion criteria for analyzing mastectomy or BCS surgical decision. Patients with HER2-positive (HER2+) tumors (HR+/HER+ and HR-/HER2+) were the most likely to undergo mastectomy (odds ratio [OR], 1.212 and 1.499 respectively, compared with HR+/HER2- patients, each P < .001). HR status alone did not affect ipsilateral surgical management as patients with HR+/HER2- and HR-/HER2- tumors demonstrated similar mastectomy rates (P = .391). Among the 108,018 who underwent mastectomy, 20% underwent CPM. After adjustment, patients with HR+/HER2+, HR-/HER2+, and HR-/HER2- were all more likely to undergo CPM (OR 1.356, 1.608, and 1.358, respectively compared with HR+/HER2- patients, each P < .001). CONCLUSION: This analysis indicates that patients with early stage breast cancer are more likely to undergo a mastectomy and CPM if they have HER2+ tumors. PMID- 28811186 TI - Identification and characterization of small molecule inhibitors of porcine reproductive and respiratory syndrome virus. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is the etiological agent of PRRS, an economically significant disease of swine worldwide. PRRSV is poorly controlled by the currently available vaccines, and alternative control strategies are needed to help prevent the continual circulation of the virus. Previously, we developed a synthetic route for the natural compound atractylodinol and demonstrated anti-PRRSV activity in vitro. However, the synthetic route was inefficient and the yield was poor. To identify PRRSV inhibitors that could be synthesized easily and cost-effectively, we synthesized a series of atractylodinol analogs and characterized their anti-PRRSV activity in vitro. A furan-substituted bis-enyne subunit was found to be critical for PRRSV inhibition. Six analogs had potent inhibitory activity against PRRSV with 50% inhibition concentration (IC50) of 0.4-1.4 MUM and 50% cytotoxic concentration (CC50) of 209-1537 MUM in MARC-145 cells. Three of the most promising compounds also demonstrated significant antiviral activity and low cytotoxicity in porcine macrophages. Inhibition of PRRSV in MARC-145 cells occurred primarily at a post entry step during PRRSV replication, between 4 and 12 h post-entry. These results suggest that atractylodinol analogs are promising antiviral candidates that could augment current PRRSV control strategies. PMID- 28811187 TI - Chiral resolution, absolute configuration, and bioactivity of a new racemic asarone derivative from the rhizome of Acorus tatarinowii. AB - A new asarone-derived racemate (1) was isolated from the rhizome of Acorus tatarinowii. The structure of 1 was established by comprehensive spectroscopic analyses, and it was successfully resolved by chiral HPLC, demonstrating that it is racemic. The absolute configurations of 1a [(-)-acortatarone A] and 1b [(+) acortatarone A] were determined using quantum chemical calculations. Compounds 1a and 1b were the first cases of asarone derivatives with the 5,7-dialkyl-6-aryl-8 oxabicyclo[3.2.1]oct-3-en-2-one core. The alpha-glucosidase inhibitory and acetylcholinesterase (AChE) inhibitory activities of 1 were evaluated, and it exhibited alpha-glucosidase inhibitory activity with potency close to that of the positive control (acarbose). PMID- 28811188 TI - Familial 1p36.3 microduplication resulting from a 1p-9q non-reciprocal translocation. AB - Unlike the 1p36 microdeletion syndrome, which has been extensively described, 1p36 microduplications have rarely been reported. We describe a three years old boy presenting with a severe global developmental delay and a few dysmorphic features. Cytogenetic analyses revealed a maternally inherited 3.35 Mb microduplication of chromosomal band 1p36.3. The maternal grandfather is also carrier of the same chromosomal rearrangement. Interestingly, the duplicated 1p36.3 segment was found to be localized at the telomeric end of the long arms of a chromosome 9, probably deriving from a 1p36.3-9qter non-reciprocal translocation. This particular type of chromosomal translocation has rarely been reported, and its mechanism is unclear. The phenotypical features associated with 1p36.3 microduplication vary due to the non-recurrent breakpoints of the rearrangements in this particular region. However when compiling the few described cases the phenotypical spectrum seems to include mainly developmental delay, mild facial dysmorphism, and neurological, cardiac and skeletal anomalies. The description of new patients carrying a 1p36.3 duplication like ours will lead to further delineation of the phenotypical spectrum and may help to find critical regions and causative genes implicated in the phenotype. PMID- 28811189 TI - Early fetal presentation of Koolen-de Vries: Case report with literature review. AB - Koolen-de Vries syndrome (MIM#610443) is a rare microdeletion syndrome involving the 17q21.31 region, which was first described by Koolen in 2006. Clinical and behavioral characteristics have been extensively reported from more than 100 postnatal cases including infants, children and young adults. The syndrome is highly clinically heterogeneous, but the main features associate characteristic cranio-facial dysmorphism, heart defects, limb, skeletal, genito-urinary anomalies, along with intellectual disability with early childhood epilepsy and behavioral disturbances. Central nervous system malformations usually consist in hydrocephalus and thin corpus callosum. We report herein an early fetal case with an apparently isolated abnormal corpus callosum diagnosed by ultrasonography, for which a medical termination of the pregnancy was achieved at 22 weeks of gestation. Postmortem examination displayed facial dysmorphism consisting of hypertelorism, short philtrum and flat and broad nose, cleft palate and left duplex ureter. Neuropathological examination revealed a mega corpus callosum that has never been reported so far in this syndrome. Array-CGH performed on thymic DNA tissue revealed a 17q21.31 microdeletion, which allowed for the confirmation of early occurring Koolen-de Vries syndrome. PMID- 28811190 TI - How to quench your thirst. The effect of water-based products varying in temperature and texture, flavour, and sugar content on thirst. AB - The sensation of thirst plays an important role in the consumption of water or other fluids to rehydrate the body in order to keep bodily functions working properly. An increase in saliva secretion, wetting the mouth by ingestion of liquids, and cooling and sour components in products can alleviate this sensation already before absorption of fluids by the body. This study aimed to investigate the thirst-quenching ability of water-based products differing in temperature and texture (cold solids and cool liquids), flavour (flavoured and non-flavoured) and sugar content in two consecutive experiments. The first experiment tested four products of 10ml each (flavoured popsicles, flavoured beverages, ice cubes, and water). 45 healthy, thirsty participants (8 men and 37 women, mean age 25.7years SD+/-6.6) were randomly assigned to a flavour group representing the flavour of the popsicles and beverages: mint, lemon, raspberry. Each flavour group tasted all four products (popsicles, beverages, water, ice cubes) in four sessions on consecutive days. Participants rated their thirst and four attributes (flavour intensity, thirst-quenching, refreshing, saliva stimulating) during 3min of consumption on a 100mm VAS scale and ranked all four products on thirst-quenching ability at the end of the last session. The second experiment was performed similarly (n=61, 6 men and 55 women, mean age 23.5years SD+/-2.87), but used sugar-reduced popsicles to compare to the regular popsicles from the first experiment. In addition, saliva was collected before and after consumption. In the first experiment, cold solid (55.8+/-0.99) and flavoured (55.9+/-0.95) products were found to be more thirst-quenching than cool liquid (52.8+/-0.96) and non-flavoured products (52.8+/-0.96). The second experiment confirmed that saliva production increased upon consumption of these popsicles, with an increase of saliva weight from 1.7g SD +/-0.15 before consumption to 2.0 SD +/-0.22 after consumption. Sugar-reduced popsicles were similar in thirst-quenching ability compared to regular popsicles. Overall, cold, solid, flavoured products (such as popsicles) performed best in quenching thirst, and it appeared that sugar reduction in these products to create healthier alternatives can be achieved without compromising on thirst-quenching abilities. These results can be useful for optimisation of products to alleviate thirst in daily life, as well as in clinical settings for patients where fluid restriction is needed. PMID- 28811191 TI - Can psychological well-being scales and hormone levels be used to predict acute performance of anaerobic training tasks in elite female volleyball players? AB - The purpose of this study was to examine relationships between pre-training psychological well-being assessment scales (General Health Questionnaire-28-GHQ 28, Competitive State Anxiety Inventory-2-CSAI-2, Sport Competition Anxiety Test SCAT, State-Trait Anxiety Inventory-S-STAI-S, Oviedo Sleep Questionnaire-OSQ and Psychological Characteristics Related to Sport Performance-PCSP), and pre training stress hormone concentrations (cortisol-C, total testosterone-TT, free testosterone-FT, adrenocorticotropic hormone-ACTH and testosterone/cortisol-T/C ratios), on acute neuromuscular performance (ANP) in female volleyballers. Forty elite female volleyballers (27+/-4yrs.; 178.3+/-8.5cm; 67.9+/-7.2kg) participated. Bivariate correlations were performed between psychological assessments and hormone levels with ANP. All psychological scales presented at least one significant (p<0.05) relationship or prediction of ANP. Contrastingly, among hormones, the only significant relationship was between TT/C ratio and Overhead Medicine Ball Throw (r=0.34; p<0.05). Therefore, our data shows that results of general and sport-specific psychological well-being scales prior to training are more consistently related to performance in elite female volleyballers than pre-training stress hormone concentrations. PMID- 28811192 TI - Relative reinforcing effects of second-generation synthetic cathinones: Acquisition of self-administration and fixed ratio dose-response curves in rats. AB - "Bath salts" preparations contain synthetic cathinones which interact with monoamine transporters and function as either monoamine uptake inhibitors or releasers. 3,4-Methylenedioxypyrovalerone (MDPV), 3,4-methylenedioxymethcathinone (methylone), and 4-methylmethcathinone (mephedrone) were three of the most common cathinones (i.e., "first-generation" cathinones); however, after the US Drug Enforcement Administration placed them under Schedule I regulations, they were replaced with structurally related cathinones that were not subject to regulations (i.e., "second-generation" cathinones). Although the reinforcing effects of some second-generation cathinones have been described (e.g., alpha pyrrolidinopentiophenone [alpha-PVP]), little is known about how structural modifications, particularly those involving the methylenedioxy moiety and alpha alkyl side chain, impact the abuse liability of other second-generation cathinones (e.g., alpha-pyrrolidinopropiophenone [alpha-PPP], 3,4-methylenedioxy alpha-pyrrolidinobutiophenone [MDPBP], and 3,4-methylenedioxy-alpha pyrrolidinopropiophenone [MDPPP]). The present study used male Sprague-Dawley rats (n = 12 per drug) to directly compare: (1) the acquisition of responding for alpha-PVP (0.032 mg/kg/inf), alpha-PPP (0.32 mg/kg/inf), MDPBP (0.1 mg/kg/inf), and MDPPP (0.32 mg/kg/inf) under a fixed ratio (FR) 1 schedule of reinforcement; and (2) full dose-response curves for each drug to maintain responding under an FR5 schedule of reinforcement. The average number of days (~4 days) and percentage (100%) of rats that acquired self-administration was similar for each drug. The observed rank order potency to maintain responding under an FR5 schedule of reinforcement (alpha-PVP ~ MDPBP>alpha-PPP > MDPPP) is consistent with their potencies to inhibit dopamine uptake. These are the first studies to report on the reinforcing effects of the unregulated second-generation cathinones MDPBP, MDPPP, and alpha-PPP and indicate all three compounds are readily self administered, suggesting each possesses high potential for abuse. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.' PMID- 28811194 TI - Immunogenetic studies of the hepatitis C virus infection in an era of pan genotype antiviral therapies - Effective treatment is coming. AB - What are the factors that influence human hepatitis C virus (HCV) infection, hepatitis status establishment, and disease progression? Firstly, one has to consider the genetic background of the host and HCV genotypes. The immunogenetic host profile will reflect how each infected individual deals with infection. Secondly, there are environmental factors that drive susceptibility or resistance to certain viral strains. These will dictate (I) the susceptibility to infection; (II) whether or not an infected person will promote viral clearance; (III) the immune response and the response profile to therapy; and (IV) whether and how long it would take to the development of HCV-associated diseases, as well as their severity. Looking at this scenario, this review addresses clinical aspects of HCV infection, following by an update of molecular and cellular features of the immune response against the virus. The evasion mechanisms used by HCV are presented, considering the potential role of exosomes in infection. Genetic factors influencing HCV infection and pathogenesis are the main topics of the article. Shortly, HLAs, MBLs, TLRs, ILs, and IFNLs genes have relevant roles in the susceptibility to HCV infection. In addition, ILs, IFNLs, as well as TLRs genes are important modulators of HCV-associated diseases. The viral aspects that influence HCV infection are presented, followed by a discussion about evolutionary aspects of host and HCV interaction. HCV and HIV infections are close related. Thus, we also present a discussion about HIV/HCV co-infection, focusing on cellular and molecular aspects of this interaction. Pharmacogenetics and treatment of HCV infection are the last topics of this review. The understanding of how the host genetics interacts with viral and environmental factors is crucial for the development of new strategies to prevent HCV infection, even in an era of potential development of pan-genotypic antivirals. PMID- 28811193 TI - A novel detection procedure for mutations in the 23S rRNA gene of Mycoplasma pneumoniae with peptide nucleic acid-mediated loop-mediated isothermal amplification assay. AB - Rapid and easy detection of a single nucleotide point mutation of bacterial genes, which is directly linked to drug susceptibility, is essential for the proper use of antimicrobial agents. Here, we established a detection method using a peptide nucleic acid mediated loop-mediated amplification (LAMP) assay for macrolide (ML)-susceptible Mycoplasma pneumoniae. This assay specifically detected the absence of missense mutations encoding the central loop of domain V in the gene encoding 23S rRNA, which can reduce the affinity for MLs and subsequently generate ML-resistant strains of M. pneumoniae. Reactions were performed at 62 degrees C for 60min and targeted gene amplifications were detected by real-time turbidity with a turbidimeter and naked-eye inspection of a color change. The assay had an equivalent detection limit of 100.0fg of DNA with the turbidimeter and showed specificity against 54 types of pathogens, whereas amplification was completely blocked, even at 100.0pg of DNA per reaction, in the presence of point mutations at 2063A and 2064A. The expected LAMP products were confirmed through identical melting curves in real-time LAMP procedures. This method would be a simple and rapid protocol for single nucleotide polymorphism genotyping as point-of-care testing technology without amplification of the sequences carrying the point mutations 2063A and 2064A in ML-resistant M. pneumoniae strains. PMID- 28811195 TI - Epileptic interictal discharges are more frequent during NREM slow wave downstates. AB - Epileptiform activity in various but not all epilepsy and recording types and cerebral areas is more frequent in NREM sleep, and especially during sleep periods with high-amplitude EEG slow waves. Slow waves synchronize high-frequency oscillations: physiological activity from the theta through the gamma band usually appears during scalp-positive upstates while epileptiform activity occurs at transitory phases and the scalp-negative downstate. It has been proposed that interictal discharges (IIDs) are facilitated by the high degree of neuronal firing synchrony during slow wave transitory and downstates. This would suggest that their occurrence increases as a function of slow wave synchronization, indicated by greater amplitude, steeper slopes and higher EEG signal synchronization. We investigated the occurrence of IIDs during NREM sleep slow waves in epileptic patients undergoing presurgical electrophysiological monitoring. Intracranially registered IIDs preferentially occurred during the scalp-negative downstates of frontal scalp slow waves in all subjects. IID occurrence was more frequent during larger slow waves in the pooled sample and a subset of subjects. However, slow wave slope steepness and EEG signal synchronization between two frontal scalp channels was not significantly associated with IID occurrence. Our results indicate that IIDs indeed do not occur at the same slow wave phase as physiological rhythms, but contrary to previous hypotheses their occurrence is not strongly affected by EEG synchronization. PMID- 28811196 TI - Inhibitions of PKC and CaMK-II synergistically rescue ischemia-induced astrocytic dysfunction. AB - Ischemic neuronal death is presumably caused by glutamate-induced excitotoxicity, in which the increased glutamate release and impaired glutamate reuptake lead to glutamate accumulation. Mechanisms underlying the ischemic deficiency of astrocytic glutamate reuptake remain unclear, which we have studied by analyzing the effect of calmodulin-dependent protein kinase II (CaMK-II) and protein kinase C (PKC) inhibitions on astrocytic glutamate transporter during ischemia. Glutamate transporter current was recorded on the astrocytes in cortical slices. KN-62 (CaMK-II inhibitor) or chelerythrine (PKC inhibitor) partially reverses the ischemic deficiency of astrocytic glutamate transporter. A combined use of PKC and CaMK-II inhibitors synergistically reverses this deficiency. Thus, one of potential therapeutic strategies is to secure the ischemia-induced deficiency of astrocytic glutamate reuptake by inhibiting PKC and CaMK-II. PMID- 28811197 TI - Seasonal changes in plasma testosterone and cortisol suggest an androgen mediated regulation of the pituitary adrenal axis in the Tarabul's gerbil Gerbillus tarabuli (Thomas, 1902). AB - In the desert gerbil Gerbillus tarabuli (Thomas, 1902), cortisol is the main glucocorticosteroid produced by the adrenal glands. Plasma cortisol concentrations show highest values when testosterone is reduced and lowest values during the breeding season which occurs from early winter to late spring. In order to specify the implication of testicular androgens in these corticosteroid seasonal variations we investigated the effects induced by gonadectomy performed during the breeding season on the pituitary adrenal axis. The animals collected in winter were assessed into three groups: sham-operated (Controls; n=13), gonadectomised (GDX; n=13) and testosterone replaced gonadectomised (GDX+T; n=13). Physiological replacement of testosterone enanthate (75ug/100gb.w./twice daily) was applied during one week, while GDX group received the vehicle (40uL sesame oil) alone. The right adrenal glands removed from euthanized animals were fixed for histomorphometry and androgen receptors (ARs) immunohistochemistry and the left ones were frozen with plasma samples until hormonal assays. Gonadectomy induces the enlargement of the adrenal cortex essentially due to that of zonae fasciculata (ZF) and reticularis (ZR) and perimedullary connective tissue which is abundant in the gerbil adrenals. The ARs immunostaining present at both cytoplasmic and nucleus level, is enhanced intensely in the ZR and moderately in the ZF and zona glomerulosa (ZG) cells. GDX group shows reduced plasma ACTH concentration (p=0.0126) by 61% despite the increase in cortisol concentration occurring both in plasma (+216%; p=0.0436) and adrenal tissue (+117%; p=0.0348). Plasma aldosterone is also enhanced significantly (p=0.0147) by 189% but androstenedione synthesis increased in adrenal tissue (p=0.0459) by 65% instead a decrease at circulatory level (p=0.0355) by 58% due to lack of testicular origin. So, testosterone deprivation activates corticosteroidogenesis also evidenced by the adrenal structure changes and the gonadectomy-induced increase in the plasma cholesterol. All of the gonadectomy-induced responses are reversible after physiological testosterone replacement. We conclude that the assessment of circulating adrenocorticotropic hormone (ACTH) concentrations together with cortisol levels essentially, reflecting the hypothalamic-pituitary adrenal (HPA) axis feedback loop control during the annual endogenous changes of testosterone secretion, represents a well-adapted response of this desert species living in an extreme environment. PMID- 28811198 TI - House sparrows mitigate growth effects of post-natal glucocorticoid exposure at the expense of longevity. AB - Acute, short-term effects of early-life stress and associated glucocorticoid upregulation on physiology and survival are widely documented across vertebrates. However, the persistence and severity of these effects are largely unknown, especially through the adult stage and for natural systems. Here, we investigate physiological, morphological, and survival effects of post-natal glucocorticoid upregulation across the nestling, juvenile, and adult life stages in house sparrows (Passer domesticus). We manipulate circulating corticosterone concentration in wild, free-living house sparrow nestlings and monitor body size, size-corrected mass, two measures of health (hematocrit and phytohemagglutinin induced skin swelling), and survival in a captive environment until adulthood. We find that early-life corticosterone exposure depresses nestling size-corrected mass in both sexes, with no strong effect of the treatment on body size or our two measures of health. Birds are able to compensate for negative effects of high early-life corticosterone exposure in the long-term and this effect largely disappears by the juvenile and adult stages. However, treatment has a negative effect on survival through one year of age, suggesting that long-term compensation comes at a price. PMID- 28811199 TI - Comparison of analytical methods of brain [18F]FDG-PET after severe traumatic brain injury. AB - BACKGROUND: Loss of consciousness has been shown to reduce cerebral metabolic rates of glucose (CMRglc) measured by brain [18F]FDG-PET. Measurements of regional metabolic patterns by normalization to global cerebral metabolism or cerebellum may underestimate widespread reductions. NEW METHOD: The aim of this study was to compare quantification methods of whole brain glucose metabolism, including whole brain [18F]FDG uptake normalized to uptake in cerebellum, normalized to injected activity, normalized to plasma tracer concentration, and two methods for estimating CMRglc. Six patients suffering from severe traumatic brain injury (TBI) and ten healthy controls (HC) underwent a 10min static [18F]FDG-PET scan and venous blood sampling. RESULTS: Except from normalizing to cerebellum, all quantification methods found significant lower level of whole brain glucose metabolism of 25-33% in TBI patients compared to HC. In accordance these measurements correlated to level of consciousness. COMPARISON WITH EXISTING METHODS: Our study demonstrates that the analysis method of the [18F]FDG PET data has a substantial impact on the estimated whole brain cerebral glucose metabolism in patients with severe TBI. Importantly, the SUVR method which is often used in a clinical setting was not able to distinguish patients with severe TBI from HC at the whole-brain level. CONCLUSION: We recommend supplementing a static [18F]FDG scan with a single venous blood sample in future studies of patients with severe TBI or reduced level of consciousness. This can be used for simple semi-quantitative uptake values by normalizing brain activity uptake to plasma tracer concentration, or quantitative estimates of CMRglc. PMID- 28811200 TI - Globular adiponectin reverses osteo-sarcopenia and altered body composition in ovariectomized rats. AB - Adiponectin regulates various metabolic processes including glucose flux, lipid breakdown and insulin response. We recently reported that adiponectin receptor1 (adipoR1) activation by a small molecule reverses osteopenia in leptin receptor deficient db/db (diabetic) mice. However, the role of adiponectin in bone metabolism under the setting of post-menopausal (estrogen-deficiency) osteopenia and associated metabolic derangements has not been studied. Here, we studied the therapeutic effect of the globular form of adiponectin (gAd), which is predominantly an adipoR1 agonist, in aged ovariectomized (OVX) rats and compared it with standard-of-care anti-osteoporosis drugs. In OVX rats with established osteopenia, gAd completely restored BMD and load bearing capacity and improved bone quality. Skeletal effects of gAd were comparable to PTH (osteoanabolic) but better than alendronate (anti-catabolic). Both osteoanabolic and anti-catabolic mechanisms led to the anti-osteoporosis effect of gAd. In cultured osteoblasts and bones, gAd increased a) adipoR1 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1alpha) expression to promote mitochondrial respiration, which likely fueled osteoblast differentiation, b) suppressed sclerostin (a wnt antagonist) in a sirtuin1-dependent manner and c) decreased receptor-activator of nuclear factor kappaB ligand (RANKL) to achieve its anti-catabolic effect. The OVX-induced sarcopenia and insulin resistance were also improved by gAd. We conclude that gAd has therapeutic efficacy in estrogen deficiency-induced osteoporosis, sarcopenia and insulin resistance and hold metabolic disease modifying potential in postmenopausal women. PMID- 28811201 TI - The unmet need in rheumatology: Reports from the targeted therapies meeting 2017. AB - The 19th annual international Targeted Therapies meeting brought together over 100 leading basic scientists and clinical researchers from around the world in the field of immunology, molecular biology and rheumatology and other specialties. During the meeting, breakout sessions were held consisting of 5 disease-specific groups with 20-40 experts assigned to each group based on clinical or scientific expertise. Specific groups included: rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, systemic lupus erythematous, connective tissue diseases (e.g. Sjogren's syndrome, Systemic sclerosis, vasculitis including Bechet's and IgG4 related disease), and a basic science immunology group spanning all of the above clinical domains. In each group, experts were asked to consider and update previously identified unmet needs in 3 categorical areas: basic/translational science, clinical science and therapeutic development, and clinical care. Overall, similar primary unmet needs were identified within each disease foci, and several additional needs were identified since the time of last year's congress. Within translational/basic science, the need for better understanding the heterogeneity within each disease was highlighted so that predictive tools for therapeutic responses can be developed. Within clinical science and therapeutic trials, a strong focus was placed upon the need to identify pre-clinical states of disease allowing prevention in those at risk. The ability to cure remains perhaps the ultimate unmet need. Further, the need to develop new and affordable therapeutics, as well as to conduct strategic trials of currently approved therapies was again highlighted. Within the clinical care realm, improved co-morbidity management and patient-centered care were identified as unmet needs. Lastly, it was strongly felt there was a need to develop a scientific infrastructure for well-characterized, longitudinal cohorts paired with biobanks and mechanisms to support data-sharing. This infrastructure could facilitate many of the unmet needs identified within each disease area. PMID- 28811202 TI - Aggregation of zein in aqueous ethanol dispersions: Effect on cast film properties. AB - In this study, we evaluate the influence of zein aggregation in aqueous ethanol dispersions on the properties of zein films. The effects of zein concentration, ethanol content and temperature on transmittance of zein dispersions were investigated. Dynamic light scattering was used to measure the degree of zein aggregation in the dispersions. The results indicate that particle size of zein increased with higher zein concentration, lower ethanol level and at lower temperatures. Zein films were prepared by casting from 70% and 90% aqueous ethanol dispersions at different drying temperatures and were evaluated for appearance, thermomechanical and mechanical properties. Higher ethanol levels and higher drying temperatures promoted the formation of more homogenous films. Films made from higher ethanol dispersions had lower glass transition temperatures than those made from lower ethanol dispersions. Moreover, the fragility factor classified the films as strong systems. Mechanical properties of films were measured at different drying temperatures. Stiffer and more resistant films were developed as the drying temperature increased. In conclusion, film properties can be tailored by controlling the composition of the film casting solvent and the drying temperature. Differences in film properties were found to relate to differences in initial degree of aggregation of zein dispersions. PMID- 28811203 TI - BPN, a marine-derived PTP1B inhibitor, activates insulin signaling and improves insulin resistance in C2C12 myotubes. AB - Insulin resistance is a key feature of type 2 diabetes mellitus (T2DM) and is characterized by defects in insulin signaling. Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator of insulin signaling cascade and has attracted intensive investigation in recent T2DM therapy study. BPN, a marine derived bromophenol compound, was isolated from the red alga Rhodomela confervoides. This study investigated the effects of BPN on the insulin signaling pathway in insulin-resistant C2C12 myotubes by inhibiting PTP1B. Molecular docking study and analysis of small- molecule interaction with PTP1B all showed BPN inhibited PTP1B activity via binding to the catalytic site through hydrogen bonds. We then found that BPN permeated into C2C12 myotubes, on the one hand, activated insulin signaling in an insulin-independent manner in C2C12 cells; on the other hand, ameliorated palmitate-induced insulin resistance through augmenting insulin sensitivity. Moreover, our studies also showed that PTP1B inhibition by BPN increased glucose uptake in normal and insulin-resistant C2C12 myotubes through glucose transporter 4 (GLUT4) translocation. Taken together, BPN activates insulin signaling and alleviates insulin resistance and represents a potential candidate for further development as an antidiabetic agent. PMID- 28811204 TI - Heterologous expression and biochemical characterization of a novel thermostable Sclerotinia sclerotiorum GH45 endoglucanase in Pichia pastoris. AB - Enzymatic saccharification of lignocellulosic biomass has been widely studied. Mainly endoglucanases were found to be a prerequisite for the quick initial biomass liquefaction. In the present study, Pichia pastoris was used as a host for the heterologous expression of a Sclerotinia sclerotiorum GH45 endoglucanase, Endo2. The recombinant plasmid pPICZalphaA was used to transform Pichia pastoris. Pichia culture supernatants expressing the recombinant Endo2 (rEndo2) were used for the purification and biochemical characterization of this enzyme. Therefore, rEndo2 was purified 6.7 fold to homogeneity with 34% yield and gave 19U/mg specific activity. It also showed maximum activity at pH 7.0 and 60 degrees C (against pH 5.0 and 50 degrees C for the native enzyme) and was thermostable at relatively high temperatures. Furthermore, rEndo2 retained its activity in a wide pH range (from 5 to 8). Besides, the recombinant endoglucanase was produced as an active 47kDa enzyme. This molecular weight differs from the one of the native enzyme (34kDa), which suggested a potential glycosylation of the recombinant enzyme. Moreover, rEndo2 was able to produce fermentable sugars after enzymatic assay on various cellulosic substrates with an interesting yield. Therefore, all these features offer prospects for large-scale production and industrial application of the recombinant endoglucanase. PMID- 28811205 TI - Extraction and characterization of acid-soluble and pepsin-soluble collagen from skin of loach (Misgurnus anguillicaudatus). AB - Acid-soluble collagen (ASC) and pepsin-soluble collagen (PSC) were extracted from loach skin. The yields of ASC and PSC were 22.42% and 27.32%, respectively. Sodium dodecyl sulfate-polyacrylamide-gel electrophoresis and peptide mass fingerprint analysis revealed that loach skin contained type I collagen. There were 212 imino acids/1000 residues in ASC and 193 imino acids/1000 residues in PSC. Fourier transform infrared spectrometry analysis, UV measurements and circular dichroism confirmed that loach skin collagen had a triple helical structure. The denaturation temperatures of ASC and PSC were 36.03 degrees C and 33.61 degrees C, respectively. Zeta potential analysis revealed that net zero charge values of ASC and PSC were 6.42 and 6.51, respectively. Therefore, loach skin collagen may be an alternative to terrestrial mammalian collagen and may enhance the added value of this fish species. PMID- 28811206 TI - Production and physicochemical properties of carboxymethyl cellulose films enriched with spent coffee grounds polysaccharides. AB - Extracts rich in polysaccharides were obtained by alkali pretreatment (PA) or autohydrolysis (PB) of spent coffee grounds, and incorporated into a carboxymethyl cellulose (CMC)-based film aiming at the development of bio-based films with new functionalities. Different concentrations of PA or PB (up to 0.20% w/v) were added to the CMC-based film and the physicochemical properties of the final films were determined. Scanning electron microscopy, Fourier-transform infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, as well as determinations of optical and mechanical properties, moisture content, solubility in water, water vapor permeability, contact angle and sorption isotherms were performed. The addition of PA or PB resulted in important changes in the properties of the CMC-based film, mainly in color and opacity. The polysaccharides incorporation significantly improved the light barrier of the film and provided an enhancement or at least a preservation in the physicochemical properties. PMID- 28811207 TI - Anion-pi interactions in active centers of superoxide dismutases. AB - We investigated 1060 possible anion-pi interactions in a data set of 41 superoxide dismutase active centers. Our observations indicate that majority of the aromatic residues are capable to form anion-pi interactions, mainly by long range contacts, and that there is preference of Trp over other aromatic residues in these interactions. Furthermore, 68% of total predicted interactions in the dataset are multiple anion-pi interactions. Anion-pi interactions are distance and orientation dependent. We analyzed the energy contribution resulting from anion-pi interactions using ab initio calculations. The results showed that, while most of their interaction energies lay in the range from -0 to -4kcalmol-1, those energies can be up to -9kcalmol-1 and about 34% of interactions were found to be repulsive. Majority of the suggested anion-pi interacting residues in ternary complexes are metal-assisted. Stabilization centers for these proteins showed that all the six residues found in predicted anion-pi interactions are important in locating one or more of such centers. The anion-pi interacting residues in these proteins were found to be highly conserved. We hope that these studies might contribute useful information regarding structural stability and its interaction in future designs of novel metalloproteins. PMID- 28811208 TI - Macromolecular crowding induces molten globule state in the native myoglobin at physiological pH. AB - Here, we report the formation of molten globule state of the native myoglobin in crowded environment. We have used Soret absorption spectroscopy and far-UV circular dichroism to monitor changes in tertiary and secondary structures of myoglobin, respectively. Our results reveal that in the presence of ficoll 70, the secondary structure of myoglobin remains unchanged while tertiary structure is lost significantly. 1-anilinonaphthalene-8-sulfonate binding experiments showed that myoglobin in the presence of various concentrations of ficoll 70, has newly exposed hydrophobic surfaces. Dynamic light scattering measurements show that there is almost 1.5 times increase in the hydrodynamic volume of myoglobin in the crowded environment. These structural characteristics of myoglobin in the presence of 300mg/ml ficoll 70 resemble those of molten globule state. Isothermal titration calorimetric (ITC) measurements show that ficoll 70 binds to myoglobin, whereas it shows no interaction with apo form of the protein. ITC results indicate that the reason behind this unique behavior of ficoll 70 towards myoglobin may be interaction of ficoll 70 with the heme group of myoglobin, which was further confirmed by the docking studies. We hypothesize that the soft interactions between heme and ficoll 70 leads to the formation of molten globule in myoglobin. PMID- 28811209 TI - Prevalence of pulmonary embolism in patients presenting to the emergency department with syncope. AB - OBJECTIVES: A recent study reported a high prevalence of pulmonary embolism (PE) among patients admitted with syncope. We sought to determine whether these findings were validated in our patient population. METHODS: We performed a retrospective, secondary analysis of prospectively gathered data from patients presenting with syncope to an academic emergency department (ED) from July 2010 to December 2015. We analyzed baseline information from the time of the ED visit, recorded outcomes during the hospital stay, and contacted patients by phone at least 30days after the ED visit. The primary study outcome was the diagnosis of acute PE in the ED, during inpatient admission or ED observation unit stay, or by patient report over a 30-day follow-up period. RESULTS: Over the 5.5-year study period, 348 patients with syncope agreed to participate in the study. 52% of patients were female [95% confidence interval (CI): 46.6-57.4] and the average age was 48.4years. Of the enrolled patients, 50.1% (CI: 44.8-55.2) underwent further evaluation for syncope beyond the ED stay: 27% (CI: 22.6-31.9) of patients were admitted to an inpatient unit for further work-up and 23.9% (CI: 19.7-28.6) of patients were placed in the ED observation unit. The overall rate of PE among patients presenting to the ED with syncope was 1.4% (CI: 0.6-3.3%). 2 patients (0.6%, CI: 0.2-2.1) were diagnosed with a PE while in the ED. None of the patients were diagnosed with a PE during hospital admission or the observation stay associated with the index ED visit. 3 patients (0.9%, CI: 0.3 2.5) reported they had been diagnosed with a PE during the 30days following their ED visit, two of whom had been admitted to the hospital at the index ED visit but were not diagnosed with a PE at that time. All patients diagnosed with a PE at the time of the ED visit or during the follow-up period were Pulmonary Embolism Rule Out Criteria (PERC) positive and reported shortness of breath in the ED. CONCLUSION: In contrast to a previous study, our findings do not support a high rate of PE among ED patients presenting with syncope. PMID- 28811210 TI - Safe and effective administration of lactulose retention enema in the ED using specialized rectal medication administration catheter. PMID- 28811211 TI - 72h returns: A trigger tool for diagnostic error. AB - BACKGROUND: Patients who return to the Emergency Department (ED) within 72h of discharge are often used for ED Quality Assurance efforts, however little is known about the yield of this kind of review and the types of errors it identifies. Our objective was to identify the prevalence, types and severity of errors in these cases. METHODS: Retrospective review of patients who presented to an urban, university affiliated ED between 10/1/2012-9/30/2015 who returned within 72 h requiring hospital admission. RESULTS: There were 413,167 ED visits during the study period with 2001 (0.48%) patients who returned within 72h and were admitted to the hospital. An event requiring further investigation was identified in 59 (2.95%) of these patients and 50 (2.49%) of them were deemed to represent a deviation from optimal care. Of these, 48 (96%) represented diagnostic error. When a standard diagnostic process of care framework was applied to these, the majority of cases represented failures in the initial diagnostic pathway (29 cases, 60.4%). When Error Severity Codes were applied, 16 (32%) resulted in minor harm and 34 (68%) resulted in major harm or death. CONCLUSION: Screening of 72h ED returns has low yield in identifying suboptimal care, with less than 3% of cases representing deviations from standard care. Of these, the majority represent cognitive errors in the diagnostic pathway. These reviews may be useful as a tool for Ongoing Professional Practice Evaluation of individual clinicians, however likely serve less value in identifying systems issues contributing to unsafe care. PMID- 28811212 TI - Incidence and risk factors of delayed intracranial hemorrhage in the emergency department. AB - OBJECTIVES: This study was performed to identify the risk factors for delayed intracranial hemorrhage and develop a risk stratification system for disposition of head trauma patients with negative initial brain imaging. METHODS: The data source was National Health Insurance Service-National Sample Cohort of Korea. We analyzed adult patients presenting to the ER from January 2004 to September 2012, who underwent brain imaging and discharged with or without short-term observation no longer than two days. The primary outcome was defined as any intracranial bleeding within a month defined by a new appearance of any of the diagnostic codes for intracranial hemorrhage accompanied by a new claim for brain imaging(s) within a month of the index visit. We performed a multivariable logistic regression analysis and built a parsimonious model for variable selection to develop a simple scoring system for risk stratification. RESULTS: During the study period, a total of 19,723 head injury cases were identified from the cohort and a total of 149 cases were identified as having delayed intracranial hemorrhage within 30days. In multivariable logistic regression model, old age, craniofacial fracture, neck injury, diabetes mellitus and hypertension were independent risk factors for delayed intracranial hemorrhage. We constructed the parsimonious model included age, craniofacial fracture and diabetes mellitus. The score showed area under the curve of 0.704 and positive predictive value of the score system was 0.014 when the score>=2. CONCLUSIONS: We found old age, associated craniofacial fracture, any neck injury, diabetes mellitus and hypertension are the independent risk factors of delayed intracranial hemorrhage. PMID- 28811213 TI - Hemodynamic characteristics of suspected stroke in the emergency department. AB - BACKGROUND: Systemic hemodynamic characteristics of patients with suspected acute ischemic stroke are poorly described. The objective of this study was to identify baseline hemodynamic characteristics of emergency department (ED) patients with suspected acute stroke. METHODS: This was a planned analysis of the stroke cohort from a multicenter registry of hemodynamic profiling of ED patients. The registry prospectively collected non-invasive hemodynamic measurements of patients with suspicion for acute stroke within 12h of symptom onset. K-means cluster analysis identified hemodynamic phenotypes of all suspected stroke patients, and we performed univariate hemodynamic comparisons based on final diagnoses. RESULTS: There were 72 patients with suspected acute stroke, of whom 38 (53%) had a final diagnosis of ischemic stroke, 10 (14%) had hemorrhagic stroke, and 24 (33%) had transient ischemic attack (TIA). Analysis defined three phenotypic clusters based on low or normal cardiac index (CI) and normal or high systemic vascular resistance index (SVRI). Patients with TIA had lower mean CI (2.3L/min/m2) compared to hemorrhagic or ischemic stroke patients (p<0.01). CONCLUSIONS: The study demonstrates the feasibility of defining hemodynamic phenotypes of ED patients with suspected stroke. PMID- 28811214 TI - Semi-empirical modeling of microalgae photosynthesis in different acclimation states - Application to N. gaditana. AB - The development of mathematical models capable of accurate predictions of the photosynthetic productivity of microalgae under variable light conditions is paramount to the development of large-scale production systems. The process of photoacclimation is particularly important in outdoor cultivation systems, whereby seasonal variation of the light irradiance can greatly influence microalgae growth. This paper presents a dynamic model that captures the effect of photoacclimation on the photosynthetic production. It builds upon an existing semi-empirical model describing the processes of photoproduction, photoregulation and photoinhibition via the introduction of acclimation rules for key parameters. The model is calibrated against a dataset comprising pulsed amplitude modulation fluorescence, photosynthesis rate, and antenna size measurements for the microalga Nannochloropsis gaditana in several acclimation states. It is shown that the calibrated model is capable of accurate predictions of fluorescence and respirometry data, both in interpolation and in extrapolation. PMID- 28811215 TI - Molecular mechanisms underlying protection against H9N2 influenza virus challenge in mice by recombinant Lactobacillus plantarum with surface displayed HA2-LTB. AB - It has been considered that the Avian influenza virus (AIV) causes severe threats to poultry industry. In this study, we constructed a series of recombinant Lactobacillus plantarum (L. plantarum) with surface displayed hemagglutinin subunit 2 (HA2) alone or together with heat-labile toxin B subunit (LTB) from enterotoxigenic Escherichia coli. Balb/c mice were used as model to evaluate the protective effects of recombinant L. plantarum strains against H9N2 subtype challenge. The results showed that the presence of LTB significantly increased the percentages of CD3+CD4+IL-4+, CD3+CD4+IFN-gamma+ and CD3+CD4+IL-17+ T cells, as well as CD3+CD8+IFN-gamma+ T cells in spleen and MLNs determined by Fluorescence-Activated Cell Sorting assay. Similar increased production of serum IFN-gamma was also confirmed by enzyme linked immunosorbent assay (ELISA). The L. plantarum with surface displayed HA2-LTB also dramatically increased the percentages of B220+ IgA+ B cells in peyer patch, in consistent with elevated production of mucosal SIgA antibody determined by ELISA. Finally, the orally administrated HA2-LTB expressing strain efficiently protected mice against H9N2 subtype AIV challenge shown by increased survival percentages, body weight gains and decreased lung lesions in histopathologic analysis. In conclusion, this study provides more detail mechanisms underlying the adjuvant effects of LTB on heterologous antigen produced in recombinant lactic acid bacteria. PMID- 28811216 TI - Complete genome sequence of Maribacter sp. T28, a polysaccharide-degrading marine flavobacteria. AB - The degradation of plant polysaccharides by enzymes is an industry of increasing importance. Here we present the complete genome sequence of a marine flavobacteria, Maribacter sp. T28 (=CGMCC 1.15788). The genome comprises 4,271,158bp in a circular chromosome with a G+C content of 34.4% and contains genes encoding xylanolytic, alginolytic and pectinolytic enzymes. Genes encoding alginate lyases and a pectin degradation protein (kdgF) are located on a polysaccharide utilization locus. Maribacter sp. T28 has the ability to utilize xylan, alginate and pectin for growth. The key degradation products xylose and 2 keto-3- deoxy-gluconate were detected from xylan and pectin, respectively. The Maribacter species genomes provide genetic information regarding polysaccharide degrading enzymes. PMID- 28811217 TI - Regulation and phylogeny of skeletal muscle regeneration. AB - One of the most fascinating questions in regenerative biology is why some animals can regenerate injured structures while others cannot. Skeletal muscle has a remarkable capacity to regenerate even after repeated traumas, yet limited information is available on muscle repair mechanisms and how they have evolved. For decades, the main focus in the study of muscle regeneration was on muscle stem cells, however, their interaction with their progeny and stromal cells is only starting to emerge, and this is crucial for successful repair and re establishment of homeostasis after injury. In addition, numerous murine injury models are used to investigate the regeneration process, and some can lead to discrepancies in observed phenotypes. This review addresses these issues and provides an overview of some of the main regulatory cellular and molecular players involved in skeletal muscle repair. PMID- 28811218 TI - Wnt signaling positively regulates endothelial cell fate specification in the Fli1a-positive progenitor population via Lef1. AB - During vertebrate embryogenesis, vascular endothelial cells (ECs) and primitive erythrocytes become specified within close proximity in the posterior lateral plate mesoderm (LPM) from a common progenitor. However, the signaling cascades regulating the specification into either lineage remain largely elusive. Here, we analyze the contribution of beta-catenin dependent Wnt signaling to EC and erythrocyte specification during zebrafish embryogenesis. We generated novel beta catenin dependent Wnt signaling reporters which, by using destabilized fluorophores (Venus-Pest, dGFP), specifically allow us to detect Wnt signaling responses in narrow time windows as well as in spatially restricted domains, defined by Cre recombinase expression (Tg(axin2BAC:Venus-Pest)mu288; Tg(14TCF:loxP-STOP-loxP-dGFP)mu202). We therefore can detect beta-catenin dependent Wnt signaling activity in a subset of the Fli1a-positive progenitor population. Additionally, we show that mesodermal Wnt3a-mediated signaling via the transcription factor Lef1 positively regulates EC specification (defined by kdrl expression) at the expense of primitive erythrocyte specification (defined by gata1 expression) in zebrafish embryos. Using mesoderm derived from human embryonic stem cells, we identified the same principle of Wnt signaling dependent EC specification in conjunction with auto-upregulation of LEF1. Our data indicate a novel role of beta-catenin dependent Wnt signaling in regulating EC specification during vasculogenesis. PMID- 28811220 TI - Euphorbia lunulata extract acts on multidrug resistant gastric cancer cells to inhibit cell proliferation, migration and invasion, arrest cell cycle progression, and induce apoptosis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The milky sap or the aboveground part of the plant Euphorbia lunulata has long been used by Chinese people to treat noncancerous growths and cancerous ailments but the specific mode of action and the action mechanism remain to be elucidated. AIM OF THE STUDY: To investigate the effects of Euphorbia lunulata extract on cell proliferation, migration, invasion, cell cycle progression, and apoptosis of multidrug resistant human gastric cancer cells; To study the mechanism of apoptosis induction by Euphorbia lunulata extract in multidrug resistant human gastric cancer cells. MATERIALS AND METHODS: The aboveground part of fresh Euphorbia lunulata plant was extracted first with ethanol and then with n-hexane. The aseptic extract at varying concentrations was used to treat the multidrug resistant human gastric cancer SGC7901/ADR cells. After treatment, the inhibition of cell proliferation was examined by MTT assay. The inhibitions of cell migration and invasion were detected by Transwell method. The alteration of cell cycle progression was studied by flow cytometry. The morphological changes of cell nuclei were observed with fluorescence microscopy following Hoechst 33258 staining and the apoptotic indexes were calculated. The activation of caspase enzymes was analyzed by spectrophotometry. The sub-cellular distribution of cytochrome complex and the expression of Bax and Bcl-2 proteins were determined by Western blot. RESULTS: The proliferation, migration, and invasion of SGC7901/ADR cells were significantly inhibited by Euphorbia lunulata extract, which showed time- and dose-dependent manners. Cell cycle was arrested in G2/M phase. Significant apoptotic morphological changes were observed in the nuclei of the treated cells, and apoptotic indexes were increased significantly; these changes were diminished when Z-VAD-FMK, a caspase inhibitor, was also presented. The activities of caspase-3, caspase-8, and caspase-9 were increased. The sub-cellular distribution of cytochrome complex was altered----reduced in the mitochondria and increased in the cytoplasm. The expression of Bax was upregulated, while that of Bcl-2 was downregulated. CONCLUSION: Euphorbia lunulata extract inhibited the proliferation, migration, and invasion of SGC7901/ADR cells, arrested cell cycle progression, and induced cell apoptosis; the mechanism of apoptosis induction involved both the extrinsic and the intrinsic pathways. PMID- 28811219 TI - Trinucleotide repeat containing 6c (TNRC6c) is essential for microvascular maturation during distal airspace sacculation in the developing lung. AB - GW182 (also known asTNRC6) family members are critically involved in the final effector phase of miRNA-mediated mRNA repression. The three mammalian paralogs, TNRC6a, b and c, are thought to be redundant based on Argonaute (Ago) binding, tethering assays, and RNAi silencing of individual members in cell lines. To test this idea, we generated TNRC6a, b and c knockout mice. TNRC6a mutants die at mid gestation, while b- and c- deleted mice are born at a Mendelian ratio. However, the majority of TNRC6b and all TNRC6c mutants die within 24h after birth, the latter with respiratory failure. Necropsy of TNRC6c mutants revealed normal appearing airways that give rise to abnormally thick-walled distal gas exchange sacs. Immunohistological analysis of mutant lungs demonstrated a normal distribution of bronchiolar and alveolar cells, indicating that loss of TNRC6c did not abrogate epithelial cell differentiation. The cellular kinetics and relative proportions of endothelial, epithelial, and mesenchymal cells were also not altered. However, the underlying capillary network was simplified and endothelial cells had failed to become tightly apposed to the surface epithelium in TNRC6c mutants, presumably causing the observed respiratory failure. TGFbeta family mutant mice exhibit a similar lung phenotype of thick-walled air sacs and neonatal lethality, and qRT-PCR confirmed dynamic downregulation of TGFbeta1 and TGFbetaR2 in TNRC6c mutant lungs during sacculation. VEGFR, but not VEGF-A ligand, was also lower, likely reflecting the overall reduced capillary density in TNRC6c mutants. Together, these results demonstrate that GW182 paralogs are not functionally redundant in vivo. Surprisingly, despite regulating a general cellular process, TNRC6c is selectively required only in the distal lung and not until late in gestation for proper expression of the TGFbeta family genes that drive sacculation. These results imply a complex and indirect mode of regulation of sacculation by TNRC6c, mediated in part by dynamic transcriptional repression of an inhibitor of TGFbeta family gene expression. PMID- 28811221 TI - Is the hype around the reproductive health claims of maca (Lepidium meyenii Walp.) justified? AB - ETHNOPHARMACOLOGICAL RELEVANCE: Maca - Lepidium meyenii Walp. has been cultivated and used by Andean people for over 1300-2000 years in Peru as food and medicine. Starting in the late 1990's it has developed into an important herbal medicine in China and is now cultivated there widely, too AIM OF STUDY: This study aims to provide an insight into the emergence of maca on the global market as an alternative remedy to treat reproductive health related problems in both men and women and to critically assess these health claims. METHODOLOGY: A search of electronic databases such as EMBASE and a hand-search was done to acquire peer reviewed articles and reports about maca. RESULTS AND DISCUSSION: Lepidium meyenii is used traditionally as a tonic, fertility enhancer for both humans and cattle, and to treat a variety of ailments such as rheumatism, respiratory disorders and anaemia among others. Maca root is cooked, baked, fermented as a drink and made into porridge. In the last twenty years, maca was introduced onto the global market and demand has dramatically grown over this time with its promotion on the internet, as the 'Peruvian Ginseng' for libido and fertility enhancement. It has also been said to treat menopausal symptoms, erectile dysfunction and benign prostatic hyperplasia. The sky-rocketing demand for the plant has seen a shift from traditional cultivation methods to mass production practices with the use of fertilisers and also pesticides; as maca is now grown in areas other than the Andes such as in the Yunnan province in China. This can potentially affect the phytochemistry and composition of the plant and thus, the quality, safety and efficacy of maca products. Meanwhile, research into maca's medicinal properties has followed the spike in popularity of maca and has been focused mainly on maca's aphrodisiac and fertility enhancing properties. So far, the in vivo studies and clinical trials conducted have yielded inconclusive results. Some of the key limitations reside in methodology and sample size. Chemical profiling, led to the discovery of new compounds unique to maca, such as, 'macamides' and also other active metabolites like the glucosinolates; to which the medicinal effects of maca have been ascribed but cannot be confirmed due to lack of data. CONCLUSIONS: To date, the health claims of maca cannot be fully supported from a scientific standpoint and more research is needed. It appears that the indigenous local knowledge about the health benefits of maca has been dragged out of context to fit the demands of a growing market for herbal remedies. This globalisation (or hype esp. in China) also has had serious consequences for the local producers in Peru. The lack of protocols to regulate the production and marketing of maca during this rapid expansion, poses a threat to both the safety of consumers and the sustainability of supply. PMID- 28811222 TI - Antitussive, antispasmodic, bronchodilating and cardiac inotropic effects of the essential oil from Blepharocalyx salicifolius leaves. AB - ETHNOPHARMACOLOGY RELEVANCE: Blepharocalyx salicifolius (Kunth) O. Berg (Myrtaceae) is a tree native to Argentina and Uruguay that grows and is cultivated along the riverside of the Rio de la Plata. The leaves of this plant species, locally known as "anacahuita" are used in South America to prepare infusions for the empiric treatment of cough and bronchospasm, as well as diarrhoea and other intestinal disorders. Although previous phytochemical studies have been performed with the essential oil extracted from Blepharocalyx salicifolius, pharmacological evidence supporting its traditional use is still lacking. AIM OF THE STUDY: To experimentally evaluate the pharmacological properties of Blepharocalyx salicifolius based on its traditional use. The studies were performed with tincture (T-Bs) and essential oil (EO-Bs) prepared from its leaves, in isolated rat trachea, intestine and heart preparations. METHODS: The ex-vivo effects of T-Bs and EO-Bs were evaluated with the agonists carbachol (CCh) and calcium chloride (Ca2+) in the contractile concentration response curves (CRC) of the isolated intestine. The muscle relaxant effect of EO Bs was evaluated in the isolated trachea and compared with the effect achieved with papaverine as a positive control. The T-Bs and EO-Bs cardiac effects were analysed by perfusion of an isolated rat heart before a period of ischemia/reperfusion (stunning model). The antitussive effect of both T-Bs and EO Bs was evaluated in mice exposed to ammonia using codeine as a positive control. RESULTS: Both T-Bs and EO-Bs induced a non-competitive inhibition of the CCh-CRC in the rat intestine, with IC50 values of 170.3 +/- 48.5ug T-Bs/mL (n = 6) and 5.9 +/- 1.6ug EO-Bs/mL (n = 6), respectively. EO-Bs also inhibited non competitively the Ca2+-CRC, with IC50 value of 1.8 +/- 0.3ug EO-Bs/mL (n = 8). A similar effect was obtained with the main active component of the EO-Bs 1,8 cineole. In isolated trachea, EO-Bs induced the relaxation of the CCh-contracted tissue (1.7 +/- 0.2ug EO-Bs/mL, n = 11) up to a maximal relaxation that was 1.9 times higher than that of papaverine. In the isolated heart, EO-Bs induced a poor negative inotropic response, and did not improve the contractile and energetic recovery after ischemia and reperfusion. In the mouse cough model, EO-Bs (90mg/Kg) was as effective as codeine (30mg/Kg) in reducing cough frequency. CONCLUSIONS: The results indicate that the preparations from Blepharocalyx salicifolius leaves were effective as central antitussive, bronchodilating and antispasmodic agents, suggestive of a mechanism associated with the inhibition of Ca2+ influx into smooth muscle. The EO-Bs displayed only a poor ability to reduce cardiac inotropism, and was devoid of any cardioprotective properties. Thus, the present study validates the traditional use of this South American plant for asthma, cough and bronchospasm, shedding new light into its potency and putative mechanism of action. PMID- 28811223 TI - Influence and mechanism of 5-aminolevulinic acid-photodynamic therapy on the metastasis of esophageal carcinoma. AB - BACKGROUD: Photodynamic therapy (PDT) for the treatment of esophageal cancer was more and more popularly used since it was approved for the treatment of advanced esophageal cancer in 1996. It has been reported to influence the tumor growth and metastasis via a variety of signaling pathways, but its mechanism remains to be further studied. This research studied the effects of ALA-PDT on esophageal carcinoma in vitro and in vivo, discovering its molecular regulating mechanism and the way to enhence the PDT effect. METHODS: Eca-109 cells were incubated with a medium containing EGFR tyrphostin AG1478 or PI3K inhibitor LY294002, then with ALA, and the cells were irradiated with the laser 6h later. The cell viability was measured with MTT assay, and the migration ability was detected by transwell experiments 24h post-ALA-PDT. The gene and protein expression on EGFR/PI3K/AKT signaling pathway was analyzed by realtime PCR and Western blotting respectively. Then, RFP-Eca-109 burdened nude mice model was constructed, and were treated with ALA-PDT when the tumor volume reached 150-350mm3. The gene and protein expression were analyzed 24h and 50days post-ALA-PDT. RESULTS: Our study showed that ALA-PDT respectively combined with AG1478, LY294002 could synergistically reduce the growth and migration ability of the Eca-109 cells in vitro and significantly down regulate the protein expression of EGFR/PI3K and PI3K/AKT, meanwhile, significantly down-regulate the gene expression of EGFR when combining with AG1478. Forthermore, ALA-PDT could significantly decrease the tumor growth and metastasis and down-regulate the gene expression of EGFR and the protein expression of EGFR and PI3K in the tumor of mice. CONCLUSION: This study revealed a molecular mechanism of ALA-PDT and developed a new modality application of therapy, by combining ALA-PDT with small molecular inhibitors, for better effect in the clinical practice of esophageal carcinoma. PMID- 28811224 TI - Hypericin cytotoxicity in tumor and non-tumor cell lines: A chemometric study. AB - Hypericin (HY) is an excellent photoactive compound that has been investigated for the photodynamic treatment of cancer as well as for microorganism inactivation. In this study, chemometric analysis was applied for the first time on photodynamic assays to investigate the cytotoxicity of HY in tumor (HEp-2) and non-tumor (Vero and HUVEC) cell lines. The experimental planning was based on eight assays using the 23 full factorial design combining three important variables for PDT: photosensitizer concentrations, incubation time of cells in HY solutions and employed light dose (lambda=590+/-10nm). The statistical data analysis evidenced the relative significance of such variables and the correlations among them on the cell death. The chemometric results suggested that long incubation time and a low HY concentration and/or light dose allow killing selectively tumor cells. The chemometric analysis could be a new useful empiric method to a previous prediction of the IC50. In this study, the estimated values were in agreement with the experimental IC50 values. PMID- 28811225 TI - Alpha-synuclein ferrireductase activity is detectible in vivo, is altered in Parkinson's disease and increases the neurotoxicity of DOPAL. AB - The normal cellular role of alpha-synuclein is of potential importance in understanding diseases in which an aggregated form of the protein has been implicated. A potential loss or change in the normal function of alpha-synuclein could play a role in the aetiology of diseases such as Parkinson's disease. Recently, it has been suggested that alpha-synuclein could cause the enzymatic reduction of iron and a cellular increase in Fe(II) levels. Experiments were carried out to determine if such activity could be measured in vivo. Experiments with rats overexpressing human alpha-synuclein in nigral dopaminergic neurons demonstrated a correlation between alpha-synuclein expression and ferrireductase activity. Furthermore, studies on tissue from Parkinson's disease patient brains showed a significant decrease in ferrireductase activity, possibly due to deposition of large amounts of inactive protein. Cellular studies suggest that increase ferrireductase activity results in increased levels of dopamine metabolites and increased sensitivity to the toxicity of DOPAL. These findings demonstrate that alpha-synuclein ferrireductase activity is present in vivo and its alteration may play a role in neuron loss in disease. PMID- 28811226 TI - Characterization and expression analysis of six interleukin-17 receptor genes in grouper (Epinephelus coioides) after Cryptocaryon irritans infection. AB - Interleukin-17 receptors (IL17Rs) mediate the activation of several downstream signal pathways to induce inflammatory response and contribute to the pathology of many autoimmune diseases. In this study, six IL17Rs (IL17RA1, RA2, RB, RC, RD and RE) were cloned and characterized from Epinephelus coioides, an orange spotted grouper. Multiple sequence alignment and structural analysis revealed that all members of IL17Rs were low in sequence identity with each other. But their structures were conservative in grouper, which contain signal peptide, extracellular FNIII domain (IL17RA1/RA2/RB) or IL-17_R_N domain (IL17RC/RD/RE), transmembrane domain and SEFIR domain in their intracellular region. The analysis of tissue distribution showed these six genes were ubiquitously and differentially expressed in all major types of tissues. What's more, it is interesting to find their high expression in immune tissues (liver, gill, skin and thymus). IL17RA1 and IL17RA2 were significantly down-regulated at all time points in gill and spleen after Cryptocaryon irritans infection, however, there was no significant change in other grouper IL17Rs. It suggests that the C. irritans may escape from the host immunity or the host prevents serious inflammation by inhibiting the expression of ILl7Rs. PMID- 28811228 TI - Curcumin in Alzheimer's disease: Can we think to new strategies and perspectives for this molecule? AB - Population aging is an irreversible global trend with economic and socio political consequences. One of the most invalidating outcomes of aging in the elderly is cognitive decline, leading to dementia and often related to neurodegenerative disorders. Among these latter, Alzheimer's disease (AD) is the major cause of dementia, affecting more than 30 million of individuals worldwide. To date, the treatment of AD remains a challenge because of an incomplete understanding of the events that lead to the selective neurodegeneration typical of Alzheimer's brains. There is an enormous global demand for new effective therapies and researchers are investigating new fields. One promising strategy is the use of nutraceuticals as integrative, complementary and preventive therapy. Curcumin is one example of natural product with anti-AD properties, with promising potential for prevention, treatment and diagnostic. The limitations in the use of curcumin as therapeutic are represented by its pharmacokinetics profile and the low bioavailability after oral administration. However, curcumin has been the focus of intense research for new drug development. Here we analyzed some new approaches that have been applied in the attempt to improve its use, particularly new formulations, changes in the way of administration, nanotechnology-based delivery systems and the hybridization strategy. PMID- 28811227 TI - The chemotherapeutic agent paclitaxel selectively impairs reversal learning while sparing prior learning, new learning and episodic memory. AB - Chemotherapy is widely used to treat patients with systemic cancer. The efficacy of cancer therapies is frequently undermined by adverse side effects that have a negative impact on the quality of life of cancer survivors. Cancer patients who receive chemotherapy often experience chemotherapy-induced cognitive impairment across a variety of domains including memory, learning, and attention. In the current study, the impact of paclitaxel, a taxane derived chemotherapeutic agent, on episodic memory, prior learning, new learning, and reversal learning were evaluated in rats. Neurogenesis was quantified post-treatment in the dentate gyrus of the same rats using immunostaining for 5-Bromo-2'-deoxyuridine (BrdU) and Ki67. Paclitaxel treatment selectively impaired reversal learning while sparing episodic memory, prior learning, and new learning. Furthermore, paclitaxel-treated rats showed decreases in markers of hippocampal cell proliferation, as measured by markers of cell proliferation assessed using immunostaining for Ki67 and BrdU. This work highlights the importance of using multiple measures of learning and memory to identify the pattern of impaired and spared aspects of chemotherapy-induced cognitive impairment. PMID- 28811229 TI - Necrotizing fasciitis following venomous snakebites in a tertiary hospital of southwest Taiwan. AB - BACKGROUND: Necrotizing fasciitis following venomous snakebites is uncommon. The purpose of this study was to describe the initial clinical features of necrotizing fasciitis after snakebites, and to identify the risk factors for patients with cellulitis who later developed necrotizing fasciitis. METHODS: Sixteen patients with surgically confirmed necrotizing fasciitis and 25 patients diagnosed with cellulitis following snakebites were retrospectively reviewed over a 6-year period. Differences in patient characteristics, clinical presentations, snake species and laboratory data were compared between the necrotizing fasciitis and the cellulitis groups. RESULTS: None of the 41 patients died after being bitten by a snake. Twenty-nine patients (70.7%) were bitten by a cobra. Enterococcus species and Morganella morganii were the most common pathogens identified in wound cultures. Relative to the cellulitis group, the necrotizing fasciitis group had significantly higher rates of hemorrhagic bullae (p=0.000), patients with underlying chronic disease (p=0.019), white blood cell counts (p=0.035), segmented white cell counts (p=0.02), and days of hospitalization (p=0.001). CONCLUSIONS: Victims of venomous snakebites should be admitted for close monitoring of secondary wound infections. The risk factors of developing necrotizing fasciitis from cellulitis following snakebites were associated with chronic underlying diseases and leukocytosis (total white blood-cell counts >=10000cells/mm3 and >=80% of segmented leukocyte forms). Physicians should be alert to a worsening wound condition after a snakebite, and surgical interventions should be performed for established necrotizing fasciitis with the empirical use of third-generation cephalosporins plus other regimens. PMID- 28811230 TI - Commentary on "Late Dacron Patch Inflammatory Reaction After Carotid Endarterectomy". PMID- 28811231 TI - A Step Forward in Precision Medicine on "One Belt One Road". PMID- 28811233 TI - Stimulation of ovarian cell proliferation by tetrabromobisphenol A but not tetrachlorobisphenol A through G protein-coupled receptor 30. AB - Tetrabromobisphenol A (TBBPA) and tetrachlorobisphenol A (TCBPA) are bisphenol A (BPA) analogs, where the phenolic moieties are substituted with halogens (Br or Cl). Previous studies indicate that BPA has significant proliferative effects on in vitro cultured epithelial ovarian cancer (EOC) cells. Considering this, we analyzed the effects of both TBBPA and TCBPA at 1, 10, and 50nM on ovarian cancer cell proliferation. The majority of malignant ovarian tumors are epithelial in origin, but approximately 10% are classified as ovarian sex cord tumors, with the most common type being granulosa cell tumors (GCTs). OVCAR-3 and KGN cells were used as in vitro models to represent EOCs and GCTs, respectively. Here, we found that TBBPA, but not TCBPA, stimulated OVCAR-3 and KGN cell proliferation, with lower potency than BPA. The stimulatory effects of TBBPA and BPA on cell proliferation were reversed by pre-treatment with a G protein-coupled receptor 30 (GPR30) antagonist in both cell lines, which possess similar basal GPR30 expression levels. Taken together, our results show for the first time that TBBPA, which has lower potency than BPA, stimulates ovarian cancer cell proliferation through the GPR30 pathway. PMID- 28811232 TI - CYP2A6 Polymorphisms Associate with Outcomes of S-1 Plus Oxaliplatin Chemotherapy in Chinese Gastric Cancer Patients. AB - Gastric carcinoma is a heterogeneous malignant disease involving genetic factors. To identify predictive markers for gastric cancer treatment in Chinese patients, we evaluated the association between polymorphisms of the gene encoding cytochrome P450 2A6 (CYP2A6) and outcomes of S-1 plus oxaliplatin (SOX) chemotherapy treatment. Clinical data on 60 consecutive gastric cancer patients receiving SOX regimen were collected prospectively. We sequenced all exons of CYP2A6 and a total of 22 different polymorphisms were detected in the present study. Comprehensive analyses of these genetic polymorphisms were performed to determine their association with both safety and efficacy of SOX regimen. Our results showed that polymorphisms of CYP2A6 were associated with the safety and efficacy of SOX treatment. Among them, missense mutations CYP2A6 rs60823196 and rs138978736 could be possible risk factors (P<0.05) for severe diarrhea induced by SOX, whereas CYP2A6 rs138978736 could be a conceivable predictor for overall survival of patients treated with SOX adjuvant chemotherapy. Further large-scale randomized prospective studies are warranted to confirm these findings. PMID- 28811236 TI - Interleukin-26 is overexpressed in Behcet's disease and enhances Th17 related cytokines. AB - Behcet's disease (BD) is a multi-systemic inflammatory disorder characterized by the "triple symptom complex". Several pro-inflammatory cytokines, mainly derived from the immune Th17 axis, seem to be involved in different pathogenic pathways leading to development of the clinical manifestations. Here, we have analyzed the expression and role of IL-26 in active BD patients, an inflammatory disorder characterized by bronchoalveolar lavage fluid (BAL) and cerebrospinal fluid (CSF) inflammation. On this basis, the primary aim of our work was to study IL-26 levels in serum, BAL CSF) from active BD patients. Samples were collected from 95 BD patients (55 patients were in active stage) and 50 healthy controls (HC). They were investigated with ELISA for estimation of cytokines levels. Serum concentration of IL-26 resulted higher in both active [4.80+/-1.32] and inactive [2.77+/-1.026] BD than HC [0.31+/-0.14ng/ml; p<0.0001]. Level of IL-26 was associated with the BD clinical severity score from moderate to severe (P<0.0001). IL-26 was highly expressed in CSF [10.80+/-2.05ng/ml] and in BAL [12.89+/-3.03ng/ml] fluid from BD patients comparatively to their respective controls. IL-26 levels in CSF and in BAL fluid showed positive correlations with IL-17 level and an inversely correlation with IL-37. Interestingly, IL-26 stimulated CD4+ T cells and monocytes promote the generation of Th17 (IL-17A, IL 23) and suppress Treg (IL-10, TGF-beta) cytokines. Our findings may suggest a signature of IL-26 probably responsible for the inflammatory process to correlate positively with Th17 cytokines and inversely with Treg mediators. This evidence could contribute to improve the knowledge regarding the role of IL-26 in BD severity. For the first time, IL-26 expression is demonstrated in BAL and CSF, supporting a role for this cytokine in the pathogenesis of BD. IL-26 thereby appears as a novel proinflammatory cytokine favoring the generation of Th17 cytokines. PMID- 28811235 TI - Sodium butyrate ameliorates S100/FCA-induced autoimmune hepatitis through regulation of intestinal tight junction and toll-like receptor 4 signaling pathway. AB - BACKGROUND AND AIM: Recent investigation revealed that dysbiosis in the gut flora and disruption of permeability of intestinal barrier are possible causes for the development of autoimmune hepatitis. Supplementation of sodium butyrate has been suggested to protect liver injury from disrupted permeability of small intestine. In current study, we employed S100/Freund's complete adjuvant induced autoimmune hepatitis to investigate therapeutic efficacy of sodium butyrate and its mechanism in the liver and upper small intestine. METHODS: C57BL/6 mice were employed and divided into three groups - control group (n=8), autoimmune hepatitis group (n=12) and autoimmune hepatitis with treatment of sodium butyrate group (n=12). Histological staining and western blot analyses were employed to evaluate liver and upper small intestine morphology and gene expression respectively. RESULTS: The findings revealed that S100/Freund's complete adjuvant caused liver injury and disruption of upper small intestine villi. Sodium butyrate attenuated the injuries and prevented migration of Escherichia coli into the liver. Moreover, the effect of sodium butyrate on protection of injuries of the liver and upper small intestine could be due to inhibition of toll-like receptor 4 signaling pathway, as well as its down-regulation of inflammatory cytokines - interleukin-6 and tumor necrosis factor-a. CONCLUSIONS: Sodium butyrate can prevent liver injury by maintaining the integrity of small intestine and inhibiting inflammatory response in S100/Freund's complete adjuvant induced autoimmune hepatitis. PMID- 28811237 TI - The (in-)validity of volatile POCT parameters from patients beyond normothermia. AB - BACKGROUND: A common characteristic of all blood gas analyzers on the market is that measurements are processed at 37 degrees C, not at the real patients' temperature. Subsequently temperature-sensitive parameters can be mathematically corrected (alpha-stat method) or used directly (pH-stat method). National rules in Germany (Rili-BAEK) demand defined accuracy and precision without any restriction to samples' temperatures or corrections. As consequence in the investigation at hand we tried to find out whether blood gas analyzers can fulfill the regulations for pCO2 and pO2 when normothermia of the matrix is not given. METHODS: Five matrices (blood from intensive care unit (ICU) patients, blood from healthy donors and 3 levels of bovine based quality control material) were tonometered at "high" and "low" partial pressures of O2 and CO2 within the RiLi-BAEK controlled range at 32, 37 and 40 degrees C. One mL material was aspired into each blood gas (BG) syringe and analysis was accomplished immediately after. The procedure was repeated 10-fold for "high" and "low" gas concentrations and run on 4 different analyzers. At 18 degrees C instead to the "high" one a "median" gas (n=10 as well) was employed. Every condition which constitutes of temperature (4), matrix (5), analyzer (4) and level of the partial pressure (2) led to a total of 1600 measurements. RESULTS: At 32 degrees C or 37 degrees C matrix temperature 7.5% to 27.5% of the pCO2(T) and between 14.5% and 28.1% of the pO2(T) results were outside the borders required by the RiLi-BAEK. At 18 degrees C or 40 degrees C the number of results beyond the allowed borders grows up to 82.5% for pCO2(T) and 73% for pO2(T) depending on the partial pressure (PP) level. CONCLUSIONS: High precision in automated quality control (at a constant matrix temperature) is given in modern BGAnalyzers but is counteracted in practice by non normothermic patient's temperature and unavoidable sample handling effects. PMID- 28811238 TI - I index is not an accurate indicator of icteria in conjugated hyperbilirubinemia. AB - INTRODUCTION: Serum indices have become a standard in assessing degree of endogenous interferences in serum and plasma samples. The aim of this study was to evaluate accuracy of I index in comparison with total bilirubin concentration in icteric samples with ranging amount of conjugated bilirubin. MATERIALS AND METHODS: This study retrospectively analyzed data from laboratory information system. Total, conjugated bilirubin and I index are measured on Abbott Architect c8000 (N=900). Agreement between total bilirubin and I index in subgroups according to proportion of direct bilirubin (<50% and >=50%) was investigated using Bland-Altman analysis. RESULTS: In samples where percentage of direct bilirubin accounts for <50% of total bilirubin there was no statistically significant constant difference, while small proportional difference was observed (2.5%) between total bilirubin and I index. In samples where percentage of direct bilirubin accounts for >=50% of total bilirubin, significant constant (26.6) and proportional difference (22.2%) were observed between total bilirubin and I index. CONCLUSION: I index is not accurate indicator of icteria if >50% of bilirubin is conjugated. Manufacturers should declare icteria interference with both, bilirubin concentration and value of I index. PMID- 28811239 TI - Gamma-glutamyltransferase and risk of chronic kidney disease: A prospective cohort study. AB - BACKGROUND: Elevated serum gamma-glutamyltransferase (GGT) activity has been linked with an increased risk of chronic kidney disease (CKD) in Asian populations. We aimed to assess the prospective association of serum GGT with risk of CKD in a Caucasian population. MATERIALS AND METHODS: We related GGT activity to the incidence of CKD in 2338 men aged 42-61years of the Kuopio Ischemic Heart Disease study with normal kidney function at baseline. Repeat measurements of GGT were used to correct for within-person variability. RESULTS: During a median follow-up of 25.6years, 221 men developed new-onset CKD. The age adjusted regression dilution ratio of loge GGT was 0.70 (95% CI: 0.64-0.75). Gamma-glutamyltransferase was log-linearly associated with risk of CKD in age adjusted analysis. In Cox regression analysis adjusted for age, the hazard ratio (95% CIs) for CKD per standard deviation increase in loge baseline GGT was 1.25 (1.09-1.43) which was attenuated to 1.01 (0.86-1.19) on further adjustment for several confounders. CONCLUSION: Contrary to previous evidence of an independent association between elevated GGT and increased risk of CKD in Asian populations, initial evidence of an association between GGT and CKD in Caucasian men was confounded by body mass index, lifestyle factors, and lipids. PMID- 28811240 TI - Changes in mucosal and serum immunoglobulin levels of California sea lions during early development. AB - To date, most studies on pinniped immunoglobulins have focused on circulating antibodies. However, systemic and local immune activities differ in terms of maturation, intensity, and types of effectors that participate. Here, we examined levels of three immunoglobulin isotypes, IgG, IgM and IgA, in the blood and mucosal membranes of free-living California sea lion pups. We investigated whether age, body condition and sex influenced their concentration. Isotype levels varied among tissues, with age-related patterns that could be indicative of differential regulation along development. Serum IgG and IgA increased linearly with age, reaching adult levels at five months of age, while IgM remained unchanged. Mucosal isotypes tended to be low in newborns and remained so until five months of age. Regardless of age, pups with better condition tended to have higher anal IgG levels and higher genital IgA levels, suggesting that their synthesis and transport to the mucosal membranes is costly. Intersex differences were only observed in the genital mucosa, where all isotypes differed between male and female pups, regardless of age, presumably due to histological and anatomical differences. PMID- 28811241 TI - Utility of prior cultures in predicting antibiotic resistance of bloodstream infections due to Gram-negative pathogens: a multicentre observational cohort study. AB - OBJECTIVES: Appropriate empiric antibiotic therapy in patients with bloodstream infections due to Gram-negative pathogens can improve outcomes. We evaluated the utility of prior microbiologic results for guiding empiric treatment in Gram negative bloodstream infections. METHODS: We conducted a multicentre observational cohort study in two large health systems in Canada and the United States, including 1832 hospitalized patients with Gram-negative bloodstream infection (community, hospital and intensive care unit acquired) from April 2010 to March 2015. RESULTS: Among 1832 patients with Gram-negative bloodstream infection, 28% (n = 504) of patients had a documented prior Gram-negative organism from a nonscreening culture within the previous 12 months. A most recent prior Gram-negative organism resistant to a given antibiotic was strongly predictive of the current organism's resistance to the same antibiotic. The overall specificity was 0.92 (95% confidence interval (CI) 0.91-0.93), and positive predictive value was 0.66 (95% CI 0.61-0.70) for predicting antibiotic resistance. Specificities and positive predictive values ranged from 0.77 to 0.98 and 0.43 to 0.78, respectively, across different antibiotics, organisms and patient subgroups. Increasing time between cultures was associated with a decrease in positive predictive value but not specificity. An heuristic based on a prior resistant Gram-negative pathogen could have been applied to one in four patients and in these patients would have changed therapy in one in five. CONCLUSIONS: In patients with a bloodstream infection with a Gram-negative organism, identification of a most recent prior Gram-negative organism resistant to a drug of interest (within the last 12 months) is highly specific for resistance and should preclude use of that antibiotic. PMID- 28811242 TI - Natural NS5A inhibitor resistance associated substitutions in hepatitis C virus genotype 1 infected patients from Italy. AB - OBJECTIVES: Genetic variability in NS5A is associated with different levels of resistance to the currently licensed NS5A inhibitors. The aim of this study was to detect NS5A inhibitor resistance associated substitutions (RASs) in hepatitis C virus (HCV) genotype 1 (GT1) patients who are naive to direct-acting HCV antivirals. METHODS: Amplification, Sanger sequencing and phylogenetic analysis of the HCV NS5A region were performed on plasma obtained from 122 consecutive patients with HCV chronic infection attending four different clinics in Italy. RESULTS: NS5A inhibitor RASs were detected in 14/61 (23.0%) HCV GT1b and 3/61 (4.9%) HCV GT1a infected patients (p 0.007). The pan-genotypic RAS Y93H was detected in 1 (1.6%) GT1a and 4 (6.6%) GT1b patients. GT1a sequences clustered into two different clades with RASs detected in 1/34 (2.9%) clade I and 2/27 (7.4%) clade II sequences. CONCLUSIONS: Although the impact of naturally occurring NS5A RASs might be limited with upcoming pan-genotypic treatment regimens, this information is still useful to map naturally occurring HCV variants in different geographic areas in the context of current HCV therapy. PMID- 28811243 TI - Preserving the 'commons': addressing the sustainable use of antibiotics through an economic lens. AB - BACKGROUND: As the growth of antibiotic resistance has resulted in large part from widespread use of antibiotics, every effort must be made to ensure their sustainable use. AIMS: This narrative review aims to assess the potential contribution of health economic analyses to sustainable use efforts. SOURCES: The work draws on existing literature and experience with health economic tools. CONTENT: The study examines some of the weaknesses in the health, regulatory, and industry arenas that could contribute to inappropriate or suboptimal prescribing of antibiotics and describes how economic analysis could be used to improve current practice by comparing both costs and health outcomes to maximize societal wellbeing over the longer-term. It finds that economic considerations underpinning current antibiotic prescribing strategies are incomplete and short termist, with the result that they may foster suboptimal use. It also stresses that perverse incentives that drive antibiotic sales and inappropriate prescribing practices must be dis-entangled for sustainable use policies to gain traction. Finally, payment structures can be used to re-align incentives and promote optimal prescribing and sustainable use more generally. In particular, eliminating or altering reimbursement differentials could help steer clinical practice more deliberately towards the minimization of selection pressure and the resulting levels of antibiotic resistance. IMPLICATIONS: This work highlights the need for appropriately designed cost-effectiveness analyses, incentives analysis, and novel remuneration systems to underpin sustainable use policies both within and beyond the health sector. PMID- 28811245 TI - Low prevalence of MCR-1-producing Klebsiella pneumoniae in bloodstream infections in China. PMID- 28811244 TI - Comparison of the clinical course of Clostridium difficile infection in glutamate dehydrogenase-positive toxin-negative patients diagnosed by PCR to those with a positive toxin test. AB - OBJECTIVES: To evaluate the potential role of PCR-based assays in the over diagnosis of Clostridium difficile infection (CDI) by using a validated diagnostic algorithm in daily clinical practice. METHODS: We performed a retrospective cohort study evaluating all C. difficile-positive stool samples identified at our institution during a 12-month period, to compare outcomes and recurrence rates between patients with a positive enzyme immunoassay (EIA) for both glutamate dehydrogenase (GDH) and toxin A/B ('toxin-positive group'), with those with GDH-positive, toxin-negative samples in whom the diagnosis was made by a positive PCR-based assay ('toxin-/PCR+ group'). Medical records were reviewed by two independent investigators blinded to the mode of diagnosis. RESULTS: We analysed 231 first CDI episodes (106 (45.8 %) in the 'toxin-positive group' and 125 (54.1%) in the 'toxin-/PCR+ group'). Both groups had similar baseline characteristics. Patients in the 'toxin-positive group' presented more frequently with a severe/severe complicated form than those in the 'toxin-/PCR+ group' (36 (33.9%) versus 24 (19.2%); p 0.011) and had more recurrences (27 (25.5%) versus 9 (7.2%); p 0.001). Diagnosis of CDI based on a GDH/toxin-positive EIA independently predicted severe/severe-complicated course (adjusted OR 2.11; 95% CI 1.06-4.22; p 0.033) and recurrence (adjusted OR 3.79; 95% CI 1.65-8.69; p 0.002). There were no differences in all-cause mortality (12.3% versus 12.0%; p 0.95) or CDI-attributable mortality (4.7% versus 4.8%; p 0.93). CONCLUSIONS: Toxin-positive patients were more likely to have severe-complicated forms of CDI and recurrences. Nevertheless, CDI-related complications may still occasionally occur among toxin-negative patients diagnosed by PCR, which stresses the need for individualized clinical evaluation. PMID- 28811246 TI - Microbial Metagenomics Mock Scenario-based Sample Simulation (M3S3). AB - OBJECTIVES: Shotgun sequencing is increasingly applied in clinical microbiology for unbiased culture-independent diagnosis. While software solutions for metagenomics proliferate, integration of metagenomics in clinical care requires method standardization and validation. Virtual metagenomics samples could underpin validation by substituting real samples and thus we sought to develop a novel solution for simulation of metagenomics samples based on user-defined clinical scenarios. METHODS: We designed the Microbial Metagenomics Mock Scenario based Sample Simulation (M3S3) workflow, which allows users to generate virtual samples from raw reads or assemblies. The M3S3 output is a mock sample in FASTQ or FASTA format. M3S3 was tested by generating virtual samples for 10 challenging infectious disease scenarios, involving a background matrix 'spiked' in silico with pathogens including mixtures. Replicate samples (seven per scenario) were used to represent different compositional ratios. Virtual samples were analysed using Taxonomer and Kraken db. RESULTS: The 10 challenge scenarios were successfully applied, generating 80 samples. For all tested scenarios, the virtual samples showed sequence compositions as predicted from the user input. Spiked pathogen sequences were identified with the majority of the replicates and most exhibited acceptable abundance (deviation between expected and observed abundance of spiked pathogens), with slight differences observed between software tools. CONCLUSIONS: Despite demonstrated proof-of-concept, integration of clinical metagenomics in routine microbiology remains a substantial challenge. M3S3 is capable of producing virtual samples on-demand, simulating a spectrum of clinical diagnostic scenarios of varying complexity. The M3S3 tool can therefore support the development and validation of standardized metagenomics applications. PMID- 28811247 TI - Pharmacological analysis of Poecilotheria spider venoms in mice provides clues for human treatment. AB - Bites of tiger spiders belonging to Poecilotheria genus cause moderate to severe pain and long-lasting local or generalized muscle cramps in humans. Bites occur in regions of the spiders' natural habitat, India and Sri Lanka, but the popularity of these colorful tarantulas as pets leads to reports of envenomation cases worldwide. Treatment is predominantly symptomatic and often inadequate since there is almost no clinical or toxicology research data available, and physicians outside India or Sri Lanka typically have no experience in treating such cases. We report toxicity studies of venom from nine Poecilotheria species in laboratory mice (Mus musculus Balb/C males). LD50 values are 5-14 mg of lyophilized crude venom per 1 kg (i.v.). The major symptoms of envenomation include tonic-clonic seizures, jerks, characteristic motor stereotypy, and hyperalgesia and point to voltage-gated sodium channels as a potential target of the venom components. Poecilotheria fasciata venom effects were studied in detail at a sub-lethal dose of 5 mg/kg (LD50 = 12 mg/kg). 13 widely used pharmacological agents (atropine, chloropyramine, chlorpromazine, diazepam, ethanol, flupirtine, haloperidol, ketotifen, lamotrigine, oxcarbazepine, tolperisone, xylazine, and CaCl2) were checked for ability to suppress the envenomation symptoms. Chlorpromazine (10 mg/kg, i.p.), oxcarbazepine (60 mg/kg, p.o.), tolperisone (50 mg/kg, s.c.) and xylazine (2.5 mg/kg, i.p.) were found effective as a pretreatment to mitigate muscle cramps and motor stereotypy. When administered after envenomation chlorpromazine (5 mg/kg, i.v.) effectively reduced the cramps, while oxcarbazepine (30 mg/kg, i.v.) and xylazine (1 mg/kg, i.v.) suppressed the stereotypy. PMID- 28811248 TI - Development of an elisa for the diagnosis of reactive IgE antibodies anti therapeutic horse sera. AB - Hypersensitive diseases that involve IgE reactivity are important concern of public, especially those encompassing the potential pathogenesis from the administration of horse serum-based therapeutics such as antivenoms. A method for the definitive diagnosis of reactive IgE is important for identifying allergic patients to control severe collateral effects during planned and emergency application of immunotherapies when the allergy source cannot be avoided for treatment. To date, no tests have been developed to accompany the wide range of antivenoms produced from horse sera. The aim of this was to develop a cost effective ELISA of high sensitivity and specificity to detect circulating patient IgE that binds horse IgG3, the most prevalent antibody class in passive antibody therapies. Horse IgG3 was purified in a single step on jacalin-Sepharose and absorbed to standard ELISA plates as the capture molecule for reactive human IgE. The direct performance evaluation with allergenic and non-allergenic patient, together with competitive peptides assays, showed high sensitivity and specificity to detect human IgE that recognized horse IgG3. The analytical sensitivity and ED50 were calculated to be 0.01 MUg mL-1 and 0.052 MUg mL-1, respectively. The intra- and inter-assay coefficient of variation ranged from 3.3 to 11.1% and 4.0-8.0%, respectively. The horse IgG3-based ELISA assay can detect reactive allergenic IgE at picomolar concentrations. The coefficient of variation suggests that it can be easily standardized between laboratories, provide rapid and can be applied to population surveillance. Patient management during treatment for envenomation would be greatly improved by a robust and reliable diagnostic test for preexisting allergies to mitigate life-threating consequences of hypersensitivity. PMID- 28811249 TI - Male-specific pulmonary hemorrhage and cytokine gene expression in golden hamster in early-phase Leptospira interrogans serovar Hebdomadis infection. AB - Leptospirosis causes severe clinical signs more frequently in men than in women, but the mechanism underlying the gender differences in leptospirosis remains unclear. In this study, petechial hemorrhage was observed in male but not in female hamster lung tissues infected with Leptospira interrogans serovar Hebdomadis at 120 h pi, demonstrating that male hamsters were more susceptible to the development of a severe disease upon Leptospira infection. No leptospiral DNA was detected in the lung tissues at 120 h pi when pulmonary hemorrhage was observed, indicating that pulmonary hemorrhage is attributable to the immune reactions of the host rather than from the direct effect of leptospires. The upregulation of nitric oxide synthase genes in the hamsters without pulmonary hemorrhage, inos and enos in female hamsters at 96 h pi and enos in male animals without hemorrhage at 120 h pi, may suggest that nitric oxide has a suppressive effect on leptospirosis-associated pulmonary hemorrhage. PMID- 28811250 TI - Deficiency in perilipin 5 reduces mitochondrial function and membrane depolarization in mouse hearts. AB - Myocardial triglycerides stored in lipid droplets are important in regulating the intracellular delivery of fatty acids for energy generation in mitochondria, for membrane biosynthesis, and as agonists for intracellular signaling. Previously, we showed that deficiency in the lipid droplet protein perilipin 5 (Plin5) markedly reduces triglyceride storage in cardiomyocytes and increases the flux of fatty acids into phospholipids. Here, we investigated whether Plin5 deficiency in cardiomyocytes alters mitochondrial function. We found that Plin5 deficiency reduced mitochondrial oxidative capacity. Furthermore, in mitochondria from Plin5 /- hearts, the fatty acyl composition of phospholipids in mitochondrial membranes was altered and mitochondrial membrane depolarization was markedly compromised. These findings suggest that mitochondria isolated from hearts deficient in Plin5, have specific functional defects. PMID- 28811251 TI - Deletion in HSP110 T17: correlation with wild-type HSP110 expression and prognostic significance in microsatellite-unstable advanced gastric cancers. AB - Deletion of the HSP110 T17 mononucleotide repeat has recently been identified as a prognostic marker that is correlated with wild-type HSP110 (HSP110wt) expression in microsatellite instability-high (MSI-H) colorectal cancers. The aim of this study was to assess the correlation between deletion of the HSP110 T17 repeat and expression of HSP110wt using DNA testing and immunohistochemistry and to determine the prognostic implications of HSP110 T17 deletion in MSI-H advanced gastric cancers (GCs). The status of HSP110wt expression was evaluated by immunohistochemistry using an HSP110wt-specific antibody in 142 MSI-H advanced GCs. The size of the HSP110 T17 repeat deletion was analyzed in 96 MSI-H advanced GCs; deletions were divided into small (0-2base pairs) and large deletions (3 5base pairs). Low and high expressions of HSP110wt were detected in 38 (26.8%) and 104 (73.2%) of the 142 cases, respectively. The HSP110 T17 deletion was observed in 45 (46.9%) of the 96 MSI-H GC samples. Tumors with high expression of HSP110wt showed a tendency to have small or no deletion of HSP110 T17. In Kaplan Meier survival analysis, tumors with a large HSP110 T17 deletion were associated with favorable overall survival and disease-free survival compared with those with small/no deletion of HSP110 T17. However, HSP110 T17 deletion size was not an independent prognostic factor in multivariate analysis. In summary, deletion of the HSP110 T17 repeat was frequently observed in MSI-H GCs, and HSP110 T17 deletion size was inversely correlated with HSP110wt expression status. Large HSP110 T17 was not a prognostic indicator in MSI-H GCs. PMID- 28811252 TI - Expression of ALCAM (CD166) and PD-L1 (CD274) independently predicts shorter survival in malignant pleural mesothelioma. AB - Diffuse malignant mesothelioma of the pleura is a highly aggressive tumor typically associated with short survival. ALCAM (CD166), a type I transmembrane protein, is a member of the immunoglobulin superfamily. In normal cells, ALCAM regulates physiological processes such as angiogenesis and immune response. In cancer, it is associated with neoplastic progression, including invasion, migration, and metastasis. Furthermore, ALCAM is considered one of the cancer stem cell markers such as ALDH1 (ALDH1A1) and SALL4. The PD-L1 (CD274)/PD-1 (PDCD1, CD279) pathway is crucial for the modulation of immune responses in normal cells. Nevertheless, pathologic activation of the PD-L1/PD-1 pathway participates in immune evasion by tumor cells. Many PD-L1-expressing tumor cells have been identified in different types of cancer, including malignant mesothelioma. In this study, 175 well-characterized primary diffuse pleural mesotheliomas, including the epithelioid (n = 148), biphasic (n = 15), and sarcomatoid (n = 12) histotypes, were evaluated immunohistochemically for cancer stem cell markers (ALCAM, ALDH1, and SALL4) and PD-L1 expression. Twenty-five percent of the mesotheliomas (43/175) expressed ALCAM, whereas ALDH1 and SALL4 positivity was seen in 1% to 2% of cases. Thirty-three percent of the analyzed tumors (57/175) contained PD-L1-positive cells. Overall survival was significantly decreased in the cohort of patients with ALCAM- or PD-L1-positive tumors (both P < .01). Furthermore, the multivariate Cox hazards regression analysis identified ALCAM and PD-L1 (both P < 0.01) as potential independent risk factors. Thus, a combination of these 2 markers might be useful for prognostication and planning the treatment of patients with malignant pleural mesothelioma. PMID- 28811253 TI - MicroRNAs, promising biomarkers in the diagnosis of Xp11 translocation RCC-reply. PMID- 28811254 TI - Parsing the neural signatures of reduced error detection in older age. AB - Recent work has demonstrated that explicit error detection relies on a neural evidence accumulation process that can be traced in the human electroencephalogram (EEG). Here, we sought to establish the impact of natural aging on this process by recording EEG from young (18-35 years) and older adults (65-88 years) during the performance of a Go/No-Go paradigm in which participants were required to overtly signal their errors. Despite performing the task with equivalent accuracy, older adults reported substantially fewer errors, and the timing of their reports were both slower and more variable. These behavioral differences were linked to three key neurophysiological changes reflecting distinct parameters of the error detection decision process: a reduction in medial frontal delta/theta (2-7 Hz) activity, indicating diminished top-down input to the decision process; a slower rate of evidence accumulation as indexed by the rate of rise of a centro-parietal signal, known as the error positivity; and a higher motor execution threshold as indexed by lateralized beta-band (16-30 Hz) activity. Our data provide novel insight into how the natural aging process affects the neural underpinnings of error detection. PMID- 28811255 TI - Cortical layers: Cyto-, myelo-, receptor- and synaptic architecture in human cortical areas. AB - Cortical layers have classically been identified by their distinctive and prevailing cell types and sizes, as well as the packing densities of cell bodies or myelinated fibers. The densities of multiple receptors for classical neurotransmitters also vary across the depth of the cortical ribbon, and thus determine the neurochemical properties of cyto- and myeloarchitectonic layers. However, a systematic comparison of the correlations between these histologically definable layers and the laminar distribution of transmitter receptors is currently lacking. We here analyze the densities of 17 different receptors of various transmitter systems in the layers of eight cytoarchitectonically identified, functionally (motor, sensory, multimodal) and hierarchically (primary and secondary sensory, association) distinct areas of the human cerebral cortex. Maxima of receptor densities are found in different layers when comparing different cortical regions, i.e. laminar receptor densities demonstrate differences in receptorarchitecture between isocortical areas, notably between motor and primary sensory cortices, specifically the primary visual and somatosensory cortices, as well as between allocortical and isocortical areas. Moreover, considerable differences are found between cytoarchitectonical and receptor architectonical laminar patterns. Whereas the borders of cyto- and myeloarchitectonic layers are well comparable, the laminar profiles of receptor densities rarely coincide with the histologically defined borders of layers. Instead, highest densities of most receptors are found where the synaptic density is maximal, i.e. in the supragranular layers, particularly in layers II-III. The entorhinal cortex as an example of the allocortex shows a peculiar laminar organization, which largely deviates from that of all the other cortical areas analyzed here. PMID- 28811256 TI - Cognitive estimation: Performance of patients with focal frontal and posterior lesions. AB - The Cognitive Estimation Test (CET) is a widely used test to investigate estimation abilities requiring complex processes such as reasoning, the development and application of appropriate strategies, response plausibility checking as well as general knowledge and numeracy (e.g., Shallice and Evans, 1978; MacPherson et al., 2014). Thus far, it remains unknown whether the CET is both sensitive and specific to frontal lobe dysfunction. Neuroimaging techniques may not represent a useful methodology for answering this question since the complex processes involved are likely to be associated with a large network of brain regions, some of which are not functionally necessary to successfully carry out the CET. Instead, neuropsychological studies may represent a more promising investigation tool for identifying the brain areas necessary for CET performance. We recently developed two new versions of the CET (CET-A and CET-B; MacPherson et al., 2014). We investigated the overall performance and conducted an error analysis on CET-A in patients with focal, unilateral, frontal (n = 38) or posterior (n = 22) lesions and healthy controls (n = 39). We found that frontal patients' performance was impaired compared to healthy controls on CET. We also found that frontal patients generated significantly poorer estimates than posterior patients on CET-A. This could not be explained by impairments in fluid intelligence. The error analyses suggested that for CET-A, extreme and very extreme responses are impaired following frontal lobe damage. However, only very extreme responses are significantly more impaired following frontal lobe than posterior damage and so represent a measure restricted to frontal "executive" impairment, in addition to overall CET performance. PMID- 28811258 TI - Category-selective human brain processes elicited in fast periodic visual stimulation streams are immune to temporal predictability. AB - Recording direct neural activity when periodically inserting exemplars of a particular category in a rapid visual stream of other objects offers an objective and efficient way to quantify perceptual categorization and characterize its spatiotemporal dynamics. However, since periodicity entails predictability, perceptual categorization processes identified within this framework may be partly generated or modulated by temporal expectations. Here we present a stringent test of the hypothesis that temporal predictability generates or modulates category-selective neural processes as measured in a rapid periodic visual stimulation stream. In Experiment 1, we compare neurophysiological responses to periodic and nonperiodic (i.e., unpredictable) variable face stimuli in a fast (12Hz) visual stream of nonface objects. In Experiment 2, we assess potential responses to rare (10%) omissions of periodic face events (i.e., violations of periodicity) in the same fast visual stream. Overall, our observations indicate that category(face)-selective processes elicited in a fast periodic stream of visual objects are immune to temporal predictability. These observations do not support a predictive coding framework interpretation of category-change detection in the human brain and have important implications for understanding automatic human perceptual categorization in a rapidly changing (i.e., dynamic) visual scene. PMID- 28811257 TI - Auditory conflict and congruence in frontotemporal dementia. AB - Impaired analysis of signal conflict and congruence may contribute to diverse socio-emotional symptoms in frontotemporal dementias, however the underlying mechanisms have not been defined. Here we addressed this issue in patients with behavioural variant frontotemporal dementia (bvFTD; n = 19) and semantic dementia (SD; n = 10) relative to healthy older individuals (n = 20). We created auditory scenes in which semantic and emotional congruity of constituent sounds were independently probed; associated tasks controlled for auditory perceptual similarity, scene parsing and semantic competence. Neuroanatomical correlates of auditory congruity processing were assessed using voxel-based morphometry. Relative to healthy controls, both the bvFTD and SD groups had impaired semantic and emotional congruity processing (after taking auditory control task performance into account) and reduced affective integration of sounds into scenes. Grey matter correlates of auditory semantic congruity processing were identified in distributed regions encompassing prefrontal, parieto-temporal and insular areas and correlates of auditory emotional congruity in partly overlapping temporal, insular and striatal regions. Our findings suggest that decoding of auditory signal relatedness may probe a generic cognitive mechanism and neural architecture underpinning frontotemporal dementia syndromes. PMID- 28811259 TI - Should I trust you? Learning and memory of social interactions in dementia. AB - Social relevance has an enhancing effect on learning and subsequent memory retrieval. The ability to learn from and remember social interactions may impact on susceptibility to financial exploitation, which is elevated in individuals with dementia. The current study aimed to investigate learning and memory of social interactions, the relationship between performance and financial vulnerability and the neural substrates underpinning performance in 14 Alzheimer's disease (AD) and 20 behavioural-variant frontotemporal dementia (bvFTD) patients and 20 age-matched healthy controls. On a "trust game" task, participants invested virtual money with counterparts who acted either in a trustworthy or untrustworthy manner over repeated interactions. A non-social "lottery" condition was also included. Participants' learning of trust/distrust responses and subsequent memory for the counterparts and nature of the interactions was assessed. Carer-rated profiles of financial vulnerability were also collected. Relative to controls, both patient groups showed attenuated learning of trust/distrust responses, and lower overall memory for social interactions. Despite poor learning performance, both AD and bvFTD patients showed better memory of social compared to non-social interactions. Importantly, better memory for social interactions was associated with lower financial vulnerability in AD, but not bvFTD. Learning and memory of social interactions was associated with medial temporal and temporoparietal atrophy in AD, whereas a wider network of frontostriatal, insular, fusiform and medial temporal regions was implicated in bvFTD. Our findings suggest that although social relevance influences memory to an extent in both AD and bvFTD, this is associated with vulnerability to financial exploitation in AD only, and is underpinned by changes to different neural substrates. Theoretically, these findings provide novel insights into potential mechanisms that give rise to vulnerability in people with dementia, and open avenues for possible interventions. PMID- 28811260 TI - Cophylogenetic analyses reveal extensive host-shift speciation in a highly specialized and host-specific symbiont system. AB - Host-shift speciation and cospeciation are the two major processes driving symbiont macroevolutionary diversification. Cospeciation is expected to be frequent in vertically transmitted and host-specific symbionts, and leads to congruent host-symbiont phylogenies. However, the cophylogenetic dynamics of many groups of highly specialized host-specific symbionts is largely unstudied. Thus, the relevance of cospeciation vs. host-shift speciation remains largely unknown. Here, we investigated this question by performing the largest cophylogenetic study of feather mites to date, using both distance and event-based cophylogenetic methods. For these analyses, we inferred phylogenies based on all protein coding genes of the mitochondrial genome of Proctophyllodes and Trouessartia feather mite species living on European passerine birds. Results show high incongruence among bird and feather mite phylogenies, because of extensive host-switching. We conclude that host-shift speciation, rather than cospeciation, may be the main driver of symbiont diversification even for highly specialized symbionts with low host-switching potential. PMID- 28811261 TI - Mechanosensing: From proteins to tissues. PMID- 28811262 TI - Probe microscopy methods and applications in imaging of biological materials. AB - Atomic force microscopy is an emerging tool for investigating the biomolecular aspects of cellular interactions; however, cell and tissue analyses must frequently be performed in aqueous environment, over rough surfaces, and on complex adhesive samples that complicate the imaging process and readily facilitate the blunting or fouling of the AFM probe. In addition, the shape and surface chemistry of the probe determine the quality and types of data that can be acquired from biological materials, with certain information becoming available only within a specific range of tip lengths or diameters, or through the assistance of specific chemical or biological functionalization procedures. Consequently, a broad range of probe modification techniques has been developed to extend the capabilities and overcome the limitations of biological AFM measurements, including the fabrication of AFM tips with specialized morphologies, surface coating with biologically affine molecules, and the attachment of proteins, nucleic acids and cells to AFM probes. In this review, we underline the importance of probe choice and modification for the AFM analysis of biomaterials, discuss the recent literature on the use of non-standard AFM tips in life sciences research, and consider the future utility of tip functionalization methods for the investigation of fundamental cell and tissue interactions. PMID- 28811263 TI - The role of ESCRT during development and functioning of the nervous system. AB - The endosomal sorting complex required for transport (ESCRT) is made of subcomplexes (ESCRT 0-III), crucial to membrane remodelling at endosomes, nuclear envelope and cell surface. ESCRT-III shapes membranes and in most cases cooperates with the ATPase VPS4 to mediate fission of membrane necks from the inside. The first ESCRT complexes mainly serve to catalyse the formation of ESCRT III but can be bypassed by accessory proteins like the Alg-2 interacting protein X (ALIX). In the nervous system, ALIX/ESCRT controls the survival of embryonic neural progenitors and later on the outgrowth and pruning of axons and dendrites, all necessary steps to establish a functional brain. In the adult brain, ESCRTs allow the endosomal turn over of synaptic vesicle proteins while stable ESCRT complexes might serve as scaffolds for the postsynaptic parts. The necessity of ESCRT for the harmonious function of the brain has its pathological counterpart, the mutations in CHMP2B of ESCRT-III giving rise to several neurodegenerative diseases. PMID- 28811264 TI - Protein coding genes as hosts for noncoding RNA expression. AB - With the emergence of high-throughput sequence characterization methods and the subsequent improvements in gene annotations, it is becoming increasingly clear that a large proportion of eukaryotic protein-coding genes (as many as 50% in human) serve as host genes for non-coding RNA genes. Amongst the most extensively characterized embedded non-coding RNA genes, small nucleolar RNAs and microRNAs represent abundant families. Encoded individually or clustered, in sense or antisense orientation with respect to their host and independently expressed or dependent on host expression, the genomic characteristics of embedded genes determine their biogenesis and the extent of their relationship with their host gene. Not only can host genes and the embedded genes they harbour be co-regulated and mutually modulate each other, many are functionally coupled playing a role in the same cellular pathways. And while host-non-coding RNA relationships can be highly conserved, mechanisms have been identified, and in particular an association with transposable elements, allowing the appearance of copies of non coding genes nested in host genes, or the migration of embedded genes from one host gene to another. The study of embedded non-coding genes and their relationship with their host genes increases the complexity of cellular networks and provides important new regulatory links that are essential to properly understand cell function. PMID- 28811265 TI - Molecular cloning, heterologous expression and functional characterization of gamma tocopherol methyl transferase (gamma-TMT) from Glycine max. AB - gamma-Tocopherol methyltransferase (gamma-TMT) (EC 2.1.1.95) is the last enzyme in the tocopherol biosynthetic pathway and it catalyzes the conversion of gamma tocopherol into alpha-tocopherol, the nutritionally significant and most bioactive form of vitamin E. Although the gamma-TMT gene has been successfully overexpressed in many crops to enhance their alpha-tocopherol content but still only few attempts have been made to uncover its structural, functional and regulation aspects at protein level. In this study, we have cloned the complete 909bp coding sequence of Glycine max gamma-TMT (Gm gamma-TMT) gene that encodes the corresponding protein comprising of 302 amino acid residues. The deduced Gm gamma-TMT protein showed 74-87% sequence identity with other characterized plant gamma-TMTs. Gm gamma-TMT belongs to Class I Methyl Transferases that have a Rossmann-like fold which consists of a seven-stranded beta sheet joined by alpha helices. Heterologous expression of Gm gamma-TMT in pET29a expression vector under the control of bacteriophage T7 promoter produced a 37.9 kDa recombinant Gm gamma-TMT protein with histidine hexamer tag at its C-terminus. The expression of recombinant Gm gamma-TMT protein was confirmed by western blotting using anti-His antibody. The recombinant protein was purified by Ni2+-NTA column chromatography. The purified protein showed SAM dependent methyltransferase activity. The alpha tocopherol produced in the in-vitro reaction catalyzed by the purified enzyme was detected using reverse phase HPLC. This study has laid the foundation to unveil the biochemical understanding of Gm gamma-TMT enzyme which can be further explored by studying its kinetic behaviour, substrate specificity and its interaction with other biomolecules. PMID- 28811266 TI - Expression and purification of a difficult sarcomeric protein: Telethonin. AB - Telethonin anchors the N-terminal region of titin in the Z-disk of the sarcomere by binding to two immunoglobulin-like (Ig) domains (Z1 and Z2) of titin (Z1Z2). Thereby telethonin plays an important role in myofibril assembly and in muscle development and functional regulation. The expression and purification of recombinant telethonin is very challenging. In previous studies, recombinant telethonin expressed from E. coli was refolded in the presence of Z1Z2. Here, we report various strategies to establish a reliable and efficient protocol for the preparation of telethonin and titin Z1Z2 protein. First, a co-expression strategy was designed to obtain soluble Z1Z2/telethonin complexes. The concentration of antibiotics and the type of expression vector were found to be important for achieving high yields of purified complex. Second, the five cysteine residues of telethonin were mutated to serine to avoid severe problems with cysteine oxidation. Third, a short version of telethonin (telethonin1-90) was designed to avoid the proteolytic degradation observed for longer constructs of the protein. The short telethonin formed a highly stable complex with Z1Z2 with no degradation being observed for 30 days at 4 degrees C. Fourth, an improved refolding protocol was developed to achieve high yields of Z1Z2/telethonin complex. Finally, based on the crystal structure in which Z1Z2 and telethonin1-90 assemble into a 2:1 complex, a single chain fusion protein was designed, comprising two Z1Z2 modules that are connected by flexible linkers N- and C-terminally of the telethonin1-90. Expression of this fusion protein, named ZTZ, affords high yields of soluble expressed and purified protein. PMID- 28811268 TI - Antecedent ADHD, dementia, and metabolic dysregulation: A U.S. based cohort analysis. AB - INTRODUCTION: Epidemiological and genetic studies have reported a link between antecedent ADHD and dementia. The underpinning mechanisms of these associations are not known and have generated considerable speculation. METHODS: We have extracted hospitalization discharge data on dementia and ADHD (representing a severe phenotype) from the Healthcare Cost and Utilization Project (HCUPnet) and utilized a Poisson regression with two-ways fixed effects to investigate this association. RESULTS: An unadjusted ten-year lagged measure of a severe ADHD phenotype increases hospitalization risk for an all-listed Lewy Body Dementia (LBD) diagnosis (IRR: 1.21, 95% C.I. 1.08-1.35) and Alzheimer's disease (AD) discharge diagnosis (IRR: 1.15, 95% C.I.: 1.05-1.27). However, these relationships may be dependent upon the extent of metabolic dysregulation in a subtype-specific manner, as controlling for diabetes removes the significant association between antecedent ADHD and risk of AD but not LBD. DISCUSSION: These results indicate that the association between antecedent ADHD and dementia risk may be uniquely influenced by metabolic dysregulation, building upon prior discussion in this journal of a purported link between AD and diabetes. We tie the current findings to environmental risk factors that we have previously implicated in the etiology of ADHD to generate testable hypotheses on the underlying brain neurochemistry that may facilitate the link between metabolic dysregulation and dementia subtype risk. PMID- 28811269 TI - Point-of-Sale Tobacco Advertising and Display Bans: Policy Evaluation Study in Five Russian Cities. AB - BACKGROUND: The tobacco industry uses point-of-sale (POS) advertising, promotion, and product display to increase consumption of its products among current users, to attract new consumers, and to encourage former customers to resume tobacco use. As part of a comprehensive tobacco control effort, Russia-having one of the highest tobacco use prevalence rates in the world-enacted legislation that banned tobacco POS advertising, effective November 15, 2013, and banned the display of tobacco and the sale of cigarettes in kiosks, effective June 1, 2014. OBJECTIVE: The objective of the study was to evaluate the implementation of the national law by assessing the state of POS advertising, promotion, and product display, and sales in kiosks across Russia. METHODS: Two waves of observations were conducted to measure compliance with the POS restrictions: wave 1 took place in April-May 2014 after the advertising ban was in effect and again in August-September 2014 after the display ban and elimination of tobacco sales in kiosks came into effect. Observations were conducted by local trained staff that traveled to 5 populous cities in different regions of Russia (Moscow, St. Petersburg, Kazan, Ekaterinburg, and Novosibirsk). Staff followed a published POS evaluation protocol and used mobile phones to collect data. Observations were conducted in a roughly equal number of supermarket chains, convenience stores, and kiosks. Observed items included advertising at POS, product displays, and cigarette sales in kiosks. RESULTS: Observations were made in 780 venues in wave 1 and in 779 revisited venues in wave 2. In wave 1, approximately a third of supermarkets and convenience stores (34.2%, 184/538) were advertising cigarettes using light boxes, and over half of observed venues (54.3%, 292/538) had signage such as banners or shelf liners that used colors or images related to cigarette brands. Product displays were common in wave 1. In wave 2, compliance with advertising restrictions was very good: there were virtually no light boxes (1.0%, 5/489); banners or shelf liners were observed in 30.5% (149/489) of supermarkets/convenience stores; approximately 7.4% (36/489) of venues were still displaying products in a powerwall. In wave 2, 41.3% (100/242) of kiosks continued to sell tobacco. CONCLUSIONS: Russia's compliance with POS bans was excellent. Remaining compliance issues are largely with the use of cigarette brand colors or images used in banners or shelf liners; this type of infraction is more difficult to enforce as inspectors need to be deeply familiar with tobacco industry products and marketing practices. A sizable proportion of kiosks continue to sell tobacco post restrictions. PMID- 28811270 TI - Developing and Evaluating JIApp: Acceptability and Usability of a Smartphone App System to Improve Self-Management in Young People With Juvenile Idiopathic Arthritis. AB - BACKGROUND: Flare-ups in juvenile idiopathic arthritis (JIA) are characterized by joint pain and swelling and often accompanied with fatigue, negative emotions, and reduced participation in activities. To minimize the impact of JIA on the physical and psychosocial development and well-being of young people (YP), it is essential to regularly monitor disease activity and side effects, as well as to support self-management such as adherence to treatment plans and engagement in general health-promoting behaviors. Smartphone technology has the potential to engage YP with their health care through convenient self-monitoring and easy access to information. In addition, having a more accurate summary of self reported fluctuations in symptoms, behaviors, and psychosocial problems can help both YP and health care professionals (HCPs) better understand the patient's condition, identify barriers to self-management, and assess treatment effectiveness and additional health care needs. No comprehensive smartphone app has yet been developed in collaboration with YP with JIA, their parents, and HCPs involved in their care. OBJECTIVES: The objective of this study was to design, develop, and evaluate the acceptability and usability of JIApp, a self-management smartphone app system for YP with JIA and HCPs. METHODS: We used a qualitative, user-centered design approach involving YP, parents, and HCPs from the rheumatology team. The study was conducted in three phases: (1) phase I focused on developing consensus on the features, content, and design of the app; (2) phase II was used for further refining and evaluating the app prototype; and (3) phase III focused on usability testing of the app. The interview transcripts were analyzed using qualitative content analysis. RESULTS: A total of 29 YP (aged 10 23, median age 17) with JIA, 7 parents, and 21 HCPs were interviewed. Major themes identified as the ones that helped inform app development in phase I were: (1) remote monitoring of symptoms, well-being, and activities; (2) treatment adherence; and (3) education and support. During phase II, three more themes emerged that informed further refinement of the app prototype. These included (4) adapting a reward system to motivate end users for using the app; (5) design of the app interface; and (6) clinical practice integration. The usability testing during phase III demonstrated high rates of overall satisfaction and further affirmed the content validity of the app. CONCLUSIONS: We present the development and evaluation of a smartphone app to encourage self-management and engagement with health care for YP with JIA. The app was found to have high levels of acceptability and usability among YP and HCPs and has the potential to improve health care and outcomes for this age group. Future feasibility testing in a prospective study will firmly establish the reliability, efficacy, and cost effectiveness of such an app intervention for patients with arthritis. PMID- 28811272 TI - Sex robots: the irreplaceable value of humanity. PMID- 28811267 TI - APP/Abeta structural diversity and Alzheimer's disease pathogenesis. AB - The amyloid cascade hypothesis of Alzheimer's disease (AD) proposes amyloid- beta (Abeta) is a chief pathological element of dementia. AD therapies have targeted monomeric and oligomeric Abeta 1-40 and 1-42 peptides. However, alternative APP proteolytic processing produces a complex roster of Abeta species. In addition, Abeta peptides are subject to extensive posttranslational modification (PTM). We propose that amplified production of some APP/Abeta species, perhaps exacerbated by differential gene expression and reduced peptide degradation, creates a diverse spectrum of modified species which disrupt brain homeostasis and accelerate AD neurodegeneration. We surveyed the literature to catalog Abeta PTM including species with isoAsp at positions 7 and 23 which may phenocopy the Tottori and Iowa Abeta mutations that result in early onset AD. We speculate that accumulation of these alterations induce changes in secondary and tertiary structure of Abeta that favor increased toxicity, and seeding and propagation in sporadic AD. Additionally, amyloid-beta peptides with a pyroglutamate modification at position 3 and oxidation of Met35 make up a substantial portion of sporadic AD amyloid deposits. The intrinsic physical properties of these species, including resistance to degradation, an enhanced aggregation rate, increased neurotoxicity, and association with behavioral deficits, suggest their emergence is linked to dementia. The generation of specific 3D-molecular conformations of Abeta impart unique biophysical properties and a capacity to seed the prion-like global transmission of amyloid through the brain. The accumulation of rogue Abeta ultimately contributes to the destruction of vascular walls, neurons and glial cells culminating in dementia. A systematic examination of Abeta PTM and the analysis of the toxicity that they induced may help create essential biomarkers to more precisely stage AD pathology, design countermeasures and gauge the impacts of interventions. PMID- 28811271 TI - "Am I normal?" The Wishes of Patients With Lymphoma to Compare Their Patient Reported Outcomes With Those of Their Peers. AB - BACKGROUND: Providing feedback to patients on their patient-reported outcomes (PROs) can help patients in monitoring their functioning and symptoms and may help empower them. OBJECTIVE: The objective of this study was to investigate whether patients with lymphoma wished to receive PRO feedback, including the option to compare their scores with those of their peers, and how this feedback was evaluated. METHODS: We invited 64 patients participating in a lymphoma cohort who were eligible for a follow-up questionnaire and gave them the option to receive PRO feedback. Patients completed questions about health-related quality of life (HRQoL) and symptoms. PRO feedback was provided via bar charts. RESULTS: Of the 64 invited patients, 45 participated (response rate 70%) and 36 of those (80%) wished to receive PRO feedback. The vast majority (34/36, 94%) compared their scores with those of a lymphoma reference cohort, and 64% (23/36) compared their score with those of a normative population without cancer. All patients wished to receive feedback on their HRQoL, and 29 (81%) to 33 (92%) wanted feedback on their functioning, fatigue, neuropathy, anxiety, and depressive symptoms. Of the 36 participants wishing to receive PRO feedback, 35 (97%) viewed it as being useful, with reassurance and knowledge about their own functioning in relation to what is "normal" being the most frequently mentioned reasons. CONCLUSIONS: A high number of patients with lymphoma wished to receive PRO feedback. Patients reported the comparison of their scores versus a lymphoma reference cohort as most valuable. Further research should investigate whether PRO feedback could increase empowerment and possibly improve HRQoL. PMID- 28811273 TI - Private GP who ran autism clinic is banned from seeing patients pending investigation. PMID- 28811275 TI - Health Education England asks doctors for input on ARCPs. PMID- 28811276 TI - Is it possible to recruit 21 000 extra staff for mental health services? PMID- 28811274 TI - Hypoxia in Combination With Muscle Contraction Improves Insulin Action and Glucose Metabolism in Human Skeletal Muscle via the HIF-1alpha Pathway. AB - Skeletal muscle insulin resistance is the hallmark of type 2 diabetes and develops long before the onset of the disease. It is well accepted that physical activity improves glycemic control, but the knowledge on underlying mechanisms mediating the beneficial effects remains incomplete. Exercise is accompanied by a decrease in intramuscular oxygen levels, resulting in induction of HIF-1alpha. HIF-1alpha is a master regulator of gene expression and might play an important role in skeletal muscle function and metabolism. Here we show that HIF-1alpha is important for glucose metabolism and insulin action in skeletal muscle. By using a genome-wide gene expression profiling approach, we identified RAB20 and TXNIP as two novel exercise/HIF-1alpha-regulated genes in skeletal muscle. Loss of Rab20 impairs insulin-stimulated glucose uptake in human and mouse skeletal muscle by blocking the translocation of GLUT4 to the cell surface. In addition, exercise/HIF-1alpha downregulates the expression of TXNIP, a well-known negative regulator of insulin action. In conclusion, we are the first to demonstrate that HIF-1alpha is a key regulator of glucose metabolism in skeletal muscle by directly controlling the transcription of RAB20 and TXNIP These results hint toward a novel function of HIF-1alpha as a potential pharmacological target to improve skeletal muscle insulin sensitivity. PMID- 28811277 TI - David Oliver: In support of acute internal medicine. PMID- 28811278 TI - Lipodystrophic laminopathy: Lamin A mutation relaxes chromatin architecture to impair adipogenesis. AB - The familial partial Dunnigan lipodystrophy, characterized by subcutaneous fat loss, is frequently caused by an R482W mutation in lamin A. In this issue, Oldenburg et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201701043) demonstrate that this mutation impairs the ability of lamin A to repress the anti adipogenic miR-335, providing a potential molecular mechanism for the disease. PMID- 28811279 TI - Zebrafish earns its stripes for in vivo ASC speck dynamics. AB - Assembly of the ASC speck is critical for signaling by the inflammasome. In this issue, Kuri et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201703103) use live microscopy to track fluorescently tagged endogenous ASC in the zebrafish, describing the molecular domains driving ASC speck assembly and identifying a key role for macrophages in ASC speck removal in vivo. PMID- 28811281 TI - Multimorbidity, dementia and health care in older people:a population-based cohort study. AB - BACKGROUND: Little is known about how multimorbidity, dementia and increasing age combine to influence health outcomes or utilization. Our objective was to examine the joint associations between age, dementia and burden of morbidity with mortality and other clinical outcomes. METHODS: We did a retrospective population based cohort study of all adults aged 65 years and older residing in Alberta, Canada, between 2002 and 2013. We used validated algorithms applied to administrative and laboratory data from the provincial health ministry to assess the presence/absence of dementia and 29 other morbidities, and their associations with mortality (our primary outcome), other clinical outcomes (emergency department visits, all-cause hospital admissions) and a proxy for loss of independent living (discharge to long-term care). Cox and Poisson models were adjusted for year-varying covariates. A 3-way interaction was modelled for dementia, the number of comorbidities, and age. RESULTS: There were 610 457 adults aged 65 years and older living in Alberta over the study period. Over median follow-up of 6.8 years, 153 125 (25.1%) participants died and 5569 (0.9%) were discharged to long-term care. The prevalence of people with at least 3 morbidities was 33.7% in 2003 and 50.2% in 2012. The prevalence of dementia rose from 6.2% in fiscal year 2003 to 8.3% in fiscal year 2012, representing a net increase of approximately 13 700 people. The likelihood of all 4 outcomes increased with age and with greater burden of morbidity; the presence of dementia further increased these risks. For example, the risk of mortality increased by 1.54 to 6.38 in the presence of dementia, depending on age and morbidity burden. The risk associated with dementia was attenuated by increasing comorbidity. INTERPRETATION: Older age, multimorbidity and dementia are all strongly correlated with adverse health outcomes as well as a proxy for loss of independent living. The increasing prevalences of dementia and multimorbidity over time suggest the need for coordinated national strategies aimed at mitigating the health challenges associated with the aging of the population. PMID- 28811282 TI - Empathy, please! PMID- 28811280 TI - DAN (NBL1) promotes collective neural crest migration by restraining uncontrolled invasion. AB - Neural crest cells are both highly migratory and significant to vertebrate organogenesis. However, the signals that regulate neural crest cell migration remain unclear. In this study, we test the function of differential screening selected gene aberrant in neuroblastoma (DAN), a bone morphogenetic protein (BMP) antagonist we detected by analysis of the chick cranial mesoderm. Our analysis shows that, before neural crest cell exit from the hindbrain, DAN is expressed in the mesoderm, and then it becomes absent along cell migratory pathways. Cranial neural crest and metastatic melanoma cells avoid DAN protein stripes in vitro. Addition of DAN reduces the speed of migrating cells in vivo and in vitro, respectively. In vivo loss of function of DAN results in enhanced neural crest cell migration by increasing speed and directionality. Computer model simulations support the hypothesis that DAN restrains cell migration by regulating cell speed. Collectively, our results identify DAN as a novel factor that inhibits uncontrolled neural crest and metastatic melanoma invasion and promotes collective migration in a manner consistent with the inhibition of BMP signaling. PMID- 28811284 TI - Patients being put at risk from unfilled out-of-hours shifts, GPs warn. PMID- 28811283 TI - Prognosis and Its Predictors After Incident Stroke in Patients With Type 1 Diabetes. AB - OBJECTIVE: Although patients with type 1 diabetes have a poor prognosis after a stroke, predictors of survival after an incident stroke in these patients are poorly studied. RESEARCH DESIGN AND METHODS: In this observational study, a total of 144 patients of 4,083 with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study suffered an incident stroke in 1997-2010, and were followed for a mean 3.4 +/- 3.1 years after the stroke. Information was recorded on hard cardiovascular events and death as a result of cardiovascular or diabetes related cause, collectively referred to as vascular composite end point. Information was collected from medical records, death certificates, and the National Care Register of Health Care. Predictors at the time of the incident stroke were studied for the end points. RESULTS: During follow-up, 104 (72%) patients suffered a vascular composite end point. Of these, 33 (32%) had a recurrent stroke, 33 (32%) a hard cardiovascular event, and 76 (53%) died of cardiovascular or diabetes-related causes, with an overall 1-year survival of 76% and 5-year survival of 58%. The predictors of a vascular composite end point were hemorrhagic stroke subtype (hazard ratio 2.03 [95% CI 1.29-3.19]), as well as chronic kidney disease stage 2 (2.48 [1.17-5.24]), stage 3 (3.04 [1.54-6.04]), stage 4 (3.95 [1.72-9.04]), and stage 5 (6.71 [3.14-14.34]). All-cause mortality increased with deteriorating kidney function. CONCLUSIONS: Patients with type 1 diabetes with an incident stroke have a poor cardiovascular prognosis and a high risk of all-cause mortality. In particular, hemorrhagic stroke subtype and progression of diabetic kidney disease conveys worse outcome. PMID- 28811285 TI - Heartbeat: Renin-angiotensin system blockade for prevention of cardiovascular disease. PMID- 28811286 TI - Acute arrhythmias in adults with congenital heart disease. PMID- 28811288 TI - Sixty seconds on . . . baby boxes. PMID- 28811287 TI - A plant effector-triggered immunity signaling sector is inhibited by pattern triggered immunity. AB - Since signaling machineries for two modes of plant-induced immunity, pattern triggered immunity (PTI) and effector-triggered immunity (ETI), extensively overlap, PTI and ETI signaling likely interact. In an Arabidopsis quadruple mutant, in which four major sectors of the signaling network, jasmonate, ethylene, PAD4, and salicylate, are disabled, the hypersensitive response (HR) typical of ETI is abolished when the Pseudomonas syringae effector AvrRpt2 is bacterially delivered but is intact when AvrRpt2 is directly expressed in planta These observations led us to discovery of a network-buffered signaling mechanism that mediates HR signaling and is strongly inhibited by PTI signaling. We named this mechanism the ETI-Mediating and PTI-Inhibited Sector (EMPIS). The signaling kinetics of EMPIS explain apparently different plant genetic requirements for ETI triggered by different effectors without postulating different signaling machineries. The properties of EMPIS suggest that information about efficacy of the early immune response is fed back to the immune signaling network, modulating its activity and limiting the fitness cost of unnecessary immune responses. PMID- 28811289 TI - Primary Tumors Limit Metastasis Formation through Induction of IL15-Mediated Cross-Talk between Patrolling Monocytes and NK Cells. AB - Metastases are responsible for the vast majority of cancer-related deaths. Although tumor cells can become invasive early during cancer progression, metastases formation typically occurs as a late event. How the immune response to primary tumors may dictate this outcome remains poorly understood, which hampers our capacity to manipulate it therapeutically. Here, we used a two-step experimental model, based on the highly aggressive B16F10 melanoma, that temporally segregates the establishment of primary tumors (subcutaneously) and the formation of lung metastases (from intravenous injection). This allowed us to identify a protective innate immune response induced by primary tumors that inhibits experimental metastasis. We found that in the presence of primary tumors, increased numbers of natural killer (NK) cells with enhanced IFNgamma, granzyme B, and perforin production were recruited to the lung upon metastasis induction. These changes were mirrored by a local accumulation of patrolling monocytes and macrophages with high expression of MHC class II and NOS2. Critically, the protective effect on metastasis was lost upon patrolling monocyte or NK cell depletion, IL15 neutralization, or IFNgamma ablation. The combined analysis of these approaches allowed us to establish a hierarchy in which patrolling monocytes, making IL15 in response to primary tumors, activate NK cells and IFNgamma production that then inhibit lung metastasis formation. This work identifies an innate cell network and the molecular determinants responsible for "metastasis immunosurveillance," providing support for using the key molecular mediator, IL15, to improve immunotherapeutic outcomes. Cancer Immunol Res; 5(9); 812-20. (c)2017 AACR. PMID- 28811290 TI - Only a quarter of physicians feel valued by employer, survey finds. PMID- 28811291 TI - Margaret McCartney: The cult of CPR. PMID- 28811292 TI - Dapagliflozin slows the progression of the renal and liver fibrosis associated with type 2 diabetes. AB - Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic oral agents indicating promising effects on cardiovascular and renal end points. However, the renoprotective effects of SGLT2 inhibitors are not fully understood. Also, metabolic effects of SGLT2 inhibition on other organ systems, such as effects on hepatic steatosis, are not fully understood. This study sought to address these questions by treating 18-wk-old uninephrectomized db/db mice with the selective SGLT2 inhibitor dapagliflozin. Untreated db/db mice developed progressive albuminuria, glomerular mesangial matrix expansion, and fatty liver associated with increased renal expression of TGFbeta1, PAI-1, type IV collagen and fibronectin, and liver deposition of fibronectin, type I and III collagen, and laminin. Treatment with dapagliflozin (1 mg.kg-1.day-1) via gel diet from 18 to 22 wk of age not only reduced blood glucose (371.14 +/- 55.02 mg/dl in treated db/db vs. 573.53 +/- 21.73 mg/dl in untreated db/db, P < 0.05) and Hb A1c levels (9.47 +/- 0.79% in treated db/db vs. 12.1 +/- 0.73% in untreated db/db, P < 0.05) but also ameliorated the increases in albuminuria and markers of glomerulosclerosis and liver injury seen in untreated db/db mice. Furthermore, both renal expressions of NF-kB p65, MCP-1, Nox4, Nox2, and p47phox and urine TBARS levels and liver productions of myeloperoxidase and reactive oxygen species, the markers of tissue inflammation and oxidative stress, were increased in untreated db/db mice, which were reduced by dapagliflozin administration. These results demonstrate that dapagliflozin not only improves hyperglycemia but also slows the progression of diabetes-associated glomerulosclerosis and liver fibrosis by improving hyperglycemia-induced tissue inflammation and oxidative stress. PMID- 28811293 TI - The glucagon-like peptide-1 receptor in the ventromedial hypothalamus reduces short-term food intake in male mice by regulating nutrient sensor activity. AB - Pharmacological activation of the glucagon-like peptide-1 receptor (GLP-1R) in the ventromedial hypothalamus (VMH) reduces food intake. Here, we assessed whether suppression of food intake by GLP-1R agonists (GLP-1RA) in this region is dependent on AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR). We found that pharmacological inhibition of glycolysis, and thus activation of AMPK, in the VMH attenuates the anorectic effect of the GLP-1R agonist exendin-4 (Ex4), indicating that glucose metabolism and inhibition of AMPK are both required for this effect. Furthermore, we found that Ex4-mediated anorexia in the VMH involved mTOR but not acetyl-CoA carboxylase, two downstream targets of AMPK. We support this by showing that Ex4 activates mTOR signaling in the VMH and Chinese hamster ovary (CHO)-K1 cells. In contrast to the clear acute pharmacological impact of the these receptors on food intake, knockdown of the VMH Glp1r conferred no changes in energy balance in either chow- or high-fat-diet fed mice, and the acute anorectic and glucose tolerance effects of peripherally dosed GLP-1RA were preserved. These results show that the VMH GLP-1R regulates food intake by engaging key nutrient sensors but is dispensable for the effects of GLP-1RA on nutrient homeostasis. PMID- 28811294 TI - Dihydrocapsiate improved age-associated impairments in mice by increasing energy expenditure. AB - Metabolic dysfunction is associated with aging and results in age-associated chronic diseases, including type 2 diabetes mellitus, cardiovascular disease, and stroke. Hence, there has been a focus on increasing energy expenditure in aged populations to protect them from age-associated diseases. Dihydrocapsiate (DCT) is a compound that belongs to the capsinoid family. Capsinoids are capsaicin analogs that are found in nonpungent peppers and increase whole body energy expenditure. However, their effect on energy expenditure has been reported only in young populations, and to date the effectiveness of DCT in increasing energy expenditure in aged populations has not been investigated. In this study, we investigated whether DCT supplementation in aged mice improves age-associated impairments. We obtained 5-wk-old and 1-yr-old male C57BL/6J mice and randomly assigned the aged mice to two groups, resulting in a total of three groups: 1) young mice, 2) old mice, and 3) old mice supplemented with 0.3% DCT. After 12 wk of supplementation, blood and tissue samples were collected and analyzed. DCT significantly suppressed age-associated fat accumulation, adipocyte hypertrophy, and liver steatosis. In addition, the DCT treatment dramatically suppressed age associated increases in hepatic inflammation, immune cell infiltration, and oxidative stress. DCT exerted these suppression effects by increasing energy expenditure linked to upregulation of both the oxidative phosphorylation gene program and fatty acid oxidation in skeletal muscle. These results indicate that DCT efficiently improves age-associated impairments, including liver steatosis and inflammation, in part by increasing energy expenditure via activation of the fat oxidation pathway in skeletal muscle. PMID- 28811295 TI - Circulating soluble RAGE isoforms are attenuated in obese, impaired-glucose tolerant individuals and are associated with the development of type 2 diabetes. AB - The soluble receptor for advanced glycation end products (sRAGE) may be protective against inflammation associated with obesity and type 2 diabetes (T2DM). The aim of this study was to determine the distribution of sRAGE isoforms and whether sRAGE isoforms are associated with risk of T2DM development in subjects spanning the glucose tolerance continuum. In this retrospective analysis, circulating total sRAGE and endogenous secretory RAGE (esRAGE) were quantified via ELISA, and cleaved RAGE (cRAGE) was calculated in 274 individuals stratified by glucose tolerance status (GTS) and obesity. Group differences were probed by ANOVA, and multivariate ordinal logistic regression was used to test the association between sRAGE isoform concentrations and the proportional odds of developing diabetes, vs. normal glucose tolerance (NGT) or impaired glucose tolerance (IGT). When stratified by GTS, total sRAGE, cRAGE, and esRAGE were all lower with IGT and T2DM, while the ratio of cRAGE to esRAGE (cRAGE:esRAGE) was only lower (P < 0.01) with T2DM compared with NGT. When stratified by GTS and obesity, cRAGE:esRAGE was higher with obesity and lower with IGT (P < 0.0001) compared with lean, NGT. In ordinal logistic regression models, greater total sRAGE (odds ratio, 0.91; P < 0.01) and cRAGE (odds ratio, 0.84; P < 0.01) were associated with lower proportional odds of developing T2DM. Reduced values of sRAGE isoforms observed with both obesity and IGT are independently associated with greater proportional odds of developing T2DM. The mechanisms by which each respective isoform contributes to obesity and insulin resistance may reveal novel treatment strategies for diabetes. PMID- 28811296 TI - A novel D2O tracer method to quantify RNA turnover as a biomarker of de novo ribosomal biogenesis, in vitro, in animal models, and in human skeletal muscle. AB - Current methods to quantify in vivo RNA dynamics are limited. Here, we developed a novel stable isotope (D2O) methodology to quantify RNA synthesis (i.e., ribosomal biogenesis) in cells, animal models, and humans. First, proliferating C2C12 cells were incubated in D2O-enriched media and myotubes +/-50 ng/ml IGF-I. Second, rat quadriceps (untrained, n = 9; 7-wk interval-"like" training, n = 13) were collected after ~3-wk D2O (70 atom %) administration, with body-water enrichment monitored via blood sampling. Finally, 10 (23 +/- 1 yr) men consumed 150-ml D2O followed by 50 ml/wk and undertook 6-wk resistance exercise (6 * 8 repetitions, 75% 1-repetition maximum 3/wk) with body-water enrichment monitored by saliva sampling and muscle biopsies (for determination of RNA synthesis) at 0, 3, and 6 wk. Ribose mole percent excess (r-MPE) from purine nucleotides was analyzed via GC-MS/MS. Proliferating C2C12 cell r-MPE exhibited a rise to plateau, whereas IGF-I increased myotube RNA from 76 +/- 3 to 123 +/- 3 ng/MUl and r-MPE by 0.39 +/- 0.1% (both P < 0.01). After 3 wk, rat quadriceps r-MPE had increased to 0.25 +/- 0.01% (P < 0.01) and was greater with running exercise (0.36 +/- 0.02%; P < 0.01). Human muscle r-MPE increased to 0.06 +/- 0.01 and 0.13 +/- 0.02% at 3/6 wk, respectively, equating to synthesis rates of ~0.8%/day, increasing with resistance exercise to 1.7 +/- 0.3%/day (P < 0.01) and 1.2 +/- 0.1%/day (P < 0.05) at 3/6 wk, respectively. Therefore, we have developed and physiologically validated a novel technique to explore ribosomal biogenesis in a multimodal fashion. PMID- 28811298 TI - The future: surgical advances in MEN1 therapeutic approaches and management strategies. AB - Multiple endocrine neoplasia type 1 (MEN1) is a hereditary autosomal dominant disorder associated with numerous neuroendocrine tumors (NETs). Recent advances in the management of MEN1 have led to a decrease in mortality due to excess hormones; however, they have also led to an increase in mortality from malignancy, particularly NETs. The main challenges are to localize these tumors, to select those that need therapy because of the risk of aggressive behavior and to select the appropriate therapy associated with minimal morbidity. This must be applied to a hereditary disease with a high risk of recurrence. The overall aim of management in MEN1 is to ensure that the patient remains disease- and symptom free for as long as possible and maintains a good quality of life. Herein, we review the changes that occurred in the last 20 years in the surgical management of MEN1-associated functional and non-functional pancreatico-duodenal NETs and thymic and bronchial NETs. PMID- 28811297 TI - Patterns of NSAIDs Use and Their Association with Other Analgesic Use in CKD. AB - BACKGROUND AND OBJECTIVES: Avoiding nonsteroidal anti-inflammatory drugs is important for safe CKD care. This study examined nonsteroidal anti-inflammatory drug use patterns and their association with other analgesic use in CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Chronic Renal Insufficiency Cohort Study is an observational cohort study that enrolled 3939 adults ages 21-74 years old with CKD between 2003 and 2008 using age-based eGFR inclusion criteria. Annual visits between June of 2003 and December of 2011 were organized into 15,917 visit-pairs (with an antecedent and subsequent visit) for 3872 participants with medication information. Demographics, kidney function, and clinical factors were ascertained along with report of nonsteroidal anti inflammatory drug or other analgesic use in the prior 30 days. RESULTS: In our study, 24% of participants reported nonsteroidal anti-inflammatory drug use at baseline or at least one follow-up study visit. Having a 10 ml/min per 1.73 m2 higher eGFR level at an antecedent visit was associated with higher odds of starting nonsteroidal anti-inflammatory drugs at a subsequent visit (odds ratio, 1.44; 95% confidence interval, 1.34 to 1.56). Seeing a nephrologist at the antecedent visit was associated with lower odds of starting or staying on nonsteroidal anti-inflammatory drugs at a subsequent visit (odds ratio, 0.70; 95% confidence interval, 0.56 to 0.87 and odds ratio, 0.61; 95% confidence interval, 0.46 to 0.81, respectively). Starting and stopping nonsteroidal anti-inflammatory drugs were both associated with higher odds of increasing the number of other analgesics (odds ratio, 1.52; 95% confidence interval, 1.25 to 1.85 and odds ratio, 1.78; 95% confidence interval, 1.39 to 2.28, respectively) and higher odds of increasing the number of opioid analgesics specifically (odds ratio, 1.92; 95% confidence interval, 1.48 to 2.48 and odds ratio, 1.46; 95% confidence interval, 1.04 to 2.03, respectively). CONCLUSIONS: Nonsteroidal anti-inflammatory drug use is common among patients with CKD but less so among those with worse kidney function or those who see a nephrologist. Initiation or discontinuation of nonsteroidal anti-inflammatory drugs is often associated with supplementation with or replacement by, respectively, other analgesics, including opioids, which introduces possible drug-related problems when taking these alternative analgesics. PMID- 28811299 TI - Twenty years of menin: emerging opportunities for restoration of transcriptional regulation in MEN1. AB - Since the discovery of the multiple endocrine neoplasia type 1 (MEN1) gene in 1997, elucidation of the molecular function of its protein product, menin, has been a challenge. Biochemical, proteomics, genetics and genomics approaches have identified various potential roles, which converge on gene expression regulation. The most consistent findings show that menin connects transcription factors and chromatin-modifying enzymes, in particular, the histone H3K4 methyltransferase complexes MLL1 and MLL2. Chromatin immunoprecipitation combined with next generation sequencing has enabled studying genome-wide dynamics of chromatin binding by menin. We propose that menin regulates cell type-specific transcriptional programs by linking chromatin regulatory complexes to specific transcription factors. In this fashion, the MEN1 gene is a tumor suppressor gene in the endocrine tissues that are affected in MEN1. Recent studies have hinted at possibilities to pharmacologically restore the epigenetic changes caused by loss of menin function as therapeutic strategies for MEN1, for example, by inhibition of histone demethylases. The current lack of appropriate cellular model systems for MEN1-associated tumors is a limitation for compound testing, which needs to be addressed in the near future. In this review, we look back at the past twenty years of research on menin and the mechanism of disease of MEN1. In addition, we discuss how the current understanding of the molecular function of menin offers future directions to develop novel treatments for MEN1-associated endocrine tumors. PMID- 28811302 TI - Effects of temperature and UVR on organic matter fluxes and the metabolic activity of Acropora muricata. AB - Coral bleaching events are predicted to occur more frequently in the coming decades with global warming. The susceptibility of corals to bleaching during thermal stress episodes depends on many factors, including the magnitude of thermal stress and irradiance. The interactions among these two factors, and in particular with ultra-violet radiation (UVR), the most harmful component of light, are more complex than assumed, and are not yet well understood. This paper explores the individual and combined effects of temperature and UVR on the metabolism of Acropora muricata, one of the most abundant coral species worldwide. Particulate and dissolved organic matter (POM/DOM) fluxes and organic matter (OM) degradation by the mucus-associated bacteria were also monitored in all conditions. The results show that UVR exposure exacerbated the temperature induced bleaching, but did not affect OM fluxes, which were only altered by seawater warming. Temperature increase induced a shift from POM release and DOM uptake in healthy corals to POM uptake and DOM release in stressed ones. POM uptake was linked to a significant grazing of pico- and nanoplankton particles during the incubation, to fulfil the energetic requirements of A. muricata in the absence of autotrophy. Finally, OM degradation by mucus-associated bacterial activity was unaffected by UVR exposure, but significantly increased under high temperature. Altogether, our results demonstrate that seawater warming and UVR not only affect coral physiology, but also the way corals interact with the surrounding seawater, with potential consequences for coral reef biogeochemical cycles and food webs. PMID- 28811300 TI - Epigenetic regulation by the menin pathway. AB - There is a trend of increasing prevalence of neuroendocrine tumors (NETs), and the inherited multiple endocrine neoplasia type 1 (MEN1) syndrome serves as a genetic model to investigate how NETs develop and the underlying mechanisms. Menin, encoded by the MEN1 gene, at least partly acts as a scaffold protein by interacting with multiple partners to regulate cellular homeostasis of various endocrine organs. Menin has multiple functions including regulation of several important signaling pathways by controlling gene transcription. Here, we focus on reviewing the recent progress in elucidating the key biochemical role of menin in epigenetic regulation of gene transcription and cell signaling, as well as posttranslational regulation of menin itself. In particular, we will review the progress in studying structural and functional interactions of menin with various histone modifiers and transcription factors such as MLL, PRMT5, SUV39H1 and other transcription factors including c-Myb and JunD. Moreover, the role of menin in regulating cell signaling pathways such as TGF-beta, Wnt and Hedgehog, as well as miRNA biogenesis and processing will be described. Further, the regulation of the MEN1 gene transcription, posttranslational modifications and stability of menin protein will be reviewed. These various modes of regulation by menin as well as regulation of menin by various biological factors broaden the view regarding how menin controls various biological processes in neuroendocrine organ homeostasis. PMID- 28811303 TI - Adaptive camouflage: what can be learned from the wetting behaviour of the tropical flat bugs Dysodius lunatus and Dysodiusmagnus. AB - The neotropical flat bug species Dysodius lunatus and Dysodius magnus show a fascinating camouflage principle, as their appearance renders the animal hardly visible on the bark of trees. However, when getting wet due to rain, bark changes its colour and gets darker. In order to keep the camouflage effect, it seems that some Dysodius species benefit from their ability to hold a water film on their cuticle and therefore change their optical properties when also wetted by water. This camouflage behaviour requires the insect to have a hydrophilic surface and passive surface structures which facilitate the liquid spreading. Here we show morphological and chemical characterisations of the surface, especially the cuticular waxes of D. magnus Scanning electron microscopy revealed that the animal is covered with pillar-like microstructures which, in combination with a surprising chemical hydrophilicity of the cuticle waxes, render the bug almost superhydrophilic: water spreads immediately across the surface. We could theoretically model this behaviour assuming the effect of hemi-wicking (a state in which a droplet sits on a rough surface, partwise imbibing the structure around). Additionally the principle was abstracted and a laser-patterned polymer surface, mimicking the structure and contact angle of Dysodius wax, shows exactly the behaviour of the natural role model - immediate spreading of water and the formation of a thin continuous water film changing optical properties of the surface. PMID- 28811304 TI - Selectin catch-bonds mechanotransduce integrin activation and neutrophil arrest on inflamed endothelium under shear flow. AB - E-selectin extends from the plasma membrane of inflamed endothelium and serves to capture leukocytes from flowing blood via long-lived catch-bonds that support slow leukocyte rolling under shear stress. Its ligands are glycosylated with the tetrasaccharide sialyl Lewisx (sLex), which contributes to bond affinity and specificity. E-selectin-mediated rolling transmits signals into neutrophils that trigger activation of high-affinity beta2-integrins necessary for transition to shear-resistant adhesion and transendothelial migration. Rivipansel is a glycomimetic drug that inhibits E-selectin-mediated vaso-occlusion induced by integrin-dependent sickle-red blood cell-leukocyte adhesion. How Rivipansel antagonizes ligand recognition by E-selectin and blocks outside-in signaling of integrin-mediated neutrophil arrest while maintaining rolling immune-surveillance is unknown. Here, we demonstrate that sLex expressed on human L-selectin is preferentially bound by E-selectin and, on ligation, initiates secretion of MRP8/14 that binds TLR4 to elicit the extension of beta2-integrin to an intermediate affinity state. Neutrophil rolling over E-selectin at precise shear stress transmits tension and catch-bond formation with L-selectin via sLex, resulting in focal clusters that deliver a distinct signal to upshift beta2 integrins to a high-affinity state. Rivipansel effectively blocked formation of selectin catch-bonds, revealing a novel mechanotransduction circuit that rapidly converts extended beta2-integrins to high-affinity shear-resistant bond clusters with intracellular adhesion molecule 1 on inflamed endothelium. PMID- 28811307 TI - An interview with Jenny Nichols. AB - Jennifer Nichols is a Principal Investigator at the Cambridge Stem Cell Institute and Department of Physiology, Development and Neuroscience at the University of Cambridge, UK. Her lab works on lineage segregation and the establishment of pluripotency in the mammalian embryo. In 2017 she was awarded the British Society for Developmental Biology's Cheryll Tickle Medal, given to mid-career female scientists with outstanding achievements in developmental biology. We met Jenny in her Cambridge office to talk about pluripotency in vitro and in vivo, the importance of collaboration in her career path, and what playing a musical instrument has in common with research. PMID- 28811305 TI - Red blood cells in thrombosis. AB - Red blood cells (RBCs) have historically been considered passive bystanders in thrombosis. However, clinical and epidemiological studies have associated quantitative and qualitative abnormalities in RBCs, including altered hematocrit, sickle cell disease, thalassemia, hemolytic anemias, and malaria, with both arterial and venous thrombosis. A growing body of mechanistic studies suggests that RBCs can promote thrombus formation and enhance thrombus stability. These findings suggest that RBCs may contribute to thrombosis pathophysiology and reveal potential strategies for therapeutically targeting RBCs to reduce thrombosis. PMID- 28811308 TI - Wilms' tumour 1 (WT1) in development, homeostasis and disease. AB - The study of genes mutated in human disease often leads to new insights into biology as well as disease mechanisms. One such gene is Wilms' tumour 1 (WT1), which plays multiple roles in development, tissue homeostasis and disease. In this Primer, I summarise how this multifaceted gene functions in various mammalian tissues and organs, including the kidney, gonads, heart and nervous system. This is followed by a discussion of our current understanding of the molecular mechanisms by which WT1 and its two major isoforms regulate these processes at the transcriptional and post-transcriptional levels. PMID- 28811309 TI - Cellular and molecular mechanisms coordinating pancreas development. AB - The pancreas is an endoderm-derived glandular organ that participates in the regulation of systemic glucose metabolism and food digestion through the function of its endocrine and exocrine compartments, respectively. While intensive research has explored the signaling pathways and transcriptional programs that govern pancreas development, much remains to be discovered regarding the cellular processes that orchestrate pancreas morphogenesis. Here, we discuss the developmental mechanisms and principles that are known to underlie pancreas development, from induction and lineage formation to morphogenesis and organogenesis. Elucidating such principles will help to identify novel candidate disease genes and unravel the pathogenesis of pancreas-related diseases, such as diabetes, pancreatitis and cancer. PMID- 28811306 TI - Replication and validation of genetic polymorphisms associated with survival after allogeneic blood or marrow transplant. AB - Multiple candidate gene-association studies of non-HLA single-nucleotide polymorphisms (SNPs) and outcomes after blood or marrow transplant (BMT) have been conducted. We identified 70 publications reporting 45 SNPs in 36 genes significantly associated with disease-related mortality, progression-free survival, transplant-related mortality, and/or overall survival after BMT. Replication and validation of these SNP associations were performed using DISCOVeRY-BMT (Determining the Influence of Susceptibility COnveying Variants Related to one-Year mortality after BMT), a well-powered genome-wide association study consisting of 2 cohorts, totaling 2888 BMT recipients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome, and their HLA-matched unrelated donors, reported to the Center for International Blood and Marrow Transplant Research. Gene-based tests were used to assess the aggregate effect of SNPs on outcome. None of the previously reported significant SNPs replicated at P < .05 in DISCOVeRY-BMT. Validation analyses showed association with one previously reported donor SNP at P < .05 and survival; more associations would be anticipated by chance alone. No gene-based tests were significant at P < .05. Functional annotation with publicly available data shows these candidate SNPs most likely do not have biochemical function; only 13% of candidate SNPs correlate with gene expression or are predicted to impact transcription factor binding. Of these, half do not impact the candidate gene of interest; the other half correlate with expression of multiple genes. These findings emphasize the peril of pursing candidate approaches and the importance of adequately powered tests of unbiased genome-wide associations with BMT clinical outcomes given the ultimate goal of improving patient outcomes. PMID- 28811310 TI - Live fate-mapping of joint-associated fibroblasts visualizes expansion of cell contributions during zebrafish fin regeneration. AB - The blastema is a mass of progenitor cells responsible for regeneration of amputated salamander limbs and fish fins. Previous studies have indicated that resident cell sources producing the blastema contribute lineage-restricted progeny to regenerating tissue. However, these studies have labeled general cell types rather than granular cell subpopulations, and they do not explain the developmental transitions that must occur for distal structures to arise from cells with proximal identities in the appendage stump. Here, we find that regulatory sequences of tph1b, which encodes an enzyme that synthesizes serotonin, mark a subpopulation of fibroblast-like cells restricted to the joints of uninjured adult zebrafish fins. Amputation stimulates serotonin production in regenerating fin fibroblasts, yet targeted tph1b mutations abrogating this response do not disrupt fin regeneration. In uninjured animals, tph1b-expressing cells contribute fibroblast progeny that remain restricted to joints throughout life. By contrast, upon amputation, tph1b+ joint cells give rise to fibroblasts that distribute across the entire lengths of regenerating fin rays. Our experiments visualize and quantify how incorporation into an appendage blastema broadens the progeny contributions of a cellular subpopulation that normally has proximodistal restrictions. PMID- 28811311 TI - Linking the environment, DAF-7/TGFbeta signaling and LAG-2/DSL ligand expression in the germline stem cell niche. AB - The developmental accumulation of proliferative germ cells in the C. elegans hermaphrodite is sensitive to the organismal environment. Previously, we found that the TGFbeta signaling pathway links the environment and proliferative germ cell accumulation. Neuronal DAF-7/TGFbeta causes a DAF-1/TGFbetaR signaling cascade in the gonadal distal tip cell (DTC), the germline stem cell niche, where it negatively regulates a DAF-3 SMAD and DAF-5 Sno-Ski. LAG-2, a founding DSL ligand family member, is produced in the DTC and activates the GLP-1/Notch receptor on adjacent germ cells to maintain germline stem cell fate. Here, we show that DAF-7/TGFbeta signaling promotes expression of lag-2 in the DTC in a daf-3-dependent manner. Using ChIP and one-hybrid assays, we find evidence for direct interaction between DAF-3 and the lag-2 promoter. We further identify a 25 bp DAF-3 binding element required for the DTC lag-2 reporter response to the environment and to DAF-7/TGFbeta signaling. Our results implicate DAF-3 repressor complex activity as a key molecular mechanism whereby the environment influences DSL ligand expression in the niche to modulate developmental expansion of the germline stem cell pool. PMID- 28811312 TI - Myosin II is not required for Drosophila tracheal branch elongation and cell intercalation. AB - The Drosophila tracheal system consists of an interconnected network of monolayered epithelial tubes that ensures oxygen transport in the larval and adult body. During tracheal dorsal branch (DB) development, individual DBs elongate as a cluster of cells, led by tip cells at the front and trailing cells in the rear. Branch elongation is accompanied by extensive cell intercalation and cell lengthening of the trailing stalk cells. Although cell intercalation is governed by Myosin II (MyoII)-dependent forces during tissue elongation in the Drosophila embryo that lead to germ-band extension, it remained unclear whether MyoII plays a similar active role during tracheal branch elongation and intercalation. Here, we have used a nanobody-based approach to selectively knock down MyoII in tracheal cells. Our data show that, despite the depletion of MyoII function, tip cell migration and stalk cell intercalation (SCI) proceed at a normal rate. This confirms a model in which DB elongation and SCI in the trachea occur as a consequence of tip cell migration, which produces the necessary forces for the branching process. PMID- 28811313 TI - A key role for foxQ2 in anterior head and central brain patterning in insects. AB - Anterior patterning of animals is based on a set of highly conserved transcription factors but the interactions within the protostome anterior gene regulatory network (aGRN) remain enigmatic. Here, we identify the red flour beetle Tribolium castaneum ortholog of foxQ2 (Tc-foxQ2) as a novel upstream component of the aGRN. It is required for the development of the labrum and higher order brain structures, namely the central complex and the mushroom bodies. We reveal Tc-foxQ2 interactions by RNAi and heat shock-mediated misexpression. Surprisingly, Tc-foxQ2 and Tc-six3 mutually activate each other, forming a novel regulatory module at the top of the aGRN. Comparisons of our results with those of sea urchins and cnidarians suggest that foxQ2 has acquired more upstream functions in the aGRN during protostome evolution. Our findings expand the knowledge on foxQ2 gene function to include essential roles in epidermal development and central brain patterning. PMID- 28811315 TI - Quantitative Whole Genome Sequencing of Circulating Tumor Cells Enables Personalized Combination Therapy of Metastatic Cancer. AB - Much effort has been dedicated to developing circulating tumor cells (CTC) as a noninvasive cancer biopsy, but with limited success as yet. In this study, we combine a method for isolation of highly pure CTCs using immunomagnetic enrichment/fluorescence-activated cell sorting with advanced whole genome sequencing (WGS), based on long fragment read technology, to illustrate the utility of an accurate, comprehensive, phased, and quantitative genomic analysis platform for CTCs. Whole genomes of 34 CTCs from a patient with metastatic breast cancer were analyzed as 3,072 barcoded subgenomic compartments of long DNA. WGS resulted in a read coverage of 23* per cell and an ensemble call rate of >95%. These barcoded reads enabled accurate detection of somatic mutations present in as few as 12% of CTCs. We found in CTCs a total of 2,766 somatic single nucleotide variants and 543 indels and multi-base substitutions, 23 of which altered amino acid sequences. Another 16,961 somatic single nucleotide variant and 8,408 indels and multi-base substitutions, 77 of which were nonsynonymous, were detected with varying degrees of prevalence across the 34 CTCs. On the basis of our whole genome data of mutations found in all CTCs, we identified driver mutations and the tissue of origin of these cells, suggesting personalized combination therapies beyond the scope of most gene panels. Taken together, our results show how advanced WGS of CTCs can lead to high-resolution analyses of cancers that can reliably guide personalized therapy. Cancer Res; 77(16); 4530 41. (c)2017 AACR. PMID- 28811316 TI - Weighing the Causal Evidence That Associates Short Sleep Duration With Obesity. PMID- 28811317 TI - Sleep Duration and Risk of Type 2 Diabetes. AB - BACKGROUND: Associations between sleep duration and type 2 diabetes (T2D) risk markers in childhood have been little studied. We examined associations between self-reported sleep duration and T2D risk markers in children. METHODS: Cross sectional study of 4525 multiethnic UK children aged 9 to 10 years. Sleep time was calculated from self-reported usual time of going to bed and getting up on a school day, validated in a subset using accelerometers. Fasting blood samples provided levels of serum lipids and insulin, plasma glucose, and HbA1c. Physical measures included height, weight, bioimpedance, and blood pressure. Multilevel linear regression models of anthropometric, T2D, and cardiovascular risk markers with sleep duration were adjusted for sex, age, month, ethnicity, socioeconomic position, observer (physical measures only), and random effect of school. RESULTS: On average, children slept 10.5 hours per night (95% range 8.0-12.0 hours). There were strong inverse graded relationships between sleep duration, adiposity, and diabetes risk markers. In adjusted models, a 1-hour-longer sleep duration was associated with 0.19 lower BMI (95% confidence interval [CI] 0.09 to 0.28), 0.03 kg/m5 lower fat mass index (95% CI 0.00 to 0.05 kg/m5), 2.9% lower homeostasis model assessment insulin resistance (95% CI 1.2% to 4.4%), and 0.24% lower fasting glucose (95% CI 0.03% to 0.44%); there was no association with HbA1c or cardiovascular risk. Associations with insulin and glucose remained after an additional adjustment for adiposity markers. CONCLUSIONS: The finding of an inverse association between sleep duration and T2D risk markers in childhood is novel. Intervention studies are needed to establish the causality of these associations, which could provide a simple strategy for early T2D prevention. PMID- 28811318 TI - The beta-cell assassin: IAPP cytotoxicity. AB - Islet amyloid polypeptide (IAPP) forms cytotoxic oligomers and amyloid fibrils in islets in type 2 diabetes (T2DM). The causal factors for amyloid formation are largely unknown. Mechanisms of molecular folding and assembly of human IAPP (hIAPP) into beta-sheets, oligomers and fibrils have been assessed by detailed biophysical studies of hIAPP and non-fibrillogenic, rodent IAPP (rIAPP); cytotoxicity is associated with the early phases (oligomers/multimers) of fibrillogenesis. Interaction with synthetic membranes promotes beta-sheet assembly possibly via a transient alpha-helical molecular conformation. Cellular hIAPP cytotoxicity can be activated from intracellular or extracellular sites. In transgenic rodents overexpressing hIAPP, intracellular pro-apoptotic signals can be generated at different points in beta-cell protein synthesis. Increased cellular trafficking of proIAPP, failure of the unfolded protein response (UPR) or excess trafficking of misfolded peptide via the degradation pathways can induce apoptosis; these data indicate that defects in intracellular handling of hIAPP can induce cytotoxicity. However, there is no evidence for IAPP overexpression in T2DM. Extracellular amyloidosis is directly related to the degree of beta-cell apoptosis in islets in T2DM. IAPP fragments, fibrils and multimers interact with membranes causing disruption in vivo and in vitro These findings support a role for extracellular IAPP in beta-sheet conformation in cytotoxicity. Inhibitors of fibrillogenesis are useful tools to determine the aberrant mechanisms that result in hIAPP molecular refolding and islet amyloidosis. However, currently, their role as therapeutic agents remains uncertain. PMID- 28811319 TI - Galectin-8 activates dendritic cells and stimulates antigen-specific immune response elicitation. AB - Galectin-8 (Gal-8) is a mammalian beta-galactoside-binding lectin, endowed with proinflammatory properties. Given its capacity to enhance antigen-specific immune responses in vivo, we investigated whether Gal-8 was also able to promote APC activation to sustain T cell activation after priming. Both endogenous [dendritic cells (DCs)] and bone marrow-derived DCs (BMDCs) treated with exogenous Gal-8 exhibited a mature phenotype characterized by increased MHC class II (MHCII), CD80, and CD86 surface expression. Moreover, Gal-8-treated BMDCs (Gal-8-BMDCs) stimulated antigen-specific T cells more efficiently than immature BMDCs (iBMDCs). Proinflammatory cytokines IL-3, IL-2, IL-6, TNF, MCP-1, and MCP-5, as well as growth factor G-CSF, were augmented in Gal-8-BMDC conditioned media, with IL-6 as the most prominent. Remarkably, BMDCs from Gal-8-deficient mice (Lgals8-/ BMDC) displayed reduced CD86 and IL-6 expression and an impaired ability to promote antigen-specific CD4 T cell activation. To test if Gal-8-induced activation correlates with the elicitation of an effective immune response, soluble Gal-8 was coadministrated with antigen during immunization of BALB/cJ mice in the experimental foot-and-mouth disease virus (FMDV) model. When a single dose of Gal-8 was added to the antigen formulation, an increased specific and neutralizing humoral response was developed, sufficient to enhance animal protection upon viral challenge. IL-6 and IFN-gamma, as well as lymphoproliferative responses, were also incremented in Gal-8/antigen-immunized animals only at 48 h after immunization, suggesting that Gal-8 induces the elicitation of an inflammatory response at an early stage. Taking together, these findings argue in favor of the use of Gal-8 as an immune-stimulator molecule to enhance the adaptive immune response. PMID- 28811321 TI - Identification of drivers for the metamorphic transition of HIV-1 reverse transcriptase. AB - Recent structural characterizations of the p51 and p66 monomers have established an important starting point for understanding the maturation pathway of the human immunodeficiency virus (HIV)-1 reverse transcriptase p66/p51 heterodimer. This process requires a metamorphic transition of the polymerase domain leading to formation of a p66/p66' homodimer that exists as a structural heterodimer. To better understand the drivers for this metamorphic transition, we have performed NMR studies of 15N-labeled RT216 - a construct that includes the fingers and most of the palm domains. These studies are consistent with the conclusion that the p66 monomer exists as a spring-loaded complex. Initial dissociation of the fingers/palm : connection complex allows the fingers/palm to adopt an alternate, more stable structure, reducing the rate of reassociation and facilitating subsequent maturation steps. One of the drivers for an initial extension of the fingers/palm domains is identified as a straightening of helix E relative to its conformation in the monomer by eliminating a bend of ~50 degrees near residue Phe160. NMR and circular dichroism data also are consistent with the conclusion that a hydrophobic surface of palm domain that becomes exposed after the initial dissociation, as well as the intrinsic conformational preferences of the palm domain C-terminal segment, facilitates the formation of the beta-sheet structure that is unique to the active polymerase subunit. Spectral comparisons based on 15N-labeled constructs are all consistent with previous structural conclusions based on studies of 13C-methyl-labeled constructs. PMID- 28811322 TI - Analysis of sphingolipids, sterols, and phospholipids in human pathogenic Cryptococcus strains. AB - Cryptococcus species cause invasive infections in humans. Lipids play an important role in the progression of these infections. Independent studies done by our group and others provide some detail about the functions of these lipids in Cryptococcus infections. However, the pathways of biosynthesis and the metabolism of these lipids are not completely understood. To thoroughly understand the physiological role of these Cryptococcus lipids, a proper structure and composition analysis of Cryptococcus lipids is demanded. In this study, a detailed spectroscopic analysis of lipid extracts from Cryptococcus gattii and Cryptococcus grubii strains is presented. Sphingolipid profiling by LC ESI-MS/MS was used to analyze sphingosine, dihydrosphingosine, sphingosine-1 phosphate, dihydrosphingosine-1-phosphate, ceramide, dihydroceramide, glucosylceramide, phytosphingosine, phytosphingosine-1-phosphate, phytoceramide, alpha-hydroxy phytoceramide, and inositolphosphorylceramide species. A total of 13 sterol species were identified using GC-MS, where ergosterol is the most abundant species. The 31P-NMR-based phospholipid analysis identified phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phosphatidyl-N,N-dimethylethanolamine, phosphatidyl-N monomethylethanolamine, phosphatidylglycerol, phosphatidic acid, and lysophosphatidylethanolamine. A comparison of lipid profiles among different Cryptococcus strains illustrates a marked change in the metabolic flux of these organisms, especially sphingolipid metabolism. These data improve our understanding of the structure, biosynthesis, and metabolism of common lipid groups of Cryptococcus and should be useful while studying their functional significance and designing therapeutic interventions. PMID- 28811323 TI - IL-22 induces Reg3gamma and inhibits allergic inflammation in house dust mite induced asthma models. AB - Previous studies have shown that IL-22, one of the Th17 cell-related cytokines, plays multiple roles in regulating allergic airway inflammation caused by antigen specific Th2 cells; however, the underlying mechanism remains unclear. Here, we show that allergic airway inflammation and Th2 and Th17 cytokine production upon intratracheal administration of house dust mite (HDM) extract, a representative allergen, were exacerbated in IL-22-deficient mice. We also found that IL-22 induces Reg3gamma production from lung epithelial cells through STAT3 activation and that neutralization of Reg3gamma significantly exacerbates HDM-induced eosinophilic airway inflammation and Th2 cytokine induction. Moreover, exostatin like 3 (EXTL3), a functional Reg3gamma binding protein, is expressed in lung epithelial cells, and intratracheal administration of recombinant Reg3gamma suppresses HDM-induced thymic stromal lymphopoietin and IL-33 expression and accumulation of type 2 innate lymphoid cells in the lung. Collectively, these results suggest that IL-22 induces Reg3gamma production from lung epithelial cells and inhibits the development of HDM-induced allergic airway inflammation, possibly by inhibiting cytokine production from lung epithelial cells. PMID- 28811326 TI - $10M Gift Supports "Data Recycling" at UCSF. AB - The University of California, San Francisco's Institute for Computational Health Sciences has received a $10 million gift to support "data recycling" investigations. The approach to medical research involves mining existing data to potentially uncover new uses for existing drugs and help improve clinical care. PMID- 28811327 TI - Resistance Genes Identified. AB - A CRISPR-based screen of all 19,050 genes in the genome has revealed around 100 genes that cancer cells must express in order for T cells-and, thus, immunotherapies-to effectively recognize and kill tumors. PMID- 28811324 TI - The transcriptional program, functional heterogeneity, and clinical targeting of mast cells. AB - Mast cells are unique tissue-resident immune cells that express an array of receptors that can be activated by several extracellular cues, including antigen immunoglobulin E (IgE) complexes, bacteria, viruses, cytokines, hormones, peptides, and drugs. Mast cells constitute a small population in tissues, but their extraordinary ability to respond rapidly by releasing granule-stored and newly made mediators underpins their importance in health and disease. In this review, we document the biology of mast cells and introduce new concepts and opinions regarding their role in human diseases beyond IgE-mediated allergic responses and antiparasitic functions. We bring to light recent discoveries and developments in mast cell research, including regulation of mast cell functions, differentiation, survival, and novel mouse models. Finally, we highlight the current and future opportunities for therapeutic intervention of mast cell functions in inflammatory diseases. PMID- 28811328 TI - Transglutaminase 2 Is a Direct Target Gene of YAP/TAZ-Letter. PMID- 28811329 TI - Transglutaminase 2 Is a Direct Target Gene of YAP-TAZ-Response. PMID- 28811330 TI - Epithelial-to-Mesenchymal and Mesenchymal-to-Epithelial Transition in Mesenchymal Tumors: A Paradox in Sarcomas? AB - The epithelial-to-mesenchymal transition (EMT) is a reversible process comprised of various subprograms via which epithelial cells reduce their intercellular adhesions and proliferative capacity while gaining a mesenchymal phenotype with increased migratory and invasive properties. This process has been well described in several carcinomas, which are cancers of epithelial origin, and is crucial to metastatic tumor cell dissemination and drug resistance. In contrast, the precise role of EMT-related processes in tumors originating from mesenchymal tissues, such as bone and soft-tissues sarcomas, is still largely unclear. In fact, although the existence of the EMT in sarcomas appears paradoxical because these cancers are, by definition, mesenchymal ab initio, accumulating evidence suggests that many sarcomas can undergo EMT-related processes, which may be associated with aggressive clinical behavior. These processes may be especially operative in certain sarcoma subtypes, such as carcinosarcomas displaying a biphenotypic morphology with characteristics of both mesenchymal and epithelial tumors. In this review, we discuss findings regarding the potential existence of EMT-related processes in sarcomas and propose that sarcomas can reside in a metastable state, enabling them to become either more mesenchymal or epithelial under specific conditions, which likely has important clinical implications. Cancer Res; 77(17); 4556-61. (c)2017 AACR. PMID- 28811332 TI - De Novo Lipid Synthesis Facilitates Gemcitabine Resistance through Endoplasmic Reticulum Stress in Pancreatic Cancer. AB - Pancreatic adenocarcinoma is moderately responsive to gemcitabine-based chemotherapy, the most widely used single-agent therapy for pancreatic cancer. Although the prognosis in pancreatic cancer remains grim in part due to poor response to therapy, previous attempts at identifying and targeting the resistance mechanisms have not been very successful. By leveraging The Cancer Genome Atlas dataset, we identified lipid metabolism as the metabolic pathway that most significantly correlated with poor gemcitabine response in pancreatic cancer patients. Furthermore, we investigated the relationship between alterations in lipogenesis pathway and gemcitabine resistance by utilizing tissues from the genetically engineered mouse model and human pancreatic cancer patients. We observed a significant increase in fatty acid synthase (FASN) expression with increasing disease progression in spontaneous pancreatic cancer mouse model, and a correlation of high FASN expression with poor survival in patients and poor gemcitabine responsiveness in cell lines. We observed a synergistic effect of FASN inhibitors with gemcitabine in pancreatic cancer cells in culture and orthotopic implantation models. Combination of gemcitabine and the FASN inhibitor orlistat significantly diminished stemness, in part due to induction of endoplasmic reticulum (ER) stress that resulted in apoptosis. Moreover, direct induction of ER stress with thapsigargin caused a similar decrease in stemness and showed synergistic activity with gemcitabine. Our in vivo studies with orthotopic implantation models demonstrated a robust increase in gemcitabine responsiveness upon inhibition of fatty acid biosynthesis with orlistat. Altogether, we demonstrate that fatty acid biosynthesis pathway manipulation can help overcome the gemcitabine resistance in pancreatic cancer by regulating ER stress and stemness. Cancer Res; 77(20); 5503-17. (c)2017 AACR. PMID- 28811333 TI - Arabidopsis LORELEI, a Maternally Expressed Imprinted Gene, Promotes Early Seed Development. AB - In flowering plants, the female gametophyte controls pollen tube reception immediately before fertilization and regulates seed development immediately after fertilization, although the controlling mechanisms remain poorly understood. Previously, we showed that LORELEI (LRE), which encodes a putative glycosylphosphatidylinositol-anchored membrane protein, is critical for pollen tube reception by the female gametophyte before fertilization and the initiation of seed development after fertilization. Here, we show that LRE is expressed in the synergid, egg, and central cells of the female gametophyte and in the zygote and proliferating endosperm of the Arabidopsis (Arabidopsis thaliana) seed. Interestingly, LRE expression in the developing seeds was primarily from the matrigenic LRE allele, indicating that LRE expression is imprinted. However, LRE was biallelically expressed in 8-d-old seedlings, indicating that the patrigenic allele does not remain silenced throughout the sporophytic generation. Regulation of imprinted LRE expression is likely novel, as LRE was not expressed in pollen or pollen tubes of mutants defective for MET1, DDM1, RNA-dependent DNA methylation, or MSI-dependent histone methylation. Additionally, the patrigenic LRE allele inherited from these mutants was not expressed in seeds. Surprisingly, and contrary to the predictions of the parental conflict hypothesis, LRE promotes growth in seeds, as loss of the matrigenic but not the patrigenic LRE allele caused delayed initiation of seed development. Our results showed that LRE is a rare imprinted gene that functions immediately after double fertilization and supported the model that a passage through the female gametophyte establishes monoalleleic expression of LRE in seeds and controls early seed development. PMID- 28811334 TI - Argonaute 8 (AGO8) Mediates the Elicitation of Direct Defenses against Herbivory. AB - In Nicotiana attenuata, specific RNA-directed RNA polymerase (RdR1) and the Dicer like (DCL3 and DCL4) proteins are recruited during herbivore attack to mediate the regulation of defense responses. However, the identity and role(s) of Argonautes (AGOs) involved in herbivory remain unknown. Of the 11 AGOs in the N. attenuata genome, we silenced the expression of 10. Plants silenced in NaAGO8 expression grew normally but were highly susceptible to herbivore attack. Larvae of Manduca sexta grew faster when consuming inverted-repeat stable transformants (irAGO8) plants but did not differ from the wild type when consuming plants silenced in AGO1 (a, b, and c), AGO2, AGO4 (a and b), AGO7, or AGO10 expression. irAGO8 plants were significantly compromised in herbivore-induced levels of defense metabolites such as nicotine, phenolamides, and diterpenoid glycosides. Time-course analyses revealed extensively altered microRNA profiles and the reduced accumulation of MYB8 transcripts and of the associated genes of the phenolamide and phenylpropanoid pathways as well as the nicotine biosynthetic pathway. A possible AGO8-modulated microRNA-messenger RNA target network was inferred. Furthermore, comparative analysis of domains revealed the diversity of AGO conformations, particularly in the small RNA-binding pocket, which may influence substrate recognition/binding and functional specificity. We infer that AGO8 plays a central role in the induction of direct defenses by modulating several regulatory nodes in the defense signaling network during herbivore response. Thus, our study identifies the effector AGO of the herbivore-induced small RNA machinery, which in N. attenuata now comprises RdR1, DCL3/4, and AGO8. PMID- 28811335 TI - The Conserved and Unique Genetic Architecture of Kernel Size and Weight in Maize and Rice. AB - Maize (Zea mays) is a major staple crop. Maize kernel size and weight are important contributors to its yield. Here, we measured kernel length, kernel width, kernel thickness, hundred kernel weight, and kernel test weight in 10 recombinant inbred line populations and dissected their genetic architecture using three statistical models. In total, 729 quantitative trait loci (QTLs) were identified, many of which were identified in all three models, including 22 major QTLs that each can explain more than 10% of phenotypic variation. To provide candidate genes for these QTLs, we identified 30 maize genes that are orthologs of 18 rice (Oryza sativa) genes reported to affect rice seed size or weight. Interestingly, 24 of these 30 genes are located in the identified QTLs or within 1 Mb of the significant single-nucleotide polymorphisms. We further confirmed the effects of five genes on maize kernel size/weight in an independent association mapping panel with 540 lines by candidate gene association analysis. Lastly, the function of ZmINCW1, a homolog of rice GRAIN INCOMPLETE FILLING1 that affects seed size and weight, was characterized in detail. ZmINCW1 is close to QTL peaks for kernel size/weight (less than 1 Mb) and contains significant single nucleotide polymorphisms affecting kernel size/weight in the association panel. Overexpression of this gene can rescue the reduced weight of the Arabidopsis (Arabidopsis thaliana) homozygous mutant line in the AtcwINV2 gene (Arabidopsis ortholog of ZmINCW1). These results indicate that the molecular mechanisms affecting seed development are conserved in maize, rice, and possibly Arabidopsis. PMID- 28811336 TI - Catastrophic Unbalanced Genome Rearrangements Cause Somatic Loss of Berry Color in Grapevine. AB - Grape (Vitis vinifera) color somatic variants that can be used to develop new grapevine cultivars occasionally appear associated with deletion events of uncertain origin. To understand the mutational mechanisms generating somatic structural variation in grapevine, we compared the Tempranillo Blanco (TB) white berry somatic variant with its black berry ancestor, Tempranillo Tinto. Whole genome sequencing uncovered a catastrophic genome rearrangement in TB that caused the hemizygous deletion of 313 genes, including the loss of the functional copy for the MYB transcription factors required for anthocyanin pigmentation in the berry skin. Loss of heterozygosity and decreased copy number delimited interspersed monosomic and disomic regions in the right arm of linkage groups 2 and 5. At least 11 validated clustered breakpoints involving intrachromosomal and interchromosomal translocations between three linkage groups flanked the deleted fragments, which, according to segregation analyses, are phased in a single copy of each of the affected chromosomes. These hallmarks, along with the lack of homology between breakpoint joins and the randomness of the order and orientation of the rearranged fragments, are all consistent with a chromothripsis-like pattern generated after chromosome breakage and illegitimate rejoining. This unbalanced genome reshuffling has additional consequences in reproductive development. In TB, lack of sexual transmission of rearranged chromosomes associates with low gamete viability, which compromises fruit set and decreases fruit production. Our findings show that catastrophic genome rearrangements arise spontaneously and stabilize during plant somatic growth. These dramatic rearrangements generate new interesting phenotypes that can be selected for the improvement of vegetatively propagated plant species. PMID- 28811338 TI - Emerging functions of the Fanconi anemia pathway at a glance. AB - Fanconi anemia (FA) is a rare disease, in which homozygous or compound heterozygous inactivating mutations in any of 21 genes lead to genomic instability, early-onset bone marrow failure and increased cancer risk. The FA pathway is essential for DNA damage response (DDR) to DNA interstrand crosslinks. However, proteins of the FA pathway have additional cytoprotective functions that may be independent of DDR. We have shown that many FA proteins participate in the selective autophagy pathway that is required for the destruction of unwanted intracellular constituents. In this Cell Science at a Glance and the accompanying poster, we briefly review the role of the FA pathway in DDR and recent findings that link proteins of the FA pathway to selective autophagy of viruses and mitochondria. Finally, we discuss how perturbations in FA protein-mediated selective autophagy may contribute to inflammatory as well as genotoxic stress. PMID- 28811339 TI - Heritable Bovine Rumen Bacteria Are Phylogenetically Related and Correlated with the Cow's Capacity To Harvest Energy from Its Feed. AB - Ruminants sustain a long-lasting obligatory relationship with their rumen microbiome dating back 50 million years. In this unique host-microbiome relationship, the host's ability to digest its feed is completely dependent on its coevolved microbiome. This extraordinary alliance raises questions regarding the dependent relationship between ruminants' genetics and physiology and the rumen microbiome structure, composition, and metabolism. To elucidate this relationship, we examined the association of host genetics with the phylogenetic and functional composition of the rumen microbiome. We accomplished this by studying a population of 78 Holstein-Friesian dairy cows, using a combination of rumen microbiota data and other phenotypes from each animal with genotypic data from a subset of 47 animals. We identified 22 operational taxonomic units (OTUs) whose abundances were associated with rumen metabolic traits and host physiological traits and which showed measurable heritability. The abundance patterns of these microbes can explain high proportions of variance in rumen metabolism and many of the host physiological attributes such as its energy harvesting efficiency. Interestingly, these OTUs shared higher phylogenetic similarity between themselves than expected by chance, suggesting occupation of a specific ecological niche within the rumen ecosystem. The findings presented here suggest that ruminant genetics and physiology are correlated with microbiome structure and that host genetics may shape the microbiome landscape by enriching for phylogenetically related taxa that may occupy a unique niche.IMPORTANCE Dairy cows are an essential nutritional source for the world's population; as such, they are extensively farmed throughout our planet and subsequently impact our environment. The microbial communities that reside in the upper digestive tract of these animals in a compartment named the rumen degrade and ferment the plant biomass that the animal ingests. Our recent efforts, as well as those of others, have shown that this microbial community's composition and functionality are tightly linked to the cow's capacity to harvest energy from its feed, as well as to other physiological traits. In this study, we identified microbial groups that are heritable and also linked to the cow's production parameters. This finding could potentially allow us to apply selection programs on specific rumen microbial components that are linked to the animal's physiology and beneficial to production. Hence, it is a steppingstone toward microbiome manipulation for increasing food availability while lowering environmental impacts such as methane emission. PMID- 28811340 TI - Type III Interferon-Mediated Signaling Is Critical for Controlling Live Attenuated Yellow Fever Virus Infection In Vivo. AB - Yellow fever virus (YFV) is an arthropod-borne flavivirus, infecting ~200,000 people worldwide annually and causing about 30,000 deaths. The live attenuated vaccine strain, YFV-17D, has significantly contributed in controlling the global burden of yellow fever worldwide. However, the viral and host contributions to YFV-17D attenuation remain elusive. Type I interferon (IFN-alpha/beta) signaling and type II interferon (IFN-gamma) signaling have been shown to be mutually supportive in controlling YFV-17D infection despite distinct mechanisms of action in viral infection. However, it remains unclear how type III IFN (IFN-lambda) integrates into this antiviral system. Here, we report that while wild-type (WT) and IFN-lambda receptor knockout (lambdaR-/-) mice were largely resistant to YFV 17D, deficiency in type I IFN signaling resulted in robust infection. Although IFN-alpha/beta receptor knockout (alpha/betaR-/-) mice survived the infection, mice with combined deficiencies in both type I signaling and type III IFN signaling were hypersusceptible to YFV-17D and succumbed to the infection. Mortality was associated with viral neuroinvasion and increased permeability of the blood-brain barrier (BBB). alpha/betaR-/- lambdaR-/- mice also exhibited distinct changes in the frequencies of multiple immune cell lineages, impaired T cell activation, and severe perturbation of the proinflammatory cytokine balance. Taken together, our data highlight that type III IFN has critical immunomodulatory and neuroprotective functions that prevent viral neuroinvasion during active YFV-17D replication. Type III IFN thus likely represents a safeguard mechanism crucial for controlling YFV-17D infection and contributing to shaping vaccine immunogenicity.IMPORTANCE YFV-17D is a live attenuated flavivirus vaccine strain recognized as one of the most effective vaccines ever developed. However, the host and viral determinants governing YFV-17D attenuation and its potent immunogenicity are still unknown. Here, we analyzed the role of type III interferon (IFN)-mediated signaling, a host immune defense mechanism, in controlling YFV-17D infection and attenuation in different mouse models. We uncovered a critical role of type III IFN-mediated signaling in preserving the integrity of the blood-brain barrier and preventing viral brain invasion. Type III IFN also played a major role in regulating the induction of a potent but balanced immune response that prevented viral evasion of the host immune system. An improved understanding of the complex mechanisms regulating YFV-17D attenuation will provide insights into the key virus-host interactions that regulate host immune responses and infection outcomes as well as open novel avenues for the development of innovative vaccine strategies. PMID- 28811341 TI - The U.S. Culture Collection Network Responding to the Requirements of the Nagoya Protocol on Access and Benefit Sharing. AB - The U.S. Culture Collection Network held a meeting to share information about how culture collections are responding to the requirements of the recently enacted Nagoya Protocol on Access to Genetic Resources and the Fair and Equitable Sharing of Benefits Arising from their Utilization to the Convention on Biological Diversity (CBD). The meeting included representatives of many culture collections and other biological collections, the U.S. Department of State, U.S. Department of Agriculture, Secretariat of the CBD, interested scientific societies, and collection groups, including Scientific Collections International and the Global Genome Biodiversity Network. The participants learned about the policies of the United States and other countries regarding access to genetic resources, the definition of genetic resources, and the status of historical materials and genetic sequence information. Key topics included what constitutes access and how the CBD Access and Benefit-Sharing Clearing-House can help guide researchers through the process of obtaining Prior Informed Consent on Mutually Agreed Terms. U.S. scientists and their international collaborators are required to follow the regulations of other countries when working with microbes originally isolated outside the United States, and the local regulations required by the Nagoya Protocol vary by the country of origin of the genetic resource. Managers of diverse living collections in the United States described their holdings and their efforts to provide access to genetic resources. This meeting laid the foundation for cooperation in establishing a set of standard operating procedures for U.S. and international culture collections in response to the Nagoya Protocol. PMID- 28811342 TI - Bacteriophages of Gordonia spp. Display a Spectrum of Diversity and Genetic Relationships. AB - The global bacteriophage population is large, dynamic, old, and highly diverse genetically. Many phages are tailed and contain double-stranded DNA, but these remain poorly characterized genomically. A collection of over 1,000 phages infecting Mycobacterium smegmatis reveals the diversity of phages of a common bacterial host, but their relationships to phages of phylogenetically proximal hosts are not known. Comparative sequence analysis of 79 phages isolated on Gordonia shows these also to be diverse and that the phages can be grouped into 14 clusters of related genomes, with an additional 14 phages that are "singletons" with no closely related genomes. One group of six phages is closely related to Cluster A mycobacteriophages, but the other Gordonia phages are distant relatives and share only 10% of their genes with the mycobacteriophages. The Gordonia phage genomes vary in genome length (17.1 to 103.4 kb), percentage of GC content (47 to 68.8%), and genome architecture and contain a variety of features not seen in other phage genomes. Like the mycobacteriophages, the highly mosaic Gordonia phages demonstrate a spectrum of genetic relationships. We show this is a general property of bacteriophages and suggest that any barriers to genetic exchange are soft and readily violable.IMPORTANCE Despite the numerical dominance of bacteriophages in the biosphere, there is a dearth of complete genomic sequences. Current genomic information reveals that phages are highly diverse genomically and have mosaic architectures formed by extensive horizontal genetic exchange. Comparative analysis of 79 phages of Gordonia shows them to not only be highly diverse, but to present a spectrum of relatedness. Most are distantly related to phages of the phylogenetically proximal host Mycobacterium smegmatis, although one group of Gordonia phages is more closely related to mycobacteriophages than to the other Gordonia phages. Phage genome sequence space remains largely unexplored, but further isolation and genomic comparison of phages targeted at related groups of hosts promise to reveal pathways of bacteriophage evolution. PMID- 28811343 TI - Comparative Genomics of Escherichia coli Isolated from Skin and Soft Tissue and Other Extraintestinal Infections. AB - Escherichia coli, an intestinal Gram-negative bacterium, has been shown to be associated with a variety of diseases in addition to intestinal infections, such as urinary tract infections (UTIs), meningitis in neonates, septicemia, skin and soft tissue infections (SSTIs), and colisepticemia. Thus, for nonintestinal infections, it is categorized as extraintestinal pathogenic E. coli (ExPEC). It is also an opportunistic pathogen, causing cross infections, notably as an agent of zoonotic diseases. However, comparative genomic data providing functional and genetic coordinates for ExPEC strains associated with these different types of infections have not proven conclusive. In the study reported here, ExPEC E. coli isolated from SSTIs was characterized, including virulence and drug resistance profiles, and compared with isolates from patients suffering either pyelonephritis or septicemia. Results revealed that the majority of the isolates belonged to two pathogenic phylogroups, B2 and D. Approximately 67% of the isolates were multidrug resistant (MDR), with 85% producing extended-spectrum beta-lactamase (ESBL) and 6% producing metallo-beta-lactamase (MBL). The blaCTX-M 15 genotype was observed in at least 70% of the E. coli isolates in each category, conferring resistance to an extended range of beta-lactam antibiotics. Whole-genome sequencing and comparative genomics of the ExPEC isolates revealed that two of the four isolates from SSTIs, NA633 and NA643, belong to pandemic sequence type ST131, whereas functional characteristics of three of the ExPEC pathotypes revealed that they had equal capabilities to form biofilm and were resistant to human serum. Overall, the isolates from a variety of ExPEC infections demonstrated similar resistomes and virulomes and did not display any disease-specific functional or genetic coordinates.IMPORTANCE Infections caused by extraintestinal pathogenic E. coli (ExPEC) are of global concern as they result in significant costs to health care facilities management. The recent emergence of a multidrug-resistant pandemic clone, Escherichia coli ST131, is of primary concern as a global threat. In developing countries, such as India, skin and soft tissue infections (SSTIs) associated with E. coli are marginally addressed. In this study, we employed both genomic analysis and phenotypic assays to determine relationships, if any, among the ExPEC pathotypes. Similarity between antibiotic resistance and virulence profiles was observed, ST131 isolates from SSTIs were reported, and genomic similarities among strains isolated from different disease conditions were detected. This study provides functional molecular infection epidemiology insight into SSTI-associated E. coli compared with ExPEC pathotypes. PMID- 28811346 TI - Erratum for Yin et al., "Novel Plasmid-Mediated Colistin Resistance Gene mcr-3 in Escherichia coli". PMID- 28811345 TI - Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral Pathogens. AB - Epigenetic regulation is based on a network of complexes that modulate the chromatin character and structure of the genome to impact gene expression, cell fate, and development. Thus, epigenetic modulators represent novel therapeutic targets used to treat a range of diseases, including malignancies. Infectious pathogens such as herpesviruses are also regulated by cellular epigenetic machinery, and epigenetic therapeutics represent a novel approach used to control infection, persistence, and the resulting recurrent disease. The histone H3K27 methyltransferases EZH2 and EZH1 (EZH2/1) are epigenetic repressors that suppress gene transcription via propagation of repressive H3K27me3-enriched chromatin domains. However, while EZH2/1 are implicated in the repression of herpesviral gene expression, inhibitors of these enzymes suppressed primary herpes simplex virus (HSV) infection in vitro and in vivo Furthermore, these compounds blocked lytic viral replication following induction of HSV reactivation in latently infected sensory ganglia. Suppression correlated with the induction of multiple inflammatory, stress, and antipathogen pathways, as well as enhanced recruitment of immune cells to in vivo infection sites. Importantly, EZH2/1 inhibitors induced a cellular antiviral state that also suppressed infection with DNA (human cytomegalovirus, adenovirus) and RNA (Zika virus) viruses. Thus, EZH2/1 inhibitors have considerable potential as general antivirals through the activation of cellular antiviral and immune responses.IMPORTANCE A significant proportion of the world's population is infected with herpes simplex virus. Primary infection and subsequent recurrent reactivation can result in diseases ranging from mild lesions to severe ocular or neurological damage. Herpesviruses are subject to epigenetic regulation that modulates viral gene expression, lytic replication, and latency-reactivation cycles. Thus, epigenetic pharmaceuticals have the potential to alter the course of infection and disease. Here, while the histone methyltransferases EZH2/1 are implicated in the suppression of herpesviruses, inhibitors of these repressors unexpectedly suppress viral infection in vitro and in vivo by induction of key components of cellular innate defense pathways. These inhibitors suppress infection by multiple viral pathogens, indicating their potential as broad-spectrum antivirals. PMID- 28811344 TI - The Capacity of Mycobacterium tuberculosis To Survive Iron Starvation Might Enable It To Persist in Iron-Deprived Microenvironments of Human Granulomas. AB - This study was conducted to investigate the role of iron deprivation in the persistence of Mycobacterium tuberculosis We present evidence of iron restriction in human necrotic granulomas and demonstrate that under iron starvation M. tuberculosis persists, refractive to antibiotics and capable of restarting replication when iron is made available. Transcriptomics and metabolomic analyses indicated that the persistence of M. tuberculosis under iron starvation is dependent on strict control of endogenous Fe utilization and is associated with upregulation of pathogenicity and intrinsic antibiotic resistance determinants. M. tuberculosis mutants compromised in their ability to survive Fe starvation were identified. The findings of this study advance the understanding of the physiological settings that may underpin the chronicity of human tuberculosis (TB) and are relevant to the design of effective antitubercular therapies.IMPORTANCE One-third of the world population may harbor persistent M. tuberculosis, causing an asymptomatic infection that is refractory to treatment and can reactivate to become potentially lethal tuberculosis disease. However, little is known about the factors that trigger and maintain M. tuberculosis persistence in infected individuals. Iron is an essential nutrient for M. tuberculosis growth. In this study, we show, first, that in human granulomas the immune defense creates microenvironments in which M. tuberculosis likely experiences drastic Fe deprivation and, second, that Fe-starved M. tuberculosis is capable of long-term persistence without growth. Together, these observations suggest that Fe deprivation in the lung might trigger a state of persistence in M. tuberculosis and promote chronic TB. We also identified vulnerabilities of iron-restricted persistent M. tuberculosis, which can be exploited for the design of new antitubercular therapies. PMID- 28811347 TI - TIFA Signaling in Gastric Epithelial Cells Initiates the cag Type 4 Secretion System-Dependent Innate Immune Response to Helicobacter pylori Infection. AB - Helicobacter pylori is a bacterial pathogen that colonizes the human stomach, causing inflammation which, in some cases, leads to gastric ulcers and cancer. The clinical outcome of infection depends on a complex interplay of bacterial, host genetic, and environmental factors. Although H. pylori is recognized by both the innate and adaptive immune systems, this rarely results in bacterial clearance. Gastric epithelial cells are the first line of defense against H. pylori and alert the immune system to bacterial presence. Cytosolic delivery of proinflammatory bacterial factors through the cag type 4 secretion system (cag T4SS) has long been appreciated as the major mechanism by which gastric epithelial cells detect H. pylori Classically attributed to the peptidoglycan sensor NOD1, recent work has highlighted the role of NOD1-independent pathways in detecting H. pylori; however, the bacterial and host factors involved have remained unknown. Here, we show that bacterially derived heptose-1,7-bisphosphate (HBP), a metabolic precursor in lipopolysaccharide (LPS) biosynthesis, is delivered to the host cytosol through the cag-T4SS, where it activates the host tumor necrosis factor receptor-associated factor (TRAF)-interacting protein with forkhead-associated domain (TIFA)-dependent cytosolic surveillance pathway. This response, which is independent of NOD1, drives robust NF-kappaB-dependent inflammation within hours of infection and precedes NOD1 activation. We also found that the CagA toxin contributes to the NF-kappaB-driven response subsequent to TIFA and NOD1 activation. Taken together, our results indicate that the sequential activation of TIFA, NOD1, and CagA delivery drives the initial inflammatory response in gastric epithelial cells, orchestrating the subsequent recruitment of immune cells and leading to chronic gastritis.IMPORTANCEH. pylori is a globally prevalent cause of gastric and duodenal ulcers and cancer. H. pylori antibiotic resistance is rapidly increasing, and a vaccine remains elusive. The earliest immune response to H. pylori is initiated by gastric epithelial cells and sets the stage for the subsequent immunopathogenesis. This study revealed that host TIFA and H. pylori-derived HBP are critical effectors of innate immune signaling that account for much of the inflammatory response to H. pylori in gastric epithelial cells. HBP is delivered to the host cell via the cag T4SS at a time point that precedes activation of the previously described NOD1 and CagA inflammatory pathways. Manipulation of the TIFA-driven immune response in the host and/or targeting of ADP-heptose biosynthesis enzymes in H. pylori may therefore provide novel strategies that may be therapeutically harnessed to achieve bacterial clearance. PMID- 28811348 TI - A Critical Role of Glutamine and Asparagine gamma-Nitrogen in Nucleotide Biosynthesis in Cancer Cells Hijacked by an Oncogenic Virus. AB - While glutamine is a nonessential amino acid that can be synthesized from glucose, some cancer cells primarily depend on glutamine for their growth, proliferation, and survival. Numerous types of cancer also depend on asparagine for cell proliferation. The underlying mechanisms of the glutamine and asparagine requirement in cancer cells in different contexts remain unclear. In this study, we show that the oncogenic virus Kaposi's sarcoma-associated herpesvirus (KSHV) accelerates the glutamine metabolism of glucose-independent proliferation of cancer cells by upregulating the expression of numerous critical enzymes, including glutaminase 2 (GLS2), glutamate dehydrogenase 1 (GLUD1), and glutamic oxaloacetic transaminase 2 (GOT2), to support cell proliferation. Surprisingly, cell crisis is rescued only completely by supplementation with asparagine but minimally by supplementation with alpha-ketoglutarate, aspartate, or glutamate upon glutamine deprivation, implying an essential role of gamma-nitrogen in glutamine and asparagine for cell proliferation. Specifically, glutamine and asparagine provide the critical gamma-nitrogen for purine and pyrimidine biosynthesis, as knockdown of four rate-limiting enzymes in the pathways, including carbamoylphosphate synthetase 2 (CAD), phosphoribosyl pyrophosphate amidotransferase (PPAT), and phosphoribosyl pyrophosphate synthetases 1 and 2 (PRPS1 and PRPS2, respectively), suppresses cell proliferation. These findings indicate that glutamine and asparagine are shunted to the biosynthesis of nucleotides and nonessential amino acids from the tricarboxylic acid (TCA) cycle to support the anabolic proliferation of KSHV-transformed cells. Our results illustrate a novel mechanism by which an oncogenic virus hijacks a metabolic pathway for cell proliferation and imply potential therapeutic applications in specific types of cancer that depend on this pathway.IMPORTANCE We have previously found that Kaposi's sarcoma-associated herpesvirus (KSHV) can efficiently infect and transform primary mesenchymal stem cells; however, the metabolic pathways supporting the anabolic proliferation of KSHV-transformed cells remain unknown. Glutamine and asparagine are essential for supporting the growth, proliferation, and survival of some cancer cells. In this study, we have found that KSHV accelerates glutamine metabolism by upregulating numerous critical metabolic enzymes. Unlike most cancer cells that primarily utilize glutamine and asparagine to replenish the TCA cycle, KSHV-transformed cells depend on glutamine and asparagine for providing gamma-nitrogen for purine and pyrimidine biosynthesis. We identified four rate-limiting enzymes in this pathway that are essential for the proliferation of KSHV-transformed cells. Our results demonstrate a novel mechanism by which an oncogenic virus hijacks a metabolic pathway for cell proliferation and imply potential therapeutic applications in specific types of cancer that depend on this pathway. PMID- 28811350 TI - Defining the DNA Binding Site Recognized by the Fission Yeast Zn2Cys6 Transcription Factor Pho7 and Its Role in Phosphate Homeostasis. AB - Fission yeast phosphate homeostasis entails transcriptional induction of genes encoding phosphate-mobilizing proteins under conditions of phosphate starvation. Transcription factor Pho7, a member of the Zn2Cys6 family of fungal transcription regulators, is the central player in the starvation response. The DNA binding sites in the promoters of phosphate-responsive genes have not been defined, nor have any structure-function relationships been established for the Pho7 protein. Here we narrow this knowledge gap by (i) delineating an autonomous DNA-binding domain (DBD) within Pho7 that includes the Zn2Cys6 module, (ii) deploying recombinant Pho7 DBD in DNase I footprinting and electrophoretic mobility shift assays (EMSAs) to map the Pho7 recognition sites in the promoters of the phosphate-regulated pho1 and tgp1 genes to a 12-nucleotide sequence motif [5' TCG(G/C)(A/T)xxTTxAA], (iii) independently identifying the same motif as a Pho7 recognition element via in silico analysis of available genome-wide ChIP-seq data, (iv) affirming that mutations in the two Pho7 recognition sites in the pho1 promoter efface pho1 expression in vivo, and (v) establishing that the zinc binding cysteines and a pair of conserved arginines in the DBD are essential for Pho7 activity in vivoIMPORTANCE Fungi respond to phosphate starvation by inducing the transcription of a set of phosphate acquisition genes that comprise a phosphate regulon. Pho7, a member of the Zn2Cys6 family of fungal transcription regulators, is the central player in the phosphate starvation response in fission yeast. The present study identifies a 12-nucleotide Pho7 DNA binding motif [5' TCG(G/C)(A/T)xxTTxAA] in the promoters of phosphate-regulated genes, pinpoints DNA and protein features important for Pho7 binding to DNA, and correlates them with Pho7-dependent gene expression in vivo The results highlight distinctive properties of Pho7 vis-a-vis other fungal zinc binuclear cluster transcription factors as well as the divergent cast of transcription factors deployed for phosphate homeostasis in fission yeast versus budding yeast. PMID- 28811349 TI - Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral Suppressed Macaques: a Functional Latent Reservoir. AB - A human immunodeficiency virus (HIV) infection cure requires an understanding of the cellular and anatomical sites harboring virus that contribute to viral rebound upon treatment interruption. Despite antiretroviral therapy (ART), HIV associated neurocognitive disorders (HAND) are reported in HIV-infected individuals on ART. Biomarkers for macrophage activation and neuronal damage in cerebrospinal fluid (CSF) of HIV-infected individuals demonstrate continued effects of HIV in brain and suggest that the central nervous system (CNS) may serve as a viral reservoir. Using a simian immunodeficiency virus (SIV)/macaque model for HIV encephalitis and AIDS, we evaluated whether infected cells persist in brain despite ART. Eight SIV-infected pig-tailed macaques were virally suppressed with ART, and plasma and CSF viremia levels were analyzed longitudinally. To assess whether virus persisted in brain macrophages (BrMPhi) in these macaques, we used a macrophage quantitative viral outgrowth assay (MPhi QVOA), PCR, and in situ hybridization (ISH) to measure the frequency of infected cells and the levels of viral RNA and DNA in brain. Viral RNA in brain tissue of suppressed macaques was undetectable, although viral DNA was detected in all animals. The MPhi-QVOA demonstrated that the majority of suppressed animals contained latently infected BrMPhi. We also showed that virus produced in the MPhi-QVOAs was replication competent, suggesting that latently infected BrMPhi are capable of reestablishing productive infection upon treatment interruption. This report provides the first confirmation of the presence of replication competent SIV in BrMPhi of ART-suppressed macaques and suggests that the highly debated issue of viral latency in macrophages, at least in brain, has been addressed in SIV-infected macaques treated with ART.IMPORTANCE Resting CD4+ T cells are currently the only cells that fit the definition of a latent reservoir. However, recent evidence suggests that HIV/SIV-infected macrophages persist despite ART. Markers of macrophage activation and neuronal damage are observed in the CSF of HIV-infected individuals and of SIV-infected macaques on suppressive ART regimens, suggesting that the CNS has continued virus infection and latent infection. A controversy exists as to whether brain macrophages represent a latent source of replication-competent virus capable of reestablishing infection upon treatment interruption. In this study, we demonstrated the presence of the latent macrophage reservoir in brains of SIV-infected ART-treated macaques and analyzed the reservoir using our established outgrowth assay to quantitate macrophages harboring replication-competent SIV genomes. Our results support the idea of the existence of other latent reservoirs in addition to resting CD4+ T cells and underscore the importance of macrophages in developing strategies to eradicate HIV. PMID- 28811352 TI - Patient Acceptable Symptom State in Knee Osteoarthritis Patients Succeeds Across Different Patient-reported Outcome Measures Assessing Physical Function, But Fails Across Other Dimensions and Rheumatic Diseases. AB - OBJECTIVE: The aims of this study are (1) to establish the Patient Acceptable Symptom State (PASS) cutoff values of different patient-reported outcome measures (PROM) assessing physical function in patients with knee osteoarthritis (OA), and (2) to assess the influence of sex, age, duration of symptoms, and presence of depressive feelings on being in PASS. METHODS: Patients fulfilling the clinical American College of Rheumatology knee OA criteria received standardized nonsurgical treatment and completed different questionnaires at baseline and 3 months assessing physical function: Knee Injury and Osteoarthritis Outcome Score, Lequesne Algofunctional Index, Lower Extremity Functional Scale, numerical rating scale, and the physical function subscale of the Western Ontario and McMaster Universities Osteoarthritis Index. PASS values were defined as the 75th percentile of the score of questionnaires for those patients who consider their state acceptable. RESULTS: Of the 161 included patients, 62% were women with a mean age of 59 years (SD 9) and body mass index of 30 kg/m2 (SD 5). Standardized PASS values (95% CI) for different questionnaires for physical function varied between 48 (44-54) and 54 (50-56). Female patients and patients feeling depressed were found to have a lower probability to be in PASS for physical function, with OR (95% CI) varying from 0.45 (0.23-0.91) to 0.50 (0.26-0.97) and from 0.27 (0.14 0.55) to 0.38 (0.19-0.77), respectively. CONCLUSION: PASS cutoff values for physical function are robust across different PROM in patients with knee OA. Our results indicate that PASS values are not consistent across dimensions and rheumatic diseases, and that the use of a generic PASS value for patients with OA or even patients with other rheumatic diseases might not be justifiable. PMID- 28811351 TI - Content and Construct Validity, Reliability, and Responsiveness of the Rheumatoid Arthritis Flare Questionnaire: OMERACT 2016 Workshop Report. AB - OBJECTIVE: The Outcome Measures in Rheumatology (OMERACT) Rheumatoid Arthritis (RA) Flare Group was established to develop a reliable way to identify and measure RA flares in randomized controlled trials (RCT). Here, we summarized the development and field testing of the RA Flare Questionnaire (RA-FQ), and the voting results at OMERACT 2016. METHODS: Classic and modern psychometric methods were used to assess reliability, validity, sensitivity, factor structure, scoring, and thresholds. Interviews with patients and clinicians also assessed content validity, utility, and meaningfulness of RA-FQ scores. RESULTS: People with RA in observational trials in Canada (n = 896) and France (n = 138), and an RCT in the Netherlands (n = 178) completed 5 items (11-point numerical rating scale) representing RA Flare core domains. There was moderate to high evidence of reliability, content and construct validity, and responsiveness. Factor analysis supported unidimensionality. Rasch analysis showed acceptable fit to the Rasch model, with items and people covering a broad measurement continuum and evidence of appropriate targeting of items to people, ordered thresholds, minimal differential item functioning by language, sex, or age. A summative score across items is defensible, yielding an interval score (0-50) where higher scores reflect worsening flare. The RA-FQ received endorsement from 88% of attendees that it passed the OMERACT Filter 2.0 "Eyeball Test" for instrument selection. CONCLUSION: The RA-FQ has been developed to identify and measure RA flares. Its review through OMERACT Filter 2.0 shows evidence of reliability, content and construct validity, and responsiveness. These properties merit its further validation as an outcome for clinical trials. PMID- 28811353 TI - The OMERACT Rheumatoid Arthritis Magnetic Resonance Imaging (MRI) Scoring System: Updated Recommendations by the OMERACT MRI in Arthritis Working Group. AB - OBJECTIVE: The Outcome Measures in Rheumatology (OMERACT) Rheumatoid Arthritis (RA) Magnetic Resonance Imaging (MRI) scoring system (RAMRIS), evaluating bone erosion, bone marrow edema/osteitis, and synovitis, was introduced in 2002, and is now the standard method of objectively quantifying inflammation and damage by MRI in RA trials. The objective of this paper was to identify subsequent advances and based on them, to provide updated recommendations for the RAMRIS. METHODS: MRI studies relevant for RAMRIS and technical and scientific advances were analyzed by the OMERACT MRI in Arthritis Working Group, which used these data to provide updated considerations on image acquisition, RAMRIS definitions, and scoring systems for the original and new RA pathologies. Further, a research agenda was outlined. RESULTS: Since 2002, longitudinal studies and clinical trials have documented RAMRIS variables to have face, construct, and criterion validity; high reliability and sensitivity to change; and the ability to discriminate between therapies. This has enabled RAMRIS to demonstrate inhibition of structural damage progression with fewer patients and shorter followup times than has been possible with conventional radiography. Technical improvements, including higher field strengths and improved pulse sequences, allow higher image resolution and contrast-to-noise ratio. These have facilitated development and validation of scoring methods of new pathologies: joint space narrowing and tenosynovitis. These have high reproducibility and moderate sensitivity to change, and can be added to RAMRIS. Combined scores of inflammation or joint damage may increase sensitivity to change and discriminative power. However, this requires further research. CONCLUSION: Updated 2016 RAMRIS recommendations and a research agenda were developed. PMID- 28811354 TI - Safety and Efficacy of Baricitinib Through 128 Weeks in an Open-label, Longterm Extension Study in Patients with Rheumatoid Arthritis. AB - OBJECTIVE: To assess the safety and efficacy of baricitinib in patients with rheumatoid arthritis (RA) up to 128 weeks in a phase IIb study (NCT01185353). METHODS: After a 24-week blinded period, eligible patients entered an initial 52 week open-label extension (OLE); patients receiving 8 mg once daily (QD) continued with that dose and all others received 4 mg QD. Doses could be escalated to 8 mg QD at 28 or 32 weeks at investigator discretion when >= 6 tender and >= 6 swollen joints were present. Patients completing the first OLE were eligible to enter a second 52-week OLE and receive 4 mg QD regardless of previous dose. RESULTS: In the 4-mg (n = 108) and 8-mg (n = 93) groups, treatment emergent adverse events (AE) occurred in 63% and 67%, serious AE in 16% and 13%, infections in 35% and 40%, and serious infections in 5% and 3% of patients, respectively. Exposure-adjusted incidence rates for AE for all baricitinib groups in the second OLE were similar to or lower than rates observed in the first OLE. No opportunistic infections, tuberculosis cases, or lymphomas were observed through 128 weeks; 1 death occurred during the first OLE. Among all patients in both OLE, the proportions who achieved disease improvement at Week 24 were similar or increased at weeks 76 and 128. CONCLUSION: In a phase IIb study in RA, the safety and tolerability profile of baricitinib, up to 128 weeks, remained consistent with earlier observations, without unexpected late signals. Clinical improvements seen in the 24-week blinded period were maintained during the OLE. PMID- 28811355 TI - Evidence for Updating the Core Domain Set of Outcome Measures for Juvenile Idiopathic Arthritis: Report from a Special Interest Group at OMERACT 2016. AB - OBJECTIVE: The current Juvenile Idiopathic Arthritis (JIA) Core Set was developed in 1997 to identify the outcome measures to be used in JIA clinical trials using statistical and consensus-based techniques, but without patient involvement. The importance of patient/parent input into the research process has increasingly been recognized over the years. An Outcome Measures in Rheumatology (OMERACT) JIA Core Set Working Group was formed to determine whether the outcome domains of the current core set are relevant to those involved or whether the core set domains should be revised. METHODS: Twenty-four people from the United States, Canada, Australia, and Europe, including patient partners, formed the working group. Guided by the OMERACT Filter 2.0 process, we performed (1) a systematic literature review of outcome domains, (2) a Web-based survey (142 patients, 343 parents), (3) an idea-generation study (120 parents), (4) 4 online discussion boards (24 patients, 20 parents), and (5) a Special Interest Group (SIG) activity at the OMERACT 13 (2016) meeting. RESULTS: A MEDLINE search of outcome domains used in studies of JIA yielded 5956 citations, of which 729 citations underwent full-text review, and identified additional domains to those included in the current JIA Core Set. Qualitative studies on the effect of JIA identified multiple additional domains, including pain and participation. Twenty-one participants in the SIG achieved consensus on the need to revise the entire JIA Core Set. CONCLUSION: The results of qualitative studies and literature review support the need to expand the JIA Core Set, considering, among other things, additional patient/parent-centered outcomes, clinical data, and imaging data. PMID- 28811356 TI - Clinical Characteristics of Heart Involvement in Chinese Patients with Takayasu Arteritis. AB - OBJECTIVE: To understand the characteristics of heart involvement in Chinese patients with Takayasu arteritis (TA). METHODS: The medical charts of 411 patients with TA (325 women, 86 men) were retrospectively reviewed. The comparison of clinical manifestations was carried out between the patients with TA with (n = 164) and without (n = 247) heart involvement. RESULTS: The median age at disease onset was 23.0 years (18.0-30.0) in 411 patients with TA, and 23.0 years (17.3-30.0) in 164 patients with heart involvement. The disease duration of the heart involvement group (median: 24.0 mos) was significantly longer than those patients without heart involvement (the control group, median: 16.0 mos). Hypertension (57.3% vs 46.6%; p = 0.033), renal dysfunction (17.1% vs 7.7%; p = 0.003), and bruit in the subclavian artery (45.1% vs 34.4%; p = 0.029) were more common in the heart involvement group than patients without. Valvular abnormalities were found in 134 (81.7%) patients in the heart involvement group, myocardial abnormalities in 26 (15.9%), and coronary artery abnormalities in 19 patients (11.6%). The age at onset (yrs) and disease duration (mos) of patients with myocardial, valvular, and coronary arterial abnormalities were 18.8/13.0, 23.8/23.5, and 26.8/57.0, respectively. In the heart involvement group, 22 patients (84.6%) with myocardial abnormalities, 15 (78.9%) with coronary arterial abnormalities, and 89 (66.4%) with valvular abnormalities had Numano type V vessel involvement. The level of high-sensitivity C-reactive protein was higher in the heart involvement group (median: 10.0 mg/l), and the difference was significant when compared to the control group (median: 7.0 mg/l; p = 0.017). CONCLUSION: Patients with TA complicated with cardiac abnormalities are not rare, especially in patients with Numano type V vessel involvement. We suggest that echocardiogram screening may be a helpful tool to understand the whole feature of patients with TA. PMID- 28811357 TI - Autophagy attenuates endothelial-to-mesenchymal transition by promoting Snail degradation in human cardiac microvascular endothelial cells. AB - Endothelial-to-mesenchymal transition (EndMT) mainly exists in cardiovascular development and disease progression, and is well known to contribute to cardiac fibrosis. Recent studies indicated that autophagy also participates in the regulation of cardiac fibrosis. However, the precise role of autophagy in cardiac fibrosis and the underlying molecular mechanism remain unclear. The present study aimed to explore the role of autophagy in EndMT, reveal the underlying molecular mechanism, and seek new therapy for cardiac fibrosis. In the present study, we found that EndMT and autophagy were induced simultaneously by hypoxia in human cardiac microvascular endothelial cells (HCMECs). Rapamycin, an autophagy enhancer, attenuated EndMT with promoting angiogenesis, while 3-methyladenine (3 MA) and chloroquine (CQ), agents that inhibit autophagy, accelerated the progression accompanied by the decrease in counts of tube formation under hypoxia conditions. Interestingly, intervening autophagy by rapamycin, 3-MA, or CQ did not affect hypoxia-induced autocrine TGFbeta signaling, but changed the expression of Snail protein without alterations in the expression of Snail mRNA. Furthermore, the colocalization of LC3 and Snail indicated that autophagy might mediate Snail degradation under hypoxia conditions in HCMECs. Interaction of p62, the substrate of autophagy, with Snail by co-immunoprecipitation especially in hypoxia-incubated cells confirmed the hypothesis. In conclusion, autophagy serves as a cytoprotective mechanism against EndMT to promote angiogenesis by degrading Snail under hypoxia conditions, suggesting that autophagy targetted therapeutic strategies may be applicable for cardiac fibrosis by EndMT. PMID- 28811358 TI - Fasting insulin, insulin resistance, and risk of cardiovascular or all-cause mortality in non-diabetic adults: a meta-analysis. AB - Studies on elevated fasting insulin or insulin resistance (IR) and cardiovascular or all-cause mortality risk in non-diabetic individuals have yielded conflicting results. This meta-analysis aimed to evaluate the association of elevated fasting insulin levels or IR as defined by homeostasis model assessment of IR (HOMA-IR) with cardiovascular or all-cause mortality in non-diabetic adults. We searched for relevant studies in PubMed and Emabse databases until November 2016. Only prospective observational studies investigating the association of elevated fasting insulin levels or HOMA-IR with cardiovascular or all-cause mortality risk in non-diabetic adults were included. Risk ratio (RR) with its 95% confidence intervals (CIs) was pooled for the highest compared with the lowest category of fasting insulin levels or HOMA-IR. Seven articles involving 26976 non-diabetic adults were included. The pooled, adjusted RR of all-cause mortality comparing the highest with the lowest category was 1.13 (95% CI: 1.00-1.27; P=0.058) for fasting insulin levels and 1.34 (95% CI: 1.11-1.62; P=0.002) for HOMA-IR, respectively. When comparing the highest with the lowest category, the pooled adjusted RR of cardiovascular mortality was 2.11 (95% CI: 1.01-4.41; P=0.048) for HOMA-IR in two studies and 1.40 (95% CI: 0.49-3.96; P=0.526) for fasting insulin levels in one study. IR as measured by HOMA-IR but not fasting insulin appears to be independently associated with greater risk of cardiovascular or all-cause mortality in non-diabetic adults. However, the association of fasting insulin and HOMA-IR with cardiovascular mortality may be unreliable due to the small number of articles included. PMID- 28811359 TI - Exercise training prevents skeletal muscle plasma membrane cholesterol accumulation, cortical actin filament loss, and insulin resistance in C57BL/6J mice fed a western-style high-fat diet. AB - Insulin action and glucose disposal are enhanced by exercise, yet the mechanisms involved remain imperfectly understood. While the causes of skeletal muscle insulin resistance also remain poorly understood, new evidence suggest excess plasma membrane (PM) cholesterol may contribute by damaging the cortical filamentous actin (F-actin) structure essential for GLUT4 glucose transporter redistribution to the PM upon insulin stimulation. Here, we investigated whether PM cholesterol toxicity was mitigated by exercise. Male C57BL/6J mice were placed on low-fat (LF, 10% kCal) or high-fat (HF, 45% kCal) diets for a total of 8 weeks. During the last 3 weeks of this LF/HF diet intervention, all mice were familiarized with a treadmill for 1 week and then either sham-exercised (0 m/min, 10% grade, 50 min) or exercised (13.5 m/min, 10% grade, 50 min) daily for 2 weeks. HF-feeding induced a significant gain in body mass by 3 weeks. Sham or chronic exercise did not affect food consumption, water intake, or body mass gain. Prior to sham and chronic exercise, "pre-intervention" glucose tolerance tests were performed on all animals and demonstrated that HF-fed mice were glucose intolerant. While sham exercise did not affect glucose tolerance in the LF or HF mice, exercised mice showed an improvement in glucose tolerance. Muscle from sham-exercised HF-fed mice showed a significant increase in PM cholesterol, loss of cortical F-actin, and decrease in insulin-stimulated glucose transport compared to sham-exercised LF-fed mice. These HF-fed skeletal muscle membrane/cytoskeletal abnormalities and insulin resistance were improved in exercised mice. These data reveal a new therapeutic aspect of exercise being regulation of skeletal muscle PM cholesterol homeostasis. Further studies on this mechanism of insulin resistance and the benefits of exercise on its prevention are needed. PMID- 28811360 TI - Involvement of midkine in the development of pulmonary fibrosis. AB - Midkine is a low-molecular-weight heparin-binding protein that is strongly expressed mainly in the midgestation period and has various physiological activities such as in development and cell migration. Midkine has been reported to be strongly expressed in cancer cells and in inflammation and repair processes, and to be involved in the pathogenesis of various diseases. However, its role in the lung is poorly understood. In this study, we analyzed the clinical characteristics of idiopathic pulmonary fibrosis patients in relation to midkine expression and used a mouse bleomycin-induced pulmonary fibrosis model to investigate the role of midkine in pulmonary fibrosis. In the idiopathic pulmonary fibrosis patients, the serum midkine level was significantly higher than in healthy subjects, and midkine levels in the serum and bronchoalveolar lavage (BAL) fluid correlated positively with the percentage of inflammatory cells in the BAL fluid. In wild-type mice, intratracheal bleomycin administration increased midkine expression in lung tissue. Additionally, compared with wild type mice, midkine-deficient mice showed low expression of both collagen and alpha-smooth muscle actin, as well as a low value for the pathological lung fibrosis score after bleomycin administration. Furthermore, the total cell count and lymphocyte percentage in the BAL fluid, as well as TNF-alpha and transforming growth factor-beta expression in lung tissue, were significantly lower in the midkine-deficient mice compared with wild-type mice. These results suggest that midkine is involved in the development of pulmonary fibrosis by regulating inflammatory cell migration into the lung, and TNF-alpha and transforming growth factor-beta expression. PMID- 28811361 TI - Chemoradiotherapy Resistance in Colorectal Cancer Cells is Mediated by Wnt/beta catenin Signaling. AB - Activation of Wnt/beta-catenin signaling plays a central role in the development and progression of colorectal cancer. The Wnt-transcription factor, TCF7L2, is overexpressed in primary rectal cancers that are resistant to chemoradiotherapy and TCF7L2 mediates resistance to chemoradiotherapy. However, it is unclear whether the resistance is mediated by a TCF7L2 inherent mechanism or Wnt/beta catenin signaling in general. Here, inhibition of beta-catenin by siRNAs or a small-molecule inhibitor (XAV-939) resulted in sensitization of colorectal cancer cells to chemoradiotherapy. To investigate the potential role of Wnt/beta-catenin signaling in controlling therapeutic responsiveness, nontumorigenic RPE-1 cells were stimulated with Wnt-3a, a physiologic ligand of Frizzled receptors, which increased resistance to chemoradiotherapy. This effect could be recapitulated by overexpression of a degradation-resistant mutant of beta-catenin (S33Y), also boosting resistance of RPE-1 cells to chemoradiotherapy, which was, conversely, abrogated by siRNA-mediated silencing of beta-catenin. Consistent with these findings, higher expression levels of active beta-catenin were observed as well as increased TCF/LEF reporter activity in SW1463 cells that evolved radiation resistance due to repeated radiation treatment. Global gene expression profiling identified several altered pathways, including PPAR signaling and other metabolic pathways, associated with cellular response to radiation. In summary, aberrant activation of Wnt/beta-catenin signaling not only regulates the development and progression of colorectal cancer, but also mediates resistance of rectal cancers to chemoradiotherapy.Implications: Targeting Wnt/beta-catenin signaling or one of the downstream pathways represents a promising strategy to increase response to chemoradiotherapy. Mol Cancer Res; 15(11); 1481-90. (c)2017 AACR. PMID- 28811362 TI - Nuclear Envelope Rupture Is Enhanced by Loss of p53 or Rb. AB - The mammalian nuclear envelope (NE) forms a stable physical barrier between the nucleus and the cytoplasm, normally breaking down only during mitosis. However, spontaneous transient NE rupture in interphase can occur when NE integrity is compromised, such as when the nucleus experiences mechanical stress. For instance, deficiencies in the nuclear lamins and their associated proteins can cause NE rupture that is promoted by forces exerted by actin filaments. NE rupture can allow cytoplasmic nucleases to access chromatin, potentially compromising genome integrity. Importantly, spontaneous NE rupture was noted in several human cancer cell lines, but the cause of this defect is not known. Here, we investigated the mechanistic contributions of two major tumor suppressors, p53 (TP53) and Rb (RB1), to the repression of NE rupture. NE rupture was induced in normal human epithelial RPE-1 cells upon impairment of either Rb or p53 achieved by shRNA knockdown and CRISPR/Cas9 gene editing. NE rupture did not involve diminished expression of NE components or greater cell motility. However, cells that underwent NE rupture displayed a larger nuclear projection area. In conclusion, the data indicate that NE rupture in cancer cells is likely due to loss of either the Rb or the p53 pathway.Implications: These findings imply that tumor suppression by Rb and p53 includes the ability to prevent NE rupture, thereby protecting against genome alterations. Mol Cancer Res; 15(11); 1579-86. (c)2017 AACR. PMID- 28811363 TI - Targeting AR Variant-Coactivator Interactions to Exploit Prostate Cancer Vulnerabilities. AB - Castration-resistant prostate cancer (CRPC) progresses rapidly and is incurable. Constitutively active androgen receptor splice variants (AR-Vs) represent a well established mechanism of therapeutic resistance and disease progression. These variants lack the AR ligand-binding domain and, as such, are not inhibited by androgen deprivation therapy (ADT), which is the standard systemic approach for advanced prostate cancer. Signaling by AR-Vs, including the clinically relevant AR-V7, is augmented by Vav3, an established AR coactivator in CRPC. Using mutational and biochemical studies, we demonstrated that the Vav3 Diffuse B-cell lymphoma homology (DH) domain interacted with the N-terminal region of AR-V7 (and full length AR). Expression of the Vav3 DH domain disrupted Vav3 interaction with and enhancement of AR-V7 activity. The Vav3 DH domain also disrupted AR-V7 interaction with other AR coactivators: Src1 and Vav2, which are overexpressed in PC. This Vav3 domain was used in proof-of-concept studies to evaluate the effects of disrupting the interaction between AR-V7 and its coactivators on CRPC cells. This disruption decreased CRPC cell proliferation and anchorage-independent growth, caused increased apoptosis, decreased migration, and resulted in the acquisition of morphological changes associated with a less aggressive phenotype. While disrupting the interaction between FL-AR and its coactivators decreased N-C terminal interaction, disrupting the interaction of AR-V7 with its coactivators decreased AR-V7 nuclear levels.Implications: This study demonstrates the potential therapeutic utility of inhibiting constitutively active AR-V signaling by disrupting coactivator binding. Such an approach is significant, as AR-Vs are emerging as important drivers of CRPC that are particularly recalcitrant to current therapies. Mol Cancer Res; 15(11); 1469-80. (c)2017 AACR. PMID- 28811365 TI - A model explaining the matrilateral bias in alloparental investment. AB - Maternal grandmothers invest more in childcare than paternal grandmothers. This bias is large where the expression of preferences is unconstrained by residential and lineage norms, and is detectable even where marriage removes women from their natal families. We maintain that the standard evolutionary explanation, paternity uncertainty, is incomplete, and present an expanded model incorporating effects of alloparents on the mother as well as on her children. Alloparenting lightens a mother's load and increases her residual nepotistic value: her expected fitness from later investments in personal reproduction and in her natal relatives. The mother's mother derives fitness from all such investments, whereas her mother-in law gains only from further investment in children sired by her son, and thus has less incentive to assist the mother even if paternity is certain. This logic extends to kin other than grandmothers. We generate several hypotheses for future research. PMID- 28811364 TI - Mechanosensing drives acuity of alphabeta T-cell recognition. AB - T lymphocytes use surface [Formula: see text] T-cell receptors (TCRs) to recognize peptides bound to MHC molecules (pMHCs) on antigen-presenting cells (APCs). How the exquisite specificity of high-avidity T cells is achieved is unknown but essential, given the paucity of foreign pMHC ligands relative to the ubiquitous self-pMHC array on an APC. Using optical traps, we determine physicochemical triggering thresholds based on load and force direction. Strikingly, chemical thresholds in the absence of external load require orders of magnitude higher pMHC numbers than observed physiologically. In contrast, force applied in the shear direction ([Formula: see text]10 pN per TCR molecule) triggers T-cell Ca2+ flux with as few as two pMHC molecules at the interacting surface interface with rapid positional relaxation associated with similarly directed motor-dependent transport via [Formula: see text]8-nm steps, behaviors inconsistent with serial engagement during initial TCR triggering. These synergistic directional forces generated during cell motility are essential for adaptive T-cell immunity against infectious pathogens and cancers. PMID- 28811366 TI - Inflammation correlates with symptoms in chronic fatigue syndrome. PMID- 28811367 TI - Amplification of local changes along the timescale processing hierarchy. AB - Small changes in word choice can lead to dramatically different interpretations of narratives. How does the brain accumulate and integrate such local changes to construct unique neural representations for different stories? In this study, we created two distinct narratives by changing only a few words in each sentence (e.g., "he" to "she" or "sobbing" to "laughing") while preserving the grammatical structure across stories. We then measured changes in neural responses between the two stories. We found that differences in neural responses between the two stories gradually increased along the hierarchy of processing timescales. For areas with short integration windows, such as early auditory cortex, the differences in neural responses between the two stories were relatively small. In contrast, in areas with the longest integration windows at the top of the hierarchy, such as the precuneus, temporal parietal junction, and medial frontal cortices, there were large differences in neural responses between stories. Furthermore, this gradual increase in neural differences between the stories was highly correlated with an area's ability to integrate information over time. Amplification of neural differences did not occur when changes in words did not alter the interpretation of the story (e.g., sobbing to "crying"). Our results demonstrate how subtle differences in words are gradually accumulated and amplified along the cortical hierarchy as the brain constructs a narrative over time. PMID- 28811368 TI - Fluctuation spectra and force generation in nonequilibrium systems. AB - Many biological systems are appropriately viewed as passive inclusions immersed in an active bath: from proteins on active membranes to microscopic swimmers confined by boundaries. The nonequilibrium forces exerted by the active bath on the inclusions or boundaries often regulate function, and such forces may also be exploited in artificial active materials. Nonetheless, the general phenomenology of these active forces remains elusive. We show that the fluctuation spectrum of the active medium, the partitioning of energy as a function of wavenumber, controls the phenomenology of force generation. We find that, for a narrow, unimodal spectrum, the force exerted by a nonequilibrium system on two embedded walls depends on the width and the position of the peak in the fluctuation spectrum, and oscillates between repulsion and attraction as a function of wall separation. We examine two apparently disparate examples: the Maritime Casimir effect and recent simulations of active Brownian particles. A key implication of our work is that important nonequilibrium interactions are encoded within the fluctuation spectrum. In this sense, the noise becomes the signal. PMID- 28811369 TI - Obesity-associated gene TMEM18 has a role in the central control of appetite and body weight regulation. AB - An intergenic region of human chromosome 2 (2p25.3) harbors genetic variants which are among those most strongly and reproducibly associated with obesity. The gene closest to these variants is TMEM18, although the molecular mechanisms mediating these effects remain entirely unknown. Tmem18 expression in the murine hypothalamic paraventricular nucleus (PVN) was altered by changes in nutritional state. Germline loss of Tmem18 in mice resulted in increased body weight, which was exacerbated by high fat diet and driven by increased food intake. Selective overexpression of Tmem18 in the PVN of wild-type mice reduced food intake and also increased energy expenditure. We provide evidence that TMEM18 has four, not three, transmembrane domains and that it physically interacts with key components of the nuclear pore complex. Our data support the hypothesis that TMEM18 itself, acting within the central nervous system, is a plausible mediator of the impact of adjacent genetic variation on human adiposity. PMID- 28811370 TI - Decoding ants' olfactory system sheds light on the evolution of social communication. PMID- 28811371 TI - Angular reconstitution-based 3D reconstructions of nanomolecular structures from superresolution light-microscopy images. AB - Superresolution light microscopy allows the imaging of labeled supramolecular assemblies at a resolution surpassing the classical diffraction limit. A serious limitation of the superresolution approach is sample heterogeneity and the stochastic character of the labeling procedure. To increase the reproducibility and the resolution of the superresolution results, we apply multivariate statistical analysis methods and 3D reconstruction approaches originally developed for cryogenic electron microscopy of single particles. These methods allow for the reference-free 3D reconstruction of nanomolecular structures from two-dimensional superresolution projection images. Since these 2D projection images all show the structure in high-resolution directions of the optical microscope, the resulting 3D reconstructions have the best possible isotropic resolution in all directions. PMID- 28811372 TI - Pictures of the prologue to neurotransmitter release. PMID- 28811373 TI - Friction law and hysteresis in granular materials. AB - The macroscopic friction of particulate materials often weakens as the flow rate is increased, leading to potentially disastrous intermittent phenomena including earthquakes and landslides. We theoretically and numerically study this phenomenon in simple granular materials. We show that velocity weakening, corresponding to a nonmonotonic behavior in the friction law, [Formula: see text], is present even if the dynamic and static microscopic friction coefficients are identical, but disappears for softer particles. We argue that this instability is induced by endogenous acoustic noise, which tends to make contacts slide, leading to faster flow and increased noise. We show that soft spots, or excitable regions in the materials, correspond to rolling contacts that are about to slide, whose density is described by a nontrivial exponent [Formula: see text] We build a microscopic theory for the nonmonotonicity of [Formula: see text], which also predicts the scaling behavior of acoustic noise, the fraction of sliding contacts [Formula: see text], and the sliding velocity, in terms of [Formula: see text] Surprisingly, these quantities have no limit when particles become infinitely hard, as confirmed numerically. Our analysis rationalizes previously unexplained observations and makes experimentally testable predictions. PMID- 28811374 TI - Recruitment of CRISPR-Cas systems by Tn7-like transposons. AB - A survey of bacterial and archaeal genomes shows that many Tn7-like transposons contain minimal type I-F CRISPR-Cas systems that consist of fused cas8f and cas5f, cas7f, and cas6f genes and a short CRISPR array. Several small groups of Tn7-like transposons encompass similarly truncated type I-B CRISPR-Cas. This minimal gene complement of the transposon-associated CRISPR-Cas systems implies that they are competent for pre-CRISPR RNA (precrRNA) processing yielding mature crRNAs and target binding but not target cleavage that is required for interference. Phylogenetic analysis demonstrates that evolution of the CRISPR-Cas containing transposons included a single, ancestral capture of a type I-F locus and two independent instances of type I-B loci capture. We show that the transposon-associated CRISPR arrays contain spacers homologous to plasmid and temperate phage sequences and, in some cases, chromosomal sequences adjacent to the transposon. We hypothesize that the transposon-encoded CRISPR-Cas systems generate displacement (R-loops) in the cognate DNA sites, targeting the transposon to these sites and thus facilitating their spread via plasmids and phages. These findings suggest the existence of RNA-guided transposition and fit the guns-for-hire concept whereby mobile genetic elements capture host defense systems and repurpose them for different stages in the life cycle of the element. PMID- 28811377 TI - Measuring the effects of farming on human skull morphology. PMID- 28811375 TI - Temperature increase reduces global yields of major crops in four independent estimates. AB - Wheat, rice, maize, and soybean provide two-thirds of human caloric intake. Assessing the impact of global temperature increase on production of these crops is therefore critical to maintaining global food supply, but different studies have yielded different results. Here, we investigated the impacts of temperature on yields of the four crops by compiling extensive published results from four analytical methods: global grid-based and local point-based models, statistical regressions, and field-warming experiments. Results from the different methods consistently showed negative temperature impacts on crop yield at the global scale, generally underpinned by similar impacts at country and site scales. Without CO2 fertilization, effective adaptation, and genetic improvement, each degree-Celsius increase in global mean temperature would, on average, reduce global yields of wheat by 6.0%, rice by 3.2%, maize by 7.4%, and soybean by 3.1%. Results are highly heterogeneous across crops and geographical areas, with some positive impact estimates. Multimethod analyses improved the confidence in assessments of future climate impacts on global major crops and suggest crop- and region-specific adaptation strategies to ensure food security for an increasing world population. PMID- 28811378 TI - Opinion: Climate policymakers and assessments must get serious about climate engineering. PMID- 28811376 TI - In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer. AB - Epithelial ovarian cancer (EOC) is a deadly cancer, and its prognosis has not been changed significantly during several decades. To seek new therapeutic targets for EOC, we performed an in vivo dropout screen in human tumor xenografts using a pooled shRNA library targeting thousands of druggable genes. Then, in follow-up studies, we performed a second screen using a genome-wide CRISPR/Cas9 library. These screens identified 10 high-confidence drug targets that included well-known oncogenes such as ERBB2 and RAF1, and novel oncogenes, notably KPNB1, which we investigated further. Genetic and pharmacological inhibition showed that KPNB1 exerts its antitumor effects through multiphase cell cycle arrest and apoptosis induction. Mechanistically, proteomic studies revealed that KPNB1 acts as a master regulator of cell cycle-related proteins, including p21, p27, and APC/C. Clinically, EOC patients with higher expression levels of KPNB1 showed earlier recurrence and worse prognosis than those with lower expression levels of KPNB1. Interestingly, ivermectin, a Food and Drug Administration-approved antiparasitic drug, showed KPNB1-dependent antitumor effects on EOC, serving as an alternative therapeutic toward EOC patients through drug repositioning. Last, we found that the combination of ivermectin and paclitaxel produces a stronger antitumor effect on EOC both in vitro and in vivo than either drug alone. Our studies have thus identified a combinatorial therapy for EOC, in addition to a plethora of potential drug targets. PMID- 28811379 TI - Geography of intergenerational mobility and child development. AB - Recent research by Chetty and colleagues finds that children's chances of upward mobility are affected by the communities in which they grow up [Chetty R, Hendren N (2016) Working paper 23002]. However, the developmental pathways through which communities of origin translate into future economic gain are not well understood. In this paper we examine the association between Chetty and Hendren's county-level measure of intergenerational mobility and children's cognitive and behavioral development. Focusing on children from low-income families, we find that growing up in a county with high upward mobility is associated with fewer externalizing behavioral problems by age 3 years and with substantial gains in cognitive test scores between ages 3 and 9 years. Growing up in a county with 1 SD better intergenerational mobility accounts for ~20% of the gap in developmental outcomes between children from low- and high-income families. Collectively, our findings suggest that the developmental processes through which residential contexts promote upward mobility begin early in childhood and involve the enrichment of both cognitive and social-emotional development. PMID- 28811380 TI - Reply to Remy et al.: Local and global limitations to forest productivity as mediators of biogeochemical response to forest edge effects. PMID- 28811381 TI - Edge effects in temperate forests subjected to high nitrogen deposition. PMID- 28811383 TI - Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling. AB - Pathogens deploy immune evasion strategies to successfully establish infections within their hosts. Naturally, the host responds by acquiring mechanisms to counter these strategies. There is increasing evidence that the three interleukin 36 (IL-36) cytokines, IL-36alpha, IL-36beta and IL-36gamma, play important roles in host immunity. With a focus on the skin as a target for microbial and viral invasion, the current knowledge of IL-36 functions is reviewed. Furthermore, the hypothesis that the IL-36s have evolved to counteract virulence factors is presented using viruses as an example. The IL-36s are related to IL-1alpha, IL 1beta, IL-18, and IL-33. Numerous viruses affecting the skin have developed immune evasion strategies that neutralize IL-1alpha, IL-1beta, or IL-18 signaling or combinations of these pathways. Through small differences in activation mechanisms and receptor utilization, it is possible that IL-36 signaling may proceed unhindered in the presence of these viral inhibitors. Thus, one physiological function of the IL-36s may be to counteract microbial immune evasion. PMID- 28811384 TI - Loss of SPDEF and gain of TGFBI activity after androgen deprivation therapy promote EMT and bone metastasis of prostate cancer. AB - Androgen deprivation therapy (ADT) targeting the androgen receptor (AR) is a standard therapeutic regimen for treating prostate cancer. However, most tumors progress to metastatic castration-resistant prostate cancer after ADT. We identified the type 1, 2, and 4 collagen-binding protein transforming growth factor-beta (TGFbeta)-induced protein (TGFBI) as an important factor in the epithelial-to-mesenchymal transition (EMT) and malignant progression of prostate cancer. In prostate cancer cell lines, AR signaling stimulated the activity of the transcription factor SPDEF, which repressed the expression of TGFBI ADT, AR antagonism, or overexpression of TGFBI inhibited the activity of SPDEF and enhanced the proliferation rates of prostate cancer cells. Knockdown of TGFBI suppressed migration and proliferation in cultured cells and reduced prostate tumor growth and brain and bone metastasis in xenograft models, extending the survival of tumor-bearing mice. Analysis of prostate tissue samples collected before and after ADT from the same patients showed that ADT reduced the nuclear abundance of SPDEF and increased the production of TGFBI. Our findings suggest that induction of TGFBI promotes prostate cancer growth and metastasis and can be caused by dysregulation or therapeutic inhibition of AR signaling. PMID- 28811382 TI - An engineered S1P chaperone attenuates hypertension and ischemic injury. AB - Endothelial dysfunction, a hallmark of vascular disease, is restored by plasma high-density lipoprotein (HDL). However, a generalized increase in HDL abundance is not beneficial, suggesting that specific HDL species mediate protective effects. Apolipoprotein M-containing HDL (ApoM+HDL), which carries the bioactive lipid sphingosine 1-phosphate (S1P), promotes endothelial function by activating G protein-coupled S1P receptors. Moreover, HDL-bound S1P is limiting in several inflammatory, metabolic, and vascular diseases. We report the development of a soluble carrier for S1P, ApoM-Fc, which activated S1P receptors in a sustained manner and promoted endothelial function. In contrast, ApoM-Fc did not modulate circulating lymphocyte numbers, suggesting that it specifically activated endothelial S1P receptors. ApoM-Fc administration reduced blood pressure in hypertensive mice, attenuated myocardial damage after ischemia/reperfusion injury, and reduced brain infarct volume in the middle cerebral artery occlusion model of stroke. Our proof-of-concept study suggests that selective and sustained targeting of endothelial S1P receptors by ApoM-Fc could be a viable therapeutic strategy in vascular diseases. PMID- 28811385 TI - Circulating miR-200c is up-regulated in paediatric patients with familial hypercholesterolaemia and correlates with miR-33a/b levels: implication of a ZEB1 dependent mechanism. AB - Hypercholesterolaemia provokes reactive oxygen species (ROS) increase and is a major risk factor for cardiovascular disease (CVD) development. We previously showed that circulating miR-33a/b expression levels were up-regulated in children with familial hypercholesterolaemia (FH). miR-33a/b control cholesterol homoeostasis and recently miR-33b has been demonstrated to directly target the transcription factor zinc finger E-box-binding homeobox 1 (ZEB1). The latter acts in a negative feedback loop with the miR-200 family. Our previous studies showed that the ROS-dependent miR-200c up-regulation induces endothelial dysfunction and provokes a ZEB1-dependent apoptosis and senescence. In the present study, we aimed to verify whether circulating miR-200c was induced in FH children, and whether a correlation existed with miR-33a/b Total RNA was extracted from plasma of 28 FH children and 25 age-matched healthy subjects (HS) and miR-200c levels were measured. We found that miR-200c was up-regulated in FH compared with HS (4.00 +/- 0.48-fold increase, P<0.05) and exhibited a positive correlation with miR-33a/b. miR-200c did not correlate with plasma lipids, but correlated with C reactive protein (CRP) plasma levels and glycaemia (GLI). Ordinary least squares (OLS) regression analysis revealed that miR-200c was significantly affected by GLI and by miR-33a (P<0.01; P<0.001 respectively). Moreover, we found that miR-33 overexpression, in different cell lines, decreased ZEB1 expression and up regulated both the intracellular and the extracellular miR-200c expression levels. In conclusion, circulating miR-200c is up-regulated in FH, probably due to oxidative stress and inflammation and via a miR-33a/b-ZEB1-dependent mechanism. The present study could provide the first evidence to point to the use of miR-33a/b and miR-200c, as early biomarkers of CVD, in paediatric FH. PMID- 28811386 TI - Trimetazidine protects retinal ganglion cells from acute glaucoma via the Nrf2/Ho 1 pathway. AB - Acute glaucoma is one of the leading causes of irreversible vision impairment characterized by the rapid elevation of intraocular pressure (IOP) and consequent retinal ganglion cell (RGC) death. Oxidative stress and neuroinflammation have been considered critical for the pathogenesis of RGC death in acute glaucoma. Trimetazidine (TMZ), an anti-ischemic drug, possesses antioxidative and anti inflammatory properties, contributing to its therapeutic potential in tissue damage. However, the role of TMZ in acute glaucoma and the underlying molecular mechanisms remain elusive. Here, we report that treatment with TMZ significantly attenuated retinal damage and RGC death in mice with acute glaucoma, with a significant decrease in reactive oxygen species (ROS) and inflammatory cytokine production in the retina. Furthermore, TMZ treatment directly decreased ROS production and rebalanced the intracellular redox state, thus contributing to the survival of RGCs in vitro TMZ treatment also reduced the production of inflammatory cytokines in vitro Mechanistically, the TMZ-mediated inhibition of apoptosis and inflammatory cytokine production in RGCs occurred via the regulation of the nuclear factor erythroid 2-related factor 2/heme oxygenase 1/caspase-8 pathway. Moreover, the TMZ-mediated neuroprotection in acute glaucoma was abrogated when an HO-1 inhibitor, SnPP, was used. Our findings identify potential mechanisms of RGC apoptosis and propose a novel therapeutic agent, TMZ, which exerts a precise neuroprotective effect against acute glaucoma. PMID- 28811387 TI - Selection Constrains High Rates of Tandem Repetitive DNA Mutation in Daphnia pulex. AB - A long-standing evolutionary puzzle is that all eukaryotic genomes contain large amounts of tandemly-repeated DNA whose sequence motifs and abundance vary greatly among even closely related species. To elucidate the evolutionary forces governing tandem repeat dynamics, quantification of the rates and patterns of mutations in repeat copy number and tests of its selective neutrality are necessary. Here, we used whole-genome sequences of 28 mutation accumulation (MA) lines of Daphnia pulex, in addition to six isolates from a non-MA population originating from the same progenitor, to both estimate mutation rates of abundances of repeat sequences and evaluate the selective regime acting upon them. We found that mutation rates of individual repeats were both high and highly variable, ranging from additions/deletions of 0.29-105 copies per generation (reflecting changes of 0.12-0.80% per generation). Our results also provide evidence that new repeat sequences are often formed from existing ones. The non-MA population isolates showed a signal of either purifying or stabilizing selection, with 33% lower variation in repeat copy number on average than the MA lines, although the level of selective constraint was not evenly distributed across all repeats. The changes between many pairs of repeats were correlated, and the pattern of correlations was significantly different between the MA lines and the non-MA population. Our study demonstrates that tandem repeats can experience extremely rapid evolution in copy number, which can lead to high levels of divergence in genome-wide repeat composition between closely related species. PMID- 28811389 TI - News Feature: Putting fossils to work in hopes of restoration. PMID- 28811388 TI - Hill-Robertson Interference Reduces Genetic Diversity on a Young Plant Y Chromosome. AB - X and Y chromosomes differ in effective population size (Ne ), rates of recombination, and exposure to natural selection, all of which can affect patterns of genetic diversity. On Y chromosomes with suppressed recombination, natural selection is expected to eliminate linked neutral variation, and lower the Ne of Y compared to X chromosomes or autosomes. However, female-biased sex ratios and high variance in male reproductive success can also reduce Y-linked Ne , making it difficult to infer the causes of low Y-diversity. Here, we investigate the factors affecting levels of polymorphism during sex chromosome evolution in the dioecious plant Rumexhastatulus (Polygonaceae). Strikingly, we find that neutral diversity for genes on the Y chromosome is, on average, 2.1% of the value for their X-linked homologs, corresponding to a chromosome-wide reduction of 93% compared to the standard neutral expectation. We demonstrate that the magnitude of this diversity loss is inconsistent with reduced male Ne caused by neutral processes. Instead, using forward simulations and estimates of the distribution of deleterious fitness effects, we show that Y chromosome diversity loss can be explained by purifying selection acting in aggregate over a large number of genetically linked sites. Simulations also suggest that our observed level of Y-diversity is consistent with the joint action of purifying and positive selection, but only for models in which there were fewer constrained sites than we empirically estimated. Given the relatively recent origin of R. hastatulus sex chromosomes, our results imply that Y-chromosome degeneration in the early stages may be largely driven by selective interference rather than by neutral genetic drift of silenced Y-linked genes. PMID- 28811391 TI - Cardiac implantable electronic device lead extraction using the lead-locking device system: keeping it simple, safe, and inexpensive with mechanical tools and local anesthesia. AB - OBJECTIVE: We have previously reported our successful approach for percutaneous cardiac implantable electronic device (CIED) lead extraction using inexpensive tools, which we have continued over the years. Herein we report the results of the systematic use of a unique stylet, the lead-locking device (LLD), which securely locks the entire lead lumen, aided with non-powered telescoping sheaths in 54 patients to extract 98 CIED leads. METHODS: This prospective observational clinical study included 38 men and 16 women aged 68.9+/-13.1 years undergoing lead extraction for device infection (n=46), lead malfunction (n=5), or prior to defibrillator implant (n=3). Leads were in place for 6.7+/-4.3 years. Infections were more commonly due to Staphylococcus species (n=40). There were 78 pacing (31 ventricular, 37 atrial, 4 VDD, and 6 coronary sinus leads) and 20 defibrillating leads. RESULTS: Using simple traction (6 leads) and the LLD stylets (92 leads) aided with telescoping sheaths (15 patients), 96 (98%) leads in 52 (96.3%) patients were successfully removed, with all but one leads removed using a subclavian approach; in 1 patient, the right femoral approach was also required. In 2 patients, distal fragments from one ventricular pacing and one defibrillating lead could not be removed. Finally, lead removal was completely (52/54) (96.3%) or partially (2/54) (3.7%) successful in 54 patients for 96 of 98 leads (98%) without major complications. CONCLUSION: Percutaneous lead extraction can be successful with mechanical tools using the LLD locking stylet aided with non-powered telescoping sheaths through a simplified, safe, and inexpensive procedure using local anesthesia. PMID- 28811392 TI - Role of sympathetic cotransmitter galanin on autonomic balance in heart failure: an active player or a bystander? AB - OBJECTIVE: Galanin, a cotransmitter similar to neuropeptide Y (NPY), aggravates autonomic imbalance in systolic heart failure (HF) by attenuating vagal tonus after burst sympathetic activity. In animal HF models, galanin antagonists have improved cardiac function. To determine whether galanin is a promising therapeutic target in HF, we studied its concentrations in HF patients and evaluated its correlation with NPY, markers of humoral activity such as pro-BNP and copeptin, and echocardiographic parameters of HF severity. METHODS: After recording demographic and echocardiographic characteristics of 87 individuals (57 HF patients and 30 control subjects), fasting serum concentrations of galanin, NPY, copeptin, and pro-BNP were determined. RESULTS: Unlike pro-BNP, copeptin, and NPY, which were significantly elevated in HF patients (p<0.001, p<0.001, and p=0.001, respectively), galanin was similar in HF patients and control subjects (p=0.9). NPY correlated with the echocardiographic parameters of HF severity (r= 0.22, p=0.03 for EF; r=0.3, p=0.005 for Tei index of RV; r=-0.23, p=0.03 for TAPSE; and r=0.24, p=0.024 for E/e') and pro-BNP (r=0.22, p=0.046). NPY levels were also associated with beta blocker (BB) use, wherein BB significantly decreased NPY in both HF patients and control subjects. Galanin correlated with humoral biomarkers, pro-BNP and copeptin (r=0.39, p<0.001 and r=0.41, p<0.001, respectively). Although current smoking, BB therapy, pro-BNP, copeptin, and body mass index were associated with galanin in univariate analyses, the multiple linear regression model revealed that pro-BNP was the only significant determinant of galanin levels in HF patients. CONCLUSION: Our findings confirmed the role of NPY in autonomic balance and suggest that galanin is associated with the proadrenergic state, but its role in HF in humans remains unclear. PMID- 28811393 TI - Analysis of geographical variations in the epidemiology and management of non valvular atrial fibrillation: results from the RAMSES registry. AB - OBJECTIVE: This study aimed to determine the differences in terms of demographic characteristics and preferred stroke prevention strategies for patients with non valvular atrial fibrillation living in seven geographical regions of Turkey. METHODS: In total, 6273 patients were enrolled to this prospective, observational RAMSES study. The patients were divided into seven groups based on the geographical region of residence. RESULTS: In terms of the geographical distribution of the overall Turkish population, the highest number of patients were enrolled from Marmara (1677, 26.7%). All demographic characteristics were significantly different among regions. Preferred oral anticoagulants (OACs) also differed between geographical regions; non-vitamin K OACs were preceded by warfarin in East Anatolia, Aegean, Southeast Anatolia, and Black Sea. Nearly one third of the patients (28%) did not receive any OAC therapy. However, the number of patients not receiving any OAC therapy was higher in Southeast Anatolia (51.1%) and East Anatolia (46.8%) compared with other geographical regions of Turkey. Inappropriate use of OACs was also more common in East and Southeast Anatolia. CONCLUSION: This study was the first to show that the demographic differences among the geographical regions may result in different preferences of stroke prevention strategies in Turkey. OACs are still under- or inappropriately utilized, particularly in the eastern provinces of Turkey. PMID- 28811394 TI - Overview and current management of computerized adaptive testing in licensing/certification examinations. AB - Computerized adaptive testing (CAT) has been implemented in high-stakes examinations such as the National Council Licensure Examination-Registered Nurses in the United States since 1994. Subsequently, the National Registry of Emergency Medical Technicians in the United States adopted CAT for certifying emergency medical technicians in 2007. This was done with the goal of introducing the implementation of CAT for medical health licensing examinations. Most implementations of CAT are based on item response theory, which hypothesizes that both the examinee and items have their own characteristics that do not change. There are 5 steps for implementing CAT: first, determining whether the CAT approach is feasible for a given testing program; second, establishing an item bank; third, pretesting, calibrating, and linking item parameters via statistical analysis; fourth, determining the specification for the final CAT related to the 5 components of the CAT algorithm; and finally, deploying the final CAT after specifying all the necessary components. The 5 components of the CAT algorithm are as follows: item bank, starting item, item selection rule, scoring procedure, and termination criterion. CAT management includes content balancing, item analysis, item scoring, standard setting, practice analysis, and item bank updates. Remaining issues include the cost of constructing CAT platforms and deploying the computer technology required to build an item bank. In conclusion, in order to ensure more accurate estimations of examinees' ability, CAT may be a good option for national licensing examinations. Measurement theory can support its implementation for high-stakes examinations. PMID- 28811395 TI - A new experimental community pharmacy internship module for undergraduate pharmacy students in western Nepal: overview and reflections. AB - Community pharmacies in Nepal and other South Asian countries are in a mediocre state due to poor regulation and the fact that many pharmacies are run by people with insufficient training in dispensing. This has led to the inappropriate use of medicines. The problems due to poor regulation and the mediocre state of community pharmacies in South Asia encompass both academia and clinical practice. In this paper, a 2-week community pharmacy internship programme completed by 2 graduating pharmacy students of Pokhara University (a Nepalese public university) at Sankalpa Pharmacy, Pokhara, Nepal is illustrated. During the internship, they were systematically trained on store management, pharmaceutical care, counselling skills, the use of medical devices, pharmaceutical business plans, medicine information sources, and adverse drug reaction reporting. An orientation, observations and hands-on training, case presentation, discussion, and feedback from 2 senior pharmacists were used as the training method. A proper community pharmacy internship format, good pharmacy practice standards, and a better work environment for pharmacists may improve the quality of community pharmacies. PMID- 28811396 TI - Influence of Fracture Width on Sealability in High-Strength and Ultra-Low Permeability Concrete in Seawater. AB - For cementitious composites and materials, the sealing of fractures can occur in water by the precipitation of calcium compounds. In this study, the sealing behavior in a macro-fractured high-strength and ultra-low-permeability concrete (HSULPC) specimen was investigated in simulated seawater using micro-focus X-ray computed tomography (CT). In particular, the influence of fracture width (0.10 and 0.25 mm) on fracture sealing was investigated. Precipitation occurred mainly at the outermost parts of the fractured surface of the specimen for both fracture widths. While significant sealing was observed for the fracture width of 0.10 mm, sealing was not attained for the fracture width of 0.25 mm within the observation period (49 days). Examination of the sealed regions on the macro-fracture was performed using a three-dimensional image registration technique and applying image subtraction between the CT images of the HSULPC specimen before and after maintaining the specimen in simulated seawater. The temporal change of the sealing deposits for the fracture width of 0.10 mm was much larger than that for the fracture width of 0.25 mm. Therefore, it is concluded that the sealability of the fracture in the HSULPC is affected by the fracture width. PMID- 28811397 TI - A Review of Luminescent Anionic Nano System: d10 Metallocyanide Excimers and Exciplexes in Alkali Halide Hosts. AB - Dicyanoaurate, dicyanoargentate, and dicyanocuprate ions in solution and doped in different alkali halide hosts exhibit interesting photophysical and photochemical behavior, such as multiple emission bands, exciplex tuning, optical memory, and thermochromism. This is attributed to the formation of different sizes of nanoclusters in solution and in doped hosts. A series of spectroscopic methods (luminescence, UV-reflectance, IR, and Raman) as well as theoretical calculations have confirmed the existence of excimers and exciplexes. This leads to the tunability of these nano systems over a wide wavelength interval. The population of these nanoclusters varies with temperature and external laser irradiation, which explains the thermochromism and optical memory. DFT calculations indicate an MLCT transition for each nanocluster and the emission energy decreases with increasing cluster size. This is in agreement with the relatively long life-time for the emission peaks and the multiple emission peaks dependence upon cluster concentration. PMID- 28811398 TI - Localized Overheating Phenomena and Optimization of Spark-Plasma Sintering Tooling Design. AB - The present paper shows the application of a three-dimensional coupled electrical, thermal, mechanical finite element macro-scale modeling framework of Spark Plasma Sintering (SPS) to an actual problem of SPS tooling overheating, encountered during SPS experimentation. The overheating phenomenon is analyzed by varying the geometry of the tooling that exhibits the problem, namely by modeling various tooling configurations involving sequences of disk-shape spacers with step-wise increasing radii. The analysis is conducted by means of finite element simulations, intended to obtain temperature spatial distributions in the graphite press-forms, including punches, dies, and spacers; to identify the temperature peaks and their respective timing, and to propose a more suitable SPS tooling configuration with the avoidance of the overheating as a final aim. Electric currents-based Joule heating, heat transfer, mechanical conditions, and densification are imbedded in the model, utilizing the finite-element software COMSOLTM, which possesses a distinguishing ability of coupling multiple physics. Thereby the implementation of a finite element method applicable to a broad range of SPS procedures is carried out, together with the more specific optimization of the SPS tooling design when dealing with excessive heating phenomena. PMID- 28811399 TI - A Fundamental Limitation of Small Diameter Single-Walled Carbon Nanotube Synthesis-A Scaling Rule of the Carbon Nanotube Yield with Catalyst Volume. AB - Understanding the fundamental mechanisms and limiting processes of the growth of single-walled carbon nanotube (SWCNT) would serve as a guide to achieve further control on structural parameters of SWCNT. In this paper, we have studied the growth kinetics of a series of SWCNT forests continuously spanning a wide range of diameters (1.9-3.2 nm), and have revealed an additional fundamental growth limiting process where the mass of the individual SWCNT is determined by the individual catalyst volume. Calculation of the conversion rate of carbon atoms into CNTs per Fe atom is 2 * 102 atoms per second. This rate limiting process provides an important understanding where the larger diameter SWCNT would grow faster, and thus be more suited for mass production. PMID- 28811400 TI - Spinnability and Characteristics of Polyvinylidene Fluoride (PVDF)-based Bicomponent Fibers with a Carbon Nanotube (CNT) Modified Polypropylene Core for Piezoelectric Applications. AB - This research explains the melt spinning of bicomponent fibers, consisting of a conductive polypropylene (PP) core and a piezoelectric sheath (polyvinylidene fluoride). Previously analyzed piezoelectric capabilities of polyvinylidene fluoride (PVDF) are to be exploited in sensor filaments. The PP compound contains a 10 wt % carbon nanotubes (CNTs) and 2 wt % sodium stearate (NaSt). The sodium stearate is added to lower the viscosity of the melt. The compound constitutes the fiber core that is conductive due to a percolation CNT network. The PVDF sheath's piezoelectric effect is based on the formation of an all-trans conformation beta phase, caused by draw-winding of the fibers. The core and sheath materials, as well as the bicomponent fibers, are characterized through different analytical methods. These include wide-angle X-ray diffraction (WAXD) to analyze crucial parameters for the development of a crystalline beta phase. The distribution of CNTs in the polymer matrix, which affects the conductivity of the core, was investigated by transmission electron microscopy (TEM). Thermal characterization is carried out by conventional differential scanning calorimetry (DSC). Optical microscopy is used to determine the fibers' diameter regularity (core and sheath). The materials' viscosity is determined by rheometry. Eventually, an LCR tester is used to determine the core's specific resistance. PMID- 28811401 TI - Diffusion Study by IR Micro-Imaging of Molecular Uptake and Release on Mesoporous Zeolites of Structure Type CHA and LTA. AB - The presence of mesopores in the interior of microporous particles may significantly improve their transport properties. Complementing previous macroscopic transient sorption experiments and pulsed field gradient NMR self diffusion studies with such materials, the present study is dedicated to an in depth study of molecular uptake and release on the individual particles of mesoporous zeolitic specimens, notably with samples of the narrow-pore structure types, CHA and LTA. The investigations are focused on determining the time constants and functional dependences of uptake and release. They include a systematic variation of the architecture of the mesopores and of the guest molecules under study as well as a comparison of transient uptake with blocked and un-blocked mesopores. In addition to accelerating intracrystalline mass transfer, transport enhancement by mesopores is found to be, possibly, also caused by a reduction of transport resistances on the particle surfaces. PMID- 28811402 TI - Effect of Ni Core Structure on the Electrocatalytic Activity of Pt-Ni/C in Methanol Oxidation. AB - Methanol oxidation catalysts comprising an outer Pt-shell with an inner Ni-core supported on carbon, (Pt-Ni/C), were prepared with either crystalline or amorphous Ni core structures. Structural comparisons of the two forms of catalyst were made using transmission electron microscopy (TEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS), and methanol oxidation activity compared using CV and chronoamperometry (CA). While both the amorphous Ni core and crystalline Ni core structures were covered by similar Pt shell thickness and structure, the Pt-Ni(amorphous)/C catalyst had higher methanol oxidation activity. The amorphous Ni core thus offers improved Pt usage efficiency in direct methanol fuel cells. PMID- 28811403 TI - Millimeter Wave Radiations Affect Membrane Hydration in Phosphatidylcholine Vesicles. AB - A clear understanding of the response of biological systems to millimeter waves exposure is of increasing interest for the scientific community due to the recent convincing use of these radiations in the ultrafast wireless communications. Here we report a deuterium nuclear magnetic resonance spectroscopy (2H-NMR) investigation on the effects of millimeter waves in the 53-78 GHz range on phosphocholine bio-mimetic membranes. Millimeter waves significantly affect the polar interface of the membrane causing a decrease of the heavy water quadrupole splitting. This effect is as important as inducing the transition from the fluid to the gel phase when the membrane exposure occurs in the neighborhood of the transition point. On the molecular level, the above effect can be well explained by membrane dehydration induced by the radiation. PMID- 28811404 TI - Cytotoxic Effects of Hydroxylated Fullerenes in Three Types of Liver Cells. AB - Fullerenes C60 have attracted considerable attention in the biomedical field due to their interesting properties. Although there has been a concern that C60 could be metabolized to hydroxylated fullerenes (C60(OH)x) in vivo, there is little information on the effect of hydroxylated C60 on liver cells. In the present study, we evaluated the cytotoxic effects of fullerene C60 and various hydroxylated C60 derivatives, C60(OH)2, C60(OH)6-12, C60(OH)12 and C60(OH)36, with three different types of liver cells, dRLh-84, HepG2 and primary cultured rat hepatocytes. C60, C60(OH)2 and C60(OH)36 exhibited little or no cytotoxicity in all of the cell types, while C60(OH)6-12 and C60(OH)12 induced cytotoxic effects in dRLh-84 cells, accompanied by the appearance of numerous vacuoles around the nucleus. Moreover, mitochondrial activity in liver cells was significantly inhibited by C60(OH)6-12 and C60(OH)12. These results indicate that the number of hydroxyl groups on C60(OH)x contribute to the difference of their cytotoxic potential and mitochondrial damage in liver cells. PMID- 28811405 TI - Fractional Factorial Design Study on the Performance of GAC-Enhanced Electrocoagulation Process Involved in Color Removal from Dye Solutions. AB - The aim of this study was to determine the effects of main factors and interactions on the color removal performance from dye solutions using the electrocoagulation process enhanced by adsorption on Granular Activated Carbon (GAC). In this study, a mathematical approach was conducted using a two-level fractional factorial design (FFD) for a given dye solution. Three textile dyes: Acid Blue 74, Basic Red 1, and Reactive Black 5 were used. Experimental factors used and their respective levels were: current density (2.73 or 27.32 A/m2), initial pH of aqueous dye solution (3 or 9), electrocoagulation time (20 or 180 min), GAC dose (0.1 or 0.5 g/L), support electrolyte (2 or 50 mM), initial dye concentration (0.05 or 0.25 g/L) and current type (Direct Current-DC or Alternative Pulsed Current-APC). GAC-enhanced electrocoagulation performance was analyzed statistically in terms of removal efficiency, electrical energy, and electrode material consumptions, using modeling polynomial equations. The statistical significance of GAC dose level on the performance of GAC enhanced electrocoagulation and the experimental conditions that favor the process operation of electrocoagulation in APC regime were determined. The local optimal experimental conditions were established using a multi-objective desirability function method. PMID- 28811406 TI - The Influence of Processing and the Polymorphism of Lignocellulosic Fillers on the Structure and Properties of Composite Materials-A Review. AB - Cellulose is the most important and the most abundant plant natural polymer. It shows a number of interesting properties including those making it attractive as a filler of composite materials with a thermoplastic polymer matrix. Production of such composite materials, meeting the standards of green technology, has increased from 0.36 million tons in 2007 to 2.33 million tons in 2012. It is predicted that by 2020 their production will reach 3.45 million tons. Production of biocomposites with lignocellulosic components poses many problems that should be addressed. This paper is a review of the lignocellulosic materials currently used as polymer fillers. First, the many factors determining the macroscopic properties of such composites are described, with particular attention paid to the poor interphase adhesion between the polymer matrix and a lignocellulosic filler and to the effects of cellulose occurrence in polymorphic varieties. The phenomenon of cellulose polymorphism is very important from the point of view of controlling the nucleation abilities of the lignocellulosic filler and hence the mechanical properties of composites. Macroscopic properties of green composites depend also on the parameters of processing which determine the magnitude and range of shearing forces. The influence of shearing forces appearing upon processing the supermolecular structure of the polymer matrix is also discussed. An important problem from the viewpoint of ecology is the possibility of composite recycling which should be taken into account at the design stage. The methods for recycling of the composites made of thermoplastic polymers filled with renewable lignocellulosic materials are presented and discussed. This paper is a review prepared on the basis of currently available literature which describes the many aspects of the problems related to the possibility of using lignocellulosic components for production of composites with polymers. PMID- 28811407 TI - Synthesis of New RE3+ Doped Li1+xTa1-xTixO3 (RE: Eu, Sm, Er, Tm, and Dy) Phosphors with Various Emission Colors. AB - New phosphors with various emission colors for RE3+ doped Li1+xTa1-xTixO3 (LTT) (RE: Eu, Sm, Er, Tm, and Dy) were synthesized by electric furnace at 1423 K for 15 h. The microstructure of the host material and the photoluminescence (PL) property were determined and compared to those of RE3+ doped Li1+xNb1-xTixO3 (LNT). In the LTT phosphor, the highest PL intensity was achieved for the mixture composition Li1.11Ta0.89Ti0.11O3 with a LiTaO3 structure, although it has an M phase superstructure. In the LTT host material, the effective activators were Eu3+ and Sm3+ ions, in contrast to the LNT host material. Here, we discuss the relationship between PL property and the host material's structure. PMID- 28811408 TI - Amino Alcohol Oxidation with Gold Catalysts: The Effect of Amino Groups. AB - Gold catalysts have been prepared by sol immobilization using Tetrakis(hydroxymethyl) phosphonium chloride (THPC) as a protective and reducing agent or by deposition on different supports (Al2O3, TiO2, MgAl2O4, and MgO). The catalytic systems have been tested in the liquid phase oxidation of aminoalcohols (serinol and ethanolamine) and the corresponding polyols (glycerol and ethylene glycol). This comparison allowed us to state that the presence of amino groups has a crucial effect on the catalytic performance, in particular decreasing the durability to the catalysts, but did not substantially vary the selectivity. A support effect has been as well established. PMID- 28811409 TI - Persistent Luminescence in Non-Eu2+-Doped Compounds: A Review. AB - During the past few decades, the research on persistent luminescent materials has focused mainly on Eu2+-doped compounds. However, the yearly number of publications on non-Eu2+-based materials has also increased steadily. By now, the number of known persistent phosphors has increased to over 200, of which over 80% are not based on Eu2+, but rather, on intrinsic host defects, transition metals (manganese, chromium, copper, etc.) or trivalent rare earths (cerium, terbium, dysprosium, etc.). In this review, we present an overview of these non-Eu2+-based persistent luminescent materials and their afterglow properties. We also take a closer look at some remaining challenges, such as the excitability with visible light and the possibility of energy transfer between multiple luminescent centers. Finally, we summarize the necessary elements for a complete description of a persistent luminescent material, in order to allow a more objective comparison of these phosphors. PMID- 28811410 TI - Optical Constants of Crystallized TiO2 Coatings Prepared by Sol-Gel Process. AB - Titanium oxide coatings have been deposited by the sol-gel dip-coating method. Crystallization of titanium oxide coatings was then achieved through thermal annealing at temperatures above 400 degrees C. The structural properties and surface morphology of the crystallized coatings were studied by micro-Raman spectroscopy and atomic force microscopy, respectively. Characterization technique, based on least-square fitting to the measured reflectance and transmittance spectra, is used to determine the refractive indices of the crystallized TiO2 coatings. The stability of the synthesized sol was also investigated by dynamic light scattering particle size analyzer. The influence of the thermal annealing on the optical properties was then discussed. The increase in refractive index with high temperature thermal annealing process was observed, obtaining refractive index values from 1.98 to 2.57 at He-Ne laser wavelength of 633 nm. The Raman spectroscopy and atomic force microscopy studies indicate that the index variation is due to the changes in crystalline phase, density, and morphology during thermal annealing. PMID- 28811411 TI - Self-Healing of Microcracks in Engineered Cementitious Composites (ECC) Under a Natural Environment. AB - This paper builds on previous self-healing engineered cementitious composites (ECC) research by allowing ECC to heal outdoors, in the natural environment, under random and sometimes extreme environmental conditions. Development of an ECC material that can heal itself in the natural environment could lower infrastructure maintenance costs and allow for more sustainable development in the future by increasing service life and decreasing the amount of resources and energy needed for repairs. Determining to what extent current ECC materials self heal in the natural environment is the first step in the development of an ECC that can completely heal itself when exposed to everyday environmental conditions. This study monitored outdoor ECC specimens for one year using resonant frequency (RF) and mechanical reloading to determine the rate and extent of self-healing in the natural environment. It was found that the level of RF, stiffness, and first cracking strength recovery increased as the duration of natural environment exposure increased. For specimens that underwent multiple damage cycles, it was found that the level of recovery was highly dependent on the average temperature and amount of precipitation between each damage event. However, RF, stiffness, and first cracking strength recovery data for specimens that underwent multiple loading cycles suggest that self-healing functionality can be maintained under multiple damage events. PMID- 28811412 TI - Synthesis and Enhanced Phosphate Recovery Property of Porous Calcium Silicate Hydrate Using Polyethyleneglycol as Pore-Generation Agent. AB - The primary objective of this paper was to synthesize a porous calcium silicate hydrate (CSH) with enhanced phosphate recovery property using polyethyleneglycol (PEG) as pore-generation agent. The formation mechanism of porous CSH was proposed. PEG molecules were inserted into the void region of oxygen-silicon tetrahedron chains and the layers of CSH. A steric hindrance layer was generated to prevent the aggregation of solid particles. A porous structure was formed due to the residual space caused by the removal of PEG through incineration. This porous CSH exhibited highly enhanced solubility of Ca2+ and OH- due to the decreased particle size, declined crystalline, and increased specific surface area (SBET) and pore volume. Supersaturation was increased in the wastewater with the enhanced solubility, which was beneficial to the formation of hydroxyapatite (HAP) crystallization. Thus, phosphate can be recovered from wastewater by producing HAP using porous CSH as crystal seed. In addition, the regenerated phosphate-containing products (HAP) can be reused to achieve sustainable utilization of phosphate. The present research could provide an effective approach for the synthesis of porous CSH and the enhancement of phosphate recovery properties for environmental applications. PMID- 28811413 TI - Role of Fluxes in Optimizing the Optical Properties of Sr0.95Si2O2N2:0.05Eu2+ Green-Emitting Phosphor. AB - Chlorides of NH4Cl and SrCl2 and fluorides of AlF3 and SrF2 were added to raw materials acting as the flux for preparing the SrSi2O2N2:Eu2+ phosphor. The effects of the fluxes on the phase formation, particle morphology, particle size, and photoluminescence properties were investigated. The results revealed that particle size, particle morphology and photoluminescence intensity were largely dominated by the type of the flux material and its adding amount. The chloride based flux was found to favor the formation of the SrSi2O2N2:Eu2+ phase. Among the chloride-based fluxes, the sample added with the SrCl2 flux presented the narrow particle distribution and cleaner surface, with enhanced emission intensity and an increased external quantum efficiency by 68% and 22%, respectively, compared with those of the sample without any flux adding. PMID- 28811414 TI - Polymeric Materials Reinforced with Multiwall Carbon Nanotubes: A Constitutive Material Model. AB - In this paper we have modified an existing material model introduced by Cantournet and co-workers to take into account softening and residual strain effects observed in polymeric materials reinforced with carbon nanotubes when subjected to loading and unloading cycles. In order to assess the accuracy of the modified material model, we have compared theoretical predictions with uniaxial extension experimental data obtained from reinforced polymeric material samples. It is shown that the proposed model follows experimental data well as its maximum errors attained are lower than 2.67%, 3.66%, 7.11% and 6.20% for brominated isobutylene and paramethylstyrene copolymer reinforced with multiwall carbon nanotubes (BIMSM-MWCNT), reinforced natural rubber (NR-MWCNT), polybutadiene carbon black (PB-CB), and PC/ABS reinforced with single-wall carbon nanotubes (SWCNT), respectively. PMID- 28811416 TI - Order-Induced Selectivity Increase of Cu60Pd40 in the Semi-Hydrogenation of Acetylene. AB - The two structural modifications of Cu60Pd40 were synthesized as bulk powders and tested as unsupported model catalysts in the semi-hydrogenation of acetylene. The partly ordered low-temperature modification (CsCl type of structure) showed an outstanding ethylene selectivity of >90% over 20 h on stream while the disordered high-temperature modification (Cu type of structure) was 20% less selective, indicating an influence of the degree of order in the crystal structure on the catalytic properties. The results are supported by XRD and in situ XPS experiments. The latter suggest the existence of partly isolated Pd sites on the surface. In situ PGAA investigations proved the absence of metal hydride formation during reaction. Quantum chemical calculations of the electronic structure of both modifications using the CPA-FPLO framework revealed significant differences in their respective density of states, thus still leaving open the question of whether the degree of structural order or/and the electronic hybridization is the decisive factor for the observed difference in selectivity. PMID- 28811415 TI - Self-Ordered Titanium Dioxide Nanotube Arrays: Anodic Synthesis and Their Photo/Electro-Catalytic Applications. AB - Metal oxide nanotubes have become a widely investigated material, more specifically, self-organized titania nanotube arrays synthesized by electrochemical anodization. As a highly investigated material with a wide gamut of applications, the majority of published literature focuses on the solar-based applications of this material. The scope of this review summarizes some of the recent advances made using metal oxide nanotube arrays formed via anodization in solar-based applications. A general methodology for theoretical modeling of titania surfaces in solar applications is also presented. PMID- 28811417 TI - In Vivo Osteogenic Differentiation of Human Embryoid Bodies in an Injectable in Situ-Forming Hydrogel. AB - In this study, we examined the in vivo osteogenic differentiation of human embryoid bodies (hEBs) by using an injectable in situ-forming hydrogel. A solution containing MPEG-b-(polycaprolactone-ran-polylactide) (MCL) and hEBs was easily prepared at room temperature. The MCL solution with hEBs and osteogenic factors was injected into nude mice and developed into in situ-forming hydrogels at the injection sites; these hydrogels maintained their shape even after 12 weeks in vivo, thereby indicating that the in situ-forming MCL hydrogel was a suitable scaffold for hEBs. The in vivo osteogenic differentiation was observed only in the in situ gel-forming MCL hydrogel in the presence of hEBs and osteogenic factors. In conclusion, this preliminary study suggests that hEBs and osteogenic factors embedded in an in situ-forming MCL hydrogel may provide numerous benefits as a noninvasive alternative for allogeneic tissue engineering applications. PMID- 28811418 TI - Preparation and Characterization of New Geopolymer-Epoxy Resin Hybrid Mortars. AB - The preparation and characterization of metakaolin-based geopolymer mortars containing an organic epoxy resin are presented here for the first time. The specimens have been prepared by means of an innovative in situ co-reticulation process, in mild conditions, of commercial epoxy based organic resins and geopolymeric slurry. In this way, geopolymer based hybrid mortars characterized by a different content of normalized sand (up to 66% in weight) and by a homogeneous dispersion of the organic resin have been obtained. Once hardened, these new materials show improved compressive strength and toughness in respect to both the neat geopolymer and the hybrid pastes since the organic polymer provides a more cohesive microstructure, with a reduced amount of microcracks. The microstructural characterization allows to point out the presence of an Interfacial Transition Zone similar to that observed in cement based mortars and concretes. A correlation between microstructural features and mechanical properties has been studied too. PMID- 28811419 TI - Charged Polymers Transport under Applied Electric Fields in Periodic Channels. AB - By molecular dynamics simulations, we investigated the transport of charged polymers in applied electric fields in confining environments, which were straight cylinders of uniform or non-uniform diameter. In the simulations, the solvent was modeled explicitly and, also, the counterions and coions of added salt. The electrophoretic velocities of charged chains in relation to electrolyte friction, hydrodynamic effects due to the solvent, and surface friction were calculated. We found that the velocities were higher if counterions were moved away from the polymeric domain, which led to a decrease in hydrodynamic friction. The topology of the surface played a key role in retarding the motion of the polyelectrolyte and, even more so, in the presence of transverse electric fields. The present study showed that a possible way of improving separation resolution is by controlling the motion of counterions or electrolyte friction effects. PMID- 28811420 TI - The Influence of Alkoxy Substitutions on the Properties of Diketopyrrolopyrrole Phenyl Copolymers for Solar Cells. AB - A previously reported diketopyrrolopyrrole (DPP)-phenyl copolymer is modified by adding methoxy or octyloxy side chains on the phenyl spacer. The influence of these alkoxy substitutions on the physical, opto-electronic properties, and photovoltaic performance were investigated. It was found that the altered physical properties correlated with an increase in chain flexibility. Well defined oligomers were synthesized to verify the observed structure-property relationship. Surprisingly, methoxy substitution on the benzene spacer resulted in higher melting and crystallization temperatures in the synthesized oligomers. This trend is not observed in the polymers, where the improved interactions are most likely counteracted by the larger conformational possibilities in the polymer chain upon alkoxy substitution. The best photovoltaic performance was obtained for the parent polymer: fullerene blends whereas the modifications on the other two polymers result in reduced open-circuit voltage and varying current densities under similar processing conditions. The current densities could be related to different polymer: fullerene blend morphologies. These results show that supposed small structural alterations such as methoxy substitution already significantly altered the physical properties of the parent polymer and also that oligomers and polymers respond divergent to structural alterations made on a parent structure. PMID- 28811421 TI - UV Spectrometric Indirect Analysis of Brominated MWCNTs with UV Active Thiols and an Alkene-Reaction Kinetics, Quantification and Differentiation of Adsorbed Bromine and Oxygen. AB - Indirect UV-absorption spectrometry was shown to be a valuable tool for chemical characterization of functionalized carbon nanotubes (CNTs). It complements data from X-ray photoelectron spectroscopy (XPS) or FTIR analysis since it helps to clarify the type and concentration of functional groups. The principles of indirect application of UV-spectrometry and its mathematical interpretation are discussed. Their facile application, together with their adequate sensitivity and high flexibility, make UV-absorption-based approaches a valuable alternative to fluorescence spectrometry. Here, the approach was applied to the chemical analysis of oxidizing substances on CNTs. For this, pristine CNTs of low but finite oxygen content as well as brominated CNTs were analyzed by reaction in suspension with UV-active thiol reagents and a styrene derivative. It was shown that carefully selected reagents allow differentiation and quantification of bromine and generally oxidizing entities like oxygen. For brominated CNTs, it was shown that physisorbed bromine may dominate the overall bromine content. PMID- 28811422 TI - Enrichment of Large-Diameter Single-Walled Carbon Nanotubes (SWNTs) with Metallo Octaethylporphyrins. AB - We report here a detailed experimental investigation on noncovalent functionalization of single-walled carbon nanotubes (SWNTs) with four different metallo-octaethylporphyrins (MOEPs). It has been found that the identity of the center metal of MOEP strongly influences the solubilization of SWNTs. MnOEPs and ZnOEPs successfully extracted SWNTs in methanol, as confirmed by absorption spectroscopy, while CoOEPs and CuOEPs were not able to extract SWNTs at all. Atomic force microscopy (AFM) studies revealed that large SWNTs bundles could be exfoliated into either individual SWNTs or very small bundles by complexation with ZnOEP molecules. As for enrichment of SWNTs, ZnOEPs and MnOEPs show similar diameter discrimination ability toward 76-CoMoCAT, providing the extracted SWNTs with relatively large diameters. PMID- 28811423 TI - Red, Green, and Blue Photoluminescence of Ba2SiO4:M (M = Eu3+, Eu2+, Sr2+) Nanophosphors. AB - Divalent europium doped barium orthosilicate is a very important phosphor for the production of light emitting diodes (LEDs), generally associated to the green emission color of micron-sized crystals synthesized by means of solid-state reactions. This work presents the combustion synthesis as an energy and time saving preparation method for very small nano-sized Ba2SiO4 particles, flexibly doped to acquire different emission energies. The size of the resulting spherical nanoparticles (NPs) of the green emitting Ba2SiO4:Eu2+ was estimated to about 35 nm applying the Scherrer equation and further characterized with aid of atomic force microscopy (AFM) as well as scanning electron microscopy (SEM). This phosphor is able to build homogeneous luminescent suspensions and was successfully down-sized without changing the optical properties in comparison to the bulk phosphors. Besides the X-ray diffraction (XRD) analysis and the different types of microscopy, the samples were characterized by luminescence spectroscopy. Undoped Ba2SiO4 NPs are not luminescent, but show characteristic red emission of the 5D0 -> 7FJ (J = 0-4) electronic transitions when doped with Eu3+ ions. Moreover, these orthosilicate nanoparticles generate blue light at low temperatures due to impurity-trapped excitons, introduced by the partial substitution of the Ba2+ with Sr2+ ions in the Ba2SiO4 lattice causing a substantial distortion. A model for the temperature behavior of the defect luminescence as well as for their nature is provided, based on temperature dependent luminescence spectra and lifetime measurements. PMID- 28811424 TI - Integration of Carbon Nanotubes in Microsystems: Local Growth and Electrical Properties of Contacts. AB - Carbon nanotubes (CNTs) have been directly grown onto a silicon microsystem by a local synthesis method. This method has potential for wafer-level complimentary metal-oxide-semiconductor (CMOS) transistor-compatible integration of CNTs into more complex Si microsystems; enabling, e.g., gas sensors at low cost. In this work, we demonstrate that the characteristics of CNTs grown on specific locations can be changed by tuning the synthesis conditions. We also investigate the role of the contact between CNTs and the Si microsystem; observing a large influence on the electrical characteristics of our devices. Different contact modes can render either an ohmic or Schottky-like rectifying characteristics. PMID- 28811425 TI - Use of Slag/Sugar Cane Bagasse Ash (SCBA) Blends in the Production of Alkali Activated Materials. AB - Blast furnace slag (BFS)/sugar cane bagasse ash (SCBA) blends were assessed for the production of alkali-activated pastes and mortars. SCBA was collected from a lagoon in which wastes from a sugar cane industry were poured. After previous dry and grinding processes, SCBA was chemically characterized: it had a large percentage of organic matter (ca. 25%). Solutions of sodium hydroxide and sodium silicate were used as activating reagents. Different BFS/SCBA mixtures were studied, replacing part of the BFS by SCBA from 0 to 40% by weight. The mechanical strength of mortar was measured, obtaining values about 60 MPa of compressive strength for BFS/SCBA systems after 270 days of curing at 20 degrees C. Also, microstructural properties were assessed by means of SEM, TGA, XRD, pH, electrical conductivity, FTIR spectroscopy and MIP. Results showed a good stability of matrices developed by means of alkali-activation. It was demonstrated that sugar cane bagasse ash is an interesting source for preparing alkali-activated binders. PMID- 28811426 TI - Effect of Boron-Doped Diamond Interlayer on Cutting Performance of Diamond Coated Micro Drills for Graphite Machining. AB - Thin boron doped diamond (BDD) film is deposited from trimethyl borate/acetone/hydrogen mixture on Co-cemented tungsten carbide (WC-Co) micro drills by using the hot filament chemical vapor deposition (HFCVD) technique. The boron peak on Raman spectrum confirms the boron incorporation in diamond film. This film is used as an interlayer for subsequent CVD of micro-crystalline diamond (MCD) film. The Rockwell indentation test shows that boron doping could effectively improve the adhesive strength on substrate of as deposited thin diamond films. Dry drilling of graphite is chosen to check the multilayer (BDD + MCD) film performance. For the sake of comparison, machining tests are also carried out under identical conditions using BDD and MCD coated micro drills with no interlayer. The wear mechanism of the tools has been identified and correlated with the criterion used to evaluate the tool life. The results show that the multilayer (BDD + MCD) coated micro drill exhibits the longest tool life. Therefore, thin BDD interlayer is proved to be a new viable alternative and a suitable option for adherent diamond coatings on micro cutting tools. PMID- 28811427 TI - Use of Cement Kiln Dust, Blast Furnace Slag and Marble Sludge in the Manufacture of Sustainable Artificial Aggregates by Means of Cold Bonding Pelletization. AB - In this work, three different samples of solid industrial wastes cement kiln dust (CKD), granulated blast furnace slag and marble sludge were employed in a cold bonding pelletization process for the sustainable production of artificial aggregates. The activating action of CKD components on the hydraulic behavior of the slag was explored by evaluating the neo-formed phases present in several hydrated pastes. Particularly, the influence of free CaO and sulfates amount in the two CKD samples on slag reactivity was evaluated. Cold bonded artificial aggregates were characterized by determining physical and mechanical properties of two selected size fractions of the granules for each studied mixture. Eighteen types of granules were employed in C28/35 concrete manufacture where coarser natural aggregate were substituted with the artificial ones. Finally, lightweight concretes were obtained, proving the suitability of the cold bonding pelletization process in artificial aggregate sustainable production. PMID- 28811428 TI - Local Synthesis of Carbon Nanotubes in Silicon Microsystems: The Effect of Temperature Distribution on Growth Structure. AB - Local synthesis and direct integration of carbon nanotubes (CNTs) into microsystems is a promising method for producing CNT-based devices in a single step, low-cost, and wafer-level, CMOS/MEMS-compatible process. In this report, the structure of the locally grown CNTs are studied by transmission imaging in scanning electron microscopy-S(T)EM. The characterization is performed directly on the microsystem, without any post-synthesis processing required. The results show an effect of temperature on the structure of CNTs: high temperature favors thin and regular structures, whereas low temperature favors "bamboo-like" structures. PMID- 28811429 TI - Inorganic Nanoparticle-Modified Poly(Phenylene Sulphide)/ Carbon Fiber Laminates: Thermomechanical Behaviour. AB - Carbon fiber (CF)-reinforced high-temperature thermoplastics such as poly(phenylene sulphide) (PPS) are widely used in structural composites for aerospace and automotive applications. The porosity of CF-reinforced polymers is a very important topic for practical applications since there is a direct correlation between void content and mechanical properties. In this study, inorganic fullerene-like tungsten disulphide (IF-WS2) lubricant nanoparticles were used to manufacture PPS/IF-WS2/CF laminates via melt-blending and hot-press processing, and the effect of IF-WS2 loading on the quality, thermal and mechanical behaviour of the hybrid composites was investigated. The addition of IF-WS2 improved fiber impregnation, resulting in lower degree of porosity and increased delamination resistance, compression and flexural properties; their reinforcement effect was greater at temperatures above the glass transition (Tg). IF-WS2 contents higher than 0.5 wt % increased Tg and the heat deflection temperature while reduced the coefficient of thermal expansion. The multiscale laminates exhibited higher ignition point and notably reduced peak heat release rate compared to PPS/CF. The coexistence of micro- and nano-scale fillers resulted in synergistic effects that enhanced the stiffness, strength, thermal conductivity and flame retardancy of the matrix. The results presented herein demonstrate that the IF-WS2 are very promising nanofillers to improve the thermomechanical properties of conventional thermoplastic/CF composites. PMID- 28811430 TI - A Perspective on the Flame Spray Synthesis of Photocatalyst Nanoparticles. AB - The synthesis of functional nanoparticles via one-step flame spray pyrolysis (FSP), especially those of catalytic nature, has attracted the interests of scientists and engineers, as well as industries. The rapid and high temperature continuous synthesis yields nanoparticles with intrinsic features of active catalysts, that is, high surface area and surface energetics. For these reasons, FSP finds applications in various thermally inducible catalytic reactions. However, the design and synthesis of photocatalysts by FSP requires a knowledge set which is different from that established for thermal catalysts. Unknown to many, this has resulted in frustrations to those entering the field unprepared, especially since FSP appears to be an elegant tool in synthesising oxide nanoparticles of any elemental construct. From simple oxide to doped-oxide, and mixed metal oxide to the in situ deposition of noble metals, this Perspective gives an overview on the development of photocatalysts made by FSP in the last decade that led to a better understanding of the design criteria. Various challenges and opportunities are also highlighted, especially those beyond simple metal oxides, which perhaps contain the greatest potential for the exploitation of photocatalysts design by FSP. PMID- 28811431 TI - Fluorescent Magnetic Bioprobes by Surface Modification of Magnetite Nanoparticles. AB - Bimodal nanoprobes comprising both magnetic and optical functionalities have been prepared via a sequential two-step process. Firstly, magnetite nanoparticles (MNPs) with well-defined cubic shape and an average dimension of 80 nm were produced by hydrolysis of iron sulfate and were then surface modified with silica shells by using the sol-gel method. The Fe3O4@SiO2 particles were then functionalized with the fluorophore, fluorescein isothiocyanate (FITC), mediated by assembled shells of the cationic polyelectrolyte, polyethyleneimine (PEI). The Fe3O4 functionalized particles were then preliminary evaluated as fluorescent and magnetic probes by performing studies in which neuroblast cells have been contacted with these nanomaterials. PMID- 28811432 TI - A New Metasurface Superstrate Structure for Antenna Performance Enhancement. AB - A new metasurface superstrate structure (MSS)-loaded dual band microstrip line fed small patch antenna is presented in this paper. The proposed antenna was designed on a ceramic-filled bioplastic sandwich substrate with a high dielectric constant. The proposed 7 * 6 element, square-shaped, single-sided MSS significantly improved the bandwidth and gain of the proposed antenna. The proposed MSS incorporated a slotted patch antenna that effectively increased the measured operating bandwidth from 13.3% to 18.8% and from 14.8% to 23.2% in the lower and upper bands, respectively. Moreover, the average gain of the proposed MSS-based antenna was enhanced from 2.12 dBi to 3.02 dBi in the lower band and from 4.10 dBi to 5.28 dBi in the upper band compared to the patch antenna alone. In addition to the bandwidth and gain improvements, more directive radiation characteristics were also observed from the MSS antenna compared to the patch itself. The effects of the MSS elements and the ground plane length on the reflection coefficient of the antenna were analyzed and optimized. The overall performance makes the proposed antenna appropriate for RFID and WLAN applications. PMID- 28811433 TI - Dynamic Initiation and Propagation of Multiple Cracks in Brittle Materials. AB - Brittle materials such as rock and ceramic usually exhibit apparent increases of strength and toughness when subjected to dynamic loading. The reasons for this phenomenon are not yet well understood, although a number of hypotheses have been proposed. Based on dynamic fracture mechanics, the present work offers an alternate insight into the dynamic behaviors of brittle materials. Firstly, a single crack subjected to stress wave excitations is investigated to obtain the dynamic crack-tip stress field and the dynamic stress intensity factor. Second, based on the analysis of dynamic stress intensity factor, the fracture initiation sizes and crack size distribution under different loading rates are obtained, and the power law with the exponent of -2/3 is derived to describe the fracture initiation size. Third, with the help of the energy balance concept, the dynamic increase of material strength is directly derived based on the proposed multiple crack evolving criterion. Finally, the model prediction is compared with the dynamic impact experiments, and the model results agree well with the experimentally measured dynamic increasing factor (DIF). PMID- 28811434 TI - Properties of Cast Films Made from Different Ratios of Whey Protein Isolate, Hydrolysed Whey Protein Isolate and Glycerol. AB - Whey protein isolate (WPI)-based cast films are very brittle, due to several chain interactions caused by a large amount of different functional groups. In order to overcome film brittleness, plasticizers, like glycerol, are commonly used. As a result of adding plasticizers, the free volume between the polymer chains increases, leading to higher permeability values. The objective of this study was to investigate the effect of partially substituting glycerol by hydrolysed whey protein isolate (h-WPI) in WPI-based cast films on their mechanical, optical and barrier properties. As recently published by the author, it is proven that increasing the h-WPI content in WPI-based films at constant glycerol concentrations significantly increases film flexibility, while maintaining the barrier properties. The present study considered these facts in order to increase the barrier performance, while maintaining film flexibility. Therefore glycerol was partially replaced by h-WPI in WPI-based cast films. The results clearly indicate that partially replacing glycerol by h-WPI reduces the oxygen permeability and the water vapor transmission rate, while the mechanical properties did not change significantly. Thus, film flexibility was maintained, even though the plasticizer concentration was decreased. PMID- 28811435 TI - Bactericidal Activity of Aqueous Acrylic Paint Dispersion for Wooden Substrates Based on TiO2 Nanoparticles Activated by Fluorescent Light. AB - The photocatalytic effect of TiO2 has great potential for the disinfection of surfaces. Most studies reported in the literature use UV activation of TiO2, while visible light has been used only in a few applications. In these studies, high concentrations of TiO2, which can compromise surface properties, have been used. In this work, we have developed an acrylic-water paint dispersion containing low TiO2 content (2 vol %) for the inactivation of microorganisms involved in hospital-acquired infections. The nanoparticles and the coating have been characterized using spectroscopic techniques and transmission electron microscopy, showing their homogenous dispersion in the acrylic urethane coating. A common fluorescent light source was used to activate the photocatalytic activity of TiO2. The paint dispersion showed antimicrobial activity against Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa. The coating containing the TiO2 nanoparticles maintained good UV stability, strong adhesion to the substrate and high hardness. Therefore, the approach used is feasible for paint formulation aimed at disinfection of healthcare surfaces. PMID- 28811436 TI - In Vitro Activity of Gentamicin-Loaded Bioabsorbable Beads against Different Microorganisms. AB - Osteomyelitis is responsible for high treatment costs, long hospital stays, and results in substantial morbidity. Treatment with surgical debridement and antibiotic-impregnated Polymethylmetacrylate (PMMA) beads is the standard of care, providing high local but low serum antibiotic concentrations, thereby avoiding systemic toxicity. However, for several reasons, the beads require surgical removal. Alternative antibiotic delivery systems should improve the treatment of bone infection, actively encourage bone healing and require no additional surgery for removal. We investigated the activity of gentamicin-loaded bioabsorbable beads against different microorganisms (Staphylococcus epidermidis, S. aureus, Escherichia coli, Enterococcus faecalis, Candida albicans) commonly causing surgical site bone infection, by microcalorimetry. Calcium sulphate beads containing gentamicin were incubated in microcalorimetry ampoules containing different concentrations of the corresponding microorganism. Growth medium with each germ and unloaded beads was used as positive control, growth medium with loaded beads alone as negative control. Bacterial growth-related heat production at 37 degrees C was measured for 24 h. Cultures without gentamicin-loaded beads produced heat-flow peaks corresponding to the exponential growth of the corresponding microorganisms in nutrient-rich medium. In contrast, cultures with gentamicin-loaded beads completely suppressed heat production during 24 h, demonstrating their antibiotic activity. Gentamicin-loaded beads effectively inhibited growth of susceptible microorganisms, under the described in vitro conditions. PMID- 28811437 TI - Comparison of Extruded and Sonicated Vesicles for Planar Bilayer Self-Assembly. AB - Lipid vesicles are an important class of biomaterials that have a wide range of applications, including drug delivery, cosmetic formulations and model membrane platforms on solid supports. Depending on the application, properties of a vesicle population such as size distribution, charge and permeability need to be optimized. Preparation methods such as mechanical extrusion and sonication play a key role in controlling these properties, and yet the effects of vesicle preparation method on vesicular properties and integrity (e.g., shape, size, distribution and tension) remain incompletely understood. In this study, we prepared vesicles composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid by either extrusion or sonication, and investigated the effects on vesicle size distribution over time as well as the concomitant effects on the self-assembly of solid-supported planar lipid bilayers. Dynamic light scattering (DLS), quartz crystal microbalance with dissipation (QCM-D) monitoring, fluorescence recovery after photobleaching (FRAP) and atomic force microscopy (AFM) experiments were performed to characterize vesicles in solution as well as their interactions with silicon oxide substrates. Collectively, the data support that sonicated vesicles offer more robust control over the self-assembly of homogenous planar lipid bilayers, whereas extruded vesicles are vulnerable to aging and must be used soon after preparation. PMID- 28811438 TI - Surface Stability and Growth Kinetics of Compound Semiconductors: An Ab Initio Based Approach. AB - We review the surface stability and growth kinetics of III-V and III-nitride semiconductors. The theoretical approach used in these studies is based on ab initio calculations and includes gas-phase free energy. With this method, we can investigate the influence of growth conditions, such as partial pressure and temperature, on the surface stability and growth kinetics. First, we examine the feasibility of this approach by comparing calculated surface phase diagrams of GaAs(001) with experimental results. In addition, the Ga diffusion length on GaAs(001) during molecular beam epitaxy is discussed. Next, this approach is systematically applied to the reconstruction, adsorption and incorporation on various nitride semiconductor surfaces. The calculated results for nitride semiconductor surface reconstructions with polar, nonpolar, and semipolar orientations suggest that adlayer reconstructions generally appear on the polar and the semipolar surfaces. However, the stable ideal surface without adsorption is found on the nonpolar surfaces because the ideal surface satisfies the electron counting rule. Finally, the stability of hydrogen and the incorporation mechanisms of Mg and C during metalorganic vapor phase epitaxy are discussed. PMID- 28811439 TI - Microstructural Characterization of Calcite-Based Powder Materials Prepared by Planetary Ball Milling. AB - In this work, a planetary ball milling was used to modify the surface properties of calcite-based material from waste oyster shell under the rotational speed of 200-600 rpm, grinding time of 5-180 min and sample mass of 1-10 g. The milling significantly changed the microstructural properties of the calcite-based minerals (i.e., surface area, pore volume, true density, and porosity). The surface characterization of the resulting powder should be macroporous and/or nonporous based on the nitrogen adsorption/desorption isotherms. Under the optimal conditions at the rotational speed of 400 rpm, grinding time of 30 min and sample mass of 5 g, the resulting calcite-based powder had larger specific surface area (i.e., 10.64 m2.g-1) than the starting material (i.e., 4.05 m2.g-1). This finding was also consistent with the measurement of laser-diffraction (i.e., 9.7 vs. 15.0 MUm of mean diameter). In addition, the results from the scanning electron microscope (SEM) observation indicated that surface roughness can be enhanced as particle size decreases as a result of particle-particle attrition. Thus, grinding the aquacultural bioresource by a high-energy ball milling can create the fine materials, which may be applied in the fields of inorganic minerals like aggregate and construction material. PMID- 28811440 TI - Effect of Annealing Temperature on the Water Contact Angle of PVD Hard Coatings. AB - Various PVD (physical vapor deposition) hard coatings including nitrides and metal-doped diamond-like carbons (Me-DLC) were applied in plastic injection and die-casting molds to improve wear resistance and reduce sticking. In this study, nitrides hcp-AlN (hexagonal close-packed AlN), Cr2N, (CrAl)2N) and Me-DLC (Si-DLC and Cr-DLC) coatings were prepared using a closed field unbalanced magnetron reactive sputtering system. The coatings were annealed in air for 2 h at various temperatures, after which the anti-sticking properties were assessed using water contact angle (WCA) measurements. The as-deposited hcp-AlN, Cr2N and (CrAl)2N coatings exhibit hydrophobic behavior and exhibit respective WCAs of 119 degrees , 106 degrees and 101 degrees . The as-deposited Si-DLC and Cr-DLC coatings exhibit hydrophilic behavior and exhibit respective WCAs of 74 degrees and 88 degrees . The annealed Cr2N and (CrAl)2N coatings exhibit hydrophobic behavior with higher WCAs, while the annealed hcp-AlN, Si-DLC and Cr-DLC coatings are hydrophilic. The increased WCA of the annealed Cr2N and (CrAl)2N coatings is related to their crystal structure and increased roughness. The decreased WCA of the annealed hcp-AlN, Si-DLC and Cr-DLC coatings is related to their crystal structures and has little correlation with roughness. PMID- 28811441 TI - Thermal Fatigue Behavior of Air-Plasma Sprayed Thermal Barrier Coating with Bond Coat Species in Cyclic Thermal Exposure. AB - The effects of the bond coat species on the delamination or fracture behavior in thermal barrier coatings (TBCs) was investigated using the yclic thermal fatigue and thermal-shock tests. The interface microstructures of each TBC showed a good condition without cracking or delamination after flame thermal fatigue (FTF) for 1429 cycles. The TBC with the bond coat prepared by the air-plasma spray (APS) method showed a good condition at the interface between the top and bond coats after cyclic furnace thermal fatigue (CFTF) for 1429 cycles, whereas the TBCs with the bond coats prepared by the high-velocity oxygen fuel (HVOF) and low pressure plasma spray (LPPS) methods showed a partial cracking (and/or delamination) and a delamination after 780 cycles, respectively. The TBCs with the bond coats prepared by the APS, HVOF and LPPS methods were fully delaminated (>50%) after 159, 36, and 46 cycles, respectively, during the thermal-shock tests. The TGO thickness in the TBCs was strongly dependent on the both exposure time and temperature difference tested. The hardness values were found to be increased only after the CFTF, and the TBC with the bond coat prepared by the APS showed the highest adhesive strength before and after the FTF. PMID- 28811442 TI - Optimization of Microwave-Based Heating of Cellulosic Biomass Using Taguchi Method. AB - This study discusses the application of microwave-based heating for the pretreatment of biomass material, with Pennisetum purpureum selected for pretreatment. The Taguchi method was used to plan optimization experiments for the pretreatment parameter levels, and to measure the dynamic responses. With a low number of experiments, this study analyzed and determined a parameter combination in which Pennisetum purpureum can be rapidly heated to 190 degrees C. The experimental results suggested that the optimal parameter combination is: vessel capacity of 150 mL (level 2), heating power of 0.5 kW (level 1), and mass of Pennisetum purpureum of 5 g (level 1). The mass of Pennisetum purpureum is a key factor affecting system performance. An eight-order ARX model (Auto Regressive eXogeneous) was representative of the actual system performance, and the fit was 99.13%. The results proved that microwave-based heating, with the assistance of the Taguchi method for pretreatment of the biomass material, can reduce the parameter combination variations. PMID- 28811443 TI - Recycling of Pre-Washed Municipal Solid Waste Incinerator Fly Ash in the Manufacturing of Low Temperature Setting Geopolymer Materials. AB - In this work, three samples of municipal solid waste incinerators fly ash (MSWI FA) have been stabilized in systems containing coal fly ash to create geopolymers through a polycondensation reaction. Monolithic products have been obtained with both MSWI fly ash as received and after the partial removal of chloride and sulfate by water washing. The polycondensation products have been characterized qualitatively by means of Fourier transform infrared spectroscopy, X-ray diffraction and scanning electron microscopy and quantitatively, through the determination of the volume of reacted water and silicate. Furthermore, the heavy metals and chloride releases together with the physico-mechanical properties have been evaluated on the hardened products. In conclusion, considering the technological and environmental performances of the obtained geopolymers, they could be suitable for many non-structural applications, such as backfilling of abandoned quarries, decorative materials or brick fireplaces, hearths, patios, etc. PMID- 28811444 TI - Self-Healing Characteristics of Damaged Rock Salt under Different Healing Conditions. AB - Salt deposits are commonly regarded as ideal hosts for geologic energy reservoirs. Underground cavern construction-induced damage in salt is reduced by self-healing. Thus, studying the influencing factors on such healing processes is important. This research uses ultrasonic technology to monitor the longitudinal wave velocity variations of stress-damaged rock salts during self-recovery experiments under different recovery conditions. The influences of stress-induced initial damage, temperature, humidity, and oil on the self-recovery of damaged rock salts are analyzed. The wave velocity values of the damaged rock salts increase rapidly during the first 200 h of recovery, and the values gradually increase toward stabilization after 600 h. The recovery of damaged rock salts is subjected to higher initial damage stress. Water is important in damage recovery. The increase in temperature improves damage recovery when water is abundant, but hinders recovery when water evaporates. The presence of residual hydraulic oil blocks the inter-granular role of water and restrains the recovery under triaxial compression. The results indicate that rock salt damage recovery is related to the damage degree, pore pressure, temperature, humidity, and presence of oil due to the sealing integrity of the jacket material. PMID- 28811445 TI - Manufacturing and Characterization of 18Ni Marage 300 Lattice Components by Selective Laser Melting. AB - The spreading use of cellular structures brings the need to speed up manufacturing processes without deteriorating mechanical properties. By using Selective Laser Melting (SLM) to produce cellular structures, the designer has total freedom in defining part geometry and manufacturing is simplified. The paper investigates the suitability of Selective Laser Melting for manufacturing steel cellular lattice structures with characteristic dimensions in the micrometer range. Alternative lattice topologies including reinforcing bars in the vertical direction also are considered. The selected lattice structure topology is shown to be superior over other lattice structure designs considered in literature. Compression tests are carried out in order to evaluate mechanical strength of lattice strut specimens made via SLM. Compressive behavior of samples also is simulated by finite element analysis and numerical results are compared with experimental data in order to assess the constitutive behavior of the lattice structure designs considered in this study. Experimental data show that it is possible to build samples of relative density in the 0.2456-0.4367 range. Compressive strength changes almost linearly with respect to relative density, which in turns depends linearly on the number of vertical reinforces. Specific strength increases with cell and strut edge size. Numerical simulations confirm the plastic nature of the instability phenomena that leads the cellular structures to collapse under compression loading. PMID- 28811446 TI - Cyclic Deformation of Ultra-Fine Grained Commercial Purity Aluminum Processed by Accumulative Roll-Bonding. AB - Accumulative Roll-Bonding (ARB) is one of the more recently developed techniques capable of producing bulk ultra-fine grained (ufg) metals. There are still many aspects of the behavior of ufg metals that lacks an in-depth understanding, such as a generalized view of the factors that govern the cyclic deformation mechanism(s). This study aims to advance the understanding of the cyclic deformation behavior of ufg metals through the systematic investigation of ARB processed aluminum upon cyclic loading. It was found that the cyclic softening response often reported for ufg metals is largely influenced by the microstructure stability as the cyclic softening response is facilitated by grain coarsening which becomes inhibited with highly stable microstructure. On one hand, shear bands resembling braids of dislocations trespassing multiple grains have been observed to operate for the accommodation of the imposed cyclic strain in cases where grain coarsening is largely restricted. On the other hand, it was found that the microstructure stability can be overcome at higher applied cyclic plastic strain levels, leading to grain coarsening and thus a cyclic softening response. The findings in this study have further confirmed that the cyclic softening behavior found in many ufg metals, which may be detrimental in practical applications, can be inhibited by improvements in the microstructure stability. PMID- 28811447 TI - Study of Radio Frequency Plasma Treatment of PVDF Film Using Ar, O2 and (Ar + O2) Gases for Improved Polypyrrole Adhesion. AB - Improvement of the binding of polypyrrole with PVDF (polyvinylidene fluoride) thin film using low pressure plasma was studied. The effects of various plasma gases i.e., Ar, O2 and Ar + O2 gases on surface roughness, surface chemistry and hydrophilicity were noted. The topographical change of the PVDF film was observed by means of scanning electron microscopy and chemical changes by X-ray photoelectron spectroscopy, with adhesion of polypyrrole (PPy) by abrasion tests and sheet resistance measurements. Results showed that the increase in roughness and surface functionalization by oxygen functional groups contributed to improved adhesion and Ar + O2 plasma gave better adhesion. PMID- 28811448 TI - Effects on the Thermo-Mechanical and Crystallinity Properties of Nylon 6,6 Electrospun Fibres Reinforced with One Dimensional (1D) and Two Dimensional (2D) Carbon. AB - Electrospun one dimensional (1D) and two dimensional (2D) carbon based polymer nanocomposites are studied in order to determine the effect provided by the two differently structured nanofillers on crystallinity and thermo-mechanical properties of the nanofibres. The nanomaterials studied are pristine carbon nanotubes, oxidised carbon nanotubes, reduced graphene oxide and graphene oxide. Functional groups associated with the order structure of the polymers are analysed by infrared and Raman spectroscopies; the morphology is studied by scanning electron microscopy and the crystallinity properties are investigated by differential scanning calorimetry and X-ray diffraction. Differences in crystallisation behaviour between 1D and 2D carbon based nanofibres are shown by their crystallinity degree and their crystal sizes. The nanocomposite crystal sizes perpendicular to the plane (100) decrease with nanofiller content in all cases. The crystallinity trend and crystal sizes are in accordance with storage modulus response. The results also suggest that functionalisation favours interfacial bonding and dispersion of the nanomaterials within the polymer matrix. As a consequence the number of nucleating sites increases which in turn decreases the crystal size in the nanocomposites. These features explain the improved thermo-mechanical properties in the nanocomposites. PMID- 28811449 TI - Small-Scale Morphological Features on a Solid Surface Processed by High-Pressure Abrasive Water Jet. AB - Being subjected to a high-pressure abrasive water jet, solid samples will experience an essential variation of both internal stress and physical characteristics, which is closely associated with the kinetic energy attached to the abrasive particles involved in the jet stream. Here, experiments were performed, with particular emphasis being placed on the kinetic energy attenuation and turbulent features in the jet stream. At jet pressure of 260 MPa, mean velocity and root-mean-square (RMS) velocity on two jet-stream sections were acquired by utilizing the phase Doppler anemometry (PDA) technique. A jet-cutting experiment was then carried out with Al-Mg alloy samples being cut by an abrasive water jet. Morphological features and roughness on the cut surface were quantitatively examined through scanning electron microscopy (SEM) and optical profiling techniques. The results indicate that the high-pressure water jet is characterized by remarkably high mean flow velocities and distinct velocity fluctuations. Those irregular pits and grooves on the cut surfaces indicate both the energy attenuation and the development of radial velocity components in the jet stream. When the sample is positioned with different distances from the nozzle outlet, the obtained quantitative surface roughness varies accordingly. A descriptive model highlighting the behaviors of abrasive particles in jet-cutting process is established in light of the experimental results and correlation analysis. PMID- 28811450 TI - The Influence of Phase Change Materials on the Properties of Self-Compacting Concrete. AB - The aim of this paper is to research new thermally-efficient concrete walls, analyzing the mechanical behavior of a self-compacting concrete to manufacture an uncoated solid structural panel, with the incorporation of a micro-encapsulated phase change material as additive. Different dosages are tested and mechanical properties of the product obtained from the molding of concrete specimens are evaluated, testing mechanical compressive strength, slump flow, and density. The results reveal the optimum percentage of additive in the mixture that enables compliance with the technical specifications required by the product to be manufactured. A test is also performed for measuring the thermal conductivity for the optimal sample obtained and it evidences the reduction thereof. PMID- 28811451 TI - Synthesis, Structural Characterization, and Antitumor Activity of a Ca(II) Coordination Polymer Based on 1,6-Naphthalenedisulfonate and 4,4'-Bipyridyl. AB - A novel Ca(II) coordination polymer, [CaL(4,4'-bipyridyl)(H2O)4]n (L = 1,6 naphthalenedisulfonate), was synthesized by reaction of calcium perchlorate with 1,6-naphthalenedisulfonic acid disodium salt and 4,4'-bipyridyl in CH3CH2OH/H2O. It was characterized by elemental analysis, IR, molar conductivity and thermogravimetric analysis. X-ray crystallography reveals that the Ca(II) coordination polymer belongs to the orthorhombic system, with space group P212121. The geometry of the Ca(II) ion is a distorted CaNO6 pengonal bipyramid, arising from its coordination by four water molecules, one nitrogen atom of 4,4' bipyridyl molecule, and two oxygen atoms from two L ligands. The complex molecules form a helical chain by self-assembly. The antitumor activity of 1,6 naphthalenedisulfonic acid disodium salt and the Ca(II) coordination polymer against human hepatoma smmc-7721 cell line and human lung adenocarcinoma A549 cell line reveals that the Ca(II) coordination polymer inhibits cell growth of human lung adenocarcinoma A549 cell line with IC50 value of 27 MUg/mL, and is more resistive to human lung adenocarcinoma A549 cell line as compared to 1,6 naphthalenedisulfonic acid disodium salt. PMID- 28811452 TI - Periodic Mesoporous Organosilica Functionalized with Sulfonic Acid Groups as Acid Catalyst for Glycerol Acetylation. AB - A Periodic Mesoporous Organosilica (PMO) functionalized with sulfonic acid groups has been successfully synthesized via a sequence of post-synthetic modification steps of a trans-ethenylene bridged PMO material. The double bond is functionalized via a bromination and subsequent substitution obtaining a thiol functionality. This is followed by an oxidation towards a sulfonic acid group. After full characterization, the solid acid catalyst is used in the acetylation of glycerol. The catalytic reactivity and reusability of the sulfonic acid modified PMO material is investigated. The catalyst showed a catalytic activity and kinetics that are comparable with the commercially available resin, Amberlyst 15, and furthermore our catalyst can be recycled for several subsequent catalytic runs and retains its catalytic activity. PMID- 28811453 TI - Study of Lysozyme-Loaded Poly-L-Lactide (PLLA) Porous Microparticles in a Compressed CO2 Antisolvent Process. AB - Lysozyme (LSZ)-loaded poly-L-lactide (PLLA) porous microparticles (PMs) were successfully prepared by a compressed CO2 antisolvent process in combination with a water-in-oil emulsion process using LSZ as a drug model and ammonium bicarbonate as a porogen. The effects of different drug loads (5.0%, 7.5% and 10.0%) on the surface morphology, particle size, porosity, tapped density and drug release profile of the harvested PMs were investigated. The results show that an increase in the amount of LSZ added led to an increase in drug load (DL) but a decrease in encapsulation efficiency. The resulting LSZ-loaded PLLA PMs (LSZ-PLLA PMs) exhibited a porous and uneven morphology, with a density less than 0.1 g.cm-3, a geometric mean diameter of 16.9-18.8 MUm, an aerodynamic diameter less than 2.8 MUm, a fine particle fraction (FPF) of 59.2%-66.8%, and a porosity of 78.2%-86.3%. According to the results of differential scanning calorimetry, the addition of LSZ improved the thermal stability of PLLA. The Fourier transform infrared spectroscopy analysis and circular dichroism spectroscopy measurement reveal that no significant changes occurred in the molecular structures of LSZ during the fabrication process, which was further confirmed by the evaluation of enzyme activity of LSZ. It is demonstrated that the emulsion-combined precipitation with compressed antisolvent (PCA) process could be a promising technology to develop biomacromolecular drug-loaded inhalable carrier for pulmonary drug delivery. PMID- 28811454 TI - Hydrothermal Growth of Vertically Aligned ZnO Nanorods Using a Biocomposite Seed Layer of ZnO Nanoparticles. AB - Well aligned ZnO nanorods have been prepared by a low temperature aqueous chemical growth method, using a biocomposite seed layer of ZnO nanoparticles prepared in starch and cellulose bio polymers. The effect of different concentrations of biocomposite seed layer on the alignment of ZnO nanorods has been investigated. ZnO nanorods grown on a gold-coated glass substrate have been characterized by X-ray diffraction (XRD) and field emission scanning electron microscopy (FESEM) techniques. These techniques have shown that the ZnO nanorods are well aligned and perpendicular to the substrate, and grown with a high density and uniformity on the substrate. Moreover, ZnO nanorods can be grown with an orientation along the c-axis of the substrate and exhibit a wurtzite crystal structure with a dominant (002) peak in an XRD spectrum and possessed a high crystal quality. A photoluminescence (PL) spectroscopy study of the ZnO nanorods has revealed a conventional near band edge ultraviolet emission, along with emission in the visible part of the electromagnetic spectrum due to defect emission. This study provides an alternative method for the fabrication of well aligned ZnO nanorods. This method can be helpful in improving the performance of devices where alignment plays a significant role. PMID- 28811455 TI - Drift in Diffusion Gradients. AB - The longstanding problem of Brownian transport in a heterogeneous quasi one dimensional medium with space-dependent self-diffusion coefficient is addressed in the overdamped (zero mass) limit. A satisfactory mesoscopic description is obtained in the Langevin equation formalism by introducing an appropriate drift term, which depends on the system macroscopic observables, namely the diffuser concentration and current. The drift term is related to the microscopic properties of the medium. The paradoxical existence of a finite drift at zero current suggests the possibility of designing a Maxwell demon operating between two equilibrium reservoirs at the same temperature. PMID- 28811456 TI - Fabrication of Super-Hydrophobic Microchannels via Strain-Recovery Deformations of Polystyrene and Oxygen Reactive Ion Etch. AB - In this article, we report a simple approach to generate micropillars (whose top portions are covered by sub-micron wrinkles) on the inner surfaces of polystyrene (PS) microchannels, as well as on the top surface of the PS substrate, based on strain-recovery deformations of the PS and oxygen reactive ion etch (ORIE). Using this approach, two types of micropillar-covered microchannels are fabricated. Their widths range from 118 MUm to 132 MUm, depths vary from 40 MUm to 44 MUm, and the inclined angles of their sidewalls are from 53 degrees to 64 degrees . The micropillars enable these microchannels to have super-hydrophobic properties. The contact angles observed on the channel-structured surfaces are above 162 degrees , and the tilt angles to make water drops roll off from these channel structured substrates can be as small as 1 degrees . PMID- 28811457 TI - The Effect of a Rapid Heating Rate, Mechanical Vibration and Surfactant Chemistry on the Structure-Property Relationships of Epoxy/Clay Nanocomposites. AB - The role of processing conditions and intercalant chemistry in montmorillonite clays on the dispersion, morphology and mechanical properties of two epoxy/clay nanocomposite systems was investigated in this paper. This work highlights the importance of employing complementary techniques (X-ray diffraction, small angle X-ray scattering, optical microscopy and transmission electron microscopy) to correlate nanomorphology to macroscale properties. Materials were prepared using an out of autoclave manufacturing process equipped to generate rapid heating rates and mechanical vibration. The results suggested that the quaternary ammonium surfactant on C30B clay reacted with the epoxy during cure, while the primary ammonium surfactant (I.30E) catalysed the polymerisation reaction. These effects led to important differences in nanocomposite clay morphologies. The use of mechanical vibration at 4 Hz prior to matrix gelation was found to facilitate clay dispersion and to reduce the area fraction of I.30E clay agglomerates in addition to increasing flexural strength by over 40%. PMID- 28811458 TI - Progress in Titanium Metal Powder Injection Molding. AB - Metal powder injection molding is a shaping technology that has achieved solid scientific underpinnings. It is from this science base that recent progress has occurred in titanium powder injection molding. Much of the progress awaited development of the required particles with specific characteristics of particle size, particle shape, and purity. The production of titanium components by injection molding is stabilized by a good understanding of how each process variable impacts density and impurity level. As summarized here, recent research has isolated the four critical success factors in titanium metal powder injection molding (Ti-MIM) that must be simultaneously satisfied-density, purity, alloying, and microstructure. The critical role of density and impurities, and the inability to remove impurities with sintering, compels attention to starting Ti MIM with high quality alloy powders. This article addresses the four critical success factors to rationalize Ti-MIM processing conditions to the requirements for demanding applications in aerospace and medical fields. Based on extensive research, a baseline process is identified and reported here with attention to linking mechanical properties to the four critical success factors. PMID- 28811459 TI - Broadband Luminescence in Rare Earth Doped Sr2SiS4: Relating Energy Levels of Ce3+ and Eu2. AB - Sr2SiS4:Ce3+ is an efficient blue-emitting (460 nm) phosphor, excitable with light of wavelengths up to 420 nm. From the excitation spectrum, we construct the energy level scheme and use it to check the predictive power of the Dorenbos model, relating the positions of the Ce3+ energy levels with those of Eu2+ in the same host. For strontium thiosilicate, this method gives excellent results and allows us to determine which of two available crystallographic sites is occupied by cerium. We use the Dorenbos method for extracting information on the coordination of Ce3+ from the observed crystal field splitting. PMID- 28811460 TI - Prevention of Atrial Fibrillation by Using Sarcoplasmic Reticulum Calcium ATPase Pump Overexpression in a Rabbit Model of Rapid Atrial Pacing. AB - BACKGROUND Recent research suggests that abnormal Ca2+ handling plays a role in the occurrence and maintenance of atrial fibrillation (AF). Therefore, Ca2+ release and ingestion depend on properties of the ryanodine receptor (RyR) and sarcoplasmic reticulum Ca2+ATPase2a (SERCA2a). This study aimed to detect whether SERCA2a gene overexpression has a preventive effect on atrial fibrillation caused by rapid pacing right atrium. MATERIAL AND METHODS Forty-eight New Zealand white rabbits were randomly divided into a control group, AF group, AAV9/GFP group, and AAV9/SERCA2a group. The right atrium was rapidly paced at 600 beats/min for 30 days after an intraperitoneal injection of an adeno-associated virus expressing the SERCA2a gene and GFP. The AF induction rate and the effective refraction period (ERP) were measured after 0, 4, 8, 12, and 24 h of pacing. Western blot analysis was used to test for the expression of SERCA2a. Changes in atrial tissue structure were observed by H&E staining and electron microscopy. RESULTS The AF induction rate was higher in the AF groups than in the AAV9/SERCA2a group at different time points of pacing. After 12 h of pacing, ERP was significantly prolonged in the AAV9/SERCA2a group compared to the AF and AAV9/GFP groups (p<0.05). SERCA2a protein expression was significantly lower in the AF and AAV9/GFP groups compared to the control group (p<0.05), while expression was significantly higher in the AAV9/SERCA2a group than in the AF and AAV9/GFP groups (p<0.05). The myocardial structure of the AAV9/SERCA2a group was significantly improved compared with the AF group, indicating that SERCA2a overexpression relieved the structural remodeling of atrial fibrillation. CONCLUSIONS SERCA2a overexpression is capable of suppressing ERP shortening and AF induced by rapid pacing atrium. SERCA2a gene therapy is expected to be a new anti-atrial fibrillation strategy. PMID- 28811461 TI - Sparse orthogonal population representation of spatial context in the retrosplenial cortex. AB - Sparse orthogonal coding is a key feature of hippocampal neural activity, which is believed to increase episodic memory capacity and to assist in navigation. Some retrosplenial cortex (RSC) neurons convey distributed spatial and navigational signals, but place-field representations such as observed in the hippocampus have not been reported. Combining cellular Ca2+ imaging in RSC of mice with a head-fixed locomotion assay, we identified a population of RSC neurons, located predominantly in superficial layers, whose ensemble activity closely resembles that of hippocampal CA1 place cells during the same task. Like CA1 place cells, these RSC neurons fire in sequences during movement, and show narrowly tuned firing fields that form a sparse, orthogonal code correlated with location. RSC 'place' cell activity is robust to environmental manipulations, showing partial remapping similar to that observed in CA1. This population code for spatial context may assist the RSC in its role in memory and/or navigation.Neurons in the retrosplenial cortex (RSC) encode spatial and navigational signals. Here the authors use calcium imaging to show that, similar to the hippocampus, RSC neurons also encode place cell-like activity in a sparse orthogonal representation, partially anchored to the allocentric cues on the linear track. PMID- 28811462 TI - Observation of hybrid Tamm-plasmon exciton- polaritons with GaAs quantum wells and a MoSe2 monolayer. AB - Strong light matter coupling between excitons and microcavity photons, as described in the framework of cavity quantum electrodynamics, leads to the hybridization of light and matter excitations. The regime of collective strong coupling arises, when various excitations from different host media are strongly coupled to the same optical resonance. This leads to a well-controllable admixture of various matter components in three hybrid polariton modes. Here, we study a cavity device with four embedded GaAs quantum wells hosting excitons that are spectrally matched to the A-valley exciton resonance of a MoSe2 monolayer. The formation of hybrid polariton modes is evidenced in momentum resolved photoluminescence and reflectivity studies. We describe the energy and k-vector distribution of exciton-polaritons along the hybrid modes by a thermodynamic model, which yields a very good agreement with the experiment.Light and matter excitations from host media can hybridize in the strong coupling regime, resulting in the formation of hybrid polariton modes. Here, the authors demonstrate hybridization between tightly bound excitons in a MoSe2 monolayer and excitons in GaAs quantum wells via coupling to a cavity resonance. PMID- 28811463 TI - A light-regulated host-guest-based nanochannel system inspired by channelrhodopsins protein. AB - The light-controlled gating of ion transport across membranes is central to nature (e.g., in protein channels). Herein, inspired by channelrhodopsins, we introduce a facile non-covalent approach towards light-responsive biomimetic channelrhodopsin nanochannels using host-guest interactions between a negative pillararene host and a positive azobenzene guest. By switching between threading and dethreading states with alternating visible and UV light irradiation, the functional channels can be flexible to regulate the inner surface charge of the channels, which in turn was exploited to achieve different forms of ion transport, for instance, cation-selective transport and anion-selective transport. Additionally, the pillararene-azobenzene-based nanochannel system could be used to construct a light-activated valve for molecular transport. Given these promising results, we suggest that this system could not only provide a better understanding of some biological processes, but also be applied for drug delivery and various biotechnological applications.Light-controlled gating of ion transport across membranes occurs in nature via channelrhodopsin nanochannels. Here, the authors show facile non-covalent approach towards light-responsive biomimetic nanochannels using host-guest interactions between a negative pillararene host and a positive azobenzene guest. PMID- 28811464 TI - The origin of a primordial genome through spontaneous symmetry breaking. AB - The heredity of a cell is provided by a small number of non-catalytic templates the genome. How did genomes originate? Here, we demonstrate the possibility that genome-like molecules arise from symmetry breaking between complementary strands of self-replicating molecules. Our model assumes a population of protocells, each containing a population of self-replicating catalytic molecules. The protocells evolve towards maximising the catalytic activities of the molecules to increase their growth rates. Conversely, the molecules evolve towards minimising their catalytic activities to increase their intracellular relative fitness. These conflicting tendencies induce the symmetry breaking, whereby one strand of the molecules remains catalytic and increases its copy number (enzyme-like molecules), whereas the other becomes non-catalytic and decreases its copy number (genome-like molecules). This asymmetry increases the equilibrium cellular fitness by decreasing mutation pressure and increasing intracellular genetic drift. These results implicate conflicting multilevel evolution as a key cause of the origin of genetic complexity.Early molecules of life likely served both as templates and catalysts, raising the question of how functionally distinct genomes and enzymes arose. Here, the authors show that conflict between evolution at the molecular and cellular levels can drive functional differentiation of the two strands of self-replicating molecules and lead to copy number differences between the two. PMID- 28811465 TI - Lorentz-violating type-II Dirac fermions in transition metal dichalcogenide PtTe2. AB - Topological semimetals have recently attracted extensive research interests as host materials to condensed matter physics counterparts of Dirac and Weyl fermions originally proposed in high energy physics. Although Lorentz invariance is required in high energy physics, it is not necessarily obeyed in condensed matter physics, and thus Lorentz-violating type-II Weyl/Dirac fermions could be realized in topological semimetals. The recent realization of type-II Weyl fermions raises the question whether their spin-degenerate counterpart-type-II Dirac fermions-can be experimentally realized too. Here, we report the experimental evidence of type-II Dirac fermions in bulk stoichiometric PtTe2 single crystal. Angle-resolved photoemission spectroscopy measurements and first principles calculations reveal a pair of strongly tilted Dirac cones along the Gamma-A direction, confirming PtTe2 as a type-II Dirac semimetal. Our results provide opportunities for investigating novel quantum phenomena (e.g., anisotropic magneto-transport) and topological phase transition.Whether the spin degenerate counterpart of Lorentz-violating Weyl fermions, the Dirac fermions, can be realized remains as an open question. Here, Yan et al. report experimental evidence of such type-II Dirac fermions in bulk PtTe2 single crystal with a pair of strongly tilted Dirac cones. PMID- 28811466 TI - Time-lapse crystallography snapshots of a double-strand break repair polymerase in action. AB - DNA polymerase (pol) MU is a DNA-dependent polymerase that incorporates nucleotides during gap-filling synthesis in the non-homologous end-joining pathway of double-strand break repair. Here we report time-lapse X-ray crystallography snapshots of catalytic events during gap-filling DNA synthesis by pol MU. Unique catalytic intermediates and active site conformational changes that underlie catalysis are uncovered, and a transient third (product) metal ion is observed in the product state. The product manganese coordinates phosphate oxygens of the inserted nucleotide and PPi. The product metal is not observed during DNA synthesis in the presence of magnesium. Kinetic analyses indicate that manganese increases the rate constant for deoxynucleoside 5'-triphosphate insertion compared to magnesium. The likely product stabilization role of the manganese product metal in pol MU is discussed. These observations provide insight on structural attributes of this X-family double-strand break repair polymerase that impact its biological function in genome maintenance.DNA polymerase (pol) MU functions in DNA double-strand break repair. Here the authors use time-lapse X-ray crystallography to capture the states of pol u during the conversion from pre-catalytic to product complex and observe a third transiently bound metal ion in the product state. PMID- 28811468 TI - Inferring structural connectivity using Ising couplings in models of neuronal networks. AB - Functional connectivity metrics have been widely used to infer the underlying structural connectivity in neuronal networks. Maximum entropy based Ising models have been suggested to discount the effect of indirect interactions and give good results in inferring the true anatomical connections. However, no benchmarking is currently available to assess the performance of Ising couplings against other functional connectivity metrics in the microscopic scale of neuronal networks through a wide set of network conditions and network structures. In this paper, we study the performance of the Ising model couplings to infer the synaptic connectivity in in silico networks of neurons and compare its performance against partial and cross-correlations for different correlation levels, firing rates, network sizes, network densities, and topologies. Our results show that the relative performance amongst the three functional connectivity metrics depends primarily on the network correlation levels. Ising couplings detected the most structural links at very weak network correlation levels, and partial correlations outperformed Ising couplings and cross-correlations at strong correlation levels. The result was consistent across varying firing rates, network sizes, and topologies. The findings of this paper serve as a guide in choosing the right functional connectivity tool to reconstruct the structural connectivity. PMID- 28811467 TI - The mTORC1-4E-BP-eIF4E axis controls de novo Bcl6 protein synthesis in T cells and systemic autoimmunity. AB - Post-transcriptional modifications can control protein abundance, but the extent to which these alterations contribute to the expression of T helper (TH) lineage defining factors is unknown. Tight regulation of Bcl6 expression, an essential transcription factor for T follicular helper (TFH) cells, is critical as aberrant TFH cell expansion is associated with autoimmune diseases, such as systemic lupus erythematosus (SLE). Here we show that lack of the SLE risk variant Def6 results in deregulation of Bcl6 protein synthesis in T cells as a result of enhanced activation of the mTORC1-4E-BP-eIF4E axis, secondary to aberrant assembly of a raptor-p62-TRAF6 complex. Proteomic analysis reveals that this pathway selectively controls the abundance of a subset of proteins. Rapamycin or raptor deletion ameliorates the aberrant TFH cell expansion in mice lacking Def6. Thus deregulation of mTORC1-dependent pathways controlling protein synthesis can result in T-cell dysfunction, indicating a mechanism by which mTORC1 can promote autoimmunity.Excessive expansion of the T follicular helper (TFH) cell pool is associated with autoimmune disease and Def6 has been identified as an SLE risk variant. Here the authors show that Def6 limits proliferation of TFH cells in mice via alteration of mTORC1 signaling and inhibition of Bcl6 expression. PMID- 28811469 TI - RGD delivery of truncated coagulase to tumor vasculature affords local thrombotic activity to induce infarction of tumors in mice. AB - Induction of thrombosis in tumor vasculature represents an appealing strategy for combating cancer. Herein, we combined unique intrinsic coagulation properties of staphylocoagulase with new acquired functional potentials introduced by genetic engineering, to generate a novel bi-functional fusion protein consisting of truncated coagulase (tCoa) bearing an RGD motif on its C-terminus for cancer therapy. We demonstrated that free coagulase failed to elicit any significant thrombotic activity. Conversely, RGD delivery of coagulase retained coagulase activity and afforded favorable interaction of fusion proteins with prothrombin and alphavbeta3 endothelial cell receptors, as verified by in silico, in vitro, and in vivo experiments. Although free coagulase elicited robust coagulase activity in vitro, only targeted coagulase (tCoa-RGD) was capable of producing extensive thrombosis, and subsequent infarction and massive necrosis of CT26 mouse colon, 4T1 mouse mammary and SKOV3 human ovarian tumors in mice. Additionally, systemic injections of lower doses of tCoa-RGD produced striking tumor growth inhibition of CT26, 4T1 and SKOV3 solid tumors in animals. Altogether, the nontoxic nature, unique shortcut mechanism, minimal effective dose, wide therapeutic window, efficient induction of thrombosis, local effects and susceptibility of human blood to coagulase suggest tCoa-RGD fusion proteins as a novel and promising anticancer therapy for human trials. PMID- 28811470 TI - Bias induced up to 100% spin-injection and detection polarizations in ferromagnet/bilayer-hBN/graphene/hBN heterostructures. AB - We study spin transport in a fully hBN encapsulated monolayer-graphene van der Waals heterostructure at room temperature. A top-layer of bilayer-hBN is used as a tunnel barrier for spin-injection and detection in graphene with ferromagnetic cobalt electrodes. We report surprisingly large and bias-induced (differential) spin-injection (detection) polarizations up to 50% (135%) at a positive voltage bias of + 0.6 V, as well as sign inverted polarizations up to -70% (-60%) at a reverse bias of -0.4 V. This demonstrates the potential of bilayer-hBN tunnel barriers for practical graphene spintronics applications. With such enhanced spin injection and detection polarizations, we report a record two-terminal (inverted) spin-valve signals up to 800 Omega with a magnetoresistance ratio of 2.7%, and achieve spin accumulations up to 4.1 meV. We propose how these numbers can be increased further, for future technologically relevant graphene based spintronic devices.In 2D spin-valve devices, effective spin injection and detection can be potentially realised combining graphene with an ideal hBN tunnel barrier. Here, the authors report that a bilayer hBN tunnel barrier allows up to 100% spin injection and detection in a fully hBN-encapsulated graphene heterostructure. PMID- 28811471 TI - Two-magnon scattering in the 5d all-in-all-out pyrochlore magnet Cd2Os2O7. AB - 5d pyrochlore oxides with all-in-all-out magnetic order are prime candidates for realizing strongly correlated, topological phases of matter. Despite significant effort, a full understanding of all-in-all-out magnetism remains elusive as the associated magnetic excitations have proven difficult to access with conventional techniques. Here we report a Raman spectroscopy study of spin dynamics in the all in-all-out magnetic state of the 5d pyrochlore Cd2Os2O7. Through a comparison between the two-magnon scattering and spin-wave theory, we confirm the large single ion anisotropy in this material and show that the Dzyaloshinskii-Moriya and exchange interactions play a significant role in the spin-wave dispersions. The Raman data also reveal complex spin-charge-lattice coupling and indicate that the metal-insulator transition in Cd2Os2O7 is Lifshitz-type. Our work establishes Raman scattering as a simple and powerful method for exploring the spin dynamics in 5d pyrochlore magnets.Pyrochlore 5d transition metal oxides are expected to have interesting forms of magnetic order but are hard to study with conventional probes. Here the authors show that Raman scattering can be used to measure magnetic excitations in Cd2Os2O7 and that it exhibits complex spin-charge-lattice coupling. PMID- 28811472 TI - The universal existence of myodural bridge in mammals: an indication of a necessary function. AB - The "myodural bridge" was described in literatures as a dense fibrous tissue connecting the sub-occipital musculature with the spinal dura mater in human studies. Now the concept of "myodural bridge" was perceived as an exact anatomical structure presumably essential for critical physiological functions in human body, and might exist in other mammals as well. To determine the existence of the "myodural bridge" in other mammals and to lay a foundation for the functional study, we examined representatives in five different mammalian orders. Based on the anatomical dissections, P45 plastinated sections and histological sections, we found that a dense fibrous tissue connected the rectus capitisdorsalis minor and the spinal dura mater through the dorsal atlanto occipital interspace with or without the medium of the posterior atlanto occipital membrane. These observed connective tissues were very similar to the "myodural bridge" previously described in humans. We proposed that the "myodural bridge", as an evolutionally conserved structure, presents in many other mammals. Moreover, we believed that the "myodural bridge" might be a homologous organ in mammals. Thus, this study could provide an insight for our understanding the physiological significance of the "myodural bridge", especially in human. PMID- 28811473 TI - Plant-made polio type 3 stabilized VLPs-a candidate synthetic polio vaccine. AB - Poliovirus (PV) is the causative agent of poliomyelitis, a crippling human disease known since antiquity. PV occurs in two distinct antigenic forms, D and C, of which only the D form elicits a robust neutralizing response. Developing a synthetically produced stabilized virus-like particle (sVLP)-based vaccine with D antigenicity, without the drawbacks of current vaccines, will be a major step towards the final eradication of poliovirus. Such a sVLP would retain the native antigenic conformation and the repetitive structure of the original virus particle, but lack infectious genomic material. In this study, we report the production of synthetically stabilized PV VLPs in plants. Mice carrying the gene for the human PV receptor are protected from wild-type PV when immunized with the plant-made PV sVLPs. Structural analysis of the stabilized mutant at 3.6 A resolution by cryo-electron microscopy and single-particle reconstruction reveals a structure almost indistinguishable from wild-type PV3.Despite the success of current vaccination against poliomyelitis, safe, cheap and effective vaccines remain sought for continuing eradication effort. Here the authors use plants to express stabilized virus-like particles of type 3 poliovirus that can induce a protective immune response in mice transgenic for the human poliovirus receptor. PMID- 28811475 TI - Microsecond Pulse I-V Approach to Understanding Defects in High Mobility Bi-layer Oxide Semiconductor Transistor. AB - The carrier transport and device instability of amorphous oxide semiconductor devices are influenced by defects that are exponentially distributed in energy, because of amorphous phase channels and front/back interfaces with a large number of sub-gap states. Thus, understanding defects and charge trapping in oxide semiconductor transistors is required for being core device element in reliable production lines. In this paper, we present the transient charging effect, the charge trapping mechanism, and the dynamic charge transport of high-mobility bilayer oxide semiconductor transistors. To this end, we exploited microsecond ramps, pulse ID-VG, transient current, and discharge current analysis methods. The mobility enhancement rate of single HfInZnO (HIZO) and bilayer HfInZnO-InZnO (HIZO-IZO) were 173.8 and 28.8%, respectively, in the charge-trapping-free environment. Transient charge trapping can be classified to temperature insensitive fast charging and thermally activated slow charging with two different trap energies. Insignificant fast transient charging of a bilayer-oxide high-mobility thin film transistor(TFT) can be explained by the low density of sub-gap states in the oxide semiconductor. Understanding defects and transient charging in the oxide semiconductor helps to determine the origin of device instability of oxide TFTs, and finally, to solve this problem. PMID- 28811474 TI - The mycobacterial phosphatase PtpA regulates the expression of host genes and promotes cell proliferation. AB - Mycobacterium tuberculosis PtpA is a secreted effector protein that dephosphorylates several proteins in the host cell cytoplasm, such as p-JNK, p p38, and p-VPS33B, leading to suppression of host innate immunity. Here we show that, in addition, PtpA enters the nucleus of host cells and regulates the expression of host genes, some of which are known to be involved in host innate immunity or in cell proliferation and migration (such as GADD45A). PtpA can bind directly to the promoter region of GADD45A in vitro. Both phosphatase activity and DNA-binding ability of PtpA are important in suppressing host innate immune responses. Furthermore, PtpA-expressing Mycobacterium bovis BCG promotes proliferation and migration of human lung adenoma A549 cells in vitro and in a mouse xenograft model. Further research is needed to test whether mycobacteria, via PtpA, might affect cell proliferation or migration in humans. Mycobacterium tuberculosis secretes a protein, PtpA, that dephosphorylates proteins in the host cell cytoplasm, weakening immune responses. Here, the authors show that PtpA also enters the nucleus, affects the expression of several host genes, and promotes proliferation and migration of a cancer cell line. PMID- 28811477 TI - Deep carbon storage potential of buried floodplain soils. AB - Soils account for the largest terrestrial pool of carbon and have the potential for even greater quantities of carbon sequestration. Typical soil carbon (C) stocks used in global carbon models only account for the upper 1 meter of soil. Previously unaccounted for deep carbon pools (>1 m) were generally considered to provide a negligible input to total C contents and represent less dynamic C pools. Here we assess deep soil C pools associated with an alluvial floodplain ecosystem transitioning from agricultural production to restoration of native vegetation. We analyzed the soil organic carbon (SOC) concentrations of 87 surface soil samples (0-15 cm) and 23 subsurface boreholes (0-3 m). We evaluated the quantitative importance of the burial process in the sequestration of subsurface C and found our subsurface soils (0-3 m) contained considerably more C than typical C stocks of 0-1 m. This deep unaccounted soil C could have considerable implications for global C accounting. We compared differences in surface soil C related to vegetation and land use history and determined that flooding restoration could promote greater C accumulation in surface soils. We conclude deep floodplain soils may store substantial quantities of C and floodplain restoration should promote active C sequestration. PMID- 28811478 TI - Reduced and unstratified crust in CV chondrite parent body. AB - Early Solar System planetesimal thermal models predict the heating of the chondritic protolith and the preservation of a chondritic crust on differentiated parent bodies. Petrological and geochemical analyses of chondrites have suggested that secondary alteration phases formed at low temperatures (<300 degrees C) by fluid-rock interaction where reduced and oxidized Vigarano type Carbonaceous (CV) chondrites witness different physicochemical conditions. From a thermodynamical survey of Ca-Fe-rich secondary phases in CV3 chondrites including silica activity (aSiO2), here we show that the classical distinction between reduced and oxidized chondrites is no longer valid and that their Ca-Fe-rich secondary phases formed in similar reduced conditions near the iron-magnetite redox buffer at low aSiO2 (log(aSiO2) <-1) and moderate temperature (210-610 degrees C). The various lithologies in CV3 chondrites are inferred to be fragments of an asteroid percolated heterogeneously via porous flow of hydrothermal fluid. Putative 'onion shell' structures are not anymore a requirement for the CV parent body crust.Meteorites may unlock the history of the early solar system. Here, the authors find, through Ca-Fe-rich secondary phases, that the distinction between reduced and oxidized CV chondrites is invalid; therefore, CV3 chondrites are asteroid fragments that percolated heterogeneously via porous flow of hydrothermal fluid. PMID- 28811476 TI - Lyn and Fyn function as molecular switches that control immunoreceptors to direct homeostasis or inflammation. AB - Immunoreceptors can transduce either inhibitory or activatory signals depending on ligand avidity and phosphorylation status, which is modulated by the protein kinases Lyn and Fyn. Here we show that Lyn and Fyn control immune receptor signaling status. SHP-1 tyrosine 536 phosphorylation by Lyn activates the phosphatase promoting inhibitory signaling through the immunoreceptor. By contrast, Fyn-dependent phosphorylation of SHP-1 serine 591 inactivates the phosphatase, enabling activatory immunoreceptor signaling. These SHP-1 signatures are relevant in vivo, as Lyn deficiency exacerbates nephritis and arthritis in mice, whereas Fyn deficiency is protective. Similarly, Fyn-activating signature is detected in patients with lupus nephritis, underlining the importance of this Lyn-Fyn balance. These data show how receptors discriminate negative from positive signals that respectively result in homeostatic or inflammatory conditions.Src-family kinases Fyn and Lyn are signaling components downstream of ITAM-bearing antigen receptors. Here the authors show that by phosphorylating SHP 1 at different residues, Lyn and Fyn can have opposing regulatory effects on ITAM receptors. PMID- 28811479 TI - Membrane-free culture and real-time barrier integrity assessment of perfused intestinal epithelium tubes. AB - In vitro models that better reflect in vivo epithelial barrier (patho-)physiology are urgently required to predict adverse drug effects. Here we introduce extracellular matrix-supported intestinal tubules in perfused microfluidic devices, exhibiting tissue polarization and transporter expression. Forty leak tight tubules are cultured in parallel on a single plate and their response to pharmacological stimuli is recorded over 125 h using automated imaging techniques. A study comprising 357 gut tubes is performed, of which 93% are leak tight before exposure. EC50-time curves could be extracted that provide insight into both concentration and exposure time response. Full compatibility with standard equipment and user-friendly operation make this Organ-on-a-Chip platform readily applicable in routine laboratories.Efforts to determine the effects of drugs on epithelial barriers could benefit from better in vitro models. Here the authors develop a microfluidic device supporting the growth and function of extracellular matrix-supported intestinal tubules, and evaluate the effect of staurosporine and acetylsalicylic acid on barrier integrity. PMID- 28811481 TI - Leaky Integrate and Fire Neuron by Charge-Discharge Dynamics in Floating-Body MOSFET. AB - Neuro-biology inspired Spiking Neural Network (SNN) enables efficient learning and recognition tasks. To achieve a large scale network akin to biology, a power and area efficient electronic neuron is essential. Earlier, we had demonstrated an LIF neuron by a novel 4-terminal impact ionization based n+/p/n+ with an extended gate (gated-INPN) device by physics simulation. Excellent improvement in area and power compared to conventional analog circuit implementations was observed. In this paper, we propose and experimentally demonstrate a compact conventional 3-terminal partially depleted (PD) SOI- MOSFET (100 nm gate length) to replace the 4-terminal gated-INPN device. Impact ionization (II) induced floating body effect in SOI-MOSFET is used to capture LIF neuron behavior to demonstrate spiking frequency dependence on input. MHz operation enables attractive hardware acceleration compared to biology. Overall, conventional PD SOI-CMOS technology enables very-large-scale-integration (VLSI) which is essential for biology scale (~1011 neuron based) large neural networks. PMID- 28811480 TI - Formation pathways of mesoporous silica nanoparticles with dodecagonal tiling. AB - Considerable progress in the fabrication of quasicrystals demonstrates that they can be realized in a broad range of materials. However, the development of chemistries enabling direct experimental observation of early quasicrystal growth pathways remains challenging. Here, we report the synthesis of four surfactant directed mesoporous silica nanoparticle structures, including dodecagonal quasicrystalline nanoparticles, as a function of micelle pore expander concentration or stirring rate. We demonstrate that the early formation stages of dodecagonal quasicrystalline mesoporous silica nanoparticles can be preserved, where precise control of mesoporous silica nanoparticle size down to <30 nm facilitates comparison between mesoporous silica nanoparticles and simulated single-particle growth trajectories beginning with a single tiling unit. Our results reveal details of the building block size distributions during early growth and how they promote quasicrystal formation. This work identifies simple synthetic parameters, such as stirring rate, that may be exploited to design other quasicrystal-forming self-assembly chemistries and processes.Probing the growth pathways of quasicrystalline materials, where tiling units arrange with local but no long-range order, remains challenging. Here, the authors demonstrate that dodecagonal tiling of mesoporous silica nanoparticles occurs via irreversible packing of micelles with non-uniform size distribution. PMID- 28811482 TI - Efficacy and safety of core-needle biopsy in initially detected thyroid nodules via propensity score analysis. AB - We compared the efficacy and complications of core-needle biopsy (CNB) with those of fine-needle aspiration (FNA) in a large population of patients with initially detected thyroid nodules via a propensity score analysis. Outpatients with initially detected thyroid nodules, who had undergone CNB or FNA between January 2013 and December 2013, were selected. This study included 4,822 thyroid nodules from 4,553 consecutive patients. Adjustments for significant differences in patients' baseline characteristics were facilitated via propensity score analysis. Subgroup analyses were performed according to nodule sizes >= 1 cm. The non-diagnostic result rate, malignancy rate, complication rate, and diagnostic accuracy were compared. A 1:1 matching of 1,615 patients yielded no significant differences between two groups for any covariate. The non-diagnostic result rate was significantly lower in the core-needle biopsy group than in the fine-needle aspiration group (5.2% vs. 12.1%), while the malignancy rate (23.7% vs. 11.8%) and sensitivity (75.9% vs. 55.6%) were significantly higher. However, the specificities were similar (100% and 99.9%, respectively). Propensity score and subgroup analyses showed similar results. The complication rate was similar between groups in matched cohorts. CNB is a promising and safe diagnostic tool for patients with initially detected thyroid nodules. PMID- 28811483 TI - The impact of human population pressure on flying fox niches and the potential consequences for Hendra virus spillover. AB - Hendra virus (HeV) is an emerging pathogen of concern in Australia given its ability to spillover from its reservoir host, pteropid bats, to horses and further on to humans, and the severe clinical presentation typical in these latter incidental hosts. Specific human pressures over recent decades, such as expanding human populations, urbanization, and forest fragmentation, may have altered the ecological niche of Pteropus species acting as natural HeV reservoirs and may modulate spillover risk. This study explored the influence of inter decadal net human local migration between 1970 and 2000 on changes in the habitat suitability to P. alecto and P. conspicillatus from 1980 to 2015 in eastern Australia. These ecological niches were modeled using boosted regression trees and subsequently fitted, along with additional landscape factors, to HeV spillovers to explore the spatial dependency of this zoonosis. The spatial model showed that the ecological niche of these two flying fox species, the human footprint, and proximity to woody savanna were each strongly associated with HeV spillover and together explained most of the spatial dependency exhibited by this zoonosis. These findings reinforce the potential for anthropogenic pressures to shape the landscape epidemiology of HeV spillover. PMID- 28811484 TI - Sea of Majorana fermions from pseudo-scalar superconducting order in three dimensional Dirac materials. AB - We suggest that spin-singlet pseudo-scalar s-wave superconducting pairing creates a two dimensional sea of Majorana fermions on the surface of three dimensional Dirac superconductors (3DDS). This pseudo-scalar superconducting order parameter Delta5, in competition with scalar Dirac mass m, leads to a topological phase transition due to band inversion. We find that a perfect Andreev-Klein reflection is guaranteed by presence of anomalous Andreev reflection along with the conventional one. This effect manifests itself in a resonant peak of the differential conductance. Furthermore, Josephson current of the Delta5|m|Delta5 junction in the presence of anomalous Andreev reflection is fractional with 4pi period. Our finding suggests another search area for condensed matter realization of Majorana fermions which are beyond the vortex-core of p-wave superconductors. The required Delta5 pairing can be extrinsically induced by a conventional s-wave superconductor into a three dimensional Dirac material (3DDM). PMID- 28811485 TI - Direct Detection Electron Energy-Loss Spectroscopy: A Method to Push the Limits of Resolution and Sensitivity. AB - In many cases, electron counting with direct detection sensors offers improved resolution, lower noise, and higher pixel density compared to conventional, indirect detection sensors for electron microscopy applications. Direct detection technology has previously been utilized, with great success, for imaging and diffraction, but potential advantages for spectroscopy remain unexplored. Here we compare the performance of a direct detection sensor operated in counting mode and an indirect detection sensor (scintillator/fiber-optic/CCD) for electron energy-loss spectroscopy. Clear improvements in measured detective quantum efficiency and combined energy resolution/energy field-of-view are offered by counting mode direct detection, showing promise for efficient spectrum imaging, low-dose mapping of beam-sensitive specimens, trace element analysis, and time resolved spectroscopy. Despite the limited counting rate imposed by the readout electronics, we show that both core-loss and low-loss spectral acquisition are practical. These developments will benefit biologists, chemists, physicists, and materials scientists alike. PMID- 28811486 TI - Detecting human melanoma cell re-differentiation following BRAF or heat shock protein 90 inhibition using photoacoustic and magnetic resonance imaging. AB - Targeted therapies specific to the BRAF-MEK-ERK signaling pathway have shown great promise in the treatment of malignant melanoma in the last few years, with these drugs now commonly used in clinic. Melanoma cells treated using these agents are known to exhibit increased levels of melanin pigment and tyrosinase activity. In this study we assessed the potential of non-invasive imaging approaches (photoacoustic imaging (PAI) and magnetic resonance imaging (MRI)) to detect melanin induction in SKMEL28 human melanoma cells, following inhibition of Hsp90 and BRAF signaling using 17-AAG and vemurafenib, respectively. We confirmed, using western blot and spectrophotometry, that Hsp90 or BRAF inhibitor induced melanoma cell differentiation resulted in an upregulation of tyrosinase and melanin expression levels, in comparison to control cells. This post treatment increase in cellular pigmentation induced a significant increase in PAI signals that are spectrally identifiable and shortening of the MRI relaxation times T 1 and [Formula: see text]. This proof-of-concept study demonstrates the potential of MRI and PAI for detecting the downstream cellular changes induced by Hsp90 and BRAF-MEK-targeted therapies in melanoma cells with potential significance for in vivo imaging. PMID- 28811487 TI - A Tri-part Protein Complementation System Using Antibody-Small Peptide Fusions Enables Homogeneous Immunoassays. AB - Protein-fragment complementation is a valuable tool for monitoring protein interactions. In complementation assays, the reporter fragments are directly fused to the interacting proteins, eliminating the possibility of monitoring native interactions. In principle, complementation could be achieved by placing the reporter fragments on antibodies which bind to the proteins of interest, enabling the monitoring of endogenous protein interactions or detection of a single protein in a homogeneous immunoassay. Previous reports have demonstrated proof-of-concept of this approach; however, current complementation systems have not met the practical requirements as suitable fusion partners for antibodies while providing the sensitivity needed for immunoassays. To surmount these challenges, we created a first-in-class, tri-part split luciferase consisting of two 11-residue peptides that are used as the antibody appendages. As an initial proof-of-concept, we used antibody-peptide fusions and found them to be capable of quantifying pg/mL concentrations of soluble or cell-bound HER2, proving this unique complementation system overcomes previous limitations and transforms this approach from merely possible to practical and useful. As shown herein, this dual peptide system provides a rapid, simple, and sensitive "add-and-read" homogeneous immunoassay platform that can be broadly adapted as an alternative to traditional immunoassays, and in the future should enable complementation to be expanded to monitoring endogenous protein interactions. PMID- 28811488 TI - Deregulation of ZPR1 causes respiratory failure in spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is caused by the low levels of survival motor neuron (SMN) protein and is characterized by motor neuron degeneration and muscle atrophy. Respiratory failure causes death in SMA but the underlying molecular mechanism is unknown. The zinc finger protein ZPR1 interacts with SMN. ZPR1 is down regulated in SMA patients. We report that ZPR1 functions downstream of SMN to regulate HoxA5 levels in phrenic motor neurons that control respiration. Spatiotemporal inactivation of Zpr1 gene in motor neurons down-regulates HoxA5 and causes defects in the function of phrenic motor neurons that results in respiratory failure and perinatal lethality in mice. Modulation in ZPR1 levels directly correlates and influences levels of HoxA5 transcription. In SMA mice, SMN-deficiency causes down-regulation of ZPR1 and HoxA5 that result in degeneration of phrenic motor neurons. Identification of ZPR1 and HoxA5 as potential targets provides a paradigm for developing strategies to treat respiratory distress in SMA. PMID- 28811489 TI - High temperature stress during flowering and grain filling offsets beneficial impact of elevated CO2 on assimilate partitioning and sink-strength in rice. AB - Elevated [CO2] (e[CO2]) environments have been predicted to improve rice yields under future climate. However, a concomitant rise in temperature could negate e[CO2] impact on plants, presenting a serious challenge for crop improvement. High temperature (HT) stress tolerant NL-44 and high yielding basmati Pusa 1121 rice cultivars, were exposed to e[CO2] (from panicle initiation to maturity) and a combination of e[CO2] + HT (from heading to maturity) using field based open top chambers. Elevated [CO2] significantly increased photosynthesis, seed-set, panicle weight and grain weight across both cultivars, more prominently with Pusa 1121. Conversely, e[CO2] + HT during flowering and early grain filling significantly reduced seed-set and 1000 grain weight, respectively. Averaged across both the cultivars, grain yield was reduced by 18 to 29%. Despite highly positive response with e[CO2], Pusa 1121 exposure to e[CO2] + HT led to significant reduction in seed-set and sink starch metabolism enzymatic activity. Interestingly, NL-44 maintained higher seed-set and resilience with starch metabolism enzymes under e[CO2] + HT exposure. Developing rice cultivars with higher [CO2] responsiveness incorporated with increased tolerance to high temperatures during flowering and grain filling using donors such as NL-44, will minimize the negative impact of heat stress and increase global food productivity, benefiting from [CO2] rich environments. PMID- 28811490 TI - Mammary Tumors Induce Central Pro-inflammatory Cytokine Expression, but Not Behavioral Deficits in Balb/C Mice. AB - Breast cancer survivors are more likely to develop mood disorders and cognitive deficits than women in the general population. Previous studies suggest that peripheral tumors elicit central pro-inflammatory cytokine production, in turn leading to depression and cognitive deficits. In the current study, two cohorts of female Balb/C mice received bilateral orthotopic injections of syngeneic 67NR, 4T07, or 4T1cells (1 * 105 cells per injection) to induce mammary tumors. Approximately three weeks later, learned fear (via fear conditioning) or depressive-like behavior (via tail suspension and forced swim test) was assessed. Proinflammatory cytokine levels were increased in the serum (IL-1beta, TNFalpha, IFNgamma) and livers (IL-1beta, IL-6, TNFalpha) of mice with 4T07 or 4T1 tumors compared to 67NR tumors and the vehicle control. IL-1beta was increased in both the hippocampus and cortex of mice injected with 4T07 or 4T1 cell lines relative to the other treatment groups. However, mammary tumors had no effect on hippocampal doublecortin + and did not alter depressive-like behavior or learned fear. These data demonstrate that similarly sized tumors can produce differential immune responses and that tumor-induced central pro-inflammatory cytokine production can exist in the absence of depressive-like behavior or cognitive deficits. PMID- 28811491 TI - High-fat diet-induced acceleration of osteoarthritis is associated with a distinct and sustained plasma metabolite signature. AB - Metabolic changes induced by high fat diet (HFD) that contribute to osteoarthritis (OA) are poorly understood. We investigated longitudinal changes to metabolites and their contribution to OA pathogenesis in response to HFD. HFD fed mice exhibited acceleration of spontaneous age-related and surgically-induced OA compared to lean diet (LD)-fed mice. Using metabolomics, we identified that HFD-fed mice exhibited a distinct and sustained plasma metabolite signature rich in phosphatidylcholines (PC) and lysophosphatidylcholines (lysoPCs), even after resumption of normal chow diet. Using receiver operator curve analysis and prediction modelling, we showed that the concentration of these identified metabolites could efficiently predict the type of diet and OA risk with an accuracy of 93%. Further, longitudinal evaluation of knee joints of HFD- compared to LD- fed mice showed a greater percentage of leptin-positive chondrocytes. Mechanistic data showed that leptin-treated human OA chondrocytes exhibited enhanced production of lysoPCs and expression of autotaxin and catabolic MMP-13. Leptin-induced increased MMP13 expression was reversed by autotaxin inhibition. Together, this study is the first to describe a distinct and sustained HFD induced metabolite signature. This study suggests that in addition to increased weight, identified metabolites and local leptin-signaling may also contribute in part, towards the accelerated OA-phenotype observed in HFD mice. PMID- 28811492 TI - Interferon-alpha treatment rapidly clears Hepatitis E virus infection in humanized mice. AB - Antiviral treatment options for chronic Hepatitis E Virus (HEV) infections are limited and immunological determinants of viral persistence remain largely unexplored. We studied the antiviral potency of pegylated interferon-alpha (pegIFNalpha) against HEV infections in humanized mice and modelled intrahepatic interferon stimulated gene (ISG) responses. Human gene expression levels in humanized mouse livers were analyzed by qPCR and Nanostring. Human CXCL10 was measured in mouse serum. HEV genotype 3 (gt3) infections were cleared from liver and feces within 8 pegIFNalpha doses in all mice and relapsed after a single pegIFNalpha injection in only half of treated animals. Rapid viral clearance by pegIFNalpha was confirmed in HEV gt1, but not in Hepatitis B Virus infected animals. No ISG induction was observed in untreated HEV gt3 and gt1 infected humanized livers compared to control chimeric mice, irrespective of the human hepatocyte donor, viral isolate or HEV infection duration. Human specific ISG transcript levels in mouse liver increased significantly after pegIFNalpha treatment and induced high circulating human CXCL10 in mouse serum. In conclusion, HEV gt1 and gt3 infections do not elicit innate intrahepatic immune responses and remain highly sensitive to pegIFNalpha in immunocompromised humanized mice. PMID- 28811493 TI - Fragile temporal prediction in patients with schizophrenia is related to minimal self disorders. AB - Patients with schizophrenia have difficulty in making sensory predictions, in the time domain, which have been proposed to be related to self-disorders. However experimental evidence is lacking. We examined both voluntary and automatic forms of temporal prediction in 28 patients and 24 matched controls. A visual cue predicted (temporal cue) or not (neutral cue) the time (400 ms/1000 ms) at which a subsequent target was presented. In both patients and controls, RTs were faster for targets presented after long versus short intervals due to the temporal predictability inherent in the elapse of time ("hazard function"). This RT benefit was correlated with scores on the EASE scale, which measures disorders of the self: patients with a high 'self-awareness and presence' score did not show any significant benefit of the hazard function, whereas this ability was preserved in patients with a low score. Moreover, all patients were abnormally sensitive to the presence of "catch" trials (unexpected absence of a target) within a testing block, with RTs actually becoming slower at long versus short intervals. These results indicate fragility in patients' ability to continuously extract temporally predictive information from the elapsing interval. This deficit might contribute to perturbations of the minimal self in patients. PMID- 28811494 TI - On the shape and likelihood of oceanic rogue waves. AB - We consider the observation and analysis of oceanic rogue waves collected within spatio-temporal (ST) records of 3D wave fields. This class of records, allowing a sea surface region to be retrieved, is appropriate for the observation of rogue waves, which come up as a random phenomenon that can occur at any time and location of the sea surface. To verify this aspect, we used three stereo wave imaging systems to gather ST records of the sea surface elevation, which were collected in different sea conditions. The wave with the ST maximum elevation (happening to be larger than the rogue threshold 1.25H s) was then isolated within each record, along with its temporal profile. The rogue waves show similar profiles, in agreement with the theory of extreme wave groups. We analyze the rogue wave probability of occurrence, also in the context of ST extreme value distributions, and we conclude that rogue waves are more likely than previously reported; the key point is coming across them, in space as well as in time. The dependence of the rogue wave profile and likelihood on the sea state conditions is also investigated. Results may prove useful in predicting extreme wave occurrence probability and strength during oceanic storms. PMID- 28811495 TI - Low protein-induced increases in FGF21 drive UCP1-dependent metabolic but not thermoregulatory endpoints. AB - Dietary protein restriction increases adipose tissue uncoupling protein 1 (UCP1), energy expenditure and food intake, and these effects require the metabolic hormone fibroblast growth factor 21 (FGF21). Here we test whether the induction of energy expenditure during protein restriction requires UCP1, promotes a resistance to cold stress, and is dependent on the concomitant hyperphagia. Wildtype, Ucp1-KO and Fgf21-KO mice were placed on control and low protein (LP) diets to assess changes in energy expenditure, food intake and other metabolic endpoints. Deletion of Ucp1 blocked LP-induced increases in energy expenditure and food intake, and exacerbated LP-induced weight loss. While LP diet increased energy expenditure and Ucp1 expression in an FGF21-dependent manner, neither LP diet nor the deletion of Fgf21 influenced sensitivity to acute cold stress. Finally, LP-induced energy expenditure occurred even in the absence of hyperphagia. Increased energy expenditure is a primary metabolic effect of dietary protein restriction, and requires both UCP1 and FGF21 but is independent of changes in food intake. However, the FGF21-dependent increase in UCP1 and energy expenditure by LP has no effect on the ability to acutely respond to cold stress, suggesting that LP-induced increases in FGF21 impact metabolic but not thermogenic endpoints. PMID- 28811496 TI - Genome-wide expression differences in anti-Vegf and dexamethasone treatment of inflammatory angiogenesis in the rat cornea. AB - Angiogenesis as a pathological process in the eye can lead to blindness. In the cornea, suppression of angiogenesis by anti-VEGF treatment is only partially effective while steroids, although effective in treating inflammation and angiogenesis, have broad activity leading to undesirable side effects. In this study, genome-wide expression was investigated in a suture-induced corneal neovascularization model in rats, to investigate factors differentially targeted by dexamethasone and anti-Vegf. Topical treatment with either rat-specific anti Vegf, dexamethasone, or normal goat IgG (sham) was given to sutured corneas for 48 hours, after which in vivo imaging, tissue processing for RNA microarray, and immunofluorescence were performed. Dexamethasone suppressed limbal vasodilation (P < 0.01) and genes in PI3K-Akt, focal adhesion, and chemokine signaling pathways more effectively than anti-Vegf. The most differentially expressed genes were confirmed by immunofluorescence, qRTPCR and Western blot. Strong suppression of Reg3g and the inflammatory chemokines Ccl2 and Cxcl5 and activation of classical complement pathway factors C1r, C1s, C2, and C3 occurred with dexamethasone treatment, effects absent with anti-Vegf treatment. The genome-wide results obtained in this study provide numerous potential targets for specific blockade of inflammation and angiogenesis in the cornea not addressed by anti Vegf treatment, as possible alternatives to broad-acting immunosuppressive therapy. PMID- 28811497 TI - Vertical ocean heat redistribution sustaining sea-ice concentration trends in the Ross Sea. AB - Several processes have been hypothesized to explain the slight overall expansion of Antarctic sea ice over the satellite observation era, including externally forced changes in local winds or in the Southern Ocean's hydrological cycle, as well as internal climate variability. Here, we show the critical influence of an ocean-sea-ice feedback. Once initiated by an external perturbation, it may be sufficient to sustain the observed sea-ice expansion in the Ross Sea, the region with the largest and most significant expansion. We quantify the heat trapped at the base of the ocean mixed layer and demonstrate that it is of the same order of magnitude as the latent heat storage due to the long-term changes in sea-ice volume. The evidence thus suggests that the recent ice coverage increase in the Ross Sea could have been achieved through a reorganization of energy within the near-surface ice-ocean system.The mechanisms responsible for the overall expansion of Antarctic sea-ice in recent decades remain unclear. Here, using observations and model results, the authors show that ice-ocean feedbacks, triggered by an external perturbation, could be responsible for changes in sea ice extent observed in the Ross Sea. PMID- 28811499 TI - The role of Dermcidin isoform-2 in the occurrence and severity of Diabetes. AB - Diabetes is now epidemic worldwide. Several hundred-million peoples are presently suffering from this disease with other secondary-disorders. Stress, hypertension, sedentary life-style, carbohydrate/lipid metabolic-disorders due to genetic or environmental factors attributes to type-1 and/or type-2 diabetes. Present investigation demonstrates that stress-induced protein dermcidin isoform-2 (DCN 2) which appears in the serum of diabetic-patients play a key-role in this disease pathogenesis/severity. DCN-2 suppresses insulin production-release from liver/pancreas. It also increases the insulin-resistance. Stress-induction at the onset/progression of this disease is noticed as the high-level of lipid peroxides/low-level of free-thiols in association with increase of inflammatory markers c-reactive protein and TNF-alpha. DCN-2 induced decrease in the synthesis of glucose-activated nitric oxide synthase (GANOS) and lower production of NO in liver has been shown here where NO is demonstrated to lower the expression of glucose trabsporter-4 (GLUT-4) and its translocation on liver membrane surface. This finally impairs glucose transport to organs from the extracellular fluid. Low level of glucose uptake further decreases glucose-induced insulin synthesis. The central role of DCN-2 has been demonstrated in type-1/type-2 diabetic individuals, in rodent hepatocytes and pancreatic-cell, tissue-slices, in-vitro and in-vivo experimental model. It can be concluded that stress-induced decrease in insulin synthesis/function, glucose transport is an interactive consequence of oxidative threats and inflammatory events. PMID- 28811498 TI - Genome re-sequencing reveals the history of apple and supports a two-stage model for fruit enlargement. AB - Human selection has reshaped crop genomes. Here we report an apple genome variation map generated through genome sequencing of 117 diverse accessions. A comprehensive model of apple speciation and domestication along the Silk Road is proposed based on evidence from diverse genomic analyses. Cultivated apples likely originate from Malus sieversii in Kazakhstan, followed by intensive introgressions from M. sylvestris. M. sieversii in Xinjiang of China turns out to be an "ancient" isolated ecotype not directly contributing to apple domestication. We have identified selective sweeps underlying quantitative trait loci/genes of important fruit quality traits including fruit texture and flavor, and provide evidences supporting a model of apple fruit size evolution comprising two major events with one occurring prior to domestication and the other during domestication. This study outlines the genetic basis of apple domestication and evolution, and provides valuable information for facilitating marker-assisted breeding and apple improvement.Apple is one of the most important fruit crops. Here, the authors perform deep genome resequencing of 117 diverse accessions and reveal comprehensive models of apple origin, speciation, domestication, and fruit size evolution as well as candidate genes associated with important agronomic traits. PMID- 28811500 TI - Human microcephaly protein RTTN interacts with STIL and is required to build full length centrioles. AB - Mutations in many centriolar protein-encoding genes cause primary microcephaly. Using super-resolution and electron microscopy, we find that the human microcephaly protein, RTTN, is recruited to the proximal end of the procentriole at early S phase, and is located at the inner luminal walls of centrioles. Further studies demonstrate that RTTN directly interacts with STIL and acts downstream of STIL-mediated centriole assembly. CRISPR/Cas9-mediated RTTN gene knockout in p53-deficient cells induce amplification of primitive procentriole bodies that lack the distal-half centriolar proteins, POC5 and POC1B. Additional analyses show that RTTN serves as an upstream effector of CEP295, which mediates the loading of POC1B and POC5 to the distal-half centrioles. Interestingly, the naturally occurring microcephaly-associated mutant, RTTN (A578P), shows a low affinity for STIL binding and blocks centriole assembly. These findings reveal that RTTN contributes to building full-length centrioles and illuminate the molecular mechanism through which the RTTN (A578P) mutation causes primary microcephaly.Mutations in many centriolar protein-encoding genes cause primary microcephaly. Here the authors show that human microcephaly protein RTTN directly interacts with STIL and acts downstream of STIL-mediated centriole assembly, contributing to building full-length centrioles. PMID- 28811501 TI - Characterisation of sterol biosynthesis and validation of 14alpha-demethylase as a drug target in Acanthamoeba. AB - The soil amoebae Acanthamoeba causes Acanthamoeba keratitis, a severe sight threatening infection of the eye and the almost universally fatal granulomatous amoebic encephalitis. More effective treatments are required. Sterol biosynthesis has been effectively targeted in numerous fungi using azole compounds that inhibit the cytochrome P450 enzyme sterol 14alpha-demethylase. Herein, using Gas Chromatography Mass Spectrometry (GCMS), we demonstrate that the major sterol of Acanthamoeba castellanii is ergosterol and identify novel putative precursors and intermediate sterols in its production. Unlike previously reported, we find no evidence of 7-dehydrostigmasterol or any other phytosterol in Acanthamoeba. Of five azoles tested, we demonstrate that tioconazole and voriconazole have the greatest overall inhibition for all isolates of Acanthamoeba castellanii and Acanthamoeba polyphaga tested. While miconazole and sulconazole have intermediate activity econazole is least effective. Through GCMS, we demonstrate that voriconazole inhibits 14alpha-demethylase as treatment inhibits the production of ergosterol, but results in the accumulation of the lanosterol substrate. These data provide the most complete description of sterol metabolism in Acanthamoeba, provide a putative framework for their further study and validate 14alpha demethylase as the target for azoles in Acanthamoeba. PMID- 28811502 TI - Sex Steroid Hormones Regulate Leptin Transcript Accumulation and Protein Secretion in 3T3-L1 Cells. AB - Leptin is an adipokine produced by fat cells that regulates food consumption and metabolic activity. Sexual dimorphism in leptin and fat stores have been observed in humans and rodents with females having more leptin and greater levels of subcutaneous fat than males. One potential mechanism leading to this dimorphism is steroid hormone regulated synthesis of transcripts encoding leptin. Identification of direct regulatory mechanisms is difficult in animals or primary adipocytes due to these intertwined dimorphisms. We used well-characterized 3T3 L1 murine adipocytes to demonstrate that dihydrotestosterone (DHT) reduced Leptin (Lep) transcript abundance and cytosolic and secreted leptin protein. The magnitude of this effect was greatest on secreted leptin, which was decreased by DHT to 30% of the control. In contrast, 17beta-estradiol significantly increased the abundance of transcripts encoding leptin and increased secreted leptin to 230% of the control. Treatment with estrogen and androgen receptor antagonists had opposite effects on Lep transcript abundance to steroid treatments, indicating that these transcriptional effects are mediated through the canonical steroid hormone signaling pathways. These results indicate that short-term treatments with steroid hormones are sufficient to alter both Lep transcript accumulation and leptin protein secretion, and may play a role in the sexual dimorphism of this adipokine. PMID- 28811503 TI - Lacrimal Gland Repair after Short-term Obstruction of Excretory Duct in Rabbits. AB - Aqueous tear-deficient dry eye is a multifactorial chronic disorder in which the lacrimal glands fail to produce enough tears to maintain a healthy ocular surface. The existence of lacrimal gland stem/progenitor cells was proposed in several species, yet their origin and characteristics are not very clear. Here, we investigated the presence of resident progenitor cells and their regenerative potential in a rabbit model with lacrimal gland main excretory duct ligation induced injury. The ligation-injured lacrimal glands temporarily decreased in weight and had impaired tear secretion. Protein expression profiles and transcriptional profiles were obtained from injured tissue. Isolated lacrimal gland progenitor cells were tested and characterized by stem cell-related marker evaluation, single cell clonal assay and three-dimensional (3-D) culture. The results of our study indicate that lacrimal glands are capable of tissue repair after duct ligation-induced injury, likely involving resident stem/progenitor cells and epithelial-mesenchymal transitions. Lacrimal gland progenitor cells isolated from ligated tissue can differentiate in 3-D culture. The results provide further insights into lacrimal gland stem/progenitor cell physiology and their potential for treating severe cases of tear deficiency. PMID- 28811504 TI - Complementarity among natural enemies enhances pest suppression. AB - Natural enemies have been shown to be effective agents for controlling insect pests in crops. However, it remains unclear how different natural enemy guilds contribute to the regulation of pests and how this might be modulated by landscape context. In a field exclusion experiment in oilseed rape (OSR), we found that parasitoids and ground-dwelling predators acted in a complementary way to suppress pollen beetles, suggesting that pest control by multiple enemies attacking a pest during different periods of its occurrence in the field improves biological control efficacy. The density of pollen beetle significantly decreased with an increased proportion of non-crop habitats in the landscape. Parasitism had a strong effect on pollen beetle numbers in landscapes with a low or intermediate proportion of non-crop habitats, but not in complex landscapes. Our results underline the importance of different natural enemy guilds to pest regulation in crops, and demonstrate how biological control can be strengthened by complementarity among natural enemies. The optimization of natural pest control by adoption of specific management practices at local and landscape scales, such as establishing non-crop areas, low-impact tillage, and temporal crop rotation, could significantly reduce dependence on pesticides and foster yield stability through ecological intensification in agriculture. PMID- 28811505 TI - Identification and quantification of plasma free salusin-beta, an endogenous parasympathomimetic peptide. AB - Salusin-beta is an endogenous parasympathomimetic proatherosclerotic peptide. Salusin-beta was initially predicted from bioinformatic analyses and later immunologically detected in human biofluids. However, elucidation of salusin-beta bioactivity has faced enormous challenges because of its unique physicochemical characteristics that cause it to strongly adhere to laboratory apparatus materials. In the strictest sense, the discovery of bioactive peptides is not complete until their exact native sequences have been confirmed in the peripheral circulation. In this study, we determined the plasma molecular form and levels of free salusin-beta to determine its pathophysiological significance. Ultra-high yield enrichment and preseparation of non-tryptic human plasma was followed by LC MS/MS, and full-length salusin-beta and seven different endogenous fragment sequences were identified. We established a new ELISA that specifically detects plasma free salusin-beta without cross-reacting with any of its identified endogenous fragments. Free salusin-beta levels exhibited a profound early morning nadir and rapidly decreased in response to parasympathetic nervous augmentation. Our technical advance in plasma native peptide analysis successfully identified a hard-to-detect bioactive peptide, salusin-beta, together with its formerly unrecognized fragments, and further suggests that conventional immunological measurements of target peptides may not be fully representative. PMID- 28811506 TI - An amphibian chemical defense phenotype is inducible across life history stages. AB - Inducible phenotypic responses to environmental variation are ubiquitous across the tree of life, but it remains an open question whether amphibian chemical defense phenotypes are inducible. Tetrodotoxin (TTX) is a key chemical defense trait in North American and Eurasian newts (Salamandridae). We tested if TTX can be induced by exposing populations of adult and larval California newts (Taricha torosa) to sustained stressful conditions while longitudinally quantifying TTX concentrations. Adult newts rapidly increased chemical defenses in response to simulated predator attacks and consistently maintained elevated TTX concentrations relative to wild, non-captive individuals. We also found that laboratory-reared larvae maintained chemical defenses nearly three-fold greater than those of siblings reared in streams. Collectively, our results indicate that amphibian chemical defenses are not fixed. Instead, toxins are maintained at a baseline concentration that can quickly be increased in response to perceived risk with substantial increases to toxicity. Therefore, it is crucial that inducible variation be accounted for when considering ecological dynamics of chemically defended animals and coevolutionary predator-prey and mimic-model relationships. PMID- 28811507 TI - Global mapping of miRNA-target interactions in cattle (Bos taurus). AB - With roles in development, cell proliferation and disease, micro-RNA (miRNA) biology is of great importance and a potential therapeutic target. Here we used cross-linking immunoprecipitation (CLIP) and ligation of miRNA-target chimeras on the Argonaute (AGO) protein to globally map miRNA interactions in the cow. The interactome is the deepest reported to date. miRNA targeting principles are consistent with observations in other species, but with expanded pairing rules. Experimental mapping robustly predicted functional miR-17 regulatory sites. From miRNA-specific targeting for >5000 mRNAs we determined gene ontologies (GO). This confirmed repression of genes important for embryonic development and cell cycle progress by the let-7 family, and repression of those involved in cell cycle arrest by the miR-17 family, but also suggested a number of unappreciated miRNA functions. Our results provide a significant resource for understanding of bovine and species-conserved miRNA regulation, and demonstrate the power of experimental methods for establishing comprehensive interaction maps. PMID- 28811508 TI - Discrimination of plant root zone water status in greenhouse production based on phenotyping and machine learning techniques. AB - Plant-based sensing on water stress can provide sensitive and direct reference for precision irrigation system in greenhouse. However, plant information acquisition, interpretation, and systematical application remain insufficient. This study developed a discrimination method for plant root zone water status in greenhouse by integrating phenotyping and machine learning techniques. Pakchoi plants were used and treated by three root zone moisture levels, 40%, 60%, and 80% relative water content. Three classification models, Random Forest (RF), Neural Network (NN), and Support Vector Machine (SVM) were developed and validated in different scenarios with overall accuracy over 90% for all. SVM model had the highest value, but it required the longest training time. All models had accuracy over 85% in all scenarios, and more stable performance was observed in RF model. Simplified SVM model developed by the top five most contributing traits had the largest accuracy reduction as 29.5%, while simplified RF and NN model still maintained approximately 80%. For real case application, factors such as operation cost, precision requirement, and system reaction time should be synthetically considered in model selection. Our work shows it is promising to discriminate plant root zone water status by implementing phenotyping and machine learning techniques for precision irrigation management. PMID- 28811509 TI - Determining causal miRNAs and their signaling cascade in diseases using an influence diffusion model. AB - In recent studies, miRNAs have been found to be extremely influential in many of the essential biological processes. They exhibit a self-regulatory mechanism through which they act as positive/negative regulators of expression of genes and other miRNAs. This has direct implications in the regulation of various pathophysiological conditions, signaling pathways and different types of cancers. Studying miRNA-disease associations has been an extensive area of research; however deciphering miRNA-miRNA network regulatory patterns in several diseases remains a challenge. In this study, we use information diffusion theory to quantify the influence diffusion in a miRNA-miRNA regulation network across multiple disease categories. Our proposed methodology determines the critical disease specific miRNAs which play a causal role in their signaling cascade and hence may regulate disease progression. We extensively validate our framework using existing computational tools from the literature. Furthermore, we implement our framework on a comprehensive miRNA expression data set for alcohol dependence and identify the causal miRNAs for alcohol-dependency in patients which were validated by the phase-shift in their expression scores towards the early stages of the disease. Finally, our computational framework for identifying causal miRNAs implicated in diseases is available as a free online tool for the greater scientific community. PMID- 28811510 TI - Temporal changes in the radiocesium distribution in forests over the five years after the Fukushima Daiichi Nuclear Power Plant accident. AB - To elucidate the temporal changes in the radiocesium distribution in forests contaminated by the Fukushima Daiichi Nuclear Power Plant accident, we monitored the 137Cs concentration and inventory within forests from 2011 to 2015 across nine plots containing variable tree species and different contamination levels. The 137Cs concentrations in needles and branches decreased exponentially at all coniferous plots, with effective ecological half-lives of 0.45-1.55 yr for needles and 0.83-1.69 yr for branches. By contrast, the 137Cs concentration in deciduous konara oak leaves did not change over the five years. The concentration of 137Cs in oak wood increased by 37-75%, whereas that in Japanese red pine decreased by 63% over the five years. In Japanese cedar and hinoki cypress, the 137Cs concentration in wood showed an increasing trend in half of the plots. The changes in 137Cs in the organic and mineral soil layers were not strongly related to the tree species or contamination level. Our multi-site, multi-species monitoring results revealed that the pattern of temporal changes in radiocesium in the 9 forest plots was similar overall; however, changes in 137Cs in needles/leaves and wood differed among tree species. PMID- 28811511 TI - From metabolome to phenotype: GC-MS metabolomics of developing mutant barley seeds reveals effects of growth, temperature and genotype. AB - The development of crop varieties tolerant to growth temperature fluctuations and improved nutritional value is crucial due to climate change and global population growth. This study investigated the metabolite patterns of developing barley seed as a function of genotype and growth temperature for ideal vegetable protein production and for augmented beta-glucan production. Seeds from three barley lines (Bomi, lys3.a and lys5.f) were sampled eight times during grain filling and analysed for metabolites using gas chromatography-mass spectrometry (GC-MS). The lys3.a mutation disrupts a regulator gene, causing an increase in proteins rich in the essential amino acid lysine, while lys5.f carries a mutation in an ADP glucose transporter gene leading to a significant increase in production of mixed linkage beta-glucan at the expense of alpha-glucan. Unique metabolic patterns associated with the tricarboxylic acid cycle, shikimate-phenylpropanoid pathway, mevalonate, lipid and carbohydrate metabolism were observed for the barley mutants, whereas growth temperature primarily affected shikimate-phenylpropanoid and lipid metabolism. The study applied recently developed GC-MS metabolomics methods and demonstrated their successful application to link genetic and environmental factors with the seed phenotype of unique and agro-economically important barley models for optimal vegetable protein and dietary fibre production. PMID- 28811512 TI - Projected climate change impacts in rainfall erosivity over Brazil. AB - The impacts of climate change on soil erosion may bring serious economic, social and environmental problems. However, few studies have investigated these impacts on continental scales. Here we assessed the influence of climate change on rainfall erosivity across Brazil. We used observed rainfall data and downscaled climate model output based on Hadley Center Global Environment Model version 2 (HadGEM2-ES) and Model for Interdisciplinary Research On Climate version 5 (MIROC5), forced by Representative Concentration Pathway 4.5 and 8.5, to estimate and map rainfall erosivity and its projected changes across Brazil. We estimated mean values of 10,437 mm ha-1 h-1 year-1 for observed data (1980-2013) and 10,089 MJ mm ha-1 h-1 year-1 and 10,585 MJ mm ha-1 h-1 year-1 for HadGEM2-ES and MIROC5, respectively (1961-2005). Our analysis suggests that the most affected regions, with projected rainfall erosivity increases ranging up to 109% in the period 2007 2040, are northeastern and southern Brazil. Future decreases of as much as -71% in the 2071-2099 period were estimated for the southeastern, central and northwestern parts of the country. Our results provide an overview of rainfall erosivity in Brazil that may be useful for planning soil and water conservation, and for promoting water and food security. PMID- 28811513 TI - Altered Cerebellar Biochemical Profiles in Infants Born Prematurely. AB - This study aims to compare the cerebellar biochemical profiles in preterm (PT) infants evaluated at term equivalent age (TEA) and healthy full-term newborns using proton magnetic resonance spectroscopy (1H-MRS). We explore the associations between altered cerebellar metabolite profiles and brain injury topography, severity of injury, and prematurity-related clinical complications. We prospectively collected high quality 1H-MRS in 59 premature infants born <=32 weeks and 61 healthy full term controls. 1H-MRS data were processed using LCModel software to calculate absolute metabolite concentration for N-acetyl-aspartate (NAA), choline (Cho) and creatine (Cr). PT infants had significantly lower cerebellar NAA (p < 0.025) and higher Cho (p < 0.001) at TEA when compared to healthy controls. Creatine was not different between the two groups. The presence of cerebellar injury was consistently associated with reduced concentrations for NAA, Cho, and Cr. Postnatal infection was negatively associated with NAA and Cr (p < 005), while cerebral cortical brain injury severity was inversely associated with both Cho and Cr (p < 0.01). We report for the first time that premature birth is associated with altered cerebellar metabolite profiles when compared to term born controls. Infection, cerebellar injury and supratentorial injury are important risk factors for impaired preterm cerebellar biochemistry. PMID- 28811514 TI - Differential epitope recognition in the immunodominant staphylococcal antigen A of Staphylococcus aureus by mouse versus human IgG antibodies. AB - The immunodominant staphylococcal antigen A (IsaA) is a potential target for active or passive immunization against the important human pathogen Staphylococcus aureus. Consistent with this view, monoclonal antibodies against IsaA were previously shown to be protective against S. aureus infections in mouse models. Further, patients with the genetic blistering disease epidermolysis bullosa (EB) displayed high IsaA-specific IgG levels that could potentially be protective. Yet, mice actively immunized with IsaA were not protected against S. aureus infection. The present study was aimed at explaining these differences in IsaA-specific immune responses. By epitope mapping, we show that the protective human monoclonal antibody (humAb) 1D9 recognizes a conserved 62-residue N terminal domain of IsaA. The same region of IsaA is recognized by IgGs in EB patient sera. Further, we show by immunofluorescence microscopy that this N terminal IsaA domain is exposed on the S. aureus cell surface. In contrast to the humAb 1D9 and IgGs from EB patients, the non-protective IgGs from mice immunized with IsaA were shown to predominantly bind the C-terminal domain of IsaA. Altogether, these observations focus attention on the N-terminal region of IsaA as a potential target for future immunization against S. aureus. PMID- 28811515 TI - Localization of photoperiod responsive circadian oscillators in the mouse suprachiasmatic nucleus. AB - The circadian pacemaker in the suprachiasmatic nucleus (SCN) yields photoperiodic response to transfer seasonal information to physiology and behavior. To identify the precise location involved in photoperiodic response in the SCN, we analyzed circadian Period1 and PERIOD2 rhythms in horizontally sectioned SCN of mice exposed to a long or short day. Statistical analyses of bioluminescence images with respective luciferase reporters on pixel level enabled us to identify the distinct localization of three oscillating regions; a large open-ring-shape region, the region at the posterior end and a sharply demarcated oval region at the center of the SCN. The first two regions are the respective sites for the so called evening and morning oscillators, and the third region is possibly a site for mediating photic signals to the former oscillators. In these regions, there are two classes of oscillating cells in which Per1 and Per2 could play differential roles in photoperiodic responses. PMID- 28811516 TI - Q-factor enhancement of Fano resonance in all-dielectric metasurfaces by modulating meta-atom interactions. AB - We numerically investigated the effects of meta-atom interactions on the Fano resonance in all-dielectric metasurfaces by introducing alternately flipped asymmetric paired bars (APBs) and split asymmetric paired bars (SAPBs). With alternately flipped configurations, the Q-factor of the Fano resonance is significantly enhanced up to one order of magnitude, and the electric field is strengthened by more than twice. Abnormally, the Q-factor increases with gap size in the alternately flipped SAPBs. These are attributed to the destructive interaction among nearest-neighbor dipole resonators. The Q-factor of 108 and Raman enhancement factor of 109 in the gap can be realized with the alternately flipped SAPBs made of Si. Our study provides a way to improve performance of practical devices such as ultrasensitive sensors, nonlinear optics, and quantum emitters. PMID- 28811517 TI - Heritability of the Symbiodinium community in vertically- and horizontally transmitting broadcast spawning corals. AB - The dinoflagellate-coral partnership influences the coral holobiont's tolerance to thermal stress and bleaching. However, the comparative roles of host genetic versus environmental factors in determining the composition of this symbiosis are largely unknown. Here we quantify the heritability of the initial Symbiodinium communities for two broadcast-spawning corals with different symbiont transmission modes: Acropora tenuis has environmental acquisition, whereas Montipora digitata has maternal transmission. Using high throughput sequencing of the ITS-2 region to characterize communities in parents, juveniles and eggs, we describe previously undocumented Symbiodinium diversity and dynamics in both corals. After one month of uptake in the field, Symbiodinium communities associated with A. tenuis juveniles were dominated by A3, C1, D1, A-type CCMP828, and D1a in proportional abundances conserved between experiments in two years. M. digitata eggs were predominantly characterized by C15, D1, and A3. In contrast to current paradigms, host genetic influences accounted for a surprising 29% of phenotypic variation in Symbiodinium communities in the horizontally-transmitting A. tenuis, but only 62% in the vertically-transmitting M. digitata. Our results reveal hitherto unknown flexibility in the acquisition of Symbiodinium communities and substantial heritability in both species, providing material for selection to produce partnerships that are locally adapted to changing environmental conditions. PMID- 28811518 TI - Anomalous in situ Activation of Carbon-Supported Ni2P Nanoparticles for Oxygen Evolving Electrocatalysis in Alkaline Media. AB - Electrochemical water splitting is one of the most promising systems by which to store energy produced from sustainable sources, such as solar and wind energy. Designing robust and stable electrocatalysts is urgently needed because of the relatively sluggish kinetics of the anodic reaction, i.e. the oxygen evolution reaction (OER). In this study, we investigate the anomalous in situ activation behaviour of carbon-supported Ni2P nanoparticles (Ni2P/C) during OER catalysis in alkaline media. The activated Ni2P/C shows an exceptionally high activity and stability under OER conditions in which the overpotential needed to achieve 10 mA cm-2 was reduced from approximately 350 mV to approximately 300 mV after 8,000 cyclic voltammetric scans. In situ and ex situ characterizations indicate that the activity enhancement of Ni2P catalysts is due to a favourable phase transformation of the Ni centre to beta-NiOOH, including increases in the active area induced by structural deformation under the OER conditions. These findings provide new insights towards designing transition metal/phosphide-based materials for an efficient water splitting catalyst. PMID- 28811519 TI - High-resolution mapping based on an Unmanned Aerial Vehicle (UAV) to capture paleoseismic offsets along the Altyn-Tagh fault, China. AB - The recent dramatic increase in millimeter- to centimeter- resolution topographic datasets obtained via multi-view photogrammetry raises the possibility of mapping detailed offset geomorphology and constraining the spatial characteristics of active faults. Here, for the first time, we applied this new method to acquire high-resolution imagery and generate topographic data along the Altyn Tagh fault, which is located in a remote high elevation area and shows preserved ancient earthquake surface ruptures. A digital elevation model (DEM) with a resolution of 0.065 m and an orthophoto with a resolution of 0.016 m were generated from these images. We identified piercing markers and reconstructed offsets based on both the orthoimage and the topography. The high-resolution UAV data were used to accurately measure the recent seismic offset. We obtained the recent offset of 7 +/- 1 m. Combined with the high resolution satellite image, we measured cumulative offsets of 15 +/- 2 m, 20 +/- 2 m, 30 +/- 2 m, which may be due to multiple paleo-earthquakes. Therefore, UAV mapping can provide fine-scale data for the assessment of the seismic hazards. PMID- 28811520 TI - Chronic post-stroke aphasia severity is determined by fragmentation of residual white matter networks. AB - Many stroke survivors with aphasia in the acute period experience spontaneous recovery within the first six months after the stroke. However, approximately 30 40% sustain permanent aphasia and the factors determining incomplete recovery are unclear. Suboptimal recovery may be influenced by disruption of areas seemingly spared by the stroke due to loss of white matter connectivity and network integrity. We reconstructed individual anatomical whole-brain connectomes from 90 left hemisphere stroke survivors using diffusion MR images. We measured the modularity of the residual white matter network organization, the probability of brain regions clustering together, and the degree of fragmentation of left hemisphere networks. Greater post-stroke left hemisphere network fragmentation and higher modularity index were associated with more severe chronic aphasia, controlling for the size of the stroke lesion. Even when the left hemisphere was relatively spared, subjects with disorganized community structure had significantly worse aphasia, particularly when key temporal lobe regions were isolated into segregated modules. These results suggest that white matter integrity and disorganization of neuronal networks could be important determinants of chronic aphasia severity. Connectome white matter organization measured through modularity and other topological features could be used as a personalized variable for clinical staging and aphasia treatment planning. PMID- 28811521 TI - Decadal trends in Red Sea maximum surface temperature. AB - Ocean warming is a major consequence of climate change, with the surface of the ocean having warmed by 0.11 degrees C decade-1 over the last 50 years and is estimated to continue to warm by an additional 0.6 - 2.0 degrees C before the end of the century1. However, there is considerable variability in the rates experienced by different ocean regions, so understanding regional trends is important to inform on possible stresses for marine organisms, particularly in warm seas where organisms may be already operating in the high end of their thermal tolerance. Although the Red Sea is one of the warmest ecosystems on earth, its historical warming trends and thermal evolution remain largely understudied. We characterized the Red Sea's thermal regimes at the basin scale, with a focus on the spatial distribution and changes over time of sea surface temperature maxima, using remotely sensed sea surface temperature data from 1982 2015. The overall rate of warming for the Red Sea is 0.17 +/- 0.07 degrees C decade-1, while the northern Red Sea is warming between 0.40 and 0.45 degrees C decade-1, all exceeding the global rate. Our findings show that the Red Sea is fast warming, which may in the future challenge its organisms and communities. PMID- 28811522 TI - The lichen secondary metabolite atranorin suppresses lung cancer cell motility and tumorigenesis. AB - Lichens are symbiotic organisms that produce various secondary metabolites. Here, different lichen extracts were examined to identify secondary metabolites with anti-migratory activity against human lung cancer cells. Everniastrum vexans had the most potent inhibitory activity, and atranorin was identified as an active subcomponent of this extract. Atranorin suppressed beta-catenin-mediated TOPFLASH activity by inhibiting the nuclear import of beta-catenin and downregulating beta catenin/LEF and c-jun/AP-1 downstream target genes such as CD44, cyclin-D1 and c myc. Atranorin decreased KAI1 C-terminal interacting tetraspanin (KITENIN) mediated AP-1 activity and the activity of the KITENIN 3'-untranslated region. The nuclear distribution of the AP-1 transcriptional factor, including c-jun and c-fos, was suppressed in atranorin-treated cells, and atranorin inhibited the activity of Rho GTPases including Rac1, Cdc42, and RhoA, whereas it had no effect on epithelial-mesenchymal transition markers. STAT-luciferase activity and nuclear STAT levels were decreased, whereas total STAT levels were moderately reduced. The human cell motility and lung cancer RT2 Profiler PCR Arrays identified additional atranorin target genes. Atranorin significantly inhibited tumorigenesis in vitro and in vivo. Taken together, our results indicated that E. vexans and its subcomponent atranorin may inhibit lung cancer cell motility and tumorigenesis by affecting AP-1, Wnt, and STAT signaling and suppressing RhoGTPase activity. PMID- 28811523 TI - Strong, Ductile, and Thermally Stable bcc-Mg Nanolaminates. AB - Magnesium has attracted attention worldwide because it is the lightest structural metal. However, a high strength-to-weight ratio remains its only attribute, since an intrinsic lack of strength, ductility and low melting temperature severely restricts practical applications of Mg. Through interface strains, the crystal structure of Mg can be transformed and stabilized from a simple hexagonal (hexagonal close packed hcp) to body center cubic (bcc) crystal structure at ambient pressures. We demonstrate that when introduced into a nanocomposite bcc Mg is far more ductile, 50% stronger, and retains its strength after extended exposure to 200 C, which is 0.5 times its homologous temperature. These findings reveal an alternative solution to obtaining lightweight metals critically needed for future energy efficiency and fuel savings. PMID- 28811524 TI - Synthesis of Sulfo-Sialic Acid Analogues: Potent Neuraminidase Inhibitors in Regards to Anomeric Functionality. AB - The design, synthesis and application of N-acetylneuraminic acid-derived compounds bearing anomeric sulfo functional groups are described. These novel compounds, which we refer to as sulfo-sialic acid analogues, include 2-decarboxy 2-deoxy-2-sulfo-N-acetylneuraminic acid and its 4-deoxy-3,4-dehydrogenated pseudoglycal. While 2-decarboxy-2-deoxy-2-sulfo-N-acetylneuraminic acid contains no further modifications of the 2-deoxy-pyranose ring, it is still a more potent inhibitor of avian-origin H5N1 neuraminidase (NA) and drug-resistant His275Tyr NA as compared to the oxocarbenium ion transition state analogue 2,3-dehydro-2-deoxy N-acetylneuraminic acid. The sulfo-sialic acid analogues described in this report are also more potent inhibitors of influenza NA (up to 40-fold) and bacterial NA (up to 8.5-fold) relative to the corresponding anomeric phosphonic acids. These results confirm that this novel anomeric sulfo modification offers great potential to improve the potency of next-generation NA inhibitors including covalent inhibitors. PMID- 28811525 TI - Totipotency segregates between the sister blastomeres of two-cell stage mouse embryos. AB - Following fertilization in mammals, it is generally accepted that totipotent cells are exclusive to the zygote and to each of the two blastomeres originating from the first mitotic division. This model of totipotency was inferred from a minority of cases in which blastomeres produced monozygotic twins in mice. Was this due to experimental limitation or biological constraint? Here we removed experimental obstacles and achieved reliable quantification of the prevalence of dual totipotency among mouse two-cell stage blastomeres. We separated the blastomeres of 1,252 two-cell embryos, preserving 1,210 of the pairs. Two classes of monozygotic twins became apparent at the blastocyst stage: 27% formed a functional epiblast in both members (concordant), and 73% did so in only one member of the pair (discordant) - a partition that proved insensitive to oocyte quality, sperm-entry point, culture environment and pattern of cleavage. In intact two-cell embryos, the ability of sister blastomeres to generate epiblast was also skewed. Class discovery clustering of the individual blastomeres' and blastocysts' transcriptomes points to an innate origin of concordance and discordance rather than developmental acquisition. Our data place constraints on the commonly accepted idea that totipotency is allocated equally between the two cell stage blastomeres in mice. PMID- 28811526 TI - Observation of the unexpected morphology of graphene wrinkle on copper substrate. AB - Graphene, a two-dimensional material, has a wide range of unique properties and could be used in the development of varieties of mechanic, electronic and photonic devices, therefore methods to synthesis large-area high-quality graphene films are urgently required. Chemical vapor deposition (CVD) has been of particular interest recently due to its simplicity and low cost. However, because of the mismatch of thermal expansion coefficients, high densities of wrinkles are commonly observed. Despite their prevalence and potential impact on large-scale graphene properties, relatively little is known about their structural morphology and formation mechanism. In this article, morphologies of graphene obtained by CVD are experimentally investigated by an atomic force microscope (AFM) and results show that the profiles of wrinkles are much larger than they should be. By using theoretical methods and molecular dynamics simulations (MD), we find internal molecules created during CVD process which supply additional pressure is the main mechanism. PMID- 28811527 TI - Atherosusceptible Shear Stress Activates Endoplasmic Reticulum Stress to Promote Endothelial Inflammation. AB - Atherosclerosis impacts arteries where disturbed blood flow renders the endothelium susceptible to inflammation. Cytokine activation of endothelial cells (EC) upregulates VCAM-1 receptors that target monocyte recruitment to atherosusceptible regions. Endoplasmic reticulum (ER) stress elicits EC dysregulation in metabolic syndrome. We hypothesized that ER plays a central role in mechanosensing of atherosusceptible shear stress (SS) by signaling enhanced inflammation. Aortic EC were stimulated with low-dose TNFalpha (0.3 ng/ml) in a microfluidic channel that produced a linear SS gradient over a 20mm field ranging from 0-16 dynes/cm2. High-resolution imaging of immunofluorescence along the monolayer provided a continuous spatial metric of EC orientation, markers of ER stress, VCAM-1 and ICAM-1 expression, and monocyte recruitment. VCAM-1 peaked at 2 dynes/cm2 and decreased to below static TNFalpha-stimulated levels at atheroprotective-SS of 12 dynes/cm2, whereas ICAM-1 rose to a maximum in parallel with SS. ER expansion and activation of the unfolded protein response also peaked at 2 dynes/cm2, where IRF-1-regulated VCAM-1 expression and monocyte recruitment also rose to a maximum. Silencing of PECAM-1 or key ER stress genes abrogated SS regulation of VCAM-1 transcription and monocyte recruitment. We report a novel role for ER stress in mechanoregulation at arterial regions of atherosusceptible SS inflamed by low-dose TNFalpha. PMID- 28811528 TI - Prenatal hypoxia leads to hypertension, renal renin-angiotensin system activation and exacerbates salt-induced pathology in a sex-specific manner. AB - Prenatal hypoxia is associated with growth restriction and adverse cardiovascular outcomes. Here, we describe renal and cardiovascular outcomes in ageing mouse offspring prenatally exposed to hypoxia (12% O2) from embryonic day 14.5 until birth. At 12 months of age, both male and female offspring exposed to prenatal hypoxia had elevated mean arterial pressure. Glomerular number was reduced by 25% in hypoxia-exposed male, but not female, offspring and this was associated with increased urinary albumin excretion, glomerular hypertrophy and renal fibrosis. Hypoxia-exposed offspring of both sexes were more susceptible to salt-induced cardiac fibrosis, however, renal fibrosis was exacerbated by high salt in males only. In male but not female hypoxia-exposed offspring, renal renin mRNA was increased at weaning. By 12 months, renal renin mRNA expression and concentrations were elevated in both sexes. mRNA expression of At 1a R was also elevated in male hypoxia-exposed offspring at 12 months. These results demonstrate that prenatal hypoxia programs elevated blood pressure and exacerbates salt-induced cardiovascular and renal pathology in a sex specific manner. Given sex differences observed in RAS expression and nephron number, future studies may consider RAS blockade as a therapeutic target in this model. PMID- 28811529 TI - Disturbance of Plasma Lipid Metabolic Profile in Guillain-Barre Syndrome. AB - Guillain-Barre Syndrome (GBS) is an inflammatory disease of the peripheral nervous system. Given that plasma metabolic profiles in GBS patients have never been explored, plasma samples of 38 GBS patients, 22 multiple sclerosis (MS) patients, and 40 healthy controls were analyzed by using untargeted and targeted metabolomics analysis. The untargeted analysis showed that levels of a set of plasma lipid metabolites were significantly decreased in GBS patients compared to the controls. Furthermore, the targeted analysis demonstrated that levels of 41 metabolites in GBS patients were significantly changed compared to either the controls or MS patients. A further metabolic analysis showed that 12 of 41 metabolites were significantly lower in classical GBS patients compared to Miller Fisher syndrome. Among them, each of PCae C34:0, PCae C42:2, PCae C42:3, and SM C24:0 was inversely correlated with Hughes functional grading scale of GBS patients at both nadir and discharge. Receiver operating characteristic curve analysis of combination of three metabolites (PCaa C42:2, PCae C36:0 and SM C24:0) showed a good discrimination between the GBS and the controls (area under curve = 0.86). This study has demonstrated disruption of lipid metabolites in GBS may be potential biomarkers to indicate disease severity and prognosis of GBS. PMID- 28811530 TI - Evidence for ice-ocean albedo feedback in the Arctic Ocean shifting to a seasonal ice zone. AB - Ice-albedo feedback due to the albedo contrast between water and ice is a major factor in seasonal sea ice retreat, and has received increasing attention with the Arctic Ocean shifting to a seasonal ice cover. However, quantitative evaluation of such feedbacks is still insufficient. Here we provide quantitative evidence that heat input through the open water fraction is the primary driver of seasonal and interannual variations in Arctic sea ice retreat. Analyses of satellite data (1979-2014) and a simplified ice-upper ocean coupled model reveal that divergent ice motion in the early melt season triggers large-scale feedback which subsequently amplifies summer sea ice anomalies. The magnitude of divergence controlling the feedback has doubled since 2000 due to a more mobile ice cover, which can partly explain the recent drastic ice reduction in the Arctic Ocean. PMID- 28811531 TI - The selective antifungal activity of Drosophila melanogaster metchnikowin reflects the species-dependent inhibition of succinate-coenzyme Q reductase. AB - Insect-derived antifungal peptides have a significant economic potential, particularly for the engineering of pathogen-resistant crops. However, the nonspecific antifungal activity of such peptides could result in detrimental effects against beneficial fungi, whose interactions with plants promote growth or increase resistance against biotic and abiotic stress. The antifungal peptide metchnikowin (Mtk) from Drosophila melanogaster acts selectively against pathogenic Ascomycota, including Fusarium graminearum, without affecting Basidiomycota such as the beneficial symbiont Piriformospora indica. Here we investigated the mechanism responsible for the selective antifungal activity of Mtk by using the peptide to probe a yeast two-hybrid library of F. graminearum cDNAs. We found that Mtk specifically targets the iron-sulfur subunit (SdhB) of succinate-coenzyme Q reductase (SQR). A functional assay based on the succinate dehydrogenase (SDH) activity of mitochondrial complex II clearly demonstrated that Mtk inhibited the SDH activity of F. graminearum mitochondrial SQR by up to 52%, but that the equivalent enzyme in P. indica was unaffected. A phylogenetic analysis of the SdhB family revealed a significant divergence between the Ascomycota and Basidiomycota. SQR is one of the key targets of antifungal agents and we therefore propose Mtk as an environmentally sustainable and more selective alternative to chemical fungicides. PMID- 28811532 TI - Protein expression changes caused by spaceflight as measured for 18 Russian cosmonauts. AB - The effects of spaceflight on human physiology is an increasingly studied field, yet the molecular mechanisms driving physiological changes remain unknown. With that in mind, this study was performed to obtain a deeper understanding of changes to the human proteome during space travel, by quantitating a panel of 125 proteins in the blood plasma of 18 Russian cosmonauts who had conducted long duration missions to the International Space Station. The panel of labeled prototypic tryptic peptides from these proteins covered a concentration range of more than 5 orders of magnitude in human plasma. Quantitation was achieved by a well-established and highly-regarded targeted mass spectrometry approach involving multiple reaction monitoring in conjunction with stable isotope-labeled standards. Linear discriminant function analysis of the quantitative results revealed three distinct groups of proteins: 1) proteins with post-flight protein concentrations remaining stable, 2) proteins whose concentrations recovered slowly, or 3) proteins whose concentrations recovered rapidly to their pre-flight levels. Using a systems biology approach, nearly all of the reacting proteins could be linked to pathways that regulate the activities of proteases, natural immunity, lipid metabolism, coagulation cascades, or extracellular matrix metabolism. PMID- 28811533 TI - Plasma metabolomics profiling of maintenance hemodialysis based on capillary electrophoresis - time of flight mass spectrometry. AB - Uremia has been a rapidly increasing health problem in China. Hemodialysis (HD) is the main renal replacement therapy for uremia. The results of large-scale clinical trials have shown that the HD pattern is crucial for long-term prognosis of maintenance hemodialysis (MHD) in uremic patients. Plasma metabolism is very important for revealing the biological insights linked to the therapeutic effects of the HD pattern on uremia. Alteration of plasma metabolites in uremic patients in response to HD therapy has been reported. However, HD-pattern-dependent changes in plasma metabolites remain poorly understood. To this end, a capillary electrophoresis-time of flight mass spectrometry (CE-TOF/MS)-based metabolomics method was performed to systemically study the differences between HD and high flux hemodialysis (HFD) on plasma metabolite changes in patients. Three hundred and one plasma samples from three independent human cohorts (i.e., healthy controls, patients with pre-HD/post-HD, and patients with pre-HFD/post-HFD) were used in this study. Metabolites significantly changed (p < 0.05) after a single HD or HFD process. However, 11 uremic retention solutes could be more efficiently removed by HFD. Our findings indicate that a CE-TOF/MS-based metabolomics approach is promising for providing novel insights into understanding the effects of different dialysis methods on metabolite alterations of uremia. PMID- 28811534 TI - Distinct projection patterns of different classes of layer 2 principal neurons in the olfactory cortex. AB - The broadly-distributed, non-topographic projections to and from the olfactory cortex may suggest a flat, non-hierarchical organization in odor information processing. Layer 2 principal neurons in the anterior piriform cortex (APC) can be divided into 2 subtypes: semilunar (SL) and superficial pyramidal (SP) cells. Although it is known that SL and SP cells receive differential inputs from the olfactory bulb (OB), little is known about their projections to other olfactory regions. Here, we examined axonal projections of SL and SP cells using a combination of mouse genetics and retrograde labeling. Retrograde tracing from the OB or posterior piriform cortex (PPC) showed that the APC projects to these brain regions mainly through layer 2b cells, and dual-labeling revealed many cells extending collaterals to both target regions. Furthermore, a transgenic mouse line specifically labeling SL cells showed that they send profuse axonal projections to olfactory cortical areas, but not to the OB. These findings support a model in which information flow from SL to SP cells and back to the OB is mediated by a hierarchical feedback circuit, whereas both SL and SP cells broadcast information to higher olfactory areas in a parallel manner. PMID- 28811535 TI - Delimiting species of Protaphorura (Collembola: Onychiuridae): integrative evidence based on morphology, DNA sequences and geography. AB - Species delimitation remains a significant challenge when the diagnostic morphological characters are limited. Integrative taxonomy was applied to the genus Protaphorura (Collembola: Onychiuridae), which is one of most difficult soil animals to distinguish taxonomically. Three delimitation approaches (morphology, molecular markers and geography) were applied providing rigorous species validation criteria with an acceptably low error rate. Multiple molecular approaches, including distance- and evolutionary model-based methods, were used to determine species boundaries based on 144 standard barcode sequences. Twenty two molecular putative species were consistently recovered across molecular and geographical analyses. Geographic criteria were was proved to be an efficient delimitation method for onychiurids. Further morphological examination, based on the combination of the number of pseudocelli, parapseudocelli and ventral mesothoracic chaetae, confirmed 18 taxa of 22 molecular units, with six of them described as new species. These characters were found to be of high taxonomical value. This study highlights the potential benefits of integrative taxonomy, particularly simultaneous use of molecular/geographical tools, as a powerful way of ascertaining the true diversity of the Onychiuridae. Our study also highlights that discovering new morphological characters remains central to achieving a full understanding of collembolan taxonomy. PMID- 28811536 TI - IgE Trimers Drive SPE-7 Cytokinergic Activity. AB - Degranulation of mast cells and basophils, with release of agents of the allergic response, ensues when multivalent antigens bind to and cross-link the cells' receptor-bound IgE antibodies. A widely used commercial monoclonal IgE antibody, SPE-7 IgE from Sigma, was found to possess the radically anomalous property, termed "cytokinergic", of inducing basophil degranulation without the intervention of an antigen. We show here that the IgE monomer, freed of protein contaminants, is devoid of this activity, and that the source of the anomaly is a trace impurity, identified as a dissociation-resistant IgE trimer. Possible models for the formation of IgE trimers and the manner in which they cross-link cell surface receptors are suggested herein. PMID- 28811537 TI - Prognostic significance and function of mammalian target of rapamycin in tongue squamous cell carcinoma. AB - Despite improvement in preoperative imaging, surgical technique, and adjuvant therapy, the prognosis of patients with tongue squamous cell carcinoma (SCC) is still unsatisfactory. The mammalian target of rapamycin (mTOR) play a key role in the regulation of tumor cell proliferation and survival. However, the significance of mTOR on the prognosis of tongue SCC remains largely undefined. In the present study, immunohistochemistry was performed to evaluate the expression of phosphorylated mTOR (p-mTOR) in 160 surgically resected tongue SCC, and correlated with survival. Univariate analysis revealed that p-mTOR overexpression (P = 0.006) was associated with inferior overall survival. In multivariate comparison, p-mTOR overexpression (P = 0.002, hazard ratio = 2.082) remained independently associated with worse overall survival. In vitro study, tongue cancer cells treated with everolimus, the specific mTOR inhibitor, or transfected with mTOR-mediated siRNAs dramatically attenuated the abilities of cell proliferation by MTT and BrdU assays. In 4-NQO-induced tongue cancer murine model, mTOR inhibitors significantly decreased the incidence of tongue SCC. In conclusion, p-mTOR overexpression was independently associated with poor prognosis of patients with tongue SCC. In vitro and vivo, mTOR inhibition showed the promising activity in tongue SCC. Our results suggest that inhibition of mTOR signaling pathway may be a novel therapeutic target for tongue SCC. PMID- 28811538 TI - Fine Structure of Posterior Alpha Rhythm in Human EEG: Frequency Components, Their Cortical Sources, and Temporal Behavior. AB - Heterogeneity of the posterior alpha rhythm (AR) is a widely assumed but rarely tested phenomenon. We decomposed the posterior AR in the cortical source space with a 3-way PARAFAC technique, taking into account the spatial, frequency, and temporal aspects of mid-density EEG. We found a multicomponent AR structure in 90% of a group of 29 healthy adults. The typical resting-state structure consisted of a high-frequency occipito-parietal component of the AR (ARC1) and a low-frequency occipito-temporal component (ARC2), characterized by individual dynamics in time. In a few cases, we found a 3-component structure, with two ARC1s and one ARC2. The AR structures were stable in their frequency and spatial features over weeks to months, thus representing individual EEG alpha phenotypes. Cortical topography, individual stability, and similarity to the primate AR organization link ARC1 to the dorsal visual stream and ARC2 to the ventral one. Understanding how many and what kind of posterior AR components contribute to the EEG is essential for clinical neuroscience as an objective basis for AR segmentation and for interpreting AR dynamics under various conditions, both normal and pathological, which can selectively affect individual components. PMID- 28811539 TI - Intraoperative Parathyroid Localization with Near-Infrared Fluorescence Imaging Using Indocyanine Green during Total Parathyroidectomy for Secondary Hyperparathyroidism. AB - The detection of all glands during total parathyroidectomy (TPTX) in secondary hyperparathyroidism (SHPT) patients is often difficult due to their variability in number and location. The objective of this study was to evaluate the feasibility of near-infrared fluorescence (NIRF) imaging using indocyanine green (ICG) for intraoperative parathyroid gland (PTG) localization in SHPT patients. Twenty-nine patients with SHPT were divided into two groups with or without intraoperative NIRF imaging. ICG was administered in patients undergoing intraoperative imaging, and the fluorescence of PTGs was assessed. Clinical and histopathologic variables were analyzed to determine factors associated with ICG uptake. Comparisons between NIRF and preoperative imaging, as well as differences between groups with or without NIRF imaging, were carried out to evaluate the efficacy of this technique. Most PTGs could be clearly identified, including one ectopic gland. The sensitivity of NIRF imaging is 91.1% in contrast to 81.82% for ultrasonography (US), 62.34% for 99mTc-MIBI and 85.71% for computed tomography (CT). In addition, intraoperative NIRF imaging can reduce the operation time and improve the complete resection rate compared with the group not using it. Intraoperative NIRF imaging using ICG during TPTX is technically feasible and reliable for assisting surgeons in detecting and confirming PTGs. PMID- 28811540 TI - Ultralow Lattice Thermal Conductivity of the Random Multilayer Structure with Lattice Imperfections. AB - Randomizing the layer thickness of superlattices (SL) can lead to localization of coherent phonons and thereby reduces the lattice thermal conductivity kappa l . In this work, we propose strategies that can suppress incoherent phonon transport in the above random multilayer (RML) structure to further reduce kappa l . Molecular dynamics simulations are conducted to investigate phonon heat conduction in SLs and RMLs with lattice imperfections. We found that interfacial species mixing enhances thermal transport across single interfaces and few-period SLs through the phonon "bridge" mechanism, while it substantially reduces the kappa l of many-period SLs by breaking the phonon coherence. This is a clear manifestation of the transition from incoherent-phonon-dominated to coherent phonon-dominated heat conduction in SLs when the number of interface increases. In contrast, interfacial species mixing always increases the kappa l of RMLs owing to the dominance of incoherent phonons. Moreover, we found that doping a binary RML with impurities can reduce kappa l significantly, especially when the impurity atom has an atomic mass lower or higher than both of the two base elements. This work reveals the critical effect of lattice imperfections on thermal transport in SLs and RMLs, and provides a unique strategy to hierachically suppress coherent and incoherent phonon transport concurrently. PMID- 28811541 TI - Effects of Cations on the Behaviour of Lipid Cubic Phases. AB - Inverse bicontinuous cubic structures formed by lipids have been demonstrated in a wide variety of applications, from a host matrix for proteins for crystallisation, to templates for nanoscale structures. Recent work has focused on tuning their properties to realize such applications, often by manipulating the structure by introducing other lipids with different properties such as charge or packing. However, they are often prepared in the presence of solutions containing salt, counteracting the effects, for example, charged lipids, and fundamentally changing the structures obtained. Here, we demonstrate the delicate interplay between electrostatic swelling in bicontinuous structures formed by monoolein (MO) doped with both negatively charged dioleyl phosphatidylglycerol (DOPG), and zwitterionic dioleyl phosphatidylethanolamine (DOPE), with the addition of mono- and divalent salts. The effect of adding salt to the charged phase changes the structure from the primitive cubic ([Formula: see text]) to the double diamond phase ([Formula: see text]) whilst still allowing for modest increases in lattice parameter of up to a nanometer. Contrasting this, the addition of salts to the non-charged phase, has minimal effect on the lattice parameter but now the transition from the ([Formula: see text]) to the inverse hexagonal phase (H II ) is observed occurring at higher mole fractions of DOPE than in pure water. PMID- 28811542 TI - Identification, replication and characterization of epigenetic remodelling in the aging genome: a cross population analysis. AB - Aging is a complex biological process regulated by multiple cellular pathways and molecular mechanisms including epigenetics. Using genome-wide DNA methylation data measured in a large collection of Scottish old individuals, we performed discovery association analysis to identify age-methylated CpGs and replicated them in two independent Danish cohorts. The double-replicated CpGs were characterized by distribution over gene regions and location in relation to CpG islands. The replicated CpGs were further characterized by involvement in biological pathways to study their functional implications in aging. We identified 67,604 age-associated CpG sites reaching genome-wide significance of FWER <0.05, 86% demethylated with increasing age. Double-replication resulted in 5,168 CpGs (39% age-methylated and 61% age-demethylated) which were characterized by high concentration of age-methylated CpGs at 1stExon and TSS200 and a dominant pattern of age-demethylated CpGs at other gene regions, and by overwhelming age related methylation in CpG islands and demethylation at shore/shelf and open sea. The differential distribution patterns over gene regions for methylated and demethylated CpGs both relate to reduced gene activity during aging. Pathway analysis showed that age-dependent methylations were especially involved in cellular signalling activities while demethylations particularly linked to functions of the extracellular matrix, all implicated in the aging process and age-related disease risk. PMID- 28811543 TI - 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD) suppresses HIV1-gp120 mediated production of IL6 and IL8 but not CCL5. AB - Human immunodeficiency virus (HIV) has been associated with inflammatory effects that may potentially result in neurodegenerative changes and a number of newer chemotherapeutic agents are being tested to ameliorate these effects. In this study, we investigated the anti-neuroinflammatory activity of a novel resveratrol analog 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD) against HIV1-gp120 induced neuroinflammation in SVG astrocytes. SVG astrocytic cells were pretreated with TIMBD or resveratrol (RES) and then transfected with a plasmid encoding HIV1 gp120. The mRNA and protein expression levels of proinflammatory cytokines IL6, IL8 and CCL5 were determined. Protein expression levels of NF-kappaB, AP1, p STAT3, p-AKT, p-IKKs and p-p38 MAPK were also determined. TIMBD inhibited gp120 induced RNA and protein expression levels of IL6 and IL8, but not that of CCL5 in SVG astrocytes. Moreover, TIMBD attenuated gp120-induced phosphorylation of cJUN, cFOS, STAT3, p38-MAPK, AKT and IKKs, and the nuclear translocation of NF-kappaB p 65 subunit whereas RES mostly affected NF-kappaB protein expression levels. Our results suggest that TIMBD exerts anti-inflammatory effects better than that of RES in SVG astrocytes in vitro. These effects seem to be regulated by AP1, STAT-3 and NF-kappaB signaling pathways. TIMBD may thus have a potential of being a novel agent for treating HIV1-gp120-mediated neuroinflammatory diseases. PMID- 28811544 TI - Mutations in the promoter, intron and CDS of two FAD2 generate multiple alleles modulating linoleic acid level in yellow mustard. AB - Linoleic acid (C18:2) is an important polyunsaturated fatty acid in the seed oil of many crops. Here, we report that mutations in the promoter, intron and CDS of the FAD2 genes SalFAD2.LIA1 and SalFAD2.LIA2 generate three alleles LIA 1a , LIA 1b and lia 1 and two alleles LIA 2 and lia 2, respectively, controlling the C18:2 variation (4.4-32.7%) in yellow mustard. The allelic effect on increasing C18:2 content is LIA 1a > LIA 1b > lia 1 , LIA 2 > lia 2, and LIA 1a > LIA 2. The five FAD 2 alleles each contain two exons, one intron and a promoter adjacent to exon 1. LIA 1a has a 1152 bp CDS, a 1221 bp intron with promoter function and a 607 bp promoter. Compared with LIA 1a , the intron of LIA 1b has reduced promoter activity and that of LIA 2 and lia 2 has no promoter function due to extensive SNP and indel mutations. lia 1 differed from LIA 1b by having an insertion of 1223 bp retrotransposon in its intron. lia 2 with mutations in the promoter has reduced promoter activity compared with LIA 2 . This study revealed that complex quantitative variation of trait phenotype in plants could be modulated by multiple alleles of oligogenic loci resulting from mutations in the regulatory region and CDS. PMID- 28811545 TI - Sealing the Pores of PEO Coating with Mg-Al Layered Double Hydroxide: Enhanced Corrosion Resistance, Cytocompatibility and Drug Delivery Ability. AB - In recent years, magnesium (Mg) alloys show a promising application in clinic as degradable biomaterials. Nevertheless, the poor corrosion resistance of Mg alloys is the main obstacle to their clinical application. Here we successfully seal the pores of plasma electrolytic oxidation (PEO) coating on AZ31 with Mg-Al layered double hydroxide (LDH) via hydrothermal treatment. PEO/LDH composite coating possess a two layer structure, an inner layer made up of PEO coating (~5 MUm) and an outer layer of Mg-Al LDH (~2 MUm). Electrochemical and hydrogen evolution tests suggest preferable corrosion resistance of the PEO/LDH coating. Cytotoxicity, cell adhesion, live/dead staining and proliferation data of rat bone marrow stem cells (rBMSCs) demonstrate that PEO/LDH coating remarkably enhance the cytocompatibility of the substrate, indicating a potential application in orthopedic surgeries. In addition, hemolysis rate (HR) test shows that the HR value of PEO/LDH coating is 1.10 +/- 0.47%, fulfilling the request of clinical application. More importantly, the structure of Mg-Al LDH on the top of PEO coating shows excellent drug delivery ability. PMID- 28811546 TI - Serum-derived extracellular vesicles (EVs) impact on vascular remodeling and prevent muscle damage in acute hind limb ischemia. AB - Serum is an abundant and accessible source of circulating extracellular vesicles (EVs). Serum-EV (sEV) pro-angiogenic capability and mechanisms are herein analyzed using an in vitro assay which predicts sEV angiogenic potential in vivo. Effective sEVs (e-sEVs) also improved vascular remodeling and prevented muscle damage in a mouse model of acute hind limb ischemia. e-sEV angiogenic proteomic and transcriptomic analyses show a positive correlation with matrix metalloproteinase activation and extracellular matrix organization, cytokine and chemokine signaling pathways, Insulin-like Growth Factor and platelet pathways, and Vascular Endothelial Growth Factor signaling. A discrete gene signature, which highlights differences in e-sEV and ineffective-EV biological activity, was identified using gene ontology (GO) functional analysis. An enrichment of genes associated with the Transforming Growth Factor beta 1 (TGFbeta1) signaling cascade is associated with e-sEV administration but not with ineffective-EVs. Chromatin immunoprecipitation analysis on the inhibitor of DNA binding I (ID1) promoter region, and the knock-down of small mother against decapentaplegic (SMAD)1-5 proteins confirmed GO functional analyses. This study demonstrates sEV pro-angiogenic activity, validates a simple, sEV pro-angiogenic assay which predicts their biological activity in vivo, and identifies the TGFbeta1 cascade as a relevant mediator. We propose serum as a readily available source of EVs for therapeutic purposes. PMID- 28811547 TI - Up-regulation of NADPH oxidase-mediated redox signaling contributes to the loss of barrier function in KRIT1 deficient endothelium. AB - The intracellular scaffold KRIT1/CCM1 is an established regulator of vascular barrier function. Loss of KRIT1 leads to decreased microvessel barrier function and to the development of the vascular disorder Cerebral Cavernous Malformation (CCM). However, how loss of KRIT1 causes the subsequent deficit in barrier function remains undefined. Previous studies have shown that loss of KRIT1 increases the production of reactive oxygen species (ROS) and exacerbates vascular permeability triggered by several inflammatory stimuli, but not TNF alpha. We now show that endothelial ROS production directly contributes to the loss of barrier function in KRIT1 deficient animals and cells, as targeted antioxidant enzymes reversed the increase in permeability in KRIT1 heterozygous mice as shown by intravital microscopy. Rescue of the redox state restored responsiveness to TNF-alpha in KRIT1 deficient arterioles, but not venules. In vitro, KRIT1 depletion increased endothelial ROS production via NADPH oxidase signaling, up-regulated Nox4 expression, and promoted NF-kappaB dependent promoter activity. Recombinant yeast avenanthramide I, an antioxidant and inhibitor of NF-kappaB signaling, rescued barrier function in KRIT1 deficient cells. However, KRIT1 depletion blunted ROS production in response to TNF-alpha. Together, our data indicate that ROS signaling is critical for the loss of barrier function following genetic deletion of KRIT1. PMID- 28811548 TI - Ligand binding modes from low resolution GPCR models and mutagenesis: chicken bitter taste receptor as a test-case. AB - Bitter taste is one of the basic taste modalities, warning against consuming potential poisons. Bitter compounds activate members of the bitter taste receptor (Tas2r) subfamily of G protein-coupled receptors (GPCRs). The number of functional Tas2rs is species-dependent. Chickens represent an intriguing minimalistic model, because they detect the bitter taste of structurally different molecules with merely three bitter taste receptor subtypes. We investigated the binding modes of several known agonists of a representative chicken bitter taste receptor, ggTas2r1. Because of low sequence similarity between ggTas2r1 and crystallized GPCRs (~10% identity, ~30% similarity at most), the combination of computational approaches with site-directed mutagenesis was used to characterize the agonist-bound conformation of ggTas2r1 binding site between TMs 3, 5, 6 and 7. We found that the ligand interactions with N93 in TM3 and/or N247 in TM5, combined with hydrophobic contacts, are typically involved in agonist recognition. Next, the ggTas2r1 structural model was successfully used to identify three quinine analogues (epiquinidine, ethylhydrocupreine, quinidine) as new ggTas2r1 agonists. The integrated approach validated here may be applicable to additional cases where the sequence identity of the GPCR of interest and the existing experimental structures is low. PMID- 28811549 TI - Diagnosing peri-implant disease using the tongue as a 24/7 detector. AB - Our ability of screening broad communities for clinically asymptomatic diseases critically drives population health. Sensory chewing gums are presented targeting the tongue as 24/7 detector allowing diagnosis by "anyone, anywhere, anytime". The chewing gum contains peptide sensors consisting of a protease cleavable linker in between a bitter substance and a microparticle. Matrix metalloproteinases in the oral cavity, as upregulated in peri-implant disease, specifically target the protease cleavable linker while chewing the gum, thereby generating bitterness for detection by the tongue. The peptide sensors prove significant success in discriminating saliva collected from patients with peri implant disease versus clinically asymptomatic volunteers. Superior outcome is demonstrated over commercially available protease-based tests in saliva. "Anyone, anywhere, anytime" diagnostics are within reach for oral inflammation. Expanding this platform technology to other diseases in the future features this diagnostic as a massive screening tool potentially maximizing impact on population health.Early detection of gum inflammation caused by dental implants helps prevent tissue damage. Here, the authors present a peptide sensor that generates a bitter taste when cleaved by proteases present in peri-implant disease, embed it in a chewing gum, and compare the probe to existing sensors using patient saliva. PMID- 28811550 TI - Application of galangin, an active component of Alpinia officinarum Hance (Zingiberaceae), for use in drug-eluting stents. AB - In clinical pathology, stent interposition is used to treat vascular disease but can lead to restenosis. Drug-eluting stents (DES) are most commonly used to suppress restenosis but can also have side effects. Therefore, we investigated the anti-proliferative effect and its possible target in vitro and in vivo. We found that Alpinia officinarum Hance (AO) extract efficiently inhibited VSMC proliferation by arresting the transition from the G0/G1 to the S phase via the up-regulation of p27KIP1 expression. Galangin (GA) was determined to be a significant component of this extract, with the same anti-proliferative activity as the raw extract. Immunoblotting and immunofluorescence staining showed that both the AO extract and GA targeted the up-regulation of p27KIP1 expression. Therefore, we next examined the effect of these compounds in a cuff-injured neointimal hyperplasia model in vivo. In this animal model, both the AO extract and GA completely suppressed the neointima formation, and this inhibitory effect was also demonstrated to target the up-regulation of p27KIP1, including the suppression of proliferating cell nuclear antigen expression. Our findings indicate that AO extract and GA have a potent anti-proliferative activity, targeting the up-regulation of p27 expression. Thus, GA may represent an alternative medicine for use in DES. PMID- 28811551 TI - Nano metamaterials for ultrasensitive Terahertz biosensing. AB - As a candidate for a rapid detection of biomaterials, terahertz (THz) spectroscopy system can be considered with some advantage in non-destructive, label-free, and non-contact manner. Because protein-ligand binding energy is in the THz range, especially, most important conformational information in molecular interactions can be captured by THz electromagnetic wave. Based on the THz time domain spectroscopy system, THz nano-metamaterial sensing chips were prepared for great enhancing of detection sensitivity. A metamaterial sensing chip was designed for increasing of absorption cross section of the target sample, related to the transmitted THz near field enhancement via the composition of metamaterial. The measured THz optical properties were then analyzed in terms of refractive index and absorption coefficient, and compared with simulation results. Also, virus quantification regarding various concentrations of the viruses was performed, showing a clear linearity. The proposed sensitive and selective THz detection method can provide abundant information of detected biomaterials to help deep understanding of fundamental optical characteristics of them, suggesting rapid diagnosis way especially useful for such dangerous and time-sensitive target biomaterials. PMID- 28811552 TI - Deregulation of transcription factors controlling intestinal epithelial cell differentiation; a predisposing factor for reduced enteroendocrine cell number in morbidly obese individuals. AB - Morbidly obese patients exhibit impaired secretion of gut hormones that may contribute to the development of obesity. After bariatric surgery there is a dramatic increase in gut hormone release. In this study, gastric and duodenal tissues were endoscopically collected from lean, and morbidly obese subjects before and 3 months after laparoscopic sleeve gastrectomy (LSG). Tissue morphology, abundance of chromogranin A, gut hormones, alpha-defensin, mucin 2, Na+/glucose co-transporter 1 (SGLT1) and transcription factors, Hes1, HATH1, NeuroD1, and Ngn3, were determined. In obese patients, the total number of enteroendocrine cells (EEC) and EECs containing gut hormones were significantly reduced in the stomach and duodenum, compared to lean, and returned to normality post-LSG. No changes in villus height/crypt depth were observed. A significant increase in mucin 2 and SGLT1 expression was detected in the obese duodenum. Expression levels of transcription factors required for differentiation of absorptive and secretory cell lineages were altered. We propose that in obesity, there is deregulation in differentiation of intestinal epithelial cell lineages that may influence the levels of released gut hormones. Post-LSG cellular differentiation profile is restored. An understanding of molecular mechanisms controlling epithelial cell differentiation in the obese intestine assists in the development of non-invasive therapeutic strategies. PMID- 28811554 TI - A new method to investigate the catalytic mechanism of YhdE pyrophosphatase by using a pyrophosphate fluorescence probe. AB - YhdE is a Maf (multicopy associated filamentation) proteins from Escherichia coli which exhibits pyrophosphatase activity towards selected nucleotides, although its catalytic mechanism remains unclear. Herein we used a novel fluorescence probe (4-isoACBA-Zn(II) complex) to characterize the enzymatic properties of YhdE and its mutant, establishing a new method for assaying pyrophosphatase catalytic function. Our results reveal for the first time that the new fluorescence sensor confers high sensitivity and specificity and pyrophosphate (PPi) is the direct catalytic product of YhdE. Crystal structures of a mutant in the active-site loop (YhdE_E33A) show conformational flexibility implicated in the catalytic mechanism of YhdE. ITC experiments and computational docking further reveal that Asp70 and substrate dTTP coordinate Mn2+. Quantum mechanics calculations indicate that YhdE hydrolysis appears to follow a stepwise pathway in which a water molecule first attacks the alpha-phosphorus atom in the substrate, followed by the release of PPi from the pentavalent intermediate. PMID- 28811555 TI - Identification of novel microRNAs in the sheep heart and their regulation in heart failure. AB - Study of microRNA (miRNAs) using sheep models is limited due to lack of miRNA information. We therefore investigated oar-miRNAs and their regulation in an ovine model of heart failure (HF). Left ventricular (LV) tissue was collected from normal (Cont), HF (LV pacing @ ~220bpm for 13-days) and HF-recovery sheep (HF-R, 26-days after pacing cessation). MiRNA expression was profiled using next generation sequencing (NGS) and miRNA array, and validated by stem-loop qPCR. Detected sequences were mapped against the ovine genome (Oar v4.0) and aligned with known miRNAs (miRBase v21). A total of 36,438,340 raw reads were obtained with a peak distribution of 18-23 nt. Of these, 637 miRNAs were detected by NGS and mapped to the ovine genome. With cut-off at 10 counts, 275 novel miRNAs were identified (with 186 showing 100% alignment and 89 showing 70-99% alignment with human/mouse and/or rat miRNAs, respectively), and 78 known oar-miRNAs. Cardiac enriched miRNA-1, -133a, -208a/b and -499 were highly expressed in the LV. With HF induction, miRNA-133b-3p, -208b-3p, -125a-5p, -125b-5p, -126-3p, -21-5p, -210 3p, -29a-3p, -320a and -494-3p were significantly up-regulated relative to Cont and tended to return to normal levels following HF-recovery. This study has expanded the sheep miRNA database, and demonstrated HF-induced regulation of miRNAs. PMID- 28811556 TI - Evolutionary mechanisms of runaway chromosome number change in Agrodiaetus butterflies. AB - Despite predictions of the classic, hybrid-sterility model of chromosomal speciation, some organisms demonstrate high rate of karyotype evolution. This rate is especially impressive in Agrodiaetus butterflies that rapidly evolved the greatest chromosome number diversity known in animal kingdom within a single subgenus. Here we analyzed karyotype evolution in Agrodiaetus using phylogenetic comparative methods. We found that chromosome numbers possess a strong phylogenetic signal. This disproves the chromosome megaevolution model that proposes multiple chromosome rearrangements to accumulate independently in each of closely related species. We found that Brownian motion gives a more adequate description of observed trait changes than Ornstein-Uhlenbeck model. This indicates that chromosome numbers evolve via random walk along branches of the phylogeny. We discovered a correlation between karyotype changes and phylogeny branch lengths. This gradual pattern is inconsistent with the hybrid-sterility model which, due to association of major chromosome changes with cladogenetic events, predicts a high degree of punctualism in karyotype evolution. Thus, low underdominace of chromosomal rearrangements and/or prevalence of the recombination-suppression model over the hybrid-sterility model of chromosome speciation are the most common engines of the runaway chromosome number change observed. PMID- 28811557 TI - Separating Vegetation Greening and Climate Change Controls on Evapotranspiration trend over the Loess Plateau. AB - Evapotranspiration (ET) is a key ecological process connecting the soil vegetation-atmosphere system, and its changes seriously affects the regional distribution of available water resources, especially in the arid and semiarid regions. With the Grain-for-Green project implemented in the Loess Plateau (LP) since 1999, water and heat distribution across the region have experienced great changes. Here, we investigate the changes and associated driving forces of ET in the LP from 2000 to 2012 using a remote sensing-based evapotranspiration model. Results show that annual ET significantly increased by 3.4 mm per year (p = 0.05) with large interannual fluctuations during the study period. This trend is higher than coincident increases in precipitation (2.0 mm yr-2), implying a possible pressure of water availability. The correlation analysis showed that vegetation change is the major controlling factor on interannual variability of annual ET with ~52.8% of pixels scattered in the strip region from the northeastern to southwestern parts of the LP. Further factorial analysis suggested that vegetation greening is the primary driver of the rises of ET over the study period relative to climate change. Our study can provide an improved understanding of the effects of vegetation and climate change on terrestrial ecosystem ET in the LP. PMID- 28811558 TI - Cross-modal plasticity in the deaf enhances processing of masked stimuli in the visual modality. AB - Compensatory changes as a result of auditory deprivation in the deaf lead to higher visual processing skills. In two experiments, we explored if such brain plasticity in the deaf modulates processing of masked stimuli in the visual modality. Deaf and normal-hearing participants responded to targets either voluntarily or by instruction. Masked primes related to the response were presented briefly before the targets at the center and the periphery. In Experiment 1, targets appeared only at the foveal region whereas, in Experiment 2, they appeared both at the fovea and the periphery. The deaf showed higher sensitivity to masked primes in both the experiments. They chose the primed response more often and also were faster during congruent responses compared to the normal hearing. These results suggest that neuroplasticity in the deaf modulates how they perceive and use information with reduced visibility for action selection and execution. PMID- 28811559 TI - Two-color heterodyne laser interferometry for long-distance stage measurement with correction of uncertainties in measured optical distances. AB - We designed a new system that eliminates deviations by correcting uncertainty in optical distance measurements in the laser two-color heterodyne interferometer. In simulations, eliminating the uncertainty from the atmosphere, the deviation in the uncertainty of the optical distance was 50 times greater with the two-color method than with the one-color method. Adding a correction arm reduces the deviation caused by the uncertainties in measured optical distances. The uncertainty in the measured path length is reduced to 20 nm over a path length of 1500 mm, giving a relative uncertainty of 1.34 * 10 -8. PMID- 28811553 TI - Cascaded Multi-view Canonical Correlation (CaMCCo) for Early Diagnosis of Alzheimer's Disease via Fusion of Clinical, Imaging and Omic Features. AB - The introduction of mild cognitive impairment (MCI) as a diagnostic category adds to the challenges of diagnosing Alzheimer's Disease (AD). No single marker has been proven to accurately categorize patients into their respective diagnostic groups. Thus, previous studies have attempted to develop fused predictors of AD and MCI. These studies have two main limitations. Most do not simultaneously consider all diagnostic categories and provide suboptimal fused representations using the same set of modalities for prediction of all classes. In this work, we present a combined framework, cascaded multiview canonical correlation (CaMCCo), for fusion and cascaded classification that incorporates all diagnostic categories and optimizes classification by selectively combining a subset of modalities at each level of the cascade. CaMCCo is evaluated on a data cohort comprising 149 patients for whom neurophysiological, neuroimaging, proteomic and genomic data were available. Results suggest that fusion of select modalities for each classification task outperforms (mean AUC = 0.92) fusion of all modalities (mean AUC = 0.54) and individual modalities (mean AUC = 0.90, 0.53, 0.71, 0.73, 0.62, 0.68). In addition, CaMCCo outperforms all other multi-class classification methods for MCI prediction (PPV: 0.80 vs. 0.67, 0.63). PMID- 28811560 TI - Evidence for the importance of post-transcriptional regulatory changes in ovarian cancer progression and the contribution of miRNAs. AB - High-throughput technologies have identified significant changes in patterns of mRNA expression over cancer development but the functional significance of these changes often rests upon the assumption that observed changes in levels of mRNA accurately reflect changes in levels of their encoded proteins. We systematically compared the expression of 4436 genes on the RNA and protein levels between discrete tumor samples collected from the ovary and from the omentum of the same OC patient. The overall correlation between global changes in levels of mRNA and their encoding proteins is low (r = 0.38). The majority of differences are on the protein level with no corresponding change on the mRNA level. Indirect and direct evidence indicates that a significant fraction of the differences may be mediated by microRNAs. PMID- 28811561 TI - Analysis of risk factors of rapid thyroidal radioiodine-131 turnover in Graves' disease patients. AB - Rapid iodine-131(131I) turnover in the thyroid gland is an important feature of Graves' disease (GD) and also a strong predictor of radioiodine therapy failure. The aim of this study was to explore the predictors of rapid 131I turnover. The clinical data on 2543 patients were retrospectively reviewed. Patients were divided into 2 groups depending on present or absent with rapid 131I turnover defined as a 4-hour to 24-hour 131I uptake ratio of >=1. Overall, 590 cases (23.2%) had a rapid 131I turnover. In the univariate analysis, gender, age, FT3/FT4 concentration, disease duration, with or without antithyroid drugs (ATD), time of ATD, thyroid weight and thyroid textures displayed significant differences. Cutoff values of age, FT3 and thyroid weight to predict rapid 131I turnover were 38 years, 35 pmol/l and 56 g by receiver operating characteristic curves. Binary logistic regression analysis further revealed higher probability of rapid 131I turnover in patients with thyroid weight >=56 g (odds ratio [OR]:3.7, 95% confidence interval [CI]: 3.032-4.559), age <38 years (OR:2.3, 95%CI: 1.906-2.856), FT3 concentration >=35 pmol/l (OR:7.6, 95%CI: 5.857-8.563) and females (OR:2.2, 95%CI: 1.757-2.791). In conclusion, larger goiters, younger age, higher FT3 concentration and females are independently associated with rapid 131I turnover in GD patients. PMID- 28811562 TI - Loop quantum cosmology and singularities. AB - Loop quantum gravity is believed to eliminate singularities such as the big bang and big crunch singularity. This belief is based on studies of so-called loop quantum cosmology which concerns symmetry-reduced models of quantum gravity. In this paper, the problem of singularities is analysed in the context of the Bohmian formulation of loop quantum cosmology. In this formulation there is an actual metric in addition to the wave function, which evolves stochastically (rather than deterministically as the case of the particle evolution in non relativistic Bohmian mechanics). Thus a singularity occurs whenever this actual metric is singular. It is shown that in the loop quantum cosmology for a homogeneous and isotropic Friedmann-Lemaitre-Robertson-Walker space-time with arbitrary constant spatial curvature and cosmological constant, coupled to a massless homogeneous scalar field, a big bang or big crunch singularity is never obtained. This should be contrasted with the fact that in the Bohmian formulation of the Wheeler-DeWitt theory singularities may exist. PMID- 28811564 TI - Computational identification of Y-linked markers and genes in the grass carp genome by using a pool-and-sequence method. AB - The molecular analysis of sex in vertebrates is important, as it has the potential to provide vital information for theoretical and applied research alike. Teleost fish are the ancient vertebrates that present a broad sex chromosome system but lack differentiated sex chromosomes in most species. Hence understanding the sex in fish would not only illuminate the sex determination evolution in vertebrates but also shed light on fish farming. In the present study, we used grass carp as a teleost fish model, studied the Y chromosome by using a pool-and-sequence strategy in combination with fragment-ratio method. In total, we identified five Y-linked scaffolds (totaling 347 Kb) and six Y-specific sequences that could be used as sex-specific markers, demonstrating the suitability of NGS-based re-sequencing of pooled DNAs for the identification of sex markers in fish. Moreover, 14 putative Y-linked genes were described for the first time. All the genes, except for un-y1, un-y2, and ubq-y, showed high similarity to their female homologs. RT-PCR revealed that ubq-y was only expressed in the male hypothalamus and pituitary. These findings provided an abundant resource for the Y chromosome of grass carp, and may help elucidate sex chromosome evolution in cyprinid fish. PMID- 28811563 TI - Crosstalk between diurnal rhythm and water stress reveals an altered primary carbon flux into soluble sugars in drought-treated rice leaves. AB - Plants retain rhythmic physiological responses when adapting to environmental challenges. However, possible integrations between drought conditions and those responses have not received much focus, especially regarding crop plants, and the relationship between abiotic stress and the diurnal cycle is generally not considered. Therefore, we conducted a genome-wide analysis to identify genes showing both diurnal regulation and water-deficiency response in rice (Oryza sativa). Among the 712 drought-responsive genes primary identified, 56.6% are diurnally expressed while 47.6% of the 761 that are down-regulated by drought are also diurnal. Using the beta-glucuronidase reporter system and qRT-PCR analyses, we validated expression patterns of two candidate genes, thereby supporting the reliability of our transcriptome data. MapMan analysis indicated that diurnal genes up-regulated by drought are closely associated with the starch-sucrose pathway while those that are down-regulated are involved in photosynthesis. We then confirmed that starch-sucrose contents and chlorophyll fluorescence are altered in a diurnal manner under drought stress, suggesting these metabolic diurnal alterations as a novel indicator to evaluate the drought response in rice leaves. We constructed a functional gene network associated with the starch sucrose KEGG metabolic pathway for further functional studies, and also developed a regulatory pathway model that includes OsbZIP23 transcription factor. PMID- 28811565 TI - iSS-PC: Identifying Splicing Sites via Physical-Chemical Properties Using Deep Sparse Auto-Encoder. AB - Gene splicing is one of the most significant biological processes in eukaryotic gene expression, such as RNA splicing, which can cause a pre-mRNA to produce one or more mature messenger RNAs containing the coded information with multiple biological functions. Thus, identifying splicing sites in DNA/RNA sequences is significant for both the bio-medical research and the discovery of new drugs. However, it is expensive and time consuming based only on experimental technique, so new computational methods are needed. To identify the splice donor sites and splice acceptor sites accurately and quickly, a deep sparse auto-encoder model with two hidden layers, called iSS-PC, was constructed based on minimum error law, in which we incorporated twelve physical-chemical properties of the dinucleotides within DNA into PseDNC to formulate given sequence samples via a battery of cross-covariance and auto-covariance transformations. In this paper, five-fold cross-validation test results based on the same benchmark data-sets indicated that the new predictor remarkably outperformed the existing prediction methods in this field. Furthermore, it is expected that many other related problems can be also studied by this approach. To implement classification accurately and quickly, an easy-to-use web-server for identifying slicing sites has been established for free access at: http://www.jci-bioinfo.cn/iSS-PC. PMID- 28811566 TI - Injectable Phosphorescence-based Oxygen Biosensors Identify Post Ischemic Reactive Hyperoxia. AB - Novel injectable biosensors were used to measure interstitial oxygenation before, during, and after transient ischemia. It is well known that reactive hyperemia occurs following a period of ischemia. However, increased blood flow does not necessarily mean increased oxygen tension in the tissue. Therefore, the purpose of this study was to test the hypothesis that tissue reactive hyperoxia occurs following release of hind-limb tourniquet occlusions. Rats were injected with bilateral hind-limb biosensors and were simultaneously subjected to a unilateral femoral vessel ligation. After approximately one and three months, the rats underwent a series of oxygenation challenges, including transient hind-limb tourniquet occlusion. Along with the biosensors, near infrared spectroscopy was used to measure percent oxyhemoglobin in capillaries and laser Doppler flowmetry was used to measure blood flow. Post-occlusion reactive hyperemia was observed. It was accompanied by tissue reactive hyperoxia, affirming that the post occlusion oxygen supply must have exceeded the expected increased oxygen consumption. The measurement of the physiologic phenomenon of reactive hyperoxia could prove clinically beneficial for both diagnosis and optimizing therapy. PMID- 28811567 TI - Engineered endothelium provides angiogenic and paracrine stimulus to grafted human ovarian tissue. AB - Despite major advances in tissue cryopreservation and auto-transplantation, reperfusion ischemia and hypoxia have been reported as major obstacles to successful recovery of the follicular pool within grafted ovarian tissue. We demonstrate a benefit to follicular survival and function in human ovarian tissue that is co-transplanted with exogenous endothelial cells (ExEC). ExECs were capable of forming functionally perfused vessels at the host/graft interface and increased both viability and follicular volume in ExEC-assisted grafts with resumption of antral follicle development in long-term grafts. ExECs that were engineered to constitutively express anti-mullerian hormone (AMH) induced a greater proportion of quiescent primordial follicles than control ExECs, indicating suppression of premature mobilization that has been noted in the context of ovarian tissue transplantation. These findings present a cell-based strategy that combines accelerated perfusion with direct paracrine delivery of a bioactive payload to transplanted ovarian tissue. PMID- 28811568 TI - Dynamic X-ray radiography reveals particle size and shape orientation fields during granular flow. AB - When granular materials flow, the constituent particles segregate by size and align by shape. The impacts of these changes in fabric on the flow itself are not well understood, and thus novel non-invasive means are needed to observe the interior of the material. Here, we propose a new experimental technique using dynamic X-ray radiography to make such measurements possible. The technique is based on Fourier transformation to extract spatiotemporal fields of internal particle size and shape orientation distributions during flow, in addition to complementary measurements of velocity fields through image correlation. We show X-ray radiography captures the bulk flow properties, in contrast to optical methods which typically measure flow within boundary layers, as these are adjacent to any walls. Our results reveal the rich dynamic alignment of particles with respect to streamlines in the bulk during silo discharge, the understanding of which is critical to preventing destructive instabilities and undesirable clogging. The ideas developed in this paper are directly applicable to many other open questions in granular and soft matter systems, such as the evolution of size and shape distributions in foams and biological materials. PMID- 28811570 TI - Association between fasting glucose and all-cause mortality according to sex and age: a prospective cohort study. AB - The association of fasting glucose with the risk of death according to sex and age remains unclear, and insufficient information is available on sex- and age specific glucose concentrations within ethnic groups. This study analyzed a sample of 12,455,361 Korean adults who participated in health examinations during 2001-2004, and were followed up until 2013. Men had 3.0 mg/dL (0.167 mmol/L) higher mean glucose concentrations than women (94.7 vs. 91.7 mg/dL), although women over 73 years had higher levels. For glucose levels of 100-199 mg/dL, each 18 mg/dL (1 mmol/L) increase in fasting glucose increased mortality by 13% (HR = 1.13, [95% CI 1.12 to 1.13], p < 0.001). In individuals with fasting glucose levels of 100-125 mg/dL, each 18 mg/dL increase in fasting glucose was associated with a 30% increase in the risk for mortality (1.30, [1.18 to 1.43]) in those aged 18-34 years, a 32% increase (1.32, [1.26 to 1.39]) in those aged 35-44 years, and a 10% increase (1.10, [1.02 to 1.19]) in those aged 75-99 years. The fasting glucose levels associated with the lowest mortality were 80-94 mg/dL regardless of sex and age. Prediabetes (100-125 mg/dL) was associated with higher mortality. The associations of hyperglycemia with mortality were stronger at younger ages. PMID- 28811569 TI - Transcriptional response to stress is pre-wired by promoter and enhancer architecture. AB - Programs of gene expression are executed by a battery of transcription factors that coordinate divergent transcription from a pair of tightly linked core initiation regions of promoters and enhancers. Here, to investigate how divergent transcription is reprogrammed upon stress, we measured nascent RNA synthesis at nucleotide-resolution, and profiled histone H4 acetylation in human cells. Our results globally show that the release of promoter-proximal paused RNA polymerase into elongation functions as a critical switch at which a gene's response to stress is determined. Highly transcribed and highly inducible genes display strong transcriptional directionality and selective assembly of general transcription factors on the core sense promoter. Heat-induced transcription at enhancers, instead, correlates with prior binding of cell-type, sequence-specific transcription factors. Activated Heat Shock Factor 1 (HSF1) binds to transcription-primed promoters and enhancers, and CTCF-occupied, non-transcribed chromatin. These results reveal chromatin architectural features that orient transcription at divergent regulatory elements and prime transcriptional responses genome-wide.Heat Shock Factor 1 (HSF1) is a regulator of stress-induced transcription. Here, the authors investigate changes to transcription and chromatin organization upon stress and find that activated HSF1 binds to transcription-primed promoters and enhancers, and to CTCF occupied, untranscribed chromatin. PMID- 28811571 TI - Identification of a Gene Encoding Slow Skeletal Muscle Troponin T as a Novel Marker for Immortalization of Retinal Pigment Epithelial Cells. AB - Human pluripotent stem cells (hPSCs) are leading candidate raw materials for cell based therapeutic products (CTPs). In the development of hPSC-derived CTPs, it is imperative to ensure that they do not form tumors after transplantation for safety reasons. Because cellular immortalization is a landmark of malignant transformation and a common feature of cancer cells, we aimed to develop an in vitro assay for detecting immortalized cells in CTPs. We employed retinal pigment epithelial (RPE) cells as a model of hPSC-derived products and identified a gene encoding slow skeletal muscle troponin T (TNNT1) as a novel marker of immortalized RPE cells by comprehensive microarray analysis. TNNT1 mRNA was commonly upregulated in immortalized RPE cells and human induced pluripotent stem cells (hiPSCs), which have self-renewal ability. Additionally, we demonstrated that TNNT1 mRNA expression is higher in several cancer tissues than in normal tissues. Furthermore, stable expression of TNNT1 in ARPE-19 cells affected actin filament organization and enhanced their migration ability. Finally, we established a simple and rapid qRT-PCR assay targeting TNNT1 transcripts that detected as low as 3% of ARPE-19 cells contained in normal primary RPE cells. Purified hiPSC-derived RPE cells showed TNNT1 expression levels below the detection limit determined with primary RPE cells. Our qRT-PCR method is expected to greatly contribute to process validation and quality control of CTPs. PMID- 28811572 TI - Inhibition of connexin hemichannels alleviates non-alcoholic steatohepatitis in mice. AB - While gap junctions mediate intercellular communication and support liver homeostasis, connexin hemichannels are preferentially opened by pathological stimuli, including inflammation and oxidative stress. The latter are essential features of non-alcoholic steatohepatitis. In this study, it was investigated whether connexin32 and connexin43 hemichannels play a role in non-alcoholic steatohepatitis. Mice were fed a choline-deficient high-fat diet or normal diet for 8 weeks. Thereafter, TAT-Gap24 or TAT-Gap19, specific inhibitors of hemichannels composed of connexin32 and connexin43, respectively, were administered for 2 weeks. Subsequently, histopathological examination was carried out and various indicators of inflammation, liver damage and oxidative stress were tested. In addition, whole transcriptome microarray analysis of liver tissue was performed. Channel specificity of TAT-Gap24 and TAT-Gap19 was examined in vitro by fluorescence recovery after photobleaching analysis and measurement of extracellular release of adenosine triphosphate. TAT-Gap24 and TAT-Gap19 were shown to be hemichannel-specific in cultured primary hepatocytes. Diet-fed animals treated with TAT-Gap24 or TAT-Gap19 displayed decreased amounts of liver lipids and inflammatory markers, and augmented levels of superoxide dismutase, which was supported by the microarray results. These findings show the involvement of connexin32 and connexin43 hemichannels in non-alcoholic steatohepatitis and, simultaneously, suggest a role as potential drug targets in non-alcoholic steatohepatitis. PMID- 28811573 TI - Simultaneous Separation of Actinium and Radium Isotopes from a Proton Irradiated Thorium Matrix. AB - A new method has been developed for the isolation of 223,224,225Ra, in high yield and purity, from a proton irradiated 232Th matrix. Herein we report an all aqueous process using multiple solid-supported adsorption steps including a citrate chelation method developed to remove >99.9% of the barium contaminants by activity from the final radium product. A procedure involving the use of three columns in succession was developed, and the separation of 223,224,225Ra from the thorium matrix was obtained with an overall recovery yield of 91 +/- 3%, average radiochemical purity of 99.9%, and production yields that correspond to physical yields based on previously measured excitation functions. PMID- 28811574 TI - Interactions count: plant origin, herbivory and disturbance jointly explain seedling recruitment and community structure. AB - Herbivory and disturbance are major drivers of biological invasions, but it is unclear how they interact to determine exotic vs. native seedling recruitment and what consequences arise for biodiversity and ecosystem functioning. Previous studies neglected the roles of different, potentially interacting, guilds of generalist herbivores such as rodents and gastropods. We therefore set up a full factorial rodent exclusion x gastropod exclusion x disturbance x seed-addition experiment in a grassland community in Central Germany and measured early seedling recruitment, as well as species richness, species composition and aboveground biomass. Gastropod herbivory reduced the positive effect of disturbance on seedling recruitment, particularly for exotic species. Rodent herbivory had weak positive effects on seedling recruitment at undisturbed sites, irrespective of species origin. This effect was likely driven by their strong negative effect on productivity. Interactive effects between both herbivore guilds became only evident for species richness and composition. How many species established themselves depended on disturbance, but was independent of species origin. The fewer exotic species that established themselves increased productivity to a stronger extent compared to native species. Our study highlights that joint effects of disturbance, herbivory and species origin shape early recruitment, while they only weakly affect biodiversity and ecosystem functioning. PMID- 28811575 TI - Biological and functional characterization of bone marrow-derived mesenchymal stromal cells from patients affected by primary immunodeficiency. AB - Mesenchymal stromal cells (MSCs) represent a key component of bone marrow (BM) microenvironment and display immune-regulatory properties. We performed a detailed analysis of biological/functional properties of BM-MSCs derived from 33 pediatric patients affected by primary immune-deficiencies (PID-MSCs): 7 Chronic Granulomatous Disease (CGD), 15 Wiskott-Aldrich Syndrome (WAS), 11 Severe Combined Immunodeficiency (SCID). Results were compared with MSCs from 15 age matched pediatric healthy-donors (HD-MSCs). Clonogenic and proliferative capacity, differentiation ability, immunophenotype, immunomodulatory properties were analyzed. WB and RT-qPCR for CYBB, WAS and ADA genes were performed. All PID MSCs displayed clonogenic and proliferative capacity, morphology and immunophenotype comparable with HD-MSCs. PID-MSCs maintained the inhibitory effect on T- and B-lymphocyte proliferation, except for decreased inhibitory ability of SCID-MSCs at MSC:PBMC ratio 1:10. While HD- and CGD-MSCs were able to inhibit monocyte maturation into immature dendritic cells, in SCID- and WAS-MSCs this ability was reduced. After Toll-like Receptor priming, PID-MSCs displayed in vitro an altered gene expression profile of pro- and anti-inflammatory soluble factors. PID-MSCs displayed lower PPARgamma levels and WAS- and SCID-MSCs higher levels of key osteogenic markers, as compared with HD-MSCs. Our results indicate that PID-MSCs may be defective in some functional abilities; whether these defects contribute to disease pathophysiology deserves further investigation. PMID- 28811576 TI - Microclimatic temperatures increase the potential for vector-borne disease transmission in the Scandinavian climate. AB - We quantified the difference between the meteorological temperature recorded by the Danish Meteorological Institute (DMI) weather stations and the actual microclimatic temperatures at two or three different heights at six potential insect habitats. We then compared the impact of the hourly temperature on the extrinsic incubation period (EIP) of six pathogens. Finally, we developed a regression model, enabling us to predict the microclimatic temperatures of different habitats based on five standard meteorological parameters readily available from any meteorological institution. Microclimatic habitats were on average 3.5-5 degrees C warmer than the DMI recorded temperatures during midday and 1-3 degrees C cooler at midnight. The estimated EIP for five of the six microclimatic habitats was shorter than the estimates based on DMI temperatures for all pathogens studied. The microclimatic temperatures also predicted a longer season for virus development compared to DMI temperatures. Based on DMI data of hourly temperature, solar radiation, wind speed, rain and humidity, we were able to predict the microclimatic temperature of different habitats with an R2 of 0.87 0.96. Using only meteorological temperatures for vector-borne disease transmission models may substantially underestimate both the daily potential for virus development and the duration of the potential transmission season. PMID- 28811577 TI - Dirac point induced ultralow-threshold laser and giant optoelectronic quantum oscillations in graphene-based heterojunctions. AB - The occurrence of zero effective mass of electrons at the vicinity of the Dirac point is expected to create new paradigms for scientific research and technological applications, but the related discoveries are rather limited. Here, we demonstrate that a simple architecture composed of graphene quantum dots sandwiched by graphene layers can exhibit several intriguing features, including the Dirac point induced ultralow-threshold laser, giant peak-to-valley ratio (PVR) with ultra-narrow spectra of negative differential resistance and quantum oscillations of current as well as light emission intensity. In particular, the threshold of only 12.4 nA cm-2 is the lowest value ever reported on electrically driven lasers, and the PVR value of more than 100 also sets the highest record compared with all available reports on graphene-based devices. We show that all these intriguing phenomena can be interpreted based on the unique band structures of graphene quantum dots and graphene as well as resonant quantum tunneling.In graphene, electrons possess zero effective mass in proximity to the Dirac point, an unusual feature that could trigger the development of novel photonic devices. Here, the authors combine graphene quantum dots with two graphene layers and observe laser action with ultralow threshold. PMID- 28811578 TI - An epithelial-to-mesenchymal transition-inducing potential of granulocyte macrophage colony-stimulating factor in colon cancer. AB - Growing evidence shows that granulocyte macrophage colony-stimulating factor (GM CSF) has progression-promoting potentials in certain solid tumors, which is largely attributed to the immunomodulatory function of this cytokine in tumor niches. However, little is known about the effect of GM-CSF on cancer cells. Herein, we show that chronic exposure of colon cancer cells to GM-CSF, which harbor its receptor, leads to occurrence of epithelial to mesenchymal transition (EMT), in time and dose-dependent manners. These GM-CSF-educated cancer cells exhibit enhanced ability of motility in vitro and in vivo. Furthermore, GM-CSF stimulation renders colon cancer cells more resistant to cytotoxic agents. Mechanistic investigation reveals that MAPK/ERK signaling and EMT-inducing transcription factor ZEB1 are critical to mediate these effects of GM-CSF. In specimen of CRC patients, high-level expression of GM-CSF positively correlates with local metastases in lymph nodes. Moreover, the co-expression of GM-CSF and its receptors as well as phosphorylated ERK1/2 are observed. Thus, our study for the first time identifies a progression-promoting function of GM-CSF in colon cancer by inducing EMT. PMID- 28811579 TI - CXCL12 enhances angiogenesis through CXCR7 activation in human umbilical vein endothelial cells. AB - Angiogenesis is the process by which new vessels form from existing vascular networks. Human umbilical vein endothelial cells (HUVECs) may contribute to the study of vascular repair and angiogenesis. The chemokine CXCL12 regulates multiple cell functions, including angiogenesis, mainly through its receptor CXCR4. In contrast to CXCL12/CXCR4, few studies have described roles for CXCR7 in vascular biology, and the downstream mechanism of CXCR7 in angiogenesis remains unclear. The results of the present study showed that CXCL12 dose-dependently enhanced angiogenesis in chorioallantoic membranes (CAMs) and HUVECs. The specific activation of CXCR7 with TC14012 (a CXCR7 agonist) resulted in the significant induction of tube formation in HUVECs and in vivo. Further evidence suggested that CXCL12 induced directional polarization and migration in the HUVECs, which is necessary for tube formation. Moreover, CXCR7 translocalization was observed during the polarization of HUVECs in stripe assays. Finally, treatment with TC14012 also significantly increased PI3K/Akt phosphorylation, and tube formation was blocked by treating HUVECs with an Akt inhibitor. Overall, this study indicated that CXCL12-stimulated CXCR7 acts as a functional receptor to activate Akt for angiogenesis in HUVECs and that CXCR7 may be a potential target molecule for endothelial regeneration and repair after vascular injury. PMID- 28811580 TI - Betaeta 2-glycoprotein I protects mice against gram-negative septicaemia in a sexually dimorphic manner. AB - The immune responses of males and females to bacterial infections display differences. The mechanisms that underlie this sexual dimorphism are multifactorial. Lipopolysaccharide (LPS) contributes to the pathogenesis of endotoxaemia. We have previously demonstrated that the plasma protein beta-2 glycoprotein-1 (beta2GPI) reduces LPS-induced inflammation in male mice. In the present study using a more robust infection model of septicaemia the role of beta2GPI is examined in both male and female wild type (WT) and beta2GPI deficient (beta2GPI-/-) mice challenged with Escherichia coli (E. coli) intravenously. beta2GPI deficiency led to an increase of E. coli colony forming units (CFU) in the circulation of both male and female mice. In male beta2GPI-/- mice this was associated with a worse clinical severity score. This difference was not observed between female beta2GPI-/- and female WT mice. Male WT mice had decreased levels of total and increased levels of free thiol beta2GPI following administration of LPS or E. coli. This pattern of sexual dimorphic response was also observed in our cohort of humans with sepsis. These findings support a role for beta2GPI in modulating the sex-specific susceptibility to gram-negative septicaemia. PMID- 28811581 TI - The key energy scales of Gd-based metallofullerene determined by resonant inelastic x-ray scattering spectroscopy. AB - Endohedral metallofullerenes, formed by encaging Gd inside fullerenes like C80, can exhibit enhanced proton relaxitivities compared with other Gd-chelates, making them the promising contrast agents for magnetic resonance imaging (MRI). However, the underlying key energy scales of Gd x Sc3-x N@C80 (x = 1-3) remain unclear. Here, we carry out resonant inelastic x-ray scattering (RIXS) experiments on Gd x Sc3-x N@C80 at Gd N 4,5-edges to directly study the electronic structure and spin flip excitations of Gd 4f electrons. Compared with reference Gd2O3 and contrast agent Gadodiamide, the features in the RIXS spectra of all metallofullerenes exhibit broader spectral lineshape and noticeable energy shift. Using atomic multiplet calculations, we have estimated the key energy scales such as the inter-site spin exchange field, intra-atomic 4f-4f Coulomb interactions, and spin-orbit coupling. The implications of these parameters to the 4f states of encapsulated Gd atoms are discussed. PMID- 28811583 TI - Bacterial diversity among four healthcare-associated institutes in Taiwan. AB - Indoor microbial communities have important implications for human health, especially in health-care institutes (HCIs). The factors that determine the diversity and composition of microbiomes in a built environment remain unclear. Herein, we used 16S rRNA amplicon sequencing to investigate the relationships between building attributes and surface bacterial communities among four HCIs located in three buildings. We examined the surface bacterial communities and environmental parameters in the buildings supplied with different ventilation types and compared the results using a Dirichlet multinomial mixture (DMM)-based approach. A total of 203 samples from the four HCIs were analyzed. Four bacterial communities were grouped using the DMM-based approach, which were highly similar to those in the 4 HCIs. The alpha-diversity and beta-diversity in the naturally ventilated building were different from the conditioner-ventilated building. The bacterial source composition varied across each building. Nine genera were found as the core microbiota shared by all the areas, of which Acinetobacter, Enterobacter, Pseudomonas, and Staphylococcus are regarded as healthcare associated pathogens (HAPs). The observed relationship between environmental parameters such as core microbiota and surface bacterial diversity suggests that we might manage indoor environments by creating new sanitation protocols, adjusting the ventilation design, and further understanding the transmission routes of HAPs. PMID- 28811582 TI - A new class of hybrid secretion system is employed in Pseudomonas amyloid biogenesis. AB - Gram-negative bacteria possess specialised biogenesis machineries that facilitate the export of amyloid subunits for construction of a biofilm matrix. The secretion of bacterial functional amyloid requires a bespoke outer-membrane protein channel through which unfolded amyloid substrates are translocated. Here, we combine X-ray crystallography, native mass spectrometry, single-channel electrical recording, molecular simulations and circular dichroism measurements to provide high-resolution structural insight into the functional amyloid transporter from Pseudomonas, FapF. FapF forms a trimer of gated beta-barrel channels in which opening is regulated by a helical plug connected to an extended coil-coiled platform spanning the bacterial periplasm. Although FapF represents a unique type of secretion system, it shares mechanistic features with a diverse range of peptide translocation systems. Our findings highlight alternative strategies for handling and export of amyloid protein sequences.Gram-negative bacteria assemble biofilms from amyloid fibres, which translocate across the outer membrane as unfolded amyloid precursors through a secretion system. Here, the authors characterise the structural details of the amyloid transporter FapF in Pseudomonas. PMID- 28811584 TI - Nanopriming technology for enhancing germination and starch metabolism of aged rice seeds using phytosynthesized silver nanoparticles. AB - Application of nanomaterials for agriculture is relatively new as compared to their use in biomedical and industrial sectors. In order to promote sustainable nanoagriculture, biocompatible silver nanoparticles (AgNPs) have been synthesized through green route using kaffir lime leaf extract for use as nanopriming agent for enhancing seed germination of rice aged seeds. Results of various characterization techniques showed the successful formation of AgNPs which were capped with phytochemicals present in the plant extract. Rice aged seeds primed with phytosynthesized AgNPs at 5 and 10 ppm significantly improved germination performance and seedling vigor compared to unprimed control, AgNO3 priming, and conventional hydropriming. Nanopriming could enhance alpha-amylase activity, resulting in higher soluble sugar content for supporting seedlings growth. Furthermore, nanopriming stimulated the up-regulation of aquaporin genes in germinating seeds. Meanwhile, more ROS production was observed in germinating seeds of nanopriming treatment compared to unprimed control and other priming treatments, suggesting that both ROS and aquaporins play important roles in enhancing seed germination. Different mechanisms underlying nanopriming-induced seed germination were proposed, including creation of nanopores for enhanced water uptake, rebooting ROS/antioxidant systems in seeds, generation of hydroxyl radicals for cell wall loosening, and nanocatalyst for fastening starch hydrolysis. PMID- 28811585 TI - Age-related changes in crowding and reading speed. AB - Crowding, the inability to recognize objects in clutter, is known to play a role in developmental changes in reading speed. Here, we investigated whether crowding also plays a role in age-related changes in reading speed. We recruited 18 young (mean age: 22.6 +/- 3.5; range: 18~31) and 21 older adults (mean age: 58.2 +/- 7.0; range: 50~73) with normal vision. Reading speed was measured with short blocks of text. The degree of crowding was determined by measuring crowding zone (the distance between a target and flankers required to yield a criterion recognition accuracy) and the size of the visual span (an uncrowded window in the visual field within which letters can be recognizable reliably). Measurements were made across the central 16-degree visual field using letter-recognition tasks. Our results showed that, compared to young adults, older adults exhibited significantly slower reading speed (a decrease by 30%) and larger crowding: an enlargement of crowding zone (an increase by 31%) and shrinkage of the visual span (a decrease by 6.25 bits). We also observed significant correlations between reading speed and each of the crowding measures. Our results suggest that crowding increases with age. Age-related changes in crowding may in part explain slower reading in older adults. PMID- 28811587 TI - Comparisons of magnetic charge and axial charge meson cloud distributions in the PCQM. AB - The meson cloud distributions in r-space are extracted from the nucleon electromagnetic and axial form factors which are derived in the perturbative chiral quark model. The theoretical results indicate that the magnetic charge and axial charge distributions of the three-quark core have the similar distributions in r-space, the magnetic charge distributions of the meson cloud and three-quark core are more or less in the same region and peak at distances of around 0.4 fm, which is in good agreement with the finding of works in the framework of chiral perturbation theory, but the axial charge meson cloud distributes mainly inside the three-quark core. PMID- 28811586 TI - Modulating Sound with Acoustic Metafiber Bundles. AB - Acoustic metamaterials and metasurfaces provide great flexibility for manipulating sound waves and promise unprecedented functionality, ranging from transformation acoustics, acoustic cloaking, acoustic imaging to acoustic rerouting. However, the design of artificial structures with both broad bandwidth and multifunctionality remains challenging with traditional design approaches. Here we present a design and realization of a broadband acoustic metafiber bundle. Very different from previously reported acoustic metamaterials and metasurfaces, not only the metafiber structure is simple, flexible and tunable, but also the metafiber bundle has the advantages of broad bandwidth, high transmission, no resonance-induced energy loss and unchangeable output wavefront owing to eigenmodes in the passbands of the metafiber. Besides, it could also achieve arbitrary complex modulations of cylindrical and plane acoustic wavefronts. The metafiber bundles realize the exciting multifunctionality of both acoustic metamaterials and metasurfaces in a broad frequency range, which provides diverse routes to design novel acoustic devices with versatile applications. PMID- 28811588 TI - Dynamics of nano-confined water in Portland cement - comparison with synthetic C S-H gel and other silicate materials. AB - The dynamics of water confined in cement materials is still a matter of debate in spite of the fact that water has a major influence on properties such as durability and performance. In this study, we have investigated the dynamics of water confined in Portland cement (OPC) at different curing ages (3 weeks and 4 years after preparation) and at three water-to-cement ratios (w/c, 0.3, 0.4 and 0.5). Using broadband dielectric spectroscopy, we distinguish four different dynamics due to water molecules confined in the pores of different sizes of cements. Here we show how water dynamics is modified by the evolution in the microstructure (maturity) and the w/c ratio. The fastest dynamics (processes 1 and 2, representing very local water dynamics) are independent of water content and the degree of maturity whereas the slowest dynamics (processes 3 and 4) are dependent on the microstructure developed during curing. Additionally, we analyze the differences regarding the water dynamics when confined in synthetic C-S-H gel and in the C-S-H of Portland cement. PMID- 28811589 TI - Patients with IgG1-anti-red blood cell autoantibodies show aberrant Fc glycosylation. AB - Autoimmune hemolytic anemia (AIHA) is a potentially severe disease in which red blood cells (RBC) are destroyed by IgG anti-RBC autoantibodies which can lead to hemolysis. We recently found IgG Fc-glycosylation towards platelet and RBC alloantigens to be skewed towards decreased fucosylation, increased galactosylation and sialylation. The lowered core-fucosylation increases the affinity of the pathogenic alloantibodies to FcgammaRIIIa/b, and hence RBC destruction. It is known that in autoimmune diseases plasma IgG1 galactosylation and sialylation are lowered, but Fc-glycosylation of RBC-specific autoantibodies has never been thoroughly analyzed. We investigated by mass spectrometry the N linked RBC autoantibody and plasma IgG1 Fc-glycosylation in relation to occurrence of hemolysis for 103 patients with a positive direct antiglobulin test (DAT). We observed that total IgG1 purified from plasma of patients with RBC bound antibodies showed significantly decreased galactosylation and sialylation levels compared to healthy controls, similar to what previously has been shown for other autoimmune diseases. The anti-RBC- autoantibodies showed a profile with even lower galactosylation, but higher sialylation and lower bisection levels. In contrast to alloantibodies against RBCs, RBC-bound IgG1 Fc-fucosylation was not different between healthy controls and patients. Analysis of anti-RBC Fc glycoprofiles suggested that lower bisection and higher galactosylation associate with lower Hb levels. PMID- 28811590 TI - Structural analysis of Wss1 protein from saccharomyces cerevisiae. AB - Wss1 is a DNA-protein crosslinks (DPCs) repair protein, which is responsible for degradation of the protein components in DPCs. In this investigation, crystal structure of the protease domain from saccharomyces cerevisiae Wss1 (ScWss1) was solved and was compared with the known crystal structure of Schizosaccharomyces prombe Wss1 (SpWss1). It is found that the cleft near zinc ion to be the most conserved core region of Wss1 and that the electronic surface distributions vary greatly between the two homologs. Solution architecture of the full-length ScWss1 was further investigated by small-angle X-ray scattering (SAXS), which indicated the protein contains a flexible region inside. Finally, based on the structural information, a mechanism was proposed about how the enzyme is activated by DNA substrates. PMID- 28811591 TI - Alteration of sheep coat color pattern by disruption of ASIP gene via CRISPR Cas9. AB - Coat color is an important characteristic and economic trait in domestic sheep. Aiming at alteration of Chinese merino sheep coat color by genome manipulation, we disrupted sheep agouti signaling protein gene by CRISPR/Cas9. A total of seven indels were identified in 5 of 6 born lambs. Each targeted lamb happened at least two kinds of modifications, and targeted lambs with multiple modifications displayed variety of coat color patterns. Three lambs with 4 bp deletion showed badgerface with black body coat color in two lambs, and brown coat color with light ventral pigmentation in another one. The black-white spotted color was observed in two lambs with 2 bp deletion. Further analysis unraveled that modifications happened in one or more than two copies of ASIP gene, and moreover, the additional spontaneous mutations of D9 and/or D5 preceding the targeting modification could also involve the formation of coat color patterns. Taken together, the entanglement of ASIP modifications by CRISPR/Cas9, spontaneous D9/D5 mutations, and ASIP gene duplications contributed to the variety of coat color patterns in targeted lambs. PMID- 28811592 TI - High-performance therapeutic quercetin-doped adhesive for adhesive-dentin interfaces. AB - Almost half of dental restorations have failed in less than 10 years, and approximately 60% of practice time has been consumed to replace these dental restorations. As such, contemporary dentin adhesives should be modified to treat secondary caries and prevent the degradation of adhesive-dentin interfaces. To achieve this goal, we developed a versatile therapeutic adhesive in the present study by incorporating quercetin, which is a naturally derived plant extract, into a commercial adhesive at three concentrations (100, 500 and 1000 ug/mL). An unmodified adhesive served as a control. The antibacterial ability on Streptococcus mutans biofilm, conversion degree, microtensile bond strength, failure modes, in situ zymography, nanoleakage expression and cytotoxicity of quercetin-doped adhesive were comprehensively evaluated. Results showed that the quercetin-doped adhesive (500 ug/mL) preserved its bonding properties against collagenase ageing and inhibited the growth of S. mutans biofilm. Efficient bonding interface sealing ability, matrix metalloproteinase inhibition and acceptable biocompatibility were also achieved. Thus, a simple, safe and workable strategy was successfully developed to produce therapeutic adhesives for the extension of the service life of adhesive restorations. PMID- 28811593 TI - Prognostic value of routine laboratory variables in prediction of breast cancer recurrence. AB - The prognostic value of routine laboratory variables in breast cancer has been largely overlooked. Based on laboratory tests commonly performed in clinical practice, we aimed to develop a new model to predict disease free survival (DFS) after surgical removal of primary breast cancer. In a cohort of 1,596 breast cancer patients, we analyzed the associations of 33 laboratory variables with patient DFS. Based on 3 significant laboratory variables (hemoglobin, alkaline phosphatase, and international normalized ratio), together with important demographic and clinical variables, we developed a prognostic model, achieving the area under the curve of 0.79. We categorized patients into 3 risk groups according to the prognostic index developed from the final model. Compared with the patients in the low-risk group, those in the medium- and high-risk group had a significantly increased risk of recurrence with a hazard ratio (HR) of 1.75 (95% confidence interval [CI] 1.30-2.38) and 4.66 (95% CI 3.54-6.14), respectively. The results from the training set were validated in the testing set. Overall, our prognostic model incorporating readily available routine laboratory tests is powerful in identifying breast cancer patients who are at high risk of recurrence. Further study is warranted to validate its clinical application. PMID- 28811594 TI - Spatio-temporal variations of PM2.5 concentrations and the evaluation of emission reduction measures during two red air pollution alerts in Beijing. AB - To effectively improve air quality during pollution episodes, Beijing released two red alerts in 2015. Here we examined spatio-temporal variations of PM2.5 concentrations during two alerts based on multiple data sources. Results suggested that PM2.5 concentrations varied significantly across Beijing. PM2.5 concentrations in southern parts of Beijing were higher than those in northern areas during both alerts. In addition to unfavorable meteorological conditions, coal combustion, especially incomplete coal combustion contributed significantly to the high PM2.5 concentrations. Through the CAMx model, we evaluated the effects of emission-reduction measures on PM2.5 concentrations. Through simulation, emergency measures cut down 10% - 30% of the total emissions and decreased the peaks of PM2.5 concentrations by about 10-20% during two alerts. We further examined the scenario if emergency measures were implemented several days earlier than the start of red alerts. The results proved that the implementation of emission reduction measures 1-2 days before red alerts could lower the peak of PM2.5 concentrations significantly. Given the difficulty of precisely predicting the duration of heavy pollution episodes and the fact that successive heavy pollution episodes may return after red alerts, emergency measures should also be implemented one or two days after the red alerts. PMID- 28811595 TI - Delayed effects of transcriptional responses in Mycobacterium tuberculosis exposed to nitric oxide suggest other mechanisms involved in survival. AB - Mycobacterium tuberculosis has succeeded as a human pathogen for tens of thousands of years thanks to its ability to resist and adapt to the adverse conditions it encounters upon infection. Bacterial adaptation to stress is commonly viewed in the context of transcriptional regulation, with the implicit expectation that an initial transcriptomic response is tightly coupled to an ensuing proteomic response. However, after challenging M. tuberculosis with nitric oxide we found that the rapid transcriptional responses, detectable within minutes of nitric oxide exposure, typically took several hours to manifest on the protein level. Furthermore, early proteomic responses were dominated by the degradation of a set of proteins, specifically those containing damaged iron sulphur clusters. Overall, our findings are consistent with transcriptional responses participating mostly in late-stage recovery rather than in generating an immediate resistance to nitric oxide stress, suggesting that survival of M. tuberculosis under acute stress is contingent on mechanisms other than transcriptional regulation. These findings provide a revised molecular understanding of an important human pathogen. PMID- 28811596 TI - Complete alanine scanning of the Escherichia coli RbsB ribose binding protein reveals residues important for chemoreceptor signaling and periplasmic abundance. AB - The Escherichia coli RbsB ribose binding protein has been used as a scaffold for predicting new ligand binding functions through in silico modeling, yet with limited success and reproducibility. In order to possibly improve the success of predictive modeling on RbsB, we study here the influence of individual residues on RbsB-mediated signaling in a near complete library of alanine-substituted RbsB mutants. Among a total of 232 tested mutants, we found 10 which no longer activated GFPmut2 reporter expression in E. coli from a ribose-RbsB hybrid receptor signaling chain, and 13 with significantly lower GFPmut2 induction than wild-type. Quantitative mass spectrometry abundance measurements of 25 mutants and wild-type RbsB in periplasmic space showed four categories of effects. Some (such as D89A) seem correctly produced and translocated but fail to be induced with ribose. Others (such as N190A) show lower induction probably as a result of less efficient production, folding and translocation. The third (such as N41A or K29A) have defects in both induction and abundance. The fourth category consists of semi-constitutive mutants with increased periplasmic abundance but maintenance of ribose induction. Our data show how RbsB modeling should include ligand binding as well as folding, translocation and receptor binding. PMID- 28811597 TI - Vitamin D Receptor Gene Polymorphisms Modify Cardiometabolic Response to Vitamin D Supplementation in T2DM Patients. AB - There is conflicting evidence on the favorable effects of vitamin D supplementation on metabolic profile in Type 2 diabetes mellitus (T2DM) patients and this might be due to genetic variations in vitamin D receptors (VDRs). Thus, we studied the metabolic effects of a 12-month vitamin D supplementation in T2DM patients according to VDR polymorphisms. A total of 204 T2DM subjects received 2000 IU vitamin D3 daily for 12 months. Serum 25(OH)D and metabolic profiles were measured at baseline and after 12 months. VDR polymorphisms (Taq-I, Bsm-I, Apa-I and Fok-I) were identified using TaqMan genotyping assays. Vitamin D supplementation significantly increased HOMA beta-cell function (p = 0.003) as well as significantly decreased triglycerides, total and LDL-cholesterol (p < 0.001). The lowest increment in 25(OH)D levels was detected in patients with Fok I CC genotypes (p < 0.0001). With vitamin D supplementation, Taq-I GG genotype carriers showed significant improvements in triglycerides, LDL- and total cholesterol, insulin, HbA1c and HOMA-IR (p < 0.005, 0.01, < 0.001, < 0.005, 0.03 and 0.01, respectively). Similarly, Bsm-I TT genotype carriers showed significant improvements in triglycerides (p = 0.01), insulin and HOMA-IR (p-values < 0.05). In conclusion, improvements in metabolic profile due to vitamin D supplementation is influenced by VDR polymorphisms, specifically for carriers of Taq-I GG and Bsm I TT genotypes. PMID- 28811598 TI - Effects of contaminants of emerging concern on Megaselia scalaris (Lowe, Diptera: Phoridae) and its microbial community. AB - Drought, rising temperatures, and expanding human populations are increasing water demands. Many countries are extending potable water supplies by irrigating crops with wastewater. Unfortunately, wastewater contains biologically active, long-lived pharmaceuticals, even after treatment. Run-off from farms and wastewater treatment plant overflows contribute high concentrations of pharmaceuticals to the environment. This study assessed the effects of common pharmaceuticals on a cosmopolitan saprophagous insect, Megaselia scalaris (Diptera: Phoridae). Larvae were reared on artificial diets spiked with contaminants of emerging concern (CECs) at environmentally relevant concentrations. Female flies showed no oviposition preference for treated or untreated diets. Larvae exposed to caffeine in diets showed increased mortality, and larvae fed antibiotics and hormones showed signs of slowed development, especially in females. The normal sex ratio observed in M. scalaris from control diets was affected by exposure to caffeine and pharmaceutical mixture treatments. There was an overall effect of treatment on the flies' microbial communities; notably, caffeine fed insects displayed higher microbial variability. Eight bacterial families accounted for approximately 95% of the total microbes in diet and insects. Our results suggest that CECs at environmentally relevant concentrations can affect the biology and microbial communities of an insect of ecological and medical importance. PMID- 28811599 TI - Histone deacetylase 6 (HDAC6) is an essential factor for oocyte maturation and asymmetric division in mice. AB - Tubastatin A (Tub-A), a highly selective histone deacetylase 6 (HDAC6) inhibitor, has been widely used as a cytotoxic anticancer agent, or for the treatment of patients with asthma. However, the potential toxicity of Tub-A on oocyte maturation and asymmetric division is still unclear. Therefore, the present study was designed to examine the effect and potential regulatory role of Tub-A on the meiotic maturation of oocytes. We observed that Tub-A treatment induced an increased level of the acetylation of alpha-tubulin, and a failure of spindle migration and actin cap formation. Based on the spindle structure, most Tub-A treated oocytes were arrested in an MI-like or a GVBD-like stage and exhibited decondensed chromosomes in a dose dependent manner. Moreover, Tub-A treatment decreased the protein expression of mTOR, a factor responsible for spindle formation, and the expression of mDia1, an inhibitor of actin assembly, in an HDAC6 expression-dependent manner. Importantly, following Tub-A supplementation, most oocytes failed to extrude the first polar body, which indicates that these defects are closely linked to abnormal oocyte maturation. Taken together, our data demonstrates that HDAC6 is one of the essential factors for oocyte maturation and asymmetric division via the HDAC6/mTOR or mDia1 pathway in mice. PMID- 28811600 TI - Exploring Leishmania secretory proteins to design B and T cell multi-epitope subunit vaccine using immunoinformatics approach. AB - Visceral leishmaniasis (VL) is a fatal form of leishmaniasis which affects 70 countries, worldwide. Increasing drug resistance, HIV co-infection, and poor health system require operative vaccination strategy to control the VL transmission dynamics. Therefore, a holistic approach is needed to generate T and B memory cells to mediate long-term immunity against VL infection. Consequently, immunoinformatics approach was applied to design Leishmania secretory protein based multi-epitope subunit vaccine construct consisting of B and T cell epitopes. Further, the physiochemical characterization was performed to check the aliphatic index, theoretical PI, molecular weight, and thermostable nature of vaccine construct. The allergenicity and antigenicity were also predicted to ensure the safety and immunogenic behavior of final vaccine construct. Moreover, homology modeling, followed by molecular docking and molecular dynamics simulation study was also performed to evaluate the binding affinity and stability of receptor (TLR-4) and ligand (vaccine protein) complex. This study warrants the experimental validation to ensure the immunogenicity and safety profile of presented vaccine construct which may be further helpful to control VL infection. PMID- 28811601 TI - Autonomic versus perceptual accounts for tactile hypersensitivity in autism spectrum disorder. AB - Tactile atypicality in individuals with autism spectrum disorder (ASD) has harmful effects on their everyday lives including social interactions. However, whether tactile atypicality in ASD reflects perceptual and/or autonomic processes is unknown. Here, we show that adults with ASD have hypersensitivity to tactile stimuli in the autonomic but not perceptual domain. In particular, adults with ASD showed a greater skin conductance response (SCR) to tactile stimuli compared to typically developing (TD) adults, despite an absence of differences in subjective responses. Furthermore, the level of the SCR was correlated with sensory sensitivity in daily living. By contrast, in perceptual discriminative tasks that psychophysically measured thresholds to tactile stimuli, no differences were found between the ASD and TD groups. These results favor the hypothesis that atypical autonomic processing underlies tactile hypersensitivity in ASD. PMID- 28811602 TI - Identification of ciguatoxins in a shark involved in a fatal food poisoning in the Indian Ocean. AB - Severe food poisoning events after the consumption of sharks have been reported since the 1940s; however, there has been no clear understanding of their cause. Herein, we report for the first time the presence of ciguatoxins (CTXs) in sharks. The identification by mass spectrometry of CTXs, including two new analogues, in a bull shark (Carcharhinus leucas) that was consumed by humans, causing the poisoning and death of 11 people in Madagascar in 2013 is described. Typical neurotoxic ciguatera symptoms were recorded in patients, and toxicological assays on extracts of the shark demonstrated CTX-like activity. These results confirm this episode as a ciguatera poisoning event and expand the range of pelagic fish species that are involved in ciguatera in the Indian Ocean. Additionally, gambieric acid D, a molecule originally described in CTX-producing microalgae, was identified for the first time in fish. This finding can contribute to a better understanding of trophic relations within food webs. The present work confirms that consumption of sharks from the Indian Ocean should be considered a ciguatera risk, and actions should be taken to evaluate its magnitude and risk in order to manage shark fisheries. PMID- 28811603 TI - 2,4,6-Trinitrotoluene Induces Apoptosis via ROS-Regulated Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in HepG2 and Hep3B Cells. AB - 2,4,6-trinitrotoluene (TNT) has been reported to cause numerous adverse effects. However, the detailed molecular mechanisms underlying TNT-induced liver toxicity need to be elucidated. In this study, we used HepG2 (p53wt) and Hep3B (p53null) cell lines to investigate the cytotoxic effects of TNT. At first, we found that TNT significantly decreased cell viability and induced DNA damage. Thereafter, through transcriptomic analysis, we observed that the diverse biological functions affected included mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Mitochondrial dysfunction was evidenced by the loss of mitochondrial membrane potential, increased expression of cleaved-caspase-9&-3 and increased caspase-3/7 activity, indicating that apoptosis had occurred. In addition, the expressions of some ER stress-related proteins had increased. Next, we investigated the role of reactive oxygen species (ROS) in TNT-induced cellular toxicity. The levels of DNA damage, mitochondrial dysfunction, ER stress and apoptosis were alleviated when the cells were pretreated with N-acetyl-cysteine (NAC). These results indicated that TNT caused the ROS dependent apoptosis via ER stress and mitochondrial dysfunction. Finally, the cells transfected with CHOP siRNA significantly reversed the TNT-induced apoptosis, which indicated that ER stress led to apoptosis. Overall, we examined TNT-induced apoptosis via ROS dependent mitochondrial dysfunction and ER stress in HepG2 and Hep3B cells. PMID- 28811604 TI - Multimerization is required for antigen binding activity of an engineered IgM/IgG chimeric antibody recognizing a skin-related antigen. AB - Monoclonal antibodies offer great tools for research. We encountered a potentially useful mouse IgM monoclonal antibody whose antigen is expressed in normal skin but lost in human skin cancer. Because IgM is difficult to work with and the antigen was unknown, we decided to convert the IgM (u) to IgG (gamma) version. After cDNA for the antibody was obtained by RACE PCR, we made a series of molecules with different combinations of IgM and IgG domains. Whereas VH-Cu1 Cu2-Cgamma3 and VH-Cu1-Cu2-Hinge-Cgamma2-Cgamma3 functionally bound to the antigen, VH-Cgamma1-Hinge-Cgamma2-Cgamma3, VH-Cu1-Hinge-Cgamma2-Cgamma3, and VH Cu1-Cu2-Cgamma2-Cgamma3 did not. Gel filtration analyses revealed that the functional molecules tend to form multimers and the multimeric forms retained antigen binding activity. Furthermore, the mutation of amino acid residue p.309Q > C of mouse IgG and addition of IgM tailpiece to the C-terminus of the molecules induced multimer formation, dramatically enhanced antibody functionality and all non-functional molecules became strongly functional. The functional molecules could be bound by protein A/protein G and other IgG specific reagents and therefore should be useful for further characterization of the antigen. Our study revealed that multimerization of converted IgM is functionally important for antigen binding activity of engineered IgM/IgG chimeric antibodies. PMID- 28811605 TI - Spatial and viewpoint selectivity for others' observed actions in monkey ventral premotor mirror neurons. AB - The spatial location and viewpoint of observed actions are closely linked in natural social settings. For example, actions observed from a subjective viewpoint necessarily occur within the observer's peripersonal space. Neurophysiological studies have shown that mirror neurons (MNs) of the monkey ventral premotor area F5 can code the spatial location of live observed actions. Furthermore, F5 MN discharge can also be modulated by the viewpoint from which filmed actions are seen. Nonetheless, whether and to what extent MNs can integrate viewpoint and spatial location of live observed actions remains unknown. We addressed this issue by comparing the activity of 148 F5 MNs while macaque monkeys observed an experimenter grasping in three different combinations of viewpoint and spatial location, namely, lateral view in the (1) extrapersonal and (2) peripersonal space and (3) subjective view in the peripersonal space. We found that the majority of MNs were space-selective (60.8%): those selective for the peripersonal space exhibited a preference for the subjective viewpoint both at the single-neuron and population level, whereas space-unselective neurons were view invariant. These findings reveal the existence of a previously neglected link between spatial and viewpoint selectivity in MN activity during live-action observation. PMID- 28811606 TI - Identification of potential impacts of climate change and anthropogenic activities on streamflow alterations in the Tarim River Basin, China. AB - Understanding contributions of climate change and human activities to changes in streamflow is important for sustainable management of water resources in an arid area. This study presents quantitative analysis of climatic and anthropogenic factors to streamflow alteration in the Tarim River Basin (TRB) using the double mass curve method (DMC) and the Budyko methods. The time series (1960~2015) are divided into three periods: the prior impacted period (1960~1972) and the two post impacted periods, 1973~1986 and 1987~2015 with trend analysis. Our results suggest that human activities played a dominant role in deduction in the streamflow in TRB with contribution of 144.6% to 120.68% during the post impacted period I and 228.68% to 140.38% during the post impacted period II. Climatic variables accounted for 20.68%~44.6% of the decrease during the post impacted period I and 40.38% ~128.68% during the post impacted period II. Sensitivity analysis indicates that the streamflow alteration was most sensitive to changes in landscape parameters. The aridity index and all the elasticities showed an obvious increasing trend from the upstream to the downstream in the TRB. Our study suggests that it is important to take effective measures for sustainable development of eco-hydrological and socio-economic systems in the TRB. PMID- 28811607 TI - Localized iron accumulation precedes nucleation and growth of magnetite crystals in magnetotactic bacteria. AB - Many magnetotactic bacteria (MTB) biomineralize magnetite crystals that nucleate and grow inside intracellular membranous vesicles that originate from invaginations of the cytoplasmic membrane. The crystals together with their surrounding membranes are referred to magnetosomes. Magnetosome magnetite crystals nucleate and grow using iron transported inside the vesicle by specific proteins. Here we address the question: can iron transported inside MTB for the production of magnetite crystals be spatially mapped using electron microscopy? Cultured and uncultured MTB from brackish and freshwater lagoons were studied using analytical transmission electron microscopy in an attempt to answer this question. Scanning transmission electron microscopy was used at sub-nanometric resolution to determine the distribution of elements by implementing high sensitivity energy dispersive X-ray (EDS) mapping and electron energy loss spectroscopy (EELS). EDS mapping showed that magnetosomes are enmeshed in a magnetosomal matrix in which iron accumulates close to the magnetosome forming a continuous layer visually appearing as a corona. EELS, obtained at high spatial resolution, confirmed that iron was present close to and inside the lipid bilayer magnetosome membrane. This study provides important clues to magnetite formation in MTB through the discovery of a mechanism where iron ions accumulate prior to magnetite biomineralization. PMID- 28811608 TI - Large spontaneous exchange bias in a weak ferromagnet Pb6Ni9(TeO6)5. AB - We report the magnetic and dielectric behavior of Pb6Ni9(TeO6)5, a new compound comprising the honeycomb-like layers of S = 1 spins, through detailed structural, magnetic and dielectric investigation. An antiferromagnetic-type transition at 25 K (T N ) with weak-ferromagnetic behavior is revealed. Interestingly, a large value of coercive field of 1.32 T at 2 K is observed. The isothermal magnetization after zero-field-cooled condition, it exhibits the presence of large spontaneous exchange bias (SEB) with a magnitude of 0.19 T at 2 K; which is rare in single bulk materials, especially without external doping. The value of |H EB| further enhances to 0.24 T under 16 T field-cooled condition, confirming the presence of large exchange bias in the material. PMID- 28811609 TI - Rapid and accurate in silico solubility screening of a monoclonal antibody library. AB - Antibodies represent essential tools in research and diagnostics and are rapidly growing in importance as therapeutics. Commonly used methods to obtain novel antibodies typically yield several candidates capable of engaging a given target. The development steps that follow, however, are usually performed with only one or few candidates since they can be resource demanding, thereby increasing the risk of failure of the overall antibody discovery program. In particular, insufficient solubility, which may lead to aggregation under typical storage conditions, often hinders the ability of a candidate antibody to be developed and manufactured. Here we show that the selection of soluble lead antibodies from an initial library screening can be greatly facilitated by a fast computational prediction of solubility that requires only the amino acid sequence as input. We quantitatively validate this approach on a panel of nine distinct monoclonal antibodies targeting nerve growth factor (NGF), for which we compare the predicted and measured solubilities finding a very close match, and we further benchmark our predictions with published experimental data on aggregation hotspots and solubility of mutational variants of one of these antibodies. PMID- 28811610 TI - Antibiotic-induced release of small extracellular vesicles (exosomes) with surface-associated DNA. AB - Recently, biological roles of extracellular vesicles (which include among others exosomes, microvesicles and apoptotic bodies) have attracted substantial attention in various fields of biomedicine. Here we investigated the impact of sustained exposure of cells to the fluoroquinolone antibiotic ciprofloxacin on the released extracellular vesicles. Ciprofloxacin is widely used in humans against bacterial infections as well as in cell cultures against Mycoplasma contamination. However, ciprofloxacin is an inducer of oxidative stress and mitochondrial dysfunction of mammalian cells. Unexpectedly, here we found that ciprofloxacin induced the release of both DNA (mitochondrial and chromosomal sequences) and DNA-binding proteins on the exofacial surfaces of small extracellular vesicles referred to in this paper as exosomes. Furthermore, a label-free optical biosensor analysis revealed DNA-dependent binding of exosomes to fibronectin. DNA release on the surface of exosomes was not affected any further by cellular activation or apoptosis induction. Our results reveal for the first time that prolonged low-dose ciprofloxacin exposure leads to the release of DNA associated with the external surface of exosomes. PMID- 28811611 TI - The antibacterial and antifungal activity of six essential oils and their cyto/genotoxicity to human HEL 12469 cells. AB - Six essential oils (from oregano, thyme, clove, lavender, clary sage, and arborvitae) exhibited different antibacterial and antifungal properties. Antimicrobial activity was shown against pathogenic (Escherichia coli, Salmonella typhimurium, Yersinia enterocolitica, Staphylococcus aureus, Listeria monocytogenes, and Enterococcus faecalis) and environmental bacteria (Bacillus cereus, Arthrobacter protophormiae, Pseudomonas fragi) and fungi (Chaetomium globosum, Penicillium chrysogenum, Cladosporium cladosporoides, Alternaria alternata, and Aspergillus fumigatus). Oregano, thyme, clove and arborvitae showed very strong antibacterial activity against all tested strains at both full strength and reduced concentrations. These essential oils showed different fungistatic and fungicidal activities when tested by direct application and in the vapor phase. The genotoxic effects of these oils on HEL 12469 human embryo lung cells were evaluated using an alkaline comet assay for the first time, revealing that none of the oils induced significant DNA damage in vitro after 24 h. This study provides novel approaches for assessing the antimicrobial potential of essential oils in both direct contact and the vapor phase and also demonstrates the valuable properties of the phenol-free arborvitae oil. These results suggest that all the tested essential oils might be used as broad spectrum anti-microbial agents for decontaminating an indoor environment. PMID- 28811612 TI - Coenzyme Q10 Improves Lipid Metabolism and Ameliorates Obesity by Regulating CaMKII-Mediated PDE4 Inhibition. AB - Our recent studies revealed that supplementation with the reduced form of coenzyme Q10 (CoQ10H2) inhibits oxidative stress and slows the process of aging in senescence-accelerated mice. CoQ10H2 inhibits adipocyte differentiation and regulates lipid metabolism. In the present study, we show that dietary supplementation with CoQ10H2 significantly reduced white adipose tissue content and improved the function of brown adipose tissue by regulating expression of lipid metabolism-related factors in KKAy mice, a model of obesity and type 2 diabetes. In the liver, CoQ10H2 reduced cytoplasmic Ca2+ levels and consequently inhibited the phosphorylation of CaMKII. CoQ10H2 also regulated the activity of the transcription factor C-FOS and inhibited gene expression of PDE4, a cAMP degrading enzyme, via the CaMKII-MEK1/2-ERK1/2 signaling pathway, thereby increasing intracellular cAMP. This increased cAMP activated AMPK, enhanced oxidative decomposition of lipids, and inhibited de novo synthesis of fatty acids, inhibiting the development and progression of obesity and type 2 diabetes. These results suggest that CoQ10H2 supplementation may be useful as a treatment for metabolic disorders associated with obesity. PMID- 28811614 TI - Retarded saturation of the areal capacitance using 3D-aligned MnO2 thin film nanostructures as a supercapacitor electrode. AB - The supercapacitive properties of manganese oxide (MnO2) thin films electrodeposited on three-dimensionally (3D) aligned inverse-opal nickel nanostructures are investigated. Compared to conventional planar or two dimensionally (2D) aligned nanostructures, 3D-aligned nanostructures can provide considerably increased and controllable contacts between the electrode and electrolyte. As a result, saturation of the areal capacitance with the electrode thickness and associated decrease of the specific capacitance, C sp , become much slower than those of the planar and 2D-aligned electrode systems. While, for planar MnO2 electrodes, the C sp of a 60-cycle electrodeposited electrode is only the half of the 10-cycle electrodeposited one, the value of the 3D-nanostructured electrode remains unchanged under the same condition. The maximum C sp value of 864 F g-1, and C sp retention of 87.7% after 5000 cycles of galvanostatic charge discharge are obtained. The voltammetric response is also improved significantly and the C sp measured at 200 mV s-1 retains 71.7% of the value measured at 10 mV s-1. More quantitative analysis on the effect of this 3D-aligned nanostructuring is also performed using a deconvolution of the capacitive elements in the total capacitance of the electrodes. PMID- 28811613 TI - Transcriptomic analysis of nickel exposure in Sphingobium sp. ba1 cells using RNA seq. AB - Nickel acts as cofactor for a number of enzymes of many bacteria species. Its homeostasis is ensured by proteins working as ion efflux or accumulation systems. These mechanisms are also generally adopted to counteract life-threatening high extra-cellular Ni2+ concentrations. Little is known regarding nickel tolerance in the genus Sphingobium. We studied the response of the novel Sphingobium sp. ba1 strain, able to adapt to high Ni2+ concentrations. Differential gene expression in cells cultured in 10 mM Ni2+, investigated by RNA-seq analysis, identified 118 differentially expressed genes. Among the 90 up-regulated genes, a cluster including genes coding for nickel and other metal ion efflux systems (similar to either cnrCBA, nccCBA or cznABC) and for a NreB-like permease was found. Comparative analyses among thirty genomes of Sphingobium species show that this cluster is conserved only in two cases, while in the other genomes it is partially present or even absent. The differential expression of genes encoding proteins which could also work as Ni2+-accumulators (HupE/UreJ-like protein, NreA and components of TonB-associated transport and copper-homeostasis systems) was also detected. The identification of Sphingobium sp. ba1 strain adaptive mechanisms to nickel ions, can foster its possible use for biodegradation of poly aromatic compounds in metal-rich environments. PMID- 28811615 TI - Coherent tunneling in an AlGaN/AlN/GaN heterojunction captured through an analogy with a MOS contact. AB - Due to their wide band gaps, III-N materials can exhibit behaviors ranging from the semiconductor class to the dielectric class. Through an analogy between a Metal/AlGaN/AlN/GaN diode and a MOS contact, we make use of this dual nature and show a direct path to capture the energy band diagram of the nitride system. We then apply transparency calculations to describe the forward conduction regime of a III-N heterojunction diode and demonstrate it realizes a tunnel diode, in contrast to its regular Schottky Barrier Diode designation. Thermionic emission is ruled out and instead, a coherent electron tunneling scenario allows to account for transport at room temperature and higher. PMID- 28811616 TI - Synthesis-free PET imaging of brown adipose tissue and TSPO via combination of disulfiram and 64CuCl2. AB - PET imaging is a widely applicable but a very expensive technology. On-site synthesis is one important contributor to the high cost. In this report, we demonstrated the feasibility of a synthesis-free method for PET imaging of brown adipose tissue (BAT) and translocator protein 18 kDa (TSPO) via a combination of disulfiram, an FDA approved drug for alcoholism, and 64CuCl2 (termed 64Cu-Dis). In this method, a step-wise injection protocol of 64CuCl2 and disulfiram was used to accomplish the purpose of synthesis-free. Specifically, disulfiram, an inactive 64Cu ligand, was first injected to allow it to metabolize into diethyldithiocarbamate (DDC), a strong 64Cu ligand, which can chelate 64CuCl2 from the following injection to form the actual PET tracer in situ. Our blocking studies, western blot, and tissue histological imaging suggested that the observed BAT contrast was due to 64Cu-Dis binding to TSPO, which was further confirmed as a specific biomarker for BAT imaging using [18F]-F-DPA, a TSPO specific PET tracer. Our studies, for the first time, demonstrated that TSPO could serve as a potential imaging biomarker for BAT. We believe that our strategy could be extended to other targets while significantly reducing the cost of PET imaging. PMID- 28811617 TI - Cell surface binding, uptaking and anticancer activity of L-K6, a lysine/leucine rich peptide, on human breast cancer MCF-7 cells. AB - Cell surface binding and internalization are critical for the specific targeting and biofunctions of some cationic antimicrobial peptides (CAPs) with anticancer activities. However, the detailed cellular process for CAPs interacting with cancer cells and the exact molecular basis for their anticancer effects are still far from being fully understood. In the present study, we examined the cell surface binding, uptaking and anti-cancer activity of L-K6, a lysine/leucine-rich CAP, in human MCF-7 breast cancer cells. We found that L-K6 preferentially interact with MCF-7 cells. This tumor-targeting property of L-K6 might be partially due to its interactions with the surface exposed and negatively charged phosphatidylserine. Subsequently, L-K6 could internalize into MCF-7 cells mainly through a clathrin-independent macropinocytosis, without significant cell surface disruption. Finally, the internalized L-K6 induced a dramatic nuclear damage and MCF-7 cell death, without significant cytoskeleton disruption and mitochondrial impairment. This cytotoxicity of L-K6 against MCF-7 cancer cells could be further confirmed by using a mouse xenograft model. In summary, all these findings outlined the cellular process and cytotoxicity of L-K6 in MCF-7 cancer cells, and might help understand the complicated interactions between CAPs and cancer cells. PMID- 28811618 TI - Assessment of the role of ageing and non-ageing factors in death from non communicable diseases based on a cumulative frequency model. AB - To quantify the effects of ageing and non-ageing factors, a characterization of the effects of ageing, genetic, and exogenous variables on 12 major non communicable diseases was evaluated using a model assessing cumulative frequency of death and survival by age group from dead and surviving populations based on mortality statistics. Indices (0-1) of the roles of ageing (ARD), genetics (GRD) and exogenous (ERD) variables in deaths due to disease were established, and the sum of ARD, GRD and ERD was 1 (value of each indices was <1). Results showed that ageing plays an important role in death from chronic disease; exogenous factors may contribute more to the pattern of chronic disease than genetic factors (ARD, GRC and ERD were 0.818, 0.058 and 0.124 respectively for all non-communicable diseases). In descending order, ERD for non-communicable diseases were breast cancer, leukaemia, cancer of the cervix uteri and uterus, liver cancer, nephritis and nephropathy, stomach cancer, lung cancer, diabetes, cerebrovascular disease, coronary heart disease, COPD, and Alzheimer's disease, while a smaller ERD indicated a tendency of natural death. An understanding of the aforementioned complex relationships of specific non-communicable diseases will be beneficial in designing primary prevention measures for non-communicable diseases in China. PMID- 28811619 TI - Comparative mitogenomic analysis of Aposthonia borneensis and Aposthonia japonica (Embioptera: Oligotomidae) reveals divergent evolution of webspinners. AB - In this study, we report the complete mitochondrial genome (mitogenome, mtDNA) of Aposthonia borneensis and compare it with another sequenced webspinner, Aposthonia japonica. The A. borneensis mitogenome is smaller than A. japonica, but the size of each gene and the A + T content of protein-coding genes (PCGs) are almost identical in the two mitogenomes. Among the PCGs, atp6 shows the highest evolutionary rate and cox1 the lowest. The mtDNA map in A. borneensis is similar to Drosophila yakuba, but distinctly different from A. japonica, which has extensive rearrangement. Phylogenetic analyses dated the divergence time of the two webspinners at ca. 103 Ma. We speculate that the most recent common ancestor (MRCA) of A. borneensis and A. japonica was divided into several geographic groups during the Pangea breakup. Geographic isolation between the Japanese islands and the continental southeastern Asia resulted in the divergent evolution of A. borneensis and A. japonica, thus generating mtDNA structural variations between the two species. Based on the phylogenetic analyses and specific distributional features, the genus Aposthonia was supported as non monophyly, and we speculate that both highly rearranged and relatively conserved mitogenomes exist in other webspinners. PMID- 28811620 TI - A new anthracycline-type metabolite from Streptomyces sp. NEAU-L3. AB - A new anthracycline-type metabolite, designated as tetracenoquinocin A (1), was isolated from the fermentation broth of Streptomyces sp. NEAU-L3. Its structure was determined on the basis of spectroscopic analysis, including 1D and 2D NMR techniques as well as ESI-MS and comparison with data from the literature. Compound 1 showed potent cytotoxic activity against three cancer cell lines (HepG2, A549, HCT-116) with IC50 values of 5.57, 24.30 and 20.82 MUM, respectively. PMID- 28811621 TI - Morphological differences of the reproductive system could be used to predict the optimum Grapholita molesta (Busck) control period. AB - The oriental fruit moth (OFM), Grapholita molesta (Busck), is one of the dominant fruit-boring pests worldwide. In order to conduct integrated control of OFM effectively, it is important to predict the optimum control period. OFM populations have been monitored either by the number of trapped male moths exposed to sex pheromones or by the number of trapped male and female moths using food traps in orchards. The mating status and development stage of the trapped moths have not been characterized. The present paper studies the anatomical morphology of the OFM reproductive system at different development periods. The results revealed that OFM ovarian development can be divided into six stages. The average daily fecundity of OFM had an excellent positive correlation (r = 0.86) with the percentages of OFM in the egg maturation & oviposition stage, which could be used as an indicator in field population prediction work. There were obvious differences in the morphology of the corpus bursa and the heavy muscular area of the ductus ejaculatorius simplex before and after mating, and these differences could be used to increase the accuracy in predicting the optimum OFM control period. PMID- 28811622 TI - Dipeptidyl peptidase-4 inhibitors and cancer risk in patients with type 2 diabetes: a meta-analysis of randomized clinical trials. AB - Some recent studies have suggested that the use of dipeptidyl peptidase-4 inhibitors (DPP4i) is associated with cancer development. However, some other studies suggest no such association. The aim of the present study was to evaluate the effect of DPP4i on the risk of developing cancers. The electronic databases PubMed, Medline, EMBASE, Web of Science and Cochrane Library and the clinical trial registry were searched for published and unpublished randomized clinical trials on humans. Eligible studies were RCTs conducted in patients with type 2 diabetes mellitus, comparing DPP4i with a placebo or other active drugs. A total of 72 trials with 35,768 and 33,319 patients enrolled for DPP4i and the comparison drugs, respectively. Overall, no significant associations were detected between the use of DPP4i and cancer development, in comparison with the use of other active drugs or placebo. The results were consistent across pre defined subgroups stratified by type of DPP4i, type of cancer, drug for comparison, trial duration, or baseline characteristics. The results of this meta analysis suggest that patients with type 2 diabetes treated with DPP4i do not have a higher risk of developing cancers than patients treated with a placebo or other drugs. PMID- 28811623 TI - Immune dysregulation in patients with carpal tunnel syndrome. AB - Peripheral immunity plays a key role in maintaining homeostasis and conferring crucial neuroprotective effects on the injured nervous system, while at the same time may contribute to increased vulnerability to neuropathic pain. Little is known about the reciprocal relationship between entrapment neuropathy and peripheral immunity. This study investigated immune profile in patients with carpal tunnel syndrome (CTS), the most prevalent entrapment neuropathy. All patients exhibited neurophysiological abnormalities in the median nerve, with the majority reporting neuropathic pain symptoms. We found a significant increase in serum CCL5, CXCL8, CXCL10 and VEGF, and in CD4+ central and effector memory T cells in CTS patients, as compared to healthy controls. CCL5 and VEGF were identified as having the highest power to discriminate between patients and controls. Interestingly, and contrary to the prevailing view of CCL5 as a pro nociceptive factor, the level of circulating CCL5 was inversely correlated with neuropathic pain intensity and median nerve motor latency. In contrast, the level of central memory T cells was positively associated with abnormal neurophysiological findings. These results suggest that entrapment neuropathy is associated with adaptive changes in the homeostasis of memory T cells and an increase in systemic inflammatory modulating cytokines/chemokines, which potentially regulate neuropathic symptoms. PMID- 28811624 TI - Pupil Size Tracks Attentional Performance In Attention-Deficit/Hyperactivity Disorder. AB - Attention-deficit/hyperactivity disorder (ADHD) diagnosis is based on reported symptoms, which carries the potential risk of over- or under-diagnosis. A biological marker that helps to objectively define the disorder, providing information about its pathophysiology, is needed. A promising marker of cognitive states in humans is pupil size, which reflects the activity of an 'arousal' network, related to the norepinephrine system. We monitored pupil size from ADHD and control subjects, during a visuo-spatial working memory task. A sub group of ADHD children performed the task twice, with and without methylphenidate, a norepinephrine-dopamine reuptake inhibitor. Off-medication patients showed a decreased pupil diameter during the task. This difference was no longer present when patients were on-medication. Pupil size correlated with the subjects' performance and reaction time variability, two vastly studied indicators of attention. Furthermore, this effect was modulated by medication. Through pupil size, we provide evidence of an involvement of the noradrenergic system during an attentional task. Our results suggest that pupil size could serve as a biomarker in ADHD. PMID- 28811625 TI - Interleukin-7 in the transition of bone marrow progenitors to the thymus. AB - Interleukin-7 (IL-7) is essential for the development of T cells in humans and mice where deficiencies in IL-7 signaling result in severe immunodeficiency. T cells require IL-7 at multiple points during development; however, it is unclear when IL-7 is first necessary. We observed that mice with impaired IL-7 signaling had a large reduction in the number of early thymic progenitors (ETPs) while mice that overexpress IL-7 had greatly increased numbers of ETPs. These results indicated that the development of ETPs is sensitive to IL-7. Bone marrow progenitors of ETP are present in normal numbers in mice with impaired IL-7 signaling (IL-7Ralpha449F) and were efficiently recruited to the thymus. Furthermore, ETPs and their progenitors from IL-7Ralpha449F mice did not undergo increased apoptosis and proliferate normally compared to WT cells. Mixed bone marrow chimeras demonstrated that IL-7 signaling has a cell-intrinsic role in ETP development but was not required for development of bone marrow progenitors. We have shown a novel role for IL-7 signaling in the development of ETPs that is distinct from classic mechanisms of IL-7 regulating survival and proliferation. PMID- 28811626 TI - Outbreak and genotyping of canine distemper virus in captive Siberian tigers and red pandas. AB - In this study, four canine distemper virus (CDV) strains were isolated from captive Siberian tigers (Panthera tigris altaica) and red pandas (Ailurus fulgens) during two separate CDV outbreaks in a zoo in Guangdong province, China. Sequence alignment and phylogenetic analyses based on the full-length hemagglutinin (H) and fusion (F) genes showed that they were closely identical to genotype Asia-1. Prior to confirmation of CDV in Siberian tigers, to control spread of the disease, a live attenuated combination CDV vaccine was used among almost all carnivore animals except for red pandas in which another recombinant combination CDV vaccine was used. However, about two months later, CDV re-emerged and caused the death among red pandas. Based on the vaccination records, the live combination vaccine could be considered an ideal weapon against CDV in zoo carnivore animals. Although the recombinant combination CDV vaccine was safe for red pandas, its protection effectiveness remains to be further investigated. Moreover, according to the outbreak interval time and sequence characterization, we suspected that stray cats circulating in the zoo were the intermediate host, which contributed to CDV spread from stray dogs to zoo animals. This study revealed the importance of vaccination and biosecurity for zoo animals. PMID- 28811627 TI - Impact of Ocean Warming on Tropical Cyclone Size and Its Destructiveness. AB - The response of tropical cyclone (TC) destructive potential to global warming is an open issue. A number of previous studies have ignored the effect of TC size change in the context of global warming, which resulted in a significant underestimation of the TC destructive potential. The lack of reliable and consistent historical data on TC size limits the confident estimation of the linkage between the observed trend in TC size and that in sea surface temperature (SST) under the background of global climate warming. A regional atmospheric model is used in the present study to investigate the response of TC size and TC destructive potential to increases in SST. The results show that a large-scale ocean warming can lead to not only TC intensification but also TC expansion. The TC size increase in response to the ocean warming is possibly attributed to the increase in atmospheric convective instability in the TC outer region below the middle troposphere, which facilitates the local development of grid-scale ascending motion, low-level convergence and the acceleration of tangential winds. The numerical results indicate that TCs will become stronger, larger, and unexpectedly more destructive under global warming. PMID- 28811628 TI - A complex network analysis of ethnic conflicts and human rights violations. AB - News reports in media contain records of a wide range of socio-economic and political events in time. Using a publicly available, large digital database of news records, and aggregating them over time, we study the network of ethnic conflicts and human rights violations. Complex network analyses of the events and the involved actors provide important insights on the engaging actors, groups, establishments and sometimes nations, pointing at their long range effect over space and time. We find power law decays in distributions of actor mentions, co actor mentions and degrees and dominance of influential actors and groups. Most influential actors or groups form a giant connected component which grows in time, and is expected to encompass all actors globally in the long run. We demonstrate how targeted removal of actors may help stop spreading unruly events. We study the cause-effect relation between types of events, and our quantitative analysis confirm that ethnic conflicts lead to human rights violations, while it does not support the converse. PMID- 28811629 TI - Forces and Disease: Electrostatic force differences caused by mutations in kinesin motor domains can distinguish between disease-causing and non-disease causing mutations. AB - The ability to predict if a given mutation is disease-causing or not has enormous potential to impact human health. Typically, these predictions are made by assessing the effects of mutation on macromolecular stability and amino acid conservation. Here we report a novel feature: the electrostatic component of the force acting between a kinesin motor domain and tubulin. We demonstrate that changes in the electrostatic component of the binding force are able to discriminate between disease-causing and non-disease-causing mutations found in human kinesin motor domains using the receiver operating characteristic (ROC). Because diseases may originate from multiple effects not related to kinesin microtubule binding, the prediction rate of 0.843 area under the ROC plot due to the change in magnitude of the electrostatic force alone is remarkable. These results reflect the dependence of kinesin's function on motility along the microtubule, which suggests a precise balance of microtubule binding forces is required. PMID- 28811630 TI - Solid-state 31P and 1H chemical MR micro-imaging of hard tissues and biomaterials with magic angle spinning at very high magnetic field. AB - In this work, we show that it is possible to overcome the limitations of solid state MRI for rigid tissues due to large line broadening and short dephasing times by combining Magic Angle Spinning (MAS) with rotating pulsed field gradients. This allows recording ex vivo 31P 3D and 2D slice-selected images of rigid tissues and related biomaterials at very high magnetic field, with greatly improved signal to noise ratio and spatial resolution when compared to static conditions. Cross-polarization is employed to enhance contrast and to further depict spatially localized chemical variations in reduced experimental time. In these materials, very high magnetic field and moderate MAS spinning rate directly provide high spectral resolution and enable the use of frequency selective excitation schemes for chemically selective imaging. These new possibilities are exemplified with experiments probing selectively the 3D spatial distribution of apatitic hydroxyl protons inside a mouse tooth with attached jaw bone with a nominal isotropic resolution nearing 100 um. PMID- 28811631 TI - Development of a Primary Human Co-Culture Model of Inflamed Airway Mucosa. AB - Neutrophil breach of the mucosal surface is a common pathological consequence of infection. We present an advanced co-culture model to explore neutrophil transepithelial migration utilizing airway mucosal barriers differentiated from primary human airway basal cells and examined by advanced imaging. Human airway basal cells were differentiated and cultured at air-liquid interface (ALI) on the underside of 3 um pore-sized transwells, compatible with the study of transmigrating neutrophils. Inverted ALIs exhibit beating cilia and mucus production, consistent with conventional ALIs, as visualized by micro-optical coherence tomography (uOCT). uOCT is a recently developed imaging modality with the capacity for real time two- and three-dimensional analysis of cellular events in marked detail, including neutrophil transmigratory dynamics. Further, the newly devised and imaged primary co-culture model recapitulates key molecular mechanisms that underlie bacteria-induced neutrophil transepithelial migration previously characterized using cell line-based models. Neutrophils respond to imposed chemotactic gradients, and migrate in response to Pseudomonas aeruginosa infection of primary ALI barriers through a hepoxilin A3-directed mechanism. This primary cell-based co-culture system combined with uOCT imaging offers significant opportunity to probe, in great detail, micro-anatomical and mechanistic features of bacteria-induced neutrophil transepithelial migration and other important immunological and physiological processes at the mucosal surface. PMID- 28811632 TI - Atomic-scale study of the amorphous-to-crystalline phase transition mechanism in GeTe thin films. AB - The underlying mechanism driving the structural amorphous-to-crystalline transition in Group VI chalcogenides is still a matter of debate even in the simplest GeTe system. We exploit the extreme sensitivity of 57Fe emission Mossbauer spectroscopy, following dilute implantation of 57Mn (T1/2 = 1.5 min) at ISOLDE/CERN, to study the electronic charge distribution in the immediate vicinity of the 57Fe probe substituting Ge (FeGe), and to interrogate the local environment of FeGe over the amorphous-crystalline phase transition in GeTe thin films. Our results show that the local structure of as-sputtered amorphous GeTe is a combination of tetrahedral and defect-octahedral sites. The main effect of the crystallization is the conversion from tetrahedral to defect-free octahedral sites. We discover that only the tetrahedral fraction in amorphous GeTe participates to the change of the FeGe-Te chemical bonds, with a net electronic charge density transfer of ~ 1.6 e/a0 between FeGe and neighboring Te atoms. This charge transfer accounts for a lowering of the covalent character during crystallization. The results are corroborated by theoretical calculations within the framework of density functional theory. The observed atomic-scale chemical structural changes are directly connected to the macroscopic phase transition and resistivity switch of GeTe thin films. PMID- 28811633 TI - Rapid replacement by non-vaccine pneumococcal serotypes may mitigate the impact of the pneumococcal conjugate vaccine on nasopharyngeal bacterial ecology. AB - There is growing concern that interventions that alter microbial ecology can adversely affect health. We characterised the impact of the seven-valent pneumococcal conjugate vaccine (PCV7) on pneumococcal carriage and the bacterial component of the nasopharyngeal microbiome during infancy. Newborns were recruited into three groups as follows: Group1 (n = 33) was the control group and comprised infants who received PCV7 after 6 months and came from unvaccinated communities. Group 2 (n = 30) came from unvaccinated communities and Group 3 (n = 39) came from vaccinated communities. Both group 2 and 3 received PCV7 at 2, 3 and 4 months. Culture and 16 S rRNA gene sequencing were performed on nasopharyngeal specimens collected at regular intervals from infants. Nasopharyngeal carriage of PCV7 serotypes in Group 1 was significantly higher than in Group 2 and 3 (p < 0.01). However, pneumococcal carriage remained comparable due to an expansion of non-vaccine serotypes in Groups 2 and 3. Determination of phylogenetic dis(similarities) showed that the bacterial community structures were comparable across groups. A mixed effects model showed no difference in community richness (p = 0.15) and Shannon alpha-diversity (p = 0.48) across the groups. Immediate replacement of pneumococcal vaccine serotypes with non-vaccine serotypes may mitigate the impact of PCV7 on nasopharyngeal bacterial community structure and ecology. PMID- 28811634 TI - Molecular Cloning and Expression of Osmotin in a Baculovirus-Insect System: Purified Osmotin Mitigates Amyloid-beta Deposition in Neuronal Cells. AB - Osmotin is a pathogenesis-related plant protein, have gained focus of research because of its homology with mammalian adiponectin. The therapeutic properties of osmotin have been explored in recent years as it exhibits neuroprotective effects against amyloid beta-, glutamate- and ethanol-induced synaptic dysfunction and neurodegeneration. In the present study, the full-length gene of the tobacco plant osmotin was cloned and expressed in the Sf9 insect cell line using the baculovirus expression system. In vitro analysis of purified Osmotin protein showed excellent cell viability, p-AMPK activation and a reduction in amyloid beta deposition. Immunofluorescent analysis showed significant reduction in amyloid beta deposition in APP over expressing neuronal cells. Osmotin inhibited amyloid beta deposition by influencing expression of APP processing genes including APP, ADAM 10 and BACE 1. Purified Osmotin showed reduction in amyloid beta deposition in different in vitro models as well. Osmotin showed similar mechanism when compared with mammalian adiponectin in different in vitro models. The present method will be an excellent approach for the efficient and cost effective production of the functional protein to be utilized for therapeutic purposes. Reduction in amyloid beta deposition by activation of p-AMPK influencing APP processing genes makes osmotin a potent therapeutic candidate for neurodegenerative diseases. PMID- 28811635 TI - Majorana charges, winding numbers and Chern numbers in quantum Ising models. AB - Mapping a many-body state on a loop in parameter space is a simple way to characterize a quantum state. The connections of such a geometrical representation to the concepts of Chern number and Majorana zero mode are investigated based on a generalized quantum spin system with short and long-range interactions. We show that the topological invariants, the Chern numbers of corresponding Bloch band, is equivalent to the winding number in the auxiliary plane, which can be utilized to characterize the phase diagram. We introduce the concept of Majorana charge, the magnitude of which is defined by the distribution of Majorana fermion probability in zero-mode states, and the sign is defined by the type of Majorana fermion. By direct calculations of the Majorana modes we analytically and numerically verify that the Majorana charge is equal to Chern numbers and winding numbers. PMID- 28811636 TI - Mussel Inspired Polynorepinephrine Functionalized Electrospun Polycaprolactone Microfibers for Muscle Regeneration. AB - Electrospun scaffolds with excellent mechanical properties, high specific surface area and a commendable porous network are widely used in tissue engineering. Improving the hydrophilicity and cell adhesion of hydrophobic substrates is the key point to enhance the effectiveness of electrospun scaffolds. In this study, polycaprolactone (PCL) fibrous membranes with appropriate diameter were selected and coated by mussel-inspired poly norepinephrine (pNE). And norepinephrine is a catecholamine functioning as a hormone and neurotransmitter in the human brain. The membrane with smaller diameter fibers, a relative larger specific surface area and the suitable pNE functionalization provided more suitable microenvironment for cell adhesion and proliferation both in vitro and in vivo. The regenerated muscle layer can be integrated well with fibrous membranes and surrounding tissues at the impaired site and thus the mechanical strength reached the value of native tissue. The underlying molecular mechanism is mediated via inhibiting myostatin expression by PI3K/AKT/mTOR hypertrophy pathway. The properly functionalized fibrous membranes hold the potential for repairing muscle injuries. Our current work also provides an insight for rational design and development of better tissue engineering materials for skeletal muscle regeneration. PMID- 28811637 TI - Non-diffraction propagation of acoustic waves in a rapidly modulated stratified medium. AB - A rapidly modulated stratified medium with a large mass density modulation depth (LMMD) is proposed to achieve non-diffraction propagation (NDP) of acoustic waves. It is found that the NDP in LMMD medium is independent of the incident angle and can be operated in a broad-band manner. Such an NDP is robust and is unhampered by medium losses. An effective medium theory (EMT) is developed for acoustic waves propagating in the LMMD medium based on the first-principles method. The LMMD EMT is verified by using the transfer-matrix method (TMM) for both propagating and evanescent waves. Furthermore, we discuss the influence of the geometry on NDP, and finite element simulations are conducted to verify the NDP in the LMMD medium. PMID- 28811638 TI - The CpG dinucleotide content of the HIV-1 envelope gene may predict disease progression. AB - The clinical course of HIV-1 varies greatly among infected individuals. Despite extensive research, virus factors associated with slow-progression remain poorly understood. Identification of unique HIV-1 genomic signatures linked to slow progression remains elusive. We investigated CpG dinucleotide content in HIV-1 envelope gene as a potential virus factor in disease progression. We analysed 1808 HIV-1 envelope gene sequences from three independent longitudinal studies; this included 1280 sequences from twelve typical-progressors and 528 sequences from six slow-progressors. Relative abundance of CpG dinucleotides and relative synonymous codon usage (RSCU) for CpG-containing codons among HIV-1 envelope gene sequences from typical-progressors and slow-progressors were analysed. HIV-1 envelope gene sequences from slow-progressors have high-CpG dinucleotide content and increased number of CpG-containing codons as compared to typical-progressors. Our findings suggest that observed differences in CpG-content between typical progressors and slow-progressors is not explained by differences in the mononucleotide content. Our results also highlight that the high-CpG content in HIV-1 envelope gene from slow-progressors is observed immediately after seroconversion. Thus CpG dinucleotide content of HIV-1 envelope gene is a potential virus-related factor that is linked to disease progression. The CpG dinucleotide content of HIV-1 envelope gene may help predict HIV-1 disease progression at early stages after seroconversion. PMID- 28811639 TI - Phylogeny and morphological analyses of Penicillium section Sclerotiora (Fungi) lead to the discovery of five new species. AB - Phylogeny of Penicillium section Sclerotiora is still limitedly investigated. In this study, five new species of Penicillium are identified from the samples collected from different places of China, and named P. austrosinicum, P. choerospondiatis, P. exsudans, P. sanshaense and P. verrucisporum. The conidiophores of P. austrosinicum and P. exsudans are monoverticillate like most members of the section, while the rest species are biverticillate similar to the only two species P. herquei and P. malachiteum previously reported in the section Sclerotiora. The phylogenetic positions of the new taxa are determined based on the sequence data of ITS, BenA, CaM and RPB2 regions, which reveals that all the species with biverticillate condiophores form a well-supported subclade in the section. The new Penicillium species clearly differ from the existing species of the genus in culture characteristics on four standard growth media, microscopic features, and sequence data. Morphological discrepancies are discussed between the new species and their allies. PMID- 28811640 TI - A Reciprocal Interaction between beta-Catenin and Osterix in Cementogenesis. AB - Although accumulating evidence indicates that both beta-catenin and osterix (Osx) are essential for bone and tooth development, few studies have investigated the interaction of these two key proteins in the context of cementogenesis. In this study, we used transgenic mice with constitutively active beta-catenin and inactive Osx in the dental mesenchyme to address this question. We found that cementoblasts with constitutively active beta-catenin require Osx to produce excessive cellular cementum, and that ablation of Osx prevents this abnormal accumulation. Importantly, cementoblasts transduced with retrovirus expressing constitutively active beta-catenin exhibited upregulation of Osx expression through direct binding to the promoter region of Osx. Osx regulates Lef1 expression and consequently could regulate T-cell factor/lymphoid enhancer factor (Tcf/Lef) binding activity in Wnt/beta-catenin signaling. However, the loss of Tcf/Lef binding activity by Osx ablation was not rescued by transduction of retrovirus expressing constitutively active beta-catenin or ectopic Lef1 overexpression. These results suggest that the Tcf/Lef binding activity of Wnt/beta-catenin signaling is Osx-dependent during cementogenesis. Moreover, Osx differentially regulates the expression of various Tcf family members, suggesting that Osx regulates cementogenesis by utilizing various Tcf/Lef-dependent mechanisms. This is the first report to show that downstream Osx signaling through Tcf/Lefs is critical for cementogenesis. PMID- 28811641 TI - Joint inflammation related citrullination of functional arginines in extracellular proteins. AB - We report the extent, specific sites and structural requirements of joint inflammation related citrullination in extracellular proteins. A total of 40 synovial fluid samples derived from chronically inflamed human joints were analysed by heparin-agarose fractionation and LC-MS/MS. Citrullination of 55 arginines in extracellular proteins was detected. Importantly, 20% of the sites have a characterized function related to the hallmarks of destructive joint inflammation. E.g. four arginine residues, shown here to be citrullinated, are also affected by mutations in inherited diseases causing haemolysis or blood clotting dysfunction. Citrullination of integrin ligands was selected for further studies since fibronectin R234 in isoDGR was among the most frequently citrullinated arginines in synovial fluid. Assays with synovial fibroblasts and integrin alphaVbeta3 indicated decreased affinity to the enzymatically citrullinated integrin binding sites. To conclude, our data indicate that in inflamed joints extensive citrullination affects the functional arginine residues in extracellular proteins. PMID- 28811642 TI - Octahedron Iron Oxide Nanocrystals Prohibited Clostridium difficile Spore Germination and Attenuated Local and Systemic Inflammation. AB - Clinical management of Clostridium difficile infection is still far from satisfactory as bacterial spores are resistant to many chemical agents and physical treatments. Certain types of nanoparticles have been demonstrated to exhibit anti-microbial efficacy even in multi-drug resistance bacteria. However, most of these studies failed to show biocompatibility to the mammalian host cells and no study has revealed in vivo efficacy in C. difficile infection animal models. The spores treated with 500 ug/mL Fe3-deltaO4 nanoparticles for 20 minutes, 64% of the spores were inhibited from transforming into vegetative cells, which was close to the results of the sodium hypochlorite-treated positive control. By cryo-electron micro-tomography, we demonstrated that Fe3-deltaO4 nanoparticles bind on spore surfaces and reduce the dipicolinic acid (DPA) released by the spores. In a C. difficile infection animal model, the inflammatory level triple decreased in mice with colonic C. difficile spores treated with Fe3-deltaO4 nanoparticles. Histopathological analysis showed a decreased intense neutrophil accumulation in the colon tissue of the Fe3-deltaO4 nanoparticle-treated mice. Fe3-deltaO4 nanoparticles, which had no influence on gut microbiota and apparent side effects in vivo, were efficacious inhibitors of C. difficile spore germination by attacking its surface and might become clinically feasible for prophylaxis and therapy. PMID- 28811644 TI - The Link between ENSO-like Forcing and Hydroclimate Variability of Coastal East Asia during the Last Millennium. AB - Inconsistent reconstructions of East Asian hydroclimate for the last millennium significantly limit our understanding of the mechanisms behind climate variability during the medieval climate anomaly (MCA) and little ice age (LIA) in the region. In this study, we present new high-resolution multiproxy records (diatom, delta13C, C/N, TS) from the Mulyoungari swamp, Jeju Island, South Korea. Our results indicate that El Nino southern oscillation-like variations caused the dry MCA/wet LIA pattern in the study area. Recent paleo-ENSO studies generally support the hypothesis that the MCA was characterized by more persistent El Nino like conditions. During El Nino events, the genesis of typhoons affecting coastal East Asia tends to diminish because of warm anomalies of eastern tropical Pacific (ETP) SSTs and downward motions over the western tropical Pacific. Therefore, coastal East Asia likely experienced a decline in typhoon-related precipitation during the MCA, in contrast to monsoon-dominated northern China. Our results additionally imply that SST anomalies in the ETP need to be carefully checked to better understand current hydroclimate variability in coastal East Asia, one of the most populated areas on earth. PMID- 28811643 TI - Overexpressed somatic alleles are enriched in functional elements in Breast Cancer. AB - Asymmetric allele content in the transcriptome can be indicative of functional and selective features of the underlying genetic variants. Yet, imbalanced alleles, especially from diploid genome regions, are poorly explored in cancer. Here we systematically quantify and integrate the variant allele fraction from corresponding RNA and DNA sequence data from patients with breast cancer acquired through The Cancer Genome Atlas (TCGA). We test for correlation between allele prevalence and functionality in known cancer-implicated genes from the Cancer Gene Census (CGC). We document significant allele-preferential expression of functional variants in CGC genes and across the entire dataset. Notably, we find frequent allele-specific overexpression of variants in tumor-suppressor genes. We also report a list of over-expressed variants from non-CGC genes. Overall, our analysis presents an integrated set of features of somatic allele expression and points to the vast information content of the asymmetric alleles in the cancer transcriptome. PMID- 28811645 TI - Inhibin-A and Decorin Secreted by Human Adult Renal Stem/Progenitor Cells Through the TLR2 Engagement Induce Renal Tubular Cell Regeneration. AB - Acute kidney injury (AKI) is a public health problem worldwide. Several therapeutic strategies have been made to accelerate recovery and improve renal survival. Recent studies have shown that human adult renal progenitor cells (ARPCs) participate in kidney repair processes, and may be used as a possible treatment to promote regeneration in acute kidney injury. Here, we show that human tubular ARPCs (tARPCs) protect physically injured or chemically damaged renal proximal tubular epithelial cells (RPTECs) by preventing cisplatin-induced apoptosis and enhancing proliferation of survived cells. tARPCs without toll-like receptor 2 (TLR2) expression or TLR2 blocking completely abrogated this regenerative effect. Only tARPCs, and not glomerular ARPCs, were able to induce tubular cell regeneration process and it occurred only after damage detection. Moreover, we have found that ARPCs secreted inhibin-A and decorin following the RPTEC damage and that these secreted factors were directly involved in cell regeneration process. Polysaccharide synthetic vesicles containing these molecules were constructed and co-cultured with cisplatin damaged RPTECs. These synthetic vesicles were not only incorporated into the cells, but they were also able to induce a substantial increase in cell number and viability. The findings of this study increase the knowledge of renal repair processes and may be the first step in the development of new specific therapeutic strategies for renal repair. PMID- 28811646 TI - PAFAH1B1 haploinsufficiency disrupts GABA neurons and synaptic E/I balance in the dentate gyrus. AB - Hemizygous mutations in the human gene encoding platelet-activating factor acetylhydrolase IB subunit alpha (Pafah1b1), also called Lissencephaly-1, can cause classical lissencephaly, a severe malformation of cortical development. Children with this disorder suffer from deficits in neuronal migration, severe intellectual disability, intractable epilepsy and early death. While many of these features can be reproduced in Pafah1b1+/- mice, the impact of Pafah1b1+/- on the function of individual subpopulations of neurons and ultimately brain circuits is largely unknown. Here, we show tangential migration of young GABAergic interneurons into the developing hippocampus is slowed in Pafah1b1+/- mice. Mutant mice had a decreased density of parvalbumin- and somatostatin positive interneurons in dentate gyrus, but no change in density of calretinin interneurons. Whole-cell patch-clamp recordings revealed increased excitatory and decreased inhibitory synaptic inputs onto granule cells of Pafah1b1+/- mice. Mutant animals developed spontaneous electrographic seizures, as well as long term deficits in contextual memory. Our findings provide evidence of a dramatic shift in excitability in the dentate gyrus of Pafah1b1+/- mice that may contribute to epilepsy or cognitive impairments associated with lissencephaly. PMID- 28811648 TI - Scale-dependent changes in the functional diversity of macrophytes in subtropical freshwater lakes in south China. AB - Ecological processes are generally scale-dependent and there is little consensus about the relative importance of deterministic versus stochastic processes in driving patterns of biological diversity. We investigated how the relationship between functional dispersion and environmental gradients changes with spatial scale in subtropical freshwater lakes. The functional alpha and beta dispersions of all the tested traits were significantly under-dispersed across spatial scales and along environmental gradients. Results showed more functional similarity within communities in leaf dry mass content and flowering duration but less functional turnover among communities in all the tested traits at regional scales (Yunnan-Guizhou plateau and the middle and low reaches of the Yangtze River). The strengths and directions of environmental effects on the functional alpha and beta dispersions depended on the selected traits, diversity metrics and spatial scales. Surprisingly, broad-scale factors - elevation and water transparency - decreased the functional turnover for most traits along the gradients, whereas fine-scale factors - water depth - produced the opposite patterns along the gradient, depending on the trait selected. Our study highlights the dominant role of deterministic assembly processes in structuring the local functional composition and governing the spatial functional turnover of macrophyte communities across multiple spatial scales. PMID- 28811647 TI - Biogenesis of Pro-senescent Microparticles by Endothelial Colony Forming Cells from Premature Neonates is driven by SIRT1-Dependent Epigenetic Regulation of MKK6. AB - Senescent cells may exert detrimental effect on microenvironment through the secretion of soluble factors and the release of extracellular vesicles, such as microparticles, key actors in ageing and cardiovascular diseases. We previously reported that sirtuin-1 (SIRT1) deficiency drives accelerated senescence and dysfunction of endothelial colony-forming cells (ECFC) in PT neonates. Because preterm birth (PT) increases the risk for cardiovascular diseases during neonatal period as well as at adulthood, we hypothesized that SIRT1 deficiency could control the biogenesis of microparticles as part of a senescence-associated secretory phenotype (SASP) of PT-ECFC and investigated the related molecular mechanisms. Compared to control ECFC, PT-ECFC displayed a SASP associated with increased release of endothelial microparticles (EMP), mediating a paracrine induction of senescence in naive endothelial cells. SIRT1 level inversely correlated with EMP release and drives PT-ECFC vesiculation. Global transcriptomic analysis revealed changes in stress response pathways, specifically the MAPK pathway. We delineate a new epigenetic mechanism by which SIRT1 deficiency regulates MKK6/p38MAPK/Hsp27 pathway to promote EMP biogenesis in senescent ECFC. These findings deepen our understanding of the role of ECFC senescence in the disruption of endothelial homeostasis and provide potential new targets towards the control of cardiovascular risk in individuals born preterm. PMID- 28811649 TI - Spin-Selective Transmission and Devisable Chirality in Two-Layer Metasurfaces. AB - Chirality is a nearly ubiquitous natural phenomenon. Its minute presence in most naturally occurring materials makes it incredibly difficult to detect. Recent advances in metasurfaces indicate that they exhibit devisable chirality in novel forms; this finding offers an effective opening for studying chirality and its features in such nanostructures. These metasurfaces display vast possibilities for highly sensitive chirality discrimination in biological and chemical systems. Here, we show that two-layer metasurfaces based on twisted nanorods can generate giant spin-selective transmission and support engineered chirality in the near infrared region. Two designed metasurfaces with opposite spin-selective transmission are proposed for treatment as enantiomers and can be used widely for spin selection and enhanced chiral sensing. Specifically, we demonstrate that the chirality in these proposed metasurfaces can be adjusted effectively by simply changing the orientation angle between the twisted nanorods. Our results offer simple and straightforward rules for chirality engineering in metasurfaces and suggest intriguing possibilities for the applications of such metasurfaces in spin optics and chiral sensing. PMID- 28811650 TI - Diet-induced obesity leads to metabolic dysregulation in offspring via endoplasmic reticulum stress in a sex-specific manner. AB - BACKGROUND/OBJECTIVES: Exposure to metabolic stress has been suggested to influence the susceptibility to metabolic disorders in offspring according to epidemiological and animal studies. Nevertheless, molecular mechanisms remain unclear. We investigated impacts of diet-induced paternal obesity on metabolic phenotypes in offspring and its underlying molecular mechanism. SUBJECTS/METHODS: Male founder mice (F0), fed with control diet (CD) or high-fat diet (HFD), were mated with CD-fed females. F1 progenies were mated with outbred mice to generate F2 mice. All offspring were maintained on CD. Metabolic phenotypes, metabolism related gene expression and endoplasmic reticulum (ER) stress markers were measured in serum or relevant tissues of F2 mice. DNA methylation in sperm and testis of the founder and in the liver of F2 mice was investigated. RESULTS: Male founder obesity, instigated by HFD, led to glucose dysregulation transmitted down to F2. We found that F2 males to HFD founders were overweight and had a high fasting glucose relative to F2 to CD founders. F2 females to HFD founders, in contrast, had a reduced bodyweight relative to F2 to CD founders and exhibited an early onset of impaired glucose homeostasis. The sex-specific difference was associated with distinct transcriptional patterns in metabolism-related organs, showing altered hepatic glycolysis and decreased adipose Glucose transporter 4 (Glut4) in males and increased gluconeogenesis and lipid synthesis in females. Furthermore, the changes in females were linked to hepatic ER stress, leading to suppressed insulin signaling and non-obese hyperglycemic phenotypes. DNA methylation analysis revealed that the Nr1h3 locus was sensitive to HFD at founder germ cells and the alteration was also detected in the liver of F2 female. CONCLUSION: Our findings demonstrate that male founder obesity influences impaired glucose regulation in F2 progeny possibly via ER stress in a sex specific manner and it is, in part, contributed by altered DNA methylation at the Nr1h3 locus. PMID- 28811651 TI - iNKT cells prevent obesity-induced hepatic steatosis in mice in a C-C chemokine receptor 7-dependent manner. AB - Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis are characterized by an increase in hepatic triglyceride content with infiltration of immune cells, which can cause steatohepatitis and hepatic insulin resistance. C-C chemokine receptor 7 (CCR7) is primarily expressed in immune cells, and CCR7 deficiency leads to the development of multi-organ autoimmunity, chronic renal disease and autoimmune diabetes. Here, we investigated the effect of CCR7 on hepatic steatosis in a mouse model and its underlying mechanism. Our results demonstrated that body and liver weights were higher in the CCR7-/- mice than in the wild-type (WT) mice when they were fed a high-fat diet. Further, glucose tolerance and insulin sensitivity were markedly diminished in CCR7-/- mice. The number of invariant natural killer T (iNKT) cells was reduced in the livers of the CCR7-/- mice. Moreover, liver inflammation was detected in obese CCR7-/- mice, which was ameliorated by the adoptive transfer of hepatic mononuclear cells from WT mice, but not through the transfer of hepatic mononuclear cells from CD1d /- or interleukin-10-deficient (IL-10-/-) mice. Overall, these results suggest that CCR7+ mononuclear cells in the liver could regulate obesity-induced hepatic steatosis via induction of IL-10-expressing iNKT cells. PMID- 28811652 TI - Sources of variability in childhood obesity indicators and related behaviors. AB - The purpose of this study was to describe sources of variability in obesity related variables in 6022 children aged 9-11 years from 12 countries. The study design involved recruitment of students, nested within schools, which were nested within study sites. Height, weight and waist circumference (WC) were measured and body mass index (BMI) was calculated; sleep duration and total and in-school moderate-to-vigorous physical activity (MVPA) and sedentary time were measured by accelerometry; and diet scores were obtained by questionnaire. Variance in most variables was largely explained at the student level: BMI (91.9%), WC (93.5%), sleep (75.3%), MVPA (72.5%), sedentary time (76.9%), healthy diet score (88.3%), unhealthy diet score (66.2%), with the exception of in-school MVPA (53.8%) and in school sedentary time (25.1%). Variance explained at the school level ranged from 3.3% for BMI to 29.8% for in-school MVPA, and variance explained at the site level ranged from 3.2% for WC to 54.2% for in-school sedentary time. In general, more variance was explained at the school and site levels for behaviors than for anthropometric traits. Given the variance in obesity-related behaviors in primary school children explained at school and site levels, interventions that target policy and environmental changes may enhance obesity intervention efforts. PMID- 28811653 TI - Meal timing effects on insulin sensitivity and intrahepatic triglycerides during weight loss. AB - BACKGROUND: Several human and rodent studies suggest that in addition to the amount of energy consumed, timing of food intake contributes to body weight regulation. Consuming most energy in the morning has favorable effects on weight loss and weight maintenance. Whether this also affects glucose metabolism and liver fat independently from weight loss is unknown. OBJECTIVE: We hypothesized that during weight loss, consuming most energy in the morning improves insulin sensitivity and reduces hepatic fat content more than consuming most energy in the evening. METHODS: Twenty-three obese insulin resistant men (age 59.9+/-7.9 years, body mass index 34.4+/-3.8 kg m-2) followed a 4-week hypocaloric diet intervention with either 50% of daily energy consumed in the morning (BF group) or evening (D group). Insulin sensitivity, measured with a two-step hyperinsulinemic euglycemic clamp using a glucose tracer, intrahepatic triglycerides (IHTG), measured using magnetic resonance spectroscopy, and resting energy expenditure (REE) were assessed before and after the diet intervention. RESULTS: Meal macronutrient composition and weight loss (6.5+/-1.5% vs 6.2+/ 1.9%, respectively, P=0.70) did not differ between the BF and D groups. Endogenous glucose production (P?0.001), hepatic and peripheral insulin sensitivity (P=0.002; P=0.001, respectively) as well as IHTG content (P?0.001) all significantly improved with weight loss, but were not different between the BF and D groups. In addition, both groups decreased REE and respiratory quotient equally. CONCLUSIONS: During weight loss, consuming most energy in the morning instead of the evening does not have additional beneficial effects on insulin sensitivity and IHTG content. These results do not support weight independent effects of meal timing on glucose metabolism and IHTG in hypocaloric conditions in obese men. PMID- 28811654 TI - Characterization of the Mollusc RIG-I/MAVS Pathway Reveals an Archaic Antiviral Signalling Framework in Invertebrates. AB - Despite the mitochondrial antiviral signalling protein (MAVS)-dependent RIG-I like receptor (RLR) signalling pathway in the cytosol plays an indispensable role in the antiviral immunity of the host, surprising little is known in invertebrates. Here we characterized the major members of RLR pathway and investigated their signal transduction a Molluscs. We show that genes involved in RLR pathway were significantly induced during virus challenge, including CgRIG-I 1, CgMAVS, CgTRAF6 (TNF receptor-associated factor 6), and CgIRFs (interferon regulatory factors. Similar to human RIG-I, oyster RIG-I-1 could bind poly(I:C) directly in vitro and interact with oyster MAVS via its caspase activation and recruitment domains. We also show that transmembrane domain-dependent self association of CgMAVS may be crucial for its signalling and that CgMAVS can recruit the downstream signalling molecule, TRAF6, which can subsequently activate NF-kappaB signal pathway. Moreover, oyster IRFs appeared to function downstream of CgMAVS and were able to activate the interferon beta promoter and interferon stimulated response elements in mammalian cells. These results establish invertebrate MAVS-dependent RLR signalling for the first time and would be helpful for deciphering the antiviral mechanisms of invertebrates and understanding the development of the vertebrate RLR network. PMID- 28811655 TI - A Tissue Engineered Blood Vessel Model of Hutchinson-Gilford Progeria Syndrome Using Human iPSC-derived Smooth Muscle Cells. AB - Hutchison-Gilford Progeria Syndrome (HGPS) is a rare, accelerated aging disorder caused by nuclear accumulation of progerin, an altered form of the Lamin A gene. The primary cause of death is cardiovascular disease at about 14 years. Loss and dysfunction of smooth muscle cells (SMCs) in the vasculature may cause defects associated with HGPS. Due to limitations of 2D cell culture and mouse models, there is a need to develop improved models to discover novel therapeutics. To address this need, we produced a functional three-dimensional model of HGPS that replicates an arteriole-scale tissue engineered blood vessel (TEBV) using induced pluripotent stem cell (iPSC)-derived SMCs from an HGPS patient. To isolate the effect of the HGPS iSMCs, the endothelial layer consisted of human cord blood derived endothelial progenitor cells (hCB-EPCs) from a separate, healthy donor. TEBVs fabricated from HGPS iSMCs and hCB-EPCs show reduced vasoactivity, increased medial wall thickness, increased calcification and apoptosis relative to TEBVs fabricated from normal iSMCs or primary MSCs. Additionally, treatment of HGPS TEBVs with the proposed therapeutic Everolimus, increases HGPS TEBV vasoactivity and increases iSMC differentiation in the TEBVs. These results show the ability of this iPSC-derived TEBV to reproduce key features of HGPS and respond to drugs. PMID- 28811656 TI - PhageTerm: a tool for fast and accurate determination of phage termini and packaging mechanism using next-generation sequencing data. AB - The worrying rise of antibiotic resistance in pathogenic bacteria is leading to a renewed interest in bacteriophages as a treatment option. Novel sequencing technologies enable description of an increasing number of phage genomes, a critical piece of information to understand their life cycle, phage-host interactions, and evolution. In this work, we demonstrate how it is possible to recover more information from sequencing data than just the phage genome. We developed a theoretical and statistical framework to determine DNA termini and phage packaging mechanisms using NGS data. Our method relies on the detection of biases in the number of reads, which are observable at natural DNA termini compared with the rest of the phage genome. We implemented our method with the creation of the software PhageTerm and validated it using a set of phages with well-established packaging mechanisms representative of the termini diversity, i.e. 5'cos (Lambda), 3'cos (HK97), pac (P1), headful without a pac site (T4), DTR (T7) and host fragment (Mu). In addition, we determined the termini of nine Clostridium difficile phages and six phages whose sequences were retrieved from the Sequence Read Archive. PhageTerm is freely available (https://sourceforge.net/projects/phageterm), as a Galaxy ToolShed and on a Galaxy-based server (https://galaxy.pasteur.fr). PMID- 28811657 TI - Colorimetric Fingerprints of Gold Nanorods for Discriminating Catecholamine Neurotransmitters in Urine Samples. AB - Catecholamine neurotransmitters, generally including dopamine (DA), epinephrine (EP) and norepinephrine (NE) are known as substantial indicators of various neurological diseases. Simultaneous detection of these compounds and their metabolites is highly recommended in early clinical diagnosis. To this aim, in the present contribution, a high performance colorimetric sensor array has been proposed for the detection and discrimination of catecholamines based on their reducing ability to deposit silver on the surface of gold nanorods (AuNRs). The amassed silver nanoshell led to a blue shift in the longitudinal localized surface plasmon resonance (LSPR) peak of AuNRs, creating a unique pattern for each of the neurotransmitters. Hierarchical cluster analysis (HCA) and linear discriminate analysis (LDA) pattern recognition techniques were employed to identify DA, EP and NE. The proposed colorimetric array is able to differentiate among individual neurotransmitters as well as their mixtures, successfully. Finally, it was shown that the sensor array can identify these neurotransmitters in human urine samples. PMID- 28811658 TI - Political Pressures Increased Vulnerability to Climate Hazards for Nomadic Livestock in Inner Mongolia, China. AB - Herders in Inner Mongolia experienced two completely different political periods during their last nomadic period between 1961 and 1986. However, climate and technical factors were very similar between these two periods according to statistical analyses. We retrieved historical climate and livestock population data and performed a retrospective study using generalized additive models to analyze three major livestock population demographic metrics changes between these two periods. We found that the sociopolitical factors significantly impacted all three major demographic metrics (adult mortality, neonatal mortality and birthrate) between the two periods for both large (cattle, horse, and camel) and small livestock (sheep and goat). We also identified the interaction effects between sociopolitical factor and climate factors for adult and neonatal mortality, while birthrate was not affected by these interactions. When exposed to climate hazards, adult and neonatal livestock mortality rates were significantly higher, while birthrate was significantly lower in social movement period than in peaceful period. We concluded that political movements had indeed increased the vulnerability of herders' livestock to climate hazards. External political pressures deprived hazard-resistance entitlements of herders, which may explain the elevated effects of political pressures on livestock vulnerability. PMID- 28811659 TI - Identification, synthesis and biological activity of alkyl-guanidine oligomers as potent antibacterial agents. AB - In the last two decades, the repertoire of clinically effective antibacterials is shrinking due to the rapidly increasing of multi-drug-resistant pathogenic bacteria. New chemical classes with innovative mode of action are required to prevent a return to the pre-antibiotic era. We have recently reported the identification of a series of linear guanidine derivatives and their antibacterial properties. A batch of a promising candidate for optimization studies (compound 1) turned out to be a mixture containing two unknown species with a better biological activity than the pure compound. This serendipitous discovery led us to investigate the chemical nature of the unknown components of the mixture. Through MS analysis coupled with design and synthesis we found that the components were spontaneously generated oligomers of the original compound. Preliminary biological evaluations eventually confirmed the broad-spectrum antibacterial activity of this new family of molecules. Interestingly the symmetric dimeric derivative (2) exhibited the best profile and it was selected as lead compound for further studies. PMID- 28811660 TI - Transcription factor ZNF148 is a negative regulator of human muscle differentiation. AB - Muscle differentiation is a complex process in which muscle progenitor cells undergo determination and eventually cellular fusion. This process is heavily regulated by such master transcription factors as MYOD and members of the MEF2 family. Here, we show that the transcription factor ZNF148 plays a direct role in human muscle cell differentiation. Downregulation of ZNF148 drives the formation of a muscle phenotype with rapid expression of myosin heavy chain, even in proliferative conditions. This phenotype was most likely mediated by the robust and swift upregulation of MYOD and MEF2C. PMID- 28811662 TI - Fractal properties of shoreline changes on a storm-exposed island. AB - Extreme storm events and their consequent shoreline changes are of great importance for understanding coastal evolution and assessing storm hazards. This work investigates the fractal properties of the spatial distributions of shoreline changes caused by storms. Wavelet analysis and upper-truncated power law (UTPL) fitting are used to study the power spectra of shoreline changes and to evaluate the upper limits of the cross-shore erosion and accretion. During a period affected by storms, the alongshore shoreline change patterns are strong on the 15 km scale but are weak with lower spectral power on the 20 km scale. The areas adjacent to the eroded shoreline are usually accrete, and the cross-shore extent of erosion is larger than that of accretion when the coast is affected by storms. The fractal properties of shoreline changes due to storms are found to be temporally continuous: the effects of later storms build on the preceding shoreline conditions, including both the effects of previous storms and the subsequent shoreline recoveries. This work provides a new perspective on the various scales of the spatial variations of the morphodynamics of storm-affected shorelines. PMID- 28811661 TI - Myst2/Kat7 histone acetyltransferase interaction proteomics reveals tumour suppressor Niam as a novel binding partner in embryonic stem cells. AB - MYST histone acetyltransferases have crucial functions in transcription, replication and DNA repair and are hence implicated in development and cancer. Here we characterise Myst2/Kat7/Hbo1 protein interactions in mouse embryonic stem cells by affinity purification coupled to mass spectrometry. This study confirms that in embryonic stem cells Myst2 is part of H3 and H4 histone acetylation complexes similar to those described in somatic cells. We identify a novel Myst2 associated protein, the tumour suppressor protein Niam (Nuclear Interactor of ARF and Mdm2). Human NIAM is involved in chromosome segregation, p53 regulation and cell proliferation in somatic cells, but its role in embryonic stem cells is unknown. We describe the first Niam embryonic stem cell interactome, which includes proteins with roles in DNA replication and repair, transcription, splicing and ribosome biogenesis. Many of Myst2 and Niam binding partners are required for correct embryonic development, implicating Myst2 and Niam in the cooperative regulation of this process and suggesting a novel role for Niam in embryonic biology. The data provides a useful resource for exploring Myst2 and Niam essential cellular functions and should contribute to deeper understanding of organism early development and survival as well as cancer. Data are available via ProteomeXchange with identifier PXD005987. PMID- 28811663 TI - Monitoring molecular response in adult T-cell leukemia by high-throughput sequencing analysis of HTLV-1 clonality. PMID- 28811664 TI - Structure-based cross-docking analysis of antibody-antigen interactions. AB - Antibody-antigen interactions are critical to our immune response, and understanding the structure-based biophysical determinants for their binding specificity and affinity is of fundamental importance. We present a computational structure-based cross-docking study to test the identification of native antibody antigen interaction pairs among cognate and non-cognate complexes. We picked a dataset of 17 antibody-antigen complexes of which 11 have both bound and unbound structures available, and we generated a representative ensemble of cognate and non-cognate complexes. Using the Rosetta interface score as a classifier, the cognate pair was the top-ranked model in 80% (14/17) of the antigen targets using bound monomer structures in docking, 35% (6/17) when using unbound, and 12% (2/17) when using the homology-modeled backbones to generate the complexes. Increasing rigid-body diversity of the models using RosettaDock's local dock routine lowers the discrimination accuracy with the cognate antibody-antigen pair ranking in bound and unbound models but recovers additional top-ranked cognate complexes when using homology models. The study is the first structure-based cross-docking attempt aimed at distinguishing antibody-antigen binders from non binders and demonstrates the challenges to address for the methods to be widely applicable to supplement high-throughput experimental antibody sequencing workflows. PMID- 28811665 TI - Optimization of Storage Temperature for Retention of Undifferentiated Cell Character of Cultured Human Epidermal Cell Sheets. AB - Cultured epidermal cell sheets (CES) containing undifferentiated cells are useful for treating skin burns and have potential for regenerative treatment of other types of epithelial injuries. The undifferentiated phenotype is therefore important for success in both applications. This study aimed to optimize a method for one-week storage of CES for their widespread distribution and use in regenerative medicine. The effect of storage temperatures 4 degrees C, 8 degrees C, 12 degrees C, 16 degrees C, and 24 degrees C on CES was evaluated. Analyses included assessment of viability, mitochondrial reactive oxygen species (ROS), membrane damage, mitochondrial DNA (mtDNA) integrity, morphology, phenotype and cytokine secretion into storage buffer. Lowest cell viability was seen at 4 degrees C. Compared to non-stored cells, ABCG2 expression increased between temperatures 8-16 degrees C. At 24 degrees C, reduced ABCG2 expression coincided with increased mitochondrial ROS, as well as increased differentiation, cell death and mtDNA damage. P63, C/EBPdelta, CK10 and involucrin fluorescence combined with morphology observations supported retention of undifferentiated cell phenotype at 12 degrees C, transition to differentiation at 16 degrees C, and increased differentiation at 24 degrees C. Several cytokines relevant to healing were upregulated during storage. Importantly, cells stored at 12 degrees C showed similar viability and undifferentiated phenotype as the non-stored control suggesting that this temperature may be ideal for storage of CES. PMID- 28811667 TI - Genome editing: CRISPR-Cas becoming more human. PMID- 28811668 TI - Cancer biology: The skin's power of elimination. PMID- 28811666 TI - The essential kinase ATR: ensuring faithful duplication of a challenging genome. AB - One way to preserve a rare book is to lock it away from all potential sources of damage. Of course, an inaccessible book is also of little use, and the paper and ink will continue to degrade with age in any case. Like a book, the information stored in our DNA needs to be read, but it is also subject to continuous assault and therefore needs to be protected. In this Review, we examine how the replication stress response that is controlled by the kinase ataxia telangiectasia and Rad3-related (ATR) senses and resolves threats to DNA integrity so that the DNA remains available to read in all of our cells. We discuss the multiple data that have revealed an elegant yet increasingly complex mechanism of ATR activation. This involves a core set of components that recruit ATR to stressed replication forks, stimulate kinase activity and amplify ATR signalling. We focus on the activities of ATR in the control of cell cycle checkpoints, origin firing and replication fork stability, and on how proper regulation of these processes is crucial to ensure faithful duplication of a challenging genome. PMID- 28811669 TI - Paraventricular Thalamic Control of Food Intake and Reward: Role of Glucagon-Like Peptide-1 Receptor Signaling. AB - Paraventricular thalamic nucleus (PVT) neurons receive hindbrain and hypothalamic inputs, and project to forebrain sites involved in reward and motivation function. The role of PVT in energy balance and reward control is however understudied. Given that PVT neurons express glucagon-like peptide-1 receptors (GLP-1R), which are critical to feeding and body weight control, we tested the hypothesis that PVT GLP-1R signaling contributes to food intake and reward inhibition. To assess the hypothesis, behavioral tests including chow and high fat diet intake, meal patterns, conditioned place preference for high-fat food, cue-induced reinstatement of sucrose-seeking, and motivation to work for sucrose were employed following intra-PVT delivery of either GLP-1R agonist, exendin-4 (Ex4), or GLP-1R antagonist, exendin-9-39 (Ex9). Anatomical and electrophysiological experiments were conducted to examine the neural connections and cellular mechanisms of GLP-1R signaling on PVT-to-nucleus accumbens (NAc) projecting neurons. PVT GLP-1R agonism reduced food intake, food-motivation, and food-seeking, while blocking endogenous PVT GLP-1R signaling increased meal size and food intake. PVT neurons receive GLP-1 innervation from nucleus tractus solitarius preproglucagon neurons that were activated by food intake; these GLP-1 fibers formed close appositions to putative GLP-1R-expressing PVT cells that project to the NAc. Electrophysiological recordings of PVT-to-NAc neurons revealed that GLP-1R activation reduced their excitability, mediated in part via suppression of excitatory synaptic drive. Collectively, these behavioral, electrophysiological and anatomical data illuminate a novel function for PVT GLP 1R signaling in food intake control and suggest a role for the PVT-to-NAc pathway in mediating the effects of PVT GLP-1R activation. PMID- 28811671 TI - Microsatellite evidence of dispersal mechanism of red swamp crayfish (Procambarus clarkii) in the Pearl River basin and implications for its management. AB - Discerning the dispersal patterns of invasive species is critically important for the design of effective management strategies and the development of appropriate theoretical models predicting the spatial expansion of introduced populations. Post-introduction dispersal may occur naturally or via human transport, but for many organisms, assessing the relative contribution of each of these factors is difficult using traditional methods. Here, we explored the genetic patterns associated with the spread of red swamp crayfish (Procambarus clarkii) among 21 populations in the Pearl River basin and 2 peripheral populations in the Yangtze River basin. We found the genetic diversity of P. clarkii in the Pearl River basin was somewhat lower than in the Yangtze River basin. We also found (1) there was significant genetic differentiation between populations, (2) genetic differentiation was not related to geographic distance (i.e., isolation by distance), and (3) a Bayesian assignment analysis revealed three distinct genetic clusters and genetic admixture. Our results therefore provide evidence that human mediated multiple introductions occurred in the Pearl River basin. Anthropogenic activities such as commercial transportation were likely responsible for the long distance dispersal of P. clarkii. This study provides useful information for developing management strategies. PMID- 28811672 TI - An Evaluation of the in vivo Safety of Nonporous Silica Nanoparticles: Ocular Topical Administration versus Oral Administration. AB - Nonporous silica nanoparticles (SiNPs) have potential as promising carriers for ophthalmic drugs. However, the in vivo safety of ocular topical SiNPs remains unclear. This study investigated the in vivo safety of oral and ocular topical applications of 100 nm-sized SiNPs in Sprague-Dawley rats. The rats were divided into the following four groups: low-dose oral administration (total 100 mg/kg of SiNPs mixed with food for one week), high-dose oral administration (total 1000 mg/kg of SiNPs mixed with food for one week), ocular topical administration (10 mg/ml concentration, one drop, applied to the right eyes four times a day for one month), or a negative control (no SiNP treatment). The rats were observed for 12 weeks to investigate any signs of general or ocular toxicity. During the observation period, no differences were observed in the body weights, food and water intakes, behaviors and abnormal symptoms of the four groups. No animal deaths occurred. After 12 weeks, hematologic, blood biochemical parameters and ophthalmic examinations revealed no abnormal findings in any of the animals. The lack of toxicity of the SiNPs was further verified in autopsy findings of brain, liver, lung, spleen, heart, kidneys, intestine, eyeballs, and ovaries or testes. PMID- 28811673 TI - Improving a genetically encoded voltage indicator by modifying the cytoplasmic charge composition. AB - An improved genetically encoded voltage indicator (GEVI) was achieved by altering the charge composition of the region linking the voltage-sensing domain of the GEVI to a pH-sensitive fluorescent protein. Negatively charged linker segments reduced the voltage-dependent optical signal while positively charged linkers increased the signal size. Arginine scanning mutagenesis of the linker region improved the signal size of the GEVI, Bongwoori, yielding fluorescent signals as high as 20% DeltaF/F during the firing of action potentials. The speed of this new sensor was also capable of optically resolving action potentials firing at 65 Hz. This large signal size enabled individual pixels to become surrogate electrodes. Plotting the highest correlated pixels based only on fluorescence changes reproduced the image of the neuron exhibiting activity. Furthermore, the use of a pH-sensitive fluorescent protein facilitated the detection of the acidification of the neuron during the firing of action potentials. PMID- 28811670 TI - Sex-Dependent Effects of Cannabis and Cannabinoids: A Translational Perspective. AB - Recent policy changes have led to significant increases in the use of cannabis for both medical and recreational purposes. Although men are more likely to endorse past month cannabis use and are more frequently diagnosed with Cannabis Use Disorder relative to women, a growing proportion of medical cannabis users are reported to be women. The increased popularity of cannabis for medical purposes and the narrowing gap in prevalence of use between men and women raises questions regarding sex-dependent effects related to therapeutic efficacy and negative health effects of cannabis and cannabinoids. The objective of this review is to provide a translational perspective on the sex-dependent effects of cannabis and cannabinoids by synthesizing findings from preclinical and clinical studies focused on sex comparisons of their therapeutic potential and abuse liability, two specific areas that are of significant public health relevance. Hormonal and pharmacological mechanisms that may underlie sex differences in the effects of cannabis and cannabinoids are highlighted. PMID- 28811675 TI - Biomarkers: Matching mutations to immunotherapy response. PMID- 28811676 TI - SCALING UP NON-COMMUNICABLE DISEASE CONTROL: LESSONS TO BE LEARNT FROM THE INFECTIOUS DISEASE PARADIGM IN KENYA. AB - Non-communicable diseases (NCD) are emerging as the leading cause of morbidity & mortality globally, with the greatest rise in incidence of cardiovascular disease cases observed in Sub-Saharan Africa. This is in addition to the heavy burden of infectious diseases already present in this setting. Describing the cross-cutting epidemiology of NCDs and infectious diseases with focus on the interaction between tuberculosis and diabetes mellitus, HIV and cardiovascular disease, HIV and cervical cancer as well as assessing the disparities in funding and service delivery systems between NCDs and infectious diseases; we review this rising double burden of infectious and non-infectious diseases and propose four lessons that can be learnt from the HIV response and adapted to inform the scale up of NCD control in Kenya which are also applicable in other African countries. PMID- 28811674 TI - Regenerative medicine and cell-based approaches to restore pancreatic function. AB - The pancreas is a complex organ with exocrine and endocrine components. Many pathologies impair exocrine function, including chronic pancreatitis, cystic fibrosis and pancreatic ductal adenocarcinoma. Conversely, when the endocrine pancreas fails to secrete sufficient insulin, patients develop diabetes mellitus. Pathology in either the endocrine or exocrine pancreas results in devastating economic and personal consequences. The current standard therapy for treating patients with type 1 diabetes mellitus is daily exogenous insulin injections, but cell sources of insulin provide superior glycaemic regulation and research is now focused on the goal of regenerating or replacing beta cells. Stem-cell-based models might be useful to study exocrine pancreatic disorders, and mesenchymal stem cells or secreted factors might delay disease progression. Although the standards that bioengineered cells must meet before being considered as a viable therapy are not yet established, any potential therapy must be acceptably safe and functionally superior to current therapies. Here, we describe progress and challenges in cell-based methods to restore pancreatic function, with a focus on optimizing the site for cell delivery and decreasing requirements for immunosuppression through encapsulation. We also discuss the tools and strategies being used to generate exocrine pancreas and insulin-producing beta-cell surrogates in situ and highlight obstacles to clinical application. PMID- 28811677 TI - The Relationship between VEGFA and TGFB1 Polymorphisms and Target Lesion Revascularization after Elective Percutaneous Coronary Intervention. AB - BACKGROUND AND AIM: The specific association between genetic variation and in stent restenosis is still only partly understood. The aim of this study is to analyze the relationship between functional polymorphisms in the genes encoding vascular endothelial growth factor A (VEGF-A; rs699947) and transforming growth factor beta 1 (TGF-beta1; rs1800470) and target lesion revascularization (TLR) risk. METHODS: A total of 676 patients (805 lesions) with stable coronary artery disease (SCAD) who received elective percutaneous coronary intervention (PCI) with at least one bare-metal stent implantation were included. The primary study endpoint was TLR at a 4-year follow-up. RESULTS: The TLR rate was higher in patients with the VEGFA A/A genotype (15.4%) than in patients with the VEGFA A/C (7.9%) and C/C (8.9%) genotypes (p = 0.009). The VEGFA A/A genotype, after adjustment for clinical and procedural covariates, remained significantly and independently associated with the TLR (hazard ratio-2.09 [95% confidence interval 1.32-3.33, p = 0.0017]). However, we found no association between TLR and the TGFB1 genotype. CONCLUSION: The VEGFA A/A genotype is significantly and independently associated with TLR risk in Polish SCAD patients who received elective PCI with bare-metal stent implantation. PMID- 28811678 TI - Patchoulene Epoxide Isolated from Patchouli Oil Suppresses Acute Inflammation through Inhibition of NF-kappaB and Downregulation of COX-2/iNOS. AB - According to the GC-MS analysis, compositional variation was observed between samples of patchouli oil, of which an unknown compound identified as patchoulene epoxide (PAO) was found only in the long-stored oil, whose biological activity still remains unknown. Therefore, the present study aimed to evaluate the potential anti-inflammatory activity with three in vivo inflammatory models: xylene-induced ear edema, acetic acid-induced vascular permeability, and carrageenan-induced paw edema. Further investigation into its underlying mechanism on carrageenan-induced paw edema was conducted. Results demonstrated that PAO significantly inhibited the ear edema induced by xylene, lowered vascular permeability induced by acetic acid and decreased the paw edema induced by carrageenan. Moreover, PAO markedly decreased levels of tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), prostaglandin E2 (PGE2), and nitric oxide (NO), but increased levels of interleukin-4 (IL-4) and interleukin-10 (IL-10). PAO was also shown to significantly downregulate the protein and mRNA expressions of cyclooxygenase-2 (COX-2) and inducible nitric-oxide synthase (iNOS). Western blot analysis revealed that PAO remarkably inhibited p50 and p65 translocation from the cytosol to the nucleus by suppressing IKKbeta and IkappaBalpha phosphorylation. In conclusion, PAO exhibited potent anti-inflammatory activity probably by suppressing the activation of iNOS, COX-2 and NF-kappaB signaling pathways. PMID- 28811679 TI - Bisphenol A Does Not Mimic Estrogen in the Promotion of the In Vitro Response of Murine Dendritic Cells to Toll-Like Receptor Ligands. AB - Sex hormones affect immune responses and might promote autoimmunity. Endocrine disrupting chemicals such as bisphenol A (BPA) may mimic their immune effects. Conventional dendritic cells (cDCs) are pivotal initiators of immune responses upon activation by danger signals coming from pathogens or distressed tissues through triggering of the Toll-like receptors (TLRs). We generated in vitro murine cDCs in the absence of estrogens and measured the effects of exogenously added estrogen or BPA on their differentiation and activation by the TLR ligands LPS and CpG. Estrogen enhanced the differentiation of GM-CSF-dependent cDCs from bone marrow precursors in vitro, and the selective estrogen receptor modulators (SERMs) tamoxifen and fulvestrant blocked these effects. Moreover, estrogen augmented the upregulation of costimulatory molecules and proinflammatory cytokines (IL-12p70 and TNFalpha) upon stimulation by TLR9 ligand CpG, while the response to LPS was less estrogen-dependent. These effects are partially explained by an estrogen-dependent regulation of TLR9 expression. BPA did not promote cDC differentiation nor activation upon TLR stimulation. Our results suggest that estrogen promotes immune responses by increasing DC activation, with a preferential effect on TLR9 over TLR4 stimulation, and highlight the influence of estrogens in DC cultures, while BPA does not mimic estrogen in the DC functions that we tested. PMID- 28811680 TI - The Antimicrobial Peptide Human Beta-Defensin-3 Is Induced by Platelet-Released Growth Factors in Primary Keratinocytes. AB - Platelet-released growth factors (PRGF) and its related clinically used formulations (e.g., Vivostat Platelet-Rich Fibrin (PRF(r))) contain a variety of chemokines, cytokines, and growth factors and are therefore used to support healing of chronic, hard-to-heal, or infected wounds. Human beta-defensin-3 (hBD 3) is an antimicrobial peptide inducibly expressed in human keratinocytes especially upon wounding. The potent antimicrobial activity of hBD-3 together with its wound closure-promoting activities suggests that hBD-3 may play a crucial role in wound healing. Therefore, we analyzed the influence of PRGF on hBD-3 expression in human primary keratinocytes in vitro. In addition, we investigated the influence of Vivostat PRF on hBD-3 expression in artificially generated human skin wounds in vivo. PRGF treatment of primary keratinocytes induced a significant, concentration- and time-dependent increase in hBD-3 gene expression which was partially mediated by the epidermal growth factor receptor (EGFR). In line with these cell culture data, in vivo experiments revealed an enhanced hBD-3 expression in experimentally produced human wounds after the treatment with Vivostat PRF. Thus, the induction of hBD-3 may contribute to the beneficial effects of thrombocyte concentrate lysates in the treatment of chronic or infected wounds. PMID- 28811682 TI - Cell Free Fetal DNA: Marker for Predicting Pregnancy Outcomes. PMID- 28811681 TI - Osteopontin Impacts West Nile virus Pathogenesis and Resistance by Regulating Inflammasome Components and Cell Death in the Central Nervous System at Early Time Points. AB - Osteopontin (OPN) is a molecule that is common in central nervous system (CNS) pathologies, which participates in the activation, migration, and survival of inflammatory cells. However, the mechanisms by which OPN modulates inflammatory pathways are not clear. To understand the role of OPN in CNS viral infections, we used a lethal mouse model of West Nile virus (WNV), characterized by the injection of high doses of the Eg101 strain of WNV, causing the increase of OPN levels in the brain since early time points. To measure the impact of OPN in neuropathogenesis and resistance, we compared C57BI/6 WT with mice lacking the OPN gene (OPN KO). OPN KO presented a significantly higher mortality compared to WT mice, detectable since day 5 pi. Our data suggests that OPN expression at early time points may provide protection against viral spread in the CNS by negatively controlling the type I IFN-sensitive, caspase 1-dependent inflammasome, while promoting an alternative caspase 8-associated pathway, to control the apoptosis of infected cells during WNV infection in the CNS. Overall, we conclude that the expression of OPN maintains a critical threshold in the innate immune response that controls apoptosis and lethal viral spread in early CNS infection. PMID- 28811683 TI - Methylenetetrahydrofolate Reductase C677T Polymorphism and Risk for Male Infertility in Asian Population. AB - Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme of folate pathway and required for DNA synthesis and methylation. MTHFE C677T polymorphisms is reported as risk factors for various diseases and disorders like birth defects, metabolic, neurological, psychiatric disorders, and cancers. Several studies have investigated association between the MTHFR C677T polymorphism and male infertility. To assess the risk associated with MTHFR C677T polymorphism in Asian population, a meta-analysis was performed. Included articles were collected from the following electronic databases: PubMed, Google Scholar, and Science direct up to March 2015. Risk was estimated as pooled odds ratios (ORs) with confidence intervals (CIs) for assessment. Seventeen case-control studies involving 4392 breast infertile males and 3667 fertile males were found suitable for the inclusion in the present meta-analysis. Results showed that the C677T polymorphism was significantly associated with male infertility in Asian population using all the five genetic models (ORT vs. C (allele contrast model) = 1.86, 95% CI 1.7-2.0; ORTT vs. CC (homozygote model) = 1.96, 95% CI 1.67-2.30; ORCT vs. CC (co-dominant model) = 1.40, 95% CI 1.18-1.62; ORTT+CT vs. CC (dominant model) = 1.53, 95% CI 1.30-1.77; ORTT vs. CT+CC (recessive model) = 1.67, 95% CI 1.44-1.92). In conclusion, results of present meta-analysis strongly supported an association between C677T polymorphism and male infertility in Asians. PMID- 28811684 TI - Lead as a Risk Factor for Osteoporosis in Post-menopausal Women. AB - Lead exposure is increasingly becoming an important risk factor for osteoporosis. In adults, approximately 80-90 % of absorbed lead is stored in the bones. These bone lead deposits are released into the blood during periods of enhanced bone resorption like menopause, forming a potential endogenous source of lead exposure. Postmenopausal women are at a higher risk for bone lead release because of hormonal and age related changes in bone metabolism. Estrogen deficiency is associated with increase in osteoclasts number and activity leading to both the early and late form of osteoporosis. Hence, high blood lead level coupled with concomitant environmental exposure exposes women in this age group to lead related adverse outcomes like hypertension, reduced kidney and neurocognitive functions as well as increased risk of atherosclerosis and cardiovascular mortality. A few studies have also identified coexisting variates like ethnicity, occupation, residence, education, smoking, alcohol medications, water etc. as significant determinants of bone and blood lead in women, thus increasing the magnitude of postmenopausal bone changes. Hence, interventions focused on reducing the intensity of bone resorption during menopause will help decrease exposure to endogenous lead. This would play a significant role in decreasing the morbidity and mortality associated with menopause. Also, identification of modifiable factors that prevent bone lead release will reduce the risk of chronic lead exposure and improve the health outcomes of post-menopausal women. PMID- 28811685 TI - Mutation Analyses in Selected Exons of the MUT Gene in Indian Patients with Methylmalonic Acidemia. AB - Deficiency or diminished activity of a cobalamin dependent enzyme methylmalonyl CoA mutase causes inborn error of metabolism called methylmalonic acidemia (MMA). In this study we elucidated the spectrum of mutations in 21 Indian mut MMA patients by direct sequencing. Sequence analysis identified a total of 70 mutations in exon 2, 9, 11 and 12 of MUT gene. Out of which 26 mutations were predicted to be deleterious and rest were benign. The 23 novel mutations consist of four nonsense mutations (p.N6*, p.G539*, p.E609* and p.I671*), twelve missense mutations (p.K128I, p.N547T, p.D554Y, p.A558T, p.R559P, p.A631T, p.I647T, p.E656D, p.V657E, p.Q660H, p.K679N, and p.G696Y) and seven frame shift mutations (c.375_376insA, c.1642delA, c.1655delC, c.1825_1826insT, c.1957delGA, c.2014delA and c.2062_2063insGA). All of them are point mutations or micro rearrangements. Three of these mutations (p.K621N, p.G648D, p.G630E) have been previously reported; all of them are missense mutations. The mutations are distributed throughout the exon 2, 9, 11 and 12, 38.4 % mutation are located in exon 12. PMID- 28811686 TI - Influence of the Flavonoid, Quercetin on Antioxidant Status, Lipid Peroxidation and Histopathological Changes in Hyperammonemic Rats. AB - We have studied the ability of quercetin (a bioflavonoid) in tackling oxidative stress to alleviate the symptoms during ammonium chloride-induced hyperammonemia. Hyperammonemia was induced by the treatment of ammonium chloride (AC) 100 mg/kg b.w for 56 days. Hyperammonemic rats exhibited reduced urea (in plasma) and increased ammonia (in blood), uric acid (in plasma), creatinine (in serum), oxidative stress markers (thiobarbituric acid reactive substances (TBARS) and hydroperoxides (HP) and decreased levels of antioxidants (enzymatic and non enzymatic) superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH) in plasma and tissues (liver and brain) vitamins E and C (in plasma)). The expression of liver inflammatory markers such as, interleukin 6 (IL-6), inducible nitric oxide synthase (iNOS) and nuclear transcription factor-kappaB (NF-kappaB) (by western blotting) were investigated. Histological damages (in liver, brain and kidney) were observed under hyperammonemia and the administration of quercetin (1) normalized the histopathological alterations, (2) reduced the levels of TBARS and HP, (3) elevated the antioxidants (SOD, CAT, GPx, GSH, vitamins E and C), (4) declined the activities of liver marker enzymes (AST, ALT and ALP) and (5) down regulated the expression of IL-6, iNOS and NF-kappaB. Our results suggest that quercetin might exert defense to AC-induced hyperammonemic rats to tackle (1) oxidative stress and (2) inflammation owing to its antioxidant, anti-inflammatory and cytoprotective effects. PMID- 28811687 TI - A Preliminary Study on Investigation of Serum alpha-Synuclein and Tau Protein Levels in Children with Attention Deficit Hyperactivity Disorder. AB - Neurodegenerative molecules play an important role in maintaining a supply for synaptic vesicles; and they are also likely to help regulate the dopamine release which is the primary mechanism of action in pharmacological treatments for attention deficit hyperactivity disorder (ADHD). It is suggested that there could be interactions between alpha-synuclein and tau in cytoskeletal disorganization and synaptic dystrophy. Therefore, we aim to determine the serum levels of neurodegenerative molecules such as alpha-synuclein and tau in children with ADHD. The study group consisted of 25 children, aged 6-10, diagnosed with ADHD according to DSM-IV criteria and who appeared at Dicle University, Faculty of Medicine, and Department of Child Psychiatry in Diyarbakir, Turkey. 25 children, having no psychiatric disorders and medical illnesses, were selected as healthy control group. Serum alpha-synuclein and tau concentrations were determined by Enzyme-Linked Immuno Sorbent Assay. The alpha-synuclein levels of ADHD were not significantly different than those of controls. The tau levels of ADHD were found to be statistically significantly higher than those of controls. Moreover, alpha synuclein levels showed a statistically significantly positive correlation with tau levels in children with ADHD. The results of our preliminary study can suggest that ADHD might possibly share a common disease mechanism with other diseases in terms of tau pathology. Increased serum tau level may be an indication of disturbance of microtubule transportation in the brains of children with ADHD. PMID- 28811688 TI - Genetic Variation in CD166 Gene and Its Association with Bladder Cancer Risk in North Indian Population. AB - Adhesion molecules play a key role in cancer progression and tumorigenesis. Genetic polymorphism of adhesion molecules may alter the normal functioning thereby leading to bladder cancer susceptibility. Hence we aimed to evaluate three SNPs of CD166 gene (CD166rs6437585 C/T, CD166rs10511244 C/T, and CD166rs1157 A/G) in bladder cancer patients and normal controls of North Indian population. A total of 270 healthy controls and 240 confirmed bladder cancer patients were recruited for this study. Three SNPs of CD166 gene viz. CD166rs6437585 C/T, CD166rs10511244 C/T, and CD166rs1157 A/G were selected for this study. CD166rs6437585 C/T and CD166rs10511244 C/T were genotyped by Taqman allelic discrimination assay and CD166rs1157 A/G was genotyped by PCR-RFLP. The statistical analysis was done using the SPSS software, version 16.0 (SPSS, Chicago, IL), and p < 0.05 was considered statistically significant. Haplotypic analysis was done by using SNP analyzer version 1.2A. CD166rs6437585 C/T and CD166rs10511244 C/T showed significant association with reduced risk in bladder cancer while CD166rs1157 A/G showed significant high risk along with association at genotypic and allelic levels. Haplotypic analysis showed 1.8-folds risk in CCG combination, whereas CTA and TCG showed significant association with reduced risk. Further stratification on the basis of smoking, tumor grade/stage and BGC therapy revealed no association of these three polymorphic sites of CD166. Our study suggests that CD166rs6437585 C/T and CD166rs10511244 C/T are predictive for the reduced risk of bladder cancer, whereas CD166rs1157 A/G had shown significant association with high risk of bladder cancer in North Indians. This somehow suggests that CD166rs1157 A/G can be used as a marker for risk prediction of bladder cancer. PMID- 28811689 TI - Expression of Telomere Binding Proteins (RAP1 and POT1) in Renal Cell Carcinoma and Their Correlation with Clinicopathological Parameters. AB - Telomere stability is indispensable for continuous proliferation of cells. Telomere structure is maintained by group of six proteins termed as shelterin. RAP1 and POT1 proteins are significant members of shelterin complex. Expression of RAP1 and POT1 are crucial for telomere maintenance and hence uncontrolled division of cells. Notably, expression of RAP1 and POT1 is unknown in renal cell carcinoma (RCC). In view of these facts, the present study was initiated to investigate the expression of RAP1 and POT1 in RCC and their relationships with clinicopathological features. In total 65 histopathologically confirmed RCC cases and their adjacent normal renal parenchyma were analyzed for gene expression. The mRNA expression of telomere binding proteins RAP1 and POT1 were measured using RT PCR. Expression of RAP1 was observed to be significantly increased in tumour tissues as compared to corresponding normal renal tissues (P = 0.004). The gene expression of RAP1 was documented to be related to grades of RCC (P = 0.002) and subtypes of RCC (P = 0.01). Although, POT1 expression was up-regulated in RCC tissue, however it was not statistically significant. Also, POT1 expression was not related to grades, stages and subtypes of RCC. This is the first study which shows correlation RAP1 with grades and subtypes of RCC. PMID- 28811690 TI - Biochemical Profile of Nonalcoholic Fatty Liver Disease Patients in Eastern India with Histopathological Correlation. AB - Aminotransferase assay is often used as a screening test as well as an endpoint for resolution of disease in nonalcoholic fatty liver disease (NAFLD). Aim of the study was to evaluate the relationship of transaminase level with metabolic variables and histology in NAFLD. Single center observational study was conducted in a gastroenterology clinic at Cuttack in coastal Odisha. Subjects were consecutive patients presenting with functional bowel disease and undergoing abdominal sonography. All participants were evaluated for the presence of metabolic syndrome (MS), insulin resistance, liver function test and lipid profile. Various parameters were compared between NAFLD subjects and controls. 53.5 % of NAFLD had normal serum transaminases, whereas 20.8 % of healthy controls had transaminitis. NAFLD patients had significantly higher BMI, fasting plasma glucose, serum transaminases, serum triglycerides, serum insulin and homeostatic model assessment (HOMA) IR than controls. NAFLD patients who had transaminitis had significantly higher incidence of MS and higher mean HOMA IR than those without. There was no significant difference in histopathological features between NAFLD with and without transaminitis. To conclude, over half of NAFLD subjects do not have transaminitis while transaminitis is present in a fifth of healthy people without fatty liver. Hence serum transaminase should not be used as screening test for NAFLD. NAFLD patients with transaminitis had a higher incidence of MS and insulin resistance than those without. However, there was no significant difference in histopathological features between these two groups. PMID- 28811691 TI - Association of Prooxidant-Antioxidant Balance with Clinical and Laboratory Parameters and Its Relation to Different Drug Regimens in Polycystic Ovary Syndrome Women with Normal BMI. AB - Polycystic ovarian syndrome is one of the most common hormonally leading cause infertility disorders. The effect of oxidant-antioxidant imbalance on disease progression has been studied in many disorders. The present study was aimed to evaluate prooxidant-antioxidant balance (PAB) in patients with polycystic ovarian syndrome compared to healthy subjects. We also studied the possible effect of treatment with available drugs on serum PAB. In this case-control study 100 polycystic ovary syndrome (PCOS) patients and 100 healthy individuals were enrolled in the study. The laboratory features of patients and controls like as serum LH and FSH concentration and hematological examinations were collected. PAB was evaluated by a colorimetric method. Serum PAB value was significantly higher before treatment compared to after treatment and healthy subjects. PAB values were also higher in subjects with irregular menstrual cycle compared to normal subjects. Our results represented that serum PAB values has an indirect significant correlation with serum LH concentration. We also found that drugs regimen containing spironolactone effectively reduced the serum PAB values. Our results showed that PCOS patients had increased level of PAB and treatment with spironolactone mainly decreases the level of serum PAB. Our results indicate that the measurements of PAB may be used as a potential laboratory marker for assessment of PCOS patients. PMID- 28811692 TI - Experimental Validation of Antidiabetic and Antioxidant Potential of Cassia tora (L.): An Indigenous Medicinal Plant. AB - The present study was undertaken to evaluate antidiabetic and antioxidant activities of Cassia tora (C. tora) seeds extract against streptozotocin induced diabetes in experimental rats to scientifically validate its use against diabetes. Ethanolic extract of C. tora seeds extract and standard drug (glibenclamide) prepared in aqueous gum acacia (2 %, w/v) suspension and fed orally to streptozotocin induced male adult diabetic rats of Charles Foster strain for 15 days. Biochemical parameters in normal, diabetic control, standard (600 MUg/kg bw p.o.) and treated (500 mg/kg bw p.o.) animal groups were quantified and compared. Treatment of streptozotocin induced diabetic rats with ethanolic seeds extract caused significant (p < 0.001) reduction in blood glucose (270-220 mg/dl), total cholesterol (140-104 mg/dl), triglyceride (149-99 mg/dl), phospholipids (100-74 mg/dl), free fatty acid (2.39-2.00 MUmol/l), lipid peroxide (9-5.63 nmol MDA/dl) and significantly increased post heparin lipolytic activity (11-14 nmol FFA released/h/l plasma) (p < 0.001). Furthermore, the seeds extract (100-400 MUg) when tested for its antioxidant activity in vitro, showed significant (p < 0.001) inhibition in the generation of super oxide anions in enzymic system a (46-37, 33, 23, 21 nmol uric acid formed/min), in enzymic system b (113-91, 77, 60, 51 nmol formazon formed/min), non-enzymic system (324-230, 211, 161, 141 nmol uric acid formed/min) and hydroxyl radicals in enzymic system (544-501, 411, 319, 291 nmol 2,3-dihydroxybenzoate formed/h) and non-enzymic system (28-21, 17, 14, 12). The results of the present study demonstrated antidiabetic, antidyslipidemic and antioxidant activities of C. tora seeds which could help in prevention of diabeticdyslipidemia and related complications. PMID- 28811693 TI - Beneficial Effect of Aqueous Garlic Extract on Inflammation and Oxidative Stress Status in the Kidneys of Type 1 Diabetic Rats. AB - One of the most important complications of diabetes is nephropathy. This study investigates the effects of aqueous garlic extract on inflammation and oxidative stress status in the kidneys of diabetic rats. Male rats were divided into four groups- control rats, diabetic rats, garlic extract-treated diabetic rats, garlic extract-treated normal rats. The glucose, urea, uric acid, and creatinine levels were measured in sera using colorimetric methods. To determine the oxidative stress condition in the kidney tissues, total antioxidant capacity (TAC), malondialdehyde (MDA), and total oxidant status (TOS) were measured using colorimetric methods. Inflammation status was evaluated by the determination of tumor necrosis factor-alpha (TNF-alpha) gene and protein expression using qRT-PCR and ELISA respectively, while nitric oxide (NO) level in these tissues was measured using the Griess method. Histological examination of Kidneys was carried out by H&E staining. The levels of glucose, urea, and uric acid were found to increase in the serum of diabetic rats and decrease in that of diabetic rats after treatment with garlic. Measurement of MDA, TOS, and TAC revealed oxidative stress in diabetic rats, which improved after receiving the extract. The NO and TNF-alpha protein levels in diabetic rats were higher than those in control rats. After treatment with garlic, the levels of TNF-alpha protein and NO became close to the normal levels. Histological results confirmed certain other data as well. Garlic has antioxidant properties; therefore, it can reduce oxidative stress, which plays an important role in the development of diabetic nephropathy. Reduction in oxidative stress has beneficial effects on inflammation because it leads to a decrease in the level of TNF-alpha. PMID- 28811694 TI - Estimation of Upper Limit of Normal for Serum Alanine Transaminase in Healthy South Indian Population. AB - Alanine aminotransferase (ALT) is the most common and cost effective screening test for asymptomatic liver disease. There is paucity of data on normal ALT among healthy individuals in India. An observational cross sectional study was conducted from January to July 2013 to estimate the upper limit of normal for ALT in healthy south Indian population. Adults undergoing voluntary or pre-employment health screening were included. Those with current and past alcoholism or smoking, acute illness or hospitalization during preceding 12 months, non steroidal anti-inflammatory or over the counter medication use within a month, current or past intake of herbal medications, any chronic medical illness, abnormal body mass index (BMI), fatty liver in ultrasound, abnormality in haemoglobin, platelet count, blood sugar, creatinine, lipid profile and thyroid function test and positive serology (Hepatitis B, C or HIV) were excluded. A total of 2600 subjects were screened. 344 were included for analysis. Mean age was 35 years in men and 34.83 years in women, with a mean BMI of 22.2 kg/m2 in men and 21.8 kg/m2 in women. The mean ALT in men and women were 21.87 +/- 2.9 (97.5th percentile 28 U/L) and 19.35 +/- 3.3 (97.5th percentile 24 U/L) respectively. In conclusion, mean and upper limit of ALT (97.5th percentile) in south Indian men was 21.87 and 28 IU/L and women were 19.35 and 24 IU/L respectively. There is a need to re-consider ALT levels in our population for better detection of individuals at risk for liver disease. PMID- 28811695 TI - PAI-1 Study in Thalassemia Major Patients Receiving Multiple Blood Transfusion. AB - Thalassemia is a congenital hemolytic disease which is treated by repeated blood transfusion. Chronic iron overload is currently considered to be the primary cause of mortality in beta-thalassemia, mainly due to the induction of left-sided cardiac failure. Iron overload results from a number of mechanisms associated with the disease itself. In addition to chronic iron overload thalassemic patients are more prone for procoagulant status which in turn lead to clinical thrombotic events. The hypercoagulable state in thalassemia is due to multiple elements, a combination of which is often the drive behind a clinical thromboembolic events. PAI-1 study was done in thalassemia major patients receiving multiple blood transfusion as a marker for procoagulant status. Total of 30 thalassemic patients on repeated blood transfusion was included in the study and total of 30 healthy age and sex matched controls were included in the study. It was also found that there was significant differences between cases and controls. The mean level of PAI 1 in controls was 3047 +/- 414 pg/ml, the value in cases was 3683 +/- 358 pg/ml. The level was significantly increased (p < 0.05) in the cases compared to controls. PAI-1 levels were also compared with the total number of blood transfusion which correlates well. PMID- 28811696 TI - Relationship Between Fetal Loss and Serum Gonadal Hormones Level in Experimental Antiphospholipid Syndrome Mouse. AB - To investigate the effects of antiphospholipid antibodies on establishment of pregnancy and changes in hormones such as estradiol-17beta (E2) and progesterone (P) levels in circulation. Hence, mice were immunized with human beta2 Glycoprotein I (beta2GPI) and the effect of these antibodies on fetuses weight, placental obsrvation, Serum levels of P and E2 in pregnant mice, hematological were observed. Immunization of mice with human beta2-GPI resulted in elevated levels of antiphospholipid antibodies. The experimentally induced antiphospholipid syndrome mouse showed higher rate of fetal resorption, low number of viable fetuses, and "placental abnormalities". In these animals, serum E2 and P levels were reduced significantly. In addition, the blood cell variation among APS induced and control mice were determined. No significant variations were observed in number of Red Blood Cell count, White Blood Cell count and Hemoglobin content, while platelet number was significantly reduced as compared to control. These results clearly demonstrate that human beta2-GPI might be involved in causing gestational failure in APS by exerting their effect on serum hormones. PMID- 28811697 TI - Role of Iron and Copper in the Pathogenesis of Parkinson's Disease. AB - Parkinson's disease (PD) is an old age disorder of basal ganglia which involves oligomerization of alpha-synuclein protein and formation of intercellular inclusions known as "Lewy bodies" in substantia nigra and caudate nuclei in brain which is progressive in nature. It is second most prevalent neurodegenerative disorder characterized by tremor at rest, muscle rigidity, slowness of movement (bradykinesia, akinesia), and changes in posture (instability). Both excess and deficiency in levels of transition metals (especially iron, copper) can be detrimental to the central nervous system. Abnormalities in iron (Fe) and copper (Cu) metabolism have been reported to produce oxidative stress which is one of the major cause in pathogenesis of PD. In the present study 35 PD patients and 33 controls of Northern Indian population were included and serum levels of Fe, Cu and ceruloplasmin (Cp) were measured. Serum Fe (p < 0.01) and Cu (p < 0.01) levels were found to be significantly decreased in PD, whereas there was no significant change in Cp levels in PD patients as compared to controls. These results suggest the existence of a defect in iron which over the time, may hasten the entry of iron into the brain and decrease iron in the extracellular compartment in PD patients. PMID- 28811698 TI - Effect of Tulsi (Ocimum sanctum Linn.) Supplementation on Metabolic Parameters and Liver Enzymes in Young Overweight and Obese Subjects. AB - Ocimum sanctum Linn. (also known as Tulsi) is a sacred Indian plant, the beneficial role of which, in obesity and diabetes is described traditionally. This is a randomized, parallel group, open label pilot study to investigate the effect of O. sanctum on metabolic and biochemical parameters in thirty overweight/obese subjects, divided into two groups A and B. Group A (n = 16) received one 250 mg capsule of Tulsi (O. sanctum) extract twice daily in empty stomach for 8 weeks and group B (n = 14) received no intervention. Statistically significant improvements in the values of serum triglycerides (p = 0.019); low density lipoprotein (p = 0.001); high density lipoprotein (p = 0.001); very low density lipoprotein (p = 0.019); Body Mass Index, BMI (p = 0.005); plasma insulin (p = 0.021) and insulin resistance (p = 0.049) were observed after 8 weeks in the O. sanctum intervention group. The improvement in HDL-C in the intervention group when compared to the control group was also statistically significant (p = 0.037). There was no significant alteration of the liver enzymes SGOT and SGPT in both the intervention (p = 0.141; p = 0.074) and control arms (p = 0.102; p = 0.055) respectively. These observations clearly indicate the beneficial effects of O. sanctum on various biochemical parameters in young overweight/obese subjects. PMID- 28811699 TI - CYSTINURIA: Crystals that Make a Baby Cry. AB - Cystinuria is a common aminoaciduria due to a COAL transporter defect in renal tubular epithelium. Increased level of cystine in urine with occasional cystine crystal can be diagnostic. With reference to clinical examinations, symptoms and laboratory reports we present a case of primary cystinuria. Prevention of complication in cystinuric relies on detection at early stage and targeting treatment towards maintaining low level of urinary cystine level. PMID- 28811700 TI - Primary Myoglobinuria: Differentiate Myoglobinuria from Hemoglobinuria. AB - Myoglobin is dark red colour heme containing protein, stored in muscle. Change in permeability of myolemma causes myoglobin leak in plasma, which is cleared by kidney swiftly. Differentiating myoglobinuria from hemoglobinuria is important. Clinicians concern over myoglobinuria is to protect the patient from acute renal disease. We present a case of primary myoglobinuria, its clinical symptoms, diagnosis and treatment. PMID- 28811701 TI - Colorectal cancer in young adults: A difficult challenge. AB - Sporadic colorectal cancer (CRC) is traditionally diagnosed after the sixth decade of life, and current recommendations for surveillance include only patients older than 50 years of age. However, an increasing incidence of CRC in patients less than 40 years of age has been reported. This occurrence has been attributed to different molecular features and low suspicion of CRC in young symptomatic individuals. When confronting young-onset CRC with older patients, issues such as biological aggressiveness, stage at diagnosis and clinical outcomes seem to differ in many aspects. In the future, the identification of the molecular profile underlying the early development of sporadic CRC will help to plan tailored screening recommendations and improve management. Besides that, differential diagnosis with CRC linked with hereditary syndromes is necessary to provide adequate patient treatment and family screening. Until we find the answers to some of these doubts, doctors should raise suspicion when evaluating an young adult and be aware of this risk and consequences of a late diagnosis. PMID- 28811702 TI - Precision medicine: In need of guidance and surveillance. AB - Precision medicine, currently a hotspot in mainstream medicine, has been strongly promoted in recent years. With rapid technological development, such as next generation sequencing, and fierce competition in molecular targeted drug exploitation, precision medicine represents an advance in science and technology; it also fulfills needs in public health care. The clinical translation and application of precision medicine - especially in the prevention and treatment of tumors - is far from satisfactory; however, the aims of precision medicine deserve approval. Thus, this medical approach is currently in its infancy; it has promising prospects, but it needs to overcome numbers of problems and deficiencies. It is expected that in addition to conventional symptoms and signs, precision medicine will define disease in terms of the underlying molecular characteristics and other environmental susceptibility factors. Those expectations should be realized by constructing a novel data network, integrating clinical data from individual patients and personal genomic background with existing research on the molecular makeup of diseases. In addition, multi-omics analysis and multi-discipline collaboration will become crucial elements in precision medicine. Precision medicine deserves strong support, and its development demands directed momentum. We propose three kinds of impetus (research, application and collaboration impetus) for such directed momentum toward promoting precision medicine and accelerating its clinical translation and application. PMID- 28811703 TI - Barrett's oesophagus: Current controversies. AB - Oesophageal adenocarcinoma is rapidly increasing in Western countries. This tumour frequently presents late in its course with metastatic disease and has a very poor prognosis. Barrett's oesophagus is an acquired condition whereby the native squamous mucosa of the lower oesophagus is replaced by columnar epithelium following prolonged gastro-oesophageal reflux and is the recognised precursor lesion for oesophageal adenocarcinoma. There are multiple national and society guidelines regarding screening, surveillance and management of Barrett's oesophagus, however all are limited regarding a clear evidence base for a well demonstrated benefit and cost-effectiveness of surveillance, and robust risk stratification for patients to best use resources. Currently the accepted risk factors upon which surveillance intervals and interventions are based are Barrett's segment length and histological interpretation of the systematic biopsies. Further patient risk factors including other demographic features, smoking, gender, obesity, ethnicity, patient age, biomarkers and endoscopic adjuncts remain under consideration and are discussed in full. Recent evidence has been published to support earlier endoscopic intervention by means of ablation of the metaplastic Barrett's segment when the earliest signs of dysplasia are detected. Further work should concentrate on establishing better risk stratification and primary and secondary preventative strategies to reduce the risk of adenocarcinoma of the oesophagus. PMID- 28811705 TI - Colorectal cancer screening: An updated review of the available options. AB - Colorectal cancer (CRC) is a significant cause of morbidity and mortality worldwide. However, colon cancer incidence and mortality is declining over the past decade owing to adoption of effective screening programs. Nevertheless, in some parts of the world, CRC incidence and mortality remain on the rise, likely due to factors including "westernized" diet, lifestyle, and lack of health-care infrastructure and resources. Participation and adherence to different national screening programs remain obstacles limiting the achievement of screening goals. Different modalities are available ranging from stool based tests to radiology and endoscopy with varying sensitivity and specificity. However, the availability of these tests is limited to areas with high economic resources. Recently, FDA approved a blood-based test (Epi procolon(r)) for CRC screening. This blood based test may serve to increase the participation and adherence rates. Hence, leading to increase in colon cancer detection and prevention. This article will discuss various CRC screening tests with a particular focus on the data regarding the new approved blood test. Finally, we will propose an algorithm for a simple cost effective CRC screening program. PMID- 28811707 TI - Myo-inositol reduces beta-catenin activation in colitis. AB - AIM: To assess dietary myo-inositol in reducing stem cell activation in colitis, and validate pbeta-cateninS552 as a biomarker of recurrent dysplasia. METHODS: We examined the effects of dietary myo-inositol treatment on inflammation, pbeta cateninS552 and pAkt levels by histology and western blot in IL-10-/- and dextran sodium sulfate-treated colitic mice. Additionally, we assessed nuclear pbeta cateninS552 in patients treated with myo-inositol in a clinical trial, and in patients with and without a history of colitis-induced dysplasia. RESULTS: In mice, pbeta-cateninS552 staining faithfully reported the effects of myo-inositol in reducing inflammation and intestinal stem cell activation. In a pilot clinical trial of myo-inositol administration in patients with a history of low grade dysplasia (LGD), two patients had reduced numbers of intestinal stem cell activation compared to the placebo control patient. In humans, pbeta-cateninS552 staining discriminated ulcerative colitis patients with a history of LGD from those with benign disease. CONCLUSION: Enumerating crypts with increased numbers of pbeta-cateninS552 - positive cells can be utilized as a biomarker in colitis associated cancer chemoprevention trials. PMID- 28811704 TI - Gastrointestinal neuroendocrine peptides/amines in inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is a chronic recurrent condition whose etiology is unknown, and it includes ulcerative colitis, Crohn's disease, and microscopic colitis. These three diseases differ in clinical manifestations, courses, and prognoses. IBD reduces the patients' quality of life and is an economic burden to both the patients and society. Interactions between the gastrointestinal (GI) neuroendocrine peptides/amines (NEPA) and the immune system are believed to play an important role in the pathophysiology of IBD. Moreover, the interaction between GI NEPA and intestinal microbiota appears to play also a pivotal role in the pathophysiology of IBD. This review summarizes the available data on GI NEPA in IBD, and speculates on their possible role in the pathophysiology and the potential use of this information when developing treatments. GI NEPA serotonin, the neuropeptide Y family, and substance P are proinflammatory, while the chromogranin/secretogranin family, vasoactive intestinal peptide, somatostatin, and ghrelin are anti-inflammatory. Several innate and adaptive immune cells express these NEPA and/or have receptors to them. The GI NEPA are affected in patients with IBD and in animal models of human IBD. The GI NEPA are potentially useful for the diagnosis and follow-up of the activity of IBD, and are candidate targets for treatments of this disease. PMID- 28811706 TI - Therapeutic potential of flavonoids in inflammatory bowel disease: A comprehensive review. AB - The inflammatory process plays a central role in the development and progression of numerous pathological situations, such as inflammatory bowel disease (IBD), autoimmune and neurodegenerative diseases, metabolic syndrome, and cardiovascular disorders. IBDs involve inflammation of the gastrointestinal area and mainly comprise Crohn's disease (CD) and ulcerative colitis (UC). Both pathological situations usually involve recurring or bloody diarrhea, pain, fatigue and weight loss. There is at present no pharmacological cure for CD or UC. However, surgery may be curative for UC patients. The prescribed treatment aims to ameliorate the symptoms and prevent and/or delay new painful episodes. Flavonoid compounds are a large family of hydroxylated polyphenolic molecules abundant in plants, including vegetables and fruits which are the major dietary sources of these compounds for humans, together with wine and tea. Flavonoids are becoming very popular because they have many health-promoting and disease-preventive effects. Most interest has been directed towards the antioxidant activity of flavonoids, evidencing a remarkable free-radical scavenging capacity. However, accumulating evidence suggests that flavonoids have many other biological properties, including anti inflammatory, antiviral, anticancer, and neuroprotective activities through different mechanisms of action. The present review analyzes the available data about the different types of flavonoids and their potential effectiveness as adjuvant therapy of IBDs. PMID- 28811708 TI - Involvement of CRF2 signaling in enterocyte differentiation. AB - AIM: To determine the role of corticotropin releasing factor receptor (CRF2) in epithelial permeability and enterocyte cell differentiation. METHODS: For this purpose, we used rat Sprague Dawley and various colon carcinoma cell lines (SW620, HCT8R, HT-29 and Caco-2 cell lines). Expression of CRF2 protein was analyzed by fluorescent immunolabeling in normal rat colon and then by western blot in dissociated colonic epithelial cells and in the lysates of colon carcinoma cell lines or during the early differentiation of HT-29 cells (ten first days). To assess the impact of CRF2 signaling on colonic cell differentiation, HT-29 and Caco-2 cells were exposed to Urocortin 3 recombinant proteins (Ucn3, 100 nmol/L). In some experiments, cells were pre-exposed to the astressin 2b (A2b) a CRF2 antagonist in order to inhibit the action of Ucn3. Intestinal cell differentiation was first analyzed by functional assays: the trans-cellular permeability and the para-cellular permeability were determined by Dextran-FITC intake and measure of the transepithelial electrical resistance respectively. Morphological modifications associated to epithelial dysfunction were analyzed by confocal microscopy after fluorescent labeling of actin (phaloidin-TRITC) and intercellular adhesion proteins such as E-cadherin, p120ctn, occludin and ZO-1. The establishment of mature adherens junctions (AJ) was monitored by following the distribution of AJ proteins in lipid raft fractions, after separation of cell lysates on sucrose gradients. Finally, the mRNA and the protein expression levels of characteristic markers of intestinal epithelial cell (IEC) differentiation such as the transcriptional factor kruppel like factor 4 (KLF4) or the dipeptidyl peptidase IV (DPPIV) were performed by RT PCR and western blot respectively. The specific activities of DPPIV and alkaline phosphatase (AP) enzymes were determined by a colorimetric method. RESULTS: CRF2 protein is preferentially expressed in undifferentiated epithelial cells from the crypts of colon and in human colon carcinoma cell lines. Furthermore, CRF2 expression is down regulated according to the kinetic of HT-29 cell differentiation. By performing functional assays, we found that Ucn3-induced CRF2 signaling alters both para- and trans-cellular permeability of differentiated HT 29 and Caco-2 cells. These effects are partly mediated by Ucn3-induced morphological changes associated with the disruption of mature AJ in HT-29 cells and tight junctions (TJ) in Caco-2 cells. Ucn3-mediated activation of CRF2 decreases mRNA and protein expression levels of KLF4 a transcription factor involved in IEC differentiation. This signaling is correlated to a down regulation of key IEC markers such as DPPIV and AP, at both transcriptional and post-transcriptional levels. CONCLUSION: Our findings suggest that CRF2 signaling could modulate IEC differentiation. These mechanisms could be relevant to the stress induced epithelial alterations found in inflammatory bowel diseases. PMID- 28811709 TI - Bone marrow-derived monocyte infusion improves hepatic fibrosis by decreasing osteopontin, TGF-beta1, IL-13 and oxidative stress. AB - AIM: To evaluate the therapeutic effects of bone marrow-derived CD11b+CD14+ monocytes in a murine model of chronic liver damage. METHODS: Chronic liver damage was induced in C57BL/6 mice by administration of carbon tetrachloride and ethanol for 6 mo. Bone marrow-derived monocytes isolated by immunomagnetic separation were used for therapy. The cell transplantation effects were evaluated by morphometry, biochemical assessment, immunohistochemistry and enzyme-linked immunosorbent assay. RESULTS: CD11b+CD14+ monocyte therapy significantly reduced liver fibrosis and increased hepatic glutathione levels. Levels of pro inflammatory cytokines, including tumor necrosis factor-alpha, interleukin (IL)-6 and IL-1beta, in addition to pro-fibrotic factors, such as IL-13, transforming growth factor-beta1 and tissue inhibitor of metalloproteinase-1 also decreased, while IL-10 and matrix metalloproteinase-9 increased in the monocyte-treated group. CD11b+CD14+ monocyte transplantation caused significant changes in the hepatic expression of alpha-smooth muscle actin and osteopontin. CONCLUSION: Monocyte therapy is capable of bringing about improvement of liver fibrosis by reducing oxidative stress and inflammation, as well as increasing anti-fibrogenic factors. PMID- 28811710 TI - Single amino acid mutation of SR-BI decreases infectivity of hepatitis C virus derived from cell culture in a cell culture model. AB - AIM: To investigate the effect of a single amino acid mutation in human class B scavenger receptor I (SR-BI) on the infectivity of cell culture-derived hepatitis C virus (HCVcc) in SR-BI knock-down Huh7-siSR-BI cells. METHODS: Site-directed mutagenesis was used to construct the SR-BI S112F mutation, and the mutation was confirmed by nucleotide sequencing. SR-BI knock-down Huh7-siSR-BI cells were transfected with SR-BI S112F, SR-BI wild type (WT) and control plasmids, and then infected with HCVpp (HCV pseudoparticles) and hepatitis C virus derived from cell culture (HCVcc). A fluorescence assay was performed to analyze the effect of the S112F mutation on HCV entry; quantitative real-time PCR, immunofluorescence, and Western blot assays were used to analyze the effect of the S112F mutation on HCV infectivity. CHO cells expressing WT and SR-BI S112F were incubated with the HCV E2 protein expressed in HEK 293T cells, and flow cytometry was performed to examine the ability of SR-BI S112F to bind to the HCV E2 protein. Huh7-siSR-BI cells were transfected with SR-BI WT and the S112F mutant, and then DiI-HDL was added and images captured under the microscope to assess the ability of SR-BI S112F to take up HDL. RESULTS: The SR-BI S112F mutation was successfully constructed. The S112F mutation decreased the expression of the SR-BI mRNA and protein. SR-BI S112F decreased HCV entry and HCVcc infectivity in Huh7-siSR-BI cells. The S112F mutation impaired the binding of SR-BI to HCV E2 protein and decreased the HDL uptake of SR-BI. CONCLUSION: The S112F single amino acid mutation in SR-BI decreased the levels of the SR-BI mRNA and protein, as well as the ability of SR-BI to bind to the HCV E2 protein. Amino acid 112 in SR-BI plays important roles in HCV entry and the infectivity of HCVcc in vitro. PMID- 28811711 TI - Fibroblast-derived CXCL12/SDF-1alpha promotes CXCL6 secretion and co-operatively enhances metastatic potential through the PI3K/Akt/mTOR pathway in colon cancer. AB - AIM: To investigate the underlying mechanism by which CXCL12 and CXCL6 influences the metastatic potential of colon cancer and internal relation of colon cancer and stromal cells. METHODS: Western blotting was used to detect the expression of CXCL12 and CXCL6 in colon cancer cells and stromal cells. The co-operative effects of CXCL12 and CXCL6 on proliferation and invasion of colon cancer cells and human umbilical vein endothelial cells (HUVECs) were determined by enzyme linked immunosorbent assay, and proliferation and invasion assays. The angiogenesis of HUVECs through interaction with cancer cells and stromal cells was examined by angiogenesis assay. We eventually investigated activation of PI3K/Akt/mTOR signaling by CXCL12 involved in the metastatic process of colon cancer. RESULTS: CXCL12 was expressed in DLD-1 cancer cells and fibroblasts. The secretion level of CXCL6 by colon cancer cells and HUVECs were significantly promoted by fibroblasts derived from CXCL12. CXCL6 and CXCL2 could significantly enhance HUVEC proliferation and migration (P < 0.01). CXCL6 and CXCL2 enhanced angiogenesis by HUVECs when cultured with fibroblast cells and colon cancer cells (P < 0.01). CXCL12 also enhanced the invasion of colon cancer cells. Stromal cell derived CXCL12 promoted the secretion level of CXCL6 and co-operatively promoted metastasis of colon carcinoma through activation of the PI3K/Akt/mTOR pathway. CONCLUSION: Fibroblast-derived CXCL12 enhanced the CXCL6 secretion of colon cancer cells, and both CXCL12 and CXCL6 co-operatively regulated the metastasis via the PI3K/Akt/mTOR signaling pathway. Blocking this pathway may be a potential anti-metastatic therapeutic target for patients with colon cancer. PMID- 28811712 TI - Association between CYP24A1 polymorphisms and the risk of colonic polyps and colon cancer in a Chinese population. AB - AIM: To determine the pathogenesis and potential single nucleotide polymorphisms (SNPs) as screening sites for colonic polyps, colon cancer and ulcerative colitis, and to analyze the possible association between these genetic polymorphisms and the three diseases. METHODS: We evaluated genetic polymorphisms in 144 newly diagnosed colonic polyp patients, 96 colon cancer patients and 44 ulcerative colitis patients. The four SNPs genotyped were rs4809957, rs6068816, rs6091822 and rs8124792. The control group consisted of 504 East Asians enrolled in the 1000 Genomes Project. Correlations between CYP24A1 SNPs and the diseases were analyzed by Fisher's exact probability test. RESULTS: CYP24A1 polymorphisms rs4809957 A/G and rs6068816 C/T showed a statistically significant association with risk of the three diseases, when both the genotypes and allele frequencies were considered. With regard to rs6091822 G/T, all three diseases were related to risk allele carriers (GT + TT) vs wild-type (GG), but the associations between the allele frequencies and the diseases were not significant. The risk of colonic polyps and colon cancer was related to the allele frequencies of rs8124792 G/A, and this association remained for genotype frequencies of this SNP. CONCLUSION: Four SNPs are related to the risk of colonic polyps and colon cancer. G allele in rs6091822 G/T may play an anti-cancer role only if it is homozygous. The A allele, which is a minor component of rs8124792, may be indicated in the diagnosis of colonic polyps or colon cancer rather than ulcerative colitis. PMID- 28811713 TI - Clinical significance of glycemic parameters on venous thromboembolism risk prediction in gastrointestinal cancer. AB - AIM: To investigate the possible predictive role of routinely used glycemic parameters for a first venous thromboembolism (VTE) episode in gastrointestinal (GI) cancer ambulatory patients - with or without clinically diagnosed type 2 diabetes (T2D) or obesity - treated with chemotherapy. METHODS: Pre-treatment fasting blood glucose, insulin, glycated hemoglobin (HbA1c) and homeostasis model of risk assessment (HOMA) were retrospectively evaluated in a cohort study of 342 GI cancer patients. Surgery was performed in 142 (42%) patients with primary cancer, 30 (21%) and 112 (79%) of whom received neoadjuvant and adjuvant therapies, respectively. First-line chemotherapy was administered in 200 (58%) patients with metastatic disease. The study outcome was defined as the occurrence of a first symptomatic or asymptomatic VTE episode during active treatment. RESULTS: Impaired glucose tolerance (IGT) or T2D were diagnosed in 30% of GI cancer patients, while overweight/obesity had an incidence of 41%. VTE occurred in 9.4% of patients (7% of non-diabetic non-obese), especially in those with a high ECOG score (P = 0.025). No significant association was found between VTE incidence and T2D, obesity, different tumor types, metastatic disease, Khorana class of risk, or different anti-cancer drugs, although VTE rates were substantially higher in patients receiving bevacizumab (17% vs 8%, P = 0.044). Conversely, all glucose metabolic indexes were associated with increased VTE risk at ROC analysis. Multivariate Cox proportional analyses confirmed that HOMA index (HR = 4.13, 95%CI: 1.63-10.5) or fasting blood glucose (HR = 3.56, 95%CI: 1.51 8.39) were independent predictors of VTE occurrence during chemotherapy. CONCLUSION: The results here reported demonstrate that evaluating glucose metabolic asset may allow for VTE risk stratification in GI cancer, helping to identify chemotherapy-treated patients who might benefit from thromboprophylaxis. Further multicenter prospective studies involving a larger number of patients are presently needed. PMID- 28811714 TI - Sex-dependent difference in the effect of metformin on colorectal cancer-specific mortality of diabetic colorectal cancer patients. AB - AIM: To assess factors associated with the higher effect of metformin on mortality in diabetic colorectal cancer (CRC) patients, since the factors related to the effectiveness of metformin have not been identified yet. METHODS: Between January 2000 and December 2010, 413 patients diagnosed with both stage 3/4 CRC and diabetes mellitus were identified. Patients' demographics and clinical characteristics were analyzed. The effect of metformin on CRC-specific mortality and the interactions between metformin and each adjusted factor were evaluated. RESULTS: Total follow-up duration was median 50 mo (range: 1-218 mo). There were 85 deaths (45.9%) and 72 CRC-specific deaths (38.9%) among 185 patients who used metformin, compared to 130 total deaths (57.0%) and 107 CRC-specific deaths (46.9%) among 228 patients who did not use metformin. In multivariate analysis, survival benefit associated with metformin administration was identified (HR = 0.985, 95%CI: 0.974-0.997, P = 0.012). Interaction test between metformin and sex after adjustment for relevant factors revealed that female CRC patients taking metformin exhibited a significantly lower CRC-specific mortality rate than male CRC patients taking metformin (HR = 0.369, 95%CI: 0.155-0.881, P = 0.025). Furthermore, subgroup analysis revealed significant differences in CRC-specific mortality between the metformin and non-metformin groups in female patients (HR = 0.501, 95%CI: 0.286-0.879, P = 0.013) but not male patients (HR = 0.848, 95%CI: 0.594-1.211, P = 0.365). There were no significant interactions between metformin and other adjusted factors on CRC-specific mortality. CONCLUSION: We showed a strong sex-dependent difference in the effect of metformin on CRC-specific mortality in advanced stage CRC patients with diabetes. PMID- 28811715 TI - Sex-influenced association of non-alcoholic fatty liver disease with colorectal adenomatous and hyperplastic polyps. AB - AIM: To investigate the relationship between non-alcoholic fatty liver disease (NAFLD) and colorectal adenomatous and hyperplastic polyps. METHODS: A retrospective cross-sectional study was conducted on 3686 individuals undergoing health checkups (2430 males and 1256 females). All subjects underwent laboratory testing, abdominal ultrasonography, colonoscopy, and an interview to ascertain the baseline characteristics and general state of health. Multinomial logistic regression analysis was performed to examine the association between NAFLD and the prevalence of colorectal adenomatous and hyperplastic polyps. Furthermore, the relationship was analyzed in different sex groups. Subgroup analysis was performed based on number, size, and location of colorectal polyps. RESULTS: The prevalence of colorectal polyps was 38.8% in males (16.2% for adenomatous polyps and 9.8% for hyperplastic polyps) and 19.3% in females (8.4% for adenomatous polyps and 3.9% for hyperplastic polyps). When adjusting for confounding variables, NAFLD was significantly associated with the prevalence of adenomatous polyps (OR = 1.28, 95%CI: 1.05-1.51, P < 0.05) and hyperplastic polyps (OR = 1.35, 95%CI: 1.01-1.82, P < 0.05). However, upon analyzing adenomatous and hyperplastic polyps in different sex groups, the significant association remained in males (OR = 1.53, 95%CI: 1.18-2.00, P < 0.05; OR = 1.42, 95%CI: 1.04-1.95, P < 0.05) but not in females (OR = 0.44, 95%CI: 0.18-1.04, P > 0.05; OR = 1.18, 95%CI: 0.50-2.78, P > 0.05). CONCLUSION: NAFLD is specifically associated with an increased risk of colorectal adenomatous and hyperplastic polyps in men. However, NAFLD may not be a significant factor in the prevalence of colorectal polyps in women. PMID- 28811716 TI - Development and validation of a simple and multifaceted instrument, GERD-TEST, for the clinical evaluation of gastroesophageal reflux and dyspeptic symptoms. AB - AIM: To evaluate the psychometric properties of a newly developed questionnaire, known as the gastroesophageal reflux and dyspepsia therapeutic efficacy and satisfaction test (GERD-TEST), in patients with GERD. METHODS: Japanese patients with predominant GERD symptoms recruited according to the Montreal definition were treated for 4 wk using a standard dose of proton pump inhibitor (PPI). The GERD-TEST and the Medical Outcome Study Short Form-8 Health Survey (SF-8) were administered at baseline and after 4 wk of treatment. The GERD-TEST contains three domains: the severity of GERD and functional dyspepsia (FD) symptoms (5 items), the level of dissatisfaction with daily life (DS) (4 items), and the therapeutic efficacy as assessed by the patients and medication compliance (4 items). RESULTS: A total of 290 patients were eligible at baseline; 198 of these patients completed 4 wk of PPI therapy. The internal consistency reliability as evaluated using the Cronbach's alpha values for the GERD, FD and DS subscales ranged from 0.75 to 0.82. The scores for the GERD, FD and DS items/subscales were significantly correlated with the physical and mental component summary scores of the SF-8. After 4 wk of PPI treatment, the scores for the GERD items/subscales were greatly reduced, ranging in value from 1.51 to 1.87 and with a large effect size (P < 0.0001, Cohen's d; 1.29-1.63). Statistically significant differences in the changes in the scores for the GERD items/subscales were observed between treatment responders and non-responders (P < 0.0001). CONCLUSION: The GERD-TEST has a good reliability, a good convergent and concurrent validity, and is responsive to the effects of treatment. The GERD-TEST is a simple, easy to understand, and multifaceted PRO instrument applicable to both clinical trials and the primary care of GERD patients. PMID- 28811717 TI - Modified B-ultrasound method for measurement of antral section only to assess gastric function and guide enteral nutrition in critically ill patients. AB - AIM: To establish a modified B-ultrasound method of measuring the antral section only to assess gastric motility in healthy people, and evaluate its application in guiding enteral nutrition (EN) in critically ill patients. METHODS: First, 30 healthy volunteers were selected. The modified B-ultrasound method and the traditional B-ultrasound method were applied to assess gastric function. The correlation of indices of gastric function between the two groups was analyzed statistically. In addition, 64 critically ill patients were selected, and the modified B-ultrasound method and the gastric juice withdrawal method were applied to guide the implementation of EN. Daily caloric value, the time required to achieve complete EN, ICU stay, hospitalization time, and serum prealbumin and albumin levels were recorded and compared between the two groups. Kaplan-Meier survival curve was used to compare the complications of EN between the two groups. RESULTS: In healthy subjects, there was a good correlation among gastric emptying time, antral contraction frequency and antral motility index between the two groups (r = 0.57, 0.61 and 0.54, respectively). The study on critically ill patients also revealed that a better effect of EN was achieved in the modified B ultrasound method group, in which patients had shorter ICU stay and hospitalization time and higher levels of serum prealbumin and albumin. The Kaplan-Meier survival analysis revealed that the improved B-ultrasound method was associated with significantly fewer EN complications (P = 0.031). CONCLUSION: The modified B-ultrasound method can provide a good real-time assessment of gastric function and has a better effect than the traditional method in guiding EN in critically ill patients. PMID- 28811718 TI - Chronic liver failure-consortium acute-on-chronic liver failure and acute decompensation scores predict mortality in Brazilian cirrhotic patients. AB - AIM: To validate prognostic scores for acute decompensation of cirrhosis and acute-on-chronic liver failure in Brazilian patients. METHODS: This is a prospective cohort study designed to assess the prognostic performance of the chronic liver failure-consortium (CLIF-C) acute decompensation score (CLIF-C AD) and CLIF-C acute-on-chronic liver failure score (CLIF-C ACLF), regarding 28-d and 90-d mortality, as well as to compare them to other prognostic models, such as Model for End-Stage Liver Disease (MELD), MELD Sodium (MELD-Na), Child-Pugh (CP) score, and the CLIF-C Organ Failure score (CLIF-C OF). All participants were adults with acute decompensation of cirrhosis admitted to the Emergency Department of a tertiary hospital in southern Brazil. Prognostic performances were evaluated by means of the receiver operating characteristic (ROC) curves, area under the curves (AUC) and 95%CI. RESULTS: One hundred and thirteen cirrhotic patients were included. At admission, 18 patients had acute-on-chronic liver failure (ACLF) and 95 individuals had acute decompensation (AD) without ACLF, of which 24 eventually developed ACLF during the course of hospitalization (AD evolving to ACLF group). The AD group had significantly lower 28-d (9.0%) and 90-d (18.3%) mortality as compared to the AD evolving to ACLF group and to the ACLF group (both P < 0.001). On the other hand, 28-d and 90-d mortalities were not significantly different between AD evolving to ACLF group and ACLF group (P = 0.542 and P = 0.708, respectively). Among patients with ACLF, at 28 d from the diagnosis, CLIF-C ACLF was the only score able to predict mortality significantly better than the reference line, with an AUC (95%CI) of 0.71 (95%CI: 0.54-0.88, P = 0.021). Among patients with AD, all prognostic scores performed significantly better than the reference line regarding 28-d mortality, presenting with similar AUCs: CLIF-C AD score 0.75 (95%CI: 0.63-0.88), CP score 0.72 (95%CI: 0.59-0.85), MELD score 0.75 (95%CI: 0.61-0.90), MELD-Na score 0.76 (95%CI: 0.61-0.90), and CLIF-C OF score 0.74 (95%CI: 0.60-0.88). The same occurred concerning AUCs for 90 d mortality: CLIF-C AD score 0.70 (95%CI: 0.57-0.82), CP score 0.73 (95%CI: 0.62 0.84), MELD score 0.71 (95%CI: 0.59-0.83), MELD-Na score 0.73 (95%CI: 0.62-0.84), and CLIF-C OF score 0.65 (95%CI: 0.52-0.78). CONCLUSION: This study demonstrated that CLIF-C ACLF is the best available score for the prediction of 28-d mortality among patients with ACLF. CLIF-C AD score is also useful for the prediction of mortality among cirrhotic patients with AD not fulfilling diagnostic criteria for ACLF, but it was not superior to other well-established prognostic scores. PMID- 28811721 TI - University of the twentyfirst century:: Opportunities and challenges for medical education. PMID- 28811719 TI - Refractory hepatic encephalopathy in a patient with hypothyroidism: Another element in ammonia metabolism. AB - Hepatic encephalopathy (HE) remains a diagnosis of exclusion due to the lack of specific signs and symptoms. Refractory HE is an uncommon but serious condition that requires the search of hidden precipitating events (i.e., portosystemic shunt) and alternative diagnosis. Hypothyroidism shares clinical manifestations with HE and is usually considered within the differential diagnosis of HE. Here, we describe a patient with refractory HE who presented a large portosystemic shunt and post-ablative hypothyroidism. Her cognitive impairment, hyperammonaemia, electroencephalograph alterations, impaired neuropsychological performance, and magnetic resonance imaging and spectroscopy disturbances were highly suggestive of HE, paralleled the course of hypothyroidism and normalized after thyroid hormone replacement. There was no need for intervention over the portosystemic shunt. The case findings support that hypothyroidism may precipitate HE in cirrhotic patients by inducing hyperammonaemia and/or enhancing ammonia brain toxicity. This case led us to consider hypothyroidism not only in the differential diagnosis but also as a precipitating factor of HE. PMID- 28811720 TI - Endoscopic occlusion with silicone spigots for the closure of refractory esophago bronchiole fistula after esophagectomy. AB - A 65-year-old man with cT1bN0M0 stage I middle thoracic esophageal cancer underwent subtotal esophagectomy and gastric tube reconstruction through the posterior mediastinal route after preoperative carbon-ion radiotherapy and chemotherapy in a clinical trial. Anastomotic leakage occurred, but it spontaneously improved. At six months after the operation, he was rehospitalized with a cough and dysphagia. An esophago-bronchiole fistula and stenosis of the gastric tube were observed. He first underwent stent placement in the gastric tube. Two weeks later, the syringeal epithelium was burned by argon plasma coagulation after stent removal. Endoscopic occlusion was then performed for the fistula with two guidewire-assisted silicone spigots. Two weeks later, he was discharged on an oral diet, and he has not developed recurrence of the fistula or cancer for three years. This is the first report of endoscopic occlusion with a guidewire-assisted silicone spigot through the esophagus. PMID- 28811722 TI - A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) test to detect the common mutation (35delG) in the connexin-26 gene. AB - OBJECTIVE: To develop a polymerase chain reaction (PCR) based test for the detection of a common frame-shift mutation (35delG) in the connexin-26 (GJB2) gene, and to investigate the status of this mutation in Oman. METHOD: A PCR test, based on site-directed mutagenesis, was developed for the 35delG mutation. A mutagenesis primer generated an EcoN I site in a short (87 bp) DNA fragment amplified from the connexin-26 gene. The EcoN I site is generated only if the 35delG mutation is present. Thus, a restriction fragment length polymorphism (RFLP) analysis of the amplified DNA fragment with EcoN I allowed us to detect the 35delG mutation in the connexin 26 gene. RESULT: After validating the test using quality control DNA samples, which contained the 35delG mutation in either homozygous or heterozygous form, 120 healthy subjects and 35 unrelated Omani patients with nosyndromic autosomal recessive deafness (NARD), were screened for 35delG mutation. The mutation was not present in any individual tested. CONCLUSION: We have been able to develop a new PCR-RFLP test for detecting the 35delG common mutation in the connexin 26 gene. Our preliminary results from application of this test on a limited number of Omani patients indicate that the 35delG mutation may not be associated with NARD in Oman. PMID- 28811723 TI - Occurence of autoantibodies in healthy Omani individuals. AB - OBJECTIVES: To investigate the occurence of various autoantibodies in the Omani population. METHOD: Sera from 392 healthy Omani individuals comprising 183 pregnant women and 209 blood donors (183 men and 26 women) were investigated. Autoantibodies were detected using immunofluorescence, haemagglutination and latex agglutination techniques. RESULT: Low levels of autoantibodies were detected in approximately 50% of the subjects; very few subjects showed high autoantibody titres. Anti smooth muscle autoantibodies (ASMA) were the most prevalent, and were detected in 31.6% of the individuals. Anti thyroid microsomal autoantibodies (ATMA) and anti thyroglobulin autoantibodies (ATA) were present in 5.9% and 4.9% of individuals respectively. The other autoantibodies were detected much less frequently, viz. anti nuclear autoantibodies (ANA) in 1.5%, anti parietal cells autoantibodies (APCA) in 1.8%, anti reticulin autoantibodies patterns (ARAP) in 3.0% and rheumatoid factor (RF) in 1.0% of the subjects. CONCLUSION: The data indicate that autoantibodies do exist in healthy Omani individuals and the results of clinical tests for these autoantibodies must be interpreted with caution. PMID- 28811724 TI - Prevalence of asthma symptoms in Omani schoolchildren. AB - OBJECTIVES: To determine the prevalence of asthma in Omani schoolchildren using the International Study of Asthma and Allergies in Children (ISAAC) protocols. METHOD: The ISAAC-written questionnaire was completed by a total of 7,067 Omani schoolchildren (3,893 children aged 6-7 years of which 56% were boys and 3,174 aged 13-14 years of which 51% were boys) from the 10 health regions in the country. RESULTS: The estimated mean national 12-month prevalence of any wheeze, night waking with wheeze, speech limiting wheeze and exercise wheeze were respectively 7.8%, 3.5%, 3.2% and 6.9% for the 6-7 year age group and 8.9%, 2.9%, 4.0% and 19.2% for the 13-14 year age group. Both age groups reported high prevalence of night cough (19.6% and 20.9% in the younger and the older children respectively). The prevalence of self-reported asthma diagnosis was higher in the older age group (20.7% vs. 10.5%, p<0.001). In the younger age group, the diagnosis of asthma was more common in boys (12.5% vs. 8.0%, p>0.001), but there was no significant difference between the two sexes in the older age group (22.0% of boys vs. 20.5% of girls). There was nearly three-fold difference in the prevalence of self-reported diagnosis of asthma between the regions with the highest and the lowest prevalence of asthma for both young and older children (from 5.3% and 9.5% in Musandam to 14.2% and 30.6% in South Sharqiya, respectively). CONCLUSION: The results of this first epidemiological survey of asthma in Oman indicate that asthma is common in Omani children and adolescents. Night cough is the most frequent symptom. There is also significant regional variation in prevalence of asthma symptoms and diagnosis within the country and this requires further investigation. PMID- 28811725 TI - Are scintigraphy and ultrasonography necessary before fine-needle aspiration cytology for thyroid nodules? AB - OBJECTIVE: To evaluate the efficacy of scintigraphy, ultrasound and fine-needle aspiration in thyroid nodules and to establish the best diagnostic pathway in detecting thyroid cancer. METHOD: Two hundred and sixteen patients with thyroid nodules were examined using high-resolution ultrasonography, 99mTc thyroid scintigraphy and ultrasound-guided fine-needle aspiration. Of these, 113 patients subsequently underwent thyroidectomy. The remaining 103 were followed up for two years without any evidence of malignancy. RESULTS: Cytopathology classified 71% of the aspirate as benign, 3% as positive for malignancy, 21% as suspected neoplasia and 5% as unsatisfactory. Fine-needle aspiration cytology had a sensitivity of 87.5% and specificity of 80%. On ultrasound 33% of malignant nodules were hypo-echoic and on scintigraphy 16% of solitary cold nodules were malignant. Neither test could reliably diagnose thyroid cancer. CONCLUSION: Ultrasound-guided fine-needle aspiration cytology should be the first test performed in euthyroid patients with a thyroid nodule. Scintigraphy and ultrasound imaging should be reserved for follow-up studies and patients who have suppressed levels of thyroid stimulating hormone. PMID- 28811726 TI - Clinical profile of stroke:: The experience at King Abdulaziz University Hospital. AB - OBJECTIVES: To determine the pattern and risk factors of stroke in Saudi nationals and non-Saudis, at King Abdulaziz University Hospital (KAUH), in the western province of Saudi Arabia. METHOD: All cases of stroke admitted to KAUH in the period between January 1995 and December 1999 were studied. Demographic data of the patients, stroke types, risk factors and mortality were reported. RESULTS: Of the 103 patients studied, 56% were Saudis and 44 % non-Saudis with male predominance and mean ages of 66 and 62 years respectively. In Saudis, the stroke types were 74% ischemic, 10% hemorrhagic and 16% unspecified, whereas in non Saudis, the figures were respectively 62%, 29% and 9%. The frequency of stroke increased steadily with age in Saudis but dropped after the sixth decade in non Saudis. There was no significant difference between the Saudis and the non-Saudis in the occurrence of risk factors for stroke or in mortality. CONCLUSION: The pattern and risk factors of cases of stroke treated at KAUH are similar to those reported from other regions of Saudi Arabia and other parts of the world. PMID- 28811727 TI - Metered-dose inhaler technique among healthcare providers practising in Oman. AB - OBJECTIVE: To evaluate the correctness of metered-dose inhaler (MDI) technique in a sample of healthcare providers practising in Oman, considering that poor inhaler technique is a common problem both in asthma patients and healthcare providers, which contributes to poor asthma control. METHOD: A total of 150 healthcare providers (107 physicians, 33 nurses and 10 pharmacists) who were participants in symposia on asthma management conducted in five regions of Oman, volunteered for the study. After the participants answered a questionnaire aimed at identifying their involvement in MDI prescribing and counselling, a trained observer assessed their MDI technique using a checklist of nine steps. RESULTS: Of the 150 participants, 148 (99%) were involved in teaching inhaler techniques to patients, and 103 of 107 physicians (96%) had prescribed inhaled medications. However only 22 participants (15%) performed all steps correctly. Physicians performed significantly better than non-physicians (20% vs. 2%, p <0.05) Among the physicians, internists performed better (26%) than general practitioners (5%) and accident and emergency doctors (9%). CONCLUSION: The majority of health-care providers responsible for instructing patients on the correct MDI technique were unable to perform this technique correctly indicating the need for regular formal training programmes on inhaler techniques. PMID- 28811728 TI - Growth pattern of primary schoolchildren in Benghazi, Libya. AB - OBJECTIVE: To find the growth trends in a sample of schoolchildren in Benghazi (Libya), and to compare it with international and other local growth charts, as a step for setting the national curves. METHOD: From 25th February to 31st October 1993, a sample of 2,022 pupils (1,160 boys and 862 girls) were randomly selected from three public primary schools in three different socio-economic areas in Benghazi. A questionnaire consisting of social and scholastic items was distributed to teachers a few days before the examination. The height and weight of all the pupils were measured according to the standards of Jellife, Gorstein, WHO, and de Onis. Data were analysed and compared with both the reference standard of the United States National Center for Health Statistics (NCHS-USA), and the local standards of Tripoli-1986. RESULTS: The boys and girls in the lowest age-group had a pattern similar to that of the reference population for both height/age and weight/age, but it dropped sharply from mid-school years. The Benghazi curves were consistently higher than those of Tripoli, particularly for height/age. CONCLUSION: The nutritional status of these children, which was good before the beginning of schooling, was negatively affected during the school years. This could be attributed either to births in the family and consequent neglect, or to the school's negative effects on the child, such as lack of appetite created by anxiety or other factors. Further studies from different regions of the country are needed to set national growth curves. PMID- 28811729 TI - Synchronous bilateral endometrioid ovarian cancer and uterine adenocarcinoma in a young woman. AB - Synchronous carcinomas involving both the ovary and uterine corpus are relatively uncommon. These tumours represent a diagnostic and therapeutic challenge, particularly if they have similar histology. Here we present the case of a 34 year-old woman with bilateral endometrioid cancers of both ovaries and adenocarcinoma of the uterus. PMID- 28811730 TI - Racial Differences in Prostate Cancer Treatment: The Role of Socioeconomic Status. AB - OBJECTIVE: This study examines whether socioeconomic status (SES), measured at both the individual and neighborhood levels, is associated with receipt of definitive treatment for localized prostate cancer and whether these associations mediate racial differences in treatment between non-Hispanic White and non Hispanic Black men. DESIGN: The Philadelphia Area Prostate Cancer Access Study (P2 Access) is a mailed, cross-sectional survey of men sampled from the Pennsylvania Cancer Registry, combined with neighborhood Census data. SETTING: Eight counties in southeastern Pennsylvania. PARTICIPANTS: 2,386 men with prostate adenocarcinoma. MAIN MEASURES: Receipt of definitive treatment, race, self-reported income, education, employment status, and neighborhood SES. RESULTS: Overall, Black and White men were equally likely to receive definitive treatment. Men living in neighborhoods with higher SES were more likely to receive definitive treatment (OR 1.57, 95%CI 1.01, 2.42). Among men who received definitive treatment, Black men were significantly less likely to receive radical prostatectomy compared with White men (OR .71, 95% CI .52, .98), as were men with some college education compared with those with a high school education or less (OR .66, 95% CI .47, .94). SES does not mediate racial differences in receipt of definitive treatment or the type of definitive treatment received, and associations with income or employment status were not significant. CONCLUSIONS: These results stress the importance of examining racial disparities within geographic areas and highlight the unique associations that different measures of SES, particularly neighborhood SES and education, may have with prostate cancer treatment. PMID- 28811731 TI - Perceived Discrimination and Reported Trust and Satisfaction with Providers in African Americans: The Jackson Heart Study. AB - OBJECTIVES: 1) To examine the association of multiple dimensions of discrimination with reported trust and satisfaction with providers; 2) to report within-group differences among African Americans (AAs). MAIN MEASURES: Measures of perceived discrimination included everyday, lifetime, burden from lifetime discrimination, and stress from discrimination. Outcomes included trust and satisfaction with providers. METHODS: Descriptive cross sectional study. The study population included AAs aged 35 to 84 years from the Jackson Heart Study (JHS) (N=5,301). Poisson regression (PR) was used to quantify the association between perceived discrimination and reported trust and satisfaction with providers before and after controlling for selected characteristics. RESULTS: The mean everyday discrimination score was 2.11 (SD+/-1.02), and the mean lifetime discrimination score was 2.92 (SD+/-2.12). High (vs low) levels of everyday discrimination were associated with a 3% reduction in the prevalence of trust in providers (PR .97, 95% CI .96, .99) in all models. In fully-adjusted models, high (vs low) lifetime discrimination was associated with a 4% reduction in the prevalence of trust and satisfaction (PR .96, 95% CI .95, .98). Burden of discrimination was not associated with trust or satisfaction, but stress from discrimination was inversely associated with satisfaction. CONCLUSIONS: The significant association between discrimination and mistrust and dissatisfaction suggests that health care providers should be made aware of AA perceptions of discrimination, which likely affects their levels of trust and satisfaction. PMID- 28811732 TI - Exposure to and Use of Electronic Cigarettes: Does Language Matter? AB - OBJECTIVES: To determine whether patients who are English proficient become aware of e-cigarettes through different marketing tactics and have dissimilar patterns of use than patients who are non-English speaking. DESIGN: This was a cross sectional study surveying adult English- and Spanish-speaking patients. ANOVA and chi-squared tests were used to examine differences between groups. SETTING: A large public, safety-net hospital in Los Angeles County, California. RESULTS: Respondents (N=1899) were predominately Hispanic (78%), foreign-born (68%), and reported Spanish as a primary language (64%). Native English speakers reported the highest use of e-cigarettes (26%), followed by non-native (13%) and non English speakers (2%) (P<.001). In terms of marketing, native and non-native English speakers were more likely to have friends and family as sources of e cigarette information (P<.001). Native speakers were more likely to see advertisements for e-cigarettes on storefronts (P=.004) and on billboards (P<.001). Non-English speakers were most likely to learn about e-cigarettes on the news (P<.001) and in advertisements on the television and radio (P=.002). Differences in reasons for use were not significant between the three groups. CONCLUSIONS: Native and non-native English speakers become aware of e-cigarettes through different mechanisms and use e-cigarettes at a significantly higher rate than non-English speakers. These results highlight an opportunity for public health programs to concentrate on specific channels of communication that introduce patient populations to e-cigarettes to slow the spread of e-cigarette usage. PMID- 28811733 TI - Community Partners in Care: 6-Month Outcomes of Two Quality Improvement Depression Care Interventions in Male Participants. AB - OBJECTIVE: Limited data exist on approaches to improve depression services for men in under-resourced communities. This article explores this issue using a sub analysis of male participants in Community Partners in Care (CPIC). DESIGN: Community partnered, cluster, randomized trial. SETTING: Hollywood-Metropolitan and South Los Angeles, California. PARTICIPANTS: 423 adult male clients with modified depression (PHQ-8 score>=10). INTERVENTIONS: Depression collaborative care implementation using community engagement and planning (CEP) across programs compared with the more-traditional individual program, technical assistance (Resources for Services, RS). MAIN OUTCOME MEASURES: Depressive symptoms (PHQ-8 score), mental health-related quality of life (MHRQL), mental wellness, services utilization and settings. RESULTS: At screening, levels of probable depression were moderate to high (17.5%-47.1%) among men across services sectors. Intervention effects on primary outcomes (PHQ-8 score and MHRQL) did not differ. Men in CEP compared with RS had improved mental wellness (OR 1.85, 95% CI 1.00 3.42) and reduced hospitalizations (OR .40, 95% CI .16-.98), with fewer mental health specialty medication visits (IRR 0.33, 95% CI .15-.69), and a trend toward greater faith-based depression visits (IRR 2.89, 95% CI .99-8.45). CONCLUSIONS: Exploratory sub-analyses suggest that high rates of mainly minority men in under resourced communities have high prevalence of depression. A multi-sector coalition approach may hold promise for improving community-prioritized outcomes, such as mental wellness and reduced hospitalizations for men, meriting further development of this approach for future research and program design. PMID- 28811734 TI - Differential Response to Exercise in African Americans with High Levels of Inflammation. AB - PURPOSE: Systemic inflammation, measured by C-reactive protein (CRP), is an important risk factor for cardiovascular disease (CVD) and mortality. We investigated whether aerobic exercise training (AEXT) affects African Americans with high inflammation (HI) the same way it does African Americans with low inflammation (LI) in terms of CVD risk factors. METHODS: 23 African Americans with CRP levels <3 mg/L (LI) and 14 African Americans with CRP >=3 mg/L (HI) underwent six months of AEXT. Participants were sedentary, non-diabetic, non smoking, with clinical blood pressure <160/100 mm Hg, were non-hyperlipidemic, had no signs of cardiovascular, renal, or pulmonary disease, and were not on medication. Measures included CD62E+ endothelial microparticles (EMPs), a measure of early stage endothelial dysfunction, as well as lipid and glucose profile, aerobic fitness, body composition, and blood pressure. RESULTS: The LI group improved aerobic fitness by 10%, body mass index by 3%, and plasma triglycerides by 20%, with no change being observed in HI group for these variables. The HI group improved fasting plasma glucose levels by 10%, with no change occurring in the LI group. Both groups improved CD62E+ EMPs by 38% and 59% for the LI and HI group, respectively. CONCLUSIONS: A standard AEXT intervention differentially affected CVD risk factors among African Americans with high and low inflammation. This may indicate that, in African Americans with high inflammation, AEXT alone may not be enough to reap the same benefits as their low-inflammation peers in terms of CVD risk modification. PMID- 28811735 TI - Asian American Dietary Sources of Sodium and Salt Behaviors Compared with Other Racial/ethnic Groups, NHANES, 2011-2012. AB - OBJECTIVE: Asian Americans consume more sodium than other racial/ethnic groups. The purpose of this analysis was to describe major sources of sodium intake to inform sodium reduction initiatives. METHODS: Cross-sectional data on adults (aged >18 years) from the National Health and Nutrition Examination Survey (NHANES) 2011-2012 with one 24-hour dietary recall were analyzed (n=5,076). Population proportions were calculated from "What We Eat in America" (WWEIA) food categories. RESULTS: Asian Americans had a higher sodium density vs adults of other racial/ethnic groups (means in mg/1000kcal: Asian American, 2031.1; Hispanic,1691.6; White: 1666.5; Black: 1655.5; P<.05, all). Half of sodium consumed by Asian Americans came from the top 10 food categories, in contrast to Hispanics (43.6%), Whites (39.0%), and Blacks (36.0%). Four food categories were a top source of sodium for Hispanics, Whites, Blacks, and others, but not among Asian Americans: cold cuts and cured meats; meat mixed dishes; eggs and omelets; and cheese. The top three food category sources of sodium among Asians were soups, rice, and yeast breads accounting for 28.9% of dietary sodium. Asian Americans were less likely to add salt at the table, but used salt in food preparation 'very often' (P for both <.01). CONCLUSIONS: Mean sodium consumption and sources vary across racial/ethnic groups with highest consumption in Asian Americans. Given the smaller number of food categories contributing to sodium intake in Asian Americans, results imply that targeted activities on a few food items would have a large impact on reducing sodium intake in this group. PMID- 28811736 TI - Mentored Training to Increase Diversity among Faculty in the Biomedical Sciences: The NHLBI Summer Institute Programs to Increase Diversity (SIPID) and the Programs to Increase Diversity among Individuals Engaged in Health-related Research (PRIDE). AB - OBJECTIVE: To report baseline characteristics of junior-level faculty participants in the Summer Institute Programs to Increase Diversity (SIPID) and the Programs to Increase Diversity among individuals engaged in Health-Related Research (PRIDE), which aim to facilitate participants' career development as independent investigators in heart, lung, blood, and sleep research. DESIGN AND SETTING: Junior faculty from groups underrepresented in the biomedical-research workforce attended two, 2-3 week, annual summer research-education programs at one of six sites. Programs provided didactic and/or laboratory courses, workshops to develop research, writing and career-development skills, as well as a mentoring component, with regular contact maintained via phone, email and webinar conferences. Between summer institutes, trainees participated in a short mid-year meeting and an annual scientific meeting. Participants were surveyed during and after SIPID/PRIDE to evaluate program components. PARTICIPANTS: Junior faculty from underrepresented populations across the United States and Puerto Rico participated in one of three SIPID (2007-2010) or six PRIDE programs (2011-2014). RESULTS: Of 204 SIPID/PRIDE participants, 68% were female; 67% African American and 27% Hispanic/Latino; at enrollment, 75% were assistant professors and 15% instructors, with most (96%) on non-tenure track. Fifty-eight percent had research doctorates (PhD, ScD) and 42% had medical (MD, DO) degrees. Mentees' feedback about the program indicated skills development (eg, manuscript and grant writing), access to networking, and mentoring were the most beneficial elements of SIPID and PRIDE programs. Grant awards shifted from primarily mentored research mechanisms to primarily independent investigator awards after training. CONCLUSIONS: Mentees reported their career development benefited from SIPID and PRIDE participation. PMID- 28811737 TI - Learning and Developing Individual Exercise Skills (L.A.D.I.E.S.) for a Better Life: A Church-Based Physical Activity Intervention - Baseline Participant Characteristics. AB - OBJECTIVE: Physical activity (PA) is beneficial for health, yet most African American women do not achieve recommended levels. Successful, sustainable strategies could help to address disparities in health outcomes associated with low levels of PA. The Learning and Developing Individual Exercise Skills (L.A.D.I.E.S.) for a Better Life study compared a faith-based and a secular intervention for increasing PA with a self-guided control group. DESIGN SETTING AND PARTICIPANTS: This cluster randomized, controlled trial was conducted from 2010 - 2011 in African American churches (n=31) in suburban North Carolina. Participants were 469 self-identified low active African American women. MEASURES: Baseline data were collected on participant demographics, objective and self-reported PA, and constructs related to social ecological theory and social cognitive theory. RESULTS: Complete baseline data were available for 417 participants who were aged 51.4 +/- 12.9 years, with average BMI (kg/m2) 35.8 +/- 9.9; 73% of participants were obese (BMI >30). Participants averaged 3,990 +/- 1,828 pedometer-assessed daily steps and 23.9 +/- 37.7 accelerometer-assessed minutes of daily moderate-to-vigorous PA, and self-reported 25.4 +/- 45.4 minutes of weekly walking and moderate- and vigorous-intensity PA. Baseline self-reported religiosity and social support were high. CONCLUSIONS: L.A.D.I.E.S. is one of the largest PA trials focused on individual behavior change in African American women. Baseline characteristics suggest participants are representative of the general population. Findings from the study will contribute toward understanding appropriate strategies for increasing PA in high-risk populations. PMID- 28811738 TI - Predictors of Retention among African Americans in a Randomized Controlled Trial to Test the Healthy Eating and Active Living in the Spirit (HEALS) Intervention. AB - INTRODUCTION: Retention of racial/ethnic minority groups into research trials is necessary to fully understand and address health disparities. This study was conducted to identify participants' characteristics associated with retention of African Americans (AAs) in a randomized controlled trial (RCT) of a behavioral intervention. METHODS: Using data from an RCT conducted from 2009 to 2012 among AAs, participant-level factors were examined for associations with retention between three measurement points (ie, baseline, 3-month, and 12-month). Chi square tests and logistic regression analyses were conducted to compare retained participants to those who were not retained in order to identify important predictors of retention. RESULTS: About 57% of participants (n=238) were retained at 12 months. Baseline characteristics that showed a statistically significant association with retention status were age, marital status, body mass index (BMI), intervention group, enrollment of a partner in the study, and perceived stress score (PSS). Multivariable logistic regression that adjusted for age, BMI, and PSS showed the odds of being retained among participants who enrolled with a partner was 2.95 (95% CI: 1.87-4.65) compared with participants who had no study partner enrolled. The odds of being retained among participants who were obese and morbidly obese were .32 and .27 (95% CI: .14-.74 and .11-.69), respectively, compared with participants who had normal weight. CONCLUSION: Having a partner enrolled in behavioral interventions may improve retention of study participants. Researchers also need to be cognizant of participants' obesity status and potentially target retention efforts toward these individuals. PMID- 28811739 TI - A FEM-Experimental Approach for the Development of a Conceptual Linear Actuator Based on Tendril's Free Coiling. AB - Within the vastness of the plant species, certain living systems show tendril structures whose motion is of particular interest for biomimetic engineers. Tendrils sense and coil around suitable grips, and by shortening in length, they erect the remaining plant body. To achieve contraction, tendrils rotate along their main axis and shift from a linear to a double-spring geometry. This phenomenon is denoted as the free-coiling phase. In this work, with the aim of understanding the fundamentals of the mechanics behind the free coiling, a reverse-engineering approach based on the finite element method was firstly applied. The model consisted of an elongated cylinder with suitable material properties, boundary, and loading conditions, in order to reproduce the kinematics of the tendril. The simulation succeeded in mimicking coiling faithfully and was therefore used to validate a tentative linear actuator model based on the plant's working principle. More in detail, exploiting shape memory alloy materials to obtain large reversible deformations, the main tendril features were implemented into a nickel-titanium spring-based testing model. The results of the experimental tests confirmed the feasibility of the idea in terms of both functioning principles and actual performance. It can be concluded that the final set-up can be used as a base for a prototype design of a new kind of a linear actuator. PMID- 28811740 TI - Multiple Testing in the Context of Gene Discovery in Sickle Cell Disease Using Genome-Wide Association Studies. AB - The issue of multiple testing, also termed multiplicity, is ubiquitous in studies where multiple hypotheses are tested simultaneously. Genome-wide association study (GWAS), a type of genetic association study that has gained popularity in the past decade, is most susceptible to the issue of multiple testing. Different methodologies have been employed to address the issue of multiple testing in GWAS. The purpose of the review is to examine the methodologies employed in dealing with multiple testing in the context of gene discovery using GWAS in sickle cell disease complications. PMID- 28811742 TI - Respiratory T-Wave Inversion in a Patient With Chest Pain. AB - T-wave inversion on electrocardiogram (ECG) is always a concerning finding as it is often associated with myocardial ischemia or ventricular strain. Respiratory variation in the T-wave morphology has been reported in the literature; however, the frequency of this observation remains unknown as this is not routinely evaluated. Although the exact physiological mechanisms underlying this ECG change are unclear, it is proposed to be due to the respiratory variation of the heart position resulting in an alteration in T-wave polarity. We describe a case of a patient who presented with chest pain with T-wave inversions in inferior and lateral ECG leads. On repeating ECG with breath held in end inspiration, the T waves became positive. The pain was found to be musculoskeletal in origin. This case is a reminder of an under-recognized physiological phenomenon involving the cardiac conduction. Variation of T-wave morphology with respiration may suggest a noncardiac cause of chest pain. PMID- 28811741 TI - Consistency and Variability of DNA Methylation in Women During Puberty, Young Adulthood, and Pregnancy. AB - Prior DNA methylation (DNA-m) analyses have identified cytosine-phosphate-guanine (CpG) sites, which show either a significant change or consistency during lifetime. However, the proportion of CpGs that are neither significantly different nor consistent over time (indifferent CpGs) is unknown. We investigated the methylation dynamics, both longitudinal changes and consistency, in women from preadolescence to late pregnancy using DNA-m of peripheral blood cells. Consistency of cell type-adjusted DNA-m between paired individuals was assessed by regressing CpGs of subsequent age on the prior, stability by intraclass correlation coefficients (>0.5), and changes by linear mixed models. In the first 2 transitions (10-18 years and 18 years to early pregnancy), 19.5% and 20.9% CpGs were consistent, but only 0.35% in the third transition (from early to late pregnancy). Significant changes in methylation were found in 0.7%, 5.6%, and 0% CpGs, respectively. Functional enrichment analyses of genes with significant changes in DNA-m in early pregnancy (5.6%) showed that the maternal DNA-m seems to reflect signaling pathways between the uterus and the trophoblast. The transition from early to late pregnancy showed low consistency/stability and no changes, suggesting the presence of a large proportion of indifferent CpGs in late pregnancy. PMID- 28811743 TI - Retroperitoneal Bleeding: An Experience During Prophylactic Anticoagulation in a Patient With Nephrotic Syndrome. AB - The association between nephrotic syndrome (NS) and a hypercoagulable state has been demonstrated. Controlling the blood clotting activity may therefore be attractive for patients with nephrosis in terms of thromboembolism prophylaxis. We herein report a 75-year-old woman with minimal change disease who developed pains in the right back, groin, and thigh because of retroperitoneal bleeding during prophylactic anticoagulation with unfractionated heparin. Although this procedure has not been accepted as the standard of care for patients with nephrosis, pharmacologic prophylaxis may already be practiced empirically, as in the present patient. We believe that our experience highlights the pitfalls of such a management in patients with nephrosis, implying the need for a diagnostic strategy for identifying those patients with NS who can benefit from prophylactic anticoagulation. Several concerns that emerged in this case are also discussed. PMID- 28811744 TI - Cytogenetic Profile and FLT3 Gene Mutations of Childhood Acute Lymphoblastic Leukemia. AB - BACKGROUND: Childhood acute lymphoblastic leukemia (ALL) is characterized by recurrent genetic aberrations. The identification of those abnormalities is clinically important because they are considered significant risk-stratifying markers. AIMS: There are insufficient data of cytogenetic profiles in Saudi Arabian patients with childhood ALL leukemia. We have examined a cohort of 110 cases of ALL to determine the cytogenetic profiles and prevalence of FLT3 mutations and analysis of the more frequently observed abnormalities and its correlations to other biologic factors and patient outcomes and to compare our results with previously published results. MATERIALS AND METHODS: Patients-We reviewed all cases from 2007 to 2016 with an established diagnosis of childhood ALL. Of the 110 patients, 98 were B-lineage ALL and 12 T-cell ALL. All the patients were treated by UKALL 2003 protocol and risk stratified according previously published criteria. Cytogenetic analysis-Chromosome banding analysis and fluorescence in situ hybridization were used to detect genetic aberrations. Analysis of FLT3 mutations-Bone marrow or blood samples were screened for FLT3 mutations (internal tandem duplications, and point mutations, D835) using polymerase chain reaction methods. RESULT: Cytogenetic analysis showed chromosomal anomalies in 68 out of 102 cases with an overall incidence 66.7%. The most frequent chromosomal anomalies in ALL were hyperdiploidy, t(9;22), t(12;21), and MLL gene rearrangements. Our data are in accordance with those published previously and showed that FLT3 mutations are not common in patients with ALL (4.7%) and have no prognostic relevance in pediatric patients with ALL. On the contrary, t(9;22), MLL gene rearrangements and hypodiploidy were signs of a bad prognosis in childhood ALL with high rate of relapse and shorter overall survival compared with the standard-risk group (P = .031).The event-free survival was also found to be worse (P = .040). CONCLUSIONS: Our data are in accordance with those published previously, confirming the overall frequency of cytogenetic abnormalities and their prognostic relevance. PMID- 28811746 TI - Oral Care and Prevention of Pneumonia in Hospitalized Patients With Psychiatric Disorders in Japan. AB - PURPOSE: Oral care in hospitalized patients with psychiatric disorders is important. However, some patients with psychiatric disorders cannot undergo oral care because of psychiatric symptoms and cognitive decline. The effect of a standardized oral hygiene intervention on the prevention of pneumonia in hospitalized patients with psychiatric disorders was investigated. METHOD: Patients were divided into 2 groups: control group (N = 259), patients without standardized intervention who were enrolled on April 2014 as the time point of baseline, and intervention group (N = 263), patients with standardized intervention who were enrolled on April 2015 as the time point of baseline. Two end points were evaluated: (1) pneumonia onset within 1 year after the enrollment and (2) no pneumonia for 1 year after the enrollment. The following parameters were compared between the groups: sex, age, psychiatric disorders, past history of diseases of the respiratory system, hypertension, diabetes, hyperlipidemia, heart impairment, and pneumonia. RESULTS: No statistically significant differences were found between the 2 groups in the distributions of characteristics except pneumonia by univariate analysis. The presence of pneumonia was significantly associated with age and the absence of the standardized oral hygiene intervention by multivariate logistic regression analysis. CONCLUSIONS: The standardized oral hygiene intervention appears to be effective for preventing pneumonia in patients with psychiatric disorders. PMID- 28811745 TI - Inhibition of Inflammation Mediated Through the Tumor Necrosis Factor alpha Biochemical Pathway Can Lead to Favorable Outcomes in Alzheimer Disease. AB - Tumor necrosis factor alpha (TNF-alpha) inhibitors have long been used as disease modifying agents in immune disorders. Recently, research has shown a role of chronic neuroinflammation in the pathophysiology of neurodegenerative diseases such as Alzheimer disease, and interest has been generated in the use of anti-TNF agents and TNF-modulating agents for prevention and treatment. This article extensively reviewed literature on animal studies testing these agents. The results showed a role for direct and indirect TNF-alpha inhibition through agents such as thalidomide, 3,6-dithiothalidomide, etanercept, infliximab, exendin-4, sodium hydrosulfide, minocycline, imipramine, and atorvastatin. Studies were performed on mice, rats, and monkeys, with induction of neurodegenerative physiology either through the use of chemical agents or through the use of transgenic animals. Most of these agents showed an improvement in cognitive function as tested with the Morris water maze, and immunohistochemical and histopathological staining studies consistently showed better outcomes with these agents. Brains of treated animals showed significant reduction in pro inflammatory TNF-alpha and reduced the burden of neurofibrillary tangles, amyloid precursor protein, and beta-amyloid plaques. Also, recruitment of microglial cells in the central nervous system was significantly reduced through these drugs. These studies provide a clearer mechanistic understanding of the role of TNF-alpha modulation in Alzheimer disease. All studies in this review explored the use of these drugs as prophylactic agents to prevent Alzheimer disease through immune modulation of the TNF inflammatory pathway, and their success highlights the need for further research of these drugs as therapeutic agents. PMID- 28811747 TI - What establishes an excellent nurse? A focus group and Delphi panel approach. AB - BACKGROUND: Over the past few years, the complexity of the health care system in which nurses are required to practice has increased considerably, magnifying the need for excellent professionals with a specific set of knowledge, skills and attitudes. However, the characteristics that distinguish an excellent nurse have not yet been clarified. The aim of this study was to determine nurses' perspectives regarding characteristics associated with an excellent nurse in order to elicit a conceptual profile. METHOD: A focus group design followed by Delphi panel content validation was utilized. Information regarding nurses' perspectives was derived from six focus group discussions comprising 19 nurses involved in hospital practice and 24 nurses with experience in mental health care. The analysis of the focus group discussions resulted in nine domains whereby content validity was achieved with contributions from a Delphi panel survey with 26 professionals. RESULTS: As determined by the survey, a combination of these specified aspects characterize an excellent nurse: analytical, communicative, cooperative, coordinating, disseminates knowledge, empathic, evidence-driven, innovative and introspective. CONCLUSION: Determining what establishes an excellent nurse according to experienced nurses is valuable as this information can influence the broadening curriculum for educating future nurses to meet the needs in the professional field, contributing to the quality of care. This conceptual profile can be used as a reference guide for supervisors and professionals to personally improve their clinical practice as well as for education. PMID- 28811748 TI - Salivary diagnostic markers in males and females during rest and exercise. AB - BACKGROUND: Saliva is a useful diagnostic tool for analysis in sports, exercise and nutrition research, as collection is easy and non-invasive and it contains a large number of analytes affected by a range of physiological and pathological stressors and conditions. This study examined key salivary electrolytes and stress and immune markers in males and females at rest and during exercise. METHODS: Unstimulated whole saliva from 20 healthy, recreationally active participants (8 males and 12 females) was analysed for flow rate, osmolality, sodium (Na+), potassium (K+), chloride (Cl-), secretory immunoglobulin A (SIgA), alpha-amylase activity and cortisol during both rest and moderate intensity (70% peak power) cycling exercise in a randomised crossover design. Each trial lasted 60 min and sampling was carried out at 15 and 45 min after the start of the trial. Saliva was collected using the gold-standard drool method; participants were required to provide at least 1 mL sample over 2 or 3-min period. RESULTS: Females showed a greater response to steady-state exercise stress than males, with significant increases in osmolality (P < 0.001), alpha-amylase activity (P = 0.001) and secretion rate (P = 0.023) and SIgA secretion rate (P = 0.023), with trends for an increase in K+ (P = 0.053) and decrease in Cl- (P = 0.067). There were no differences between rest and exercise for any salivary analytes in males. In addition, females showed a trend for higher levels of cortisol than males at both rest (P = 0.099) and exercise (P = 0.070), as well as a higher heart rate (P < 0.001) and greater ratings of perceived exertion (P < 0.001) during the exercise trial. The coordination of the two stress response pathways (alpha amylase vs cortisol) was positive in males (r = 0.799; P = 0.017) yet negative in females (r = -0.475; P = 0.036). CONCLUSIONS: Males and females show a markedly different response to steady-state exercise stress as measured in unstimulated whole saliva. PMID- 28811749 TI - Acute cocoa Flavanols intake has minimal effects on exercise-induced oxidative stress and nitric oxide production in healthy cyclists: a randomized controlled trial. AB - BACKGROUND: Cocoa flavanols (CF) can stimulate vasodilation by improved nitric oxide (NO) synthesis and have antioxidant and anti-inflammatory capacities. This study aimed to examine whether acute CF intake can affect exercise-induced changes in antioxidant capacity, oxidative stress, inflammation and NO production, as well as exercise performance and recovery in well-trained cyclists. METHODS: Twelve well-trained male cyclists (mean +/- SD age, VO2max: 30 +/- 3 years, 63.0 +/- 3.5 ml/kg/min) participated in this randomized, double blind, cross over study. On 2 separate occasions, subjects performed two 30-min time trials 1.5 (TT1) and 3 (TT2) hours after CF (900 mg CF) or placebo (PL, 13 mg CF) intake, interposed by passive rest. Lactate, glucose, heartrate, rating of perceived exertion (RPE) and power output were measured during the TTs. Blood was drawn at baseline, before and after each TT and analyzed for epicatechin serum concentrations, trolox equivalent antioxidative capacity (TEAC), uric acid (UA), malonaldehyde (MDA), L-arginine/ADMA, citrulline, interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-alpha plasma concentrations. Relative changes in blood markers and pacing strategy during TT were analysed by repeated measured ANOVA. TT performance was compared between PL and CF by paired t-test. RESULTS: Epicatechin concentrations were increased by CF intake. Exercise-induced increase in TEAC/UA was improved by CF intake (F(1) = 5.57; p = .038) (post-TT1: PL: 113.34 +/- 3.9%, CF: 117.64 +/- 3.96%, post-TT2: PL: 108.59 +/- 3.95%, CF: 123.72 +/- 7.4% to baseline), while exercise-induced increases in MDA, IL-1 and IL-6 were not affected by CF intake. TNF-alpha was unaltered by exercise and by CF. Exercise-induced decreases in L-arginine/ADMA and increases in citrulline were not affected by CF intake. TT1 and TT2 performance and exercise-induced physiological changes were unaffected by CF intake. CONCLUSION: Acute CF intake increased total antioxidant capacity in rest and during exercise, but did not affect exercise-induced lipid peroxidation, inflammation, nor NO production in healthy athletes. Acute CF intake did not improve TT performance and recovery. TRIAL REGISTRATION: ISRCTN32875, 21-11-2016, retrospectively registered. PMID- 28811750 TI - Availability of a sports dietitian may lead to improved performance and recovery of NCAA division I baseball athletes. AB - BACKGROUND: The purpose was to survey dietary habits (DH) and nutrient timing (NT) practices of baseball student-athletes (mean +/- SD; 20.7 +/- 1.4 yr.) from three NCAA Division I institutions, and examine the effect of a sports dietitian (SD) in regard to nutrition practices. METHODS: Descriptive statistics and Pearson X2 analyses were run. Responses on 10 DH and 5 NT items differed (p <= 0.10) between athletes who sought dietary planning from a SD (n = 36) versus those who consulted a strength and conditioning coach (SCC, n = 42). RESULTS: In regard to DH items, the SD group found it easier to eat before activity (92% vs. 71%, p = 0.03), did not consume fast food (31% vs. 14%, p = 0.02), caffeinated beverages (57% vs. 46%, p = 0.02), or soda (56% vs. 37%, p = 0.10), prepared their own meals more often (86% vs. 73%, p = 0.07), and took daily multi-vitamins (56% vs. 32%, p = 0.02). The SCC group ate more at burger locations (21% vs. 6%, p = 0.02). In regard to NT items, the SD group ate breakfast before training/lifting sessions (67% vs. 37%, p = 0.02), and had post-workout nutrition options provided (61% vs. 27%, p = 0.01). The SCC group reported pre-competition meals of fast food (58% vs. 45%, p = 0.01), and sport coaches who were less aware of healthy food options (39% vs. 65%, p = 0.05). CONCLUSIONS: The SD is as a valuable asset to an intercollegiate athletics program. In the current study, athletes from the SD group consumed less high calorie/low nutrient dense items, ate before exercise, and consumed healthier options post-exercise. The presence of a SD was linked to provision of healthier food options during team trips. The evidence-based eating strategies and dietary plan provided by a SD may lead to improved performance and recovery. PMID- 28811751 TI - Bioactive Potential of 3D-Printed Oleo-Gum-Resin Disks: B. papyrifera, C. myrrha, and S. benzoin Loading Nanooxides-TiO2, P25, Cu2O, and MoO3. AB - This experimental study investigates the bioactive potential of filaments produced via hot melt extrusion (HME) and intended for fused deposition modeling (FDM) 3D printing purposes. The oleo-gum-resins from benzoin, myrrha, and olibanum in pure state and also charged with 10% of metal oxide nanoparticles, TiO2, P25, Cu2O, and MoO3, were characterized by ultraviolet-visible (UV-Vis) and Fourier transform infrared (FTIR) spectroscopy, energy-dispersive X-ray microanalysis (EDXMA), scanning electron microscopy (SEM), and differential scanning calorimetry (DSC). Disks were 3D-printed into model geometries (10 * 5 mm) and the disk-diffusion methodology was used for the evaluation of antimicrobial and antifungal activity of materials in study against the clinical isolates: Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Candida albicans. Due to their intrinsic properties, disks containing resins in pure state mostly prevent surface-associated growth; meanwhile, disks loaded with 10% oxides prevent planktonic growth of microorganisms in the susceptibility assay. The microscopy analysis showed that part of nanoparticles was encapsulated by the biopolymeric matrix of resins, in most cases remaining disorderly dispersed over the surface of resins. Thermal analysis shows that plant resins have peculiar characteristics, with a thermal behavior similar to commercial available semicrystalline polymers, although their structure consists of a mix of organic compounds. PMID- 28811752 TI - Occurrence and Epidemics of Bacterial Canker of Kiwifruit in Korea. AB - Bacterial canker is the largest limiting factor in the cultivation and production of kiwifruit worldwide. Typical symptoms comprise necrotic spots on leaves, canker and dieback on canes and trunks, twig wilting, and blossom necrosis. Pseudomonas syringae pv. actinidiae (Psa), which is the causal agent of kiwifruit bacterial canker, is divided into four biovars based on multilocus sequence analysis of different genes, additional PCR testing of pathogenic genes (argKtox cluster, cfl, and various effector genes), and biochemical and physiological characterization. Bacterial canker caused by Psa biovar 2 designated Psa2 was detected for the first time on the green-fleshed kiwifruit cultivar Hayward in 1988 and the yellow-fleshed kiwifruit cultivar Hort16A in 2006 in Korea. Psa biovar 3 designated Psa3, responsible for the current global pandemics of kiwifruit bacterial canker, began to appear in Korea in 2011 and caused tremendous economic losses by destroying many vines or orchards of yellow-fleshed kiwifruit cultivars in one or several growing seasons. Bacterial canker epidemics caused by both Psa2 and Psa3 are prevalent in Korea in recent years. In this review, we summarize the symptomatology, etiology, disease cycle, diagnosis, and epidemiology of kiwifruit bacterial canker in Korea. PMID- 28811753 TI - Characterization of the Rosellinia necatrix Transcriptome and Genes Related to Pathogenesis by Single-Molecule mRNA Sequencing. AB - White root rot disease, caused by the pathogen Rosellinia necatrix, is one of the world's most devastating plant fungal diseases and affects several commercially important species of fruit trees and crops. Recent global outbreaks of R. necatrix and advances in molecular techniques have both increased interest in this pathogen. However, the lack of information regarding the genomic structure and transcriptome of R. necatrix has been a barrier to the progress of functional genomic research and the control of this harmful pathogen. Here, we identified 10,616 novel full-length transcripts from the filamentous hyphal tissue of R. necatrix (KACC 40445 strain) using PacBio single-molecule sequencing technology. After annotation of the unigene sets, we selected 14 cell cycle-related genes, which are likely either positively or negatively involved in hyphal growth by cell cycle control. The expression of the selected genes was further compared between two strains that displayed different growth rates on nutritional media. Furthermore, we predicted pathogen-related effector genes and cell wall-degrading enzymes from the annotated gene sets. These results provide the most comprehensive transcriptomal resources for R. necatrix, and could facilitate functional genomics and further analyses of this important phytopathogen. PMID- 28811754 TI - Comparative Genome Analysis of Rathayibacter tritici NCPPB 1953 with Rathayibacter toxicus Strains Can Facilitate Studies on Mechanisms of Nematode Association and Host Infection. AB - Rathayibacter tritici, which is a Gram positive, plant pathogenic, non-motile, and rod-shaped bacterium, causes spike blight in wheat and barley. For successful pathogenesis, R. tritici is associated with Anguina tritici, a nematode, which produces seed galls (ear cockles) in certain plant varieties and facilitates spread of infection. Despite significant efforts, little research is available on the mechanism of disease or bacteria-nematode association of this bacterium due to lack of genomic information. Here, we report the first complete genome sequence of R. tritici NCPPB 1953 with diverse features of this strain. The whole genome consists of one circular chromosome of 3,354,681 bp with a GC content of 69.48%. A total of 2,979 genes were predicted, comprising 2,866 protein coding genes and 49 RNA genes. The comparative genomic analyses between R. tritici NCPPB 1953 and R. toxicus strains identified 1,052 specific genes in R. tritici NCPPB 1953. Using the BlastKOALA database, we revealed that the flexible genome of R. tritici NCPPB 1953 is highly enriched in 'Environmental Information Processing' system and metabolic processes for diverse substrates. Furthermore, many specific genes of R. tritici NCPPB 1953 are distributed in substrate-binding proteins for extracellular signals including saccharides, lipids, phosphates, amino acids and metallic cations. These data provides clues on rapid and stable colonization of R. tritici for disease mechanism and nematode association. PMID- 28811755 TI - A Novel Recombined Potato virus Y Isolate in China. AB - This study reports the findings of a distinct Potato virus Y (PVY) isolate found in Northeast China. One hundred and ten samples (leaves and tubers) were collected from potato plants showing mosaic symptoms around the city of Harbin in Heilongjiang province of China. The collected tubers were planted and let to grow in a greenhouse. New potato plants generated from these tubers showed similar symptoms, except for one plant. Subsequent serological analyses revealed PVY as the causing agent of the disease. A novel PVY isolate (referred to as HLJ-C-44 in this study) was isolated from this sample showing unique mild mosaic and crisped leaf margin symptoms. The complete genome of this isolate was analyzed and determined. The results showed that HLJ-C-44 is a typical PVY isolate. Phylogenetic analysis indicated that this isolate belongs to the N-Wi strain group of PVY recombinants (PVYN-Wi) and also shared the highest overall sequence identity (nucleotide and amino acid) with other members of this strain group. However, recombination analysis of isolate HLJ-C-44 revealed a recombination pattern that differed from that of other PVYN-Wi isolates. Moreover, biological assays in four different potato cultivars and in Nicotiana tabacum also revealed a different phenotypic response than that of a typical PVYN-Wi isolate. This data, combined, suggest that HLJ-C-44 is a novel PVY recombinant with distinct biological properties. PMID- 28811756 TI - Pseudomonas oleovorans Strain KBPF-004 Culture Supernatants Reduced Seed Transmission of Cucumber green mottle mosaic virus and Pepper mild mottle virus, and Remodeled Aggregation of 126 kDa and Subcellular Localization of Movement Protein of Pepper mild mottle virus. AB - Efforts to control viral diseases in crop production include several types of physical or chemical treatments; antiviral extracts of a number of plants have also been examined to inhibit plant viral infection. However, treatments utilizing naturally selected microorganisms with activity against plant viruses are poorly documented. Here we report isolation of a soil inhabiting bacterium, Pseudomonas oleovorans strain KBPF-004 (developmental code KNF2016) which showed antiviral activity against mechanical transmission of tobamoviruses. Antiviral activity was also evaluated in seed transmission of two tobamoviruses, Pepper mild mottle virus (PMMoV) and Cucumber green mottle mosaic virus (CGMMV), by treatment of seed collected from infected pepper and watermelon, respectively. Pepper and watermelon seeds were treated with culture supernatant of P. oleovorans strain KBPF-004 or control strain ATCC 8062 before planting. Seeds germinated after treatment with water or ATCC 8062 yielded about 60% CGMMV or PMMoV positive plants, whereas < 20% of KBPF-004-treated seeds were virus infected, a significantly reduced seed transmission rate. Furthermore, supernatant of P. oleovorans strain KBPF-004 remodeled aggregation of PMMoV 126 kDa protein and subcellular localization of movement protein in Nicotiana benthamiana, diminishing aggregation of the 126 kDa protein and essentially abolishing association of the movement protein with the microtubule network. In leaves agroinfiltrated with constructs expressing the coat protein (CP) of either PMMoV or CGMMV, less full-size CP was detected in the presence of supernatant of P. oleovorans strain KBPF-004. These changes may contribute to the antiviral effects of P. oleovorans strain KBPF-004. PMID- 28811758 TI - Pathological Interrelations of Soil-Borne Diseases in Cucurbits Caused by Fusarium Species and Meloidogyne incognita. AB - Pathological interrelations of two soil-borne diseases in cucurbits (watermelon, oriental melon, shintosa and cucumber) caused by Fusarium isolates (FI) and the root-knot nematode (RKN), Meloidogyne incognita were characterized by the fusarium disease severity index (DI), RKN gall index (GI) and eggmass index (EI) in inoculation tests using FI and RKN. Virulence of FI as determined by DI at 4 weeks after inoculation was mostly in the higher order of Fusarium proliferatum F6, F5 and Fusarium oxysporum f. sp. melonis or Fusarium oxysporum f. sp. niveum with no significant differential interactions among the cucurbits and RKN co infection. Significant increases of DI due to RKN coinfection were noticed in watermelon and oriental melon infected with F. proliferatum isolates, suggesting the DI increase due to RKN coinfection may depend upon the virulence of FI relative to aggressiveness of RKN on the cucurbits. For the coinfection of FI and RKN, GI and EI were mostly reduced logarithmically with the increase of DI, largely more in EI than GI, in all cucurbits except for shintosa. Microscopic examination of the root tissues showed histopathological features characteristic to infection types; formation of fungal hyphae and/or spores and plant defense structures (tyloses and mucilage) in variable degrees and formation of giant cells at variable developmental stages and with variable cytoplasmic depletion or degeneration which were visualized in relations with the values of DI, GI and EI. These findings will be helpful to develop control strategies of the soil-borne disease complex based on their pathological characteristics. PMID- 28811757 TI - Cyclic Dipeptides from Bacillus vallismortis BS07 Require Key Components of Plant Immunity to Induce Disease Resistance in Arabidopsis against Pseudomonas Infection. AB - Cyclic dipeptides (CDPs) are one of the simplest compounds produced by living organisms. Plant-growth promoting rhizobacteria (PGPRs) also produce CDPs that can induce disease resistance. Bacillus vallismortis strain BS07 producing various CDPs has been evaluated as a potential biocontrol agent against multiple plant pathogens in chili pepper. However, plant signal pathway triggered by CDPs has not been fully elucidated yet. Here we introduce four CDPs, cyclo(Gly-L-Pro) previously identified from Aspergillus sp., and cyclo(L-Ala-L-Ile), cyclo(L-Ala-L Leu), and cyclo(LLeu-L-Pro) identified from B. vallismortis BS07, which induce disease resistance in Arabidopsis against Pseudomonas syringae infection. The CDPs do not directly inhibit fungal and oomycete growth in vitro. These CDPs require PHYTOALEXIN DEFICIENT4, SALICYLIC ACID INDUCTION DEFICIENT2, and NONEXPRESSOR OF PATHOGENESIS-RELATED PROTEINS1 important for salicylic acid dependent defense to induce resistance. On the other hand, regulators involved in jasmonate-dependent event, such as ETHYLENE RECEPTOR1, JASMONATE RESPONSE1, and JASMONATE INSENSITIVE1, are necessary to the CDP-induced resistance. Furthermore, treatment of these CDPs primes Arabidopsis plants to rapidly express PATHOGENESIS RELATED PROTEIN4 at early infection phase. Taken together, we propose that these CDPs from PGPR strains accelerate activation of jasmonate-related signaling pathway during infection. PMID- 28811759 TI - Seed Transmission of Tomato yellow leaf curl virus in White Soybean (Glycine max). AB - Tomato yellow leaf curl virus (TYLCV) infection of the common bean (Phaseolus vulgaris) has been reported, but soybean (Glycine max) has not previously been identified as a TYLCV host. Five cultivars of white soybean were agro-inoculated using an infectious TYLCV clone. At 30 days post-inoculation, they showed infection rates of 25% to 100%. Typical TYLCV symptoms were not observed in any inoculated plants. To examine whether TYLCV was transmitted in soybean seeds, DNA was isolated from bundles of five randomly selected seeds from TYLCV-inoculated soybean plants and amplified with a TYLCV-specific primer set. With the exception of one bundle, all bundles of seeds were verified to be TYLCV-infected. Virus dissemination was also confirmed in three of the 14 bunches. Viral replication was also identified in seeds and seedlings. This is the first report demonstrating that soybean is a TYLCV host, and that TYLCV is a seed transmissible virus in white soybean. PMID- 28811760 TI - The Use of a Tobacco mosaic virus-Based Expression Vector System in Chrysanthemum. AB - Chrysanthemums (Chrysanthemum morifolium) are susceptible to tobacco mosaic virus (TMV). TMV-based expression vectors have been used in high-throughput experiments for production of foreign protein in plants and also expressing green fluorescent protein (GFP) to allow visualization of TMV movement. Here, we used TMV expressing the GFP to examine the infection of chrysanthemum by a TMV-based expression vector. Viral replication, movement and GFP expression by TMV-GFP were verified in upper leaves of chrysanthemums up to 73 days post inoculation (dpi) by RT-PCR. Neither wild-type TMV nor TMV-GFP induced symptoms. GFP fluorescence was seen in the larger veins of the inoculated leaf, in the stem above the inoculation site and in petioles of upper leaves, although there was no consistent detection of GFP fluorescence in the lamina of upper leaves under UV. Thus, a TMV-based expression vector can infect chrysanthemum and can be used for the in vivo study of gene functions. PMID- 28811761 TI - Incidence Rates of Major Diseases of Kiwiberry in 2015 and 2016. AB - Incidence rates of diseases in kiwiberry orchards were investigated monthly from late June to late September in Gwangyang and Boseong in 2015 and 2016. The impact of postharvest fruit rot was investigated during ripening after harvest. Bacterial canker was only observed on one single tree in 2015, but black rot, powdery mildew, leaf spot and blight, and postharvest fruit rot diseases were problematic throughout the study period in both 2015 and 2016. Incidence rates of the diseases varied with kiwiberry cultivar, region and sampling time. Incidence rates of powdery mildew, leaf spot and blight diseases increased significantly during the late growing stages near fruit harvest, while black rot peaked in late August. Incidence rate of postharvest fruit rot on fruit without fruit stalks was less than half of fruit with fruit stalks, regardless of kiwiberry cultivars. Among the four cultivars, Mansu was relatively resistant to black rot and postharvest fruit rot diseases. In our knowledge, this is the first report of various potential pathogens of kiwiberry in Korea. PMID- 28811762 TI - Revisiting the Randomized Controlled Trial. PMID- 28811763 TI - Microalbuminuria in Type-2 Diabetes Mellitus; the tip of iceberg of diabetic complications. AB - OBJECTIVE: To determine the prevalence of microalbuminuria and its association with hypertension and other diabetic complications among Type-2 diabetic patients attending at Aga Khan University Hospital Karachi. METHODS: 1280 Type-2 diabetes patients who visited the outpatient department of Aga Khan University Hospital from September 2014 to August 2016 were included in the study. Microalbuminuria was diagnosed if spot urinary microalbumin excretion was confirmed to be more than 20mg/l. Hypertension was diagnosed if BP >140/90 or already on antihypertensive medications. Other demographic, clinical and laboratory data were also recorded. RESULTS: Microalbuminuria was diagnosed in 404(31.56%) patients and among these albuminuric patients 335(82.9%) had hypertension. They were also dyslipidemic, having raised triglyceride levels, lower HDL levels, with more prevalence of background diabetic retinopathy and peripheral neuropathy. They also showed higher HbA1C levels and longer duration of diabetes. CONCLUSION: The prevalence of the microalbuminuria in our patients with Type-2 diabetes is 31.56% and is not only an early sign of diabetic nephropathy but also a host of other diabetic complications and should be dealt early with strict control of their hyperglycemia and hypertension to help prevent the future complications. PMID- 28811764 TI - Revisional Laparoscopic Sleeve Gastrectomy in failed gastric banding and effects of exercise and frequent sweet-eating on its outcome. AB - OBJECTIVE: To find out effectiveness of revisional laparoscopic sleeve gastrectomy (RLSG) in the patients who had laparoscopic adjustable gastric banding (LAGB) and failed to reduce or regained the weight and effectiveness of sweet abstaining and exercise on postoperative weight loss. METHODS: This retrospective observational study was conducted at AlMoosa Hospital, Al-Ahsa, Kingdom of Saudi Arabia from December 2011 to November 2016. The patients who failed to reduce, regained the weight or had complications after LAGB, were performed RLSG. They were followed-up at three, six, twelve and twenty-four months intervals. Their weight, percent excess weight loss (%EWL) and body mass index (BMI) at pre-RLSG were compared with post-RLSG. The data was recorded in SPSS 22 and analyzed. RESULTS: Thirty-six patients with male/female ratio of 1:5 underwent RLSG. Twelve (33.3%) were frequent sweet-eaters and twenty-four (66.7%) were not. Fourteen (38.88%) did not have exercise, while twenty-two (61.11%) had daily regular exercise. Their mean pre-RLSG weight, percent excess weight loss (%EWL)and BMI were compared with post-RLSG at the period of three, six, twelve and twenty-four months. Their mean weight reduced from 111.69 kilograms to 96.94, 87.25, 79.56 and 76.11 kilograms respectively. Their mean of the percent excess weight loss (%EWL) reduced to 22.08, 45.75, 59.64 and 66.42 kilograms respectively. Their mean pre-RLSG BMI was 43.50 kg.m-2, which reduced to the mean of 37.79, 34.02, 30.97 and 29.70 respectively. There were no post-operative complications in thirty (83.3%), mild like wound infection and seroma in four (11.1%) and bleeding in two (5.6%) patients. None of the patients had leakage. The patients who kept themselves abstained from sweet consumption and performed regular postoperative exercise had better results. They also had considerable reduction in appetite after RLSG. CONCLUSION: RLSG is an effective procedure after failed LAGB in terms of weight loss having minimal rate of complications. Moreover, abstaining from sweet consumption and continuing exercise postoperatively has better results. PMID- 28811765 TI - Regression of right ventricular systolic pressure after successful percutaneous mitral commissurotomy in patients with isolated severe mitral stenosis. AB - OBJECTIVE: To know the regression of right ventricular pressure after successful percutaneous transluminalmitral commissurotomy (PTMC) in patients with severe isolated mitral stenosis. METHODS: This descriptive study was performed in inpatient and outpatient department of National Institute of Cardiovascular Disease from 1st February 2016 to 31st August 2016. Echocardiography of all patients with successful PTMC were recorded 24 hours and 06 months following PTMC to see for Regression of right ventricular pressure along with other baseline echocardiographic parameters. RESULTS: A total of 99 patients with severe isolated mitral stenosis who had undergone successful PTMC were studied. Females were 65(65.7%) and males 34(34.3%). Mean age was 27.44+/-6.26 years. TTE performed before and after PTMC showed significant difference in mean mitral valve area (0.89cm +/-0.089cm2 vs. 1.68+/-0.128 cm2, p valve <0.001) and mean left atrial diameter (4.66+/- .82cm vs. 4.46+/- 0.65cm). Mean mitral valve gradient pre PTMC was significantly higher (16.38+/-2.51 mm of Hg) than that of post PTMC 24 hours (4.75+/-1.31 mm of Hg) and Post PTMC 06 months (5.22+/-1.21 mm of Hg), p valve <0.001. Mean right ventricular systolic pressure (RVSP) pre PTMC was significantly higher 62.3+/-10.91 mm of Hg than that of post PTMC 24 hour's 57.51+/-9.67 mm of Hg and post PTMC 06 moths 46.49+/-7.8mm of Hg, p value 0.001. Mean LVEF 50.14+/- 5.82. CONCLUSION: There was a significant regression of right ventricular pressure following successful PTMC in mid-term (06 months) follow up of severe isolated mitral stenosis patients. PMID- 28811766 TI - Prognostic Factors Determining Morbidity and Mortality in Organophosphate Poisoning. AB - OBJECTIVE: Our aim in this retrospective study was to determine the factors affecting poor prognosis and mortality of organophosphate (OP) poisoning by reviewing patient data. We also reviewed present knowledge to make conclusions on certain longstanding debates in light of the literature. METHODS: In this retrospective descriptive study, patients who were admitted to and hospitalized in the emergency department (ED) or intensive care unit (ICU) of a university hospital with the diagnosis of OP poisoning between December 2010 and December 2015 were evaluated. All the data were obtained from electronic and manual patient files. A total of 80 patients were included in the study. RESULTS: The mean age of the study patients was 32.4+/-15.0 (13-94). Forty-nine (61.2%) patients were female. Twenty-two (27.5%) patients were seriously poisoned and needed mechanical ventilation (MV) support. Low pseudocholinesterase (PChE), high creatinine (Cr), low Glasgow Coma Scale (GCS) scores and long hospitalization durations were all found to be poor prognostics in MV patients. Low PChE and high Cr levels were found to be independent predictors of the hospitalization duration and high Cr was found to be an independent predictor of the intubation duration of MV patients in regression analyses. Ten (45.5%) of the MV patients were unresponsive to medical treatment and Therapeutic plasma exchange (TPE) was performed. Seven patients were discharged healthy. Three patients with low PChE levels and comorbidities died. CONCLUSIONS: Prolongation of respiratory depression necessitating MV support, comorbidities, long hospital stay, elevated creatinine, low GCS scores and low PcHE levels without regeneration in the first 48 hours of admission are all found to be poor prognostic factors for organophosphate (OP) poisoning. PMID- 28811767 TI - Effectiveness and safety of recombinant human brain natriuretic peptide in the treatment of acute myocardial infarction in elderly in combination with cardiac failure. AB - OBJECTIVE: To investigate the effects and safety of recombinant human brain natriuretic peptide (rhBNP) in the treatment of elderly acute myocardial infarction induced cardiac failure. METHODS: One hundred and forty-six patients who were diagnosed as elderly acute myocardial infarction induced cardiac failure in the hospital from July 2014 to July 2015 were selected. They were divided into a test group and a control group, 73 each. Patients in both groups were given conventional treatment such as stabilization of atherosclerotic plaques, anti platelet and remodeling and reversion of myocardium. The curative effects and the incidence of adverse reactions of the two groups were observed. RESULTS: The overall efficacy of the test group and the control group was 87.7% and 65.8% respectively, and the difference had statistical significance (P<0.05). The heart rate, urine volume, n-terminal pro-brain natriuretic peptide level and left ventricular ejection fraction (LVEF) of both groups significantly improved after treatment, and the improvement of the test group was superior to that of the control group (P<0.05). The serum creatinine of the test group remarkably reduced after treatment (P<0.05). The incidence of hypotension and arrhythmia of the test group was lower than that of the control group during hospitalization period (P<0.05). CONCLUSION: rhBNP can effectively relieve the clinical symptoms, cardiac function indexes and hemodynamic indexes of patients with elderly acute myocardial infarction induced cardiac failure, with a high safety. It can be extensively applied in the treatment of acute myocardial infarction in combination with cardiac failure. PMID- 28811768 TI - Clinical predictors of an abnormal ultrasound in patients presenting with suspected nephrolithiasis. AB - OBJECTIVE: To determine any clinical features associated with an abnormal ultrasound in patients with suspected nephrolithiasis in an out-patient setting. METHODS: The study design was cross-sectional in nature. The study was conducted at an out-patient nephrology department of a tertiary care facility over a 3 month period. Patients included in the study were 18-80 years old, who presented with unilateral flank or costovertebral angle pain with or without other clinical features suggestive of renal or ureteric calculus based on clinician's judgement. Every patient's history was reviewed to obtain information on age, gender, location and radiation of pain, onset, severity and nature of pain, associated urinary and systemic symptoms and past history of nephrolithiasis. An ultrasound was considered to be abnormal if there was documented presence of renal or ureteric stone and/or unilateral hydronephrosis. RESULTS: A total of 209 patients were included in the study. Of these patients, 126 (60.3%) were males and 83 (39.7%) were females, 60 (28.7%) had prior history of nephrolithiasis. Ultrasound was abnormal in 110 patients (52.9%). On a multivariate logistic regression analysis, only past history of nephrolithiasis (OR 3.3, 95% CI 1.65-6.7) was associated with an abnormal ultrasound. CONCLUSION: In the absence of any significant clinical predictors use of ultrasound is justified in patients with suspected nephrolithiasis especially in those with prior history of stones. PMID- 28811769 TI - Significance of electronic health records: A comparative study of vaccination rates in patients with sickle cell disease. AB - OBJECTIVE: In this study, we investigated the influence of electronic health records (EHR) and electronic vaccination schedule applications on the vaccination status of patients who were admitted to our Center for the treatment of sickle cell disease (SCD). METHODS: The vaccination status against influenza and pneumococcus infection was determined in 93 patients who were admitted to the hematology outpatient clinic, Baskent University Adana Hospital from April 2004 to March 2009. The vaccination status was then re-evaluated following establishment of EHR and electronic vaccination schedules in 2012. RESULTS: Of the 93 patients with SCD 21.5% (n = 20) were vaccinated against pneumococcus and 21.5% (n = 20) were regularly vaccinated against influenza. When the vaccination rates of 59 of 93 patients who presented for their regular control examinations were analyzed following establishment of EHR and vaccination schedules in 2012, these rates were 49.2% (n = 29) and 50.8% (n = 30) for influenza and pneumococcus, respectively, after EHR; there were 23.7% (n = 14) and 20.3% (n = 12), respectively, before EHR. A statistically significant difference was found between the vaccination rates before and after EHR (p < 0.05). CONCLUSION: Although viral and bacterial infections are life-threatening health problems in patients with SCD, the vaccination rates were low in high-risk patients. However, these rates increased after application of electronic vaccination schedules. PMID- 28811770 TI - Clinical and laboratory profile of children with Cystic Fibrosis: Experience of a tertiary care center in Pakistan. AB - OBJECTIVE: To determine the clinical presentation, diagnostic investigations and laboratory workup done in admitted children with cystic fibrosis at Aga Khan University Hospital Karachi, Pakistan. METHODS: This is athree years retrospective study from January 2013 to December 2015 conducted at The Aga Khan University Hospital Karachi Pakistan, enrolling admitted patient from birth to 15 years of either gender, diagnosed with CF on the basis of clinical features and positive sweat chloride test. Different clinical presentations were noted including initial presentations. Sweat chloride values more than 60mmol/L were labeled as positive and consistent with diagnosis of CF. Available Delta F-508 mutation analyses were noted. Relevant laboratory and radiological investigations including sputum culture and HR-CT chest findings were documented. Results were analyzed using SPSS version 20. RESULTS: Total 43 children were selected according to the inclusion criteria. Chronic cough (69.76%) was the most common initial clinical presentation. Mean age at onset of symptoms was 14.41+/- 26.18 months and mean age at diagnosis was 47.20 +/- 45.80 months Respiratory features were most common in our cohort including chronic productive cough (90.71%), recurrent bronchopneumonia (72.09%) and asthma like presentation (44.19%) with wheezing and cough. 86% patients presented with failure to thrive. Gastroenterological features including steatorrhea were seen in 55.81% patients and 44.19% patients had abdominal distension. Mean sweat chloride value in our population was 82.70+/- 22.74. Gene analysis for Delta F-508 was identified in 12 (27.90%) patients. Bronchiectatic pulmonary changes on HRCT were seen in 18 patients (41.86%). Pseudomonas grew in 12 patients (27.90%) in sputum cultures at the time of diagnosis. CONCLUSION: Respiratory presentations predominate in CF children followed by gastrointestinal features. Nearly half of our patient had bronchiectatic changes on CT scan chest and more than quarter had pseudomonas colonization in the airways at the time of diagnosis. Delta F-508 mutation was found to be uncommon in our study population. There is significant delay in diagnosing patients with CF. PMID- 28811771 TI - Predictive value of stathmin-1 and osteopontin expression for taxan resistance in metastatic castrate-resistant prostate cancer. AB - OBJECTIVE: Several pathways are known to be activated during metastasis and treatment of cancer. We investigated the role of osteopontin (OPN) and stathmin-1 (STHMN1) in metastatic castrate-resistant (mCRPC). METHODS: We included 30 patients who received at least 6 cycles of taxane regimen for metastatic mPC in the present study. For this study retrospective data was taken from Firat University, Faculty of Medicine, Medical Oncology Department between 2009 and 2015. OPN expression and STHMN1 expression were retrospectively evaluated by immunohistochemical staining in biopsy specimens. The relationship between the expression levels of OPN and STMN1 and the response to taxane based regimen and survival was analyzed. RESULTS: There was mild or strong overexpression of OPN and STHMN1 in all the patients. STHMN1 expression was mildly positive (+2) in four of the cases (13.2%) while it was strongly positive (+3) in 25 (83.4%) cases. Similarly, OPN expression was mildly positive (+2) and strongly positive (+3) in five (16.6%) and 25 (87.4%) patients, respectively. There was no significant correlation between the expression levels of STHMN1 and OPN, survival, and response to taxane based regimen (p>0.05); however, OPN overexpression showed a significant correlation with lower Gleason scores (GS) (p:0.032). CONCLUSIONS: STHMN1 and OPN may be prognostic markers although they are not predictive markers of response to treatment in mCRPC. The overexpression of OPN may help identifying patients with lower GS. PMID- 28811772 TI - Values of procalcitonin and C-reactive proteins in the diagnosis and treatment of chronic obstructive pulmonary disease having concomitant bacterial infection. AB - OBJECTIVE: To observe the changes in the levels of C-reactive protein (CRP) and procalcitonin (PCT) in serum of patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and to compare with the values of CRP in combination with PCT in the diagnosis and treatment of infective exacerbation of COPD. METHODS: One hundred and sixty-four patients who developed acute exacerbation of COPD and admitted to the Binzhou People's Hospital from March 2014 to December 2015 were selected. They were divided into an infection group (N=98) and a non-infection group (N=66) according to bacterial culture results of sputum and lung computer tomography (CT) examination results. Moreover, 50 healthy people were selected as a normal control group. The levels of PCT and CRP of the three groups were determined respectively; patients in the infection group and non-infection group were determined again after administration of antibacterial drugs for a period of time. The results were all recorded. RESULTS: The levels of PCT and CRP of the infection group were significantly higher than those of the non-infection group and the normal control group before treatment, and the difference had statistical significance (P<0.05). The levels of PCT and CRP were (1.97+/-0.13) MUg/L and (7.34+/-2.66) mg/L respectively in the infection group after treatment, which was much lower than the levels before treatment (P<0.05). The level of PCT of the infection group was remarkably higher than that of the non-infection group after treatment (P<0.05), but the difference of CRP level between the infection group and non-infection group had no statistical significance (P>0.05). The specificity and sensitivity of diagnosing COPD in combination with bacterial infection with PCT or CRP were lower than those of PCT in combination with CRP. CONCLUSION: Levels of CRP in combination with PCT is a reliable index for determining the existence of bacterial infection, which is of great clinical guidance significance to the treatment and prognosis assessment of AECOPD patients. PMID- 28811773 TI - Transepithelial corneal crosslinking in treatment of progressive keratoconus: 12 months' clinical results. AB - OBJECTIVE: The purpose of this study was to evaluate the safety and efficacy of transepithelial corneal collagen cross linking (TE-CXL) with modified riboflavin and accelerated UVA irradiance in thin corneas with pachymetry less than 400 microns at thinnest point, untreatable by epithelium off corneal collagen cross linking (CXL) in adult Pakistani population with progressive keratoconus. METHODS: This quasi experimental study included twenty six eyes of 26 patients with progressive keratoconus who underwent accelerated transepithelial CXL in Armed forced institute of ophthalmology with 12 months follow up. Modified riboflavin, ParaCel ((riboflavin 0.25%, Benzalkonium chloride, EDTA, Trometamol, hydroxypropyl methylcellulose) and vibeX Xtra (riboflavin 0.25%) (Avedro, USA)) were applied to cornea in two stages. Uncorrected and Corrected Distant Visual Acuities (UDVA, CDVA), spherical equivalent (SE), astigmatism, pachymetry at thinnest point (Pachy thin), apex keratometry (Kmax), simulated and steep keratometry (Sim K, steep K) were measured at baseline and at 3, 6 and 12 months post operatively. The cornea was then exposed to accelerated UVA irradiance of 9mW/cm2 for 10 min (total dose 30 mW/cm2). RESULTS: The mean age of the patient was 24.54+/-5.16 years. UDVA, CDVA, SE, astigmatism significantly improved at all postoperative test points (p=0.000, 0.004, 0.000, 0.004 respectively). Kmax and pachy thin were significantly reduced over baseline at 1 year (p=0.000, 0.004 respectively). Topographic indices Sim K and steep K did not show significant changes. No intra or post-operative complications were reported. CONCLUSION: Transepithelial accelerated CXL with modified riboflavin is a safe and effective procedure which halt disease progression in thin corneas with progressive keratoconus. PMID- 28811774 TI - Effects of supervised structured aerobic exercise training program on fasting blood glucose level, plasma insulin level, glycemic control, and insulin resistance in type 2 diabetes mellitus. AB - OBJECTIVE: To determine the effects of supervised structured aerobic exercise training (SSAET) program on fasting blood glucose level (FBGL), plasma insulin level (PIL), glycemic control (GC), and insulin resistance (IR) in type 2 diabetes mellitus (T2DM). METHODS: Riphah Rehabilitation and Research Centre (RRRC) was the clinical setting for this randomized controlled trial, located at Pakistan Railways General Hospital (PRGH), Rawalpindi, Pakistan. Study duration was 18 months from January 1, 2015 to June 30, 2016. Patients of both genders ranging 40-70 years of age with at least one year of history of T2DM were considered eligible according to WHO criteria, while patients with other chronic diseases, history of smoking, regular exercise and diet plan were excluded. Cohorts of 195 patients were screened out of whom 120 fulfilled the inclusion criteria. Amongst them 102 agreed to participate and were assigned to experimental (n=51) and control (n=51) groups. Experimental group underwent SSAET program, routine medication and dietary plan, whereas the control group received routine medication and dietary plan, while both group received treatment for 25 weeks. The blood samples were taken at baseline and on the completion of 25 weeks. The investigation of fasting blood glucose level, plasma insulin level, and glycemic control was conducted to calculate IR. RESULTS: Patients with T2DM in experimental group (n=51) treated with SSAET program, routine medication and dietary plan significantly improved FBGL (pre-mean= 276.41+/-25.31, post mean=250.07+/-28.23), PIL (pre-mean=13.66+/-5.31, post-mean=8.91+/-3.83), GC (pre mean=8.31+/-1.79, post-mean 7.28+/-1.43), and IR (pre-mean=64.95+/-27.26, post mean 37.97+/-15.58), as compared with patients in control group treated with routine medication and dietary plan in whom deteriorations were noted in FBGL (pre-mean=268.19+/-22.48, post-mean=281.41+/-31.30), PIL(pre-mean=14.14+/-5.48, post-mean=14.85+/-5.27) GC (pre-mean=8.15+/-1.74, post-mean=8.20+/-1.44, and IR (pre-mean=64.49+/-23.63. post-mean=70.79 +/-23.30). Statistically at the baseline the results were not significant (p>0.05), but at the completion of 25 weeks intervention all the variable showed significant results (p<0.05. CONCLUSION: It is concluded that a 25 weeks SSAET program along with routine medical management is more effective treatment in the management of fasting blood glucose level, glycemic control, plasma insulin level and insulin resistance as compared with routine medical management and dietary plan in the management of T2DM. PMID- 28811775 TI - Metformin attenuate PTZ-induced apoptotic neurodegeneration in human cortical neuronal cells. AB - OBJECTIVE: Seizures are one of the neurodegenerative disorders of human being. Metformin has antioxidant properties and commonly used as an oral antidiabetic drug. The current study was aimed to observe the neuroprotective effect of metformin against PTZ-induced apoptotic neurodegeneration in human cortical neuronal cell culture. METHODS: To observe that exposure of pentylenetetrazol (PTZ) at the dose of (30mM) for 30 minutes induced neuronal cell death by activation of caspase-3 in human cortical neuronal 2 (HCN-2) cell line. While the metformin at the dose of (20mM) along with PTZ for 30 minutes showed neuroprotection against PTZ-induced neuronal cell loss by MTT assay and Western blot analysis. RESULTS: The results of this study showed that PTZ-induced neuronal cell death by activation of pro apoptotic proteins caspase-3 and 9 whereas the exposure of metformin showed its protective effect against neuronal loss in HCN-2 cell line. Finally, our results showed that exposure of metformin can prevent the harmful effect induced by PTZ in neuronal cells cultures. CONCLUSIONS: Our finding suggest that metformin exposure attenuates PTZ-induced neuronal cell death may act as a safe therapeutics and neuroprotective agent for the treatment of neuronal loss as result of seizure. PMID- 28811776 TI - Role of Ramadan specific diabetes education (RSDE); A prospective study. AB - OBJECTIVE: To observe the role of Ramadan Specific Diabetes Education (RSDE) in the management of fasting patients with diabetes. METHODS: This prospective study was carried out at out-patients department (OPD) of Baqai Institute of Diabetology & Endocrinology (BIDE), in 2012. Recruitment of patients started a month prior to Ramadan. Muslim patients with diabetes whether had their first or on follow up visit to the OPD and showed intention to hold fast in the month of Ramadan, were included. A printed broacher focused on six cardinal areas of fasting and diabetes identified in Ramadan specific guidelines was given to all participants. All patients had their first visit to the OPD (n=32) were also given RSDE on one-to-one basis (Group A). Whereas patients had follow up visit were advised to attend a group session on RSDE. Those attended (n= 25) and those did not opt (n=45) the group session were included in Group B and Group C respectively. All participants were instructed to visit the OPD after Ramadan. Group D was constituted after Ramadan. It included patients who had not visited the OPD during induction period thus did not receive RSDE (n=76) they however hold fast in the month of Ramadan. Data regarding compliance to structured education through different modes was collected during post Ramadan visit. RESULTS: Comparisons among groups who received education(A with B with C) revealed non-significant difference in self-monitoring of blood glucose, alteration of drug dosage and timing, appreciation of hypoglycemia and action taken on development of hypoglycemic symptoms. However, significant differences were noted when group who received education was compared individually with group who did not receive education. CONCLUSION: Patients who receive Pre-Ramadan diabetes education were found to be significantly better in following Ramadan specific diabetes management recommendations compared to patients who did not receive education. Further large scale studies are needed to validate our findings. PMID- 28811777 TI - Acute renal morbidities with obstetrical emergencies: An important women health issue. AB - OBJECTIVE: To observe the impact of acute renal morbidities with obstetrical emergencies on maternal health. METHODS: In this study pregnant women between 28 40 weeks gestational period and delivered women in their puerperal period up to 42 days after delivery having acute renal problems associated with obstetrical emergencies were included. Pregnant and delivered women with obstetrical emergencies and associated other morbidities were excluded. These women were registered on the predesigned proforma after taking written informed consent and taking approval from institutional ethic research committee. The data was collected and analyzed on SPSS version 21. RESULT: Out of these 196 total registered women, majority of these women 81(41.32%) were between 21-30 years of age and multiparous women with parity four and above were 83(42.34%). Commonest presenting symptoms were generalized oedema 123(62.75%) and oligouria 92(46.93%). Frequent obstetrical emergencies observed were pre-eclampsia 53(27.04%), post partum haemorrhage 48(24.48%) and ante partum haemorrhage 36(18.36%) women. The complete recovery was observed in 86(43.87%) women, while mortality was seen in 56(28.57%) women. CONCLUSION: Renal morbidities were more frequently observed in obstetrical emergencies leading to high morbidity and mortality rate. PMID- 28811778 TI - Effects of blood lipid stability on progression of carotid atherosclerosis. AB - OBJECTIVE: To evaluate the effects of blood lipid stability on progression of carotid atherosclerosis. METHODS: A total of 416 patients who had physical examination in our hospital annually from January 2010 to December 2015 were selected and divided into a progression group (n=216) and a non-progression group (n=200) according to the intima-media thickness measured by carotid ultrasound. The levels of lipid-related parameters within five years were retrospectively analyzed to calculate the smoothness index (SI = x+/-/s). RESULTS: The cross sectional TG, HDL-C, ApoAI, ApoB, ApoE and Lpa levels were similar in the two groups (p>0.05). The non-progression group had significantly higher TC ((4.15+/ 0.82 vs. 4.50+/-1.04) mmol/L) and LDL-C ((2.53+/-0.76 vs. 2.99+/-1.03) mmol/L) levels than those of the progression group (p<0.05). The progression group had significantly lower TC SI (5.29+/-1.28 vs. 5.65+/-1.76), TG SI (2.13+/-0.71 vs. 2.79+/-0.82), LDL-C SI (3.66+/-1.17 vs. 4.36+/-1.58), ApoB SI (3.37+/-0.88 vs. 3.62+/-0.95) and Lpa SI (1.53+/-0.49 vs. 1.62+/-0.43) than those of the non progression group (p<0.05). CONCLUSION: Compared with cross-sectional results, SI was better correlated with the progression of atherosclerosis. The progression group had lower SI values. PMID- 28811779 TI - Effect of exercise and morphine on psychological and physical dependencies, BDNF and TrkB gene expression in rat's hippocampus. AB - OBJECTIVES: To compare the effect of exercise and morphine on abstinence syndrome and hippocampal gene expression in rat model. METHODS: Thirty adult male rats were exposed to voluntary wheel exercise (low, medium, high) for 28 days. The subjects entered Conditioned Place Preference (CPP) apparatus and experienced morphine (low, medium, high) CPP and followed by naloxone test. Correlation between exercise level, morphine injection, concurrent morphine administration and exercise with morphine CPP, BDNF and TrkB genes was determined. Rats were euthanized, decapitated and the hippocampus was removed. The expression of BDNF and TrkB genes were evaluated by real time PCR. RESULTS: Active rats ran an average of 839.18 m/d. A significant (P<0.001) correlation between exercise level, morphine injection, concurrent morphine administration and exercise with morphine CPP and BDNFand TrKB gene expressions was found. CONCLUSION: Voluntary exercise in different levels potentiates the brain rewarding system, CPP scale, and hippocampal BDNF and TrKB expressions. High range of voluntary exercise demonstrated an increase in the likelihood of developing addictive and drug seeking behavior. PMID- 28811780 TI - Role of Vitamin D in reducing number of acute exacerbations in Chronic Obstructive Pulmonary Disease (COPD) patients. AB - BACKGROUND AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is characterized by chronic incompletely reversible poor airflow and air trapping and usually this debilitating disorder limits the outside activities of the patients depriving them of sunlight which is a rich source of Vitamin D. The objective of this study was to determine the effect of vitamin D supplementation in reducing number of acute exacerbation in COPD patients. METHODS: This randomized control trial was conducted at East Medical Ward Mayo Hospital Lahore from January to December 2015 as exacerbations of COPD are season dependent. Diagnosis was confirmed by performing Pulmonary Function Tests (PFTs). Basic demographical information was obtained and baseline PFTs of the patient was done. Only Group A patients was treated with oral vitamin D intake of 2000 IU daily for 6 months. Vitamin D level was measured at 0, 2, 4, and 6 months and exacerbation of COPD, FEV1 and FVC was measured weekly. Both the groups were given standard treatment for exacerbation of COPD. Spirometry was repeated at each visit. Blood samples were collected every 2 months for vitamin D. Supplementation was stopped if vitamin D level exceeded 100ng/ml. RESULTS: The mean age of the patients was 46.28+/-8.83 years, the male to female ratio was 1.8:1. The mean 25(OH) level at baseline was 24.08+/-2.58 and at 6th month was 29.60+/-8.74. The mean FVC at baseline was 77.83+/-5.49 and at 6th month was 91.34+/-5.52. The exacerbation at baseline was present in all 120(100%) patients and at 6th month was reduced to 4(3.3%). CONCLUSION: Vitamin D supplementation has significant effect in reducing number of acute exacerbation in COPD patients when it is given for prolonged period. PMID- 28811781 TI - Screening of adult dental patients visiting Khyber College of Dentistry, Peshawar for HBV and HCV infections and identifying the associated risk factors. AB - OBJECTIVE: To screen out adult patients for HBV and HCV infections visiting Khyber College of Dentistry Peshawar (KCD) for different dental treatments and to identify the associated risk factors. METHOD: This cross-sectional study was conducted at Khyber College of Dentistry, Peshawar in the year 2013. A total of 1540 patients >15 years, visiting KCD for seeking different dental treatments were screened for hepatitis B & C. Informed consent was taken before blood collection and filling of a structured questionnaire. Blood samples were tested against HBsAg and anti HCV by using ICT that were further confirmed by ELISA. The data was analyzed using Epi info version 6. RESULTS: A total of 1540 patients were screened during the study. Among these 36.4%(561) were males and 63.6%(979) were females. Overall prevalence of HBV and HCV was 5.12%(79). On screening, 2.14%(33) were found to be HBs Ag positive of which 2.5%(14) were males and 1.9%(19) were females. HCV was found positive in 2.98%(46) individuals having male to female ratio of 1.6% and 3.8%. Frequency of HBsAg was high in age group 56-65 year and HCV in 36-45 year group. Previous history of IV/IM injections, spouse patient of hepatitis, blood transfusion, surgical operation were found significant risk factors in the transmission of both hepatitis B and C, while previous history of dental treatment and sharing of clippers were significant risk factor in spreading hepatitis C infection only. CONCLUSIONS: Overall prevalence of HCV was higher than HBV. Previous history of injections, spouse patient of hepatitis, blood transfusion, surgical operation were found significant risk factors in the transmission of both hepatitis B and C. PMID- 28811782 TI - Clinical effects of pulmonary surfactant in combination with nasal continuous positive airway pressure therapy on neonatal respiratory distress syndrome. AB - OBJECTIVE: To analyze the therapeutic effect of pulmonary surfactant (PS) in combination with nasal continuous positive airway pressure (NCPAP) therapy on neonatal respiratory distress syndrome (NRDS). METHODOLOGY: Forty-nine neonates who were diagnosed as NRDS and admitted in our hospital from May 2014 to June 2015 were selected and divided into an observation group and a control group. The observation group was treated with PS and NCPAP. The control group was treated only with NCPAP. The clinical symptoms, pulmonary X-ray, arterial partial pressure of oxygen (PaO2) and prognosis of the two groups were observed. RESULTS: Twelve hours after treatment, the partial pressure of carbon dioxide and oxygenation index decreased significantly (P<0.05), and PaO2 and ratio of arterial/pulmonary oxygen partial pressures increased significantly (P<0.05). Pulmonary X-ray examination showed that 78.3% of the observation group and 53.8% of the control group were relieved 12-24 hour after treatment, between which the difference was statistically significant (P<0.05). The improvement rate of the observation group was significantly higher than that of the control group (82.6% vs. 57.7%, P<0.05), the incidence of complications was significantly lower in the observation group (P<0.05), and the average length of stay in the observation group was significantly shorter (P<0.05). CONCLUSION: Both methods effectively treated NRDS, but PS in combination with NCPAP better improved oxygenation, reduced mortality and incidence of complications. PMID- 28811783 TI - Incidence and associated risk factors of low birth weight babies born in Shaikh Khalifa Bin Zayad Al-Nayan Hospital Muzaffarabad, Azad Jammu and Kashmir. AB - BACKGROUND AND OBJECTIVE: Birth weight is the most important factor that affects infant and child mortality. The most common cause of low birth is malnutrition before and during the pregnancy period. The present study was conducted to explore the associated risk factors of low birth weight which will be helpful to undertake effective measures to reduce the incidence of the low birth weight babies. METHODS: The study was conducted at Shaikh Khalifa Bin Zayad Al-Nayan Hospital Muzaffarabad. A sample size of 1603 live births over a period of five months were analyzed. The pregnant women were recruited in the last trimester of their pregnancy and followed up till their delivery. Information regarding maternal age, parity, income of family, gestational age, maternal occupation, degree of illiteracy, birth interval was collected. The birth weight was recorded within 24 hours of delivery. Data analysis was done using Graph Pad Prism version 6.0. RESULTS: Data of 1863 birth out of which 1603 were live births and among these live births, 1442 were normal birth weight babies and 161 number of low birth weight (LBW) were analyzed. The incidence of LBW in this study was (10.04%). LBW was more common in female (n=84) than in male (n=77) babies. However, this difference was statistically insignificant. Among different risk factors maternal age (p<0.05), parity (P = 0.0167), income of family (P = 0.0190), has a statically significant association with incidence of LBW. The gestational age of mother, maternal occupation, degree of illiteracy was found to affect the incidence of LBW babies, however the difference was found to be statistically insignificant for LBW. Birth interval less than three years and low hemoglobin level (P<0.0260) was found to have a significant association with LBW babies. CONCLUSION: LBW a common problem in Pakistan is an important factor for perinatal mortality and morbidity. Among different risk factors maternal age, parity, income of family, gestational age of mother, maternal occupation, degree of illiteracy, birth interval less than three years were found to be the important risk factors contributing to LBW babies born in Shaikh Khalifa Bin Zayad Al- Nayan Hospital Muzaffarabad. PMID- 28811784 TI - Does the effectiveness of core stability exercises correlate with the severity of spinal stenosis in patients with lumbar spinal stenosis? AB - OBJECTIVE: To determine whether the effectiveness of core stability exercises correlates with the severity of spinal stenosis in patients with degenerative lumbar spinal stenosis. METHODS: Forty-two patients with degenerative lumbar spinal stenosis treated in the department of orthopedics of our hospital between May 2013 and January 2016 were included in the study. All the patients performed core stability exercises once daily for six weeks, and the clinical outcomes were evaluated using Japanese Orthopaedic Association (JOA) score and self-reported walking capacity. The anteroposterior osseous spinal canal diameter was measured to evaluate the severity of spinal stenosis. The correlation between the stenosis degree and the differences of Japanese Orthopaedic Association score or self reported walking capacity at baseline and after treatment were analyzed. RESULTS: The patients were divided into three groups according to the spinal stenosis degree. In the three groups, there was no significant difference in JOA or self reported walking distance at baseline (p>0.05) and after treatment (p>0.05). The JOA scores and self-reported walking distance were significantly increased after treatment (p<0.05) in any of the three groups when compared to the baseline. Also, there was no significant correlation between the stenosis degree and the difference of JOA (p>0.05) or self-reported walking distance (p>0.05). CONCLUSION: There was no significantcorrelation between the effectiveness of core stability exercises and the severity of spinal stenosis in patients with degenerative lumbar spinal stenosis. PMID- 28811785 TI - Estimation of body fat in Pakistani adult: A comparison of equations based upon skinfold thickness measurements. AB - OBJECTIVE: To compare three different body fats estimation equations using skin fold measurements with bioelectrical impedance analysis. METHODS: A total of 130 subjects were included from Department of Endocrinology and Metabolism, Services Hospital, Lahore from 1st April 2016 to 30th Sep. 2016. The triceps, biceps, subscapular, chest, thigh, abdominal, suprailiac skinfold thickness of the subjects was measured with skin-fold calipers (Harpenden) on non-dominant side. The percentage fat mass (%FM) predicted by using each skin-fold-thickness equations namely Durnin & Womersley, Jackson & Pollock and Sloan was compared with %FM measured using a bioelectrical impedance analyzer (BIA). RESULTS: The mean age of subjects was 48.75+/-10.7 years, mean BMI was 29.08+/-6.09 kg/m2. The mean %FM calculated by Durnin & Womersley (32.408+/-0.584), Jackson & Pollock (24.658+/-0.527), Sloan (20.40+/-0.545). The %FM by BIA was 38.182+/-0.529. All three equations showed positive correlation but underestimated %FM as compared to BIA. CONCLUSION: All three BF estimation equations underestimate body fat percentage compared to BIA. Among the three, Durnin & Womersley equation shows best positive correlation and hence it can be used for estimation of percentage fat mass as an alternate to BIA. PMID- 28811786 TI - Examining the postural awareness and flexibility changes in physical therapy students who took clinical Pilates class. AB - OBJECTIVE: This study aimed to evaluate postural awareness and changes in posture and flexibility of students who took Clinical Pilates class as an elective course at the undergraduate level. METHODS: The study conducted from 2013-2016 included 98 students who took Clinical Pilates class at the Department of Physical Therapy and Rehabilitation, School of Health Sciences, Istanbul Medipol University, Turkey. The flexibility levels of the study participants were measured before and after the Clinical Pilates education using finger-to-floor test and modified Schober's test. Observational posture analysis and postural awareness were recorded using the scale prepared by the researchers. RESULTS: The post-education evaluations showed that postural distortions were fixed, and a significant increase in the postural awareness of the students was observed compared with the pre-education period. The results of both modified Schober's test and finger-to floor test, which were used to measure the flexibility levels, showed a statistically significant increase in post-education scores compared with those of the pre-education period. CONCLUSION: This study showed that the Clinical Pilates course increased postural awareness and flexibility of physical therapy students and fixed postural distortions. Thus, the inclusion of Clinical Pilates class in the undergraduate education is considered to be important. PMID- 28811787 TI - Association between Vitamin D deficiency and Breast Cancer. AB - OBJECTIVE: To determine the association between vitamin D deficiency and breast cancer. METHODS: This case control study included 94 female patients aged 20-75 years of any marital status and parity. Newly diagnosed 42 breast cancer patients who presented to surgical OPD of Dow University Hospital from Jan 2016 to June 2016 were included into the study as "cases" after informed consent. Age-matched 52 females who presented to OPD for complain other than breast pathology were included as the "control group". The sociodemographic of both cases and controls and histopathological characteristics of cases were recorded. Serum 25-(OH)2D levels were studied by the ELISA technique and recorded in ng/ml. Vitamin D deficiency was considered at serum level less than 20 ng/ml. RESULTS: Mean age was 40.1 Years for controls and 47.6 Years for cases. Mean height, weight and BMI did not differ between cases and controls. Serum Vitamin D levels were significantly lower in cases (85.7%) than controls (55.8%). The unadjusted and adjusted ORs for breast cancer in cases and controls showed a statistically significantly increased risk of breast cancer with low vitamin D concentration (p value0.003). After adjustment for age, parity, BMI, sun exposure, economic status and education status the ORs (95% CIs) for breast cancer risk was7.8 (1.99 - 30.58) for women with vitamin D concentrations <20 ng/mL. CONCLUSION: Findings of our study conclude that vitamin D deficiency is associated with risk of breast cancer. PMID- 28811788 TI - Clinical results of femoral head fracture-dislocation treated according to the Pipkin classification. AB - OBJECTIVE: To summarize the clinical results of femoral head fracture-dislocation treated according to Pipkin classification. METHODS: Atotal of 19 patients with femoral head fracture-dislocation were retrospectively analyzed from Mar. 2008 to Mar. 2015. According to the classification of Pipkin criteria, there were 4 cases in Type-I, 6 cases in Type-II, 6 cases in Type-IIIand 3 cases in Type-IV. Various procedures were taken according to the different types of the fracture, the time of the fracture, and the age of the patients. X-ray was examined during the follow-up period and functional evaluation was carried out by Harris Hip Score's criteria. The clinical therapeutic effects were analyzed. RESULTS: All the patientsgot a mean follow-up of 18 months (9-36 months). No patient suffered from infection, skin flap necrosis and X-ray showed no implants loosening or breakage. According to the Harris Hip Score's criteria, in Type-I, 4 cases were rated as excellent. In Type-II, 2 cases rated as excellent, 3 cases as good and 1 case as fair. In Type-III, 3 cases rated as good, 2 cases as fair and 1 case as poor. In Type-IV, 1 case rated as excellent, 1 case as good and 1 case as fair. The overall rate of excellent and good was 73.7%. CONCLUSIONS: Pipkin classification is helpful to make preoperative plan and judging the prognosis in cases of femoral head fracture-dislocation. However, multiple factors such as the time from injury to surgery, the ages of patients, the selection of implants should also be considered, which may affect the clinical results. PMID- 28811789 TI - Single incision laparoscopic cholecystectomy with conventional instruments and ports: Initial experience at tertiary care public sector Hospital. AB - OBJECTIVE: To find out safety and feasibility of single incision laparoscopic cholecystectomy (SLIC) using conventional instruments. METHODS: This study was conducted at surgical department of LUMHS Jamshoro Pakistan from Jan: 2014 to Dec: 2015. All cases of symptomatic cholelithiasis that consented for laparoscopic surgery were included. The exclusion criteria were acute cholecystitis, acute gall stone pancreatitis, common bile duct stones and patients with co-morbid. A midline 3cm incision made supraumbilically and 10mm port placed. Two 5mm ports placed on either side of umbilicus slightly superior and laterally in or-der to triangulate. A 2/0 prolene suture placed through the infundibulum of the gall bladder to achieve retraction. The rest of the procedure is like standard 4 ports laparoscopic cholecystectomy. RESULTS: Total no of cases were 50. The age ranged from 30-59 years (mean 35.20 years +/-4.886.) There were 43(86%) females and 07(14%) males. The mean operating time was 80 minutes (range 50-120 +/-16.020). Four (8%) cases were converted to standard four ports laparoscopic cholecystectomy due to bleeding and difficult dissection in Calot's triangle. Minimal blood loss was observed during the procedure with no postoperative complications. The range of hospital stay was 1-2 days (mean 1.08 +/-0.274). CONCLUSION: SILC is a safe and feasible procedure with conventional laparoscopic instruments without additional cost of single port and articulated instruments. The cosmetic results are excellent with minimal increase in the operating time. PMID- 28811790 TI - Cardiorespiratory fitness and its association with adiposity indices in young adults. AB - OBJECTIVE: This study investigated the relationship between cardiorespiratory fitness (CRF) and adiposity in young adults. METHODS: Data was collected from 133 students of a medical college of Pakistan. The study was conducted on young adults, aged 17-24 years, recruited from Jinnah Medical & Dental College, Karachi, between Aug-Dec, 2015. Queen's College Step Test was conducted to measure CRF and maximal oxygen uptake (VO2max) evaluated. Anthropometric measurements (body mass index, body fat, visceral fat, waist circumference) were taken to assess adiposity. Associations of VO2max and adiposity were analyzed. RESULTS: The prevalence of overweight/obesity was 44% overall. The VO2max (ml/kg/min) of males and females was 55.41+/-9.45 and 39.91+/-3.14, respectively, the gender difference being highly significant (p<0.001). Quartiles of VO2max showed strong inverse relationship between adiposity and VO2max, obese individuals having low VO2max (1st quartile) and normal weight individuals having high VO2max (4th quartile). VO2max correlated greatest with body fat in males (r = -0.600; p<0.001), and waist circumference in females (r = -0.319; p=0.004). CONCLUSION: The results indicate low CRF in young females and a strong inverse relationship between fitness levels and adiposity in young adults of both genders. Improving these parameters in our young population may prevent development of chronic non-communicable disease in later life. PMID- 28811791 TI - Differentiation of beta thalassemia trait from iron deficiency anemia by hematological indices. AB - OBJECTIVE: We aimed at finding out reliable parameter in the differentiation of iron deficiency anemia (IDA) and beta-thalassemia trait (beta-TT) in the adult population subjected to Saudi Arabian Premarital Screening Program. METHODS: A total of 620 adults (age range 21-36 years) reported during February 2012 to November 2012. Tests for serum iron and ferritin were carried out in individuals showing low hemoglobin (Hb). All the selected subjects' samples were subjected to blood morphology, comparison of MCV, RBC count. Red Cell Distribution Width (RDW) was noted from the Coulter Report whereas Red Cell Distribution Width Index (RDWI) value was calculated for all the samples. RESULTS: A total of one hundred &thirty-five individuals with hypochromic microcytic anemia having normal hemoglobin F and hemoglobin A2 < 3.2% were inducted in the study. Ninety-three were diagnosed having IDA, whereas thirty-two were having betaTT. Ten individuals revealed other causes of anemia. The RBC count was higher, and MCV was much lower in betaTT as compared to IDA. Both groups were subjected to RDW and RDWI, however, RDWI which showed better sensitivity and specificity for betaTT. CONCLUSION: RDWI is a reliable and useful index for differentiation among IDA and betaTT, as compared to RDW. PMID- 28811792 TI - Antimicrobial susceptibility patterns of clinical isolates of Pseudomonas aeruginosa isolated from patients of respiratory tract infections in a Tertiary Care Hospital, Peshawar. AB - OBJECTIVE: This study aims to determine the prevalence and susceptibility pattern of Pseudomonas aeruginosa and multidrug-resistant (MDR) isolates in patients suffering from respiratory tract infection. METHODS: A cross sectional study was conducted from January to December 2014 in Northwest General Hospital and Research Centre, Peshawar. A total of 615 sputum samples were collected from both in and out-patients. Sputum samples were collected as per standard procedure and were inoculated on Blood, MacConkey and Chocolate agar. The isolates were identified by standard protocols using biochemical tests. The antibiotic susceptibility pattern of each isolate was checked as per Clinical and Laboratory Standards Institute (CLSI) guidelines using Kirby-Bauer's disc diffusion method. RESULTS: Out of 615 sputum samples, 354 (57.56%) were culture positive. Out of these a total of 71 (20.05%) strains of Pseudomonas were isolated, where 54.93% was from males and 45.07% were from females (Mean age was 44.29 +/- 22.72:). Highest sensitivity was seen to Amikacin (92.86%) followed by Meropenem (91.55%) while lowest sensitivity was seen to Cefoperazone + Sulbactam (16.9%). There were 39.44% MDR strains, out of which 25% were Extensively Drug Resistant (XDR) and 10.71% were Pan Drug Resistant (PDR). In vitro susceptibility of MDR isolates showed highest sensitivity to Amikacin (82.14%) followed by Carbapenems (78.57%). All MDR isolates were resistant to Cefoperazone + Sulbactam. Resistance to Piperacillin + Tazobactam was 96.43%. CONCLUSION: Pseudomonas aeruginosa is one of the commonly isolated organisms and it is becoming more resistant to commonly used antibiotics. Carbapenems and aminoglycosides were the two classes of drugs that showed highest activity against Pseudomonas aeruginosa. PMID- 28811793 TI - Effectiveness and safety of percutaneous vertebroplasty in the treatment of spinal metastatic tumor. AB - OBJECTIVE: To evaluate the effectiveness, safety and feasibility of percutaneous vertebroplasty in the treatment of spinal metastatic tumor. METHODS: Thirty-four patients with spinal metastatic tumor who received treatment in the First Affiliated Hospital of Zhengzhou University from May 2014 to June 2015 were selected. Totally fifty diseased vertebrae were treated by percutaneous vertebroplasty. The curative effects were evaluated according to visual analogue scale (VAS) score, Oswestry Dability Index (ODI) and dose of pain reliever. The leakage conditions of bone cement and clinical complications were observed. The patients were followed up for 3 to 12 months. RESULTS: The average VAS score and ODI 24 h after treatment were much lower than those before treatment, and the difference had statistical significance (P<0.05). The average VAS score and ODI at different follow-up periods after treatment were not significantly different (P>0.05). During follow up, nine patients stopped taking pain reliever, the dose of 18 patients had obvious reduction, and 7 patients kept previous dose; the incidence of bone cement leakage was 38.25%. Six patients had fever after surgery, but recovered after expectant treatment; 2 patients felt uncomfortable in the right lower limbs, but relieved after expectant treatment. CONCLUSION: Percutaneous vertebroplasty can relieve pain efficiently, improve the daily living ability, and significantly enhance the living quality of patients with spinal metastatic tumors, with small trauma and high safety. PMID- 28811794 TI - Comparing the effects of two different contact lenses on corneal re epithelialization after corneal collagen cross-linking. AB - OBJECTIVE: To investigate whether keratoconus (KC) patients who applied the corneal collagen cross-linking (CXL) and two different contact lens (CL) showed any differences in complaints and findings following the CXL. METHODS: This prospective, comparative, double-blind clinical study involved 60 eyes of 60 patients (38 female and 22 male). At the end of the CXL procedure, CL (Balafilcon A) was inserted in 29 patients (Group-1) while CL with different material content (Hioxifilcon A) designed for therapeutic/bandage purposes were inserted in 31 patients (Group-2). RESULTS: On the 1st and 3th day after the CXL, there were no statistically significant differences between the groups in terms of the postoperative symptoms. On the 3th day after the CXL, all cases of both two groups were found to complete the corneal re-epithelialization. There was more PE ratio in the patients who had allergic conjunctivitis. CONCLUSIONS: With the use of Balafilcon A and Hioxifilcon A lens materials, KC patients who underwent the CXL were found to have similar symptoms and clinical findings after the CXL. However, epithelial staining and PE were observed more in KC cases accompanied by allergic conjunctivitis. PMID- 28811795 TI - Comparison of adjunctive therapy with metformin and acarbose in patients with Type-1 diabetes mellitus. AB - OBJECTIVE: All the aforementioned data have stimulated interest in studying other potential therapies for T1DM including noninsulin pharmacological therapies. The present study attempts to investigate the effect of adjunctive therapy with metformin and acarbose in patients with Type-1 diabetes mellitus. METHOD: In a single-center, placebo-controlled study (IRCT201102165844N1) we compared the results of two clinical trials conducted in two different time periods on 40 patients with Type-1 diabetes mellitus. In the first section, metformin was given to the subjects. After six months, metformin was replaced with acarbose in the therapeutic regimen. In both studies, subjects were checked for their BMI, FBS, HbA1C, TGs, Cholesterol, LDL, HDL, 2hpp, unit of NPH and regular insulin variations. RESULTS: Placebo-controlled evaluation of selected factors has showna significant decrease in FBS and TG levels in the metformin group during follow up but acarbose group has shown substantial influence on two hour post prandial (2hpp) and regular insulin intake decline. Moreover, Comparison differences after intervention between two test groups has shown that metformin has had superior impact on FBS and HbA1C decline in patients. Nonetheless, acarbose treatment had noteworthy influence on 2hpp, TGs, Cholesterol, LDL, and regular insulin intake control. CONCLUSION: The results of this experiment demonstrate that the addition of acarbose or metformin to patients with Type-1 diabetes mellitus who are controlled with insulin is commonly well tolerated and help to improve metabolic control in patients. PMID- 28811796 TI - Visual outcome after phacoemulsification with lens implant in diabetic and non diabetic patients; A comparative study. AB - OBJECTIVE: To compare the visual outcomes of phacoemulsification surgery with intraocular lens (IOL) in persons with and without diabetes at end of follow-up. METHODS: This was a comparative, cross sectional, observational study with Non probability, purposive sampling. After approval from "Research Ethical Committee of Isra Post-graduate Institute of Ophthalmology Karachi, 92 patients with cataract in one eye were selected. Patients were divided into two groups. Group A consisted of 48 diabetics and group B consisted of 44 non- diabetics with or without diabetes in the age group >= 30 years were included. Patients with small Pupil, Pseudo exfoliation Syndrome, Diabetic Retinopathy, and positive history of Uveitis, Glaucoma, and Macular Degeneration were excluded. Data analysis was performed by SPSS Version 20.0. RESULTS: Best Corrected Visual Acuity (BCVA) in diabetic patients improved from 0.813 +/- 0.181 Log MAR pre operatively to 0.183 +/- 0.143 after the period of six months post-operatively. Corresponding results in non-diabetics were 0.66 +/- 0.31 and 0.08 +/- 0.092 Log Mar (P value = 0.001). If WHO criteria was considered, 87.5% diabetics and 92% non-diabetics achieved normal vision (Log Mar 0 to 0.5; >= 6/12,) on the first post-operative day. Remaining 12.5% diabetics and 8% non-diabetics achieved moderate vision (0.6 to 1 Log MAR) on first post-operative day improving to normal vision within a week. CONCLUSION: Visual outcomes in diabetics after phacoemulsification with intra ocular lens implant is almost as good as that in non-diabetic patient if the diabetics have no retinopathy and have good glycemic control. PMID- 28811797 TI - CT findings and features of postoperative abdominal infection patients with pancreatic carcinoma. AB - OBJECTIVE: To investigate the values of Computed Tomography (CT) in diagnosing postoperative pancreatic surgeryabdominalinfection and its efficacy and to provide a reasonable method for the diagnosis of abdominal infection. METHODS: Seventy-two patients who were confirmed as resectablepancreatic carcinoma by physical examination, CT, positron emission tomography (PET)/CT, endoscopic retrograde cholangiopancreatography (ER-CP), endoscopic ultrasonography and mesenteric angiography and were admitted to the Binzhou People's Hospital, Shandong, China, from July 2013 to July 2015 were randomly selected. The plain CT images and clinical data of the patients were retrospectively analyzed. RESULTS: Among 72 patients, 32 patients were diagnosed as abdominal infection by CT, three patients were misdiagnosed (two cases of intestinal obstruction and one case of intraperitoneal abscess), and 2 patients were wrongly diagnosed as suppurative abdominal inflammation. As regards distribution of CT imaging positive performance, the number of patients with intestinal loop abscess accounted for 41.7%, subphrenic abscess for 16.7%, pelvic abscess for 33.3%, the existence of septation for 25%, and emphysema sign for 16.7%. As to the distribution of CT findings of intestinal obstruction, 46.1% of patients had dilatation of intestine, 30.8% for bowel wall thickening, 7.7% had abnormal enhancement, 11.1% had density abnormality, and 15.4% had mesenteric effusion. CT features of purulent peritonitis showed 57.1% of patients had peritoneal thickening, 42.9% had peritoneal effusion, 42.9% had free intraperitoneal air, 14.3% had intestinal walls edema, and 28.6% had mesenteric edema. CONCLUSION: The diagnosis of postoperative abdominal infection of patients with pancreatic carcinoma using CT is quick and efficient showing the pattern and distribution of collection and the gross reaction to the exciting infection. PMID- 28811798 TI - An experience with mesh versus darn repair in inguinal hernias. AB - BACKGROUND & OBJECTIVE: The inguinal hernia accounts for 50 percent in old age males. A Lichtenstein type of operation has now become the method of choice in most developed countries but in the developing world traditional simple suture repair is still in common practice in resource limited hospitals due to the scarcity and expensive nature of the commercial prosthetic mesh. Our objective was to compare the rates of complications in Lichtenstein repair to tension free Darn repair. METHODS: Ninety two male patients from 20-60 years of age reported for direct or indirect inguinal hernia with open Mesh/Lichtenstein or darn repair in emergency or electively from January 2014 to December 2015 were enrolled in this prospective randomized control trial (RCT). The primary end point was to compare the surgical site infection, length of hospital stay and hernia recurrence with different techniques. RESULTS: The hospital stay was higher in patients who had Lichtenstein repair, Superficial surgical site infections in cohort A (6.5%) and cohort B (4.36%)were noted. Complications of recurrence in Group-A were (1.5%) as compared to Group-B which had a recurrence of 6.52%. CONCLUSION: Lichtenstein is more promising in comparison to Darn repair in terms of recurrence in inguinal hernia. PMID- 28811799 TI - Diversity, Physiochemical and Phylogenetic Analyses of Bacteria Isolated from Various Drinking Water Sources. AB - OBJECTIVE: To evaluate the indigenous bacterial strains of drinking water from the most commercial water types including bottled and filtered water that are currently used in Saudi Arabia. METHODS: Thirty randomly selected commercial brands of bottled water were purchased from Saudi local markets. Moreover, samples from tap water and filtered water were collected in sterilized glass bottles and stored at 4 degrees C. Biochemical analyses including pH, temperature, lactose fermentation test (LAC), indole test (IND), methyl red test (MR), Voges-Proskauer test (VP), urease test (URE), catalase test (CAT), aerobic and anaerobic test (Ae/An) were measured. Molecular identification and comparative sequence analyses were done by full length 16S rRNA gene sequences using gene bank databases and phylogenetic trees were constructed to see the closely related similarity index between bacterial strains. RESULTS: Among 30 water samples tested, 18 were found positive for bacterial growth. Molecular identification of four selected bacterial strains indicated the alarming presence of pathogenic bacteria Bacillus spp. in most common commercial types of drinking water used in Saudi Arabia. CONCLUSION: The lack of awareness about good sanitation, poor personal hygienic practices and failure of safe water management and supply are the important factors for poor drinking water quality in these sources, need to be addressed. PMID- 28811800 TI - A comparative study of functional outcome of treatment of intra articular fractures of distal radius fixed with percutaneous Kirschner's wires vs T-plate. AB - BACKGROUND & OBJECTIVE: Fractures of the distal radius are common with a variable prognosis in case of intra articular extension. The available options include Plaster, External fixation, Prefabricated Splintage using Ligamentotaxis, K-wire fixation, and open reduction internal fixation with T-plate without an as yet clear advantage of one over the others. If these fractures are allowed to collapse, radial shortening, angulation and articular incongruity may cause permanent deformity and loss of function. This limited small scale study was intended to compare the functional results of treatment of these fractures with a T plate and K-wires. METHODS: This was a prospective experimental study conducted at department of Orthopedics of PGMI/Lahore General Hospital, Lahore. Total 30 patients were included and randomized into two groups of 15 patients each. Group A patients were treated with Krischner's wires and Group-B patients were treated with a T-Plate with open reduction. Informed consent was taken. Post operative follow up was done for 12 weeks for the outcome parameters (Green and O'Brien score). RESULTS: Mean age of patients in Group-A and B was 36.13+/-9.81 and 44.73+/-7.86 years respectively. In Group-A there were 10 male and 5 female patients and in Group-B there were 8 male and seven female patients respectively. In Group-A nine patients presented with Fernandez type-II and six patients presented with Fernandez type-III fracture. While in Group-B 10 patients presented with Fernandez type-II and five patients presented with Fernandez type III fracture. Among Group-A patient's final outcome was excellent in 86.67% patients while in Group-B only 53.33% patients had excellent outcome at three months follow up. CONCLUSION: Percutaneous Kirschner's wires appeared to be more effective as compared to T-Plate fixation in terms of functional outcome for treating intra-articular distal radius fractures. PMID- 28811801 TI - Pakistan Journal of Medical Sciences: A bibliometric assessment 2001-2010. AB - OBJECTIVE: The aim of this study was to measure the growth of scientific research, authors' productivity, affiliation with the institute and geographic locations published in the Pakistan Journal of Medical Sciences during the period of 2001 - 2010. METHODS: This numerical analysis was conducted during mid-August 2016 to mid-October, 2016. The data for the study was downloaded from websites of e-journal of Pakistan Journal of Medical Sciences (PJMS) and Pak Medi-Net Com. RESULTS: A total number of 1199 articled were covered by PJMS in 10 volumes and 40 issues with contribution of 3798 (3%) authors during 2001 - 2010. The average number of papers per issue is 30%. A gender wise contribution of males was higher 3050 (80%) than the females 748 (20%). A majority of articles were multi-authored 1052 (87%) as opposed to single author contribution 147 (13%). All 1199 articles were covered under four major disciplines i.e Basic medical sciences, medicine & allied, surgery & allied and radiological sciences and 39 sub-specialties according to medical subject headings (MeSH). It observed that 467 (39%) articles were published in Pakistan and 732 (61%) articles produced by other 32 countries. The Karachi city of Pakistan has produced 199 (16%) articles as highest as its national level and followed by Tehran (Iran) 77 (6%) as followed internationally. CONCLUSION: This study reveals that the participation of 32 countries in the PJMS publications proves it to be an internationally circulated journal to support research with the constant approach of publishing articles to each volume in basic medical sciences, biomedical, clinical and public health sciences. Abbreviations: DOAJ: Directory of Open Access Journals IMEMR: Index Medicus Eastern Mediterranean Region HEC: Higher Education Commission (Pakistan) PJMS: Pakistan Journal of Medical Sciences MeSH: Medical Subject Headings PMDC: Pakistan Medical & Dental Council SCIE: Science Citation Index Expanded. PMID- 28811802 TI - Clinical features and risk factors for irritable bowel syndrome in Migraine patients. AB - OBJECTIVE: Clinical and basic research increasingly suggests a correlation between migraine and irritable bowel syndrome (IBS). In this study, we aimed to explore the clinical features and risk factors for IBS in migraine patients. METHODS: This was a retrospective, cross-sectional study. A total of 1,112 consecutive patients from the internal medicine and emergency departments of three hospitals from June 2014 through 2016. A comprehensive interviewer administered questionnaire was designed based on the International Classification of Headache Disorders, 3rd edition (beta version). RESULTS: The response rate was 94.6%. Among 1,052 participants, 287 suffered from migraine (27.3%) and 312 suffered from IBS (29.7%). A total of 79 patients suffered from both migraine and IBS (comorbidity rate: 7.5%). The migraine cohort exhibited a higher frequency of IBS than did the comparison cohort at baseline (P<0.05). Migraine patients with higher headache frequency, longer length of headache history, and anxiety disorders were more likely to also suffer from IBS (P=0.015). There were no significant differences between the two groups in age, sex, family history, duration of headache attack, migraine aura, headache intensity, or depression disorders (P>0.05). Multiple regression analysis indicated length of headache history and headache frequency were associated with IBS. CONCLUSION: Migraine patients with a long headache history, recurrent episodic headache attacks, and anxiety were more likely to have IBS. PMID- 28811803 TI - A study of Galactin-3 on fine needle aspiration as a diagnostic marker differentiating benign from malignant thyroid neoplasm. AB - BACKGROUND & OBJECTIVE: Thyroid nodules are very common in our setup and their diagnosis on fine needle aspiration is not easy and is a taxing affair. It is a challenge to differentiate between follicular adenoma and follicular carcinoma without histology. Our objective was to investigate the role of Galectin-3 in fine needle aspirates of thyroid nodules as a prospective diagnostic marker and consequently its ability to differentiate benign from malignant neoplasms. METHODS: The research was conducted at the department of Pathology, King Edward Medical University, in association with other teaching institutions of Lahore from June 2012 to July 2014.. Sixty cases of solitary thyroid nodules were included in the study. Haematoxylin and eosin staining of the fixed smears and Galectin-3 immunohistochemical staining of the sections prepared from the cell block was performed. RESULTS: There were 60 patients in our study with a mean age of 33.35 years. The Bethesda system for reporting thyroid cytopathology was used to classify the smears and only categories IV, V and VI were included. On histological examination of the resected nodules there were 38.3% (23/60) cases of follicular adenoma, 46.6% (28/60) were of papillary carcinoma and follicular carcinoma made up to 15% (9/60) of all cases. Galectin-3 was negative in 100% (23/23) cases of follicular adenomas. Out of 37 malignant cases 65% lesions showed positivity, while 35% showed negativity for this immunomarker. Considering the malignant lesions, 75% cases of papillary carcinomas showed a positive reaction while only 33% of follicular carcinomas were positive for the immunomarker. This showed that the positive expression was more common in papillary as compared to follicular carcinomas. CONCLUSION: Galectin 3immunomarker is considerably expressed in malignant tumors, but it is not expressed in benign follicular lesions. PMID- 28811804 TI - Prevalence of sexual dysfunction in saudi women with Type 2 diabetes: Is it affected by age, glycemic control or obesity? AB - OBJECTIVE: Sexual dysfunction (SD), as a diabetes mellitus (DM)-related complication, is common among patients having diabetes. This study aimed to ascertain the prevalence of SD in Saudi women with type 2 DM and to determine whether age, glycemic control, and obesity are associated with SD or not. METHODS: A total of 275 Saudi women with type 2 diabetes took part in this cross sectional study and filled out the Female Sexual Function Index through a fill coded questionnaire in primary care clinics in King Khalid University Hospital, Riyadh, in the period between January 2013 and May 2013. The level of glycosylated hemoglobin and the body mass index were assessed to evaluate the DM control status and obesity among the patients. RESULTS: SD was reported by 88.7% of the Saudi women with type 2 diabetes. The results showed a significant association between the presence of SD and the increase in age of patients at 92% in the age group above 50 years. Glycemic control did not show a significant association with SD. The obesity factor showed a slight increase in SD by weight, but it was not statistically significant. CONCLUSION: The prevalence of SD among the Saudi women having type 2 diabetes is high and increases with age. No association was found between SD and glycemic control. PMID- 28811805 TI - Diagnosis and phenotypic assessment of Pakistani Haemophilia B carriers. AB - OBJECTIVES: 1: To assess the diagnostic utility of three polymorphisms (DdeI, XmnI and TaqI) and direct sequencing in haemophilia B (HB) carrier detection in Pakistani families. 2: To compare phenotypes of HB carriers with those of healthy females. METHODS: The study was conducted from March 2014 till February 2016 at Khyber Medical University Peshawar and National Institute of Blood Diseases, Karachi. Individuals from HB families of Khyber Pakhtunkhwa (KP) and Federally Administered Tribal Areas (FATA) with known F9 mutation in the proband were enrolled into the study. FIX activity (FIX: C) levels were determined in all the participants. Bleeding scores (BS) and complete blood counts were performed in the female participants. Linkage analysis followed by targeted Sanger sequencing was carried out in all the study participants. Heterozygosity rate was determined for each polymorphism. Healthy females and the carrier groups were compared for bleeding phenotypes. RESULTS: A total of 30 males and 48 females from 13 HB families were studied. The polymorphisms had a low heterozygosity rate. Direct sequencing determined the carrier status in all cases. The mean FIX: C was reduced whereas BS was raised in the carriers when compared with healthy females. A significant raise in white blood cells (WBCs) count was observed in the carriers. CONCLUSION: The three polymorphisms have a low heterozygosity rate in HB families from KP and FATA. Sanger sequencing is conclusive in determining carrier status in all the cases. FIX: C is low and BS is raised in the HB carriers in comparison to that of normal females. The mean WBCs count is significantly higher in the HB carriers than the normal females. PMID- 28811806 TI - Comparison of right and left trans-radial catheterization for coronary angiography and intervention in patients with Acute myocardial infarction. AB - OBJECTIVE: To compare the clinical characteristics between the right and left radial approach in treating acute myocardial infarction, helping physicians make treatment strategies correctly. METHODS: The patients admitted at our institution and undergoing percutaneous coronary angiography and interventional procedures by left or right radial approach between November 2013 and July 2016 were retrospectively reviewed. The access time, compression time, ambulation time, the amount of contrast material used, fluoroscopy time, interventional procedural time, the number of catheters used, the percentage of procedures completed using the assigned approach and the major vascular complications were recorded and compared between the two groups. RESULTS: There were no significant differences in access time, compression time, the amount of contrast material used, number of catheters used as well as the time to ambulation between the two groups (p>0.05), but the fluoroscopy time and interventional procedural time were significantly longer in right radial approach group than those in left radial approach group (p<0.05). The left radial approach group presented with a higher percentage of procedures completed using the assigned approach than that of right radial approach group (p<0.05). CONCLUSION: The left radial approach has more advantages than right radial approach in treating acute myocardial infarction. PMID- 28811807 TI - Impact of 24-hour helpline service for people with diabetes. AB - OBJECTIVE: To evaluate the impact and effectiveness of 24-hour helpline service in providing information and educating patients about self-management of diabetes. METHOD: The study was conducted at Baqai Institute of Diabetology & Endocrinology (BIDE), a tertiary diabetes care center, Karachi, Pakistan. People with diabetes attending the outpatient department from November 2012 to October 2014 were included in this study. After providing diabetes education, a helpline number was provided for emergency situations. Calls of registered patients were received by diabetes educators stationed at the BIDE around the clock. Data was collected through specially designed interface of HMS (health management system) in which the current complaint of caller and the advice of educator was recorded. RESULT: A total of 4842 calls were received. Out of those, 4268 (88%) were made by Type-2 diabetics and 526 calls (10%) were made by Type-1 diabetics. The average age of patients was 47.6 years. Three seventy-four calls (7.7%) were received with complaint of Hypoglycemia (72-80mg/dl). Six hundred and ninety eight calls (14.4%) were received with complaint of hyperglycemia (>200mg/dl). Insulin dose was adjusted on 935 calls (19.3%). Calls regarding other special situations such as (insulin handling, technique, medicine information) 2014 (41.6%) were received. CONCLUSION: Station based 24-hour telephonic helpline service is an effective tool for providing continuous support to people with diabetes and their families, for the self-management of diabetes. It can help in the management of various acute complication of diabetes, thereby preventing unnecessary hospital visits and admission. PMID- 28811808 TI - Prevention of anesthesia-induced injection pain of propofol in pediatric anesthesia. AB - OBJECTIVE: Propofol is a new anesthetic agent in clinical practice, but randomized double-blinded prospective studies on its role in pediatric anesthesia remain limited. We aimed to compare the preventive effects of pre-injected lidocaine or ketamine and its pre-mixture on the anesthesia-induced injection pain of propofol using a randomized double-blinded prospective method, and to compare the outcomes with those of medium-/long-chain propofol (M/LCT). METHODS: A total of 360 pediatric patients (aged 5-12 years old) who received elective surgery were randomly divided into six groups (n= 60) as follows. S group: control group; L group: lidocaine group; L + P group: lidocaine + propofol group; K group: ketamine group; K + P group: ketamine + propofol group; M group: M/LCT group. After the drug fluid completely entered the cubital vein, the venous access was closed. During propofol injection, the injection pain was scored using the VRS 4-point scale. Meanwhile, the heart rates before and during injection were recorded, the adverse reactions during and after injection were observed, and the incidence rate and degree of pain were evaluated. RESULTS: The VRS 4 point scale showed that the incidence rates of injection pain of S group, L group, L + P group, K group, K + P group and M group were 78.3%, 66.67%, 51.66%, 43.33%, 48.33% and 45% respectively. The incidence rates of injection pain of all experimental groups were significantly lower than that of S group (P<0.01). The incidence rates of injection pain of L + P group, K group, K + P group and M group were significantly lower than that of L group (P<0.05). The differences among the other groups were not statistically significant. CONCLUSIONS: Intravenous pre-injection of lidocaine, ketamine or those mixed with propofol can all significantly reduce the incidence rate of injection pain of propofol. PMID- 28811809 TI - Peppered and rare - Gastric and Duodenal Pseudomelanosis: A case series. AB - Upper Gastrointestinal (GI) pseudomelanosis is an uncommon entity characterized by endoscopic visualization of speckled dark mucosal pigmentation. While described in the rectum and colon, 'melanosis' or more aptly 'pseudomelanosis' is rare in the duodenum and exceedingly rare in the stomach. Five cases of pseudomelanosis were encountered at our department. Four females and one male were diagnosed, with a mean age of 70 years. All patients exhibited duodenal pseudomelanosis, with one demonstrating gastric antral pseudomelanosis as well. Common features among these patients included iron deficiency anemia, hypertension, chronic kidney disease, hydralazine use and iron supplementation. Biopsy specimens stained at least partially positive for iron and stains for calcium and copper were negative. Histochemical analysis revealed the pigment of pseudomelanosis to be mainly iron sulfide, exhibiting unpredictable staining patterns, hypothesized to be secondary to varying sulfur content and iron oxidation. It is visualized as dark deposits in macrophages at the tips of the duodenal villi. Upper GI pseudomelanosis remains a poorly understood finding, weakly associated with chronic kidney disease, diabetes, hypertension, iron supplements and anti-hypertensive medications. While the pathogenesis, clinical and prognostic significance remains unclear, it is thus far considered a benign condition. PMID- 28811810 TI - What is done when endoscopic examination reveals borderline bowel ischemia in patients with sigmoid volvulus? AB - Sigmoid volvulus (SV) is a rare colonic obstruction in which the sigmoid colonwraps around itself. The principal strategy for the treatment of uncomplicated SV is emergency endoscopic detorsion, while emergency surgery is needed in complicated SV with bowel gangrene, bowel perforation, peritonitis, or unsuccessful endoscopic treatment. In the endoscopic examination of SV, endoscopic detorsion is performed if the bowels are viable, while emergency surgery is needed if the bowels are gangrenous. However, the treatment approach is not clear when endoscopic examination reveals borderline bowel ischemia, and in this short report, the possible treatment strategies are discussed. PMID- 28811811 TI - Transient hypoglossal nerve palsy after transoral intubation for general anesthesia. AB - Hypoglossal nerve palsy induces palsy in the ipsilateral lingual muscles, resulting in tongue deviation and articulation disorder. It is a rare condition that may stem from a variety of causes. Therefore, it is important to consider the possible causes of hypoglossal nerve palsy related to surgery or anesthesia, including intubation, the surgical positions, and mask ventilation during recovery. PMID- 28811812 TI - Lower thoracic syndrome. AB - The role of thoracic spine related dysfunction in producing lower extremity symptoms is not clear. This case study describes the assessment and treatment of a patient with low back pain and bilateral lower extremity (BLE) symptoms. It was found that patient education about postural awareness and passive mobilization are valuable aids to decrease BLE symptoms due to sympathetic nervous system (SNS) dysfunction and lower thoracic hypomobility. The clinicians need to consider examination and treatment of the lower thoracic area in patients with BLE symptoms. More research is required to explore the role of SNS dysfunction in producing BLE symptoms. PMID- 28811813 TI - Osteonecrosis in the both femoral heads in a patient with Neuro-Behcet's Disease. AB - Neuro-Behcet's disease (NBD) is a rare clinical entity that frequently presents neuro-psychiatric symptoms, and mesodiencephalic and pontobulbar lesions. There is only one published report about osteonecrosis in NBD. We report a patient whose first presentation was neurological NBD with presenting bilateral femoral heads osteonecrosis. A 36-year-old male was hospitalized with gait disorder, diplopia and speech disorder. The past medical history of the patient was unremarkable. The MR image showed mesencephalic lesion with oedemaas a hyperintense area. The present case was diagnosed as NBD and treated with methylprednisolone (1g /day) only for five days. One year after, bilateral hip pain developed. MR image of both hips showed well-demarcated areas of osteonecrosis in the bilateral femoral heads. The patient was operated by an orthopedic surgeon. Because early diagnosis and immediate treatment of osteonecrosis is very important, the physician must bear in mind that osteonecrosis might result from impaired microvascular involvement in even NBD. PMID- 28811814 TI - Apert Syndrome: Report of a rare congenital malformation. AB - A rare case of an adult male with malformation of the skull, face, hands and feet called acrocephalosyndactly or Apert syndrome is presented. Its probable cause, features and treatment is discussed. It is a unique case who survived upto the age of 32 years without any operative intervention and adjusted in the society though he has all the stigmas of the above syndrome. We have concluded and made a point that in the adult sufferer, facial deformity is not so important and urgent for the treatment than syndactyly, which handicaps the sufferer in performing the daily routine work. PMID- 28811815 TI - Hepatosplenic mucormycosis post autologous stem cell transplant. AB - Mucormycosis is a life threatening fungal infection and remains an important cause of morbidity and mortality in immunocompromised patients after hematopoietic stem cell transplant. We report here a case of hepatosplenic mucormycosis in a patient after autologous stem cell transplant. A young man with anaplastic large cell lymphoma underwent autologous hematopoietic stem cell transplant after achieving complete remission with standard chemotherapy and consolidative radiotherapy. He was found to have incidental hepatosplenic hypodensities on follow up imaging, that were proved to be mucormycosis on histopathology after getting CT-guided biopsy of splenic lesions. He was treated with intravenous amphotericin-B followed by complete radiological resolution of hepatosplenic lesions. Although these infections are often life threatening but limited disease may have better outcome if diagnosed and treated early and aggressively. PMID- 28811816 TI - Unicornuate uterus with a rudimentary horn diagnosed at scheduled third Cesarean Section. AB - A unicornuate uterus with a rudimentary horn is an anomaly caused by defective fusion of the Mullerian duct, estimated to occur in one in 76,000 pregnancies. Life threateningly heavy bleeding is a highly expected clinical consequence of such pregnancies. According to the known literature, only two living twins and few living singleton pregnancies have been reported up to now. Here we report on an incidentally diagnosed unicornuate uterus with a communicating rudimentary horn, found during a cesarean section of a gravida 3, parity 2 (G3 P2) patient. This case is rather unique since the patient has had three full term pregnancies and three cesarean sections without significant fetal compromise. This delivery and the existing literature showed us that extensive uterine correction surgeries need not be automatically proposed when a unicornuate uterus is diagnosed in the preconception period. Such deliveries indicate that women with this uterine anomaly may have the potential to carry pregnancies to full term. PMID- 28811817 TI - A New Model for PhD Elective Course. PMID- 28811818 TI - Prototype Generation Using Self-Organizing Maps for Informativeness-Based Classifier. AB - The k nearest neighbor is one of the most important and simple procedures for data classification task. The kNN, as it is called, requires only two parameters: the number of k and a similarity measure. However, the algorithm has some weaknesses that make it impossible to be used in real problems. Since the algorithm has no model, an exhaustive comparison of the object in classification analysis and all training dataset is necessary. Another weakness is the optimal choice of k parameter when the object analyzed is in an overlap region. To mitigate theses negative aspects, in this work, a hybrid algorithm is proposed which uses the Self-Organizing Maps (SOM) artificial neural network and a classifier that uses similarity measure based on information. Since SOM has the properties of vector quantization, it is used as a Prototype Generation approach to select a reduced training dataset for the classification approach based on the nearest neighbor rule with informativeness measure, named iNN. The SOMiNN combination was exhaustively experimented and the results show that the proposed approach presents important accuracy in databases where the border region does not have the object classes well defined. PMID- 28811819 TI - Adaptive Resource Utilization Prediction System for Infrastructure as a Service Cloud. AB - Infrastructure as a Service (IaaS) cloud provides resources as a service from a pool of compute, network, and storage resources. Cloud providers can manage their resource usage by knowing future usage demand from the current and past usage patterns of resources. Resource usage prediction is of great importance for dynamic scaling of cloud resources to achieve efficiency in terms of cost and energy consumption while keeping quality of service. The purpose of this paper is to present a real-time resource usage prediction system. The system takes real time utilization of resources and feeds utilization values into several buffers based on the type of resources and time span size. Buffers are read by R language based statistical system. These buffers' data are checked to determine whether their data follows Gaussian distribution or not. In case of following Gaussian distribution, Autoregressive Integrated Moving Average (ARIMA) is applied; otherwise Autoregressive Neural Network (AR-NN) is applied. In ARIMA process, a model is selected based on minimum Akaike Information Criterion (AIC) values. Similarly, in AR-NN process, a network with the lowest Network Information Criterion (NIC) value is selected. We have evaluated our system with real traces of CPU utilization of an IaaS cloud of one hundred and twenty servers. PMID- 28811820 TI - Modified Mahalanobis Taguchi System for Imbalance Data Classification. AB - The Mahalanobis Taguchi System (MTS) is considered one of the most promising binary classification algorithms to handle imbalance data. Unfortunately, MTS lacks a method for determining an efficient threshold for the binary classification. In this paper, a nonlinear optimization model is formulated based on minimizing the distance between MTS Receiver Operating Characteristics (ROC) curve and the theoretical optimal point named Modified Mahalanobis Taguchi System (MMTS). To validate the MMTS classification efficacy, it has been benchmarked with Support Vector Machines (SVMs), Naive Bayes (NB), Probabilistic Mahalanobis Taguchi Systems (PTM), Synthetic Minority Oversampling Technique (SMOTE), Adaptive Conformal Transformation (ACT), Kernel Boundary Alignment (KBA), Hidden Naive Bayes (HNB), and other improved Naive Bayes algorithms. MMTS outperforms the benchmarked algorithms especially when the imbalance ratio is greater than 400. A real life case study on manufacturing sector is used to demonstrate the applicability of the proposed model and to compare its performance with Mahalanobis Genetic Algorithm (MGA). PMID- 28811821 TI - Prognostic Factors Affecting Long-Term Survival after Resection for Noncolorectal, Nonneuroendocrine, and Nonsarcoma Liver Metastases. AB - AIM: To evaluate feasibility and long-term outcome after hepatic resection for noncolorectal, nonneuroendocrine, and nonsarcoma (NCNNNS) liver metastases in a single center. METHODS: We retrospectively reviewed our experience on patients who underwent surgery for NCNNNS liver metastases from 1995 to 2015. Patient baseline characteristics, tumor features, treatment options, and postoperative outcome were retrieved. RESULTS: We included 47 patients. The overall 5-year survival (OS) rate after hepatectomy was 27.6%, with a median survival of 21 months. Overall survival was significantly longer for patients operated for nongastrointestinal liver metastases when compared with gastrointestinal (41 versus 10 months; p = 0.027). OS was significantly worse in patients with synchronous metastases than in those with metachronous disease (10 versus 22 months; p = 0.021). The occurrence of major postoperative complication negatively affected long-term prognosis (OS 23.5 versus 9.0 months; p = 0.028). Preoperative tumor characteristics (number and size of the lesions), intraoperative features (extension of resection, need for transfusions, and Pringle's maneuver), and R0 at pathology were not associated with differences in overall survival. CONCLUSION: Liver resection represents a possible curative option for patients with NCNNNS metastases. The origin of the primary tumor and the timing of metastases presentation may help clinicians to better select which patients could take advantages from surgical intervention. PMID- 28811822 TI - Overall Survival of Elderly Patients Having Surgery for Colorectal Cancer Is Comparable to Younger Patients: Results from a South Asian Population. AB - INTRODUCTION: There has been a continuous debate on whether elderly patients with colorectal cancer (CRC) fair worse. The aim of this study is to assess the thirty day mortality (TDM) and overall survival (OS) of elderly patients undergoing surgery for CRC. METHOD: OS between two groups (>=70 versus <70 years) having surgery for CRC was analyzed. Demographics, tumour characteristics, and serological markers were considered as independent factors. Multivariable analysis was done using the Cox proportional hazard model. We also compared overall survival in the elderly versus those <60 and <50 years. RESULTS: 477 patients, 160 elderly (55% male; median age 75, range 70-89) and 317 younger patients (49% male; median age 55, range 16 to 69), were studied. Overall survival in CRC patients >=70 is comparable to <70 (P = 0.45) and <60 years (P = 0.08). Poor OS was observed in the >=70 versus <50 years (P = 0.03). TDM in the elderly was poor (P < 0.05). Postoperative cardiac complication was the only determinant affecting survival in the elderly (P = 0.01). CONCLUSION: OS in elderly CRC patients having surgery is not worse compared to <70 and <60 years although the TDM was higher. Postoperative cardiac complications significantly affected OS in those >=70 compared to those <50 years. Chronological age alone should not negatively influence surgical decision-making in the elderly. PMID- 28811823 TI - Protective barrier properties of Rhinosectan(r) spray (containing xyloglucan) on an organotypic 3D airway tissue model (MucilAir): results of an in vitro study. AB - BACKGROUND: To evaluate barrier protective properties of Rhinosectan(r) spray, a medical device containing xyloglucan, on nasal epithelial cells (MucilAir). METHODS: MucilAir-Nasal, a three-dimensional organotypic (with different cell types) airway tissue model, was treated with the medical device Rhinosectan(r) (30 uL) or with controls (Rhinocort-budesonide-or saline solution). The protective barrier effects of Rhinosectan(r) were evaluated by: TEER (trans epithelial electrical resistance) (preservation of tight junctions), Lucifer Yellow assay (preservation of paracellular flux) and confocal immunofluorescence microscopy (localization of tight junction proteins). RESULTS: Exposure of MucilAir with Rhinosectan(r) protected cell tight junctions (increases in TEER of 13.1% vs -6.3% with saline solution after 1 h of exposure), and preserved the paracellular flux, even after exposure with pro-inflammatory compounds (TNF-alpha and LPS from Pseudomonas aeruginosa 10). Results of confocal immunofluorescence microscopy demonstrated that, after treatment with the pro-inflammatory mixture, Rhinosectan(r) produced a slight relocation of zona occludens-1 in the cytosol compartment (while Rhinocort induced expression of zona-occludens-1), maintaining the localization of occludin (similarly to negative control). CONCLUSIONS: Results of our study indicates that Rhinosectan(r) creates a protective physical barrier on nasal epithelial cells in vitro, allowing the avoidance of allergens and triggering factors, thus confirming the utility of this medical device in the management of nasal respiratory diseases, as rhinitis or rhinosinusitis. PMID- 28811824 TI - Preparation of Galla Chinensis Oral Solution as well as Its Stability, Safety, and Antidiarrheal Activity Evaluation. AB - BACKGROUND OF THE STUDY: As a widely used traditional medicine, Galla Chinensis is rich in tannins. However, there are few detailed studies about pharmaceutical preparations of Galla Chinensis tannin extract (GTE). In the present experiments, for better application and to investigate the possibility that Galla Chinensis tannin extract can be used as an antidiarrheal drug, we prepared Galla Chinensis oral solution (GOS). MATERIALS AND METHODS: GOS was prepared with GTE, and its physicochemical and microbiological stability was evaluated. The oral acute toxicity of GOS was calculated by the 50% lethal dose (LD50). The antidiarrheal activity was determined in a castor oil-induced diarrhea model in mice through diarrhea symptoms, fluid accumulation ratio, and percentage of distance moved by charcoal meal. RESULTS: The tannin content of GTE was 47.75%. GOS could endure a high temperature without a significant decrease of tannin content. After storage for six months, the tannin content of GOS was still more than 90%. GOS was determined to be nontoxic. Meanwhile, GOS showed significant antidiarrheal activity in a castor oil-induced diarrhea model in mice (P < 0.01). CONCLUSION: The results suggested that GOS is an effective and stable antidiarrheal drug that can be used to complement other therapies. PMID- 28811825 TI - Ethanol Extract of Mylabris phalerata Inhibits M2 Polarization Induced by Recombinant IL-4 and IL-13 in Murine Macrophages. AB - Mylabris phalerata (MP) is an insect used in oriental herbal treatments for tumor, tinea infections, and stroke. Recent studies have shown that tumor associated macrophages (TAM) have detrimental roles such as tumor progression, angiogenesis, and metastasis. Although TAM has phenotypes and characteristics in common with M2-polarized macrophages, M1 macrophages have tumor suppression and immune stimulation effects. Medicines polarizing macrophages to M1 have been suggested to have anticancer effects via the modulation of the tumor microenvironment. In this line, we screened oriental medicines to find M1 polarizing medicines in M2-polarized macrophages. Among approximately 400 types of oriental medicine, the ethanol extract of M. phalerata (EMP) was the most proficient in increasing TNF-alpha secretion in M2-polarized macrophages and TAM. Although EMP enhanced the levels of an M1 cytokine (TNF-alpha) and a marker (CD86), it significantly reduced the levels of an M2 marker (arginase-1) in M2 polarized macrophages. In addition, EMP-treated macrophages increased the levels of M1 markers (Inos and Tnf-alpha) and reduced those of the enhanced M2 markers (Fizz-1, Ym-1, and arginase-1). EMP-treated macrophages significantly reduced Lewis lung carcinoma cell migration in a transwell migration assay and inhibited EL4-luc2 lymphoma proliferation. In our mechanism study, EMP was found to inhibit STAT3 phosphorylation in M2-polarized macrophages. These results suggest that EMP is effective in treating TAM-mediated tumor progression and metastasis. PMID- 28811826 TI - Anti-Inflammatory Effect of Piper attenuatum Methanol Extract in LPS-Stimulated Inflammatory Responses. AB - Piper attenuatum is used as a traditional medicinal plant in India. One of the substances in P. attenuatum has been suggested to have anti-inflammatory effects. However, there is insufficient research about the anti-inflammatory mechanisms of action of P. attenuatum. The effects of P. attenuatum methanol extract (Pa-ME) on the production of inflammatory mediators nitric oxide (NO) and prostaglandin E2 (PGE2), the expression of proinflammatory genes, the translocation level of transcription factors, and intracellular signaling activities were investigated using macrophages. Pa-ME suppressed the production of NO and PGE2 in lipopolysaccharide- (LPS-), pam3CSK4-, and poly(I:C)-stimulated RAW264.7 cells without displaying cytotoxicity. The mRNA expression levels of inducible NO synthase (iNOS) and cyclooxygenase 2 (COX-2) were decreased by Pa-ME. P-ME reduced the translocation of p50/NF-kappaB and AP-1 (c-Jun and c-Fos), as well as the activity of their upstream enzymes Src, Syk, and TAK1. Immunoprecipitation analysis showed failure of binding between their substrates, phospho- (p-) p85 and p-MKK3/6. p-p85 and p-MKK3/6, which were induced by overexpression of Src, Syk, and TAK1, were also reduced by Pa-ME. Therefore, these results suggest that Pa-ME exerts its anti-inflammatory effects by targeting Src and Syk in the NF kappaB signaling pathway and TAK1 in the AP-1 signaling pathway. PMID- 28811827 TI - Pharmacodynamics and Medicinal Chemistry of an External Chinese Herbal Formula for Mammary Precancerous Lesions. AB - Ruyan Neixiao Cream (RYNXC) is a traditional Chinese herbal formula for treating mammary precancerous disease. This study was carried out to investigate in vivo anticancer effect of RYNXC and multiple constituents. 32 virginal Sprague-Dawley rats were randomly divided into blank control group (BC), mammary precancer models group (MODEL), tamoxifen group (TAM), and Ruyan Neixiao Cream group (RYNXC). TAM was intervened by tamoxifen; RYNXC was intervened by Ruyan Neixiao Cream. The chromatographic separation was performed by high performance liquid chromatography (HPLC) coupled with mass spectrometry (MS). RYNXC showed significant improvement in erythrocyte aggregation index (EAI), hematocrit (HCT), fibrinogen (FIB), spleen coefficient, and uterus coefficient compared with MODEL. In RYNXC and TAM groups, atypical hyperplasia was observed in pathological mammary tissues; meanwhile in MODEL group, ductal carcinoma was observed in situ. Moreover, fifteen compounds were characterized according to HPLC-MS data, including organic acids, tannin, alkaloid, volatile oil, anthraquinones, and flavonoids. The study suggests that RYNXC was an effective Chinese herbal formula for mammary precancerous lesions and provides a scientific basis for the quality standard and the pharmacology of RYNXC. It will be beneficial to the future clinical application of RYNXC. PMID- 28811828 TI - Nonvitamin, Nonmineral Dietary Supplement Use among Adults with Fibromyalgia: United States, 2007-2012. AB - BACKGROUND: Fibromyalgia (FMS) is a pain condition affecting 2-6% of US adults; effective treatment remains limited. Determinants of nonvitamin, nonmineral dietary supplement (NVNM) use among adults with FMS are not well-studied. We investigated the relation of NVNM use to FMS, and trends, in two nationally representative samples of US adults >=18 years. METHODS: Data were drawn from 2007 and 2012 National Health Interview Surveys (N's = 20127 and 30672, resp.). Logistic regression was used to examine associations of FMS to NVNM use (past 12 months) and evaluate potential modifying influences of gender and comorbidities. Multivariate models adjusted for sampling design, demographic, lifestyle, and health-related factors. RESULTS: FMS was significantly higher in 2012 than in 2007 (1.7% versus 1.3%), whereas NVNM use decreased (57% versus 41%; p < 0.0001). Adults reporting diagnosis were more likely to use NVNMs within 12 months, 30 days, or ever relative to adults without; positive associations remained significant after controlling for demographics, lifestyle characteristics, medical history, and other confounders (ranges: 2007 and 2012 AORs = 2.3-2.7; 1.5 1.6, resp.; p's < 0.0001). CONCLUSION: In this cross-sectional study of two national samples, NVNM use was strongly and positively associated with FMS, highlighting the need for further study. PMID- 28811829 TI - Metabolomics Analysis for Defining Serum Biochemical Markers in Colorectal Cancer Patients with Qi Deficiency Syndrome or Yin Deficiency Syndrome. AB - Colorectal cancer is one of the leading causes of tumor-associated death, and traditional Chinese medicine (TCM) classifies colorectal cancer into various subtypes mainly according to the symptomatic pattern identification (ZHENG). Here, we investigated the difference in metabolic profiles of serum by comparing colorectal cancer subjects with Nondeficiency (ND), Qi deficiency (QD), and Yin deficiency (YD). The ratio of subjects with carcinoembryonic antigen (CEA) was higher in YD pattern, and the ratio of subjects with carbohydrate antigen 19-9 (CA19-9) was higher both in YD and in QD, compared with ND. As a result of metabolomics analysis, twenty-five metabolites displayed differences between QD and ND, while twenty-eight metabolites displayed differences between YD and ND. The downregulated metabolites in QD/ND and YD/ND mainly include carbohydrates and the upregulated metabolites mainly include amino acids and fatty acids, suggesting conversion obstruction of carbohydrates, fatty acids, and amino acids occurs in patients with QD and YD compared with ND. Our results demonstrate that colorectal cancer patients with QD or YD were associated with metabolic disorders and the variations of serum metabolic profiles may serve as potential biochemical markers for diagnosis and prognosis of colorectal cancer patients displayed QD or YD patterns. PMID- 28811830 TI - Changes of Blood Flux at BL21 and Points along BL Meridian Resulted from Acupuncture or Moxibustion: Case Cross Design Study. AB - Acupuncture (Acup) and moxibustion (Moxi) are commonly used interventions in clinical practice. However, the difference between Acup and moxibustion mechanisms is unclear. In current study, blood perfusion responses resulted from Acup or Moxi at Weishu acupoint (BL21) and control points were explored, respectively. The time series of blood flux signals at BL21 and control points were transformed with Morlet wavelet, and the differences in each frequency interval were observed. The results suggested that acupoint response to different stimulation is a comprehensive process which related to all components of blood perfusion signals. Whereas the different response at control points was not observed, there has been significant difference coherence value between Acup and Moxi stimulation. The results suggested the influence of Acup and Moxi not only on the level of blood perfusion at local area; the intrinsic relevance after stimulation which can be evaluated by coherence analysis is also an appropriate index to distinguish different stimulations. PMID- 28811831 TI - Potent Phosphodiesterase Inhibition and Nitric Oxide Release Stimulation of Anti Impotence Thai Medicinal Plants from "MANOSROI III" Database. AB - Seven plants in the top rank were selected from the "MANOSROI III" database using the two Thai keywords which meant impotence and sexual tonic. Boesenbergia rotunda (L.) Mansf. extract [EDP1-001(1)] gave the highest PDE inhibition activity of 4.36-fold sildenafil, a standard anti-impotence drug. Plumbago indica Linn. extract [EDP2-001(1)] exhibited the highest NO release stimulation activity of 666.85% which was 1.50-fold acetylcholine, a standard drug. Most selected plant extracts were nontoxic to EA.hy926 cells at 1.0 mg/mL. EDP1-001(1) exhibited the LD50 value of acute oral toxicity in male ICR mice of over 5,000 mg/kg body weight. EDP1-001(1) also indicated the improvement of sexual behaviors in the paroxetine-induced sexual dysfunction male mice with the evaluation of number of courtships (NC), mount frequency (MF), intromission frequency (IF), and ejaculatory frequency (EF) at 87.67 +/- 6.17, 121.00 +/- 23.50, 36.00 +/- 3.21, and 13.67 +/- 2.96 which were 2.63-, 1.27-, 0.53-, and 0.62-fold sildenafil treated mice at day 14 of the treatments, respectively. The present study has not only confirmed the traditional use of Thai plants for the treatment of ED but also indicated the potential and application of the "MANOSROI III" database for Thai plant selection to be developed as ED food supplements. PMID- 28811833 TI - NSiteMatch: Prediction of Binding Sites of Nucleotides by Identifying the Structure Similarity of Local Surface Patches. AB - Nucleotides play a central role in life-form metabolism, by interacting with proteins and mediating the function of proteins. It is estimated that nucleotides constitute about 15% of the biologically relevant ligands included in PDB. Prediction of binding sites of nucleotides is useful in understanding the function of proteins and can facilitate the in silico design of drugs. In this study, we propose a nucleotide-binding site predictor, namely, NSiteMatch. The NSiteMatch algorithm integrates three different strategies: geometrical analysis, energy calculation, and template comparison. Unlike a traditional template-based predictor, which identifies global similarity between target structure and template, NSiteMatch concerns the local similarity between a surface patch of the target protein and the binding sites of template. To this end, NSiteMatch identifies more templates than traditional template-based predictors. The NSiteMatch predictor is compared with three representative methods, Findsite, Q SiteFinder, and MetaPocket. An extensive evaluation demonstrates that NSiteMatch achieves higher success rates than Findsite, Q-SiteFinder, and MetaPocket, in prediction of binding sites of ATP, ADP, and AMP. PMID- 28811832 TI - DHA increases adiponectin expression more effectively than EPA at relative low concentrations by regulating PPARgamma and its phosphorylation at Ser273 in 3T3 L1 adipocytes. AB - BACKGROUND: Enhancing circulating adiponectin is considered as a potential approach for the prevention and treatment of non-communicable diseases (NCDs). Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were reported to increase adiponectin by previous studies using a mixture of them. However, their individual effects on adiponectin and the underlying mechanisms are still unclear. In the present study, we observed and compared the individual effect of DHA and EPA on adiponectin in 3T3-L1 adipocytes, and further tested whether DHA or EPA regulated adiponectin by peroxisome proliferator-activated receptor gamma (PPARgamma) and its phosphorylation at Ser273 to provide a plausible explanation for their distinct actions. METHODS: Firstly, 3T3-L1 adipocytes were treated with different doses of DHA or EPA for 24 h. Secondly, 3T3-L1 adipocytes were treated with DHA or EPA in the presence or absence of GW9662. Thirdly, 3T3-L1 adipocytes were pretreated with DHA or EPA for 24 h, followed by being respectively co incubated with tumor necrosis factor alpha (TNF-alpha) or roscovitine for another 2 h. Bovine serum albumin treatment served as the control. After treatments, cellular and secreted adiponectin, cellular PPARgamma and its phosphorylation at Ser273 were determined. RESULTS: Compared with the control, DHA increased cellular and secreted adiponectin at 50 and 100 MUmol/L, while EPA increased them at 100 and 200 MUmol/L. Adiponectin expressions in DHA treated groups were significantly higher than those in EPA treated groups at 50 and 100 MUmol/L. Both DHA and EPA enhanced PPARgamma expression, but DHA was more effective. GW9662 blocked DHA- and EPA-induced increases in PPARgamma as well as adiponectin. Remarkably, an opposite regulation of PPARgamma phosphorylation was detected after fatty acids treatment: DHA inhibited it but EPA stimulated it. TNF-alpha blocked DHA-induced decrease in PPARgamma phosphorylation, which eventually led to a decrease in adiponectin. Roscovitine blocked EPA-induced increase in PPARgamma phosphorylation, but the corresponding increase in adiponectin was non significant. CONCLUSION: DHA compared with EPA led to a greater increase in cellular and secreted adiponectin at relative low concentrations by increasing PPARgamma expression and inhibiting its phosphorylation at Ser273. DHA may be more beneficial than EPA in reducing risks of NCDs. PMID- 28811834 TI - High risk human papilloma viruses (HPVs) are present in benign prostate tissues before development of HPV associated prostate cancer. AB - BACKGROUND: Although high risk HPVs are associated with an increased risk of prostate cancer it is not known if they have a causal role. The purpose of this study is to investigate the potential role of human papilloma viruses (HPVs) in prostate cancer. The aims are (i) to investigate the presence and confirm the identity of high risk HPVs in benign prostate tissues prior to the development of HPV positive prostate cancer in the same patients, and (ii) to determine if HPVs are biologically active. METHODS: We used polymerase chain reaction (PCR) to identify HPVs in specimens from 52 Australian men with benign prostate biopsies who 1 to 10 years later developed prostate cancer. Immunohistochemistry (IHC) was used to assess the expression of HPV E7 oncoproteins, cytokeratin and prostate specific antigen (PSA). We used RNASeq data from The Cancer Genome Atlas (TCGA) to identify possible HPV RNA sequences in prostate cancer. RESULTS: HPV screening using standard PCR was conducted on 28 of the 52 sets of benign and later prostate cancers. HPV L1 genes were identified in 13 (46%) benign and 8 (29%) of 28 later prostate cancers in the same patients. HPV E7 genes were identified in 23 (82%) benign and 19 (68%) of 28 subsequent prostate cancers in the same patients. The same HPV types were present in both the benign and subsequent prostate cancers in 9 sets of specimens. HPV type 16 was identified in 15% of benign and 3% of prostate cancers. HPV type 18 was identified in 26% of benign and 16% of prostate cancers. Small numbers of HPV types 45, 47, 76 and 115 were also identified. High confidence RNA-Seq evidence for high risk HPV types 16 and 18 was identified in 12 (2%) of the 502 TCGA prostate cancer transcriptomes. High risk HPV E7 oncoprotein was positively expressed in 23 (82%) of 28 benign prostate specimens but only in 8 (29%) of 28 of the later prostate cancer specimens. This difference is statistically significant (p = 0.001). Prostate specific antigen (PSA) was more highly expressed in 26 (50%) of 52 prostate cancer specimens as compared to prior benign prostate specimens in the same patients. CONCLUSIONS: High risk HPVs are present in benign prostate tissues prior to the development of HPV positive prostate cancer. There is a significantly higher expression of HPV E7 oncoproteins in benign prostate tissues as compared to late prostate cancer that subsequently developed in the same patients. This observation suggests that HPV oncogenic activity is an early phenomenon in a majority of prostate oncogenesis. TCGA RNA-Seq data suggests that HPV is biologically active in some prostate tumour samples. PMID- 28811836 TI - Introduction to LJPC issue 9.4. July/August 2017. PMID- 28811837 TI - An interview with Samuel Shem, author of 'The House of God'. AB - Dr Stephen Bergman, Professor of medical humanities at New York University, writes under the name Samuel Shem. He is an acclaimed author of several novels, plays and textbooks, and his work has been translated into several languages 'The House of God' his first novel has sold over 3 million copies. His work exposes the potential moral challenges of the medical workplace and the connection between values, good relationships and healing. In 2015 he visited the UK for medical humanities academic tour which included keynote talks at the RCGP 2015 Annual Conference and at the Royal Society of Medicine. Claire Brash interviewed him at the Royal Society of Medicine. PMID- 28811835 TI - Mental health care providers' perceptions of the barriers to suicide prevention amongst people with substance use disorders in South Africa: a qualitative study. AB - BACKGROUND: Substance use is a well-established, and potentially modifiable, risk factor for suicide. Suicide prevention interventions are typically framed within the biomedical paradigm and focus on addressing individual risk factors, improving access to psychiatric care, and improving the skills of medical personnel to recognise at-risk individuals. Few studies have focused on contextual factors that hinder suicide prevention in people with substance use disorders, particularly in low-resource settings. The aim of this qualitative study was to explore mental health care providers' perceptions of barriers to suicide prevention in people with substance use disorders in South Africa. METHODS: Semi-structured interviews were conducted with 18 mental health care providers who worked with suicidal people with substance use disorders in Cape Town, South Africa. Data were analysed using thematic analysis and Atlas.ti software was used to code the data inductively. RESULTS: Two superordinate themes were identified: structural issues in service provision and broad contextual issues that pose barriers to suicide prevention. Participants thought that inadequate resources and insufficient training hindered them from preventing suicide. Fragmented service provision was perceived to lead to patients not receiving the psychiatric, psychological, and social care that they needed. Contextual problems such as poverty and inequality, the breakdown of family, and stigma made participants think that preventing suicide in people with substance use disorders was almost impossible. CONCLUSIONS: These findings suggest that structural, social, and economic issues serve as barriers to suicide prevention. This challenges individual risk-factor models of suicide prevention and highlights the need to consider a broad range of contextual and socio-cultural factors when planning suicide prevention interventions. Findings suggest that the responsibility for suicide prevention may need to be distributed between multiple stakeholders, necessitating intersectoral collaboration, more integrated health services, cautious use of task shifting, and addressing contextual factors in order to effectively prevent suicide in people with substance use disorders. PMID- 28811838 TI - Ethical religion in primary care. AB - Religion is increasingly significant in UK society, and is highly significant for many patients and primary care practitioners. An important task for the practitioner is to ensure that the place of religion in the patient/practitioner relationship is treated with the same ethical seriousness as every other aspect of that relationship. The article finds the 'four principles of biomedical ethics' to be applicable, and recent GMC guidelines to be consistent with the four principles. The article applies the four principles to the particular case of practitioners wearing religious symbolism. PMID- 28811839 TI - Three ways for art to stimulate the mind. AB - The relevance of the arts to medical practice is not always immediately apparent. Here, three examples are given from literature, visual arts and music which demonstrate links not normally found in medical texts. PMID- 28811840 TI - Francis Bacon and his invisible rooms: human emotions so felt but not so easily seen. PMID- 28811841 TI - Bacteriophages in the gastrointestinal tract and their implications. AB - The gut microbiota plays an essential role in health and disease of humans. Bacteriophages are the most abundant members of the gut virobiota and display great diversity. Phages can translocate through the mucosa to lymph and internal organs and play a role as regulators of the bacterial population in the gut. Increasing abundance of phages in the gut mucosa may reduce colonization by bacteria. Moreover, phages may have an immunomodulatory role in the immune response in the human gut. The role of phages in inflammatory bowel disease (IBD) remains unknown. Phages may take part in the development of IBD, but there are also data suggesting the protective role of phages in the gut of patients with IBD. Furthermore, recent data suggest that phages may mediate the beneficial effects of fecal microbiota transplantation (FMT). Therefore, evidence is accumulating to highlight the protective immunomodulating activity of the gut phages. PMID- 28811842 TI - The effect of three different exercise training modalities on cognitive and physical function in a healthy older population. AB - BACKGROUND: Older adults are encouraged to participate in regular physical activity to counter the age-related declines in physical and cognitive health. Literature on the effect of different exercise training modalities (aerobic vs resistance) on these health-related outcomes is not only sparse, but results are inconsistent. In general, it is believed that exercise has a positive effect on executive cognitive function, possibly because of the physiological adaptations through increases in fitness. Indications are that high-intensity interval training is a potent stimulus to improve cardiovascular fitness, even in older adults; however, its effect on cognitive function has not been studied before. Therefore, the purpose of this study was to compare the effects of resistance training, high-intensity aerobic interval training and moderate continuous aerobic training on the cognitive and physical functioning of healthy older adults. METHODS: Sixty-seven inactive individuals (55 to 75 years) were randomly assigned to a resistance training (RT) group (n = 22), high-intensity aerobic interval training (HIIT) group (n = 13), moderate continuous aerobic training (MCT) group (n = 13) and a control (CON) group (n = 19) for a period of 16 weeks. Cognitive function was assessed with a Stroop task and physical function with the Timed-Up-and-Go (TUG) and submaximal Bruce treadmill tests. RESULTS: No significant GROUP x TIME interaction was found for Stroop reaction time (P > .05). The HIIT group showed the greatest practical significant improvement in reaction time on the information processing task, i.e. Stroop Neutral (ES = 1.11). MCT group participants had very large practical significant improvements in reaction time on the executive cognitive tasks, i.e. Stroop Incongruent and Interference (ES = 1.28 and 1.31, respectively). The HIIT group showed the largest practically significant increase in measures of physical function, i.e. walking endurance (ES = 0.91) and functional mobility (ES = 0.36). CONCLUSIONS: MCT and RT proved to be superior to HIIT for the enhancement of older individuals' executive cognitive function; whereas HIIT were most beneficial for improvement in information processing speed. HIIT also induced the largest gains in physical function. PMID- 28811843 TI - Transcriptomics and methylomics in chronic periodontitis with tobacco use: a pilot study. AB - BACKGROUND: Accumulating evidence suggests that tobacco smoking affects the susceptibility to and severity of chronic periodontitis. Epigenetics may explain the role of smoking in the development and progress of periodontal disease. In this study, we performed transcriptomic and methylomic analyses of non periodontitis and periodontitis-affected gingival tissues according to smoking status. METHODS: Human gingival tissues were obtained from 20 patients, including non-smokers with and without periodontitis (n = 5 per group) and smokers with and without periodontitis (n = 5 per group). Total RNA and genomic DNA were isolated, and their quality was validated according to strict standards. The Illumina NextSeq500 sequencing system was used to generate transcriptome and methylome datasets. RESULTS: Comprehensive analysis, including between-group correlation, differential gene expression, DNA methylation, gene set enrichment, and protein protein interaction, indicated that smoking may change the transcription and methylation states of extracellular matrix (ECM) organization-related genes, which exacerbated the periodontal condition. CONCLUSIONS: Our results suggest that smoking-related changes in DNA methylation patterns and subsequent alterations in the expression of genes coding for ECM components may be causally related to the increased susceptibility to periodontitis in smokers as they could influence ECM organization, which in turn may have an effect on disease characteristics. PMID- 28811846 TI - Some Mushrooms are Hard to Digest: Gastrostomy Tube Exchange. AB - BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) is an effective and safe mode of enteral nutrition for patients needing chronic enteric nutritional support. Exchanging PEG tubes may result in complications due to inexperience as well as due to lack of protocol. CASE REPORT: We encountered a 73 year-old female with unnoticed, accidently detached portion of the internal bumper of a PEG tube in the gastric lumen after a challenging gastrostomy tube exchange. CONCLUSIONS: This case report discusses the complications associated with gastrostomy tube exchange and proposes a planned protocol for successful gastrostomy tube exchange. PMID- 28811844 TI - LSD1 dual function in mediating epigenetic corruption of the vitamin D signaling in prostate cancer. AB - BACKGROUND: Lysine-specific demethylase 1A (LSD1) is a key regulator of the androgen (AR) and estrogen receptors (ER), and LSD1 levels correlate with tumor aggressiveness. Here, we demonstrate that LSD1 regulates vitamin D receptor (VDR) activity and is a mediator of 1,25(OH)2-D3 (vitamin D) action in prostate cancer (PCa). METHODS: Athymic nude mice were xenografted with CWR22 cells and monitored weekly after testosterone pellet removal. Expression of LSD1 and VDR (IHC) were correlated with tumor growth using log-rank test. TRAMP tumors and prostates from wild-type (WT) mice were used to evaluate VDR and LSD1 expression via IHC and western blotting. The presence of VDR and LSD1 in the same transcriptional complex was evaluated via immunoprecipitation (IP) using nuclear cell lysate. The effect of LSD1 and 1,25(OH)2-D3 on cell viability was evaluated in C4-2 and BC1A cells via trypan blue exclusion. The role of LSD1 in VDR-mediated gene transcription was evaluated for Cdkn1a, E2f1, Cyp24a1, and S100g via qRT-PCR TaqMan and via chromatin immunoprecipitation assay. Methylation of Cdkn1a TSS was measured via bisulfite sequencing, and methylation of a panel of cancer-related genes was quantified using methyl arrays. The Cancer Genome Atlas data were retrieved to identify genes whose status correlates with LSD1 and DNA methyltransferase 1 (DNMT1). Results were correlated with patients' survival data from two separate cohorts of primary and metastatic PCa. RESULTS: LSD1 and VDR protein levels are elevated in PCa tumors and correlate with faster tumor growth in xenograft mouse models. Knockdown of LSD1 reduces PCa cell viability, and gene expression data suggest a dual coregulatory role of LSD1 for VDR, acting as a coactivator and corepressor in a locus-specific manner. LSD1 modulates VDR dependent transcription by mediating the recruitment of VDR and DNMT1 at the TSS of VDR-targeted genes and modulates the epigenetic status of transcribed genes by altering H3K4me2 and H3K9Ac and DNA methylation. Lastly, LSD1 and DNMT1 belong to a genome-wide signature whose expression correlates with shorter progression-free survival and overall survival in primary and metastatic patients' samples, respectively. CONCLUSIONS: Results demonstrate that LSD1 has a dual coregulatory role as corepressor and coactivator for VDR and defines a genomic signature whose targeting might have clinical relevance for PCa patients. PMID- 28811845 TI - Role of Contrast Enhancement and Corrected Attenuation Values of Renal Tumors in Predicting Renal Cell Carcinoma (RCC) Subtypes: Protocol for a Triphasic Multi Slice Computed Tomography (CT) Procedure. AB - BACKGROUND: To distinguish RCC subtypes based on contrast enhancement features of CT images. MATERIAL/METHODS: In total, 59 lesions from 57 patients were included. All patients underwent multi-slice CT imaging with a triphasic protocol, which included non-contrast, corticomedullary, nephrographic and urographic phases. Contrast enhancement features of renal masses were evaluated in terms of CT attenuation values (AV) and differences in contrast density; the aorta or renal parenchyma were evaluated based on corrected or relative values. RESULTS: Clear cell RCC (ccRCC) showed more intense contrast enhancement than other RCC subtypes. When differentiating ccRCC from other RCC subtypes, a cut-off AV of 86 89 HU, aorta-based corrected AV of 89-95 HU and renal parenchyma-based corrected AV of 87-95 HU showed a diagnostic accuracy of 81-86%, 86-88% and 74-78%, respectively, in the corticomedullary phase. Furthermore, a cutoff of 2.42-2.72 for the relative contrast enhancement ratio, a cutoff of 2.59-2.74 for the aorta based corrected relative contrast enhancement ratio and a cutoff of 2.63-2.76 for the renal parenchyma-based attenuation ratio showed a diagnostic accuracy of 83 88%, 88-90% and 81%, respectively. CONCLUSIONS: The most reliable parameters for differentiating ccRCC from other RCC subtypes are aorta-based corrected AV and aorta-based corrected relative contrast enhancement values in the corticomedullary phase. PMID- 28811847 TI - A Rare Case of Adult Rhabdomyosarcoma. AB - BACKGROUND: Rhabdomyosarcoma is a rare, soft tissue malignancy, diagnosed particularly in adults. It commonly metastasizes to the bone marrow. We present a rare case of an adult rhabdomyosarcoma which illustrates the importance of magnetic resonance imaging in identifying early changes in the internal bone structure. CASE REPORT: A 50-year-old male presented with acute urinary retention. The patient initially had a CT scan of the lumbar spine which only revealed a protrusion of the L5-S1 intervertebral disc and no apparent cause for the patient's symptoms. One week later, an MRI was performed which showed extensive bone marrow metastases throughout the lumbar spine and a soft tissue mass in the lower sacral region. The bony metastases were not evident on the CT scan and the soft tissue mass was out of the coverage area of the CT. Subsequent biopsy of the soft tissue mass was performed and histopathology concluded the tissue to be a rhabdomyosarcoma. Unfortunately, the patient died one week after diagnosis. CONCLUSIONS: Although adult rhabdomyosarcomas are very rare, this case highlights the advantage of MRI over CT in identifying early changes in the internal bone structure. Therefore, CT should not be relied upon to exclude bony metastases, particularly in the setting of primary cancer with a known tendency to metastasize to the bone marrow. PMID- 28811848 TI - Skull Base Tumors and Tumor-Like Lesions: A Pictorial Review. AB - A number of tumors and tumor-like non-neoplastic lesions with different cell types on histology occur in the skull base. A wide variety in disease and lesion appearance often complicates the process of radiological diagnosis. The main role of radiographic imaging is the detection and characterization of skull base lesions, with evaluation of the extent of invasion or preservation of adjacent critical organs. Evaluation of the skull base anatomy and surgical planning by using image guidance are also important for surgeons. Computed tomography (CT) and magnetic resonance (MR) imaging are the preferred modalities for the evaluation of skull base lesions. CT and MR are used for lesion detection, tissue characterization and assessment of neurovascular and bone involvement by the lesions. Both modalities provide useful information, one sometimes of greater value than the other. T1-weighted MR imaging is useful in detecting skull base lesions, typically surrounded by abundant fatty bone marrow. T2-weighted MR imaging is generally useful for tumor tissue characterization. CT surpasses MR imaging in evaluating intratumoral calcification and bone destruction or hyperostosis. To date, imaging features have been well-reported in individual skull base tumors; however, correct diagnosis by imaging alone still presents a challenge. Knowledge of clinical issues and awareness of variants of skull base tumors are of help in making a diagnosis. The purpose of this article is to review pertinent clinical issues, typical imaging appearances and certain imaging variations of common skull base lesions. PMID- 28811849 TI - Meniere's Disease and Vestibular Migraine: Updates and Review of the Literature. AB - The diagnosis of Meniere's disease (MD) and vestibular migraine (VM) is primarily based on clinical criteria and their differentiation is often difficult. Currently, there are no known definitive diagnostic tests that can reliably distinguish the two conditions. Patients with MD and patients with VM are treated differently, therefore improving the diagnosis of these two pathologies should avoid errors in management. A systematic review was conducted according to PRISMA guidelines. Medline-Ovid and Embase databases were used to conduct a thorough search of English-language publications dating from 1948 to March 2016. The primary search objective was to identify all papers explicitly comparing MD and VM in order to clarify and validate the diagnosis of these two diseases. A total of 13 articles out of 831 were reviewed. Among other differences, MD showed later age of onset, more hearing loss, tinnitus, aural fullness, abnormal nystagmus, abnormal caloric testing results, abnormal vestibular evoked myogenic potential and endolymphatic hydrops. VM showed more headaches, photophobia, vomiting and aura. Even though differences were noted between the two diseases, only one study focused on assessing the differences between VM, MD and patients fulfilling both diagnostic criteria (MDVM). This study showed no difference between the three groups. Since the introduction of the new International Headache Society and Barany Society criteria for VM, no studies have focused on comparing these three groups. We strongly encourage authors to focus on comparing MD and VM from MDVM in future studies to help adequately distinguish the diagnosis of both diseases. PMID- 28811851 TI - Epidemiology of Infective Endocarditis in Rural Upstate New York, 2011 - 2016. AB - BACKGROUND: The epidemiology of infective endocarditis (IE) depends on a number of host factors whose prevalence can vary globally. The usual patient population affected by IE is sicker and older, often with many comorbid conditions. The risk is growing in younger populations due to the emerging epidemic of intravenous (IV) drug use. We have performed a temporal trend analysis of various factors of IE in the rural counties covering a major part of central Upstate New York. METHODS: We performed a retrospective analysis of electronic medical records of patients who were admitted in a tertiary care hospital in rural Upstate New York and diagnosed with IE from January 1, 2011 to December 31, 2016. Forty-five patients were identified with definite IE and nine with possible IE. RESULTS: Total incidence of IE was 3.5 cases per 100,000 person years in the total population and 4.4 if we consider total population >= 18 years in the denominator. A significant (P = 0.022) increase in incidence of IE from 2011 to 2016 was seen by univariate analysis. Incidence was higher in males (P = 0.029) and for those aged 65 or older (P = 0.0003). IV drug use among cases is noted to be more prevalent in 2015 and 2016 compared to previous years. CONCLUSION: In this study of patients in a rural region of New York, an increase in the incidence of IE was seen over the study period with changes in patient characteristics and etiology over this time. We speculate that an increase in IV drug use could be a leading factor in the recent and future increased incidence of IE in the area. PMID- 28811850 TI - Effect of Sodium Glucose Cotransporter 2 Inhibitors With Low SGLT2/SGLT1 Selectivity on Circulating Glucagon-Like Peptide 1 Levels in Type 2 Diabetes Mellitus. AB - Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that improve glycemic control by inhibiting reabsorption of glucose filtered through the renal glomerulus. Use of drugs in this class has increased because of their effect of decreasing body weight and a low risk for hypoglycemia, in addition to a relatively strong glucose-lowering effect. SGLT2 inhibitors such as canagliflozin and sotagliflozin (a SGLT1/SGLT2 dual inhibitor) also have a mild or moderate intestinal and renal SGLT1 inhibitory effect because of their relatively weak selectivity for SGLT2 over SGLT1. Recent evidence shows that these SGLT2 inhibitors with low SGLT2/SGLT1 selectivity elevate the level of circulating glucagon like peptide-1 (GLP-1), an incretin hormone that promotes insulin secretion in pancreatic beta cells. This effect probably occurs partly via inhibition of intestinal SGLT1, and the elevation of active GLP-1 levels is especially apparent when these drugs are co-administered with dipeptidyl peptidase 4 (DPP4) inhibitors. These findings suggest that a combination of canagliflozin or sotagliflozin and a DPP4 inhibitor can provide a beneficial effect associated with elevation of circulating active GLP-1 and may serve as a treatment for patients with type 2 diabetes. PMID- 28811852 TI - The Cluster of Abnormalities Related to Metabolic Syndrome Is Associated With Reduced Glomerular Filtration Rate and Raised Albuminuria in Patients With Type 2 Diabetes Mellitus. AB - BACKGROUND: As association of metabolic syndrome (MS) with chronic kidney disease (CKD) has not been extensively studied in patients with type 2 diabetes, we addressed these issues. METHODS: Intrapersonal means of 12 measurements of waist circumference, blood pressure and high-density lipoprotein (HDL) cholesterol and those of six measurements of fasting triglycerides during 12 months were calculated in a cohort of 168 previously reported Japanese patients with type 2 diabetes. Based on these means, MS was diagnosed according to the modified National Cholesterol Education Program Adult Treatment Panel III criteria with the Asian definition of abdominal obesity. CKD was defined as the presence of low estimated glomerular filtration rate (eGFR < 60 mL/min/1.73 m2), albuminuria (urinary albumin/creatinine ratio (ACR) >= 30 mg/g) or both. RESULTS: Of 168 patients, 77 patients (46 %) had MS and 67 (40 %) had CKD. As the number of MS components increased from 1 through 5, the prevalence of albuminuria (9%, 38%, 30%, 41%, and 50%, P < 0.001), low eGFR (0%, 10%, 24%, 22%, and 50%, P < 0.001) and consequently, CKD increased (9%, 41%, 48%, 52%, and 75%, P < 0.001). Urinary ACR increased and eGFR decreased as a function of the number of MS components. As compared to patients without MS, prevalence of low eGFR (26% vs. 7%, P = 0.001) and CKD (52% vs. 30%, P = 0.005) was higher in patients with MS but prevalence of albuminuria did not differ (36% vs. 27%, P = 0.2). CONCLUSION: In Japanese patients with type 2 diabetes, the cluster of abnormalities related to MS was associated not only with higher prevalence of albuminuria, reduced kidney function and hence the increase in CKD but also with corresponding changes in urinary ACR and eGFR. PMID- 28811853 TI - Effects of Sevelamer Hydrochloride on Uremic Toxins Serum Indoxyl Sulfate and P Cresyl Sulfate in Hemodialysis Patients. AB - BACKGROUND: Beside the phosphate binding effect, non-calcium non-aluminum phosphate binder, namely sevelamer hydrochloride (SH), has many other effects in dialysis patients. It can absorb many other compounds, decrease low-density lipoprotein cholesterol (LDL-C) level, and attenuate the progression of vascular calcification; it has been reported to have anti-inflammatory effect. However, it is not clear whether it has any effect on uremic toxins, i.e. serum indoxyl sulfate (IS) and p-cresyl sulfate, (PCS) in hemodialysis (HD) patients. This study was carried out to appraise the effect of sevelamer on serum IS and PCS in HD patients. METHODS: Five adult HD patients from a single medical center were enrolled in this study; these patients were treated with 800 mg of sevelamer thrice per day for 3 months; a series of biochemical parameters, serum IS and PCS were monitored concurrently. RESULTS: There was a significant reduction in the mean level of phosphate from 7.20 +/- 0.70 mg/dL (mean +/- SD) before treatment to 5.40 +/- 0.50 mg/dL (mean +/- SD) after treatment, total cholesterol from 151.00 +/- 37.40 mg/dL (mean +/- SD) before treatment to 119.20 +/- 29.40 mg/dL (mean +/- SD) after treatment, and PCS from 31.30 +/- 10.60 mg/L (mean +/- SD) before treatment to 19.70 +/- 10.50 mg/L (mean +/- SD) after treatment. On the contrary, this treatment had no effect on IS. CONCLUSION: A statistically significant reduction of serum phosphate and PCS in HD patients treated with SH suggests that beside the action of lowering serum phosphate, sevelamer may have an important role in the treatment of uremic syndrome by decreasing the uremic toxin. PMID- 28811854 TI - Factors Associated With Psycho-Cognitive Functions in Patients With Persistent Pain After Surgery for Femoral Neck Fracture. AB - BACKGROUND: The aim of the study was to address issues arising from fracture of the femoral neck in elderly individuals, the prevalence of which continues to increase in Japan. The prevalence is increasing in Japan and there have been many reports on physical functions such as prevention of a fall. However, there have been a few studies that focus on psycho-cognitive functions. We must examine factors in patients with fractured femur necks to develop methods to assist affected patients. The current study aimed to examine factors associated with psycho-cognitive functions after surgery for fractured femoral neck in the Japanese elderly. METHODS: In this study, we examined the relationships among sex, age, fracture site, operative procedure, body mass index, lifestyle, psycho cognitive functions, and types of pain in 142 patients, performed multiple regression analysis using the mini-mental state examination (MMSE) and the Montgomery-Asberg depression rating scale (MADRS) scores as dependent variables, and created MMSE and MADRS models. RESULTS: Analysis of MMSE and MADRS models identified night pain and the number of family members as factors that affected mental function in a population with persistent pain for 1 week after surgery for fractured femoral neck. In addition, the number of family members was identified in multiple regression analysis models as a factor associated with psycho cognitive functions. Pain, and night pain in particular, affect psycho-cognitive functions. CONCLUSIONS: We speculated that emotional changes were associated with number of family members. Patients living with family members maintained psycho cognitive functions better than did those living alone, even when they experienced pain in their daily lives. PMID- 28811855 TI - Impact of the Great East Japan Earthquake and Fukushima Nuclear Power Plant Accident on Assisted Reproductive Technology in Fukushima Prefecture: The Fukushima Health Management Survey. AB - BACKGROUND: The aim of the study was to evaluate the incidences and obstetric outcomes of women who conceived using assisted reproductive technology (ART) procedures in Fukushima Prefecture before and after the Great East Japan Earthquake and Fukushima nuclear power plant accident. METHODS: Information was collected and analyzed from 12,070 women who conceived with or without ART in Fukushima Prefecture during the 9 months before and after the disaster. RESULTS: During the 9 months before and after the disaster, 138 (2.0%) and 102 (1.9%) women conceived with in vitro fertilization-embryo transfer (IVF-ET), respectively. The proportion of women who conceived with IVF-ET decreased during the 2 months immediately after the disaster, but returned to pre-disaster levels 3 months after the disaster. In the case of women who conceived without IVF-ET, the incidences of preterm birth and low birth weight increased after the disaster. In contrast, women who conceived with IVF-ET did not differ significantly in obstetric outcomes before and after the disaster but had a higher incidence of cesarean section and low birth weight compared to those conceived without IVF-ET, regardless of the study period. CONCLUSION: The influence of the disaster on woman who conceived using ART procedures was minimal. PMID- 28811857 TI - Concordance of Toxoplasma gondii Infection Markers Among Heterosexual Couples. AB - BACKGROUND: Very little is known about concordance of Toxoplasma gondii (T. gondii) infection markers among couples. Through a cross-sectional study, we sought to determine the correlation of T. gondii infection in a sample of 119 heterosexual couples in Durango State, Mexico. METHODS: Participants were examined for the presence of anti-T. gondii IgG and IgM antibodies using enzyme linked immunoassays. IgG and IgM seropositive couples were further analyzed for the presence of T. gondii DNA by using polymerase chain reaction (PCR). RESULTS: Anti-T. gondii IgG antibodies were found in 71 (59.7%) men and in 63 (52.9%) women (odds ratio (OR) = 1.31; 95% confidence interval (CI): 0.78 - 2.19; P = 0.29). Of the 71 seropositive men, 40 (56.3%) had a seropositive couple; in contrast, of the 63 seropositive women, 40 (63.5%) had a seropositive couple (OR = 0.74; 95% CI: 0.37 - 1.48; P = 0.39). In total, 65 (54.6%) couples had concordant results (both IgG positive or both IgG negative), and 54 (45.4%) had discordant results (a seropositive man with a seronegative woman, or a seropositive woman with a seronegative man) (kappa index = 0.08; 95% CI: -0.09 - 0.26). With respect to high (> 150 IU/mL) levels of anti-T. gondii IgG antibodies, 79 (66.4%) of the 119 couples had concordant results and 40 (33.6%) had discordant results (kappa index = -0.15; 95% CI: -0.03 - 0.33). Forty couples were positive for anti-T. gondii IgM antibodies. Of them, 21 (52.5%) had concordant results, and 19 (47.5%) had discordant results (kappa index = -0.01; 95% CI: -0.39 - 0.28). Concerning PCR, eight (50%) of 16 couples were positive for T. gondii DNA. Of them, 11 (68.8%) had concordant results, and five (31.2%) had discordant results (kappa index = 0.31; 95% CI: -0.17 - 0.79). CONCLUSIONS: Results suggest a poor concordance of serological and molecular markers of T. gondii infection among heterosexual couples. Further studies to confirm our results should be conducted. PMID- 28811856 TI - Serum Betatrophin Levels and Clinical Features in Patients With Poorly Controlled Type 2 Diabetes. AB - BACKGROUND: Betatrophin is a hormone mainly secreted by the liver that influences lipid metabolisms. The main purposes of this study were to investigate the effect of canagliflozin (a sodium glucose transporter 2 inhibitor) on circulating betatrophin levels, and to investigate the correlation of various markers associated with glucose and lipid metabolisms with betatrophin in patients with poorly controlled type 2 diabetes. METHODS: Patients were randomly divided into a control group (n = 15) and a canagliflozin-treated group (n = 15). After hospitalization, the canagliflozin-treated group took 100 mg/day of canagliflozin for 3 days. Blood tests were performed at baseline and after 3 days of treatment. RESULTS: Canagliflozin treatment for 3 days did not significantly change fasting and postprandial serum betatrophin levels. On the other hand, betatrophin levels had a significant positive correlation with hemoglobin A1c, fasting plasma glucose, and high-density lipoprotein cholesterol levels at baseline. CONCLUSIONS: The current study suggests that short-term treatment by canagliflozin does not influence circulating betatrophin levels, and that betatrophin is positively associated with markers of glycemic control and high density lipoprotein cholesterol in patients with poorly controlled type 2 diabetes. PMID- 28811858 TI - Effectiveness of Ipragliflozin for Reducing Hemoglobin A1c in Patients With a Shorter Type 2 Diabetes Duration: Interim Report of the ASSIGN-K Study. AB - BACKGROUND: Ipragliflozin is a selective sodium glucose co-transporter 2 inhibitor. The ASSIGN-K study is investigating the efficacy and safety of ipragliflozin for type 2 diabetes mellitus (T2DM) in the real-world clinical setting. METHODS: Japanese T2DM patients with inadequate glycemic control despite diet and exercise with/without pharmacotherapy were enrolled in an investigator driven, multicenter, prospective, observational study examining the efficacy and safety of ipragliflozin treatment (50 mg/day for 52 weeks). We performed interim analysis after 24 weeks. RESULTS: In 367 patients completing 24-week ipragliflozin therapy, hemoglobin A1c (HbA1c) decreased significantly from 8.07% at baseline to 7.26% in week 24 (P < 0.001). The change in HbA1c from treatment initiation to week 24 was -0.88% in patients < 65 years old versus -0.55% in those >= 65 years and -0.92% in men versus -0.70% in women (all P < 0.001). When baseline HbA1c was < 7%, 7% to < 8%, and >= 8%, the change was -0.18%, -0.45%, and -1.48%, respectively (P = 0.5352, P < 0.001, and P < 0.001, respectively). When baseline body mass index (BMI) was < 25, 25 to < 30, and >= 30, the change was -1.05%, -0.65%, and -0.87%, respectively (all P < 0.001). Multiple regression analysis showed that HbA1c decreased more in patients with a higher baseline HbA1c or shorter duration of diabetes. An HbA1c < 7% was achieved in 33.3% of the patients, and their baseline HbA1c was significantly lower than that of patients failing to achieve it (P < 0.001). Adverse events (AEs) occurred in 106/451 patients (23.5%), including 29.1% of patients aged 65 or older. Common AEs were vulvovaginal candidiasis (3.1%) and genital pruritus (1.8%). Serious AEs included urinary tract infection, unstable angina, and ketosis, which occurred in patients who did not suspend medication during acute illness. CONCLUSIONS: Ipragliflozin significantly improved HbA1c in T2DM patients with inadequate glycemic control. Improvement in HbA1c was significant irrespective of age, sex, baseline HbA1c, or BMI, but efficacy was greater with a higher baseline HbA1c and shorter duration of diabetes. For safe continuation of treatment, patients should be advised to suspend medication during acute illness. PMID- 28811859 TI - Long-Term Effect of Alogliptin on Glycemic Control in Japanese Patients With Type 2 Diabetes: A 3.5-Year Observational Study. AB - BACKGROUND: The goal of the current study was to investigate the long-term effects (after 3 years or more) of alogliptin on glycemic control in Japanese patients with type 2 diabetes. METHODS: We retrospectively studied the effect of alogliptin on glycemic control in the patients with type 2 diabetes who had participated in our previous 3-month study and who continued to take alogliptin for at least 36 months. RESULTS: The mean duration of alogliptin treatment was 42.8 +/- 2.2 months. In all 39 patients, a significant reduction in hemoglobin A1c (HbA1c) levels was noted between the baseline and final visit: 7.8+/-0.6% to 7.2+/-1.0% (P = 0.0001). A significant reduction in HbA1c levels was found in a subgroup of patients who did not change their anti-diabetic drugs or did decrease the dose of their sulfonylureas (SUs) or did change to a lower strength repaglinide (n = 32): 7.7+/-0.6% to 7.2+/-1.0% (P = 0.0005). A significant decrease in low-density lipoprotein cholesterol (LDL-C) levels was observed in all of the patients that had LDL-C levels determined (P = 0.0406) (n = 37), and in a subgroup of patients who had not taken either statins, fibrates, or pioglitazone, or who had taken one or more of these drugs but the doses were not changed during the observation period (P = 0.0250) (n = 27). CONCLUSION: The current study found that alogliptin performed well for glycemic control when evaluated by HbA1c levels in a long-term observation period exceeding 3 years in Japanese patients with type 2 diabetes. Alogliptin may also decrease circulating LDL-C levels with long-term use. PMID- 28811860 TI - The Apelin Receptor APJ in Hematopoietic Stem Cells/Progenitor Cells in the Early Stage of Non-Alcoholic Steatohepatitis. AB - BACKGROUND: Non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis and inflammation with or without fibrosis. The apelin receptor (APJ) is related to angiotensin-like-receptor 1 (AGTRL1). The present study aimed to evaluate APJ as an indicator of the pathophysiology of early-stage NASH. METHODS: APJ expression was evaluated in six tissue samples with histologically proven early-stage NASH using immunohistochemistry (IHC) and immunoelectron microscopy (IEM). RESULTS: On IHC, in control liver tissue, APJ was mainly localized in the aortic artery, although APJ was detected only slightly in the sinusoids. In early NASH liver tissue, on IEM, APJ was observed mainly at the sites of sinusoidal lining cells around the central vein and periportal regions, and at arterial capillaries in the portal tract. With regard to endothelial cells (ECs), one sample showed a hematopoietic stem cell (HSC)/progenitor cell (HPC) partially wrapped with an EC. CONCLUSION: HSCs/HPCs expressing APJ may contribute to the angiogenesis of liver tissue in early-stage NASH. PMID- 28811861 TI - Importance of Distinguishing Between Mitochondrial Encephalomyopathy With Elderly Onset of Stroke-Like Episodes and Cerebral Infarction. AB - The most common disease-causing mitochondrial DNA (mtDNA) mutation in mitochondrial encephalomyopathy (ME) with lactic acidosis and stroke-like episodes (MELAS) is m.3243A>G. In the future, the incidence of patients with cerebral infarction and diabetes mellitus is expected to increase tremendously. Additionally, the A3243G mutation typical of diabetes is estimated to be present in approximately 2% of all diabetes patients, which suggests that the potential disease population with a mitochondrial disorder is greater than previously thought, and there may have been many cases among the elderly that were misdiagnosed. Considering this background, MELAS with the onset of stroke-like episodes should be considered an important differential diagnosis for elderly patients with cerebral infarction, although it might have been overlooked until now. A 68-year-old Japanese female developed convulsive seizures and was admitted to Hospital of International University of Health and Welfare for epilepsy. She had been hospitalized twice in the previous year for cerebral infarction and seizures. She experienced sensorineural hearing loss at a young age. Thus, although she was elderly, we suspected MELAS and detected elevations of pyruvic and lactic acid. A genetic test revealed a point mutation in the mtDNA (m.3243A>G) that led to a definitive diagnosis of MELAS. To date, MELAS has been regarded as a disease of the relatively young. The incidence of patients with cerebral infarction and diabetes mellitus is expected to greatly increase. Thus, we should evaluate cerebral infarction in the elderly with caution to prevent missed diagnoses of MELAS. PMID- 28811862 TI - Allergic profiles of mothers and fathers in the Japan Environment and Children's Study (JECS): a nationwide birth cohort study. AB - BACKGROUND: The Japan Environment and Children's Study (JECS) is a nationwide, multicenter, prospective birth cohort investigation launched by the Ministry of Environment in Japan. The purpose of the JECS is to evaluate the influence of prenatal and postnatal exposures to environmental factors on the postnatal health of the children. In this study, we evaluated the allergic characteristics of parents within the JECS cohort. METHODS: This study covered a wide geographical area and encompassed 15 regional centers. We obtained information regarding doctor diagnosed allergic diseases by using maternal and/or paternal self administered questionnaires during the first trimester of pregnancy. Blood samples were also obtained from mothers and/or fathers to detect serum IgE concentrations. RESULTS: The prevalences of asthma, allergic rhinitis (hay fever), atopic dermatitis, and food allergy were 10.9, 36.0, 15.7 and 4.8%, respectively, among 99,013 mothers; these prevalences among 49,991 fathers were 10.8, 30.3, 11.2 and 3.3%, respectively. Any positive antigen-specific IgE sensitization was found in 73.9% of mothers. The most abundant antigen sensitization in mothers was to Japanese cedar (55.6%), followed by Der p 1 (48%); only 1.0% of mothers were sensitized to egg white. CONCLUSIONS: This is the first epidemiological report on allergic disorders and allergen sensitization of parents during pregnancy among the Japanese general population. PMID- 28811864 TI - Identification of Four Oxidative Stress-Responsive MicroRNAs, miR-34a-5p, miR 1915-3p, miR-638, and miR-150-3p, in Hepatocellular Carcinoma. AB - Increasing evidence suggests that oxidative stress plays an essential role during carcinogenesis. However, the underlying mechanism between oxidative stress and carcinogenesis remains unknown. Recently, microRNAs (miRNAs) are revealed to be involved in oxidative stress response and carcinogenesis. This study aims to identify miRNAs in hepatocellular carcinoma (HCC) cells which might involve in oxidative stress response. An integrated analysis of miRNA expression signature was performed by employing robust rank aggregation (RRA) method, and four miRNAs (miR-34a-5p, miR-1915-3p, miR-638, and miR-150-3p) were identified as the oxidative stress-responsive miRNAs. Pathway enrichment analysis suggested that these four miRNAs played an important role in antiapoptosis process. Our data also revealed miR-34a-5p and miR-1915-3p, but not miR-150-3p and miR-638, were regulated by p53 in HCC cell lines under oxidative stress. In addition, clinical investigation revealed that these four miRNAs might be involved in oxidative stress response by targeting oxidative stress-related genes in HCC tissues. Kaplan-Meier analysis showed that these four miRNAs were associated with patients' overall survival. In conclusion, we identified four oxidative stress responsive miRNAs, which were regulated by p53-dependent (miR-34a-5p and miR-1915 3p) and p53-independent pathway (miR-150-3p and miR-638). These four miRNAs may offer new strategy for HCC diagnosis and prognosis. PMID- 28811865 TI - Oxidative Biochemistry Disbalance and Changes on Proteomic Profile in Salivary Glands of Rats Induced by Chronic Exposure to Methylmercury. AB - Methylmercury (MeHg) is one of the most toxic mercury species, which can cause many systemic damages, but little is known about its effect in the salivary glands. This study aimed to analyze the mercury levels, oxidative stress, and proteomic profile in parotid, submandibular, and sublingual salivary glands of rats, after chronic MeHg intoxication. Two groups of twenty male Wistar rats (90 days of age) were used on the experiment. MeHg group was intoxicated by intragastric gavage with MeHg at a dose of 0.04 mg/kg/day for 60 days, while the control group received only oil. After the period of intoxication, the glands were collected for evaluation of total mercury levels, proteomic profile, and oxidative balance by analyzing the antioxidant capacity against peroxyl radicals (ACAP), lipid peroxidation (LPO), and nitrite levels. Our results have showed that mercury levels were significant in all three glands compared to the respective control. It also showed lower levels of ACAP, as well as higher LPO and nitrite levels. The proteomic profile presented impairments on structural components of cytoskeleton, metabolic pathways, and oxidative biochemistry. Thus, the exposure to MeHg was able to generate oxidative stress that could be associated with changes in the proteomic profile of salivary glands. PMID- 28811866 TI - Preliminary Data on the Interaction between Some Biometals and Oxidative Stress Status in Mild Cognitive Impairment and Alzheimer's Disease Patients. AB - Increased interest regarding the biometal mechanisms of action and the pathways in which they have regulatory roles was lately observed. Particularly, it was shown that biometal homeostasis dysregulation may lead to neurodegeneration including Alzheimer's disease, Parkinson disease, or prion protein disease, since important molecular signaling mechanisms in brain functions implicate both oxidative stress and redox active biometals. Oxidative stress could be a result of a breakdown in metal-ion homeostasis which leads to abnormal metal protein chelation. In our previous work, we reported a strong correlation between Alzheimer's disease and oxidative stress. Consequently, the aim of the present work was to evaluate some of the biometals' levels (magnesium, manganese, and iron), the specific activity of some antioxidant enzymes (superoxide dismutase and glutathione peroxidase), and a common lipid peroxidation marker (malondialdehyde concentration), in mild cognitive impairment (n = 15) and Alzheimer's disease (n = 15) patients, compared to age-matched healthy subjects (n = 15). We found increased lipid peroxidation effects, low antioxidant defense, low magnesium and iron concentrations, and high manganese levels in mild cognitive impairment and Alzheimer's disease patients, in a gradual manner. These data could be relevant for future association studies regarding the prediction of Alzheimer's disease development risk or circling through stages by analyzing both active redox metals, oxidative stress markers, and the correlations in between. PMID- 28811863 TI - Long Noncoding RNAs and RNA-Binding Proteins in Oxidative Stress, Cellular Senescence, and Age-Related Diseases. AB - Cellular senescence is a complex biological process that leads to irreversible cell-cycle arrest. Various extrinsic and intrinsic insults are associated with the onset of cellular senescence and frequently accompany genomic or epigenomic alterations. Cellular senescence is believed to contribute to tumor suppression, immune response, and tissue repair as well as aging and age-related diseases. Long noncoding RNAs (lncRNAs) are >200 nucleotides long, poorly conserved, and transcribed in a manner similar to that of mRNAs. They are tightly regulated during various cellular and physiological processes. Although many lncRNAs and their functional roles are still undescribed, the importance of lncRNAs in a variety of biological processes is widely recognized. RNA-binding proteins (RBPs) have a pivotal role in posttranscriptional regulation as well as in mRNA transport, storage, turnover, and translation. RBPs interact with mRNAs, other RBPs, and noncoding RNAs (ncRNAs) including lncRNAs, and they are involved in the regulation of a broad spectrum of cellular processes. Like other cell fate regulators, lncRNAs and RBPs, separately or cooperatively, are implicated in initiation and maintenance of cellular senescence, aging, and age-related diseases. Here, we review the current understanding of both lncRNAs and RBPs and their association with oxidative stress, senescence, and age-related diseases. PMID- 28811867 TI - Modulation of Glutathione Hemostasis by Inhibition of 12/15-Lipoxygenase Prevents ROS-Mediated Cell Death after Hepatic Ischemia and Reperfusion. AB - BACKGROUND: Reactive oxygen species- (ROS-) mediated ischemia-reperfusion injury (IRI) detrimentally impacts liver transplantation and resection. 12/15 Lipoxygenase (12/15-LOX), an antagonistic protein of the glutathione peroxidase 4 (GPX4) signaling cascade, was proven to mediate cell death in postischemic cerebral and myocardial tissue. The aim of this study was to investigate the impact of 12/15-LOX inhibition on hepatic IRI. METHODS: Livers of C57BL/6 mice were exposed to 60 minutes of partial warm ischemia and 90 minutes of reperfusion after previous Baicalein administration, an inhibitor of 12/15-LOX. Tissue samples were analyzed by TUNEL assay, Western blot, and spectral photometry. RESULTS: TUNEL labeling showed a significant reduction of hepatic cell death following baicalein pretreatment. Western Blot analysis revealed a significant downregulation of Jun-amino-terminal-kinase (JNK), caspase-3, and poly-ADP-ribose polymerase (PARP), besides considerably lowered p44/42-MAP-kinase (ERK1/2) expression after Baicalein administration. A significant elevation of glutathione oxidation was measured in Baicalein pretreated livers. CONCLUSION: Our data show that inhibition of 12/15-lipoxygenase causes significant cell death reduction after hepatic ischemia and reperfusion by enhancing glutathione metabolism. We conclude that GPX4-dependent cell death signaling cascade might play a major role in development of hepatic IRI, in which the investigated proteins JNK, caspase-3, ERK1/2, and PARP might contribute to tissue damage. PMID- 28811868 TI - Selaginella bryopteris Aqueous Extract Improves Stability and Function of Cryopreserved Human Mesenchymal Stem Cells. AB - The effective long-term cryopreservation of human mesenchymal stem cells (MSCs) is an essential prerequisite step and represents a critical approach for their sustained supply in basic research, regenerative medicine, and tissue engineering applications. Therefore, attempts have been made in the present investigation to formulate a freezing solution consisting of a combination of Selaginella bryopteris water-soluble extract with and without dimethyl sulfoxide (Me2SO) for the efficient long-term storage of human umbilical cord blood- (hUCB-) derived MSCs. The cryopreservation experiment using the formulated freezing solution was further performed with hUCB MSCs in a controlled rate freezer. A significant increase in postthaw cell viability and cell attachment of MSCs was achieved with freezing medium containing Selaginella bryopteris water extract along with 10% Me2SO as compared to the freezing medium containing Me2SO (10% v/v) alone. Furthermore, the decreasing apoptotic events and reactive oxygen species production along with increasing expression of heat shock proteins also confirmed the beneficial effect of Selaginella bryopteris water extract. The beneficial effect of Selaginella bryopteris water extract was validated by its ability to render postpreservation high cell viability. In conclusion, the formulated freezing solution has been demonstrated to be effective for the standardization of cryopreservation protocol for hMSCs. PMID- 28811870 TI - Meat inspection of reindeer - a rich source of data for monitoring food safety and animal and environmental health in Sweden. AB - Background: This study scrutinized carcass conditions recorded in post mortem inspections (PMI) of reindeer (Rangifer tarandus tarandus, L.) during 2015-2016 because of the importance for monitoring food safety and animal and environmental health threats. Material and methods: PMI results were retrieved from the National Food Agency. A negative binomial regression model was applied. For actual parameters, incident risk rate (IRR) with confidence intervals was calculated. Results and discussion: The number of conditions found in PMI varied widely between years and batches. The most common conditions (43 and 57% of all reindeer slaughtered in 2015 and 2016, respectively) derived from non-zoonotic parasites as the most abundant one, Hypoderma tarandi. Setaria sp. as well as both inflammatory processes and trauma were found in low prevalences. Further investigation of interactions with slaughterhouse size and inspector experience is needed. The conditions found rarely indicated food safety hazards and no epizooties or zoonoses have been recorded in the past two decades. Visual PMI with complementary sampling for specific hazards in slaughterhouses could thus be a helpful tool for monitoring the health and welfare of the reindeer population, the food safety risks with reindeer meat, and the status of the environment. . PMID- 28811871 TI - Do All Patients with Atrial Fibrillation Need Long-Term Anticoagulation? AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide with an estimated number of 2.7-6.1 million cases in the United States (US) alone. The incidence of AF is expected to increase 2.5 fold over the next 50 years in the US. The management of AF is complex and includes mainly three aspects; restoration of sinus rhythm, control of ventricular rate and prevention of systemic thromboembolism. AF as a cause of systemic embolization has been well known for many years, and majority of patients are on oral anticoagulants (OACs) to prevent this. Many times, a patient may not be in AF chronically, nor is the AF burden (the amount of time patient is in AF out of the total monitored time) calculated. We present three cases of new onset transient AF triggered by temporary stressors. We were able to restore normal sinus rhythm (NSR) with chemical cardioversion. As per 2014 American College of Cardiology (ACC)/American Heart Association (AHA) recommendations, we started all three patients on OACs based on CHA2DS2VASc score >=2. However, the patients refused long term OACs after restoration of NSR and correction of the temporary enticing stressors. In any case, the decision to start OACs would have had its own risks. Here we describe how antiarrhythmic drugs were used to maintain NSR, all while they were continuously monitored to determine the need to continue OACs. PMID- 28811872 TI - Current and emerging treatment options for mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma with typically aggressive behavior. The genetic signature is the chromosomal translocation t(11;14)(q13;q32) resulting in overexpression of cyclin D1. Asymptomatic newly diagnosed MCL patients with low tumor burden can be closely observed, deferring therapy to the time of disease progression. Although MCL classically responds to upfront chemotherapy, it remains incurable with standard approaches. For patients in need of frontline therapy, the initial decision is whether to proceed with an intensive treatment strategy or a non-intensive treatment strategy. In general, given the unfavorable risk-benefit profile, older MCL patients should be spared intensive strategies, while younger and fit patients can be considered for intensive strategies. The bendamustine and rituximab (BR) regimen is becoming an increasingly popular treatment option among the elderly population, with improved progression-free survival (PFS) and acceptable side-effect profile. Although rituximab maintenance after R-CHOP improves survival outcomes in elderly patients, no clinical trial to date has shown statistical significance to support the use of rituximab maintenance after BR induction in older patients. In young and fit patients with MCL, an intensive strategy to maximize the length of first remission has emerged as a worldwide standard of care. With current high-dose cytarabine-containing immunochemotherapy regimens followed by autologous stem cell transplantation, the median PFS has exceeded 7 years. In the relapsed or refractory (R/R) setting, reduced intensity conditioning allogeneic hematopoietic stem cell transplantation may offer the highest likelihood of long-term survival in young R/R MCL patients, at the cost of increased risk of non-relapse mortality and chronic graft versus host disease. Novel agents targeting activated pathways in MCL cells, such as bortezomib, lenalidamide, ibrutinib and temsirolimus are now available for the management of R/R disease. PMID- 28811873 TI - A human plasma derived supplement preserves function of human vascular cells in absence of fetal bovine serum. AB - Current techniques for cell culture routinely use animal-derived components. Fetal bovine serum (FBS) is the most widely applied supplement, but it often displays significant batch-to-batch variations and is generally not suitable for clinical applications in humans. A robust and xeno-free alternative to FBS is of high interest for cellular therapies, from early in vitro testing to clinical trials in human subjects. In the current work, a highly consistent human plasma derived supplement (SCC) has been tested, as a potential substitute of FBS in primary human vascular cells culture. Our results show that SCC is able to support proliferation, preserve cellular morphology and potentiate functionality analogously to FBS. We conclude that SCC is a viable substitute of FBS for culture and expansion of cells in advanced therapies using human vascular cells and fibroblasts. PMID- 28811869 TI - Pro- and Antioxidant Functions of the Peroxisome-Mitochondria Connection and Its Impact on Aging and Disease. AB - Peroxisomes and mitochondria are the main intracellular sources for reactive oxygen species. At the same time, both organelles are critical for the maintenance of a healthy redox balance in the cell. Consequently, failure in the function of both organelles is causally linked to oxidative stress and accelerated aging. However, it has become clear that peroxisomes and mitochondria are much more intimately connected both physiologically and structurally. Both organelles share common fission components to dynamically respond to environmental cues, and the autophagic turnover of both peroxisomes and mitochondria is decisive for cellular homeostasis. Moreover, peroxisomes can physically associate with mitochondria via specific protein complexes. Therefore, the structural and functional connection of both organelles is a critical and dynamic feature in the regulation of oxidative metabolism, whose dynamic nature will be revealed in the future. In this review, we will focus on fundamental aspects of the peroxisome-mitochondria interplay derived from simple models such as yeast and move onto discussing the impact of an impaired peroxisomal and mitochondrial homeostasis on ROS production, aging, and disease in humans. PMID- 28811874 TI - Functional roles of an engineer species for coastal benthic invertebrates and demersal fish. AB - Through their tissues or activities, engineer species create, modify, or maintain habitats and alter the distribution and abundance of many plants and animals. This study investigates key ecological functions performed by an engineer species that colonizes coastal ecosystems. The gregarious tubiculous amphipod Haploops nirae is used as a biological model. According to previous studies, the habitat engineered by H. nirae (i.e., Haploops habitat) could provide food and natural shelter for several benthic species such as benthic diatoms belonging to the gender Navicula, the micrograzer Geitodoris planata, or the bivalve Polititapes virgineus. Using data from scientific surveys conducted in two bays, this study explored whether (1) the Haploops sandy-mud community modifies invertebrate and ichthyologic community structure (diversity and biomass); (2) H. nirae creates a preferential feeding ground; and (3) this habitat serves as a refuge for juvenile fish. Available Benthic Energy Coefficients, coupled with more traditional diversity indices, indicated higher energy available in Haploops habitat than in two nearby habitats (i.e., Sternaspis scutata and Amphiura filiformis/Owenia fusiformis habitats). The use of isotopic functional indices (IFIs) indicated (1) a higher functional richness in the Haploops habitat, related to greater diversity in food sources and longer food chains; and (2) a higher functional divergence, associated with greater consumption of a secondary food source. At the invertebrate-prey level, IFIs indicated little specialization and little trophic redundancy in the engineered habitat, as expected for homogenous habitats. Our results partly support empirical knowledge about engineered versus nonengineered habitats and also add new perspectives on habitat use by fish and invertebrate species. Our analyses validated the refuge-area hypothesis for a few fish species. Although unique benthic prey assemblages are associated with Haploops habitat, the hypothesis that it is a preferential feeding area was not verified. However, specialist feeding behavior was observed for predators, which calls for further investigation. PMID- 28811875 TI - Ecosystem size predicts eco-morphological variability in a postglacial diversification. AB - Identifying the processes by which new phenotypes and species emerge has been a long-standing effort in evolutionary biology. Young adaptive radiations provide a model to study patterns of morphological and ecological diversification in environmental context. Here, we use the recent radiation (ca. 12k years old) of the freshwater fish Arctic charr (Salvelinus alpinus) to identify abiotic and biotic environmental factors associated with adaptive morphological variation. Arctic charr are exceptionally diverse, and in postglacial lakes there is strong evidence of repeated parallel evolution of similar morphologies associated with foraging. We measured head depth (a trait reflecting general eco-morphology and foraging ecology) of 1,091 individuals across 30 lake populations to test whether fish morphological variation was associated with lake bathymetry and/or ecological parameters. Across populations, we found a significant relationship between the variation in head depth of the charr and abiotic environmental characteristics: positively with ecosystem size (i.e., lake volume, surface area, depth) and negatively with the amount of littoral zone. In addition, extremely robust-headed phenotypes tended to be associated with larger and deeper lakes. We identified no influence of co-existing biotic community on Arctic charr trophic morphology. This study evidences the role of the extrinsic environment as a facilitator of rapid eco-morphological diversification. PMID- 28811876 TI - Individual quality and age but not environmental or social conditions modulate costs of reproduction in a capital breeder. AB - Costs associated with reproduction are widely known to play a role in the evolution of reproductive tactics with consequences to population and eco evolutionary dynamics. Evaluating these costs as they pertain to species in the wild remains an important goal of evolutionary ecology. Individual heterogeneity, including differences in individual quality (i.e., among-individual differences in traits associated with survival and reproduction) or state, and variation in environmental and social conditions can modulate the costs of reproduction; however, few studies have considered effects of these factors simultaneously. Taking advantage of a detailed, long-term dataset for a population of feral horses (Sable Island, Nova Scotia, Canada), we address the question of how intrinsic (quality, age), environmental (winter severity, location), and social conditions (group size, composition, sex ratio, density) influence the costs of reproduction on subsequent reproduction. Individual quality was measured using a multivariate analysis on a combination of four static and dynamic traits expected to depict heterogeneity in individual performance. Female quality and age interacted with reproductive status of the previous year to determine current reproductive effort, while no effect of social or environmental covariates was found. High-quality females showed higher probabilities of giving birth and weaning their foal regardless of their reproductive status the previous year, while those of lower quality showed lower probabilities of producing foals in successive years. Middle-aged (prime) females had the highest probability of giving birth when they had not reproduced the year before, but no such relationship with age was found among females that had reproduced the previous year, indicating that prime-aged females bear higher costs of reproduction. We show that individual quality and age were key factors modulating the costs of reproduction in a capital breeder but that environmental or social conditions were not, highlighting the importance of considering multiple factors when studying costs of reproduction. PMID- 28811877 TI - Alternative reproductive strategies and the maintenance of female color polymorphism in damselflies. AB - Genetic polymorphisms are powerful model systems to study the maintenance of diversity in nature. In some systems, polymorphisms are limited to female coloration; these are thought to have arisen as a consequence of reducing male mating harassment, commonly resulting in negative frequency-dependent selection on female color morphs. One example is the damselfly Ischnura elegans, which shows three female color morphs and strong sexual conflict over mating rates. Here, we present research integrating male tactics, and female evolutionary strategies (female mating behavior and morph-specific female fecundity) in populations with different morph-specific mating frequencies, to obtain an understanding of mating rates in nature that goes beyond the mere measure of color frequencies. We found that female morph behavior differed significantly among but not within morphs (i.e., female morph behavior was fixed). In contrast, male tactics were strongly affected by the female morph frequency in the population. Laboratory work comparing morph-specific female fecundity revealed that androchrome females have lower fecundity than both of the gynochrome female morphs in the short term (3-days), but over a 10-day period one of the gynochrome female morphs became more fecund than either of the other morphs. In summary, our study found sex-specific dynamics in response to different morph frequencies and also highlights the importance of studying morph-specific fecundities across different time frames to gain a better understanding of the role of alternative reproductive strategies in the maintenance of female-limited color polymorphism. PMID- 28811878 TI - Magellanic penguin telomeres do not shorten with age with increased reproductive effort, investment, and basal corticosterone. AB - All species should invest in systems that enhance longevity; however, a fundamental adult life-history trade-off exists between the metabolic resources allocated to maintenance and those allocated to reproduction. Long-lived species will invest more in reproduction than in somatic maintenance as they age. We investigated this trade-off by analyzing correlations among telomere length, reproductive effort and output, and basal corticosterone in Magellanic penguins (Spheniscus magellanicus). Telomeres shorten with age in most species studied to date, and may affect adult survival. High basal corticosterone is indicative of stressful conditions. Corticosterone, and stress, has been linked to telomere shortening in other species. Magellanic penguins are a particularly good model organism for this question as they are an unusually long-lived species, exceeding their mass-adjusted predicted lifespan by 26%. Contrary to our hypothesis, we found adults aged 5 years to over 24 years of age had similar telomere lengths. Telomeres of adults did not shorten over a 3-year period, regardless of the age of the individual. Neither telomere length, nor the rate at which the telomeres changed over these 3 years, correlated with breeding frequency or investment. Older females also produced larger volume clutches until approximately 15 years old and larger eggs produced heavier fledglings. Furthermore, reproductive success (chicks fledged/eggs laid) is maintained as females aged. Basal corticosterone, however, was not correlated with telomere length in adults and suggests that low basal corticosterone may play a role in the telomere maintenance we observed. Basal corticosterone also declined during the breeding season and was positively correlated with the age of adult penguins. This higher basal corticosterone in older individuals, and consistent reproductive success, supports the prediction that Magellanic penguins invest more in reproduction as they age. Our results demonstrate that telomere maintenance may be a component of longevity even with increased reproductive effort, investment, and basal corticosterone. PMID- 28811879 TI - Growth and fecundity of fertile Miscanthus * giganteus ("PowerCane") compared to feral and ornamental Miscanthus sinensis in a common garden experiment: Implications for invasion. AB - Perennial grasses are promising candidates for bioenergy crops, but species that can escape cultivation and establish self-sustaining naturalized populations (feral) may have the potential to become invasive. Fertile Miscanthus * giganteus, known as "PowerCane," is a new potential biofuel crop. Its parent species are ornamental, non-native Miscanthus species that establish feral populations and are sometimes invasive in the USA. As a first step toward assessing the potential for "PowerCane" to become invasive, we documented its growth and fecundity relative to one of its parent species (Miscanthus sinensis) in competition with native and invasive grasses in common garden experiments located in Columbus, Ohio and Ames, Iowa, within the targeted range of biofuel cultivation. We conducted a 2-year experiment to compare growth and reproduction among three Miscanthus biotypes-"PowerCane," ornamental M. sinensis, and feral M. sinensis-at two locations. Single Miscanthus plants were subjected to competition with a native grass (Panicum virgatum), a weedy grass (Bromus inermis), or no competition. Response variables were aboveground biomass, number of shoots, basal area, and seed set. In Iowa, all Miscanthus plants died after the first winter, which was unusually cold, so no further results are reported from the Iowa site. In Ohio, we found significant differences among biotypes in growth and fecundity, as well as significant effects of competition. Interactions between these treatments were not significant. "PowerCane" performed as well or better than ornamental or feral M. sinensis in vegetative traits, but had much lower seed production, perhaps due to pollen limitation. In general, ornamental M. sinensis performed somewhat better than feral M. sinensis. Our findings suggest that feral populations of "PowerCane" could become established adjacent to biofuel production areas. Fertile Miscanthus * giganteus should be studied further to assess its potential to spread via seed production in large, sexually compatible populations. PMID- 28811880 TI - Population genetic structure in six sympatric and widespread aquatic plants inhabiting diverse lake environments in China. AB - Many aquatic plant species are distributed over large areas and diverse environments with populations interconnected by abiotic and biotic mediators. Here, we examined differences and similarities in the population genetic structure of six sympatric and widespread aquatic plant species. We sampled the aquatic species from six Chinese lakes found on plateaus, plains, and different river systems and analyzed them using inter-simple sequence repeat (ISSR) markers. Samples originating from each lake tended to cluster together. Of the six species, only Nymphoides peltata and Myriophyllum spicatum could be divided into plateau and plain groups, once Taihu Lake individuals were excluded. Genetic similarities between populations connected by the Yangtze River were not consistently higher than unconnected populations. Populations from Taihu Lake and/or Weishanhu Lake were distant from other lake populations for all species except Potamogeton lucens. The Taihu and Weishanhu populations clustered for Ceratophyllum demersum and Typha latifolia. Hydrophilous C. demersum had the lowest gene flow (Nm = 0.913), whereas the entomophilous Hydrocharis dubia (Nm = 2.084) and N. peltata (Nm = 2.204) had the highest gene flow. The genetic relationships among distant populations of aquatic plants reflect the comprehensive effects of environmental selection pressure and biotic and abiotic connectivity. Differences in environmental factors between plateau and plain lakes and long distance hydrochory have limited importance on aquatic plant genetic structures. Among multiple evolutionary forces, gene flow mediated by birds may play the most important role in the formation of genetic patterns in the six species examined. For example, the close genetic relationship between Taihu Lake and Weishanhu Lake populations, each in different river systems and with different climates, may be related to the migration routes of birds. Differences in gene flow among the six aquatic plants may be attributable to different bird-transport and the fruit traits of each species. PMID- 28811881 TI - Self- and intra-morph incompatibility and selection analysis of an inconspicuous distylous herb growing on the Tibetan plateau (Primula tibetica). AB - There is discussion over whether pollen limitation exerts selection on floral traits to increase floral display or selects for traits that promote autonomous self-fertilization. Some studies have indicated that pollen limitation does not mediate selection on traits associated with either pollinator attraction or self fertilization. Primula tibetica is an inconspicuous cross-fertilized plant that may suffer from pollen limitation. We conducted a selection analysis on P. tibetica to investigate whether pollen limitation results in selection for an increased floral display in case the evolution of autonomous self-fertilization has been difficult for this plant. The self- and intra-morph incompatibility features, the capacity for autonomous self-fertilization, and the magnitude of pollen limitation were examined through hand-pollination experiments. In 2016, we applied selection analysis on the flowering time, corolla width, stalk height, flower tube length, and flower number in P. tibetica by tagging 76 open pollinated plants and 37 hand-pollinated plants in the field. Our results demonstrated that P. tibetica was strictly self- and intra-morph incompatible. Moreover, the study population underwent severe pollen limitation during the 2016 flowering season. The selection gradients were found to be significantly positive for flowering time, flower number, and corolla width, and marginally significant for the stalk height. Pollinator-mediated selection was found to be significant on the flower number and corolla width, and marginally significant on stalk height. Our results indicate that the increased floral display may be a vital strategy for small distylous species that have faced difficulty in evolving autonomous self-fertilization. PMID- 28811882 TI - Seasonal changes in leaf chemistry and leaf selection of the Japanese giant flying squirrel upon two tree species. AB - Tree leaves are important food sources for arboreal herbivores, such as primates, rodents, and marsupials. These animals do not eat leaves randomly in habitats with many tree species but rather choose based on the chemical components of leaves, such as sugars, fibers, proteins, and toxins. However, the effects of the microscale distribution of these chemicals within each leaf have not been examined for these animals. The giant flying squirrels Petaurista leucogenys are entirely arboreal, nocturnal herbivores, usually feeding on leaves and dropping leaf debris on the ground after partially consuming them. Therefore, we could easily assess which species of trees and which parts of the individual leaves they preferred to eat. We also examined microscale distributions of phenolics, sugar, and water within individual leaves. Of the two dominant food tree species, the deciduous Quercus acutissima was preferred over the evergreen Q. sessilifolia. The latter tree is only used during winter to early spring when the former had no leaves. Our chemical analyses revealed that Q. acutissima contained much more glucose than Q. sessilifolia in all seasons. Three types of leaf debris, eaten apically, basally, or centrally with a hole, were found. In Q. sessilifolia, which had low phenolic concentrations, apical eating was most common, whereas central eating was rare. In Q. acutissima, which had high phenolics, basal or central eating was common. Central feeding may be caused by avoiding the periphery because of a higher phenolic concentration in the leaf margin. Thus, microscale distributions of phenolics within individual leaves affect which parts P. leucogenys eats, whereas leaf sugar concentration is an important factor affecting which species of leaves they eat. PMID- 28811883 TI - Effect of habitat degradation on competition, carrying capacity, and species assemblage stability. AB - Changes in species' trophic niches due to habitat degradation can affect intra- and interspecific competition, with implications for biodiversity persistence. Difficulties of measuring species' interactions in the field limit our comprehension of competition outcomes along disturbance gradients. Thus, information on how habitat degradation can destabilize food webs is scarce, hindering predictions regarding responses of multispecies systems to environmental changes. Seagrass ecosystems are undergoing degradation. We address effects of Posidonia oceanica coverage reduction on the trophic organization of a macroinvertebrate community in the Tyrrhenian Sea (Italy), hypothesizing increased trophic generalism, niche overlap among species and thus competition and decreased community stability due to degraded conditions. Census data, isotopic analysis, and Bayesian mixing models were used to quantify the trophic niches of three abundant invertebrate species, and intra- and interspecific isotopic and resource-use similarity across locations differing in seagrass coverage. This allowed the computation of (1) competition strength, with respect to each other and remaining less abundant species and (2) habitat carrying capacity. To explore effects of the spatial scale on the interactions, we considered both individual locations and the entire study area ("'meadow scale"). We observed that community stability and habitat carrying capacity decreased as P. oceanica coverage declined, whereas niche width, similarity of resource use and interspecific competition strength between species increased. Competition was stronger, and stability lower, at the meadow scale than at the location scale. Indirect effects of competition and the spatial compartmentalization of species interactions increased stability. Results emphasized the importance of trophic niche modifications for understanding effects of habitat loss on biodiversity persistence. Calculation of competition coefficients based on isotopic distances is a promising tool for describing competitive interactions in real communities, potentially extendible to any subset of ecological niche axes for which specimens' positions and pairwise distances can be obtained. PMID- 28811884 TI - Factors contributing to the accumulation of reproductive isolation: A mixed model approach. AB - The analysis of large datasets describing reproductive isolation between species has been extremely influential in the study of speciation. However, the statistical methods currently used for these data limit the ability to make direct inferences about the factors predicting the evolution of reproductive isolation. As a result, our understanding of iconic patterns and rules of speciation rely on indirect analyses that have clear statistical limitations. Phylogenetic mixed models are commonly used in ecology and evolution, but have not been applied to studies of reproductive isolation. Here I describe a flexible framework using phylogenetic mixed models to analyze data collected at different evolutionary scales, to test both categorical and continuous predictor variables, and to test the effect of multiple predictors on rates and patterns of reproductive isolation simultaneously. I demonstrate the utility of this framework by re-analyzing four classic datasets, from both animals and plants, and evaluating several hypotheses that could not be tested in the original studies: In the Drosophila and Bufonidae datasets, I found support for more rapid accumulation of reproductive isolation in sympatric species pairs compared to allopatric species pairs. Using Silene and Nolana, I found no evidence supporting the hypothesis that floral differentiation elevates postzygotic reproductive isolation. The faster accumulation of postzygotic isolation in sympatry is likely the result of species coexistence determined by the level of postzygotic isolation between species. In addition, floral trait divergence does not appear to translate into pleiotropic effects on postzygotic reproductive isolation. Overall, these methods can allow researchers to test new hypotheses using a single statistical method, while remedying the statistical limitations of several previous methods. PMID- 28811885 TI - Manipulation of habitat isolation and area implicates deterministic factors and limited neutrality in community assembly. AB - Theory predicts deterministic and stochastic factors will contribute to community assembly in different ways: Environmental filters should regulate those species that establish in a particular area resulting in the ecological requirements of species being the primary driver of species distributions, while chance and dispersal limitation should dictate the likelihood of species reaching certain areas with the ecology of species being largely neutral. These factors are specifically relevant for understanding how the area and isolation of different habitats or islands interact to affect community composition. Our review of the literature found few experimental studies have examined the interactive effect of habitat area and isolation on community assembly, and the results of those experiments have been mixed. We manipulated the area and isolation of rock "islands" created de novo in a grassland matrix to experimentally test how deterministic and stochastic factors shape colonizing animal communities. Over 64 weeks, the experiment revealed the primacy of deterministic factors in community assembly, with habitat islands of the same size exhibiting remarkable consistency in community composition and diversity, irrespective of isolation. Nevertheless, tangible differences still existed in abundance inequality among taxa: Large, near islands had consistently higher numbers of common taxa compared to all other island types. Dispersal limitation is often assumed to be negligible at small spatial scales, but our data shows this not to be the case. Furthermore, the dispersal limitation of a subset of species has potentially complex flow-on effects for dictating the type of deterministic factors affecting other colonizing species. PMID- 28811886 TI - Comparison of photo-matching algorithms commonly used for photographic capture recapture studies. AB - Photographic capture-recapture is a valuable tool for obtaining demographic information on wildlife populations due to its noninvasive nature and cost effectiveness. Recently, several computer-aided photo-matching algorithms have been developed to more efficiently match images of unique individuals in databases with thousands of images. However, the identification accuracy of these algorithms can severely bias estimates of vital rates and population size. Therefore, it is important to understand the performance and limitations of state of-the-art photo-matching algorithms prior to implementation in capture-recapture studies involving possibly thousands of images. Here, we compared the performance of four photo-matching algorithms; Wild-ID, I3S Pattern+, APHIS, and AmphIdent using multiple amphibian databases of varying image quality. We measured the performance of each algorithm and evaluated the performance in relation to database size and the number of matching images in the database. We found that algorithm performance differed greatly by algorithm and image database, with recognition rates ranging from 100% to 22.6% when limiting the review to the 10 highest ranking images. We found that recognition rate degraded marginally with increased database size and could be improved considerably with a higher number of matching images in the database. In our study, the pixel-based algorithm of AmphIdent exhibited superior recognition rates compared to the other approaches. We recommend carefully evaluating algorithm performance prior to using it to match a complete database. By choosing a suitable matching algorithm, databases of sizes that are unfeasible to match "by eye" can be easily translated to accurate individual capture histories necessary for robust demographic estimates. PMID- 28811887 TI - Lessons from the Tohoku tsunami: A model for island avifauna conservation prioritization. AB - Earthquake-generated tsunamis threaten coastal areas and low-lying islands with sudden flooding. Although human hazards and infrastructure damage have been well documented for tsunamis in recent decades, the effects on wildlife communities rarely have been quantified. We describe a tsunami that hit the world's largest remaining tropical seabird rookery and estimate the effects of sudden flooding on 23 bird species nesting on Pacific islands more than 3,800 km from the epicenter. We used global positioning systems, tide gauge data, and satellite imagery to quantify characteristics of the Tohoku earthquake-generated tsunami (11 March 2011) and its inundation extent across four Hawaiian Islands. We estimated short term effects of sudden flooding to bird communities using spatially explicit data from Midway Atoll and Laysan Island, Hawai'i. We describe variation in species vulnerability based on breeding phenology, nesting habitat, and life history traits. The tsunami inundated 21%-100% of each island's area at Midway Atoll and Laysan Island. Procellariformes (albatrosses and petrels) chick and egg losses exceeded 258,500 at Midway Atoll while albatross chick losses at Laysan Island exceeded 21,400. The tsunami struck at night and during the peak of nesting for 14 colonial seabird species. Strongly philopatric Procellariformes were vulnerable to the tsunami. Nonmigratory, endemic, endangered Laysan Teal (Anas laysanensis) were sensitive to ecosystem effects such as habitat changes and carcass-initiated epizootics of avian botulism, and its populations declined approximately 40% on both atolls post-tsunami. Catastrophic flooding of Pacific islands occurs periodically not only from tsunamis, but also from storm surge and rainfall; with sea-level rise, the frequency of sudden flooding events will likely increase. As invasive predators occupy habitat on higher elevation Hawaiian Islands and globally important avian populations are concentrated on low lying islands, additional conservation strategies may be warranted to increase resilience of island biodiversity encountering tsunamis and rising sea levels. PMID- 28811888 TI - Performance test and verification of an off-the-shelf automated avian radar tracking system. AB - Microwave radar is an important tool for observation of birds in flight and represents a tremendous increase in observation capability in terms of amount of surveillance space that can be covered at relatively low cost. Based on off-the shelf radar hardware, automated radar tracking systems have been developed for monitoring avian movements. However, radar used as an observation instrument in biological research has its limitations that are important to be aware of when analyzing recorded radar data. This article describes a method for exploring the detection capabilities of a dedicated short-range avian radar system used inside the operational Smola wind-power plant. The purpose of the testing described was to find the maximum detection range for various sized birds, while controlling for the effects of flight tortuosity, flight orientation relative to the radar and ground clutter. The method was to use a dedicated test target in form of a remotely controlled unmanned aerial vehicle (UAV) with calibrated radar cross section (RCS), which enabled the design of virtually any test flight pattern within the area of interest. The UAV had a detection probability of 0.5 within a range of 2,340 m from the radar. The detection performance obtained by the RCS calibrated test target (-11 dBm2, 0.08 m2 RCS) was then extrapolated to find the corresponding performance of differently sized birds. Detection range depends on system sensitivity, the environment within which the radar is placed and the spatial distribution of birds. The avian radar under study enables continuous monitoring of bird activity within a maximum range up to 2 km dependent on the size of the birds in question. While small bird species may be detected up to 0.5 1 km, larger species may be detected up to 1.5-2 km distance from the radar. PMID- 28811889 TI - Genome size in arthropods; different roles of phylogeny, habitat and life history in insects and crustaceans. AB - Despite the major role of genome size for physiology, ecology, and evolution, there is still mixed evidence with regard to proximate and ultimate drivers. The main causes of large genome size are proliferation of noncoding elements and/or duplication events. The relative role and interplay between these proximate causes and the evolutionary patterns shaped by phylogeny, life history traits or environment are largely unknown for the arthropods. Genome size shows a tremendous variability in this group, and it has a major impact on a range of fitness-related parameters such as growth, metabolism, life history traits, and for many species also body size. In this study, we compared genome size in two major arthropod groups, insects and crustaceans, and related this to phylogenetic patterns and parameters affecting ambient temperature (latitude, depth, or altitude), insect developmental mode, as well as crustacean body size and habitat, for species where data were available. For the insects, the genome size is clearly phylogeny-dependent, reflecting primarily their life history and mode of development, while for crustaceans there was a weaker association between genome size and phylogeny, suggesting life cycle strategies and habitat as more important determinants. Maximum observed latitude and depth, and their combined effect, showed positive, and possibly phylogenetic independent, correlations with genome size for crustaceans. This study illustrate the striking difference in genome sizes both between and within these two major groups of arthropods, and that while living in the cold with low developmental rates may promote large genomes in marine crustaceans, there is a multitude of proximate and ultimate drivers of genome size. PMID- 28811890 TI - Beyond temperature coupling: Effects of temperature on ectotherm signaling and mate choice and the implications for communication in multispecies assemblages. AB - Many organisms share communication channels, generating complex signaling environments that increase the risk of signal interference. Variation in abiotic conditions, such as temperature, may further exacerbate signal interference, particularly in ectotherms. We tested the effects of temperature on the pulse rate of male signals in a community of Oecanthus tree crickets, and for one focal species we also assessed its effect on female pulse rate preferences and motivation to seek mates. We confirm prior findings of temperature-dependent signals that result in increasing signal similarity at lower temperatures. Temperature also affected several aspects of female preferences: The preferred pulse rate value was temperature dependent, and nearly perfectly coupled with signal pulse rate; the range of pulse rate values that females found attractive also increased with temperature. By contrast, the motivation of females to perform phonotaxis was unaffected by temperature. Thus, at lower temperatures the signals of closely related species were more similar and females more discriminating. However, because signal similarity increased more strongly than female discrimination, signal interference and the likelihood of mismating may increase as temperatures drop. We suggest that a community approach will be useful for understanding the role of environmental variability in the evolution of communication systems. PMID- 28663788 TI - Using spectral decomposition of the signals from laurdan-derived probes to evaluate the physical state of membranes in live cells. AB - Background: We wanted to investigate the physical state of biological membranes in live cells under the most physiological conditions possible. Methods: For this we have been using laurdan, C-laurdan or M-laurdan to label a variety of cells, and a biphoton microscope equipped with both a thermostatic chamber and a spectral analyser. We also used a flow cytometer to quantify the 450/530 nm ratio of fluorescence emissions by whole cells. Results: We find that using all the information provided by spectral analysis to perform spectral decomposition dramatically improves the imaging resolution compared to using just two channels, as commonly used to calculate generalized polarisation (GP). Coupled to a new plugin called Fraction Mapper, developed to represent the fraction of light intensity in the first component in a stack of two images, we obtain very clear pictures of both the intra-cellular distribution of the probes, and the polarity of the cellular environments where the lipid probes are localised. Our results lead us to conclude that, in live cells kept at 37 degrees C, laurdan, and M laurdan to a lesser extent, have a strong tendency to accumulate in the very apolar environment of intra-cytoplasmic lipid droplets, but label the plasma membrane (PM) of mammalian cells ineffectively. On the other hand, C-laurdan labels the PM very quickly and effectively, and does not detectably accumulate in lipid droplets. Conclusions: From using these probes on a variety of mammalian cell lines, as well as on cells from Drosophila and Dictyostelium discoideum, we conclude that, apart from the lipid droplets, which are very apolar, probes in intracellular membranes reveal a relatively polar and hydrated environment, suggesting a very marked dominance of liquid disordered states. PMs, on the other hand, are much more apolar, suggesting a strong dominance of liquid ordered state, which fits with their high sterol contents. PMID- 28811892 TI - P-wave dispersion in different clinical situations: Expanding list with resembling mechanisms. PMID- 28811893 TI - Knowledge of obstetric danger signs and associated factors among pregnant women attending antenatal care at health facilities of Yirgacheffe town, Gedeo zone, Southern Ethiopia. AB - BACKGROUND: Obstetric danger signs are not the literal obstetric complications, merely symptoms that are well named by non-clinical personnel. The identification of these danger signs and its relation with complications during pregnancy would increase the capacity of women, their partners and families to seek for timely health care, following the appropriate steps to insure a safe birth and post partum. The aim of this study was to assess the knowledge of obstetric danger signs and associated factors among pregnant women attending antenatal care in Yirgacheffe town, Gedeo zone, Southern Ethiopia. METHOD: Institutional-based cross-sectional study was conducted from March 15-April 15, 2016. Data on pregnant women were collected using a pre-tested and interviewer administered structured questionnaire from 342 women using systematic random sampling technique. Bivariate and multivariate logistic regression was performed using SPSS version 20.0 software. RESULT: A total of 342 (90%) pregnant women were included in the study. The level of obstetric knowledge of danger signs was 21.9% (95% CI: 20.2-55.65%). Maternal education (AOR = 0.26, CI: 0.08, 0.88), paternal education (AOR = 0.13, CI; 0.04, 04) and time taken to reach health facilities on foot (AOR = 0.06, CI: 0.02, 0.17) were negatively associated factors while maternal age (AOR = 3.68, CI: 1.30, 10.46), paternal occupation (AOR = 4.65, CI: 1.82, 11.87), place of residence (AOR = 2.61, CI: 1.35, 5.04) were positively associated factors with knowledge of obstetric danger signs. CONCLUSION: Maternal and paternal education, maternal age, paternal occupation, place of residence and time taken to reach health facility on foot were the main factors for knowledge of obstetric danger signs. Increasing knowledge of key danger signs, creating and promoting income generating mechanisms need to be continuously done at the health facility and the community as it makes ready women and their families for prompt and appropriate decisions and measures in case of obstetric danger signs. PMID- 28811894 TI - The conceptual advances of carcinogenic sequence model in high-grade serous ovarian cancer. AB - The present review focuses on the current status of molecular pathology in high grade serous cancer (HGSC) and preneoplastic conditions. This article reviews the English-language literature on HGSC, precursor, fallopian tubal epithelium, secretory cells, ciliated cells, secretory cell expansion, secretory cell outgrowth (SCOUT), p53 signature, serous tubal intraepithelial carcinoma (STIC), DNA damage and immunohistochemistry in an effort to identify the precursor carcinoma sequence in HGSC. The majority of HGSC originates from the fimbriated end of the fallopian tube secretory epithelial cells, while the small part of this disease may develop from ovarian cortical inclusion cyst (CIC). A series of morphological changes from normal fallopian epithelium to preneoplastic to neoplastic lesions were concomitant with the multistep accumulation of molecular and genetic alterations. Recent studies provide a stepwise progression of fallopian tubal epithelium to precursor lesions to carcinoma, with the aid of a 'secretory cell-SCE-SCOUT-p53 signature-STIC-HGSC sequence' model. Immunohistochemical markers, including p53, STMN1, EZH2, CCNE1, Ki67 and gamma H2AX, were gradually increased during the SCOUT-p53 signature-STIC-HGSC sequence. Conversely, PAX2 expression was decreased during the early phase of SCOUT development. Potential genes and proteins are involved in the evolutionary trajectory of the precursor-cancer lineage model. In the present review we examined detailed aspects of the molecular changes involved in malignant transformation from fallopian tube epithelium to HGSC. A precursor condition originating in 'field cancerization' may gain a growth advantage, leading to HGSC. PMID- 28811895 TI - Long-term rearrangement of retinal structures in a novel mutation of X-linked retinoschisis. AB - The aim of the present study was to report a novel mutation in the retinoschisin 1 (RS1) gene in a Caucasian family affected by X-linked juvenile retinoschisis (XLRS) and to describe the long-term modification of retinal structure. Two brothers with an early onset maculopathy were diagnosed with XLRS. Fundus photography, fluorescein angiography, spectral domain optical coherence tomography and electroretinogram analyses were performed. Their sister was also examined. All subjects were screened for mutations in the RS1 gene. XLRS patients demonstrated a marked reduction of best-corrected visual acuity. SD-OCT scans reported a cystic degeneration primarily involving the inner nuclear layer, though some cysts were detected in the outer plexiform layer and in the ganglion cell layer. During the ten-year follow-up, a progressive retinal thickening and coalescence of the cysts was observed. Genetic testing revealed a novel mutation (p.Ile212Asn) in the RS1 gene in both XLRS patients, whereas their sister was not a genetic carrier. Several mutations of the RS1 gene were recognized to be responsible for XLRS. Although the correspondence between genotype and phenotype is still under debate, is reasonable that siblings affected by XLRS could share other genetic and/or epigenetic factors capable to influence clinical course of the disease. PMID- 28811896 TI - Effect of Achillea wilhelmsii extract on expression of the human telomerase reverse transcriptase mRNA in the PC3 prostate cancer cell line. AB - Evidence has indicated that human telomerase reverse transcriptase (hTERT) was overexpressed in prostate cancer (PCa). Achillea wilhelmsii (AW) is a plant that has been traditionally used for its medicinal properties. The aim of current study was to evaluate the effects of AW extract on a PCa cell line. The cytotoxic activity of the hydroalcoholic extract of AW was studied on the PCa PC3 cell line using MTT assay. Flow cytometry was used to evaluate the effects of the extract on the apoptosis. The expression of hTERT mRNA was analyzed by the reverse transcription-quantitative polymerase chain reaction method. The ELISA method was used to measure the levels of telomerase enzyme. The hydroalcoholic AW extract demonstrated the appropriate inhibitory effect in 150 ug/ml concentration (IC50) on PC3 cell line following 48 h treatment. Treatment of the PC3 cells with AW resulted in a significant increase in early and late apoptotic cells and a decrease in live cells (P<0.001), in a dose-dependent manner. Moreover, the early apoptotic cells were significantly higher than late apoptotic cells. The hTERT mRNA expression was decreased following 24 h treatment of AW extract, although it was not different between 2, 4, 8 and 12 h treatments or 24, 48 and 72 h treatments. In addition, the hTERT concentration was significantly decreased following 24 h treatment of AW extract with the marginal P-value. There was no significant difference regarding hTERT concentration between 2, 4, 8 and 12 h treatments or 24, 48 and 72 h treatments. The hydroalcoholic extract of AW induced potent antiproliferative and apoptotic effects in PC3 cell line, which could be explainable by its high potency to inhibit expression of the prominent oncogene hTERT in PCa. Therefore, targeting telomerase represents a promising strategy for PCa therapy, and AW may have considerable potential for development as a novel natural anticancer agent. PMID- 28811897 TI - Impact of in vitro chemosensitivity test-guided platinum-based adjuvant chemotherapy on the surgical outcomes of patients with p-stage IIIA non-small cell lung cancer that underwent complete resection. AB - The impact of in vitro chemosensitivity test-guided platinum-based adjuvant chemotherapy on the surgical outcomes of patients undergoing complete resection for locally advanced non-small cell lung cancer (NSCLC) has yet to be elucidated. In the present study, the utility of adjuvant chemotherapy based on the collagen gel droplet embedded culture drug sensitivity test (CD-DST) in patients with p (pathology)-stage IIIA NSCLC was retrospectively analyzed. A series of 39 patients that had received platinum-based adjuvant chemotherapy following complete resection between 2007 and 2012 were enrolled. Their surgical specimens were subjected to the CD-DST. The patients were subsequently classified into two groups on the basis of in vitro anti-cancer drug sensitivity data obtained using the CD-DST: The sensitive group (25 patients) were treated with regimens including one or two of the anti-cancer drug(s) that were indicated to be effective by the CD-DST, whereas the non-sensitive group (14 patients) were treated with chemotherapy regimens that did not include any CD-DST-selected anti cancer drugs. There were no significant differences in the background characteristics of the two groups [including in respect of the pathological TN (tumor-lymph node) stage, tumor histology, epidermal growth factor receptor mutation status, the frequency of each chemotherapy regimen, and the number of administered cycles]. The 5-year disease-free survival (DFS) rate of the sensitive group was 32.3%, whereas that of the non-sensitive group was 14.3% (P=0.037). In contrast, no difference in overall survival (OS) was observed (P=0.76). Multivariate analysis revealed that adjuvant chemotherapy based on the CD-DST had a significant favorable effect on the DFS (P=0.01). Therefore, the present study has demonstrated that CD-DST data obtained from surgical specimens aid the selection of effective platinum-based adjuvant chemotherapy regimens for patients undergoing complete resection for p-stage IIIA NSCLC. The use of CD-DST guided platinum-based regimens may have a beneficial impact on the DFS of such patients. PMID- 28811898 TI - Lentinula edodes mycelia extract plus adjuvant chemotherapy for breast cancer patients: Results of a randomized study on host quality of life and immune function improvement. AB - Anthracycline-based chemotherapies for breast cancer are known to adversely affect patients' quality of life (QOL) and immune function. For that reason, adjuvants that improve those impairments are required. A randomized double-blind study was conducted to evaluate the effectiveness of Lentinula edodes mycelia extract (LEM), which is an oral biological response modifier (BRM) medicine for cancer patients as such an adjuvant. A total of 47 breast cancer patients who were scheduled to receive postoperative adjuvant anthracycline-based chemotherapy, i.e., 5-fluorouracil (5-FU) + cyclophosphamide + epirubicin (FEC regimen), 5-FU + cyclophosphamide + doxorubicin/pirarubicin (FAC regimen), cyclophosphamide + doxorubicin/pirarubicin (AC regimen) and cyclophosphamide + epirubicin (EC regimen), were entered in the study. The patients were randomly divided into either an LEM or a placebo tablet group; the tablets were orally ingested daily over 2 courses of each therapy. In the placebo group, the total scores for QOL were lower on day 8 of the second course of chemotherapy compared with the baseline scores, whereas in the LEM group the scores had not decreased. In the placebo group, the QOL functional well-being score was lower on day 8 after both the first and second courses of chemotherapy compared with the baseline score, but it had not decreased in the LEM group. Evaluation of immunological parameters indicated that an increase in the proportion of regulatory T cells to peripheral blood CD4+ cells tended to be inhibited in the LEM group compared with the placebo group. Oral LEM that was coadministered with anthracycline-based chemotherapies was useful for maintaining patients' QOL and immune function. Thus, LEM appears to be a useful oral adjuvant for patients receiving anthracycline-based chemotherapy. PMID- 28811899 TI - Angiomyofibroblastoma of the vulva diagnosed preoperatively: A case report. AB - A 50-year-old woman (gravida 2, para 2) first noticed a small nodule in the right labium majus 2 years prior to the initial visit to the Hachinohe Red Cross Hospital (Hachinohe, Japan), which had gradually increased in size. On physical examination, a well-circumscribed, elastic, firm, goose egg-sized, subcutaneous mass protruding from the right labium majus was identified. On magnetic resonance imaging (MRI), the lesion was hypointense on T1-weighted images and was well circumscribed, strongly enhanced and homogeneous on gadolinium-enhanced images, measuring 7.5*4 cm. The same tumor had measured 2.6 cm on an MRI performed 6 years earlier. Based on the clinical course and imaging findings, angiomyofibroblastoma was diagnosed and surgical resection of the tumor was performed. The tumor was well-circumscribed and highly vascular. The intraoperative blood loss was 70 ml. Histopathologically, the tumor cells were concentrated around blood vessels, were spindle-shaped to oval with mild atypia, and were positive for vimentin, desmin, neural cell adhesion molecule (N-CAM), CD 34, estrogen receptor and progesterone receptor, and negative for S-100. Based on these findings, the diagnosis of angiomyofibroblastoma was confirmed. Angiomyofibroblastoma is a benign mesenchymal tumor that occurs in the female external genitalia. Differentiation of this tumor from aggressive angiomyxoma, a fast-growing infiltrative malignancy that occurs in the same region, may be challenging. The diagnosis of angiomyofibroblastoma is usually based on the histopathological findings of the resected specimen. The present case is of value, as the angiomyofibroblastoma was successfully diagnosed preoperatively based on the clinical course and imaging findings. PMID- 28811900 TI - SLPI and AnxA2 expression in neoplasm-free palatine tonsils is associated with smoking habit of individuals. AB - In order to confirm the inverse correlation between secretory leucocyte protease inhibitor (SLPI) expression, and human papillomavirus (HPV) infection previously observed in head and neck squamous-cell carcinoma, the present study retrospectively investigated the association between SLPI and Annexin A2 (AnxA2) expression, and HPV status in non-neoplastic chronic tonsillitis (n=118), and tonsillar hyperplasia (n=96) tissue. We hypothesised that smoking induces the upregulation of SLPI, resulting in reduced binding of HPV to AnxA2, a known modulator of HPV entry into the cell. SLPI and cyclin-dependent kinase inhibitor 2A (p16INK4A) protein expression was measured using immunohistochemistry in 214 specimens; SLPI and AnxA2 gene expression was measured using reverse transcription-quantitative polymerase chain reaction in 213 cases; and DNA was isolated from all the specimens to determine HPV status. The association between the results of the aforementioned analyses and the smoking habits of patients was analysed. The samples were HPV-negative. p16INK4A expression demonstrated moderate and strong staining in 38, and 0 cases, respectively. SLPI expression presented negative, weak and moderate signals in 163, 45, and 6 cases, respectively. A positive correlation was identified between smoking and SLPI (P=0.0001). Gene expression analysis (n=213) revealed that smoking (n=48) resulted in a significant increase in SLPI and AnxA2 expression. A significant positive correlation between AnxA2 and SLPI, indicating a surplus of AnxA2 in relation to SLPI, was exclusively identified in non-smokers. The data demonstrated that smoking results in increased SLPI and AnxA2 expression also in non-neoplastic tonsillar tissue. The observed surplus of AnxA2 in relation to SLPI identified exclusively in the tonsillar tissue of non-smokers indicates a higher possibility of a successful HPV infection of the tonsillar tissue of non smokers, given the properties of AnxA2 to function as an infection modulator. PMID- 28811901 TI - Perioperative safety analysis of transcatheter arterial chemoembolization for hepatocellular carcinoma patients with preprocedural leukopenia or thrombocytopenia. AB - Patients with hepatocellular carcinoma (HCC) exhibit a high incidence of concomitant cirrhosis with leukopenia and/or thrombocytopenia. In the present study, perioperative changes in the white blood cell (WBC) and platelet (PLT) counts and associated complications were investigated to assess the safety of transcatheter arterial chemoembolization (TACE) for HCC patients with preprocedural leukopenia or thrombocytopenia. The records of 1,461 HCC patients who received TACE between January 2012 and December 2013 were retrospectively reviewed. The incidence of complications during the perioperative period and changes in the WBC and PLT counts were recorded. A Chi-squared test was used to evaluate the associations between postoperative infection and preprocedural WBC count and between bleeding at the puncture site and preprocedural PLT count. The WBC count of the majority of the patients increased within 3 days and returned to the preprocedural level within 30 days after TACE. The PLT count decreased within 3 days and returned to the preprocedural level within 30 days after TACE. The major complications were liver decompensation (n=66), puncture site bleeding (n=45), infection (n=33), severe thrombocytopenia (n=8), upper gastrointestinal bleeding (n=6), tumor bleeding (n=4) and agranulocytosis (n=3). A Chi-squared test revealed that postoperative infection was not associated with preprocedural WBC count and puncture site bleeding was not associated with decreased PLT count due to hypersplenism. Therefore, TACE was found to be safe for HCC patients with preprocedural thrombocytopenia or leukopenia due to hypersplenism, with a low incidence of major complications during the perioperative period. PMID- 28811902 TI - A case-control study of the association between psychosocial factors and the occurrence of laryngeal cancer. AB - The aim of the present study was to investigate the association between social psychological factors and the occurrence of laryngeal cancer. A 1:1 matched case control study was conducted. The participants completed questionnaires that included general information, such as the Life Event Scale, the Social Support Rating Scale, and the Eysenck Personality Questionnaire (EPQ). Scores were compared between the groups using paired t-tests and Wilcoxon's signed-rank tests. No significant difference in the psychoticism scale of the EPQ was observed between the two groups (P>0.05). However, significant differences were observed in scores on the life events and social support scales and in the remaining dimensions of the EPQ (all P-values <0.05). Positive life events may be protective factors for laryngeal cancer, whereas reduced utilization of social support may be a risk factor for laryngeal cancer. PMID- 28811904 TI - Concurrence of nivolumab-induced interstitial lung disease and cancer invasion. AB - Nivolumab improves overall survival rates of patients with advanced or recurrent non-small-cell lung cancer (NSCLC). Among immune-related adverse events caused by nivolumab, interstitial lung disease (ILD) is a clinically serious and potentially life-threatening toxicity, for which appropriate treatment is needed immediately. However, ILD is sometimes difficult to distinguish from invasive lung adenocarcinoma using only computed tomography (CT) findings. A 71-year-old man was diagnosed with advanced lung adenocarcinoma. The patient developed dyspnoea after eight cycles of nivolumab, when chest CT indicated ILD classified with a cryptogenic organizing pneumonia (COP) pattern. Although immunosuppressive therapies improved the CT findings temporarily, dyspnoea was re-exacerbated 2 months later. The CT findings helped in making the diagnosis of a combination of ILD and invasive lung cancer, confirmed by a transbronchial lung biopsy. In conclusion, nivolumab-related ILD and cancer invasion may concur and aggressive biopsy should be considered if nivolumab-related ILD is refractory to immunosuppressive therapy. PMID- 28811903 TI - Value of neutrophil-to-lymphocyte ratio for predicting lung cancer prognosis: A meta-analysis of 7,219 patients. AB - Current evidence suggests that the neutrophil-to-lymphocyte ratio (NLR) may be a biomarker for poor prognosis in lung cancer, although this association remains controversial. Therefore, a meta-analysis was performed to evaluate the association between NLR and lung cancer outcome. A systematic literature search was performed through the PubMed, Embase and Cochrane Library databases (until July 30, 2016), to identify studies evaluating the association between NLR and overall survival (OS) and/or progression-free survival (PFS) among patients with lung cancer. Based on the results of this search, data from 18 studies involving 7,219 patients with lung cancer were evaluated. The pooled hazard ratio (HR) suggested that elevated pretreatment NLR predicted poor OS [HR=1.46, 95% confidence interval (CI): 1.30-1.64] and poor PFS (HR=1.42, 95% CI: 1.15-1.75) among patients with lung cancer. Subgroup analysis revealed that the prognostic value of NLR for predicting poor OS increased among patients who underwent surgery (HR=1.50, 95% CI: 1.21-1.84) or patients with early-stage disease (HR=1.64, 95% CI: 1.37-1.97). An NLR cut-off value of >=4 significantly predicted poor OS (HR=1.56, 95% CI: 1.31-1.85) and PFS (HR=1.54, 95% CI: 1.13-1.82), particularly in the cases of small-cell lung cancer. Thus, the results of the present meta-analysis suggested that an elevated pretreatment NLR (e.g., >=4) may be considered as a biomarker for poor prognosis in patients with lung cancer. PMID- 28811905 TI - Surgical sympathectomy for Buerger's disease. AB - Buerger's disease is characterized by recurring progressive inflammation and occlusions in small and medium arteries and veins of the limbs. Its cause is unknown, but it is most common in young men with a history of tobacco use. It is responsible for ischemic ulcers and extreme pain in the hands and feet. In many cases, notably in patients with the most severe presentations, there is no possibility of improving the condition with surgery (limb revascularisation), and therefore, alternative therapies (e.g. sympathectomy) is used. This review assessed the effectiveness of surgical sympathectomy compared with any other therapy in patients with Buerger's disease. As a result, only one randomised controlled study (162 participants) compared sympathectomy with prostacyclin analogue (iloprost) was incorporated to the review. Such comparison shown that iloprost is more effective than sympathectomy to complete healing ulcers at four weeks (risk ratio 0.65; 95% confidence interval 0.45 to 0.95; P = 0.02; very low quality evidence) and at twenty four weeks (risk ratio 0.62; 95% confidence interval 0.48 to 0.82; P < 0.01; very low quality evidence) after the start of treatment and to relief rest pain at four weeks (risk ratio 1.90; 95% confidence interval 1.17 to 3.10; P = 0.01; very low quality evidence) but not more effective at twenty four weeks (risk ratio 1.68; 95% confidence interval 1.00 to 2.84; P = .10; very low quality evidence) after the start of treatment. We concluded, with very low quality of evidence, that intravenous iloprost is more effective than lumbar sympathectomyin the healing of ischemic ulcers and pain at rest in patients with Buerger's disease. Therefore, until now, the preference of the usage of intravenous iloprost over the lumbar sympathectomy (and vice versa) does not find robust evidence for its routine use. PMID- 28811906 TI - Induced vomiting for attention seeking and secondary gain: An unusual cause of pseudo-resistant hypertension. AB - In patients with complex psychosocial history presenting with resistant hypertension, observed therapy should be implemented early on to avoid unnecessary investigations and delayed diagnosis. PMID- 28811907 TI - Factors associated with antibiotic prescriptions for the viral origin diseases in office-based practices, 2006-2012. AB - OBJECTIVE: To test the potential association between time spent with a doctor and antibiotic overprescriptions in case of the common cold, runny nose, bronchitis, chest colds, flu, sore throats, and fluid in the middle ear. DESIGN: Cross sectional study. SETTING: Office-based physicians in the US. PARTICIPANTS: A total of 261,623 patient visits recorded to office-based physicians in the US. MAIN OUTCOME MEASURES: The interest outcome was unnecessary antibiotic prescription. RESULTS: The analysis revealed five significant predictors of antibiotic prescriptions for suspected viral infections: length of doctor-patient encounter time, patient gender, spending time with a family medicine doctor, type of insurance, and the rate of antibiotic prescriptions per physician. For every additional minute a patient spent with a physician during a visit, the mean predicted probability of receiving unnecessary antibiotics decreased by 2.4%. CONCLUSIONS: This study provided evidence that physicians continue to prescribe antibiotics in avoidable cases. Policies that would monitor antibiotic prescription in office-based settings should be considered in order to control spreading of antibiotic resistance and eventually improve population health. PMID- 28811908 TI - Bilateral arthrodesis of the distal tibiofibular joint for deforming osteochondromatas. AB - The first case of bilateral distal tibiofibular joint fusions for osteochondromas is reported with excellent long-term outcomes. PMID- 28811910 TI - Falls in Scottish homicide: lessons for homicide reduction in mental health patients. AB - The sustained fall in Scottish homicide rates follows crime reduction measures informed by the epidemiology of suicide. The violence reduction unit targeted young men carrying knives in public. The restriction of weapons immediately to hand appears to have caused an absolute fall in homicide just as suicide reduction was observed following changes to domestic gas supply. Further homicide reduction may be accomplished in the domestic setting with targeted changes in kitchen knife design in home safety planning for high-risk households. Most commonly homicides involving those in recent contact with mental health services in the UK have domestic characteristics and similar safety planning may be targeted at those with mental disorder and a history of violence. PMID- 28811911 TI - Evaluation of the 13-item Hypomania Checklist and a brief 3-item manic features questionnaire in primary care. AB - Aims and method The mean delay for bipolar disorder diagnosis is 10 years. Identification of patients with previous hypomania is challenging, sometimes resulting in misdiagnosis. The aims of this study were: (a) to estimate the proportion of primary care patients with depression currently taking antidepressants who have undiagnosed bipolar disorder and (b) to compare a brief 3-item manic features questionnaire with the Hypomania Checklist (HCL-13). The sample comprised patients with a recorded diagnosis of depression, either on long term antidepressant therapy or with previous multiple courses of antidepressants. Results Of 149 participants assessed, 24 (16.1%) satisfied criteria for bipolar disorder. Areas under the curve (AUC) for the 3-item questionnaire and the HCL-13 were similar (0.79 and 0.72, respectively) but positive predictive values (PPV) were low. Clinical implications Bipolar disorder may be underdiagnosed in primary care. A 3-item questionnaire could be used by general practitioners to screen for bipolar disorder in their patients with depression. PMID- 28811909 TI - A fourth subtype of retinoic acid receptor-related orphan receptors is activated by oxidized all-trans retinoic acid in medaka (Oryzias latipes). AB - BACKGROUND: The three known subtypes of the retinoic acid receptor-related orphan receptor (ROR) have been implicated in the control of immunity, brain function, and circadian rhythm in mammals. Here, we demonstrate by phylogenetic analysis that there were originally four subtypes of RORs in vertebrates. One of the novel ror paralogs, rord1 (rorca in the Ensembl database), is conserved among teleosts, but absent in mammals. Using medaka (Oryzias latipes) as a model teleost, we evaluated the expression pattern of this gene, its transactivational properties for endogenic chemicals, and its ability to activate the promoters of putative target genes. RESULTS: In eyes, the transcript of rord1 was expressed at higher levels during the day than at night. Interestingly, cholesterol derivatives, which are well-known ligands for mammalian RORs, did not efficiently promote transcriptional activity via RORd1. Thus we sought to identify the ligands that regulate the transcriptional activity of RORd1 using a luciferase reporter cell based screening system. Using this system, we identified two metabolites of all trans retinoic acid (ATRA), 4OH-ATRA and 4-keto ATRA, as potential ligands of RORd1. Moreover, RORd1 activated the promoter of cyp26a1 in a 4OH-ATRA -dependent manner. CONCLUSIONS: A novel ror subtype, rord has two paralogs, rord1 and rord2, in teleost. Rord1 mRNA is highly abundant in the eyes of medaka during light periods, suggesting that rord1 expression is involved in the regulation of circadian rhythm. We identified two ATRA metabolites, 4OH-ATRA and 4 K-ATRA, as endogenous candidate ligands of RORd1. We also show that 4-oxygenated ATRA metabolites have the potential to activate cyp26a1, the metabolic enzyme of ATRA. Our results support the notion that RORd1 is involved in the metabolism of ATRA in medaka. PMID- 28811912 TI - Flexible assertive community treatment (FACT) model in specialist psychosis teams: an evaluation. AB - Aims and method The impact of flexible assertive community treatment (FACT) has been observed in people previously supported by assertive community treatment (ACT) teams, but its effect on those previously with a community mental health team (CMHT) has not been studied in the UK. An observational study was conducted of 380 people from 3 CMHTs and 95 people from an ACT team, all with a history of psychosis, following service reconfiguration to 3 FACT teams. Results People previously with a CMHT required less time in hospital when the FACT model was introduced. A smaller reduction was observed in people coming from the ACT team. Both groups required less crisis resolution home treatment (CRHT) team input. Clinical implications FACT may be a better model than standard CMHT care for people with a history of psychosis, as a result of reduced need for acute (CRHT and in-patient) services. PMID- 28811914 TI - The impact of transforming care on the care and safety of patients with intellectual disabilities and forensic needs. AB - NHS England recently published a national plan to develop community services for people with intellectual disabilities and autism who display challenging behaviour by using resources from the closure of a large number of hospital beds. An ambitious timescale has been set to implement this plan. The bed closure programme is moving ahead rapidly, but there has been little progress in developing community services to support it. This paper discusses the impact of the gap between policy and practice on the care and safety of patients with intellectual disabilities and forensic needs who form a distinct subgroup of the target population and are being disproportionately affected by this government policy. PMID- 28811913 TI - Burnout and psychiatric morbidity among doctors in the UK: a systematic literature review of prevalence and associated factors. AB - Aims and method To systematically review the prevalence and associated factors of burnout and stress-related psychiatric disorders among UK doctors. An extensive search was conducted of PubMed, EBSCOhost and British medical journals for studies published over a 20-year span measuring the prevalence of psychiatric morbidity (using the General Health Questionnaire) and burnout (using the Maslach Burnout Inventory). Results Prevalence of psychiatric morbidity ranged from 17 to 52%. Burnout scores for emotional exhaustion ranged from 31 to 54.3%, depersonalisation 17.4 to 44.5% and low personal accomplishment 6 to 39.6%. General practitioners and consultants had the highest scores. Factors significantly associated with increase in the prevalence of burnout and psychiatric morbidity include low job satisfaction, overload, increased hours worked and neuroticism. Clinical implications The results indicate a worryingly high rate of burnout and psychiatric morbidity among UK doctors, which could have a huge negative impact on healthcare provision in general. Factors at personal and organisational levels contribute to burnout and psychiatric morbidity, and so efforts made to counter these problems should target both levels. PMID- 28811915 TI - Prevent: what is pre-criminal space? AB - Prevent is a UK-wide programme within the government's anti-terrorism strategy aimed at stopping individuals from supporting or taking part in terrorist activities. NHS England's Prevent Training and Competencies Framework requires health professionals to understand the concept of pre-criminal space. This article examines pre-criminal space, a new term which refers to a period of time during which a person is referred to a specific Prevent-related safeguarding panel, Channel. It is unclear what the concept of pre-criminal space adds to the Prevent programme. The term should be either clarified or removed from the Framework. PMID- 28811916 TI - Drug information update. Atypical antipsychotics and neuroleptic malignant syndrome: nuances and pragmatics of the association. AB - Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal adverse event associated with the use of antipsychotics. Although atypical antipsychotics were initially considered to carry no risk of NMS, reports have accumulated over time implicating them in NMS causation. Almost all atypical antipsychotics have been reported to be associated with NMS. The clinical profile of NMS caused by certain atypical antipsychotics such as clozapine has been reported to be considerably different from the NMS produced by typical antipsychotics, with diaphoresis encountered more commonly, and rigidity and tremor encountered less frequently. This article briefly discusses the evidence relating to the occurrence, presentation and management of NMS induced by atypical antipsychotics. PMID- 28811917 TI - Drug information update. Lithium and chronic kidney disease: debates and dilemmas. AB - Lithium is an established treatment for bipolar disorder and an augmenting agent for treatment-resistant depression. Despite awareness of renal adverse effects, including chronic kidney disease, for the past five decades, there has been a lack of research evidence. This has led to debates around the existence and magnitude of the risk. This article discusses the current evidence base regarding the link between lithium and chronic kidney disease, monitoring of renal functions and its clinical implications. PMID- 28811918 TI - Shared decision-making in medication management: development of a training intervention. AB - Shared decision-making is a collaborative process in which clinicians and patients make treatment decisions together. Although it is considered essential to patient-centred care, the adoption of shared decision-making into routine clinical practice has been slow, and there is a need to increase implementation. This paper describes the development and delivery of a training intervention to promote shared decision-making in medication management in mental health as part of the Shared Involvement in Medication Management Education (ShIMME) project. Three stakeholder groups (service users, care coordinators and psychiatrists) received training in shared decision-making, and their feedback was evaluated. The programme was mostly well received, with all groups rating interaction with peers as the best aspect of the training. This small-scale pilot shows that it is feasible to deliver training in shared decision-making to several key stakeholders. Larger studies will be required to assess the effectiveness of such training. PMID- 28811919 TI - Trainee experiences of intellectual disability psychiatry and an innovative leaderless support group: a qualitative study. AB - Aims and method There is very little research into the challenges of training in intellectual disability psychiatry or into interventions which may address these challenges. Using focus groups, we explored the experiences of intellectual disability psychiatry trainees, and evaluated a leaderless trainee support group developed in Bristol. Results Five distinct themes were identified via framework analysis: that trainees felt unprepared for the difference from previous posts; the need for support; the value of the group; that trainees were concerned about judgement in supervision; that the group structure was valued. Clinical implications Our findings highlight the support needs specific to intellectual disability psychiatry trainees. Leaderless peer support groups may be a valued resource to address such issues, and may be a useful model to be considered by other training schemes. PMID- 28811920 TI - Scottish independence: the view of psychiatry from Edinburgh. PMID- 28811921 TI - Patient admission and caregiver stress. PMID- 28811923 TI - To educate or to entertain? PMID- 28811922 TI - Being sensible about suicides. PMID- 28811924 TI - Seeing, spots and blots. PMID- 28811925 TI - Vitamin D deficiency is to be expected due to immune changes related to mental health problems. PMID- 28811926 TI - Postinjection delirium/sedation syndrome in patients with schizophrenia receiving olanzapine long-acting injection: results from a large observational study. AB - BACKGROUND: Postinjection delirium/sedation syndrome (PDSS) has been reported uncommonly during treatment with olanzapine long-acting injection (LAI), a sustained-release formulation of olanzapine. AIMS: The primary aim of the study was to estimate the incidence per injection and per patient of PDSS events in adult patients with schizophrenia who were receiving olanzapine LAI in real-world clinical practice. Secondary aims were to further characterise the clinical presentation of PDSS events, to identify potential risk factors associated with PDSS events and to characterise hospitalisations at baseline and post-baseline. METHOD: A prospective observational study of adult patients with schizophrenia receiving olanzapine LAI from 24 countries. Data were collected on patient characteristics, olanzapine LAI treatment and any adverse events (AEs). All AEs were reviewed and adjudicated for PDSS using predetermined criteria. RESULTS: There were 46 confirmed PDSS events (0.044% of the 103 505 injections) in 45 patients (1.17% of the 3858 patients). Based on 45 confirmed events with time-to onset information, 91.1% (n=41) occurred within 1 h of injection. Time-to recovery from the event was within 72 h for 95.6% of patients (range 6 h to 11 days). Risk factors for PDSS (per-injection) included high dose (odds ratio (OR)high/low=3.95; P=0.006) and male gender (ORfemale/male=0.42; P=0.017). CONCLUSIONS: Results of this study confirm previously reported PDSS rates, time to onset and recovery, and the severity of PDSS events, and suggest that higher doses and male gender are potential risk factors associated with PDSS. DECLARATION OF INTEREST: All authors are full-time employees and hold stock/stock options in Eli Lilly, which funded this study. This post-authorisation safety study (PASS) was proposed by Eli Lilly when submitting the original marketing authorisation application for olanzapine LAI in 2007. The protocol and final study report for this European Union regulatory commitment are publicly accessible via the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) European Union PASS Register (www.encepp.eu/encepp/viewResource.htm?id=16847). The current manuscript describes the results within the final study report. COPYRIGHT AND USAGE: (c) The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC ND) license. PMID- 28811927 TI - Premature deaths among individuals with severe mental illness after discharge from long-term hospitalisation in Japan: a naturalistic observation during a 24 year period. AB - BACKGROUND: Premature death in individuals with severe mental illness (SMI) in countries without nationally collected data, including Japan, is structurally underreported. AIMS: To elucidate excess mortality among individuals with SMI in Japan. METHOD: We retrospectively investigated all deaths among users of a non clinical community-based mental health service provider in suburban Tokyo from 1992 to 2015. RESULTS: During the study period, 45 individuals died among 254 qualified registrants. Deaths were by natural causes in 33 cases (73.3%). The mean years of life lost was 22.2 years and the overall standard mortality ratio (SMR) was 3.28 (95% CI 2.40-4.39). The cause-specific SMR was 5.09 (95% CI 2.33 9.66) for cardiovascular disease and 7.38 (95% CI 2.40-17.22) for suicide. CONCLUSIONS: Although Japan leads the world in longevity, individuals with SMI suffer premature death and excess mortality due to physical conditions as well as suicide. Revealing this underreported disparity of life is the first step to improving physical care for individuals with SMI. DECLARATION OF INTEREST: S.K. received personal fees from Pfizer and Dainippon-Sumitomo, outside the submitted work, and was a medical adviser to Sudachi-kai. Y.K. received grants from Japan Foundation for Neuroscience and Mental Health (JFNMH), during the conduct of the study, and personal fees from Dainippon-Sumitomo, outside the submitted work. K.K. received grants from Japan Society for the Promotion of Science (JSPS) and Japan Agency for Medical Research and Development (AMED), during the conduct of the study; personal fees from Daiichi-Sankyo, Otsuka, Meiji-Seika Pharma, Yoshitomi, Mochida and Fuji-Film RI Pharma; grants and personal fees from MSD, Astellas, Dainippon-Sumitomo and Eisai; and grants from Lily, Takeda and Tanabe Mitsubishi, outside the submitted work. COPYRIGHT AND USAGE: (c) The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license. PMID- 28811928 TI - Hepatocellular carcinoma with disseminated skeletal muscle metastasis. AB - Hepatocellular carcinoma (HCC) is the commonest primary tumor of the liver and carries a poor prognosis when diagnosed late or left untreated. Treatment relies heavily on the stage of the tumor when diagnosed. Extrahepatic metastasis is known to occur; these are mainly reported via autopsy studies or isolated case reports. Knowledge of extrahepatic metastasis is crucial in order to avoid unnecessary surgery. We report a rare case of a patient at our center, diagnosed to have HCC, who underwent treatment successfully, only to come back with extrahepatic metastasis to the skeletal muscles. PMID- 28811929 TI - Dual-energy computed tomography angiography: virtual calcified plaque subtraction in a vascular phantom. AB - BACKGROUND: Material decomposition of dual-energy computed tomography (DECT) enables subtraction of calcified plaque. PURPOSE: To evaluate the accuracy of lumen area measurement in calcified plaque by subtraction of DECT and to determine the effect of contrast material concentration, lumen diameter, density, and thickness of calcified plaque for the measurement. MATERIAL AND METHODS: Vessel phantoms were made with six lumen diameters (5.7, 4.9, 3.9, 3.0, 1.9, and 1.3 mm) and six types of calcified plaques with three densities and two thicknesses were attached. CT scans were performed with three contrast material concentrations (62, 111, and 170 mg iodine/mL). Lumen area discrepancy (AD) was calculated by subtracting the measured lumen area from a reference value. The lumen area underestimation percentage (AU), defined as (AD/reference value) * 100, was calculated. General linear model analysis was used to test the effect of variables for log-transformed AU (ln_AU). RESULTS: The AD and AU was calculated to be 6.1 +/- 4.8 mm2 and 69.8 +/- 29.4%, respectively. Ln_AU was significantly affected by contrast material concentration (P < 0.001), calcium density (P = 0.001), plaque thickness (P = 0.010), and lumen diameter (P < 0.001). Ln_AU was significantly higher in 62 mg iodine/mL than in 111 or 170 mg iodine/mL (P < 0.001 for both). Ln_AU was significantly lower at a lumen diameter of 5.7 mm than 3.9 mm (P = 0.001) or 3.0 (P < 0.001). CONCLUSION: Calcified plaque subtraction in DECT substantially underestimates measurements of lumen area. Higher enhancement in larger vessels ensures more accurate subtraction of calcified plaque. PMID- 28811930 TI - Improved CT-detection of acute bowel ischemia using frequency selective non linear image blending. AB - BACKGROUND: Computed tomography (CT) as a fast and reliable diagnostic technique is the imaging modality of choice for acute bowel ischemia. However, diagnostic is often difficult mainly due to low attenuation differences between ischemic and perfused segments. PURPOSE: To compare the diagnostic efficacy of a new post processing tool based on frequency selective non-linear blending with that of conventional linear contrast-enhanced CT (CECT) image blending for the detection of bowel ischemia. MATERIAL AND METHODS: Twenty-seven consecutive patients (19 women; mean age = 73.7 years, age range = 50-94 years) with acute bowel ischemia were scanned using multidetector CT (120 kV; 100-200 mAs). Pre-contrast and portal venous scans (65-70 s delay) were acquired. All patients underwent surgery for acute bowel ischemia and intraoperative diagnosis as well as histologic evaluation of explanted bowel segments was considered "gold standard." First, two radiologists read the conventional CECT images in which linear blending was adapted for optimal contrast, and second (three weeks later) the frequency selective non-linear blending (F-NLB) image. Attenuation values were compared, both in the involved and non-involved bowel segments creating ratios between unenhanced and CECT. RESULTS: The mean attenuation difference between ischemic and non-ischemic wall in the portal venous scan was 69.54 HU (reader 2 = 69.01 HU) higher for F-NLB compared with conventional CECT. Also, the attenuation ratio between contrast-enhanced and pre-contrast CT data for the non-ischemic walls showed significantly higher values for the F-NLB image (CECT: reader 1 = 2.11 (reader 2 = 3.36), F-NLB: reader 1 = 4.46 (reader 2 = 4.98)]. Sensitivity in detecting ischemic areas increased significantly for both readers using F-NLB (CECT: reader 1/2 = 53%/65% versus F-NLB: reader 1/2 = 62%/75%). CONCLUSION: Frequency selective non-linear blending improves detection of bowel ischemia compared with conventional CECT by increasing attenuation differences between ischemic and perfused segments. PMID- 28811931 TI - Non-traumatic rupture of the superior thyroid artery with concomitant parathyroid adenoma and multinodular goiter. AB - Cervical hemorrhage due to non-traumatic, spontaneous rupture of the thyroid artery is rare, which usually results from arterial abnormalities or parathyroid or thyroid disorders. This report describes a 72-year-old woman who presented with a sore throat and slight neck swelling. Computed tomography (CT) revealed a large hematoma in the neck and mediastinum, due to extravasation from the major branch of the left superior thyroid artery. A follow-up CT the next day demonstrated that the extravasation had resolved. Subsequent surgery revealed both parathyroid adenoma and multinodular goiter in the resected thyroid gland. A transient elevation of parathyroid hormone occurred immediately after the hemorrhage, suggesting that the hemorrhage may have been related to the parathyroid adenoma. However, ruptured thyroid arteries were not observed on histopathological examination of the resected tissue. PMID- 28811932 TI - Two novel direct SPIO labels and in vivo MRI detection of labeled cells after acute myocardial infarct. AB - BACKGROUND: Acute myocardial infarction (AMI) is a leading cause of morbidity and mortality worldwide. Cellular decay due hypoxia requires rapid and validated methods for possible therapeutic cell transplantation. PURPOSE: To develop direct and rapid superparamagnetic iron oxide (SPIO) cell label for a large-animal model and to assess in vivo cell targeting by magnetic resonance imaging (MRI) in an experimental AMI model. MATERIAL AND METHODS: Bone marrow mononuclear cells (BMMNCs) were labeled with SPIO particles using two novel direct labeling methods (rotating incubation method and electroporation). Labeling, iron incorporation in cells and label distribution, cellular viability, and proliferation were validated in vitro. An AMI porcine model was used to evaluate the direct labeling method (rotating incubation method) by examining targeting of labeled BMMNCs using MRI and histology. RESULTS: Labeling (1 h) did not alter either cellular differentiation potential or viability of cells in vitro. Cellular relaxation values at 9.4 T correlated with label concentration and MRI at 1.5 T showing 89 +/- 4% signal reduction compared with non-labeled cells in vitro. In vivo, a high spatial correlation between MRI and histology was observed. The extent of macroscopic pathological myocardial changes (hemorrhage) correlated with altered function detected on MRI. CONCLUSION: We demonstrated two novel direct SPIO labeling methods and demonstrated the feasibility of clinical MRI for monitoring targeting of the labeled cells in animal models of AMI. PMID- 28811934 TI - The Estimates of Retinal Ganglion Cell Counts Performed Better than Isolated Structure and Functional Tests for Glaucoma Diagnosis. AB - PURPOSE: To evaluate the diagnostic accuracy of retinal ganglion cell (RGC) counts as estimated by combining data from standard automated perimetry (SAP) and spectral domain optical coherence tomography (SD-OCT). METHODS: Healthy individuals and glaucoma patients were included in this cross-sectional study. All eyes underwent 24-2 SITA SAP and structural imaging tests. RGC count estimates were obtained using a previously described algorithm, which combines estimates of RGC numbers from SAP sensitivity thresholds and SD-OCT retinal nerve fiber layer (RNFL) average thickness. RESULTS: A total of 119 eyes were evaluated, including 75 eyes of 48 healthy individuals and 44 eyes of 29 glaucoma patients. RGC count estimates performed better than data derived from SD-OCT RNFL average thickness or SAP mean deviation alone (area under ROC curves: 0.98, 0.92, and 0.79; P < 0.001) for discriminating healthy from glaucomatous eyes, even in a subgroup of eyes with mild disease (0.97, 0.88, and 0.75; P < 0.001). There was a strong and significant correlation between estimates of RGC numbers derived from SAP and SD-OCT (R2 = 0.74; P < 0.001). CONCLUSION: RGC count estimates obtained by combined structural and functional data showed excellent diagnostic accuracy for discriminating the healthy from the glaucomatous eyes and performed better than isolated structural and functional parameters. PMID- 28811933 TI - Nuclear matrix metalloproteinases: functions resemble the evolution from the intracellular to the extracellular compartment. AB - Matrix metalloproteinase (MMP) is defined as an endopeptidase in the extracellular matrix (ECM), which plays essential roles in physiological processes such as organogenesis, wound healing, angiogenesis, apoptosis and motility. MMPs are produced and assembled in the cytoplasm as proenzymes with a cytoplasmic domain and require extracellular activation. MMPs can degrade receptors, extracellular matrix proteins, PARPs and release apoptotic substances. MMPs have been found in the cytosol, organelles and extracellular compartments and recently many types of MMPs have been found in the nucleus. However, the mechanisms and roles of MMPs inside the cell nucleus are still poorly understood. Here we summarized the nuclear localization mechanisms of MMPs and their functions in the nucleus such as apoptosis, tissue remodeling upon injury and cancer progression. Most importantly, we found that nuclear MMPs have evolved to translocate to membrane and target ECM possibly through evolution of nuclear localization signal (NLS), natural selection and anti-apoptotic survival. Thus, the knowledge about the evolution and regulation of nuclear MMPs appears to be essential in understanding a variety of cellular processes along with the development of MMP-targeted therapeutic drugs against the progression of certain diseases. PMID- 28811935 TI - Pars Plana Vitrectomy with Internal Limiting Membrane Peeling in Traumatic Macular Hole: 14% Perfluoropropane (C3F8) versus Silicone Oil Tamponade. AB - PURPOSE: To evaluate the outcome of 23 G PPV and ILM peeling with 14% C3F8 compared with silicone oil tamponade in cases of TMHs without spontaneous closure. METHODS: A retrospective comparative study included 33 eyes with TMHs; 7 eyes healed spontaneously, and the remaining 26 eyes have been treated with PPV and ILM peeling. Silicone oil was used as a tamponade for children or adults who refused to adopt face-down position (10 cases). In all other cases (16 cases), 14% C3F8 was used. These cases were followed up for 6 months postoperatively. RESULTS: 26 cases (22 males and 4 females) were reviewed, including 10 cases treated with silicone oil and 16 cases treated with 14% C3F8. Patients' age ranged from 9 to 54 years. The success rate was 90% in the silicone-filled (9/10) and 94% in the gas-filled (15/16) eyes. At 6 months, the mean BCVA was 0.3 +/- 0.25 in the silicone group and 0.2 +/- 0.13 in the gas group (p < 0.05). CONCLUSIONS: Cases of TMHs should be observed for spontaneous closure. PPV with ILM peeling should be conducted for nonclosing cases. Gas and silicone oil tamponades are equally successful in anatomical and visual outcomes. This trial is registered with CTRI/2017/06/008765. PMID- 28811936 TI - Real-Life Management of Patients with Retinal Vein Occlusion Using I-Macula Web Platform. AB - AIM: Real-life evaluation in the management of patients affected by macular edema secondary to retinal vein occlusion. MATERIAL AND METHODS: A retrospective, observational study using the I-Macula Web platform. RESULTS: Thirty-five patients (37 eyes; 15 females and 20 male) affected by RVO were analysed. At 12 months, there was a statistically significant improvement of best-corrected visual acuity (p = 0.0235) and central macular thickness (p < 0.0001). The mean change in visual acuity was 8.9 letters. Twenty-seven eyes underwent DEX implant (n = 62; mean: 2.29) only. Of these, 8, 4, 14, and 1 eyes underwent 1, 2, 3, and 4 DEX implants, respectively. The remaining 10 eyes were also injected with ranibizumab (n = 49; mean: 4.9). At 12 months, 12 eyes (32.5%) presented a dry macula, whereas the remaining 25 eyes (67.5%) still had macular edema. Mean interval between the first and second treatment (T1) and between the second and third treatment (T2) were 5.15 and (T2) 3.7 months, respectively. Where only DEX implants were received, T1 and T2 was 5.1 and 4.9 months, respectively. CONCLUSIONS: This study confirms that DEX implants and/or anti-VEGF drugs improve visual acuity and central macular thickness in patients affected by RVO. PMID- 28811937 TI - Association between Salivary Leptin Levels and Taste Perception in Children. AB - The satiety inducing hormone leptin acts not only at central nervous system but also at peripheral level. Leptin receptors are found in several sense related organs, including the mouth. A role of leptin in sweet taste response has been suggested but, until now, studies have been based on in vitro experiments, or in assessing the levels of the hormone in circulation. The present study investigated whether the levels of leptin in saliva are related to taste perception in children and whether Body Mass Index (BMI) affects such relationship. Sweet and bitter taste sensitivity was assessed for 121 children aged 9-10 years and unstimulated whole saliva was collected for leptin quantification, using ELISA technique. Children females with lower sweet taste sensitivity presented higher salivary leptin levels, but this is only in the normal weight ones. For bitter taste, association between salivary leptin and caffeine threshold detection was observed only in preobese boys, with higher levels of salivary hormone in low sensitive individuals. This study is the first presenting evidences of a relationship between salivary leptin levels and taste perception, which is sex and BMI dependent. The mode of action of salivary leptin at taste receptor level should be elucidated in future studies. PMID- 28811938 TI - Neuropsychological Characteristics of Children with Mixed Autism and ADHD. AB - Clinical heterogeneity is a well-established characteristic of autism spectrum disorder (ASD). While the comorbidity of ASD and ADHD is well known in clinical practice, relatively little research has examined the neuropsychological profile of children with ASD + ADHD. Our study showed significant differences in the neuropsychological characteristics of children with ASD + ADHD compared to those with ASD only. Children with ASD + ADHD showed higher symptoms of anxiety, worse working memory, and less empathy, as measured by the "Reading the Mind in the Eyes." This suggests that having ADHD brings further challenges to individuals with ASD and may negatively impact their management and outcome. Our findings may have implications for clinical assessment as well as for intervention. PMID- 28811939 TI - ABO Gene Polymorphism and Thrombomodulin -33G>A Polymorphism Were Not Risk Factors for Myocardial Infarction in Javanese Men. AB - Genetic factors contribute to about a half of coronary artery diseases. During the last several decades, some studies suggested that non-O blood group and thrombomodulin polymorphism -33G>A are the risk factors of coronary artery disease especially in Asia. There was no prior study in Indonesia regarding this issue. Hence, this study was designed to investigate the correlation of ABO polymorphism and thrombomodulin polymorphism -33G>A with the incidence of acute myocardial infarction (AMI). A total of 192 subjects were enrolled in this case control study. AMI patients were diagnosed based on World Health Organization criteria. Healthy patients were subjects with AMI risk factor without any sign and symptoms of AMI. Patients with diabetes mellitus, cancer, and arrhythmia were excluded from this study. Genotyping for both polymorphisms was performed by PCR RFLP methods. The result of this study suggested that ABO polymorphism and thrombomodulin polymorphism -33G>A were not risk factors of AMI, p = 0.727 and p = 0.699, respectively. Furthermore, the analysis to identify the synergy of these polymorphisms failed to prove their correlation with AMI (p = 0.118). Conclusively, this study showed that ABO polymorphism and thrombomodulin polymorphism -33G>A were not risk factors of AMI. PMID- 28811940 TI - Recurrent Wheezing and Cough Caused by Double Aortic Arch, Not Asthma. AB - INTRODUCTION: Double aortic arch is a congenital vascular abnormality in which the connected segments and their branches course between and compress the trachea and esophagus, often resulting in invariable airway compression. CASE PRESENTATION: A 4-year-old boy with a history of recurrent wheezing was admitted to our hospital for evaluation of asthma based on his past medical history, persistent cough, wheezing, and airway hyperresponsiveness by lung function test. Double aortic arch was diagnosed with computed tomography angiogram. After surgery, the respiratory infection improved strikingly. Early diagnosis and treatment may prevent chronic, irreversible complications. CONCLUSION: We present a case of double aortic arch masquerading as asthma. PMID- 28811941 TI - Seizure Associated Takotsubo Syndrome: A Rare Combination. AB - Takotsubo cardiomyopathy (TC) is increasingly recognized in neurocritical care population especially in postmenopausal females. We are presenting a 61-year-old African American female with past medical history of epilepsy, bipolar disorder, and hypertension who presented with multiple episodes of seizures due to noncompliance with antiepileptic medications. She was on telemetry which showed ST alarm. Electrocardiogram (ECG) was ordered and showed ST elevation in anterolateral leads and troponins were positive. Subsequently Takotsubo cardiomyopathy was diagnosed by left ventriculography findings and absence of angiographic evidence of obstructive coronary artery disease. Echocardiogram showed apical hypokinesia, ejection fraction of 40%, and systolic anterior motion of mitral valve with hyperdynamic left ventricle, in the absence of intracoronary thrombus formation in the angiogram. Electroencephalography showed evidence of generalized tonic-clonic seizure. She was treated with supportive therapy. This case illustrates importance of ECG in all patients with seizure irrespective of cardiac symptoms as TC could be the cause of Sudden Unexpected Death in Epilepsy (SUDEP) and may be underdiagnosed and so undertreated. PMID- 28811942 TI - Spontaneous Complete Remission in a Patient with Acute Myeloid Leukemia and Severe Sepsis. AB - Without treatment, acute myeloid leukemia (AML) is almost always fatal. Spontaneous remission of AML is a rare phenomenon and usually with a short duration. The exact mechanisms are unknown. However, its association with infection and blood transfusions has been described. We report a 53-year-old male who presented with severe sepsis and who was diagnosed with AML (M4). He has experienced complete spontaneous remission with relatively long duration. To the best of our knowledge, it is the first case of spontaneous remission described in Iran. PMID- 28811943 TI - Reviewing the Emergence of Lactococcus garvieae: A Case of Catheter Associated Urinary Tract Infection Caused by Lactococcus garvieae and Escherichia coli Coinfection. AB - Lactococcus garvieae is considered a low virulence organism which is rarely associated with human infections. Most of the reported cases have been associated with bacteremia with or without endocarditis. We report a rare case of catheter associated urinary tract infection (CAUTI) caused by Lactococcus garvieae and Escherichia coli coinfection without any bacteremia in a patient with indwelling urinary catheter placed for benign prostatic hyperplasia (BPH). The patient also had a history of gastroesophageal reflux disease (GERD) with long standing famotidine treatment. In our case, Lactococcus garvieae was initially misidentified as Enterococcus species but was later detected by automated microbial identification system VITEK-2 (BioMerieux, Marcy-l'Etoile, France) and was confirmed with API 32 Strep system (BioMerieux, Marcy-l'Etoile, France). The patient responded well to a two-week course of cephalosporin. Interestingly, apart from the acid suppressive treatment, no other risk factors were identified. PMID- 28811944 TI - Successful Resuscitation of a Patient with Life-Threatening Metabolic Acidosis by Hemodialysis: A Case of Ethylene Glycol Intoxication. AB - BACKGROUND: Ethylene glycol intoxication causes severe metabolic acidosis and acute kidney injury. Fomepizole has become available as its antidote. Nevertheless, a prompt diagnosis is not easy because patients are often unconscious. Here we present a case of ethylene glycol intoxication who successfully recovered with prompt hemodialysis. CASE PRESENTATION: A 52-year-old Japanese male was admitted to a local hospital due to suspected food poisoning. The patient presented with nausea and vomiting, but his condition rapidly deteriorated, with worsening conscious level, respiratory distress requiring mechanical ventilation, hypotension, and severe acute kidney injury. He was transferred to the university hospital; hemodialysis was initiated because of hyperkalemia and severe metabolic acidosis. On recovering consciousness, he admitted having ingested antifreeze solution. Thirty-seven days after admission, the patient was discharged without requiring HD. CONCLUSIONS: We reported a case of ethylene glycol intoxication who presented with a life-threatening metabolic acidosis. In a state of severe circulatory shock requiring catecholamines, hemodialysis should be avoided, and continuous hemodiafiltration may be a preferred approach. However, one should be aware of the possibility of intoxication by unknown causes, and hemodialysis could be life-saving with its superior ability to remove toxic materials in such cases. PMID- 28811945 TI - Corrigendum to "Prenatal Diagnosis of Cardiac Diverticulum with Pericardial Effusion in the First Trimester of Pregnancy with Resolution after Early Pericardiocentesis". AB - [This corrects the article DOI: 10.1155/2015/154690.]. PMID- 28811946 TI - Are All Mutations the Same? A Rare Case Report of Coexisting Mutually Exclusive KRAS and BRAF Mutations in a Patient with Metastatic Colon Adenocarcinoma. AB - 29-year-old Hispanic woman presented to the clinic with complaints of abdominal pain, nausea, fatigue, and constipation. Laboratory tests indicated the presence of iron deficiency anemia and transaminitis. Imaging evaluation revealed marked hepatomegaly with multiple hepatic metastases and pelvic lymphadenopathy. Biopsy of the hepatic lesions showed adenocarcinoma positive for pan-cytokeratin, CMA5.2, villin, and CDX2. She was positive for tumor markers CA 19-9, CA-125, and CEA. Upon further evaluation, she was found to have colorectal cancer positive for KRAS and BRAF mutations. Unfortunately, her disease progressed rapidly and she expired within 3 months from the time of her first diagnosis. KRAS and BRAF mutations are rare enough to be considered virtually mutually exclusive but coexistent mutations appear to be a distinct molecular and clinical subset with aggressive course of illness, which is in dire need of new treatment strategies. Panitumumab and Cetuximab are approved for patients with wild type KRAS CRC. Vemurafenib is a potent inhibitor of the kinase domain in mutant BRAF and its use in BRAF mutated colon cancer remains to be well established. Our report highlights the need to obtain tissue samples from these patients for analysis and to evaluate the benefit of Vemurafenib in colorectal cancers. PMID- 28811947 TI - Solitary Skull Metastasis as the First Presentation of a Metachronous Primary Lung Cancer in a Survivor from Pancreatic Cancer. AB - Skull metastasis from lung cancer is relatively common, yet the first presentation for this malignant disease is a rare occurrence. We herein report a case of a 54-year-old female, who had a good outcome following Whipple procedure for periampullary adenocarcinoma five years before her current presentation. During a routine follow-up, she was found to have a slowly progressive painless right parietal swelling. The systemic screening workup revealed no abdominal disease, but a solitary pulmonary nodule was identified. The presence of these two lesions raised the diagnosis of metastases from a previously treated pancreatic adenocarcinoma. The patient underwent complete excision of the skull lesion and subsequent lung biopsy, both of which proved on histopathological examination to be consistent with a primary lung cancer. This case emphasizes the importance of imaging and histopathological correlation in the diagnosis of solitary skull metastases and their effect on the subsequent management. PMID- 28811948 TI - The Dorsoulnar Artery Perforator Adipofascial Flap in the Treatment of Distal Radioulnar Synostosis. AB - Posttraumatic radioulnar synostosis (RUS) is a rare event following forearm fractures. Consequences are disabling for patients who suffer from functional limitation in forearm pronosupination. Distal RUS are even more rare and more difficult to treat because of high recurrence rates. The patient we describe in this paper came to our attention with a double distal RUS recurrence and a Darrach procedure already performed. We performed a radical excision of RUS and interposition with a vascularized dorsoulnar artery (DUA) adipofascial perforator flap. Four years after surgery, the patient shows the same complete range of motion in pronosupination, and MRI confirms that the flap is still in place with signs of vascularization. Simple synostosis excision has been proven ineffective in many cases. Interposition is recommended after excision, and biological material interposition seems to be more effective than foreign material. Surgeons are increasingly performing vascularized interposition, and the results are very encouraging. PMID- 28811949 TI - Surgical Hip Dislocation for Management of Acetabular Osteochondroma in an Adult. AB - The purpose of this study is to report a rare case of acetabular osteochondroma with a unique clinical presentation occurring in an adult with normally developed hips. The distinctive size and location of the lesion required an open approach with surgical dislocation of the hip for complete resection. PMID- 28811950 TI - Autoscopic Hallucination in Alcohol Dependence Syndrome: A Rare or Missed Phenomenon? AB - Autoscopic phenomenon, a psychic illusionary duplication of one's own self, has been the subject of interest in the literature and science for years. It has been reported in various diseases of the central nervous system but with an unknown mechanism. Hallucinations are a common presentation in alcohol dependence syndrome during delirium tremens and as induced disorder. However, autoscopic hallucination has been rarely reported in the cases of alcohol dependence. We present a case of a 40-year-old man who experienced autoscopic hallucination during the withdrawal state of alcohol. He was successfully treated with detoxification and an antipsychotic medication and was doing well. The case highlights the need for strong suspicion and exploration of the autoscopic hallucination and autoscopic phenomenon in general in cases of alcohol dependence syndrome. PMID- 28811951 TI - Granulomatosis with Polyangiitis Presenting as Pyrexia of Unknown Origin, Leukocytosis, and Microangiopathic Haemolytic Anemia. AB - A 66-year-old woman presented to the Emergency Department with a florid sepsis like picture, a two-week history of fever, relative hypotension with end organ ischemia (unexplained liver enzyme and troponin elevations), and nonspecific constitutional symptoms. She was initially found to have a urinary tract infection but, despite appropriate treatment, her fever persisted and her white blood cell count continued to rise. During her hospitalization the patient manifested leukocytosis to 47,000 WBC/MUL, ESR 67 mm/hr (normal range 0-42 mm/hr), CRP 17.5 mg/dL (normal range 0.02-1.20 mg/dL), and microangiopathic haemolytic anemia, with declining haemoglobin and haematocrit. An infectious aetiology was not found despite extensive bacteriologic studies and radiographic imaging. The patient progressed to acute kidney injury with "active" urinary sediment and proteinuria. Kidney biopsy results and serological titres of myeloperoxidase positive perinuclear-antineutrophil cytoplasmic antibodies (MPO+ p-ANCA) led to a diagnosis of granulomatosis with polyangiitis. Immunosuppressive treatment with high dose methylprednisolone and rituximab led to resolution of the leukocytosis and return of the haemoglobin and haematocrit values toward normal without further signs of hemolysis. PMID- 28811952 TI - Divorce and Severity of Coronary Artery Disease: A Multicenter Study. AB - The association between marital status and coronary artery disease (CAD) is supported by numerous epidemiological studies. While divorce may have an adverse effect on cardiac outcomes, the relationship between divorce and severe CAD is unclear. We conducted a multicenter, observational study of consecutive patients undergoing coronary angiography during the period between April 1, 2013, and March 30, 2014. Of 1,068 patients, 124 (12%) were divorced. Divorce was more frequent among women (27%) compared to men (6%). Most divorced patients had been divorced only once (49%), but a subset had been divorced 2 (38%) or >=3 (12%) times. After adjusting for baseline differences, there was no significant association between divorce and severe CAD in men. In women, there was a significant adjusted association between divorce and severe MVD (OR 2.31 [1.16, 4.59]) or LMD (OR 5.91 [2.19, 15.99]). The modification of the association between divorce and severe CAD by gender was statistically significant for severe LMD (Pinteraction 0.0008) and marginally significant for CAD (Pinteraction 0.05). Among women, there was a significant adjusted association between number of divorces and severe CAD (OR 2.4 [95% CI 1.2, 4.5]), MVD (OR 2.0 [95% CI 1.4, 3.0]), and LMD (OR 3.4 [95% CI 1.9, 5.9]). In conclusion, divorce, particularly multiple divorces, is associated with severe CAD, MVD, and LMD in women but not in men. PMID- 28811954 TI - Is Neutrophil-to-Lymphocyte Ratio a Predictor of Coronary Artery Disease in Western Indians? AB - INTRODUCTION: The current study was designed to evaluate the association of neutrophil-to-lymphocyte ratio (NLR) with coronary artery disease (CAD) presence. We also aimed to propose a suitable cut-off of NLR for diagnosis of CAD in Western Indians. METHODS: Total 324 patients undergoing coronary angiography were enrolled and were subdivided into two groups: group 1 (n = 99; population without CAD) and group 2 (n = 225; population with CAD). RESULTS: The results indicated significant (p < 0.05) positive association between elevated levels of WBC, neutrophil, monocyte, NLR, hs-CRP, CPK-MB, and troponin I and disease presence. According to subgroup analysis, the association was more profound in male and older population. Among all the markers NLR showed the strongest predictive potential for CAD with highest odds ratio (1.495; 95% CI: 0.942-2.371; p < 0.048). Optimum cut-off of NLR for diagnosis of CAD was 2.13 (AUC-0.823; p < 0.001; sensitivity: 83.64%; specificity: 63.46%). Association of NLR with other biochemical markers such as hs-CRP, CPK-MB, and troponin I was also observed in quartile analysis. CONCLUSION: NLR is a simple indicator that could be effectively used for the diagnosis of CAD with a cut-off of 2.13 in Western Indian population. PMID- 28811955 TI - The Effects of Group-Based versus Individual-Based Tai Chi Training on Nonmotor Symptoms in Patients with Mild to Moderate Parkinson's Disease: A Randomized Controlled Pilot Trial. AB - OBJECTIVE: To compare the effects of group-based and individual-based Tai Chi training on nonmotor symptoms in patients with mild to moderate Parkinson's disease. DESIGN: Randomized controlled pilot study. METHODS: 36 community dwelling patients with Parkinson's disease (PD) were randomly assigned to either group-based training group (n = 19) or individual-based group (n = 17). Both groups received same content of Tai Chi training 3 times a week for 13 weeks. Participants were also asked to perform home exercises daily. The Non-Motor Symptoms Scale was used to assess global nonmotor symptoms change. Sleep quality, depression, and cognition were evaluated by Parkinson's Disease Sleep Scale, Hamilton Depression Scale, and Beijing version-Montreal Cognitive Assessment, respectively. Home exercise compliance was recorded. RESULTS: There was no significant difference between two groups at baseline. After 13 weeks, there were no statistical significance between two groups. However, the within-group effect was different. Participants in group-based and individual-based groups showed a significant improvement on global nonmotor symptoms (P < 0.001, P = 0.004) and sleep (P < 0.001, P < 0.001). But only group-based training patients presented a significant improvement in cognitive impairment compared with baseline (P = 0.002, P - 0.116). For depression, no group gained a significant improvement(P = 0.123, P = 0.170). Group-based participants had a higher home-exercise compliance rate (HeCR) than individual-based participants did (P = 0.019), and HeCR showed a moderate correlation with MoCA-BJ and NMSS scores changes in this study. CONCLUSION: Group-based Tai Chi training is considered to be a more effective and a more labor-saving method in the clinical settings, and patients tend to have a higher compliance rate in their home exercise program. This study is registered with ChiCTR-IPR-17010388. PMID- 28811956 TI - Spectrophotometric Methods for Simultaneous Determination of Oxytetracycline HCl and Flunixin Meglumine in Their Veterinary Pharmaceutical Formulation. AB - Four precise, accurate, selective, and sensitive UV-spectrophotometric methods were developed and validated for the simultaneous determination of a binary mixture of Oxytetracycline HCl (OXY) and Flunixin Meglumine (FLU). The first method, dual wavelength (DW), depends on measuring the difference in absorbance (DeltaA 273.4-327 nm) for the determination of OXY where FLU is zero while FLU is determined at DeltaA 251.7-275.7 nm. The second method, first-derivative spectrophotometric method (1D), depends on measuring the peak amplitude of the first derivative selectively at 377 and 266.7 nm for the determination of OXY and FLU, respectively. The third method, ratio difference method, depends on the difference in amplitudes of the ratio spectra at DeltaP 286.5-324.8 nm and DeltaP 249.6-286.3 nm for the determination of OXY and FLU, respectively. The fourth method, first derivative of ratio spectra method (1DD), depends on measuring the amplitude peak to peak of the first derivative of ratio spectra at 296.7 to 369 nm and 259.1 to 304.7 nm for the determination of OXY and FLU, respectively. Different factors affecting the applied spectrophotometric methods were studied. The proposed methods were validated according to ICH guidelines. Satisfactory results were obtained for determination of both drugs in laboratory prepared mixture and pharmaceutical dosage form. The developed methods are compared favourably with the official ones. PMID- 28811953 TI - From Inflammation to Current and Alternative Therapies Involved in Wound Healing. AB - Wound healing is a complex event that develops in three overlapping phases: inflammatory, proliferative, and remodeling. These phases are distinct in function and histological characteristics. However, they depend on the interaction of cytokines, growth factors, chemokines, and chemical mediators from cells to perform regulatory events. In this article, we will review the pathway in the skin healing cascade, relating the major chemical inflammatory mediators, cellular and molecular, as well as demonstrating the local and systemic factors that interfere in healing and disorders associated with tissue repair deficiency. Finally, we will discuss the current therapeutic interventions in the wounds treatment, and the alternative therapies used as promising results in the development of new products with healing potential. PMID- 28811957 TI - Mapping the human T cell repertoire to recurrent driver mutations in MYD88 and EZH2 in lymphoma. AB - Oncogenic "driver" mutations are theoretically attractive targets for the immunotherapy of lymphoid cancers, yet the proportion that can be recognized by T cells remains poorly defined. To address this issue without any confounding effects of the patient's immune system, we assessed T cells from 19 healthy donors for recognition of three common driver mutations in lymphoma: MYD88L265P, EZH2Y641F , and EZH2Y641N . Donors collectively expressed the 10 most prevalent HLA class I alleles, including HLA-A*02:01. Peripheral blood T cells were primed with peptide-loaded dendritic cells (DC), and reactive T cells were assessed for recognition of naturally processed mutant versus wild type full-length proteins. After screening three driver mutations across 17-26 HLA class I alleles and 3 * 106-3 * 107 T cells per donor, we identified CD4+ T cells against EFISENCGEII from EZH2Y641N (presented by HLA-DRB1*13:02) and CD8+ T cells against RPIPIKYKA from MYD88L265P (presented by HLA-B*07:02). We failed to detect RPIPIKYKA specific T cells in seven other HLA-B*07:02-positive donors, including two lymphoma patients. Thus, healthy donors harbor T cells specific for common driver mutations in lymphoma. However, such responses appear to be rare due to the combined limitations of antigen processing, HLA restriction, and T cell repertoire size, highlighting the need for highly individualized approaches for selecting targets. PMID- 28811958 TI - Soluble NKG2D ligands are biomarkers associated with the clinical outcome to immune checkpoint blockade therapy of metastatic melanoma patients. AB - The introduction of immune checkpoint blockade into the clinical practice resulted in improvement of survival of a significant portion of melanoma patients. Consequently, predictive biomarkers of response are needed to optimize patient's stratification and the development of combination therapies. The aim of this study was to determine whether levels of soluble NKG2D ligands (MICA, MICB, ULBP1, 2 and 3; sNKG2DLs) in the serum of melanoma patients can serve as useful predictors of response to the treatment with immune checkpoint blockade. sNKG2DLs were measured by ELISA in baseline and post-treatment serum and these results were correlated with the clinical outcome of melanoma patients (N = 194). The same determinations were performed also in a cohort of patients (N = 65) treated with either chemotherapy, radiotherapy, or mutated BRAF inhibitors (BRAFi). Absence of soluble MICB and ULBP-1 in baseline serum correlated with improved survival (OS = 21.6 and 25.3 mo and p = 0.02 and 0.01, respectively) of patients treated with immunological therapies while detectable levels of these molecules were found in poor survivors (OS = 8.8 and 12.1 mo, respectively). Multivariate analysis showed that LDH (p <0.0001), sULBP-1 (p = 0.02), and sULBP-2 (p = 0.02) were independent predictors of clinical outcome for the cohort of melanoma patients treated with immune checkpoint blockade. Only LDH but not sNKG2DLs was significantly associated with the clinical outcome of patients treated with standard or BRAFi regimens. These findings highlight the relevance of sNKG2DLs in the serum of melanoma patients as biomarkers for patients' stratification and optimization of immune checkpoint inhibition regimens. PMID- 28811959 TI - T-helper and T-regulatory cells modulation in head and neck squamous cell carcinoma. AB - Head and neck squamous cell carcinoma (HNSCC) is one of the most diffused cancer types, characterized by a high reoccurrence rate, mainly due to the inability of current therapeutic approaches to completely eradicate cancer cells. HNSCC patients often have defective immune functions, thus allowing cancer immune escape and cancer spreading. Particularly important in driving immune escape during HNSCC progression are T-helper and T-regulatory cells. New insights into their mechanisms of action might support the development of effective and long lasting immunotherapy. PMID- 28811961 TI - PD-L1 immune suppression in cancer: Tumor cells or host cells? AB - Four recent publications reported the role of PD-L1 expression on host versus malignant cells within the tumor for PD-1/PD-L1 checkpoint blockade therapy. All four research groups harmoniously report: PD-L1 expressed by both host as well as tumor cells are capable of suppressing T cell functions. Thus, checkpoint therapy can be effective, if malignant cells do not express PD-L1. PMID- 28811960 TI - Rehmannia glutinosa polysaccharide induces toll-like receptor 4 dependent spleen dendritic cell maturation and anti-cancer immunity. AB - Rehmannia glutinosa polysaccharide (RGP) has shown an activation of immune cells in vitro. However, the immune stimulatory effect of RGP in a mouse in vivo is not well studied. In this study, we examined the effect of RGP on dendritic cell (DC) activation and anticancer immunity in vivo. Treatments of RGP in C56BL/6 mice induced increased levels of co-stimulatory molecule expression and pro inflammatory cytokine production in spleen DCs dependent on toll-like receptor 4 (TLR4), and those DCs promoted interferon-gamma (IFNgamma) production in CD4+ and CD8+ T cells. RGP also enhanced ovalbumin (OVA) antigen (Ag)-specific immune activation in tumor-bearing mice, including Ag presentation in DCs, OT-I and OT II T-cell proliferation, migration of OT-I and OT-II T cells into the B16-OVA tumor, OVA-specific IFNgamma production, and the specific killing of OVA-coated splenocytes, which consequently inhibited B16-OVA tumor growth dependent on TLR4 and CD8+ T cells. Finally, the combination of RGP and self-Ag treatment efficiently inhibited CT26 carcinoma and B16 melanoma tumor growth in BLAB/c and C57BL/6 mice, respectively. These data demonstrate that RGP could be a useful adjuvant molecule for immunotherapy against cancer. PMID- 28811962 TI - An ROR1 bi-specific T-cell engager provides effective targeting and cytotoxicity against a range of solid tumors. AB - We have developed a humanized bi-specific T-cell engager (BiTE) targeting receptor tyrosine kinase-like orphan receptor 1 (ROR1), a cell surface antigen present on a range of malignancies and cancer-initiating cells. Focusing initially on pancreatic cancer, we demonstrated that our ROR1 BiTE results in T cell mediated and antigen-specific cytotoxicity against ROR1-expressing pancreatic cancer cell lines in vitro at exceedingly low concentrations (0.1 ng/mL) and low effector to target ratios. Our BiTE prevented engraftment of pancreatic tumor xenografts in murine models and reduced the size of established subcutaneous tumors by at least 3-fold. To validate its wider therapeutic potential, we next demonstrated significant cytotoxicity against ovarian cancer in an in vitro and in vivo setting and T-cell-mediated killing of a range of histologically distinct solid tumor cell lines. Overall, our ROR1 BiTE represents a promising immunotherapy approach, because of its ability to target a broad range of malignancies, many with significant unmet therapeutic needs. PMID- 28811963 TI - Characterization of the cryoablation-induced immune response in kidney cancer patients. AB - Cryoablation is one of treatment modalities for kidney cancer and is expected to induce strong local immune responses as well as systemic T-cell-mediated immune reactions that may lead to the regression of distant metastatic lesions. Thus, the characterization of T cell repertoire and immune environment in tumors before and after treatment should contribute to the better understanding of the cryoablation-induced anticancer immune responses. In this study, we collected tumor tissues from 22 kidney cancer patients, before cryoablation and at 3 mo after cryoablation. In addition, blood samples were collected from 14 patients at the same time points. We applied a next generation sequencing approach to characterize T cell receptor beta (TCRB) repertoires using RNAs isolated from tumor tissues and peripheral blood mononuclear cells. TCRB repertoire analysis revealed the expansion of certain T cell clones in tumor tissues by cryoablation. We also found that proportions of abundant TCRB clonotypes (defined as clonotypes with >= 1% frequency among total TCRB reads) were significantly increased in the post-cryoablation tissue samples than those of pre-cryoablation tumor samples. Some of these TCRB clonotypes were found to be increased in peripheral blood. Expression analysis of immune-related genes in the tissues of pre- and post cryoablation showed significantly elevated transcriptional levels of CD8+ , CD4+ , Granzyme A (GZMA), and CD11c along with a high CD8/FOXP3 ratio in the post cryoablation tissue samples. Our findings revealed that cryoablation could induce strong immune reactions in tumors with oligoclonal expansion of antitumor T cells, which circulate systemically. PMID- 28811964 TI - PD-L2 expression in colorectal cancer: Independent prognostic effect and targetability by deglycosylation. AB - Colorectal cancer (CRC) is the second leading cause of cancer death worldwide, and immune checkpoint blockade therapy provides an opportunity for improving the outcome of CRC patients. Recent studies suggest that programmed death ligand-1 (PD-L1) is only expressed in 12% of CRCs. Here, we demonstrate that PD-L2 is expressed in approximately 40% CRCs, and its expression independently associates with poor survival of CRC patients. By detection of PD-L2 expression by immunofluorescence in 124 CRC cases with 10-y survival data, we found significant association between PD-L2 overexpression in cancer cells and worse overall survival (46.3 vs 69.1 mo; p = 0.0004). The association remained significant in multivariate COX regression analysis (hazard ratio = 2.778, 95% confidence interval [CI] = 1.668-4.627; p < 0.0001). In the validation CRC data set, significant association between PD-L2 overexpression and poor survival was supported by the univariate analysis (27.1 vs. 88.9 mo; p = 0.0002) and multivariate model (hazard ratio = 7.09, 95%CI 1.78-28.16; p = 0.005). Western Blot revealed strong induction of PD-L2 expression by interferon-gamma (IFNgamma) in CRC cells, and the mRNA levels of both genes were significantly correlated in CRC tissue samples. Suppression of glycosylation with tunicamycin caused a shift in molecular weight and significant decrease in the expression of PD-L2 protein. In conclusion, PD-L2 overexpression in CRC cells, under the regulation by IFNgamma and glycosylation, associates with poor survival of patients with colorectal cancer. These findings highlight PD-L2 as a promising therapeutic target in CRC and suggest potential routes to control PD-L2 expression in CRC cells. PMID- 28811965 TI - Adjuvant immunotherapy with autologous dendritic cells for hepatocellular carcinoma, randomized phase II study. AB - Our previous phase I/IIA study showed that autologous dendritic cells (DCs) pulsed with tumor-associated antigens are well tolerated in patients with hepatocellular carcinoma (HCC). In this randomized, multicenter, open-label, phase II trial, we investigated the efficacy and safety of this DC-based adjuvant immunotherapy with 156 patients, who treated for HCC with no evidence of residual tumor after standard treatment modalities. Patients were randomly assigned to immunotherapy (n = 77; injection of 3 * 107 DC cells, six times over 14 weeks) or control (n = 79; no treatment). The primary end point was recurrence-free survival (RFS), and the secondary endpoints were immune response and safety. The RFS between the immunotherapy and control groups was not significantly different (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.60-1.56; p = 0.90). However, post-hoc subgroup analyses revealed that DC immunotherapy significantly reduced the risk of tumor recurrence of non-radiofrequency ablation (non-RFA) group patients (n = 83, HR, 0.49; 95% CI, 0.26-0.94; p = 0.03), whereas unexpectedly increased the risk of recurrence in RFA group (n = 61, p = 0.01). Tumor-specific immune responses were significantly enhanced (both p < 0.01) in the immunotherapy group. Baseline serum interleukin (IL)-15 was statistically correlated with RFS prolongation (HR, 0.16; 95% CI, 0.03-1.58; p = 0.001) within the immunotherapy groups. Overall adverse events were more frequent in the immunotherapy group (p < 0.001) but were mainly mild to moderate in severity. In conclusion, adjuvant immunotherapy with DC vaccine reduces the risk of tumor recurrence in HCC patients who underwent standard treatment modalities other than RFA. Baseline IL-15 might be a candidate biomarker for DC-based HCC immunotherapy. PMID- 28811967 TI - IL-18 receptor marks functional CD8+ T cells in non-small cell lung cancer. AB - IL-18 is an inflammasome-related cytokine, member of the IL-1 family, produced by a wide range of cells in response to signals by several pathogen- or damage associated molecular patterns. It can be highly represented in tumor patients, but its relevance in human cancer development is not clear. In this study, we provide evidence that IL-18 is principally expressed in tumor cells and, in concert with other conventional Th1 cell-driven cytokines, has a pivotal role in establishing a pro-inflammatory milieu in the tumor microenvironment of human non small cell lung cancer (NSCLC). Interestingly, the analysis of tumor-infiltrating CD8+ T cell populations showed that (i) the relative IL-18 receptor (IL-18R) is significantly more expressed by the minority of cells with a functional phenotype (T-bet+Eomes+), than by the majority of those with the dysfunctional phenotype T bet-Eomes+ generally resident within tumors; (ii) as a consequence, the former are significantly more responsive than the latter to IL-18 stimulus in terms of IFNgamma production ex vivo; (iii) PD-1 expression does not discriminate these two populations. These data indicate that IL-18R may represent a biomarker of the minority of functional tumor-infiltrating CD8+ T cells in adenocarcinoma NSCLC patients. In addition, our results lead to envisage the possible therapeutic usage of IL-18 in NSCLC, even in combination with other checkpoint inhibitor approaches. PMID- 28811966 TI - CEACAM1 as a multi-purpose target for cancer immunotherapy. AB - CEACAM1 is an extensively studied cell surface molecule with established functions in multiple cancer types, as well as in various compartments of the immune system. Due to its multi-faceted role as a recently appreciated immune checkpoint inhibitor and tumor marker, CEACAM1 is an attractive target for cancer immunotherapy. Herein, we highlight CEACAM1's function in various immune compartments and cancer types, including in the context of metastatic disease. This review outlines CEACAM1's role as a therapeutic target for cancer treatment in light of these properties. PMID- 28811968 TI - IL-32alpha-induced inflammation constitutes a link between obesity and colon cancer. AB - Growing evidence indicates that adipose tissue inflammation is an important mechanism whereby obesity promotes cancer risk and progression. Since IL-32 is an important inflammatory and remodeling factor in obesity and is also related to colon cancer (CC) development, the aim of this study was to explore whether IL-32 could function as an inflammatory factor in human obesity-associated CC promoting a microenvironment favorable for tumor growth. Samples obtained from 84 subjects [27 lean (LN) and 57 obese (OB)] were used in the study. Enrolled subjects were further subclassified according to the established diagnostic protocol for CC (49 without CC and 35 with CC). We show, for the first time, that obesity (p = 0.009) and CC (p = 0.026) increase circulating concentrations of IL-32alpha. Consistently, we further showed that gene (p < 0.05) and protein (p < 0.01) expression levels of IL-32alpha were upregulated in VAT from obese patients with CC. Additionally, we revealed that IL32 expression levels are enhanced by hypoxia and inflammation-related factors in HT-29 CC cells as well as that IL-32alpha is involved in the upregulation of inflammation (IL8, TNF, and CCL2) and extracellular matrix (ECM) remodeling (SPP1 and MMP9) genes in HT-29 cancer cells. Additionally, we also demonstrate that the adipocyte-conditioned medium obtained from obese patients stimulates (p < 0.05) the expression of IL32 in human CC cells. These findings provide evidence of the potential involvement of IL-32 in the development of obesity-associated CC as a pro-inflammatory and ECM remodeling cytokine. PMID- 28811969 TI - K27M-mutant histone-3 as a novel target for glioma immunotherapy. AB - Mutation-specific vaccines have become increasingly important in glioma immunotherapy; however, shared neoepitopes are rare. For diffuse gliomas, a driver mutation in the gene for isocitrate dehydrogenase type-1 has been shown to produce an immunogenic epitope currently targeted in clinical trials. For highly aggressive midline gliomas, a recurrent point mutation in the histone-3 gene (H3F3A) causes an amino acid change from lysine to methionine at position 27 (K27M). Here, we demonstrate that a peptide vaccine against K27M-mutant histone-3 is capable of inducing effective, mutation-specific, cytotoxic T-cell- and T helper-1-cell-mediated immune responses in a major histocompatibility complex (MHC)-humanized mouse model. By proving an immunologically effective presentation of the driver mutation H3K27M on MHC class II in human H3K27M-mutant gliomas, our data provide a basis for the further clinical development of vaccine-based or cell-based immunotherapeutic approaches targeting H3K27M. PMID- 28811971 TI - Preclinical immunoPET/CT imaging using Zr-89-labeled anti-PD-L1 monoclonal antibody for assessing radiation-induced PD-L1 upregulation in head and neck cancer and melanoma. AB - Radiation therapy (RT) can induce upregulation of programmed death ligand 1 (PD L1) on tumor cells or myeloid cells, which may affect response to PD-1-based immunotherapy. PD-L1 upregulation during RT is a dynamic process that has been difficult to monitor during treatment. The aim of this study was to evaluate the RT-induced PD-L1 upregulation in the tumor and its microenvironment using immunoPET/CT imaging of two syngeneic murine tumor models (HPV+ head and neck squamous cell carcinoma (HNSCC) or B16F10 melanoma). Tumors were established in two locations per mouse (neck and flank), and fractionated RT (2 Gy * 4 or 2 Gy * 10) was delivered only to the neck tumor, alone or during anti-PD-1 mAb immunotherapy. PD-L1 expression was measured by PET/CT imaging using Zr-89 labeled anti-mouse PD-L1 mAb, and results were validated by flow cytometry. PET/CT imaging demonstrated significantly increased tracer uptake in irradiated neck tumors compared with non-irradiated flank tumors. Ex vivo analysis by biodistribution and flow cytometry validated PD-L1 upregulation specifically in irradiated tumors. In the HNSCC model, RT-induced PD-L1 upregulation was only observed after 2 Gy * 10 fractionated RT, while in the B16F10 model upregulation of PD-L1 occurred after 2 Gy * 4 fractionated RT. Fractionated RT, but not anti PD-1 therapy, upregulated PD-L1 expression on tumor and infiltrating inflammatory cells in murine models, which could be non-invasively monitored by immunoPET/CT imaging using Zr-89 labeled anti-mouse PD-L1 mAb, and differentially identified anti-PD-1 responsive as well as selectively irradiated tumors in vivo. PMID- 28811972 TI - Uncovering the immunotherapeutic cycle initiated by p19Arf and interferon-beta gene transfer to cancer cells: An inducer of immunogenic cell death. AB - Simultaneous reestablishment of p53/p19Arf and interferon-beta pathways in melanoma cells culminates in a cell death process that displays features of necroptosis along with the release of immunogenic cell death molecules and unleashes an antitumor immune response mediated by natural killer cells, neutrophils as well as CD4+ and CD8+ T lymphocytes. PMID- 28811973 TI - NK cell dysfunction in chronic lymphocytic leukemia is associated with loss of the mature cells expressing inhibitory killer cell Ig-like receptors. AB - A prospective analysis of natural killer (NK) cell phenotype and function was performed on fresh peripheral blood samples from untreated patients with B-cell chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Compared to healthy controls, CD56dim NK cells in CLL patients displayed reduced expression of the NKG2D activating receptor and increased CD27 expression, which indicates declines in mature cells. In addition, NK cells from CLL patients showed reduced degranulation responses toward transformed B cells alone or with rituximab and were more sensitive to activation-induced cell death. We further noted a striking reduction in the frequency and viability of NK cells expressing the inhibitory killer cell Ig-like receptors (KIR)2DL1 and/or KIR3DL1, which progressed over time in most patients. Comparisons between a CLL patient and healthy monozygotic twin were consistent with our results in the larger cohorts. Functional and biomarker alterations were less pronounced on NK cells from SLL patients, which have lower tumor burden in peripheral blood than CLL, but significant reduction in degranulation under ADCC conditions and lower frequency and viability of KIR-expressing NK cells were still evident in SLL. We conclude that mature KIR-expressing NK cells respond to the high circulating B cell tumor burden in CLL, but undergo activation-induced apoptosis. Consequently, CLL patients may benefit from therapies that augment NK cell survival and function. PMID- 28811970 TI - Trial watch: Dendritic cell-based anticancer immunotherapy. AB - Dendritic cell (DC)-based vaccines against cancer have been extensively developed over the past two decades. Typically DC-based cancer immunotherapy entails loading patient-derived DCs with an appropriate source of tumor-associated antigens (TAAs) and efficient DC stimulation through a so-called "maturation cocktail" (typically a combination of pro-inflammatory cytokines and Toll-like receptor agonists), followed by DC reintroduction into patients. DC vaccines have been documented to (re)activate tumor-specific T cells in both preclinical and clinical settings. There is considerable clinical interest in combining DC-based anticancer vaccines with T cell-targeting immunotherapies. This reflects the established capacity of DC-based vaccines to generate a pool of TAA-specific effector T cells and facilitate their infiltration into the tumor bed. In this Trial Watch, we survey the latest trends in the preclinical and clinical development of DC-based anticancer therapeutics. We also highlight how the emergence of immune checkpoint blockers and adoptive T-cell transfer-based approaches has modified the clinical niche for DC-based vaccines within the wide cancer immunotherapy landscape. PMID- 28811974 TI - Ex-vivo assessment of drug response on breast cancer primary tissue with preserved microenvironments. AB - Interaction between cancerous, non-transformed cells, and non-cellular components within the tumor microenvironment plays a key role in response to treatment. However, short-term culture or xenotransplantation of cancer specimens in immunodeficient animals results in dramatic modifications of the tumor microenvironment, thus preventing reliable assessment of compounds or biologicals of potential therapeutic relevance. We used a perfusion-based bioreactor developed for tissue engineering purposes to successfully maintain the tumor microenvironment of freshly excised breast cancer tissue obtained from 27 breast cancer patients and used this platform to test the therapeutic effect of antiestrogens as well as checkpoint-inhibitors on the cancer cells. Viability and functions of tumor and immune cells could be maintained for over 2 weeks in perfused bioreactors. Next generation sequencing authenticated cultured tissue specimens as closely matching the original clinical samples. Anti-estrogen treatment of cultured estrogen receptor positive breast cancer tissue as well as administration of pertuzumab to a Her2 positive breast cancer both had an anti proliferative effect. Treatment with anti-programmed-death-Ligand (PD-L)-1 and anti-cytotoxic T lymphocyte-associated protein (CTLA)-4 antibodies lead to immune activation, evidenced by increased lymphocyte proliferation, increased expression of IFNgamma, and decreased expression of IL10, accompanied by a massive cancer cell death in ex vivo triple negative breast cancer specimens. In the era of personalized medicine, the ex vivo culture of breast cancer tissue represents a promising approach for the pre-clinical evaluation of conventional and immune mediated treatments and provides a platform for testing of innovative treatments. PMID- 28811975 TI - Chemotherapeutic agent-mediated elimination of myeloid-derived suppressor cells. AB - Immunotherapy has shown great promise in the fight against cancer, as evidenced by the clinical efficacy of chimeric antigen receptor T cells in hematologic malignancies and checkpoint blockade in certain solid tumors. However, a considerable number of patients fail to respond to these therapies. Induction of myeloid-derived suppressor cells (MDSCs) by growing tumors has been shown to be one important factor limiting the efficacy of cancer immunotherapy. Recently, several chemotherapeutic agents used in conventional cancer chemotherapy have been found to reduce MDSC numbers in tumor tissues as well as in the peripheral lymphoid organs, and combining these agents with immunotherapy improved survival of tumor-bearing hosts. In this review, we will highlight the effects of chemotherapeutic agents on MDSC accumulation, and examine the various factors likely to influence these effects. PMID- 28811976 TI - Long-lived pancreatic ductal adenocarcinoma slice cultures enable precise study of the immune microenvironment. AB - Pancreatic ductal adenocarcinoma (PDA) remains a deadly disease that is rarely cured, despite many recent successes with immunotherapy for other malignancies. As the human disease is heavily infiltrated by effector T cells, we postulated that accurately modeling the PDA immune microenvironment would allow us to study mechanisms of immunosuppression that could be overcome for therapeutic benefit. Using viable precision-cut slices from fresh PDA, we developed an organotypic culture system for this purpose. We confirmed that cultured slices maintain their baseline morphology, surface area, and microenvironment after at least 6 d in culture, and demonstrated slice survival by MTT assay and by immunohistochemistry staining with Ki-67 and cleaved-Caspase-3 antibodies. Immune cells, including T cells (CD3+, CD8+, and FOXP3+) and macrophages (CD68+, CD163+ and HLA-DR+), as well as stromal myofibroblasts (alphaSMA+) were present throughout the culture period. Global profiling of the PDA proteome before and after 6 d slice culture indicated that the majority of the immunological proteins identified remain stable during the culture process. Cytotoxic effects of drug treatment (staurosporine, STS and cycloheximide, CHX) on PDA slices culture confirmed that this system can be used to assess functional response and cell survival following drug treatment in both a treatment time- and dose-dependent manner. Using multicolor immunofluorescence, we stained live slices for both cancer cells (EpCAM+) and immune cells (CD11b+ and CD8+). Finally, we confirmed that autologous CFSE-labeled splenocytes readily migrate into co-cultured tumor slices. Thus, our present study demonstrates the potential to use tumor slice cultures to study the immune microenvironment of PDA. PMID- 28811977 TI - Epigenetic regulation of the extrinsic oncosuppressor PTX3 gene in inflammation and cancer. AB - PTX3 is a component of the humoral arm of innate immunity and an extrinsic oncosuppressor gene taming tumor-promoting inflammation. Here, we show that two enhancers differently regulate PTX3 expression: enhancer 1, located 230 kb upstream of PTX3 promoter, mediated the action of inflammatory transcription factors; and enhancer 2, encompassing PTX3 second exon, was implicated in pre initiation complex assembly. Polycomb repressive complex 2 silenced these regulatory elements and the promoter in basal condition. Enhancer 1 was epigenetically inactivated in early colorectal cancer (CRC) stages, while the promoter and enhancer 2 showed increasingly DNA methylation during CRC progression from adenomas to stage II and III CRC. Inhibition of DNA methylation rescued PTX3 expression in CRC. Finally, enhancer 1 acquired the binding of STAT3 in stage I CRC, and inhibition of STAT3 phosphorylation restored PTX3 activity and decreased enhancer 1 methylation. Thus, the expression of PTX3 is under the control of two enhancers, which emerge as important fine regulators of PTX3 expression in inflammation and cancer. PMID- 28811978 TI - Development and characterization of naive single-type tumor antigen-specific CD8+ T lymphocytes from murine pluripotent stem cells. AB - Optimal approaches to differentiate tumor antigen-specific cytotoxic T lymphocytes (CTLs) from pluripotent stem cells (PSCs) remain elusive. In the current study, we showed that combination of in vitro priming through Notch ligands and in vivo development facilitated the generation of tumor Ag-specific CTLs that effectively inhibited tumor growth. We co-cultured the murine induced PSCs (iPSCs) genetically modified with tyrosinase-related protein 2 (TRP2) specific T cell receptors with OP9 cell line expressing both Notch ligands Delta like 1 and 4 (OP9-DL1/DL4) for a week before adoptively transferred into recipient C67BL/6 mice. Three weeks later, B16 melanoma cells were inoculated subcutaneously, and the antitumor activity of the iPSC-derived T cells was assessed. We observed the development of the TRP2-specific iPSC-CD8+ T cells that responded to Ag stimulation and infiltrated into melanoma tissues, significantly inhibited the tumor growth, and improved the survival of the tumor-bearing mice. Thus, this approach may provide a novel effective strategy to treatment of malignant tumors. PMID- 28811979 TI - PD-L1 blockade for urothelial carcinoma. PMID- 28811981 TI - "How to Write a Scientific Paper": Tips and Highlights from the Global Spine Congress Members-Only Session. PMID- 28811980 TI - ERAP1 overexpression in HPV-induced malignancies: A possible novel immune evasion mechanism. AB - Immune evasion of tumors poses a major challenge for immunotherapy. For human papillomavirus (HPV)-induced malignancies, multiple immune evasion mechanisms have been described, including altered expression of antigen processing machinery (APM) components. These changes can directly influence epitope presentation and thus T-cell responses against tumor cells. To date, the APM had not been studied systematically in a large array of HPV+ tumor samples. Therefore in this study, systematic expression analysis of the APM was performed on the mRNA and protein level in a comprehensive collection of HPV16+ cell lines. Subsequently, HPV+ cervical tissue samples were examined by immunohistochemistry. ERAP1 (endoplasmic reticulum aminopeptidase 1) was the only APM component consistently altered - namely overexpressed - in HPV16+ tumor cell lines. ERAP1 was also found to be overexpressed in cervical intraepithelial neoplasia and cervical cancer samples; expression levels were increasing with disease stage. On the functional level, the influence of ERAP1 expression levels on HPV16 E7-derived epitope presentation was investigated by mass spectrometry and in cytotoxicity assays with HPV16 specific T-cell lines. ERAP1 overexpression did not cause a complete destruction of any of the HPV epitopes analyzed, however, an influence of ERAP1 overexpression on the presentation levels of certain HPV epitopes could be demonstrated by HPV16-specific CD8+ T-cells. These showed enhanced killing toward HPV16+ CaSki cells whose ERAP1 expression had been attenuated to normal levels. ERAP1 overexpression may thus represent a novel immune evasion mechanism in HPV induced malignancies, in cases when presentation of clinically relevant epitopes is reduced by overactivity of this peptidase. PMID- 28811982 TI - A Matched Cohort Analysis Comparing Stand-Alone Cages and Anterior Cervical Plates Used for Anterior Cervical Discectomy and Fusion. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To compare perioperative characteristics of stand-alone cages and anterior cervical plates used for anterior cervical discectomy and fusion (ACDF). METHODS: We reviewed 40 adult patients who received a stand-alone cage for elective ACDF and matched them with 40 patients who received an anterior cervical plate. We statistically compared operative time, length of stay, proportion of ambulatory cases, overall complications necessitating a trip to the ED, readmission, or reoperation related to index procedure. RESULTS: There were 21 women and 19 men in the plate cohort with average ages of 53 years +/- 12 and 20 women and 20 men in the stand-alone group with an average age of 52 years +/- 11. With no statistical difference in total number, the plate group experienced 4 short-term (within 90 days of discharge) complications, including 3 patients who visited the emergency department for dysphagia and 1 who visited the emergency department for severe back pain, while the stand-alone group experienced 0 complications. There was no significant difference in operative time between the stand-alone group (75.35 min) and the plate group (81.35 min; P = .37). There was a significant difference between the proportion of ambulatory cases in the stand-alone group (25) and the plate group (6; P < .0001). CONCLUSION: Our results demonstrate that stand-alone cages have fewer complications compared to anterior plating, with a lower trend of incidence of postoperative dysphagia. Stand-alone cages may offer the advantage of sending patients home ambulatory after ACDF surgery. PMID- 28811983 TI - A Novel Spinal Implant for Fusionless Scoliosis Correction: A Biomechanical Analysis of the Motion Preserving Properties of a Posterior Periapical Concave Distraction Device. AB - STUDY DESIGN: Biomechanical study. OBJECTIVE: Recently, a posterior concave periapical distraction device for fusionless scoliosis correction was introduced. The goal of this study was to quantify the effect of the periapical distraction device on spinal range of motion (ROM) in comparison with traditional rigid pedicle screw-rod instrumentation. METHODS: Using a spinal motion simulator, 6 human spines were loaded with 4 N m and 6 porcine spines with 2 N m to induce flexion-extension (FE), lateral bending (LB), and axial rotation (AR). ROM was measured in 3 conditions: untreated, periapical distraction device, and rigid pedicle screw-rod instrumentation. RESULTS: The periapical distraction device caused a significant (P < .05) decrease in ROM of FE (human, -40.0% and porcine, 55.9%) and LB (human, -18.2% and porcine, -17.9%) as compared to the untreated spine, while ROM of AR remained unaffected. In comparison, rigid instrumentation caused a significantly (P < .05) larger decrease in ROM of FE (human, -80.9% and porcine, -94.0%), LB (human, -75.0% and porcine, -92.2%), and AR (human, -71.3% and porcine, -86.9%). CONCLUSIONS: Although no destructive forces were applied, no device failures were observed. Spinal ROM was significantly less constrained by the periapical distraction device compared to rigid pedicle screw-rod instrumentation. Therefore, provided that scoliosis correction is achieved, a more physiological spinal motion is expected after scoliosis correction with the posterior concave periapical distraction device. PMID- 28811984 TI - ACDF Graft Selection by Surgeons: Survey of AOSpine Members. AB - STUDY DESIGN: Cross-sectional survey study. OBJECTIVE: To determine what are the most commonly used graft materials in anterior cervical discectomy and fusion and whether the choice of graft is affected by surgeon's training, years in practice, geographic location, practice setting, or surgeon's perceived difficulty in achieving fusion. METHODS: A 23-question survey was sent out to 5334 surgeons using the Global AO Spine database. Response data was then stratified into surgeon training, years of practice, practice type, and global region. RESULTS: Overall, surgeons believe that graft selection affects fusion rates (89.3% of surgeons) and affects time to fusion (86.0% of surgeons). The use of a cage is currently the most common structural graft component used worldwide at 64.1%. Of surgeons that use cages, the PEEK Cage makes up 84%. North American surgeons differ from this global trend and use composite allograft more commonly. The choice to add a nonstructural graft component was reported at 74%. This result was similar for performing multilevel fusions at 72.8%. The selection of nonstructural graft material depends on whether the type of surgery is considered simple or complex. Most surgeons are not satisfied with available literature comparing effectiveness of grafts but believed that there was sufficient evidence to support the use of their chosen graft. CONCLUSION: Almost all surgeons believe that fusion is important to anterior cervical discectomy and fusion surgery outcomes and that most surgeons believe graft choice affects fusion. However, this survey indicates that there is great variability in the type of graft material used by spine surgeons across the world. PMID- 28811985 TI - Incidence, Impact, and Risk Factors for 30-Day Wound Complications Following Elective Adult Spinal Deformity Surgery. AB - STUDY DESIGN: Case-control study. OBJECTIVE: To determine the incidence, impact, and risk factors for wound complications within 30 days following elective adult spinal deformity surgery. METHODS: Current Procedural Terminology and International Classification of Diseases, Ninth Edition, diagnosis codes were used to query the database for adults who underwent spinal deformity surgery from 2010 to 2014. Patients were separated into groups of those with and without wound complications. Univariate analysis and multivariate logistic regression were used to analyze the influence of patient factors, operative variables, and clinical characteristics on the incidence of postoperative wound complication. This study was qualified as exempt by the Mount Sinai Hospital Institutional Review Board. RESULTS: A total of 5803 patients met the criteria for this study. Wound complications occurred in 140 patients (2.4%) and were significantly associated with other adverse outcomes, including higher rates of unplanned reoperation (P < .0001) and prolonged length of stay (P < .0001). Regardless of fusion length, wound complication rates were higher with a posterior approach (short = 2.7%; long = 3.7%) than an anterior one (short = 2.2%; long = 2.7). According to the multivariate analysis, posterior fusion (odds ratio [OR] = 1.8; P = .010), obese class II (OR = 1.7; P = .046), obese class III (OR = 2.8; P < .0001), preoperative blood transfusion (OR = 6.1; P = .021), American Society of Anesthesiologists class >=3 (OR = 1.7; P = .009), and operative time >4 hours (OR = 1.8; P = .006) were statistically significant risk factors for wound complications. CONCLUSION: The 30-day incidence of wound complication in adult spinal deformity surgery is 2.4%. The risk factors for wound complication are multifactorial. This data should provide a step toward developing quality improvement measures aimed at reducing complications in high-risk adults. PMID- 28811986 TI - Elderly Age as a Risk Factor for 30-Day Postoperative Outcomes Following Elective Anterior Cervical Discectomy and Fusion. AB - STUDY DESIGN: Retrospective analysis of prospectively collected data. OBJECTIVE: Anterior cervical discectomy and fusion (ACDF) is one of the most commonly performed spinal procedures. Considering the high success and low complications rate of ACDF and high prevalence of age-related degeneration of the cervical spine, the rates of ACDF are expected to continually rise. The objective is to identify the association between patient age and 30-day postoperative outcomes following elective ACDF. METHODS: The 2010-2014 ACS-NSQIP database was queried using Current Procedural Terminology (CPT) codes 22551 or 22554. Patients were divided into age quartiles (18-45, 46-52, 53-60, and >=61 years). Bivariate and multivariate logistic regression analyses were employed to quantify the increased risk of 30-day postoperative complications in the elderly patient population. RESULTS: A total of 20 563 patients met the inclusion criteria for the study. The analyses found quartile 4 had an increased odds of length of stay (LOS) >=5 days (odds ratio [OR] = 2.05, confidence interval [CI ] = 1.62-2.60), pulmonary complications (OR = 3.25, CI = 1.81-5.84), urinary tract infections (UTI) (OR = 2.25, 1.04-4.87, P = .038), cardiac complication (OR = 6.01, CI = 1.36-26.62, P = .018), and sepsis (OR = 4.38, CI = 1.30-14.70, P = .017). Quartiles 2 and 4 had an increased odds of venous thromboembolism (OR = 3.13, CI = 1.14-8.56, P = .026; OR = 3.83, CI = 1.44-10.20, P = .007). Quartiles 3 and 4 experienced an increased odds of unplanned readmission (OR = 1.44, CI = 1.01-2.05, P = .045; OR = 1.88, CI = 1.33-2.66). All P values are <.001 unless otherwise noted. CONCLUSION: Elderly patients experienced an increased odds of LOS >=5 days, pulmonary complications, cardiac compilations, venous thromboembolism, UTI, sepsis, and unplanned readmission. Identification of these factors can improve the selection of appropriate surgical candidates and postoperative safety. PMID- 28811987 TI - Early Complications and Outcomes in Adult Spinal Deformity Surgery: An NSQIP Study Based on 5803 Patients. AB - STUDY DESIGN: Retrospective analysis. OBJECTIVE: The purpose of this study is to determine the incidence, impact, and risk factors for short-term postoperative complications following elective adult spinal deformity (ASD) surgery. METHODS: Current Procedural Terminology codes were used to query the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) for adults who underwent spinal deformity surgery from 2010 to 2014. Patients were separated into groups of those with and without complications. Univariate analysis and multivariate logistic regression were used to assess the impact of patient characteristics and operative features on postoperative outcomes. RESULTS: In total, 5803 patients were identified as having undergone ASD surgery in the NSQIP database. The average patient age was 59.5 (+/-13.5) years, 59.0% were female, and 81.1% were of Caucasian race. The mean body mass index was 29.5(+/-6.6), with 41.9% of patients having a body mass index of 30 or higher. The most common comorbidities were hypertension requiring medication (54.5%), chronic obstructive pulmonary disease (4.9%), and bleeding disorders (1.2%). Nearly a half of the ASD patients had an operative time >4 hours. The posterior fusion approach was more common (56.9%) than an anterior one (39.6%). The mean total relative value unit was 73.4 (+/-28.8). Based on multivariate analyses, several patient and operative characteristics were found to be predictive of morbidity. CONCLUSION: Surgical correction of ASD is associated with substantial risk of intraoperative and postoperative complications. Preoperative and intraoperative variables were associated with increased morbidity and mortality. This data may assist in developing future quality improvement activities and saving costs through measurable improvement in patient safety. PMID- 28811988 TI - Effect of Preoperative Anemia on the Outcomes of Anterior Cervical Discectomy and Fusion. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: Preoperative anemia has been associated with an increased need for blood transfusions and postoperative complications. The effects of anemia on the outcomes of anterior cervical discectomy and fusion (ACDF) have not been explored. The present study aimed to evaluate the association between preoperative anemia and 30-day complications following ACDF surgery. METHODS: Data from the American College of Surgeons National Surgical Quality Improvement Program (2005-2012) was used. Preoperative anemia was defined as hematocrit <39% for males and <36% for females. A bivariate analysis was performed on demographic and perioperative variables. Multivariable logistic regression models were employed, adjusting for patient variables, to identify independent risk factors for complications. RESULTS: A total of 3500 patients were included of which 444 (12.7%) were anemic patients. Multivariate analysis was used to quantify the predictive power of anemia on key postoperative outcomes, while controlling for the other statistically significant. Preoperative anemia was found to be a statistically significant predictor of any complication (odds ratio [OR] = 1.853; 95% confidence interval [CI] = 1.17-2.934; P = .0086), pulmonary complications (OR = 3.269; 95% CI = 1.745-6.126; P = .0002), intraoperative blood transfusion (OR = 4.364; 95% CI = 1.48-12.866; P = 0.0076), return to operating theatre (OR = 2.655; 95% CI = 1.539-4.582; P = .0005), and length of hospital stay more than 5 days (OR = 2.151; 95% CI = 1.499-3.085; P < .0001). CONCLUSION: Preoperative anemia appears to be a significant predictor of perioperative complications, reoperation, and extended length of hospital stay in patients undergoing elective ACDF. Future studies should explore outcomes of treatment of preoperative anemia prior to surgery to determine the optimal management strategy. PMID- 28811989 TI - Postoperative Kinetics of C-Reactive Protein and Erythrocyte Sediment Rate in One , Two-, and Multilevel Posterior Spinal Decompressions and Instrumentations. AB - STUDY DESIGN: Prospective study. OBJECTIVE: To characterize the normal pattern of kinetics of postoperative C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) after decompression, spinal instrumentation, and posterolateral fusion in 1, 2, and more than 2 levels. METHODS: Blood specimens were obtained from patients who underwent posterior decompression, instrumentation with pedicular screws, and posterolateral fusion from June 2009 to January 2011. CRP and ESR levels were measured on the day before surgery and on postoperative days 1, 3, 7, 11, 14, 28, and 42. RESULTS: Mean CRP levels peaked on the third day postoperatively in all groups. By day 7 postoperatively, it had dropped rapidly. At the 14th and 28th postoperative days, decreases to normal CRP levels were found in 16% and 80% of all patients, respectively. The pattern of decline in CRP was similar among groups. Values of ESR increased and peaked between the third and seventh postoperative days. ESR values gradually decreased. At the 42 day postoperatively, ESR level still remain above normal values in all groups. CONCLUSIONS: We compared conventional operation groups of 1-, 2-, and more than 2 level posterior instrumentation and found no statistically significant differences in the peak of CRP level, the ESR value, and the pattern of decline. CRP levels of 80% of the patients returned to normal within 4 weeks. PMID- 28811990 TI - Clinical Outcomes of Total Disc Replacement Versus Anterior Lumbar Interbody Fusion for Surgical Treatment of Lumbar Degenerative Disc Disease. AB - STUDY DESIGN: The authors performed a retrospective controlled study of patients diagnosed with lumbar degenerative disc disease who received surgical intervention (either total disc replacement [TDR]/Activ-L or anterior lumbar interbody fusion [ALIF]) at a single tertiary-care hospital from 2007-2010. OBJECTIVES: To investigate the clinical outcomes after TDR in comparison with ALIF for surgical treatment of lumbar degenerative disc disease (DDD). METHODS: Analyzed data included intra-operative blood loss, time to return to work, and clinical outcomes as evaluated through the Oswestry Disability Index (ODI) and the Visual Analog Scale (VAS) pain questionnaires pre-operatively and at 6 weeks, 3 months, 6 months, and 1 year postoperative follow-up. RESULTS: At the univariate analysis, patients submitted to TDR presented significantly lower VAS pain scores than patients who received ALIF starting at 6 weeks (P < .001) and continuing through one year postoperatively (P = .007). Patients submitted to TDR also presented significantly lower ODI disability scores at all time points. There was a significant difference in the number of days to return to work, with TDR patients returning to work on average 65 days sooner than ALIF patients (P = .011). There was no significant difference in the total blood loss between both groups. CONCLUSIONS: The results of this retrospective controlled study suggest that, in comparison with patients submitted to ALIF, patients submitted to TDR present quicker return to work, less back pain, and lower disability scores at 1 year follow-up. PMID- 28811991 TI - Systematic Review of the Outcomes of Surgical Treatment of Prostate Metastases to the Spine. AB - STUDY DESIGN: Systematic review. OBJECTIVE: Surgical decompression and reconstruction of symptomatic spinal metastases has improved the quality of life in cancer patients. However, most data has been collected on cohorts of patients with mixed tumor histopathology. We systematically reviewed the literature for prognostic factors specific to the surgical treatment of prostate metastases to the spine. METHODS: A systemic review of the literature was conducted to answer the following questions: Question 1. Describe the survival and functional outcomes of surgery or vertebral augmentation for prostate metastases to the spine. Question 2. Determine whether overall tumor burden, Gleason score, preoperative functional markers, and hormonal naivety favor operative intervention. Question 3. Establish whether clinical outcomes vary with the evolution of operative techniques. RESULTS: A total of 16 studies met the preset inclusion criteria. All included studies were retrospective series with a level of evidence of IV. Included studies consistently showed a large effect of hormone naivety on overall survival. Additionally, studies consistently demonstrated an improvement in motor function and the ability to maintain/regain ambulation following surgery resulting in moderate strength of recommendation. All other parameters were of insufficient or low strength. CONCLUSIONS: There is a dearth of literature regarding the surgical treatment of prostate metastases to the spine, which represents an opportunity for future research. Based on existing evidence, it appears that the surgical treatment of prostate metastases to the spine has consistently favorable results. While no consistent preoperative indicators favor nonoperative treatment, hormone-naivety and high Karnofsky performance scores have positive effects on survival and clinical outcomes. PMID- 28811993 TI - Posterolateral Fusion Versus Interbody Fusion for Degenerative Spondylolisthesis: Systematic Review and Meta-Analysis. AB - STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: Current surgical management of degenerative spondylolisthesis (DS) involves decompression of the spinal canal followed by fusion with or without interbody. The additional functional and operative benefits derived from interbody inclusion has yet to be thoroughly established with a number of recent studies producing conflicting results. Thus, we aim to compare the functional and operative outcomes after fusion against interbody fusion in the treatment of DS. METHODS: This systematic review of the literature comparing posterolateral fusion (PLF) and posterior lumbar interbody fusion (PLIF) outcomes in the treatment of DS was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Electronic searches of 6 databases yielded 386 articles from database inception to July 2016, which were screening against established criteria for inclusion into this study. RESULTS: A total of 6 studies, satisfied criteria and reported outcomes for 721 patients. Fusion alone was performed in 458 (63.5%) patients and interbody fusion was performed in 263 (36.5%) patients. Functional outcomes Oswestry Disability Index (P = .29) and visual analog scale (P = .13) were not statistically different between the 2 approaches. Furthermore, there was no significant inferiority between fusion alone and with interbody in terms of the operative outcomes of blood loss (P = .38), reoperation rate (P = .66), hospital stay (P = .96), complication rate (P = .78), or fusion rate (P = .15). CONCLUSIONS: There was no statistically significant difference in functional and operative outcomes following fusion alone versus with interbody. Additional subgroup analysis of intrinsic DS features in future large, prospective, randomized controlled trials will improve the validity of these findings. PMID- 28811994 TI - The measurement of liver fat from single-energy quantitative computed tomography scans. AB - BACKGROUND: Studies of soft tissue composition using computed tomography (CT) scans are often semi-quantitative and based on Hounsfield units (HU) measurements that have not been calibrated with a quantitative CT (QCT) phantom. We describe a study to establish the water (H2O) and dipotassium hydrogen phosphate (K2HPO4) basis set equivalent densities of fat and fat-free liver tissue. With this information liver fat can be accurately measured from any abdominal CT scan calibrated with a suitable phantom. METHODS: Liver fat content was measured by comparing single-energy QCT (SEQCT) HU measurements of the liver with predicted HU values for fat and fat-free liver tissue calculated from their H2O and K2HPO4 equivalent densities and calibration data from a QCT phantom. The equivalent densities of fat were derived from a listing of its constituent fatty acids, and those of fat-free liver tissue from a dual-energy QCT (DEQCT) study performed in 14 healthy Chinese subjects. This information was used to calculate liver fat from abdominal SEQCT scans performed in a further 541 healthy Chinese subjects (mean age 62 years; range, 31-95 years) enrolled in the Prospective Urban Rural Epidemiology (PURE) Study. RESULTS: The equivalent densities of fat were 941.75 mg/cm3 H2O and -43.72 mg/cm3 K2HPO4, and for fat-free liver tissue 1,040.13 mg/cm3 H2O and 21.34 mg/cm3 K2HPO4. Liver fat in the 14 subjects in the DEQCT study varied from 0-17.9% [median: 4.5%; interquartile range (IQR): 3.0-7.9%]. Liver fat in the 541 PURE study subjects varied from -0.3-29.9% (median: 4.9%; IQR: 3.4-6.9%). CONCLUSIONS: We have established H2O and K2HPO4 equivalent densities for fat and fat-free liver tissue that allow a measurement of liver fat to be obtained from any abdominal CT scan acquired with a QCT phantom. Although radiation dose considerations preclude the routine use of QCT to measure liver fat, the method described here facilitates its measurement in patients having CT scans performed for other purposes. Further studies comparing the results with magnetic resonance (MR) measurements of liver fat are required to validate the method as a useful clinical tool. PMID- 28811992 TI - Analysis of the Literature on Cervical Spine Fractures in Ankylosing Spinal Disorders. AB - STUDY DESIGN: Narrative literature review. OBJECTIVE: The numbers of low-energy cervical fractures seen in patients suffering from ankylosing spondylitis (also known as Bechterew disease) or diffuse idiopathic skeletal hyperostosis (also known as Forestier disease) have greatly increased over recent decades. These fractures tend to be particularly overlooked, leading to delayed diagnosis and secondary neurological deterioration. The aim of the present evaluation was to summarize current knowledge on cervical fractures in patients with ankylosing spinal disorders (ASDs). METHODS: The literature was analyzed through an extensive PubMed search focusing on cervical fractures, especially with delayed diagnosis. RESULTS: In ASDs, it was mainly the cervical spine that was found to be affected by fractures. Fifty percent of ASD patients had neurological deficits at admission, with a high probability of secondary deterioration due to an initially missed diagnosis. Multislice high-resolution imaging techniques should be the radiological standard of care if a vertebral fracture is suspected. Nevertheless, many of these spinal fractures are overlooked, leading to feared secondary deterioration of existing unstable fractures. Long posterior instrumentations were found to be the treatment of choice, followed by anterior and combined anterior-posterior instrumentations. CONCLUSIONS: Delayed diagnosis of cervical fractures in ASDs contributes to initially misinterpreted clinical symptoms, inadequate imaging techniques, and a lack of knowledge about this disease entity due to its peculiarities. Thorough assessment of the patients' neurological morbidity at admission might reduce the occurrence of the associated fractures. The biomechanical behavior of ASD fractures is completely different from that of non-ASD fractures, so that the treatment strategy for these patients should be at least surgical, in combination with long dorsal instrumentations or combined anterior-posterior approaches. PMID- 28811995 TI - Agreement between gamma passing rates using computed tomography in radiotherapy and secondary cancer risk prediction from more advanced dose calculated models. AB - BACKGROUND: During the past decades, in radiotherapy, the dose distributions were calculated using density correction methods with pencil beam as type 'a' algorithm. The objectives of this study are to assess and evaluate the impact of dose distribution shift on the predicted secondary cancer risk (SCR), using modern advanced dose calculation algorithms, point kernel, as type 'b', which consider change in lateral electrons transport. METHODS: Clinical examples of pediatric cranio-spinal irradiation patients were evaluated. For each case, two radiotherapy treatment plans with were generated using the same prescribed dose to the target resulting in different number of monitor units (MUs) per field. The dose distributions were calculated, respectively, using both algorithms types. A gamma index (gamma) analysis was used to compare dose distribution in the lung. The organ equivalent dose (OED) has been calculated with three different models, the linear, the linear-exponential and the plateau dose response curves. The excess absolute risk ratio (EAR) was also evaluated as (EAR = OED type 'b' / OED type 'a'). RESULTS: The gamma analysis results indicated an acceptable dose distribution agreement of 95% with 3%/3 mm. Although, the gamma-maps displayed dose displacement >1 mm around the healthy lungs. Compared to type 'a', the OED values from type 'b' dose distributions' were about 8% to 16% higher, leading to an EAR ratio >1, ranged from 1.08 to 1.13 depending on SCR models. CONCLUSIONS: The shift of dose calculation in radiotherapy, according to the algorithm, can significantly influence the SCR prediction and the plan optimization, since OEDs are calculated from DVH for a specific treatment. The agreement between dose distribution and SCR prediction depends on dose response models and epidemiological data. In addition, the gamma passing rates of 3%/3 mm does not translate the difference, up to 15%, in the predictions of SCR resulting from alternative algorithms. Considering that modern algorithms are more accurate, showing more precisely the dose distributions, but that the prediction of absolute SCR is still very imprecise, only the EAR ratio could be used to rank radiotherapy plans. PMID- 28811996 TI - Experimental method and statistical analysis to fit tumor growth model using SPECT/CT imaging: a preclinical study. AB - BACKGROUND: Over the last decade, several theoretical tumor-models have been developed to describe tumor growth. Oncology imaging is performed using various modalities including computed tomography (CT), magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT) and fluorodeoxyglucose positron emission tomography (FDG-PET). Our goal is to extract useful, otherwise hidden, quantitative biophysical parameters (such as growth-rate, tumor-necrotic factor, etc.) from these serial images of tumors by fitting mathematical models to images. These biophysical features are intrinsic to the tumor types and specific to the study-subject, and expected to add valuable information on the tumor containment or spread and help treatment plans. Thus, fitting realistic but practical models and assessing parameter-errors and degree of fit is important. METHODS: We implemented an existing theoretical ode-compartment model and variants and applied them for the first time, in vivo. We developed an inversion algorithm to fit the models for tumor growth for simulated as well as in vivo experimental data. Serial SPECT/CT scans of mice breast-tumors were acquired, and SPECT data was used to segment the proliferating-layers of tumors. RESULTS: Results of noisy data simulation and inversion show that 5 out of 7 parameters were recovered to within 4.3% error. In particular, tumor "growth-rate" parameter was recovered to 0.07% error. For model fitting to in vivo mice-tumors, regression analysis on the P-layer volume showed R2 of 0.99 for logistic and Gompertzian while surface area model yielded R2=0.96. For the necrotic layer the R2 values were 0.95, 0.93 and 0.94 respectively for surface-area, logistic and Gompertzian. The Akaike Information Criterion (AIC) weights of the models (giving their relative probability of being the best Kullback-Leibler (K-L) model among the set of candidate models) were ~0, 0.43 and 0.57 for surface-area, logistic and Gompertzian models. CONCLUSIONS: Model-fitting to mice tumor studies demonstrates feasibility of applying the models to in vivo imaging data to extract features. Akaike information criterion (AIC) evaluations show Gompertzian or logistic growth model fits in vivo breast-tumors better than surface-area based growth model. PMID- 28811997 TI - Estimation of kidneys and urinary bladder doses based on the region of interest in 18fluorine-fluorodeoxyglucose positron emission tomography/computed tomography examination: a preliminary study. AB - BACKGROUND: Kidneys and urinary bladder are common physiologic uptake sites of 18fluorine-fluorodeoxyglucose (18F-FDG) causing increased exposure of low energy ionizing radiation to these organs. Accurate measurement of organ dose is vital as 18F-FDG is directly exposed to the organs. Organ dose from 18F-FDG PET is calculated according to the injected 18F-FDG activity with the application of dose coefficients established by International Commission on Radiological Protection (ICRP). But this dose calculation technique is not directly measured from these organs; rather it is calculated based on total injected activity of radiotracer prior to scanning. This study estimated the 18F-FDG dose to the kidneys and urinary bladder in whole body positron emission tomography/computed tomography (PET/CT) examination by comparing dose from total injected activity of 18F-FDG (calculated dose) and dose from organs activity based on the region of interest (ROI) (measured dose). METHODS: Nine subjects were injected intravenously with the mean 18F-FDG dose of 292.42 MBq prior to whole body PET/CT scanning. Kidneys and urinary bladder doses were estimated by using two approaches which are the total injected activity of 18F-FDG and organs activity concentration of 18F-FDG based on drawn ROI with the application of recommended dose coefficients for 18F-FDG described in the ICRP 80 and ICRP 106. RESULTS: The mean percentage difference between calculated dose and measured dose ranged from 98.95% to 99.29% for the kidneys based on ICRP 80 and 98.96% to 99.32% based on ICRP 106. Whilst, the mean percentage difference between calculated dose and measured dose was 97.08% and 97.27% for urinary bladder based on ICRP 80 while 96.99% and 97.28% based on ICRP 106. Whereas, the range of mean percentage difference between calculated and measured organ doses derived from ICRP 106 and ICRP 80 for kidney doses were from 17.00% to 40.00% and for urinary bladder dose was 18.46% to 18.75%. CONCLUSIONS: There is a significant difference between calculated dose and measured dose. The use of organ activity estimation based on drawn ROI and the latest version of ICRP 106 dose coefficient should be explored deeper to obtain accurate radiation dose to patients. PMID- 28811998 TI - Paracoccidioidomycosis: level of pulmonary sequelae in high resolution computed tomography images from patients of two endemic regions of Brazil. AB - BACKGROUND: The purpose of the present study was to evaluate differences in lung damage in patients with paracoccidioidomycosis (PCM) in two endemic regions of Brazil (Botucatu, SP, in the southeastern region and Campo Grande, MS, in the west central region). METHODS: The study sought to objectively quantify fibrosis and emphysema treated patients using high-resolution computed tomography (HRCT) that was performed according to an established and validated computational method. The analysis was based on clinical data that were associated with objective quantifications of pulmonary sequelae. We performed a retrospective analysis of HRCT exams from 32 successfully treated patients with the chronic form of PCM. The two groups had similar characteristics with regard to age, symptom duration, smoking history, and titers on a diagnostic serologic test. RESULTS: The statistical analysis revealed more severe cases and a higher percentage of emphysema in the Campo Grande group. The mean percentages of emphysema were 40.2% and 13.6% in the Campo Grande and Botucatu groups, respectively. The percentage of fibrosis was significantly higher in the Botucatu group (11.3%) than in the Campo Grande group (2.3%). CONCLUSIONS: The present results may reflect differences in cryptic species of P. brasiliensis in these two geographic regions of Brazil. Further studies should be done to clarify the differences observed herein. Such findings may help unveil differences among cryptic species in terms of the pulmonary consequences that are caused by this disease, which would be highly beneficial to PCM patients. PMID- 28811999 TI - Quantitative analysis of epicardial fat volume: effects of scanning protocol and reproducibility of measurements in non-contrast cardiac CT vs. coronary CT angiography. AB - BACKGROUND: Several studies have focused on the role of epicardial fat in the pathogenesis of cardiovascular disease (CVD). The main purpose of the study was to evaluate a computerized method for the quantitative analysis of epicardial fat volume (EFV) by non-contrast cardiac CT (NCT) for coronary calcium scan and coronary CT angiography (coronary CTA). METHODS: Thirty patients (61+/-12.5 years, 73% male, body mass index (BMI) =25.9+/-6.3 kg/m2) referred to our Institution for suspected coronary artery disease (CAD) underwent NCT and coronary CTA. Epicardial boundaries were traced by 2 experienced operators (operator 1, operators 2) on 3 and 6 short-axis (SA) slices. EFV was computed with a semi-automatic method using an in-house developed software based on spherical harmonic representation of the epicardial surface. In order to analyze the inter-observer variability both the Coefficient of Repeatability (CR) and Intra Class Correlation (ICC) were computed. RESULTS: The total EFV was 103.62+/ 50.97 and 94.96+/-67.91 cc in NCT and coronary CTA with non-significant difference (P=0.292). CR error was 10.22 cc for operator 1 and 11.31 cc for operator 2 in NCT and 7.99 cc for operator 1 and 7.75 cc for operator 2 in coronary CTA. To analyze the inter-observer variability CR and ICC were computed. CR was 8.17 and 8.39 cc with NCT and 7.07 and 7.21 cc with CTA for 6 and 3 SA slices respectively. ICC values >0.99 were obtained in all cases. The right ventricular EFV was 67.23+/-31.4 and 57.41+/-34.3 cc for NCT and coronary CTA respectively; the corresponding values for left ventricular EFV were 38.01+/-19.1 and 35.27+/-25.9 cc. CONCLUSIONS: Both NCT and coronary CTA can be used with low intra- and inter-observer variability for computer-assisted measurements of EFV. Cardiac CT may allow a fast and reliable computation of EFV in clinical setting. PMID- 28812000 TI - Diagnostic imaging features of necrotizing enterocolitis: a narrative review. AB - Necrotizing enterocolitis (NEC) is an inflammatory process, characterized by intestinal necrosis of variable extension, leading to perforation, generalized peritonitis and death. The classical pathogenetic theory focuses on mucosal damage related to a stress induced intestinal ischemia leading to mucosal injury and bacterial colonization of the wall. A more recent hypothesis emphasizes the role of immaturity of gastrointestinal and immune system, particularly of the premature, responsible of bowel wall vulnerability and suffering. NEC is the most common gastrointestinal emergency in the newborn, with a higher incidence in the preterm; improvement of neonatal resuscitation techniques enables the survival of premature of very low birth weight (VLBW) with prolongation of hospital stay for perinatal and neonatal care and a higher risk of NEC. Clinical presentation of NEC in newborn ranges from mild forms with moderate gastrointestinal tract disorder and that can heal spontaneously, to very serious forms with fulminant course characterized by perforation, peritonitis, sepsis, disseminated intravascular coagulation (DIC) and shock. Imaging modality in the diagnosis of NEC is historically represented by the plain-film abdominal radiographs which can be performed every 6 hours because of the rapid evolution that may occur in the patient's clinical condition. However ultrasound (US), in recent years, is playing an increasingly important role in the evaluation of early stages of the disease as it provides images in real time of the abdominal structures being able to assess the presence and validity of peristalsis of the bowel loops, detect the thickness of the intestinal wall and the presence of minimal amounts of fluid in the peritoneal cavity. In this paper we review the pathogenesis, clinical presentation and imaging of NEC with a particular attention to the emergent role of US in the diagnosis of the disease. PMID- 28812001 TI - Recent advances in terahertz technology for biomedical applications. AB - Terahertz instrumentation has improved significantly in recent years such that THz imaging systems have become more affordable and easier to use. THz systems can now be operated by non-THz experts greatly facilitating research into many potential applications. Due to the non-ionising nature of THz light and its high sensitivity to soft tissues, there is an increasing interest in biomedical applications including both in vivo and ex vivo studies. Additionally, research continues into understanding the origin of contrast and how to interpret terahertz biomedical images. This short review highlights some of the recent work in these areas and suggests some future research directions. PMID- 28812003 TI - Imaging evaluation of catheter integrity prevent potentially fatal complication of pinch-off syndrome: illustration of two cases. PMID- 28812002 TI - Image-guided thermal ablation with MR-based thermometry. AB - Thermal ablation techniques such as radiofrequency, microwave, high intensity focused ultrasound (HIFU) and laser have been used as minimally invasive strategies for the treatment of variety of cancers. MR thermometry methods are readily available for monitoring thermal distribution and deposition in real time, leading to decrease of incidents of normal tissue damage around targeted lesion. HIFU and laser-induced thermal therapy (LITT) are the two widely accepted tumor ablation techniques because of their compatibility with MR systems. MRI provides multiple temperature dependent parameters for thermal imaging, such as signal intensity, T1, T2, diffusion coefficient, magnetization transfer, proton resonance frequency shift (PRFS, including phase imaging and spectroscopy) as well as frequency shift of temperature sensitive contrast agents. Absolute temperature mapping techniques, including both spectroscopic imaging using metabolites as a reference and phase imaging using fat as a reference, are immune to susceptibility effects and are not dependent on phase differences. These techniques are intrinsically more reliable than relative temperature measurement by phase mapping methods. If the limitation of low temporal and spatial resolution could be overcome, these methods may be preferred for MR-guided thermal ablation systems. As of today, the most popular MR thermal imaging method applied in tumor thermal ablation surgery is, however, still PRFS based phase mapping technique, which only provides relative temperature change and is prone to motion artifacts. PMID- 28812004 TI - Orbitofrontal cholesterol granuloma: case report and review of the literature. PMID- 28812005 TI - Left ventricular 'rigid body rotation' in a patient with acromegaly (from the MAGYAR-Path Study). PMID- 28812006 TI - Main pulmonary artery trifurcation in association with persistent right common pulmonary vein: a piece of embryological puzzle. PMID- 28812007 TI - Erratum to a comprehensive literatures update of clinical researches of superparamagnetic resonance iron oxide nanoparticles for magnetic resonance imaging. AB - [This corrects the article DOI: 10.21037/qims.2017.02.09.]. PMID- 28812008 TI - Evaluation of Adrenal Function in Nonhospitalized Patients with Cirrhosis. AB - BACKGROUND: Patients with cirrhosis and advancing hepatic insufficiency may show various degrees of other organ malfunction, including brain, kidney, and lung. Several studies have also shown a high prevalence of adrenal insufficiency in cirrhotic patients that may cause hemodynamic instability. MATERIALS AND METHODS: In this study we prospectively evaluated adrenal function in a population of nonhospitalized cirrhotic patients. Categorization of liver disease severity was done according to model for end-stage liver disease (MELD) score. Adrenocorticotropic hormone stimulation testing was performed on subjects using 250 MUg of synthetic short acting hormone; radio immunoassay was used to measure plasma cortisol levels. RESULTS: Of 105 cirrhotic patients, 15.23% had evidence of adrenal insufficiency. These patients were not statistically different from those with normal adrenal function in levels of serum creatinine or bilirubin, MELD score, or presence of cirrhosis related complications. Significant differences were seen in mean international normalized ratio and serum sodium. Patients with a sodium level < 135 mEq/L had a higher rate (31.25%) of adrenal insufficiency. CONCLUSION: Adrenal dysfunction was identified in a population of stable nonhospitalized cirrhotic patients. Our results suggest a possible role for adrenal dysfunction as a contributing factor in hyponatremia in cirrhosis independent of other known factors of neurohormonal activation secondary to systemic vasodilation. PMID- 28812009 TI - The Bacteriological Quality, Safety, and Antibiogram of Salmonella Isolates from Fresh Meat in Retail Shops of Bahir Dar City, Ethiopia. AB - The habit of raw meat consumption in addition to the poor hygienic standards and lack of knowledge contribute to food-borne diseases outbreaks. The objective of this research was to assess the bacterial quality and safety of fresh meat from retail Bahir Dar City, Ethiopia. A total of 30 fresh meat samples were collected from butcher shops. Standard bacteriological methods were used to isolate and enumerate bacteria. Kirby-Bauer disk diffusion method was used for antimicrobial susceptibility testing of Salmonella isolates. The mean counts of AMB, TC, and S. aureus were log104.53, 3.97, and 3.88 log10cfu/g, respectively. Salmonella was isolated from 21 (70%) of the samples. Salmonella isolates in this study were highly susceptible to ciprofloxacin, gentamycin, and norfloxacin while they were resistant to erythromycin and tetracycline. High rate of multiple drug resistance was also noticed in Salmonella isolates. The microbial loads of meat were above the recommended microbial safety limits. Besides this, the isolation rate of Salmonella was high and high levels of drug resistance were documented for Salmonella isolates. Measures on handling and appropriate personal hygiene practices of workers in the retail shops are recommended to reduce the change of forborne disease outbreaks. PMID- 28812010 TI - The Diagnostic Accuracy of Ultrasound in Assessment of Myometrial Invasion in Endometrial Cancer: Subjective Assessment versus Objective Techniques. AB - The aim of this study was to assess the diagnostic accuracy of subjective ultrasound evaluation of myometrial invasion of endometrial cancer and to compare its accuracy to objective methods. All consecutive patients with histologically proven endometrial cancer, who underwent ultrasound evaluation followed by surgical staging between January 2009 and December 2011, were prospectively enrolled. Myometrial invasion was evaluated by subjective assessment using ultrasound (<50% or >=50%) and calculated as deepest invasion/normal myometrium ratio (Gordon's ratio) and as tumor/uterine anteroposterior diameter ratio (Karlsson's ratio). Histological assessment from hysterectomy was considered the gold standard. Altogether 210 patients were prospectively included. Subjective assessment and two objective ratios were found to be statistically significant predictors of the myometrial invasion (AUC = 0.65, p value < 0.001). Subjective assessment was confirmed as the most reliable method to assess myometrial invasion (79.3% sensitivity, 73.2% specificity, and 75.7% overall accuracy). Deepest invasion/normal myometrium (Gordon's) ratio (cut-off 0.5) reached 69.6% sensitivity, 65.9% specificity, and 67.3% overall accuracy. Tumor/uterine anteroposterior diameter (Karlsson's) ratio with the same cut-off reached 56.3% sensitivity, 76.4% specificity, and 68.1% overall accuracy. The subjective ultrasound evaluation of myometrial invasion performed better than objective methods in nearly all measures but showed statistically significantly better outcomes only in case of sensitivity. PMID- 28812011 TI - Oil Characterization and Lipids Class Composition of Pomegranate Seeds. AB - This study aims to investigate the physicochemical characteristics, phenolics content, and oil composition of pomegranate oil seeds (PSO). Quality indices, pigments, phenolics content, and antioxidant activity were determined. PSO was fractioned into polar lipids: glycolipids (GL) and phospholipids (PL). Sterols profile and fatty acids composition of total lipids (TL), GL, and PL were determined by GC/FID. The free acidity, the peroxide value, and the specific extinction coefficients were, respectively, 1.69%, 3.42 in milliequivalents of active oxygen per kilogram of oil, 4.15, and 3.95. PSO is rich in phenols (93.42 mg/Kg) but poor in pigments. The sterols markers were beta-sitosterol (77.94%), Delta5-avenasterol (7.45%), and campesterol (6.35%). Oil content was 12.2%, wherein 23.9% were GL and 24.35% were PL. TL were rich in unsaturated fatty acids (63.17%), while saturated fatty acids were more present in PL and GL (71.97% and 66.29%, resp.). Conjugated fatty acids were about 13.30%, 2.03%, and 4.91%, respectively, in TL, PL, and GL. The cis/trans ratio of TL, PL, and GL was, respectively, 49.82%, 42.91%, and 27.39%. Monounsaturated fatty acids were more bound in PL, whereas polyunsaturated fatty acids were more bound in GL. PSO is a good source of essential fatty acids, phenolics compounds, phytosterols, and lipid-soluble fractions. PMID- 28812012 TI - Spinal Cord Injury due to Tumour or Metastasis in Aragon, Northeastern Spain (1991-2008): Incidence, Time Trends, and Neurological Function. AB - PURPOSE: Understanding the presentation of spinal cord injury (SCI) due to tumours considering population distribution and temporal trends is key to managing SCI health services. This study quantified incidence rates, function scores, and trends of SCI due to tumour or metastasis over an 18-year time period in a defined region in Spain. METHODS: A retrospective cohort study included in and outpatients with nontraumatic SCI due to tumour or metastasis admitted to a metropolitan hospital in Spain between 1991 and 2008. Main outcome measures were crude and age- and sex-adjusted incidence rates, tumour location and type, distribution by spinal level, neurological level of injury, and impairment ASIA scores. RESULTS: Primary tumour or metastasis accounted for 32.5% of nontraumatic SCI with an incidence rate of 4.1 per million population. Increasing rates with age and over time were observed. Major pathology groups were intradural extramedullary masses from which meningiomas and neurinomas accounted for 40%. Lesions were mostly incomplete with predominant ASIA Grade D. CONCLUSIONS: Increasing incidence rates of tumour-related SCI over time in the middle-aged and the elderly suggest a growing need for neurooncology health resources in the future. PMID- 28812013 TI - Intelligent Techniques Using Molecular Data Analysis in Leukaemia: An Opportunity for Personalized Medicine Support System. AB - The use of intelligent techniques in medicine has brought a ray of hope in terms of treating leukaemia patients. Personalized treatment uses patient's genetic profile to select a mode of treatment. This process makes use of molecular technology and machine learning, to determine the most suitable approach to treating a leukaemia patient. Until now, no reviews have been published from a computational perspective concerning the development of personalized medicine intelligent techniques for leukaemia patients using molecular data analysis. This review studies the published empirical research on personalized medicine in leukaemia and synthesizes findings across studies related to intelligence techniques in leukaemia, with specific attention to particular categories of these studies to help identify opportunities for further research into personalized medicine support systems in chronic myeloid leukaemia. A systematic search was carried out to identify studies using intelligence techniques in leukaemia and to categorize these studies based on leukaemia type and also the task, data source, and purpose of the studies. Most studies used molecular data analysis for personalized medicine, but future advancement for leukaemia patients requires molecular models that use advanced machine-learning methods to automate decision-making in treatment management to deliver supportive medical information to the patient in clinical practice. PMID- 28812014 TI - Surgical Approach May Influence Survival of Large-Diameter Head Metal-on-Metal Total Hip Arthroplasty: A 6- to 10-Year Follow-Up Study. AB - Large-diameter head (LDH) metal-on-metal (MoM) total hip arthroplasty (THA) has lost popularity because of metal allergy or ALTRs (adverse local tissue reactions) in the past decade. Whether the surgical approach may influence the survival of LDH-MoM-THA has not been reported. From 2006 to 2009, we performed 96 LDH-MoM-THAs on 80 patients using an in situ head-neck assembly technique through a modified Watson-Jones approach. With a mean follow-up of 8.4 years (range, 6.3 10.1 years), the implant survival rate was 100%. All patients were satisfied with the results and the Harris Hip Score improved from 52 points to 98 points. No ALTRs were found, but 17.7% of the 96 hips (17 adverse events) experienced adverse events related to the cup, including 5 cases of outlier cup malposition, 11 cases of inadequate cup seating, and 1 acetabular fracture. The tissue tension that was improved by a muscle-sparing approach might lessen the chance of microseparation or edge-loading that is taken as the major risk for early implant failure. Further investigation of whether these LDH-MoM-THAs would fail or not would require a longer follow-up or even retrieval analysis in the future. PMID- 28812015 TI - MRI Texture Analysis of Background Parenchymal Enhancement of the Breast. AB - PURPOSE: The purpose of this study was to determine texture parameters reflecting the background parenchymal enhancement (BPE) of the breast, which were acquired using texture analysis (TA). METHODS: We investigated 52 breasts of the 26 subjects who underwent dynamic contrast-enhanced MRI. One experienced reader scored BPE visually (i.e., minimal, mild, moderate, and marked). TA, including 12 texture parameters, was performed to distinguish the BPE scores quantitatively. Relationships between the visual BPE scores and texture parameters were evaluated using analysis of variance and receiver operating characteristic analysis. RESULTS: The variance and skewness of signal intensity were useful for differentiating between moderate and mild or minimal BPE or between mild and minimal BPE, respectively, with the cutoff value of 356.7 for variance and that of 0.21 for skewness. Some TA features could be useful for defining breast lesions from the BPE. CONCLUSION: TA may be useful for quantifying the BPE of the breast. PMID- 28812016 TI - Syntool: A Novel Region-Based Intolerance Score to Single Nucleotide Substitution for Synonymous Mutations Predictions Based on 123,136 Individuals. AB - BACKGROUND: Synonymous mutation is the single nucleotide change that does not cause an amino acid change but can affect the rate and efficiency of translation. So recent increase in our knowledge has revealed a substantial contribution of synonymous mutations to human disease risk and other complex traits. Nevertheless, there are still rarely synonymous mutation prediction methods. METHODS: Nonsynonymous and synonymous coding SNPs show similar likelihood and effect size of human disease association. Here we defined synonymous and missense variation as single nucleotide substitution variation. And then we evaluated the intolerance of genic transcripts to single nucleotide substitution variation based on gnomAD 123136 individuals. After regressing all variations on common variations, we defined residuals of regression model as every genomics region intolerance scores. RESULTS: We constructed a total of 24799 nonoverlapped region based intolerance score by their intolerance to single nucleotide substitution variation (Syntool). The results show that Syntool score can discriminate synonymous disease causing mutations in Human Gene Mutation Database (HGMD Professional) and ClinVar database much better than others. Taken together, this study provides a novel prediction system for synonymous mutations, called Syntool, which could be helpful in identifying candidate synonymous disease causing mutations. PMID- 28812018 TI - Effects of Fungicides on Rat's Neurosteroid Synthetic Enzymes. AB - Exposure to environmental endocrine disruptors may interfere with nervous system's activity. Fungicides such as tebuconazole, triadimefon, and vinclozolin have antifungal activities and are used to prevent fungal infections in agricultural plants. In the present study, we studied effects of tebuconazole, triadimefon, and vinclozolin on rat's neurosteroidogenic 5alpha-reductase 1 (5alpha-Red1), 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD), and retinol dehydrogenase 2 (RDH2). Rat's 5alpha-Red1, 3alpha-HSD, and RDH2 were cloned and expressed in COS-1 cells, and effects of these fungicides on them were measured. Tebuconazole and triadimefon competitively inhibited 5alpha-Red1, with IC50 values of 8.670 +/- 0.771 * 10-6 M and 17.390 +/- 0.079 * 10-6 M, respectively, while vinclozolin did not inhibit the enzyme at 100 * 10-6 M. Triadimefon competitively inhibited 3alpha-HSD, with IC50 value of 26.493 +/- 0.076 * 10-6 M. Tebuconazole and vinclozolin weakly inhibited 3alpha-HSD, with IC50 values about 100 * 10-6 M, while vinclozolin did not inhibit the enzyme even at 100 * 10-6 M. Tebuconazole and triadimefon weakly inhibited RDH2 with IC50 values over 100 * 10 6 M and vinclozolin did not inhibit this enzyme at 100 * 10-6 M. Docking study showed that tebuconazole, triadimefon, and vinclozolin bound to the steroid binding pocket of 3alpha-HSD. In conclusion, triadimefon potently inhibited rat's neurosteroidogenic enzymes, 5alpha-Red1 and 3alpha-HSD. PMID- 28812017 TI - Valve Calcification in Aortic Stenosis: Etiology and Diagnostic Imaging Techniques. AB - Aortic stenosis is the most common valvulopathy in the Western world. Its prevalence has increased significantly in recent years due to population aging; hence, up to 8% of westerners above the age of 84 now have severe aortic stenosis (Lindroos et al., 1993). This causes increased morbidity and mortality and therein lies the importance of adequate diagnosis and stratification of the degree of severity which allows planning the best therapeutic option in each case. Long understood as a passive age-related degenerative process, it is now considered a rather more complex entity involving mechanisms and factors similar to those of atherosclerosis (Stewart et al., 1997). In this review, we summarize the pathophysiological mechanisms underlying the onset and progression of the disease and analyze the current role of cardiac imaging techniques for diagnosis. PMID- 28812019 TI - Whole-Body SPECT/CT versus Planar Bone Scan with Targeted SPECT/CT for Metastatic Workup. AB - PURPOSE: The use of SPECT/CT in bone scans has been widespread in recent years, but there are no specific guidelines concerning the optimal acquisition protocol. Two strategies have been proposed: targeted SPECT/CT for equivocal lesions detected on planar images or systematic whole-body SPECT/CT. Our aim was to compare the diagnostic accuracy of the two approaches. METHODS: 212 consecutive patients with a history of cancer were referred for bone scans to detect bone metastases. Two experienced readers randomly evaluated for each patient either planar images with one-field SPECT/CT targeted on equivocal focal uptakes (targeted SPECT/CT) or a whole-body (two-field) SPECT/CT acquisition from the base of the skull to the proximal femurs (whole-body SPECT/CT). The exams were categorized as "nonmetastatic," "equivocal," or "metastatic" on both protocols. The presence or absence of any extra-axial skeletal lesions was also assessed. The sensitivity and specificity of both strategies were measured using the results of subsequent imaging follow-up as the reference standard. RESULTS: Whole body SPECT/CT had a significantly higher sensitivity than targeted SPECT/CT to detect bone metastases (p = 0.0297) and to detect extra-axial metastases (p = 0.0266). There was no significant difference in specificity among the two approaches. CONCLUSION: Whole-body SPECT/CT is the optimal modality of choice for metastatic workup, including detection of extra-axial lesions, with improved sensitivity and similar specificity compared to targeted SPECT/CT. PMID- 28812020 TI - Pretreatment Serum Cystatin C Levels Predict Renal Function, but Not Tumor Characteristics, in Patients with Prostate Neoplasia. AB - To evaluate the role of Cystatin C (Cys-C) in tumorigenesis and progression of prostate cancer (PCa), we retrospectively collected the clinical information from the records of 492 benign prostatic hyperplasia (BPH), 48 prostatic intraepithelial neoplasia (PIN), and 173 PCa patients, whose disease was newly diagnosed and histologically confirmed. Pretreatment serum Cys-C levels were compared across the various groups and then analyzed to identify relationships, if any, with clinical and pathological characteristics of the PCa patient group. There were no significant differences in serum Cys-C levels among the three groups (P > 0.05). In PCa patients with normal SCr levels, patient age was correlated with serum Cys-C level (P <= 0.001) but did not correlate with alkaline phosphatase (AKP), lactate dehydrogenase (LDH), prostate specific antigen (PSA), Gleason score, or bone metastasis status (P > 0.05). Age and SCr contributed in part to the variations in serum Cys-C levels of PCa patients (r = 0.356, P <= 0.001; r = 0.520, P <= 0.001). In conclusion, serum Cys-C levels predict renal function in patients with prostate neoplasia, but were not a biomarker for the development of prostate neoplasia, and were not correlated with the clinicopathological characteristics of PCa. PMID- 28812021 TI - Association Analysis of Arsenic-Induced Straighthead in Rice (Oryza sativa L.) Based on the Selected Population with a Modified Model. AB - A rice physiological disorder makes mature panicle keep erect with empty grains termed as "straighthead." Straighthead causes yield losses and is a serious threat to rice production worldwide. Here, a new study of association mapping was conducted to identify QTL involved in straighthead. A subset of 380 accessions was selected from the USDA rice core collection and genotyped with 72 genome-wide SSR markers. An optimal model implemented with principle components (PCs) was used in this association mapping. As a result, five markers were identified to be significantly associated with straighthead. Three of them, RM263, RM169, and RM224, were consistent with a previous study. Three markers, RM475, RM263, and RM19, had a resistant allele associated with a decrease in straighthead rating (straighthead rating <= 4.8). In contrast, the two other marker loci RM169 and RM224 had a few susceptible alleles associated with an increase in straighthead rating (straighthead rating >= 8.7). Interestingly, RM475 is close to QTL "qSH-2" and "AsS" with straighthead resistance, which was reported in two studies on linkage mapping of straighthead. This finding adds to previous work and is useful for further genetic study of straighthead. PMID- 28812022 TI - Histopathologic Differences between Jewish and Arab Population in Israel at First Time Presentation with Bladder Cancer. AB - BACKGROUND: Pathology of urothelial carcinoma may vary in different populations at diagnosis. Our aim was to evaluate the histopathologic differences between Jewish and Arab patients in Israel at first diagnosis of urothelial cancer. PATIENTS AND METHODS: We retrospectively collected data of all patients with confirmed urothelial cancer, treated at our department between January 2010 and January 2015. We examined the distribution of the histopathologic data among the studied populations. To compare the categorical variables we used the Chi-Square Pearson test. Comparison of independent variables was made by Student's t-test. P value below 0.05 was considered significant. RESULTS: The study group included 413 patients, 345 Jews and 68 Arabs. The major differences were that Arab patients were younger (62.61 versus 68.55 years, P = 0.001), had more aggressive tumors that were detected at a more advanced stage, and had also a higher rate of metastatic disease (7.4% versus 3.2%, P = 0.05). Nonurothelial cell tumors were 2.3 times more prevalent in Arab population. Unlike Jewish population, Arab women had higher rate of invasive/metastatic disease compared with Arab men (40% versus 22.4%). CONCLUSION: At time of diagnosis the tumors were more aggressive in Arab patients, especially in Arab women. The reasons for those differences constitute a target for a separate research. These results should have an impact on prevention medicine and education of physicians treating mixed populations. PMID- 28812023 TI - Use of a Polyethylene Bag to Reduce Perioperative Regional and Whole-Body Heat Losses in Low-Birth-Weight Neonates. AB - In the delivery room, wrapping a low-birth-weight neonate (defined as <=2.499 g) in a polyethylene bag reduces the risk of hypothermia. However, extended use of the bag (e.g., during neonatal surgery) might conceivably increase the risk of thermal stress and thus body overheating. Here, we assessed the efficacy of a polyethylene bag in infants assigned to wrap (W) or nonwrap (NW, control) groups during placement of a percutaneous vena cava catheter by applying a new mathematical model that calculates heat exchanges for covered and uncovered body segments. At the end of the placement procedure, the W and NW groups did not differ significantly in terms of whole-body heat loss (15.80 versus 14.97 kJ.h 1.kg-1, resp.), whereas the abdominal skin temperature was slightly but significantly higher (by 0.32 degrees C) in the W group. Greater evaporation in the W group (2.49 kJ.h-1.kg-1) was primarily balanced by greater whole-body radiant heat loss (3.44 kJ.h-1.kg-1). Wrapping the neonate in a polyethylene bag provides a small thermal benefit when catheter placement takes a long time. Given that polyethylene is transparent to radiant energy, it might be of value to incorporate polymers that are less transparent at infrared wavelengths. PMID- 28812024 TI - Influence of Human Papillomavirus Infection on the Natural History of Cervical Intraepithelial Neoplasia 1: A Meta-Analysis. AB - OBJECTIVE: To provide a scientific basis for the prevention and treatment of cervical intraepithelial neoplasia grade 1 (CIN1). This study evaluated the impact of human papillomavirus (HPV) infection on the natural history of CIN1. METHODS: Electronic databases of Cochrane Library, EMBASE, PubMed, CNKI, CBM, and Wanfang were searched in April 2016. The eligibility criteria were documented by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We used the Newcastle-Ottawa scale (NOS) to assess study quality. RESULTS: Thirty eight studies out of 3,246 identified papers were eligible for inclusion. The risk of CIN1 progression (relative risk [RR]: 3.04; 95% confidence interval [CI]: 2.41-3.83; P < 0.00001) and persistence (RR: 1.48; 95% CI: 1.17-1.87; P = 0.001) was higher in the HPV-positive group than HPV-negative group. Specifically, the risk of CIN1 progression (RR: 13.91; 95% CI: 3.46-55.90; P = 0.000) was higher among persistent high-risk HPV-positive patients and the ratio of CIN1 regression (RR: 0.65; 95% CI: 0.59-0.71; P < 0.00001) was lower in the HPV-positive group than HPV-negative group. CONCLUSION: HPV infection resulted in an increased risk of CIN1 progression and decreased disease reversibility. Persistent high-risk HPV infection resulted in a further increased risk of CIN1 progression. PMID- 28812025 TI - Baseline Characteristics of the Paediatric Observation Priority Score in Emergency Departments outside Its Centre of Derivation. AB - OBJECTIVES AND BACKGROUND: Scoring systems in Emergency Departments (EDs) are rarely validated. This study aimed to examine the Paediatric Observation Priority Score (POPS), a method of quantifying patient acuity, in EDs in the United Kingdom, and determine baseline performance characteristics. METHODS: POPS was implemented in 4 EDs for children (ages of 0 to 16) with participants grouped into 3 categories: discharged from ED, discharged but with return within 7 days, and admitted for less or more than 24 hours. RESULTS: 3323 participants with POPS scores ranging from 0 to 11 (mean = 2.33) were included. The proportion of each POPS score varied between sites with approximately 10-20% being POPS 0 and 12-25% POPS greater than 4. Odds ratio of readmission with POPS 5-9 against 0-4 was 2.05 (CI 1.20 to 3.52). POPS 0-4 showed no significant difference (p = 0.93) in relation to admission/discharge rates between sites with a significant difference found (p < 0.01) for POPS > 5. CONCLUSION: It is feasible to implement POPS into EDs with similar performance characteristics to the original site of development. There is now evidence to support a wider health service evaluation to refine and improve the performance of POPS. PMID- 28812026 TI - Evidence of Immunosuppressive and Th2 Immune Polarizing Effects of Antidiabetic Momordica charantia Fruit Juice. AB - The mechanism of action of the antidiabetic capacity of Momordica charantia is still under investigation. Here, we assessed phytochemical compositions, antioxidant activity, and effects of total and filtered fruit and leafy stem juices of Momordica charantia on human T cell proliferation and differentiation through quantification of Th1/Th2 cytokines. In the absence of stimulation, total fruit and leafy stem juices induced significant T cell proliferation. Under PHA stimulation, both juices potentiated plant-induced T cell proliferation. However, the filtered fruit and leafy stem juices significantly inhibited PHA-stimulated T cell proliferation, while neither juice influenced T cell proliferation. Moreover, total and filtered fruit juice increased IL-4 secretion, while total and filtered leafy stem juice enhanced IFN-gamma production. Phytochemical screening revealed the presence of tannins, flavonoids, anthocyans, steroids, and triterpenoids in both juices. Alkaloids, quinone derivatives, cardenolides, and cyanogenic derivatives were undetectable. The saponins present in total juices were undetectable after filtration. Moreover, both juices had appreciable antioxidant capacity. Our study supports the type 1 antidiabetic effect of filtered fruit juice of M. charantia which may be related to its immunosuppressive and T-helper 2 cell inducing capacities. Due to their immune stimulatory activities and their ability to increase T-helper 1 cell cytokines, total fruit and leafy stem juices may serve in the treatment of immunodeficiency and certain infections. PMID- 28812027 TI - L-Theanine Administration Modulates the Absorption of Dietary Nutrients and Expression of Transporters and Receptors in the Intestinal Mucosa of Rats. AB - L-theanine has various advantageous functions for human health; whether or not it could mediate the nutrients absorption is unknown yet. The effects of L-theanine on intestinal nutrients absorption were investigated using rats ingesting L theanine solution (0, 50, 200, and 400 mg/kg body weight) per day for two weeks. The decline of insulin secretion and glucose concentration in the serum was observed by L-theanine. Urea and high-density lipoprotein were also reduced by 50 mg/kg L-theanine. Jejunal and ileac basic amino acids transporters SLC7a1 and SLC7a9, neutral SLC1a5 and SLC16a10, and acidic SLC1a1 expression were upregulated. The expression of intestinal SGLT3 and GLUT5 responsible for carbohydrates uptake and GPR120 and FABP2 associated with fatty acids transport were inhibited. These results indicated that L-theanine could inhibit the glucose uptake by downregulating the related gene expression in the small intestine of rats. Intestinal gene expression of transporters responding to amino acids absorption was stimulated by L-theanine administration. PMID- 28812028 TI - Expression Profile of Genes Potentially Associated with Adequate Glycemic Control in Patients with Type 2 Diabetes Mellitus. AB - Despite increasing research in type 2 diabetes mellitus (T2D), there are few studies showing the impact of the poor glycemic control on biological processes occurring in T2D. In order to identify potential genes related to poorly/well controlled patients with T2D, our strategy of investigation included a primary screen by microarray (Human Genome U133) in a small group of individuals followed by an independent validation in a greater group using RT-qPCR. Ninety patients were divided as follows: poorly controlled T2D (G1), well-controlled T2D (G2), and normoglycemic individuals (G3). After using affy package in R, differentially expressed genes (DEGs) were prospected as candidate genes potentially relevant for the glycemic control in T2D patients. After validation by RT-qPCR, the obtained DEGs were as follows-G1 + G2 versus G3: HLA-DQA1, SOS1, and BRCA2; G2 versus G1: ENO2, VAMP2, CCND3, CEBPD, LGALS12, AGBL5, MAP2K5, and PPAP2B; G2 versus G3: HLA-DQB1, MCM4, and SEC13; and G1 versus G3: PPIC. This demonstrated a systemic exacerbation of the gene expression related to immune response in T2D patients. Moreover, genes related to lipid metabolisms and DNA replication/repair were influenced by the glycemic control. In conclusion, this study pointed out candidate genes potentially associated with adequate glycemic control in T2D patients, contributing to the knowledge of how the glycemic control could systemically influence gene expression. PMID- 28812029 TI - Expanded Normal Weight Obesity and Insulin Resistance in US Adults of the National Health and Nutrition Examination Survey. AB - This study aims to expand the evaluation of normal weight obesity (NWO) and its association with insulin resistance using an NHANES (1999-2006) sample of US adults. A cross-sectional study including 5983 men and women (50.8%) was conducted. Body fat percentage (BF%) was assessed using dual-energy X-ray absorptiometry. Expanded normal weight obesity (eNWO) categories, pairings of BMI and body fat percentage classifications, were created using standard cut-points for BMI and sex-specific median for BF%. Homeostatic model assessment-insulin resistance (HOMA-IR) levels were used to index insulin resistance. Mean +/- SE values were BMI: 27.9 +/- 0.2 (women) and 27.8 +/- 0.1 (men); body fat percentage: 40.5 +/- 0.2 (women) and 27.8 +/- 0.2 (men); and HOMA-IR: 2.04 +/- 0.05 (women) and 2.47 +/- 0.09 (men). HOMA-IR differed systematically and in a dose-response fashion across all levels of the eNWO categories (F = 291.3, P < 0.0001). As BMI levels increased, HOMA-IR increased significantly, and within each BMI category, higher levels of body fat were associated with higher levels of HOMA-IR. Both high BMI and high BF% were strongly related to insulin resistance. Insulin resistance appears to increase incrementally according to BMI levels primarily and body fat levels secondarily. Including a precise measure of body fat with BMI adds little to the utility of BMI in the prediction of insulin resistance. PMID- 28812030 TI - Safety of Human Papillomavirus 9-Valent Vaccine: A Meta-Analysis of Randomized Trials. AB - Vaccination against human papillomavirus (HPV) has been progressively implemented in most developed countries for approximately 10 years. In order to increase the protection of the vaccines, a 9-valent vaccine (HPV9) was developed, which provides protection against nine types of the virus. Studies evaluating its safety are rare. Thus, we performed a meta-analysis of three clinical trials assessing adverse effects on women randomly vaccinated with HPV9 or tetravalent vaccine (HPV4), with the objective of analyzing whether the HPV9 is as safe as HPV4. An electronic data search was performed through the PubMed, Embase, Scopus, Web of Science, and SciELO databases. The studies selected 27,465 women who received one of the two vaccines. Pain (OR 1.72; 95% CI 1.62-1.82) and erythema (OR 1.29; 95% CI 1.21-1.36) occurred significantly more in the HPV9 group. However, there was no significant difference between the groups for the following adverse effects: headache (OR 1.07; 95% CI 0.99-1.15), dizziness (OR 1.09; 95% CI 0.93-1.27), and fatigue (OR 1.09; 95% CI 0.91-1.30), and the occurrence of serious events related to vaccination was similarly rare among those vaccinated. Therefore, our findings demonstrate that HPV9 in female patients is as safe as the tetravalent vaccine. PMID- 28812031 TI - Early Single-Sport Specialization: A Survey of 3090 High School, Collegiate, and Professional Athletes. AB - BACKGROUND: Youth participation in organized sports in the United States is rising, with many athletes focusing on a single sport at an increasingly younger age. PURPOSE: To retrospectively compare single-sport specialization in current high school (HS), collegiate, and professional athletes with regard to the rate and age of specialization, the number of months per year of single-sport training, and the athlete's perception of injury related to specialization. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A survey was distributed to HS, collegiate, and professional athletes prior to their yearly preparticipation physical examination. Athletes were asked whether they had chosen to specialize in only 1 sport, and data were then collected pertaining to this decision. RESULTS: A total of 3090 athletes completed the survey (503 HS, 856 collegiate, and 1731 professional athletes). A significantly greater percentage of current collegiate athletes specialized to play a single sport during their childhood/adolescence (45.2% of HS athletes, 67.7% of collegiate athletes, and 46.0% of professional athletes; P < .001). The age of single-sport specialization differed between groups and occurred at a mean age of 12.7 +/- 2.4 (HS), 14.8 +/- 2.5 (collegiate), and 14.1 +/- 2.8 years (professional) (P < .001). Current HS (39.9%) and collegiate athletes (42.1%) recalled a statistically greater incidence of sport-related injury than current professional athletes (25.4%) (P < .001). The majority (61.7%) of professional athletes indicated that they believed specialization helps the athlete play at a higher level, compared with 79.7% of HS and 80.6% of collegiate athletes (P < .001). Notably, only 22.3% of professional athletes said they would want their own child to specialize to play only 1 sport during childhood/adolescence. CONCLUSION: This study provides a foundation for understanding current trends in single-sport specialization in all athletic levels. Current HS athletes specialized, on average, 2 years earlier than current collegiate and professional athletes surveyed. These data challenge the notion that success at an elite level requires athletes to specialize in 1 sport at a very young age. PMID- 28812032 TI - Nonoperative Management of Osteochondritis Dissecans of the Knee: Progression to Osteoarthritis and Arthroplasty at Mean 13-Year Follow-up. AB - BACKGROUND: Osteochondritis dissecans (OCD) is a disorder of subchondral bone that commonly affects the knee. PURPOSE: To (1) evaluate the rate of arthritis and knee arthroplasty in a population-based cohort of patients with OCD lesions treated nonoperatively and (2) evaluate factors that may predispose patients to knee osteoarthritis and arthroplasty. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Eighty-six patients (mean age, 21.4 years) with OCD lesions treated nonoperatively were identified between 1976 and 2014. Information related to the diagnosis, laterality of lesion, details of treatment, and progression to arthritis was obtained from the medical record. Factors predictive of arthritis and arthroplasty (age, sex, body mass index [BMI], and lesion location) were examined. RESULTS: At a mean +/- SD follow-up of 12.6 +/- 9.8 years from diagnosis, 13 patients (15%) were diagnosed with arthritis, corresponding to a cumulative incidence of 5.0% at 5 years, 10.0% at 10 years, 20.0% at 25 years, and 30.0% at 35 years. The cumulative incidence of arthroplasty was 1.0% at 5 years, 3.0% at 10 years, 8.0% at 25 years, and 8.0% at 35 years. BMI at diagnosis greater than 25 kg/m2 (hazard ratio [HR], 15.4; 95% CI, 1.9-124.5), patellar OCD lesions (HR, 15.0; 95% CI, 1.3-345.3), and diagnosis as an adult (HR, 21.7; 95% CI, 2.7-176.3) were factors associated with an increased risk of arthritis. CONCLUSION: Arthritis after nonoperative treatment of OCD lesions is a challenging problem, with an estimated 30% cumulative incidence at 35 years after diagnosis. In contrast, the long-term rate of arthroplasty is low. BMI at diagnosis greater than 25 kg/m2 and patellar OCD lesions are predisposing factors for arthritis. Diagnosis of OCD as an adult was associated with a greater risk of arthritis. PMID- 28812033 TI - Epidemiology of Injuries Identified at the NFL Scouting Combine and Their Impact on Performance in the National Football League: Evaluation of 2203 Athletes From 2009 to 2015. AB - BACKGROUND: At the annual National Football League (NFL) Scouting Combine, the medical staff of each NFL franchise performs a comprehensive medical evaluation of all athletes potentially entering the NFL. Currently, little is known regarding the overall epidemiology of injuries identified at the combine and their impact on NFL performance. PURPOSE: To determine the epidemiology of injuries identified at the combine and their impact on initial NFL performance. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: All previous musculoskeletal injuries identified at the NFL Combine from 2009 to 2015 were retrospectively reviewed. Medical records and imaging reports were examined. Game statistics for the first 2 seasons of NFL play were obtained for all players from 2009 to 2013. Analysis of injury prevalence and overall impact on the draft status and position-specific performance metrics of each injury was performed and compared with a position-matched control group with no history of injury or surgery. RESULTS: A total of 2203 athletes over 7 years were evaluated, including 1490 (67.6%) drafted athletes and 1040 (47.2%) who ultimately played at least 2 years in the NFL. The most common sites of injury were the ankle (1160, 52.7%), shoulder (1143, 51.9%), knee (1128, 51.2%), spine (785, 35.6%), and hand (739, 33.5%). Odds ratios (ORs) demonstrated that quarterbacks were most at risk of shoulder injury (OR, 2.78; P = .001), while running backs most commonly sustained ankle (OR, 1.39; P = .040) and shoulder injuries (OR, 1.55; P = .020) when compared with all other players. Ultimately, defensive players demonstrated a greater negative impact due to injury than offensive players, with multiple performance metrics significantly affected for each defensive position analyzed, whereas skilled offensive players (eg, quarterbacks, running backs) demonstrated only 1 metric significantly affected at each position. CONCLUSION: The most common sites of injury identified at the combine were (1) ankle, (2) shoulder, (3) knee, (4) spine, and (5) hand. Overall, performance in the NFL tended to worsen with injury history, with a direct correlation found between injury at a certain anatomic location and position of play. Defensive players tended to perform worse compared with offensive players if injury history was present. PMID- 28812034 TI - The Influence of Medical Insurance on Patient Access to Orthopaedic Surgery Sports Medicine Appointments Under the Affordable Care Act. AB - BACKGROUND: The goal of the Patient Protection and Affordable Care Act (PPACA) was to expand patient access to health care. Since the rollout of the PPACA, Medicaid patients have demonstrated difficulty obtaining appointments in some specialty care settings. PURPOSE: To assess the effect of insurance type (Medicaid and private) on patient access to orthopaedic surgery sports medicine specialists for a semiurgent evaluation of a likely operative bucket-handle meniscus tear. The study was designed to determine whether disparities in access exist since the PPACA rollout. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: The design was to call 180 orthopaedic surgery sports medicine specialists in 6 representative states (California, Ohio, New York, Florida, Texas, and North Carolina) between June 2015 and December 2015. An appointment was requested for the caller's fictitious 25-year-old-brother who had suffered a bucket-handle meniscus tear. Each office was called twice to assess the ease of obtaining an appointment: once for patients with Medicaid and once for patients with private insurance. For each call, data pertaining to whether an appointment was given, wait times, and barriers to receiving an appointment were recorded. RESULTS: A total of 177 surgeons were called within the study period. Overall, 27.1% of offices scheduled an appointment for a patient with Medicaid, compared with 91.2% (P < .0001) for a patient with private insurance. Medicaid patients were significantly more likely to be denied an appointment due to lack of referral compared with private patients (40.2% vs 3.7%, P < .0001), and Medicaid patients were more likely to experience longer wait times for an appointment (15 vs 12 days, P < .029). No significant differences were found in patients' access to orthopaedic surgery sports medicine specialists between Medicaid-expanded and nonexpanded states. Medicaid reimbursement for knee arthroscopy with meniscus repair was not significantly correlated with appointment success rate or patient waiting periods. CONCLUSION: Despite the passage of the PPACA, patients with Medicaid have reduced access to care. In addition, patients with Medicaid confront more barriers to receiving appointments than patients with private insurance and wait longer for an appointment. PMID- 28812035 TI - Bioabsorbable Versus Metal Screw in the Fixation of Tibial Tubercle Transfer: A Cadaveric Biomechanical Study. AB - BACKGROUND: In tibial tubercle transfer (TTT) procedures, the osteotomized and transferred tibial tubercle is usually fixed into the host bone using metal screws. PURPOSE: To compare the strength of fixation provided by a single bioabsorbable screw versus a metal screw for TTT. STUDY DESIGN: Controlled laboratory study. METHODS: Twenty-two pairs of human cadaveric tibiae were used to compare the fixation strength of a single 4.5-mm bicortical bioabsorbable or metal screw for TTT. In our 2-phase biomechanical testing protocol, the specimens were first subjected to a cyclic-loading test (1500 loading cycles between 50 and 300 N at 0.5 Hz frequency), after which they were loaded to failure (single-cycle load-to-failure test). To control for possible differences in bone quality, volumetric bone mineral density was determined using peripheral quantitative computed tomography. RESULTS: No significant displacement differences were observed between the 2 groups for the cyclic-loading test. In the subsequent single-cycle load-to-failure test, the mean yield load was 566 +/- 234 N in the bioabsorbable screw group and 984 +/- 630 N in the metal screw group (P = .002). The failure mode of bioabsorbable screws was breakage and/or bending, and that of metal screws was bending and/or pull-out. Bone density was similar in the 2 groups. CONCLUSION: A metal screw seems to provide greater fixation strength than a biodegradable screw in the TTT of a human cadaveric knee. However, considering the maximum quadriceps pull in vivo, the strength of fixation provided by a biodegradable screw seems clinically sufficient. CLINICAL RELEVANCE: Bioabsorbable screws, particularly if used in duplicate, could provide a viable option for metal screws in TTT fixation. PMID- 28812036 TI - Incidence of Sports-Related Concussion Among NCAA Women's Ice Hockey Athletes. AB - BACKGROUND: There are limited data on the incidence of concussion and concussion symptom nondisclosure among collegiate women's ice hockey athletes. PURPOSE: To determine the incidence of sports-related concussion (SRC) in National Collegiate Athletic Association (NCAA) women's ice hockey athletes. STUDY DESIGN: Descriptive epidemiology study. METHODS: An anonymous online survey was completed by 459 NCAA women's ice hockey athletes. Players reported diagnosed concussions as well as incidents where they experienced an impact or blow to the head followed by symptoms associated with a concussion; reports spanned the duration of the 2014-2015 season and throughout players' organized hockey career. RESULTS: About half (n = 219, 47.7%) of respondents reported at least 1 diagnosed concussion over the duration of their entire organized ice hockey career. A total of 13.3% (n = 61) of respondents reported a diagnosed concussion during the 2014 2015 season. The incidence rate was 1.18 (95% CI, 0.92-1.51) per 1000 athlete exposures to a game or practice and 0.58 (95% CI, 0.45-0.74) per 1000 hours of ice time. One-third (34.2%, n = 157) of players reported at least 1 impact where they experienced concussion-like symptoms during the 2014-2015 season; 82.8% of these players reported that they continued to play after at least 1 of these impacts, and 66.8% of players reported at least 1 impact where they never disclosed any symptoms. CONCLUSION: There is a high incidence of SRC in collegiate women's ice hockey and a concerning level of symptom nondisclosure. Additional research is needed to understand the causes of concussion and reasons for the lack of symptom disclosure, including factors specific to female athletes and contextual issues specific to women's collegiate ice hockey. PMID- 28812037 TI - A Retrospective Analysis of Concurrent Pathology in ACL-Reconstructed Knees of Elite Alpine Ski Racers. AB - BACKGROUND: Anterior cruciate ligament (ACL) tear is the most frequent injury in alpine ski racing, and there is a high prevalence of ACL reinjury. Limited data exist on the concurrent pathology with primary ACL tears in elite alpine ski racers and the magnitude of injury progression after primary ACL reconstruction (ACLR). PURPOSE: To evaluate (1) the involvement of intra-articular and multiligament pathologies at the time of primary ACLR, (2) the subsequent progression in meniscal/chondral injuries, and (3) the occurrence of ACL reinjury in elite alpine ski racers. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Primary ACLR operative reports (n = 28) were obtained for 32 elite alpine ski racers along with the reports of 20 operative procedures that occurred subsequent to primary ACLR. Operative reports were evaluated to identify the presence/location of multiligament injury, meniscal tears, and chondral lesions. RESULTS: At the time of primary ACLR, a majority of knees (82%; 23/28) demonstrated concurrent injury compared with isolated ACL tears; 32% of knees sustained multiligament injuries (9/28), and 8 involved the ipsilateral medial collateral ligament (MCL). Of the ACL-injured knees, 54% had chondral lesions, of which 73% were sustained in the lateral knee compartment, and 82% of meniscal tears (14/17) were complex in nature. Bilateral ACL tears were seen in 22% of the participants, and 28% underwent ACL revision. In the case of ACL revision or future meniscal/chondral surgery, 60% of meniscal tears and 80% of chondral lesions had worsened since the time of primary ACLR. CONCLUSION: Concurrent injury was common in this group of elite ski racers. Primary ACL tears were typically accompanied by lateral compartment chondral lesions and complex meniscal tears that worsened over time. ACL/MCL tears were the most common multiligament injury pattern. PMID- 28812038 TI - Should Patients With Frozen Shoulder Be Screened for Diabetes Mellitus? AB - BACKGROUND: Idiopathic frozen shoulder (nontraumatic) is commonly encountered in patients between the ages of 35 and 60 years in general orthopaedic practice. While the prevalence of frozen shoulder among the general population is estimated to be between 2% and 4%, a significantly higher prevalence of 10% to 22% has been reported in patients with diabetes mellitus. Since diabetic patients are more prone to develop frozen shoulder than nondiabetics, the question arises as to whether patients diagnosed as having idiopathic frozen shoulder are at greater risk to develop diabetes mellitus and should be routinely screened for this condition. PURPOSE: To compare the prevalence of diabetes mellitus and prediabetes among patients diagnosed with idiopathic frozen shoulder who are not known to have either diabetes mellitus or prediabetic conditions with that of an age-matched group from the general population. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Patients at a shoulder clinic with a diagnosis of idiopathic frozen shoulder were asked to participate in the study if they were aged between 35 to 60 years and had no known previous diagnosis of diabetes mellitus or prediabetic conditions. These patients underwent a 2-hour oral glucose tolerance test. According to their fasting and 2-hour plasma glucose levels, patients were diagnosed as normal glucose tolerance, prediabetic, or diabetic. Findings were matched with the prevalence in an age-matched general population. RESULTS: Fifty patients completed the test. Four patients with idiopathic frozen shoulder (8%) were found to be prediabetic. No patient was found to be diabetic. All 4 patients reported a history of diabetes in their parents or siblings. CONCLUSION: Patients diagnosed with idiopathic frozen shoulder who are 60 years or younger and are not known diabetics have a similar probability of having diabetes or prediabetes to an age-matched population. No routine diabetic workup is warranted specifically for these patients. PMID- 28812039 TI - Three-Dimensional Biomechanical Analysis of Rearfoot and Forefoot Running. AB - BACKGROUND: In the running community, a forefoot strike (FFS) pattern is increasingly preferred compared with a rearfoot strike (RFS) pattern. However, it has not been fully understood which strike pattern may better reduce adverse joint forces within the different joints of the lower extremity. PURPOSE: To analyze the 3-dimensional (3D) stress pattern in the ankle, knee, and hip joint in runners with either a FFS or RFS pattern. STUDY DESIGN: Descriptive laboratory study. METHODS: In 22 runners (11 habitual rearfoot strikers, 11 habitual forefoot strikers), RFS and FFS patterns were compared at 3.0 m/s (6.7 mph) on a treadmill with integrated force plates and a 3D motion capture analysis system. This combined analysis allowed characterization of the 3D biomechanical forces differentiated for the ankle, knee, and hip joint. The maximum peak force (MPF) and maximum loading rate (LR) were determined in their 3 ordinal components: vertical, anterior-posterior (AP), and medial-lateral (ML). RESULTS: For both strike patterns, the vertical components of the MPF and LR were significantly greater than their AP or ML components. In the vertical axis, FFS was generally associated with a greater MPF but significantly lower LR in all 3 joints. The AP components of MPF and LR were significantly lower for FFS in the knee joint but significantly greater in the ankle and hip joints. The ML components of MPF and LR tended to be greater for FFS but mostly did not reach a level of significance. CONCLUSION: FFS and RFS were associated with different 3D stress patterns in the ankle, knee, and hip joint, although there was no global advantage of one strike pattern over the other. The multimodal individual assessment for the different anatomic regions demonstrated that FFS seems favorable for patients with unstable knee joints in the AP axis and RFS may be recommended for runners with unstable ankle joints. CLINICAL RELEVANCE: Different strike patterns show different 3D stress in joints of the lower extremity. Due to either rehabilitation after injuries or training in running sports, rearfoot or forefoot running should be preferred to prevent further damage or injuries caused by inadequate biomechanical load. Runners with a history of knee joint injuries may benefit from FFS whereas RFS may be favorable for runners with a history of ankle joint injuries. PMID- 28812040 TI - Effect of Changes in Artificial Turf on Sports Injuries in Male University Soccer Players. AB - BACKGROUND: Studies comparing the types and severity of trauma and injuries caused by different types of field surfaces have been conducted. However, there have been no studies on sports injuries caused by temporal deterioration of long pile artificial turf fields and related decreases in the rubber chip and silica sand infill. PURPOSE: To investigate the influence of an artificial turf field on sports injuries in a university soccer team. STUDY DESIGN: Descriptive epidemiological study. METHODS: A total of 397 male soccer players who were members of a single university soccer team were surveyed over a 12-year period, from April 2003 to March 2015. During this period, the team played for 4 years on a soil field (2003-2006) and 8 years on artificial turf (2007-2014). We analyzed the effect of changes in the artificial turf on the incidence rate of sports injuries (injury rate per 1000 athlete-exposures). We calculated the incidence rate of injuries sustained by the team and compared the results for each year of the study. RESULTS: After conversion of the field to artificial turf, there was a significant increase in the incidence of upper extremity trauma (P < .05). There was a significant increase in lower extremity sprains from 2007 to 2008, 1 year after the conversion from soil to artificial turf (P < .05). Analysis of the incidence of lower extremity muscle strain indicated that although the injury rate increased progressively, it decreased significantly after the insertion of additional rubber chips in 2014 (P < .05). CONCLUSION: After conversion to artificial turf, there was a significant increase in the incidence of upper extremity trauma. After the refurbishing with additional rubber chips, the incidence of lower extremity muscle strain significantly declined. When analyzing measures that could prevent sports injuries related to soccer, it is necessary to take into consideration the changes that occur to the artificial turf over time. PMID- 28812041 TI - Anthropometric and Skeletal Parameters Predict 2-Strand Semitendinosus Tendon Size in Double-Bundle Anterior Cruciate Ligament Reconstruction. AB - BACKGROUND: Few studies have examined whether skeletal parameters predict hamstring graft size during anterior cruciate ligament reconstruction (ACLR). PURPOSE/HYPOTHESIS: The purpose of this study was to examine whether preoperative anthropometric and radiographic skeletal parameters could predict hamstring graft size during ACLR. We hypothesized that both anthropometric and skeletal parameters can be used to predict graft size in our double-bundle procedure and that the use of skeletal parameters will improve the accuracy of graft size prediction. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A total of 200 patients were recruited and underwent double-bundle ACLR using a semitendinosus (ST) graft. The harvested tendon was measured to determine graft length (GL) and then split at its midpoint. The graft diameters of the anteromedial (GDAM) and posterolateral bundles (GDPL) were measured at the femoral aspect of the 2-stranded graft. The mean diameters of both bundles were included in the analysis. On the coronal radiograph, femorotibial angle (FTA), femoral interepicondylar distance (IED), and tibial plateau width (coronal tibial width [CTW]) were measured. Blumensaat line length (BLL) and the lateral tibial width (LTW) were measured on the lateral radiograph. A linear regression analysis was conducted using graft size as the dependent variable and age, sex, height, weight, Tegner activity score, and skeletal parameters as the independent variables. RESULTS: Mean GL was 258.9 +/- 21.9 mm, GDAM was 5.9 +/- 0.5 mm, and GDPL was 5.7 +/- 0.6 mm. Single regression analysis showed that GL was significantly predicted by sex, height, weight, Tegner activity score, IED, CTW, BLL, and LTW (R2 range, 0.033-0.342). GD was predicted by sex, height, weight, IED, CTW, BLL, and LTW (R2 range, 0.094-0.207). Stepwise multiple linear regression analysis significantly confirmed sex, height, and age as the variables to comprehensively predict GL (R2 = 0.384). With regard to GD, stepwise multiple regression confirmed height and IED as significant variables (R2 = 0.224). CONCLUSION: Both preoperative anthropometric and radiographic parameters on plain radiographs were able to predict harvested GL and 2-strand GD. Multivariate regression slightly improved the prediction of graft dimensions compared with univariate regression. PMID- 28812042 TI - Visual outcomes 24 months after LaserACE. AB - BACKGROUND: To evaluate the effects on near and intermediate visual performance after bilateral Laser Anterior Ciliary Excision (LaserACE) procedure. METHODS: LaserACE surgery was performed using the VisioLite 2.94 MUm erbium: yttrium aluminum-garnet (Er:YAG) ophthalmic laser system in 4 oblique quadrants on the sclera over the ciliary muscle in 3 critical zones of physiological importance (over the ciliary muscles and posterior zonules) with the aim to improve natural dynamic accommodative forces. LaserACE was performed on 26 patients (52 eyes). Outcomes were analyzed using visual acuity testing, Randot stereopsis, and the CatQuest 9SF patient survey. RESULTS: Binocular uncorrected near visual acuity (UNVA) improved from +0.20 +/- 0.16 logMAR preoperatively, to +0.12 +/- 0.14 logMAR at 24 months postoperatively (p = 0.0014). There was no statistically significant loss in distance corrected near visual acuity (DCNVA). Binocular DCNVA improved from +0.21 +/- 0.17 logMAR preoperatively, to +0.11 +/- 0.12 logMAR at 24 months postoperatively (p = 0.00026). Stereoacuity improved from 74.8 +/- 30.3 s of arc preoperatively, to 58.8 +/- 22.9 s of arc at 24 months postoperatively (p = 0.012). There were no complications such as persistent hypotony, cystoid macular edema, or loss of best-corrected visual acuity (BCVA). Patients surveyed indicated reduced difficulty in areas of near vision, and were overall satisfied with the procedure. CONCLUSIONS: Preliminary results of the LaserACE procedure show promising results for restoring visual performance for near and intermediate visual tasks without compromising distance vision and without touching the visual axis. The visual function and visual acuity improvements had clinical significance. Patient satisfaction was high postoperatively and sustained over 24 months. TRIAL REGISTRATION: NCT01491360 (https://clinicaltrials.gov/ct2/show/NCT01491360). Registered 22 November 2011. PMID- 28812043 TI - Swallowing markers in spinal and bulbar muscular atrophy. AB - OBJECTIVE: We examined the characteristics of dysphagia in spinal and bulbar muscular atrophy, a hereditary neuromuscular disease causing weakness of limb, facial, and oropharyngeal muscles via a videofluoroscopic swallowing study, and investigated the plausibility of using these outcome measures for quantitative analysis. METHODS: A videofluoroscopic swallowing study was performed on 111 consecutive patients with genetically confirmed spinal and bulbar muscular atrophy and 53 age- and sex-matched healthy controls. Swallowing of 3-mL liquid barium was analyzed by the Logemann's Videofluorographic Examination of Swallowing worksheet. RESULTS: Of more than 40 radiographic findings, the most pertinent abnormal findings in patients with spinal and bulbar muscular atrophy, included vallecular residue after swallow (residue just behind the tongue base), nasal penetration, and insufficient tongue movement (P < 0.001 for each) compared with healthy controls. Quantitative analyses showed that pharyngeal residue after initial swallowing, oral residue after initial swallowing, multiple swallowing sessions, and the penetration-aspiration scale were significantly worse in these patients (P <= 0.005 for each) than in controls. In patients with spinal and bulbar muscular atrophy, laryngeal penetration was observed more frequently in those without subjective dysphagia. INTERPRETATION: Dysphagia of spinal and bulbar muscular atrophy was characterized by impaired tongue movement in the oral phase and nasal penetration followed by pharyngeal residues, which resulted in multiple swallowing sessions and laryngeal penetration. Although major limitations of reproducibility and radiation exposure still exist with videofluoroscopy, pharyngeal residue after initial swallowing and the penetration aspiration scale might serve as potential outcome measures in clinical studies. PMID- 28812044 TI - Monte Carlo simulations of randomized clinical trials in epilepsy. AB - BACKGROUND: The placebo response in epilepsy randomized clinical trials (RCTs) has recently been shown to largely reflect underlying natural variability in seizure frequency. Based on this observation, we sought to explore the parameter space of RCT design to optimize trial efficiency and cost. METHODS: We used one of the world's largest patient reported seizure diary databases, SeizureTracker.com to derive virtual patients for simulated RCTs. We ran 1000 randomly generated simulated trials using bootstrapping (sampling with replacement) for each unique combination of trial parameters, sweeping a large set of parameters in durations of the baseline and test periods, number of patients, eligibility criteria, drug effect size, and patient dropout. We studied the resulting trial efficiency and cost. RESULTS: A total of 6,732,000 trials were simulated, drawing from 5097 patients in the database. We found that the strongest regression predictors of placebo response were durations of baseline and test periods. Drug effect size had a major impact on trial efficiency and cost. Dropout did not have a major impact on trial efficiency or cost. Eligibility requirements impacted trial efficiency to a limited extent. Cost was minimized while maintaining statistical integrity with very short RCT durations. DISCUSSION: This study suggests that RCT parameters can be improved over current practice to reduce costs while maintaining statistical power. In addition, use of a large-scale population dataset in a massively parallel computing analysis allows exploration of the wider parameter space of RCT design prior to running a trial, which could help accelerate drug discovery and approval. PMID- 28812045 TI - Soluble ST2 predicts outcome and hemorrhagic transformation after acute stroke. AB - OBJECTIVE: ST2 is a member of the toll-like receptor superfamily that can alter inflammatory signaling of helper T-cells. We investigated whether soluble ST2 (sST2) could independently predict outcome and hemorrhagic transformation (HT) in the setting of stroke. METHODS: We measured sST2 in patients enrolled in the Specialized Program of Translational Research in Acute Stroke (SPOTRIAS) network biomarker study. 646 patients had plasma samples collected at the time of hospital admission and 210 patients had a second sample collected 48 h after stroke onset. Functional outcome was assessed using the modified Rankin Scale (mRS), with good and poor outcomes defined as mRS 0-2 and 3-6, respectively. HT was classified using ECASS criteria. The relationships between sST2, outcome, and HT were evaluated using multivariable logistic regression, Kaplan-Meier survival analysis and receiver operating characteristic curves. RESULTS: 646 patients were included in the analysis (mean age 69 years; 44% women), with a median NIHSS of 5 [IQR: 2-12]. The median sST2 level on hospital admission was 35.0 ng/mL [IQR: 25.7-49.8 ng/mL] and at 48 h it was 37.4 ng/mL [IQR 27.9-55.6 ng/mL]. sST2 was independently associated with poor outcome (OR: 2.77, 95% CI: 1.54-5.06; P = 0.003) and mortality (OR: 3.56, 95% CI: 1.58-8.38, P = 0.001) after multivariable adjustment. Plasma sST2 was also associated with hemorrhagic transformation after adjustment for traditional risk factors (OR: 5.58, 95% CI: 1.40-37.44, P = 0.039). INTERPRETATION: Soluble ST2 may serve as a prognostic biomarker for outcome and hemorrhagic transformation in patients with acute stroke. ST2 may link neuroinflammation and secondary injury after stroke. PMID- 28812046 TI - Extra-virgin olive oil ameliorates cognition and neuropathology of the 3xTg mice: role of autophagy. AB - OBJECTIVE: Consumption of extra virgin olive oil (EVOO), a major component of the Mediterranean diet, has been associated with reduced incidence of Alzheimer's disease (AD). However, the mechanisms involved in this protective action remain to be fully elucidated. METHODS: Herein, we investigated the effect of daily consumption of EVOO on the AD-like phenotype of a mouse mode of the disease with plaques and tangles. RESULTS: Triple transgenic mice (3xTg) received either regular chow or a chow diet supplemented with EVOO starting at 6 months of age for 6 months, then assessed for the effect of the diet on the AD-like neuropathology and behavioral changes. Compared with controls, mice receiving the EVOO-rich diet had an amelioration of their behavioral deficits, and a significant increase in the steady state levels of synaptophysin, a protein marker of synaptic integrity. In addition, they had a significant reduction in insoluble Abeta peptide levels and deposition, lower amount of phosphorylated tau protein at specific epitopes, which were secondary to an activation of cell autophagy. INTERPRETATION: Taken together, our findings support a beneficial effect of EVOO consumption on all major features of the AD phenotype (behavioral deficits, synaptic pathology, Abeta and tau neuropathology), and demonstrate that autophagy activation is the mechanism underlying these biological actions. PMID- 28812047 TI - Selected missense mutations impair frataxin processing in Friedreich ataxia. AB - OBJECTIVE: Frataxin (FXN) is a highly conserved mitochondrial protein. Reduced FXN levels cause Friedreich ataxia, a recessive neurodegenerative disease. Typical patients carry GAA repeat expansions on both alleles, while a subgroup of patients carry a missense mutation on one allele and a GAA repeat expansion on the other. Here, we report that selected disease-related FXN missense mutations impair FXN localization, interaction with mitochondria processing peptidase, and processing. METHODS: Immunocytochemical studies and subcellular fractionation were performed to study FXN import into the mitochondria and examine the mechanism by which mutations impair FXN processing. Coimmunoprecipitation was performed to study the interaction between FXN and mitochondrial processing peptidase. A proteasome inhibitor was used to model traditional therapeutic strategies. In addition, clinical profiles of subjects with and without point mutations were compared in a large natural history study. RESULTS: FXNI154F and FXNG130V missense mutations decrease FXN 81-210 levels compared with FXNWT, FXNR165C, and FXNW155R, but do not block its association with mitochondria. FXNI154F and FXNG130V also impair FXN maturation and enhance the binding between FXN 42-210 and mitochondria processing peptidase. Furthermore, blocking proteosomal degradation does not increase FXN 81-210 levels. Additionally, impaired FXN processing also occurs in fibroblasts from patients with FXNG130V. Finally, clinical data from patients with FXNG130V and FXNI154F mutations demonstrates a lower severity compared with other individuals with Friedreich ataxia. INTERPRETATION: These data suggest that the effects on processing associated with FXNG130V and FXNI154F mutations lead to higher levels of partially processed FXN, which may contribute to the milder clinical phenotypes in these patients. PMID- 28812048 TI - Sensorimotor rhythm neurofeedback as adjunct therapy for Parkinson's disease. AB - Neurofeedback may enhance compensatory brain mechanisms. EEG-based sensorimotor rhythm neurofeedback training was suggested to be beneficial in Parkinson's disease. In a placebo-controlled study in parkinsonian nonhuman primates we here show that sensorimotor rhythm neurofeedback training reduces MPTP-induced parkinsonian symptoms and both ON and OFF scores during classical L-DOPA treatment. Our findings encourage further development of sensorimotor rhythm neurofeedback training as adjunct therapy for Parkinson's disease which might help reduce L-DOPA-induced side effects. PMID- 28812049 TI - Importance of adiponectin activity in the pathogenesis of Alzheimer's disease. AB - A recent study suggested that insulin resistance may play a central role in the pathogenesis of Alzheimer's disease (AD). In this regard, it is of note that upregulation of plasma adiponectin (APN), a benign adipokine that sensitizes the insulin receptor signaling pathway and suppresses inflammation, has recently been associated with the severities of amyloid deposits and cognitive deficits in the elderly, suggesting that APN may enhance the risk of AD. These results are unanticipated because AD has been linked to type II diabetes and other metabolic disorders in which hypoadiponectinemia has been firmly established, and because APN ameliorated neuropathological features in a mouse model of neurodegeneration. Therefore, the objective of this study is to discuss the possible mechanisms underlying the biological actions of APN in the context of AD. Given that insulin receptor signaling is required for normal function of the nervous system, we predict that APN may be upregulated to compensate for compromised activity of the insulin receptor signaling pathway. However, increased APN might be sequestered by tau in the brain, leading to neurotoxic protein aggregation in AD. Alternatively, misfolding of APN may result in downregulation of the insulin/APN signal transduction network, leading to decreased neuroprotective and neurotrophic activities. Thus, it is possible that both 'gain of function' and 'loss of function' of APN may underlie synaptic dysfunction and neuronal cell death in AD. Such a unique biological mechanism underlying APN function in AD may require a novel therapeutic strategy that is distinct from previous treatment for metabolic disorders. PMID- 28812051 TI - Comment on: PH20 is not expressed in murine CNS and oligodendrocyte precursor cells. PMID- 28812050 TI - Caveats in the Established Understanding of CMT1A. AB - Charcot-Marie-Tooth disease type-1A (CMT1A) is one of the most common types of inherited peripheral nerve diseases. It is caused by the trisomy of chromosome 17p12 (c17p12), a large DNA segment of 1.4 Mb containing PMP22 plus eight other genes. The size of c17p12 is formidable for any cloning technique to manipulate, and thus precludes production of models in vitro and in vivo that can precisely recapitulate the genetic alterations in humans with CMT1A. This limitation and other factors have led to several assumptions, which have yet been carefully scrutinized, serving as key principles in our understanding of the disease. For instance, one extra copy of c17p12 in patients with CMT1A results in a higher gene dosage of PMP22, thereby expected to produce a higher level of PMP22 mRNA/proteins that cause the disease. However, there has been increasing evidence that PMP22 levels are highly variable among patients with CMT1A and may fall into the normal range at a given time point. This raises an alternative mechanism causing the disease by dysregulation of PMP22 expression or excessive fluctuation of PMP22 levels, not the absolute increase of PMP22. This has become a pressing issue since recent clinical trials using ascorbic acid failed to alter the clinical outcome of CMT1A patients, leaving no effective therapy for the disease. In this article, we will discuss how this fundamental issue might be investigated. In addition, several other key issues in CMT1A will be discussed, including potential mechanisms responsible for the uniform slowing of conduction velocities. A clear understanding of these issues could radically change how therapies should be developed against CMT1A. PMID- 28812052 TI - The Superior Labial Frenulum in Newborns: What Is Normal? AB - Introduction and Objectives: There has been an emergence of procedures to release the superior labial frenula in infants, yet little is known about the normal appearance or incidence of severe attachment, or "lip-tie." The objective of this article was to develop a classification system for superior labial frenula and to estimate the incidence of different degrees of attachment. Methods: A prospective cross-sectional study. Newborns were examined and had photographs taken of their upper frenula. Relevant medical professionals rated the appearance of the labial frenula using a previously described Kotlow classification system. The raters assessed each photograph twice and were blinded to their previous rating and to other raters' scores. Results: All newborns have a labial frenula, with most attached at the gingival margins (83%). Raters had poor intra- and interrater reliability (64% to 74% and 8%, respectively), using the Kotlow classification system, which improved when the classification system was simplified. Conclusions: The Kotlow classification of lip-tie fails to be reproducible by relevant experts. The majority of infants had a significant level of attachment of the labial frenulum. As more procedures are done to release the upper lip frenulum, it is important to understand what degree of attachment is normal, or more common. PMID- 28812053 TI - Emergency Medical Service Personnel Recognize Pediatric Concussions. AB - Concussions are a major cause of morbidity in pediatrics. Many concussions occur during activities with emergency medical service (EMS) providers present to determine if a higher level of care is needed. Data are limited on how capable these providers are. We assessed the ability of EMS providers to recognize pediatric concussions. Fifty-six total responses were included, 38 from EMS and 18 from our MD/RN (medical doctor/registered nurse) group. No statistical differences were found between the 2 groups when adjusted for age, gender, number of years in practice, and number of pediatric concussions managed. This first of its kind pilot study was designed to assess EMS personnel's ability to recognize and triage pediatric concussions. Our findings show EMS providers are statistically identical in their ability to recognize and triage concussions to physicians. The performance of our MD participants was lower than expected. Larger studies are needed to further investigate EMS providers' ability to recognize a concussion. PMID- 28812054 TI - Influenza A Virus Infection and Nucleotide Sequencing in HIV-Infected Children: A Case Report and Review of Literature. PMID- 28812055 TI - Clinical Versus Objective Assessment of Overweight and Obese Children Among Primary Care Physicians. PMID- 28812056 TI - Initiating a Standardized Regional Referral and Counter-Referral System in Guatemala: A Mixed-Methods Study. AB - Background:Few data exist for referral processes in resource-limited settings. We utilized mixed-methods to evaluate the impact of a standardized algorithm and training module developed for locally identified needs in referral/counter referral procedures between primary health centers (PHCs) and a Guatemalan referral hospital. Methods: PHC personnel and hospital physicians participated in surveys and focus groups pre-implementation and 3, 6, and 12 months post implementation to evaluate providers' experience with the system. Referred patient records were reviewed to evaluate system effectiveness. Results: A total of 111 initial focus group participants included 96 (86.5%) from PHCs and 15 from the hospital. Of these participants, 53 PHC physicians and nurses and 15 hospital physicians initially completed written surveys. Convenience samples participated in follow-up. Eighteen focus groups achieved thematic saturation. Four themes emerged: effective communication; provision of timely, quality patient care with adequate resources; educational opportunities; and development of empowerment and relationships. Pre- and post-implementation surveys demonstrated significant improvement at the PHCs (P < .001) and the hospital (P = .02). Chart review included 435 referrals, 98 (22.5%) pre-implementation and 337 (77.5%) post implementation. There was a trend toward an increased percentage of appropriately referred patients requiring medical intervention (30% vs 40%, P = .08) and of patients requiring intervention who received it prior to transport (55% vs 73%, P = .06). Conclusions: Standardizing a referral/counter-referral system improved communication, education, and trust across different levels of pediatric health care delivery. This model may be used for extension throughout Guatemala or be modified for use in other countries. Mixed-methods research design can evaluate complex systems in resource-limited settings. PMID- 28812057 TI - Screening for Syphilis in Cases of Suspected Gonorrhea and Chlamydia Infections. AB - Background. In all cases of suspected sexually transmitted infections (STIs), it has been routine practice to screen for syphilis with a blood sample. The incidence of syphilis seems to be lower than that of commonly screened STIs. Objective. The objective of our study was to determine whether it is cost effective to screen for syphilis with serological testing in cases of suspected gonorrhea and chlamydia infections. Hypothesis. Our hypothesis is that it is not cost-effective to screen for syphilis in cases of presumed gonorrhea and chlamydia infections. Methods. Our study is a New York Medical College institutional review board-approved retrospective study. During the period January 2004 to August 12, 2006, the laboratory work of all patients tested for gonorrhea and chlamydia in our emergency department was reviewed. The charts were reviewed for the following tests: gonorrhea DNA probe, chlamydia DNA probe, and syphilis IgG (immunoglobulin G)/RPR (rapid plasma reagin). The results of these tests were obtained and analyzed. Results. The total number of patients screened for gonorrhea and chlamydia during this period was 196. Seventy-eight patients tested positive for gonorrhea and chlamydia. All these 78 patients, tested negative for syphilis. The overall prevalence of positivity for STIs was 39.8% (78/196). The prevalence of chlamydia alone was 85.9% (67/78) and gonorrhea alone was 7.69% (6/78). The prevalence of combined both chlamydia and gonorrhea was 6.4% (5/78). Statistics. We used online SILICO 2 * 4 Fisher exact test. By comparing positive and negative results of serology RPR, GC, and chlamydia trap, the resultant 2-tailed P value is <.0001, which is statistically significant. Conclusions. Per our study, the yield of syphilis testing was negligible. It may not be cost-effective to screen for syphilis in cases of STIs such as gonorrhea and chlamydia. PMID- 28812059 TI - Clinician's Update on the Benign, Premalignant, and Malignant Skin Tumours of the Vulva: The Dermatologist's View. AB - Correct and rapid diagnosis of skin tumours often requires biopsy and histopathological examination to differentiate benign lesions such as seborrhoeic keratoses or melanocytic naevi from premalignant and malignant lesions such as malignant melanoma. Particularly, to the untrained eye, any benign skin tumour pigmented or nonpigmented-is easily mistaken for a malignant lesion. Qualified clinical evaluation is paramount in order to reduce the frequency of unwarranted skin biopsies. Herein, the most common benign, premalignant, and malignant vulvar skin tumours are reviewed. PMID- 28812058 TI - Environmental Pollutants and Neurodevelopment: Review of Benefits From Closure of a Coal-Burning Power Plant in Tongliang, China. AB - Background. Understanding preventable causes of neurodevelopmental disorders is a public health priority. Polycyclic aromatic hydrocarbons (PAH) from combustion of fossil fuel, lead, and mercury are among known neurodevelopmental toxicants. Method. For the first time, we comprehensively review the findings from a study by the Columbia Center for Children's Environmental Health and Chinese partners that followed 2 groups of mother-child pairs, one from 2002 and another from 2005, in Tongliang County, China. Pregnant mothers in the 2 cohorts experienced different exposure to PAH because a local coal-burning power plant was shut down in 2004. Investigators assessed change in prenatal PAH exposure, measured using a biomarker (benzo[a]pyrene [BaP]-DNA adducts in cord blood). Developmental quotients were measured using the Gesell Developmental Scales at age 2 and IQ was assessed using the Wechsler Intelligence Scale for Children at age 5. Biologic markers of preclinical response were measured in cord blood: methylation status of long interspersed nuclear elements (LINE1), an indicator of genomic stability, and brain-derived neurotrophic factor (BDNF), a neuronal growth promoter. Analyses accounted for co-exposure to lead and mercury. Results. BaP-DNA adducts were significantly inversely associated with Gesell Developmental Scales scores in the first cohort but not in the second cohort; and levels of BDNF and LINE1 methylation were higher in the second cohort. Conclusion. In this study, reduced exposure to PAH was associated with beneficial effects on neurodevelopment as well as molecular changes related to improved brain development and health. These benefits should encourage further efforts to limit exposure to these toxic pollutants. PMID- 28812060 TI - Reolysin and Histone Deacetylase Inhibition in the Treatment of Head and Neck Squamous Cell Carcinoma. AB - Oncolytic viruses (OVs) are emerging as powerful anti-cancer agents and are currently being tested for their safety and efficacy in patients. Reovirus (Reolysin), a naturally occurring non-pathogenic, double-stranded RNA virus, has natural oncolytic activity and is being tested in phase I-III clinical trials in a variety of tumor types. With its recent US Food and Drug Administration (FDA) orphan drug designation for several tumor types, Reolysin is a potential therapeutic agent for various cancers, including head and neck squamous cell carcinomas (HNSCCs), which have a 5-year survival of ~55%. Histone deacetylase inhibitors (HDACis) comprise a structurally diverse class of compounds with targeted anti-cancer effects. The first FDA-approved HDACi, vorinostat (suberoylanilide hydroxamic acid [SAHA]), is currently being tested in patients with head and neck cancer. Recent findings indicate that HDAC inhibition in myeloma cells results in the upregulation of the Reolysin entry receptor, junctional adhesion molecule 1 (JAM-1), facilitating reovirus infection and tumor cell killing both in vitro and in vivo. In this study, we tested the anti-tumor efficacy of HDAC inhibitors AR-42 or SAHA in conjunction with Reolysin in HNSCCs. While HDAC inhibition increased JAM-1 and reovirus entry, the impact of this combination therapy was tested on the development of anti-tumor immune responses. PMID- 28812063 TI - Self-organization of amino-acid-derived NDI assemblies into a nanofibrillar superstructure with humidity sensitive n-type semiconducting properties. AB - The hierarchical self-assembly of l-tyrosine substituted naphthalenediimide has been explored in solution by NMR spectroscopy and in the solid-state by atomic force microscopy. Spontaneous non-covalent polymerisation led to the formation of a three-dimensional fibre-like supramolecular polymer with n-type semiconducting properties. PMID- 28812062 TI - Clinical and experimental studies of a novel P525R FUS mutation in amyotrophic lateral sclerosis. AB - OBJECTIVE: To describe the clinical features of a novel fused in sarcoma (FUS) mutation in a young adult female amyotrophic lateral sclerosis (ALS) patient with rapid progression of weakness and to experimentally validate the consequences of the P525R mutation in cellular neuronal models. METHODS: We conducted sequencing of genomic DNA from the index patient and her family members. Immunocytochemistry was performed in various cellular models to determine whether the newly identified P525R mutant FUS protein accumulated in cytoplasmic inclusions. Clinical features of the index patient were compared with 19 other patients with ALS carrying the P525L mutation in the same amino acid position. RESULTS: A novel mutation c.1574C>G (p.525P>R) in the FUS gene was identified in the index patient. The clinical symptoms are similar to those in familial ALS patients with the P525L mutation at the same position. The P525R mutant FUS protein showed cytoplasmic localization and formed large stress granule-like cytoplasmic inclusions in multiple cellular models. CONCLUSIONS: The clinical features of the patient and the cytoplasmic inclusions of the P525R mutant FUS protein strengthen the notion that mutations at position 525 of the FUS protein result in a coherent phenotype characterized by juvenile or young adult onset, rapid progression, variable positive family history, and female preponderance. PMID- 28812064 TI - Chiral cobalt(ii) complex catalyzed Friedel-Crafts aromatization for the synthesis of axially chiral biaryldiols. AB - An efficient atroposelective synthesis of axially chiral biaryldiols via asymmetric Friedel-Crafts aromatization between p-quinones and 2-naphthols was developed. A chiral cobalt(ii) complex of N,N'-dioxide enabled the process to generate axially chiral biaryldiols in up to 98% yield and 95% ee. A large range of substituents at different positions of p-quinones and 2-naphthols was tolerable. The configuration of the product and the chiral N,N'-dioxide-Co(ClO4)2 catalyst was identified by X-ray crystal diffraction analysis and a possible catalytic model was suggested. PMID- 28812061 TI - Behavioral Comorbidities and Drug Treatments in a Zebrafish scn1lab Model of Dravet Syndrome. AB - Loss-of-function mutations in SCN1A cause Dravet syndrome (DS), a catastrophic childhood epilepsy in which patients experience comorbid behavioral conditions, including movement disorders, sleep abnormalities, anxiety, and intellectual disability. To study the functional consequences of voltage-gated sodium channel mutations, we use zebrafish with a loss-of-function mutation in scn1lab, a zebrafish homolog of human SCN1A. Homozygous scn1labs552/s552 mutants exhibit early-life seizures, metabolic deficits, and early death. Here, we developed in vivo assays using scn1labs552 mutants between 3 and 6 d postfertilization (dpf). To evaluate sleep disturbances, we monitored larvae for 24 h with locomotion tracking software. Locomotor activity during dark (night phase) was significantly higher in mutants than in controls. Among anticonvulsant drugs, clemizole and diazepam, but not trazodone or valproic acid, decreased distance moved at night for scn1labs552 mutant larvae. To monitor exploratory behavior in an open field, we tracked larvae in a novel arena. Mutant larvae exhibited impaired exploratory behavior, with increased time spent near the edge of the arena and decreased mobility, suggesting greater anxiety. Both clemizole and diazepam, but not trazodone or valproic acid, decreased distance moved and increased time spent in the center of the arena. Counting inhibitory neurons in vivo revealed no differences between scn1labs552 mutants and siblings. Taken together, our results demonstrate conserved features of sleep, anxiety, and movement disorders in scn1lab mutant zebrafish, and provide evidence that a zebrafish model allows effective tests of treatments for behavioral comorbidities associated with DS. PMID- 28812065 TI - Visible light-induced cyclization reactions for the synthesis of 1,2,4 triazolines and 1,2,4-triazoles. AB - A novel method for concisely synthesizing 1,2,4-triazolines via [3+2] cyclization under visible light is reported. These compounds can be easily converted into 1,2,4-triazoles under basic or photoredox conditions. The application of the 1,2,4-triazoles was also investigated via mild operations. PMID- 28812066 TI - Highly stable and efficient Pd6(SR)12 cluster catalysts for the hydrogen and oxygen evolution reactions. AB - Atomically precise Pd6(SC12H26)12 nanoclusters were synthesized and investigated as electrocatalysts for the hydrogen and oxygen evolution reactions. The present study shows the high catalytic performances of the Pd6 clusters, the key role of the outer-shell electronic state of the metal core in mediating the catalytic properties and the double-edged function of the protecting ligand in the catalytic reactions. PMID- 28812067 TI - Nonlinear imaging microscopy for assessing structural and photochemical modifications upon laser removal of dammar varnish on photosensitive substrates. AB - The nonlinear optical microscopy (NLM) modalities of Multi-Photon Excited Fluorescence (MPEF) and Third Harmonic Generation (THG) have been combined in this work to characterize as a function of depth with micrometric resolution the type and extent of morphological and photochemical modifications that take place upon ultraviolet (UV) pulsed laser removal of a dammar varnish layer applied on a photosensitive substrate. The latter consists on a layer of the synthetic polymer poly-methyl methacrylate doped with a photosensitizer, the aromatic compound 1,4 di[2-(5-phenyloxazolyl)] benzene, that strongly fluoresces upon UV light illumination. A number of laser conditions for partial or total elimination of the varnish coating were explored, namely different wavelengths (266, 248 and 213 nm) and pulse durations, in the nanosecond, picosecond and femtosecond ranges. Changes in the MPEF signals upon laser ablation of the outermost varnish layer successfully signpost photochemical modifications of the varnish or of the photosensitive under-layer, and their dependence with the laser ablation parameters, i.e., wavelength and pulse duration. In turn, THG signals mark the presence of layer boundaries and the reduction by laser ablation of the thickness of the varnish coating. The obtained MPEF and THG data are complemented by morphological observation by optical microscopy and measurements of laser induced fluorescence and micro-Raman spectra of the samples before and after laser ablation at the selected laser irradiation conditions. The results acquired through these non-destructive NLM imaging techniques serve to understand the phenomena that are induced upon laser ablation and to determine the best operating conditions that ensure controlled removal of the varnish with minimal morphological and chemical modifications to the under-layers. This research is of direct application to the UV pulsed laser cleaning of paintings and demonstrates the potential of NLM as a novel assessment tool for non-destructive, on line monitoring of the laser cleaning process. PMID- 28812068 TI - Mechanistic investigations of the 2-coumaranone chemiluminescence. AB - 2-Coumaranones are evolving as a new, efficient, versatile, and synthetically accessible platform for the next generation chemiluminescent probes. Despite the favorable quantum yields, the exact mechanism of their chemiluminescence remains elusive. Here, we analyze the details of the mechanism of the 2-coumaranone chemiluminescence using a combination of experimental and computational methods. By using EPR spectroscopy we show that superoxide radical anions are involved in the reactions, in support of the hypothesis that the mechanism includes a single electron transfer step. The decomposition of the high-energy intermediate, 1,2 dioxetanone, is described in the ground state and in the first three excited singlet states, and indicates that there is at least one conical intersection, which is crucial for generation of excited-state molecules. A peroxy anion that is generated was found to be able to undergo a side reaction that leads to the same (isolated) product as in the light-generating reaction. These results demonstrate the applicability of 2-coumaranones as a model system for several bioluminescence reactions and may lead to the design of new 2-coumaranone derivatives with superior emission characteristics for bioanalytical applications. PMID- 28812069 TI - The sensitivity of folding free energy landscapes of trpzips to mutations in the hydrophobic core. AB - The sensitivity of the stability of folded states and free energy landscapes to the differences in the hydrophobic content of the core residues has been studied for the set of 16-residue trpzips, namely, Trpzip4, Trpzip5 and Trpzip6. The combination of principal component analysis and different secondary structure order metrics as reaction coordinates has been used to characterize and identify all the underlying attractive basins corresponding to the folded and the unfolded states for each trpzip at 300 K. Our results reveal that even a single mutation in the hydrophobic core perturbs the stability of the folded peptide and the conformational preferences for the partially folded and unfolded states significantly, leading to concomitant alterations in the free energy landscape of trpzips. Trpzip4 is observed to have the most rugged and variegated free energy landscape with occurrence of four metastable unfolded states in addition to the folded native state. In contrast, Trpzip5 and Trpzip6 are characterized by two such metastable states. The order metrics pertaining to the rigidity of the turn residues and the distances between the side chains of the hydrophobic core residues have been found to be most revealing to understand the degree of discrimination among the folded states of different peptides in addition to the unfolded states. Our results suggest that both turn propensity and hydrophobic interactions influence the thermodynamics of the folding pathways of trpzips. The implications of the sequence dependent response of amino acids, effect of aromatic stacking interactions and packing of protein's interior for shaping the free energy landscape of the peptides have been highlighted. PMID- 28812070 TI - Correction: Using anion recognition to control the folding and unfolding of a single chain phosphorescent polymer. AB - Correction for 'Using anion recognition to control the folding and unfolding of a single chain phosphorescent polymer' by Xiaofan Ji et al., Chem. Commun., 2017, 53, 8774-8777. PMID- 28812071 TI - Towards completing the cyclopropenylidene cycle: rovibrational analysis of cyclic N3+, CNN, HCNN+, and CNC. AB - The simple aromatic hydrocarbon, cyclopropenylidene (c-C3H2), is a known, naturally-occurring molecule. The question remains as to whether its isoelectronic, cyclic, fellow aromatics of c-N3+, c-CNN, HCNN+, and c-CNC- are as well. Each of these are exciting objects for observation of Titan, and the rotational constants and vibrational frequencies produced here will allow for remote sensing of Titan's atmosphere or other astrophysical or terrestrial sources. None of these four aromatic species are vibrationally strong absorbers/emitters, but the two ions, HCNN+ and c-CNC-, have dipole moments of greater than 3 D and 1 D, respectively, making them good targets for rotational spectroscopic observation. Each of these molecules is shown here to exhibit its own, unique vibrational properties, but the general trends put the vibrational behavior for corresponding fundamental modes within close ranges of one another, even producing nearly the same heavy atom, symmetric stretching frequencies for HCNN+ and c-C3H2 at 1600 cm-1. The c-N3+ cation is confirmed to be fairly unstable and has almost no intensity in its nu2 fundamental. Hence, it will likely remain difficult to characterize experimentally. PMID- 28812072 TI - Critical universality and asymmetry of ionic solution {iodobenzene + 1-decyl-3 methyl-imidazolium bis(trifluorosulfonyl)imide}. AB - The liquid-liquid coexistence curve, heat capacity in the critical and noncritical regions, and the turbidity in critical one-phase and two-phase regions of the binary solution {iodobenzene + 1-decyl-3-methylimidazolium bis(trifluorosulfonyl)imide ([C10mim][NTf2])} have been precisely measured. From the data collected in the critical region, the critical exponents alpha, beta, gamma and nu, as well as the universal critical amplitude ratios RB and X were obtained and were shown to agree well with their theoretical values for the 3D Ising universality class, which further confirmed the 3D-Ising criticality of ionic solutions even in a very low relative permittivity solvent. The coulombic character of the studied system was suggested by the small values of the RPM reduced critical temperature and density. Furthermore, it was found that both the asymmetric behaviors of the diameter of the coexistence curve and the osmotic compressibility could be well described using the complete scaling theory. PMID- 28812073 TI - Controllable access to multi-substituted imidazoles via palladium(ii)-catalyzed C C coupling and C-N condensation cascade reactions. AB - A novel and efficient protocol for the synthesis of various 2,4-disubstituted, 1,2,4-trisubstituted and 1,2,4,5-tetra-substituted imidazoles via cascade palladium catalyzed C-C coupling followed by intramolecular C-N bond formation was developed. Readily accessible boronic acids and N-substituted-2 aminoacetonitriles were firstly reported as starting materials to construct di-, tri-, and tetra-substituted imidazoles in good to excellent yield. PMID- 28812074 TI - Three-dimensional microtissues as an in vitro model for personalized radiation therapy. AB - This paper describes the use of 3D microtissues as an intermediate model between the 2D cell culture and the animal model to assess radiation-induced cellular and DNA damage in the context of personalized radiation therapy. An agarose microwell array was used to generate 3D microtissues with controlled size and shape. The microtissues were exposed to X-ray radiation of various doses, and the radiation damage to cells was examined using a variety of techniques with different end points. Damage to cell membranes and reduction in metabolic activity were examined with the MTT assay and dye inclusion assay. DNA damage was tested with the micronucleus assay, gamma-H2AX immunostaining, and HaloChip assay. 3D microtissues exposed to X-rays are smaller compared to unexposed ones in extended cultures, indicating that X-ray radiation can retard the growth of cells in 3D microtissues, where cells at the outer shells of microtissues can prevent further damage to those inside. PMID- 28812075 TI - Evidence for coherent mixing of excited and charge-transfer states in the major plant light-harvesting antenna, LHCII. AB - LHCII, the major light harvesting antenna from plants, plays a dual role in photosynthesis. In low light it is a light-harvester, while in high light it is a quencher that protects the organism from photodamage. The switching mechanism between these two orthogonal conditions is mediated by protein dynamic disorder and photoprotective energy dissipation. The latter in particular is thought to occur in part via spectroscopically 'dark' states. We searched for such states in LHCII trimers from spinach, at both room temperature and at 77 K. Using 2D electronic spectroscopy, we explored coherent interactions between chlorophylls absorbing on the low-energy side of LHCII, which is the region that is responsible for both light-harvesting and photoprotection. 2D beating frequency maps allow us to identify four frequencies with strong excitonic character. In particular, our results show the presence of a low-lying state that is coupled to a low-energy excitonic state. We assign this to a mixed excitonic-charge transfer state involving the state with charge separation within the Chl a603-b609 heterodimer, borrowing some dipole strength from the Chl a602-a603 excited states. Such a state may play a role in photoprotection, in conjunction with specific and environmentally controlled realizations of protein dynamic disorder. Our identification and assignment of the coherences observed in the 2D frequency maps suggests that the structure of exciton states as well as a mixing of the excited and charge-transfer states is affected by coupling of these states to resonant vibrations in LHCII. PMID- 28812076 TI - A hydrophilic inorganic framework based on a sandwich polyoxometalate: unusual chemoselectivity for aldehydes/ketones with in situ generated hydroxylamine. AB - A hydrophilic inorganic porous catalyst was prepared via the hydrothermal method. The combination of [WZn3(H2O)2(ZnW9O34)2]12- and Co(ii) provides a synergistical catalytic way to promote oximation of aldehyde/ketone with in situ generated hydroxylamine that initially produces an oxime, which further either dehydrates into a nitrile or undergoes a Beckmann rearrangement to form an amide. PMID- 28812077 TI - A first principles study of p-type defects in LaCrO3. AB - Recently, Sr-doped LaCrO3 has been experimentally introduced as a new p-type transparent conducting oxide. It is demonstrated that substituting Sr for La results in inducing p-type conductivity in LaCrO3. Performing first principles calculations we study the electronic structure and formation energy of various point defects in LaCrO3. Our results for the formation energies show that in addition to Sr, two more divalent defects, Ca and Ba, substituting for La in LaCrO3, behave as shallow acceptors in line with previous experimental reports. We further demonstrate that under oxygen-poor growth conditions, these shallow acceptors will be compensated by intrinsic donor-like defects (an oxygen vacancy and Cr on an oxygen site), but in the oxygen-rich growth regime the shallow acceptors have the lowest formation energies between all considered defects and will lead to p-type conductivity. PMID- 28812078 TI - Evolution of the linear band dispersion of monolayer and bilayer germanene on Cu(111). AB - The structural and electronic properties of germanene are always strongly modulated by the hybridization effects with metal substrates. In order to see what will happen when a buffer layer is introduced in-between germanene and metal substrates, we study the structural and electronic properties of the recently synthesized monolayer and bilayer germanene on Cu(111) though first-principles calculations. Our results show that the monolayer germanene on Cu(111) displays a nearly flat configuration and interface states form between the Ge pz and Cu sp like states, with the Ge pi states maintaining the Dirac character. For bilayer germanene on Cu(111), interactions with Cu(111) are reduced due to germanene inter-layer interactions, which is beneficial for the transfer of germanene. In comparison with the bottom germanene layer, the Ge pz character of the upper germanene layer can be maintained near the Fermi level. Since the linear band dispersion is at the heart of the novel quantum phenomenon, our results will facilitate research into the synthesis, extraordinary quantum properties, and applications based on the two-dimensional (2D) germanium system. PMID- 28812079 TI - Computational evaluation of aluminophosphate zeotypes for CO2/N2 separation. AB - Zeolites and structurally related materials (zeotypes) have received considerable attention as potential adsorbents for selective carbon dioxide adsorption. Within this group, zeotypes with aluminophosphate composition (AlPOs) could be an interesting alternative to the more frequently studied aluminosilicate zeolites. So far, however, only a few AlPOs have been characterised experimentally in terms of their CO2 adsorption properties. In this study, force-field based grand canonical Monte Carlo (GCMC) simulations were used to evaluate the potential of AlPOs for CO2/N2 separation, a binary mixture that constitutes a suitable model system for the removal of carbon dioxide from flue gases. A total of 51 frameworks were considered, all of which have been reported either as pure AlPOs or as heteroatom-containing AlPO derivatives. Prior to the GCMC simulations, all structures were optimised using dispersion-corrected density-functional theory calculations. The potential of these 51 systems for CO2/N2 separation was assessed in preliminary calculations (Henry constants and CO2 uptake at selected pressures). On the basis of these calculations, 21 AlPOs of particular interest were selected, for which 15 : 85 CO2/N2 mixture adsorption isotherms were calculated up to 10 bar. For adsorption-based separations using an adsorption pressure of 1 bar (vacuum-swing adsorption), AlPOs with GIS, ATN, ATT, and SIV topologies were predicted to be most attractive, as they combine high CO2/N2 selectivities (75 to 140) and reasonable CO2 working capacities (1 to 1.7 mmol g 1). Under pressure-swing adsorption conditions, there is a tradeoff between selectivity and working capacity: while highly selective AlPOs like GIS reach only moderate working capacities, the frameworks with the highest working capacities above 2 mmol g-1, AFY, KFI, and SAV, have lower selectivities between 25 and 35. To gain atomic-level insights into the host-guest interactions, interaction energy maps were computed for selected AlPOs. The computational assessment presented here can guide future experimental efforts in the development and optimisation of AlPO-based adsorbents for selective CO2 adsorption. PMID- 28812080 TI - Computational design of pH-switchable control agents for nitroxide mediated polymerization. AB - In the present work we use accurate quantum chemistry to evaluate several known and novel nitroxides bearing acid-base groups as pH-switchable control agents for room temperature NMP. Based on G3(MP2,CC)(+)//M06-2X/6-31+G(d) calculations with UAKS-CPCM/M06-2X/6-31+G(d) solvation corrections, a number of novel nitroxides are predicted to be suitable for controlled polymerization of bulk styrene at room temperature when deprotonated (i.e. negatively charged), while remaining inert when neutral. These include an alpha-ethyl analogue of 3-carboxy-PROXYL and novel derivatives of 2,2,5-trimethyl-4-phenyl-3-azahexane-3-nitroxide (TIPNO) that have been modified to include acidic groups. Among the other species evaluated, 3,4-dicarboxy-PROXYL, alpha-carboxylated PROXYL and the phosphoric acid derivative of N-(2-methylpropyl)-N-(1-diethylphosphono-2,2-dimethylpropyl)-N oxyl (SG1) are predicted to undergo suitable pH-switching at around 60 degrees C, and may also be fitting for some applications. PMID- 28812081 TI - Solvent basicity promotes the hydride-mediated electron transfer doping of carbon nanotubes. AB - This study investigates the hydride-mediated electron transfer doping of single walled carbon nanotubes using absorption spectroscopy and thermoelectric measurements. Specific solvent basicity is found to be important for the efficient n-type doping of carbon nanotubes. This progress is an essential requirement for the future development of electronic and energy devices. PMID- 28812082 TI - A broader view on ion heating in traveling-wave devices using fragmentation of CsI clusters and extent of H migration as molecular thermometers. AB - Electron transfer dissociation (ETD) is becoming increasingly important in mass spectrometry-based analysis of peptides and proteins. Supplemental collisional activation of undissociated electron transfer products can significantly increase fragmentation yield and sequence coverage, but hydrogen rearrangements - specifically, transfer of a hydrogen radical from a c to a z fragment - lead to distorted isotope distributions and increased potential for signal overlap. Concomitant collisional activation during the ion/ion reaction significantly reduces these rearrangements, but, in ion traps, also leads to lower reaction rates and reduced overlap of anion and cation clouds. In traveling-wave ion mobility devices, it has been reported - although not under ETD conditions - that significant ion activation can occur depending on the T-wave height and velocity. Here, we investigate this phenomenon in more detail using a commercial instrument (Waters Synapt G2) and report that a similar effect can be induced within the traveling-wave Trap cell where the ETD reaction occurs, using fairly typical T wave settings. This ion 'heating' is demonstrated by analyzing the observed isotope distributions (sensitive to the aforementioned hydrogen rearrangements) of ETD fragments of ubiquitin and substance P. A more detailed investigation of ion activation using cesium iodide clusters (without ETD reagent anions present) shows that the observed behavior is consistent with the known dynamics of ions within traveling-wave devices. The insights gained in this work are potentially relevant both for 'native ETD' studies (in which tuning needs to be optimized to avoid unintentional ion activation) as well as the design of future T-wave ETD devices (where this 'heating' effect might be exploited to promote fragment release). PMID- 28812083 TI - Visible-light-enhanced power generation in microbial fuel cells coupling with 3D nitrogen-doped graphene. AB - A new visible-light-assisted microbial fuel cell composed of a three-dimensional nitrogen-doped graphene self-standing sponge anode and a photoresponsive cathode has been developed for achieving multiple energy conversion and a higher power output. PMID- 28812084 TI - Naphthol synthesis: annulation of nitrones with alkynes via rhodium(iii) catalyzed C-H activation. AB - An efficient and redox-neutral naphthol synthesis has been realized via rhodium(iii) catalyzed C-H activation of alpha-carbonyl nitrones and annulation with alkynes, where the nitrone group functioned as a traceless directing group. PMID- 28812085 TI - High-Tc superconducting phases in organic molecular intercalated iron selenides: synthesis and crystal structures. AB - Hybrid iron-based superconductors were synthesized by sonochemical insertion of organic molecules into FeSe layers. High quality of the samples first enabled reliable phase identifications and three structure types were discovered. Structure determination based on neutron data further facilitated the understanding of their structural stability, doping levels and temperature driven structural transitions. PMID- 28812086 TI - Different natures of surface electronic transitions of carbon nanoparticles. AB - The photoluminescence behaviour of carbon-based nanodots is still debated. Both core and surface structures are involved in the emission mechanism, and the electronic transitions can be modified by external agents such as metal ions or pH, but the general relation between the structure and the optical function is poorly understood. Here, we report a comparative study on the effects of these variables, changing the core structure from crystalline to amorphous, and modifying the surface structure by different passivation procedures. Our results highlight that the emission mechanism of the tunable visible fluorescence is identical for crystalline and amorphous samples, indicating the independence of the emission from the core structure. Furthermore, surface functionalization weakly influences the emission peak position, but has large consequences on their interaction with different metal ions. This suggests the involvement of quasi degenerate electronic states originating from the high density of different interacting groups on the surface. Finally, we report the presence of an unusual ultraviolet emission band for the amorphous sample, likely involving localized molecular-type chromophores with carboxyl ends. Our findings provide new information on the emission mechanisms of CDs and can be used to engineer sub types of CDs displaying very similar emission features, but specifically tailored for different sensing applications. PMID- 28812087 TI - Spatial differentiation of Bronsted acid sites by probe molecule in zeolite USY using synchrotron X-ray powder diffraction. AB - By combining synchrotron X-ray powder diffraction, Rietveld refinement and the use of a probe molecule, Bronsted Acid Sites (BAS) of different strengths in steam-treated USY zeolite can be for the first time spatially differentiated: this enables the analysis of different acid-catalysed reactions of dimethylfuran (biomass) by the zeolite using a definitive site blockage strategy. PMID- 28812088 TI - Consecutive reduction, radical-cyclization, and oxidative-dehydrogenation reaction of ortho-substituted diboryl compounds. AB - An elegant synthetic route to a ladder-type di-borate compound 2a was reported based on the reduction, radical-cyclization, and oxidative-dehydrogenation reaction of 1. The existence of the biradical intermediate [1]2- was supported by both EPR measurements and DFT calculations. PMID- 28812090 TI - Zero-charged catanionic lamellar liquid crystals doped with fullerene C60 for potential applications in tribology. AB - The formation of lamellar liquid crystals (LLCs) has been demonstrated in a few salt-free catanionic surfactant systems and their properties have been well documented. However, examples of their combination with other materials are relatively rare. Herein, a salt-free zero-charged catanionic surfactant with low chain melting temperature was prepared by mixing equimolar tetradecyltrimethylammonium oxide (TTAOH) and oleic acid (OA) in water, and its concentration-dependent aggregate transition was investigated. In the dilute region (cTTAO <= 5 wt%), fluorescence microscopy observations revealed the formation of vesicles (the Lalphav phase). Further increasing cTTAO induced a transition from the Lalphav phase to LLCs via a region where vesicles and lamellae coexist. With ordered hydrophobic domains, the LLCs can be used as hosts for the doping of fullerene C60 (refers to C60 hereafter) with the highest C60/TTAO weight ratio of 0.04. The doping of C60 effectively improves the viscoelasticity of the LLCs confirmed by rheological characterization while only slight modifications on their matrixes have been detected using small angle X-ray scattering measurements. The LLC/C60 hybrids with cTTAO = 80 wt% were then subjected to tribological measurements, and an obvious reduction in their friction coefficients and wear volumes was observed. The C60/TTAO weight ratio at which the best tribological performance appears was determined to be 0.01. Our results indicate that the combination of C60 and catanionic LLCs could lead to the appearance of a new generation of environmentally-benign lubricants. PMID- 28812089 TI - Large-scale, all polycrystalline diamond structures transferred onto flexible Parylene-C films for neurotransmitter sensing. AB - Boron-doped diamond (BDD) has superior electrochemical properties for bioelectronic systems. However, due to its high synthesis temperature, traditional microfabrication methods have limits to integrating BDD with emerging classes of flexible, polymer-based bioelectronic systems. This paper introduces a novel fabrication solution to this challenge, which features (i) a wafer-scale substrate transfer process with all diamond structures transferred onto a flexible Parylene-C substrate and (ii) Parylene anchors introduced to strengthen the bonding between BDD and Parylene substrates, as demonstrated by a peeling test. The electrochemical properties of the transferred BDD-polymer electrodes are evaluated using (i) an outer sphere redox couple Ru(NH3)62+/3+ to study the electron transfer process and (ii) quantitative and qualitative studies of the neurotransmitter redox couple dopamine/dopamine-o-quinone. A linear response of the BDD sensor to dopamine concentrations of 0.5 MUM to 100 MUM is observed (R2 = 0.999) with a sensitivity of 0.21 MUA cm-2 MUM-1. These examples of fabricated diamond-polymer devices suggest a broad application in advanced bioelectronics and optoelectronics. PMID- 28812091 TI - Influence of surface tension in the surfactant-driven fracture of closely-packed particulate monolayers. AB - A phase-field model is used to capture the surfactant-driven formation of fracture patterns in particulate monolayers. The model is intended for the regime of closely-packed systems in which the mechanical response of the monolayer can be approximated as that of a linearly elastic solid. The model approximates the loss in tensile strength of the monolayer with increasing surfactant concentration through the evolution of a damage field. Initial-boundary value problems are constructed and spatially discretized with finite element approximations to the displacement and surfactant damage fields. A comparison between model-based simulations and existing experimental observations indicates a qualitative match in both the fracture patterns and temporal scaling of the fracture process. The importance of surface tension differences is quantified by means of a dimensionless parameter, revealing thresholds that separate different regimes of fracture. These findings are supported by newly performed experiments that validate the model and demonstrate the strong sensitivity of the fracture pattern to differences in surface tension. PMID- 28812092 TI - Effect of ligand structure on the size control of mono- and bi-thiolate-protected silver nanoclusters. AB - Ligand structure could control the size and structure of thiolate-protected silver nanoclusters (Ag NCs) in water. Small alkane-thiols, medium-sized aromatic thiols, and bulky thiol-containing tri-peptides direct the formation of Ag25(SR)18, Ag44(SR)30, and Ag9-15(SR)5-10, respectively. In addition, small alkane-thiol collocates well with other types of thiolate ligand to generate bi thiolate-protected Ag25 NCs with controlled ligand landscapes on their surfaces. PMID- 28812093 TI - A convenient approach to facilitate monitoring Gaucher disease progression and therapeutic response. AB - Gaucher disease (GD) is caused by mutations on the GBA1 gene leading to deficiency in acid beta-glucosidase (GCase) and subsequent accumulation of its substrates, glucosylceramide (GlcC) and glucosylsphingosine (GlcS). GlcS in plasma has been proposed as a highly sensitive and specific biomarker for the diagnosis of GD and for monitoring disease progression and response to therapy. Here we report a novel robust and accurate hydrophilic interaction liquid chromatography tandem mass spectrometric method (HILIC-MS/MS) for the direct measurement of glucosylsphingosine (GlcS) in dried plasma spots (DPS). The method was also capable of resolving the isomeric pair, glucosylsphingosine and galactosylsphingosine, the latter of which was proposed as a promising biomarker for Krabbe disease. The method was fully validated and applied to the analysis of 19 GD patients and carriers. The GlcS levels in 9 GD type I patients who have been on enzyme replacement therapy (ERT) were reduced to a mean of 31.0 nM, much lower compared to a pre-treated specimen at a level of 85.8 nM, but still significantly elevated compared to healthy controls. GlcS concentrations in three treated type III GD patients were much lower compared to an untreated patient. In our preclinical GD studies, 4L;C* mice (subacute nGD model) exhibited comparable levels of plasma GlcS, but had much higher GlcS accumulation in the brain than those of 9V/null mice (chronic neuropathic GD model). Our method for the measurement of GlcS in DPS proved to be a very convenient approach for sample collection, storage and shipping nationwide and internationally. PMID- 28812094 TI - Force percolation of contractile active gels. AB - Living systems provide a paradigmatic example of active soft matter. Cells and tissues comprise viscoelastic materials that exert forces and can actively change shape. This strikingly autonomous behavior is powered by the cytoskeleton, an active gel of semiflexible filaments, crosslinks, and molecular motors inside cells. Although individual motors are only a few nm in size and exert minute forces of a few pN, cells spatially integrate the activity of an ensemble of motors to produce larger contractile forces (~nN and greater) on cellular, tissue, and organismal length scales. Here we review experimental and theoretical studies on contractile active gels composed of actin filaments and myosin motors. Unlike other active soft matter systems, which tend to form ordered patterns, actin-myosin systems exhibit a generic tendency to contract. Experimental studies of reconstituted actin-myosin model systems have long suggested that a mechanical interplay between motor activity and the network's connectivity governs this contractile behavior. Recent theoretical models indicate that this interplay can be understood in terms of percolation models, extended to include effects of motor activity on the network connectivity. Based on concepts from percolation theory, we propose a state diagram that unites a large body of experimental observations. This framework provides valuable insights into the mechanisms that drive cellular shape changes and also provides design principles for synthetic active materials. PMID- 28812095 TI - [Working hour preferences of female and male residents : Developments over 4 years of postgraduate medical training in Germany]. AB - OBJECTIVES: This article addresses developments regarding working hours and working hour preferences of residents undergoing postgraduate training in Germany and analyses if, and for what reasons, full-time or part-time working models are preferred. METHODS: The source of data is the KarMed study, which is based on yearly postal surveys carried out among graduates of the year 2008/2009 from seven medical faculties in Germany. The interviews took place during the entire postgraduate training period. Response rates were 48% in the first year, with subsequent rates of above 85%. For analysis, descriptive statistics and regression models were applied. RESULTS: There is a considerable discrepancy between the actual and the preferred working hours of residents undergoing postgraduate training. Postgraduate training is mostly linked to full-time contracts, usually with additional overtime, even though a considerable proportion of doctors prefer a part-time position. More female residents want to work part-time than male doctors. The same applies for the period after medical specialism: in particular, female doctors with children, female doctors trained in former Western Germany states, and those seeking an occupation in outpatient care request part-time contracts for their professional future. A similar trend has been increasingly observed over the years for male doctors. CONCLUSION: Despite the huge number of residents requesting part-time contracts - during postgraduate training and afterward - the reality is still far behind this model. It is apparent that measures should be taken for both genders. Those measures should facilitate the implementation of the favored working-time model. PMID- 28812096 TI - Perceived racism and incident diabetes in the Black Women's Health Study. AB - AIMS/HYPOTHESIS: Our aim was to assess the association of perceived racism with type 2 diabetes, and the possible mediating influence of diet and BMI. METHODS: The Black Women's Health Study, a follow-up of 59,000 African-American women, began in 1995. Over 16 years 5344 incident cases of diabetes occurred during 576,577 person-years. Cox proportional hazards models were used to estimated HRs and 95% CIs for categories of 'everyday racism' (interpersonal racism in daily life) and 'lifetime racism' (reporting ever treated unfairly due to race with respect to police, housing or work) and incident type 2 diabetes. Models were adjusted for age, questionnaire cycle, marital status, socioeconomic status, education, family history of diabetes, physical activity, alcohol use and smoking status, with and without inclusion of terms for dietary patterns and adult BMI. RESULTS: Compared with women in the lowest quartile of exposure, women in the highest quartile of exposure to everyday racism had a 31% increased risk of diabetes (HR 1.31; 95% CI 1.20, 1.42) and women with the highest exposure to lifetime racism had a 16% increased risk (HR 1.16; 95% CI 1.05, 1.27). Mediation analysis estimated that BMI accounted for half of the association between either the everyday or lifetime racism measure and incident diabetes. CONCLUSIONS/INTERPRETATION: Perceived everyday and lifetime racism were associated with increased risk of type 2 diabetes in this cohort of African American women and appear to be at least partly mediated by BMI. PMID- 28812097 TI - [The best multimodal treatment for locally advanced nasopharyngeal carcinoma : An update of the MAC-NPC data]. PMID- 28812098 TI - [Radiological response assessment of modern immunotherapy using iRECIST]. AB - CLINICAL/METHODICAL ISSUE: Modern immunotherapies in oncology show tumor response patterns differing from conventional chemotherapies including initial pseudo progression. STANDARD RADIOLOGICAL METHODS: Response evaluation criteria in solid tumors (RECIST 1.1) represent the currently most used response criteria for conventional chemotherapy of solid tumors. However, atypical response patterns of immunotherapies are not correctly classified using RECIST 1.1 so that the effectiveness is also incorrectly interpreted. METHODICAL INNOVATIONS: In order to correctly interpret these atypical response patterns, special immune-related response criteria in solid tumors (iRECIST) have been published. In contrast to RECIST 1.1 according to iRECIST an initially unconfirmed progressive disease (iUPD) requires confirmation (iCPD) in clinically stable patients by subsequent control imaging after 4-8 weeks. New lesions are separately assessed within iRECIST. PERFORMANCE: The iRECIST procedure allows a standardized objective assessment of a possible pseudo-progression which can occur in up to 10% of cases depending on the immunomodulating drug and tumor entity. ACHIEVEMENTS: In principle, iRECIST was developed only for usage in trials testing modern immunotherapeutics. PRACTICAL RECOMMENDATIONS: The iRECIST procedure might also be helpful as an additional objective response criterium for clinical treatment decisions, taking the limitations into account. PMID- 28812099 TI - Thrombotic microangiopathy and breastfeeding: where is the link? Questions. PMID- 28812100 TI - [Junior partner is often ostensibly self-employed : Bad news for professional conduct communities]. PMID- 28812101 TI - [New requirements for medical consultation with patients whose first language is not German]. PMID- 28812102 TI - [Minimum quantities: the agony of numbers or means of quality assurance?] PMID- 28812104 TI - [Laparoscopic proctocolectomy technique : Restorative proctocolectomy with ileal pouch-anal anastomosis in ulcerative colitis. Video article]. AB - Laparoscopic restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) constitutes a curative treatment option for therapy-refractory ulcerative colitis. A two-stage procedure with loop ileostomy at the time of IPAA is the most frequent variant of surgery. The aim of the procedure is the complete removal of the colon and rectum with simultaneous restoration of gastrointestinal continuity and preservation of continence functions. Long-term quality of life following laparoscopic proctocolectomy with IPAA is good and comparable with a healthy reference population. The surgical technique is demonstrated in detail with the help of a video of the operation, which is available online. PMID- 28812103 TI - Re-expression of pro-fibrotic, embryonic preserved mediators in irradiated arterial vessels of the head and neck region. AB - PURPOSE: Surgical treatment of head and neck malignancies frequently includes microvascular free tissue transfer. Preoperative radiotherapy increases postoperative fibrosis-related complications up to transplant loss. Fibrogenesis is associated with re-expression of embryonic preserved tissue developmental mediators: osteopontin (OPN), regulated by sex-determining region Y-box 9 (Sox9), and homeobox A9 (HoxA9) play important roles in pathologic tissue remodeling and are upregulated in atherosclerotic vascular lesions; dickkopf-1 (DKK1) inhibits pro-fibrotic and atherogenic Wnt signaling. We evaluated the influence of irradiation on expression of these mediators in arteries of the head and neck region. MATERIALS AND METHODS: DKK1, HoxA9, OPN, and Sox9 expression was examined immunohistochemically in 24 irradiated and 24 nonirradiated arteries of the lower head and neck region. The ratio of positive cells to total cell number (labeling index) in the investigated vessel walls was assessed semiquantitatively. RESULTS: DKK1 expression was significantly decreased, whereas HoxA9, OPN, and Sox9 expression were significantly increased in irradiated compared to nonirradiated arterial vessels. CONCLUSION: Preoperative radiotherapy induces re-expression of embryonic preserved mediators in arterial vessels and may thus contribute to enhanced activation of pro-fibrotic downstream signaling leading to media hypertrophy and intima degeneration comparable to fibrotic development steps in atherosclerosis. These histopathological changes may be promoted by HoxA9-, OPN-, and Sox9-related inflammation and vascular remodeling, supported by downregulation of anti-fibrotic DKK1. Future pharmaceutical strategies targeting these vessel alterations, e. g., bisphosphonates, might reduce postoperative complications in free tissue transfer. PMID- 28812107 TI - Australasian Musculoskeletal Imaging Group (AMSIG) Annual Scientific Meeting Melbourne, May 6-7, 2017. PMID- 28812106 TI - [Costs associated with multiresistant bacteria in neurorehabilitation]. AB - BACKGROUND AND OBJECTIVES: The number of patients with multiresistant bacteria (MRB) in rehabilitation facilities is increasing. The increasing costs of hygienic isolation measures reduce resources available for core rehabilitation services. In addition to the existing lack of care, patients with MRB are at further risk of being given lower priority for admission to rehabilitation facilities. Therefore, the Hygiene Commission of the German Society for Neurorehabilitation (DGNR) attempted to quantify the overall risk for deterioration of rehabilitation care due to the financial burden of MRB. MATERIALS AND METHODS: To analyze the added costs associated with the rehabilitation of patients with MBR, the DGNR Hygiene Commission identified criteria for a cost assessment. Direct (consumables, personnel and miscellaneous costs) and indirect costs of loss of opportunity were evaluated in seven neurorehabilitation centers in different states across Germany. RESULTS: On average, hygienic isolation measures amounted to direct costs of 144 ? per day (47 ? consumables, 92 ? personnel, 5 ? for other costs such as extra transportation expenditure) and indirect costs of 274 ?, totaling 418 ? per patient with MRB per day. Given that approximately 10% of patients had MRB, the added costs of hygienic isolation measures equaled about one tenth of the overall budget of a rehabilitation center and can be expected to rise with the increasing numbers of patients with MRB. CONCLUSIONS: Admission of patients carrying MRB to neurorehabilitation centers triggers added costs that critically diminish the overall capacity for centers to provide their core rehabilitation services. PMID- 28812108 TI - Ultra-early Detection of Microcirculatory Injury as Predictor of Developing Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage. AB - PURPOSE: Delayed cerebral ischemia (DCI) still remains a major complication after subarachnoid hemorrhage (SAH). The aim of our study was to evaluate whether flow analysis of admission digital subtraction angiography (DSA) using parametric color coding (PCC), a postprocessing algorithm, allows ultra-early identification of SAH patients at risk for developing subsequent symptomatic vasospasm. METHODS: In this study 52 patients who suffered SAH from aneurysm rupture, were retrospectively enrolled. Of the patients 26 developed DCI and angiographically proven cerebral vasospasm and 26 age, gender-and clinical status-matched SAH patients without DCI served as controls. Using PCC, the following flow parameters were calculated: cerebral circulation time (CirT), cortical relative time to peak (rTTP) and microvascular transit time (TT). RESULTS: Mean cerebral CirT and cortical rTTP were longer in the DCI group (6.42 s +/- 1.54 and 3.16 s +/- 0.86, respectively) than in the non-DCI group (5.77 s +/- 1.86 and 3.11 s +/- 1.41, respectively), but without statistical significance. The mean microvascular TT was statistically significantly (p = 0.04) longer in the DCI group (3.19 s +/- 0.78) than in the non-DCI group (2.67 s +/- 0.73). CONCLUSION: Angiographic flow analysis might be suitable for ultra-early detection and quantitative assessment of microcirculatory injury in SAH patients, predictive of developing subsequent DCI. Prolonged microvascular TT seems to be a significant independent factor positively associated with DCI development. Identifying SAH patients at risk for DCI ultra-early after ictus might contribute to initiate prophylactic therapies before clinical deterioration. PMID- 28812109 TI - Vibratory perineal stimulation for the treatment of female stress urinary incontinence: a systematic review. AB - INTRODUCTION AND HYPOTHESIS: The pelvic floor muscles (PFM) play an important part in the urinary continence mechanism. Changes in their structure and functionality may lead to a predisposition to pelvic floor dysfunction such as urinary incontinence (UI), which is the involuntary loss of urine. Some techniques for conservative treatment of UI are already well documented. However, new approaches have been found that require scientific proof of their effectiveness, such as vibratory stimulation (VS). Thus, we performed a systematic review of studies that investigated the use of perineal VS (PVS) for the treatment of stress UI. MATERIALS AND METHODS: This study followed the recommendations of the Cochrane Collaboration for systematic reviews. Studies that used PVS for the treatment of female UI were eligible. RESULTS: A total of 56 studies were found, of which ten were duplicates and were excluded. Analysis of the titles and abstracts led to the exclusion of 30 studies, leaving 16 for detailed analysis. Of these, only three were included as they fulfilled all the eligibility criteria previously established for the present study. In spite of the heterogeneity of the protocols, all the studies had the goal of assessing the effects of vibration on the PFM, and the stimulation was found to be effective in reducing urinary leakage, improving muscle strength and consequently the patients' quality of life. CONCLUSIONS: Because of the heterogeneity and the small number of studies, it is not possible to draw a conclusion as to the effectiveness of PVS for the treatment of stress UI, and further studies are needed to provide scientific support for its use. PMID- 28812110 TI - [Extra-axial tumors of the central nervous system]. AB - Extra-axial tumors are intracranial neoplasms but are not located within the brain parenchyma. The localization of intracranial neoplasms helps to narrow down the possible differential diagnoses and also plays a deciding role in the treatment strategy and the prognosis. For this reason exact localization of these lesions is extremely important. Extra-axial tumors are the most common neoplasms among adults. They can be divided in a broad spectrum of histopathological subgroups. The most common extra-axial tumors are meningiomas, which arise from the dura mater. In the vast majority of cases they are benign and slowly growing. Only a few rare subgroups show aggressive behavior. PMID- 28812112 TI - Open Researcher and Contributor ID (ORCID): vital for surgical endoscopy. PMID- 28812111 TI - Syndrome of inappropriate anti-diuresis induces volume-dependent hypercalciuria. AB - : Hyponatremia is associated with bone demineralization. We hypothesized that, during hyponatremia, calciuria and calcium balance depend on volemic status. We evaluated calciuria in patients with hyponatremia, secondary to SIAD or hypovolemia. Patients with SIAD exhibited a volemic expansion that was associated with hypercalciuria. Calciuria was proportional to markers of volemia. INTRODUCTION: Chronic mild hyponatremia has been associated with bone demineralization of unknown mechanisms. During chronic hyponatremia, arginine vasopressin secretion can result from hypovolemia or from syndrome of inappropriate anti-diuresis (SIAD) that leads to a slightly volemic expansion. Since volemia determines renal calcium excretion and balance, we evaluated calcium homeostasis in patients with chronic hyponatremia, related to SIAD or to hypovolemia. METHODS: We retrospectively included all patients referred to our Department between May 2006 and May 2014 for hyponatremia, resulting from SIAD or chronic hypovolemia. None had edema, cirrhosis, cardiac, or renal insufficiency. Exploration included estimation of volemia, extracellular fluid volume (ECFV) measurement with inulin, and calcium homeostasis. RESULTS: In total, the SIAD and hypovolemic groups included 22 and 7 patients, respectively. The SIAD group exhibited signs of increased volemia: higher glomerular filtration rate, higher fractional excretion of uric acid, and lower plasma renin. ECFV exceeded that of the hypovolemic group and was above usual values. There was no difference between the two groups regarding plasma calcium, PTH, and vitamin D. However, in the SIAD group, calciuria was higher than in the hypovolemic group, reaching levels of hypercalciuria. Furthermore, there was a positive correlation between calciuria and markers of volemia. CONCLUSIONS: Our results show that SIAD results in a volemic expansion tendency that is associated with a decrease in renal calcium reabsorption and thus hypercalciuria, whereas in the hypovolemic group, calciuria was not increased. Therefore, renal loss of calcium and bone demineralization in SIAD patients could be partly induced by volemic expansion. PMID- 28812113 TI - [Pathophysiology of intracranial injuries]. AB - Traumatic brain injury (TBI) constitutes a heterogeneous condition that affects the most complex organ of the human body. It is commonly classified by its location as focal injury (e.g. epidural hematoma) and diffuse injury (e.g. diffuse axonal shearing injury) as well as by primary and secondary tissue injury. Accordingly, direct mechanical force causes the primary insult. The tissue damage occurring afterwards is subsumed under the term secondary brain damage. Some of these processes are overlapping and include in the early phase local cerebral ischemia resulting in excitotoxicity, which together with the triggered neuroinflammatory cascade causes the formation of cerebral edema and ultimately increased intracranial pressure once the intracranial compliance is exhausted. In survivors the long-term sequelae of the late stage include seizures caused by synaptic reorganization (incidence depending on the severity of TBI), persistent neuroinflammation promoting further neurodegeneration and increased risk for Alzheimer's disease probably because of TBI-related protein misfolding (tauopathy). Acute phase biomarkers of TBI should ideally originate from the injured brain. They should help distinguish disease severity and predict morbidity and mortality; however, the most commonly used biomarkers (S-100beta and neurone-specific enolase) show a low specificity. In theory their successors (i. e. GFAP, pNF-H) seem more specific; however, these "new kids on the block" still need to be thoroughly investigated in large scale studies. PMID- 28812114 TI - [Thoracic and abdominal imaging in immunocompromised patients]. AB - The number of patients with immunosuppression is rising worldwide. The spectrum of diseases and pathogens in these patients differs widely from that of immunocompetent patients due to frequent opportunistic infections. Symptoms are sometimes unspecific, and imaging plays a key role in the management of these patients. The lungs are a frequent site of infection in immunosuppressed patients. Chest X-ray is the starting point for radiological diagnostics, but shows only limited sensitivity and specificity for infections with atypical pathogens. Thus, computed tomography (CT) is of great importance and allows a better distinction between viral, bacterial, or fungal infections, as well as other noninfectious diseases. Even with CT, however, is exact specification of the pathogen unfortunately not possible. CT is also the main diagnostic tool for assessment of the abdomen, particularly in patients presenting with acute abdomen or when sonographic findings are inconclusive. Moreover, CT allows diagnostic and therapeutic interventions such as percutaneous biopsies, or abscess and fluid drainage. PMID- 28812115 TI - [Smooth muscle hamartoma in volar skin]. AB - We report the case of a 12-year-old girl with a smooth muscle hamartoma of the right index finger. Smooth muscle hamartoma (SMH) is a congenital, relatively common disorder typically with predominance of autochthonal arrector pili muscles. An SMH can also rarely originate from smooth muscles of vessels in palmoplantar skin with the absence of pilosebaceous units. Because of overlapping histological features, the possibility of Becker's nevus being identical or associated with SMH has often been suspected by some authors. PMID- 28812117 TI - [Extracorporeal membrane oxygenation for treatment of acute respiratory failure : Outcome of patients with interstitial lung disease]. PMID- 28812116 TI - SLCO1B1 521T > C polymorphism associated with rosuvastatin-induced myotoxicity in Chinese coronary artery disease patients: a nested case-control study. AB - PURPOSE: This nested case-control study aimed to evaluate the association of candidate genetic variants with statin-induced myotoxicity in Chinese patients with coronary artery disease (CAD). METHODS: One hundred forty-eight Chinese patients experiencing statin-induced myotoxicity were included in our study, and 255 patients without muscular side effects served as controls. Five SNPs in CYP3A5, SLCO1B1, and APOE were genotyped. The effect of genetic variants on statin-induced myotoxicity was assessed. RESULTS: Patients who carried at least one SLCO1B1 521C allele had a higher risk for myotoxicity (OR = 1.69, 95%CI = 1.07-2.67, P = 0.024). Significant association was found between SLCO1B1 521C mutant allele mutation and risk of myotoxicity in individuals that received rosuvastatin (OR = 3.67, 95%CI = 1.42-9.47, P = 0.007). However, non-significant association was observed between 521C mutant allele and risk of myotoxicity (P > 0.5) in patients that received atorvastatin and simvastatin. The other four single nucleotide polymorphisms (SNPs), namely rs776746, rs2306283, rs7412, and rs429358, showed no significant association with any statin induced myotoxicity (P > 0.5). CONCLUSIONS: SLCO1B1 (rs4149056, 521T > C) is associated with statin induced myotoxicity in Chinese patients with coronary artery disease. In addition, SLCO1B1 521C mutant allele increased the risk of rosuvastatin associated myotoxicity. PMID- 28812118 TI - [Long-term results of colorectal cancer screening using sigmoidoscopy : UK flexible sigmoidoscopy screening trial (UKFSST)]. PMID- 28812119 TI - Attention holding elicited by direct-gaze faces is reflected in saccadic peak velocity. AB - Manual response times to peripherally presented targets have been reported to be greater in the presence of task-irrelevant pictorial faces at fixation which establish an eye contact with the observer. This effect is interpreted as evidence that direct-gaze faces hold attention. In three experiments, we investigated whether this attention-holding effect is also reflected in saccadic response times. Participants were asked to make a saccade towards a symbolic target that could appear rightwards or leftwards, in the presence of a task irrelevant centrally placed face with either direct gaze or closed eyes. Unexpectedly, saccadic response times did not show any consistent response pattern as a function of whether the faces were presented with direct gaze vs. closed eyes. Interestingly, saccadic peak velocities were found to be lower in the presence of faces with direct gaze rather than closed eyes (Experiment 1). This effect emerged even in the presence of non-human primate faces (Experiment 2), and no differences between direct gaze and closed eyes emerged when the faces were presented inverted rather than upright (Experiment 3). Overall, these findings suggest that eye contact can have an impact on the saccadic generation system. PMID- 28812120 TI - Risk-adapted robotic stereotactic body radiation therapy for inoperable early stage non-small-cell lung cancer. AB - PURPOSE: To evaluate efficacy and toxicity of stereotactic body radiation therapy (SBRT) with CyberKnife(r) (Accuray, Sunnyvale, CA, USA) in a selected cohort of primary, medically inoperable early-stage non-small cell lung cancer (NSCLC) patients. METHODS: From 2012 to 2016, 106 patients (median age 74 years, range 50 94 years) with primary NSCLC were treated with SBRT using CyberKnife(r). Histologic confirmation was available in 87 patients (82%). For mediastinal staging, 92 patients (87%) underwent 18F-fluorodeoxyglucose positron-emission tomography (18-FDG-PET) and/or endobronchial ultrasound (EBUS)-guided lymph node biopsy or mediastinoscopy. Tumor stage (UICC8, 2017) was IA/B (T1a-c, 1-3 cm) in 86 patients (81%) and IIA (T2a/b, 3-5 cm) in 20 patients (19%). Depending on tumor localization, three different fractionation schedules were used: 3 fractions of 17Gy, 5 fractions of 11Gy, or 8 fractions of 7.5 Gy. Tracking was based on fiducial implants in 13 patients (12%) and on image guidance without markers in 88%. RESULTS: Median follow-up was 15 months (range 0.5-46 months). Acute side effects were mild (fatigue grade 1-2 in 20% and dyspnea grade 1-2 in 17%). Late effects were observed in 4 patients (4%): 3 patients developed pneumonitis requiring therapy (grade 2) and 1 patient suffered a rib fracture (grade 3). In total, 9/106 patients (8%) experienced a local recurrence, actuarial local control rates were 88% (95% confidence interval, CI, 80-96%) at 2 years and 77% (95%CI 56-98%) at 3 years. The median disease-free survival time was 27 months (95%CI 23-31 months). Overall survival was 77% (95%CI 65-85%) at 2 years and 56% (95%CI 39-73%) at 3 years. CONCLUSION: CyberKnife(r) lung SBRT which allows for real-time tumor tracking and risk-adapted fractionation achieves satisfactory local control and low toxicity rates in inoperable early-stage primary lung cancer patients. PMID- 28812121 TI - [Teaching in orthopaedic and trauma surgery]. AB - The scramble for available places to study medicine in Germany continues. One of the core points within the "Master Plan 2020", which has been recently adopted, is the reform of teaching concepts at German medical faculties. In the future, students of human medicine are to be trained primarily based upon competence oriented, integrated curricula. The present paper is intended to present modern teaching concepts and methods, as well as current examination formats, which play a special role in student training in orthopaedics and traumatology. Knowledge in the field of medical and evidence-based treatment strategies, clinical examination techniques, diagnostic/therapeutic procedures and hygienic working conditions are especially important. Individual courses with a focus on research , practice- and competence-orientation are intended to help the students grasp the depth of the subject. PMID- 28812122 TI - [How does knowledge reach health care practice? : Implementation research and knowledge circulation]. AB - BACKGROUND: Evidence-based knowledge is among the most important resources in health care. However, relevant knowledge is often not implemented. There are about 100 different concepts for the "knowledge-to-practice gap". OBJECTIVES: We conducted this review to identify relevant concepts that describe and try to overcome this situation: implementation research and knowledge translation or circulation. MATERIALS AND METHODS: We initially conducted a systematic search in the databases CINAHL, Embase, ERIC, Medline, PsycINFO, Scopus, Cochrane Library and Web of Science without time or language restrictions. Owing to the huge number of relevant articles and their heterogeneity, we decided to focus on the most important concepts thus perform a narrative review. RESULTS: Implementation research is the scientific study of methods of systematically promoting the uptake of current research findings and other evidence-based practices into routine practice, with the aim of improving the quality and effectiveness of health services. From this definition, the affinity with health services research seems to be clear. Knowledge translation has a wider spectrum and includes the synthesis of knowledge. The term "knowledge circulation" seems to fit better, because it underlines the sharing of knowledge between research and practice. CONCLUSION: Implementation research and knowledge circulation are similar research approaches, which try to develop micro-, meso-, and macro-level strategies for health services to bring knowledge into practice. This results in often complex research questions, which should be processed in interdisciplinary teams. PMID- 28812123 TI - [Promoting a balanced diet and physical activity among children : Conditions for the successful implementation and maintenance of multi-level interventions and policies: Results of two qualitative case studies]. AB - BACKGROUND: To date, conditions for successfully implementing and maintaining multi-level interventions and policies for the promotion of a balanced diet and physical activity are not well understood from the perspective of stakeholders. OBJECTIVE: The aim of this article is to examine which factors are regarded as facilitating or impeding introduction, implementation and maintenance of multi level interventions and policies from the standpoint of stakeholders. MATERIALS AND METHODS: Semi-structured face-to-face interviews with stakeholders of one multi-level intervention (Identification and prevention of Dietary- and lifestyle induced health EFfects In Children and infantS [IDEFICS] for the prevention of childhood obesity, n = 4) and one policy (Federal state offices coordinating networks for the provision of healthy food options in schools, n = 3) were analysed using qualitative content analysis. RESULTS: In both cases, the use of existing structures facilitated introduction, implementation and maintenance. Additionally, training of staff for implementation according to standardised protocols or concepts and taking structures and work conditions of settings into account during implementation were considered essential. In both cases, conflicting interests in interdisciplinary stakeholder teams regarding intervention content and implementation were identified as a barrier. A lack of political support and insecure long-term funding only played a role in regard to the implementation and maintenance of policies. On the other hand, target groups of the multi-level intervention were not sufficiently involved in the development of intervention materials which resulted in a lack of tailoring and acceptance in the target groups. CONCLUSIONS: The results provide important insights into the long-term implementation of multi-level interventions and policies in different settings. PMID- 28812125 TI - Recombinant expression and biochemical characterization of Mycobacterium tuberculosis 3Fe-4S ferredoxin Rv1786. AB - Ferredoxins are iron-sulfur protein that mediate electron transfer in cytochrome P450 mono-oxygenase (CYP)-related catalytic reactions in a wide variety of organisms. Rv1786 is a putative ferredoxin, encoded by a gene located downstream of the gene encoding CYP143A1 in the Mycobacterium tuberculosis genome. However, the structure and function of Rv1786 have remained unclear. Here, the recombinant Mtb Rv1786 was expressed, purified as a His-tagged form and characterized with [3Fe-4S] clusters as its cofactors using a series of measurements including SDS PAGE, western blot, UV/Visible, MALDI-TOF/TOF-MS, and electron paramagnetic resonance spectroscopic analysis. Based on the assessments of surface plasmon resonance (SPR) and steady state kinetic assays, Rv1786 was found to be able to couple with both ferredoxin reductase A (FdrA) and flavoprotein reductase A (FprA) as redox partner, but with a stronger binding to FprA and a better coupling activity to FdrA. Preliminary structural and biochemical characterization of Mtb Rv1786 as a redox partner is presented here. PMID- 28812124 TI - Clozapine, chlorpromazine and risperidone dose-dependently reduce emotional hyperthermia, a biological marker of salience. AB - RATIONALE: We recently introduced a new rat model of emotional hyperthermia in which a salient stimulus activates brown adipose tissue (BAT) thermogenesis and tail artery constriction. Antipsychotic drugs, both classical and second generation, act to reduce excessive assignment of salience to objects and events in the external environment. The close association between salient occurrences and increases in body temperature suggests that antipsychotic drugs may also reduce emotional hyperthermia. OBJECTIVES: We determined whether chlorpromazine, clozapine, and risperidone dose dependently reduce emotionally elicited increases in BAT thermogenesis, cutaneous vasoconstriction, and body temperature in rats. METHODS: Rats, chronically instrumented for measurement of BAT and body temperature and tail artery blood flow, singly housed, were confronted with an intruder rat (confined within a small wire-mesh cage) after systemic pre treatment of the resident rat with vehicle or antipsychotic agent. BAT and body temperatures, tail blood flow, and behavioral activity were continuously measured. RESULTS: Clozapine (30 MUg-2 mg/kg), chlorpromazine (0.1-5 mg/kg), and risperidone (6.25 MUg-1 mg/kg) robustly and dose-relatedly reduced intruder elicited BAT thermogenesis and tail artery vasoconstriction, with consequent dose related reduction in emotional hyperthermia. CONCLUSIONS: Chlorpromazine, a first generation antipsychotic, as well as clozapine and risperidone, second-generation agents, dose-dependently reduce emotional hyperthermia. Dopamine D2 receptor antagonist properties of chlorpromazine do not contribute to thermoregulatory effects. Interactions with monoamine receptors are important, and these monoamine receptor interactions may also contribute to the therapeutic effects of all three antipsychotics. Thermoregulatory actions of putative antipsychotic agents may constitute a biological marker of their therapeutic properties. PMID- 28812126 TI - Myocardial iodine concentration measurement using dual-energy computed tomography for the diagnosis of cardiac amyloidosis: a pilot study. AB - OBJECTIVE: To measure myocardium iodine concentration (MIC) in patients with cardiac amyloidosis (CA) using dual-energy computed tomography (DECT). METHODS: Twenty-two patients with CA, 13 with non-amyloid hypertrophic cardiomyopathies (CH) and 10 control patients were explored with pre-contrast, arterial and 5 minute DECT acquisition (Iomeprol; 1.5 mL/kg). Inter-ventricular septum (IVS) thickness, blood pool iodine concentration (BPIC), MIC (mg/mL), iodine ratio and extra-cellular volume (ECV) were calculated. RESULTS: IVS thickness was significantly (p < 0.001) higher in CA (17 +/- 4 mm) and CH (15 +/- 3 mm) patients than in control patients (10 +/- 1 mm). CA patients exhibited significantly (p < 0.001) higher 5-minute MIC [2.6 (2.3-3.1) mg/mL], 5-minute iodine ratio (0.88 +/- 0.12) and ECV (0.56 +/- 0.07) than CH [1.7 (1.4-2.2) mg/mL, 0.57 +/- 0.07 and 0.36 +/- 0.05, respectively] and control patients [1.9 (1.7-2.4) mg/mL, 0.58 +/- 0.07 and 0.35 +/- 0.04, respectively). CH and control patients exhibited similar values (p = 0.9). The area under the curve of 5-minute iodine ratio for the differential diagnosis of CA from CH patients was 0.99 (0.73 1.0; p = 0.001). With a threshold of 0.65, the sensitivity and specificity of 5 minute iodine ratio were 100% and 92%, respectively. CONCLUSION: Five-minute MIC and iodine ratio were increased in CA patients and exhibited best diagnosis performance to diagnose CA in comparison to other parameters. KEY POINT: * Dual energy computed tomography can be used to detect cardiac amyloidosis * Five minute myocardial iodine concentration and iodine ratio increase in cardiac amyloidosis * Among iodine parameters, 5-minute iodine ratio has the best diagnosis performance. PMID- 28812127 TI - [Uveitis in juvenile idiopathic arthritis]. AB - BACKGROUND: Uveitis is the most common extra-articular manifestation of juvenile idiopathic arthritis (JIA). It occurs, according to German registry data, in around 12% of JIA patients and can lead to a loss of vision, especially in cases of delayed diagnosis and/or inadequate therapy. OBJECTIVE: A review of current aspects of diagnosis and therapy was carried out. MATERIAL AND METHODS: This is a review article of the current literature. RESULTS: The risk of uveitis is significantly elevated in patients with an oligoarticular course of JIA, ANA positivity and young age at onset of JIA. During the mostly asymptomatic course of uveitis severe complications, such as cataracts, glaucoma or macular edema can occur, limiting visual acuity. Early detection of uveitis and interdisciplinary cooperation of uveitis specialists and pediatric rheumatologists is of major importance to ensure a favorable long-term prognosis. The initial therapy consists of topical steroids; however, in cases of insufficient response or complicated course of uveitis, conventional synthetic (mainly methotrexate) or biological disease-modifying antirheumatic drugs (bDMARDs) are required. In respect to bDMARDs, the highest evidence exists for treatment with adalimumab; however, depending on the clinical course of disease, other bDMARDs, such as infliximab, golimumab, tocilizumab, abatacept or rituximab may also have a beneficial effect. Despite these treatment options, uveitis or arthritis may frequently persist into adult age. Adequate and early recognition and treatment of uveitis-related complications is of major importance to ensure a good long term visual prognosis. CONCLUSION: Early diagnosis of JIA-associated uveitis and early implementation of effective treatment, especially steroid-sparing DMARD therapy, aims at achieving uveitis inactivity and prevention of ocular damage. PMID- 28812128 TI - Protective effect of cigarette smoke on the course of dextran sulfate sodium induced colitis is accompanied by lymphocyte subpopulation changes in the blood and colon. AB - BACKGROUND: Cigarette smoke (CS) exerts protective effect against ulcerative colitis. The mechanism of this phenomenon remains unknown. One of the possible explanation by which CS exerts its anti-inflammatory action is modulation of immune system. Therefore, the aim of the study was to evaluate the effect of CS on the course of inflammation and subpopulations of lymphocytes in the blood and colon in mice with dextran sulfate sodium (DSS)-induced colitis. METHODS: C57BL6/cmdb mice were exposed to CS for 4 weeks. Colitis was induced with 3.5% DSS given for 10 days. Severity of colitis was determined by disease activity index (DAI), body weight changes, and macro- and microscopic characteristics of inflammation. Peripheral subpopulations of lymphocytes were assessed by flow cytometry (blood) or immunohistochemistry (colonic tissue). RESULTS: Mice treated with 3.5% DSS developed severe colitis with significantly decreased body weight, increased DAI, and macroscopic and histological features of colonic inflammation. These findings were diminished after concomitant exposure to CS. Mice exposed to DSS alone demonstrated significantly decreased percentage of total CD4+ cells (73.1 vs. 52%, p = 0.0007), accompanied by increase of CD8+ cells (18.4 vs. 39.5%, p = 0.0001). Concomitant CS exposure reversed inappropriate CD4+/CD8+ ratio both in the blood and colon and significantly increased B cell presence in the colon. CONCLUSIONS: Our study has demonstrated that CS exposure decreases severity of DSS-induced colitis. This phenomenon was accompanied by changes in CD4/CD8 ratio and B cell level in the peripheral blood and colon. These mechanisms may be responsible for protective effect of smoking in ulcerative colitis. PMID- 28812129 TI - [Device-based remote monitoring : Current evidence]. AB - Telemedicine is increasingly used in clinical cardiology. It offers early detection of arrhythmias, technical device follow-up and support of heart failure management. Regarding technical device follow-up, remote monitoring significantly reduces usage of the health care system. Furthermore, remote monitoring is associated with a significantly reduced time from device malfunction to physician's perception of the event. Using remote monitoring, inappropriate ICD (implantable cardioverter defibrillator) shocks can be significantly reduced compared to routine in-office follow-up. In retrospective studies and meta analyses a prognostic benefit with respect to mortality has been shown. Device based detection of atrial fibrillation and atrial high rate episodes is feasible. However, clinical relevance is currently studied in prospective randomized clinical trials. Heart failure management based on surrogate parameters has not been shown to significantly improve outcome. However, therapeutic management based on pulmonary artery pressure has been shown to significantly reduce morbidity and mortality. This review offers a comprehensive overview on the role of remote monitoring in heart failure management, technical device follow-up and detection of atrial fibrillation and atrial high rate episodes. PMID- 28812130 TI - Studies on the radiographic visibility of the periodontal ligament in lower third molars: can the Olze method be used in the Chinese population? AB - The purpose of the present research is to study the radiographic visibility of the periodontal ligament in third molars from a northern Chinese population to determine if this methodology could be used for the 18-year threshold. A total of 1300 conventional orthopantomograms from 650 males and 650 females of northern Chinese subjects aged between 15 and 40 years were analyzed. The radiographic visibility of the periodontal membrane of fully mineralized third molars was assessed using the stages described by Olze et al. (2010). Stage 0 first appeared at the age of 17.05 years in males and at the age of 18.76 years in females. Stage 1 was first detected at 18.52 years in males and 19.59 years in females. Stage 2 was first achieved by males at the age of 22.33 years and by females at the age of 21.37 years. The earliest appearance of stage 3 was 26.85 years in males and 24.92 years in females. If stage 1 is determined, it is possible to prove that an individual has already attained the age of 18 years. Stages 2 and 3 can be used to determine that a person is over 21 years of age. However, it should also be noted that in 271 cases of tooth 38 and 255 cases of tooth 48, the visibility stage could not be reliably assessed because of fused roots or narrowed furcations. Therefore, this method seems to be of limited value for age estimation in the Chinese population. PMID- 28812131 TI - DNA degrades during storage in formalin-fixed and paraffin-embedded tissue blocks. AB - Formalin-fixed paraffin-embedded (FFPE) tissue blocks are widely used to identify clinically actionable molecular alterations or perform retrospective molecular studies. Our goal was to quantify degradation of DNA occurring during mid to long term storage of samples in usual conditions. We selected 46 FFPE samples of surgically resected carcinomas of lung, colon, and urothelial tract, of which DNA had been previously extracted. We performed a second DNA extraction on the same blocks under identical conditions after a median period of storage of 5.5 years. Quantitation of DNA by fluorimetry showed a 53% decrease in DNA quantity after storage. Quantitative PCR (qPCR) targeting KRAS exon 2 showed delayed amplification of DNA extracted after storage in all samples but one. The qPCR/fluorimetry quantification ratio decreased from 56 to 15% after storage (p < 0.001). Overall, remaining proportion of DNA analyzable by qPCR represented only 11% of the amount obtained at first extraction. Maximal length of amplifiable DNA fragments assessed with a multiplex PCR was reduced in DNA extracted from stored tissue, indicating that DNA fragmentation had increased in the paraffin blocks during storage. Next-generation sequencing was performed on 12 samples and showed a mean 3.3-fold decrease in library yield and a mean 4.5-fold increase in the number of single-nucleotide variants detected after storage. In conclusion, we observed significant degradation of DNA extracted from the same FFPE block after 4 to 6 years of storage. Better preservation strategies should be considered for storage of FFPE biopsy specimens. PMID- 28812132 TI - Bowel preparation in CT colonography: Is diet restriction necessary? A randomised trial (DIETSAN). AB - OBJECTIVES: To investigate whether diet restriction affects quality of colon cleansing and patient tolerance during reduced bowel preparation for CT colonography (CTC). METHODS: Asymptomatic and symptomatic patients were enrolled in this pragmatic, single-centre, randomised trial. All patients were randomly assigned (1:1 ratio, blocks of ten) to receive a reduced bowel preparation and faecal tagging with (Diet-Restriction-Group [DR]) or without (No-Diet-Restriction Group [NDR]) dietary restriction. Five readers performed a blinded subjective image analysis, by means of 4-point Likert-scales from 0 (highest score) to 3 (worst score). Endpoints were the quality of large bowel cleansing and tolerance to the assigned bowel preparation regimen. The trial is registered at ClinicalTrial.gov (URomLSDBAL1). RESULTS: Ninety-five patients were randomly allocated to treatments (48 in NDR-group, 47 in DR-group). Both groups resulted in optimal colon cleansing. The mean residual stool (0.22, 95%CI 0.00-0.44) and fluid burden (0.39, 95%CI 0.25-0.53) scores for patients in DR-group were similar to those in patients in NDR-group (0.25, 95%CI 0.03-0.47 [p = 0.82] and 0.49, 95%CI 0.30-0.67 [p = 0.38], respectively). Tolerance was significantly better in NDR-group. CONCLUSION: A reduced bowel preparation in association with faecal tagging and without any dietary restriction demonstrated optimal colon cleansing effectiveness for CTC, providing better patient compliance compared with dietary restriction. KEY POINTS: * Dietary restriction in reduced bowel preparation regimen can be avoided. * The quality of colon cleansing is not affected by dietary restriction. * The quality of faecal tagging is not affected by dietary restriction. * Avoidance of dietary restriction improves patients' tolerance for CTC. PMID- 28812133 TI - [Watchful waiting as a therapeutic principle for diseases of the vitreoretinal interface]. AB - Elective surgery of the vitreoretinal interface is currently the most common reason for vitrectomy in Germany. The evaluation and correct interpretation of spectral domain optical coherence tomography (SD-OCT) images is of great importance but the indications for vitrectomy in macular surgery should be based more on patient symptoms and not only the OCT findings. Watchful waiting is highlighted as an alternative therapeutic option in individual patients. This article addresses a number of aspects and discrepancies between findings and patients' level of suffering based on binocular symptoms. Postoperative retinal thickening and irregular surface of the macula after peeling operations may still allow excellent function and often require no therapeutic measures. The difficulties in differentiating between cystoid macular edema after cataract operations with simultaneous epiretinal gliosis and gliosis as the cause of macular edema are highlighted. PMID- 28812134 TI - Elevated tumor-to-liver uptake ratio (TLR) from 18F-FDG-PET/CT predicts poor prognosis in stage IIA colorectal cancer following curative resection. AB - PURPOSE: The prognostic value of the tumor-to-liver uptake ratio (TLR) from 18 fluoro-2-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in the early stage of colorectal cancer (CRC) is unclear. Notably, some stage IIA CRC patients experience early recurrence even after curative resection and might benefit from neoadjuvant or adjuvant chemotherapy. This study aims to evaluate whether elevated TLR from 18F-FDG-PET/CT can predict poor prognosis in stage IIA CRC patients undergoing curative resection. METHODS: From April 2010 to December 2013, 504 consecutive CRC patients with different TNM stages (I-IV) underwent 18F-FDG-PET/CT scans at the 6th Affiliated Hospital of Sun Yat-Sen University. Among the patients, 118 with stage IIA CRC who accepted preoperative 18F-FDG-PET/CT scanning and were treated with curative surgery alone were reviewed retrospectively. The maximum standardized uptake value (SUVmax) in the primary tumor, TLR, and demographic, clinical, histopathological, and laboratory data were analyzed. Receiver operating characteristic (ROC) curve, univariate and multivariate analyses were performed to identify prognostic factors associated with patient disease-free survival (DFS) and overall survival (OS). RESULTS: ROC curve analysis demonstrated that TLR was superior to primary tumor SUVmax in predicting the risk of recurrence in stage IIA CRC. The optimal TLR cutoff was 6.2. Univariate analysis indicated that elevated TLR, tumor size, and lymphovascular/neural invasion correlated with DFS (P = 0.001, P = 0.002, and P = 0.001, respectively) and OS (P = 0.001, P = 0.003, and P < 0.001, respectively). The 1-, 3-, and 5-year DFS rates were 98.4%, 96.9%, and 96.9% for stage IIA CRC patients with lower TLR (<=6.2) versus 77.8%, 60.6%, and 60.6% for those with elevated TLR (>6.2), respectively. The 1-, 3-, and 5-year OS rates were 100.0%, 100.0%, and 98.3% for the patients with lower TLR versus 98.1%, 83.3%, and 74.3% for those with elevated TLR. Cox regression analysis showed that elevated TLR [>6.2; hazard ratio (HR): 3.109-57.463; P < 0.001] and tumor size (>4.4 cm; HR: 1.636-19.155; P = 0.006) were independent risk factors for DFS. Meanwhile, elevated TLR (>6.2; HR: 1.398-84.945; P = 0.023) and lymphovascular/neural invasion (positive; HR: 1.278-12.777; P = 0.017) were independent risk factors for OS. CONCLUSION: Elevated TLR predicted worse DFS and OS for stage IIA CRC patients and might serve as a potential radiological index to identify candidates for neoadjuvant or adjuvant chemotherapy. Stage IIA CRC patients with elevated TLR should be monitored carefully for early detection of possible recurrence. PMID- 28812135 TI - Pulmonary mucormycosis: serial morphologic changes on computed tomography correlate with clinical and pathologic findings. AB - PURPOSE: To evaluate serial computed tomography (CT) findings of pulmonary mucormycosis correlated with peripheral blood absolute neutrophil count (ANC). MATERIALS AND METHODS: Between February 1997 and June 2016, 20 immunocompromised patients (10 males, 10 females; mean age, 48.9 years) were histopathologically diagnosed as pulmonary mucormycosis. On initial (n=20) and follow-up (n=15) CT scans, the patterns of lung abnormalities and their changing features on follow up scans were evaluated, and the pattern changes were correlated with ANC changes. RESULTS: All patients were immunocompromised. On initial CT scans, nodule (<=3cm)/mass (>3cm) or consolidation with surrounding ground-glass opacity halo (18/20, 90%)) was the most common pattern. On follow-up CT, morphologic changes (13/15, 87%) could be seen and they included reversed halo (RH) sign, central necrosis, and air-crescent sign. Although all cases did not demonstrate the regular morphologic changes at the same timeline, various combinations of pattern change could be seen in all patients. Sequential morphologic changes were related with recovering of ANC in 13 of 15 patients. CONCLUSION: Pulmonary mucormycosis most frequently presents as consolidation or nodule/mass with halo sign at CT. Morphologic changes into RH sign, central necrotic cavity or air crescent sign occur with treatment and recovery of ANC. KEY POINTS: * Pulmonary mucormycosis showed various CT-morphology including CT halo sign * Pulmonary mucormycosis had trends of serial morphologic changes on follow-ups * Recovery of absolute neutrophil count changed CT-morphology of mucormycosis in immune compromised patients. PMID- 28812136 TI - Clinical outcomes of Y90 radioembolization for recurrent hepatocellular carcinoma following curative resection. AB - PURPOSE: To assess safety/efficacy of yttrium-90 radioembolization (Y90) in patients with recurrent hepatocellular carcinoma (HCC) following curative surgical resection. METHODS: With IRB approval, we searched our prospectively acquired database for patients that were treated with Y90 for recurrent disease following resection. Baseline characteristics and bilirubin toxicities following Y90 were evaluated. Intention-to-treat overall survival (OS) and time-to progression (TTP) from Y90 were assessed. RESULTS: Forty-one patients met study inclusion criteria. Twenty-six (63%) patients had undergone minor (<=3 hepatic segments) resection while 15 (37%) patients underwent major (>3 hepatic segments) resections. Two patients (5%) had biliary-enteric anastomoses created during surgical resection. The median time from HCC resection to the first radioembolization was 17 months (95% CI: 13-37). The median number of Y90 treatment sessions was 1 (range: 1-5). Ten patients received (entire remnant) lobar Y90 treatment while 31 patients received selective (<=2 hepatic segments) treatment. Grades 1/2/3/4 bilirubin toxicity were seen in nine (22%), four (10%), four (10%), and zero (0%) patients following Y90. No differences in bilirubin toxicities were identified when comparing lobar with selective approaches (P = 0.20). No post-Y90 infectious complications were identified. Median TTP and OS were 11.3 (CI: 6.5-15.5) and 22.1 months (CI: 10.3-31.3), respectively. CONCLUSIONS: Radioembolization is a safe and effective method for treating recurrent HCC following surgical resection, with prolonged TTP and promising survival outcomes. PMID- 28812137 TI - Myoglobinemia markers with potential applications in forensic sample analysis: lipid markers in myoglobinemia for postmortem blood. AB - The crush syndrome, in which rhabdomyolysis and trauma occur as a result of heat stroke and drug intoxication, can lead to myoglobinemia. This condition can be diagnosed by measuring myoglobin (Mb) levels in blood and urine. However, postmortem Mb levels are unreliable indicators, since blood Mb concentration drastically increases within a very short time after death and urine cannot always be obtained at dissection; this makes it difficult to diagnose myoglobinemia in a corpse. To address this issue, in this study, we used a lipidomics approach to identify markers that can be used to detect myoglobinemia in postmortem blood samples. We found that increases in levels of fatty acid oxides such as stearic, oleic, linoleic, and arachidonic acid and decreases in levels of plasmalogens and phosphatidylethanolamine in the blood were associated with high Mb level. These results demonstrate that postmortem samples are amenable to lipidomics analysis and provide a set of markers other than Mb that can be used for postmortem diagnosis of myoglobinemia. PMID- 28812138 TI - [Telemetric follow-up of implantable electronic cardiac devices : Optimisation of care in clinical practice]. AB - Remote follow-up of patients with implantable electronic cardiac devices (IECD) is a scientifically well-evaluated and technically mature method. Advantages over conventional follow-up include rapid detection of clinically relevant events (i. e. arrhythmias) and of technical problems. Additionally, telemetric follow-up of IECDs has a high degree of acceptance among both patients as well as health care professionals and carries the potential to reduce health care costs. The implementation of a remote follow-up programme is associated with organisational, infrastructural and legal aspects, which are reviewed. PMID- 28812139 TI - Groin hernia diagnostics: dynamic inguinal ultrasound (DIUS). AB - PURPOSE: Although clinical examination is the gold standard for the diagnosis of groin hernia, imaging procedures can improve the detection of femoral hernias, incipient hernias, and less-common types of hernias (e.g., an obturator hernia). The aim of this study is to evaluate the sensitivity and specificity of dynamic inguinal ultrasound (DIUS). MATERIALS AND METHODS: Between July 2010 and June 2015, 4951 clinical and ultrasound examinations of the groin area were conducted at the Hanse-Hernienzentrum in Hamburg, Germany. The ultrasonographic findings were prospectively evaluated to determine the number of inguinal and femoral hernia diagnoses that were ultrasonically confirmed and also to consider cases in which clinical examination overlooked these diagnoses. The results were compared with the intraoperative findings. RESULTS: The results show that standardized ultrasound examination of the groin area with high-frequency, small-part linear transducers also serves to accurately display femoral and small or occult groin hernias. The high-level specificity (0.9980) and sensitivity (0.9758) are proof of the procedure's quality. CONCLUSIONS: To ensure high-quality hernia treatment, regular use of standardized ultrasound examinations is recommended. PMID- 28812140 TI - Blistering eruptions in Henoch-Schonlein syndrome: more common than assumed. PMID- 28812141 TI - Next generation of ventricular catheters for hydrocephalus based on parametric designs. AB - BACKGROUND: The flow pattern of the cerebrospinal fluid is probably the most important factor related to obstruction of ventricular catheters during the normal treatment of hydrocephalus. To better comprehend the flow pattern, we have carried out a parametric study via numerical models of ventricular catheters. In previous studies, the flow was studied under steady and, recently, in pulsatile boundary conditions by means of computational fluid dynamics (CFD) in three dimensional catheter models. OBJECTIVE: This study aimed to bring in prototype models of catheter CFD flow solutions as well to introduce the theory behind parametric development of ventricular catheters. METHODS: A preceding study allowed deriving basic principles which lead to designs with improved flow patterns of ventricular catheters. The parameters chosen were the number of drainage segments, the distances between them, the number and diameter of the holes on each segment, as well as their relative angular position. RESULTS: CFD results of previously unreleased models of ventricular catheter flow solutions are presented in this study. Parametric development guided new designs with better flow distribution while lowering the shear stress of the catheters holes. High-resolution 3D printed catheter solutions of three models and basic benchmark testing are introduced as well. CONCLUSIONS: The next generation of catheter with homogeneous flow patterns based on parametric designs may represent a step forward for the treatment of hydrocephalus, by possibly broadening their lifespan. PMID- 28812142 TI - TCDD administered on activated carbon eliminates bioavailability and subsequent shifts to a key murine gut commensal. AB - Activated carbon (AC) is an increasingly attractive remediation alternative for the sequestration of dioxins at contaminated sites globally. However, the potential for AC to reduce the bioavailability of dioxins in mammals and the residing gut microbiota has received less attention. This question was partially answered in a recent study examining 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced hallmark toxic responses in mice administered with TCDD sequestered by AC or freely available in corn oil by oral gavage. Results from that study support the use of AC to significantly reduce the bioavailability of TCDD to the host. Herein, we examined the bioavailability of TCDD sequestered to AC on a key murine gut commensal and the influence of AC on the community structure of the gut microbiota. The analysis included qPCR to quantify the expression of segmented filamentous bacteria (SFB) in the mouse ileum, which has responded to TCDD induced host toxicity in previous studies and community structure via sequencing the 16S ribosomal RNA (rRNA) gene. The expression of SFB 16S rRNA gene and functional genes significantly increased with TCDD administered with corn oil vehicle. Such a response was absent when TCDD was sequestered by AC. In addition, AC appeared to have a minimal influence on murine gut community structure and diversity, affecting only the relative abundance of Lactobacillaceae and two other groups. Results of this study further support the remedial use of AC for eliminating bioavailability of TCDD to host and subsequent influence on the gut microbiome. PMID- 28812143 TI - Serotonin in psychiatry: in vitro disease modeling using patient-derived neurons. AB - Several lines of evidence implicate serotonin in the etiology of multiple psychiatric disorders, especially mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BD). Much of our current understanding of biological mechanisms underlying serotonergic alterations in mood disorders comes from animal studies. Innovation in induced pluripotent stem cell and transdifferentiation technologies for deriving neurons from adult humans has enabled the study of disease-relevant cellular phenotypes in vitro. In this context, human serotonergic neurons can now be generated using three recently published methodologies. In this mini-review, we broadly discuss evidence linking altered serotonergic neurotransmission in MDD and BD and focus on recently published methods for generating human serotonergic neurons in vitro. PMID- 28812144 TI - [Trends in retinal detachment surgery : What has changed compared to 2001?] AB - INTRODUCTION: In 2001 a survey among retinal surgeons regarding the treatment of rhegmatogenous retinal detachment either with scleral buckling methods or primary vitrectomy was performed. Due to the technical progress of vitrectomy and observational systems, it seemed appropriate to renew and update this survey supplemented with current aspects. METHODS: In this study 78 vitreoretinal surgeons from German-speaking countries were surveyed via an anonymous online questionnaire on their treatment decisions for defined retinal detachment constellations. Furthermore, general aspects, such as surgical experience, timing of surgery and anesthesia were queried. The results were compared to the results of 2001. RESULTS: Only 31.1% of the surgeons had performed more than 1000 scleral buckling procedures, whereas 80.8% had performed more than 1000 primary vitrectomies, 72.7% use mainly 23 gauge, 19.5% use 20 gauge and 7.8% use 25 gauge vitrectomy systems. Of the participants 88.5% perform retinal detachment surgery also on weekends and 85.9% in emergency services. In cases of one-hole configuration 73.1% of surgeons would choose treatment with a scleral buckle and only 7.7% with primary vitrectomy. The willingness to perform scleral buckling procedure decreases with coexisting risk factors. In the presence of two adjacent retinal tears but still treatable by scleral buckling, only 56.9% would perform a conventional buckling technique but 33.3% primary vitrectomy. In a more complex retinal hole configuration but still treatable with scleral buckling elements, only 6.4% would chose scleral buckling whereas 71.8% primary vitrectomy. In comparison with the 2001 survey, there is a marked trend in retinal detachment surgery in favor of primary vitrectomy not only in pseudophakic eyes. General anesthesia was the preferred anesthesia method and in a macular-on situation nearly 50% of the responders would perform surgery on the next day. CONCLUSION: The results of our survey confirm an obvious tendency away from buckling surgery towards primary vitrectomy in the treatment of rhegmatogenous retinal detachment. PMID- 28812145 TI - Clarification on the role of LV untwisting in LV "relaxation" and diastolic filling. PMID- 28812146 TI - Engineering Rhodosporidium toruloides for the production of very long-chain monounsaturated fatty acid-rich oils. AB - Erucic acid (cis-docosa-13-enoic acid, C22:1?13) and nervonic acid (cis-tetracosa 15-enoic acid, C24:1 ?15) are important renewable feedstocks in plastic, cosmetic, nylon, and lubricant industries. Furthermore, nervonic acid is also applied to the treatment of some neurological diseases. However, the production of these two very long-chain fatty acids (VLCFA) is very limited as both are not present in the main vegetable oils (e.g., soybean, rapeseed, sunflower, and palm). Ectopic integration and heterologous expression of fatty acid elongases (3 ketoacyl-CoA synthases, KCS) from different plants in Rhodosporidium toruloides resulted in the de novo synthesis of erucic acid and nervonic acid in this oleaginous yeast. Increasing KCS gene copy number or the use of a push/pull strategy based on the expression of elongases with complementary substrate preferences increased significantly the amount of these two fatty acids in the microbial oils. Oil titers in 7-L bioreactors were above 50 g/L, and these two VLCFA represented 20-30% of the total fatty acids. This is the first time that microbial production of these types of oils is reported. PMID- 28812147 TI - Can polyp detection rate be used prospectively as a marker of adenoma detection rate? AB - BACKGROUND: Adenoma detection rate (ADR) is a quality indicator for screening colonoscopy, but its calculation is time-consuming. Polyp detection rate (PDR) has been found to correlate with ADR; however, its use as a quality indicator has been criticized out of concern for endoscopists artificially inflating the PDR. We aim to evaluate whether active monitoring affects PDR. METHODS: In March 2015, 14 endoscopists were made aware that their personal PDRs would be tracked monthly as a quality improvement project. Endoscopists received a report of their individual monthly and cumulative PDR, departmental averages, and a benchmark PDR. Following the intervention, data were collected for consecutive patients undergoing average risk screening colonoscopy for six months. PDR, ADR, and adenoma to polyp detection ratio quotient (APDRQ) were compared to a six-month pre-intervention period. RESULTS: 2203 patients were included in the study. There was no statistically significant difference in PDR when comparing pre- and post intervention (44 vs. 45%, OR 1.04; 95% CI 0.77-1.36). No statistically significant difference in ADR was observed when comparing pre- and post intervention (29 vs. 30%, OR 1.03; 95% CI 0.64-1.52). There was no statistically significant difference in APDRQ when comparing pre- and post-intervention (0.67 vs. 0.66, OR 0.99; 95% CI 0.69-1.33). CONCLUSIONS: Monthly report cards did not result in a change in PDR or APDRQ. In some environments, PDR can be used as a surrogate marker of ADR, despite endoscopist awareness that PDR is being measured. PMID- 28812148 TI - Local recurrence of squamous cell carcinoma of the head and neck after radio(chemo)therapy: Diagnostic performance of FDG-PET/MRI with diffusion weighted sequences. AB - PURPOSE: To determine the diagnostic performance of FDG-PET/MRI with diffusion weighted imaging (FDG-PET/DWIMRI) for detection and local staging of head and neck squamous cell carcinoma (HNSCC) after radio(chemo)therapy. MATERIALS AND METHODS: This was a prospective study that included 74 consecutive patients with previous radio(chemo)therapy for HNSCC and in whom tumour recurrence or radiation induced complications were suspected clinically. The patients underwent hybrid PET/MRI examinations with morphological MRI, DWI and FDG-PET. Experienced readers blinded to clinical/histopathological data evaluated images according to established diagnostic criteria taking into account the complementarity of multiparametric information. The standard of reference was histopathology with whole-organ sections and follow-up >=24 months. Statistical analysis considered data clustering. RESULTS: The proof of diagnosis was histology in 46/74 (62.2%) patients and follow-up (mean +/- SD = 34 +/- 8 months) in 28/74 (37.8%). Thirty eight patients had 43 HNSCCs and 46 patients (10 with and 36 without tumours) had 62 benign lesions/complications. Sensitivity, specificity, and positive and negative predictive value of PET/DWIMRI were 97.4%, 91.7%, 92.5% and 97.1% per patient, and 93.0%, 93.5%, 90.9%, and 95.1% per lesion, respectively. Agreement between imaging-based and pathological T-stage was excellent (kappa = 0.84, p < 0.001). CONCLUSION: FDG-PET/DWIMRI yields excellent results for detection and T classification of HNSCC after radio(chemo)therapy. KEY POINTS: * FDG-PET/DWIMRI yields excellent results for the detection of post-radio(chemo)therapy HNSCC recurrence. * Prospective one-centre study showed excellent agreement between imaging-based and pathological T-stage. * 97.5% of positive concordant MRI, DWI and FDG-PET results correspond to recurrence. * 87% of discordant MRI, DWI and FDG-PET results correspond to benign lesions. * Multiparametric FDG-PET/DWIMRI facilitates planning of salvage surgery in the irradiated neck. PMID- 28812149 TI - [Uveitis in spondyloarthritis]. AB - Acute anterior uveitis (AAU) is the most frequent uveitis subtype. It is often associated with HLA-B27 and with inflammatory rheumatic diseases, in particular with spondyloarthritis (SpA), which itself is strongly associated with HLA-B27. About 40-60% of patients with AAU have an associated spondyloarthritis, and 20 40% of patients with spondyloarthritis also have uveitis. The incidence of AAU in patients with SpA clearly correlates with disease duration. The AAU has an acute onset, usually affects only one eye at a time, and shows a tendency for recurrence. Early therapy of AAU with topical steroids is relevant for good visual outcomes. Minimum duration of therapy of flares of AAU is 6-8 weeks in order to prevent early recurrency. The rate of local complications correlates with the rate of AAU flares and the visual outcome is often good. Refractory uveitis and frequent recurrencies of AAU may be treated with conventional disease modifying antirheumatic drugs (DMARDs, such as sulfasalazine and methotrexate) and biologicals (e.g. TNF-alpha inhibitors). Any first episode of AAU diagnosed by an ophthalmologist should prompt referral to rheumatology for suspected SpA, particularly if rheumatic symptoms are present. PMID- 28812150 TI - Respiratory complications after colonic procedures in chronic obstructive pulmonary disease: does laparoscopy offer a benefit? AB - BACKGROUND: Patients with severe chronic obstructive pulmonary disease (COPD) are at a higher risk for postoperative respiratory complications. Despite the benefits of a minimally invasive approach, laparoscopic pneumoperitoneum can substantially reduce functional residual capacity and raise alveolar dead space, potentially increasing the risk of respiratory failure which may be poorly tolerated by COPD patients. This raises controversy as to whether open techniques should be preferentially employed in this population. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database from 2011 to 2014 was used to examine the clinical data from patients with COPD who electively underwent laparoscopic and open colectomy. Patients defined as having COPD demonstrated either functional disability, chronic use of bronchodilators, prior COPD-related hospitalization, or reduced forced expiratory reserve volumes on lung testing (FEV1 <75%). Demographic data and preoperative characteristics were compared. Linear and logistic regressions were utilized to perform multivariate analysis and determine risk-adjusted outcomes. RESULTS: Of the 4397 patients with COPD, 53.8% underwent laparoscopic colectomy (LC) while 46.2% underwent open colectomy (OC). The LC and OC groups were similar with respect to demographic data and preoperative comorbidities. Equivalent frequencies of exertional dyspnea (LC 35.4 vs OC 37.7%, P = 0.11) were noted. After multivariate risk adjustment, OC demonstrated an increased rate of overall respiratory complications including pneumonia, reintubation, and prolonged ventilator dependency when compared to LC (OR 1.60, 95% CI 1.30-1.98, P < 0.01). OC was associated with longer length of stay (10 +/- 8 vs. 6.7 +/- 7 days, P < 0.01) and higher readmission (OR 1.36, 95% CI 1.09-1.68, P < 0.01) compared to LC. CONCLUSION: Despite the potential risks of laparoscopic pneumoperitoneum in the susceptible COPD population, a minimally invasive approach was associated with lower risk of postoperative respiratory complications, shorter length of stay, and decrease in postoperative morbidity. PMID- 28812151 TI - High clinical impact and diagnostic accuracy of EUS-guided biopsy sampling of subepithelial lesions: a prospective, comparative study. AB - BACKGROUND: In a tertiary center setting we aimed to study the diagnostic accuracy and clinical impact of EUS-guided biopsy sampling (EUS-FNB) with a reverse bevel needle compared with that of fine needle aspiration (EUS-FNA) in the work-up of subepithelial lesions (SEL). METHODS: All patients presenting with SELs referred for EUS-guided sampling were prospectively included in 2012-2015. After randomization of the first pass modality, dual sampling with both EUS-FNB and EUS-FNA was performed in each lesion. Outcome measures in an intention-to diagnose analysis were the diagnostic accuracy, technical failures, and adverse events. The clinical impact was measured as the performance of additional diagnostic procedures post-EUS and the rate of unwarranted resections compared with a reference cohort of SELs sampled in the same institution 2006-2011. RESULTS: In 70 dual sampling procedures of unique lesions (size: 6-220 mm) the diagnostic sensitivity for malignancy and the overall accuracy of EUS-FNB was superior to EUS-FNA compared head-to-head (90 vs 52%, and 83 vs 49%, both p < 0.001). The adverse event rate of EUS-FNB was low (1.2%). EUS-FNB in 2012-2015 had a positive clinical impact in comparison with the reference cohort demonstrated by less cases referred for an additional diagnostic procedure, 12/83 (14%) vs 39/73 (53%), p < 0.001, and fewer unwarranted resections in cases subjected to surgery, 3/48 (6%) vs 12/35 (34%), p = 0.001. CONCLUSIONS: EUS-FNB with a reverse bevel needle is safe and superior to EUS-FNA in providing a conclusive diagnosis of subepithelial lesions. This biopsy sampling approach facilitates a rational clinical management and accurate treatment. PMID- 28812152 TI - Native arbuscular mycorrhizal symbiosis alters foliar bacterial community composition. AB - The effects of arbuscular mycorrhizal (AM) fungi on plant-associated microbes are poorly known. We tested the hypothesis that colonization by an AM fungus affects microbial species richness and microbial community composition of host plant tissues. We grew the grass, Deschampsia flexuosa in a greenhouse with or without the native AM fungus, Claroideoglomus etunicatum. We divided clonally produced tillers into two parts: one inoculated with AM fungus spores and one without AM fungus inoculation (non-mycorrhizal, NM). We characterized bacterial (16S rRNA gene) and fungal communities (internal transcribed spacer region) in surface sterilized leaf and root plant compartments. AM fungus inoculation did not affect microbial species richness or diversity indices in leaves or roots, but the AM fungus inoculation significantly affected bacterial community composition in leaves. A total of three OTUs in leaves belonging to the phylum Firmicutes positively responded to the presence of the AM fungus in roots. Another six OTUs belonging to the Proteobacteria (Alpha, Beta, and Gamma) and Bacteroidetes were significantly more abundant in NM plants when compared to AM fungus-inoculated plants. Further, there was a significant correlation between plant dry weight and leaf microbial community compositional shift. Also, there was a significant correlation between leaf bacterial community compositional shift and foliar nitrogen content changes due to AM fungus inoculation. The results suggest that AM fungus colonization in roots has a profound effect on plant physiology that is reflected in leaf bacterial community composition. PMID- 28812153 TI - Establishing the learning curve of transanal minimally invasive surgery for local excision of rectal neoplasms. AB - INTRODUCTION: Transanal minimally invasive surgery (TAMIS) is an endoscopic operating platform for local excision of rectal neoplasms. However, it may be technically demanding, and its learning curve has yet to be adequately defined. The objective of this study was to determine the number of TAMIS procedures for the local excision of rectal neoplasm required to reach proficiency. METHODS AND PROCEDURES: All TAMIS cases performed from 07/2009 to 12/2016 at a single high volume tertiary care institution for local excision of benign and malignant rectal neoplasia were identified from a prospective database. A cumulative summation (CUSUM) analysis was performed to determine the number of cases required to reach proficiency. The main proficiency outcome was rate of margin positivity (R1 resection). The acceptable and unacceptable R1 rates were defined as the R1 rate of transanal endoscopic microsurgery (TEM-10%) and traditional transanal excision (TAE-26%), which was obtained from previously published meta analyses. Comparisons of patient, tumor, and operative characteristics before and after TAMIS proficiency were performed. RESULTS: A total of 254 TAMIS procedures were included in this study. The overall R1 resection rate was 7%. The indication for TAMIS was malignancy in 57%. CUSUM analysis reported that TAMIS reached an acceptable R1 rate between 14 and 24 cases. Moving average plots also showed that the mean operative times stabilized by proficiency gain. The mean lesion size was larger after proficiency gain (3.0 cm (SD 1.5) vs. 2.3 cm (SD 1.3), p = 0.008). All other patient, tumor, and operative characteristics were similar before and after proficiency gain. CONCLUSIONS: TAMIS for local excision of rectal neoplasms is a complex procedure that requires a minimum of 14-24 cases to reach an acceptable R1 resection rate and lower operative duration. PMID- 28812154 TI - Robotic versus laparoscopic versus open colorectal surgery: towards defining criteria to the right choice. AB - OBJECTIVE: Analysis of various parameters related to the patient, the disease, and the needed surgical maneuvers to develop guidance for preoperative selection of the appropriate and the best approach for a given patient. Rapid advances in minimally invasive surgical technology are fascinating and challenging alike. It can be difficult for surgeons to keep up with new modalities that come on to the market place and to assess their true value, i.e., distinguish between fashionable trends versus scientific evidence. Laparoscopy established minimally invasive surgery and has revolutionized surgical concepts and approaches to diseases since its advent in the early 1990s. Now, with robotic surgery rapidly gaining traction in this high-tech surgical landscape, it remains to be seen how the long-term surgical landscape will be affected. METHODS: Review of the surgical evolution, published data and cost factors to reflect on advantages and disadvantages in order to develop a broader perspective on the role of various technology platforms. RESULTS: Advocates for robotic technology tout its advantages of 3D views, articulating wrists, lack of hand tremor, and surgeon comfort, which may extend the scope of minimally invasive surgery by allowing for operations in places that are more difficult to access for laparoscopic surgery (e.g., the deep pelvis), for complex tasks (e.g., intracorporeal suturing), and by decreasing the learning curve. But conventional laparoscopy has also evolved and offers high-definition 3D vision to all team members. It remains to be seen whether all together the robot features outweigh the downsides of higher cost, operative times, lack of tactile feedback, possibly unusual complications, inability to move the operative table with ease, and the difficulty to work in different quadrants. CONCLUSIONS: While technical and design developments will likely address some shortcomings, the value-based impact of the various approaches will have to be examined in general and on a case-by-case basis. Value as the ratio of quality over cost depends on numerous parameters (disease, complications, patient, efficiency, finances). PMID- 28812155 TI - Type 2 diabetes mellitus outcomes after laparoscopic gastric bypass in patients with BMI <35 kg/m2 using strict remission criteria: early outcomes of a prospective study among Mexicans. AB - BACKGROUND: Mild obesity (BMI 30-34.9 kg/m2) is highly prevalent worldwide and is associated with type 2 diabetes mellitus. The efficacy of bariatric surgery remains unclear, including among Mexicans. The criteria for diabetes remission are inconsistent, as they are based on different thresholds for glycated hemoglobin, with remission rates ranging from 43 to 73%. METHODS: Mildly obese patients with type 2 diabetes mellitus who underwent laparoscopic gastric bypass were prospectively analyzed. The primary objective was to determine the impact of surgery on their metabolic profiles. Demographic, clinical, and biochemical parameters were measured at baseline and at 3, 6, 9, 12, and 18 months. Diabetes remission rate was defined as an HbA1c <5.7%. Complications within 30 days and weight loss (% total weight loss) were also analyzed. RESULTS: Twenty-three Mexican patients underwent surgery. Of the 19 patients, evaluable at 18 months, nine (47.4%) achieved complete diabetes remission, seven (36.8%) showed partial remission, and three (15.8%) showed improvement. Significant improvements in lipid profile, cardiovascular risk, blood pressure, and every metabolic parameter were observed, beginning at the first month and throughout the study. The final total percentage weight loss was 24.9%. Three patients (13%) experienced complications, but none required reoperation or died. CONCLUSION: Laparoscopic gastric bypass is a safe and effective method to improve the metabolic profile of mildly obese Mexican patients with type 2 diabetes mellitus, inducing high remission rates even when the strictest model is used. PMID- 28812156 TI - Accredited residents perform colonoscopy to the same high standards as consultants. AB - BACKGROUND: Endoscopy remains a critical component of General Surgery and Gastroenterology training. Whilst residents need to gain experience, the quality of endoscopy which patients receive cannot be compromised. We conducted this study to compare quality indicators between consultants and residents with regards to colonoscopy. METHODS: A review of colonoscopies from a prospectively collected database was performed from September 2011 to February 2016. Quality indicators such as caecum intubation rate, adenoma detection rate, adherence to a 6-min withdrawal rule, mean number of polyps detected per colonoscope, and complications were collected and compared between the two groups. RESULTS: In total, out of 25,749 colonoscopies that were performed, 14,168 (55.0%) were performed by Consultants. Consultants achieved a better caecum intubation rate compared with residents (96.0% vs 94.9%, p < 0.001), and were more compliant to the 6-min withdrawal rule (74.7% vs 68.6%, p < 0.001). There were, however, no statistically significant differences in the adenoma detection rate (33.5% vs 34.5%, p = 0.098). Bleeding was a rare complication that was encountered more frequently in colonoscopies performed by consultants than for residents (0.002% vs 0.00008%, p < 0.001). There were only three (%) perforations in the entire series, and all were from colonoscopies performed by Consultants. CONCLUSION: Given the proper training, residents are able to perform colonoscopy with the same level of competence as consultants. Whilst colonoscopic related complications are often tied to the difficulty of the procedures, the adherence to the 6-min withdrawal rule must be reinforced and continually educated to both residents and consultants. PMID- 28812157 TI - Augmented reality in a tumor resection model. AB - BACKGROUND: Augmented Reality (AR) guidance is a technology that allows a surgeon to see sub-surface structures, by overlaying pre-operative imaging data on a live laparoscopic video. Our objectives were to evaluate a state-of-the-art AR guidance system in a tumor surgical resection model, comparing the accuracy of the resection with and without the system. Our system has three phases. Phase 1: using the MRI images, the kidney's and pseudotumor's surfaces are segmented to construct a 3D model. Phase 2: the intra-operative 3D model of the kidney is computed. Phase 3: the pre-operative and intra-operative models are registered, and the laparoscopic view is augmented with the pre-operative data. METHODS: We performed a prospective experimental study on ex vivo porcine kidneys. Alginate was injected into the parenchyma to create pseudotumors measuring 4-10 mm. The kidneys were then analyzed by MRI. Next, the kidneys were placed into pelvictrainers, and the pseudotumors were laparoscopically resected. The AR guidance system allows the surgeon to see tumors and margins using classical laparoscopic instruments, and a classical screen. The resection margins were measured microscopically to evaluate the accuracy of resection. RESULTS: Ninety tumors were segmented: 28 were used to optimize the AR software, and 62 were used to randomly compare surgical resection: 29 tumors were resected using AR and 33 without AR. The analysis of our pathological results showed 4 failures (tumor with positive margins) (13.8%) in the AR group, and 10 (30.3%) in the Non-AR group. There was no complete miss in the AR group, while there were 4 complete misses in the non-AR group. In total, 14 (42.4%) tumors were completely missed or had a positive margin in the non-AR group. CONCLUSIONS: Our AR system enhances the accuracy of surgical resection, particularly for small tumors. Crucial information such as resection margins and vascularization could also be displayed. PMID- 28812158 TI - Effect of submucosal tunneling endoscopic resection for submucosal tumors at esophagogastric junction and risk factors for failure of en bloc resection. AB - BACKGROUND AND AIMS: Most submucosal tumors (SMTs) in the esophagogastric junction (EGJ) are irregularly shaped and different from those in the esophagus, where submucosal tunneling endoscopic resection (STER) has been proven effective and safe. However, few reports paid attention to STER for SMTs in the EGJ. The aim of the study was not only to evaluate the effect of STER in patients with SMTs in the EGJ but to analyze the risk factors for failure of en bloc resection. METHODS: A consecutive of 47 patients with SMTs originating from the muscularis propria (MP) layer in the EGJ underwent STER were retrospectively included between September 2012 and December 2016. Thirty-five tumors underwent en bloc resection, and the other 12 tumors received piecemeal resection. The tumor size, operation time, en bloc resection rate, complications, residual, and local recurrence were achieved and compared between the two groups. RESULTS: Forty-six of 47 lesions (97.9%) were successfully resected. The mean lesion size was 29.7 +/- 16.3 mm. Both the en bloc resection rate and complete resection rate were 74.5% (35/47). No severe complications occurred in the 47 patients. Patients in the piecemeal resection group had more irregularly shaped lesions, longer tumor diameter, larger tumor size (>=40 mm), longer operation time, and longer hospital stay after procedure (P < 0.05), and there were no statistically differences between the two groups in in-operative complications, post-operative complications, and residual rate (P > 0.05). By univariate analysis and stepwise logistic regression analysis, irregular shape and tumor diameter >=20 mm were two risk factors for failure of en bloc resection. CONCLUSIONS: STER is an effective and safe technique for the treatment of SMTs arising from the MP layer in the EGJ. Irregular shape and tumor diameter >=20 mm are the reliable risk factors for en bloc resection failure. PMID- 28812159 TI - Anatomical and embryological perspectives in laparoscopic complete mesocoloic excision of splenic flexure cancers. AB - BACKGROUND: Laparoscopic complete mesocoloic excision (CME) with central vascular ligation for splenic flexure cancer is technically challenging because of its anatomical complexity. Although embryological and anatomical consideration should be helpful to perform CME in colorectal cancer surgery, such studies on the splenic flexure are lacking. METHODS: The splenic flexure is located embryologically between the terminal portion of the midgut and the beginning of the hindgut, and is supplied by the superior mesenteric and inferior mesenteric arteries. The mesentery of the transverse and descending colon originally is a continuous sheet, although they rotate and partially fuse to each other during development. Our surgical strategy was excision of the transverse and descending mesocolon with ligation of the left colic artery and left branch of the middle colic artery, and extraction of the specimen in an intact package wrapped by the embryological planes. RESULTS: We performed laparoscopic surgery according to our surgical strategy in 17 patients with splenic flexure colon cancer. There were no conversions to open surgery or serious intraoperative complications. Two patients had pathological stage (pStage) I, 5 pStage II, 9 pStage III, and 1 pStage IV disease. No patient had recurrence except for 1 with pStage IV cancer, with a median follow-up of 16 months. CONCLUSIONS: Our laparoscopic CME technique is feasible for treatment of splenic flexure cancer. Knowledge of anatomy based on embryology is essential to perform this surgery. PMID- 28812160 TI - Robotic versus open pancreatoduodenectomy: a propensity score-matched analysis based on factors predictive of postoperative pancreatic fistula. AB - BACKGROUND: Improvement in morbidity of pancreatoduodenectomy (PD) largely depends on the reduction in the incidence of clinically relevant (CR) postoperative pancreatic fistula (POPF). METHODS: After internal validation of the clinical risk score (CRS) of POPF, and identification of other predictive factors for POPF, robotic (RPD), and open (OPD) PDs were stratified into risk categories and matched by propensity scores. The primary endpoint of this study was incidence of CR-POPF. Secondary endpoints were 90-day morbidity and mortality, and sample size calculation for randomized controlled trials (RCT). RESULTS: No patient undergoing RPD was classified at negligible risk for POPF, and no CR-POPF occurred in 7 RPD at low risk. The matching process identified 48 and 11 pairs at intermediate and high risk for POPF, respectively. In the intermediate-risk group, RPD was associated with higher rates of CR-POPF (31.3% vs 12.5%) (p = 0.0026), with equivalent incidence of grade C POPF. In the high risk group, CR-POPF occurred frequently, but in similar percentages, after either procedures. Starting from an unadjusted point estimate of the effect size of 1.71 (0.91-3.21), the pair-matched odds ratio for CR-POPF after RPD was 2.80 (1.01 7.78) for the intermediate-risk group, and 0.20 (0.01-4.17) for the high-risk group. Overall morbidity and mortality were equivalent in matched study groups. Sample size calculation for a non-inferiority RCT demonstrated that a total of 31,669 PDs would be required to randomize 682 patients at intermediate risk and 1852 patients at high risk. CONCLUSIONS: In patients at intermediate risk, RPD is associated with higher rates of CR-POPF. Incidence of grade C POPF is similar in RPD and OPD, making overall morbidity and mortality also equivalent. A RCT, with risk stratification for POPF, would require an enormous number of patients. Implementation of an international registry could be the next step in the assessment of RPD. PMID- 28812161 TI - A proficiency-based virtual reality endoscopy curriculum improves performance on the fundamentals of endoscopic surgery examination. AB - INTRODUCTION: The fundamentals of endoscopic surgery (FES) examination is a national test of knowledge and skill in flexible gastrointestinal endoscopy. The skill portion of the examination involves five tasks that assesses the following skills: scope navigation, loop reduction, mucosal inspection, retroflexion, and targeting. This project aimed to assess the efficacy of a proficiency-based virtual reality (VR) curriculum in preparing residents for the FES skills exam. METHODS: Experienced (>100 career colonoscopies) and inexperienced endoscopists (<50 career colonoscopies) were recruited to participate. Six VR modules were identified as reflecting the skills tested in the exam. All participants were asked to perform each of the selected modules twice, and median performance was compared between the two groups. Inexperienced endoscopists were subsequently randomized in matched pairs into a repetition (10 repetitions of each task) or proficiency curriculum. After completion of the respective curriculum, FES scores and pass rates were compared to national data and historical institutional control data (endoscopy-rotation training alone). RESULTS: Five experienced endoscopists and twenty-three inexperienced endoscopists participated. Construct valid metrics were identified for six modules and proficiency benchmarks were set at the median performance of experienced endoscopists. FES scores of inexperienced endoscopists in the proficiency group had significantly higher FES scores (530 +/- 86) versus historical control (386.7 +/- 92.2, p = 0.0003) and higher pass rate (proficiency: 100%, historical control 61.5%, p = 0.01). CONCLUSION: Trainee engagement in a VR curriculum yields superior FES performance compared to an endoscopy rotation alone. Compared to the 2012-2016 national resident pass rate of 80, 100% of trainees in a proficiency-based curriculum passed the FES manual skills examination. PMID- 28812162 TI - Molecular characterization of a beet ringspot nepovirus isolated from Begonia ricinifolia in Hungary. AB - A nepovirus was isolated from Begonia ricinifolia showing chlorotic ringspot and line pattern symptoms. The purified virus had spherical particles of ca. 30 nm and contained a single coat protein subunit of ca. 56 kDa. The complete nucleotide sequence of the bipartite viral genome was determined. RNA 1 is 7394 nucleotides long, flanked by 5' and 3' untranslated regions (UTR), and followed by a 3' poly-A tail. It contains a single 6810 nt long open reading frame (ORF), which is translated into a 255 kDa polyprotein composed of 2269 amino acids. The 4684 nt long RNA 2 has a 4053 nt long ORF which encodes a single polyprotein of 1350 amino acids with a molecular weight of 149 kDa. Sequence comparisons revealed that the virus isolated from B. ricinifolia has the highest sequence similarity to beet ringspot virus and should be considered as a strain of BRSV. This is the first report on the occurrence of BRSV in B. ricinifolia and the presence of this virus outside Scotland. PMID- 28812163 TI - Editorial: postoperative chylothorax-a cause for concern. PMID- 28812164 TI - Efficacy of fractional lasers in treating alopecia: a literature review. AB - Hair loss stemming from different types of alopecia, such as androgenic alopecia and alopecia areata, negatively affects over half the population and, in many circumstances, causes serious psychosocial distress. Current treatment options for alopecia, such as minoxidil, anthralin, and intralesional corticosteroids, vary efficacy and side effect profiles. It is known that low-level laser/light therapies (LLLT), or photobiomodulations, such as the US FDA-cleared HairMax Lasercomb(r), He-Ne laser, and excimer laser, are relatively affordable, user friendly, safe, and effective forms of treatment for hair loss. While less is known about the effectiveness of fractional lasers for combating hair loss, research suggests that by creating microscopic thermal injury zones, fractional lasers may cause an increase in hair growth from a wound healing process, making them potential therapeutic options for alopecia. A literature review was performed to evaluate the effectiveness of fractional lasers on hair regrowth. The specific fractional laser therapies include the 1550-nm nonablative fractional erbium-glass laser, the ablative fractional 2940-nm erbium:YAG laser, and the ablative fractional CO2 fractional laser. Additional randomized controlled trials are necessary to further evaluate the effectiveness of the lasers, as well as to establish appropriate parameters and treatment intervals. PMID- 28812165 TI - Methane enhances aluminum resistance in alfalfa seedlings by reducing aluminum accumulation and reestablishing redox homeostasis. AB - Methane (CH4) is emerging as a candidate of signal molecule recently. However, whether or how CH4 enhances plant adaptation to aluminum (Al)-contaminated environment is still unknown. In this report, the physiological roles and possible molecular mechanisms of CH4 in the modulation of Al toxicity in alfalfa seedlings were characterized. Our results showed that, CH4 pretreatment could alleviate Al-induced seedling growth inhibition and redox imbalance. The defensive effects of CH4 against Al toxicity including the remission of Al induced root elongation inhibition, nutrient disorder, and relative electrolyte leakage. Moreover, contents of organic acids, including citrate, malate, and oxalate, were increased by CH4. These results were paralleled by the findings of CH4 regulated organic acids metabolism and transport genes, citrate synthase, malate dehydrogenase, aluminum-activated malate transporter, and aluminum activated citrate transporter. Consistently, Al accumulation in seedling roots was decreased after CH4 treatment. In addition, Al-induced oxidative stress was also alleviated by CH4, through the regulation of the activities of anti oxidative enzymes, such as ascorbate peroxidase, superoxide dismutase, and peroxidase, as well as their corresponding transcripts. Our data clearly suggested that CH4 alleviates Al toxicity by reducing Al accumulation in organic acid-dependent fashion, and reestablishing redox homeostasis. PMID- 28812166 TI - Part II: U.S.-Sub-Saharan Africa Educational Partnerships for Medical Device Design. PMID- 28812167 TI - Superficial hemangioma is better treated by topical 5-aminolevulinic followed by 595-nm pulsed dye laser therapy rather than 595-nm laser therapy alone. AB - The aim of this study was to compare the efficacy and adverse effects of a 595-nm pulsed dye laser therapy alone (PDL alone) with a 5-aminolevulinic (5-ALA) local application followed by a 595-nm PDL (5-ALA PDL) in the treatment of superficial hemangioma (SH). A prospectively randomized study in 181 patients with SH was carried out over a period of 24 months. One hundred and ninety-three patients were seen. One hundred and eighty-one patients with SH were enrolled, of which 165 completed final follow-up. One hundred and nineteen patients received PDL alone and 46 received 5-ALA PDL. The patients were assessed clinically and the patient's parents were given a satisfaction questionnaire. Baseline patient data (gender, lesion size, lesion site, treatment times, cure rate, and adverse reactions) were recorded and the results of the treatment of the two groups were analyzed and compared. Complete clearing of the lesion (recovery grade 4) was achieved in 44/119 (37.0%) of the PDL alone group and 31/46 (67.4%) of the 5-ALA PDL group (X 2 = 10.30, p < 0.001). Atrophic scars, hyper- and hypopigmentation occurred in both groups (X 2 = 3.32, p = 0.564). The patients' parents' satisfaction was greater in the 5-ALA PDL group. The clinical outcome of 5-ALA PDL was superior to that of PDL alone in the treatment of SH and only minor adverse events occurred in each group. PMID- 28812168 TI - A Wireless Pressure Sensor for Continuous Monitoring of Intraocular Pressure in Conscious Animals. AB - An important aspect of eye health in humans and animal models of human diseases is intraocular pressure (IOP). IOP is typically measured by hand with a tonometer, so data are sparse and sporadic and round-the-clock variations are not well characterized. Here we present a novel system for continuous wireless IOP and temperature measurement in small animals. The system consists of a cannula implanted in the anterior chamber of the eye connected to pressure sensing electronics that can be worn by rats or implanted in larger mammals. The system can record IOP with 0.3 mmHg accuracy and negligible drift at a rate of 0.25 Hz for 1-2 months on a regulated battery or indefinitely at rates up to 250 Hz via RF energy harvesting. Chronic recordings from conscious rats showed that IOP follows a diurnal rhythm, averaging 16.5 mmHg during the day and 21.7 mmHg at night, and that the IOP rhythm lags a diurnal rhythm in body temperature by 2.1 h. IOP and body temperature fluctuations were positively correlated from moment to-moment as well. This technology allows researchers to monitor for the first time the precise IOP history of rat eyes, a popular model for glaucoma studies. PMID- 28812170 TI - A Novel Approach to Utilize Icariin as Icariin-Derived ECM on Small Intestinal Submucosa Scaffold for Bone Repair. AB - Icariin (Ic) has been demonstrated as a potent osteoinductive compound for bone tissue engineering. However, toxic side effects of the drug and poor biocompatibility of drug delivery systems (DDSs) still limit its application for bone repair in the clinic. To overcome these disadvantages and utilize the osteoinductivity of Ic, we developed a novel method to utilize Ic as an Ic derived osteoinductive extracellular matrix (ECM) on small intestinal submucosa (SIS) (Ic-ECM-SIS). The generated Ic-ECM-SIS scaffolds, as a natural construct, exhibited much better biocompatibility (including cell adhesion, cell survival and cell proliferation) than Ic-SIS scaffolds generated by traditional DDSs. Meanwhile, osteogenic differentiation was promoted by Ic-ECM-SIS with higher expression of alkaline phosphatase, bone sialoprotein and osteocalcin than ECM SIS, which was same as Ic-SIS. BMP-4 expression was further increased in the cells on Ic-ECM-SIS compared to that on Ic-SIS. A mouse calvarial defect model was introduced to evaluate the function of Ic-ECM-SIS on bone regeneration in vivo. The bone regeneration was enhanced in the defects implanted with Ic-ECM SIS, with a higher new bone formation ratio (BV/TV) than the defects implanted with ECM-SIS or Ic-SIS. Angiogenesis was also promoted by Ic-ECM-SIS implantation when compared with ECM-SIS or Ic-SIS. Thus, this work proposes a novel method for applying a drug as a drug-derived ECM-modified scaffold for bone tissue engineering. PMID- 28812169 TI - Bond strength of etch-and-rinse and self-etch adhesive systems to enamel and dentin irradiated with a novel CO2 9.3 MUm short-pulsed laser for dental restorative procedures. AB - The objective of this study was to evaluate the influence of CO2 9.3 MUm short pulsed laser irradiation on the shear bond strength of composite resin to enamel and dentin. Two hundred enamel and 210 dentin samples were irradiated with a 9.3 um carbon dioxide laser (Solea, Convergent Dental, Inc., Natick, MA) with energies which either enhanced caries resistance or were effective for ablation. OptiBond Solo Plus [OptiBondTE] (Kerr Corporation, Orange, CA) and Peak Universal Bond light-cured adhesive [PeakTE] (Ultradent Products, South Jordan, UT) were used. In addition, Scotchbond Universal [ScotchbondSE] (3M ESPE, St. Paul, MN) and Peak SE self-etching primer with Peak Universal Bond light-cured adhesive [PeakSE] (Ultradent Products) were tested. Clearfil APX (Kuraray, New York, NY) was bonded to the samples. After 24 h, a single plane shear bond test was performed. Using the caries preventive setting on enamel resulted in increased shear bond strength for all bonding agents except for self-etch PeakSE. The highest overall bond strength was seen with PeakTE (41.29 +/- 6.04 MPa). Etch-and rinse systems achieved higher bond strength values to ablated enamel than the self-etch systems did. PeakTE showed the highest shear bond strength with 35.22 +/- 4.40 MPa. OptiBondTE reached 93.8% of its control value. The self-etch system PeakSE presented significantly lower bond strength. The shear bond strength to dentin ranged between 19.15 +/- 3.49 MPa for OptiBondTE and 43.94 +/- 6.47 MPa for PeakSE. Etch-and-rinse systems had consistently higher bond strength to CO2 9.3 um laser-ablated enamel. Using the maximum recommended energy for dentin ablation, the self-etch system PeakSE reached the highest bond strength (43.9 +/- 6.5 MPa). PMID- 28812171 TI - Complete genome sequence of a novel, virulent Ahjdlikevirus bacteriophage that infects Enterococcus faecium. AB - A novel virulent bacteriophage named vB_EfaP_IME199 that specifically infects Enterococcus faecium was isolated and characterized. Its optimal multiplicity of infection was 0.01, and it had a 30 minute outbreak period. High-throughput sequencing revealed that the phage has a dsDNA genome of 18,838 bp with 22 open reading frames. The genome has very low homology to all other bacteriophage sequences in the GenBank database. Run-off sequencing experiments confirmed that vB_EfaP_IME199 has short inverted terminal repeats. Phylogenetic analysis indicated that vB_EfaP_IME199 can be taxonomically classified as a new member of the genus Ahjdlikevirus of family Podoviridae. PMID- 28812172 TI - Delayed post mastectomy breast reconstructions with allogeneic acellular dermal matrix prepared by a new decellularizationmethod. AB - Acellular dermal matrix (ADM) is a tissue graft of allogeneic origin from post mortem tissue donors prepared by an innovative decellularization process. The newly developed non-toxic and low cost decellularization process of cadaver origin dermis included ADM in breast reconstruction procedures proved to help coverage of the lower-pole of breast expanders or implants. As the results have shown, it did help to eliminate autologous dermis donor site morbidity along with shortening the operation time by avoiding elevation of additional muscle or fascia during the operation. Main aims of this article include histology evaluation of allogeneic acellular dermal matrix prepared by a new decellularization method and presentation of clinical results of its use. A total of 22 patients underwent 26 ADM based breast reconstructions. The mean patient's follow up was 12.6 months. Average total size of ADM used for one breast was 273 cm2. Post-operative complications occurred in 3 patients including one expander infection, one expander extrusion and one expander pocket disfiguration. Microscopic analysis of tissue samples has confirmed incorporation of the acellular dermal matrices into the surrounding connective tissue without any noticeable immune reaction. In a majority of the ADM samples we found pseudocapsullar formation on implant side of samples without acute or chronic inflammatory cells. The use of ADM prepared by new preparation method in expansive post mastectomy breast reconstruction was associated by a relatively low complication rate resulting in good outcomes. PMID- 28812173 TI - Melatonin Attenuates Pain Hypersensitivity and Decreases Astrocyte-Mediated Spinal Neuroinflammation in a Rat Model of Oxaliplatin-Induced Pain. AB - Neuroinflammatory response in spinal dorsal horn has been demonstrated to be a critical factor in oxaliplatin-induced pain. Melatonin has been shown to have anti-inflammatory and anti-allodynia effects in both preclinical and clinical studies. In the present study, we investigated the role of systemic administration of melatonin on oxaliplatin-induced pain. Intraperitoneal (i.p.) injection with oxaliplatin induced significantly mechanical allodynia and thermal hyperalgesia. Melatonin (i.p.) significantly alleviated mechanical allodynia and thermal hyperalgesia in the oxaliplatin but not sham-treated rats. The attenuation of nociceptive response persisted at least to 3 days after melatonin injection, throughout the entire observing window. Immunohistochemistry showed that oxaliplatin induced a significant increase of glial fibrillary acidic protein (GFAP) immunodensities, which could be suppressed by melatonin. Western blotting showed that GFAP protein levels were significantly elevated in the oxaliplatin-vehicle group. Melatonin significantly decreased oxaliplatin-induced upregulation of GFAP expressions. Oxaliplatin injection also enhanced the messenger RNA (mRNA) expressions of cytokines including interleukin-1beta (IL 1beta) and tumor necrosis factor-alpha (TNF-alpha) and chemokines including monocyte chemoattractant protein-1 (MCP-1) and monocyte inflammatory protein-1 (MIP-1alpha) in the spinal dorsal horn, which could be significantly repressed by melatonin. In vitro study showed that mRNA levels of TNF-alpha, IL-1beta, MCP-1, and MIP-1alpha in primarily astrocytes were significantly increased after lipopolysaccharide (LPS, 1 MUg/ml) stimulation. Melatonin (10 and 100 MUM) greatly inhibited synthesis of these inflammatory mediators, in a dose-related manner. Conclusively, our data provide a novel implication of anti-nociceptive mechanism of melatonin in chemotherapy-related pain. PMID- 28812174 TI - [Magnetic resonance imaging (MRI) diagnostics in axial spondyloarthritis]. AB - BACKGROUND: Axial spondyloarthritis (axSpA) is a frequent disorder, which is difficult to diagnose in the early phase. Currently, magnetic resonance imaging (MRI) of the sacroiliac joints and the spine is frequently applied in this phase, when conventional X rays still provide inconclusive results. OBJECTIVE: To explain the typical pathological results and the role of MRI in diagnosing axSpA. RESULTS: The use of MRI of the sacroiliac joints plays a central role in the assessment of the Spondyloarthritis International Association Society (ASAS) classification criteria of axSpA. Bone marrow edema is central to the definition of a positive MRI of the sacroiliac joints. In addition, chronic changes in the sacroiliac joints, such as fat depositions and erosion are taken into account in making the diagnosis of axSpA. When the results are not clear, an additional MRI of the area of the spine in which the patient reports the most pronounced complaints can be performed. A bone marrow edema in at least three vertebral edges can be associated with axSpA. CONCLUSION: The MRI investigation of the sacroiliac joints has evolved into one of the most important methods in diagnosing axSpA. PMID- 28812176 TI - Effects of Sodium Houttuyfonate on Pulmonary Inflammation in COPD Model Rats. AB - The anti-inflammatory effect of sodium houttuyfonate (SH), an herbal-originated drug that used in China clinically, was investigated on chronic obstructive pulmonary disease (COPD) inflammatory model rats induced by combination usage of cigarette smoke (CS) and lipopolysaccharide (LPS). The morphology of the lung tissue, the expression levels of cytokines in the bronchoalveolar lavage fluid (BALF), the protein levels of TLR4, NF-kappaB p65, and SIGIRR, and the mRNA levels of TLR4, MyD88, NF-kappaB p65, and SIGIRR in lung tissues were investigated, respectively. After treated by SH (24.3 mg/kg), the abnormal morphology changes of lung tissues in COPD rats, such as neutrophil infiltration and airway obstruction, were considerably alleviated, as well as both proinflammatory cytokines, TNF-alpha and IL-1beta, significantly decreased in BALF. The mRNA level of TLR4, MyD88, and NF-kappaB p65 and protein expression of TLR4 and NF-kappaB p65 in lung tissues decreased significantly after SH treatment, while both SIGIRR mRNA and protein levels increased significantly. These results suggest that SH markedly attenuated the pulmonary inflammation induced by CS and LPS and protected the lung tissue in COPD model rat. The anti inflammatory effects were related to suppress the TLR4/NF-kappaB pathway dependent on MyD88. TIR8/SIGIRR might contribute to the protective effects of SH on pulmonary inflammation. PMID- 28812177 TI - Host Plant Species Differentiation in a Polyphagous Moth: Olfaction is Enough. AB - Polyphagous herbivorous insects need to discriminate suitable from unsuitable host plants in complex plant communities. While studies on the olfactory system of monophagous herbivores have revealed close adaptations to their host plant's characteristic volatiles, such adaptive fine-tuning is not possible when a large diversity of plants is suitable. Instead, the available literature on polyphagous herbivore preferences suggests a higher level of plasticity, and a bias towards previously experienced plant species. It is therefore necessary to take into account the diversity of plant odors that polyphagous herbivores encounter in the wild in order to unravel the olfactory basis of their host plant choice behaviour. In this study we show that a polyphagous moth, Spodoptera littoralis, has the sensory ability to distinguish five host plant species using olfaction alone, this being a prerequisite to the ability to make a choice. We have used gas chromatography mass spectrometry (GC-MS) and gas chromatography electroantennographic detection (GC-EAD) in order to describe host plant odor profiles as perceived by S. littoralis. We find that each plant emits specific combinations and proportions of GC-EAD active volatiles, leading to statistically distinct profiles. In addition, at least four of these plants show GC-EAD active compound proportions that are conserved across individual plants, a characteristic that enables insects to act upon previous olfactory experiences during host plant choice. By identifying the volatiles involved in olfactory differentiation of alternative host plants by Spodoptera littoralis, we set the groundwork for deeper investigations of how olfactory perceptions translate into behaviour in polyphagous herbivores. PMID- 28812178 TI - Sludge quantification at water treatment plant and its management scenario. AB - Large volume of sludge is generated at the water treatment plants during the purification of surface water for potable supplies. Handling and disposal of sludge require careful attention from civic bodies, plant operators, and environmentalists. Quantification of the sludge produced at the treatment plants is important to develop suitable management strategies for its economical and environment friendly disposal. Present study deals with the quantification of sludge using empirical relation between turbidity, suspended solids, and coagulant dosing. Seasonal variation has significant effect on the raw water quality received at the water treatment plants so forth sludge generation also varies. Yearly production of the sludge in a water treatment plant at Ghaziabad, India, is estimated to be 29,700 ton. Sustainable disposal of such a quantity of sludge is a challenging task under stringent environmental legislation. Several beneficial reuses of sludge in civil engineering and constructional work have been identified globally such as raw material in manufacturing cement, bricks, and artificial aggregates, as cementitious material, and sand substitute in preparing concrete and mortar. About 54 to 60% sand, 24 to 28% silt, and 16% clay constitute the sludge generated at the water treatment plant under investigation. Characteristics of the sludge are found suitable for its potential utilization as locally available construction material for safe disposal. An overview of the sustainable management scenario involving beneficial reuses of the sludge has also been presented. PMID- 28812175 TI - A prospective non-randomized controlled, multicenter trial comparing Appendectomy and Conservative Treatment for Patients with Uncomplicated Acute Appendicitis (the ACTUAA study). AB - PURPOSE: Acute appendicitis (AA) is among the most common causes of lower abdominal pain and admissions to the emergency department. Over the past 20 years, there has been a renewed interest in the conservative management of uncomplicated AA, and several studies demonstrated that an antibiotic-first strategy is a viable treatment option for uncomplicated AA. The aim of this prospective non-randomized controlled, multicenter trial is to compare antibiotic therapy and emergency appendectomy as treatment for patients with uncomplicated AA confirmed by US and/or CT or MRI scan. METHODS: All adult patients in the age range 18 to 65 years with suspected AA, consecutively admitted to the Surgical Department of the 13 participating Italian Hospitals, will be invited to take part in the study. A multicenter prospective collected registry developed by surgeons, radiologists, and pathologists with expertise in the diagnosis and treatment of uncomplicated acute appendicitis represents the best research method to assess the long-term role of antibiotics in the management of the disease. Comparison will be made between surgical and antibiotic-first approaches to uncomplicated AA through the analysis of the primary outcome measure of complication-free treatment success rate based on 1-year follow-up. Quality of life, length of hospital stay, pain evaluation, and time to return to normal activity will be evaluated as secondary outcome measures. TRIAL REGISTRATION: Clinicaltrials.gov ID: NCT03080103. PMID- 28812179 TI - A hybrid co-culture model with endothelial cells designed for the hepatic tissue engineering. AB - The cultured hepatic cells in vitro are prone to losing their characteristic morphologies and biological functions. To avoid this problem, a hybrid co-culture system was proposed to elucidate the effect of cellular communication on the phenotype of hepatic cells. A monolayer of endothelial cells (ECs) was co cultured on the surface of a three-dimensional (3D) scaffold embedded with HepG2 cells. In this hybrid co-culture system, the growth of encapsulated hepatic cells is barely influenced by the co-cultured ECs. However, the liver-special functions of hepatic cells, including the albumin secretion and the expression levels of hepatocyte-specific genes, are significantly improved. It is deduced that the improved liver-special functions is likely related to the paracrine mechanisms. Hence, this hybrid co-culture model may open a window for the co-cultivation of the multi-type of cells as well as the study of cell-cell signaling interaction. PMID- 28812180 TI - Effect of continuous positive airway pressure on glucose metabolism in adults with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. AB - Obstructive sleep apnea (OSA) has many serious consequences, and one of these may be the exacerbation of type 2 diabetes mellitus (T2DM). Reports on the effect of continuous positive airway pressure (CPAP) on glucose metabolism in people with T2DM and OSA are conflicting. Therefore, the purpose of this review was to examine the effect of CPAP treatment on glucose metabolism by synthesizing findings from randomized controlled trials. The PRISMA review protocol was developed and registered in PROSPERO. A systematic search of PubMed, CINAHL, Embase, Web of Science, PsycInfo, and Cochrane was conducted from inception to March 2017. The Cochrane risk of bias tool was used to assess the study quality. Review Manager (v5.2) was used for the meta-analyses, and the standardized mean difference was calculated. Six studies consisting of 496 participants were included in this review. The meta-analyses indicated that CPAP treatment did not have significant impact on glucose metabolism measured by A1C (mean difference = 0.05, 95% CI - 0.14 to 0.24, P = 0.61), fasting insulin level (mean difference = 2.34, 95% CI - 8.19 to 3.51, P = 0.43), and fasting glucose (mean difference = - 0.05, 95% CI - 0.52 to 0.42, P = 0.84). As expected, CPAP treatment can improve daytime sleepiness (mean difference = - 2.68, 95% CI - 3.91 to - 1.54, P < 0.001). Findings of this meta-analysis do not substantiate a positive effect of CPAP on glucose metabolism in people with T2DM and coexisting OSA. Future large scale clinical trials with a longer treatment duration and better CPAP compliance are warranted. PMID- 28812181 TI - Visit Attendance Patterns in Nurse-Family Partnership Community Sites. AB - We examined visit attendance patterns of mothers enrolled in the Nurse-Family Partnership (NFP) home visitation program and associations between these patterns and characteristics of the families and sites, with the goal of increasing participant engagement. We utilized repeated measures latent class analysis to identify attendance patterns among 66,967 mothers in NFP sites across the USA. Mothers enrolled from 1996 to 2010. Data were collected by home visitors and aggregated by the NFP National Service Office. Five visit attendance patterns were identified. Consistent attenders (22%) remained engaged for the full program and attended 51.3 visits on average. Inconsistent attenders (9%) remained engaged but missed many visits, with an average of 36.4 visits. The remaining patterns were characterized by when participants left the program: early (28%; 6.7 visits), gradually (27%; 19.4 visits), or late (15%; 35.3 visits). Consistent and inconsistent attenders were less likely to use English as their primary language than other participants (R = 0.12; p < .001). Participants with more nurse changes per visit attended were more likely to drop out early (R = 0.11; p < .001). Sites with a higher percent of missing data had smaller portions of mothers who remained consistently engaged in the program over time (b = - 0.032; p < .01) and greater portions in the late (b = 0.007; p < .04) and gradual attrition classes (b = 0.018; p < .01). The large number of participants who dropped out early is concerning. Further exploration of this group may optimize use of resources by improving either retention or targeting of potential participants. PMID- 28812182 TI - Rheological Characterization of Molten Polymer-Drug Dispersions as a Predictive Tool for Pharmaceutical Hot-Melt Extrusion Processability. AB - PURPOSE: The aim of this study was to investigate (i) the influence of drug solid state (crystalline or dissolved in the polymer matrix) on the melt viscosity and (ii) the influence of the drug concentration, temperature and shear rate on polymer crystallization using rheological tests. METHODS: Poly (ethylene oxide) (PEO) (100.000 g/mol) and physical mixtures (PM) containing 10-20-30-40% (w/w) ketoprofen or 10% (w/w) theophylline in PEO were rheologically characterized. Rheological tests were performed (frequency and temperature sweeps in oscillatory shear as well as shear-induced crystallization experiments) to obtain a thorough understanding of the flow behaviour and crystallization of PEO-drug dispersions. RESULTS: Theophylline did not dissolve in PEO as the complex viscosity (eta*) of the drug-polymer mixture increased as compared to that of neat PEO. In contrast, ketoprofen dissolved in PEO and acted as a plasticizer, decreasing eta*. Acting as a nucleating agent, theophylline induced the crystallization of PEO upon cooling from the melt. On the other hand, ketoprofen inhibited crystallization upon cooling. Moreover, higher concentrations of ketoprofen in the drug-polymer mixture increasingly inhibited polymer crystallization. However, shear-induced crystallization was observed for all tested mixtures containing ketoprofen. CONCLUSION: The obtained rheological results are relevant for understanding and predicting HME processability (e.g., barrel temperature selection) and downstream processing such as injection moulding (e.g., mold temperature selection). PMID- 28812183 TI - Anti-Dll4 Antibody Inhibits the Differentiation of Th17 Cells in Asthmatic Mice. AB - T helper 17 (Th17) cells play an important role in allergic asthma, and the Notch ligand Delta-like ligand (Dll)4 has been reported to direct the differentiation of Th17 cells. In this study, experimental animals were divided into five groups (control group, asthma group, physiological saline group, anti-Dll4 antibody group, and immunoglobulin G group). The study aimed to explore the effect of anti Dll4 antibody on the differentiation of Th17 cell in asthmatic mice. Dll4 protein expressions were performed by immunohistochemical imaging. The proportion of Th17 cells in mouse spleen-isolated CD4+ T cells were measured by flow cytometry. The protein expression of Th17 transcription factor retinoid-related orphan nuclear receptor (RORgammat) was detected by Western blotting. Interleukin (IL)-17 levels in serum were measured by enzyme-linked immunosorbent assay (ELISA). The study found that the expression of Dll4 in lung tissue from the asthma group significantly increased compared with the anti-Dll4 antibody group. The ratio of Th17 cells in CD4+ T cells was significantly downregulated, and the protein expression of RORgammat in spleen significantly reduced in the anti-Dll4 antibody group compared with the asthma group. Moreover, the IL-17 level in serum from the anti-Dll4 antibody group significantly reduced compared with the asthma group. These results suggested that anti-Dll4 antibody could inhibit the differentiation of Th17 cells in asthmatic mice. PMID- 28812184 TI - Ozone generated by air purifier in low concentrations: friend or foe? AB - Ozone helps decontamination environments due to its oxidative power, however present toxicity when it is in high concentrations, by long periods of exposition. This study aimed to assess the safety of ozone generator air purifier at concentrations of 0.05 ppm in rats exposed to 3 and 24 h/day for 14 and 28 days. No significant differences are observed between groups in clinical signs, feed and water intake, relative body weight gain and relative weight of organs, macroscopy and microscopy of lungs, and oxidative plasma assay. In this exposure regime, ozone does not cause genotoxicity and no significant changes in pulmonary histology indicative of toxicity. Ozone generated in low concentrations, even in exposure regimes above the recommended is safe, both acute and sub-acute exposition. PMID- 28812185 TI - Reliability of standing weight-bearing (0.25T) MR imaging findings and positional changes in the lumbar spine. AB - OBJECTIVE: To test the reliability and absolute agreement of common degenerative findings in standing positional magnetic resonance imaging (pMRI). METHODS AND MATERIALS: Low back pain patients with and without sciatica were consecutively enrolled to undergo a supine and standing pMRI. Three readers independently evaluated the standing pMRI for herniation, spinal stenosis, spondylolisthesis, HIZ lesions and facet joint effusion. The evaluation included a semi-quantitative grading of spinal stenosis, foraminal stenosis and spinal nerve root compression. The standing pMRI images were evaluated with full access to supine MRI. In case lower grades or the degenerative findings were not present in the supine images, this was reported separately as position-dependent changes. A subsample of 20 pMRI examinations was reevaluated after two months. The reproducibility was assessed by inter- and intra-reader reliability (kappa statistic) and absolute agreement between readers. RESULTS: Fifty-six patients were included in this study. There was fair-to-substantial inter-reader reliability (kappa 0.47 to 0.82) and high absolute agreement (72.3% to 99.1%) for the pMRI findings. The intra-reader assessment showed similar reliability and agreement (kappa 0.36 to 0.85; absolute agreement: 62.5% to 98.8%). Positional changes between the supine and standing position showed a fair-to-moderate inter- and intra-reader reliability (kappa 0.25 to 0.52; absolute agreement: 97.0% to 99.1). CONCLUSION: Evaluation of the lumbar spine for degenerative findings by standing pMRI has acceptable reproducibility; however, positional changes from the supine to the standing position as an independent outcome should be interpreted with caution because of lower reliability, which calls for further standardisation. PMID- 28812186 TI - The European Board of Interventional Radiology Examination: A Cross-Sectional Web Based Survey. AB - INTRODUCTION: The Cardiovascular and Interventional Radiology Society of Europe established the European Board of Interventional Radiology (EBIR) as an international examination in Interventional Radiology (IR), in 2010. The main objective of this study was to examine candidates' variables which could influence examination success. The secondary objective was to evaluate candidate feedback. MATERIALS AND METHODS: This study was a cross-sectional web-based survey incorporating 30 questions which reviewed candidates' demographics; use of English language; education; and radiology training. Free-text responses provided perspective on the examination process and any potential career implications. This survey was distributed via SurveygizmoTM and emailed to 227 candidates, and the results were then anonymised and analysed. RESULTS: A total of 115 candidates responded to the survey. 4.4% (N = 5/115) of candidates were women, and 38.3% (N = 44/115) of candidates were fluent in English. Over 45.2% (N = 52/115) of the respondents achieved a distinction, or >70% equivalent in their medical degree, and 60.8% (N = 70/115) achieved some form of higher degree after medical school. 54.8% (N = 63/115) spent time in other medical specialties, of which the majority (33.8%, N = 39/115) was in surgery. 67.5% (N = 77/114) completed a dedicated fellowship in IR. 61.9% (70/113) felt the EBIR qualification helped their career, for example with academic promotion or increased clinical privileges. CONCLUSION: EBIR applicants were predominantly male (>95%). Clinical training, prior to radiology training, was very common in this cohort. Overall, most candidates expressed satisfaction with the examination process, and many felt this qualification helped their career. The recent recognition by national accreditation bodies should hopefully improve the profile of the examination greatly. PMID- 28812187 TI - Thrombotic microangiopathy and breastfeeding: where is the link? Answers. PMID- 28812188 TI - Comparative efficacy of cold polypectomy techniques for diminutive colorectal polyps: a systematic review and network meta-analysis. AB - BACKGROUND: Although cold polypectomy techniques are preferred over polypectomy with electrocautery in the management of diminutive polyps, comprehensive comparisons among various cold polypectomy techniques have not yet been fully performed. METHODS: We searched for all relevant randomized controlled trials published up until October 2016 examining the efficacy of cold polypectomy techniques for diminutive polyps. Cold polypectomy techniques were classified as cold forceps polypectomy (CFP), jumbo forceps polypectomy (JFP), traditional cold snare polypectomy (CSP), and dedicated CSP, according to the type of device. A network meta-analysis was performed to calculate the direct and indirect estimates of efficacy among the cold polypectomy techniques. RESULTS: Seven studies with 703 patients and 968 polyps were included in the meta-analysis. Regarding comparative efficacy for complete histological eradication, there was no inconsistency in the network (Cochran's Q test, df = 4, P = 0.22; I 2 = 30%). In terms of complete histological eradication, both dedicated and traditional CSP were superior to CFP (odds ratio [OR] [95% confidence interval [CI]] 4.31 [1.92 9.66] and 2.45 [1.30-4.63], respectively); dedicated CSP was superior to traditional CSP (OR [95% CI] 1.76 [1.07-2.89]); and there was no difference between JFP versus CFP (OR [95% CI] 1.36 [0.40-4.61]). Regarding tissue retrieval rate, there was no difference between dedicated versus traditional CSP (OR [95% CI] 1.03 [0.44-2.38]). The procedure time for CSP was comparable to that of CFP. CONCLUSIONS: Dedicated CSP was shown to be superior to other cold polypectomy techniques in terms of complete histological eradication. Cold polypectomy using a dedicated snare can be recommended for the removal of diminutive colorectal polyps. PMID- 28812189 TI - Nutrient intake of Swiss toddlers. AB - PURPOSE: During the first years of life, food preferences are shaped that might last throughout a person's entire life affecting his/her health in the long term. However, knowledge on early feeding habits is still limited for toddlers. Therefore, the goal of the present study was to: (1) assess toddlers' nutrient intake; (2) compare the findings to past studies as well as to national feeding recommendations and (3) identify major food sources for energy and macronutrients. METHODS: A food survey using a 4-day diary was conducted. The dietary software nut.s(r) was used to analyse the data. RESULTS: A cohort of 188 healthy toddlers (aged 1-3 years) was analysed. The energy intake of most toddlers was below the recommended daily intake (RDI) but in accordance with earlier studies. Protein intake was three- to fourfold higher than the RDI and reached the proposed upper limit of 15% of total energy intake. Fat intake was in accordance with the RDI, but the balance of saturated and unsaturated fatty acids should be improved. Carbohydrate intake met the RDI. For the micronutrients, iron and vitamin D intakes showed critical values. CONCLUSION: As in other European countries, the diet of Swiss toddlers in general seems adequate but does not meet all nutritional requirements. In particular, the quality of the fats and vitamin D supplementation should be improved. For proteins and iron, additional research is needed to gain more confidence in the recommendations. PMID- 28812190 TI - Diagnostic value of the stand-alone synthetic image in digital breast tomosynthesis examinations. AB - OBJECTIVE: To demonstrate the non-inferiority of synthetic image (SI) mammography versus full-field digital mammography (FFDM) in breast tomosynthesis (DBT) examinations. METHODS: An observational, retrospective, single-centre, multireader blinded study was performed, using 2384 images to directly compare SI and FFDM based on Breast Imaging Reporting and Data System (BIRADS) categorisation and visibility of radiological findings. Readers had no access to digital breast tomosynthesis slices. Multiple reader, multiple case (MRMC) receiver operating characteristic (ROC) methodology was used to compare the diagnostic performance of SI and FFDM images. The kappa statistic was used to estimate the inter-reader and intra-reader reliability. RESULTS: The area under the ROC curves (AUC) reveals the non-inferiority of SI versus FFDM based on BIRADS categorisation [difference between AUC (DeltaAUC), -0.014] and lesion visibility (DeltaAUC, -0.001) but the differences were not statistically significant (p=0.282 for BIRADS; p=0.961 for lesion visibility). On average, 77.4% of malignant lesions were detected with SI versus 76.5% with FFDM. Sensitivity and specificity of SI are superior to FFDM for malignant lesions scored as BIRADS 5 and breasts categorised as BIRADS 1. CONCLUSIONS: SI is not inferior to FFDM when DBT slices are not available during image reading. SI can replace FFDM, reducing the dose by 45%. KEY POINTS: * Stand-alone SI demonstrated performance not inferior for lesion visibility as compared to FFDM. * Stand-alone SI demonstrated performance not inferior for lesion BIRADS categorisation as compared to FFDM. * Synthetic images provide important dose savings in breast tomosynthesis examinations. PMID- 28812191 TI - Improved outcome of childhood acute myeloid leukemia in an Eastern European country: Lithuanian experience. AB - : The reported treatment outcomes of children treated for cancer in Eastern European countries are inferior to those in Northern/Western Europe. We hypothesized that recent survival rates could be comparable to the current standards and performed a population-based analysis of treatment outcome of childhood acute myeloid leukemia (AML) in Lithuania, a small Eastern European country. Children < 18 years old who were treated for AML from 2000 to 2013 were included (n = 54). Estimates of 5-year event-free (EFS5y) and overall survival (OS5y) rates were analyzed. Comparing periods 2000-2006 (n = 32) and 2007-2013 (n = 22), the EFS5y improved from 31 to 63% (p = 0.04), and the OS5y improved from 31 to 72% (p = 0.02) because of reductions in toxicity-related mortality (42 vs. 15%, p = 0.08) and relapse (43 vs. 25%, p = 0.08). The most significant improvement was demonstrated in high-risk patients (OS5y improved from 26 to 75%, p = 0.02) who benefited from hematopoietic stem cell transplantation: the post transplant EFS5y increased from 13 to 86% (p = 0.01). CONCLUSIONS: The current survival rate of Lithuanian children treated for AML was comparable to the expected rate in other parts of Europe. What is Known: * In the last three decades, significant improvement has been achieved in treating childhood cancer, with an overall survival (OS) rate of > 80% in high-income countries. The difference in survival rates between Northern/Western and Eastern European countries as well as between high- and middle-/low-income countries is as much as 20%. Recently, the 5-year event-free survival rate of acute myeloid leukemia (AML) has reached > 60% in high-income countries. The survival rates for myeloproliferative diseases were the lowest in Eastern European countries. * The reported inferior survival rates were calculated based on outcome data of patients treated until 2007. The recent survival rates in Eastern European countries are unknown. What is New: * Being a small Eastern European country, Lithuania has experienced good economic growth during the last decade. We hypothesized that economic growth and gain of experience could result in better survival rates of children treated for cancer in our country in recent years. * A population-based analysis of treatment outcome of childhood AML treated in Lithuania in the recent years was performed for the first time. The survival rates of childhood AML in Lithuania are comparable to those of other high-income countries. Current survival rates of children treated for cancer in Eastern European countries could be comparable to the best current standards contributing to better European survival rates of childhood cancer in general. PMID- 28812192 TI - Safety of vaccination against brucellosis with the rough strain in pregnant cattle. AB - Brucellosis is an infectious and contagious disease that profoundly impacts public health. However, in many countries, disease prevention is restricted to the vaccination of calves, and there is no prophylactic strategy for pregnant heifers and cows. The aim of this study was to evaluate the safety of the rough strain vaccine against brucellosis in pregnant cattle. Crossbred cows (N = 96) at three gestational periods (early, mid, or late pregnancy) were randomly allocated into the vaccine treatment group or to the control group. We then compared the percentage of pregnancies reaching full term, live calves 60 days after delivery, and seropositive calves. There was no effect of vaccination in any of the gestational periods on the evaluation endpoints. In conclusion, vaccination against brucellosis with the rough strain is safe for pregnant cattle at all gestational periods. PMID- 28812193 TI - Cost analysis of robot-assisted choledochotomy and common bile duct exploration as an option for complex choledocholithiasis. AB - AIM: The aim of this study is to evaluate the clinical outcomes and cost effectiveness of elective, robot-assisted choledochotomy and common bile duct exploration (RCD/CBDE) compared to open surgery for ERCP refractory choledocholithiasis. METHOD: A prospective database of all RCD/CBDE has been maintained since our first procedure in April 2007 though April 2016. With ethics approval, this database was compared with all contemporaneous elective open procedures (OCD/CBDE) performed since March 2005. Emergency procedures were excluded from analysis. Cost analysis was calculated using a micro-costing approach. Outcomes were analyzed on the basis of intent-to-treat. A p value of 0.05 denoted statistical significance. RESULTS: A total of 80 cases were performed since 2005 compromising 50 consecutive, unselected RCD/CBDE and 30 OCD/CBDE. Comparing RCD/CBDE to OCD/CBDE there were no significant differences between groups with respect to age (65 +/- 20 vs. 67 +/- 18 years, p = 0.09), gender (14/30 vs. 16/25 male/female, p = 0.52), ASA class or co-morbidities. The mean duration of surgery for RCD/CBDE trended longer compared to OCD/CBDE (205 +/ 70 min vs. 174 +/- 73 min, p = 0.08). However, there was significant reduction in postoperative complications with RCD/CBDE versus OCD/CBDE (22% vs. 56%, p = 0.002). Median hospital stay was also significantly reduced (6 vs 12 days, p = 0.01). The net overall hospital cost for RCD/CBDE was lower ($8449.88 CAD vs. $11671.2 CAD). CONCLUSION: In this single-centre, cohort study, robotic-assisted CD/CBDE for ERCP refractory common bile duct stones provides the dominating strategy of improved patient outcomes with a reduction of overall cost. PMID- 28812194 TI - Amorphous Silica-Promoted Lysine Dimerization: a Thermodynamic Prediction. AB - It has long been suggested that mineral surfaces played a crucial role in the abiotic polymerization of amino acids that preceded the origin of life. Nevertheless, it remains unclear where the prebiotic process took place on the primitive Earth, because the amino acid-mineral interaction and its dependence on environmental conditions have yet to be understood adequately. Here we examined experimentally the adsorption of L-lysine (Lys) and its dimer (LysLys) on amorphous silica over a wide range of pH, ionic strength, adsorbate concentration, and the solid/water ratio, and determined the reaction stoichiometries and the equilibrium constants based on the extended triple-layer model (ETLM). The retrieved ETLM parameters were then used, in combination with the equilibrium constant for the peptide bond formation in bulk water, to calculate the Lys-LysLys equilibrium in the presence of amorphous silica under various aqueous conditions. Results showed that the silica surface favors Lys dimerization, and the influence varies greatly with changing environmental parameters. At slightly alkaline pH (pH 9) in the presence of a dilute NaCl (1 mM), the thermodynamically attainable LysLys from 0.1 mM Lys reached a concentration around 50 times larger than that calculated without silica. Because of the versatility of the ETLM, which has been applied to describe a wide variety of biomolecule-mineral interactions, future experiments with the reported methodology are expected to provide a significant constraint on the plausible geological settings for the condensation of monomers to polymers, and the subsequent chemical evolution of life. PMID- 28812195 TI - Design and evaluation of a compact photocatalytic reactor for water treatment. AB - A compact reactor for photocatalytic oxidation and photocatalytic ozonation water treatment was developed and evaluated by using four model pollutants. Additionally, combinations of pollutants were evaluated. Specially produced Al2O3 porous reticulated monolith foams served as TiO2 carriers, offering a high surface area support. UV lamps were placed in the interior to achieve reduced dimensions of the reactor (12 cm in diameter * 20 cm in height). Despite its small size, the overall photocatalytic cleaning capacity was substantial. It was evaluated by measuring the degradation of LAS + PBIS and RB19 as representatives of surfactants and textile dyes, respectively. These contaminants are commonly found in household grey wastewater with phenol as a trace contaminant. Three different commercial photocatalysts and one mixture of photocatalysts (P25, P90, PC500 and P25 + PC500) were introduced in the sol-gel processing and immobilized on foamed Al2O3 monoliths. RB19 and phenol were easily degradable, while LAS and PBIS were more resistant. The experiments were conducted at neutral-acidic pH because alkaline pH negatively influences both photocatalyic ozonation (PCOZ) and photocatalysis. The synergistic effect of PCOZ was generally much more expressed in mineralization reactions. Total organic carbon TOC half lives were in the range of between 13 and 43 min in the case of individual pollutants in double deionized water. However, for the mixed pollutants in tap water, the TOC half life only increased to 53 min with the most efficient catalyst (P90). In comparison to photocatalysis, the PCOZ process is more suitable for treating wastewater with a high loading of organic pollutants due to its higher cleaning capacity. Therefore, PCOZ may prove more effective in industrial applications. PMID- 28812196 TI - Convergent validation and transfer of learning studies of a virtual reality-based pattern cutting simulator. AB - INTRODUCTION: Research has clearly shown the benefits of surgical simulators to train laparoscopic motor skills required for positive patient outcomes. We have developed the Virtual Basic Laparoscopic Skill Trainer (VBLaST) that simulates tasks from the Fundamentals of Laparoscopic Surgery (FLS) curriculum. This study aims to show convergent validity of the VBLaST pattern cutting module via the CUSUM method to quantify learning curves along with motor skill transfer from simulation environments to ex vivo tissue samples. METHODS: 18 medical students at the University at Buffalo, with no prior laparoscopic surgical skills, were placed into the control, FLS training, or VBLaST training groups. Each training group performed pattern cutting trials for 12 consecutive days on their respective simulation trainers. Following a 2-week break period, the trained students performed three pattern cutting trials on each simulation platform to measure skill retention. All subjects then performed one pattern cutting task on ex vivo cadaveric peritoneal tissue. FLS and VBLaST pattern cutting scores, CUSUM scores, and transfer task completion times were reported. RESULTS: Results indicate that the FLS and VBLaST trained groups have significantly higher task performance scores than the control group in both the VBLaST and FLS environments (p < 0.05). Learning curve results indicate that three out of seven FLS training subjects and four out of six VBLaST training subjects achieved the "senior" performance level. Furthermore, both the FLS and VBLaST trained groups had significantly lower transfer task completion times on ex vivo peritoneal tissue models (p < 0.05). CONCLUSION: We characterized task performance scores for trained VBLaST and FLS subjects via CUSUM analysis of the learning curves and showed evidence that both groups have significant improvements in surgical motor skill. Furthermore, we showed that learned surgical skills in the FLS and VBLaST environments transfer not only to the different simulation environments, but also to ex vivo tissue models. PMID- 28812197 TI - Predicting Resectability in Gallbladder Cancer: the Tata Memorial Hospital Staging System. PMID- 28812198 TI - Laparoscopic colectomy reduces complications and hospital length of stay in colon cancer patients with liver disease and ascites. AB - BACKGROUND: Ascites increases perioperative complications and risk of death, but is not an absolute contraindication for colectomy in patients with colon cancer. It remains unclear whether postoperative risks can be minimized using a laparoscopic versus open approach. METHODS: Data were retrospectively analyzed from 2152 patients with ascites who underwent laparoscopic or open partial colectomy with diagnosis of colon cancer from 2005 to 2013 using the American College of Surgeons National Surgical Quality Improvement Program database. Postoperative outcomes were analyzed using two-sample tests of proportions and two-sample T tests. Adjusted odds ratios (OR) or beta coefficients for postoperative complications, hospital length of stay, and 30-day mortality were calculated using multivariable logistic or linear regression. P values <0.05 two tailed were considered statistically significant. RESULTS: 205 patients (9.53%) with ascites underwent laparoscopic colectomy (LC). There was no significant difference in operative time between laparoscopic versus open surgery (145 vs. 146 min, P = 0.69). LC was associated with decreased likelihood of overall complications (adjusted OR 0.7 95% CI 0.4-1.0, P = 0.046) and shorter hospital length of stay (9 days vs. 15 days, adjusted beta = -4.2, 95% CI -7.7 to -0.7, P = 0.018). There was no difference in 30-day mortality (adjusted OR 0.82, 95% CI 0.50-1.35, P = 0.429). CONCLUSIONS: Laparoscopic colectomy decreases postoperative complications and hospital length of stay in patients with colon cancer and ascites. Laparoscopic approach should be considered for patients in this high-risk population. PMID- 28812199 TI - Complete genome sequence of a putative new caulimovirus which exists as endogenous pararetroviral sequences in Angelica dahurica. AB - A virus isolate designated Angelica bushy stunt virus (AnBSV), provisionally representing a new species in the genus Caulimovirus, was discovered in the medicinal plant Angelica dahurica. The complete 8,300-nt genomic DNA of AnBSV had seven putative open reading frames containing conserved domains/motifs, which are typical features of caulimoviruses, and showed the greatest nucleotide sequence identity (74% identity and 27% query coverage) to a lamium leaf distortion virus isolate. Interestingly, the new caulimovirus exists as endogenous pararetroviral sequences in the host plant and is considered to have multiple defective plant genome-integrated copies that may lead to the generation of subgenomic DNA species. PMID- 28812200 TI - Dust emission and dispersion from mineral storage piles. AB - Dust pollution is a complex problem of growing interest because of its environmental, health, economic and political impact. Environmental impact assessment methods for dust pollution management are often based on the simulation of dust dispersion, which requires a precise characterization of the source term and of the source parameters. The source term model should be as simple and as accurate as possible and requires low time consumption in order to be easily connected to a more complex algorithm for the dispersion calculations. This work focuses on dust emissions from mineral storage piles, which are usually modelled as source terms by means of the algorithm proposed in the AP-42 US EPA standard. Unfortunately, this algorithm tends to overestimate emissions, and when coupled with a Gaussian dispersion model, it leads to inaccurate results in terms of estimation of both concentration and spatial distribution. This paper proposes a new methodology drawn from the original standard US EPA AP-42 https://www3.epa.gov/ttnchie1/ap42/ch13/ scheme with the purpose to account for the actual dynamics of erosion and to enhance the accuracy of the concentration and the pollutant spatial distribution assessment, thereby considering the effects of the wind interactions. The standard EPA methodology and the new one were compared by means of the AERMOD and CALPUFF dispersion models. Results are superimposable in terms of concentration values, leading to a quantification of the same order of magnitude, although with a different and more variable spatial distribution. PMID- 28812201 TI - Effectiveness of navigation-guided cyst aspiration before resection of large cystic brain tumors: a proof of concept for more radical surgery. AB - BACKGROUND: Resection of tumors close to the corticospinal tract (CST) carries a high risk of damage to the CST. For cystic tumors, aspirating the cyst before resection may reduce the risk of damage to vital structures. This study evaluated the effectiveness of cyst aspiration, by comparing the results before and after aspiration of diffusion tensor image (DTI) tractography. METHODS: This study enrolled 23 patients with large cystic brain tumors (>20 cm3) between 2012 and 2016. All underwent magnetic resonance imaging (MRI), including DTI tractography, followed by navigation-guided aspiration of the cyst and subsequent tumor resection via craniotomy. Distances between the tumor margin and CST before and after cyst aspiration, volume reduction, and postoperative outcomes were assessed. RESULTS: Median tumor volume decreased from 88 cm3 (range, 25-153) to 29 cm3 (range, 20-80) and distances between tumor margins and the CST increased from 5.7 mm (range, 0.6-22.0) to 14.8 mm (range, 0.6-41.4) after aspiration. Neurological symptoms of patients immediately improved after cyst aspiration. All patients, except for one with a secondary glioblastoma, underwent gross total resection of the tumor. No neurological deterioration was observed after tumor resection. CONCLUSIONS: Navigation-guided cyst aspiration followed by resection is a useful and safe procedure for brain tumors with large cystic components. Cyst aspiration resulted in expansion of the compressed brain tissue between the tumor margins and vital structures, making maximal safe resection possible. PMID- 28812202 TI - Diagnosis of inguinal hernia by prone- vs. supine-position computed tomography. AB - PURPOSE: The aim of this study was to investigate the efficacy of prone-position computed tomography (CT) for detecting and classifying inguinal hernia relative to supine-position CT before laparoscopic inguinal hernia repair. METHODS: Seventy-nine patients who underwent laparoscopic transabdominal preperitoneal repair of inguinal hernia were enrolled in this prospective study. Patients diagnosed with inguinal hernia by physical examination underwent abdominal CT in the supine and prone positions for preoperative assessment. The anatomy of the right and left inguinal regions was confirmed during the surgery and compared with the preoperative CT findings. RESULTS: The 79 cases included 87 operated lesions and 71 non-operated contralateral inguinal sites. Of the 84 clinical hernias, inguinal hernia was detected significantly more frequently on prone position CT images (84, 100%) than on supine-position CT images (55, 65.5%). In addition, the inguinal hernia type was determined with significantly greater accuracy on prone-position CT images (96.4%) than on supine-position CT images (58.3%). Twenty-two occult hernias were detected by laparoscopy. The detection rate and accuracy for determining the type of occult hernia were significantly greater when using prone-position CT images [19 of 22 lesions (86.4%) and 77.3%, respectively] than when using supine-position CT images [8 of 22 lesions (36.4%) and 27.3%, respectively]. CONCLUSIONS: Prone-position CT is adequate for detecting and classifying inguinal hernia and for evaluating occult hernia. PMID- 28812203 TI - Assessment of methodologies to calculate intraventricular pressure differences in computational models and patients. AB - Intraventricular pressure differences (IVPDs) govern left ventricular (LV) efficient filling and are a significant determinant of LV diastolic function. Our primary aim is to assess the performance of available methods (color M-mode (CMM) and 1D/2D MRI-based methods) to determine IVPDs from intracardiac flow measurements. Performance of three methods to calculate IVPDs was first investigated via an LV computational fluid dynamics (CFD) model. CFD velocity data were derived along a modifiable scan line, mimicking ultrasound/MRI acquisition of 1D (IVPDCMM/IVPD1D MRI) and 2D (IVPD2D MRI) velocity-based IVPD information. CFD pressure data (IVPDCFD) was used as a ground truth. Methods were also compared in a small cohort (n = 13) of patients with heart failure with preserved ejection fraction (HFpEF). In silico data showed a better performance of the IVPD2D MRI approach: RMSE values for a well-aligned scan line were 0.2550 mmHg (IVPD1D MRI), 0.0798 mmHg (IVPD2D MRI), and 0.2633 mmHg (IVPDCMM). In vivo data exhibited moderate correlation between techniques. Considerable differences found may be attributable to different timing of measurements and/or integration path. CFD modeling demonstrated an advantage using 2D velocity information to compute IVPDs, and therefore, a 2D MRI-based method should be favored. However, further studies are needed to support the clinical significance of MRI-based computation of IVPDs over CMM. PMID- 28812205 TI - Values in Time Discounting. AB - Controversies about time discounting loom large in decisions about climate change. Prominently, a particularly controversial debate about time discounting in climate change decision-making has been conducted within climate economics, between the authors of Stern et al. (Stern review on the economics of climate change, 2006) and their critics (most prominently Dasgupta in Comments on the Stern review's economics of climate change, 2006; Tol in Energy Environ 17(6):977 981, 2006; Weitzman in J Econ Lit XLV:703-724, 2007; Nordhaus in J Econ Lit XLV:686-702, 2007). The article examines the role of values in this debate. Firstly, it is shown that time discounting is a case in which values are key because it is at heart an ethical problem. Secondly, it is argued that time discounting in climate economics is a case of economists making frequent and routine references to ethical values and indeed conduct ethical debates with each other. Thirdly, it is argued that there is evidence for deep and pervasive entanglement between facts and values in the prevalent methodologies for time discounting. Finally, it is argued that this means that economists have given up the 'value-free ideal' concerning time discounting, and discussed how the current methodology of time discounting in economics can be improved. PMID- 28812204 TI - Multivariable Adaptive Artificial Pancreas System in Type 1 Diabetes. AB - PURPOSE OF REVIEW: The review summarizes the current state of the artificial pancreas (AP) systems and introduces various new modules that should be included in future AP systems. RECENT FINDINGS: A fully automated AP must be able to detect and mitigate the effects of meals, exercise, stress and sleep on blood glucose concentrations. This can only be achieved by using a multivariable approach that leverages information from wearable devices that provide real-time streaming data about various physiological variables that indicate imminent changes in blood glucose concentrations caused by meals, exercise, stress and sleep. The development of a fully automated AP will necessitate the design of multivariable and adaptive systems that use information from wearable devices in addition to glucose sensors and modify the models used in their model-predictive alarm and control systems to adapt to the changes in the metabolic state of the user. These AP systems will also integrate modules for controller performance assessment, fault detection and diagnosis, machine learning and classification to interpret various signals and achieve fault-tolerant control. Advances in wearable devices, computational power, and safe and secure communications are enabling the development of fully automated multivariable AP systems. PMID- 28812206 TI - Differences in femoral neck structure between elderly Caucasian and Chinese populations: a cross-sectional study of Perth-Beijing cohorts. AB - : Structural skeletal differences of the femoral neck of older Beijing-Chinese and Perth-Caucasian women were compared; adjusting for frame size-related differences, Beijing-Chinese have lower periosteal width; however, indices of internal bone distribution suggest that Beijing-Chinese may exhibit increased resistance to fracture that may relate to the reduced hip fracture incidence. INTRODUCTION: Ethnic differences in skeletal structure may relate to differences in hip fracture risk in Chinese and Caucasian populations. 2D mass, size, and structural biomechanics were compared in the two populations. METHODS: Quantitative computed tomography-derived geometric variables were compared in age matched community-derived female populations, 196 Beijing-Chinese 76.5 +/- 4.8 (mean +/- SD) years and 237 Perth-Caucasians 77.1 +/- 5.0 years. These included scanned area (A), periosteal width (W), bone mineral content (BMC), aBMD, bone cross-sectional area (bCSA), section modulus (Z) and buckling ratio (BR). Assumption-free measures included sigma (sigma), related to the distribution of bone in the scanned image previously identified as a predictor of hip fracture, and delta (delta), the center-of-mass displacement from the geometric center. RESULTS: Compared to Beijing-Chinese, Perth-Caucasians were heavier (Beijing Chinese 58.7 +/- 11.8; Perth-Caucasians 66.1 +/- 11.0 kg), taller (154.9 +/- 16.7 vs 158.9 +/- 6.0 cm), and had higher BMC, A, and W. After adjustment for frame size, BMC was not significantly different but W remained higher in Perth Caucasians. Differences in variables aBMD, Z, BR, and sigma favored higher resistance to failure with Beijing-Chinese before and after adjustment for frame size. delta was similar in both populations; bCSA was higher in Beijing-Chinese before adjustment for frame size but not after. CONCLUSIONS: Bone mass differences in two populations were related to frame size differences. However, femoral neck width remained smaller in Beijing-Chinese suggesting effects of local genetic and environmental factors. In Beijing-Chinese participants compared to Perth-Caucasians, internal bone distribution suggests increased resistance to deformation if exposed to same force that may, in-part, relate to reduced incidence of hip fracture in Beijing-Chinese. PMID- 28812207 TI - The Vaginal Microbiome and its Potential to Impact Efficacy of HIV Pre-exposure Prophylaxis for Women. AB - PURPOSE OF REVIEW: This review describes existing evidence addressing the potential modulation of pre-exposure prophylaxis (PrEP) products, specifically 1% tenofovir (TFV) gel and oral tenofovir-based PrEP, by vaginal dysbiosis and discusses future considerations for delivering novel, long-acting PrEP products to women at high risk for vaginal dysbiosis and HIV. RECENT FINDINGS: We describe results from analyses investigating the modification of PrEP efficacy by vaginal dysbiosis and studies of biological mechanisms that could render PrEP ineffective in the presence of specific microbiota. A secondary analysis from the CAPRISA-004 cohort demonstrated that there is no effect of the 1% TFV gel in the presence of non-Lactobacillus dominant microbiota. Another recent analysis comparing oral tenofovir-based PrEP efficacy among women with and without bacterial vaginosis in the Partners PrEP Study found that oral PrEP efficacy is not modified by bacterial vaginosis. Gardnerella vaginalis, commonly present in women with vaginal dysbiosis, can rapidly metabolize TFV particularly when it is locally applied and thereby prevent TFV integration into cells. Given that vaginal dysbiosis appears to modulate efficacy for 1% TFV gel but not for oral tenofovir based PrEP, vaginal dysbiosis is potentially less consequential to HIV protection from TFV in the context of systemic drug delivery and high product adherence. Vaginal dysbiosis may undermine the efficacy of 1% TFV gel to protect women from HIV but not the efficacy of oral PrEP. Ongoing development of novel ring, injectable, and film-based PrEP products should investigate whether vaginal dysbiosis can reduce efficacy of these products, even in the presence of high adherence. PMID- 28812208 TI - Genetic Testing in Inherited Heart Diseases: Practical Considerations for Clinicians. AB - PURPOSE OF REVIEW: Genetic testing has become an important element in the care of patients with inherited cardiac conditions (ICCs). The purpose of this review is to provide clinicians with insights into the utility of genetic testing as well as challenges associated with interpreting results. RECENT FINDINGS: Genetic testing may be indicated for individuals who are affected with or who have family histories of various ICCs. Various testing options are available and determining the most appropriate test for any given clinical scenario is key when interpreting results. Newly published guidelines as well as various publicly accessible tools are available to clinicians to help with interpretation of genetic findings; however the subjectivity with respect to variant classification can make accurate assessment challenging. Genetic information can provide highly useful and relevant information for patients, their family members, and their healthcare providers. Given the potential ramifications of variant misclassification, expertise in both clinical phenotyping and molecular genetics is imperative in order to provide accurate diagnosis, management recommendations, and family risk assessment for this patient population. PMID- 28812209 TI - Effect of vitamin D supplementation in chronic widespread pain: a systematic review and meta-analysis. AB - Chronic non-specific widespread pain (CWP) including fibromyalgia (FMS) is characterized by widespread pain, reduced pain threshold, and multiple tender points on examination, causing disability and decreased quality of life. Vitamin D has been proposed as an associated factor in CWP. This meta-analysis aimed to explore the benefit of vitamin D supplementation in the management of CWP. A comprehensive search of the CENTRAL, MEDLINE, and Embase databases was performed from inception through January 2017. The inclusion criterion was the randomized clinical trials' evaluating the effects of vitamin D treatment in adult subjects with CWP or FMS. CWP was defined as chronic recurrent musculoskeletal pain without secondary causes; FMS patients met the American College of Rheumatology criteria for FMS. Study outcome was assessed using visual analog scale (VAS) of pain intensity. Pooled mean difference (MD) of VAS and 95% confidence interval (CI) were calculated using a random-effect meta-analysis. Meta-regression analysis using a random-effects model was performed to explore the effects of change in vitamin D in the treatment group on difference in the mean of VAS. Sensitivity analysis was performed to evaluate the robustness of results. The between-study heterogeneity of effect size was quantified using the Q statistic and I 2. Data were extracted from four randomized controlled trials involving 287 subjects. Pooled result demonstrated a significantly lower VAS in CWP patients who received vitamin D treatment compared with those who received placebo (MD = 0.46; 95% CI 0.09-0.89, I 2 = 48%). Meta-regression analysis revealed no significant relationship between the changes of vitamin D and VAS (coefficient = 0.04 (95% CI -0.01 to 0.08), p = 0.10). In this meta-analysis, we conclude that vitamin D supplementation is able to decrease pain scores and improve pain despite no significant change in VAS after increasing serum vitamin D level. Further studies need to be conducted in order to explore the improvement of functional status, quality of life, and the pathophysiological change that improves chronic widespread pain. PMID- 28812210 TI - Increased IL-6 expression on THP-1 by IL-34 stimulation up-regulated rheumatoid arthritis Th17 cells. AB - IL-34 is a pleiotropic cytokine, which is a key regulator of monocytes/macrophages and might participate in the pathogenesis of RA. In this study, we aimed to explore the effect of IL-34 on the monocyte-like cell line THP 1 and the quantitative variation of Th17 cells in THP-1 and RA CD4+T cells coculture system. CD4+T cells were purified from RA PBMC using immunomagnetic beads. THP-1 were cultured with RA CD4+T cells. The frequency of Th17 cells was determined by FACS. Fluorscence indensity and expression of ROS were detected by FACS and cell staining, respectively. The expression of IL-6, IL-23, IL-21, TNF alpha and IL-1beta in the coculture supernatants were detected by ELISA. We found that CSF-1R was constitutively expressed on peripheral monocytes as well as THP 1, but not on the T/B cells. IL-34-CSF-1R binding could activate THP-1 to secret IL-6. IL-34 could up-regulate the numbers of Th17 cells in coculture system, which was possibly via the production of IL-6. We further observed ROS levels were increased in the coculture system. The percentage of Th17 cells was reduced when ROS production was inhibited by NAC, a specific inhibitor of ROS production. In addition, TNFRII antagonist but not IL-1betaR antagonist could restrict the production of ROS, expression of IL-6 and generation of Th17 cells. In conclusion, IL-34-stimulated THP-1 can produce higher levels of ROS, which promoted IL-6 secretion and up-regulated Th17 cells. Our study suggests a novel mechanistic insight into how the interaction of IL-34-stimulated monocytes and CD4+T cells participates in the RA pathogenesis. PMID- 28812212 TI - Obesity Treatment with Botulinum Toxin-A Is Not Effective: a Systematic Review and Meta-Analysis. AB - The effectiveness of gastric injections of botulinum toxin-A (BTA) as primary treatment for obesity is not well known since results in literature are discrepant. Hence, we aimed to systematically review and meta-analyze the available data to assess the real effect of BTA therapy. We searched MEDLINE, Embase, Cochrane, SCOPUS, EBSCO, LILACS, and BVS. We considered eligible only randomized controlled trials enrolling obese patients comparing BTA versus saline injections. Our initial search identified 8811 records. Six studies fulfilled eligibility criteria. After critical appraisal, two articles were excluded and we meta-analyzed the remainder. The mean difference for absolute weight loss and BMI reduction were 0.12 [CI 95%, - 1.14, 1.38] and - 0.06 [95% CI, - 0.92, 0.81], respectively. Therefore, we concluded that treatment of obesity with BTA is not effective. PMID- 28812211 TI - The Immune System in Obesity: Developing Paradigms Amidst Inconvenient Truths. AB - PURPOSE OF REVIEW: Adipose tissue (AT) houses both innate and adaptive immune systems that are crucial for preserving AT function and metabolic homeostasis. In this review, we summarize recent information regarding progression of obesity associated AT inflammation and insulin resistance. We additionally consider alterations in AT distribution and the immune system in males vs. females and among different racial populations. RECENT FINDINGS: Innate and adaptive immune cell-derived inflammation drives insulin resistance both locally and systemically. However, new evidence also suggests that the immune system is equally vital for adipocyte differentiation and protection from ectopic lipid deposition. Furthermore, roles of anti-inflammatory immune cells such as regulatory T cells, "M2-like" macrophages, eosinophils, and mast cells are being explored, primarily due to promise of immunotherapeutic applications. Both immune responses and AT distribution are strongly influenced by factors like sex and race, which have been largely underappreciated in the field of metabolically associated inflammation, or meta-flammation. More studies are required to recognize factors that switch inflammation from controlled to uncontrolled in obesity-associated pathogenesis and to integrate the combined effects of meta flammation and immunometabolism. It is critical to recognize that the AT associated immune system can be alternately beneficial and destructive; therefore, simply blocking immune responses early in obesity may not be the best clinical approach. The dearth of information on gender and race-associated disparities in metabolism, AT distribution, and the immune system suggest that a greater understanding of such differences will be critical to develop personalized treatments for obesity and the associated metabolic dysfunction. PMID- 28812214 TI - The role of human papillomavirus on the prognosis and treatment of oropharyngeal carcinoma. AB - Human papillomavirus positive oropharyngeal cancer (HPV-positive OPC) is a distinct subtype of head and neck carcinoma (HNC) distinguished from HPV-negative HNC by its risk factor profile, clinical behavior, and molecular biology. Compared to HPV-negative HNC, HPV-positive OPC exhibits significantly better prognosis and an enhanced response to treatment. Recognition of the survival benefit of HPV-positive tumors has led to therapeutic de-intensification strategies aiming to mitigate treatment-related toxicities while maintaining high response rates. In this review, we summarize key aspects of oral HPV infection and the molecular mechanisms of HPV-related carcinogenesis. We review the clinical and molecular characteristics of HPV-positive OPC that contribute to its improved prognosis compared to HPV-negative HNC. We also discuss current and emerging treatment strategies, emphasizing potential mechanisms of treatment sensitivity and the role of therapeutic de-intensification in HPV-positive OPC. Lastly, we examine literature on the management and prognosis of recurrent/metastatic HPV-positive OPC with a focus on the role of salvage surgery in its management. PMID- 28812213 TI - Heterogeneity in the Beta-Cell Population: a Guided Search Into Its Significance in Pancreas and in Implants. AB - PURPOSE OF REVIEW: Intercellular differences in function have since long been noticed in the pancreatic beta-cell population. Heterogeneity in cellular glucose responsiveness is considered of physiological and pathological relevance. The present review updates evidence for the physiologic significance of beta-cell heterogeneity in the pancreas. It also briefly discusses what this role would imply for beta-cell implants in diabetes. RECENT FINDINGS: Over the past 3 years, functionally different beta cells have been related to mechanisms that may underlie their heterogeneity in the pancreas, such as the stage in their life cycle and the degree of their clustering to islets with varying vascularization. Markers were identified for detecting these subpopulations in tissues. The existence of a functional heterogeneity in the pancreatic beta-cell population is further supported. Views on its origin and methods for its analysis in pancreas and implants will help guide the search into its significance in beta-cell biology, pathology, and therapy. PMID- 28812217 TI - What Shall We Talk about in Farsi? : Content of Everyday Conversations in Iran. AB - Previous empirical studies have suggested that language is primarily used to exchange social information, but our evidence on this derives mainly from English speakers. We present data from a study of natural conversations among Farsi (Persian) speakers in Iran and show that not only are conversation groups the same size as those observed in Europe and North America, but people also talk predominantly about social topics. We argue that these results reinforce the suggestion that language most likely evolved for the transmission of information about the social world. We also explore sex differences in conversational behavior: while the pattern is broadly similar between the sexes, men may be more sensitive than women are to discussing some topics in the presence of many other people. PMID- 28812215 TI - Proteomic Alterations Associated with Biomechanical Dysfunction are Early Processes in the Emilin1 Deficient Mouse Model of Aortic Valve Disease. AB - Aortic valve (AV) disease involves stiffening of the AV cusp with progression characterized by inflammation, fibrosis, and calcification. Here, we examine the relationship between biomechanical valve function and proteomic changes before and after the development of AV pathology in the Emilin1-/- mouse model of latent AV disease. Biomechanical studies were performed to quantify tissue stiffness at the macro (micropipette) and micro (atomic force microscopy (AFM)) levels. Micropipette studies showed that the Emilin1-/- AV annulus and cusp regions demonstrated increased stiffness only after the onset of AV disease. AFM studies showed that the Emilin1-/- cusp stiffens before the onset of AV disease and worsens with the onset of disease. Proteomes from AV cusps were investigated to identify protein functions, pathways, and interaction network alterations that occur with age- and genotype-related valve stiffening. Protein alterations due to Emilin1 deficiency, including changes in pathways and functions, preceded biomechanical aberrations, resulting in marked depletion of extracellular matrix (ECM) proteins interacting with TGFB1, including latent transforming growth factor beta 3 (LTBP3), fibulin 5 (FBLN5), and cartilage intermediate layer protein 1 (CILP1). This study identifies proteomic dysregulation is associated with biomechanical dysfunction as early pathogenic processes in the Emilin1-/- model of AV disease. PMID- 28812218 TI - Neural correlates of emotional valence processing in Parkinson's disease: dysfunction in the subcortex. AB - Parkinson's disease (PD) is frequently accompanied by cognitive and neuropsychiatric symptoms including impairments in affective processing. Despite this, mechanisms underlying vulnerability to deficits in affective processing remain unclear. In this study, we utilized functional Magnetic Resonance Imaging (fMRI) and an Affective Go-NoGo paradigm, to examine the neural correlates of emotional valence processing in PD. Results suggest that PD is associated with aberrant processing of emotional valence in subcortical limbic structures. Specifically, we found significant group-by-valence interactions in the ventral striatum and amygdala in response to words of differing emotional valence. Our findings contribute to a broader understanding of affective processing in PD and may provide insights into the mechanisms underlying vulnerability to mood disorders in PD. PMID- 28812216 TI - An overview of in vitro and in vivo glycation of albumin: a potential disease marker in diabetes mellitus. AB - Non-enzymatic glycation of macromolecules, especially proteins leading to their oxidation is increased in diabetes mellitus due to hyperglycaemia and play an important role in associated complications of the disease. Protein glycation mostly occurs in intra chain lysine residues resulting in the formation of early stage Amadori products which are finally converted to advance glycation end products (AGEs). This review deals with the structural studies of in vitro and in vivo glycated human serum albumin (HSA). The aim of this review is to explain the disturbance in secondary and tertiary structure of albumin upon glucosylation and the immunogenic potential of modified albumin. Amadori-albumin may have enough potential to provoke the immunoregulatry cells and generate autoantibodies in diabetic patients. Role of Amadori-albumin in the induction of autoantibodies in type2 diabetes especially in chronic kidney disease (CKD) patients has been discussed. This review also considers various studies that investigate the effects of glycation on the structural and immunological properties of HSA. The use of glycated albumin (GA) as a short to intermediate term marker for glycaemic control in diabetes is also focused. PMID- 28812220 TI - Sphingosine 1-Phosphate Receptor Modulators for the Treatment of Multiple Sclerosis. AB - Sphingosine 1-phosphate receptor (S1PR) modulators possess a unique mechanism of action in the treatment of multiple sclerosis (MS). Subtype 1 of the S1PR is expressed on the surface of lymphocytes and is important in regulating egression from lymph nodes. The S1PR modulators indirectly antagonize the receptor's function leading to sequestration of lymphocytes in the lymph nodes. Fingolimod was the first S1PR modulator to receive regulatory approval for relapsing remitting MS after 2 phase III trials demonstrated potent efficacy, safety, and tolerability. Fingolimod can cause undesirable effects as a result of its interaction with other S1PR subtypes, which are expressed in diverse tissues, including cardiac myocytes. As such, agents that more selectively target subtype 1 of the S1PR are of interest and are at various stages of development. These include ponesimod (ACT128800), siponimod (BAF312), ozanimod (RPC1063), ceralifimod (ONO-4641), GSK2018682, and MT-1303. Data from phase II trials and early results from phase III studies have been promising and will be presented in this review. Of special interest are results from the EXPAND study of siponimod, which suggest a potential role for S1PR modulators in secondary progressive MS. PMID- 28812219 TI - Eminent Sources of Adult Mesenchymal Stem Cells and Their Therapeutic Imminence. AB - In the recent times, stem cell biology has garnered the attention of the scientific fraternity and the general public alike due to the immense therapeutic potential that it holds in the field of regenerative medicine. A breakthrough in this direction came with the isolation of stem cells from human embryo and their differentiation into cell types of all three germ layers. However, the isolation of mesenchymal stem cells from adult tissues proved to be advantageous over embryonic stem cells due to the ethical and immunological naivety. Mesenchymal Stem Cells (MSCs) isolated from the bone marrow were found to differentiate into multiple cell lineages with the help of appropriate differentiation factors. Furthermore, other sources of stem cells including adipose tissue, dental pulp, and breast milk have been identified. Newer sources of stem cells have been emerging recently and their clinical applications are also being studied. In this review, we examine the eminent sources of Mesenchymal Stem Cells (MSCs), their immunophenotypes, and therapeutic imminence. PMID- 28812222 TI - Ethics and Phishing Experiments. AB - Phishing is a fraudulent form of email that solicits personal or financial information from the recipient, such as a password, username, or social security or bank account number. The scammer may use the illicitly obtained information to steal the victim's money or identity or sell the information to another party. The direct costs of phishing on consumers are exceptionally high and have risen substantially over the past 12 years. Phishing experiments that simulate real world conditions can provide cybersecurity experts with valuable knowledge they can use to develop effective countermeasures and prevent people from being duped by phishing emails. Although these experiments contravene widely accepted informed consent requirements and involve deception, we argue that they can be conducted ethically if risks are minimized, confidentiality and privacy are protected, potential participants have an opportunity to opt out of the research before it begins, and human subjects are debriefed after their participation ends. PMID- 28812221 TI - Multimodal Neuroimaging in Schizophrenia: Description and Dissemination. AB - In this paper we describe an open-access collection of multimodal neuroimaging data in schizophrenia for release to the community. Data were acquired from approximately 100 patients with schizophrenia and 100 age-matched controls during rest as well as several task activation paradigms targeting a hierarchy of cognitive constructs. Neuroimaging data include structural MRI, functional MRI, diffusion MRI, MR spectroscopic imaging, and magnetoencephalography. For three of the hypothesis-driven projects, task activation paradigms were acquired on subsets of ~200 volunteers which examined a range of sensory and cognitive processes (e.g., auditory sensory gating, auditory/visual multisensory integration, visual transverse patterning). Neuropsychological data were also acquired and genetic material via saliva samples were collected from most of the participants and have been typed for both genome-wide polymorphism data as well as genome-wide methylation data. Some results are also presented from the individual studies as well as from our data-driven multimodal analyses (e.g., multimodal examinations of network structure and network dynamics and multitask fMRI data analysis across projects). All data will be released through the Mind Research Network's collaborative informatics and neuroimaging suite (COINS). PMID- 28812223 TI - Prognostic potential of KLOTHO and SFRP1 promoter methylation in head and neck squamous cell carcinoma. AB - Hypermethylation in the CpG island promoter regions of tumor suppressors is known to play a significant role in the development of HNSCC and the detection of which can aid the classification and prognosis of HNSCC. This study aims to profile the methylation patterns in a panel of key genes including CDKN2A, CDKN2B, KLOTHO (KL), RASSF1A, RARB, SLIT2, and SFRP1, in a group of HNSCC samples from Saudi Arabia. The extent of methylation in these genes is determined using the MethyLight assay and correlated with known clinicopathological parameters in our samples of 156 formalin-fixed and paraffin-embedded HNSCC tissues. SLIT2 methylation had the highest frequency (64.6%), followed by RASSF1A (41.3%), RARB (40.7%), SFRP1 (34.9), KL (30.7%), CKDN2B (29.6%), and CKDN2A (29.1%). KL and SFRP1 methylation were more predominant in nasopharyngeal tumors (P = 0.001 and P = 0.031 respectively). Kaplan Meier analysis showed that patients with moderately differentiated tumors who display SFRP1 methylation have significantly worse overall survival in comparison with other samples. In contrast, better clinical outcomes were seen in patients with KL methylation. In conclusion, our findings suggest that the detection of frequent methylation in SFRP1 and KL genes' promoters could serve as prognostic biomarkers for HNSCC. PMID- 28812224 TI - Risk factors for totally implantable venous access device-associated complications in cystic fibrosis. AB - BACKGROUND: Candidaemia is an important nosocomial infection, seen frequently in immunocompromised and critically ill patients and increasingly recognised in cystic fibrosis (CF) patients with totally implantable venous access devices (TIVADs). This study aims to investigate the incidence and risk factors for the development of TIVAD-associated candidaemia and to assess the rate of TIVAD related complications in CF patients. METHODS: A 10-year retrospective study was carried out on adult CF patients attending a single centre. Complications were recorded including the incidence of candidaemia and correlated to clinical parameters. Complication rates were calculated based on incidence per 1000 catheter days. Statistical analysis was performed using Mann-Whitney U test and Fisher's exact test. RESULTS: Fourteen cases of candidaemia were observed in the CF cohort, primarily caused by Candida parapsilosis and Candida albicans. Candidaemia was associated with lower FEV1 (p = 0.0117) and higher frequency of pulmonary exacerbation (p < 0.0001). A TIVAD complication rate of 0.337/1000 catheter days was observed in the CF cohort. Complications included venous thrombosis, stenosis, and port extrusion; complications were independently associated with more frequent pulmonary exacerbations (p = 0.04). CONCLUSIONS: TIVAD complications are observed more commonly in those with lower FEV1 and frequent pulmonary exacerbations, suggesting that candidaemia may be related to antibiotic use and furthermore can occur following invasive procedures causing translocation of fungal species allowing transformation from colonisation to pathogenic infection. PMID- 28812225 TI - Enhancement of ocular efficacy of aceclofenac using biodegradable PLGA nanoparticles: formulation and characterization. AB - In the present study, an effort was made to design poly (D, L-lactide-co glycolide) acid nanoparticles of aceclofenac by direct precipitation method. The nanoparticles were found to have adequate particle size range for ocular administration of 162.6 to 244.13 nm with nearly spherical shape and with zeta potential of - 21.5 to - 25.5 mV. Drug entrapment efficiency of nanoparticle formulations ranged from 42.9 to 92.68%. Differential scanning calorimetric (DSC) and powder X-ray diffraction (PXRD) studies depicted that the drug incorporated in nanoparticles was found to be in amorphous state. Moreover, nanoparticles showed prolonged in vitro drug release profile and followed Higuchi-square-root release kinetics. Nanoparticles showed two folds higher permeation than aqueous solution of aceclofenac. Nanoparticles were well tolerated with no signs of corneal damage in in vitro transcorneal permeation studies. The formulation was quite stable. In vivo ocular anti-inflammatory study in the rabbit eyes confirmed better efficacy of nanoparticles as compared with the aqueous solution and its potential application in ocular inflammatory conditions. PMID- 28812226 TI - In light of recently published clinical trials and their implication for clinical practice, does a large catchment area acute hospital require 24 hour CT neck and head angiography and/or neuro-interventional services in the setting of acute ischaemic stroke? AB - BACKGROUND: Recently published clinical trials have resulted in a significant change in the guidelines used to manage patients suffering an acute ischaemic stroke. New neuro-interventional techniques have revolutionised stroke outcomes. Currently, such services are only available in two specialist centres. AIMS: We attempted to evaluate the need for the provision of routine computed tomography (CT) angiography and neuro-interventional services at a university teaching hospital in Limerick. METHODS: A retrospective study was performed based on data collated by the stroke service, University Hospital Limerick (UHL). All patients with a suspected acute ischaemic stroke of anterior circulation and known evolution were included. Baseline clinical and imaging characteristics, thrombolysis data, stroke unit admission rates and discharge destinations were recorded. RESULTS: All 141 patients were suitable for CT angiography and should be performed in accordance with guidelines. Additionally, 165 patients excluded from the study due to an unknown stroke evolution timeframe may have benefitted. Non-contrast CT scan confirmed just 12 anterior circulation strokes. The need for neuro-interventional services proved more difficult to assess, primarily due to the lack of provision of routine CT angiography, employed to confirm anterior circulation occlusion. Secondary results showed a thrombolysis rate of 10.8% and confirmed that time efficiencies result in higher thrombolysis eligibility rates. Stroke unit admissions and discharge destinations were also recorded. CONCLUSION: UHL should provide routine CT angiography to all patients presenting with acute ischaemic stroke in line with current guidelines. The need for provision of neuro interventional services on-site proved more difficult to assess and requires further analysis. PMID- 28812227 TI - Effects of Fluoride on Surface Structure of Primary Culture Leydig Cells in Mouse. AB - Fluoride (F) is known to induce reproduction toxicity, and the elucidation of its underlying mechanisms is an ongoing research. These findings aim to provide deeper insights into roles of soduim fluoride (NaF) in testis damage, which could contribute to a better understanding of fluoride-induced male reproductive toxicity. The Leydig cells were administrated by 0, 5, 10, and 20 mg/L NaF for 24 h, respectively. Scanning electron microscope was used to identify the change of surface structure in the Leydig cells. The results showed that fluoride exposure of high-dose induced bulged balloon in the membrane of the Leydig cell. We speculated that high doses of NaF inhibited cell proliferation and induced cell apoptosis in Leydig cells. This is the first time that we have reported that fluoride impaired cytomembrane and cytoskeleton of the Leydig cells in vitro treated with different doses of fluoride for 24 h by using a scanning electron microscope. Damage to the cytoskeleton and cytomembrane may be one of the reasons of male reproductive toxicity induced by fluoride. PMID- 28812228 TI - E-commerce Review System to Detect False Reviews. AB - E-commerce sites have been doing profitable business since their induction in high-speed and secured networks. Moreover, they continue to influence consumers through various methods. One of the most effective methods is the e-commerce review rating system, in which consumers provide review ratings for the products used. However, almost all e-commerce review rating systems are unable to provide cumulative review ratings. Furthermore, review ratings are influenced by positive and negative malicious feedback ratings, collectively called false reviews. In this paper, we proposed an e-commerce review system framework developed using the cumulative sum method to detect and remove malicious review ratings. PMID- 28812229 TI - Economics and Cost-Effectiveness of Multiple Sclerosis Therapies in the USA. AB - Multiple sclerosis (MS) is a disabling, chronic disease that imposes a significant economic burden on patients and the US healthcare system. The largest cost component for individuals with MS are prescription drugs, specifically disease-modifying therapies (DMTs). Despite an increase in the number and diversity of DMTs over the past 10 years, acquisition costs for all DMTs have escalated dramatically at rates substantially higher than medical inflation. Currently, costs for most DMTs exceed $70,000 a year. Recent cost-effectiveness studies suggest the cost for nearly all DMTs exceeds generally accepted thresholds for what is considered a good value in the USA, even after factoring expected rebates. The high cost of DMTs is symptomatic of systemic dysfunction in the pharmaceutical market. Strategies aimed at reigning in high-cost medications include proposals ranging from increasing pricing transparency to allowing Medicare to negotiate directly with manufacturers. Because the economics of pharmaceuticals are inherently complex, a diversity of approaches will be required. PMID- 28812230 TI - Simulation of Left Ventricular Dynamics Using a Low-Order Mathematical Model. AB - The eventual goal of this study is to develop methods for estimating dynamic stresses in the left ventricle (LV) that could be used on-line in clinical settings, based on routinely available measurements. Toward this goal, a low order theoretical model is presented, in which LV shape is represented using a small number of parameters, allowing rapid computational simulations of LV dynamics. The LV is represented as a thick-walled prolate spheroid containing helical muscle fibers with nonlinear passive and time-dependent active contractile properties. The displacement field during the cardiac cycle is described by three time-dependent parameters, using a family of volume-preserving mappings based on prolate spheroidal coordinates. Stress equilibrium is imposed in weak form and the resulting force balance equations are coupled to a lumped parameter model of the circulation, leading to a system of differential-algebraic equations, whose numerical solution yields predictions of LV pressure and volume, together with spatial distributions of stresses and strains throughout the cardiac cycle. When static loading of the passive LV is assumed, this approach yields displacement and stress fields that closely match results from a standard finite-element approach. When dynamic motion with active contraction is simulated, substantial variations of fiber stress and strain through the myocardium are predicted. This approach allows simulations of LV dynamics that run faster than real time, and could be used to determine patient-specific parameters of LV performance on-line from clinically available measurements, with the eventual goal of real-time, patient-specific analysis of cardiac parameters. PMID- 28812231 TI - The Neuroprotective Effect of Conditioned Medium from Human Adipose-Derived Mesenchymal Stem Cells is Impaired by N-acetyl Cysteine Supplementation. AB - Oxidative stress is a common feature in neurodegenerative diseases associated with neuroinflammation, and therefore, has been proposed as a key target for novel therapies for these diseases. Recently, adipose-derived stem cell (ASC) based cell therapy has emerged as a novel strategy for neuroprotection. In this study, we evaluate the therapeutic role of ASC-conditioned medium (ASC-CM) against H2O2-induced neurotoxicity in a new in vitro model of ec23/brain-derived neurotrophic factor (BDNF)-differentiated human SH-SY5Y neuron-like cells (SH SY5Yd). In the presence of ASC-CM, stressed SH-SY5Yd cells recover normal axonal morphology (with an almost complete absence of H2O2-induced axonal beading), electrophysiological features, and cell viability. This beneficial effect of ASC CM was associated with its antioxidant capacity and the presence of growth factors, namely, BDNF, glial cell line-derived neurotrophic factor, and transforming growth factor beta1. Moreover, the neuroprotective effect of ASC-CM was very similar to that obtained from treatment with BDNF, an essential factor for SH-SY5Yd cell survival. Importantly, we also found that the addition of the antioxidant agent N-acetyl cysteine to ASC-CM abolished its restorative effect; this was associated with a strong reduction in reactive oxygen species (ROS), in contrast to the moderate decrease in ROS produced by ASC-CM alone. These results suggest that neuronal restorative effect of ASC-CM is associated with not only the release of essential neurotrophic factors, but also the maintenance of an appropriate redox state to preserve neuronal function. PMID- 28812232 TI - Introgression of heat shock protein (Hsp70 and sHsp) genes into the Malaysian elite chilli variety Kulai (Capsicum annuum L.) through the application of marker assisted backcrossing (MAB). AB - Backcrossing together with simple sequence repeat marker strategy was adopted to improve popular Malaysian chilli Kulai (Capsicum annuum L.) for heat tolerance. The use of molecular markers in backcross breeding and selection contributes significantly to overcoming the main drawbacks such as increase linkage drag and time consumption, in the ancient manual breeding approach (conventional), and speeds up the genome recovery of the recurrent parent. The strategy was adopted to introgress heat shock protein gene(s) from AVPP0702 (C. annuum L.), which are heat-tolerant, into the genetic profile of Kulai, a popular high-yielding chilli but which is heat sensitive. The parents were grown on seed trays, and parental screening was carried out with 252 simple sequence repeat markers. The selected parents were crossed and backcrossed to generate F1 hybrids and backcross generations. Sixty-eight markers appeared to be polymorphic and were used to assess the backcross generation; BC1F1, BC2F1 and BC3F1. The average recipient allele of the selected four BC1F1 plants was 80.75% which were used to produce the BC2F1 generation. BC1-P7 was the best BC1F1 plant because it had the highest recovery at 83.40% and was positive to Hsp-linked markers (Hsp70-u2 and AGi42). After three successive generations of backcrossing, the average genome recovery of the recurrent parent in the selected plants in BC3F1 was 95.37%. Hsp gene expression analysis was carried out on BC1F1, BC2F1 and BC3F1 selected lines. The Hsp genes were found to be up-regulated when exposed to heat treatment. The pattern of Hsp expression in the backcross generations was similar to that of the donor parent. This confirms the successful introgression of a stress-responsive gene (Hsp) into a Kulai chilli pepper variety. Furthermore, the yield performance viz. plant height, number of fruits, fruit length and weight and total yield of the improved plant were similar with the recurrent parent except that the plant height was significantly lower than the Kulai (recurrent) parent. PMID- 28812233 TI - Synthesis and Photophysical Study of New Green Fluorescent TPA Based Poly(azomethine)s. AB - A series of poly(azomethine)s (PAMs) were synthesized from N1-(4-aminophenyl)-N1 (4-phenoxyphenyl)benzene-1,4-diamine (DA) and various dialdehydes to investigate the influence of structure of polymer chain and triphenylamine-based phenoxy pendant group on the optoelectronic properties. The structural characterization of the resulting poly(azomethine)s was carried out by solubility test, gel permeation chromatography, viscosity measurement, fourier transform infrared (FTIR) spectral and CHN elemental analysis. The photophysical and electrochemical properties of the materials were scrutinized by UV-vis, photoluminescence, time correlation photon counting spectral analysis (TCSP) and cyclic voltammetry. The thermal stability of the poly(azomethine)s was assessed by differential scanning calorimetry and thermogravimetric analysis found to be stable upto 300 degrees C. These polymers exhibit moderate inherent viscosity range from 0.99 to 1.15 g dL- 1 and appreciable organosolubility. The presence of triphenylamine and azomethine (CH = N) linkage in our synthesized materials rendered them fluorescent, emitting green light upon excitation at 375 nm with quantum efficiencies of 3.9-8.5%. The pendant phenoxy group at para-position in new poly(azomethine)s has also lowered the onset oxidation potentials and elevated the HOMO levels. Additionally, the presence of conjugation increases the fluorescence time of the excited state in conjugated polymers which was found in the range 9.22-11.17 ns, sufficient to be use in future optoelectronic applications. PMID- 28812234 TI - Temperature dependence of band gap in MoSe2 grown by molecular beam epitaxy. AB - We report on a temperature-dependent band gap property of epitaxial MoSe2 ultrathin films. We prepare uniform MoSe2 films epitaxially grown on graphenized SiC substrates with controlled thicknesses by molecular beam epitaxy. Spectroscopic ellipsometry measurements upon heating sample in ultra-high vacuum showed temperature-dependent optical spectra between room temperature to 850 degrees C. We observed a gradual energy shift of optical band gap depending on the measurement temperature for different film thicknesses. Fitting with the vibronic model of Huang and Rhys indicates that the constant thermal expansion accounts for the steady decrease of band gap. We also directly probe both optical and stoichiometric changes across the decomposition temperature, which should be useful for developing high-temperature electronic devices and fabrication process with the similar metal chalcogenide films. PMID- 28812235 TI - Patent Ethics: The Misalignment of Views Between the Patent System and the Wider Society. AB - Concerns have been voiced about the ethical implications of patenting practices in the field of biotechnology. Some of these have also been incorporated into regulation, such as the European Commission Directive 98/44 on the legal protection of biotechnological inventions. However, the incorporation of ethically based restrictions into patent legislation has not had the effect of satisfying all concerns. In this article, we will systematically compare the richness of ethical concerns surrounding biotech patenting, with the limited scope of ethical concerns actually addressed in the patent system. As sources of our analyses we will use literature and document studies and a survey with important stakeholders and experts related to Norwegian patenting in the aquacultural biotechnology sector. We will structure the analyses with an ethical matrix, developed for this purpose. Showing the misalignment of the discussions within and outside the patent system, we suggest that an important reason for the ethical controversy still surrounding patenting is that ethical questions keep being framed in a narrow way within the system. Until a richer set of ethical considerations is addressed head-on within the patent system, the patent system will continue to evoke academic and interest group criticism, potentially contributing to a legitimacy crisis of the whole system. PMID- 28812236 TI - An Integrated Curriculum to Enhance Research Literacy. PMID- 28812237 TI - Pharmacological Effects on Ceroid Lipofuscin and Neuronal Structure in Cln3 ?ex7/8 Mouse Brain Cultures. AB - Juvenile Batten disease (JBD) is an inherited disorder that is characterized by the development of blindness, seizures, and progressive motor, psychiatric, and cognitive impairment. A model of JBD expressing the predominant human mutation (Cln3 ?ex7/8 ) has been explored. Dissociated brain cultures from Cln3 ?ex7/8 knock-in mice were compared to wild type (WT) for effects on granules of ceroid lipofuscin (CL) and neuronal structure. Utilizing high content image analysis of CL granules identified with antibodies to mitochondrial ATP synthase subunit c or tripeptidyl peptidase-1, significant increases in the areas for both immunoreactive granules were observed in Cln3 ?ex7/8 cultures in comparison to WT. CL granules also exhibit autofluorescence at 488 and 560 nm, and the areas of these autofluorescent spots were found to be significantly increased in Cln3 ?ex7/8 cultures in comparison to WT. Progressive increases in CL granule area in Cln3 ?ex7/8 cultures were observed during culture development. Because current therapies for JBD provide only symptomatic support, a therapeutic strategy has been explored based on the observations that JBD-related tissues are deficient in beta-galactosyl ceramide. Treatment of cultures for 40 h with a potent analog of beta-galactosyl ceramide (SNB-4050) produced significant decreases in CL granule area in the Cln3 ?ex7/8 cultures; whereas identical studies on WT cultures produced no detectible changes. Significant decreases in average neurite length and neurite branch point number were also observed in the Cln3 ?ex7/8 cultures that were attenuated by treatment with 1 nM SNB-4050. These studies indicate Cln3 ?ex7/8 brain cultures may be useful to screen therapeutic agents for treatment of JBD. PMID- 28812238 TI - Women's Progress for Men's Gain? Gender-Specific Changes in the Return to Education as Measured by Family Standard of Living, 1990 to 2009-2011. AB - This study investigates gender-specific changes in the total financial return to education among persons of prime working ages (35-44 years) using U.S. Census data from 1990 and 2000, and the 2009-2011 American Community Survey. We define the total financial return to education as the family standard of living as measured by family income adjusted for family size. Our results indicate that women experienced significant progress in educational attainment and labor market outcomes over this time period. Ironically, married women's progress in education and personal earnings has led to greater improvement in the family standard of living for married men than for women themselves. Gender-specific changes in assortative mating are mostly responsible for this paradoxical trend. Because the number of highly educated women exceeds the number of highly educated men in the marriage market, the likelihood of educational marrying up has substantially increased for men over time while women's likelihood has decreased. Sensitivity analyses show that the greater improvement in the family standard of living for men than for women is not limited to prime working-age persons but is also evident in the general population. Consequently, women's return to education through marriage declined while men's financial gain through marriage increased considerably. PMID- 28812239 TI - Social Status, Discrimination, and Minority Individuals' Mental Health: a Secondary Analysis of US National Surveys. AB - OBJECTIVES: Our study measured minority individuals' social status factors and frequency of discrimination experiences, in order to delineate social mechanisms linking race/ethnicity to mental status (specifically, to current mood/anxiety disorder and self-rated mental health). METHODS: In this nationally representative secondary research, our data analyses drew on the cross-sectional "Collaborative Psychiatric Epidemiology Surveys," dating 2001-2003. The sample for the final model numbered 9368 respondents (2016 Asians, 2676 Latinos, 4676 blacks). RESULTS: Across races/ethnicities, better mental health was associated with male gender, higher income, marriage, more education, and less-frequent discrimination experiences; discrimination experiences could impair health, especially among blacks. Marriage's strong contribution to Asians' mental health did not hold among blacks; education's contribution to Latinos' mental health did not hold among blacks either. Blacks' mental health was unaffected by immigration status, but Asian and Latino immigrants showed less-robust mental health than native-born counterparts. CONCLUSIONS: Across the three racial/ethnic groups studied, differences were noted in relationships between self-reported mental health status and the employed social status and discrimination factors. PMID- 28812240 TI - Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for pseudomyxoma peritonei and appendix tumours in elderly patients: Is it justified? AB - BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for pseudomyxoma peritonei and appendix tumours are widespread in the world. It is unclear what should be the attitude in elderly patients. METHODS: This retrospective multicenter study collected the database from ten Spanish centers from Spanish Group of Peritoneal Cancer Surgery. The study period was between November 2002 and March 2014. Seventeen patients with age greater than or equal to 75 years with peritoneal carcinomatosis from pseudomyxoma peritonei and appendix tumours met the selection criteria for the study. Outcomes in terms of morbidity and mortality such as disease-free and overall survival were analyzed. RESULTS: Median PCI was 16 (range 6-39). Ten postoperative adverse events were detected in nine patients (44.4%). 28% were grade I-II and 17% were grade III-IV. Disease-free survival at 1 and 3 years was 67 and 44%, respectively. Overall survival at 1 and 3 years was 100 and 88%, respectively. Only cytoreduction was related to worst disease free survival after univariate (p = 0.007) and multivariate (OR 11.639, 95% CI 1.24-109.74, p = 0.03) analyses. Cytoreduction was related to the worst overall survival after univariate analysis (p = 0.046). CONCLUSION: Cytoreductive surgery and HIPEC for pseudomyxoma peritonei and appendix tumours in elderly patients it is a procedure with feasible postoperative morbi-mortality and survival outcomes. TRIAL REGISTRATION: researchregistry1587 (retrospectively registered). PMID- 28812241 TI - Plasma Glycoproteomic Study of Therapeutic Hypothermia Reveals Novel Markers Predicting Neurologic Outcome Post-cardiac Arrest. AB - Therapeutic hypothermia (TH) is a neuroprotective treatment post-cardiac arrest but is grossly underutilized. After TH induction, traditional biomarkers and parameters can no long predict clinical outcome due to a lack of understanding of hypothermic response. Innovative approaches to better understand the clinical effect of TH will help to prognosticate outcome and expand beneficial population. Protein glycosylation is an important extracellular post-translational modification, regulating various extracellular signaling pathways. Here, we used glycoproteomics to investigate the association of plasma glycoproteins with the prognosis of TH-treated cardiac arrest patients. Using lectin affinity chromatography and mass spectrometry, we identified 640 glycoproteins in the plasma of cardiac arrest patients undergoing TH treatment, of which 23 were up regulated and 14 were down-regulated in good outcome patients as compared with poor outcome ones. Notably, two glycoproteins with antioxidant activity, ceruloplasmin (CP) and haptoglobin (HP), were found to be associated with favorable neurologic outcome. This was further supported by ELISA assay in a large patients cohort, in which glycosylated CP and HP enriched by concanavilin A (ConA) and wheat germ agglutinin (WGA) lectins were significantly increased in patients developing good outcome (ConA-CP: p = 0.033; ConA-HP: p = 0.04; WGA-HP: p = 0.021). Furthermore, ROC analysis demonstrated the predictive potential of ConA-CP, ConA-HP, and WGA-HP (ConA-CP: AUC = 0.732, p = 0.031; ConA-HP: AUC = 0.746, p = 0.022; WGA-HP: AUC = 0.714, p = 0.046) and combination of them improved the predictive power (AUC = 0.830, p = 0.002). Our results suggested that glycosylated CP and HP as well as other glycoproteins may play critical roles in neuroprotection and serve as sensitive prognostic markers for TH treatments. PMID- 28812244 TI - Fabrication of Ordered Nanopattern by using ABC Triblock Copolymer with Salt in Toluene. AB - Ordered nanopatterns of triblock copolymer polystyrene-block-poly(2 vinylpyridine)-block- poly (ethylene oxide)(PS-b-P2VP-b-PEO) have been achieved by the addition of lithium chloride (LiCl). The morphological and structural evolution of PS-b-P2VP-b-PEO/LiCl thin films were systematically investigated by varying different experimental parameters, including the treatment for polymer solution after the addition of LiCl, the time scale of ultrasonic treatment and the molar ratio of Li+ ions to the total number of oxygen atoms (O) in PEO block and the nitrogen atoms (N) in P2VP block. When toluene was used as the solvent for LiCl, ordered nanopattern with cylinders or nanostripes could be obtained after spin-coating. The mechanism of nanopattern transformation was related to the loading of LiCl in different microdomains. PMID- 28812243 TI - A two-stage predictive model to simultaneous control of trihalomethanes in water treatment plants and distribution systems: adaptability to treatment processes. AB - The trihalomethanes (TTHMs) and others disinfection by-products (DBPs) are formed in drinking water by the reaction of chlorine with organic precursors contained in the source water, in two consecutive and linked stages, that starts at the treatment plant and continues in second stage along the distribution system (DS) by reaction of residual chlorine with organic precursors not removed. Following this approach, this study aimed at developing a two-stage empirical model for predicting the formation of TTHMs in the water treatment plant and subsequently their evolution along the water distribution system (WDS). The aim of the two stage model was to improve the predictive capability for a wide range of scenarios of water treatments and distribution systems. The two-stage model was developed using multiple regression analysis from a database (January 2007 to July 2012) using three different treatment processes (conventional and advanced) in the water supply system of Aljaraque area (southwest of Spain). Then, the new model was validated using a recent database from the same water supply system (January 2011 to May 2015). The validation results indicated no significant difference in the predictive and observed values of TTHM (R 2 0.874, analytical variance <17%). The new model was applied to three different supply systems with different treatment processes and different characteristics. Acceptable predictions were obtained in the three distribution systems studied, proving the adaptability of the new model to the boundary conditions. Finally the predictive capability of the new model was compared with 17 other models selected from the literature, showing satisfactory results prediction and excellent adaptability to treatment processes. PMID- 28812245 TI - Association of Elements with Schizophrenia and Intervention of Selenium Supplements. AB - The purpose of this study is to explore more trace elements (zinc, potassium, copper, iron, boron, manganese, selenium, chromium and cadmium elements) in addition to calcium, magnesium, lead and arsenic in the sera of patients with schizophrenia and the general population in China and to determine the effect of selenium on schizophrenia patients. Participants were collected from the Pingyin County Mental Health Hospital and Pingyin County. A t test was used to analyse the differences between schizophrenia patients and healthy subjects, and element content differences in gender. Logistic multivariate regression analysis was applied to analyse the influence of elements to schizophrenia. Repeated measures analysis of variance was used to analyse differences in the elements after 1 and 3 months. Mn, Se, Cd, Pb, Ca, Cu and Fe were lower than those in the normal group, and B, Cr, As, K and Mg were higher than those in the control group. The odd ratios (ORs) of serum As and serum K were 2.624 and 1.035, respectively. The ORs of sera Cr, Mn, Se, Ca and Cu were all below one. After intervention of 'selenium weikang' about 1 and 3 months, the serum As was decreased and the serum selenium and copper were increased. Cr, Mn, Se, Ca and Cu might have beneficial, statistically significant effects on schizophrenia. Elements As and K might be harmful to schizophrenia with statistical significance. After selenium supplementation, the schizophrenia patients improved in some factors, like the appetite and memory, and the As element decreased. PMID- 28812246 TI - DNA Tetrahedron Delivery Enhances Doxorubicin-Induced Apoptosis of HT-29 Colon Cancer Cells. AB - As a nano-sized drug carrier with the advantage of modifiability and proper biocompatibility, DNA tetrahedron (DNA tetra) delivery is hopeful to enhance the inhibitory efficiency of nontargeted anticancer drugs. In this investigation, doxorubicin (Dox) was assembled to a folic acid-modified DNA tetra via click chemistry to prepare a targeted antitumor agent. Cellular uptake efficiency was measured via fluorescent imaging. Cytotoxicity, inhibition efficiency, and corresponding mechanism on colon cancer cell line HT-29 were evaluated by MTT assay, cell proliferation curve, western blot, and flow cytometry. No cytotoxicity was induced by DNA tetra, but the cellular uptake ratio increased obviously resulting from the DNA tetra-facilitated penetration through cellular membrane. Accordingly, folic acid-DNA tetra-Dox markedly increased the antitumor efficiency with increased apoptosis levels. In details, 100 MUM was the effective concentration and a 6-h incubation period was needed for apoptosis induction. In conclusion, nano-sized DNA tetrahedron was a safe and effective delivery system for Dox and correspondingly enhanced the anticancer efficiency. PMID- 28812247 TI - Towards Robot-Assisted Echocardiographic Monitoring in Catheterization Laboratories : Usability-Centered Manipulator for Transesophageal Echocardiography. AB - This paper proposes a robotic Transesophageal Echocardiography (TOE) system concept for Catheterization Laboratories. Cardiovascular disease causes one third of all global mortality. TOE is utilized to assess cardiovascular structures and monitor cardiac function during diagnostic procedures and catheter-based structural interventions. However, the operation of TOE underlies various conditions that may cause a negative impact on performance, the health of the cardiac sonographer and patient safety. These factors have been conflated and evince the potential of robot-assisted TOE. Hence, a careful integration of clinical experience and Systems Engineering methods was used to develop a concept and physical model for TOE manipulation. The motion of different actuators of the fabricated motorized system has been tested. It is concluded that the developed medical system, counteracting conflated disadvantages, represents a progressive approach for cardiac healthcare. PMID- 28812248 TI - Building a Community of Health Professionals to Establish a Shared Learning Experience in Psychiatry and Substance Use Disorders for Health Professions Students. PMID- 28812249 TI - Long-term disability and progression in spinal onset multiple sclerosis. AB - The aim of this study is to investigate the long-term effects of the initial spinal cord (SC) involvement in MS patients. In this retrospective, single-center study, 824 patients with definite MS were screened. A total of 348 patients were excluded for ambiguous documentation of the initial relapse, pediatric onset, diagnosis of primary progressive disease, irregular assessments or visits causing doubt on the onset of progression time, and clinical follow-up duration less than 12 months. Eventually, 476 MS patients were included. Data regarding the demographics, initial symptoms, the degree of recovery from the initial relapse, neuroimaging, cerebrospinal fluid analysis, long-term disability, and progression were collected from the medical registry. The mean duration of follow-up was 7.49 +/- 5.30 years. The percentage of patients entering the progressive disease course was 23.3 in the whole group. A total of 157 patients (33.0%) had SC involvement during the first clinical relapse. These patients were significantly older at disease onset (31.69 +/- 10.18 vs. 29.55 +/- 9.49; p = 0.028), had higher rates of progression (32.5 vs. 18.8%; p = 0.001), and had higher disability scores in long-term follow-up (3.41 +/- 2.19 vs. 2.62 +/- 1.81; p < 0.001). Mean age at the transition of progressive phase was 41.4 +/- 11.2 years. The degree of recovery from the initial relapse significantly affected the long term disability. The poor recovery from the initial relapse was associated with older onset age and higher EDSS scores. Being older than 40 years during MS onset and poor recovery from the initial relapse exerted an increased risk for progression. The initial SC involvement was related to a more severe relapse with less chance of complete recovery and higher risk for progression. Confirmation of risk factors in different MS cohorts would increase our understanding of the complex disease mechanisms. PMID- 28812251 TI - In Vitro Study of Influence of Au Nanoparticles on HT29 and SPEV Cell Lines. AB - Cell culture models are excellent tools for potential toxicity of nanoparticles and fundamental investigations in cancer research. Thus, information about AuNP potential toxicity and effects on human health is necessary for the use of nanomaterials in clinical settings. The aim of our research is to examine the effects of AuNPs on the epithelial origin cell lines: continuous and oncogenic. Embryonic porcine kidney epithelial inoculated (SPEV) cell line and colorectal carcinoma cell line (HT29) were used. In the test cultures, the cell proliferation, necrosis/apoptosis, and multicellular spheroids generation were evaluated. We demonstrated that AuNP concentrations of 6-12 MUg/ml reduced the proliferation of SPEV and HT29 cells and increased the cell number at early and late stages of apoptosis and necrosis. It was shown that small concentrations of AuNPs (1-3 MUg/ml) stimulate multicellular spheroid formation by HT29 and SPEV cells. However, higher AuNP concentrations (6-12 MUg/ml) had both cytotoxic and anti-cohesive effects on cell in suspension. The large sensitiveness to the action of AuNPs was shown by the line of HT29 (6 MUg/ml) as compared to the SPEV cells (12 MUg/ml). This experimental study of the effect of AuNPs on SPEV and HT29 cell lines will justify their further application in AuNP-mediated anticancer treatment. PMID- 28812250 TI - MIV-150 and zinc acetate combination provides potent and broad activity against HIV-1. AB - We previously showed that the combination of the non-nucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 with zinc acetate (ZA) formulated in a carrageenan (CG; MZC) gel provided macaques significant protection against vaginal simian-human immunodeficiency virus-RT (SHIV-RT) challenge, better than either MIV-150/CG or ZA/CG. The MZC gel was shown to be safe in a phase 1 clinical trial. Herein, we used in vitro approaches to study the antiviral properties of ZA and the MIV-150/ZA combination, compared to other NNRTIs. Like other NNRTIs, MIV-150 has EC50 values in the subnanomolar to nanomolar range against wild type and NNRTI or RT-resistant HIVs. While less potent than NNRTIs, ZA was shown to be active in primary cells against laboratory-adapted and primary HIV-1 isolates and HIV-1 isolates/clones with NNRTI and RT resistance mutations, with EC50 values between 20 and 110 MUM. The MIV-150/ZA combination had a potent and broad antiviral activity in primary cells. In vitro resistance selection studies revealed that previously described NNRTI-resistant mutations were selected by MIV-150. ZA-resistant virus retained susceptibility to MIV-150 (and other RTIs) and MIV-150-selected virus remained sensitive to ZA. Notably, resistant virus was not selected when cultured in the presence of both ZA and MIV 150. This underscores the potency and breadth of the MIV-150/ZA combination, supporting preclinical macaque studies and the advancement of MZC microbicides into clinical testing. PMID- 28812252 TI - Secondary fracture prevention in hip fracture patients requires cooperation from general practitioners. AB - : Despite individual recommendations on osteoporosis management in patients after hip fracture surgery, addressed by orthopedic surgeons to Czech general practitioners, the patients remained undiagnosed and untreated because of provider-level barriers to post-fracture secondary prevention. PURPOSE: The goal of the study was to assess whether an individual recommendation on osteoporosis treatment addressed to a hip fracture patient's GP would lead to better osteoporosis management. METHODS: Two groups of patients who suffered hip fractures and were treated at the Orthopedic Department were evaluated. In 111 patients, general recommendations on osteoporosis treatment and fracture prevention were provided in a discharge report addressed to the GP. In the second group, 96 patients were provided individually with a detailed written set of recommendations on osteoporosis examination, treatment, and fracture prevention, which was also provided in the discharge report. A questionnaire to assess the provided care was mailed to the patients 5.3 +/- 1.2 months of discharge. Those patients who did not return the questionnaires were contacted by phone. RESULTS: The questionnaires were received from 44% and 49% of patients from the general and detailed recommendation groups, respectively. Along with the phone call, we were able to contact 78 (70.3%) and 68 (70.8%) patients from the general and detailed recommendation groups, respectively. GPs secured osteoporosis evaluation in 14.6% of the patients. Calcium supplementation and vitamin D supplementation were newly provided in 42.7 and 36.4% of the patients, respectively. Anti resorptive therapy was newly provided in 8.3% of the patients. No significant differences between the groups were observed in osteoporosis evaluation, calcium and vitamin D supplementation, and anti-osteoporosis treatments. Out of 207 patients, further examination or treatment was requested by 45 patients (21.7%); 75 patients (36.2%) declared no interest in further care. CONCLUSION: Recommendations on osteoporosis management addressed to Czech GPs after surgical fracture management had little effect on treatment. As the anti-osteoporotic preparations can only be prescribed by specialists, the availability of necessary examinations and treatment is limited by the motivation of GPs. Consequently, the implementation of Fracture Liaison Services to help close the care gap may be limited in the absence of participation by Czech GPs. PMID- 28812253 TI - The land of no milk and no honey: force feeding in Israel. AB - In 2015, the Israeli Knesset passed the force-feeding act that permits the director of the Israeli prison authority to appeal to the district court with a request to force-feed a prisoner against his expressed will. A recent position paper by top Israeli clinicians and bioethicists, published in Hebrew, advocates for force-feeding by medical professionals and presents several arguments that this would be appropriate. Here, we first posit three interrelated questions: 1. Do prisoners have a right to hunger-strike? 2. Should governing institutions force-feed prisoners and/or is it ethical to force-feed prisoners? 3. Should healthcare professionals force-feed prisoners? We then focus on the first and third questions. We first briefly provide several arguments to support the right of prisoners to refuse treatment. Next, we critically review the arguments presented in the Israeli position paper, demonstrating that they are all misguided at best. Lastly, we briefly present arguments against force-feeding by medical professionals. We conclude that healthcare providers should not participate in the force-feeding of prisoners. PMID- 28812254 TI - Endemic Publishiasis: Redux and Growing. PMID- 28812255 TI - Persisting Racial Disparities in Colonoscopy Screening of Persons with a Family History of Colorectal Cancer. AB - With 23 and 47% higher colorectal cancer (CRC) incidence and mortality, respectively, among African Americans vs. Whites, CRC screening studies are important. Screening guidelines recommend 5-yearly colonoscopy screening of persons with a family history of CRC (first-degree relatives, FDRs), beginning at 40 years of age. For this elevated-risk group, colonoscopy screening is preferred because of the risk of more aggressive cancer that may elude early detection by other methods. African Americans with a family history of CRC are at the intersection of two elevated risk demographics, race and FDR status. This study explored racial disparities in colonoscopy screening of FDRs using 2005, 2010, and 2015 national survey data on 3220 Whites and 466 African Americans.Despite increasing colonoscopy rates among FDRs (72.3 and 62.2% in 2015 among Whites and African Americans, respectively), the 40-49 age group showed substantial racial disparities each year, persisting through 2015 (58.8, 31.7, and 35.3% lower among African Americans in 2005, 2010, and 2015, respectively). Adjusted analysis of the pooled 3-year sample showed that FDRs aged 40-49 years had one-third the colonoscopy likelihood of the 50-plus age group. African Americans without college education were 40 and 60% less likely than Whites without college and with college education, respectively, to have had a colonoscopy. The sustained, high screening disparity, and low colonoscopy rates in the 40-49 age group overall, call for novel approaches to reduce CRC mortality disparities, such as, patient navigation programs to reach out to younger FDRs, particularly, less educated African Americans. PMID- 28812257 TI - Robotic-assisted microvascular surgery: skill acquisition in a rat model. AB - Microsurgery is a technically demanding field with long learning curves. Robotic assisted microsurgery has the ability to decrease these learning curves. We, therefore, sought to assess the feasibility of robotic-assisted microvascular surgery in a rat model, and whether this could be translated into a worthwhile skills acquisition exercise for residents. Twenty-eight rats underwent microvascular anastomosis. Procedures were performed by a trained microvascular surgeon with no robotic experience (n = 14), or a trained robotic surgeon with no microvascular experience (n = 14). Anesthetized rats were subjected to complete transection and end-to-end anastomosis of the abdominal aorta using 10-0 prolene. Manually (n = 6) and robotic-assisted (n = 8) procedures were performed by both surgeons. A successful procedure required a patent anastomosis and no bleeding. After approximately 35 days, angiography and histopathological studies of the anastomoses were performed. Median times for robotic-assisted anastomoses were 37.5 (34.2-42.7) min for the microsurgeon and 38.5 (32.7-52) min for robotic surgeon. In the manual group, it took 17 (13.5-23) min for microsurgeon and 44 (34.5-60) min for robotic surgeon. Within the robotic-assisted group, there was a trend toward improvement in both surgeons, but greater in the microsurgeon. Robotic-assisted microvascular anastomosis in a rat model is a feasible skill acquisition exercise. By eliminating the need for a skilled microsurgical assistant, as well as, improved microsurgical technology, the robotic system may prove to be a crucial player in future microsurgical skill training. PMID- 28812256 TI - The Potential for Emerging Microbiome-Mediated Therapeutics in Asthma. AB - PURPOSE OF REVIEW: In terms of immune regulating functions, analysis of the microbiome has led the development of therapeutic strategies that may be applicable to asthma management. This review summarizes the current literature on the gut and lung microbiota in asthma pathogenesis with a focus on the roles of innate molecules and new microbiome-mediated therapeutics. RECENT FINDINGS: Recent clinical and basic studies to date have identified several possible therapeutics that can target innate immunity and the microbiota in asthma. Some of these drugs have shown beneficial effects in the treatment of certain asthma phenotypes and for protection against asthma during early life. Current clinical evidence does not support the use of these therapies for effective treatment of asthma. The integration of the data regarding microbiota with technologic advances, such as next generation sequencing and omics offers promise. Combining comprehensive bioinformatics, new molecules and approaches may shape future asthma treatment. PMID- 28812258 TI - Chromosomal flhB1 gene of the alphaproteobacterium Azospirillum brasilense Sp245 is essential for correct assembly of both constitutive polar flagellum and inducible lateral flagella. AB - Azospirillum brasilense has the ability of swimming and swarming motility owing to the work of a constitutive polar flagellum and inducible lateral flagella, respectively. The interplay between these flagellar systems is poorly understood. One of the key elements of the flagellar export apparatus is the protein FlhB. Two predicted flhB genes are present in the genome of A. brasilense Sp245 (accession nos. HE577327-HE577333). Experimental evidence obtained here indicates that the chromosomal coding sequence (CDS) AZOBR_150177 (flhB1) of Sp245 is essential for the production of both types of flagella. In an flhB1:: Omegon-Km mutant, Sp245.1063, defects in polar and lateral flagellar assembly and motility were complemented by expressing the wild-type flhB1 gene from plasmid pRK415. It was found that Sp245.1063 lost the capacity for slight but statistically significant decrease in mean cell length in response to transfer from solid to liquid media, and vice versa; in the complemented mutant, this capacity was restored. It was also shown that after the acquisition of the pRK415-harbored downstream CDS AZOBR_150176, cells of Sp245 and Sp245.1063 ceased to elongate on solid media. These initial data suggest that the AZOBR_150176-encoded putative multisensory hybrid sensor histidine kinase-response regulator, in concert with FlhB1, plays a role in morphological response of azospirilla to changes in the hardness of a milieu. PMID- 28812260 TI - Zinc Metabolism and Metallothioneins. AB - Among the trace elements, zinc is one of the most used elements in biological systems. Zinc is found in the structure of more than 2700 enzymes, including hydrolases, transferases, oxyreductases, ligases, isomerases, and lyases. Not surprisingly, it is present in almost all body cells. Preserving the stability and integrity of biological membranes and ion channels, zinc is also an intracellular regulator and provides structural support to proteins during molecular interactions. It acts as a structural element in nucleic acids or other gene-regulating proteins. Metallothioneins, the low molecular weight protein family rich in cysteine groups, are involved significantly in numerous physiological and pathological processes including particularly oxidative stress. A critical role of metallothioneins (MT) is to bind zinc with high affinity and to serve as an intracellular zinc reservoir. By releasing free intracellular zinc when needed, MTs mediate the unique physiological roles of zinc. MT expression is induced by zinc elevation, and thus, zinc homeostasis is maintained. That MT mediates the effects of zinc, besides having strong radical scavenging effects, points to the critical part it plays in oxidative stress. The present review aims to give information on metallothioneins, which have critical importance in the metabolism and molecular pathways of zinc. PMID- 28812259 TI - Evolutionary dynamics in the fungal polarization network, a mechanistic perspective. AB - Polarity establishment underlies proper cell cycle completion across virtually all organisms. Much progress has been made in generating an understanding of the structural and functional components of this process, especially in model species. Here we focus on the evolutionary dynamics of the fungal polarization protein network in order to determine general components and mechanistic principles, species- or lineage-specific adaptations and the evolvability of the network. The currently available genomic and proteomic screens in a variety of fungal species have shown three main characteristics: (1) certain proteins, processes and functions are conserved throughout the fungal clade; (2) orthologous functions can never be assumed, as various cases have been observed of homologous loci with dissimilar functions; (3) species have, typically, various species- or lineage-specific proteins incorporated in their polarization network. Further large-scale comparative and experimental studies, including those on non-model species representing the great fungal diversity, are needed to gain a better understanding of the evolutionary dynamics and generalities of the polarization network in fungi. PMID- 28812261 TI - Backbone and side-chain 1H, 15N and 13C resonance assignments of two Sac10b family members Mvo10b and Mth10bTQQA from archaea. AB - The Sac10b family proteins, also named as Alba, are small, basic, nucleic acid binding proteins widely distributed in archaea. They possess divergent physiological functions such as binding to both DNA and RNA with a high affinity and involving in genomic DNA compaction, RNA transactions and transcriptional regulations. The structures of many Sac10b family proteins from hyperthermophilic archaea have been reported, while those from thermophilic and mesophilic archaea are largely unknown. As was pointed out, the homologous members from thermophilic and mesophilic archaea may have functions different from the hyperthermophilic members. Therefore, comparison of these homologous members can provide biophysical and structural insight into the functional diversity and thermal adaptation mechanism. The present work mainly focused on the NMR study of two Sac10b family members, Mvo10b and Mth10b, from the mesophilic and thermophilic archaea, respectively. To overcome the difficulties caused by the oligomerization and conformation heterogeneity of Mth10b, a M13T/L17Q/I20Q/P56A mutant Mth10b (Mth10bTQQA) was constructed and used together with Mvo10b for multi-dimensional NMR experiments. The resonance assignments of Mvo10b and Mth10bTQQA are reported for further structural determination which is a basis for understanding the functional diversity and their thermal adaption mechanisms. PMID- 28812262 TI - Systolic Dysfunction in Infarcted Mice Does Not Necessarily Lead to Heart Failure: Need to Refine Preclinical Models. AB - Heart failure (HF) is a major cause of death and hospitalization worldwide. Despite advances in reducing mortality, prognosis remains poor and prevalence has reached epidemic proportions. The limitations of available preclinical models represent a major hurdle in the development of new therapies. Myocardial infarction (MI) is a main cause of HF in humans, and mouse models of MI are often used to study HF mechanisms and experimental treatments. We investigated whether MI in mice constitutes an appropriate model of HF. Permanent ligation of the left coronary artery induced severe and persistent systolic dysfunction and ventricular dilatation. Mouse follow-up for 10 months showed no significant evidence of lung congestion or other pulmonary defects associated with HF. No difference was observed in the capacity of infarcted mice to exercise compared to control animals. These results indicate that severe cardiac dysfunction in mice is not sufficient to demonstrate the presence of HF. PMID- 28812264 TI - Oxytocin and Steroid Actions. AB - Biosynthesis and secretion of the hypothalamic nonapeptide oxytocin largely depends on steroid hormones. Estradiol, corticosterone, and vitamin D seem to be the most prominent actors. Due to their lipophilic nature, systemic steroids are thought to be capable of crossing the blood-brain barrier, thus mediating central functions including neuroendocrine and behavioral control. The actual mode of action of steroids in hypothalamic circuitry is still unknown: Most of the oxytocinergic perikarya lack nuclear steroid receptors but express proteins suspected to be membrane receptors for steroids. Oxytocin expressing neurons contain enzymes important for intrinsic steroid metabolism. Furthermore, they produce and probably liberate specific steroid-binding globulins. Rapid responses to steroid hormones may involve these binding proteins and membrane-associated receptors, rather than classic nuclear receptors and genomic pathways. Neuroendocrine regulation, reproductive behaviors, and stress response seem to depend on these mechanisms. PMID- 28812263 TI - Molecular Basis of Oxytocin Receptor Signalling in the Brain: What We Know and What We Need to Know. AB - Oxytocin (OT), a hypothalamic neuropeptide involved in regulating the social behaviour of all vertebrates, has been proposed as a treatment for a number of neuropsychiatric disorders characterised by deficits in the social domain. Over the last few decades, advances focused on understanding the social effects of OT and its role in physiological conditions and brain diseases, but much less has been done to clarify the molecular cascade of events involved in mediating such effects and in particular the cellular and molecular pharmacology of OT and its target receptor (OTR) in neuronal and glial cells.The entity and persistence of OT activity in the brain is closely related to the expression and regulation of the OTR expressed on the cell surface, which transmits the signal intracellularly and permits OT to affect cell function. Understanding the various signalling mechanisms mediating OTR-induced cell responses is crucial to determine the different responses in different cells and brain regions, and the success of OT and OT-derived analogues in the treatment of neurodevelopmental and psychiatric diseases depends on how well we can control such responses. In this review, we will consider the most important aspects of OT/OTR signalling by focusing on the molecular events involved in OT binding and coupling, on the main signalling pathways activated by the OTR in neuronal cells and on intracellular and plasma membrane OTR trafficking, all of which contribute to the quantitative and qualitative features of OT responses in the brain. PMID- 28812265 TI - Oxytocin and Olfaction. AB - Social signals are identified through processing in sensory systems to trigger appropriate behavioral responses. Social signals are received primarily in most mammals through the olfactory system. Individuals are recognized based on their unique blend of odorants. Such individual recognition is critical to distinguish familiar conspecifics from intruders and to recognize offspring. Social signals can also trigger stereotyped responses like mating behaviors. Specific sensory pathways for individual recognition and eliciting stereotyped responses have been identified both in the early olfactory system and its connected cortices. Oxytocin is emerging as a major state modulator of sensory processing with distinct functions in early and higher olfactory brain regions. The brain state induced through Oxytocin influences social perception. Oxytocin acting on different brain regions can promote either exploration and recognition towards same- or other-sex conspecifics, or association learning. Region-specific deletion of Oxytocin receptors suffices to disrupt these behaviors. Together, these recent insights highlight that Oxytocin's function in social behaviors cannot be understood without considering its actions on sensory processing. PMID- 28812267 TI - Oxytocin and Parental Behaviors. AB - The oxytocin/vasopressin ancestor molecule has been regulating reproductive and social behaviors for more than 500 million years. In all mammals, oxytocin is the hormone indispensable for milk-ejection during nursing (maternal milk provision to offspring), a process that is crucial for successful mammalian parental care. In laboratory mice, a remarkable transcriptional activation occurs during parental behavior within the anterior commissural nucleus (AC), the largest magnocellular oxytocin cell population within the medial preoptic area (although the transcriptional activation was limited to non-oxytocinergic neurons in the AC). Furthermore, there are numerous recent reports on oxytocin's involvement in positive social behaviors in animals and humans. Given all those, the essential involvement of oxytocin in maternal/parental behaviors may seem obvious, but basic researchers are still struggling to pin down the exact role oxytocin plays in the regulation of parental behaviors. A major aim of this review is to more clearly define this role. The best conclusion at this moment is that OT can facilitate the onset of parental behavior, or parental behavior under stressful conditions.In this chapter, we will first review the basics of rodent parental behavior. Next, the neuroanatomy of oxytocin systems with respect to parental behavior in laboratory mice will be introduced. Then, the research history on the functional relationship between oxytocin and parental behavior, along with advancements in various techniques, will be reviewed. Finally, some technical considerations in conducting behavioral experiments on parental behavior in rodents will be addressed, with the aim of shedding light on certain pitfalls that should be avoided, so that the progress of research in this field will be facilitated. In this age of populism, researchers should strive to do even more scholarly works with further attention to methodological details. PMID- 28812268 TI - Oxytocin and Human Evolution. AB - A small, but powerful neuropeptide, oxytocin coordinates processes that are central to both human reproduction and human evolution. Also embedded in the evolution of the human nervous system are unique pathways necessary for modern human sociality and cognition. Oxytocin is necessary for facilitating the birth process, especially in light of anatomical restrictions imposed by upright human locomotion, which depends on a fixed pelvis. Oxytocin, by facilitating birth, allowed the development of a large cortex and a protective bony cranium. The complex human brain in turn permitted the continuing emergence of social sensitivity, complex thinking, and language. After birth is complete, oxytocin continues to support human development by providing direct nutrition, in the form of human milk, and emotional and intellectual support through high levels of maternal behavior and selective attachment. Oxytocin also encourages social sensitivity and reciprocal attunement, on the part of both the mother and child, which are necessary for human social behavior and for rearing an emotionally healthy human child. Oxytocin supports growth during development, resilience, and healing across the lifespan. Oxytocin dynamically moderates the autonomic nervous system, and effects of oxytocin on vagal pathways allowing high levels of oxygenation and digestion necessary to support adaptation in a complex environment. Finally, oxytocin has anti-oxidant and anti-inflammatory effects, helping to explain the pervasive adaptive consequences of social behavior for emotional and physical health. PMID- 28812269 TI - Oxytocin Signaling in the Early Life of Mammals: Link to Neurodevelopmental Disorders Associated with ASD. AB - Oxytocin plays a role in various functions including endocrine and immune functions but also parent-infant bonding and social interactions. It might be considered as a main neuropeptide involved in mediating the regulation of adaptive interactions between an individual and his/her environment. Recently, a critical role of oxytocin in early life has been revealed in sensory processing and multi-modal integration that are essential for normal postnatal neurodevelopment. An early alteration in the oxytocin-system may disturb its maturation and may have short-term and long-term pathological consequences such as autism spectrum disorders. Here, we will synthesize the existing literature on the development of the oxytocin system and its role in the early postnatal life of mammals (from birth to weaning) in a normal or pathological context. Oxytocin is required in critical windows of time that play a pivotal role and that should be considered for therapeutical interventions. PMID- 28812266 TI - Oxytocin and Social Relationships: From Attachment to Bond Disruption. AB - Social relationships throughout life are vital for well-being and physical and mental health. A significant amount of research in animal models as well as in humans suggests that oxytocin (OT) plays an important role in the development of the capacity to form social bonds, the mediation of the positive aspects of early life nurturing on adult bonding capacity, and the maintenance of social bonding. Here, we focus on the extensive research on a socially monogamous rodent model organism, the prairie vole (Microtus ochrogaster). OT facilitates mating-induced pair bonds in adults through interaction with the mesolimbic dopamine system. Variation in striatal OT receptor density predicts resilience and susceptibility to neonatal social neglect in female prairie voles. Finally, in adults, loss of a partner results in multiple disruptions in OT signaling, including decreased OT release in the striatum, which is caused by an activation of the brain corticotropin releasing factor (CRF) system. The dramatic behavioral consequence of partner loss is increased depressive-like behavior reminiscent of bereavement. Importantly, infusions of OT into the striatum of adults prevents the onset of depressive-like behavior following partner loss, and evoking endogenous OT release using melanocortin agonists during neonatal social isolation rescues impairments in social bonding in adulthood. This work has important translational implications relevant to the disruptions of social bonds in childhood and in adults. PMID- 28812270 TI - Oxytocin and Facial Emotion Recognition. AB - The expression of emotion in faces serves numerous meaningful functions, such as conveying messages of danger or approach, facilitating communication, and promoting the formation of social bonds and relationships. The study of facial expressions of emotion has become integral to research in social psychology and social neuroscience, particularly with respect to the neuropeptide oxytocin. This chapter examines how oxytocin influences the processing of emotion in faces by reviewing intranasal administration studies of automatic processing, selective attention, and emotion recognition. Two important trends in the literature have been identified: exogenous oxytocin attenuates early attentional biases towards negative stimuli and increases selective attention and recognition of emotional cues in faces, particularly around the eyes. Both of these effects can be traced to well-delineated neural circuits involving amygdala, early visual processing areas, and reward circuits, and both purportedly facilitate approach-related behavior when affiliative opportunities are available. These data are integrated into a conceptual model incorporating contextual factors and moderating influences, as oxytocinergic effects on cognition and social behavior appear to vary in persons along indices of social competence, interpersonal sensitivity, and early adversity. Limitations of this literature and future directions for research are briefly discussed. PMID- 28812271 TI - Oxytocin and Interpersonal Relationships. AB - The neuropeptide oxytocin (OT) has emerged as a potent modulator of diverse aspects of interpersonal relationships. OT appears to work in close interaction with several other neurotransmitter networks, including the dopaminergic reward circuit, and to be dependent on sex-specific hormonal influences. In this chapter, we focus on four main domains of OT and interpersonal relationships, including (1) the protective effect of OT on an individual's ability to withstand stress (i.e., stress buffering), (2) the effect of OT on emotion recognition and empathy, (3) OT's ability to enhance social synchrony and cooperation among individuals, and (4) the effect of OT on an individual's perception of social touch. We then illustrate the connection between OT and loneliness while grieving the loss of a loved one. We finish by discussing the clinical potential of OT, focusing on its potential role as an adjunct to psychotherapy, its enhancement through sex-specific hormonal influences, and the difficulties that present themselves when considering OT as a therapy. Overall, we argue that OT continues to hold strong therapeutic promise, but that it is strongly dependent on internal and external influences, for instance the patient's personal past experiences and interaction with the therapist, in order to provide the best possible therapy. PMID- 28812272 TI - Oxytocin and Borderline Personality Disorder. AB - Borderline personality disorder (BPD) is a prevalent and severe mental disorder with affect dysregulation, impulsivity, and interpersonal dysfunction as its core features. Up to now, six studies have been performed to investigate the role of oxytocin in the pathogenesis of BPD. While a beneficial effect of oxytocin on threat processing and stress responsiveness was found, other studies using an oxytocin challenge design presented with rather heterogeneous results. Future studies have to include a sufficiently large sample of patients, control for gender, and focus on mechanisms known to be related to aversive early life experiences. PMID- 28812274 TI - Oxytocin and Anxiety Disorders. AB - In the present chapter, we review the literature focusing on oxytocin (OT) centered research in anxiety spectrum conditions, comprising separation anxiety disorder, specific phobias, social anxiety disorder (SAD), panic disorder, generalized anxiety disorder, and anxiety-related endophenotypes (e.g., trust behavior, behavioral inhibition, neuroticism, and state/trait anxiety). OT receptor gene (OXTR) polymorphisms have been implicated in gene-environment interactions with attachment style and childhood maltreatment and to influence clinical outcomes, including SAD intensity and limbic responsiveness. Epigenetic OXTR DNA methylation patterns have emerged as a link between categorical, dimensional, neuroendocrinological, and neuroimaging SAD correlates, highlighting them as potential peripheral surrogates of the central oxytocinergic tone. A pathophysiological framework of OT integrating the dynamic nature of epigenetic biomarkers and the summarized genetic and peripheral evidence is proposed. Finally, we emphasize opportunities and challenges of OT as a key network node of social interaction and fear learning in social contexts. In conjunction with multi-level investigations incorporating a dimensional understanding of social affiliation and avoidance in anxiety spectrum disorders, these concepts will help to promote research for diagnostic, state, and treatment response biomarkers of the OT system, advancing towards indicated preventive interventions and personalized treatment approaches. PMID- 28812275 TI - A Method for Improving the Integrity of Peer Review. AB - Peer review is the most important aspect of reputable journals. Without it, we would be unsure about whether the material published was as valid and reliable as is possible. However, with the advent of the Internet, scientific literature has now become subject to a relatively new phenomenon: fake peer reviews. Some dishonest researchers have been manipulating the peer review process to publish what are often inferior papers. There are even papers that explain how to do it. This paper discusses one of those methods and how editors can defeat it by using a special review ID. This method is easy to understand and can be added to current peer review systems easily. PMID- 28812273 TI - A Precision Medicine Approach to Oxytocin Trials. AB - In this chapter, we introduce a new area of social pharmacology that encompasses the study of the role of neuromodulators in modulating a wide range of social behaviors and brain function, with the interplay of genetic and epigenetic factors. There are increasing evidences for the role of the neuropeptide oxytocin in modulating a wide range of social behaviors, in reducing anxiety, and in impacting the social brain network. Oxytocin also promotes social functions in patients with neuropsychiatric disorders, such as autism and reduces anxiety and fear in anxiety disorders. In this chapter, we will emphasize the importance of integrating basic research and clinical human research in determining optimal strategies for drug discoveries for social dysfunctions and anxiety disorders. We will highlight the significance of adopting a precision medicine approach to optimize targeted treatments with oxytocin in neuropsychiatry. Oxytocin effects on social behavior and brain function can vary from one individual to another based on external factors, such as heterogeneity in autism phenotype, childhood experiences, personality, attachment style, and oxytocin receptor polymorphisms. Hence, targeted therapies for subgroups of patients can help alleviating some of the core symptoms and lead to a better future for these patients and their families. PMID- 28812276 TI - Arundic Acid Increases Expression and Function of Astrocytic Glutamate Transporter EAAT1 Via the ERK, Akt, and NF-kappaB Pathways. AB - Glutamate is the major excitatory neurotransmitter in the brain, but excessive synaptic glutamate must be removed to prevent excitotoxic injury and death. Two astrocytic glutamate transporters, excitatory amino acid transporter (EAAT) 1 and 2, play a major role in eliminating excess glutamate from the synapse. Dysregulation of EAAT1 contributes to the pathogenesis of multiple neurological disorders, such as Alzheimer's disease (AD), ataxia, traumatic brain injuries, and glaucoma. In the present study, we investigated the effect of arundic acid on EAAT1 to determine its efficacy in enhancing the expression and function of EAAT1, and its possible mechanisms of action. The studies were carried out in human astrocyte H4 cells as well as in human primary astrocytes. Our findings show that arundic acid upregulated EAAT1 expression at the transcriptional level by activating nuclear factor kappa-light-chain-enhancer of activated B cells (NF kappaB). Arundic acid increased astrocytic EAAT1 promoter activity, messenger RNA (mRNA)/protein levels, and glutamate uptake, while pharmacological inhibition of NF-kappaB or mutation on NF-kappaB binding sites in the EAAT1 promoter region abrogated these effects. Arundic acid increased NF-kappaB reporter activity and induced NF-kappaB nuclear translocation as well as its bindings to the EAAT1 promoter. Furthermore, arundic acid activated the Akt and ERK signaling pathways to enhance EAAT1 mRNA/protein levels. Finally, arundic acid attenuated manganese induced decrease in EAAT1 expression by inhibiting expression of the transcription factor Ying Yang 1 (YY1). These results demonstrate that arundic acid increases the expression and function of EAAT1 via the Akt, ERK, and NF kappaB signaling pathways, and reverses Mn-induced EAAT1 repression by inhibiting the Mn-induced YY1 activation. PMID- 28812277 TI - Milonine, an Alkaloid of Cissampelos sympodialis Eichl. (Menispermaceae) Inhibits Histamine Release of Activated Mast Cells. AB - Milonine is an alkaloid of Cissampelos sympodialis Eichl. (Menispermaceae), a plant used in the northeast of Brazil to treat allergies such as asthma, rhinitis, and other conditions. Previously, several alkaloids were isolated from its roots and leaves with pharmacological properties in asthma and acute inflammation models. Therefore, the aim of this study was to evaluate the milonine effect on mast cells degranulation in vivo and in vitro. Swiss mice (n = 8) were used in models of paw edema induced by carrageenan, compound 48/80, or histamine. One hour before challenge, the animals were treated with milonine (at different doses) or standard drugs and, at different time points, the edema formation was measured. In addition, other different methods, such as anaphylactic shock reaction and scratching behavior models both induced by compound 48/80, a mast cell degranulator, were used to assess milonine effect histamine release in vivo. Moreover, milonine effect on mast cell degranulation in vitro was also carried out. Firstly, it was observed that milonine significantly decreased the carrageenan edema formation only at the beginning of the reaction (i.e., up to 2 h after challenge). Furthermore, this alkaloid decreased the edema induced by compound 48/80, maintained the paw tissue integrity, without modulating histamine-induced paw edema. In anaphylactic shock reaction, milonine increased the time of animal survival when compared with compound 48/80 group. Milonine also significantly decreased the scratching behavior induced by compound 48/80 with decreasing of mast cell degranulation in vitro. Therefore, these data indicated that milonine presents anti-allergic properties by decreasing mast cell degranulation rather than acting on histamine effect. PMID- 28812278 TI - Monomer-dependent secondary nucleation in amyloid formation. AB - Secondary nucleation of monomers on the surface of an already existing aggregate that is formed from the same kind of monomers may lead to autocatalytic amplification of a self-assembly process. Such monomer-dependent secondary nucleation occurs during the crystallization of small molecules or proteins and self-assembled materials, as well as in protein self-assembly into fibrous structures. Indications of secondary nucleation may come from analyses of kinetic experiments starting from pure monomers or monomers supplemented with a low concentration of pre-formed aggregates (seeds). More firm evidence requires additional experiments, for example those employing isotope labels to distinguish new aggregates arising from the monomer from those resulting from fragmentation of the seed. In cases of amyloid formation, secondary nucleation leads to the formation of toxic oligomers, and inhibitors of secondary nucleation may serve as starting points for therapeutic developments. Secondary nucleation displays a high degree of structural specificity and may be enhanced by mutations or screening of electrostatic repulsion. PMID- 28812279 TI - The Effects of Li/Nb Ratio on the Preparation and Photocatalytic Performance of Li-Nb-O Compounds. AB - The effects of Li/Nb ratio on the preparation of Li-Nb-O compounds by a hydrothermal method were studied deeply. Li/Nb ratio has a great impact on the formation of LiNbO3; the ratio smaller than 3:1 is beneficial to the formation of LiNbO3, while larger than 3:1, forms no LiNbO3 at all and the morphology and chemical bond of Nb2O5 raw material are totally modified by Li ions. The reason can be attributed to the large content of LiOH, which is beneficial to form Li3NbO4 not LiNbO3, and also, even if LiNbO3 particle locally forms, it is easily dissolved in LiOH solution with strong alkalinity. Pure LiNb3O8 powders are obtained with two absolutely opposite Li/Nb ratios: 8:1 and 1:3; the former shows a unique porous and hollow structure, quite different from the particle aggregation (the latter shows). Compared with Li/Nb = 1:3, the 4.2 times higher photocatalytic performance of LiNb3O8 (Li/Nb = 8:1) are observed and it can be attributed to the unique porous and hollow structure, which provides a high density of active sites for the degradation of MB. Compared to LiNbO3, the improved photocatalytic performance of LiNb3O8 can be attributed to its layered structure type with the reduced symmetry enhancing the separation of electrons and holes. PMID- 28812280 TI - Effect of Missing Inter-Beat Interval Data on Heart Rate Variability Analysis Using Wrist-Worn Wearables. AB - Most of the wrist-worn devices on the market provide a continuous heart rate measurement function using photoplethysmography, but have not yet provided a function to measure the continuous heart rate variability (HRV) using beat-to beat pulse interval. The reason for such is the difficulty of measuring a continuous pulse interval during movement using a wearable device because of the nature of photoplethysmography, which is susceptible to motion noise. This study investigated the effect of missing heart beat interval data on the HRV analysis in cases where pulse interval cannot be measured because of movement noise. First, we performed simulations by randomly removing data from the RR interval of the electrocardiogram measured from 39 subjects and observed the changes of the relative and normalized errors for the HRV parameters according to the total length of the missing heart beat interval data. Second, we measured the pulse interval from 20 subjects using a wrist-worn device for 24 h and observed the error value for the missing pulse interval data caused by the movement during actual daily life. The experimental results showed that mean NN and RMSSD were the most robust for the missing heart beat interval data among all the parameters in the time and frequency domains. Most of the pulse interval data could not be obtained during daily life. In other words, the sample number was too small for spectral analysis because of the long missing duration. Therefore, the frequency domain parameters often could not be calculated, except for the sleep state with little motion. The errors of the HRV parameters were proportional to the missing data duration in the presence of missing heart beat interval data. Based on the results of this study, the maximum missing duration for acceptable errors for each parameter is recommended for use when the HRV analysis is performed on a wrist-worn device. PMID- 28812281 TI - Preclinical development of an automated injection device for intradermal delivery of a cell-based therapy. AB - Current methods for intradermal delivery of therapeutic products in clinical use include manual injection via the Mantoux technique and the use of injection devices, primarily developed for the delivery of vaccines and small molecules. A novel automated injection device is presented specifically designed for accurate delivery of multiple doses of product through a number of adjustable injection parameters, including injection depth, dose volume and needle insertion speed. The device was originally conceived for the delivery of a cell-based therapy to patients with skin wounds caused by epidermolysis bullosa. A series of preclinical studies was conducted (i) to evaluate the performance of the pre production model (PreCTCDV01) and optimise the final design, (ii) to confirm that a cell therapy product can be effectively delivered through the injection system and (iii) to test whether the device can be safely and effectively operated by potential end-users. Results from these studies confirmed that the device is able to consistently deliver repeated doses of a liquid to the intradermal layer in an ex vivo skin model. In addition, the device can support delivery of a cell therapy product through a customised microbore tubing without compromising cell viability. Finally, the device was shown to be safe and easy to use as evidenced by usability testing. The clinical device has since been granted European market access and plans for clinical use are currently underway. The device is expected to find use in the emerging area of cell therapies and a broad spectrum of traditional parenteral drug delivery applications. PMID- 28812282 TI - Implementation of an Integrated Care Learning Experience Within the Psychiatry Clerkship: Nutrition Education of Patients with Serious Mental Illness. PMID- 28812283 TI - Hydrodynamic rupture of liver in combat patient: a case of successful application of "damage control" tactic in area of the hybrid war in East Ukraine. AB - BACKGROUND: The hybrid war of Russia against Ukraine has been started in certain districts of Donetsk and Luhansk oblasts within the Donbas area in 2014. CASE PRESENTATION: We report a clinical case of a combat patient who was injured after the multiple launcher rocket system "Grad" shelling, diagnosed with hydrodynamic liver rupture followed by medical management with application of damage control (DC) tactic in conditions of hybrid war. The patient underwent relaparatomy, liver resection, endoscopic papillosphincterotomy, endoscopic retrograde cholecystopancreatography, stenting of the common bile duct, and VAC-therapy. Applied treatment modalities were effective; the patient was discharged on the 49th day after injury. CONCLUSIONS: To our best knowledge, this is the first report describing a successful application of DC tactic in the hybrid war in East Ukraine. From this case, we suggest that application of DC tactic at all levels of combat medical care could save more lives. PMID- 28812284 TI - New nanocomposites of polystyrene with polyaniline doped with lauryl sulfuric acid. AB - This work is concentrated on synthesis and investigation of new core-shell nanocomposites of polystyrene (PS) with doped polyaniline (PANI). The latex containing PS nanoparticles with sizes of 15-30 nm was prepared by microemulsion polymerization of styrene in water media. The PS/PANI nanocomposites were synthesized by chemical oxidative polymerization of aniline in the PS latex media in a presence of lauryl sulfuric acid (LSA), which served as both dopant and plasticizer. The real content of PANI in the synthesized nanocomposites was determined by UV-Vis spectroscopy method. The composition of the nanocomposites and oxidation state of the doped polyaniline were characterized by FTIR spectroscopy. The core-shell morphology of the nanocomposite nanoparticles was proved by transmission and scanning electron microscopy. It was found that conductivity and thermal behavior in air of these nanocomposites not only nonlinearly depended on the doped polyaniline content but also were strongly effected both by plasticizing properties of the acid-dopant and presence of the polyaniline shell. A possibility of application of these nanocomposites as sensor materials has been demonstrated. PMID- 28812285 TI - The reliability of eyetracking to assess attentional bias to threatening words in healthy individuals. AB - Eyetracking is commonly used to investigate attentional bias. Although some studies have investigated the internal consistency of eyetracking, data are scarce on the test-retest reliability and agreement of eyetracking to investigate attentional bias. This study reports the test-retest reliability, measurement error, and internal consistency of 12 commonly used outcome measures thought to reflect the different components of attentional bias: overall attention, early attention, and late attention. Healthy participants completed a preferential looking eyetracking task that involved the presentation of threatening (sensory words, general threat words, and affective words) and nonthreatening words. We used intraclass correlation coefficients (ICCs) to measure test-retest reliability (ICC > .70 indicates adequate reliability). The ICCs(2, 1) ranged from -.31 to .71. Reliability varied according to the outcome measure and threat word category. Sensory words had a lower mean ICC (.08) than either affective words (.32) or general threat words (.29). A longer exposure time was associated with higher test-retest reliability. All of the outcome measures, except second run dwell time, demonstrated low measurement error (<6%). Most of the outcome measures reported high internal consistency (alpha > .93). Recommendations are discussed for improving the reliability of eyetracking tasks in future research. PMID- 28812287 TI - Racial Discrimination and Mental Health in the USA: Testing the Reverse Racism Hypothesis. AB - OBJECTIVE: The present study examined whether the health disadvantages consequent of racial discrimination experienced by four racial/ethnic minority groups are equivalent with that of the dominant racial group. METHOD: Data was derived from the 2013 National Epidemiologic Survey on Alcohol and Related Conditions. Logistic regression and heterogeneous choice models were used to test the moderating role of race/ethnicity in regards to the associations between racial discrimination and ten DSM-V diagnoses. RESULTS: Non-Hispanic blacks reported the highest levels of experiencing racial discrimination, while Non-Hispanic whites reported the lowest. Exposure to racial discrimination was associated with higher odds of psychiatric disorders for non-Hispanic blacks, non-Hispanic Asian/Pacific Islanders, and Hispanics than it was for non-Hispanic whites, while non-Hispanic American Indians/Alaska Natives had lower odds of psychiatric disorders. CONCLUSIONS: Analyses indicated that racial discrimination poses stronger mental health disadvantages on racial/ethnic minorities than it does to non-Hispanic whites. This finding not only refutes the notion of reverse racism, but also calls for more efforts to close the racial/ethnic health gap for those exposed to racial discrimination. PMID- 28812286 TI - Occupational Exposures and Health Outcomes Among Immigrants in the USA. AB - PURPOSE OF REVIEW: Immigrants experience higher rates of occupational injury and fatality than their native-born counterparts. This review summarizes the current data related to occupational/environmental exposures and explores potential reasons for the disparities. RECENT FINDINGS: Immigrant workers are employed in sectors that expose them to dangerous working conditions. They experience increased risk for exposure to heat, pesticides, hazardous chemicals, and cleaning agents, as well as physical hazards such as falls. Immigrant workers are at increased risk for occupational injury and fatality due to the nature of the work they traditionally perform, a lack of enforced safety regulations, and limited access to health care or worker's compensation benefits. PMID- 28812289 TI - Biography-David Menter. PMID- 28812288 TI - Effect of step-feeding on the performance of lab-scale columns simulating vertical flow-horizontal flow constructed wetlands. AB - The effect of step-feeding (untreated wastewater by-pass) on the performance of lab-scale columns simulating a hybrid vertical flow (VF)-horizontal flow (HF) constructed wetland (CW) system was studied. Step-feeding strategies have been adopted in several kinds of CW, but this is the first report about the use of step-feeding in VF + HF hybrid systems treating domestic wastewater. Applied loading rates were 7-11 g BOD5/m2 day and 2.1-3.4 g TN/m2 day (overall system). Removal efficiency reached 98% TSS and COD and 99% BOD5 on average, whilst a 50% by-pass improved TN removal from 31 to 50%. Maximum surface nitrification rate (5.5 g N/m2 day) was obtained in VF unit, whilst maximum denitrification rate (1.8 g N/m2 day) was observed in HF unit. Referred to the overall system, maximum surface nitrification and denitrification rates were 2.2 and 1.6 g N/m2 day, respectively. However, potential nitrifying and denitrifying activities (batch assays) were 15.0 and 58.9 g N/m2 day, respectively. Even at 50% by-pass, operational conditions in HF unit (dissolved oxygen, redox, COD/TN ratio) were not suitable enough for denitrification. However, methane emissions were not observed and nitrous oxide emissions were relatively low. PMID- 28812290 TI - A preliminary report of cerebral white matter microstructural changes associated with adolescent sports concussion acutely and subacutely using diffusion tensor imaging. AB - Diffusion tensor imaging (DTI) has demonstrated its utility in detecting microscopic post-concussion cerebral white matter structural changes, which are not routinely evident on conventional neuroimaging modalities. In this study, we compared 10 adolescents with sports concussion (SC) to 12 orthopedically-injured (OI) individuals within 96 h and three months post injury to 12 typically developing (TD) participants using DTI and volumetric analyses. In terms of volume, no group differences were noted between SC, OI and TD groups at both 96 h and three months post concussion. Results did not show significant differences between SC, OI, and TD groups for both fractional anisotropy (FA) and apparent diffusion coefficient (ADC) in all regions of interest within 96 h post concussion. However, at three months post-injury, the SC group exhibited significantly lower FA than the TD group in various regions of interest. In terms of ADC, significant group differences between SC and TD groups were found in some regions, with SC group having higher ADC than TD. No group differences for FA and ADC were noted between SC and OI groups at three months post-injury. However, several moderate effect sizes on between-group analyses were noted such that FA was lower and ADC was higher in SC relative to OI. Longitudinally, the SC group demonstrated decreased FA and increased ADC in some areas. The findings highlight the fact that the brain continues to change during the post-injury recovery period, and raises the possibility that adverse changes may result from the neurometabolic cascade that purportedly ensues following SC. DTI may potentially be used to characterize the nature of brain changes that occur following sports related concussions. PMID- 28812291 TI - Technology Games: Using Wittgenstein for Understanding and Evaluating Technology. AB - In the philosophy of technology after the empirical turn, little attention has been paid to language and its relation to technology. In this programmatic and explorative paper, it is proposed to use the later Wittgenstein, not only to pay more attention to language use in philosophy of technology, but also to rethink technology itself-at least technology in its aspect of tool, technology-in-use. This is done by outlining a working account of Wittgenstein's view of language (as articulated mainly in the Investigations) and by then applying that account to technology-turning around Wittgenstein's metaphor of the toolbox. Using Wittgenstein's concepts of language games and form of life and coining the term 'technology games', the paper proposes and argues for a use-oriented, holistic, transcendental, social, and historical approach to technology which is empirically but also normatively sensitive, and which takes into account implicit knowledge and know-how. It gives examples of interaction with social robots to support the relevance of this project for understanding and evaluating today's technologies, makes comparisons with authors in philosophy of technology such as Winner and Ihde, and sketches the contours of a phenomenology and hermeneutics of technology use that may help us to understand but also to gain a more critical relation to specific uses of concrete technologies in everyday contexts. Ultimately, given the holism argued for, it also promises a more critical relation to the games and forms of life technologies are embedded in-to the ways we do things. PMID- 28812292 TI - Effect of Low-Selenium/High-Fat Diet on Pig Peripheral Blood Lymphocytes: Perspectives from Selenoproteins, Heat Shock Proteins, and Cytokines. AB - The aim of the present study was to clarify the effect of low selenium (Se)/high fat on the mRNA expression of selenoproteins, heat shock proteins (HSPs) and cytokines in pig peripheral blood lymphocytes. Forty crossbred boar piglets with healthy lean body weights of 10 kg were randomly divided into four treatment groups (group C, group L-Se, group H-fat, and group L-Se-H-fat) (n = 10/group) and fed with the corresponding diet for 16 weeks. The pig peripheral blood lymphocytes were extracted, and the mRNA expression of selenoproteins, HSPs, and cytokines was measured. Most mRNA levels for selenoproteins decreased in group L Se, group H-fat, and group L-Se-H-fat, except Gpx1, Gpx2, Selt, and Selm, which were elevated in group H-fat. At the same time, low-Se/high-fat diet increased the expression of HSPs (HSP40, HSP60, HSP70, and HSP90) and inflammatory cytokines (IL-1alpha, IL-1beta, IL-6, IL-8, IL-9, iNOS, COX-2, NF-kappaB, and TNF alpha) in group L-Se, group H-fat, and group L-Se-H-fat, and genes in group L-Se H-fat showed greater increases. Also, low-Se/high-fat diet inhibits the expression of TGF-beta1 and IFN-gamma. In summary, a low-Se/high-fat diet can cause relevant selenoprotein expression changes and promote the expression of pro inflammatory factors and HSPs, and low Se enhances the expression of HSPs and inflammation factors induced by high fat. This information is helpful for understanding the effects of low-Se and high-fat diet on pig peripheral blood lymphocytes. PMID- 28812293 TI - Overview of the "Ionic Liquids meet Biomolecules" session at the 19th international IUPAB and 11th EBSA congress. PMID- 28812294 TI - Teaching to See Behaviors-Using Machine Learning? PMID- 28812296 TI - MXR7 facilitates liver cancer metastasis via epithelial-mesenchymal transition. AB - MXR7 is a cell-surface protein and highly expressed in hepatocellular carcinoma (HCC). The aim of this study is to determine the expression profile of MXR7 in HCC and investigate the influence of MXR7 on invasion and metastasis of HCC cells. For this purpose, immunohistochemical assay was used to identify the differential expression of MXR7 in 94 HCC specimens. Expression of MXR7 in 4 pairs of HCC and portal vein tumor thrombus (PVTT) was also tested. The motility of HCC cells were characterized by transwell migration and matrigel invasion assays. In vivo metastasis potential was determined via tail vein injection assay. Moreover, compared with noninvasive HCC tumors or human HCC cell lines with low metastatic potential, invasive HCC samples and HCC cell lines with high metastatic potential exhibited higher MXR7 expression. Furthermore, forced expression of MXR7 in SMMC-7721 promoted cell proliferation, migration and invasion in vitro and accelerated tumor growth and metastasis in vivo. Conversely, knockdown of MXR7 expression in HuH7 cells inhibited proliferation and motility of cells. Mechanically, overexpression of MXR7 promoted epithelial mesenchymal transition (EMT) progress, and MXR7 depletion repressed the EMT phenotype. In conclusion, MXR7 is a mediator of EMT and metastasis in HCC and may serve as a novel therapeutic target. PMID- 28812295 TI - Just Like in Their Home Country? A Multinational Perspective on Living Arrangements of Older Immigrants in the United States. AB - Older immigrants are more likely to share residence with their adult children and other family members than are U.S.-born older adults. Because socioeconomic factors only partially explain these differences and direct measures of cultural preferences are seldom available, the persistently high rates of intergenerational coresidence among the older foreign-born are often interpreted as driven by cultural preferences and/or a lack of assimilation. To challenge this interpretation, this study investigates the extent to which older immigrants' living arrangements deviate from those of older adults in their home countries. The analysis combines data on immigrants from the 2008-2012 American Community Survey (ACS) with census data from three major immigrant-sending countries: Mexico, the Dominican Republic, and Vietnam. Despite persistent differences from U.S.-born whites, coresidence in later life is significantly less common than in the sending countries among the older foreign-born who migrated as young adults, and especially among those who migrated as children. The older foreign-born who migrated after age 50, however, are more likely to coreside and less likely to live independently than the older adults in their home countries. The similarity of these patterns across the three immigrant subgroups suggests that the unusually high coresidence among late-life immigrants is driven by U.S. family reunification policy and not simply by cultural influences. PMID- 28812297 TI - Neomycin biosynthesis is regulated positively by AfsA-g and NeoR in Streptomyces fradiae CGMCC 4.7387. AB - Neomycins are a group of aminoglycoside antibiotics with both clinical and agricultural applications. To elucidate the regulatory mechanism of neomycin biosynthesis, we completed draft genome sequencing of a neomycin producer Streptomyces fradiae CGMCC 4.7387 from marine sediments, and the neomycin biosynthesis gene cluster was identified. Inactivation of the afsA-g gene encoding a gamma-butyrolactone (GBL) synthase in S. fradiae CGMCC 4.7387 resulted in a significant decrease of neomycin production. Quantitative RT-PCR analysis revealed that the transcriptional level of neoR and the aphA-neoGH operon were reduced in the afsA-g::aac(3)IV mutant. Interestingly, a conserved binding site of AdpA, a key activator in the GBL regulatory cascade, was discovered upstream of neoR, a putative regulatory gene encoding a protein with an ATPase domain and a tetratricopeptide repeat domain. When neoR was inactivated, the neomycin production was reduced about 40% in comparison with the WT strain. Quantitative RT-PCR analysis revealed that the transcriptional levels of genes in the aphA neoGH operon were reduced clearly in the neoR::aac(3)IV mutant. Finally, the titers of neomycin were improved considerably by overexpression of afsA-g and neoR in S. fradiae CGMCC 4.7387. PMID- 28812298 TI - A GATA-type transcription factor AcAREB for nitrogen metabolism is involved in regulation of cephalosporin biosynthesis in Acremonium chrysogenum. AB - In filamentous fungi, nitrogen metabolism is repressed by GATA-type zinc finger transcription factors. Nitrogen metabolite repression has been found to affect antibiotic production, but the mechanism is still poorly understood. AcareB, encoding a homologue of fungal GATA-type regulatory protein, was cloned from Acremonium chrysogenum. Gene disruption and genetic complementation demonstrated that AcareB plays a key role in utilization of ammonium, glutamine and urea. In addition, significant reduction of cephalosporin production in the AcareB disruption mutant indicated that AcareB is important for cephalosporin production. In consistence with it, the transcriptional level of cephalosporin biosynthetic genes was significantly decreased in the AcareB disruption mutant. Electrophoretic mobility shift assay showed that AcAREB directly bound to the intergenic regions of pcbAB-pcbC, cefD1-cefD2 and cefEF-cefG. Sequence analysis showed that all the AcAREB binding sites contained the consensus GATA elements. AcareB is negatively autoregulated during cephalosporin production. Moreover, another GATA zinc-finger protein encoded by AcareA positively regulates the transcription of AcareB. However, AcareB does not regulate the transcription of AcareA. These results indicated that AcAREB plays an important role in both regulation of nitrogen metabolism and cephalosporin production in A. chrysogenum. PMID- 28812299 TI - Conversion of the high-yield salinomycin producer Streptomyces albus BK3-25 into a surrogate host for polyketide production. AB - An ideal surrogate host for heterologous production of various natural products is expected to have efficient nutrient utilization, fast growth, abundant precursors and energy supply, and a pronounced gene expression. Streptomyces albus BK3-25 is a high-yield industrial strain producing type-I polyketide salinomycin, with a unique ability of bean oil utilization. Its potential of being a surrogate host for heterologous production of PKS was engineered and evaluated herein. Firstly, introduction of a three-gene cassette for the biosynthesis of ethylmalonyl-CoA resulted in accumulation of ethylmalonyl-CoA precursor and salinomycin, and subsequent deletion of the salinomycin biosynthetic gene cluster resulted in a host with rich supplies of common polyketide precursors, including malonyl-CoA, methylmalonyl-CoA, and ethylmalonyl CoA. Secondly, the energy and reducing force were measured, and the improved accumulation of ATP and NADPH was observed in the mutant. Furthermore, the strength of a series of selected endogenous promoters based on microarray data was assessed at different growth phases, and a strong constitutive promoter was identified, providing a useful tool for further engineered gene expression. Finally, the potential of the BK3-25 derived host ZXJ-6 was evaluated with the introduction of the actinorhodin biosynthetic gene cluster from Streptomyces coelicolor, and the heterologous production of actinorhodin was obtained. This work clearly indicated the potential of the high-yield salinomycin producer as a surrogate host for heterologous production of polyketides, although more genetic manipulation should be conducted to streamline its performance. PMID- 28812300 TI - Fay Hlubocky on Recognizing and Addressing Clinician Burnout. PMID- 28812301 TI - Changing Treatment Paradigms for Brain Metastases From Melanoma-Part 1: Diagnosis, Prognosis, Symptom Control, and Local Treatment. AB - Melanoma is the third most common cause of brain metastases, after lung and breast cancer. The management of melanoma brain metastases can be broadly divided into symptom control and therapeutic strategies. Supportive treatments include corticosteroids to reduce peritumoral edema, antiepileptics for seizure control, and medications to preserve cognitive function. Until recently, therapeutic strategies consisted primarily of local treatments, including surgery, whole brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS). Surgery, WBRT, and SRS-alone and in various combinations-still play an important role in treatment, especially in patients with few and/or smaller brain lesions. Much work has been done recently to try to determine the optimal settings for these therapies, the most effective ways to combine them, and ideal radiation dose and fractions. PMID- 28812302 TI - Management of Sleep-Wake Disturbances Comorbid With Cancer. AB - It is critical that clinicians and healthcare systems adopt routine screening and affordable interventions to reduce chronic insomnia and improve the quality of life in cancer patients and survivors. We provide expert clinical advice on how to manage sleep-wake disturbances that occur comorbidly with cancer. Our discussion focuses on the etiology, screening, and assessment of sleep-wake disturbances, and on both nonpharmacologic and pharmacologic interventions to manage sleep disturbances, insomnia, and sleep-related breathing disorders. We share a simplified sleep management algorithm based on evidence-based guidelines and resources from the National Cancer Institute, National Comprehensive Cancer Network, and Oncology Nursing Society, as well as case studies that illustrate how oncology professionals can use the algorithm. Finally, we describe ways to strengthen the partnership between clinicians and patients in the management of sleep-wake disorders and related symptoms. PMID- 28812303 TI - Circulating Tumor DNA as a Liquid Biopsy: Current Clinical Applications and Future Directions. AB - Tumor genomic sequencing has become part of routine oncology practice in many tumor types, in order to identify potentially targetable mutations and to personalize cancer care. Plasma genotyping via circulating tumor DNA analysis is a noninvasive and rapid alternative method of detecting and monitoring genomic alterations throughout the course of disease. Multiple assays have been developed to date, each with different test characteristics and degrees of clinical validation. Here we review the clinical data supporting these different plasma genotyping methodologies, and present a practical approach to the interpretation of the results of these tests. While the clinical application of plasma genotyping has been most extensively validated in the metastatic setting-for the detection of targetable alterations at the time of initial diagnosis or disease progression-this technology holds significant promise across many tumor types and stages of disease. We will also review emerging applications of plasma genotyping that are currently under clinical investigation. PMID- 28812304 TI - Management of Castration-Resistant, Taxane-Resistant Prostate Cancer. AB - Metastatic castration-resistant prostate cancer that is progressing despite docetaxel chemotherapy is difficult to treat and often aggressive. If not previously used, modern androgen signaling inhibitors have established clinical activity in this setting. Cabazitaxel and radium-223 have also been shown to extend survival in appropriately selected patients. Carboplatin-containing chemotherapy regimens have not been studied in randomized trials with a survival endpoint, but they have demonstrated activity in phase II trials and are occasionally considered in the post-docetaxel setting. Recent identification of potentially exploitable targets in the molecular makeup of advanced prostate cancer has created opportunities for clinical trials of novel targeted agents, with poly(ADP-ribose) polymerase inhibitors yielding compelling early results in molecularly selected patients. Much remains to be done to improve the lot of patients with docetaxel-unresponsive metastatic castration-resistant prostate cancer. PMID- 28812305 TI - Point: Should Radiation Therapy After Surgery for Ductal Carcinoma In Situ Be Standard Practice: Adjuvant RT Remains the Standard of Care at This Time. PMID- 28812306 TI - Barber-led sexual health education intervention for Black male adolescents and their fathers. AB - OBJECTIVE: To explore barbers' attitudes and beliefs regarding the feasibility and acceptability of a barber- led STI/HIV risk reduction intervention for fathers and their preadolescent and adolescent sons. DESIGN AND SAMPLE: A qualitative descriptive design was used. Twenty-two barbers were recruited from barbershops and a barber school in central North Carolina. MEASURES: A combination of five focus groups and two key informant interviews were conducted. RESULTS: The following themes were generated: (1) The barbershop was embraced as a venue for an adolescent sexual health father-son intervention, (2) Barbers desired more information about STIs and HIV among Black male youth, (3) The use of incentives to engage barbers and fathers was important, and (4) Time commitment of barbers for a barber-led intervention varied. CONCLUSION: The trust established between barbers and the Black community presents an opportunity for pre-adolescent and adolescent STI/HIV risk reduction programs that include the role of fathers. Intervention programs can be tailored to address this important intervention opportunity. PMID- 28812307 TI - The development of perceptual averaging: learning what to do, not just how to do it. AB - The mature visual system condenses complex scenes into simple summary statistics (e.g., average size, location, orientation, etc.). However, children, often perform poorly on perceptual averaging tasks. Children's difficulties are typically thought to represent the suboptimal implementation of an adult-like strategy. This paper examines another possibility: that children actually make decisions in a qualitatively different way to adults (optimal implementation of a non-ideal strategy). Ninety children (6-7, 8-9, 10-11 years) and 30 adults were asked to locate the middle of randomly generated dot-clouds. Nine plausible decision strategies were formulated, and each was fitted to observers' trial-by trial response data (Reverse Correlation). When the number of visual elements was low (N < 6), children used a qualitatively different decision strategy from adults: appearing to "join up the dots" and locate the gravitational center of the enclosing shape. Given denser displays, both children and adults used an ideal strategy of arithmetically averaging individual points. Accounting for this difference in decision strategy explained 29% of children's lower precision. These findings suggest that children are not simply suboptimal at performing adult-like computations, but may at times use sensible, but qualitatively different strategies to make perceptual judgments. Learning which strategy is best in which circumstance might be an important driving factor of perceptual development. PMID- 28812308 TI - Transcriptional regulation of the protein kinase a subunits in Saccharomyces cerevisiae during fermentative growth. AB - Yeast cells can adapt their growth in response to the nutritional environment. Glucose is the favourite carbon source of Saccharomyces cerevisiae, which prefers a fermentative metabolism despite the presence of oxygen. When glucose is consumed, the cell switches to the aerobic metabolism of ethanol, during the so called diauxic shift. The difference between fermentative and aerobic growth is in part mediated by a regulatory mechanism called glucose repression. During glucose derepression a profound gene transcriptional reprogramming occurs and genes involved in the utilization of alternative carbon sources are expressed. Protein kinase A (PKA) controls different physiological responses following the increment of cAMP as a consequence of a particular stimulus. cAMP-PKA is one of the major pathways involved in the transduction of glucose signalling. In this work the regulation of the promoters of the PKA subunits during respiratory and fermentative metabolism are studied. It is demonstrated that all these promoters are upregulated in the presence of glycerol as carbon source through the Snf1/Cat8 pathway. However, in the presence of glucose as carbon source, the regulation of each PKA promoter subunits is different and only TPK1 is repressed by the complex Hxk2/Mig1 in the presence of active Snf1. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28812309 TI - Murine pulmonary imaging at 7T: T2* and T1 with anisotropic UTE. AB - PURPOSE: To measure the T2* and T1 of mouse lung at 7T via anisotropic-resolution radial ultrashort echo-time imaging with ellipsoidal k-space coverage. METHODS: Ellipsoidal field-of-view was created by expanding uniform spherical k-space coverage. The effects of T2* and ellipsoidal sampling on image resolution were investigated by using point-spread-function analysis and resolution phantoms. Finally, this ellipsoidal sampling approach was used to measure the lung T2* and T1 of healthy C57BL/6 mice at the increasingly common preclinical field strength of 7T. RESULTS: Lung parenchyma T2* of 17- to 23-week-old mice at 7T was 0.395 +/ 0.033 ms. T1 of lung and left- and right-heart ventricles was 1452.5 +/- 87.0 ms, 1810.5 +/- 54.6 ms, and 1602.6 +/- 120.9 ms, respectively. Ellipsoidal k space sampling provides enhanced resolution for a fixed scanning time or provides equivalent (although anisotropic) spatial resolution with reduced scanning times, while simultaneously avoiding fold-in artifacts. CONCLUSION: Using these techniques, the first T2* and T1 measures of mouse lung at 7T are reported. Ultrashort echo-time imaging with ellipsoidal k-space coverage significantly increases in-plane resolution without increasing scanning time, or equivalently, decreases scanning time while maintaining equivalent in-plane resolution. Magn Reson Med 79:2254-2264, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28812310 TI - Gliosarcoma arising from oligodendroglioma, IDH mutant and 1p/19q codeleted. AB - Herein, we present a rare case of gliosarcoma arising from oligodendroglioma, isocitrate dehydrogenase (IDH) mutant and 1p/19q codeleted. A 36-year-old man presented with a non-enhanced calcified abnormal lesion on the right frontal lobe. The patient underwent subtotal surgical resection, PAV chemotherapy (procarbazine, nimustine (ACNU) and vincristine), and fractionated radiotherapy with 50 Gy. The pathological diagnosis was oligodendroglioma, IDH mutant and 1p/19q codeleted, World Health Organization 2016 grade II. Six years later, a new enhanced lesion appeared, and the recurrent tumor was surgically removed. Although the histopathological findings indicated gliosarcoma, the recurrent tumor still demonstrated the IDH mutation and 1p/19q codeleted. Thus, the recurrent tumor was considered to originate from oligodendroglioma, rather than being newly generated after chemoradiotherapy. Interestingly, the second recurrent tumor responded well to temozolomide chemotherapy. Based on the findings of this case, oligodendrogliomas have the potential for mesenchymal transformation on progression, while keeping their genotype. PMID- 28812312 TI - A systematic review of silver diamine fluoride: Effectiveness and application in older adults. AB - OBJECTIVE: This systematic review examines the effectiveness of silver diamine fluoride (SDF) in the management of caries in older adults. BACKGROUND: Silver diamine fluoride has been extensively researched and proven effective for caries prevention and arrest in children. Limited studies support its effectiveness in adult and older adult populations. MATERIALS AND METHODS: Multiple databases were searched according to specified inclusion-exclusion criteria. Quality assessment used modified Centre for Evidence-Based Medicine worksheets. RESULTS: Three randomised controlled trials were identified that addressed the effectiveness of SDF on root caries in older adults, but none addressed coronal caries. Root caries prevented fraction and arrest rate for SDF were significantly higher than placebo. The prevented fraction for caries prevention for SDF compared to placebo was 71% in a 3-year study and 25% in a 2-year study. The prevented fraction for caries arrest for SDF was 725% greater in a 24-month study and 100% greater than placebo in a 30-month study. No severe adverse effects were observed. CONCLUSION: This systematic review evaluates the use of SDF for both root caries prevention and arrest in older adults. Existing reports of SDF trials support effectiveness in root caries prevention and arrest, remineralization of deep occlusal lesions and treatment of hypersensitive dentin. PMID- 28812311 TI - NAD replenishment with nicotinamide mononucleotide protects blood-brain barrier integrity and attenuates delayed tissue plasminogen activator-induced haemorrhagic transformation after cerebral ischaemia. AB - BACKGROUND AND PURPOSE: Tissue plasminogen activator (tPA) is the only approved pharmacological therapy for acute brain ischaemia; however, a major limitation of tPA is the haemorrhagic transformation that follows tPA treatment. Here, we determined whether nicotinamide mononucleotide (NMN), a key intermediate of nicotinamide adenine dinucleotide biosynthesis, affects tPA-induced haemorrhagic transformation. EXPERIMENTAL APPROACH: Middle cerebral artery occlusion (MCAO) was achieved in CD1 mice by introducing a filament to the left MCA for 5 h. When the filament was removed for reperfusion, tPA was infused via the tail vein. A single dose of NMN was injected i.p. (300 mg.kg-1 ). Mice were killed at 24 h post ischaemia, and their brains were evaluated for brain infarction, oedema, haemoglobin content, apoptosis, neuroinflammation, blood-brain barrier (BBB) permeability, the expression of tight junction proteins (TJPs) and the activity/expression of MMPs. KEY RESULTS: In the mice infused with tPA at 5 h post ischaemia, there were significant increases in mortality, brain infarction, brain oedema, brain haemoglobin level, neural apoptosis, Iba-1 staining (microglia activation) and myeloperoxidase staining (neutrophil infiltration). All these tPA-induced alterations were significantly prevented by NMN administration. Mechanistically, the delayed tPA treatment increased BBB permeability by down-regulating TJPs, including claudin-1, occludin and zonula occludens-1, and enhancing the activities and protein expression of MMP9 and MMP2. Similarly, NMN administration partly blocked these tPA-induced molecular changes. CONCLUSIONS AND IMPLICATIONS: Our results demonstrate that NMN ameliorates tPA-induced haemorrhagic transformation in brain ischaemia by maintaining the integrity of the BBB. PMID- 28812313 TI - Current and potential pharmacological and psychosocial interventions for anxiety symptoms and disorders in patients with schizophrenia: structured review. AB - OBJECTIVE: Between 30% and 62% of patients with schizophrenia present with co morbid anxiety disorders that are associated with increased overall burden. Our aim was to summarize current and potential interventions for anxiety in schizophrenia. DESIGN: Structured review, summarizing pharmacological and psychosocial interventions used to reduce anxiety in schizophrenia and psychosis. RESULTS: Antipsychotics have been shown to reduce anxiety, increase anxiety, or have no effect. These may be augmented with another antipsychotic, anxiolytic, or antidepressant. Novel agents, such as L-theanine, pregabalin, and cycloserine, show promise in attenuating anxiety in schizophrenia. Psychosocial therapies have been developed to reduce the distress of schizophrenia. Cognitive behavioural therapy (CBT) has shown that benefit and refinements in the therapy have been successful, for example, for managing worry in schizophrenia. CBT usually involves more than 16 sessions, as short courses of CBT do not attenuate the presentation of anxiety in schizophrenia. To address time and cost, the development of manualized CBT to address anxiety in schizophrenia is being developed. CONCLUSIONS: The presence of coexisting anxiety symptoms and co-morbid anxiety disorders should be ascertained when assessing patients with schizophrenia or other psychoses as a range of pharmacological and psychosocial treatments are available. PMID- 28812314 TI - Self-assembled chiral nanostructures of amphiphilic peptide: from single molecule to aggregate. AB - We report interesting hierarchical self-assembled architectures from a designed amphiphilic peptide. The bisignate cotton effects in circular dichroism spectra show typical peptide aggregation-induced. The observation of peptide assembly structures from initial particles and fibrils to ribbon structures is supported by microscopy (atomic force microscopy and transmission electron microscopy). The visualization of individual peptide at the single molecular level offered insights of the intermolecular interactions responsible for the formation of aggregates, which is investigated by scanning tunneling microscopy. The orientation of intermolecular bonds between carboxylic and amine group and the hydrophobic interactions between alanine residues could be the dominant driving force for the assembly chirality at near-neutral pH. The single molecular and aggregate level evidence in this manuscript will shed light on the understanding of hierarchical chiral self-assembly pathway and the underlying mechanism. Copyright (c) 2017 European Peptide Society and John Wiley & Sons, Ltd. PMID- 28812315 TI - Metabolite-cycled STEAM and semi-LASER localization for MR spectroscopy of the human brain at 9.4T. AB - PURPOSE: Metabolite cycling (MC) is an MRS technique for the simultaneous acquisition of water and metabolite spectra that avoids chemical exchange saturation transfer effects and for which water may serve as a reference signal or contain additional information in functional or diffusion studies. Here, MC was developed for human investigations at ultrahigh field. METHODS: MC-STEAM and MC-semi-LASER are introduced at 9.4T with an optimized inversion pulse and elaborate coil setup. Experimental and simulation results are given for the implementation of adiabatic inversion pulses for MC. The two techniques are compared, and the effect of frequency and phase correction based on the MC water spectra is evaluated. Finally, absolute quantification of metabolites is performed. RESULTS: The proposed coil configuration results in a maximum B1 + of 48 MUTau in a voxel within the occipital lobe. Frequency and phase correction of single acquisitions improve signal-to-noise ratio (SNR) and linewidth, leading to high-resolution spectra. The improvement of SNR of N-acetylaspartate (SNRNAA ) for frequency aligned data, acquired with MC-STEAM and MC-semi-LASER, are 37% and 30%, respectively (P < 0.05). Moreover, a doubling of the SNRNAA for MC-semi LASER in comparison with MC-STEAM is observed (P < 0.05). Concentration levels for 18 metabolites from the human occipital lobe are reported, as acquired with both MC-STEAM and MC-semi-LASER. CONCLUSION: This work introduces a novel methodology for single-voxel MRS on a 9.4T whole-body scanner and highlights the advantages of semi-LASER compared to STEAM in terms of excitation profile. In comparison with MC-STEAM, MC-semi-LASER yields spectra with higher SNR. Magn Reson Med 79:1841-1850, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28812317 TI - Seven dangerous Ps of pregnancy and challenges of caring for pregnant women with complex needs. PMID- 28812316 TI - Literacy acquisition influences children's rapid automatized naming. AB - Previous research has established that learning to read improves children's performance on reading-related phonological tasks, including phoneme awareness (PA) and nonword repetition. Few studies have investigated whether literacy acquisition also promotes children's rapid automatized naming (RAN). We tested the hypothesis that literacy acquisition should influence RAN in an international, longitudinal population sample of twins. Cross-lagged path models evaluated the relationships among literacy, PA, and RAN across four time points from pre-kindergarten through grade 4. Consistent with previous research, literacy showed bidirectional relationships with reading-related oral language skills. We found novel evidence for an effect of earlier literacy on later RAN, which was most evident in children at early phases of literacy development. In contrast, the influence of earlier RAN on later literacy was predominant among older children. These findings imply that the association between these two related skills is moderated by development. Implications for models of reading development and for dyslexia research are discussed. PMID- 28812318 TI - The development and flexibility of gaze alternations in bonobos and chimpanzees. AB - Infants' early gaze alternations are one of their first steps towards a sophisticated understanding of the social world. This ability, to gaze alternate between an object of interest and another individual also attending to that object, has been considered foundational to the development of many complex social-cognitive abilities, such as theory of mind and language. However, to understand the evolution of these abilities, it is important to identify whether and how gaze alternations are used and develop in our closest living relatives, bonobos (Pan paniscus) and chimpanzees (Pan troglodytes). Here, we evaluated the development of gaze alternations in a large, developmental sample of bonobos (N = 17) and chimpanzees (N = 35). To assess the flexibility of ape gaze alternations, we tested whether they produced gaze alternations when requesting food from a human who was either visually attentive or visually inattentive. Similarly to human infants, both bonobos and chimpanzees produced gaze alternations, and did so more frequently when a human communicative partner was visually attentive. However, unlike humans, who gaze alternate frequently from early in development, chimpanzees did not begin to gaze alternate frequently until adulthood. Bonobos produced very few gaze alternations, regardless of age. Thus, it may be the early emergence of gaze alternations, as opposed gaze alternations themselves, that is derived in the human lineage. The distinctively early emergence of gaze alternations in humans may be a critical underpinning for the development of complex human social-cognitive abilities. PMID- 28812319 TI - Poorly differentiated chordoma with loss of SMARCB1/INI1 expression in pediatric patients: A report of two cases and review of the literature. AB - Identification of loss of SMARCB1/INI1 expression in poorly differentiated (PD) chordoma in pediatric patients suggests that PD chordoma is an entity molecularly distinct from conventional chordoma or atypical teratoid/rhabdoid tumor, which is also characterized by loss of SMARCB1/INI1 expression by inactivating mutation of the SMARCB1/INI gene. So far, around 20 cases of pediatric PD chordoma with loss of SMARCB1/INI1 expression have been reported. Here, we report two cases of pediatric PD chordoma with loss of SMARCB1/INI1 expression, which is very rare among the pediatric chordoma types. Both patients presented clival masses on preoperative MRI. Histologically, both tumors had nonclassic histologic features for conventional chordoma: sheets of large epithelioid to spindle cells with vesicular nuclei and prominent nucleoli. Both cases revealed nuclear expression of brachyury, loss of SMARCB1/INI1 expression and lack of embryonal, neuroectodermal, or epithelial component. One case showed heterozygous loss of EWSR1 gene by break-apart fluorescence in situ hybridization that reflected loss of SMARCB1/INI1 gene. Based on the clival location and histologic findings along with the loss of SMARCB1/INI1 expression and positivity for nuclear brachyury staining, the final pathologic diagnosis for both cases was PD chordoma. PMID- 28812320 TI - The relationship between periodontal disease, tooth loss and decreased skeletal bone mineral density in ageing women. AB - AIM: Osteoporosis and periodontitis are both chronic diseases characterised by bone loss. Potential association is of great clinical importance because of multifactorial aetiology and common risk factors. The aim of this study was to determine relationship between bone mineral density (BMD), tooth loss and periodontal status taking into account age, number of years since onset of menopause and educational level. With increasing age, number of years since onset of menopause and lower educational level, decreased BMD, deteriorating periodontal status and greater tooth loss are expected. MATERIALS AND METHODS: Cross-sectional study included 112 women aged 45-80 years (mean 58.3 years). BMD was determined for lumbar spine region and proximal femur by DEXA technology. Dental status and periodontal status were evaluated clinically and on panoramic radiographs. For the analysis of tooth loss frequency, participants were divided into four age groups. RESULTS: Significant inverse correlation was found between number of lost teeth and BMD at hip region (r = -.227; P = .028) but not at the lumbar spine (r = -.05; P = .669). Several indicators of the periodontal condition were significantly correlated with BMD, but not with postmenopausal period length. Important result is that participants missing one or more incisors or canines had significantly lower mean value of BMD comparing to those who had all the incisors and canines remained. CONCLUSION: Although osteoporosis is not the main cause of periodontitis, it may be a factor that leads to enhanced periodontal pocket depth and greater risk of tooth loss in ageing women. PMID- 28812321 TI - Prognostic impact of intensive statin therapy on N-terminal pro-BNP level in non ST-segment elevation acute myocardial infarction patients. AB - OBJECTIVE: This study explored the impact of intensive daily dosing of atorvastatin on in-hospital N-terminal pro-B-type natriuretic peptide level, left ventricular systolic function and incidence of major adverse cardiac events in non-ST-segment elevation myocardial infarction patients. BACKGROUND: Several studies showed that early initiation of statin therapy in acute coronary syndrome patients has a favorable prognostic impact. METHODS: Hundred statin naive patients were prospectively enrolled. Once eligible, patients were randomly assigned to receive either a moderate daily dose that is, 20 mg (Group A) or an intensified daily dose that is, 80 mg (Group B) of atorvastatin, in addition to an equally divided loading dose given 24 and 12 h before coronary angiography (80 mg each). N-terminal pro-B-type natriuretic peptide levels were recorded before and after coronary intervention. Collected data after 3 months included; N terminal pro-B-type natriuretic peptide levels, left ventricle systolic function and major adverse cardiac events. RESULTS: Mean age of the study cohort was 55 +/ 10 years, 68% being males. There was no significant difference between both groups concerning procedural data. Group B patients showed a significantly lower N-terminal pro-B-type natriuretic peptide levels at both sampling occasions, i.e., after coronary intervention and 3 months later (P < 0.001). After 3 months, the same group showed higher left ventricle ejection fraction (P < 0.05), with no significant difference between both groups regarding incidence of major adverse cardiac events. CONCLUSION: Intensive atorvastatin therapy in non-ST-segment elevation myocardial infarction patients undergoing percutaneous coronary intervention is associated with; lower in-hospital N-terminal pro BNP level and higher LVEF after 3 months. PMID- 28812322 TI - Reactivity of Silanes with (tBu PONOP)Ruthenium Dichloride: Facile Synthesis of Chloro-Silyl Ruthenium Compounds and Formic Acid Decomposition. AB - The coordination of tBu PONOP (tBu PONOP=2,6-bis(ditert butylphosphinito)pyridine) to different ruthenium starting materials, to generate (tBu PONOP)RuCl2 , was investigated. The resultant (tBu PONOP)RuCl2 reactivity with three different silanes was then investigated and contrasted dramatically with the reactivity of (iPr PONOP)RuCl2 (DMSO) (iPr PONOP=2,6 bis(diisopropylphosphinito)pyridine) with the same silanes. The 16-electron species (tBu PONOP)Ru(H)Cl was produced from the reaction of triethylsilane with (tBu PONOP)RuCl2 . Reactions of (tBu PONOP)RuCl2 with both phenylsilane or diphenylsilane afforded the 16-electron hydrido-silyl species (tBu PONOP)Ru(H)(PhSiCl2 ) and (tBu PONOP)Ru(H)(Ph2 SiCl), respectively. Reactions of all three of these complexes with silver triflate afforded the simple salt metathesis products of (tBu PONOP)Ru(H)(OTf), (tBu PONOP)Ru(H)(PhSiCl(OTf)), and (tBu PONOP)Ru(H)(Ph2 Si(OTf)). Formic acid dehydrogenation was performed in the presence of triethylamine (TEA), and each species proved competent for gas pressure generation of CO2 and H2 . The hydride species (tBu PONOP)Ru(H)Cl, (tBu PONOP)Ru(H)(OTf), and (tBu PONOP)Ru(H)(PhSiCl2 ) exhibited faster catalytic activity than the other compounds tested. PMID- 28812323 TI - A comparison of methods for estimating the temporal change in a continuous variable: Example of HbA1c in patients with diabetes. AB - PURPOSE: To compare the more complex technique, functional principal component analysis (FPCA), to simpler methods of estimating values of sparse and irregularly spaced continuous variables at given time points in longitudinal data using a diabetic patient cohort from UK primary care. METHODS: The setting for this study is the Clinical Practice Research Datalink (CPRD), a UK general practice research database. For 16,034 diabetic patients identified in CPRD, with at least 2 measures in a 30-month period, HbA1c was estimated after temporarily omitting (i) the final and (ii) middle known values using linear interpolation, simple linear regression, arithmetic mean, random effects, and FPCA. Performance of each method was assessed using mean prediction error. The influence on predictive accuracy of (1) more homogeneous populations and (2) number and range of known HbA1c values was explored. RESULTS: When estimating the last observation, the predictive accuracy of FPCA was highest with over half of predicted values within 0.4 units, equivalent to laboratory measurement error. Predictive accuracy improved when estimating the middle observation with almost 60% predicted values within 0.4 units for FPCA. These results were marginally better than that achieved by simpler approaches, such as last-occurrence-carried forward linear interpolation. This pattern persisted with more homogeneous populations as well as when variability in HbA1c measures coupled with frequency of data points were considered. CONCLUSIONS: When estimating change from baseline to prespecified time points in electronic medical records data, a marginal benefit to using the more complex modelling approach of FPCA exists over more traditional methods. PMID- 28812324 TI - Parents' adverse childhood experiences and mental health screening using home visiting programs: A pilot study. AB - BACKGROUND: Adverse childhood experiences (ACEs) are associated with adult high risk behaviors and diseases. There is value in screening parents for ACEs given the repercussions parental ACEs may have on parenting behaviors and child development. The primary aim of this study was to assess the feasibility of parental ACE screening in the home setting. A secondary aim was to evaluate whether or not maternal ACEs correlated with maternal mental health measures. METHODS: Two home visiting programs that support early childhood development and conduct parental mental health screening implemented ACE screening for parents of infants <1 year of age. Descriptive statistics were produced for population surveillance of ACEs as well as standard practice screens for depression, anxiety, substance use, and intimate partner violence. Logistic models were used to examine associations between ACE score and mental health measures. RESULTS: A total of 110 parents completed the ACE screen. All possible ACE score outcomes were represented (0-10). A trend toward association of positive prenatal maternal depression screen with ACE score was identified (p = .05). CONCLUSION: This novel prospective home-based screening program for parental ACEs was feasible and identified a trend toward increasing ACE score association with positive prenatal maternal depression screen. PMID- 28812325 TI - Ambiguity in a masculine world: Being a BRCA1/2 mutation carrier and a man with prostate cancer. AB - OBJECTIVE: Increased risk of prostate cancer (PCa) is observed in men with BRCA1/BRCA2 mutations. Sex and gender are key determinants of health and disease although unequal care exists between the sexes. Stereotypical male attitudes are shown to lead to poor health outcomes. METHODS: Men with BRCA1/2 mutations and diagnosed with PCa were identified and invited to participate in a qualitative interview study. Data were analysed using a framework approach. "Masculinity theory" was used to report the impact of having both a BRCA1/2 mutation and PCa. RESULTS: Eleven of 15 eligible men were interviewed. The umbrella concept of "Ambiguity in a Masculine World" was evident. Men's responses often matched those of women in a genetic context. Men's BRCA experience was described, as "on the back burner" but "a bonus" enabling familial detection and early diagnosis of PCa. Embodiment of PCa took precedence as men revealed stereotypical "ideal" masculine responses such as stoicism and control while creating new "masculinities" when faced with the vicissitudes of having 2 gendered conditions. CONCLUSION: Health workers are urged to take a reflexive approach, void of masculine ideals, a belief in which obfuscates men's experience. Research is required regarding men's support needs in the name of equality of care. PMID- 28812326 TI - Effect of Dietary Components from Antarctic Krill on Atherosclerosis in apoE Deficient Mice. AB - SCOPE: Antarctic krill is a great source of n-3 fatty acids and high-quality proteins. Aim of the study was to evaluate the effect of Antarctic krill components on plasma lipids and atherosclerosis development. METHODS AND RESULTS: Sixty apoEKO mice were divided into four groups and fed Western diet (CONTROL) or Western-like diets, differing for protein or fat content. Specifically, casein or fat in CONTROL was partially replaced by krill proteins (PRO), krill oil (KRILL OIL), or both (KRILL OIL+PRO). In KRILL OIL+PRO and KRILL OIL, cholesterol levels were significantly lower than in CONTROL group. Atherosclerosis in aorta of PRO, KRILL OIL and KRILL OIL+PRO was lower than in CONTROL, whereas, at the aortic sinus, atherosclerosis reduction was only observed in KRILL OIL. Liver steatosis, commonly present in CONTROL and PRO animals, was sporadic in KRILL OIL+PRO and KRILL OIL mice. Krill oil containing diets affected the expression of genes involved in cholesterol metabolism, mainly HMG-CoA reductase. No reduced systemic inflammation was found in all groups. CONCLUSION: Krill oil containing diets were able to reduce cholesterol levels, inhibit plaque development and prevent liver damage. Krill proteins also reduced atherosclerosis development through mechanisms not involving lipid metabolism. PMID- 28812327 TI - Design and Synthesis of Terephthalic Acid-Based Histone Deacetylase Inhibitors with Dual-Stage Anti-Plasmodium Activity. AB - In this work we aimed to develop parasite-selective histone deacetylase inhibitors (HDAC) inhibitors with activity against the disease-causing asexual blood stages of Plasmodium as well as causal prophylactic and/or transmission blocking properties. We report the design, synthesis, and biological testing of a series of 13 terephthalic acid-based HDAC inhibitors. All compounds showed low cytotoxicity against human embryonic kidney (HEK293) cells (IC50 : 8->51 MUm), with 11 also having sub-micromolar in vitro activity against drug-sensitive (3D7) and multidrug-resistant (Dd2) asexual blood-stage P. falciparum parasites (IC50 ~0.1-0.5 MUm). A subset of compounds were examined for activity against early- and late-stage P. falciparum gametocytes and P. berghei exo-erythrocytic-stage parasites. While only moderate activity was observed against gametocytes (IC50 >2 MUm), the most active compound (N1 -((3,5-dimethylbenzyl)oxy)-N4 hydroxyterephthalamide, 1 f) showed sub-micromolar activity against P. berghei exo-erythrocytic stages (IC50 0.18 MUm) and >270-fold better activity for exo erythrocytic forms than for HepG2 cells. This, together with asexual-stage in vitro potency (IC50 ~0.1 MUm) and selectivity of this compound versus human cells (SI>450), suggests that 1 f may be a valuable starting point for the development of novel antimalarial drug leads with low host cell toxicity and multi-stage anti plasmodial activity. PMID- 28812329 TI - Acid-Labile Acyclic Cucurbit[n]uril Molecular Containers for Controlled Release. AB - Stimuli-responsive molecular containers are of great importance for controlled drug delivery and other biomedical applications. A new type of acid labile acyclic cucurbit[n]uril (CB[n]) molecular containers is presented that can degrade and release the encapsulated cargo at accelerated rates under mildly acidic conditions (pH 5.5-6.5). These containers retain the excellent recognition properties of CB[n]-type hosts. A cell culture study demonstrated that the cellular uptake of cargos could be fine-tuned by complexation with different containers. The release and cell uptake of cargo dye was promoted by acidic pH. PMID- 28812328 TI - Prognostic significance of Daxx NCR (Nuclear/Cytoplasmic Ratio) in gastric cancer. AB - In addition to regulating apoptosis via its interaction with the death domain of Fas receptor, death domain associated protein 6 (Daxx) is also known to be involved in transcriptional regulation, suggesting that the function of Daxx depends on its subcellular localization. In this study, we aimed to explore Daxx subcellular localization in gastric cancer (GC) cells and correlate the findings with clinical data in GC patients. Seventy pairs of tissue samples (GC and adjacent normal tissue) were analyzed immunohistochemically for Daxx expression and localization (nuclear and cytoplasmic). The Daxx Nuclear/Cytoplasmic ratio (Daxx NCR) values in tissue microarray data with 522 tumor samples were further analyzed. The defined Prior cohort (n = 277, treatment between 2006 and 2009) and Recent cohort (n = 245, treatment between 2010 and 2011) were then used to examine the relationship between Daxx NCR and clinical data. The Daxx NCR was found to be clinically informative and significantly higher in GC tissue. Using Daxx NCR (risk ratio = 2.0), both the Prior and Recent cohorts were divided into high- and low-risk groups. Relative to the low-risk group, the high-risk patients had a shorter disease free survival (DFS) and overall survival (OS) in both cohorts. Importantly, postoperative chemotherapy was found having differential effect on high- and low-risk patients. Such chemotherapy brought no survival benefit, (and could potentially be detrimental,) to high-risk patients after surgery. Daxx NCR could be used as a prognosis factor in GC patients, and may help select the appropriate population to benefit from chemotherapy after surgery. PMID- 28812331 TI - Total Synthesis of Crocagin A. AB - Crocagin A (1) combines an attractive molecular structure with an unusual biosynthesis and bioactivity. An efficient synthesis of crocagin A is presented that hinges on an early formation of the heterotricyclic core, an electrophilic amination, and the stereoselective hydrogenation of a tetrasubstituted double bond. This synthesis confirms the absolute configuration of crocagin A and provides access to the natural product and derivatives thereof for further biological testing. PMID- 28812330 TI - Black and minority ethnic group involvement in health and social care research: A systematic review. AB - BACKGROUND: Patient and public involvement (PPI) in research is growing internationally, but little is known about black and minority ethnic (BME) involvement and the factors influencing their involvement in health and social care research. OBJECTIVES: To characterize and critique the empirical literature on BME-PPI involvement in health and social care research. SEARCH STRATEGY: Systematic searches of six electronic bibliographic databases were undertaken, utilizing both MeSH and free-text terms to identify international empirical literature published between 1990 and 2016. INCLUSION CRITERIA: All study designs that report primary data that involved BME groups in health or social care research. Screening was conducted by two reviewers. DATA EXTRACTION AND SYNTHESIS: Data extraction and quality appraisal were performed independently. Data extraction focused on the level(s) of PPI involvement and where PPI activity occurred in the research cycle. Studies were quality-assessed using the guidelines for measuring the quality and impact of user involvement in research. Data were analysed using a narrative approach. MAIN RESULTS: Forty-five studies were included with the majority undertaken in the USA focusing on African Americans and indigenous populations. Involvement most commonly occurred during the research design phase and least in data analysis and interpretation. CONCLUSION: This is the first systematic review investigating BME involvement in health and social care research internationally. While there is a widespread support for BME involvement, this is limited to particular phases of the research and particular ethnic subgroups. There is a need to understand factors that influence BME involvement in all parts of the research cycle. PMID- 28812333 TI - Race with Fibrillating Atria. PMID- 28812332 TI - Live Cell Imaging Using Photoswitchable Diarylethene-Doped Fluorescent Polymer Dots. AB - Fluorescence photoswitching using nanomaterials has recently emerged as a promising approach for the imaging of biological targets. However, despite intensive research efforts during the last decade, practical microscopy of biological targets using photoswitchable nanoparticles in real time remains challenging. To address this problem, we have developed live macrophage cell imaging and single particle imaging methods, using photoswitchable fluorescent diarylethene-doped polymer nanoparticles (P-dots) under Xe lamp irradiation. We established a 34-times prolonged "off-state", using P-dots doped with a diarylethene-containing methoxy substituent, upon visible-light irradiation using a Xe lamp and a green fluorescent protein filter cube. To demonstrate the practicality of doped P-dots imaging, we imaged lysosomes in macrophage cells, and observed 11-times slower recovery of the fluorescence from the "off-state" to the "on-state", indicating their potential for cellular imaging. PMID- 28812334 TI - Epidemiology of Atrial Fibrillation - An Indian Perspective. PMID- 28812335 TI - Professor of Cardiology, SGPGIMS, Lucknow, Uttar Pradesh. AB - Atrial fibrillation (AF) is the most common supraventricular tachycardia and its incidence increases with age. The pathophysiology of AF has been studied extensively and is a subject of continuing research. The primary pathologic change seen in AF is progressive fibrosis of the atria and hence structural remodeling, is the mainstay in many forms of AF. Dilation of the atria can be due to almost any structural abnormality of the heart which includes valvular heart disease, hypertension or congestive heart failure. Electrical remodeling promotes AF by acting on fundamental arrhythmia mechanism: focal ectopic activity and reentry. Rapidly firing foci initiating paroxysmal AF arise most commonly from the atrial myocardial sleeves that extend into pulmonary veins. The evolution of AF from paroxysmal to persistent to permanent forms through atrial remodeling can be caused by the arrhythmia itself and/or progression of underlying heart disease. The development of functional reentry substrates contribute to persistent AF. AF-related reentry is currently thought to occur through two main concepts: (1) the leading- circle concept and (2) spiral wave reentry. The multiple wavelets hypothesis, particularly in advanced structural and electrical remodelling are present, maintains AF survival, causing the most frequent common final pathway in sustained AF. PMID- 28812336 TI - Clinical Spectrum of Acute or New-Onset Atrial Fibrillation. PMID- 28812337 TI - Management of Acute Atrial Fibrillation. PMID- 28812338 TI - Role of Ibutilide in Atrial Fibrillation. PMID- 28812339 TI - Young people, HIV, and life goals. PMID- 28812340 TI - Substrate-Controlled Selectivity Switch in a Three-Component Reaction: A Ag Catalyzed Strategy for the Synthesis of Functionalized Imidazoles. AB - An efficient Ag-catalyzed three-component reaction of amidines, ynals, and alcohols, phenols, or water has been developed. This strategy provides a wide range of substrates and represents a simple process for the preparation of different imidazole derivatives in good yields with high regioselectivities. PMID- 28812341 TI - Efficient Sky-Blue Perovskite Light-Emitting Devices Based on Ethylammonium Bromide Induced Layered Perovskites. AB - Low-dimensional organometallic halide perovskites are actively studied for the light-emitting applications due to their properties such as solution processability, high luminescence quantum yield, large exciton binding energy, and tunable band gap. Introduction of large-group ammonium halides not only serves as a convenient and versatile method to obtain layered perovskites but also allows the exploitation of the energy-funneling process to achieve a high efficiency light emission. Herein, we investigate the influence of the addition of ethylammonium bromide on the morphology, crystallite structure, and optical properties of the resultant perovskite materials and report that the phase transition from bulk to layered perovskite occurs in the presence of excess ethylammonium bromide. On the basis of this strategy, we report green perovskite light-emitting devices with the maximum external quantum efficiency of ca. 3% and power efficiency of 9.3 lm/W. Notably, blue layered perovskite light-emitting devices with the Commission Internationale de I'Eclairage coordinates of (0.16, 0.23) exhibit the maximum external quantum efficiency of 2.6% and power efficiency of 1 lm/W at 100 cd/m2, representing a large improvement over the previously reported analogous devices. PMID- 28812342 TI - Achieving a Collapsible, Strong, and Highly Thermally Conductive Film Based on Oriented Functionalized Boron Nitride Nanosheets and Cellulose Nanofiber. AB - Boron nitride nanosheet (BNNS) films receive wide attention in both academia and industry because of their high thermal conductivity (TC) and good electrical insulation capability. However, the brittleness and low strength of the BNNS film largely limit its application. Herein, functionalized BNNSs (f-BNNSs) with a well maintained in-plane crystalline structure were first prepared utilizing urea in the aqueous solution via ball-milling for the purpose of improving their stability in water and enhancing the interaction with the polymer matrix. Then, a biodegradable and highly thermally conductive film with an orderly oriented structure based on cellulose nanofibers (CNFs) and f-BNNSs was prepared just by simple vacuum-assisted filtration. The modification of the BNNS and the introduction of the CNF result in a better orientation of the f-BNNS, sufficient connection between f-BNNS themselves, and strong interaction between f-BNNS and CNF, which not only make the prepared composite film strong and tough but also possess higher in-plane TC. An increase of 70% in-plane TC, 63.2% tensile strength, and 77.8% elongation could be achieved for CNF/f-BNNS films, compared with that for CNF/BNNS films at the filler content of 70%. Although at such a high f-BNNS content, this composite film can be bended and folded. It is even more interesting to find that the in-plane TC could be greatly enhanced with the decrease of the thickness of the film, and a value of 30.25 W/m K can be achieved at the thickness of ~30 MUm for the film containing 70 wt % f-BNNS. We believe that this highly thermally conductive film with good strength and toughness could have potential applications in next-generation highly powerful and collapsible electronic devices. PMID- 28812343 TI - Xanthohumol Suppresses Mylip/Idol Gene Expression and Modulates LDLR Abundance and Activity in HepG2 Cells. AB - Xanthohumol, a prenylated flavonoid found in hops (Humulus lupulus L.), exhibits multiple biological activities such as antiatherosclerosis and hypolipidemic activities. In this study, we aim to investigate the hypocholesterolemic effects and molecular mechanisms of xanthohumol in hepatic cells. We found that xanthohumol (10 and 20 MUM) increased the amount of cell-surface low-density lipoprotein receptor (LDLR) from 100.0 +/- 2.1% to 115.0 +/- 1.3% and 135.2 +/- 2.7%, and enhanced the LDL uptake activity from 100.0 +/- 0.9% to 139.1 +/- 13.2% in HepG2 cells (p < 0.01). The mRNA levels of LDLR, HMGCR, and PCSK9 were not altered. Xanthohumol (20 MUM) reduced the expression of inducible degrader of the LDL receptor (Mylip/Idol) mRNA and protein by approximately 45% (p < 0.01), which was reported to be associated with increases of LDLR level. We demonstrated that xanthohumol suppressed hepatic Mylip/Idol expression via counteracting liver X receptor (LXR) activation. The molecular docking results predicted that xanthohumol has a high binding affinity to interact with the LXRalpha ligand binding domain, which may result in attenuation of LXRalpha-induced Mylip/Idol expression. Finally, we demonstrated that the Mylip/Idol expression and LDLR activity were synergistically changed by a combination of xanthohumol and simvastatin treatment. Our findings indicated that xanthohumol may regulate the LXR-Mylip/Idol axis to modulate hepatic LDLR abundance and activity. PMID- 28812344 TI - In Vitro Bile Acid Binding Capacities of Red Leaf Lettuce and Cruciferous Vegetables. AB - In the present study, we tested the bile acid binding capacity of red leaf lettuce, red cabbage, red kale, green kale, and Brussels sprouts through in vitro digestion process by simulating mouth, gastric, and intestinal digestion using six bile acids at physiological pH. Green and red kale exhibited significantly higher (86.5 +/- 2.9 and 89.7 +/- 0.9%, respectively) bile acid binding capacity compared to the other samples. Further, three different compositions of bile acids were tested to understand the effect on different health conditions. To predict the optimal dose for bile acid binding, we established a logistic relationship between kale dose and bile acid binding capacity. The results indicated that kale showed significantly higher bile acid binding capacity (82.5 +/- 2.9% equivalent to 72.06 mg) at 1.5 g sample and remained constant up to 2.5 g. In addition, minimally processed (microwaved 3 min or steamed 8 min) green kale showed significantly enhanced bile acid binding capacity (91.1 +/- 0.3 and 90.2 +/- 0.7%, respectively) compared to lyophilized kale (85.5 +/- 0.24%). Among the six bile acids tested, kale preferentially bound hydrophobic bile acids chenodeoxycholic acid and deoxycholic acid. Therefore, regular consumption of kale, especially minimally processed kale, can help excrete more bile acids and, thus, may lower the risk of hypercholesterolemia. PMID- 28812345 TI - Performance Enhancement of a Microfabricated Resonator Using Electrospun Nanoporous Polymer Wire. AB - A nanoporous poly(methyl methacrylate) (PMMA) wire was prepared by electrospinning under high humidity and attached between two prongs of a microfabricated quartz tuning fork (QTF). Exposure of the QTF to ethanol vapor caused a frequency shift due to a decrease in the modulus of the PMMA wire, and the frequency change increased as the concentration of ethanol vapor increased. The nanoporous wire-coated QTF exhibited higher sensitivity and faster response time than a plain wire-coated QTF, which was attributed to the high surface area and pore networks facilitating the transport of ethanol molecules inside the PMMA wire. PMID- 28812346 TI - Metal-Free Synthesis of 2-Aminobenzothiazoles via Iodine-Catalyzed and Oxygen Promoted Cascade Reactions of Isothiocyanatobenzenes with Amines. AB - In this paper, a highly efficient and sustainable synthesis of 2 aminobenzothiazoles through the cascade reactions of isothiocyanatobenzenes with primary or secondary amines by using iodine as a catalyst and oxygen as an oxidant is presented. Mechanistically, the formation of the title compounds involves the in situ formation of the required benzothiourea intermediate followed by its intramolecular cross dehydrogenative coupling of a C(sp2)-H bond and a S-H bond. To our knowledge, this should be the first example in which 2 aminobenzothiazoles are efficiently prepared from simple and cheap isothiocyanates and amines under metal-free conditions by using iodine as a catalyst and molecular oxygen as an oxidant with water as the byproduct. Compared with literature protocols, this method eliminates the use of ortho-halo substituted precursors, expensive transition-metal catalysts, and hazardous oxidants. PMID- 28812347 TI - Rational Design of Polymeric Nanoparticles with Tailorable Biomedical Functions for Cancer Therapy. AB - Polymeric nanoparticles (NPs) play a key role in nanoscale formulations for bioimaging, cancer treatment, and theranostics. In this work, we designed and synthesized a series of hydrophobic polymers (P1-6) with different pendent groups via one-step multicomponent Passerini reaction. These polymers possessed similar molecular structures and various biomedical functions. Interestingly, they could self-assemble into stable NPs in aqueous media. All formed NPs were redox sensitive because of the existence of disulfide bonds in the backbone. The stability of NPs in aqueous media with or without glutathione was systematically evaluated and compared. The optical performance, including fluorescence resonance energy transfer, was characterized under different conditions for those polymers with fluorescent components. Importantly, all formed NPs showed good cytocompatibility toward HeLa cells and different biological functions, including drug loading and delivery, bioimaging with variable fluorescence, and photodynamic activity, as evidenced by experiments in vitro and in vivo. These results demonstrate the great potential of multicomponent reaction to customize versatile polymeric nanoparticles for biomedical applications. PMID- 28812348 TI - Inhibition of Heterogeneous Ice Nucleation by Bioinspired Coatings of Polyampholytes. AB - Control of heterogeneous ice nucleation (HIN) on foreign surfaces is of great importance for anti-ice-nucleation material design. In this work, we studied the HIN behaviors on various ion-modified poly(butylene succinate) (PBS) surfaces via chain-extension reaction. Inspired by antifreeze proteins (AFPs), the PBS-based polyampholytes, containing both negative and positive charge groups on a single chain, show excellent performance of ice nucleation inhibition and freezing delay. Unlike the extremely high price and low availability of AFPs, these PBS based polyampholytes can be commercially synthesized under mild reaction conditions. Through water freezing tests on a wide range of substrates at different temperatures, these PBS-based polyampholytes have shown application value of tuning ice nucleation via a simple spin-coating method. PMID- 28812349 TI - Purification and Characterization of Latent Polyphenol Oxidase from Apricot (Prunus armeniaca L.). AB - Polyphenol oxidase from apricot (Prunus armeniaca) (PaPPO) was purified in its latent form (L-PaPPO), and the molecular weight was determined to be 63 kDa by SDS-PAGE. L-PaPPO was activated in the presence of substrate at low pH. The activity was enhanced by CuSO4 and low concentrations (<= 2 mM) of SDS. PaPPO has its pH and temperature optimum at pH 4.5 and 45 degrees C for catechol as substrate. It showed diphenolase activity and highest affinity toward 4 methylcatechol (KM = 2.0 mM) and chlorogenic acid (KM = 2.7 mM). L-PaPPO was found to be spontaneously activated during storage at 4 degrees C, creating a new band at 38 kDa representing the activated form (A-PaPPO). The mass of A-PaPPO was determined by mass spectrometry as 37 455.6 Da (Asp102 -> Leu429). Both L PaPPO and A-PaPPO were identified as polyphenol oxidase corresponding to the known PaPPO sequence (UniProt O81103 ) by means of peptide mass fingerprinting. PMID- 28812350 TI - Green-Solvent-Processable, Dopant-Free Hole-Transporting Materials for Robust and Efficient Perovskite Solar Cells. AB - In addition to having proper energy levels and high hole mobility (MUh) without the use of dopants, hole-transporting materials (HTMs) used in n-i-p-type perovskite solar cells (PSCs) should be processed using green solvents to enable environmentally friendly device fabrication. Although many HTMs have been assessed, due to the limited solubility of HTMs in green solvents, no green solvent-processable HTM has been reported to date. Here, we report on a green solvent-processable HTM, an asymmetric D-A polymer (asy-PBTBDT) that exhibits superior solubility even in the green solvent, 2-methylanisole, which is a known food additive. The new HTM is well matched with perovskites in terms of energy levels and attains a high MUh (1.13 * 10-3 cm2/(V s)) even without the use of dopants. Using the HTM, we produced robust PSCs with 18.3% efficiency (91% retention after 30 days without encapsulation under 50%-75% relative humidity) without dopants; with dopants (bis(trifluoromethanesulfonyl) imide and tert butylpyridine, a 20.0% efficiency was achieved. Therefore, it is a first report for a green-solvent-processable hole-transporting polymer, exhibiting the highest efficiencies reported so far for n-i-p devices with and without the dopants. PMID- 28812351 TI - Structural Investigation of Cesium Lead Halide Perovskites for High-Efficiency Quantum Dot Light-Emitting Diodes. AB - We have investigated the effect of reaction temperature of hot-injection method on the structural properties of CsPbX3 (X: Br, I, Cl) perovskite nanocrystals (NCs) using small- and wide-angle X-ray scattering. It is confirmed that the size of the NCs decreased as the reaction temperature decreased, resulting in stronger quantum confinement. The cubic-phase perovskite NCs formed despite the fact that the reaction temperatures increased from 140 to 180 degrees C; however, monodispersive NC cubes that are required for densely packing self-assembly film were formed only at lower temperatures. From the X-ray scattering measurements, the spin-coated film from more monodispersive perovskite nanocubes synthesized at lower temperatures resulted in more preferred orientation. This dense-packing perovskite film with preferred orientation yielded efficient light-emitting diode (LED) performance. Thus the dense-packing structure of NC assemblies formed after spin-coating should be considered for high-efficient LEDs based on perovskite quantum dots in addition to quantum confinement effect of the quantum dots. PMID- 28812352 TI - Ca-alpha-SiAlON:Eu Phosphors: Oxidation States, Energy Transfer, and Emission Enhancement by Incorporation-Aimed Surface Engineering. AB - Ca-alpha-SiAlON:Eu is one of the most promising phosphors exhibiting potential applications in high power LEDs owing to its excellent thermal stability and relatively high luminescence efficiency comparable to YAG:Ce commercial phosphors. The oxidation states of Eu ions in Ca-alpha-SiAlON:Eu are still questionable, and furthermore it exhibits lower luminescence intensity than commercial yellow phosphors. Therefore, in the present work, the valences of Eu ions in Ca-alpha-SiAlON have been examined, from which a mixture of divalence and trivalence is observed. Further improvement in emission intensity involves finding a way to increase the incorporation of larger Eu ions into the Ca-alpha SiAlON. Here, we observed preferred doping of Eu around phosphor grain surface and then propose a surface engineering strategy involving HF pickling of glassy surface layer, formation of Eu-rich precursors, and finally post-annealing, aiming to increase surface incorporation of Eu ions. The surface engineered samples exhibit great enhancement in emission intensity with a maximum increment by 80%. PMID- 28812353 TI - Dopamine-Incorporated Dual Bioactive Electroactive Shape Memory Polyurethane Elastomers with Physiological Shape Recovery Temperature, High Stretchability, and Enhanced C2C12 Myogenic Differentiation. AB - Soft tissue engineering needs elastic biomaterials not only mimicking the elasticity of soft tissue but also possessing multiple bioactivity to promote cell adhesion, proliferation, and differentiation, which still remain ongoing challenges. Herein, we synthesized a series of dopamine-incorporated dual bioactive electroactive shape memory polyurethane elastomers by combining the properties of elastomeric poly(citric acid-co-polycaprolactone) (CA-PCL) polyurethane elastomer, bioactive dopamine (DA), and electroactive aniline hexamer (AH). The chemical structures, electroactivity, conductivity, thermal properties, hydrophilicity and hydration ability, mechanical properties, and degradability of the polyurethane elastomers were systematically characterized. The elastomers showed excellent shape fixity ratio and shape recovery ability under physiological conditions. The elastomers' elongation and stress were tailored by the AH content, whereas the hydrophilicity and hydration ability of the elastomers were adjusted by the content of DA and AH, as well as the doping state of AH. The viability and proliferation results of C2C12 cells seeded on the elastomers showed their excellent cytocompatibility. Additionally, by analyzing the protein and gene level, the promotion effect on myogenic differentiation of C2C12 cells by these elastomers compared to that by control groups (PCL80 000, CA PCL elastomer, and CA-PCL elastomer with the DA segment) was demonstrated. Furthermore, the results from subcutaneous implantation confirmed the elastomers' mild host response in vivo. These results represent that these dopamine incorporated dual bioactive electroactive shape memory polyurethane elastomers are promising candidates for soft tissue regeneration that is sensitive to electrical signals. PMID- 28812354 TI - Three-Dimensional-Moldable Nanofiber-Reinforced Transparent Composites with a Hierarchically Self-Assembled "Reverse" Nacre-like Architecture. AB - Achieving a structural hierarchy and a uniform nanofiller dispersion simultaneously remains highly challenging for obtaining a robust polymer nanocomposite of immiscible components. In this study, a remarkably facile Pickering emulsification approach is developed to fabricate hierarchical composites of immiscible acrylic polymer and native cellulose nanofibers by taking advantage of the dual role of the nanofibers as both emulsion stabilizer and polymer reinforcement. The composites feature a unique "reverse" nacre-like microstructure reinforced with a well-dispersed two-tier hierarchical nanofiber network, leading to a synergistic high strength, modulus, and toughness (20, 50, and 53 times that of neat polymer, respectively), high optical transparency (89%), high flexibility, and a drastically low thermal expansion (13 ppm K-1, 1/15th of the neat polymer). The nanocomposites have a three-dimensional-shape moldability, also their surface can be patterned with micro/nanoscale features with high fidelity by in situ compression molding, making them attractive as the substrate for flexible displays, smart contact lens devices, and photovoltaics. The Pickering emulsification approach should be broadly applicable for the fabrication of novel functional materials of various immiscible components. PMID- 28812355 TI - Adaptively Recognizing Parallel-Stranded Duplex Structure for Fluorescent DNA Polarity Analysis. AB - Besides the canonical Watson-Crick (WC) linked antiparallel-stranded duplex (aps DNA), DNA is also able to form bioactive parallel-stranded duplex (ps-DNA) with the two involving strands adopting the equal 5'-3' polarity. Discriminating ps DNA from aps-DNA with an ideal selectivity is more challenging because of their comparable duplex topologies. Herein, we designed a unique probe of HPIN to fluorescently recognize ps-DNA but to keep an almost nonfluorescent response in binding with aps-DNA. The success of the Hoogsteen hydrogen bonding pattern in lighting up the HPIN fluorescence over the reverse Watson-Crick (rWC) one suggests the critical role of HPIN in structurally adaptive recognition to the strand polarity-determined base-pairing peculiarity. The turn-on fluorescence should result from restriction of the HPIN cis/trans isomerization upon the adaptive Hoogsteen base pair binding. Such high performance in recognizing ps-DNA against aps-DNA demonstrates the promising applications of HPIN in developing unique DNA polarity-based sensors. PMID- 28812356 TI - Single Molecule Nanopore Spectrometry for Peptide Detection. AB - Sensing and characterization of water-soluble peptides is of critical importance in a wide variety of bioapplications. Single molecule nanopore spectrometry (SMNS) is based on the idea that one can use biological protein nanopores to resolve different sized molecules down to limits set by the blockade duration and noise. Previous work has shown that this enables discrimination between polyethylene glycol (PEG) molecules that differ by a single monomer unit. This paper describes efforts to extend SMNS to a variety of biologically relevant, water-soluble peptides. We describe the use of Au25(SG)18 clusters, previously shown to improve PEG detection, to increase the on- and off-rate of peptides to the pore. In addition, we study the role that fluctuations play in the single molecule nanopore spectrometry (SMNS) methodology and show that modifying solution conditions to increase peptide flexibility (via pH or chaotropic salt) leads to a nearly 2-fold reduction in the current blockade fluctuations and a corresponding narrowing of the peaks in the blockade distributions. Finally, a model is presented that connects the current blockade depths to the mass of the peptides, which shows that our enhanced SMNS detection improves the mass resolution of the nanopore sensor more than 2-fold for the largest cationic peptides studied. PMID- 28812357 TI - Importance of Terminal Amino Acid Residues to the Transport of Oligopeptides across the Caco-2 Cell Monolayer. AB - The objective of this paper was to investigate the effects of terminal amino acids on the transport of oligopeptides across the Caco-2 cell monolayer. Ala based tetra- and pentapeptides were designed, and the N- or C-terminal amino acid residues were replaced by different amino acids. The results showed that the oligopeptides had a wide range of transport permeability across the Caco-2 cell monolayer and could be divided into four categories: non-/poor permeability, low permeability, intermediate permeability, and good permeability. Tetrapeptides with N-terminal Leu, Pro, Ile, Cys, Met, and Val or C-terminal Val showed the highest permeability, with apparent permeability coefficient (Papp) values over 10 * 10-6 cm/s (p < 0.05), suggesting that nonpolar hydrophobic aliphatic amino acids or polar sulfur-containing amino acids were the best for the transport of tetrapeptides. Pentapeptides with N- or C-terminal Tyr also showed high permeability levels, with Papp values of about 10 * 10-6 cm/s. The amino acids Glu, Asn, and Thr at the N terminus or Lys, Asp, and Arg at the C terminus were also beneficial for the transport of tetra- and pentapeptides, with Papp values ranging from 1 * 10-6 to 10 * 10-6 cm/s. In addition, peptides with amino acids replaced at the N terminus generally showed higher permeability than those with amino acids replaced at the C terminus (p < 0.05), suggesting that N-terminal amino acids were more important for the transport of oligopeptides across the Caco-2 cell monolayer. PMID- 28812358 TI - Bioinspired "Active" Stealth Magneto-Nanomicelles for Theranostics Combining Efficient MRI and Enhanced Drug Delivery. AB - The mononuclear phagocyte system (MPS) with key roles in recognition and clearance of foreign particles, is a major constraint to nanoparticle-based delivery systems. The desire to improve the delivery efficiency has prompted the search for stealthy long-circulating nanoplatforms. Herein, we design an antiphagocytic delivery system with "active" stealth behavior for cancer theranostics combining efficient MRI and enhanced drug delivery. We modify self peptide, a synthetic peptide for active immunomodulation, to biodegradable poly(lactide-glycolide)-poly(ethylene glycol) (PLGA-PEG), then utilize the self assembly properties of PLGA-PEG to form nanomicelles that encapsulating iron oxide (IO) nanoparticles and anticancer drug paclitaxel (PTX). Through the interaction of self-peptide with the receptor SIRPalpha, which is expressed on phagocytes, the as-prepared nanomicelles can disguise as "self" to avoid being recognized as foreign particles by MPS, leading to improved blood circulation time and delivery efficiency. Compared to the "passive" stealth effect generating by PEG or zwitterionic polymers that only passively delay the physisorption of serum proteins to nanocarriers, the "active self" nanomicelles can more efficiently inhibit the MPS-mediated immune clearance and reduce "accelerated blood clearance" phenomenon. Furthermore, this one-step clustering of IO nanoparticles and loading of PTX endow the resulted magneto-nanomicelles with enhanced T2 MRI contrast performance and antitumor effect. We believe that this study provides a novel approach in designing of efficient stealth antiphagocytic delivery systems that resisting the MPS-mediated clearance for cancer theranostics. PMID- 28812359 TI - Continuous-Flow Electrophoresis of DNA and Proteins in a Two-Dimensional Capillary-Well Sieve. AB - Continuous-flow electrophoresis of macromolecules is demonstrated using an integrated capillary-well sieve arranged into a two-dimensional anisotropic array on silicon. The periodic array features thousands of entropic barriers, each resulting from an abrupt interface between a 2 MUm deep well (channel) and a 70 nm capillary. These entropic barriers owing to two-dimensional confinement within the capillaries are vastly steep in relation to those arising from slits featuring one-dimensional confinement. Thus, the sieving mechanisms can sustain relatively large electric field strengths over a relatively small array area. The sieve rapidly sorts anionic macromolecules, including DNA chains and proteins in native or denatured states, into distinct trajectories according to size or charge under electric field vectors orthogonally applied. The baseline separation is achieved in less than 1 min within a horizontal migration length of ~1.5 mm. The capillaries are self-enclosed conduits in cylindrical profile featuring a uniform diameter and realized through an approach that avoids advanced patterning techniques. The approach exploits a thermal reflow of a layer of doped glass for shape transformation into cylindrical capillaries and for controllably shrinking the capillary diameter. Lastly, atomic layer deposition of alumina is introduced for the first time to fine-tune the capillary diameter as well as to neutralize the surface charge, thereby suppressing undesired electroosmotic flows. PMID- 28812360 TI - Silicon Cations Intermixed Indium Zinc Oxide Interface for High-Performance Thin Film Transistors Using a Solution Process. AB - Solution-processed amorphous metal-oxide thin-film transistors (TFTs) utilizing an intermixed interface between a metal-oxide semiconductor and a dielectric layer are proposed. In-depth physical characterizations are carried out to verify the existence of the intermixed interface that is inevitably formed by interdiffusion of cations originated from a thermal process. In particular, when indium zinc oxide (IZO) semiconductor and silicon dioxide (SiO2) dielectric layer are in contact and thermally processed, a Si4+ intermixed IZO (Si/IZO) interface is created. On the basis of this concept, a high-performance Si/IZO TFT having both a field-effect mobility exceeding 10 cm2 V-1 s-1 and a on/off current ratio over 107 is successfully demonstrated. PMID- 28812361 TI - Ultrasensitive and Accurate Assay of Human Methyltransferase Activity at the Single-Cell Level Based on a Single Integrated Magnetic Microprobe. AB - Human DNA methyltransferase (MTase) activity expression patterns and inhibition response are linked to related cancer initiation, progression, and therapeutic responses. Sensitive and accurate human MTase activity assay in cancer cells, especially at the single-cell level, is essential for biological study, clinical diagnosis, and therapy. Here, we developed an ultrasensitive and accurate DNA (cytosine-5)-methyltransferase 1 (Dnmt1) activity assay at the single-cell level based on a single integrated magnetic microprobe of functionalized double stranded DNA (dsDNA) anchored to a single magnetic microbead surface. Functionalized dsDNA is designed with a hemimethylated DNA site for Dnmt1 recognition and a single-stranded tail to trigger in situ rolling circle amplification (RCA). Under the action of Dnmt1, hemimethylated dsDNA could be recognized and catalyzed to fully methylated dsDNA, which would protect them from the cleavage of BssHII. However, the dsDNA without full methylation would be cut by BssHII, making single-stranded tail separated from the single integrated microprobe. Subsequently, full methylation-protected in situ RCA could be performed, and multiple signal probes were hybridized to the single integrated microprobe for amplified signal accumulation. Finally, Dnmt1 activity could be evaluated by reading the fluorescence of the single integrated microprobe. Meanwhile, to minimize matrix interferences, magnetic separation was performed in the process. In this strategy, the single integrated magnetic microprobe was provided with integrated capacities of target recognition, signal amplification, signal accumulation, and matrix isolation. Therefore, an ultralow detection limit of 0.007 U/mL Dnmt1 was obtained, and accurate Dnmt1 activity assays in multiple cell lysates at the single-cell level were achieved. Furthermore, the inhibition effect of RG108 was evaluated conveniently. These results indicate that the single integrated magnetic microprobe-based strategy is an excellent candidate for sensitive monitoring of Dnmt1 activity and screening of anticancer drugs. PMID- 28812362 TI - Nitrogen-Doped Porous Graphdiyne: A Highly Efficient Metal-Free Electrocatalyst for Oxygen Reduction Reaction. AB - Metal-free catalysts for oxygen reduction reaction (ORR) are the desired materials for low-cost proton exchange membrane fuel cells. Graphdiyne (GDY), a novel type of two-dimensional carbon allotrope, is featured by its sp- and sp2 hybridized carbon atoms, different from the other existing carbon materials. Thus, nitrogen (N) can be doped in new styles by substituting sp-hybridized carbon atoms, effective for ORR, which has been displayed in this study using both experimental and theoretical technologies. The N-doped GDY was synthesized with pyridine and NH3 as N sources successively, expressing an electrocatalytic activity at a potential above 0.8 V similar to that of commercial Pt/C for ORR in alkaline solution and higher stability and better methanol tolerance than those of Pt/C. PMID- 28812363 TI - Influence of Oxygen Vacancies on the Frictional Properties of Nanocrystalline Zinc Oxide Thin Films in Ambient Conditions. AB - Oxygen vacancy is the most studied point defect and has been found to significantly influence the physical properties of zinc oxide (ZnO). By using atomic force microscopy (AFM), we show that the frictional properties on the ZnO surface at the nanoscale greatly depend on the amount of oxygen vacancies present in the surface layer and the ambient humidity. The photocatalytic effect (PCE) is used to qualitatively control the amount of oxygen vacancies in the surface layer of ZnO and reversibly switch the surface wettability between hydrophobic and superhydrophilic states. Because oxygen vacancies in the ZnO surface can attract ambient water molecules, during the AFM friction measurement, water meniscus can form between the asperities at the AFM tip-ZnO contact due to the capillary condensation, leading to negative dependence of friction on the logarithm of tip sliding velocity. Such dependence is found to be a strong function of relative humidity and can be reversibly manipulated by the PCE. Our results indicate that it is possible to control the frictional properties of ZnO surface at the nanoscale using optical approaches. PMID- 28812364 TI - Catalytic Asymmetric Desymmetrization of Cyclopentendiones via Diels-Alder Reaction of 3-Hydroxy-2-pyrones: Construction of Multifunctional Bridged Tricyclic Lactones. AB - An unprecedented asymmetric Diels-Alder reaction of 3-hydroxy-2-pyrones with prochiral cyclopentene-1,3-diones via desymmetrization was efficiently realized with high stereoselective control with the aid of fine-tunable cinchona alkaloid derived bifunctional amine-thiourea catalysts bearing multiple hydrogen-bonding donors. This protocol provides an expedient access to the multifunctional-bridged tricyclic lactones featuring four contiguous stereogenic centers and one remote quaternary stereogenic center with a broad substrate scope. The cycloadduct can be readily elaborated into enantioenriched cyclopentane-1,3-diones via ring opening/aromatization. PMID- 28812365 TI - Correction to "The Conformation of Thermoresponsive Polymer Brushes Probed by Optical Reflectivity". PMID- 28812366 TI - A combination of experimental measurement, constitutive damage model, and diffusion tensor imaging to characterize the mechanical properties of the human brain. AB - Understanding the mechanical properties of the human brain is deemed important as it may subject to various types of complex loadings during the Traumatic Brain Injury (TBI). Although many studies so far have been conducted to quantify the mechanical properties of the brain, there is a paucity of knowledge on the mechanical properties of the human brain tissue and the damage of its axon fibers under the various types of complex loadings during the Traumatic Brain Injury (TBI). Although many studies so far have been conducted to quantify the mechanical properties of the brain, there is a paucity of knowledge on the mechanical properties of the human brain tissue and the damage of its axon fibers under the frontal lobe of the human brain. The constrained nonlinear minimization method was employed to identify the brain coefficients according to the axial and transversal compressive data. The pseudo-elastic damage model data was also well compared with that of the experimental data and it not only up to the primary loading but also the discontinuous softening could well address the mechanical behavior of the brain tissue. PMID- 28812367 TI - The usefulness of diffusion-weighted magnetic resonance imaging performed in the acute phase as an early predictor of delayed neuropsychiatric sequelae in acute carbon monoxide poisoning. AB - Delayed onset of neuropsychiatric symptoms after apparent recovery from acute carbon monoxide (CO) poisoning has been described as delayed neuropsychiatric sequelae (DNS). No previous study has determined whether early use of diffusion weighted magnetic resonance imaging (DWI) can predict which patients will develop DNS in the acute CO poisoning. This retrospective observational study was performed on adult patients with acute CO poisoning consecutively treated over a 17-month period. All included patients with acute CO poisoning underwent DWI to evaluate brain injury within 72 h after CO exposure. DWI was evaluated as follows: (1) presence of pathology, (2) number of pathologies, (3) asymmetry, and (4) location of pathology. Patients were divided into two groups. The DNS group was composed of patients with delayed sequelae, while the non-DNS group included patients with no sequelae. A total of 102 patients with acute CO poisoning were finally enrolled in this study. DNS developed in 10 patients (9.8%). Between the DNS group and the non-DNS group, presence of pathology on DWI and initial Glasgow Coma Scale (GCS) showed significant difference. There was also a statistical difference between the non-DNS group and DNS group in terms of CO exposure time, troponin I, rhabdomyolysis, acute kidney injury, and pneumonia. The presence of pathology in DWI and initial GCS (cutoff: <12) at the emergency department served as an early predictors of DNS. PMID- 28812369 TI - Two new cassane diterpene lactams from the fruits of Caesalpinia mimosoides Lam. AB - Two new cassane ditepenoid lactams, caesmimotam A (1) and B (2), along with eight known compounds (3-10) were isolated from the fruits of Caesalpinia mimosoides Lam. Their structures were identified by 1D and 2D NMR spectral data. Compounds 1 and 2 were evaluated for their cytotoxicity on HL-60, SMMC-7721, A-549, MCF-7 and SW-480 human cancer cell lines, but they were inactive. PMID- 28812368 TI - How Psychiatrists Recommend Treatment and Its Relationship with Patient Uptake. AB - Consultations for patients with chronic mental health conditions are conceived as meetings of experts: medical and experiential, respectively. Treatment decisions, in these terms, become a joint responsibility rather than handed down ex cathedra. One resource for constituting decisions as 'shared' is the treatment recommendation - decisional authority can be invoked through its design. There is concern that people diagnosed with schizophrenia are infrequently involved in treatment decisions. However, the methods psychiatrists actually employ remain undefined. This article advances our understanding of psychiatric practice by mapping alternative methods used by psychiatrists to recommend treatment in outpatient consultations in situ. First, we unpack the types of treatments psychiatrists recommend. Then, we ask how psychiatrists recommend treatment? Applying a novel coding taxonomy, informed by the conversation analytic principle that recommendations represent different social actions, we identify the distribution of alternative formulations for psychiatrists' recommendations (pronouncements, suggestions, proposals, and offers). We also propose one linguistic dimension, personal pronouns, on which recommending actions often depend, implicative for who is projected as 'accountable' for the decision. Finally, we examine the relationship between action type and patient uptake: is a particular type of recommendation more likely to attract acceptance/resistance from patients? And how does this relate to decisional accountability? PMID- 28812370 TI - Rauvolfianine, a new antimycobacterial glyceroglycolipid and other constituents from Rauvolfia caffra. Sond (Apocynaceae). AB - The chemical investigation of the extract of the dried leaves of Rauvolfia caffra (Sond) (synonym Rauvolfia macrophylla) (Apocynaceae) led to isolation of a new glycoside derivative, rauvolfianine (1) as well as six known compounds: oleanolic acid (2), sitosterol-3-O-beta-D-glucopyranoside (3), betulinic acid (4), vellosimine (5), sarpagine (6) and D-fructofuranosyl-beta-(2->1)-alpha-D glucopyranoside (7). Compounds 1, 2, 3, 4 and 7 were evaluated for antitubercular activity. Compounds 1 and 2 were the most active (MIC = 7.8125 and 31.25 MUg/mL) towards the Isoniazid resistant strain of Mycobacterium tuberculosis AC45. Their structures and relative stereochemistry were elucidated by spectroscopic methods. PMID- 28812371 TI - Two Physical Activity Measures: Paffenbarger Physical Activity Questionnaire Versus Aerobics Center Longitudinal Study as Predictors of Adult-Onset Type 2 Diabetes in a Follow-Up Study. AB - PURPOSE: To compare 2 self-report methods of measuring weekly minutes of physical activity based on the Aerobics Center Longitudinal Study (ACLS) questionnaire and question 6 of the Paffenbarger Physical Activity Questionnaire (PPAQ) to determine the better predictor of adult-onset type 2 diabetes mellitus (T2DM). DESIGN: An observational, prospective study. SETTING: Survey data from the Adventist Health Study-2 (AHS-2) collected between 2002 and 2006 (baseline) and the Psychosocial Manifestations of Religion Sub-Study (PsyMRS), an AHS-2 subset collected 1 to 4 years later. PATIENTS: Nine thousand eight hundred seventy-three male and female participants aged 23 to 106 years (mean, 63 years). Three hundred eighty participants reported adult-onset T2DM at follow-up. MEASURES: Question 6 from the PPAQ and a question adopted from the ACLS were assessed at baseline. Incident diabetes was defined as participants who reported receiving treatment for adult-onset T2DM in the last 12 months in the PsyMRS and not at baseline. ANALYSIS: Multivariate logistic regression analyses controlled for age, gender, ethnicity, education, body mass index (BMI), diet, and sedentary activity. Each exposure variable was compared to nonexercisers. RESULTS: The PPAQ (odds ratio [OR]: 0.998; 95% confidence interval [CI]: 0.997-1.000) and the ACLS (OR: 0.999; 95% CI: 0.998-1.001) exhibited similar likelihood of predicting incident adult onset T2DM in a healthy, mixed-gender population when controlling for several confounders. CONCLUSIONS: The demonstrative nomenclature of the PPAQ may be more effectual in capturing physically active individuals than the ACLS notwithstanding generalizability and response bias limitations. PMID- 28812372 TI - Factors associated with depression detection in a New Hampshire mental health outreach program. AB - OBJECTIVES: For mental health outreach programs for older adults, accurately detecting depression is key to quality service provision. Multiple factors, including gender, cognitive impairment, or recent bereavement may affect depression detection, but this is under-studied. Therefore, we sought to both establish rates of depressive symptom detection and to examine factors associated with inaccuracies of detecting depression among participants in a mental health outreach program serving older adults. METHOD: We conducted a chart review of 1126 cases in an older adult-focused mental health outreach program in New Hampshire, the Referral Education Assistance & Prevention (REAP) program. Accuracy of depression detection was identified by comparing screen-positive scores for depressive symptoms on the 15-item Geriatric Depression Scale (GDS) to depression identification by counselors on a 'presenting concerns' list. RESULTS: Inaccurate depression detection (positive on the GDS but depression not identified by counselors) occurred in 27.6% of cases. Multivariate regression analyses indicated that anxiety, cognitive concerns, and rurality were all associated with detection innaccuracy. CONCLUSION: This study appears to be the first to examine factors influencing depression detection in a mental health outreach program. Future efforts should help ensure that all older mental health outreach clients have depression detected at optimal rates. PMID- 28812373 TI - Evaluation of factors in development of Vis/NIR spectroscopy models for discriminating PSE, DFD and normal broiler breast meat. AB - 1. To evaluate the performance of visible and near-infrared (Vis/NIR) spectroscopic models for discriminating true pale, soft and exudative (PSE), normal and dark, firm and dry (DFD) broiler breast meat in different conditions of preprocessing methods, spectral ranges, characteristic wavelength selection and water-holding capacity (WHC) indexes were assessed. 2. Quality attributes of 214 intact chicken fillets (pectoralis major), such as lightness (L*), pH and WHC indicators including drip loss (DL), water gain and expressible fluid were measured. Fillets were grouped into PSE, normal and DFD categories based on combination of L*, pH and WHC threshold criteria. Classification models were developed using support vector machine based methods on characteristic wavelengths selected from the unprocessed or 2nd-derivative spectra, respectively, in three spectral subsets of 400-2500, 400-1100 and 1100-2500 nm. 3. Better classification of three meat groups was obtained based on unprocessed spectra (72-94%) than 2nd-derivative spectra (55-72%). The classification based on 400-2500 nm (91% average) and 400-1100 nm (89% average) performed better than that on 1100-2500 nm (78% average). In terms of the three different WHC indicators, the combination of L*, pH and DL produced better results than the other two groups, with recognition accuracy of 94.4% using 400-2500-nm range. 4. These analytical results suggest that for a better classification of true PSE, normal and DFD broiler breast meat with Vis/NIR spectra, unprocessed spectra wavelengths should be used, ranges of 400-1000 nm should be included in the data collection, and DL as an indicator of WHC might provide a better prediction model. PMID- 28812374 TI - An evaluation scheme for assessing the effectiveness of intersection movement assist (IMA) on improving traffic safety. AB - OBJECTIVE: Intersection movement assist (IMA) has been recognized as one of the prominent countermeasures to reduce angle crashes at intersections, which constitute 22% of total crashes in the United States. Utilizing vehicle-based sensors, vehicle-to-vehicle (V2V), and vehicle-to-infrastructure (V2I) communications, IMA offers extended vision to provide early warning for an imminent crash. However, most of IMA-related research implements their methods and strategies only in simulations, test tracks, or driving simulator studies that have quite a few assumptions and limitations and hence the effectiveness evaluations reported may not be transferable or comparable. METHODS: This study seeks to develop a generalized evaluation scheme that can be used not only to assess the effectiveness of IMA on improving traffic safety at intersections but to facilitate comparisons across similar studies. The proposed evaluation scheme utilizes the concepts of traffic conflict in terms of time-to-collision (TTC) as a crash surrogate. This approach avoids the issue of having insufficient crash frequency data for system evaluation. To measure the effectiveness of IMA on reducing traffic conflicts, a relative risk is calculated for comparing the risk of with/without using the IMA. As a proof-of-concept study, this study applied the proposed evaluation scheme and reported the effectiveness of IMA on improving traffic safety in a field operation test (FOT). Seven test scenarios were conducted at 4 intersections, and a total of 40 participants were recruited to use the IMA for 6 months. RESULTS: It was estimated that IMA users have 26% fewer conflicts with TTC less than 5 s and have 15% fewer conflicts with TTC less than 4 s. However, the results vary across different sites and different definitions of conflicts in terms of TTC. CONCLUSIONS: Overall, IMA is promising to effectively reduce angle crashes related to sight obstruction and has potential to reduce not only crash frequency but crash severity. PMID- 28812375 TI - The family caregiver experience - examining the positive and negative aspects of compassion satisfaction and compassion fatigue as caregiving outcomes. AB - OBJECTIVES: Caregiving results in both positive and negative outcomes for caregivers. The purpose of this study was to examine compassion fatigue and compassion satisfaction in family caregivers. METHODS: Using a cross sectional descriptive survey design with a convenience sample, 168 family caregivers of individuals with chronic illness completed a web-based survey. Measures included a demographic questionnaire, Caregiver Burden Interview, Brief COPE inventory and Professional Quality of Life (ProQOL). RESULTS: The majority of participants (71%) reported high levels of caregiver burden, moderate to low levels of the compassion fatigue concepts of burnout (59.5%) and secondary traumatic stress (STS) (50%), and moderate levels of compassion satisfaction (82.7%). Regression analyses showed that caregiver burden, time caregiving, coping, social support, and caregiving demands explained a total variance of 57.1%, F(11,119) = 14.398, p < .00 in burnout and a total variance of 56%, F(11, 119) = 13.64, p < .00 in STS. Specifically, behavioral disengagement is a predicator that may indicate early compassion fatigue. CONCLUSION: Findings suggest that despite high caregiver burden and moderate compassion fatigue, family caregivers are able to provide care and find satisfaction in the role. This study supports the use of compassion fatigue and compassion satisfaction as alternative or additional outcomes to consider in future research. PMID- 28812376 TI - Probiotic nomenclature matters redux: confusion on Bifidobacterium longum subsp. infantis taxonomy persists. PMID- 28812377 TI - A cross-sectional study of coping resources and mental health of Chinese older adults in the United States. AB - OBJECTIVES: This study examined the potential influence of coping resources at individual (sense of mastery), family (spousal and family support, children's filial piety), and community levels (community cohesion) on the mental health (depression, anxiety) of U.S. Chinese older adults. METHODS: The data were derived from the Population Study of Chinese Elderly in Chicago (N= 3,159). Negative binomial regressions were performed to predict depression and anxiety, respectively, by entering the three sets of coping resources separately and jointly, controlling for socio-demographic and acculturation variables. RESULTS: Stronger sense of mastery and greater perception of children's filial piety were associated with better mental health outcomes. Spousal support was not associated with any mental health outomes, and family support was actually assciated with greater depression and anxiety. Stronger community cohesion was associated with fewer depressive symptoms but greater anxiety. CONCLUSION: Older immigrants' sense of control and perception that children adhere to traditional family norms are important mental health protective factors. Whereas depending on families for support may compromise their well-being, community cohesion could be a double edged sword for their mental health. Future studies shall further disentangle the associations among sense of mastery, reliance on family and ethnic enclaves for support, and older immigrants' well-being. PMID- 28812378 TI - Bevacizumab in advanced lung cancer: state of the art. AB - Despite recent advances in metastatic lung cancer treatment with the advent of immune checkpoint inhibitors and molecules targeting addictive genomic abnormalities, prognosis of most of the patients remains unfavorable. Combination approaches with older drugs, such as bevacizumab, should be thus envisioned. Bevacizumab is a monoclonal anti-VEGF antibody, approved by the US FDA and the EMA in first-line and maintenance settings of advanced nonsquamous non-small-cell lung cancer (NSCLC) treatment, in association with platinum-based chemotherapy. In the years to come, bevacizumab might be associated with new molecular therapies or immuno-oncology drugs, in order to optimize response rates and overcome resistances. This review summarizes the pharmacologic properties, clinical efficacy and safety of bevacizumab in advanced lung cancer treatment, with a focus on NSCLC, EGFR-mutant NSCLC and small-cell lung cancer. PMID- 28812379 TI - Dietary polyphenols for atherosclerosis: A comprehensive review and future perspectives. AB - Atherosclerosis is one of the most prevalent reasons for premature death in adults. Despite the several conventional drugs in the market; many patients are not completely treated. Here we comprehensively review current clinical evidence regarding the efficacy of dietary polyphenols in atherosclerosis and related complications. PubMed, Cochrane library and Scopus were searched from inception until August 2016 to obtain clinical trials in which polyphenols were evaluated in cardiovascular parameters related to atherosclerosis. From total of 13031 results, 49 clinical trials were finally included. Tyrosol derivatives from virgin olive oil, catechins and theaflavins from green and black tea, cocoa polyphenols, and red grape resveratrol, as well as anthocyanins were the most studied polyphenolic compounds which could regulate lipid profile, inflammation and oxidative stress, blood pressure, endothelial function, and cell adhesion molecules. The most important limitations of the included trials were small sample size, short follow up, and unqualified methodology. Future well-designed clinical trials are necessary to provide better level of evidence for clinical decision making. PMID- 28812380 TI - Analysis of an 8-hour acetylcysteine infusion protocol for repeated supratherapeutic ingestion (RSTI) of paracetamol. AB - OBJECTIVES: In Australia, the treatment guideline for patients with repeated supratherapeutic ingestion (RSTI) of paracetamol recommends an abbreviated acetylcysteine regimen if the paracetamol concentration is low (<10 mg/L) and alanine aminotransferase (ALT) is normal or static after 8 hours of infusion. There are currently no studies of this recommendation. METHOD: A retrospective review of paracetamol overdose presentations from October 2009 to August 2016 in two hospital toxicology networks was performed. All cases of RSTI treated with acetylcysteine were extracted. RESULTS: Of the 2249 paracetamol overdose presentations, 91 cases of RSTI were treated with acetylcysteine. Median time to initial blood tests was 6 hours post-last paracetamol dose (IQR 4-6). Sixty-three (69%) presentations had an initial detectable paracetamol concentration, median 30 mg/L (IQR 18-60). Median ALT on presentation was 48 IU/L (IQR 18-109). After 8 hours of acetylcysteine infusion, median ALT was 34 IU/L (IQR 16-71) in those receiving abbreviated treatment and 74 IU/L (IQR 40-231) in those continuing acetylcysteine. Thirty-nine presentations (43%) had an abbreviated regimen. Nine (10%) patients had an initial ALT >=50 IU/L and subsequently developed hepatotoxicity (ALT >1000 IU/L). No patients with an initial ALT <50 IU/L developed hepatotoxicity. Median duration of acetylcysteine infusion for those receiving a non-abbreviated regimen was 20 hours (IQR 20-25) vs. 10.4 hours (IQR 4.8-12.0) who received an abbreviated regimen. There were no re-presentations with hepatotoxicity. CONCLUSIONS: An 8-hour acetylcysteine infusion regimen for treatment of paracetamol RSTI may be safe and is likely to reduce length of stay for patients at low risk of hepatotoxicity. Larger prospective studies are needed to examine the efficacy of this abbreviated acetylcysteine protocol. PMID- 28812381 TI - Retrospective review of SGLT2 inhibitor exposures reported to 13 poison centers. AB - BACKGROUND: SGLT2 inhibitors are a new class of oral antidiabetics prescribed in the United States since 2013. They act by inhibiting reabsorption of glucose in the proximal convoluted tubule of the kidney, allowing excess glucose to be excreted. Little has been reported regarding effects of non-therapeutic exposure to this class of medication. METHODS: Retrospective records from 13 poison centers were examined for human exposures to SGLT2 inhibitors between 1st January 2013 and 31st December 2016. Exclusion criteria included multi-substance exposures and exposures without any follow-up call. Data examined included patient age, chronicity of exposure, clinical effects, management site, treatments administered, duration of follow-up, and outcome. RESULTS: Eighty eight cases met inclusion criteria. Patient age ranged from 1 to 75 years; 49 were evaluated in a health care facility with 18 admissions. No symptoms developed in 80 (91%) patients, 6 (7%) developed minor symptoms, and 2 (2%) developed moderate symptoms. Hypoglycemia was not observed. Mean time to final follow-up was 9.3 h, ranging from 1 to 42 h; median was 6 h. Of the two patients who developed moderate symptoms, one was a 65 year old male who developed metabolic acidosis and hypokalemia while taking canagliflozin therapeutically; the other a 43-year-old female who developed tachycardia and mild hypertension following the intentional ingestion of 6000 mg of canagliflozin. DISCUSSIONS: The number of patients evaluated in a health care facility is most likely reflective of a cautious approach to dealing with a new class of drug. Exposures were generally well-tolerated and managed with minimal intervention. CONCLUSIONS: In this retrospective series, acute ingestions of SGLT2 inhibitors were well tolerated with no hypoglycemia and only minor effects. For young children with unintentional ingestions, a reasonable approach to home management would include at least one follow-up for signs and symptoms of possible toxicity including mental status changes, polyuria, or tachypnea. PMID- 28812382 TI - Can elevated lactate and LDH produce a false positive enzymatic ethanol result in live patients presenting to the emergency department? AB - BACKGROUND: There have been allegations in the courtroom that elevated serum lactic acid in trauma victims can yield a falsely elevated serum ethanol assay. Most hospitals utilize an indirect method of ethanol measurement where a serum sample is added to a mix of alcohol dehydrogenase and oxidized nicotinamide adenine dinucleotide (NAD+). This allows any ethanol in the patient's serum to be metabolized to acetaldehyde, and in the process results in the reduction of NAD + to NADH. NADH is then measured using spectrophotometry. The courtroom allegation stems from the concept that oxidation of lactate to pyruvate by lactate dehydrogenase (LDH) results in the same molar-for-molar reduction of NAD + to NADH, and could therefore theoretically cause patients with elevated lactate and LDH to have a falsely elevated ethanol concentration. METHODS: Patients with elevated lactic acid and LDH concentrations who presented to a university hospital from 20 April 2015 to 13 December 2015 were identified to provide possible test specimens. If a sufficient amount of serum was available, the sample was used to re-run the lactate and LDH concentration simultaneously with an enzymatic ethanol assay. Any samples that had elevated lactic acid and LDH concentrations on this retesting, and also yielded a positive ethanol concentration, were sent for confirmatory gas chromatography testing of ethanol concentrations. A control group of 20 samples with normal lactate and LDH were included. RESULTS: A total of 37 samples were included in the final analysis. Only 4 patients had an elevated enzymatic ethanol concentration, and all 4 also had a measurable GC ethanol concentration. The lactate in this dataset ranged from 2.4 to 24.2 mmol/L, with a mean of 6.53 mmol/L (normal value 0.5-2.2). The LDH ranged from 242 to 8838 U/L with a mean of 1695 U/L (normal value 122-225 U/L). Twenty control samples were run on patients with normal lactate and LDH, none of which yielded a positive enzymatic ethanol result. CONCLUSIONS: This data does not support the contention that an elevated LDH and lactate can yield a false positive serum ethanol result as run by enzymatic ethanol assay in live patients presenting to the emergency department. PMID- 28812383 TI - Evaluation of relationship between coronary artery status evaluated by coronary computed tomography angiography and development of cardiomyopathy in carbon monoxide poisoned patients with myocardial injury: a prospective observational study. AB - OBJECTIVES: Whether coronary artery changes are a main mechanism in the development of carbon monoxide (CO)-induced cardiomyopathy remains unknown. We investigated the effects of coronary artery stenosis on the presence or patterns of cardiomyopathy in CO-poisoned patients with myocardial injury defined as elevation of troponin I. MATERIALS AND METHODS: This prospective observational study collected data from consecutive patients who were diagnosed with CO poisoning and myocardial injury during the 24-month study period. Transthoracic echocardiography (TTE) and coronary computed tomography angiography (CCTA) were performed to evaluate cardiac function and coronary artery status. RESULTS: TTE and CCTA were performed in 32 consecutive patients. The observed echocardiographic patterns included non-cardiomyopathy (59.4%), left ventricular global dysfunction (25%), Takotsubo cardiomyopathy (6.3%), and cardiomyopathy matching the distribution of the left anterior descending (LAD) artery (9.4%). Four patients had more than moderate stenosis, while stenoses of the LAD, left circumflex, and right coronary arteries were observed in two (6.3%), three (9.4%), and zero patients, respectively. Patients with coronary artery stenosis did not develop cardiomyopathy except for one patient; this patient also did not have regional wall motion abnormalities (RWMA) matched with the stenosis territory. CONCLUSIONS: Because there was no difference in coronary artery stenosis according to the presence or patterns of CO-induced cardiomyopathy, coronary artery stenosis is not the main mechanism for the development of CO induced cardiomyopathy. Thus, the evaluation of coronary arteries is not necessary in all patients with CO-induced cardiomyopathy unless there is RWMA consistent with ischemic changes in electrocardiograms and elevated troponin I levels. PMID- 28812384 TI - Identification of risk factors associated with postoperative acute kidney injury after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: a retrospective study. AB - BACKGROUND: Acute kidney injury (AKI) is a postoperative complication associated with significant morbidity and mortality. The incidence and risks factors for AKI after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS HIPEC) have not been fully studied. The purpose of this study was to identify perioperative risk factors predictive of AKI after CRS-HIPEC. METHODS: This retrospective study collected demographic, tumour-related, intraoperative and postoperative data from 475 patients who underwent CRS-HIPECs. AKI was defined using the acute kidney injury network criteria and calculated on postoperative days 1, 2, 3, 7 and day of hospital discharge. We conducted univariate and multivariate analyses to assess the association between variables of interest and AKI. A p value of <0.05 was considered statistically significant. RESULTS: The incidence of AKI was 21.3%. The multivariate analysis identified six predictor factors independently associated with the development of AKI (OR: [95%CI]); age: 1.16 (1.05-1.29, p < 0.005), BMI (overweight: 1.97 [1.00-3.88], p = 0.05) and obesity: 2.88 (1.47-5.63), p < 0.002)), preoperative pregabalin: 3.04 (1.71-5.39, p < 0.037), platinum-based infusion: 3.04 (1.71-5.39, p < 0.001) and EBL: 1.77 (1.27-2.47, p < 0.001). Splenectomy had a protective effect (OR: 0.44 (0.25-0.76, p < 0.003). CONCLUSIONS: Our study demonstrates that the incidence of AKI is high. While other studies have reported that AKI is associated with platinum based infusion, age and obesity, we report for the first time a negative association between pregabalin use and AKI. More studies are needed to confirm our results. PMID- 28812385 TI - Increased acetaminophen related calls to Finnish PIC better reflect acetaminophen sales than serious poisonings. AB - OBJECTIVE: Acetaminophen (APAP) or paracetamol is a commonly encountered medicine in poisonings. We studied the changes in APAP related calls to the Finnish poison information centre (FPIC), and serious intoxications, involving hepatotoxicity or death in 2001-2014. These data were compared with paracetamol sales in Finland. METHODS: This is a retrospective analysis of the FPIC database calls, national cause of death registry, registries of liver transplantations and molecular adsorbent recycling system (MARS)-treated patients from Helsinki University Hospital together with the National Institute of Health and Welfare registry of patients hospitalized. Data on APAP sales were obtained from the Finnish Medicines Agency. RESULTS: Between 2001 and 2014, the number of calls/year related to human APAP exposures to the FPIC increased from 227 to 1058. No change in the age distribution of enquiries was seen. Most calls involved minors: 58% (range 52-64%) for children under 6 years old, and 9% (range 6-14%) for children of 6-15 years. In Finland, APAP related fatalities have gradually increased from an average of 7/year (range 4-10) in 2000-2005 to an average of 11/year (range 6 17) in 2010-2013, whereas the number of liver transplantations remained low, average 0.6/year (range 0-2). For patients in need of MARS-treatment, a slight decrease was seen. Total APAP sales increased from 5.6 (47% prescription, 53% OTC) to 29.7 (81% prescription, 19% OTC). DDD/1000 inhabitants/day from 2001 to 2014 is recorded. Best linear relationship (R2 = 0.97; p < .001) was observed between total FPIC calls and total sales of APAP in 2001-2014. Fatalities show a weaker relationship with sales (R2 = 0.317; p = .045). CONCLUSIONS: During the study period, we see an increase in FPIC exposure calls accompanied by an increase in APAP sales. Changes in the chosen indicators for serious poisonings show only a weak association. Despite an evident trend between sales and fatalities, the correlation with fatality remains weak due to the small number of fatalities. PMID- 28812386 TI - Reported use of technology in stroke rehabilitation by physical and occupational therapists. AB - PURPOSE: With the patient care experience being a healthcare priority, it is concerning that patients with stroke reported boredom and a desire for greater fostering of autonomy, when evaluating their rehabilitation experience. Technology has the potential to reduce these shortcomings by engaging patients through entertainment and objective feedback. Providing objective feedback has resulted in improved outcomes and may assist the patient in learning how to self manage rehabilitation. Our goal was to examine the extent to which physical and occupational therapists use technology in clinical stroke rehabilitation home exercise programs. MATERIALS AND METHODS: Surveys were sent via mail, email and online postings to over 500 therapists, 107 responded. RESULTS: Conventional equipment such as stopwatches are more frequently used compared to newer technology like Wii and Kinect games. Still, less than 25% of therapists' report using a stopwatch five or more times per week. Notably, feedback to patients is based upon objective data less than 50% of the time by most therapists. At the end of clinical rehabilitation, patients typically receive a written home exercise program and non-technological equipment, like theraband and/or theraputty to continue rehabilitation efforts independently. CONCLUSIONS: The use of technology is not pervasive in the continuum of stroke rehabilitation. Implications for Rehabilitation The patient care experience is a priority in healthcare, so when patients report feeling bored and desiring greater fostering of autonomy in stroke rehabilitation, it is troubling. Research examining the use of technology has shown positive results for improving motor performance and engaging patients through entertainment and use of objective feedback. Physical and occupational therapists do not widely use technology in stroke rehabilitation. Therapists should consider using technology in stroke rehabilitation to better meet the needs of the patient. PMID- 28812387 TI - Reply to 'Recent advances in systemic targeted therapy for cutaneous T-cell lymphoma'. PMID- 28812388 TI - Silk nanoparticles: proof of lysosomotropic anticancer drug delivery at single cell resolution. AB - Silk nanoparticles are expected to improve chemotherapeutic drug targeting to solid tumours by exploiting tumour pathophysiology, modifying the cellular pharmacokinetics of the payload and ultimately resulting in trafficking to lysosomes and triggering drug release. However, experimental proof for lysosomotropic drug delivery by silk nanoparticles in live cells is lacking and the importance of lysosomal pH and enzymes controlling drug release is currently unknown. Here, we demonstrate, in live single human breast cancer cells, the role of the lysosomal environment in determining silk nanoparticle-mediated drug release. MCF-7 human breast cancer cells endocytosed and trafficked drug-loaded native and PEGylated silk nanoparticles (~100 nm in diameter) to lysosomes, with subsequent drug release from the respective carriers and nuclear translocation within 5 h of dosing. A combination of low pH and enzymatic degradation facilitated drug release from the silk nanoparticles; perturbation of the acidic lysosomal pH and inhibition of serine, cysteine and threonine proteases resulted in a 42% +/- 2.2% and 33% +/- 3% reduction in nuclear-associated drug accumulation for native and PEGylated silk nanoparticles, respectively. Overall, this study demonstrates the importance of lysosomal activity for anticancer drug release from silk nanoparticles, thereby providing direct evidence for lysosomotropic drug delivery in live cells. PMID- 28812389 TI - Evolocumab for the treatment of hypercholesterolemia. AB - INTRODUCTION: Evolocumab is a fully human monoclonal immunoglobulin G2 directed against human proprotein convertase subtilisin/kexin type 9 (PCSK9). It is administered by subcutaneous injection every 2 weeks or once monthly. Area covered: Herein, the authors discuss the rationale for inhibiting PCSK9 and describe the pharmacodynamics, pharmacokinetics and clinical trials with evolocumab. Evolocumab reduces low density lipoprotein cholesterol (LDL-C) levels by 50 to 60% in most patients with and without background treatment with statins or other lipid lowering agents. The safety profile appears satisfactory from the completed clinical studies and concerns regarding the risk of neurocognitive events have largely been dispelled. Expert opinion: The reduction of LDL-C with evolocumab to previously unattainable levels has resulted in a reduction in the composite cardiovascular event endpoint in the FOURIER trial and this is likely to impact on future lipid management guidelines. The clinical outcome data and excellent tolerability profile clearly support the use of evolocumab in patients at high cardiovascular risk, including those with heterozygous or homozygous familial hypercholesterolemia, who are unable to achieve LDL-C targets with statins with or without other lipid-lowering drugs. The high cost of evolocumab will restrict its use, however. PMID- 28812390 TI - Response to comment by G. Borasi. PMID- 28812391 TI - pH-sensitive polymersomes: controlling swelling via copolymer structure and chemical composition. AB - pH-sensitive vesicles used as drug delivery systems (DDSs) are generally composed of protonable copolymers. The disaggregation of these nanoparticles (NPs) during drug release implies the dispersion of positively charged cytotoxic polyelectrolytes in the human body. To alleviate such issue, we synthesised A(BC)n amphiphilic block copolymers with linear (n = 1) and branched (n = 2) architectures to obtain pH-sensitive vesicles capable of releasing drugs in acidic conditions via controlled swelling instead of disaggregation. We obtained this feature by fine-tuning the relative amount of pH-sensitive and hydrophobic monomers. We studied pH-driven swelling by measuring NPs size in neutral and acidic conditions, the latter typical of tumours or inflamed tissues (pH~6) and lysosomes (pH~4.5). Dynamic light scattering (DLS) and zeta potential data provided useful indications about the influence of architecture and chemical composition on NPs swelling, stability and polycation release. Results demonstrated that vesicles made of linear copolymers with ~22-28% in mol of protonable monomers in the 'BC' block swelled more than other species following a pH change from pH 7.4 to pH 4.5. We finally evaluated the cytotoxicity of vesicles composed of linear species, and paclitaxel (PTX) release from the latter in both cancer and normal cells. PMID- 28812392 TI - Psychometric properties of the performing arts module of the Disabilities of the Arm, Shoulder, and Hand questionnaire. AB - BACKGROUND: The Disabilities of the Arm, Shoulder, and Hand questionnaire (DASH) offers an optional performing arts module. The goal was to examine the psychometric properties of this module in musicians. METHODS: This study is a secondary analysis of a randomized controlled trial on the effectiveness of a biopsychosocial intervention to prevent or reduce playing-related disability in conservatory students. Baseline data were used to examine internal consistency and discriminative validity of the performing arts module of the DASH questionnaire. Construct validity was analyzed by hypotheses testing. The performing arts module outcomes were compared to scores from the general DASH questionnaire, pain disability index, Short-Form 36, playing-related musculoskeletal disorder (PRMD) intensity, and pain intensity. RESULTS: Questionnaires completed by 130 conservatory students were analyzed, 55% of the population was female. Median age was 20 years (IQR 4). The performing arts module showed good internal consistency (Cronbach's alpha 0.893). Discriminative validity between students with and without PRMDs was good. Three out of six hypotheses were accepted, indicating moderate construct validity. CONCLUSIONS: The performing arts module showed good internal consistency, good discriminative validity and moderate construct validity in a population of conservatory students. Implications for Rehabilitation Musicians suffer frequently from musculoskeletal disorders, mostly in the upper extremity. The Disabilities of the Arm, Shoulder, and Hand questionnaire is a well-known outcome measure, which also includes a performing arts module. This study is the first to explore psychometric properties of the performing arts module. The performing arts module of the Disabilities of the Arm, Shoulder, and Hand questionnaire showed good internal consistency, good discriminative validity, and moderate construct validity. PMID- 28812393 TI - Innate lymphoid cells: the role in respiratory infections and lung tissue damage. AB - INTRODUCTION: Innate lymphoid cells (ILCs) represent a diverse family of cells of the innate immune system, which play an important role in regulation of tissue homeostasis, immunity and inflammation. Emerging evidence has highlighted the importance of ILCs in both protective immunity to respiratory infections and their pathological roles in the lungs. Therefore, the aim of this review is to summarize the current knowledge, interpret and integrate it into broader perspective, enabling greater insight into the role of ILCs in respiratory diseases. Areas covered: In this review we highlighted the role of ILCs in the lungs, citing the most recent studies in this area. PubMed searches (2004- July 2017) were conducted using the term 'innate lymphoid cells respiratory viral infections' in combination with other relevant terms including various respiratory viruses. Expert commentary: Since studies of ILCs have opened new areas of investigation, understanding the role of ILCs in respiratory infections may help to clarify the mechanisms underlying viral-induced exacerbations of lung diseases, providing the basis for novel therapeutic strategies. Potential therapeutic targets have already been identified. So far, the most promising strategy is cytokine-targeting, although further clinical trials are needed to verify its effectiveness. PMID- 28812394 TI - The use of sustained low efficiency dialysis (SLED) in massive paracetamol overdose. AB - CONTEXT: Massive paracetamol ingestion causing mitochondrial dysfunction is uncommon. Use of sustained low-efficiency dialysis (SLED) to improve acidaemia and enhance paracetamol elimination has not been previously described. CASE DETAILS: A 44-year-old male presented to the emergency department 2.5 hours post overdose of 200 g (2.5 g/kg) of paracetamol. Examination revealed a BP 85/60 mmHg, pulse 112 bpm, temperature 33.9 degrees C and blood glucose of 13.9 mmol/l. Venous blood gas 5.5-hours post-ingestion showed a pH 6.9, pCO2 58 mmHg, HCO3 13 mmol/l and lactate 14 mmol/l. Fifty-grams of nasogastric activated charcoal and double-strength intravenous acetylcysteine were administered. Paracetamol concentration peaked at 4207 umol/l six hours post-ingestion. SLED was commenced nine-hours post ingestion and acetylcysteine dose was doubled again during dialysis. Paracetamol extraction ratio was 47-52%. Plasma paracetamol clearance was steady throughout SLED (53-58 ml/min). Hepatotoxicity did not develop and the patient recovered. DISCUSSIONS: Intermittent hemodialysis (IHD) is more efficient than SLED or continuous renal replacement therapy for enhancing paracetamol elimination and clearance. IHD plasma clearance is reported to range from 36 to 215 ml/min compared with endogenous clearance of 224 ml/70 kg/min. CONCLUSIONS: SLED improved acidaemia with only moderate overall increase in paracetamol plasma clearance. Lack of development of hepatotoxicity was likely the result of early administration of acetylcysteine rather than any effect of SLED on paracetamol elimination. PMID- 28812395 TI - Current research on circular RNAs associated with colorectal cancer. AB - Representing a novel type of endogenous noncoding RNAs, circular RNAs (circRNAs) have recently gained much attention for their involvement in multiple biological processes. CircRNAs are ubiquitously expressed in eukaryotic cells and modulate gene expression by acting as sponges of microRNAs (miRNAs) or other proteins, such as RNA-binding proteins (RBPs). Due to their unique structure, circRNAs are more stable than linear RNAs. Expression profiles of circRNAs are associated with clinicopathological characteristics of colorectal cancer patients, such as differentiation, TNM classification and distant metastasis. Furthermore, circRNAs play crucial roles in multiple processes associated with malignant phenotypes, including cell proliferation/cycle, apoptosis and invasion. Improvements in RNA sequencing methods have helped researchers to elucidate molecular interactions between circRNAs and colorectal cancer. This review provides a comprehensive overview of the features and functions of circRNAs, as well as insights into their roles in the onset and development of colorectal cancer. Combined with the reported results, the identification of circRNAs associated with colorectal cancer will certainly contribute to early detection and help to design treatment strategies for colorectal cancer. Screening for circRNAs may provide an accessible, noninvasive yet highly sensitive diagnosis for colorectal cancer. Furthermore, a better understanding of the roles of circRNAs may also provide a novel predictive feature in colorectal cancer therapy and prognosis. PMID- 28812396 TI - The influence of lower-limb prostheses technology on Paracanoeing time-trial performance. AB - Within the Paracanoeing discipline, it is important to ensure that appropriate control is achieved by a paddler with a disability. However, this Paralympic Games discipline has seen very little attention to date. The aims of this study were to understand the kinematic impact to a paracanoeist when not utilizing the use of a prosthetic lower-limb. A kayaker with a uni-lateral transfemoral amputation completed several 200 m maximal efforts both with and without their prosthesis. When the prosthetic limb was removed, there were significant differences found in stroke rate, stroke speed, stroke length and overall power output. Sagittal and frontal video analysis demonstrated the residual limb movements when paddling and indicated where support would be required to improve the kayak's control. It is recommended that those with lower-limb absence wishing to paddle a kayak competitively utilize the use of a prostheses designed for the kayaking environment that supports the residual limb at both the upper and inner thigh and the distal end. Implications for rehabilitation This paper is the first study to investigate both biomechanical and assistive technology-related issues in the new Paralympic Games sport of Paracanoeing. For participants possessing lower-limb absence, a prosthetic limb that is designed specifically for the kayaking environment is recommended when Paracanoeing to maximize efficient propulsion. Use of an ergometer and multiple 2D cameras provides practitioners the ability to optimize both the comfort and fit of a prosthetic limb. Use of an ergometer and multiple 2D cameras provides both athletes and practitioners the ability to optimize the points of human contact within a kayak to ensure comfort and control. PMID- 28812397 TI - To what extent can soft-tissue releases improve hip displacement in cerebral palsy? AB - Background and purpose - Hip displacement is frequent in nonambulatory children with cerebral palsy (CP) and treatment is controversial. This prospective study assesses the effectiveness of soft-tissue releases to treat hip subluxation, analyses prognostic factors for outcome, and identifies time to failure in hips with poor outcome. Patients and methods - 37 children (16 girls) with hip subluxation were recruited from the population-based screening program for children with CP in Norway. They had consecutively undergone soft-tissue releases (bilateral tenotomies of adductors and iliopsoas) at a mean age of 5.0 (2.8-7.2) years. Functional classification was Gross Motor Function Classification System (GMFCS) level III in 9 children, level IV in 10, and level V in 18 children. The outcome was termed good if the patient had not undergone further hip surgery and if the migration percentage (MP) of the worst hip at the latest follow-up was <50%. The mean follow-up time was 7.3 (5.1-9.8) years. Results - The outcome was good in all the ambulatory children and in 17 of 28 of the nonambulatory children. The only independent preoperative risk factor for poor outcome was MP >=50%. The mean time to failure was 2.2 (1-5) years postoperatively and the reasons for failure were insufficient initial correction and later deterioration of displacement. Interpretation - Bilateral soft-tissue release is recommended in both ambulatory and nonambulatory children with hip sub-luxation. The operation should be performed before the hip displacement reaches 50%. PMID- 28812399 TI - Canthal cutdown for emergent treatment of orbital compartment syndrome. AB - This article evaluates the use of a "canthal cutdown" technique in orbital compartment syndrome in a cadaveric model. Twelve cadaver orbits were used to simulate orbital compartment syndrome using a blood analog solution. Two pressure probes, in different orbital locations, were used to monitor orbital pressure. Pressure was monitored during successive procedures: canthotomy, cantholysis, and canthal cutdown. Orbits were then re-injected with solution, simulating an active orbital hemorrhage, and pressure measurements were recorded over a 10-minute duration. No statistically significant difference was found between the two orbital pressure monitoring devices at each measurement point (p = 0.99). Significant pressure reductions, for both probes, were observed after canthal cutdown compared to initial measurement after injection of 20 mL blood analog (p < 0.001 and p = 0.005). When comparing the orbital pressure following canthotomy and inferior cantholysis versus canthal cutdown, the cutdown procedure provided an additional 74% in orbital pressure reduction (p =0.01). After re-injection of 10 mL of solution and 10 minutes of egress, pressure returned to baseline (probe 1: baseline 7 mm Hg vs. post-cutdown at 10 minutes 7 mm Hg; p = 0.83; and probe 2: 5 mm Hg vs. 5 mm Hg; p = 0.83). The canthal cutdown technique provides further reduction in orbital pressure versus canthotomy and cantholysis alone. The technique may be effective for treatment of static orbital compartment syndrome and temporizing treatment of compartment syndrome from active orbital hemorrhages. PMID- 28812398 TI - Specific exercises for subacromial pain. AB - Background and purpose - We have previously shown that specific exercises reduced the need for surgery in subacromial pain patients at 1-year follow-up. We have now investigated whether this result was maintained after 5 years and compared the outcomes of surgery and non-surgical treatment. Patients and methods - 97 patients were included in the previously reported randomized study of patients on a waiting list for surgery. These patients were randomized to specific or unspecific exercises. After 3 months of exercises the patients were asked if they still wanted surgery and this was also assessed at the present 5-year follow-up. The 1-year assessment included Constant-Murley score, DASH, VAS at night, rest and activity, EQ-5D, and EQ-VAS. All these outcome assessments were repeated after 5 years in 91 of the patients. Results - At the 5-year follow-up more patients in the specific exercise group had declined surgery, 33 of 47 as compared with 16 of 44 (p = 0.001) in the unspecific exercise group. The mean Constant-Murley score continued to improve between the 1- and 5-year follow-ups in both surgically and non-surgically treated groups. On a group level there was no clinically relevant change between 1 and 5 years in any of the other outcome measures regardless of treatment. Interpretation - This 5-year follow-up of a previously published randomized controlled trial found that specific exercises reduced the need for surgery in patients with subacromial pain. Patients not responding to specific exercises may achieve similar good results with surgery. These findings emphasize that a specific exercise program may serve as a selection tool for surgery. PMID- 28812400 TI - New benzodiazepine and Z-hypnotic users and disability pension: an eight-year nationwide observational follow-up study. AB - OBJECTIVE: To compare how newly initiated treatment with benzodiazepines, Z hypnotics or both associates with the reception of disability pension among 40,661 individuals of a working age. DESIGN: Prescription register study. SETTING: Norwegian nationwide prescriptions socio-economic and disability status data. METHODS: Cox regression analyses. SUBJECTS: New benzodiazepine or Z hypnotic users. MAIN OUTCOME MEASURE: Time to receive disability pension given benzodiazepine or Z-hypnotic use or both. Additional analyses focused on the benzodiazepine first redeemed. RESULTS: Among new users 8.65% of Z-hypnotic users, 12.29% of benzodiazepines users and 13.96% of combined Z-hypnotic and benzodiazepine users became disability pensioners. Z-hypnotic users were weaker associated with becoming disability pensioners (HR = 0.78, CI: 0.73-0.84) and combined users were stronger associated (HR = 1.09, CI: 1.01-1.17), than benzodiazepine users. Women had higher risk than men for becoming disability pensioners. Higher age, lower education, previous drug use and psychiatrist as first prescriber were risk factors. Comparing first benzodiazepine redeemed; clonazepam initiators were stronger associated with becoming disability pensioners than diazepam initiators were (HR = 2.22, CI: 1.81-2.71). No differences between other benzodiazepine users were found. CONCLUSIONS: Adjusting for known risk factors gave lower risk for Z-hypnotic users compared to benzodiazepine users for receiving disability pension. Combined use increased the risk further. Clonazepam initiators are especially at risk. These findings may be helpful in prescribing situations to identify and guide individuals at risk for becoming disability pensioners. PMID- 28812401 TI - Management of complicated skin and skin structure infections - a call for infectious disease specialists. PMID- 28812402 TI - Older persons' experiences of a home-based exercise program with behavioral change support. AB - BACKGROUND: It is a challenge to promote exercise among older persons. Knowledge is needed regarding the maintenance of exercise aiming at preventing falls and promoting health and well-being in older persons. PURPOSE: This descriptive study used a qualitative inductive approach to describe older persons' experiences of a fall-preventive, home-based exercise program with support for behavioral change. METHODS: Semi-structured interviews were conducted with 12 elderly persons aged 75 years or older, and a qualitative content analysis was performed. RESULTS: Four categories emerged: facilitators of performing exercise in everyday life, the importance of support, perceived gains from exercise, and the existential aspects of exercise. CONCLUSION: With support from physiotherapists (PTs), home based exercise can be adapted to individual circumstances in a meaningful way. Including exercises in everyday life and daily routines could support the experience of being stronger, result in better physical functioning, and give hope for an extended active life in old age. PMID- 28812403 TI - Text messaging (SMS) as a tool to facilitate weight loss and prevent metabolic deterioration in clinically healthy overweight and obese subjects: a randomised controlled trial. AB - OBJECTIVE: To examine whether SMS text messaging facilitates a reduction of weight and waist circumference (WC) and favourable changes in lipid profile and insulin levels in clinically healthy overweight and obese subjects. DESIGN: A randomised controlled trial. SETTING AND INTERVENTION: Primary care health centre in Riga, Latvia. Text messaging once in two weeks. SUBJECTS: A total of 123 overweight and obese men and women aged 30-45 years with no cardiovascular diseases (CVDs) or diabetes. MAIN OUTCOME MEASURES: changes in anthropometric parameters (weight, WC, body mass index (BMI)) and biochemical parameters (lipids, fasting glucose and insulin). RESULTS: We found a statistically significant decrease in weight (2.4%), BMI and WC (4.8%) in the intervention group, while the control group showed a statistically non-significant increase in weight and BMI and decrease in WC. Between group results obtained over the course of a year showed statistically significant mean differences between weight (-3.4 kg (95% CI -5.5, -1.3)), BMI kg/m2 (-1.14 (95% CI -1.9, -0.41)), WC (-4.6 cm (95% CI -6.8, -2.3)), hip circumference (-4.0 cm (95% CI -5.9, -2.0)) and fasting insulin (2.43 MUU/ml (95% CI 0.6, 4.3)). Mean differences of changes in glucose and lipid levels were statistically non significant: fasting glucose (-0.01 mmol/l (95% CI -0.19, 0.17)), TC mmol/l (-0.04 mmol/l (95% CI -0.29, 0.21)), HDL C (0.14 mmol/l (95% CI -0.65, 0.09)), LDL-C (-0.02 mmol/l (95% CI -0.22, 0.18)) and TG (0.23 mmol/l (95% CI -0.06, 0.52)). CONCLUSIONS: SMS messaging in clinically healthy overweight and obese subjects facilitates a slight decrease in weight, BMI and WC. It is anticipated that the implications of this strategy might facilitate the design of preventive and promotive strategies among high risk groups in Latvia. PMID- 28812404 TI - Effects of a low-resistance, interval bicycling intervention in Parkinson's Disease. AB - Previous studies have shown that people with Parkinson's disease (PD) benefit from a variety of exercise modalities with respect to symptom management and function. Among the possible exercise modalities, speedwork has been identified as a promising strategy, with direct implications for the rate and amplitude of nervous system involvement. Considering that previous speed-based exercise for PD has often been equipment, personnel and/or facility dependent, and often time intensive, our purpose was to develop a population-specific exercise program that could be self-administered with equipment that is readily found in fitness centers or perhaps the home. Fourteen individuals with PD (Hoehn-Yahr (H-Y) stage of 3.0 or less) participated in twelve 30-min sessions of low-resistance interval training on a stationary recumbent bicycle. Motor examination section of the Unified Parkinson's Disease Rating Scale (UPDRS), 10-meter walk (10mW), timed-up and-go (TUG), functional reach, four-square step test (4SST), nine-hole peg test (9HPT) and simple reaction time scores all exhibited significant improvements (p < 0.05). These results add further support to the practice of speedwork for people with PD and outline a population-amenable program with high feasibility. PMID- 28812405 TI - Simple screening tools predict death and cardiovascular events in patients with rheumatic disease. AB - OBJECTIVES: Patients with rheumatic disease (RD) have an increased mortality risk compared with the general population, mainly due to cardiovascular disease (CVD). We aimed to identify patients at high risk of CVD and mortality by comparing three screening tools suitable for clinical practice. METHOD: In this prospective, single-centre study, consecutive patients with rheumatoid arthritis (RA), systemic autoimmune disease (SAI), or spondyloarthritides (SpA) including psoriatic arthritis underwent a comprehensive cardiovascular risk assessment. Patients were predefined as being at high risk for cardiovascular events or death if any of the following were present: European Systematic COronary Risk Evaluation (SCORE) >= 3%, N-terminal pro-brain natriuretic peptide (NT-proBNP) >= 200 pg/mL, or any pathological electrocardiogram pattern. RESULTS: The patient population (n = 764) comprised 352 patients with RA, 260 with SAI, and 152 with SpA. After a median follow-up of 5.2 years, 6.0% of RD patients had died (7.0%, 7.2%, and 1.4% of patients in the RA, SAI, and SpA subgroups), and 5.0% had experienced a cardiovascular event (5.0%, 6.4%, and 2.8%, respectively). For all RD patients and the RA and SAI subgroups, NT-proBNP >= 200 pg/mL and SCORE >= 3% identified patients with a 3.5-5-fold increased risk of all-cause death and cardiovascular events. Electrocardiogram pathology was associated with increased mortality risk, but not with cardiovascular events. CONCLUSION: NT-proBNP >= 200 pg/mL or SCORE >= 3% identifies RA and SAI patients with increased risk of cardiovascular events and death. Both tools are suitable as easy screening tools in daily practice to identify patients at risk for further diagnostics and closer long-term follow-up. PMID- 28812406 TI - Types of orbital osteoma - A descriptive analysis. AB - AIMS: This study describes different types of orbital osteoma based on clinical per-operative morphology and radiological findings to facilitate communication between ophthalmologists and surgical management for a better patient outcome. MATERIALS AND METHODS: The study was conducted in the Orbit and Oculoplastics Department of Al-Shifa Trust Eye Hospital, Rawalpindi, Pakistan, from July 1, 2001 to June 30, 2014. A retrospective analysis of 520 diagnosed orbital tumours who presented to us was carried out and the prevalence of orbital osteoma was determined. The sampling technique was non-randomized sampling. Based on the clinical morphology observed during surgical intervention as well as the radiological findings of the orbital osteoma, a simple yet useful description of orbital osteoma was introduced. RESULTS: The retrospective analysis of 520 diagnosed orbital tumours revealed a prevalence of 2.3% (n = 12) of orbital osteoma. Based on our observation of the 12 (n = 12) cases of orbital osteoma, we have classified orbital osteoma into a combination of seven types: "sessile" or broad-based osteoma; "pedunculated" or mushroom osteoma with a thin cylindrical stalk of origin; "dumb-bell"-shaped osteoma with the simultaneous presence in orbital and adjoining sinus/nasal cavity; "wrapped" osteoma, covered by a thin cartilaginous layer; "naked" osteoma, without any such covering; "homogenous" or uniformly dense osteoma; and "heterogeneous", soft-dense osteoma with varying areas of density. CONCLUSION: This study attempts to introduce a simple description of different types of orbital osteoma based on clinical per-operative morphology and radiological findings for the first time to facilitate the surgical removal of orbital osteoma. PMID- 28812407 TI - Scaling the punctum and canaliculus in patients undergoing punctoplasty surgery: A prospective cohort study. AB - Optical Coherence Tomography (OCT) is a safe and non-invasive method of high resolution cross-sectional imaging of tissue microstructures using infrared radiation. This study investigates how the appearance of the punctum and proximal canaliculus differs pre- and post-operatively in patients undergoing punctoplasty surgery. Patients with symptomatic punctal stenosis warranting punctoplasty surgery were prospectively invited to enrol from a single centre. Spectral OCT images of the lower punctae were captured with a Topcon 3D OCT 2000 machine pre- and post-operatively (at their follow-up appointment). Measurements were made of the maximal punctal diameter, canalicular diameter and canalicular depth. Pre- and post-operative measurements were compared using a paired t-test. Twenty-three punctae of 18 patients with punctal stenosis were included in the study. They were 10 males and 8 females with a median age 71.0 (SD 12.1). Mean canalicular cross-sectional area was 56.9 * 10-3 mm2 pre-operatively and 267.2 * 10-3 mm2 post-operatively, showing a statistically significant increase (p = 0.0004). There was an increase in both mean canalicular width (0.253 to 0.524mm (p = 0.0001)) and depth (0.433 to 0.852mm (p = 0.0001)) from pre- to post-operatively. There was a significant improvement in symptoms from pre- to post-operatively, as measured subjectively by the Lac-Q questionnaire (p = 0.021). This study describes the change in the appearance of the punctum and proximal canaliculus in patients undergoing punctoplasty operations, by using spectral OCT to capture in vivo high-resolution images. It demonstrates that punctal OCT can be successfully applied to quantify the morphological changes of the punctum and canaliculus pre- and post-punctoplasty. PMID- 28812408 TI - Calcium pyrophosphate deposition disease: a frequent finding in patients with long-standing erosive gout. AB - OBJECTIVE: To characterize patients with both monosodium urate (MSU) and calcium pyrophosphate (CPP) crystals in their synovial fluid (SF). METHOD: Forty-nine gout patients with acute arthritis were included. Those patients with MSU crystals only in their SF were compared to those patients with both MSU and CPP crystals in their SF. RESULTS: A total of 36 out of 49 patients (73.5%) had only MSU crystals, whereas 13 out of 49 (26.5%) had both MSU and CPP crystals in their SF. Co-deposition of CPP crystals was associated with long-standing gout disease (p = 0.022), kidney dysfunction (p = 0.024), and erosive arthritis (p = 0.049), but not with age. CONCLUSION: Long-standing gout may be a risk factor for CPP deposition disease, and the frequency of CPP co-deposition may be higher than expected. PMID- 28812409 TI - Tumor reduction and symptom relief after electrochemotherapy in a patient with aggressive fibromatosis - a case report. PMID- 28812410 TI - Good outcome scores and high satisfaction rate after primary total ankle replacement. AB - Background and purpose - Total ankle replacement (TAR) is gaining popularity for treatment of end-stage ankle arthritis. Large patient-centered outcome studies are, however, few. Here, we report data from the Swedish Ankle Registry. Patients and methods - We examined outcomes after primary TAR in patients from the Swedish Ankle Registry using PROMs (Patient Reported Outcome Measures; generic: EQ-5D and SF-36, region specific: SEFAS (Self-Reported Foot and Ankle Score), and a question on satisfaction). We included 241 patients registered with primary TAR between 2008 and 2016 and who completed PROMs preoperatively and postoperatively up to 24 months. We evaluated changes in PROMs following surgery and estimated effects of age, diagnosis, prosthetic design, and preoperative functional score on the outcomes. Results - All absolute scores improved from preoperative to 24 months after surgery (p <= 0.001). 71% of the patients were satisfied or very satisfied at the latest follow-up and 12% dissatisfied or very dissatisfied. Postoperative SEFAS correlated with age (r = 0.2, p = 0.01) and preoperative SEFAS (r = 0.3, p < 0.001), as did patient satisfaction (r = -0.2; p <= 0.03). Postoperative SEFAS and EQ-5D were similar between different diagnoses or prosthetic designs. Preoperative SF-36 was associated with diagnosis (p <= 0.03), postoperative SF-36 with age (r = 0.2, p = 0.01) and diagnosis (p < 0.03). Interpretation - We found statistically and clinically significant improvements in patient-reported outcomes following TAR surgery. The postoperative region specific SEFAS was positively associated with older age. Prosthetic design seemed not to influence patient-reported outcome, whereas diagnosis partly did. Studies with longer follow-up are necessary to establish the long-term outcome of TAR and to elucidate whether short- and mid-term outcomes may predict implant failure. PMID- 28812411 TI - Earlier may be better: the role of extracorporeal photopheresis (ECP) as prevention of GVHD after allogeneic transplant. PMID- 28812412 TI - An investigation into discharge, visual perception, and appearance concerns of prosthetic eye wearers. AB - We investigate prosthetic eye wearers' initial and current concerns about mucoid discharge, visual perception, and appearance, and the reasons for their concerns. A retrospective, cross-sectional study of private practice patients was designed. Participants were 217 experienced prosthetic eye wearers, aged at least 16 years. An anonymous questionnaire was e-mailed or mailed to participants. Descriptive and inferential statistics were used to investigate differences or correlations between variables. Content analysis was used to analyze participants' open responses. Participants were equally concerned about discharge, visual perception, and appearance during the first three months following eye loss and at least 2 years later, even though their concerns decreased. Older participants were less concerned about appearance, while females were more concerned about current discharge and appearance. The greater the frequency and volume of discharge, the greater was the concern. Participants' initial discharge concern was due to a negative interpretation of what it meant, but later, it was due to discomfort from wiping, and how discharge looked to others. Loss of depth perception and reduced visual range were equally concerning. Initial appearance concerns related to disguisability of the prosthesis, but over time, changes to the socket and eyelids became more important. Loss of self-image is commonly considered to be the major concern of anophthalmic patients, but discharge and visual perception concerns are of equal importance. Reasons given for these concerns provide greater insight into patients' personal experience of eye loss. PMID- 28812413 TI - Unusual retinopathy in a child with severe combined immune deficiency. AB - We describe a case of an infant diagnosed with severe combined immune deficiency (Adenosine Deaminase (ADA), SCID) with severe retinopathy and associated low vision in both eyes at first examination. An extensive infectious work up revealed an enterovirus infection, which suggested an early infectious and severe retinopathy. Genetic causes of congenital retinitis pigmentosa/ Leber's congenital amaurosis could be excluded by whole exome sequencing. PMID- 28812415 TI - Quality of life after orbito-facial trauma. AB - In the wake of high incidence of orbito-facial trauma, there has been a growing need to assess not only the visual outcome, but also the psychological impact of the traumatic event. This is a single questionnaire based evaluation of 100 consecutive patients with orbito-facial trauma (blow-out and Le fort type II and III fractures) at six months of trauma. 84% of the patients had a NEI VFQ- 25 score of less than 50, with 49% having a score less than 25, reflecting the grim impact the trauma has on the quality of life. The three parameters of the questionnaire - general health, difficulty with activities and response to vision problems were significantly positively correlated. Quality of life is considerably affected following orbito-facial trauma, disturbing physical, mental and social health. Poor vision is positively correlated with poor general health. Psycho-social impact of trauma needs to be recognized as an important sphere in the management of orbito-facial trauma. PMID- 28812414 TI - Adipokine genes and radiographic hand osteoarthritis in Finnish women: a cross sectional study. AB - OBJECTIVES: Available evidence suggests that genetic factors and overweight play major roles in the aetiology of osteoarthritis (OA). We analysed the association of 18 single-nucleotide polymorphisms (SNPs) from nine adipokine and adipokine receptor genes (LEP, LEPR, ADIPOQ, RETN, NAMPT, SERPINA12, ITLN1, RARRES2, and APLN) with radiographic hand OA. METHOD: The study design was cross-sectional. Bilateral hand radiographs of 542 occupationally active Finnish female dentists and teachers aged 45-63 years were examined and classified for the presence of hand OA using reference images. Hand OA was defined as at least three finger joints with radiographic OA of grade 2-4. The genotypes were determined using polymerase chain reaction-based methods. Body mass index (BMI) was calculated based on self-reported height and measured weight. Associations of the individual SNPs and their haplotypes with hand OA were tested using logistic regression analysis. RESULTS: The minor allele of RETN rs10401670 was associated with a decreased [odds ratio (OR) = 0.73, 95% confidence interval (CI) 0.55-0.97, p = 0.03] and RARRES2 rs4721 with an increased (OR 1.41, 95% CI 1.07-1.87, p = 0.01) prevalence of hand OA. Also, LEPR AC (OR 1.54, 95% CI 1.01-2.35, p = 0.05) and RETN GGTT (OR 0.58, 95% CI 0.37-0.93, p = 0.02) haplotypes were associated with hand OA. These associations were modified by BMI when comparing normal and overweight women. However, the associations lost their statistical significance after adjusting for multiple testing. CONCLUSION: Our results suggest weak associations between the studied variations in LEPR, RARRES2, and RETN genes and hand OA in Finnish women, and that the associations are modified by BMI. However, these associations could not be verified in the current study. PMID- 28812417 TI - Lacrimal gland abscesses: Case series and literature review. AB - Acute dacryoadenitis with abscess formation has been rarely described. We describe four cases that resolved with incision and drainage. This includes a retrospective case series of four patients with radiologically confirmed lacrimal gland abscesses and a review of the reported cases in the literature. Computed tomography showed characteristic rim enhancing collections with central attenuation in all four cases. All patients presented with ptosis, upper eyelid erythema, and severe pain similar to scleritis. Injection of the conjunctiva and sclera was present in two patients, and a third patient presented with expression of purulent discharge onto the ocular surface upon palpation of the lacrimal gland. All patients were treated with intravenous antibiotics and underwent incision and drainage with subsequent improvement. All were monitored for 24 to 48 hours and discharged on oral antibiotics. There were no complications or recurrences. Lacrimal gland abscess formation is a rare complication of dacryoadenitis, and in our experience these patients respond well to incision and drainage in combination with systemic antibiotics. PMID- 28812418 TI - Neurotoxicity of cGMP in the vertebrate retina: from the initial research on rd mutant mice to zebrafish genetic approaches. AB - Zebrafish are an excellent animal model for research on vertebrate development and human diseases. Sophisticated genetic tools including large-scale mutagenesis methodology make zebrafish useful for studying neuronal degenerative diseases. Here, we review zebrafish models of inherited ophthalmic diseases, focusing on cGMP metabolism in photoreceptors. cGMP is the second messenger of phototransduction, and abnormal cGMP levels are associated with photoreceptor death. cGMP concentration represents a balance between cGMP phosphodiesterase 6 (PDE6) and guanylate cyclase (GC) activities in photoreceptors. Various zebrafish cGMP metabolism mutants were used to clarify molecular mechanisms by which dysfunctions in this pathway trigger photoreceptor degeneration. Here, we review the history of research on the retinal degeneration (rd) mutant mouse, which carries a genetic mutation of PDE6b, and we also highlight recent research in photoreceptor degeneration using zebrafish models. Several recent discoveries that provide insight into cGMP toxicity in photoreceptors are discussed. PMID- 28812416 TI - Role of branchiomotor neurons in controlling food intake of zebrafish larvae. AB - The physical act of eating or feeding involves the coordinated action of several organs like eyes and jaws, and associated neural networks. Moreover, the activity of the neural networks controlling jaw movements (branchiomotor circuits) is regulated by the visual, olfactory, gustatory and hypothalamic systems, which are largely well characterized at the physiological level. By contrast, the behavioral output of the branchiomotor circuits and the functional consequences of disruption of these circuits by abnormal neural development are poorly understood. To begin to address these questions, we sought to evaluate the feeding ability of zebrafish larvae, a direct output of the branchiomotor circuits, and developed a qualitative assay for measuring food intake in zebrafish larvae at 7 days post-fertilization. We validated the assay by examining the effects of ablating the branchiomotor neurons. Metronidazole mediated ablation of nitroreductase-expressing branchiomotor neurons resulted in a predictable reduction in food intake without significantly affecting swimming ability, indicating that the assay is robust. Laser-mediated ablation of trigeminal motor neurons resulted in a significant decrease in food intake, indicating that the assay is sensitive. Importantly, in larvae of a genetic mutant with severe loss of branchiomotor neurons, food intake was abolished. These studies establish a foundation for dissecting the neural circuits driving a motor behavior essential for survival. PMID- 28812419 TI - The effects of exergaming and treadmill training on gait, balance, and cognition in a person with Parkinson's disease: A case study. AB - BACKGROUND: Parkinson's disease (PD) commonly impairs posture, gait, and cognition. Exercise in the form of aerobic activity as well as exergaming may improve motor ability and cognition in persons with PD. Exergaming and treadmill training can be a practical form of exercise within the home; however, there is minimal research on this combined multimodal intervention for persons with PD. OBJECTIVE: We investigated the effects of this combined intervention on cognition, balance, and gait in a person with PD through supervised lab sessions augmented by home-based sessions. METHODS: This case study utilized an ABA single subject experimental design with 4 weeks of pre-intervention, followed by 8 weeks of intervention, and 4 weeks of post-intervention. The intervention consisted of treadmill walking and Xbox Kinect exergaming, 30 minutes each, performed unsupervised at home and at supervised lab sessions. The two standard deviation band method was used to determine significance. RESULTS: MiniBEST test, 2-minute walk distance, sway area, endurance test, and a few parameters of gait initiation and gait improved significantly throughout the intervention period. Only a few measures sustained the improvement 4 weeks after completion of intervention. CONCLUSION: Eight weeks of treadmill and exergaming intervention with a person with PD improved static and dynamic postural control measures, but not gait, cognition, endurance, and clinical measures of balance. Longer and more intense multimodal intervention may be warranted. PMID- 28812420 TI - A Novel Approach for Streamlining Delivery of Brief Motivational Interventions to Mandated College Students: Using Group and Individual Sessions Matched to Level of Risk. AB - BACKGROUND: Mandated college students (those in violation of a campus alcohol policy) are heterogenous with respect to alcohol consumption. Thus, when universities consider required treatment for mandated students, one promising option is to match treatment intensity according to level of alcohol involvement. The present study evaluates such an approach with minimal resources. METHODS: Mandated students (N = 285) were required to complete a baseline assessment. Participants identified as high-risk (5+ past month alcohol problems AND 2+ past month heavy drinking episodes) received a one session individual Brief Motivational Intervention (I-BMI) whereas those identified as low-risk (all others) received a one session group Brief Motivational Intervention (G-BMI). I BMI and G-BMI sessions were delivered by doctoral students in Clinical Psychology. Follow-up assessments were collected 1 month post-intervention (response rate = 73%). RESULTS: The vast majority of students complied with their requirement. Participants assigned to I-BMI reported an 82% reduction in drinks per week, a 58% reduction in heavy episodic drinking, and a 74% reduction in alcohol-related problems at a 1 month follow-up. Participants assigned to G-BMI reported a 61% reduction in drinks per week and a 42% reduction in alcohol related problems at follow-up relative to baseline. Conclusion/Importance: We demonstrate that matching intervention intensity on baseline alcohol involvement with mandated students is feasible and associated with short-term reductions in alcohol use and consequences. Universities may wish to consider the procedure outlined here as a way of allocating more resources to those who drink at problematic levels. PMID- 28812421 TI - Right hemispatial ipsilesional neglect with chronic right hemisphere strokes. AB - BACKGROUND: Patients who present with spatial neglect after stroke often perform normally on tests for neglect after a few weeks. Whereas tests for neglect are often performed directly in front of a patient, in their actual environments many important stimuli may be present within their left or right hemispace. The presence and severity of neglect often depends on the hemisphere injured. It is possible, in chronic stroke, for spatial judgments to be influenced by an interaction of stroke laterality and the spatial location of stimuli. The objective of this study was to learn if unilateral hemispheric chronic strokes contribute to a spatial bias with laterally presented stimuli. METHOD: There were 70 participants, 62 with unilateral chronic strokes (>6 months post onset) including 35 with left hemisphere damage (LHD), 27 with right hemisphere damage (RHD), and 8 demographically similar people without history of stroke. Participants were asked to bisect 300 lines presented with distractors on the left, right, or both sides of the line, or no distractor, on a touch-screen monitor in right, center or left hemispace. RESULTS: There was a significant interaction between the side of the hemispheric lesion and the side of the body where these lines were presented. Specifically, in right space, patients with RHD deviated leftward in comparison to the other groups. Furthermore, there was an interaction between group and distractor induced bias. All three groups approached the left distractor, and the patients with LHD also approached the right distractor. CONCLUSIONS: Although spatial neglect is more severe in contralesional than ipsilesional hemispace in the period immediately following a stroke, over time patients with RHD may develop ipsilesional neglect that is more severe in ipsilesional than contralesional space. The mechanism underlying this bias is not known and may be related to attempted compensation or the development of a contralateral attentional/intentional grasp. PMID- 28812422 TI - Novel Influenza D virus: Epidemiology, pathology, evolution and biological characteristics. AB - In 2011, a new virus was isolated from pigs with influenza-like symptoms and subsequently also from cattle, which are the main reservoir of the virus. It is similar to Influenza C virus (ICV), a (predominantly) human pathogen, causing respiratory disease in children. Since the virus is unable to reassort with ICV (and based on several other criteria as discussed in the text) it is now officially named as Influenzavirus D (IDV), a new genus of the Orthomyxoviridae. We summarize the epidemiology, pathology and evolution of IDV and its biological characteristics with emphasis on the only glycoprotein HEF. Based on the limited data available we finally consider whether IDV represent a public health threat. PMID- 28812423 TI - A study on different therapies and prognosis-related factors for 101 patients with SCLC and brain metastases. AB - OBJECTIVE: There is a need to explore multi-discipline general treatment modes to improve the survival period of patients with SCLC and brain metastases undergoing standard radiotherapy treatment. METHODS: A total of 101 patients with SCLC and brain metastases were included into this study. These patients were classified into 4 groups, based on different treatment modes: chemotherapy group, brain radiotherapy group, brain radiotherapy combined with sequential chemotherapy, and chemotherapy combined with sequential brain radiotherapy. Recent and long-term curative effects were compared among the 4 groups. RESULTS: A RR of 42.57% was determined for all 4 groups, and median PFS and OS was 11.56 and 17.32 months, respectively. After SCLC with brain metastases manifested in the limited stage, the difference in median survival period was not statistically significant among the 4 treatment groups (P = 0.29). At the extensive stage of SCLC, survival period was superior in the brain radiotherapy combined with sequential chemotherapy group, compared with other groups (P<0.05). Furthermore, median survival period in the brain radiotherapy combined with sequential chemotherapy group was 15.5 +/- 1.03 months. This was followed by 12.0 +/- 3.06 months in the chemotherapy combined with sequential brain radiotherapy group, 8.0 +/- 1.49 months in the chemotherapy group, and 8.0 +/- 0.43 months in the brain radiotherapy group. CONCLUSION: Combining chemotherapy with brain radiotherapy is a better treatment mode compared with single therapy for treating SCLC with brain metastases. Furthermore, it is recommended for patients in the extensive stage to initially receive brain radiotherapy. PMID- 28812424 TI - Remember some or remember all? Ageing and strategy effects in visual working memory. AB - Recent research has indicated that visual working memory capacity for unidimensional items might be boosted by focusing on all presented items, as opposed to a subset of them. However, it is not clear whether the same outcomes would be observed if more complex items were used which require feature binding, a potentially more demanding task. The current experiments, therefore, examined the effects of encoding strategy using multidimensional items in tasks that required feature binding. Effects were explored across a range of different age groups (Experiment 1) and task conditions (Experiment 2). In both experiments, participants performed significantly better when focusing on a subset of items, regardless of age or methodological variations, suggesting this is the optimal strategy to use when several multidimensional items are presented and binding is required. Implications for task interpretation and visual working memory function are discussed. PMID- 28812425 TI - Nasunin inhibits the lipopolysaccharide-induced pro-inflammatory mediator production in RAW264 mouse macrophages by suppressing ROS-mediated activation of PI3 K/Akt/NF-kappaB and p38 signaling pathways. AB - Nasunin is a major anthocyanin in eggplant peel. The purpose of this study was to examine the anti-inflammatory effects of nasunin in lipopolysaccharide (LPS) stimulated RAW264 macrophages and to identify the molecular mechanisms underlying these effects. We found that nasunin reduced the LPS-induced secretion of tumor necrosis factor-alpha, interleukin-6 and nitric oxide, and expression of inducible nitric oxide synthase in a dose-dependent manner. Nasunin diminished LPS-induced nuclear factor-kappaB (NF-kappaB) activation by suppressing the degradation of inhibitor of kappaB-alpha and nuclear translocation of p65 subunit of NF-kappaB. Nasunin also attenuated the phosphorylation of Akt and p38, signaling molecules involved in pro-inflammatory mediator production. Moreover, nasunin inhibited the intracellular accumulation of ROS, leading to the suppression of NF-kappaB activation, Akt and p38 phosphorylation, and subsequent pro-inflammatory mediator production. These findings suggest that nasunin exerts an anti-inflammatory effect and this effect is mediated, at least in part, by its antioxidant activity. PMID- 28812426 TI - The expression of ETAR in liver cirrhosis and liver cancer. AB - BACKGROUND: To investigate the expression of endothelin receptors in liver diseases and discuss its role in the process of liver cirrhosis and liver cancer. RESEARCH DESIGN AND METHODS: We examined the expressions of ETAR, ETBR and alpha SMA in tissue samples using western blotting analysis. Furthermore, immunofluorescence was used to locate ETAR expression in hepatic stellate cells (HSCs) and hepatic sinusoidal endothelial cells (HSECs), we calculated the percentage of positive cells and then analyzed its relation with clinical indexes. RESULTS: According to the western blotting analysis, the expression of ETAR was high in hepatic hemangioma and liver cancer tissues and ETBR was highly expressed in cirrhosis tissues. The immunofluorescence results demonstrated that the expression of ETAR was elevated in hepatic hemangioma and liver cancer tissues. Moreover, ETAR expression was found in both HSCs and HSECs. Finally, the statistical analysis revealed that the number of positive ETAR cells was correlated with the clinical index platelets (PLT), alanine transaminase (ALT) and diameter of portal vein. CONCLUSION: Endothelin receptors express differently in liver cirrhosis and liver cancer tissues and play a role in hepatic diseases by affecting HSCs and HSECs. PMID- 28812427 TI - Biosynthesis of anthraquinone derivatives in a Sesamum indicum hairy root culture. AB - In order to investigate the intermediacy of 2-(4-methylpent-3-en-1 yl)anthraquinone (MPAQ), a possible intermediate for the biosynthesis of anthraquinone derivatives in sesame (Sesamum indicum), 2H-labeled MPAQ was administered to a hairy root culture of S. indicum. Efficient conversion of fed MPAQ to 2-[(Z)-4-methylpenta-1,3-dien-1-yl]anthraquinone ((Z)-MPDEAQ) was observed. Furthermore, administration experiment with 2H-labeled 2-geranyl-1,4 naphthohydroquinone, another possible intermediate, showed that it was converted to MPAQ and (Z)-MPDEAQ. The results clearly demonstrated that these substrates are the actual precursors for the production of (Z)-MPDEAQ. In contrast, neither MPAQ nor 2-geranyl-1,4-naphthohydroquinone was converted to anthrasesamone B and 2,3-epoxyanthrasesamone B, other anthraquinone derivatives in the hairy roots, suggesting that these substrates may not be the common precursors in the biosynthesis of anthraquinone derivatives. PMID- 28812428 TI - Microvascular perfusion in cardiac arrest: a review of microcirculatory imaging studies. AB - Cardiac arrest represents a leading cause of mortality and morbidity in developed countries. Extracorporeal cardiopulmonary resuscitation (ECPR) increases the chances for a beneficial outcome in victims of refractory cardiac arrest. However, ECPR and post-cardiac arrest care are affected by high mortality rates due to multi-organ failure syndrome, which is closely related to microcirculatory disorders. Therefore, microcirculation represents a key target for therapeutic interventions in post-cardiac arrest patients. However, the evaluation of tissue microcirculatory perfusion is still demanding to perform. Novel videomicroscopic technologies (Orthogonal polarization spectral, Sidestream dark field and Incident dark field imaging) might offer a promising way to perform bedside microcirculatory assessment and therapy monitoring. This review aims to summarise the recent body of knowledge on videomicroscopic imaging in a cardiac arrest setting and to discuss the impact of extracorporeal reperfusion and other therapeutic modalities on microcirculation. PMID- 28812430 TI - Erratum. PMID- 28812429 TI - Metastatic colon adenocarcinoma has a significantly elevated expression of IL-10 compared with primary colon adenocarcinoma tumors. AB - Classical anti-inflammatory cytokines are known to play a role in both cancer progression as well as cancer elimination. We evaluated the anti-inflammatory cytokines IL-10 and TGF-beta in patients with colon adenocarcinoma and metastatic colon adenocarcinoma using immunohistochemical assays to determine the expression of the cytokines between various malignant tissues. We found tissues stained with TGF-beta showed no significant upregulation within malignant tumors when compared with normal tissue controls. We observed high levels of TGF-beta presence in most tissues similar to GAPDH expression. Within both colon adenocarcinoma and metastatic carcinomas there was a significant variability among patients in the expression of IL-10. While some patients experienced insignificant increases in the cytokine compared with controls, other patients had a clear upregulation of the protein within their tissue. In addition, there was an increase in the number of patients positive for IL-10 upregulation within metastatic tumors when compared with primary tumors. These data indicate that there is substantial variability between patients in regards to IL-10 expression, which may further aid in characterizing tumors and evaluating metastatic potential. PMID- 28812432 TI - Addressing Compassion Fatigue and Stress of Special Education Teachers and Professional Staff Using Mindfulness and Prayer. AB - Alternative therapies are promising nursing interventions for improvement of compassion fatigue in educators working in special education. A convenience sample of 27 teachers and professional staff working in special education participated in a quasi-experimental pilot study and completed a pre/posttest of demographic questions, the Perceived Stress Scale (PSS) (10-item) and Professional Quality of Life (ProQOL). All attended a presentation on stress, compassion satisfaction (CS), mindfulness, prayer, and social support. Nearly, one half received weekly electronic text message reminders encouraging use of mindfulness and prayer. All were offered support groups. Use of alternative therapies was self-selected and self-reported. Significant improvement occurred in posttest PSS scores ( p = .0485) of participants with the highest reported levels of use of mindfulness. ProQOL CS scores ( p = .0289) and PSS scores ( p = .0244) significantly improved when evaluating difference in means between groups with the highest levels and lowest levels of prayer and mindfulness. ProQOL burnout scores ( p = <.0001) increased from pretest to posttest. Findings were not significant in regard to reminders and social support. PMID- 28812431 TI - Oral administration of curcumin attenuates visceral hyperalgesia through inhibiting phosphorylation of TRPV1 in rat model of ulcerative colitis. AB - Background Curcumin has been reported to have anti-inflammatory and anti nociceptive effects. The present study was designed to explore the potential therapeutic effects of curcumin on visceral hyperalgesia and inflammation in a rat model of ulcerative colitis. We observed the effects of orally administered curcumin on the disease activity index, histological change in colon, colorectal distension-induced abdominal withdrawal reflex, the expression of transient receptor potential vanilloid 1 (TRPV1) and phosphorylated TRPV1 in dextran sulfate sodium-induced colitis rats. In addition, a HEK293 cell line stably expressing human TRPV1 (hTRPV1) was used to examine the effects of curcumin on the change in membrane expression of TRPV1 induced by phorbol myristate acetate (a protein kinase C activator). Results Repeated oral administration of curcumin inhibited the increase in abdominal withdrawal reflex score induced by dextran sulfate sodium without affecting dextran sulfate sodium-induced histological change of colon and the disease activity index. A significant increase in colonic expression of TRPV1 and pTRPV1 was observed in dextran sulfate sodium-treated rats and this was reversed by oral administration of curcumin. TRPV1 expression in L6-S1 dorsal root ganglion was increased in the small- to medium-sized isolectin B4-positive non-peptidergic and calcitonin gene-related peptide positive peptidergic neurons in dextran sulfate sodium-treated rats and oral administration of curcumin mitigated such changes. In the HEK293 cell line stably expressing hTRPV1, curcumin (1, 3 um) inhibited phorbol myristate acetate-induced upregulation of membrane TRPV1. Conclusion Oral administration of curcumin alleviates visceral hyperalgesia in dextran sulfate sodium-induced colitis rats. The anti-hyperalgesic effect is partially through downregulating the colonic expression and phosphorylation of TRPV1 on the afferent fibers projected from peptidergic and non-peptidergic nociceptive neurons of dorsal root ganglion. PMID- 28812433 TI - Regulation of SQSTM1/p62 via UBA domain ubiquitination and its role in disease. AB - Macroautophagy/autophagy can be a selective degradative process via the utilization of various autophagic receptor proteins. Autophagic receptors selectively recognize ubiquitinated cargoes and deliver them to phagophores, the precursors to autophagosomes, for their degradation. For example, SQSTM1/p62 directly binds to ubiquitinated protein aggregates via its UBA domain and sequesters them into inclusion bodies via its PB1 domain. SQSTM1also interacts with phagophores via its LC3-interacting (LIR) motif. However, a regulatory mechanism for autophagic receptors is not yet understood. PMID- 28812434 TI - [pemetrexed + sildenafil], via autophagy-dependent HDAC downregulation, enhances the immunotherapy response of NSCLC cells. AB - Pemetrexed is an approved therapeutic in NSCLC and ovarian cancer. Our studies focused on the ability of [pemetrexed + sildenafil] exposure to alter the immunogenicity of lung and ovarian cancer cells. Treatment of lung and ovarian cancer cells with [pemetrexed + sildenafil] in vitro rapidly reduced the expression of PD-L1, PD-L2 and ornithine decarboxylase (ODC), and increased the expression of class I MHCA. In a cell-specific fashion, some cells also released the immunogenic nuclear protein HMGB1 into the extracellular environment. [Pemetrexed + sildenafil] reduced the expression of multiple histone deacetylases that was blocked by knock down of autophagy regulatory proteins. [Pemetrexed + sildenafil] lethality was enhanced by the histone deacetylase inhibitors AR42 and sodium valproate; AR42 and valproate as single agents also rapidly reduced the expression of PD-L1, PD-L2 and ODC, and increased expression of MHCA and CerS6. Nitric oxide and CerS6 signaling was required for drug-induced death receptor activation and tumor cell killing. In vivo, [pemetrexed + sildenafil] lethality against lung cancer cells was enhanced by sodium valproate. Using syngeneic mouse lung cancer cells [pemetrexed + sildenafil] enhanced the anti-tumor effects of antibodies directed to inhibit PD-1 or CTLA4. [Pemetrexed + sildenafil] interacted with the anti-PD-1 antibody to strongly enhance tumor infiltration by M1 macrophages; activated NK cells and activated T cells. Our data demonstrate that treatment of tumor cells with [pemetrexed + sildenafil] results in tumor cell killing and via autophagy-dependent downregulation of HDACs, it opsonizes the remaining tumor cells to anti-tumor immunotherapy antibodies. PMID- 28812435 TI - Transcatheter aortic valve implantation compared with surgical aortic valve replacement in patients with anaemia. AB - OBJECTIVES: We compared the outcome of anaemic patients undergoing transcatheter (TAVI) and surgical aortic valve replacement (SAVR) for severe aortic valve stenosis. METHODS: Anaemic patients (haemoglobin <13.0 g/dL in men and <12.0 g/dL in women) undergoing TAVI and SAVR from the OBSERVANT study were the subjects of this analysis. RESULTS: Preoperative anaemia was an independent predictor of 3 year mortality after either TAVI (HR 1.37, 95% CI 1.12-1.68) and SAVR (HR 1.63, 95% CI 1.37-1.99). Propensity score matching resulted in 302 pairs with similar characteristics. Patients undergoing SAVR had similar 30-d mortality (3.6% versus 3.3%, p = .81) and stroke (1.3% versus 2.0%, p = .53) compared with TAVI. The rates of pacemaker implantation (18.6% versus 3.0%, p < .001), major vascular damage (5.7% versus 0.4%, p < .001) and mild-to-severe paravalvular regurgitation (47.4% versus 9.3%, p < .001) were higher after TAVI, whereas acute kidney injury (50.7% versus 27.9%, p < .001) and blood transfusion (70.0% versus 38.6%, p < .001) were more frequent after SAVR. At 3-year, survival was 74.0% after SAVR and 66.3% after TAVI, respectively (p = .065), and freedom from MACCE was 67.6% after SAVR and 58.7% after TAVI, respectively (p = .049). CONCLUSIONS: These results suggest that TAVI is not superior to SAVR in patients with anaemia. PMID- 28812436 TI - The mechanism of protective effect of crocin against liver mitochondrial toxicity caused by arsenic III. AB - In this study, we want to understand whether crocin could prevent mitochondrial damage caused by As III. For this purpose, we determined different mitochondrial toxicity endpoints caused by As III. We evaluated mitochondrial ROS formation, lipid peroxidation, mitochondrial membrane potential (MMP) collapse, mitochondrial outer membrane integrity and cytochrome c release. Our results showed that pretreatment with crocin at a concentration of 25 ug/ml significantly (p < 0.001) reduced As III-induced mitochondrial ROS formation, lipid peroxidation, MMP collapse and mitochondrial swelling. Crocin also protected the mitochondria by decreasing the mitochondrial outer membrane damage that leads to reduce the amount of cytochrome c release. These results demonstrated that crocin is a promising antidotal candidate by ameliorating As III-induced oxidative stress through mitochondrial targeting. PMID- 28812438 TI - Acute formaldehyde exposure induced early Alzheimer-like changes in mouse brain. AB - Alzheimer's disease (AD) is a serious, common, global disease, yet its etiology and pathogenesis are incompletely understood. Although an association between AD and exposure to air pollutants has been discussed, the effects of pollutants on the functioning of the brain remain unclear. The indoor environment is where exposure to formaldehyde (FA) can occur. Whether exposure to FA contributes to the development of AD needs to be investigated. To determine the objective, C57BL/6 mice were exposed daily to FA (0, 0.155, 1.55 and 15.5 mg/kg/day) for 1 week. After acute FA exposure, some early AD-like changes [cognitive deficits, pathological alterations in the mouse brain, accumulation of total beta-amyloid plaques 1-42 (Abeta1-42) and hyper-phosphorylated tau (Tau-P) in the cerebral cortex] were detected after exposure to high concentrations of FA (1.55 or 15.5 mg/kg/day). The permeability of the blood-brain barrier (BBB), activation of astrocyte and microglia, oxidative stress (OS) and inflammation were analyzed to explore the toxicity mechanisms behind the development of early AD-like changes. While exposed to a low concentration of FA (0.155 mg/kg/day) had little or no adverse effects on the mouse brain. The results indicated that acute FA exposure induced early AD-like changes in mouse brain, increased the susceptibility of AD in mouse. PMID- 28812437 TI - Autophagy-induced KDR/VEGFR-2 activation promotes the formation of vasculogenic mimicry by glioma stem cells. AB - Antiangiogenesis with bevacizumab, an antibody against vascular endothelial growth factor (VEGF), has been used for devascularization to limit the growth of malignant glioma. However, the benefits are transient due to elusive mechanisms underlying resistance to the antiangiogenic therapy. Glioma stem cells (GSCs) are capable of forming vasculogenic mimicry (VM), an alternative microvascular circulation independent of VEGF-driven angiogenesis. Herein, we report that the formation of VM was promoted by bevacizumab-induced macroautophagy/autophagy in GSCs, which was associated with tumor resistance to antiangiogenic therapy. We established a 3-dimensional collagen scaffold to examine the formation of VM and autophagy by GSCs, and found that rapamycin increased the number of VM and enhanced KDR/VEGFR-2 phosphorylation. Treatment with chloroquine, or knockdown of the autophagy gene ATG5, inhibited the formation of VM and KDR phosphorylation in GSCs. Notably, neutralization of GSCs-produced VEGF with bevacizumab failed to recapitulate the effect of chloroquine treatment and ATG5 knockdown, suggesting that autophagy-promoted formation of VM was independent of tumor cell-derived VEGF. ROS was elevated when autophagy was induced in GSCs and activated KDR phosphorylation through the phosphoinositide 3-kinase (PI3K)-AKT pathway. A ROS inhibitor, N-acetylcysteine, abolished KDR phosphorylation and the formation of VM by GSCs. By examination of the specimens from 95 patients with glioblastoma, we found that ATG5 and p-KDR expression was strongly associated with the density of VM in tumors and poor clinical outcome. Our results thus demonstrate a crucial role of autophagy in the formation of VM by GSCs, which may serve as a therapeutic target in drug-resistant glioma. PMID- 28812439 TI - Evaluating disease prediction models using a cohort whose covariate distribution differs from that of the target population. AB - Personal predictive models for disease development play important roles in chronic disease prevention. The performance of these models is evaluated by applying them to the baseline covariates of participants in external cohort studies, with model predictions compared to subjects' subsequent disease incidence. However, the covariate distribution among participants in a validation cohort may differ from that of the population for which the model will be used. Since estimates of predictive model performance depend on the distribution of covariates among the subjects to which it is applied, such differences can cause misleading estimates of model performance in the target population. We propose a method for addressing this problem by weighting the cohort subjects to make their covariate distribution better match that of the target population. Simulations show that the method provides accurate estimates of model performance in the target population, while un-weighted estimates may not. We illustrate the method by applying it to evaluate an ovarian cancer prediction model targeted to US women, using cohort data from participants in the California Teachers Study. The methods can be implemented using open-source code for public use as the R-package RMAP (Risk Model Assessment Package) available at http://stanford.edu/~ggong/rmap/ . PMID- 28812440 TI - Old Voters on New Dimensions: Why Do Voters Vote for Pensioners' Parties? The Case of the Netherlands. AB - This article analyzes the electoral support of the Dutch pensioners' party 50Plus. Due to its open electoral system and aging population, the Netherlands is a key case to study pensioners' parties. Our study shows that this pensioners' party appeals to voters who are characterized by their age and their dependence on the welfare state as well as their policy positions on new lines of political conflict. In particular, their position on the new economic dimension (which concerns welfare state reform) and the new cultural dimension (which concerns immigration and EU integration) is distinct. Moreover, even when the majority of voters for this new party once supported the larger mainstream parties, they are now dissatisfied with the established politics. With rapidly aging populations across established democracies, this study is not just relevant for those studying pensioners' parties, but rather gives an important insight into the electoral dynamics and popular support for mainstream politics, the welfare state, and social security. PMID- 28812441 TI - The indirect effect of perceived burdensomeness on the relationship between indices of social support and suicide ideation in college students. AB - OBJECTIVE: Research has demonstrated that a lack of social support is related to suicide risk. This study examines perceived burdensomeness and thwarted belongingness, of the Interpersonal Theory of Suicide, as mechanisms of the social support-suicide relationship in college students. METHOD: The study consisted of 207 students from a Midwestern university. Data were collected from 2007 to 2008. Two multiple mediation analyses were conducted to examine whether perceived burdensomeness and thwarted belongingness mediated the relationship between indices of social support and suicide ideation. RESULTS: Perceived burdensomeness mediated the relationships between perceived social support and suicide ideation (95% confidence interval [CI] -.02 to -.00, effect size = -.01) and social connectedness and suicide ideation (95% CI -.03 to -.00, effect size = -.03). Thwarted belongingness did not mediate either relationship. CONCLUSIONS: Results suggest that a lack of social support could lead to perceptions of being a burden on others, which could lead to suicide ideation. PMID- 28812442 TI - Clarification by Richard Leblanc. PMID- 28812443 TI - An evaluation of general practitioners learning preferences in dermatology. PMID- 28812444 TI - A psychometric analysis of the Ottawa self-injury inventory-f. AB - OBJECTIVE: This study seeks to evaluate the psychometric properties of the Ottawa Self-Injury Inventory-Functions (OSI-F) for assessing nonsuicidal self-injury (NSSI), a condition for further study in the DSM-5. PARTICIPANTS: Participants included 345 students who indicated a history of self-injury in a university counseling center over six semesters from August 2009 to May 2012. METHOD: Participants completed the OSI-F as a measure on the psychological intake for the university counseling center. RESULTS: Factor analysis, Cronbach's alpha coefficients, independent sample t tests, and correlations were examined and demonstrated adequate reliability and validity. CONCLUSIONS: A three-factor solution emerged from the restructured OSI-F relating to Affect Regulation, Exhilaration, and Release. Affect regulation dimensions were predictive of continuing to self-injure and related to depression, anxiety, and overall mental health. Additionally, women were more likely to attribute self-injuring to affect regulation. PMID- 28812445 TI - 'Half a woman, half a man; that is how they make me feel': a qualitative study of rural Jordanian women's experience of infertility. AB - Infertility is a health problem encompassing physical, psychological and social consequences that may threaten women's quality of life. Few studies have been conducted in Jordan examining rural women's experiences of infertility. This study aimed to explore responses to infertility and its consequences in the Jordanian rural sociocultural context. Using a descriptive qualitative design, data were collected between April and September 2016 from a fertility clinic in a military hospital in Northern Jordan. Semi-structured interviews were conducted with 14 purposively selected Jordanian women. Data were analysed using thematic analysis. Findings revealing women's responses to infertility included: submission and docility, self-isolation, internalisation and persistence in getting pregnant by seeking modern and traditional methods of treatment. The impact of infertility complicated women's everyday living through their experiences of violence, kinship and patriarchal interference, stigma, negative perceptions of the infertile woman, and other's surveillance of their sexuality. Women living in rural areas of Jordan have negative experiences of infertility that are ingrained in sociocultural beliefs about fertility and reproduction. Healthcare professionals are encouraged to raise public awareness about infertility's adverse consequences and to help families by enhancing positive responses to infertility. PMID- 28812447 TI - The role of the family in HIV status disclosure among women in Vietnam: Familial dependence and independence. AB - Insights into disclosure by people living with HIV and AIDS (PLWHA) can inform strategies for treatment and support, yet Vietnamese women's self-disclosure patterns are poorly understood. We conducted interviews with 12 HIV-positive women, identifying three principal factors influencing disclosure to family members: patrilocal residence, desire to protect own family, and the need for financial support. Women's decision-making about disclosure was significantly affected by dependence on or independence of parents-in-law and their own parents. We believe that our findings reveal the complex interplay of stigma and disclosure within Vietnamese families, highlighting the need for specific social measures that promote self-disclosure combined with family support for female PLWHA. PMID- 28812446 TI - Higher dietary intake of vitamin D may influence total cholesterol and carbohydrate profile independent of body composition in men with Chronic Spinal Cord Injury. AB - STUDY DESIGN: A case-control design. OBJECTIVES: To determine the effects of dietary vitamin D intake on insulin sensitivity (Si), glucose effectiveness (Sg), and lipid profile in individuals with spinal cord injury (SCI). METHODS: 20 male, paraplegic (T3-L1) with chronic (> one year) motor complete SCI (AIS A or B) were recruited. Three-day dietary records were analyzed for dietary vitamin D (calciferol), and participants were assigned to one of two groups, a high vitamin D intake group and a low vitamin D intake group based on the mid-point of vitamin D frequency distribution. Individuals in both groups were matched based on age, weight, time since injury and level of injury. Sg, Si and lipid profiles were measured of the two groups. RESULTS: The high vitamin D group had an average intake of 5.33 +/- 4.14 mcg compared to low vitamin D group, 0.74 +/- 0.24 mcg. None of the 20 participants met the recommended guidelines for daily vitamin D intake. The higher vitamin D group had a significantly lower (P = 0.035) total cholesterol (148.00 +/- 14.12 mg/dl) than the lower vitamin D group (171.80 +/- 36.22 mg/dl). Vitamin D adjusted to total dietary intake was positively correlated to improvement in Si and Sg (P<0.05). CONCLUSION: The findings suggest that persons with SCI consume much less than the recommended guidelines for daily vitamin D intake. However, a higher dietary intake of vitamin D may influence total cholesterol and carbohydrate profile as demonstrated by a significant decrease in total cholesterol and improvement in glucose homeostasis independent of body composition changes after SCI. PMID- 28812448 TI - Peer network influence on intimate partner violence perpetration among urban Tanzanian men. AB - Male perpetration of intimate partner violence (IPV) against women in Tanzania is widespread. Theory and empirical evidence suggest peer networks may play an important role in shaping IPV perpetration, although research on this topic in sub-Saharan Africa is limited. Grounded in social learning theory, social influence theory, and the theory of gender and power, the purpose of this study was to examine whether and how peer networks influence men's perpetration of IPV in Dar es Salaam, Tanzania. We conducted in-depth interviews (n = 40) with a sub sample of 20 men enrolled in the control condition of an ongoing cluster randomised controlled trial. We purposively sampled participants who previously reported perpetrating physical IPV. To analyse the data, we generated narrative summaries and conducted thematic and interpretative coding. We saw no evidence that men self-selected into peer networks with certain values or behaviours. Rather, men described several mechanisms through which their peers influenced the perpetration of IPV, including: (1) the internalisation of peer network norms, (2) pressure to conform to peer network norms and (3) the direct involvement of peers in shaping couple power dynamics. Our findings suggest that peer networks influence men's perpetration of IPV and should be targeted in future programmes and interventions. PMID- 28812449 TI - Balancing performance-based expectations with a holistic perspective on coaching: a qualitative study of Swedish women's national football team coaches' practice experiences. AB - PURPOSE: The purpose of this study was to explore how an exclusive sample of women's national football team coaches described how they implement careful coaching while facing social and organizational pressure to win medals. METHOD: To consider coaches' negotiations, we drew on Noddings' concept of caring. Using an interpretive research paradigm, we conducted in-depth interviews with five Swedish women's national football team coaches. An abductive approach was used to simultaneously process the theoretical framework of "ethics of care" and the empirical data. RESULTS: The coaches unanimously adopted a holistic perspective to coaching. The coaching strategies they described included promoting players' development, well-being, and sustainable elite performance; listening to the players' voices and engaging in dialogue; and creating a positive environment and promoting fair play. CONCLUSIONS: These findings demonstrate that the women coaches, despite performance pressure, adopt caring coaching in the form of Noddings' pedagogical modelling, dialogue, and confirmation strategies, and provide an example of how coaches can adopt caring, holistic, and athlete-centred coaching while working at the highest level of competitive sport and achieving competitive success. PMID- 28812450 TI - Sexual Satisfaction Among Older Australian Heterosexual Men and Women: Findings from the Sex, Age & Me Study. AB - This study explored sexual satisfaction in older heterosexual Australians using data from a national sample of 1,583 men and women aged 60+ who hoped or planned to have sex in the future. Data collection took place in 2015; participants were recruited using a variety of online and offline advertisements. Less than half the sample (46%) reported they were very or extremely satisfied with their sexual lives. Those who had sex more often and were more interested in sex were more likely to be satisfied, while those who wanted sex more often in the future were less likely to be satisfied, as were men who had experienced sexual difficulties. Sexual satisfaction was also associated with life satisfaction in men and positive mental health in women. Factors associated with satisfaction in this study will help guide strategies to support older people in realizing the sexual lives they desire. PMID- 28812451 TI - Nonmedical use of over-the-counter medications is significantly associated with nonmedical use of prescription drugs among university students. AB - OBJECTIVE: To examine the association between nonmedical use of over-the-counter medications (NMUOTC) and nonmedical use of prescription drugs (NMUPD). PARTICIPANTS: University students surveyed on NMUOTC and NMUPD between August and December 2011 (N = 939). METHODS: Cross-sectional data analysis of online survey. RESULTS: The majority of respondents were women, undergraduate, Caucasian, and not affiliated with Greek life. NMUPD and NMUOTC were reported by 21.4% and 11.2% of students, respectively. NMUOTC was significantly associated with NMUPD in unadjusted analyses and after adjustment for gender, age, race/ethnicity, and Greek membership (odds ratio: 3.37, 95% confidence interval: 2.17, 5.23). Secondary analyses showed a relationship between over-the-counter (OTC) cough medication misuse and NMUPD, OTC stimulant misuse and prescription stimulant misuse, and OTC sleep aid misuse with prescription depressant misuse. CONCLUSIONS: Results suggest the importance of both measuring the prevalence of OTC misuse and incorporating its misuse into assessments of polydrug use in the university population. PMID- 28812452 TI - National Trends in Hospital Emergency Department Visits among Those with and without Multiple Chronic Conditions, 2007-2012. AB - Emergency department (ED) visits and the number of adults with multiple chronic conditions (MCC) have been increasing over the last decade, but little is known about the trends in ED use for patients with MCC. This study examined national trends in ED use for those with MCC compared with one chronic condition and no chronic conditions and used data from the 2007-2012 National Emergency Department Sample, limited to patients 45 years old or older. ED visits for encounters with one chronic condition and MCC increased at significantly greater rates than for those with no chronic conditions both overall and for all subgroups examined. PMID- 28812453 TI - Ergonomic evaluation of a new truck seat design: a field study. AB - A postural evaluation of commercial licensed truck drivers was conducted to determine the ergonomic benefits of a truck seat prototype in comparison with an industry standard seat. Twenty commercially licensed truck drivers were recruited to perform a 90-min driving task. Postures were assessed using accelerometers and a backrest and seat pan pressure mapping system. Subjective discomfort measurements were monitored using two questionnaires: ratings of perceived discomfort (RPD) and the automotive seating discomfort questionnaire (ASDQ). Participants reported significantly higher discomfort scores when sitting in the industry standard seat. Participants sat with more lumbar lordosis and assumed a more extended thoracic posture when seated in the prototype. Pairing the gluteal backrest panel with the adjustable seat pan also helped reduce the average sitting pressure on both the seat pan and the backrest. The prototype provided several postural benefits for commercially certified truck drivers, as it did for a young and healthy population. PMID- 28812454 TI - Risk factors for intrapartum acidemia - a cohort study. AB - PURPOSE: Birth acidemia is associated with short- and long-term morbidity in the child. Optimal intrapartum surveillance and timely interventions may reduce the incidence of these outcomes. Knowledge about conditions which increase the risks might be beneficial for optimal care. The aim with this study was to identify factors which increased the risk for lactacidemia in fetal scalp blood. MATERIALS AND METHODS: A secondary analysis of a cohort study performed at Karolinska University Hospital Stockholm Sweden between February 2009 and February 2011. The study population included 1070 women in labor where fetal scalp blood sampling (FBS) was performed. RESULTS: In a univariate logistic regression analysis for lactate >4.8 mmol/L at FBS, minor language barriers (OR 2.54; 95%CI 1.26-5.11), active bearing down (OR 2.46; 95%CI 1.12-5.39) and maternal height <155 cm (OR 2.15; 95%CI 1.08-4.26) were found as risk factors. In a multivariate logistic regression analysis, minor language barriers (OR 2.21; 95%CI 1.05-4.67) and active pushing (OR 2.68; 95%CI 1.20-6.00) remained significant. CONCLUSIONS: Language barriers, active pushing and short stature were found to be significant risk factors for intrapartum lactacidemia. In the group with minor language problems better use of interpreters might be beneficial. PMID- 28812455 TI - Prognostic factors for change in self-reported anxiety and depression in spondyloarthritis patients: data from the population-based SpAScania cohort from southern Sweden. AB - OBJECTIVES: Anxiety and depression symptoms are more common in patients with spondyloarthritis (SpA) than in the general population. This study describes prognostic factors for change in self-reported anxiety and depression over 2 years in a well-defined SpA cohort. METHOD: In 2009, 3716 adult patients from the SpAScania cohort received a postal questionnaire to assess quality of life (QoL) and physical and mental functioning. A follow-up survey was performed in 2011. The Hospital Anxiety and Depression Scale indicated 'no', 'possible', and 'probable' cases of anxiety and depression. Transitions between the three different categories were analysed and logistic regression analysis determined prognostic factors (patient-reported outcomes and characteristics) for improvement or deterioration. RESULTS: In total, 1629 SpA patients responded to both surveys (44%) (mean +/- SD age 55.8 +/- 13.1 years, disease duration 14.6 +/ 11.7 years); 27% had ankylosing spondylitis, 55% psoriatic arthritis, and 18% undifferentiated SpA. The proportion of patients reporting possible/probable anxiety decreased from 31% to 25% over 2 years, while no changes in depression were seen. Factors associated with deterioration or improvement were largely the same for anxiety as for depression: fatigue, general health, QoL, level of functioning, disease activity, and self-efficacy. However, reporting chronic widespread pain (CWP) at baseline increased the risk of becoming depressed and decreased the probability of recovering from anxiety. CONCLUSION: Self-reported anxiety and depression is common and fairly stable over time in SpA patients. The association between mental health and CWP indicates that both comorbidities need to be acknowledged and treated in the clinic. PMID- 28812456 TI - Value congruence, control, sense of community and demands as determinants of burnout syndrome among hospitality workers. AB - Employees working in the hospitality industry are constantly exposed to occupational stressors that may lead employees into experiencing burnout syndrome. Research addressing the interactive effects of control, community and value congruence to alleviate the impact of workplace demands on experiencing burnout is relatively limited. The present study examined relationships among control, community and value congruence, workplace demands and the three components of burnout. A sample of 418 employees working in a variety of hospitality associations including restaurants and hotels in Spain were recruited. Moderation analyses and linear regressions analyzed the predictive power of control, community and value congruence as moderating variables. Results indicate that control, community and value congruence were successful buffers in the relationships between workplace demands and the burnout dimensions. The present findings offer suggestions for future research on potential moderating variables, as well as implications for reducing burnout among hospitality employees. PMID- 28812457 TI - From 'half-dead' to being 'free': resistance to HIV stigma, self-disclosure and support for PMTCT/HIV care among couples living with HIV in Kenya. AB - In sub-Saharan Africa, self-disclosure of HIV-positive status may be a pivotal action for improving access to prevention of mother-to-child transmission services. However, understanding of HIV stigma and disclosure, and their effects on demand for care remains incomplete - particularly in the current context of new antiretroviral therapy guidelines. The purpose of this study was to explore these issues among self-disclosed couples living in southwest Kenya. We conducted 38 in-depth interviews with HIV-positive pregnant or postpartum women and their male partners. Of the 19 couples, 10 were HIV seroconcordant and 9 were serodiscordant. The textual analysis showed that HIV stigma continues to restrict full participation in community life and limit access to care by promoting fear, isolation and self-censorship. Against this backdrop, however, participants' narratives revealed varying forms and degrees of resistance to HIV stigma, which appeared to both produce and emerge from acts of self-disclosure. Such disclosure enabled participants to overcome fears and gain critical support for engaging in HIV care while further resisting HIV stigma. These findings suggest that programme interventions designed explicitly to stimulate and support processes of HIV stigma resistance and safe self-disclosure may be key to improving demand for and retention in HIV services. PMID- 28812458 TI - Congenital Cystic Lung Lesions: Evolution From In-utero Detection to Pathology Diagnosis-A Multidisciplinary Approach. AB - Congenital cystic lung lesions are a group of rare pathologies that are usually diagnosed in the prenatal period. The majority of these lesions are diagnosed at pathology examination as congenital pulmonary airway malformations (CPAM) and bronchopulmonary sequestration (BPS). These lesions are typically managed by surgical intervention within the first year of life and have an excellent prognosis. We examined the evolution of imaging appearances from prenatal diagnosis to postnatal work-up of these lesions and correlate imaging and pathological findings. An 8-year retrospective review of the perinatal and pathology database of a single tertiary care center identified 42 cases of congenital cystic lung lesions of which 36 had known prenatal ultrasound and prenatal course available. Final pathologic diagnoses were 15 CPAM (41%), 7 BPS (19%), and 9 hybrid BPS and CPAM lesions (25%). Five cases with bronchial atresia were also identified (either in isolation or associated with CPAM or BPS). The overall characteristics of these lesions by prenatal ultrasound, postnatal imaging, and ultimate histopathologic diagnosis are described. PMID- 28812459 TI - ALOX15 Immunohistochemistry Aids in the Diagnosis of Eosinophilic Esophagitis on Pauci-eosinophilic Biopsies in Children. AB - Histologically, esophageal biopsies should have >=15 intraepithelial eosinophils (IEEs) per high power field (HPF) to support a clinicopathologic diagnosis of eosinophilic esophagitis (EoE). Children with clinically apparent EoE may show pauci-eosinophilic biopsies due to patchy involvement. Immunostaining (Immunohistochemistry) for arachidonate-15 lipooxygenase (ALOX15) has been demonstrated to be a sensitive marker for EoE. We retrospectively assessed the expression of ALOX15 in 48 biopsies from 21 patients with established diagnosis of EoE and with tissue fragments below the threshold of 15 IEEs/HPF. Fragments were classified into pauci-eosinophilic and non-pauci-eosinophilic groups using cutoffs of 10 and 15 IEEs/HPF. Controls included patients with reflux and normal biopsies. Sixty-five (43.9%) fragments showed <10 IEEs/HPF and 83 (56.1%) showed >=10 IEEs/HPF. Using a cutoff of 15 IEEs/HPF, 87 (58.7%) fragments showed <15 IEEs/HPF while 61 fragments (41.2%) had >=15 IEEs/HPF. ALOX15 was positive in 53/65 (81.5%) of fragments with <10 IEEs/HPF versus 82/83 (98.8%) of fragments with >=10 IEEs/HPF ( P < .001). For a cutoff of 15 IEEs/HPF, 75/87 (86.2%) of pauci-eosinophilic fragments were ALOX15-positive, while 60/61(98.4%) of biopsies meeting the threshold were positive ( P < .001). In 3/21 (14.3%) patients with EoE, all of the fragments (n = 7) were pauci-eosinophilic and all of them were positive for ALOX15. Two of 24 patients with reflux (one with 9 and one with 14 IEEs/HPF) were also positive. Fragments from normal controls (0 IEEs/HPF) were negative. Our results support the utility of ALOX15 immunohistochemistry in supporting the diagnosis of EoE in rare situations with strong clinical suspicion where no fragments reach 15 IEEs/HPF. PMID- 28812460 TI - Myopathic mtDNA Depletion Syndrome Due to Mutation in TK2 Gene. AB - Whole-exome sequencing was used to identify the disease gene(s) in a Spanish girl with failure to thrive, muscle weakness, mild facial weakness, elevated creatine kinase, deficiency of mitochondrial complex III and depletion of mtDNA. With whole-exome sequencing data, it was possible to get the whole mtDNA sequencing and discard any pathogenic variant in this genome. The analysis of whole exome uncovered a homozygous pathogenic mutation in thymidine kinase 2 gene ( TK2; NM_004614.4:c.323 C>T, p.T108M). TK2 mutations have been identified mainly in patients with the myopathic form of mtDNA depletion syndromes. This patient presents an atypical TK2-related myopathic form of mtDNA depletion syndromes, because despite having a very low content of mtDNA (<20%), she presents a slower and less severe evolution of the disease. In conclusion, our data confirm the role of TK2 gene in mtDNA depletion syndromes and expanded the phenotypic spectrum. PMID- 28812461 TI - Soft Tissue Perineurioma in a Child With Neurofibromatosis Type 1: A Case Report and Review of the Literature. AB - Soft tissue perineurioma is a rare benign peripheral nerve sheath tumor, especially in children. This manuscript presents an unusual case of soft tissue perineurioma in a 10-year-old boy with neurofibromatosis type 1. The patient presented with a lump in the region of the right breast. A subcutaneous, well circumscribed mass was removed. The cut surface was cream with a vaguely nodular appearance. Histology showed a spindle cell lesion with variable architecture and biphasic morphology. There was no nuclear atypia or pleomorphism. The differential diagnosis and other soft tissue lesions that can be seen in neurofibromatosis type 1 are discussed. PMID- 28812462 TI - Severe Intrauterine Amputations in One Dichorionic Twin With Pentalogy of Cantrell: Further Evidence and Consideration for Mechanical Teratogenesis. AB - Pentalogy of Cantrell (PC) is characterized by midline supraumbilical abdominal wall defect, lower sternum defect, anterior diaphragmatic and pericardial defect, and congenital cardiac anomalies. Several etiological influences have been postulated, however, most of the reported cases are sporadic. In addition, evidence for mechanical teratogenesis in PC is limited. Here, we describe in one dichorionic twin with complete PC, additional severe intrauterine amputations (mainly head and neck) not previously reported resultant from mechanical teratogenesis. This morphologic constellation prompts us to emphasize the consideration of this etiological influence and provides further evidence. In fact, the pattern of anomalies in the affected fetus provides new insight into the severity and presentation of PC due to mechanical teratogenesis, which is a significant etiological consideration in clinical evaluation and implies that the syndrome involves a complex defective fetal development. PMID- 28812463 TI - Novel COL1A1 Mutation c.3290G>T Associated With Severe Form of Osteogenesis Imperfecta in a Fetus. AB - Osteogenesis imperfecta is a genetically and clinically heterogenous group of skeletal dysplasias characterized by bone fragility. Its severity ranges from nearly asymptomatic individuals to perinatal lethality. The majority of cases are caused by mutations in either the COL1A1 or the COL1A2 gene coding for alpha 1 and alpha 2 chains of collagen type 1, respectively, and a large number of pathogenic variants of these genes has been identified. We describe a novel COL1A1 mutation associated with prenatally diagnosed severe form of osteogenesis imperfecta. PMID- 28812464 TI - Congenital Diaphragmatic Hernia with Liver Herniation into the Pericardial Sac in a 30-Week Gestation Infant. AB - Anterior diaphragmatic defects with pericardial involvement are extremely rare and diagnostically challenging entities encountered perinatally. While a majority of diaphragmatic defects occur in isolation, others are associated with multiple defects forming a complex of syndromes such as Pentalogy of Cantrell. Liver herniation into the pericardial sac poses a particular challenge and can mimic a pericardial tumor on prenatal ultrasound, yielding a different management course. The following case is an unusual presentation of a 30-week gestation female with an anterior midline diaphragmatic defect with liver herniation mimicking as a pericardial tumor, diagnosed at time of autopsy. Postmortem studies also found multiple congenital anomalies including an atrioventricular septal defect and midline gumline defect suggesting at least a partial Pentalogy of Cantrell or variant. Early recognition and screening for associated anomalies are essential for management in this subset of patients. PMID- 28812465 TI - Melanotic Neuroectodermal Tumor of Infancy Presenting With Fast-Growing Scrotal Swelling: A Case Report and Literature Review. AB - Testicular melanotic neuroectodermal tumor of infancy (MNTI) is extremely rare, with 2 cases reported in the literature. Its rarity and rapid and infiltrative growth pattern pose a diagnostic challenge. A previously healthy 3-month-old male, presented with a history of worsening left hemiscrotal swelling for 1 week. An outside ultrasound was suggestive of testicular torsion. Left orchiectomy demonstrated a mass occupying almost entire testicle with a variegated cut surface, with areas of pigmentation, necrosis, and hemorrhage. Histological examination confirmed MNTI of the testis and epididymis. MNTI should be included in differential diagnosis in infants presenting with fast-growing scrotal swelling. PMID- 28812466 TI - Florid Intussusceptive-like Microvascular Dysangiogenesis in a Preterm Lung. AB - The cellular mechanisms underlying the microvascular dysangiogenesis of bronchopulmonary dysplasia (chronic lung disease of the newborn) remain largely undetermined. We report unusual pulmonary vascular findings in a 27-week gestation male newborn who died on the second day of life from intractable respiratory failure, following a pregnancy complicated by prolonged membrane rupture and persistent severe oligohydramnios. As expected, postmortem examination revealed pulmonary hypoplasia (lung/body weight ratio: 2.23%; 10th percentile for 27 weeks: 2.59%). In addition, lung microscopy revealed complex networks of non-sprouting, tortuous, and bulbously dilated capillaries, randomly distributed in widened airspace septa. Anti-smooth muscle actin immunohistochemistry demonstrated immunoreactive central densities within capillary lumina, suggestive of intravascular pillar formation. The plexus forming, non-sprouting type of angiogenesis and apparent transluminal pillar formation are consistent with intussusceptive ("longitudinal splitting") angiogenesis. In concordance with previous observations made in human fetal lung xenografts, these findings support the notion that human postcanalicular lungs have the capacity to switch from sprouting to non-sprouting, intussusceptive-like angiogenesis, possibly representing an adaptive response activated by hemodynamic flow alterations and/or hypoxia. The possible relationship between the intussusceptive-like vascular changes observed in this case and the microvascular dysangiogenesis characteristic of bronchopulmonary dysplasia remains to be determined. PMID- 28812467 TI - Vessel Perforation and False Tracking Resulting From Umbilical Artery Catheterization: A Case Report and Literature Review. AB - We report an extremely low-birth-weight neonate who developed umbilical artery perforation and false tracking. There was no life-threatening event relating to the complication. Diagnosis was made at postmortem examination. Little information exists regarding the anatomic and vascular effects of umbilical artery catheterization placement in newborns. We report a new complication of umbilical artery catheterization. We raise the awareness regarding the potential life threat due to this rare but very serious complication. PMID- 28812468 TI - The First Reported Case of Meckel-Gruber Syndrome Associated With Abnormal Karyotype Mosaic Trisomy 17. AB - Meckel-Gruber syndrome (MKS) is a rare lethal autosomal recessive disorder with typical anomalies including encephalocele, multicystic renal dysplasia, congenital liver fibrosis, and polydactyly. MKS is caused by mutations of genes localized on different chromosomes. Karyotypes of published Meckel-Gruber syndrome cases are without any aberrations. We present a male fetus with meningoencephalocele, multicystic renal dysplasia, congenital liver fibrosis, and other anomalies. Standard cytogenetic examination of cultured fetal skin and muscle fibroblasts showed mosaic trisomy 17. Homozygous deletion in CC2D2A gene was found by Sanger sequencing. This is to our knowledge the first case of genetically confirmed Meckel-Gruber syndrome with incidental cofinding of mosaic trisomy 17. Abnormal karyotype does not exclude diagnosis of MKS with risk of recurrence 25% in next pregnancy. In the case of anomalies typical for Meckel Gruber syndrome, genetic analysis is indicated. PMID- 28812469 TI - Placental Pathologic Associations With Morbidly Adherent Placenta: Potential Insights Into Pathogenesis. AB - Background The pathology that underlies morbidly adherent placenta (MAP) is poorly understood. The objective of this study was to describe the placental pathology, especially implantation site pathology, associated with MAP. Methods This was a single institution, retrospective case-control study design examining placentas of patients who delivered between January 2008 and September 2013. MAP cases were defined by the need for clinical intervention at delivery beyond spontaneous placental delivery or simple manual extraction of the placenta. Controls consisted of patients with placentas sent for examination due to a history of maternal malignancy with no clinical suspicion of accreta. Placental pathologic findings of maternal vascular underperfusion (MVU), acute inflammation, chronic inflammation, fetal vascular obstruction, and hemorrhage were recorded and compared using bivariable and multivariable analyses. Results Three categories of pathologic changes were seen more commonly in MAP placentas (N = 101) than control placentas (N = 110): chronic basal inflammation, villous changes of MVU, and retromembranous and subchorionic/intervillous hemorrhage. In multivariable analyses adjusted for confounders, basal chronic villitis (aOR 5.6, 1.73-18.18), plasma cell deciduitis (aOR 2.63, 1.08-6.39), increased syncytial knots (aOR 3.92, 1.57-9.75), villous agglutination (aOR 24.85, 2.78-221.75), increased perivillous fibrin (aOR 5.08, 1.49-17.34), and the presence of subchorionic/intervillous thrombi (aOR 4.01, 1.63-9.86) remained associated with MAP. Conclusions MAP is highly associated with evidence of intraparenchymal placental hemorrhage, villous changes of MVU, and a lymphoplasmacytic infiltrate at the implantation site. The contribution of this basal chronic inflammatory infiltrate to MAP requires further investigation. PMID- 28812470 TI - Oral administration of ovalbumin after sensitization attenuates symptoms in a mouse model of food allergic enteropathy. AB - Oral immunotherapy (OIT) is a promising treatment of food allergy. To administer an appropriate oral dose of an allergenic component as OIT to individuals sensitized with a food allergen may prevent inducing food allergic inflammation in them. So we attempted to establish a mouse model to evaluate efficacy for oral administration of food allergen after sensitization. In BALB/c mice sensitized by injecting ovalbumin (OVA) with alum twice, OVA was administered before inducing inflammation by feeding the mice with egg white (EW) diet. Severe inflammatory responses, such as enteropathy, weight loss, IL-4 production, and increase of IgE antibody levels, were suppressed by administration with 4 mg of OVA 7 times before feeding EW diet. OVA administration alone induced a slight Th2 response, but no symptoms. The current study demonstrated that severe food allergic enteropathy could be prevented by pre-administration with appropriate dose of OVA to sensitized mice. PMID- 28812471 TI - Effectiveness and tolerability of parenteral testosterone undecanoate: a post marketing surveillance study. AB - This observational post-marketing study of parenteral testosterone undecanoate (TU) in a non-selected population aimed to: examine the effectiveness of TU as treatment of hypogonadism; record adverse drug reactions (ADR) quantitatively particularly regarding polycythemia, prostate safety and cardiovascular-related metabolic risk factors; and verify whether recommended injection intervals apply to routine clinical practice. Eight hundred and seventy subjects from 259 outpatient units scheduled to visit the clinic six times were included. Effectiveness and tolerability of TU administration were assessed on a 4-point scale. Body weight, waist girth, blood pressure, hemoglobin levels, hematocrit, prostate-specific antigen (PSA), and digital rectal prostate examination were assessed. Over 90% of subjects completed the observational duration of 52.8 +/- 9.7 weeks (mean +/- SD) and 56% judged effectiveness as very good, 30.8% as good. 63.1% judged tolerability as very good, and 24.4% as good. No adverse effects on indicators of cardiovascular risk were observed. Polycythemia occurred in one subject and a supranormal hematocrit in one subject. Four subjects developed supranormal PSA levels. Prostate carcinoma was found in one subject, one subject had recurrence of a previously surgically treated prostate carcinoma, and the other two showed no indication of malignancy. Parenteral TU is safe, effective, and well-tolerated in clinical practice proving a good therapeutic option for hypogonadism. PMID- 28812473 TI - Implementation of a Pathway for the Treatment of Fever and Neutropenia in Pediatric Patients With Cancer. AB - Fever and neutropenia is an oncologic emergency. Time-to-antibiotics (TTA) refers to the amount of time from initial provider evaluation for fever and neutropenia to intravenous antibiotic administration. Research supports that rapid time-to antibiotics (RTTA) is associated with improved patient outcomes. This quality improvement project evaluated the success of implementing an RTTA pathway in pediatric oncology patients with fever and neutropenia. The setting was an advanced practice nurse-managed pediatric ambulatory infusion center where patients with fever and neutropenia were often evaluated and treated. In order to improve TTA, a multidisciplinary pathway was implemented with a goal of TTA that was less than 60 minutes from initial provider evaluation. Implementation of the RTTA pathway included discussion of shared expectations with the pharmacy and education departments and discussion of shared expectations with the bedside nurses and advanced practice nurses staffing the unit. Additionally, a preliminary lab test was utilized. Success of the implementation was evaluated through 2 measures: TTA and nurses' knowledge of fever and neutropenia and the importance of RTTA. The aims of this project were to improve TTA as well as nurses' knowledge of fever and neutropenia and the importance of RTTA, and both these aims were successfully attained. PMID- 28812474 TI - Protective effect of raisin (currant) against spatial memory impairment and oxidative stress in Alzheimer disease model. AB - OBJECTIVES: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive pathological changes of the brain. A number of studies demonstrated compelling evidence of the importance of oxidative processes in AD pathogenesis. Raisin contains polyphenol, phenolic acid, and tannin compounds, which have antioxidant and anti-inflammatory properties. The present study was aimed to evaluate the protective effect of raisin on neurobehavioral and histological changes in rats with Alzheimer. METHODS: Animal model of AD was induced by intraperitoneal injection of aluminium chloride for 60 days (100 mg/kg body weight). During these 60 days both Alzheimer's and control rats were given 6 g of raisin per rat. At the end of the treatment, blood was collected for biochemical assessment. We used a Morris water task and passive avoidance test to assess spatial memory. RESULTS: Our results showed that aluminium exposure significantly decreased the memory in the MWT and passive avoidance test, but in the raisin + AlCl3 group, it significantly increased spatial memory in both tests. Also, Aluminium exposure significantly increased malondialdehyde (MDA) and decreased ferric reducing ability of plasma (ferric reducing/antioxidant power (FRAP)), while treatment with raisin significantly decreased MDA and increased FRAP in plasma of blood. DISCUSSION: Our findings showed that raisin has a neuroprotective effect and improves the spatial memory in AD animal models. PMID- 28812472 TI - Modifiable risk factors associated with bronchiolitis. AB - BACKGROUND: We sought to clarify possibly modifiable risk factors related to pollution responsible for acute bronchiolitis in hospitalized infants. METHODS: For this observational study, we recruited 213 consecutive infants with bronchiolitis (cases: median age: 2 months; age range: 0.5-12 months; boys: 55.4%) and 213 children aged <3 years (controls: median age: 12 months; age range: 0.5-36 months; boys: 54.5%) with a negative medical history for lower respiratory tract diseases hospitalized at 'Sapienza' University Rome and IRCCS Bambino Gesu Hospital. Infants' parents completed a standardized 53-item questionnaire seeking information on social-demographic and clinical characteristics, indoor pollution, eating habits and outdoor air pollution. Multivariate logistic regression analyses were run to assess the independent effect of risk factors, accounting for confounders and effect modifiers. RESULTS: In the 213 hospitalized infants the questionnaire identified the following risk factors for acute bronchiolitis: breastfeeding ?3 months (OR: 2.1, 95% confidence interval [CI]: 1.2-3.6), presence of older siblings (OR: 2.8, 95% CI: 1.7-4.7), ?4 cohabitants (OR: 1.5, 95% CI: 1.1-2.1), and using seed oil for cooking (OR: 1.7, 95% CI: 1.2-2.6). Having renovated their home in the past 12 months and concurrently being exposed daily to smoking, involving more than 11 cigarettes and two or more smoking cohabitants, were more frequent factors in cases than in controls ( p = 0.021 and 0.05), whereas self-estimated proximity to road and traffic was similar in the two groups. CONCLUSIONS: We identified several risk factors for acute bronchiolitis related to indoor and outdoor pollution, including inhaling cooking oil fumes. Having this information would help public health authorities draw up effective preventive measures - for example, teach mothers to avoid handling their child when they have a cold and eliminate exposure to second-hand tobacco smoke. PMID- 28812475 TI - Rise in acid attacks prompts call for guidelines for emergency staff. AB - Emergency department clinicians and ambulance crews should have clear guidance on dealing with acid attacks, leading emergency doctors say. PMID- 28812476 TI - Developing nurses' transformational leadership skills. AB - Healthcare is a complex area with significant potential for service improvement despite the effects of increasing economic and social pressures on the quality and safety of patient care. As the largest group of healthcare professionals in direct contact with patients, nurses are well positioned to contribute to improvements in healthcare services and to the development of new policies. To influence healthcare improvements and policies effectively, nurses require leadership skills. Historically, it was thought that only nurses in management roles required leadership skills; however, the ability to influence change is a requirement at all levels of clinical practice. Transformational leadership competencies provide nurses with the skills to contribute to improvements in the quality and safety of patient care, while enhancing their career satisfaction. This article examines how nurses can apply transformational leadership to their practice. It also informs nurses how to conduct an initial self-assessment of their leadership skills and to formulate a transformational leadership development plan. PMID- 28812477 TI - A bursary for men is an insult. AB - As a man, who trained many years ago as a nurse, I object strongly to this sort of measure ('Coventry University offers bursaries to encourage more men into nursing', online news, 4 August). PMID- 28812480 TI - New guide helps carers use art in dementia care. AB - Nurses who supervise art workshops for people with dementia can refer to a new guide to help things run smoothly. PMID- 28812479 TI - Student life - International experience. AB - I was one of more than 40 nursing students who travelled to Berlin in June for a five-day trip focusing on the health and care of refugees and asylum seekers - an area I previously knew little about. PMID- 28812481 TI - Readers' panel - Has management bashing gone too far? AB - Our experts consider a hot topic of the day. PMID- 28812482 TI - No wonder we all hate hospitals. AB - 'I hate hospitals,' patients often say, and I always agree with them. I don't know why they are surprised - maybe they forget nurses are human too, with our own baggage. Perhaps they think we are so dedicated to our work that every moment in harness is a delight. PMID- 28812484 TI - App designed with the help of nurses aims to combat obesity in the profession. AB - An interactive resource has been launched with the aim of helping busy nurses who are obese or overweight achieve and maintain a healthier weight. PMID- 28812483 TI - First world war: 'The first big test of professional nursing'. AB - When Helen Fairchild, a young nurse in Pennsylvania, volunteered to take her skills to Europe in the first world war, she was glad to go but felt sorry for her mother. 'If she would only not worry so much', she wrote to her brother Ned. PMID- 28812485 TI - The sharp descent into poverty. AB - When breast cancer treatment stopped mental health nurse Kath Clayson from working for six months, she quickly found herself sliding into debt. PMID- 28812486 TI - Nine in ten largest trusts in England short of nurses. AB - Nine out of ten of England's 50 largest NHS hospital trusts are not staffed with nurses to the level planned by their own management, the RCN said. PMID- 28812487 TI - Modern Management of Perinatal Psychiatric Disorders (Second edition) Henshaw Carol Cox John Barton Joanne Modern Management of Perinatal Psychiatric Disorders (Second edition) 330pp L35 RCPsych Publications 9781909726772 190972677X [Formula: see text]. AB - This book presents a comprehensive synthesis of the evidence on perinatal mental health disorders. Written by perinatal and child psychiatrists, the book provides information for midwives, nurses and other professionals on the care of women with perinatal mental health disorders. PMID- 28812488 TI - Fast Facts: Parkinson's Disease (Fourth edition) Chaudhuri K Ray Fung Victor SC Fast Facts: Parkinson's Disease (Fourth edition) 168p L15 Health Press 9781908541932 1908541938 [Formula: see text]. AB - Although small, this book is easy to read, well-structured and contains a vast amount of information on Parkinson's disease and its associated syndromes. PMID- 28812489 TI - Evaluating Outcomes in Health and Social Care Dickinson Helen Evaluating Outcomes in Health and Social Care 144pp L12.99 Janine O'Flynn Policy Press 9781447329763 1447329767 [Formula: see text]. AB - One of a series of five books on interagency partnership in public health and social care, this book focuses on evaluation. It guides the reader through the outcomes evaluation process beginning with an explanation of what evaluation and outcomes are and why they matter. PMID- 28812490 TI - Advice on hep B vaccine shortage. AB - Guidance for health professionals has been issued after global shortages of the hepatitis B vaccine has severely affected UK supply. PMID- 28812492 TI - Will this surprise plan work? AB - The government's announcement that it will fund an extra 10,000 training places for nurses, midwives and allied health professionals (AHPs) in England has taken the profession by surprise. PMID- 28812493 TI - Risk of heart attack heightened for five years following stroke. AB - Stroke survivors who seem fully recovered are at a heightened risk of dying or experiencing a heart attack for at least five years after the event, research has shown. PMID- 28812494 TI - Diabetes nurse Sian's care for her patients radiates from her. AB - I meet many people through my health condition and they always talk about senior diabetes nurse Sian Bodman with high regard. Reputations are important, especially in the valley community where I live. PMID- 28812495 TI - Caring robots are here to help. AB - Robots, along with sensors and telemedicine, have been identified as technologies that can assist and prolong independent living for older people, with robots especially being used to help prevent social isolation and depression. PMID- 28812496 TI - Walking the dog gets older people out rain or shine. AB - Older dog owners are likely to be more physically active in the winter than people of similar age are in the summer, a study has found. PMID- 28812497 TI - 'Follow your heart, not the crowd'. AB - Zena Aldridge qualified as a mental health nurse in 2003 at the University of East Anglia. In 2013, she was appointed as the first Admiral Lead Nurse for Norfolk, and is now Admiral Nurse for Norfolk, Suffolk and Cambridgeshire, working for Dementia UK. PMID- 28812498 TI - Towards a smoke-free generation. AB - Essential facts Just over 15% of adults in the UK smoke, the lowest level since records began. However, smoking remains the single biggest cause of preventable deaths. PMID- 28812500 TI - Football charity trains to tackle mental ill health. AB - A mental health nurse is helping volunteers for a football club's charity learn how to tackle mental ill health. PMID- 28812501 TI - Taking antidepressants during pregnancy linked to autism. AB - Children exposed to antidepressants in utero are at a slightly higher risk of autism than children of mothers with psychiatric disorders who were not treated with antidepressants, a study has found. PMID- 28812502 TI - Post-discharge care for patients following stoma formation: what the nurse needs to know. AB - Rationale and key points This article discusses post-discharge care for patients following stoma formation. While the patient is taught the practicalities of managing the stoma appliance in hospital, this learning should be integrated into their daily life following discharge from hospital. Nurses are required to consider and address any issues that might affect the patient in the long term. These include changes in body image, adapting to having a stoma, preventing or treating complications associated with a stoma, and long-term follow-up. " Most patients manage successfully with their stoma following a period of adaptation. " Follow-up for patients with a stoma can occur over the telephone and/or face-to face in the patient's home or in the clinic. " There are several support groups in the UK that can be accessed by patients with a stoma. " Patients should seek advice and assistance from a stoma specialist nurse if any issues related to the stoma arise, such as leakage or sore peristomal skin. PMID- 28812503 TI - Lung screening prompts some smokers to seek help to stop. AB - Smokers who undergo a computed tomography (CT) scan of their lungs are more likely to quit than those who do not, a study suggests. PMID- 28812504 TI - Practising mindfulness. AB - What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The article examined the use of mindfulness techniques and how by learning to care for themselves, nurses can enhance the care they provide for patients. The concept of mindfulness has had widespread publicity, from meditation courses to adult colouring books, but I wanted to learn how mindfulness can be applied to nursing. PMID- 28812506 TI - Don't keep FGM hidden. AB - Annual figures from NHS Digital, published in early July, show that there were 5,391 newly recorded cases of female genital mutilation (FGM) in England in 2016 17. PMID- 28812507 TI - Advice on how to make a programme successful. AB - Before taking on a degree-nurse apprentice, organisations need to consider what is involved and who should be part of the planning process. PMID- 28812510 TI - Make Jeremy Hunt read NS! AB - Jeremy Hunt should be put in a darkened room with a supply of Nursing Standard and - over a 12-hour shift with a snatched toilet break/cup of coffee - forced to read from cover to cover. PMID- 28812511 TI - I can't believe the NMC. AB - I was disgusted to read, at a time when nurses are fighting for a pay award of above 1%, that the Nursing and Midwifery Council sees fit to increase the remuneration package of their chief executive by L36,000 (news, 26 July). PMID- 28812512 TI - I'm heartened by the public's support for our summer of protest. AB - Nurses and other health professionals are joining our summer of protest, voicing their anger at the pay cap. The level of support from the public is heartening, with a growing number of people, including members of the government, understanding the need to scrap the cap. PMID- 28812513 TI - How to convince yourself you've got what it takes. AB - After submitting a job application, you must of course wait to hear if you have passed the first hurdle. It can be a frustrating period but there's nothing you can do to alter this outcome. PMID- 28812514 TI - Shortages take their toll. AB - Every nurse who leaves an organisation incurs big costs. Research shows the financial impact of nurse turnover on an employer is equivalent to at least several months' salary per nurse. Lost productivity, and the time and cost of finding replacement nurses, are major concerns for most NHS trusts. At a time of nursing shortages, these problems are exacerbated. PMID- 28812515 TI - Recognising and responding to care erosion: part 1. AB - This article is the first in a two-part series discussing declining standards of care. Many healthcare organisations, particularly hospitals, are under increased pressure to maintain standards of care while experiencing funding and staff shortages, and increasing patient numbers and demand for services. One of the main risks associated with these competing demands is a gradual decline in care standards, described as 'care erosion' in this article. Understanding the psychosocial mechanisms that can lead to care erosion is important in preventing its occurrence. This article uses the theory of cognitive dissonance to explain how nurses reflect on, and maintain, quality of care. If practice is suboptimal or substandard and inconsistent with nursing values, standards or regulations, nurses are likely to experience inner conflict or 'dissonance discomfort' and will usually attempt to reduce this feeling by enhancing the quality of care they provide. Conversely, nurses may defend, deny, trivialise or ignore substandard care. The authors suggest that this is the mechanism that leads to care erosion. This article uses three scenarios to explore the nurse's role in care erosion. Part two of this article discusses the wider involvement of individuals, organisations and nurse education in preventing care erosion. PMID- 28812516 TI - Letter. AB - I find this to be extremely wrong; I cannot believe it is being applauded. It is completely supporting gender discrimination. PMID- 28812518 TI - Trust's nurse of the year. AB - Nursing student Christina O'Loughlin has had a tram named after her in her home city of Nottingham. The tram bears her name in recognition of her winning Nottingham University Hospitals NHS Trust's nurse of the year award after a public vote. PMID- 28812517 TI - We deserve a 55% pay rise. AB - It's good news to recruit more nurses, but now plan the retention bit (news, 9 August). Professionals deserve more. I suggest a 55% rise for nurses and 35% rise for junior doctors. Senior clinical staff should raise staff establishments to safe levels. Not ministers. PMID- 28812519 TI - Department of Health's public utterances reek of complacency. AB - Read a news story about a problem afflicting the NHS and invariably there is a quote attributed to a spokesperson from the Department of Health (DH). PMID- 28812520 TI - Maintaining dignity in death. AB - When I started my nursing degree last February, I set myself goals I wanted to achieve by the end of my first year. One of these was to care for a patient at the end of life and perform last offices. PMID- 28812521 TI - Nursing Now! campaign to support and empower nurses. AB - Nurses are too often 'invisible, taken for granted and prevented from being as effective as they could be', a former health minister and NHS leader spearheading a global campaign to boost the profile of nursing said. PMID- 28812522 TI - Dietary advice for children has good effect on parents too. AB - Nutrition advice given to children can also improve parents' diets, an ongoing study has revealed. PMID- 28812523 TI - Funding changes will threaten vital services. AB - The government has highlighted the need to address the growing demands on the NHS and social care services, stating the importance of preventing ill health and promoting well-being. However, its actions do not appear to match its rhetoric. PMID- 28812524 TI - Biologically important hydrazide-containing fused azaisocytosines as antioxidant agents. AB - OBJECTIVES: Two important classes of hydrazide-containing fused azaisocytosines were evaluated as possible antioxidants and characterised by UV spectroscopy. METHODS: 2,2-Diphenyl-1-picrylhydazyl (DPPH), nitric oxide (NO), hydrogen peroxide (H2O2) scavenging potencies and reducing power of molecules were evaluated. RESULTS: The strongest DPPH scavengers were found to be 9, showing the potency superior to that of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate (PG) and 6-hydroxy-2,5,7,8 tetramethylchroman-2-carboxylic acid (Trolox) and comparable to that of ascorbic acid (AA), and 6, revealing the antioxidant potency superior to that of BHA, BHT, PG and Trolox. In turn, 3 and 9 were the most promising NO scavengers, exhibiting the potency superior to that of BHA, BHT (3 and 9) and AA (3). The most potent H2O2 scavengers proved to be 10 and 9 showing similar or even better neutralising potency than that of Trolox, BHT and BHA. Simultaneously, the majority of hydrazides revealed higher ferric reducing abilities than that of AA and BHT. Some structure-activity relationships were explored. A possible mechanism for the DPPH radical scavenging ability of hydrazide-containing molecules was proposed. DISCUSSION: Hydrazides 3, 6 and 9 with an antioxidant potential better or comparable to that of the well-known antioxidants are proposed as new antioxidant candidates. PMID- 28812525 TI - A cross-cultural exploration of abortion fund patients in the USA and the Republic of Ireland, Northern Ireland and the Isle of Man. AB - This paper details results of a study examining administrative case data from 2010-2015 from abortion funds serving the USA and the Republic of Ireland, Northern Ireland and the Isle of Man. Driven by the available data, the researchers compared organisational characteristics, patient characteristics, procedural costs, patient resources and the ratio between patient resources and procedural costs. Independent t-tests were conducted to assess whether differences in characteristics, costs or resources were significant. The number of patients serviced by abortion funds across the two datasets increased yearly from 2010-2015. While patients in the USA had more resources, on average, to contribute to their abortion procedure, Irish, Northern Irish and Manx patients had the resources to pay for a greater percentage of their costs, on average, which was mainly attributable to the differences in gestational age of those helped by the different abortion funds. Patients across all nations were similar in terms of their marital status, average age and number of existing children. Patients across these countries face expensive procedures and a lack of resources that are bridged in part by abortion fund assistance. PMID- 28812526 TI - Parvovirus Infection Is Associated With Myocarditis and Myocardial Fibrosis in Young Dogs. AB - Perinatal parvoviral infection causes necrotizing myocarditis in puppies, which results in acute high mortality or progressive cardiac injury. While widespread vaccination has dramatically curtailed the epidemic of canine parvoviral myocarditis, we hypothesized that canine parvovirus 2 (CPV-2) myocardial infection is an underrecognized cause of myocarditis, cardiac damage, and/or repair by fibrosis in young dogs. In this retrospective study, DNA was extracted from formalin-fixed, paraffin-embedded tissues from 40 cases and 41 control dogs under 2 years of age from 2007 to 2015. Cases had a diagnosis of myocardial necrosis, inflammation, or fibrosis, while age-matched controls lacked myocardial lesions. Conventional polymerase chain reaction (PCR) and sequencing targeting the VP1 to VP2 region detected CPV-2 in 12 of 40 cases (30%; 95% confidence interval [CI], 18%-45%) and 2 of 41 controls (5%; 95% CI, 0.1%-16%). Detection of CPV-2 DNA in the myocardium was significantly associated with myocardial lesions ( P = .003). Reverse transcription quantitative PCR amplifying VP2 identified viral messenger RNA in 12 of 12 PCR-positive cases and 2 of 2 controls. PCR results were confirmed by in situ hybridization, which identified parvoviral DNA in cardiomyocytes and occasionally macrophages of juvenile and young adult dogs (median age 61 days). Myocardial CPV-2 was identified in juveniles with minimal myocarditis and CPV-2 enteritis, which may indicate a longer window of cardiac susceptibility to myocarditis than previously reported. CPV-2 was also detected in dogs with severe myocardial fibrosis with in situ hybridization signal localized to cardiomyocytes, suggesting prior myocardial damage by CPV-2. Despite the frequency of vaccination, these findings suggest that CPV-2 remains an important cause of myocardial damage in dogs. PMID- 28812527 TI - Cytokine Concentrations Measured by Multiplex Assays in Canine Peripheral Blood Samples. AB - Cytokines are known to play important roles in a wide range of pathologic conditions spanning all organ systems in every species studied. As our knowledge of the physiology of individual cytokines expands and our ability to measure multiple cytokines in smaller biological samples increases, we gain more insight into the significance and function of each cytokine and the importance of cytokine networks. Previous studies that reported measurements of cytokine concentrations from serum or plasma in dogs with infectious, autoimmune, metabolic, endocrine, and neoplastic diseases yield an appreciation for the complexity of cytokine control and potential applications for cytokine measurements in the diagnosis, prognosis, and therapy of a variety of disease conditions. In this review, we highlight the benefits of multiplex cytokine analysis, summarize clinical and experimental reports that have used this technology in dogs, and discuss the strengths and limitations of data analysis for the interpretation of results in these studies. We describe how differences in technical acuity, data reporting tactics, statistical analysis, study population selection criteria, and cross-sectional experimental design methods may affect interpretation of results from this technology. We also suggest methods for analysis in future studies, such as reporting median fluorescence intensity values, analyzing the proportion of patients above population medians, and performing longitudinal studies. PMID- 28812528 TI - Acute Leukemia in Horses. AB - Leukemia is broadly divided into acute and chronic lymphocytic and myeloid types based on the proportion of blasts, morphology of cells, and expression of specific antigens on neoplastic cells. Classifying leukemia in horses can be challenging if blasts predominate and since few antibodies to identify cell types are available. The objective of this study was to describe in detail the clinical and pathologic features of acute leukemia in horses. Twelve horses ranging from 0.2 to 25.9 years of age were diagnosed with acute leukemia. Six cases were classified as acute lymphocytic leukemia (ALL) based on predominance of blasts, lack of granulocytic or monocytic differentiation, and detection of CD3, CD20, and/or CD79a antigens by immunohistochemistry. Six other cases were classified as acute myeloid leukemia (AML) with myelomonocytic ( n = 4), basophilic ( n = 1), and eosinophilic ( n = 1) differentiation based on > 20% bone marrow blasts and partial leukocytic differentiation. Reactivity with antibodies to Iba-1/AIF-1, CD172a, and CD163 was determined for all cases of AML. Eleven horses had thrombocytopenia, 10 had neutropenia, 8 had anemia, all had blasts on blood films, and none had leukocytosis. Ten horses had increased serum acute phase proteins. Bone marrow cellularity ranged from 30% to 100%, and the proportion of blasts ranged from 80% to 100% and 30% to 60% in ALL and AML, respectively. Horses were severely ill at diagnosis and euthanized within days or weeks. Unique features of acute leukemia in horses compared to other species were variable lymphocyte antigen expression (ALL) and frequent inflammation (ALL and AML). PMID- 28812530 TI - Feline Herpesvirus Pneumonia: Investigations Into the Pathogenesis. AB - Feline herpesvirus type 1 (FeHV-1) is one of the etiological agents of feline respiratory disease. FeHV-1 is an epitheliotropic and cytopathic virus that mainly causes rhinitis and conjunctivitis, although pneumonia is also occasionally seen. In this study, the authors investigated the pathogenesis of FeHV-1-associated pneumonia, comparing natural cases with viral infection of tracheal ring and cell cultures in vitro, using histology, immunohistology, double immunofluorescence, and transmission electron microscopy as investigative tools. The results confirm that FeHV-1 targets both respiratory epithelial cells and pneumocytes and indicate that FeHV-1 pneumonia is the consequence of continuous cell-to-cell viral spread from the upper airways via the trachea into the lungs. They provide strong evidence that FeHV-1-infected cells die primarily via apoptosis, following loss of cell-to-cell contact, rounding, and detachment. However, virus-induced lesions in vivo are dominated by marked neutrophil infiltration and extensive necrosis with less prominent apoptosis; in the airways, the tissue necrosis can extend into the submucosa. The necrosis appears to result from virus-induced neutrophil influx and release of proteolytic enzymes, such as matrix metalloproteinase-9, from the neutrophils. PMID- 28812531 TI - Prolactinoma in a Dog. AB - A 12-year-old male Yorkshire Terrier was presented because of decreased appetite. Physical examination revealed mammary gland swelling and galactorrhea. Contrast enhanced computed tomographic scanning of the skull indicated an enlarged pituitary gland, compatible with a pituitary tumor. The serum prolactin concentration was markedly elevated. One week after the start of treatment with the dopamine agonist cabergoline, the serum prolactin concentration normalized and the galactorrhea resolved. Cabergoline was administered for approximately 4 months and then discontinued. Subsequently, serum prolactin concentration increased again, and mammary gland swelling and galactorrhea reappeared. The dog was euthanized 10 months after the first detection of the galactorrhea because of problems not directly related to pituitary disease. Postmortem examination revealed an infiltrative adenoma of the pituitary gland with immunolabeling for prolactin. The clinical and histopathologic findings indicated the diagnosis of a functional prolactinoma in a male dog. PMID- 28812529 TI - Approaches to Evaluate Lung Inflammation in Translational Research. AB - Inflammation is a common feature in several types of lung disease and is a frequent end point to validate lung disease models, evaluate genetic or environmental impact on disease severity, or test the efficacy of new therapies. Questions relevant to a study should be defined during experimental design and techniques selected to specifically address these scientific queries. In this review, the authors focus primarily on the breadth of techniques to evaluate lung inflammation that have both clinical and preclinical applications. Stratification of approaches to assess lung inflammation can diminish weaknesses inherent to each technique, provide data validation, and increase the reproducibility of a study. Specialized techniques (eg, imaging, pathology) often require experienced personnel to collect, evaluate, and interpret the data; these experts should be active contributors to the research team through reporting of the data. Scoring of tissue lesions is a useful method to transform observational pathologic data into semiquantitative or quantitative data for statistical analysis and enhanced rigor. Each technique to evaluate lung inflammation has advantages and limitations; understanding these parameters can help identify approaches that best complement one another to increase the rigor and translational significance of data. PMID- 28812532 TI - Spontaneous, Experimentally Induced, and Transmissible AA Amyloidosis in Japanese Quail ( Coturnix japonica). AB - The authors describe a spontaneous case of amyloid A (AA) amyloidosis in an adult female Japanese quail ( Coturnix japonica). The bird developed AA amyloidosis secondary to chronic peritonitis caused by a Gram-negative bacillus infection. Mild amyloid deposition was also identified in the intestinal tract of apparently healthy adult individuals, suggesting that quail may develop intestinal amyloidosis with age. Based on these observations, it was hypothesized that quail can develop AA amyloidosis following inflammatory stimulation with lipopolysaccharide (LPS). Therefore, adult quail were repeatedly injected with LPS and the development of AA amyloidosis was confirmed. The amyloid deposition in this model increased when quail amyloid was intravenously injected as an amyloid-enhancing factor. The experiments were repeated with young quail, but amyloid deposits were not observed following LPS injections. However, AA amyloidosis did develop when quail amyloid was injected in addition to LPS. These results indicated that adult quail develop AA amyloidosis after inflammatory stimulation with LPS. Furthermore, quail AA amyloidosis was shown to have transmissibility regardless of age. Interestingly, the authors found that administration of chicken amyloid fibrils also induced AA amyloidosis in young quail. This is the first report of cross-species transmission of avian AA amyloidosis. PMID- 28812533 TI - Immunoreactivity of Canine Liposarcoma to Muscle and Brown Adipose Antigens. AB - Liposarcoma, rhabdomyosarcoma, and hibernoma share some overlapping histologic and immunohistochemical features. Although immunohistochemistry (IHC) is commonly used in the diagnosis of these neoplasms, expression of muscle markers has been reported in human liposarcoma and canine hibernoma in addition to rhabdomyosarcoma. Thus, these neoplasms are a diagnostic challenge but important to distinguish because of differences in prognosis and treatment. Rhabdomyosarcoma and liposarcoma are both malignant, but rhabdomyosarcoma has a higher potential for metastasis. In contrast, hibernomas are benign with low risk of recurrence. This study investigated expression of the muscle markers desmin, myogenin, and alpha-smooth muscle actin (alpha-SMA) and the brown fat marker uncoupling protein 1 (UCP1) in 25 cases of canine liposarcoma using IHC. Oil red O histochemistry was performed to confirm the presence of lipid and the diagnosis of liposarcoma in cases that were not well-differentiated. The 25 cases included 15 well-differentiated, 5 pleomorphic, 3 myxoid, and 2 dedifferentiated subtypes of liposarcoma. By IHC, 23 of 25 expressed UCP1, 7 of 25 expressed alpha-SMA, 7 of 25 expressed desmin, and 3 of 25 expressed myogenin with no clear relationship of antigen expression and tumor subtype. These findings clarify the immunohistochemical profile of canine liposarcoma and suggest overlap in the expression of several muscle antigens and UCP1 between liposarcoma, hibernoma, and rhabdomyosarcoma. PMID- 28812534 TI - Microsatellite instability status predicts response to anti-PD-1/PD-L1 therapy regardless the histotype: A comment on recent advances. PMID- 28812535 TI - Associating mutations causing cystinuria with disease severity with the aim of providing precision medicine. AB - BACKGROUND: Cystinuria is an inherited disease that results in the formation of cystine stones in the kidney, which can have serious health complications. Two genes (SLC7A9 and SLC3A1) that form an amino acid transporter are known to be responsible for the disease. Variants that cause the disease disrupt amino acid transport across the cell membrane, leading to the build-up of relatively insoluble cystine, resulting in formation of stones. Assessing the effects of each mutation is critical in order to provide tailored treatment options for patients. We used various computational methods to assess the effects of cystinuria associated mutations, utilising information on protein function, evolutionary conservation and natural population variation of the two genes. We also analysed the ability of some methods to predict the phenotypes of individuals with cystinuria, based on their genotypes, and compared this to clinical data. RESULTS: Using a literature search, we collated a set of 94 SLC3A1 and 58 SLC7A9 point mutations known to be associated with cystinuria. There are differences in sequence location, evolutionary conservation, allele frequency, and predicted effect on protein function between these mutations and other genetic variants of the same genes that occur in a large population. Structural analysis considered how these mutations might lead to cystinuria. For SLC7A9, many mutations swap hydrophobic amino acids for charged amino acids or vice versa, while others affect known functional sites. For SLC3A1, functional information is currently insufficient to make confident predictions but mutations often result in the loss of hydrogen bonds and largely appear to affect protein stability. Finally, we showed that computational predictions of mutation severity were significantly correlated with the disease phenotypes of patients from a clinical study, despite different methods disagreeing for some of their predictions. CONCLUSIONS: The results of this study are promising and highlight the areas of research which must now be pursued to better understand how mutations in SLC3A1 and SLC7A9 cause cystinuria. The application of our approach to a larger data set is essential, but we have shown that computational methods could play an important role in designing more effective personalised treatment options for patients with cystinuria. PMID- 28812536 TI - eDGAR: a database of Disease-Gene Associations with annotated Relationships among genes. AB - BACKGROUND: Genetic investigations, boosted by modern sequencing techniques, allow dissecting the genetic component of different phenotypic traits. These efforts result in the compilation of lists of genes related to diseases and show that an increasing number of diseases is associated with multiple genes. Investigating functional relations among genes associated with the same disease contributes to highlighting molecular mechanisms of the pathogenesis. RESULTS: We present eDGAR, a database collecting and organizing the data on gene/disease associations as derived from OMIM, Humsavar and ClinVar. For each disease associated gene, eDGAR collects information on its annotation. Specifically, for lists of genes, eDGAR provides information on: i) interactions retrieved from PDB, BIOGRID and STRING; ii) co-occurrence in stable and functional structural complexes; iii) shared Gene Ontology annotations; iv) shared KEGG and REACTOME pathways; v) enriched functional annotations computed with NET-GE; vi) regulatory interactions derived from TRRUST; vii) localization on chromosomes and/or co localisation in neighboring loci. The present release of eDGAR includes 2672 diseases, related to 3658 different genes, for a total number of 5729 gene disease associations. 71% of the genes are linked to 621 multigenic diseases and eDGAR highlights their common GO terms, KEGG/REACTOME pathways, physical and regulatory interactions. eDGAR includes a network based enrichment method for detecting statistically significant functional terms associated to groups of genes. CONCLUSIONS: eDGAR offers a resource to analyze disease-gene associations. In multigenic diseases genes can share physical interactions and/or co-occurrence in the same functional processes. eDGAR is freely available at: edgar.biocomp.unibo.it. PMID- 28812537 TI - Leveraging network analytics to infer patient syndrome and identify causal genes in rare disease cases. AB - BACKGROUND: Next-generation sequencing is widely used to identify disease-causing variants in patients with rare genetic disorders. Identifying those variants from whole-genome or exome data can be both scientifically challenging and time consuming. A significant amount of time is spent on variant annotation, and interpretation. Fully or partly automated solutions are therefore needed to streamline and scale this process. RESULTS: We describe Phenotype Driven Ranking (PDR), an algorithm integrated into Ingenuity Variant Analysis, that uses observed patient phenotypes to prioritize diseases and genes in order to expedite causal-variant discovery. Our method is based on a network of phenotype-disease gene relationships derived from the QIAGEN Knowledge Base, which allows for efficient computational association of phenotypes to implicated diseases, and also enables scoring and ranking. CONCLUSIONS: We have demonstrated the utility and performance of PDR by applying it to a number of clinical rare-disease cases, where the true causal gene was known beforehand. It is also shown that PDR compares favorably to a representative alternative tool. PMID- 28812538 TI - Development of pathogenicity predictors specific for variants that do not comply with clinical guidelines for the use of computational evidence. AB - BACKGROUND: Strict guidelines delimit the use of computational information in the clinical setting, due to the still moderate accuracy of in silico tools. These guidelines indicate that several tools should always be used and that full coincidence between them is required if we want to consider their results as supporting evidence in medical decision processes. Application of this simple rule certainly decreases the error rate of in silico pathogenicity assignments. However, when predictors disagree this rule results in the rejection of potentially valuable information for a number of variants. In this work, we focus on these variants of the protein sequence and develop specific predictors to help improve the success rate of their annotation. RESULTS: We have used a set of 59,442 protein sequence variants (15,723 pathological and 43,719 neutral) from 228 proteins to identify those cases for which pathogenicity predictors disagree. We have repeated this process for all the possible combinations of five known methods (SIFT, PolyPhen-2, PON-P2, CADD and MutationTaster2). For each resulting subset we have trained a specific pathogenicity predictor. We find that these specific predictors are able to discriminate between neutral and pathogenic variants, with a success rate different from random. They tend to outperform the constitutive methods but this trend decreases as the performance of the constitutive predictor improves (e.g. with PON-P2 and PolyPhen-2). We also find that specific methods outperform standard consensus methods (Condel and CAROL). CONCLUSION: Focusing development efforts on the case of variants for which known methods disagree we may obtain pathogenicity predictors with improved performances. Although we have not yet reached the success rate that allows the use of this computational evidence in a clinical setting, the simplicity of the approach indicates that more advanced methods may reach this goal in a close future. PMID- 28812540 TI - Quantifying Transmission. AB - Transmissibility is the defining characteristic of infectious diseases. Quantifying transmission matters for understanding infectious disease epidemiology and designing evidence-based disease control programs. Tracing individual transmission events can be achieved by epidemiological investigation coupled with pathogen typing or genome sequencing. Individual infectiousness can be estimated by measuring pathogen loads, but few studies have directly estimated the ability of infected hosts to transmit to uninfected hosts. Individuals' opportunities to transmit infection are dependent on behavioral and other risk factors relevant given the transmission route of the pathogen concerned. Transmission at the population level can be quantified through knowledge of risk factors in the population or phylogeographic analysis of pathogen sequence data. Mathematical model-based approaches require estimation of the per capita transmission rate and basic reproduction number, obtained by fitting models to case data and/or analysis of pathogen sequence data. Heterogeneities in infectiousness, contact behavior, and susceptibility can have substantial effects on the epidemiology of an infectious disease, so estimates of only mean values may be insufficient. For some pathogens, super-shedders (infected individuals who are highly infectious) and super-spreaders (individuals with more opportunities to transmit infection) may be important. Future work on quantifying transmission should involve integrated analyses of multiple data sources. PMID- 28812539 TI - Investigating Ebola virus pathogenicity using molecular dynamics. AB - BACKGROUND: Ebolaviruses have been known to cause deadly disease in humans for 40 years and have recently been demonstrated in West Africa to be able to cause large outbreaks. Four Ebolavirus species cause severe disease associated with high mortality in humans. Reston viruses are the only Ebolaviruses that do not cause disease in humans. Conserved amino acid changes in the Reston virus protein VP24 compared to VP24 of other Ebolaviruses have been suggested to alter VP24 binding to host cell karyopherins resulting in impaired inhibition of interferon signalling, which may explain the difference in human pathogenicity. Here we used protein structural analysis and molecular dynamics to further elucidate the interaction between VP24 and KPNA5. RESULTS: As a control experiment, we compared the interaction of wild-type and R137A-mutant (known to affect KPNA5 binding) Ebola virus VP24 with KPNA5. Results confirmed that the R137A mutation weakens direct VP24-KPNA5 binding and enables water molecules to penetrate at the interface. Similarly, Reston virus VP24 displayed a weaker interaction with KPNA5 than Ebola virus VP24, which is likely to reduce the ability of Reston virus VP24 to prevent host cell interferon signalling. CONCLUSION: Our results provide novel molecular detail on the interaction of Reston virus VP24 and Ebola virus VP24 with human KPNA5. The results indicate a weaker interaction of Reston virus VP24 with KPNA5 than Ebola virus VP24, which is probably associated with a decreased ability to interfere with the host cell interferon response. Hence, our study provides further evidence that VP24 is a key player in determining Ebolavirus pathogenicity. PMID- 28812541 TI - Systematic review of interventions for treating or preventing antipsychotic induced tardive dyskinesia. AB - BACKGROUND: Antipsychotic medication can cause tardive dyskinesia (TD) - late onset, involuntary, repetitive movements, often involving the face and tongue. TD occurs in > 20% of adults taking antipsychotic medication (first-generation antipsychotics for > 3 months), with this proportion increasing by 5% per year among those who continue to use these drugs. The incidence of TD among those taking newer antipsychotics is not different from the rate in people who have used older-generation drugs in moderate doses. Studies of TD have previously been found to be limited, with no treatment approach shown to be effective. OBJECTIVES: To summarise the clinical effectiveness and safety of treatments for TD by updating past Cochrane reviews with new evidence and improved methods; to undertake public consultation to gauge the importance of the topic for people living with TD/the risk of TD; and to make available all data from relevant trials. DATA SOURCES: All relevant randomised controlled trials (RCTs) and observational studies. REVIEW METHODS: Cochrane review methods, network meta analysis (NMA). DESIGN: Systematic reviews, patient and public involvement consultation and NMA. SETTING: Any setting, inpatient or outpatient. PARTICIPANTS: For systematic reviews, adults with TD who have been taking a stable antipsychotic drug dose for > 3 months. INTERVENTIONS: Any, with emphasis on those relevant to UK NHS practice. MAIN OUTCOME MEASURES: Any measure of TD, global assessments and adverse effects/events. RESULTS: We included 112 studies (nine Cochrane reviews). Overall, risk of bias showed little sign of improvement over two decades. Taking the outcome of 'TD symptoms improved to a clinically important extent', we identified two trials investigating reduction of antipsychotic dose [n = 17, risk ratio (RR) 0.42, 95% confidence interval (CI) 0.17 to 1.04; very low quality]. Switching was investigated twice in trials that could not be combined (switching to risperidone vs. antipsychotic withdrawal: one RCT, n = 42, RR 0.45, 95% CI 0.23 to 0.89; low quality; switching to quetiapine vs. haloperidol: one RCT, n = 45, RR 0.80, 95% CI 0.52 to 1.22; low quality). In addition to RCTs, six observational studies compared antipsychotic discontinuation with decreased or increased dosage, and there was no clear evidence that any of these strategies had a beneficial effect on TD symptoms (very low-quality evidence). We evaluated the addition to standard antipsychotic care of several treatments, but not anticholinergic treatments, for which we identified no trials. We found no clear effect of the addition of either benzodiazepines (two RCTs, n = 32, RR 1.12, 95% CI 0.6 to 2.09; very low quality) or vitamin E (six RCTs, n = 264, RR 0.95, 95% CI 0.89 to 1.01; low quality). Buspirone as an adjunctive treatment did have some effect in one small study (n = 42, RR 0.53, 95% CI 0.33 to 0.84; low quality), as did hypnosis and relaxation (one RCT, n = 15, RR 0.45, 95% CI 0.21 to 0.94; very low quality). We identified no studies focusing on TD in people with dementia. The NMA model found indirect estimates to be imprecise and failed to produce useful summaries on relative effects of interventions or interpretable results for decision-making. Consultation with people with/at risk of TD highlighted that management of TD remains a concern, and found that people are deeply disappointed at the length of time it has taken researchers to address the issue. LIMITATIONS: Most studies remain small and poorly reported. CONCLUSIONS: Clinicians, policy-makers and people with/at risk of TD are little better informed than they were decades ago. Underpowered trials of limited quality repeatedly fail to provide answers. FUTURE WORK: TD reviews have data from current trials extracted, tabulated and traceable to source. The NMA highlights one context in which support for this technique is ill advised. All relevant trials, even if not primarily addressing the issue of TD, should report appropriate binary outcomes on groups of people with this problem. Randomised trials of treatments for people with established TD are indicated. These should be large (> 800 participants), necessitating accrual through accurate local/national registers, including an intervention with acceptable treatments and recording outcomes used in clinical practice. STUDY REGISTRATION: This study is registered as PROSPERO CRD4201502045. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 28812542 TI - The effect of molecular weight and concentration of hyaluronan on the recovery of the rat sciatic nerve sustaining acute traumatic injury. AB - Acute traumatic peripheral nerve injury remains a significant clinical issue affecting mostly young individuals and their productivity in spite of advances in current medicine. Hyaluronan has been explored in this scenario for its anti adhesive and high biocompatibility properties for decades. The molecular weight and concentration of the locally applied hyaluronan has been overlooked and not optimized. We used different molecular weights and concentrations of hyaluronan in a rat sciatic nerve crush injury model and found better overall outcomes with high molecular weight (3000 kDa) hyaluronan. The anti-inflammatory effect of the higher molecular weight hyaluronan may have a more favorable effect. We conclude that the optimization of hyaluronan is necessary when incorporating hyaluronan in the engineering of biomaterials for use in acute traumatic peripheral nerve injury. PMID- 28812543 TI - Assessing the performance of self-consistent hybrid functional for band gap calculation in oxide semiconductors. AB - In this paper we assess the predictive power of the self-consistent hybrid functional scPBE0 in calculating the band gap of oxide semiconductors. The computational procedure is based on the self-consistent evaluation of the mixing parameter alpha by means of an iterative calculation of the static dielectric constant using the perturbation expansion after discretization method and making use of the relation [Formula: see text]. Our materials dataset is formed by 30 compounds covering a wide range of band gaps and dielectric properties, and includes materials with a wide spectrum of applications such as thermoelectrics, photocatalysis, photovoltaics, transparent conducting oxides, and refractory materials. Our results show that the scPBE0 functional provides better band gaps than the non self-consistent hybrids PBE0 and HSE06, but scPBE0 does not show significant improvement on the description of the static dielectric constants. Overall, the scPBE0 data exhibit a mean absolute percentage error of 14% (band gaps) and 10% ([Formula: see text]). For materials with weak dielectric screening and large excitonic biding energies scPBE0, unlike PBE0 and HSE06, overestimates the band gaps, but the value of the gap becomes very close to the experimental value when excitonic effects are included (e.g. for SiO2). However, special caution must be given to the compounds with small band gaps due to the tendency of scPBE0 to overestimate the dielectric constant in the proximity of the metallic limit. PMID- 28812544 TI - Photoelectric response properties under UV/red light irradiation of ZnO nanorod arrays coated with vertically aligned MoS2 nanosheets. AB - MoS2 with layered structure and distinct physical properties has attracted attention for electronic or optoelectronic devices. The photoelectric response properties of MoS2/ZnO heterojunctions based devices fabricated by spin-coating MoS2 nanosheets solutions on ZnO nanorod arrays (NRs) were investigated. The results revealed that MoS2 nanosheets were vertically aligned on the surface of ZnO NRs and the devices exhibit good photoresponse stability and reproducibility under UV and red light illuminations. The vertically aligned MoS2 nanosheets facilitate the fast photogenerated carrier separation and transport. The devices with few-layered MoS2 nanosheets show a high responsivity and detectivity under UV and red light illuminations, which can be attributed to small contact resistance between MoS2 nanosheets and ZnO NRs. These results provide important insights in the facile fabrication strategy and understanding electronic and optoelectronic devices based on the heterostructures with vertically aligned MoS2. PMID- 28812545 TI - Dynamics of microtubules: highlights of recent computational and experimental investigations. AB - Microtubules are found in most eukaryotic cells, with homologs in eubacteria and archea, and they have functional roles in mitosis, cell motility, intracellular transport, and the maintenance of cell shape. Numerous efforts have been expended over the last two decades to characterize the interactions between microtubules and the wide variety of microtubule associated proteins that control their dynamic behavior in cells resulting in microtubules being assembled and disassembled where and when they are required by the cell. We present the main findings regarding microtubule polymerization and depolymerization and review recent work about the molecular motors that modulate microtubule dynamics by inducing either microtubule depolymerization or severing. We also discuss the main experimental and computational approaches used to quantify the thermodynamics and mechanics of microtubule filaments. PMID- 28812546 TI - Corrigendum: Earliest signs of life on land preserved in ca. 3.5 Ga hot spring deposits. AB - This corrects the article DOI: 10.1038/ncomms15263. PMID- 28812549 TI - Changing the agriculture and environment conversation. PMID- 28812550 TI - Marine ecology: Genetics from a drop in the ocean. PMID- 28812548 TI - Bacteroidales recruit IL-6-producing intraepithelial lymphocytes in the colon to promote barrier integrity. AB - Interactions between the microbiota and distal gut are important for the maintenance of a healthy intestinal barrier; dysbiosis of intestinal microbial communities has emerged as a likely contributor to diseases that arise at the level of the mucosa. Intraepithelial lymphocytes (IELs) are positioned within the epithelial barrier, and in the small intestine they function to maintain epithelial homeostasis. We hypothesized that colon IELs promote epithelial barrier function through the expression of cytokines in response to interactions with commensal bacteria. Profiling of bacterial 16S ribosomal RNA revealed that candidate bacteria in the order Bacteroidales are sufficient to promote IEL presence in the colon that in turn produce interleukin-6 (IL-6) in a MyD88 (myeloid differentiation primary response 88)-dependent manner. IEL-derived IL-6 is functionally important in the maintenance of the epithelial barrier as IL-6-/- mice were noted to have increased paracellular permeability, decreased claudin-1 expression, and a thinner mucus gel layer, all of which were reversed by transfer of IL-6+/+ IELs, leading to protection of mice in response to Citrobacter rodentium infection. Therefore, we conclude that microbiota provide a homeostatic role for epithelial barrier function through regulation of IEL-derived IL-6. PMID- 28812551 TI - The developmental basis for the recurrent evolution of deuterostomy and protostomy. AB - The mouth opening of bilaterian animals develops either separate from (deuterostomy) or connected to (protostomy) the embryonic blastopore, the site of endomesoderm internalization. Although this distinction preluded the classification of bilaterian animals in Deuterostomia and Protostomia, and has influenced major scenarios of bilaterian evolution, the developmental basis for the appearance of these different embryonic patterns remains unclear. To identify the underlying mechanisms, we compared the development of two brachiopod species that show deuterostomy (Novocrania anomala) and protostomy (Terebratalia transversa), respectively. We show that the differential activity of Wnt signalling, together with the timing and location of mesoderm formation, correlate with the differential behaviour and fate of the blastopore. We further assess these principles in the spiral-cleaving group Annelida, and propose that the developmental relationships of mouth and blastoporal openings are secondary by-products of variations in axial and mesoderm development. This challenges the previous evolutionary emphasis on extant blastoporal behaviours to explain the origin and diversification of bilaterian animals. PMID- 28812552 TI - Competition along trajectories governs adaptation rates towards antimicrobial resistance. AB - The increasing availability of genotype-phenotype maps for different combinations of mutations has empowered evolutionary biologists with the tools to interrogate the predictability of adaptive evolution, especially in the context of the evolution of antimicrobial resistance. Large microbial populations are known to generate competing beneficial mutations, but determining how these mutations contribute to the adaptive trajectories that are most likely to be followed remains a challenge. Despite a recognition that there may also be competition between successive alleles on the same trajectory, prior studies have not fully considered how this impacts adaptation rates along, or likelihood of following, individual trajectories. Here, we develop a metric that quantifies the competition between successive alleles along adaptive trajectories and show how this competition largely governs the rate of evolution in simulations on empirical fitness landscapes for proteins involved in drug resistance in two species of malaria (Plasmodium falciparum and P. vivax). Our findings reveal that a trajectory with a larger-than-average initial fitness increase may have smaller fitness increases in later steps, which slows adaptation. In some circumstances, these trajectories may be outcompeted by alleles on faster alternative trajectories that are being explored simultaneously. The ability to predict adaptation rates along accessible trajectories has implications for efforts to manage antimicrobial resistance in real-world settings and for the broader intellectual pursuit of predictive evolution in complex adaptive fitness landscapes for a variety of application domains. PMID- 28812547 TI - Lung epithelial cells: therapeutically inducible effectors of antimicrobial defense. AB - Lung epithelial cells are increasingly recognized to be active effectors of microbial defense, contributing to both innate and adaptive immune function in the lower respiratory tract. As immune sentinels, lung epithelial cells detect diverse pathogens through an ample repertoire of membrane-bound, endosomal, and cytosolic pattern-recognition receptors (PRRs). The highly plastic epithelial barrier responds to detected threats via modulation of paracellular flux, intercellular communications, mucin production, and periciliary fluid composition. Epithelial PRR stimulation also induces production of cytokines that recruit and sculpt leukocyte-mediated responses, and promotes epithelial generation of antimicrobial effector molecules that are directly microbicidal. The epithelium can alternately enhance tolerance to pathogens, preventing tissue damage through PRR-induced inhibitory signals, opsonization of pathogen associated molecular patterns, and attenuation of injurious leukocyte responses. The inducibility of these protective responses has prompted attempts to therapeutically harness epithelial defense mechanisms to protect against pneumonias. Recent reports describe successful strategies for manipulation of epithelial defenses to protect against a wide range of respiratory pathogens. The lung epithelium is capable of both significant antimicrobial responses that reduce pathogen burdens and tolerance mechanisms that attenuate immunopathology. This manuscript reviews inducible lung epithelial defense mechanisms that offer opportunities for therapeutic manipulation to protect vulnerable populations against pneumonia. PMID- 28812553 TI - Rapid recovery of Patagonian plant-insect associations after the end-Cretaceous extinction. AB - The Southern Hemisphere may have provided biodiversity refugia after the Cretaceous/Palaeogene (K/Pg) mass extinction. However, few extinction and recovery studies have been conducted in the terrestrial realm using well-dated macrofossil sites that span the latest Cretaceous (late Maastrichtian) and early Palaeocene (Danian) outside western interior North America (WINA). Here, we analyse insect-feeding damage on 3,646 fossil leaves from the latest Maastrichtian and three time slices of the Danian in Chubut, Patagonia, Argentina (palaeolatitude approximately 50 degrees S). We test the southern refugial hypothesis and the broader hypothesis that the extinction and recovery of insect herbivores, a central component of terrestrial food webs, differed substantially from WINA at locations far south of the Chicxulub impact structure in Mexico. We find greater insect-damage diversity in Patagonia than in WINA during both the Maastrichtian and Danian, indicating a previously unknown insect richness. As in WINA, the total diversity of Patagonian insect damage decreased from the Cretaceous to the Palaeocene, but recovery to pre-extinction levels occurred within approximately 4 Myr compared with approximately 9 Myr in WINA. As for WINA, there is no convincing evidence for survival of any of the diverse Cretaceous leaf miners in Patagonia, indicating a severe K/Pg extinction of host specialized insects and no refugium. However, a striking difference from WINA is that diverse, novel leaf mines are present at all Danian sites, demonstrating a considerably more rapid recovery of specialized herbivores and terrestrial food webs. Our results support the emerging idea of large-scale geographic heterogeneity in extinction and recovery from the end-Cretaceous catastrophe. PMID- 28812554 TI - Why biodiversity matters. PMID- 28812555 TI - Phylogenetic and environmental context of a Tournaisian tetrapod fauna. AB - The end-Devonian to mid-Mississippian time interval has long been known for its depauperate palaeontological record, especially for tetrapods. This interval encapsulates the time of increasing terrestriality among tetrapods, but only two Tournaisian localities previously produced tetrapod fossils. Here we describe five new Tournaisian tetrapods (Perittodus apsconditus, Koilops herma, Ossirarus kierani, Diploradus austiumensis and Aytonerpeton microps) from two localities in their environmental context. A phylogenetic analysis retrieved three taxa as stem tetrapods, interspersed among Devonian and Carboniferous forms, and two as stem amphibians, suggesting a deep split among crown tetrapods. We also illustrate new tetrapod specimens from these and additional localities in the Scottish Borders region. The new taxa and specimens suggest that tetrapod diversification was well established by the Tournaisian. Sedimentary evidence indicates that the tetrapod fossils are usually associated with sandy siltstones overlying wetland palaeosols. Tetrapods were probably living on vegetated surfaces that were subsequently flooded. We show that atmospheric oxygen levels were stable across the Devonian/Carboniferous boundary, and did not inhibit the evolution of terrestriality. This wealth of tetrapods from Tournaisian localities highlights the potential for discoveries elsewhere. PMID- 28812556 TI - Coupling phenotypic persistence to DNA damage increases genetic diversity in severe stress. AB - Mutation rate balances the need to protect genome integrity with the advantage of evolutionary innovations. Microorganisms increase their mutation rate when stressed, perhaps addressing the growing need for evolutionary innovation. Such a strategy, however, is only beneficial under moderate stresses that allow cells to divide and realize their mutagenic potential. In contrast, severe stresses rapidly kill the majority of the population with the exception of a small minority of cells that are in a phenotypically distinct state termed persistence. Although persisters were discovered many decades ago, the stochastic event triggering persistence is poorly understood. We report that spontaneous DNA damage triggers persistence in Saccharomyces cerevisiae by activating the general stress response, providing protection against a range of harsh stress and drug environments. We further show that the persister subpopulation carries an increased load of genetic variants in the form of insertions, deletions or large structural variations, which are unrelated to their stress survival. This coupling of DNA damage to phenotypic persistence may increase genetic diversity specifically in severe stress conditions, where diversity is beneficial but the ability to generate de novo mutations is limited. PMID- 28812557 TI - Palaeoecology: North-South recovery divide. PMID- 28812558 TI - Microbial community ecology: Function over phylogeny. PMID- 28812559 TI - Evolution alters the consequences of invasions in experimental communities. AB - Evolution has the capacity to alter the course of biological invasions, although such changes remain mostly unexplored by experiments. Integrating evolution into studies of invasions is important, because species traits can potentially evolve in ways that either moderate or exacerbate the impacts of invasions. We have assessed whether species evolved during experimental invasions by comparing the performance of founder populations and their potentially evolved descendants in communities of ciliates and rotifers. Residents (analogous to native species) that have previous experience with invaders consistently reduced the performance of naive invaders, supporting the emergence of increased biotic resistance as one consequence of evolution during invasions. Experienced invaders exhibited both increased and decreased performance depending on the invader species considered. Through its influence on performance and species abundance, evolution also changed community composition during the course of invasions. The idiosyncratic patterns of evolutionary changes in invading and resident species complicate predictions about the long-term consequences of invasions from initial post invasion dynamics. PMID- 28812560 TI - An invasive social insect overcomes genetic load at the sex locus. AB - Some invasive hymenopteran social insects found new populations with very few reproductive individuals. This is despite the high cost of founder effects for such insects, which generally require heterozygosity at a single locus-the complementary sex determiner, csd-to develop as females. Individuals that are homozygous at csd develop as either infertile or subfertile diploid males or not at all. Furthermore, diploid males replace the female workers that are essential for colony function. Here we document how the Asian honey bee (Apis cerana) overcame the diploid male problem during its invasion of Australia. Natural selection prevented the loss of rare csd alleles due to genetic drift and corrected the skew in allele frequencies caused by founder effects to restore high average heterozygosity. Thus, balancing selection can alleviate the genetic load at csd imposed by severe bottlenecks, and so facilitate invasiveness. PMID- 28812562 TI - Invasion ecology: Unpredictable arms race in a jam jar. PMID- 28812561 TI - Widespread maintenance of genome heterozygosity in Schmidtea mediterranea. AB - Loss of heterozygosity through inbreeding or mitotic errors leads to reductions in progeny survival and fertility. Loss of heterozygosity is particularly exacerbated in geographically isolated populations, which are prone to inbreeding depression and faster rates of extinction. The regenerative capacities of the hermaphroditic biotype of the planarian Schmidtea mediterranea allowed us to perform a systematic genetic test of Mendelian segregation and study the loss of heterozygosity in the Spiralian superclade in general and planarians in particular. We discovered that ~300 Mb (~37.5%) of the genome retains heterozygosity even after ten generations of inbreeding, and show that these chromosomal regions have low diversity and recombination rates in wild populations. Our genetic and genomic analyses establish S. mediterranea as a genetically tractable system. The research also opens the door to study the evolutionary basis of non-Mendelian mechanisms, the adaptive advantages of chromosome structural heterozygotes and their potential relationship to the robust regenerative capacities of planarians. PMID- 28812563 TI - Multicopy plasmids potentiate the evolution of antibiotic resistance in bacteria. AB - Plasmids are thought to play a key role in bacterial evolution by acting as vehicles for horizontal gene transfer, but the role of plasmids as catalysts of gene evolution remains unexplored. We challenged populations of Escherichia coli carrying the blaTEM-1 beta-lactamase gene on either the chromosome or a multicopy plasmid (19 copies per cell) with increasing concentrations of ceftazidime. The plasmid accelerated resistance evolution by increasing the rate of appearance of novel TEM-1 mutations, thereby conferring resistance to ceftazidime, and then by amplifying the effect of TEM-1 mutations due to the increased gene dosage. Crucially, this dual effect was necessary and sufficient for the evolution of clinically relevant levels of resistance. Subsequent evolution occurred by mutations in a regulatory RNA that increased the plasmid copy number, resulting in marginal gains in ceftazidime resistance. These results uncover a role for multicopy plasmids as catalysts for the evolution of antibiotic resistance in bacteria. PMID- 28812564 TI - Three billion years of research and development. PMID- 28812565 TI - It takes two to tango. PMID- 28812566 TI - Policy knowledge. PMID- 28812567 TI - High taxonomic variability despite stable functional structure across microbial communities. AB - Understanding the processes that are driving variation of natural microbial communities across space or time is a major challenge for ecologists. Environmental conditions strongly shape the metabolic function of microbial communities; however, other processes such as biotic interactions, random demographic drift or dispersal limitation may also influence community dynamics. The relative importance of these processes and their effects on community function remain largely unknown. To address this uncertainty, here we examined bacterial and archaeal communities in replicate 'miniature' aquatic ecosystems contained within the foliage of wild bromeliads. We used marker gene sequencing to infer the taxonomic composition within nine metabolic functional groups, and shotgun environmental DNA sequencing to estimate the relative abundances of these groups. We found that all of the bromeliads exhibited remarkably similar functional community structures, but that the taxonomic composition within individual functional groups was highly variable. Furthermore, using statistical analyses, we found that non-neutral processes, including environmental filtering and potentially biotic interactions, at least partly shaped the composition within functional groups and were more important than spatial dispersal limitation and demographic drift. Hence both the functional structure and taxonomic composition within functional groups of natural microbial communities may be shaped by non-neutral and roughly separate processes. PMID- 28812568 TI - Gene expression plasticity as a mechanism of coral adaptation to a variable environment. AB - Local adaptation is ubiquitous, but the molecular mechanisms that give rise to this ecological phenomenon remain largely unknown. A year-long reciprocal transplant of mustard hill coral (Porites astreoides) between a highly environmentally variable inshore habitat and a more stable offshore habitat demonstrated that populations exhibit phenotypic signatures that are consistent with local adaptation. We characterized the genomic basis of this adaptation in both coral hosts and their intracellular symbionts (Symbiodinium sp.) using genome-wide gene expression profiling. Populations differed primarily in their capacity for plasticity: following transplantation to a novel environment, inshore-origin coral expression profiles became significantly more similar to the local population's profiles than those in offshore-origin corals. Furthermore, elevated plasticity of the environmental stress response expression was correlated with lower susceptibility to a natural summer bleaching event, suggesting that plasticity is adaptive in the inshore environment. Our results reveal a novel genomic mechanism of resilience to a variable environment, demonstrating that corals are capable of a more diverse molecular response to stress than previously thought. PMID- 28812569 TI - The transcriptional architecture of phenotypic dimorphism. AB - The profound differences in gene expression between the sexes are increasingly used to study the molecular basis of sexual dimorphism, sexual selection and sexual conflict. Studies of transcriptional architecture, based on comparisons of gene expression, have also been implemented for a wide variety of other intra specific polymorphisms. These efforts are based on key assumptions regarding the relationship between transcriptional architecture, phenotypic variation and the target of selection. Some of these assumptions are better supported by available evidence than others. In all cases, the evidence is largely circumstantial, leaving considerable gaps in our understanding of the relationship between transcriptional and phenotypic dimorphism. PMID- 28812570 TI - Independent evolution of shape and motility allows evolutionary flexibility in Firmicutes bacteria. AB - Functional morphological adaptation is an implicit assumption across many ecological studies. However, despite a few pioneering attempts to link bacterial form and function, functional morphology is largely unstudied in prokaryotes. One intriguing candidate for analysis is bacterial shape, as multiple lines of theory indicate that cell shape and motility should be strongly correlated. Here we present a large-scale use of modern phylogenetic comparative methods to explore this relationship across 325 species of the phylum Firmicutes. In contrast to clear predictions from theory, we show that cell shape and motility are not coupled, and that transitions to and from flagellar motility are common and strongly associated with lifestyle (free-living or host-associated). We find no association between shape and lifestyle, and contrary to recent evidence, no indication that shape is associated with pathogenicity. Our results suggest that the independent evolution of shape and motility in this group might allow a greater evolutionary flexibility. PMID- 28812571 TI - Identifying species threat hotspots from global supply chains. AB - Identifying hotspots of species threat has been a successful approach for setting conservation priorities. One important challenge in conservation is that, in many hotspots, export industries continue to drive overexploitation. Conservation measures must consider not just the point of impact, but also the consumer demand that ultimately drives resource use. To understand which species threat hotspots are driven by which consumers, we have developed a new approach to link a set of biodiversity footprint accounts to the hotspots of threatened species on the IUCN Red List of Threatened Species. The result is a map connecting consumption to spatially explicit hotspots driven by production on a global scale. Locating biodiversity threat hotspots driven by consumption of goods and services can help to connect conservationists, consumers, companies and governments in order to better target conservation actions. PMID- 28812572 TI - Population characteristics of a large whale shark aggregation inferred from seawater environmental DNA. AB - Population genetics is essential for understanding and managing marine ecosystems, but sampling remains challenging. We demonstrate that high-throughput sequencing of seawater environmental DNA can provide useful estimates of genetic diversity in a whale shark (Rhincodon typus) aggregation. We recover similar mitochondrial haplotype frequencies in seawater compared to tissue samples, reliably placing the studied aggregation in a global genetic context and expanding the applications of environmental DNA to encompass population genetics of aquatic organisms. PMID- 28812573 TI - Adjusting diet-outcome associations for random error: comparison of associations based on observed and estimated usual intakes. AB - BACKGROUND/OBJECTIVES: To compare linear regression coefficients adjusted for random errors with true coefficients. SUBJECTS/METHODS: Three hundred and two individuals from the city of Rio de Janeiro, Brazil answered 20 non-consecutive 24-hr. Means of 20 24-hr were used as an approximation of the usual dietary intakes. It was simulated outcomes with pre-defined linear regression coefficient (beta=1.0, referred as 'true coefficient') for usual coffee and soft-drink intakes as explanatory variables controlled for sex and age. Regression calibration was applied in each 1000 random combinations of j days of intake (j=2, 4 and 6), and adjusted coefficients were compared with true one. RESULTS: Mean-adjusted coefficients were 1.06 to 1.03 (coffee) and 1.17 to 1.11 (soft drink). The association was not detected (95% CI included zero) in 33 to 23% (coffee) and 37 to 23% (soft drink) when using two and six collection days, respectively, compared with 20% when using observed usual intake. Frequency of consumption as covariate in the regression calibration model increased the precision of the adjusted coefficients. CONCLUSIONS: Adjustment for random errors de-attenuates the association but its precision depends mainly on the number of collection days and sample size. PMID- 28812574 TI - Challenge in interpretation of Mendelian randomization studies using lactase persistence as instrumental variable. PMID- 28812575 TI - Response to 'Challenge in interpretation of Mendelian randomization studies using lactase persistence as instrumental variable'. PMID- 28812576 TI - Docosahexaenoic acid enrichment in NAFLD is associated with improvements in hepatic metabolism and hepatic insulin sensitivity: a pilot study. AB - This corrects the article DOI: 10.1038/ejcn.2017.9. PMID- 28812577 TI - A professional life in nutrition sciences and training. PMID- 28812578 TI - Throw caution to the wind: is refeeding syndrome really a cause of death in acute care? AB - BACKGROUND/OBJECTIVES: Refeeding syndrome (RFS), a life-threatening medical condition, is commonly associated with acute or chronic starvation. While the prevalence of patients at risk of RFS in hospital reportedly ranges from 0 to 80%, the prevalence and types of patients who die as a result of RFS is unknown. We aimed to measure the prevalence rate and examine the case histories of patients who passed away with RFS listed as a cause of death. SUBJECTS/METHODS: Patients were eligible for inclusion provided their death occurred within a Queensland hospital. Medical charts were reviewed, for medical, clinical and nutrition histories with results presented using descriptive statistics. RESULTS: Across 18 years (1997-2015) and ~260000 hospital deaths, five individuals (4F, 74 (37-87)yrs) were identified. No patient had a past or present diagnosis, such as anorexia nervosa, that would classify them as at high risk for RFS. RFS was not listed as the primary cause of death for any patient. No individual consumed >3400 kJ per day. Limited consensus was observed in the signs and symptoms used to diagnose RFS, although all patients experienced low levels of potassium, phosphate and/or magnesium. Eighty percent of electrolytes improved before death. CONCLUSIONS: RFS was a rare underlying cause of death, despite reported high prevalence rates of risk. Patient groups usually considered to be at high risk were not identified, suggesting a level of imprecision with the interpretation of criteria used to identify RFS risk. More detailed research is warranted to assist in the identification of those distinctly at risk of RFS. PMID- 28812579 TI - Reproducibility and relative validity of a food frequency questionnaire to estimate intake of dietary phylloquinone and menaquinones. AB - BACKGROUND/OBJECTIVES: This study aims to investigate the reproducibility and relative validity of the Dutch food frequency questionnaire (FFQ), to estimate intake of dietary phylloquinone and menaquinones compared with 24-h dietary recalls (24HDRs) and plasma markers of vitamin K status. SUBJECTS/METHODS: In a cross-sectional study among 63 men and 58 women, the FFQ was completed three times over a 1-year period and the reproducibility was calculated over these measurements. Twelve-monthly 24HDR were collected to estimate relative validity. In addition, the relative validity of the FFQ, compared with plasma phylloquinone and desphospho-uncarboxylated matrix Gla protein (dpucMGP), was assessed cross sectionally among 507 postmenopausal women. RESULTS: Intraclass correlations showed a good reproducibility, with correlations ranging from 0.65 to 0.83. The relative validity for phylloquinone intake compared with 24HDR was lower for women (rs=0.28) than men (rs=0.40). The relative validity, compared with 24HDR, for intake of short-chain menaquinones were ranging between 0.30 and 0.34. Long chain menaquinones showed good relative validity (rs=0.60-0.69). Plasma phylloquinone concentrations were weakly correlated with phylloquinone intake (rs=0.16 (0.07-0.24). Plasma dpucMGP was negatively but weakly correlated with phylloquinone intake (rs=-0.09 (-0.18; -0.01)) and long-chain menaquinones (rs= 0.13 (-0.21; -0.04)), but not with short-chain menaquinones (rs=-0.04 (-0.13; 0.05)). CONCLUSIONS: The FFQ is reproducible to rank subjects for phylloquinone and menaquinone intake.The relative validity of our FFQ, compared with 24HDR, to estimate intake of phylloquinone and short-chain menaquinones was low, but the relative validity for long-chain menaquinones was good. The relative validity of our FFQ, compared with plasma phylloquinone and dpucMGP, was relatively low for both phylloquinone and menaquinone intake. PMID- 28812580 TI - Lactate dehydrogenase activity drives hair follicle stem cell activation. AB - Although normally dormant, hair follicle stem cells (HFSCs) quickly become activated to divide during a new hair cycle. The quiescence of HFSCs is known to be regulated by a number of intrinsic and extrinsic mechanisms. Here we provide several lines of evidence to demonstrate that HFSCs utilize glycolytic metabolism and produce significantly more lactate than other cells in the epidermis. Furthermore, lactate generation appears to be critical for the activation of HFSCs as deletion of lactate dehydrogenase (Ldha) prevented their activation. Conversely, genetically promoting lactate production in HFSCs through mitochondrial pyruvate carrier 1 (Mpc1) deletion accelerated their activation and the hair cycle. Finally, we identify small molecules that increase lactate production by stimulating Myc levels or inhibiting Mpc1 carrier activity and can topically induce the hair cycle. These data suggest that HFSCs maintain a metabolic state that allows them to remain dormant and yet quickly respond to appropriate proliferative stimuli. PMID- 28812583 TI - De-extinction needs consultation. PMID- 28812581 TI - NFIA co-localizes with PPARgamma and transcriptionally controls the brown fat gene program. AB - Brown fat dissipates energy as heat and protects against obesity. Here, we identified nuclear factor I-A (NFIA) as a transcriptional regulator of brown fat by a genome-wide open chromatin analysis of murine brown and white fat followed by motif analysis of brown-fat-specific open chromatin regions. NFIA and the master transcriptional regulator of adipogenesis, PPARgamma, co-localize at the brown-fat-specific enhancers. Moreover, the binding of NFIA precedes and facilitates the binding of PPARgamma, leading to increased chromatin accessibility and active transcription. Introduction of NFIA into myoblasts results in brown adipocyte differentiation. Conversely, the brown fat of NFIA knockout mice displays impaired expression of the brown-fat-specific genes and reciprocal elevation of muscle genes. Finally, expression of NFIA and the brown fat-specific genes is positively correlated in human brown fat. These results indicate that NFIA activates the cell-type-specific enhancers and facilitates the binding of PPARgamma to control the brown fat gene program. PMID- 28812585 TI - Laws of nature. PMID- 28812584 TI - Revisiting the biodiversity-ecosystem multifunctionality relationship. AB - A recent and prominent claim for the value of biodiversity is its importance for sustaining multiple ecosystem functions. The general idea is intuitively appealing: since all species are to some extent unique, each will be important for a different set of functions. Therefore, as more functions are considered, a greater diversity of species is necessary to sustain all functions simultaneously. However, we show here that the relationship between biodiversity and ecosystem functioning does not change with the number of functions considered. Biodiversity affects the level of multifunctionality via non-additive effects on individual functions, and the effect on multifunctionality equals the average effect on single functions. These insights run counter to messages in the literature. In the light of our simulations, we present limitations and pitfalls with current methods used to study biodiversity-multifunctionality, which together provide a perspective for future studies. PMID- 28812582 TI - Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism. AB - Most differentiated cells convert glucose to pyruvate in the cytosol through glycolysis, followed by pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial pyruvate carrier (MPC), which is required for efficient mitochondrial pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial pyruvate oxidation. We sought to understand the role this transition from glycolysis to pyruvate oxidation plays in stem cell maintenance and differentiation. Loss of the MPC in Lgr5-EGFP-positive stem cells, or treatment of intestinal organoids with an MPC inhibitor, increases proliferation and expands the stem cell compartment. Similarly, genetic deletion of the MPC in Drosophila intestinal stem cells also increases proliferation, whereas MPC overexpression suppresses stem cell proliferation. These data demonstrate that limiting mitochondrial pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells. PMID- 28812586 TI - The neglected geography of human pathogens and diseases. PMID- 28812587 TI - ISS observations offer insights into plant function. PMID- 28812588 TI - Urgent need to strengthen the international commitment to IPBES. PMID- 28812591 TI - Body size shifts and early warning signals precede the historic collapse of whale stocks. AB - Predicting population declines is a key challenge in the face of global environmental change. Abundance-based early warning signals have been shown to precede population collapses; however, such signals are sensitive to the low reliability of abundance estimates. Here, using historical data on whales harvested during the 20th century, we demonstrate that early warning signals can be present not only in the abundance data, but also in the more reliable body size data of wild populations. We show that during the period of commercial whaling, the mean body size of caught whales declined dramatically (by up to 4 m over a 70-year period), leading to early warning signals being detectable up to 40 years before the global collapse of whale stocks. Combining abundance and body size data can reduce the length of the time series required to predict collapse, and decrease the chances of false positive early warning signals. PMID- 28812590 TI - Island biodiversity conservation needs palaeoecology. AB - The discovery and colonization of islands by humans has invariably resulted in their widespread ecological transformation. The small and isolated populations of many island taxa, and their evolution in the absence of humans and their introduced taxa, mean that they are particularly vulnerable to human activities. Consequently, even the most degraded islands are a focus for restoration, eradication, and monitoring programmes to protect the remaining endemic and/or relict populations. Here, we build a framework that incorporates an assessment of the degree of change from multiple baseline reference periods using long-term ecological data. The use of multiple reference points may provide information on both the variability of natural systems and responses to successive waves of cultural transformation of island ecosystems, involving, for example, the alteration of fire and grazing regimes and the introduction of non-native species. We provide exemplification of how such approaches can provide valuable information for biodiversity conservation managers of island ecosystems. PMID- 28812592 TI - Widely used marine seismic survey air gun operations negatively impact zooplankton. AB - Zooplankton underpin the health and productivity of global marine ecosystems. Here we present evidence that suggests seismic surveys cause significant mortality to zooplankton populations. Seismic surveys are used extensively to explore for petroleum resources using intense, low-frequency, acoustic impulse signals. Experimental air gun signal exposure decreased zooplankton abundance when compared with controls, as measured by sonar (~3-4 dB drop within 15-30 min) and net tows (median 64% decrease within 1 h), and caused a two- to threefold increase in dead adult and larval zooplankton. Impacts were observed out to the maximum 1.2 km range sampled, which was more than two orders of magnitude greater than the previously assumed impact range of 10 m. Although no adult krill were present, all larval krill were killed after air gun passage. There is a significant and unacknowledged potential for ocean ecosystem function and productivity to be negatively impacted by present seismic technology. PMID- 28812589 TI - Connecting Earth observation to high-throughput biodiversity data. AB - Understandably, given the fast pace of biodiversity loss, there is much interest in using Earth observation technology to track biodiversity, ecosystem functions and ecosystem services. However, because most biodiversity is invisible to Earth observation, indicators based on Earth observation could be misleading and reduce the effectiveness of nature conservation and even unintentionally decrease conservation effort. We describe an approach that combines automated recording devices, high-throughput DNA sequencing and modern ecological modelling to extract much more of the information available in Earth observation data. This approach is achievable now, offering efficient and near-real-time monitoring of management impacts on biodiversity and its functions and services. PMID- 28812593 TI - Invasions everywhere. PMID- 28812594 TI - Ecological homogenization of residential macrosystems. PMID- 28812596 TI - Targeted therapies: SOLO2 confirms olaparib maintenance in ovarian cancer. PMID- 28812597 TI - Haematological cancer: Lenalidomide improves survival after ASCT. PMID- 28812595 TI - Compulsive-Like Sufentanil Vapor Self-Administration in Rats. AB - Opioid misuse is at historically high levels in the United States, with inhalation (ie, smoking and vaping) being one of the most common routes of consumption. We developed and validated a novel preclinical model of opioid self administration by inhalation that does not require surgery and reliably produces somatic and motivational signs of dependence. Rats were trained to perform an operant response (nosepoke) to receive 10 s of vaporized sufentanil, a potent opioid, in 2 h daily sessions. Rats readily and concentration-dependently self administered vaporized sufentanil. Rats exhibited a significant increase in responding for sufentanil when given the preferential MU-opioid receptor inverse agonist naloxone, suggesting the participation of MU-opioid receptors in the reinforcing properties of sufentanil vapor. Serum sufentanil concentrations significantly correlated with the number of sufentanil vapor deliveries. Rats that were given long access (LgA; 12 h/day) but not short access (ShA; 1 h/day) to vaporized sufentanil escalated their drug intake over time and exhibited both naloxone-precipitated somatic signs of opioid withdrawal and spontaneous withdrawal-induced mechanical hypersensitivity. After 6 months of forced drug abstinence, LgA rats returned to pre-escalation baseline levels of responding for sufentanil and mechanical sensitivity. Upon subsequent re-escalation (ie, after the return to extended access to sufentanil vapor), LgA rats again developed naloxone-precipitated somatic signs of withdrawal and spontaneous withdrawal induced mechanical hypersensitivity. These findings demonstrate that the operant sufentanil vapor self-administration model has both face and construct validity and therefore will be useful for investigating the neurobiological basis of opioid addiction. PMID- 28812598 TI - Breast cancer: 10-year follow-up of the TEAM cohort reported. PMID- 28812599 TI - Colorectal cancer: Nivolumab effective against MSI tumours. PMID- 28812600 TI - Prostate cancer: Chemotherapy outcomes similar in mCRPC. PMID- 28812601 TI - Recent extinctions disturb path to equilibrium diversity in Caribbean bats. AB - Islands are ideal systems to model temporal changes in biodiversity and reveal the influence of humans on natural communities. Although theory predicts biodiversity on islands tends towards an equilibrium value, the recent extinction of large proportions of island biotas complicates testing this model. The well preserved subfossil record of Caribbean bats-involving multiple insular radiations-provides a rare opportunity to model diversity dynamics in an insular community. Here, we reconstruct the diversity trajectory in noctilionoid bats of the Greater Antilles by applying a dynamic model of colonization, extinction and speciation to phylogenetic and palaeontological data including all known extinct and extant species. We show species richness asymptotes to an equilibrium value, a demonstration of natural equilibrium dynamics across an entire community. However, recent extinctions-many caused by humans-have wiped out nearly a third of island lineages, dragging diversity away from equilibrium. Using a metric to measure island biodiversity loss, we estimate it will take at least eight million years to regain pre-human diversity levels. Our integrative approach reveals how anthropogenic extinctions can drastically alter the natural trajectory of biological communities, resulting in evolutionary disequilibrium. PMID- 28812602 TI - Prenatal development supports a single origin of laryngeal echolocation in bats. AB - Bat laryngeal echolocation is considered as one of the most complex and diverse modes of auditory sensory perception in animals and its evolutionary history has been the cause of many scientific controversies in the past two decades. To date, the majority of scientific evidence supports that bats (Chiroptera) are divided into two subordinal groups: Yinpterochiroptera, containing the laryngeal echolocating superfamily Rhinolophidae as sister taxa to the non-laryngeal echolocating family Pteropodidae; and Yangochiroptera, containing all other laryngeal echolocating lineages. This topology has led to an unanswered question in mammalian biology: was laryngeal echolocation lost in the ancestral pteropodids or gained convergently in the echolocating bat lineages? To date, there is insufficient and conflicting evidence from fossil, genomic, morphological and phylogenomic data to resolve this question. We detail an ontogenetic study of fetal cochlear development from seven species of bats and five outgroup mammals and show that in early fetal development, all bats including the non-laryngeal echolocating pteropodids have a similarly large cochlea typically associated with laryngeal echolocation abilities. The subsequent cochlear growth rate in the pteropodids is the slowest of all mammals and leads to the pteropodids and the non-echolocating lineages eventually sharing a similar cochlear morphospace as adults. The results suggest that pteropodids maintain a vestigial developmental stage indicative of past echolocation capabilities and thus support a single origin of laryngeal echolocation in bats. PMID- 28812603 TI - Climate change upends selection on ornamentation in a wild bird. AB - Secondary sexual traits have high heritabilities and are exposed to strong, environmentally sensitive selection, and so are expected to evolve rapidly in response to sustained environmental change. We examine the eco-evolutionary dynamics of ornament expression in a long-term study population of collared flycatchers, Ficedula albicollis, in which forehead patch size, which positively influences male reproductive success, declined markedly over 34 years. Annual fitness selection on forehead patch size switched from positive to negative during the study, a reversal that is accounted for by rising spring temperatures at the breeding site: highly ornamented males were selectively favoured following cold breeding seasons but selected against following warm breeding seasons. An 'individual animal model' describes a decline in the genetic values of breeding males during the study, which simulations showed was unlikely to result from drift alone. These results are thus consistent with adaptive evolution of a sexually selected trait in response to climate change. PMID- 28812604 TI - Stand age and species richness dampen interannual variation of ecosystem-level photosynthetic capacity. AB - The total uptake of carbon dioxide by ecosystems via photosynthesis (gross primary productivity, GPP) is the largest flux in the global carbon cycle. A key ecosystem functional property determining GPP is the photosynthetic capacity at light saturation (GPPsat), and its interannual variability (IAV) is propagated to the net land-atmosphere exchange of CO2. Given the importance of understanding the IAV in CO2 fluxes for improving the predictability of the global carbon cycle, we have tested a range of alternative hypotheses to identify potential drivers of the magnitude of IAV in GPPsat in forest ecosystems. Our results show that while the IAV in GPPsat within sites is closely related to air temperature and soil water availability fluctuations, the magnitude of IAV in GPPsat is related to stand age and biodiversity (R2 = 0.55, P < 0.0001). We find that the IAV of GPPsat is greatly reduced in older and more diverse forests, and is higher in younger forests with few dominant species. Older and more diverse forests seem to dampen the effect of climate variability on the carbon cycle irrespective of forest type. Preserving old forests and their diversity would therefore be beneficial in reducing the effect of climate variability on Earth's forest ecosystems. PMID- 28812606 TI - Global marine protected areas to prevent extinctions. AB - One goal of global marine protected areas (MPAs) is to ensure they represent a breadth of taxonomic biodiversity. Ensuring representation of species in MPAs, however, would require protecting vast areas of the global oceans and does not explicitly prioritize species of conservation concern. When threatened species are considered, a recent study found that only a small fraction of their geographic ranges are within the global MPA network. Which global marine areas, and what conservation actions beyond MPAs could be prioritized to prevent marine extinctions (Convention on Biological Diversity Aichi Target 12), remains unknown. Here, we use systematic conservation planning approaches to prioritize conservation actions for sharks, rays and chimaeras (class Chondrichthyes). We use chondrichthyans as they have the highest proportion of threatened species of any marine class. We find that expanding the MPA network by 3% in 70 nations would cover half of the geographic range of 99 imperilled endemic chondrichthyans. Our hotspot analysis reveals that just 12 nations harbour more than half (53) of the imperilled endemics. Four of these hotspot nations are within the top ten chondrichthyan fishing nations in the world, but are yet to implement basic chondrichthyan fisheries management. Given their geopolitical realities, conservation action for some countries will require relief and reorganization to enable sustainable fisheries and species protection. PMID- 28812607 TI - Sensory biology: Bats united by cochlear development. PMID- 28812608 TI - In praise of bats. PMID- 28812605 TI - Experimental test and refutation of a classic case of molecular adaptation in Drosophila melanogaster. AB - Identifying the genetic basis for adaptive differences between species requires explicit tests of historical hypotheses concerning the effects of past changes in gene sequence on molecular function, organismal phenotype and fitness. We address this challenge by combining ancestral protein reconstruction with biochemical experiments and physiological analysis of transgenic animals that carry ancestral genes. We tested a widely held hypothesis of molecular adaptation-that changes in the alcohol dehydrogenase protein (ADH) along the lineage leading to Drosophila melanogaster increased the catalytic activity of the enzyme and thereby contributed to the ethanol tolerance and adaptation of the species to its ethanol rich ecological niche. Our experiments strongly refute the predictions of the adaptive ADH hypothesis and caution against accepting intuitively appealing accounts of historical molecular adaptation that are based on correlative evidence. The experimental strategy we employed can be used to decisively test other adaptive hypotheses and the claims they entail about past biological causality. PMID- 28812609 TI - Please do not disturb ecosystems further. PMID- 28812610 TI - Genome-wide interrogation advances resolution of recalcitrant groups in the tree of life. AB - Much progress has been achieved in disentangling evolutionary relationships among species in the tree of life, but some taxonomic groups remain difficult to resolve despite increasing availability of genome-scale data sets. Here we present a practical approach to studying ancient divergences in the face of high levels of conflict, based on explicit gene genealogy interrogation (GGI). We show its efficacy in resolving the controversial relationships within the largest freshwater fish radiation (Otophysi) based on newly generated DNA sequences for 1,051 loci from 225 species. Initial results using a suite of standard methodologies revealed conflicting phylogenetic signal, which supports ten alternative evolutionary histories among early otophysan lineages. By contrast, GGI revealed that the vast majority of gene genealogies supports a single tree topology grounded on morphology that was not obtained by previous molecular studies. We also reanalysed published data sets for exemplary groups with recalcitrant resolution to assess the power of this approach. GGI supports the notion that ctenophores are the earliest-branching animal lineage, and adds insight into relationships within clades of yeasts, birds and mammals. GGI opens up a promising avenue to account for incompatible signals in large data sets and to discern between estimation error and actual biological conflict explaining gene tree discordance. PMID- 28812611 TI - Divergent demographic strategies of plants in variable environments. AB - One of the best-supported patterns in life history evolution is that organisms cope with environmental fluctuations by buffering their most important vital rates against them. This demographic buffering hypothesis is evidenced by a tendency for temporal variation in rates of survival and reproduction to correlate negatively with their contribution to fitness. Here, we show that widespread evidence for demographic buffering can be artefactual, resulting from natural relationships between the mean and variance of vital rates. Following statistical scaling, we find no significant tendency for plant life histories to be buffered demographically. Instead, some species are buffered, whereas others have labile life histories with higher temporal variation in their more important vital rates. We find phylogenetic signal in the strength and direction of variance-importance correlations, suggesting that clades of plants are prone to being either buffered or labile. Species with simple life histories are more likely to be demographically labile. Our results suggest important evolutionary nuances in how species deal with environmental fluctuations. PMID- 28812612 TI - Phylogenomics: Constrained gene tree inference. PMID- 28812613 TI - Making sure the blue economy is green. PMID- 28812614 TI - Climate change ecology: Hot under the collar. PMID- 28812615 TI - Lateralization of mother-infant interactions in a diverse range of mammal species. AB - Left-cradling bias is a distinctive feature of maternal behaviour in humans and great apes, but its evolutionary origin remains unknown. In 11 species of marine and terrestrial mammal, we demonstrate consistent patterns of lateralization in mother-infant interactions, indicating right hemisphere dominance for social processing. In providing clear evidence that lateralized positioning is beneficial in mother-infant interactions, our results illustrate a significant impact of lateralization on individual fitness. PMID- 28812616 TI - Legacy effects of developmental stages determine the functional role of predators. AB - Predators are instrumental in structuring natural communities and ecosystem processes. The strong effects of predators are often attributed to their high trophic position in the food web. However, most predators have to grow and move up the food chain before reaching their final trophic position, and during this developmental process their traits, interactions and abundances change. Here, we show that this process of 'moving up' the food chain during development strongly determines the ecological role of a predator. By experimentally manipulating the succession of developmental stages of a predatory salamander in a seasonal aquatic ecosystem, we found that the effects of this apex predator on the ecosystem typically declined with age and size. Furthermore, younger, smaller predator stages had long-lasting effects on community structure and ecosystem function that determined the effects of subsequent older, larger stages. Consequently, the legacy effects of early stages largely shaped the impact of the predator on the ecosystem, which could not simply be inferred from its final trophic position. Our results highlight that accounting for all life stages when managing natural populations is crucial to preserve the functioning of natural ecosystems, especially given that early life stages of species are often particularly vulnerable to natural and anthropogenic disturbances. PMID- 28812617 TI - Improved tree-ring archives will support earth-system science. PMID- 28812619 TI - Ecology: Signals of impending change. PMID- 28812618 TI - Plant spatial patterns identify alternative ecosystem multifunctionality states in global drylands. AB - The response of drylands to environmental gradients can be abrupt rather than gradual. These shifts largely occur unannounced and are difficult to reverse once they happen; their prompt detection is of crucial importance. The distribution of vegetation patch sizes may indicate the proximity to these shifts, but the use of this metric is hampered by a lack of large-scale studies relating these distributions to the provision of multiple ecosystem functions (multifunctionality) and comparing them to other ecosystem attributes, such as total plant cover. Here we sampled 115 dryland ecosystems across the globe and related their vegetation attributes (cover and patch size distributions) to multifunctionality. Multifunctionality followed a bimodal distribution across our sites, suggesting alternative states in the functioning of drylands. Although plant cover was the strongest predictor of multifunctionality when linear analyses were used, only patch size distributions reflected the bimodal distribution of multifunctionality observed. Differences in the coupling between nutrient cycles and in the importance of self-organizing biotic processes characterized the two multifunctionality states observed. Our findings support the use of vegetation patterns as indicators of ecosystem functioning in drylands and pave the way for developing effective strategies to monitor desertification processes. PMID- 28812620 TI - Tipping points in the dynamics of speciation. AB - Speciation can be gradual or sudden and involve few or many genetic changes. Inferring the processes generating such patterns is difficult, and may require consideration of emergent and non-linear properties of speciation, such as when small changes at tipping points have large effects on differentiation. Tipping points involve positive feedback and indirect selection stemming from associations between genomic regions, bi-stability due to effects of initial conditions and evolutionary history, and dependence on modularity of system components. These features are associated with sudden 'regime shifts' in other cellular, ecological, and societal systems. Thus, tools used to understand other complex systems could be fruitfully applied in speciation research. PMID- 28812621 TI - Erratum: Competition along trajectories governs adaptation rates towards antimicrobial resistance. PMID- 28812622 TI - Species-rich networks and eco-evolutionary synthesis at the metacommunity level. AB - Understanding how ecological and evolutionary processes interdependently structure biosphere dynamics is a major challenge in the era of worldwide ecosystem degradation. However, our knowledge of 'eco-evolutionary feedbacks' depends largely on findings from simple systems representing limited spatial scales and involving few species. Here we review recent conceptual developments for the understanding of multispecies coevolutionary processes and then discuss how new lines of concepts and methods will accelerate the integration of ecology and evolutionary biology. To build a research workflow for integrating insights into spatiotemporal dynamics of species-rich systems, we focus on the roles of 'metacommunity hub' species, whose population size and/or genetic dynamics potentially control landscape- or regional-scale phenomena. As large amounts of network data are becoming available with high-throughput sequencing of various host-symbiont, prey-predator, and symbiont-symbiont interactions, we suggest it is now possible to develop bases for the integrated understanding and management of species-rich ecosystems. PMID- 28812623 TI - A thousand empirical adaptive landscapes and their navigability. AB - The adaptive landscape is an iconic metaphor that pervades evolutionary biology. It was mostly applied in theoretical models until recent years, when empirical data began to allow partial landscape reconstructions. Here, we exhaustively analyse 1,137 complete landscapes from 129 eukaryotic species, each describing the binding affinity of a transcription factor to all possible short DNA sequences. We find that the navigability of these landscapes through single mutations is intermediate to that of additive and shuffled null models, suggesting that binding affinity-and thereby gene expression-is readily fine tuned via mutations in transcription factor binding sites. The landscapes have few peaks that vary in their accessibility and in the number of sequences they contain. Binding sites in the mouse genome are enriched in sequences found in the peaks of especially navigable landscapes and the genetic diversity of binding sites in yeast increases with the number of sequences in a peak. Our findings suggest that landscape navigability may have contributed to the enormous success of transcriptional regulation as a source of evolutionary adaptations and innovations. PMID- 28812624 TI - Perceptive costs of reproduction drive ageing and physiology in male Drosophila. AB - Costs of reproduction are thought to result from natural selection optimizing organismal fitness within putative physiological constraints. Phenotypic and population genetic studies of reproductive costs are plentiful across taxa, but an understanding of their mechanistic basis would provide important insight into the diversity in life-history traits, including reproductive effort and ageing. Here, we dissect the causes and consequences of specific costs of reproduction in male Drosophila melanogaster. We find that key survival and physiological costs of reproduction arise from perception of the opposite sex, and they are reversed by the act of mating. In the absence of pheromone perception, males are free from reproductive costs on longevity, stress resistance and fat storage. The costs of perception and the benefits of mating are both mediated by evolutionarily conserved neuropeptidergic signalling molecules, as well as the transcription factor dFoxo. These results provide a molecular framework in which certain costs of reproduction arise as a result of self-imposed 'decisions' in response to perceptive neural circuits, which then orchestrate the control of life-history traits independently of physical or energetic effects associated with mating itself. PMID- 28812625 TI - Larval fish dispersal in a coral-reef seascape. AB - Larval dispersal is a critical yet enigmatic process in the persistence and productivity of marine metapopulations. Empirical data on larval dispersal remain scarce, hindering the use of spatial management tools in efforts to sustain ocean biodiversity and fisheries. Here we document dispersal among subpopulations of clownfish (Amphiprion percula) and butterflyfish (Chaetodon vagabundus) from eight sites across a large seascape (10,000 km2) in Papua New Guinea across 2 years. Dispersal of clownfish was consistent between years, with mean observed dispersal distances of 15 km and 10 km in 2009 and 2011, respectively. A Laplacian statistical distribution (the dispersal kernel) predicted a mean dispersal distance of 13-19 km, with 90% of settlement occurring within 31-43 km. Mean dispersal distances were considerably greater (43-64 km) for butterflyfish, with kernels declining only gradually from spawning locations. We demonstrate that dispersal can be measured on spatial scales sufficient to inform the design of and test the performance of marine reserve networks. PMID- 28812626 TI - Dispersal governs the reorganization of ecological networks under environmental change. AB - Ecological networks, such as food webs, mutualist webs and host-parasite webs, are reorganizing as species abundances and spatial distributions shift in response to environmental change. Current theoretical expectations for how this reorganization will occur are available for competition or for parts of interaction networks, but these may not extend to more complex networks. Here we use metacommunity theory to develop new expectations for how complex networks will reorganize under environmental change, and show that dispersal is crucial for determining the degree to which networks will retain their composition and structure. When dispersal between habitat patches is low, all types of species interactions act as a strong determinant for whether species can colonize suitable habitats. This colonization resistance drives species turnover, which breaks apart current networks and leads to the formation of new networks. However, when dispersal rates are increased, colonists arrive in high abundance in habitats where they are well adapted, so interactions with resident species contribute less to colonization success. Dispersal ensures that species associations are maintained as they shift in space, so networks retain similar composition and structure. The crucial role of dispersal reinforces the need to manage habitat connectivity to sustain species and interaction diversity into the future. PMID- 28812627 TI - Direct observation of increasing recovery length before collapse of a marine benthic ecosystem. AB - Ecosystems can experience catastrophic transitions to alternative states, yet recent results have suggested that slowing down in rates of recovery after a perturbation may provide advance warning that a critical transition is approaching. Perturbation experiments with microbial populations have supported this hypothesis under controlled laboratory conditions, but evidence from natural ecosystems remains rare. Here, we manipulated rocky intertidal canopy algae to test the hypothesis that the spatial scale at which the system recovers from a perturbation in space should increase as the system approaches the tipping point, marking the transition from a canopy-dominated to a turf-dominated state. Empirical estimates of recovery length, a recently proposed spatial indicator of an approaching tipping point, were obtained by comparing the spatial scale at which algal turfs propagated into canopy-degraded regions with decreasing canopy cover. We show that recovery length increased along the gradient in canopy degradation, providing field-based evidence of spatial signatures of critical slowing down in natural conditions. PMID- 28812628 TI - The deepening of Darwin's abominable mystery. PMID- 28812629 TI - Confronting the risks of large-scale invasive species control. PMID- 28812630 TI - Our path to better science in less time using open data science tools. AB - Reproducibility has long been a tenet of science but has been challenging to achieve-we learned this the hard way when our old approaches proved inadequate to efficiently reproduce our own work. Here we describe how several free software tools have fundamentally upgraded our approach to collaborative research, making our entire workflow more transparent and streamlined. By describing specific tools and how we incrementally began using them for the Ocean Health Index project, we hope to encourage others in the scientific community to do the same so we can all produce better science in less time. PMID- 28812631 TI - Contrasting effects of environment and genetics generate a continuum of parallel evolution. AB - Parallel evolution of similar traits by independent populations in similar environments is considered strong evidence for adaptation by natural selection. Often, however, replicate populations in similar environments do not all evolve in the same way, thus deviating from any single, predominant outcome of evolution. This variation might arise from non-adaptive, population-specific effects of genetic drift, gene flow or limited genetic variation. Alternatively, these deviations from parallel evolution might also reflect predictable adaptation to cryptic environmental heterogeneity within discrete habitat categories. Here, we show that deviations from parallel evolution are the consequence of environmental variation within habitats combined with variation in gene flow. Threespine stickleback (Gasterosteus aculeatus) in adjoining lake and stream habitats (a lake-stream 'pair') diverge phenotypically, yet the direction and magnitude of this divergence is not always fully parallel among 16 replicate pairs. We found that the multivariate direction of lake-stream morphological divergence was less parallel between pairs whose environmental differences were less parallel. Thus, environmental heterogeneity among lake-stream pairs contributes to deviations from parallel evolution. Additionally, likely genomic targets of selection were more parallel between environmentally more similar pairs. In contrast, variation in the magnitude of lake-stream divergence (independent of direction) was better explained by differences in lake-stream gene flow; pairs with greater lake-stream gene flow were less morphologically diverged. Thus, both adaptive and non-adaptive processes work concurrently to generate a continuum of parallel evolution across lake-stream stickleback population pairs. PMID- 28812632 TI - Climate warming reduces gut microbiota diversity in a vertebrate ectotherm. AB - Climate change is now considered to be the greatest threat to biodiversity and ecological networks, but its impacts on the bacterial communities associated with plants and animals remain largely unknown. Here, we studied the consequences of climate warming on the gut bacterial communities of an ectotherm, the common lizard (Zootoca vivipara), using a semi-natural experimental approach. We found that 2-3 degrees C warmer climates cause a 34% loss of populations' microbiota diversity, with possible negative consequences for host survival. PMID- 28812633 TI - Diversity begets diversity in competition for space. AB - Competition can profoundly affect biodiversity patterns by determining whether similar species are likely to coexist. When species compete directly for space, competitive ability differences should theoretically promote trait and phylogenetic clustering, provided that niche differences are otherwise minimal. Yet many sessile communities exhibit high biodiversity despite minimal reliance on niche differentiation. A potential explanation is that intransitive competition ('rock-paper-scissors' competition) not only promotes species richness but also fosters coexistence among highly dissimilar species with different competitive strategies. Here, we test this hypothesis using a combination of empirical and analytical approaches. In an experimental system comprising 37 wood-decay basidiomycete fungi grown in nutrient-rich agar media, pairwise displacement was maximized when species had widely different competitive traits and divergent evolutionary histories. However, when these interactions were embedded in models of species-rich communities, high levels of intransitivity ultimately overwhelmed the pairwise relationships, allowing the weakest and most dissimilar species to survive. In line with theoretical expectations, these multispecies assemblages exhibited reduced functional and phylogenetic diversity, yet the smallest losses were likewise observed in species rich communities. By demonstrating that species richness can act as a self reinforcing buffer against competitive exclusion, these results contribute to our understanding of how biodiversity is maintained in natural systems. PMID- 28812635 TI - Divergent plant-soil feedbacks could alter future elevation ranges and ecosystem dynamics. AB - Plant-soil feedbacks (PSF) are important interactions that may influence range dynamics in a changing world. What remains largely unknown is the generality of plant-soil biotic interactions across populations and the potential role of specific soil biota, both of which are key for understanding how PSF might change future communities and ecosystems. We combined landscape-level field observations and experimental soil treatments to test whether a dominant tree alters soil environments to impact its own performance and range shifts towards higher elevations. We show: (1) soil conditioning by trees varies with elevation, (2) soil biota relate to PSF, (3) under simulated conditions, biotic PSF constrain range shifts at lower elevations but allow for expansions at higher elevations, and (4) differences in soil conditioning predict feedback outcomes in specific range-shift scenarios. These results suggest that variable plant-soil biotic interactions may influence the migration and fragmentation of tree species, and that models incorporating soil parameters will more accurately predict future species distributions. PMID- 28812634 TI - Optimization of lag phase shapes the evolution of a bacterial enzyme. AB - Mutations provide the variation that drives evolution, yet their effects on fitness remain poorly understood. Here we explore how mutations in the essential enzyme adenylate kinase (Adk) of Escherichia coli affect multiple phases of population growth. We introduce a biophysical fitness landscape for these phases, showing how they depend on molecular and cellular properties of Adk. We find that Adk catalytic capacity in the cell (the product of activity and abundance) is the major determinant of mutational fitness effects. We show that bacterial lag times are at a well-defined optimum with respect to Adk's catalytic capacity, while exponential growth rates are only weakly affected by variation in Adk. Direct pairwise competitions between strains show how environmental conditions modulate the outcome of a competition where growth rates and lag times have a tradeoff, shedding light on the multidimensional nature of fitness and its importance in the evolutionary optimization of enzymes. PMID- 28812636 TI - Fossil eukaryotes: Fungal origins? PMID- 28812637 TI - Spatial conservation prioritization of biodiversity spanning the evolutionary continuum. AB - Accounting for evolutionary relationships between and within species is important for biodiversity conservation planning, but is rarely considered in practice. Here we introduce a novel framework to identify priority conservation areas accounting for phylogenetic and intraspecific diversity, integrating concepts from phylogeny, phylogeography, spatial statistics and spatial conservation prioritization. The framework allows planners to incorporate and combine different levels of evolutionary diversity and can be applied to any taxonomic group and to any region in the world. We illustrate our approach using amphibian and reptile species occurring in a biodiversity hotspot region, the Iberian Peninsula. We found that explicitly incorporating phylogenetic and intraspecific diversity in systematic conservation planning provides advantages in terms of maximizing overall biodiversity representation while enhancing its persistence and evolutionary potential. Our results emphasize the need to account for the evolutionary continuum in order to efficiently implement biodiversity conservation planning decisions. PMID- 28812638 TI - Reproductive behaviour: Make love, then war. PMID- 28812639 TI - Late Pliocene environmental change during the transition from Australopithecus to Homo. AB - It has long been hypothesized that the transition from Australopithecus to Homo in eastern Africa was linked to the spread of open and arid environments near the Plio-Pleistocene boundary, but data for the latest Pliocene are scarce. Here we present new stable carbon isotope data from the late Pliocene mammalian fauna from Ledi-Geraru, in the lower Awash Valley (LAV), Ethiopia, and mammalian community analyses from the LAV and Turkana Basin. These data, combined with pedogenic carbonate stable isotopes, indicate that the two regions were largely similar through the Plio-Pleistocene, but that important environmental differences existed during the emergence of Homo around 2.8 million years ago. The mid-Pliocene to late Pliocene interval in the LAV was characterized by increasingly C4-dominated, arid and seasonal environments. The early Homo mandible LD 350-1 has a carbon isotope value similar to that of earlier Australopithecus from the LAV, possibly indicating that the emergence of Homo from Australopithecus did not involve a dietary shift. Late Pliocene LAV environments contrast with contemporaneous environments in the Turkana Basin, which were more woody and mesic. These findings have important implications for the environmental conditions surrounding the emergence of Homo, as well as recent hypotheses regarding Plio-Pleistocene environmental change in eastern Africa. PMID- 28812640 TI - Five palaeobiological laws needed to understand the evolution of the living biota. AB - The foundations of several disciplines can be expressed as simple quantitative laws, for example, Newton's laws or the laws of thermodynamics. Here I present five laws derived from fossil data that describe the relationships among species extinction and longevity, species richness, origination rates, extinction rates and diversification. These statements of our palaeobiological knowledge constitute a dimension largely hidden from view when studying the living biota, which are nonetheless crucial to the study of evolution and ecology even for groups with poor or non-existent fossil records. These laws encapsulate: the critical fact of extinction; that species are typically geologically short-lived, and thus that the number of extinct species typically dwarfs the number of living species; that extinction and origination rates typically have similar magnitudes; and, that significant extinction makes it difficult to infer much about a clade's early history or its current diversity dynamics from the living biota alone. Although important strides are being made to integrate these core palaeontological findings into our analysis of the living biota, this knowledge needs to be incorporated more widely if we are to understand their evolutionary dynamics. PMID- 28812641 TI - Young voices. PMID- 28812642 TI - IPBES calls for peer review of its draft assessments. PMID- 28812644 TI - A radical form of genetic novelty. PMID- 28812643 TI - A submarine volcanic eruption leads to a novel microbial habitat. AB - Submarine volcanic eruptions are major catastrophic events that allow investigation of the colonization mechanisms of newly formed seabed. We explored the seafloor after the eruption of the Tagoro submarine volcano off El Hierro Island, Canary Archipelago. Near the summit of the volcanic cone, at about 130 m depth, we found massive mats of long, white filaments that we named Venus's hair. Microscopic and molecular analyses revealed that these filaments are made of bacterial trichomes enveloped within a sheath and colonized by epibiotic bacteria. Metagenomic analyses of the filaments identified a new genus and species of the order Thiotrichales, Thiolava veneris. Venus's hair shows an unprecedented array of metabolic pathways, spanning from the exploitation of organic and inorganic carbon released by volcanic degassing to the uptake of sulfur and nitrogen compounds. This unique metabolic plasticity provides key competitive advantages for the colonization of the new habitat created by the submarine eruption. A specialized and highly diverse food web thrives on the complex three-dimensional habitat formed by these microorganisms, providing evidence that Venus's hair can drive the restart of biological systems after submarine volcanic eruptions. PMID- 28812645 TI - Marine microbial ecology: Life after volcanic destruction. PMID- 28812646 TI - The energy expansions of evolution. AB - The history of the life-Earth system can be divided into five 'energetic' epochs, each featuring the evolution of life forms that can exploit a new source of energy. These sources are: geochemical energy, sunlight, oxygen, flesh and fire. The first two were present at the start, but oxygen, flesh and fire are all consequences of evolutionary events. Since no category of energy source has disappeared, this has, over time, resulted in an expanding realm of the sources of energy available to living organisms and a concomitant increase in the diversity and complexity of ecosystems. These energy expansions have also mediated the transformation of key aspects of the planetary environment, which have in turn mediated the future course of evolutionary change. Using energy as a lens thus illuminates patterns in the entwined histories of life and Earth, and may also provide a framework for considering the potential trajectories of life planet systems elsewhere. PMID- 28812647 TI - Corrigendum: A submarine volcanic eruption leads to a novel microbial habitat. AB - This corrects the article DOI: 10.1038/s41559-017-0144. PMID- 28812648 TI - Fungus-like mycelial fossils in 2.4-billion-year-old vesicular basalt. AB - Fungi have recently been found to comprise a significant part of the deep biosphere in oceanic sediments and crustal rocks. Fossils occupying fractures and pores in Phanerozoic volcanics indicate that this habitat is at least 400 million years old, but its origin may be considerably older. A 2.4-billion-year-old basalt from the Palaeoproterozoic Ongeluk Formation in South Africa contains filamentous fossils in vesicles and fractures. The filaments form mycelium-like structures growing from a basal film attached to the internal rock surfaces. Filaments branch and anastomose, touch and entangle each other. They are indistinguishable from mycelial fossils found in similar deep-biosphere habitats in the Phanerozoic, where they are attributed to fungi on the basis of chemical and morphological similarities to living fungi. The Ongeluk fossils, however, are two to three times older than current age estimates of the fungal clade. Unless they represent an unknown branch of fungus-like organisms, the fossils imply that the fungal clade is considerably older than previously thought, and that fungal origin and early evolution may lie in the oceanic deep biosphere rather than on land. The Ongeluk discovery suggests that life has inhabited submarine volcanics for more than 2.4 billion years. PMID- 28812649 TI - Decreased male reproductive success in association with mitochondrial dysfunction. AB - The reproductive success of men with mitochondrial disease is to date unreported. We compared the age- and era-adjusted reproductive success of 94 British male patients with mitochondrial disease to that of the UK general male population. The reproductive success of men with mitochondrial disease was 65% of that in the general population (95% confidence interval: 53%; 79%), and the effect magnitude was related to the disease severity. This contrasts with the two previous studies finding that the reproductive success of women with mitochondrial DNA disease is not impaired. We conclude that the reproductive health of men with mitochondrial disease merits increased clinical attention. PMID- 28812651 TI - Battling the illegal wildlife trade. PMID- 28812650 TI - Autosomal recessive cone-rod dystrophy can be caused by mutations in the ATF6 gene. AB - Inherited retinal dystrophies (IRDs) are clinically and genetically highly heterogeneous, making clinical diagnosis difficult. The advances in high throughput sequencing (ie, panel, exome and genome sequencing) have proven highly effective on defining the molecular basis of these disorders by identifying the underlying variants in the respective gene. Here we report two siblings affected by an IRD phenotype and a novel homozygous c.1691A>G (p.(Asp564Gly)) ATF6 (activating transcription factor 6A) missense substitution identified by whole exome sequencing analysis. The pathogenicity of the variant was confirmed by functional analyses done on patients' fibroblasts and on recombinant p.(Asp564Gly) protein. The ATF6Asp564Gly/Asp564Gly variant shows impaired production of the ATF6 cleaved transcriptional activator domain in response to endoplasmic reticulum stress. Detailed phenotypic examination revealed extinguished cone responses but also decreased rod responses together with the ability to discriminate some colours suggestive rather for cone-rod dystrophy than achromatopsia. PMID- 28812652 TI - Parasites dominate hyperdiverse soil protist communities in Neotropical rainforests. AB - High animal and plant richness in tropical rainforest communities has long intrigued naturalists. It is unknown if similar hyperdiversity patterns are reflected at the microbial scale with unicellular eukaryotes (protists). Here we show, using environmental metabarcoding of soil samples and a phylogeny-aware cleaning step, that protist communities in Neotropical rainforests are hyperdiverse and dominated by the parasitic Apicomplexa, which infect arthropods and other animals. These host-specific parasites potentially contribute to the high animal diversity in the forests by reducing population growth in a density dependent manner. By contrast, too few operational taxonomic units (OTUs) of Oomycota were found to broadly drive high tropical tree diversity in a host specific manner under the Janzen-Connell model. Extremely high OTU diversity and high heterogeneity between samples within the same forests suggest that protists, not arthropods, are the most diverse eukaryotes in tropical rainforests. Our data show that protists play a large role in tropical terrestrial ecosystems long viewed as being dominated by macroorganisms. PMID- 28812653 TI - Adaptation of phytoplankton to a decade of experimental warming linked to increased photosynthesis. AB - Phytoplankton photosynthesis is a critical flux in the carbon cycle, accounting for approximately 40% of the carbon dioxide fixed globally on an annual basis and fuelling the productivity of aquatic food webs. However, rapid evolutionary responses of phytoplankton to warming remain largely unexplored, particularly outside the laboratory, where multiple selection pressures can modify adaptation to environmental change. Here, we use a decade-long experiment in outdoor mesocosms to investigate mechanisms of adaptation to warming (+4 degrees C above ambient temperature) in the green alga Chlamydomonas reinhardtii, in naturally assembled communities. Isolates from warmed mesocosms had higher optimal growth temperatures than their counterparts from ambient treatments. Consequently, warm adapted isolates were stronger competitors at elevated temperature and experienced a decline in competitive fitness in ambient conditions, indicating adaptation to local thermal regimes. Higher competitive fitness in the warmed isolates was linked to greater photosynthetic capacity and reduced susceptibility to photoinhibition. These findings suggest that adaptive responses to warming in phytoplankton could help to mitigate projected declines in aquatic net primary production by increasing rates of cellular net photosynthesis. PMID- 28812654 TI - Transitions between phases of genomic differentiation during stick-insect speciation. AB - Speciation can involve a transition from a few genetic loci that are resistant to gene flow to genome-wide differentiation. However, only limited data exist concerning this transition and the factors promoting it. Here, we study phases of speciation using data from >100 populations of 11 species of Timema stick insects. Consistent with early phases of genic speciation, adaptive colour pattern loci reside in localized genetic regions of accentuated differentiation between populations experiencing gene flow. Transitions to genome-wide differentiation are also observed with gene flow, in association with differentiation in polygenic chemical traits affecting mate choice. Thus, intermediate phases of speciation are associated with genome-wide differentiation and mate choice, but not growth of a few genomic islands. We also find a gap in genomic differentiation between sympatric taxa that still exchange genes and those that do not, highlighting the association between differentiation and complete reproductive isolation. Our results suggest that substantial progress towards speciation may involve the alignment of multi-faceted aspects of differentiation. PMID- 28812655 TI - The placenta as a model for understanding the origin and evolution of vertebrate organs. AB - How organs originate and evolve is a question fundamental to understanding the evolution of complex multicellular life forms. Vertebrates have a relatively standard body plan with more or less the same conserved set of organs. The placenta is a comparatively more recently evolved organ, derived in many lineages independently. Using placentas as a model, we discuss the genetic basis for organ origins. We show that the evolution of placentas occurs by acquiring new functional attributes to existing tissues, changes in the patterning and development of tissues, and the evolution of novel cell types. We argue that a diversity of genomic changes facilitated these physiological transformations and that these changes are likely to have occurred during the evolution of organs more broadly. Finally, we argue that a key aspect to understanding the evolutionary origin of organs is that they are likely to result from novel interactions between distinct cell populations. PMID- 28812656 TI - Experimental evidence for homeostatic sex allocation after sex-biased reintroductions. AB - First principles predict negative frequency-dependent sex allocation, but it is unproven in field studies and seldom considered, despite far-reaching consequences for theory and practice in population genetics and dynamics as well as animal ecology and behaviour. Twenty-four years of rhinoceros calving after 45 reintroductions across southern Africa provide the first in situ experimental evidence that unbalanced operational sex ratios predicted offspring sex and offspring sex ratios. Our understanding of population dynamics, especially reintroduction and invasion biology, will be significantly impacted by these findings. PMID- 28812657 TI - Diminishing-returns epistasis decreases adaptability along an evolutionary trajectory. AB - Populations evolving in constant environments exhibit declining adaptability. Understanding the basis of this pattern could reveal underlying processes determining the repeatability of evolutionary outcomes. In principle, declining adaptability can be due to a decrease in the effect size of beneficial mutations, a decrease in the rate at which they occur, or some combination of both. By evolving Escherichia coli populations started from different steps along a single evolutionary trajectory, we show that declining adaptability is best explained by a decrease in the size of available beneficial mutations. This pattern reflected the dominant influence of negative genetic interactions that caused new beneficial mutations to confer smaller benefits in fitter genotypes. Genome sequencing revealed that starting genotypes that were more similar to one another did not exhibit greater similarity in terms of new beneficial mutations, supporting the view that epistasis acts globally, having a greater influence on the effect than on the identity of available mutations along an adaptive trajectory. Our findings provide support for a general mechanism that leads to predictable phenotypic evolutionary trajectories. PMID- 28812658 TI - Biodiversity: Complementary canopies. PMID- 28812659 TI - Predicting zoonoses. PMID- 28812660 TI - Global determinants of zoogeographical boundaries. AB - The distribution of living organisms on Earth is spatially structured. Early biogeographers identified the existence of multiple zoogeographical regions, characterized by faunas with homogeneous composition that are separated by biogeographical boundaries. Yet, no study has deciphered the factors shaping the distributions of terrestrial biogeographical boundaries at the global scale. Here, using spatial regression analyses, we show that tectonic movements, sharp changes in climatic conditions and orographic barriers determine extant biogeographical boundaries. These factors lead to abrupt zoogeographical transitions when they act in concert, but their prominence varies across the globe. Clear differences exist among boundaries representing profound or shallow dissimilarities between faunas. Boundaries separating zoogeographical regions with limited divergence occur in areas with abrupt climatic transitions. In contrast, plate tectonics determine the separation between deeply divergent biogeographical realms, particularly in the Old World. Our study reveals the multiple drivers that have shaped the biogeographical regions of the world. PMID- 28812661 TI - Human population growth offsets climate-driven increase in woody vegetation in sub-Saharan Africa. AB - The rapidly growing human population in sub-Saharan Africa generates increasing demand for agricultural land and forest products, which presumably leads to deforestation. Conversely, a greening of African drylands has been reported, but this has been difficult to associate with changes in woody vegetation. There is thus an incomplete understanding of how woody vegetation responds to socio economic and environmental change. Here we used a passive microwave Earth observation data set to document two different trends in land area with woody cover for 1992-2011: 36% of the land area (6,870,000 km2) had an increase in woody cover largely in drylands, and 11% had a decrease (2,150,000 km2), mostly in humid zones. Increases in woody cover were associated with low population growth, and were driven by increases in CO2 in the humid zones and by increases in precipitation in drylands, whereas decreases in woody cover were associated with high population growth. The spatially distinct pattern of these opposing trends reflects, first, the natural response of vegetation to precipitation and atmospheric CO2, and second, deforestation in humid areas, minor in size but important for ecosystem services, such as biodiversity and carbon stocks. This nuanced picture of changes in woody cover challenges widely held views of a general and ongoing reduction of the woody vegetation in Africa. PMID- 28812662 TI - Spending limited resources on de-extinction could lead to net biodiversity loss. AB - There is contentious debate surrounding the merits of de-extinction as a biodiversity conservation tool. Here, we use extant analogues to predict conservation actions for potential de-extinction candidate species from New Zealand and the Australian state of New South Wales, and use a prioritization protocol to predict the impacts of reintroducing and maintaining populations of these species on conservation of extant threatened species. Even using the optimistic assumptions that resurrection of species is externally sponsored, and that actions for resurrected species can share costs with extant analogue species, public funding for conservation of resurrected species would lead to fewer extant species that could be conserved, suggesting net biodiversity loss. If full costs of establishment and maintenance for resurrected species populations were publicly funded, there could be substantial sacrifices in extant species conservation. If conservation of resurrected species populations could be fully externally sponsored, there could be benefits to extant threatened species. However, such benefits would be outweighed by opportunity costs, assuming such discretionary money could directly fund conservation of extant species. Potential sacrifices in conservation of extant species should be a crucial consideration in deciding whether to invest in de-extinction or focus our efforts on extant species. PMID- 28812663 TI - The highly threatened and little known Amazonian savannahs. PMID- 28812665 TI - Erratum: Evolution alters the consequences of invasions in experimental communities. PMID- 28812664 TI - Biogeography: Drivers of bioregionalization. PMID- 28812666 TI - Unknown risks to soil biodiversity from commercial fungal inoculants. PMID- 28812667 TI - Greening peace in Colombia. PMID- 28812668 TI - Evolutionary transitions towards eusociality in snapping shrimps. AB - Animal social organization varies from complex societies where reproduction is dominated by a single individual (eusociality) to those where reproduction is more evenly distributed among group members (communal breeding). Yet, how simple groups transition evolutionarily to more complex societies remains unclear. Competing hypotheses suggest that eusociality and communal breeding are alternative evolutionary endpoints, or that communal breeding is an intermediate stage in the transition towards eusociality. We tested these alternative hypotheses in sponge-dwelling shrimps, Synalpheus spp. Although species varied continuously in reproductive skew, they clustered into pair-forming, communal and eusocial categories based on several demographic traits. Evolutionary transition models suggested that eusocial and communal species are discrete evolutionary endpoints that evolved independently from pair-forming ancestors along alternative paths. This 'family-centred' origin of eusociality parallels observations in insects and vertebrates, reinforcing the role of kin selection in the evolution of eusociality and suggesting a general model of animal social evolution. PMID- 28812669 TI - The evo-devo of plant speciation. AB - Speciation research bridges the realms of macro- and microevolution. Evolutionary developmental biology (evo-devo) has classically dealt with macroevolutionary questions through a comparative approach to distantly related organisms, but the field later broadened in focus to address recent speciation and microevolution. Here we review available evidence of the power of evo-devo approaches to understand speciation in plants at multiple scales. At a macroevolutionary scale, evidence is accumulating for evolutionary developmental mechanisms giving rise to key innovations promoting speciation. At the macro microevolution transition, we review instances of evo-devo change underlying both the origin of reproductive barriers and phenotypic changes distinguishing closely related species. At the microevolutionary scale, the study of developmental variation within species provides insight into the processes that generate the raw material for evolution and speciation. We conclude by advocating a strong interaction between developmental biology and evolutionary biology at multiple scales to gain a deeper understanding of plant speciation. PMID- 28812670 TI - Moment of truth for the Cerrado hotspot. PMID- 28812672 TI - Rapid and direct recoveries of predators and prey through synchronized ecosystem management. AB - One of the twenty-first century's greatest environmental challenges is to recover and restore species, habitats and ecosystems. The decision about how to initiate restoration is best-informed by an understanding of the linkages between ecosystem components and, given these linkages, an appreciation of the consequences of choosing to recover one ecosystem component before another. However, it remains difficult to predict how the sequence of species' recoveries within food webs influences the speed and trajectory of restoration, and what that means for human well-being. Here, we develop theory to consider the ecological and social implications of synchronous versus sequential (species-by species) recovery in the context of exploited food webs. A dynamical systems model demonstrates that synchronous recovery of predators and prey is almost always more efficient than sequential recovery. Compared with sequential recovery, synchronous recovery can be twice as fast and produce transient fluctuations of much lower amplitude. A predator-first strategy is particularly slow because it counterproductively suppresses prey recovery. An analysis of real world predator-prey recoveries shows that synchronous and sequential recoveries are similarly common, suggesting that current practices are not ideal. We highlight policy tools that can facilitate swift and steady recovery of ecosystem structure, function and associated services. PMID- 28812673 TI - Craniofacial diversification in the domestic pigeon and the evolution of the avian skull. AB - A central question in evolutionary developmental biology is how highly conserved developmental systems can generate the remarkable phenotypic diversity observed among distantly related species. In part, this paradox reflects our limited knowledge about the potential for species to both respond to selection and generate novel variation. Consequently, the developmental links between small scale microevolutionary variations within populations to larger macroevolutionary patterns among species remain unbridged. Domesticated species, such as the pigeon, are unique resources for addressing this question, because a history of strong artificial selection has significantly increased morphological diversity, offering a direct comparison of the developmental potential of a single species to broader evolutionary patterns. Here, we demonstrate that patterns of variation and covariation within and between the face and braincase in domesticated breeds of the pigeon are predictive of avian cranial evolution. These results indicate that selection on variation generated by a conserved developmental system is sufficient to explain the evolution of crania as different in shape as the albatross or eagle, parakeet or hummingbird. These 'rules' of cranio-facial variation are a common pattern in the evolution of a broad diversity of vertebrate species and may ultimately reflect structural limitations of a shared embryonic bauplan on functional variation. PMID- 28812674 TI - Red list of a black box. PMID- 28812675 TI - Spatial complementarity in tree crowns explains overyielding in species mixtures. AB - Deciphering the mechanisms that link biodiversity with ecosystem functions is critical to understanding the consequences of changes in biodiversity. The hypothesis that complementarity and selection effects drive relationships between biodiversity and ecosystem functions is well accepted, and an approach to statistically untangle the relative importance of these effects has been widely applied. In contrast, empirical demonstrations of the biological mechanisms that underlie these relationships remain rare. Here, on the basis of a field experiment with young trees, we provide evidence that one form of complementarity in plant communities-complementarity among crowns in canopy space-is a mechanism, related to light interception and use, that links biodiversity with ecosystem productivity. Stem biomass overyielding increased sharply in mixtures with greater crown complementarity. Inherent differences among species in crown architecture led to greater crown complementarity in functionally diverse species mixtures. Intraspecific variation, specifically neighbourhood-driven plasticity in crowns, further modified spatial complementarity and strengthened the positive relationship with overyielding-crown plasticity and inherent interspecific differences contributed near equally in explaining patterns of overyielding. We posit that crown complementarity is an important mechanism that may contribute to diversity-enhanced productivity in forests. PMID- 28812676 TI - Spotlight on South America. PMID- 28812677 TI - Species-specific responses to ocean acidification should account for local adaptation and adaptive plasticity. AB - Global stressors, such as ocean acidification, constitute a rapidly emerging and significant problem for marine organisms, ecosystem functioning and services. The coastal ecosystems of the Humboldt Current System (HCS) off Chile harbour a broad physical-chemical latitudinal and temporal gradient with considerable patchiness in local oceanographic conditions. This heterogeneity may, in turn, modulate the specific tolerances of organisms to climate stress in species with populations distributed along this environmental gradient. Negative response ratios are observed in species models (mussels, gastropods and planktonic copepods) exposed to changes in the partial pressure of CO2 (pCO2) far from the average and extreme pCO2 levels experienced in their native habitats. This variability in response between populations reveals the potential role of local adaptation and/or adaptive phenotypic plasticity in increasing resilience of species to environmental change. The growing use of standard ocean acidification scenarios and treatment levels in experimental protocols brings with it a danger that inter population differences are confounded by the varying environmental conditions naturally experienced by different populations. Here, we propose the use of a simple index taking into account the natural pCO2 variability, for a better interpretation of the potential consequences of ocean acidification on species inhabiting variable coastal ecosystems. Using scenarios that take into account the natural variability will allow understanding of the limits to plasticity across organismal traits, populations and species. PMID- 28812680 TI - De-extinction: Costs, benefits and ethics. PMID- 28812678 TI - The multilayer nature of ecological networks. AB - Although networks provide a powerful approach to study a large variety of ecological systems, their formulation does not typically account for multiple interaction types, interactions that vary in space and time, and interconnected systems such as networks of networks. The emergent field of 'multilayer networks' provides a natural framework for extending analyses of ecological systems to include such multiple layers of complexity, as it specifically allows one to differentiate and model 'intralayer' and 'interlayer' connectivity. The framework provides a set of concepts and tools that can be adapted and applied to ecology, facilitating research on high-dimensional, heterogeneous systems in nature. Here, we formally define ecological multilayer networks based on a review of previous, related approaches; illustrate their application and potential with analyses of existing data; and discuss limitations, challenges, and future applications. The integration of multilayer network theory into ecology offers largely untapped potential to investigate ecological complexity and provide new theoretical and empirical insights into the architecture and dynamics of ecological systems. PMID- 28812682 TI - Reach out. PMID- 28812681 TI - More protist genomes needed. PMID- 28812683 TI - Megafaunal isotopes reveal role of increased moisture on rangeland during late Pleistocene extinctions. AB - The role of environmental change in the late Pleistocene megafaunal extinctions remains a key question, owing in part to uncertainty about landscape changes at continental scales. We investigated the influence of environmental changes on megaherbivores using bone collagen nitrogen isotopes (n = 684, 63 new) as a proxy for moisture levels in the rangelands that sustained late Pleistocene grazers. An increase in landscape moisture in Europe, Siberia and the Americas during the Last Glacial-Interglacial Transition (LGIT; ~25-10 kyr bp) directly affected megaherbivore ecology on four continents, and was associated with a key period of population decline and extinction. In all regions, the period of greatest moisture coincided with regional deglaciation and preceded the widespread formation of wetland environments. Moisture-driven environmental changes appear to have played an important part in the late Quaternary megafaunal extinctions through alteration of environments such as rangelands, which supported a large biomass of specialist grazers. On a continental scale, LGIT moisture changes manifested differently according to regional climate and geography, and the stable presence of grasslands surrounding the central forested belt of Africa during this period helps to explain why proportionally fewer African megafauna became extinct during the late Pleistocene. PMID- 28812684 TI - Genome evolution: Shellfish genes. PMID- 28812686 TI - Interactions of microplastic debris throughout the marine ecosystem. AB - Marine microscopic plastic (microplastic) debris is a modern societal issue, illustrating the challenge of balancing the convenience of plastic in daily life with the prospect of causing ecological harm by careless disposal. Here we develop the concept of microplastic as a complex, dynamic mixture of polymers and additives, to which organic material and contaminants can successively bind to form an 'ecocorona', increasing the density and surface charge of particles and changing their bioavailability and toxicity. Chronic exposure to microplastic is rarely lethal, but can adversely affect individual animals, reducing feeding and depleting energy stores, with knock-on effects for fecundity and growth. We explore the extent to which ecological processes could be impacted, including altered behaviours, bioturbation and impacts on carbon flux to the deep ocean. We discuss how microplastic compares with other anthropogenic pollutants in terms of ecological risk, and consider the role of science and society in tackling this global issue in the future. PMID- 28812685 TI - Scallop genome provides insights into evolution of bilaterian karyotype and development. AB - Reconstructing the genomes of bilaterian ancestors is central to our understanding of animal evolution, where knowledge from ancient and/or slow evolving bilaterian lineages is critical. Here we report a high-quality, chromosome-anchored reference genome for the scallop Patinopecten yessoensis, a bivalve mollusc that has a slow-evolving genome with many ancestral features. Chromosome-based macrosynteny analysis reveals a striking correspondence between the 19 scallop chromosomes and the 17 presumed ancestral bilaterian linkage groups at a level of conservation previously unseen, suggesting that the scallop may have a karyotype close to that of the bilaterian ancestor. Scallop Hox gene expression follows a new mode of subcluster temporal co-linearity that is possibly ancestral and may provide great potential in supporting diverse bilaterian body plans. Transcriptome analysis of scallop mantle eyes finds unexpected diversity in phototransduction cascades and a potentially ancient Pax2/5/8-dependent pathway for noncephalic eyes. The outstanding preservation of ancestral karyotype and developmental control makes the scallop genome a valuable resource for understanding early bilaterian evolution and biology. PMID- 28812687 TI - Community structure follows simple assembly rules in microbial microcosms. AB - Microorganisms typically form diverse communities of interacting species, whose activities have tremendous impact on the plants, animals and humans they associate with. The ability to predict the structure of these complex communities is crucial to understanding and managing them. Here, we propose a simple, qualitative assembly rule that predicts community structure from the outcomes of competitions between small sets of species, and experimentally assess its predictive power using synthetic microbial communities composed of up to eight soil bacterial species. Nearly all competitions resulted in a unique, stable community, whose composition was independent of the initial species fractions. Survival in three-species competitions was predicted by the pairwise outcomes with an accuracy of ~90%. Obtaining a similar level of accuracy in competitions between sets of seven or all eight species required incorporating additional information regarding the outcomes of the three-species competitions. Our results demonstrate experimentally the ability of a simple bottom-up approach to predict community structure. Such an approach is key for anticipating the response of communities to changing environments, designing interventions to steer existing communities to more desirable states and, ultimately, rationally designing communities de novo. PMID- 28812688 TI - Reimagining ocean governance using the keystone species concept. PMID- 28812689 TI - Safe and effective biocontrol of common carp. PMID- 28812691 TI - A macroecological theory of microbial biodiversity. AB - Microorganisms are the most abundant, diverse and functionally important organisms on Earth. Over the past decade, microbial ecologists have produced the largest ever community datasets. However, these data are rarely used to uncover law-like patterns of commonness and rarity, test theories of biodiversity, or explore unifying explanations for the structure of microbial communities. Using a global scale compilation of >20,000 samples from environmental, engineered and host-related ecosystems, we test the power of competing theories to predict distributions of microbial abundance and diversity-abundance scaling laws. We show that these patterns are best explained by the synergistic interaction of stochastic processes that are captured by lognormal dynamics. We demonstrate that lognormal dynamics have predictive power across scales of abundance, a criterion that is essential to biodiversity theory. By understanding the multiplicative and stochastic nature of ecological processes, scientists can better understand the structure and dynamics of Earth's largest and most diverse ecological systems. PMID- 28812690 TI - Young inversion with multiple linked QTLs under selection in a hybrid zone. AB - Fixed chromosomal inversions can reduce gene flow and promote speciation in two ways: by suppressing recombination and by carrying locally favoured alleles at multiple loci. However, it is unknown whether favoured mutations slowly accumulate on older inversions or if young inversions spread because they capture pre-existing adaptive quantitative trait loci (QTLs). By genetic mapping, chromosome painting and genome sequencing, we have identified a major inversion controlling ecologically important traits in Boechera stricta. The inversion arose since the last glaciation and subsequently reached local high frequency in a hybrid speciation zone. Furthermore, the inversion shows signs of positive directional selection. To test whether the inversion could have captured existing, linked QTLs, we crossed standard, collinear haplotypes from the hybrid zone and found multiple linked phenology QTLs within the inversion region. These findings provide the first direct evidence that linked, locally adapted QTLs may be captured by young inversions during incipient speciation. PMID- 28812692 TI - Gene flow from domesticated escapes alters the life history of wild Atlantic salmon. AB - Interbreeding between domesticated and wild animals occurs in several species. This gene flow has long been anticipated to induce genetic changes in life history traits of wild populations, thereby influencing population dynamics and viability. Here, we show that individuals with high levels of introgression (domesticated ancestry) have altered age and size at maturation in 62 wild Atlantic salmon Salmo salar populations, including seven ancestral populations to breeding lines of the domesticated salmon. This study documents widespread changes to life-history traits in wild animal populations following gene flow from selectively bred, domesticated conspecifics. The continued high abundance of escaped, domesticated Atlantic salmon thus threatens wild Atlantic salmon populations by inducing genetic changes in fitness-related traits. Our results represent key evidence and a timely warning concerning the potential ecological impacts of the globally increasing use of domesticated animals. PMID- 28812693 TI - Direct benefits and evolutionary transitions to complex societies. AB - The selective forces that drive the evolution of cooperation have been intensely debated. Evolutionary transitions to cooperative breeding, a complex form of cooperation, have been hypothesized to be linked to low degrees of promiscuity, which increases intragroup relatedness and the indirect (that is, kin selected) benefits of helping. However, ecological factors also promote cooperative breeding, and may be more important than relatedness in some contexts. Identifying the key evolutionary drivers of cooperative breeding therefore requires an integrated assessment of these hypotheses. Here we show, using a phylogenetic framework that explicitly evaluates mating behaviours and ecological factors, that evolutionary transitions to cooperative breeding in cichlid fishes were not associated with social monogamy. Instead, group living, biparental care and diet type directly favoured the evolution of cooperative breeding. Our results suggest that cichlid fishes exhibit an alternative path to the evolution of complex societies compared to other previously studied vertebrates, and these transitions are driven primarily by direct fitness benefits. PMID- 28812694 TI - Finding space for large carnivores. PMID- 28812695 TI - Ecology: From genes to metapopulations. PMID- 28812696 TI - Skeletal trauma reflects hunting behaviour in extinct sabre-tooth cats and dire wolves. AB - Skeletal-injury frequency and distribution are likely to reflect hunting behaviour in predatory vertebrates and might therefore differ between species with distinct hunting modes. Two Pleistocene predators from the Rancho La Brea asphalt seeps, the sabre-tooth cat, Smilodon fatalis, and dire wolf, Canis dirus, represent ambush and pursuit predators, respectively. On the basis of a collection of over 1,900 pathological elements, the frequency of traumatic injury across skeletal elements in these two species was calculated. Here we show that the frequency of trauma in the sabre-tooth cat exceeds that of the dire wolf (4.3% compared to 2.8%), implying that the killing behaviour of S. fatalis entailed greater risk of injury. The distribution of traumatic injuries also differed between the two species. S. fatalis, an ambush predator, was injured more often than expected across the lumbar vertebrae and shoulders whereas C. dirus, a pursuit predator, had higher than expected levels of injury in the limbs and cervical vertebrae. Spatial analysis was used to quantify differences in the distribution of putative hunting injuries. Analysis of injury locations discriminated true hotspots from injury-dense areas and facilitated interpretation of predatory behaviour, demonstrating the use of spatial analyses in the study of vertebrate behaviour and evolution. These results suggest that differences in trauma distribution reflect distinct hazards of each species' hunting mode. PMID- 28812697 TI - Fish pool their experience to solve problems collectively. AB - Access to information is a key advantage of grouping. Although experienced animals can lead others to solve problems, less is known about whether partially informed individuals can pool experiences to overcome challenges collectively. Here we provide evidence of such 'experience-pooling'. We presented shoals of sticklebacks (Gasterosteus aculeatus) with a two-stage foraging task requiring them to find and access hidden food. Individual fish were either inexperienced or had knowledge of just one of the stages. Shoals containing individuals trained in each of the stages pooled their expertise, allowing more fish to access the food, and to do so more rapidly, compared with other shoal compositions. Strong social effects were identified: the presence of experienced individuals increased the likelihood of untrained fish completing each stage. These findings demonstrate that animal groups can integrate individual experience to solve multi-stage problems, and have implications for our understanding of social foraging, migration and social systems. PMID- 28812698 TI - Urbanization erodes ectomycorrhizal fungal diversity and may cause microbial communities to converge. AB - Urbanization alters the physicochemical environment, introduces non-native species and causes ecosystem characteristics to converge. It has been speculated that these alterations contribute to loss of regional and global biodiversity, but so far most urban studies have assessed macro-organisms and reported mixed evidence for biodiversity loss. We studied five cities on three continents to assess the global convergence of urban soil microbial communities. We determined the extent to which communities of bacteria, archaea and fungi are geographically distributed, and to what extent urbanization acts as a filter on species diversity. We discovered that microbial communities in general converge, but the response differed among microbial domains; soil archaeal communities showed the strongest convergence, followed by fungi, while soil bacterial communities did not converge. Our data suggest that urban soil archaeal and bacterial communities are not vulnerable to biodiversity loss, whereas urbanization may be contributing to the global diversity loss of ectomycorrhizal fungi. Ectomycorrhizae decreased in both abundance and species richness under turf and ruderal land-uses. These data add to an emerging pattern of widespread suppression of ectomycorrhizal fungi by human land-uses that involve physical disruption of the soil, management of the plant community, or nutrient enrichment. PMID- 28812699 TI - Primate brain size is predicted by diet but not sociality. AB - The social brain hypothesis posits that social complexity is the primary driver of primate cognitive complexity, and that social pressures ultimately led to the evolution of the large human brain. Although this idea has been supported by studies indicating positive relationships between relative brain and/or neocortex size and group size, reported effects of different social and mating systems are highly conflicting. Here, we use a much larger sample of primates, more recent phylogenies, and updated statistical techniques, to show that brain size is predicted by diet, rather than multiple measures of sociality, after controlling for body size and phylogeny. Specifically, frugivores exhibit larger brains than folivores. Our results call into question the current emphasis on social rather than ecological explanations for the evolution of large brains in primates and evoke a range of ecological and developmental hypotheses centred on frugivory, including spatial information storage, extractive foraging and overcoming metabolic constraints. PMID- 28812700 TI - Evo-devo: Developmental constraints. PMID- 28812702 TI - Evolution: Eating away at the social brain. PMID- 28812701 TI - Contentious relationships in phylogenomic studies can be driven by a handful of genes. AB - Phylogenomic studies have resolved countless branches of the tree of life, but remain strongly contradictory on certain, contentious relationships. Here, we use a maximum likelihood framework to quantify the distribution of phylogenetic signal among genes and sites for 17 contentious branches and 6 well-established control branches in plant, animal and fungal phylogenomic data matrices. We find that resolution in some of these 17 branches rests on a single gene or a few sites, and that removal of a single gene in concatenation analyses or a single site from every gene in coalescence-based analyses diminishes support and can alter the inferred topology. These results suggest that tiny subsets of very large data matrices drive the resolution of specific internodes, providing a dissection of the distribution of support and observed incongruence in phylogenomic analyses. We submit that quantifying the distribution of phylogenetic signal in phylogenomic data is essential for evaluating whether branches, especially contentious ones, are truly resolved. Finally, we offer one detailed example of such an evaluation for the controversy regarding the earliest branching metazoan phylum, for which examination of the distributions of gene wise and site-wise phylogenetic signal across eight data matrices consistently supports ctenophores as the sister group to all other metazoans. PMID- 28812703 TI - The impact of architecture on collective behaviour. PMID- 28812704 TI - Biological extinction at the Vatican. PMID- 28812705 TI - Functional trait diversity maximizes ecosystem multifunctionality. AB - Understanding the relationship between biodiversity and ecosystem functioning has been a core ecological research topic over the past decades. Although a key hypothesis is that the diversity of functional traits determines ecosystem functioning, we do not know how much trait diversity is needed to maintain multiple ecosystem functions simultaneously (multifunctionality). Here, we uncovered a scaling relationship between the abundance distribution of two key plant functional traits (specific leaf area, maximum plant height) and multifunctionality in 124 dryland plant communities spread over all continents except Antarctica. For each trait, we found a strong empirical relationship between the skewness and the kurtosis of the trait distributions that cannot be explained by chance. This relationship predicted a strikingly high trait diversity within dryland plant communities, which was associated with a local maximization of multifunctionality. Skewness and kurtosis had a much stronger impact on multifunctionality than other important multifunctionality drivers such as species richness and aridity. The scaling relationship identified here quantifies how much trait diversity is required to maximize multifunctionality locally. Trait distributions can be used to predict the functional consequences of biodiversity loss in terrestrial ecosystems. PMID- 28812706 TI - A decade of insights into grassland ecosystem responses to global environmental change. AB - Earth's biodiversity and carbon uptake by plants, or primary productivity, are intricately interlinked, underlie many essential ecosystem processes, and depend on the interplay among environmental factors, many of which are being changed by human activities. While ecological theory generalizes across taxa and environments, most empirical tests of factors controlling diversity and productivity have been observational, single-site experiments, or meta-analyses, limiting our understanding of variation among site-level responses and tests of general mechanisms. A synthesis of results from ten years of a globally distributed, coordinated experiment, the Nutrient Network (NutNet), demonstrates that species diversity promotes ecosystem productivity and stability, and that nutrient supply and herbivory control diversity via changes in composition, including invasions of non-native species and extinction of native species. Distributed experimental networks are a powerful tool for tests and integration of multiple theories and for generating multivariate predictions about the effects of global changes on future ecosystems. PMID- 28812708 TI - Public literacy in evolution. PMID- 28812707 TI - The rise and fall of malaria under land-use change in frontier regions. AB - Land-use change is the main force behind ecological and social change in many countries around the globe; it is primarily driven by resource needs and external economic incentives. Concomitantly, transformations of the land are the main drivers for the emergence and re-emergence of malaria. An understanding of malaria population dynamics in transforming landscapes is lacking, despite its relevance for developmental and public health policies. We develop a mathematical model that couples malaria epidemiology with the socio-economic and demographic processes that occur in a landscape undergoing land-use change. This allows us to identify different types of malaria dynamics that can arise in early stages of this transformation. In particular, we show that an increase in transmission followed by either a decline, or a further enhancement, of risk is a common outcome. This increase results from the asymmetry between the relatively fast ecological changes in transformed landscapes, and the slower pace of investment in malaria protection. These results underscore the importance of reducing ecological risk, while providing services and economic opportunities to early migrants for longer periods. Consideration of these socio-ecological processes and, more importantly, the temporal scale on which they act, is critical to avoid potential bifurcations that lead to long-lasting endemic malaria. PMID- 28812709 TI - Adaptation to deep-sea chemosynthetic environments as revealed by mussel genomes. AB - Hydrothermal vents and methane seeps are extreme deep-sea ecosystems that support dense populations of specialized macro-benthos such as mussels. But the lack of genome information hinders the understanding of the adaptation of these animals to such inhospitable environments. Here we report the genomes of a deep-sea vent/seep mussel (Bathymodiolus platifrons) and a shallow-water mussel (Modiolus philippinarum). Phylogenetic analysis shows that these mussel species diverged approximately 110.4 million years ago. Many gene families, especially those for stabilizing protein structures and removing toxic substances from cells, are highly expanded in B. platifrons, indicating adaptation to extreme environmental conditions. The innate immune system of B. platifrons is considerably more complex than that of other lophotrochozoan species, including M. philippinarum, with substantial expansion and high expression levels of gene families that are related to immune recognition, endocytosis and caspase-mediated apoptosis in the gill, revealing presumed genetic adaptation of the deep-sea mussel to the presence of its chemoautotrophic endosymbionts. A follow-up metaproteomic analysis of the gill of B. platifrons shows methanotrophy, assimilatory sulfate reduction and ammonia metabolic pathways in the symbionts, providing energy and nutrients, which allow the host to thrive. Our study of the genomic composition allowing symbiosis in extremophile molluscs gives wider insights into the mechanisms of symbiosis in other organisms such as deep-sea tubeworms and giant clams. PMID- 28812710 TI - Developmental constraints shape the evolution of the nematode mid-developmental transition. AB - Evolutionary theory assumes that genetic variation is uniform and gradual in nature, yet morphological and gene expression studies have revealed that different life-stages exhibit distinct levels of cross-species conservation. In particular, a stage in mid-embryogenesis is highly conserved across species of the same phylum, suggesting that this stage is subject to developmental constraints, either by increased purifying selection or by a strong mutational bias. An alternative explanation, however, holds that the same 'hourglass' pattern of variation may result from increased positive selection at the earlier and later stages of development. To distinguish between these scenarios, we examined gene expression variation in a population of the nematode Caenorhabditis elegans using an experimental design that eliminated the influence of positive selection. By measuring gene expression for all genes throughout development in 20 strains, we found that variations were highly uneven throughout development, with a significant depletion during mid-embryogenesis. In particular, the family of homeodomain transcription factors, whose expression generally coincides with mid-embryogenesis, evolved under high constraint. Our data further show that genes responsible for the integration of germ layers during morphogenesis are the most constrained class of genes. Together, these results provide strong evidence for developmental constraints as the mechanism underlying the hourglass model of animal evolution. Understanding the pattern and mechanism of developmental constraints provides a framework to understand how evolutionary processes have interacted with embryogenesis and led to the diversity of animal life on Earth. PMID- 28812711 TI - Arrhythmias: Safety backups to keep the pace. PMID- 28812712 TI - Developmental biology: Formation of hybrid myocardial zone. PMID- 28812713 TI - Female plasticity tends to reduce sexual conflict. AB - Sexual conflict is the divergence of evolutionary interests between the sexes. A neglected aspect of sexual conflict theory is that the conflict often occurs within the female's body, which can lead to a power asymmetry between the sexes. In particular, the female may often be able to respond flexibly to the actions of the male, and so exhibits plasticity. Here, we consider the implications of female plasticity, and find that it tends to result in lower levels of sexual conflict. We then relate our results to a comparison of pre- versus post copulatory sexual conflict, and we also show that this asymmetry between males and females reduces the likelihood of runaway selection, preventing co evolutionary arms races. Finally, we discuss our results in the context of the evolution of adaptive harm and sexual conflict when there are direct benefits. PMID- 28812714 TI - Grand challenges for the study of cultural evolution. PMID- 28812715 TI - Anniversary: Maria Sibylla Merian and metamorphosis. PMID- 28812716 TI - Bolster legal boundaries to stay within planetary boundaries. PMID- 28812717 TI - Palaeontology: Darwin's dilemma dissolved. PMID- 28812718 TI - Evolution-informed maternal-infant health. PMID- 28812719 TI - Bioaccumulation of persistent organic pollutants in the deepest ocean fauna. AB - The legacy and reach of anthropogenic influence is most clearly evidenced by its impact on the most remote and inaccessible habitats on Earth. Here we identify extraordinary levels of persistent organic pollutants in the endemic amphipod fauna from two of the deepest ocean trenches (>10,000 metres). Contaminant levels were considerably higher than documented for nearby regions of heavy industrialization, indicating bioaccumulation of anthropogenic contamination and inferring that these pollutants are pervasive across the world's oceans and to full ocean depth. PMID- 28812720 TI - Antagonistic pleiotropy and mutation accumulation influence human senescence and disease. AB - Senescence has long been a public health challenge as well as a fascinating evolutionary problem. There is neither a universally accepted theory for its ultimate causes, nor a consensus about what may be its impact on human health. Here we test the predictions of two evolutionary explanations of senescence mutation accumulation and antagonistic pleiotropy-which postulate that genetic variants with harmful effects in old ages can be tolerated, or even favoured, by natural selection at early ages. Using data from genome-wide association studies (GWAS), we study the effects of genetic variants associated with diseases appearing at different periods in life, when they are expected to have different impacts on fitness. Data fit theoretical expectations. Namely, we observe higher risk allele frequencies combined with large effect sizes for late-onset diseases, and detect a significant excess of early-late antagonistically pleiotropic variants that, strikingly, tend to be harboured by genes related to ageing. Beyond providing systematic, genome-wide evidence for evolutionary theories of senescence in our species and contributing to the long-standing question of whether senescence is the result of adaptation, our approach reveals relationships between previously unrelated pathologies, potentially contributing to tackling the problem of an ageing population. PMID- 28812722 TI - Ecotoxicology: Pollutants plumb the depths. PMID- 28812721 TI - Predicting evolution. AB - The face of evolutionary biology is changing: from reconstructing and analysing the past to predicting future evolutionary processes. Recent developments include prediction of reproducible patterns in parallel evolution experiments, forecasting the future of individual populations using data from their past, and controlled manipulation of evolutionary dynamics. Here we undertake a synthesis of central concepts for evolutionary predictions, based on examples of microbial and viral systems, cancer cell populations, and immune receptor repertoires. These systems have strikingly similar evolutionary dynamics driven by the competition of clades within a population. These dynamics are the basis for models that predict the evolution of clade frequencies, as well as broad genetic and phenotypic changes. Moreover, there are strong links between prediction and control, which are important for interventions such as vaccine or therapy design. All of these are key elements of what may become a predictive theory of evolution. PMID- 28812723 TI - The unconstrained evolution of fast and efficient antibiotic-resistant bacterial genomes. AB - Evolutionary trajectories are constrained by trade-offs when mutations that benefit one life history trait incur fitness costs in other traits. As resistance to tetracycline antibiotics by increased efflux can be associated with an increase in length of the Escherichia coli chromosome of 10% or more, we sought costs of resistance associated with doxycycline. However, it was difficult to identify any because the growth rate (r), carrying capacity (K) and drug efflux rate of E. coli increased during evolutionary experiments where the species was exposed to doxycycline. Moreover, these improvements remained following drug withdrawal. We sought mechanisms for this seemingly unconstrained adaptation, particularly as these traits ought to trade-off according to rK selection theory. Using prokaryote and eukaryote microorganisms, including clinical pathogens, we show that r and K can trade-off, but need not, because of 'rK trade-ups'. r and K trade-off only in sufficiently carbon-rich environments where growth is inefficient. We then used E. coli ribosomal RNA (rRNA) knockouts to determine specific mutations, namely changes in rRNA operon (rrn) copy number, than can simultaneously maximize r and K. The optimal genome has fewer operons, and therefore fewer functional ribosomes, than the ancestral strain. It is, therefore, unsurprising for r-adaptation in the presence of a ribosome-inhibiting antibiotic, doxycycline, to also increase population size. We found two costs for this improvement: an elongated lag phase and the loss of stress protection genes. PMID- 28812724 TI - The genomic landscape of evolutionary convergence in mammals, birds and reptiles. AB - Many lineage-defining (nodal) mutations possess high functionality. However, differentiating adaptive nodal mutations from those that are functionally compensated remains challenging. To address this challenge, we identified functional nodal mutations (fNMs) in ~3,400 nuclear DNA (nDNA) and 4 mitochondrial DNA (mtDNA) protein structures from 91 and 1,003 species, respectively, representing the entire mammalian, bird and reptile phylogeny. A screen for candidate compensatory mutations among co-occurring amino acid changes in close structural proximity revealed that such compensated fNMs encompass 37% and 27% of the mtDNA and nDNA datasets, respectively. Analysis of the remaining (non-compensated) mutations, which are enriched for adaptive mutations, showed that birds and mammals share most such recurrent fNMs (N = 51). Among the latter, we discovered mutations in thermoregulation-related genes. These represent the best candidates to explain the molecular basis of convergent body thermoregulation in birds and mammals. Our analysis reveals the landscape of possible mutational compensation and convergence in amniote phylogeny. PMID- 28812725 TI - Phylogenetics: Tertiary protein structures needed. PMID- 28812726 TI - Biocontrol of common carp in Australia poses risks to biosecurity. PMID- 28812727 TI - Exceptionally preserved Cambrian loriciferans and the early animal invasion of the meiobenthos. AB - Microscopic animals that live among and between sediment grains (meiobenthic metazoans) are key constituents of modern aquatic ecosystems, but are effectively absent from the fossil record. We describe an assemblage of microscopic fossil loriciferans (Ecdysozoa, Loricifera) from the late Cambrian Deadwood Formation of western Canada. The fossils share a characteristic head structure and minute adult body size (~300 MUm) with modern loriciferans, indicating the early evolution and subsequent conservation of an obligate, permanently meiobenthic lifestyle. The unsuspected fossilization potential of such small animals in marine mudstones offers a new search image for the earliest ecdysozoans and other animals, although the anatomical complexity of loriciferans points to their evolutionary miniaturization from a larger-bodied ancestor. The invasion of animals into ecospace that was previously monopolized by protists will have contributed considerably to the revolutionary geobiological feedbacks of the Proterozoic/Phanerozoic transition. PMID- 28812728 TI - Antibiotic resistance: Evolution without trade-offs. PMID- 28812730 TI - Palaeoecology: Agriculture emerges from the calm. PMID- 28812731 TI - Cooperation facilitates the colonization of harsh environments. AB - Animals living in harsh environments, where temperatures are hot and rainfall is unpredictable, are more likely to breed in cooperative groups. As a result, harsh environmental conditions have been accepted as a key factor explaining the evolution of cooperation. However, this is based on evidence that has not investigated the order of evolutionary events, so the inferred causality could be incorrect. We resolved this problem using phylogenetic analyses of 4,707 bird species and found that causation was in the opposite direction to that previously assumed. Rather than harsh environments favouring cooperation, cooperative breeding has facilitated the colonization of harsh environments. Cooperative breeding was, in fact, more likely to evolve from ancestors occupying relatively cool environmental niches with predictable rainfall, which had low levels of polyandry and hence high within-group relatedness. We also found that polyandry increased after cooperative breeders invaded harsh environments, suggesting that when helpers have limited options to breed independently, polyandry no longer destabilizes cooperation. This provides an explanation for the puzzling cases of polyandrous cooperative breeding birds. More generally, this illustrates how cooperation can play a key role in invading ecological niches, a pattern observed across all levels of biological organization from cells to animal societies. PMID- 28812733 TI - Cultural evolution: Evolution of female genital cutting. PMID- 28812732 TI - Genome of the pitcher plant Cephalotus reveals genetic changes associated with carnivory. AB - Carnivorous plants exploit animals as a nutritional source and have inspired long standing questions about the origin and evolution of carnivory-related traits. To investigate the molecular bases of carnivory, we sequenced the genome of the heterophyllous pitcher plant Cephalotus follicularis, in which we succeeded in regulating the developmental switch between carnivorous and non-carnivorous leaves. Transcriptome comparison of the two leaf types and gene repertoire analysis identified genetic changes associated with prey attraction, capture, digestion and nutrient absorption. Analysis of digestive fluid proteins from C. follicularis and three other carnivorous plants with independent carnivorous origins revealed repeated co-options of stress-responsive protein lineages coupled with convergent amino acid substitutions to acquire digestive physiology. These results imply constraints on the available routes to evolve plant carnivory. PMID- 28812734 TI - Human behaviour as a long-term ecological driver of non-human evolution. AB - Due to our intensive subsistence and habitat-modification strategies-including broad-spectrum harvesting and predation, widespread landscape burning, settlement construction, and translocation of other species-humans have major roles as ecological actors who influence fundamental trophic interactions. Here we review how the long-term history of human-environment interaction has shaped the evolutionary biology of diverse non-human, non-domesticated species. Clear examples of anthropogenic effects on non-human morphological evolution have been documented in modern studies of substantial changes to body size or other major traits in terrestrial and aquatic vertebrates, invertebrates, and plants in response to selective human harvesting, urbanized habitats, and human-mediated translocation. Meanwhile, archaeological records of harvested marine invertebrates and terrestrial vertebrates suggest that similar processes extend considerably into prehistory, perhaps to 50,000 yr BP or earlier. These results are consistent with palaeoenvironmental and other records that demonstrate long term human habitat modification and intensive harvesting practices. Thus, while considerable attention has been focused on recent human impacts on 'natural' habitats, integrated evidence from modern biology and archaeology suggests a deep history of human entanglement with our ecosystems including substantial effects on the evolutionary biology of non-human taxa. The number and magnitude of such effects will probably increase given the continued intensification of anthropogenic activities and ecosystem impacts, including climate change and direct genetic modification. PMID- 28812738 TI - Human world. PMID- 28812737 TI - Human exposure and sensitivity to globally extreme wildfire events. AB - Extreme wildfires have substantial economic, social and environmental impacts, but there is uncertainty whether such events are inevitable features of the Earth's fire ecology or a legacy of poor management and planning. We identify 478 extreme wildfire events defined as the daily clusters of fire radiative power from MODIS, within a global 10 * 10 km lattice, between 2002 and 2013, which exceeded the 99.997th percentile of over 23 million cases of the SigmaFRP 100 km 2 in the MODIS record. These events are globally distributed across all flammable biomes, and are strongly associated with extreme fire weather conditions. Extreme wildfire events reported as being economically or socially disastrous (n = 144) were concentrated in suburban areas in flammable-forested biomes of the western United States and southeastern Australia, noting potential biases in reporting and the absence of globally comprehensive data of fire disasters. Climate change projections suggest an increase in days conducive to extreme wildfire events by 20 to 50% in these disaster-prone landscapes, with sharper increases in the subtropical Southern Hemisphere and European Mediterranean Basin. PMID- 28812739 TI - Frequency-dependent female genital cutting behaviour confers evolutionary fitness benefits. AB - Female genital cutting (FGC) has immediate and long-term negative health consequences that are well-documented, and its elimination is a priority for policymakers. The persistence of this widespread practice also presents a puzzle for evolutionary anthropologists due to its potentially detrimental impact on survival and reproductive fitness. Using multilevel modelling on demographic health survey datasets from five West African countries, here we show that FGC behaviour is frequency-dependent; the probability that girls are cut varies in proportion to the FGC frequency found in their ethnic group. We also show that this frequency-dependent behaviour is adaptive in evolutionary fitness terms; in ethnic groups with high FGC frequency, women with FGC have significantly more surviving offspring than their uncut peers, and the reverse is found in ethnic groups with low FGC frequency. Our results demonstrate how evolutionary and cultural forces can drive the persistence of harmful behaviours. PMID- 28812740 TI - Higher-order interactions capture unexplained complexity in diverse communities. AB - Natural communities are well known to be maintained by many complex processes. Despite this, the practical aspects of studying them often require some simplification, such as the widespread assumption that direct, additive competition captures the important details about how interactions between species impact community diversity. More complex non-additive 'higher-order' interactions are assumed to be negligible or absent. Notably, these assumptions are poorly supported and have major consequences for the accuracy with which patterns of natural diversity are modelled and explained. We present a mathematically simple framework for incorporating biologically meaningful complexity into models of diversity by including non-additive higher-order interactions. We further provide empirical evidence that such higher-order interactions strongly influence species' performance in natural plant communities, with variation in seed production (as a proxy for per capita fitness) explained dramatically better when at least some higher-order interactions are considered. Our study lays the groundwork for a long-overdue shift in how species interactions are used to study the diversity of natural communities. PMID- 28812741 TI - Persistent tropical foraging in the highlands of terminal Pleistocene/Holocene New Guinea. AB - The terminal Pleistocene/Holocene boundary (approximately 12-8 thousand years ago) represented a major ecological threshold for humans, both as a significant climate transition and due to the emergence of agriculture around this time. In the highlands of New Guinea, climatic and environmental changes across this period have been highlighted as potential drivers of one of the earliest domestication processes in the world. We present a terminal Pleistocene/Holocene palaeoenvironmental record (12-0 thousand years ago ) of carbon and oxygen isotopes in small mammal tooth enamel from the site of Kiowa. The results show that tropical highland forest and open mosaics, and the human subsistence focused on these environments, remained stable throughout the period in which agriculture emerged at nearby Kuk Swamp. This suggests the persistence of tropical forest foraging among highland New Guinea groups and highlights that agriculture in the region was not adopted as a unilinear or dramatic, forced event but was locally and historically contingent. PMID- 28812742 TI - Forest vision. PMID- 28812744 TI - Benzene-centred tripodal diglycolamides for the sequestration of trivalent actinides: metal ion extraction and luminescence spectroscopic investigations in a room temperature ionic liquid. AB - Three benzene-centred tripodal diglycolamide (Bz-T-DGA) ligands, where the diglycolamide (DGA) moieties are attached to a central benzene ring through ethylene spacers (LI), amide groups (LII) or ether linkages (LIII), were evaluated for their extraction behaviour towards trivalent actinide and lanthanide ions in a room temperature ionic liquid (RTIL), viz. 1-butyl-3 methylimidazolium bis(trifluoromethane)sulfonimide ([C4mim][Tf2N]). The extraction behaviour of these ligands in [C4mim][Tf2N] medium was compared with that obtained in the molecular solvent n-dodecane showing an opposite selectivity of LIII > LII > LIvs. LI > LII > LIII. In contrast to the n-dodecane medium, where a solvation extraction mechanism prevailed, a cation exchange mechanism was found to be operative in the RTIL medium. The stoichiometry of the extracted Am3+complex was found to be 1 : 2 (metal/ligand) and a nitrate ion was absent in the extracted complex. The luminescence spectroscopy of the Eu3+/ligand extracted complexes in the [C4mim][Tf2N] phase confirmed the absence of water molecules and that all the primary coordination sites of the metal ion are occupied by the ligands. The ligands display very large Pu/U, Am/U and Eu/U separation factor in the RTIL medium. PMID- 28812743 TI - Cross-realm assessment of climate change impacts on species' abundance trends. AB - Climate change, land-use change, pollution and exploitation are among the main drivers of species' population trends; however, their relative importance is much debated. We used a unique collection of over 1,000 local population time series in 22 communities across terrestrial, freshwater and marine realms within central Europe to compare the impacts of long-term temperature change and other environmental drivers from 1980 onwards. To disentangle different drivers, we related species' population trends to species- and driver-specific attributes, such as temperature and habitat preference or pollution tolerance. We found a consistent impact of temperature change on the local abundances of terrestrial species. Populations of warm-dwelling species increased more than those of cold dwelling species. In contrast, impacts of temperature change on aquatic species' abundances were variable. Effects of temperature preference were more consistent in terrestrial communities than effects of habitat preference, suggesting that the impacts of temperature change have become widespread for recent changes in abundance within many terrestrial communities of central Europe. PMID- 28812745 TI - Hysteresis and bonding reconstruction in the pressure-induced B3-B1 phase transition of 3C-SiC. AB - The determination of kinetic factors affecting phase metastability is crucial for the design of materials out of the ambient conditions. At a given temperature, the kinetic barrier associated with the reconstruction of the bonding network of a pressure-induced phase transition can be only overcome at pressures where the available vibrational energy of the system is equal or higher than the corresponding activation energy. Our work demonstrates that these pressures provide boundaries to hysteresis cycles that can be evaluated following a three step computational strategy: (i) total energy electronic structure calculations, (ii) determination of vibrational contributions by means of a simple Debye model, and (iii) description of the energetic profile along the transition path in the framework of the martensitic approximation. In the 3C-SiC polytype, our results reveal that the high pressure rock-salt (B1) structure can not be quenched on release of pressure unless temperature is close to 0 K. The B1 phase transforms back to the low-pressure zinc blende (B3) polymorph at 300 K if pressure is below 30 GPa, in very good agreement with experimental observations. These results are supported by a full characterization of the B3-B1 energetic transition profile in terms of the chemical changes of the bonding network topologically analysed with the electron localization function. PMID- 28812746 TI - Redox titration of gold and platinum surface oxides at porous microelectrodes. AB - The extension of the surface interrogation mode of scanning electrochemical microscopy (SI-SECM) is demonstrated for porous electrode materials. These materials are often high surface area powders which are very important electrocatalysts for instance in fuel cells or water electrolyzers. The powdered electrocatalyst material is filled into a cavity-microelectrode which is then operated as the sample electrode in SECM. After a surface oxide generation step, the oxides on the porous sample are reduced by [Ru(NH3)6]2+ formed at the microelectrode probe of the SECM while the sample is at open circuit potential. Such porous electrodes pose the difficulty to cope with unavoidable variations in the filling of the cavity and to access the entire surface by the mediator. The electrochemically active surface area is used to compensate the variation in filling. It can also be used for calculating coverages of surface oxides for a better comparison between different electrodes. We found a complete and fast accessibility for all investigated porous electrodes which is based on electron transfer. Therefore, we propose a "vertical feedback" mechanism analogous to SECM feedback experiments on extended flat samples at open circuit potential. Moreover, the current transients indicate that distinctive oxide species with different kinetics are present. Taken together, these measures ensure consistent determination of oxide coverages for nanoporous gold and carbon-supported platinum nanoparticles. PMID- 28812747 TI - Identifying the charge generation dynamics in Cs+-based triple cation mixed perovskite solar cells. AB - Triple cation based perovskite solar cells offer enhanced moisture tolerance and stability compared to mixed perovskites. Slight substitution of methyl ammonium or formamidinium cation by cesium (Cs+), was also reported to eliminate halide segregation due to its smaller size. To elucidate the device kinetics and understand the role of the Cs, we undertook different modes of scanning probe microscopy and electrochemical impedance spectroscopy (EIS) experiments. Kelvin probe force microscopy revealed that the incorporation of the Cs cation increases the contact potential difference (CPD), this CPD further increases when Spiro OMeTAD is used as a hole transport material. The current at the nanoscale level shows improvement with Cs inclusion and further enhancement by the Spiro-OMeTAD deposition, studied under light illumination, which supports the high photocurrent density obtained from the cells. EIS demonstrates that in a triple cation environment, reduced carrier recombination at the TiO2/perovskite interface was also obtained which in turn allow us to achieve a higher Voc value. PMID- 28812748 TI - Cyclometalated iridium(iii) N-heterocyclic carbene complexes as potential mitochondrial anticancer and photodynamic agents. AB - Metal N-heterocyclic carbene (NHC) complexes represent a promising class of anticancer therapeutic agents. In this work, four cyclometalated iridium(iii) complexes (Ir1-Ir4) containing N-heterocyclic carbene ligands have been explored as mitochondrial anticancer and photodynamic agents. These complexes are more cytotoxic than cisplatin against the cancer cells screened, can quickly penetrate into A549 cells and are mainly localized in the mitochondria. Mechanism studies show that these complexes exert their anticancer efficacy by increasing the intracellular ROS level, reducing the mitochondrial membrane potential (MMP) and inducing apoptosis. Additionally, Ir1-Ir4 exhibited two orders of magnitude higher cytotoxicity upon irradiation at 450 nm LED light. Our work provides a strategy for the design of highly effective anticancer photodynamic therapeutic agent based phosphorescent iridium complexes. PMID- 28812749 TI - Radical-driven processes within a peptidic sequence of type I collagen upon single-photon ionisation in the gas phase. AB - We report on an experimental single-photon absorption study on gas-phase protonated collagen peptides employing a combination of mass spectrometry and synchrotron radiation. Partial ion yields for the main photoabsorption products vary steadily with photon energy over the range from 14 to 545 eV. At low energy, non-dissociative photoionisation competes with neutral molecule loss from the precursor ion, whereas fragmentation of the peptide backbone dominates at soft X ray energies. Neutral molecule losses from the ionised peptide are found to have low energy barriers and most likely involve amino-acid residue side-chains with radical character, in particular aspartic acid. A particularly interesting finding is photoinduced loss of proline hydroxylation. The loss of this typical collagen post-translational modification might play a destabilizing role in the collagen structure. PMID- 28812750 TI - Synthesis and characterization of FeIII(MU-OH)ZnII complexes: effects of a second coordination sphere and increase in the chelate ring size on the hydrolysis of a phosphate diester and DNA. AB - The synthesis and characterization of three ligands and their respective heterobinuclear FeIIIZnII complexes were carried out, with the goal of mimicking the active site of purple acid phosphatases (PAPs). The ligand 2-hydroxy-3-(((2 hydroxy-5-methyl-3-(((2-(pyridin-2-yl)ethyl)(pyridin-2 ylmethyl)amino)methyl)benzyl)(pyridin-2ylmethyl)amino)methyl)-5 methylbenzaldehyde (H2L2) was synthesized and its complex (FeIIIZnIIL2) was used as a basis for comparison with similar complexes previously published in the literature. Subsequent modifications were conducted in the aldehyde group, where 1,2-ethanediamine and 1,4-diaminobutane were used as side chain derivatives. The compounds FeIIIZnIIL2 (1), FeIIIZnIIL2-et (2) and FeIIIZnIIL2-but (3) were characterized by spectroscopic methods (infrared and UV-Vis) and ESI-MS spectrometry. Theoretical calculations were performed to provide insights into the complex structures with FeIIIZnII structures. The hydrolytic activity was analyzed both with the model substrate 2,4-BDNPP and with DNA catalyzed by complexes 1, 2 and 3. PMID- 28812751 TI - Hydrogen-bonded rosettes comprising pi-conjugated systems as building blocks for functional one-dimensional assemblies. AB - Hydrogen-bonded supermacrocycles (rosettes) are attractive disk-shaped noncovalent synthons for extended functional columnar nanoassemblies. They can serve not only as noncovalent monomer units for supramolecular polymers and discrete oligomers in a dilute solution but also as constituent entities for soft matters such as gels and lyotropic/thermotropic liquid crystals. However, what are the merits of using supramolecular rosettes instead of using expanded pi conjugated covalent molecules? This review covers the self-assembly of photochemically and electrochemically active pi-conjugated molecules through the formation of supramolecular rosettes via directional complementary multiple hydrogen-bonding interactions. These rosettes comprising pi-conjugated covalent functional units stack into columnar nanoassemblies with unique structures and properties. By overviewing the design principle, characterization, and properties and functionalities of various examples, we illustrate the merits of utilizing rosette motifs. Basically, one can easily access a well-defined expanded pi surface composed of multi-chromophoric systems, which can ultimately afford stable extended nanoassemblies even in a dilute solution due to the higher association constants of supermacrocyclized pi-systems. Importantly, these columnar nanoassemblies exhibit unique features in self-assembly processes, chiroptical, photophysical and electrochemical properties, nanoscale morphologies, and bulk properties. Moreover, the stimuli responsiveness of individual building blocks can be amplified to a greater extent by exploiting rosette intermediates to organize them into one-dimensional columnar structures. In the latter parts of the review, we also highlight the application of rosettes in supramolecular polymer systems, photovoltaic devices, and others. PMID- 28812752 TI - Extending charge separation lifetime and distance in patterned dye-sensitized SnO2-TiO2 MUm-thin films. AB - A simple method for the preparation of patterned dye-sensitized SnO2-TiO2 thin films, designed to prolong the lifetime of the interfacial charge separated state is presented. Using microfluidic technology, the thin films were sensitized with the organic sensitizer D35 such that they contain SnO2-TiO2 areas with dye and SnO2 dye-free areas at which injected electrons can be accumulated. Single wavelength transient absorption spectroscopy confirmed significantly extended charge separation lifetime at the dye-semiconductor interface. Sufficiently high density of injected electrons results in substantial decrease of charge recombination rate constants (kcr); a factor of ~50 compared to dye-sensitized TiO2 thin films and a factor of ~2000 compared to dye-sensitized SnO2 thin films. Furthermore, the potential of this approach was confirmed by photoinduced conduction band mediated electron transfer from the dye to a model electron acceptor, Co protoporphyrin IX, which was adsorbed to the SnO2-only regions. PMID- 28812753 TI - Cyanide vs. azide "magnetic arm wrestling": MnII-NbIV and MnII-MoIV magnetic coordination polymers with mixed bridging. AB - Two magnetic coordination polymers with mixed cyanide-azide bridging based on octacyanoniobate(iv) and octacyanomolybdate(iv) are reported: {(NH4)[(H2O)MnII (MU-N3)-MnII(H2O)][MIV(CN)8].3H2O}n Mn2MN3 (M = Nb or Mo). Cyanide ligands form the 3-D framework of Mn2MN3, while azide ligands connect two MnII centres together. Both CN- and N3- are known in magnetochemistry for their marked magnetic coupling abilities which in the case of Mn2NbN3 lead to competitive antiferromagnetic interactions within the NbIV-CN-MnII and MnII-N3-MnII structural motifs. This competition results in a peculiar magnetic behaviour consistent with a non-collinear magnetic structure. PMID- 28812754 TI - Towards well-defined MoS2 nanoribbons on a large scale. AB - High quality molybdenum dioxide plates are engineered as templates for epitaxial growth of well-defined MoS2 nanoribbons (MNRs). The obtained MNRs possess prominent ferromagnetism, suggesting edge zigzag topologies. Our findings have opened an alternative route to large-scale synthesis of well-defined 1D materials. PMID- 28812758 TI - A metalloporphyrin-based porous organic polymer as an efficient catalyst for the catalytic oxidation of olefins and arylalkanes. AB - A metalloporphyrin-based porous organic polymer, Mn-PPOP-1, was constructed in high yield via the ketoenamine condensation of robust porphyrin tetraamines (TBPP) with 1,3,5-triformylphloroglucinol. The stable keto-enamine form in the synthesized polymer was unambiguously confirmed by 13C CP-MAS solid state NMR. Noticeably, besides the high thermal and chemical stability, this material contains both micropores and mesopores, which are favorable for mass transfer in the catalytic application. Mn-PPOP-1 exhibits significantly high catalytic oxidation of olefins and arylalkanes at room temperature. The catalytic activity and stability of Mn-PPOP-1 are apparently superior to those of the homogeneous manganese porphyrins. These results indicate that the metalloporphyrin-based porous organic polymer is a promising candidate for efficient heterogeneous catalysts. PMID- 28812760 TI - Porous crystalline materials: closing remarks. AB - This paper is derived from my 'closing remarks' lecture at the 287th Faraday Discussions meeting on New Directions in Porous Crystalline Materials, Edinburgh, UK, 5-7 June, 2017. This meeting comprised sessions on the design of porous networks, and their capture, storage, separation, conducting properties, catalysts, resistance to chemicals and moisture, simulation, and electronic structures. This paper details the achievements and developments in the field, as reflected in invited speakers' papers and discussions with the attendees during the meeting. PMID- 28812762 TI - A facile synthesis of CuFe2O4/Cu9S8/PPy ternary nanotubes as peroxidase mimics for the sensitive colorimetric detection of H2O2 and dopamine. AB - Synergistic effects play an important role in improving the catalytic activity for enzyme-like reactions. Compared to individual nanomaterials, a system consisting of multiple components usually exhibits enhanced catalytic activity as an enzyme mimic. Herein we describe the synthesis of CuFe2O4/Cu9S8/polypyrrole (PPy) ternary nanotubes as an efficient peroxidase mimic via a three-step approach involving an electrospinning process, annealing treatment and hydrothermal reaction. The remarkably enhanced catalytic activity of CuFe2O4/Cu9S8/PPy ternary nanotubes as peroxidase mimics over individual CuFe2O4 nanofibers, CuFe2O4/CuO composite nanofibers, CuFe2O4/CuS composite nanofibers, and PPy materials has been achieved, demonstrating the presence of a synergistic effect among the components. The steady-state kinetic experiment suggests a good catalytic efficiency of the CuFe2O4/Cu9S8/PPy ternary nanotubes. On the basis of high catalytic activity, a colorimetric platform for the sensitive detection of H2O2 and dopamine has been developed. This work not only offers a simple approach for the fabrication of a high performance peroxidase-like nanocatalyst, but also provides its promising potential applications in biosensors, medical diagnosis, and environmental monitoring. PMID- 28812763 TI - Enhancing the solubility and bioactivity of anticancer drug tamoxifen by water soluble pillar[6]arene-based host-guest complexation. AB - A water-soluble pillar[6]arene functions as a solubilizing agent to enhance the solubility and bioactivity of poorly water-soluble anticancer drug tamoxifen by host-guest complexation between it and tamoxifen. PMID- 28812765 TI - Rational design of polymeric core shell ratiometric oxygen-sensing nanostructures. AB - A new approach for the fabrication of luminescent ratiometric sensing nanosensors is described using core-shell nanoparticles in which the probe and reference are spatially separated into the shell and core of the nanostructure respectively. The isolation of the reference in the core of the particle ensures a stable emission reference signal unaffected by the external environment. The core shell structure was prepared by engineering structurally well-defined Ru-conjugated block copolymers which acted as emulsifiers in the miniemulsion polymerisation of BODIPY loaded styrene nanoparticles. The resulting particles are highly stable and show excellent size monodispersity. The nanosensors exhibit dual emission under a single excitation wavelength with a reversible and quantitative ratiometric response to the O2 content in aqueous media. In the presence of a low concentration of CTAB, the particles cross the cell membrane and the particles show negligible cytotoxicity. Such an approach to sensor nanoparticles should be of value across a range of applications where a stable ratiometric signal in diverse environments is required. PMID- 28812766 TI - Modulatory effects of arginine, glutamine and branched-chain amino acids on heat shock proteins, immunity and antioxidant response in exercised rats. AB - Heat shock proteins (HSPs) are endogenous proteins whose function is to maintain the cell's tolerance to insult, and glutamine supplementation is known to increase HSP expression during intense exercise. Since few studies have addressed the possibility that supplementation with other amino acids could have similar effects to that of glutamine, our objective was to evaluate the effects of leucine, valine, isoleucine and arginine as potential stimulators of HSPs 25, 60, 70 and 90 in rats subjected to acute exercise as a stressing factor. The immune markers, antioxidant system, blood parameters, glycogen and amino acid profile responses were also assessed. Male Wistar rats were divided into seven groups: control (rest, without gavage), vehicle (water), l-leucine, l-isoleucine, l valine, l-arginine and l-glutamine. Except for the control, all animals were exercised and received every amino acid by oral gavage. Arginine supplementation up-regulated muscle HSP70 and HSP90 and serum HSP70, however, none of the amino acids affected the HSP25. All amino acids increased exercise-induced HSP60 expression, except for valine. Antioxidant enzymes were reduced by exercise, but both glutamine and arginine restored glutathione peroxidase, while isoleucine and valine restored superoxide dismutase. Exercise reduced monocyte, platelet, lymphocyte and erythrocyte levels, while leucine stimulated immune response, preserved the levels of the lymphocytes and increased leukocytes and maintained platelets at control levels. Plasma and muscle amino acid profiles showed specific metabolic features. The data suggest that the tissue-protecting effects of arginine could proceed by enhancing specific HSPs in the body. PMID- 28812767 TI - Mild synthesis of triarylsulfonium salts with arynes. AB - Reactions between arynes and alkyl sulfides have been extensively studied over the past few decades. These reactions commonly end with a dealkylation process and thus deliver thioethers as final products. In contrast, the transformation described furnishes valuable triarylsulfonium salts, in lieu of thioethers, from arynes and diarylsulfides. The reaction features mild conditions and a broad substrate scope. A suite of functional groups such as ketones, esters, nitriles, aryl ethers and aryl halides is tolerated, which can be issues faced by traditional synthetic methods. The practicality of the reaction and its extension to the synthesis of triphenyl selenonium salt are also exhibited herein. PMID- 28812768 TI - Chemical, nutritive composition and a wide range of bioactive properties of honey mushroom Armillaria mellea (Vahl: Fr.) Kummer. AB - A. mellea fruiting bodies collected from nature were chemically characterized and shown to be rich in carbohydrates (81.25 g per 100 g dw), ash, fat and proteins (8.84 g per 100 g dw, 1.97 g per 100 g dw and 1.81 g per 100 g dw, respectively). Mannitol was the main free sugar while malic acid was the most abundant organic acid. delta-Tocopherol was the dominant form of tocopherols with 42.41 MUg per 100 g dw. Polyunsaturated fatty acids were predominant, followed by saturated and monounsaturated fatty acids. A methanolic extract prepared from these samples was tested for antioxidant, quorum sensing and antimicrobial assays, as well as for its cytotoxicity effects. The extract showed antimicrobial activity against all tested microorganisms, including Candida albicans. Furthermore, when tested at sub-MIC concentration, it showed reduction of virulence factors and biofilm formation against Pseudomonas aeruginosa. The extract also exhibited antioxidant activity and did not show toxicity against tumor and non-tumor cells. Due to the observed bioactive properties and compounds of the honey mushroom and its well balanced nutrients, this mushroom emerges as an interesting functional food and a source of nutraceuticals with applications in different diseases based on antioxidant and antimicrobial effects. PMID- 28812769 TI - Multiplex coaxial flow focusing for producing multicompartment Janus microcapsules with tunable material compositions and structural characteristics. AB - We propose a simple but efficient multiplex coaxial flow focusing (MCFF) process for single-step fabrication of multicompartment Janus microcapsules (MJMs) in a wide range of operating parameters. The produced MJMs consist of a multicompartmental core-shell structure with material compositions tunable in individual shell and core compartments. Potential applications of such a MJM agent are demonstrated in both benchtop and in vitro experiments. For the benchtop experiment, magnetic nanoparticles are loaded into one of the shell compartments and photopolymerized under ultraviolet light for controlled alignment and rotation of the microcapsules in a magnetic field. For the in vitro experiment, four different types of cells are encapsulated in the desired compartments of sodium alginate MJMs and co-cultured for seven days. By increasing the number of coaxial needles, we are also able to produce MJMs with three or more compartments. Our studies have shown that the proposed MCFF process is able to produce MJMs with desired material compositions and narrow size distribution. This process is inexpensive and scalable for mass production of various MJMs in its potential applications in biomedical imaging, drug delivery, and regenerative medicine. PMID- 28812773 TI - Side-by-side observation of the interfacial improvement of vertical graphene coated silicon nanocone anodes for lithium-ion batteries by patterning technology. AB - We report that vertical graphene coating can greatly improve the electrochemical performance and the interfacial stability of silicon nanocone (SNC) anodes for lithium-ion batteries. The coating patterning technology is innovatively employed for side-by-side demonstration of the exclusive influences of graphene coating on the solid-electrolyte interphase (SEI) formation and the structural stability of the SNC electrode. The silicon nanocone-graphene (SNC-G) electrode achieves a longer cycle life (1715 cycles), higher Coulombic efficiency (average 98.2%), better rate capability, and lower electrode polarization than the SNC electrode. The patterning of the graphene coating provides a much direct and convincing morphological comparison between the SNC-G structure and the SNC structure, showing clearly that the SNC-G area maintains a thin SEI layer and stable nanostructure after cycling, while the SNC area is gradually damaged and covered with a thick SEI layer after 100 cycles. Our results clearly indicate the improved electrochemical performance and interfacial stability attributed to the vertical graphene coating, and the as-proposed patterning technology also paves a new way for comparative research on coating materials for lithium-ion batteries. PMID- 28812774 TI - Self-adaptive hydrogels to mineralization. AB - Mineralized biological tissues, whose behavior can range from rigid to compliant, are an essential component of vertebrates and invertebrates. Little is known about how the behavior of mineralized yet compliant tissues can be tuned by the degree of mineralization. In this work, a synthesis route to tune the structure and mechanical response of agarose gels via ionic crosslinking and mineralization has been developed. A combination of experimental techniques demonstrates that crosslinking via cooperative hydrogen bonding in agarose gels is disturbed by calcium ions, but they promote ionic crosslinking that modifies the agarose network. Further, it is shown that the rearrangement of the hydrogel network helps to accommodate precipitated minerals into the network -in other words, the hydrogel self-adapts to the precipitated mineral- while maintaining the viscoelastic behavior of the hydrogel, despite the reinforcement caused by mineralization. This work not only provides a synthesis route to design biologically inspired soft composites, but also helps to understand the change of properties that biomineralization can cause to biological tissues, organisms and biofilms. PMID- 28812775 TI - Polymorphic light eruption and IL-1 family members: any difference with allergic contact dermatitis? AB - Polymorphic light eruption (PLE) is described as a delayed-type hypersensitivity reaction (DTHR) toward a de novo light-induced antigen, yet to be identified. In effect, the inflammatory pathways of PLE and allergic contact dermatitis (ACD) share common patterns in terms of the mediators involved from the innate and adaptive immune system participating in the DTHR. As we have previously highlighted the role of interleukin (IL)-1 family members in ACD, we hypothesised that the same mediators could have similar functions in PLE. Our research aimed to assess the expression of certain IL-1family members in PLE patients vs. controls, and to compare it with ACD. The study population comprised 17 patients with PLE, 5 affected by ACD and 10 healthy controls in the same age range. Lesional and healthy skin samples were collected respectively from patients and donors. IL-36alpha, IL-36beta, IL-36gamma, IL-36 receptor antagonist (Ra), IL 1beta, IL-33 gene and protein expressions were evaluated through RT-PCR and immunohistochemistry. Circulating proteins in the PLE patients were analysed by using western blot. The IL-36gamma gene expression was significantly increased in PLE lesions compared to that in healthy controls and ACD lesions (***p < 0.001; ##p < 0.01 respectively), whereas the other analyzed ILs were more expressed in ACD. Immunohistochemical analysis revealed that IL-36alpha and IL-36gamma protein levels were increased in PLE lesions compared to those of the healthy samples (***p < 0.001). Furthermore the IL-36gamma plasma level was increased in PLE patients vs. controls (*p < 0.05). Our findings indicate that the IL-1 family pro inflammatory members are increased in PLE with distinct differences from those in ACD, in particular with regard to IL-36gamma mRNA regulation. Their role as activators of the local, and perhaps systemic, immune response, or as inhibitors of the immune tolerance machinery, needs further investigation. PMID- 28812776 TI - Labelled sunscreen SPFs may overestimate protection in natural sunlight. AB - Limited evidence exists to indicate that sunscreen protection factors determined in the laboratory are higher than those in natural sunlight. In this article we propose an explanation for this difference and estimate the expected SPFs of sunscreen products in natural sunlight and those expected from laboratory testing. Our results indicate that the labelled SPF, determined by in vivo assay using a UV solar simulator, overestimates the SPF that would be expected in natural sunlight to the extent that for products labelled SPF50+, it may not be possible to achieve a protection against sunlight of more than 25-fold. The popular interpretation of the SPF that it can be thought of as how much longer skin covered with sunscreen takes to burn in sunlight compared with unprotected skin, can no longer be defended. PMID- 28812777 TI - A mild two-step propargylation of aromatic bioactive small molecules. AB - A two-step method for introducing a propargyl group in aromatic bioactive small molecules has been developed. This method features propargylation of aromatic groups using a cationic propargyl hexacarbonyl complex in the presence of cesium carbonate, and decomplexation of the resultant cobalt complexes using 2,2,6,6 tetramethylpiperidine-1-oxoammonium tetrafluoroborate. These reactions proceed under mild conditions, and thus are applicable for acid- and/or oxidant-sensitive aromatic bioactive small molecules. PMID- 28812779 TI - The first total synthesis and solution structure of a polypeptin, PE2, a cyclic lipopeptide with broad spectrum antibiotic activity. AB - The first total synthesis of a polypeptin, PE2, as well as its solution structure is reported. Synthesis in optically pure form confirms the proposed stereochemistry of the polypeptins at the 3-position on the 3-hydroxy depsipeptide moiety. We have also determined the NMR structure of PE2 in aqueous solution, showing it to form a stable ring conformation. The synthetic peptide shows anti-bacterial activity consistent with reports for naturally derived counterparts. PMID- 28812780 TI - Early loading of mandibular full-arch bridges screw retained after 1 week to four to five Monotype(r) implants: 3-year results from a prospective multicentre study. AB - OBJECTIVES: This prospective multicentre study provides clinical experience up to 3 years to support a simplified treatment for mandibular edentulism within 1 week by using one-stage implant surgery and a screw-retained full-arch bridge. METHODS: Two hundred and fifty ITI Monotype(r) implants were installed in 62 patients out of 66 patients; 60 patients got four implants each and two got five implants. After 1 week, a final bridge was in function. Radiographs were taken as baseline for vertical bone loss up to 3 years post-loading for the whole cluster and specific effects of gender, centre, age, bone class, implant length over time were compiled. Clinical (mPI, SBI) and subjective parameters such as general oral hygiene and patient satisfaction were recorded and repeated at specified intervals up to 3 years. RESULTS: Four patients were excluded at surgery and are not involved in the follow-ups. At 1 year, 61 patients (244 implants) were evaluable and all bridges were in function. After 3 years, 49 patients (194 implants) came to control. Eight patients died during the follow-up period. Three patients lost one implant each. The cumulative implant survival rate was 98.55% and the success rate for the prosthesis was 100%. As calculated from measurable radiographs, the mean bone level at baseline was 1.63+/-0.78 and at 1 and 3 years 2.50+/-0.60 and 2.56+/-0.74, respectively. Using the mixed model analysis and Friedman test, the time in situ, centre and bone class had significant effect on the bone resorption and to some small extent even, the implant length. Gender and age were unaffected. Oral hygiene and patient satisfaction of the treatment were improved. CONCLUSIONS: The results indicate that one-part self-tapping sandblasted, large-grit, acid-etched (SLA) implants are suitable for loading within 1 week. In the whole period, the mean bone crestal resorption was <1 mm, which is in agreement with other similar studies. PMID- 28812781 TI - Improving the Quality and Quantity of HIV Data in the Middle East and North Africa: Key Challenges and Ways Forward. AB - Although the HIV pandemic is witnessing a decline in the number of new infections in most regions of the world, the Middle East and North Africa (MENA) has a rapidly growing HIV problem. While generating HIV data has been consistently increasing since 2005, MENA's contribution to the global HIV literature is just over 1% and the existing evidence often falls behind the academic standards. Several factors could be at play that contribute to the limited quantity and quality of HIV data in MENA. This editorial tries to explore and explain the barriers to collecting high-quality HIV data and generating precise estimates in MENA. These barriers include a number of logistic and socio-political challenges faced by researchers, public health officials, and policy-makers. Looking at successful regional HIV programs, we explore examples were policies have shifted and lessons could be learned in developing appropriate responses to HIV across the region. PMID- 28812782 TI - The Development of Public Policies to Address Non-communicable Diseases in the Caribbean Country of Barbados: The Importance of Problem Framing and Policy Entrepreneurs. AB - BACKGROUND: Government policy measures have a key role to play in the prevention and control of non-communicable diseases (NCDs). The Caribbean, a middle-income region, has the highest per capita burden of NCDs in the Americas. Our aim was to examine policy development and implementation between the years 2000 and 2013 on NCD prevention and control in Barbados, and to investigate factors promoting, and hindering, success. METHODS: A qualitative case study design was used involving a structured policy document review and semi-structured interviews with key informants, identified through stakeholder analysis and 'cascading.' Documents were abstracted into a standard form. Interviews were recorded, transcribed verbatim and underwent framework analysis, guided by the multiple streams framework (MSF). There were 25 key informants, from the Ministry of Health (MoH), other government Ministries, civil society organisations, and the private sector. RESULTS: A significant policy window opened between 2005 and 2007 in which new posts to address NCDs were created in the MoH, and a government supported multi sectoral national NCD commission was established. Factors contributing to this government commitment and funding included a high level of awareness, throughout society, of the NCD burden, including media coverage of local research findings; the availability of policy recommendations by international bodies that could be adopted locally, notably the framework convention on tobacco control (FCTC); and the activities of local highly respected policy entrepreneurs with access to senior politicians, who were able to bring together political concern for the problem with potential policy solutions. However, factors were also identified that hindered multi-sectoral policy development in several areas, including around nutrition, physical activity, and alcohol. These included a lack of consensus (valence) on the nature of the problem, often framed as being predominantly one of individuals needing to take responsibility for their health rather than requiring government-led environmental changes; lack of appropriate detailed policy guidance for local adaptation; conflicts with other political priorities, such as production and export of alcohol, and political reluctance to use legislative and fiscal measures. CONCLUSION: The study's findings indicate mechanisms to promote and support NCD policy development in the Caribbean and similar settings. PMID- 28812784 TI - The Frequency of Alcohol Use in Iranian Urban Population: The Results of a National Network Scale Up Survey. AB - BACKGROUND: In Islamic countries alcohol consumption is considered as against religious values. Therefore, estimation of frequency of alcohol consumptions using direct methods is prone to different biases. In this study, we indirectly estimated the frequency of alcohol use in Iran, in network of a representative sample using network scale up (NSU) method. METHODS: In a national survey, about 400 participants aged above 18 at each province, around 12 000 in total, were recruited. In a gender-match face to face interview, respondents were asked about the number of those who used alcohol (even one episode) in previous year in their active social network, classified by age and gender. The results were corrected for the level of visibility of alcohol consumption. RESULTS: The relative frequency of alcohol use at least once in previous year, among general population aged above 15, was estimated at 2.31% (95% CI: 2.12%, 2.53%). The relative frequency among males was about 8 times higher than females (4.13% versus 0.56%). The relative frequency among those aged 18 to 30 was 3 times higher than those aged above 30 (3.97% versus 1.36%). The relative frequency among male aged 18 to 30 was about 7%. CONCLUSION: It seems that the NSU is a feasible method to monitor the relative frequency of alcohol use in Iran, and possibly in countries with similar culture. Alcohol use was lower than non-Muslim countries, however, its relative frequency, in particular in young males, was noticeable. PMID- 28812785 TI - Mitigating Evidentiary Bias in Planning and Policy-Making Comment on "Reflective Practice: How the World Bank Explored Its Own Biases?" AB - The field of cognitive psychology has increasingly provided scientific insights to explore how humans are subject to unconscious sources of evidentiary bias, leading to errors that can affect judgement and decision-making. Increasingly these insights are being applied outside the realm of individual decision-making to the collective arena of policy-making as well. A recent editorial in this journal has particularly lauded the work of the World Bank for undertaking an open and critical reflection on sources of unconscious bias in its own expert staff that could undermine achievement of its key goals. The World Bank case indeed serves as a remarkable case of a global policy-making agency making its own critical reflections transparent for all to see. Yet the recognition that humans are prone to cognitive errors has been known for centuries, and the scientific exploration of such biases provided by cognitive psychology is now well-established. What still remains to be developed, however, is a widespread body of work that can inform efforts to institutionalise strategies to mitigate the multiple sources and forms of evidentiary bias arising within administrative and policy-making environments. Addressing this gap will require a programme of conceptual and empirical work that supports robust development and evaluation of institutional bias mitigation strategies. The cognitive sciences provides a scientific basis on which to proceed, but a critical priority will now be the application of that science to improve policy-making within those agencies taking responsibility for social welfare and development programmes. PMID- 28812783 TI - District Health Officer Perceptions of PEPFAR's Influence on the Health System in Uganda, 2005-2011. AB - BACKGROUND: Vertically oriented global health initiatives (GHIs) addressing the HIV/AIDS epidemic, including the President's Emergency Plan for AIDS Relief (PEPFAR), have successfully contributed to reducing HIV/AIDS related morbidity and mortality. However, there is still debate about whether these disease specific programs have improved or harmed health systems overall, especially with respect to non-HIV health needs. METHODS: As part of a larger evaluation of PEPFAR's effects on the health system between 2005-2011, we collected qualitative and quantitative data through semi-structured interviews with District Health Officers (DHOs) from all 112 districts in Uganda. We asked DHOs to share their perceptions about the ways in which HIV programs (largely PEPFAR in the Ugandan context) had helped and harmed the health system. We then identified key themes among their responses using qualitative content analysis. RESULTS: Ugandan DHOs said PEPFAR had generally helped the health system by improving training, integrating HIV and non-HIV care, and directly providing resources. To a lesser extent, DHOs said PEPFAR caused the health system to focus too narrowly on HIV/AIDS, increased workload for already overburdened staff, and encouraged doctors to leave public sector jobs for higher-paid positions with HIV/AIDS programs. CONCLUSION: Health system leaders in Uganda at the district level were appreciative of resources aimed at HIV they could often apply for broader purposes. As HIV infection becomes a chronic disease requiring strong health systems to manage sustained patient care over time, Uganda's weak health systems will require broad infrastructure improvements inconsistent with narrow vertical health programming. PMID- 28812786 TI - Policy Choices for Progressive Realization of Universal Health Coverage Comment on "Ethical Perspective: Five Unacceptable Trade-offs on the Path to Universal Health Coverage". AB - In responses to Norheim's editorial, this commentary offers reflections from Thailand, how the five unacceptable trade-offs were applied to the universal health coverage (UHC) reforms between 1975 and 2002 when the whole 64 million people were covered by one of the three public health insurance systems. This commentary aims to generate global discussions on how best UHC can be gradually achieved. Not only the proposed five discrete trade-offs within each dimension, there are also trade-offs between the three dimensions of UHC such as population coverage, service coverage and cost coverage. Findings from Thai UHC show that equity is applied for the population coverage extension, when the low income households and the informal sector were the priority population groups for coverage extension by different prepayment schemes in 1975 and 1984, respectively. With an exception of public sector employees who were historically covered as part of fringe benefits were covered well before the poor. The private sector employees were covered last in 1990. Historically, Thailand applied a comprehensive benefit package where a few items are excluded using the negative list; until there was improved capacities on technology assessment that cost effectiveness are used for the inclusion of new interventions into the benefit package. Not only cost-effectiveness, but long term budget impact, equity and ethical considerations are taken into account. Cost coverage is mostly determined by the fiscal capacities. Close ended budget with mix of provider payment methods are used as a tool for trade-off service coverage and financial risk protection. Introducing copayment in the context of fee-for-service can be harmful to beneficiaries due to supplier induced demands, inefficiency and unpredictable out of pocket payment by households. UHC achieves favorable outcomes as it was implemented when there was a full geographical coverage of primary healthcare coverage in all districts and sub-districts after three decade of health infrastructure investment and health workforce development since 1980s. The legacy of targeting population group by different prepayment mechanisms, leading to fragmentation, discrepancies and inequity across schemes, can be rectified by harmonization at the early phase when these schemes were introduced. Robust public accountability and participation mechanisms are recommended when deciding the UHC strategy. PMID- 28812787 TI - Defining Sub-Saharan Africa's Health Workforce Needs: Going Forwards Quickly Into the Past Comment on "Non-physician Clinicians in Sub-Saharan Africa and the Evolving Role of Physicians". AB - Recent proposals for re-defining the roles Africa's health workforce are a continuation of the discussions that have been held since colonial times. The proposals have centred on basing the continent's healthcare delivery on non physician clinicians (NPCs) who can be quickly trained and widely distributed to treat majority of the common diseases. Whilst seemingly logical, the success of these proposals will depend on the development of clearly defined professional duties for each cadre of healthcare workers (HCW) taking the peculiarities of each country into consideration. As such the continent-wide efforts aimed at health-professional curriculum reforms, more effective utilisation of task shifting as well as the intra - and inter-disciplinary collaborations must be encouraged. Since physicians play a major role in the training mentoring and supervision of physician and non-physician health-workers alike, the maintenance of the standards of university medical education is central to the success of all health system models. It must also be recognized that, efforts at improving Africa's health systems can only succeed if the necessary socio-economic, educational, and technological infrastructure are in place. PMID- 28812788 TI - The Need for Global Application of the Accountability for Reasonableness Approach to Support Sustainable Outcomes Comment on "Expanded HTA: Enhancing Fairness and Legitimacy". AB - The accountability for reasonableness (AFR) concept has been developed and discussed for over two decades. Its interpretation has been studied in several ways partly guided by the specific settings and the researchers involved. This has again influenced the development of the concept, but not led to universal application. The potential use in health technology assessments (HTAs) has recently been identified by Daniels et al as yet another excellent justification for AFR-based process guidance that refers to both qualitative and a broader participatory input for HTA, but it has raised concerns from those who primarily support the consistency and objectivity of more quantitative and reproducible evidence. With reference to studies of AFR-based interventions and the through these repeatedly documented motivation for their consolidation, we argue that it can even be unethical not to take AFR conditions beyond their still mainly formative stage and test their application within routine health systems management for their expected support to more sustainable health improvements. The ever increasing evidence and technical expertise are necessary but at times contradictory and do not in isolation lead to optimally accountable, fair and sustainable solutions. Technical experts, politicians, managers, service providers, community members, and beneficiaries each have their own values, expertise and preferences, to be considered for necessary buy in and sustainability. Legitimacy, accountability and fairness do not come about without an inclusive and agreed process guidance that can reconcile differences of opinion and indeed differences in evidence to arrive at a by all understood, accepted, but not necessarily agreed compromise in a current context - until major premises for the decision change. AFR should be widely adopted in projects and services under close monitoring and frequent reviews. PMID- 28812789 TI - Non-physician Clinicians - A Gain for Physicians' Working in Sub-Saharan Africa Comment on "Non-physician Clinicians in Sub-Saharan Africa and the Evolving Role of Physicians". AB - The changing demands on the health sectors in low- and middle-income countries especially sub-Saharan African countries continue to challenge efforts to address critical shortages of the health workforce. Addressing these challenges have led to the evolution of "non-physician clinicians" (NPCs), that assume some physician roles and thus mitigate the continuing shortage of doctors in these countries. While it is agreed that changes are needed in physicians' roles and their training as part of the new continuum of care that includes NPCs, we disagree that such training should be geared solely at ensuring physicians dominated health systems. Discussions on the workforce models to suit low-income countries must avoid an endorsement of a culture of physician focused health systems as the only model for sub-Saharan Africa (SSA). It is also essential that training for NPCs be harmonized with that of physicians to clarify the technical roles of both. PMID- 28812790 TI - Coordinating Between Medical Professions' Tasks to Optimize Sub-Saharan Health Systems: A Response to Recent Commentaries. PMID- 28812792 TI - A Case for Open Network Health Systems: Systems as Networks in Public Mental Health. AB - Increases in incidents involving so-called confused persons have brought attention to the potential costs of recent changes to public mental health (PMH) services in the Netherlands. Decentralized under the (Community) Participation Act (2014), local governments must find resources to compensate for reduced central funding to such services or "innovate." But innovation, even when pressure for change is intense, is difficult. This perspective paper describes experience during and after an investigation into a particularly violent incident and murder. The aim was to provide recommendations to improve the functioning of local PMH services. The investigation concluded that no specific failure by an individual professional or service provider facility led to the murder. Instead, also as a result of the Participation Act that severed communication lines between individuals and organizations, information sharing failures were likely to have reduced system level capacity to identify risks. The methods and analytical frameworks employed to reach this conclusion, also lead to discussion as to the plausibility of an unconventional solution. If improving communication is the primary problem, non-hierarchical information, and organizational networks arise as possible and innovative system solutions. The proposal for debate is that traditional "health system" definitions, literature and narratives, and operating assumptions in public (mental) health are 'locked in' constraining technical and organization innovations. If we view a "health system" as an adaptive system of economic and social "networks," it becomes clear that the current orthodox solution, the so-called integrated health system, typically results in a "centralized hierarchical" or "tree" network. An overlooked alternative that breaks out of the established policy narratives is the view of a 'health systems' as a non-hierarchical organizational structure or 'Open Network.' In turn, this opens new technological and organizational possibilities in seeking policy solutions, and suggests an alternative governance model of huge potential value in public health both locally and globally. PMID- 28812791 TI - Global Developments in Priority Setting in Health. AB - Countries around the world are experiencing an ever-increasing need to make choices in investments in health and healthcare. This makes it incumbent upon them to have formal processes in place to optimize the legitimacy of eventual decisions. There is now growing experience among countries of the implementation of stakeholder participation, and a developing convergence of methods to support decision-makers within health authorities in making tough decisions when faced with the stark reality of limited resources. We call for further interaction among health authorities, and the research community to develop best practices in order to confront the difficult choices that need to be made. PMID- 28812793 TI - The Importance of Community Consultations for Generating Evidence for Health Reform in Ukraine. AB - BACKGROUND: The paper presents the results of community consultations about the health needs and healthcare experiences of the population of Ukraine. The objective of community consultations is to engage a community in which a research project is studying, and to gauge feedback, criticism and suggestions. It is designed to seek advice or information from participants directly affected by the study subject of interest. The purpose of this study was to collect first-hand perceptions about daily life, health concerns and experiences with the healthcare system. This study provides policy-makers with additional evidence to ensure that health reforms would include a focus not only on health system changes but also social determinants of health (SDH). METHODS: The data collection consisted of the 21 community consultations conducted in 2012 in eleven regions of Ukraine in a mix of urban and rural settings. The qualitative data was coded in MAXQDA 11 software and thematic analysis was used as a method of summarizing and interpreting the results. RESULTS: The key findings of this study point out the importance of the SDH in the lives of Ukrainians and how the residents of Ukraine perceive that health inequities and premature mortality are shaped by the circumstances of their daily lives, such as: political and economic instability, environmental pollution, low wages, poor diet, insufficient physical activity, and unsatisfactory state of public services. Study participants repeatedly discussed these conditions as the reasons for the perceived health crisis in Ukraine. The dilapidated state of the healthcare system was discussed as well; high out-of-pocket (OOP) payments and lack of trust in doctors appeared as significant barriers in accessing healthcare services. Additionally, the consultations highlighted the economic and health gaps between residents of rural and urban areas, naming rural populations among the most vulnerable social groups in Ukraine. CONCLUSION: The study concludes that any meaningful reforms of the health sector in Ukraine must include a broad range of factors, including the healthcare system but importantly, must extend to SDH approach and include the prioritization of health promotion, limiting alcohol and tobacco availability and enforcing environmental protection. PMID- 28812794 TI - Being Single as a Social Barrier to Access Reproductive Healthcare Services by Iranian Girls. AB - BACKGROUND: Iranian single women are deprived of reproductive healthcare services, though the provision of such services to the public has increased. This study aimed to explore the experiences of Iranian single women on their access to reproductive health services. METHODS: A qualitative design using a conventional content analysis method was used. Semi-structured interviews were held with 17 single women and nine health providers chosen using the purposive sampling method. RESULTS: Data analysis resulted in the development of three categories: 'family's attitudes and performance about single women's reproductive healthcare,' 'socio-cultural factors influencing reproductive healthcare,' and 'cultural factors influencing being a single woman.' CONCLUSION: Cultural and contextual factors affect being a single woman in every society. Therefore, healthcare providers need to identify such factors during the designing of strategies for improving the facilitation of access to reproductive healthcare services. PMID- 28812795 TI - The Contribution of Ageing to Hospitalisation Days in Hong Kong: A Decomposition Analysis. AB - BACKGROUND: Ageing has become a serious challenge in Hong Kong and globally. It has serious implications for health expenditure, which accounts for nearly 20% of overall government expenditure. Here we assess the contribution of ageing and related factors to hospitalisation days in Hong Kong. We used hospital discharge data from all publicly funded hospitals in Hong Kong between 2001 and 2012. METHODS: A decomposition method was used to examine the factors that account for the change of total hospitalisation days during the two periods, 2001-2004 and 2004-2012. The five factors include two demographic factors - population size and age-gender composition - and three service components - hospital discharge rate, number of discharge episodes per patient, and average length of stay (LOS) - which are all measured at age-gender group level. In order to assess the health cost burden in the future, we also project the total hospitalisation days up to 2041, for a range of scenarios. RESULTS: During the decreasing period of hospitalisation days (2001-2004), the reduction of LOS contributed to about 60% of the reduction. For the period of increase (2004-2012), ageing is associated with an increase in total hospitalisation days of 1.03 million, followed by an increase in hospital discharge rates (0.67 million), an increase in the number of discharge episodes per patient (0.62 million), and population growth (0.43 million). The reduction of LOS has greatly offset these increases (-2.19 million days), and has become one of the most significant factors in containing the increasing number of hospitalisation days. Projected increases in total hospitalisation days under different scenarios have highlighted that the contribution of ageing will become even more prominent after 2022. CONCLUSION: Hong Kong is facing increasing healthcare burden caused by the rapid increase in demand for inpatient services due to ageing. Better management of inpatient services with the aim of increasing efficiency and reducing LOS, avoidable hospitalisation and readmission, without compromising patient satisfaction and quality of service, are crucial for containing the rapid and enormous increases in total hospitalisation days for Hong Kong. The results would be relevant to many rapidly ageing societies in this region. PMID- 28812796 TI - Business as Usual: A Lack of Institutional Innovation in Global Health Governance Comment on "Global Health Governance Challenges 2016 - Are We Ready?" AB - There were once again high expectations that a major global health event - the Ebola virus outbreak of 2014-2015 - would trigger meaningfully World Health Organization (WHO) reform and strengthen global health governance (GHG). Rather than a "turning point," however, the global community has gone back to business as usual. This has occurred against a backdrop of worldwide political turmoil, characterised by a growing rejection of existing political leaders and state centric institutions. Debates about GHG so far have given insufficient attention to the need for institutional innovation. This entails rethinking the traditional bureaucratic model of postwar intergovernmental organizations which is disconnected from the transboundary, fast-paced nature of today's globalizing world. PMID- 28812797 TI - A New Gilded Age, and What It Means for Global Health Comment on "Global Health Governance Challenges 2016 - Are We Ready?" AB - New contours of global inequality present new challenges for global health, and require that we consider new kinds of health issues as global. I provide a number of illustrations, arguing the need for a political science of health that goes beyond conventional preoccupations with formal institutional and inter-state interactions and takes into account how globalization has affected the health policy landscape and restructured the distribution of economic and political power not only among countries, but also within them. PMID- 28812798 TI - The Devil Is in the Details! On Regulating Cannabis Use in Canada Based on Public Health Criteria Comment on "Legalizing and Regulating Marijuana in Canada: Review of Potential Economic, Social, and Health Impacts". AB - This commentary to the editorial of Hajizadeh argues that the economic, social and health consequences of legalizing cannabis in Canada will depend in large part on the exact stipulations (mainly from the federal government) and on the implementation, regulation and practice of the legalization act (on provincial and municipal levels). A strict regulatory framework is necessary to minimize the health burden attributable to cannabis use. This includes prominently control of production and sale of the legal cannabis including control of price and content with ban of marketing and advertisement. Regulation of medical marijuana should be part of such a framework as well. PMID- 28812799 TI - Current Models of Investor State Dispute Settlement Are Bad for Health: The European Union Could Offer an Alternative Comment on "The Trans-Pacific Partnership: Is It Everything We Feared for Health?" AB - In this commentary, we endorse concerns about the health impact of the trans pacific partnership (TPP), paying particular attention to its mechanisms for investor state dispute settlement. We then describe the different, judge-led approach being advocated by the European Commission team negotiating the Trans Atlantic Trade and Investment Partnership, arguing that, while not perfect, it offers significant advantages. PMID- 28812800 TI - Legalizing Marijuana in Canada - A Double-Edged Sword: A Response to Recent Commentaries. PMID- 28812801 TI - Four Challenges That Global Health Networks Face. AB - Global health networks, webs of individuals and organizations with a shared concern for a particular condition, have proliferated over the past quarter century. They differ in their effectiveness, a factor that may help explain why resource allocations vary across health conditions and do not correspond closely with disease burden. Drawing on findings from recently concluded studies of eight global health networks-addressing alcohol harm, early childhood development (ECD), maternal mortality, neonatal mortality, pneumonia, surgically-treatable conditions, tobacco use, and tuberculosis-I identify four challenges that networks face in generating attention and resources for the conditions that concern them. The first is problem definition: generating consensus on what the problem is and how it should be addressed. The second is positioning: portraying the issue in ways that inspire external audiences to act. The third is coalition building: forging alliances with these external actors, particularly ones outside the health sector. The fourth is governance: establishing institutions to facilitate collective action. Research indicates that global health networks that effectively tackle these challenges are more likely to garner support to address the conditions that concern them. In addition to the effectiveness of networks, I also consider their legitimacy, identifying reasons both to affirm and to question their right to exert power. PMID- 28812802 TI - Diplomacy and Health: The End of the Utilitarian Era. AB - Cost-effectiveness analysis (CEA), as a system of allocative efficiency for global health programs, is an influential criterion for resource allocation in the context of diplomacy and inherent foreign policy decisions therein. This is because such programs have diplomatic benefits and costs that can be uploaded from the recipient and affect the broader foreign policy interests of the donor and the diplomacy landscape between both parties. These diplomatic implications are vital to the long-term success of both the immediate program and any subsequent programs; hence it is important to articulate them alongside program performance, in terms of how well their interrelated interventions were perceived by the communities served. Consequently, the exclusive focus of cost effectiveness on medical outcomes ignores (1) the potential non-health benefits of less cost-effective interventions and (2) the potential of these collateral gains to form compelling cases across the interdisciplinary spectrum to increase the overall resource envelope for global health. The assessment utilizes the Kevany Riposte's "K-Scores" methodology, which has been previously applied as a replicable evaluation tool1 and assesses the trade-offs of highly cost-effective but potentially "undiplomatic" global health interventions. Ultimately, we apply this approach to selected HIV/AIDS interventions to determine their wider benefits and demonstrate the value alternative evaluation and decision-making methodologies. Interventions with high "K-Scores" should be seriously considered for resource allocation independent of their cost-effectiveness. "Oregon Plan" thresholds2 are neither appropriate nor enforceable in this regard while "K Score" results provide contextual information to policy-makers who may have, to date, considered only cost-effectiveness data. While CEA is a valuable tool for resource allocation, its use as a utilitarian focus should be approached with caution. Policy-makers and global health program managers should take into account a wide range of outcomes before agreeing upon selection and implementation. PMID- 28812804 TI - Barriers to the Implementation of the Health and Rehabilitation Articles of the United Nations Convention on the Rights of Persons with Disabilities in South Africa. AB - BACKGROUND: The United Nations (UN) Convention on the Rights of Persons with Disabilities (CRPD) is a milestone in the recognition of the human rights of persons with disabilities, including the right to health and rehabilitation. South Africa has signed and ratified the CRPD but still has a long way to go in reforming policies and systems in order to be in compliance with the convention. This paper seeks to fill a gap in the literature by exploring what the barriers to the implementation of the health and rehabilitation articles of the CRPD are, as identified by representatives of the disability community. METHODS: This investigation used a qualitative, exploratory methodology. 10 semi-structured interviews of a purposive sample of representatives of disabled persons organizations (DPOs), non-governmental organizations (NGOs), and service providers in South Africa were conducted. Participants were drawn from urban, peri-urban, and rural settings in order to reflect diverse perspectives within South Africa. Data was analysed using a multi-stage coding process to establish the main categories and relationships between them. RESULTS: Six main categories of barriers to the implementation of the health and rehabilitation articles of the CRPD were identified. Attitude barriers including stigma and negative assumptions about persons with disabilities were seen as an underlying cause and influence on all of the other categories; which included political, financial, health systems, physical, and communication barriers. CONCLUSION: The findings of this study have important implications for strategies and actions to implement the CRPD. Given the centrality of attitudinal barriers, greater sensitization around the area of disability is needed. Furthermore, disability should be better integrated and mainstreamed into more general initiatives to develop the health system and improve the lives of persons living in poverty in South Africa. PMID- 28812803 TI - Sustainability of Long-term Care: Puzzling Tasks Ahead for Policy-Makers. AB - BACKGROUND: The sustainability of long-term care (LTC) is a prominent policy priority in many Western countries. LTC is one of the most pressing fiscal issues for the growing population of elderly people in the European Union (EU) Member States. Country recommendations regarding LTC are prominent under the EU's European Semester. METHODS: This paper examines challenges related to the financial- and organizational sustainability of LTC systems in the EU. We combined a targeted literature review and a descriptive selected country analysis of: (1) public- and private funding; (2) informal care and externalities; and (3) the possible role of technology in increasing productivity. Countries were selected via purposive sampling to establish a cohort of country cases covering the spectrum of differences in LTC systems: public spending, private funding, informal care use, informal care support, and cash benefits. RESULTS: The aging of the population, the increasing gap between availability of informal care and demand for LTC, substantial market failures of private funding for LTC, and fiscal imbalances in some countries, have led to structural reforms and enduring pressures for LTC policy-makers across the EU. Our exploration of national policies illustrates different solutions that attempt to promote fairness while stimulating efficient delivery of services. Important steps must be taken to address the sustainability of LTC. First, countries should look deeper into the possibilities of complementing public- and private funding, as well as at addressing market failures of private funding. Second, informal care externalities with spill-over into neighboring policy areas, the labor force, and formal LTC workers, should be properly addressed. Thirdly, innovations in LTC services should be stimulated to increase productivity through technology and process innovations, and to reduce costs. CONCLUSION: The analysis shows why it is difficult for EU Member State governments to meet all their goals for sustainable LTC, given the demographic- and fiscal circumstances, and the complexities of LTC systems. It also shows the usefulness to learn from policy design and implementation of LTC policy in other countries, within and outside the EU. Researchers can contribute by studying conditions, under which the strategies explored might deliver solutions for policy-makers. PMID- 28812806 TI - Universal Health Coverage and Primary Healthcare: Lessons From Japan Comment on "Achieving Universal Health Coverage by Focusing on Primary Care in Japan: Lessons for Low- and Middle-Income Countries". AB - A recent editorial by Naoki Ikegami has proposed three key lessons from Japan's experience of achieving virtually universal coverage with primary healthcare services: the need to integrate the existing providers of primary healthcare services into the organised health system; the need to limit government commitments to finance hospital services and the need to empower providers of primary healthcare to influence decisions that influence their livelihoods. Although the context of low- and middle-income countries (LMICs) differs in many ways from Japan in the late 19th and early 20th centuries, the lesson that short term initiatives to achieve universal coverage need to be complemented by an understanding of the factors influencing long-term change management remains highly relevant. PMID- 28812805 TI - Changes in Socio-Economic Inequality in Neonatal Mortality in Iran Between 1995 2000 and 2005-2010: An Oaxaca Decomposition Analysis. AB - BACKGROUND: Exploring changes in health inequality and its determinants over time is of policy interest. Accordingly, this study aimed to decompose inequality in neonatal mortality into its contributing factors and then explore changes from 1995-2000 to 2005-2010 in Iran. METHODS: Required data were drawn from two Iran's demographic and health survey (DHS) conducted in 2000 and 2010. Normalized concentration index (CI) was used to measure the magnitude of inequality in neonatal mortality. The contribution of various determinants to inequality was estimated by decomposing concentration indices in 1995-2000 and 2005-2010. Finally, changes in inequality were investigated using Oaxaca-type decomposition technique. RESULTS: Pro-rich inequality in neonatal mortality was declined by 16%, ie, the normalized CI dropped from -0.1490 in 1995-2000 to -0.1254 in 2005 2010. The largest contribution to inequality was attributable to mother's education (32%) and household's economic status (49%) in 1995-2000 and 2005-2010, respectively. Changes in mother's educational level (121%), use of skilled birth attendants (79%), mother's age at the delivery time (25-34 years old) (54%) and using modern contraceptive (29%) were mainly accountable for the decrease in inequality in neonatal mortality. CONCLUSION: Policy actions on improving households' economic status and maternal education, especially in rural areas, may have led to the reduction in neonatal mortality inequality in Iran. PMID- 28812807 TI - Health Technology Assessment: Global Advocacy and Local Realities Comment on "Priority Setting for Universal Health Coverage: We Need Evidence-Informed Deliberative Processes, Not Just More Evidence on Cost-Effectiveness". AB - Cost-effectiveness analysis (CEA) can help countries attain and sustain universal health coverage (UHC), as long as it is context-specific and considered within deliberative processes at the country level. Institutionalising robust deliberative processes requires significant time and resources, however, and countries often begin by demanding evidence (including local CEA evidence as well as evidence about local values), whilst striving to strengthen the governance structures and technical capacities with which to generate, consider and act on such evidence. In low- and middle-income countries (LMICs), such capacities could be developed initially around a small technical unit in the health ministry or health insurer. The role of networks, development partners, and global norm setting organisations is crucial in supporting the necessary capacities. PMID- 28812808 TI - History, Structure and Agency in Global Health Governance Comment on "Global Health Governance Challenges 2016 - Are We Ready?" AB - Ilona Kickbusch's thought provoking editorial is criticized in this commentary, partly because she fails to refer to previous critical work on the global conditions and policies that sustain inequality, poverty, poor health and damage to the biosphere and, as a result, she misreads global power and elides consideration of the fundamental historical structures of political and material power that shape agency in global health governance. We also doubt that global health can be improved through structures and processes of multilateralism that are premised on the continued reproduction of the ecologically myopic and socially unsustainable market civilization model of capitalist development that currently prevails in the world economy. This model drives net financial flows from poor to rich countries and from the poor to the affluent and super wealthy individuals. By contrast, we suggest that significant progress in global health requires a profound and socially just restructuring of global power, greater global solidarity and the "development of sustainability." PMID- 28812809 TI - Trade Policy and Health: Adding Retrospective Studies to the Research Agenda Comment on "The Trans-Pacific Partnership: Is It Everything We Feared for Health?" AB - Prospective studies of the potential health consequences of trade and investment treaties, such as the Trans-Pacific Partnership, are critical. These studies can make visible to trade policy-makers the potential negative impacts associated to such treaties and can influence the outcomes of such negotiations. However, few researchers have examined retrospectively the consequences of trade agreements. With more than 400 trade agreements and more than 2000 investment treaties currently in force, researchers have a large corpus of agreements to analyse in order to assess not only their potential impacts on health system and population health, but also their actual impacts. This comment suggests some research questions that would benefit from retrospective inquiry. PMID- 28812810 TI - The TPP Is Dead, Long Live the TPP? A Response to Recent Commentaries. PMID- 28812811 TI - The Rise of Post-truth Populism in Pluralist Liberal Democracies: Challenges for Health Policy. AB - Recent years have witnessed the rise of populism and populist leaders, movements and policies in many pluralist liberal democracies, with Brexit and the election of Trump the two most recent high profile examples of this backlash against established political elites and the institutions that support them. This new populism is underpinned by a post-truth politics which is using social media as a mouthpiece for 'fake news' and 'alternative facts' with the intention of inciting fear and hatred of 'the other' and thereby helping to justify discriminatory health policies for marginalised groups. In this article, we explore what is meant by populism and highlight some of the challenges for health and health policy posed by the new wave of post-truth populism. PMID- 28812812 TI - A Cost Analysis of the Jan Aushadhi Scheme in India. AB - Medicines constitute a substantial proportion of out-of-pocket (OOP) expenses in Indian households. In order to address this issue, the Government of India launched the Jan Aushadhi (Medicine for the Masses) Scheme (JAS) to provide cheap generic medicines to the patients (http://janaushadhi.gov.in/about_jan_aushadhi.html). These medicines are provided through the Jan Aushadhi stores established across the country. The objective of this study was to do a quick assessment for policy-makers regarding the objective of the JAS. Implications on cost savings for patients and policy implications of the scheme were analyzed. Secondary data sources were used to obtain prices of medicines under the JAS and prices of branded medicines of the same formulations. A cost analysis design was used. There are substantial differences between the JAS price and the cheapest branded medicine available in the market. However, not all JAS prices are lower than branded medicines. For example, the cheapest branded cefuroxime axetil (500 mg) (antibiotic) in the market is almost three times cheaper than its JAS price. Hence, there are cheaper brands available for some commonly prescribed medicines. From the policy perspective, it raises serious questions regarding the pricing of medicines in the JAS and its overarching goal. Since patients are dependent on physicians for medicine prescriptions and have little knowledge of the price variations among branded and generic medicines, the JAS may not provide the cheapest alternative for the patients. Hence, the government should urgently review the JAS prices to achieve its goal of providing low-cost affordable medicines. PMID- 28812813 TI - Do Management and Leadership Practices in the Context of Decentralisation Influence Performance of Community Health Fund? Evidence From Iramba and Iringa Districts in Tanzania. AB - BACKGROUND: In early 1990s, Tanzania like other African countries, adopted health sector reform (HSR). The most strongly held centralisation system that informed the nature of services provision including health was, thus, disintegrated giving rise to decentralisation system. It was within the realm of HSR process, user fees were introduced in the health sector. Along with user fees, various types of health insurances, including the Community Health Fund (CHF), were introduced. While the country's level of enrolment in the CHF is low, there are marked variations among districts. This paper highlights the role of decentralised health management and leadership practices in the uptake of the CHF in Tanzania. METHODS: A comparative exploratory case study of high and low performing districts was carried out. In-depth interviews were conducted with the members of the Council Health Service Board (CHSB), Council Health Management Team (CHMT), Health Facility Committees (HFCs), in-charges of health facilities, healthcare providers, and Community Development Officers (CDOs). Minutes of the meetings of the committees and district annual health plans and district annual implementation reports were also used to verify and triangulate the data. Thematic analysis was adopted to analyse the collected data. We employed both inductive and deductive (mixed coding) to arrive to the themes. RESULTS: There were no differences in the level of education and experience of the district health managers in the two study districts. Almost all district health managers responsible for the management of the CHF had attended some training on management and leadership. However, there were variations in the personal initiatives of the top-district health leaders, particularly the district health managers, the council health services board and local government officials. Similarly, there were differences in the supervision mechanisms, and incentives available for the health providers, HFCs and board members in the two study districts. CONCLUSION: This paper adds to the stock of knowledge on CHFs functioning in Tanzania. By comparing the best practices with the worst practices, the paper contributes valuable insights on how CHF can be scaled up and maintained. The study clearly indicates that the performance of the community based health financing largely depends on the personal initiatives of the top district health leaders, particularly the district health managers and local government officials. This implies that the regional health management team (RHMT) and the Ministry of Health and Social Welfare (MoHSW) should strengthen supportive supervision mechanisms to the district health managers and health facilities. More important, there is need for the MoHSW to provide opportunities for the well performing districts to share good practices to other districts in order to increase uptake of the community-based health insurance. PMID- 28812814 TI - A Comparison of Iran and UK EQ-5D-3L Value Sets Based on Visual Analogue Scale. AB - BACKGROUND: Preference weights for EQ-5D-3L based on visual analogue scale (VAS) has recently been developed in Iran. The aim of the current study was to compare performance of this value set against the UK VAS-based value set. METHODS: The mean scores for all possible 243 health states were compared using Student t test. Absolute agreement and consistency were investigated using concordance correlation coefficient (CCC) and Bland-Altman plot. Health gains for 29 403 possible transitions between pairs of EQ-5D-3L health states were compared. Responsiveness to change and discriminative ability across subgroups of health transitions were assessed. RESULTS: The mean EQ-5D-3L scores were similar for two value sets (mean = 0.31, P = 1.00). For 36% of health states, the absolute differences were greater than 0.10. There were three pairwise logical inconsistencies in the Iranian value set. The Iranian scores were lower (higher) for severe (mild) health states than the United Kingdom. The CCC (95% CI) was 0.85 (0.81 to 0.88) and Bland-Altman plot showed good agreement. The mean health gain for all possible transitions predicted by the Iranian value set was higher (0.22 vs. 0.20, P < .001) and two value sets predicted opposite transitions in 15% of transitions. The responsiveness of these two value sets were similar with lower discriminative ability for Iranian value set. CONCLUSION: The Iranian value set attribute lower values to most severe health states and higher values to mild health states compared with the UK value set. Such systematic differences might translate into discrepant health gains and cost-effectiveness which should be taking into account for informed decision-making. PMID- 28812815 TI - Stakeholders Perspectives on the Success Drivers in Ghana's National Health Insurance Scheme - Identifying Policy Translation Issues. AB - BACKGROUND: Ghana's National Health Insurance Scheme (NHIS), established by an Act of Parliament (Act 650), in 2003 and since replaced by Act 852 of 2012 remains, in African terms, unprecedented in terms of growth and coverage. As a result, the scheme has received praise for its associated legal reforms, clinical audit mechanisms and for serving as a hub for knowledge sharing and learning within the context of South-South cooperation. The scheme continues to shape national health insurance thinking in Africa. While the success, especially in coverage and financial access has been highlighted by many authors, insufficient attention has been paid to critical and context-specific factors. This paper seeks to fill that gap. METHODS: Based on an empirical qualitative case study of stakeholders' views on challenges and success factors in four mutual schemes (district offices) located in two regions of Ghana, the study uses the concept of policy translation to assess whether the Ghana scheme could provide useful lessons to other African and developing countries in their quest to implement social/NHISs. RESULTS: In the study, interviewees referred to both 'hard and soft' elements as driving the "success" of the Ghana scheme. The main 'hard elements' include bureaucratic and legal enforcement capacities; IT; financing; governance, administration and management; regulating membership of the scheme; and service provision and coverage capabilities. The 'soft' elements identified relate to: the background/context of the health insurance scheme; innovative ways of funding the NHIS, the hybrid nature of the Ghana scheme; political will, commitment by government, stakeholders and public cooperation; social structure of Ghana (solidarity); and ownership and participation. CONCLUSION: Other developing countries can expect to translate rather than re-assemble a national health insurance programme in an incomplete and highly modified form over a period of years, amounting to a process best conceived as germination as opposed to emulation. The Ghana experience illustrates that in adopting health financing systems that function well, countries need to customise systems (policy customisation) to suit their socio-economic, political and administrative settings. Home-grown health financing systems that resonate with social values will also need to be found in the process of translation. PMID- 28812816 TI - The Challenges of Projecting the Public Health Impacts of Marijuana Legalization in Canada Comment on "Legalizing and Regulating Marijuana in Canada: Review of Potential Economic, Social, and Health Impacts". AB - A recent editorial in this journal provides a summary of key economic, social, and public health considerations of the forthcoming legislation to legalize, regulate, and restrict access to marijuana in Canada. As our government plans to implement an evidence-based public health framework for marijuana legalization, we reflect and expand on recent discussions of the public health implications of marijuana legalization, and offer additional points of consideration. We select two commonly cited public concerns of marijuana legalization - adolescent usage and impaired driving - and discuss how the underdeveloped and equivocal body of scientific literature surrounding these issues limits the ability to predict the effects of legalization. Finally, we discuss the potential for some potential public health benefits of marijuana legalization - specifically the potential for marijuana to be used as a substitute to opioids and other risky substance use - that have to date not received adequate attention. PMID- 28812817 TI - Is It Time to Say Farewell to the ISDS System? Comment on "The Trans-Pacific Partnership: Is It Everything We Feared for Health?" AB - Investor-state dispute settlement (ISDS) continues to plague health-oriented government regulation. This is particularly reflected in recent challenges to tobacco control measures through bilateral investment agreements. There are numerous reform proposals circulating within the public health community. However, I suggest that perhaps it is time for the community to explore a stronger position on ISDS. I draw from mounting evidence on the problematic uses of the ISDS to explore the proposition that ISDS is no longer justified. I tackle the normative question of should the ISDS system persist and point out that the ISDS system is not justifiable from a development perspective and because of its nefarious use, is of no added value to a system that could rely on domestic courts. PMID- 28812818 TI - Assessing the Health Impact of Trade: A Call for an Expanded Research Agenda Comment on "The Trans-Pacific Partnership: Is It Everything We Feared for Health?" AB - Labonte et al provide an insightful analysis of the Trans-Pacific Partnership (TPP) and its impact on a selection of important health determinants. Their work confirms concerns raised by previous analyses of leaked drafts and offers governments serious and timely reasons to carefully consider provisions of the agreement prior to moving forward with ratification. It also contributes more generally to a growing literature focused on identifying the health impacts of trade. This commentary uses the authors' analysis as a starting point to reflect on two interrelated issues relevant both for taking seriously one of the article's main recommendations and future work in the area of trade and health. PMID- 28812819 TI - Advancing Public Health on the Changing Global Trade and Investment Agenda Comment on "The Trans-Pacific Partnership: Is It Everything We Feared for Health?" AB - Concerns regarding the Trans-Pacific Partnership (TPP) have raised awareness about the negative public health impacts of trade and investment agreements. In the past decade, we have learned much about the implications of trade agreements for public health: reduced equity in access to health services; increased flows of unhealthy commodities; limits on access to medicines; and constrained policy space for health. Getting health on the trade agenda continues to prove challenging, despite some progress in moving towards policy coherence. Recent changes in trade and investment agendas highlight an opportunity for public health researchers and practitioners to engage in highly politicized debates about how future economic policy can protect and support equitable public health outcomes. To fulfil this opportunity, public health attention now needs to turn to strengthening policy coherence between trade and health, and identifying how solutions can be implemented. Key strategies include research agendas that address politics and power, and capacity building for both trade and health officials. PMID- 28812820 TI - Defining Integrated Knowledge Translation and Moving Forward: A Response to Recent Commentaries. PMID- 28812821 TI - (Re) Making the Procrustean Bed? Standardization and Customization as Competing Logics in Healthcare. AB - Recent years have witnessed a parallel and seemingly contradictory trend towards both the standardization and the customization of healthcare and medical treatment. Here, we explore what is meant by 'standardization' and 'customization' in healthcare settings and explore the implications of these changes for healthcare delivery. We frame the paradox of these divergent and opposing factors in terms of institutional logics - the socially constructed rules, practices and beliefs which perpetuate institutional behaviour. As the tension between standardization and customization is fast becoming a critical fault-line within many health systems, there remains an urgent need for more sustained work exploring how these competing logics are articulated, adapted, resisted and co-exist on the front line of care delivery. PMID- 28812822 TI - How Could Private Healthcare Better Contribute to Healthcare Coverage in Vietnam? AB - Private healthcare services in Vietnam are seen as a major part of the solution to the rapid increase in need and demand for healthcare services. Formally recognized over 20 years ago, the private health services coexist with public services and are available all over the country. However, the scale and size of private sector is still small compared to the public sector and public acceptance and reputation still limited. There are substantial concerns with the quality of services and the adequacy of regulation. Human resource for health is currently inadequate to support growth in both public and private sectors. The role of the private sector in achieving Vietnam's population health objectives is not clear. In this emerging economy, there is significant potential for increased dependency on private healthcare to increase health access inequities. This paper discusses how private healthcare could better contribute to healthcare coverage in Vietnam. PMID- 28812823 TI - An Assessment of National Maternal and Child Health Policy-Makers' Knowledge and Capacity for Evidence- Informed Policy-Making in Nigeria. AB - BACKGROUND: There is increasing interest globally in the use of more rigorous processes to ensure that maternal, newborn, and child health (MNCH) care recommendations are informed by the best available research evidence use. The purpose of this study was to engage Nigerian MNCH policy-makers and other stakeholders to consider issues around research to policy and practice interface and to assess their existing knowledge and capacity on the use of research evidence for policy-making and practice. METHODS: The study design is a cross sectional evaluation of MNCH stakeholders' knowledge as it pertains different dimensions of research to practice. This was undertaken during a national MNCH stakeholders' engagement event convened under the auspices of the West African Health Organization (WAHO) and the Federal Ministry of Health (FMoH) in Abuja, Nigeria. A questionnaire was administered to participants, which was designed to assess participants' knowledge, capacity and organizational process of generation, synthesis and utilization of research evidence in policy-making regarding MNCH. RESULTS: A total of 40 participants signed the informed consent form and completed the questionnaire. The mean ratings (MNRs) of participants' knowledge of electronic databases and capacity to identify and obtain relevant research evidence from electronic databases ranged from 3.62-3.68 on the scale of 5. The MNRs of participants' level of understanding of a policy brief, a policy dialogue and the role of researchers in policy-making ranged from 3.50-3.86. The MNRs of participants' level of understanding of evidence in policy-making context, types and sources of evidence, capacity to identify, select, adapt, and transform relevant evidence into policy ranged from 3.63-4.08. The MNRs of the participants' organization's capacity to cover their geographical areas of operation were generally low ranging from 3.32-3.38 in terms of manpower, logistics, facilities, and external support. The lowest MNR of 2.66 was recorded in funding. CONCLUSION: The outcomes of this study suggest that a stakeholders' engagement event can serve as an important platform to assess policy-makers' knowledge and capacity for evidence-informed policy-making and for the promotion of evidence use in the policy process. PMID- 28812824 TI - The Life Story Experience of "Migrant Dentists" in Australia: Potential Implications for Health Workforce Governance and International Cooperation. AB - BACKGROUND: The migration of dentists is a major policy challenge facing both developing and developed countries. Dentists from over 120 countries migrate to Australia, and a large proportion are from developing countries. The aim of the study was to assess the life story experience (LSE) of migrant dentists in Australia, in order to address key policy challenges facing dentist migration. METHODS: A national survey of all migrant dentists resident in Australia was conducted in 2013. Migrant experiences were assessed through a suite of LSE scales, developed through a qualitative-quantitative study. Respondents rated experiences using a five-point Likert scale. RESULTS: A total of 1022 migrant dentists responded to the survey (response rate = 54.5%). LSE1 (health system and general lifestyle concerns in home country), LSE2 (appreciation towards Australian way of life) and LSE3 (settlement concerns in Australia) scales varied by migrant dentist groups, sex, and years since arrival to Australia (chi-square, P < .05). In a logistic regression model, migrants mainly from developing countries (ie, the examination pathway group) faced greater health system and general lifestyle concerns in their home countries (9.32; 3.51-24.72) and greater settlement challenges in Australia (5.39; 3.51-8.28), compared to migrants from well-developed countries, who obtained direct recognition of qualifications. Migrants also are more appreciative towards the Australian way of life if they had lived at least ten years in Australia (1.97; 1.27-3.05), compared to migrants who have lived for less than ten years. CONCLUSION: Migrant dentists, mainly from developing countries, face challenges both in their home countries and in Australia. Our study offers evidence for multi-level health workforce governance and calls for greater consensus towards an international agenda to address dentist migration. Better integration of dentist migration with the mainstream health workforce governance is a viable and opportunistic way forward. PMID- 28812825 TI - Evaluating Global Health Partnerships: A Case Study of a Gavi HPV Vaccine Application Process in Uganda. AB - BACKGROUND: Global health partnerships have grown rapidly in number and scope, yet there has been less emphasis on their evaluation. Gavi, the Vaccine Alliance, is one such public-private partnership; in Gavi-eligible countries partnerships are dynamic networks of immunization actors who work together to support all stages and aspects of Gavi support. This paper describes a conceptual framework - the partnership framework - and analytic approach for evaluating the perceptions of partnerships' added value as well as the results from an application to one case in Uganda. METHODS: We used a mixed-methods case study design embedded in the Gavi Full Country Evaluations (FCE) to test the partnership framework on Uganda's human papillomavirus (HPV) vaccine application partnership. Data from document review, interviews, and social network surveys enabled the testing of the relationships between partnership framework domains (context, structure, practices, performance, and outcomes). Topic guides were based on the framework domains and network surveys identified working together relationships, professional trust, and perceptions of the effectiveness, efficiency, and legitimacy of the partnership's role in this process. RESULTS: Data from seven in depth interviews, 11 network surveys and document review were analyzed according to the partnership framework, confirming relationships between the framework domains. Trust was an important contributor to the perceived effectiveness of the process. The network was structured around the EPI program, who was considered the leader of this process. While the structure and composition of the network was largely viewed as supporting an effective and legitimate process, the absence of the Ministry of Education (MoE) may have had downstream consequences if this study's results had not been shared with the Ministry of Health (MoH) and acted upon. The partnership was not perceived to have increased the efficiency of the process, perhaps as a result of unclear or absent guidelines around roles and responsibilities. CONCLUSION: The health and functioning of global health partnerships can be evaluated using the framework and approach presented here. Network theory and methods added value to the conceptual and analytic processes and we recommend applying this approach to other global health partnerships to ensure that they are meeting the complex challenges they were designed to address. PMID- 28812826 TI - A Policy Analysis on the Proactive Prevention of Chronic Disease: Learnings from the Initial Implementation of Integrated Measurement for Early Detection (MIDO). AB - Mexico, like many low- and middle-income countries (LMICs), faces an epidemic of chronic non-communicable diseases (NCDs), specifically diabetes, hypertension, obesity, and lipid disorders. Many people with these NCDs may not be aware that they have a disease, pointing to the need for broader screening programs. The traditional prevention policy in Mexico was based on screening with a paper-based risk factor questionnaire. However, this was used to screen patients already seeking healthcare services at facilities, and screening goals were set as a function of the number of questionnaires applied, not number of individuals screened. Due to this, Fundacion Carlos Slim developed Medicion Integrada para la Deteccion Oportuna (MIDOTM), or Integrated Measurement for Early Detection, an NCD screening and proactive prevention policy. This document is a policy analysis based on early learnings from the initial implementation of MIDO in eight primary healthcare centers in two central Mexican states. MIDO was found to expand screening programs beyond clinic walls, systematize community screening strategies, emphasize the detection of pre-disease phases, incorporate lifestyle counseling, and propose screening goals based on population targets. In collaboration with the Mexican Ministry of Health, MIDO has successfully screened over 500 000 individuals-about 40% of whom would not have been screened under previous policies. Of these more than 500 000 screened individuals, 13.4% had pre diabetes (fasting glucose between 100 and 125 mg/dL), and 5.8% had undiagnosed diabetes (defined as fasting glucose above 126 mg/dL or random glucose above 200 mg/dL). However, there is still room for improvement in linking positive results from screening with disease confirmation and with patient incorporation into disease management. The experience of implementing MIDO in Mexico suggests that primary and secondary prevention programs in other parts of the world should consider the need for population-based screening targets, a greater focus on pre disease stages, and the streamlining of the transition between screening, confirmation of diagnosis, and incorporation of patients into the healthcare system. PMID- 28812827 TI - "Seeing" the Difference: The Importance of Visibility and Action as a Mark of "Authenticity" in Co-production Comment on "Collaboration and Co-production of Knowledge in Healthcare: Opportunities and Challenges". AB - The Rycroft-Malone paper states that co-production relies on 'authentic' collaboration as a context for action. Our commentary supports and extends this assertion. We suggest that 'authentic' co-production involves processes where participants can 'see' the difference that they have made within the project and beyond. We provide examples including: the use of design in health projects which seek to address power issues and make contributions visible through iteration and prototyping; and the development of 'actionable outputs' from research that are the physical embodiment of co-production. Finally, we highlight the elements of the Collaboration for Leadership in Applied Health Research and Care (CLAHRC) architecture that enables the inclusion of such collaborative techniques that demonstrate visible co-production. We reinforce the notion that maintaining collaboration requires time, flexible resources, blurring of knowledge producer user boundaries, and leaders who promote epistemological tolerance and methodological exploration. PMID- 28812828 TI - How the Spectre of Societal Homogeneity Undermines Equitable Healthcare for Refugees Comment on "Defining and Acting on Global Health: The Case of Japan and the Refugee Crisis". AB - Recourse to a purported ideal of societal homogeneity has become common in the context of the refugee reception crisis - not only in Japan, as Leppold et al report, but also throughout Europe. Calls for societal homogeneity in Europe originate from populist movements as well as from some governments. Often, they go along with reduced social support for refugees and asylum seekers, for example in healthcare provision. The fundamental right to health is then reduced to a citizens' right, granted fully only to nationals. Germany, in spite of welcoming many refugees in 2015, is a case in point: entitlement and access to healthcare for asylum seekers are restricted during the first 15 months of their stay. We show that arguments brought forward to defend such restrictions do not hold, particularly not those which relate to maintaining societal homogeneity. European societies are not homogeneous, irrespective of migration. But as migration will continue, societies need to invest in what we call "globalization within." Removing entitlement restrictions and access barriers to healthcare for refugees and asylum seekers is one important element thereof. PMID- 28812829 TI - The Trans-Pacific Partnership: Should We "Fear the Fear"? Comment on "The Trans Pacific Partnership: Is It Everything We Feared for Health?" AB - RLabonte et al entitle their paper in this issue of the International Journal of Health Policy and Management "The Trans-Pacific Partnership: Is It Everything We Feared for Health?" Tantalisingly, they do not directly answer the question they pose, and in this commentary, we suggest that it is the wrong question; we should not 'fear' the Trans-Pacific Partnership (TPP) at all, rather we should ask how we are to respond. The public health community is right to be concerned with the potential implications of trade and investment agreements (TIAs) for health, particularly with shifts from multilateral to regional/bilateral agreements including provisions with greater risk to public health. But it is critical to understand also the potential health benefits, and especially the mitigating policy and governance mechanisms to respond to adverse TIA implications. Given entrenched and divergent sectoral worldviews and perspectives between trade and health communities on these issues, achieving the requisite understanding will also likely require characterisation of these perspectives and identification of areas of common understanding and agreed solutions. PMID- 28812830 TI - The Global Health Crisis of Solidarity: A Response to Recent Commentaries. PMID- 28812831 TI - Multisectoral Actions for Health: Challenges and Opportunities in Complex Policy Environments. AB - Multisectoral actions for health, defined as actions undertaken by non-health sectors to protect the health of the population, are essential in the context of inter-linkages between three dimensions of sustainable development: economic, social, and environmental. These multisectoral actions can address the social and economic factors that influence the health of a population at the local, national, and global levels. This editorial identifies the challenges, opportunities and capacity development for effective multisectoral actions for health in a complex policy environment. The root causes of the challenges lie in poor governance such as entrenched political and administrative corruption, widespread clientelism, lack of citizen voice, weak social capital, lack of trust and lack of respect for human rights. This is further complicated by the lack of government effectiveness caused by poor capacity for strong public financial management and low levels of transparency and accountability which leads to corruption. The absence of or rapid changes in government policies, and low salary in relation to living standards result in migration out of qualified staff. Tobacco, alcohol and sugary drink industries are major risk factors for non-communicable diseases (NCDs) and had interfered with health policy through regulatory capture and potential law suits against the government. Opportunities still exist. Some World Health Assembly (WHA) and United Nations General Assembly (UNGA) resolutions are both considered as external driving forces for intersectoral actions for health. In addition, Thailand National Health Assembly under the National Health Act is another tool providing opportunity to form trust among stakeholders from different sectors. Capacity development at individual, institutional and system level to generate evidence and ensure it is used by multisectoral agencies is as critical as strengthening the health literacy of people and the overall good governance of a country. PMID- 28812832 TI - Exploring the Functioning of Decision Space: A Review of the Available Health Systems Literature. AB - BACKGROUND: The concept of decision space holds appeal as an approach to disaggregating the elements that may influence decision-making in decentralized systems. This narrative review aims to explore the functioning of decision space and the factors that influence decision space. METHODS: A narrative review of the literature was conducted with searches of online databases and academic journals including PubMed Central, Emerald, Wiley, Science Direct, JSTOR, and Sage. The articles were included in the review based on the criteria that they provided insight into the functioning of decision space either through the explicit application of or reference to decision space, or implicitly through discussion of decision-making related to organizational capacity or accountability mechanisms. RESULTS: The articles included in the review encompass literature related to decentralisation, management and decision space. The majority of the studies utilise qualitative methodologies to assess accountability mechanisms, organisational capacities such as finance, human resources and management, and the extent of decision space. Of the 138 articles retrieved, 76 articles were included in the final review. CONCLUSION: The literature supports Bossert's conceptualization of decision space as being related to organizational capacities and accountability mechanisms. These functions influence the decision space available within decentralized systems. The exact relationship between decision space and financial and human resource capacities needs to be explored in greater detail to determine the potential influence on system functioning. PMID- 28812833 TI - Evaluating the Implementation and Feasibility of a Web-Based Tool to Support Timely Identification and Care for the Frail Population in Primary Healthcare Settings. AB - BACKGROUND: Understanding and addressing the needs of frail persons is an emerging health priority for Nova Scotia and internationally. Primary healthcare (PHC) providers regularly encounter frail persons in their daily clinical work. However, routine identification and measurement of frailty is not standard practice and, in general, there is a lack of awareness about how to identify and respond to frailty. A web-based tool called the Frailty Portal was developed to aid in identifying, screening, and providing care for frail patients in PHC settings. In this study, we will assess the implementation feasibility and impact of the Frailty Portal to: (1) support increased awareness of frailty among providers and patients, (2) identify the degree of frailty within individual patients, and (3) develop and deliver actions to respond to frailtyl in community PHC practice. METHODS: This study will be approached using a convergent mixed method design where quantitative and qualitative data are collected concurrently, in this case, over a 9-month period, analyzed separately, and then merged to summarize, interpret and produce a more comprehensive understanding of the initiative's feasibility and scalability. Methods will be informed by the 'Implementing the Frailty Portal in Community Primary Care Practice' logic model and questions will be guided by domains and constructs from an implementation science framework, the Consolidated Framework for Implementation Research (CFIR). DISCUSSION: The 'Frailty Portal' aims to improve access to, and coordination of, primary care services for persons experiencing frailty. It also aims to increase primary care providers' ability to care for patients in the context of their frailty. Our goal is to help optimize care in the community by helping community providers gain the knowledge they may lack about frailty both in general and in their practice, support improved identification of frailty with the use of screening tools, offer evidence based severity-specific care goals and connect providers with local available community supports. PMID- 28812834 TI - Cost-Effectiveness of Rural Incentive Packages for Graduating Medical Students in Lao PDR. AB - BACKGROUND: The dearth of health workers in rural settings in Lao People's Democratic Republic (PDR) and other developing countries limits healthcare access and outcomes. In evaluating non-wage financial incentive packages as a potential policy option to attract health workers to rural settings, understanding the expected costs and effects of the various programs ex ante can assist policy makers in selecting the optimal incentive package. METHODS: We use discrete choice experiments (DCEs), costing analyses and recent empirical results linking health worker density and health outcomes to estimate the future location decisions of physicians and determine the cost-effectiveness of 15 voluntary incentives packages for new physicians in Lao PDR. Our data sources include a DCE survey completed by medical students (n = 329) in May 2011 and secondary cost, economic and health data. Mixed logit regressions provide the basis for estimating how each incentive package influences rural versus urban location choice over time. We estimate the expected rural density of physicians and the cost-effectiveness of 15 separate incentive packages from a societal perspective. In order to generate the cost-effectiveness ratios we relied on the rural uptake probabilities inferred from the DCEs, the costing data and prior World Health Organization (WHO) estimates that relate health outcomes to health worker density. RESULTS: Relative to no program, the optimal voluntary incentive package would increase rural physician density by 15% by 2016 and 65% by 2041. After incorporating anticipated health effects, seven (three) of the 15 incentive packages have anticipated average cost-effectiveness ratio less than the WHO threshold (three times gross domestic product [GDP] per capita) over a 5-year (30 year) period. The optimal package's incremental cost-effectiveness ratio is $1454/QALY (quality-adjusted life year) over 5 years and $2380/QALY over 30 years. Capital intensive components, such as housing or facility improvement, are not efficient. CONCLUSION: Conditional on using voluntary incentives, Lao PDR should emphasize non-capital intensive options such as advanced career promotion, transport subsidies and housing allowances to improve physician distribution and rural health outcomes in a cost-effective manner. Other countries considering voluntary incentive programs can implement health worker/trainee DCEs and costing surveys to determine which incentive bundles improve rural uptake most efficiently but should be aware of methodological caveats. PMID- 28812835 TI - Impact of Health Research Systems on Under-5 Mortality Rate: A Trend Analysis. AB - BACKGROUND: Between 1990 and 2015, under-5 mortality rate (U5MR) declined by 53%, from an estimated rate of 91 deaths per 1000 live births to 43, globally. The aim of this study was to determine the share of health research systems in this decrease alongside other influential factors. METHODS: We used random effect regression models including the 'random intercept' and 'random intercept and random slope' models to analyze the panel data from 1990 to 2010. We selected the countries with U5MRs falling between the first and third quartiles in 1990. We used both the total articles (TA) and the number of child-specific articles (CSA) as a proxy of the health research system. In order to account for the impact of other factors, measles vaccination coverage (MVC) (as a proxy of health system performance), gross domestic product (GDP), human development index (HDI), and corruption perception index (CPI) (as proxies of development), were embedded in the model. RESULTS: Among all the models, 'the random intercept and random slope models' had lower residuals. The same variables of CSA, HDI, and time were significant and the coefficient of CSA was estimated at -0.17; meaning, with the addition of every 100 CSA, the rate of U5MR decreased by 17 per 1000 live births. CONCLUSION: Although the number of CSA has contributed to the reduction of U5MR, the amount of its contribution is negligible compared to the countries' development. We recommend entering different types of researches into the model separately in future research and including the variable of 'exchange between knowledge generator and user.' PMID- 28812836 TI - Understanding Internal Accountability in Nigeria's Routine Immunization System: Perspectives From Government Officials at the National, State, and Local Levels. AB - BACKGROUND: Routine immunization coverage in Nigeria has remained low, and studies have identified a lack of accountability as a barrier to high performance in the immunization system. Accountability lies at the heart of various health systems strengthening efforts recently launched in Nigeria, including those related to immunization. Our aim was to understand the views of health officials on the accountability challenges hindering immunization service delivery at various levels of government. METHODS: A semi-structured questionnaire was used to interview immunization and primary healthcare (PHC) officials from national, state, local, and health facility levels in Niger State in north central Nigeria. Individuals were selected to represent a range of roles and responsibilities in the immunization system. The questionnaire explored concepts related to internal accountability using a framework that organizes accountability into three axes based upon how they drive change in the health system. RESULTS: Respondents highlighted accountability challenges across multiple components of the immunization system, including vaccine availability, financing, logistics, human resources, and data management. A major focus was the lack of clear roles and responsibilities both within institutions and between levels of government. Delays in funding, especially at lower levels of government, disrupted service delivery. Supervision occurred less frequently than necessary, and the limited decision space of managers prevented problems from being resolved. Motivation was affected by the inability of officials to fulfill their responsibilities. Officials posited numerous suggestions to improve accountability, including clarifying roles and responsibilities, ensuring timely release of funding, and formalizing processes for supervision, problem solving, and data reporting. CONCLUSION: Weak accountability presents a significant barrier to performance of the routine immunization system and high immunization coverage in Nigeria. As one stakeholder in ensuring the performance of health systems, routine immunization officials reveal critical areas that need to be prioritized if emerging interventions to improve accountability in routine immunization are to have an effect. PMID- 28812837 TI - Labonte Identifies Key Issues for Health Promoters in the New World Order Comment on "Health Promotion in an Age of Normative Equity and Rampant Inequality". AB - For over 35 years Ronald Labonte has been critically analyzing the state of health promotion in Canada and the world. In 1981, he identified the shortcomings of the groundbreaking Lalonde Report by warning of the seductive appeal of so called lifestyle approaches to health. Since then, he has left a trail of critical work identifying the barriers to - and opportunities for -health promotion work. More recently, he has shown how the rise of economic globalization and acceptance of neo-liberal ideology has come to threaten the health of those in both developed and developing nations. In his recent commentary, Labonte shows how the United Nations' 2015 Sustainable Development Goals (SDGs) can offer a new direction for health promoters in these difficult times. PMID- 28812838 TI - Forced Migration and Global Responsibility for Health Comment on "Defining and Acting on Global Health: The Case of Japan and the Refugee Crisis". AB - Forced migration has become a world-wide phenomenon in the past century, affecting increasing numbers of countries and people. It entails important challenges from a global health perspective. Leppold et al have critically discussed the Japanese interpretation of global responsibility for health in the context of forced migration. This commentary complements their analysis by outlining three priority areas of global health responsibility for European Union (EU) countries. We highlight important stages of the migration phases related to forced migration and propose three arguments. First, the chronic neglect of the large number of internally displaced persons (IDPs) in the discourses on the "refugee crisis" needs to be corrected in order to develop sustainable solutions with a framework of the Sustainable Development Goals (SDGs). Second, protection gaps in the global system of protection need to be effectively closed to resolve conflicts with border management and normative global health frameworks. Third, effective policies need to be developed and implemented to meet the health and humanitarian needs of forced migrants; at the same time, the solidarity crisis within the EU needs to be overcome. These stakes are high. EU countries, being committed to global health, should urgently address these areas. PMID- 28812839 TI - Just Say No to the TPP: A Democratic Setback for American and Asian Public Health Comment on "The Trans-Pacific Partnership: Is It Everything We Feared for Health?" AB - (TPP) policy and the severe threats to public health that it implies for 12 Pacific Rim populations from the Americas and Asia (Australia, Brunei, Canada, Chile, Japan, Malaysia, Mexico, New Zealand, Peru, Singapore, United States, and Vietnam). With careful and analytic precision the authors convincingly unearth many aspects of this piece of legislation that undermine the public health achievements of most countries involved in the TTP. Our comments complement their policy analysis with the aim of providing a positive heuristic tool to assist in the understanding of the TPP, and other upcoming treaties like the even more encompassing Transatlantic Trade and Investment Partnership (TTIP), and in so doing motivate the public health community to oppose the implementation of the relevant provisions of the agreements. The aims of this commentary on the study of Labonte et al are to show that an understanding of the health effects of the TPP is incomplete without a political analysis of policy formation, and that realist methods can be useful to uncover the mechanisms underlying TPP's political and policy processes. PMID- 28812840 TI - "Not Everything That Is Faced Can Be Changed, but Nothing Can Be Changed Until It Is Faced": A Response to Recent Commentaries. PMID- 28812841 TI - University of Global Health Equity's Contribution to the Reduction of Education and Health Services Rationing. AB - The inadequate supply of health workers and demand-side barriers due to clinical practice that heeds too little attention to cultural context are serious obstacles to achieving universal health coverage and the fulfillment of the human rights to health, especially for the poor and vulnerable living in remote rural areas. A number of strategies have been deployed to increase both the supply of healthcare workers and the demand for healthcare services. However, more can be done to improve service delivery as well as mitigate the geographic inequalities that exist in this field. To contribute to overcoming these barriers and increasing access to health services, especially for the most vulnerable, Partners In Health (PIH), a US non-governmental organization specializing in equitable health service delivery, has created the University of Global Health Equity (UGHE) in a remote rural district of Rwanda. The act of building this university in such a rural setting signals a commitment to create opportunities where there have traditionally been few. Furthermore, through its state-of-the art educational approach in a rural setting and its focus on cultural competency, UGHE is contributing to progress in the quest for equitable access to quality health services. PMID- 28812842 TI - Governance and Capacity to Manage Resilience of Health Systems: Towards a New Conceptual Framework. AB - The term resilience has dominated the discourse among health systems researchers since 2014 and the onset of the Ebola outbreak in West Africa. There is wide consensus that the global community has to help build more resilient health systems. But do we really know what resilience means, and do we all have the same vision of resilience? The present paper presents a new conceptual framework on governance of resilience based on systems thinking and complexity theories. In this paper, we see resilience of a health system as its capacity to absorb, adapt and transform when exposed to a shock such as a pandemic, natural disaster or armed conflict and still retain the same control over its structure and functions. PMID- 28812843 TI - Collaboration Between Researchers and Knowledge Users in Health Technology Assessment: A Qualitative Exploratory Study. AB - BACKGROUND: Collaboration between researchers and knowledge users is increasingly promoted because it could enhance more evidence-based decision-making and practice. These complex relationships differ in form, in the particular goals they are trying to achieve, and in whom they bring together. Although much is understood about why partnerships form, relatively little is known about how collaboration works: how the collaborative process is shaped through the partners' interactions, especially in the field of health technology assessment (HTA)? This study aims at addressing this gap in the literature in the specific context of HTA. METHODS: We used a qualitative descriptive design for this exploratory study. Semi-structured interviews with three researchers and two decision-makers were conducted on the practices related to the collaboration. We also performed document analysis, observation of five team meetings, and informal discussion with the participants. We thematically analyzed data using the structuration theory and a collective impact framework. RESULTS: This study showed that three main contextual factors helped shape the collaboration between researchers and knowledge users: the use of concepts related to each field; the use of related expertise; and a lack of clearly defined roles in the project. Previous experiences with the topic of the research project and a partnership based on "a give and take" relationship emerged as factors of success of this collaboration. CONCLUSION: By shedding light on the structuration of the collaboration between researchers and knowledge users, our findings open the door to a poorly documented field in the area of HTA, and additional studies that build on these early observations are welcome. PMID- 28812844 TI - Clinician Perspectives of Barriers to Effective Implementation of a Rapid Response System in an Academic Health Centre: A Focus Group Study. AB - BACKGROUND: Systemic and structural issues of rapid response system (RRS) models can hinder implementation. This study sought to understand the ways in which acute care clinicians (physicians and nurses) experience and negotiate care for deteriorating patients within the RRS. METHODS: Physicians and nurses working within an Australian academic health centre within a jurisdictional-based model of clinical governance participated in focus group interviews. Verbatim transcripts were analysed using thematic content analysis. RESULTS: Thirty-four participants (21 physicians and 13 registered nurses [RNs]) participated in six focus groups over five weeks in 2014. Implementing the RRS in daily practice was a process of informal communication and negotiation in spite of standardised protocols. Themes highlighted several systems or organisational-level barriers to an effective RRS, including (1) responsibility is inversely proportional to clinical experience; (2) actions around system flexibility contribute to deviation from protocol; (3) misdistribution of resources leads to perceptions of inadequate staffing levels inhibiting full optimisation of the RRS; and (4) poor communication and documentation of RRS increases clinician workloads. CONCLUSION: Implementing a RRS is complex and multifactorial, influenced by various inter- and intra-professional factors, staffing models and organisational culture. The RRS is not a static model; it is both reflexive and iterative, perpetually transforming to meet healthcare consumer and provider demands and local unit contexts and needs. Requiring more than just a strong initial implementation phase, new models of care such as a RRS demand good governance processes, ongoing support and regular evaluation and refinement. Cultural, organizational and professional factors, as well as systems-based processes, require consideration if RRSs are to achieve their intended outcomes in dynamic healthcare settings. PMID- 28812846 TI - To What Extent Is Long-term Care Representative of Elderly Care? A Case Study of Elderly Care Financing in Lombardy, Italy. AB - The ageing of European population has been rapidly increasing during the last decades, and the problem of elderly care financing has become an issue for policy makers. Long-term care (LTC) financing is considered a suitable proxy of the resources committed to elderly care by each government, but the preciseness of this approximation depends on the extent to which LTC is representative of elderly care within each country. Since there is a broad heterogeneity in LTC funding, organization and setting among European States, it is difficult to find a common parameter representing the public resources destined to the elderly care. We address these topics employing as a case study an Italian region, Lombardy, which in terms of population, dimension, healthcare organization and economic development could be compared to other European countries. The method we suggest, which consists basically in a careful estimate of all the public resources employed in the provision of services exclusively destined to the elderly, could be applied, with the due differences, to other European countries or regions. PMID- 28812845 TI - A Qualitative Assessment of the Evidence Utilization for Health Policy-Making on the Basis of SUPPORT Tools in a Developing Country. AB - BACKGROUND: SUPPORT tools consist of 18 articles addressing the health policy makers so that they can learn how to make evidence-informed health policies. These tools have been particularly recommended for developing countries. The present study tries to explain the process of evidence utilization for developing policy documents in the Iranian Ministry of Health and Medical Education (MoHME) and to compare the findings with those of SUPPORT tools. METHODS: A qualitative research was conducted, using the framework analysis approach. Participants consisted of senior managers and technicians in MoHME. Purposeful sampling was done, with a maximum variety, for the selection of research participants: individuals having at least 5 years of experience in preparing evidence-based policy documents. Face-to-face interviews were conducted for data collection. As a guideline for the interviews, 'the Utilization of Evidence in Policy-Making Organizations' procedure was used. The data were analyzed through the analysis of the framework method using MAXQDA 10 software. RESULTS: The participants acquired the research evidence in a topic-based form, and they were less likely to search on the basis of the evidence pyramid. To assess the quality of evidence, they did not use standard critical tools; to adapt the evidence and interventions with the local setting, they did not use the ideas and experiences of all stakeholders, and in preparing the evidence-based policy documents, they did not take into consideration the window of opportunity, did not refrain from using highly technical terms, did not write user-friendly summaries, and did not present alternative policy options. In order to develop health policies, however, they used the following innovations: attention to the financial burden of policy issues on the agenda, sensitivity analysis of the preferred policy option on the basis of technical, sociopolitical, and economic feasibility, advocacy from other scholars, using the multi-criteria decision-making models for the prioritization of policy options, implementation of policy based on the degree of readiness of policy-implementing units, and the classification of policy documents on the basis of different conditions of policy-making (urgent, short-term, and long term). CONCLUSION: Findings showed that the process of evidence utilization in IR MoH enjoys some innovations for the support of health policy development. The present study provides IR-MoH with considerable opportunities for the improvement of evidence-informed health policy-making. Moreover, the SUPPORT process and tools are recommended to be used in developing countries. PMID- 28812847 TI - Evidence-Informed Deliberative Processes for Universal Health Coverage: Broadening the Scope Comment on "Priority Setting for Universal Health Coverage: We Need Evidence-Informed Deliberative Processes, Not Just More Evidence on Cost Effectiveness". AB - Universal health coverage (UHC) is high on the global health agenda, and priority setting is fundamental to the fair and efficient pursuit of this goal. In a recent editorial, Rob Baltussen and colleagues point to the need to go beyond evidence on cost-effectiveness and call for evidence-informed deliberative processes when setting priorities for UHC. Such processes are crucial at every step on the path to UHC, and hopefully we will see intensified efforts to develop and implement processes of this kind in the coming years. However, if this does happen, it will be essential to ensure a sufficiently broad scope in at least two respects. First, the design of evidence-informed priority-setting processes needs to go beyond a simple view on the relationship between evidence and policy and adapt to a diverse set of factors shaping this relationship. Second, these processes should go beyond a focus on clinical services to accommodate also public health interventions. Together, this can help strengthen priority-setting processes and bolster progress towards UHC and the Sustainable Development Goals. PMID- 28812848 TI - The Elephants in the Room: Sex, HIV, and LGBT Populations in MENA. Intersectionality in Lebanon Comment on "Improving the Quality and Quantity of HIV Data in the Middle East and North Africa: Key Challenges and Ways Forward". AB - In response to this insightful editorial, we wish to provide commentary that seeks to highlight recent successes and illuminate the often unspoken hurdles at the intersections of culture, politics, and taboo. We focus on sexual transmission and draw examples from Lebanon, where the pursuit of data in quality and quantity is teaching us lessons about the way forward and where we are experiencing many of the challenges referenced in the editorial such as discrepancies between national statistics and rates derived via research as well as the impact of protracted political conflict and displacement. Two important points were raised in the editorial about HIV in Middle East and North Africa (MENA) that we would like to expand further: (1) The epidemic is largely driven by drug-related and sexual behavior among key populations; and (2) Several key populations continue to be criminalized and excluded from surveillance programs. PMID- 28812849 TI - Global Health in the Anthropocene: Moving Beyond Resilience and Capitalism Comment on "Health Promotion in an Age of Normative Equity and Rampant Inequality". AB - There has been much reflection on the need for a new understanding of global health and the urgency of a paradigm shift to address global health issues. A crucial question is whether this is still possible in current modes of global governance based on capitalist values. Four reflections are provided. (1) Ecological -centered values must become central in any future global health framework. (2) The objectives of 'sustainability' and 'economic growth' present a profound contradiction. (3) The resilience discourse maintains a gridlock in the functioning of the global health system. (4) The legitimacy of multi-stakeholder governance arrangements in global health requires urgent attention. A dual track approach is suggested. It must be aimed to transform capitalism into something better for global health while in parallel there is an urgent need to imagine a future and pathways to a different world order rooted in the principles of social justice, protecting the commons and a central role for the preservation of ecology. PMID- 28812850 TI - Global Alcohol Harm Network: Struggling or Emerging? A Response to Shiffman. PMID- 28812851 TI - Novel Treatments for Airway Disease PMID- 28812852 TI - Treating Anxiety and Depression in Primary Care: Reducing Barriers to Access. PMID- 28812853 TI - What's on Your Mind? PMID- 28812854 TI - The Key to Getting Through Chemo. PMID- 28812855 TI - The Ethics of Caring for Friends or Family. PMID- 28812856 TI - Which Quality Measures Should You Report? PMID- 28812857 TI - Building Capacity to Care for Refugees. PMID- 28812858 TI - Reducing Frustration and Increasing Fulfillment: Mindfulness. PMID- 28812866 TI - Directly Coating a Multifunctional Interlayer on the Cathode via Electrospinning for Advanced Lithium-Sulfur Batteries. AB - The lithium-sulfur battery is considered as a prospective candidate for a high energy-storage system because of its high theoretical specific capacity and energy. However, the dissolution and shutter of polysulfides lead to low active material utilization and fast capacity fading. Electrospinning technology is employed to directly coat an interlayer composed of polyacrylonitrile (PAN) and nitrogen-doped carbon black (NC) fibers on the cathode. Benefiting from electrospinning technology, the PAN-NC fibers possess good electrolyte infiltration for fast lithium-ion transport and great flexibility for adhering on the cathode. The NC particles provide good affinity for polysufides and great conductivity. Thus, the polysulfides can be trapped on the cathode and reutilized well. As a result, the PAN-NC-coated sulfur cathode (PAN-NC@cathode) exhibits the initial discharge capacity of 1279 mAh g-1 and maintains the reversible capacity of 1030 mAh g-1 with capacity fading of 0.05% per cycle at 200 mA g-1 after 100 cycles. Adopting electrospinning to directly form fibers on the cathode shows a promising application. PMID- 28812867 TI - Ultrasensitive Silicon Nanowire Sensor Developed by a Special Ag Modification Process for Rapid NH3 Detection. AB - Surface functionalization is very effective in enhancing sensing properties of a chemiresistive gas sensor. In this work, we develop a novel and cost-effective process to prepare Ag-modified silicon nanowire (SiNW) sensors and further suggest a resistance effect model to clarify the enhanced sensing mechanism of Ag modified SiNWs. The SiNWs were formed via metal-assisted chemical etching (MACE), and the Ag nanoparticle (NP) modification was achieved in situ based on the MACE produced Ag dendrites by involving a crucial anisotropic postetching of TMAH. The TMAH etching induces a loose array of needle-like, rough SiNWs (RNWs) with firm attachment of tiny Ag NPs. Comparative investigations for NH3-sensing properties indicate that the RNWs modified by discrete Ag NPs (Ag@RNWs) display an ~3-fold enhancement in gas response at room temperature compared with pristine SiNWs. Meanwhile, transient response and ultrafast recovery are observed for the Ag@RNW sensor (tres <= 2 s and trec <= 9 s to 0.33-10 ppm of NH3). The study demonstrates the considerable effect and potential of the Ag modification process developed in this work. A resistance effect model was further suggested to clarify the underlying mechanism of the enhanced response and the response saturation characteristic of the Ag@RNWs. The promotion of TMAH etching-induced microstructure modulation to sensing properties was also demonstrated. PMID- 28812868 TI - Light and Strong Hierarchical Porous SiC Foam for Efficient Electromagnetic Interference Shielding and Thermal Insulation at Elevated Temperatures. AB - A novel light but strong SiC foam with hierarchical porous architecture was fabricated by using dough as raw material via carbonization followed by carbothermal reduction with silicon source. A significant synergistic effect is achieved by embedding meso- and nanopores in a microsized porous skeleton, which endows the SiC foam with high-performance electromagnetic interference (EMI) shielding, thermal insulation, and mechanical properties. The microsized skeleton withstands high stress. The meso- and nanosized pores enhance multiple reflection of the incident electromagnetic waves and elongate the path of heat transfer. For the hierarchical porous SiC foam with 72.8% porosity, EMI shielding can be higher than 20 dB, and specific EMI effectiveness exceeds 24.8 dB.cm3.g-1 at a frequency of 11 GHz at 25-600 degrees C, which is 3 times higher than that of dense SiC ceramic. The thermal conductivity reaches as low as 0.02 W.m-1.K-1, which is comparable to that of aerogel. The compressive strength is as high as 9.8 MPa. Given the chemical and high-temperature stability of SiC, the fabricated SiC foam is a promising candidate for modern aircraft and automobile applications. PMID- 28812869 TI - Entry Inhibitors: A Perspective for Prevention of Hepatitis C Virus Infection in Organ Transplantation. AB - Entry inhibitors are emerging as an attractive class of therapeutics for hepatitis C virus (HCV) infection. Entry inhibitors target either virion associated factors or cellular factors necessary for infection. By blocking entry into cells, entry inhibitors prevent both the establishment of persistent reservoirs and the emergence of resistant variants during viral replication. Furthermore, entry inhibitors protect naive cells from virus-induced alterations. Combining entry inhibitors with direct-acting antivirals (DAAs) may therefore improve treatment outcomes, particularly in the context of organ transplantation. The role of DAAs in transplantation, while still under clinical investigation, carries the risk of recipient infection and HCV-induced disease, since DAAs act only after infection is established. Thus, entry inhibitors provide a perspective to improve patient outcomes during organ transplantation. Applying this approach for transplant of organs from HCV-positive donors to HCV-negative recipients may also contribute to alleviate the medical burden of organ shortage. PMID- 28812870 TI - Antifouling Thermoplastic Composites with Maleimide Encapsulated in Clay Nanotubes. AB - An antifouling ethylene-vinyl acetate copolymer (EVA) coating with halloysite clay nanotubes loaded with maleimide (TCPM) is prepared. Such antifoulant encapsulation allowed for extended release of TCPM and a long-lasting, efficient protection of the coated surface against marine microorganisms proliferation. Halloysite also induces the composite's anisotropy due to parallel alignment of the nanotubes. The maleimide loaded halloysite incorporated into the polymer matrix allowed for 12-month release of the bacterial inhibitor preventing fouling; it is much longer than the 2-3 month protection when TCPM is directly admixed into EVA. The antifouling properties of the EVA-halloysite nanocomposites were tested by monitoring surface adhesion and proliferation of marine V. natriegens bacteria with SEM. As compared to the composite directly doped with TCPM-antifoulant, there were much less bacteria accumulated on the EVA-halloysite TCPM coating after a 2-month exposure to seawater. Field tests at South China Sea marine station further confirmed the formulation efficiency. The doping of 28 wt % TCPM loaded halloysite drastically enhanced material antifouling property, which promises wide applications for protective marine coating. PMID- 28812871 TI - High-Performance Porous Molybdenum Oxynitride Based Fiber Supercapacitors. AB - Scalable manufacturing of flexible, fiber-shaped energy-storage devices has enabled great technological advances in wearable and portable technology. Replacing inefficient oxides with inexpensive and high-performance oxynitrides with more favorable three-dimensional (3D) structures is critical if the practical applications of these technologies are to be realized. Here, we developed a facile and controllable approach for the synthesis of 3D porous micropillars of molybdenum oxynitride (MON), which exhibit high conductivity, robust stability, and excellent energy-storage properties. Our fiber electrode, containing a 3D hierarchical MON-based anode, yields remarkable linear and areal specific capacitances of 64.8 mF cm-1 and 736.6 mF cm-2, respectively, at a scan rate of 10 mV s-1. Moreover, a wearable asymmetric supercapacitor based on TiN/MON//TiN/MnO2 demonstrates good cycling stability with a linear capacitance of 12.7 mF cm-1 at a scan rate of 10 mV s-1. These remarkable electrochemical properties are mainly attributed to the synergistic effect between the chemical composition of oxynitride and the robust 3D porous structure composed of interconnected nanocrystalline morphology. The presented strategy for the controllable design and synthesis of novel-oxide-derived functional materials offers prospects in developing portable and wearable electronic devices. We also demonstrate that these fiber supercapacitors can be combined with an organic solar cell to construct a self-powered system for broader applications. PMID- 28812872 TI - Effect of Mineral Dissolution/Precipitation and CO2 Exsolution on CO2 transport in Geological Carbon Storage. AB - Geological carbon sequestration (GCS) in deep saline aquifers is an effective means for storing carbon dioxide to address global climate change. As the time after injection increases, the safety of storage increases as the CO2 transforms from a separate phase to CO2(aq) and HCO3- by dissolution and then to carbonates by mineral dissolution. However, subsequent depressurization could lead to dissolved CO2(aq) escaping from the formation water and creating a new separate phase which may reduce the GCS system safety. The mineral dissolution and the CO2 exsolution and mineral precipitation during depressurization change the morphology, porosity, and permeability of the porous rock medium, which then affects the two-phase flow of the CO2 and formation water. A better understanding of these effects on the CO2-water two-phase flow will improve predictions of the long-term CO2 storage reliability, especially the impact of depressurization on the long-term stability. In this Account, we summarize our recent work on the effect of CO2 exsolution and mineral dissolution/precipitation on CO2 transport in GCS reservoirs. We place emphasis on understanding the behavior and transformation of the carbon components in the reservoir, including CO2(sc/g), CO2(aq), HCO3-, and carbonate minerals (calcite and dolomite), highlight their transport and mobility by coupled geochemical and two-phase flow processes, and consider the implications of these transport mechanisms on estimates of the long term safety of GCS. We describe experimental and numerical pore- and core-scale methods used in our lab in conjunction with industrial and international partners to investigate these effects. Experimental results show how mineral dissolution affects permeability, capillary pressure, and relative permeability, which are important phenomena affecting the input parameters for reservoir flow modeling. The porosity and the absolute permeability increase when CO2 dissolved water is continuously injected through the core. The MRI results indicate dissolution of the carbonates during the experiments since the porosity has been increased after the core-flooding experiments. The mineral dissolution changes the pore structure by enlarging the throat diameters and decreasing the pore specific surface areas, resulting in lower CO2/water capillary pressures and changes in the relative permeability. When the reservoir pressure decreases, the CO2 exsolution occurs due to the reduction of solubility. The CO2 bubbles preferentially grow toward the larger pores instead of toward the throats or the finer pores during the depressurization. After exsolution, the exsolved CO2 phase shows low mobility due to the highly dispersed pore-scale morphology, and the well dispersed small bubbles tend to merge without interface contact driven by the Ostwald ripening mechanism. During depressurization, the dissolved carbonate could also precipitate as a result of increasing pH. There is increasing formation water flow resistance and low mobility of the CO2 in the presence of CO2 exsolution and carbonate precipitation. These effects produce a self-sealing mechanism that may reduce unfavorable CO2 migration even in the presence of sudden reservoir depressurization. PMID- 28812873 TI - Ultrathin Manganese-Based Metal-Organic Framework Nanosheets: Low-Cost and Energy Dense Lithium Storage Anodes with the Coexistence of Metal and Ligand Redox Activities. AB - We herein demonstrate the fabrication of Mn- and Ni-based ultrathin metal-organic framework nanosheets with the same coordination mode (termed "Mn-UMOFNs" and "Ni UMOFNs", respectively) through an expedient and versatile ultrasonic approach and scrutinize their electrochemical properties as anode materials for rechargeable lithium batteries for the first time. The obtained Mn-UMOFNs with structure advantages over Ni-UMOFNs (thinner nanosheets, smaller metal-ion radius, higher specific surface area) exhibit high reversible capacity (1187 mAh g-1 at 100 mA g 1 for 100 cycles), excellent rate capability (701 mAh g-1 even at 2 A g-1), rapid Li+ diffusion coefficient (2.48 * 10-9 cm2 s-1), and a reasonable charge discharge profile with low average operating potential at 0.4 V. On the grounds of the low-cost and environmental benignity of Mn metals and terephthalic acid linkers, our Mn-UMOFNs show alluring promise as a low-cost high-energy anode material for future LIBs. Furthermore, the lithiation-delithiation chemistry of Mn-UMOFNs was unequivocally studied by a combination of magnetic measurements, electron paramagnetic resonance, and synchrotron-based soft X-ray spectroscopy (O K-edge and Mn L-edge) experiments, the results of which substantiate that both the aromatic chelating ligands and the Mn2+ centers participate in lithium storage. PMID- 28812874 TI - Three-Dimensional Highly Stretchable Conductors from Elastic Fiber Mat with Conductive Polymer Coating. AB - The manufacture of stretchable conductors with well-reserved electrical performance under large-degree deformations via scalable processes remains of great importance. In this work, a highly stretchable 3D conductive framework consisting of a polyurethane fiber mat (PUF) and poly(3,4-ethylenedioxythiophene) (PEDOT) is reported through facile approaches, electrospinning, and in situ interfacial polymerization, which was then backfilled with poly(dimethylsiloxane) to obtain 3D conductors. The excellent stretchability of the 3D conductive network imparted the as-prepared electrode a superior mechanical durability. Moreover, the applied strains can be effectively accommodated by the arrangement and orientation of the fibers resulting in a relatively stable electrical performance with only a 20% increased resistance at 100% stretching. Meanwhile, the resistance of the conductor could remain constant during 2000 bending cycles and showed a slight increase during 100 cycles of 50% stretching. The potential in the applications of large-area stretchable electrodes was demonstrated by the construction of LED arrays with the PUF-based conductors as electrical connections. PMID- 28812875 TI - One-Pot Synthesis of Size- and Composition-Controlled Ni-Rich NiPt Alloy Nanoparticles in a Reverse Microemulsion System and Their Application. AB - Bimetallic nanoparticles have been the subject of numerous research studies in the nanotechnology field, in particular for catalytic applications. Control of the size, morphology, and composition has become a key challenge due to the relationship between these parameters and the catalytic behavior of the particles in terms of activity, selectivity, and stability. Here, we present a one-pot air synthesis of 2 nm Ni9Pt1 nanoparticles with a narrow size distribution. Control of the size and composition of the alloy particles is achieved at ambient temperature, in the aqueous phase, by the simultaneous reduction of nickel and platinum precursors with hydrazine, using a reverse microemulsion system. After deposition on an alumina support, this Ni-rich nanoalloy exhibits unprecedented stability under the harsh conditions of methane dry reforming. PMID- 28812876 TI - Cocatalyzing Pt/PtO Phase-Junction Nanodots on Hierarchically Porous TiO2 for Highly Enhanced Photocatalytic Hydrogen Production. AB - Phase-junctions between a cocatalyst and its semiconductor host are quite effective to enhance the photocatalytic activity and are widely studied, while reports on the phase-juncted cocatalyst are still rare. In this work, we report the deposition of the Pt/PtO phase-juncted nanodots as cocatalyst via NaOH modification of an interconnected meso-macroporous TiO2 network with high surface area and inner-particle mesopores to enhance the performance of photocatalytic H2 production. Our results show that NaOH modification can largely influence Pt/PtO phase-juncted nanodot formation and dispersity. Compared to the TiO2 nanoparticles, the hierarchically meso-macroporous TiO2 network containing 0.18 wt % Pt/PtO phase-juncted cocatalyst demonstrates a highest photocatalytic H2 rate of 13 mmol g-1 h-1 under simulated solar light, and possesses a stable cycling activity without obvious decrease after five cycles. Such high H2 production performance can be attributed to both the phase-juncted Pt/PtO providing more active sites while PtO suppresses the undesirable hydrogen back reaction, and the special hierarchically porous TiO2 network with inner-particle mesopores presenting short diffusion path lengths for photogenerated electrons and enhanced light harvesting efficiency. This work suggests that Pt/PtO phase juncted cocatalyst on hierarchically porous TiO2 nanostructures is a promising strategy for advanced photocatalytic H2 production. PMID- 28812877 TI - ScRu2B3 and Sc2RuB6: Borides Featuring a 2D Infinite Boron Clustering. AB - Two borides, ScRu2B3 and Sc2RuB6, were obtained by argon-arc melting of the elements followed by annealing at 800 degrees C. ScRu2B3 exhibits a new structure type with the space group Cmcm (a = 3.0195(2) A, b = 15.4056(8) A, c = 5.4492(3) A; single crystal X-ray data; RF2 = 0.0105). Sc2RuB6 adopts the Y2ReB6 type structure (space group Pbam; a = 8.8545(2) A, b = 11.1620(3) A, c = 3.4760(1) A; single crystal X-ray data; RF2 = 0.0185). ScRu2B3 displays an unusual intergrowth of CeCo3B2- and AlB2-related slabs; a striking feature is a boat configuration of puckered boron hexagons within infinite graphite like boron layers (63 nets). Sc2RuB6 presents two-dimensional planar nets of condensed boron pentagons, hexagons, and heptagons sandwiched between metal layers. In Sc/Y substituted Y2ReB6-type, Y atoms are distributed exclusively inside the boron heptagons. Exploration of the Sc-Ru-B system at 800 degrees C including binary boundaries employing EPMA and powder X-ray diffraction technique furthermore rules out the existence of previously reported "ScRuB4" but confirms the formation and crystal structure of Sc2Ru5B4. ScRu4B4 forms in cast alloys (LuRu4B4-type structure; space group I41/acd (No. 142), a = 7.3543(2) A, c = 14.92137(8) A). Cell parameters and atomic coordinates have been refined for ScRu2B3, Sc2RuB6, and ScRu4B4 in the scope of the generalized gradient approximation. Ab initio electronic structure calculations indicate a moderate electronic density of states at the Fermi level situated near the upper edge of essentially filled d-bands. Electrical resistivity measurements characterize ScRu2B3 and Sc2RuB6 as metals in concord with electronic band structure calculations. PMID- 28812878 TI - Nanomechanical Imaging of the Diffusion of Fullerene into Conjugated Polymer. AB - The large Young's modulus difference between chemically modified fullerene (PCBM) and a conjugated polymer was used to nanomechanically map the diffusion of PCBM into PTB7, a high-efficiency low-band-gap conjugated polymer. The sharp tip in nanomechanical atomic force microscopy ensures a high-resolution nanomechanical characterization of the diffusion front, with the intrinsic benefits of revealing the mechanical properties of the mixtures. Localized structure changes induced by diffusion were investigated by grazing incidence X-ray diffraction methods. We found a most unusual diffusion behavior that shows Case II characteristics, where a front of PTB7 saturated with PCBM moves into the pure PTB7 with a linear time dependence. This diffusion is due mainly to a majority fraction of the disordered PTB7 that has continuous paths for PCBM diffusion without obvious energetic barriers, and as diffusion proceeds, the paths for diffusion gets larger, leading to a step in the concentration profile. The donor/acceptor-dependent diffusion constants may also contribute to the observed Case-II-like diffusion front. PMID- 28812879 TI - Germanium and Tin Monoxides Trapped by Oxophilic Germylene and Stannylene Ligands. AB - Germanium and tin monoxides (MO, M = Ge, Sn) were trapped by the 1,2,4 diazaphospholide-based germylene and stannylene M[3,5-tBu2dp]2 (M = Ge (2), Sn (3)), resulting in the Lewis acid-base adduct of composition M(MU-O)[M{eta1(N) (3,5-tBu2dp)}2]2 (M = Ge (4), Sn (5)). Compounds 4 and 5 were characterized by single-crystal X-ray structural analysis. The bonding features of 4 and 5 were supported by DFT calculations. PMID- 28812880 TI - An Exceptionally Narrow Band-Gap (~4 eV) Silicate Predicted in the Cubic Perovskite Structure: BaSiO3. AB - The electronic structures of 35 A2+B4+O3 ternary cubic perovskite oxides, including their hypothetical chemical compositions, were calculated by a hybrid functional method with the expectation that peculiar electronic structures and unique carrier transport properties suitable for semiconductor applications would be hidden in high-symmetry cubic perovskite oxides. We found unique electronic structures of Si-based oxides (A = Mg, Ca, Sr, and Ba, and B = Si). In particular, the unreported cubic BaSiO3 has a very narrow band gap (4.1 eV) compared with conventional nontransition-metal silicates (e.g., ~9 eV for SiO2 and the calculated value of 7.3 eV for orthorhombic BaSiO3) and a small electron effective mass (0.3m0, where m0 is the free electron rest mass). The narrow band gap is ascribed to the nonbonding state of Si 3s and the weakened Madelung potential. The existence of the predicted cubic perovskite structure of BaSiO3 was experimentally verified by applying a high pressure of 141 GPa. The present finding indicates that it could be possible to develop a new transparent oxide semiconductor of earth abundant silicates if the symmetry of its crystal structure is appropriately chosen. Cubic BaSiO3 is a candidate for high performance oxide semiconductors if this phase can be stabilized at room temperature and ambient pressure. PMID- 28812881 TI - Predicting Microbial Fuel Cell Biofilm Communities and Bioreactor Performance using Artificial Neural Networks. AB - The complex interactions that occur in mixed-species bioelectrochemical reactors, like microbial fuel cells (MFCs), make accurate predictions of performance outcomes under untested conditions difficult. While direct correlations between any individual waste stream characteristic or microbial community structure and reactor performance have not been able to be directly established, the increase in sequencing data and readily available computational power enables the development of alternate approaches. In the current study, 33 MFCs were evaluated under a range of conditions including eight separate substrates and three different wastewaters. Artificial Neural Networks (ANNs) were used to establish mathematical relationships between wastewater/solution characteristics, biofilm communities, and reactor performance. ANN models that incorporated biotic interactions predicted reactor performance outcomes more accurately than those that did not. The average percent error of power density predictions was 16.01 +/ 4.35%, while the average percent error of Coulombic efficiency and COD removal rate predictions were 1.77 +/- 0.57% and 4.07 +/- 1.06%, respectively. Predictions of power density improved to within 5.76 +/- 3.16% percent error through classifying taxonomic data at the family versus class level. Results suggest that the microbial communities and performance of bioelectrochemical systems can be accurately predicted using data-mining, machine-learning techniques. PMID- 28812883 TI - Activation of Molecular Oxygen by a Molybdenum(IV) Imido Compound. AB - Activation of molecular dioxygen at a molybdenum(IV) imido compound led to the isolation and full characterization of a remarkably stable transition-metal imidoperoxido complex. PMID- 28812884 TI - Controlling Bdellovibrio bacteriovorus Gene Expression and Predation Using Synthetic Riboswitches. AB - Bdellovibrio bacteriovorus is a predatory bacterium that feeds on Gram-negative bacteria including a wide range of pathogens and thus has potential applications as a biocontrol agent. Owing to its unique life cycle, however, there are limited tools that enable genetic manipulation of B. bacteriovorus. This work describes our first steps toward engineering the predatory bacterium for practical applications by developing basic genetic parts to control gene expression. Specifically, we evaluated four robust promoters that are active during the attack phase of B. bacteriovorus. Subsequently, we tested several synthetic riboswitches that have been reported to function in Escherichia coli, and identified theophylline-activated riboswitches that function in B. bacteriovorus. Finally, we inserted the riboswitch into the bacterial chromosome to regulate expression of the flagellar sigma factor fliA, which was previously predicted to be essential for predation, and observed that the engineered strain shows a faster predation kinetics in the presence of theophylline. PMID- 28812882 TI - Aberrantly Large Single-Channel Conductance of Polyhistidine Arm-Containing Protein Nanopores. AB - There have been only a few studies reporting on the impact of polyhistidine affinity tags on the structure, function, and dynamics of proteins. Because of the relatively short size of the tags, they are often thought to have little or no effect on the conformation or activity of a protein. Here, using membrane protein design and single-molecule electrophysiology, we determined that the presence of a hexahistidine arm at the N-terminus of a truncated FhuA-based protein nanopore, leaving the C-terminus untagged, produces an unusual increase in the unitary conductance to ~8 nS in 1 M KCl. To the best of our knowledge, this is the largest single-channel conductance ever recorded with a monomeric beta-barrel outer membrane protein. The hexahistidine arm was captured by an anti polyhistidine tag monoclonal antibody added to the side of the channel-forming protein addition, but not to the opposite side, documenting that this truncated FhuA-based protein nanopore inserts into a planar lipid bilayer with a preferred orientation. This finding is in agreement with the protein insertion in vivo, in which the large loops face the extracellular side of the membrane. The aberrantly large single-channel conductance, likely induced by a greater cross-sectional area of the pore lumen, along with the vectorial insertion into a lipid membrane, will have profound implications for further developments of engineered protein nanopores. PMID- 28812885 TI - Ecological Risk Assessment of Nano-enabled Pesticides: A Perspective on Problem Formulation. AB - Plant protection products containing nanomaterials that alter the functionality or risk profile of active ingredients (nano-enabled pesticides) promise many benefits over conventional pesticide products. These benefits may include improved formulation characteristics, easier application, better targeting of pest species, increased efficacy, lower application rates, and enhanced environmental safety. After many years of research and development, nano-enabled pesticides are starting to make their way into the market. The introduction of this technology raises a number of issues for regulators, including how does the ecological risk assessment of nano-enabled pesticide products differ from that of conventional plant protection products? In this paper, a group drawn from regulatory agencies, academia, research, and the agrochemicals industry offers a perspective on relevant considerations pertaining to the problem formulation phase of the ecological risk assessment of nano-enabled pesticides. PMID- 28812886 TI - Room-Temperature Ring-Opening of Quinoline, Isoquinoline, and Pyridine with Low Valent Titanium. AB - The complex (PNP)Ti?CHtBu(CH2tBu) (PNP = N[2-PiPr2-4-methylphenyl]2-) dehydrogenates cyclohexane to cyclohexene by forming a transient low-valent titanium-alkyl species, [(PNP)Ti(CH2tBu)], which reacts with 2 equiv of quinoline (Q) at room temperature to form H3CtBu and a Ti(IV) species where the less hindered C2?N1 bond of Q is ruptured and coupled to another equivalent of Q. The product isolated from this reaction is an imide with a tethered cycloamide group, (PNP)Ti?N[C18H13N] (1). Under photolytic conditions, intramolecular C-H bond activation across the imide moiety in 1 occurs to form 2, and thermolysis reverses this process. The reaction of 2 equiv of isoquinoline (Iq) with intermediate [(PNP)Ti(CH2tBu)] results in regioselective cleavage of the C1?N2 and C1-H bonds, which eventually couple to form complex 3, a constitutional isomer of 1. Akin to 1, the transient [(PNP)Ti(CH2tBu)] complex can ring-open and couple two pyridine molecules, to produce a close analogue of 1, complex (PNP)Ti?N[C10H9N] (4). Multinuclear and multidimensional NMR spectra confirm structures for complexes 1-4, whereas solid-state structural analysis reveals the structures of 2, 3, and 4. DFT calculations suggest an unprecedented mechanism for ring-opening of Q where the reactive intermediate in the low-spin manifold crosses over to the high-spin surface to access a low-energy transition state but returns to the low-spin surface immediately. This double spin-crossover constitutes a rare example of a two-state reactivity, which is key for enabling the reaction at room temperature. The regioselective behavior of Iq ring-opening is found to be due to electronic effects, where the aromatic resonance of the bicycle is maintained during the key C-C coupling event. PMID- 28812887 TI - Copper-Catalyzed Aerobic Oxidative Regioselective Thiocyanation of Aromatics and Heteroaromatics. AB - A copper-catalyzed aerobic oxidative reaction between aromatics or heteroaromatics with KSCN is developed by using O2 as the oxidant. The combination of Cu(OTf)2, N,N,N',N'-tetramethylethylenediamine (TMEDA) and BF3.Et2O provides an efficient catalytic system, affording substituted thiocyanation products and 2-aminobenzothiazoles in excellent yields. The reaction also possesses a good functional group tolerance for both strong electron-withdrawing and electron-donating groups. PMID- 28812888 TI - Triply Bonded Gallium=Phosphorus Molecules: Theoretical Designs and Characterization. AB - The effect of substitution on the potential energy surfaces of triple-bonded RGa=PR (R = F, OH, H, CH3, SiH3, SiMe(SitBu3)2, SiiPrDis2, Tbt (C6H2-2,4,6 {CH(SiMe3)2}3), and Ar* (C6H3-2,6-(C6H2-2,4,6-i-Pr3)2)) compounds was theoretically examined by using density functional theory (i.e., M06-2X/Def2 TZVP, B3PW91/Def2-TZVP, and B3LYP/LANL2DZ+dp). The theoretical evidence strongly suggests that all of the triple-bonded RGa=PR species prefer to select a bent form with an angle (?Ga-P-R) of about 90 degrees . Moreover, the theoretical observations indicate that only the bulkier substituents, in particular, for the strong donating groups (e.g., SiMe(SitBu3)2 and SiiPrDis2) can efficiently stabilize the Ga=P triple bond. In addition, the bonding analyses (based on the natural bond orbital, the natural resonance theory, and the charge decomposition analysis) reveal that the bonding characters of such triple-bonded RGa=PR molecules should be regarded as [Formula: see text]. In other words, the Ga=P triple bond involves one traditional sigma bond, one traditional pi bond, and one donor-acceptor pi bond. Accordingly, the theoretical conclusions strongly suggest that the Ga=P triple bond in such acetylene analogues (RGa=PR) should be very weak. PMID- 28812889 TI - Influence of Small Fluorophilic and Lipophilic Organic Molecules on Dipalmitoylphosphatidylcholine Bilayers. AB - In this study, we investigate the effect of a series of additive molecules with different types of philicities on the structure and dynamics of dipalmitoylphosphatidylcholine (DPPC) bilayers. To this aim, we performed extensive force field molecular dynamics simulations of the systems, using our recently developed perfluoroalkane force field. We found that addition of perfluoro-n-decane and fluorotelomer alcohol at 323 K leads to a phase transition of the membrane from liquid crystalline to the gel phase, whereas the addition of n-decane and partially fluorinated n-decane leaves the liquid crystalline phase intact. The systems in the gel phase show a significantly reduced diffusivity for both DPPC and additive molecules. The addition of nonfluorinated and partially fluorinated n-decane even leads to an increased DPPC diffusivity. While nonfluorinated n-decane and partially fluorinated n-decane are found mainly in the middle of the bilayer, perfluoro-n-decane penetrates significantly deeper into the membrane leaflet. Fluorotelomer alcohol is found almost exclusively inside the leaflet, with its hydroxyl groups forming a strong hydrogen bond network to the ester oxygen atoms in the head group of DPPC. A slight increase in temperature by only 10 K is already sufficient to dynamically overcome this hydrogen bond network, such that no phase transition occurs in that case. PMID- 28812890 TI - Jaqpot Quattro: A Novel Computational Web Platform for Modeling and Analysis in Nanoinformatics. AB - Engineered nanomaterials (ENMs) are increasingly infiltrating our lives as a result of their applications across multiple fields. However, ENM formulations may result in the modulation of pathways and mechanisms of toxic action that endanger human health and the environment. Alternative testing methods such as in silico approaches are becoming increasingly popular for assessing the safety of ENMs, as they are cost- and time-effective. Additionally, computational approaches support the industrial safer-by-design challenge and the REACH legislation objective of reducing animal testing. Because of the novelty of the field, there is also an evident need for harmonization in terms of databases, ontology, and modeling infrastructures. To this end, we present Jaqpot Quattro, a comprehensive open-source web application for ENM modeling with emphasis on predicting adverse effects of ENMs. We describe the system architecture and outline the functionalities, which include nanoQSAR modeling, validation services, read-across predictions, optimal experimental design, and interlaboratory testing. PMID- 28812891 TI - Catalytic Alkynylation of Cyclic Acetals and Ketals Enabled by Synergistic Gold(I)/Trimethylsilyl Catalysis. AB - A completely regioselective and challenging gold(I)-catalyzed ring-opening of cyclic 1,3-dioxolanes and dioxanes by trimethylsilyl alkynes to set diol-derived propargyl trimethylsilyl bis-ethers is reported. This unprecedented and not trivial transformation does not operate with the catalytic methodologies recently reported for catalytic alkynylation of acyclic acetals/ketals, and is uniquely enabled by the application of a recently introduced synergistic gold(I)-silicon catalysis concept capable of producing simultaneously catalytic amounts of two key players, a silicon-based Lewis superacid and a nucleophilic gold acetylide. PMID- 28812893 TI - alpha-Sulfinyl Benzoates as Precursors to Li and Mg Carbenoids for the Stereoselective Iterative Homologation of Boronic Esters. AB - The stereoselective reagent-controlled homologation of boronic esters is one of a small number of iteratable synthetic transformations that if automated could form the basis of a veritable molecule-making machine. Recently, alpha-stannyl triisopropylbenzoates and alpha-sulfinyl chlorides have emerged as useful building blocks for the iterative homologation of boronic esters. However, alpha stannyl benzoates need to be prepared using stoichiometric amounts of the (+)- or (-)-enantiomer of the scarcely available and expensive diamine sparteine; also, these building blocks, together with the byproducts that are generated during homologation, are perceived as being toxic. On the other hand, alpha-sulfinyl chlorides are difficult to prepare with high levels of enantiopurity and are prone to undergo deleterious acid-base side-reactions under the reaction conditions for homologation, leading to low stereospecificity. Here, we show that the use of a hybrid of these two building blocks, namely, alpha-sulfinyl triisopropylbenzoates, largely overcomes the above drawbacks. Through either the sulfinylation of alpha-magnesiated benzoates with either enantiomer of Andersen's readily available menthol-derived sulfinate or the alpha-alkylation of enantiopure S-chiral alpha-sulfinyl benzoates, we have prepared a range of highly enantiopure mono- and disubstituted alpha-sulfinyl benzoates, some bearing sensitive functional groups. Barbier-type reaction conditions have been developed that allow these building blocks to be converted into lithium (t-BuLi) and magnesium (i-PrMgCl.LiCl) carbenoids in the presence of boronic esters, thus allowing efficient and highly stereospecific homologation. The use of magnesium carbenoids allows carbon chains to be grown with the incorporation of sensitive functional groups, such as alkyl/aryl halides, azides, and esters. The use of lithium carbenoids, which are less sensitive to steric hindrance, allows sterically encumbered carbon-carbon bonds to be forged. We have also shown that these building blocks can be used consecutively in three- and four-step iterative homologation processes, without intervening column chromatography, to give contiguously substituted carbon chains with very high levels of enantio- and diastereoselectivity. PMID- 28812892 TI - DESIGNER Extracts as Tools to Balance Estrogenic and Chemopreventive Activities of Botanicals for Women's Health. AB - Botanical dietary supplements contain multiple bioactive compounds that target numerous biological pathways. The lack of uniform standardization requirements is one reason that inconsistent clinical effects are reported frequently. The multifaceted biological interactions of active principles can be disentangled by a coupled pharmacological/phytochemical approach using specialized ("knock-out") extracts. This is demonstrated for hops, a botanical for menopausal symptom management. Employing targeted, adsorbent-free countercurrent separation, Humulus lupulus extracts were designed for pre- and postmenopausal women by containing various amounts of the phytoestrogen 8-prenylnaringenin (8-PN) and the chemopreventive constituent xanthohumol (XH). Analysis of their estrogenic (alkaline phosphatase), chemopreventive (NAD(P)H-quinone oxidoreductase 1 [NQO1]), and cytotoxic bioactivities revealed that the estrogenicity of hops is a function of 8-PN, whereas their NQO1 induction and cytotoxic properties depend on XH levels. Antagonization of the estrogenicity of 8-PN by elevated XH concentrations provided evidence for the interdependence of the biological effects. A designed postmenopausal hop extract was prepared to balance 8-PN and XH levels for both estrogenic and chemopreventive properties. An extract designed for premenopausal women contains reduced 8-PN levels and high XH concentrations to minimize estrogenic while retaining chemopreventive properties. This study demonstrates the feasibility of modulating the concentrations of bioactive compounds in botanical extracts for potentially improved efficacy and safety. PMID- 28812894 TI - Enhanced Production of kappa-Carrageenase and kappa-Carrageenan Oligosaccharides through Immobilization of Thalassospira sp. Fjfst-332 with Magnetic Fe3O4 Chitosan Microspheres. AB - In this study, immobilized bacteria (IMB) microsphere was prepared by embedding kappa-carrageenase-producing Thalassospira sp. Fjfst-332 (TF332) onto a magnetic Fe3O4-chitosan carrier. The performance of Fe3O4-chitosan carrier was optimized by comparing its bacteria immobilization capacity at different Fe3O4:chitosan ratios and temperatures, while the functions of IMB microspheres were characterized by examining their kappa-carrageenase production at different temperatures, pH's, and reuse cycles. At the 1:1 (w:w) Fe3O4:chitosan ratio, the Fe3O4-chitosan carriers possessed sufficient anchoring capacity for bacterial immobilization without significant compromise of their magnetism for magnetic separation of IMB from culture media. The spectroscopic analysis of IMB microspheres indicated that the immobilization of TF332 might affect the amide groups in chitosan. Compared to free bacteria, IMB can produce kappa-carrageenase at higher temperature, wider pH range, and faster rate. More importantly, the kappa-carrageenase-producing activity was sustained for at least seven reuse cycles. The major kappa-carrageenan degradation products of IMB-derived kappa carrageenase were the oligosaccharides containing two to six monosaccharide units. Overall, this Fe3O4-chitosan-TF-332 microsphere has the potential to become a stable and reusable platform for large-scale production of kappa carrageenan oligosaccharides. PMID- 28812895 TI - Correlating Free-Volume Hole Distribution to the Glass Transition Temperature of Epoxy Polymers. AB - A new algorithm is developed to quantify the free-volume hole distribution and its evolution in coarse-grained molecular dynamics simulations of polymeric networks. This is achieved by analyzing the geometry of the network rather than a voxelized image of the structure to accurately and efficiently find and quantify free-volume hole distributions within large scale simulations of polymer networks. The free-volume holes are quantified by fitting the largest ellipsoids and spheres in the free-volumes between polymer chains. The free-volume hole distributions calculated from this algorithm are shown to be in excellent agreement with those measured from positron annihilation lifetime spectroscopy (PALS) experiments at different temperature and pressures. Based on the results predicted using this algorithm, an evolution model is proposed for the thermal behavior of an individual free-volume hole. This model is calibrated such that the average radius of free-volumes holes mimics the one predicted from the simulations. The model is then employed to predict the glass-transition temperature of epoxy polymers with different degrees of cross-linking and lengths of prepolymers. Comparison between the predicted glass-transition temperatures and those measured from simulations or experiments implies that this model is capable of successfully predicting the glass-transition temperature of the material using only a PDF of the initial free-volume holes radii of each microstructure. This provides an effective approach for the optimized design of polymeric systems on the basis of the glass-transition temperature, degree of cross-linking, and average length of prepolymers. PMID- 28812896 TI - Free Energy of Nucleation and Interplay between Size and Composition in CuNi Systems. AB - Using molecular simulation, we shed light on the crystal nucleation process in systems of Cu, Ni, and their nanoalloy. For each system, we simulate the formation of the crystal nucleus along the entire nucleation pathway and determine the free energy barrier overcome by the system to form a critical nucleus. Comparing the results obtained for the pure metals to those for the nanoalloy, we analyze the impact of alloying on the free energy of nucleation, as well as on the size and structure of the crystal nucleus. Specifically, we relate the greater free energy of nucleation, and bigger critical nuclei, obtained for the nanoalloy, to the difference in size and cohesive energy between the two metals. Furthermore, we characterize the dependence of the local composition of the incipient crystal cluster on its size, which is of key significance for the applications of bimetallic nanoparticles in catalysis. PMID- 28812897 TI - Selective Formation of Functionalized alpha-Quaternary Malononitriles toward 5,5 Disubstituted Pyrrolopyrimidinones. AB - A modular, selective approach to complex alpha-tertiary substituted malononitriles is reported. The method takes advantage of beta-ester-substituted alpha,alpha-dinitrile alkenes as highly reactive, chemoselective electrophiles for 1,4-additions with organometallic nucleophiles to produce functionally and sterically dense all-carbon quaternary centers. In the presence of a chiral ester auxiliary bearing an aromatic ring, the 1,4-addition occurs with good to excellent selectivity due to favorable cation-pi interactions. The highly functionalized malononitriles represent versatile building blocks and can be applied toward efficient, highly selective syntheses of 5,5-disubstituted pyrrolopyrimidinones. PMID- 28812898 TI - Enantioselective N-Heterocyclic Carbene Catalyzed Synthesis of Functionalized Indenes. AB - An enantioselective NHC (N-heterocyclic carbene) catalyzed synthesis of indenes from bifunctional alpha,beta-unsaturated acyl fluorides and TMS enol ethers has been discovered. The reaction has broad generality (31 examples) and proceeds with high levels of enantioselectivity (most >92:8 er). Mechanistically the reaction likely occurs via a Michael/beta-lactonization/decarboxylation sequence. Derivatization studies and limitations are discussed. PMID- 28812899 TI - Synthesis and Characterization of a Boron-Nitrogen-Boron Zigzag-Edged Benzo[fg]tetracene Motif. AB - The boron-nitrogen-boron (BNB) zigzag edged benzo[fg]tetracene is accessible from 4-butyl-2,6-diphenylaniline in four steps in good yields. The two mesityl groups stabilize the boron centers toward nucleophilic attack and result in two enantiomeric forms in the solid state. The title compound has a large optical gap, shows blue fluorescence, and is quite resistant toward oxidation and reduction. PMID- 28812900 TI - Single Reactant Replacement Approach of Passerini Reaction: One-Pot Synthesis of beta-Acyloxyamides and Phthalides. AB - The Passerini reaction is a classical and well-known multicomponent reaction for accessing alpha-acyloxy amides. A single reactant replacement (SRR) approach of Passerini reaction is described, which involves aldehydes, carboxylic acids, and ynamides to constitute a one-pot synthesis of beta-acyloxy amides in a convergent manner. When this method was subject to intramolecular reaction, the process would produce phthalide products. The scalability was demonstrated, and a crossover reaction was conducted to elucidate a plausible mechanism. PMID- 28812901 TI - Behavior of Methylammonium Dipoles in MAPbX3 (X = Br and I). AB - Dielectric constants of MAPbX3 (X = Br, I) in the 1 kHz-1 MHz range show strong temperature dependence near room temperature, in contrast to the nearly temperature-independent dielectric constant of CsPbBr3. This strong temperature dependence for MAPbX3 in the tetragonal phase is attributed to the MA+ dipoles rotating freely within the probing time scale. This interpretation is supported by ab initio molecular dynamics simulations on MAPbI3 that establish these dipoles as randomly oriented with a rotational relaxation time scale of ~7 ps at 300 K. Further, we probe the intriguing possibility of transient polarization of these dipoles following a photoexcitation process with important consequences on the photovoltaic efficiency, using a photoexcitation pump and second harmonic generation efficiency as a probe with delay times spanning 100 fs-1.8 ns. The absence of a second harmonic signal at any delay time rules out the possibility of any transient ferroelectric state under photoexcitation. PMID- 28812902 TI - Charge Effects on the Efflorescence in Single Levitated Droplets. AB - The influence of electrical excess charges on the crystallization from supersaturated aqueous sodium chloride solutions is reported. This is accomplished by efflorescence studies on single levitated microdroplets using optical and electrodynamic levitation. Specifically, a strong increase in efflorescence humidity is observed as a function of the droplet's negative excess charge, ranging up to -2.1 pC, with a distinct threshold behavior, increasing the relative efflorescence humidity, at which spontaneous nucleation occurs, from 44% for the neutral microparticle to 60%. These findings are interpreted by using molecular dynamics simulations for determining plausible structural patterns located near the particle surface that could serve as suitable precursors for the formation of critical clusters overcoming the nucleation barrier. These results, facilitating heterogeneous nucleation in the case of negatively charged microparticles, are compared to recent work on charge-induced nucleation of neat supercooled water, where a distinctly different nucleation behavior as a function of droplet charge has been observed. PMID- 28812903 TI - Synergic on/off Photoswitching Spin State and Magnetic Coupling between Spin Crossover Centers. AB - The existence of a correlation between spin crossover and dielectric properties is a hot topic in the field of multiresponse materials, which has potential applications in the memory devices, switches, and sensors. One formidable challenge is the simultaneous and rapid on/off switching of spin states of the spin carriers and magnetic coupling between them, which is crucial for both reversible photomagnetic behavior and variations in dielectric properties. Here, we report a dinuclear Fe(II) spin crossover complex, wherein each Fe(II) center exhibits an interconversion between FeIIHS (HS = high-spin) and FeIILS (LS = low spin) achieved upon heating and cooling. Moreover, the spin state of respective Fe(II) ions and the antiferromagnetic interaction between them can be switched bidirectionally under alternating irradiation with 532 and 808 nm light, resulting in interconversion between paramagnetic and diamagnetic properties. Interestingly, the spin crossover can also induce variations in dielectric tensors. This result provides a strategy to simultaneously and bidirectionally switch spin state, magnetic coupling, and dielectric properties using external stimuli. PMID- 28812904 TI - Pd-Catalyzed Regioselective Asymmetric Addition Reaction of Unprotected Pyrimidines to Alkoxyallene. AB - Catalytic asymmetric synthesis of N-heterocyclic glycosides free of protecting and directing groups is reported. The key reaction is highlighted by the atom efficient and regioselective addition of unprotected pyrimidines to highly functionalized alkoxyallene. Numerous acyclic and cyclic N-heterocyclic glycosides are accessed with minimal formation of organic byproducts. The synthetic utility of the reaction is demonstrated by the first catalytic asymmetric synthesis of anticancer pharmaceutical (-)-Tegafur and stereoselective synthesis of an oxepane nucleoside derivative. PMID- 28812905 TI - Correlation of Solubility with the Metastable Limit of Nucleation Using Gauge Cell Monte Carlo Simulations. AB - We present a novel simulation-based investigation of the nucleation of nanodroplets from solution and from vapor. Nucleation is difficult to measure or model accurately, and predicting when nucleation should occur remains an open problem. Of specific interest is the "metastable limit", the observed concentration at which nucleation occurs spontaneously, which cannot currently be estimated a priori. To investigate the nucleation process, we employ gauge-cell Monte Carlo simulations to target spontaneous nucleation and measure thermodynamic properties of the system at nucleation. Our results reveal a widespread correlation over 5 orders of magnitude of solubilities, in which the metastable limit depends exclusively on solubility and the number density of generated nuclei. This three-way correlation is independent of other parameters, including intermolecular interactions, temperature, molecular structure, system composition, and the structure of the formed nuclei. Our results have great potential to further the prediction of nucleation events using easily measurable solute properties alone and to open new doors for further investigation. PMID- 28812907 TI - Insights into Asthma Therapies, Cardiovascular Effects, and Mechanisms from Recent Clinical Trials. PMID- 28812908 TI - A Quantitative Assessment of the Risk of Human Salmonellosis Arising from the Consumption of Pecans in the United States. AB - A quantitative risk assessment was conducted to assess the risk of human salmonellosis acquired from consumption of pecans in the United States. The model considered the potential for Salmonella survival, growth, and recontamination of pecans from the sheller to the consumer, including steps such as immersion in water, drying, conditioning, cracking, partitioning, and storage. Five theoretical microbial reduction treatment levels (1 to 5 log CFU) were modeled. Data from the 2010 to 2013 surveys by the National Pecan Shellers Association were used for initial prevalence and contamination levels. The impacts of atypical situations in the pecan production system were also evaluated. Higher initial contamination levels, recontamination during processing, and a delay in drying postconditioning were the modeled atypical situations. The baseline model predicted a mean risk of salmonellosis in the United States from consumption of in-shell and shelled pecans processed by cold conditioning with no microbial reduction treatment and no further home cooking as 1 case per 775,193 servings (95% confidence interval [CI]: 1 case per 1,915,709 to 178,253 servings). This predicted risk per serving was estimated as a mean of 529 cases of salmonellosis per year (95% CI: 213 to 2,295 cases). Hot conditioning for shelled pecans and microbial reduction treatment of both shelled and in-shell pecans had a significant impact on the predicted mean risk of illness. Assuming 77% of the shelled pecans sold at retail (i.e., 80% of the retail supply) received hot conditioning, the mean estimated salmonellosis cases per year from consumption of in-shell and shelled pecans uncooked at home was 203 (95% CI: 81 to 882 cases) if no additional microbial reduction treatment were applied. The predicted risk of illness per serving was higher for all atypical situations modeled compared with the baseline model, and delay in drying had the greatest impact on risk. PMID- 28812909 TI - Chronic orbital inflammatory disease and optic neuropathy associated with long term intranasal cocaine abuse: 2 cases and literature review. AB - Orbital inflammatory disease and secondary optic neuropathy is a rare but devastating complication of long-term intranasal cocaine abuse. We describe 2 patients with a history of intranasal cocaine consumption who presented with subacute onset of unilateral vision loss from optic neuropathy and limitation of abduction in the affected eye. Magnetic resonance imaging findings included an orbital mass in combination with absent nasal septum and partial destruction of the paranasal sinuses. Biopsies and histopathologic examination of the nasal cavity and the orbital mass revealed chronic inflammation. Both patients were treated with oral corticosteroids, ocular movements completely normalized but no improvement of visual acuity was noted. Intranasal cocaine abuse can cause orbital complications from chronic sinonasal inflammatory disease and these patients are at risk to develop optic neuropathy. Optic neuropathy may be caused by compression, infiltration, or ischaemia. PMID- 28812906 TI - Recent Advances in Computed Tomography Imaging in Chronic Obstructive Pulmonary Disease. AB - Lung imaging is increasingly being used to diagnose, quantify, and phenotype chronic obstructive pulmonary disease (COPD). Although spirometry is the gold standard for the diagnosis of COPD and for severity staging, the role of computed tomography (CT) imaging has expanded in both clinical practice and research. COPD is a heterogeneous disease with considerable variability in clinical features, radiographic disease, progression, and outcomes. Recent studies have examined the utility of CT imaging in enhancing diagnostic certainty, improving phenotyping, predicting disease progression and prognostication, selecting patients for intervention, and also in furthering our understanding of the complex pathophysiology of this disease. Multiple CT metrics show promise for use as imaging biomarkers in COPD. PMID- 28812910 TI - Orbital cancer: A second cancer in exenterated patients. PMID- 28812911 TI - Isolated orbital mucoceles in the absence of obstructive sinus disease. AB - Orbital surgeons are quite familiar with the diagnosis and management of paranasal sinus mucoceles due their frequent involvement of the orbit. These benign masses form and expand following sinus outflow obstruction secondary to various causes including trauma, inflammation and malignancy, amongst others. The authors present two cases of isolated orbital mucoceles without associated sinus outflow obstruction. There were notably no connections between the paranasal sinuses and the lesions. The mucoceles were diagnosed following orbitotomies and excisional biopsies with confirmatory histopathology. These rare orbital lesions should be considered when evaluating cystic orbital lesions, and the orbital surgeon should be familiar with the proposed pathophysiology and treatment recommendations. PMID- 28812912 TI - A case of orbital dirofilariasis in New York. AB - A 39-year-old female presented with a 5-day history of left inferonasal periocular swelling and associated intermittent itching. Ophthalmologic examination demonstrated a 4 * 8 mm subcutaneous painless mass localized anterior to the medial left lower orbital rim. An excision of the mass was performed, and pathology revealed Dirofilaria. The patient improved over the 3 months of postoperative follow-up. Although several human cases of pulmonary dirofilariasis have been reported in the United States, periocular dirofilariasis has been rarely reported in the United States. The case report is in compliance with the Health Insurance Portability and Accountability Act. PMID- 28812913 TI - Transcanalicular laser-assisted dacryocystorhinostomy with diode laser. AB - This article compares the efficacy of transcanalicular laser assisted dacryocystorhinostomy (TL DCR) with conventional external dacryocystorhinostomy (Ex DCR). All patients were randomly divided into two groups - Group A included patients who underwent TL DCR and Group B included patients who underwent Ex DCR. 168 operations were done in a total of 163 patients; 79 patients in group A and 84 patients in group B. The overall success rate was 90.12% in group A and 95.40% in group B. The mean total surgical time was 17.41 min in group A and 49.49 min in group B. The duration of stay in hospital was about 3 hours for group A and about 48 hours for group B. Intra and post operative complications were more in group B than in group A. TL DCR can offer a minimally invasive technique with comparable results and better patient satisfaction than Ex DCR. PMID- 28812914 TI - Retrospective chart review of the use of imaging and biopsy in the diagnosis of optic nerve sheath meningiomas and intra-conal orbital lymphomas at a single institution. AB - Optic nerve sheath meningiomas (ONSM) and intra-conal orbital lymphomas are common entities on the differential of a retrobulbar optic nerve involving space occupying lesion. In this study, we compare the pre-surgical diagnosis, based on clinical presentation and neuroimaging, to the surgical pathology results of intra-conal orbital lymphomas and ONSM. This is an IRB approved retrospective chart review of orbital lymphomas and optic nerve sheath meningiomas biopsied by a single surgeon over a 4-year period at a single institution. Pre-surgical diagnosis and surgical pathology were compared. Fifteen cases of orbital lymphoma were identified. Fourteen were excluded based on extra-conal location. The single histologically confirmed intra-conal orbital lymphoma had a pre-surgical diagnosis of ONSM. Four cases of optic nerve sheath meningioma were identified. Three of the 4 cases of histologically confirmed ONSM had a pre-surgical diagnosis of ONSM. One of the 4 had a pre-surgical diagnosis of lymphoma. Diagnosis based on surgical pathology differed from the pre-surgical diagnosis in 2 out of 5 cases showing that clinical diagnosis does not always correlate with histologic diagnosis. Although both diseases are typically managed with radiation therapy, the treatment dosage and systemic disease implications are very different. These findings emphasis the importance of biopsy in the diagnosis of orbital lesions surrounding the optic nerve. PMID- 28812915 TI - Kardiovize Brno 2030, a prospective cardiovascular health study in Central Europe: Methods, baseline findings and future directions. AB - Background Atherosclerotic cardiovascular disease is highly prevalent in Eastern and Central Europe, where the incidence is the highest in the world. The Kardiovize Brno 2030 study was designed as a prospective cohort study to investigate the complex relationships of cardiovascular disease and outcomes with a range of biological, psychosocial, environmental, behavioral, and economic factors in an urban population of the Czech Republic. Methods We randomly selected a 1% sample of the city of Brno residents aged 25-64 years stratified by sex and age. The study assessed traditional and novel cardiovascular disease risk factors, including sociodemographic and smoking status, physical activity, diet, depression, stress, body fat, cardio-ankle vascular index, and intima media thickness, complemented by blood tests; biological samples were stored for future analyses. Results The study enrolled 2160 participants (54.8% women), with a mean age of 47 +/- 11.3 years. They were mostly full-time employed (75.6%) and married (62.1%). Hyperlipidemia was highly prevalent (70.7% in men, and 67.1% in women, NS). Hypertension and diabetes mellitus were more prevalent in men than in women (54.3% vs. 38.7% and 7.1% vs. 3.5%, respectively, P < 0.001 for both). A total of 25.3% of men and 21.9% of women smoked, whereas 20.0% and 43.0% of men and 18.1% and 26.6% of women were obese and overweight, respectively. Conclusions Cardiovascular risk factors are highly prevalent in the city of Brno, an urban population from Central Europe. The Kardiovize Brno 2030 study will provide unique multidimensional and longitudinal cardiovascular health data from a region where epidemiological studies are scarce. PMID- 28812916 TI - Strength and aerobic exercise training in coronary artery disease; it's not 'either-or'. PMID- 28812917 TI - Predictive role of CHA2DS2-VASc score for cardiovascular events and death in patients with arterial hypertension and stable sinus rhythm. AB - Background The CHA2DS2-VASc score well stratifies the risk for thromboembolic events in non-valvular atrial fibrillation (NVAF) patients. This score may also predict thromboembolic events in sinus rhythm populations. Purpose The purpose of this study was to assess the prognostic role of CHA2DS2-VASc in a Caucasian community population of patients with arterial hypertension and sinus rhythm. Methods A total of 12,599 arterial hypertension residents not receiving anticoagulation were selected from a community population in Trieste between November 2009 and October 2014: 11,159 sinus rhythm and 1440 NVAF patients. We considered thromboembolic events, cardiovascular hospitalisation and all-cause death in all patients divided according to CHA2DS2-VASc. Results Sinus rhythm patients were 74 (interquartile range 65-81) years old, 50% were women, 32% with CAD, mean CHA2DS2-VASc 3.68 +/- 1.47 points, significantly lower than NVAF patients (4.26 +/- 1.50, P < 0.001). After 37 months follow-up, an increasing CHA2DS2-VASc corresponded to a higher rate of thromboembolic events in sinus rhythm patients, ranging from 0% in patients with a score of 1 or 2 to 2.6% in those with a score of 6 or greater ( P < 0.0001). A similar trend was found in the reference NVAF group. At Cox multivariable analysis, CHA2DS2-VASc predicted thromboembolic events (hazard ratio (HR) 2.12), cardiovascular hospitalisation (HR 1.55) and all-cause death (HR 1.57). The predictive accuracy of CHA2DS2-VASc was similar in sinus rhythm and NVAF patients for thromboembolic events, cardiovascular hospitalisation and all-cause death (area under the curve statistic 0.76 vs. 0.76, 0.68 vs. 0.66, 0.64 vs. 0.64, respectively). Conclusions In a community population of Caucasian arterial hypertension patients in sinus rhythm, CHA2DS2-VASc rather well stratifies for adverse clinical events at mid term follow-up with a similar accuracy to NVAF patients. These results might be clinically relevant in this setting of sinus rhythm patients. PMID- 28812918 TI - Tyrosine kinase inhibitors for advanced or metastatic thyroid cancer: a meta analysis of randomized controlled trials. AB - BACKGROUND AND AIMS: Radioiodine-refractory advanced or metastatic thyroid cancer has poor prognosis. We conducted a meta-analysis of randomized controlled trials to evaluate the effectiveness and safety of tyrosine kinase inhibitors (TKIs) for advanced or metastatic thyroid cancer treatment. METHODS: Studies published up to April 2017 were selected. The pooled effect size was calculated through meta analysis by using random effects models. Outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (RR), and adverse events (AEs). RESULTS: Six studies examining 1615 patients were included. TKI treatment significantly improved PFS in patients with differentiated thyroid cancer (DTC; hazard ratio [HR] = 0.43; 95% confidence interval [CI], 0.23-0.82) and those with medullary thyroid cancer (MTC; HR = 0.36; 95% CI, 0.22-0.58). TKI treatment significantly prolonged OS in patients with DTC (HR = 0.74; 95% CI, 0.58-0.95). The TKI treatment group exhibited a significantly improved partial response rate (risk ratio = 15.8; 95% CI, 1.77-140.69) but a significantly higher number of AEs compared with the control group. CONCLUSION: TKIs significantly improved PFS and RR in patients with advanced or metastatic DTC or MTC. We recommend thoroughly evaluating patients' health status and cautiously using TKIs to maximize their benefits and minimize their toxicity. PMID- 28812919 TI - Comparison of primary and secondary enucleation for uveal melanoma. AB - We investigated operative course and post-operative findings of patients undergoing primary enucleation for uveal melanoma versus those requiring secondary enucleation after brachytherapy. A retrospective chart review was performed with IRB approval on patients receiving treatment for uveal melanoma. Patients with enucleation as initial treatment and patients enucleated after plaque brachytherapy were analyzed for demographic data, operative course, and post-enucleation outcome. Further cause analysis for secondary enucleations was investigated. No significant difference was seen in age, laterality, or gender between the primarily enucleated (n = 54) and secondarily enucleated (n = 34) groups. Greater difficulty with surgery was noted in 28/32 (87.5%) of secondary enucleations compared to 1/54 (1.8%) of primary enucleations (p < 0.0001). Operative time was >2 hours in 3/51 (6%) of primary enucleations (vs. 8 of 32, 25%, p = 0.02). Average implant size was similar in the 2 groups (20.6 mm), however 2/34 (6%) of secondary enucleations required dermis fat grafting. Post enucleation anophthalmic ptosis occurred after 8/49 (16%) of primary cases (vs. 13/30, 43%, p = 0.02) and prosthetic enophthalmos after none (0%) of primary cases (vs. 5/30, 17%, p = 0.006). Class 2 gene expression profile was found in 6/8 (60%) of eyes enucleated for treatment failure. Secondary enucleation performed after plaque brachytherapy was technically more difficult, and had more anophthalmic socket and eyelid complications compared to primary enucleation for uveal melanoma. Primary enucleation may avoid additional surgery and morbidity in a subset of patients with contraindications to plaque brachytherapy. PMID- 28812920 TI - Orbital myxoma comorbid with acute myelomonocytic leukemia. AB - We report the first case of orbital myxoma in a 10-year-old girl with a history of acute myelomonocytic leukemia diagnosed at the age of 10 months. She presented with a mass in the right orbit, which was excised completely. There was no recurrence during the 6 months of follow-up. PMID- 28812921 TI - A case of concurrent silent sinus syndrome, thyroid eye disease, idiopathic orbital inflammatory syndrome, and dacryoadenitis. AB - This is a retrospective case description of a single female patient found to have concomitant bilateral silent sinus syndrome, bilateral thyroid eye disease, unilateral dacryoadenitis, and idiopathic orbital inflammation that presented as progressive unilateral right-sided proptosis. The spectrum of inflammatory orbital diseases can make discerning between different entities challenging, but more unique in this case was the simultaneous presentation with bilateral silent sinus syndrome, a rare entity in its own right. Identifying each of these concurrent disease processes is important to establishing a multidisciplinary treatment approach to address all the patient's orbital and peri-orbital pathology. We hope to highlight the clinical and radiographic findings unique to each of these entities and share our approach to treatment in this complex case. PMID- 28812923 TI - The use of prophylactic Nunchaku stents to reduce the risk of nasolacrimal duct obstruction in patients with midfacial tumours undergoing radiotherapy. AB - The treatment of midfacial tumours with radiotherapy, chemotherapy and radio iodine can cause nasolacrimal duct fibrosis resulting in epiphora. Nasolacrimal patency can be maintained by stenting. We report our experience of prophylatic Nunchaku stent insertion in 5 patients prior to midfacial radiotherapy. Four out of 5 patients (80%) had patent nasolacrimal ducts without any symptoms of epiphora following removal of the stents. One patient was initially asymptomatic with patent nasolacrimal duct, but subsequently developed epiphora. Nunchaku stents may provide a simple and effective way of preventing epiphora, obviate the need for nasal retrieval that is required for other nasolacrimal stents, and reduce the risk of requiring further lacrimal surgery. PMID- 28812922 TI - A Circulating Micro-RNA Signature Serves as a Diagnostic and Prognostic Indicator in Sarcoidosis. AB - Micro-RNAs (miRNAs) act as post-transcriptional regulators of gene expression. In sarcoidosis, aberrant miRNA expression may enhance immune responses mounted against an unknown antigenic agent. We tested whether a distinct miRNA signature functions as a diagnostic biomarker and explored its role as an immune modulator in sarcoidosis. Expression of miRNAs from peripheral blood mononuclear cells from subjects that met clinical and histopathologic criteria for sarcoidosis were compared to those from matched controls in the ACCESS study. Signature miRNAs were determined by miRNA microarray analysis and validated by quantitative reverse transcription PCR (RT-qPCR). Microarray analysis identified 54 differentially expressed feature mature human miRNAs between groups. Significant feature miRNAs that distinguish sarcoidosis from controls were selected by use of probabilistic models adjusted for clinical variables. Eight signature miRNAs were chosen to verify the diagnosis of sarcoidosis in a validation cohort and distinguished sarcoidosis from controls with a positive predictive value of 88%. We identified both novel and previously described genes and molecular pathways associated with sarcoidosis as targets of these signature miRNAs. Additionally, we demonstrate that signature miRNAs (hsa-miR-150-3p and hsa-miR-342-5p) are significantly associated with reduced lymphocytes and airflow limitations, known markers of poor prognosis. Together, these findings suggest that a circulating miRNA signature serves as a non-invasive biomarker that supports the diagnosis of sarcoidosis. Future studies will test the miRNA signature as a prognostication tool associated with poor clinical outcomes in sarcoidosis. PMID- 28812925 TI - Medical Teacher in Ten Minutes. PMID- 28812924 TI - Susceptibility testing and reporting of new antibiotics with a focus on tedizolid: an international working group report. AB - Inappropriate use and overuse of antibiotics are among the most important factors in resistance development, and effective antibiotic stewardship measures are needed to optimize outcomes. Selection of appropriate antimicrobials relies on accurate and timely antimicrobial susceptibility testing. However, the availability of clinical breakpoints and in vitro susceptibility testing often lags behind regulatory approval by several years for new antimicrobials. A Working Group of clinical/medical microbiologists from Brazil, Canada, Mexico, Saudi Arabia, Russia and the UK recently examined issues surrounding antimicrobial susceptibility testing for novel antibiotics. While commercially available tests are being developed, potential surrogate antibiotics may be used as marker of susceptibility. Using tedizolid as an example of a new antibiotic, this special report makes recommendations to optimize routine susceptibility reporting. PMID- 28812926 TI - Top-rated AMEE MedEdPublish Papers - May to Mid-June 2017. PMID- 28812927 TI - A Community Health Advisor Program to Reduce Cancer Screening Disparities in the Deep South and Appalachia: The American Cancer Society's CHA Collaborative. AB - INTRODUCTION: Cancer disparities continue to exist in the United States. Community health advisors (CHAs) can play a critical role in addressing cancer disparities. The American Cancer Society (ACS) implemented a 3-year pilot CHA program in the South based on an evidence-based program to increase breast cancer screening. STUDY DESIGN: Evaluation assessed the extent to which ACS successfully implemented the program. Quantitative data were tracked and reported by ACS staff, and qualitative data were collected through focus groups and interviews with volunteer participants. SETTING/PARTICIPANTS: The pilot was implemented in 28 communities in nine states. ACS staff recruited volunteer community network partners (CNPs) as local advisory groups, and volunteer CHAs to conduct outreach, education, and screening navigation. MEASURES: Outcome measures included number of individuals educated and screened, and number of communities reaching education and screening targets. Process measures included number of volunteers recruited, number of communities reaching recruitment targets, and implementation process, challenges, and successes. RESULTS: A total of 383 CHAs were recruited and recruitment goals were met in 68%; 31,439 individuals were educated, and 93% of communities reached education goals. In all, 5,056 individuals were screened, but screening goals were attained in only 36% of communities. CONCLUSION: This pilot demonstrates the ability of ACS to adapt and disseminate an evidence-based program to fit into its volunteer-based outreach model. ACS built community network partnerships, recruited a cadre of volunteers, and trained them to conduct education and screening navigation. PMID- 28812928 TI - Health Education Careers in a Post-Health Reform Era. AB - Since enactment of the Patient Protection and Affordable Care Act in 2010, health education specialists (HES) have made important contributions in implementing the law's provisions at the individual, family, and population levels. Using their health education competencies and subcompetencies, HES are improving public understanding of health insurance literacy and enrollment options, conducting community health needs assessments required of nonprofit hospitals, modifying policies or systems to improve access to health screenings and preventive health services, strengthening clinical and community linkages, and working with employee benefit plans. In addition to educating stakeholders about their complementary training and roles with respect to clinical providers, HES must keep abreast of rapid changes catalyzed by the Affordable Care Act in terms of health standards, payment models, government regulations, statistics, and business practices. For continued career growth, HES must continually acquire new knowledge and skills, access and analyze data, and develop interprofessional partnerships that meet the evolving needs of employers as the nation pursues health for all. PMID- 28812929 TI - Message Received: African American Women and Breast Cancer Screening. AB - African American women are more likely than other women to be diagnosed with breast cancer at a young age, to be diagnosed at a late stage, and to die from the disease. Yet we see evidence of irregular screening and follow-up. Previous research on psychosocial factors influencing decisions to screen reveals barriers: fear, fatalistic perceptions of cancer, inaccurate perceptions of risk, and associations with stigma. The current qualitative research with, largely, insured African American women ( n = 26), health navigators ( n = 6), and community stakeholders ( n = 24) indicates both positive and negative factors influencing decision making. The women in our sample believe in the value of early detection and are motivated to screen in response to encouragement from health providers. However, they also report several factors that contribute to their decisions to delay or not screen. These include (1) perceptions that the health community itself is confused about the need for screening, (2) perceptions that White women are the priority population for breast cancer, (3) family roles that prohibit self-care and encourage secrecy, and (4) fear of diagnosis. Participants report not feeling included in national-level health promotion campaigns. It is argued that African American women, in particular, may benefit from more nuanced health information about their risk. PMID- 28812930 TI - Increasing Colorectal Cancer Screening at an Urban FQHC Using iFOBT and Patient Navigation. AB - INTRODUCTION: Colorectal cancer is the second leading cause of cancer death in the United States. Black Americans suffer even higher incidence and death rates than the general population. Genetics and patient perceptions explain some of this difference, however, modifiable health care system factors such as lack of access to colon cancer screening also contribute. Partnering an academic health center with local community groups, we piloted a colorectal cancer screening program at a Federally Qualified Health Center (FQHC) serving predominately low socioeconomic status Black Americans. The program was designed to identify and remove barriers to screening and improve screening rates. METHOD: At a single center FQHC, we developed an outreach program centered around (1) patient and provider education, (2) immunochemical fecal occult blood test (iFOBT) distribution, and (3) patient navigation. We identified 402 eligible patients, of which 228 (56.7%) completed screening. RESULTS: Our 56.7% screening rate represented a twofold increase above prepilot levels at the clinic. Nine (4%) iFOBT returned positive. Three of these nine patients completed colonoscopy. Screening rates and follow through were higher under a single navigator model. CONCLUSIONS: Our academic-community partnership provided an effective, evidence based, and sustainable model for increasing colorectal cancer screening in a high risk, low resource community. PMID- 28812931 TI - Advocacy and Public Policy Perceptions and Involvement of Master Certified Health Education Specialists. AB - Master Certified Health Education Specialists (MCHES; n = 186) participated in a mail survey on advocacy and public policy. Over half of participants reported that they had contacted a public official or provided policy-related information to consumers or other professionals. Participants identified barriers and benefits to influencing public policy. The greatest benefit was identified as improving the health or welfare of the public while the greatest barrier was that they were busy with other priorities. Participants also described their level of involvement, knowledge, training in advocacy, and their self-efficacy in performing various advocacy activities. Most MCHES reported voting and other basic advocacy functions while far fewer had participated in more advanced advocacy activities. Although nearly 73% had formal training on advocacy and policy, only 26% received it through college coursework. Factors predictive of advocacy and policy involvement were determined through a stepwise regression analysis. Five independent variables predicted the total number of advocacy activities and when combined accounted for nearly 61% of the variance. Government level health educators' misconception that they cannot participate in advocacy and public policy issues should be dispelled. Health education specialists with the MCHES credential need coursework and additional training on how to effectively influence public health policy. PMID- 28812933 TI - Use of bilayer matrix wound dressing in the exenterated socket. AB - To describe the novel use of a bilayer dermal substitute to reconstruct exenterated orbits. A retrospective chart review was performed in the practices of two surgeons (RET and PDL) of all patients who had undergone orbital exenteration between April 2014 and June 2016 and whose subsequent reconstruction included lining the socket with Integra bilayer. Patient demographics, pathologic diagnoses, surgical and post-operative complications, graft integrity, and patient acceptance were recorded. The charts of 7 patients (4 men and 3 women, ages 60-87 years) were reviewed. In all cases, the Integra graft had taken well to the socket bed at the time of silicone removal 3-4 weeks after surgery. Epithelialization of the socket occurred rapidly over the Integra graft (within several weeks) without incident in each case and with minimal postoperative management. No intraoperative or postoperative complications were noted. Integra dermal substitute is an ideal graft for the lining of an exenterated orbit. It is readily available in large quantities, handles easily, lines the socket smoothly, epithelializes rapidly, and requires minimal postoperative care. It offers minimal morbidity compared to skin grafting or free flap reconstruction, but greatly speeds epithelialization compared to laissez faire management. Surgeons should consider reconstructing exenterated orbits with the Integra matrix, both for its ease of use and its ability to epithelialize rapidly. PMID- 28812934 TI - Timing of surgical correction for the treatment of unilateral congenital ptosis: Effects on cosmetic and functional results. AB - The authors analyzed the cosmetic and functional results of a series of patients with unilateral congenital ptosis who underwent levator resection, to compare the outcome of surgery according to the age of intervention, and to evaluate the chance of ptosis recurrence in different age groups. Analysis of the clinical charts of 44 patients who underwent a unilateral levator muscle resection under the care of one surgeon from February 2000 to March 2012 was performed. Age at the time of surgery ranged from 2.1 to 12 years. The study population was divided into different groups according to the age of surgery. Preoperative evaluation included measurements of upper eyelid margin reflex distance (MRD1), levator function, frontalis function, and complete extraocular motility examination. This study adheres to the principles outlined in the Declaration of Helsinki. The patients' follow-up ranged between 2 and 12 years. The outcome of surgery was more satisfactory (MRD1 increase: p < 0.002) and the increase of levator function was better (p < 0.0001) when surgery was performed in children aged 2 to 4 years. No ptosis recurrence was observed in children aged 2 to 4 years, as opposed to 6 (22%) children of other groups (p = 0.067). Unilateral levator resection effectively reduces the asymmetry between eyelids. The age of the operation appears to influence the outcome of surgery, as in this series cosmetic and functional results are better and the rate of ptosis recurrence is lower if the child is operated on before the age of 4 years. PMID- 28812935 TI - Motivations for learning of family medicine residents trained in competency-based education. AB - BACKGROUND AND OBJECTIVE: Family physicians regularly encounter clinical uncertainty and ambiguity and thus, are expected to engage in on-going learning to respond to changing needs of family practice. Using Achievement Goal Theory, the objective of this study was to examine motivations for learning of family medicine residents in a competency-based program. METHOD: This was a cross sectional study, employing a survey methodology with family medicine residents at the mid-point of training at a Canadian university. Multivariate analyses of variance and covariance were used to examine residents' goal orientations (performance approach, mastery approach, performance avoidance, mastery avoidance) for the group as a whole and to test for the effects of residents' gender and program stream (urban/rural), respectively. RESULTS: A total of 52 (67%) residents completed the survey. Overall, residents scored highest on mastery approach and lowest on performance avoidance, thus, exhibiting adaptive motivations for learning. Male residents demonstrated higher levels of performance approach, performance avoidance, and mastery avoidance than female residents. No significant differences in goal orientations were found between urban and rural residents. CONCLUSIONS: Family medicine residents trained in the culture of competency-based education appear to be mastery approach oriented. This motivation orientation is critical in the dynamic practice of family medicine and is consistent with the life-long learning mandate of the medical profession. PMID- 28812932 TI - Celebrating wobble decoding: Half a century and still much is new. AB - A simple post-transcriptional modification of tRNA, deamination of adenosine to inosine at the first, or wobble, position of the anticodon, inspired Francis Crick's Wobble Hypothesis 50 years ago. Many more naturally-occurring modifications have been elucidated and continue to be discovered. The post transcriptional modifications of tRNA's anticodon domain are the most diverse and chemically complex of any RNA modifications. Their contribution with regards to chemistry, structure and dynamics reveal individual and combined effects on tRNA function in recognition of cognate and wobble codons. As forecast by the Modified Wobble Hypothesis 25 years ago, some individual modifications at tRNA's wobble position have evolved to restrict codon recognition whereas others expand the tRNA's ability to read as many as four synonymous codons. Here, we review tRNA wobble codon recognition using specific examples of simple and complex modification chemistries that alter tRNA function. Understanding natural modifications has inspired evolutionary insights and possible innovation in protein synthesis. PMID- 28812936 TI - Investigation of goldmann perimetry in evaluation of patients for upper eyelid blepharoplasty. AB - PURPOSE: To determine if preoperative Goldmann Visual Field (GVF) testing in patients with functional dermatochalasis accurately depicts the postoperative superior visual field (SVF) outcome. METHODS: A prospective cohort study was done to compare preoperative and postoperative GVF field tests in patients undergoing upper eyelid blepharoplasty for treatment of dermatochalasis. This study was conducted in accordance with the Declaration of Helsinki and approved by the University of Arkansas for Medical Sciences institutional review board. A preoperative GVF was obtained with the eyelids in the natural position (untaped) and then again with excess skin elevated (taped). One month post-blepharoplasty, another GVF was conducted with eyelids untaped. The pre- and post GVF tests were analyzed to determine if preoperative testing accurately predicts the SVF improvement post-blepharoplasty. RESULTS: Forty-six eyelids (23 patients) who underwent blepharoplasty for dermatochalasis were included. The preoperative testing underestimated 76% (35/46) of cases by a mean of 61%; and overestimated the final outcome in 24% (11/46) of cases by mean of 23%. Overall, the preoperative GVF testing underestimated the postoperative outcome by a mean of 35%. CONCLUSION: Improvement of the SVF after a blepharoplasty is typically greater than the preoperative GVF testing predicts. PMID- 28812937 TI - Genetic and Molecular Characterization of Leaf Rust Resistance in Two Durum Wheat Landraces. AB - Leaf rust, caused by Puccinia triticina, is a constraint to durum wheat (Triticum turgidum subsp. durum) production, and landraces are reported to be an important source of resistance. Two Portuguese landraces (Aus26582 and Aus26579) showed resistance against durum-specific P. triticina races and were crossed with a susceptible landrace (Bansi) to develop recombinant inbred line (RIL) populations. Monogenic segregation for leaf rust resistance was observed among both RIL populations. The underlying locus, temporarily named LrAW2, was mapped to the short arm of chromosome 6B in the Aus26582/Bansi population and five DArTseq markers cosegregated with LrAW2. Simple sequence repeat markers sun683 and sun684, developed from the chromosome survey sequence (CSS) contig 6BS_2963854, identified through BlastN search of cosegregating DArTseq markers in the International Wheat Genome Sequencing Consortium database, cosegregated with LrAW2. Comparison of the CSS contig 6BS_2963854-based sequences amplified from parental genotypes led to the development of marker sunKASP_60, which also showed close linkage with LrAW2. Markers sun684 and sunKASP_60 showed close association with LrAW2 in both RIL populations. The amplification of LrAW2-specific products by linked markers in Aus26582, Aus26579, and Guayacan (Lr61) indicated that LrAW2 may be Lr61. The alternate amplicon or haplotype produced with LrAW2-linked markers in Australian durum cultivars demonstrated their effectiveness in marker assisted selection. PMID- 28812938 TI - Unilateral optic perineuritis due to nonspecific orbital inflammation: A case report. AB - Nonspecific orbital inflammation is an idiopathic chronic tumor-like inflammation process that usually affects the orbital tissues of both eyes. Isolated optic nerve involvement by an idiopathic inflammatory process is a rare finding. Here, we report a patient with unilateral sudden onset severe orbital pain and headache with visual loss to no light perception that could only be attributed to perineuritis. Radiological findings enabled making the correct diagnosis. Various relevant diagnoses are also discussed. PMID- 28812939 TI - Removing dysfunctional mitochondria from axons independent of mitophagy under pathophysiological conditions. AB - Chronic mitochondrial dysfunction has been implicated in major neurodegenerative diseases. Long-term cumulative pathological stress leads to axonal accumulation of damaged mitochondria. Therefore, the early removal of defective mitochondria from axons constitutes a critical step of mitochondrial quality control. We recently investigated the axonal mitochondrial response to mild stress in wild type neurons and chronic mitochondrial defects in amyotrophic lateral sclerosis (ALS)- and Alzheimer disease (AD)-linked neurons. We demonstrated that remobilizing stressed mitochondria is critical for maintaining axonal mitochondrial integrity. The selective release of the mitochondrial anchoring protein SNPH (syntaphilin) from stressed mitochondria enhances their retrograde transport toward the soma before PARK2/Parkin-mediated mitophagy is activated. This SNPH-mediated response is robustly activated during the early disease stages of ALS-linked motor neurons and AD-related cortical neurons. Our study thus reveals a new mechanism for the maintenance of axonal mitochondrial integrity through SNPH-mediated coordination of mitochondrial stress and motility that is independent of mitophagy. PMID- 28812940 TI - Odontogenic orbital abscess with intracranial and pulmonary involvement. AB - A 58-year-old woman presented to the emergency department with left ptosis and complete ophthalmoplegia. Imaging demonstrated a left orbital abscess. Her past medical history included cavitatory lung disease and "aseptic" meningitis 2 months previously. An anaerobic organism and commensal of the oral flora, Peptostreptococcus sp., was cultured from the orbital abscess. The patient was found to have a carious upper molar with chronic buccal abscess, which was extracted. This case presents an uncommon pathogen arising from an odontogenic infection as the etiology for orbital abscess, cavitatory lung disease, and meningitis in one patient. PMID- 28812941 TI - Self-retaining magnetic implant: A novel design of orbital prosthesis for the exenterated orbit. AB - Orbital exenteration can lead to significant disfigurement causing considerable functional, cosmetic and psychological disturbances to the patient. Orbital prosthesis is important for the patient's cosmetic and psychological rehabilitation. A 49-year-old man received orbital exenteration and postoperative radiotherapy for malignant orbital carcinoma. In view of uncertain suitability and survival of osseointegrated implant in his case, a novel design of ocular implant consisting of a self-retaining magnetic spring retainer and a coupling silicone prosthesis was used. This novel design was shown to provide the patient with ease of use, good cosmetic outcome and better quality of life. PMID- 28812943 TI - Tear osmolarity is sensitive to exercise-induced fluid loss but is not associated with common hydration measures in a field setting. AB - : This investigation (i) examined changes in tear osmolarity in response to fluid loss that occurs with exercise in a field setting, and (ii) compared tear osmolarity with common field and laboratory hydration measures. Sixty-three participants [age 27.8 +/- 8.4 years, body mass 72.15 +/- 10.61 kg] completed a self-paced 10 km run outside on a predetermined course. Body mass, tear fluid, venous blood and urine samples were collected immediately before and after exercise. Significant (p < 0.001) reductions in body mass (1.71 +/- 0.44%) and increases in tear osmolarity (8 +/- 15 mOsm.L-1), plasma osmolality (7 +/- 8 mOsm.kg-1), and urine specific gravity (0.0014 +/- 0.0042 g.mL-1; p = 0.008) were observed following exercise. Pre- to post-exercise change in tear osmolarity was not significantly correlated (all p > 0.05) with plasma osmolality (rs = 0.24), urine osmolality (rs = 0.14), urine specific gravity (rs = 0.13) or relative body mass loss (r = 0.20). Tear osmolarity is responsive to exercise-induced fluid loss but does not correlate with the changes observed using other common measures of hydration status in the field setting. Practitioners shouldn't directly compare or replace other common hydration measures with tear osmolarity in the field. ABBREVIATIONS: BML: Body Mass Loss; CV: Coefficient of Variation; Posm: Plasma osmolality; SD: Standard Deviation; Tosm: Tear Osmolarity; Uosm: Urine Osmolality; USG: Urine Specific Gravity; WBGT: Wet bulb globe thermometer. PMID- 28812942 TI - Acute hypertensive response in patients with intracerebral hemorrhage pathophysiology and treatment. AB - Acute hypertensive response is a common systemic response to occurrence of intracerebral hemorrhage which has gained unique prominence due to high prevalence and association with hematoma expansion and increased mortality. Presumably, the higher systemic blood pressure predisposes to continued intraparenchymal hemorrhage by transmission of higher pressure to the damaged small arteries and may interact with hemostatic and inflammatory pathways. Therefore, intensive reduction of systolic blood pressure has been evaluated in several clinical trials as a strategy to reduce hematoma expansion and subsequent death and disability. These trials have demonstrated either a small magnitude benefit (second intensive blood pressure reduction in acute cerebral hemorrhage trial and efficacy of nitric oxide in stroke trial) or no benefit (antihypertensive treatment of acute cerebral hemorrhage 2 trial) with intensive systolic blood pressure reduction compared with modest or standard blood pressure reduction. The differences may be explained by the variation in intensity of systolic blood pressure reduction between trials. A treatment threshold of systolic blood pressure of >=180 mm with the target goal of systolic blood pressure reduction to values between 130 and 150 mm Hg within 6 h of symptom onset may be best supported by current evidence. PMID- 28812944 TI - Binding forces between a novel Schiff base palladium(II) complex and two carrier proteins: human serum albumi and beta-lactoglobulin. AB - Ligand binding studies on carrier proteins are crucial in determining the pharmacological properties of drug candidates. Here, a new palladium(II) complex was synthesized and characterized. The in vitro binding studies of this complex with two carrier proteins, human serum albumin (HSA), and beta-lactoglobulin (betaLG) were investigated by employing biophysical techniques as well as computational modeling. The experimental results showed that the Pd(II) complex interacted with two carrier proteins with moderate binding affinity (Kb ~ .5 * 104 M-1 for HSA and .2 * 103 M-1 for betaLG). Binding of Pd(II) complex to HSA and betaLG caused strong fluorescence quenching of both proteins through static quenching mechanism. In two studied systems hydrogen bonds and van der Waals forces were the major stabilizing forces in the drug-protein complex formation. UV-Visible and FT-IR measurements indicated that the binding of above complex to HSA and betaLG may induce conformational and micro-environmental changes of two proteins. Protein-ligand docking analysis confirmed that the Pd(II) complex binds to residues located in the subdomain IIA of HSA and site A of betaLG. All these experimental and computational results suggest that betaLG and HSA might act as carrier protein for Pd(II) complex to deliver it to the target molecules. PMID- 28812945 TI - Phase of Illness in palliative care: Cross-sectional analysis of clinical data from community, hospital and hospice patients. AB - BACKGROUND: Phase of Illness describes stages of advanced illness according to care needs of the individual, family and suitability of care plan. There is limited evidence on its association with other measures of symptoms, and health related needs, in palliative care. AIMS: The aims of the study are as follows. (1) Describe function, pain, other physical problems, psycho-spiritual problems and family and carer support needs by Phase of Illness. (2) Consider strength of associations between these measures and Phase of Illness. DESIGN AND SETTING: Secondary analysis of patient-level data; a total of 1317 patients in three settings. Function measured using Australia-modified Karnofsky Performance Scale. Pain, other physical problems, psycho-spiritual problems and family and carer support needs measured using items on Palliative Care Problem Severity Scale. RESULTS: Australia-modified Karnofsky Performance Scale and Palliative Care Problem Severity Scale items varied significantly by Phase of Illness. Mean function was highest in stable phase (65.9, 95% confidence interval = 63.4-68.3) and lowest in dying phase (16.6, 95% confidence interval = 15.3-17.8). Mean pain was highest in unstable phase (1.43, 95% confidence interval = 1.36-1.51). Multinomial regression: psycho-spiritual problems were not associated with Phase of Illness ( chi2 = 2.940, df = 3, p = 0.401). Family and carer support needs were greater in deteriorating phase than unstable phase (odds ratio (deteriorating vs unstable) = 1.23, 95% confidence interval = 1.01-1.49). Forty nine percent of the variance in Phase of Illness is explained by Australia modified Karnofsky Performance Scale and Palliative Care Problem Severity Scale. CONCLUSION: Phase of Illness has value as a clinical measure of overall palliative need, capturing additional information beyond Australia-modified Karnofsky Performance Scale and Palliative Care Problem Severity Scale. Lack of significant association between psycho-spiritual problems and Phase of Illness warrants further investigation. PMID- 28812946 TI - Nurse researchers' perspectives on research ethics in China. AB - BACKGROUND: In China, research ethics is a subject of increasingly formal regulation. However, little is known about how nursing researchers understand the concept of research ethics and the ways in which they can maintain ethical standards in their work. AIM: The aim of this study is to examine nursing researchers' perspectives on research ethics in China. RESEARCH DESIGN: We conducted a descriptive qualitative study. Qualitative research methods enabled us to gain an in-depth understanding of nursing researchers' views on research ethics. Participants and research context: We carefully selected and extensively interviewed 28 nursing researchers, nursing faculty, and clinical nurses who had been involved in research or who may undertake research in the future. We collected data between October 2014 and March 2015. Ethical considerations: This study was approved by the institutional review boards of Yale University and Central South University. FINDINGS: We grouped the data into five categories based on the interviewees' responses: (1) perceptions of ethics, bioethics, and research ethics; (2) perception of the ethics review process; (3) perception of the function of institutional review boards; (4) the need for comprehensive ethical guidelines for future studies; and (5) ethical challenges faced by the interviewees. DISCUSSION AND CONCLUSION: This study contributes new insights into nursing researchers' views on research ethics in China and finds considerable shortcomings in researchers' understanding and implementation of ethical principles. Intensive educational efforts are needed to provide nursing researchers, institutional review board members, and even study subjects with accurate and up-to-date information and guidance on research ethics. In addition, while Western research ethics theoretically have guided Chinese clinical research for several years, the ways in which nursing researchers have implemented these ethical standards highlight the differences between the Eastern and Western ethical paradigms. This finding suggests the need for ethical standards that are more tailored to the Chinese context. PMID- 28812947 TI - A concept analysis of professional commitment in nursing. AB - BACKGROUND: The concept of professional commitment is being widely studied at present. However, although it is considered an indicator for the most human part of nursing care, there is no clear definition for it, and different descriptors are being used indiscriminately to reference it. OBJECTIVE: The aim of this study is to clarify the concept of professional commitment in nursing through the Rodgers' evolutionary concept analysis process. DESIGN: Systematic search using English and Spanish descriptors and concept analysis. Studies published between 2009 and June 2015, front-to-back analysis of the Nursing Ethics journal and manual check of articles cited in studies related to the Nijmegen Professionalism Scale. RESEARCH DESIGN: The procedure of concept analysis developed by Rodgers was used. Ethical considerations: Although the topic was not labeled as sensitive and subject to ethical approval, its realization was approved by the Ethical Committee of Clinical Research of Aragon (CEICA) approved the study on 18 March 2015 and also careful procedures have been followed according to ethics expressed in the Declaration of Helsinki. FINDINGS AND DISCUSSION: A total of 17 published studies. A clear definition of the concept was made, and surrogate terms, concept dimension, differential factors related to the concept, sociocultural variations and consequences for nursing practice were identified. CONCLUSION: There is a need for continuous advancement in the development of the concept, specific actions to encourage this and the improvement of evaluation methods for its study. PMID- 28812948 TI - Age-Related Resistance in Arabidopsis thaliana Involves the MADS-Domain Transcription Factor SHORT VEGETATIVE PHASE and Direct Action of Salicylic Acid on Pseudomonas syringae. AB - Arabidopsis thaliana exhibits a developmentally regulated disease-resistance response known as age-related resistance (ARR), a process that requires intercellular accumulation of salicylic acid (SA), which is thought to act as an antimicrobial agent. ARR is characterized by enhanced resistance to some pathogens at the late adult-vegetative and reproductive stages. While the transition to flowering does not cause the onset of ARR, both processes involve the MADS-domain transcription factor SHORT VEGETATIVE PHASE (SVP). In this study, ARR-defective svp mutants were found to accumulate reduced levels of intercellular SA compared with wild type in response to Pseudomonas syringae pv. tomato. Double mutant and overexpression analyses suggest that SVP and SOC1 (SUPPRESSOR OF OVEREXPRESSION OF CO 1) act antagonistically, such that SVP is required for ARR to alleviate the negative effects of SOC1 on SA accumulation. In vitro, SA exhibited antibacterial and antibiofilm activity at concentrations similar to those measured in the intercellular space during ARR. In vivo, P. syringae pv. tomato formed biofilm-like aggregates in young susceptible plants, while this was drastically reduced in mature ARR-competent plants, which accumulate intercellular SA. Collectively, these results reveal a novel role for the floral regulators SVP and SOC1 in disease resistance and provide evidence that SA acts directly on pathogens as an antimicrobial agent. [Formula: see text] Copyright (c) 2017 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license . PMID- 28812949 TI - 'I'm sure we made it a better study...': Experiences of adults with intellectual disabilities and parent carers of patient and public involvement in a health research study. AB - Patient and public involvement is considered integral to health research in the United Kingdom; however, studies documenting the involvement of adults with intellectual disabilities and parent carers in health research studies are scarce. Through group interviews, this study explored the perspectives and experiences of a group of adults with intellectual disabilities and a group of parent carers about their collaborative/participatory involvement in a 3-year study which explored the effectiveness of annual health checks for adults with intellectual disabilities. Thematic analysis identified five key themes consistent across both groups; authenticity of participation, working together, generating new outcome measures, dissemination of findings and involvement in future research. Although reported anecdotally rather than originating from the analysis, increased self-confidence is also discussed. The groups' unique perspectives led to insights not previously considered by the research team which led to important recommendations to inform healthcare practice. PMID- 28812950 TI - Expression of cytochrome P450 regulators in cynomolgus macaque. AB - 1. Cytochrome P450 (P450) regulators including nuclear receptors and transcription factors have not been fully investigated in cynomolgus macaques, an important species used in drug metabolism studies. In this study, we analyzed 17 P450 regulators by sequence and phylogenetic analysis, and tissue expression. 2. Gene and genome structures of 17 P450 regulators were similar to the human orthologs, and the deduced amino acid sequences showed high sequence identities (92-95%) and more closely clustered in a phylogenetic tree, with the human orthologs. 3. Many of the P450 regulator mRNAs were preferentially expressed in the liver, kidney, and/or jejunum. Among the P450 regulator mRNAs, PXR was most abundant in the liver and jejunum, and HNF4alpha in the kidney. In the liver, the expression of most P450 regulator mRNAs did not show significant differential expression (>2.5-fold) between cynomolgus macaques bred in Cambodia, China, and Indonesia, or rhesus macaques. 4. By correlation analysis, most of the P450 regulators were significantly (p < 0.05) correlated to other P450 regulators, and many of them were also significantly (p < 0.05) correlated with P450s. 5. These results suggest that 17 P450 regulators of cynomolgus macaques had similar molecular characteristics to the human orthologs. PMID- 28812951 TI - Evolution of a Profession: The Role of Accreditation in Lactation Education. PMID- 28812952 TI - Impact of Adult Attachment Anxiety on Deception Judgments: Examining the Moderating Effect of Motivation. AB - Several psychologists have paid attention to individual differences in deception detection, but only a few studies have found significant results. The present study aimed to explore the relationship between attachment anxiety and deception judgment when there are no obvious cues to distinguish lies from truth, and to examine the moderating effect of motives. Participants were instructed to judge each of 10 audios on whether they were true or false. Subsequently, the attachment anxiety of participants was assessed using the Experiences in Close Relationships questionnaire. Results revealed that, compared with people who had low attachment anxiety, those with high attachment anxiety tend to have higher truth biases in the low-motive condition and lower accuracy in the high-motive condition. PMID- 28812953 TI - Workplace Bullying and Turnover Intention: Exploring Work Engagement as a Potential Mediator. AB - Employees' turnover intentions may entail expensive consequences for companies. The study examined the mediating effect of work engagement in the relationship between workplace bullying and turnover intention. Using a cross-sectional sample of 373 employees, structural equation modeling and mediation analysis showed that perceptions of work- and person-related bullying were linked to low levels of vigor and dedication which in turn were associated with high turnover intention. Work engagement partially mediated the effect of high workplace bullying on high turnover intention. The results were interpreted from a social cognitive perspective and recommendations for practice were made. PMID- 28812954 TI - Mesenchymal chondrosarcoma of the orbit: A case report with 5 years of follow-up. AB - Mesenchymal chondrosarcoma is a rare orbital tumor. Several case reports of this rare tumor have been published in the literature but only 6 cases have documented a follow up of 5 years or more. We report a case of 28 year-old female who presented with left orbital mass. Computed Tomography (CT) revealed a lobulated mass in the superior extraconal space with dense intralesional calcification. Patient underwent complete resection of the mass and histopathology was suggestive of mesenchymal chondrosarcoma. He was given adjuvant radiotherapy and there was no recurrence or metastasis at 5 years of follow-up. The case highlights that a complete resection with adjuvant radiotherapy in cases of orbital mesenchymal chondrosarcoma offers excellent prognosis. PMID- 28812956 TI - Toxicity identification and evaluation for the effluent from a nonmetallic mineral mining facility in Korea using D. magna. AB - Industrial wastewater has attracted increasing attention in recent years because of its impact on ecosystems and human health. Whole-effluent tests are generally used to monitor toxicities of unknown chemicals and conventional pollutants from industrial effluent discharges. This study described identification evaluation (TIE) procedures to determine the acute toxicity of a nonmetallic mineral mining facility effluent that was toxic to Daphnia magna. In the characterization step (TIE phase I), toxic effects of heavy metals, organic compounds, oxidants, volatile organic compounds, suspended solids, and ammonia were screened. Results revealed that the source of toxicity was beyond these toxicants. Chemical analysis (TIE phase II) of total dissolved solid showed that the concentration of chloride ion (15,302.5 mg/L) was substantially higher than the predicted EC50 value for D. magna. Chemical analysis for heavy metal and ionic materials used ion chromatography and induced coupled plasma-optic emission spectroscopy. In the confirmation step (TIE phase III), using spiking and deletion approaches, it was demonstrated that chloride ion was the main toxicant in this effluent. Concentrations of potassium (317.5 mg/L), magnesium (970.5 mg/L), sodium (8595.3 mg/L), and sulfate (2854.3 mg/L) were not high enough to cause toxicity to D. magna. Finally, we concluded that chloride was the main toxicant in the nonmetallic mineral mining facility effluent. Based on these results, advanced treatment processes such as ion exchange and reverse osmosis technology are recommended to treat wastewater in this and similar situations. Further research is needed to provide technical support for toxin identification and evaluation of various types of wastewater treatment plant discharge. PMID- 28812957 TI - Examining gender bias in the feedback shared with family medicine residents. AB - OBJECTIVES: Competency-based education places increasing emphasis on formative feedback to learners as part of the assessment process. We wished to determine if gender bias was present in the feedback shared with post-graduate medical trainees (residents) in a two-year family medicine residency program at a Canadian university. METHODS: We performed secondary data analyses of documented feedback (FieldNotes) extracted from the Competency-Based Achievement System database. Between 2012 and 2016, 464 preceptors (188 female (F); 276 male (M)) wrote in total 7316 FieldNotes for 192 residents (104 F; 88 M), forming four gender dyads. Descriptive statistics were used to examine trends in FieldNotes frequencies, competencies (Sentinel Habits; SH), progress levels (PL), and the use of adjectives (agentic/competency-based; communal/warmth-based) by preceptors in the FieldNotes. RESULTS: Male and female preceptors wrote on average 7 and 14 FieldNotes, respectively. Female residents received on average more feedback comments from female preceptors (7 notes) than from male preceptors (4 notes). The M-M and M-F resident-preceptor dyads had, respectively, the least and the most 'Stop, Important correction' FieldNotes in both the PGY1 and PGY2 groups. Although preceptors used agentic adjectives more frequently than communal adjectives overall, the F-M resident-preceptor dyad contained the highest proportion of communal adjectives and the lowest proportion of agentic adjectives. CONCLUSIONS: Residents would benefit from multiple opportunities for feedback from both male and female preceptors throughout their residency training. Faculty development to bring attention to potential gender bias may be useful to ensure equitable teaching and quality feedback for learners. PMID- 28812955 TI - IgG cooperativity - Is there allostery? Implications for antibody functions and therapeutic antibody development. AB - A central dogma in immunology is that an antibody's in vivo functionality is mediated by 2 independent events: antigen binding by the variable (V) region, followed by effector activation by the constant (C) region. However, this view has recently been challenged by reports suggesting allostery exists between the 2 regions, triggered by conformational changes or configurational differences. The possibility of allosteric signals propagating through the IgG domains complicates our understanding of the antibody structure-function relationship, and challenges the current subclass selection process in therapeutic antibody design. Here we review the types of cooperativity in IgG molecules by examining evidence for and against allosteric cooperativity in both Fab and Fc domains and the characteristics of associative cooperativity in effector system activation. We investigate the origin and the mechanism of allostery with an emphasis on the C region-mediated effects on both V and C region interactions, and discuss its implications in biological functions. While available research does not support the existence of antigen-induced conformational allosteric cooperativity in IgGs, there is substantial evidence for configurational allostery due to glycosylation and sequence variations. PMID- 28812958 TI - A Microcosting Study of Establishing a Baby Cafe(r) in Texas. AB - BACKGROUND: This article focuses on the costs of opening and running a Baby Cafe. A Baby Cafe is an intervention that focuses on providing peer-to-peer support for breastfeeding mothers. Research aim: This study aimed to estimate the costs of establishing and running a Baby Cafe. METHODS: The authors used a microcosting approach to identifying costs using the case of a Baby Cafe located in San Antonio, Texas, and modeled after other existing cafes in the United States. They also used extensive literature review and conducted an informal interview with a manager of an existing Baby Cafe in the United States to validate our cost data. The cost analysis was done from the provider perspective. RESULTS: Costs of starting a Baby Cafe were $36,000, whereas annual operating costs totaled $47,000. Total discounted costs for a 5-year period amounted to $250,000, resulting in a cost per Baby Cafe session of $521 and cost per mother of $104. Varying the number of sessions per week and number of mothers attending each session, the discounted cost per Baby Cafe session ranged between $460 and $740 and the cost per mother varied between $65 and $246. CONCLUSION: These findings can be used by policy makers and organizations to evaluate local resource requirements for starting a Baby Cafe. Further research is needed to evaluate the effectiveness of this intervention against other breastfeeding promoting initiatives. PMID- 28812961 TI - Community managed services for persons with intellectual disability: Andhra Pradesh experience. AB - In resource poor settings innovative and bottom-up approaches are required to provide services to people with with disabilities. In this context, the present paper explains a community-based model of manpower development and coordination of services for people with intellectual disabilities in unified state of Andhra Pradesh in India. Women with disabilities from the village were identified, and those willing to be trained to work as community resource persons (CRPs) were selected and given hands-on training in a phased manner. A total of 130 women were trained in five groups of 25-30 per group and were deployed in the community to screen, identify and refer children with intellectual disabilities. The training content included basic stimulation and interface with functionaries of other government departments of health, education and welfare to ensure comprehensive service delivery. Neighbourhood centres (NHCs) were established where the CRPs could meet with families collectively. The results indicated that the CRPs were welcomed by the families. The NHCs established primarily as recreation centres, promoted inclusion and functioned as information dissemination centre. The services provided by the CRPs were owned and monitored by the Women's self-help group and the disability groups thus ensuring sustainability of the model. PMID- 28812959 TI - Periocular manifestations of trigeminal trophic syndrome: A case series and literature review. AB - Trigeminal trophic syndrome (TTS) is a condition whereby persistent facial ulceration presents consequent to central or peripheral insult to the trigeminal nerve. Lesions are created by repetitive self-inflicted manipulation and trauma of dysaesthetic skin within the trigeminal dermatome. We discuss four cases with aetiologies varied from presumed microvascular compromise to resection of cerebral meningioma, cerebrovascular accident, and herpes zoster ophthalmicus. We discuss the management of the under-recognised associated periocular skin ulcerations that result from physical manipulation of dysesthic skin and prove to be persistent and challenging to treat. Patient education and counselling are crucial in understanding and preventing the detrimental effect of physical manipulation of the skin. Occlusive dressings can reduce recurrent trauma. Topical lubricants, antibiotics, or autologous serum may be needed in cases with corneal involvement or exposure. Surgical interventions may be used, but frequently fail if the underlying neurological pathology and skin manipulation has not been adequately addressed. TTS should be suspected in persistent or recurrent facial ulceration with concomitant anaesthesia and paraesthesia in the trigeminal distribution, with alar nasi involvement being a key feature. PMID- 28812963 TI - Service delivery models for people with intellectual disabilities in low and middle income countries: Strategies and solutions can emerge from within. PMID- 28812964 TI - The National Trust: A viable model of care for adults with intellectual disabilities in India. AB - The longevity of people with intellectual disabilities is increasing in developing nations. However, developing nations lack a proper system of care for aging persons with intellectual disabilities. Until now the care has been provided by parents and relatives in the home environment in developing countries, but this scenario is also changing; therefore, there is a strong need to explore a plan of care for this population which is also feasible and replicable. The National Trust is an autonomous body of the Government of India which has developed a comprehensive plan of care for adults with intellectual disabilities. In this article, the National Trust is discussed using a socioecological model. The replicability and suitability of this model for other developing countries are discussed. PMID- 28812965 TI - Meeting the communication support needs of children and young people with intellectual disabilities in the Bolivian Andes. AB - Services available for people with disabilities in Bolivia tend to be fragmented and costly. Children and adults with intellectual disabilities are more likely to have a related communication disability and are thus both literally and metaphorically excluded from having a voice. The following research aimed to explore the experiences of accessing services by people with communication disabilities in Bolivia through semi-structured interviews and one focus group carried out with family members, professionals, service providers, educators and policymakers. It aimed to establish the nature of current services in Bolivia where knowledge, information and resources are scarce. Findings indicated the need to consider an alternative to a medical model approach through a focus on empowering other stakeholders to participate more fully in meeting communication support needs. Conclusions plot ideas for future service delivery and emphasize the central power of sharing practical and expert knowledge. PMID- 28812966 TI - A snapshot of intellectual disabilities in Lao PDR: Challenges for the development of services. AB - Lao People's Democratic Republic (PDR) has experienced significant economic growth in the last two decades. While access to education, health, and employment for people with disabilities has also improved markedly, people with intellectual disabilities are still among the most vulnerable in society. This article presents findings from a screening survey of 2469 participants, a focus group discussion with key stakeholders in intellectual disabilities, and a case study of the Association for Autism. The screening survey suggests 1.9% of working age participants (18-59) and 0.7% of children (6-17) have intellectual disabilities. The qualitative data illustrate poor understanding and stigmatization of people with intellectual disabilities, lack of services, and development of a parent association to improve the life prospects for children with autism and intellectual disabilities. People with intellectual disabilities in Lao PDR remain particularly vulnerable. Parents and other disability advocates are raising awareness and demonstrating the effectiveness of specialized services. PMID- 28812967 TI - Tanshinone-induced ERs suppresses IGFII activation to alleviate Ang II-mediated cardiac hypertrophy. AB - Cardiomyopathy involves changes in myocardial ultrastructure and cardiac hypertrophy. Angiotensin II (AngII) has previously been shown to stimulate the expression of IGF-2 and IGF-2R in H9c2 cardiomyoblasts and increase of blood pressure, and cardiac hypertrophy. Estrogen receptors (ERs) exert protective effects, such as anti-hypertrophy in cadiomyocytes. Tanshinone IIA (TSN), a main active ingredient from a Chinese medical herb, Salvia miltiorrhiza Bunge (Danshen), was shown to protect cardiomyocytes hypertrophy by different stress signals. We aimed to investigate whether TSN protected H9c2 cardiomyocytes from AngII-induced activation of IGF-2R pathway and hypertrophy by mediating through ERs. AngII resulted in H9c2 cardiomyoblast hypertrophy and increased inflammatory molecular markers. These were down-regulated by TSN via estrogen receptors. AngII resulted in elevation in MAPKs, IGF-2R and hypertrophic protein markers. These, again, were reduced by addition of the phytoestrogen with activation of ERs. Finally, AngII induced phosphorylation of heat shock factor-1 (HSF1) and decreased sirtuin-1 (SIRT1). In addition, AngII also caused an increase in distribution of IGF-2R molecules on cell membrane. In contrast, TSN reduced HSF1 phosphorylation and cell surface IGF-2R while elevating SIRT1 via ERs. TSN was capable of attenuating AngII-induced IGF-2R pathway and hypertrophy through ERs in H9c2 cardiomyoblast cells. PMID- 28812968 TI - JNK pathway in osteoarthritis: pathological and therapeutic aspects. AB - CONTEXT: Osteoarthritis (OA) is a common chronic degenerative joint disease resulting in physical disability and reduced quality of life. Different biochemical signaling pathways are involved in the progression of OA, including the c-Jun NH2-terminal kinase (JNK) signal transduction pathway. OBJECTIVE: In this study, we have reviewed the recent updates on the association of JNK pathway with OA. METHODS: In this review, we have explored the databases like PubMed, Google Scholar, Medline, Scopus, etc., and collected the most relevant papers of JNK signaling pathway involved in the pathogenesis and therapeutics of OA Results: JNK has been shown by scientific studies to be activated (phosphorylated) in OA that can play a key role in the cartilage destruction. Activation of JNK causes the phosphorylation of c-Jun that causes decreased proteoglycan synthesis and enhanced production of matrix metalloproteinase 13 (MMP-13). Overproduction of MMP-13 by chondrocytes plays a central role in cartilage degeneration in OA. Thus, targeting JNK pathway might be a promising therapeutic application for the prevention and treatment of OA. A number of JNK inhibitors have been used in vitro and in vivo studies; however, not yet been translated into human use. CONCLUSIONS: This review study indicates that JNK pathway plays an important role in development and progression of OA, and targeting the JNK pathway might be a potential approach for the treatment of OA in future. PMID- 28812969 TI - Functional expression of BMP7 receptors in oral epithelial cells. Interleukin-17F production in response to BMP7. AB - BACKGROUND: Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta (TGF-beta) superfamily. Recently, BMP7 has been demonstrated to be produced by salivary glands and contribute to embryonic branching in mice. The BMP7 in saliva is thought to be delivered to the oral cavity and is expected to contact with stratified squamous epithelial cells which line the surface of oral mucosa. In this study, we attempted to investigate the effects of BMP7 on oral epithelial cells. METHODS: The expression of BMP receptors was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). OSCCs were stimulated with human recombinant BMP7 (hrBMP7) and the phosphorylation status of Smad1/5/8 was examined by western blotting. For microarray analysis, Ca9-22 cells were stimulated with 100 ng/mL of hrBMP7 and total RNA was extracted and subjected to real-time PCR. The 5'-untranslated region (5'-UTR) of IL-17 F gene was cloned to pGL4-basic vector and used for luciferase assay. Ca9-22 cells were pre-incubated with DM3189, a specific inhibitor of Smad1/5/8, for inhibition assay. RESULTS: All isoforms of type I and type II BMP receptors were expressed in both Ca9-22 and HSC3 cells and BMP7 stimulation resulted in the phosphorylation of Smad1/5/8 in both cell lines. The microarray analysis revealed the induction of interleukin 17 F (IL-17 F), netrin G2 (NTNG2) and hyaluronan synthase 1 (HAS1). Luciferase assay using the 5'-UTR of the IL-17 F gene revealed transcriptional regulation. Induced IL-17 F production was further confirmed at the protein level by ELISA. Smad1/5/8 inhibitor pretreatment decreased IL-17 F expression levels in the cells. PMID- 28812970 TI - Indole-3-carbinol induces G1 cell cycle arrest and apoptosis through aryl hydrocarbon receptor in THP-1 monocytic cell line. AB - OBJECTIVES: The role of aryl hydrocarbon receptor (AhR) in carcinogenesis has been studied recently. Indole-3-carbinol (I3C) is an AhR agonist and a potential anticancer agent. Here, we investigated the effects of I3C on cell cycle progression and apoptosis through activation of AhR on THP-1 acute myeloid leukemia (AML) cell line. METHODS: MTT viability assay was used to measure the cytotoxic effects of I3C on THP-1 cells. Apoptosis and cell cycle assays were investigated using flow cytometry. Real time RT-PCR was conducted to measure the alterations in the expression of AhR gene, key genes associated with AhR activation (IL1beta and CYP1A1) and major genes involved in cell cycle regulation and apoptosis including P27, P21, CDK2, P53, BCL2 and FasR. RESULTS: Our findings revealed that I3C inhibits the proliferation of THP-1 cells in a dose- and time dependent manner with minimal toxicity over normal monocytes. The AhR target genes (CYP1A1, IL1beta) were overexpressed upon I3C treatment (p < .05 to p < .001). The antiproliferative effects of I3C were in association with programed cell death. I3C downregulated BCL2 and upregulated FasR in THP-1 cells (p < .05 to p < .001). G1 cell cycle arrest was also observed using flow cytometry. G1 acting cell cycle genes (P21, P27 and P53) were overexpressed (p < .05 to p < .001), while CDK2 was downregulated upon I3C treatment (p < .01 to p < .001). CONCLUSIONS: I3C could exert its antileukemic effects through AhR activation which is associated with programed cell death and G1 cell cycle arrest in a dose- and time-dependent manner. Therefore, AhR could be targeted as a novel treatment possibility in AML. PMID- 28812971 TI - Novel Treatments for Airway Disease. PMID- 28812972 TI - Barbershop Prostate Cancer Education: Factors Associated With Client Knowledge. AB - The purpose of this paper is to identify characteristics of Black barbershop clients and barbers in an urban Midwestern city participating in a health promotion program called Affecting Cancer Together (ACT) that are associated with client knowledge about prostate cancer. Statistical analyses examined client and barber characteristics for their potential association with client prostate cancer knowledge, while controlling for ACT variables. Study findings suggested clients who are married (beta = 0.99; CI [0.38, 1.59]; p < .01) and have higher levels of education (beta = 0.34; CI [0.01, 0.67]; p = .04) may be more likely to know more about prostate cancer. Barbers with at least "some college" education may be more effective in increasing client knowledge (beta = 0.85; CI [0.05, 1.64]; p = .04). Trained peer-helper programs may consider prioritizing limited educational resources for barbers with at least some college education and incorporating the social support of spouses for making informed decisions. Considering the potential of barbershop programs to reach Black men about a serious racially disproportionate health issue, ameliorating adoption, implementation, effectiveness, and sustainment are an important public health priority for underserved populations. PMID- 28812973 TI - Parent-adolescent attachment and procrastination: The mediating role of self worth. AB - Within the theoretical framework of attachment theory, the author examined associations between adolescents' procrastination and their attachment relationships with both mothers and fathers, and explored the potential mediation role of self-worth in these associations. Participants were 384 Chinese adolescents (49.6% boys, average age 15.13 years) from public schools in Shanghai, China. They completed self-report measures of 3 dimensions of parental attachment (i.e., trust, communication, and alienation), general self-worth, and procrastination. The results indicated that both paternal and maternal trust and paternal communication were negatively associated with higher levels of procrastination whereas both paternal and maternal alienation were positively associated with procrastination. In addition, self-worth mediated the associations among 3 dimensions of parental attachment and procrastination. The findings highlighted the importance of parental attachment-based intervention strategies to reduce procrastination among adolescents. PMID- 28812974 TI - The Psychological Effects of Unemployment and Unsatisfactory Employment on Young Adults: Findings from a 10-Year Longitudinal Study. AB - The purpose of the present study was to extend the external validity of an earlier longitudinal study of school leavers by including participants from a representative sample of secondary schools. Questionnaires were administered annually to a sample of South Australian school leavers over a 10-year period. At Time 1 participants were in the last compulsory year of high school aged around 15 years and at Time 10 they were aged around 25 years. Results confirmed those from an earlier longitudinal study showing that the transition from school to satisfactory employment was associated with significant improvements in psychological well-being, whereas transition from school to unemployment or unsatisfactory employment showed no change in psychological well-being. The current findings extended the external validity of the earlier study because whereas participants in the earlier study were sampled from co-educational metropolitan public high schools, the current study included participants from every kind of high school: single sex as well as co-educational, rural as well as metropolitan, and private as well as public. PMID- 28812975 TI - Sexuality, Gender, and Women's Health. PMID- 28812977 TI - Uterus transplants in India: yawning regulatory gaps. PMID- 28812978 TI - CIOMS 2016. PMID- 28812976 TI - Learning and recognition of tactile temporal sequences by mice and humans. AB - The world around us is replete with stimuli that unfold over time. When we hear an auditory stream like music or speech or scan a texture with our fingertip, physical features in the stimulus are concatenated in a particular order. This temporal patterning is critical to interpreting the stimulus. To explore the capacity of mice and humans to learn tactile sequences, we developed a task in which subjects had to recognise a continuous modulated noise sequence delivered to whiskers or fingertips, defined by its temporal patterning over hundreds of milliseconds. GO and NO-GO sequences differed only in that the order of their constituent noise modulation segments was temporally scrambled. Both mice and humans efficiently learned tactile sequences. Mouse sequence recognition depended on detecting transitions in noise amplitude; animals could base their decision on the earliest information available. Humans appeared to use additional cues, including the duration of noise modulation segments. PMID- 28812979 TI - Truth in research labelling. AB - This report describes the background and context of a currently circulating petition to the US Congress that seeks amendment of Section 801 of the Public Health Services Act (42 U.S.C. 282) to close a loophole in existing law which makes possible post hoc adjustment of randomised controlled trial (RCT) results reported to the Food and Drug Administration that differ from those reported to ClinicalTrials.gov and to medical journals. The report describes the petition's rationale, underlying assumptions, and support for its proposed remedy in deontological, consequentialist, and casuist philosophical ethics theories. It addresses the several reservations of the World Association of Medical Editors (WAME) with citations of evidence for the petition's assertions. The report suggests that some medical journals are not unknowing victims but rather complicit enablers of the post hoc adjusted RCT results that they publish. Its closing remarks dwell on the negative impact that embrace of a neoliberal, anti regulatory philosophy of government will likely have on any regulatory reform to promote the integrity of biomedical science and the future of evidence-based medicine. PMID- 28812980 TI - Application of an in vitro digestion model for 210Po bioaccessibility assessment in seafood. AB - This study aims to investigate the bioaccessibility of 210Po in seafood and the impact of food preparation on this radionuclide. Polonium bioaccessibility is the fraction of 210Po mobilised from food matrices into digestive extractants when applying an in vitro digestion model. The degree of bioaccessibility of 210Po in food has important implications for estimating ingestion doses from this radionuclide. The simulation of gastrointestinal digestion was divided into three stages through the use of synthetic saliva, gastric and bile-pancreas solutions. Following pre-treatment with a saliva solution, raw and cooked seafood samples underwent one of the following treatments: (a) simulated gastric digestion only or (b) simulated complete gastrointestinal digestion (gastric digestion followed by bile-pancreas digestion). No significant difference (P > 0.05) in 210Po mobility was found between samples that underwent gastric digestion compared to those that only underwent gastro-intestinal digestion. However, a significant difference (P < 0.05) in 210Po bioaccessibility was found between raw and cooked seafood undergoing both gastric and gastro-intestinal digestion. PMID- 28812981 TI - The experimental study on the emanation power of a flow-through thoron source made from incandescent gas mantles. AB - To improve the quality of the calibration of thoron concentration activity measurement, an experimental study on the emanation power of a flow-through thoron source based on incandescent gas mantles was carried out in this paper. The thoron activity concentrations of the outflowed air from the flow-through source were measured using RAD7, and the quantitative relationship between thoron concentrations and flowrates was studied through theoretical analysis, and the thoron emanation powers were obtained from the fitting of the relationship above. Results show that the thoron concentration decreased with the increasing flowrate in the gas path, and the thoron emanation powers of three batches of gas mantles obtained by fitting were 1.33% +/- 0.17%, 0.77% +/- 0.10% and 0.57% +/- 0.07% respectively in low humidity condition. Those results were checked using the gamma spectroscopy method, and were consistent within the error range. PMID- 28812982 TI - Quantitative criteria to benchmark new and existing bio-inks for cell compatibility. AB - Recent advancements in 3D bioprinting have led to the fabrication of more complex, more precise, and larger printed tissue constructs. As the field continues to advance, it is critical to develop quantitative benchmarks to compare different bio-inks for key cell-biomaterial interactions, including (1) cell sedimentation within the ink cartridge, (2) cell viability during extrusion, and (3) cell viability after ink curing. Here we develop three simple protocols for quantitative analysis of bio-ink performance. These methods are used to benchmark the performance of two commonly used bio-inks, poly(ethylene glycol) diacrylate (PEGDA) and gelatin methacrylate (GelMA), against three formulations of a novel bio-ink, Recombinant-protein Alginate Platform for Injectable Dual crosslinked ink (RAPID ink). RAPID inks undergo peptide-self-assembly to form weak, shear-thinning gels in the ink cartridge and undergo electrostatic crosslinking with divalent cations during curing. In the one hour cell sedimentation assay, GelMA, the RAPID inks, and PEGDA with xanthan gum prevented appreciable cell sedimentation, while PEGDA alone or PEGDA with alginate experienced significant cell settling. To quantify cell viability during printing, 3T3 fibroblasts were printed at a constant flow rate of 75 MUl min-1 and immediately tested for cell membrane integrity. Less than 10% of cells were damaged using the PEGDA and GelMA bio-inks, while less than 4% of cells were damaged using the RAPID inks. Finally, to evaluate cell viability after curing, cells were exposed to ink-specific curing conditions for five minutes and tested for membrane integrity. After exposure to light with photoinitiator at ambient conditions, over 50% of cells near the edges of printed PEGDA and GelMA droplets were damaged. In contrast, fewer than 20% of cells found near the edges of RAPID inks were damaged after a 5 min exposure to curing in a 10 mM CaCl2 solution. As new bio-inks continue to be developed, these protocols offer a convenient means to quantitatively benchmark their performance against existing inks. PMID- 28812984 TI - Modelling the effects of quinidine, disopyramide, and E-4031 on short QT syndrome variant 3 in the human ventricles. AB - OBJECTIVE: Short QT syndrome (SQTS) is an inherited cardiac channelopathy, but at present little information is available on its pharmacological treatment. SQT3 variant (linked to the inward rectifier potassium current I K1) of SQTS, results from a gain-of-function mutation (Kir2.1 D172N) in the KCNJ2-encoded channels, which is associated with ventricular fibrillation (VF). Using biophysically detailed human ventricular computer models, this study investigated the potential effects of quinidine, disopyramide, and E-4031 on SQT3. APPROACH: The ten Tusscher et al model of human ventricular myocyte action potential (AP) was modified to recapitulate the changes in I K1 due to heterozygous and homozygous forms of the D172N mutation. Wild-type (WT) and mutant WT-D172N and D172N formulations were incorporated into one-dimensional (1D) and 2D tissue models with transmural heterogeneities. Effects of drugs on channel-blocking activity were modelled using half-maximal inhibitory concentration (IC50) and Hill coefficient (nH) values. Effects of drugs on AP duration (APD), effective refractory period (ERP) and QT interval of pseudo-ECGs were quantified, and both temporal and spatial vulnerability to re-entry was measured. Re-entry was simulated in the 2D ventricular tissue. MAIN RESULTS: At the single cell level, the drugs quinidine, disopyramide, and E-4031 prolonged APD at 90% repolarization (APD90), and decreased maximal transmural voltage heterogeneity (deltaV); this caused the decreased transmural dispersion of APD90. Quinidine prolonged the QT interval and decreased the T-wave amplitude. Furthermore, quinidine increased ERP and reduced temporal vulnerability and increased spatial vulnerability, resulting in a reduced susceptibility to arrhythmogenesis in SQT3. In the 2D tissue, quinidine was effective in terminating and preventing re-entry associated with the heterozygous D172N condition. Quinidine exhibited significantly better therapeutic effects on SQT3 than disopyramide and E-4031. SIGNIFICANCE: This study substantiates a causal link between quinidine and QT interval prolongation in SQT3 Kir2.1 mutations and highlights possible pharmacological agent quinidine for treating SQT3 patients. PMID- 28812983 TI - A microfluidic platform for modeling metastatic cancer cell matrix invasion. AB - Invasion of the extracellular matrix is a critical step in the colonization of metastatic tumors. The invasion process is thought to be driven by both chemokine signaling and interactions between invading cancer cells and physical components of the metastatic niche, including endothelial cells that line capillary walls and serve as a barrier to both diffusion and invasion of the underlying tissue. Transwell chambers, a tool for generating artificial chemokine gradients to induce cell migration, have facilitated recent work to investigate the chemokine contributions to matrix invasion. These chambers, however, are poorly designed for imaging, which limits their use in investigating the physical cell-cell and cell-matrix interactions driving matrix invasion. Microfluidic devices offer a promising model in which the invasion process can be imaged. Many current designs, however, have limited surface areas and possess intricate geometries that preclude the use of standard staining protocols to visualize cells and matrix proteins. In this work, we present a novel microfluidic platform for imaging cell-cell and cell-matrix interactions driving metastatic cancer cell matrix invasion. Our model is applied to investigate how endothelial cell secreted matrix proteins and the physical endothelial monolayer itself interact with invading metastatic breast cancer cells to facilitate invasion of an underlying type I collagen gel. The results show that matrix invasion of metastatic breast cancer cells is significantly enhanced in the presence of live endothelial cells. Probing this interaction further, our platform revealed that, while the fibronectin-rich matrix deposited by endothelial cells was not sufficient to drive invasion alone, metastatic breast cancer cells were able to exploit components of energetically inactivated endothelial cells to gain entry into the underlying matrix. These findings reveal novel cell-cell interactions driving a key step in the colonization of metastatic tumors and have important implications for designing drugs targeted at preventing cancer metastasis. PMID- 28812985 TI - Interventions to Support Integrated Psychological Care and Holistic Health Outcomes in Paediatrics. AB - There are strong calls from many national and international bodies for there to be a 'holistic' and integrated approach to the understanding and management of psychological and physical health needs. Such holistic approaches are characterized by the treatment of the whole person, taking into account mental and social factors, rather than just the symptoms of a disease. Holistic approaches can impact on mental and physical health and are cost-effective. Several psychological interventions have demonstrated efficacy in improving holistic health outcomes, for example Cognitive Behaviour Therapy, Behavioural Therapies and Problem Solving Therapies. They have shown to impact upon a wide range of outcomes, including psychological distress, pain, physical health, medication adherence, and family outcomes. There is increasing recognition that the holistic goals of the child and family should be prioritised, and that interventions and outcomes should reflect these goals. A focus on holistic goals in therapy can be achieved through a combination of personalised goal-based outcomes in addition to symptom-based measures. PMID- 28812987 TI - A Microneedle Functionalized with Polyethyleneimine and Nanotubes for Highly Sensitive, Label-Free Quantification of DNA. AB - The accurate measure of DNA concentration is necessary for many DNA-based biological applications. However, the current methods are limited in terms of sensitivity, reproducibility, human error, and contamination. Here, we present a microneedle functionalized with polyethyleneimine (PEI) and single-walled carbon nanotubes (SWCNTs) for the highly sensitive quantification of DNA. The microneedle was fabricated using ultraviolet (UV) lithography and anisotropic etching, and then functionalized with PEI and SWCNTs through a dip coating process. The electrical characteristics of the microneedle change with the accumulation of DNA on the surface. Current-voltage measurements in deionized water were conducted to study these changes in the electrical properties of the sensor. The sensitivity test found the signal to be discernable from the noise level down to 100 attomolar (aM), demonstrating higher sensitivity than currently available UV fluorescence and UV absorbance based methods. A microneedle without any surface modification only had a 100 femtomolar (fM) sensitivity. All measurement results were consistent with fluorescence microscopy. PMID- 28812988 TI - Comment on Piscitelli et al. Hospitalizations in Pediatric and Adult Patients for All Cancer Type in Italy: The EPIKIT Study under the E.U. COHEIRS Project on Environment and Health. Int. J. Environ. Res. Public Health 2017, 14, 495. AB - In the "Epikit study" [1], P. Piscitelli with 27 co-authors from 20 scientific institutions estimated the absolute number of hospital admissions for newly diagnosed cancer in people aged 0-19 in Italian provinces and regions in 2007 2011.[...]. PMID- 28812989 TI - Small, Smart, Fast, and Cheap: Microchip-Based Sensors to Estimate Air Pollution Exposures in Rural Households. AB - Over the last 20 years, the Kirk R. Smith research group at the University of California Berkeley-in collaboration with Electronically Monitored Ecosystems, Berkeley Air Monitoring Group, and other academic institutions-has developed a suite of relatively inexpensive, rugged, battery-operated, microchip-based devices to quantify parameters related to household air pollution. These devices include two generations of particle monitors; data-logging temperature sensors to assess time of use of household energy devices; a time-activity monitoring system using ultrasound; and a CO2-based tracer-decay system to assess ventilation rates. Development of each system involved numerous iterations of custom hardware, software, and data processing and visualization routines along with both lab and field validation. The devices have been used in hundreds of studies globally and have greatly enhanced our understanding of heterogeneous household air pollution (HAP) concentrations and exposures and factors influencing them. PMID- 28812986 TI - Epigenome Aberrations: Emerging Driving Factors of the Clear Cell Renal Cell Carcinoma. AB - Clear cell renal cell carcinoma (ccRCC), the most common form of Kidney cancer, is characterized by frequent mutations of the von Hippel-Lindau (VHL) tumor suppressor gene in ~85% of sporadic cases. Loss of pVHL function affects multiple cellular processes, among which the activation of hypoxia inducible factor (HIF) pathway is the best-known function. Constitutive activation of HIF signaling in turn activates hundreds of genes involved in numerous oncogenic pathways, which contribute to the development or progression of ccRCC. Although VHL mutations are considered as drivers of ccRCC, they are not sufficient to cause the disease. Recent genome-wide sequencing studies of ccRCC have revealed that mutations of genes coding for epigenome modifiers and chromatin remodelers, including PBRM1, SETD2 and BAP1, are the most common somatic genetic abnormalities after VHL mutations in these tumors. Moreover, recent research has shed light on the extent of abnormal epigenome alterations in ccRCC tumors, including aberrant DNA methylation patterns, abnormal histone modifications and deregulated expression of non-coding RNAs. In this review, we discuss the epigenetic modifiers that are commonly mutated in ccRCC, and our growing knowledge of the cellular processes that are impacted by them. Furthermore, we explore new avenues for developing therapeutic approaches based on our knowledge of epigenome aberrations of ccRCC. PMID- 28812990 TI - Human Leukocyte Antigen C*12:02:02 and Killer Immunoglobulin-Like Receptor 2DL5 are Distinctly Associated with Ankylosing Spondylitis in the Taiwanese. AB - Human leukocyte antigen (HLA) class I ligands and Killer immunoglobulin-like receptors (KIRs) regulate the cytolytic activity of natural killer (NK) cells and certain T cells. We examined their genetic predisposition to disease susceptibility and clinical phenotypes in Taiwanese ankylosing spondylitis (AS) patients. KIR genotyping and Human Leucocyte Antigen C (HLA-C) sequencing were performed in 653 Taiwanese AS patients and 952 healthy controls. KIR genotype distributions and HLA-C allele frequencies were compared in patients and controls and among patients with and without HLA-B27 positivity, early age onset and spinal syndesmophytes. HLA-C alleles were functionally characterized using 3D structural modelling with peptide simulation. This study discovered that the HLA C*12:02:02 allele (43.42% vs. 3.31%; p < 0.00001 odds ratio (OR), 16.88; 95% confidence intervals (CI): 11.27-25.28) confers a strong risk for Taiwanese AS development. The 3D modelling results identified four unique amino acid polymorphisms, Ala73, Trp156, Arg219 and Met304, that may affect the function of the HLA-C*12:02:02 allele. KIR2DL5 (p = 0.0047; pFDR = 0.0423) and the KIR Bx haplotype (p = 0.0000275) were protective against Taiwanese AS, while KIR 2DS4/1D (22 base pair truncated deletion; p = 0.0044; pFDR = 0.1998) appeared to be a risk factor for it. KIR2DL5 combined with the HLA-C1/C2 heterozygous genotype showed a protective effect (AS 5.97% vs. normal 11.66%; p = 0.002; pFDR = 0.0127, OR, 0.48 95% CI: 0.33-0.70); in contrast, KIR 2DS4/1D combined with the HLA-C1C1 homozygous genotype (AS 45.33% vs. normal 35.92%; p = 0.002; pFDR = 0.0127, OR, 1.48 95% CI: 1.21-1.81) represented a risk factor for AS development. Our data suggested that interactions between KIRs and their cognate HLA-C ligands may contribute to the pathogenesis of AS. PMID- 28812992 TI - Endolysosomal Degradation of Allergenic Ole e 1-Like Proteins: Analysis of Proteolytic Cleavage Sites Revealing T Cell Epitope-Containing Peptides. AB - Knowledge of the susceptibility of proteins to endolysosomal proteases provides valuable information on immunogenicity. Though Ole e 1-like proteins are considered relevant allergens, little is known about their immunogenic properties and T cell epitopes. Thus, six representative molecules, i.e., Ole e 1, Fra e 1, Sal k 5, Che a 1, Phl p 11 and Pla l 1, were investigated. Endolysosomal degradation and peptide generation were simulated using microsomal fractions of JAWS II dendritic cells. Kinetics and peptide patterns were evaluated by gel electrophoresis and mass spectrometry. In silico MHC (major histocompatibility complex) class II binding prediction was performed with ProPred. Cleavage sites were assigned to the primary and secondary structure, and in silico docking experiments between the protease cathepsin S and Ole e 1 were performed. Different kinetics during endolysosomal degradation were observed while similar peptide profiles especially at the C-termini were detected. Typically, the identified peptide clusters comprised the previously-reported T cell epitopes of Ole e 1, consistent with an in silico analysis of the T cell epitopes. The results emphasize the importance of the fold on allergen processing, as also reflected by conserved cleavage sites located within the large flexible loop. In silico docking and mass spectrometry results suggest that one of the first Ole e 1 cleavages might occur at positions 107-108. Our results provided kinetic and structural information on endolysosomal processing of Ole e 1-like proteins. PMID- 28812991 TI - The Retinoblastoma (RB) Tumor Suppressor: Pushing Back against Genome Instability on Multiple Fronts. AB - The retinoblastoma (RB) tumor suppressor is known as a master regulator of the cell cycle. RB is mutated or functionally inactivated in the majority of human cancers. This transcriptional regulator exerts its function in cell cycle control through its interaction with the E2F family of transcription factors and with chromatin remodelers and modifiers that contribute to the repression of genes important for cell cycle progression. Over the years, studies have shown that RB participates in multiple processes in addition to cell cycle control. Indeed, RB is known to interact with over 200 different proteins and likely exists in multiple complexes. RB, in some cases, acts through its interaction with E2F1, other members of the pocket protein family (p107 and p130), and/or chromatin remodelers and modifiers. RB is a tumor suppressor with important chromatin regulatory functions that affect genomic stability. These functions include the role of RB in DNA repair, telomere maintenance, chromosome condensation and cohesion, and silencing of repetitive regions. In this review we will discuss recent advances in RB biology related to RB, partner proteins, and their non transcriptional functions fighting back against genomic instability. PMID- 28812993 TI - Enhanced Corrosion Resistance of Carbon Steel in Hydrochloric Acid Solution by Eriobotrya Japonica Thunb. Leaf Extract: Electrochemical Study. AB - The biodegradable inhibitors, which could effectively reduce the rate of corrosion of carbon steel, were investigated by potentiodynamic polarization and electrochemical impedance spectroscopy (EIS). The mixed-type inhibitors extracted from Eriobotrya japonica Thunb. leaf exhibited excellent inhibition performance, and the inhibition efficiency for carbon steel reached 90.0% at 298 K in hydrochloric acid. Moreover, the adsorption mechanism of the inhibitors on a carbon steel surface is described by the Langmuir adsorption isotherm. Simultaneously, the corrosion morphology of the carbon steel and the inhibitor structure were analyzed by scanning electron microscope (SEM) and Fourier transform infrared spectroscopy (FT-IR), respectively. PMID- 28812995 TI - Optimizing Waveform Maximum Determination for Specular Point Tracking in Airborne GNSS-R. AB - Airborne GNSS-R campaigns are crucial to the understanding of signal interactions with the Earth's surface. As a consequence of the specific geometric configurations arising during measurements from aircraft, the reflected signals can be difficult to interpret under certain conditions like over strongly attenuating media such as forests, or when the reflected signal is contaminated by the direct signal. For these reasons, there are many cases where the reflectivity is overestimated, or a portion of the dataset has to be flagged as unusable. In this study we present techniques that have been developed to optimize the processing of airborne GNSS-R data, with the goal of improving its accuracy and robustness under non-optimal conditions. This approach is based on the detailed analysis of data produced by the instrument GLORI, which was recorded during an airborne campaign in the south west of France in June 2015. Our technique relies on the improved determination of reflected waveform peaks in the delay dimension, which is related to the loci of the signals contributed by the zone surrounding the specular point. It is shown that when developing techniques for the correct localization of waveform maxima under conditions of surfaces of low reflectivity, and/or contamination from the direct signal, it is possible to correct and extract values corresponding to the real reflectivity of the zone in the neighborhood of the specular point. This algorithm was applied to a reanalysis of the complete campaign dataset, following which the accuracy and sensitivity improved, and the usability of the dataset was improved by 30%. PMID- 28812996 TI - Reliable Detection of Herpes Simplex Virus Sequence Variation by High-Throughput Resequencing. AB - High-throughput sequencing (HTS) has resulted in data for a number of herpes simplex virus (HSV) laboratory strains and clinical isolates. The knowledge of these sequences has been critical for investigating viral pathogenicity. However, the assembly of complete herpesviral genomes, including HSV, is complicated due to the existence of large repeat regions and arrays of smaller reiterated sequences that are commonly found in these genomes. In addition, the inherent genetic variation in populations of isolates for viruses and other microorganisms presents an additional challenge to many existing HTS sequence assembly pipelines. Here, we evaluate two approaches for the identification of genetic variants in HSV1 strains using Illumina short read sequencing data. The first, a reference-based approach, identifies variants from reads aligned to a reference sequence and the second, a de novo assembly approach, identifies variants from reads aligned to de novo assembled consensus sequences. Of critical importance for both approaches is the reduction in the number of low complexity regions through the construction of a non-redundant reference genome. We compared variants identified in the two methods. Our results indicate that approximately 85% of variants are identified regardless of the approach. The reference-based approach to variant discovery captures an additional 15% representing variants divergent from the HSV1 reference possibly due to viral passage. Reference-based approaches are significantly less labor-intensive and identify variants across the genome where de novo assembly-based approaches are limited to regions where contigs have been successfully assembled. In addition, regions of poor quality assembly can lead to false variant identification in de novo consensus sequences. For viruses with a well-assembled reference genome, a reference-based approach is recommended. PMID- 28812994 TI - Organ-Organ Crosstalk and Alcoholic Liver Disease. AB - Alcohol consumption is a common custom worldwide, and the toxic effects of alcohol on several target organs are well-understood. Given the poor prognosis of treating clinically-relevant alcoholic liver disease (ALD) (i.e., alcoholic hepatitis (AH) and cirrhosis), additional research is required to develop more effective therapies. While the stages of ALD have been well-characterized, targeted therapies to prevent or reverse this process in humans are still needed. Better understanding of risk factors and mechanisms underlying disease progression can lead to the development of rational therapies to prevent or reverse ALD in the clinic. A potential area of targeted therapy for ALD may be organ-organ communication in the early stages of the disease. In contrast to AH and end-stage liver diseases, the involvement of multiple organs in the development of ALD is less understood. The impact of these changes on pathology to the liver and other organs may not only influence disease progression during the development of the disease, but also outcomes of end stages diseases. The purpose of this review is to summarize the established and proposed communication between the liver and other organ systems that may contribute to the development and progression of liver disease, as well as to other organs. Potential mechanisms of this organ-organ communication are also discussed. PMID- 28812997 TI - Distribution of FMR1 and FMR2 Repeats in Argentinean Patients with Primary Ovarian Insufficiency. AB - The premutation state of FMR1 (Fragile X Mental Retardation 1) has been associated with primary ovarian insufficiency (POI), and is the most common known genetic cause for 46,XX patients. Nevertheless, very few studies have analyzed its frequency in Latin American populations. Additionally, a relationship between alleles carrying a cryptic microdeletion in the 5'UTR of FMR2 and the onset of POI has only been studied in one population. Our aim was to analyze the incidence of FMR1 premutations and putative microdeletions in exon 1 of FMR2 in a cohort of Argentinean women with POI. We studied 133 patients and 84 controls. Fluorescent PCR was performed, and the FMR2 exon 1 was further sequenced in samples presenting less than 11 repeats. We found the frequency of FMR1 premutations to be 6.7% and 2.9% for familial and sporadic patients, respectively. Among controls, 1/84 women presented a premutation. In addition, although we did not find microdeletions in FMR2, we observed a change (T >C) adjacent to the repeats in two sisters with POI. Given the repetitive nature of the sequence involved, we could not ascertain whether this represents a single nucleotide polymorphism (SNP) or a deletion. Therefore, a relationship between FMR2 and POI could not be established for our population. PMID- 28812998 TI - A Framework Based on Reference Data with Superordinate Accuracy for the Quality Analysis of Terrestrial Laser Scanning-Based Multi-Sensor-Systems. AB - Terrestrial laser scanning (TLS) is an efficient solution to collect large-scale data. The efficiency can be increased by combining TLS with additional sensors in a TLS-based multi-sensor-system (MSS). The uncertainty of scanned points is not homogenous and depends on many different influencing factors. These include the sensor properties, referencing, scan geometry (e.g., distance and angle of incidence), environmental conditions (e.g., atmospheric conditions) and the scanned object (e.g., material, color and reflectance, etc.). The paper presents methods, infrastructure and results for the validation of the suitability of TLS and TLS-based MSS. Main aspects are the backward modelling of the uncertainty on the basis of reference data (e.g., point clouds) with superordinate accuracy and the appropriation of a suitable environment/infrastructure (e.g., the calibration process of the targets for the registration of laser scanner and laser tracker data in a common coordinate system with high accuracy) In this context superordinate accuracy means that the accuracy of the acquired reference data is better by a factor of 10 than the data of the validated TLS and TLS-based MSS. These aspects play an important role in engineering geodesy, where the aimed accuracy lies in a range of a few mm or less. PMID- 28812999 TI - Synthesis and Evaluation of a Sodium Alginate-4-Aminosalicylic Acid Based Microporous Hydrogel for Potential Viscosupplementation for Joint Injuries and Arthritis-Induced Conditions. AB - A microporous hydrogel was developed using sodium alginate (alg) and 4 aminosalicylic acid (4-ASA). The synthesized hydrogel was characterized using various analytical techniques such as Fourier transform infrared spectroscopy (FTIR), Carbon-13 nuclear magnetic resonance (13C-NMR), X-ray powder diffraction (XRD), scanning electron microscopy (SEM), and differential scanning calorimetry (DSC). Additonal carboxyl and hydroxyl functional groups of 4-ASA provided significant lubrication and stress-triggered sol-gel transition to the conjugated hydrogel. In addition, cytotoxicity analysis was undertaken on the conjugated hydrogel using human dermal fibroblast-adult (HDFa) cells, displaying non-toxic characteristics. Drug release profiles displaying 49.6% in the first 8 h and 97.5% within 72 h, similar to the native polymer (42.8% in first 8 h and 90.1% within 72 h). Under applied external stimuli, the modified hydrogel displayed significant gelling properties and structure deformation/recovery behaviour, confirmed using rheological evaluation (viscosity and thixotropic area of 8095.3 mPas and 26.23%, respectively). The modified hydrogel, thus, offers great possibility for designing smart synovial fluids as a biomimetic aqueous lubricant for joint-related injuries and arthritis-induced conditions. In addtion, the combination of thixotropy, non-toxicity, and drug release capabilities enables potential viscosupplementation for clinical application. PMID- 28813000 TI - An Ameliorated Prediction of Drug-Target Interactions Based on Multi-Scale Discrete Wavelet Transform and Network Features. AB - The prediction of drug-target interactions (DTIs) via computational technology plays a crucial role in reducing the experimental cost. A variety of state-of-the art methods have been proposed to improve the accuracy of DTI predictions. In this paper, we propose a kind of drug-target interactions predictor adopting multi-scale discrete wavelet transform and network features (named as DAWN) in order to solve the DTIs prediction problem. We encode the drug molecule by a substructure fingerprint with a dictionary of substructure patterns. Simultaneously, we apply the discrete wavelet transform (DWT) to extract features from target sequences. Then, we concatenate and normalize the target, drug, and network features to construct feature vectors. The prediction model is obtained by feeding these feature vectors into the support vector machine (SVM) classifier. Extensive experimental results show that the prediction ability of DAWN has a compatibility among other DTI prediction schemes. The prediction areas under the precision-recall curves (AUPRs) of four datasets are 0 . 895 (Enzyme), 0 . 921 (Ion Channel), 0 . 786 (guanosine-binding protein coupled receptor, GPCR), and 0 . 603 (Nuclear Receptor), respectively. PMID- 28813001 TI - Dual-Band Band-Pass Filter with Fixed Low Band and Fluidically-Tunable High Band. AB - In this work, we present a dual-band band-pass filter with fixed low-band resonant frequency and tunable high-band resonant frequency. The proposed filter consists of two split-ring resonators (SRRs) with a stub and microfluidic channels. The lower resonant frequency is determined by the length of the SRR alone, whereas the higher resonant frequency is determined by the lengths of the SRR and the stub. Using this characteristic, we fix the lower resonant frequency by fixing the SRR length and tune the higher resonant frequency by controlling the stub length by injecting liquid metal in the microfluidic channel. We fabricated the filter on a Duroid substrate. The microfluidic channel was made from polydimethylsiloxane (PDMS), and eutectic gallium-indium (EGaIn) was used as the liquid metal. This filter operates in two states-with, and without, the liquid metal. In the state without the liquid metal, the filter has resonant frequencies at 1.85 GHz and 3.06 GHz, with fractional bandwidths of 4.34% and 2.94%, respectively; and in the state with the liquid metal, it has resonant frequencies at 1.86 GHz and 2.98 GHz, with fractional bandwidths of 4.3% and 2.95%, respectively. PMID- 28813002 TI - Application of Surfactant Micelle-Entrapped Eugenol for Prevention of Growth of the Shiga Toxin-Producing Escherichia coli in Ground Beef. AB - Beef safety may be compromised by O157 and non-O157 Shiga toxin-producing Escherichia coli (STEC) contamination. The capacity of surfactant micelles loaded with the plant-derived antimicrobial eugenol to reduce STEC on beef trimmings that were later ground and refrigerated for five days at 5 +/- 1 degrees C was tested to determine their utility for beef safety protection. STEC-inoculated trimmings were treated with free eugenol, micelle-encapsulated eugenol, 2% lactic acid (55 degrees C), sterile distilled water (25 degrees C), or left untreated (control). Following treatment, trimmings were coarse-ground and stored aerobically at 5 +/- 1 degrees C. Ground beef was then sampled for STEC immediately post-grinding, and again at three and five days of storage. STEC minimum inhibitory concentrations (MICs) in liquid medium for free eugenol and 1% sodium dodecyl sulfate (SDS)-loaded micelles were 0.5% and 0.125%, respectively. STEC numbers on beef trimmings treated by sterile water (6.5 log10 CFU/g), free eugenol (6.5 log10 CFU/g), micelle-loaded eugenol (6.4 log10 CFU/g), and lactic acid (6.4 log10 CFU/g) did not differ compared to untreated controls (6.6 log10 CFU/g) (p = 0.982). Conversely, STEC were significantly reduced by refrigerated storage (0.2 and 0.3 log10 CFU/g at three and five days of storage, respectively) (p = 0.014). Antimicrobial treatments did not significantly decontaminate ground beef, indicating their low utility for beef safety protection. PMID- 28813003 TI - Self-Assessment of Antimicrobial Stewardship in Primary Care: Self-Reported Practice Using the TARGET Primary Care Self-Assessment Tool. AB - Multifaceted antimicrobial stewardship (AMS) interventions including: antibiotic guidance, reviews of antibiotic use using audits, education, patient facing materials, and self-assessment, are successful in improving antimicrobial use. We aimed to measure the self-reported AMS activity of staff completing a self assessment tool (SAT). The Royal College of General Practitioners (RCGP)/Public Health England (PHE) SAT enables participants considering an AMS eLearning course to answer 12 short questions about their AMS activities. Questions cover guidance, audit, and reflection about antibiotic use, patient facing materials, and education. Responses are recorded digitally. Data were collated, anonymised, and exported into Microsoft Excel. Between November 2014 and June 2016, 1415 users completed the SAT. Ninety eight percent reported that they used antibiotic guidance for treating common infections and 63% knew this was available to all prescribers. Ninety four percent of GP respondents reported having used delayed prescribing when appropriate, 25% were not using Read codes, and 62% reported undertaking a practice-wide antibiotic audit in the last two years, of which, 77% developed an audit action plan. Twenty nine percent had undertaken other antibiotic-related clinical courses. Fifty six percent reported sharing patient leaflets covering infection. Many prescribers reported undertaking a range of AMS activities. GP practice managers should ensure that all clinicians have access to prescribing guidance. Antibiotic audits should be encouraged to enable GP staff to understand their prescribing behaviour and address gaps in good practice. Prescribers are not making full use of antibiotic prescribing-related training opportunities. Read coding facilitates more accurate auditing and its use by all clinicians should be encouraged. PMID- 28813004 TI - Lactose Binding Induces Opposing Dynamics Changes in Human Galectins Revealed by NMR-Based Hydrogen-Deuterium Exchange. AB - Galectins are beta-galactoside-binding proteins implicated in a myriad of biological functions. Despite their highly conserved carbohydrate binding motifs with essentially identical structures, their affinities for lactose, a common galectin inhibitor, vary significantly. Here, we aimed to examine the molecular basis of differential lactose affinities amongst galectins using solution-based techniques. Consistent dissociation constants of lactose binding were derived from nuclear magnetic resonance (NMR) spectroscopy, intrinsic tryptophan fluorescence, isothermal titration calorimetry and bio-layer interferometry for human galectin-1 (hGal1), galectin-7 (hGal7), and the N-terminal and C-terminal domains of galectin-8 (hGal8NTD and hGal8CTD, respectively). Furthermore, the dissociation rates of lactose binding were extracted from NMR lineshape analyses. Structural mapping of chemical shift perturbations revealed long-range perturbations upon lactose binding for hGal1 and hGal8NTD. We further demonstrated using the NMR-based hydrogen-deuterium exchange (HDX) that lactose binding increases the exchange rates of residues located on the opposite side of the ligand-binding pocket for hGal1 and hGal8NTD, indicative of allostery. Additionally, lactose binding induces significant stabilisation of hGal8CTD across the entire domain. Our results suggested that lactose binding reduced the internal dynamics of hGal8CTD on a very slow timescale (minutes and slower) at the expense of reduced binding affinity due to the unfavourable loss of conformational entropy. PMID- 28813005 TI - Identification and Functional Divergence Analysis of WOX Gene Family in Paper Mulberry. AB - The WOX (WUSCHEL-related homeobox) is a plant-specific transcription factor involved in plant development and stress response. However, few studies have been reported on the WOX gene in woody plants. In this study, 10 BpWOX genes were isolated from paper mulberry by RACE-PCR and categorized into three clades through phylogenetic analysis, ancient, intermediate and WUS clade. Among them, five members had the transcriptional activity detected by yeast one-hybrid and seven were uniquely localized to the nucleus through green fluorescent protein (GFP) observation. The expression patterns of BpWOX genes in different tissues and under diverse treatments were quantified by the qRT-PCR method. Results showed that BpWUS was expressed in the apical bud, stem and root, BpWOX5 and BpWOX7 functioned only in the root tip, and three BpWOXs regulated leaf development redundantly. BpWOX9 and BpWOX10 were induced by indole-3-acetic acid (IAA) or jasmonic acid (JA), while BpWOX2 was repressed by five phytohormones. Interestingly, most BpWOX genes were responsive to the abiotic stress stimuli of drought, salt, cold, and cadmium (CdCl2). Together, our study revealed that BpWOXs were functionally divergent during paper mulberry development and environmental adaptation, which might be related to their evolutionary relationships. Our work will benefit the systematic understanding of the precise function of WOX in plant development and environmental stress responses. PMID- 28813006 TI - Samarium Monosulfide (SmS): Reviewing Properties and Applications. AB - In this review, we give an overview of the properties and applications of samarium monosulfide, SmS, which has gained considerable interest as a switchable material. It shows a pressure-induced phase transition from the semiconducting to the metallic state by polishing, and it switches back to the semiconducting state by heating. The material also shows a magnetic transition, from the paramagnetic state to an antiferromagnetically ordered state. The switching behavior between the semiconducting and metallic states could be exploited in several applications, such as high density optical storage and memory materials, thermovoltaic devices, infrared sensors and more. We discuss the electronic, optical and magnetic properties of SmS, its switching behavior, as well as the thin film deposition techniques which have been used, such as e-beam evaporation and sputtering. Moreover, applications and possible ideas for future work on this material are presented. Our scope is to present the properties of SmS, which were mainly measured in bulk crystals, while at the same time we describe the possible deposition methods that will push the study of SmS to nanoscale dimensions, opening an intriguing range of applications for low-dimensional, pressure-induced semiconductor-metal transition compounds. PMID- 28813007 TI - The Efficacy of Bifidobacterium longum BORI and Lactobacillus acidophilus AD031 Probiotic Treatment in Infants with Rotavirus Infection. AB - A total of 57 infants hospitalized with rotavirus disease were included in this study. The children were randomly divided into the study's two treatment groups: three days of the oral administration of (i) a probiotics formula containing both Bifidobacterium longum BORI and Lactobacillus acidophilus AD031 (N = 28); or (ii) a placebo (probiotic-free skim milk, N = 29) and the standard therapy for diarrhea. There were no differences in age, sex, or blood characteristics between the two groups. When the 57 cases completed the protocol, the duration of the patients' diarrhea was significantly shorter in the probiotics group (4.38 +/- 1.29, N = 28) than the placebo group (5.61 +/- 1.23, N = 29), with a p-value of 0.001. Symptoms such as duration of fever (p = 0.119), frequency of diarrhea (p = 0.119), and frequency of vomiting (p = 0.331) tended to be ameliorated by the probiotic treatment; however, differences were not statistically significant between the two groups. There were no serious, adverse events and no differences in the frequency of adverse events in both groups. PMID- 28813009 TI - Well-Being and the Social Environment of Work: A Systematic Review of Intervention Studies. AB - There is consistent evidence that a good social environment in the workplace is associated with employee well-being. However, there has been no specific review of interventions to improve well-being through improving social environments at work. We conducted a systematic review of such interventions, and also considered performance as an outcome. We found eight studies of interventions. Six studies were of interventions that were based on introducing shared social activities into workgroups. Six out of the six studies demonstrated improvements in well being across the sample (five studies), or for an identifiable sub-group (one study). Four out of the five studies demonstrated improvements in social environments, and four out of the five studies demonstrated improvements in indicators of performance. Analysis of implementation factors indicated that the interventions based on shared activities require some external facilitation, favorable worker attitudes prior to the intervention, and several different components. We found two studies that focused on improving fairness perceptions in the workplace. There were no consistent effects of these interventions on well being or performance. We conclude that there is some evidence that interventions that increase the frequency of shared activities between workers can improve worker well-being and performance. We offer suggestions for improving the evidence base. PMID- 28813008 TI - Dietary Fructose Enhances the Ability of Low Concentrations of Angiotensin II to Stimulate Proximal Tubule Na+ Reabsorption. AB - Fructose-enriched diets cause salt-sensitive hypertension. Proximal tubules (PTs) reabsorb 70% of the water and salt filtered through the glomerulus. Angiotensin II (Ang II) regulates this process. Normally, dietary salt reduces Ang II allowing the kidney to excrete more salt, thereby preventing hypertension. We hypothesized that fructose-enriched diets enhance the ability of low concentrations of Ang II to stimulate PT transport. We measured the effects of a low concentration of Ang II (10-12 mol/L) on transport-related oxygen consumption (QO2), and Na/K-ATPase and Na/H-exchange (NHE) activities and expression in PTs from rats consuming tap water (Control) or 20% fructose (FRUC). In FRUC-treated PTs, Ang II increased QO2 by 14.9 +/- 1.3 nmol/mg/min (p < 0.01) but had no effect in Controls. FRUC elevated NHE3 expression by 19 +/- 3% (p < 0.004) but not Na/K-ATPase expression. Ang II stimulated NHE activity in FRUC PT (Delta + 0.7 +/- 0.1 Arbitrary Fluorescent units (AFU)/s, p < 0.01) but not in Controls. Na/K-ATPase activity was not affected. The PKC inhibitor Go6976 blocked the ability of FRUC to augment the actions of Ang II. FRUC did not alter the inhibitory effect of dopamine on NHE activity. We conclude that dietary fructose increases the ability of low concentrations of Ang II to stimulate PT Na reabsorption via effects on NHE. PMID- 28813010 TI - Characterization of Breakfast Cereals Available in the Mexican Market: Sodium and Sugar Content. AB - Preschool Mexican children consume 7% of their total energy intake from processed breakfast cereals. This study characterized the nutritional quality and labelling (claims and Guideline Daily Amount (GDA)) of the packaged breakfast cereals available in the Mexican market. Photographs of all breakfast cereals available in the 9 main food retail chains in the country were taken. The nutrition quality of cereals was assessed using the United Kingdom Nutrient Profiling Model (UKNPM). Claims were classified using the International Network for Food and Obesity/non-communicable Diseases Research, Monitoring and Action Support (INFORMAS) taxonomy and the GDA was defined according to the Mexican regulation, NOM-051. Overall, a total of 371 different breakfast cereals were analysed. The nutritional profile showed that 68.7% were classified as "less healthy". GDAs and claims were displayed more frequently on the "less healthy" cereals. Breakfast cereals within the "less healthy" category had significantly higher content of energy, sugar and sodium (p < 0.001). Most of the claims were displayed in the "less healthy" cereals (n = 313). This study has shown that there is a lack of consistency between the labelling on the front of the pack and the nutritional quality of breakfast cereals. PMID- 28813011 TI - Insights into the Effect of the G245S Single Point Mutation on the Structure of p53 and the Binding of the Protein to DNA. AB - The transcription factor p53 is a potent tumor suppressor dubbed as the "guardian of the genome" because of its ability to orchestrate protective biological outputs in response to a variety of oncogenic stresses. Mutation and thus inactivation of p53 can be found in 50% of human tumors. The majority are missense mutations located in the DNA binding region. Among them, G245S is known to be a structural hotspot mutation. To understand the behaviors and differences between the wild-type and mutant, both a dimer of the wild type p53 (wt-p53) and its G245S mutant (G245S-mp53), complexed with DNA, were simulated using molecular dynamics for more than 1 MUs. wt-p53 and G245S-mp53 apo monomers were simulated for 1 MUs as well. Conformational analyses and binding energy evaluations performed underline important differences and therefore provide insights to understand the G245S-mp53 loss of function. Our results indicate that the G245S mutation destabilizes several structural regions in the protein that are crucial for DNA binding when found in its apo form and highlight differences in the mutant-DNA complex structure compared to the wt protein. These findings not only provide means that can be applied to other p53 mutants but also serve as structural basis for further studies aimed at the development of cancer therapies based on restoring the function of p53. PMID- 28813012 TI - Inhibitory Effect of Lycopene on Amyloid-beta-Induced Apoptosis in Neuronal Cells. AB - Alzheimer's disease (AD) is a fatal neurodegenerative disease. Brain amyloid-beta deposition is a crucial feature of AD, causing neuronal cell death by inducing oxidative damage. Reactive oxygen species (ROS) activate NF-kappaB, which induces expression of Nucling. Nucling is a pro-apoptotic factor recruiting the apoptosome complex. Lycopene is an antioxidant protecting from oxidative stress induced cell damage. We investigated whether lycopene inhibits amyloid-beta stimulated apoptosis through reducing ROS and inhibiting mitochondrial dysfunction and NF-kappaB-mediated Nucling expression in neuronal SH-SY5Y cells. We prepared cells transfected with siRNA for Nucling or nontargeting control siRNA to determine the role of Nucling in amyloid-beta-induced apoptosis. The amyloid-beta increased intracellular and mitochondrial ROS levels, apoptotic indices (p53, Bax/Bcl-2 ratio, caspase-3 cleavage), NF-kB activation and Nucling expression, while cell viability, mitochondrial membrane potential, and oxygen consumption rate decreased in SH-SY5Y cells. Lycopene inhibited these amyloid beta-induced alterations. However, amyloid-beta did not induce apoptosis, determined by cell viability and apoptotic indices (p53, Bax/Bcl-2 ratio, caspase 3 cleavage), in the cells transfected with siRNA for Nucling. Lycopene inhibited apoptosis by reducing ROS, and by inhibiting mitochondrial dysfunction and NF kappaB-target gene Nucling expression in neuronal cells. Lycopene may be beneficial for preventing oxidative stress-mediated neuronal death in patients with neurodegeneration. PMID- 28813013 TI - Recent Advances in Electrospun Nanofiber Interfaces for Biosensing Devices. AB - Electrospinning has emerged as a very powerful method combining efficiency, versatility and low cost to elaborate scalable ordered and complex nanofibrous assemblies from a rich variety of polymers. Electrospun nanofibers have demonstrated high potential for a wide spectrum of applications, including drug delivery, tissue engineering, energy conversion and storage, or physical and chemical sensors. The number of works related to biosensing devices integrating electrospun nanofibers has also increased substantially over the last decade. This review provides an overview of the current research activities and new trends in the field. Retaining the bioreceptor functionality is one of the main challenges associated with the production of nanofiber-based biosensing interfaces. The bioreceptors can be immobilized using various strategies, depending on the physical and chemical characteristics of both bioreceptors and nanofiber scaffolds, and on their interfacial interactions. The production of nanobiocomposites constituted by carbon, metal oxide or polymer electrospun nanofibers integrating bioreceptors and conductive nanomaterials (e.g., carbon nanotubes, metal nanoparticles) has been one of the major trends in the last few years. The use of electrospun nanofibers in ELISA-type bioassays, lab-on-a-chip and paper-based point-of-care devices is also highly promising. After a short and general description of electrospinning process, the different strategies to produce electrospun nanofiber biosensing interfaces are discussed. PMID- 28813014 TI - Antibacterial Properties of Nonwoven Wound Dressings Coated with Manuka Honey or Methylglyoxal. AB - Manuka honey (MH) is used as an antibacterial agent in bioactive wound dressings via direct impregnation onto a suitable substrate. MH provides unique antibacterial activity when compared with conventional honeys, owing partly to one of its constituents, methylglyoxal (MGO). Aiming to investigate an antibiotic free antimicrobial strategy, we studied the antibacterial activity of both MH and MGO (at equivalent MGO concentrations) when applied as a physical coating to a nonwoven fabric wound dressing. When physically coated on to a cellulosic hydroentangled nonwoven fabric, it was found that concentrations of 0.0054 mg cm 2 of MGO in the form of MH and MGO were sufficient to achieve a 100 colony forming unit % bacteria reduction against gram-positive Staphylococcus aureus and gram-negative Klebsiella pneumoniae, based on BS EN ISO 20743:2007. A 3- to 20 fold increase in MGO concentration (0.0170-0.1 mg cm-2) was required to facilitate a good antibacterial effect (based on BS EN ISO 20645:2004) in terms of zone of inhibition and lack of growth under the sample. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) was also assessed for MGO in liquid form against three prevalent wound and healthcare associated pathogens, i.e., Staphylococcus aureus, gram-negative Pseudomonas aeruginosa and gram-positive Enterococcus faecalis. Other than the case of MGO containing fabrics, solutions with much higher MGO concentrations (128 mg L-1 1024 mg L-1) were required to provide either a bacteriostatic or bactericidal effect. The results presented in this study therefore demonstrate the relevance of an MGO-based coating as an environmentally friendly strategy for the design of functional dressings with antibiotic-free antimicrobial chemistries. PMID- 28813015 TI - Transcriptional Responses of Creeping Bentgrass to 2,3-Butanediol, a Bacterial Volatile Compound (BVC) Analogue. AB - Bacterial volatile compounds (BVCs) have been reported to enhance plant growth and elicit plant defenses against fungal infection and insect damage. The objective of this study was to determine transcriptomic changes in response to synthetic BVC that could be associated with plant resistance to Rhizoctonia solani in creeping bentgrass. The 2,3-butanediol (BD) (250 uM) was sprayed on creeping bentgrass leaves grown in jam jars. The result showed that synthetic BD induced plant defense against R. solani for creeping bentgrass. Transcriptomic analysis demonstrated that more genes were repressed by BD while less showed up regulation. BD suppressed the expression of some regular stress-related genes in creeping bentgrass, such as pheromone activity, calcium channel activity, photosystem II oxygen evolving complex, and hydrolase activity, while up regulated defense related transcription factors (TFs), such as basic helix-loop helix (bHLH) TFs, cysteine2-cysteine2-contans-like (C2C2-CO) and no apical meristem TFs (NAC). Other genes related to disease resistance, such as jasmonic acid (JA) signaling, leucine rich repeats (LRR)-transmembrane protein kinase, pathogen-related (PR) gene 5 receptor kinase and nucleotide binding site-leucine rich repeats (NBS-LRR) domain containing plant resistance gene (R-gene) were also significantly up-regulated. These results suggest that BD may induce changes to the plant transcriptome in induced systemic resistance (ISR) pathways. PMID- 28813017 TI - A Wireless ExG Interface for Patch-Type ECG Holter and EMG-Controlled Robot Hand. AB - This paper presents a wearable electrophysiological interface with enhanced immunity to motion artifacts. Anti-artifact schemes, including a patch-type modular structure and real-time automatic level adjustment, are proposed and verified in two wireless system prototypes of a patch-type electrocardiogram (ECG) module and an electromyogram (EMG)-based robot-hand controller. Their common ExG readout integrated circuit (ROIC), which is reconfigurable for multiple physiological interfaces, is designed and fabricated in a 0.18 MUm CMOS process. Moreover, analog pre-processing structures based on envelope detection are integrated with one another to mitigate signal processing burdens in the digital domain effectively. PMID- 28813016 TI - A Novel High-Mannose Specific Lectin from the Green Alga Halimeda renschii Exhibits a Potent Anti-Influenza Virus Activity through High-Affinity Binding to the Viral Hemagglutinin. AB - We have isolated a novel lectin, named HRL40 from the green alga Halimeda renschii. In hemagglutination-inhibition test and oligosaccharide-binding experiment with 29 pyridylaminated oligosaccharides, HRL40 exhibited a strict binding specificity for high-mannose N-glycans having an exposed (alpha1-3) mannose residue in the D2 arm of branched mannosides, and did not have an affinity for monosaccharides and other oligosaccharides examined, including complex N-glycans, an N-glycan core pentasaccharide, and oligosaccharides from glycolipids. The carbohydrate binding profile of HRL40 resembled those of Type I high-mannose specific antiviral algal lectins, or the Oscillatoria agardhii agglutinin (OAA) family, which were previously isolated from red algae and a blue green alga (cyanobacterium). HRL40 potently inhibited the infection of influenza virus (A/H3N2/Udorn/72) into NCI-H292 cells with half-maximal effective dose (ED50) of 2.45 nM through high-affinity binding to a viral envelope hemagglutinin (KD, 3.69 * 10-11 M). HRL40 consisted of two isolectins (HRL40-1 and HRL40-2), which could be separated by reverse-phase HPLC. Both isolectins had the same molecular weight of 46,564 Da and were a disulfide -linked tetrameric protein of a 11,641 Da polypeptide containing at least 13 half-cystines. Thus, HRL40, which is the first Type I high-mannose specific antiviral lectin from the green alga, had the same carbohydrate binding specificity as the OAA family, but a molecular structure distinct from the family. PMID- 28813018 TI - Biophysical and Computational Studies of the vCCI:vMIP-II Complex. AB - Certain viruses have the ability to subvert the mammalian immune response, including interference in the chemokine system. Poxviruses produce the chemokine binding protein vCCI (viral CC chemokine inhibitor; also called 35K), which tightly binds to CC chemokines. To facilitate the study of vCCI, we first provide a protocol to produce folded vCCI from Escherichia coli (E. coli.) It is shown here that vCCI binds with unusually high affinity to viral Macrophage Inflammatory Protein-II (vMIP-II), a chemokine analog produced by the virus, human herpesvirus 8 (HHV-8). Fluorescence anisotropy was used to investigate the vCCI:vMIP-II complex and shows that vCCI binds to vMIP-II with a higher affinity than most other chemokines, having a Kd of 0.06 +/- 0.006 nM. Nuclear magnetic resonance (NMR) chemical shift perturbation experiments indicate that key amino acids used for binding in the complex are similar to those found in previous work. Molecular dynamics were then used to compare the vCCI:vMIP-II complex with the known vCCI:Macrophage Inflammatory Protein-1beta/CC-Chemokine Ligand 4 (MIP 1beta/CCL4) complex. The simulations show key interactions, such as those between E143 and D75 in vCCI/35K and R18 in vMIP-II. Further, in a comparison of 1 MUs molecular dynamics (MD) trajectories, vMIP-II shows more overall surface binding to vCCI than does the chemokine MIP-1beta. vMIP-II maintains unique contacts at its N-terminus to vCCI that are not made by MIP-1beta, and vMIP-II also makes more contacts with the vCCI flexible acidic loop (located between the second and third beta strands) than does MIP-1beta. These studies provide evidence for the basis of the tight vCCI:vMIP-II interaction while elucidating the vCCI:MIP-1beta interaction, and allow insight into the structure of proteins that are capable of broadly subverting the mammalian immune system. PMID- 28813019 TI - Grafting Modification of the Reactive Core-Shell Particles to Enhance the Toughening Ability of Polylactide. AB - In order to overcome the brittleness of polylactide (PLA), reactive core-shell particles (RCS) with polybutadiene as core and methyl methacrylate-co-styrene-co glycidyl methacrylate as shell were prepared to toughen PLA. Tert-dodecyl mercaptan (TDDM) was used as chain transfer agent to modify the grafting properties (such as grafting degree, shell thickness, internal and external grafting) of the core-shell particles. The introduction of TDDM decreased the grafting degree, shell thickness and the Tg of the core phase. When the content of TDDM was lower than 1.15%, the RCS particles dispersed in the PLA matrix uniformly-otherwise, agglomeration took place. The addition of RCS particles induced a higher cold crystallization temperature and a lower melting temperature of PLA which indicated the decreased crystallization ability of PLA. Dynamic mechanical analysis (DMA) results proved the good miscibility between PLA and the RCS particles and the increase of TDDM in RCS induced higher storage modulus of PLA/RCS blends. Suitable TDDM addition improved the toughening ability of RCS particles for PLA. In the present research, PLA/RCS-T4 (RCS-T4: the reactive core shell particles with 0.76 wt % TDDM addition) blends displayed much better impact strength than other blends due to the easier cavitation/debonding ability and good dispersion morphology of the RCS-T4 particles. When the RCS-T4 content was 25 wt %, the impact strength of PLA/RCS-T4 blend reached 768 J/m, which was more than 25 times that of the pure PLA. PMID- 28813020 TI - Nine New Triterpene Glycosides, Magnumosides A1-A4, B1, B2, C1, C2 and C4, from the Vietnamese Sea Cucumber Neothyonidium (=Massinium) magnum: Structures and Activities against Tumor Cells Independently and in Synergy with Radioactive Irradiation. AB - Nine new sulfated triterpene glycosides, magnumosides A1 (1), A2 (2), A3 (3), A4 (4), B1 (5), B2 (6), C1 (7), C2 (8) and C4 (9) as well as a known colochiroside B2 (10) have been isolated from the tropical Indo-West Pacific sea cucumber Neothynidium (=Massinium) magnum (Phyllophoridae, Dendrochirotida) collected in the Vietnamese shallow waters. The structures of new glycosides were elucidated by 2D NMR spectroscopy and mass-spectrometry. All the isolated new glycosides were characterized by the non-holostane type lanostane aglycones having 18(16) lactone and 7(8)-double bond and differed from each other by the side chains and carbohydrate moieties structures. Magnumoside A1 (1) has unprecedented 20(24) epoxy-group in the aglycone side chain. Magnumosides of the group A (1-4) contained disaccharide monosulfated carbohydrate moieties, of the group B (5, 6) tetrasaccharide monosulfated carbohydrate moieties and, finally, of the group C (7-9)-tetrasaccharide disulfated carbohydrate moieties. The cytotoxic activities of the compounds 1-9 against mouse spleen lymphocytes, the ascites form of mouse Ehrlich carcinoma cells, human colorectal carcinoma DLD-1 cells as well as their hemolytic effects have been studied. Interestingly, the erythrocytes were more sensitive to the glycosides action than spleenocytes and cancer cells tested. The compounds 3 and 7 significantly inhibited the colony formation and decreased the size of colonies of DLD-1 cancer cells at non-cytotoxic concentrations. Moreover, the synergism of effects of radioactive irradiation and compounds 3 and 7-9 at subtoxic doses on proliferation of DLD-1 cells was demonstrated. PMID- 28813021 TI - Enhanced Cell Growth of Adipocyte-Derived Mesenchymal Stem Cells Using Chemically Defined Serum-Free Media. AB - The multipotency and anti-inflammatory effects of mesenchymal stem cells (MSCs) make them attractive for cell therapy in regenerative medicine. A large number of MSCs is required for efficient therapy owing to the low homing efficiency of MSCs to target sites. Furthermore, owing to limitations in obtaining sufficient amounts of MSCs, in vitro expansion of MSCs that preserves their differentiation and proliferative potential is essential. The animal factor included in culture media also limits clinical application. In this study, adipose-derived MSCs showed a significantly higher proliferation rate in STK2, a chemically-defined medium, than in DMEM/FBS. The expression of MSC surface markers was increased in the culture using STK2 compared to that using DMEM/FBS. Tri-lineage differentiation analyses showed that MSCs cultured in STK2 were superior to those cultured in DMEM/FBS. In addition, MSCs cultured in STK2 showed a reduced senescence rate, small and homogenous cell size, and were more genetically stable compared to those cultured in DMEM/FBS. Furthermore, secretome analysis showed that the expression of factors related to proliferation/migration, anti inflammation, and differentiation were increased in STK2 culture medium compared to DMEM/FBS. Taken together, these results suggest that culture using STK2 medium offers many advantages through which it is possible to obtain safer, superior, and larger numbers of MSCs. PMID- 28813022 TI - Impact of Orientation on the Vitamin D Weighted Exposure of a Human in an Urban Environment. AB - The vitamin D3-weighted UV exposure of a human with vertical posture was calculated for urban locations to investigate the impact of orientation and obstructions on the exposure. Human exposure was calculated by using the 3D geometry of a human and integrating the radiance, i.e., the radiant energy from the direct solar beam and the diffuse sky radiation from different incident and azimuth angles. Obstructions of the sky are derived from hemispherical images, which are recorded by a digital camera with a fisheye lens. Due to the low reflectivity of most surfaces in the UV range, the radiance from obstructed sky regions was neglected. For spring equinox (21 March), the exposure of a human model with winter clothing in an environment where obstructions cover 40% of the sky varies by up to 25%, depending on the orientation of the human model to the sun. The calculation of the accumulated vitamin D3-weighted exposure of a human with winter clothing walking during lunch break shows that human exposure is reduced by the obstruction of buildings and vegetation by 40%. PMID- 28813023 TI - Accuracy of Flight Altitude Measured with Low-Cost GNSS, Radar and Barometer Sensors: Implications for Airborne Radiometric Surveys. AB - Flight height is a fundamental parameter for correcting the gamma signal produced by terrestrial radionuclides measured during airborne surveys. The frontiers of radiometric measurements with UAV require light and accurate altimeters flying at some 10 m from the ground. We equipped an aircraft with seven altimetric sensors (three low-cost GNSS receivers, one inertial measurement unit, one radar altimeter and two barometers) and analyzed ~3 h of data collected over the sea in the (35-2194) m altitude range. At low altitudes (H < 70 m) radar and barometric altimeters provide the best performances, while GNSS data are used only for barometer calibration as they are affected by a large noise due to the multipath from the sea. The ~1 m median standard deviation at 50 m altitude affects the estimation of the ground radioisotope abundances with an uncertainty less than 1.3%. The GNSS double-difference post-processing enhanced significantly the data quality for H > 80 m in terms of both altitude median standard deviation and agreement between the reconstructed and measured GPS antennas distances. Flying at 100 m the estimated uncertainty on the ground total activity due to the uncertainty on the flight height is of the order of 2%. PMID- 28813024 TI - Advances in Understanding of Penile Carcinogenesis: The Search for Actionable Targets. AB - Penile cancer (PeCa) is a rare malignancy with potentially devastating effects. Squamous cell carcinoma is the most common variant with distinct precancerous lesions before development into invasive disease. Involvement of the inguinal lymph nodes is the most important prognostic factor in PeCa, and once disease is present outside the groin, prognosis is poor. Metastatic PeCa is challenging to treat and often requires multidisciplinary approaches in management. Due to its rarity, molecular understanding of the disease continues to be limited with most studies based on small, single center series. Thus far, it appears PeCa has diverse mechanisms of carcinogenesis affecting similar molecular pathways. In this review, we evaluate the current landscape of the molecular carcinogenesis of PeCa and explore ongoing research on potential actionable targets of therapy. The emergence of anti-epidermal growth factor receptor (EGFR) and other immunotherapeutic strategies may improve outcomes for PeCa patients. PMID- 28813025 TI - Association between Promoter Methylation of Gene ERCC3 and Benzene Hematotoxicity. AB - Benzene is a primary industrial chemical and a ubiquitous environmental pollutant. ERCC3 is a key player in nucleotide excision repair. Recent studies suggested that site-specific methylation is a possible mechanism of the transcriptional dysregulation by blocking transcription factors binding. We previously found that the average promoter methylation level of ERCC3 was increased in benzene-exposed workers. In order to test whether specific CpG sites of ERCC3 play an important role in benzene-induced epigenetic changes and whether the specific methylation patterns are associated with benzene hematotoxicity, we analyzed the promoter methylation levels of individual CpG sites, transcription factor binding motif and the correlation between aberrant CpG methylation and hematotoxicity in 76 benzene-exposed workers and 24 unexposed controls in China. Out of all the CpGs analyzed, two CpG units located 43 bp upstream and 99 bp downstream of the transcription start site of ERCC3 (CpG 2-4 and CpG 17-18, respectively), showed the most pronounced increase in methylation levels in benzene-exposed workers, compared with unexposed controls (Mean +/- SD: 5.86 +/- 2.77% vs. 4.92 +/- 1.53%, p = 0.032; 8.45 +/- 4.09% vs. 6.79 +/- 2.50%, p = 0.024, respectively). Using the JASPAR CORE Database, we found that CpG 2-4 and CpG 17-18 were bound by three putative transcription factors (TFAP2A, E2F4 and MZF1). Furthermore, the methylation levels for CpG 2-4 were correlated negatively with the percentage of neutrophils (beta = -0.676, p = 0.005) in benzene-exposed workers. This study demonstrates that CpG-specific DNA methylation in the ERCC3 promoter region may be involved in benzene-induced epigenetic modification and it may contribute to benzene-induced hematotoxicity. PMID- 28813026 TI - Breath-Figure Self-Assembly, a Versatile Method of Manufacturing Membranes and Porous Structures: Physical, Chemical and Technological Aspects. AB - The review is devoted to the physical, chemical, and technological aspects of the breath-figure self-assembly process. The main stages of the process and impact of the polymer architecture and physical parameters of breath-figure self-assembly on the eventual pattern are covered. The review is focused on the hierarchy of spatial and temporal scales inherent to breath-figure self-assembly. Multi-scale patterns arising from the process are addressed. The characteristic spatial lateral scales of patterns vary from nanometers to dozens of micrometers. The temporal scale of the process spans from microseconds to seconds. The qualitative analysis performed in the paper demonstrates that the process is mainly governed by interfacial phenomena, whereas the impact of inertia and gravity are negligible. Characterization and applications of polymer films manufactured with breath-figure self-assembly are discussed. PMID- 28813027 TI - Sulfonamide-Linked Ciprofloxacin, Sulfadiazine and Amantadine Derivatives as a Novel Class of Inhibitors of Jack Bean Urease; Synthesis, Kinetic Mechanism and Molecular Docking. AB - Sulfonamide derivatives serve as an important building blocks in the drug design discovery and development (4D) process. Ciprofloxacin-, sulfadiazine- and amantadine-based sulfonamides were synthesized as potent inhibitors of jack bean urease and free radical scavengers. Molecular diversity was explored and electronic factors were also examined. All 24 synthesized compounds exhibited excellent potential against urease enzyme. Compound 3e (IC50 = 0.081 +/- 0.003 uM), 6a (IC50 = 0.0022 +/- 0.0002 uM), 9e (IC50 = 0.0250 +/- 0.0007 uM) and 12d (IC50 = 0.0266 +/- 0.0021 uM) were found to be the lead compounds compared to standard (thiourea, IC50 = 17.814 +/- 0.096 uM). Molecular docking studies were performed to delineate the binding affinity of the molecules and a kinetic mechanism of enzyme inhibition was propounded. Compounds 3e, 6a and 12d exhibited a mixed type of inhibition, while derivative 9e revealed a non-competitive mode of inhibition. Compounds 12a, 12b, 12d, 12e and 12f showed excellent radical scavenging potency in comparison to the reference drug vitamin C. PMID- 28813029 TI - Joint Mobile Data Collection and Wireless Energy Transfer in Wireless Rechargeable Sensor Networks. AB - In wireless rechargeable sensor networks (WRSNs), there is a way to use mobile vehicles to charge node and collect data. It is a rational pattern to use two types of vehicles, one is for energy charging, and the other is for data collecting. These two types of vehicles, data collection vehicles (DCVs) and wireless charging vehicles (WCVs), are employed to achieve high efficiency in both data gathering and energy consumption. To handle the complex scheduling problem of multiple vehicles in large-scale networks, a twice-partition algorithm based on center points is proposed to divide the network into several parts. In addition, an anchor selection algorithm based on the tradeoff between neighbor amount and residual energy, named AS-NAE, is proposed to collect the zonal data. It can reduce the data transmission delay and the energy consumption for DCVs' movement in the zonal. Besides, we design an optimization function to achieve maximum data throughput by adjusting data rate and link rate of each node. Finally, the effectiveness of proposed algorithm is validated by numerical simulation results in WRSNs. PMID- 28813031 TI - Pt-Co Alloys-Loaded Cubic SiC Electrode with Improved Photoelectrocatalysis Property. AB - A novel composite photocatalyst was synthesized by loading 5 wt % of platinum cobalt alloy on 3C-SiC nanowires and powder (Pt-Co-SiC) respectively via a simple polyol reduction method. Pt-Co-SiC were comprehensively characterized by SEM, HRTEM, XRD, PL, and XPS. The results indicated that Pt-Co nanoparticles in the size of 2-5 nm were dispersed homogeneously in the SiC nanowires and powders. The photocurrent response of the Pt-Co-SiC increased remarkably with increasing Pt content and the best performance was observed with the sample of Pt3Co-SiC. Especially, the Pt3Co-SiC nanowires photoelectrode exhibited improved cathodic current density (0.14 mA.cm-2) under the simulated sunlight, which was about 10 times higher than the Pt3Co-SiC powders. The H2 production rate for the Pt3Co-SiC nanowires is 30 times more than that of the pure SiC nanowires. The enhancement of the Pt-Co-SiC properties could be ascribed to the fact that more visible light was harvested and the photogenerated electron and the interfacial electron transfered more easily. PMID- 28813030 TI - An Overview of Factors Associated with Adherence to Lifestyle Modification Programs for Weight Management in Adults. AB - This review aims to provide an overview of the factors associated with adherence reported in existing literature on lifestyle modification programs for weight management among the adult population. An electronic search was performed using PubMed, Medline, PsycINFO and PsycARTICLE to identify studies that examined the factors of adherence to lifestyle modification programs with explicit definition of adherence indicators. We identified 19 studies published between 2004 and 2016. The most commonly used indicator of adherence was attrition, followed by attendance, self-monitoring and dietary adherence. A broad array of factors has been studied but only few studies exploring each factor. Limited evidence suggested older age, higher education, healthier eating and physical activity behaviours, higher stage of change at baseline and higher initial weight loss may predict better adherence. On the other hand, having depression, stress, strong body shape concern and full-time job may predict poor adherence. Inconsistent findings were obtained for self-efficacy, motivation, male gender and previous weight loss attempt. This review highlights the need for more rigorous studies to enhance our knowledge on factors related to adherence. Identification of the factors of adherence could provide important implication for program improvement, ultimately improving the effectiveness and the cost-effectiveness of lifestyle modification program. PMID- 28813032 TI - Diterpenoid Alkaloids from Consolida regalis S. F.Gray subsp.paniculata (Host) Soo var. paniculata. AB - Seven diterpenoid alkaloids : delcosine(1), delsoline(2), gigactonine(3), lycoctonine(4), takaosamine(5), atisine(6) and hetisinone(7) have been isolated from the aerial parts of Consolida regalis subsp. paniculata var. paniculata. The presence of compounds 1,2,5,6 and 7 in this plant has not been previously reported. PMID- 28813028 TI - Detection Methodologies for Pathogen and Toxins: A Review. AB - Pathogen and toxin-contaminated foods and beverages are a major source of illnesses, even death, and have a significant economic impact worldwide. Human health is always under a potential threat, including from biological warfare, due to these dangerous pathogens. The agricultural and food production chain consists of many steps such as harvesting, handling, processing, packaging, storage, distribution, preparation, and consumption. Each step is susceptible to threats of environmental contamination or failure to safeguard the processes. The production process can be controlled in the food and agricultural sector, where smart sensors can play a major role, ensuring greater food quality and safety by low cost, fast, reliable, and profitable methods of detection. Techniques for the detection of pathogens and toxins may vary in cost, size, and specificity, speed of response, sensitivity, and precision. Smart sensors can detect, analyse and quantify at molecular levels contents of different biological origin and ensure quality of foods against spiking with pesticides, fertilizers, dioxin, modified organisms, anti-nutrients, allergens, drugs and so on. This paper reviews different methodologies to detect pathogens and toxins in foods and beverages. PMID- 28813034 TI - Incontinence: Shockwave treatment promotes urethral smooth muscle proliferation. PMID- 28813033 TI - A Vision-Based Wayfinding System for Visually Impaired People Using Situation Awareness and Activity-Based Instructions. AB - A significant challenge faced by visually impaired people is 'wayfinding', which is the ability to find one's way to a destination in an unfamiliar environment. This study develops a novel wayfinding system for smartphones that can automatically recognize the situation and scene objects in real time. Through analyzing streaming images, the proposed system first classifies the current situation of a user in terms of their location. Next, based on the current situation, only the necessary context objects are found and interpreted using computer vision techniques. It estimates the motions of the user with two inertial sensors and records the trajectories of the user toward the destination, which are also used as a guide for the return route after reaching the destination. To efficiently convey the recognized results using an auditory interface, activity-based instructions are generated that guide the user in a series of movements along a route. To assess the effectiveness of the proposed system, experiments were conducted in several indoor environments: the sit in which the situation awareness accuracy was 90% and the object detection false alarm rate was 0.016. In addition, our field test results demonstrate that users can locate their paths with an accuracy of 97%. PMID- 28813035 TI - Bladder cancer: The promise of liquid biopsy ctDNA analysis. PMID- 28813036 TI - Prostate cancer: The pathway to progression: DHT biosynthesis. PMID- 28813038 TI - Prostate cancer: A variety of therapy: ARVs mediate DDR. PMID- 28813037 TI - Concomitant bladder cancer and prostate cancer: challenges and controversies. AB - Radical cystoprostatectomy (RCP) followed by bilateral pelvic lymphadenectomy and urinary diversion remains the gold-standard therapy for men with localized muscle invasive bladder cancer (MIBC). Prostate cancer might be incidentally detected at the time of RCP with a reported prevalence of 24-51%. Typically, these patients are considered to have clinically insignificant disease, but data from emerging series challenge this assumption and suggest that some of these tumours might be aggressive, or somehow increase the aggressiveness of the associated MIBC, and can negatively influence the patient's overall survival outcomes. Furthermore, the potential use of prostate-sparing cystectomy in patients with less-aggressive MIBC might lead to newly diagnosed incidental cases of prostate cancer, with characteristics suggestive of clinically significant disease, requiring a specific, separate workup. The development of evidence-based, validated protocols to define the necessary steps for diagnosis of prostate cancer in these patients, including the role of serum PSA testing, digital rectal examination, the role of imaging methods and the indication and type of biopsy protocol, is of major importance to the multidisciplinary management of patients with urological cancer. Finally, the retrospective nature of the available data account for much of the variability in the prevalence of coexisting bladder and prostate cancer and emphasizes the need for randomized trials in this controversial area of urological oncology. PMID- 28813040 TI - Enhanced selectivity of methane production for photocatalytic reduction by the piezoelectric effect. AB - Under simultaneous full arc light and ultrasonic irradiation, photo-generated electrons are brought together by piezoelectric potential, and thus dense electrons induce the reduction of carbon dioxide on the surface of piezoelectric semiconductors, resulting in an improved selectivity of methane production to a greater degree. PMID- 28813039 TI - Comparative assessment of SSR and SNP markers for inferring the population genetic structure of the common fungus Armillaria cepistipes. AB - During the last years, simple sequence repeats (SSRs, also known as microsatellites) and single-nucleotide polymorphisms (SNPs) have become the most popular molecular markers for describing neutral genetic variation in populations of a wide range of organisms. However, only a limited number of studies has focused on comparing the performance of these two types of markers for describing the underlying genetic structure of wild populations. Moreover, none of these studies targeted fungi, the group of organisms with one of the most complex reproductive strategies. We evaluated the utility of SSRs and SNPs for inferring the neutral genetic structure of Armillaria cepistipes (basidiomycetes) at different spatial scales. For that, 407 samples were collected across a small (150 km2) area in the Ukrainian Carpathians and a large (41 000 km2) area in the Swiss Alps. All isolates were analyzed at 17 SSR loci distributed throughout the whole genome and at 24 SNP loci located in different single-copy conserved genes. The two markers showed different patterns of structure within the two spatial scales studied. The multi-allelic SSR markers seemed to be best suited for detecting genetic structure in indigenous fungal populations at a rather small spatial scale (radius of ~50-100 km). The pattern observed at SNP markers rather reflected ancient divergence of distant (~1000 km) populations that in addition are separated by mountain ranges. Despite these differences, both marker types were suitable for detecting the weak genetic structure of the two A. cepistipes populations investigated. PMID- 28813041 TI - Supported nickel-rhenium catalysts for selective hydrogenation of methyl esters to alcohols. AB - The addition of Re to Ni on TiO2 yields efficient catalysts for the hydrogenation of acids and esters to alcohols under mild conditions. Rhenium promotes the formation of atomically dispersed and sub-nanometre-sized bimetallic species interacting strongly with the oxide support. PMID- 28813042 TI - The carotenoid pathway: what is important for excitation quenching in plant antenna complexes? AB - Plant light-harvesting is regulated by the Non-Photochemical Quenching (NPQ) mechanism involving the reversible formation of excitation quenching sites in the Photosystem II (PSII) antenna in response to high light. While the major antenna complex, LHCII, is known to be a site of NPQ, the precise mechanism of excitation quenching is not clearly understood. A preliminary model of the quenched crystal structure of LHCII implied that quenching arises from slow energy capture by Car pigments. It predicted a thoroughly quenched system but offered little insight into the defining aspects of this quenching. In this work, we present a thorough theoretical investigation of this quenching, addressing the factors defining the quenching pathway and possible mechanism for its (de)activation. We show that quenching in LHCII crystals is the result of slow energy transfer from chlorophyll to the centrally-bound lutein Cars, predominantly the Lut620 associated with the chlorophyll 'terminal emitter', one of the proposed in vivo pathways. We show that this quenching is rather independent of the particular species of Car and excitation 'site' energy. The defining parameter is the resonant coupling between the pigment co-factors. Lastly, we show that these interactions must be severely suppressed for a light-harvesting state to be recovered. PMID- 28813043 TI - Folic acid supramolecular ionogels. AB - Herein, we report on folic acid (FA, a low molecular weight gelator) thermoreversible supramolecular organo (in 1 : 1 (v/v) water-DMSO binary solvent), and ionogels made in 1-ethyl-3-methyl imidazolium chloride, [C2mim][Cl], and 1-octyl-3-methyl imidazolium chloride, [C8mim][Cl], solutions with 0.1 <= [IL] <= 5% (w/v). The self-assembled fibrils of folic acid were largely formed due to secondary forces, such as pi-pi stacking, H-bonding, and hydrophobic interactions above a gelator concentration of 0.2% (w/v) at room temperature, 20 degrees C. Fragile gels (FGs) having a low frequency storage modulus G0 ~ 4-6 Pa were formed when 0.2 <= [FA] <= 0.5% (w/v) in the binary solvent, and at higher gelator concentration (0.5 <= [FA] <= 2.5% (w/v)) formation of strong gels (SGs) with a G0 value of 140 Pa-5 kPa was noticed. In the IL environment, for a given gelator concentration of [FA] = 1% (w/v), SG formation (with G0 ~ 2-5 kPa) was noticed when 0.1 <= [IL] <= 0.5% (w/v), whereas very strong gels (VSGs) with remarkably high gel strengths were formed with G0 ~ 11-15 kPa. Gelation temperature Tgel could be varied from 45 to 75 degrees C by varying the FA concentration in the binary solvent, whereas the ionogels exhibited an almost 10 degrees C rise in gelation temperature. The information obtained from the relative network density nur (ratio of network density in iono- to organo gel), differential free-energy and enthalpy of gelation, DeltaGW-IL and DeltaHW-IL (difference in free-energy and enthalpy of organo to ionogel), implied that [C2mim][Cl] ionogels had enhanced homogeneity, and higher crosslink density and gel strength. A 3-D plot of Tgel and G0versus gelator concentration clearly defines a phase diagram that describes the contour of the gelation domains of this biologically important gelator. PMID- 28813044 TI - Short bent-core molecules: X-ray, polarization, dielectricity, texture and electro-optics investigations. AB - Bent-core liquid crystals based on 1,2,4-oxadiazole as a central unit have been the first mesogens to exhibit a ferroelectric response in the nematic phase. This behavior has been widely recognized as due to the presence of smectic-like polar cybotactic clusters permeating the nematic phase. Unfortunately, these compounds exhibited rather high melting points, about 120 degrees C, due to the presence of four benzene rings in the molecules. Here we describe the synthesis and physical characterization of a new series of BC mesogens, featuring the same bent core as the previous compounds but shorter outer substituents. By keeping only two benzene rings, we were able to lower the melting points to about 70 degrees C. However, while X-ray diffraction and dielectric spectroscopy measurements confirm the cybotactic nature of the nematic phase of these compounds, polarization and electro-optical measurements ascribe their polar response to flexoelectricity rather than to spontaneous polarization. Finally, texture investigation suggests the biaxiality of the nematic phase, which is indicated also by conoscopic measurements. These results are important for recognizing size and rigidity limitations in designing bent-core liquid crystal molecules suitable for applications. PMID- 28813046 TI - Cold atom-atom-ion three-body recombination of 4He-4He-X- (X = H or D). AB - The atom-atom-ion three-body recombination (TBR) of mixed 4He and X- (X = H or D) systems is investigated by solving the Schrodinger equation using the adiabatic hyperspherical representation method. It is shown that the dominant products after a TBR in the ultracold limit (E <= 0.1 mK * kB) are different for the two systems. For the 4He4HeH- system, the rate of TBR into the 4HeH- ion is nearly two orders of magnitude larger than that of TBR into the neutral 4He2 molecule. In contrast, the yield of 4He2 is a little higher than that of 4HeD- for the 4He4HeD- system. Furthermore, since the adiabatic potentials become more attractive and the nonadiabatic couplings become much stronger by substituting D for H in the 4He4HeH- system, the total TBR rate for the 4He4HeD- system is nearly two orders of magnitude larger than that for the 4He4HeH- system. PMID- 28813049 TI - Unprecedented solvent induced inter-conversion between monomeric and dimeric silylene-zinc iodide adducts. AB - Usually, when a silylene reacts with a transition metal Lewis acid, it forms an adduct which could be either monomeric or dimeric. However, we present here that a silylene, [PhC(NtBu)2SiN(SiMe3)2] can form both monomeric [PhC(NtBu)2Si{N(SiMe3)2} -> ZnI2].THF (1) and dimeric [{PhC(NtBu)2}(N(SiMe3)2)SiZnI,(MU-I)]2 (2) adducts upon reaction with ZnI2. The formation of 1 and 2 relies upon the solvent used for the reaction or crystallization. When the crystallization is carried out in THF complex 1 is formed, however, when the reaction and crystallization are performed in acetonitrile complex 2 is obtained. Both 1 and 2 were structurally authenticated and the nature of the Si-Zn bond in these complexes was determined by quantum chemical calculations. In addition, a spontaneous inter-conversion between 1 and 2 just by changing the solvents has been also observed; a feature presently not known for silylene-transition metal Lewis adducts. PMID- 28813050 TI - On-surface synthesis of heptacene and its interaction with a metal surface. AB - Heptacene was generated by surface-assisted didecarbonylation of an alpha diketone precursor on a Ag(111) surface. Monitoring of the surface reaction and characterization of the adsorbed heptacene was performed with scanning tunneling microscopy (STM), X-ray photoelectron spectroscopy (XPS), near-edge X-ray absorption fine structure (NEXAFS) spectroscopy, and density functional theory (DFT) calculations. The surface-assisted formation of heptacene occurs around 460 K. Both the heptacene and the precursor molecules are oriented along the high symmetry directions of the (111) surface and their molecular pi systems face towards the substrate. The interaction with the Ag(111) substrate is not laterally uniform, but appears to be strongest on the central part of the molecule, in line with the expectations from Clar's rule. In the STM images, heptacene shows a dumbbell shape, which may correspond to the substantial out-of plane deformations of heptacene on Ag(111). As revealed by DFT, the center of the molecule is closer to the surface than the outer parts. In addition, the inner rings are most affected by charge redistribution between surface and molecule. Heptacene acts as an acceptor and receives a negative charge of -0.6e from the Ag(111) surface. Since vacuum-sublimable alpha-diketone precursors for even larger acenes are available, the approach is promising for the on-surface synthesis of higher acene homologues such as octacene and nonacene. PMID- 28813052 TI - Mixed-ligand iridium(iii) complexes as photodynamic anticancer agents. AB - Many phosphorescent iridium complexes are potent candidates as photodynamic therapeutic agents. In this work, a series of mixed-ligand phosphorescent iridium complexes (Ir1: [Ir(L1)(bpy)Cl](PF6)2; Ir2: [Ir(L1)(ppy)Cl](PF6); Ir3: [Ir(L2)(bpy)Cl](PF6)2; Ir4: [Ir(L2)(ppy)Cl](PF6). L1 = 2,6-bis(2 benzimidazolyl)pyridine; bpy = 2,2'-bipyridine; L2 = 2,6-bis(1-methyl benzimidazol-2-yl)pyridine; ppy = 2-phenylpyridine) have been synthesized and characterized. These complexes display high luminescence quantum yields and long phosphorescence lifetimes. All the complexes are resistant to hydrolysis in aqueous solutions, and can produce singlet oxygen (1O2) effectively upon irradiation. Ir1 and Ir2 show pH-sensitive emission properties. Interestingly, higher cellular uptake efficiency is observed for Ir2 and Ir4 with the cyclometalated ppy ligand in human lung adenocarcinoma A549 cells. Ir2 with pH sensitive emission properties can selectively image lysosomes, and Ir4 can specifically target mitochondria. Both Ir2 and Ir4 exhibit potent photodynamic therapy (PDT) effects, with Ir2 displaying a higher phototoxicity index (PI) especially in A549 cells (PI > 54). Mechanism studies indicate that Ir2 and Ir4 can induce apoptosis through reactive oxygen species (ROS) generation and caspase activation upon visible light (425 nm) irradiation. As expected, Ir2 can damage lysosomes more effectively with a pH-sensitive singlet oxygen (1O2) yield, while Ir4 tends to impair mitochondrial function. Nevertheless, the practical application of Ir2 and Ir4 for PDT may be limited to superficial tumors due to the short excitation wavelength (425 nm). Our study gives insights into the design and anticancer mechanisms of new metal-based PDT anticancer agents. PMID- 28813053 TI - Copper(ii)-benzimidazole complexes as efficient fluorescent probes for l-cysteine in water. AB - Copper(ii) complexes [Cu(L1)(H2O)2](SO3CF3)21 and [Cu(L2)(H2O)2](SO3CF3)22 based on 2,6-bis(benzimidazolyl)pyridine were synthesized and are reported herein as highly selective "turn-on" optical probes for l-cysteine. The Cu(ii)/Cu(i) redox potential of probe 1 (0.14 V vs. NHE) was lower than that of 2 (0.233 V vs. NHE) in water. The molecular structure of 2 adopted a square pyramidal geometry (tau = 0.2545), with the Cu-Npy bond (1.958 A) of its middle pyridine unit being shorter than the other two Cu-Nbenzim bonds (Cu-N, 1.995, 2.000 A). The axial Cu-O2 bond distance (2.247 A) was slightly longer than the equatorial Cu-O1 bond distance (1.953 A). The square-based geometry was further supported by the A? value of 156 * 10-4 cm-1 in EPR at 70 K. The d-d and ligand-based transitions appeared at 662 and 314-356 nm for 1 and 651 and 313-360 nm for 2, respectively, in HEPES buffer at pH 7.34. These probes showed selective and efficient "turn-on" fluorescence behaviour towards Cys over other natural amino acids with a binding constant for 1 of 5.4 * 104 and 1.30 * 104 M-1 for 2 and a limit of detection of 2.9 * 10-8 M and 3.32 * 10-8 M, respectively, for 1 and 2 at pH 7.34. The quantum yield for the detection of Cys by 1 (14.7%) was much lower than by 2 (23%). The fluorescence intensity of 1 and 2 were also slightly enhanced by histidine, but at a relatively lower level than that exhibited by Cys. PMID- 28813058 TI - Fine tuning of catalytic and sorption properties of metal-organic frameworks via in situ ligand exchange. AB - Metal-organic frameworks (MOFs) are gaining considerable attention not only because of their diverse structures but also due to their interesting properties and potential applications. However, fabrication of MOFs with desired structures and properties remains a great challenge. In this study, a strategy based on ligand exchange via single-crystal-to-single-crystal (SCSC) transformation has been undertaken, which can be used to achieve MOFs not available by direct synthesis and also to enrich the family of isoreticular MOFs. Direct X-ray crystallographic observation provides undoubted evidence that the pyrazine (pyz) ligand in [Cu3(L)2(pyz)(H2O)] (L3- = [1,1':3',1''-terphenyl]-4,4'',5' tricarboxylate) was replaced by its derivatives without damaging the framework. Furthermore, the catalytic and sorption properties of the MOFs are able to be fine-tuned by introducing definite substituent group decorated on the pore surface. Thus, it is expected that the ligand exchange will be powerful for replacing linker molecules with others having desirable substituents, and as a result to afford desired MOFs. PMID- 28813055 TI - Multivesicular droplets: a cell model system to study compartmentalised biochemical reactions. AB - Multivesicular vesicles (MVVs) are artificial liposomal structures widely used as a platform to study the compartmentalisation of cells and as a scaffold for artificial cell/protocell models. Current preparation techniques for MVVs, however, offer poor control on the size, lamellarity, and loading of inner lipid vesicles. Here, we introduce a microfluidic device for the production of multivesicular droplets (MVDs): a novel model system combining the ease of use and control of droplet microfluidics with the biological relevance of MVVs. We use a perfluorinated carrier phase with a biocompatible surfactant to generate monodisperse droplets of an aqueous giant unilamellar lipid vesicle suspension. The successful on-chip formation and stability of MVDs is verified through high speed microscopy. For bright field or fluorescence microscopy inspection, the MVDs are trapped in an array where the integrity of both lipid vesicles and droplets is preserved for up to 15 minutes. Finally, we show a two-step enzymatic reaction that takes place across the lipid vesicle membranes; the second reaction step occurs in the vesicle's interior, where the enzyme is encapsulated, while both the substrate and fluorescent product permeate across the membrane. Our approach opens the possibility to mimic artificial organelles with optimised reaction parameters (pH, ions, etc.) in each compartment. PMID- 28813061 TI - Indole synthesis by palladium-catalyzed tandem allylic isomerization - furan Diels-Alder reaction. AB - A Pd(0)-catalyzed elimination of an allylic acetate generates a pi-allyl complex that is postulated to initiate a novel intramolecular Diels-Alder cycloaddition to a tethered furan (IMDAF). Under the reaction conditions, this convergent, microwave-accelerated cascade process provides substituted indoles in moderate to good yields after Pd-hydride elimination, aromatization by dehydration, and in situ N-Boc cleavage. PMID- 28813063 TI - Tuning mass transport in magnetic nanoparticle-filled viscoelastic hydrogels using low-frequency rotating magnetic fields. AB - This study investigates the response of magnetic nanoparticles (MNPs), dispersed in a viscoelastic hydrogel, to an external rotating magnetic field (RMF) for the purpose of developing a new class of magneto-responsive materials with tunable mass transport properties. Ferrogels were prepared by chemical cross-linking and polymerization of acrylamide in colloidal dispersions of thermally blocked MNPs of cobalt ferrite. Magnetization measurements of ferrogels in a swollen state revealed a transitional state from ferromagnetism to superparamagnetism through the shrinkage of hysteresis loops and the reduction of remanent magnetization. A quantitative analysis of magnetization data indicated the existence of hydrodynamically free MNPs, susceptible to Brownian relaxation along with the blocked ones. It was found through rheological analysis that inclusion of MNPs within the polymer matrix significantly alters the ferrogel's elasticity. At low chemical crosslinking ratios, MNPs improve elasticity through the formation of physical crosslinks ensued by reduction in the fraction of the free MNPs. As the crosslinking ratio was increased, the polymer network showed a tendency toward blockage of more MNPs. Effective diffusion coefficients in both particle-free hydrogels and ferrogels were obtained by measuring the release kinetics of a model compound in the absence and presence of an external low-frequency RMF. Experimental results showed that conversion of magnetic energy to kinetic energy by rotational movement of the free MNPs in a RMF escalates mass transport provided that hydrodynamically free MNPs are available within the ferrogels. The effectiveness of excitation by a RMF showed correlation with the density of free MNPs. Release experiments at constant RMF intensity and various frequencies revealed augmentation of effective diffusivities as the frequency was increased from 10 to 75 Hz. PMID- 28813066 TI - Multivalent mesoporous silica nanoparticles photo-delivering nitric oxide with carbon dots as fluorescence reporters. AB - Amino-terminated mesoporous silica nanoparticles embedding carbon dots (MSCD) formed by calcination were functionalized with a nitric oxide (NO) photodonor (1) to give a robust MSCD-1 conjugate. The intense fluorescence of MSCDs was strongly quenched in MSCD-1 by effective energy transfer. Visible light excitation of MSCD 1 liberates NO, suppresses the energy transfer mechanism and leads to concomitant fluorescence restoration of the MSCD scaffold, which acts as an optical reporter for the released NO. The MSCD-1 hybrid is also able to encapsulate the highly hydrophobic photosensitizer temoporfin, preserving the fluorescence reporting function. PMID- 28813067 TI - Total syntheses of smenothiazoles A and B. AB - Concise total syntheses of smenothiazoles A (1) and B (2), two distinguished vinyl chloride containing natural products isolated from the marine sponge S. aurea, have been developed. Silastannation, Stille reaction and a carefully controlled desilylchlorination were employed as key steps to construct unique polyketide acid fragments, and the optimized reaction conditions avoided migration of 2,5-diene to a 2,4-conjugated system. This report unambiguously confirmed the structures of both natural products. PMID- 28813068 TI - Cultural adaptation of the short Self-Regulation Questionnaire: suggestions for the speech area. AB - Purpose: To present the translated and linguistic and culturally adapted version of the Short self-regulation Questionnaire (SSRQ) for the Brazilian Portuguese and to check its applicability to patients with dysphonia. Methods: The SSRQ is a tool used to evaluate the ability to self-regulate behavior; it has 31 items and generates three scores: total index of individual self-regulation capacity and partial scores for goal setting and impulse control. Each item should be scored by means of a Likert-type 5-point scale; the total score ranges from 29 to 145 points. The original instrument was translated and culturally adapted to Brazilian Portuguese by two English-speaking speech therapists who combined their translations and made linguistic adjustments to compose a single final version. This version was back-translated by a third speech therapist with experience in validation studies and without knowledge of the original instrument. The translation and the back-translation were compared with each other and with the original English version by five speech therapists that reached a consensus on additional changes. In this way, the final version was produced. This was called "Questionario Reduzido de Autorregulacao" (QRAR). The QRAR was applied to 45 randomly chosen subjects with and without dysphonia in a teaching clinic. Results: No item had to be eliminated, since the respondents did not find it difficult to indicate their answers. Conclusion: The "Questionario Reduzido de Autorregulacao" (QRAR) has been successfully translated and culturally and linguistically adapted to Brazilian and Portuguese and can be applied to individuals with voice problems. PMID- 28813070 TI - Neonatal Hearing Screening in primary health care and family health care. AB - Purpose: The Universal Newborn Hearing Screening (UNHS) looks for early diagnosis and rehabilitation of newborns at risk or not of hearing impairment. The purpose is analyze the flow of Universal Newborn Hearing Screening in the family health care strategy unit through the tracking and monitoring of children. Methods: This is a quantitative and retrospective study. The trace begins with the third copy of the Live Newborn Declaration, filled in at the maternity ward. An interview with parents and guardians was made by a community agent at the Health Unit or at the home of the newborn. Monitoring was conducted by live birth declaration and the information collected by the interviewer from maternal and child health booklet and the follow-up at high complexity services. Results: The sample was made up of 50 neonates. 52% were between 30 and 89 days and 54% were male. 12% of newborns presented a risk factor for hearing loss and the neonatal screening was performed in 86% of cases. Hearing health measures show integrality in hearing impairment care at the basic health unit to high complexity hospital. Conclusion: The flow of care for newborn hearing screening is in agreement with the child health care guidelines in Curitiba, however, it is not yet universal. In conclusion, the participation of the family health strategy unit in the tracking and monitoring of children submitted to the Universal newborn hearing screening program is feasible and recommended. PMID- 28813071 TI - Content validation: clarity/relevance, reliability and internal consistency of enunciative signs of language acquisition. AB - Purpose: To analyze the results of the validation of building enunciative signs of language acquisition for children aged 3 to 12 months. Methods: The signs were built based on mechanisms of language acquisition in an enunciative perspective and on clinical experience with language disorders. The signs were submitted to judgment of clarity and relevance by a sample of six experts, doctors in linguistic in with knowledge of psycholinguistics and language clinic. In the validation of reliability, two judges/evaluators helped to implement the instruments in videos of 20% of the total sample of mother-infant dyads using the inter-evaluator method. The method known as internal consistency was applied to the total sample, which consisted of 94 mother-infant dyads to the contents of the Phase 1 (3-6 months) and 61 mother-infant dyads to the contents of Phase 2 (7 to 12 months). The data were collected through the analysis of mother-infant interaction based on filming of dyads and application of the parameters to be validated according to the child's age. Data were organized in a spreadsheet and then converted to computer applications for statistical analysis. Results: The judgments of clarity/relevance indicated no modifications to be made in the instruments. The reliability test showed an almost perfect agreement between judges (0.8 <= Kappa >= 1.0); only the item 2 of Phase 1 showed substantial agreement (0.6 <= Kappa >= 0.79). The internal consistency for Phase 1 had alpha = 0.84, and Phase 2, alpha = 0.74. This demonstrates the reliability of the instruments. Conclusion: The results suggest adequacy as to content validity of the instruments created for both age groups, demonstrating the relevance of the content of enunciative signs of language acquisition. PMID- 28813072 TI - Stage of readiness of patients with behavioral dysphonia in pre and post-group voice therapy assessments. AB - Purpose: To verify the efficacy of group voice therapy in the stage of readiness and identify which items of the URICA-Voice range are more sensitive to post therapy change in patients with behavioral dysphonia. Methods: An intervention study was conducted on 49 patients with behavioral dysphonia. An eclectic approach to group therapy was implemented over eight sessions, the first and last sessions consisting of assessments. The URICA-Voice range was used to evaluate the stage of readiness at pre- and post-therapy assessments. A descriptive and inferential statistical analysis was implemented for the results. Results: Most participants were female, did not make professional use of voice, and had membranous vocal fold lesions. Most of them were in the Contemplation stage at in both moments, pre- and post-therapy. There was no significant change in the comparison of pre- and post-therapy scores. The majority of patients showed a reduction in the stage of readiness and some advanced to a higher stage. In the comparison of URICA-V range items, seven questions had equal or inferior responses in the post-therapy assessment. Conclusion: There was no statistical difference when comparing the pre- and post-therapy total average score of the URICA-Voice range. There were significant changes in the stage of readiness of patients in pre- and post-group speech therapy assessments. PMID- 28813073 TI - Functional health literacy and quality of life of high-school adolescents in state schools in Belo Horizonte. AB - Purpose: To investigate the association between functional health literacy and sociodemographic factors, quality of life, self-perception of health, and perception of contexts of violence in adolescents in state schools in Belo Horizonte. Methods: This is a cross-sectional analytical observational study with a probabilistic sample of 384 adolescents between 15 and 19 years old. Data collection was carried out in schools and included self-reporting questionnaires to assess the functional health literacy, socioeconomic classification, self perceived health, and quality of life. The reliability of internal consistency of the functional health literacy instrument was determined by calculating Cronbach's alpha coefficient. A multivariate logistic regression analysis was performed using hierarchical data entry according to the level of determination of the theoretical model established. In order to evaluate the association, a significance level of 5% was considered, while the Odds Ratio used as a measure of the magnitude of the associations. Results: The functional health literacy instrument presented a coefficient of 0.766, indicating adequate internal consistency. More than half of teenagers presented good functional health literacy. In the final model of multivariate analysis, the variables not practicing a religion (p = 0.006; OR = 2.108); social domain of quality of life (p = 0.004; OR = 1.022); and educational domain of quality of life (p = 0.009; OR = 1.019) remained associated with functional health literacy. Conclusion: Not practicing a religion and the increase in the scores of social and educational domains of quality of life increased the chances of better functional health literacy. PMID- 28813074 TI - Oral narrative of individuals with Fetal Alcohol Spectrum Disorder. AB - Purpose: To investigate and compare the oral narrative of individuals with FASD and individuals with typical language development (TLD), as well as to correlate the narrative performance with the score from 4-Digit Diagnostic Code. Methods: Participants were 20 individuals with FASD, of both genders, with chronological age between 6 and 16 years, and 20 individuals with TLD, same gender and similar to the FASD group in age and socioeconomic status. The oral narrative was elicited using the book Frog, where are you? and the data were analyzed in terms of macrostructure, microstructure and global coherence level. Measures regarding the macrostructure included the presence of typical structural elements of storytelling, while the microstructural aspects included words (total and different words), communication units (C-Units), lexical diversity, and mean length of C-Units. Results: Low performance was found in the FASD group for all macrostructural aspects, with the exception of linguistic markers. Among the microstructural aspects, lexical diversity and incomplete C-Units were different between the FASD and TLD groups. The FASD group presented lower global coherence level compared to the TLD group. Negative correlations were found between macrostructural aspects, facial characteristics, and Central Nervous System impairment. Conclusion: Restricted use of typical structural elements of storytelling with lower levels of coherence and reduced vocabulary distinguished the FASD from the TDL group. Future studies may explore whether the association between narrative performance and the 4-Digit Diagnostic Code items present predictive values in the narrative performance of individuals with FASD. PMID- 28813075 TI - Violence in schools and the voice of teachers. AB - Purpose: To correlate self-reporting of voice disorders with habits that impact voice production and situations of violence experienced by teachers. Methods: The study involved 41 elementary-school teachers of rural and urban areas. Two instruments were used for data collection: The Vocal Production Condition - Teacher (CPV-P) questionnaire and the Screening Index for Voice Disorders - ITDV. The chi-square test was used to verify association among variables with a significance level of 5%. Results: The sample consisted of 8 men and 33 women aged 25-66 years with a median of 39 years. Regarding vocal habits, 33 people (80.5%) mentioned the screaming as usual practice, 40 people (97.5%) declared they talk a lot. As for voice care, 31 people (73.1%) reported drinking water while using their voice. As for the ITDV total score, 30 teachers (73.1%) were above the score threshold set for predisposition to vocal disorders. Statistical analysis revealed a significant association between female participants and complaint of graffiti writings as a type of violence. No significant correlation between the ITDV results with gender and the ITDV with forms of violence evaluated in the study was indicated. Conclusion: Self-reporting of voice disorders showed no significant relationship with acts of violence. However, analysis of the context of violence in schools and vocal problems are issues worthy of attention, particularly the observed naturalization of gender inssues, which is seldom problematized. PMID- 28813076 TI - Quality of life in Parkinson's disease. PMID- 28813077 TI - Duchenne muscular dystrophy: classical and new therapeutic purposes and future perspectives. PMID- 28813078 TI - Quality of life in Parkinson's disease patients: progression markers of mild to moderate stages. AB - Objective: To investigate which factors are associated with the quality of life decline in Parkinson's disease patients from mild to moderate stages. Methods: The Unified Parkinson's Disease Rating Scale and Parkinson's Disease Questionnaire-39 were used to evaluate clinical/functional data and the quality of life. Results: The markers of clinical/functional worsening were drooling (p < 0.004), need for assistance with hygiene (p = 0.02), greater freezing frequency (p = 0.042), bradykinesia (p = 0.031), greater intensity of the resting tremor (p = 0.035) and "pill rolling" (p = 0.001). The decline in quality of life was related to stigma (p = 0.043), greater impairment in cognition (p = 0.002), mobility (p = 0.013) and for daily living activities (p = 0.05), and was considered more significant in men, married, older individuals, and those with a longer time of disease. Conclusions: The quality of life worsening markers at the moderate stage were related to stigma, worsening of cognition, and to greater impairment in mobility and daily living activities. PMID- 28813079 TI - Diffusion tensor imaging of brain white matter in Huntington gene mutation individuals. AB - Objective: To evaluate the role of the involvement of white matter tracts in huntingtin gene mutation patients as a potential biomarker of the progression of the disease. Methods: We evaluated 34 participants (11 symptomatic huntingtin gene mutation, 12 presymptomatic huntingtin gene mutation, and 11 controls). We performed brain magnetic resonance imaging to assess white matter integrity using diffusion tensor imaging, with measurement of fractional anisotropy. Results: We observed a significant decrease of fractional anisotropy in the cortical spinal tracts, corona radiate, corpus callosum, external capsule, thalamic radiations, superior and inferior longitudinal fasciculus, and inferior frontal-occipital fasciculus in the Huntington disease group compared to the control and presymptomatic groups. Reduction of fractional anisotropy is indicative of a degenerative process and axonal loss. There was no statistically significant difference between the presymptomatic and control groups. Conclusion: White matter integrity is affected in huntingtin gene mutation symptomatic individuals, but other studies with larger samples are required to assess its usefulness in the progression of the neurodegenerative process. PMID- 28813080 TI - The relationship between motor function, cognition, independence and quality of life in myelomeningocele patients. AB - Motor function, cognition, functional independence and quality of life have been described in myelomeningocele patients, but no study has investigated their relationships. We aimed to investigate the relationships between motor function, cognition, functional independence, quality of life, age, and lesion level in myelomeningocele patients, and investigate the influence of hydrocephalus on these variables. We assessed 47 patients with the Gross Motor Function Measure (motor function), Raven's Colored Progressive Matrices (cognition), Pediatric Evaluation of Disability Inventory (functional independence) and the Autoquestionnaire Qualite de vie Enfant Image (quality of life). Spearman's correlation tests determined relationships between the variables. The Friedman ANOVAs determined the influence of hydrocephalus. Motor function was strongly related to mobility and lesion level, and moderately related to cognition, self care and social function. Cognition and quality of life were moderately related to functional independence. Age correlated moderately with functional independence and quality of life. Hydrocephalus resulted in poorer motor/cognitive outcomes and lower functional independence. PMID- 28813081 TI - Epidemiological and clinical factors impact on the benefit of riluzole in the survival rates of patients with ALS. AB - Objective: To investigate the impact of epidemiological and clinical factors on the benefit of riluzole in patients with amyotrophic lateral sclerosis (ALS). Methods: The survival rate of 578 patients with ALS (1999-2011) was analyzed by descriptive statistics and Kaplan-Meier curves. Considering the median of the sample survival time (19 months), patients were divided in two groups: below (B19) and above the median (A19). Kaplan-Meier curves compared the survival rates of patients treated with riluzole and with patients who did not take the medication. Results: Riluzole increased the survival rates of patients with lower limb onset who were diagnosed after the first appointment in B19. Patients with bulbar onset and diagnosed on the first, or after the first appointment showed higher survival rates in A19. Males lived longer than females in both groups. Conclusion: Epidemiological and clinical factors influenced the benefit of riluzole in the survival rates of patients with ALS. PMID- 28813082 TI - Middle cerebral artery aneurysms: aneurysm angiographic morphology and its relation to pre-operative and intra-operative rupture. AB - Objective: Correlate the middle cerebral artery bifurcation aneurysm morphology with the pre-operative and intra-operative risk of rupture. Methods: Forty patients with 46 middle cerebral artery bifurcation aneurysms were treated microsurgically by the same surgeon. Aneurysms were classified according to shape and the Fisher test was applied to analyze the effect of morphology on the pre operative and intra-operative rupture. Results: Pre-operative and intra-operative ruptures were observed in 8/46 patients (17.4%) and 14/46 patients (30.4%) respectively. Thirty-two cases (69.6%) had no symptoms postoperatively, modified Rankin score (MRS) of 0; 6.5% had MRS of 1 (no significant disability); 13% had MRS of 2 (slight disability); 4.3% had moderately severe disability (MRS of 4); and there were 3 deaths (6.5%) post-operatively. The morphology was not directly related to the rupture rate. Conclusion: In general, ruptures are not affected by the morphology or the studied variables. Larger series are needed to validate these outcomes. PMID- 28813083 TI - Ankle-brachial index and diabetic neuropathy: study of 225 patients. AB - Objective: To evaluate neuropathic pain and peripheral vascular disease in diabetics and compare this with the length of time since diagnosis in type 1, and type 2 diabetes. Methods: A cross-sectional study with 225 diabetics chosen from their responses on the DN4 questionnaire, who were then evaluated with the ankle brachial index (ABI), separating type 1 diabetes from type 2 diabetes. Results: A higher incidence of neuropathic pain in those over 60 years of age showed an ABI > 1.3. Neuropathic pain was related to an abnormal ABI in 144 patients (64.2%). A statistically significant value was obtained in type 2 diabetes patients with more than 10 years from disease onset, 69 with altered ABI and 25 with normal ABI. There was an altered ABI (< 0.9) observed in 33% of type 1 diabetes patients and in 67% of type 2 diabetes patients. Conclusion: The ABI test in type 1 diabetes and type 2 diabetes patients is important even in those who are asymptomatic. A diagnosis of more than 10 years prior, regardless of the presence of neuropathic pain or ischemic signs, altered the ABI. PMID- 28813084 TI - Bereitschaftspotential preceding eyelid blinks in Parkinson's disease. AB - Methods: Ten PD patients in stages 1 and 2 of the Hoehn & Yahr classification were compared to 18 healthy controls. Artifact-free EEG segments of two seconds preceding the onset of the blink potential were averaged and analyzed, and the statistical significance of the measured amplitudes were evaluated by analysis of variance models. Results: The presence of a BP in the PD patients was demonstrated. The mean amplitudes at 0 ms were respectively 0.6 uV and 3.3 uV for the BP patients and the normal controls, respectively. Conclusions: The BP amplitudes were significantly smaller in PD patients than normal participants. The amplitudes of the BP were not modified by levodopa. PMID- 28813085 TI - Curcumin decreases astrocytic reaction after gliotoxic injury in the rat brainstem. AB - Recent studies have demonstrated that curcumin (Cur) has antioxidant, anti inflammatory and anti-fibrotic effects. Ethidium bromide (EB) injections into the central nervous system (CNS) are known to induce local oligodendroglial and astrocytic loss, resulting in primary demyelination and neuroinflammation. Peripheral astrogliosis is seen around the injury site with increased immunoreactivity to glial fibrillary acidic protein (GFAP). This investigation aimed to evaluate the effect of Cur administration on astrocytic response following gliotoxic injury. Wistar rats were injected with EB into the cisterna pontis and treated, or not, with Cur (100 mg/kg/day, intraperitoneal route) during the experimental period. Brainstem sections were collected at 15, 21 and 31 days after EB injection and processed for GFAP immunohistochemical staining. Astrocytic reactivity was measured in a computerized system for image analysis. In Cur-treated rats, the GFAP-stained area around the lesion was significantly smaller in all periods after EB injection compared to untreated animals, showing that Cur reduces glial scar development following injury. PMID- 28813069 TI - ? PMID- 28813086 TI - Translation and validation of the Life Satisfaction Index for Adolescents scale with neuromuscular disorders: LSI-A Brazil. AB - Objective: To validate the Life Satisfaction Index for Adolescents (LSI-A) scale, parent version and patient version, for Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA) and limb-girdle muscular dystrophy (LGMD). Methods: The parent version of the instrument was divided into Groups A, B, C and D; and the patient version, divided into B, C and D. For the statistical calculation, the following tests were used: Cronbach's alpha, ICC, Pearson and the ROC Curve. Results: The parent and patient versions of the instrument are presented, with the following results in the overall score, respectively: Cronbach's alpha, 0.87 and 0.89; reliability, r 0.98 and 0.97; reproducibility, ICC 0.69 and 0.80; sensitivity, 0.78 and 0.72; specificity, 0.5 and 0.69; and accuracy, 64% and 70.4%. Conclusion: According to the validity and reproducibility values, the LSI A Brazil parent and patient versions, are clinically useful to assess quality of life in DMD, SMA or LGMD and may also be useful for other neuromuscular disorders. PMID- 28813087 TI - Validation of the Expression and Emotion Scale for Children with attention deficit hyperactivity disorder into Brazilian Portuguese. AB - Objective: To validate the parent-rated Expression and Emotion Scale for Children (EESC) for patients with attention-deficit/hyperactivity disorder (ADHD). Methods: The EESC was applied to parents of children with and without ADHD. The children were divided into age groups: Group A, between six and eight years old; Group B, between nine and 11 years old; and Group C, between 12 and 15 years old. The validation was carried out according to the steps proposed by Guillemin et al. For the statistical calculation, Cronbach's alpha, Pearson's correlation, the ICC and ROC curve were used. Results: The statistical tests showed satisfactory coefficients: Cronbach's alpha = 0.76; Pearson's correlation r = 0.91 with CI 95%; replicability ICC = 0.66; sensitivity 0.75; specificity 0.67; accuracy 71%. Conclusion: According to psychometric data on internal and external consistency (reliability, reproducibility), sensitivity, and specificity, the parent-rated EESC for ADHD is useful in assessing emotional expression. PMID- 28813088 TI - Cognitive dysfunction in corticobasal degeneration. AB - Corticobasal degeneration (CBD) was originally described as a distinct clinicopathological entity in 1967. Since then, different phenotypic presentations have emerged as possible manifestations of CBD histopathological findings. In addition, pathophysiological findings and the molecular basis have been delineated and several aspects of its cognitive manifestations have been clarified. Thus, not only the spectrum of what is currently designated as CBD has expanded, but overlap with other degenerative and even secondary disorders has made clinical diagnostic certainty even more challenging in the absence of specific and readily-available markers. Cognitive deficits in CBD are now recognized as a frequent initial presentation and may appear up to eight years before the motor symptoms, depending on the phenotypic variant. Characteristic cognitive features of CBD involve language deficits, visuospatial and executive dysfunctions, apraxia, and behavioral disorders. Semantic and episodic memories are usually preserved, while language is often impaired in the early stages. PMID- 28813089 TI - Polyspecific antibodies without persisting antigen in multiple sclerosis, neurolupus and Guillain-Barre syndrome: immune network connectivity in chronic diseases. AB - The polyspecific antibody synthesis in multiple sclerosis (MS) gained diagnostic relevance with the frequent combination of measles-, rubella- and varicella zoster antibodies (MRZ-antibody reaction) but their pathophysiological role remains unknown. This review connects the data for intrathecal polyspecific antibody synthesis in MS and neurolupus with observations in the blood of patients with Guillain-Barre syndrome (GBS). Simultaneously increased antibody and autoantibody titers in GBS blood samples indicate that the polyspecific antibodies are based on a general property of an immune network, supported by the deterministic day-to-day concentration variation of antibodies in normal blood. Strongly correlated measles- and rubella- antibody variations point to a particular connectivity between the MRZ antibodies. The immune network, which provides serological memory in the absence of an antigen, implements the continuous change of the MRZ pattern in blood, not followed by the earlier immigrated B cells without corresponding connectivity in the brain. This may explain the different antibody patterns in cerebrospinal fluid, aqueous humor and blood of the individual MS patient. A complexity approach must implement a different view on causation in chronic diseases and causal therapies. PMID- 28813090 TI - Brazilian consensus on Duchenne muscular dystrophy. Part 1: diagnosis, steroid therapy and perspectives. AB - Significant advances in the understanding and management of Duchenne muscular dystrophy (DMD) took place since international guidelines were published in 2010. Our objective was to provide an evidence-based national consensus statement for multidisciplinary care of DMD in Brazil. A combination of the Delphi technique with a systematic review of studies from 2010 to 2016 was employed to classify evidence levels and grade of recommendations. Our recommendations were divided in two parts. We present Part 1 here, where we describe the guideline methodology and overall disease concepts, and also provide recommendations on diagnosis, steroid therapy and new drug treatment perspectives for DMD. The main recommendations: 1) genetic testing in diagnostic suspicious cases should be the first line for diagnostic confirmation; 2) patients diagnosed with DMD should have steroids prescribed; 3) lack of published results for phase 3 clinical trials hinders, for now, the recommendation to use exon skipping or read-through agents. PMID- 28813091 TI - Guillain-Barre syndrome: celebrating a century. AB - A hundred years ago, Guillain, Barre and Strohl described a syndrome with a predominant motor acute or subacute polyneuritis, albumin-cytologic dissociation in the cerebrospinal fluid, and a benign course. Before them, many other authors, such as Landry, Dumenil, Osler, and Grainger Stewart had described similar cases although they had not performed lumbar punctures. In this work, we outline certain features of the beginning of this famous syndrome. PMID- 28813092 TI - Congenital Zika syndrome: an epidemic of neurologic disability. PMID- 28813093 TI - Where is sugarcane cropping expanding in the brazilian cerrado, and why? A case study. AB - Sugarcane growing area in Brazil sharply expanded between 2000 and 2010 due to the increasing world demand for sugar and ethanol. Since this expansion of sugarcane is said to occur in areas covered by degraded pastures, it is likely not threatening the environment or food production. In order to verify this assumption, we investigate at farm and field levels which types of land use sugarcane cropping replaced between 2005 and 2010 and the reasons for farmers shifting or not shifting to sugarcane, as a case study in two counties in the state of Goias. Within the studied period, sugarcane cropping expansion was related to large farms, lower risk perceived by farmers, and higher profitability compared with soybean and beef cattle-raising. For smallholders, particularly dairy farmers, the need to comply with the set-aside rules under Brazilian Forest Code (Codigo Florestal Brasileiro) made a shift to sugarcane less attractive, as it would have forced them to reduce farm cultivable area, with loss of incomes. From 30,408 ha under sugarcane surveyed, 45.7% had used to be pastures, 31% had previously been pastures rotated with soybean and maize, and 23.3% had been cropped exclusively with soybean or maize. PMID- 28813094 TI - Fatty acid profile in vertical strata of elephant grass subjected to intermittent stocking. AB - The milk and meat from animals with a pasture-based diet have higher proportions of CLA and C18:3 and lower omega-6:omega-3 ratios than products from animals with diets based on corn silage and concentrate. However, most of the published studies have evaluated fatty acid profiles in temperate climate grasses and the literature with tropical grasses is scarce. Thus, the aim of this study was to evaluate the morphological and fatty acid compositions in the vertical strata of elephant grass (Pennisetum purpureum Schum.) swards subjected to grazing heights (90 or 120 cm pre-grazing heights) and levels of defoliation (50% or 70% removal of the initial pre-grazing height). There were no interactions among pre-grazing height, the level of defoliation and grazing stratum. However, higher proportion of C18:3 (58% and 63%) was found in the 90-cm swards and in the half upper stratum. A higher proportion of C18:3 was associated with a higher leaf proportion and crude protein content. Thus, the upper stratum of sward or a grazing management scheme (e.g. first-last stocking) resulting in a higher proportion of leaves and crude protein both provide higher proportions of C18:3 to animals grazing in elephant grass swards. PMID- 28813095 TI - Evaluation of cell proliferation and endometrial thickness of bitches in different periods of diestrus. AB - This study aimed to determine the histological features of the endometrium of bitches, as well as the cell proliferation at specific moments of diestrus, 10, 20, 30, 40, 50 and 60 days post ovulation, correlating the endometrial thickness with the uterine cell proliferation and the metabolic state (weight, blood glucose and plasma cholesterol) of the animals. Therefore, the right and left uterine horns of 26 clinically healthy bitches submitted to ovariohysterectomy were histologically analyzed 10, 20, 30, 40, 50 and 60 days post ovulation. The hematoxylin-eosin and AgNOR staining techniques were performed. All parameters were evaluated by ANOVA and post-hoc Tukey test (p<0.05). The correlation between endometrial thickness and uterine cell proliferation, weight, blood glucose and plasma cholesterol of animals was observed using the Pearson method (p<0.05). In the present study, it is concluded that endometrial thickness does not differ at any of the moments analyzed in diestrus. The endometrial thickness is not influenced by hormones, weight, blood glucose or serum cholesterol of bitches in this phase of the estrous cycle. However, there is greater cell proliferation in the endometrium at day 40 compared to day 60 post ovulation under the influence of the endocrine profile. PMID- 28813096 TI - Cytotoxicity and bacterial membrane destabilization induced by Annona squamosa L. extracts. AB - This study aimed to further investigate the cytotoxicity against tumor cell lines and several bacterial strains of Annona squamosa and its mode of action. Methanol extracts of A. squamosa leaves (ASL) and seeds (ASS) were used. ASL showed significant antibacterial activity against S. aureus, K. pneumoniae and E. faecalis with MIC values of 78, 78 and 39 ug/mL respectively. Moreover, ASL exhibited significant biofilm disruption, rapid time dependent kinetics of bacterial killing, increased membrane permeability and significantly reduced the cell numbers and viability. Regarding the cytotoxicity against tumor cell lines, ASS was more active against Jurkat and MCF-7 cells, with CI50 1.1 and 2.1 ug/mL, respectively. ASL showed promising activity against Jurkat and HL60, with CI50 4.2 and 6.4 ug/mL, respectively. Both extracts showed lower activity against VERO cells and reduced the clonogenic survival at higher concentrations (IC90) to MCF 7 and HCT-116 lineages. The alkaloids anonaine, asimilobine, corypalmine, liriodenine nornuciferine and reticuline were identified in extracts by UPLC-ESI MS/MS analysis. This study reinforced that A. squamosa presents a remarkable phytomedicinal potential and revealed that its antimicrobial mechanism of action is related to bacterial membrane destabilization. PMID- 28813097 TI - Avian Communities in the Amazonian Cangas Vegetation: Biogeographic Affinities, Components of Beta-Diversity and Conservation. AB - The Amazonian cangas is a vegetation type distributed as patches of open vegetation embedded in a matrix of tropical forest and that grows over iron-rich soils in the Serra dos Carajas region. To characterize cangas avifauna, we surveyed birds in eight patches varying from 43 to 1,366 hectares. Cangas avifauna has compositional affinities with savannas widespread throughout the Amazon and other biomes, and we estimate that more than 200 bird species occurs in this habitat. Species composition was relatively homogeneous, and the similarity among cangas patches was the dominant component of the beta-diversity. Bird communities in cangas patches exhibited statistically significant nested structure in respect to species richness and patch size. In contrast, the nested site arrangement was not affected by the isolation of patches. Number of species and composition are moderately affected by the area of cangas patches but not by its degree of isolation. To conserve this unique habitat are necessary a strict protection of carefully chosen patches of cangas and an investigation of the conservation value of secondary vegetation recovered by the mining companies. PMID- 28813098 TI - Modeling and mapping basal area of Pinus taeda L. plantation using airborne LiDAR data. AB - Basal area (BA) is a good predictor of timber stand volume and forest growth. This study developed predictive models using field and airborne LiDAR (Light Detection and Ranging) data for estimation of basal area in Pinus taeda plantation in south Brazil. In the field, BA was collected from conventional forest inventory plots. Multiple linear regression models for predicting BA from LiDAR-derived metrics were developed and evaluated for predictive power and parsimony. The best model to predict BA from a family of six models was selected based on corrected Akaike Information Criterion (AICc) and assessed by the adjusted coefficient of determination (adj. R2) and root mean square error (RMSE). The best model revealed an adj. R2=0.93 and RMSE=7.74%. Leave one out cross-validation of the best regression model was also computed, and revealed an adj. R2 and RMSE of 0.92 and 8.31%, respectively. This study showed that LiDAR derived metrics can be used to predict BA in Pinus taeda plantations in south Brazil with high precision. We conclude that there is good potential to monitor growth in this type of plantations using airborne LiDAR. We hope that the promising results for BA modeling presented herein will stimulate to operate this technology in Brazil. PMID- 28813099 TI - Leaf area estimation of cassava from linear dimensions. AB - The objective of this study was to determine predictor models of leaf area of cassava from linear leaf measurements. The experiment was carried out in greenhouse in the municipality of Botucatu, Sao Paulo state, Brazil. The stem cuttings with 5-7 nodes of the cultivar IAC 576-70 were planted in boxes filled with about 320 liters of soil, keeping soil moisture at field capacity, monitored by puncturing tensiometers. At 80 days after planting, 140 leaves were randomly collected from the top, middle third and base of cassava plants. We evaluated the length and width of the central lobe of leaves, number of lobes and leaf area. The measurements of leaf areas were correlated with the length and width of the central lobe and the number of lobes of the leaves, and adjusted to polynomial and multiple regression models. The linear function that used the length of the central lobe LA = -69.91114 + 15.06462L and linear multiple functions LA = 69.9188 + 15.5102L + 0.0197726K - 0.0768998J or LA = -69.9346 + 15.0106L + 0.188931K - 0.0264323H are suitable models to estimate leaf area of cassava cultivar IAC 576-70. PMID- 28813100 TI - First Assessment of Carbon Stock in the Belowground Biomass of Brazilian Mangroves. AB - Studies on belowground roots biomass have increasingly reported the importance of the contribution of this compartment in carbon stock maintenance in mangrove forests. To date, there are no estimates of this contribution in Brazilian mangrove forests, although the country has the second largest area of mangroves worldwide. For this study, trenches dug in fringing forests in Guaratiba State Biological Reserve (Rio de Janeiro, Brazil) were used to evaluate the contribution of the different classes of roots and the vertical stratification of carbon stock. The total carbon stock average in belowground roots biomass in these forests was 104.41 +/- 20.73 tC.ha-1. From that, an average of 84.13 +/- 21.34 tC.ha-1 corresponded to the carbon stock only in fine roots, which have diameters smaller than 5 mm and are responsible for over 80% of the total belowground biomass. Most of the belowground carbon stock is concentrated in the first 40 cm below the surface (about 70%). The root:shoot ratio in this study is 1.14. These estimates demonstrate that the belowground roots biomass significantly contributes, more than 50%, to the carbon stock in mangrove forests. And the mangrove root biomass can be greater than that of other Brazilian ecosystems. PMID- 28813101 TI - Forage potential of native ecotypes of Paspalum notatum and P. guenoarum. AB - The Paspalum genus includes several species that are important for livestock in Rio Grande do Sul, such as P. notatum and P. guenoarum, typical of native pastures of the Pampa biome. The aim of this study was to investigate forage production and chemical composition of four ecotypes of these species in relation to the cv. 'Pensacola' (P. notatum). Ecotypes of P. guenoarum (Azulao and Baio) and P. notatum (Andre da Rocha and Bagual) and the cv. 'Pensacola' were evaluated for two years, during which four cuts/year were made. The work was carried out under field conditions at the Agronomic Experimental Station of the Federal University of Rio Grande do Sul (30 degrees 05'S; 51 degrees 39'W), in a completely randomized design. P. guenoarum stood out for higher productivity and greater tolerance to cold; the Azulao ecotype showed more autumn production in relation to the other ecotypes. Crude protein content ranged from 14 (Baio) to 15% ('Pensacola'); for neutral detergent fiber, the variation was 68 (Azulao) to 71% ('Pensacola') and for acid detergent fiber there was a variation of 38 ('Pensacola') to 43% (Baio). The data demonstrates the potential of native genotypes for use as cattle feeding in southern Brazil. PMID- 28813102 TI - Terpene Esters from Natural Products: Synthesis and Evaluation of Cytotoxic Activity. AB - Natural steroids and triterpenes such as b-sitosterol, stigmasterol, lupeol, ursolic and betulinic acids were transformed into its hexanoic and oleic esters, to evaluate the influence of chemical modification towards the cytotoxic activities against tumor cells. The derivatives were evaluated against five tumor cell lines [OVCAR-8 (ovarian carcinoma); SF-295 (glioblastoma); HCT-116 (colon adenocarcinoma); HL-60 (leukemia); and PC-3 (prostate carcinoma)] and the results showed only betulinic acid hexyl ester exhibits cytotoxic potential activity. PMID- 28813103 TI - Nutrition facts and limits for micronutrients in tree species used in urban forestry. AB - There is a huge lack of researches that evaluate the nutritional limits in tree species used in urban forestry, especially in terms of micronutrients. This study aimed to establish limits and range of micronutrients levels for the proper development of tree species utilized in urban forestry. The study was conducted in the city of Santa Maria-RS-Brazil. Through forest inventory, 23 forest species present in urban forest were selected, and 05 vegetative branches of each tree were collected, in which the contents of B, Cu, Fe, Mn and Zn were analyzed. Ranges of micronutrients' contents were developed for class limits criteria. Nutritional problems were detected for B, Cu and Zn in G. robusta and S. cumini, indicating a need of fertilization and management of these trees. The levels of Mn were within an adequate range only for the species C. illinoensis and H. chrysotrichus. The contents of B were higher than the level considered adequate for H. chrysotrichusand M. nigra. The rates of Fe showed high levels for E. japonica, H. chrysotrichusand S. babylonica. The estimated nutritional limits enable a greater control in the classification of the results for each tree species utilized in urban forestry. PMID- 28813104 TI - Poly(methylene blue)-modified electrode for indirect electrochemical sensing of OH radicals and radical scavengers. AB - A new modified electrode for indirect sensing of OH. and radical scavengers was described. The electrochemical polymerization of methylene blue in aqueous solutions and the properties of the resulting films on a glassy carbon electrode were carried out using cyclic voltammetry. A surface coverage of 1.11 * 109mol cm2 was obtained, revealing a complete surface coverage of the polymeric film on the electrode surface. OH. was able to destroy the poly(methylene blue) film by exposure to a Fenton solution. The loss of the electrochemical signal of the residual polymeric film attached to the electrode surface was related to the extent of its dissolution. The applicability of the sensor was demonstrated by evaluating the OH radical scavenging effect on different concentrations of ascorbic acid. The obtained radical scavenging capacity were 31.4%, 55.7%, 98.9% and 65.7% for the ascorbic acid concentrations of 5, 10, 30 and 50 mM, respectively. PMID- 28813105 TI - A scientific survey on 1550 cases of oral lesions diagnosed in a Brazilian referral center. AB - The present study aimed to perform an epidemiological survey on the prevalence rate of oral lesions diagnosed in a referral center in Brazil and to establish association between the lesions and the age and gender of the affected patients. This analytical observational study analyzed 3521 medical records of anatomopathological exams of the Pathological Anatomy and Cytopathology Laboratory of the Cancer Hospital of the state of Mato Grosso (Brazil), from December 2011 to September 2015. A total of 1550 relevant medical records was detected. Patients aging between 41 and 60 consisted of 42.84% of the sample. Males were more affected than females (60.13%). Inflammatory processess consisted of the most prevalent diagnosis (43.29%), followed by squamous cell carcinoma (6.06%), and periapical granuloma (5.23%). Oral health public policies must give major attention to Brazilian males aged between the fourth and sixth decades of life in order to improve their quality of life. PMID- 28813106 TI - First record of Scybalocanthon nigriceps (Harold, 1868) (Coleoptera: Scarabaeidae: Scarabaeinae) in Rio Grande do Sul state, southern Brazil. AB - The dung beetle, Scybalocanthon nigriceps (Harold, 1868), is recorded in Rio Grande do Sul state, Brazil, for the first time, at the Moreno Fortes Biological Reserve, municipality of Dois Irmaos das Missoes, northwest region of the state, expanding the area of occurrence and distribution of this species in the country. PMID- 28813107 TI - Climatic characteristics of the 2010-2016 drought in the semiarid Northeast Brazil region. AB - This study discusses the climatological aspects of the most severe drought ever recorded in the semiarid region Northeast Brazil. Droughts are recurrent in the region and while El Nino has driven some of these events others are more dependent on the tropical North Atlantic sea surface temperature fields. The drought affecting this region during the last 5 years shows an intensity and impact not seen in several decades in the regional economy and society. The analysis of this event using drought indicators as well as meteorological fields shows that since the middle 1990s to 2016, 16 out of 25 years experienced rainfall below normal. This suggests that the recent drought may have in fact started in the middle-late 1990s, with the intense droughts of 1993 and 1998, and then the sequence of dry years (interrupted by relatively wet years in 2007, 2008, 2009 and 2011) after that may have affected the levels of reservoirs in the region, leading to a real water crisis that was magnified by the negative rainfall anomalies since 2010. PMID- 28813108 TI - Consequences of gestational diabetes to the brain and behavior of the offspring. AB - Gestational diabetes mellitus (GD) is a form of insulin resistance triggered during the second/third trimesters of pregnancy in previously normoglycemic women. It is currently estimated that 10% of all pregnancies in the United States show this condition. For many years, the transient nature of GD has led researchers and physicians to assume that long-term consequences were absent. However, GD diagnosis leads to a six-fold increase in the risk of developing type 2 diabetes (T2D) in women and incidence of obesity and T2D is also higher among their infants. Recent and concerning evidences point to detrimental effects of GD on the behavior and cognition of the offspring, which often persist until adolescence or adulthood. Considering that the perinatal period is critical for determination of adult behavior, it is expected that the intra-uterine exposure to hyperglycemia, hyperinsulinemia and pro-inflammatory mediators, hallmark features of GD, might affect brain development. Here, we review early clinical and experimental evidence linking GD to consequences on the behavior of the offspring, focusing on memory and mood disorders. We also discuss initial evidence suggesting that downregulation of insulin signaling cascades are seen in the brains of GD offspring and could contribute to the consequences on their behavior. PMID- 28813109 TI - Assessment of inhibitory control in crack and/or cocaine users: a systematic review. AB - OBJECTIVE: Impairments involving inhibitory control have been considered central deficits in drug users, but it appears that dysfunctions may be specific to users' drug of choice. This article aims to review recent findings on inhibitory control impairment in samples of crack and/or cocaine users. METHODS: Searches were conducted on the PubMed, PsycINFO, and Web of Knowledge databases in two stages according to eligibility criteria. Initially, databases were searched and the titles and abstracts of results were analyzed and then selected articles were read in full. Inclusion criteria were: empirical articles written in English, Portuguese, or Spanish, published in the last ten years and involving the assessment of inhibitory control in crack and/or cocaine users. RESULTS: The database searches returned a total of 3,796 titles, 56 of them were selected initially and then a further 20 were excluded. Thirty-six articles were included in this review. In 90% of the studies reviewed the presence of inhibitory control deficits was reported, verified by impaired cognitive processing and response monitoring, as well as high levels of impulsiveness, regardless of the pattern of crack and/or cocaine consumption (recreational or chronic). Former users showed high levels of impulsiveness even after long periods of abstinence. CONCLUSIONS: Crack and/or cocaine users may have inhibitory control deficits, irrespective of different consumption patterns. High levels of impulsiveness can represent a factor of vulnerability to drug use and relapse. PMID- 28813111 TI - Mental disorders and heart diseases: from William Harvey to today. PMID- 28813110 TI - Trait vs. state anxiety in different threatening situations. AB - OBJECTIVE: Anxiety as a uni- or multidimensional construct has been under discussion. The unidimensional approach assumes that there is a general trait anxiety, which predisposes the individuals to increases in state anxiety in various threatening situations. In this case, there should be a correlation between state and trait anxiety in any situation of threat. Therefore, the aim of this study was to investigate the correlation between trait and state anxiety in participants exposed to two different anxiogenic situations: interpersonal threat (Video-Monitored Stroop Test - VMST) and physical threat (third molar extraction TME). METHODS: Participants with various levels of trait anxiety (general trait: State-Trait Anxiety Inventory - STAI, Hospital Anxiety and Depression Scale; specific trait: Social Phobia Inventory, Dental Anxiety Scale) had their anxious state evaluated (STAI, self-evaluation of tension level, heart rate, electromyogram activity) before, during and after the VMST or the TME. RESULTS: In VMST, trait anxiety correlated to state anxiety (psychological parameters) in all test phases. However, in TME, the only trait measurement that correlated to state anxiety (psychological parameters) was the Dental Anxiety Scale. CONCLUSION: Trait anxiety correlates positively to state anxiety in situations of interpersonal threat, but not of physical threat. PMID- 28813112 TI - What do Cochrane systematic reviews say about the clinical effectiveness of screening and diagnostic tests for cancer? AB - CONTEXT AND OBJECTIVE:: The purpose of screening tests for cancer is to detect it at an early stage in order to increase the chances of treatment. However, their unrestrained use may lead to unnecessary examinations, overdiagnosis and higher costs. It is thus necessary to evaluate their clinical effects in terms of benefits and harm. DESIGN AND SETTING:: Review of Cochrane systematic reviews, carried out in the Discipline of Evidence-Based Medicine, Escola Paulista de Medicina, Universidade Federal de Sao Paulo. METHODS:: Cochrane reviews on the clinical effectiveness of cancer screening procedures were included. Study titles and abstracts were independently assessed by two authors. Conflicts were resolved by another two authors. Findings were summarized and discussed. RESULTS:: Seventeen reviews were selected: fifteen on screening for specific cancers (bladder, breast, colorectal, hepatic, lung, nasopharyngeal, esophageal, oral, prostate, testicular and uterine) and two others on cancer in general. The quality of evidence of the findings varied among the reviews. Only two reviews resulted in high-quality evidence: screening using low-dose computed tomography scans for high-risk individuals seems to reduce lung cancer mortality; and screening using flexible sigmoidoscopy and fecal occult blood tests seems to reduce colorectal cancer mortality. CONCLUSION:: The evidence found through Cochrane reviews did not support most of the commonly used screening tests for cancer. It is recommended that patients should be informed of the possibilities of false positives and false negatives before they undergo the tests. Further studies to fully assess the effectiveness of cancer screening tests and adverse outcomes are required. PMID- 28813113 TI - Impact of inequalities in health care on the mortality risk of individuals with severe mental illnesses. PMID- 28813114 TI - Dimensions of youth psychopathy differentially predict concurrent pro- and antisocial behavior. AB - Objective:: To investigate the unique contribution of narcissism and impulsivity, in addition to callous-unemotional (CU) traits, in explaining concurrent prosocial and antisocial behavior. Method:: Two hundred and forty-nine schoolchildren (53% female; age 9-12 years) completed the self-report Strengths and Difficulties Questionnaire (SDQ) and the Antisocial Process Screening Device (APSD). Two statistical models were tested, predicting conduct problems (CP) and prosocial behavior (PB). In the first one, CU traits and gender were entered into the equation. The second model added narcissism and impulsivity. Results:: Gender, narcissism and impulsivity, but not CU, were statistically significant predictors of CP in the second model (F3,226 = 45.07, p < 0.001, R2 = 43.7%; betas: gender = -0.20, narcissism = 0.29, impulsivity = 0.36, CU = 0.06). PB was significantly predicted by all domains except gender (F3,226 = 42.57, p < 0.001, R2 = 42.4%; betas: gender = 0.08, narcissism = -0.16, impulsivity = -0.23, CU = 0.41). Conclusion:: Our results confirmed that CU traits refer to a distinct manifestation of psychopathy in youth, but we also found that narcissism and impulsivity are equally important when predicting CP. Previous reports of sex differences on APSD and SDQ domains were also corroborated. PMID- 28813115 TI - Analyzing leukocyte telomere length in bipolar disorder. PMID- 28813116 TI - Analyzing leukocyte telomere length in bipolar disorder: Authors' reply. PMID- 28813117 TI - BDNF Val66Met polymorphism and memory performance in older adults: the Met carrier effect is more complex than previously thought. PMID- 28813118 TI - BDNF Val66Met polymorphism and memory performance in older adults: the Met carrier effect is more complex than previously thought: Authors' reply. PMID- 28813119 TI - Biomarkers in first-degree relatives of patients with bipolar disorder: what can they tell us? PMID- 28813120 TI - Psychosis: glia, immunity, and melatonin. PMID- 28813121 TI - Impairments of kleptomania: what are they? PMID- 28813122 TI - Morphological alterations in the jejunal mucosa of aged rats and the possible protective role of green tea. AB - INTRODUCTION: Gastrointestinal disorders become more prevalent with ageing. This study is aimed to describe morphological changes that occur in the jejunal mucosa of male albino rats as a result of ageing and the protec-tive effect of green tea (GT) extract. MATERIAL AND METHODS: The experiment was performed on sixty rats: thirty young-adult (6-month old, body mass 200-220 g) and thirty old (24-month old, body mass 220-260 g) animals. Each group was further divided into two subgroups (n = 15 each): control rats and GT-treated rats that received 1.5 mL (300 mg/kg/day) of GT extract for 14 weeks by oral gavage. Sections of the jejunum were stained with hematoxylin and eosin, periodic acid Schiff, toluidine blue and Mallory trichrome methods. The presence of proliferating cell nuclear antigen (PCNA)- and CD68-positive cells was evaluated by immunohistochemical staining. Ultrathin sections were prepared and examined by a transmission electron microscope (TEM). RESULTS: Jejunal sections of the old control rats showed distortion of submucosa and attenuated muscularis externa with decreased height of intestinal villi. The villi also showed partial loss of acidophilic brush border with wide spaces between enterocytes. Swollen, short, blunt or broad villi with abundant mononuclear cell infiltration of lamina propria and congested blood vessels were evident both by light and electron microscopy. The number of PCNA- and CD68-positive cells in jejunal mucosa of old rats was higher than in young rats. The activity of glutathione peroxidase (GPX) and total antioxidant capacity (TAC) in the mucosa of old control rats were lower, whereas malondialdehyde (MDA) levels were higher in the jejunal homogenates of old rats as compared to young control rats. Administration of GT extract protected the jejunal mucosa from age-related changes by restoring its histological structure. The treatment of old rats with GT extract significantly decreased MDA levels in the jejunum and increased TAC and GPX activity. CONCLUSIONS: The age-related changes of the morphology of rat jejunum could be ameliorated by prolonged supplementation of the green tea extract. PMID- 28813123 TI - Pharmacotherapy for hypertension in adults aged 18 to 59 years. AB - BACKGROUND: Hypertension is an important risk factor for adverse cardiovascular events including stroke, myocardial infarction, heart failure and renal failure. The main goal of treatment is to reduce these events. Systematic reviews have shown proven benefit of antihypertensive drug therapy in reducing cardiovascular morbidity and mortality but most of the evidence is in people 60 years of age and older. We wanted to know what the effects of therapy are in people 18 to 59 years of age. OBJECTIVES: To quantify antihypertensive drug effects on all-cause mortality in adults aged 18 to 59 years with mild to moderate primary hypertension. To quantify effects on cardiovascular mortality plus morbidity (including cerebrovascular and coronary heart disease mortality plus morbidity), withdrawal due adverse events and estimate magnitude of systolic blood pressure (SBP) and diastolic blood pressure (DBP) lowering at one year. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to January 2017: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We contacted authors of relevant papers regarding further published and unpublished work. SELECTION CRITERIA: Randomized trials of at least one year' duration comparing antihypertensive pharmacotherapy with a placebo or no treatment in adults aged 18 to 59 years with mild to moderate primary hypertension defined as SBP 140 mmHg or greater or DBP 90 mmHg or greater at baseline, or both. DATA COLLECTION AND ANALYSIS: The outcomes assessed were all-cause mortality, total cardiovascular (CVS) mortality plus morbidity, withdrawals due to adverse events, and decrease in SBP and DBP. For dichotomous outcomes, we used risk ratio (RR) with 95% confidence interval (CI) and a fixed-effect model to combine outcomes across trials. For continuous outcomes, we used mean difference (MD) with 95% CI and a random-effects model as there was significant heterogeneity. MAIN RESULTS: The population in the seven included studies (17,327 participants) were predominantly healthy adults with mild to moderate primary hypertension. The Medical Research Council Trial of Mild Hypertension contributed 14,541 (84%) of total randomized participants, with mean age of 50 years and mean baseline blood pressure of 160/98 mmHg and a mean duration of follow-up of five years. Treatments used in this study were bendrofluazide 10 mg daily or propranolol 80 mg to 240 mg daily with addition of methyldopa if required. The risk of bias in the studies was high or unclear for a number of domains and led us to downgrade the quality of evidence for all outcomes.Based on five studies, antihypertensive drug therapy as compared to placebo or untreated control may have little or no effect on all-cause mortality (2.4% with control vs 2.3% with treatment; low quality evidence; RR 0.94, 95% CI 0.77 to 1.13). Based on 4 studies, the effects on coronary heart disease were uncertain due to low quality evidence (RR 0.99, 95% CI 0.82 to 1.19). Low quality evidence from six studies showed that drug therapy may reduce total cardiovascular mortality and morbidity from 4.1% to 3.2% over five years (RR 0.78, 95% CI 0.67 to 0.91) due to reduction in cerebrovascular mortality and morbidity (1.3% with control vs 0.6% with treatment; RR 0.46, 95% CI 0.34 to 0.64). Very low quality evidence from three studies showed that withdrawals due to adverse events were higher with drug therapy from 0.7% to 3.0% (RR 4.82, 95% CI 1.67 to 13.92). The effects on blood pressure varied between the studies and we are uncertain as to how much of a difference treatment makes on average. AUTHORS' CONCLUSIONS: Antihypertensive drugs used to treat predominantly healthy adults aged 18 to 59 years with mild to moderate primary hypertension have a small absolute effect to reduce cardiovascular mortality and morbidity primarily due to reduction in cerebrovascular mortality and morbidity. All-cause mortality and coronary heart disease were not reduced. There is lack of good evidence on withdrawal due to adverse events. Future trials in this age group should be at least 10 years in duration and should compare different first-line drug classes and strategies. PMID- 28813124 TI - Novel Treatments for Airway Disease. PMID- 28813125 TI - Exercise Type in Dieting Obese Older Adults. PMID- 28813126 TI - Case 14-2017: A Man with Pain and Swelling of the Left Calf and a Purpuric Rash. PMID- 28813132 TI - Novel Treatments for Airway Disease. PMID- 28813133 TI - Novel Treatments for Airway Disease. PMID- 28813134 TI - Preface PMID- 28813135 TI - Novel Treatments for Airway Disease. PMID- 28813136 TI - Targeting of Cellular Organelles by Fluorescent Plasmid DNA Nanoparticles. AB - The development of a suitable delivery system and the targeting of intracellular organelles are both essential for the success of drug and gene therapies. The conception of fluorescent ligands, displaying targeting specificity together with low toxicity, is an emerging and reliable tool to develop innovative delivery systems. Biocompatible BSA or pDNA/ligand nanoparticles were synthesized by a coprecipitation method and were shown to display adequate sizes and morphology for delivery purposes, and positive surface charges. Additionally, these fluorescent vectors can target specific intracellular organelles. In vitro transfection mediated by BSA or pDNA based carriers can result in the accumulation of BSA in the cytosol, lysosomes, and mitochondria or the expression of the plasmid-encoded protein, respectively. Moreover, the therapeutic effect of pDNA/ligand vectors in cancer gene therapy instigates further research aiming clinical translation. PMID- 28813137 TI - Site A-Mediated Partial Unfolding of Cytochrome c on Cardiolipin Vesicles Is Species-Dependent and Does Not Require Lys72. AB - Measurements at pH 8 allow evaluation of binding of 100% cardiolipin vesicles to site A of cytochrome c without interference from other known binding sites. Site A encompasses Lys72, Lys73, Lys86, and Lys87, located in or adjacent to Omega loop D (residues 70-85), which positions Met80 for binding to the heme. Binding of cytochrome c to cardiolipin disrupts Met80 heme binding, permitting peroxidase activity. Binding of cardiolipin to yeast iso-1-cytochrome c versus human cytochrome c is compared to assess how binding of cardiolipin to site A has evolved for cytochrome c from species that do not have a complete intrinsic apoptotic pathway to species that do. Using a nondestructive method of quantifying cardiolipin concentration, highly reproducible binding curves are obtained. The results indicate two sequential structural rearrangements on the surface of 100% cardiolipin vesicles. The first, more modest, structural rearrangement occurs at an exposed (outer leaflet) lipid:protein ratio of 8-10 for both cytochromes c. The second, occurring at higher lipid:protein ratios, causes significant unfolding of cytochrome c and requires a much higher lipid:protein ratio for human versus yeast cytochrome c. Higher lipid:protein ratios enhance the peroxidase activity of cytochrome c, suggesting that human cytochrome c has evolved a more stringent on/off switch for cardiolipin peroxidation in the early stages of apoptosis. For both human and yeast cytochrome c, the K72A mutation has only minor effects on binding to site A, suggesting that other nearby lysines can compensate for the lack of Lys72. PMID- 28813138 TI - Quantifying Lake Water Quality Evolution: Coupled Geochemistry, Hydrodynamics, and Aquatic Ecology in an Acidic Pit Lake. AB - Assessment of water quality evolution in the thousands of existing and future mine pit lakes worldwide requires new numerical tools that integrate geochemical, hydrological, and biological processes. A coupled model was used to test alternative hypothesized controls on water quality in a pit lake over ~8 years. The evolution of pH, Al, and Fe were closely linked; field observations were reproduced with generic solubility equilibrium controls on Fe(III) and Al and a commonly reported acceleration of the abiotic Fe(II) oxidation rate by 2-3 orders of magnitude. Simulations indicated an ongoing acidity loading at the site, and the depletion of Al mineral buffering capacity after ~5 years. Simulations also supported the existence of pH limitation on nitrification, and a limitation on phytoplankton growth other than the commonly postulated P and DIC limitations. Furthermore, the model reproduced the general patterns of salinity, pH, Al, and Fe during an uncontrolled river breach in 2011, however, incorporating sediment biogeochemical feedbacks is required to reproduce the observed postbreach internal alkalinity generation in the lake. The modeling approach is applicable to the study of hydrological, geochemical, and biological interactions for a range of lake and reservoir management challenges. PMID- 28813139 TI - Tunable, Injectable Hydrogels Based on Peptide-Cross-Linked, Cyclized Polymer Nanoparticles for Neural Progenitor Cell Delivery. AB - A PEG-based cyclized vinyl polymer was synthesized via one-step RAFT polymerization and used as a precursor of injectable hydrogels. Dithiol linkers including laminin-derived peptides containing IKVAV and YIGSR sequences and DTT were used for gelation. Fast and adjustable gelation rate was achieved through nucleophile-initiated thiol-Michael reaction under physiological conditions. Low swelling ratio and moderate degradation rate of the formed hydrogels were observed. 3D encapsulation of neural progenitor cells in the synthetic hydrogel showed good cell viability over 8 days. The long-term cell survival and proliferation were promoted by the introduction of laminin-derived peptides. This hydrogel platform based on peptide-cross-linked, cyclized vinyl polymers can be used as a universal hydrogel template for 3D cell encapsulation. PMID- 28813140 TI - Robust Pitaya-Structured Pyrite as High Energy Density Cathode for High-Rate Lithium Batteries. AB - To solve the serious problems (the agglomeration of nano-Fe0, dissolution of polysulfide, and low electronic conductivity of Li2S) of earth-abundant pyrite (FeS2) cathodes for lithium batteries, a simple in situ encapsulation and transformation route has been successfully developed to synthesis pitaya structured porous carbon embedded with FeS2 nanoparticles. Due to such a hierarchical architecture design, this cathode of pitaya-structured FeS2@C can effectively avoid the serious agglomeration and coarsening of small Fe nanoparticles, reduce the dissolution of polysulfide, and provide superior kinetics toward lithium storage, resulting in enhanced reversibility and rate capability. Cycling in the voltage region of 1.0-3.0 V at 0.3 A g-1, the current conversion-based FeS2@C cathode displays a high and stable energy density (about 1100 Wh kg-1), ultrahigh rate capability (a reversible capability of 660, 609, 554, 499, 449, and 400 mA h g-1 at 0.2, 0.5, 1.0, 2.0, 5.0, and 10 A g-1, respectively), and stable cycling performance. PMID- 28813141 TI - Weavable, Conductive Yarn-Based NiCo//Zn Textile Battery with High Energy Density and Rate Capability. AB - With intrinsic safety and much higher energy densities than supercapacitors, rechargeable nickel/cobalt-zinc-based textile batteries are promising power sources for next generation personalized wearable electronics. However, high performance wearable nickel/cobalt-zinc-based batteries are rarely reported because there is a lack of industrially weavable and knittable highly conductive yarns. Here, we use scalably produced highly conductive yarns uniformly covered with zinc (as anode) and nickel cobalt hydroxide nanosheets (as cathode) to fabricate rechargeable yarn batteries. They possess a battery level capacity and energy density, as well as a supercapacitor level power density. They deliver high specific capacity of 5 mAh cm-3 and energy densities of 0.12 mWh cm-2 and 8 mWh cm-3 (based on the whole solid battery). They exhibit ultrahigh rate capabilities of 232 C (liquid electrolyte) and 116 C (solid electrolyte), which endows the batteries excellent power densities of 32.8 mW cm-2 and 2.2 W cm-3 (based on the whole solid battery). These are among the highest values reported so far. A wrist band battery is further constructed by using a large conductive cloth woven from the conductive yarns by a commercial weaving machine. It powers various electronic devices successfully, enabling dual functions of wearability and energy storage. PMID- 28813142 TI - Atomic Force Microscopy-Infrared Spectroscopy of Individual Atmospheric Aerosol Particles: Subdiffraction Limit Vibrational Spectroscopy and Morphological Analysis. AB - Chemical analysis of atmospheric aerosols is an analytical challenge, as aerosol particles are complex chemical mixtures that can contain hundreds to thousands of species in attoliter volumes at the most abundant sizes in the atmosphere (~100 nm). These particles have global impacts on climate and health, but there are few methods available that combine imaging and the detailed molecular information from vibrational spectroscopy for individual particles <500 nm. Herein, we show the first application of atomic force microscopy with infrared spectroscopy (AFM IR) to detect trace organic and inorganic species and probe intraparticle chemical variation in individual particles down to 150 nm. By detecting photothermal expansion at frequencies where particle species absorb IR photons from a tunable laser, AFM-IR can study particles smaller than the optical diffraction limit. Combining strengths of AFM (ambient pressure, height, morphology, and phase measurements) with photothermal IR spectroscopy, the potential of AFM-IR is shown for a diverse set of single-component particles, liquid-liquid phase separated particles (core-shell morphology), and ambient atmospheric particles. The spectra from atmospheric model systems (ammonium sulfate, sodium nitrate, succinic acid, and sucrose) had clearly identifiable features that correlate with absorption frequencies for infrared-active modes. Additionally, molecular information was obtained with <100 nm spatial resolution for phase separated particles with a ~150 nm shell and 300 nm core. The subdiffraction limit capability of AFM-IR has the potential to advance understanding of particle impacts on climate and health by improving analytical capabilities to study water uptake, heterogeneous reactivity, and viscosity. PMID- 28813143 TI - Effect of Structure and Disorder on the Charge Transport in Defined Self Assembled Monolayers of Organic Semiconductors. AB - Self-assembled monolayer field-effect transistors (SAMFETs) are not only a promising type of organic electronic device but also allow detailed analyses of structure-property correlations. The influence of the morphology on the charge transport is particularly pronounced, due to the confined monolayer of 2D-pi stacked organic semiconductor molecules. The morphology, in turn, is governed by relatively weak van-der-Waals interactions and is thus prone to dynamic structural fluctuations. Accordingly, combining electronic and physical characterization and time-averaged X-ray analyses with the dynamic information available at atomic resolution from simulations allows us to characterize self assembled monolayer (SAM) based devices in great detail. For this purpose, we have constructed transistors based on SAMs of two molecules that consist of the organic p-type semiconductor benzothieno[3,2-b][1]benzothiophene (BTBT), linked to a C11 or C12 alkylphosphonic acid. Both molecules form ordered SAMs; however, our experiments show that the size of the crystalline domains and the charge transport properties vary considerably in the two systems. These findings were confirmed by molecular dynamics (MD) simulations and semiempirical molecular orbital electronic-structure calculations, performed on snapshots from the MD simulations at different times, revealing, in atomistic detail, how the charge transport in organic semiconductors is influenced and limited by dynamic disorder. PMID- 28813144 TI - Stimulated Raman Imaging Reveals Aberrant Lipogenesis as a Metabolic Marker for Azole-Resistant Candida albicans. AB - Candida albicans is the single most prevalent cause of fungal bloodstream infections worldwide causing significant mortality as high as 50 percent. This high mortality rate is, in part, due to the inability to initiate an effective antifungal therapy early in the disease process. Mortality rates significantly increase after 12 hours of delay in initiating the appropriate antifungal therapy following a positive blood culture. Early administration of appropriate antifungal therapy is hampered by the slow turnovers of the conventional antimicrobial testing techniques, which require days of incubation. To address this unmet need, we explored the potential of employing stimulated Raman scattering (SRS) imaging to probe for metabolic differences between fluconazole susceptible and -resistant strains at a single cell level in search of a metabolic signature. Metabolism is integral to pathogenicity. Since only a few hours are needed to observe a full metabolic cycle in C. albicans, metabolic profiling provides an avenue for rapid antimicrobial susceptibility testing. C-H frequency (2850 cm-1) SRS imaging revealed a substantial difference in lipogenesis between the fluconazole-susceptible and -resistant C. albicans. Exposure to fluconazole, an antimicrobial drug that targets ergosterol biosynthesis, only affected the lipogenesis in the susceptible strain. These results show that single cell metabolic imaging via SRS microscopy can be used for rapid detection of antimicrobial susceptibility. PMID- 28813145 TI - Selective Uptake and Bioaccumulation of Antidepressants in Fish from Effluent Impacted Niagara River. AB - The continuous release of pharmaceuticals and personal care products (PPCPs) into freshwater systems impacts the health of aquatic organisms. This study evaluates the concentrations and bioaccumulation of PPCPs and the selective uptake of antidepressants in fish from the Niagara River, which connects two of the North American Great lakes (Erie and Ontario). The Niagara River receives PPCPs from different wastewater treatment plants (WWTPs) situated along the river and Lake Erie. Of the 22 targeted PPCPs, 11 were found at part-per-billion levels in WWTP effluents and at part-per-trillion levels in river water samples. The major pollutants observed were the antidepressants (citalopram, paroxetine, sertraline, venlafaxine, and bupropion, and their metabolites norfluoxetine and norsertraline) and the antihistamine diphenhydramine. These PPCPs accumulate in various fish organs, with norsertraline exhibiting the highest bioaccumulation factor (up to about 3000) in the liver of rudd (Scardinius erythrophthalmus), which is an invasive species to the Great Lakes. The antidepressants were selectively taken up by various fish species at different trophic levels, and were further metabolized once inside the organism. The highest bioaccumulation was found in the brain, followed by liver, muscle, and gonads, and can be attributed to direct exposure to WWTP effluent. PMID- 28813146 TI - A Monomeric Tricobalt(II)-Substituted Dawson-Type Polyoxometalate Decorated by a Metal Carbonyl Group: [P2W15O56Co3(H2O)3(OH)3Mn(CO)3]8. AB - A monomeric tricobalt(II)-substituted phosphotungstate polyanion, [H9P2W15O62Co3]9-, is stabilized by the attachement of an organometallic group, {Mn(CO)3}, for the first time. The resulting polyoxometalate-supported [Mn(CO)3]+ complex (1) can be used as an efficient catalyst in the cycloaddition of CO2 with epoxides under mild reaction conditions with pyrrolidinium bromide as a cocatalyst. Besides, magnetic measurements show that the compound exhibits weaker ferromagnetic interactions at low temperature. PMID- 28813147 TI - Synthesis and Evaluation of Asymmetric Acyclic Nucleoside Bisphosphonates as Inhibitors of Plasmodium falciparum and Human Hypoxanthine-Guanine-(Xanthine) Phosphoribosyltransferase. AB - Acyclic nucleoside bisphosphonates (ANbPs) have previously been shown to be good inhibitors of human hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and Plasmodium falciparum (Pf) hypoxanthine-guanine-xanthine phosphoribosyltransferase (PfHGXPRT). On the basis of this scaffold, a new series of ANbPs was synthesized. One of these new ANbPs, [3-(guanine-9-yl)-2-((2 phosphonoethoxy)methyl)propoxy]methylphosphonic acid, exhibited Ki values of 6 and 70 nM for human HGPRT and Pf HGXPRT, respectively. These low Ki values were achieved by inserting an extra carbon atom in the linker connecting the N9 atom of guanine to one of the phosphonate groups. The crystal structure of this ANbP in complex with human HGPRT was determined at 2.0 A resolution and shows that it fills three key pockets in the active site. The most potent phosphoramidate prodrugs of these compounds have IC50 values in the low micromolar range in Pf lines and low toxicity in human A549 cells, demonstrating that these ANbPs are excellent antimalarial drug leads. PMID- 28813148 TI - Chitosan-Coated Cinnamon/Oregano-Loaded Solid Lipid Nanoparticles to Augment 5 Fluorouracil Cytotoxicity for Colorectal Cancer: Extract Standardization, Nanoparticle Optimization, and Cytotoxicity Evaluation. AB - This study aimed to coat lipid-based nanocarriers with chitosan to encapsulate nutraceuticals, minimize opsonization, and facilitate passive-targeting. Phase one was concerned with standardization according to the World Health Organization. Qualitative analysis using liquid chromatography-high-resolution mass spectrometry (LC-HRMS/MS) investigated the active constituents, especially reported cytotoxic agents. Cinnamaldehyde and rosmarinic acid were selected to be quantified using high-performance liquid chromatography. Phase two was aimed to encapsulate both extracts in solid lipid nanoparticles (core) and chitosan (shell) to gain the advantages of both materials properties. The developed experimental model suggested an optimum formulation with 2% lipid, 2.3% surfactant, and 0.4% chitosan to achieve a particle size of 254.77 nm, polydispersity index of 0.28, zeta potential of +15.26, and entrapment efficiency percentage of 77.3% and 69.1% for cinnamon and oregano, respectively. Phase three was focused on the evaluation of cytotoxic activity unencapsulated/encapsulated cinnamon and oregano extracts with/without 5-fluorouracil on HCT-116 cells. This study confirmed the success of the suggested combination with 5-fluorouracil for treating human colon carcinoma with a low dose leading to decreasing side effects and allowing uninterrupted therapy. PMID- 28813149 TI - Quantifying Short-Chain Chlorinated Paraffin Congener Groups. AB - Accurate quantification of short-chain chlorinated paraffins (SCCPs) poses an exceptional challenge to analytical chemists. SCCPs are complex mixtures of chlorinated alkanes with variable chain length and chlorination level; congeners with a fixed chain length (n) and number of chlorines (m) are referred to as a "congener group" CnClm. Recently, we resolved individual CnClm by mathematically deconvolving soft ionization high-resolution mass spectra of SCCP mixtures. Here we extend the method to quantifying CnClm by introducing CnClm specific response factors (RFs) that are calculated from 17 SCCP chain-length standards with a single carbon chain length and variable chlorination level. The signal pattern of each standard is measured on APCI-QTOF-MS. RFs of each CnClm are obtained by pairwise optimization of the normal distribution's fit to the signal patterns of the 17 chain-length standards. The method was verified by quantifying SCCP technical mixtures and spiked environmental samples with accuracies of 82-123% and 76-109%, respectively. The absolute differences between calculated and manufacturer-reported chlorination degrees were -0.9 to 1.0%Cl for SCCP mixtures of 49-71%Cl. The quantification method has been replicated with ECNI magnetic sector MS and ECNI-Q-Orbitrap-MS. CnClm concentrations determined with the three instruments were highly correlated (R2 > 0.90) with each other. PMID- 28813150 TI - Organoselenium-Catalyzed Oxidative C?C Bond Cleavage: A Relatively Green Oxidation of Alkenes into Carbonyl Compounds with Hydrogen Peroxide. AB - A relatively green oxidative C?C bond cleavage of alkenes was achieved by organoselenium-catalyzed alkene oxidation reaction in ethanol with hydrogen peroxide, affording carbonyl compounds under relatively mild conditions. It is a new reaction style for the organoselenium-catalyzed oxidation of alkenes and largely contributes to the growing field of organoselenium catalysis. PMID- 28813151 TI - Medicinal and Biological Chemistry (MBC) Library: An Efficient Source of New Hits. AB - Identification of new hits is one of the biggest challenges in drug discovery. Creating a library of well-characterized drug-like compounds is a key step in this process. Our group has developed an in-house chemical library called the Medicinal and Biological Chemistry (MBC) library. This collection has been successfully used to start several medicinal chemistry programs and developed in an accumulation of more than 30 years of experience in drug design and discovery of new drugs for unmet diseases. It contains over 1000 compounds, mainly heterocyclic scaffolds. In this work, analysis of drug-like properties and comparative study with well-known libraries by using different computer software are presented here. PMID- 28813152 TI - Coherent Exciton Delocalization in a Two-State DNA-Templated Dye Aggregate System. AB - Coherent exciton delocalization in dye aggregate systems gives rise to a variety of intriguing optical phenomena, including J- and H-aggregate behavior and Davydov splitting. Systems that exhibit coherent exciton delocalization at room temperature are of interest for the development of artificial light-harvesting devices, colorimetric detection schemes, and quantum computers. Here, we report on a simple dye system templated by DNA that exhibits tunable optical properties. At low salt and DNA concentrations, a DNA duplex with two internally functionalized Cy5 dyes (i.e., dimer) persists and displays predominantly J aggregate behavior. Increasing the salt and/or DNA concentrations was found to promote coupling between two of the DNA duplexes via branch migration, thus forming a four-armed junction (i.e., tetramer) with H-aggregate behavior. This H tetramer aggregate exhibits a surprisingly large Davydov splitting in its absorbance spectrum that produces a visible color change of the solution from cyan to violet and gives clear evidence of coherent exciton delocalization. PMID- 28813153 TI - Copper-Catalyzed TBHP-Mediated Radical Cross-Coupling Reaction of Sulfonylhydrazides with Thiols Leading to Thiosulfonates. AB - A tert-butyl hydroperoxide (TBHP)-mediated coupling of sulfonylhydrazides with thiols catalyzed by CuBr2 to afford thiosulfonates via a radical process is described. PMID- 28813154 TI - Roles of Free Electrons and H2O2 in the Optical Breakdown-Induced Photochemical Reduction of Aqueous [AuCl4]. AB - Free electrons and H2O2 formed in an optical breakdown plasma are found to directly control the kinetics of [AuCl4]- reduction to form Au nanoparticles (AuNPs) during femtosecond laser-assisted synthesis of AuNPs. The formation rates of both free electrons and H2O2 strongly depend on the energy and duration of the 800 nm laser pulses over the ranges of 10-2400 MUJ and 30-1500 fs. By monitoring the conversion of [AuCl4]- to AuNPs using in situ UV-vis spectroscopy during laser irradiation, the first- and second-order rate constants in the autocatalytic rate law, k1 and k2, were extracted and compared to the computed free electron densities and experimentally measured H2O2 formation rates. For laser pulse energies of 600 MUJ and lower at all pulse durations, the first-order rate constant, k1, was found to be directly proportional to the theoretically calculated plasma volume, in which the electron density exceeds the threshold value of 1.8 * 1020 cm-3. The second-order rate constant, k2, was found to correlate with the measured H2O2 formation rate at all pulse energies and durations, resulting in the empirical relationship k2 ~ H2O20.5. We have demonstrated that the relative composition of free electrons and H2O2 in the optical breakdown plasma may be controlled by changing the pulse energy and duration, which may make it possible to tune the size and dispersity of AuNPs and other metal nanoparticle products synthesized with femtosecond laser-based methods. PMID- 28813155 TI - Research on Controllable Degradation of Novel Sulfonylurea Herbicides in Acidic and Alkaline Soils. AB - The degradation issue of sulfonylurea (SU) has become one of the biggest challenges that hamper the development and application of this class of herbicides, especially in the alkaline soils of northern China. On the basis of the previous discovery that some substituents on the fifth position of the benzene ring in Chlorsulfuron could hasten its degradation rate, apparently in acidic soil, this work on Metsulfuron-methyl showed more convincing results. Two novel compounds (I-1 and I-2) were designed and synthesized, and they still retained potent herbicidal activity in tests against both dicotyledons and monocotyledons. The half-lives of degradation (DT50) assay revealed that I-1 showed an accelerated degradation rate in acidic soil (pH 5.59). Moreover, we delighted to find that the degradation rate of I-1 was 9-10-fold faster than that of Metsulfuron-methyl and Chlorsulfuron when in alkaline soil (pH 8.46), which has more practical value. This research suggests that a modified structure that has potent herbicidal activity as well as accelerated degradation rate could be realized and this approach may provide a way to improve the residue problem of SUs in farmlands with alkaline soil. PMID- 28813156 TI - The Spatial Resolution Limit for an Individual Domain Wall in Magnetic Nanowires. AB - Magnetic nanowires are the foundation of several promising nonvolatile computing devices, most notably magnetic racetrack memory and domain wall logic. Here, we determine the analog information capacity in these technologies, analyzing a magnetic nanowire containing a single domain wall. Although wires can be deliberately patterned with notches to define discrete positions for domain walls, the line edge roughness of the wire can also trap domain walls at dimensions below the resolution of the fabrication process, determining the fundamental resolution limit for the placement of a domain wall. Using a fractal model for the edge roughness, we show theoretically and experimentally that the analog information capacity for wires is limited by the self-affine statistics of the wire edge roughness, a relevant result for domain wall devices scaled to regimes where edge roughness dominates the energy landscape in which the walls move. PMID- 28813157 TI - Palladium-Catalyzed Sequential Nucleophilic Addition/Oxidative Annulation of Bromoalkynes with Benzoic Acids To Construct Functionalized Isocoumarins. AB - An efficient and robust protocol for the preparation of 3-substituted isocoumarins via palladium-catalyzed nucleophilic addition/oxidative annulation of bromoalkynes with benzoic acids has been developed. Remarkably, preliminary mechanistic studies indicated that the transformation might proceed via a stereo- and regioselective nucleophilic addition and C-H functionalization procedure. PMID- 28813158 TI - Continuous Flow Synthesis of Morpholines and Oxazepanes with Silicon Amine Protocol (SLAP) Reagents and Lewis Acid Facilitated Photoredox Catalysis. AB - Photocatalytic coupling of aldehydes and silicon amine protocol (SLAP) reagents enables the simple, scalable synthesis of substituted morpholines, oxazepanes, thiomorpholines, and thiazepanes under continuous flow conditions. Key to the success of this process is the combination of an inexpensive organic photocatalyst (TPP) and a Lewis acid additive, which form an amine radical cation that is easily reduced to complete the catalytic cycle. Di- and trisubstituted SLAP reagents are formed in one step by an iron-catalyzed aminoetherification of olefins. PMID- 28813159 TI - Enhancing Enzyme Activity and Immobilization in Nanostructured Inorganic-Enzyme Complexes. AB - Understanding the chemical and physical interactions at the interface of protein surfaces and inorganic crystals has important implications in the advancement of immobilized enzyme catalysis. Recently, enzyme-inorganic hybrid complexes have been demonstrated as effective materials for enzyme immobilization. The precipitation of phosphate nanocrystals in the presence of enzymes creates enzyme Cu3(PO4)2.3H2O particles with high surface-to-volume ratios, enhanced activity, and increased stability. Here, we begin to develop a mechanistic understanding of enzyme loading in such complexes. Using a series of enzymes including horseradish peroxidase (HRP), a thermostable alcohol dehydrogenase (AdhD), diaphorase, catalase, glucose oxidase (GOx), and the protein bovine serum albumin (BSA), we identified a correlation between particle synthesis temperature, overall enzyme charge, and enzyme loading. The model enzyme HRP has a high predicted pI of ~7.5 and maintains an overall positive charge under the synthesis conditions, phosphate buffer pH 7.4. HRP loading in HRP-Cu3(PO4)2 complexes was enhanced by 4.2-fold when synthesis was carried out at 37 degrees C in comparison with synthesis at 4 degrees C. HRP loading was further enhanced with synthesis at pH 8.0, correlating with a decrease in overall enzyme charge. Proteins with lower predicted pI values and negative overall charge (AdhD, pI of 5.6; diaphorase, pI of 6.8; GOx, pI of 5.2; catalase, pI of 6.9; and, BSA, pI of 5.7) exhibited higher enzyme loadings with 4 degrees C synthesis, 2.7-, 2.6-, 2.5-, 1.8-, and 1.7-fold protein loading enhancements, respectively. Using HRP as a model system, we also demonstrate that activity increased concomitantly with enzyme loading, and that particle nanostructure was minimally affected by synthesis temperature. Combined, the results presented here demonstrate the control of enzyme loading in enzyme-inorganic particles opening up new possibilities in enzyme and multienzyme catalysis. PMID- 28813161 TI - Circulating Mitochondrial DNA as a Mechanism-based, Prognostic Biomarker for Idiopathic Pulmonary Fibrosis. PMID- 28813160 TI - A Strain-Driven Antiferroelectric-to-Ferroelectric Phase Transition in La-Doped BiFeO3 Thin Films on Si. AB - A strain-driven orthorhombic (O) to rhombohedral (R) phase transition is reported in La-doped BiFeO3 thin films on silicon substrates. Biaxial compressive epitaxial strain is found to stabilize the rhombohedral phase at La concentrations beyond the morphotropic phase boundary (MPB). By tailoring the residual strain with film thickness, we demonstrate a mixed O/R phase structure consisting of O phase domains measuring tens of nanometers wide within a predominant R phase matrix. A combination of piezoresponse force microscopy (PFM), transmission electron microscopy (TEM), polarization-electric field hysteresis loop (P-E loop), and polarization maps reveal that the O-R structural change is an antiferroelectric to ferroelectric (AFE-FE) phase transition. Using scanning transmission electron microscopy (STEM), an atomically sharp O/R MPB is observed. Moreover, X-ray absorption spectra (XAS) and X-ray linear dichroism (XLD) measurements reveal a change in the antiferromagnetic axis orientation from out of plane (R-phase) to in plane (O-phase). These findings provide direct evidence of spin-charge-lattice coupling in La-doped BiFeO3 thin films. Furthermore, this study opens a new pathway to drive the AFE-FE O-R phase transition and provides a route to study the O/R MPB in these films. PMID- 28813162 TI - Through the Looking Glass and What Was Found There: Imaging Biomarkers of Chronic Obstructive Pulmonary Disease. PMID- 28813163 TI - Can Treatment of Obstructive Sleep Apnea with Continuous Positive Airway Pressure Still Improve Kidney Outcomes? PMID- 28813165 TI - Love in the Time of Cancer. PMID- 28813164 TI - Pembrolizumab in Patients With Extensive-Stage Small-Cell Lung Cancer: Results From the Phase Ib KEYNOTE-028 Study. AB - Purpose The safety and efficacy of pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), were assessed in patients with programmed death ligand 1 (PD-L1)-expressing extensive-stage small-cell lung cancer (SCLC) in the multicohort, phase Ib open-label KEYNOTE-028 study ( ClinicalTrials.gov identifier: NCT02054806). Methods Patients with SCLC received pembrolizumab 10 mg/kg every 2 weeks for 24 months or until disease progression or intolerable toxicity occurred. PD-L1 expression was assessed by immunohistochemistry. PD-L1 positive patients had membranous PD-L1 expression in >= 1% of tumor and associated inflammatory cells or positive staining in stroma. Response was assessed by investigator per Response Evaluation Criteria in Solid Tumors version 1.1 every 8 weeks for the first 6 months and every 12 weeks thereafter. Adverse events (AEs) were reported per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Primary end points were safety, tolerability, and objective response rate (ORR). Secondary end points included progression-free survival, overall survival, and duration of response. Results Twenty-four patients with PD-L1-expressing SCLC were enrolled and received at least one pembrolizumab dose. At the data cutoff date (June 20, 2016), the median follow-up duration was 9.8 months (range, 0.5 to 24 months). All 24 patients experienced AEs; the most common were asthenia (n = 7), fatigue (n = 7), and cough (n = 6). Two patients experienced grade 3 to 5 treatment-related AEs: one patient had elevated bilirubin, and one patient had asthenia, grade 5 colitis, and intestinal ischemia. One patient had a complete response, and seven patients had partial responses, resulting in an ORR of 33% (95% CI, 16% to 55%). Conclusion The safety of pembrolizumab was consistent with the known safety profile in other tumor types. Pembrolizumab demonstrated promising antitumor activity in patients with pretreated, PD-L1-expressing SCLC. PMID- 28813166 TI - Are inner-city children with asthma receiving specialty care as recommended in national asthma guidelines? AB - OBJECTIVE: To examine whether children with asthma in an urban health care network are receiving asthma specialty care, and which factors, if any, are associated with the receipt of this care, including child's racial/ethnic group, age, socio-economic status (SES), insurance, and/or acute care utilization. METHODS: This study is a retrospective cohort study of children aged 7-17 years who received primary care at an urban medical center in 2012 and had a primary or secondary ICD9 code for asthma. Data on asthma-related health care utilization from 1997 to 2012 were accessed using a software application linked to the electronic medical record. Analyses included descriptive statistics (means and percentages) as well as bivariate and multivariable logistic regressions. RESULTS: The participants were 4959 children (59% Hispanic and 37% Black, Non Hispanic) with a mean age = 11.1 years +/- 3.05, with 56.8% males. Only 19% of the children had outpatient asthma specialist care: pulmonary (16%) and/or allergy (7%). Only 42% with an asthma-related hospitalization had an outpatient asthma specialist visit. The receipt of specialty care did not vary by race/ethnicity, SES or private vs. public insurance, but was more likely with hospitalization for asthma (OR 3.4) or >=2 lifetime ED visits (OR 2.6) and less likely for those who were uninsured (OR 0.7). CONCLUSIONS: In contrast to guideline recommendations, few inner-city children with high asthma morbidity in this sample had seen asthma specialists. Efforts are needed to ensure that inner city children with asthma are receiving guideline-recommended asthma specialty care. PMID- 28813169 TI - The Elephant in the Room. PMID- 28813167 TI - Lipophagy maintains energy homeostasis in the kidney proximal tubule during prolonged starvation. AB - Macroautophagy/autophagy is a self-degradation process that combats starvation. Lipids are the main energy source in kidney proximal tubular cells (PTCs). During starvation, PTCs increase fatty acid (FA) uptake, form intracellular lipid droplets (LDs), and hydrolyze them for use. The involvement of autophagy in lipid metabolism in the kidney remains largely unknown. Here, we investigated the autophagy-mediated regulation of renal lipid metabolism during prolonged starvation using PTC-specific Atg5-deficient (atg5-TSKO) mice and an in vitro serum starvation model. Twenty-four h of starvation comparably induced LD formation in the PTCs of control and atg5-TSKO mice; however, additional 24 h of starvation reduced the number of LDs in control mice, whereas increases were observed in atg5-TSKO mice. Autophagic degradation of LDs (lipophagy) in PTCs was demonstrated by electron microscopic observation and biochemical analysis. In vitro pulse-chase assays demonstrated that lipophagy mobilizes FAs from LDs to mitochondria during starvation, whereas impaired LD degradation in autophagy deficient PTCs led to decreased ATP production and subsequent cell death. In contrast to the in vitro assay, despite impaired LD degradation, kidney ATP content was preserved in 48-h starved atg5-TSKO mice, probably due to increased utilization of ketone bodies. This compensatory mechanism was accompanied by a higher plasma FGF21 (fibroblast growth factor 21) level and its expression in the PTCs; however, this was not essential for the production of ketone bodies in the liver during prolonged starvation. In conclusion, lipophagy combats prolonged starvation in PTCs to avoid cellular energy depletion. PMID- 28813168 TI - Examining Women's Alcohol Consumption: The Theory of Planned Behavior and Self Identity. AB - BACKGROUND: Changing trends demonstrate that women, in several economically developed countries, are drinking at higher levels than ever before. OBJECTIVE: This study applied an extended Theory of Planned Behavior (TPB), including self identity, to examine women's intentions to consume alcohol. METHODS: Women (N = 1069) aged 18-87 years, completed a questionnaire measuring their intentions to engage in binge drinking and frequent drinking. As research indicates that drinking trends are a function of age, hierarchical multiple regressions were conducted separately for four age groups (18-24, 25-34, 35-44, 45, and above). RESULTS: Results supported the predictive utility of the TPB, (particularly Attitudes and Perceived Behavioral Control). Across the age groups, the final models explained between 48% and 62% of the variance in intentions to binge drink and between 33% and 51% of the variance in intentions to drink frequently. Subjective norms were significant associated with the youngest group (18-24 years) and the oldest group (45+ years). Self-identity was significantly associated with intentions to binge drink in younger women. CONCLUSIONS: Implications are discussed with regard to the predictive utility of an extended TPB to include self-identity in determining women's intentions to consume alcohol. Key factors that influence women's decisions to engage in risky drinking behaviors have been underlined to inform future interventions. PMID- 28813170 TI - SURVEY OF AQUATIC TURTLES ON THE SAVANNAH RIVER SITE, SOUTH CAROLINA, USA, FOR PREVALENCE OF RANAVIRUS. AB - : Ranaviruses have the ability to infect amphibians, fish, and reptiles, and they have caused multiple amphibian die-off events in the US and Europe. Their prevalence in amphibian populations is much more commonly studied than in chelonian populations. We examined blood samples ( n=286) from eight aquatic turtle species collected during 2008-14 on the Savannah River Site, South Carolina, US, as part of long-term mark-recapture efforts. Previous studies in the southeastern US found high prevalence of Ranavirus in amphibians, but we did not detect Ranavirus in any of the turtles sampled, suggesting the absence of the virus or its presence at a very low prevalence in aquatic turtles across the Savannah River Site during the years tested. PMID- 28813172 TI - Rabbit Neutering in Primary-Care Education: Insights from a Surgical Clinic. AB - Involvement in canine and feline surgical neutering clinics is generally considered to be a key element of primary-care veterinary education, yet opportunities for veterinary students to develop their surgical skills with rabbit patients are uncommon. This is despite the fact that rabbits are currently estimated to be the third most popular companion animal species and the fact that the British Small Animal Veterinary Association (BSAVA) recommends that all non breeding rabbits be neutered soon after they attain sexual maturity. We describe a pilot rabbit-neutering clinic designed to provide high-quality care for rabbit patients while offering opportunities for undergraduate surgical and case management skills development. We report on the clinical outcomes for patients. Rates of morbidity (n=18) and mortality (n=1) were low. Of complications reported, the majority (n=16) were considered minor. Challenges included ensuring that staff and students were trained in the specific features of rabbit anesthesia and recovery behavior. We conclude that rabbit surgical clinics offer excellent learning opportunities for undergraduate veterinary students. With prior training in handling and close individual supervision, it is possible to achieve good clinical outcomes and to have a positive impact on the welfare of companion animal populations. PMID- 28813171 TI - Anti-EDAR Agonist Antibody Therapy Resolves Palate Defects in Pax9-/- Mice. AB - To date, surgical interventions are the only means by which craniofacial anomalies can be corrected so that function, esthetics, and the sense of well being are restored in affected individuals. Unfortunately, for patients with cleft palate-one of the most common of congenital birth defects-treatment following surgery is prolonged over a lifetime and often involves multidisciplinary regimens. Hence, there is a need to understand the molecular pathways that control palatogenesis and to translate such information for the development of noninvasive therapies that can either prevent or correct cleft palates in humans. Here, we use the well-characterized model of the Pax9-/- mouse, which displays a consistent phenotype of a secondary cleft palate, to test a novel therapeutic. Specifically, we demonstrate that the controlled intravenous delivery of a novel mouse monoclonal antibody replacement therapy, which acts as an agonist for the ectodysplasin (Eda) pathway, can resolve cleft palate defects in Pax9-/- embryos in utero. Such pharmacological interventions did not reverse the arrest in tooth, thymus, and parathyroid gland development, suggesting that the relationship of Pax9 to the Eda/Edar pathway is both unique and essential for palatogenesis. Expression analyses and unbiased gene expression profiling studies offer a molecular explanation for the resolution of palatal defects, showing that Eda and Edar-related genes are expressed in normal palatal tissues and that the Eda/Edar signaling pathway is downstream of Pax9 in palatogenesis. Taken together, our data uncover a unique relationship between Pax9 and the Eda/Edar signaling pathway that can be further exploited for the development of noninvasive, safe, and effective therapies for the treatment of cleft palate conditions and other single-gene disorders affecting the craniofacial complex. PMID- 28813173 TI - Development of a Dermatology Diagnostic Techniques Teaching Session: A Nine-Step Approach. AB - Creating effective learning experiences for veterinary clinical skills and procedures can be a challenging task. Drawing from both medical and veterinary education literature and personal experiences as practicing veterinarians and educators, the authors share nine key steps that describe the development process of a pre-clinical veterinary clinical skills teaching session. Relevant research and pedagogical principles supporting the effectiveness of the proposed nine-step process were identified and discussed. The aims of this article were to describe the development of a dermatology techniques teaching session and to provide the reader with a structured approach that can be used as a template to design or audit other clinical skills teaching sessions. PMID- 28813174 TI - Depressive Symptoms and Drinking Outcomes: The Mediating Role of Drinking Motives and Protective Behavioral Strategies Among College Students. AB - BACKGROUND: College students with depressive symptoms tend to engage in more hazardous drinking and experience more alcohol-related consequences to cope with their symptoms. Given the perceived tension reducing effects of alcohol among these students, it is important to explore how protective factors, such as protective behavioral strategies, account for the relationships among depressive symptoms, drinking motives, and alcohol-related outcomes. OBJECTIVE: To examine the mediating role of drinking motives and protective behavioral strategies on the associations that depressive symptoms have with typical weekly alcohol consumption, hazardous drinking, and alcohol-related negative consequences in a sample of college student drinkers. METHODS: Traditional age college students (n = 566, 73% women; 58% White, non-Hispanic) completed measures of depression, drinking motives, protective behavioral strategies, weekly alcohol use, hazardous drinking, and alcohol-related negative consequences. RESULTS: Coping with depression motives and controlled consumption PBS explained the association between depression and weekly alcohol consumption and hazardous drinking whereas coping with depression motives and serious harm reduction PBS explained the depression-negative consequences relationship. Conformity motives and serious harm reduction PBS explained the association between depression and hazardous drinking and alcohol-related negative consequences. CONCLUSIONS: Findings suggest that students with more depressive symptoms would benefit from clinical interventions tailored to address negative reinforcement drinking motives and, by extension, increase student utilization of PBS related to minimizing harm. Clinical and research implications are provided. PMID- 28813175 TI - Qualitative Analysis of Registered Nurses' Perceptions of Lactation Assessment Tools: Why and How They Are Completed. AB - BACKGROUND: Although lactation assessment tools are consistently used in clinical practice, there is no evidence describing registered nurses' perspectives regarding the purpose and thought processes involved when conducting a breastfeeding assessment. Research aim: This study aimed to explore registered nurses' perceptions on the purpose of lactation assessment tools and the thought processes involved in completing one. METHODS: Seven focus groups were held from April 2015 through July 2015, in coordination with regional and international lactation and perinatal conferences. Participants included 28 hospital-based registered nurses who routinely used a lactation assessment tool to assess postpartum mothers with healthy breastfeeding newborns. Focus groups were audiotaped, transcribed verbatim, and content analyzed by two lactation researchers to identify relevant themes and subthemes. RESULTS: The analyses identified four different purposes of breastfeeding assessment tools (Teaching and Assessing Simultaneously, Infant Safety, Standardized Practice, and "It's Your Job!") and four themes related to the thought processes used in completing the tool (Novice vs. Expert, Real-Time vs. Recalled Documentation, Observation or Not, and "Fudging the Score"). CONCLUSION: Registered nurses found lactation assessment tool completion to be an essential part of their job and that it ensured infant safety, standardized care, maternal instruction, and lactation assessment. Differences in the lactation assessment tool completion process were described, based on staff expertise, workload, hospital policies, and varying degrees of compliance with established protocols. These findings provide critical insight for the development of future breastfeeding assessment tools. PMID- 28813176 TI - Validating the Concept of COPD Control: A Real-world Cohort Study from the United Kingdom. AB - The concept of Chronic Obstructive Pulmonary Disease (COPD) control has been developed to inform therapeutic decision-making. We explored the validity of a definition of COPD control in a representative population of patients with COPD in the United Kingdom. Electronic medical records and linked COPD questionnaire data from the Optimum Patient Care Research Database were used to characterize control status. Patients were aged >=40 years, with spirometry-confirmed COPD, current or ex-smokers, and continuous records throughout the study period. Control was evaluated based on COPD stability and patients' (i) clinical features or (ii) COPD Assessment Test (CAT) score over a three-month baseline period and linked to time to first exacerbation. Of 2788 eligible patients, 2511 (90%) had mild/moderate COPD and 277 (10%) had severe/very severe COPD based on Body Mass Index, Obstruction, Dyspnoea, Exacerbations (BODEx) cut-off of 4. Within the mild/moderate cohort, 4.5% of patients were controlled at baseline according to clinical features and 21.5% according to CAT threshold of 10. Within the severe/very severe cohort, no patients were controlled at baseline according to the proposed clinical features and 8.3% were controlled according to CAT threshold of 20. Compared with uncontrolled patients, time to first exacerbation was longer for controlled patients with mild/moderate COPD but not for those with severe/very severe COPD. Lowering the BODEx threshold for severity classification to 2 increased the number of patients achieving control. CAT scores were not good predictors of the risk of future exacerbation. With the proposed definition, very few patients were defined as controlled. PMID- 28813177 TI - How Single-Cell Genomics Is Changing Evolutionary and Developmental Biology. AB - The recent flood of single-cell data not only boosts our knowledge of cells and cell types, but also provides new insight into development and evolution from a cellular perspective. For example, assaying the genomes of multiple cells during development reveals developmental lineage trees-the kinship lineage-whereas cellular transcriptomes inform us about the regulatory state of cells and their gradual restriction in potency-the Waddington lineage. Beyond that, the comparison of single-cell data across species allows evolutionary changes to be tracked at all stages of development from the zygote, via different kinds of stem cells, to the differentiating cells. We discuss recent insights into the evolution of stem cells and initial attempts to reconstruct the evolutionary cell type tree of the mammalian forebrain, for example, by the comparative analysis of neuron types in the mesencephalic floor. These studies illustrate the immense potential of single-cell genomics to open up a new era in developmental and evolutionary research. PMID- 28813179 TI - Clinical Internships for the Next Generation of International Board Certified Lactation Consultants. PMID- 28813178 TI - Centriole Biogenesis: From Identifying the Characters to Understanding the Plot. AB - The centriole is a beautiful microtubule-based organelle that is critical for the proper execution of many fundamental cellular processes, including polarity, motility, and division. Centriole biogenesis, the making of this miniature architectural wonder, has emerged as an exemplary model to dissect the mechanisms governing the assembly of a eukaryotic organelle. Centriole biogenesis relies on a set of core proteins whose contributions to the assembly process have begun to be elucidated. Here, we review current knowledge regarding the mechanisms by which these core characters function in an orderly fashion to assemble the centriole. In particular, we discuss how having the correct proteins at the right place and at the right time is critical to first scaffold, then initiate, and finally execute the centriole assembly process, thus underscoring fundamental principles governing organelle biogenesis. PMID- 28813180 TI - Inflammatory signaling cascades and autophagy in cancer. AB - Tumor-associated inflammation is predictive of poor prognosis and drives a variety of tumorigenic phenotypes, including tumor proliferation and survival, angiogenesis, invasiveness, and metastasis. Here, we review mammalian data addressing the interaction of macroautophagy/autophagy with key signaling cascades associated with tumor inflammation. Although our understanding of this area remains incomplete, certain inflammatory pathways have emerged as important mediators of the crosstalk between autophagy and inflammation in tumors. Consistent with the multifaceted roles for autophagy in tumor cells, results to date support the hypothesis that inflammatory pathways can suppress or induce autophagy in a context-dependent manner; in turn, autophagy suppresses or promotes inflammation in cancers. Furthermore, emerging data suggest that autophagy may influence cytokine production and secretion via diverse mechanisms, which has implications for the immune and inflammatory microenvironment in tumors. PMID- 28813181 TI - Pathway choice between proteasomal and autophagic degradation. AB - Efficient degradation of abnormal or aggregated proteins is crucial to protect the cell against proteotoxic stress. Selective targeting and disposal of such proteins usually occurs in a ubiquitin-dependent manner by proteasomes and macroautophagy/autophagy. Whereas proteasomes are efficient in degrading abnormal soluble proteins, protein aggregates are typically targeted for degradation by autophagic vesicles. Both processes require ubiquitin-binding receptors, which are targeted to proteasomes via ubiquitin-like domains or to phagophores (the precursors to autophagosomes) via Atg8/LC3 binding motifs, respectively. The use of substrate modification by ubiquitin in both pathways raised the question of how degradative pathway choice is achieved. In contrast to previous models, proposing different types of ubiquitin linkages for substrate targeting, we find that pathway choice is a late event largely determined by the oligomeric state of the receptors. Monomeric proteasome receptors bind soluble substrates more efficiently due to their higher affinity for ubiquitin. Upon substrate aggregation, autophagy receptors with lower ubiquitin binding affinity gain the upper hand due to higher avidity achieved by receptor bundling. Thus, our work suggests that ubiquitination is a shared signal of an adaptive protein quality control system, which targets substrates for the optimal proteolytic pathway. PMID- 28813182 TI - Impact of Selection Bias on Treatment Effect Size Estimates in Randomized Trials of Oral Health Interventions: A Meta-epidemiological Study. AB - Emerging evidence suggests that design flaws of randomized controlled trials can result in over- or underestimation of the treatment effect size (ES). The objective of this study was to examine associations between treatment ES estimates and adequacy of sequence generation, allocation concealment, and baseline comparability among a sample of oral health randomized controlled trials. For our analysis, we selected all meta-analyses that included a minimum of 5 oral health randomized controlled trials and used continuous outcomes. We extracted data, in duplicate, related to items of selection bias (sequence generation, allocation concealment, and baseline comparability) in the Cochrane Risk of Bias tool. Using a 2-level meta-meta-analytic approach with a random effects model to allow for intra- and inter-meta-analysis heterogeneity, we quantified the impact of selection bias on the magnitude of ES estimates. We identified 64 meta-analyses, including 540 randomized controlled trials analyzing 137,957 patients. Sequence generation was judged to be adequate (at low risk of bias) in 32% ( n = 173) of trials, and baseline comparability was judged to be adequate in 77.8% of trials. Allocation concealment was unclear in the majority of trials ( n = 458, 84.8%). We identified significantly larger treatment ES estimates in trials that had inadequate/unknown sequence generation (difference in ES = 0.13; 95% CI: 0.01 to 0.25) and inadequate/unknown allocation concealment (difference in ES = 0.15; 95% CI: 0.02 to 0.27). In contrast, baseline imbalance (difference in ES = 0.01, 95% CI: -0.09 to 0.12) was not associated with inflated or underestimated ES. In conclusion, treatment ES estimates were 0.13 and 0.15 larger in trials with inadequate/unknown sequence generation and inadequate/unknown allocation concealment, respectively. Therefore, authors of systematic reviews using oral health randomized controlled trials should perform sensitivity analyses based on the adequacy of sequence generation and allocation concealment. PMID- 28813186 TI - Multi-Normalization and Interpolation Protocol to Improve Norovirus Immunoagglutination Assay from Paper Microfluidics with Smartphone Detection. AB - Norovirus (NoV) is one of the leading causes of acute gastroenteritis, affecting 685 million people per year around the world. The best preventive measure is to screen water for possible NoV contamination, not from infected humans, preferably using rapid and field-deployable diagnostic methods. While enzyme immunoassays (EIAs) can be used for such detection, the low infectious dose as well as the generally inferior sensitivity and low titer of available NoV antibodies render critical challenges in using EIAs toward NoV detection. In this work, we demonstrated smartphone-based Mie scatter detection of NoV with immunoagglutinated latex particles on paper microfluidic chips. Using only three different concentrations of anti-NoV-conjugated particles, we were able to construct a single standard curve that covered seven orders of magnitude of NoV antigen concentrations. Multiple normalization steps and interpolation procedures were developed to estimate the optimum amount of antibody-conjugated particles that matched to the target NoV concentration. A very low detection limit of 10 pg/mL was achieved without using any concentration or enrichment steps. This method can also be adapted for detection of any other virus pathogens whose antibodies possess low sensitivity and low antibody titer. PMID- 28813183 TI - Quality-of-Life in Children with Orofacial Clefts and Caregiver Well-being. AB - Quality of life is a valid patient-reported parameter that provides an assessment of treatment need or outcomes complementary to standard clinical measures. Such patient-reported assessments are particularly salient when examining chronic conditions with prolonged treatment trajectories, such as cleft lip and palate. This critical review identifies key questions related to ongoing research on the oral health-related quality of life (OHRQoL) in children with cleft and caregiver well-being. Details of the design and results from 2 longitudinal multicenter studies are presented. This article also provides an update on recent published reports regarding OHRQoL in individuals with cleft. Methodological issues in OHRQoL research are discussed, including condition-specific versus generic instruments, incorporating positive items in OHRQoL instruments, calculating minimally important differences in OHRQoL, implementing mixed methods design, and utilizing validated short assessment forms in OHRQoL research. Finally, new directions for research in cleft as a chronic condition are identified and discussed. PMID- 28813187 TI - Twelve Steps, Two Factors: Coping Strategies Moderate the Association Between Craving and Daily 12-Step Use in a College Recovery Community. AB - BACKGROUND: Affiliating with 12-step groups appears to reduce relapse risk. By relying on between-person designs, extant research has been unable to examine daily mechanisms through which 12-step group affiliation contributes to recovery. OBJECTIVES: To examine the daily use and factor structure of the 12 steps and intrapersonal predictors and moderators of 12-step use. To determine whether the 12 steps were used in response to daily craving and, if so, which steps and in what contexts. METHODS: Data comprised 1304 end-of-day diary data entries from 55 young adults collected in 2008 from members of a college recovery community, combined with person-level baseline measures. Exploratory factor analysis examined the factor structure, and multi-level models examined both day-level and person-level predictors and moderators of step use, including meeting attendance, drug and alcohol dependence, social support, and coping strategies. RESULTS: Analyses produced two factors: Everyday steps, comprising surrender and maintenance steps, and action steps. Moderation analyses revealed that only action steps were significantly associated with craving, suggesting that craving can spur their use, but only among individuals pursuing certain general strategies for coping with stress: Separate median-split models produced significant associations between craving and action steps only among individuals high in avoidance, high in support-seeking, and/or low in problem-solving. Conclusions/Importance: This is the first study to empirically discern a 2-factor structure underlying the 12 steps, and to show that the two sets of steps are used in different contexts. The study also illustrates the value of person centered approaches to recovery research and practice. PMID- 28813188 TI - Cannabis-Related Problems and Social Anxiety: The Mediational Role of Post-Event Processing. AB - BACKGROUND: Cannabis is the most commonly used illicit drug in the US, and is associated with a range of psychological, social, and physical health-related problems. Individuals who endorse elevated levels of social anxiety are especially at risk for experiencing cannabis-related problems, including cannabis use disorder, despite not using cannabis more often than those with more normative social anxiety. Identification of mechanisms that underlie the relationship between social anxiety and cannabis-related problems may inform treatment and prevention efforts. Post-event processing (PEP, i.e., cognitively reviewing past social interactions/performances) is a social anxiety-related phenomenon that may be one such mechanism. OBJECTIVES: The current study sought to test PEP as a mediator of the relationship between social anxiety and cannabis related problems, adjusting for cannabis use frequency. METHOD: Cannabis-using (past 3-month) undergraduate students recruited in 2015 (N = 244; 76.2% female; 74.2% Non-Hispanic Caucasian) completed an online survey of cannabis use, cannabis-related problems, social anxiety, and PEP. RESULTS: Bootstrap estimate of the indirect effect of social anxiety through PEP was significant, suggesting PEP is a mediator of the social anxiety-cannabis-related problems relationship. Conclusions/Importance: Treatment and prevention efforts may benefit from targeting PEP among individuals with elevated social anxiety and cannabis-related problems. PMID- 28813189 TI - What Enables Oncologists to Discuss Goals of Care With Their Patients? Practical Ways Toward a Culture of Kindness, Transparency, and Responsibility. PMID- 28813190 TI - Under Pressure: The Tension Between Access and Abuse of Opioids in Cancer Pain Management. PMID- 28813192 TI - Palliative Care in Special Settings of Cancer Care. PMID- 28813191 TI - Effect and Efficiency of an Embedded Palliative Care Nurse Practitioner in an Oncology Clinic. AB - PURPOSE: To test a simultaneous care model for palliative care for patients with advanced cancer by embedding a palliative care nurse practitioner (NP) in an oncology clinic. METHODS: We evaluated the effect of the intervention in two oncologists' clinics beginning March 2014 by using implementation strategies, including use of a structured referral mechanism, routine symptom screening, integration of a psychology-based cancer supportive care center, implementation team meetings, team training, and a metrics dashboard for continuous quality improvement. After 1 year of implementation, we evaluated key process and outcome measures for supportive oncology and efficiency of the model by documenting tasks completed by the NP during a subset of patient visits and time-motion studies. RESULTS: Of approximately 10,000 patients with active cancer treated in the health system, 2,829 patients had advanced cancer and were treated by 42 oncologists. Documentation of advance care planning increased for patients of the two intervention oncologists compared with patients of the other oncologists. Hospice referral before death was not different at baseline, but was significantly higher for patients of intervention oncologists compared with patients of control oncologists (53% v 23%; P = .02) over the intervention period. Efficiency evaluation revealed that approximately half the time spent by the embedded NP potentially could have been completed by other staff (eg, a nurse, a social worker, or administrative staff). CONCLUSION: An embedded palliative care NP model using scalable implementation strategies can improve advance care planning and hospice use among patients with advanced cancer. PMID- 28813193 TI - Local detection of PtdIns3P at autophagosome biogenesis membrane platforms. AB - Phosphatidylinositol 3-phosphate (PtdIns3P) is a key player of membrane trafficking regulation, mostly synthesized by the PIK3C3 lipid kinase. The presence of PtdIns3P on endosomes has been demonstrated; however, the role and dynamics of the pool of PtdIns3P dedicated to macroautophagy/autophagy remains elusive. Here we addressed this question by studying the mobilization of PtdIns3P in time and space during autophagosome biogenesis. We compared different dyes known to specifically detect PtdIns3P by fluorescence microscopy analysis, based on PtdIns3P-binding FYVE and PX domains, and show that these transfected dyes induce defects in endosomal dynamics as well as artificial and sustained autophagosome formation. In contrast, indirect use of recombinant FYVE enabled us to track and discriminate endosomal and autophagosomal pools of PtdIns3P. We used this method to analyze localization and dynamics of PtdIns3P subdomains on the endoplasmic reticulum, at sites of pre-autophagosome associated protein recruitment such as the PtdIns3P-binding ZFYVE1/DFCP1 and WIPI2 autophagy regulators. This approach thus revealed the presence of a specific pool of PtdIns3P at the site where autophagosome assembly is initiated. PMID- 28813194 TI - Characterization of Small (< 4 cm) Focal Renal Lesions: Diagnostic Accuracy of Spectral Analysis Using Single-Phase Contrast-Enhanced Dual-Energy CT. AB - OBJECTIVE: The purpose of this study is to determine whether single-phase contrast-enhanced dual-energy quantitative spectral analysis improves the accuracy of diagnosis of small (< 4.0 cm) renal lesions, compared with conventional single-energy attenuation measurements. MATERIALS AND METHODS: In this retrospective study, 136 consecutive patients (95 men and 41 women; mean age, 54 years) with 144 renal lesions (111 benign and 33 malignant) underwent single-energy unenhanced and dual-energy contrast-enhanced CT of the abdomen. For each renal lesion, attenuation measurements were obtained, and an attenuation change of 15 HU or greater was considered evidence of enhancement. Dual-energy spectral attenuation curves were generated for each lesion. The slope of each curve was measured between 40 and 50 keV (lambdaHU40-50), 40 and 70 keV (lambdaHU40-70), and 40 and 140 keV (lambdaHU40-140). Mean lesion attenuation values and spectral attenuation curve parameters were compared between benign and malignant renal lesions by use of the two-sample t test. Diagnostic accuracy was assessed and validated using cross-validation analysis. RESULTS: With the use of cross-validated optimal thresholds at 100% sensitivity, specificity for differentiating between benign and malignant renal lesions improved significantly when both lambdaHU40-70 and lambdaHU40-140 were used, compared with conventional enhancement measurements (93% [103/111; 95% CI, 86-97%] vs 81% [90/111; 95% CI, 73-88%]) (p = 0.02). The sensitivity of lambdaHU40-70 and lambdaHU40-140 was also higher than that of conventional enhancement measurements, although it was not statistically significant. CONCLUSION: Single-phase contrast-enhanced dual-energy quantitative spectral analysis significantly improves the specificity for characterization of small (< 4.0 cm) renal lesions, compared with conventional single-energy attenuation measurements. PMID- 28813195 TI - Prediction of Therapeutic Response of Hepatocellular Carcinoma to Transcatheter Arterial Chemoembolization Based on Pretherapeutic Dynamic CT and Textural Findings. AB - OBJECTIVE: The objective of our study was to assess the value of CT texture analysis for prediction of therapeutic response of hepatocellular carcinoma (HCC) to transcatheter arterial chemoembolization (TACE) with pretherapeutic dynamic CT. MATERIALS AND METHODS: We retrospectively analyzed 132 HCCs in 96 patients treated with TACE who underwent dynamic CT before initial TACE. Imaging findings and arterial enhancement ratios were analyzed. All HCCs were manually segmented, and their texture features were quantitatively extracted using in-house software. CT texture was quantified with 2D and 3D analysis. HCCs were classified as with and without complete response (CR) according to modified Response Evaluation Criteria in Solid Tumors. Predictive factors for CR were assessed with multivariate analysis. Radiologic responses were correlated with time to progression (TTP). RESULTS: Of the 132 HCCs, CR was achieved in 75 (56.8%). Tumor size, subjective arterial tumor attenuation, and arterial enhancement ratios were significantly associated with CR. On 2D and 3D analysis, tumors with CR showed significantly lower homogeneity and higher mean attenuation, gray-level co occurrence matrix (GLCM) moments, and CT number percentiles (p < 0.05). On multivariate analysis, higher subjective tumor attenuation (adjusted odds ratio [OR] = 23.35), arterial enhancement ratio (OR = 14.07), GLCM moments (OR = 6.57), smaller tumor size (OR = 17.26), and lower homogeneity (OR = 0.69) were significant predictors of CR compared with incomplete response (p < 0.05). Median survival value for TTP was significantly longer in tumors with CR (p < 0.001). CONCLUSION: Pretherapeutic dynamic CT texture analysis can be valuable to predict CR of HCC to TACE. Higher arterial enhancement and GLCM moments, lower homogeneity, and smaller tumor size are significant predictors of CR after TACE. PMID- 28813196 TI - Hepatic Parenchymal Heterogeneity as a Marker for Oxaliplatin-Induced Sinusoidal Obstruction Syndrome: Correlation With Treatment Response of Colorectal Cancer Liver Metastases. AB - OBJECTIVE: The objective of our study was to evaluate the influence of oxaliplatin-based chemotherapy (OBC)-induced hepatic parenchymal heterogeneity detected on contrast-enhanced CT scans on response of liver metastasis. We chose to study hepatic parenchymal heterogeneity on the basis of the assumption that hepatic parenchymal heterogeneity may indicate the presence of chemotherapy induced sinusoidal obstruction syndrome (SOS). MATERIALS AND METHODS: For this retrospective study, 104 patients with hepatic metastases from colorectal cancer (male-female ratio, 66:38; age range, 20-80 years) who had undergone OBC and serial CT studies were consecutively registered. Two blinded imagers independently scored CT images using a 5-point scale to determine the severity of newly developed hepatic parenchymal heterogeneity after OBC. Subsequently, two radiologists evaluated tumor response to OBC using a 4-point ordinal scale. We performed generalized estimating equation (GEE) analysis using cumulative logits to account for the effect of hepatic parenchymal heterogeneity severity on the cumulative tumor response probability. RESULTS: The interobserver agreements for the severity of hepatic parenchymal heterogeneity were excellent (kappa = 0.825). GEE analyses showed that the severity of post-OBC hepatic parenchymal heterogeneity, number of chemotherapy sessions, and presence of other organ metastases were significant predictors of tumor response; these three factors also showed significance in the final GEE model (p < 0.0001 for severity of hepatic parenchymal heterogeneity for both readers; p = 0.011 and 0.010 for the number of chemotherapy sessions for readers 1 and 2; p = 0.046 and 0.012 for the presence of other organ metastases for readers 1 and 2). CONCLUSION: Hepatic parenchymal heterogeneity detected on contrast-enhanced CT of patients with hepatic metastases from colorectal cancer who have undergone OBC may indicate the presence of SOS, and the more severe the SOS, the worse the tumor response of hepatic metastasis to oxaliplatin is expected to be. PMID- 28813197 TI - Split-Bolus Injection Producing Simultaneous Late Arterial and Portal Venous Phases in CT Enterography: Preliminary Results. AB - OBJECTIVE: The purpose of this article is to evaluate the image quality and added value of split-bolus contrast agent injection combining late arterial and portal venous phases compared with single-bolus contrast agent injection late arterial phase CT enterography. MATERIALS AND METHODS: Consecutive patients who underwent CT enterography before and after implementation of a single-bolus CT enterography protocol were included. Attenuation and contrast-to-noise ratio (CNR) were assessed by ROI measurements of the bowel wall and arterial and venous structures. Subjective enhancement of the bowel wall (1, arterial; 2, mucosal; 3, transmural; 4, transmural with mucosal hyperenhancement) and bowel abnormalities were assessed by two independent readers. MR enterography examinations, endoscopy reports, and surgery reports within 30 days after CT enterography were used to produce a composite outcome. RESULTS: Sixty-six patients were included in our study: 33 (mean [+/- SD] age, 46.0 +/- 19.8 years) who underwent split-bolus CT enterography and 33 (mean age, 49.9 +/- 19.0 years) who underwent single-bolus CT enterography. Bowel wall attenuation and CNR were higher for split-bolus CT enterography than for single-bolus CT enterography at 120 kVp (enhancement, 98.7 +/- 23.1 HU vs 85.1 +/- 23.3 HU; CNR, 6.4 +/- 2.5 vs 4.4 +/- 2.3; p < 0.01). Subjective ratings of bowel wall enhancement were higher with the split-bolus CT enterography than the single-bolus CT enterography (2.6 +/- 0.8 vs 2.3 +/- 0.6; p < 0.001). Split-bolus CT enterography led to a higher detection rate of mucosal hyperenhancement than did single-bolus CT enterography in patients with active inflammatory bowel disease (100.0% [7/7; 95% CI, 59.0-100.0%] vs 33.3% [2/6; 95% CI, 4.3-77.7%]; p = 0.02), whereas both protocols had a specificity of 100.0% (9/9). CONCLUSION: Split-bolus CT enterography led to improved CNR (47%) compared with single-bolus CT enterography and significantly increased the detection rate of mucosal hyperenhancement in patients with active inflammatory bowel disease. PMID- 28813198 TI - Radial Scars of the Breast Encountered at Core Biopsy: Review of Histologic, Imaging, and Management Considerations. AB - OBJECTIVE: The purposes of this article are to place the controversy over the management of radial scars diagnosed at core biopsy in perspective and to define reasonable management options. CONCLUSION: The management of radial scars after image-guided core biopsy of the breast for diagnosis remains controversial. Although current literature suggests no premalignant potential of these lesions, it does not fully explain the small but real percentage of these lesions that are upgraded to malignancy after surgical excision. This upgrade phenomenon is probably best explained by core biopsy sampling error. A recommendation minimizing this possibility based on lesion size seems reasonable. PMID- 28813199 TI - Hypoglossal Canal Lesions: Distinctive Imaging Features and Simple Diagnostic Algorithm. AB - OBJECTIVE: The objective of this study is to compare the prevalence of hypoglossal canal lesions and identify differentiating imaging features. MATERIALS AND METHODS: A 15-year retrospective review of lesions of the hypoglossal nerve and hypoglossal canal, excluding those in patients with metastasis or prior head and neck cancer and those treated with radiation or surgery, was performed. Clinical findings and lesion imaging features were documented. The contrast-enhanced T1-weighted nonenhancing cystic component of hypoglossal schwannomas was compared with size-matched pathologically proven vestibular schwannomas. RESULTS: Our review identified 40 lesions encroaching on the hypoglossal canal, located within the hypoglossal canal, or found in both locations: 16 hypoglossal schwannomas, 15 juxtaarticular cysts, and nine purely cystic hypoglossal canal lesions. Hypoglossal schwannomas, which were intradural when involving the premedullary cistern, most commonly enhanced heterogeneously, with a thick peripheral enhancing component, a central enhancing component, or both enhancing components. Juxtaarticular cysts encroaching on the hypoglossal canal were extradural, were contiguous with a craniocervical junction synovial joint, and showed thin rim enhancement. Hypoglossal canal nonenhancing cystic lesions were confined to the hypoglossal canal, had signal intensity equivalent to CSF, and lacked any contrast enhancement. CONCLUSION: Although hypoglossal schwannomas, juxtaarticular cysts, and hypoglossal canal nonenhancing cystic lesions may all encroach on or lie within the hypoglossal canal, purely cystic lesions are unlikely to be schwannomas. A diagnostic algorithm applying key imaging and clinical findings allows differentiation of these lesions, which have vastly different treatment regimens. PMID- 28813200 TI - Brain Microstructural Abnormalities in Patients With Cirrhosis Without Overt Hepatic Encephalopathy: A Voxel-Based Diffusion Kurtosis Imaging Study. AB - OBJECTIVE: This study aimed to investigate whole-brain microstructural abnormalities and their correlation with cognitive impairment in patients with cirrhosis using diffusion kurtosis imaging (DKI). SUBJECTS AND METHODS: Eighteen patients with cirrhosis and 17 healthy control subjects underwent DKI. Cognition was measured using psychometric hepatic encephalopathy (HE) scores. Whole-brain voxel-based analyses were performed to investigate between-group differences in DKI-derived parameters, including mean kurtosis, axial kurtosis, and radial kurtosis. RESULTS: Compared with control subjects, the patients with cirrhosis had lower psychometric HE scores, indicating cognitive impairments. The patients with cirrhosis had significantly lower global mean kurtosis, axial kurtosis, and radial kurtosis in gray matter (GM) and white matter (WM). Voxel-based analyses showed that patients with cirrhosis had decreased mean kurtosis, axial kurtosis, and radial kurtosis in diffuse GM regions (particularly in the cingulate cortex, precuneus, insular cortex, frontal areas, basal ganglia, hippocampus and parahippocampal gyrus, supramarginal gyrus and angular gyrus, postcentral and precentral gyrus, and cerebellum) and WM regions (particularly in the corpus callosum, internal capsule, frontal regions, parietal regions, occipital regions, and cerebellum). The DKI metrics were positively correlated with psychometric HE score among patients. CONCLUSION: Lower DKI parameters suggest decreased brain microstructural complexity in patients with cirrhosis, which may contribute to the neurobiologic basis of cognitive impairment. PMID- 28813201 TI - Applying Movement Ecology to Marine Animals with Complex Life Cycles. AB - Marine animals with complex life cycles may move passively or actively for fertilization, dispersal, predator avoidance, resource acquisition, and migration, and over scales from micrometers to thousands of kilometers. This diversity has catalyzed idiosyncratic and unfocused research, creating unsound paradigms regarding the role of movement in ecology and evolution. The emerging movement ecology paradigm offers a framework to consolidate movement research independent of taxon, life-history stage, scale, or discipline. This review applies the framework to movement among life-history stages in marine animals with complex life cycles to consolidate marine movement research and offer insights for scientists working in aquatic and terrestrial realms. Irrespective of data collection or simulation strategy, breaking each life-history stage down into the fundamental units of movement allows each unit to be studied independently or interactively with other units. Understanding these underlying mechanisms of movement within each life-history stage can then be used to construct lifetime movement paths. These paths can allow further investigation of the relative contributions and interdependencies of steps and phases across a lifetime and how these paths influence larger research topics, such as population level movements. PMID- 28813202 TI - Artificial Hydration at the End of Life. AB - Initiation or continuation of artificial hydration (AH) at the end of life requires unique considerations. A combination of ethical precedents and medical literature may provide clinical guidance on how to use AH at the end of life. The purpose of this review is to describe the ethical framework for and review current literature relating to the indications, benefits, and risks of AH at the end of life. Provider, patient, and family perspectives will also be discussed. PMID- 28813204 TI - The Prefrontal Cortex and Neurological Impairments of Active Thought. AB - This article reviews the effects of lesions to the frontal cortex on the ability to carry out active thought, namely, to reason, think flexibly, produce strategies, and formulate and realize plans. We discuss how and why relevant neuropsychological studies should be carried out. The relationships between active thought and both intelligence and language are considered. The following basic processes necessary for effective active thought are reviewed: concentration, set switching, inhibiting potentiated responses, and monitoring and checking. Different forms of active thought are then addressed: abstraction, deduction, reasoning in well-structured and ill-structured problem spaces, novel strategy generation, and planning. We conclude that neuropsychological findings are valuable for providing information on systems rather than networks, especially information concerning prefrontal lateralization of function. We present a synthesis of the respective roles of the left and right lateral prefrontal cortex in active thought. PMID- 28813205 TI - Combining 2 Commonly Adopted Nutrition Instruments in the Critical Care Setting Is Superior to Administering Either One Alone. AB - BACKGROUND: This study aimed to determine the agreement between the modified Nutrition Risk in Critically ill Score (mNUTRIC) and the Subjective Global Assessment (SGA) and compare their ability in discriminating and quantifying mortality risk independently and in combination. METHODS: Between August 2015 and October 2016, all patients in a Singaporean hospital received the SGA within 48 hours of intensive care unit admission. Nutrition status was dichotomized into presence or absence of malnutrition. The mNUTRIC of patients was retrospectively calculated at the end of the study, and high mNUTRIC was defined as scores >=5. RESULTS: There were 439 patients and 67.9% had high mNUTRIC, whereas only 28% were malnourished. Hospital mortality was 29.6%, and none was lost to follow-up. Although both tools had poor agreement (kappa statistics: 0.13, P < .001), they had similar discriminative value for hospital mortality (C-statistics [95% confidence interval (CI)], 0.66 [0.62-0.70] for high mNUTRIC and 0.61 [0.56-0.66] for malnutrition, P = .12). However, a high mNUTRIC was associated with higher adjusted odds for hospital mortality compared with malnutrition (adjusted odds ratio [95% CI], 5.32 [2.15-13.17], P < .001, and 4.27 [1.03-17.71], P = .046, respectively). Combination of both tools showed malnutrition and high mNUTRIC were associated with the highest adjusted odds for hospital mortality (14.43 [5.38-38.78], P < .001). CONCLUSION: The mNUTRIC and SGA had poor agreement. Although they individually provided a fair discriminative value for hospital mortality, the combination of these approaches is a better discriminator to quantify mortality risk. PMID- 28813206 TI - Levamisole in Illicit Trafficking Cocaine Seized: A One-Year Study. AB - Cocaine use is increasing around the world and its purity is frequently altered through dilution, substitution, contamination, and adulteration. Sugars, talc, starch, and carbonates represent the principal diluents of cocaine, while phenacetin, levamisole, caffeine, and lidocaine are its major adulterants in Europe. Levamisole is used because it is an odorless powder, with physical properties similar to cocaine, and it has reasonable cost and availability, being widely used in veterinary medicine. For this study, we analyzed 88 cocaine samples. The seized cocaine analyzed showed an average purity of 55% and the most frequent adulterants identified were: levamisole (31.8%), caffeine (6.8%), lidocaine (2.3%), acetaminophen (2.3%), and phenacetin (1.1%). Our aim is the study of the presence of levamisole, over other adulterants in seized cocaine samples, due to its recognized human toxicity. The chronic use of levamisole adulterated cocaine represents a serious public health issue because it may be responsible for side-effects such as dermal vasculopathy, leukoencephalopathy, leukopenia, agranulocytosis, pulmonary hemorrhage, multiple emboli, and several other effects. Moreover, aminorex can cause idiopathic pulmonary hypertension, presenting another harmful and mostly lethal side-effect from cocaine cut with levamisole. In conclusion, levamisole determination should be performed in routine toxicological analysis in deaths due to cocaine use. PMID- 28813207 TI - Examination of Synthetic Cannabinoid and Cathinone Use among a Drug-Using Offender Sample, 2013-2015. AB - Use of novel psychoactive substances (NPS) such as synthetic cannabinoids (e.g., "Spice," "Serenity") and cathinones (e.g., "bath salts") has proliferated in recent years; however, there is a gap in research examining prevalence among offender samples. This study examined demographics, drug use, mental health characteristics, and criminal histories of NPS users compared to non-NPS users within an offender sample entering drug treatment. Using logistic regression analysis, combined 2013-2015 assessment data were examined (N = 8,791). NPS users offended more often (x = 10.3), were more likely to have experienced homelessness (12.2%), and to have lived in a metro area (59.0%). NPS users reported significantly more past-year drug use, including substances not readily detected by standard urine analysis (e.g., hallucinogens, alcohol, and inhalants). Individuals with higher anxiety symptom counts (OR = 1.07; p < .001) and those who reported drinking to intoxication (OR = 1.30; p < .001) had an increased likelihood of NPS use. Older individuals (OR = 0.95; p < .001) and those who began using drugs at an older age (OR = 0.95; p < .001) were less likely to report NPS use. NPS use may be a marker of more severe using patterns in an offender sample. Future investigation should focus on NPS use as a possible method for bypassing drug testing measures. PMID- 28813208 TI - Substance use and dependence among current reserve and former military members: Cross-sectional findings from the National Survey on Drug Use and Health, 2010 2014. AB - Maladjustment after leaving the military may contribute to poor health outcomes, including increased risk for substance use and dependence. The authors examined differences in substance use and dependence on the basis of military involvement in a large nationally representative sample. Data are from a subset of the 2010 2014 waves of the National Survey on Drug Use and Health (n = 5,608). The sample included men (81.9%) and women (18.1%) aged 20-49 years who had either separated/retired from the military (n = 4,862) or were a current reserve service member (n = 746). The sample was 70.8% Non-Hispanic White with a median family income between $50,000 and $74,999. Those who were separated/retired from the military had a higher odds of past month smoking (adjusted odds ratio [AOR] = 1.73, 95% confidence interval [CI]: 1.27, 2.36; p = 0.001), nonmedical use of prescription painkillers (AOR = 4.07, 95% CI: 1.88, 8.83; p < 0.001), illicit drug use (AOR = 2.75, 95% CI: 1.79, 4.24; p < 0.001), alcohol dependence (AOR = 2.17, 95% CI: 1.20, 3.93; p = 0.011), nicotine dependence (AOR = 2.03, 95% CI: 1.25, 3.28; p = 0.004), and illicit drug dependence (AOR = 5.89; 95% CI: 2.19, 15.85; p = 0.001), compared to current reserve service members, controlling for sex, age, race, and income. Service members are leaving the military at an increasing rate and substance use may increase after separation. Across a range of substances, those who are separated/retired from the military have a higher likelihood of substance use/dependence than current reserve service members. Care models that assist in the transition from discharge to civilian life should be considered. PMID- 28813209 TI - Galangin, a natural flavonoid reduces mitochondrial oxidative damage in streptozotocin-induced diabetic rats. AB - OBJECTIVE: We designed this study to observe the effect of galangin on damaged mitochondria in the liver of diabetic rats. METHODS: Male albino Wistar rats were made diabetic by injecting streptozotocin (STZ) intraperitoneally (40 mg kg-1 body weight (BW)). Galangin (8 mg kg-1 BW) or glibenclamide (600 ug kg-1 BW) was given orally daily once for 45 days to both healthy and diabetic rats. RESULTS: Diabetic rats showed significant (P < 0.05) increase in liver mitochondrial oxidant [Thiobarbituric acid reactive substance (TBARS)] level and a significant decrease in enzymatic [superoxide dismutase (SOD), glutathione peroxidase (GPx)] and non-enzymatic (reduced glutathione (GSH)) antioxidant levels when compared with healthy rats. The mitochondrial enzymes isocitrate dehydrogenase (ICDH), alpha-ketoglutarate dehydrogenase (alpha-KGDH), succinate dehydrogenase (SDH) and malate dehydrogenase (MDH) and mitochondrial respiratory chain enzymes NADH dehydrogenase and Cytochrome c-oxidase were decreased significantly (P < 0.05) in diabetic rats when compared with healthy rats. A natural flavonoid galangin administered to hyperglycemia-induced rats resulted in the following findings as compared to hyperglycemia-induced control rats: the oxidant levels decreased significantly (P < 0.05); the enzymatic and non-enzymatic antioxidant levels increased significantly (P < 0.05) and the function of mitochondrial enzymes and the mitochondrial respiratory chain enzymes increased significantly (P < 0.05). CONCLUSION: From the results, we conclude that galangin could maintain liver mitochondrial function in diabetic rats. PMID- 28813210 TI - Public Opinion about the Future of the Affordable Care Act. PMID- 28813211 TI - A Nicotine-Focused Framework for Public Health. PMID- 28813212 TI - Changing the Discussion about On-Pump versus Off-Pump CABG. PMID- 28813213 TI - Aspirin to Prevent Preeclampsia. PMID- 28813215 TI - Eczema Herpeticum. PMID- 28813216 TI - Kinetics of Zika Viral Load in Semen. PMID- 28813217 TI - Saying Goodbye to Lectures in Medical School - Paradigm Shift or Passing Fad? PMID- 28813219 TI - Association of Reference Pricing with Drug Selection and Spending. AB - Background In the United States, prices for therapeutically similar drugs vary widely, which has prompted efforts by public and private insurers to steer patients toward the lower-priced options. Under reference pricing, the insurer or employer establishes a maximum contribution it will make toward the price of a drug or procedure, and the patient pays the remainder. Methods We used difference in-differences multivariable regression methods to analyze changes in prescriptions and pricing for 1302 drugs in 78 therapeutic classes in the United States, before and after implementation of reference pricing by an alliance of private employers. We assessed trends for the study group relative to those for an employee group that was not subject to reference pricing. The study included 1,122,741 prescriptions that were reimbursed during the period from 2010 through 2014. Results Implementation of reference pricing was associated with a higher percentage of prescriptions that were filled for the lowest-priced reference drug within its therapeutic class (difference in probability, 7.0 percentage points; 95% confidence interval [CI], 4.0 to 9.9), a lower average price paid per prescription (-13.9%; 95% CI, -23.8 to -2.7), and a higher rate of copayment by patients (5.2%; 95% CI, 0.2 to 10.4) than in the comparison group. During the first 18 months after implementation, spending for employers was $1.34 million lower and the amount of copayments for employees was $0.12 million higher than in the comparison group. Conclusions Implementation of reference pricing was associated with significant changes in drug selection and spending for a population of patients covered by employment-based insurance in the United States. (Funded by the Agency for Healthcare Research and Quality and the Genentech Foundation.). PMID- 28813220 TI - Case 25-2017. PMID- 28813221 TI - Inflammatory Bowel Disease and the NLRP3 Inflammasome. PMID- 28813222 TI - Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy. PMID- 28813223 TI - Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy. PMID- 28813218 TI - Five-Year Outcomes after On-Pump and Off-Pump Coronary-Artery Bypass. AB - BACKGROUND: Coronary-artery bypass grafting (CABG) surgery may be performed either with cardiopulmonary bypass (on pump) or without cardiopulmonary bypass (off pump). We report the 5-year clinical outcomes in patients who had been included in the Veterans Affairs trial of on-pump versus off-pump CABG. METHODS: From February 2002 through June 2007, we randomly assigned 2203 patients at 18 medical centers to undergo either on-pump or off-pump CABG, with 1-year assessments completed by May 2008. The two primary 5-year outcomes were death from any cause and a composite outcome of major adverse cardiovascular events, defined as death from any cause, repeat revascularization (CABG or percutaneous coronary intervention), or nonfatal myocardial infarction. Secondary 5-year outcomes included death from cardiac causes, repeat revascularization, and nonfatal myocardial infarction. Primary outcomes were assessed at a P value of 0.05 or less, and secondary outcomes at a P value of 0.01 or less. RESULTS: The rate of death at 5 years was 15.2% in the off-pump group versus 11.9% in the on pump group (relative risk, 1.28; 95% confidence interval [CI], 1.03 to 1.58; P=0.02). The rate of major adverse cardiovascular events at 5 years was 31.0% in the off-pump group versus 27.1% in the on-pump group (relative risk, 1.14; 95% CI, 1.00 to 1.30; P=0.046). For the 5-year secondary outcomes, no significant differences were observed: for nonfatal myocardial infarction, the rate was 12.1% in the off-pump group and 9.6% in the on-pump group (P=0.05); for death from cardiac causes, the rate was 6.3% and 5.3%, respectively (P=0.29); for repeat revascularization, the rate was 13.1% and 11.9%, respectively (P=0.39); and for repeat CABG, the rate was 1.4% and 0.5%, respectively (P=0.02). CONCLUSIONS: In this randomized trial, off-pump CABG led to lower rates of 5-year survival and event-free survival than on-pump CABG. (Funded by the Department of Veterans Affairs Office of Research and Development Cooperative Studies Program and others; ROOBY-FS ClinicalTrials.gov number, NCT01924442 .). PMID- 28813224 TI - Signs. PMID- 28813225 TI - Pediatric Intestinal Failure. PMID- 28813226 TI - Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. PMID- 28813227 TI - Medical Education in the Era of Alternative Facts. PMID- 28813228 TI - Acute Ocular Graft-versus-Host Disease. PMID- 28813229 TI - Cortical Networks for Correcting Errors in Sensorimotor Synchronization Depend on the Direction of Asynchrony. AB - Recent work provides clues that different cortical mechanisms may be employed when correcting for errors in sensorimotor synchronization that increase tap-tone asynchrony compared with those that decrease it. The authors tested this hypothesis by recording 64-channel electroencephalography while participants synchronized with an auditory metronome. We systematically introduced positive and negative phase-shift perturbations that were either liminal (10%) and subliminal (3%). We used a distributed source modeling approach to evaluate oscillatory activity and connectivity of discrete cortical sources. Three key findings support our hypothesis. First was a theta band response indicative of error detection and top-down control observed in frontomedial presupplementary motor area (pre-SMA) and anterior cingulate for liminal positive perturbations. Second was an increase in theta band coupling between the SMA and contralateral motor cortex exclusively for positive perturbations suggesting a top-down modulation of motor parameters. Third, when compared with other conditions, liminal positive perturbations result in an increase in postmovement beta rebound within contralateral primary motor cortex. The authors propose that frontomedial motor areas exert a top-down inhibitory influence over the primary motor cortex to effectively lengthen tap intervals in response to lengthening tap-tone asynchronies. PMID- 28813230 TI - Dietary Supplements Commonly Used by Cancer Survivors: Are There Any Benefits? AB - Following a cancer diagnosis, dietary supplements are reportedly used by 20%-80% of individuals. Supplements are most commonly used by breast cancer survivors, followed by patients with prostate, colorectal, and lung cancers, which is not surprising since these are the most common types of cancer diagnosed in adults. Reasons cited for such use include improving quality of life, reducing symptoms related to treatment and/or the disease process, and recommendation from medical practitioners; family and friends may also be an influence. However, controversy surrounds the use of dietary supplements, particularly during treatment specifically, whether supplements affect treatment efficacy is unknown. This article discusses the evidence related to common dietary supplements used to prevent cancer or a recurrence. PMID- 28813231 TI - Time-Frequency Cross Mutual Information Analysis of the Brain Functional Networks Underlying Multiclass Motor Imagery. AB - To study the physiologic mechanism of the brain during different motor imagery (MI) tasks, the authors employed a method of brain-network modeling based on time frequency cross mutual information obtained from 4-class (left hand, right hand, feet, and tongue) MI tasks recorded as brain-computer interface (BCI) electroencephalography data. The authors explored the brain network revealed by these MI tasks using statistical analysis and the analysis of topologic characteristics, and observed significant differences in the reaction level, reaction time, and activated target during 4-class MI tasks. There was a great difference in the reaction level between the execution and resting states during different tasks: the reaction level of the left-hand MI task was the greatest, followed by that of the right-hand, feet, and tongue MI tasks. The reaction time required to perform the tasks also differed: during the left-hand and right-hand MI tasks, the brain networks of subjects reacted promptly and strongly, but there was a delay during the feet and tongue MI task. Statistical analysis and the analysis of network topology revealed the target regions of the brain network during different MI processes. In conclusion, our findings suggest a new way to explain the neural mechanism behind MI. PMID- 28813232 TI - Understanding Peripartum Cardiomyopathy. AB - Peripartum cardiomyopathy (PPCM) is the unexplained loss of maternal cardiac systolic function in the period surrounding parturition. PPCM affects women worldwide and is a leading cause of maternal mortality. The cause of PPCM has remained elusive until recently. We review here the epidemiology of PPCM, recent findings that strongly indicate hormonal and genetic contributions to the development of PPCM, and implications for the management of women with PPCM. PMID- 28813233 TI - * Special Issue on Strategic Directions in Musculoskeletal Tissue Engineering. PMID- 28813234 TI - Cardiac MR Strain: A Noninvasive Biomarker of Fibrofatty Remodeling of the Left Atrial Myocardium. AB - Purpose To determine whether left atrial (LA) strain quantification with cardiac magnetic resonance (MR) imaging feature tracking is associated with the severity of LA fibrofatty myocardial remodeling at histologic analysis. Materials and Methods This prospective case-control study was approved by the institutional review board. LA strain was evaluated with cardiac MR feature tracking between January 2014 and March 2015 in 13 consecutive patients (mean age, 61 years +/- 19; nine male) with mitral regurgitation in the 24 hours before mitral valve surgery and 13 age- and sex-matched healthy control subjects. LA strain parameters were compared first between control subjects and patients and then according to atrial fibrillation and mitral regurgitation status. Associations between LA strain and histology of preoperative biopsies were reported by using receiver operating characteristic curve analysis and Spearman correlation. Results Peak longitudinal atrial strain (PLAS) was significantly lower in patients with mitral regurgitation than in healthy control subjects (P < .001). Increased LA remodeling was significantly related to altered LA strain, and the strongest association was found between PLAS and the degree of fibrofatty myocardial replacement at histologic analysis (r = -0.75, P = .017). LA end diastolic volume was increased in patients with mitral regurgitation when compared with that in healthy volunteers (P < .001) because of volume overload; however, volume did not correlate with the histologic degree of LA fibrofatty replacement (r = -0.35, P = .330). Conclusion LA strain, especially PLAS, correlates strongly with the degree of fibrofatty replacement at histologic analysis. Such functional imaging biomarker in combination with LA volumetry could help to guide clinical decisions, since myocardial structural remodeling is a known morphologic substrate of LA dysfunction leading to atrial fibrillation with adverse outcome. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28813214 TI - Cognitive Function in a Randomized Trial of Evolocumab. AB - Background Findings from clinical trials of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors have led to concern that these drugs or the low levels of low-density lipoprotein (LDL) cholesterol that result from their use are associated with cognitive deficits. Methods In a subgroup of patients from a randomized, placebo-controlled trial of evolocumab added to statin therapy, we prospectively assessed cognitive function using the Cambridge Neuropsychological Test Automated Battery. The primary end point was the score on the spatial working memory strategy index of executive function (scores range from 4 to 28, with lower scores indicating a more efficient use of strategy and planning). Secondary end points were the scores for working memory (scores range from 0 to 279, with lower scores indicating fewer errors), episodic memory (scores range from 0 to 70, with lower scores indicating fewer errors), and psychomotor speed (scores range from 100 to 5100 msec, with faster times representing better performance). Assessments of cognitive function were performed at baseline, week 24, yearly, and at the end of the trial. The primary analysis was a noninferiority comparison of the mean change from baseline in the score on the spatial working memory strategy index of executive function between the patients who received evolocumab and those who received placebo; the noninferiority margin was set at 20% of the standard deviation of the score in the placebo group. Results A total of 1204 patients were followed for a median of 19 months; the mean (+/-SD) change from baseline over time in the raw score for the spatial working memory strategy index of executive function (primary end point) was 0.21+/-2.62 in the evolocumab group and -0.29+/-2.81 in the placebo group (P<0.001 for noninferiority; P=0.85 for superiority). There were no significant between-group differences in the secondary end points of scores for working memory (change in raw score, -0.52 in the evolocumab group and -0.93 in the placebo group), episodic memory (change in raw score, -1.53 and -1.53, respectively), or psychomotor speed (change in raw score, 5.2 msec and 0.9 msec, respectively). In an exploratory analysis, there were no associations between LDL cholesterol levels and cognitive changes. Conclusions In a randomized trial involving patients who received either evolocumab or placebo in addition to statin therapy, no significant between-group difference in cognitive function was observed over a median of 19 months. (Funded by Amgen; EBBINGHAUS ClinicalTrials.gov number, NCT02207634 .). PMID- 28813235 TI - Temporary Hearing Threshold Shift in Healthy Volunteers with Hearing Protection Caused by Acoustic Noise Exposure during 3-T Multisequence MR Neuroimaging. AB - Purpose To determine whether a single 51-minute exposure to acoustic noise during 3-T multisequence magnetic resonance (MR) neuroimaging could affect the hearing threshold of healthy adults with earplugs and sponge mats as hearing protection. Materials and Methods With earplugs and motion-refraining sponge mats as hearing protection, 26 healthy young adults underwent 3-T MR neuroimaging imaging that included T1-weighted three-dimensional gradient-echo sequence, T2-weighted fast spin-echo sequence, diffusion-tensor imaging, diffusion-kurtosis imaging, T2* weighted three-dimensional multiecho gradient-echo sequence, and blood oxygen level-dependent imaging. Automated auditory brainstem response (ABR) was used to measure the hearing thresholds within 24 hours before, within 20 minutes after, and 25 days after the MR examination. One-way repeated-measure analysis of variance with Bonferroni adjustment was used to compare automated ABR results among the three tests and partial eta2 (etap2) was reported as a measure of effect size. Results Automated ABR results showed significantly increased mean threshold shift of 5.0 dB +/- 8.1 (standard deviation) (left ear: 4.8 dB +/- 9.2 [95% confidence interval: 1.09, 8.53], etap2 = 0.221, P = .013; right ear: 5.2 dB +/- 6.9 [95% confidence interval: 2.36, 8.02], etap2 = 0.364, P = .001) immediately after the MR examination compared with the baseline study. This shift is below the temporary threshold shift of 40-50 dB that is associated with cochlea nerve changes. Automated ABR obtained at day 25 after MR imaging showed no significant differences from baseline (left ear: -2.3 dB +/- 8.6 [95% confidence interval: -5.79, 1.78], etap2 = 0.069, P = .185; right ear: 0.4 dB +/- 7.3 [95% confidence interval: -3.35, 2.58], etap2 = 0.003, P = .791). Conclusion A 3-T MR neuroimaging examination with the acoustic noise at equivalent sound pressure level of 103.5-111.3 dBA lasting 51 minutes can cause temporary hearing threshold shift in healthy volunteers with hearing protection. (c) RSNA, 2017. PMID- 28813236 TI - Ethics and Intimate Sexual Activity in Long-Term Care. AB - A case is presented in which the staff of a long-term care facility discovers that the husband of a resident with dementia is engaged in sexual activity with her. The case illustrates a dilemma for long-term care facilities that create a home-like environment with a goal of maximizing residents' autonomy while ensuring their safety. An approach to assessing capacity to consent to intimate sexual activity is described, followed by guidelines that nursing homes can implement to support residents who wish to engage in sexual activity. Recommendations are also offered for supporting long-term care staff and family members of residents who are interested in intimate sexual activity. PMID- 28813237 TI - Should Dementia Be Accepted as a Disability to Help Restore Hope during Cognitive Decline? AB - Dementia is a common condition that impacts the patient, the family, and society. Currently, a diagnosis of dementia evokes hopelessness in the afflicted, and society provides few resources or systematic support for caregivers or for demented patients. In this commentary, we discuss the origins of hopelessness in dementia, the World Health Organization's six-stage framework of dementia care, and barriers to "normalizing" the experience of dementia in order to provide beneficent and humane care for patients with dementia. We also offer recommendations for clinicians who care for patients who feel that a life with dementia is not worth living. PMID- 28813238 TI - Strategies for Building Trust with the Caregiver of a Patient with End-Stage Dementia. AB - This case describes a patient with advanced dementia and an unrealistic spouse, presenting an apparent dilemma about nutrition for physicians. By eliciting the perspective of the caregiver, the physicians can gain insight and rebuild trust that protects the interests of both the patient and the spouse. Their goal needs to shift from resolving the professional ethical dilemma to affirming the immeasurable contribution of the caregiver, acknowledging her journey, asking for her advice, and enabling the work of making meaning in the time available. PMID- 28813239 TI - How Should Clinicians Counsel a Woman with a Strong Family History of Early-Onset Alzheimer's Disease about Her Pregnancy? AB - Counseling patients regarding the benefits, harms, and dilemmas of genetic testing is one of the greatest ethical challenges facing reproductive medicine today. With or without test results, clinicians grapple with how to communicate potential genetic risks as patients weigh their reproductive options. Here, we consider a case of a woman with a strong family history of early-onset Alzheimer's disease (EOAD). She is early in her pregnancy and unsure about learning her own genetic status. We address the ethical ramifications of each of her options, which include genetic testing, genetic counseling, and termination versus continuation of the pregnancy. Our analysis foregrounds clinicians' role in helping to ensure autonomous decision making as the patient reflects on these clinical options in light of her goals and values. PMID- 28813240 TI - When Does Therapeutic Misconception Affect Surrogates' or Subjects' Decision Making about Whether to Participate in Dementia Research? AB - "Therapeutic misconception" (TM) refers to inappropriate assumptions and beliefs on the part of research participants regarding key distinctions between the purpose, methods, intended benefits, and potential disadvantages of research compared to those of clinical care. Despite an extensive literature describing TM across varied types of research and populations, minimal work has addressed TM in the context of dementia research. This is a serious gap, for several reasons: people with dementia are at significant risk of diminished capacity; surrogate decision makers are typically asked to provide consent on behalf of the person with dementia; and available treatments for dementia are quite limited. More research is needed on the prevalence, nature, and impact of TM in the context of clinical dementia research. PMID- 28813241 TI - Should Potential Risk of Chronic Traumatic Encephalopathy Be Discussed with Young Athletes? AB - As participation in youth sports has risen over the past two decades, so has the incidence of youth sports injuries. A common topic of concern is concussion, or mild traumatic brain injury, in young athletes and whether concussions sustained at a young age could lead to lifelong impairment such as chronic traumatic encephalopathy (CTE). While the pathway from a concussed young athlete to an adult with CTE remains unknown, current research is attempting to provide more clarity. This article discusses how health care professionals can help foster an informed, balanced decision-making process regarding participation in contact sports that involves the parents as well as the children. PMID- 28813242 TI - Transcending the Tragedy Discourse of Dementia: An Ethical Imperative for Promoting Selfhood, Meaningful Relationships, and Well-Being. AB - Supporting people living with dementia in maintaining selfhood, relationships, and well-being requires seeing beyond the common negative focus on disability. Furthermore, prioritizing the person rather than the disease requires rejecting the tragedy discourse, which is the negative lens through which dementia is typically considered. In this paper, we highlight qualitative research on dementia involving people living with dementia as active participants. Recognizing that many people living with dementia remain capable of making decisions that affect their lives, we highlight a research-based approach to support known as "authentic partnerships" that includes people living with dementia as equal partners. We conclude by proposing eight beliefs to mobilize positive change in transcending the tragedy discourse of dementia, thereby opening a space for selfhood, relationships, and well-being. PMID- 28813243 TI - Arts Participation: Counterbalancing Forces to the Social Stigma of a Dementia Diagnosis. AB - A diagnosis of dementia profoundly impacts a person in terms of both the functional progression of the disease and the social stigma associated with the diagnosis. A growing body of research demonstrates the effectiveness of innovative programs such as the Alzheimer's Poetry Project, Meet Me at MoMA, and TimeSlipsTM in counterbalancing social stigma by building a social and emotional framework for strength-based living for people diagnosed with dementia through arts participation. These programs focus on supporting autonomy and generativity through creative expression to help sustain the social, emotional, and community fabric of people's lives in the face of significant counterbalancing forces (e.g., the disease itself, stigma, and institution-centered approaches to care). PMID- 28813244 TI - Framing Confusion: Dementia, Society, and History. AB - This essay will briefly sketch historical changes in the framing of dementia since the late nineteenth century. In broad terms, this period has seen a shift from viewing dementia as a pathological variant of normal aging to viewing it as a distinct disease. Although this broad reframing of dementia was clearly positive in raising awareness and funding for research, it had some negative aspects that should be considered. Caregiving came to seem less important than research aimed at a cure, and the stigma surrounding dementia has, if anything, increased. PMID- 28813245 TI - Damnum versus Quaestus. AB - Not only is bioethics fundamental to determining or guiding how we live and die, its role as the key interconnecting strand between various disciplines, the public, and decision makers is unique. The works featured here are from a collection entitled "Damnum versus Quaestus" (loss versus gain). They are informed by the lived experience of being with someone (described here as "the patient") as he or she lives through the process of dying. PMID- 28813246 TI - The benefits of data mining. AB - Careful analysis of a database populated by physicians and patients sheds new light on the side effects of drugs. PMID- 28813249 TI - Neuroendocrine mechanisms for parental sensitivity: overview, recent advances and future directions. AB - Early parent-infant relationships play important roles in infants' development. New parents adapt to the developing relationship with their infants to coordinate parenting behaviors in the milieu of infant needs, hormones, moods, and stress. This review highlights research from the past two years, using non-invasive brain imaging techniques and naturalistic tasks in mothers and fathers in relation to psychological, and endocrine measures. Recent work also connects parental brain physiology with parental sensitive behavior, parent/child outcomes and parent psychotherapy. Understanding neurobiological mechanisms underlying parenting thoughts, behaviors and moods (see Figure 1) will help identify mental health risks and contribute to parental mental health interventions and resilience. PMID- 28813248 TI - Early stress, parental motivation, and reproductive decision-making: applications of life history theory to parental behavior. AB - This review focuses on the impact of parental behavior on child development, as interpreted from an evolutionary-developmental perspective. We employ psychosocial acceleration theory to reinterpret the effects of variation in parental investment and involvement on child development, arguing that these effects have been structured by natural selection to match the developing child to current and expected future environments. Over time, an individual's development, physiology, and behavior are organized in a coordinated manner (as instantiated in 'life history strategies') that facilitates survival and reproductive success under different conditions. We review evidence to suggest that parental behavior (1) is strategic and contingent on environmental opportunities and constraints and (2) influences child life history strategies across behavioral, cognitive, and physiological domains. PMID- 28813247 TI - Switch-like Arp2/3 activation upon WASP and WIP recruitment to an apparent threshold level by multivalent linker proteins in vivo. AB - Actin-related protein 2/3 (Arp2/3) complex activation by nucleation promoting factors (NPFs) such as WASP, plays an important role in many actin-mediated cellular processes. In yeast, Arp2/3-mediated actin filament assembly drives endocytic membrane invagination and vesicle scission. Here we used genetics and quantitative live-cell imaging to probe the mechanisms that concentrate NPFs at endocytic sites, and to investigate how NPFs regulate actin assembly onset. Our results demonstrate that SH3 (Src homology 3) domain-PRM (proline-rich motif) interactions involving multivalent linker proteins play central roles in concentrating NPFs at endocytic sites. Quantitative imaging suggested that productive actin assembly initiation is tightly coupled to accumulation of threshold levels of WASP and WIP, but not to recruitment kinetics or release of autoinhibition. These studies provide evidence that WASP and WIP play central roles in establishment of a robust multivalent SH3 domain-PRM network in vivo, giving actin assembly onset at endocytic sites a switch-like behavior. PMID- 28813250 TI - Parenting and sleep in early childhood. AB - The development of sleep is influenced by complex interactions between biologically driven forces and diverse socio-environmental factors. Among those factors, parents have a critical role. The present review focuses on new studies regarding the links between parenting and the development of sleep in early childhood in the context of a transactional model. Recent findings from longitudinal studies and large cohort studies highlight the contribution of various parenting factors, such as parental bedtime behaviors, parental cognitions, cry tolerance, maternal mood, stress, and the parents' couple relationship, to the development of child sleep. Recent research also demonstrates the effectiveness of behavioral sleep interventions in which parents are the main agents of change in the behavioral aspects of child sleep. PMID- 28813251 TI - Genetic differential susceptibility to the effects of parenting. AB - Intervention efforts aimed at remediating or preventing problems in children typically prove only moderately effective due to substantial heterogeneity in their efficacy. It thus becomes important to account for such variation in intervention efficacy. Here we summarize illustrative evidence that, due to their genetic make-up, some children benefit more from interventions targeting parenting than do others. Whereas some work documents the role of single, 'candidate' genes, other work reveals the utility of compositing multiple genes and genetic pathways. Collectively, this research extends prior observational work indicating that children most negatively affected by adverse experiences also benefit the most from supportive ones, while underscoring the need for research illuminating underlying neurobiological mechanisms that instantiate differential susceptibility to environmental influences. PMID- 28813252 TI - Oxytocin: a parenting hormone. AB - In non-human mammals mothering is hormone-dependent, with crucial roles for oxytocin and prolactin. While human parenting is not hormone-dependent, hormonal changes in oxytocin, vasopressin, prolactin, testosterone, and cortisol prime and accompany the expression of parenting. In the following we focus on oxytocin (OT) as a key hormone in human parenting. OT is a nine-amino-acid neuropeptide hormone which evolved from the ancient vasotocin molecule approximately 650 MYO. OT is implicated in sociality across vertebrate evolution and substantial research has pinpointed its role in birth, lactation, and maternal care in mammals. Over the last decade, studies have begun to examine peripheral levels of OT - in plasma, saliva, urine, and to lesser extend CSF - in humans as well as OT administration to parents. Correlational and experimental studies indicate that OT is associated with increased parent-child synchrony, sensitive parenting, and parental contact; interacts with other hormones, such as vasopressin, cortisol, or testosterone to create parent-specific effects; is associated with activation of key nodes in the parental brain, and is altered in conditions of high risk or parental psychopathology. We conclude by discussing the potential role of OT in interventions for high-risk parenting. PMID- 28813253 TI - Attachment theory: progress and future directions. AB - Attachment is a key subfield in the area of parenting and parent-child relationships research. In this brief overview, we summarise what we consider to be the state-of-the-art of attachment research, focusing primarily on the nature and significance of attachment in infancy and early childhood. We review 4 major topics that are central issues in the scientific literature on attachment: (1) the role of the environment in the development of attachment, (2) the intergenerational transmission of patterns of attachment, (3) the stability of attachment patterns through early adulthood, and (4) the role of attachment in adjustment and maladjustment. We conclude by highlighting several critical unresolved issues and priorities for future research. PMID- 28813255 TI - Parenting intervention effects on children's externalizing behavior: the moderating role of genotype and temperament. AB - Recent research suggests that children's heightened susceptibility to parenting may have a (poly)genetic basis, and may be grounded in children's temperament. However, much current evidence is of a preliminary-correlational-nature. Because in correlational designs alternative explanations for gene-environment (G*E) or temperament-environment (T*E) interactions cannot be discounted, it is pivotal to conduct experimental studies in which parenting is actively manipulated. Based on data from a recently conducted randomized trial (n=387) of the Incredible Years parenting intervention, experimental evidence is provided for G*E and T*E interactions in an at-risk population of children aged 4-8 years. The discussion centers around the use of polygenetic data and microtrial designs, and provides suggestions for how to integrate endophenotypes in tests of G*E and T*E. PMID- 28813254 TI - Adapting to the changing needs of adolescents: parenting practices and challenges to sensitive attunement. AB - Changes in adolescents' motivations and capabilities pose unique challenges to parents who play a continuing role in ensuring the youth's safety and well-being. We describe sensitively attuned parenting as an optimal response to this challenge and summarize practices of positive engagement, supervision/guidance and open communication that support sensitive attunement and facilitate the continuing development of the adolescent's self-confidence, autonomous decision making, and communication skills. We then consider factors that require parents to adapt their practices to the particular needs and developmental level of the adolescent. Individual differences that may challenge parent's effectiveness in implementing these practices include: biological vulnerabilities, differential sensitivity to parenting, relationship history and temperament. Clinical interventions that seek to improve parenting offer an opportunity to test sensitive attunement as a mechanism for reducing adolescents' symptoms and problem behaviors. PMID- 28813256 TI - Parenting and HIV. AB - With the widespread use of antiretroviral therapy and successful prevention of mother-to-child transmission the development of HIV-negative children with HIV positive parents has become an important focus. There is considerable evidence that children's developmental risk is heightened because a parental HIV-diagnosis is associated with a range of potential problems such as depression, stigma and financial difficulties. Up to a third of children in sub-Saharan Africa (SSA) are cared for by an HIV-positive parent or caregiver. We review the mechanisms by which HIV affects parenting including its negative effects on parental responsiveness in the early years of parenting and parental avoidant coping styles and parenting deficits in the later years. We describe low-cost parenting interventions suited for low resourced HIV endemic settings. PMID- 28813258 TI - The added value of rodent models in studying parental influence on offspring development: opportunities, limitations and future perspectives. AB - Over the past decades, the influence of parental care on offspring development has been a topic of extensive research in both human and animal models. Rodent models offer several unique advantages over human studies, allowing for higher levels of environmental control, exploration of interventions, genetic control and examination of underlying neurobiological mechanisms in greater spatiotemporal detail. Although exploitation of these opportunities has led to increased understanding of the neurobiological mechanisms underlying susceptibility to the early-life environment, translation of results to human parenting and child development appears to be challenging. Attuning animal models to the human situation and application of novel structural and functional techniques is therefore of crucial importance to reduce the gap between rodent and human research. PMID- 28813257 TI - Social-learning parenting intervention research in the era of translational neuroscience. AB - In the decades since social learning parenting interventions emerged, many evidence-based programs have been implemented at scale in community settings, and much research is now focusing on ways to maintain fidelity and impact during the implementation process. Notably, a considerable amount of theoretical confluence has occurred in parenting interventions from social learning, attachment, and other theoretical perspectives, with parent coaching as an example of this new generation of relational interventions. In addition, research examining the neurobiological effects of early adverse experiences is providing insight into key mediating and moderating mechanisms underlying the effectiveness of social learning parenting interventions, and new strategies for tailoring interventions to the needs of specific populations are being developed, making interventions more efficient, precise, and effective. PMID- 28813259 TI - Alternatives for abandoned children: insights from the Bucharest Early Intervention Project. AB - The Bucharest Early Intervention Project is the first and only randomized controlled trial of foster care as an alternative to institutional care for orphaned and abandoned children. Across various domains of brain and behavioral development we demonstrated that children in families developed more favorably than children in institutions, that foster care remediates some but not all compromises associated with institutional placement and that earlier placement in foster care leads to more developmental gains in some but not all domains. In addition to early placement, higher quality of care provided and more stable placements for children all enhanced outcomes. These results have important implications for science, practice and policy. PMID- 28813260 TI - Pairing attachment theory and social learning theory in video-feedback intervention to promote positive parenting. AB - Video-feedback Intervention to promote Positive Parenting and Sensitive Discipline (VIPP-SD) is a social-learning and attachment-based intervention using video feedback to support sensitive parenting and at the same time setting firm limits. Empirical studies and meta-analyses have shown that sensitive parenting is the key determinant to promote secure child-parent attachment relationships and that adequate parental discipline contributes to fewer behavior problems in children. Building on this evidence, VIPP-SD has been tested in various populations of at-risk parents and vulnerable children (in the age range of zero to six years), as well as in the context of child care. In twelve randomized controlled trials including 1116 parents and caregivers, VIPP-SD proved to be effective in promoting sensitive caregiving, while positive social-emotional child outcomes were also found. PMID- 28813261 TI - Current research on parenting styles, dimensions, and beliefs. AB - For decades, parenting has been characterized in terms of broad global styles, with authoritative parenting seen as most beneficial for children's development. Concerns with greater sensitivity to cultural and contextual variations have led to greater specificity in defining parenting in terms of different parenting dimensions and greater consideration of the role of parenting beliefs in moderating links between parenting and adjustment. New research includes 'domain specific' models that describe parents as flexibly deploying different practices depending on their goals, children's needs, and the types of behaviors towards which parenting is directed. These trends are described, and directions for future research are discussed. PMID- 28813262 TI - Parenting in acculturation: two contemporary research designs and what they tell us. AB - Massive population transfers are common today. To understand how immigrants negotiate variation and adjustment as they settle in a new culture, researchers have explored acculturation, the changes that individuals and groups undergo as a result of contact with a culture not their own. Parents have crucial roles to play in acculturation. Parenting is instantiated in cognitions and practices, and cognitions and practices of parents are multifaceted and influenced by many factors, including parents' own individual characteristics, their children, and their cultural experiences. This article describes, evaluates, and illustrates two unique research designs that are used today to study acculturation of parenting cognitions and practices. In one design, parenting in acculturating cultures in the same culture of destination are compared; in the second design, parents in a culture of origin, parents from that culture of origin acculturating to a new culture, and parents in that culture of destination are compared. Acculturation is one of the most prominent individual-difference constructs in contemporary psychology, and understanding parents' cognitions and practices is fundamental to understanding parenting and acculturation. PMID- 28813263 TI - Children's physiological responses to childcare. AB - This review focuses on children's physiological responses to out-of-home childcare. The finding that children's cortisol levels are higher at childcare than at home has been well-replicated. Here we summarize recent evidence examining possible correlates of elevated cortisol levels. Reviewed studies suggest that childcare quality matters, whereas group sizes and type of care do not. As for child characteristics, elevated cortisol at childcare is more pronounced in toddlers than in infants, and in inhibited and aggressive children. We discuss recent advances focusing on hair cortisol analysis and immunomarkers of stress, and suggest that there is a need for experimental and longitudinal studies to examine causal relations and possible negative long-term consequences for children's health and development. PMID- 28813264 TI - The neurobiology of fatherhood. AB - Only about 5% of mammalian species exhibit paternal caregiving in nature, and paternal behavior has evolved multiple times independently among mammals. The most parsimonious way to evolve paternal behavior may be to utilize pre-existing neural systems that are in place for maternal behavior. Despite evidence for similarity in the neurobiology of maternal and paternal behavior in rodents, paternal behavior also has its own dedicated neural circuitry in some species. Human fathers engage conserved subcortical systems that motivate caregiving in rodent parents and human mothers, as well as cortical systems involved with empathy that they share with human mothers. Finally, paternal behavior is modulated by similar hormones and neuropeptides in rodents, non-human primates, and humans. PMID- 28813265 TI - Parenting and globalization in western countries: explaining differences in parent-child interactions. AB - We review research on intra-cultural differences in parenting, and the sources of those differences. Ethnic-minority parents differ from majority parents in parenting values, childrearing goals and resources-differences that affect parenting practices and children's development. Within-country comparisons indicate less sensitivity, more authoritarian discipline, less child-focused communications, and less engagement in learning activities in ethnic-minority compared to ethnic-majority parents, which help account for disparities in children. Despite group differences in parenting, associations between parenting and child development generalize across cultures, with rare exceptions. However, a focus on intra-cultural differences is based on comparisons of group 'averages', which masks the enormous variation within ethnic-minority samples. Within-group variation can be partly explained by stressors associated with low socioeconomic status (SES), acculturation and discrimination. PMID- 28813267 TI - Protective parenting: neurobiological and behavioral dimensions. AB - The current review focuses on a dimension of parenting that has largely been neglected in studies on human parenting, namely parental protection. Human protective parenting can be observed already during pregnancy, when mothers experiencing morning sickness avoid foods that are likely to carry pathogens and thus could be harmful to the fetus. After the birth of the baby, one of the foremost anxieties of parents is that their child will be abused or killed by strangers. Protective parenting seems to be a species-wide evolutionary-based behavior complementary to the innate bias of each newborn to strive for proximity to a potentially protective attachment figure. Most important target for future work might be to describe, explain and uncover the correlates and consequences of individual differences in the quality of protection-in parents and other caregivers. PMID- 28813266 TI - Intuitive parenting: understanding the neural mechanisms of parents' adaptive responses to infants. AB - When interacting with an infant, parents intuitively enact a range of behaviours that support infant communicative development. These behaviours include altering speech, establishing eye contact and mirroring infant expressions and are argued to occur largely in the absence of conscious intent. Here, we describe studies investigating early, pre-conscious neural responses to infant cues, which we suggest support aspects of parental intuitive behaviour towards infants. This work has provided converging evidence for rapid differentiation of infant cues from other salient social signals in the adult brain. In particular, the orbitofrontal cortex may be important in supporting quick orienting responses and privileged processing of infant cues, processes fundamental to intuitive parenting behaviour. PMID- 28813268 TI - Parents with intellectual disability. AB - Questions around parents with intellectual disability have changed according to sociocultural shifts in the position and rights of people with intellectual disability. The early research focus on capacity for parenting has given way to a contextual model of parenting and child outcomes, increasingly tested in population-based samples. Epidemiological research shows that contextual variables such as low income, exposure to violence, and poor mental health partly account for negative outcomes. As theoretical models developed for other at risk populations prove increasingly helpful for understanding the challenges of parenting with intellectual disability, it becomes viable to adapt existing evidence-based parenting interventions and test these for this population. Ultimately, parenting research should become fully inclusive. PMID- 28813270 TI - Depression and parenting: the need for improved intervention models. AB - The impact of maternal depression on parenting is well established and there is a clear interaction between maternal depression and parenting that is predictive of child outcomes. The research on paternal depression is more limited but suggests the father's mental health may be an independent risk factor for both parenting and child outcomes. There is insufficient evidence that treatment of depression alone - be it through pharmacological or psychological interventions - is able to substantially reduce the impact of depression on child outcomes. The evidence of interventions aimed at parenting and/or child outcomes in the context of depression is limited and the findings that are available are mixed. PMID- 28813269 TI - Parenting and addiction: neurobiological insights. AB - Addiction remains a significant public health concern that affects multiple generations within families, and in particular the early relationship between parents and their developing child. This article will discuss recent advances in our understanding of the neurobiology of parenting and addiction. Specifically, the discussion will focus on the reward-stress dysregulation model of addicted parenting, which proposes that the dysregulation of stress and reward neural circuits by addiction represents a neurobiological pathway through which to understand how caregiving may be compromised in addicted parents. Empirical research in parents and non-parents will be discussed in support of this model and critical consideration of the model and its limitations will be provided. PMID- 28813271 TI - Prenatal parenting. AB - Parenting begins before birth. This includes prenatal maternal and paternal bonding with the baby, and biological effects on fetal development. Recent research has confirmed how prenatal maternal stress can alter the development of the fetus and the child, and that this can persist until early adulthood. Children are affected in different ways depending, in part, on their own genetic makeup. The fetus may also have a direct effect on prenatal maternal mood and later parenting behaviour via the placenta. The father is important prenatally too. An abusive partner can increase the mother's prenatal stress and alter fetal development, but he can also be an important source of emotional support. New research suggests the potential benefits of prenatal interventions, including viewing of prenatal scans and cognitive behavioural therapy. PMID- 28813272 TI - Religiosity and parenting: recent directions in process-oriented research. AB - Most faith traditions, in principle, promote family life and positive parent child relationships. In recent years, research has moved beyond questions of whether religion supports positive parenting towards addressing more nuanced process-oriented questions, including how, why, and when religion is linked with adaptive or maladaptive parenting. Relations between religion and multiple specific parenting behaviors (e.g., involvement, warmth, authoritative parenting, communication) are identified, including contexts for when and why relations between religion and parenting are adaptive or maladaptive. A next step for research is the development and testing of theoretical models to more comprehensively account for process relations between religion and parenting. PMID- 28813273 TI - Adoptive parenting. AB - Challenges in adoptive parenting continue to emerge as adoption policies and practices evolve. We review three areas of research in adoptive parenting that reflect contemporary shifts in adoption. First, we highlight recent findings concerning openness in adoption contact arrangements, or contact between a child's families of birth and rearing. Second, we examine research regarding racial and cultural socialization in transracial and international adoptions. Finally, we review investigations of parenting experiences of lesbian and gay adoptive parents. Overall, parenting processes (e.g., supportive vs. problematic family interaction) are better predictors of child adjustment than are group differences (e.g., open vs. closed adoptions; adoption by heterosexual vs. same sex parents). The distinctive needs of adopted children call for preparation of adoption-competent mental health, casework, education, and health care professionals. PMID- 28813274 TI - Parenting in new family forms. AB - This paper reviews research on parenting and child development in new family forms including families created by assisted reproductive technologies, same-sex parent families, and families headed by single mothers by choice. The research is examined in the context of the issues and concerns that have been raised regarding these families. The findings not only contest popular assumptions about the psychological consequences for children of being raised in new family forms but also challenge the supremacy of the traditional family. It is concluded that the quality of family relationships and the wider social environment appear to be more influential in children's psychological development and adjustment than are the number, gender, sexual orientation or biological relatedness of their parents. PMID- 28813275 TI - Child maltreatment: the central roles of parenting capacities and attachment. PMID- 28813276 TI - Fathers, fathering and child psychopathology. AB - The last few years have seen a steady increase in research addressing the potential influence of fathers on their children's development. There has also been a clearer acknowledgement of the need to study families as a complex system, rather than just focusing on individual aspects of functioning in one or other parent. Increased father involvement and more engaged styles of father-infant interactions are associated with more positive outcomes for children. Studies of paternal depression and other psychopathology have begun to elucidate some of the key mechanisms by which fathers can influence their children's development. These lessons are now being incorporated into thinking about engaging both mothers and fathers in effective interventions to optimise their children's health and development. PMID- 28813277 TI - Incredible Years parenting interventions: current effectiveness research and future directions. AB - The Incredible Years parenting intervention is a social learning theory-based programme for reducing children's conduct problems. Dozens of randomized trials, many by independent investigators, find consistent effects of Incredible Years on children's conduct problems across multiple countries and settings. However, in common with other interventions, these average effects hide much variability in the responses of individual children and families. Innovative moderator research is needed to enhance scientific understanding of why individual children and parents respond differently to intervention. Additionally, research is needed to test whether there are ways to make Incredible Years more effective and accessible for families and service providers, especially in low resource settings, by developing innovative delivery systems using new media, and by systematically testing for essential components of parenting interventions. PMID- 28813278 TI - Editorial overview: Multidisciplinary and interdisciplinary perspectives on parenting. PMID- 28813279 TI - Protecting relationships from stress. AB - Although partners in close social relationships often enable one another to manage stress, stress can also undermine the many benefits that these relationships provide. We review interventions designed to reduce the effects of stress on relationships, distinguishing (a) couple-targeted interventions that aim to build couples' skills in managing stress from (b) stress-targeted interventions intended to eliminate stress itself. Recent examples of these approaches are presented and evaluated. Couple-targeted and stress-targeted interventions both hold promise for empowering couples to sustain their relationship and the well-being of their children, and additional empirical work will help clarify the conditions under which different strategies prove most effective. PMID- 28813280 TI - Breakthroughs in understanding addiction and close relationships. AB - Substance use is one aspect of life that can serve to bring couples together or tear them apart. Evidence has accumulated for both substance use affecting relationship distress (e.g., partners of substance users report poorer individual and relational outcomes) as well as relationship conflict affecting subsequent substance use (e.g., individuals use substances as a way to cope with interpersonal conflict and distress). We discuss several determinants of each association, including individual difference and relationship-specific constructs. We conclude by considering how conceptualizing addiction as an interdependent-rather than independent-process is critical for future theory refinement and intervention development. PMID- 28813281 TI - Romantic relationships and mental health. AB - This paper reviews the research on relationships and mental health. Individuals who are more mentally healthy are more likely to select into relationships, but relationships are also demonstrably associated with mental health. The type of relationship matters - evidence suggests that more established, committed relationships, such as marriage, are associated with greater benefits than less committed unions such as cohabitation. The association between relationships and mental health is clearly bidirectional, however, stronger effects are observed when mental health is the outcome and relationships are the predictor, suggesting that the causal arrow flows more strongly from relationships to mental health than vice versa. Moreover, improving relationships improves mental health, but improving mental health does not reliably improve relationships. Our review of research corroborates the view that relationships are a keystone component of human functioning that have the potential to influence a broad array of mental health outcomes. PMID- 28813282 TI - Autonomy promotion, responsiveness, and emotion regulation promote effective social support in times of stress. AB - Adult attachment theory provides guidance for providing optimal social support in intimate relationships. According to attachment theory, facilitating autonomy (secure base support) sometimes is more important than providing nurturance (safe haven support). In addition, it is important that couples celebrate one another's triumphs and successes (another form of secure base support). A key construct that explains the development of attachment is responsiveness to the individual's needs. Support that is delivered in a responsive manner (i.e., that leads the individual to feel understood, validated, and cared for) is more likely to enhance the relationship and less likely to damage self-esteem than assistance that is not responsive. A responsive exchange is more likely if emotion dysregulation can be prevented. Attachment theory offers explanations for why people vary in their effectiveness at emotion regulation. Appropriate emotion regulation is more likely if disclosures of current difficulties can be made in a way that is not defensive or accusatory, an ability that varies as a function of attachment orientation. Attachment theory also offers guidance regarding the optimal forms of social support for specific individuals. All these insights from adult attachment theory can be integrated into interventions to help couples become more effective support providers. PMID- 28813283 TI - Stress and coping in couples facing infertility. AB - Infertility presents an ideal setting for examining how stress impacts couple relationships. The effect of facing fertility problems on couple relationships is highly varied. Traditional stress and coping models are limited, because they do not account for partner interdependence. We propose a stress and coping in couples model which argues that couples whose approaches to managing infertility (i.e., their appraisal and coping efforts) are compatible will experience more positive communication, and be more likely to experience a strengthening of their relationship; whereas couples with incompatible approaches will be more likely to experience negative communication and a weakening of their relationship. Evidence in support of this model is reviewed. Our approach to counseling couples emerges from the proposed model and represents a specific application of Integrative Behavioral Couples Therapy. PMID- 28813285 TI - Cognitive-behavioral couple therapy. AB - This article describes how cognitive-behavioral couple therapy (CBCT) provides a good fit for intervening with a range of stressors that couples experience from within and outside their relationship. It takes an ecological perspective in which a couple is influenced by multiple systemic levels. We provide an overview of assessment and intervention strategies used to modify negative behavioral interaction patterns, inappropriate or distorted cognitions, and problems with the experience and regulation of emotions. Next, we describe how CBCT can assist couples in coping with stressors involving (a) a partner's psychological disorder (e.g. depression), (b) physical health problems (e.g. cancer), (c) external stressors (e.g. financial strain), and (d) severe relational problems (e.g. partner aggression). PMID- 28813284 TI - Gene-environment interplay in the context of romantic relationships. AB - A growing body of research supports an important role for genetic factors on intimate, romantic relationships. In this article, we review research that has examined the interplay between genetic and environmental influences on romantic relationships and the associations between relationship outcomes and important individual differences related to relationships. We first elaborate on how behavioral genetic and molecular genetic methods can be used to understand the etiology of relationship outcomes. We then review empirical studies that have examined gene-environment correlations and gene-by-environment interactions in predicting romantic relationship outcomes (e.g., relationship formation, relationship quality and functioning, relationship dissolution) and their association with the physical health, mental health, and well-being of relationship partners. PMID- 28813286 TI - Effects of job stress on family relationships. AB - In the short-term, daily job stressors influence family interactions through their impact on the employed person's mood, thoughts, and coping behaviors. In the long-term, family relationships can be shaped by those experiences in both positive and negative ways. Some spouse 'cross-over' effects appear to represent accommodations of the employed partner under stress-for instance, a spouse's increased provision of social support and involvement with children-and are evidence of dynamics that go beyond a simple and direct transfer of stress from work to home. PMID- 28813287 TI - Marital satisfaction and divorce in couples in stepfamilies. AB - We review research and theory examining stress and coping in stepfamilies as predictors of marital quality and divorce. Although the divorce rate in first marriages has stabilized after years of increase in North America, the divorce rate of remarriages continues to increase. We argue that depression and marital distress are both mechanisms through which stepfamily stress impacts marital stability, with parenting stressors particularly potent determinants of divorce. We draw upon our own research predicting divorce across 20 years in 112 married couples in stepfamilies, as well as from the larger literature on stepfamilies. PMID- 28813288 TI - Adult attachment, stress, and romantic relationships. AB - In this article, we discuss theory and research on how individuals who have insecure adult romantic attachment orientations typically think, feel, and behave when they or their romantic partners encounter certain types of chronic or acute stress. We first review basic principles of attachment theory and then discuss how two forms of attachment insecurity-anxiety and avoidance-are associated with unique patterns of emotion regulation in response to certain types of threatening/distressing situations. We then discuss a Diathesis-Stress Process Model that has guided our research, highlighting studies that provide support for certain pathways of the model. PMID- 28813289 TI - The transition to parenthood: impact on couples' romantic relationships. AB - The birth of the first baby-often referred to as the transition to parenthood (TTP)-is both a time of great joy and great stress for new parents. Although the literature is mixed, the preponderance of evidence suggests that the TTP has a negative effect on relationship functioning for most couples. However, as children age, the relationship functioning of parents and non-parents converge. Notably, there are important moderators of this average trajectory; couples with higher levels of pre-birth relationship problems, insecurely attached parents, temperamentally difficult infants, and TTP following biological birth rather than adoption are associated with larger post-birth declines. Fortunately, several effective couple-focused interventions are available to help buffer the negative effects of the TTP. PMID- 28813290 TI - Same-sex relationships and minority stress. AB - Same-sex relationships are stigmatized in a culture that privileges heterosexual relationships. This stigma creates minority stress in the lives of same-sex couples. We review current research on minority stress and same-sex relationships using an ecological framework to conceptualize the sources of minority stress that impact couples. Findings from this review suggest a need for research that moves conceptually and methodologically beyond a focus on the individual to a focus on the dyad and the interpersonal, institutional, and cultural sources of minority stress that affect couple relationships. Focusing on the strengths and resiliencies of same-sex couples will also extend the research. Creating effective dyadic interventions will promote the health and well-being of same-sex couples and their families. PMID- 28813291 TI - An ecological model of mediators of change in Couple Relationship Education. AB - Couple Relationship Education (RE) seeks to enrich couples' relationships, and assist them to manage stressful life events [1]. In the current paper we present an ecological model of couple relationships intended to guide the practice of RE, analyze the mediators of RE effects, and suggest future research needs to assess moderators and mediators of RE effects in order to enhance the impact of RE. PMID- 28813292 TI - Re-thinking dyadic coping in the context of chronic illness. AB - In the past two decades scholars have increasingly recognized the importance of viewing chronic illness in a relationship context. However, questions remain regarding how couples make sense of illness, how they negotiate and coordinate coping, and the extent to which viewing the illness as a shared problem is beneficial for individual and relationship outcomes. This article seeks to clarify the role that couple relationships play in chronic illness adaptation by first describing major theoretical frameworks that have guided research in this area. Next, we propose a new model that emphasizes cognitive processes occurring before appraisal begins and throughout the coping process. We conclude by positing future research directions and implications for couple-based psychosocial interventions. PMID- 28813293 TI - Effects of relationship functioning on the biological experience of stress and physical health. AB - In this paper, we outline how relationship functioning affects the biological experience of stress and its consequences for physical health. Negative relationship perceptions and processes, such as attachment insecurity, hostility, and frequent conflict, tend to heighten stress responses and generate worse health over time, whereas positive relationship perceptions and processes, such as responsiveness, support, and intimacy, are generally associated with reduced or buffered stress responses and improved health (with some caveats). Future research should focus on the mechanisms behind these effects, the extent to which they can be changed or reversed, incorporating developmental perspectives, and effects of individual differences on these processes. PMID- 28813294 TI - Weathering the storm? The impact of trauma on romantic relationships. AB - The current paper reviews the recent literature examining the impact of trauma on romantic relationships. We introduce the Dyadic Responses to Trauma (DRT) Model as a framework for organizing existing research and guiding future research. A traumatic event affects romantic relationships for the better or for the worse depending on the diverse trauma-related experiences people can have, influencing the way partners interact with each other and ultimately the quality of the relationship. In addition, recent research demonstrates how romantic partners can demonstrate resiliency in spite of a negative trauma experience depending on how they interpret and cope with the experience individually and as a couple. PMID- 28813295 TI - The use and effects of pornography in romantic relationships. AB - In this article we discuss associations between pornography use by one or both romantic partners and the well-being of the relationship. We highlight several shortcomings of existing empirical research that limit conclusions that can be made about the negative, neutral or positive effects of pornography use on relationship processes. Lastly, we review extant dyadic research on pornography use in a relationship context, and propose the Antecedents-Context-Effects (ACE) model as a guide for future research on this important topic. PMID- 28813296 TI - Couple conflict: insights from an attachment perspective. AB - The experience of conflict is often cited as a highly stressful relational phenomenon by romantic couples, and can have negative implications for relationship satisfaction and for the longevity of romantic relationships. In this paper, we review extant research on couple conflict in romantic relationships from an attachment theory perspective. The research we review is underpinned by two central tenets: firstly, severe or persistent conflict activates the attachment system; secondly, responses to couple conflict involve complex attachment dynamics, shaped by partners' attachment anxiety and avoidance. The research reviewed has important implications for both research and practice in the area of couple conflict, and clearly demonstrates how conflict can act as a stressor that shapes relationship functioning. PMID- 28813297 TI - Creating relationships that foster resilience in Emotionally Focused Therapy. AB - Emotionally Focused Therapy for Couples (EFT) is an evidence-based couple therapy based in attachment theory. Research has amassed over the past three decades pointing to the role of relationships in health and and well-being. Affective neuroscience suggests that secure relationships appear to foster adaptive stress co-regulation. The effectiveness of EFT has been demonstrated in couples facing high levels of stress, and has been shown to reduce depressive and post-traumatic stress symptoms. Furthermore, EFT has been shown to help couples regulate their neurophysiological stress response. In this paper we review the literature in attachment, affective neuroscience and EFT and propose that creating secure attachment bonds for couples can help foster resilience. PMID- 28813298 TI - Infidelity in romantic relationships. AB - This article summarizes the current state of research on the prediction of infidelity and provides a foundation for advancing knowledge on this topic by offering specific recommendations for future research. The prevalence, terminological diversity, and impact of infidelity on numerous indicators of wellness is first discussed. This is followed by a discussion of the individual, relationship, and contextual factors that have received systematic attention in attempting to predict infidelity. Highlights include various demographics, the closing gender gap, cohabitation, religion, and the role of the internet in facilitating infidelity. The article concludes with 8 recommendations for more informative research to advance understanding of sexual infidelity. PMID- 28813299 TI - Stress and wellbeing during chronic illness and partner death in later-life: the role of social support. AB - Chronic illness and the death of a romantic partner are two of the most significant stressors reported by older adults, resulting in various physical and mental health consequences. Evidence suggests that social support is a key factor in understanding the association between chronic illness and widowhood and the wellbeing of older adults. Nevertheless, research into social support is often approached in an atheoretical manner when investigating these stressors in older adulthood. We attempt to address this theoretical chasm by proposing an integrative model to explain social support processes in older couples which draws on models of social support and attachment theory. Our model provides an important framework for understanding existing research findings as well as guiding future research. PMID- 28813300 TI - Sexual dysfunction and relationship stress: how does this association vary for men and women? AB - This paper examines the association between relationship stress and sexual dysfunction. The results demonstrated a strong association between female sexual dysfunction (FSD) and relationship stress, and between male sexual dysfunction (MSD) and relationship stress among their female partners. No studies examined the association between FSD and relationship stress of male partners. Treatment for MSD was associated with improved relationship stress for female partners, but no studies were located that examined this association for treatment of FSD. These findings suggest that FSD and relationship stress are strongly related, but the association does not seem to be so strong for men. The review highlights the need for further research in this field to inform therapy for both sexual dysfunction and relationship problems. PMID- 28813301 TI - Stress and child development: a review of the Family Stress Model. AB - In the present report, we provide an illustrative review of the Family Stress Model (FSM) framework [1] to understand how family stress influences children across development in physical, social-emotional, and cognitive domains. We note that the FSM as a theory has evolved through inspection of: (a) new explanatory pathways (mediators); (b) factors that moderate FSM pathways; and (c) joint tests of competing models. Also important, most researchers cited in this review used longitudinal designs to test the proposed causal ordering of FSM pathways, which replicated among a diverse set of families varied in structure, ethnic background, and geographic location. We encourage continued FSM scholarship with prevention and intervention efforts in mind. PMID- 28813302 TI - Divorce and health: good data in need of better theory. AB - A very large literature links the experiences of marital separation and divorce to risk for a range of poor distal health outcomes, including early death. What is far less clear, however, is the mechanistic pathways that convey this risk. Several plausible mechanisms are identified in the literature, and the central thesis of this paper is that the empirical study of divorce and health will benefit enormously from a renewed reliance on theory to dictate how these mechanisms of action may unfold over time. This review emphasizes the roles of attachment and social baseline theories in making specific mechanistic predictions and highlights the ways in which these perspectives can contribute new empirical knowledge on risk and resilience following marital dissolution. PMID- 28813303 TI - Stress and its associations with relationship satisfaction. AB - Stress is an all too common experience for people around the world. In the past 30 years, researchers have built upon traditional models of stress, which have focused on the individual, to explore stress' systemic effects. As such, the once thought individual experience of stress can now be conceptualized as a dyadic construct that affects both individuals within an interdependent dyad. Reviewing a selection of the literature published after Randall and Bodenmann's [1] seminal review on the impact of stress on close relationships, this review conceptualizes the associations between different types of stressors-particularly those that originate outside (external) and inside (internal) the relationship-and relationship satisfaction within romantic relationships. Implications for future research and clinical interventions are discussed. PMID- 28813304 TI - Editorial overview: Contemporary insights into the relationships and stress nexus: Contexts, processes and outcomes. PMID- 28813305 TI - Trauma and PTSD in older adults: Prevalence, course, concomitants and clinical considerations. AB - This review presents recent empirical developments on Posttraumatic Stress Disorder (PTSD) in older adults, highlighting some of the most interesting lines of investigation that have taken place over the past few years. The majority of the extant literature has focused on male veterans or former prisoners of war, Caucasians, and those from the United States. Major advances have taken place in terms longitudinal investigations of representative samples of veterans and their health and functioning in relation to traumatic exposure. The current review explores the prevalence and impact, course and associated consequences, as well as available treatment for older adult survivors of traumatic experiences in an effort to increase education and awareness to improve overall health and functioning among this population. PMID- 28813307 TI - The innate alarm system in PTSD: conscious and subconscious processing of threat. AB - The innate alarm system (IAS), comprised of functionally connected brain regions including the brainstem, amygdala, pulvinar, and frontotemporal cortex, is a fast subcortical brain network facilitating rapid responses to threat. Post-traumatic stress disorder (PTSD) features subconscious and conscious threat detection, together contributing to hyperarousal symptoms. Emerging literature identifies aberrant threat-related neurocircuitry involved in subconscious and conscious threat processing in PTSD. We review this literature, focusing on subconscious threat processing and its relation to the IAS. Available evidence indicates increased neural activity and functional connectivity between IAS brain regions (e.g. locus coeruleus, superior colliculus, amygdala, and prefrontal cortex). These alterations are observed during both subconscious threat processing and at rest, suggesting increased defensive posturing, maintained in the absence of overt threat. PMID- 28813306 TI - Telehealth and eHealth interventions for posttraumatic stress disorder. AB - This paper presents existing research describing how telehealth and eHealth technologies can be used to improve mental health services for trauma survivors, either by enhancing existing treatment approaches or as a stand-alone means of delivering trauma-relevant information and interventions. The potential ways in which telemedicine technologies aide in overcoming barriers to care is first addressed in terms of providing mental health treatment. We then outline how different telehealth and eHealth tools can be used for key therapeutic tasks, including the provision of self-guided interventions, remote delivery of psychotherapy, and augmentation of psychological treatments. We conclude by discussing key emergent issues that are shaping current and future use of telemedicine technologies as part of the continuum of care for trauma survivors. PMID- 28813308 TI - Pharmacological management of posttraumatic stress disorder. AB - Posttraumatic stress disorder (PTSD) has been conceptualized as an inability to cope with overwhelming stress that is followed by a distinctive pattern of symptoms. This concept has made it possible to develop therapeutic approaches for PTSD that include medication and psychotherapy options. In this article we summarize research studies on pharmacotherapies for PTSD and review new findings in the neurobiology of PTSD that are promoting the development of targeted treatment options. Research findings that have improved our understanding of psychobiological abnormalities associated with PTSD offer clinicians improved treatment strategies. We review those findings, the developments in the medication management of PTSD and common co-occurring disorders, and new areas of pharmacological research on PTSD treatment. PMID- 28813309 TI - Theory-driven models of self-directed violence among individuals with PTSD. AB - PTSD is a well-established risk factor for the full range of self-directed violence (SDV). It is also one of the few psychological conditions that distinguish those who think about suicide from those who attempt suicide. Despite considerable evidence supporting these points, very little is understood about the mechanisms by which PTSD increases the risk for SDV at the present time. This knowledge gap is largely due to the absence of research driven by empirically supported models of suicide. More recently, this knowledge gap has been slowly filled by a growing number of studies informed by two particular conceptual models: the fluid vulnerability theory and the interpersonal psychological theory. Findings supporting each model are discussed, as are implications for future research. PMID- 28813310 TI - Redefining posttraumatic stress disorder for DSM-5. AB - Posttraumatic stress disorder (PTSD) was substantially redefined for DSM-5, with significant changes in nosology, definition of a traumatic stressor, and number and nature of symptom criteria. These updates, motivated by decades of empirical findings and clinical observation, provide better coverage of the full range of trauma-related clinical presentations while maintaining backward compatibility with previous versions of PTSD. Nonetheless, they have been criticized as being unwarranted, creating excessively complex criteria, and generating unacceptable levels of diagnostic discordance. However, when the goals and expectable effects of the DSM-5 PTSD revision process are considered in light of a growing number of relevant studies, the DSM-5 PTSD criteria perform well and represent a valuable incremental step in the ongoing evolution of the PTSD construct. PMID- 28813311 TI - Acute stress disorder. AB - Acute stress disorder (ASD) was introduced in DSM-IV to describe posttraumatic stress disorder (PTSD) symptoms that (a) occur in the initial month after trauma and (b) predict subsequent PTSD. Longitudinal studies have shown that most people who develop PTSD do not initially meet ASD criteria, which led to the decision in DSM-5 to limit the ASD diagnosis to describing acute stress reactions without any predictive function. Controlled trials have shown that trauma-focused cognitive behavior therapy is the treatment of choice for ASD, and is superior to pharmacological interventions. Recent longitudinal studies have challenged previous conceptualizations of the course of posttraumatic stress, and highlighted that people follow different trajectories of adaptation that are influenced by events that occur after the acute posttraumatic period. PMID- 28813312 TI - Neuroendocrine and neuroimmune markers in PTSD: pre-, peri- and post-trauma glucocorticoid and inflammatory dysregulation. AB - We review current knowledge on how posttraumatic stress disorder (PTSD) is associated with dysregulation of the most commonly studied markers of the endocrine and immune systems pre-, peri- and post-trauma. Lower basal cortisol output, enhanced glucocorticoid receptor function, and a proinflammatory state have been most consistently found in PTSD, with considerable variability among studies and participants. Longitudinal research is scarce, but there is converging evidence that biological dysregulation is present before PTSD onset. Biological dysregulation may become more apparent with increasing time since trauma, and may be reversible with and predict effective treatment. However, considering the variability of findings and the complex interplay of these systems with other factors, the current clinical application of these findings remains limited. PMID- 28813313 TI - Role of social context in posttraumatic stress disorder (PTSD). AB - Research has increasingly focused on the role that social circumstances before, during, and after trauma exposure play in risk for posttraumatic stress disorder (PTSD). In this article, we provide an overview of conceptual and methodological challenges to the study of social context's role in PTSD and propose strategies that can mitigate these challenges. Throughout the article, we draw from the current literature to illustrate how attention to these issues can lead to advances in our knowledge of the role of social context in PTSD. PMID- 28813314 TI - Cognitive factors in the development, maintenance, and treatment of post traumatic stress disorder. AB - Cognitive content and processes are central to theories of post-traumatic stress disorder (PTSD). In this paper, we highlight recent findings on cognitive factors in PTSD. Evidence for the role of negative post-traumatic cognitions in PTSD has continued to mount, with cognitions mediating PTSD symptoms and predicting PTSD over and above other key variables. Researchers have also continued to implicate cognitive processes like rumination in the development and maintenance of PTSD. Finally, we review how cognitive-behavioral therapies interrupt dysfunctional cognitive processes in PTSD and highlight research supporting the theory that changes in cognitions are the mechanism of these treatments. PMID- 28813315 TI - Using experimental methodologies to assess posttraumatic stress. AB - The assessment of PTSD is hindered by the absence of an objective biological measure. There is no blood test or stress test or similar objective measurement that reliably indicates the presence or absence of PTSD. In this article we focus on experimental assessments of PTSD. The focus will be on psychobiological indices that have been shown to be dysregulated in PTSD sufferers and that are responsive to treatment for PTSD. This includes psychophysiological startle, cortisol, and related assessments that will be covered succinctly below. We will end this article with future directions in the experimental assessment of PTSD that include novel measures incorporated in the immediate aftermath of trauma to assess current impact and prediction of the development of PTSD. PMID- 28813317 TI - Mindfulness in PTSD treatment. AB - In recent years, the field has witnessed considerable enthusiasm for the ancient practice of mindfulness. The skills derived from this experience, including focused attention, nonjudgmental acceptance of internal experiences and reduced autonomic reactivity, may be helpful in counteracting pathological responses to trauma. Several types of interventions that incorporate principles of mindfulness have been examined for treatment of posttraumatic stress disorder (PTSD). This nascent literature is inconsistent and methodologically limited but does suggest that mindfulness is a potentially important tool for creating psychological change. The interventions described herein generally would not yet be considered first-line treatments for PTSD. Nonetheless, evidence is building, and mindfulness may provide an impetus for better understanding how to personalize psychological interventions and to evaluate their outcomes. PMID- 28813316 TI - Perspectives on the conceptualization of the dissociative subtype of PTSD and implications for treatment. AB - A dissociative subtype of PTSD was added to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) to denote a distinct presentation of PTSD marked by symptoms of derealization and depersonalization. The subtype has brought renewed interest in the conceptualization of dissociation in PTSD, and raised questions about its treatment. We review the evidence for two models of PTSD-related dissociative symptoms and the treatment approaches that align with each. We find support for the contributions of biologically-based trait-level factors to dissociation, and suggest that empirically supported treatments for PTSD demonstrate efficacy for patients with the subtype. PMID- 28813318 TI - Gender and PTSD: different pathways to a similar phenotype. AB - Whereas research supports the existence of a single posttraumatic stress disorder (PTSD) phenotype across women and men, there may be important gender differences in the pathophysiology of, or mechanisms underlying, the disorder. This paper reviews recent literature on gender differences in emotional, cognitive, and neurobiological factors, and their relations with PTSD and relevant comorbidities. Key findings and limitations from both human and animal studies are discussed. Overall, more work is needed that utilizes objective measures in addition to self-report. Studies explicitly examining gender differences and those examining mechanisms within single-gender samples each have the potential to improve our understanding of gender discrepancies in PTSD and inform tailored interventions for women and men. PMID- 28813319 TI - Reward functioning in posttraumatic stress and substance use disorders. AB - Posttraumatic stress disorder (PTSD) and substance use disorders (SUD) are complex psychiatric conditions that commonly co-occur. Research on PTSD-SUD comorbidity has increasingly focused upon better understanding biopsychosocial factors that may contribute to their co-occurring etiology, maintenance, and treatment. Anhedonia, defined as a lack of pleasure from or interest in rewards, stems from deficits in reward functioning and is associated with specific neurocircuitries. Few studies have investigated the role of reward functioning in PTSD-SUD. The overarching aims of this review are to: define the major facets of reward functioning, summarize the research on reward functioning-PTSD and reward functioning-SUD, review the literature on associations between reward functioning and PTSD-SUD comorbidity, and discuss clinical implications and future directions. PMID- 28813320 TI - The genetics and epigenetics of PTSD: overview, recent advances, and future directions. AB - This paper provides a brief summary and commentary on the growing literature and current developments related to the genetic underpinnings of posttraumatic stress disorder (PTSD). We first briefly provide an overview of the behavioral genetic literature on PTSD, followed by a short synopsis of the substantial candidate gene literature with a focus on genes that have been meta-analyzed. We then discuss the genome-wide association studies (GWAS) that have been conducted, followed by an introduction to other molecular platforms used in PTSD genomic studies, such as epigenetic and expression approaches. We close with a discussion of developments in the field that include the creation of the PTSD workgroup of the Psychiatric Genomics Consortium, statistical advances that can be applied to GWAS data to answer questions of heritability and genetic overlap across phenotypes, and bioinformatics techniques such as gene pathway analyses which will further advance our understanding of the etiology of PTSD. PMID- 28813321 TI - Focusing on trauma-focused psychotherapy for posttraumatic stress disorder. AB - Trauma-focused psychotherapy for posttraumatic stress disorder (PTSD) includes a range of theoretical approaches, but primarily is based on cognitive-behavioral theory. Eye Movement Desensitization and Reprocessing is another type of trauma focused psychotherapy. Although there is some evidence to support present centered and interpersonal approaches, trauma-focused psychotherapies have the most empirical support and are the most effective for treating PTSD and related problems. PMID- 28813322 TI - Anger and aggression in PTSD. AB - Trauma and posttraumatic stress disorder have massive negative consequences; associated anger and aggression are particularly damaging. This overview focuses on these relationships and their potential mechanisms, and offers treatment considerations. Research and theory suggests that trauma impacts anger and aggression through social information processing mechanisms, and an aggression model incorporating impelling, instigating, and disinhibiting factors helps us understand who is at risk under specific circumstances. The association between PTSD and anger and aggression appears stronger for men than women, perhaps reflecting differences in internalizing versus externalizing responses to trauma. Some research indicates that intervention for those with PTSD and anger/aggression problems is effective, and recent studies indicate the benefits of trauma-informed violence prevention for trauma-exposed populations more broadly. PMID- 28813323 TI - Emotions and emotion regulation in posttraumatic stress disorder. AB - Posttraumatic stress disorder (PTSD) has been associated with negative emotions such as shame, guilt, anger, and disgust, as well as impairments in the ability to effectively regulate these emotional states. There is evidence showing that each of these negative emotions and emotion regulation difficulties are related to the severity of PTSD stemming from various trauma types. In contrast, much less is known about the temporal relationship between these features and PTSD. Studies have found that treatments for PTSD often lead to improvements in these negative emotions and in emotion regulation difficulties, but how these features impact the efficacy of various PTSD treatments is less clear. PMID- 28813324 TI - Cannabinoids as therapeutic for PTSD. AB - Limited efficacy for current pharmacotherapy for PTSD indicates that improved pharmacological treatments are needed. Neurobiological research points to cannabinoids as possible therapeutic agents of interest. Moreover, observational reports indicate that there is growing popular interest in therapeutic use of cannabinoids for the alleviation of trauma symptoms. The aim of this review was to present an up-to-date look at current research on the possible therapeutic value of cannabinoids for PTSD. Experimental, preclinical, and clinical findings are discussed. PMID- 28813325 TI - Sleep in PTSD: Conceptual model and novel directions in brain-based research and interventions. AB - Peri-traumatic sleep disturbances are growingly recognized as biologically relevant and modifiable predisposing, precipitating, and perpetuating factors in posttraumatic stress disorder (PTSD). The exponential growth of the literature on sleep in PTSD over the last two decades has stimulated a paradigm shift in the conceptualization of the relationship between sleep and PTSD. A conceptual framework that captures this paradigm shift is offered. New research on existing and promising sleep-focused treatments for augmenting PTSD treatment outcomes is then summarized. New findings on the neurobiological correlates and underpinnings of the relationship between sleep and PTSD are also discussed. Informed by these recent findings and foundational literature, opportunities for innovation in clinical and experimental research are proposed. PMID- 28813326 TI - Transdiagnostic mechanisms of change and cognitive-behavioral treatments for PTSD. AB - This paper reviews the current status of transdiagnostic mechanisms of change targeted in cognitive-behavioral interventions, with a focus on mechanisms that are also relevant to emotional disorders that frequently co-occur with PTSD. First, an overview of the rationale for and key features of identifying mechanisms of change is presented, with a discussion of why it is crucial to examine mechanisms that are relevant across diagnostic boundaries. A review of the current evidence for five promising transdiagnostic mechanisms (hope, neuroticism, emotion regulation, cognitive reappraisal, and anxiety sensitivity) is then provided. Finally, the implications of the increasing evidence of transdiagnostic mechanisms of change are discussed in relation to recently developed transdiagnostic treatment protocols that provide an alternative treatment approach for PTSD. PMID- 28813327 TI - Recent developments in understanding ethnocultural and race differences in trauma exposure and PTSD. AB - Our understanding of demographic specifications that put certain individuals at greater risk for trauma exposure and subsequent development of post-traumatic stress disorder (PTSD) has grown significantly over the past few decades. This brief review specifically examines the studies exploring the potential influence of ethnocultural and racial group status on trauma exposure and PTSD, with a focus on findings published recently in the past five years. We first provide a brief review of current epidemiological data examining associations among ethnicity/culture/race and trauma exposure/PTSD. We then explore a few related constructs (namely, stigma, acculturation/ethnic identity, and discrimination) in relation to trauma exposure and PTSD, with a focus on what is currently known about how these variables are empirically related to one another. PMID- 28813328 TI - Editorial overview: Advances in science and practice in traumatic stress. AB - This issue provides an expansive overview of the field of posttraumatic stress disorder (PTSD). The featured articles highlight novel, creative, and innovative topics and methodologies, consolidate recent scientific advances, and delineate future directions. The content spans various topics in the field of traumatic stress, including assessment, biopsychosocial correlates, clinical considerations, including comorbidity, anger, self-directed violence, and dissociative manifestations, evidence-based interventions, and innovative delivery formats that maximize dissemination and implementation. The issue's overarching goal is to stimulate creative, multidisciplinary, methodologically rigorous, and theoretically grounded research to advance knowledge and practice in PTSD and related conditions. PMID- 28813329 TI - Ego depletion in sports: highlighting the importance of self-control strength for high-level sport performance. AB - Athletes are constantly confronted with self-control demands, but previous research has delivered sound empirical evidence that athletes are not always capable of dealing with these demands. According to the strength model of self control, individuals have a limited amount of self-control strength, which can become temporarily depleted following self-control demands (e.g., attention regulation). When self-control strength is depleted, that is, in a state of ego depletion, athletes are less persistent during strenuous physical exercise, are less likely to follow their exercise regimens, and tend to perform worse under pressure. The aim of this review article is to highlight the importance of ego depletion in the field of sports and exercise and to discuss the recent research and controversies surrounding it. PMID- 28813330 TI - Personality and performance: moving beyond the Big 5. AB - In this review, we examine the literature in relation to personality and performance. Much of the extant work in this area has focused on the role of the Big 5 traits (i.e., extraversion, conscientiousness, openness to experience, agreeableness, and neuroticism), at the expense of other personality variables that have a strong performance-focused rationale. Further, a focus on main effects has dominated the literature, without recourse to consider person*environment interactions. In this review we go beyond the Big 5 and consider the role of two personality traits, narcissism and alexithymia, in relation to performance. We demonstrate that both traits have considerable potential to explain differences in performance and that the personality performance relationship is best viewed from an interactionist perspective. We close with a call for researchers to give more attention to personality in relation to performance. PMID- 28813331 TI - Athlete burnout: review and recommendations. AB - Over the last two decades, growing concerns regarding the negative implications of athlete burnout have spurred empirical research on the topic. In their citation network analysis of the burnout literature, Gustafsson et al. (2014), cited well over 100 publications on the syndrome. Despite considerable investigation into athlete burnout, there remain a number of unresolved questions and issues. Four main aims guide the current review. First, we highlight various models of athlete burnout. Second, we discuss the measurement of athlete burnout. Third, we describe the symptoms, antecedents, and consequences of athlete burnout with a focus on social perceptions and perfectionism. Finally, we provide suggestions for the prevention and treatment of athlete burnout via an illustration of links between theory and practice. It is our hope that this review can stimulate future research in order to help athletes avoid burnout and other severe forms of training maladaptation. PMID- 28813332 TI - Team building: conceptual, methodological, and applied considerations. AB - Team building has been identified as an important method of improving the psychological climate in which teams operate, as well as overall team functioning. Within the context of sports, team building interventions have consistently been found to result in improvements in team effectiveness. In this paper we review the extant literature on team building in sport, and address a range of conceptual, methodological, and applied considerations that have the potential to advance theory, research, and applied intervention initiatives within the field. This involves expanding the scope of team building strategies that have, to date, primarily focused on developing group cohesion. PMID- 28813333 TI - Athletic identity foreclosure. AB - Athletic identity foreclosure refers to commitment to the athlete role in the absence of exploration of occupational or ideological alternatives. This article traces the theoretical underpinnings of the construct, examines the role of sport participation in identity development, and provides an overview of the course, correlates, and consequences of athletic identity foreclosure. Implications for future research are discussed. PMID- 28813334 TI - The future for PETTLEP: a modern perspective on an effective and established tool. AB - Over the past 15 years there has been much research into the PETTLEP model of motor imagery, originally designed to improve the quality and impact of imagery interventions on sport performance. This article reviews the most recent trends within this research. Despite a suggested change of underpinning mechanisms involved, there is much support for the positive impact of the model when applied within the sporting context and with engaged participants. The model also appears to have provided impact in fields other than sport, such as medicine and music. Therefore we suggest that it has largely met its desired aims. However, not all research has optimised the model's guidelines, with a distinct failure to account for personal relevance when designing imagery scripts or selecting tasks for use in studies. Other recent and pertinent findings relate to the mediating role of expectancy and beneficial augmentation through movement observation. Future research should, however, seek exploitation and clarification towards contemporary issues in motor control, namely; automaticity, the relative merits of internal and external foci and subconscious goal priming. Finally, we endorse the application of imagery, as a conscious intervention, even for execution of unconscious, fast-actions. PMID- 28813335 TI - Cultural sport psychology: a critical review of empirical advances. AB - Despite a long standing assertion that sociocultural domain is one of the factors constituting human psychological phenomena, sport psychological science has only recently begun to examine culture as the principal basis of physical activity and sport participants' behaviour, wellbeing, engagement, and performance outcomes. Emphasizing the centrality of culture in bringing meaning to athlete careers and life projects, I summarise empirical literature explicitly positioned within cultural sport psychology (CSP). Specifically, I focus on two areas of psychological inquiry - acculturation and athletic career - in which the CSP theoretical tenets and agenda stimulated emergence of novel research trajectories. I conclude by suggesting directions for future work in CSP. PMID- 28813336 TI - Searching for the elusive gift: advances in talent identification in sport. AB - The incentives for sport organizations to identify talented athletes from a young age continue to grow, yet effective talent identification remains a challenging task. This opinion paper examines recent advances in talent identification, focusing in particular on the emergence of new approaches that may offer promise to identify talent (e.g., small-sided games, genetic testing, and advanced statistical analyses). We appraise new multi-disciplinary and large-scale population studies of talent identification, provide a consideration of the most recent psychological predictors of performance, examine the emergence of new approaches that strive to diminish biases in talent identification, and look at the rise in interest in talent identification in Paralympic sport. PMID- 28813337 TI - Professional development for sport psychology practice. AB - Applied sport psychology practice and research date back to the late 19th century. During this period investigators have largely examined the interventions practitioners employ to help athletes. More recently, researchers have begun addressing the person employing those interventions, including identifying their attributes and how they develop expertise, in recognition that practitioners are central to effective practice. Research focused on practitioners can inform educational and registration pathways, helping trainees to develop the knowledge, skills, and characteristics needed to meet their clients' needs. In this article major lines of inquiry in this area are reviewed. It is suggested that examining practitioner identity represents novel research that has educational and applied value. PMID- 28813338 TI - Self-talk effectiveness and attention. AB - Self-talk interventions in sport have been receiving increased research attention in recent years. The findings have provided robust support that self-talk strategies enhance sport performance. Identifying the mechanisms that explain the beneficial effects of self-talk is important for developing a comprehensive self talk theory and informing practice. Among the mechanisms proposed to explaining the effectiveness of self-talk, is its attentional effects. This article reviews the literature considering the effects of self-talk on attention. The findings suggest that self-talk can help enhancing attentional focus and attentional performance, but also help countering the aversive effects of distraction and ego depletion. The present evidence suggests that attention is a potential key mechanism in the self-talk performance relationship. PMID- 28813339 TI - Ethical issues in sport psychology. AB - The field of sport psychology is dynamic and growing. To continue building credibility with the public and allied professionals, effective and ethical practice is crucial. Advances in technology have allowed sport psychology professionals to consult with athletes from a distance, but practitioners must be mindful of their competency to use technology, confidentiality concerns, and the suitability of technology for their clients. Movement toward defining competency and clarifying issues of title usage are additional areas in which the field is gaining momentum. Recent attention has also been drawn to the topics of professional development and cultural competency. With the unique settings in which applied sport psychology practice takes place, attention to multiple relationships is another key ethical issue. PMID- 28813340 TI - Athletes with eating disorder symptomatology, a specific population with specific needs. AB - This review presents recent studies into the prevalence, process, treatment and prevention of eating disorders in athletes. Most prevalence studies showed that increased risk for athletes exists. Methodological challenges for future prevalence studies concern the choice of methods, measurements, categorization, and sampling. To determine why athletes are at increased risk, more prospective studies using multi-factorial models and multiple risk pathways are needed. Epidemiological risk factor studies, however, do not provide us with a true understanding of the eating disorder process. The narrative approach focuses on what an eating disorder means to an athlete, which might produce more relevant clues for interventions. More research attention should be dedicated to effective treatment and facilitating recovery. Finally, prevention should add attitudinal and behavioral interventions to the current knowledge-focused approach and programs needs to go beyond coaches and athletes to become more effective. PMID- 28813341 TI - Coaching effectiveness: the coach-athlete relationship at its heart. AB - Coaching has been often viewed as a context within which coaches operate to largely bring about changes in athlete's performance and wellbeing. One key factor to successful outcomes in coaching is the quality of the relationship between coaches and athletes. In this article, I propose that the coach-athlete relationship is at the heart of coaching. Moreover, the aim is to describe and explain how the quality of the relationship coaches and athletes develop and maintain over the course of their sporting partnership alongside coaches and athletes' knowledge and outcomes, form a system that is capable of defining coaching effectiveness and success. PMID- 28813342 TI - Recent developments in team resilience research in elite sport. AB - In this paper we review recent developments in team resilience research in elite sport. Although resilience has become a popular and well-researched topic from an individual (psychological) perspective, less attention has been paid to whether this construct is conceptually and operationally robust at a group level. In this review, we provide an overview of definitional aspects of team resilience followed by an outline of research in the general psychology literature, and a discussion of the findings of the first two studies of team resilience in elite sport. Recent developments in this area of sport psychology research suggest that an understanding of how teams mobilize their collective psychosocial resources to withstand stressors is essential for optimal performance. PMID- 28813343 TI - Prevalence of interpersonal violence against athletes in the sport context. AB - Despite progress in recent years on understanding the magnitude of the problem of interpersonal violence against athletes in the sport context, this research area is still very understudied. Yet, many researchers have advocated for the urgent need to carry out prevalence studies in this field to base prevention efforts on empirical evidence and to convince public decision makers about the necessity to address this issue. The present paper widens the focus on violence in sport, beyond the traditional player and spectator violence literature. We present recent prevalence data on less studied issues, such as sexual, physical and psychological violence against athletes, in and outside the field, and from coaches, opponents and teammates. PMID- 28813344 TI - Mental toughness: progress and prospects. AB - Mental toughness (MT) has become a popular area of investigation and practice within sport and exercise psychology over the past two decades. Since the turn of the twenty first century, there have been hundreds of studies published on mental toughness, yet concerns remain about the conceptualisation and measurement of mental toughness. In this paper, I take stock of past work with the goal of clarifying and elaborating the most fundamental and common aspects of MT. I also look to the future and outline key substantive and methodological issues that may offer the greatest potential for refining the conceptualisation of MT and contributing to theory building on this concept. My hope is that this information will provide a platform from which to foster coherent and systematic scholarly work on MT. PMID- 28813345 TI - Choking under pressure: theoretical models and interventions. AB - In sport, choking under pressure is a major concern for athletes, coaches and sport psychologists because athletes fail to meet self-imposed performance expectations in critical situations (when it counts the most), which is devastating and embarrassing. Researchers have debated choking under pressure definitions, identified personality characteristics that exacerbate choking outcomes, and examined models to determine mechanisms for choking. Based on these investigations, several interventions to prevent choking have been developed and tested. In this review, we specifically discuss current self-presentation and attention models and theory-driven interventions that help to alleviate choking in order to facilitate the understanding of this complex phenomenon by athletes, sport psychologists and researchers. PMID- 28813346 TI - Current opinion in clinical sport psychology: from athletic performance to psychological well-being. AB - Clinical sport psychology (CSP) is a contemporary, empirically informed model that employs a scope, style, and mode of practice built upon cutting-edge findings from both clinical and sport sciences, and that follows the sound methodological traditions of clinical psychology [1**]. Conceptualizing athletic performance and well-being through the context of empirical research in both athletic and nonathletic domains of functioning, CSP practice can involve the enhancement of athletic performance, and also the personal development and psychological well-being of performers. CSP intervention options expand (if desired) to include those currently considered to be outside of the purview of traditional sport psychology and within the domains of clinical/counseling psychology. Importantly, CSP does not imply that its practitioners must choose a population. CSPers can, if appropriate, assess and intervene with psychological disorders, performance dysfunction, and performance improvement, and/or can make appropriate referrals. Despite whether one personally addresses the variety of interpersonal, non-diagnosable, and clinical issues potentially presented, they must support a comprehensive, client-specific approach and engage in interventions based on sound evidence. Expanding practice boundaries, and with it one's roles and responsibilities, also results in expanded job opportunities. This scope highlights the clinical sport psychologist as the human behavior expert in the athletic milieu. PMID- 28813347 TI - Mindfulness-based and acceptance-based interventions in sport and performance contexts. AB - Since mindfulness-based and acceptance-based practice models were first conceptualized and applied in sport in an attempt to enhance performance and overall well-being of athletes and performers, these state-of-the-art theoretical and practice models have substantially broadened our knowledge base and have been successfully incorporated into sport and performance practice domains worldwide. Evolving from a sound empirical foundation, mindfulness-based and acceptance based models in sport psychology have accumulated a strong basic and applied empirical foundation. In the nearly 20 years since their incorporation in the context of sport, empirical findings have demonstrated efficacious outcomes associated with performance and personal well-being, as well as supported their theorized mechanisms of change. Particularly as sport and performance environments increasingly call upon practitioners to provide more comprehensive care to clientele, including a range of care from performance enhancement and maintenance, to general personal well-being, to subclinical and clinical issues, mindfulness-based and acceptance-based practitioners have the tools to offer robust, empirically informed interventions that can enhance skills and quality of life, and/or ameliorate personal struggles. PMID- 28813348 TI - Moral behavior in sport. AB - In this review paper, we provide an overview of recent research on prosocial and antisocial behaviors, in the context of sport, focusing mainly on antecedents and consequences of these behaviors. Motivational variables such as task orientation, mastery climate, autonomous motivation, and autonomy supportive climate are likely to promote prosocial behavior, whereas ego orientation, performance climate, controlled motivation, and controlling climate may lead to antisocial behavior. The effects of some motivational variables (i.e., controlled motivation and controlling climate) on antisocial behavior may be mediated by moral disengagement, which has been consistently linked to antisocial behavior across a number of studies. Two moral variables, moral identity and empathy have been found to inhibit antisocial behavior, and their effects are due to anticipated guilt for acting antisocially. With respect to consequences of teammate behavior, some evidence suggests that prosocial behavior may enhance the recipient's enjoyment, effort, commitment, and performance, whereas antisocial behavior could lead to anger. Finally, the frequency of prosocial and antisocial behaviors varies as a function of context: Student athletes display more antisocial behavior towards their opponents compared to their fellow students but also more prosocial behavior towards their teammates than towards their fellow students. In sum, both motivational and moral variables predict prosocial and antisocial behaviors in sport, and these behaviors can have important consequences for the recipient. PMID- 28813349 TI - Advances in athlete development: understanding conditions of and constraints on optimal practice. AB - The development of elite, high performance athletes reflects the complex interaction of biological and genetic factors with important environmental influences. Over the past two decades, discussions of athlete development have largely focused on the role of 'deliberate' practice, and more recently, researchers have begun exploring the means by which practice can be best used to maximize the rate of talent development across the different stages of athlete development. In this article, we summarize recent developments in understanding how athletes maximize practice including (a) antecedents of practice involvement, (b) environmental constraints of practice involvement, (c) the value of diversification for athlete development, (d) and methodological advancements in this area. Collectively, sustained focus on issues of athlete development and researchers' use of more advanced approaches to novel questions extend our understanding of the nuances associated with this process. PMID- 28813350 TI - Anxiety and performance: perceptual-motor behavior in high-pressure contexts. AB - When the pressure is on and anxiety levels increase it is not easy to perform well. In search of mechanisms explaining the anxiety-performance relationship, we revisit the integrated model of anxiety and perceptual-motor performance (Nieuwenhuys and Oudejans, 2012) and provide a critical review of contemporary literature. While there is increasing evidence that changes in attentional control affect the execution of goal-directed action, based on our model and emerging evidence from different scientific disciplines, we argue for a more integrated, process-based approach. That is, anxiety can affect performance on different levels of operational control (i.e., attentional, interpretational, physical) and - moving beyond the execution of action - have implications for different aspects of perceptual-motor behavior, including situational awareness and decision making. PMID- 28813351 TI - Motor heuristics and embodied choices: how to choose and act. AB - Human performance requires choosing what to do and how to do it. The goal of this theoretical contribution is to advance understanding of how the motor and cognitive components of choices are intertwined. From a holistic perspective I extend simple heuristics that have been tested in cognitive tasks to motor tasks, coining the term motor heuristics. Similarly I extend the concept of embodied cognition, that has been tested in simple sensorimotor processes changing decisions, to complex sport behavior coining the term embodied choices. Thus both motor heuristics and embodied choices explain complex behavior such as studied in sport and exercise psychology. PMID- 28813352 TI - Optimizing motivation and attention for motor performance and learning. AB - We review three lines of recent research at an intersection of motor learning and sport psychology as they relate to motor skill acquisition: enhanced expectancies, autonomy support, and external attentional focus. Findings within these lines of research have been integrated into a new theory, the OPTIMAL (Optimizing Performance through Intrinsic Motivation and Attention for Learning) theory (i.e., OPTIMAL theory, Wulf and Lewthwaite, 2016), and have been applied in motor skill acquisition and performance. Implications range from more effective skill development in children and novice performers to athletes and performers in many fields, including clinical rehabilitation. PMID- 28813353 TI - Motor cognition and neuroscience in sport psychology. AB - Advances in technology have allowed research in cognitive neuroscience to contribute significantly to the discipline of sport psychology. In most cases, the research has become more rigorous and has directed current thinking on the mechanisms subserving a number of psychological theories and models of practice. Currently, the three most common neuroscience techniques informing sport and exercise research are electroencephalography, transcranial magnetic stimulation and functional magnetic resonance imaging. In this review, we highlight and discuss the contributions to sport psychology that have been made in recent years by applying these techniques, with a focus on the development of expertise, motor cognition, motor imagery and action observation. PMID- 28813354 TI - New directions in the psychology of optimal performance in sport: flow and clutch states. AB - Csikszentmihalyi's conceptualisation of flow is the primary framework for understanding the psychology of optimal experience and performance in sport. However, emerging evidence suggests a more dynamic, multi-state perspective. This review focuses primarily on recent studies highlighting a second, overlapping 'clutch' state which - in addition to flow - underlies optimal performance in sport. We also examine how the nature of goals ('open' or 'fixed') athletes pursue influence the experience of flow and clutch respectively. This new, integrated model of psychological states underlying optimal performance raises questions around conceptualisation and methodology employed in the field to date. These implications are outlined, and recommendations are provided for more critical and accurate measurement of both flow and clutch as overlapping, yet distinct, states. PMID- 28813355 TI - The generalizability of working-memory capacity in the sport domain. AB - Working-memory capacity has been implicated as an influential variable when performing and learning sport-related skills. In this review, we critically evaluate evidence linking working-memory capacity with performing under pressure, tactical decision making, motor skill acquisition, and sport expertise. Laboratory experiments link low working-memory capacity with poorer performance under pressure and poorer decision making when required to inhibit distractions or resolve conflict. However, the generalizability of these findings remains unknown. While working-memory capacity is associated with the acquisition of simple motor skills, there is no such evidence from the available data for complex motor skills. Likewise, currently there is no evidence to suggest that a larger working-memory capacity facilitates the attainment of sport expertise. PMID- 28813356 TI - Athlete leadership: a review of the theoretical, measurement, and empirical literature. AB - Athlete leadership is defined as an athlete who occupies a formal or informal leadership role within a team and influences team members to achieve a common objective. The area of athlete leadership has been shaped by theories and measurement tools from organizational and sport coaching literatures. The present article describes the conceptual developments within athlete leadership by providing an operational definition of this construct, followed by the theories and measurement tools used to examine athlete leadership. Finally, the present paper describes both qualitative and quantitative research that has emerged over the last decade. The results suggest the importance of this source of leadership within sport teams. PMID- 28813357 TI - Anticipation in sport. AB - Anticipation has become an increasingly important research area within sport psychology since its infancy in the late 1970s. Early work has increased our fundamental understanding of skilled anticipation in sports and how this skill is developed. With increasing theoretical and practical insights and concurrent technological advancements, researchers are now able to tackle more detailed questions with sophisticated methods. Despite this welcomed progress, some fundamental questions and challenges remain to be addressed, including the (relative) contributions of visual and motor experience to anticipation, intraindividual and interindividual variation in gaze behaviour, and the impact of non-kinematic (contextual or situational) information on performance and its interaction with advanced kinematic cues during the planning and execution of (re)actions in sport. The aim of this opinion paper is to shortly sketch the state of the art, and then to discuss recent work that has started to systematically address open challenges thereby inspiring promising future routes for research on anticipation and its application in practice. PMID- 28813358 TI - Crisis-transitions in athletes: current emphases on cognitive and contextual factors. AB - During the last decade, the field of athlete career research has seen much expansion. Researchers established the holistic lifespan and ecological approaches, introduced cultural praxis of athletes' careers paradigm, and updated the taxonomy of athletes' transitions. However, recent transition research focused mainly on the transition process and factors contributing to successful transitions, while crisis-transitions and factors contributing to ineffective coping have been largely ignored. The aim of this paper is to facilitate relevant research and practice through (1) positioning athletes' developmental crises within the context of the current transition literature, (2) introducing two new approaches (termed 'cognitive turn' and 'cultural turn') with a potential to enhance our understanding of the phenomenon, and (3) outlining crisis-coping interventions. PMID- 28813359 TI - The psychology of doping. AB - Doping is increasingly becoming a problem in both elite and recreational sports. It is therefore important to understand the psychological factors which can explain doping behavior in order to prevent it. The present paper briefly presents evidence on the prevalence of doping use in competitive sports and the measurement approaches to assess doping behavior and doping-related variables. Furthermore, the integrative theoretical approaches used to describe the psychological processes underlying doping use are discussed. Finally, the paper provides suggestions for appropriate measurement of doping behavior and doping related variables, key preventive efforts against doping as well as avenues for future research. PMID- 28813360 TI - A short review of perfectionism in sport, dance and exercise: out with the old, in with the 2*2. AB - The purpose of the current paper is to review research examining multidimensional perfectionism in sport, dance, and exercise. We start by providing a conceptual overview of perfectionism. We then describe three main approaches to examining perfectionism. These approaches are an independent effects approach, the tripartite model, and the 2*2 model of perfectionism. Alongside the description of each approach, research findings are summarized. We close the paper by explaining how the development of the 2*2 model has likely rendered the tripartite model obsolete. PMID- 28813361 TI - Transformational leadership in sport: current status and future directions. AB - Borrowed from organizational psychology, the concept of transformational leadership has now been applied to a sport context for a decade. Our review covers and critically discusses empirical articles published on this growing topic. However, because the majority of studies used cross-sectional designs and single-source questionnaires to tap what has been a fuzzy construct, current theoretical and methodological issues impede understanding of whether transformational leadership matters for sport outcomes. To make a difference to applied practice and policy, the transformational leadership construct requires a refined definition and stronger empirical tests allowing for robust causal inference. We highlight avenues for advancing research on transformational leadership in the sport context. PMID- 28813362 TI - People have feelings! Exercise psychology in paradigmatic transition. AB - Exercise psychology has yet to produce intervention methods capable of increasing exercise and physical activity behavior in a sustainable manner. This situation is forcing a critical reevaluation of current conceptual models, especially the assumption that behavioral decisions are driven solely by the rational evaluation of information. Like other behavioral sciences, exercise psychology is transitioning to dual-process models that acknowledge the importance of non reflective processes. Emerging evidence suggests that the pleasure or displeasure experienced during exercise may influence subsequent physical activity. These data raise the possibility of inactivity resulting from a conflict between positively evaluated information on health benefits and unpleasant affective experiences. Thus, researchers must devise methods to make exercise and physical activity more pleasant and enjoyable across the lifespan. PMID- 28813363 TI - Psychosocial factors and sport injuries: prediction, prevention and future research directions. AB - This review provides an overview of recent theoretical and empirical developments regarding psychosocial factors related to the prediction and prevention of sport injuries, and highlights some of the most interesting areas of investigation that have been carried out in the past few years. For instance, a systematic review of the most cited and used theoretical framework in the field has recently been performed, which supports the model's suggestion that psychosocial variables, as well as psychologically based interventions, can influence injury risk among athletes. Based on substantial empirical evidence it is also shown that changes in stress and perceived recovery appear to predict injury occurrence in sport. Current studies, focusing on overuse injuries, also suggest that cultural norms and rules can be seen as factors that can indirectly influence the risk of becoming injured. Future research directions are presented such as the need for interdisciplinary injury prevention programs based on a combination of physiological and psychological interventions. PMID- 28813364 TI - Parenting in sport. AB - This paper provides a brief summary and commentary on the growing literature on parenting in sport, with a particular emphasis on literature from the last 2-3 years. Following a brief introduction overviewing the topic area, we firstly focus on the influence of parental involvement on children. Specifically, we examine the range of factors that influence children's perceptions of parental involvement and the consequences of different behaviors. Next we discuss the factors influencing parental involvement, such as the challenges and stressors associated with parenting children in sport and the culture within different sports. Finally, our review focuses upon the strategies developed by parents to facilitate their involvement in their children's sport, as well as the few papers focused upon parent education and support. We conclude by examining the need for further research and examination of support strategies for parents. PMID- 28813365 TI - "Yes, we can!" review on team confidence in sports. AB - During the last decade, team confidence has received more and more attention in the sport psychology literature. Research has demonstrated that athletes who are more confident in their team's abilities exert more effort, set more challenging goals, are more resilient when facing adversities, and ultimately perform better. This article reviews the existing literature in order to provide more clarity in terms of the conceptualization and the operationalization of team confidence. We thereby distinguish between collective efficacy (i.e., process-oriented team confidence) and team outcome confidence (i.e., outcome-oriented team confidence). In addition, both the sources as well as the outcomes of team confidence will be discussed. Furthermore, we will go deeper into the dispersion of team confidence and we will evaluate the current guidelines on how to measure both types of team confidence. Building upon this base, the article then highlights interesting avenues for future research in order to further improve both our theoretical knowledge on team confidence and its application to the field. PMID- 28813366 TI - Editorial overview: Trending Topics in Sport Psychology. PMID- 28813367 TI - Electron transfer processes occurring on platinum neural stimulating electrodes: pulsing experiments for cathodic-first, charge-balanced, biphasic pulses for 0.566 ? k ? 2.3 in rat subcutaneous tissues. AB - OBJECTIVE: Our mission is twofold: (1) find a way to safely inject more charge through platinum electrodes than the Shannon limit (k = 1.75) permits and (2) nurture an interest in the neural stimulation community to understand the electron transfer process occurring on neural stimulating electrodes. APPROACH: We report here on measurements of the electrode potential, performed on platinum neural stimulating electrodes in the subcutaneous space of an anesthetized rat under neural stimulation conditions. MAIN RESULTS: The results for six platinum electrodes with areas ranging from 0.2 mm2 to 12.7 mm2 were similar to prior results in sulfuric acid, except that the measured potentials were shifted negative 0.36 V because of the pH difference between the two media. The anodic 'end' potential, measured at t = 20 ms after the onset of the biphasic current pulse, was the primary focus of the data collected because previous results had shown that as charge injection crosses the Shannon limit (k = 1.75), this potential moves into a range where platinum surface oxidation and dissolution is likely to occur. The behavior of V e(t = 20 ms) over a range of electrode surface areas studied was consistent with our sulfuric acid study. Implicit, but little noticed, in Shannon's formulation is that small and large platinum electrodes behave the same in terms of k value; our data supports this idea. SIGNIFICANCE: We hypothesize that the k = 1.75 Shannon limit for safe stimulation designates a charge-injection boundary above which platinum toxicity becomes a relevant consideration for living cells around an electrode, a possibility that can be directly tested, and is a vital step forward in mission (1). PMID- 28813368 TI - Electronic transport properties of graphene doped by gallium. AB - In this work we present the effect of low dose gallium (Ga) deposition (<4 ML) performed in UHV (10-7 Pa) on the electronic doping and charge carrier scattering in graphene grown by chemical vapor deposition. In situ graphene transport measurements performed with a graphene field-effect transistor structure show that at low Ga coverages a graphene layer tends to be strongly n-doped with an efficiency of 0.64 electrons per one Ga atom, while the further deposition and Ga cluster formation results in removing electrons from graphene (less n-doping). The experimental results are supported by the density functional theory calculations and explained as a consequence of distinct interaction between graphene and Ga atoms in case of individual atoms, layers, or clusters. PMID- 28813369 TI - Gas-sensing enhancement methods for hydrothermal synthesized SnO2 based sensors. AB - The gas sensing enhancement methods for hydrothermal synthesized SnO2-based gas sensors could be performed from three areas: structural improvement, composition optimization and processing improvement, which were aimed to improve the performance of the gas sensors. There was 0-D, 1-D and 3-D structures reported in literatures. Controllable synthesis of different structures was deployed to increase specific surface area. Change of composition would intensively tailor the SnO2 structure, which affected the gas sensing performance. Besides, doping and compounding methods were adopted to promote gas-sensing performance by adjusting surface condition of SnO2 crystal and constructing heterojunction. As for processing area, it was very important to find the optimal reaction time and temperature. In this paper, gas-solid reaction rate constant was proposed to evaluate gas-sensing property and find the excellent hydrothermal synthesized SnO2-based gas sensor at present. PMID- 28813370 TI - Chronic Systemic Toxicity Study of Copper Intrauterine Devices in Female Wistar Rats. AB - BACKGROUND The aim of this study was to evaluate the chronic systemic and local toxicity of a copper intrauterine device in a rat model. MATERIAL AND METHODS Cu IUD fragments were inserted into the uterine horns of female Wistar rats for 26 weeks (equivalent 15.42-17.33 years in humans). We tested copper at 20, 40, and 60 times the clinical dosages to study copper toxicity under severe conditions. Classic chronic systemic toxicity evaluations, including body weight, hematology, organ coefficient, and tissue reactions, were performed. RESULTS The body weight of the rats increased during the 26 weeks, which showed that the Cu-IUD implant had no effect on animal growth. Histological examinations and organ coefficients of the uterus and other major organs indicated no obvious systemic or local impairment. Blood tests confirmed that the hepatic and renal functions remained normal. CONCLUSIONS These results obtained at different dosages and long-term implantation provide solid data confirming the safety of long-term use of Cu IUDs. However, the elevated leucocyte levels found in this study warrant further investigation. PMID- 28813371 TI - Return of the Missing Daughters. PMID- 28813372 TI - Beyond XX and XY. PMID- 28813373 TI - Navigating by Touch. PMID- 28813374 TI - Change of Heartbeat. PMID- 28813375 TI - Is There a "Female" Brain? PMID- 28813376 TI - A Moth's Eye. PMID- 28813378 TI - This Is Not A Women's IssueWhy the New Science of Sex &Gender Matters for Everyone. PMID- 28813377 TI - Women's Work. PMID- 28813379 TI - End the Assault on Women's Health. PMID- 28813380 TI - The End. PMID- 28813381 TI - Mind the Gap. PMID- 28813382 TI - The Face of Evil. PMID- 28813383 TI - The Brilliance Trap. PMID- 28813384 TI - Cut That Last Cord. PMID- 28813386 TI - Welcome to Everybody's Issue. PMID- 28813385 TI - Cutting through the Fog. PMID- 28813387 TI - Girl Code. PMID- 28813388 TI - Letters. PMID- 28813389 TI - Postmodernism vs. Science. PMID- 28813390 TI - Recommended. PMID- 28813392 TI - Living Large. PMID- 28813391 TI - Pediatric Predicament. PMID- 28813393 TI - The Woman Who Saved the Planet. PMID- 28813395 TI - Baby's Rainbow. PMID- 28813394 TI - Night Owl Genes. PMID- 28813396 TI - Promiscuous Men, Chaste Women and Other Gender Myths. PMID- 28813397 TI - The Oldest Homo sapiens? PMID- 28813398 TI - Not Just for Men. PMID- 28813399 TI - Life before Roe. PMID- 28813401 TI - Skinlike Sunscreen. PMID- 28813400 TI - Africa's CDC Can End Malaria. PMID- 28813402 TI - The Blogger and the Trolls. PMID- 28813404 TI - When Sex and Gender Collide. PMID- 28813403 TI - Quick Hits. PMID- 28813405 TI - Wood Is the New Steel. PMID- 28813406 TI - 50, 100 &150 Years Ago. PMID- 28813407 TI - Global health: Probiotic prevents infections in newborns. PMID- 28813408 TI - Biochemistry: A toxin that fuels metabolism. PMID- 28813409 TI - The rise of algae in Cryogenian oceans and the emergence of animals. AB - The transition from dominant bacterial to eukaryotic marine primary productivity was one of the most profound ecological revolutions in the Earth's history, reorganizing the distribution of carbon and nutrients in the water column and increasing energy flow to higher trophic levels. But the causes and geological timing of this transition, as well as possible links with rising atmospheric oxygen levels and the evolution of animals, remain obscure. Here we present a molecular fossil record of eukaryotic steroids demonstrating that bacteria were the only notable primary producers in the oceans before the Cryogenian period (720-635 million years ago). Increasing steroid diversity and abundance marks the rapid rise of marine planktonic algae (Archaeplastida) in the narrow time interval between the Sturtian and Marinoan 'snowball Earth' glaciations, 659-645 million years ago. We propose that the incumbency of cyanobacteria was broken by a surge of nutrients supplied by the Sturtian deglaciation. The 'Rise of Algae' created food webs with more efficient nutrient and energy transfers, driving ecosystems towards larger and increasingly complex organisms. This effect is recorded by the concomitant appearance of biomarkers for sponges and predatory rhizarians, and the subsequent radiation of eumetazoans in the Ediacaran period. PMID- 28813410 TI - Identification of CMTM6 and CMTM4 as PD-L1 protein regulators. AB - The clinical benefit for patients with diverse types of metastatic cancers that has been observed upon blockade of the interaction between PD-1 and PD-L1 has highlighted the importance of this inhibitory axis in the suppression of tumour specific T-cell responses. Notwithstanding the key role of PD-L1 expression by cells within the tumour micro-environment, our understanding of the regulation of the PD-L1 protein is limited. Here we identify, using a haploid genetic screen, CMTM6, a type-3 transmembrane protein of previously unknown function, as a regulator of the PD-L1 protein. Interference with CMTM6 expression results in impaired PD-L1 protein expression in all human tumour cell types tested and in primary human dendritic cells. Furthermore, through both a haploid genetic modifier screen in CMTM6-deficient cells and genetic complementation experiments, we demonstrate that this function is shared by its closest family member, CMTM4, but not by any of the other CMTM members tested. Notably, CMTM6 increases the PD L1 protein pool without affecting PD-L1 (also known as CD274) transcription levels. Rather, we demonstrate that CMTM6 is present at the cell surface, associates with the PD-L1 protein, reduces its ubiquitination and increases PD-L1 protein half-life. Consistent with its role in PD-L1 protein regulation, CMTM6 enhances the ability of PD-L1-expressing tumour cells to inhibit T cells. Collectively, our data reveal that PD-L1 relies on CMTM6/4 to efficiently carry out its inhibitory function, and suggest potential new avenues to block this pathway. PMID- 28813411 TI - Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolism. AB - The folate-driven one-carbon (1C) cycle is a fundamental metabolic hub in cells that enables the synthesis of nucleotides and amino acids and epigenetic modifications. This cycle might also release formaldehyde, a potent protein and DNA crosslinking agent that organisms produce in substantial quantities. Here we show that supplementation with tetrahydrofolate, the essential cofactor of this cycle, and other oxidation-prone folate derivatives kills human, mouse and chicken cells that cannot detoxify formaldehyde or that lack DNA crosslink repair. Notably, formaldehyde is generated from oxidative decomposition of the folate backbone. Furthermore, we find that formaldehyde detoxification in human cells generates formate, and thereby promotes nucleotide synthesis. This supply of 1C units is sufficient to sustain the growth of cells that are unable to use serine, which is the predominant source of 1C units. These findings identify an unexpected source of formaldehyde and, more generally, indicate that the detoxification of this ubiquitous endogenous genotoxin creates a benign 1C unit that can sustain essential metabolism. PMID- 28813412 TI - The primed SNARE-complexin-synaptotagmin complex for neuronal exocytosis. AB - Synaptotagmin, complexin, and neuronal SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) proteins mediate evoked synchronous neurotransmitter release, but the molecular mechanisms mediating the cooperation between these molecules remain unclear. Here we determine crystal structures of the primed pre-fusion SNARE-complexin-synaptotagmin-1 complex. These structures reveal an unexpected tripartite interface between synaptotagmin-1 and both the SNARE complex and complexin. Simultaneously, a second synaptotagmin-1 molecule interacts with the other side of the SNARE complex via the previously identified primary interface. Mutations that disrupt either interface in solution also severely impair evoked synchronous release in neurons, suggesting that both interfaces are essential for the primed pre-fusion state. Ca2+ binding to the synaptotagmin-1 molecules unlocks the complex, allows full zippering of the SNARE complex, and triggers membrane fusion. The tripartite SNARE-complexin synaptotagmin-1 complex at a synaptic vesicle docking site has to be unlocked for triggered fusion to start, explaining the cooperation between complexin and synaptotagmin-1 in synchronizing evoked release on the sub-millisecond timescale. PMID- 28813413 TI - Polylox barcoding reveals haematopoietic stem cell fates realized in vivo. AB - Developmental deconvolution of complex organs and tissues at the level of individual cells remains challenging. Non-invasive genetic fate mapping has been widely used, but the low number of distinct fluorescent marker proteins limits its resolution. Much higher numbers of cell markers have been generated using viral integration sites, viral barcodes, and strategies based on transposons and CRISPR-Cas9 genome editing; however, temporal and tissue-specific induction of barcodes in situ has not been achieved. Here we report the development of an artificial DNA recombination locus (termed Polylox) that enables broadly applicable endogenous barcoding based on the Cre-loxP recombination system. Polylox recombination in situ reaches a practical diversity of several hundred thousand barcodes, allowing tagging of single cells. We have used this experimental system, combined with fate mapping, to assess haematopoietic stem cell (HSC) fates in vivo. Classical models of haematopoietic lineage specification assume a tree with few major branches. More recently, driven in part by the development of more efficient single-cell assays and improved transplantation efficiencies, different models have been proposed, in which unilineage priming may occur in mice and humans at the level of HSCs. We have introduced barcodes into HSC progenitors in embryonic mice, and found that the adult HSC compartment is a mosaic of embryo-derived HSC clones, some of which are unexpectedly large. Most HSC clones gave rise to multilineage or oligolineage fates, arguing against unilineage priming, and suggesting coherent usage of the potential of cells in a clone. The spreading of barcodes, both after induction in embryos and in adult mice, revealed a basic split between common myeloid erythroid development and common lymphocyte development, supporting the long-held but contested view of a tree-like haematopoietic structure. PMID- 28813414 TI - A randomized synbiotic trial to prevent sepsis among infants in rural India. AB - Sepsis in early infancy results in one million annual deaths worldwide, most of them in developing countries. No efficient means of prevention is currently available. Here we report on a randomized, double-blind, placebo-controlled trial of an oral synbiotic preparation (Lactobacillus plantarum plus fructooligosaccharide) in rural Indian newborns. We enrolled 4,556 infants that were at least 2,000 g at birth, at least 35 weeks of gestation, and with no signs of sepsis or other morbidity, and monitored them for 60 days. We show a significant reduction in the primary outcome (combination of sepsis and death) in the treatment arm (risk ratio 0.60, 95% confidence interval 0.48-0.74), with few deaths (4 placebo, 6 synbiotic). Significant reductions were also observed for culture-positive and culture-negative sepsis and lower respiratory tract infections. These findings suggest that a large proportion of neonatal sepsis in developing countries could be effectively prevented using a synbiotic containing L. plantarum ATCC-202195. PMID- 28813415 TI - CDK4/6 inhibition triggers anti-tumour immunity. AB - Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and are required for the initiation and progression of various malignancies. Pharmacological inhibitors of CDK4/6 have shown significant activity against several solid tumours. Their primary mechanism of action is thought to be the inhibition of phosphorylation of the retinoblastoma tumour suppressor, inducing G1 cell cycle arrest in tumour cells. Here we use mouse models of breast carcinoma and other solid tumours to show that selective CDK4/6 inhibitors not only induce tumour cell cycle arrest, but also promote anti-tumour immunity. We confirm this phenomenon through transcriptomic analysis of serial biopsies from a clinical trial of CDK4/6 inhibitor treatment for breast cancer. The enhanced anti-tumour immune response has two underpinnings. First, CDK4/6 inhibitors activate tumour cell expression of endogenous retroviral elements, thus increasing intracellular levels of double-stranded RNA. This in turn stimulates production of type III interferons and hence enhances tumour antigen presentation. Second, CDK4/6 inhibitors markedly suppress the proliferation of regulatory T cells. Mechanistically, the effects of CDK4/6 inhibitors both on tumour cells and on regulatory T cells are associated with reduced activity of the E2F target, DNA methyltransferase 1. Ultimately, these events promote cytotoxic T-cell-mediated clearance of tumour cells, which is further enhanced by the addition of immune checkpoint blockade. Our findings indicate that CDK4/6 inhibitors increase tumour immunogenicity and provide a rationale for new combination regimens comprising CDK4/6 inhibitors and immunotherapies as anti cancer treatment. PMID- 28813416 TI - Large turbulent reservoirs of cold molecular gas around high-redshift starburst galaxies. AB - Starburst galaxies at the peak of cosmic star formation are among the most extreme star-forming engines in the Universe, producing stars over about 100 million years (ref. 2). The star-formation rates of these galaxies, which exceed 100 solar masses per year, require large reservoirs of cold molecular gas to be delivered to their cores, despite strong feedback from stars or active galactic nuclei. Consequently, starburst galaxies are ideal for studying the interplay between this feedback and the growth of a galaxy. The methylidyne cation, CH+, is a most useful molecule for such studies because it cannot form in cold gas without suprathermal energy input, so its presence indicates dissipation of mechanical energy or strong ultraviolet irradiation. Here we report the detection of CH+ (J = 1-0) emission and absorption lines in the spectra of six lensed starburst galaxies at redshifts near 2.5. This line has such a high critical density for excitation that it is emitted only in very dense gas, and is absorbed in low-density gas. We find that the CH+ emission lines, which are broader than 1,000 kilometres per second, originate in dense shock waves powered by hot galactic winds. The CH+ absorption lines reveal highly turbulent reservoirs of cool (about 100 kelvin), low-density gas, extending far (more than 10 kiloparsecs) outside the starburst galaxies (which have radii of less than 1 kiloparsec). We show that the galactic winds sustain turbulence in the 10 kiloparsec-scale environments of the galaxies, processing these environments into multiphase, gravitationally bound reservoirs. However, the mass outflow rates are found to be insufficient to balance the star-formation rates. Another mass input is therefore required for these reservoirs, which could be provided by ongoing mergers or cold-stream accretion. Our results suggest that galactic feedback, coupled jointly to turbulence and gravity, extends the starburst phase of a galaxy instead of quenching it. PMID- 28813417 TI - CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity. AB - Cancer cells exploit the expression of the programmed death-1 (PD-1) ligand 1 (PD L1) to subvert T-cell-mediated immunosurveillance. The success of therapies that disrupt PD-L1-mediated tumour tolerance has highlighted the need to understand the molecular regulation of PD-L1 expression. Here we identify the uncharacterized protein CMTM6 as a critical regulator of PD-L1 in a broad range of cancer cells, by using a genome-wide CRISPR-Cas9 screen. CMTM6 is a ubiquitously expressed protein that binds PD-L1 and maintains its cell surface expression. CMTM6 is not required for PD-L1 maturation but co-localizes with PD L1 at the plasma membrane and in recycling endosomes, where it prevents PD-L1 from being targeted for lysosome-mediated degradation. Using a quantitative approach to profile the entire plasma membrane proteome, we find that CMTM6 displays specificity for PD-L1. Notably, CMTM6 depletion decreases PD-L1 without compromising cell surface expression of MHC class I. CMTM6 depletion, via the reduction of PD-L1, significantly alleviates the suppression of tumour-specific T cell activity in vitro and in vivo. These findings provide insights into the biology of PD-L1 regulation, identify a previously unrecognized master regulator of this critical immune checkpoint and highlight a potential therapeutic target to overcome immune evasion by tumour cells. PMID- 28813418 TI - Mechanism of intracellular allosteric beta2AR antagonist revealed by X-ray crystal structure. AB - G-protein-coupled receptors (GPCRs) pose challenges for drug discovery efforts because of the high degree of structural homology in the orthosteric pocket, particularly for GPCRs within a single subfamily, such as the nine adrenergic receptors. Allosteric ligands may bind to less-conserved regions of these receptors and therefore are more likely to be selective. Unlike orthosteric ligands, which tonically activate or inhibit signalling, allosteric ligands modulate physiologic responses to hormones and neurotransmitters, and may therefore have fewer adverse effects. The majority of GPCR crystal structures published to date were obtained with receptors bound to orthosteric antagonists, and only a few structures bound to allosteric ligands have been reported. Compound 15 (Cmpd-15) is an allosteric modulator of the beta2 adrenergic receptor (beta2AR) that was recently isolated from a DNA-encoded small-molecule library. Orthosteric beta-adrenergic receptor antagonists, known as beta-blockers, are amongst the most prescribed drugs in the world and Cmpd-15 is the first allosteric beta-blocker. Cmpd-15 exhibits negative cooperativity with agonists and positive cooperativity with inverse agonists. Here we present the structure of the beta2AR bound to a polyethylene glycol-carboxylic acid derivative (Cmpd 15PA) of this modulator. Cmpd-15PA binds to a pocket formed primarily by the cytoplasmic ends of transmembrane segments 1, 2, 6 and 7 as well as intracellular loop 1 and helix 8. A comparison of this structure with inactive- and active state structures of the beta2AR reveals the mechanism by which Cmpd-15 modulates agonist binding affinity and signalling. PMID- 28813419 TI - Vaccine-driven pharmacodynamic dissection and mitigation of fenethylline psychoactivity. AB - Fenethylline, also known by the trade name Captagon, is a synthetic psychoactive stimulant that has recently been linked to a substance-use disorder and 'pharmacoterrorism' in the Middle East. Although fenethylline shares a common phenethylamine core with other amphetamine-type stimulants, it also incorporates a covalently linked xanthine moiety into its parent structure. These independently active pharmacophores are liberated during metabolism, resulting in the release of a structurally diverse chemical mixture into the central nervous system. Although the psychoactive properties of fenethylline have been reported to differ from those of other synthetic stimulants, the in vivo chemical complexity it manifests upon ingestion has impeded efforts to unambiguously identify the specific species responsible for these effects. Here we develop a 'dissection through vaccination' approach, called DISSECTIV, to mitigate the psychoactive effects of fenethylline and show that its rapid-onset and distinct psychoactive properties are facilitated by functional synergy between theophylline and amphetamine. Our results demonstrate that incremental vaccination against a single chemical species within a multi-component mixture can be used to uncover emergent properties arising from polypharmacological activity. We anticipate that DISSECTIV will be used to expose unidentified active chemical species and resolve pharmacodynamic interactions within other chemically complex systems, such as those found in counterfeit or illegal drug preparations, post-metabolic tissue samples and natural product extracts. PMID- 28813420 TI - Biogeochemistry: Food for early animal evolution. PMID- 28813421 TI - Stromal R-spondin orchestrates gastric epithelial stem cells and gland homeostasis. AB - The constant regeneration of stomach epithelium is driven by long-lived stem cells, but the mechanism that regulates their turnover is not well understood. We have recently found that the gastric pathogen Helicobacter pylori can activate gastric stem cells and increase epithelial turnover, while Wnt signalling is known to be important for stem cell identity and epithelial regeneration in several tissues. Here we find that antral Wnt signalling, marked by the classic Wnt target gene Axin2, is limited to the base and lower isthmus of gastric glands, where the stem cells reside. Axin2 is expressed by Lgr5+ cells, as well as adjacent, highly proliferative Lgr5- cells that are able to repopulate entire glands, including the base, upon depletion of the Lgr5+ population. Expression of both Axin2 and Lgr5 requires stroma-derived R-spondin 3 produced by gastric myofibroblasts proximal to the stem cell compartment. Exogenous R-spondin administration expands and accelerates proliferation of Axin2+/Lgr5- but not Lgr5+ cells. Consistent with these observations, H. pylori infection increases stromal R-spondin 3 expression and expands the Axin2+ cell pool to cause hyperproliferation and gland hyperplasia. The ability of stromal niche cells to control and adapt epithelial stem cell dynamics constitutes a sophisticated mechanism that orchestrates epithelial regeneration and maintenance of tissue integrity. PMID- 28813422 TI - Perceived public transport infrastructure modifies the association between public transport use and mental health: Multilevel analyses from the United Kingdom. AB - AIMS: Investments to promote public transport utilisation are being championed to achieve sustainable development, but the potential co-benefits for mental health are comparatively under-researched. We hypothesised that frequent users of public transport would be more likely to have better mental health (possibly due to increased levels of physical activity), but among the more frequent users, less favourable perceptions of public transport infrastructure (PPTI) could have a negative influence on mental health. METHODS: Multilevel linear and logistic regressions were fitted on 30,214 participants in the UK Household Longitudinal Study with lagged PPTI and confounder measures at baseline and indicators of active travel and mental health (General Health Questionnaire (GHQ), SF-12 Mental Component Scale (MCS) and the Warwick Edinburgh Mental Well Being Scale (WEMWBS)) at follow-up. RESULTS: Compared to participants expressing poor PPTI, those who felt it was excellent were 1.29 (95%CI 1.15, 1.45) times more likely to be frequent users of public transport and 1.53 (95%CI 1.33, 1.76) times more likely to choose to walk or cycle journeys of less than two to three miles. Frequent use of public transport was found to be consistently associated with better mental health for GHQ caseness (OR 0.85, 95%CI 0.79, 0.91), GHQ score (coefficient 0.28, 95%CI -0.41, -0.16), MCS (coefficient 0.45, 95%CI 0.23, 0.66), and WEMWBS (coefficient 0.30, 95%CI 0.19, 0.40). Among frequent users of public transport, participants expressing poor PPTI were 1.46 (95%CI 1.11, 1.93) times more likely to report poorer mental health according to the GHQ caseness indicator, compared to frequent users that regarded PPTI as excellent. Similar results were observed for the other indicators of mental health. CONCLUSIONS: These findings indicate that while the provision of public transport infrastructure is a necessary pre condition for stimulating population increases in physical activity, PPTI improvements needs to be prioritised to leverage the full mental health-related co-benefits of active travel. PMID- 28813423 TI - Health needs and care seeking behaviours of Yazidis and other minority groups displaced by ISIS into the Kurdistan Region of Iraq. AB - BACKGROUND: During the summer of 2014, ISIS overran Nineveh governorate in Northern Iraq. Yazidis and other religious minorities were subjected to brutal attacks and forced to seek refuge into the neighbouring Kurdistan Region, where they remain living in local communities or in camps. This survey provides a population-based assessment of the health needs and care seeking behaviours of Yazidis and other groups currently residing in camps. METHODS: The survey covered 13 camps managed by the Kurdish Board of Relief and Humanitarian Affairs. A systematic random sample of 1,300 households with a total of 8,360 members were interviewed between November and December 2015. Participants were asked if any household members had needed care for a health condition in the two weeks preceding the survey, and whether care was obtained from the camp primary health care centre, an outside public hospital or a private clinic. If care was received, the out-of-pocket payment was recorded; otherwise, the reason for not seeking care was queried. RESULTS: In 33.9% (CI: 31.0-37.0) of households one or more members had needed care for a health condition in the two weeks preceding the survey. The most likely to have needed care were older persons (18.5%; CI: 13.6-24.6) and infants (18.0%; CI: 11.6-26.8). The reported health conditions revealed a complex picture of communicable and non-communicable diseases as well as mental health problems and physical injuries. Care was primarily sought from private clinics (41.8%; CI: 36.4-47.4) or public hospitals (27.3%; CI: 22.6-32.7) rather than from the camp primary health care clinics (23.6%; CI: 19.5-28.2). The mean out-of-pocket payment for care received was nearly 3 times higher in public hospitals than in the camp primary health care clinics and nearly 11 times higher in private clinics. Cost was the main perceived barrier to obtaining health services. CONCLUSION: Demand for health services was high among Yazidis and other minorities living in camps. Private services were preferred in spite of the tenuous economic circumstances of displaced households. Declines in public sector funding may further restrict access from camp clinics stressing the need for alternative access strategies. PMID- 28813424 TI - Risk factors and causative organisms in microbial keratitis in daily disposable contact lens wear. AB - PURPOSE: This study investigated independent risk factors and causative organisms in microbial keratitis in daily disposable contact lens (CL)-wearers. METHODS: A multisite prospective case-control study was undertaken. Cases were daily disposable CL-wearers attending Moorfields Eye Hospital with microbial keratitis and those reported through a one-year surveillance study in Australia and in New Zealand. A population-based telephone survey identified daily disposable CL wearing controls. Subjects completed a questionnaire describing CL-wear history, hygiene and demographics. The sample used for risk factor analysis was weighted in proportion to the CL-wearing population at each location. Corneal scrape results were accessed. Independent risk factors were determined using multiple binary logistic regression. Causative organisms in different CL-wear modalities were compared using a chi-squared test. RESULTS: 963 daily disposable CL-wearers were identified, from which 67 cases and 374 controls were sampled. Independent risk factors were; wearing CLs every day compared with less frequent use (OR 10.4x; 95% CI 2.9-56.4), any overnight wear (OR 1.8x; 95% CI 1.6-2.1), less frequent hand washing (OR 1.8x; 95% CI 1.6-2.0), and smoking (OR 1.3x; 95% CI 1.1 1.6). Certain daily disposable CLs (OR 0.2x; 95% CI 0.1-0.2) had protective effects. Environmental organisms were less frequently recovered with daily disposable CLs (20%), compared with other modalities (36%; p<0.02). CONCLUSION: Overnight wear, increased exposure in daily wear, smoking and poor hand hygiene are significant risk factors for microbial keratitis with daily disposable CLs. Risk varied with daily disposable CL type. The profile of causative organisms is consistent with less severe disease. PMID- 28813425 TI - Effectiveness of two distinct web-based education tools for bedside nurses on medication administration practice for venous thromboembolism prevention: A randomized clinical trial. AB - BACKGROUND: Venous thromboembolism (VTE) is a common cause of preventable harm in hospitalized patients. While numerous successful interventions have been implemented to improve prescription of VTE prophylaxis, a substantial proportion of doses of prescribed preventive medications are not administered to hospitalized patients. The purpose of this trial was to evaluate the effectiveness of nurse education on medication administration practice. METHODS: This was a double-blinded, cluster randomized trial in 21 medical or surgical floors of 933 nurses at The Johns Hopkins Hospital, an academic medical center, from April 1, 2014 -March 31, 2015. Nurses were cluster-randomized by hospital floor to receive either a linear static education (Static) module with voiceover or an interactive learner-centric dynamic scenario-based education (Dynamic) module. The primary and secondary outcomes were non-administration of prescribed VTE prophylaxis medication and nurse-reported satisfaction with education modules, respectively. RESULTS: Overall, non-administration improved significantly following education (12.4% vs. 11.1%, conditional OR: 0.87, 95% CI: 0.80-0.95, p = 0.002) achieving our primary objective. The reduction in non administration was greater for those randomized to the Dynamic arm (10.8% vs. 9.2%, conditional OR: 0.83, 95% CI: 0.72-0.95) versus the Static arm (14.5% vs. 13.5%, conditional OR: 0.92, 95% CI: 0.81-1.03), although the difference between arms was not statistically significant (p = 0.26). Satisfaction scores were significantly higher (p<0.05) for all survey items for nurses in the Dynamic arm. CONCLUSIONS: Education for nurses significantly improves medication administration practice. Dynamic learner-centered education is more effective at engaging nurses. These findings suggest that education should be tailored to the learner. TRIAL REGISTRATION: ClinicalTrials.gov NCT02301793. PMID- 28813426 TI - Sexual reproduction in plagiogrammacean diatoms: First insights into the early pennates. AB - The genera Plagiogramma and Dimeregramma are members of a small, but evolutionarily important group of diatoms, the "basal" araphids. They are sister to all other pennates, both araphid and raphid taxa. Thus, their phylogenetic position carries the potential for providing insights into the earliest pennates. We documented sexual reproduction, mating system and sex cell development in the first members of the "basal" araphid clade ever investigated. The mating system in all these species involved heterothally. It was, however, more complex in P. tsawwassen, where in addition to heterothallic clones, intraclonal and polysexual clones also exist. Auxospore development and wall structure was similar in all three species and demonstrated several characters also reported from "core" araphids. Of these, vigorous, pseudopodial motility of male secondary spermatocytes and gametes was most notable because it indicates that this character was likely present in the last common ancestor of all the pennates. Pseudopodial motility of the male sex cells might have afforded sufficient compensation and/or benefits to the emerging pennates for replacing flagellated sperm, present in centrics. The characters thus far uniquely present among our plagiogrammaceans but not reported from other pennates were: the "gametic" fusion between sex-compatible secondary spermatocytes, in some cases before completion of Meiosis II in males, transverse perizonial bands produced all together or in quick succession rather than being added to the auxospore apex one at a time, and expanding auxospores with 3-4 nuclei. An initial epivalve, similar in morphology to what in some diatoms had been interpreted as a "longitudinal" perizonium, may be more widespread among pennates than thus far appreciated. In addition, we discovered two species new to science (D. acutumontgo, P. tsawwassen), and refined delineation of P. staurophorum by including metric data from the original material. PMID- 28813427 TI - Electromagneto squeezing rotational flow of Carbon (C)-Water (H2O) kerosene oil nanofluid past a Riga plate: A numerical study. AB - This article predicts the electromagneto squeezing rotational flow of carbon water nanofluid between two stretchable Riga plates. Riga plate is known as electromagnetic actuator which is the combination of permanent magnets and a span wise aligned array of alternating electrodes mounted on a plane surface. Mathematical model is developed for the flow problem with the phenomena of melting heat transfer, viscous dissipation and heat generation/absorption. Water and kerosene oil are utilized as the base fluids whereas single and multi-wall carbon nanotubes as the nanomaterials. Numerical solutions of the dimensionless problems are constructed by using built in shooting method. The correlation expressions for Nusselt number and skin friction coefficient are developed and examined through numerical data. Characteristics of numerous relevant parameters on the dimensionless temperature and velocity are sketched and discussed. Horizontal velocity is found to enhance for higher modified Hartman number. PMID- 28813428 TI - Soil features in rookeries of Antarctic penguins reveal sea to land biotransport of chemical pollutants. AB - The main soil physical-chemical features, the concentrations of a set of pollutants, and the soil microbiota linked to penguin rookeries have been studied in 10 selected sites located at the South Shetland Islands and the Antarctic Peninsula (Maritime Antarctica). This study aims to test the hypothesis that biotransport by penguins increases the concentration of pollutants, especially heavy metals, in Antarctic soils, and alters its microbiota. Our results show that penguins do transport certain chemical elements and thus cause accumulation in land areas through their excreta. Overall, a higher penguin activity is associated with higher organic carbon content and with higher concentrations of certain pollutants in soils, especially cadmium, cooper and arsenic, as well as zinc and selenium. In contrast, in soils that are less affected by penguins' faecal depositions, the concentrations of elements of geochemical origin, such as iron and cobalt, increase their relative weighted contribution, whereas the above mentioned pollutants maintain very low levels. The concentrations of pollutants are far higher in those penguin rookeries that are more exposed to ship traffic. In addition, the soil microbiota of penguin-influenced soils was studied by molecular methods. Heavily penguin-affected soils have a massive presence of enteric bacteria, whose relative dominance can be taken as an indicator of penguin influence. Faecal bacteria are present in addition to typical soil taxa, the former becoming dominant in the microbiota of penguin-affected soils, whereas typical soil bacteria, such as Actinomycetales, co-dominate the microbiota of less affected soils. Results indicate that the continuous supply by penguin faeces, and not the selectivity by increased pollutant concentrations is the main factor shaping the soil bacterial community. Overall, massive penguin influence results in increased concentrations of certain pollutants and in a strong change in taxa dominance in the soil bacterial community. PMID- 28813429 TI - The impact of tree age on biomass growth and carbon accumulation capacity: A retrospective analysis using tree ring data of three tropical tree species grown in natural forests of Suriname. AB - The world's forests play a pivotal role in the mitigation of global climate change. By photosynthesis they remove CO2 from the atmosphere and store carbon in their biomass. While old trees are generally acknowledged for a long carbon residence time, there is no consensus on their contribution to carbon accumulation due to a lack of long-term individual tree data. Tree ring analyses, which use anatomical differences in the annual formation of wood for dating growth zones, are a retrospective approach that provides growth patterns of individual trees over their entire lifetime. We developed time series of diameter growth and related annual carbon accumulation for 61 trees of the species Cedrela odorata L. (Meliacea), Hymenaea courbaril L. (Fabacea) and Goupia glabra Aubl. (Goupiacea). The trees grew in unmanaged tropical wet-forests of Suriname and reached ages from 84 to 255 years. Most of the trees show positive trends of diameter growth and carbon accumulation over time. For some trees we observed fluctuating growth-periods of lower growth alternate with periods of increased growth. In the last quarter of their lifetime trees accumulate on average between 39 percent (C. odorata) and 50 percent (G. glabra) of their final carbon stock. This suggests that old-growth trees in tropical forests do not only contribute to carbon stocks by long carbon resistance times, but maintain high rates of carbon accumulation at later stages of their life time. PMID- 28813430 TI - Reprogramming human gallbladder cells into insulin-producing beta-like cells. AB - The gallbladder and cystic duct (GBCs) are parts of the extrahepatic biliary tree and share a common developmental origin with the ventral pancreas. Here, we report on the very first genetic reprogramming of patient-derived human GBCs to beta-like cells for potential autologous cell replacement therapy for type 1 diabetes. We developed a robust method for large-scale expansion of human GBCs ex vivo. GBCs were reprogrammed into insulin-producing pancreatic beta-like cells by a combined adenoviral-mediated expression of hallmark pancreatic endocrine transcription factors PDX1, MAFA, NEUROG3, and PAX6 and differentiation culture in vitro. The reprogrammed GBCs (rGBCs) strongly induced the production of insulin and pancreatic endocrine genes and these responded to glucose stimulation in vitro. rGBCs also expressed an islet-specific surface marker, which was used to enrich for the most highly reprogrammed cells. More importantly, global mRNA and microRNA expression profiles and protein immunostaining indicated that rGBCs adopted an overall beta-like state and these rGBCs engrafted in immunodeficient mice. Furthermore, comparative global expression analyses identified putative regulators of human biliary to beta cell fate conversion. In summary, we have developed, for the first time, a reliable and robust genetic reprogramming and culture expansion of primary human GBCs-derived from multiple unrelated donors into pancreatic beta-like cells ex vivo, thus showing that human gallbladder is a potentially rich source of reprogrammable cells for autologous cell therapy in diabetes. PMID- 28813431 TI - Skeleton of an unusual, cat-sized marsupial relative (Metatheria: Marsupialiformes) from the middle Eocene (Lutetian: 44-43 million years ago) of Turkey. AB - We describe a near-complete, three-dimensionally preserved skeleton of a metatherian (relative of modern marsupials) from the middle Eocene (Lutetian: 44 43 million years ago) Luluk member of the Uzuncarsidere Formation, central Turkey. With an estimated body mass of 3-4 kg, about the size of a domestic cat (Felis catus) or spotted quoll (Dasyurus maculatus), it is an order of magnitude larger than the largest fossil metatherians previously known from the Cenozoic of the northern hemisphere. This new taxon is characterised by large, broad third premolars that probably represent adaptations for hard object feeding (durophagy), and its craniodental morphology suggests the capacity to generate high bite forces. Qualitative and quantitative functional analyses of its postcranial skeleton indicate that it was probably scansorial and relatively agile, perhaps broadly similar in locomotor mode to the spotted quoll, but with a greater capacity for climbing and grasping. Bayesian phylogenetic analysis of a total evidence dataset comprising 259 morphological characters and 9kb of DNA sequence data from five nuclear protein-coding genes, using both undated and "tip and-node dating" approaches, place the new taxon outside the marsupial crown clade, but within the clade Marsupialiformes. It demonstrates that at least one metatherian lineage evolved to occupy the small-medium, meso- or hypo-carnivore niche in the northern hemisphere during the early Cenozoic, at a time when there were numerous eutherians (placentals and their fossil relatives) filling similar niches. However, the known mammal fauna from Uzuncarsidere Formation appears highly endemic, and geological evidence suggests that this region of Turkey was an island for at least part of the early Cenozoic, and so the new taxon may have evolved in isolation from potential eutherian competitors. Nevertheless, the new taxon reveals previously unsuspected ecomorphological disparity among northern hemisphere metatherians during the first half of the Cenozoic. PMID- 28813432 TI - Basic reversal-learning capacity in flies suggests rudiments of complex cognition. AB - The most basic models of learning are reinforcement learning models (for instance, classical and operant conditioning) that posit a constant learning rate; however many animals change their learning rates with experience. This process is sometimes studied by reversing an existing association between cues and rewards, and measuring the rate of relearning. Augmented reversal-learning, where learning rates increase with practice, can be an important component of behavioral flexibility; and may provide insight into higher cognition. Previous studies of reversal-learning in Drosophila have not measured learning rates, but have tended to focus on measuring gross deficits in reversal-learning, as the ratio of two timepoints. These studies have uncovered a diversity of mechanisms underlying reversal-learning, but natural genetic variation in this trait has yet to be assessed. We conducted a reversal-learning regime on a diverse panel of Drosophila melanogaster genotypes. We found highly significant genetic variation in their baseline ability to learn. We also found that they have a consistent, and strong (1.3*), increase in their learning speed with reversal. We found no evidence, however, that there was genetic variation in their ability to increase their learning rates with experience. This may suggest that Drosophila have a hitherto unrecognized ability to integrate acquired information, and improve their decision making; but that their mechanisms for doing so are under strong constraints. PMID- 28813433 TI - Diabetes risks and outcomes in chronic obstructive pulmonary disease patients: Two nationwide population-based retrospective cohort studies. AB - OBJECTIVE: The relationship between chronic obstructive pulmonary disease (COPD) and diabetes remains incompletely understood. This study evaluated diabetes risk and post-diabetes outcomes in COPD patients with and without exacerbations. METHODS: We identified 4671 adults newly diagnosed with COPD exacerbations and 9342 adults newly diagnosed with COPD without exacerbations during 2000-2008 using Taiwan's National Health Insurance Research Database. A comparison cohort of 18684 adults without COPD, matched by age and sex, was randomly selected from the same dataset for the control group. Diabetes events during 2000-2013 were ascertained from medical claims during the follow-up period. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of diabetes associated with COPD with or without exacerbations were calculated. We conducted another nested cohort study of 395516 patients with diabetes hospitalization during 2002-2013 and calculated adjusted odds ratios (ORs) and 95% CIs of histories of COPD and COPD exacerbations associated with adverse events after diabetes admission. RESULTS: During the follow-up period, the incidences of diabetes for patients without COPD and for patients with COPD without or with exacerbations were 3.4, 4.1 and 7.4 per 1000 person-years, respectively (P < 0.0001). Increased risk of diabetes for patients with COPD without exacerbations (HR 1.09, 95% CI 1.02-1.17) and COPD with exacerbations (HR 2.18, 95% CI 1.88-2.52) was noted. Post-diabetes pneumonia (OR 3.28, 95% CI 3.13-3.43), intensive care admission (OR 1.32, 95% CI 1.26-1.39) and mortality (OR 2.06, 95% CI 1.88-2.25) were associated with COPD exacerbations. CONCLUSION: Prevention and intervention strategies for diabetes and post-diabetes outcomes are needed for this susceptible population. PMID- 28813434 TI - Detection of anti-HspX antibodies and HspX protein in patient sera for the identification of recent latent infection by Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis is a pathogen causing tuberculosis (TB) a spectrum of disease including acute and asymptomatic latent stages. Identifying and treating latently-infected patients constitutes one of the most important impediments to TB control efforts. Those individuals can remain undiagnosed for decades serving as potential reservoirs for disease reactivation. Tests for the accurate diagnosis of latent infection currently are unavailable. HspX protein (alpha crystallin), encoded by Rv2031c gene, is produced in vitro by M. tuberculosis during stationary growth phase and hypoxic or acidic culture conditions. In this study, using standard, and Luminex xMAP(r) bead capture ELISA, respectively, we report on detection of anti-HspX IgG and IgM antibodies and HspX protein in sera from acute and latent TB patients. For the antibody screen, levels of IgG and IgM antibodies were similar between non-infected and active TB patients; however, individuals classified into the group with latent TB showed higher values of anti HspX IgM (p = 0.003) compared to active TB patients. Using the bead capture antigen detection assay, HspX protein was detected in sera from 56.5% of putative latent cases (p< 0.050) compared to the background median with an average of 9,900 pg/ml and a range of 1,000 to 36,000 pg/ml. Thus, presence of anti-HspX IgM antibodies and HspX protein in sera may be markers of latent TB. PMID- 28813435 TI - Chronic imaging through "transparent skull" in mice. AB - Growing interest in long-term visualization of cortical structure and function requires methods that allow observation of an intact cortex in longitudinal imaging studies. Here we describe a detailed protocol for the "transparent skull" (TS) preparation based on skull clearing with cyanoacrylate, which is applicable for long-term imaging through the intact skull in mice. We characterized the properties of the TS in imaging of intrinsic optical signals and compared them with the more conventional cranial window preparation. Our results show that TS is less invasive, maintains stabile transparency for at least two months, and compares favorably to data obtained from the conventional cranial window. We applied this method to experiments showing that a four-week treatment with the antidepressant fluoxetine combined with one week of monocular deprivation induced a shift in ocular dominance in the mouse visual cortex, confirming that fluoxetine treatment restores critical-period-like plasticity. Our results demonstrate that the TS preparation could become a useful method for long-term visualization of the living mouse brain. PMID- 28813436 TI - Enhancement of the production of L-glutaminase, an anticancer enzyme, from Aeromonas veronii by adaptive and induced mutation techniques. AB - Microbial anti-cancer enzymes have been proven to be effective and economical agents for cancer treatment. Aeromonas veronii has been identified as a microorganism with the potential to produce L-glutaminase, an anticancer agent effective against acute lymphocytic leukaemia. In this study, a selective medium of Aeromonas veronii was used to culture the microorganism. Strain improvement was done by adaptive and induced mutational techniques. A selective minimal agar media was incorporated for the growth of the strain which further supports adaptive mutation. Strains were also UV-irradiated and successively treated with N-methyl-N'-nitro-N-nitrosoguanidine to find a resilient strain capable of producing L-glutaminase efficiently. The Plackett-Burman design and central composite designs were used to screen and optimize additional carbon and nitrogen sources. Adaptive mutation resulted in promising yield improvements compared to native strain (P<0.001). The mean yield of 30 treated colonies from the induced mutation was significantly increased compared to the non-induced strain (P< 0.001). The economically feasible statistical designs were found to reinforce each other in order to maximize the yield of the enzyme. The interactions of nutrient factors were understood from the 3D response surface plots. The model was found to be a perfect fit in terms of maximizing enzyme yield, with the productivity improving at every stage to a fourfold output of enzyme (591.11 +/ 7.97 IU/mL) compared to the native strain (135+/-3.51 IU/mL). PMID- 28813437 TI - A systematic review of the relationship between internet use, self-harm and suicidal behaviour in young people: The good, the bad and the unknown. AB - BACKGROUND: Research exploring internet use and self-harm is rapidly expanding amidst concerns regarding influences of on-line activities on self-harm and suicide, especially in young people. We aimed to systematically review evidence regarding the potential influence of the internet on self-harm/suicidal behaviour in young people. METHODS: We conducted a systematic review based on an electronic search for articles published between 01/01/2011 and 26/01/2015 across databases including Medline, Cochrane and PsychInfo. Articles were included if: the study examined internet use by individuals who engaged in self-harm/ suicidal behaviour, or internet use clearly related to self-harm content; reported primary empirical data; participants were aged under 25 years. New studies were combined with those identified in a previous review and subject to data extraction, quality rating and narrative synthesis. RESULTS: Forty-six independent studies (51 articles) of varying quality were included. Perceived influences were: positive for 11 studies (38191 participants); negative for 18 studies (119524 participants); and mixed for 17 studies (35235 participants). In contrast to previous reviews on this topic studies focused on a wide range of internet mediums: general internet use; internet addiction; online intervention/treatment; social media; dedicated self-harm websites; forums; video/image sharing and blogs. A relationship between internet use and self-harm/suicidal behaviour was particularly associated with internet addiction, high levels of internet use, and websites with self-harm or suicide content. While there are negative aspects of internet use the potential for isolation reduction, outreach and as a source of help and therapy were also identified. CONCLUSIONS: There is significant potential for harm from online behaviour (normalisation, triggering, competition, contagion) but also the potential to exploit its benefits (crisis support, reduction of social isolation, delivery of therapy, outreach). Young people appear to be increasingly using social media to communicate distress, particularly to peers. The focus should now be on how specific mediums' (social media, video/image sharing) might be used in therapy and recovery. Clinicians working with young people who self-harm or have mental health issues should engage in discussion about internet use. This should be a standard item during assessment. A protocol for this review was registered with the PROSPERO systematic review protocol registry: (http://www.crd.york.ac.uk/prospero/display_record.asp?ID=CRD42015019518). PMID- 28813438 TI - Heritability Estimation using a Regularized Regression Approach (HERRA): Applicable to continuous, dichotomous or age-at-onset outcome. AB - The popular Genome-wide Complex Trait Analysis (GCTA) software uses the random effects models for estimating the narrow-sense heritability based on GWAS data of unrelated individuals without knowing and identifying the causal loci. Many methods have since extended this approach to various situations. However, since the proportion of causal loci among the variants is typically very small and GCTA uses all variants to calculate the similarities among individuals, the estimation of heritability may be unstable, resulting in a large variance of the estimates. Moreover, if the causal SNPs are not genotyped, GCTA sometimes greatly underestimates the true heritability. We present a novel narrow-sense heritability estimator, named HERRA, using well-developed ultra-high dimensional machine-learning methods, applicable to continuous or dichotomous outcomes, as other existing methods. Additionally, HERRA is applicable to time-to-event or age at-onset outcome, which, to our knowledge, no existing method can handle. Compared to GCTA and LDAK for continuous and binary outcomes, HERRA often has a smaller variance, and when causal SNPs are not genotyped, HERRA has a much smaller empirical bias. We applied GCTA, LDAK and HERRA to a large colorectal cancer dataset using dichotomous outcome (4,312 cases, 4,356 controls, genotyped using Illumina 300K), the respective heritability estimates of GCTA, LDAK and HERRA are 0.068 (SE = 0.017), 0.072 (SE = 0.021) and 0.110 (SE = 5.19 x 10-3). HERRA yields over 50% increase in heritability estimate compared to GCTA or LDAK. PMID- 28813439 TI - Comparative ecophysiology of a critically endangered (CR) ectotherm: Implications for conservation management. AB - Captive breeding is a vital conservation tool for many endangered species programs. It is often a last resort when wild animal population numbers drop to below critical minimums for natural reproduction. However, critical ecophysiological information of wild counterparts may not be well documented or understood, leading to years of minimal breeding successes. We collected endocrine and associated ecological data on a critically endangered ectotherm concurrently in the wild and in captivity over several years. We tracked plasma concentrations of steroid stress and reproductive hormones, body condition, activity, and environmental parameters in three populations (one wild and two geographically distinct captive) of ploughshare tortoise (Astrochelys yniphora). Hormone profiles along with environmental and behavioral data are presented and compared. We show that animals have particular seasonal environmental requirements that can affect annual reproduction, captivity affects reproductive state, and sociality may be required at certain times of the year for breeding to be successful. Our data suggest that changes in climatic conditions experienced by individuals, either due to decades-long shifts or hemispheric differences when translocated from their native range, can stifle breeding success for several years while the animals physiologically acclimatize. We also found that captivity affects stress (plasma corticosterone) and body condition of adults and juveniles differently and seasonally. Our results indicate that phenotypic plasticity in reproduction and behavior is related to environmental cues in long-lived ectotherms, and detailed ecophysiological data should be used when establishing and improving captive husbandry conditions for conservation breeding programs. Further, considering the recent revelation of this tortoises' possible extirpation from the wild, these data are critically opportune and may be key to the survival of this species. PMID- 28813440 TI - Invasive Australian Acacia seed banks: Size and relationship with stem diameter in the presence of gall-forming biological control agents. AB - Australian Acacia are invasive in many parts of the world. Despite significant mechanical and biological efforts to control their invasion and spread, soil stored seed banks prevent their effective and sustained removal. In response South Africa has had a strong focus on employing seed reducing biological control agents to deal with Australian Acacia invasion, a programme that is considered as being successful. To provide a predictive understanding for their management, seed banks of four invasive Australian acacia species (Acacia longifolia, A. mearnsii, A. pycnantha and A. saligna) were studied in the Western Cape of South Africa. Across six to seven sites for each species, seed bank sizes were estimated from dense, monospecific stands by collecting 30 litter and soil samples. Average estimated seed bank size was large (1017 to 17261 seed m-2) as was annual input into the seed bank, suggesting that these seed banks are not residual but are replenished in size annually. A clear relationship between seed bank size and stem diameter was established indicating that mechanical clearing should be conducted shortly after fire-stimulated recruitment events or within old populations when seed banks are small. In dense, monospecific stands seed feeding biological control agents are not effective in reducing seed bank size. PMID- 28813441 TI - Cross-over endocytosis of claudins is mediated by interactions via their extracellular loops. AB - Claudins (Cldns) are transmembrane tight junction (TJ) proteins that paracellularly seal endo- and epithelial barriers by their interactions within the TJs. However, the mechanisms allowing TJ remodeling while maintaining barrier integrity are largely unknown. Cldns and occludin are heterophilically and homophilically cross-over endocytosed into neighboring cells in large, double membrane vesicles. Super-resolution microscopy confirmed the presence of Cldns in these vesicles and revealed a distinct separation of Cldns derived from opposing cells within cross-over endocytosed vesicles. Colocalization of cross-over endocytosed Cldn with the autophagosome markers as well as inhibition of autophagosome biogenesis verified involvement of the autophagosomal pathway. Accordingly, cross-over endocytosed Cldns underwent lysosomal degradation as indicated by lysosome markers. Cross-over endocytosis of Cldn5 depended on clathrin and caveolin pathways but not on dynamin. Cross-over endocytosis also depended on Cldn-Cldn-interactions. Amino acid substitutions in the second extracellular loop of Cldn5 (F147A, Q156E) caused impaired cis- and trans interaction, as well as diminished cross-over endocytosis. Moreover, F147A exhibited an increased mobility in the membrane, while Q156E was not as mobile but enhanced the paracellular permeability. In conclusion, the endocytosis of TJ proteins depends on their ability to interact strongly with each other in cis and trans, and the mobility of Cldns in the membrane is not necessarily an indicator of barrier permeability. TJ-remodeling via cross-over endocytosis represents a general mechanism for the degradation of transmembrane proteins in cell-cell contacts and directly links junctional membrane turnover to autophagy. PMID- 28813442 TI - A parallel metaheuristic for large mixed-integer dynamic optimization problems, with applications in computational biology. AB - BACKGROUND: We consider a general class of global optimization problems dealing with nonlinear dynamic models. Although this class is relevant to many areas of science and engineering, here we are interested in applying this framework to the reverse engineering problem in computational systems biology, which yields very large mixed-integer dynamic optimization (MIDO) problems. In particular, we consider the framework of logic-based ordinary differential equations (ODEs). METHODS: We present saCeSS2, a parallel method for the solution of this class of problems. This method is based on an parallel cooperative scatter search metaheuristic, with new mechanisms of self-adaptation and specific extensions to handle large mixed-integer problems. We have paid special attention to the avoidance of convergence stagnation using adaptive cooperation strategies tailored to this class of problems. RESULTS: We illustrate its performance with a set of three very challenging case studies from the domain of dynamic modelling of cell signaling. The simpler case study considers a synthetic signaling pathway and has 84 continuous and 34 binary decision variables. A second case study considers the dynamic modeling of signaling in liver cancer using high-throughput data, and has 135 continuous and 109 binaries decision variables. The third case study is an extremely difficult problem related with breast cancer, involving 690 continuous and 138 binary decision variables. We report computational results obtained in different infrastructures, including a local cluster, a large supercomputer and a public cloud platform. Interestingly, the results show how the cooperation of individual parallel searches modifies the systemic properties of the sequential algorithm, achieving superlinear speedups compared to an individual search (e.g. speedups of 15 with 10 cores), and significantly improving (above a 60%) the performance with respect to a non-cooperative parallel scheme. The scalability of the method is also good (tests were performed using up to 300 cores). CONCLUSIONS: These results demonstrate that saCeSS2 can be used to successfully reverse engineer large dynamic models of complex biological pathways. Further, these results open up new possibilities for other MIDO-based large-scale applications in the life sciences such as metabolic engineering, synthetic biology, drug scheduling. PMID- 28813443 TI - Monitoring of Schmallenberg virus in Spanish wild artiodactyls, 2006-2015. AB - Schmallenberg disease is an emerging disease that affects domestic and wild ruminants in Europe. An epidemiological survey was carried out to assess exposure to Schmallenberg virus (SBV) in wild artiodactyls in Spain between 2006 and 2015. A total of 1751 sera from wild artiodactyls, including 1066 red deer, 304 fallow deer, 192 mouflon, 109 wild boar, 49 roe deer and 31 Spanish ibex were tested for antibodies against SBV by ELISA and confirmed by virus neutralization test. SBV was not detected between the 2006/2007 and the 2010/2011 hunting seasons. Overall seroprevalence (including samples collected between the 2011/2012 and 2014/2015 hunting seasons) was 14.6% (160/1099; 95%CI: 12.7-16.6). Mean SBV seroprevalence was 13.3+/-2.6% in red deer, 23.9+/-4.2% in fallow deer, 16.4+/-6.1% in mouflon and 2.8+/-3.1% in wild boar. No antibodies against SBV were found in roe deer or Spanish ibex. The presence of SBV RNA was confirmed in three of 255 (1.2%) spleen samples from wild ruminants analysed by rRT-PCR. In a multivariate mixed-effects logistic regression model, the main risk factors associated with SBV seroprevalence were: species (fallow deer, red deer and mouflon), age (adults) and interactions between hunting areas of more than 1000 hectares and hunting season (2012/2013, 2013/2014 and 2014/2015). The hypothesis of endemic circulation of SBV in the last few years is supported by the detection of SBV RNA in animals sampled in 2011 and 2015, as well as antibodies detected at low level in juveniles in 2012, 2013 and 2014. The results indicate that SBV circulated in wild ruminant populations in Spain during the same period when the virus was first reported in northern Europe, and at least five months before the first case was officially reported in livestock in Spain. PMID- 28813444 TI - Effect of a brief intervention for alcohol and illicit drug use on trauma recidivism in a cohort of trauma patients. AB - OBJECTIVE: Estimate the effectiveness of brief interventions in reducing trauma recidivism in hospitalized trauma patients who screened positive for alcohol and/or illicit drug use. METHODS: Dynamic cohort study based on registry data from 1818 patients included in a screening and brief intervention program for alcohol and illicit drug use for hospitalized trauma patients. Three subcohorts emerged from the data analysis: patients who screened negative, those who screened positive and were offered brief intervention, and those who screened positive and were not offered brief intervention. Follow-up lasted from 10 to 52 months. Trauma-free survival, adjusted hazard rate ratios (aHRR) and adjusted incidence rate ratios (aIRR) were calculated, and complier average causal effect (CACE) analysis was used. RESULTS: We found a higher cumulative risk of trauma recidivism in the subcohort who screened positive. In this subcohort, an aHRR of 0.63 (95% CI: 0.41-0.95) was obtained for the group offered brief intervention compared to the group not offered intervention. CACE analysis yielded an estimated 52% reduction in trauma recidivism associated with the brief intervention. CONCLUSION: The brief intervention offered during hospitalization in trauma patients positive for alcohol and/or illicit drug use can halve the incidence of trauma recidivism. PMID- 28813445 TI - Transition of the intestinal microbiota of cats with age. AB - The transition of intestinal microbiota with age has been well described in humans. However, the age-related changes in intestinal microbiota of cats have not been well studied. In the present study, we investigated the composition of intestinal microbiota of cats in 5 different age groups (pre-weanling, weanling, young, aged, senile) with a culture-based method. For lactobacilli and bifidobacteria, we also quantified with molecular-based method, real-time PCR. The results suggested that the composition of the feline intestinal microbiota changes with age, while the changes were different from those of humans and dogs. Bifidobacteria which are predominant in human intestine or lactobacilli which are predominant in dog intestine, did not appear to be important in cat intestines. Enterococci, instead, seem to be major lactic acid producing bacteria in cats. We also identified lactobacilli and bifidobacteria at the species level based on 16S rRNA gene sequences and found that the species composition of Lactobacillus also changed with age. PMID- 28813446 TI - Variable stretch reduces the pro-inflammatory response of alveolar epithelial cells. AB - Mechanical ventilation has the potential to increase inflammation in both healthy and injured lungs. Several animal studies have shown that variable ventilation recruits the lungs and reduces inflammation. However, it is unclear which cellular mechanisms are involved in those findings. We hypothesized that variable stretch of LPS-stimulated alveolar epithelial cells (AECs) reduces the production of pro-inflammatory cytokines compared to non-variable stretch. AECs were subjected to non-variable or variable cyclic stretch (sinusoidal pattern), with and without LPS stimulation. The expression and release of interleukin-6, CXCL-2 and CCL-2 mRNA were analyzed after 4 hours. The phosphorylation of the MAPKs ERK1/2 and SAPK/JNK was determined by Western Blot analysis at 0, 15, 30, 45 and 60 min of cyclic stretch. In LPS-stimulated AECs, variable cyclic cell stretching led to reduced cytokine expression and release compared to non-variable cell stretching. Furthermore, the phosphorylation of the MAPK ERK1/2 was increased after 30 minutes in non-variable stretched AECs, whereas variable stretched cells demonstrated only the non-stretched level of phosphorylation. After the 4h period of cyclic cell stretch and inhibition of the ERK1/2, but not the SAPK/JNK, signaling pathway, the gene expression of investigated cytokines increased in variable stretched, and decreased in non-variable stretched AECs. We conclude that in LPS-stimulated AECs, variable stretch reduced the pro-inflammatory response compared to non-variable stretch. This effect was mediated by the ERK1/2 signaling pathway, and might partly explain the findings of reduced lung inflammation during mechanical ventilation modes that enhance breath-by-breath variability of the respiratory pattern. PMID- 28813448 TI - A prospective comparative assessment of the accuracy of the FibroScan in evaluating liver steatosis. AB - BACKGROUND/AIMS: Recent studies have demonstrated the utility of the FibroScan(r) device in diagnosing liver steatosis, but its usefulness has not been thoroughly appraised. We investigated the usefulness of the controlled attenuation parameter (CAP) in detecting and quantifying liver steatosis. METHODS: A prospective analysis was applied to 79 chronic liver disease patients who underwent a liver biopsy, a FibroScan investigation, ultrasonography, and hepatic steatosis index (HSI). The presence and degree of steatosis as measured by the FibroScan device, ultrasonography and HSI were compared with the results for the liver biopsy tissue. RESULTS: There was substantial concordance between the liver biopsy results and the CAP as evaluated by the kappa (kappa) index test for detecting liver steatosis (kappaCAP = 0.77, P<0.001; kappaultrasonography = 0.60, P<0.001; kappaHSI = 0.47, P<0.001). The areas under the receiver operating characteristic curve (AUROCs) of the CAP, ultrasonography, and HSI were 0.899 [95% confidence interval (CI) = 0.826-0.972)], 0.859 (95% CI = 0.779-0.939), and 0.766 (95% CI = 0.655-0.877), respectively. The optimal CAP cutoff value for differentiating between normal and hepatic steatosis was 247 dB/m, which produced sensitivity and specificity values of 91.9% and 85.7%, respectively, as well as a positive predictive value of 85.0% and a negative predictive value of 92.3%. CONCLUSION: The CAP produces results that are highly concordant with those of a liver biopsy in detecting steatosis. Therefore, the CAP is a noninvasive and reliable tool for evaluating liver steatosis, even in the early stages. PMID- 28813447 TI - The use of high-throughput small RNA sequencing reveals differentially expressed microRNAs in response to aster yellows phytoplasma-infection in Vitis vinifera cv. 'Chardonnay'. AB - Phytoplasmas are cell wall-less plant pathogenic bacteria responsible for major crop losses throughout the world. In grapevine they cause grapevine yellows, a detrimental disease associated with a variety of symptoms. The high economic impact of this disease has sparked considerable interest among researchers to understand molecular mechanisms related to pathogenesis. Increasing evidence exist that a class of small non-coding endogenous RNAs, known as microRNAs (miRNAs), play an important role in post-transcriptional gene regulation during plant development and responses to biotic and abiotic stresses. Thus, we aimed to dissect complex high-throughput small RNA sequencing data for the genome-wide identification of known and novel differentially expressed miRNAs, using read libraries constructed from healthy and phytoplasma-infected Chardonnay leaf material. Furthermore, we utilised computational resources to predict putative miRNA targets to explore the involvement of possible pathogen response pathways. We identified multiple known miRNA sequence variants (isomiRs), likely generated through post-transcriptional modifications. Sequences of 13 known, canonical miRNAs were shown to be differentially expressed. A total of 175 novel miRNA precursor sequences, each derived from a unique genomic location, were predicted, of which 23 were differentially expressed. A homology search revealed that some of these novel miRNAs shared high sequence similarity with conserved miRNAs from other plant species, as well as known grapevine miRNAs. The relative expression of randomly selected known and novel miRNAs was determined with real-time RT-qPCR analysis, thereby validating the trend of expression seen in the normalised small RNA sequencing read count data. Among the putative miRNA targets, we identified genes involved in plant morphology, hormone signalling, nutrient homeostasis, as well as plant stress. Our results may assist in understanding the role that miRNA pathways play during plant pathogenesis, and may be crucial in understanding disease symptom development in aster yellows phytoplasma-infected grapevines. PMID- 28813449 TI - Influenza virus infections among patients attending emergency department according to main reason to presenting to ED: A 3-year prospective observational study during seasonal epidemic periods. AB - OBJECTIVE: The role of influenza virus in patients presenting at ED during seasonal-epidemic periods has not previously been specified. Our objective was to determine its frequency according to clinical presentation. METHODS: This is a prospective observational study conducted during three-consecutive seasonal Influenza epidemics (2013-2015), including patients presenting i) community acquired pneumonia (CAP); ii) severe acute symptoms (SAS): respiratory failure (RF), hemodynamic failure (HF), cardiac failure (CF), and miscellaneous symptoms (M); iii) symptoms suggesting influenza (PSSI). Patients were tested for influenza using specific PCR on naso-pharyngeal swabs. RESULTS: Of 1,239 patients, virological samples were taken from 784 (63.3%), 213 (27.2%) of whom were positive for the influenza virus: CAP 52/177 (29.4%), SAS 115/447 (25.7%) and PSSI 46/160 (28.8%) (p = 0.6). In the SAS group positivity rates were: RF 76/263 (28.9%), HF 5/29 (17.2%), CF 15/68 (22.1%), and M 19/87 (21.8%) (p = 0.3). Among the major diagnostic categories, the influenza virus positivity rates were: asthma 60/231 (26%), acute exacerbation of chronic obstructive pulmonary disease 18/86 (20.9%), HIV 5/21 (23.8%) and cardiac failure 33/131 (25.2%). The positivity of the samples has not been associated (p>0.1) nor the presence of signs of severity or admission rate in medical ward nor intensive care unit. CONCLUSIONS: Our results indicate that during seasonal influenza epidemics, Influenza virus-positivity rate is similar in patients attending ED for influenza compatible clinical features, patients with acute symptoms including pneumonia, respiratory, hemodynamic and cardiac distress, and patients presenting for acute decompensation of chronic respiratory and cardiac diseases. PMID- 28813450 TI - Oral microbial community assembly under the influence of periodontitis. AB - Several ecological hypotheses (e.g., specific plaque, non-specific plaque and keystone pathogen) regarding the etiology of periodontitis have been proposed since the 1990s, most of which have been centered on the concept of dysbiosis associated with periodontitis. Nevertheless, none of the existing hypotheses have presented mechanistic interpretations on how and why dysbiosis actually occurs. Hubbell's neutral theory of biodiversity offers a powerful null model to test hypothesis regarding the mechanism of community assembly and diversity maintenance from the metagenomic sequencing data, which can help to understand the forces that shape the community dynamics such as dysbiosis. Here we reanalyze the dataset from Abusleme et al.'s comparative study of the oral microbial communities from periodontitis patients and healthy individuals. Our study demonstrates that 14 out of 61 communities (23%) passed the neutrality test, a percentage significantly higher than the previous reported neutrality rate of 1% in human microbiome (Li & Ma 2016, Scientific Reports). This suggests that, while the niche selection may play a predominant role in the assembly and diversity maintenance in oral microbiome, the effect of neutral dynamics may not be ignored. However, no statistically significant differences in the neutrality passing rates were detected between the periodontitis and healthy treatments with Fisher's exact probability test and multiple testing corrections, suggesting that the mechanism of community assembly is robust against disturbances such as periodontitis. In addition, our study confirmed previous finding that periodontitis patients exhibited higher biodiversity. These findings suggest that while periodontitis may significantly change the community composition measured by diversity (i.e., the exhibition or 'phenotype' of community assembly), it does not seem to cause the 'mutation' of the 'genotype" (mechanism) of community assembly. We argue that the 'phenotypic' changes explain the observed link (not necessarily causal) between periodontitis and community dysbiosis, which is certainly worthy of further investigation. PMID- 28813451 TI - Schistosoma mansoni reinfection: Analysis of risk factors by classification and regression tree (CART) modeling. AB - Praziquantel (PZQ) is an effective chemotherapy for schistosomiasis mansoni and a mainstay for its control and potential elimination. However, it does not prevent against reinfection, which can occur rapidly in areas with active transmission. A guide to ranking the risk factors for Schistosoma mansoni reinfection would greatly contribute to prioritizing resources and focusing prevention and control measures to prevent rapid reinfection. The objective of the current study was to explore the relationship among the socioeconomic, demographic, and epidemiological factors that can influence reinfection by S. mansoni one year after successful treatment with PZQ in school-aged children in Northeastern Minas Gerais state Brazil. Parasitological, socioeconomic, demographic, and water contact information were surveyed in 506 S. mansoni-infected individuals, aged 6 to 15 years, resident in these endemic areas. Eligible individuals were treated with PZQ until they were determined to be negative by the absence of S. mansoni eggs in the feces on two consecutive days of Kato-Katz fecal thick smear. These individuals were surveyed again 12 months from the date of successful treatment with PZQ. A classification and regression tree modeling (CART) was then used to explore the relationship between socioeconomic, demographic, and epidemiological variables and their reinfection status. The most important risk factor identified for S. mansoni reinfection was their "heavy" infection at baseline. Additional analyses, excluding heavy infection status, showed that lower socioeconomic status and a lower level of education of the household head were also most important risk factors for S. mansoni reinfection. Our results provide an important contribution toward the control and possible elimination of schistosomiasis by identifying three major risk factors that can be used for targeted treatment and monitoring of reinfection. We suggest that control measures that target heavily infected children in the most economically disadvantaged households would be most beneficial to maintain the success of mass chemotherapy campaigns. PMID- 28813453 TI - Metabolomics reveals that vine tea (Ampelopsis grossedentata) prevents high-fat diet-induced metabolism disorder by improving glucose homeostasis in rats. AB - BACKGROUND: Vine tea (VT), derived from Ampelopsis grossedentata (Hand.-Mazz.) W.T. Wang, is an alternative tea that has been consumed widely in south China for hundreds of years. It has been shown that drinking VT on a daily basis improves hyperlipidemia and hyperglycemia. However, little is known about the preventive functions of VT for metabolic dysregulation and the potential pathological mechanisms involved. This paper elucidates the preventive effects of VT on the dysregulation of lipid and glucose metabolism using rats maintained on a high-fat diet (HFD) in an attempt to explain the potential mechanisms involved. METHODS: Sprague Dawley (SD) rats were divided into five groups: a group given normal rat chow and water (control group); a group given an HFD and water (HFD group); a group given an HFD and Pioglitazone (PIO group), 5 mg /kg; and groups given an HFD and one of two doses of VT: 500 mg/L or 2000 mg/L. After 8 weeks, changes in food intake, tea consumption, body weight, serum and hepatic biochemical parameters were determined. Moreover, liver samples were isolated for pathology histology and liquid chromatography-mass spectrometry (LC-MS)-based metabolomic research. RESULTS: VT reduced the serum levels of glucose and total cholesterol, decreased glucose area under the curve in the insulin tolerance test and visibly impaired hepatic lipid accumulation. Metabolomics showed that VT treatment modulated the contents of metabolic intermediates linked to glucose metabolism (including gluconeogenesis and glycolysis), the TCA cycle, purine metabolism and amino acid metabolism. CONCLUSION: The current results demonstrate that VT may prevent metabolic impairments induced by the consumption of an HFD. These effects may be caused by improved energy-related metabolism (including gluconeogenesis, glycolysis and TCA cycle), purine metabolism and amino acid metabolism, and reduced lipid levels in the HFD-fed rats. PMID- 28813454 TI - Applying machine learning to identify autistic adults using imitation: An exploratory study. AB - Autism spectrum condition (ASC) is primarily diagnosed by behavioural symptoms including social, sensory and motor aspects. Although stereotyped, repetitive motor movements are considered during diagnosis, quantitative measures that identify kinematic characteristics in the movement patterns of autistic individuals are poorly studied, preventing advances in understanding the aetiology of motor impairment, or whether a wider range of motor characteristics could be used for diagnosis. The aim of this study was to investigate whether data-driven machine learning based methods could be used to address some fundamental problems with regard to identifying discriminative test conditions and kinematic parameters to classify between ASC and neurotypical controls. Data was based on a previous task where 16 ASC participants and 14 age, IQ matched controls observed then imitated a series of hand movements. 40 kinematic parameters extracted from eight imitation conditions were analysed using machine learning based methods. Two optimal imitation conditions and nine most significant kinematic parameters were identified and compared with some standard attribute evaluators. To our knowledge, this is the first attempt to apply machine learning to kinematic movement parameters measured during imitation of hand movements to investigate the identification of ASC. Although based on a small sample, the work demonstrates the feasibility of applying machine learning methods to analyse high-dimensional data and suggest the potential of machine learning for identifying kinematic biomarkers that could contribute to the diagnostic classification of autism. PMID- 28813452 TI - Plasma metabolomics reveals membrane lipids, aspartate/asparagine and nucleotide metabolism pathway differences associated with chloroquine resistance in Plasmodium vivax malaria. AB - BACKGROUND: Chloroquine (CQ) is the main anti-schizontocidal drug used in the treatment of uncomplicated malaria caused by Plasmodium vivax. Chloroquine resistant P. vivax (PvCR) malaria in the Western Pacific region, Asia and in the Americas indicates a need for biomarkers of resistance to improve therapy and enhance understanding of the mechanisms associated with PvCR. In this study, we compared plasma metabolic profiles of P. vivax malaria patients with PvCR and chloroquine sensitive parasites before treatment to identify potential molecular markers of chloroquine resistance. METHODS: An untargeted high-resolution metabolomics analysis was performed on plasma samples collected in a malaria clinic in Manaus, Brazil. Male and female patients with Plasmodium vivax were included (n = 46); samples were collected before CQ treatment and followed for 28 days to determine PvCR, defined as the recurrence of parasitemia with detectable plasma concentrations of CQ >=100 ng/dL. Differentially expressed metabolic features between CQ-Resistant (CQ-R) and CQ-Sensitive (CQ-S) patients were identified using partial least squares discriminant analysis and linear regression after adjusting for covariates and multiple testing correction. Pathway enrichment analysis was performed using Mummichog. RESULTS: Linear regression and PLS-DA methods yielded 69 discriminatory features between CQ-R and CQ-S groups, with 10-fold cross-validation classification accuracy of 89.6% using a SVM classifier. Pathway enrichment analysis showed significant enrichment (p<0.05) of glycerophospholipid metabolism, glycosphingolipid metabolism, aspartate and asparagine metabolism, purine and pyrimidine metabolism, and xenobiotics metabolism. Glycerophosphocholines levels were significantly lower in the CQ-R group as compared to CQ-S patients and also to independent control samples. CONCLUSIONS: The results show differences in lipid, amino acids, and nucleotide metabolism pathways in the plasma of CQ-R versus CQ-S patients prior to antimalarial treatment. Metabolomics phenotyping of P. vivax samples from patients with well-defined clinical CQ-resistance is promising for the development of new tools to understand the biological process and to identify potential biomarkers of PvCR. PMID- 28813455 TI - Maternal serum C-reactive protein concentration and intra-amniotic inflammation in women with preterm prelabor rupture of membranes. AB - OBJECTIVE: To evaluate maternal serum C-reactive protein (CRP) concentrations in pregnancies complicated by preterm prelabor rupture of membranes (PPROM) in relation to the presence of microbial invasion of the amniotic cavity (MIAC) and/or intra-amniotic inflammation (IAI). METHODS: Two hundred and eighty-seven women with singleton pregnancies complicated by PPROM between 2014 and 2016 were included in this study. Maternal blood and amniotic fluid samples were collected at the time of admission. Maternal serum CRP concentration was measured using a high-sensitivity immunoturbidimetric assay. Interleukin-6 (IL-6) concentration was measured using a point-of-care test. MIAC was diagnosed based on a positive polymerase chain reaction result for Ureaplasma species, Mycoplasma hominis, and/or Chlamydia trachomatis and for the 16S rRNA gene. IAI was characterized by an amniotic fluid IL-6 concentration of >= 745 pg/mL. RESULT: Women with MIAC and IAI had higher maternal serum CRP concentrations than did women without (with MIAC: median 6.9 mg/L vs. without MIAC: median 4.9 mg/L; p = 0.02; with IAI: median 8.6 mg/L vs. without IAI: median 4.7 mg/L; p < 0.0001). When women were split into four subgroups based on the presence of MIAC and/or IAI, women with the presence of both MIAC and IAI had higher maternal serum CRP than did women with IAI alone, with MIAC alone, and women without MIAC and IAI (both MIAC and IAI: median: 13.1 mg/L; IAI alone: 6.0 mg/L; MIAC alone: 3.9 mg/L; and without MIAC and IAI: median 4.8 mg/L; p < 0.0001). The maternal serum CRP cutoff value of 17.5 mg/L was the best level to identify the presence of both MIAC and IAI, with sensitivity of 47%, specificity of 96%, positive predictive value of 42%, negative predictive value of 96%, and the positive likelihood ratio of 10.9. CONCLUSION: The presence of both MIAC and IAI was associated with the highest maternal serum CRP concentrations. Maternal serum CRP concentration in women with PPROM at the time of admission can rule out the presence of the combined condition of both MIAC and IAI, therefore, it may serve as a non-invasive screening tool to distinguish between women with PPROM who are at high or at low risk for the presence of both MIAC and IAI. PMID- 28813457 TI - A large-scale examination of the effectiveness of anonymous marking in reducing group performance differences in higher education assessment. AB - The present research aims to more fully explore the issues of performance differences in higher education assessment, particularly in the context of a common measure taken to address them. The rationale for the study is that, while performance differences in written examinations are relatively well researched, few studies have examined the efficacy of anonymous marking in reducing these performance differences, particularly in modern student populations. By examining a large archive (N = 30674) of assessment data spanning a twelve-year period, the relationship between assessment marks and factors such as ethnic group, gender and socio-environmental background was investigated. In particular, analysis focused on the impact that the implementation of anonymous marking for assessment of written examinations and coursework has had on the magnitude of mean score differences between demographic groups of students. While group differences were found to be pervasive in higher education assessment, these differences were observed to be relatively small in practical terms. Further, it appears that the introduction of anonymous marking has had a negligible effect in reducing them. The implications of these results are discussed, focusing on two issues, firstly a defence of examinations as a fair and legitimate form of assessment in Higher Education, and, secondly, a call for the re-examination of the efficacy of anonymous marking in reducing group performance differences. PMID- 28813456 TI - A simple molecular mechanism explains multiple patterns of cell-size regulation. AB - Increasingly accurate and massive data have recently shed light on the fundamental question of how cells maintain a stable size trajectory as they progress through the cell cycle. Microbes seem to use strategies ranging from a pure sizer, where the end of a given phase is triggered when the cell reaches a critical size, to pure adder, where the cell adds a constant size during a phase. Yet the biological origins of the observed spectrum of behavior remain elusive. We analyze a molecular size-control mechanism, based on experimental data from the yeast S. cerevisiae, that gives rise to behaviors smoothly interpolating between adder and sizer. The size-control is obtained from the accumulation of an activator protein that titrates an inhibitor protein. Strikingly, the size control is composed of two different regimes: for small initial cell size, the size-control is a sizer, whereas for larger initial cell size, it is an imperfect adder, in agreement with recent experiments. Our model thus indicates that the adder and critical size behaviors may just be different dynamical regimes of a single simple biophysical mechanism. PMID- 28813458 TI - Joint modelling of longitudinal 3MS scores and the risk of mortality among cognitively impaired individuals. AB - BACKGROUND: Modified Mini-Mental State Examination (3MS) is an instrument administered by trained personnel to examine levels of participants' cognitive function. However, the association between changes in scores over time and the risk of death (mortality) is not known. The aims of this study are to examine the association between 3MS scores and mortality via cognitive impairment among older women and to determine individuals' risk of changes in scores to better predict their survival and mortality rates. METHODS: We propose a Bayesian joint modelling approach to determine mortality due to cognitive impairment via repeated measures of 3MS scores trajectories over a 21-year follow-up period. Data for this study are taken from the Osteoporotic Fracture longitudinal study among women aged 65+ which started in 1986-88. RESULTS: The standard relative risk model from the analyses with a baseline 3MS score after adjusting for all the significant covariates demonstrates that, every unit decrease in a 3MS score corresponds to a non-significant 1.059 increase risk of mortality with a 95% CI of (0.981, 1.143), while the extended model results in a significant 0.09% increased risk in mortality. The joint modelling approach found a strong association between the 3MS scores and the risk of mortality, such that, every unit decrease in 3MS scores results in a 1.135 (13%) increased risk of death via cognitive impairment with a 95% CI of (1.056, 1.215). CONCLUSION: It has been demonstrated that a decrease in 3MS results has a significant increase risk of mortality due to cognitive impairment via joint modelling, but insignificant when considered under the standard relative risk approach. PMID- 28813459 TI - beta2-microglobulin gene duplication in cetartiodactyla remains intact only in pigs and possibly confers selective advantage to the species. AB - Several beta2-microglobulin (B2M) -bound protein complexes undertake key roles in various immune system pathways, including the neonatal Fc receptor (FcRn), cluster of differentiation 1 (CD1) protein, non-classical major histocompatibility complex (MHC), and well-known MHC class I molecules. Therefore, the duplication of B2M may lead to an increase in the biological competence of organisms to the environment. Based on the pig genome assembly SSC10.2, a segmental duplication of ~45.5 kb, encoding the entire B2M protein, was identified in pig chromosome 1. Through experimental validation, we confirmed the functional duplication of the B2M gene with a completely identical coding sequence between two copies in pigs. Considering the importance of B2M in the immune system, we performed the phylogenetic analysis of B2M duplication in ten mammalian species, confirming the presence of B2M duplication in cetartioldactyls, like cattle, sheep, goats, pigs and whales, but non cetartiodactyl species, like mice, cats, dogs, horses, and humans. The density of long interspersed nuclear element (LINE) at the edges of duplicated blocks (39 to 66%) was found to be 2 to 3-fold higher than the average (20.12%) of the pig genome, suggesting its role in the duplication event. The B2M mRNA expression level in pigs was 12.71 and 7.57 times (2-DeltaDeltaCt values) higher than humans and mice, respectively. However, we were unable to experimentally demonstrate the difference in the level of B2M protein because species specific anti-B2M antibodies are not available. We reported, for the first time, the functional duplication of the B2M gene in animals. The identification of partially remaining duplicated B2M sequences in the genomes of only cetartiodactyls indicates that the event was lineage specific. B2M duplication could be beneficial to the immune system of pigs by increasing the availability of MHC class I light chain protein, B2M, to complex with the proteins encoded by the relatively large number of MHC class I heavy chain genes in pigs. Further studies are necessary to address the biological meaning of increased expression of B2M. PMID- 28813460 TI - Mechanisms for pattern specificity of deep-brain stimulation in Parkinson's disease. AB - Deep brain stimulation (DBS) has become a widely used technique for treating advanced stages of neurological and psychiatric illness. In the case of motor disorders related to basal ganglia (BG) dysfunction, several mechanisms of action for the DBS therapy have been identified which might be involved simultaneously or in sequence. However, the identification of a common key mechanism underlying the clinical relevant DBS configurations has remained elusive due to the inherent complexity related to the interaction between the electrical stimulation and the neural tissue, and the intricate circuital structure of the BG-thalamocortical network. In this work, it is shown that the clinically relevant range for both, the frequency and intensity of the electrical stimulation pattern, is an emergent property of the BG anatomy at the system-level that can be addressed using mean field descriptive models of the BG network. Moreover, it is shown that the activity resetting mechanism elicited by electrical stimulation provides a natural explanation to the ineffectiveness of irregular (i.e., aperiodic) stimulation patterns, which has been commonly observed in previously reported pathophysiology models of Parkinson's disease. Using analytical and numerical techniques, these results have been reproduced in both cases: 1) a reduced mean field model that can be thought as an elementary building block capable to capture the underlying fundamentals of the relevant loops constituting the BG thalamocortical network, and 2) a detailed model constituted by the direct and hyperdirect loops including one-dimensional spatial structure of the BG nuclei. We found that the optimal ranges for the essential parameters of the stimulation patterns can be understood without taking into account biophysical details of the relevant structures. PMID- 28813461 TI - Epidemiology of Clostridium difficile in infants in Oxfordshire, UK: Risk factors for colonization and carriage, and genetic overlap with regional C. difficile infection strains. AB - BACKGROUND: Approximately 30-40% of children <1 year of age are Clostridium difficile colonized, and may represent a reservoir for adult C. difficile infections (CDI). Risk factors for colonization with toxigenic versus non toxigenic C. difficile strains and longitudinal acquisition dynamics in infants remain incompletely characterized. METHODS: Predominantly healthy infants (<=2 years) were recruited in Oxfordshire, UK, and provided >=1 fecal samples. Independent risk factors for toxigenic/non-toxigenic C. difficile colonization and acquisition were identified using multivariable regression. Infant C. difficile isolates were whole-genome sequenced to assay genetic diversity and prevalence of toxin-associated genes, and compared with sequenced strains from Oxfordshire CDI cases. RESULTS: 338/365 enrolled infants provided 1332 fecal samples, representing 158 C. difficile colonization or carriage episodes (107[68%] toxigenic). Initial colonization was associated with age, and reduced with breastfeeding but increased with pet dogs. Acquisition was associated with older age, Caesarean delivery, and diarrhea. Breastfeeding and pre-existing C. difficile colonization reduced acquisition risk. Overall 13% of CDI C. difficile strains were genetically related to infant strains. 29(18%) infant C. difficile sequences were consistent with recent direct/indirect transmission to/from Oxfordshire CDI cases (<=2 single nucleotide variants [SNVs]); 79(50%) shared a common origin with an Oxfordshire CDI case within the last ~5 years (0-10 SNVs). The hypervirulent, epidemic ST1/ribotype 027 remained notably absent in infants in this large study, as did other lineages such as STs 10/44 (ribotype 015); the most common strain in infants was ST2 (ribotype 020/014)(22%). CONCLUSIONS: In predominantly healthy infants without significant healthcare exposure C. difficile colonization and acquisition reflect environmental exposures, with pet dogs identified as a novel risk factor. Genetic overlap between some infant strains and those isolated from CDI cases suggest common community reservoirs of these C. difficile lineages, contrasting with those lineages found only in CDI cases, and therefore more consistent with healthcare-associated spread. PMID- 28813462 TI - A comprehensive profiling of T- and B-lymphocyte receptor repertoires from a Chinese-origin rhesus macaque by high-throughput sequencing. AB - Due to the close genetic background, high similarity of physiology, and susceptibility to infectious and metabolic diseases with humans, rhesus macaques have been widely used as an important animal model in biomedical research, especially in the study of vaccine development and human immune-related diseases. In recent years, high-throughput sequencing based immune repertoire sequencing (IR-SEQ) has become a powerful tool to study the dynamic adaptive immune responses. Several previous studies had analyzed the responses of B cells to HIV 1 trimer vaccine or T cell repertoire of rhesus macaques using this technique, however, there are little studies that had performed a comprehensive analysis of immune repertoire of rhesus macaques, including T and B lymphocytes. Here, we did a comprehensive analysis of the T and B cells receptor repertoires of a Chinese rhesus macaque based on the 5'-RACE and IR-SEQ. The detailed analysis includes the distribution of CDR3 length, the composition of amino acids and nucleotides of CDR3, V, J and V-J combination usage, the insertion and deletion length distribution and somatic hypermutation rates of the framework region 3 (FR3). In addition, we found that several positions of FR3 region have high mutation frequencies, which may indicate the existence of new genes/alleles that have not been discovered and/or collected into IMGT reference database. We believe that a comprehensive profiling of immune repertoire of rhesus macaque will facilitate the human immune-related diseases studies. PMID- 28813463 TI - Genetic diversity of Bemisia tabaci species colonizing cassava in Central African Republic characterized by analysis of cytochrome c oxidase subunit I. AB - After 2007, upsurges of whiteflies on cassava plants and high incidences of cassava diseases were observed in Central African Republic. This recent upsurge in the abundance of Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) was directly linked to serious damage to cassava crops resulting from spread of whitefly-borne cassava mosaic geminiviruses (CMGs). There is currently very little information describing whitefly populations on cassava and associated crops in Central African Republic. The current study aimed to address this gap, and to determine whether the increasing damage associated with B. tabaci whiteflies was the consequence of a new invasion, or an upsurge of a local population. The molecular genetic identification and phylogenetic relationships of 898 B. tabaci adult individuals collected from representative locations (54) throughout CAR were determined based on their mitochondrial cytochrome oxidase I sequences (mtCOI). Field and ecological data were also collected from each site, including whitefly abundance, CMD incidence, host plants colonized by B. tabaci and agro-ecological zone. Phylogenetic analysis of the whitefly mtCOI sequences indicated that SSA1 (-SG1, -SG2), SSA3, MED, MEAM1 and Indian Ocean (IO) putative species occur in CAR. One specific haplotype of SSA1-SG1 (SSA1-SG1-P18F5) predominated on most cassava plants and at the majority of sites. This haplotype was identical to the SSA1-SG1 Mukono8-4 (KM377961) haplotype that was recorded from Uganda but that also occurs widely in CMD pandemic-affected areas of East Africa. These results suggest that the SSA1-SG1-P18F5 haplotype occurring in CAR represents a recent invasive population, and that it is the likely cause of the increased spread and severity of CMD in CAR. Furthermore, the high mtDNA sequence diversity observed for SSA1 and its broad presence on all sites and host plants sampled suggest that this genetic group was the dominant resident species even before the arrival of this new invasive haplotype. PMID- 28813464 TI - Representation of three-dimensional space in the auditory cortex of the echolocating bat P. discolor. AB - The auditory cortex is an essential center for sound localization. In echolocating bats, combination sensitive neurons tuned to specific delays between call emission and echo perception represent target distance. In many bats, these neurons are organized as a chronotopically organized map of echo delay. However, it is still unclear to what extend these neurons can process directional information and thereby form a three-dimensional representation of space. We investigated the representation of three-dimensional space in the auditory cortex of Phyllostomus discolor. Specifically, we hypothesized that combination sensitive neurons encoding target distance in the AC can also process directional information. We used typical echolocation pulses of P. discolor combined with simulated echoes from different positions in virtual 3D-space and measured the evoked neuronal responses in the AC of the anesthetized bats. Our results demonstrate that combination sensitive neurons in the AC responded selectively to specific positions in 3-D space. While these neurons were sharply tuned to echo delay and formed a precise target distance map, the neurons' specificity in azimuth and elevation depended on the presented sound pressure level. Our data further reveal a topographic distribution of best elevation of the combination sensitive neurons along the rostro-caudal axis i.e., neurons in the rostral part of the target distance map representing short delays prefer elevations below the horizon. Due to their spatial directionality and selectivity to specific echo delays representing target distance, combination sensitive cortical neurons are suited to encode three-dimensional spatial information. PMID- 28813465 TI - Long-term persistent infection of HPV 16 E6 up-regulate SP1 and hTERT by inhibiting LKB1 in lung cancer cells. AB - HPV 16 E6 upregulates hTERT expression in lung cancer cells. However, the underlying molecular mechanism is unclear. In this paper, E6, LKB1, SP1, and hTERT mRNA expression levels were detected in brushing cells of patients with lung cancer (n = 106) and with benign lung disease (n = 68) by qRT-PCR. The mRNA expression levels of E6, SP1, and hTERT were significantly increased in the malignant group compared with the benign group (P < 0.01). Conversely, the mRNA expression level of LKB1 was significantly decreased in the malignant group (P < 0.01). Furthermore, the correlation between E6, Sp1, hTERT, and LKB1 was performed, our results indicated that E6, Sp1, and hTERT with positive, but LKB1 with negative correlation (P < 0.01). To investigate the potential relationship between these genes, using double directional genetic manipulation, we showed that overexpression of E6 in H1299 cells down-regulated LKB1 mRNA and protein expression but up-regulated SP1 and hTERT as well as the transcriptional activity of Sp1. In contrast, knockdown of E6 in A549 cells by short-interference RNAs (siRNAs) up-regulated LKB1 expression, but down-regulated SP1 and hTERT expression as well as Sp1 activity. LKB1 loss upregulated both SP1 and hTERT at the protein and mRNA level as well as SP1 activity. To verify that the role of E6 on hTERT was mediated by SP1, siRNA knockdown of SP1 was performed on both H1299 and A549 cell lines. Inhibition of SP1 downregulated hTERT expression. Our results indicate that HPV16 E6 indirectly upregulated the expression of hTERT by inhibition of LBK1 expression and upregulation of Sp1 expression, thus suggesting a HPV-LKB1-SP1-hTERT axis for the tumorigenesis of lung cancer. Our study also provides new evidence to support the critical role of SP1 and LKB1 in the pathogenesis of HPV-related lung cancer, and suggests novel therapeutic targets. PMID- 28813466 TI - Comprehensive comparison of neonate and adult human platelet transcriptomes. AB - Understanding the underlying mechanisms of the well-substantiated platelet hyporeactivity in neonates is of interest given their implications for the clinical management of newborns, a population at higher bleeding risk than adults (especially sick and preterm infants), as well as for gaining insight into the regulatory mechanisms of platelet biology. Transcriptome analysis is useful in identifying mRNA signatures affecting platelet function. However, human fetal/neonatal platelet transcriptome analysis has never before been reported. We have used mRNA expression array for the first time to compare platelet transcriptome changes during development. Microarray analysis was performed in pure platelet RNA obtained from adult and cord blood, using the same platform in two independent laboratories. A high correlation was obtained between array results for both adult and neonate platelet samples. There was also good agreement between results in our adult samples and outcomes previously reported in three different studies. Gene enrichment analysis showed that immunity- and platelet function-related genes are highly expressed at both developmental stages. Remarkably, 201 genes were found to be differentially expressed throughout development. In particular, neonatal platelets contain higher levels of mRNA that are associated with protein synthesis and processing, while carrying significantly lower levels of genes involved in calcium transport/metabolism and cell signaling (including GNAZ). Overall, our results point to variations in platelet transcriptome as possibly underlining the hypo-functional phenotype of neonatal platelets and provide further support for the role of platelets in cellular immune response. Better characterization of the platelet transcriptome throughout development can contribute to elucidate how transcriptome changes impact different pathological conditions. PMID- 28813467 TI - Meat consumption reduction in Italian regions: Health co-benefits and decreases in GHG emissions. AB - INTRODUCTION: Animal agriculture has exponentially grown in recent decades in response to the rise in global demand for meat, even in countries like Italy that traditionally eat a Mediterranean, plant-based diet. Globalization related dietary changes are contributing to the epidemic of non-communicable diseases and to the global climate crisis, and are associated with huge carbon and water footprints. The objective of the study is to assess inequalities in health impacts and in attributable greenhouse gases-GHG emissions in Italy by hypothesizing different scenarios of reduction in red and processed meat consumption towards healthier consumption patterns more compliant with the recommendations of the Mediterranean food pyramid. METHODS: We used demographic and food consumption patterns from national surveys and risk relationships between meat intake and cardiovascular and colorectal cancer mortality from IARC and other meta-analyses. From the baseline data (year 2005-2006, average 406 gr/week beef and 245 gr/week processed meat), we considered hypothetical meat reduction scenarios according to international dietary guidelines such as the Mediterranean pyramid targets. For each geographical area (Northwest, Northeast, Centre, and South) and gender, we calculated the number of avoidable deaths from colorectal cancer, and cardiovascular disease among the adult population. Moreover, years of life gained by the adult population from 2012 to 2030 and changes in life expectancy of the 2012 birth cohort were quantified using gender specific life tables. GHG emission reductions under Mediterranean scenario were estimated only for beef by applying the Global Warming Potential (GWP) coefficient to total consumption and to a low carbon food substitution in adult diet. RESULTS: The deaths avoidable (as percentage change compared to baseline) according to the three reduction scenarios for beef consumption were between 2.3% and 4.5% for colorectal cancer, and between 2.1% and 4.0% for cardiovascular disease; higher benefits would be observed in Northwestern areas and among males. In parallel, 5% and 6.4% of colorectal cancer and CVD deaths would be avoided if the Italian population ate the advised quantity of processed meat. Life table analysis suggests that the scenario that is fully compliant with the Mediterranean diet model would save 5 million years of life lost prematurely among men and women over the next 18 years and would increase average life expectancy of future generations by over 7 months. Considering the environmental impact, emissions associated with the actual total intake of beef range from 12,900 to 21,800 Gg CO2 eq; emissions saved according to the Mediterranean scenario are in the range 8000-14000 Gg CO2 eq per year. The per capita reduction is 263 KgCO2eq/year/person with higher reductions in Northwestern and Central areas. CONCLUSIONS: In Italy, scenarios for reducing beef consumption are consistent with significant health and environmental co-benefits on current and future generations. Results support introducing policies to promote healthier behavior towards red and processed meat in the adult population within an overall balanced and healthy dietary pattern. Interventions should address gender, vulnerable population groups, and geographical differences in order to be more effective. PMID- 28813468 TI - Proteomic comparison by iTRAQ combined with mass spectrometry of egg white proteins in laying hens (Gallus gallus) fed with soybean meal and cottonseed meal. AB - Cottonseed meal (CSM) is commonly used in hens' diets to replace soybean meal (SBM). However, the molecular consequences of this substitution remains unclear. To investigate the impact of this substitution at the molecular level, iTRAQ combined with biochemical analysis was performed in Hy-Line W-36 hens supplemented with a mixed diet of CSM and SBM. Egg weight, albumen height, and Haugh unit were significantly reduced in the CSM100 group (100% crude protein of SBM replaced by CSM) compared with the SBM group (P<0.05). A total of 15 proteins, accounting for 75% of egg white proteins with various biological functions of egg whites, were found to be reduced. This finding may relate to the decrease of albumen quality in the CSM100 group. Oviduct magnum morphology and hormone analysis indicated that a reduced level of plasma progesterone caused reduced growth of the tubular gland and epithelial cells in the magnum, further decreasing egg white protein synthesis in the magnum. These findings help demonstrate the molecular mechanisms of a CSM diet that cause adverse effects on albumen quality, while also showing that SBM should not be totally replaced with CSM in a hen diet. PMID- 28813469 TI - Phytoplasma infection of a tropical root crop triggers bottom-up cascades by favoring generalist over specialist herbivores. AB - Global interest on plant-microbe-insect interactions is rapidly growing, revealing the multiple ways in which microorganisms mediate plant-herbivore interactions. Phytopathogens regularly alter whole repertoires of plant phenotypic traits, and bring about shifts in key chemical or morphological characteristics of plant hosts. Pathogens can also cause cascading effects on higher trophic levels, and eventually shape entire plant-associated arthropod communities. We tested the hypothesis that a Candidatus Phytoplasma causing cassava witches' broom (CWB) on cassava (Manihot esculenta Grantz) is altering species composition of invasive herbivores and their associated parasitic hymenopterans. We conducted observational studies in cassava fields in eastern Cambodia to assess the effect of CWB infection on abundance of specialist and generalist mealybugs (Homoptera: Pseudococcidae), and associated primary and hyper-parasitoid species. CWB infection positively affects overall mealybug abundance and species richness at a plant- and field-level, and disproportionately favors a generalist mealybug over a specialist feeder. CWB phytoplasma infection led to increased parasitoid richness and diversity, with richness of 'comparative' specialist taxa being the most significantly affected. Parasitism rate did not differ among infected and uninfected plants, and mealybug host suppression was not impacted. CWB phytoplasma modifies host plant quality for sap-feeding homopterans, differentially affects success rates of two invasive species, and generates niche opportunities for higher trophic orders. By doing so, a Candidatus phytoplasma affects broader food web structure and functioning, and assumes the role of an ecosystem engineer. Our work unveils key facets of phytoplasma ecology, and sheds light upon complex multi-trophic interactions mediated by an emerging phytopathogen. These findings have further implications for invasion ecology and management. PMID- 28813470 TI - Comparison of macrophage migration inhibitory factor and neutrophil gelatinase associated lipocalin-2 to predict acute kidney injury after liver transplantation: An observational pilot study. AB - INTRODUCTION: Several biomarkers have been suggested as early predictors of acute kidney injury (AKI) after orthotopic liver transplantation (OLT). Neutrophil gelatinase-associated lipocalin-2 (NGAL) appears to be a promising predictor of AKI after OLT, but the clinical benefit remains to be proven. Recently, systemic macrophage migration inhibitory factor (MIF) has been proposed as early indicator for requirement of renal replacement therapy after OLT. The aim of this prospective, observational pilot study was to compare the predictive values of serum and urinary MIF for severe AKI after OLT to those of serum and urinary NGAL. METHODS: Concentrations of MIF and NGAL were measured in serum and urine samples collected from patients undergoing OLT. Acute kidney injury was classified according to the KDIGO criteria, with stages 2 and 3 summarized as severe AKI. Areas under the receiver operating curves (AUC) were calculated to assess predictive values of MIF and NGAL for the development of severe AKI. RESULTS: Forty-five patients (mean age 55+/-8 years) were included. Nineteen patients (38%) developed severe AKI within 48 hours after reperfusion. At the end of OLT, serum MIF was predictive of severe AKI (AUC 0.73; 95% confidence intervals, CI 0.55-0.90; P = 0.03), whereas urinary MIF, serum NGAL, and urinary NGAL were not. On the first postoperative day, serum MIF (AUC 0.78; CI 0.62-0.93; P = 0.006), urinary MIF (AUC 0.71; CI 0.53-0.88; P = 0.03), and urinary NGAL (AUC 0.79; CI 0.64-0.93; P = 0.02) were predictive for severe AKI, while serum NGAL was not. CONCLUSION: In the setting of OLT, MIF and NGAL had similar predictive values for the development of severe AKI. PMID- 28813471 TI - Mitochondrial genome evolution in the Saccharomyces sensu stricto complex. AB - Exploring the evolutionary patterns of mitochondrial genomes is important for our understanding of the Saccharomyces sensu stricto (SSS) group, which is a model system for genomic evolution and ecological analysis. In this study, we first obtained the complete mitochondrial sequences of two important species, Saccharomyces mikatae and Saccharomyces kudriavzevii. We then compared the mitochondrial genomes in the SSS group with those of close relatives, and found that the non-coding regions evolved rapidly, including dramatic expansion of intergenic regions, fast evolution of introns and almost 20-fold higher rearrangement rates than those of the nuclear genomes. However, the coding regions, and especially the protein-coding genes, are more conserved than those in the nuclear genomes of the SSS group. The different evolutionary patterns of coding and non-coding regions in the mitochondrial and nuclear genomes may be related to the origin of the aerobic fermentation lifestyle in this group. Our analysis thus provides novel insights into the evolution of mitochondrial genomes. PMID- 28813472 TI - An intronic LINE-1 insertion in MERTK is strongly associated with retinopathy in Swedish Vallhund dogs. AB - The domestic dog segregates a significant number of inherited progressive retinal diseases, several of which mirror human retinal diseases and which are collectively termed progressive retinal atrophy (PRA). In 2014, a novel form of PRA was reported in the Swedish Vallhund breed, and the disease was mapped to canine chromosome 17. The causal mutation was not identified, but expression analyses of the retinas of affected Vallhunds demonstrated a 6-fold increased expression of the MERTK gene compared to unaffected dogs. Using 24 retinopathy cases and 97 controls with no clinical signs of retinopathy, we replicated the chromosome 17 association in Swedish Vallhunds from the UK and aimed to elucidate the causal variant underlying this association using whole genome sequencing (WGS) of an affected dog. This revealed a 6-8 kb insertion in intron 1 of MERTK that was not present in WGS of 49 dogs of other breeds. Sequencing and BLASTN analysis of the inserted segment was consistent with the insertion comprising a full-length intact LINE-1 retroelement. Testing of the LINE-1 insertion for association with retinopathy in the UK set of 24 cases and 97 controls revealed a strong statistical association (P-value 6.0 x 10-11) that was subsequently replicated in the original Finnish study set (49 cases and 89 controls (P-value 4.3 x 10-19). In a pooled analysis of both studies (73 cases and 186 controls), the LINE-1 insertion was associated with a ~20-fold increased risk of retinopathy (odds ratio 23.41, 95% confidence intervals 10.99-49.86, P-value 1.3 x 10-27). Our study adds further support for regulatory disruption of MERTK in Swedish Vallhund retinopathy; however, further work is required to establish a functional overexpression model. Future work to characterise the mechanism by which this intronic mutation disrupts gene regulation will further improve the understanding of MERTK biology and its role in retinal function. PMID- 28813473 TI - The availability of pharmacies in the United States: 2007-2015. AB - IMPORTANCE: Despite their increasingly important role in health care delivery, little is known about the availability, and characteristics, of community pharmacies in the United States. OBJECTIVES: (1) To examine trends in the availability of community pharmacies and pharmacy characteristics (24-hour, drive up, home delivery, e-prescribing, and multilingual staffing) associated with access to prescription medications in the U.S. between 2007 and 2015; and (2) to determine whether and how these patterns varied by pharmacy type (retail chains, independents, mass retailers, food stores, government and clinic-based) and across counties. METHODS: Retrospective analysis using annual data from the National Council for Prescription Drug Programs. Pharmacy locations were mapped and linked to the several publically-available data to derive information on county-level population demographics, including annual estimates of total population, percent of population that is non-English speaking, percent with an ambulatory disability and percent aged >=65 years. The key outcomes were availability of pharmacies (total number and per-capita) and pharmacy characteristics overall, by pharmacy type, and across counties. RESULTS: The number of community pharmacies increased by 6.3% from 63,752 (2007) to 67,753 (2015). Retail chain and independent pharmacies persistently accounted for 40% and 35% of all pharmacies, respectively, while the remainder were comprised of mass retailer (12%), food store, (10%), clinic-based (3%) or government (<1%) pharmacies. With the exception of e-prescribing, there was no substantial change in pharmacy characteristics over time. While the number of pharmacies per 10,000 people (2.11) did not change between 2007 and 2015 at the national-level, it varied substantially across counties ranging from 0 to 13.6 per-capita in 2015. We also found that the majority of pharmacies do not offer accommodations that facilitate access to prescription medications, including home-delivery, with considerable variation by pharmacy type and across counties. For example, the provision of home-delivery services ranged from less than <1% of mass retailers to 67% of independent stores and was not associated with county demographics, including ambulatory disability population and percent of the population aged >=65 years. CONCLUSIONS: Despite modest growth of pharmacies in the U.S., the availability of pharmacies, and pharmacy characteristics associated with access to prescription medications, vary substantially across local areas. Policy efforts aimed at improving access to prescription medications should ensure the availability of pharmacies and their accommodations align with local population needs. PMID- 28813474 TI - Binge-like sucrose consumption reduces the dendritic length and complexity of principal neurons in the adolescent rat basolateral amygdala. AB - A compelling body of evidence suggests that the worldwide obesity epidemic is underpinned by excessive sugar consumption, typified by the modern western diet. Furthermore, evidence is beginning to emerge of maladaptive changes in the mesolimbic reward pathway of the brain in relation to excess sugar consumption that highlights the importance of examining this neural circuitry in an attempt to understand and subsequently mitigate the associated morbidities with obesity. While the basolateral amygdala (BLA) has been shown to mediate the reinforcing properties of drugs of abuse, it has also been shown to play an important role in affective and motivated behaviours and has been shown to undergo maladaptive changes in response to drugs of abuse and stress. Given the overlap in neural circuitry affected by drugs of abuse and sucrose, we sought to examine the effect of short- and long-term binge-like sucrose consumption on the morphology of the BLA principal neurons using an intermittent-access two-bottle choice paradigm. We used Golgi-Cox staining to impregnate principal neurons from the BLA of short- (4 week) and long-term (12 week) sucrose consuming adolescent rats and compared these to age-matched water controls. Our results indicate possibly maladaptive changes to the dendritic architecture of BLA principal neurons, particularly on apical dendrites following long-term sucrose consumption. Specifically, our results show reduced total dendritic arbor length of BLA principal neurons following short- and long-term sucrose consumption. Additionally, we found that long-term binge-like sucrose consumption caused a significant reduction in the length and complexity of apical dendrites. Taken together, our results highlight the differences between short- and long-term binge-like sucrose consumption on BLA principal neuron morphology and are suggestive of a perturbation in the diverse synaptic inputs to these neurons. PMID- 28813475 TI - Evaluation of the adaptogenic potential exerted by ginsenosides Rb1 and Rg1 against oxidative stress-mediated neurotoxicity in an in vitro neuronal model. AB - BACKGROUND: Ginseng (Panax sp.) is a drug with multiple pharmacological actions that has been largely used in traditional medicines for the treatment of many health problems. In the therapy of neurodegenerative disorders, it has been employed due to its capacity to strengthen mental processes by enhancing cognitive performance and psychological function. Current work aimed at evaluating the adaptogenic potential of Rb1 and Rg1 against oxidative-stress mediated degeneration in a model of nervous cells. METHODS: Oxidative stress and mitochondrial dysfunction were achieved by exposing SH-SY5Y cells to the mitochondrial complex I inhibitor rotenone. The cytoprotective activity of pre treatments with ginsenosides Rb1 and Rg1 against rotenone was assessed by determining biochemical markers regarding oxidative stress (ROS scavenging, glutathione and lipid peroxidation levels, SOD activity and Nrf2 activation) and apoptosis-related alterations (mitochondrial membrane potential, calcium levels, aconitase activity and pro/antiapoptotic proteins). Their capacity to cross the blood brain barrier was also estimated. RESULTS: At their optimal doses, ginsenosides Rb1 and Rg1 significantly ameliorated redox status within the cells; they reduced ROS and TBARS levels and improved the glutathione system, as well as they enhanced SOD activity and Nrf2 pathway activation. They protected neuronal cells against MMP loss, calcium homeostasis disruption and aconitase inhibition. Consequently, apoptotic cell death was attenuated by the pre-treatment with ginsenosides, as evidenced by the reduction in caspase-3 and Bax, and the increase in Bcl-2 expressions; also, lower levels of cytochrome C were found in the cytosol. Poor BBB permeation was demonstrated for both ginsenosides. CONCLUSIONS: In conclusion, ginsenosides Rb1 and Rg1 exhibit neuroprotective potential which is achieved, at least in part, via mitochondrial protection and the plausible involvement of Nrf2 pathway activation. Our results contribute to validate the traditional use of ginseng for cognitive-enhancing purposes and provide basis to encourage further research on the potential of ginsenosides in the treatment of neurodegenerative diseases. PMID- 28813476 TI - Paratubular basement membrane insudative lesions predict renal prognosis in patients with type 2 diabetes and biopsy-proven diabetic nephropathy. AB - AIMS: Glomerular insudative lesions are a pathological hallmark of diabetic nephropathy (DN). However, paratubular basement membrane insudative lesions (PTBMIL) have not attracted much attention, and the association between such lesions and the renal prognosis remains unclear. METHODS: Among 142 patients with biopsy-proven DN and type 2 diabetes encountered from 1998 to 2011, 136 patients were enrolled in this study. Patients were classified into 3 groups (Group 1: mild, Group 2: moderate, Group 3: severe) according to the extent of cortical and medullary PTBMIL. The endpoint was a decline of the estimated glomerular filtration rate (eGFR) by >= 40% from baseline or commencement of dialysis for end-stage renal disease. The Cox proportional hazard model was employed to calculate hazard ratios (HRs) and 95% confidence interval (CIs) for the death censored endpoint. RESULTS: During a median follow-up period of 1.8 years (IQR: 0.9-3.5), the endpoint occurred in 104 patients. Baseline mean eGFR was 43.9 +/- 22.8 ml/min/1.73 m2, and 125 patients (92%) had overt proteinuria. After adjusting for known indicators of DN progression, the HR for the endpoint was 2.32 (95% CI: 1.20-4.51) in PTBMIL Group 2 and 3.12 (1.48-6.58) in PTBMIL Group 3 versus PTBMIL Group 1. Furthermore, adding the PTBMIL Group to a multivariate model including known promoters of DN progression improved prediction of the endpoint (c-index increased by 0.02 [95% CI: 0.00-0.04]). CONCLUSIONS: PTBMIL may be useful for predicting the renal prognosis of patients with biopsy-proven DN, but further investigation of these lesions in various stages of DN is needed. PMID- 28813478 TI - Development and validation of a multi-dimensional measure of intellectual humility. AB - This paper presents five studies on the development and validation of a scale of intellectual humility. This scale captures cognitive, affective, behavioral, and motivational components of the construct that have been identified by various philosophers in their conceptual analyses of intellectual humility. We find that intellectual humility has four core dimensions: Open-mindedness (versus Arrogance), Intellectual Modesty (versus Vanity), Corrigibility (versus Fragility), and Engagement (versus Boredom). These dimensions display adequate self-informant agreement, and adequate convergent, divergent, and discriminant validity. In particular, Open-mindedness adds predictive power beyond the Big Six for an objective behavioral measure of intellectual humility, and Intellectual Modesty is uniquely related to Narcissism. We find that a similar factor structure emerges in Germanophone participants, giving initial evidence for the model's cross-cultural generalizability. PMID- 28813477 TI - Colonization prevalence and antibiotic susceptibility of Group B Streptococcus in pregnant women over a 6-year period in Dongguan, China. AB - This study investigated the prevalence of recto-vaginal Group B Streptococcus (GBS) colonization, serotype distribution, and antimicrobial susceptibility patterns among pregnant women in Dongguan, China. Recto-vaginal swabs were collected from pregnant women at gestational age 35-37 weeks between January 1st 2009 and December 31st 2014. Isolates were serotyped by latex-agglutination and were tested against seven antimicrobials by disk diffusion. Of 7,726 pregnant women who completed GBS testing, 636 (8.2%) were GBS carriers. Of 153 GBS isolates available for typing, 6 serotypes (Ia, Ib, III, V, VI and VIII) were identified with type III being predominant, while 9 (5.9%) were non-typable isolates. All isolates were sensitive to penicillin, ceftriaxone, linezolid and vancomycin, whereas 52.4% were resistant to clindamycin, 25.9% were resistant to levofloxacin and 64.9% were resistant to erythromycin. This study showed the recto-vaginal colonization prevalence of GBS in Dongguan is significant. Due to 100% susceptibility to penicillin of all GBS samples, penicillin remains the first recommendation for treatment and prevention against GBS infection. Susceptibility testing should be performed for women allergic to penicillin in order to choose the most appropriate antibacterial agents for treatment and prevention of vertical transmission to neonates. In addition, we suggest establishing standard processes for GBS culture and identification in China as early as possible. PMID- 28813479 TI - Metabolomic profiling of amines in sepsis predicts changes in NOS canonical pathways. AB - RATIONALE: Nitric oxide synthase (NOS) is a biomarker/target in sepsis. NOS activity is driven by amino acids, which cycle to regulate the substrate L arginine in parallel with cycles which regulate the endogenous inhibitors ADMA and L-NMMA. The relationship between amines and the consequence of plasma changes on iNOS activity in early sepsis is not known. OBJECTIVE: Our objective was to apply a metabolomics approach to determine the influence of sepsis on a full array of amines and what consequence these changes may have on predicted iNOS activity. METHODS AND MEASUREMENTS: 34 amino acids were measured using ultra purification mass spectrometry in the plasma of septic patients (n = 38) taken at the time of diagnosis and 24-72 hours post diagnosis and of healthy volunteers (n = 21). L-arginine and methylarginines were measured using liquid-chromatography mass spectrometry and ELISA. A top down approach was also taken to examine the most changed metabolic pathways by Ingenuity Pathway Analysis. The iNOS supporting capacity of plasma was determined using a mouse macrophage cell-based bioassay. MAIN RESULTS: Of all the amines measured 22, including L-arginine and ADMA, displayed significant differences in samples from patients with sepsis. The functional consequence of increased ADMA and decreased L-arginine in context of all cumulative metabolic changes in plasma resulted in reduced iNOS supporting activity associated with sepsis. CONCLUSIONS: In early sepsis profound changes in amine levels were defined by dominant changes in the iNOS canonical pathway resulting in functionally meaningful changes in the ability of plasma to regulate iNOS activity ex vivo. PMID- 28813480 TI - Paleogenetic study on the 17th century Korean mummy with atherosclerotic cardiovascular disease. AB - While atherosclerotic cardiovascular disease (ASCVD) is known to be common among modern people exposed to various risk factors, recent paleopathological studies have shown that it affected ancient populations much more frequently than expected. In 2010, we investigated a 17th century Korean female mummy with presumptive ASCVD signs. Although the resulting report was a rare and invaluable conjecture on the disease status of an ancient East Asian population, the diagnosis had been based only on anatomical and radiological techniques, and so could not confirm the existence of ASCVD in the mummy. In the present study, we thus performed a paleogenetic analysis to supplement the previous conventional diagnosis of ASCVD. In aDNA extracted from the same Korean mummy, we identified the risk alleles of seven different SNPs (rs5351, rs10757274, rs2383206, rs2383207, rs10757278, rs4380028 and rs1333049) that had already been revealed to be the major risk loci of ASCVD in East Asian populations. The reliability of this study could be enhanced by cross-validation using two different analyses: Sanger and SNaPshot techniques. We were able to establish that the 17th century Korean female had a strong genetic predisposition to increased risk of ASCVD. The current paleogenetic diagnosis, the first of its kind outside Europe, re-confirms its utility as an adjunct modality for confirmatory diagnosis of ancient ASCVD. PMID- 28813481 TI - Method matters: Experimental evidence for shorter avian sperm in faecal compared to abdominal massage samples. AB - Birds are model organisms in sperm biology. Previous work in zebra finches, suggested that sperm sampled from males' faeces and ejaculates do not differ in size. Here, we tested this assumption in a captive population of house sparrows, Passer domesticus. We compared sperm length in samples from three collection techniques: female dummy, faecal and abdominal massage samples. We found that sperm were significantly shorter in faecal than abdominal massage samples, which was explained by shorter heads and midpieces, but not flagella. This result might indicate that faecal sampled sperm could be less mature than sperm collected by abdominal massage. The female dummy method resulted in an insufficient number of experimental ejaculates because most males ignored it. In light of these results, we recommend using abdominal massage as a preferred method for avian sperm sampling. Where avian sperm cannot be collected by abdominal massage alone, we advise controlling for sperm sampling protocol statistically. PMID- 28813482 TI - Cysteine-rich protein 2 accelerates actin filament cluster formation. AB - Filamentous actin (F-actin) forms many types of structures and dynamically regulates cell morphology and movement, and plays a mechanosensory role for extracellular stimuli. In this study, we determined that the smooth muscle related transcription factor, cysteine-rich protein 2 (CRP2), regulates the supramolecular networks of F-actin. The structures of CRP2 and F-actin in solution were analyzed by small-angle X-ray solution scattering (SAXS). The general shape of CRP2 was partially unfolded and relatively ellipsoidal in structure, and the apparent cross sectional radius of gyration (Rc) was about 15.8 A. The predicted shape, derived by ab initio modeling, consisted of roughly four tandem clusters: LIM domains were likely at both ends with the middle clusters being an unfolded linker region. From the SAXS analysis, the Rc of F actin was about 26.7 A, and it was independent of CRP2 addition. On the other hand, in the low angle region of the CRP2-bound F-actin scattering, the intensities showed upward curvature with the addition of CRP2, which indicates increasing branching of F-actin following CRP2 binding. From biochemical analysis, the actin filaments were augmented and clustered by the addition of CRP2. This F-actin clustering activity of CRP2 was cooperative with alpha actinin. Thus, binding of CRP2 to F-actin accelerates actin polymerization and F actin cluster formation. PMID- 28813483 TI - Muroid rodent phylogenetics: 900-species tree reveals increasing diversification rates. AB - We combined new sequence data for more than 300 muroid rodent species with our previously published sequences for up to five nuclear and one mitochondrial genes to generate the most widely and densely sampled hypothesis of evolutionary relationships across Muroidea. An exhaustive screening procedure for publically available sequences was implemented to avoid the propagation of taxonomic errors that are common to supermatrix studies. The combined data set of carefully screened sequences derived from all available sequences on GenBank with our new data resulted in a robust maximum likelihood phylogeny for 900 of the approximately 1,620 muroids. Several regions that were equivocally resolved in previous studies are now more decisively resolved, and we estimated a chronogram using 28 fossil calibrations for the most integrated age and topological estimates to date. The results were used to update muroid classification and highlight questions needing additional data. We also compared the results of multigene supermatrix studies like this one with the principal published supertrees and concluded that the latter are unreliable for any comparative study in muroids. In addition, we explored diversification patterns as an explanation for why muroid rodents represent one of the most species-rich groups of mammals by detecting evidence for increasing net diversification rates through time across the muroid tree. We suggest the observation of increasing rates may be due to a combination of parallel increases in rate across clades and high average extinction rates. Five increased diversification-rate-shifts were inferred, suggesting that multiple, but perhaps not independent, events have led to the remarkable species diversity in the superfamily. Our results provide a phylogenetic framework for comparative studies that is not highly dependent upon the signal from any one gene. PMID- 28813485 TI - Magnetic Lenz lenses improve the limit-of-detection in nuclear magnetic resonance. AB - A high NMR detection sensitivity is indispensable when dealing with mass and volume-limited samples, or whenever a high spatial resolution is required. The use of miniaturised RF coils is a proven way to increase sensitivity, but situations may arise where space restrictions could prevent the use of a small resonant coil, e.g., in the interior of the smallest practicable micro-coils. We present the use of magnetic lenses, denoted as Lenz lenses due to their working principle, to focus the magnetic flux of an RF coil into a smaller volume and thereby locally enhance the sensitivity of the NMR experiment-at the expense of the total sensitive volume. Besides focusing, such lenses facilitate re-guiding or re-shaping of magnetic fields much like optical lenses do with light beams. For the first time we experimentally demonstrate the use of Lenz lenses in magnetic resonance and provide a compact mathematical description of the working principle. Through simulations we show that optimal arrangements can be found. PMID- 28813484 TI - D-cycloserine improves synaptic transmission in an animal model of Rett syndrome. AB - Rett syndrome (RTT), a leading cause of intellectual disability in girls, is predominantly caused by mutations in the X-linked gene MECP2. Disruption of Mecp2 in mice recapitulates major features of RTT, including neurobehavioral abnormalities, which can be reversed by re-expression of normal Mecp2. Thus, there is reason to believe that RTT could be amenable to therapeutic intervention throughout the lifespan of patients after the onset of symptoms. A common feature underlying neuropsychiatric disorders, including RTT, is altered synaptic function in the brain. Here, we show that Mecp2tm1.1Jae/y mice display lower presynaptic function as assessed by paired pulse ratio, as well as decreased long term potentiation (LTP) at hippocampal Schaffer-collateral-CA1 synapses. Treatment of Mecp2tm1.1Jae/y mice with D-cycloserine (DCS), an FDA-approved analog of the amino acid D-alanine with antibiotic and glycinergic activity, corrected the presynaptic but not LTP deficit without affecting deficient hippocampal BDNF levels. DCS treatment did, however, partially restore lower BDNF levels in the brain stem and striatum. Thus, treatment with DCS may mitigate the severity of some of the neurobehavioral symptoms experienced by patients with Rett syndrome. PMID- 28813486 TI - Differentiating between subtypes of primary progressive aphasia and mild cognitive impairment on a modified version of the Frontal Behavioral Inventory. AB - Behavioral assessment has been investigated in frontotemporal lobar degeneration and Alzheimer's disease, but has not been explored extensively in subtypes of primary progressive aphasia (PPA). We explored the ability of a modified version of the Frontal Behavioral Inventory (FBI-mod) to discriminate between patients with distinct subtypes of PPA and patients with mild cognitive impairment (MCI). We hypothesized that individuals with nonfluent agrammatic PPA (nfaPPA) would have higher negative behavior scores than other groups and that individuals with semantic variant PPA (svPPA) would have higher disinhibition scores than other groups. Family members and/or caregivers of 120 individuals with PPA and MCI (mean age 69.54+8.75 years; 65 (54%) female; education 16.06+/-2.68 years; disease duration 46.47+/-34.26 months) completed the FBI-mod [logopenic PPA (lvPPA) n = 40. nfaPPA n = 29, svPPA n = 27, MCI n = 24]. The groups were not significantly different in age, gender, education, or disease duration. There were no significant differences between the groups for negative behaviors (p = 0.72) and disinhibition scores (p = 0.14). When comparing negative and disinhibition scores (in percent), negative scores were significantly higher in all groups (p < 0.001). When comparing subtest items, there was a pairwise difference between lvPPA and svPPA for restlessness (lvPPA < svPPA, p = 0.02, after adjusting for multiple between-group comparisons). There was a significant difference in the proportion of severe neglect between the groups with lvPPA having a lower proportion than the other two variants (p = 0.05), and there was a significant difference in the proportion of severe poor judgment between the groups with lvPPA also having a lower proportion than nfaPPA (p = 0.04). This study reveals the greater negative behavioral disturbance than disinhibition in the PPA and MCI groups of similar age and duration since onset and identifies different profiles for some specific behaviors for the PPA groups. These findings may have clinical and practical implications. PMID- 28813487 TI - Effect of masticatory stimulation on the quantity and quality of saliva and the salivary metabolomic profile. AB - BACKGROUND: This study characterized the changes in quality and quantity of saliva, and changes in the salivary metabolomic profile, to understand the effects of masticatory stimulation. METHODS: Stimulated and unstimulated saliva samples were collected from 55 subjects and salivary hydrophilic metabolites were comprehensively quantified using capillary electrophoresis-time-of-flight mass spectrometry. RESULTS: In total, 137 metabolites were identified and quantified. The concentrations of 44 metabolites in stimulated saliva were significantly higher than those in unstimulated saliva. Pathway analysis identified the upregulation of the urea cycle and synthesis and degradation pathways of glycine, serine, cysteine and threonine in stimulated saliva. A principal component analysis revealed that the effect of masticatory stimulation on salivary metabolomic profiles was less dependent on sample population sex, age, and smoking. The concentrations of only 1 metabolite in unstimulated saliva, and of 3 metabolites stimulated saliva, showed significant correlation with salivary secretion volume, indicating that the salivary metabolomic profile and salivary secretion volume were independent factors. CONCLUSIONS: Masticatory stimulation affected not only salivary secretion volume, but also metabolite concentration patterns. A low correlation between the secretion volume and these patterns supports the conclusion that the salivary metabolomic profile may be a new indicator to characterize masticatory stimulation. PMID- 28813488 TI - Role of post-chemotherapy radiation in the management of children and adolescents with primary advanced malignant mediastinal germ cell tumors. AB - OBJECTIVE: Primary malignant mediastinal germ cell tumors (MMGCTs) are rare in children and adolescents and have a poorer prognosis than their gonadal counterparts. We report a single institutional experience of a 10-year period of primary advanced MMGCTs treated with chemotherapy, followed by radiotherapy in those who had residual mass. METHODS: Children and adolescents with primary advanced MMGCTs between 2005 and 2014 were identified from the Cancer Center, Sun Yat-Sen University. Medical records were reviewed for clinicopathological characteristics, treatments, and outcomes. RESULTS: Twenty-four children and adolescents with either stage III or IV primary advanced MMGCTs met the inclusion criteria. There were 23 males and one female with a median age of 16 (range 10 18). Seven cases were seminomas (29.2%); four (16.7%) yolk sac tumors (YST); three (12.5%) choriocarcinomas; and ten (41.6%) nonteratomatous combined germ cell tumors (CGCTs). All patients were treated with first-line cisplatin-based chemotherapy regimens (PEB: 19, VIP: 5). Thirteen (54.2%) and Twelve (50%) patients received surgery and radiotherapy, respectively. With a median follow-up of 46.2 months (range 9.6-124.8 months), a total of five (20%) patients died of disease progression; the five-year overall survival (OS) and disease-free survival (DFS) rates were 82.3% and 64.9%, respectively.-Seven patients with seminoma GCTs received post-chemotherapy irradiation were alive with sustained CR (5-year OS and DFS, 100%, respectively). Five patients with NSGCTs were administered irradiation and one relapsed 35 months later and died of metastasis (5-year OS, 100%; 5-year DFS 66.7%). Univariate analysis identified histology and stage were prognostic factors. CONCLUSION: Multimodality treatment approach of chemotherapy followed by radiation consolidation ensured long-term survival in primary advanced MMGCTs. Further research is warranted to improve the prognosis of children with primary advanced MMGCTs. PMID- 28813489 TI - Oxidative and glycolytic skeletal muscles show marked differences in gene expression profile in Chinese Qingyuan partridge chickens. AB - Oxidative and glycolytic myofibers have different structures and metabolic characteristics and their ratios are important in determining poultry meat quality. However, the molecular mechanisms underlying their differences are unclear. In this study, global gene expression profiling was conducted in oxidative skeletal muscle (obtained from the soleus, or SOL) and glycolytic skeletal muscle (obtained from the extensor digitorum longus, or EDL) of Chinese Qingyuan partridge chickens, using the Agilent Chicken Gene Expression Chip. A total of 1224 genes with at least 2-fold differences were identified (P < 0.05), of which 654 were upregulated and 570 were downregulated in SOL. GO, KEGG pathway, and co-expressed gene network analyses suggested that PRKAG3, ATP2A2, and PPARGC1A might play important roles in myofiber composition. The function of PPARGC1A gene was further validated. PPARGC1A mRNA expression levels were higher in SOL than in EDL muscles throughout the early postnatal development stages. In myoblast cells, shRNA knockdown of PPARGC1A significantly inhibited some muscle development and transition-related genes, including PPP3CA, MEF2C, and SM (P < 0.01 or P < 0.05), and significantly upregulated the expression of FWM (P < 0.05). Our study demonstrates strong transcriptome differences between oxidative and glycolytic myofibers, and the results suggest that PPARGC1A is a key gene involved in chicken myofiber composition and transition. PMID- 28813491 TI - Climate change and body size trends in aquatic and terrestrial endotherms: Does habitat matter? AB - Several studies have claimed that reduction in body size comprises a nearly universal response to global warming; however, doubts about the validity of this pattern for endothermic species have been raised recently. Accordingly, we assessed temporal changes in body mass for 27 bird and 17 mammal species, to evaluate if a reduction in body size during the 20th century is a widespread phenomenon among endothermic vertebrates. In addition, we tested if there are differences in the temporal change in size between birds and mammals, aquatic and terrestrial species, and the first and second half of the 20th century. Overall, six species increased their body mass, 21 species showed no significant changes in size, and 17 species decreased their body mass during the 20th century. Temporal changes in body mass were similar for birds and mammals, but strongly differ between aquatic and terrestrial species: while most of the aquatic species increased or did not change in body mass, most terrestrial species decreased in size. In addition, we found that, at least in terrestrial birds, the mean value of the correlation between body mass and year of collection differs between the first half and the second half of the 20th century, being close to zero for the former period but negative for the later one. To our knowledge, this is the first study showing that temporal changes in body mass differ between aquatic and terrestrial species in both mammals and birds. PMID- 28813490 TI - Low validity of Google Trends for behavioral forecasting of national suicide rates. AB - Recent research suggests that search volumes of the most popular search engine worldwide, Google, provided via Google Trends, could be associated with national suicide rates in the USA, UK, and some Asian countries. However, search volumes have mostly been studied in an ad hoc fashion, without controls for spurious associations. This study evaluated the validity and utility of Google Trends search volumes for behavioral forecasting of suicide rates in the USA, Germany, Austria, and Switzerland. Suicide-related search terms were systematically collected and respective Google Trends search volumes evaluated for availability. Time spans covered 2004 to 2010 (USA, Switzerland) and 2004 to 2012 (Germany, Austria). Temporal associations of search volumes and suicide rates were investigated with time-series analyses that rigorously controlled for spurious associations. The number and reliability of analyzable search volume data increased with country size. Search volumes showed various temporal associations with suicide rates. However, associations differed both across and within countries and mostly followed no discernable patterns. The total number of significant associations roughly matched the number of expected Type I errors. These results suggest that the validity of Google Trends search volumes for behavioral forecasting of national suicide rates is low. The utility and validity of search volumes for the forecasting of suicide rates depend on two key assumptions ("the population that conducts searches consists mostly of individuals with suicidal ideation", "suicide-related search behavior is strongly linked with suicidal behavior"). We discuss strands of evidence that these two assumptions are likely not met. Implications for future research with Google Trends in the context of suicide research are also discussed. PMID- 28813494 TI - Passive and semi-active heave compensator: Project design methodology and control strategies. AB - Heave compensator is a system that mitigates transmission of heave movement from vessels to the equipment in the vessel. In drilling industry, a heave compensator enables drilling in offshore environments. Heave compensator attenuates movement transmitted from the vessel to the drill string and drill bit ensuring security and efficiency of the offshore drilling process. Common types of heave compensators are passive, active and semi-active compensators. This article presents 4 main points. First, a bulk modulus analysis obtains a simple condition to determine if the bulk modulus can be neglected in the design of hydropneumatic passive heave compensator. Second, the methodology to design passive heave compensators with the desired frequency response. Third, four control methodologies for semi-active heave compensator are tested and compared numerically. Lastly, we show experimental results obtained from a prototype with the methodology developed to design passive heave compensator. PMID- 28813493 TI - Mpp10 represents a platform for the interaction of multiple factors within the 90S pre-ribosome. AB - In eukaryotes, ribosome assembly is a highly complex process that involves more than 200 assembly factors that ensure the folding, modification and processing of the different rRNA species as well as the timely association of ribosomal proteins. One of these factors, Mpp10 associates with Imp3 and Imp4 to form a complex that is essential for the normal production of the 18S rRNA. Here we report the crystal structure of a complex between Imp4 and a short helical element of Mpp10 to a resolution of 1.88 A. Furthermore, we extend the interaction network of Mpp10 and characterize two novel interactions. Mpp10 is able to bind the ribosome biogenesis factor Utp3/Sas10 through two conserved motifs in its N-terminal region. In addition, Mpp10 interacts with the ribosomal protein S5/uS7 using a short stretch within an acidic loop region. Thus, our findings reveal that Mpp10 provides a platform for the simultaneous interaction with multiple proteins in the 90S pre-ribosome. PMID- 28813492 TI - Point-prevalence survey of healthcare facility-onset healthcare-associated Clostridium difficile infection in Greek hospitals outside the intensive care unit: The C. DEFINE study. AB - BACKGROUND: The correlation of Clostridium difficile infection (CDI) with in hospital morbidity is important in hospital settings where broad-spectrum antimicrobial agents are routinely used, such as in Greece. The C. DEFINE study aimed to assess point-prevalence of CDI in Greece during two study periods in 2013. METHODS: There were two study periods consisting of a single day in March and another in October 2013. Stool samples from all patients hospitalized outside the ICU aged >=18 years old with diarrhea on each day in 21 and 25 hospitals, respectively, were tested for CDI. Samples were tested for the presence of glutamate dehydrogenase antigen (GDH) and toxins A/B of C. difficile; samples positive for GDH and negative for toxins were further tested by culture and PCR for the presence of toxin genes. An analysis was performed to identify potential risk factors for CDI among patients with diarrhea. RESULTS: 5,536 and 6,523 patients were screened during the first and second study periods, respectively. The respective point-prevalence of CDI in all patients was 5.6 and 3.9 per 10,000 patient bed-days whereas the proportion of CDI among patients with diarrhea was 17% and 14.3%. Logistic regression analysis revealed that solid tumor malignancy [odds ratio (OR) 2.69, 95% confidence interval (CI): 1.18-6.15, p = 0.019] and antimicrobial administration (OR 3.61, 95% CI: 1.03-12.76, p = 0.045) were independent risk factors for CDI development. Charlson's Comorbidity Index (CCI) >6 was also found as a risk factor of marginal statistical significance (OR 2.24, 95% CI: 0.98-5.10). Median time to CDI from hospital admission was shorter with the presence of solid tumor malignancy (3 vs 5 days; p = 0.002) and of CCI >6 (4 vs 6 days, p = 0.009). CONCLUSIONS: The point-prevalence of CDI in Greek hospitals was consistent among cases of diarrhea over a 6-month period. Major risk factors were antimicrobial use, solid tumor malignancy and a CCI score >6. PMID- 28813495 TI - Establishing failure predictors for the planned extubation of overweight and obese patients. AB - We investigated failure predictors for the planned extubation of overweight (body mass index [BMI] = 25.0-29.9) and obese (BMI >= 30) patients. All patients admitted to the adult intensive care unit (ICU) of a tertiary hospital in Taiwan were identified. They had all undergone endotracheal intubation for > 48 h and were candidates for extubation. During the study, 595 patients (overweight = 458 [77%]); obese = 137 [23%]) with planned extubation after weaning were included in the analysis; extubation failed in 34 patients (5.7%). Their mean BMI was 28.5 +/ 3.8. Only BMI and age were significantly different between overweight and obese patients. The mortality rate for ICU patients was 0.8%, and 2.9% for inpatients during days 1-28; the overall in-hospital mortality rate was 8.4%. Failed Extubation group patients were significantly older, had more end-stage renal disease (ESRD), more cardiovascular system-related respiratory failure, higher maximal inspiratory pressure (MIP), lower maximal expiratory pressure (MEP), higher blood urea nitrogen, and higher ICU- and 28-day mortality rates than did the Successful Extubation group. Multivariate logistic regression showed that cardiovascular-related respiratory failure (odds ratio [OR]: 2.60; 95% [confidence interval] CI: 1.16-5.80), ESRD (OR: 14.00; 95% CI: 6.25-31.35), and MIP levels (OR: 0.94; 95% CI: 0.90-0.97) were associated with extubation failure. We conclude that the extubation failure risk in overweight and obese patients was associated with cardiovascular system-related respiratory failure, ESRD, and low MIP levels. PMID- 28813496 TI - Uneven distribution of enamel, dentine and cementum in cheek teeth of domestic horses (Equus caballus): A micro computed tomography study. AB - BACKGROUND: Hypsodont equine cheek teeth possess large dental crowns, resting partly in the bony alveolus. Over a horse's life cheek teeth erupt continuously to compensate for occlusal wear of 3-4 mm per year. Parts of the crown initially resting in the bony alveolus become progressively exposed at the occlusal surface with time. Hitherto, it is unclear whether the typical structure of the equine occlusal surface, composed of a complex arrangement of enamel, dentin and cementum, remains constant or undergoes structural changes with age. Therefore, we tested the hypothesis that the occlusal surface composition does not remain constant by a quantitative analysis of the dental substances at multiple levels along the dental crown of equine cheek teeth. METHODS: Micro-computed tomography scans of 20 upper cheek teeth and 16 lower cheek teeth from 19 domestic horses were morphologically analysed using imaging and measurement software. Area for individual dental substances was measured at different levels from the apex to the occlusal surface. The data was statistically analysed to detect changes in the area of individual substance along the dental crown. The area of peripheral cementum was measured separately for levels inside and outside the bony alveolus. RESULTS: In both, upper and lower cheek teeth, enamel area decreased in an apical direction, while dentine area increased. Peripheral Cementum increased dramatically in the occlusal/coronal extra-alveolar position. CONCLUSION: With increasing age the occlusal surface content of dentine increases while the content of enamel decreases. These changes are considered relevant for the detailed explanation of forage disruption in horses as well as for the recommendation of concepts in equine dentistry. PMID- 28813497 TI - High hydrostatic pressure induces pro-osteoarthritic changes in cartilage precursor cells: A transcriptome analysis. AB - Due to the high water content of cartilage, hydrostatic pressure is likely one of the main physical stimuli sensed by chondrocytes. Whereas, in the physiological range (0 to around 10 MPa), hydrostatic pressure exerts mostly pro-chondrogenic effects in chondrocyte models, excessive pressures have been reported to induce detrimental effects on cartilage, such as increased apoptosis and inflammation, and decreased cartilage marker expression. Though some genes modulated by high pressure have been identified, the effects of high pressure on the global gene expression pattern have still not been investigated. In this study, using microarray technology and real-time PCR validation, we analyzed the transcriptome of ATDC5 chondrocyte progenitors submitted to a continuous pressure of 25 MPa for up to 24 h. Several hundreds of genes were found to be modulated by pressure, including some not previously known to be mechano-sensitive. High pressure markedly increased the expression of stress-related genes, apoptosis-related genes and decreased that of cartilage matrix genes. Furthermore, a large set of genes involved in the progression of osteoarthritis were also induced by high pressure, suggesting that hydrostatic pressure could partly mimic in vitro some of the genetic alterations occurring in osteoarthritis. PMID- 28813498 TI - Phylogeography of bivalve Meretrix petechialis in the Northwestern Pacific indicated by mitochondrial and nuclear DNA data. AB - The marine clam Meretrix petechialis is an important economic shellfish species in Northwestern Pacific, but little is known about its phylogeographical pattern. Here, we analyzed 311 samples from 22 locations along the northwestern Pacific using combined profiling of one mitochondrial gene (the first subunit of cytochrome coxidase, COI) and one nuclear DNA marker (the internal transcribed spacer region 1, ITS-1) to investigate contemporary genetic structure and reconstruct phylogenetic history of this species. The results revealed that two distinct phylogeographic lineages dominated marginal seas-the East China Sea (ECS) and the South China Sea (SCS) respectively. The estimation of divergence time between two lineages was 2.1-3.8 Ma, corresponding to a period of the early Pleistocene to late Pliocene. The vicariance of the two lineages was connected to the historical isolation of marginal seas and sea surface temperature (SST) gradient, pointing that SST might play an important role in maintaining phylogeographical patterns of M. petachialis. Significant overlaps between two lineages were observed in 23 degrees to 29 degrees N, located at the adjacent area of the ECS and SCS, which might be promoted by the connectivity of China Coast Current. However, the influence of ocean currents on mixings between two lineages was limited. In comparison, significant relationships were found between genetic distances and geographic distances if the North and South populations were analyzed separately, result of which might be due to some small reciprocal, rotating flows along coastal areas and special geographical conditions. PMID- 28813499 TI - Staphylococcus aureus biofilm elicits the expansion, activation and polarization of myeloid-derived suppressor cells in vivo and in vitro. AB - Staphylococcus aureus (S. aureus) is one of the most common causes of biofilm infections in periprosthetic joint infections (PJIs). Accumulating evidence has shown that the immunosuppressive environment established by S. aureus biofilm infection in PJIs involves the presence of myeloid-derived suppressor cells (MDSCs) and M2-macrophages. Due to the diversity of MDSCs, little is known about whether S. aureus biofilm preferentially expands specific MDSC subsets or whether MDSCs can further differentiate into M2-macrophages during S. aureus biofilm infection. Here, we show that in agreement with the results from an established rat PJI model, S. aureus biofilm cocultured with freshly isolated bone marrow cells (BMCs) in vitro significantly increases the proportions of MDSCs, total macrophages and M2-macrophages. Interestingly, we find that treatment of the BMCs in vitro with S. aureus biofilm preferentially promotes the expansion of monocytic MDSCs but not granulocytic MDSCs. Biofilm treatment also substantially enhances the overall MDSC immunosuppressive activity in addition to the MDSC expansion in vitro. Importantly, we provide evidence that S. aureus biofilm is capable of further stimulating the conversion of monocytic MDSCs into M2 macrophages in vitro and in vivo. Collectively, our studies reveal a direct link between MDSCs and M2-macrophages occurring in S. aureus-associated PJIs. PMID- 28813500 TI - Telomere biology and telomerase mutations in cirrhotic patients with hepatocellular carcinoma. AB - Telomeres are repetitive DNA sequences at linear chromosome termini, protecting chromosomes against end-to-end fusion and damage, providing chromosomal stability. Telomeres shorten with mitotic cellular division, but are maintained in cells with high proliferative capacity by telomerase. Loss-of-function mutations in telomere-maintenance genes are genetic risk factors for cirrhosis development in humans and murine models. Telomerase deficiency provokes accelerated telomere shortening and dysfunction, facilitating genomic instability and oncogenesis. Here we examined whether telomerase mutations and telomere shortening were associated with hepatocellular carcinoma (HCC) secondary to cirrhosis. Telomere length of peripheral blood leukocytes was measured by Southern blot and qPCR in 120 patients with HCC associated with cirrhosis and 261 healthy subjects. HCC patients were screened for telomerase gene variants (in TERT and TERC) by Sanger sequencing. Age-adjusted telomere length was comparable between HCC patients and healthy subjects by both Southern blot and qPCR. Four non-synonymous TERT heterozygous variants were identified in four unrelated patients, resulting in a significantly higher mutation carrier frequency (3.3%) in patients as compared to controls (p = 0.02). Three of the four variants (T726M, A1062T, and V1090M) were previously observed in patients with other telomere diseases (severe aplastic anemia, acute myeloid leukemia, and cirrhosis). A novel TERT variant, A243V, was identified in a 65-year-old male with advanced HCC and cirrhosis secondary to chronic hepatitis C virus (HCV) and alcohol ingestion, but direct assay measurements in vitro did not detect modulation of telomerase enzymatic activity or processivity. In summary, constitutional variants resulting in amino acid changes in the telomerase reverse transcriptase were found in a small proportion of patients with cirrhosis associated HCC. PMID- 28813504 TI - Effect of CO2-induced seawater acidification on growth, photosynthesis and inorganic carbon acquisition of the harmful bloom-forming marine microalga, Karenia mikimotoi. AB - Karenia mikimotoi is a widespread, toxic and non-calcifying dinoflagellate, which can release and produce ichthyotoxins and hemolytic toxins affecting the food web within the area of its bloom. Shifts in the physiological characteristics of K. mikimotoi due to CO2-induced seawater acidification could alter the occurrence, severity and impacts of harmful algal blooms (HABs). Here, we investigated the effects of elevated pCO2 on the physiology of K. mikimotoi. Using semi-continuous cultures under controlled laboratory conditions, growth, photosynthesis and inorganic carbon acquisition were determined over 4-6 week incubations at ambient (390ppmv) and elevated pCO2 levels (1000 ppmv and 2000 ppmv). pH-drift and inhibitor-experiments suggested that K. mikimotoi was capable of acquiring HCO3-, and that the utilization of HCO3- was predominantly mediated by anion-exchange proteins, but that HCO3- dehydration catalyzed by external carbonic anhydrase (CAext) only played a minor role in K. mikimotoi. Even though down-regulated CO2 concentrating mechanisms (CCMs) and enhanced gross photosynthetic O2 evolution were observed under 1000 ppmv CO2 conditions, the saved energy did not stimulate growth of K. mikimotoi under 1000 ppmv CO2, probably due to the increased dark respiration. However, significantly higher growth and photosynthesis [in terms of photosynthetic oxygen evolution, effective quantum Yield (Yield), photosynthetic efficiency (alpha), light saturation point (Ek) and ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) activity] were observed under 2000 ppmv CO2 conditions. Furthermore, elevated pCO2 increased the photo-inhibition rate of photosystem II (beta) and non-photochemical quenching (NPQ) at high light. We suggest that the energy saved through the down-regulation of CCMs might lead to the additional light stress and photo-damage. Therefore, the response of this species to elevated CO2 conditions will be determined by more than regulation and efficiency of CCMs. PMID- 28813501 TI - Durum wheat miRNAs in response to nitrogen starvation at the grain filling stage. AB - Durum wheat highly depends on nitrogen for seed development and yield, and the obtainment of varieties with a better nitrogen use efficiency is crucial to reduce production costs and environmental pollution. In this study, sequencing of two small RNA libraries obtained from tissues of Ciccio and Svevo cultivars grown under nitrogen starvation conditions produced 84 novel, and 161 conserved miRNAs. Of these, 7 novel and 13 known miRNAs were newly identified in this work. Quantitative PCR analysis of selected miRNAs highlighted that the expression levels of some of them depends on the tissue and on the cultivar, Svevo being the most responsive to nitrogen starvation. A number of target genes were predicted to be involved in nitrogen metabolism. An inverse correlation for the qPCR expression data of miRNA/target pairs miR399b/PHO2, miR393c/AFB2, ttu-novel 61/CCAAT-TF was observed in specific tissues or cultivar. Especially, ttu-novel 61 was down-regulated and its target CCAAT-TF up-regulated in almost all tissues both in Svevo and in Ciccio. Moreover, CCAAT-TF was confirmed to be cleaved by ttu-novel-61 at the expected site. The discovery of miRNAs involved in the response to nitrogen stress represents an important step towards functional analyses, with the final aim to design strategies for improving nitrogen use efficiency in durum wheat. PMID- 28813505 TI - Allostatic load as a predictor of all-cause and cause-specific mortality in the general population: Evidence from the Scottish Health Survey. AB - Allostatic load is a multiple biomarker measure of physiological 'wear and tear' that has shown some promise as marker of overall physiological health, but its power as a risk predictor for mortality and morbidity is less well known. This study has used data from the 2003 Scottish Health Survey (SHeS) (nationally representative sample of Scottish population) linked to mortality records to assess how well allostatic load predicts all-cause and cause-specific mortality. From the sample, data from 4,488 men and women were available with mortality status at 5 and 9.5 (rounded to 10) years after sampling in 2003. Cox proportional hazard models estimated the risk of death (all-cause and the five major causes of death in the population) according to allostatic load score. Multiple imputation was used to address missing values in the dataset. Analyses were also adjusted for potential confounders (sex, age and deprivation). There were 258 and 618 deaths over the 5-year and 10-year follow-up period, respectively. In the fully-adjusted model, higher allostatic load (poorer physiological 'health') was not associated with an increased risk of all-cause mortality after 5 years (HR = 1.07, 95% CI 0.94 to 1.22; p = 0.269), but it was after 10 years (HR = 1.08, 95% CI 1.01 to 1.16; p = 0.026). Allostatic load was not associated with specific causes of death over the same follow-up period. In conclusions, greater physiological wear and tear across multiple physiological systems, as measured by allostatic load, is associated with an increased risk of death, but may not be as useful as a predictor for specific causes of death. PMID- 28813503 TI - Detectable HIV-RNA in semen of HIV controllers. AB - BACKGROUND: Whether spontaneous low levels of HIV-1 RNA in blood plasma correlate with low levels of HIV-1 RNA in seminal plasma has never been investigated in HIV controller (HIC) men so far. METHODS: HIC men enrolled in the ANRS CODEX cohort were eligible for the present study if they had no symptoms of sexually transmitted infections (STI). Two paired samples of blood and semen were collected four weeks apart. HIV-RNA was quantified in blood plasma (bpVL) and in seminal plasma (spVL), and cell-associated HIV-DNA was quantified in peripheral blood mononuclear cells (PBMC) and in non-sperm cells (NSC). Spearman rho tests were used to estimate correlations between bpVL and spVL. RESULTS: Ten men were enrolled. At Day 0 (D0), spVL was detectable in four patients: 458; 552; 256 copies/mL and PCR signal detectable below limit of quantification (LoQ, 40 copies/mL). At Day 28 (D28), spVL was detectable in the same four participants in whom spVL was detectable at D0 with 582; 802; 752 and 50 copies/mL, respectively. HIV-DNA was detectable below LoQ in NSC of one patient at D0 visit. No patient had detectable HIV-DNA in NSC at D28 visit. At D0, bpVL and spVL were highly positively correlated (Spearman rho: 0.94; p = 0.0001). Similar results were found at D28. CONCLUSION: We show that HIV-RNA can be detected in the semen of HIC men, with levels positively correlated with those measured concomitantly in blood plasma. HIC men should be aware of the risk of HIV genital shedding, especially if viral blips are reported. PMID- 28813502 TI - Addressing the challenge of high-priced prescription drugs in the era of precision medicine: A systematic review of drug life cycles, therapeutic drug markets and regulatory frameworks. AB - CONTEXT: Recent public outcry has highlighted the rising cost of prescription drugs worldwide, which in several disease areas outpaces other health care expenditures and results in a suboptimal global availability of essential medicines. METHOD: A systematic review of Pubmed, the Financial Times, the New York Times, the Wall Street Journal and the Guardian was performed to identify articles related to the pricing of medicines. FINDINGS: Changes in drug life cycles have dramatically affected patent medicine markets, which have long been considered a self-evident and self-sustainable source of income for highly profitable drug companies. Market failure in combination with high merger and acquisition activity in the sector have allowed price increases for even off patent drugs. With market interventions and the introduction of QALY measures in health care, governments have tried to influence drug prices, but often encounter unintended consequences. Patent reform legislation, reference pricing, outcome based pricing and incentivizing physicians and pharmacists to prescribe low-cost drugs are among the most promising short-term policy options. Due to the lack of systematic research on the effectiveness of policy measures, an increasing number of ad hoc decisions have been made with counterproductive effects on the availability of essential drugs. Future challenges demand new policies, for which recommendations are offered. CONCLUSION: A fertile ground for high-priced drugs has been created by changes in drug life-cycle dynamics, the unintended effects of patent legislation, government policy measures and orphan drug programs. There is an urgent need for regulatory reform to curtail prices and safeguard equitable access to innovative medicines. PMID- 28813506 TI - Global and local disturbances interact to modify seagrass palatability. AB - Global change, such as warming and ocean acidification, and local anthropogenic disturbances, such as eutrophication, can have profound impacts on marine organisms. However, we are far from being able to predict the outcome of multiple interacting disturbances on seagrass communities. Herbivores are key in determining plant community structure and the transfer of energy up the food web. Global and local disturbances may alter the ecological role of herbivory by modifying leaf palatability (i.e. leaf traits) and consequently, the feeding patterns of herbivores. This study evaluates the main and interactive effects of factors related to global change (i.e. elevated temperature, lower pH levels and associated ocean acidification) and local disturbance (i.e. eutrophication through ammonium enrichment) on a broad spectrum of leaf traits using the temperate seagrass Cymodocea nodosa, including structural, nutritional, biomechanical and chemical traits. The effect of these traits on the consumption rates of the generalist herbivore Paracentrotus lividus (purple sea urchin) is evaluated. The three disturbances of warming, low pH level and eutrophication, alone and in combination, increased the consumption rate of seagrass by modifying all leaf traits. Leaf nutritional quality, measured as nitrogen content, was positively correlated to consumption rate. In contrast, a negative correlation was found between feeding decisions by sea urchins and structural, biomechanical and chemical leaf traits. In addition, a notable accomplishment of this work is the identification of phenolic compounds not previously reported for C. nodosa. Our results suggest that global and local disturbances may trigger a major shift in the herbivory of seagrass communities, with important implications for the resilience of seagrass ecosystems. PMID- 28813507 TI - Comparison of homologous and heterologous prime-boost vaccine approaches using Modified Vaccinia Ankara and soluble protein to induce neutralizing antibodies by the human cytomegalovirus pentamer complex in mice. AB - Since neutralizing antibodies (NAb) targeting the human cytomegalovirus (HCMV) pentamer complex (PC) potently block HCMV host cell entry, anti-PC NAb induction is thought to be important for a vaccine formulation to prevent HCMV infection. By developing a vaccine strategy based on soluble PC protein and using a previously generated Modified Vaccinia Ankara vector co-expressing all five PC subunits (MVA-PC), we compared HCMV NAb induction by homologous immunization using prime-boost vaccine regimen employing only PC protein or MVA-PC and heterologous immunization using prime-boost combinations of PC protein and MVA PC. Utilizing a recently isolated anti-PC NAb, we produced highly pure soluble PC protein that displayed conformational and linear neutralizing epitopes, interfered with HCMV entry, and was recognized by antibodies induced by HCMV during natural infection. Mice vaccinated by different immunization routes with the purified PC protein in combination with a clinically approved adjuvant formulation elicited high-titer and durable HCMV NAb. While MVA-PC and soluble PC protein either alone or in combination elicited robust HCMV NAb, significantly different potencies of these vaccine approaches were observed in dependence on immunization schedule. Using only two immunizations, vaccination with MVA-PC alone or prime-boost combinations of MVA-PC and PC protein was significantly more effective in stimulating HCMV NAb than immunization with PC protein alone. In contrast, with three immunizations, NAb induced by soluble PC protein either alone or combined with two boosts of MVA-PC increased to levels that exceeded NAb titer stimulated by MVA-PC alone. These results provide insights into the potency of soluble protein and MVA to elicit NAb by the HCMV PC via homologous and heterologous prime-boost immunization, which may contribute to develop clinically deployable vaccine strategies to prevent HCMV infection. PMID- 28813508 TI - Increased risk of tinnitus in patients with chronic kidney disease: A nationwide, population-based cohort study. AB - Tinnitus mostly results from central and peripheral auditory pathology. Chronic kidney disease (CKD) is a major risk factor for cerebrovascular disease. However, no studies have evaluated the association between tinnitus and CKD. The aim of this study is to investigate the risk of tinnitus in patients with CKD. This retrospective cohort study was conducted using Taiwan National Health Insurance Research Database from 2000 to 2010. We established a CKD group (n = 185,430) and a non-CKD comparison group (n = 556,290) to investigate the incidence of tinnitus. Cox proportional hazard regression analysis was used to evaluate the effects of CKD on tinnitus risk. The results showed CKD significantly increased the risk of tinnitus (adjusted hazard ratio, 3.02; 95% CI, 2.655-3.456, P<0.001). A subgroup analysis revealed the increase in risk of tinnitus is more in CKD patients with heart failure (adjusted hazard ratio, 9.975; 95% CI, 5.001-18.752) and diabetes mellitus (adjusted hazard ratio, 3.712; 95% CI, 2.856-5.007). Furthermore, compared to non-CKD patients, the risk of tinnitus was increased 4.586-fold (95% CI, 2.399-6.7) in CKD patients with dialysis and 2.461-fold (95% CI, 1.033-3.454) in CKD patients without dialysis. This study is the first to report that CKD is associated with an increased risk of tinnitus. Among CKD cohort, patients with dialysis are at a higher risk of tinnitus than those without dialysis. PMID- 28813509 TI - Associations of particulate matter and its components with emergency room visits for cardiovascular and respiratory diseases. AB - Numerous studies have revealed an association between particulate matter (PM) and emergency room (ER) visits, although few studies have investigated the association between health and PM components. The present study evaluated the associations of ER visits for cardiovascular and respiratory diseases with PM2.5 components, including organic carbon (OC), elemental carbon (EC), and ion species (SO42-, NO3-, and NH4+). Statistical analyses were performed using the time series approach, and generalized linear models with natural spline functions were used to adjust for the non-linear relationship between the confounders and ER visits. Our single-pollutant models revealed that the greatest increase in cardiovascular ER visits was associated with NH4+ (relative risk: 1.05; 95% confidence interval: 1.01-1.09), which was followed by OC, SO42-, NO3-, and EC. The associations of cardiovascular ER visits with EC and OC varied according to age and sex, with elderly and female patients exhibiting stronger associations. Lagged SO42- was associated with respiratory ER visits. To the best of our knowledge, this is the first study to evaluate the associations between ER visits and PM components in South Korea. As PM components are related to traffic and industrial sources, and exhibited positive associations with ER visits, our results may help improve air pollution regulation and public health. PMID- 28813510 TI - Construction of novel pJRD215-derived plasmids using chloramphenicol acetyltransferase (cat) gene as a selection marker for Acidithiobacillus caldus. AB - BACKGROUND: Acidithiobacillus caldus, a Gram-negative, chemolithotrophic sulfur oxidizing bacterium, is widely applied in bioleaching. The absence of an ideal selection marker has become a major obstacle to achieve high efficiency of the gene transfer system for A. caldus. Plasmid pJRD215, widely used in Acidithiobacillus spp., has severe drawbacks in molecular manipulations and potential biosafety issues due to its mobility. Therefore, finding a new selection marker and constructing new plasmids have become an urgent and fundamental work for A. caldus. RESULTS: Effective inhibitory effect of chloramphenicol on the growth of A. caldus was elucidated for the first time. The P2-cat gene cassette, including a chloramphenicol acetyltransferase gene (cat) from plasmid pACBSR and a promoter (P2) upstream of the tetracycline resistance gene on pBR322, was designed, chloramphenicol acetyltransferase was expressed in A. caldus, and the enzyme activity was assessed. A new vector pSDU1 carrying the replication and mobilization regions derived from pJRD215, the P2-cat gene cassette and a multiple cloning site from pUC19 was successfully constructed. Compared with pJRD215, pSDU1 had a 27-fold increase in electrotransformation efficiency (30.43+/-0.88*104 CFU/MUg DNA for pSDU1 and 1.09+/-0.11*104 CFU/MUg DNA for pJRD215), better carrying capacity and could offer more convenience for the restriction enzyme digestion. In addition, the generated plasmid pSDU1Deltamob, a novel non-mobilizable derivative of pSDU1 lacking some DNA sequences involved in the mobilization process, had increased copy number in A. caldus and lost its mobility for biosafety considerations. Both pSDU1 and pSDU1Deltamob exhibited stable maintenance in A. caldus within 50 passages. However, further deletion of orfEF region involved in regulating repAC operon resulted in a negative effect on transformation efficiency, copy number and stability of plasmid pSDU1DeltamobDeltaorfEF in A. caldus. CONCLUSION: Chloramphenicol was proved to be an ideal selection marker for A. caldus. Novel plasmids carrying cat gene were constructed. The utilization of these vectors will undoubtedly facilitate efficient genetic manipulations and accelerate the research progress in A. caldus. PMID- 28813511 TI - Differentiation of human embryonic stem cells into corneal epithelial progenitor cells under defined conditions. AB - The development of cell-based therapies using stem cells represents a significant breakthrough in the treatment of limbal stem cell deficiency (LSCD). The aim of this study was to develop a novel protocol to differentiate human embryonic stem cells (hESCs) into corneal epithelial progenitor cells (CEPCs), with similar features to primary cultured human limbal stem cells (LSCs), using a medium composed of DMEM/F12 and defined keratinocyte serum-free medium (KSFM) (1:1) under different carbon dioxide (CO2) levels in culture. The differentiated cells exhibited a similar morphology to limbal stem cells under 5%, 7%, and 9% CO2 and expressed the LSC markers ABCG-2 and p63; however, CK14 was only expressed in the cells cultured under 7% and 9% CO2. Quantitative reverse-transcription polymerase chain reaction (RT-PCR) analysis indicated that the ABCG2, p63, and CK14 levels in the 7% CO2 and 9% CO2 groups were higher than those in the 5% CO2 group and in undifferentiated hESCs (p<0.05). The highest expression of ABCG2 and p63 was exhibited in the cells cultured under 7% CO2 at day 6 of differentiation. Western blotting indicated that the ABCG2 and p63 levels were higher at day 6 than the other time points in the 7% CO2 and 9% CO2 groups. The highest protein expression of ABCG2 and p63 was identified in the 7% CO2 group. The neural cell-specific marker tubulin beta3 and the epidermal marker K1/10 were also detected in the differentiated cells via immunofluorescent staining; thus, cell sorting was performed via fluorescence-activated cell sorting (FACS), and ABCG2-positive cells were isolated as CEPCs. The sorted cells formed three to four layers of epithelioid cells by airlifting culture and expressed ABCG2, p63, CK14, and CK3. In conclusion, the novel induction system conditioned by 7% CO2 in this study may be an effective and feasible method for CEPC differentiation. PMID- 28813512 TI - Implementation of a comprehensive intervention for patients at high risk of cardiovascular disease in rural China: A pragmatic cluster randomized controlled trial. AB - OBJECTIVE: This study aims to assess whether a standard intervention package of cardiovascular disease (CVD) care was being delivered effectively, and if it was associated with improved lifestyle and biomedical indicators. METHODS: In rural China, we implemented a pragmatic cluster randomized controlled trial for 12 months, randomized at the township hospital level, and compared with usual care. Intervention case management guideline, training and performance monitoring meeting and patient support activities were designed to fit within the job description of family doctors in the township hospitals and comprised: 1) prescription of a standardised package of medicines targeted at those with hypertension or diabetes; 2) advice about specific lifestyle interventions; and 3) advice about medication adherence. Participants were 50-74 years old, had hypertension and CVD risk scores >20% or diabetes, but were excluded if a history of severe CVD events. We also randomly selected 100 participants from six selected clusters per arm as a panel to collect intermediate biomedical indicators over time. RESULTS: A total of 28,130 participants, in 33 intervention and 34 control township hospitals, were recruited. Compared with the control arm, participants in the intervention arm had substantially improved prescribing rates of anti-hypertensives, statins and aspirin (P<0.001), and had higher medication taking rates of aspirin and statins (P<0.001). Mean systolic and diastolic blood pressures were similar across both arms (0.15 mmHg, P = 0.79, and 0.52 mmHg, P = 0.05, respectively). In the panel, (950) rates of smoking (OR = 0.23, P = 0.02) and salt intake (OR = 2.85, P = 0.03) were significantly reduced in the intervention versus control arms, but there were no statistically significant improvement over the 12 month follow-up period in biomedical indicators (P>0.05). CONCLUSION: Implementation of the package by family doctors was feasible and improved prescribing and some lifestyle changes. Additional measures such as reducing medication costs and patient education are required. TRIAL REGISTRATION: Current Controlled Trials ISRCTN58988083. PMID- 28813513 TI - Validation of commercial Mas receptor antibodies for utilization in Western Blotting, immunofluorescence and immunohistochemistry studies. AB - Mas receptor (MasR) is a G protein-coupled receptor proposed as a candidate for mediating the angiotensin (Ang)-converting enzyme 2-Ang (1-7) protective axis of renin-angiotensin system. Because the role of this receptor is not definitively clarified, determination of MasR tissue distribution and expression levels constitutes a critical knowledge to fully understanding its function. Commercially available antibodies have been widely employed for MasR protein localization and quantification, but they have not been adequately validated. In this study, we carried on an exhaustive evaluation of four commercial MasR antibodies, following previously established criteria. Western Blotting (WB) and immunohistochemistry studies starting from hearts and kidneys from wild type (WT) mice revealed that antibodies raised against different MasR domains yielded different patterns of reactivity. Furthermore, staining patterns appeared identical in samples from MasR knockout (MasR-KO) mice. We verified by polymerase chain reaction analysis that the MasR-KO mice used were truly deficient in this receptor as MAS transcripts were undetectable in either heart or kidney from this animal model. In addition, we evaluated the ability of the antibodies to detect the human c-myc-tagged MasR overexpressed in human embryonic kidney cells. Three antibodies were capable of detecting the MasR either by WB or by immunofluorescence, reproducing the patterns obtained with an anti c-myc antibody. In conclusion, although three of the selected antibodies were able to detect MasR protein at high expression levels observed in a transfected cell line, they failed to detect this receptor in mice tissues at physiological expression levels. As a consequence, validated antibodies that can recognize and detect the MasR at physiological levels are still lacking. PMID- 28813514 TI - The Helicobacter pylori type IV secretion system promotes IL-8 synthesis in a model of pediatric airway epithelium via p38 MAP kinase. AB - Epidemiologic studies have reported an inverse relationship between childhood Helicobacter pylori infection and development of allergic asthma. Because lung epithelium plays an important role in allergic asthma pathogenesis, we hypothesized that H. pylori may directly influence airway epithelial cell innate immune function, particularly in early childhood. To test our hypothesis, we established an in vitro H. pylori infection model using primary tracheobronchial epithelial cell cultures derived from infant, juvenile and adult rhesus monkeys. Airway epithelial cell cultures were infected with wild-type or cag pathogenicity island mutant H. pylori strains, followed by evaluation of IL-8 and IL-6 protein synthesis. We found that H. pylori primarily increased IL-8 synthesis in a MOI and age-dependent fashion, with a greater than 4-fold induction in infant versus adult cultures. H. pylori-induced IL-8 synthesis in infant and juvenile cultures was significantly reduced by cag pathogenicity island mutants, indicating a requirement for the type IV secretion system. Although peptidoglycan recognition of nucleotide binding oligomerization domain-containing protein 1 (NOD1) and NF kappaB have been implicated as key cytokine signaling molecules for H. pylori infection in gastric epithelium, NOD1 (ML130) or NF-kappaB (JSH-23) inhibitors minimally affected IL-8 synthesis in airway epithelial cell cultures following H. pylori infection. In contrast, inhibition of the p38 MAP kinase pathway (SB203580) resulted in almost complete suppression of H. pylori-induced IL-8 synthesis. Collectively, these results indicate that H. pylori can preferentially elicit IL-8 synthesis in a model of pediatric airway epithelium using the type IV secretion system via p38 MAP kinase. PMID- 28813515 TI - Correction: The effects of marine traffic on the behaviour of Black Sea harbour porpoises (Phocoena phocoena relicta) within the Istanbul Strait, Turkey. AB - [This corrects the article DOI: 10.1371/journal.pone.0172970.]. PMID- 28813516 TI - Correction: Salivary inflammatory markers and microbiome in normoglycemic lean and obese children compared to obese children with type 2 diabetes. AB - [This corrects the article DOI: 10.1371/journal.pone.0172647.]. PMID- 28813517 TI - PRmePRed: A protein arginine methylation prediction tool. AB - Protein methylation is an important Post-Translational Modification (PTMs) of proteins. Arginine methylation carries out and regulates several important biological functions, including gene regulation and signal transduction. Experimental identification of arginine methylation site is a daunting task as it is costly as well as time and labour intensive. Hence reliable prediction tools play an important task in rapid screening and identification of possible methylation sites in proteomes. Our preliminary assessment using the available prediction methods on collected data yielded unimpressive results. This motivated us to perform a comprehensive data analysis and appraisal of features relevant in the context of biological significance, that led to the development of a prediction tool PRmePRed with better performance. The PRmePRed perform reasonably well with an accuracy of 84.10%, 82.38% sensitivity, 83.77% specificity, and Matthew's correlation coefficient of 66.20% in 10-fold cross-validation. PRmePRed is freely available at http://bioinfo.icgeb.res.in/PRmePRed/. PMID- 28813518 TI - Changes in the incidence of pneumonia, bacterial meningitis, and infant mortality 5 years following introduction of the 13-valent pneumococcal conjugate vaccine in a "3+0" schedule. AB - BACKGROUND: Streptococcus pneumoniae causes about 826,000 deaths of children in the world each year and many health facility visits. To reduce the burden of pneumococcal disease, many nations have added pneumococcal conjugate vaccines to their national immunization schedules. Nicaragua was the first country eligible for GAVI Alliance funding to introduce the 13-valent pneumococcal conjugate vaccine (PCV13) in 2010, provided to infants at 2, 4, and 6 months of age. The goal of this study was to evaluate the population impact of the first five years of the program. METHODS: Numbers of visits for pneumonia, pneumonia-related deaths, and bacterial meningitis in both children and adults, and infant deaths between 2008 and 2015 were collected from all 107 public health facilities in Leon Department. Vital statistics data provided additional counts of pneumonia related deaths that occurred outside health facilities. Adjusted incidence rates and incidence rate ratios (IRRa) in the vaccine (2011-2015) and pre-vaccine periods (2008-2010) were estimated retrospectively using official population estimates as exposure time. RESULTS: The IRRa for pneumonia hospitalizations was 0.70 (95% confidence interval [CI]: 0.66, 0.75) for infants, and 0.92 (95% CI: 0.85, 0.99) for one year-olds. The IRRa for post-neonatal infant mortality was 0.56 (95% CI: 0.41, 0.77). In the population as a whole, ambulatory visits and hospitalizations for pneumonia, as well as pneumonia-related mortality and rates of bacterial meningitis were lower in the vaccine period. CONCLUSIONS: During the first five years of program implementation, reductions were observed in health facility visits for pneumonia in immunized age groups and infant mortality, which would be hard to achieve with any other single public health intervention. Future study is warranted to understand whether the lack of a booster dose (e.g., at 12 months) may be responsible for the small reductions in pneumonia hospitalizations observed in one year-olds as compared to infants. PMID- 28813519 TI - Expression and inhibition of BRD4, EZH2 and TOP2A in neurofibromas and malignant peripheral nerve sheath tumors. AB - Malignant peripheral nerve sheath tumors (MPNST) are rare, highly aggressive sarcomas that can occur spontaneously or from pre-existing plexiform neurofibromas in neurofibromatosis type1 (NF1) patients. MPNSTs have high local recurrence rates, metastasize easily, are generally resistant to therapeutic intervention and frequently fatal for the patient. Novel targeted therapeutic strategies are urgently needed. Standard treatment for patients presenting with advanced disease is doxorubicin based chemotherapy which inhibits the actions of the enzyme topoisomerase IIalpha (TOP2A). Recent molecular studies using murine models and cell lines identified the bromodomain containing protein 4 (BRD4) and enhancer of zeste homolog 2 (EZH2) as novel targets for MPNST treatment. We investigated the expression and potential use of BRD4, EZH2 and TOP2A as therapeutic targets in human NF1-derived MPNSTs. The transcript levels of BRD4, EZH2 and TOP2A were determined in paired formalin-fixed paraffin-embedded (FFPE) neurofibroma/MPNST samples derived from the same NF1 patient and in a set of plexiform neurofibromas, atypical neurofibromas and MPNST. We further examined the effect on cell viability of genetic or pharmacological inhibition of BRD4, EZH2 and TOP2A in an MPNST cell line panel. Our results indicated that in MPNST samples BRD4 mRNA levels were not upregulated and that MPNST cell lines were relatively insensitive to the bromodomain inhibitor JQ1. We corroborated that EZH2 mRNA expression is increased in MPNST but failed to confirm its reported pivotal role in MPNST pathogenesis as EZH2 knockdown by siRNA did not interfere with cellular proliferation and viability. Finally, the relation between TOP2A levels and sensitivity for doxorubicin was examined, confirming reports that TOP2A mRNA levels were overexpressed in MPNST and showing that MPNST cell lines exhibited relatively high TOP2A protein levels and sensitivity to doxorubicin. We tentatively conclude that the potential for effective therapeutic intervention in MPNST by targeting BRD4, EZH2 and TOP2A individually, may be limited. Clinical studies are necessary to ultimately prove the relevance of BRD4 and EZH2 inhibition as novel therapeutic strategies for MPNST. PMID- 28813520 TI - The frequency of class1 and 2 integrons in Pseudomonas aeruginosa strains isolated from burn patients in a burn center of Ahvaz, Iran. AB - BACKGROUND: Pseudomonas aeruginosa is an opportunistic pathogen with the ability to cause severe nosocomial infections and remains a major problem in burn patients. This organism shows a remarkable antimicrobial resistance and is often resistant to multiple antibiotics. Integron genes as mobile genetic elements are playing an important role in the spread of P. aeruginosa antibiotic resistance. This study was aimed to investigate the occurrence of class 1, and 2 integron genes (int1, int2), among P. aeruginosa strains isolated from patients with burn infections. METHODS: In total 93 clinical isolates of P. aeruginosa were screened. The antimicrobial susceptibilities of 9 common antimicrobial agents were tested against the isolates using disk diffusion method. PCR amplification was performed on extracted DNAs for the detection of int1, and int2 genes using the set of specific primers. RESULTS: The majority of P. aeruginosa isolates were from wound infection (69.9%). In disk diffusion method, most isolates showed remarkable resistance to tested antibiotics with highest against gentamicin (94.62%) and ciprofloxacin (93.55%). PCR amplification revealed that 89(95.7%) of P. aeruginosa strains carried int1, but none of them harbored int2 genes. The distribution of int1 gene was highest in blood (100%), followed by wound isolates (95.38%). CONCLUSIONS: We demonstrated a high antimicrobial resistance among P. aeruginosa isolates in our setting. int1 was prevalent and seems to play an important role in multidrug resistance among the isolates. So, performance of antibiotic surveillance programs is necessary for choosing the appropriate therapy and management of infection control practices. PMID- 28813521 TI - Correction: Liver AMP-Activated Protein Kinase Is Unnecessary for Gluconeogenesis but Protects Energy State during Nutrient Deprivation. AB - [This corrects the article DOI: 10.1371/journal.pone.0170382.]. PMID- 28813522 TI - Surveillance in easy to access population subgroups as a tool for evaluating malaria control progress: A systematic review. AB - BACKGROUND: The need for surveillance systems generating targeted, data-driven, responsive control efforts to accelerate and sustain malaria transmission reduction has been emphasized by programme managers, policy makers and scientists. Surveillance using easy-to-access population subgroups (EAGs) may result in considerable cost saving compared to household surveys as the identification and selection of individuals to be surveyed is simplified, fewer personnel are needed, and logistics are simpler. We reviewed available literature on the validation of estimates of key indicators of malaria control progress derived from EAGs, and describe the options to deal with the context specific bias that may occur. METHODS: A literature search was conducted of all documents reporting validation of estimates of malaria control indicators from EAG surveys before the 31st of December 2016. Additional records were identified through cross-reference from selected records, other applicable policy documents and grey literature. After removal of duplicates, 13, 180 abstracts were evaluated and 2,653 eligible abstracts were identified mentioning surveillance in EAGs, of which 29 full text articles were selected for detailed review. The nine articles selected for systematic review compared estimates from health facility and school surveys with those of a contemporaneous sample of the same population in the same geographic area. RESULTS: Review of the available literature on EAGs suitable for surveillance of malaria control progress revealed that little effort has been made to explore the potential approach and settings for use of EAGs; and that there was wide variation in the precision of estimates of control progress between and within studies, particularly for estimates of control intervention coverage. Only one of the studies evaluated the geospatial representativeness of EAG samples, or carried out geospatial analyses to assess or control for lack of geospatial representativeness. Two studies attempted to measure the degree of bias or improve the precision of estimates by controlling for bias in a multivariate analysis; and this was only successful in one study. The observed variability in accuracy of estimates is likely to be caused by selection and/or information bias due to the inherent nature of EAGs. The reviewed studies provided insight into the design and analytical approaches that could be used to limit bias. CONCLUSION: The utility EAGs for routine surveillance of progress in malaria control at the district or sub-district programmatic level will be driven by several factors including whether serial point estimates to measure transmission reduction or more precise geospatial distribution to track 'hot spots' is required, the acceptable degree of precision, the target population, and the resources available for surveillance. The opportunities offered by novel geostatistical analyses and hybrid sampling frames to overcome bias justify a renewed exploration of use of EAGs for malaria monitoring and evaluation. PMID- 28813524 TI - Medical student, nursing student, and non-health care respondents' implicit attitudes toward doctors and patients: Development and a pilot study of a new implicit attitudes test (IAT). AB - INTRODUCTION: Medical educators have been concerned that medical students may decline in empathy for patients during the course of their training, based on studies measuring clinical empathy using psychometrically strong self-report measures. Clinical empathy is a complex construct, incorporating attitudes toward patients but also other components, such as professional detachment. Triangulation of extant measures with instruments based on nonreactive methods could provide a better understanding of whether and how physician attitudes toward patients may be changing during training. We sought to develop and pilot test such a nonreactive method. METHODS: We develop variations of an implicit association test (IAT) designed to measure attitudes toward physicians and patients based on speed of reaction to images of actors and positive and negative words. In the IATs, the same actors are photographed as doctors, clinic outpatients, hospitalized inpatients, and as a "general public" control. We examine preliminary evidence for their validity by collecting pilot data from internet participants (not involved in the health professions), medical students, and nursing students. RESULTS: Internet participants (n = 314) and nursing students (n = 31) had more negative associations (IAT scores) with doctors than did medical students (n = 89); nursing students and female internet participants had more positive associations with hospitalized patients than did medical students and male internet participants. Medical students' associations with hospitalized patients varied by year of training. DISCUSSION: This IAT may provide insight into implicit attitudes among those who enter training for the health profession and changes in those attitudes that may be inculcated during that training. PMID- 28813523 TI - ET-26 hydrochloride (ET-26 HCl) has similar hemodynamic stability to that of etomidate in normal and uncontrolled hemorrhagic shock (UHS) rats. AB - OBJECTIVE: ET-26 HCl is a promising sedative-hypnotic anesthetic with virtually no effect on adrenocortical steroid synthesis. However, whether or not ET-26 HCl also has a sufficiently wide safety margin and hemodynamic stability similar to that of etomidate and related compounds remains unknown. In this study, the effects of ET-26 HCl, etomidate and propofol on therapeutic index, heart rate (HR), mean arterial pressure (MAP), maximal rate for left ventricular pressure rise (Dmax/t), and maximal rate for left ventricular pressure decline (Dmin/t) were investigated in healthy rats and a rat model of uncontrolled hemorrhagic shock (UHS). METHODS: 50% effective dose (ED50) and 50% lethal dose (LD50) were determined after single bolus doses of propofol, etomidate, or ET-26 HCl using the Bliss method and the up and down method, respectively. All rats were divided into either the normal group and received either etomidate, ET-26 HCl or propofol, (n = 6 per group) or the UHS group and received either etomidate, ET-26 HCl or propofol, (n = 6 per group). In the normal group, after preparation for hemodynamic and heart-function monitoring, rats were administered a dose of one of the test agents twofold-higher than the established ED50, followed by hemodynamic and heart-function monitoring. Rats in the UHS group underwent experimentally induced UHS with a target arterial pressure of 40 mmHg for 1 hour, followed by administration of an ED50 dose of one of the experimental agents. Blood-gas analysis was conducted on samples obtained during equilibration with the experimental setup and at the end of the experiment. RESULTS: In the normal group, no significant differences in HR, MAP, Dmax/t and Dmin/t (all P > 0.05) were observed at any time point between the etomidate and ET-26 HCl groups, whereas HR, MAP and Dmax/t decreased briefly and Dmin/t increased following propofol administration. In the UHS group, no significant differences in HR, MAP, Dmax/t and Dmin/t were observed before and after administration of etomidate or ET-26 HCl at ED50 doses (all P > 0.05). Administration of propofol resulted in brief, statistically significant reductions in HR and Dmax/t, with a brief increase in Dmin/t (P ? 0.05), while no significant differences in MAP were observed among the three groups. The blood-lactate concentrations of rats in the ET-26 HCl group were significantly lower than those in etomidate and propofol groups (P ? 0.05). CONCLUSIONS: ET-26 HCl provides a similar level of hemodynamic stability to that obtained with etomidate in both healthy rats, and rat models of UHS. ET-26 HCl has the potential to be a novel induction anesthetic for use in critically ill patients. PMID- 28813525 TI - Is the detection of aquatic environmental DNA influenced by substrate type? AB - The use of environmental DNA (eDNA) to assess the presence-absence of rare, cryptic or invasive species is hindered by a poor understanding of the factors that can remove DNA from the system. In aquatic systems, eDNA can be transported out either horizontally in water flows or vertically by incorporation into the sediment. Equally, eDNA may be broken down by various biotic and abiotic processes if the target organism leaves the system. We use occupancy modelling and a replicated mesocosm experiment to examine how detection probability of eDNA changes once the target species is no longer present. We hypothesise that detection probability falls faster with a sediment which has a large number of DNA binding sites such as topsoil or clay, over lower DNA binding capacity substrates such as sand. Water removed from ponds containing the target species (the great crested newt) initially showed high detection probabilities, but these fell to between 40% and 60% over the first 10 days and to between 10% and 22% by day 15: eDNA remained detectable at very low levels until day 22. Very little difference in detection was observed between the control group (no substrate) and the sand substrate. A small reduction in detection probability was observed between the control and clay substrates, but this was not significant. However, a highly significant reduction in detection probability was observed with a topsoil substrate. This result is likely to have stemmed from increased levels of PCR inhibition, suggesting that incorporation of DNA into the sentiment is of only limited importance. Surveys of aquatic species using eDNA clearly need to take account of substrate type as well as other environmental factors when collecting samples, analysing data and interpreting the results. PMID- 28813526 TI - mTOR has a developmental stage-specific role in mitochondrial fitness independent of conventional mTORC1 and mTORC2 and the kinase activity. AB - The mammalian target of rapamycin (mTOR), present in mTOR complex 1 (mTORC1) and mTORC2, is a serine/threonine kinase that integrates nutrients, growth factors, and cellular energy status to control protein synthesis, cell growth, survival and metabolism. However, it remains elusive whether mTOR plays a developmental stage-specific role in tissue development and whether mTOR can function independent of its complexes and kinase activity. In this study, by inducible genetic manipulation approach, we investigated the role of mTOR and its dependence on mTOR complexes and kinase activity in mitochondrial fitness of early, progenitor stage (lineage-negative; Lin-) versus later, lineage-committed stage (lineage-positive; Lin+) of hematopoietic cells. We found that oxidative phosphorylation (OXPHOS), ATP production and mitochondrial DNA synthesis were decreased in mTOR-/- Lin- cells but increased in mTOR-/- Lin+ cells, suggesting that mTOR plays a developmental stage-specific role in OXPHOS, ATP production and mitochondrial DNA synthesis. In contrast to mTOR deletion, simultaneous deletion of Raptor, a key component of mTORC1, and Rictor, a key component of mTORC2, led to increased mitochondrial DNA in Lin- cells and decreased mitochondrial DNA and ATP production in Lin+ cells, suggesting that mTOR regulates mitochondrial DNA synthesis in Lin- and Lin+ cells and ATP production in Lin+ cells independent of mTORC1 and mTORC2. Similar to mTOR deletion, deletion of Raptor alone attenuated glycolysis and increased mitochondrial mass and mitochondrial membrane potential in Lin- cells and increased mitochondrial mass and OXPHOS in Lin+ cells, whereas deletion of Rictor alone had no effect on these mitochondrial parameters in Lin- and Lin+ cells, suggesting that mTOR regulates glycolysis and mitochondrial membrane potential in Lin- cells, OXPHOS in Lin+ cells, and mitochondrial mass in both Lin- and Lin+ cells dependent on mTORC1, but not mTORC2. Either Raptor deficiency or Rictor deficiency recapitulated mTOR deletion in decreasing OXPHOS in Lin- cells and glycolysis in Lin+ cells, suggesting that mTOR regulates OXPHOS in Lin- cells and glycolysis in Lin+ cells dependent on both mTORC1 and mTORC2. Finally, mice harboring a mTOR kinase dead D2338A knock-in mutant showed decreased glycolysis in Lin+ cells, as seen in mTOR-/- Lin+ cells, but no change in glycolysis in Lin- cells, in contrast to the decreased glycolysis in mTOR-/- Lin- cells, suggesting that mTOR regulates glycolysis in Lin+ cells dependent on its kinase activity, whereas mTOR regulates glycolysis in Lin- cells independent of its kinase activity. PMID- 28813527 TI - HIV self-testing values and preferences among sex workers, fishermen, and mainland community members in Rakai, Uganda: A qualitative study. AB - HIV self-testing may encourage greater uptake of testing, particularly among key populations and other high-risk groups, but local community perceptions will influence test uptake and use. We conducted 33 in-depth interviews and 6 focus group discussions with healthcare providers and community members in high-risk fishing communities (including sex workers and fishermen) and lower-risk mainland communities in rural Uganda to evaluate values and preferences around HIV self testing. While most participants were unfamiliar with HIV self-testing, they cited a range of potential benefits, including privacy, convenience, and ability to test before sex. Concerns focused on the absence of a health professional, risks of careless kit disposal and limited linkage to care. Participants also discussed issues of kit distribution strategies and cost, among others. Ultimately, most participants concluded that benefits outweighed risks. Our findings suggest a potential role for HIV self-testing across populations in these settings, particularly among these key populations. Program implementers will need to consider how to balance HIV self-testing accessibility with necessary professional support. PMID- 28813528 TI - Maternal and fetal risk factors for stillbirth in Northern Tanzania: A registry based retrospective cohort study. AB - BACKGROUND: Stillbirth is a major cause of perinatal mortality and occurs disproportionately in developing countries including Tanzania. However, there is scant information regarding the predictors of this condition in Tanzania. This study aimed to determine maternal and fetal risk factors for stilbirth in northen Tanzania. METHODOLOGY: A retrospective cohort study was performed using maternally-linked data from the Kilimanjaro Christian Medical Centre birth registry. A total of 47681 women who had singleton delivery at KCMC between 2000 and 2014 were analyzed. Women with multiple gestations were excluded. Descriptive statistics were summarized using proportions and frequency. Chi-square test was used to determine risk factors for stillbirth in bivariate analysis. A multivariable regression model was used to estimate adjusted odds ratios (AOR) with 95% confidence intervals for maternal and fetal factors associated with stillbirth. A p-value of less than 0.05 was considered statistically significant. RESULTS: The frequency of stillbirth was 3.5%. Pre-eclampsia (AOR 3.99; 95% CI: 3.31-4.81) and placental abruption (AOR 22.62; 95% CI: 15.41-33.19) were the strongest maternal risk factors associated with still birth. While non-cephalic presentation (AOR 6.05; 95% CI: 4.77-7.66) and low birth weight (AOR 9.66; 95%CI: 8.66-10.77) were the fetal factors with the greatest impact on stillbirth. CONCLUSION: The rate of stillbirth in our study was consistent with past studies of developing countries. Numerous maternal and fetal factors risk factors were identified. Early identification of at risk pregnancies and appropriate intervention may help to reduce the occurrence of stillbirth. PMID- 28813529 TI - Natural and artificial feeding management before weaning promote different rumen microbial colonization but not differences in gene expression levels at the rumen epithelium of newborn goats. AB - The aim of this work was to evaluate the effect of feeding management during the first month of life (natural with the mother, NAT, or artificial with milk replacer, ART) on the rumen microbial colonization and the host innate immune response. Thirty pregnant goats carrying two fetuses were used. At birth one kid was taken immediately away from the doe and fed milk replacer (ART) while the other remained with the mother (NAT). Kids from groups received colostrum during first 2 days of life. Groups of four kids (from ART and NAT experimental groups) were slaughtered at 1, 3, 7, 14, 21 and 28 days of life. On the sampling day, after slaughtering, the rumen content was sampled and epithelial rumen tissue was collected. Pyrosequencing analyses of the bacterial community structure on samples collected at 3, 7, 14 and 28 days showed that both systems promoted significantly different colonization patterns (P = 0.001). Diversity indices increased with age and were higher in NAT feeding system. Lower mRNA abundance was detected in TLR2, TLR8 and TLR10 in days 3 and 5 compared to the other days (7, 14, 21 and 28). Only TLR5 showed a significantly different level of expression according to the feeding system, presenting higher mRNA abundances in ART kids. PGLYRP1 showed significantly higher abundance levels in days 3, 5 and 7, and then experienced a decline independently of the feeding system. These observations confirmed a highly diverse microbial colonisation from the first day of life in the undeveloped rumen, and show that the colonization pattern substantially differs between pre-ruminants reared under natural or artificial milk feeding systems. However, the rumen epithelial immune development does not differentially respond to distinct microbial colonization patterns. PMID- 28813530 TI - Urban and peri-urban family-based pig-keeping in Cambodia: Characteristics, management and perceived benefits and constraints. AB - Keeping pigs in urban and peri-urban areas may not only provide many benefits for the urban households, but may also be challenging and a potential health hazard. The aim of this cross-sectional study was to describe household characteristics and to evaluate perceived benefits and constraints among pig-keepers in the urban and peri-urban areas of Phnom Penh, Cambodia. The study included 204 households and a structured questionnaire was used to interview the household member responsible for taking care of the pigs. Descriptive analyses showed that most households kept between 5 and 15 pigs and that all households kept their pigs in confinement. About 97% of the households owned the pigs themselves and the pigs were generally managed by female household members (43%). Pigs were mainly kept for commercial purposes and more than 60% of the households stated that income from pig-keeping was the main or one of the main sources of revenue for the household. More than 82% reported that they had experienced disease outbreaks among their pigs during the past three years and disease outbreaks were more commonly reported in households with lower socio-economic position (P = 0.025). Disease outbreaks were considered one of the main constraints, along with expensive feed and low payment prices for the slaughter pigs, but few households considered sanitary or other public health issues problematic. Thus, pig-keeping makes an important contribution to the livelihoods of urban and peri-urban households, but many households face external constraints on their production, such as diseases and low revenues, which may have a negative impact on their livelihoods. PMID- 28813531 TI - Short-term leprosy forecasting from an expert opinion survey. AB - We conducted an expert survey of leprosy (Hansen's Disease) and neglected tropical disease experts in February 2016. Experts were asked to forecast the next year of reported cases for the world, for the top three countries, and for selected states and territories of India. A total of 103 respondents answered at least one forecasting question. We elicited lower and upper confidence bounds. Comparing these results to regression and exponential smoothing, we found no evidence that any forecasting method outperformed the others. We found evidence that experts who believed it was more likely to achieve global interruption of transmission goals and disability reduction goals had higher error scores for India and Indonesia, but lower for Brazil. Even for a disease whose epidemiology changes on a slow time scale, forecasting exercises such as we conducted are simple and practical. We believe they can be used on a routine basis in public health. PMID- 28813532 TI - Nitrogen and carbon isotopic dynamics of subarctic soils and plants in southern Yukon Territory and its implications for paleoecological and paleodietary studies. AB - We examine here the carbon and nitrogen isotopic compositions of bulk soils (8 topsoil and 7 subsoils, including two soil profiles) and five different plant parts of 79 C3 plants from two main functional groups: herbs and shrubs/subshrubs, from 18 different locations in grasslands of southern Yukon Territory, Canada (eastern shoreline of Kluane Lake and Whitehorse area). The Kluane Lake region in particular has been identified previously as an analogue for Late Pleistocene eastern Beringia. All topsoils have higher average total nitrogen delta15N and organic carbon delta13C than plants from the same sites with a positive shift occurring with depth in two soil profiles analyzed. All plants analyzed have an average whole plant delta13C of -27.5 +/- 1.2 0/00 and foliar delta13C of -28.0 +/- 1.3 0/00, and average whole plant delta15N of -0.3 +/- 2.2 0/00 and foliar delta15N of -0.6 +/- 2.7 0/00. Plants analyzed here showed relatively smaller variability in delta13C than delta15N. Their average delta13C after suitable corrections for the Suess effect should be suitable as baseline for interpreting diets of Late Pleistocene herbivores that lived in eastern Beringia. Water availability, nitrogen availability, spacial differences and intra-plant variability are important controls on delta15N of herbaceous plants in the study area. The wider range of delta15N, the more numerous factors that affect nitrogen isotopic composition and their likely differences in the past, however, limit use of the modern N isotopic baseline for vegetation in paleodietary models for such ecosystems. That said, the positive correlation between foliar delta15N and N content shown for the modern plants could support use of plant delta15N as an index for plant N content and therefore forage quality. The modern N isotopic baseline cannot be applied directly to the past, but it is prerequisite to future efforts to detect shifts in N cycling and forage quality since the Late Pleistocene through comparison with fossil plants from the same region. PMID- 28813533 TI - 18beta-glycyrrhetinic acid derivative promotes proliferation, migration and aquaporin-3 expression in human dermal fibroblasts. AB - Licorice (Glycyrrhiza) species have been widely used as a traditional medicine and a natural sweetener in foods. The 18beta-glycyrrhetinic acid (18beta-GA) is a bioactive compound in licorice that exhibits potential anti-cancer, anti inflammatory, and anti-microbial activities. Many synthesized derivatives of 18beta-GA have been reported to be cytotoxic and suggested for the treatment of malignant diseases. In this study, we explored the possible pharmacological roles of an 18beta-GA derivative in skin biology using primary human dermal fibroblasts and HaCaT keratinocytes as cell models. We found that this 18beta-GA derivative did not cause cell death, but significantly enhanced the proliferation of dermal fibroblasts and HaCaT keratinocytes. A scratch wound healing assay revealed that the 18beta-GA derivative promoted the migration of fibroblasts. Due to the important role of aquaporin-3 in cell migration and proliferation, we also investigated the expression of aquaporin-3 and found this compound up-regulated the expression of aquaporin-3 in dermal fibroblasts and HaCaT keratinocytes. In dermal fibroblasts, the 18beta-GA derivative induced the phosphorylation of Akt, ERK, and p38. The inhibitor of Akt predominantly suppressed the 18beta-GA derivative-induced expression of aquaporin-3. Collectively, this compound had a positive effect on the proliferation, migration, and aquaporin-3 expression of skin cells, implying its potential role in the treatment of skin diseases characterized by impaired wound healing or dermal defects. PMID- 28813534 TI - The computer-assisted interview In My Shoes can benefit shy preschool children's communication. AB - Interviewing children is a cognitively, socially, and emotionally challenging situation, especially for young and shy children. Thus, finding methods that aid rapport and increase these children's communication is important. The present study investigated whether children's verbal and non-verbal communicative behavior developed differently during the rapport phase, depending on whether children were situationally shy or not, and whether the interview was conducted using the computer-assisted interview In My Shoes (IMS) or a Standard verbal interview. The sample consisted of 60 children aged 4 to 5-years-old. The results showed that for the shy children in the IMS group their talkativeness increased and their answer latency decreased including the amount of encouragement the child needed to talk, while no changes were observed for the shy children in the Standard verbal interview group. There were no significant differences in the non verbal behavior for the shy children regardless of the interview method used. For the non-shy children, overall, the interview method did not affect either the verbal or the non-verbal outcomes. Our findings indicate that IMS can be a useful tool during the rapport-building phase with shy children as it helps these children to improve their verbal communication. PMID- 28813535 TI - Modeling hypothermia induced effects for the heterogeneous ventricular tissue from cellular level to the impact on the ECG. AB - Hypothermia has a profound impact on the electrophysiological mechanisms of the heart. Experimental investigations provide a better understanding of electrophysiological alterations associated with cooling. However, there is a lack of computer models suitable for simulating the effects of hypothermia in cardio-electrophysiology. In this work, we propose a model that describes the cooling-induced electrophysiological alterations in ventricular tissue in a temperature range from 27 degrees C to 37 degrees C. To model the electrophysiological conditions in a 3D left ventricular tissue block it was essential to consider the following anatomical and physiological parameters in the model: the different cell types (endocardial, M, epicardial), the heterogeneous conductivities in longitudinal, transversal and transmural direction depending on the prevailing temperature, the distinct fiber orientations and the transmural repolarization sequences. Cooling-induced alterations on the morphology of the action potential (AP) of single myocardial cells thereby are described by an extension of the selected Bueno-Orovio model for human ventricular tissue using Q10 temperature coefficients. To evaluate alterations on tissue level, the corresponding pseudo electrocardiogram (pECG) was calculated. Simulations show that cooling-induced AP and pECG-related parameters, i.e. AP duration, morphology of the notch of epicardial AP, maximum AP upstroke velocity, AP rise time, QT interval, QRS duration and J wave formation are in good accordance with literature and our experimental data. The proposed model enables us to further enhance our knowledge of cooling-induced electrophysiological alterations from cellular to tissue level in the heart and may help to better understand electrophysiological mechanisms, e.g. in arrhythmias, during hypothermia. PMID- 28813536 TI - Tuberculosis patients in an Indian mega-city: Where do they live and where are they diagnosed? AB - OBJECTIVE: Tuberculosis (TB) is a major source of mortality in urban India, with many structural challenges to optimal care delivery. In the government TB program in Chennai, India's fourth most populous city, there is a 49% gap between the official number of smear-positive TB patients diagnosed and the official number registered in TB treatment within the city in 2014. We hypothesize that this "urban registration gap" is partly due to rural patients temporarily visiting the city for diagnostic evaluation. METHODS: We collected data for one month (May 2015) from 22 government designated microscopy centers (DMCs) in Chennai where 90% of smear-positive TB patients are diagnosed and coded patient addresses by location. We also analyzed the distribution of chest symptomatics (i.e., patients screened for TB because of pulmonary symptoms) and diagnosed smear-positive TB patients for all of Chennai's 54 DMCs in 2014. RESULTS: At 22 DMCs in May 2015, 565 of 3,543 (15.9%) chest symptomatics and 71 of 412 (17.2%) diagnosed smear positive patients had an address outside of Chennai. At the city's four high patient volume DMCs, 54 of 270 (20.0%) smear-positive patients lived out-of-city. At one of these high-volume DMCs, 31 of 59 (52.5%) smear-positive patients lived out-of-city. Out of 6,135 smear-positive patients diagnosed in Chennai in 2014, 3,498 (57%) were diagnosed at the four high-volume DMCs. The 32 DMCs with the lowest patient volume diagnosed 10% of all smear-positive patients. CONCLUSIONS: TB case detection in Chennai is centralized, with four high-volume DMCs making most diagnoses. One-sixth of patients are from outside the city, most of whom get evaluated at these high-volume DMCs. This calls for better coordination between high-volume city DMCs and rural TB units where many patients may take TB treatment. Patient mobility only partly explains Chennai's urban registration gap, suggesting that pretreatment loss to follow-up of patients who live within the city may also be a major problem. PMID- 28813537 TI - Metabolite patterns predicting sex and age in participants of the Karlsruhe Metabolomics and Nutrition (KarMeN) study. AB - Physiological and functional parameters, such as body composition, or physical fitness are known to differ between men and women and to change with age. The goal of this study was to investigate how sex and age-related physiological conditions are reflected in the metabolome of healthy humans and whether sex and age can be predicted based on the plasma and urine metabolite profiles. In the cross-sectional KarMeN (Karlsruhe Metabolomics and Nutrition) study 301 healthy men and women aged 18-80 years were recruited. Participants were characterized in detail applying standard operating procedures for all measurements including anthropometric, clinical, and functional parameters. Fasting blood and 24 h urine samples were analyzed by targeted and untargeted metabolomics approaches, namely by mass spectrometry coupled to one- or comprehensive two-dimensional gas chromatography or liquid chromatography, and by nuclear magnetic resonance spectroscopy. This yielded in total more than 400 analytes in plasma and over 500 analytes in urine. Predictive modelling was applied on the metabolomics data set using different machine learning algorithms. Based on metabolite profiles from urine and plasma, it was possible to identify metabolite patterns which classify participants according to sex with > 90% accuracy. Plasma metabolites important for the correct classification included creatinine, branched-chain amino acids, and sarcosine. Prediction of age was also possible based on metabolite profiles for men and women, separately. Several metabolites important for this prediction could be identified including choline in plasma and sedoheptulose in urine. For women, classification according to their menopausal status was possible from metabolome data with > 80% accuracy. The metabolite profile of human urine and plasma allows the prediction of sex and age with high accuracy, which means that sex and age are associated with a discriminatory metabolite signature in healthy humans and therefore should always be considered in metabolomics studies. PMID- 28813540 TI - The activity of the Research Investments in Global Health study and ways forward within the global funding and policy landscape. AB - The Research Investments in Global Health (ResIn, www.researchinvestments.org) study analyses funding trends in health research, with a predominant focus on infectious diseases. Since October 2015, the project is funded by the Bill & Melinda Gates Foundation and is now based at the University of Southampton in the UK. In 2016, Public Policy@Southampton provided ResIn with a small grant to explore developing links with policy, funding and research stakeholders with an interest in global health. Three meetings were organised in London (Wellcome Trust, 25 May 2016), Brussels (UK Research Office, 2 June 2016), and Geneva (WHO R&D Observatory, 8 June 2016). In total, 45 stakeholders attended and provided comment and critique on the study methodology and potential expansion into other disciplines. A theme that emerged across all three meetings concerned the use of a standardised categorisation system. A key benefit of the ResIn study is the ability to present granular detail in precise areas. Further work packages that could enhance the use of the collected R&D data included integration with geospatial, policy and scientometric methodologies. There was broad enthusiasm that outputs from these proposed projects would provide clear benefits in informing health policy and R&D strategy. Outputs from the ongoing study covering infection-related R&D investments in the G20 nations will be available in 2017. PMID- 28813538 TI - Genome-wide association analysis reveals genetic loci and candidate genes for feeding behavior and eating efficiency in Duroc boars. AB - Efficient use of feed resources is a challenge in the pork industry because the largest variability in expenditure is attributed to the cost of fodder. Efficiency of feeding is directly related to feeding behavior. In order to identify genomic regions controlling feeding behavior and eating efficiency traits, 338 Duroc boars were used in this study. The Illumina Porcine SNP60K BeadChip was used for genotyping. Data pertaining to individual daily feed intake (DFI), total daily time spent in feeder (TPD), number of daily visits to feeder (NVD), average duration of each visit (TPV), mean feed intake per visit (FPV), mean feed intake rate (FR), and feed conversion ratio (FCR) were collected for these pigs. Despite the limited sample size, the genome-wide association study was acceptable to detect candidate regions association with feeding behavior and eating efficiency traits in pigs. We detected three genome-wide (P < 1.40E-06) and 11 suggestive (P < 2.79E-05) single nucleotide polymorphism (SNP)-trait associations. Six SNPs were located in genomic regions where quantitative trait loci (QTLs) have previously been reported for feeding behavior and eating efficiency traits in pigs. Five candidate genes (SERPINA3, MYC, LEF1, PITX2, and MAP3K14) with biochemical and physiological roles that were relevant to feeding behavior and eating efficiency were discovered proximal to significant or suggestive markers. Gene ontology analysis indicated that most of the candidate genes were involved in the development of the hypothalamus (GO:0021854, P < 0.0398). Our results provide new insights into the genetic basis of feeding behavior and eating efficiency in pigs. Furthermore, some significant SNPs identified in this study could be incorporated into artificial selection programs for Duroc-related pigs to select for increased feeding efficiency. PMID- 28813541 TI - Reflections on 'medical tourism' from the 2016 Global Healthcare Policy and Management Forum. AB - In October 2016, the Global Healthcare Policy and Management Forum was held at Yonsei University, Seoul, South Korea. The goal of the forum was to discuss the role of the state in regulating and supporting the development of medical tourism. Forum attendees came from 10 countries. In this short report article, we identify key lessons from the forum that can inform the direction of future scholarly engagement with medical tourism. In so doing, we reference on-going scholarly debates about this global health services practice that have appeared in multiple venues, including this very journal. Key questions for future research emerging from the forum include: who should be meaningfully involved in identifying and defining categories of those travelling across borders for health services and what risks exist if certain voices are underrepresented in such a process; who does and does not 'count' as a medical tourist and what are the implications of such quantitative assessments; why have researchers not been able to address pressing knowledge gaps regarding the health equity impacts of medical tourism; and how do national-level polices and initiatives shape the ways in which medical tourism is unfolding in specific local centres and clinics? This short report as an important time capsule that summarises the current state of medical tourism research knowledge as articulated by the thought leaders in attendance at the forum while also pushing for research growth. PMID- 28813539 TI - Vectorization by nanoparticles decreases the overall toxicity of airborne pollutants. AB - Atmospheric pollution is mainly composed of volatile pollutants and particulate matter that strongly interact. However, their specific roles in the induction of cellular toxicity, in particular the impact of the vectorization of atmospheric pollutants by ultrafine particles, remains to be fully elucidated. For this purpose, non-toxic poly-lactic co-glycolic acid (PLGA) nanoparticles were synthesized and three pollutants (benzo(a)pyrene, naphthalene and di-ethyl-hexyl phthalate) were adsorbed on the surface of the nanoparticles in order to evaluate the toxicity (cytotoxicity, genotoxicity and ROS induction) of these complexes to a human airway epithelial cell line. The adsorption of the pollutants onto the nanoparticles was confirmed by HPLC analysis. Interestingly, the cytotoxicity assays (MTT, LDH and CellTox Green) clearly demonstrated that the vectorization by nanoparticles decreases the toxicity of the adsorbed pollutants. Genotoxicity was assessed by the micronucleus test and the comet assay and showed no increase in primary DNA damage or in chromosomal aberrations of nanoparticle vectorized pollutants. Neither cytotoxicity nor genotoxicity was correlated with ROS induction. To conclude, our results indicate that the vectorization of pollutants by nanoparticles does not potentiate the toxicity of the pollutants studied and that, on the contrary, adsorption onto nanoparticles could protect cells against pollutants' toxicity. PMID- 28813543 TI - Transforming Health Care in Remote Communities: report on an international conference. AB - An international conference titled "Transforming Health Care in Remote Communities" was held at the Chateau Lacombe Hotel in Edmonton, Canada, April 28 30, 2016. The event was organized by the University of Alberta's School of Public Health, in partnership with the Institute for Circumpolar Health Research in Yellowknife, Northwest Territories, and the Qaujigiartiit Health Research Centre in Iqaluit, Nunavut. There were 150 registrants from 7 countries: Canada (7 provinces and 3 territories), United States, Denmark, Iceland, Norway, Sweden, and Australia. They included representatives of academic institutions, health care agencies, government ministries, community organizations, and private industry. The Conference focused on developing solutions to address health care in remote regions. It enabled new networks to be established and existing ones consolidated. PMID- 28813542 TI - The African cholera surveillance network (Africhol) consortium meeting, 10-11 June 2015, Lome, Togo. AB - The fifth annual meeting of the African cholera surveillance network (Africhol) took place on 10-11 June 2015 in Lome, Togo. Together with international partners, representatives from the 11 member countries -Cameroon, Cote d'Ivoire, Democratic Republic of Congo, Guinea, Kenya, Mozambique, Nigeria, Tanzania, Togo, Uganda, Zimbabwe- and an invited country (Malawi) shared their experience. The meeting featured three sessions: i) cholera surveillance, prevention and control in participating countries, ii) cholera surveillance methodology, such as cholera mapping, cost-effectiveness studies and the issue of overlapping epidemics from different diseases, iii) cholera laboratory diagnostics tools and capacity building. The meeting has greatly benefitted from the input of technical expertise from participating institutions and the observations emerging from the meeting should enable national teams to make recommendations to their respective governments on the most appropriate and effective measures to be taken for the prevention and control of cholera. Recommendations for future activities included collecting precise burden estimates in surveillance sites; modeling cholera burden for Africa; setting up cross-border collaborations; strengthening laboratory capacity for the confirmation of suspected cholera cases and for vaccine impact assessment in settings where oral cholera vaccine would be used; adapting cholera surveillance to concurrent issues (e.g., Ebola); and developing national cholera control plans including rationale vaccination strategies together with other preventive and control measures such as improvements in water, sanitation and hygiene (WASH). PMID- 28813545 TI - Meeting report of the 2nd German dialectical behavior therapy for adolescents network meeting. AB - Over the past 30 years, dialectical behavior therapy has been shown to be an effective treatment for adult borderline personality disorder. The adaptation of DBT for adolescents (DBT-A) in different patient groups has also led to some promising improvements of the respective psychopathology. During the second German DBT-A network meeting in 2015 in Mainz, Germany, a need for further research and innovative approaches in treatment of adolescents became apparent and resulted in controversial discussions. Main issues were enlarging evidence of effectiveness of DBT-A strategies with regard to family interaction, i.e. involving caregivers in treatment. In general, there seems to be a dire need for disentangling different therapeutic strategies and resulting treatment outcomes, especially concerning the needs of different patient groups. Additionally, the implementation of smartphone-based real life assessment and intervention into DBT A was discussed extensively. Providing time congruent skills within an application, decreasing aversive tension and reducing dysfunctional behavior could lead to an enhanced therapist-patient interaction. This meeting report presents the core issues raised during the network meeting and discusses their implications for further research. PMID- 28813546 TI - PCSK9 Inhibitors, Statins, Low-Density Lipoprotein Cholesterol, Mevalonate Pathway, and Toxicity-Reply. PMID- 28813544 TI - Proceedings of the COST action BM1407 inaugural conference BEAT-PCD: translational research in primary ciliary dyskinesia - bench, bedside, and population perspectives. AB - Primary ciliary dyskinesia (PCD) is a rare heterogenous condition that causes progressive suppurative lung disease, chronic rhinosinusitis, chronic otitis media, infertility and abnormal situs. 'Better Experimental Approaches to Treat Primary Ciliary Dyskinesia' (BEAT-PCD) is a network of scientists and clinicians coordinating research from basic science through to clinical care with the intention of developing treatments and diagnostics that lead to improved long term outcomes for patients. BEAT-PCD activities are supported by EU Framework Programme Horizon 2020 funded COST Action (BM1407). The Inaugural Conference of BEAT-PCD was held in December 2015 in Southampton, UK. The conference attracted ninety-six scientists, clinicians, allied health professionals, industrial partners and patient representatives from twenty countries. We aimed to identify the needs for PCD research and clinical care, particularly focussing on basic science, epidemiology, diagnostic testing, clinical management and clinical trials. The multidisciplinary conference provided an interactive platform for exchanging ideas through a program of lectures, poster presentations, breakout sessions and workshops. This allowed us to develop plans for collaborative studies. In this report, we summarize the meeting, highlight developments, and discuss open questions thereby documenting ongoing developments in the field of PCD research. PMID- 28813547 TI - An Experimental and Numerical Study of Hybrid III Dummy Response to Simulated Underbody Blast Impacts. AB - Anthropometric test devices (ATDs) such as the Hybrid III dummy have been widely used in automotive crash tests to evaluate the risks of injury at different body regions. In recent years, researchers have started using automotive ATDs to study the high-speed vertical loading response caused by underbody blast impacts. This study analyzed the Hybrid III dummy responses to short-duration, large magnitude vertical accelerations in a laboratory setup. Two unique test conditions were investigated using a horizontal sled system to simulate underbody blast loading conditions. The biomechanical responses in terms of pelvis acceleration, chest acceleration, lumbar spine force, head accelerations, and neck forces were measured. Subsequently, a series of finite element (FE) analyses were performed to simulate the physical tests. The correlation between the Hybrid III test and numerical model was evaluated using the correlation and analysis (cora) version 3.6.1. The score for the Wayne State University (WSU) FE model was 0.878 and 0.790 for loading conditions 1 and 2, respectively, in which 1.0 indicated a perfect correlation between the experiment and the simulated response. With repetitive vertical impacts, the Hybrid III dummy pelvis showed a significant increase in peak acceleration accompanied by a rupture of the pelvis foam and flesh. The revised WSU Hybrid III model indicated high stress concentrations at the same location, providing a possible explanation for the material failure in actual Hybrid III tests. PMID- 28813548 TI - Incentivizing Transradial Access for Primary Percutaneous Coronary Intervention While Maintaining Timely Reperfusion. PMID- 28813549 TI - PCSK9 Inhibitors, Statins, Low-Density Lipoprotein Cholesterol, Mevalonate Pathway, and Toxicity. PMID- 28813551 TI - An Enhanced Spring-Particle Model for Red Blood Cell Structural Mechanics: Application to the Stomatocyte-Discocyte-Echinocyte Transformation. AB - Red blood cells (RBCs) are the most abundant cellular element suspended in blood. Together with the usual biconcave-shaped RBCs, i.e., discocytes, unusual-shaped RBCs are also observed under physiological and experimental conditions, e.g., stomatocytes and echinocytes. Stomatocytes and echinocytes are formed from discocytes and in addition can revert back to being discocytes; this shape change is known as the stomatocyte-discocyte-echinocyte (SDE) transformation. To-date, limited research has been conducted on the numerical prediction of the full SDE transformation. Spring-particle RBC (SP-RBC) models are commonly used to numerically predict RBC mechanics and rheology. However, these models are incapable of predicting the full SDE transformation because the typically employed bending model always leads to numerical instability with severely deformed shapes. In this work, an enhanced SP-RBC model is proposed in order to extend the capability of this model type and so that the full SDE transformation can be reproduced. This is achieved through the leveraging of an advanced bending model. Transformed vesicle and RBC shapes are predicted for a range of reduced volume and reduced membrane area difference (MAD), and very good agreement is obtained in the comparison of predicted shapes with experimental observations. Through these predictions, vesicle and SDE transformation phase diagrams are developed and, importantly, in the SDE case, shape boundaries are proposed for the first time relating RBC shape categories to RBC reduced volume and reduced MAD. PMID- 28813552 TI - Using Data to Enhance Performance and Improve Quality and Safety in Surgery. PMID- 28813550 TI - Drug-Free Interventions to Reduce Pain or Opioid Consumption After Total Knee Arthroplasty: A Systematic Review and Meta-analysis. AB - Importance: There is increased interest in nonpharmacological treatments to reduce pain after total knee arthroplasty. Yet, little consensus supports the effectiveness of these interventions. Objective: To systematically review and meta-analyze evidence of nonpharmacological interventions for postoperative pain management after total knee arthroplasty. Data Sources: Database searches of MEDLINE (PubMed), EMBASE (OVID), Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews, Web of Science (ISI database), Physiotherapy Evidence (PEDRO) database, and ClinicalTrials.gov for the period between January 1946 and April 2016. Study Selection: Randomized clinical trials comparing nonpharmacological interventions with other interventions in combination with standard care were included. Data Extraction and Synthesis: Two reviewers independently extracted the data from selected articles using a standardized form and assessed the risk of bias. A random effects model was used for the analyses. Main Outcomes and Measures: Postoperative pain and consumption of opioids and analgesics. Results: Of 5509 studies, 39 randomized clinical trials were included in the meta-analysis (2391 patients). The most commonly performed interventions included continuous passive motion, preoperative exercise, cryotherapy, electrotherapy, and acupuncture. Moderate-certainty evidence showed that electrotherapy reduced the use of opioids (mean difference, -3.50; 95% CI, -5.90 to -1.10 morphine equivalents in milligrams per kilogram per 48 hours; P = .004; I2 = 17%) and that acupuncture delayed opioid use (mean difference, 46.17; 95% CI, 20.84 to 71.50 minutes to the first patient-controlled analgesia; P < .001; I2 = 19%). There was low-certainty evidence that acupuncture improved pain (mean difference, -1.14; 95% CI, -1.90 to -0.38 on a visual analog scale at 2 days; P = .003; I2 = 0%). Very low-certainty evidence showed that cryotherapy was associated with a reduction in opioid consumption (mean difference, -0.13; 95% CI, -0.26 to -0.01 morphine equivalents in milligrams per kilogram per 48 hours; P = .03; I2 = 86%) and in pain improvement (mean difference, -0.51; 95% CI, -1.00 to -0.02 on the visual analog scale; P < .05; I2 = 62%). Low-certainty or very low-certainty evidence showed that continuous passive motion and preoperative exercise had no pain improvement and reduction in opioid consumption: for continuous passive motion, the mean differences were -0.05 (95% CI, -0.35 to 0.25) on the visual analog scale (P = .74; I2 = 52%) and 6.58 (95% CI, -6.33 to 19.49) opioid consumption at 1 and 2 weeks (P = .32, I2 = 87%), and for preoperative exercise, the mean difference was -0.14 (95% CI, -1.11 to 0.84) on the Western Ontario and McMaster Universities Arthritis Index Scale (P = .78, I2 = 65%). Conclusions and Relevance: In this meta-analysis, electrotherapy and acupuncture after total knee arthroplasty were associated with reduced and delayed opioid consumption. PMID- 28813553 TI - The Benefits of Purposeful Life Engagement on Later-Life Physical Function. PMID- 28813555 TI - Analysis of Item-Level Bias in the Bayley-III Language Subscales: The Validity and Utility of Standardized Language Assessment in a Multilingual Setting. AB - Purpose: The purpose of this study was to improve standardized language assessments among bilingual toddlers by investigating and removing the effects of bias due to unfamiliarity with cultural norms or a distributed language system. Method: The Expressive and Receptive Bayley-III language scales were adapted for use in a multilingual country (Singapore). Differential item functioning (DIF) was applied to data from 459 two-year-olds without atypical language development. This involved investigating if the probability of success on each item varied according to language exposure while holding latent language ability, gender, and socioeconomic status constant. Associations with language, behavioral, and emotional problems were also examined. Results: Five of 16 items showed DIF, 1 of which may be attributed to cultural bias and another to a distributed language system. The remaining 3 items favored toddlers with higher bilingual exposure. Removal of DIF items reduced associations between language scales and emotional and language problems, but improved the validity of the expressive scale from poor to good. Conclusions: Our findings indicate the importance of considering cultural and distributed language bias in standardized language assessments. We discuss possible mechanisms influencing performance on items favoring bilingual exposure, including the potential role of inhibitory processing. PMID- 28813554 TI - Association Between Purpose in Life and Objective Measures of Physical Function in Older Adults. AB - Importance: Higher purpose in life is hypothesized to reduce the likelihood of developing weak grip strength and slow walking speed because purpose has been linked with a range of positive health behaviors and biological processes that are potentially protective against declining physical function. However, the association between purpose in life and objective physical function has not been examined. Objective: To assess whether higher purpose in life among adequately functioning older adults is associated with lower risk of developing weak grip strength and slow walking speed over time. Design, Setting, and Participants: Data for a longitudinal cohort study were collected in 2006 and again in 2010 from the Health and Retirement Study, a nationally representative study of US adults older than 50 years. Data analysis was conducted from November 23, 2016, to June 2, 2017. Main Outcomes and Measures: The risk of developing weak grip strength (assessed as a binary yes or no outcome) or slow walking speed (yes or no) during the 4-year follow-up period. Grip strength was assessed using Smedley spring-type hand dynamometers, and walking speed was assessed by asking respondents to walk 2.5 m at their normal walking pace. Results: In this study, 4486 adults had grip scores at baseline indicating adequate function (2665 women and 1821 men; mean [SD] age, 63.0 [8.2] years) and 1461 adults had walking scores at baseline indicating adequate function (801 women and 660 men; mean [SD] age, 70.8 [6.5] years). After controlling for sociodemographic factors, each 1-SD increase in purpose was associated with a 13% decreased risk (95% CI, 1%-23%) of developing weak grip strength and a 14% decreased risk (95% CI, 8%-20%) of developing slow walking speed. Associations with walking speed were maintained in all covariate models (fully adjusted model: risk ratio, 0.89; 95% CI, 0.83-0.95), but associations with grip strength did not reach conventional levels of statistical significance after additionally adjusting for relevant baseline health factors, depressive symptoms, and health behaviors (fully adjusted model: risk ratio, 0.91; 95% CI, 0.80-1.04). Conclusions and Relevance: Purpose in life was prospectively associated with a decreased risk of developing weak grip strength and slow walking speed, although the findings were more robust for walking speed than for grip strength. These findings suggest that a sense of purpose in life, a modifiable factor, may play an important role in maintaining physical function among older adults. PMID- 28813556 TI - Pathophysiology and Treatment Considerations for Erosive Pustular Dermatosis. PMID- 28813557 TI - Facial Erosive Pustular Dermatosis After Cosmetic Resurfacing. AB - Importance: Erosive pustular dermatosis (EPD) is a rare condition that typically affects actinically damaged skin of the scalp. Characterized by sterile pustules, erosions, and crusts, EPD is difficult to treat and heals slowly. The exact cause of EPD is unknown, although trauma is an inciting factor. Objective: To describe 3 women who presented with prolonged facial erosions after cosmetic resurfacing procedures, specifically fully ablative carbon dioxide laser or medium-depth chemical peel. Design, Setting, and Participants: This case series describes the clinical features, histopathological findings, laboratory results, and treatment of 3 patients with an ultimate diagnosis most consistent with facial EPD. Patients were evaluated between September 10, 2010, and May 6, 2016, in a dermatology clinic in an academic medical center. The patients were 3 women seeking diagnostic evaluation and therapeutic options for nonhealing facial erosions occurring after ablative procedures (carbon dioxide laser resurfacing or Jessner solution/trichloroacetic acid chemical peel). Main Outcomes and Measures: Histologic examination and wound culture from initial presentation as well as clinical follow-up documenting improvement with therapeutic interventions. Results: All 3 patients were women in their 50s or 60s for whom EPD was deemed to be the best diagnosis, after infection, immunobullous disorders, and other pustular dermatoses were considered. Histologic features were nonspecific. Treatment included a combination of topical and systemic therapies, such as corticosteroids, dapsone, isotretinoin, and/or antibiotics. Watchful waiting (tincture of time) appeared to be central to the healing process. Conclusions and Relevance: After cosmetic resurfacing, patients may develop EPD isolated to the face. As a diagnosis of exclusion that should be considered in patients who have nonhealing wounds following ablative procedures, EPD is challenging to treat and may require the use of anti-inflammatory agents. Recognizing this condition is important, especially as cosmetic procedures become more widespread. PMID- 28813558 TI - Coalescing Subcutaneous Nodules. PMID- 28813559 TI - Coverage of Intravenous Immunoglobulin for Autoimmune Blistering Diseases Among US Insurers. PMID- 28813560 TI - Prevalence of Pubic Hair Grooming-Related Injuries and Identification of High Risk Individuals in the United States. AB - Importance: Pubic hair grooming is a common practice that can lead to injury and morbidity. Objective: To identify demographic and behavioral risk factors associated with pubic hair grooming-related injuries to characterize individuals with high risk of injury and develop recommendations for safe grooming practices. Design, Setting, and Participants: This cross-sectional study conducted a national survey of noninstitutionalized US adults (aged 18-65 years). The web based survey was conducted through a probability-based web panel designed to be representative of the US population. Data were collected in January 2014 and analyzed from August 1, 2016, through February 1, 2017. Main Outcomes and Measures: Grooming-related injury history (yes or no), high-frequency injuries (>5 lifetime injuries), and injury requiring medical attention. Results: Among the 7570 participants who completed the survey (4198 men [55.5%] and 3372 women [44.5%]; mean (SD) age, 41.9 [18.9] years), 5674 of 7456 (76.1%) reported a history of grooming (66.5% of men and 85.3% of women [weighted percentages]). Grooming-related injury was reported by 1430 groomers (weighted prevalence, 25.6%), with more women sustaining an injury than men (868 [27.1%] vs 562 [23.7%]; P = .01). Laceration was the most common injury sustained (818 [61.2%]), followed by burn (307 [23.0%]) and rashes (163 [12.2%]). Common areas for grooming-related injury for men were the scrotum (378 [67.2%]), penis (196 [34.8%]), and pubis (162 [28.9%]); for women, the pubis (445 [51.3%]), inner thigh (340 [44.9%]), vagina (369 [42.5%]), and perineum (115 [13.2%]). After adjustment for age, duration of grooming, hairiness, instrument used, and grooming frequency, men who removed all their pubic hair 11 times or more during their lifespan had an increased risk for grooming injury (adjusted odds ratio [AOR], 1.97; 95% CI, 1.28-3.01; P = .002) and were prone to repeated high frequency injuries (AOR, 3.89; 95% CI, 2.01-7.52; P < .001) compared with groomers who did not remove all their pubic hair. Women who removed all their pubic hair 11 times or more had increased odds of injury (AOR, 2.21; 95% CI, 1.53 3.19; P < .001) and high-frequency injuries (AOR, 2.98; 95% CI, 1.78-5.01; P < .001) compared with groomers who do not remove all their pubic hair. In women, waxing decreased the odds of high-frequency injuries (AOR, 0.11; 95% CI, 0.03 0.43; P = .001) compared with nonelectric blades. In total, 79 injuries among 5674 groomers (1.4%) required medical attention. Conclusions and Relevance: Grooming frequency and degree of grooming (ie, removing all pubic hair) are independent risk factors for injury. The present data may help identify injury prone groomers and lead to safer grooming practices. PMID- 28813561 TI - Comparison of Coronary CT Angiography, SPECT, PET, and Hybrid Imaging for Diagnosis of Ischemic Heart Disease Determined by Fractional Flow Reserve. AB - Importance: At present, the choice of noninvasive testing for a diagnosis of significant coronary artery disease (CAD) is ambiguous, but nuclear myocardial perfusion imaging with single-photon emission tomography (SPECT) or positron emission tomography (PET) and coronary computed tomography angiography (CCTA) is predominantly used for this purpose. However, to date, prospective head-to-head studies are lacking regarding the diagnostic accuracy of these imaging modalities. Furthermore, the combination of anatomical and functional assessments configuring a hybrid approach may yield improved accuracy. Objectives: To establish the diagnostic accuracy of CCTA, SPECT, and PET and explore the incremental value of hybrid imaging compared with fractional flow reserve. Design, Setting, and Participants: A prospective clinical study involving 208 patients with suspected CAD who underwent CCTA, technetium 99m/tetrofosmin labeled SPECT, and [15O]H2O PET with examination of all coronary arteries by fractional flow reserve was performed from January 23, 2012, to October 25, 2014. Scans were interpreted by core laboratories on an intention-to-diagnose basis. Hybrid images were generated in case of abnormal noninvasive anatomical or functional test results. Main Outcomes and Measures: Hemodynamically significant stenosis in at least 1 coronary artery as indicated by a fractional flow reserve of 0.80 or less and relative diagnostic accuracy of SPECT, PET, and CCTA in detecting hemodynamically significant CAD. Results: Of the 208 patients in the study (76 women and 132 men; mean [SD] age, 58 [9] years), 92 (44.2%) had significant CAD (fractional flow reserve <=0.80). Sensitivity was 90% (95% CI, 82%-95%) for CCTA, 57% (95% CI, 46%-67%) for SPECT, and 87% (95% CI, 78%-93%) for PET, whereas specificity was 60% (95% CI, 51%-69%) for CCTA, 94% (95% CI, 88% 98%) for SPECT, and 84% (95% CI, 75%-89%) for PET. Single-photon emission tomography was found to be noninferior to PET in terms of specificity (P < .001) but not in terms of sensitivity (P > .99) using the predefined absolute margin of 10%. Diagnostic accuracy was highest for PET (85%; 95% CI, 80%-90%) compared with that of CCTA (74%; 95% CI, 67%-79%; P = .003) and SPECT (77%; 95% CI, 71%-83%; P = .02). Diagnostic accuracy was not enhanced by either hybrid SPECT and CCTA (76%; 95% CI, 70%-82%; P = .75) or by PET and CCTA (84%; 95% CI, 79%-89%; P = .82), but resulted in an increase in specificity (P = .004) at the cost of a decrease in sensitivity (P = .001). Conclusions and Relevance: This controlled clinical head-to-head comparative study revealed PET to exhibit the highest accuracy for diagnosis of myocardial ischemia. Furthermore, a combined anatomical and functional assessment does not add incremental diagnostic value but guides clinical decision-making in an unsalutary fashion. PMID- 28813563 TI - Chess Study Revives Debate Over Cognition-Enhancing Drugs. PMID- 28813564 TI - Multi-inducer grouping for curve completion: Perceptual and computational exploration. AB - The human visual system excels in object recognition and scene interpretation even in scenes in which some (or even all) observed objects are partially occluded or fragmented. This highly efficient capacity is facilitated by constructive processes of contour completion between inducers to yield the perception of whole objects across gaps. A fundamental problem of the process is when and how the visual system groups different inducers in the visual scene between which completion occurs. Previous studies on this grouping problem, inspired mostly by relatability theory (Kellman & Shipley, 1991), focused on one good continuation condition that dictates whether a given pair of inducers would group together or not. Left open, however, was the question of how good continuation interacts with other grouping factors and how the perceptual system groups inducers when more than two of them are present in a scene (as would be in most typical natural stimuli). Here, we address both issues by exploring observers' perceptual response in multi-inducer scenes in which inducers and their relationships are determined by three independent factors: relative proximity, relative orientation, and curvature. Employing the dot localization paradigm, we indirectly inferred the type of inducer grouping constructed by the observer's visual system and analyzed the three-dimensional response function. Furthermore, we propose a simple parametric model that suggests an opponency relationship between two of the grouping factors and predicts subject's likely response with high accuracy. We also analyzed the discrepancy between our results and model the predictions made by the classical relatability theory. PMID- 28813565 TI - Selectivity, hyperselectivity, and the tuning of V1 neurons. AB - In this article, we explore two forms of selectivity in sensory neurons. The first we call classic selectivity, referring to the stimulus that optimally stimulates a neuron. If a neuron is linear, then this stimulus can be determined by measuring the response to an orthonormal basis set (the receptive field). The second type of selectivity we call hyperselectivity; it is either implicitly or explicitly a component of several models including sparse coding, gain control, and some linear-nonlinear models. Hyperselectivity is unrelated to the stimulus that maximizes the response. Rather, it refers to the drop-off in response around that optimal stimulus. We contrast various models that produce hyperselectivity by comparing the way each model curves the iso-response surfaces of each neuron. We demonstrate that traditional sparse coding produces such curvature and increases with increasing degrees of overcompleteness. We demonstrate that this curvature produces a systematic misestimation of the optimal stimulus when the neuron's receptive field is measured with spots or gratings. We also show that this curvature allows for two apparently paradoxical results. First, it allows a neuron to be very narrowly tuned (hyperselective) to a broadband stimulus. Second, it allows neurons to break the Gabor-Heisenberg limit in their localization in space and frequency. Finally, we argue that although gain-control models, some linear-nonlinear models, and sparse coding have much in common, we believe that this approach to hyperselectivity provides a deeper understanding of why these nonlinearities are present in the early visual system. PMID- 28813566 TI - A nonlinear generalization of the Savitzky-Golay filter and the quantitative analysis of saccades. AB - The Savitzky-Golay (SG) filter is widely used to smooth and differentiate time series, especially biomedical data. However, time series that exhibit abrupt departures from their typical trends, such as sharp waves or steps, which are of physiological interest, tend to be oversmoothed by the SG filter. Hence, the SG filter tends to systematically underestimate physiological parameters in certain situations. This article proposes a generalization of the SG filter to more accurately track abrupt deviations in time series, leading to more accurate parameter estimates (e.g., peak velocity of saccadic eye movements). The proposed filtering methodology models a time series as the sum of two component time series: a low-frequency time series for which the conventional SG filter is well suited, and a second time series that exhibits instantaneous deviations (e.g., sharp waves, steps, or more generally, discontinuities in a higher order derivative). The generalized SG filter is then applied to the quantitative analysis of saccadic eye movements. It is demonstrated that (a) the conventional SG filter underestimates the peak velocity of saccades, especially those of small amplitude, and (b) the generalized SG filter estimates peak saccadic velocity more accurately than the conventional filter. PMID- 28813562 TI - Polygenic Scores for Major Depressive Disorder and Risk of Alcohol Dependence. AB - Importance: Major depressive disorder (MDD) and alcohol dependence (AD) are heritable disorders with significant public health burdens, and they are frequently comorbid. Common genetic factors that influence the co-occurrence of MDD and AD have been sought in family, twin, and adoption studies, and results to date have been promising but inconclusive. Objective: To examine whether AD and MDD overlap genetically, using a polygenic score approach. Design, Settings, and Participants: Association analyses were conducted between MDD polygenic risk score (PRS) and AD case-control status in European ancestry samples from 4 independent genome-wide association study (GWAS) data sets: the Collaborative Study on the Genetics of Alcoholism (COGA); the Study of Addiction, Genetics, and Environment (SAGE); the Yale-Penn genetic study of substance dependence; and the National Health and Resilience in Veterans Study (NHRVS). Results from a meta analysis of MDD (9240 patients with MDD and 9519 controls) from the Psychiatric Genomics Consortium were applied to calculate PRS at thresholds from P < .05 to P <= .99 in each AD GWAS data set. Main Outcomes and Measures: Association between MDD PRS and AD. Results: Participants analyzed included 788 cases (548 [69.5%] men; mean [SD] age, 38.2 [10.8] years) and 522 controls (151 [28.9.%] men; age [SD], 43.9 [11.6] years) from COGA; 631 cases (333 [52.8%] men; age [SD], 35.0 [7.7] years) and 756 controls (260 [34.4%] male; age [SD] 36.1 [7.7] years) from SAGE; 2135 cases (1375 [64.4%] men; age [SD], 39.4 [11.5] years) and 350 controls (126 [36.0%] men; age [SD], 43.5 [13.9] years) from Yale-Penn; and 317 cases (295 [93.1%] men; age [SD], 59.1 [13.1] years) and 1719 controls (1545 [89.9%] men; age [SD], 64.5 [13.3] years) from NHRVS. Higher MDD PRS was associated with a significantly increased risk of AD in all samples (COGA: best P = 1.7 * 10-6, R2 = 0.026; SAGE: best P = .001, R2 = 0.01; Yale-Penn: best P = .035, R2 = 0.0018; and NHRVS: best P = .004, R2 = 0.0074), with stronger evidence for association after meta-analysis of the 4 samples (best P = 3.3 * 10-9). In analyses adjusted for MDD status in 3 AD GWAS data sets, similar patterns of association were observed (COGA: best P = 7.6 * 10-6, R2 = 0.023; Yale-Penn: best P = .08, R2 = 0.0013; and NHRVS: best P = .006, R2 = 0.0072). After recalculating MDD PRS using MDD GWAS data sets without comorbid MDD-AD cases, significant evidence was observed for an association between the MDD PRS and AD in the meta-analysis of 3 GWAS AD samples without MDD cases (best P = .007). Conclusions and Relevance: These results suggest that shared genetic susceptibility contributes modestly to MDD and AD comorbidity. Individuals with elevated polygenic risk for MDD may also be at risk for AD. PMID- 28813567 TI - Comparison of view-based and reconstruction-based models of human navigational strategy. AB - There is good evidence that simple animals, such as bees, use view-based strategies to return to a familiar location, whereas humans might use a 3-D reconstruction to achieve the same goal. Assuming some noise in the storage and retrieval process, these two types of strategy give rise to different patterns of predicted errors in homing. We describe an experiment that can help distinguish between these models. Participants wore a head-mounted display to carry out a homing task in immersive virtual reality. They viewed three long, thin, vertical poles and had to remember where they were in relation to the poles before being transported (virtually) to a new location in the scene from where they had to walk back to the original location. The experiment was conducted in both a rich cue scene (a furnished room) and a sparse scene (no background and no floor or ceiling). As one would expect, in a rich-cue environment, the overall error was smaller, and in this case, the ability to separate the models was reduced. However, for the sparse-cue environment, the view-based model outperforms the reconstruction-based model. Specifically, the likelihood of the experimental data is similar to the likelihood of samples drawn from the view-based model (but assessed under both models), and this is not true for samples drawn from the reconstruction-based model. PMID- 28813569 TI - SPECT, PET, and CTA-Acronyms or Better Imaging? PMID- 28813568 TI - Visual short-term memory for oriented, colored objects. AB - A central question in the study of visual short-term memory (VSTM) has been whether its basic units are objects or features. Most studies addressing this question have used change detection tasks in which the feature value before the change is highly discriminable from the feature value after the change. This approach assumes that memory noise is negligible, which recent work has shown not to be the case. Here, we investigate VSTM for orientation and color within a noisy-memory framework, using change localization with a variable magnitude of change. A specific consequence of the noise is that it is necessary to model the inference (decision) stage. We find that (a) orientation and color have independent pools of memory resource (consistent with classic results); (b) an irrelevant feature dimension is either encoded but ignored during decision making, or encoded with low precision and taken into account during decision making; and (c) total resource available in a given feature dimension is lower in the presence of task-relevant stimuli that are neutral in that feature dimension. We propose a framework in which feature resource comes both in packaged and in targeted form. PMID- 28813570 TI - Experimental and Numerical Characterization of the Mechanical Masseter Muscle Response During Biting. AB - Predictive simulations of the mastication system would significantly improve our understanding of temporomandibular joint (TMJ) disorders and the planning of cranio-maxillofacial surgery procedures. Respective computational models must be validated by experimental data from in vivo characterization of the mastication system's mechanical response. The present pilot-study demonstrates the feasibility of a combined experimental and numerical procedure to validate a computer model of the masseter muscle. An experimental setup is proposed that provides a simultaneous bite force measurement and ultrasound-based visualization of muscle deformation. The direct comparison of the experimentally observed and numerically predicted muscle response demonstrates the predictive capabilities of such anatomically accurate biting models. Differences between molar and incisor biting are investigated; muscle deformation is recorded for three different bite forces in order to capture the effect of increasing muscle fiber recruitment. The three-dimensional (3D) muscle deformation at each bite position and force-level is approximatively reconstructed from ultrasound measurements in five distinct cross-sectional areas (four horizontal and one vertical cross section). The experimental work is accompanied by numerical simulations to validate the predictive capabilities of a constitutive muscle model previously formulated. An anatomy-based, fully 3D model of the masseter muscle is created from magnetic resonance images (MRI) of the same subject. The direct comparison of experimental and numerical results revealed good agreement for maximum bite forces and masseter deformations in both biting positions. The present work therefore presents a feasible in vivo measurement system to validate numerically predicted masseter muscle contractions during mastication. PMID- 28813571 TI - Balanced Adoption of Radial Artery Access for Primary Percutaneous Coronary Intervention. PMID- 28813575 TI - Subclinical Decrease in Central Inner Retinal Activity Is Associated With Myopia Development in Children. AB - Purpose: To investigate the characteristics of retinal electrophysiological activity in relation to early myopia development in children. Methods: Fifty-six children aged 6 to 9 years with emmetropic refractive error (defined as >= -0.5 diopter [D] and <= +0.5 D) were recruited. Cycloplegic refraction, axial length, and global flash multifocal electroretinogram (MOFO mfERG) at 49% and 96% contrast levels were recorded in all children at their first visit. The refraction and axial length measurements were repeated after 1 year. The amplitudes and implicit times of the direct component (DC) and the induced component (IC) of the MOFO mfERG obtained at the initial visit were analyzed. Correlations between the MOFO mfERG parameters and changes in refractive error and axial length were investigated. Results: The mean spherical equivalent refractive error and axial length of the eyes of the children at the first visit were +0.19 +/- 0.33 D and 23.14 +/- 0.6 mm, respectively. After 1 year, the mean refractive error increased by -0.55 +/- 0.53 D, whereas axial length increased by 0.37 +/- 0.22 mm. The changes in refractive error and axial length were significantly correlated with the central IC amplitudes at 49% contrast level measured at the initial visit (rho = 0.46, P < 0.001 and rho = -0.34, P = 0.01, respectively). Conclusions: The prospective changes we have shown are believed to derive from central inner retina. These changes appear to precede myopia and could be a potential reference for juvenile myopia development. PMID- 28813574 TI - Dynamic Imaging of the Eye, Optic Nerve, and Extraocular Muscles With Golden Angle Radial MRI. AB - Purpose: The eye and its accessory structures, the optic nerve and the extraocular muscles, form a complex dynamic system. In vivo magnetic resonance imaging (MRI) of this system in motion can have substantial benefits in understanding oculomotor functioning in health and disease, but has been restricted to date to imaging of static gazes only. The purpose of this work was to develop a technique to image the eye and its accessory visual structures in motion. Methods: Dynamic imaging of the eye was developed on a 3-Tesla MRI scanner, based on a golden angle radial sequence that allows freely selectable frame-rate and temporal-span image reconstructions from the same acquired data set. Retrospective image reconstructions at a chosen frame rate of 57 ms per image yielded high-quality in vivo movies of various eye motion tasks performed in the scanner. Motion analysis was performed for a left-right version task where motion paths, lengths, and strains/globe angle of the medial and lateral extraocular muscles and the optic nerves were estimated. Results: Offline image reconstructions resulted in dynamic images of bilateral visual structures of healthy adults in only ~15-s imaging time. Qualitative and quantitative analyses of the motion enabled estimation of trajectories, lengths, and strains on the optic nerves and extraocular muscles at very high frame rates of ~18 frames/s. Conclusions: This work presents an MRI technique that enables high-frame-rate dynamic imaging of the eyes and orbital structures. The presented sequence has the potential to be used in furthering the understanding of oculomotor mechanics in vivo, both in health and disease. PMID- 28813576 TI - Joint Analysis of Nuclear and Mitochondrial Variants in Age-Related Macular Degeneration Identifies Novel Loci TRPM1 and ABHD2/RLBP1. AB - Purpose: Presently, 52 independent nuclear single nucleotide polymorphisms (nSNPs) have been associated with age-related macular degeneration (AMD) but their effects do not explain all its variance. Genetic interactions between the nuclear and mitochondrial (mt) genome may unearth additional genetic loci previously unassociated with AMD risk. Methods: Joint effects of nSNPs and selected mtSNPs were analyzed by two degree of freedom (2df) joint tests of association in the International AMD Genomics Consortium (IAMDGC) dataset (17,832 controls and 16,144 advanced AMD cases of European ancestry). Subjects were genotyped on the Illumina HumanCoreExome array. After imputation using MINIMAC and the 1000 Genomes Project Phase I reference panel, pairwise linkage disequilibrium pruning, and quality control, 3.9 million nSNPs were analyzed for interaction with mtSNPs chosen based on association in this dataset or publications: A4917G, T5004C, G12771A, and C16069T. Results: Novel locus TRPM1 was identified with genome-wide significant joint effects (P < 5.0 * 10-8) of two intronic TRPM1 nSNPs and AMD-associated nonsynonymous MT-ND2 mtSNP A4917G. Stratified analysis by mt allele identified an association only in 4917A (major allele) carriers (P = 4.4 * 10-9, odds ratio [OR] = 0.90, 95% confidence interval [CI] = 0.87-0.93). Intronic and intergenic ABHD2/RLBP1 nSNPs demonstrated genome wide significant joint effects (2df joint test P values from 1.8 * 10-8 to 4.9 * 10-8) and nominally statistically significant interaction effects with MT-ND5 synonymous mtSNP G12771A. Although a positive association was detected in both strata, the association was stronger in 12771A subjects (P = 0.0020, OR = 2.17, 95% CI = 1.34-3.60). Conclusions: These results show that joint tests of main effects and gene-gene interaction reveal associations at some novel loci that were missed when considering main effects alone. PMID- 28813577 TI - Spatial Correspondence Between Intraretinal Fluid, Subretinal Fluid, and Pigment Epithelial Detachment in Neovascular Age-Related Macular Degeneration. AB - Purpose: To identify the spatial distribution of exudative features of choroidal neovascularization in neovascular age-related macular degeneration (nAMD) based on the localization of intraretinal cystoid fluid (IRC), subretinal fluid (SRF), and pigment-epithelial detachment (PED). Methods: This retrospective cross sectional study included spectral-domain optical coherence tomography volume scans (6 * 6 mm) of 1341 patients with treatment-naive nAMD. IRC, SRF, and PED were detected on a per-voxel basis using fully automated segmentation algorithms. Two subsets of 37 volumes each were manually segmented to validate the automated results. The spatial correspondence of components was quantified by computing proportions of IRC-, SRF-, or PED-presenting A-scans simultaneously affected by the respective other pathomorphologic components on a per-patient basis. The median across the population is reported. Odds ratios between pairs of lesions were calculated and tested for significance pixel wise. Results: Automated image segmentation was successful in 1182 optical coherence tomography volumes, yielding more than 61 million A-scans for analysis. Overall, 81% of eyes showed IRC, 95% showed SRF, and 92% showed PED. IRC-presenting A-scans also showed SRF in a median 2.5%, PED in 32.9%. Of the SRF-presenting A-scans, 0.3% demonstrated IRC, 1.4% PED. Of the PED-presenting A-scans, 5.2% contained IRC, 2.0% SRF. Similar patterns were observed in the manually segmented subsets and via pixel wise odds ratio analysis. Conclusions: Automated analyses of large-scale datasets in a cross-sectional study of 1182 patients with active treatment-naive nAMD demonstrated low spatial correlation of SRF with IRC and PED in contrast to increased colocalization of IRC and PED. These morphological associations may contribute to our understanding of functional deficits in nAMD. PMID- 28813578 TI - Incomitance and Eye Dominance in Intermittent Exotropia. AB - Purpose: To determine if the deviation angle changes in subjects with intermittent exotropia as they alternate fixation between the right and left eye in primary gaze. Methods: In this prospective observational cohort study, 37 subjects with intermittent exotropia were tested for evidence of incomitance. The position of each eye was recorded with a video tracker during fixation on a small central target. A cover-uncover test was performed by occluding one eye with a shutter that passed infrared light, allowing continuous tracking of both eyes. The deviation angle was measured during periods of right eye and left eye fixation. Incomitance was assessed as a function of eye preference, fixation stability, and exotropia variability. Results: The mean exotropia was 18.2 degrees +/- 8.1 degrees . A difference between right exotropia and left exotropia was detectable in 16/37 subjects. Allowing for potential tracking error, the incomitance had a mean amplitude of 1.7 degrees . It was not related to a difference in accommodative effort, eye preference, fixation stability, or variability in deviation. Conclusions: Comitance is regarded as a feature that distinguishes strabismus from paralytic or restrictive processes. Unexpectedly, eye tracking during the cover-uncover test showed that incomitance is present in approximately 40% of subjects with intermittent exotropia. It averages 10% of the exotropia, and can equal up to 5 degrees . When substantial, it may be worth considering when planning surgical correction. PMID- 28813579 TI - The Riddle of Intermittent Exotropia. PMID- 28813583 TI - Carotid Artery Stenosis: Although Military Physicians Operate Less, They Achieve Better Outcomes. PMID- 28813584 TI - Sustained Prescription Opioid Use Among Previously Opioid-Naive Patients Insured Through TRICARE (2006-2014). PMID- 28813580 TI - Genetic Association of the PARL-ABCC5-HTR3D-HTR3C Locus With Primary Angle Closure Glaucoma in Chinese. AB - Purpose: This study evaluates the associations of haplotype-tagging single nucleotide polymorphisms (SNPs) in the PARL-ABCC5-HTR3D-HTR3C region with primary angle closure glaucoma (PACG), with a view to identify the responsible SNP in this region. Methods: Thirty SNPs from the PARL-ABCC5-HTR3D-HTR3C region were genotyped in a Hong Kong Chinese cohort of 422 PACG patients and 400 control subjects, using TaqMan SNP genotyping assays. Single marker and haplotype-based association analyses were performed. Results: Two synonymous ABCC5 SNPs, namely rs939336 (p.Cys594=; P = 0.013; odds ratio [OR] = 1.46; 95% confidence interval [CI], 1.08 to 1.97) and rs1132776 (p.Ala395=; P = 0.009; OR = 1.47; 95% CI: 1.10 to 1.95), were associated with PACG. Mild associations were detected for ABCC5 rs9838667 (P = 0.024) and HTR3D rs12493550 (P = 0.035). Conditional analysis revealed that no SNPs remained significant after adjusting for other SNPs, suggesting none of these tagging SNPs is fully responsible for the association in this region. In subgroup analysis, ABCC5 SNPs rs939336, rs1132776, and rs983667 and HTR3D rs12493550 were associated only with the chronic form of PACG. However, these associations could not withstand the correction for multiple testing. Conclusions: These findings enrich the allelic spectrum of ABCC5 in PACG. We identified no tagging SNP responsible for the association of the whole region. Further deep sequencing analysis of this region should be warranted to uncover whether there is still disease associated variant in this region. PMID- 28813586 TI - Breast cancer and exposure to aircraft, road, and railway-noise: a case-control study based on health insurance records. AB - Objectives Aircraft, road, and rail traffic noise can cause sleep disturbances. Since night work and shorter sleep durations have been linked to increased risks of breast cancer, we examined if 24-hour, or day- or night-time traffic noise exposure may also increase the risk of breast cancer. Methods To investigate the noise-related risks of breast cancer, the pseudonymized insurance records of three large statutory health companies (2005-2010) for women aged >=40 years living in the region surrounding the Frankfurt international airport were analyzed with address-specific acoustic data representing aircraft, road, and rail-traffic noise. Noise exposure among women with incident breast cancer (N=6643) were compared with that of control subjects (N=471 596) using logistic regression and adjusting for age, hormone replacement therapy, education and occupation (only available for 27.9%), and a regional proportion of persons receiving long-term unemployment benefits as an ecological indicator of socioeconomic level. Analyses were also stratified according to estrogen receptor (ER) status. Results An increased odds ratio (OR) was observed for ER negative (ER-) tumors at 24-hour aircraft noise levels 55-59 dB [OR 55-59 dB 1.41, 95% confidence interval (CI) 1.04-1.90] but not for ER positive (ER+) breast cancers (OR 55-59 dB 0.95, 95% CI 0.75-1.20). Clear associations between road and rail traffic noise were not observed. Conclusions The results indicate increased aircraft noise may be an etiologic factor for ER- breast cancers. However, information regarding potential confounding factors was largely unattainable. Further research is required to understand how environmental noise may be involved in the pathogenesis of ER- breast cancers. PMID- 28813585 TI - Association of General Surgery Resident Remediation and Program Director Attitudes With Resident Attrition. AB - Importance: Previous studies of resident attrition have variably included preliminary residents and likely overestimated categorical resident attrition. Whether program director attitudes affect attrition has been unclear. Objectives: To determine whether program director attitudes are associated with resident attrition and to measure the categorical resident attrition rate. Design, Setting, and Participants: This multicenter study surveyed 21 US program directors in general surgery about their opinions regarding resident education and attrition. Data on total resident complement, demographic information, and annual attrition were collected from the program directors for the study period of July 1, 2010, to June 30, 2015. The general surgery programs were chosen on the basis of their geographic location, previous collaboration with some coauthors, prior work in surgical education and research, or a program director willing to participate. Only categorical surgical residents were included in the study; thus, program directors were specifically instructed to exclude any preliminary residents in their responses. Main Outcomes and Measures: Five-year attrition rates (2010-2011 to 2014-2015 academic years) as well as first-time pass rates on the General Surgery Qualifying Examination and General Surgery Certifying Examination of the American Board of Surgery (ABS) were collected. High- and low-attrition programs were compared. Results: The 21 programs represented different geographic locations and 12 university-based, 3 university affiliated, and 6 independent program types. Programs had a median (interquartile range [IQR]) number of 30 (20-48) categorical residents, and few of those residents were women (median [IQR], 12 [5-17]). Overall, 85 of 966 residents (8.8%) left training during the study period: 15 (17.6%) left after postgraduate year 1, 34 (40.0%) after postgraduate year 2, and 36 (42.4%) after postgraduate year 3 or later. Forty-four residents (51.8%) left general surgery for another surgical discipline, 21 (24.7%) transferred to a different surgery program, and 18 (21.2%) exited graduate medical education altogether. Each program had an annual attrition rate ranging from 0.73% to 6.0% (median [IQR], 2.5% [1.5% 3.4%]). Low-attrition programs were more likely than high-attrition programs to use resident remediation (21.0% vs 6.8%; P < .001). Median (IQR) Qualifying Examination pass rates (93% [90%-98%] vs 92% [86%-100%]; P = .92) and Certifying Examination pass rates (83% [68%-84%] vs 81% [71%-86%]; P = .47) were similar. Program directors at high-attrition programs were more likely than their counterparts at low-attrition programs to agree with this statement: "I feel that it is my responsibility as a program director to redirect residents who should not be surgeons." Conclusions and Relevance: The overall 5-year attrition rate of 8.8% was significantly lower than previously reported. Program directors at low attrition programs were more likely to use resident remediation. Variations in attrition may be explained by program director attitudes, although larger studies are needed to further define program factors affecting attrition. PMID- 28813587 TI - REMOTE SENSING, ECOLOGICAL VARIABLES, AND WILD BIRD MIGRATION RELATED TO OUTBREAKS OF HIGHLY PATHOGENIC H5N1 AVIAN INFLUENZA PMID- 28813588 TI - Insight to the Thermal Decomposition and Hydrogen Desorption Behaviors of NaNH2 NaBH4 Hydrogen Storage Composite. AB - The lightweight compound material NaNH2-NaBH4 is regarded as a promising hydrogen storage composite due to the high hydrogen density. Mechanical ball milling was employed to synthesize the composite NaNH2-NaBH4 (2/1 molar ratio), and the samples were investigated utilizing thermogravimetric-differential thermal analysis-mass spectroscopy (TG-DTA-MS), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR) analyses. The full-spectrum test (range of the ratio of mass to charge: 0-200) shows that the released gaseous species contain H2, NH3, B2H6, and N2 in the heating process from room temperature to 400 degrees C, and possibly the impurity gas B6H12 also exists. The TG/DTA analyses show that the composite NaNH2-NaBH4 (2/1 molar ratio) is conductive to generate hydrogen so that the dehydrogenation process can be finished before 400 degrees C. Moreover, the thermal decomposition process from 200 to 400 degrees C involves two-step dehydrogenation reactions: (1) Na3(NH2)2BH4 hydride decomposes into Na3BN2 and H2 (200-350 degrees C); (2) remaining Na3(NH2)2BH4 reacts with NaBH4 and Na3BN2, generating Na, BN, NH3, N2, and H2 (350-400 degrees C). The better mechanism understanding of the thermal decomposition pathway lays a foundation for tailoring the hydrogen storage performance of the composite complex hydrides system. PMID- 28813589 TI - Regulation of the Stability of the Histone H2A-H2B Dimer by H2A Tyr57 Phosphorylation. AB - Histone H2A and H2B form a H2A-H2B heterodimer, which is a fundamental unit of nucleosome assembly and disassembly. Several posttranslational modifications change the interface between the H2A-H2B dimer and the H3-H4 tetramer and regulate nucleosome stability. However, posttranslational modifications associated with the interface between H2A and H2B have not been discussed. In this paper, it is shown that Tyr57 phosphorylation in H2A strongly influences H2A H2B dimerization. Tyr57-phosphorylated H2A was chemically synthesized and utilized to reconstitute the H2A-H2B dimer and nucleosome as well as canonical H2A. Thermal shift assays showed that phosphorylation destabilized the dimer and facilitated dissociation of H2A and H2B from the nucleosome structure. The proximity between H2A Tyr57 and the H2B alphaC helix is assumed to lead the destabilization. The DNA accessibility of the nucleosome was estimated by using micrococcal nuclease. The phosphorylated nucleosome did not change DNA accessibility compared to that of the canonical nucleosome. It is demonstrated that phosphorylation at Tyr57 changes the H2A-H2B dimer interaction but does not interfere with histone-DNA interactions. This work on the destabilization of the H2A-H2B dimer by Tyr57 phosphorylation is a promising step in elucidating control mechanisms of dynamic behavior of H2A and H2B through posttranslational modifications. PMID- 28813590 TI - Understanding the Elementary Steps in DNA Tile-Based Self-Assembly. AB - Although many models have been developed to guide the design and implementation of DNA tile-based self-assembly systems with increasing complexity, the fundamental assumptions of the models have not been thoroughly tested. To expand the quantitative understanding of DNA tile-based self-assembly and to test the fundamental assumptions of self-assembly models, we investigated DNA tile attachment to preformed "multi-tile" arrays in real time and obtained the thermodynamic and kinetic parameters of single tile attachment in various sticky end association scenarios. With more sticky ends, tile attachment becomes more thermostable with an approximately linear decrease in the free energy change (more negative). The total binding free energy of sticky ends is partially compromised by a sequence-independent energy penalty when tile attachment forms a constrained configuration: "loop". The minimal loop is a 2 * 2 tetramer (Loop4). The energy penalty of loops of 4, 6, and 8 tiles was analyzed with the independent loop model assuming no interloop tension, which is generalizable to arbitrary tile configurations. More sticky ends also contribute to a faster on rate under isothermal conditions when nucleation is the rate-limiting step. Incorrect sticky end contributes to neither the thermostability nor the kinetics. The thermodynamic and kinetic parameters of DNA tile attachment elucidated here will contribute to the future improvement and optimization of tile assembly modeling, precise control of experimental conditions, and structural design for error-free self-assembly. PMID- 28813591 TI - On-Surface Oligomerization of Self-Terminating Molecular Chains for the Design of Spintronic Devices. AB - Molecular spintronics is currently attracting a lot of attention due to its great advantages over traditional electronics. A variety of self-assembled molecule based devices are under development, but studies regarding the reliability of the growth process remain rare. Here, we present a method to control the length of molecular spintronic chains and to make their terminations chemically inert, thereby suppressing uncontrolled coupling to surface defects. The temperature evolution of chain formation was followed by X-ray photoelectron spectroscopy to determine optimal growth conditions. The final structures of the chains were then studied, using scanning tunneling microscopy, as a function of oligomerization conditions. We find that short chains are readily synthesized with high yields and that long chains, even exceeding 70mers, can be realized under optimized growth parameters, albeit with reduced yields. PMID- 28813593 TI - PtNi Nanocrystals Supported on Hollow Carbon Spheres: Enhancing the Electrocatalytic Performance through High-Temperature Annealing and Electrochemical CO Stripping Treatments. AB - PtNi nanoparticles have been proved to be a type of highly efficient electrocatalyst for the oxygen reduction reaction (ORR) among the Pt-based nanomaterials. However, how to improve the surface catalytic activity and stability of polymer-stabilized Pt-based nanocrystals is still a critical issue for their application in fuel cells. In this work, a one-step solvothermal process was used to synthesize PVP-stabilized PtNi nanocubes supported on hollow carbon spheres. With optimized metal precursor ratio (Pt/Ni = 1:1) and solvothermal temperature (130 degrees C), PtNi nanocrystals with uniform size and cubic shape can be synthesized and highly dispersed on hollow carbon spheres. To improve the electrocatalytic activity of the PtNi nanocrystals, the synthesized composite was treated by a heating annealing at 300 degrees C and a subsequent electrochemical CO stripping process. It was found that the two-step treatment can significantly enhance the catalytic activity of the PtNi nanocrystals for ORR with high durability. In addition, the prepared PtNi composite also showed higher catalytic activity and stability for methanol oxidation. The obtained peak current density on the present catalyst can reach 3.89 A/mgPt, which is 9 times as high as commercial Pt/C (0.43 A/mgPt). The present study not only demonstrates a general method to synthesize hollow carbon sphere-supported nanoparticle catalysts but also provides an efficient strategy to active the surface activity of nanoparticles. PMID- 28813592 TI - 3D-Printed pHEMA Materials for Topographical and Biochemical Modulation of Dorsal Root Ganglion Cell Response. AB - Understanding and controlling the interactions occurring between cells and engineered materials are central challenges toward progress in the development of biomedical devices. In this work, we describe materials for direct ink writing (DIW), an extrusion-based type of 3D printing, that embed a custom synthetic protein (RGD-PDL) within the microfilaments of 3D-hydrogel scaffolds to modify these interactions and differentially direct tissue-level organization of complex cell populations in vitro. The RGD-PDL is synthesized by modifying poly-d-lysine (PDL) to varying extents with peptides containing the integrin-binding motif Arg Gly-Asp (RGD). Compositional gradients of the RGD-PDL presented by both patterned and thin-film poly(2-hydroxyethyl) methacrylate (pHEMA) substrates allow the patterning of cell-growth compliance in a grayscale form. The surface chemistry dependent guidance of cell growth on the RGD-PDL-modified pHEMA materials is demonstrated using a model NIH-3T3 fibroblast cell line. The formation of a more complex cellular system-organotypic primary murine dorsal root ganglion (DRG)-in culture is also achieved on these scaffolds, where distinctive forms of cell growth and migration guidance are seen depending on their RGD-PDL content and topography. This experimental platform for the study of physicochemical factors on the formation and the reorganization of organotypic cultures offers useful capabilities for studies in tissue engineering, regenerative medicine, and diagnostics. PMID- 28813594 TI - Facile Purification of Milligram to Gram Quantities of Condensed Tannins According to Mean Degree of Polymerization and Flavan-3-ol Subunit Composition. AB - Unambiguous investigation of condensed tannin (CT) structure-activity relationships in biological systems requires well-characterized, high-purity CTs. Sephadex LH-20 and Toyopearl HW-50F resins were compared for separating CTs from acetone/water extracts, and column fractions analyzed for flavan-3-ol subunits, mean degree of polymerization (mDP), and purity. Toyopearl HW-50F generated fractions with higher mDP values and better separation of procyanidins (PC) and prodelphinidins (PD) but required a prepurification step, needed more time for large scale purifications, and gave poorer recoveries. Therefore, two gradient elution schemes were developed for CT purification on Sephadex LH-20 providing 146-2000 mg/fraction. Fractions were analyzed by thiolysis and NMR spectroscopy. In general, PC/PD ratios decreased and mDP increased during elution. 1H NMR spectroscopy served as a rapid screening tool to qualitatively determine CT enrichment and carbohydrate impurities present, guiding fractionation toward repurification or 1H-13C HSQC NMR spectroscopy and thiolysis. These protocols provide options for preparing highly pure CT samples. PMID- 28813595 TI - Activation of a Nickel-Based Oxygen Evolution Reaction Catalyst on a Hematite Photoanode via Incorporation of Cerium for Photoelectrochemical Water Oxidation. AB - There has been debate on whether Ni(OH)2 is truly catalytically active for the photo/electrocatalytic oxygen evolution reaction. In this report, we synthesized a Ni(OH)2 cocatalyst on a hematite photoanode and showed that, as has been proposed in other studies, the current density varies as a function of scan rate, which arises due to a photoinduced capacitive charging effect. We discovered that this photoinduced charging of Ni2+/3+ can be overcome by mixing cerium nitrate into the Ni precursor solution. Under illumination, the NiCeOx cocatalyst on a hematite photoanode exhibited an approximately 200 mV cathodic shift in onset potential and a ~53% enhancement in photocurrent at 1.23 V vs RHE. Material characterization by electrochemical impedance spectroscopy revealed that the Ni species create a p-n junction across the charge space region, which facilitates collection of the photogenerated holes by the cocatalyst layer, and core level X ray photoelectron spectroscopy showed that Ce incorporated into the Ni-based cocatalyst layer may possibly induce the oxidation of the Ni species. In addition, we observed a reduction in binding energies of Ni after photoelectrochemical water splitting reactions, which suggests that the lattice oxygen of the NiCeOx is consumed in the catalytic cycle, forming oxygen vacancies. The NiCeOx cocatalyst, however, was incapable of passivating the surface recombination centers of the hematite photoanode, as indicated by the unaltered flat-band potential determined with Mott-Schottky analysis. PMID- 28813597 TI - Synthesis of 4-Azido-N-acetylhexosamine Uridine Diphosphate Donors: Clickable Glycosaminoglycans. AB - Unnatural chemically modified nucleotide sugars UDP-4-N3-GlcNAc and UDP-4-N3 GalNAc were chemically synthesized for the first time. These unnatural UDP sugar products were then tested for incorporation into hyaluronan, heparosan, or chondroitin using polysaccharide synthases. UDP-4-N3-GlcNAc served as a chain termination substrate for hyaluronan or heparosan synthases; the resulting 4-N3 GlcNAc-terminated hyaluronan and heparosan were then successfully conjugated with Alexa Fluor 488 DIBO alkyne, demonstrating that this approach is generally applicable for labeling and detection of suitable glycosaminoglycans. PMID- 28813596 TI - Molecular Imaging of P-glycoprotein in Chemoresistant Tumors Using a Dual Modality PET/Fluorescence Probe. AB - Overexpression of P-glycoprotein (Pgp) has been considered a primary cause for multidrug resistance in a variety of cancers for three decades. However, clinical translation of Pgp targeted therapeutics has been hindered by lack of patient preselection based on the Pgp presence in tumors. We aim to develop a molecularly targeted probe for imaging tumoral Pgp in vivo with positron emission tomography (PET) and fluorescence, and to provide a tool for preselecting the patients with tumoral Pgp expression. Thus, a Pgp monoclonal antibody 15D3 was chemically modified with IRDye800 (IR800) and DOTA chelator. The specificity of the antibody conjugates DOTA-Pab-IR800 was verified in Pgp-expressing 3T3-MDR1 and control 3T3 cells. After radiolabeling with 64Cu, the probe was applied in small animal PET imaging of Pgp in a mouse xenograft model of NCI/ADR-Res cells, which are chemoresistant through overexpression of Pgp. Quantification analysis of the PET images demonstrated that the tumor uptake of the radioactive probe was 9.9 +/- 1.4, 12.1 +/- 1.2, and 10.5 +/- 1.0%ID/g at 4, 24, and 48 h post injection. The tumor-to-muscle ratio was 20.9 at 48 h post injection based on biodistribution studies. Fluorescence imaging was performed following PET experiments, and it demonstrated excellent tumor accumulation of this dual-modality probe in the NCI/ADR-Res tumors. Further, an image-guided surgery was successfully performed using the fluorescence modality of the probe, demonstrating potential utility of this probe in image-guided surgical removal of Pgp-positive drug resistant tumors in the patients. In conclusion, this study clearly demonstrated that the Pgp targeted antibody probe, 64Cu-DOTA-Pab-IR800, could provide a promising diagnosis tool for detection of Pgp-expressing tumors in vivo. PMID- 28813598 TI - Functional Microcapsules with Hybrid Shells Made via Sol-Gel Reaction within Double Emulsions. AB - Microcapsules with organic-inorganic hybrid shells can be used as functionally responsive delivery systems that are attractive for a broad range of applications. Hybrid-shell microcapsules have often been synthesized by the assembly of solid inorganic nanoparticles and polymers. Efforts to extend this approach to microfluidic emulsification have been hampered by problems with clogging and flow instabilities when utilizing dispersions of solid particles. In this work, hybrid shell microcapsules are synthesized through the reaction of liquid precursors, eliminating the use of solid dispersions. Our microfluidic water-oil-water emulsification technique also enables the preparation of hybrid shell microcapsules with thicker and more robust shells compared to alternative techniques. By utilizing bridged-silane precursors to form the hybrid material, we demonstrate hybrid-shell microcapsules with independently tunable functional and mechanical/barrier properties. This independent tuning of physical and functional properties allows for the production of functional organic-inorganic hybrid shell microcapsules that can be tailored to meet the demands of a wide range of applications. PMID- 28813599 TI - Tetraterpene Synthase Substrate and Product Specificity in the Green Microalga Botryococcus braunii Race L. AB - Recently, the biosynthetic pathway for lycopadiene, a C40 tetraterpenoid hydrocarbon, was deciphered from the L race of Botryococcus braunii, an alga that produces hydrocarbon oils capable of being converted into combustible fuels. The lycopadiene pathway is initiated by the squalene synthase (SS)-like enzyme lycopaoctaene synthase (LOS), which catalyzes the head-to-head condensation of two C20 geranylgeranyl diphosphate (GGPP) molecules to produce C40 lycopaoctaene. LOS shows unusual substrate promiscuity for SS or SS-like enzymes by utilizing C15 farnesyl diphosphate (FPP) and C20 phytyl diphosphate in addition to GGPP as substrates. These three substrates can be combined by LOS individually or in combinations to produce six different hydrocarbons of C30, C35, and C40 chain lengths. To understand LOS substrate and product specificity, rational mutagenesis experiments were conducted based on sequence alignment with several SS proteins as well as a structural comparison with the human SS (HSS) crystal structure. Characterization of the LOS mutants in vitro identified Ser276 and Ala288 in the LOS active site as key amino acids responsible for controlling substrate binding, and thus the promiscuity of this enzyme. Mutating these residues to those found in HSS largely converted LOS from lycopaoctaene production to C30 squalene production. Furthermore, these studies were confirmed in vivo by expressing LOS in E. coli cells metabolically engineered to produce high FPP and GGPP levels. These studies also offer insights into tetraterpene hydrocarbon metabolism in B. braunii and provide a foundation for engineering LOS for robust production of specific hydrocarbons of a desired chain length. PMID- 28813600 TI - Discovery of Enhanced Magnetoelectric Coupling through Electric Field Control of Two-Magnon Scattering within Distorted Nanostructures. AB - Electric field control of dynamic spin interactions is promising to break through the limitation of the magnetostatic interaction based magnetoelectric (ME) effect. In this work, electric field control of the two-magnon scattering (TMS) effect excited by in-plane lattice rotation has been demonstrated in a La0.7Sr0.3MnO3 (LSMO)/Pb(Mn2/3Nb1/3)-PbTiO3 (PMN-PT) (011) multiferroic heterostructure. Compared with the conventional strain-mediated ME effect, a giant enhancement of ME effect up to 950% at the TMS critical angle is precisely determined by angular resolution of the ferromagnetic resonance (FMR) measurement. Particularly, a large electric field modulation of magnetic anisotropy (464 Oe) and FMR line width (401 Oe) is achieved at 173 K. The electric-field-controllable TMS effect and its correlated ME effect have been explained by electric field modulation of the planar spin interactions triggered by spin-lattice coupling. The enhancement of the ME effect at various temperatures and spin dynamics control are promising paradigms for next generation voltage-tunable spintronic devices. PMID- 28813601 TI - Platinum-Decorated Gold Nanoparticles with Dual Functionalities for Ultrasensitive Colorimetric in Vitro Diagnostics. AB - Au nanoparticles (AuNPs) as signal reporters have been utilized in colorimetric in vitro diagnostics (IVDs) for decades. Nevertheless, it remains a grand challenge to substantially enhance the detection sensitivity of AuNP-based IVDs as confined by the inherent plasmonics of AuNPs. In this work, we circumvent this confinement by developing unique dual-functional AuNPs that were engineered by coating conventional AuNPs with ultrathin Pt skins of sub-10 atomic layers (i.e., Au@Pt NPs). The Au@Pt NPs retain the plasmonic activity of initial AuNPs while possessing ultrahigh catalytic activity enabled by Pt skins. Such dual functionalities, plasmonics and catalysis, offer two different detection alternatives: one produced just by the color from plasmonics (low-sensitivity mode) and the second more sensitive color catalyzed from chromogenic substrates (high-sensitivity mode), achieving an "on-demand" tuning of the detection performance. Using lateral flow assay as a model IVD platform and conventional AuNPs as a benchmark, we demonstrate that the Au@Pt NPs could enhance detection sensitivity by 2 orders of magnitude. PMID- 28813602 TI - Carbodicarbenes: Unexpected pi-Accepting Ability during Reactivity with Small Molecules. AB - An investigation of carbodicarbenes, the less explored member of the carbenic complex/ligand family has yielded unexpected electronic features and concomitant reactivity. Observed 1,2-addition of E-H bonds (E = B, C, Si) across the carbone central carbon and that of the flanking N-heterocyclic carbene (NHC) fragment, combined with single-crystal X-ray studies of a model Pd complex strongly suggests a significant level of pi-accepting ability at the central carbon of the NHC moiety. This feature is atypical of classic NHCs, which are strong sigma donors, with only nominal pi-accepting ability. The unanticipated pi-acidity is critical for engendering carbodicarbenes with reactivity more commonly observed with frustrated Lewis pairs (FLPs) rather than the more closely related NHCs and cyclic (alkyl)(amino)carbenes (CAACs). PMID- 28813603 TI - Modeling Optical Spectra of Large Organic Systems Using Real-Time Propagation of Semiempirical Effective Hamiltonians. AB - We present an implementation of a time-dependent semiempirical method (INDO/S) in NWChem using real-time (RT) propagation to address, in principle, the entire spectrum of valence electronic excitations. Adopting this model, we study the UV/vis spectra of medium-sized systems such as P3B2 and f-coronene, and in addition much larger systems such as ubiquitin in the gas phase and the betanin chromophore in the presence of two explicit solvents (water and methanol). RT INDO/S provides qualitatively and often quantitatively accurate results when compared with RT- TDDFT or experimental spectra. Even though we only consider the INDO/S Hamiltonian in this work, our implementation provides a framework for performing electron dynamics in large systems using semiempirical Hartree-Fock Hamiltonians in general. PMID- 28813604 TI - Experimental Study and Mathematical Modeling of Self-Sustained Kinetic Oscillations in Catalytic Oxidation of Methane over Nickel. AB - The self-sustained kinetic oscillations in the oxidation of CH4 over Ni foil have been studied at atmospheric pressure using an X-ray diffraction technique and mass spectrometry. It has been shown that the regular oscillations appear under oxygen-deficient conditions; CO, CO2, H2, and H2O are detected as the products. According to in situ X-ray diffraction measurements, nickel periodically oxidizes to NiO initiating the reaction-rate oscillations. To describe the oscillations, we have proposed a five-stage mechanism of the partial oxidation of methane over Ni and a corresponding three-variable kinetic model. The mechanism considers catalytic methane decomposition, dissociative adsorption of oxygen, transformation of chemisorbed oxygen to surface nickel oxide, and reaction of adsorbed carbon and oxygen species to form CO. Analysis of the kinetic model indicates that the competition of two processes, i.e., the oxidation and the carbonization of the catalyst surface, is the driving force of the self-sustained oscillations in the oxidation of methane. We have compared this mechanism with the detailed 18-stage mechanism described previously by Lashina et al. (Kinetics and Catalysis 2012, 53, 374-383). It has been shown that both kinetic mechanisms coupled with a continuous stirred-tank reactor model describe well the oscillatory behavior in the oxidation of methane under non-isothermal conditions. PMID- 28813606 TI - Nonepimerizing Alkylation of H-P Species to Stereospecifically Generate P Stereogenic Phosphine Oxides: A Shortcut to Bidentate Tertiary Phosphine Ligands. AB - The secondary RP-(-)-menthyl alkylphosphine oxide was confirmed as configurationally stable toward base and was used in base-promoted alkylation, stereospecifically affording P-retained bis or functional tertiary phosphine oxides in excellent yields. The alkylated products were deoxygenated using oxalyl chloride followed by ZnCl2-NaBH4 to form P-inversed bidentate phosphine boranes in high stereoselectivities. PMID- 28813605 TI - Structure-Activity Relationship Studies on a Macrocyclic Agouti-Related Protein (AGRP) Scaffold Reveal Agouti Signaling Protein (ASP) Residue Substitutions Maintain Melanocortin-4 Receptor Antagonist Potency and Result in Inverse Agonist Pharmacology at the Melanocortin-5 Receptor. AB - The melanocortin system consists of five reported receptors, agonists from the proopiomelanocortin gene transcript, and two antagonists, agouti-signaling protein (ASP) and agouti-related protein (AGRP). For both ASP and AGRP, the hypothesized Arg-Phe-Phe pharmacophores are on exposed beta-hairpin loops. In this study, the Asn and Ala positions of a reported AGRP macrocyclic scaffold (c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro]) were explored with 14-compound and 8 compound libraries, respectively, to generate more potent, selective melanocortin receptor antagonists. Substituting diaminopropionic acid (Dap), DDap, and His at the Asn position yielded potent MC4R ligands, while replacing Ala with Ser maintained MC4R potency. Since these substitutions correlate to ASP loop residues, an additional Phe to Ala substitution was synthesized and observed to maintain MC4R potency. Seventeen compounds also possessed inverse agonist activity at the MC5R, the first report of this pharmacology. These findings are useful in developing molecular probes to study negative energy balance conditions and unidentified functions of the MC5R. PMID- 28813607 TI - Nonlinear Raman Effects Enhanced by Surface Plasmon Excitation in Planar Refractory Nanoantennas. AB - We consider a nonlinear mechanism of localized light inelastic scattering within nanopatterned plasmonic and Raman-active titanium nitride (TiN) thin films exposed to continuous-wave (cw) modest-power laser light. Owing to the strong third-order nonlinear interaction between optically excited broadband surface plasmons and localized Stokes and anti-Stokes waves, both stimulated and inverse Raman effects can be observed. We provide experimental evidence for coherent amplification of the localized Raman signals using a planar square-shaped refractory antenna. PMID- 28813609 TI - Coassembly Kinetics of Graphene Oxide and Block Copolymers at the Water/Oil Interface. AB - The coassembly kinetics of graphene oxide (GO) nanosheets and diblock copolymers at the water/toluene interface is probed by tracking the dynamic interfacial tension using pendant drop tensiometry. The diblock copolymer significantly enhances the surfactancy of the GO nanosheets at the interface. It is found that diblock copolymers rapidly adsorb to the water/toluene interface and enhance the adsorption affinity of GO nanosheets to the interface. The continuous adsorption of GO at the interface leads to a random loose packing state, at which the adsorbed GO and diblock copolymers start to form an elastic film. After this transition, GO continues to adsorb to the interface, however, at a much slower speed, yielding a more solidlike elastic film in the long time equilibrium limit. PMID- 28813608 TI - Hot Air Treatment Induces Disease Resistance through Activating the Phenylpropanoid Metabolism in Cherry Tomato Fruit. AB - To explore the effects of hot air (HA, 38 degrees C for 12 h) treatment on the phenylpropanoid metabolism in cherry tomatoes, phenylpropanoid metabolite levels and the activities and expression of key enzymes were analyzed in HA-treated fruit. HA treatment enhanced phenylpropanoid metabolism, as evidenced by elevated levels of phenolics and flavonoids, higher activities of phenylalanine ammonia lyase and cinnamate-4-hydroxylase, and upregulated expression of LeCHS, LeCHI, LeF3H, and LeFLS. Levels of several phenylpropanoid metabolites were higher after HA treatment, including p-coumaric acid, caffeic acid, chlorogenic acid, isoquercitrin, quercetin, and rutin. These metabolic changes may be related to the reduced disease incidence and smaller lesion diameters observed in HA-treated fruit inoculated with Alternaria alternata (black mold) or Botrytis cinerea (gray mold). The results suggest that HA treatment induces disease resistance by activating the phenylpropanoid pathway in cherry tomato fruit. PMID- 28813610 TI - Poloxamer-Decorated Polymer Nanoparticles for Lung Surfactant Compatibility. AB - Lung-delivered polymer nanoparticles provoked dysfunction of the essential lung surfactant system. A steric shielding of the nanoparticle surface with poloxamers could minimize the unwanted interference of polymer nanoparticles with the biophysical function of lung surfactant. The extent of poly(styrene) and poly(lactide) nanoparticle-induced lung surfactant inhibition could be related to the type and content of the applied poloxamer. Escalations of the adsorbed coating layer thickness (>3 nm) as well as concentration (brush- rather than mushroom-like conformation of poly(ethylene glycol), chain-to-chain distance of <5 nm) on the colloidal surface were capable of circumventing bioadverse effects. Accordingly, specific formulations (i.e., poloxamer 188, 338, and 407) avoided a perturbation of the microstructure and surface activity of Alveofact and a depletion of the content of surfactant-associated proteins. Poloxamer-modified polymer nanoparticles represent a promising nanomedicine platform intended for respiratory delivery revealing negligible effects on the biophysical functionality of the lining layer present in the deep lungs. PMID- 28813611 TI - Intrauterine growth-restricted Yucatan miniature pigs experience early catch-up growth, leading to greater adiposity and impaired lipid metabolism as young adults. AB - Early nutrition has critical influences on cardiovascular disease risk in adulthood. The study objectives were to evaluate the impact of low birth weight on fasting and postprandial lipid metabolism and endothelium function in Yucatan miniature pigs. Intrauterine growth-restricted (IUGR) piglets (n = 6; 3 days old, 0.73 +/- 0.04 kg) were paired with normal-weight (NW) same-sex littermates (n = 6; 1.11 +/- 0.05 kg) and fed milk replacer ad libitum for 4 weeks. Thereafter, all pigs were fed a standard diet ad libitum for 5 h/day with growth, intakes, and blood samples collected for 8 months. At 9 months old, pigs were surgically fitted with venous catheters and an oral fat tolerance test was performed. At 10 months old, pigs were killed and endothelium-dependent and -independent vasodilations of isolated coronary arteries were measured using wire-myographs. IUGR pigs demonstrated catch-up growth (P < 0.05) in body weight and abdominal circumference prior to sexual maturity (<7 months old) and had more (P < 0.05) subcutaneous fat at 10 months old compared with NW pigs. IUGR pigs had consistently higher fasting plasma triglyceride concentrations from 5 to 10 months old and higher liver triglyceride and total cholesterol concentrations at 10 months old (P < 0.05). The fat tolerance test revealed delayed postprandial triglyceride clearance in IUGR pigs, but no differences in plaque formation or vascular reactivity. To conclude, IUGR and early postnatal catch-up growth are associated with increased overall body fat deposition and altered triglyceride metabolism in adult Yucatan miniature swine. PMID- 28813612 TI - Role of zinc oxide nanoparticles in alleviating hepatic fibrosis and nephrotoxicity induced by thioacetamide in rats. AB - The present research studied the influence of zinc oxide nanoparticles (ZnO-NPs; 5, 7.5, and 10 mg/kg, i.p.) on the liver and kidney injuries motivated by thioacetamide (TAA; 100 mg/kg, i.p.). Each treatment was carried out 3 times per week for 8 weeks. ZnO-NPs relieved the decrease of hepatic or renal reduced glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) induced by TAA. Moreover, ZnO-NPs lowered tissue malondialdehyde (MDA, an indicator for lipid peroxidation). TAA treatment led to a significant increase in plasma inflammatory markers (TNF-alpha, IL-6), liver enzymes (gamma-glutamyltransferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and kidney function parameters (creatinine, urea, uric acid). However, these parameters were reduced after treatment with ZnO-NPs. In addition, the hepatic fibrosis markers, hydroxyproline level, and alpha-smooth muscle actin immunopositive stain were lowered by ZnO-NPs. The protective effect of ZnO-NPs in respect to biochemical changes was also confirmed by histopathological and immunohistochemistry studies in the liver and kidney sections. Our results suggested that ZnO-NPs may attenuate TAA toxicity via suppression of oxidative stress. PMID- 28813613 TI - Methacholine Challenge: Comparison of Airway Responsiveness Produced by a Vibrating Mesh Nebulizer Versus a Jet Nebulizer. AB - BACKGROUND: The latest methacholine challenge testing (MCT) guidelines published by the European Respiratory Society recommend the characterization of nebulizers before their use in clinics and research. Such investigations are necessary for accurately determining the provocative dose of methacholine causing a 20% fall in FEV1 (PD20) delivered by a given device. The standard English Wright (Wright) jet nebulizer recommended in the 1999 guidelines by the American Thoracic Society has become difficult to obtain and possesses some characteristics that complicate the calculation of dose delivery from this device (e.g. evaporation). Our objective was to determine if the Aerogen(r) Solo (Solo) vibrating mesh nebulizer provides similar methacholine challenge test results compared to the currently used Wright jet nebulizer. METHODS: Sixty mild-to-moderate asthmatics were studied across three research sites in a randomized crossover study. Both methacholine challenges were completed at least 24 hours apart within a 2-week period. Testing with the Wright device was performed as per the 2-minute tidal breathing protocol. The Solo study arm followed the same procedure except for a shorter inhalation time of 1 minute. The provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) and the methacholine PD20 were calculated following each methacholine challenge. RESULTS: The geometric mean methacholine PC20 values for the Solo and the Wright differed statistically (0.65 mg/mL vs. 2.58 mg/mL, respectively, p < 0.00001) and clinically. Between-nebulizer geometric mean methacholine PD20 results are comparable by clinical standards [81.7 MUg (Solo) vs. 64.7 MUg (Wright)], although the slight difference in dose was statistically significant (p = 0.018). CONCLUSIONS: The comparability of PD20 values between the Solo and the Wright validates the importance of reporting airway responsiveness to methacholine in terms of dose and not concentration, as stressed in the latest testing guidelines. This finding along with several benefits associated with the Solo make it a promising nebulizer for performing MCT. PMID- 28813614 TI - Experiences with Cutting Matrix Fentanyl Patches as a Method of Dose Titration in Cancer Patients. PMID- 28813615 TI - "The Role of Role Play for a Medical Student": Pre- and Postclerkship Experiences in Palliative Care Education. PMID- 28813616 TI - Targeted Temperature Management in Nursing Care. PMID- 28813617 TI - Environmental Stress Affects the Formation of Staphylococcus aureus Persisters Tolerant to Antibiotics. AB - The ability to form persisters has been observed in many microorganisms, including Staphylococcus aureus, mainly in the context of chronic infections and the pathogenicity of these microbes. In our research, we have demonstrated that salt or oxidative stress could play a role in the formation of S. aureus persisters outside the host's intracellular interface. We pre-exposed planktonic growing bacterial culture to an oxidative or salt stress and monitored the dynamics of persister formation after ciprofloxacin and gentamicin treatment. In parallel, using the quantitative PCR (qPCR) approach, we determined the expression level of the stress sigma factor SigB. The pre-exposure of bacteria to salt stress caused a 1-2.5 order of magnitude increase in persister formation in the bacterial population after antibiotic exposure, depending on the type and concentration of the antibiotic used. In contrast, oxidative stress only minimally influenced the formation of persisters, without correlation to the antibiotic type and concentration. We have demonstrated that both stress and antibiotic exposure increase the expression of sigB in bacterial populations from very early on. And that the expression level of sigB differs with the type of antibiotic and stress, but no correlation was observed between persister formation and sigB expression. The method used could be helpful in testing the ability that strains can have, to form persisters. PMID- 28813618 TI - Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis. AB - Tooth agenesis is a common craniofacial abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been reported as contributing to the etiology. Here, we combined whole-exome sequencing, array-based genotyping, and linkage analysis to identify putative pathogenic variants in candidate disease genes for tooth agenesis in 10 multiplex Turkish families. Novel homozygous and heterozygous variants in LRP6, DKK1, LAMA3, and COL17A1 genes, as well as known variants in WNT10A, were identified as likely pathogenic in isolated tooth agenesis. Novel variants in KREMEN1 were identified as likely pathogenic in 2 families with suspected syndromic tooth agenesis. Variants in more than 1 gene were identified segregating with tooth agenesis in 2 families, suggesting oligogenic inheritance. Structural modeling of missense variants suggests deleterious effects to the encoded proteins. Functional analysis of an indel variant (c.3607+3_6del) in LRP6 suggested that the predicted resulting mRNA is subject to nonsense-mediated decay. Our results support a major role for WNT pathways genes in the etiology of tooth agenesis while revealing new candidate genes. Moreover, oligogenic cosegregation was suggestive for complex inheritance and potentially complex gene product interactions during development, contributing to improved understanding of the genetic etiology of familial tooth agenesis. PMID- 28813619 TI - Age-Related Changes in the Chorioretinal Junction: An Immunohistochemical Study. AB - The chorioretinal junction comprises the retinal pigment epithelium, Bruch's membrane (BM), and adjacent choroidal capillaries. Its significance lies in its ability to support the retina mechanically and metabolically. The aim of this cross-sectional study was to record the senescent changes affecting all the constituents of the chorioretinal junction in 40 histological specimens across the whole spectrum of the adult age range. This study included light microscopy, with hematoxylin and eosin and PAS stains, and fluorescent microscopy. Immunohistochemistry was done using antibodies against neurofilament, synaptophysin, S-100, and collagen IV. The descriptive microanatomy was corroborated by morphometry. The amount of melanin and lipofuscin granule and drusens were noted. The ratio of thickness of BM to capillary diameter reduced from 1:6 or less in the 2nd decade to 1:3 in the 10th decade. Complete hyalinization of intercapillary pillars was seen in the 10th decade. The accumulation of lipofuscin with age was documented with the diminution in the size of epithelial cells. The subepithelial accumulation of drusen was first noted in the specimen from the late 60s. We have described all senescent changes in the chorioretinal junction chronologically. Similar changes are found in a more pronounced form in age-related macular degeneration. These data might serve as a reference baseline for clinicians and pathologists. PMID- 28813620 TI - Transitioning From Paper to Digital: State Statutory and Regulatory Frameworks for Health Information Technology. AB - OBJECTIVES: In all health system sectors, electronic health information (EHI) is created, used, released, and reused. We examined states' efforts to address EHI uses in law to provide an understanding of the EHI legal environment. METHODS: Attorney researchers used WestlawNext to search for EHI-related statutes and regulations of the US states, US territories, and the District of Columbia in effect as of January 2014. The researchers independently catalogued provisions by the EHI use described in the law. Researchers resolved discrepancies through peer review meetings and recorded the consensus codes for each law. RESULTS: This study identified 2364 EHI-related laws representing 49 EHI uses in 54 jurisdictions. A total of 18 EHI uses were regulated by >=10 jurisdictions. More than 750 laws addressed 2 or more EHI uses. Jurisdictions varied by the number of EHI laws in effect, with a mean of 44 laws. Texas had the most EHI laws (n = 145). Hawaii and South Carolina had the fewest (n = 14 each). CONCLUSIONS: The EHI legal landscape is complex. The large quantity and diversity of laws complicate legal analysis, likely delay implementation of public health solutions, and might be detrimental to the development of emerging health information technology. Research is needed to understand the effect of EHI related laws. PMID- 28813621 TI - Improvement of an In Vitro Model to Assess Delivered Dose and Particle Size for a Vibrating Mesh Nebulizer During Mechanical Ventilation. AB - BACKGROUND: In an in vitro model of mechanical ventilation with gravity-dependent filter position we observed artificially high delivered doses resulting from liquid droplet collection and precipitation of aerosolized drug. We sequentially modified the model to obtain accurate reproducible measurements of delivered dose and particle size at endotracheal tube exit. METHODS: Stepwise changes in the model included (1) altering the endotracheal tube position to a gravity independent position, (2) adding fluid traps, (3) humidifying air near the test lung, and (4) simplifying test lung and filters. Delivered dose of aerosolized vancomycin and losses in different compartments were assessed under low-flow and high-flow conditions, with or without circuit humidification. Droplet size distribution (DSD) of aerosolized Amikacin Inhalation Solution at endotracheal tube exit was measured by laser diffraction. RESULTS: Changing endotracheal tube position and adding traps allowed separation of liquid droplets and aerosolized drug, providing a delivered vancomycin dose of 35.1% (high flow). Active heated humidification of exhaled air significantly reduced delivered dose (21.0%) and dose variability. Simplification of the model to improve usability had no further effect on delivered dose, which was higher under low-flow than high-flow conditions, although there was no difference between humidified (high flow, 20.3%; low flow, 45.8%) and nonhumidified (high flow, 22.8%; low flow, 47.3%) conditions. With circuit humidification, drug loss decreased in endotracheal tube and nebulizer T-piece, whereas more drug was captured in traps. Lower inspiratory flow and humidity in the circuit were associated with higher Dv50 of aerosolized Amikacin Inhalation Solution at endotracheal tube exit. CONCLUSIONS: We successfully modified our in vitro model of mechanical ventilation to allow more accurate measurement of the delivered dose of aerosolized vancomycin and DSD profile of aerosolized Amikacin Inhalation Solution at the endotracheal tube exit. PMID- 28813622 TI - The Effect of Posture on Intraocular Pressure and Systemic Hemodynamic Parameters in Treated and Untreated Patients with Primary Open-Angle Glaucoma. AB - PURPOSE: To assess intraocular pressure (IOP), systolic, diastolic, and mean arterial blood pressure (SBP, DBP, MAP) changes in the sitting, supine, and 20 degrees head-down (Trendelenburg) position in treated (tPOAG) and untreated (uPOAG) primary open-angle glaucoma patients and healthy controls. METHODS: All participants underwent IOP and systemic BP measurements in the sitting, supine, and Trendelenburg positions during office hours. IOP and BP readings in the sitting, supine, and Trendelenburg positions were analyzed. RESULTS: Twenty-one tPOAG patients, 17 uPOAG patients, and 21 controls were enrolled in the study. Compared to controls, eyes in the tPOAG and uPOAG groups had significantly larger posture-induced IOP elevation upon changing from the sitting to the supine position (P = 0.020 and P = 0.032, respectively). Compared to controls, the IOP elevation in the Trendelenburg position was statistically higher for the tPOAG (P = 0.003), but not the uPOAG group (P = 0.840). All 3 groups had a similar pattern of SBP, DBP, and MAP changes. CONCLUSIONS: Compared to controls, posture-induced IOP changes are more pronounced in treated and untreated POAG patients. PMID- 28813624 TI - TP53 Mutational Status and ROS Effect the Expression of the Survivin-Associated Radio-Adaptive Response. AB - A survivin-associated radio-adaptive response, characterized by increased radiation resistance or sensitization, was induced by exposure to 5 mGy of ionizing radiation and was correlated to the TP53 mutational status of exposed cells. Ten human cancer lines were investigated: colorectal carcinomas HCT116 and RKO [TP53 wild-type (WT)] and their respective TP53 null isogenic lines; breast adenocarcinomas MCF7 (TP53 WT) and MDA-MB-231 (TP53 Mut); lung carcinomas A549 (TP53 WT) and NCI-H1975 (TP53 Mut); and pancreatic carcinomas Hs766T (TP53 WT) and Panc-1 (TP53 Mut). Radiation induced (5 mGy) changes in the subsequent responses to 2 Gy in a multi-dose paradigm. Effects on radiation sensitivity were associated with changes in survivin's intracellular translocation to the cytoplasm (TP53 WT) or nucleus (TP53 Mut). Survival responses were determined using a colony forming assay. Intracellular localization of survivin was determined by ELISA and correlated with survival response. Two 2 Gy doses had minimal effects on the intracellular translocation of survivin. When preceded 15 min earlier by a 5 mGy exposure, survivin translocated to the cytoplasm in all of the TP53 WT cell lines, and to the nuclei in the TP53 null and Mut cells. All TP53 WT cells were protected (P < 0.001) by 5 mGy exposures, while Mut cells were sensitized (P < 0.001). HCT116 and RKO TP53 WT cells were admixed with their respective isogenic TP53 null counterparts in different proportions: 75% to 25%, 50% to 50% and 25% to 75%, respectively. All mixed confluent cultures expressed enhanced radio-sensitization (P <= 0.047) characteristic of TP53 Mut cells, which could be inhibited by their exposure to the antioxidant N-acetyl-l-cysteine (NAC) indicating a role for intercellular signaling by reactive oxygen species (ROS). ROS signaling in propagating the survivin-mediated response is involved in both intra- and intercellular communication processes. PMID- 28813625 TI - Detection of First-Line Drug Resistance Mutations and Drug-Protein Interaction Dynamics from Tuberculosis Patients in South India. AB - BACKGROUND: Diagnosis of drug-resistant tuberculosis predominantly relies on culture-based drug susceptibility testing, which take weeks to produce a result and a more time-efficient alternative method is multiplex allele-specific PCR (MAS-PCR). Also, understanding the role of mutations in causing resistance helps better drug designing. AIMS: To evaluate the ability of MAS-PCR in the detection of drug resistance and to understand the mechanism of interaction of drugs with mutant proteins in Mycobacterium tuberculosis. METHODS: Detection of drug resistant mutations using MAS-PCR and validation through DNA sequencing. MAS-PCR targeted five loci on three genes, katG 315 and inhA -15 for the drug isoniazid (INH), and rpoB 516, 526, and 531 for rifampicin (RIF). Furthermore, the sequence data were analyzed to study the effect on interaction of the anti-TB drug molecule with the target protein using in silico docking. RESULTS: We identified drug-resistant mutations in 8 out of 114 isolates with 2 of them as multidrug resistant TB using MAS-PCR. DNA sequencing confirmed only six of these, recording a sensitivity of 85.7% and specificity of 99.3% for MAS-PCR. Molecular docking showed estimated free energy of binding (DeltaG) being higher for RIF binding with RpoB S531L mutant. Codon 315 in KatG does not directly interact with INH but blocks the drug access to active site. CONCLUSIONS: We propose DNA sequencing based drug resistance detection for TB, which is more accurate than MAS-PCR. Understanding the action of resistant mutations in disrupting the normal drug protein interaction aids in designing effective drug alternatives. PMID- 28813627 TI - The Impact on Resource Utilization of Supportive Care Consults on Patients at the University of North Carolina Hospital, 2010-2012. AB - BACKGROUND: Cancer patients have a high rate of emergency department (ED) visits and inpatient hospitalizations (IHs) that may be reduced by use of outpatient palliative care services. OBJECTIVE: To determine whether the outpatient adult palliative care service at the University of North Carolina (UNC) Hospital, begun in 2008, reduced the frequency of ED visits and IH during a two-year period. DESIGN: The charts of patients with lung cancer or head and neck cancer seen by the supportive care service from 2010 to 2011, and of a contemporaneous set of potential consults that were not seen, were retrospectively reviewed to determine the impact of this care delivery model. SETTING/SUBJECTS: The number of individuals with lung cancer and head cancer seen during this two-year period was 24 and 23, respectively, permitting a statistical analysis from which meaningful conclusions could be drawn. MEASUREMENTS: The frequency of ED visits and IHs for each patient was reviewed. Descriptive statistics were used. Fisher's exact test was used for data categorized into two by two contingency tables. The nonparametric Jonckheere-Terpstra method was used to test for ordered differences across categories. RESULTS: Consultation with supportive care did not decrease overall use of ED visits. Patients with head and neck cancer showed an increase in ED visits (p = 0.08) but a reduction in inpatient admissions (p = 0.0004). In patients with lung cancer, the opposite effect was seen-an increase in inpatient visits (p = 0.02) but a decrease in ED visits. The frequency of ED visits was correlated with distance to the ED (p = 0.02), a finding that has not been noted before. CONCLUSIONS: Further work is needed to define the best model for outpatient palliative care. PMID- 28813630 TI - Gender Similarities and Differences for e-Health Behaviors Among U.S. Adults. AB - BACKGROUND: Technology access and use are increasing worldwide. Adults can potentially use technology to assist with health promotion and medical care. INTRODUCTION: The purpose of this study was to compare the prevalence of participation in online health-related activities between different genders of U.S. adults aged 18-90 years. METHODS: Primary data collected through a survey panel were used to examine associations between gender and technology ownership, Internet health-seeking behaviors and online behaviors related to health, having an app, and preferences for health information. Data were collected through an online survey panel of U.S. adults (n = 400) in March 2017. Results and Materials: Almost 75% had ever looked for health information and 56.8% had searched for information in the past month. About one-third of both genders (34.1%) reported tracking any health indicator regularly, and 24% had a health app. Compared with males, females were more likely to have ever sought health information online and to have a mobile app for health. No significant differences were observed between gender and individual or total e-health literacy scores. The top three preferences for health sources were Web sites (81.3%), in person (72.0%), and then print materials (72.0%). CONCLUSIONS: This study illustrates that U.S. adults are using the Internet for health activities; however, females are more likely to engage in different e-health behaviors than males. Additional research could determine the causal factors behind these group differences in the use of online healthcare and health implications in public health practice for each group. PMID- 28813631 TI - Rapid and targeted introgression of fgr gene through marker-assisted backcrossing in rice (Oryza sativa L.). AB - While it is crucial for developing countries like Malaysia to achieve self sufficiency in rice (Oryza sativa L.), it is equally critical to be able to produce high-quality rice, specifically fragrant rice, which demands are often met through importation. The present study was aimed at developing high-yielding fragrant rice, in a timely and cost-effective manner. A marker-assisted backcross (MABC) approach was optimised to introgress the fragrance gene (fgr) into two high-yielding Malaysian varieties, MR84 and MR219, within two years utilising less than 50 molecular markers. Coupled with phenotypic screening, one single foreground marker (fgr-SNP) and 48 background markers were selected and utilised, revealing recovery of at least 90% of recurrent parent genome (RPG) in merely two backcross generations. Collectively, the yield potential of the developed BC2F2 lines (BLs) was higher (P > 0.05) than the donor parent, MRQ74, and similar (P < 0.05) to both the recurrent parents, MR84 and MR219. In addition, some of the developed BLs showed good grain quality, such as having long grain. We believe that this is the first report comprising the validation and utilisation of the single functional marker system (fgr-SNP) in introgressing the fgr gene into different rice varieties. PMID- 28813632 TI - Eyes on New Product Development. PMID- 28813629 TI - The Impact of the Eda Pathway on Tooth Root Development. AB - The Eda pathway ( Eda, Edar, Edaradd) plays an important role in tooth development, determining tooth number, crown shape, and enamel formation. Here we show that the Eda pathway also plays a key role in root development. Edar (the receptor) is expressed in Hertwig's epithelial root sheath (HERS) during root development, with mutant mice showing a high incidence of taurodontism: large pulp chambers lacking or showing delayed bifurcation or trifurcation of the roots. The mouse upper second molars in the Eda pathway mutants show the highest incidence of taurodontism, this enhanced susceptibility being matched in human patients with mutations in EDA-A1. These taurodont teeth form due to defects in the direction of extension of the HERS from the crown, associated with a more extensive area of proliferation of the neighboring root mesenchyme. In those teeth where the angle at which the HERS extends from the crown is very wide and therefore more vertical, the mutant HERSs fail to reach toward the center of the tooth in the normal furcation region, and taurodont teeth are created. The phenotype is variable, however, with milder changes in angle and proliferation leading to normal or delayed furcation. This is the first analysis of the role of Eda in the root, showing a direct role for this pathway during postnatal mouse development, and it suggests that changes in proliferation and angle of HERS may underlie taurodontism in a range of syndromes. PMID- 28813633 TI - Unique Uses of Cooling Strategies. PMID- 28813634 TI - Hand-Assisted Laparoscopic Surgery Versus Conventional Laparoscopic Surgery for Colorectal Cancer: A Systematic Review and Meta-Analysis. AB - AIM: This meta-analysis aims to compare hand-assisted laparoscopic surgery (HALS) with conventional laparoscopic surgery (LAS) for colorectal cancer (CRC) in terms of intraoperative, postoperative, and survival outcomes. MATERIALS AND METHODS: A systematic literature search with no limits was performed in PubMed, Embase, and Medline. The last search was performed on March 31, 2017. The outcomes of interests included intraoperative outcomes (operative time, blood loss, length of incision, transfusion, conversion, and lymph nodes harvested), postoperative outcomes (length of hospital stay, time to first flatus, time to first bowel movement, postoperative complications, mortality, reoperation, ileus, anastomotic leakage, postoperative bleeding, wound infection, intra-abdominal abscess, urinary complication, cardiopulmonary complication, and readmission), and 5-year survival outcomes. RESULTS: Nine articles published between 2007 and 2016 with a total of 1307 patients were enrolled in this meta-analysis. HALS was associated with longer length of incision. No differences were found for operative time, blood loss, transfusion, conversion, lymph nodes harvested, length of hospital stay, time to first flatus, time to first bowel movement, postoperative complications, mortality, reoperation, ileus, anastomotic leakage, postoperative bleeding, wound infection, intra-abdominal abscess, urinary complication, cardiopulmonary complication, readmission, or 5-year survival outcomes. CONCLUSION: Our meta-analysis demonstrated that HALS is similar to LAS for CRC surgery in terms of intraoperative, postoperative, and survival outcomes except for the longer length of incision. PMID- 28813635 TI - Standardization and Scaling of a Community-Based Palliative Care Model. AB - BACKGROUND: Although limited, the descriptions of Community-Based Palliative Care (CBPC) demonstrates variability in team structures, eligibility, and standardization across care settings. OBJECTIVE: In 2014, Four Seasons Compassion for Life, a nonprofit hospice and palliative care (PC) organization in Western North Carolina (WNC), was awarded a Centers for Medicare and Medicaid Services Health Care Innovation (CMMI) Award to expand upon their existing innovative model to implement, evaluate, and demonstrate CBPC in the United States. The objective of this article is to describe the processes and challenges of scaling and standardizing the CBPC model. DESIGN: Four Season's CBPC model serves patients in both inpatient and outpatient settings using an interdisciplinary team to address symptom management, psychosocial/spiritual care, advance care planning, and patient/family education. Medicare beneficiaries who are >=65 years of age with a life-limiting illness were eligible for the CMMI project. RESULTS: The CBPC model was scaled across numerous counties in WNC and Upstate South Carolina. Over the first two years of the project, scaling occurred into 21 counties with the addition of 2 large hospitals, 52 nursing facilities, and 2 new clinics. To improve efficiency and effectiveness, a PC screening referral guide and a risk stratification approach were developed and implemented. Care processes, including patient referral and initial visit, were mapped. CONCLUSION: This article describes an interdisciplinary CBPC model in all care settings to individuals with life-limiting illness and offers guidance for risk stratification assessments and mapping care processes that may help PC programs as they develop and work to improve efficiencies. PMID- 28813637 TI - Erratum. PMID- 28813636 TI - Using Systems Science to Inform Population Health Strategies in Local Health Departments: A Case Study in San Antonio, Texas. AB - OBJECTIVES: Because of state and federal health care reform, local health departments play an increasingly prominent role leading and coordinating disease prevention programs in the United States. This case study shows how a local health department working in chronic disease prevention and management can use systems science and evidence-based decision making to inform program selection, implementation, and assessment; enhance engagement with local health systems and organizations; and possibly optimize health care delivery and population health. METHODS: The authors built a systems-science agent-based simulation model of diabetes progression for the San Antonio Metropolitan Health District, a local health department, to simulate health and cost outcomes for the population of San Antonio for a 20-year period (2015-2034) using 2 scenarios: 1 in which hemoglobin A1c (HbA1c) values for a population were similar to the current distribution of values in San Antonio, and the other with a hypothetical 1-percentage-point reduction in HbA1c values. RESULTS: They projected that a 1-percentage-point reduction in HbA1c would lead to a decrease in the 20-year prevalence of end stage renal disease from 1.7% to 0.9%, lower extremity amputation from 4.6% to 2.9%, blindness from 15.1% to 10.7%, myocardial infarction from 23.8% to 17.9%, and stroke from 9.8% to 7.2%. They estimated annual direct medical cost savings (in 2015 US dollars) from reducing HbA1c by 1 percentage point ranging from $6842 (myocardial infarction) to $39 800 (end-stage renal disease) for each averted case of diabetes complications. CONCLUSIONS: Local health departments could benefit from the use of systems science and evidence-based decision making to estimate public health program effectiveness and costs, calculate return on investment, and develop a business case for adopting programs. PMID- 28813638 TI - Impact of 70-Gene Signature Use on Adjuvant Chemotherapy Decisions in Patients With Estrogen Receptor-Positive Early Breast Cancer: Results of a Prospective Cohort Study. AB - Purpose Gene-expression profiles increasingly are used in addition to conventional prognostic factors to guide adjuvant chemotherapy (CT) decisions. The Dutch guideline suggests use of validated gene-expression profiles in patients with estrogen receptor (ER) -positive, early-stage breast cancer without overt lymph node metastases. We aimed to assess the impact of a 70-gene signature (70-GS) test on CT decisions in patients with ER-positive, early-stage breast cancer. Patients and Methods In a prospective, observational, multicenter study in patients younger than 70 years old who had undergone surgery for ER-positive, early-stage breast cancer, physicians were asked whether they intended to administer adjuvant CT before deployment of the 70-GS test and after the test result was available. Results Between October 1, 2013, and December 31, 2015, 660 patients, treated in 33 hospitals, were enrolled. Fifty-one percent of patients had pT1cN0, BRII, HER2-Neu-negative breast cancer. On the basis of conventional clinicopathological characteristics, physicians recommended CT in 270 (41%) of the 660 patients and recommended withholding CT in 107 (16%) of the 660 patients. For the remaining 43% of patients, the physicians were unsure and unable to give advice before 70-GS testing. In patients for whom CT was initially recommended or not recommended, 56% and 59%, respectively, were assigned to a low-risk profile by the 70-GS (kappa, 0.02; 95% CI, -0.08 to 0.11). After disclosure of the 70-GS test result, the preliminary advice was changed in 51% of patients who received a recommendation before testing; the definitive CT recommendation of the physician was in line with the 70-GS result in 96% of patients. Conclusion In this prospective, multicenter study in a selection of patients with ER-positive, early stage breast cancer, 70-GS use changed the physician-intended recommendation to administer CT in half of the patients. PMID- 28813640 TI - Innate immune signaling in the ventral tegmental area contributes to drug-primed reinstatement of cocaine seeking. AB - Cocaine addiction is a chronic relapsing disorder characterized by persistent perturbations to an organism's homeostatic processes that result in maladaptive drug seeking. Although considerable attention has been directed at the consequences of neuronal changes following chronic cocaine taking, few studies have examined the role of microglia, the brain's resident immune cells, following chronic cocaine administration. Toll-Like Receptor 4 (TLR4) is a molecular pattern receptor that recognizes pathogens, danger signals, and xenobiotics and induces proinflammatory signaling in the central nervous system. TLR4 is generally considered to be expressed primarily by microglia. Here, we used a rodent model of cocaine addiction to investigate the role of TLR4 in the ventral tegmental area (VTA) in cocaine seeking. Male Sprague-Dawley rats were trained to self-administer cocaine in daily 2-h sessions for 15days. Following self administration, rats underwent extinction training and were tested in a drug primed reinstatement paradigm. Pharmacological antagonism of TLR4 in the VTA using lipopolysaccharide from the bacterium Rhodobacter sphaeroides (LPS-RS) significantly reduced cocaine-primed reinstatement of drug seeking but had no effect on sucrose seeking. TLR4 activation within the VTA using the TLR4 activator, lipopolysaccharide, was sufficient to moderately reinstate cocaine seeking. We also assessed changes in proinflammatory cytokine expression in the VTA following cocaine self-administration. Cocaine self-administration increased the expression of mRNA for the proinflammatory cytokine interleukin-1beta, but not tumor necrosis factor alpha, in the VTA. Pharmacological antagonism of the interleukin-1 receptor in the VTA reduced cocaine-primed drug seeking. These results are consistent with the hypothesis that chronic cocaine produces inflammatory signaling that contributes to cocaine seeking. PMID- 28813641 TI - AIM2 inflammasome activation and regulation: A structural perspective. AB - Absent in melanoma 2 (AIM2) inflammasome is a multi-protein platform that recognizes aberrant cytoplasmic dsDNA and induces cytokine maturation, release and pyroptosis. It is composed of AIM2, apoptosis-associated speck-like protein containing a CARD (ASC), and caspase-1. Recent X-ray crystallographic and high resolution cryo-electron microscopic (cryo-EM) studies have revealed a series of structures in AIM2 inflammasome activation and regulation. One prominent feature common in multiple steps is the assembly of high-order structures, especially helical filaments nucleated by upstream molecules, rather than stoichiometric complexes. In this review, we track the AIM2 inflammasome activation process step by step, using high-resolution structures to illustrate the overall architecture of AIM2 inflammasome and its assembly and regulatory mechanisms. PMID- 28813642 TI - Buccal swab genomic DNA fragmentation predicts likelihood of successful HLA genotyping by next-generation sequencing. AB - Many clinical human leukocyte antigen (HLA) laboratories are adopting next generation sequencing (NGS) technology for HLA genotyping. There have been several reports of the cost-benefit and reduction in turn-around-time provided by NGS. Ninety-six percent of buccal swabs and peripheral blood samples had reportable HLA genotyping by NGS. The HLA loci most likely to fail genotyping from buccal swabs were DQB1, DPB1, and DPA1. Successful buccal swab samples had significantly less genomic DNA fragmentation compared to buccal swab samples that were unsuccessful. Increasing sequencing depth of coverage for heavily fragmented samples rescued HLA genotyping. This information provides laboratories with a quality assurance parameter that reduces the amount of repeat NGS needed to achieve high-resolution HLA genotyping. This information should further reduce laboratory and patient costs for HLA genotyping. PMID- 28813639 TI - Exploitation of Gene Expression and Cancer Biomarkers in Paving the Path to Era of Personalized Medicine. AB - Cancer therapy agents have been used extensively as cytotoxic drugs against tissue or organ of a specific type of cancer. With the better understanding of molecular mechanisms underlying carcinogenesis and cellular events during cancer progression and metastasis, it is now possible to use targeted therapy for these molecular events. Targeted therapy is able to identify cancer patients with dissimilar genetic defects at cellular level for the same cancer type and consequently requires individualized approach for treatment. Cancer therapy begins to shift steadily from the traditional approach of "one regimen for all patients" to a more individualized approach, through which each patient will be treated specifically according to their specific genetic defects. Personalized medicine accordingly requires identification of indicators or markers that guide in the decision making of such therapy to the chosen patients for more effective therapy. Cancer biomarkers are frequently used in clinical practice for diagnosis and prognosis, as well as identification of responsive patients and prediction of treatment response of cancer patient. The rapid breakthrough and development of microarray and sequencing technologies is probably the main tool for paving the way toward "individualized biomarker-driven cancer therapy" or "personalized medicine". In this review, we aim to provide an updated knowledge and overview of the current landscape of cancer biomarkers and their role in personalized medicine, emphasizing the impact of genomics on the implementation of new potential targeted therapies and development of novel cancer biomarkers in improving the outcome of cancer therapy. PMID- 28813644 TI - Rotavirus disease course among immunocompromised patients; 5-year observations from a tertiary care medical centre. AB - : Rotavirus (RV) is highly endemic inside and outside hospital-settings. Immunocompromised children and adults are at risk of complicated rotavirus gastroenteritis (RVGE), but general rotavirus disease severity in this group remains poorly described and rotavirus testing is not routinely performed beyond infancy. We assessed rotavirus disease among immunocompromised hospitalized patients. METHODS: Rotavirus infections at a Dutch tertiary-care centre were identified from 5-year laboratory records. Rotavirus disease course was evaluated by chart review for each immunocompromised patient. In a matched case-control analysis, we assessed whether being immunocompromised predisposed to RVGE. Rotavirus testing practice for suspected infectious gastroenteritis in our hospital was determined over a 3-years period. RESULTS: Out of 4584 RV tests performed, 294 were positive among hospitalized patients. Immunocompromised patients represented 57% (N = 20) of adult, and 12% (N = 32) of paediatric RVGE. A complicated disease course occurred in 81% of them and 33% required adaptations in underlying disease management. Immunocompromised adults were 7.4 times more likely todevelop RVGE compared to non-immunocompromised matched hospital controls. Rotavirus testing in adult patients with suspected infectious gastroenteritis was uncommon (12% tested). CONCLUSIONS: In our hospital, most adults with RVGE are immunocompromised compared to a much smaller proportion in children. RVGE in immunocompromised patients is associated with significant morbidity. Routine rotavirus testing beyond infancy should be recommended for immunocompromised patients with suspected infectious gastroenteritis. PMID- 28813643 TI - Multi-Connection Pattern Analysis: Decoding the representational content of neural communication. AB - The lack of multivariate methods for decoding the representational content of interregional neural communication has left it difficult to know what information is represented in distributed brain circuit interactions. Here we present Multi Connection Pattern Analysis (MCPA), which works by learning mappings between the activity patterns of the populations as a factor of the information being processed. These maps are used to predict the activity from one neural population based on the activity from the other population. Successful MCPA-based decoding indicates the involvement of distributed computational processing and provides a framework for probing the representational structure of the interaction. Simulations demonstrate the efficacy of MCPA in realistic circumstances. In addition, we demonstrate that MCPA can be applied to different signal modalities to evaluate a variety of hypothesis associated with information coding in neural communications. We apply MCPA to fMRI and human intracranial electrophysiological data to provide a proof-of-concept of the utility of this method for decoding individual natural images and faces in functional connectivity data. We further use a MCPA-based representational similarity analysis to illustrate how MCPA may be used to test computational models of information transfer among regions of the visual processing stream. Thus, MCPA can be used to assess the information represented in the coupled activity of interacting neural circuits and probe the underlying principles of information transformation between regions. PMID- 28813645 TI - LAT is essential for the mast cell stabilising effect of tHGA in IgE-mediated mast cell activation. AB - Mast cells play a central role in the pathogenesis of allergic reaction. Activation of mast cells by antigens is strictly dependent on the influx of extracellular calcium that involves a complex interaction between signalling molecules located within the cells. We have previously reported that tHGA, an active compound originally isolated from a local shrub known as Melicope ptelefolia, prevented IgE-mediated mast cell activation and passive systemic anaphylaxis by suppressing the release of interleukin-4 (IL-4) and tumour necrosis factor (TNF)-alpha from activated rat basophilic leukaemia (RBL)-2H3 cells. However, the mechanism of action (MOA) as well as the molecular target underlying the mast cell stabilising effect of tHGA has not been previously investigated. In this study, DNP-IgE-sensitised RBL-2H3 cells were pre-treated with tHGA before challenged with DNP-BSA. To dissect the MOA of tHGA in IgE mediated mast cell activation, the effect of tHGA on the transcription of IL-4 and TNF-alpha mRNA was determined using Real Time-Polymerase Chain Reaction (qPCR) followed by Calcium Influx Assay to confirm the involvement of calcium in the activation of mast cells. The protein lysates were analysed by using Western Blot to determine the effect of tHGA on various important signalling molecules in the LAT-PLCgamma-MAPK and PI3K-NFkappaB pathways. In order to identify the molecular target of tHGA in IgE-mediated mast cell activation, the LAT and LAT2 genes in RBL-2H3 cells were knocked-down by using RNA interference to establish a LAT/LAT2 competition model. The results showed that tHGA inhibited the transcription of IL-4 and TNF-alpha as a result of the suppression of calcium influx in activated RBL-2H3 cells. The results from Western Blot revealed that tHGA primarily inhibited the LAT-PLCgamma-MAPK pathway with partial inhibition on the PI3K-p65 pathway without affecting Syk. The results from RNAi further demonstrated that tHGA failed to inhibit the release of mediators associated with mast cell degranulation under the LAT/LAT2 competition model in the absence of LAT. Collectively, this study concluded that the molecular target of tHGA could be LAT and may provide a basis for the development of a mast cell stabiliser which targets LAT. PMID- 28813647 TI - Natural-Killer-like B Cells Display the Phenotypic and Functional Characteristics of Conventional B Cells. PMID- 28813648 TI - Natural-Killer-like B Cells Function as a Separate Subset of Innate B Cells. PMID- 28813646 TI - Antihelminthic drug niclosamide inhibits CIP2A and reactivates tumor suppressor protein phosphatase 2A in non-small cell lung cancer cells. AB - Protein phosphatase 2A (PP2A) is a critical tumor suppressor complex responsible for the inactivation of various oncogenes. Recently, PP2A reactivation has emerged asan anticancer strategy. Cancerous inhibitor of protein phosphatase 2A (CIP2A), an endogenous inhibitor of PP2A, is upregulated in many cancer cells, including non-small cell lung cancer (NSCLC) cells. We demonstrated that the antihelminthic drug niclosamide inhibited the expression of CIP2A and reactivated the tumor suppressor PP2A in NSCLC cells. We performed a drug-repurposing screen and identified niclosamide asa CIP2A suppressor in NSCLC cells. Niclosamide inhibited cell proliferation, colony formation, and tumor sphere formation, and induced mitochondrial dysfunction through increased mitochondrial ROS production in NSCLC cells; however, these effects were rescued by CIP2A overexpression, which indicated that the antitumor activity of niclosamide was dependent on CIP2A. We found that niclosamide increased PP2A activity through CIP2A inhibition, which reduced the phosphorylation of several oncogenic proteins. Moreover, we found that a niclosamide analog inhibited CIP2A expression and increased PP2A activity in several types of NSCLC cells. Finally, we showed that other well-known PP2A activators, including forskolin and FTY720, did not inhibit CIP2A and that their activities were not dependent on CIP2A. Collectively, our data suggested that niclosamide effectively suppressed CIP2A expression and subsequently activated PP2A in NSCLC cells. This provided strong evidence for the potential use of niclosamide asa PP2A-activating drug in the clinical treatment of NSCLC. PMID- 28813649 TI - A Case for a Human Immuno-Peptidome Project Consortium. AB - A multidisciplinary group of researchers gathered at the Honggerberg Campus at ETH Zurich, Switzerland, for the first meeting on the Human Immuno-Peptidome Project (https://hupo.org/human-immuno-peptidome-project/). The long-term goal of this project is to map the entire repertoire of peptides presented by human leukocyte antigen molecules using mass spectrometry technologies, and make its robust analysis accessible to any immunologist. Here we outline the specific challenges identified toward this goal, and within this framework, describe the structure of a multipronged program aimed at addressing these challenges and implementing solutions at a community-wide level. Pillars of that program are: (1) method and technology development, (2) standardization, (3) effective data sharing, and (4) education. If successful, this community-driven endeavor might provide a roadmap toward new paradigms in immunology. PMID- 28813650 TI - We Can Still Be Friends: IFN-gamma Breaks Up Macrophage Enhancers. AB - Interferon (IFN)-gamma can prime macrophages for inflammatory responses by several mechanisms, including enhancer establishment and gene activation. In this issue of Immunity, Kang et al. (2017) provide insight into the mechanisms of IFN gamma-mediated gene repression as they show that IFN-gamma promotes the disassembly of select active enhancers by interfering with enhancer-binding transcription factor MAF. PMID- 28813651 TI - A Rogue Foxp3 Mutant Undermines Treg Cell Function. AB - Hayatsu et al. (2017) reveal that a FOXP3 mutant found in some patients afflicted with the autoimmune disease IPEX has broadened DNA-recognition specificity, directly repressing the expression of the gene encoding the transcription factor Batf. Their findings identify Batf as critical to tissue regulatory T cell function and suggest that polymorphisms that impact FOXP3 DNA-binding specificity may contribute susceptibility to autoimmune disease. PMID- 28813652 TI - GR Extinguishes Inflamed Chromatin, and NF-kappaB Evacuates. AB - In this issue of Immunity,Oh et al. (2017) provide insight into the molecular effects of glucocorticoid receptor (GR) activation at a clinically relevant time point, after an inflammatory stimulus. They report that GR activation causes a global reduction in NF-kappaB binding, as well as time-dependent transcriptional effects. PMID- 28813653 TI - The Yolk Sac Feeds Pancreatic Tumors. AB - In this issue of Immunity, Zhu et al. (2017) report that tumor-associated macrophages in a mouse model of pancreatic ductal adenocarcinoma (PDAC) originate from both the yolk sac (YS) and bone marrow. Differential ablation of these populations indicates that only the YS-derived macrophages promote PDAC progression and growth. PMID- 28813654 TI - With Respect to Macrophages, Judge the Liver by Its Cover. AB - Kupffer cells are recognized as the sole liver-resident macrophages responsible for clearance of blood-borne pathogens reaching liver sinusoids. Sierro et al. (2017) uncover a distinct liver-resident macrophage population residing in its capsule, which creates a firewall against peritoneal infections. PMID- 28813655 TI - Making It Personal: Neoantigen Vaccines in Metastatic Melanoma. AB - Somatic mutations in cancer can be translated into peptides, termed neoantigens, which can be recognized by the immune system as "foreign" epitopes. Two recent studies in Nature (Sahin et al., 2017; Ott et al., 2017) examine the effects of neoantigen vaccines on patients with stage III or IV melanoma and demonstrate immunogenicity and intriguing clinical safety and efficacy data in phase I studies. PMID- 28813657 TI - Interferon-gamma Represses M2 Gene Expression in Human Macrophages by Disassembling Enhancers Bound by the Transcription Factor MAF. AB - Mechanisms by which interferon (IFN)-gamma activates genes to promote macrophage activation are well studied, but little is known about mechanisms and functions of IFN-gamma-mediated gene repression. We used an integrated transcriptomic and epigenomic approach to analyze chromatin accessibility, histone modifications, transcription-factor binding, and gene expression in IFN-gamma-primed human macrophages. IFN-gamma suppressed basal expression of genes corresponding to an "M2"-like homeostatic and reparative phenotype. IFN-gamma repressed genes by suppressing the function of enhancers enriched for binding by transcription factor MAF. Mechanistically, IFN-gamma disassembled a subset of enhancers by inducing coordinate suppression of binding by MAF, lineage-determining transcription factors, and chromatin accessibility. Genes associated with MAF binding enhancers were suppressed in macrophages isolated from rheumatoid arthritis patients, revealing a disease-associated signature of IFN-gamma mediated repression. These results identify enhancer inactivation and disassembly as a mechanism of IFN-gamma-mediated gene repression and reveal that MAF regulates the macrophage enhancer landscape and is suppressed by IFN-gamma to augment macrophage activation. PMID- 28813656 TI - Fcgamma Receptor Function and the Design of Vaccination Strategies. AB - Through specific interactions with distinct types of Fcgamma receptors (FcgammaRs), the Fc domain of immunoglobulin G (IgG) mediates a wide spectrum of immunological functions that influence both innate and adaptive responses. Recent studies indicate that IgG Fc-FcgammaR interactions are dynamically regulated during an immune response through the control of the Fc-associated glycan structure and Ig subclass composition on the one hand and selective FcgammaR expression on immune cells on the other, which together determine the capacity of IgG to interact in a cell-type-specific manner with specific members of the FcgammaR family. Here, we present a framework that synthesizes the current understanding of the contribution of FcgammaR pathways to the induction and regulation of antibody and T cell responses. Within this context, we discuss vaccination strategies to elicit broad and potent immune responses based on the immunomodulatory properties of Fc-FcgammaR interactions. PMID- 28813658 TI - CCCTC-Binding Factor Translates Interleukin 2- and alpha-Ketoglutarate-Sensitive Metabolic Changes in T Cells into Context-Dependent Gene Programs. AB - Despite considerable research connecting cellular metabolism with differentiation decisions, the underlying mechanisms that translate metabolite-sensitive activities into unique gene programs are still unclear. We found that aspects of the interleukin-2 (IL-2)-sensitive effector gene program in CD4+ and CD8+ T cells in type 1 conditions (Th1) were regulated by glutamine and alpha-ketoglutarate (alphaKG)-induced events, in part through changes in DNA and histone methylation states. We further identified a mechanism by which IL-2- and alphaKG-sensitive metabolic changes regulated the association of CCCTC-binding factor (CTCF) with select genomic sites. alphaKG-sensitive CTCF sites were often associated with loci containing IL-2- and alphaKG-sensitive genome organization patterns and gene expression in T cells. IL-2- and alphaKG-sensitive CTCF sites in T cells were also associated with genes from developmental pathways that had alphaKG-sensitive expression in embryonic stem cells. The data collectively support a mechanism wherein CTCF serves to translate alphaKG-sensitive metabolic changes into context dependent differentiation gene programs. PMID- 28813659 TI - The DNA Methylcytosine Dioxygenase Tet2 Sustains Immunosuppressive Function of Tumor-Infiltrating Myeloid Cells to Promote Melanoma Progression. AB - Ten-Eleven-Translocation-2 (Tet2) is a DNA methylcytosine dioxygenase that functions as a tumor suppressor in hematopoietic malignancies. We examined the role of Tet2 in tumor-tissue myeloid cells and found that Tet2 sustains the immunosuppressive function of these cells. We found that Tet2 expression is increased in intratumoral myeloid cells both in mouse models of melanoma and in melanoma patients and that this increased expression is dependent on an IL-1R MyD88 pathway. Ablation of Tet2 in myeloid cells suppressed melanoma growth in vivo and shifted the immunosuppressive gene expression program in tumor associated macrophages to a proinflammatory one, with a concomitant reduction of the immunosuppressive function. This resulted in increased numbers of effector T cells in the tumor, and T cell depletion abolished the reduced tumor growth observed upon myeloid-specific deletion of Tet2. Our findings reveal a non-cell intrinsic, tumor-promoting function for Tet2 and suggest that Tet2 may present a therapeutic target for the treatment of non-hematologic malignancies. PMID- 28813660 TI - Neutralizing Antibody Responses to Viral Infections Are Linked to the Non classical MHC Class II Gene H2-Ob. AB - Select humans and animals control persistent viral infections via adaptive immune responses that include production of neutralizing antibodies. The precise genetic basis for the control remains enigmatic. Here, we report positional cloning of the gene responsible for production of retrovirus-neutralizing antibodies in mice of the I/LnJ strain. It encodes the beta subunit of the non-classical major histocompatibility complex class II (MHC-II)-like molecule H2-O, a negative regulator of antigen presentation. The recessive and functionally null I/LnJ H2 Ob allele supported the production of virus-neutralizing antibodies independently of the classical MHC haplotype. Subsequent bioinformatics and functional analyses of the human H2-Ob homolog, HLA-DOB, revealed both loss- and gain-of-function alleles, which could affect the ability of their carriers to control infections with human hepatitis B (HBV) and C (HCV) viruses. Thus, understanding of the previously unappreciated role of H2-O (HLA-DO) in immunity to infections may suggest new approaches in achieving neutralizing immunity to viruses. PMID- 28813661 TI - Tissue-Resident Macrophages in Pancreatic Ductal Adenocarcinoma Originate from Embryonic Hematopoiesis and Promote Tumor Progression. AB - Tumor-associated macrophages (TAMs) are essential components of the cancer microenvironment and play critical roles in the regulation of tumor progression. Optimal therapeutic intervention requires in-depth understanding of the sources that sustain macrophages in malignant tissues. In this study, we investigated the ontogeny of TAMs in murine pancreatic ductal adenocarcinoma (PDAC) models. We identified both inflammatory monocytes and tissue-resident macrophages as sources of TAMs. Unexpectedly, significant portions of pancreas-resident macrophages originated from embryonic development and expanded through in situ proliferation during tumor progression. Whereas monocyte-derived TAMs played more potent roles in antigen presentation, embryonically derived TAMs exhibited a pro-fibrotic transcriptional profile, indicative of their role in producing and remodeling molecules in the extracellular matrix. Collectively, these findings uncover the heterogeneity of TAM origin and functions and could provide therapeutic insight for PDAC treatment. PMID- 28813662 TI - A Liver Capsular Network of Monocyte-Derived Macrophages Restricts Hepatic Dissemination of Intraperitoneal Bacteria by Neutrophil Recruitment. AB - The liver is positioned at the interface between two routes traversed by pathogens in disseminating infection. Whereas blood-borne pathogens are efficiently cleared in hepatic sinusoids by Kupffer cells (KCs), it is unknown how the liver prevents dissemination of peritoneal pathogens accessing its outer membrane. We report here that the hepatic capsule harbors a contiguous cellular network of liver-resident macrophages phenotypically distinct from KCs. These liver capsular macrophages (LCMs) were replenished in the steady state from blood monocytes, unlike KCs that are embryonically derived and self-renewing. LCM numbers increased after weaning in a microbiota-dependent process. LCMs sensed peritoneal bacteria and promoted neutrophil recruitment to the capsule, and their specific ablation resulted in decreased neutrophil recruitment and increased intrahepatic bacterial burden. Thus, the liver contains two separate and non overlapping niches occupied by distinct resident macrophage populations mediating immunosurveillance at these two pathogen entry points to the liver. PMID- 28813663 TI - A CRISPR Activation Screen Identifies a Pan-avian Influenza Virus Inhibitory Host Factor. AB - Influenza A virus (IAV) is a pathogen that poses significant risks to human health. It is therefore critical to develop strategies to prevent influenza disease. Many loss-of-function screens have been performed to identify the host proteins required for viral infection. However, there has been no systematic screen to identify the host factors that, when overexpressed, are sufficient to prevent infection. In this study, we used CRISPR/dCas9 activation technology to perform a genome-wide overexpression screen to identify IAV restriction factors. The major hit from our screen, B4GALNT2, showed inhibitory activity against influenza viruses with an alpha2,3-linked sialic acid receptor preference. B4GALNT2 overexpression prevented the infection of every avian influenza virus strain tested, including the H5, H9, and H7 subtypes, which have previously caused disease in humans. Thus, we have used CRISPR/dCas9 activation technology to identify a factor that can abolish infection by avian influenza viruses. PMID- 28813664 TI - Intestinal Dysbiosis and Biotin Deprivation Induce Alopecia through Overgrowth of Lactobacillus murinus in Mice. AB - Metabolism by the gut microbiota affects host physiology beyond the gastrointestinal tract. Here, we find that antibiotic-induced dysbiosis, in particular, overgrowth of Lactobacillus murinus (L. murinus), impaired gut metabolic function and led to the development of alopecia. While deprivation of dietary biotin per se did not affect skin physiology, its simultaneous treatment with vancomycin resulted in hair loss in specific pathogen-free (SPF) mice. Vancomycin treatment induced the accumulation of L. murinus in the gut, which consumes residual biotin and depletes available biotin in the gut. Consistently, L. murinus induced alopecia when monocolonized in germ-free mice fed a biotin deficient diet. Supplementation of biotin can reverse established alopecia symptoms in the SPF condition, indicating that L. murinus plays a central role in the induction of hair loss via a biotin-dependent manner. Collectively, our results indicate that luminal metabolic alterations associated with gut dysbiosis and dietary modifications can compromise skin physiology. PMID- 28813665 TI - Lineage-Restricted Mammary Stem Cells Sustain the Development, Homeostasis, and Regeneration of the Estrogen Receptor Positive Lineage. AB - The mammary gland (MG) is composed of different cell lineages, including the basal and the luminal cells (LCs) that are maintained by distinct stem cell (SC) populations. LCs can be subdivided into estrogen receptor (ER)+ and ER- cells. LCs act as the cancer cell of origin in different types of mammary tumors. It remains unclear whether the heterogeneity found in luminal-derived mammary tumors arises from a pre-existing heterogeneity within LCs. To investigate LC heterogeneity, we used lineage tracing to assess whether the ER+ lineage is maintained by multipotent SCs or by lineage-restricted SCs. To this end, we generated doxycycline-inducible ER-rtTA mice that allowed us to perform genetic lineage tracing of ER+ LCs and study their fate and long-term maintenance. Our results show that ER+ cells are maintained by lineage-restricted SCs that exclusively contribute to the expansion of the ER+ lineage during puberty and their maintenance during adult life. PMID- 28813666 TI - MicroRNA-9 Couples Brain Neurogenesis and Angiogenesis. AB - In the developing brain, neurons expressing VEGF-A and blood vessels grow in close apposition, but many of the molecular pathways regulating neuronal VEGF-A and neurovascular system development remain to be deciphered. Here, we show that miR-9 links neurogenesis and angiogenesis through the formation of neurons expressing VEGF-A. We found that miR-9 directly targets the transcription factors TLX and ONECUTs to regulate VEGF-A expression. miR-9 inhibition leads to increased TLX and ONECUT expression, resulting in VEGF-A overexpression. This untimely increase of neuronal VEGF-A signal leads to the thickening of blood vessels at the expense of the normal formation of the neurovascular network in the brain and retina. Thus, this conserved transcriptional cascade is critical for proper brain development in vertebrates. Because of this dual role on neural stem cell proliferation and angiogenesis, miR-9 and its downstream targets are promising factors for cellular regenerative therapy following stroke and for brain tumor treatment. PMID- 28813667 TI - Human GW182 Paralogs Are the Central Organizers for RNA-Mediated Control of Transcription. AB - In the cytoplasm, small RNAs can control mammalian translation by regulating the stability of mRNA. In the nucleus, small RNAs can also control transcription and splicing. The mechanisms for RNA-mediated nuclear regulation are not understood and remain controversial, hindering the effective application of nuclear RNAi and investigation of its natural regulatory roles. Here, we reveal that the human GW182 paralogs TNRC6A/B/C are central organizing factors critical to RNA-mediated transcriptional activation. Mass spectrometry of purified nuclear lysates followed by experimental validation demonstrates that TNRC6A interacts with proteins involved in protein degradation, RNAi, the CCR4-NOT complex, the mediator complex, and histone-modifying complexes. Functional analysis implicates TNRC6A, NAT10, MED14, and WDR5 in RNA-mediated transcriptional activation. These findings describe protein complexes capable of bridging RNA-mediated sequence specific recognition of noncoding RNA transcripts with the regulation of gene transcription. PMID- 28813668 TI - Subnuclear Relocalization of Structure-Specific Endonucleases in Response to DNA Damage. AB - Structure-specific endonucleases contribute to the maintenance of genome integrity by cleaving DNA intermediates that need to be resolved for faithful DNA repair, replication, or recombination. Despite advances in the understanding of their function and regulation, it is less clear how these proteins respond to genotoxic stress. Here, we show that the structure-specific endonuclease Mus81 Mms4/EME1 relocalizes to subnuclear foci following DNA damage and colocalizes with the endonucleases Rad1-Rad10 (XPF-ERCC1) and Slx1-Slx4. Recruitment takes place into a class of stress foci defined by Cmr1/WDR76, a protein involved in preserving genome stability, and depends on the E2-ubiquitin-conjugating enzyme Rad6 and the E3-ubiquitin ligase Bre1. Foci dynamics show that, in the presence of DNA intermediates that need resolution by Mus81-Mms4, Mus81 foci persist until this endonuclease is activated by Mms4 phosphorylation. Our data suggest that subnuclear relocalization is relevant for the function of Mus81-Mms4 and, probably, of the endonucleases that colocalize with it. PMID- 28813669 TI - The Phage Nucleus and Tubulin Spindle Are Conserved among Large Pseudomonas Phages. AB - We recently demonstrated that the large Pseudomonas chlororaphis bacteriophage 201phi2-1 assembles a nucleus-like structure that encloses phage DNA and segregates proteins according to function, with DNA processing proteins inside and metabolic enzymes and ribosomes outside the nucleus. Here, we investigate the replication pathway of the Pseudomonas aeruginosa bacteriophages phiKZ and phiPA3. Bacteriophages phiKZ and phiPA3 encode a proteinaceous shell that assembles a nucleus-like structure that compartmentalizes proteins and DNA during viral infection. We show that the tubulin-like protein PhuZ encoded by each phage assembles a bipolar spindle that displays dynamic instability and positions the nucleus at midcell. Our results suggest that the phage spindle and nucleus play the same functional role in all three phages, 201phi2-1, phiKZ, and phiPA3, demonstrating that these key structures are conserved among large Pseudomonas phages. PMID- 28813670 TI - NKX2-1 Is Required in the Embryonic Septum for Cholinergic System Development, Learning, and Memory. AB - The transcription factor NKX2-1 is best known for its role in the specification of subsets of cortical, striatal, and pallidal neurons. We demonstrate through genetic fate mapping and intersectional focal septal deletion that NKX2-1 is selectively required in the embryonic septal neuroepithelium for the development of cholinergic septohippocampal projection neurons and large subsets of basal forebrain cholinergic neurons. In the absence of NKX2-1, these neurons fail to develop, causing alterations in hippocampal theta rhythms and severe deficiencies in learning and memory. Our results demonstrate that learning and memory are dependent on NKX2-1 function in the embryonic septum and suggest that cognitive deficiencies that are sometimes associated with pathogenic mutations in NKX2-1 in humans may be a direct consequence of loss of NKX2-1 function. PMID- 28813671 TI - OCT4 and SOX2 Work as Transcriptional Activators in Reprogramming Human Fibroblasts. AB - SOX2 and OCT4, in conjunction with KLF4 and cMYC, are sufficient to reprogram human fibroblasts to induced pluripotent stem cells (iPSCs), but it is unclear if they function as transcriptional activators or as repressors. We now show that, like OCT4, SOX2 functions as a transcriptional activator. We substituted SOX2 VP16 (a strong activator) for wild-type (WT) SOX2, and we saw an increase in the efficiency and rate of reprogramming, whereas the SOX2-HP1 fusion (a strong repressor) eliminated reprogramming. We report that, at an early stage of reprogramming, virtually all DNA-bound OCT4, SOX2, and SOX2-VP16 were embedded in putative enhancers, about half of which were created de novo. Those associated with SOX2-VP16 were, on average, stronger than those bearing WT SOX2. Many newly created putative enhancers were transient, and many transcription factor locations on DNA changed as reprogramming progressed. These results are consistent with the idea that, during reprogramming, there is an intermediate state that is distinct from both parental cells and iPSCs. PMID- 28813672 TI - Chromatin and Transcriptional Analysis of Mesoderm Progenitor Cells Identifies HOPX as a Regulator of Primitive Hematopoiesis. AB - We analyzed chromatin dynamics and transcriptional activity of human embryonic stem cell (hESC)-derived cardiac progenitor cells (CPCs) and KDR+/CD34+ endothelial cells generated from different mesodermal origins. Using an unbiased algorithm to hierarchically rank genes modulated at the level of chromatin and transcription, we identified candidate regulators of mesodermal lineage determination. HOPX, a non-DNA-binding homeodomain protein, was identified as a candidate regulator of blood-forming endothelial cells. Using HOPX reporter and knockout hESCs, we show that HOPX regulates blood formation. Loss of HOPX does not impact endothelial fate specification but markedly reduces primitive hematopoiesis, acting at least in part through failure to suppress Wnt/beta catenin signaling. Thus, chromatin state analysis permits identification of regulators of mesodermal specification, including a conserved role for HOPX in governing primitive hematopoiesis. PMID- 28813673 TI - Multipotent Basal Stem Cells, Maintained in Localized Proximal Niches, Support Directed Long-Ranging Epithelial Flows in Human Prostates. AB - Sporadic mitochondrial DNA mutations serve as clonal marks providing access to the identity and lineage potential of stem cells within human tissues. By combining quantitative clonal mapping with 3D reconstruction of adult human prostates, we show that multipotent basal stem cells, confined to discrete niches in juxta-urethral ducts, generate bipotent basal progenitors in directed epithelial migration streams. Basal progenitors are then dispersed throughout the entire glandular network, dividing and differentiating to replenish the loss of apoptotic luminal cells. Rare lineage-restricted luminal stem cells, and their progeny, are confined to proximal ducts and provide only minor contribution to epithelial homeostasis. In situ cell capture from clonal maps identified delta homolog 1 (DLK1) enrichment of basal stem cells, which was validated in functional spheroid assays. This study establishes significant insights into niche organization and function of prostate stem and progenitor cells, with implications for disease. PMID- 28813674 TI - An Integrated Systems Biology Approach Identifies TRIM25 as a Key Determinant of Breast Cancer Metastasis. AB - At the root of most fatal malignancies are aberrantly activated transcriptional networks that drive metastatic dissemination. Although individual metastasis associated genes have been described, the complex regulatory networks presiding over the initiation and maintenance of metastatic tumors are still poorly understood. There is untapped value in identifying therapeutic targets that broadly govern coordinated transcriptional modules dictating metastatic progression. Here, we reverse engineered and interrogated a breast cancer specific transcriptional interaction network (interactome) to define transcriptional control structures causally responsible for regulating genetic programs underlying breast cancer metastasis in individual patients. Our analyses confirmed established pro-metastatic transcription factors, and they uncovered TRIM25 as a key regulator of metastasis-related transcriptional programs. Further, in vivo analyses established TRIM25 as a potent regulator of metastatic disease and poor survival outcome. Our findings suggest that identifying and targeting keystone proteins, like TRIM25, can effectively collapse transcriptional hierarchies necessary for metastasis formation, thus representing an innovative cancer intervention strategy. PMID- 28813675 TI - CD44 Interacts with HIF-2alpha to Modulate the Hypoxic Phenotype of Perinecrotic and Perivascular Glioma Cells. AB - Hypoxia-inducible factors enhance glioma stemness, and glioma stem cells have an amplified hypoxic response despite residing within a perivascular niche. Still, little is known about differential HIF regulation in stem versus bulk glioma cells. We show that the intracellular domain of stem cell marker CD44 (CD44ICD) is released at hypoxia, binds HIF-2alpha (but not HIF-1alpha), enhances HIF target gene activation, and is required for hypoxia-induced stemness in glioma. In a glioma mouse model, CD44 was restricted to hypoxic and perivascular tumor regions, and in human glioma, a hypoxia signature correlated with CD44. The CD44ICD was sufficient to induce hypoxic signaling at perivascular oxygen tensions, and blocking CD44 cleavage decreased HIF-2alpha stabilization in CD44 expressing cells. Our data indicate that the stem cell marker CD44 modulates the hypoxic response of glioma cells and that the pseudo-hypoxic phenotype of stem like glioma cells is achieved by stabilization of HIF-2alpha through interaction with CD44, independently of oxygen. PMID- 28813676 TI - Pharmacologic or Genetic Targeting of Glutamine Synthetase Skews Macrophages toward an M1-like Phenotype and Inhibits Tumor Metastasis. AB - Glutamine-synthetase (GS), the glutamine-synthesizing enzyme from glutamate, controls important events, including the release of inflammatory mediators, mammalian target of rapamycin (mTOR) activation, and autophagy. However, its role in macrophages remains elusive. We report that pharmacologic inhibition of GS skews M2-polarized macrophages toward the M1-like phenotype, characterized by reduced intracellular glutamine and increased succinate with enhanced glucose flux through glycolysis, which could be partly related to HIF1alpha activation. As a result of these metabolic changes and HIF1alpha accumulation, GS-inhibited macrophages display an increased capacity to induce T cell recruitment, reduced T cell suppressive potential, and an impaired ability to foster endothelial cell branching or cancer cell motility. Genetic deletion of macrophagic GS in tumor bearing mice promotes tumor vessel pruning, vascular normalization, accumulation of cytotoxic T cells, and metastasis inhibition. These data identify GS activity as mediator of the proangiogenic, immunosuppressive, and pro-metastatic function of M2-like macrophages and highlight the possibility of targeting this enzyme in the treatment of cancer metastasis. PMID- 28813677 TI - The IL-17F/IL-17RC Axis Promotes Respiratory Allergy in the Proximal Airways. AB - The interleukin 17 (IL-17) cytokine and receptor family is central to antimicrobial resistance and inflammation in the lung. Mice lacking IL-17A, IL 17F, or the IL-17RA subunit were compared with wild-type mice for susceptibility to airway inflammation in models of infection and allergy. Signaling through IL 17RA was required for efficient microbial clearance and prevention of allergy; in the absence of IL-17RA, signaling through IL-17RC on epithelial cells, predominantly by IL-17F, significantly exacerbated lower airway Aspergillus or Pseudomonas infection and allergic airway inflammation. In contrast, following infection with the upper respiratory pathogen Staphylococcus aureus, the IL 17F/IL-17RC axis mediated protection. Thus, IL-17A and IL-17F exert distinct biological effects during pulmonary infection; the IL-17F/IL-17RC signaling axis has the potential to significantly worsen pathogen-associated inflammation of the lower respiratory tract in particular, and should be investigated further as a therapeutic target for treating pathological inflammation in the lung. PMID- 28813678 TI - Therapeutic Antibodies to Ganglioside GD2 Evolved from Highly Selective Germline Antibodies. AB - Antibodies play a crucial role in host defense and are indispensable research tools, diagnostics, and therapeutics. Antibody generation involves binding of genomically encoded germline antibodies followed by somatic hypermutation and in vivo selection to obtain antibodies with high affinity and selectivity. Understanding this process is critical for developing monoclonal antibodies, designing effective vaccines, and understanding autoantibody formation. Prior studies have found that antibodies to haptens, peptides, and proteins evolve from polyspecific germline antibodies. The immunological evolution of antibodies to mammalian glycans has not been studied. Using glycan microarrays, protein microarrays, cell binding studies, and molecular modeling, we demonstrate that therapeutic antibodies to the tumor-associated ganglioside GD2 evolved from highly specific germline precursors. The results have important implications for developing vaccines and monoclonal antibodies that target carbohydrate antigens. In addition, they demonstrate an alternative pathway for antibody evolution within the immune system that is distinct from the polyspecific germline pathway. PMID- 28813679 TI - The Tumor Suppressor p53 Limits Ferroptosis by Blocking DPP4 Activity. AB - Ferroptosis is a form of regulated cell death that may facilitate the selective elimination of tumor cells. The tumor suppressor p53 (TP53) has been demonstrated to promote ferroptosis via a transcription-dependent mechanism. Here, we show that TP53 limits erastin-induced ferroptosis by blocking dipeptidyl-peptidase-4 (DPP4) activity in a transcription-independent manner. Loss of TP53 prevents nuclear accumulation of DPP4 and thus facilitates plasma-membrane-associated DPP4 dependent lipid peroxidation, which finally results in ferroptosis. These findings reveal a direct molecular link between TP53 and DPP4 in the control of lipid metabolism and may provide a precision medicine strategy for the treatment of colorectal cancer by induction of ferroptosis. PMID- 28813680 TI - Antibiotics Disrupt Coordination between Transcriptional and Phenotypic Stress Responses in Pathogenic Bacteria. AB - Bacterial genes that change in expression upon environmental disturbance have commonly been seen as those that must also phenotypically matter. However, several studies suggest that differentially expressed genes are rarely phenotypically important. We demonstrate, for Gram-positive and Gram-negative bacteria, that these seemingly uncoordinated gene sets are involved in responses that can be linked through topological network analysis. However, the level of coordination is stress dependent. While a well-coordinated response is triggered in response to nutrient stress, antibiotics trigger an uncoordinated response in which transcriptionally and phenotypically important genes are neither linked spatially nor in their magnitude. Moreover, a gene expression meta-analysis reveals that genes with large fitness changes during stress have low transcriptional variation across hundreds of other conditions, and vice versa. Our work suggests that cellular responses can be understood through network models that incorporate regulatory and genetic relationships, which could aid drug target predictions and genetic network engineering. PMID- 28813681 TI - Uncoupling the Mitogenic and Metabolic Functions of FGF1 by Tuning FGF1-FGF Receptor Dimer Stability. AB - The recent discovery of metabolic roles for fibroblast growth factor 1 (FGF1) in glucose homeostasis has expanded the functions of this classically known mitogen. To dissect the molecular basis for this functional pleiotropy, we engineered an FGF1 partial agonist carrying triple mutations (FGF1DeltaHBS) that diminished its ability to induce heparan sulfate (HS)-assisted FGF receptor (FGFR) dimerization and activation. FGF1DeltaHBS exhibited a severely reduced proliferative potential, while preserving the full metabolic activity of wild-type FGF1 in vitro and in vivo. Hence, suboptimal FGFR activation by a weak FGF1-FGFR dimer is sufficient to evoke a metabolic response, whereas full FGFR activation by stable and sustained dimerization is required to elicit a mitogenic response. In addition to providing a physical basis for the diverse activities of FGF1, our findings will impact ongoing drug discoveries targeting FGF1 and related FGFs for the treatment of a variety of human diseases. PMID- 28813683 TI - TET2 Regulates Mast Cell Differentiation and Proliferation through Catalytic and Non-catalytic Activities. PMID- 28813684 TI - Mimicking mechanical response of natural tissues. Strain hardening induced by transient reticulation in lactose-modified chitosan (chitlac). AB - The effect of transient cross-links has been explored on a lactose-modified chitosan, which previously had shown interesting biological features. The presence of galactose side chains and of the polyol spacer resulted particularly appealing for the reticulation by borate ions. The interaction between chitlac and borax was investigated by means of 11B NMR while rheology pointed to a marked non-linear behavior depending on the amount of borax added to the system. The presence of limited amount of cross-linking ion led to dilatant behavior when the steady flow curve was measured. In addition, strain stiffening was noticed on elastic response upon exceeding a critical stress, indicating a transient nature in the formation of the cross-links. The non-linear response of chitlac in the presence of borax compared surprisingly well with the one showed by proteins composing the natural ECM pointing at a possible role of mechanotransduction in the biological significance of the modified chitosan. PMID- 28813686 TI - Genetic and functional characterization of a novel GH10 endo-beta- 1,4-xylanase with a ricin-type beta-trefoil domain-like domain from Luteimicrobium xylanilyticum HY-24. AB - The gene (1488-bp) encoding a novel GH10 endo-beta-1,4-xylanase (XylM) consisting of an N-terminal catalytic GH10 domain and a C-terminal ricin-type beta-trefoil lectin domain-like (RICIN) domain was identified from Luteimicrobium xylanilyticum HY-24. The GH10 domain of XylM was 72% identical to that of Micromonospora lupini endo-beta-1,4-xylanase and the RICIN domain was 67% identical to that of Actinospica robiniae hypothetical protein. The recombinant enzyme (rXylM: 49kDa) exhibited maximum activity toward beechwood xylan at 65 degrees C and pH 6.0, while the optimum temperature and pH of its C-terminal truncated mutant (rXylM?RICIN: 35kDa) were 45 degrees C and 5.0, respectively. After pre-incubation of 1h at 60 degrees C, rXylM retained over 80% of its initial activity, but the thermostability of rXylM?RICIN was sharply decreased at temperatures exceeding 40 degrees C. The specific activity (254.1Umg-1) of rXylM toward oat spelts xylan was 3.4-fold higher than that (74.8Umg-1) of rXylM?RICIN when the same substrate was used. rXylM displayed superior binding capacities to lignin and insoluble polysaccharides compared to rXylM?RICIN. Enzymatic hydrolysis of beta-1,4-d-xylooligosaccharides (X3-X6) and birchwood xylan yielded X3 as the major product. The results suggest that the RICIN domain in XylM might play an important role in substrate-binding and biocatalysis. PMID- 28813687 TI - Prenylated purine alkaloids from seeds of Gleditsia japonica. AB - Three previously undescribed isoguanine glycosides with an N3-prenyl group, designated locustoside B, saikachinoside B, and saikachinoside C, have been isolated from the seed of Gleditsia japonica Miquel (Fabaceae) along with two known compounds, locustoside A and saikachinoside A. Their structures were determined from spectroscopic data and X-ray crystallographic analysis. The inhibitory activity against acid phosphatase was evaluated. PMID- 28813685 TI - Purification and characterization of two novel peroxidases from the dye decolorizing fungus Bjerkandera adusta strain CX-9. AB - Two extracellular peroxidases from Bjerkandera adusta strain CX-9, namely a lignin peroxidase (called LiP BA45) and manganese peroxidase (called MnP BA30), were purified simultaneously by applying successively, ammonium sulfate precipitation-dialysis, Mono-S Sepharose anion-exchange and Sephacryl S-200 gel filtration and biochemically characterized. The sequence of their NH2-terminal amino acid residues showed high homology with those of fungi peroxidases. Matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI TOF/MS) analysis revealed that the purified enzymes MnP BA30 and LiP BA45 were a monomers with a molecular masses 30125.16 and 45221.10Da, respectively. While MnP BA30 was optimally active at pH 3 and 70 degrees C, LiP BA45 showed optimum activity at pH 4 and 50 degrees C. The two enzymes were inhibited by sodium azide and potassium cyanide, suggesting the presence of heme-components in their tertiary structures. The Km and Vmax for LiP BA45 toward 2,4-Dichlorolphenol (2,4 DCP) were 0.099mM and 9.12U/mg, respectively and for MnP BA30 toward 2,6 Dimethylphenol (2,6-DMP), they were 0.151mM and 18.60U/mg, respectively. Interestingly, MnP BA30 and LiP BA45 demonstrated higher catalytic efficiency than that of other tested peroxidases (MnP, LiP, HaP4, and LiP-SN) and marked organic solvent-stability and dye-decolorization efficiency. Data suggest that these peroxidases may be considered as potential candidates for future applications in distaining synthetic-dyes. PMID- 28813682 TI - Circadian and Feeding Rhythms Orchestrate the Diurnal Liver Acetylome. AB - Lysine acetylation is involved in various biological processes and is considered a key reversible post-translational modification in the regulation of gene expression, enzyme activity, and subcellular localization. This post translational modification is therefore highly relevant in the context of circadian biology, but its characterization on the proteome-wide scale and its circadian clock dependence are still poorly described. Here, we provide a comprehensive and rhythmic acetylome map of the mouse liver. Rhythmic acetylated proteins showed subcellular localization-specific phases that correlated with the related metabolites in the regulated pathways. Mitochondrial proteins were over represented among the rhythmically acetylated proteins and were highly correlated with SIRT3-dependent deacetylation. SIRT3 activity being nicotinamide adenine dinucleotide (NAD)+ level-dependent, we show that NAD+ is orchestrated by both feeding rhythms and the circadian clock through the NAD+ salvage pathway but also via the nicotinamide riboside pathway. Hence, the diurnal acetylome relies on a functional circadian clock and affects important diurnal metabolic pathways in the mouse liver. PMID- 28813688 TI - Isolation and characterization of non-sulfated and sulfated triterpenoid saponins from Fagonia indica. AB - Seven previously undescribed, sulfated triterpenoid glycosides, named nayabin A-G along with a known triterpenoid glycoside were isolated from the whole plant of Fagonia indica. Their structures were elucidated through spectral studies including 1D- (1H and 13C), 2D-NMR spectroscopy (HSQC, HMBC, COSY and NOESY), and mass spectrometry (ESI-MS/MS). beta-D-Glucopyranosyl 3beta-hydroxy-23-O-beta-D glucopyranosyloxy-taraxast-20-en-28-oate, a known compound exerts glucose dependent insulin secretory activity, which seems to exhibit a decreased risk of drug-induced hypoglycemia and may offer distinct advantages as anti-diabetic agent. PMID- 28813689 TI - Large-scale machine learning of media outlets for understanding public reactions to nation-wide viral infection outbreaks. AB - From May to July 2015, there was a nation-wide outbreak of Middle East respiratory syndrome (MERS) in Korea. MERS is caused by MERS-CoV, an enveloped, positive-sense, single-stranded RNA virus belonging to the family Coronaviridae. Despite expert opinions that the danger of MERS might be exaggerated, there was an overreaction by the public according to the Korean mass media, which led to a noticeable reduction in social and economic activities during the outbreak. To explain this phenomenon, we presumed that machine learning-based analysis of media outlets would be helpful and collected a number of Korean mass media articles and short-text comments produced during the 10-week outbreak. To process and analyze the collected data (over 86 million words in total) effectively, we created a methodology composed of machine-learning and information-theoretic approaches. Our proposal included techniques for extracting emotions from emoticons and Internet slang, which allowed us to significantly (approximately 73%) increase the number of emotion-bearing texts needed for robust sentiment analysis of social media. As a result, we discovered a plausible explanation for the public overreaction to MERS in terms of the interplay between the disease, mass media, and public emotions. PMID- 28813690 TI - Deep coal mining and meningococcal meningitis in England and Wales, 1931-38: Ecological study, with implications for deep shaft mining activities worldwide. AB - The hypothesized role of deep coal mining in the development of community-based outbreaks of meningococcal meningitis has gone largely unexplored. Taking the coalfields of Britain as a historical testbed, techniques of linear and binomial logistic regression were used to assess the association between meningococcal meningitis rates and male occupation rates for coal mining in England and Wales during the national epidemic of 1931-32 and in its aftermath. Adjusting for the epidemiological effects of age, residential density, recent changes in the number of families, housing stock and low social class, the analysis yielded evidence of a significant and positive association between coal mining occupation rates and notified levels of meningitis activity in the epidemic period. Communities in areas of the world that currently maintain substantial deep coal extraction industries may be at increased risk for the epidemic transmission of meningococcal meningitis. PMID- 28813691 TI - Effects of superabsorbent polymers on the abundances of antibiotic resistance genes, mobile genetic elements, and the bacterial community during swine manure composting. AB - Superabsorbent polymers (SAPs) are considered suitable amendments for reducing the selection pressure due to heavy metals and the abundances of antibiotic resistance genes (ARGs) during composting. In this study, three SAP (sodium polyacrylate) levels (0, 5, and 15mgkg-1 of compost) were applied and their effects on the abundances of ARGs, mobile genetic elements (MGEs), and the bacterial community were investigated. After composting, the abundances of ARGs and MGEs decreased to different extent, where the removal efficiencies for tetW, dfrA7, ermX, aac(6')-ib-cr and MGEs exceeded 90%. The high SAP concentration significantly reduced the abundances of ARGs and MGEs, and changed the microbial community. Redundancy analysis indicated that the moisture content mainly explained the changes in ARGs and MGEs. Network analysis determined the potential hosts of ARGs and MGEs, and their co-occurrence. The results suggested that applying 15mgkg-1 SAP is appropriate for reducing ARGs in compost. PMID- 28813692 TI - Enhancing cell growth and lutein productivity of Desmodesmus sp. F51 by optimal utilization of inorganic carbon sources and ammonium salt. AB - The type and concentration of inorganic carbon and nitrogen sources were manipulated to improve cell growth and lutein productivity of Desmodesmus sp. F51. Using nitrate as nitrogen source, the better cell growth and lutein accumulation were obtained under 2.5% CO2 supply when compared to the addition of NaHCO3 or Na2CO3. To solve the pH variation problem of ammonium consumption, the strategy of using dual carbon sources (NaHCO3 and CO2) was explored. A lower bicarbonate-C: ammonium-N ratio led to a lower culture pH as well as lower lutein productivity, but significantly enhanced the auto-flocculation efficiency of the microalgal cells. The highest biomass productivity (939mg/L/d) and lutein productivity (5.22mg/L/d) were obtained when the bicarbonate-C/ammonium-N ratio and ammonium-N concentration were 1:1 and 150mg/L, respectively. The lutein productivity of 5.22mg/L/d is the highest value ever reported in the literature using batch phototrophic cultivation. PMID- 28813693 TI - Thyrotoxicity of arsenate and arsenite on juvenile mice at organism, subcellular, and gene levels under low exposure. AB - Arsenic contamination in drinking water is a worldwide issue, posing threat to human health. Arsenic is an endocrine system disruptor, however, limited information is available regarding its long-term effects on thyroid endocrine system at low exposure. In this study, we assessed the thyroid toxicity of arsenate (AsV) and arsenite (AsIII) at 10-100 MUg L-1 in juvenile mice after 8 week of exposure via drinking water. After 1-2 week, AsV and AsIII had little influence on thyroxine (T4) level (56.3-64.7 MUg L-1) in mouse blood compared to control mice at 57.3-60.7 MUg L-1. However, after 4-8 weeks, 10 MUg L-1 AsIII or AsV increased T4 levels to 83.8-88.8 MUg L-1 compared to control treatment at 77.2-80.0 MUg L-1, while 100 MUg L-1 AsV or AsIII decreased T4 levels except for 100 MUg L-1 AsIII for 8 weeks. Based on transmission electron microscopy, exposure to 100 MUg L-1 AsIII or AsV for 8 weeks caused thyroid gland damage. In addition, exposure to AsV or AsIII at 10 or 100 MUg L-1 impacted gene transcription of hypothalamic-pituitary-thyroid axis including thyroid stimulating hormone and iodothyronine deiodinases. Our data demonstrated that exposing to low levels of AsIII or AsV disrupted T4 homeostasis, influenced the related gene transcription and damaged the thyroid glands in juvenile mice. PMID- 28813695 TI - Risk-based remediation of polluted sites: A critical perspective. AB - Sites contaminated with chemical pollutants represent a growing challenge, and remediation of such lands is of international concern. Risk-based land management (RBLM) is an emerging approach that integrates risk assessment practices with more traditional site-specific investigations and remediation activities. Developing countries are yet to adopt RBLM strategies for remediation. RBLM is considered to be practical, scientifically defensible and cost-efficient. However, it is inherently limited by: firstly, the accuracy of risk assessment models used; secondly, ramifications of the fact that they are more likely to leave contamination in place; and thirdly, uncertainties involved and having to consider the total concentrations of all contaminants in soils that overestimate the potential risks from exposure to the contaminants. Consideration of contaminant bioavailability as the underlying basis for risk assessment and setting remediation goals of those contaminated lands that pose a risk to environmental and human health may lead to the development of a more sophisticated risk-based approach. However, employing the bioavailability concept in RBLM has not been extensively studied and/or legalized. This review highlights the extent of global land contamination, and the concept of risk-based assessment and management of contaminated sites including its advantages and disadvantages. Furthermore, the concept of bioavailability-based RBLM strategy has been proposed, and the challenges of RBLM and the priority areas for future research are summarized. Thus, the present review may help achieve a better understanding and successful implementation of a sustainable bioavailability-based RBLM strategy. PMID- 28813694 TI - Bacteria from the rhizosphere and tissues of As-hyperaccumulator Pteris vittata and their role in arsenic transformation. AB - Arsenic (As)-resistant bacteria are abundant in the rhizosphere and tissues of As hyperaccumulator Pteris vittata. However, little is known about their roles in As transformation and As uptake in P. vittata. In this study, the impacts of P. vittata tissue extracts with or without surface sterilization on As transformation in solutions containing 100 MUg L-1 AsIII or AsV were investigated. After 48 h incubation, the sterilized and unsterilized root extracts resulted in 45% and 73% oxidation of AsIII, indicating a role of both rhizobacteria and endobacteria. In contrast, AsV reduction was only found in rhizome and frond extracts at 3.7-24% of AsV. A total of 37 strains were isolated from the tissue extracts, which are classified into 18 species based on morphology and 16S rRNA. Phylogenic analysis showed that ~44% isolates were Firmicutes and others were Proteobacteria except for one strain belonging to Bacteroidetes. While most endobacteria were Firmicutes, most rhizobacteria were Proteobacteria. All isolated bacteria belonged to AsV reducers except for an As sensitive strain and one AsIII- oxidizer PVR-YHB6-1. Since As transformation was not observed in solutions after filtrating or boiling, we concluded that both rhizobacteria and endobacteria were involved in As transformation in the rhizosphere and tissues of P. vittata. PMID- 28813697 TI - Green Inclusions in Neutrophils and Monocytes Are an Indicator of Acute Liver Injury and High Mortality. PMID- 28813696 TI - Effects of Standardized Home Training in Patients with Cognitive Impairment following Geriatric Rehabilitation: A Randomized Controlled Pilot Study. AB - BACKGROUND: Post-ward geriatric rehabilitation programs have hardly been developed and validated, which leaves a substantial gap in rehabilitative care in older adults and hinders full exploitation of maintained, but often unrecognized rehabilitation potentials. Geriatric rehabilitation patients with cognitive impairment represent a highly vulnerable population which is often affected by a lack of an ongoing support at the intersection between ward-based and post-ward rehabilitation. OBJECTIVE: To determine the effect of a standardized home-based training program in geriatric patients with cognitive impairment following ward based rehabilitation. METHODS: A randomized controlled, single-blinded intervention trial (RCT) with wait list control design was used. Geriatric patients (n = 34; age: 81.9 +/- 5.7 years) with cognitive impairment (MMSE: 18.8 +/- 4.7), identified by predefined in- and exclusion criteria, were consecutively recruited from a geriatric rehab ward. Patients in the intervention group (IG, n = 17) performed a 6-week strength and functional home training. The control group (CG, n = 17) started an identical training 6 weeks later with an initial usual care period during the intervention for the IG. Functional performance (Short Physical Performance Battery; SPPB), clinically relevant functional deficits (Performance Oriented Assessment; POMA), and physical activity (Assessment of Physical Activity For Older Persons questionnaire; APAFOP) represented primary outcome measurements complemented by additional secondary outcome parameters. RESULTS: The IG significantly increased functional performances in SPPB (total score: p = 0.012; chair rise: p = 0.007, balance: p = 0.066), reduced gait and balance deficits in POMA (total score: p = 0.006; balance: p = 0.034; gait: p = 0.019), and increased physical activity (APAFOP; p = 0.05) compared to the CG. Effect sizes showed medium to large effects for significant parameters (eta2 = 0.14-0.45). Training benefits and adherence were more pronounced following the immediate onset of post-ward training compared to a delayed start (eta2 = 0.06 0.23). CONCLUSION: Results of this pilot study show that a feasible and easy to handle, home-based rehabilitation program increased functional performance and physical activity in a vulnerable, multimorbid patient group with cognitive impairment, in particular when the post-ward training onset was not postponed. PMID- 28813698 TI - Caspase-Independent Pathway is Related to Nilotinib Cytotoxicity in Cultured Cardiomyocytes. AB - BACKGROUND/AIMS: Cardiotoxicity is a predominant side-effect of nilotinib during chronic myeloid leukemia treatment. The underlying molecular mechanism remains unclear. The role of autophagy and mitochondrial signaling was investigated in nilotinib-treated cardiac H9C2 cells. METHODS: Cytotoxicity was assessed using Cell Death Detection kit. Immunoblot and immunofluorescence staining was performed, and cathepsin B and caspase3 activity was assessed in nilotinib treated H9C2 cells with or without distinct pathway inhibitor or specific siRNA. RESULTS: Nilotinib time- and dose-dependently induced H9C2 apoptosis, which was not completely prevented by the pan caspase inhibitor z-VAD-fmk. Following nilotinib treatment, mitochondrial membrane potential decreased significantly accompanied with remarkable morphological changes. Nuclear translocation of mitochondrial apoptosis inducing factor (AIF) and increased p53 was detected in nilotinib-treated cells. AIF knockdown prevented nilotinib-induced increase of p53 and apoptosis. Additionally, increased cathepsin B activity was detected, and inhibition of cathepsin B by CA-074Me prevented nilotinib-induced apoptosis and nuclear translocation of AIF. Moreover, increased Atg5 and transition of LC3-I to LC3-II was revealed following nilotinib treatment. Increased cathepsin B activity and apoptosis by nilotinib was significantly prohibited by specific autophagy inhibitor bafilomycin A and Atg5 knockdown. CONCLUSION: Our findings demonstrate that nilotinib increases autophagy and cathepsin B activity, leading to mitochondrial AIF release and nuclear translocation, which is responsible for p53 and apoptosis induction in H9C2 cells. PMID- 28813700 TI - Regenerative Medicine Approaches for Age-Related Muscle Loss and Sarcopenia: A Mini-Review. AB - Sarcopenia is a complex and multifactorial disease that includes a decrease in the number, structure and physiology of muscle fibers, and age-related muscle mass loss, and is associated with loss of strength, increased frailty, and increased risk for fractures and falls. Treatment options are suboptimal and consist of exercise and nutrition as the cornerstone of therapy. Current treatment principles involve identification and modification of risk factors to prevent the disease, but these efforts are of limited value to the elderly individuals currently affected by sarcopenia. The development of new and effective therapies for sarcopenia is challenging. Potential therapies can target one or more of the proposed multiple etiologies such as the loss of regenerative capacity of muscle, age-related changes in the expression of signaling molecules such as growth hormone, IGF-1, myostatin, and other endocrine signaling molecules, and age-related changes in muscle physiology like denervation and mitochondrial dysfunction. The present paper reviews regenerative medicine strategies that seek to restore adequate skeletal muscle structure and function including exogenous delivery of cells and pharmacological therapies to induce myogenesis or reverse the physiologic changes that result in the disease. Approaches that modify the microenvironment to provide an environment conducive to reversal and mitigation of the disease represent a potential regenerative medicine approach that is discussed herein. PMID- 28813699 TI - T1 and T2 Mapping in Cardiology: "Mapping the Obscure Object of Desire". AB - The increasing use of cardiovascular magnetic resonance (CMR) is based on its capability to perform biventricular function assessment and tissue characterization without radiation and with high reproducibility. The use of late gadolinium enhancement (LGE) gave the potential of non-invasive biopsy for fibrosis quantification. However, LGE is unable to detect diffuse myocardial disease. Native T1 mapping and extracellular volume fraction (ECV) provide knowledge about pathologies affecting both the myocardium and interstitium that is otherwise difficult to identify. Changes of myocardial native T1 reflect cardiac diseases (acute coronary syndromes, infarction, myocarditis, and diffuse fibrosis, all with high T1) and systemic diseases such as cardiac amyloid (high T1), Anderson-Fabry disease (low T1), and siderosis (low T1). The ECV, an index generated by native and post-contrast T1 mapping, measures the cellular and extracellular interstitial matrix (ECM) compartments. This myocyte-ECM dichotomy has important implications for identifying specific therapeutic targets of great value for heart failure treatment. On the other hand, T2 mapping is superior compared with myocardial T1 and ECM for assessing the activity of myocarditis in recent-onset heart failure. Although these indices can significantly affect the clinical decision making, multicentre studies and a community-wide approach (including MRI vendors, funding, software, contrast agent manufacturers, and clinicians) are still missing. PMID- 28813701 TI - Uterine Cervical Length Measurement to Reduce Length of Stay in Patients Admitted for Threatened Preterm Labor: A Randomized Trial. AB - OBJECTIVE: To study whether knowledge of cervical length (CL) is useful in reducing the length of hospital stay in women admitted because of threatened preterm labor. METHODS: We performed a single-center, parallel, randomized trial at the Hospital Clinic of Barcelona. Inclusion criteria were single pregnancy, gestational age (GA) between 24+0 and 35+6 weeks, Bishop score <6, no parturition within 24-48 h after admission, and no clinical signs of chorioamnionitis, vaginal bleeding, or nonreassuring fetal status. CL measurement was performed 24 48 h after admission. In the control group, the patient and the physician in charge were blinded. In the study group, this information was given; if CL was >25 mm, early discharge within 12-24 h from randomization was recommended. Length of hospital stay was the main outcome. RESULTS: After randomization, 149 patients had complete follow-up (control group, n = 74; study group, n = 75). The mean (SD) length of stay was significantly shorter - 3.0 (2.2) vs. 4.0 (2.0) days (p = 0.004) - in the study group, with a higher proportion of women remaining hospitalized <=3 days (relative risk [95% confidence interval] 0.43 [0.26-0.70]), with no differences in GA at delivery or preterm birth rate. CONCLUSIONS: Knowledge of CL in women admitted because of threatened preterm labor is useful in reducing length of stay, with no impact on GA at delivery or preterm birth rate. PMID- 28813702 TI - Tocolysis for in utero Surgery: Atosiban Performs Distinctly Better than Magnesium Sulfate. AB - INTRODUCTION: To compare tocolysis with magnesium sulfate versus atosiban regarding the occurrence of short-term preterm labor and maternal side effects during and after open fetal myelomeningocele (MMC) repair. MATERIAL AND METHODS: A prospective nonrandomized cohort study was performed including 30 fetal MMC cases. The first 15 cases (group 1) received magnesium sulfate according to the MOMS protocol. In the following 15 cases (group 2), magnesium sulfate was substituted by atosiban. Chorioamniotic membrane separation (CMS), premature prelabor rupture of the fetal membranes (PPROM), preterm delivery <3 weeks after fetal MMC repair, and maternal complications due to the tocolytic medication were the major endpoints. RESULTS: In both groups, one CMS but no PPROM was diagnosed <3 weeks after fetal MMC repair. One patient of group 2 delivered <3 weeks after fetal MMC repair because of an intraoperative placental abruption at 25 weeks. All women of group 1 showed an electrolyte imbalance during magnesium sulfate administration. One woman of group 1 developed several episodes of a third-degree atrioventricular block within the first 3 days after fetal surgery. Lethargy was found in all women during magnesium sulfate therapy. No maternal side effects were found under atosiban. DISCUSSION: The use of atosiban resulted in an almost identical short-term uterine outcome without any serious maternal complications as seen when magnesium sulfate was given. Thus, the authors suggest using atosiban instead of magnesium sulfate in the context of open fetal surgery. PMID- 28813703 TI - Efficacy and Safety of Adjuvant Treatment with Entacapone in Advanced Parkinson's Disease with Motor Fluctuation: A Systematic Meta-Analysis. AB - AIMS: To assess the efficacy and safety of adjuvant treatment with entacapone in the treatment of later Parkinson's disease (PD) patients with motor fluctuation. METHODS: We conducted a systematic review of relevant studies from 8 databases to June 23, 2016. RESULTS: Fourteen studies were included in this review (n = 2,804). The results showed that compared with placebo, adjuvant therapy with entacapone significantly increased on time (p < 0.01) and reduced off time (p < 0.01), the required levodopa (LD) dose (p < 0.01) and improved Parkinson's Disease Rating Scale (UPDRS) scores (activities of daily living score: p < 0.01; motor score: p < 0.01; UPDRS I-III score: p > 0.05). However, the withdrawal (OR 1.44, 95% CI 1.10-1.89, p < 0.01) due to adverse events and adverse events rates including nausea (OR 2.23, 95% CI 1.56-3.20, p < 0.01), urine discoloration (OR 14.99, 95% CI 7.63-29.44, p < 0.01), gastrointestinal disorder (OR 2.6, 95% CI 1.89-3.57, p < 0.01) and dyskinesia (OR 2.00, 95% CI 1.56-2.58, p < 0.01) increased in patients with entacapone compared with those given a placebo . CONCLUSIONS: This meta-analysis suggests that the entacapone used as adjuvant therapy to LD is effective in the management of later PD with fluctuation. However, patients on entacapone had a higher frequency of adverse events than those on placebo but no occurrence of severe adverse reactions. PMID- 28813704 TI - P38 Kinase, SGK1 and NF-kappaB Dependent Up-Regulation of Na+/Ca2+ Exchanger Expression and Activity Following TGFbeta1 Treatment of Megakaryocytes. AB - BACKGROUND: TGFbeta1, a decisive regulator of megakaryocyte maturation and platelet formation, has previously been shown to up-regulate both, store operated Ca2+ entry (SOCE) and Ca2+ extrusion by Na+/Ca2+ exchange. The growth factor thus augments the increase of cytosolic Ca2+ activity ([Ca2+]i) following release of Ca2+ from intracellular stores and accelerates the subsequent decline of [Ca2+]i. The effect on SOCE is dependent on a signaling cascade including p38 kinase, serum & glucocorticoid inducible kinase SGK1, and nuclear factor NFkappaB. The specific Na+/Ca2+ exchanger isoforms involved and the signalling regulating the Na+/Ca2+ exchangers remained, however elusive. The present study explored, whether TGFbeta1 influences the expression and function of K+ insensitive (NCX) and K+ sensitive (NCKX) Na+/Ca2+ exchangers, and aimed to shed light on the signalling involved. METHODS: In human megakaryocytic cells (MEG01) RT-PCR was performed to quantify NCX/NCKX isoform transcript levels, [Ca2+]i was determined by Fura-2 fluorescence, and Na+/Ca2+ exchanger activity was estimated from the increase of [Ca2+]i following switch from an extracellular solution with 130 or 90 mM Na+ and 0 mM Ca2+ to an extracellular solution with 0 Na+ and 2 mM Ca2+. K+ concentration was 0 mM for analysis of NCX and 40 mM for analysis of NCKX. RESULTS: TGFbeta1 (60 ng/ml, 24 h) significantly increased the transcript levels of NCX1, NCKX1, NCKX2 and NCKX5. Moreover, TGFbeta1 (60 ng/ml, 24 h) significantly increased the activity of both, NCX and NCKX. The effect of TGFbeta1 on NCX and NCKX transcript levels and activity was significantly blunted by p38 kinase inhibitor Skepinone-L (1 uM), the effect on NCX and NCKX activity further by SGK1 inhibitor GSK-650394 (10 uM) and NFkappaB inhibitor Wogonin (100 uM). CONCLUSIONS: TGFbeta1 markedly up-regulates transcription of NCX1, NCKX1, NCKX2, and NCKX5 and thus Na+/Ca2+ exchanger activity, an effect requiring p38 kinase, SGK1 and NFkappaB. PMID- 28813705 TI - The Lncrna-TUG1/EZH2 Axis Promotes Pancreatic Cancer Cell Proliferation, Migration and EMT Phenotype Formation Through Sponging Mir-382. AB - BACKGROUND/AIMS: Pancreatic carcinoma (PC) is the one of the most common and malignant cancers worldwide. LncRNA taurine upregulated gene 1 (TUG1) was initially identified as a transcript upregulated by taurine, and the abnormal expression of TUG1 has been reported in many cancers. However, the biological role and molecular mechanism of TUG1 in PC still needs further investigation. METHODS: Quantitative real-time PCR (qRT-PCR) was performed to measure the expression of TUG1 in PC cell lines and tissues. MTT and colony formation assays were used to measure the effect of TUG1 on cell proliferation. A wound healing assay, transwell assay and western blot assay were employed to determine the effect of TUG1 on cell migration and the epithelial mesenchymal transition (EMT) phenotype. RNA-binding protein immunoprecipitation (RIP) and a biotin-avidin pulldown system were performed to confirm the interaction between miR-328 and TUG1. A gene expression array analysis using clinical samples and RT-qPCR suggested that enhancer of zeste homolog 2 (EZH2) was a target of miR-382 in PC. RESULTS: In this study, we reported that TUG1 was overexpressed in PC tissues and cell lines, and high expression of TUG1 predicted poor prognosis. Further experiments revealed that overexpressed TUG1 promoted cell proliferation, migration and contributed to EMT formation, whereas silenced TUG1 led to opposing results. Additionally, luciferase reporter assays, an RIP assay and an RNA pulldown assay demonstrated that TUG1 could competitively sponge miR-382 and thereby regulate EZH2. CONCLUSION: Collectively, these findings revealed that TUG1 functions as an oncogenic lncRNA that promotes tumor progression, at least partially, by functioning as an endogenous 'sponge' and competing for miR-382 binding to the miRNA target EZH2. PMID- 28813707 TI - The Role of Physicians in Rationing Cancer Care. Attitudes of German Oncologists. AB - BACKGROUND: Against the background of limited resources, the rise in the cost of therapy as well as in the number of cancer patients fuels the discussion about the necessity to ration, i.e., setting limits to beneficial treatment for cost reasons. Recently, we presented the self-reported prevalence of bedside rationing among German oncologists. Here, we describe oncologists' views on cost containment strategies and their role therein. METHODS: We performed an online survey including structured questions and free field sections with the members of the German Society of Hematology and Oncology. RESULTS: In the perception of oncologists, cost considerations and negotiations are gaining in importance and consume considerable working time. This negatively affects job satisfaction in 72% of the 345 respondents. Oncologists are concerned that the quality of care will suffer from rationalization and implicit rationing. They are ambivalent as to who is best suited to decide about resource rationing: 66% support the view that limits for costly procedures should be set by a form of commission; nevertheless, 48% consider physicians as the best decision makers in these situations. CONCLUSION: We suggest a broad public discussion and an interdisciplinary debate among the oncology community to define and legitimize decisions on rationing by setting explicit criteria. PMID- 28813706 TI - CARTs for Solid Tumors: Feasible or Infeasible? AB - Adoptive transfer of chimeric antigen receptor-engineered T cells (CARTs) is a novel approach to cancer therapy as CARTs combine with the antigen specificity of an antibody and the activating functions of T lymphocytes. Recent results from preclinical and clinical trials with CARTs for B-cell malignancies are exciting, although different groups selected different tumor-associated antigens, binding domains, and signal domains, which make up the chimeric antigen receptor (CAR) configuration. However, there are few clinical trials with CARTs for solid tumors compared to hematologic malignancies. In this brief review, we discuss the basic principles of CAR design and clinical studies of CARTs for solid tumors. PMID- 28813708 TI - Bronchial Embolization with an Endobronchial Watanabe Spigot for Broncho-Gastric Tube Fistula. AB - Anastomotic failure of a gastric tube inserted for reconstruction following esophagectomy, which is relatively rare, causes pleural infection and persistent pleural irritation, leading to communication with the pulmonary parenchyma. Although several interventions have been reported to treat such broncho-gastric tube fistulas, refractory cases remain. We herein report the successful treatment by endoscopic bronchial occlusion with an endobronchial Watanabe spigot in 2 patients who suffered from the above complication. PMID- 28813709 TI - Natural History of Localized and Locally Advanced Atypical Lung Carcinoids after Complete Resection: A Joined French-Italian Retrospective Multicenter Study. AB - BACKGROUND: The natural history and the best modality of follow-up of atypical lung carcinoids (AC) remain ill defined. The aim of this study was to analyze recurrence-free survival (RFS) after complete resection (R0) of stage I-III pulmonary AC. Secondary objectives were prognostic parameters, the location of recurrences, and the modality of follow-up. METHODS: A retrospective review of 540 charts of AC patients treated between 1998 and 2008 at 10 French and Italian centers with experience in lung neuroendocrine tumor management was undertaken. The exclusion criteria were MEN1-related tumor, history of another cancer, referral after tumor relapse, and being lost to follow-up. A central pathological review was performed in each country. RESULTS: Sixty-two patients were included. After a median follow-up time of 91 months (mean 85, range 6-165), 35% of the patients experienced recurrence: 16% were regional recurrences and 19% were distant metastases. Median RFS was not reached. The 1-, 3-, and 5-year RFS rate was 90, 79, and 68%, respectively. In univariate analysis, lymph node involvement (p = 0.0001), stage (p = 0.0001), mitotic count (p = 0.004), and type of surgery (p = 0.043) were significantly associated with RFS. In multivariate analysis, lymph node involvement was significantly associated with RFS (HR 95% CI: 0.000 0.151; p = 0.004). During follow-up, somatostatin receptor scintigraphy, fibroscopy, and abdominal examination results were available for 22, 12, and 25 patients, respectively. The median time interval for imaging follow-up was 10 months. CONCLUSIONS: After complete resection of AC, recurrences were observed mostly within the first 5 years of follow-up, within bronchi, mediastinal nodes, the liver, and bones. In R0 patients, lymph node involvement could help to stratify follow-up intervals. Suboptimal imaging is evidenced. PMID- 28813710 TI - Is Endoscopic Vasectomy Just a Dream: An ex vivo Study on Feasibility and Reliability of Endoluminal Occlusion of Porcine Vas Deferens. AB - INTRODUCTION AND AIM: Surgical vasectomy remains the gold standard for fertility control in men. Endoluminal occlusion of the seminal ducts, thus avoiding an external incision, may become an appealing alternative to this approach. As our group has shown, nontraumatic endoscopic inspection of the seminal ducts is feasible in the human cadaver. We investigated the feasibility and reliability of occlusion using several commercially available medical sealing agents in the porcine vas deferens (VD). METHODS AND MAIN OUTCOME MEASURES: Tests were conducted using 25 porcine spermatic ducts (10 cm length) ex vivo. The explanted specimens were fixed and cannulated using the Seldinger technique. We administered 5 different agents (n-butyle-2-cyanoacrylate, n-butyle-2 cyanoacrylate in combination with a platinum vascular coil, Tissucol Duo S(r), Gelita Spon(r) and AFP Plug(r)) endoluminally. Tightness was evaluated after 5, 15, 60, 360, 720, and 1,440 min for each of the five grades, respectively, using a solution of methylene blue and saline injected under controlled pressure of 300 mm Hg followed by histological examination. RESULTS: All agents were administered into the porcine seminal ducts (4 out of 5 via a ureteric catheter). Gelita Spon(r) and Tissucol Duo S(r) did not occlude the lumen sufficiently, whereas n butyle-2-cyanoacrylate, n-butyle-2-cyanoacrylate in combination with coil, Tissucol Duo and AFP Plug(r) performed satisfactorily. In particular, cyanoacrylate combined with a coil was able to close the seminal duct tightly and for a long time. Histological findings confirmed this sealant's gapless adhesion. AFP Plug(r) application revealed similarly good results. However, its form needs to be optimized to ensure its suitability for endoscopic use. CONCLUSION: Various developments regarding minimally invasive fertility control methods have been underway for decades. Further miniaturization of endoscopy and novel materials may pave the way for endoscopic fertility control in males in the future. We demonstrated the potential of commercially available medical sealing agents to reliably occlude the porcine VD. PMID- 28813711 TI - Subjects at Risk for Genetic Late-Onset Neurological Diseases: Objective Knowledge. AB - BACKGROUND/AIMS: This study addresses the objective knowledge about the disease of subjects at risk for 3 genetic late-onset neurological diseases (LOND): familial amyloid polyneuropathy (FAP) TTR V30M, Huntington disease (HD), and Machado-Joseph disease (MJD). METHODS: Subjects at risk for FAP, HD, and MJD submitted to genetic counseling to know their status (carrier or non-carrier) and subjects at risk for hereditary hemochromatosis (HH), the control group, completed a sociodemographic questionnaire and answered the open-ended question: "What do you know about this disease?." RESULTS: From 10 categories of answers, references to the disease, quantitative answers, references to the family, and metaphors stood out. References to the disease, references to the family, and metaphors were mentioned more often by subjects at risk for LOND than by subjects at risk for HH (control group). CONCLUSION: The disease itself and its meaning as well as sick relatives play a key role in the objective knowledge about LOND. Thus, genetic counseling protocols of subjects at risk for LOND should include questions concerning family knowledge and disease experience. PMID- 28813712 TI - Management of the Perineum during Delivery with the Kiwi Omnicup: Effects of Mediolateral Episiotomy on Anal Sphincter Tears in Nulliparous Women. AB - AIM: The main objective of this study was to evaluate the association of mediolateral episiotomy with severe perineal trauma during Kiwi omnicup vacuum delivery. METHODS: This retrospective study analyzed all Kiwi omnicup vacuum deliveries between 2010 and 2015 in nulliparous women. Secondary outcomes of interest included frequency of genital tract trauma, outcome of Kiwi extraction and influence on neonatal parameters. RESULTS: A total of 572 nulliparous women who were delivered with the aid of vacuum were analyzed. Successful completion of birth was achieved in 549/572 (96%) resulting in a failure rate of 4%. Out of 572 women, 372 (65%) underwent the Kiwi vacuum delivery system in conjunction with episiotomy. Third- or fourth-degree perineal tears occurred in 38 out of the 572 (6.6%) women and the rate of severe perineal trauma was statistically and significantly lower in women who delivered with the aid of the Kiwi vacuum in conjunction with episiotomy (p = 0.0001). Besides, perineal tears of all degrees, vaginal tears and labial trauma were significantly less common in the Kiwi vacuum delivery system when combined with mediolateral episiotomy (p = 0.0001, p = 0.006, and p = 0.0001, respectively). CONCLUSION: Our data showed that the performance of a mediolateral episiotomy was associated with a decreased risk of severe perineal tears as well as vaginal and labial trauma in Kiwi omnicup vacuum deliveries. PMID- 28813713 TI - Primary Treatment Choice Over Time and Relative Survival of Prostate Cancer Patients: Influence of Age, Grade, and Stage. AB - BACKGROUND: The aim of this study was to assess associations of stage, grade, and age with the primary treatment of prostate cancer (PCa) patients comparing the incidence years 2000/2001 and 2012/2013, and to estimate the relative survival (RS) for patients diagnosed in 2000/2001. METHODS: We included 1,541 men diagnosed in 2000/2001 and 1,605 men diagnosed in 2012/2013. Multiple imputation methods were applied to missing data for stage and grade. Multinomial logistic regression analyses were used to explore the associations of stage, grade, and age with treatment. RS was estimated using the Ederer II approach. RESULTS: In 2000/2001, older patients were more likely to choose active surveillance (AS)/watchful waiting (WW) or to receive androgen deprivation therapy (ADT) compared to surgery; in 2012/2013, this association was only observed for ADT but not for AS/WW. In 2000/2001, the overall 1-, 5-, and 10-year RS was approximately 99, 94, and 92%, respectively. RS was highest for patients who underwent surgical procedures or radiotherapy and considerably lower for patients with ADT. CONCLUSION: Our data show that today AS/WW is an option not only for patients with a life expectancy of < 10 years but also for younger men with localized PCa. PCa patients have a good RS if the cancer is diagnosed at an early stage. PMID- 28813714 TI - Effects of Riboflavin and Ultraviolet Illumination on the Biomechanical Properties of Conjunctiva. AB - PURPOSE: Our experiment evaluated the biomechanical effects of riboflavin and ultraviolet A illumination, in terms of covalent bonding, permeability, and indentation rupture force, on excised cattle conjunctiva. MATERIALS AND METHODS: Cattle conjunctiva was extracted and divided into the treatment group, which was soaked in riboflavin, followed by ultraviolet light illumination, and the control group. Samples were subsequently analysed on a Fourier transform infrared spectrum test to identify the presence of amide bonds, a permeability test to assess the diffusion of methylene blue across conjunctiva, and an indentation rupture force test. RESULTS: The Fourier transform infrared spectrum test showed a significantly increased amide I band after treatment (p = 0.043), as well as in amide II, amide A, and amide B bands. The permeability test showed a reduced permeability to methylene blue after treatment (n = 25) compared to the control (n = 24; p = 0.03). The indentation rupture test showed a higher maximal rupture force in the treated samples (n = 10; p = 0.07). CONCLUSIONS: The study suggested that riboflavin and ultraviolet A illumination (commercially available as collagen crosslinking) strengthened cattle conjunctiva by increasing its amount of covalent bonds, reducing its permeability, and possibly improving its resistance to rupture. This is the first study in the collagen crosslinking literature on the biomechanical properties of conjunctival tissue. PMID- 28813715 TI - Induction of Cyclooxygenase 2 by Streptococcus pyogenes Is Mediated by Cytolysins. AB - Prostaglandin E2 (PGE2), an arachidonic acid metabolite regulating a broad range of physiological activities, is an important modulator of the severity of infection caused by Streptococcus pyogenes. Here, we investigated the role of streptococcal cytolysin S (SLS) and streptococcal cytolysin O (SLO) in the induction of cyclooxygenase-2 (COX-2), the rate-limiting enzyme in the synthesis of prostaglandins, in in vitro cultured macrophages and during in vivo infection. Macrophages were infected with S. pyogenes wild type or with the isogenic mutant strains deficient in SLS (DeltaSLS), SLO (DeltaSLO), or both (DeltaSLS/DeltaSLO), and the expression of COX-2 was determined at the transcriptional and the protein level. The results indicated that S. pyogenes induced expression of COX-2 and concomitant synthesis of PGE2 in macrophages mediated by the synergistic activity of both SLS and SLO, and involved calcium and the PKC/JNK signaling pathway. These results were validated using recombinant cytolysins. In a murine skin infection model, COX-2-positive cells were found more abundant at the site of S. pyogenes wild-type infection than at the site of infection with DeltaSLS/DeltaSLO mutant strain. These findings suggest that inhibitory targeting of SLS and SLO could ameliorate the adverse effects of high levels of prostaglandins during S. pyogenes infection. PMID- 28813716 TI - No Correlation of the Disease Severity of Influenza A Virus Infection with the rs12252 Polymorphism of the Interferon-Induced Transmembrane Protein 3 Gene. AB - The 2009 H1N1 influenza pandemic, which involved a more pathogenic virus than seasonal influenza viruses, rapidly spread around the world and caused many deaths in humans. The members of the interferon-induced transmembrane (IFITM) protein family prevent viral replication and are crucial for defending the host cell against influenza A virus (IAV). Several studies suggest that the CC genotype at the single nucleotide polymorphism (SNP) rs12252 of IFITM3 confers a genetic predisposition to pandemic influenza A in Europeans and Han Chinese, although one study in a British cohort failed to show an association. In order to examine whether an SNP of the IFITM3 gene is correlated with the disease severity of pandemic IAV (H1N1) infection in a Korean population, we investigated the genotype and allele frequencies of this polymorphism in 300 healthy Koreans by automatic direct sequencing and compared the disease severity based on epidemiological studies of the H1N1 virus reported in several countries. The frequencies of the CC genotype and the C allele in the IFITM3 polymorphism were higher in the Korean population than in the European populations, but not in Chinese and Japanese populations. The prevalence of severe cases of the pandemic 2009 IAV infection in Koreans was similar to that in Europeans (p = 0.106). In addition, the prevalence of deaths among all positive cases with pandemic 2009 IAV infection in Koreans was significantly lower than that in Europeans. These results suggest that the IFITM3 genotype may not be a determinant of disease severity of IAV infection. PMID- 28813717 TI - Exploring the Use of a Participative Design in the Early Development of a Predictive Test: The Importance of Physician Involvement. AB - In this study, we contribute to the personalized medicine and health care management literature by developing and testing a new participative design approach. We propose that involving gastroenterologists in the development of a predictive test to assist them in their clinical decision-making process for the treatment of inflammatory bowel diseases will increase the likelihood of their acceptance of the innovation. Based on data obtained from 6 focus groups across Canada from a total of 28 physicians, analyses reveal that current tools do not enable discriminating between treatment options to find the best fit for each patient. Physicians expect a new predictive tool to have the capability of showing clear reliability and significant benefits for the patient, while being accessible in a timely manner that facilitates clinical decisions. Physicians also insist on their key role in the implementation process, hence confirming the relevance and importance of participative designs in personalized medicine. PMID- 28813719 TI - ? PMID- 28813720 TI - ? PMID- 28813722 TI - ? PMID- 28813721 TI - ? PMID- 28813718 TI - Transgenic Mice Over-Expressing RBP4 Have RBP4-Dependent and Light-Independent Retinal Degeneration. AB - Purpose: Transgenic mice overexpressing serum retinol-binding protein (RBP4-Tg) develop progressive retinal degeneration, characterized by microglia activation, yet the precise mechanisms underlying retinal degeneration are unclear. Previous studies showed RBP4-Tg mice have normal ocular retinoid levels, suggesting that degeneration is independent of the retinoid visual cycle or light exposure. The present study addresses whether retinal degeneration is light-dependent and RBP4 dependent by testing the effects of dark-rearing and pharmacological lowering of serum RBP4 levels, respectively. Methods: RBP4-Tg mice reared on normal mouse chow in normal cyclic light conditions were directly compared to RBP4-Tg mice exposed to chow supplemented with the RBP4-lowering compound A1120 or dark rearing conditions. Quantitative retinal histological analysis was conducted to assess retinal degeneration, and electroretinography (ERG) and optokinetic tracking (OKT) tests were performed to assess retinal and visual function. Ocular retinoids and bis-retinoid A2E were quantified. Results: Dark-rearing RBP4-Tg mice effectively reduced ocular bis-retinoid A2E levels, but had no significant effect on retinal degeneration or dysfunction in RBP4-Tg mice, demonstrating that retinal degeneration is light-independent. A1120 treatment lowered serum RBP4 levels similar to wild-type mice, and prevented structural retinal degeneration. However, A1120 treatment did not prevent retinal dysfunction in RBP4-Tg mice. Moreover, RBP4-Tg mice on A1120 diet had significant worsening of OKT response and loss of cone photoreceptors compared to RBP4-Tg mice on normal chow. This may be related to the very significant reduction in retinyl ester levels in the retina of mice on A1120-supplemented diet. Conclusions: Retinal degeneration in RBP4-Tg mice is RBP4-dependent and light-independent. PMID- 28813723 TI - ? PMID- 28813724 TI - ? PMID- 28813725 TI - ? PMID- 28813726 TI - ? PMID- 28813727 TI - ? PMID- 28813728 TI - [Amputation of the Lower Limb - Treatment and Management]. AB - Despite modern conservative and surgical procedures, the number of amputations of the lower limb remains at a consistently high level. With the demographic changes and the consequent prevalence of atherosclerosis and diabetes mellitus, there is a steady increase of the risk factors that can lead to an amputation. The cause, which ultimately leads to the loss of the affected limb is therefore a symptom of the underlying disease. Primarily, the purpose of any medical treatment is the prevention of any amputation. If the preservation of the limb is not achievable, the surgical procedure follows. In principle the preparation of the stump should be as peripheral as possible. The actual prosthetic fitting starts with the dimension and the impression (negative-copy) of the prosthesis a few weeks following surgery. The technical requirements of a prosthesis will depend on the degree of mobility and the medical history of the patient. Prosthetic adjustments are available for all amputation levels and activities. The essential basic modules of a modern prosthesis can be combined and exchanged freely, so as to allow a change of function, form and axis. The aim of rehabilitation is the full reintegration into daily life. Especially young patients can provide amazing professional and athletic achievements. PMID- 28813729 TI - Carrier Screening: What Is New? PMID- 28813730 TI - Point-Counterpoint: TPMT Genotyping for Azathioprine in Adult Medicine. PMID- 28813731 TI - A Case of Fulminant Hepatic Failure Secondary to Congestive Heart Failure Without Evidence of Acute Cardiac Decompensation. AB - There are so far only a few reported cases of acute fulminant hepatic failure resulting from acute cardiomyopathy. This is a rare occurrence, especially in patients that do not exhibit any signs and symptoms of acute cardiac decompensation. We report a case of fulminant liver failure with nondiagnostic work up for the common causes of liver failure. This patient had concurrent history of congestive heart failure, but did not have acute decompensation. Right upper quadrant sonogram revealed hepatomegaly of 15 cm, trace amount of perihepatic ascites, pericholecystic fluid, and also thickened edematous gallbladder wall with no stones, no common bile duct stones, and no portal vein thrombosis. Echocardiogram revealed dilated left atrium and ventricle, severe mitral regurgitation, severe tricuspid regurgitation, grade 4 diastolic dysfunction, diffuse hypokinesis of left ventricle, and severely and newly reduced systolic function with an ejection fraction of 10 percent (decreased from 25 percent on last ECHO 18 months prior). Liver biopsy demonstrated marked centrilobular hepatocyte necrosis and dropout accompanied by congestion, some areas of bridging necrosis and focal confluent necrosis which was suggestive of severe congestive hepatopathy. With initiation of heart failure medications, liver function improved significantly. PMID- 28813732 TI - Gastric Zygomycosis in a Previously Healthy 56-Year-Old Male. AB - Zygomycosis refers to invasive fungal infections caused by fungi belonging to the phylum zygomycota. Infections generally occur in immunocompromised individuals. The following case is of a previously healthy 56 year-oldmale admitted to the hospital following a motor vehicle accident. During his hospitalization, there was a significant drop in hemoglobin with no obvious source of bleeding. This prompted the clinician to insert a nasogastric tube which returned at least 2 liters of black fluid and led to an upper gastrointestinal endoscopy. The endoscopy revealed numerous large crater-like gastric ulcers with adherent clot, up to 30 mm in greatest dimension. Biopsies of the ulcer margins revealed broad pauciseptate, ribbon-like, slightly refractile fungal forms, which were highlighted with periodic acid-Schiff (PAS) stain. A Gomori methanamine silver (GMS) stain was negative. These forms were suggestive of zygomycetes. A subsequent gastrectomy was performed, which revealed similar findings. The patient experienced severe trauma, which may have contributed to the progression of his condition; however, this is an unusual presentation as the patient was previously healthy, and he did not illustrate any conditions that might compromise his immunity. The severity and rarity of this condition makes this a very unique and intriguing case. PMID- 28813733 TI - Disseminated Blastomycosis Mimicking Malignancy. AB - Blastomycosis is an endemic fungal infection commonly found within the Mississippi and Ohio River basins and Great Lakes region. While patients typically present with acute pneumonia, Blastomyces dermatitidis has the potential to spread hematogenously, resulting in disseminated infection of multiple organs. In this report, we describe a 57-year-old male with disseminated blastomycosis acquired in South Dakota. The diagnostic evaluation was confounded by concern for malignancy given the involvement of multiple locations, including brain, lungs, adrenal glands, and testes. Despite aggressive therapy with amphotericin B, the patient succumbed to this infection. PMID- 28813734 TI - The 36 Hour Day, Revisited: Implementing a Caregiver Support System Into Primary Care Practice. AB - An estimated 5.3 million Americans had Alzheimer's disease in 2015. With the aging population and rapid rise in those with dementia, it is vital to not only care for the dementia patient, but also his or her primary caregiver. Caregivers often suffer from depression and neglect their own health in order to care for their loved one. In this regard, included is a review of the role of the primary care physician including the importance of discussing the diagnosis of dementia with the patient and family, providing supportive services and resources, as well as the challenges that many physicians face in tackling the care of a dementia caregiver. PMID- 28813735 TI - Duration of Antibiotics Prescribed at Hospital Discharge. AB - INTRODUCTION: A patient's transition from hospitalization to discharge may represent an additional opportunity for antibiotic stewardship. METHODS: We reviewed antimicrobial drugs prescribed at discharge to patients at our medical center over a nine-month period, and calculated the total duration of inpatient and outpatient antibiotic therapy. RESULTS: The median duration of inpatient antibiotics was three days (interquartile range [IQR] four days), of outpatient antibiotics was seven days (IQR six days), and of total antibiotics 10 days (IQR six days). CONCLUSIONS: Our results align with the only previously published study of oral antibiotics prescribed at hospital discharge, both in the duration of inpatient and outpatient therapy and in the fact that about 60 percent of the treatment duration occurred after discharge. However, the median total antibiotic duration of 10 days is longer than that recommended by national and institutional guidelines for some of the most common infections in hospitalized patients. PMID- 28813736 TI - Evolving Pharmacologic Therapies for Heart Failure. PMID- 28813737 TI - Quality Focus: Utilizing Data to Achieve Value-Based Care. PMID- 28813738 TI - Update on Medical School Accreditation. PMID- 28813739 TI - Pharmacogenetics of PPIs: Lessons Learned. PMID- 28813740 TI - West Nile Review: 15 Years of Human Disease in South Dakota, 2002-2016. AB - During the past 15 years, 2002-2016, West Nile virus (WNV) has emerged in South Dakota resulting in 509 neuroinvasive disease (NID) cases, 745 hospitalizations and 38 deaths. Culex tarsalis is the state's primary mosquito vector. South Dakota's average annual incidence of WNV-NID and death rate are the highest of any state in the U.S. WNV cases have been reported from all counties in the state. All age groups have been infected with cases peaking in the 40-44 year age group, but deaths peaking in cases 70 years and older. Although South Dakota's WNV season lasts six months, May-October, the first week of August has been the peak week of WNV disease onsets. West Nile is now enzootic in South Dakota. Every citizen, local mosquito control programs, medical and public health infrastructures must continue to prevent and respond to annual WNV outbreaks, and prepare for the next arboviral disease to emerge. PMID- 28813741 TI - A Case of an Acute Myocardial Infarction Post Thrombolytic Treatment of Ischemic Stroke - A Management Dilemma. AB - Acute ischemic stroke and myocardial infarction are emergency clinical events that require prompt intervention. Concurrent occurrence of both events magnifies the complexity of the clinical management. We present a case of a patient who presented with acute ischemic stroke, complicated by acute myocardial infarction shortly after thrombolytic was administered. This case highlights the importance of individualization of management especially in complex cases where there are no clear specific guidelines to follow. PMID- 28813742 TI - A Case of Incisional Endometrioma that Presented as an Abdominal Mass. AB - Although endometriosis is a common condition in women of reproductive age, the incidence of endometrioma in prior surgical incision sites is rare.We present a case of an abdominal wall mass in a female patient with a history of obstetrical surgery. The mass was visualized with ultrasound and computerized tomography, removed by wide excision, and identified via frozen section. This case demonstrates the importance of a thorough surgical and obstetrical history in any woman who presents with an abdominal wall mass. PMID- 28813743 TI - Combined Melanocytic Nevus, Superficial Congenital and Deep Penetrating Types with Fibroepithelioma of Pinkus, Collision Tumor - A Case Report. AB - We present a case of collision tumor composed of a combined melanocytic nevus with superficial congenital and deep penetrating components and a fibroepithelioma of Pinkus on the left lumbar back of a 21-year-old male. He presented to the dermatologist for evaluation of numerous moles, and the lesion in question was described as a brown variegated papule with slightly irregular shape and irregular borders. This case is being reported as it is very unusual to see a fibroepithelioma of Pinkus in conjunction with a melanocytic lesion. PMID- 28813744 TI - Alkaptonuria: A Case Report With Diagnostic Challenge. AB - Alkaptonuria is a rare autosomal recessive metabolic disorder caused by deficiency of homogentisic acid (HGA) oxidase, the only enzyme capable of catabolizing HGA. Deficiency of this enzyme leads to excess HGA which deposits in the connective tissue. We present a case of a 64-year-old woman who was referred to the dermatology clinic for a full body mole check and skin cancer screening. Clinically she had blue/gray pigmentation of the external ear and sclera. Also she had a domed papule on the left cheek with punctate gray pigmentation which was biopsied. Histopathological examination showed a benign dermal nevus and nonpolarizable, yellow-brown, irregular shaped fibers. Subsequent organic acid screen showed markedly elevated urinary HGA, diagnostic of alkaptonuria. On specific inquiry, the patient revealed she had a history of bilateral Achilles tendon rupture, black urine, arthritis, and external ear discoloration for many years. The pigmented material was then considered to be HGA deposition within the dermal collagen fibers. However, without the appropriate clinical data and confirmatory lab findings, the pigmented fragments on skin biopsy represent a diagnostic challenge. Measures like low protein diet and ascorbic acid supplementation will slow down the disease progression and potential complications later in life; however, there is no definitive treatment for the disease. We emphasize the prompt recognition of the clinical signs and symptoms as well as the importance of the microscopic findings. PMID- 28813745 TI - Laparoscopic Treatment of a Pyogenic Hepatic Abscess Caused by Transmural Duodenal Perforation of a Toothpick. AB - The development of pyogenic hepatic abscess resulting from perforation of the gastrointestinal tract is a rare pathologic finding. It is a condition that can be fatal making early detection and subsequent removal of the inciting foreign body critical to avoid more deleterious sequela. Yet, its initial presentation tends to be nonspecific and typically is only discovered once surgical investigation into the cause of persisting abscess formation is performed. In this study, laparoscopic treatment of a 52-year-old male with a non-resolving hepatic abscess due to transmural gastrointestinal perforation of a toothpick is presented. Although a rare finding, reports of foreign body induced hepatic abscess have recently increased in the world literature, allowing some preliminary efforts in proposing diagnostic characterization. Yet, more case studies will be required to permit validation of these findings making continued reporting of this pathologic process critical. PMID- 28813746 TI - Differences in the Manifestation of Multiple Sclerosis in African American Patients. PMID- 28813748 TI - Quality Focus: Encouraging and Communicating the Value of Immunization. PMID- 28813747 TI - Extenuating Circumstances: Data Sharing: Leading Data-Driven Population Health. PMID- 28813749 TI - Inguinal and Femoral Hernioplasty: Anatomic Repair. PMID- 28813750 TI - Point-Counterpoint: Genotype-Guided Opioid Therapy. PMID- 28813751 TI - Superior Ophthalmic Vein Thrombosis: The Role of Anticoagulation. AB - PURPOSE: To report a case of superior ophthalmic vein thrombosis (SOVT) and review the available literature to assess if anticoagulation is warranted in all cases of SOVT. OBSERVATIONS: The patient presented to an outside hospital facility with a severe headache involving the left frontal temporal area. This progressed to left-sided ptosis and facial droop. Magnetic resonance imaging revealed a left SOVT secondary to sphenoid sinusitis. Treatment was initiated with vancomycin and cefepime, and the patient was transferred to our tertiary care center for further management. Upon arrival at our facility, her symptoms had significantly improved compared to prior documented findings. CONCLUSIONS AND IMPORTANCE: Due to the rarity of SOVT, large clinical studies assessing the necessity of anticoagulation are not likely to be conducted. A review of the literature suggests the use of anticoagulation is determined on a case-by-case basis, taking into account symptom severity. Our case demonstrates that a resolution of symptoms is possible without anticoagulation. The decision to initiate anticoagulation will continue to require a clinician to perform a detailed physical examination to determine if the patient is responding to antibiotic treatment alone. PMID- 28813752 TI - Atypical Presentations of Tularemia. AB - Francisella tularensis is a gram-negative coccobacillus that causes a condition commonly referred to as tularemia. There has been a dramatic increase in tularemia cases reported in South Dakota, many of which were challenging to diagnose due to atypical clinical manifestations. We describe an interesting case of pneumonic tularemia and summarize six similar cases, several of which presented with lung nodules suggestive of malignancy. According to the literature, this is only the third outbreak of pneumonic tularemia reported in the U.S. We believe it is important for clinicians to be aware of the increased incidence of tularemia in the area and to be vigilant in the diagnosis and management of these atypically presenting cases. PMID- 28813753 TI - Pre-Guideline Trends Associated with Chest Radiograph Usage for Pediatric Community-Acquired Pneumonia in Emergency Department Settings. AB - BACKGROUND: Health care spending in the U.S. totaled $3 trillion in 2014 and continues to increase rapidly. Minimizing waste through clinical guidelines is a promising strategy to reduce spending without compromising patient care. In 2011, clinical guidelines recommended against the use of chest X-ray (CXR) for diagnosis of community-acquired pneumonia (CAP) in pediatric ambulatory settings. However, use of CXR has not changed post-guideline. Thus, understanding the drivers of CXR utilization prior to guideline implementation could improve guideline adherence. METHODS: Retrospective study using 2009 Nationwide Emergency Department Sample data set consisting of a representative sample of all emergency room admissions. Inclusion criteria consisted of: 18 years of age or younger and the diagnosis of outpatient CAP. Population was segmented by the presence of a CXR obtained during the visit. Socioeconomic status was determined by quartile classification of the estimated median household income based on patient ZIP code. RESULTS: In 2009, children living in wealthier ZIP codes presenting to the emergency department (ED) who were diagnosed with CAP were more likely to receive diagnostic CXR. The use of chest radiograph was not statistically correlated to gender, weekday versus weekend admission, number of diagnoses at discharge, or total ED charges. CONCLUSION: The research demonstrates a strong correlation between socioeconomic status of the pediatric patient and use of chest radiograph for CAP in the ED setting prior to 2011 guideline publication. Further research to determine the reason for this correlation could give rise to focused efforts to successfully encourage adherence to clinical practice guidelines. PMID- 28813754 TI - Laparoscopic Pediatric Inguinal Hernia Repair: Overview of "True Herniotomy" Technique and Review of Current Evidence. AB - Inguinal hernia repair is one of the most commonly performed operations in the pediatric population. While the majority of pediatric surgeons routinely use laparoscopy in their practices, a relatively small number prefer a laparoscopic inguinal hernia repair over the traditional open repair. This article provides an overview of the three port laparoscopic technique for inguinal hernia repair, as well as a review of the current evidence with respect to visualization and identification of hernias, recurrence rates, operative times, complication rates, postoperative pain, and cosmesis. The laparoscopic repair presents a viable alternative to open repair and offers a number of benefits over the traditional approach. These include superior visualization of the relevant anatomy, ability to assess and repair a contralateral hernia, lower rates of metachronous hernia, shorter operative times in bilateral hernia, and the potential for lower complication rates and improved cosmesis. This is accomplished without increasing recurrence rates or postoperative pain. Further research comparing the different approaches, including standardization of techniques and large randomized controlled trials, will be needed to definitively determine which is superior. PMID- 28813755 TI - Genetics of Alcoholism. AB - Consuming excessive amounts of alcohol has the potential to modify an individual's brain and lead to alcohol dependence. Alcohol use leads to 88,000 deaths every year in the U.S. alone and can lead to other health issues including cancers, such as colorectal cancer, and mental health problems. While drinking behavior varies due to environmental factors, genetic factors also contribute to the risk of alcoholism. Certain genes affecting alcohol metabolism and neurotransmitters have been found to contribute to or inhibit the risk. Geneenvironment interactions may also play a role in the susceptibility of alcoholism. With a better understanding of the different components that can contribute to alcoholism, more personalized treatment could cater to the individual. This review discusses the major genetic factors and some small variants in other genes that contribute to alcoholism, as well as considers the gene-environmental interactions. PMID- 28813756 TI - Pharmacotherapy Review of Ceftazidime-Avibactam. PMID- 28813757 TI - Quality Focus: Antimicrobial Stewardship: Cultural Change Continuing Challenge. PMID- 28813758 TI - The New Genetic Frontier: CRISPR-Cas9? PMID- 28813759 TI - Point-Counterpoint: Genotyping for SSRIs. PMID- 28813760 TI - Cutaneous Glomeruloid Hemangioma: A Report on Two Cases and a Review of Literature. PMID- 28813761 TI - Epidemiologic Study of Bacteria Zoonotic Diseases in South Dakota: 2010-2014. AB - BACKGROUND: Although the burden of infectious diseases has decreased dramatically due to advances in health care, disease prevention and numerous public health efforts and innovations, zoonotic diseases continue to pose a problem in terms of both existing and emerging diseases. These risks are of particular concern in rural areas, in which there is more contact with animals for occupational and recreational purposes. As a rural and agricultural state, South Dakota has a large percentage of its population at risk of exposure to zoonotic diseases through their substantial contact time with animals. METHODS: De-identified data from the South Dakota Department of Health containing the variables and diseases of interest from the time period of 2010-2014 was obtained. From this data were calculated the incidence rates by county, and seasonal and demographic patterns of the diseases were plotted. RESULTS: The incidence of disease in South Dakota were higher than the national rates for campylobacteriosis (threefold), cryptosporidiosis (sixfold), enterohemorrhagic E. coli (fourfold), Q fever (tenfold), salmonellosis (1.2-fold), and tularemia (14-fold). Only listeriosis had a lower incidence than the national rate among zoonoses included in this study. Seasonality of campylobacteriosis in the state was earlier in the year than is reported for the disease nationally. CONCLUSION: Zoonotic infections are a substantial threat to health in South Dakota. There is a need to develop collaboration between healthcare providers, public health professionals, livestock producers, veterinarians, and sportsmen to develop a strategy to address this issue. PMID- 28813762 TI - The Impact of a Rural Training Track on Medical Students Specialty Choice. AB - BACKGROUND: Compare the expectations and outcomes of students involved in rural medical training versus those of urban trainees. METHODS: Survey items relating to primary care interest were added to program evaluation surveys already being sent at the beginning and end of the primary clinical year. Students from the graduating class of 2016 and the class of 2017 responded to the surveys (N=115). Responses from students trained in rural sites were compared with students trained in medium or large communities. For the purposes of the survey, primary care was not specifically defined and was open to participants' interpretation. Primary care is commonly thought of as the medical care from the doctor who sees a patient first and provides treatment or decides the other specialist care that the patient may need. Primary care specialties can include family medicine, internal medicine, pediatrics and obstetrics and gynecology. RESULTS: Most students enter their primary clinical year undecided about specialty choice and preferred practice location. At the end of the primary clinical year, most students have decided on a specialty and most report wanting to practice in communities similar to where they trained during that year. Before the primary clinical year student attitudes toward primary care are not significantly different based on selected training site. However at the end of the primary clinical year, students who had been trained in small communities were significantly more likely to choose primary care compared with students trained in medium to large communities. CONCLUSIONS: For students who begin the primary clinical year undecided regarding specialty choice, and practice location, the community size of the training site plays a large role in the decisions they will make. A majority of students trained in small communities chose to go into primary care and practice in small communities. PMID- 28813763 TI - Simultaneous Onset of Deep Vein Thrombosis, Pulmonary Embolism, Cerebral Infarction, and Myocardial Infarction in a Patient with Patent Foramen Ovale. AB - Paradoxical embolism is a known complication with intra-cardiac shunts. It should be considered in the differential as the pathophysiologic mechanism of simultaneous thromboembolism in the venous and systemic vasculature. We present a case of simultaneous deep venous thrombosis, pulmonary embolism and myocardial infarction in the presence of a confirmed patent foramen ovale on echocardiography. Thrombolytic therapy was administered. Subsequent concerns of intracranial hemorrhage on imaging of the brain complicated the management and added to the challenge of co-managing the clot burden in our patient. This rare presentation highlights the importance of multisystem evaluation in making the best medical decision for the patient. PMID- 28813764 TI - Incidental Finding of Giant Left Ventricular Aneurysm: Case Report and Literature Review. AB - Left ventricular aneurysms and pseudoaneurysms are complications of myocardial infarction. With advances in percutaneous coronary intervention, development of thrombolytic agents, and early initiation of treatment with angiotensin converting enzyme inhibitors to decrease afterload and inhibit left ventricular remodeling, these complications have become much less common. Here, we report an incidental finding of a giant aneurysm of the left ventricle with associated thrombus and mural calcifications in an elderly male patient who presented to his primary care physician for abdominal pain and denied any prior coronary artery disease. In addition, a potential inflammatory mass at the rectosigmoid junction was also found by computed tomography scanning for his abdominal problem. PMID- 28813765 TI - Bronchiolitis in Infants and Children. AB - Bronchiolitis is among the most common illnesses in infants and children, and is the most common cause for hospitalization in infants in the U.S. This illness can be caused by many viruses, most commonly respiratory syncytial virus. It is diagnosed clinically by history and physical exam findings, with a narrow role for ancillary testing. Management is supportive, with medications demonstrating limited utility in multiple studies. Preventive measures include hand hygiene, breastfeeding, avoiding tobacco smoke exposure, and isolation precautions for hospitalized patients. Palivizumab prophylaxis is recommended for infants with qualifying high risk conditions. Recent evidence-based clinical practice guidelines have been published by the American Academy of Pediatrics to guide diagnosis, treatment, and prevention of bronchiolitis. PMID- 28813766 TI - Extenuating Circumstances: Children of the Nations: A Capstone in Humility, Compassion, and Patient Care. PMID- 28813767 TI - Anticoagulation in Cancer Patients. PMID- 28813768 TI - Quality Focus: Cultural Diversity in Health Care. PMID- 28813769 TI - So You Want to Be a Reviewer. PMID- 28813770 TI - Point-Counterpoint: SLCO1B1 Genotyping for Statins. PMID- 28813771 TI - Hepatic Adenoma - A Case Report. AB - Although liver lesions in the young population are relatively rare, clinicians can benefit from being familiar with a subset of common benign liver lesions which include hepatic adenoma, hepatic hemangioma, and focal nodular hyperplasia. This a case report of a 25-year-old Jehovah's Witness female on chronic oral contraception for polycystic ovarian syndrome who presented with progressive right upper quadrant abdominal pain. Ultrasound and MRI findings were consistent with hepatic adenoma. A description of her clinical work up followed by a brief description of the surgical intervention is discussed. We then elaborate on the clinical characteristics and evidence-based interventions of hepatic adenoma, hepatic hemangioma, and focal nodular hyperplasia. PMID- 28813772 TI - Pilot Study to Determine Safety and Efficacy of Paclitaxel Infusion in De Novo Peripheral Lesions Using the Atrium ClearWay Balloon. AB - OBJECTIVE: To evaluate the safety and efficacy of a one-time infusion of paclitaxel through an Atrium ClearWay balloon in infra inguinal de novo peripheral lesions. METHODS: This is a single-center prospective study looking at treatment of 50 limbs. Treatment includes standard infra inguinal endovascular revascularization followed by a pre-prescribed infusion of paclitaxel. Control is standard reintervention without subsequent paclitaxel infusion. Patients were followed at one, four, and 10 months with ankle-brachial index (ABI)s, arterial duplex of the treated limb, and Rutherford classification stage measured before and after procedures and at each follow-up. Freedom from binary restenosis was tracked with duplex ultrasound, and freedom from target lesion revascularization (TLR) was also tracked in the treatment group. Binary restenosis and TLR data was harvested from the patient record for the control group. RESULTS: Average ABI and Rutherford classification stage improved as expected. The treatment group had a freedom from TLR rate of 86 percent and a freedom from binary restenosis rate of 80 percent at 10 months. Average ABI improved from 0.65 at baseline to 0.94 at 10 months in the treatment group. The control group had a 72 percent freedom from TLR and a 58 percent freedom from binary restenosis at 10 months. Average ABI of the control group improved from 0.67 at baseline to 0.85 at 10 months in the control group. There were no amputations, open bypass revascularizations, or hypersensitivity reactions observed in the treatment group. CONCLUSIONS: Infusion of paclitaxel in de novo lesions appears to be a safe and efficacious treatment in the peripheral vasculature when compared to a historical control group. While it is early, it appears that the patients do receive some benefit from this one time infusion, and this approach should be studied further. PMID- 28813773 TI - A Case of IVIG-Induced Aseptic Chemical Meningitis. AB - Intravenous immunoglobulin (IVIG) is a commonly used and generally well-tolerated medication. Common side effects include flu-like symptoms such as fevers, headaches, myalgia, fatigue, and nausea. One of the more rare side effects is aseptic meningitis, with a reported incidence rate of around 0.067 percent of all IVIG infusions. In this paper, we describe a 47-year-old female patient with a history of myasthenia gravis who presented with a headache, neck pain, and neck stiffness while undergoing IVIG infusions for a myasthenia crisis. On admission day, the patient was afebrile with stable vital signs. A physical examination revealed nuchal rigidity and tenderness with no focal neurological deficits. Cerebrospinal fluid (CSF) cytology noted an elevated white blood cell (WBC) count of 1,138 cells/MUL with a neutrophil predominance (96 percent). CSF red blood cell count was unremarkable at 1 cell/MUL. The patient's IVIG infusions were stopped, suspecting chemical meningitis. Given the markedly elevated CSF WBC count with neutrophil predominance, she was started on vancomycin and ceftriaxone to also cover for bacterial meningitis. The patient's meningeal signs and symptoms significantly improved 24 hours after admission. Given the clear temporal relationship to IVIG administration and the rapid improvement of symptoms, IVIG-induced aseptic meningitis is strongly suspected. The patient's antibiotics were discontinued. Forty-eight hours after stopping IVIG and 24 hours after discontinuing antibiotics, her meningitis symptoms completely resolved with the use of analgesics alone. The patient was then discharged uneventfully. CSF viral and bacterial studies, including a gram stain and cultures, did not result in anything noteworthy. Our case presents an interesting diagnostic dilemma where drug-induced (IVIG) aseptic meningitis mimics bacterial meningitis clinically and on CSF analysis. The clear temporal relationship to IVIG administration and the rapid resolution of symptoms upon stopping the drug can aid in the diagnosis of this rare event and help doctors avoid the use of unnecessary antibiotic therapy. PMID- 28813774 TI - Pulmonary Embolism Caused by Popliteal Vein Aneurysm: A Case Report. AB - In this case report, we describe an unusual episode of bilateral submassive pulmonary embolism (PE) caused by a popliteal vein aneurysm (PVA). The development of PE stems from many risk factors including obesity (BMI3 30 kg/m2), hypertension, cigarette smoking (greater than 25 cigarettes per day), increasing age, surgery, immobility, malignancy, and inherited thrombophilia. A PVA is a rare but significant cause of PE. A 28-year-old male presented to the emergency department with progressive shortness of breath. He had no significant past medical history, no family history of deep vein thrombosis or PE, and no recent surgeries, travel, or trauma. A physical exam revealed he was saturating 96 percent on 2 L/minute oxygen through a nasal cannula and was noted to have a heart rate in the 90 beats per minute range that quickly increased to 150 beats per minute with minimal exertion. An initial laboratory workup was unrevealing except for an elevated D-dimer. A chest radiograph demonstrated no cardiopulmonary abnormalities. Computed tomography angiography of the chest was performed and revealed multiple bilateral pulmonary emboli. An urgent echocardiogram then revealed evidence of right heart strain with a dilated right ventricle. A subsequent bilateral venous duplex scan of the lower extremities was performed, which revealed a left PVA. Vascular surgery was performed, specifically emergent catheter-directed lysis with the placement of a temporary inferior vena cava (IVC) filter. The patient was started on rivaroxaban oral anticoagulation therapy and then discharged home without incident. Several months later, he underwent uncomplicated surgical repair of his left PVA. This case illustrates PVA as a rare but noteworthy cause of PE. Doctors should consider this diagnosis in patients with recurrent PE or when the cause of PE is unknown. Although the exact etiology is not known, inflammation, trauma, degenerative changes, and congenital weakness of venous wall have all been proposed as causes of venous aneurysms. The definitive management of a PVA is surgical repair. Some studies suggest recurrent PE in as high as 80 percent of patients on oral anticoagulation alone. Therefore, an IVC filter is often placed to prevent further thrombi progression until definitive surgical treatment of the aneurysm has been performed. PMID- 28813775 TI - So You Want To Be A Reviewer. AB - Peer review is a process for evaluating the quality of "work" of a scientist or professional as judged by others in the same or related field. In the context of the biomedical and health sciences, it primarily pertains to review of manuscripts submitted to journals for consideration of publication, abstracts for proposed presentations at professional meetings, and competitive research grant applications. Serving as a reviewer is a scholarly pursuit and a worthwhile endeavor, assuming it is approached in a conscientious, responsible manner. The purpose of this article is to define peer review and its various forms, suggest reasons for serving as a manuscript reviewer, discuss considerations prior to accepting a review assignment, and provide guidelines for the process. PMID- 28813776 TI - Assessing Risk Factors for Torsades de Pointes. PMID- 28813777 TI - Quality Focus: March is Colon Cancer Awareness Month. PMID- 28813778 TI - The Bactericidal Effect of High Temperature Is an Essential Resistance Mechanism of Chicken Macrophage against Brucella abortus Infection. AB - Knowledge of avian host responses to brucellosis is critical to understanding how birds resist this infection; however, this mechanism is not well established. On the other hand, temperature has a major involvement in the physiology of living organisms, and cell death induced by heat is attributed to protein denaturation. This study demonstrates the direct bactericidal effect of a high temperature (41oC) on Brucella abortus that resulted in the gradual reduction of intracellular bacteria and inhibited bacterial growth within avian macrophage HD11 in an increasing period of time. On the other hand, this study also revealed that high temperature does not affect the rate of bacterial uptake, as confirmed by the bacterial adherence assay. No significant difference was observed in the expression of target genes between infected and uninfected cells for both temperatures. This study suggests the susceptibility of B. abortus to bacterial death under a high temperature with an increased period of incubation, leading to suppression of bacterial growth. PMID- 28813779 TI - DNA Profiling of Leuconostoc citreum Strains in Fermented Foods by Repetitive Element Polymerase Chain Reaction. AB - To identify and discriminate the bacterial species at the subspecific level, rep PCR is a reliable genomic fingerprinting tool. Fourteen strains of bacteria were isolated from different food sources, identified as Leuconostoc citreum using 16S rRNA gene sequencing, and amplified using rep-primers (REP, ERIC, and (GTG)5). Fingerprinting patterns generated bands in the range of 300-6,000 bp with REP, 150-6,000 bp with ERIC, and 200-1,700 bp with (GTG)5 primers. In UPGMA dendrogram analysis, 14 strains were clustered into three clades (I, II, and III) with all the primers, thus differentiating them at the molecular level. The present study revealed the differentiation of L. citreum strains using rep-PCR. PMID- 28813780 TI - Microbial Diversity of Commercial Makgeolli and Its Influence on the Organoleptic Characteristics of Korean Rice Sourdough, Jeung-Pyun. AB - Sourdough is made by fermentation of dough by lactic acid bacteria (LAB) and yeast to improve bread properties like volume, flavor, and texture. A Korean traditional sourdough was made by fermenting rice flour with rice wine (makgeolli) and used to make sponge-like bread (jeung-pyun). The aim of this study was to investigate the microbial diversity of makgeolli products and their influence on the organoleptic quality of jeung-pyun. Three commercial makgeolli were tested for jeung-pyun production, with each product exhibiting varied dough swelling rates and organoleptic qualities, and among them, J-product was ranked highest in texture and taste. Microbial analysis of the three makgeolli also showed a big difference in their population and diversity. J-product had the highest LAB and yeast counts, and the predominant species were Lactobacillus casei, Lactobacillus brevis, Leuconostoc pseudomenteroides, and Saccharomyces cerevisiae. Using J-product, sourdough was fermented at 25 degrees C, 30 degrees C, and 35 degrees C, and the microbial growth in and textural properties of jeung pyun were examined by instrumental and sensory tests. At high temperature (35 degrees C), the rates of dough swelling and acidification were fast due to rapid microbial growth mainly caused by LAB, resulting in a short leavening time and soft and sour jeung-pyun. Sensory tests showed consumer preference for the soft and mild-sour jeung-pyun. This study shows that LAB in makgeolli play key roles in production of jeung-pyun, influencing the textural and sensory properties. For the production of high-quality jeung-pyun, development of LAB starters with high gas productivity and low acidity and establishment of an optimal fermentation procedure for rice dough are necessary. PMID- 28813781 TI - Bee Venom Decreases LPS-Induced Inflammatory Responses in Bovine Mammary Epithelial Cells. AB - The world dairy industry has long been challenged by bovine mastitis, an inflammatory disease, which causes economic loss due to decreased milk production and quality. Attempts have been made to prevent or treat this disease with multiple approaches, primarily through increased abuse of antibiotics, but effective natural solutions remain elusive. Bee venom (BV) contains a variety of peptides (e.g., melittin) and shows multiple bioactivities, including prevention of inflammation. Thus, in the current study, it was hypothesized that BV can reduce inflammation in bovine mammary epithelial cells (MAC-T). To examine the hypothesis, cells were treated with LPS (1 MUg/ml) to induce an inflammatory response and the anti-inflammatory effects of BV (2.5 and 5 MUg/ml) were investigated. The cellular mechanisms of BV against LPS-induced inflammation were also investigated. Results showed that BV can attenuate expression of an inflammatory protein, COX2, and pro-inflammatory cytokines such as IL-6 and TNF alpha. Activation of NF-kappaB, an inflammatory transcription factor, was significantly downregulated by BV in cells treated with LPS, through dephosphorylation of ERK1/2. Moreover, pretreatment of cells with BV attenuated LPS-induced production of intracellular reactive oxygen species (e.g., superoxide anion). These results support our hypothesis that BV can decrease LPS-induced inflammatory responses in bovine mammary epithelial cells through inhibition of oxidative stress, NF-kappaB, ERK1/2, and COX-2 signaling. PMID- 28813782 TI - Urea cycle pathway targeted therapeutic action of naringin against ammonium chloride induced hyperammonemic rats. AB - Ammonia is a well-known neurotoxin that causes liver disease and urea cycle disorder. Excessive ammonia content in the blood leads to hyperammonemic condition and affects both excitatory and inhibitory neurotransmission including brain edema and coma. Naringin, a plant bioflavonoid present in various citrus fruits and mainly extracted from the grape fruit. This study was designed to assess the protective effect of naringin on ammonium chloride (NH4Cl) induced hyperammonemic rats. Experimental hyperammonemia was induced by intraperitoneal injections (i.p) of NH4Cl (100mg/kg body weight (b.w.)) thrice a week for 8 consecutive weeks. Hyperammonemic rats were treated with naringin (80mg/kg b.w.) via oral gavage. Naringin administration significantly augmented the level of blood ammonia and plasma urea. Naringin also upregulate the expression of urea cycle enzymes such as carbamoyl phosphate synthase I (CPS I) and ornithine transcarbamylase (OTC), arininosuccinate synthase (ASS), argininosuccinate lyase (ASL) and arginase I (ARG) and metabotropic glutamate receptors (mGluRs) such as mGluRs I and mGluRs V and down regulate the expression of inflammatory markers like tumor necrosis factor (TNF-alpha), nuclear factor kappa B (NF-kB), Interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS). In addition, to this, the protective effect of naringin was also revealed through the immunohistochemical changes in tissues. Thus our present study result suggest that naringin modulates the expression of proteins involved in urea cycle pathway and suppresses the expression of inflammatory markers and acts as a potential agent to treat condition in rats. PMID- 28813783 TI - Comprehensive overview of prostatitis. AB - Prostatitis is a common urinary tract syndrome that many doctors find problematic to treat effectively. It is the third most commonly found urinary tract disease in men after prostate cancer and Benign Prostate Hyperplasia (BPH). Prostatitis may account for 25% of all office visits made to the urological clinics complaining about the genital and urinary systems all over the world. In the present study, we classified prostatitis and comprehensively elaborated the etiology, pathogenesis, diagnosis, and treatment of acute bacterial prostatitis (category I), chronic bacterial prostatitis (category II), chronic pelvic pain syndrome (CPPS) (category III), and asymptomatic prostatitis (category IV). In addition, we also tried to get some insights about other types of prostatitis like fungal, viral and gonococcal prostatitis. The aim of this review is to present the detail current perspective of prostatitis in a single review. To the best of our knowledge currently, there is not a single comprehensive review, which can completely elaborate this important topic in an effective way. Furthermore, this review will provide a solid platform to conduct future studies on different aspects such as risk factors, mechanism of pathogenesis, proper diagnosis, and rational treatment plans for fungal, viral, and gonococcal prostatitis. PMID- 28813784 TI - Longitudinal high-density EMG classification: Case study in a glenohumeral TMR subject. AB - Targeted muscle reinnervation (TMR) represents a breakthrough interface for prosthetic control in high-level upper-limb amputees. However, clinically, it is still limited to the direct motion-wise control restricted by the number of reinnervation sites. Pattern recognition may overcome this limitation. Previous studies on EMG classification in TMR patients experienced with myocontrol have shown greater accuracy when using high-density (HD) recordings compared to conventional single-channel derivations. This case study investigates the potential of HD-EMG classification longitudinally over a period of 17 months post surgery in a glenohumeral amputee. Five experimental sessions, separated by approximately 3 months, were performed. They were timed during a standard rehabilitation protocol that included intensive physio- and occupational therapy, myosignal training, and routine use of the final myoprosthesis. The EMG signals recorded by HD-EMG grids were classified into 12 classes. The first sign of EMG activity was observed in the second experimental session. The classification accuracy over 12 classes was 76% in the third session and ~95% in the last two sessions. When using training and testing sets that were acquired with a 1-h time interval in between, a much lower accuracy (32%, Session 4) was obtained, which improved upon prosthesis usage (Session 5, 67%). The results document the improvement in EMG classification accuracy throughout the TMR-rehabilitation process. PMID- 28813785 TI - A pilot study on the optimal speeds for passive wrist movements by a rehabilitation robot of stroke patients: A functional NIRS study. AB - The optimal conditions inducing proper brain activation during performance of rehabilitation robots should be examined to enhance the efficiency of robot rehabilitation based on the concept of brain plasticity. In this study, we attempted to investigate differences in cortical activation according to the speeds of passive wrist movements performed by a rehabilitation robot for stroke patients. 9 stroke patients with right hemiparesis participated in this study. Passive movements of the affected wrist were performed by the rehabilitation robot at three different speeds: 0.25 Hz; slow, 0.5Hz; moderate and 0.75 Hz; fast. We used functional near-infrared spectroscopy to measure the brain activity during the passive movements performed by a robot. Group-average activation map and the relative changes in oxy-hemoglobin (DeltaOxyHb) in two regions of interest: the primary sensory-motor cortex (SM1); premotor area (PMA) and region of all channels were measured. In the result of group-averaged activation map, the contralateral SM1, PMA and somatosensory association cortex (SAC) showed the greatest significant activation according to the movements at 0.75 Hz, while there is no significantly activated area at 0.5 Hz. Regarding DeltaOxyHb, no significant diiference was observed among three speeds regardless of region. In conclusion, the contralateral SM1, PMA and SAC showed the greatest activation by a fast speed (0.75 Hz) rather than slow (0.25 Hz) and moderate (0. 5 Hz) speed. Our results suggest an optimal speed for execution of the wrist rehabilitation robot. Therefore, we believe that our findings might point to several promising applications for future research regarding useful and empirically-based robot rehabilitation therapy. PMID- 28813786 TI - Prediction of gait events in walking activities with a Bayesian perception system. AB - In this paper, a robust probabilistic formulation for prediction of gait events from human walking activities using wearable sensors is presented. This approach combines the output from a Bayesian perception system with observations from actions and decisions made over time. The perception system makes decisions about the current gait events, while observations from decisions and actions allow to predict the most probable gait event during walking activities. Furthermore, our proposed method is capable to evaluate the accuracy of its predictions, which permits to obtain a better performance and trade-off between accuracy and speed. In our work, we use data from wearable inertial measurement sensors attached to the thigh, shank and foot of human participants. The proposed perception system is validated with multiple experiments for recognition and prediction of gait events using angular velocity data from three walking activities; level-ground, ramp ascent and ramp descent. The results show that our method is fast, accurate and capable to evaluate and adapt its own performance. Overall, our Bayesian perception system demonstrates to be a suitable high-level method for the development of reliable and intelligent assistive and rehabilitation robots. PMID- 28813787 TI - Clarification of muscle synergy structure during standing-up motion of healthy young, elderly and post-stroke patients. AB - Standing-up motion is an important daily activity. It has been known that elderly and post-stroke patients have difficulty in performing standing-up motion. The standing-up motion is retrained by therapists to maximize independence of the elderly and post-stroke patients, but it is not clear how the elderly and post stroke patients control their redundant muscles to achieve standing-up motion. This study employed the concept of muscle synergy to analyze how healthy young adults, healthy elderly people and post-stroke patients control their muscles. Experimental result verified that four muscle synergies can represent human standing-up motion. In addition, it indicated that the post-stroke patients shift the weights of muscle synergies to finish standing-up motion comparing to healthy subjects. Moreover, different muscle synergy structures were associated with the CoM and joint kinematics. PMID- 28813788 TI - A novel pneumatic stimulator for the investigation of noise-enhanced proprioception. AB - Executing coordinated movements requires that motor and sensory systems cooperate to achieve a motor goal. Impairment of either system may lead to unstable and/or inaccurate movements. In rehabilitation training, however, most approaches have focused on the motor aspects of the control loop. We are examining mechanisms that may enhance the sensory system to improve motor control. More precisely, the effects of stochastic subliminal vibratory tactile stimulation on wrist proprioception. We developed a device - based on a novel soft pneumatic actuator skin technology - to stimulate multiple sites simultaneously and independently. This device applies vibratory stimulation (amplitude < 0.50 mm, bandwidth 20-120 Hz) to the skin overlaying the tendons of a joint to target the receptors in charge of position and movement encoding. It achieves high spatial resolution (< 1 mm2), uses a soft and flexible interface, and has the potential to be used in combination with additional rehabilitation interventions. We conducted a feasibility study with 16 healthy subjects (11 younger - 6 females; 5 older - 2 females) in which a robotic manipulandum moved the subject's wrist to defined positions that had to be matched with a gauge. Comparing trials with and without stimulation we found that stochastic stimulation influenced joint position sense. The device we developed can be readily used in psycho-physical experiments, and subsequently benefit physiotherapy and rehabilitation treatments. PMID- 28813789 TI - Simulating the impact of sensorimotor deficits on reaching performance. AB - The healthy human nervous system accurately and robustly controls movements despite nonlinear dynamics, noise, and delays. After a stroke, motor ability frequently becomes impaired. To provide insight into the relative impact of specific sensorimotor deficits on motor performance, we modeled neural control of reaching with the human upper limb as a near-optimally feedback-controlled two degree-of-freedom system with biologically based parameters. We added three sensorimotor impairments commonly associated with post-stroke hemiparesis - abnormal joint coupling, increased noise on internally modeled dynamics, and muscular weakness - and examined the impact on reaching performance. We found that abnormal joint coupling unknown to the system's internal model caused systematic perturbations to trajectories, longer reach durations, and target overshoot. Increasing internal model noise and muscular weakness had little impact on motor performance unless model noise was increased by several orders of magnitude. Many reaches performed by our perturbed models replicate features commonly observed in reaches by hemiparetic stroke survivors. The sensitivity to unmodeled abnormal joint coupling agrees with experimental findings that abnormal coupling (possibly related to internal model errors) is the main cause of post stroke motor impairment. PMID- 28813790 TI - Position and torque control via rehabilitation robot and functional electrical stimulation. AB - Two common rehabilitation therapies for individuals possessing neurological conditions are functional electrical stimulation (FES) and robotic assistance. This paper focuses on combining the two rehabilitation strategies for use on the biceps brachii muscle group. FES is used to elicit muscle contractions to actuate the forearm and a rehabilitation robot is used to challenge the muscle group in its efforts. Two controllers were developed and implemented to accomplish the multifaceted objective, both of which achieve global exponential stability for position and torque tracking as proven through a Lyapunov stability analysis. Experiments performed on one able bodied individual demonstrate an average RMS error of 5.8 degrees for position tracking and 0.40 Newton-meters for torque tracking. PMID- 28813791 TI - Codification mechanisms of wrist position sense. AB - Proprioceptive signals from cutaneous, joint, tendon and muscle receptors create the basis for bodily perception and are known to be essential for motor control. However, which are the mechanisms underlying the proprioceptive signals and which are the variables that affect them is still a matter of debate. In particular, what is worth to investigate is, namely, the codification of proprioceptive information related to pointing movements of the wrist towards kinesthetic targets. In this work we asked 10 healthy adults to perform with their wrist a robot-aided proprioceptive matching task, in which the starting position of the matching movements was shifted forward or backward, in order to ascertain to which extent such shifts cause target over/under estimation and how important is movement's length on task performance. Results indicate that accuracy and precision of performance are highly correlated with the starting position and targets tended to be undershot when the active matching movements were longer. Moreover, further analysis revealed a consistent decrement of movement speed for shorter movements and conversely, faster displacement in case of backward of starting position. PMID- 28813792 TI - There is plenty of room for motor learning at the bottom of the Fugl-Meyer: Acquisition of a novel bimanual wheelchair skill after chronic stroke using an unmasking technology. AB - Many people with a stroke have a severely paretic arm, and it is often assumed that they are unable to learn novel, skilled behaviors that incorporate use of that arm. Here, we show that a group of people with chronic stroke (n = 5, upper extremity Fugl-Meyer scores: 31, 30, 26, 22, 8) learned to use their impaired arm to propel a novel, yoked-clutch lever drive wheelchair. Over six daily training sessions, each involving about 134 training movements with their "useless" arm, the users gradually achieved a 3-fold increase in wheelchair speed on average, with a 4-6 fold increase for three of the participants. They did this by learning a bimanual skill: pushing the levers with both arms while activating the yoked clutches at the right time with their ipsilesional (i.e. "good") hand to propel the wheelchair forward. They perceived the task as highly motivating and useful. The speed improvements exceeded a 1.5-factor improvement observed when young, unimpaired users learned to propel the chair. The learning rate also exceeded a sample of learning rates from a variety of classic learning studies. These results suggest that appropriately-designed assistive technologies (or "unmasking technologies - UTs") can unleash a powerful, latent ability for motor learning even for severely paretic arms. While UTs may not reduce clinical impairment, they may facilitate large improvements in a specific functional ability. PMID- 28813793 TI - The combined action of a passive exoskeleton and an EMG-controlled neuroprosthesis for upper limb stroke rehabilitation: First results of the RETRAINER project. AB - The combined use of Functional Electrical Stimulation (FES) and robotic technologies is advocated to improve rehabilitation outcomes after stroke. This work describes an arm rehabilitation system developed within the European project RETRAINER. The system consists of a passive 4-degrees-of-freedom exoskeleton equipped with springs to provide gravity compensation and electromagnetic brakes to hold target positions. FES is integrated in the system to provide additional support to the most impaired muscles. FES is triggered based on the volitional EMG signal of the same stimulated muscle; in order to encourage the active involvement of the patient the volitional EMG is also monitored throughout the task execution and based on it a happy or sad emoji is visualized at the end of each task. The control interface control of the system provides a GUI and multiple software tools to organize rehabilitation exercises and monitor rehabilitation progress. The functionality and the usability of the system was evaluated on four stroke patients. All patients were able to use the system and judged positively its wearability and the provided support. They were able to trigger the stimulation based on their residual muscle activity and provided different levels of active involvement in the exercise, in agreement with their level of impairment. A randomized controlled trial aimed at evaluating the effectiveness of the RETRAINER system to improve arm function after stroke is currently ongoing. PMID- 28813794 TI - Maintaining subject engagement during robotic rehabilitation with a minimal assist-as-needed (mAAN) controller. AB - One challenge of robotic rehabilitation interventions is devising ways to encourage and maintain high levels of subject involvement over long duration therapy sessions. Assist-as-needed controllers have been proposed which modulate robot intervention in movements based on measurements of subject involvement. This paper presents a minimal assist-as-needed controller, which modulates allowable error bounds and robot intervention based on sensorless force measurement accomplished through a nonlinear disturbance observer. While similar algorithms have been validated using healthy subjects, this paper presents a validation of the proposed mAAN control algorithm's ability to encourage user involvement with an impaired individual. User involvement is inferred from muscle activation, measured via surface electromyography (EMG). Experimental validation shows increased EMG muscle activation when using the proposed mAAN algorithm compared to non-adaptive algorithms. PMID- 28813795 TI - Electromechanical delay in the tibialis anterior muscle during time-varying ankle dorsiflexion. AB - We evaluated the electromechanical delay (EMD) for the tibialis anterior (TA) muscle during the performance of time-varying ankle dorsiflexions. Subjects were asked to track a sinusoidal trajectory, for a range of amplitudes and frequencies. Motor unit (MU) action potential trains were identified from surface electromyography (EMG) decomposition and summed to generate the cumulative spike train (CST). CST and the exerted force were cross-correlated to identify the delay between the CST and force, which was considered as an estimate of the EMD. The results showed that the EMD decreased logarithmically with the increase in the slope of the force produced. PMID- 28813796 TI - Feedforward model based arm weight compensation with the rehabilitation robot ARMin. AB - Highly impaired stroke patients at early stages of recovery are unable to generate enough muscle force to lift the weight of their own arm. Accordingly, task-related training is strongly limited or even impossible. However, as soon as partial or full arm weight support is provided, patients are enabled to perform arm rehabilitation training again throughout an increased workspace. In the literature, the current solutions for providing arm weight support are mostly mechanical. These systems have components that restrict the freedom of movement or entail additional disturbances. A scalable weight compensation for upper and lower arm that is online adjustable as well as generalizable to any robotic system is necessary. In this paper, a model-based feedforward weight compensation of upper and lower arm fulfilling these requirements is introduced. The proposed method is tested with the upper extremity rehabilitation robot ARMin V, but can be applied in any other actuated exoskeleton system. Experimental results were verified using EMG measurements. These results revealed that the proposed weight compensation reduces the effort of the subjects to 26% on average and more importantly throughout the entire workspace of the robot. PMID- 28813797 TI - Improving motor skill transfer during dyadic robot training through the modulation of the expert role. AB - In daily life it is necessary to learn skills that can be applied in different tasks and different contexts. Usually these skills are acquired by observation or by direct physical training with another expert person. The critical point is to know which is the best possible way to achieve this knowledge acquisition. In this work we have proposed a collaborative environment where subjects with different levels of expertise have to interact through the use of a robotic platform. A motor skill learning algorithm has been designed in order to allow the less skilled subjects-naives-to explore the virtual environment and to exploit the advantages of working with a skilled partner. Results show that the correct trade - off between exploration and exploitation, provided by the implemented algorithm applied during the dyadic training, allows a group of naive subjects to learn the task and generalize better the acquired skills respect to subjects trained without the proposed algorithm. PMID- 28813798 TI - A novel method for muscle fatigue assessment during robot-based tracking tasks. AB - In this work we propose a novel method based on sEMG signals, easy and fast to perform, administered with a robotic device to maximize repeatability and objectivity. Muscle fatigue, which is frequently experienced by healthy subjects, can be a highly debilitating symptom in case of neuromuscular disorders. Its assessment provides crucial information on the progression of the disability itself, on patient's muscular function and on the efficacy of the eventual clinical intervention. Hence, a robust and objective protocol for fatigue assessment is fundamental in rehabilitation practice. Therefore, the aim of this work was twofold. Firstly, we aimed to test the proposed method and highlight its strengths and drawbacks for a future optimization and implementation in a clinical context. Secondly, we meant to identify which are the most sensitive and reliable measures of muscles' performance that can quickly and optimally predict subjects' behavior. sEMG signals were collected from right Extensor and Flexor Carpi Radialis of 9 healthy subjects during a flexion-extension robotic task consisting in a haptic tracking in a viscous field. Three indicators of fatigue (Mean Frequency, Dimitrov Index, Root Mean Square) were obtained and we proposed a novel sensitive parameter which determines the Onset of Fatigue. PMID- 28813799 TI - Toward EMG-controlled force field generation for training and rehabilitation: From movement data to muscle geometry. AB - EMG signals are often used to control prostheses or assistive devices, but have been rarely used in rehabilitation. We propose a novel approach to personalised rehabilitation, based on EMG-driven force field adaptation. As a step toward this direction, here we show how EMG activity and movement data during a robot assisted motor task can be used to estimate muscle geometry. We compare three different models of muscle geometry, characterised by (i) constant moment arms (CM); (ii) a normative model, based on polynomial functions of joint angles with fixed coefficients (normative polynomial, NP); and (iii) a person-adaptive model, in which the same polynomial model is fitted to individual subjects data (fitted polynomial, FP). We found that the FP model has the best performance, specially for subjects whose size is farther from 'average'. The fitting results also emphasise the adverse effect of muscles co-contraction. PMID- 28813800 TI - The effects of control signal noise on simultaneous submovements. AB - Understanding the stereotypical characteristics of human movement can better inform rehabilitation practices by providing a template of healthy and expected human motor control. Multiplicative noise is inherent in goal-directed movement, such as reaching to grasp an object. Multiplicative noise plays an important role in computational motor control models to help support phenomena such as stereotypical kinematic profiles in time-constrained and unconstrained tasks. Most tasks are not carried out along an isolated degree-of-freedom (DOF), and modelling the contribution of noise can be difficult. Here we add a noise term proportional to the degree of simultaneity for multi-DOF tasks to approximate the contribution of system noise. With this approach, we are able to explain previously observed motor phenomena including the presence of submovements in multi-DOF tasks, and the transition from simultaneous to sequential control of joints without the presence of feedback. Inclusion of a simultaneous multiplicative noise term presents a simple theory that expands on previous research in order to describe characteristics of multiple-DOF movements. This model can be used as a guide to compare healthy human motor control to the movements of patients receiving rehabilitation in an effort to improve their motor planning. PMID- 28813801 TI - Therapeutic effects of an anti-gravity locomotor training (AlterG) on postural balance and cerebellum structure in children with Cerebral Palsy. AB - We evaluated the therapeutic effects of anti-gravity locomotor treadmill (AlterG) training on postural stability in children with Cerebral Palsy (CP) and spasticity, particularly in the lower extremity. AlterG can facilitate walking by reducing the weight of CP children by up to 80%; it can also help subjects maintain an appropriate posture during the locomotor AlterG training. Thus, we hypothesized that AlterG training, for a sufficient period of time, has a potential to produce cerebellum neuroplasticity, and consequently result in an effective permanent postural stability. AlterG training was given for 45 minutes, three times a week for two months. Postural balance was evaluated using posturography. The parameters of the Romberg based posturography were extracted to quantify the Center of Balance (CoP). The neuroplasticity of Cerebellum was evaluated using a Diffusion Tensor Imaging (DTI). The evaluations were done pre- and post-training. The Fractional Anisotropy (FA) feature was used for quantifying structural changes in the cerebellum. The results showed that AlterG training resulted in an increase in average FA value of the cerebellum white matter following the training. The results of the posturography evaluations showed a consistent improvement in postural stability. These results were consistent in all subjects. Our findings indicated that the improvement in the posture was accompanied with the enhancement of the cerebellum white matter structure. The clinical implication is that AlterG training can be considered a therapeutic tool for an effective and permanent improvement of postural stability in CP children. PMID- 28813802 TI - Movement therapy without moving - First results on isometric movement training for post-stroke rehabilitation of arm function. AB - This study explores the use of isometric movement training for arm rehabilitation after stroke. The aim of this approach is to enhance movement skill even when the person training is not moving. This is accomplished by deceptively displaying virtual motions, exploiting known cross-modal sensory interactions between vision and proprioception. This approach can be advantageous in situations where actual movement is prohibitive due to weakness, spasticity, instability, or unsafe conditions. We present early insights on usability of and tolerance to this training approach and quantitative results that can power future clinical trials. PMID- 28813803 TI - Application of support vector machines in detecting hand grasp gestures using a commercially off the shelf wireless myoelectric armband. AB - The propose of this study was to assess the feasibility of using support vector machines in analysing myoelectric signals acquired using an off the shelf device, the Myo armband from Thalmic Lab, when performing hand grasp gestures. Participants (n = 26) took part in the study wearing the armband and producing a series of required gestures. Support vector machines were used to train a model using participant training values, and to classify gestures produced by the same participants. Different Kernel functions and electrode combinations were studied. Also we contrasted different lengths of training values versus different lengths for the classification samples. The overall accuracy was 94.9% with data from 8 electrodes, and 72% where only four of the electrodes were used. The linear kernel outperformed the polynomial, and radial basis function. Exploring the number of training samples versus the achieved classification accuracy, results identified acceptable accuracies (> 90%) for training around 2.5s, and recognising grasp with 0.2s of acquired data. The best recognised grasp was the hand closed (97.6%), followed by cylindrical grasp (96.8%), the lateral grasp (93.2%) and tripod (92%). These results allows us to progress to the next stage of work where the Myo armband is used in the context of robot-mediated stroke rehabilitation and also involves more dynamic interactions as well as gross upper arm movements. PMID- 28813804 TI - Leap motion evaluation for assessment of upper limb motor skills in Parkinson's disease. AB - The main goal of this study is to investigate the potential of the Leap Motion Controller (LMC) for the objective assessment of motor dysfunctioning in patients with Parkinson's disease (PwPD). The most relevant clinical signs in Parkinson's Disease (PD), such as slowness of movements, frequency variation, amplitude variation, and speed, were extracted from the recorded LMC data. Data were clinically quantified using the LMC software development kit (SDK). In this study, 16 PwPD subjects and 12 control healthy subjects were involved. A neurologist assessed the subjects during the task execution, assigning them a score according to the MDS/UPDRS-Section III items. Features of motor performance from both subject groups (patients and healthy controls) were extracted with dedicated algorithms. Furthermore, to find out the significance of such features from the clinical point of view, machine learning based methods were used. Overall, our findings showed the moderate potential of LMC to extract the motor performance of PwPD. PMID- 28813805 TI - Improving robotic stroke rehabilitation by incorporating neural intent detection: Preliminary results from a clinical trial. AB - This paper presents the preliminary findings of a multi-year clinical study evaluating the effectiveness of adding a brain-machine interface (BMI) to the MAHI-Exo II, a robotic upper limb exoskeleton, for elbow flexion/extension rehabilitation in chronic stroke survivors. The BMI was used to trigger robot motion when movement intention was detected from subjects' neural signals, thus requiring that subjects be mentally engaged during robotic therapy. The first six subjects to complete the program have shown improvements in both Fugl-Meyer Upper Extremity scores as well as in kinematic movement quality measures that relate to movement planning, coordination, and control. These results are encouraging and suggest that increasing subject engagement during therapy through the addition of an intent-detecting BMI enhances the effectiveness of standard robotic rehabilitation. PMID- 28813806 TI - Design of continuous EMG classification approaches towards the control of a robotic exoskeleton in reaching movements. AB - Myoelectric control of rehabilitation devices engages active recruitment of muscles for motor task accomplishment, which has been proven to be essential in motor rehabilitation. Unfortunately, most electromyographic (EMG) activity-based controls are limited to one single degree-of-freedom (DoF), not permitting multi joint functional tasks. On the other hand, discrete EMG-triggered approaches fail to provide continuous feedback about muscle recruitment during movement. For such purposes, myoelectric interfaces for continuous recognition of functional movements are necessary. Here we recorded EMG activity using 5 bipolar electrodes placed on the upper-arm in 8 healthy participants while they performed reaching movements in 8 different directions. A pseudo on-line system was developed to continuously predict movement intention and attempted arm direction. We evaluated two hierarchical classification approaches. Movement intention detection triggered different movement direction classifiers (4 or 8 classes) that were trained and tested over a 5-fold cross validation. We also investigated the effect of 3 different window lengths to extract EMG features on classification. We obtained classification accuracies above 70% for both hierarchical approaches. These results highlight the viability of classifying online 8 upper-arm different directions using surface EMG activity of 5 muscles and represent a first step towards an online EMG-based control for rehabilitation devices. PMID- 28813807 TI - Identification of shoulder muscle synergies in healthy subjects during an isometric task. AB - Muscle Synergy method has been proposed in the literature to provide a lower dimensional representation of motor commands from the central nervous system (CNS). Studies on post-stroke patients highlighted how features such as the minimum number of motor synergies accounting for most of the data variance correlate with impairments and motor function. In this study, we target healthy subjects to establish normative data in isometric tasks involving shoulder muscles. Five subjects performed an isometric, two-dimensional force-matching task in twelve planar directions with two force levels across shoulder joint. Muscle synergies and their respective activation curves were computed from nine upper limb muscles via a nonnegative matrix factorization (NNMF) algorithm. Four synergies, on an average, were able to explain 95% of the variance in EMG datasets across all subjects. The cosine similarity of the muscle synergies among the subjects on an average is found to be 0.79+/-0.20. Two subjects revealed the presence of subject-specific synergies which will require further investigation before examining impaired subjects. PMID- 28813808 TI - Experimental evaluation of a sEMG-based control for elbow wearable assistive devices during load lifting tasks. AB - In this work, a surface skin electromyography(sEMG)-based control solution for elbow wearable assistive devices during load lifting tasks is presented. The goal of the controller consists in limiting the user's muscle activity during the task execution, in such a way that the assistive device can partially compensate the load-related biceps muscle effort. Since sEMG-driven control strategies based on the estimation of the joint torques generally requires complex task- and subject dependent training sessions for tuning the control algorithms, here a more direct control approach is proposed, based on a muscle activity error related proportional-integral action together with an double-threshold activation logic. The controller's parameters are easily set by means of a fast, online and automatic subject calibration procedure, ensuring a simple adjustability to different users. An experimental phase has been conducted in order to evaluate the sEMG-based control performance involving four healthy subjects, using as wearable assistive device a twisted string action module, which is particularly suitable for assistive applications because of its lightness and compactness. Results show that the control strategy is able to successfully limit the EMG activity of the subjects during the lifting tasks, providing preliminary outcomes and promising possibilities for the use of twisted string-based technologies to assist human joints and muscles. PMID- 28813809 TI - Development of elbow spasticity model for objective training of spasticity assessment of patients post stroke. AB - Reliable assessment is essential for the management of spasticity, one of the most frequent complication of various neurological diseases. For the spasticity assessment, several clinical tools have been developed and widely used in clinics. The most popular one is modified Ashworth scale (MAS). It has a simple protocol, but is subjective and qualitative. To improve its reliability, quantitative measurement and consistent training would be needed. This study presents an elbow spasticity simulator which mimics spastic response of adult post stroke survivors. First, spastic responses (i.e. resistance and joint motion) from patients with a stroke were measured during conventional MAS assessment. Each grade of MAS was quantified by using three parameters representing three characteristics of the spasticity. Based on the parameters, haptic models of MAS were developed for implementing repeatable and consistent haptic training of novice clinicians. Two experienced clinicians participated in preliminary evaluation of the models. PMID- 28813810 TI - Dissociating two sources of variability using a safety-margin model. AB - Neurological trauma can have a devastating effect on activities of daily living. One of the consequences is an increased amount of variability in the system, which can challenge individuals to stay within safe and stable regions of operation. There are multiple sources of movement variability; two of these are neuromotor noise and action-tolerance variability. The amount of neuromotor noise that is uncontrollable can impose limitations on reshaping variability. Action tolerance variability, which can be reshaped through experience, and neuromotor noise, a certain amount of which cannot be altered, are often conflated when discussing motor variability. We attempted to disambiguate the two using an adaptive model, producing distinct "signatures" of neuromotor noise and action tolerance variability within a task and compare with experimental data on stroke and healthy. Not all stroke survivors could adapt to the task, as predicted for those with greater neuromotor noise. Possible applications of this model can inform us of potential to influence distributions in stroke survivors and other individuals who have had a neurological injury. Additionally, we could design new training environments specifically tailored to the needs of the individual. This technique may also help disambiguate the type of brain injury suffered by stroke survivors. PMID- 28813811 TI - A multichannel-near-infrared-spectroscopy-triggered robotic hand rehabilitation system for stroke patients. AB - There is a demand for a new neurorehabilitation modality with a brain-computer interface for stroke patients with insufficient or no remaining hand motor function. We previously developed a robotic hand rehabilitation system triggered by multichannel near-infrared spectroscopy (NIRS) to address this demand. In a preliminary prototype system, a robotic hand orthosis, providing one degree-of freedom motion for a hand's closing and opening, is triggered by a wireless command from a NIRS system, capturing a subject's motor cortex activation. To examine the feasibility of the prototype, we conducted a preliminary test involving six neurologically intact participants. The test comprised a series of evaluations for two aspects of neurorehabilitation training in a real-time manner: classification accuracy and execution time. The effects of classification related factors, namely the algorithm, signal type, and number of NIRS channels, were investigated. In the comparison of algorithms, linear discrimination analysis performed better than the support vector machine in terms of both accuracy and training time. The oxyhemoglobin versus deoxyhemoglobin comparison revealed that the two concentrations almost equally contribute to the hand motion estimation. The relationship between the number of NIRS channels and accuracy indicated that a certain number of channels are needed and suggested a need for a method of selecting informative channels. The computation time of 5.84 ms was acceptable for our purpose. Overall, the preliminary prototype showed sufficient feasibility for further development and clinical testing with stroke patients. PMID- 28813812 TI - Characterization of surface electromyography patterns of healthy and incomplete spinal cord injury subjects interacting with an upper-extremity exoskeleton. AB - Rehabilitation exoskeletons may make use of myoelectric control to restore in patients with significant motor impairment following a spinal cord injury (SCI) a sense of volitional control over their limb - a crucial component for recovery of movement. Little investigation has been done into the feasibility of using surface electromyography (sEMG) as an exoskeleton control interface for SCI patients, whose impairment manifests in a highly variable way across the patient population. We have demonstrated that by using only a small subset of features extracted from eight bipolar electrodes recording on the upper arm and forearm muscles, we can achieve high predictive accuracy for the intended direction of motion. Five healthy subjects and two SCI subjects performed voluntary isometric contractions while wearing an exoskeleton for the wrist and elbow joints, generating six distinct single and multi-DoF motions in a total of sixteen possible directions. Using linear discriminant analysis, classification performance was then evaluated using randomly selected holdout test data from the same recording session. Commonalities across subjects, both healthy and SCI, were analyzed at the levels of selected features and the values of commonly selected features. Future work will be to investigate group-specific classification of SCI subjects' intended movements for use in the real-time control of a rehabilitation exoskeleton. PMID- 28813813 TI - Therapeutic effects of an anti-gravity treadmill (AlterG) training on gait and lower limbs kinematics and kinetics in children with cerebral palsy. AB - We aimed to investigate the effects of the lower body weight support treadmill (AlterG) training on kinetics and kinematics of the lower extremities in children with cerebral palsy (CP). We provided a 45-minute training program, 3 times a week for 8 weeks. AlterG can support the subject's weight up to 70% so that the subject will be able to walk more comfortably to reach a more correct walking pattern. The kinematics and kinetics were evaluated using an isokinetic dynamometer. The locomotion parameters were assessed in the gait laboratory. Subjects performance was evaluated at four time points: baseline (prior to training), 1 and 2 months after the beginning of training, and one month after the end of the training (as a follow-up evaluation). The results showed that the major gait, kinematic, and kinetic parameters improved after the AlterG training and were persistent. These findings suggest that the AlterG training can be considered as a therapeutic tool for improving the lower limb performance and locomotion in children with CP. PMID- 28813814 TI - Toward quantitative characterization of essential tremor for future tremor suppression. AB - Tremor is the most common movement deficit and manifests in a variety of disorders, including Essential Tremor, Parkinson's Disease, Dystonia, and Cerebellar Ataxia. Although medication and surgical interventions have significantly reduced patient suffering, they are only partially effective and can carry undesired side effects, leaving many patients without satisfactory treatment options. Wearable tremor-suppressing devices could provide an alternative to medication and surgery. Multiple research groups have developed orthotic prototypes to low-pass filter tremor, but these devices have not yet been optimized for in-vivo use. Optimizing non-invasive tremor suppression requires an understanding of where the tremor originates mechanically (which muscles) and how it propagates to the hand (where it matters most). Here we present on the beginnings of our multi-pronged work to determine the origin, propagation, and distribution of Essential Tremor, and we provide preliminary results. PMID- 28813815 TI - How do strength and coordination recovery interact after stroke? A computational model for informing robotic training. AB - Robotic devices can train strength, coordination, or a combination of both. If a robotic device focuses on coordination, what happens to strength recovery, and vice versa? Understanding this interaction could help optimize robotic training. We developed a computational neurorehabilitation model to gain insight into the interaction between strength and coordination recovery after stroke. In the model, the motor system recovers by optimizing the activity of residual corticospinal cells (focally connected, excitatory and inhibitory) and reticulospinal cells (diffusely connected and excitatory) to achieve a motor task. To do this, the model employs a reinforcement learning algorithm that uses stochastic search based on a reward signal produced by task execution. We simulated two tasks that require strength and coordination: a finger movement task and a bilateral wheelchair propulsion task. We varied the reward signal to value strength versus coordination, determined by a weighting factor. The model predicted a nonlinear relationship between strength and coordination recovery consistent with clinical data obtained for each task. The model also predicted that stroke can cause a competition between strength and coordination recovery, due to a scarcity of focal and inhibitory cells. These results provide a rationale for implementing robotic movement therapy that can adaptively alter the combination of force and coordination training to target desired components of motor recovery. PMID- 28813816 TI - Computational rehabilitation of neglect: Using state-space models to understand the recovery mechanisms. AB - Unilateral spatial neglect is a neuropsychological syndrome often observed in right hemisphere stroke patients. The symptoms differ from subject to subject. A few rehabilitation approaches, e.g. prism adaptation, have demonstrated some effect in reducing the symptoms, but the underlying mechanisms are still largely unclear. Recently, neural models have been proposed to qualitatively describe cortical lesions, the resulting neglect symptoms and the effects of treatment. However, these predictions are qualitative and cannot be used to compare different hypotheses or to interpret symptoms at individual subjects level. Here we propose a computational model of the trial-by-trial dynamics of training induced recovery from neglect. Neglect is modelled in terms of an impaired internal representation of visual stimuli in the left hemispace. The model assumes that recovery is driven by the mismatch between defective representations of visual stimuli and the corresponding hand positions. The model reproduces the main observations of prism adaptation experiments. Using standard system identification techniques, we fitted the model to data from a rehabilitation trial based on a novel rehabilitation approach based on virtual reality, involving reaching movements within an adaptive environment. Our results suggest that the model can be used to interpret data from individual subjects and to formulate testable hypotheses on the mechanisms of recovery and directions for treatment. PMID- 28813817 TI - The effects of silent visuomotor cueing on word retrieval in Broca's aphasies: A pilot study. AB - About a quarter of stroke patients worldwide suffer serious language disorders such as aphasias. Most common symptoms of Broca's aphasia are word naming disorders which highly impact verbal communication and the quality of life of aphasic patients. In order to recover disturbances in word retrieval, several cueing methods (i.e. phonemic and semantic) have been established to improve lexical access establishing effective language rehabilitation techniques. Based on recent evidence from action-perception theories, which postulate that neural circuits for speech perception and articulation are tightly coupled, in the present work, we propose and investigate an alternative type of cueing using silent articulation-related visual stimuli. We hypothesize that providing patients with primes in the form of silent videos showing lip motions representative of correct pronunciation of target words, will result in faster word retrieval than when no such cue is provided. To test our prediction, we realize a longitudinal clinical virtual reality-based trial with four post-stroke Broca's patients and compare the interaction times between the two conditions over the eight weeks of the therapy. Our results suggest that silent visuomotor cues indeed facilitate word retrieval and verbal execution, and might be beneficial in lexical relearning in chronic Broca's patients. PMID- 28813818 TI - The effect of myoelectric prosthesis control strategies and feedback level on adaptation rate for a target acquisition task. AB - The long-term performance of myoelectric prostheses is related not only to the short-term performance of the controller, but also to the user's ability to learn and adapt to the system. Different control architectures may have inherent tradeoffs between their short-term performance and the amount of relevant feedback that informs this adaptation. In this study we focused on the ability of two common types of myoelectric control interfaces: raw control with raw feedback, such as a regression, and filtered control with filtered feedback, such as a classifier, to affect user adaptation. We evaluated trial-by-trial adaptation to self-generated errors during a multi degree-of-freedom target acquisition task by fitting a linear regression model to data collected from 24 able-bodied subjects. Subjects showed significantly higher adaptation behavior to self-generated errors when using raw control with a raw feedback strategy than when using filtered control with a filtered feedback strategy, which suggests that control strategies with more feedback allow for higher adaptation. These results support our hypothesis that feedback-rich control strategies allow users to better understand the myoelectric control system, which may enable better long term performance. PMID- 28813819 TI - MIT-Skywalker: On the use of a markerless system. AB - This paper describes our efforts to employ the Microsoft Kinect as a low cost vision control system for the MIT-Skywalker, a robotic gait rehabilitation device. The Kinect enables an alternative markerless solution to control the MIT Skywalker and allows a more user-friendly set-up. A study involving eight healthy subjects and two stroke survivors using the MIT-Skywalker device demonstrates the advantages and challenges of this new proposed approach. PMID- 28813820 TI - Design of an exoskeleton ankle robot for robot-assisted gait training of stroke patients. AB - Lower Limb Exoskeleton robot that can facilitate stair walking is a big challenge, most systems could only provide level ground walking. In this study, a lightweight (0.5kg at ankle, 0.5kg at waist for control box) and autonomous exoskeleton Ankle Robot was proposed to provide power assistance for gait training of chronic stroke patients and it can facilitate three walking conditions in real-time: (1) level walking, (2) stair ascending, and (3) stair descending. Chronic stroke patients (n=3) with drop foot gait deficit and moderate motor impairment were recruited to evaluate the system under different walking conditions (Functional Ambulatory Category: FAC=4.7+/-0.5 and Fugl-Meyer Assessment for lower-extremity: FMA-LE=13.7+/-2.9). The system consisted of a specially designed carbon fiber AFO, servomotor, gear transmission system, IMU and force sensors, and control box. The IMU sensors embedded in the shank measured acceleration and angular velocity to identify distinct features in leg tilting angle and leg angular velocity between the three walking conditions. The results showed the powered ankle dorsiflexion assistance could reduce dropped foot of the stroke patients in swing phase and provide better gait pattern. A demo of the ankle robot will be conducted in the conference. PMID- 28813821 TI - Gait training assist system of a lower limb prosthetic visualizing muscle activation pattern using a color-depth sensor. AB - Some unilateral lower-limb amputees load the intact limb more than the prosthetic limb. This can cause chronic pains, fatigue, lumbago, and joint diseases, including knee osteoarthritis. To avoid and counteract these symptoms it is necessary to improve their asymmetric gait. Increasing the function of the hip abductor muscle is important to maintaining symmetrical weight distribution. Therefore, the purpose of this study is to develop a training assist system, which estimates and visualizes an abductor muscle by using a color-depth sensor. To estimate the muscle activation, first, the floor reaction force is calculated using a simple dynamic model. Then, the hip torque is calculated using joint angles. The floor reaction force and, the muscle length are calculated based on a human musculoskeletal model. Muscle activity is estimated by these parameters. Evaluation experiments of this proposed method were performed on healthy persons and unilateral trans femoral amputees, and the effectiveness of this proposed algorithm has been confirmed. PMID- 28813822 TI - A novel robot-assisted training approach for improving gait symmetry after stroke. AB - Gait asymmetry as a consequence of hemiparesis is known as a serious long-term disability, where typical compensatory gait movements are used by stroke subjects in order to cope with their daily activities. This study presents a gait symmetry training approach consisting of the adaptive robot assistance with the combination of the visual feedback integrated in Balance Assessment Robot for treadmill walking (BAR-TM). The support algorithm is based on gait temporal parameters that change the level of assistive support, which was triggered at different gait subphase events. The presented approach was evaluated on a post stroke subject in a large number of training sessions. The results have shown significant improvement of gait symmetry indicating that the proposed rehabilitation method has significant potential that should be explored in further studies. PMID- 28813823 TI - A generalized framework to achieve coordinated admittance control for multi-joint lower limb robotic exoskeleton. AB - Traditional joint space admittance controller for N-DOF robotic systems is complexity and easily leads to incongruous movement among all joints. Our study introduces a central pattern generator (CPG) network into one-dimension joint space admittance control for the custom-made lower limb robotic exoskeleton with four DOFs, to guarantee the coordinated movement and security of users. The predefined trajectories for four joints are produced by CPG. Unilateral knee joint torque of subjects is detected based on corresponding muscle EMG signals. The torque is transformed into an additional set of state variables for CPG based on the one-dimension admittance controller. CPG harmonically adjusts the predefined trajectories by the additional state variables. Finally, the robotic exoskeleton completes the predefined trajectories with a classical PID controller. PMID- 28813824 TI - The effect of haptic interaction between balance assessment robot and pelvis on muscle activation of leg muscles. AB - Admittance control is considered as a promising paradigm in rehabilitation that provides us with means to establish well controlled and adjustable interaction and cooperation between rehabilitation devices and patients. Recently we developed balance assessment robot (BAR) for studying postural responses during walking as well as for pelvis manipulation during walking that implements admittance control as a mean of interaction with user. In this study we evaluated the characteristics of transparent haptic interaction and investigated whether transparent haptic interaction induces adaptations in muscle activation patterns with respect to free walking. In one neurologically intact individual we measured interaction forces, ground reaction forces and center of pressure as well as EMG of selected leg muscles while walking free and while walking with BAR. Results show that the amplitude of interaction forces in transparent mode of operation remained below levels that could have imposed considerable adjustments in muscle activation patterns of leg muscles. PMID- 28813825 TI - Research of the BWS system for lower extremity rehabilitation robot. AB - Body weight support (BWS) system is increasingly used in conjunction with treadmills to assist the patients with neurological impairments. Owing to lower limbs of the patients unable to bear the whole weight during the rehabilitation training, some weight can be removed to help the patients recover the basic walking ability gradually. Therefore, considering the man-machine relationship and the effects of the rehabilitation, a wire-driven BWS system is designed. The main unit of the system is an active closed-loop controlled drive to generate the exact desired force. The force acted on the body is through the adjustment of the length of the rope which is connected to the harness worn by the patient. The structure designed in the research is easy to operate to realize the goal of the rehabilitation. To verify the effectiveness and practicability of the BWS system, some experiments have been curried out. From the results, not only the constant unloading force can be realized, but also the response time is limited in a small range which can bring a positive effect on correcting gait, improving balance and reducing muscle spasms. Also, compared to the traditional body weight support system, such as static system or passive elastic system, it has the advantages of the fast response, small errors and constant unloading force. PMID- 28813826 TI - Autonomous hip exoskeleton saves metabolic cost of walking uphill. AB - We have developed a hip joint exoskeleton to boost gait function in the elderly and rehabilitation of post-stroke patients. To quantitatively evaluate the impact of the power and mass of the exoskeleton, we measured the metabolic cost of walking on slopes of 0, 5, and 10% grade, once not wearing the exoskeleton and then wearing it. The exoskeleton reduced the metabolic cost by 13.5,15.5 and 9.8% (31.9, 51.6 and 45.6 W) at 0, 5, and 10% grade, respectively. The exoskeleton performance index was computed as 0.97, 1.24, and 1.24 at each grade, implicating that the hip exoskeleton was more effective on slopes than level ground in saving the metabolic cost. PMID- 28813827 TI - Biomechanical effects of robot assisted walking on knee joint kinematics and muscle activation pattern. AB - Since manual rehabilitation therapy can be taxing for both the patient and the physiotherapist, a gait rehabilitation robot has been built to reduce the physical strain and increase the efficacy of the rehabilitation therapy. The prototype of the gait rehabilitation robot is designed to provide assistance while walking for patients with abnormal gait pattern and it can also be used for rehabilitation therapy to restore an individual's normal gait pattern by aiding motor recovery. The Gait Rehabilitation Robot uses gait event based synchronization, which enables the exoskeleton to provide synchronous assistance during walking that aims to reduce the lower-limb muscle activation. This study emphasizes on the biomechanical effects of assisted walking on the lower limb by analyzing the EMG signal, knee joint kinematics data that was collected from the right leg during the various experimental conditions. The analysis of the measured data shows an improved knee joint trajectory and reduction in muscle activity with assistance. The result of this study does not only assess the functionality of the exoskeleton but also provides a profound understanding of the human-robot interaction by studying the effects of assistance on the lower limb. PMID- 28813828 TI - Active lower limb orthosis with one degree of freedom for people with paraplegia. AB - The main challenges of designing devices for paraplegic walking can be summarized into three groups, stability and comfort, high efficiency or low energy consumption, dimensions and weight. A new economical device for people with paraplegia which tackles all problems of the three groups is introduced in this paper. The main idea of this device is based on HALO mechanism. HALO is compact passive medial hip joint orthosis with contralateral hip and ankle linkage, which keeps the feet always parallel to the ground and assists swinging the leg. The medial hip joint is equipped with one actuator in the new design and the new orthosis is called @halo. Due to this update, we can achieve more stable and smoother walking patterns with decreased energy consumption of the users, yet maintain its compact and lightweight features. It is proven by the results from preliminary experiments with able-bodied subjects during which the same device with and without actuator was evaluated. Waddling and excessive vertical elevation of the center of gravity were decreased by 40% with significantly smaller standard deviations in case of the active orthosis. There was 52% less energy spent by the user wearing @halo which was calculated from the vertical excursion difference. There was measured 38.5% bigger impulse in crutches while using passive orthosis. The new @halo device is the first active orthosis for lower limbs with just one actuated degree of freedom for users with paraplegia. PMID- 28813829 TI - Development of an automatic rotational orthosis for walking with arm swing. AB - Interlimb neural coupling is often observed during normal gait and is postulated to be important for gait restoration. In order to provide a testbed for investigation of interlimb neural coupling, we previously developed a rotational orthosis for walking with arm swing (ROWAS). The present study aimed to develop and evaluate the feasibility of a new system, viz. an automatic ROWAS (aROWAS). We developed the mechanical structures of aROWAS in SolidWorks, and implemented the concept in a prototype. Normal gait data from walking at various speeds were used as reference trajectories of the shoulder, hip, knee and ankle joints. The aROWAS prototype was tested in three able-bodied subjects. The prototype could automatically adjust to size and height, and automatically produced adaptable coordinated performance in the upper and lower limbs, with joint profiles similar to those occurring in normal gait. The subjects reported better acceptance in aROWAS than in ROWAS. The aROWAS system was deemed feasible among able-bodied subjects. PMID- 28813830 TI - Toward goal-oriented robotic gait training: The effect of gait speed and stride length on lower extremity joint torques. AB - Robot-assisted gait training is becoming increasingly common to support recovery of walking function after neurological injury. How to formulate controllers capable of promoting desired features in gait, i.e. goals, is complicated by the limited understanding of the human response to robotic input. A possible method to formulate controllers for goal-oriented gait training is based on the analysis of the joint torques applied by healthy subjects to modulate such goals. The objective of this work is to understand how sagittal plane joint torque is affected by two important gait parameters: gait speed (GS) and stride length (SL). We here present the results obtained from healthy subjects walking on a treadmill at different speeds, and asked to modulate stride length via visual feedback. Via principal component analysis, we extracted the global effects of the two factors on the peak-to-peak amplitude of joint torques. Next, we used a torque pulse approximation analysis to determine optimal timing and amplitude of torque pulses that approximate the SL-specific difference in joint torque profiles measured at different values of GS. Our results show a strong effect of GS on the torque profiles in all joints considered. In contrast, SL mostly affects the torque produced at the knee joint at early and late stance, with smaller effects on the hip and ankle joints. Our analysis generated a set of torque assistance profiles that will be experimentally tested using gait training robots. PMID- 28813831 TI - The influence of the Re-Link Trainer on gait symmetry in healthy adults. AB - Walking function post-stroke is characterized by asymmetries in gait cycle parameters and joint kinematics. The Re-Link Trainer is designed to provide kinematic constraint to the paretic lower limb, to guide a physiologically normal and symmetrical gait pattern. The purpose of this pilot study was to assess the immediate influence of the Re-Link Trainer on measures of gait symmetry in healthy adults. Participants demonstrated a significantly lower cadence and a 62% reduction in walking speed in the Re-Link Trainer compared to normal walking. The step length ratio had a significant increase from 1.0 during normal walking to 2.5 when walking in the Re-Link Trainer. The results from this pilot study suggest in its current iteration the Re-Link Trainer imposes an asymmetrical constraint on lower limb kinematics. PMID- 28813832 TI - Design and experimental evaluation of a lightweight, high-torque and compliant actuator for an active ankle foot orthosis. AB - The human ankle joint plays a crucial role during walking. At the push-off phase the ankle plantarflexors generate the highest torque among the lower limb joints during this activity. The potential of the ankle plantarflexors is affected by numerous pathologies and injuries, which cause a decrease in the ability of the subject to achieve a natural gait pattern. Active orthoses have shown to have potential in assisting these subjects. The design of such robots is very challenging due to the contrasting design requirements of wearability (light weight and compact) and high torques capacity. This paper presents the development of a high-torque ankle actuator to assist the ankle joint in both dorsiflexion and plantarflexion. The compliant actuator is a spindle-driven MACCEPA (Mechanically Adjustable Compliance and Controllable Equilibrium Position Actuator). The design of the actuator was made to keep its weight as low as possible, while being able to provide high torques. As a result of this novel design, the actuator weighs 1.18kg. Some static characterization tests were perfomed on the actuator and their results are shown in the paper. PMID- 28813833 TI - An integrated gait rehabilitation training based on Functional Electrical Stimulation cycling and overground robotic exoskeleton in complete spinal cord injury patients: Preliminary results. AB - The aim of this study is to investigate the effects of an integrated gait rehabilitation training based on Functional Electrical Stimulation (FES)-cycling and overground robotic exoskeleton in a group of seven complete spinal cord injury patients on spasticity and patient-robot interaction. They underwent a robot-assisted rehabilitation training based on two phases: n=20 sessions of FES cycling followed by n= 20 sessions of robot-assisted gait training based on an overground robotic exoskeleton. The following clinical outcome measures were used: Modified Ashworth Scale (MAS), Numerical Rating Scale (NRS) on spasticity, Penn Spasm Frequency Scale (PSFS), Spinal Cord Independence Measure Scale (SCIM), NRS on pain and International Spinal Cord Injury Pain Data Set (ISCI). Clinical outcome measures were assessed before (T0) after (T1) the FES-cycling training and after (T2) the powered overground gait training. The ability to walk when using exoskeleton was assessed by means of 10 Meter Walk Test (10MWT), 6 Minute Walk Test (6MWT), Timed Up and Go test (TUG), standing time, walking time and number of steps. Statistically significant changes were found on the MAS score, NRS-spasticity, 6MWT, TUG, standing time and number of steps. The preliminary results of this study show that an integrated gait rehabilitation training based on FES-cycling and overground robotic exoskeleton in complete SCI patients can provide a significant reduction of spasticity and improvements in terms of patient-robot interaction. PMID- 28813834 TI - Comparing neural control and mechanically intrinsic control of powered ankle exoskeletons. AB - There are an infinite number of ways to control an assistive robotic device; however, there is little consensus on which ways are better than others and why. We designed this study to compare the control of powered ankle exoskeletons using neural measurements to drive control versus that using mechanically intrinsic measurements. The controller driven by neural measurements was a dynamic gain proportional myoelectric controller using user's soleus muscle activity for an actuation signal. The controller driven by mechanically intrinsic measurements was a timing-based controller using detected heel-strikes of the user to appropriately time actuation. We designed these two controllers in such a way that both had the same average actuation signal and tested them with 8 healthy subjects. Results show no significant difference in metabolic work rate between the two controllers. Both controllers resulted in reductions in metabolic work rate of 19% below walking in the devices unpowered. We found that subjects using the timing-based mechanically intrinsic controller exhibited less positive and negative total ankle power than when using the dynamic gain proportional myoelectric controller. This finding was coupled with a reduction of 11.8% in soleus muscle activity. We believe these finding can have large implications for applications in rehabilitation and lend insight to when one controller is more appropriate to use than another. PMID- 28813835 TI - Motor adaptation to lateral pelvis assistance force during treadmill walking in individuals post-stroke. AB - The goal of this study was to determine how individuals post-stroke response to the lateral assistance force applied to the pelvis during treadmill walking. Ten individuals post chronic (> 6 months) stroke were recruited to participate in this study. A controlled assistance force (~10% of body weight) was applied to the pelvis in the lateral direction toward the paretic side during stance of the paretic leg. Kinematics of the pelvis and legs were recorded. Applying pelvis assistance force facilitated weight shifting toward the paretic side, resulting in a more symmetrical gait pattern but also inducing an enlarged range of motion of the pelvis during early adaptation period. The neural system of individuals post stroke adapted to the pelvis assistance force and showed an aftereffect consists of reduced range of motion of the pelvis following load release during post adaptation period. PMID- 28813836 TI - Development of new rehabilitation robot device that can be attached to the conventional Knee-Ankle-Foot-Orthosis for controlling the knee in individuals after stroke. AB - This research developed a device that can be attached to the conventional Knee Ankle-Foot-Orthosis for controlling the knee in individuals after stroke. The device automatically assists the flexion and extension movements of the knee joint at the appropriate timing. We aimed to clarify the effect of this device on gait performance, kinematic pattern and muscle activation during gait. Seventeen participants after stroke were recruited in this study. They walked with this device for 3 minutes, and we measured the 10m gait time, number of steps, knee motion using electric goniometer and muscle activities of lower limbs during gait. The gait speed, number of steps, and range of knee joint improved by using the device with assist, and those changes remained without assist. For muscle activities measured by electromyography in the lower limbs, although the device only assists one side of the limb, it was able to alter EMG of both paretic and non-paretic limbs. By assisting only the paretic knee movements, the device was able to improve the performance, kinematic pattern and muscle activation during gait, which remained as an aftereffect. PMID- 28813837 TI - Walking speed intention model using soleus electromyogram signal of nondisabled and post-stroke hemiparetic patients. AB - It is well known that the activation of plantar flexors have a strong influence on the walking speed. If the gait speed can be predicted using this relationship, a post-stroke hemiparetic patient could control a gait rehabilitation robot according to his or her gait intention, and the robotic gait rehabilitation effect could be further improved. To find out this relationship, 9 nondisabled subjects and 4 chronic post-stroke hemiparetic subjects performed overground level walking at a comfortable pace, a slow pace, a fast pace, and an increasing pace with electromyogram sensors attached on plantar flexors. Soleus among plantar flexors showed the most stable relationship with walking speed. The relationship between maximum activation level of soleus electromyogram during stance phase before toe-off and walking speed during swing phase after the same toe-off was modeled by a polynomial regression model. The model outputs were then compared to the measured walking speeds using coefficients of determination (R2). The average R2 values are 0.594 and 0.692 for 1st. and 2nd order models respectively in the nondisabled subjects. The average R2 values are 0.598 and 0.623 for the unaffected side and 0.388 and 0.394 for the affected side in the chronic subjects. The results show the feasibility of applying the soleus-walking speed relationship to control the robot gait speed at will. A walking speed estimation method is proposed using only a walking step in real time. PMID- 28813838 TI - Developing safe fall strategies for lower limb exoskeletons. AB - One of the main challenges in the use of a powered lower limb exoskeleton (LLE) is to ensure that balance is maintained throughout the operation of the device. Since no control strategy has yet been implemented that prevents falls in the case of a loss of balance, head or other serious injuries may occur during independent use of LLEs in the event of a fall. These safety concerns limit LLEs in the community to supervised use only. Using the backward fall as a model, we used optimization techniques to develop safe fall control strategies in order to avoid head impact and mitigate the impact velocity of the hips. From available human biomechanics data, we first developed an optimization methodology to study falls of healthy people. The results showed similar kinematic and dynamic characteristics to findings of previous studies on real-life human falls. Second, we extended the optimization methodology to include characteristics of a hypothetical LLE and to generate optimal joint trajectories and optimal torque profiles for the fall duration. The results revealed that by applying the optimal fall strategy, the severity of a simulated fall was minimized compared to when the device fell with locked joints (i.e., how currently used exoskeletons fall): head impact was avoided and hip impact velocity was reduced by more than 50%. PMID- 28813839 TI - Timing of intermittent torque control with wire-driven gait training robot lifting toe trajectory for trip avoidance. AB - Gait training robots are useful for changing gait patterns and decreasing risk of trip. Previous research has reported that decreasing duration of the assistance or guidance of the robot is beneficial for efficient gait training. Although robotic intermittent control method for assisting joint motion has been established, the effect of the robot intervention timing on change of toe clearance is unclear. In this paper, we tested different timings of applying torque to the knee, employing the intermittent control of a gait training robot to increase toe clearance throughout the swing phase. We focused on knee flexion motion and designed a gait training robot that can apply flexion torque to the knee with a wire-driven system. We used a method of timing detecting for the robot conducting torque control based on information from the hip, knee, and ankle angles to establish a non-time dependent parameter that can be used to adapt to gait change, such as gait speed. We carried out an experiment in which the conditions were four time points: starting the swing phase, lifting the foot, maintaining knee flexion, and finishing knee flexion. The results show that applying flexion torque to the knee at the time point when people start lifting their toe is effective for increasing toe clearance in the whole swing phase. PMID- 28813840 TI - A novel protocol to evaluate ankle movements during reaching tasks using pediAnklebot. AB - The aim of the study is to design a novel protocol to characterize the ankle movements during dorsal and plantar flexion reaching tasks using the pediAnklebot. Five healthy children were instructed to control a pointer and hit targets appearing on the monitor, by moving their ankle alternatively up and down. The protocol consisted of 60 targets, 30 up and 30 down, reachable via dorsiflexion and plantarflexion movements, respectively. Ankle angular displacements and torques were gathered by encoders and load cells embedded in the robot. Ankle motor performance was evaluated by means of kinematic, submovements and dynamic indices. Results suggest that (i) plantarflexion movements are faster and more accurate than the dorsiflexion ones, but children are able to perform with a higher level of smoothness the latter ones; (ii) children are able to stop the ankle movement more easily at the end of dorsiflexion rather than plantarflexion; (iii) the central nervous system plans plantarflexion and dorsiflexion movements with the same efficiency; (iv) children apply different torque levels during the two motor tasks and they cannot balance the inversion and eversion moments during dorsiflexion. These findings provide an important starting point for the assessment of a reference baseline of motor indices for the ankle joint. PMID- 28813841 TI - Design and preliminary evaluation of a multi-robotic system with pelvic and hip assistance for pediatric gait rehabilitation. AB - This paper presents a modular, computationally-distributed "multi-robot" cyberphysical system designed to assist children with developmental delays in learning to walk. The system consists of two modules, each assisting a different aspect of gait: a tethered cable pelvic module with up to 6 degrees of freedom (DOF), which can modulate the motion of the pelvis in three dimensions, and a two DOF wearable hip module assisting lower limb motion, specifically hip flexion. Both modules are designed to be lightweight and minimally restrictive to the user, and the modules can operate independently or in cooperation with each other, allowing flexible system configuration to provide highly customized and adaptable assistance. Motion tracking performance of approximately 2 mm root mean square (RMS) error for the pelvic module and less than 0.1 mm RMS error for the hip module was achieved. We demonstrate coordinated operation of the two modules on a mannequin test platform with articulated and instrumented lower limbs. PMID- 28813842 TI - Using wearable physiological sensors to predict energy expenditure. AB - Lower-limb assistive robotic devices are often evaluated by measuring a reduction in the user's energy cost. Using indirect calorimetry to estimate energy cost is poorly suited for real-time estimation and long-term collection. The goal of this study was to use data from wearable sensors to predict energy cost with better temporal resolution and less variability than breath measurements. We collected physiological data (heart rate, electrodermal activity, skin temperature) and mechanical data (EMG, accelerometry) from three healthy subjects walking on a treadmill at various speeds on level ground, inclined, and backwards. Ground truth energy cost was established by averaging steady-state breath measurements. Raw physiological signals correlated well with ground truth energy cost, but raw mechanical signals did not. Correlation of mechanical signals was improved by calculating accelerometer magnitudes and linear envelope EMG signals, and further improved by averaging the signals over several seconds. A multiple linear regression including physiological and mechanical data accurately predicted ground truth energy cost across all subjects and activities tested, with less variability and better temporal resolution than breath measurements. The sensors used in this study were fully portable, and such algorithms could be used to estimate energy cost of users in the real world. This could greatly improve the design, control, and evaluation of lower-limb assistive robotic devices. PMID- 28813844 TI - Soft-stop knee brace for rehabilitation from ligament injuries: Design and pilot trial. AB - Ligaments within the human knee are commonly torn or injured as a result of sports that involve sharp direction changes, pivoting and landing. For this reason, athletes are often side-lined from their respective sports for up to 18 months after injury to rehabilitate. As part of the rehabilitation process, knee braces are often prescribed in an attempt to decrease the recovery period of the injured individual by restraining and minimizing the motion at the knee. However, the true efficacy of knee bracing is yet to be fully evaluated as studies show mixed results to whether braces actually decrease the rehabilitation period for patients. This paper describes the design and pilot trials of a simple but novel knee brace design that aims to actively aid the rehabilitation of the knee from ligament injuries, primarily the anterior cruciate ligament (ACL). The newly developed knee brace uses an angle locking mechanism with dampers to control both the range of motion of the knee joint and the resistance applied to the knee joint at the limits of extension. Using finite element analysis, these dampers were designed help build muscle strength during everyday use of the knee brace and to reduce the 'jarring effect' which causes significant pain and risk to patients using current knee brace designs. Through providing these features, this new knee brace design has the potential to help improve the extent and speed of recovery for ACL impaired patients. PMID- 28813843 TI - Addition of forelimb training reduces gains from robotic gait training in a rat model of spinal cord injury. AB - To restore locomotor function following spinal cord injury the disrupted descending supraspinal drive needs to be re-connected to regions caudal to the injury. Robotic gait training aims to facilitate recovery by stimulating the proprioceptive networks of the legs in a coordinated walking pattern while the descending supraspinal connections are re-established. In incomplete injuries, it is believed that the interneuronal networks near the injury site form relay circuits to reroute the supraspinal signals through the spared tissue. Stimulating these neurons should lead to increased arborization, and more robust relay circuits. We set out to show that robotic gait training is more effective when it is paired with training that activates interneurons at the level of the injury. Following a C4/5 over-hemisection injury the addition of skilled forelimb training actually reduced the gains found with robotic gait training alone. Not just gains within the training device, but also in independent overground locomotion. MRI imaging shows that skilled forelimb training reduces cellular activity, and reduces the organization of the axonal tracks at the injury site. This may be evidence that spared interneurons have limited resources and/or ability in establishing relay circuits to route supraspinal drive around the injury site. Skilled forelimb training and robotic gait training may not be synergistic, but competitive rehabilitative tasks. PMID- 28813845 TI - An assistance device to help people with trunk impairment maintain posture. AB - People with trunk impairment cannot lean forward because of the dysfunction of the trunk resulting from events such as cervical cord injury (CCI). It is therefore difficult for such people to work at a table because they may easily fall from their wheelchair, and it is also hard for them to return to their original position. This limits the activities of daily living (ADLs) of people with trunk impairment. These problems can be solved to some extent with equipment such as a wheelchair belt or a spinal orthosis that can help the person to maintain his or her posture. However, people cannot move freely with this equipment. Furthermore, if this equipment is used for a long time, there is a risk of physical pain and skin issues. In this study, we developed a device that assists the trunk of people with trunk impairment when they lean forward. This device supports people with trunk impairment so that they may take their meals at the table and prevents them from falling over their wheelchair without hindering their daily performance when they are sitting normally. The effectiveness of our proposed device was verified by experiments involving having a meal, operating a wheelchair, and colliding with a curb. Our device can help people with trunk impairment by improving their ADLs and quality of life (QOL). PMID- 28813846 TI - Closed-loop EMG-informed model-based analysis of human musculoskeletal mechanics on rough terrains. AB - This work aims at estimating the musculoskeletal forces acting in the human lower extremity during locomotion on rough terrains. We employ computational models of the human neuro-musculoskeletal system that are informed by multi-modal movement data including foot-ground reaction forces, 3D marker trajectories and lower extremity electromyograms (EMG). Data were recorded from one healthy subject locomoting on rough grounds realized using foam rubber blocks of different heights. Blocks arrangement was randomized across all locomotion trials to prevent adaptation to specific ground morphology. Data were used to generate subject-specific models that matched an individual's anthropometry and force generating capacity. EMGs enabled capturing subject- and ground-specific muscle activation patterns employed for walking on the rough grounds. This allowed integrating realistic activation patterns in the forward dynamic simulations of the musculoskeletal system. The ability to accurately predict the joint mechanical forces necessary to walk on different terrains have implications for our understanding of human movement but also for developing intuitive human machine interfaces for wearable exoskeletons or prosthetic limbs that can seamlessly adapt to different mechanical demands matching biological limb performance. PMID- 28813847 TI - A research on the postural stability of a person wearing the lower limb exoskeletal robot by the HAT model. AB - This paper proposes a method of detecting the postural stability of a person wearing the lower limb exoskeletal robot with the HAT(Head-Arm-Trunk) model. Previous studies have shown that the human posture is stable when the CoM(Center of Mass) of the human body is placed on the BoS(Base of Support). In the case of the lower limb exoskeletal robot, the motion data, which are used for the CoM estimation, are acquired by sensors in the robot. The upper body, however, does not have sensors in each segment so that it may cause the error of the CoM estimation. In this paper, the HAT(Head-Arm-Trunk) model which combines head, arms, and torso into a single segment is considered because the motion of head and arms are unknown due to the lack of sensors. To verify the feasibility of HAT model, the reflecting markers are attached to each segment of the whole human body and the exact motion data are acquired by the VICON to compare the COM of the full body model and HAT model. The difference between the CoM with full body and that with HAT model is within 20mm for the various motions of head and arms. Based on the HAT model, the XCoM(Extrapolated Center of Mass) which includes the velocity of the CoM is used for prediction of the postural stability. The experiment of making unstable posture shows that the XCoM of the whole body based on the HAT model is feasible to detect the instance of postural instability earlier than the CoM by 20-250 msec. This result may be used for the lower limb exoskeletal robot to prepare for any action to prevent the falling down. PMID- 28813848 TI - Preliminary assessment of a lower-limb exoskeleton controller for guiding leg movement in overground walking. AB - This paper describes the design, implementation, and preliminary validation of a controller for a powered lower-limb exoskeleton that reshapes a user's leg movement during over-ground walking. The intended application of the controller is to facilitate gait training for individuals suffering from post-stroke hemiparesis. The controller mimics a kinematic constraint between the knee and hip joints during the swing phase of gait, such that movement is not dependent on time (i.e., step time is determined entirely by the user). The controller additionally incorporates real-time path planning adjustment that allows step length to be adjusted by the user. As such, the controller provides movement coordination, but still enables a user to retain the step-to-step variability required to maintain balance during walking. As a preliminary assessment of efficacy, the controller was implemented on a lower limb exoskeleton and tested on a healthy subject, who walked at varying speeds without the use of a stability aid, with and without the proposed controller. The data indicates that the exoskeleton with controller provided the intended extent of movement coordination, while still allowing the subject to maintain walking balance. PMID- 28813849 TI - Effects of partial body-weight support and functional electrical stimulation on gait characteristics during treadmill locomotion: Pros and cons of saddle-seat type body-weight support. AB - Robotic therapy for rehabilitation of the lower extremity is currently in its early stage of development. Aiming at exploring an efficacious intervention for gait rehabilitation, we investigate the characteristics of an end-effector gait training device that combines saddle-seat-type body-weight-supported treadmill training with functional electrical stimulation (FES). This is a task-oriented approach to restoring voluntary control of locomotion in patients with neuromuscular diseases. We evaluate the differences between walking with saddle seat-type support and with harness-type support, in terms of personal preference, the preferred walking speed, profiles of kinematics and ground reaction force, and the effectiveness of FES. The results indicate that the proposed gait training device maintains subjects in a natural posture and supports important gait functions such as hip extension and ankle push-off effectively, in particular, at slow walking speed. PMID- 28813850 TI - Cross-wire assist suit concept, for mobile and lightweight multiple degree of freedom hip assistance. AB - In this paper, we present our cross-wire assist concept, for assisting a single joint in multiple degrees of freedom. It is comprised of four motor driven Bowden cable actuators (wires) per assisted joint, with the wires crossed over each other at the front and rear. Simulation results show that selectively actuating a subset of these wires allows torque to be generated in 6 directions, with the torque magnitude dependent on joint angle. We have built a fully wearable prototype of our assistance device for both hip joints, with 8 high-speed and independently controllable actuators each providing force up to 100 N. The prototype has a total mass of 9.3 kg, and is shown in motion capture testing to generate movement in 6 directions around the users joint, including internal and external rotation. Mobile, multi-degree of freedom assistance cross-wire system will enable assistive devices to better match human movement, allowing support and rehabilitation in tasks beyond straight line walking. PMID- 28813851 TI - Lokomat therapy in Colombia: Current state and cognitive aspects. AB - Neurological disorders frequently affect walking function which is one of the most fundamental skills to improve quality of life and autonomy, and Lokomat has been a key piece for gait's rehabilitation. In this study, a diagnosis about the development of the Robot-assisted therapy rehabilitation with Lokomat in Colombia is made. The study was performed by collecting some anthropometric and demographic data of the patients that use Lokomat, followed by a survey of cognitive aspects. With the purpose to compare the current state of the robotic therapies it was found that in Colombia the benefits of this treatment have not being fully exploited. Regarding the cognitive aspects, most of the patients that use Lokomat as a rehabilitation therapy feel comfortable (47%), very safe (68%) and have a perpective of significant results with the therapy (68%). However, when compared the number of patients in therapy with Lokomat with the number of the population that has gait disabilities, it is found that few Colombians have access to this type of therapy. PMID- 28813852 TI - Event-based control for sit-to-stand transition using a wearable exoskeleton. AB - Sit-to-stand transition is an essential step in a lower limb rehabilitation therapy, mainly for assisting the patient to transit from wheel chair to the next level of therapy. A mixed stiffness-damping control adaptation is proposed for this task which will help in reaching the final position with a constant velocity. A combination of control model is proposed to ensure the initiation and the final stage of the transition, such as to ensure stability and to maintain the equilibrium. The combined control model helps in reaching the goal position with equal participation from the user. For patient studies, such as with paraplegic patients, a combinational control model with muscle stimulation can be included to provide a complete assistance. The role of muscle stimulation and joint movement assistance is also considered in this control model. Further, final stage of this transition must ensure keeping or helping the user to maintain the upright position. PMID- 28813853 TI - Towards human-knee orthosis interaction based on adaptive impedance control through stiffness adjustment. AB - Rehabilitation interventions involving powered, wearable lower limb orthoses that can provide high-challenging locomotor tasks for repetitive training sessions, mainly when assist-as-needed strategies, such as adaptive impedance control, are designed. In this study, the adaptive behavior was ensured by software control of the robotic stiffness involved in the human-knee orthosis interaction in function of the gait cycle and speed. To estimate the stiffness, we analyzed the interaction torque-angle characteristics with experimental data. The speed stiffness dependency was more evident when high stiffness values are demanded by the user's effort. Experimental evidence from five healthy subjects highlight that the adaptive control strategy provides a more comfortable, natural motion, and kinematic freedom as compared to the trajectory tracking control, allowing the user to contribute to the gait training. Future insights cover the implementation of gravitational compensation and real-time estimation and control of all inner dynamic properties of the impedance control law. PMID- 28813854 TI - Automated stand-up and sit-down detection for robot-assisted body-weight support training with the FLOAT. AB - Patients with impaired walking function are often dependent on assistive devices to retrain gait and regain independence in life. To provide adequate support, gait rehabilitation devices have to be manually set to the correct support mode or have to recognize the type and starting point of a certain motion automatically. For automated motion type detection, machine learning-based classification algorithms using sensor signals from different body parts can achieve robust performance. However, until today, there is only little work available to detect motion onset. In this paper, we investigate task onset detection of sit-to-stand and stand-to-sit transitions. The focus of the current study is twofold: First, the optimal window size for the online classification algorithm shall be found. Second, the ideal sensor placement in a single sensor setup, to detect movement onset with shortest detection delays possible is of interest. For our investigations a linear discriminant analysis classifier, basic kinematic features, and a leave-one-subject-out cross validation are used. As a result, an average detection time of 56 milliseconds (SD 111) for sit-to-stand and 48 milliseconds (SD 137) for stand-to-sit were achieved with a window size of 15 and 35 milliseconds respectively at a data rate of 200 hertz. For sit-to-stand transitions, a sensor close to the tenth vertebra and for stand-to-sit transitions close to the posterior pelvis provided the smallest detection times. PMID- 28813855 TI - An optimized design of a parallel robot for gait training. AB - The guidelines for enhancing robot-assisted training for post-stroke survivors head towards increasing exercise realism and variability; in particular lower limb rehabilitation needs the patient to feel challenged to adapt his locomotion and dynamic balance capabilities to different virtual ground scenarios. This paper proposes a design for a robot whose end-effector acts as a footplate to be in permanent contact with the user's foot during practice: the structure is such that it enables the user's foot to rotate around three axis, differently from what is currently available in the research for gait training; the parallel kinematic structure and the dimensional synthesis allow a suitable range of motion and aim at limiting device mass, footprint and reaction forces on the actuators when rendering virtual ground. The employed methodology has been validated using ground reaction forces data relative to stroke survivors. PMID- 28813856 TI - Quantifying the benefit of the Kinetic Crutch Tip. AB - This research focuses on the difference between the Kinetic Crutch Tip (KCT) and a Standard Rubber Tip. Additionally, the effect of KCT stiffness on the crutch gait cycle and the reaction forces were investigated. This study also examined the maximum backward angle that a crutch is able to move forward without any external forces as well as the ratio of positive to negative horizontal forces were considered. The results were obtained in two ways: one by having subjects walk on the crutches and another to reduce the variability of human walking by measuring the resulting motion only using weights attached to the crutch tip. The results of this measurement indicate an increase in maximum backward angle for Kinetic Crutch Tips. This increase in the rotation angle shows an improvement in forward motion of the crutch. PMID- 28813857 TI - Kinematic effects of inertia and friction added by a robotic knee exoskeleton after prolonged walking. AB - The capabilities of robotic gait assistive devices are ever increasing; however, their adoption outside of the lab is still limited. A critical barrier for the functionality of these devices are the still unknown mechanical properties of the human leg during dynamic conditions such as walking. We built a robotic knee exoskeleton to address this problem. Here, we present the effects of our device on the walking pattern of four subjects. We assessed the effects after a short period of acclimation as well as after a 1.5h walking protocol. We found that the knee exoskeleton decreased (towards extension) the peak hip extension and peak knee flexion of the leg with the exoskeleton, while minimally affecting the non exoskeleton leg. Comparatively smaller changes occurred after prolonged walking. These results suggest that walking patterns attained after a few minutes of acclimation with a knee exoskeleton are stable for at least a couple of hours. PMID- 28813858 TI - Active impedance control of a knee-joint orthosis during swing phase. AB - In this paper, an active impedance control strategy for a knee-joint orthosis is proposed to assist individuals suffering from lower-limb muscular weaknesses during the swing phase of walking activities. The goal of the proposed strategy is to decrease the human effort required for ensuring a successful knee joint movement during walking without sacrificing the wearer's control priority. In this study, a gait-phase based desired knee-joint admittance model is designed by analyzing the kinematic and kinetic characteristics of the wearer's shank-foot segment during walking. Moreover, the mechanical impedance of the human/orthosis system is adapted to the desired one using an active impedance compensation. The control approach was implemented using a knee joint orthosis and tested with four healthy subjects. The EMG signals of the short head of the biceps femoris and the vastus medialis are used as metrics to evaluate the effectiveness of the proposed strategy. The experimental results show that the human effort can be significantly decreased when the wearers are assisted using the proposed approach. PMID- 28813859 TI - An assistive lower limb exoskeleton for people with neurological gait disorders. AB - Lower limb exoskeletons have already proven the capability to give back mobility to people suffering from spinal cord injury (SCI). Other important populations such as people with multiple sclerosis or muscular dystrophy, frail elderly and stroke victims, suffer from severe gait impairments and could benefit from similar technology. The work presented in the current paper describes a novel design of a 6-actuated degrees of freedom (DOFs) assistive lower limb exoskeleton for people with moderate mobility impairments. The electrical actuators are all remotely located on the back of the user for a more compact design with high dynamics. Cable driven solutions are used to transmit the flexion/extension of the hip and knee joints, while a powerful ballscrew carries out the hip adduction/abduction. The design of this exoskeleton, named AUTONOMYO, follows the key specifications of being highly back-drivable and able to perform dynamic motions at low energy consumption. AUTONOMYO is capable to assist the user's balance by providing complementary torques at the hip and the knee. Results show that the projected level of assistance for sit-to-stand transition varies from 50% to 100% in function of the user's bodyweight and height while higher level of assistance are reached for walking and stairs climbing activities. PMID- 28813860 TI - Design and evaluation of a modular lower limb exoskeleton for rehabilitation. AB - This paper deals with the evaluation of an exoskeleton designed for assisting individuals to rehabilitate compromised lower limb movements resulting from stroke or incomplete spinal cord injury. The exoskeleton is composed of lightweight tubular structures and six free joints that provide a modular feature to the system. This feature allows the exoskeleton to be adapted to assist the movement of one or more patient joints. The actuation of the exoskeleton is also modular, and can be performed passively, by means of springs and dampers, or actively through actuators. In addition, its telescopic tubular links, developed to adjust the size of the links in order to align the joints of the exoskeleton with patient joints, allows the exoskeleton to be adjustable to fit different patients. Experiments considering the interaction between a healthy subject and the exoskeleton are performed to evaluate the influence of the exoskeleton structure on kinematic and muscular activity profiles during walking. PMID- 28813861 TI - Exoskeleton for gait rehabilitation of children: Conceptual design. AB - This paper presents the conceptual design of an exoskeleton for gait rehabilitation of children. This system has electronics, mechanicals and software sections, which are implemented and tested using a mannequin of a child. The prototype uses servomotors to move robotic joints that are attached to simulated patient's legs. The design has 4 DOF (degrees of freedom) two for hip joints and other two for knee joints, in the sagittal plane. A microcontroller measures sensor signals, controls motors and exchanges data with a computer. The user interacts with a graphical interface to configure, control and monitor the exoskeleton activities. The laboratory tests show soften movements in joint angle tracking. PMID- 28813862 TI - On the stiffness analysis of a cable driven leg exoskeleton. AB - Robotic systems are being used for gait rehabilitation of patients with neurological disorder. These devices are externally powered to apply external forces on human limbs to assist the leg motion. Patients while walking with these devices adapt their walking pattern in response to the applied forces. The efficacy of a rehabilitation paradigm thus depends on the human-robot interaction. A cable driven leg exoskeleton (CDLE) use actuated cables to apply external joint torques on human leg. Cables are lightweight and flexible but can only be pulled, thus a CDLE requires redundant cables. Redundancy in CDLE can be utilized to appropriately tune a robot's performance. In this work, we present the stiffness analysis of CDLE. Different stiffness performance indices are established to study the role of system parameters in improving the human-robot interaction. PMID- 28813863 TI - Comparison of kinematic and EMG parameters between unassisted, fixed- and adaptive-stiffness robotic-assisted ankle movements in post-stroke subjects. AB - In this paper, we present an assist-as-needed scheme that effectively adapted the assistance provided by an ankle rehabilitation robot according to patient's participation and performance during therapeutic movements. We performed an error based estimation of the ankle impedance as a valid measure of the patient participation. Then, we computed the amount of robotic assistance by three steps: normalization of the combined patient-robot stiffness, optimization of patientrobot interaction, and finally, adaptation of the level of the robotic assistance according to patient's performance while playing a serious game. Four post-stroke patients evaluated our methodology using an impedance controlled robotic system to assist alternated open-ended dorsi/plantarflexion movements in sitting position. Experimental results indicated that the proposed adaptive stiffness method improves patient participation and performance compared to a fixed-stiffness assistive method and to an unassisted baseline. We also found that adaptive assistance could optimize the patient's muscular activity during movements. Our strategy effectively assisted with a lower stiffness allowing more kinematic variability in motions leaded by patient, decreasing the total amount of provided assistance without compromising the overall performance during therapy. PMID- 28813864 TI - Gait assessment system based on novel gait variability measures. AB - In this paper, a novel gait assessment system based on measures of gait variability reflected through the variability of shapes of gait cycles trajectories is proposed. The presented gait assessment system is based on SVM (support vector machine) classifier and on gait variability-based features calculated from the hip and knee joint angle trajectories recorded using wearable IMUs during walking trials. A system classifier was trained to distinguish healthy gait patterns from the pathological ones. The features were extracted by calculating the distances between the joint trajectories of the individual gait cycles using 4 different distance functions. As result, the system is able to provide a Gait Variability Index (GVI), which is a numeric value that can be used as an indicator of a degree to which a pathological gait pattern is close to a healthy gait pattern. The system and GVI were tested in three experiments, involving subjects suffering from gait disorders caused by different neurological diseases. The results demonstrated that the proposed gait assessment system would be suitable for supporting clinicians in the evaluation of gait performances during the gait rehabilitation procedures. PMID- 28813865 TI - Template model inspired leg force feedback based control can assist human walking. AB - We present a novel control approach for assistive lower-extremity exoskeletons. In particular, we implement a virtual pivot point (VPP) template model inspired leg force feedback based controller on a lower-extremity powered exoskeleton (LOPES II) and demonstrate that it can effectively assist humans during walking. It has been shown that the VPP template model is capable of stabilizing the trunk and reproduce a human-like hip torque during the stance phase of walking. With leg force and joint angle feedback inspired by the VPP template model, our controller provides hip and knee torque assistance during the stance phase. A pilot experiment was conducted with four healthy subjects. Joint kinematics, leg muscle electromyography (EMG), and metabolic cost were measured during walking with and without assistance. Results show that, for 0.6 m/s walking, our controller can reduce leg muscle activations, especially for the medial gastrocnemius (about 16.0%), while hip and knee joint kinematics remain similar to the condition without the controller. Besides, the controller also reduces 10% of the net metabolic cost during walking. This paper demonstrates walking assistance benefits of the VPP template model for the first time. The support of human walking is achieved by a force feedback of leg force applied to the control of hip and knee joints. It can help us to provide a framework for investigating walking assistance control in the future. PMID- 28813866 TI - A single session of perturbation-based gait training with the A-TPAD improves dynamic stability in healthy young subjects. AB - Gait and balance disorders are among the most common causes of falls in older adults. Most falls occur as a result of unexpected hazards while walking. In order to improve the effectiveness of current fall-prevention programs, new balance training paradigms aim to strengthen the control of the compensatory responses required after external perturbations. The aim of this study was to analyze the adaptions of reactive and proactive strategies to control stability after repeated exposures to waist-pull perturbations delivered while walking. Eight healthy young subjects participated in a single training session with the Active Tethered Pelvic assisted Device (A-TPAD). Participants were exposed to repeated multi-directional perturbations of increasing intensity. The Antero Posterior (AP) and Medio-Lateral (ML) Base of Support (BoS) and Margin of Stability (MoS) during the response to diagonal perturbations were compared before and after the training. Results showed that participants adapted both the reactive and proactive strategies to control walking balance by significantly increasing their pre- and post-perturbation stability. The changes were principally accounted for by an increment of the AP BoS and MoS and a reduction of ML BoS. This improved their ability to react to a diagonal perturbation. We envision that this system can be used to develop a perturbation-based gait training aimed at improving balance and control of stability during walking, thus reducing fall risk. PMID- 28813867 TI - Therapeutic effects of anti-gravity treadmill (AlterG) training on reflex hyper excitability, corticospinal tract activities, and muscle stiffness in children with cerebral palsy. AB - We aimed to study therapeutic effects of antigravity treadmill (AlterG) training on reflex hyper-excitability, muscle stiffness, and corticospinal tract (CST) function in children with spastic hemiplegic cerebral palsy (CP). Three children received AlterG training 3 days per week for 8 weeks as experimental group. Each session lasted 45 minutes. One child as control group received typical occupational therapy for the same amount of time. We evaluated hyper-excitability of lower limb muscles by H-reflex response. We quantified muscle stiffness by sonoelastography images of the affected muscles. We quantified CST activity by transcranial magnetic stimulation (TMS). We performed the evaluations before and after training for both groups. H response latency and maximum M-wave amplitude were improved in experimental group after training compared to control group. Two children of experimental group had TMS response. Major parameters of TMS (i.e. peak-to-peak amplitude of motor evoked potential (MEP), latency of MEP, cortical silent period, and intensity of pulse) improved for both of them. Three parameters of texture analysis of sonoelastography images were improved for experimental group (i.e. contrast, entropy, and shear wave velocity). These findings indicate that AlterG training can improve reflexes, muscle stiffness, and CST activity in children with spastic hemiplegic CP and can be considered as a therapeutic tool to improve neuromuscular abnormalities occurring secondary to CP. PMID- 28813868 TI - Relationship between assistive torque and knee biomechanics during exoskeleton walking in individuals with crouch gait. AB - Crouch or "flexed knee" gait is a pathological gait pattern affecting many individuals with cerebral palsy. One proposed method to alleviate crouch is to provide robotic assistance to knee extension during walking. The purpose of this study was to evaluate how the magnitude of knee extensor torque affects knee kinematics, kinetics, and muscle activity. Motion capture, ground reaction force and electromyography data were collected while four participants with crouch gait from cerebral palsy walked with assistance from a novel robotic exoskeleton on an instrumented treadmill. Different magnitudes of knee extensor torque were provided during the stance (range: 0.09-0.38 Nm/kg) and swing (range: 0.09-0.29 Nm/kg) phases of the gait cycle. Using a linear regression analysis, we found that greater torque from the exoskeleton was positively associated with increased knee extension (reduction in crouch) at foot contact and mid-stance, negatively associated with the biological knee extensor moment, and positively associated with knee flexor muscle activity. Determining the relationships between exoskeleton assistance and knee kinematics and kinetics will benefit the continued investigation of robotic treatment strategies for treating crouch gait. Our findings indicate the importance of properly tuned robotic control strategies for gait rehabilitation. PMID- 28813869 TI - Effects of assistance timing on metabolic cost, assistance power, and gait parameters for a hip-type exoskeleton. AB - There are many important factors in developing an exoskeleton for assisting human locomotion. For example, the weight should be sufficiently light, the assist torque should be high enough to assist joint motion, and the assistance timing should be just right. Understanding how these design parameters affect overall performance of a complex human-machine system is critical for the development of these types of systems. The present study introduces an assistance timing controller that regulates assistance timing such that peak joint velocity and peak assistance power are offset by a reference value for our hip-type exoskeleton. This is followed by measuring the manner in which various assistance timing references affect an important metric for performance, namely metabolic cost. The results indicate that net metabolic cost exhibits a concave up pattern with the most reduction of 21%, when compared to walking without the exoskeleton, at 0% assistance timing reference. The study also examines assistance timing's effect on gait parameters; increase in assistance timing reference increases step length, decreases cadence, and increases walk ratio (i.e. step length/cadence ratio) during treadmill walking. PMID- 28813870 TI - Upper limb training/assessment program using passive force controllable rehabilitation system. AB - Upper limb rehabilitation training for Hemiplegie patients has been conducted mainly by human therapists. Training methods and conditions depend strongly on their experience because of the wide range of individual differences between patients. The force control and sensing functions of rehabilitation robots are expected to be used for the qualitative assessment of next-generation computational rehabilitation. In this study, we developed a simple exercise machine for upper limbs (SEMUL) using an electro-rheological fluid brake, as a safe brake-type robotic rehabilitation system. We also developed a new upper limb training/assessment program, called "WIPE," for the SEMUL. Furthermore, we conducted clinical tests on twelve subjects (six each for the SEMUL training and for general training). We adopted the ABA design methodology for the clinical research tests. The motor functions of upper limbs were assessed using five clinical scores: Fugl-Meyer Assessment (FMA), Brunnstrome recovery stage, Simple Test for Evaluating Hand Function (STEF), Stroke Impairment Assessment Set (SIAS), and Motor Activity Log. Improvements of the FMA, STEF, and SIAS in the SEMUL training groups were found to be higher than those in the general training groups. PMID- 28813871 TI - Clinical effectiveness of combined virtual reality and robot assisted fine hand motion rehabilitation in subacute stroke patients. AB - Robot-assisted therapy is regarded as an effective and reliable method for the delivery of highly repetitive rehabilitation training in restoring motor skills after a stroke. This study focuses on the rehabilitation of fine hand motion skills due to their vital role in performing delicate activities of daily living (ADL) tasks. The proposed rehabilitation system combines an adaptive assist-as needed (AAN) control algorithm and a Virtual Reality (VR) based rehabilitation gaming system (RGS). The developed system is described and its effectiveness is validated through clinical trials on a group of eight subacute stroke patients for a period of six weeks. The impact of the training is verified through standard clinical evaluation methods and measuring key kinematic parameters. A comparison of the pre- and post-training results indicates that the method proposed in this study can improve fine hand motion rehabilitation training effectiveness. PMID- 28813872 TI - MIT-Skywalker: Evaluating comfort of bicycle/saddle seat. AB - The MIT-Skywalker is a robotic device developed for the rehabilitation of gait and balance after a neurological injury. This device has been designed based on the concept of a passive walker and provides three distinct training modes: discrete movement, rhythmic movement, and balance training. In this paper, we present our efforts to evaluate the comfort of a bicycle/saddle seat design for the system's novel actuated body weight support device. We employed different bicycle and saddle seats and evaluated comfort using objective and subjective measures. Here we will summarize the results obtained from a study of fifteen healthy subjects and one stroke patient that led to the selection of a saddle seat design for the MIT-Skywalker. PMID- 28813873 TI - Automation of motor dexterity assessment. AB - Motor dexterity assessment is regularly performed in rehabilitation wards to establish patient status and automatization for such routinary task is sought. A system for automatizing the assessment of motor dexterity based on the Fugl-Meyer scale and with loose restrictions on sensing technologies is presented. The system consists of two main elements: 1) A data representation that abstracts the low level information obtained from a variety of sensors, into a highly separable low dimensionality encoding employing t-distributed Stochastic Neighbourhood Embedding, and, 2) central to this communication, a multi-label classifier that boosts classification rates by exploiting the fact that the classes corresponding to the individual exercises are naturally organized as a network. Depending on the targeted therapeutic movement class labels i.e. exercises scores, are highly correlated-patients who perform well in one, tends to perform well in related exercises-; and critically no node can be used as proxy of others - an exercise does not encode the information of other exercises. Over data from a cohort of 20 patients, the novel classifier outperforms classical Naive Bayes, random forest and variants of support vector machines (ANOVA: p < 0.001). The novel multi-label classification strategy fulfills an automatic system for motor dexterity assessment, with implications for lessening therapist's workloads, reducing healthcare costs and providing support for home-based virtual rehabilitation and telerehabilitation alternatives. PMID- 28813874 TI - Effect of human-robot interaction on muscular synergies on healthy people and post-stroke chronic patients. AB - Robot-assisted training is a widely used technique to promote motor re-learning on post-stroke patients that suffer from motor impairment. While it is commonly accepted that robot-based therapies are potentially helpful, strong insights about their efficacy are still lacking. The motor re-learning process may act on muscular synergies, which are groups of co-activating muscles that, being controlled as a synergic group, allow simplifying the problem of motor control. In fact, by coordinating a reduced amount of neural signals, complex motor patterns can be elicited. This paper aims at analyzing the effects of robot assistance during 3D-reaching movements in the framework of muscular synergies. 5 healthy people and 3 neurological patients performed free and robot-assisted reaching movements at 2 different speeds (slow and quasi-physiological). EMG recordings were used to extract muscular synergies. Results indicate that the interaction with the robot very slightly alters healthy people patterns but, on the contrary, it may promote the emergency of physiological-like synergies on neurological patients. PMID- 28813875 TI - Rehabilitation for hemiplegia using an upper limb training system based on a force direction. AB - Hemiplegia patients have complete paralysis of half their body, and encounter many challenges in living an independent life. Rehabilitation of the lower body is more important than that of the upper body for independent living; thus, recovering upper body functions of their paralyzed side is not enough. Rehabilitation robots may be used to assist training without therapists. In this study, a small portable rehabilitation robot was developed for use at home, and a new training method was proposed. This robot consists on an omni wheel mechanism and a force sensor, and is capable of deciding the motion based on the force value. Voluntary movement of a hemiplegia patient is recovered by the rehabilitation robot and proposed training method. Thus, verification experiments were performed using participants with hemiplegia. The CCI (Co-Contraction Index) from after training were smaller than ones of before training, thus the movement skills of the participants improved with respect to controlling force direction and magnitude. Moreover, manual function test (MFT) scores increased as reflected by improvements in the motor function of the upper limb using the proposed training method. PMID- 28813876 TI - Design, control and validation of the variable stiffness exoskeleton FLExo. AB - In this paper we present the design of a one degree of freedom assistive platform to augment the strength of upper limbs. The core element is a variable stiffness actuator, closely reproducing the behavior of a pair of antagonistic muscles. The novelty introduced by this device is the analogy of its control parameters with those of the human muscle system, the threshold lengths. The analogy can be obtained from a proper tuning of the mechanical system parameters. Based on this, the idea is to control inputs by directly mapping the estimation of the muscle activations, e.g. via ElectroMyoGraphic(EMG) sensors, on the exoskeleton. The control policy resulting from this mapping acts in feedforward in a way to exploit the muscle-like dynamics of the mechanical device. Thanks to the particular structure of the actuator, the exoskeleton joint stiffness naturally results from that mapping. The platform as well as the novel control idea have been experimentally validated and the results show a substantial reduction of the subject muscle effort. PMID- 28813878 TI - Randomized, sham-controlled trial based on transcranial direct current stimulation and wrist robot-assisted integrated treatment on subacute stroke patients: Intermediate results. AB - The main goal of this study is to analyse the effects of combined transcranial direct current stimulation (tDCS) and wrist robot-assisted therapy in subacute stroke patients. Twenty-four patients were included in this study and randomly assigned to the experimental (EG) or control group (CG). All participants performed wrist robot-assisted training a) in conjunction with tDCS (real stimulation for patients in EG) or b) without tDCS (sham stimulation for patients in CG). Clinical scales and kinematic parameters recorded by the robot were used for the assessment. Clinical outcome measures show a significant decrease in motor impairment after the treatment in both groups. Kinematic data show several significant improvements after the integrated therapy in both groups. However, no significant differences in both clinical outcome measures and kinematic parameters was found between two groups. The potential advantages of combined tDCS and wrist robot-assisted therapy in subacute stroke patients are still unclear. PMID- 28813877 TI - Capture, learning, and classification of upper extremity movement primitives in healthy controls and stroke patients. AB - There currently exist no practical tools to identify functional movements in the upper extremities (UEs). This absence has limited the precise therapeutic dosing of patients recovering from stroke. In this proof-of-principle study, we aimed to develop an accurate approach for classifying UE functional movement primitives, which comprise functional movements. Data were generated from inertial measurement units (IMUs) placed on upper body segments of older healthy individuals and chronic stroke patients. Subjects performed activities commonly trained during rehabilitation after stroke. Data processing involved the use of a sliding window to obtain statistical descriptors, and resulting features were processed by a Hidden Markov Model (HMM). The likelihoods of the states, resulting from the HMM, were segmented by a second sliding window and their averages were calculated. The final predictions were mapped to human functional movement primitives using a Logistic Regression algorithm. Algorithm performance was assessed with a leave-one-out analysis, which determined its sensitivity, specificity, and positive and negative predictive values for all classified primitives. In healthy control and stroke participants, our approach identified functional movement primitives embedded in training activities with, on average, 80% precision. This approach may support functional movement dosing in stroke rehabilitation. PMID- 28813879 TI - Interaction force and motion estimators facilitating impedance control of the upper limb rehabilitation robot. AB - In order to enhance the performance of rehabilitation robots, it is imperative to know both force and motion caused by the interaction between user and robot. However, common direct measurement of both signals through force and motion sensors not only increases the complexity of the system but also impedes affordability of the system. As an alternative of the direct measurement, in this work, we present new force and motion estimators for the proper control of the upper-limb rehabilitation Universal Haptic Pantograph (UHP) robot. The estimators are based on the kinematic and dynamic model of the UHP and the use of signals measured by means of common low-cost sensors. In order to demonstrate the effectiveness of the estimators, several experimental tests were carried out. The force and impedance control of the UHP was implemented first by directly measuring the interaction force using accurate extra sensors and the robot performance was compared to the case where the proposed estimators replace the direct measured values. The experimental results reveal that the controller based on the estimators has similar performance to that using direct measurement (less than 1 N difference in root mean square error between two cases), indicating that the proposed force and motion estimators can facilitate implementation of interactive controller for the UHP in robotmediated rehabilitation trainings. PMID- 28813880 TI - Series elastic actuation of an elbow rehabilitation exoskeleton with axis misalignment adaptation. AB - Powered exoskeletons can facilitate rehabilitation of patients with upper limb disabilities. Designs using rotary motors usually result in bulky exoskeletons to reduce the problem of moving inertia. This paper presents a new linearly actuated elbow exoskeleton that consists of a slider crank mechanism and a linear motor. The linear motor is placed beside the upper arm and closer to shoulder joint. Thus better inertia properties can be achieved while lightweight and compactness are maintained. A passive joint is introduced to compensate for the exoskeleton elbow misalignment and intersubject size variation. A linear series elastic actuator (SEA) is proposed to obtain accurate force and impedance control at the exoskeleton-elbow interface. Bidirectional actuation between exoskeleton and forearm is verified, which is required for various rehabilitation processes. We expect this exoskeleton can provide a means of robot-aided elbow rehabilitation. PMID- 28813881 TI - Simulation of variable impedance as an intervention for upper extremity motor exploration. AB - Current methods in robot-assisted therapy are limited in providing predictions of the effectiveness of interventions. Our approach focuses on how robotic interaction can impact the distribution of movements expressed in the arm. Using data from a previous study with stroke survivors (n=10), we performed simulations to examine how changes in hand endpoint impedance would alter exploratory motion. We present methods for designing a custom training intervention, by relating the desired change in acceleration covariance in planar motion with a corresponding change in inertia matrix. We first characterized motor exploration in terms of overall covariance in acceleration, and secondly as covariance that varies with position in the workspace. Using a forward dynamics simulation of the hand endpoint impedance, we found that the variable change in endpoint inertia resulted in better recovery of acceleration covariance compared to the fixed change in inertia method. These results could significantly impact rehabilitation firstly in terms of design principles for altering coordination patterns through direct assistance. Furthermore, our work might serve to improve therapy by facilitating access to repeated practice of independent joint motion. PMID- 28813883 TI - Development of a series wrapping cam mechanism for energy transfer in wearable arm support applications. AB - An estimated 17 million individuals suffer a stroke each year with over 5 million resulting in permanent disability. For many of these, the provision of gravity support to the impaired upper limb can provide significant and immediate improvement in arm mobility. This added mobility has the potential to improve arm function and user independence overall, but, so far, wearable arm supports have found only limited uptake by end-users. The reasons are unclear, but it is hypothesized that device uptake is strongly affected by aspects of arm support implementation such as added weight and volume and the effectiveness of the support provided. In the interest of reducing the size and visibility of wearable arm supports, cable driven actuation was investigated, and a device called the series wrapping cam was developed. This device uses two wrapping cams to stretch a spring as the user's arm elevation decreases. It optimally uses the range of motion of a custom latex spring in a compact mechanism. A one degree-of-freedom proof-of-concept prototype of the series wrapping cam was manufactured and tested. The torque supplied by the prototype correctly responds to shoulder elevation to balance the weight of the extended arm at any level of elevation. However, the support is unaffected by the degree of elbow flexion-extension. Shoulder joint torque is a function of both shoulder elevation and elbow flexion, suggesting further benefits could be achieved through a bi-articular design. PMID- 28813882 TI - Validation of the efficiency of a robotic rehabilitation training system for recovery of severe plegie hand motor function after a stroke. AB - We have developed a rehabilitation training system called the Useful and Ultimate Rehabilitation System PARKO (UR System PARKO) to promote the recovery of motor function of the severe chronic plegic hand of stroke patients. This system was equipped with two functions to realize two conditions: (1) fixing of all fingers to a hyperextended position and (2) extending the elbow joint while applying resistance load to the fingertips. A clinical test was conducted with two patients to determine the therapeutic effect of the UR System PARKO for severe plegic hand. In both patients, the active ranges of motion of finger extension improved after training with the UR System PARKO. Moreover, the Modified Ashworth scale scores of finger extension increased. Thus, training reduced the spastic paralysis. These results suggest the effectiveness of training with the UR System PARKO for recovery of motor function as reflected in the finger extension of the severe plegic hand. PMID- 28813884 TI - Design parameters and torque profile modification of a spring-assisted hand opening exoskeleton module. AB - There is a growing demand for functional rehabilitation orthotics that can effectively assist in patient recovery from motor impairments after stroke. The hand in particular is a complex system that has proven difficult to mimic with current exoskeleton technologies. This paper presents data-driven design parameters to increase the functionality and improve the assistance profile of the ArmAssist-2.0 hand module. Improvements from the previous model include adjustable linkages to fulfill the largest population of users, new joint locations to more accurately represent biomechanics of the hand, and a more impairment-appropriate torque profile to assist in hand opening, adjustable through interchangeable springs. In most passive hand orthoses, assistance forces tend to decrease as the hand and thumb extend, opposite the needs of a typical patient hand. This project utilizes a variable spring moment arm about the revolute axes to match common patient impairment more accurately. The revised assistance profile for the hand maintains a nearly linear relationship. Results conclude that the final assembled device fits comfortably in the hand with noticeable improvements in joint locations, adjustability, and the force profile for the metacarpophalangeal (MCP) joint. An issue arises with the extension of the proximal interphalangeal (PIP) joint due to the nature of rapidly changing moment arms and multiple springs in series. The issue and possible solutions are discussed. PMID- 28813885 TI - The effect of robot dynamics on smoothness during wrist pointing. AB - The improvement of movement smoothness over the course of therapy is one of the positive outcomes observed during robotic rehabilitation. Although movements are generally robust to disturbances, certain perturbations might disrupt an individual's ability to produce these smooth movements. In this paper, we explore how a rehabilitation robot's inherent dynamics impact movement smoothness during pointing tasks. Able-bodied participants made wrist pointing movements under four different operating conditions. Despite the relative transparency of the device, inherent dynamic characteristics negatively impacted movement smoothness. Active compensation for Coulomb friction effects failed to mitigate the degradation in smoothness. Assessment of movements that involved coupled motions of the robot's joints reduced the bias seen in single degree of freedom movements. When using robotic devices for assessment of movement quality, the impact of the inherent dynamics must be considered. PMID- 28813886 TI - Exploratory design of a compliant mechanism for a dynamic hand orthosis: Lessons learned. AB - This study does not describe a success-story. Instead, it describes an exploratory process and the lessons learned while designing a compliant mechanism for a dynamic hand orthosis. Tools from engineering optimization and rapid prototyping techniques were used, with the goal to design a mechanism to compensate for hypertonic or contracted finger muscles. Results show that the mechanism did not reach its design constraints, mostly because it could not provide for the necessary stiffness and compliance at the same time. Hence, the presented approach is more suited for design problems with either lower forces or less displacement. It was concluded that physiological stiffness models are an important part when modeling hand orthoses. Moreover, further research on compliant mechanisms in dynamic hand orthoses should focus on the feasibility of implementing more complex three-dimensional shapes, i.e., compliant shell mechanisms. PMID- 28813887 TI - The effects of age and amplitude on wrist proprioceptive acuity. AB - This study examined wrist proprioception in a cross-sectional sample of 44 children aged between 8-to 14-years and a control group of 10 neurologically and physically healthy adults. Using a 3-degrees of freedom robotic device, participants performed an ipsilateral joint position matching task in which target amplitude (40% or 80% functional range of motion [fRoM]) and degrees-of freedom (Flexion/Extension [FE], Radial/Ulnar deviation [RUD], Pronation/Supination [PS]) were manipulated. Results indicated that proprioceptive function became more accurate and consistent over the developmental spectrum, but that the ability to utilize proprioceptive feedback did not reach adult levels till the age of 10-11 years. Furthermore, proprioceptive acuity was influenced by target amplitude, such that movements were more accurate for the 80% fROM compared to the 40% fROM target for both the RUD and PS DoFs, independently of age. The present results provide critical information about the typical development of wrist proprioception that will enable clinicians to chart the course of development and dysfunction in neurological disorders in children, and help establish protocols for the robotic diagnosis and assessment of neurodevelopmental disorders. PMID- 28813888 TI - Fully embedded myoelectric control for a wearable robotic hand orthosis. AB - To prevent learned non-use of the affected hand in chronic stroke survivors, rehabilitative training should be continued after discharge from the hospital. Robotic hand orthoses are a promising approach for home rehabilitation. When combined with intuitive control based on electromyography, the therapy outcome can be improved. However, such systems often require extensive cabling, experience in electrode placement and connection to external computers. This paper presents the framework for a stand-alone, fully wearable and real-time myoelectric intention detection system based on the Myo armband. The hard and software for real-time gesture classification were developed and combined with a routine to train and customize the classifier, leading to a unique ease of use. The system including training of the classifier can be set up within less than one minute. Results demonstrated that: (1) the proposed algorithm can classify five gestures with an accuracy of 98%, (2) the final system can online classify three gestures with an accuracy of 94.3% and, in a preliminary test, (3) classify three gestures from data acquired from mildly to severely impaired stroke survivors with an accuracy of over 78.8%. These results highlight the potential of the presented system for electromyography-based intention detection for stroke survivors and, with the integration of the system into a robotic hand orthosis, the potential for a wearable platform for all day robot-assisted home rehabilitation. PMID- 28813889 TI - Design of a clinically relevant upper-limb exoskeleton robot for stroke patients with spasticity. AB - The purpose of this research is to propose a design of a clinically relevant upper-limb (hand, wrist, and elbow) exoskeleton that meets the clinical requirements. At first, the proposed robot was designed to have sufficient torque for passive exercise therapy and spasticity measurement of post-stroke patients with spasticity (grade 3 or lower in Modified Ashworth Scale). Because the therapy of patients with high level spasticity could be laborious for therapists by increased muscle tone, and the patients tend not to get enough rehabilitation treatment. Secondly, this robot was designed to have user friendly features like as modularity, so that users have easy approach to assemble and disassemble for practical use. Thirdly, this robot system was designed to guarantee the safety for robot-aided passive training of patients with spasticity. As a result, we were able to see the usability of the robot system, even though it was a pilot test. This shows the possibility of measuring and classifying the spasticity. PMID- 28813890 TI - Online adaptive assistance control in robot-based neurorehabilitation therapy. AB - Repetitive and task specific robot-based rehabilitation has been proved to be effective for motor recovery over time. During a therapy, the task should improve subject's impaired movements, but also enhance their efforts for a more effective recovery. This requires an accurate tuning of the task difficulty, which should be tailored directly to the patient. In this work, we propose a system for real time assistance adaptation based on online performance evaluation for post-stroke subjects. In particular, the aim of the system is to implement the "assist-as needed" paradigm based on actual patients' motor skills during a therapy session with an active upper-limb robotic exoskeleton. The strength of the work is to propose a real-time algorithm for the assistance tuning based on an "assistance performance" relationship. Such a relationship is based on experimental measurements, and allows the algorithm to compute a straightforward calculation of the assistance required. Finally, an assessment phase will show how the system provides assistance based on the difficulties experienced from the subjects, also facilitating their adaptation during the task. PMID- 28813891 TI - Quantitative assessment of paretic limb dexterity and interlimb coordination during bilateral arm rehabilitation training. AB - In neuro-rehabilitation after stroke, the conventional constrained induced movement therapy (CIMT) has been well-accepted. Existing bilateral trainings are mostly on mirrored symmetrical motion. However, complementary bilateral movements are dominantly involved in activities of daily living (ADLs), and functional bilateral therapies may bring better skill transfer from trainings to daily life. Neurophysiological evidence is also growing. In this work, we firstly introduce our bilateral arm training system realized with a haptic interface and a motion sensor, as well as the tasks that have been designed to train both the manipulation function of the paretic arm and coordination of bilateral upper limbs. Then, we propose quantitative measures for functional assessment of complementary bilateral training performance, including kinematic behavior indices, smoothness, submovement and bimanual coordination. After that, we describe the experiments with healthy subjects and the results with respect to these quantitative measures. Feasibility and sensitivity of the proposed indices were evaluated through comparison of unilateral and bilateral training outcomes. The proposed bilateral training system and tasks, as well as the quantitative measures, have been demonstrated effective for training and assessment of unilateral and bilateral arm functions. PMID- 28813893 TI - Utilization of kinematical redundancy of a rehabilitation robot to produce compliant motions under limitation on actuator performance. AB - This paper addresses the mechanical structure and control method of a redundant drive robot (RDR) to produce compliant motions, and show how the design parameters of the RDR can effect the produced motions and the mechanical and performance limitations of the actuators of the RDR. The structure and control method of the RDR can have been proper to produce compliant motions, but the effect of the design parameters of the RDR to the mechanical and performance limitations have not been clear. Therefore, the feasibility of producing compliant motions in the case of the prototype of the RDR is confirmed by conducting simulations and experiments, and then the design parameters of the RDR to the mechanical and performance limitations are verified by conducting simulations. PMID- 28813892 TI - Comparison of two difficulty adaptation strategies for competitive arm rehabilitation exercises. AB - This paper presents two different strategies for difficulty adaptation in a competitive arm rehabilitation game: a manual adaptation strategy and an automatic performance-based adaptation strategy. The two strategies were implemented in a competitive game controlled with an inertial-sensor-based home rehabilitation device. They were first evaluated with 32 pairs of unimpaired participants, who played the game with manual adaptation, automated adaptation, or no adaptation. Each variant was played for 9 minutes. Then, the manual and automatic adaptation were also tested by 5 pairs consisting of a person with arm impairment (due to neurological injury) and their unimpaired friend or relative. Throughout the game, motivation was measured with questionnaires while exercise intensity was tracked using the inertial sensors. Results showed that both manual and automatic difficulty adaptation lead to higher motivation and exercise intensity than no adaptation. Unimpaired participants showed no clear preference between manual and automatic adaptation while 4 of 5 impaired participants preferred automatic adaptation. For future use, we propose a combination of manual and automatic adaptation that should be evaluated with more impaired participants in longer multisession experiments. PMID- 28813894 TI - Validity of a sensor-based table-top platform to measure upper limb function. AB - Objective measurement is an essential part of the assessment process in neurological dysfunction such as stroke. However, current clinical scores are insensitive and based on subjective observation from experts. Technology provides an opportunity for enhanced accuracy and specificity of objective measurement. This study describes the use of an interactive force-sensitive table-top platform for the assessment of reach in post-stroke patients, admitted as part of a three week intensive upper limb training programme. Objective measures from the reachable workspace were extracted and included normalised reach distance, normalised reached speed and reach dragging. The data was compared to standardised Fugl-Meyer (FM) clinical scores, recorded at admission (FMPRE) and discharge (FMPOST). Results indicate strong relationships between the three objective measures and subjective FM scores, with significant Spearman correlations found in all cases (|rho| > 0.5, p < 0.05). The results highlight the validity for a sensor-based table-top system to provide a simple, flexible, and objective platform for assessment of impaired upper limb motor function. PMID- 28813895 TI - Customized therapy using distributions of reaching errors. AB - While there has been recent success with robotic therapy approaches, individual differences in motor impairments motivate the need for customized therapy. Our latest work with healthy participants considered the likelihood of one's error to construct a customized force field training environment, which we termed an error field. We believe error statistics could characterize individual motor impairments for stroke survivors. Here we present preliminary results from a pilot study testing this therapy technique on individuals following stroke. We tracked the changes in error for three stroke survivors across multiple days using error field training, and found that participants' errors reduced for all target directions across sessions. We also used a modeling approach to test whether the changes in error reflected the specific mathematical structure of the intervention. These results provide encouraging preliminary evidence that error field training can be valuable for both characterizing deficits and custom tailoring therapy. PMID- 28813896 TI - Nonlinear disturbance observer based sliding mode control of a cable-driven rehabilitation robot. AB - This paper introduces a cable-driven robot for upper-limb rehabilitation. Kinematic and dynamic of this rehabilitation robot is analyzed. A sliding mode controller combined with a nonlinear disturbance observer is proposed to control this robot in the presence of disturbances. Simulation is carried out to prove the effectiveness of the proposed control scheme, and the results of the proposed controller is compared with a PID controller and a traditional sliding mode controller. Results show that the proposed controller can effectively improve the tracking performance as compared with the other two controllers and cause lower chattering as compared with a traditional sliding mode controller. PMID- 28813898 TI - Robots testing robots: ALAN-Arm, a humanoid arm for the testing of robotic rehabilitation systems. AB - Robotics is increasing in popularity as a method of providing rich, personalized and cost-effective physiotherapy to individuals with some degree of upper limb paralysis, such as those who have suffered a stroke. These robotic rehabilitation systems are often high powered, and exoskeletal systems can attach to the person in a restrictive manner. Therefore, ensuring the mechanical safety of these devices before they come in contact with individuals is a priority. Additionally, rehabilitation systems may use novel sensor systems to measure current arm position. Used to capture and assess patient movements, these first need to be verified for accuracy by an external system. We present the ALAN-Arm, a humanoid robotic arm designed to be used for both accuracy benchmarking and safety testing of robotic rehabilitation systems. The system can be attached to a rehabilitation device and then replay generated or human movement trajectories, as well as autonomously play rehabilitation games or activities. Tests of the ALAN-Arm indicated it could recreate the path of a generated slow movement path with a maximum error of 14.2mm (mean = 5.8mm) and perform cyclic movements up to 0.6Hz with low gain (<1.5dB). Replaying human data trajectories showed the ability to largely preserve human movement characteristics with slightly higher path length and lower normalised jerk. PMID- 28813897 TI - Design and testing of an under-actuated surface EMG-driven hand exoskeleton. AB - Stroke and other neurological pathologies are an increasing cause of hand impairment, involving expensive rehabilitative therapies. In this scenario, robotics applied to hand rehabilitation and assistance appears particularly promising in order to lower therapy costs and boost its efficacy. This work shows a recently conceived hand exoskeleton, from the design and realization to its preliminary evaluation. A control strategy based on surface electromyography (sEMG) signals is integrated: preliminary tests performed on healthy subjects show the validity of this choice. The testing protocol, applied on healthy subjects, demonstrated the robustness of the whole system, both in terms of mimicking a physiological distribution of finger forces across subjects, and of realizing an effective control strategy based on the user's intention. PMID- 28813899 TI - The effects of auditory and visual cues on timing synchronicity for robotic rehabilitation. AB - In this paper, we explore how the integration of auditory and visual cues can help teach the timing of motor skills for the purpose of motor function rehabilitation. We conducted a study using Amazon's Mechanical Turk in which 106 participants played a virtual therapy game requiring wrist movements. To validate that our results would translate to trends that could also be observed during robotic rehabilitation sessions, we recreated this experiment with 11 participants using a robotic wrist rehabilitation system as means to control the therapy game. During interaction with the therapy game, users were asked to learn and reconstruct a tapping sequence as defined by musical notes flashing on the screen. Participants were divided into 2 test groups: (1) control: participants only received visual cues to prompt them on the timing sequence, and (2) experimental: participants received both visual and auditory cues to prompt them on the timing sequence. To evaluate performance, the timing and length of the sequence were measured. Performance was determined by calculating the number of trials needed before the participant was able to master the specific aspect of the timing task. In the virtual experiment, the group that received visual and auditory cues was able to master all aspects of the timing task faster than the visual cue only group with p-values < 0.05. This trend was also verified for participants using the robotic arm exoskeleton in the physical experiment. PMID- 28813900 TI - Mechanical design of EFW Exo II: A hybrid exoskeleton for elbow-forearm-wrist rehabilitation. AB - The use of rehabilitation exoskeleton has become an important means for the treatment of stroke patients. A hybrid exoskeleton named EFW Exo II is developed for the motor function rehabilitation of elbow, forearm and wrist. The EFW Exo II is based on a parallel 2-URR/RRS mechanism and a serial R mechanism. It could fit both left and right arms for the symmetrical and open structure, and the distance between the elbow and wrist could automatically adjust for different forearm length. Details of the mechanical design are introduced. Brushless DC servo motors with planetary gear reducer are used as the actuators of the exoskeleton. Gear drive and belt drive are used for power transmission. A three dimensional force sensor is mounted in the handle to regulate the interaction between the exoskeleton and patient. The EFW Exo II can realize rehabilitation exercise for each joint and the ranges of motion meet the rehabilitation demands of daily living. PMID- 28813901 TI - Adaptive control based on an on-line parameter estimation of an upper limb exoskeleton. AB - This paper presents an adaptive control strategy for an upper-limb exoskeleton based on an on-line dynamic parameter estimator. The objective is to improve the control performance of this system that plays a critical role in assisting patients for shoulder, elbow and wrist joint movements. In general, the dynamic parameters of the human limb are unknown and differ from a person to another, which degrade the performances of the exoskeleton-human control system. For this reason, the proposed control scheme contains a supplementary loop based on a new efficient on-line estimator of the dynamic parameters. Indeed, the latter is acting upon the parameter adaptation of the controller to ensure the performances of the system in the presence of parameter uncertainties and perturbations. The exoskeleton used in this work is presented and a physical model of the exoskeleton interacting with a 7 Degree of Freedom (DoF) upper limb model is generated using the SimMechanics library of MatLab/Simulink. To illustrate the effectiveness of the proposed approach, an example of passive rehabilitation movements is performed using multi-body dynamic simulation. The aims is to maneuver the exoskeleton that drive the upper limb to track desired trajectories in the case of the passive arm movements. PMID- 28813902 TI - Hybrid position and orientation tracking for a passive rehabilitation table-top robot. AB - This paper presents a real time hybrid 2D position and orientation tracking system developed for an upper limb rehabilitation robot. Designed to work on a table-top, the robot is to enable home-based upper-limb rehabilitative exercise for stroke patients. Estimates of the robot's position are computed by fusing data from two tracking systems, each utilizing a different sensor type: laser optical sensors and a webcam. Two laser optical sensors are mounted on the underside of the robot and track the relative motion of the robot with respect to the surface on which it is placed. The webcam is positioned directly above the workspace, mounted on a fixed stand, and tracks the robot's position with respect to a fixed coordinate system. The optical sensors sample the position data at a higher frequency than the webcam, and a position and orientation fusion scheme is proposed to fuse the data from the two tracking systems. The proposed fusion scheme is validated through an experimental set-up whereby the rehabilitation robot is moved by a humanoid robotic arm replicating previously recorded movements of a stroke patient. The results prove that the presented hybrid position tracking system can track the position and orientation with greater accuracy than the webcam or optical sensors alone. The results also confirm that the developed system is capable of tracking recovery trends during rehabilitation therapy. PMID- 28813903 TI - Let's do this together: Bi-Manu-Interact, a novel device for studying human haptic interactive behavior. AB - Our area of interest is robotic-based rehabilitation after stroke, and our goal is to help patients achieve optimal motor learning during high-intensity repetitive movement training through the assistance of robots. It is important, that the robotic assistance is adapted to the patients' abilities, thereby ensuring that the device is only supporting the patient as necessary ("assist-as needed"). We hypothesize that natural and learning-effective human-machine interaction can be achieved by programming the robot's control, so that it emulates how a physiotherapist adaptively supports the patients' limb movement during stroke rehabilitation. This paper introduces the design of a novel interactive device Bi-Manu-Interact. This device is suited to be used as an experimental setup for the investigation of haptic human-human interaction and for collecting data to model therapists' haptic behavior. In this paper, we present mechanical and sensory specifications as well as tasks visualizations for future investigations. Results of a pilot clinical evaluation of the Bi-Manu Interact with nine stroke patients are also presented in this work. PMID- 28813904 TI - Task directionality impacts the ability of individuals with chronic hemiparetic stroke to match torques between arms: Preliminary findings. AB - Post hemiparetic stroke an individual may face difficulty performing bimanual tasks due to an asymmetry in their arms' strengths. Here, we determined whether participants with a strength asymmetry were impaired bi-directionally when matching torques between arms (i.e., paretic arm matches non-paretic arm, non paretic arm matches paretic arm). Six participants with chronic hemiparetic stroke and four participants without neurological impairments partook in this study. First, we identified the maximum voluntary torque that participants could generate about each elbow joint (taumvt). Then, we determined how accurately and precisely participants could match, bidirectionally, submaximal isometric flexion torques (0.25 . tauMVT:Reference) between arms. Results demonstrate that task directionality impacted the ability of our participants with stroke who had a strength asymmetry to match torques between arms; specifically, participants were unimpaired matching to a referenced non-paretic arm yet impaired in the opposite direction. Additionally, results reveal that the degree to which participants overshot the target torque when matching with their non-paretic arm could be predicted based on their strength asymmetry (R2Adjusted = 0.67). We propose that individuals with stroke may avoid torque matching impairments during bimanual tasks by matching their paretic arm to their non-paretic arm. PMID- 28813905 TI - Design and characterization of the OpenWrist: A robotic wrist exoskeleton for coordinated hand-wrist rehabilitation. AB - Robotic devices have been clinically verified for use in long duration and high intensity rehabilitation needed for motor recovery after neurological injury. Targeted and coordinated hand and wrist therapy, often overlooked in rehabilitation robotics, is required to regain the ability to perform activities of daily living. To this end, a new coupled hand-wrist exoskeleton has been designed. This paper details the design of the wrist module and several human related considerations made to maximize its potential as a coordinated hand-wrist device. The serial wrist mechanism has been engineered to facilitate donning and doffing for impaired subjects and to insure compatibility with the hand module in virtual and assisted grasping tasks. Several other practical requirements have also been addressed, including device ergonomics, clinician-friendliness, and ambidextrous reconfigurability. The wrist module's capabilities as a rehabilitation device are quantified experimentally in terms of functional workspace and dynamic properties. Specifically, the device possesses favorable performance in terms of range of motion, torque output, friction, and closed-loop position bandwidth when compared with existing devices. The presented wrist module's performance and operational considerations support its use in a wide range of future clinical investigations. PMID- 28813906 TI - The eWrist - A wearable wrist exoskeleton with sEMG-based force control for stroke rehabilitation. AB - Chronic wrist impairment is frequent following stroke and negatively impacts everyday life. Rehabilitation of the dysfunctional limb is possible but requires extensive training and motivation. Wearable training devices might offer new opportunities for rehabilitation. However, few devices are available to train wrist extension even though this movement is highly relevant for many upper limb activities of daily living. As a proof of concept, we developed the eWrist, a wearable one degree-of-freedom powered exoskeleton which supports wrist extension training. Conceptually one might think of an electric bike which provides mechanical support only when the rider moves the pedals, i.e. it enhances motor activity but does not replace it. Stroke patients may not have the ability to produce overt movements, but they might still be able to produce weak muscle activation that can be measured via surface electromyography (sEMG). By combining force and sEMG-based control in an assist-as-needed support strategy, we aim at providing a training device which enhances activity of the wrist extensor muscles in the context of daily life activities, thereby, driving cortical reorganization and recovery. Preliminary results show that the integration of sEMG signals in the control strategy allow for adjustable assistance with respect to a proxy measurement of corticomotor drive. PMID- 28813907 TI - Position and stiffness modulation of a wrist haptic device using myoelectric interface. AB - Modulation of stiffness provides a great deal of advantage in the way humans interact with the environment, and is very important in successfully performing activities of daily living. In the context of human-machine interactions, stiffness control could provide a safer interaction, especially when dealing with unpredictable environment. In this paper we propose a user-modulated stiffness and position control for the wrist flexion/extension degree of freedom while physically coupled to a haptic device. A virtual position tracking experiment in a varying external force field is designed in order to test the performance of the control strategy with and without co-contraction techniques. Tracking accuracy and smoothness of motion indicate better performance when subjects use co-contraction techniques, and the difference in the two types of experiment is also statistically significant. PMID- 28813908 TI - Form and function - Exemplary analysis of the significance for the design of rehabilitation devices. AB - Stroke often leads to motor impairment that could be recovered by extensive training. Multiple devices exist to support the rehabilitation process. Most systems interact directly with the patient and therefore, depend strongly on the ergonomic design which is determined by its form and function. In this work the interdependence of form and function and their particular significance for the development of rehabilitation devices are outlined. As a case study the development of a hand rehabilitation device is presented, where two approaches answering different key questions to focus either on function or form were realized at the same time to generate different concepts. The function-oriented approach led to a concept based on linkages and the form-oriented approach to one using leaf springs. In the discussion, the differences between the approaches are analyzed in respect to the creation of a geometrical-material entireness. Furthermore, new findings are discussed and the integration of both concepts into a final prototype is shown. PMID- 28813909 TI - Methodologies for determining minimal grasping requirements and sensor locations for sEMG-based assistive hand orthosis for SCI patients. AB - In this paper, we address two of the most important challenges in development and control of assistive hand orthosis. First, supported by experimental results, we present a method to determine an optimal set of grasping poses, essential for grasping daily objects. Second, we present a method for determining the minimal number of surface EMG sensors and their locations to carry out EMG-based intention recognition and to control the assistive device by differentiating between the hand poses. PMID- 28813910 TI - Reference path generation for upper-arm exoskeletons considering scapulohumeral rhythms. AB - This paper proposes a reference path generation method for upper-limb rehabilitation exoskeletons considering the scapulohumeral rhythms of the shoulder. The developed method is based on Central Nervous System's (CNS) governing rules for coordination of arm motions, and to the best of our knowledge is the first computational model to consider the motion of the inner shoulder in path generation. Existing reference generation methods which utilize computational models such as minimum jerk, minimum torque, etc, are based on the assumption that the shoulder joint does not move, and the origin of the reference frame is defined at the center of the glenohumeral (GH) joint. These computational methods are generally developed for simple point-to-point reaching movements with limited range of motion (RoM) which justifies the assumption of fixed shoulder center. However, most upper limb motions such as Activities of Daily Living (ADL) tasks include larger scale inward and outward reaching motions, during which the center of shoulder joint moves significantly. The proposed motion planning method can be used in upper-limb exoskeletons with 3 Degrees of Freedom (DoF) in shoulder and 1 DoF in elbow which are capable of supporting the motion of the shoulder girdle by moving the center of shoulder joint. The outputs of the proposed model are compared with the natural motion of arm during ADL tasks, recorded via a motion capture system. Comparison of the results show that the proposed model is able to reproduce human ADL motions, and can effectively be used for reference generation. The results of this study also confirm that neglecting the fine manipulations with wrist and fingers, ADL tasks can be modeled as large RoM reaching tasks from the perspective of elbow-shoulder coordination. PMID- 28813911 TI - Design and kinematic analysis of a novel upper limb exoskeleton for rehabilitation of stroke patients. AB - This paper details the design process and features of a novel upper limb rehabilitation exoskeleton named CLEVER (Compact, Low-weight, Ergonomic, Virtual/Augmented Reality Enhanced Rehabilitation) ARM. The research effort is focused on designing a lightweight and ergonomic upper-limb rehabilitation exoskeleton capable of producing diverse and perceptually rich training scenarios. To this end, the knowledge available in the literature of rehabilitation robotics is used along with formal conceptual design techniques. This paper briefly reviews the systematic approach used for design of the exoskeleton, and elaborates on the specific details of the proposed design concept and its advantages over other design possibilities. The kinematic structure of CLEVER ARM has eight degrees of freedom supporting the motion of shoulder girdle, glenohumeral joint, elbow and wrist. Six degrees of freedom of the exoskeleton are active, and the two degrees of freedom supporting the wrist motion are passive. Kinematics of the proposed design is studied analytically and experimentally with the aid of a 3D printed prototype. The paper is concluded by some remarks on the optimization of the design, motorization of device, and the fabrication challenges. PMID- 28813912 TI - Transverse forces versus modified ashworth scale for upper limb flexion/extension in para-sagittal plane. AB - Spasticity is a common impairment following an upper motor neuron lesion in conditions such as stroke and brain injury. A clinical issue is how to best quantify and measure spasticity. Recently, research has been performed to develop new methods of spasticity quantification using various systems. This paper follows up on previous work taking a closer look at the role of transversal forces obtained via rehabilitation robot for motions in the para-sagittal plane. Results from 45 healthy individuals and 40 individuals with acquired brain injury demonstrate that although the passive upper motions are vertical, horizontal forces into and away from the individual's body demonstrate a relationship with the Modified Ashworth Scale. This finding leads the way to new avenues of spasticity quantification and monitoring. PMID- 28813913 TI - EMU: A transparent 3D robotic manipulandum for upper-limb rehabilitation. AB - This paper introduces the EMU, a three-dimensional robotic manipulandum for rehabilitation of the upper extremity for patients with neurological injury. The device has been designed to be highly transparent, have a large workspace, and allow the use of the hand for interaction with real-world objects to provide additional contextual cues during exercises. The transparency is achieved through the use of a capstan transmission for the drive joints; a hybrid serial parallel kinematics minimising moving inertia; and lightweight materials. An experimental protocol is reported here which demonstrates the transparency through a comparison to out-of-robot movements, and with an existing rehabilitation robotic device. Additionally, an adjustable gravity compensation method is constructed, which minimises the torque required at the shoulder to carry the subject's arm. These characteristics allow the EMU to serve as a multi-purpose platform for the further development of novel robot assisted rehabilitation strategies. PMID- 28813914 TI - Data sample size needed for analysis of kinematic and muscle synergies in healthy and stroke populations. AB - Multiple studies have suggested the central nervous system (CNS) generates motions by using modular control of muscles and joints (synergies). However, the synergies reported by these studies are task dependent and might not reflect the true control strategies adopted by the CNS. Studying exploratory motions (EMs) can reveal biomechanical constraints and motor control strategies in healthy and clinical populations. The first logical step to consider EMs in study of motor synergies is to determine how much data is required to reliably and fully profile the motion patterns of an individual. Here we present how the quality of motor synergies analysis depends on the amount of EM data included in the analysis. We recruited 10 healthy and 10 post-stroke participants and collected electromyography (EMG) and joint motion data of their arms as they completed a motor exploration task. We compared the effects of clinical status and limb strength/dominance on the amount of data required to identify synergies. Clinical status had a significant eliect on the required amount of data for both datasets. Limb strength had a significant effect only for kinematic data. We determined the upper bound 95% confidence interval to set the amount of data required for synergy analysis in both populations: 235 sec for EMG data and 265 sec for kinematic data. Our results provide an important step toward using motor exploration in the study of healthy motor synergies and how stroke alters them. PMID- 28813915 TI - VIBROfocus: Design of a focal vibro-tactile robotic-assistive system for spasticity rehabilitation. AB - The main focus of spasticity treatment is to alleviate pain, improve function and reduce risk of additional complications. In this paper the design of a robotic system with enhanced focal vibro-tactile stimulation for the treatment of spasticity in the upper limbs is presented. Building on emerging evidence on the use of vibrations in the treatment of spasticity, we propose a new integrated approach. Our design combines the use of vibro-tactile stimulation of the high tone muscle with robotic movement assistance to augment rehabilitation outcomes in patients with spasticity in the upper limbs. PMID- 28813916 TI - Evaluating an open-loop functional electrical stimulation controller for holding the shoulder and elbow configuration of a paralyzed arm. AB - Functional electrical stimulation (FES) is a promising solution for restoring functional motion to individuals with paralysis, but the potential for achieving full-arm reaching motions with FES for various desired tasks has not been realized. We present an open-loop controller capable of calculating and applying the necessary muscle stimulations to hold the wrist of an individual with high tetraplegia at any desired position. We used the controller to hold the wrist at a series of static positions. The controller was capable of discriminating between different wrist positions. The average distance to the target wrist position, or accuracy, was 7.7 cm. The average radius of the 95% confidence ellipsoid for a set of trials with the same muscle stimulations, or precision, was 6.7 cm. Adding feedback or online model updates will likely improve the accuracy for tasks requiring finer control. The controller is a good first step to controlling full-arm motions with FES. PMID- 28813917 TI - Intuitive adaptive orientation control of assistive robots for people living with upper limb disabilities. AB - Robotic assistive devices enhance the autonomy of individuals living with physical disabilities in their day-to-day life. Although the first priority for such devices is safety, they must also be intuitive and efficient from an engineering point of view in order to be adopted by a broad range of users. This is especially true for assistive robotic arms, as they are used for the complex control tasks of daily living. One challenge in the control of such assistive robots is the management of the end-effector orientation which is not always intuitive for the human operator, especially for neophytes. This paper presents a novel orientation control algorithm designed for robotic arms in the context of human-robot interaction. This work aims at making the control of the robot's orientation easier and more intuitive for the user, in particular, individuals living with upper limb disabilities. The performance and intuitiveness of the proposed orientation control algorithm is assessed through two experiments with 25 able-bodied subjects and shown to significantly improve on both aspects. PMID- 28813918 TI - How to prepare a person with complete spinal cord injury to use surface electrodes for FES trike cycling. AB - Functional Electrical Stimulation (FES) cycling could benefit people with Spinal Cord Injury (SCI). The FES cycling involves large muscle groups during the training, and thus improves the cardiovascular function, increases the muscle bulk and reduces the secondary complications. This study developed an outdoor FES exercise cycling system for complete SCI persons to exercise their lower limbs without putting extra load on upper extremities. The mechanical structure of the cycling system was specially redesigned to secure the SCI persons in the cycling system. A six-phase-angle-driven control algorithm was designed to stimulate the quadriceps and hamstrings muscles. Two training modes, i.e., continuous mode and on-off mode, were designed and tested to increase the duration of the electrical stimulation to reduce muscle fatigue. A complete SCI volunteer participated in this training for six months. Beneficial effects could be observed such as paralyzed lower limb muscles had regained the muscle mass and reduced edema from the improved blood circulation. Moreover, the SCI volunteer attended the Cybathlon FES-bike competition in Zurich in October 2016 with Team Phoenix from the CUHK. PMID- 28813919 TI - Adding navigation, artificial audition and vital sign monitoring capabilities to a telepresence mobile robot for remote home care applications. AB - A telepresence mobile robot is a remote-controlled, wheeled device with wireless internet connectivity for bidirectional audio, video and data transmission. In health care, a telepresence robot could be used to have a clinician or a caregiver assist seniors in their homes without having to travel to these locations. Many mobile telepresence robotic platforms have recently been introduced on the market, bringing mobility to telecommunication and vital sign monitoring at reasonable costs. What is missing for making them effective remote telepresence systems for home care assistance are capabilities specifically needed to assist the remote operator in controlling the robot and perceiving the environment through the robot's sensors or, in other words, minimizing cognitive load and maximizing situation awareness. This paper describes our approach adding navigation, artificial audition and vital sign monitoring capabilities to a commercially available telepresence mobile robot. This requires the use of a robot control architecture to integrate the autonomous and teleoperation capabilities of the platform. PMID- 28813920 TI - Compensating for telecommunication delays during robotic telerehabilitation. AB - Rehabilitation robotic systems may afford better care and telerehabilitation may extend the use and benefits of robotic therapy to the home. Data transmissions over distance are bound by intrinsic communication delays which can be significant enough to deem the activity unfeasible. Here we describe an approach that combines unilateral robotic telerehabilitation and serious games. This approach has a modular and distributed design that permits different types of robots to interact without substantial code changes. We demonstrate the approach through an online multiplayer game. Two users can remotely interact with each other with no force exchanges, while a smoothing and prediction algorithm compensates motions for the delay in the Internet connection. We demonstrate that this approach can successfully compensate for data transmission delays, even when testing between the United States and Brazil. This paper presents the initial experimental results, which highlight the performance degradation with increasing delays as well as improvements provided by the proposed algorithm, and discusses planned future developments. PMID- 28813921 TI - Effect on the classification of motor imagery in EEG after applying anodal tDCS with a 4*1 ring montage over the motor cortex. AB - Transcranial direct stimulation (tDCS) is a technique for modulating brain excitability that has potential to be used in motor neurorehabilitation by enhancing motor activity, such as motor imagery (MI). tDCS effects depend on different factors, like current density and the position of the stimulating electrodes. This study presents preliminary results of the evaluation of the effect of current density on MI performance by measuring right-hand/feet MI accuracy of classification from electroencephalographic (EEG) measurements after anodal tDCS is applied with a 4*1 ring montage over the right-hand or feet motor cortex. Results suggest that there might be an enhancement of feet MI when tDCS is applied over the right-hand motor cortex, but further evaluation is required. If results are confirmed with a larger sample, the montage could be used to optimize feet MI performance and improve the outcome of MI-based brain-computer interfaces, which are used during motor neurorehabilitation. PMID- 28813922 TI - Actuated bed for a closed loop anti-snoring therapy. AB - Snoring is a very common often underestimated sleep disorder, which is caused by a partial blockage of the upper airways. It can easily be treated by changing the sleeping posture of the snorer. However, conventional approaches are often perceived as uncomfortable. In order to increase uptake we propose to use an actuated bed, which is equipped with microphones and controlled in closed loop. The inclination of the part of the bed which is supporting the trunk is increased to open the upper airways, whenever snoring sounds are detected. During snoring free periods the bed goes back to its original position to allow the user to move freely. The principle has successfully been applied in a proof of concept test. During this test night the bed was able to stop the snorer from snoring in four out of five occasions. PMID- 28813923 TI - A real-time and reduced-complexity approach to the detection and monitoring of static joint overloading in humans. AB - This paper proposes a novel technique for the real-time estimation of the joint torques variations in humans while performing heavy manipulation tasks. To achieve this, the method is based on the deviations of the Centre of Pressure (CoP) and Ground Reaction Force (GRF) in the presence of interaction forces. The CoP and GRF variations are calculated from the difference between the estimated values (assuming no interaction forces) using a pre-identified statically equivalent serial chain (SESC) and the measured ones (with the effect of interaction forces) using an external device. The calculated variation vectors and the measured joint angles of the human body are then used for the estimation of the overloading joint torques in real-time. We evaluated the efficacy of the proposed method both in simulations and experiments, in various poses of the human and interaction force profiles. PMID- 28813924 TI - Probabilistic vs linear blending approaches to shared control for wheelchair driving. AB - Some people with severe mobility impairments are unable to operate powered wheelchairs reliably and effectively, using commercially available interfaces. This has sparked a body of research into "smart wheelchairs", which assist users to drive safely and create opportunities for them to use alternative interfaces. Various "shared control" techniques have been proposed to provide an appropriate level of assistance that is satisfactory and acceptable to the user. Most shared control techniques employ a traditional strategy called linear blending (LB), where the user's commands and wheelchair's autonomous commands are combined in some proportion. In this paper, however, we implement a more generalised form of shared control called probabilistic shared control (PSC). This probabilistic formulation improves the accuracy of modelling the interaction between the user and the wheelchair by taking into account uncertainty in the interaction. In this paper, we demonstrate the practical success of PSC over LB in terms of safety, particularly for novice users. PMID- 28813926 TI - Development of an intrafascicular neural interface for peripheral nerve implantation. AB - This paper describes an intrafascicular neural interface for peripheral nerve implantation. The flexible penetrating microelectrode array with varying lengths (vl-FPMA), interconnection cable, wireless recording and stimulator modules were designed and fabricated to detect neural signals from the peripheral nerves or to stimulate them. The vl-FPMA consisted of silicon needles and polydimethylsiloxane (PDMS) platform supporting the needles. The length of electrode needles varied from 600 to 1000 MUm. The interconnection cable was fabricated as parylene-metal parylene sandwiched structure. The wireless recording/stimulation modules were also developed and connected with the electrodes. The integrated system was implanted in the sciatic nerve of beagles and the recording capability of the integrated system was demonstrated successfully. PMID- 28813925 TI - Stereo 3D tracking of infants in natural play conditions. AB - This paper describes the design and implementation of a multiple view stereoscopic 3D vision system and a supporting infant tracker pipeline to track limb movement in natural play environments and identify potential metrics to quantify movement behavior. So far, human pose estimation and tracking with 3D cameras has been focused primarily on adults and cannot be directly extended to infants because of differences in visual features such as shapes, sizes and appearance. With rehabilitation in mind, we propose a portable, compact, markerless, low cost and high resolution 3D vision system and a tracking algorithm that exploits infant appearance attributes and depth information. This approach achieved a mean 3D tracking error of 8.21cm and a standard deviation of 8.75cm. We also identify two potential metrics for movement behavior analysis - approximate entropy and interaction events. PMID- 28813927 TI - Simulation-based design for robotic care device: Optimizing trajectory of transfer support robot. AB - This paper presents a framework of simulation-based design for robotic care devices developed to reduce the burden of caregiver and care receivers. First, physical interaction between the user and device is quantitatively estimated by using a digital human simulator. Then we introduce a method for optimizing the design parameters according to given evaluation criteria. An example of trajectory optimization of transfer support robot is provided to demonstrate the effectiveness of the proposed method. PMID- 28813928 TI - Difficulty adaptation in a competitive arm rehabilitation game using real-time control of arm electromyogram and respiration. AB - Rehabilitation robots are often combined with serious games that motivate patients and keep them exercising at high intensities. A promising type of game are competitive rehabilitation games, but few difficulty adaptation algorithms have been presented for them. This paper thus presents the adaptation of difficulty in a competitive arm rehabilitation game based on two physiological signals: respiration and electromyography of the posterior deltoid. It consists of three smaller studies: an open-loop respiration study, a closed-loop respiration study (where a controller attempts to maintain respiration rate at preset levels), and a closed-loop electromyogram study (where a controller attempts to keep the electromyogram at preset levels). The studies control two difficulty parameters based on the physiological responses of one of the two exercising participants, though the ultimate goal is to control the physiological responses of both participants. Furthermore, all three studies are done with unimpaired participants. The closed-loop controllers achieved high correlation coefficients between desired and measured levels of respiration rate (r = 0.83) and electromyogram (r = 0.89), demonstrating that it is possible to control the physiological responses of unimpaired participants in a competitive arm rehabilitation game, thus controlling their level of workload and exercise intensity. In the future, the proposed method will be tested with patients undergoing rehabilitation. PMID- 28813929 TI - Soft brain-machine interfaces for assistive robotics: A novel control approach. AB - Robotic systems offer the possibility of improving the life quality of people with severe motor disabilities, enhancing the individual's degree of independence and interaction with the external environment. In this direction, the operator's residual functions must be exploited for the control of the robot movements and the underlying dynamic interaction through intuitive and effective human-robot interfaces. Towards this end, this work aims at exploring the potential of a novel Soft Brain-Machine Interface (BMI), suitable for dynamic execution of remote manipulation tasks for a wide range of patients. The interface is composed of an eye-tracking system, for an intuitive and reliable control of a robotic arm system's trajectories, and a Brain-Computer Interface (BCI) unit, for the control of the robot Cartesian stiffness, which determines the interaction forces between the robot and environment. The latter control is achieved by estimating in real time a unidimensional index from user's electroencephalographic (EEG) signals, which provides the probability of a neutral or active state. This estimated state is then translated into a stiffness value for the robotic arm, allowing a reliable modulation of the robot's impedance. A preliminary evaluation of this hybrid interface concept provided evidence on the effective execution of tasks with dynamic uncertainties, demonstrating the great potential of this control method in BMI applications for self-service and clinical care. PMID- 28813930 TI - BeMobil: Developing a user-friendly and motivating telerehabilitation system for motor relearning after stroke. AB - Motor relearning after stroke is a lengthy process which should be continued after patients get discharged from the clinic. This project aims at developing a system for telerehabilitation which enables stroke patients to exercise at home autonomously or under supervision of a therapist. The system includes haptic therapy devices which are more promising and beneficial for stroke rehabilitation than non-haptic approaches. In this paper, we present the results of two initial studies investigating specific design solutions for the patient's user interface. In the first study, we developed four interactive prototypes illustrating different navigation concepts. A usability test was conducted to identify the best suitable concept. In the second study we followed a participatory design approach to create a set of design solutions for a motivating instant visual feedback for exercising with the haptic devices. The current project status and next steps are described. PMID- 28813931 TI - Making neurorehabilitation fun: Multiplayer training via damping forces balancing differences in skill levels. AB - Multiplayer environments are thought to increase the training intensity in robot aided rehabilitation therapy after stroke. We developed a haptic-based environment to investigate the dynamics of two-player training performing time constrained reaching movements using the ARMin rehabilitation robot. We implemented a challenge level adaptation algorithm that controlled a virtual damping coefficient to reach a desired success rate. We tested the algorithm's effectiveness in regulating the success rate during game play in a simulation with computer-controlled players, in a feasibility study with six unimpaired players, and in a single session with one stroke patient. The algorithm demonstrated its capacity to adjust the damping coefficient to reach three levels of success rate (low [50%], moderate [70%], and high [90%]) during singleplayer and multiplayer training. For the patient - tested in single-player mode at the moderate success rate only - the algorithm showed also promising behavior. Results of the feasibility study showed that to increase the player's willingness to play at a more challenging task condition, the effect of the challenge level adaptation - regardless of being played in single player or multiplayer mode - might be more important than the provision of multiplayer setting alone. Furthermore, the multiplayer setting tends to be a motivating and encouraging therapy component. Based on these results we will optimize and expand the multiplayer training platform and further investigate multiplayer settings in stroke therapy. PMID- 28813932 TI - Quantifying infant physical interactions using sensorized toys in a natural play environment. AB - Infants with developmental delays must be detected early in their development to minimize the progression of motor and neurological impairments. Our objective is to quantify how sensorized toys in a natural play environment can promote infant toy physical interactions. We created a hanging elephant toy, equipped with an inertial measurement unit (IMU), a pressure transducer, and multiple feedback sensors, to be a hand-grasping toy. We used a 3 DoF robotic model with inputs from the IMU to calculate multiple kinematic metrics and an equation to calculate haptic metrics from the pressure transducer. Six typical infants were tested in the gym set-up. Three infants interacted with the toy for more than half the trial time. The youngest infant exhibited the largest toy displacement with DeltaD = 27.6 cm, while the oldest infant squeezed the toy with the largest mean pressure of 4.5 kPa. More data on on both typical and atypical infants needs to be collected. After testing atypical infants in the SmarToyGym set-up, we will be able to identify interaction metrics that differentiate atypical and typical infants. PMID- 28813933 TI - Robotic learning from demonstration of therapist's time-varying assistance to a patient in trajectory-following tasks. AB - The number of people with physical disabilities and impaired motion control is increasing. Consequently, there is a growing demand for intelligent assistive robotic systems to cooperate with people with disability and help them carry out different tasks. To this end, our group has pioneered the use of robot learning from demonstration (RLfD) techniques, which eliminate the need for task-specific robot programming, in robotic rehabilitation and assistive technologies settings. First, in the demonstration phase, the therapist (or in general, a helper) provides an intervention (typically assistance) and cooperatively performs a task with a patient several times. The demonstrated motion is modelled by a statistical RLfD algorithm, which will later be used in the robot controllers to reproduce a similar intervention robotically. In this paper, by proposing a Tangential-Normal Varying-Impedance Controller (TNVIC), the robotic manipulator not only follows the therapist's demonstrated motion, but also mimics his/her interaction impedance during the therapeutic/assistive intervention. The feasibility and efficacy of the proposed framework are evaluated by conducting an experiment involving a healthy adult with cerebral palsy symptoms being induced using transcutaneous electrical nerve stimulation. PMID- 28813934 TI - A hybrid brain-machine interface based on EEG and EMG activity for the motor rehabilitation of stroke patients. AB - Including supplementary information from the brain or other body parts in the control of brain-machine interfaces (BMIs) has been recently proposed and investigated. Such enriched interfaces are referred to as hybrid BMIs (hBMIs) and have been proven to be more robust and accurate than regular BMIs for assistive and rehabilitative applications. Electromyographic (EMG) activity is one of the most widely utilized biosignals in hBMIs, as it provides a quite direct measurement of the motion intention of the user. Whereas most of the existing non invasive EEG-EMG-hBMIs have only been subjected to offline testings or are limited to one degree of freedom (DoF), we present an EEG-EMG-hBMI that allows the simultaneous control of 7-DoFs of the upper limb with a robotic exoskeleton. Moreover, it establishes a biologically-inspired hierarchical control flow, requiring the active participation of central and peripheral structures of the nervous system. Contingent visual and proprioceptive feedback about the user's EEG and EMG activity is provided in the form of velocity modulation during functional task training. We believe that training with this closed-loop system may facilitate functional neuroplastic processes and eventually elicit a joint brain and muscle motor rehabilitation. Its usability is validated during a real time operation session in a healthy participant and a chronic stroke patient, showing encouraging results for its application to a clinical rehabilitation scenario. PMID- 28813935 TI - Influence of artifacts on movement intention decoding from EEG activity in severely paralyzed stroke patients. AB - Brain-machine interfaces (BMI) can be used to control robotic and prosthetic devices for rehabilitation of motor disorders, such as stroke. The calibration of these BMI systems is of paramount importance in order to establish a precise contingent link between the brain activity related to movement intention and the peripheral feedback. However, electroencephalographic (EEG) activity, commonly used to build non-invasive BMIs, can be easily contaminated by artifacts of electrical or physiological origin. The way these interferences can affect the performance of movement intention decoders has not been deeply studied, especially when dealing with severely paralyzed patients, which often generate more artifacts by compensatory movements. This paper evaluates the effects of removing artifacts from the data used to train a BMI decoder on a dataset of 28 severely paralyzed stroke patients. We show that cleaning the training datasets reduces the global BMI performance for decoding attempts of movement. Further, we demonstrate that this performance drop especially affects the test trials contaminated by artifacts (i.e., trials that might not reflect cortical activity but noise), but not the clean test trials (i.e., trials representing correct cortical activity). This paper underlines the importance of cleaning the datasets used to train BMI systems to improve their efficacy for decoding movement intention and maximize their neurorehabilitative potential. PMID- 28813936 TI - Using upper limb kinematics to assess cognitive deficits in people living with both HIV and stroke. AB - In this study, we aim to explore ways to objectively assess cognitive deficits in the stroke and HIV/stroke populations, where cognitive and motor impairments can be hard to separate. Using an upper limb rehabilitation robot called the Haptic TheraDrive, we collect performance error scores and motor learning data on the impaired and unimpaired limb during a trajectory tracking task. We compare these data to clinical cognitive scores. The preliminary results suggest a possible relationship between unimpaired upper limb performance error and visuospatial/executive function cognitive domains, but more work needs to be done to further investigate this. The potential of using robot-assisted technologies to measure unimpaired limb kinematics as a tool to assess cognitive deficits would be useful to inform more effective rehabilitation strategies for HIV, stroke, and HIV/stroke populations. PMID- 28813937 TI - Towards quantifying dynamic human-human physical interactions for robot assisted stroke therapy. AB - Human-Robot Interaction is a prominent field of robotics today. Knowledge of human-human physical interaction can prove vital in creating dynamic physical interactions between human and robots. Most of the current work in studying this interaction has been from a haptic perspective. Through this paper, we present metrics that can be used to identify if a physical interaction occurred between two people using kinematics. We present a simple Activity of Daily Living (ADL) task which involves a simple interaction. We show that we can use these metrics to successfully identify interactions. PMID- 28813938 TI - Online sparse Gaussian process based human motion intent learning for an electrically actuated lower extremity exoskeleton. AB - The most important step for lower extremity exoskeleton is to infer human motion intent (HMI), which contributes to achieve human exoskeleton collaboration. Since the user is in the control loop, the relationship between human robot interaction (HRI) information and HMI is nonlinear and complicated, which is difficult to be modeled by using mathematical approaches. The nonlinear approximation can be learned by using machine learning approaches. Gaussian Process (GP) regression is suitable for high-dimensional and small-sample nonlinear regression problems. GP regression is restrictive for large data sets due to its computation complexity. In this paper, an online sparse GP algorithm is constructed to learn the HMI. The original training dataset is collected when the user wears the exoskeleton system with friction compensation to perform unconstrained movement as far as possible. The dataset has two kinds of data, i.e., (1) physical HRI, which is collected by torque sensors placed at the interaction cuffs for the active joints, i.e., knee joints; (2) joint angular position, which is measured by optical position sensors. To reduce the computation complexity of GP, grey relational analysis (GRA) is utilized to specify the original dataset and provide the final training dataset. Those hyper-parameters are optimized offline by maximizing marginal likelihood and will be applied into online GP regression algorithm. The HMI, i.e., angular position of human joints, will be regarded as the reference trajectory for the mechanical legs. To verify the effectiveness of the proposed algorithm, experiments are performed on a subject at a natural speed. The experimental results show the HMI can be obtained in real time, which can be extended and employed in the similar exoskeleton systems. PMID- 28813939 TI - Comparison of tongue interface with keyboard for control of an assistive robotic arm. AB - This paper demonstrates how an assistive 6 DoF robotic arm with a gripper can be controlled manually using a tongue interface. The proposed method suggests that it possible for a user to manipulate the surroundings with his or her tongue using the inductive tongue control system as deployed in this study. The sensors of an inductive tongue-computer interface were mapped to the Cartesian control of an assistive robotic arm. The resulting control system was tested manually in order to compare manual control of the robot using a standard keyboard and using the tongue interface. Two healthy subjects controlled the robotic arm to precisely move a bottle of water from one location to another. The results shows that the tongue interface was able to fully control the robotic arm in a similar manner as the standard keyboard resulting in the same number of successful manipulations and an average increase in task duration of up to 30% as compared with the standard keyboard. PMID- 28813940 TI - Recording gaze trajectory of wheelchair users by a spherical camera. AB - Wheelchairs are widely used in the facilities of rehabilitation. In this paper, we propose a method of recording the gaze trajectory of wheelchair users by using a spherical camera mounted on the wheelchairs. A spherical camera has a full field of view and can observe the entire surrounding scenes. First, the gaze point of a user sitting on a wheelchair is estimated from the corneal reflection image observed by a wearable eye camera. Then, the gaze point is mapped onto the full-view image captured by the spherical camera via feature matching. Since it is not guaranteed that the gaze point in an eye image is a distinctive feature point, the matching of a gaze point between these two images cannot be carried out directly. To cope with this problem, we use a coarse-to-fine approach, in which, first, distinctive feature points are used to estimate the relative orientation between the eye camera and the spherical camera, and then, the estimated relative orientation matrix is used to determine the location of gaze points. The effectiveness of the proposed method is shown by real-world experimental results. PMID- 28813941 TI - Inverse estimation of multiple muscle activations based on linear logistic regression. AB - This study deals with a technology to estimate the muscle activity from the movement data using a statistical model. A linear regression (LR) model and artificial neural networks (ANN) have been known as statistical models for such use. Although ANN has a high estimation capability, it is often in the clinical application that the lack of data amount leads to performance deterioration. On the other hand, the LR model has a limitation in generalization performance. We therefore propose a muscle activity estimation method to improve the generalization performance through the use of linear logistic regression model. The proposed method was compared with the LR model and ANN in the verification experiment with 7 participants. As a result, the proposed method showed better generalization performance than the conventional methods in various tasks. PMID- 28813942 TI - Robotic assessment of the contribution of motor commands to wrist position sense. AB - Assessing joint position sense for rehabilitation after neurological injury provides a prognostic factor in recovery and long-term functional outcomes. A common method for testing joint position sense involves the active replication of a joint configuration presented via a passive movement. However, recent evidence showed how this sense is mediated by the centrally generated signals of motor command, such that movements produced volitionally may be coded differently from passive movements and accuracy may be different when matching targets presented actively. To verify this hypothesis we asked ten participants to actively replicate a target wrist angle with the help of a visual feedback in two conditions, which differed in the mode of target presentation: active (aaJPM) or passive (paJPM). The accuracy of target matching, directional bias and variability were analyzed, as well as speed and smoothness of the matching movement and criterion movement in the aaJPM. Overall results indicate higher accuracy and lower variability in the paJPM, while directional bias showed the tendency to overshoot the target regardless of condition. The speed did not differ in the two conditions and movements were smoother in the aaJPM, suggesting a higher confidence by participants in their matching ability. In conclusion, this study suggests that motor commands negatively affect the accuracy of joint position sense when matching involves the integration of visual and proprioceptive information. PMID- 28813943 TI - Conjunctive rehabilitation of multiple cognitive domains for chronic stroke patients in virtual reality. AB - Classically, cognitive deficits have been studied and treated in isolation from each other. A stroke patient is classified as being memory impaired, having executive dysfunction or showing attentional deficits after which a dedicated rehabilitation therapy is given. Studies seldom looked at the relationship between these different cognitive domains and syndromes, although, there is evidence that they might share common neuronal substrates and do not occur in isolation. Here, we propose a novel rehabilitation method in virtual reality to treat cognitive deficits in conjunction and report the preliminary results of an ongoing randomized controlled clinical trial. The current results suggest that in a homogeneous patient group the cognitive deficits are correlated and that the individual impairment level can be optimally addressed through an adaptive training paradigm. PMID- 28813944 TI - Robotic set-up to quantify hand-eye behavior in motor execution and learning of children with autism spectrum disorder. AB - Autism spectrum disorder (ASD) is a multifaceted neurodevelopmental disorder characterized by a persistence of social and communication impairment, and restricted and repetitive behaviors. However, motor disorders have also been described, but not objectively assessed. Most studies showed inefficient eye-hand coordination and motor learning in children with ASD; in other experiments, mechanisms of acquisition of internal models in self-generated movements appeared to be normal in autism. In this framework, we have developed a robotic protocol, recording gaze and hand data during upper limb tasks, in which a haptic pen-like handle is moved along specific trajectories displayed on the screen. The protocol includes trials of reaching under a perturbing force field and catching moving targets, with or without visual availability of the whole path. We acquired 16 typically-developing scholar-age children and one child with ASD as a case study. Speed-accuracy tradeoff, motor performance, and gaze-hand spatial coordination have been evaluated. Compared to typically developing peers, in the force field sequence, the child with ASD showed an intact but delayed learning, and more variable gazehand patterns. In the catching trials, he showed less efficient movements, but an intact capability of exploiting the available a-priori plan. The proposed protocol represents a powerful tool, easily tunable, for quantitative (longitudinal) assessment, and for subject-tailored training in ASD. PMID- 28813945 TI - Towards a situation-and-user-aware multi-modal motorized toilet system to assist older adults with disabilities: A user requirements study. AB - In the recent decades state of the art technologies appeared in many areas to assist older adults with disabilities. However, one very essential activity of daily life, the toileting remained without any relevant development. The iToilet project of the European Union focuses on the development of an intelligent and motorized toilet system to enable independent toilet use for older adults with disabilities. To begin the development, the user requirements of end-users were assessed by means of focus group interviews and questionnaires. The survey was conducted in Austria and Hungary with the participation of 74 persons in total (41 subjects with movement disorders, 21 caregivers and 12 healthcare managers). From the interviews, the ranking of functions and features based on the number of their mentions was derived. The raw ranking was modulated by the average ratings from the questionnaires that resulted in the final list of priorities. Our results suggest that a safe and intelligent motorized toilet system should have foldable handrails on both sides (especially for wheelchair users), motorized height and tilt adjusting mechanism for the toilet bowl, fixed toilet paper holder on both sides and emergency recognition with call function. Simple operation, storage and retrieval of user specific settings including bowl height, and user identification were also deemed as very important features, while the possibility to control functions with gestures was valued rather low. PMID- 28813946 TI - A user-centered design approach in the development of rehabilitation devices after stroke. AB - Involving users in iterative development processes is to be shown to increase the quality of health care devices and to prevent refusal. Successful use can only be achieved provided that the devices are accepted by its users. In this study potentials of user satisfaction surveys in the development of stroke rehabilitation devices are presented. The two arm-training devices Reha-Slide (RS) and Bi-Manu-Track (BMT) are assessed for patient satisfaction. The aim is to detect the satisfaction with the current state of certain aspects of the devices to obtain incentives for technical optimisation. Correlation analyses from the data of 18 patients show significant positive correlations between satisfaction with the introduction and the personal well-being during training with both devices, whereas no significant correlations are found between satisfaction with the introduction and the perceived safety. In the RS sample, a higher satisfaction with the training also correlates with a higher feeling of improvement. The results are used to derive improvement suggestions tailored to the systems and its users. The surveys are conducted as a method for improving the ongoing design process of innovative technical devices developed in the BMBF (Federal Ministry of Education and Research) funded project "BeMobil". PMID- 28813947 TI - Exploiting kinematic constraints to compensate magnetic disturbances when calculating joint angles of approximate hinge joints from orientation estimates of inertial sensors. AB - Inertial Measurement Units (IMUs) have become a widely used tool for rehabilitation and other application domains in which human motion is analyzed using an ambulatory or wearable setup. Since the magnetic field is inhomogeneous in indoor environments and in the proximity of ferromagnetic material, standard orientation estimation and joint angle calculation algorithms often lead to inaccurate or even completely wrong results. One approach to circumvent this is to exploit the kinematic constraint that is induced by mechanical hinge joints and also by approximate hinge joints such as the knee joint and the finger (interphalangeal) joints of the human body. We propose a quaternion-based method for joint angle measurement for approximate hinge joints moving through inhomogeneous magnetic fields. The method exploits the kinematic constraint to compensate the error that the magnetic disturbances induce in the IMU orientation estimates. This is achieved by realtime estimation and correction of the relative heading (azimuth) error that is caused by the disturbance. Since the kinematic constraint does not allow heading correction when the joint axis is vertical, we extend the proposed method such that it improves accuracy and robustness when the joint is close to that singularity. We evaluate the method by simulations of a quick hand motion and study the effect of inaccurate sensor-to-segment (anatomical) calibration and joint constraint relaxations. As a main result, the proposed method is found to reduce the root-mean-square error of the joint angle from 25.8 degrees to 2.6 degrees in the presence of large magnetic disturbances. PMID- 28813948 TI - Robotic assistance for performing vocational rehabilitation activities using BaxBot. AB - Activities of Daily Living (ADL's) refer to tasks that people do on a daily basis, such as self-feeding, cleaning the house, or bathing. These activities often require a degree of functional mobility that may be outside the ability of a person suffering from cognitive or physical impairment. This work describes methods of performing ADL's with a mobile robotic system. We examined the needs of potential users and caregivers through surveys to determine the most needed applications for robotic assistance. Using this information, we extended the functionality of our BaxBot mobile robotic system to provide meaningful, autonomous assistance in performing three specific ADL's with minimal user interaction. PMID- 28813949 TI - Monitoring brain potentials to guide neurorehabilitation of tracking impairments. AB - Motor impairments come in different forms. One class of motor impairments, relates to accuracy of tracking a moving object, as, for instance, when chasing in an attempt to catch it. Here we look at neural signals associated with errors in tracking, and the implications for brain-computer-interfaces that target impairment-tailored rehabilitation. As a starting point, we characterized EEG signals evoked by tracking errors during continuous natural motion, in healthy participants. Participants played a virtual 3D, ecologically valid haptic tennis game, and had to track a moving tennis ball in order to hit and send the ball towards the opponent's court. Sudden changes in the motion of the tennis ball elicited error related potentials. These were characterized by a negative peak at 135 msec and two positive peaks at 211 and 336 msec. The negative peak had a parietal scalp distribution, and the positive had a centro-frontal distribution. sLORETA source estimation for the peaks suggested brain activity in the somatosensory, motor, visual and anterior cingulate cortex. Implications are double: changes in the error potential characteristics provide an assessment strategy for rehabilitation; and the identified error potential can be used in the Brain computer interface feedback loop for tailored rehabilitation. Taken together, these results provide a methodology of rehabilitation systems specifically tailored to the unique impairment. PMID- 28813950 TI - Feasibility of using sphero in rehabilitation of children with autism in social and communication skills. AB - The majority of children with autism face difficulties in social interaction and communication skills. Consequently, in this paper we present a pilot study in which we explored the usability of SpheroTM as a rehabilitation tool for developing social and communication skills. We designed an interactive scenario where children with autism should verbally control the robot and utter voice commands. Our observations show that the children were very interested to interact with the robot in the given framework. They showed surprising behaviors that are promising evidences of effectiveness of using Sphero in rehabilitation of social and communication deficits. PMID- 28813951 TI - Design of an immersive simulator for assisted power wheelchair driving. AB - Driving a power wheelchair is a difficult and complex visual-cognitive task. As a result, some people with visual and/or cognitive disabilities cannot access the benefits of a power wheelchair because their impairments prevent them from driving safely. In order to improve their access to mobility, we have previously designed a semi-autonomous assistive wheelchair system which progressively corrects the trajectory as the user manually drives the wheelchair and smoothly avoids obstacles. Developing and testing such systems for wheelchair driving assistance requires a significant amount of material resources and clinician time. With Virtual Reality technology, prototypes can be developed and tested in a risk-free and highly flexible Virtual Environment before equipping and testing a physical prototype. Additionally, users can "virtually" test and train more easily during the development process. In this paper, we introduce a power wheelchair driving simulator allowing the user to navigate with a standard wheelchair in an immersive 3D Virtual Environment. The simulation framework is designed to be flexible so that we can use different control inputs. In order to validate the framework, we first performed tests on the simulator with able bodied participants during which the user's Quality of Experience (QoE) was assessed through a set of questionnaires. Results show that the simulator is a promising tool for future works as it generates a good sense of presence and requires rather low cognitive effort from users. PMID- 28813952 TI - Comparative performance analysis of M-IMU/EMG and voice user interfaces for assistive robots. AB - People with a high level of disability experience great difficulties to perform activities of daily living and resort to their residual motor functions in order to operate assistive devices. The commercially available interfaces used to control assistive manipulators are typically based on joysticks and can be used only by subjects with upper-limb residual mobilities. Many other solutions can be found in the literature, based on the use of multiple sensory systems for detecting the human motion intention and state. Some of them require a high cognitive workload for the user. Some others are more intuitive and easy to use but have not been widely investigated in terms of usability and user acceptance. The objective of this work is to propose an intuitive and robust user interface for assistive robots, not obtrusive for the user and easily adaptable for subjects with different levels of disability. The proposed user interface is based on the combination of M-IMU and EMG for the continuous control of an arm hand robotic system by means of M-IMUs. The system has been experimentally validated and compared to a standard voice interface. Sixteen healthy subjects volunteered to participate in the study: 8 subjects used the combined M-IMU/EMG robot control, and 8 subjects used the voice control. The arm-hand robotic system made of the KUKA LWR 4+ and the IH2 Azzurra hand was controlled to accomplish the daily living task of drinking. Performance indices and evaluation scales were adopted to assess performance of the two interfaces. PMID- 28813953 TI - BRIDGE - Behavioural reaching interfaces during daily antigravity activities through upper limb exoskeleton: Preliminary results. AB - People with neuromuscular diseases such as muscular dystrophy experience a distributed and evolutive weakness in the whole body. Recent technological developments have changed the daily life of disabled people strongly improving the perceived quality of life, mostly concentrating on powered wheelchairs, so to assure autonomous mobility and respiratory assistance, essential for survival. The key concept of the BRIDGE project is to contrast the everyday experience of losing functions by providing them of a system able to exploit the best their own residual capabilities in arm movements so to keep them functional and autonomous as much as possible. BRIDGE is composed by a light, wearable and powered five degrees of freedom upper limb exoskeleton under the direct control of the user through a joystick or gaze control. An inverse kinematic model allows to determine joints position so to track patient desired hand position. BRIDGE prototype has been successfully tested in simulation environment, and by a small group of healthy volunteers. Preliminary results show a good tracking performance of the implemented control scheme. The interaction procedure was easy to understand, and the interaction with the system was successful. PMID- 28813954 TI - Human-robot sensor interface for cardiac rehabilitation. AB - Cardiovascular disease is the leading cause of death in the world. A program of cardiac rehabilitation (CR) is related to physical activities or exercises to regain the optimal quality of life. CR relies on the necessity to evaluate, control and supervise a patient's status and progress. This work has two objectives: on the one hand, provide a tool for clinicians to assess the patient's status during CR. On the other hand, there is evidence that robots can motivate patients during therapeutic procedures. Our sensor interface explores the possibility to integrate a robotic agent into cardiac therapy. This work presents an exploratory experiment for on-line assessment of typical CR routines. PMID- 28813955 TI - Robotic therapy for phantom limb pain in upper limb amputees. AB - The system described in this paper combines virtual reality with haptic feedback to increase the level of immersion and invoke the sense of agency in patients with phantom limb pain with the aim of reducing perceived pain. This paper presents three case studies of an on-going clinical study. The initial results suggest an increased sense of embodiment of the virtual limb promotes a decrease in perceived levels of pain. The results strengthen the view that the cortical map does not fully "disappear" yet lays dormant. PMID- 28813956 TI - Semi-autonomous mobility assistance for power wheelchair users navigating crowded environments. AB - Power wheelchair users suffering from cognitive or physical impairment often face difficulties in maneuvering their wheelchairs through crowded environments. Currently, users need to be continuously aware of all traffic around them to actively avoid all collisions. This is an especially difficult task since many wheelchair users are unable to accurately view or perceive their surroundings. Additionally, imprecise joystick control, slowed reaction time, or imperfect interpretation of the environment can lead to unintended collisions with objects in the environment. This work looks to augment user's input with data gathered from an ultrasonic sensor ring to prevent accidental collisions. Using data gathered from the sensors, we detect objects within a certain radius of the chair. This sensor information is combined with the user input from a joystick to generate a potential field description for the intended motion of the wheelchair. An optimal motion vector is calculated which works to avoid collision with obstacles. Ultimately, this control method reduces the cognitive load on the user and enables them to navigate complex environments by providing simple and/or imprecise input to the system. PMID- 28813957 TI - An instrumented object for studying human grasping. AB - This paper proposes the use of an instrumented object for the study of the human grasping strategies. The proposed object is able to measure the grasping forces by means of three Force Sensitive Resistor (FSR) sensors and triaxial acceleration through an accelerometer. The object orientation angles (roll and pitch) can be estimated from the accelerometer output in quasi-static condition, whereas slippage events can be detected through the Power Spectrum Density (PSD) computation of the acceleration on at least one of the three axes. An experimental session on 7 healthy subjects has been performed; each subject used the instrumented object to perform 8 tripod grasp trials. All the sensory information, i.e. applied forces, object orientation and slippage, have been analyzed in order to evaluate the grasping strategies of the different subjects. PMID- 28813958 TI - Quantitative assessment of motor functions post-stroke: Responsiveness of upper extremity robotic measures and its task dependence. AB - Technology aided measures offer a sensitive, accurate and time-efflcient approach for the assessment of sensorimotor function after neurological impairment compared to standard clinical assessments. This preliminary study investigated the relationship between task definition and its effect on robotic measures using a planar, two degree of freedom, robotic-manipulator (H-Man). Four chronic stroke participants (49.5+/-11.95 years, 2 Female, FMA: 37.5+/-13.96) and eight healthy control participants (26.25+/- 4.70 years, 2 Female) participated in the study. Motor functions were evaluated using line tracing and circle tracing tasks with dominant and nondominant hand of healthy and affected vs. non affected hand of stroke participants. The results show significant dependence of quantitative measures on investigated tasks. PMID- 28813959 TI - "Wink to grasp" - comparing eye, voice & EMG gesture control of grasp with soft robotic gloves. AB - The ability of robotic rehabilitation devices to support paralysed end-users is ultimately limited by the degree to which human-machine-interaction is designed to be effective and efficient in translating user intention into robotic action. Specifically, we evaluate the novel possibility of binocular eye-tracking technology to detect voluntary winks from involuntary blink commands, to establish winks as a novel low-latency control signal to trigger robotic action. By wearing binocular eye-tracking glasses we enable users to directly observe their environment or the actuator and trigger movement actions, without having to interact with a visual display unit or user interface. We compare our novel approach to two conventional approaches for controlling robotic devices based on electromyo-graphy (EMG) and speech-based human-computer interaction technology. We present an integrated software framework based on ROS that allows transparent integration of these multiple modalities with a robotic system. We use a soft robotic SEM glove (Bioservo Technologies AB, Sweden) to evaluate how the 3 modalities support the performance and subjective experience of the end-user when movement assisted. All 3 modalities are evaluated in streaming, closed-loop control operation for grasping physical objects. We find that wink control shows the lowest error rate mean with lowest standard deviation of (0.23 +/- 0.07, mean +/- SEM) followed by speech control (0.35 +/- 0. 13) and EMG gesture control (using the Myo armband by Thalamic Labs), with the highest mean and standard deviation (0.46 +/- 0.16). We conclude that with our novel own developed eye tracking based approach to control assistive technologies is a well suited alternative to conventional approaches, especially when combined with 3D eye tracking based robotic end-point control. PMID- 28813960 TI - Towards free 3D end-point control for robotic-assisted human reaching using binocular eye tracking. AB - Eye-movements are the only directly observable behavioural signals that are highly correlated with actions at the task level, and proactive of body movements and thus reflect action intentions. Moreover, eye movements are preserved in many movement disorders leading to paralysis (or amputees) from stroke, spinal cord injury, Parkinson's disease, multiple sclerosis, and muscular dystrophy among others. Despite this benefit, eye tracking is not widely used as control interface for robotic interfaces in movement impaired patients due to poor human robot interfaces. We demonstrate here how combining 3D gaze tracking using our GT3D binocular eye tracker with custom designed 3D head tracking system and calibration method enables continuous 3D end-point control of a robotic arm support system. The users can move their own hand to any location of the workspace by simple looking at the target and winking once. This purely eye tracking based system enables the end-user to retain free head movement and yet achieves high spatial end point accuracy in the order of 6 cm RMSE error in each dimension and standard deviation of 4 cm. 3D calibration is achieved by moving the robot along a 3 dimensional space filling Peano curve while the user is tracking it with their eyes. This results in a fully automated calibration procedure that yields several thousand calibration points versus standard approaches using a dozen points, resulting in beyond state-of-the-art 3D accuracy and precision. PMID- 28813961 TI - Identifying the effects of using integrated haptic feedback for gait rehabilitation of stroke patients. AB - This paper evaluates the prospects of using a novel Integrated Haptic Feedback (IHF) system. IHF can provide over-ground gait training regimens for post-stroke ambulatory subjects. IHF system combines the use of a portable cane for kinesthetic feedback and a wearable vibrotactor array for tactile feedback. Continuous somatosensory input is aiforded to the users at the handle of cane; it serves the purpose of balance assurance at higher gait speeds. Besides, restricted use of upper limb for weight-bearing inspires the users to involve the paretic lower limbs more actively. Furthermore, tactile feedback contributes in enhancing the gait symmetry through afferent signal of vibration. Six post-stroke ambulatory individuals participated in walking trials to identity the effects of IHF system. Results indicate that while walking faster patients' body sway was not disturbed. Statistically significant increase was observed in temporal stance symmetry (p-value=0.02) and in paretic muscle (vastus medialis obliquus and semitendinosus) activation during stance phase (p-value<0.01). The IHF system can be a valuable tool to assist physical therapist in gait rehabilitation of post stroke individuals. PMID- 28813962 TI - A fundamental study on how holding a helium-filled balloon affects stability in human standing. AB - Various studies have been conducted in the field of the development/deterioration of standing and walking ability. In standing and walking control strategy, the relationship linking visual/somatosensory/vestibular-system information and physical movement is important. Researchers have previously sought to evaluate attitude control based on human sensory information. The authors have also reported that the body sway of a walking infant is mitigated when the subject holds a helium-filled balloon, with results suggesting that this approach can be applied to extend walking distance. This study was conducted to clarify how holding a balloon influences standing control strategy. A novel system was developed to quantitatively monitor and evaluate the standing state of subjects holding such a balloon. The results of the experiments conducted indicate that attitude control strategy changes in response to somatosensory information provided by the physical connection with the balloon. PMID- 28813963 TI - Novel neural interface electrode array for the peripheral nerve. AB - Peripheral neural interface (PNI) is becoming an essential technology in the field of robotic prosthesis due to its potential for providing bidirectional neural signal communication between the prosthetic arm and the brain. However, current PNIs inefficiently trade off neural signal selectivity and the invasiveness of the device. We designed and fabricated a new PNI electrode array that has high signal selectivity yet maintains low invasiveness by incorporating a design that allows for three-dimensional spiral insertion around the peripheral nerve. The neural signal acquisition capability was confirmed through impedance measurement in vitro, and the proposed device had an average impedance of 296 +/- 52 kOmega at 1000 Hz. PMID- 28813964 TI - Brain-computer interface combining eye saccade two-electrode EEG signals and voice cues to improve the maneuverability of wheelchair. AB - Brain-computer interfaces (BCIs) largely augment human capabilities by translating brain wave signals into feasible commands to operate external devices. However, many issues face the development of BCIs such as the low classification accuracy of brain signals and the tedious human-learning procedures. To solve these problems, we propose to use signals associated with eye saccades and blinks to control a BCI interface. By extracting existing physiological eye signals, the user does not need to adapt his/her brain waves to the device. Furthermore, using saccade signals to control an external device frees the limbs to perform other tasks. In this research, we use two electrodes placed on top of the left and right ears of thirteen participants. Then we use Independent Component Analysis (ICA) to extract meaningful EEG signals associated with eye movements. A sliding-window technique was implemented to collect relevant features. Finally, we classified the features as horizontal or blink eye movements using KNN and SVM. We were able to achieve a mean classification accuracy of about 97%. The two electrodes were then integrated with off-the-shelf earbuds to control a wheelchair. The earbuds can generate voice cues to indicate when to rotate the eyeballs to certain locations (i.e., left or right) or blink, so that the user can select directional commands to drive the wheelchair. In addition, through properly designing the contents of voice menus, we can generate as many commands as possible, even though we only have limited numbers of states of the identified eye saccade movements. PMID- 28813965 TI - Cheap or Robust? The practical realization of self-driving wheelchair technology. AB - To date, self-driving experimental wheelchair technologies have been either inexpensive or robust, but not both. Yet, in order to achieve real-world acceptance, both qualities are fundamentally essential. We present a unique approach to achieve inexpensive and robust autonomous and semi-autonomous assistive navigation for existing fielded wheelchairs, of which there are approximately 5 million units in Canada and United States alone. Our prototype wheelchair platform is capable of localization and mapping, as well as robust obstacle avoidance, using only a commodity RGB-D sensor and wheel odometry. As a specific example of the navigation capabilities, we focus on the single most common navigation problem: the traversal of narrow doorways in arbitrary environments. The software we have developed is generalizable to corridor following, desk docking, and other navigation tasks that are either extremely difficult or impossible for people with upper-body mobility impairments. PMID- 28813966 TI - Exergaming with a pediatric exoskeleton: Facilitating rehabilitation and research in children with cerebral palsy. AB - Effective rehabilitation of children with cerebral palsy (CP) requires intensive task-specific exercise but many in this population lack the motor capabilities to complete the desired training tasks. Providing robotic assistance is a potential solution yet the effects of this assistance are unclear. We combined a novel exoskeleton and exercise video game (exergame) to create a new rehabilitation paradigm for children with CP. We incorporated high density electroencephalography (EEG) to assess cortical activity. Movement to targets in the game was controlled by knee extension while standing. The distance between targets was the same with and without the exoskeleton to isolate the effect of robotic assistance. Our results show that children with CP maintain or increase knee extensor muscle activity during knee extension in the presence of synergistic robotic assistance. Our EEG findings also demonstrate that participants remained engaged in the exercise with robotic assistance. Interestingly we observed a developmental trajectory of sensorimotor mu rhythm in children with CP similar, though delayed, to those reported in typically developing children. While not the goal here, the exoskeleton significantly increased knee extension in 3/6 participants during use. Future work will focus on utilizing the exoskeleton to enhance volitional knee extension capability and in combination with EMG and EEG to study sensorimotor cortex response to progressive exercise in children with CP. PMID- 28813967 TI - Integration of serious games and wearable haptic interfaces for Neuro Rehabilitation of children with movement disorders: A feasibility study. AB - The past decade has seen the emergence of rehabilitation treatments using virtual reality environments. One of the advantages in using this technology is the potential to create positive motivation, by means of engaging environments and tasks shaped in the form of serious games. In this work, we propose a novel Neuro Rehabilitation System for children with movement disorders, that is based on serious games in immersive virtual reality with haptic feedback. The system design aims to enhance involvement and engagement of patients, to provide congruent multi-sensory afferent feedback during motor exercises, and to benefit from the flexibility of virtual reality in adapting exercises to the patient's needs. We present a feasibility study of the method conducted through an experimental rehabilitation session in a group of 4 children with Cerebral Palsy and Developmental Dyspraxia, 4 Typically Developing children and 4 healthy adults. Subjects and patients were able to accomplish the proposed rehabilitation session and average performance of the motor exercises in patients were lower, although comparable, to healthy subjects. Together with positive comments reported by children after the rehabilitation session, results are encouraging for application of the method in a prolonged rehabilitation treatment. PMID- 28813968 TI - Changes in neuromuscular activity during motor training with a body-machine interface after spinal cord injury. AB - Body machine interfaces (BMIs) are used by people with severe motor disabilities to control external devices, but they also offer the opportunity to focus on rehabilitative goals. In this study we introduced in a clinical setting a BMI that was integrated by the therapists in the rehabilitative treatments of 2 spinal cord injured (SCI) subjects for 5 weeks. The BMI mapped the user's residual upper body mobility onto the two coordinates of a cursor on a screen. By controlling the cursor, the user engaged in playing computer games. The BMI allowed the mapping between body and cursor spaces to be modified, gradually challenging the user to exercise more impaired movements. With this approach, we were able to change our subjects' behavior, who initially used almost exclusively their proximal upper body-shoulders and arms - for using the BMI. By the end of training, cursor control was shifted toward more distal body regions - forearms instead of upper arms - with an increase of mobility and strength of all the degrees of freedom involved in the control. The clinical tests and the electromyographic signals from the main muscles of the upper body confirmed the positive effect of the training. Encouraging the subjects to explore different and sometimes unusual movement combinations was beneficial for recovering distal arm functions and for increasing their overall mobility. PMID- 28813969 TI - Prediction of user preference over shared-control paradigms for a robotic wheelchair. AB - The design of intelligent powered wheelchairs has traditionally focused heavily on providing effective and efficient navigation assistance. Significantly less attention has been given to the end-user's preference between different assistance paradigms. It is possible to include these subjective evaluations in the design process, for example by soliciting feedback in post-experiment questionnaires. However, constantly querying the user for feedback during real world operation is not practical. In this paper, we present a model that correlates objective performance metrics and subjective evaluations of autonomous wheelchair control paradigms. Using off-the-shelf machine learning techniques, we show that it is possible to build a model that can predict the most preferred shared-control method from task execution metrics such as effort, safety, performance and utilization. We further characterize the relative contributions of each of these metrics to the individual choice of most preferred assistance paradigm. Our evaluation includes Spinal Cord Injured (SCI) and uninjured subject groups. The results show that our proposed correlation model enables the continuous tracking of user preference and offers the possibility of autonomy that is customized to each user. PMID- 28813970 TI - Modelling engagement in dementia through behaviour. Contribution for socially interactive robotics. AB - In this paper, we present a novel tool to measure engagement in people with dementia playing board games and interacting with a social robot, Pleo. We carried out two studies to reach a comprehensive inventory of behaviours accounting for engagement in dementia. The first one is an exploratory study aimed at modelling engagement in cognitive board games. The second one is a longitudinal study to investigate how people with dementia express engagement in cognitive games and in interactions with social robots. We adopted a technique coming from Ethology to mould behaviour, the ethogram. Ethogram is founded on low level behaviours, and allows hierarchical structuring. Herein, we present preliminary results consisting in the description of two ethograms and in their structuring obtained through thematic analysis. Such results show that an underlying structure of engagement exists across activities, and that different activities trigger different behavioural displays of engagement that adhere to such a structure. PMID- 28813971 TI - Feasibility study of transtibial amputee walking using a powered prosthetic foot. AB - Passive prosthetic feet are not able to provide non-amputee kinematics and kinetics for the ankle joint. Persons with amputations show reduced interlimb symmetry, slower walking speeds, and increased walking effort. To improve ankle range of motion and push off, various powered prosthetic feet were introduced. This feasibility study analyzed if predefined motor reference trajectories can be used to achieve non-amputee ankle biomechanics during walking with the powered prosthetic foot, Walk-Run Ankle. Trajectories were calculated using the desired ankle angle and ankle moment based spring deflection at a given spring stiffness. Model assumptions of the motor-spring interaction were well reflected in the experiment. The powered foot was able to improve range of motion, peak ankle power, average positive ankle power, peak ankle moment, and positive moment onset compared to a passive usage of the foot. Furthermore, symmetry improvements were identified for step length and duty factor. Further studies with an increased number of subjects are needed to show if the approach is also valid for other amputees. Using this method as a base, trajectories can be further individualized using human in the loop optimization targeting a reduction of user effort, improved stability, or gait symmetry. PMID- 28813972 TI - Novel ankle orthosis with elastomer-embedded flexible joint. AB - In this study, we propose a new ankle orthosis with elastomer-embedded flexible joints (EEFJ), composed of C-shaped springs and 3D-printed circular elastomer. This orthosis was designed to reduce burden on the tibialis anterior muscle (TA) and to achieve clearance between the tip of the toe and the ground. Fabrication method, strength testing, and gait analysis were conducted. According to the results of strength testing, the combination of the C-spring with 0.3 mm and 0.5 mm thickness and the elastomer with 30% and 60% filling density performs a supporting torque of 0.7-2.3 Nm to plantarflexion. In contrast, torques in the other directions were relatively small. According to the results of gait experiments in seven healthy young subjects, the proposed orthosis successfully reduced activation of TA on initial contact and in the swing phase, and range of motion on initial contact. PMID- 28813973 TI - Adaptive learning to speed-up control of prosthetic hands: A few things everybody should know. AB - Domain adaptation methods have been proposed to reduce the training efforts needed to control an upper-limb prosthesis by adapting well performing models from previous subjects to the new subject. These studies generally reported impressive reductions in the required number of training samples to achieve a certain level of accuracy for intact subjects. We further investigate two popular methods in this field to verify whether this result also applies to amputees. Our findings show instead that this improvement can largely be attributed to a suboptimal hyperparameter configuration. When hyperparameters are appropriately tuned, the standard approach that does not exploit prior information performs on par with the more complicated transfer learning algorithms. Additionally, earlier studies erroneously assumed that the number of training samples relates proportionally to the efforts required from the subject. However, a repetition of a movement is the atomic unit for subjects and the total number of repetitions should therefore be used as reliable measure for training efforts. Also when correcting for this mistake, we do not find any performance increase due to the use of prior models. PMID- 28813974 TI - A cosmetic prosthetic digit with bioinspired embedded touch feedback. AB - Partial hand amputation is the most frequent amputation level worldwide, accounting for approximately 90% of all upper limb amputations. Passive cosmetic prostheses represent one of the possible choices for its treatment, probably the most affordable one. However, these devices restore very limited motor function and subtle sensory feedback. The latter is an important component for restoring the body schema. In this work we present a simple yet potentially effective and low cost cosmetic digital prosthesis that embeds touch feedback; we dubbed this DESC-finger. It delivers short-lasting vibrotactile bursts when it makes and breaks contact with the environment, based on the Discrete Event-driven Sensory feedback Control (DESC) policy. One prototype was developed and used by one amputee at home, for two months. The effectiveness of the device was experimentally assessed by means of an interview and a virtual eggs test, which showed, albeit preliminarily, that time discrete feedback can improve the motor control of a partial hand prosthesis in daily life conditions. Besides targeting people that already use cosmetic digits, the DESC-finger targets those that do not use them complaining for loss of sensibility. The production costs and manufacturing process makes the DESC-finger suitable for exploitation in high- and low-income countries. PMID- 28813975 TI - A lightweight robotic ankle prosthesis with non-backdrivable cam-based transmission. AB - Below-knee level amputation significantly impacts the ability of an individual to ambulate. Transtibial amputees are typically prescribed energetically passive ankle-foot prostheses that behave as a spring or controlled damper, and therefore cannot fully replace the function of the missing limb. More recently, fully powered devices have been proposed to more closely match the power generation ability of intact limbs. However, these fully-powered devices are significantly heavier than passive devices, thus increasing the stress on the socket-residual limb interface. An alternative solution consists of using a motorized mechanism to actively reposition the foot during non-weight-bearing phases. By using this approach, the Ossur(c) PROPRIO FOOT(r) showed promising outcomes such as improved gait energetics at self-selected speed, symmetry, and comfort. However, this device cannot be used by many transtibial amputees due to large build height (180 mm). Moreover, its weight has been shown critical for socket suspension. To address these limitations, we propose a novel non-backdrivable cam-based transmission. Based on this novel transmission, we developed a compact, lightweight ankle foot prosthesis. Bench-top testing and preliminary experiments with an able-bodied subject show that the proposed design can actively reposition the foot in swing as necessary to increase foot clearance, while adapting the ankle position to the ground inclination in stance. PMID- 28813977 TI - Repeatability of grasp recognition for robotic hand prosthesis control based on sEMG data. AB - Control methods based on sEMG obtained promising results for hand prosthetics. Control system robustness is still often inadequate and does not allow the amputees to perform a large number of movements useful for everyday life. Only few studies analyzed the repeatability of sEMG classification of hand grasps. The main goals of this paper are to explore repeatability in sEMG data and to release a repeatability database with the recorded experiments. The data are recorded from 10 intact subjects repeating 7 grasps 12 times, twice a day for 5 days. The data are publicly available on the Ninapro web page. The analysis for the repeatability is based on the comparison of movement classification accuracy in several data acquisitions and for different subjects. The analysis is performed using mean absolute value and waveform length features and a Random Forest classifier. The accuracy obtained by training and testing on acquisitions at different times is on average 27.03% lower than training and testing on the same acquisition. The results obtained by training and testing on different acquisitions suggest that previous acquisitions can be used to train the classification algorithms. The inter-subject variability is remarkable, suggesting that specific characteristics of the subjects can affect repeatibility and sEMG classification accuracy. In conclusion, the results of this paper can contribute to develop more robust control systems for hand prostheses, while the presented data allows researchers to test repeatability in further analyses. PMID- 28813976 TI - Megane Pro: Myo-electricity, visual and gaze tracking data acquisitions to improve hand prosthetics. AB - During the past 60 years scientific research proposed many techniques to control robotic hand prostheses with surface electromyography (sEMG). Few of them have been implemented in commercial systems also due to limited robustness that may be improved with multimodal data. This paper presents the first acquisition setup, acquisition protocol and dataset including sEMG, eye tracking and computer vision to study robotic hand control. A data analysis on healthy controls gives a first idea of the capabilities and constraints of the acquisition procedure that will be applied to amputees in a next step. Different data sources are not fused together in the analysis. Nevertheless, the results support the use of the proposed multimodal data acquisition approach for prosthesis control. The sEMG movement classification results confirm that it is possible to classify several grasps with sEMG alone. sEMG can detect the grasp type and also small differences in the grasped object (accuracy: 95%). The simultaneous recording of eye tracking and scene camera data shows that these sensors allow performing object detection for grasp selection and that several neurocognitive parameters need to be taken into account for this. In conclusion, this work on intact subjects presents an innovative acquisition setup and protocol. The first results in terms of data analysis are promising and set the basis for future work on amputees, aiming to improve the robustness of prostheses with multimodal data. PMID- 28813978 TI - Evaluation of 3D printed anatomically scalable transfemoral prosthetic knee. AB - This case study compares a transfemoral amputee's gait while using the existing Ossur Total Knee 2000 and our novel 3D printed anatomically scalable transfemoral prosthetic knee. The anatomically scalable transfemoral prosthetic knee is 3D printed out of a carbon-fiber and nylon composite that has a gear-mesh coupling with a hard-stop weight-actuated locking mechanism aided by a cross-linked four bar spring mechanism. This design can be scaled using anatomical dimensions of a human femur and tibia to have a unique fit for each user. The transfemoral amputee who was tested is high functioning and walked on the Computer Assisted Rehabilitation Environment (CAREN) at a self-selected pace. The motion capture and force data that was collected showed that there were distinct differences in the gait dynamics. The data was used to perform the Combined Gait Asymmetry Metric (CGAM), where the scores revealed that the overall asymmetry of the gait on the Ossur Total Knee was more asymmetric than the anatomically scalable transfemoral prosthetic knee. The anatomically scalable transfemoral prosthetic knee had higher peak knee flexion that caused a large step time asymmetry. This made walking on the anatomically scalable transfemoral prosthetic knee more strenuous due to the compensatory movements in adapting to the different dynamics. This can be overcome by tuning the cross-linked spring mechanism to emulate the dynamics of the subject better. The subject stated that the knee would be good for daily use and has the potential to be adapted as a running knee. PMID- 28813979 TI - Towards low back support with a passive biomimetic exo-spine. AB - Low-Back Pain (LBP) affects a large portion of the working population. Preventive exoskeletons have been proposed to reduce the moments on the lower back, specifically around the lumbosacral (L5/S1) joint. High correlation has been shown, between reducing the moments around the L5/S1 joint and intervertebral compression forces, which in turn have been identified as a risk factor for developing LBP. However, most passive back support exoskeletons use rigid plates or stiff beams to support the spine that limit the range of motion of the wearer. A large range of motion and versatility are especially desirable for industrial applications. To overcome these limitations, a passive biomimetic exo-spine has been designed, modelled and an initial prototype tested. Its potential to allow for a large range of motion, whilst at the same time limiting the most extreme and potentially harmful postures has been shown. PMID- 28813980 TI - Human mimetic forearm mechanism towards bionic arm. AB - The paper presents a mechanical forearm mechanism to extend the pronation and supination (P/S) movement of the trans-radial amputee when he/she is able to conduct the P/S motion partially with his/her remaining forearm. The P/S motions of the existing prostheses and robotic arms developed till now are completely different from those of the human. When we are to develop the robotic prostheses for the amputees, two important issues should be considered such as cosmetic issue to look like normal arm and motion harmony issue between robotic prosthesis and the amputated living arm. Most prostheses do not realize the human-like P/S motion, but the simple rotational motion at the wrist by using the electric motor. In this paper, the well-known spatial four-bar mechanism is adopted in order to mimic human P/S motion as if the person does, because it is one of the best candidates to describe actual human forearm movement. To obtain the design parameters of the mechanism, first, 3D data of the amputated arm as well as the opposite side non-amputated arm are captured by using MRI (Magnetic Resonance Imaging) and 3D scanner. The design parameters such as link lengths, joint locations, and volumetric shape are determined from the measured data. Second, mathematical analysis is performed to simulate one degree-of-freedom P/S motion realized from the spatial four-bar mechanism, and the simulation results are suggested to confirm whether or not it acts like the relative movement between human ulnar and radius bones. Finally the effectiveness of the proposed mechanism is verified through two ADL (activities of daily living) tests. PMID- 28813981 TI - A magnetic compatible supernumerary robotic finger for functional magnetic resonance imaging (fMRI) acquisitions: Device description and preliminary results. AB - The Supernumerary robotic limbs are a recently introduced class of wearable robots that, differently from traditional prostheses and exoskeletons, aim at adding extra effectors (i.e., arms, legs, or fingers) to the human user, rather than substituting or enhancing the natural ones. However, it is still undefined whether the use of supernumerary robotic limbs could specifically lead to neural modifications in brain dynamics. The illusion of owning the part of body has been already proven in many experimental observations, such as those relying on multisensory integration (e.g., rubber hand illusion), prosthesis and even on virtual reality. In this paper we present a description of a novel magnetic compatible supernumerary robotic finger together with preliminary observations from two functional magnetic resonance imaging (fMRI) experiments, in which brain activity was measured before and after a period of training with the robotic device, and during the use of the novel MRI-compatible version of the supernumerary robotic finger. Results showed that the usage of the MR-compatible robotic finger is safe and does not produce artifacts on MRI images. Moreover, the training with the supernumerary robotic finger recruits a network of motor related cortical regions (i.e. primary and supplementary motor areas), hence the same motor network of a fully physiological voluntary motor gestures. PMID- 28813982 TI - Validation of a constrained-time movement task for use in rehabilitation outcome measures. AB - Current motor assessment tools can provide numerical indicators of performance but do not provide actionable information to target further improvement in rehabilitation interventions. Psychophysics-based outcome measures show promise to provide more useful information in the laboratory environment but have been limited in clinical implementation. Here we present a constrained-time task to assess paced and non-rhythmic movements. The task's output metrics include trial by-trial adaptation rate and the just noticeable difference of a perturbation. We show that the task's metrics are reliable (i.e. high test-retest reliability) and are responsive to changes in feedback type and experience. We also discuss the task's versatility to be used for other types of movements including grasping. The consistent, sensitive and flexible time-constrained movement task we present provides a foundation from which to develop advanced outcome measures for prosthesis users and for other rehabilitation contexts. PMID- 28813983 TI - Modeling and control of a transfemoral prosthesis embedding two infinitely variable transmissions. AB - In this paper, we report the model of an original actuation concept for a transfemoral prosthesis, relying on the combination of a single power motor, a compliant element (a spring), a mechanical differential, and two infinitely variable transmissions. It allows to manage the mechanical power flows through the device in both directions (i.e. when energy should be produced or dissipated by the knee and ankle), so that the power motor does not face the sharp load power fluctuations. The paper further reports a preliminary approach to synthesize a closed-loop controller for this device, and simulation results of this closed-loop behavior for three locomotion tasks: level-ground walking and stair ascent/descent. These results illustrate the capacity of this actuation principle to filter the load power profile, and further highlight the necessity to maximize the mechanical efficiency of each part of this actuation scheme. PMID- 28813984 TI - A passive wrist with switchable stiffness for a body-powered hydraulically actuated hand prosthesis. AB - State of art upper limb prostheses lack several degrees of freedom (DoF) and force the individuals to compensate for them by changing the motions of their arms and body. Such movements often yield to articulation injuries, nonetheless these could be prevented by adding DoFs, for instance, an articulated passive wrist. Available stiff or compliant wrists with passive flexion/extension and/or radial/ulnar deviation are sub-optimal solutions. Indeed, stiff wrists induce the individuals wearing them to perform exaggerated compensatory movements during the reaching phase while compliant wrists proved to be unpractical while manipulating heavy objects. Here we present a wrist capable of combining the benefits of stiff and compliant wrists. It is provided with two switchable levels of passive compliance that are automatically selected. The prototype was integrated in a body-powered hydraulic hand prosthesis and actuated using the same hydraulic circuit of the hand. Detailed analysis of the parameters that affect the compliance, the critical load and the performance of the prosthesis are presented. PMID- 28813985 TI - EMG pattern classification to control a hand orthosis for functional grasp assistance after stroke. AB - Wearable orthoses can function both as assistive devices, which allow the user to live independently, and as rehabilitation devices, which allow the user to regain use of an impaired limb. To be fully wearable, such devices must have intuitive controls, and to improve quality of life, the device should enable the user to perform Activities of Daily Living. In this context, we explore the feasibility of using electromyography (EMG) signals to control a wearable exotendon device to enable pick and place tasks. We use an easy to don, commodity forearm EMG band with 8 sensors to create an EMG pattern classification control for an exotendon device. With this control, we are able to detect a user's intent to open, and can thus enable extension and pick and place tasks. In experiments with stroke survivors, we explore the accuracy of this control in both non-functional and functional tasks. Our results support the feasibility of developing wearable devices with intuitive controls which provide a functional context for rehabilitation. PMID- 28813986 TI - Evaluation of the Myo armband for the classification of hand motions. AB - Pattern recognition-based control systems have been widely investigated in prostheses and virtual reality environments to improve amputees' quality of life. Most of these systems use surface electromyography (EMG) to detect user movement intentions. The Myo armband (MYB) is a wireless wearable device, developed by Thalmic Labs, which enables EMG recordings with a limited bandwidth (<100Hz). The aim of this study was to compare MYB's narrow bandwidth with a conventional EMG acquisition system (CONV) that captures the full EMG spectrum to assess its suitability for pattern recognition control. A crossover study was carried out with eight able-bodied participants, performing nine hand gestures. Six features were extracted from the data and classified by Linear Discriminant Analysis (LDA). Results showed a mean classification error of 5.82 +/- 3.63% for CONV and 9.86 +/- 8.05% for MYB with no significantly difference (P = 0.056). This implies that MYB may be suitable for pattern recognition applications despite the limitation in the bandwidth. PMID- 28813987 TI - Personalized design of a hand prosthesis considering anthropometry of a real hand extracted from radiography. AB - Commercially available prostheses do not meet patients' expectations regarding dimensions, shape and aesthetic reasons. This paper presents the design of an anthropomorphic and anthropometric prosthesis based on dimensions and shape extracted from a digitized radiograph of the healthy hand of the patient. The mobility of the hand is guaranteed by making a design of phalanges, joints, ligaments and tendons, as closest as possible to a real hand. The kinematic model is presented and validated. A proposal of the actuation system is also described. PMID- 28813988 TI - Capturing prosthetic socket fitment: Preliminary results using an ultrasound based device. AB - The acceptance of advanced prosthetic systems by users requires overcoming unique challenges of fitting prostheses to unique user anatomies to achieve systematic performance across a user base. Variations among individuals introduce complexities in fitting the sockets. Due to the difficulty of measuring socket interface characteristics, there is a lack of quantifiable diagnostic fitment information available. As a result, the process of fitting sockets is currently a laborintensive, manual approach, and can often result in sockets that are uncomfortable, unstable, or impede full range of motion. Additionally, results can be difficult to reproduce reliably. A diagnostic tool has been developed to quantify the relative movement between the socket and the residual bone during the fitting process. The approach leverages low cost and high precision ultrasound transceivers and intuitive visualization software to provide quantifiable socket fitment data. The goal is to enable a systematic socket fitting strategy that yields reliable and reproducible results. Human subject testing and results are presented that show movement tracking relative to a cuff with an ultrasound transducer with an RMSD of 0.36 mm. PMID- 28813989 TI - Quantification of information transfer rate of the human hand during a mouse clicking task with healthy adults and one adult with Duchenne muscular Dystrophy. AB - Duchenne muscular Dystrophy (DMD) Is a progressive muscle degenerative disease. Active hand assistive devices, can improve the quality of life of people with DMD. Such devices show a rejection rate due to complexity. Our hypothesis is, that a simple orthosis might prove more functional and realistic in assisting people with DMD. To investigate, we developed a portable setup that provides various visual stimuli and records the response of the subjects' fingers through a mouse clicking task. Six LEDs served as visual stimuli. The subjects' responses were obtained through mechanical interaction with two vertical mice. Different combinations of frequencies and numbers of stimuli were tested with 8 healthy subjects and one with DMD. Performance was evaluated in terms of information transfer rate (ITR), pattern accuracy and perceived workload. The outcome shows that lower complexity results in lower ITR and lower workload for all subjects. While for healthy subjects, maximum ITR was 4.3 bits/s, for DMD maximum ITR was 2.5 bits/s. Both maxima were achieved at the same trial (3 fingers at 2 Hz). This trial agrees with a pareto optimization analysis of ITR with respect to workload. The results support our hypothesis for a simple yet functional solution. Furthermore healthy subjects and the individual with DMD, in principal show similar finger control, albeit with lower absolute performance. PMID- 28813990 TI - A learning-based agent for home neurorehabilitation. AB - This paper presents the iterative development of an artificially intelligent system to promote home-based neurorehabilitation. Although proper, structured practice of rehabilitation exercises at home is the key to successful recovery of motor functions, there is no home-program out there which can monitor a patient's exercise-related activities and provide corrective feedback in real time. To this end, we designed a Learning from Demonstration (LfD) based home-rehabilitation framework that combines advanced robot learning algorithms with commercially available wearable technologies. The proposed system uses exercise-related motion information and electromyography signals (EMG) of a patient to train a Markov Decision Process (MDP). The trained MDP model can enable an agent to serve as a coach for a patient. On a system level, this is the first initiative, to the best of our knowledge, to employ LfD in an health-care application to enable lay users to program an intelligent system. From a rehabilitation research perspective, this is a completely novel initiative to employ machine learning to provide interactive corrective feedback to a patient in home settings. PMID- 28813991 TI - Voluntary phantom hand and finger movements in transhumerai amputees could be used to naturally control polydigital prostheses. AB - An arm amputation is extremely invalidating since many of our daily tasks require bi-manual and precise control of hand movements. Perfect hand prostheses should therefore offer a natural, intuitive and cognitively simple control over their numerous biomimetic active degrees of freedom. While efficient polydigital prostheses are commercially available, their control remains complex to master and offers limited possibilities, especially for high amputation levels. In this pilot study, we demonstrate the possibility for upper-arm amputees to intuitively control a polydigital hand prosthesis by using surface myoelectric activities of residual limb muscles (sEMG) associated with phantom limb movements, even if these residual arm muscles on which the phantom activity is measured were not naturally associated with hand movements before amputation. Using pattern recognition methods, three arm amputees were able, without training, to initiate 5-8 movements of a robotic hand (including individual finger movements) by simply mobilizing their phantom limb while the robotic hand was mimicking the action in real time. This innovative control approach could offer to numerous upper-limb amputees an access to recent biomimetic prostheses with multiple controllable joints, without requiring surgery or complex training; and might deeply change the way the phantom limb is apprehended by both patients and clinicians. PMID- 28813992 TI - Review of the actuators of active knee prostheses and their target design outputs for activities of daily living. AB - Active prosthetic knees have the capability to provide net positive work, which is required in daily activities like stair and ramp negotiation or sit-to-stand transfers. Adding this capability might help to increase user mobility, safety, and independence. This article summarizes the biomechanical knee requirements for different activities of daily living and critically compares them with the actuator characteristics of state-of-the-art active prosthetic knee joints. As a result of a systematic literature research 22 active prosthetic knee joints were identified. Most systems use a stiff actuator in combination with a ball screw and are capable of supporting the majority of daily tasks for the average US citizen (82.5 kg) at self-selected movement speed. Physiological requirements exceed most system specifications if increased user mass, walking speed, or inclinations are assumed. To cope with the requirements, springs and dampers are used to assist the motor. The comparison of the prostheses characteristics with anthropometric data shows that most of the devices are in the physiological range for the system height and even when being tethered it is critical to achieve a physiological mass. Also while just one active knee is commercialized so far, physiological knee biomechanics show that there is a potential for active prosthetic knee solutions. Summarized biomechanical and anthropometric data can be used as a framework to develop prototypes. Further, the overview of state-of the-art systems can provide possible solutions to deal with the task specific prosthetic knee requirements. PMID- 28813993 TI - The influence of a user-adaptive prosthetic knee on planned gait termination. AB - The added value of user-adaptive prosthetic knees has been predominantly evaluated in level walking or ramp/stair negotiation. Previous studies indicate that the activity pattern of individuals with an amputation mainly consists of short periods of continuous walking, indicating that a high percentage of ambulatory activity involves gait termination. The potential added value of user adaptive prosthetic knees in gait termination has not been studied yet. Ten individuals with an amputation were measured with their own non-microprocessor controlled prosthetic knee and with the Rheo Knee II (a user-adaptive prosthetic knee). Spatiotemporal, kinematic and kinetic variables were measured. We found that the Rheo Knee II had no effect on the studied outcome parameters when compared to the non-microprocessor controlled prosthetic knee. We also found that the intact leg was responsible for producing the deceleration forces irrespective whether the last step was made by the intact or prosthetic leg. In conclusion we found that the prosthetic leg is limited in producing deceleration forces. Although user-adaptive prosthetic knees claim to increase stance stability, the added value of the Rheo Knee II on the studied outcome parameters is limited. PMID- 28813994 TI - Two single cases treated by a new pseudoelastic upper-limb orthosis for secondary dystonia of the young. AB - The study proposes a new treatment for dystonia based on a dynamic wearable orthosis equipped with metallic materials of non-linear mechanical characteristics. Two boys with upper-limb dystonia were enrolled, as well as six healthy children. Fully-customised devices were made for the patients. They used the orthosis for one month and their performances were evaluated before and after the treatment. The assessment was done with clinical scales (Modified Ashworth Score, Melbourne Upper Limb Assessment, PedsQL), interviews and optoelectronic kinematic analysis. Normal kinematics was obtained from the healthy group for comparison. Kinematic analysis showed modifications in motor patterns for both patients, with increases in the ranges of motion of initially stiff segments, improvements in posture, emergence of multi-joint strategies. Clinical scales did not always show similar trends in the two cases. The changes in control strategies could be linked to the force field dynamically applied by the device and appear to be learnable. This interpretation will be further tested with larger groups and longer treatments. PMID- 28813995 TI - A novel human effort estimation method for knee assistive exoskeletons. AB - In this work we present a novel method to estimate online the torques at the knee joints with the goal to generate reference signals for knee assistive devices. One of the main advantages of the proposed approach is its reduced sensing requirements, which leads to an ergonomic setup with minimal instrumentation, especially above the knee and of the upper body. Indeed, only the measurement of the forces and torques exchanged between the ground and the user's feet, the posture of the shanks, and the model of the user's shank itself are needed for the estimation of the knee torque. The method does not require information of the state of the upper body and of a possible payload i.e. body pose, mass and center of mass (CoM) location. As a result, a minimalistic sensory system consisting of sensorized shoes and IMUs to track the shanks' orientation are adequate, allowing for an easily wearable and portable setup. The estimation of the knee torques is achieved by imposing an equilibrium condition to the user's shank. Several experiments were performed to test the effectiveness of the proposed estimation method under different body postures and motions (e.g. squat motion and switching foot contacts) and payloads (e.g. by holding weights at different arm postures resulting in variable upper body CoM). Finally an assistive task, conducted with the iT-Knee bipedal system is presented, where the lifted payload changed its CoM location over time. PMID- 28813996 TI - Analyzing at-home prosthesis use in unilateral upper-limb amputees to inform treatment & device design. AB - New upper limb prosthetic devices are continuously being developed by a variety of industrial, academic, and hobbyist groups. Yet, little research has evaluated the long term use of currently available prostheses in daily life activities, beyond laboratory or survey studies. We seek to objectively measure how experienced unilateral upper limb prosthesis-users employ their prosthetic devices and unaffected limb for manipulation during everyday activities. In particular, our goal is to create a method for evaluating all types of amputee manipulation, including non-prehensile actions beyond conventional grasp functions, as well as to examine the relative use of both limbs in unilateral and bilateral cases. This study employs a head-mounted video camera to record participant's hands and arms as they complete unstructured domestic tasks within their own homes. A new 'Unilateral Prosthesis-User Manipulation Taxonomy' is presented based observations from 10 hours of recorded videos. The taxonomy addresses manipulation actions of the intact hand, prostheses, bilateral activities, and environmental feature-use (aiiordances). Our preliminary results involved tagging 23 minute segments of the full videos from 3 amputee participants using the taxonomy. This resulted in over 2,300 tag instances. Observations included that non-prehensile interactions outnumbered prehensile interactions in the affected limb for users with more distal amputation that allowed arm mobility. PMID- 28813997 TI - Dynamic elasticity measurement for prosthetic socket design. AB - The paper proposes a novel apparatus to measure the dynamic elasticity of human limb in order to help the design and fabrication of the personalized prosthetic socket. To take measurements of the dynamic elasticity, the desired force generated as an exponential chirp signal in which the frequency increases and amplitude is maintained according to time progress is applied to human limb and then the skin deformation is recorded, ultimately, to obtain the frequency response of its elasticity. It is referred to as a Dynamic Elasticity Measurement Apparatus (DEMA) in the paper. It has three core components such as linear motor to provide the desired force, loadcell to implement the force feedback control, and potentiometer to record the skin deformation. After measuring the force/deformation and calculating the dynamic elasticity of the limb, it is visualized as 3D color map model of the limb so that the entire dynamic elasticity can be shown at a glance according to the locations and frequencies. For the visualization, the dynamic elasticities measured at specific locations and frequencies are embodied using the color map into 3D limb model acquired by using 3D scanner. To demonstrate the effectiveness, the visualized dynamic elasticities are suggested as outcome of the proposed system, although we do not have any opportunity to apply the proposed system to the amputees. Ultimately, it is expected that the proposed system can be utilized to design and fabricate the personalized prosthetic socket in order for releasing the wearing pain caused by the conventional prosthetic socket. PMID- 28813998 TI - Joint stiffness modulation of compliant actuators for lower limb exoskeletons. AB - Lower limb exoskeletons are being used to assist people with movement disorders during activities of daily living or rehabilitation. However, providing a natural interface that automatically adapts to the patient's movement limitations remains an open challenge. In this paper, we present a control implementation that combines a compliant actuator technology with the concept of tacit learning to improve the synchronisation between the exoskeleton and the user during locomotion. We show that this implementation can be effectively used to easily modulate the joint stiffness that is perceived by the user during locomotion. This scheme set the base for the implementation of an automatically shared control between the exoskeleton and its user. PMID- 28813999 TI - Upper-limb prosthetic control using wearable multichannel mechanomyography. AB - In this paper we introduce a robust multi-channel wearable sensor system for capturing user intent to control robotic hands. The interface is based on a fusion of inertial measurement and mechanomyography (MMG), which measures the vibrations of muscle fibres during motion. MMG is immune to issues such as sweat, skin impedance, and the need for a reference signal that is common to electromyography (EMG). The main contributions of this work are: 1) the hardware design of a fused inertial and MMG measurement system that can be worn on the arm, 2) a unified algorithm for detection, segmentation, and classification of muscle movement corresponding to hand gestures, and 3) experiments demonstrating the real-time control of a commercial prosthetic hand (Bebionic Version 2). Results show recognition of seven gestures, achieving an offline classification accuracy of 83.5% performed on five healthy subjects and one transradial amputee. The gesture recognition was then tested in real time on subsets of two and five gestures, with an average accuracy of 93.3% and 62.2% respectively. To our knowledge this is the first applied MMG based control system for practical prosthetic control. PMID- 28814000 TI - Preliminary study of a robotic foot-ankle prosthesis with active alignment. AB - Robotic prosthetic foot-ankle prostheses typically aim to replace the lost joint with revolute joints aimed at replicating normal joint biomechanics. In this paper, a previously developed robotic ankle prosthesis with active alignment is evaluated. It uses a four-bar mechanism to inject positive power into the gait cycle while altering the kinematics of the ankle joint and pylon segment to reduce loading on the residual limb. In a single-subject biomechanics analysis, there was a 10% reduction in peak limb pressures and evidence of greater gait symmetry in ground reaction forces when active alignment was implemented compared to walking with the daily use prosthesis. These results provide preliminary evidence that an alternative lower limb prosthesis may be capable of improving gait characteristics over traditional revolute designs. PMID- 28814001 TI - Design of an energy efficient transfemoral prosthesis using lockable parallel springs and electrical energy transfer. AB - Over the last decade, active lower-limb prostheses demonstrated their ability to restore a normal gait for transfemoral amputees by supplying the required positive energy balance [1]. However, the added-value of such devices is significantly impacted by their limited energetic autonomy preventing their full appropriation by the patients. There is thus a strong incentive to reduce the overall power consumption of active prostheses. Addressing this need requires to revisit the electromechanical design. For both the ankle and the knee, the present paper demonstrates that both the use of a lockable parallel spring and the transfer of electrical energy between joints can significantly improve the energetic performance for overground walking. A simulation model of such a prosthesis was implemented in order to quantify the energy gain being achievable when augmenting a classical series elastic actuator (SEA) with different parallel spring topologies. Simulations predict that adding a lockable parallel spring (LPS) to the SEA reduces the ankle motor consumption by 24% and allows the knee (naturally dissipative) to produce 38% more electrical energy. Moreover, the total energy consumption of the device is reduced to 22J/stride when the harvested electrical energy from the knee is stored and transfered to the ankle. PMID- 28814002 TI - Joint-based velocity feedback to virtual limb dynamic perturbations. AB - Despite significant research developing myoelectric prosthesis controllers, many amputees have difficulty controlling their devices due in part to reduced sensory feedback. Many attempts at providing supplemental sensory feedback have not significantly aided control. We hypothesize this is because the feedback provided contains redundant information already provided by vision. However, whereas vision provides egocentric, position-based feedback, sensory feedback tied to joint coordinates may provide information complementary to vision. In this study, we tested if providing audio feedback of joint velocities can improve performance and adaptation to dynamic perturbations while controlling a virtual limb. While subjects performed time-controlled center-out reaches, we perturbed the dynamics of the system and measured the rate subjects adapted to this change. Our results suggest that initial errors were reduced in the presence of audio feedback, and we theorize this is due to subjects identifying the perturbed limb dynamics sooner. We also noted other possible benefits including improved muscle activation detection. PMID- 28814003 TI - A springs actuated finger exoskeleton: From mechanical design to spring variables evaluation. AB - In the context of post-stroke patients, suffering of hemiparesis of the hand, robot-aided neuro-motor rehabilitation allows for intensive rehabilitation treatments and quantitative evaluation of patients' progresses. This work presents the design and evaluation of a spring actuated finger exoskeleton. In particular, the spring variables and the interaction forces between the assembly and the hand were investigated, in order to assess the effectiveness of the proposed exoskeleton. PMID- 28814004 TI - Biomimetic finger extension mechanism for soft wearable hand rehabilitation devices. AB - For the rehabilitation and assistance of the hand functions, wearable devices have been developed, and the interest in tendon driven mechanisms have especially increased since it allows light weight and compact design. The tendon driven hand rehabilitation devices provides grasping force via exo-tendons routed on the dorsal and palmar sides of the hand pulled by remotely located actuators. However, most of the devices were not able to provide natural joint extension sequence of the finger and showed hyperextension of finger joints because the tendons for extension were fixed at the fingertip, concentrating the torque at the distal interphalangeal joint. In this study, a ring-type biomimetic finger extension mechanism was developed, which mimics the origin, structure, and orientation of the extensor tendon. The biomimetic mechanism was evaluated by comparing the motion with voluntary finger extension and the motion made by other conventional tendon driven finger extension mechanisms. The biomimetic extension mechanism provided the same joint extension sequence with voluntary finger extension, and the fully extended posture was most close to the voluntary finger extension among the tendon-driven mechanisms used in the experiments. The joint angle differences between the proposed tendon mechanism and the voluntary finger extension was -1.2 degrees +/-3.4 degrees , -2.9 degrees +/-2.0 degrees , and 3.1 degrees +/-8.0 degrees for distal phalangeal, proximal phalangeal, and metacarpo-phalangeal joint, respectively. PMID- 28814005 TI - Distance-based kinematics of the five-oblique-axis thumb model with intersecting axes at the metacarpophalangeal joint. AB - This paper proposes a novel and simple method to compute all possible solutions of the inverse kinematics problem of the five-oblique-axis thumb model with intersecting axes at the metacarpophalangeal joint. This thumb model is one of the suggested results by a magnetic-resonance-imaging-based study that, in contrast to those based on cadaver fingers or on the tracking of the surface of the fingers, takes into account muscle and ligament behaviors and avoids inaccuracies resulting from the movement of the skin with respect to the bones. The proposed distance-based inverse kinematics method eliminates the use of arbitrary reference frames as is usually required by standard approaches; this is relevant because the numerical conditioning of the resulting system of equations with such traditional approaches depends on the selected reference frames. Moreover, contrary to other parametrizations (e.g., Denavit-Hartenberg parameters), the suggested distance-based parameters for the thumb have a natural, human-understandable geometric meaning that makes them easier to be determined from any posture. These characteristics make the proposed approach of interest for those working in, for instance, measuring and modeling the movement of the human hand, developing rehabilitation devices such as orthoses and prostheses, or designing anthropomorphic robotic hands. PMID- 28814006 TI - Development and evaluation of a method to measure wrist range of motion on paretic hand rehabilitation device. AB - This paper presents the development of wrist ROM measurement system that was implemented on a rehabilitation glove for paretic hand, Easy-Flex, using a rotary potentiometer. This approach enables the device to measure the angles of up to 80 degrees with the approximate resolution of 0.1 degrees . The method along with a universal goniometer and a smartphone clinometer application were tested on 17 healthy participants in terms of reliability. The three instruments were able to accurately measure three different angles (flexion: -10 degrees , neutral: 0 degrees , and extension: 20 degrees ) with measurement errors less than 2 degrees . Moreover, ICCs of the proposed method were close to 0.90 indicating the method implemented on Easy-Flex is reliable for measuring wrist flexion and extension measurement. PMID- 28814007 TI - Embroidered archimedean spiral electrodes for contactless prosthetic control. AB - With continuous advancements on active prosthetics the detection of the user's intention becomes the new technological bottleneck. While electromyography (EMG) is widely used to detect individual muscular contributions, sweat and relative sensor movements degrade the quality of the signal over time. In this paper, we bypass the problems created with the skin contact analyzing the muscular activation with Archimedean Spiral (AS) electrodes. We compare traditional EMG electrodes with AS electrodes, stacked up in textile embroidered layers to improve their functionality, and eventually adding a layer of cloth/silicon between the electrodes and the human skin to ascertain the feasibility of the method. We use n=9 volunteers to perform a loaded wrist extension and record signals from the extensor digitorum muscle group. We evaluate the amplitude and noise from all results and conclude that the AS electrode is capable of detecting muscular activation without touching the skin. As part of a low-cost prosthetic initiative, this EMG alternative can be potentially embedded to the prosthetic socket to improve usage and reduce adaptation problems. PMID- 28814008 TI - Self-aligning exoskeleton hip joint: Kinematic design with five revolute, three prismatic and one ball joint. AB - Kinematic compatibility is of paramount importance in wearable robotic and exoskeleton design. Misalignments between exoskeletons and anatomical joints of the human body result in interaction forces which make wearing the exoskeleton uncomfortable and even dangerous for the human. In this paper we present a kinematically compatible design of an exoskeleton hip to reduce kinematic incompatibilities, so called macro- and micro-misalignments, between the human's and exoskeleton's joint axes, which are caused by inter-subject variability and articulation. The resulting design consists of five revolute, three prismatic and one ball joint. Design parameters such as range of motion and joint velocities are calculated based on the analysis of human motion data acquired by motion capture systems. We show that the resulting design is capable of self-aligning to the human hip joint in all three anatomical planes during operation and can be adapted along the dorsoventral and mediolateral axis prior to operation. Calculation of the forward kinematics and FEM-simulation considering kinematic and musculoskeletal constraints proved sufficient mobility and stiffness of the system regarding the range of motion, angular velocity and torque admissibility needed to provide 50 % assistance for an 80 kg person. PMID- 28814009 TI - Preliminary results toward a naturally controlled multi-synergistic prosthetic hand. AB - Robotic hands embedding human motor control principles in their mechanical design are getting increasing interest thanks to their simplicity and robustness, combined with good performance. Another key aspect of these hands is that humans can use them very effectively thanks to the similarity of their behavior with real hands. Nevertheless, controlling more than one degree of actuation remains a challenging task. In this paper, we take advantage of these characteristics in a multi-synergistic prosthesis. We propose an integrated setup composed of Pisa/IIT SoftHand 2 and a control strategy which simultaneously and proportionally maps the human hand movements to the robotic hand. The control technique is based on a combination of non-negative matrix factorization and linear regression algorithms. It also features a real-time continuous posture compensation of the electromyographic signals based on an IMU. The algorithm is tested on five healthy subjects through an experiment in a virtual environment. In a separate experiment, the efficacy of the posture compensation strategy is evaluated on five healthy subjects and, finally, the whole setup is successfully tested in performing realistic daily life activities. PMID- 28814010 TI - Multi-modal myocontrol: Testing combined force- and electromyography. AB - Myocontrol, that is control of prostheses using bodily signals, has proved in the decades to be a surprisingly hard problem for the scientific community of assistive and rehabilitation robotics. In particular, traditional surface electromyography (sEMG) seems to be no longer enough to guarantee dexterity (i.e., control over several degrees of freedom) and, most importantly, reliability. Multi-modal myocontrol is concerned with the idea of using novel signal gathering techniques as a replacement of, or alongside, sEMG, to provide high-density and diverse signals to improve dexterity and make the control more reliable. In this paper we present an offline and online assessment of multi modal sEMG and force myography (FMG) targeted at hand and wrist myocontrol. A total number of twenty sEMG and FMG sensors were used simultaneously, in several combined configurations, to predict opening/closing of the hand and activation of two degrees of freedom of the wrist of ten intact subjects. The analysis was targeted at determining the optimal sensor combination and control parameters; the experimental results indicate that sEMG sensors alone perform worst, yielding a nRMSE of 9.1%, while mixing FMG and sEMG or using FMG only reduces the nRMSE to 5.2-6.6%. To validate these results, we engaged the subject with median performance in an online goal-reaching task. Analysis of this further experiment reveals that the online behaviour is similar to the offline one. PMID- 28814011 TI - Adaptive control of an exoskeleton robot with uncertainties on kinematics and dynamics. AB - In this paper, we propose a new adaptive control technique based on nonlinear sliding mode control (JSTDE) taking into account kinematics and dynamics uncertainties. This approach is applied to an exoskeleton robot with uncertain kinematics and dynamics. The adaptation design is based on Time Delay Estimation (TDE). The proposed strategy does not necessitate the well-defined dynamic and kinematic models of the system robot. The updated laws are designed using Lyapunov-function to solve the adaptation problem systematically, proving the close loop stability and ensuring the convergence asymptotically of the outputs tracking errors. Experiments results show the effectiveness and feasibility of JSTDE technique to deal with the variation of the unknown nonlinear dynamics and kinematics of the exoskeleton model. PMID- 28814012 TI - Quantitative measures with WREX usage. AB - This paper presents the results of two surveys conducted with users of a functional upper extremity orthosis called the Wilmington Robotic EXoskeleton (WREX). The WREX is a passive anti-gravity arm orthosis that allows people with neuromuscular disabilities to move their arms in three dimensions. An online user survey with 55 patients was conducted to determine the benefits of the WREX. The survey asked 10 questions related to upper extremity function with and without the WREX as well as subjective impressions of the device. A second survey used a phone interview based on the Canadian Occupational Performance Measure (COPM). Parents rated their child's performance and satisfaction while partaking in important activities both with and without the exoskeleton device. Scores were assessed for change between the two conditions. Twenty-five families responded to this survey. Twenty-four out of 25 subjects reported greater levels of performance and satisfaction when they were wearing the WREX. The mean change in performance score was 3.61 points, and the mean change in satisfaction score was 4.44 points. Results show a statistically significant improvement in arm function for everyday tasks with the WREX. PMID- 28814013 TI - A third arm - Design of a bypass prosthesis enabling incorporation. AB - A variety of factors affect the performance of a person using a myoelectric prosthesis, including increased control noise, reduced sensory feedback, and muscle fatigue. Many studies use able-bodied subjects to control a myoelectric prosthesis using a bypass socket in order to make comparisons to movements made with intact limbs. Depending on the goals of the study, this approach can also allow for greater subject numbers and more statistical power in the analysis of the results. As we develop assessment tools and techniques to evaluate how peripheral nerve interfaces impact prosthesis incorporation, involving normally limbed subjects in the studies becomes challenging. We have designed a novel bypass prosthesis to allow for the assessment of prosthesis incorporation in able bodied subjects. Incorporation of a prosthetic hand worn by a normally limbed subject requires that the prosthesis is a convincing, functional extension of their own body. We present the design and development of the bypass prosthesis with special attention to mounting position and angle of the prosthetic hand, the quality of the control system and the responsiveness of the feedback. The bypass prosthesis has been fitted with a myoelectrically-controlled hand that has been instrumented to measure the forces applied to the thumb, index, and middle fingers. The prosthetic hand was mounted on the bypass socket such that it is the same length as the subject's intact limb but at a medial rotation angle of 20 degrees to prevent visual occlusion of the prosthetic hand. Force feedback is provided in the form of electrical stimulation, vibration, or force applied to the intact limb with milliseconds of delay. Preliminary data results from a cross modal congruency task are included showing evidence of prosthesis incorporation in able-bodied subjects. This bypass will allow able-bodied subjects to participate in research studies that require the use of a prosthetic limb while also allowing the subjects to sense that the prosthesis is an extension of the body. PMID- 28814014 TI - Bio-inspired control of joint torque and knee stiffness in a robotic lower limb exoskeleton using a central pattern generator. AB - Robotic lower limb exoskeletons are becoming increasingly popular in therapy and recreational use. However, most exoskeletons are still rather limited in their locomotion speed and the activities of daily live they can perform. Furthermore, they typically do not allow for a dynamic adaptation to the environment, as they are often controlled with predefined reference trajectories. Inspired by human leg stiffness modulation during walking, variable stiffness actuators increase flexibility without the need for more complex controllers. Actuation with adaptable stiffness is inspired by the human leg stiffness modulation during walking. However, this actuation principle also introduces the stiffness setpoint as an additional degree of freedom that needs to be coordinated with the joint trajectories. As a potential solution to this issue a bio-inspired controller based on a central pattern generator (CPG) is presented in this work. It generates coordinated joint torques and knee stiffness modulations to produce flexible and dynamic gait patterns for an exoskeleton with variable knee stiffness actuation. The CPG controller is evaluated and optimized in simulation using a model of the exoskeleton. The CPG controller produced stable and smooth gait for walking speeds from 0.4 m/s up to 1.57 m/s with a torso stabilizing force that simulated the use of crutches, which are commonly needed by exoskeleton users. Through the CPG, the knee stiffness intrinsically adapted to the frequency and phase of the gait, when the speed was changed. Additionally, it adjusted to changes in the environment in the form of uneven terrain by reacting to ground contact forces. This could allow future exoskeletons to be more adaptive to various environments, thus making ambulation more robust. PMID- 28814015 TI - Postoperative healing patterns in elbow using electromyography: Towards the development of a wearable mechatronic elbow brace. AB - Musculoskeletal (MSK) conditions are the most common cause of severe long-term pain and physical disability. Current postoperative treatment for patients requires them to follow a long-term physiotherapy program customized for each specific case; however, this process can be complex, time-consuming and without the right therapy it may end up being ineffective. A possible solution involves the development of wearable mechatronic elbow braces that use electromyography (EMG) to identify patient intent. However, EMG characteristics change based on the health of the individual and therefore require further investigation. In order to quantify the progress of MSK injury patients and assess their neuromuscular health, EMG signals from 16 healthy individuals and 15 postoperative patients were collected and analyzed. The experiments conducted show that EMG can be used as a method for assessing MSK health. A normal range across the muscle groups has been identified to which the patient population was compared. This showed statistically significant differences in the magnitudes of muscle recruitment and activation between the two groups. Furthermore, a comparison within the patient population at the beginning of their therapy versus at the end of their therapy was conducted. Statistical differences arose in this second analysis further proving that patients' signals tend to change and show trends closer to those of the healthy population. PMID- 28814016 TI - Applying a soft-robotic glove as assistive device and training tool with games to support hand function after stroke: Preliminary results on feasibility and potential clinical impact. AB - Recent technological developments regarding wearable soft-robotic devices extend beyond the current application of rehabilitation robotics and enable unobtrusive support of the arms and hands during daily activities. In this light, the HandinMind (HiM) system was developed, comprising a soft-robotic, grip supporting glove with an added computer gaming environment. The present study aims to gain first insight into the feasibility of clinical application of the HiM system and its potential impact. In order to do so, both the direct influence of the HiM system on hand function as assistive device and its therapeutic potential, of either assistive or therapeutic use, were explored. A pilot randomized clinical trial was combined with a cross-sectional measurement (comparing performance with and without glove) at baseline in 5 chronic stroke patients, to investigate both the direct assistive and potential therapeutic effects of the HiM system. Extended use of the soft-robotic glove as assistive device at home or with dedicated gaming exercises in a clinical setting was applicable and feasible. A positive assistive effect of the soft-robotic glove was proposed for pinch strength and functional task performance 'lifting full cans' in most of the five participants. A potential therapeutic impact was suggested with predominantly improved hand strength in both participants with assistive use, and faster functional task performance in both participants with therapeutic application. PMID- 28814017 TI - Assessment of lower arm movements using one inertial sensor. AB - Reduction of the number of sensors needed to evaluate arm movements, makes a system for the assessment of human body movements more suitable for clinical practice and daily life assessments. In this study, we propose an algorithm to reconstruct lower arm orientation, velocity and position, based on a sensing system which consists of only one inertial measurement unit (IMU) to the forearm. Lower arm movements were reconstructed using a single IMU and assuming that within a measurement there are moments without arm movements. The proposed algorithm, together with a single IMU attached to the forearm, may be used to evaluate lower arm movements during clinical assessments or functional tasks. In this pilot study, reconstructed quantities were compared with an optical reference system. The limits of agreement in the magnitude of the orientation vector and the norm of the velocity vectors are respectively 4.2 deg (normalized, 5.2 percent) and 7.1 cm/s (normalized, 5.8 percent). The limit of agreement of the difference between the reconstructed positions of both sensing systems were relatively greater 7.7 cm (normalized, 16.8 percent). PMID- 28814018 TI - Time-varying impedance of the human ankle in the sagittal and frontal planes during straight walk and turning steps. AB - This paper describes the methods and experiment protocols for estimation of the human ankle impedance during turning and straight line walking. The ankle impedance of two human subjects during the stance phase of walking in both dorsiflexion plantarflexion (DP) and inversion eversion (IE) were estimated. The impedance was estimated about 8 axes of rotations of the human ankle combining different amounts of DP and IE rotations, and differentiating among positive and negative rotations at 5 instants of the stance length (SL). Specifically, the impedance was estimated at 10%, 30%, 50%, 70% and 90% of the SL. The ankle impedance showed great variability across time, and across the axes of rotation, with consistent larger stiffness and damping in DP than IE. When comparing straight walking and turning, the main differences were in damping at 50%, 70%, and 90% of the SL with an increase in damping at all axes of rotation during turning. PMID- 28814019 TI - Stiffness control of a nylon twisted coiled actuator for use in mechatronic rehabilitation devices. AB - Mechatronic rehabilitation devices, especially wearables, have been researched extensively and proven to be promising additions to physical therapy, but most designs utilize traditional actuators providing unnatural, robot-like movements. Therefore, many researchers have focused on the development of actuators that mimic biological properties to provide patients with improved results, safety, and comfort. Recently, a twisted-coiled actuator (TCA) made from nylon thread has been found to possess many of these important properties when heated, such as variable stiffness, flexibility, and high power density. So far, TCAs have been characterized in controlled environments to define their fundamental properties under simple loading configurations. However, for an actuator like this to be implemented in a biomimetic design such as an exoskeleton, it needs to be characterized and controlled as a biological muscle. One major control law that natural muscles exhibit is stiffness control, allowing humans to passively avoid injury from external forces, or move the limbs in a controlled or high impact motion. This type of control is created by the antagonistic muscle arrangement. In this paper, an antagonistic apparatus was developed to model the TCAs from a biological standpoint, the stiffness was characterized with respect to the TCA temperature, and a fully functional stiffness and position controller was implemented with an incorporated TCA thermal model. The stiffness was found to have a linear relationship to the TCA temperatures (R2=0.95). The controller performed with a stiffness accuracy of 98.95% and a position accuracy of 92.7%. A final trial with varying continuous position input and varying stepped stiffness input exhibited position control with R2=0.9638. PMID- 28814020 TI - Piecewise and unified phase variables in the control of a powered prosthetic leg. AB - Many control methods have been proposed for powered prosthetic legs, ranging from finite state machines that switch between discrete phases of gait to unified controllers that have a continuous sense of phase. In particular, recent work has shown that a mechanical phase variable can parameterize the entire gait cycle for controlling a prosthetic leg during steady rhythmic locomotion. However, the unified approach does not provide voluntary control over non-rhythmic motions like stepping forward and back. In this paper we present a phasing algorithm that uses the amputee's hip angle to control both rhythmic and non-rhythmic motion through two modes: 1) a piecewise (PW) function that provides users voluntary control over stance and swing in a piecewise manner, and 2) a unified function that continuously synchronizes the motion of the prosthetic leg with the amputee user at different walking speeds. The two phase variable approaches are compared in experiments with a powered knee-ankle prosthesis used by an above-knee amputee subject. PMID- 28814021 TI - Simultaneous estimation of human and exoskeleton motion: A simplified protocol. AB - Adequate benchmarking procedures in the area of wearable robots is gaining importance in order to compare different devices on a quantitative basis, improve them and support the standardization and regulation procedures. Performance assessment usually focuses on the execution of locomotion tasks, and is mostly based on kinematic-related measures. Typical drawbacks of marker-based motion capture systems, gold standard for measure of human limb motion, become challenging when measuring limb kinematics, due to the concomitant presence of the robot. This work answers the question of how to reliably assess the subject's body motion by placing markers over the exoskeleton. Focusing on the ankle joint, the proposed methodology showed that it is possible to reconstruct the trajectory of the subject's joint by placing markers on the exoskeleton, although foot flexibility during walking can impact the reconstruction accuracy. More experiments are needed to confirm this hypothesis, and more subjects and walking conditions are needed to better characterize the errors of the proposed methodology, although our results are promising, indicating small errors. PMID- 28814022 TI - Estimating anatomical wrist joint motion with a robotic exoskeleton. AB - Robotic exoskeletons can provide the high intensity, long duration targeted therapeutic interventions required for regaining motor function lost as a result of neurological injury. Quantitative measurements by exoskeletons have been proposed as measures of rehabilitative outcomes. Exoskeletons, in contrast to end effector designs, have the potential to provide a direct mapping between human and robot joints. This mapping rests on the assumption that anatomical axes and robot axes are aligned well, and that movement within the exoskeleton is negligible. These assumptions hold well for simple one degree-of-freedom joints, but may not be valid for multi-articular joints with unique musculoskeletal properties such as the wrist. This paper presents an experiment comparing robot joint kinematic measurements from an exoskeleton to anatomical joint angles measured with a motion capture system. Joint-space position measurements and task space smoothness metrics were compared between the two measurement modalities. The experimental results quantify the error between joint-level position measurements, and show that exoskeleton kinematic measurements preserve smoothness characteristics found in anatomical measures of wrist movements. PMID- 28814023 TI - Representing high-dimensional data to intelligent prostheses and other wearable assistive robots: A first comparison of tile coding and selective Kanerva coding. AB - Prosthetic devices have advanced in their capabilities and in the number and type of sensors included in their design. As the space of sensorimotor data available to a conventional or machine learning prosthetic control system increases in dimensionality and complexity, it becomes increasingly important that this data be represented in a useful and computationally efficient way. Well structured sensory data allows prosthetic control systems to make informed, appropriate control decisions. In this study, we explore the impact that increased sensorimotor information has on current machine learning prosthetic control approaches. Specifically, we examine the effect that high-dimensional sensory data has on the computation time and prediction performance of a true-online temporal-difference learning prediction method as embedded within a resource limited upper-limb prosthesis control system. We present results comparing tile coding, the dominant linear representation for real-time prosthetic machine learning, with a newly proposed modification to Kanerva coding that we call selective Kanerva coding. In addition to showing promising results for selective Kanerva coding, our results confirm potential limitations to tile coding as the number of sensory input dimensions increases. To our knowledge, this study is the first to explicitly examine representations for realtime machine learning prosthetic devices in general terms. This work therefore provides an important step towards forming an efficient prosthesis-eye view of the world, wherein prompt and accurate representations of high-dimensional data may be provided to machine learning control systems within artificial limbs and other assistive rehabilitation technologies. PMID- 28814024 TI - Feedback control of functional electrical stimulation for arbitrary upper extremity movements. AB - Functional electrical stimulation (FES) is a type of neuroprosthesis in which muscles are stimulated by electrical pulses in order to compensate for the loss of voluntary movement control. Modulating the stimulation intensities to reliably generate movements is a challenging control problem. For the first time, this paper presents a feedback controller for FES to control arm movements in a 2D (table-top) task space. This feedback controller is based on a recent human motor control model, which uses muscle synergies to simplify the calculations and improve control performance. The experimental results show that this control scheme can produce arbitrary movements in the 2D task space, with less than 2 cm hand position error from the specified targets. PMID- 28814025 TI - Learning from demonstration: Teaching a myoelectric prosthesis with an intact limb via reinforcement learning. AB - Prosthetic arms should restore and extend the capabilities of someone with an amputation. They should move naturally and be able to perform elegant, coordinated movements that approximate those of a biological arm. Despite these objectives, the control of modern-day prostheses is often nonintuitive and taxing. Existing devices and control approaches do not yet give users the ability to effect highly synergistic movements during their daily-life control of a prosthetic device. As a step towards improving the control of prosthetic arms and hands, we introduce an intuitive approach to training a prosthetic control system that helps a user achieve hard-to-engineer control behaviours. Specifically, we present an actor-critic reinforcement learning method that for the first time promises to allow someone with an amputation to use their non-amputated arm to teach their prosthetic arm how to move through a wide range of coordinated motions and grasp patterns. We evaluate our method during the myoelectric control of a multi-joint robot arm by non-amputee users, and demonstrate that by using our approach a user can train their arm to perform simultaneous gestures and movements in all three degrees of freedom in the robot's hand and wrist based only on information sampled from the robot and the user's above-elbow myoelectric signals. Our results indicate that this learning-from-demonstration paradigm may be well suited to use by both patients and clinicians with minimal technical knowledge, as it allows a user to personalize the control of his or her prosthesis without having to know the underlying mechanics of the prosthetic limb. These preliminary results also suggest that our approach may extend in a straightforward way to next-generation prostheses with precise finger and wrist control, such that these devices may someday allow users to perform fluid and intuitive movements like playing the piano, catching a ball, and comfortably shaking hands. PMID- 28814027 TI - Challenges in using compliant ligaments for position estimation within robotic joints. AB - The mechanical advantages of bio-inspired condylar robotic knee joints for use in prosthetics or rehabilitation has been argued extensively in literature. A common limitation of these designs is the difficulty of estimating joint angle and therefore accurately controlling the joint. Furthermore, the potential role of ligament-like structures in robotic knees is not very well established. In this work, we investigate the role of compliant stretch sensing ligaments and their integration into a condylar robotic knee. Simulations and experiments are executed out in order to establish whether measurement of stretch in these structures can be used to produce a new feedback controller for joint position. We report results from a computer model, as well as the design and construction of a robotic knee that show, for a chosen condyle shape, ligament stretch is a function of muscle force and joint velocity as well as joint angle. We have developed a genetic algorithm optimised controller incorporating ligament feedback that demonstrates improved performance for a desired joint angle in response to step inputs. The controller showed marginal improvement in response to a cyclic command signal and further investigation is required in order to use these measurements in robust control, nevertheless we believe these results demonstrate the that ligament-like structures have the potential to improve the performance of robotic knees for prosthetics and rehabilitation devices. PMID- 28814026 TI - Design and characterization of low-cost fabric-based flat pneumatic actuators for soft assistive glove application. AB - We present the design of low-cost fabric-based Hat pneumatic actuators for soft assistive glove application. The soft assistive glove is designed to assist hand impaired patients in performing activities of daily living and rehabilitation. The actuators consist of flexible materials such as fabric and latex bladder. Using zero volume actuation concept, the 2D configuration of the actuators simplifies the manufacturing process and allows the actuators to be more compact. The actuators achieve bi-directional flexion and extension motions. Compared to previously developed inflatable soft actuators, the actuators generate sufficient force and torque to assist in both finger flexion and extension at lower air pressure. Preliminary evaluation results show that the glove is able to provide both active finger flexion and extension assistance for activities of daily living and rehabilitative training. PMID- 28814028 TI - Quantitative assessment of swallowing activity by MMG measurement with PVDF film. AB - Difficulty of swallowing, called dysphagia, leads to aspiration pneumonia which is particularly a big health concern in aging societies. Therefore, prevention and treatment of dysphagia would contribute to extending healthy-life and QOL of elderly people and decreasing healthcare cost. Robotics technologies are expected as one of the effective methods to solve the problem in terms of detecting malfunction in swallowing and recovering swallowing function. The aim of this study is to investigate muscle activity during normal swallowing using mechanomyography (MMG) with PolyVinylidene DiFluoride (PVDF) film which is a ferroelectrics polymer. Measurement of MMG signal during voluntary isometric contraction of the biceps brachii muscle was conducted to confirm whether PVDF film can detect MMG signal. In the experiment, surface electromyography (sEMG) was also measured as a reference to estimate muscle activity for comparison. Then, activities of swallowing muscles during normal swallowing with different volume of bolus were measured using MMG signal. As the result, it was confirmed that swallowing activity can be quantified by the detected MMG signal from different region of neck. PMID- 28814029 TI - Vibrotactile feedback to control the amount of weight shift during walking - A first step towards better control of an exoskeleton for spinal cord injury subjects. AB - People with Spinal Cord Injury do not only lack the ability to control their muscles, but also miss the sensory information from below the level of their lesion. Therefore, it may become difficult for them to perceive the state of the body during walking, which is however often used to control wearable exoskeletons. In the present study the possibilities of providing vibrotactile feedback about the Center of Mass (CoM) during walking were investigated. The results showed that healthy subjects could successfully interpret the provided vibrotactile cues and change their walking pattern accordingly. Vibrotactile stimulation was either provided in a concurrent (over the complete CoM movement) or terminal (only when the desired CoM displacement was reached) way. The latter led to a better accuracy and can be easily implemented in a wearable exoskeleton where a certain amount of CoM displacement is needed to initiate stepping. PMID- 28814030 TI - Quantitative evaluation of hand functions using a wearable hand exoskeleton system. AB - To investigate, improve, and observe the effect of rehabilitation therapy, many studies have been conducted on evaluating the motor function quantitatively by developing various types of robotic systems. Even though the robotic systems have been developed, functional evaluation of the hand has been rarely investigated, because it is difficult to install a number of actuators or sensors to the hand due to limited space around the fingers. Therefore, in this study, a hand exoskeleton was developed to satisfy the required specifications for evaluating the hand functions including spasticity of finger flexors, finger independence, and multi-digit synergy and algorithms to evaluate such functions were proposed. The hand exoskeleton was composed with the four 4-bar linkages, two motors, and three loadcells for each finger, and it was able to flex/extend the metacarpal (MCP) and proximal interphalangeal(PIP) joints independently while measuring the pulling force at each phalanx. Using the hand exoskeleton, the hand functions of the three healthy subject were evaluated and the experimental results were analyzed. PMID- 28814031 TI - Evaluation of walking smoothness using wearable robotic system curara(r) for spinocerebellar degeneration patients. AB - This paper aimed to verify the effectiveness of the wearable robotic system "curara" for patients with spinocerebellar degeneration (SCD) by evaluating walking smoothness. The curara system supports the wearer's gait using a synchronization control method that uses a neural oscillator based on a central pattern generator network. The system reflects the motional intention by adjusting the synchronization gains. This modifies the degree of interactive coordinated motion between the curara and the wearer. As a feasibility study, we evaluated the waking smoothness of 10 patients with SCD using three gain condition settings. Harmonic ratio (HR), which has been used extensively to quantify the smoothness during walking, was used to assess their walking. The results show that most HRs in the medio-lateral, anterior-posterior, and vertical directions using the three gain conditions were higher than those for patients not wearing the system. In particular, the increasing rates of the HR in all directions during the gait support were 11.1%, 23.4%, and 23.2% compared with unassisted walking, when the gain condition settings of hip and knee joints are set at 0.4 and 0.5, respectively. Consequently, these results verified the effectiveness of the curara system for patients with SCD. PMID- 28814032 TI - Studying the implementation of iterative impedance control for assistive hand rehabilitation using an exoskeleton. AB - A positive training synergy can be obtained when two individuals attempt to learn the same motor task while mechanically coupled to one another. In this paper, we have studied how mimicking this interaction through impedance control can be exploited to improve assistance delivered by hand exoskeleton devices during rehabilitation. In this context, the machine and user take complementary roles akin to two coupled individuals. We present the derivation of a dynamic model of the human hand for the purpose of controller development for new hand exoskeleton platforms. Using this model, we have simulated the behavior of an iterative impedance controller programmed for rehabilitative training. The controller interacts with cylindrical objects to be grasped by means of an inverse kinematic mapping and tuning of mechanical impedance characteristic of the finger joints. Through fusion of concepts from motor control theory, muscle impedance and task oriented control, the controller is capable of iteratively learn to accomplish simple tasks involving grasping and lifting while cooperating with a user. The controller is also capable of adapting to more complex dynamics for more dexterous tasks, such as pulling on a hand-bar or loosening the cap of a jar. We believe the human-robot synergy established in this investigation has benefits to therapy. It can be combined with a broad range of training exercises and represents an incremental step towards mimicking natural human motor responses. PMID- 28814033 TI - Towards NIRS-based hand movement recognition. AB - This work reports on preliminary results about on hand movement recognition with Near InfraRed Spectroscopy (NIRS) and surface ElectroMyoGraphy (sEMG). Either basing on physical contact (touchscreens, data-gloves, etc.), vision techniques (Microsoft Kinect, Sony PlayStation Move, etc.), or other modalities, hand movement recognition is a pervasive function in today environment and it is at the base of many gaming, social, and medical applications. Albeit, in recent years, the use of muscle information extracted by sEMG has spread out from the medical applications to contaminate the consumer world, this technique still falls short when dealing with movements of the hand. We tested NIRS as a technique to get another point of view on the muscle phenomena and proved that, within a specific movements selection, NIRS can be used to recognize movements and return information regarding muscles at different depths. Furthermore, we propose here three different multimodal movement recognition approaches and compare their performances. PMID- 28814034 TI - Automated assessment of symptom severity changes during deep brain stimulation (DBS) therapy for Parkinson's disease. AB - Deep brain stimulation (DBS) is currently being used as a treatment for symptoms of Parkinson's disease (PD). Tracking symptom severity progression and deciding the optimal stimulation parameters for people with PD is extremely difficult. This study presents a sensor system that can quantify the three cardinal motor symptoms of PD - rigidity, bradykinesia and tremor. The first phase of this study assesses whether data recorded from the system during physical examinations can be used to correlate to clinician's severity score using supervised machine learning (ML) models. The second phase concludes whether the sensor system can distinguish differences before and after DBS optimisation by a clinician when Unified Parkinson's Disease Rating Scale (UPDRS) scores did not change. An average accuracy of 90.9 % was achieved by the best ML models in the first phase, when correlating sensor data to clinician's scores. Adding on to this, in the second phase of the study, the sensor system was able to pick up discernible differences before and after DBS optimisation sessions in instances where UPDRS scores did not change. PMID- 28814035 TI - Decoding of individual finger movements from surface EMG signals using vector autoregressive hierarchical hidden Markov models (VARHHMM). AB - In this paper we present a novel method for predicting individual fingers movements from surface electromyography (EMG). The method is intended for real time dexterous control of a multifunctional prosthetic hand device. The EMG data was recorded using 16 single-ended channels positioned on the forearm of healthy participants. Synchronously with the EMG recording, the subjects performed consecutive finger movements based on the visual cues. Our algorithm could be described in following steps: extracting mean average value (MAV) of the EMG to be used as the feature for classification, piece-wise linear modeling of EMG feature dynamics, implementation of hierarchical hidden Markov models (HHMM) to capture transitions between linear models, and implementation of Bayesian inference as the classifier. The performance of our classifier was evaluated against commonly used real-time classifiers. The results show that the current algorithm setup classifies EMG data similarly to the best among tested classifiers but with equal or less computational complexity. PMID- 28814036 TI - Prosthetic design directives: Low-cost hands within reach. AB - Although three million people around the world suffer from the lack of one or both upper limbs 80% of this number is located within developing countries. While prosthetic prices soar with technology 3D printing and low cost electronics present a sensible solution for those that cannot afford expensive prosthetics. The electronic and control design of a low-cost prosthetic hand, the Touch Hand II, is discussed. This paper shows that sensorless techniques can be used to reduce design complexities, costs, and provide easier access to the electronics. A closing and opening finite state machine (COFSM) was developed to handle the actuated digit joint control state and a supervisory switching control scheme, used for speed and grip strength control. Three torque and speed settings were created to be preset for specific grasps. The hand was able to replicate ten frequently used grasps and grip some common objects. Future work is necessary to enable a user to control it with myoelectric signals (MESs) and to solve operational problems related to electromagnetic interference (EMI). PMID- 28814037 TI - Design of a power-asymmetric actuator for a transtibial prosthesis. AB - This paper presents the design and characterization of a power-asymmetric actuator for a transtibial prosthesis. The device is designed to provide the combination of: 1) joint locking, 2) high power dissipation, and 3) low power generation. This actuator functionality allows for a prosthesis to be designed with minimal mass and power consumption relative to a fully-powered robotic prosthesis while maintaining much of the functionality necessary for activities of daily living. The actuator achieves these design characteristics while maintaining a small form factor by leveraging a combination of electromechanical and hydraulic components. The design of the actuator is described herein, and results of an experimental characterization are provided that indicate that the actuator is capable of providing the functional capabilities required of an ankle prosthesis in a compact and lightweight package. PMID- 28814038 TI - Design and preliminary assessment of Vanderbilt hand exoskeleton. AB - This paper presents the design of a hand exoskeleton intended to enable or facilitate bimanual activities of daily living (ADLs) for individuals with chronic upper extremity hemiparesis resulting from stroke. The paper describes design of the battery-powered, self-contained exoskeleton and presents the results of initial testing with a single subject with hemiparesis from stroke. Specifically, an experiment was conducted requiring the subject to repeatedly remove the lid from a water bottle both with and without the hand exoskeleton. The relative times required to remove the lid from the bottles was considerably lower when using the exoskeleton. Specifically, the average amount of time required to grasp the bottle with the paretic hand without the exoskeleton was 25.9 s, with a standard deviation of 33.5 s, while the corresponding average amount of time required to grasp the bottle with the exoskeleton was 5.1 s, with a standard deviation of 1.9 s. Thus, the task time involving the paretic hand was reduced by a factor of five, while the standard deviation was reduced by a factor of 16. PMID- 28814039 TI - Evaluating wearable multimodal sensor insoles for motion-pattern measurements in stroke rehabilitation - A pilot study. AB - The majority of stroke patients experience deficits in motoric functions, especially in gait and mobility. They need rehabilitation to regain walking independence, which is a major goal of rehabilitation after stroke. To document and assess the rehabilitation progress, instrumented motion analysis and clinical assessments are commonly used. In a clinical pilot study the applicability of an instrumented insole system in stroke rehabilitation is evaluated. Motion parameter of 35 stroke patients were gathered with the system while completing 90 s level walking and Timed Up & Go test at the beginning and end of four weeks inpatient rehabilitation. For level walking the motion parameter were gathered with the clinical reference system simultaneously. The mean stride time for level walking decreased from 1.20 s to 1.16 s (clinical system), or from 1.19 s to 1.12 s (insole system), respectively. Focusing on individual comparison of each patient's progress, 9 gait parameters are extracted for level walking, 6 sub phases of Timed Up & Go test are detected and analyzed, as well as progress of Center of Pressure in the sub-phases is examined. Although the overall data show wide distribution, the system proofed to be applicable in clinical stroke rehabilitation routine. As the system is location-independent, and has the advantage of assessing additional parameters of the Timed Up & Go test, it is additionally suitable for integration in a tele-or home rehabilitation system. PMID- 28814040 TI - Training wrist extensor function and detecting unwanted movement strategies in an EMG-controlled visuomotor task. AB - Stroke patients often suffer from severe upper limb paresis. Rehabilitation treatment typically targets motor impairments as early as possible, however, muscular contractions, particularly in the wrist and fingers, are often too weak to produce overt movements, making the initial phase of rehabilitation training difficult. Here we propose a new training tool whereby electromyographic (EMG) activity is measured in the wrist extensors and serves as a proxy of voluntary corticomotor drive. We used the Myo armband to develop a proportional EMG controller which allowed volunteers to perform a simple visuomotor task by modulating wrist extensor activity. In this preliminary study six healthy participants practiced the task for one session (144 trials), which resulted in a significant reduction of the average trial time required to move and hold a cursor in different target zones (p < 0.001, ANOVA), indicating skill learning. Additionally, we implemented an EMG based classifier to distinguish between the desired movement strategy and unwanted alternatives. Validation of the classifier indicated that accuracy for detecting rest, wrist extension and unwanted strategies was 92.5 + 6.9% (M + SD) across all participants. When performing the motor task the classification algorithm flagged 4.3 + 3.5% of the trials as 'unwanted strategies', even in healthy subjects. We also report initial feedback from a survey submitted to two chronic stroke patients to inquire about feasibility and acceptance of the general setup by patients. PMID- 28814041 TI - Assessing bradykinesia in Parkinson's disease using gyroscope signals. AB - Parkinson's disease (PD) is a neurodegenerative brain disorder that slowly brings on the dopaminergic neurons death. The depletion of the dopaminergic signal causes the onset of motor symptoms such as tremor, bradykinesia and rigidity. Usually, neurologists regularly monitor motor symptoms and motor fluctuations using the MDS-UPDRS part III clinical scale. Nevertheless, to have a more objective and quantitative evaluation, it is possible to assess the cardinal motor symptoms of PD using wearable sensors and portable robotic devices. Unfortunately while there are several research papers on the use of these devices on PD patients, their use is not so common in clinical practice. In this work we recorded specific MDS-UPDRS motor tasks using magneto-inertial devices, worn by seven PD subjects and seven age-matched controls, in order to deeply analyze the kinematic and dynamic characteristics of goal-directed movements of upper limb, in addition to extract quantitative indices (peak velocity, smoothness, etc) useful for the assessment of motor symptoms. Using only gyroscope signals we looked at those parameters useful to assess bradykinesia. We observed parameters changes from OFF to ON phase congruent with the MDS-UPDRS changes, especially in the frequency domain. Our results suggest the prono-supination task is the more consistent to describe the bradykinesia symptom with the gyroscopes. Probably because of the amplitude of the movement performed. Moreover the peak power looks appropriate for bradykinesia symptom evaluation. We can conclude that, similar to the studies in which tremor symptom is evaluated, it is possible to monitor the bradykinesia using few wearable sensors and few simple parameters. PMID- 28814042 TI - Portable haptic device for lower limb amputee gait feedback: Assessing static and dynamic perceptibility. AB - Loss of joints and severed sensory pathway cause reduced mobility capabilities in lower limb amputees. Although prosthetic devices attempt to restore normal mobility functions, lack of awareness and control of limb placement increase the risk of falling and causing amputee to have high level of visual dependency. Haptic feedback can serve as a cue for gait events during ambulation thus providing sense of awareness of the limb position. This paper presents a wireless wearable skin stretch haptic device to be fitted around the thigh region. The movement profile of the device was characterized and a preliminary work with able bodied participants and an above-knee amputee to assess the ability of users to perceive the delivered stimuli during static and dynamic mode is reported. Perceptibility was found to be increasing with stretch magnitude. It was observed that a higher magnitude of stretch was needed for the stimuli to be accurately perceived during walking in comparison to static standing, most likely due to the intense movement of the muscle and increased motor skills demand during walking activity. PMID- 28814043 TI - Design of a wearable interface for lightweight robotic arm for people with mobility impairments. AB - Many common activities of daily living like open a door or fill a glass of water, which most of us take for granted, could be an insuperable problem for people who have limited mobility or impairments. For years the unique alternative to overcame this limitation was asking for human help. Nowadays thanks to recent studies and technology developments, having an assistive devices to compensate the loss of mobility is becoming a real opportunity. Off-the-shelf assistive robotic manipulators have the capability to improve the life of people with motor impairments. Robotic lightweight arms represent one of the most spread solution, in particular some of them are designed specifically to be mounted on wheelchairs to assist users in performing manipulation tasks. On the other hand, usually their control interface relies on joystick and buttons, making the use very challenging for people affected by impaired motor abilities. In this paper, we present a novel wearable control interface for users with limb mobility impairments. We make use of muscles residual motion capabilities, captured through a Body-Machine Interface based on a combination of head tilt estimation and electromyography signals. The proposed BMI is completely wearable, wireless and does not require frequently long calibrations. Preliminary experiments showed the effectiveness of the proposed system for subjects with motor impairments, allowing them to easily control a robotic arm for activities of daily living. PMID- 28814044 TI - A survey of stakeholder perspectives on a proposed combined exoskeleton wheelchair technology. AB - BACKGROUND: Exoskeleton technology has potential benefits for wheelchair users' health and mobility. However, there are practical barriers to their everyday use as a mobility device. In particular, challenges related to travelling longer distances and transitioning between using a wheelchair and exoskeleton walking may present significant deterrents to regular exoskeleton use. In an effort to remove these barriers, a combined exoskeleton-wheelchair concept ('COMBO') has been proposed, which aims to achieve the benefits of both these mobility technologies. Given the inherent importance of including user-stakeholder opinions when designing an assistive technology solution, a study was undertaken to explore the perspectives of wheelchair users and healthcare professionals on the proposed conceptual design of the COMBO. METHODS: An online survey with quantitative and qualitative components was conducted with wheelchair users and healthcare professionals working directly with individuals with mobility impairments. Respondents rated whether they would use or recommend a COMBO for four potential reasons. Nine design features were rated and compared in terms of their importance. Content analysis was used to analyze data from an open-ended question regarding additional perceptions about using or recommending a COMBO. RESULTS: A total of 481 survey responses were analyzed, 354 from wheelchair users and 127 from healthcare professionals. Potential health benefits was the most highly rated reason for potential use or recommendation of a COMBO. Of the 9 design features, 2 had a median rating of very important: inclusion of a fall protection mechanism, and the ability for the operator to use their hands while standing. Qualitative findings indicated that health and physical benefits, use for daily life activities, and psychosocial benefits were important considerations in whether to use or recommend the COMBO. CONCLUSIONS: This study captures the opinions and perspectives of two stakeholder groups for an exoskeleton-wheelchair hybrid device. It also emphasizes the importance of fall protection, hand-use capabilities and enabling functional activities. Findings from this study can be utilized to provide insight for the refinement of the COMBO concept, as well as to guide more general mobility device research and development. PMID- 28814045 TI - Across-user adaptation for a powered lower limb prosthesis. AB - Pattern recognition algorithms have been used to control powered lower limb prostheses because they are capable of identifying the intent of the amputee user and therefore can provide a method for seamlessly transitioning between the different locomotion modes of the prosthesis. However, one major limitation of current algorithms is that they require subject-specific data from the individual user. These data are difficult and time-consuming to collect and consequently these algorithms do not generalize well across users. We have developed an adaptive pattern recognition algorithm that automatically learns new subject specific data acquired from a novel user during ambulation. We tested this adaptive algorithm with one transfemoral amputee subject walking on a powered knee-ankle prosthesis. Before adaptation, the algorithm, which was initially trained with data from two other transfemoral amputee subjects, made critical errors that prevented continuous ambulation. With adaptation, error rates dropped from 4.21% before adaptation to 1.25% after adaptation, and allowed the novel amputee user to complete all mode transitions. This study demonstrates that adaptation can decrease error rates over time and can allow pattern recognition algorithms to generalize to novel users. PMID- 28814046 TI - Adaptive control of an actuated-ankle-foot-orthosis. AB - This paper deals with the control of an active ankle foot orthosis (AAFO) to assist the gait of paretic patients. The AAFO system is driven by both, the residual human torque delivered by the muscles spanning the ankle joint and the AAFO's actuator's torque. A projection-based model reference adaptive control is proposed to assist dorsiflexion and plantar-flexion of the ankle joint during daily living walking activities. Unlike most classical model-based controllers, the proposed one does not require any prior estimation of the system's (foot AAFO) parameters. The ankle reference trajectory was extracted from healthy subjects gait activities in a clinical environment. The input-to-state stability of the foot-AAFO system with respect to a bounded human muscular torque is proved in closed-loop based on a Lyapunov analysis. Preliminary experimental results with a healthy subject walking on a treadmill, show satisfactory results in terms of tracking performance and ankle assistance throughout the gait cycle. PMID- 28814047 TI - A simple tool to measure spasticity in spinal cord injury subjects. AB - This work presents a wearable device and the algorithms for quantitative modelling of joint spasticity and its application in a pilot group of subjects with different levels of spinal cord injury. The device comprises light-weight instrumented handles to measure the interaction force between the subject and the physical therapist performing the tests, EMG sensors and inertial measurement units to measure muscle activity and joint kinematics. Experimental tests included the passive movement of different body segments, where the spasticity was expected, at different velocities. Tonic stretch reflex thresholds and their velocity modulation factor are computed, as a quantitative index of spasticity, by using the kinematics data at the onset of spasm detected through thresholding the EMG data. This technique was applied to two spinal cord injury subjects. The proposed method allowed the analysis of spasticity at muscle and joint levels. The obtained results are in line with the expert diagnosis and qualitative spasticity characterisation on each individual. PMID- 28814048 TI - A mechanism for elbow exoskeleton for customised training. AB - It is well proven that repetitive extensive training consisting of active and passive therapy is effective for patients suffering from neuromuscular deficits. The level of difficulty in rehabilitation should be increased with time to improve the neurological muscle functions. A portable elbow exoskeleton has been designed that will meet these requirements and potentially offers superior outcomes than human-assisted training. The proposed exoskeleton can provide both active and passive rehabilitation in a single structure without changing its configuration. The idea is to offer three levels of rehabilitation; namely active, passive and stiffness control in a single device using a single actuator. The mechanism also provides higher torque to weight ratio making it an energy efficient mechanism. PMID- 28814049 TI - Wearable sensing for rehabilitation after stroke: Bimanual jerk asymmetry encodes unique information about the variability of upper extremity recovery. AB - Wearable sensing is a new tool for quantifying upper extremity (UE) rehabilitation after stroke. However, it is unclear whether it provides information beyond what is available through standard clinical assessments. To investigate this question, people with a chronic stroke (n=9) wore accelerometers on both wrists for 9 hours on a single day during their daily activities. We used principal components analysis (PCA) to characterize how novel kinematic measures of jerk and acceleration asymmetry, along with conventional measures of limb use asymmetry and clinical function, explained the behavioral variance of UE recovery across participants. The first PC explained 55% of the variance and described a strong correlation between standard clinical assessments and limb use asymmetry, as has been observed previously. The second PC explained a further 31% of the variance and described a strong correlation between bimanual magnitude and jerk asymmetry. Because of the nature of PCA, this second PC is mathematically orthogonal to the first and thus uncorrelated with the clinical assessments. Therefore, kinematic metrics obtainable from bimanual accelerometry, including bimanual jerk asymmetry, encoded additional information about UE recovery. One interpretation is that the first PC relates to "functional status" and the second to "movement quality". We also describe a new graphical format for presenting bimanual wrist accelerometry data that facilitates identification of asymmetries. PMID- 28814050 TI - Segmental contributions to sagittal-plane whole-body angular momentum when using powered compared to passive ankle-foot prostheses on ramps. AB - Understanding the effects of an assistive device on dynamic balance is crucial, particularly for robotic leg prostheses. Analyses of dynamic balance commonly evaluate the range of whole-body angular momentum (H). However, the contributions of individual body segments to overall H throughout gait may yield futher insights, specifically for people with transtibial amputation using powered prostheses. We evaluated segment contributions to H using Statistical Parametric Mapping to assess the effects of prosthesis type (powered vs passive) and ramp angle on segmental coordination. The slope main effect was significant in all segments, the prosthesis main effect was significant in the prosthetic leg (device and residuum) and trunk, and the slope by prosthesis interaction effect was significant in the prosthetic leg and trunk. The magnitude of contributions to sagittal-plane H from the prosthetic leg was larger when using the powered prosthesis. The trunk contributed more positive (backward) H after prosthetic leg toe-off when using the powered prosthesis on inclines, similar to the soleus muscle. However, trunk contributions to H on declines were similar when using a powered and passive prosthesis, suggesting that the powered prosthesis may not replicate soleus function when walking downhill. Our novel assessment method evaluated robotic leg prostheses not only based on local joint mechanics, but also considering whole-body biomechanics. PMID- 28814051 TI - Design of a wearable hand exoskeleton for exercising flexion/extension of the fingers. AB - In this paper, design of a wearable hand exoskeleton system for exercising flexion/extension of the fingers, is proposed. The exoskeleton was designed with a simple and wearable structure to aid finger motions in 1 degree of freedom (DOF). A hand grasping experiment by fully-abled people was performed to investigate general hand flexion/extension motions and the polynomial curve of general hand motions was obtained. To customize the hand exoskeleton for the user, the polynomial curve was adjusted to the joint range of motion (ROM) of the user and the optimal design of the exoskeleton structure was obtained using the optimization algorithm. A prototype divided into two parts (one part for the thumb, the other for rest fingers) was actuated by only two linear motors for compact size and light weight. PMID- 28814052 TI - Grasp specific and user friendly interface design for myoelectric hand prostheses. AB - This paper presents the design and characterisation of a hand prosthesis and its user interface, focusing on performing the most commonly used grasps in activities of daily living (ADLs). Since the operation of a multi-articulated powered hand prosthesis is difficult to learn and master, there is a significant rate of abandonment by amputees in preference for simpler devices. In choosing so, amputees chose to live with fewer features in their prosthesis that would more reliably perform the basic operations. In this paper, we look simultaneously at a hand prosthesis design method that aims for a small number of grasps, a low complexity user interface and an alternative method to the current use of EMG as a preshape selection method through the use of a simple button; to enable amputees to get to and execute the intended hand movements intuitively, quickly and reliably. An experiment is reported at the end of the paper comparing the speed and accuracy with which able-bodied naive subjects are able to select the intended preshapes through the use of a simplified EMG method and a simple button. It is shown that the button was significantly superior in the speed of successful task completion and marginally superior in accuracy (success of first attempt). PMID- 28814053 TI - MoBio: A 5 DOF trans-humeral robotic prosthesis. AB - In this paper, a 5 DOF trans-humeral robotic prosthesis: MoBio is proposed. MoBio includes 2 DOF at wrist which is rare in other trans-humeral prostheses. Through anthropometric features MoBio prosthetic arm can achieve elbow flexion/extension, forearm supination/pronation, wrist radial/ulnar deviation, wrist flexion/extension and compound motion of thumb and index finger. An EMG based control method which uses EMG signals of the biceps brachii and triceps brachii, is used with a motion switching mechanism to control the prosthesis. Experimental results have verified the usability and effectiveness of MoBio in performing Activities of Daily Living. PMID- 28814054 TI - CRUX: A compliant robotic upper-extremity exosuit for lightweight, portable, multi-joint muscular augmentation. AB - Wearable robots can potentially offer their users enhanced stability and strength. These augmentations are ideally designed to actuate harmoniously with the user's movements and provide extra force as needed. The creation of such robots, however, is particularly challenging due to the underlying complexity of the human body. In this paper, we present a compliant, robotic exosuit for upper extremities called CRUX. This exosuit, inspired by tensegrity models of the human arm, features a lightweight (1.3 kg), flexible multi-joint design for portable augmentation. We also illustrate how CRUX maintains the full range of motion of the upper-extremities for its users while providing multi-DoF strength amplification to the major muscles of the arm, as evident by tracking the heart rate of an individual exercising said arm. Exosuits such as CRUX may be useful in physical therapy and in extreme environments where users are expected to exert their bodies to the fullest extent. PMID- 28814055 TI - TWIICE - A lightweight lower-limb exoskeleton for complete paraplegics. AB - This paper introduces TWIICE, a lower-limb exoskeleton that enables people suffering from complete paraplegia to stand up and walk again. TWIICE provides complete mobilization of the lower-limbs, which is a first step toward enabling the user to regain independence in activities of the daily living. The tasks it can perform include level and inclined walking (up to 20 degrees slope), stairs ascent and descent, sitting on a seat, and standing up. Participation in the world's first Cybathlon (Zurich, 2016) demonstrated good performance at these demanding tasks. In this paper, we describe the implementation details of the device and comment on preliminary results from a single user case study. PMID- 28814056 TI - Design of a lightweight, tethered, torque-controlled knee exoskeleton. AB - Lower-limb exoskeletons show promise for improving gait rehabilitation for those with chronic gait abnormalities due to injury, stroke or other illness. We designed and built a tethered knee exoskeleton with a strong lightweight frame and comfortable, four-point contact with the leg. The device is structurally compliant in select directions, instrumented to measure joint angle and applied torque, and is lightweight (0.76 kg). The exoskeleton is actuated by two off board motors. Closed loop torque control is achieved using classical proportional feedback control with damping injection in conjunction with iterative learning. We tested torque measurement accuracy and found root mean squared (RMS) error of 0.8 Nm with a max load of 62.2 Nm. Bandwidth was measured to be phase limited at 45 Hz when tested on a rigid test stand and 23 Hz when tested on a person's leg. During bandwidth tests peak extension torques were measured up to 50 Nm. Torque tracking was tested during walking on a treadmill at 1.25 m/s with peak flexion torques of 30 Nm. RMS torque tracking error averaged over a hundred steps was 0.91 Nm. We intend to use this knee exoskeleton to investigate robotic assistance strategies to improve gait rehabilitation and enhance human athletic ability. PMID- 28814057 TI - A study on the cough augmentation using a belt-driven assistive. AB - Coughing is one of the most important mechanisms performed in human body in that it removes mucus. The absence of enough ability to remove mucus leads to accumulation of the mucus on the airway, followed by possible complications such as pneumonia and atelectasis. Patients with diseases or disorders such as spinal cord injury have weakened ability in coughing. So far, there have been various treatments such as intubation surgery, mechanical insufflation-exsufflation or manual assistance provided by paramedic. But those treatments are mainly focusing on hospitalized patients. Patients showing better abilities in breathing are rarely and sporadically cared. We found that our prior research to assist breathing of these patients could also assist cough. Also, with our mechanism, now it is available that patients can care about themselves without on by own and more frequently if they needed assistance or treatment. To assist coughing, a belt-driven assistive robot are developed and effectiveness is investigated. With three healthy subjects, general breathing and coughing ability was monitored while using the robot. The result showed about 1.59 times better inhalation and exhalation. Also 1.52 times better coughing ability was measured. PMID- 28814058 TI - Towards an ankle neuroprosthesis for hybrid robotics: Concepts and current sources for functional electrical stimulation. AB - Hybrid rehabilitation robotics combine neuro-prosthetic devices (close-loop functional electrical stimulation systems) and traditional robotic structures and actuators to explore better therapies and promote a more efficient motor function recovery or compensation. Although hybrid robotics and ankle neuroprostheses (NPs) have been widely developed over the last years, there are just few studies on the use of NPs to electrically control both ankle flexion and extension to promote ankle recovery and improved gait patterns in paretic limbs. The aim of this work is to develop an ankle NP specifically designed to work in the field of hybrid robotics. This article presents early steps towards this goal and makes a brief review about motor NPs and Functional Electrical Stimulation (FES) principles and most common devices used to aid the ankle functioning during the gait cycle. It also shows a current sources analysis done in this framework, in order to choose the best one for this intended application. PMID- 28814059 TI - BioMot exoskeleton - Towards a smart wearable robot for symbiotic human-robot interaction. AB - This paper presents design of a novel modular lower-limb gait exoskeleton built within the FP7 BioMot project. Exoskeleton employs a variable stiffness actuator in all 6 joints, a directional-flexibility structure and a novel physical humanrobot interfacing, which allows it to deliver the required output while minimally constraining user's gait by providing passive degrees of freedom. Due to modularity, the exoskeleton can be used as a full lower-limb orthosis, a single-joint orthosis in any of the three joints, and a two-joint orthosis in a combination of any of the two joints. By employing a simple torque control strategy, the exoskeleton can be used to deliver user-specific assistance, both in gait rehabilitation and in assisting people suffering musculoskeletal impairments. The result of the presented BioMot efforts is a low-footprint exoskeleton with powerful compliant actuators, simple, yet effective torque controller and easily adjustable flexible structure. PMID- 28814060 TI - A soft wearable robot for the shoulder: Design, characterization, and preliminary testing. AB - In this paper, we present a soft wearable robot for the shoulder which has the potential to assist individuals suffering from a range of neuromuscular conditions affecting the shoulder to perform activities of daily living. This wearable robot combines two types of soft textile pneumatic actuators which were custom developed for this particular application to support the upper arm through shoulder abduction and horizontal flexion/extension. The advantage of a textile based approach is that the robot can be lightweight, low-profile, comfortable and non-restrictive to the wearer, and easy to don like an item of clothing. The actuator's ability to fold flat when not in use allows the robot to be almost invisible under clothing, potentially allowing the user to avoid any stigma associated with using assistive devices in public. To abduct the arm, a textilebased pneumatic actuator was developed to fit within the axilla to push the arm upwards, while a pair of smaller actuators pivot the abduction actuator to allow for horizontal extension and flexion. The individual textile actuators were experimentally evaluated before being integrated into a wearable garment. Human subject testing was performed to evaluate the ability of the robot to assist the arm by monitoring changes in biological muscle activity when comparing the robot powered on and off. Preliminary results show large reductions in muscular effort in targeted muscles, demonstrating the feasibility and promise of such a soft wearable robot for the shoulder. PMID- 28814061 TI - Modular one-to-many clutchable actuator for a soft elbow exosuit. AB - Exoskeletons have been developed for a wide range of applications, from the military to the medical field, with the aim of augmenting human performance or compensating for neuromuscular deficiencies. However, to empower the high number of degrees of freedom of the human body, they often employ a high number of motors, increasing the size, weight and power consumption of the system. We hereby present an actuation strategy to empower our elbow exosuit that adopts a single motor to drive multiple, independently actuated, degrees of freedom. This paradigm, known as One-to-many, is achieved using a modular design where each module comprises a clutchable mechanism that allows to convert a single directional motion from the prime mover to a selectable bidirectional output. Moreover, the mechanism has a locking feature that enables the wearer of the exoskeleton to hold a static load with a minimal power consumption. We present a simple controller for the clutchable unit based on a finite-state machine model, and evaluate its performance for varying input velocities. The system is shown to have a bandwidth of 1.5 Hz, sufficient for daily elbow movements, whilst retaining a compact design. PMID- 28814062 TI - Change detection technique for muscle tone during static stretching by continuous muscle viscoelasticity monitoring using wearable indentation tester. AB - Static stretching is widely performed to decrease muscle tone as a part of rehabilitation protocols. Finding out the optimal duration of static stretching is important to minimize the time required for rehabilitation therapy and it would be helpful for maintaining the patient's motivation towards daily rehabilitation tasks. Several studies have been conducted for the evaluation of static stretching; however, the recommended duration of static stretching varies widely between 15-30 s in general, because the traditional methods for the assessment of muscle tone do not monitor the continuous change in the target muscle's state. We have developed a method to monitor the viscoelasticity of one muscle continuously during static stretching, using a wearable indentation tester. In this study, we investigated a suitable signal processing method to detect the time required to change the muscle tone, utilizing the data collected using a wearable indentation tester. By calculating a viscoelastic index with a certain time window, we confirmed that the stretching duration required to bring about a decrease in muscle tone could be obtained with an accuracy in the order of 1 s. PMID- 28814063 TI - iCAVE: an open source tool for visualizing biomolecular networks in 3D, stereoscopic 3D and immersive 3D. AB - Visualizations of biomolecular networks assist in systems-level data exploration in many cellular processes. Data generated from high-throughput experiments increasingly inform these networks, yet current tools do not adequately scale with concomitant increase in their size and complexity. We present an open source software platform, interactome-CAVE (iCAVE), for visualizing large and complex biomolecular interaction networks in 3D. Users can explore networks (i) in 3D using a desktop, (ii) in stereoscopic 3D using 3D-vision glasses and a desktop, or (iii) in immersive 3D within a CAVE environment. iCAVE introduces 3D extensions of known 2D network layout, clustering, and edge-bundling algorithms, as well as new 3D network layout algorithms. Furthermore, users can simultaneously query several built-in databases within iCAVE for network generation or visualize their own networks (e.g., disease, drug, protein, metabolite). iCAVE has modular structure that allows rapid development by addition of algorithms, datasets, or features without affecting other parts of the code. Overall, iCAVE is the first freely available open source tool that enables 3D (optionally stereoscopic or immersive) visualizations of complex, dense, or multi-layered biomolecular networks. While primarily designed for researchers utilizing biomolecular networks, iCAVE can assist researchers in any field. PMID- 28814065 TI - Erratum. PMID- 28814064 TI - Electrical Properties Assessed by Bioelectrical Impedance Spectroscopy as Biomarkers of Age-related Loss of Skeletal Muscle Quantity and Quality. AB - Skeletal muscle, in addition to being comprised of a heterogeneous muscle fiber population, also includes extracellular components that do not contribute to positive tensional force production. Here we test segmental bioelectrical impedance spectroscopy (S-BIS) to assess muscle intracellular mass and composition. S-BIS can evaluate electrical properties that may be related to muscle force production. Muscle fiber membranes separate the intracellular components from the extracellular environment and consist of lipid bilayers which act as an electrical capacitor. We found that S-BIS measures accounted for ~85% of the age-related decrease in appendicular muscle power compared with only ~49% for dual-energy x-ray absorptiometry (DXA) measures. Indices of extracellular (noncontractile) and cellular (contractile) compartments in skeletal muscle tissues were determined using the Cole-Cole plot from S-BIS measures. Characteristic frequency, membrane capacitance, and phase angle determined by Cole-Cole analysis together presented a S-BIS complex model that explained ~79% of interindividual variance of leg muscle power. This finding underscores the value of S-BIS to measure muscle composition rather than lean mass as measured by DXA and suggests that S-BIS should be highly informative in skeletal muscle physiology. PMID- 28814066 TI - Mice expressing human ERAP1 variants associated with ankylosing spondylitis have altered T-cell repertoires and NK cell functions, as well as increased in utero and perinatal mortality. AB - Specific variants of endoplasmic reticulum-associated aminopeptidase 1 (ERAP1) identified by genome-wide association study modify the risk for developing ankylosing spondylitis. We previously confirmed that disease-associated ERAP1 variants have altered enzymatic abilities that can impact upon the production of pro-inflammatory cytokines from cells expressing the same ERAP1 variants. To determine if these ERAP1 variants also impacted immune responses in vivo, we generated two strains of transgenic mice expressing human ERAP1 genes containing non-synonymous single-nucleotide polymorphisms associated with an increased (ERAP1-High) or decreased (ERAP1-Low) risk for developing autoimmune disease. After vaccination with foreign antigens, ERAP1-High mice generated unique populations of antigen-specific T-cell clones. The expression of ERAP1-High also reduced MHC-I expression on the surface of multiple cell types, demonstrating a global impact on the MHC-I peptidome. ERAP1 variants also affected the innate immune system, because NK cells from murine ERAP1 (mERAP1) knockout mice and ERAP1-High/mERAP1-/- mice had decreased surface expression of the activating receptor NKG2D on their NK and T cells, and NK cells derived from mERAP1-/- mice or ERAP1-Low mice demonstrated more active NK cell killing than NK cells derived from wild-type or ERAP1-High mice. Finally, these studies were conducted in female mice, as all male ERAP1-High mice died in utero or shortly after birth, making ERAP1-High one of the only dominant lethal autosomal genes known in mammals. Together, these results present the first direct evidence that human disease-associated ERAP1 variants can greatly alter survival, as well as antigen presentation, T-cell repertoire and NK cell responses in vivo. PMID- 28814069 TI - Phlegmonous gastritis in an ankylosing spondylitis patient treated with infliximab. PMID- 28814067 TI - Neuro-immune interactions in allergic diseases: novel targets for therapeutics. AB - Recent studies have highlighted an emerging role for neuro-immune interactions in mediating allergic diseases. Allergies are caused by an overactive immune response to a foreign antigen. The peripheral sensory and autonomic nervous system densely innervates mucosal barrier tissues including the skin, respiratory tract and gastrointestinal (GI) tract that are exposed to allergens. It is increasingly clear that neurons actively communicate with and regulate the function of mast cells, dendritic cells, eosinophils, Th2 cells and type 2 innate lymphoid cells in allergic inflammation. Several mechanisms of cross-talk between the two systems have been uncovered, with potential anatomical specificity. Immune cells release inflammatory mediators including histamine, cytokines or neurotrophins that directly activate sensory neurons to mediate itch in the skin, cough/sneezing and bronchoconstriction in the respiratory tract and motility in the GI tract. Upon activation, these peripheral neurons release neurotransmitters and neuropeptides that directly act on immune cells to modulate their function. Somatosensory and visceral afferent neurons release neuropeptides including calcitonin gene-related peptide, substance P and vasoactive intestinal peptide, which can act on type 2 immune cells to drive allergic inflammation. Autonomic neurons release neurotransmitters including acetylcholine and noradrenaline that signal to both innate and adaptive immune cells. Neuro-immune signaling may play a central role in the physiopathology of allergic diseases including atopic dermatitis, asthma and food allergies. Therefore, getting a better understanding of these cellular and molecular neuro-immune interactions could lead to novel therapeutic approaches to treat allergic diseases. PMID- 28814070 TI - Human Papillomavirus Genotype-Specific Persistence and Potential Risk Factors among Korean Women: Results from a 2-Year Follow-up Study. AB - Purpose: High-risk human papillomavirus (HPV) infection progression should be considered a critical factor for preventing cervical cancer, although most infections are transient and rarely persist. This study aimed to examine the specific types of HPV infections, their change patterns, and the potential risk factors among Korean women. Materials and Methods: We included 4,588 women who visited hospitals in Busan and Suwon for cervical cancer screening, and 1,224 of thesewomen attended a 2-yearfollow-up. Infection statuswas evaluated using HPV DNA testing (Hybrid Capture 2) and genotyping testing (Linear Array). Data regarding the potential risk factors for HPV infection were collected by trained nurses using structured questionnaires. Results: Among the 1,224 women (mean age, 47 years), 105 women (8.6%) were HPV-positive at baseline. HPV infections had been cleared among 92 women (87.6%) within 2 years. Only 13 infections (12.4%) were remained, and the 10 cases of them are high-risk HPV types including genotype 33, 45, 16, 35, and 52. Among women who were negative at baseline, the HPV incidence was 4.8%. The HPV incidence was marginally associated with having multiple sexual partners (odds ratio, 2.0; 95% confidence interval, 1.0 to 3.9), although it was not significantly associated with HPV persistence. Conclusion: Most HPV infections (88%) among Korean women were cleared within 2 years, with only a small number of persistent infections. The persistent HPV genotypes were different in our study, compared to those from previous studies. Having multiple sexual partners was associated with acquiring a HPV infection, but not with persistence. PMID- 28814068 TI - The activation of NLRP3-inflammsome by stimulation of diesel exhaust particles in lung tissues from emphysema model and RAW 264.7 cell line. AB - BACKGROUND/AIMS: Diesel exhaust particles (DEPs) lead to elevation of reactive oxygen species, which can activate the nucleotide-binding oligomerization domain like receptor (NLR) family members containing the pyrin domain 3 (NLRP3)-inf lammasome. In this study, we elucidated whether NLRP3 -inf lammasome is activated by DEPs and whether antioxidants (N-acetylcysteine [NAC]) could inhibit such activation. METHODS: RAW 264.7 cells and ex vivo lung tissues explants obtained from elastase-induced emphysema animal models were stimulated with cigarette smoking extract (CSE), DEPs, and lipopolysaccharide, and levels of interleukin 1beta (IL-1beta), caspase-1 and nucleotide-binding oligomerization domain-like receptor (NLR) family members containing the pyrin domain (NLRP3)-inflammasome were assessed by Western blotting and immunohistochemistry. RESULTS: NAC and caspase-1 inhibitor suppressed CSE- and DEP-induced secretion of IL-1beta in RAW 264.7 cells. The expression levels of the NLRP3-inflammasome and caspase-1 were upregulated in RAW 264.7 cells by stimulation with CSE and DEPs and were inhibited by NAC. CSE and DEPs increased the secretion of IL-1beta in lung tissues from both the normal and elastase-induced emphysema groups. The secretion of IL-1beta by CSE and DEPs was increased in the elastin-induced emphysema group more than that in the normal group (CSE: 309 +/- 19 pg/mL vs. 151 +/- 13 pg/mL, respectively, p < 0.05; DEP: 350 +/- 24 pg/mL vs. 281 +/- 15 pg/mL, respectively, p < 0.05). NAC inhibited CSE- and DEP-induced IL-1beta secretion in both the normal and elastase-induced emphysema groups. NLRP3-inflammasome expression as determined by immunohistochemistry was increased by CSE and DEPs in both the normal and elastin-induced emphysema groups, and was suppressed by NAC. CONCLUSIONS: The NLRP3-inf lammasome is activated by DEPs in ex vivo tissue explants from elastase-induced emphysema animal model, and this activation is inhibited by NAC. PMID- 28814072 TI - Molecular Dynamics Study of Polystyrene-b-poly(ethylene oxide) Asymmetric Diblock Copolymer Systems. AB - Two polystyrene-b-poly(ethylene oxide) (PS-b-PEO) diblock copolymers differing in molecular mass (49 and 78 kDa) but possessing the same PEO cylindrical morphology are examined to elucidate their molecular dynamics. Of particular interest here is the molecular motion of the PEO blocks involved in the rigid amorphous fraction (RAF). An analysis of complementary thermal calorimetry and X-ray scattering data confirms the presence of microphase-separated morphology as well as semicrystalline structure in each copolymer. Molecular motion within the copolymer systems is monitored by dielectric and nuclear magnetic resonance spectroscopies. The results reported herein reveal the existence of two local Arrhenius-type processes attributed to the noncooperative local motion of PEO segments involved in fully amorphous and rigid amorphous PEO microphases. In both systems, two structural relaxations governed by glass-transition phenomena are identified and assigned to cooperative segmental motion in the fully amorphous phase (the alpha process) and the RAF (the alphac process). We measure the temperature dependence of the dynamics associated with all of the processes mentioned above and propose that these local processes are associated with corresponding cooperative segmental motion in both copolymer systems. In marked contrast to the thermal activation of the alpha process as discerned in both copolymers, the alphac process appears to be a sensitive probe of the copolymer nanostructure. That is, the copolymer with shorter PEO blocks exhibits more highly restricted cooperative dynamics of PEO segments in the RAF, which can be explained in terms of the greater constraint imposed by the glassy PS matrix on the PEO blocks comprising smaller cylindrical microdomains. PMID- 28814071 TI - Feasibility of Charcoal Tattooing of Cytology-Proven Metastatic Axillary Lymph Node at Diagnosis and Sentinel Lymph Node Biopsy after Neoadjuvant Chemotherapy in Breast Cancer Patients. AB - Purpose: Sentinel lymph node biopsy (SLNB) can be performed when node-positive disease is converted to node-negative status after neoadjuvant chemotherapy (NCT). Tattooing nodes might improve accuracy but supportive data are limited. This study aimed to investigate the feasibility of charcoal tattooing metastatic axillary lymph node (ALN) at presentation followed by SLNB after NCT in breast cancers. Materials and Methods: Twenty patientswith cytology-proven node metastases prospectively underwent charcoal tattooing at diagnosis. SLNB using dual tracers and axillary surgery after NCT were then performed. The detection rate of tattooed node and diagnostic performance of SLNB were analyzed. Results: All patients underwent charcoal tattooingwithout significant morbidity. Sentinel and tattooed nodes could be detected during surgery after NCT. Nodal pathologic complete response was achieved in 10 patients. Overall sensitivity, false negative rate (FNR), negative predictive value, and accuracy of hot/blue SLNB were 80.0%, 20.0%, 83.3%, and 90.0%, respectively. Retrieving more nodes and favorable nodal response were associated with improved performance. The best accuracy was observed when excised tattooed node was calculated together (FNR, 0.0%). Cold/non-blue tattooed nodes of five patients were removed during non sentinel axillary surgery but clinicopathological parameters did not differ compared to patients with hot/blue tattooed node detected during SLNB, suggesting the importance of the tattooing procedure itself to improve performance. Conclusion: Charcoal tattooing of cytology-confirmed metastatic ALN at presentation is technically feasible and does not limit SLNB after NCT. The tattooing procedure without additional preoperative localization is advantageous for improving the diagnostic performance of SLNB in this setting. PMID- 28814073 TI - Multielectron Effects in the Strong Field Sequential Ionization of Aligned CH3I Molecules. AB - Strong field sequential ionization of symmetric-top CH3I molecules is studied experimentally by using a combined method of femtosecond laser-induced impulsive alignment and time-of-flight mass spectrometry. Both alignment- and angular dependent ion yields have been measured, and the sequential ionization of a multielectron has been discussed. It is found that the maximum ionization occurs when the polarization of probe laser is perpendicular to the internuclear axis of molecules, and the signal of fragment ion peaks at the polarization of the probe laser is parallel to the internuclear axis of molecules. The angular distribution of ions indicated that ionization of pi-type orbitals corresponds to generation of charged parent ions and ionization of sigma-type orbitals corresponds to generation of fragment ions. The sequential release of multielectrons for Coulomb explosion channels is studied by analysis of the time evolutions of multicharged In+ (n = 1-4) signals. PMID- 28814074 TI - Multifunctional Yolk-Shell Nanostructure as a Superquencher for Fluorescent Analysis of Potassium Ion Using Guanine-Rich Oligonucleotides. AB - The excellent performance of a biosensor generally depends on the high signal-to noise ratio, and the superquencher plays a dominant role in fluorescent sensors. Novel nanoquenchers exhibited high quenching efficiency in various fluorescent assays of biological/chemical molecules. Here, we developed a novel nano biosensor using Fe3O4@C yolk-shell nanoparticles (YSNPs) and studied their quenching effect. We found Fe3O4@C YSNP was a superquencher and exhibited an ultrastrong quenching ability, up to almost 100% quenching efficiency, toward fluorophores. Also, Fe3O4@C YSNPs possessed the most superior fluorescence restoration efficiency, due to biomolecular recognition event, compared to the other nanoquenchers, including bare Fe3O4 NPs, graphene oxide (GO), and single wall carbon nanotubes (SWCNTs). On the basis of that, a fluorescent sensing platform for potassium-ion (K+) analysis with guanine (G)-rich oligonucleotides was designed. As a result, Fe3O4@C YSNP-based fluorescent sensors demonstrated excellent performance, with an ultrahigh sensitivity of a detection limit as low as 1.3 MUM, as well as a wide dynamic range from 50 MUM to 10 mM. The proposed method is fast, simple, and cost-effective, suggesting the great potential for practical applications in biomedical detection and clinical diagnosis. PMID- 28814075 TI - Nickel-Catalyzed Azide-Alkyne Cycloaddition To Access 1,5-Disubstituted 1,2,3 Triazoles in Air and Water. AB - Transition-metal-catalyzed or metal-free azide-alkyne cycloadditions are methods to access 1,4- or 1,5-disubstituted 1,2,3-triazoles. Although the copper catalyzed cycloaddition to access 1,4-disubstituted products has been applied to biomolecular reaction systems, the azide-alkyne cycloaddition to access the complementary 1,5-regioisomers under aqueous and ambient conditions remains a challenge due to limited substrate scope or moisture-/air-sensitive catalysts. Herein, we report a method to access 1,5-disubstituted 1,2,3-triazoles using a Cp2Ni/Xantphos catalytic system. The reaction proceeds both in water and organic solvents at room temperature. This protocol is simple and scalable with a broad substrate scope including both aliphatic and aromatic substrates. Moreover, triazoles attached with carbohydrates or amino acids are prepared via this cycloaddition. PMID- 28814076 TI - Site-Selective Catalytic Carboxylation of Unsaturated Hydrocarbons with CO2 and Water. AB - A catalytic protocol that reliably predicts and controls the site-selective incorporation of CO2 to a wide range of unsaturated hydrocarbons utilizing water as formal hydride source is described. This platform unlocks an opportunity to catalytically repurpose three abundant, orthogonal feedstocks under mild conditions. PMID- 28814077 TI - Temperature-Dependent Two-Dimensional Transition Metal Dichalcogenide Heterostructures: Controlled Synthesis and Their Properties. AB - Vertically stacked and laterally stitched heterostructures consisting of two dimensional (2D) transition metal dichalcogenides (TMDCs) are predicted to possess novel electronic and optical properties, which offer opportunities for the development of next-generation electronic and optoelectronic devices. In the present work, we report the temperature-dependent synthesis of 2D TMDC heterostructures on Si/SiO2 substrates, including MoS2-WS2, WS2-MoS2-WS2, Mo1 xWxS2-WS2, and Mo1-xWxS2 alloyed bilayer heterostructures by ambient pressure chemical vapor deposition (CVD). Raman and photoluminescence mapping studies demonstrate that the as-produced heterostructures show distinct structural and optical modulation. Our results indicate that the evolution of various 2D heterostructures originates from the competition between the adsorption and desorption of Mo atoms and the diffusion of W atoms under various growth temperatures. This work sheds light on the design and fabrication of heterostructures using controllable interfaces and junctions of diverse TMDC atomic layers. PMID- 28814078 TI - Structural Characterization and Unique Catalytic Performance of Silyl-Group Substituted Geminal Dichromiomethane Complexes Stabilized with a Diamine Ligand. AB - Stabilization by a silyl group on the methylene carbon and a diamine ligand led to the isolation of gem-dichromiomethane species. X-ray crystallography confirmed the identity of the structure of this rare example of reactive gem dimetalloalkane species. The isolated gem-dichromiomethane complex acted as a storable silylmethylidene carbene equivalent, with reactivity that could be changed dramatically upon addition of a Lewis acid (ZnCl2) and a base (TMEDA) to promote both silylalkylidenation of polar aldehydes and silylcyclopropanation of nonpolar alkenes. Identification of a key reactive species also identified the catalytic version of these transformations and provided insights into the reaction mechanism. In contrast to Simmons-Smith cyclopropanation, the real reactive species for the current cyclopropanation was a chromiocarbene species, not a chromium carbenoid species. PMID- 28814079 TI - Measuring the Edge Recombination Velocity of Monolayer Semiconductors. AB - Understanding edge effects and quantifying their impact on the carrier properties of two-dimensional (2D) semiconductors is an essential step toward utilizing this material for high performance electronic and optoelectronic devices. WS2 monolayers patterned into disks of varying diameters are used to experimentally explore the influence of edges on the material's optical properties. Carrier lifetime measurements show a decrease in the effective lifetime, taueffective, as a function of decreasing diameter, suggesting that the edges are active sites for carrier recombination. Accordingly, we introduce a metric called edge recombination velocity (ERV) to characterize the impact of 2D material edges on nonradiative carrier recombination. The unpassivated WS2 monolayer disks yield an ERV ~ 4 * 104 cm/s. This work quantifies the nonradiative recombination edge effects in monolayer semiconductors, while simultaneously establishing a practical characterization approach that can be used to experimentally explore edge passivation methods for 2D materials. PMID- 28814080 TI - Drug Delivery from a Multi-faceted Ultrasound Contrast Agent: Influence of Shell Composition. AB - Many cancer therapy regimes still rely heavily on the systemic administration of toxic chemotherapeutic agents. Ultrasound contrast agents consisting of microbubbles (MBs) have emerged as a drug delivery vehicle to overcome the challenges associated with systemic chemotherapy. Here, we describe the development of non-immunogenic, functionalized polylactic acid (PLA) MBs for use in targeted cancer therapy. Our previous studies have shown that the balance between acoustic behavior and improved immune avoidance was scalable and successful to different degrees with two different PEGylation methods and was best achieved using incorporation of PEG-PLA at 5 wt % and for a LipidPEG at 1 wt %. Capitalizing on this, we now attach a targeting ligand, tumor necrosis factor related apoptosis-inducing ligand (TRAIL), which selectively induces tumor cell death upon binding to cancer cell-specific surface receptors, initiating a transmembrane apoptosis signal. Additionally, the functionalized MBs were designed to coencapsulate doxorubicin (Dox) that can be released from the polymer shell in response to ultrasound focused at the tumor site, shielding healthy tissues from toxicity while increasing the potency and efficiency of treatment to the tumor tissue. Ligation of TRAIL reduced the encapsulation efficiency for Dox compared to those of their non-ligated counterparts (p < 0.0001) by approximately 34% for 100% PLA, 23% for 5 wt % PEG-PLA, and 30% for the 1 wt % LipidPEG platform. All platforms exhibited a burst effect (<7%, p < 0.0001), and sustained release lasted for over 150 h. This work has resulted in a choice of effective ultrasound-triggered, non-immunogenic, targeted drug delivery agents for potential use in cancer therapy. These platforms have many advantages over the systemic administration of chemotherapeutic drugs and represent a promising treatment to better serve the population with solid cancerous tumors as a whole. PMID- 28814082 TI - Environmental Processes at the Solid-Liquid Interface: What Constitutes New Physical Insights? PMID- 28814081 TI - Monitoring Genetic Population Biomarkers for Wastewater-Based Epidemiology. AB - We report a rapid "sample-to-answer" platform that can be used for the quantitative monitoring of genetic biomarkers within communities through the analysis of wastewater. The assay is based on the loop-mediated isothermal amplification (LAMP) of nucleic acid biomarkers and shows for the first time the ability to rapidly quantify human-specific mitochondrial DNA (mtDNA) from raw untreated wastewater samples. mtDNA provides a model population biomarker associated with carcinogenesis including breast, renal and gastric cancers. To enable a sample-to-answer, field-based technology, we integrated a filter to remove solid impurities and perform DNA extraction and enrichment into a low cost lateral flow-based test. We demonstrated mtDNA detection over seven consecutive days, achieving a limit of detection of 40 copies of human genomic DNA per reaction volume. The assay can be performed at the site of sample collection, with minimal user intervention, yielding results within 45 min and providing a method to monitor public health from wastewater. PMID- 28814083 TI - Spotlights: Volume 8, Issue 16. PMID- 28814084 TI - In the Limelight. PMID- 28814085 TI - Differentially regulated ADAMTS1, 8, and 18 in gastric adenocarcinoma. AB - OBJECTIVE: The aim is to investigate the expression status of ADAMTS1,8, and 18 proteases in gastric cancer (GC) and lymphatic metastasis. BACKGROUND: A disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) is a new protease family, and has important biological functions such as hemostasis, extracellular matrix remodeling and regulation of angiogenesis. METHODS: The immunostaining status of ADAMTS1,8, and 18 were investigated in formalin-fixed paraffin-embedded samples of 25 patients who underwent curative resection for GC. RESULTS: The immune reactivity scores (IRS) of ADAMTS1, 8, and 18 were significantly higher in the cancerous gastric tissue in comparison to non cancerous gastric tissue (p < 0.001). In addition, IRS scores of these three ADAMTS proteases were higher in the metastatic lymph nodes compared with healthy lymph nodes (p < 0.001). The expression status of the three ADAMTSs in cancerous gastric tissue was correlated with stage of tumor. Additionally, ADAMTS1 expression and ADAMTS8 expression in cancerous gastric tissue were found to correlate with grade and tumor size, respectively. CONCLUSION: This study showed that ADAMTS1, 8, and 18 are highly expressed in GC and its nodal metastases, suggesting important roles of these proteases in carcinogenesis and lymphatic metastasis. The findings from the present study indicate that these proteases may be promising candidates for novel and alternative treatments in GC (Tab. 3, Fig. 3, Ref. 27). PMID- 28814086 TI - Plasma nesfatin 1 level in patients with first attack psychosis. AB - OBJECTIVES: This study aimed to investigate the possible relationship between plasma concentrations of nesfatin 1 and first attack psychosis. METHODS: Totally, 32 patients with the first episode psychosis and 33 randomly selected weight- and body mass index-matched healthy volunteers admitted to Mustafa Kemal University, Faculty of Medicine, Training and Research Hospital, Psychiatry outpatient clinic were included. Healthy control subjects were matched in terms of weight and body mass index (BMI). The Positive and Negative Syndrome Scale (PANNS) was applied to the patient group. The enzyme-linked immunosorbent assay (ELISA) method was used to measure plasma nesfatin 1 levels. RESULTS: The mean nesfatin 1 level was lower in the patients with the first attack psychosis (0.60 +/- 1.00 ng/mL) than in the control group (0.75 +/- 1.07 ng/mL).However it did not reach statistical significance (t = -0.567, p = 0.573). There was no statistically significant correlation between plasma nesfatin 1 levels and total PANNS scores in the patient group (r = -0.262, p = 0.148). CONCLUSION: Our study was the first to investigate the nesfatin 1 levels in patients with the first episode psychosis. Based on our study results, nesfatin 1 might be related to some central nervous system pathologies, including the severity of a psychiatric disorder; however, further large-scale studies are required to establish a conclusion (Tab. 1, Ref. 21). PMID- 28814087 TI - Effects of sevoflurane on apoptosis, BDNF and cognitive functions in neonatal rats. AB - OBJECTIVE: To evaluate the early and late effects of sevoflurane on the neonatal brain. BACKGROUND: Sevoflurane is the most used anaesthetics in neonatal subjects. METHODS: The study included 7-day-old male Wistar-Albino rats (n = 30), which were divided into the two groups according to the anaesthetic received: sevoflurane (S) and control group (C). Half of each group was sacrificed six hours after anaesthesia (early, E) while the remaining subjects were sacrificed six weeks later (late, L). The serum brain-derived-neurotrophic factor (BDNF), brain BDNF and caspase-3 were evaluated. In addition, elevated plus arm test and Morris water test were performed in the late group. RESULTS: BDNF levels were higher in the late groups than in the early ones (p < 0.05). BDNF levels in cerebral cortex were higher in the Group CE than in the Group CL and SL (p < 0.05). There was a significant negative correlation between serum BDNF and cortex BDNF levels (p = 0.003, r = -0.425). Cortex caspase 3 levels were significantly higher in the Groups SE and SL than in the Group CE and CL (p < 0.05). There was no significant difference between the groups in the terms of open arm index, locomotor activity and Morris water test. CONCLUSIONS: Although sevoflurane induced apoptosis, it didn't affect BDNF levels and showed no long-term negative effects on learning and anxiety in neonatal rats (Tab. 1, Fig. 3, Ref. 26). PMID- 28814088 TI - Cisplatin plus norcantharidin alter the expression of TGF-beta1/Smads signaling pathway in hepatocellular carcinoma. AB - PURPOSE: To investigate the effects of cisplatin plus norcantharidin on transforming growth factor (TGF)-beta1/Smads signaling pathway in hepatocellular carcinoma cells. METHODS: Hepatocellular carcinoma cells (Hep3B) were divided into four groups: control group, cisplatin 2.0 MUg/ml group, norcantharidin 10 MUg/ml group, and cisplatin 2.0 MUg/ml plus norcantharidin 10 MUg/ml group. All cells were incubated for 24 hours. Cells proliferation was assessed using cell counting kit-8. Relative mRNA expression of TGF-beta1, Smad4 and Smad7 were assessed by quantitative RT-PCR. Protein expression of TGF-beta1 and Smad4 were investigated by western blotting. RESULTS: Cisplatin, norcantharidin and cisplatin plus norcantharidin significantly inhibited the proliferation of cells, significantly attenuated both the mRNA and protein expression of TGF-beta1 and Smad7, and significantly up-regulated the mRNA and protein expression of Smad4 in Hep3B (all p < 0.05), and cisplatin plus norcantharidin exhibited powerful effects than cisplatin and norcantharidin. CONCLUSIONS: Cisplatin, norcantharidin and cisplatin plus norcantharidin can significantly alter the expression of TGF beta1/Smads signaling pathway and inhibit the proliferation of Hep3B cells. Cisplatin plus norcantharidin exhibited powerful effects than cisplatin and norcantharidin (Fig. 4, Ref. 23). PMID- 28814089 TI - Antioxidant therapy impresses in oxidative stress-induced kidney cells. AB - INTRODUCTION: Renal cell cancer (RCC) is not a single entity, but consists of different types of tumors derived from various parts of the nephron (epithelium or renal tubules). It is known that cancer initiation and progression is related to the balance between oxidants and antioxidants directly. Interestingly, advanced stages of cancer such as metastasis, angiogenesis are associated with cell oxidative capacity. Familiar antioxidative substances such as carotenes and vitamin C inhibit oxidation of other molecules during carcinogenesis. They can define the distinction between cancer and normal cells, destroying cancer cells while stabilizing healthy cells. METHODS: apoptotic activities of kidney cells were measured with caspase Elisa kits. DNA laddering test was used to show DNA damage in H2O2 condition. RESULTS: For tumor mechanism, they act as pro oxidants, producing hydrogen peroxide that attacks the cancer, whereas, in normal conditions they act as protective antioxidants. CONCLUSIONS: The unlike reaction of specific antioxidants should be known at different cell stages. The aim of this study was to assess the antioxidative roles of alpha lipoic acid on kidney cancers during oxidative stress induction (Tab. 1, Fig. 7, Ref. 27). PMID- 28814090 TI - Melatonin: a hepatoprotective agent against radioiodine toxicity in rats. AB - OBJECTIVES: The aim of the current study was to investigate the possible radioprotective effects of melatonin against hepatic radioiodine (RAI) toxicity. METHODS: Thirty-six rats were randomly divided into three groups: untreated control (Group 1); oral radioiodine (RAI, 111 MBq) administrated rats (Group 2), and melatonin group (oral RAI and daily intraperitoneal injection of 12 mg/kg melatonin-Group 3). In the third group, melatonin administration was started two days before and continued for five days after RAI administration. Twenty-four hours after the administration of the last dose of melatonin, liver samples were taken for biochemical and histopathological evaluation. RESULTS: Oxidative stress parameters demonstrated that melatonin treatment decreased the tissue malondialdehyde (MDA), advanced the oxidation protein products (AOPP) levels, and increased the total-SH (sulphydryl) levels when compared with RAI group. The differences were statistically significant between these groups for all parameters (p < 0.05). The histopathological damage in the melatonin-treated group was significantly less than the damage in RAI group (p < 0.05 for all pathological parameters). CONCLUSION: The results of this study demonstrated that melatonin reduced the harmful effects of RAI treatment on the liver. Anti inflammatory and antioxidant activities are likely to be involved in the mechanism underlying the radio-protective effects of melatonin (Tab. 3, Fig. 1, Ref. 30). PMID- 28814091 TI - The effect of vitamin D on MCF-7 breast cancer cell metabolism. AB - The role of vitamin D in calcium absorption and bone health is known. The studies revealed that vitamin D modulates breast cancer cell growth and it is also associated with a reduced breast cancer risk. The primary objective of this study was to highlight the metabolic effect of Vitamin D on MCF-7 breast cancer cell line. For that purpose, we checked the apoptosis, energy, amino-acid and acylcarnitine levels in cancer cells, that the study propose, that 1alpha, 25(OH)2D3 could inhibit cell growth in a dose and time dependent manner. IC50 dose was calculated as 145 nM for vitamin D. We observed the apoptosis level in vitamin D groups, which were 18, 28 and 38.5 % at 24, 48 and 72 hours, respectively. During metabolic screening analysis, it was observed that glutamine, methionine and glutamic acid levels were treated more by Vitamin D groups in cell line and also, that acylcarnitine level was increased in 24 and 48 hour groups when compared to the control, but decreased in 72 hours. Further studies are needed to analyze the role of amino acids and acylcarnitines for early apoptosis and cancer metabolism (Tab. 2, Fig. 4, Ref. 24). PMID- 28814092 TI - Flow cytometric examination of apoptotic effect on brain tissue in postnatal period created by intrauterine oxcarbazepine and gabapentin exposure. AB - OBJECTIVE: For epileptics, pregnancy contains the balance between no seizure period and antiepileptic use having the least teratogenicity risk. The purpose is to analyse with flow cytometry the apoptotic effects on postnatal brain tissue caused by prenatal use of second generation antiepileptics oxcarbazepine (OXC) and gabapentin (GBP) having different effect mechanisms. METHOD: 30 (n = 5 each group) Wistar albino male rats (45-days-old) are used. First 3 groups are exposed to OXC (100 mg/kg/day), GBP (50 mg/kg/day), and saline, respectively on the 1st 5th prenatal days (preimplantation-implantation period) while the second 3 groups are exposed to the same substances on the 6th-15th prenatal days (organogenesis), respectively. After sacrifice, brain tissue samples were made into suspension with mechanic and enzymatic digestion and examined with flow cytometry. RESULTS: While apoptosis rate appeared high in rats exposed to OXC on the 1st-5th (p < 0.001) and 6th-15th days (p < 0.001), no significant difference occurred for GBP (p = 0.004; p = 0.012) and saline (p = 0.012). Considering time effect in three treatment groups, while difference was not significant for PSS and GBP groups (p = 0.847 and p = 0.934), apoptosis rate was significantly high for OXC on the 6th 15th days compared to the 1st-5th days (p < 0.001). CONCLUSION: It is observed that the use of OXC causes neurotoxicity during preimplantation, implantation and, especially, organogenesis period (neurogenesis) whereas GBP does not (Fig. 3, Ref. 32). PMID- 28814093 TI - Role of ischemic modified albumin in the early diagnosis of increased intracranial pressure and brain death. AB - AIM: Increased intracranial pressure following trauma and subsequent possible development of brain death are important factors for morbidity and mortality due to ischemic changes. We aimed to establish the role of ischemic modified albumin (IMA) in the early diagnosis of the process, starting with increased intracranial pressure and ending with brain death. MATERIALS AND METHODS: Eighteen Wistar Albino rats were divided into three groups; control (CG, n = 6), increased intracranial pressure (ICPG, n = 6), and brain death (BDG, n = 6). Intracranial pressure elevation and brain death were constituted with the inflation of a balloon of a Fogarty catheter in the epidural space. In all three groups, blood samples were drawn before the procedure, and at minutes 150 and 240 for IMA and malondialdehyde (MDA) analysis. RESULTS: Serum IMA levels at 150 and 240 minutes were higher in ICPG than in CG (p < 0.05). IMA levels were similar in ICPG and BDG. Serum MDA levels at 150 and 240 minutes increased in ICPG and BDG groups compared to CG (p < 0.05). MDA levels were similar in ICP and BD groups. CONCLUSION: IMA should be considered as a biochemical parameter in the process starting from increased intracranial pressure elevation and ending at brain death (Tab. 3, Fig. 5, Ref. 31). PMID- 28814094 TI - The role of pegaptanib sodium in the suppression of epidural fibrosis in a postlaminectomy rat model. AB - OBJECTIVE: Spinal epidural fibrosis is a clinical condition that develops after laminectomy and can compress the spine. Many agents have been tried for the treatment, but none has entered clinical use at present. Pegaptanib sodium is an antiangiogenetic drug that prevents the development of new vessels and thus adhesion by inhibiting the effect of VEGF. MATERIAL AND METHOD: 20 Wistar rats were used in this study. The rats were divided into 2 different groups as the control and pegaptanib sodium group. Three levels of laminectomy were performed. Only laminectomy was performed in the control group. A cotton ball soaked with 3 mg/kg Pegaptanib sodium diluted 1: 10 with 0.9 % NaCl was topically applied to the dura in the surgical field for 5 minutes in the pegaptanib sodium group. The rats were sacrificed 3 weeks later and histopathologically examined. The epidural fibrosis was graded. RESULTS: The epidural fibrosis grade in the pegaptanib sodium was significantly lower than in the control group c2 = 11,65; (p = 0.004)CONCLUSION: Pegaptanib sodium blocked the VEGF through its anti-VEGF effect and decreased spinal epidural fibrosis in rats that had undergone laminectomy (Tab. 2, Fig. 3, Ref. 53). PMID- 28814095 TI - Quercetin induces apoptosis and necroptosis in MCF-7 breast cancer cells. AB - OBJECTIVE: This study investigated the quercetin (Que) effects on growth of MCF-7 human cancer breast cell line and its cellular death mechanism. BACKGROUND: Quercetin has been found to be very efficacious against many different types of cancer cells. However, the study is not sufficiently powered to demonastrate anticancer mechanisms. METHODS: MCF-7cells were treated by 50 uM/ ml of Que for 48 hours. MCF-7 cells were also pretreated with 10 MUm ZVAD (apoptosis inhibitor) or 3 mM Nec-1 (necroptosis inhibitor) for evaluation of cell death induced by apoptosis or necroptosis. RESULTS: MTT and clonogenicity assays revealed that the Que induced a significant increase in cell viability and proliferation in presence of Nec-1 in comparison to the presence of ZVAD (p < 0.05). Que also increased apoptosis as revealed by DAPI staining and morphology evaluations. Following Que treatment Bcl-2 expression was significantly decreased while Bax expression was significantly increased. Que in presence of Nec-1 decreased expression of Bax gene, reduced apoptotic index, increased cell viability and proliferation of MCF-7 cells in comparison to absence of Nec-1. MCF-7 cells showed a significantly increased expression of RIPK1 and RIPK3 in response to Que plus ZVAD in comparison to absence of ZVAD. CONCLUSION: Our results revealed that the high Que toxicity for breast cancer cells depends on multiple cell death pathways, which involve mainly necroptosis (Fig. 6, Ref. 21). PMID- 28814096 TI - Ankle Block vs Single-Shot Popliteal Fossa Block as Primary Anesthesia for Forefoot Operative Procedures: Prospective, Randomized Comparison. AB - BACKGROUND: Postoperative pain is often difficult to control with oral medications, requiring large doses of opioid analgesia. Regional anesthesia may be used for primary anesthesia, reducing the need for general anesthetic and postoperative pain medication requirements in the immediate postoperative period. The purpose of this study was to compare the analgesic effects of an ankle block (AB) to a single-shot popliteal fossa block (PFB) for patients undergoing orthopedic forefoot procedures. METHODS: All patients having elective outpatient orthopedic forefoot procedures were invited to participate in the study. Patients were prospectively randomized to receive either an ultrasound-guided AB or PFB by a board-certified anesthesiologist prior to their procedure. Intraoperative conversion to general anesthesia and postanesthesia care unit (PACU) opioid requirements were recorded. Postoperative pain was assessed using the visual analog scale (VAS) at regular time intervals until 8 am on postoperative day (POD) 2. Patients rated the effectiveness of the block on a 1 to 5 scale, with 5 being very effective. A total of 167 patients participated in the study with 88 patients (53%) receiving an AB and 79 (47%) receiving a single-shot PFB. RESULTS: There was no significant difference in the rate of conversion to general anesthesia between the 2 groups (13.6% [12/88] AB vs 12.7% [10/79] PFB). PACU morphine requirements and doses were significantly reduced in the PFB group ( P = .004) when compared to the AB group. The VAS was also significantly lower for the PFB patients at 10 pm on POD 0 (4.6 vs 1.6, P < .001), 8 am on POD 1 (5.9 vs 4.2, P = .003), and 12 pm on POD 1 (5.4 vs 4.1, P = .01). Overall complication rates were similar between the groups (AB 9% vs PFB 10.1%, P = .51) and there were no significant differences in residual sensory paresthesias (AB 2.3% [2/88] vs PFB 5.1% [4/79], P = .29), motor loss (0% vs 0%), or block site pain and/or erythema (AB 6.9% [6/88] vs PFB 5.1% [4/79], P = .44). The analgesic effect of the PFB lasted significantly longer when compared to the ankle block (AB 14.5 hours vs PFB 20.9 hours, P < .001). There was no significant difference in patient perceived effectiveness of the block between the 2 groups, with both blocks being highly effective (AB 4.79/5 vs PFB 4.82/5, P = .68). CONCLUSION: Regional anesthesia was a safe and reliable adjunct to perioperative pain management and highly effective in patients undergoing elective orthopedic forefoot procedures. However, patients who received a PFB had significantly better pain management and decreased opioid requirements in the immediate perioperative period than patients who received an ankle block. LEVEL OF EVIDENCE: Level I, prospective randomized study. PMID- 28814097 TI - Prominent deep medullary veins: a predictive biomarker for stroke risk from transient ischemic attack? AB - Background Deep medullary veins (DMVs) are a biomarker of severity and prognosis in patients with acute cerebral infarction. However, their clinical significance remains unclear in patients with transient ischemic attack (TIA). Purpose To determine whether prominent deep medullary veins (PDMVs) are a predictive biomarker for stroke risk after TIA. Material and Methods Clinical and imaging data of 49 patients with TIA and 49 sex- and age-matched controls were studied. PDMVs were defined as DMVs with a score of 3 (TDMVs) or asymmetric DMVs (ADMVs), and the relationship between PDMVs and clinical features was analyzed. The DMV score based on susceptibility weighted imaging (SWI) ranged from 0 (not visible) to 3 (very prominent) and was calculated for both hemispheres separately. A different score in each hemisphere was defined as ADMVs and an equal score was defined as symmetric DMVs. The asymmetry and score of DMVs were compared between the two groups and with respect to the time from TIA onset to imaging analysis. Results Agreement between neuroradiologists for the DMV asymmetry/score on SWI was excellent. The frequency of ADMVs and TDMVs was significantly higher in patients with TIA than controls ( P < 0.05). The patients showed no correlation between the time from TIA onset to imaging and the DMV asymmetry/score ( P > 0.05); PDMVs were not correlated with age, blood pressure, or diabetes. However, PDMVs were associated with the ABCD2 score (>=4), clinical symptoms, and duration of TIA (>=10 min). Conclusion Prominent deep medullary veins is a predictive biomarker for the risk of stroke in many patients having suffered from TIA. PMID- 28814098 TI - Quantitative and qualitative MRI evaluation of cerebral small vessel disease in an elderly population: a longitudinal study. AB - Background Cerebral white matter hyperintensities (WMHs), lacunes, and microbleeds are seen on magnetic resonance imaging (MRI) in small vessel disease (SVD). Purpose To assess SVD on MRI and its evolution over five years in an elderly population and to investigate whether relative cerebral blood flow (rCBF) at baseline was related to the progression of white matter (WM) lesions. Material and Methods In a population-based study, 406 participants aged 75 years underwent morphological MRI of the brain and 252 of them again at age 80 years. At age 75 years, a perfusion scan was also done. WMHs were evaluated qualitatively (visual scoring) and quantitatively (CASCADE software). Lacunes and microbleeds were counted. Results A significant progression of the WMH score and WMH volume occurred over five years ( P < 0.0001). New lacunes were seen in 10%. Participants with new lacunes at age 80 years showed a more pronounced increase in WMHs (P < 0.0001). Microbleeds were present in 14% at age 75 years. The visual WMH score was significantly associated with the presence of microbleeds ( P < 0.0001). There was no relationship between total WM rCBF and WMH volume at age 75 years, and no significant associations between regional or total rCBF at age 75 years and changes in WMH volume over five years. The total WM and GM volume decreased significantly between the ages of 75 and 80 years ( P < 0.0001). Conclusion MRI manifestations of SVD progressed over five years in an elderly population (age range = 75-80 years). rCBF was not associated with WMH volume or progression of WMH volume. PMID- 28814099 TI - Prevalence of Mental Disorders among Older Chinese People in Tianjin City. AB - OBJECTIVE: Population aging is accelerating across the world, and older people have a higher risk of mental disorders. Most studies focus on one mental disorder, and only report the current prevalence. Besides, these studies use screening scales for symptoms of mental disorders, which may induce biased results. In this study, we used data for diagnoses based on SCID that had been administered by trained psychiatrists to explore the 1-month and lifetime prevalence of mental disorders among a Chinese aged cohort. METHODS: Data for this study was derived from the Tianjin Mental Health Survey. Participants were first screened using a General Health Questionnaire and 9 additional items on other risk factors for mental disorders, and then diagnosed with the Chinese version of Structured Clinical Interview for Diagnostic and Statistical Manual (DSM-IV) Axis I disorders. A total of 3,325 people aged 60 and above had valid information, and 1,486 completed the SCID interview. RESULTS: The weighted 1 month prevalence of mental disorders was 14.27%, whereas the lifetime prevalence of mental disorders was 24.20%. Most of these participants were female, older, currently not married, of lower education level, and with poor family economic status. Organic mental disorders had the highest 1-month prevalence (4.45%), whereas mood disorder was highest for the lifetime prevalence (9.75%). CONCLUSION: Older Chinese people had a high prevalence of mental disorders. Further research and health services innovations are needed to address the high prevalence in these subgroups among older people. PMID- 28814101 TI - Antioxidative sulphated polygalactans from marine macroalgae as angiotensin-I converting enzyme inhibitors. AB - Antioxidant and antihypertensive potential of the sulphated polygalactans isolated from the marine macroalgae Kappaphycus alvarezii and Gracilaria opuntia were assessed by utilising different in vitro systems. The galactans isolated from K. alvarezii possessed significantly greater antioxidative properties as determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH IC90 0.97 mg/mL) and 2,2'-azino bis(3-ethylbenzothiazoline-6-sulphonic acid (ABTS.+ IC90 0.72 mg/mL) scavenging activities than those isolated from G. opuntia (DPPH IC90 1.2 mg/mL and ABTS 0.86 mg/mL). The sulphated polygalactan ->4)-4-O-sulphonato-(2-O-methyl)-beta-D galactopyranosyl-(1->4)-3,6-anhydro-(2-O-methyl)-alpha-D-galactopyranan from K. alvarezii showed greater angiotensin-I-converting enzyme (ACE) inhibitory activity (IC50 0.02 MUg/mL) than ->3)-4-O-sulphonato-(6-O-acetyl)-beta-D galactopyranosyl-(1->4)-3,6-anhydro-(2-O-sulphonato)-alpha-D-galactopyranosyl-(1 >3)-4-O-sulphonato-(6-O-acetyl)-beta-D-xylosyl-(1->3)-4-O-sulphonato-(6-O-acetyl) beta-D-galactopyranosyl-(1->4)-3,6-anhydro-(2-O-sulphonato)-alpha-D galactopyranan motif extracted from G. opuntia (IC50 0.70 MUg/mL). Structure activity correlation studies displayed that the ACE inhibitory properties of titled polygalactans were directly proportional to their electronic properties and inversely with the steric and hydrophobic characteristics. Putative ACE inhibitory mechanism of action of sulphated galactans from marine macroalgae corroborated the structure bioactivity correlation analysis. PMID- 28814100 TI - Suicidal Behaviour Among Adolescents and Young Adults with Self-Reported Chronic Illness. AB - OBJECTIVE: The aims of this study were to estimate the: (1) 12-mo prevalence of suicidal thoughts, plans, and attempts in a population sample of adolescents and young adults with and without chronic illness; (2) associations among chronic illness and suicidal thoughts and behaviour (STB); and, (3) moderating roles of mood and substance use disorder on this association. METHOD: Individuals were aged 15 to 30 y ( n = 5,248) from the Canadian Community Health Survey-Mental Health. Twelve-month STB and psychiatric disorder were measured using the World Health Organization Composite International Diagnostic Interview 3.0. Multinomial logistic regression examined associations between chronic illness and STB, adjusting for relevant sociodemographic and health characteristics. Product term interactions among chronic illness, mood, and substance use disorders were included in the regression models to examine potential moderating effects. RESULTS: Prevalence of suicidal thoughts, plans, and attempts was higher in individuals with chronic illness ( P < 0.01 for all). After adjustment, chronic illness increased the odds for suicidal thoughts [OR = 1.28 (1.01 to 1.64)], plans [OR = 2.34 (1.22 to 4.39)], and attempts [OR = 4.63 (1.52 to 14.34)]. In the presence v. absence of a mood disorder, the odds for suicidal thoughts were higher among individuals with chronic illness [OR = 1.89 (1.06 to 5.28)]. CONCLUSIONS: Suicidal thoughts and behaviours are common among adolescents and young adults with chronic illness, particularly among those with comorbid mood disorders. Health professionals should routinely ask about STB during assessments of their adolescent and young adult patients. PMID- 28814102 TI - Minimally Invasive Plate Osteosynthesis Using Locking Plates for AO 43-Type Fractures: Lessons Learnt From a Prospective Study. AB - INTRODUCTION: Managing fractures of distal tibia is still a subject of debate for orthopaedic surgeons in terms of both, reduction and fixation. Subcutaneous location and soft tissue anatomy predisposes it to angular and rotational instability as well as other bony and soft tissue complexities. Minimally invasive plating offers many advantages over conventional open techniques. It causes minimal soft tissue dissection and surgical trauma to the bone. Minimally invasive plate osteosynthesis(MIPO) maintains biological configuration of distal tibia and fracture hematoma and also provides a construct, which is biomechanically more stable. OBJECTIVES: Evaluation of results of MIPO in management of distal tibia fractures considering radiological union, ankle function restoration, and complications. MATERIALS AND METHODS: In our study, 25 closed distal one-third tibia fracture with/without articular extension were taken, fulfilling the inclusion criteria (AO classification: 10, 43A1; 3, 43A2; 2, 43B1; 4, 43B2; and 6, 43C1). MIPO with locking plates was the treatment undertaken. Patients were followed up for 18 months prospectively. RESULTS: Average injury-hospital interval was 11.16 hours and average injury-operation interval was 2.44 days. All fractures showed radiological union at an average duration of 20.5 weeks (14-28 weeks). Olerud and Molander score was used for evaluation at 3, 6, and 18 months. One patient had union with valgus angulation >5 degrees but there was no nonunion. There was 1 superficial postoperative wound infection. CONCLUSION: Our study shows that plating with MIPO is an effective treatment for closed distal one-third tibia fractures, considering union time and complications rate. Younger age promotes early union and functional recovery. LEVELS OF EVIDENCE: Therapeutic, Level II: Prospective. PMID- 28814103 TI - Associations between glycaemic control and activation of the renin-angiotensin aldosterone system in participants with type 2 diabetes mellitus and hypertension. AB - Introduction Hyperglycaemia increases succinate concentrations and succinate receptor activation in the kidney resulting in renin release. The aim of our study was to determine if there is an association between glycaemic control as evidenced by glycated haemoglobin values and activation of the renin-angiotensin aldosterone system in patients with type 2 diabetes mellitus and hypertension. Methods A cross-sectional study was conducted at Galway University Hospitals between December 2014 and March 2015. Participants ( n = 66) were identified following interrogation of the electronic database for patients with type 2 diabetes mellitus. Baseline clinical demographics, aldosterone, plasma renin activity, direct renin concentration, urea and electrolytes, glycated haemoglobin, cholesterol, urine sodium and albumin creatinine ratio were recorded. Results There was a significant positive linear correlation between glycated haemoglobin and renin (both plasma renin activity [ P = 0.002] and direct renin concentration [ P = 0.008]) and between serum creatinine and aldosterone measured using both radioimmunoassay ( P = 0.008) and immunochemiluminometric assay ( P = 0.008). A significant negative linear correlation was demonstrated between serum sodium and plasma renin activity ( P = 0.005) and direct renin concentration ( P = 0.015) and between estimated glomerular filtration rate and aldosterone measured using radioimmunoassay ( P = 0.02) and immunochemiluminometric assay ( P = 0.016). A significant negative linear correlation existed between urine sodium and plasma renin activity ( P = 0.04) and aldosterone measured using radioimmunoassay ( P = 0.045). Conclusions There is a direct positive association between glycaemic control and renin. We advocate for renin measurement to be part of the diabetologist's armamentarium to assess, guide and optimize therapeutic strategies in patients with diabetes. PMID- 28814104 TI - Factors associated with low neighborhood cohesion among women living with HIV impacted by social-structural inequities in British Columbia. AB - Built and social environments, including one's perception of their environment, are important determinants of health. The intersection of gender and HIV status may complicate the role of neighborhood cohesion in safety, personal well-being, and health outcomes for populations impacted by social and structural inequities. Among women in particular, social cohesion within the neighborhood they reside in may have a greater influence on health outcomes compared to their male counterparts. We sought to examine perception of neighborhood cohesion (validated scale with a range 0-100, with higher scores indicating higher perceived neighborhood cohesion) among women living with HIV, impacted by social-structural inequities, receiving combination antiretroviral therapy, and enrolled in the Longitudinal Investigations into Supportive Ancillary health services (LISA) study in British Columbia, Canada. Cross-sectional data on neighborhood cohesion and socio-demographic data were collected in an interviewer-administered survey. Of the 1,000 LISA participants interviewed, 908 (including 249 women and 659 men) had complete data for the variables of interest. At the bivariate level, women had worse perceived neighborhood cohesion scores compared to men (median: 56 [95% CI: 44-66] vs. 60 [95% CI: 47-71]). Multivariable model results indicated that for women living with HIV in our sample, greater neighborhood cohesion scores were positively associated with stable housing (beta coefficient = 7.85; 95% CI: 3.61, 12.10, p < 0.001), and negatively associated with greater perceived HIV stigma (beta coefficient = -1.19; 95% CI: -2.24 to-0.15; p = 0.025). The results illustrate the gendered nature of experiencing built and social environments, and highlight the need for women-centred interventions to address the social determinants of HIV burden associated with negative perceptions of neighborhood cohesion. PMID- 28814106 TI - Cameroonian medicinal plants belonging to Annonaceae family: radical scavenging and antifungal activities. AB - The free-radical scavenging activity of ethanolic and methanolic extracts of leaves, stems and roots of Annona muricata, Monodora tenuifolia, Uvaria comperei, Uvaria muricata and Xylopia africana was evaluated using DPPH and ORAC assays. Further, phytochemical analysis, total phenolic and total flavonoid contents were also determined. Moreover, the antifungal activity of extracts was studied. The findings indicated that A. muricata and U. comperei extracts own antiradical activities and moderate antifungal properties. PMID- 28814107 TI - Real-world comparison of treatment patterns and effectiveness of albiglutide and liraglutide. AB - AIM: To compare medication adherence, discontinuation and glycemic control in patients receiving albiglutide versus liraglutide. PATIENTS & METHODS: Administrative claims data and glycated hemoglobin (HbA1c) results were analyzed from a sample of adult health plan members with Type 2 diabetes. RESULTS: Patients were matched 1:1 in the albiglutide (n = 2213) and liraglutide (n = 2213) overall cohorts and in 244 patients with HbA1c results from each treatment group. Mean HbA1c change from baseline was -1.0% for both groups. At 6 months, mean +/- standard deviation adherence was 0.69 +/- 0.29 versus 0.64 +/- 0.29 (p < 0.001), and discontinuation was 33.2 versus 37.8% (p = 0.002) with albiglutide versus liraglutide, but these were not statistically or clinically different at 12 months. CONCLUSION: Similar treatment patterns and clinically meaningful reductions in HbA1c were observed for both treatments in this real-world comparison. PMID- 28814108 TI - Association of Anxiety and Depression With Pain and Quality of Life in Patients With Chronic Foot and Ankle Diseases. AB - BACKGROUND: The purposes of this study were to clarify the incidence of anxiety and depression among patients with chronic foot and ankle diseases and to examine the independent association of anxiety and depression with pain and quality of life. METHODS: Patients who visited the foot and ankle clinic from April 2015 to November 2016 were recruited. Anxiety and depression in patients were assessed using the Hospital Anxiety and Depression Scale. Pain and quality of life were evaluated using the visual analog scale (VAS) and Self-Administered Foot Evaluation Questionnaire (SAFE-Q), respectively. Furthermore, patient characteristics, including age, sex, body mass index, pain in other body areas, social support, employment, and household income, were surveyed. A multiple regression analysis was performed to examine the independent association of anxiety and depression with pain and quality of life. A total of 250 patients were included in the analysis. RESULTS: The prevalence of anxiety and depression was 30% and 27%, respectively. The VAS and all SAFE-Q subscale scores were significantly worse in patients with anxiety or depression than in patients without the same (median VAS 63 vs 49 for anxiety, P = .005; 68 vs 47 for depression, P < .001). Furthermore, the multiple regression analyses showed that the presence of anxiety ( P = .02) and depression ( P < .001) was independently associated with increased pain, and it led to low scores on all SAFE-Q subscales ( P < .001 for all subscales). CONCLUSION: About 30% of patients with chronic foot and ankle disease had anxiety or depression. The presence of these psychological symptoms was independently associated with worse pain and impaired quality of life after controlling for patient characteristics. Clinicians need to recognize the possibility of concurrent anxiety and depression to provide a more holistic treatment for chronic foot and ankle disease. LEVEL OF EVIDENCE: Level IV, case series. PMID- 28814109 TI - Older Adults in Rural Appalachia: Preference and Expectations for Future Care. AB - Little is known about how rural-dwelling older adults anticipate and plan for future care needs. Using a mixed-method explanatory design, structural equation modeling ( n = 535) revealed significant associations between concerns about using services on preference for type of help; preference was associated with likelihood of using future services. Content analysis of interview data from 19 older adults who needed but were not receiving help revealed how they conceptualize their need for assistance and anticipated future care arrangements. Nine older adults were not thinking about future care needs. While most older adults articulated preferences for informal help, they indicated some openness to formal assistance. Preferences did not always align with expectations for the future. Rather, concerns about burdening family and friends outweighed concerns about community services and influenced expectations of using formal services. Understanding rural older adults' expectations for future care arrangements is necessary for advancing policy and implementing successful services options. PMID- 28814110 TI - Engaging HIV-positive clients in care: acceptability and mechanisms of action of a peer navigation program in South Africa. AB - Antiretroviral therapy (ART) could curtail the HIV epidemic, but its impact is diminished by low uptake. We developed a peer navigation program to enhance engagement in HIV care, ART adherence, and behavioral prevention. In preparation for a randomized controlled trial, the program was piloted over four months at two primary health clinics in South Africa's North West Province. Newly diagnosed, HIV-positive clients met regularly with navigators to address barriers to care, adherence, and prevention. To assess program acceptability and feasibility and characterize the mechanisms of action, we surveyed 25 clients who completed navigation services and conducted interviews with 10 clients, four navigators, and five clinic providers. Clients expressed near universal approval for the program and were satisfied with the frequency of contact with navigators. HIV stigma emerged as a primary driver of barriers to care. Navigators helped clients overcome feelings of shame through education and by modeling how to live successfully with HIV. They addressed discrimination fears by helping clients disclose to trusted individuals. These actions, in turn, facilitated clients' care engagement, ART adherence, and HIV prevention efforts. The findings suggest peer navigation is a feasible approach with potential to maximize the impact of ART-based HIV treatment and prevention strategies. PMID- 28814111 TI - Ligand efficiency metrics in drug discovery: the pros and cons from a practical perspective. AB - INTRODUCTION: Ligand efficiency metrics are almost universally accepted as a valuable indicator of compound quality and an aid to reduce attrition. Areas covered: In this review, the authors describe ligand efficiency metrics giving a balanced overview on their merits and points of weakness in order to enable the readers to gain an informed opinion. Relevant theoretical breakthroughs and drug like properties are also illustrated. Several recent exemplary case studies are discussed in order to illustrate the main fields of application of ligand efficiency metrics. Expert opinion: As a medicinal chemist guide, ligand efficiency metrics perform in a context- and chemotype-dependent manner; thus, they should not be used as a magic box. Since the 'big bang' of efficiency metrics occurred more or less ten years ago and the average time to develop a new drug is over the same period, the next few years will give a clearer outlook on the increased rate of success, if any, gained by means of these new intriguing tools. PMID- 28814112 TI - An injectable in situ gel with cubic and hexagonal nanostructures for local treatment of chronic periodontitis. AB - Periodontitis is a chronic bacterial infection, and its effective treatment is dependent on the retention of antibiotics of effective concentrations at the periodontal pockets. In this study, a solution-gel based inverse lyotropic liquid crystalline (LLC) system was explored to deliver metronidazole to the periodontal pockets for local treatment of periodontitis. It was found that the metronidazole loaded LLC precursor spontaneously transformed into gel in the presence of water in the oral cavity. The low viscosity of the precursor would allow its penetration to the rather difficult to reach infection sites, while the adhesiveness and crystalline nanostructures (inverse bicontinuous cubic Pn3m phase and inverse hexagonal phase) of the formed gel would permit its firm adhesion to the periodontal pockets. The LLC system provided sustained drug release over one week in vitro. Results from in vivo study using a rabbit periodontitis model showed that the LLC system was able to maintain the metronidazole concentrations in the periodontal pockets above the minimum inhibition concentration for over 10 days without detectable drug concentration in the blood. Owing to the spontaneous solution-gel transition in the periodontal pockets and unique liquid crystalline nanostructures, the LLC in situ gel provided effective treatment of periodontitis for a prolonged period of time with reduced systematic side effects, compared to metronidazole suspension which was effective for 24 h with detectable metronidazole concentrations in the blood after 6 h. PMID- 28814113 TI - Intracytoplasmic sperm injection using hyaluronic acid or polyvinylpyrrolidone: a time-lapse sibling oocyte study. AB - This study evaluated the effect of sperm selection and intracytoplasmic sperm injection (ICSI) on subsequent fertilization and embryo development using the hyaluronic acid-based SpermSlowTM (HA-ICSI) compared to injection with polyvinylpyrrolidone (PVP-ICSI). A total of 206 metaphase II oocytes were collected from 21 prospectively enrolled ICSI cycles at Fertility North between July 2014 and March 2015. Sibling oocytes were randomized into HA-ICSI and PVP ICSI (n = 103 per group). Subsequent fertilization outcomes and embryo development in terms of qualitative and quantitative time-lapse measures following three-day culture in the EmbryoscopeTM were compared. HA-ICSI resulted in significantly lower abnormal fertilization rates (1.9% vs 9.7%, p = 0.017), and a trend towards increased normal fertilization rates (73.8% vs 62.1%, p = 0.073) with increased injection time (2.5 vs 2.1 min, p = 0.001). No differences between HA-ICSI and PVP-ICSI were observed in (a) the proportion of good conventional morphology embryos (50% vs 53.1%, p = 0.712), (b) time-lapse qualitative measures (p > 0.05) and (c) time-lapse quantitative measures (p > 0.05). In conclusion, HA-ICSI improves fertilization outcomes although sperm injection takes longer to complete. Subsequent embryo development up to day 3 is not affected. PMID- 28814114 TI - Cross-cultural validation of the Falls Efficacy Scale-International to assess concerns about falls among Hungarian community-living older people. AB - PURPOSE: The Falls Efficacy Scale-International (FES-I) is a reliable and valid tool for assessing concerns about falling. Our aims were to translate, culturally adapt, and evaluate the main psychometric characteristics (internal consistency, reproducibility, and convergent construct validity) of the Hungarian version of the FES-I on a sample of community-living older adults. METHODS: After translating and culturally adapting the original scale, 165 community-living older adults (aged 60 years or over) participated in the measurements and filled in the questionnaire. After two weeks, a subsample of 64 persons filled in the FES-I again to determine the test-retest reliability. RESULTS: The test-retest analysis showed excellent reliability: Intraclass Correlation Coefficient was 0.831. The FES-I Hungarian consisted of two factors that showed good internal consistency: Cronbach's alpha 0.95 (Factor 1), 0.89 (Factor 2), and 0.93 (whole scale). The FES-I was able to discriminate the participants based on gender and fall history. It showed a significant correlation with the Timed Up and Go test (r = 0.740) and the general health perception (r = -0.713). CONCLUSIONS: Translation and cultural adaptation of the original scale were successful. The Hungarian version proved to be a reliable, valid tool confirming that it can be used in future clinical and scientific work with Hungarian older people. Implications for rehabilitation Excessive concerns about falls may lead to avoidance of activities, decreasing functional abilities, increasing of risk of a future fall, ultimately premature nursing home admission. The Falls Efficacy Scale-International is a widespread tool for assessing concerns about falls. The Hungarian version of Falls Efficacy Scale-International has an excellent test retest reliability, good internal consistency, and acceptable construct validity. The Hungarian version of Falls Efficacy Scale-International is a valid and reliable tool for measuring the concerns about falls among Hungarian-speaking community-living older people in everyday clinical practice and scientific studies. PMID- 28814115 TI - Neuraminidase inhibitory activity by compounds isolated from aerial parts of Rhinacanthus nasutus. AB - Rhinacanthus nasutus (L.) Kurz (Acanthaceae) is known as traditional medicine for the treatment of various diseases, such as cancer, fungal infections, herpes virus infections and several types of skin diseases in South-East Asian countries. In this study, eight compounds 1-8 were isolated from the aerial parts of R. nasutus. The structures of compounds were determined by the spectroscopic methods, including 1D and 2D NMR. The isolated compounds were evaluated for neuraminidase inhibitory activity. Several lignans, 2,3-bis[(4-hydroxy-3,5 dimethoxyphenyl)methyl]-1,4-butanediol (5) and 8,8'-bisdihydrosiringenin glucoside (6), significantly inhibited neuraminidase activity, which was comparable to the positive controls, mangiferin and oseltamivir. In addition, a structure-based virtual screening against neuraminidase using bioactive components was demonstrated. PMID- 28814116 TI - The dark side of the ring: role of the DNA sliding surface of PCNA. AB - The proliferating cell nuclear antigen (PCNA) sliding clamp lies at the heart of the accurate duplication of eukaryotic genomes. While the outer surface of the PCNA ring interacts with polymerases and other factors, the role of the inner wall facing the DNA is elusive. Recent evidence shows that conserved basic residues in the PCNA central channel create a specific surface that recognizes the DNA backbone and enables the clamp to slide by rotationally tracking the DNA helix. The sliding surface can be modulated (i) through lysine acetylation, which triggers PCNA degradation during nucleotide excision repair (NER) and stimulates repair by homologous recombination (HR) or (ii) through binding of the protein factor p15PAF, which turns off DNA lesion bypass. Thus, the inner surface of PCNA is unexpectedly highly regulated to control resistance to DNA damage. From a structural viewpoint, we reflect on these findings that open a new perspective on PCNA function and offer opportunities to develop tools to manipulate the DNA damage response in cancer treatment. PMID- 28814117 TI - Review of the mechanism of action of coal tar in psoriasis. AB - PURPOSE: Crude coal tar and its derivatives have been used in modern medicine for the treatment of psoriasis since at least 1925 as part of the Goeckerman regimen. To this day, coal tar remains a safe and highly effective option for the treatment of psoriasis vulgaris. However, the mechanism by which coal tar has its therapeutic effect is unknown. This review summarizes current knowledge of the mechanism by which coal tar has its therapeutic effect in the treatment of psoriasis vulgaris. MATERIAL AND METHODS: A Pubmed search was conducted on March 13, 2017 for relevant English language journal articles on the subject and were relevant journal articles were included in this review. RESULTS: Crude coal tar consists of thousands of ingredients, many of which are unidentified. Of these ingredients, the most research has gone into analyzing polycyclic aryl hydrocarbons. These hydrocarbons are thought to be the most likely component of crude coal tar that leads to its effects in psoriasis. Of the aryl hydrocarbons, carbazole has been the most well studied in psoriasis and is hypothesized as being responsible for the treatment efficacy of crude coal tar. CONCLUSIONS: Polycyclic aryl hydrocarbons, and specifically carbazole, are thought to be the mechanism by which crude coal tar has its effect in psoriasis. However, further research is warranted to fully characterize the mechanism of action of crude coal tar, with the potential to create new therapies for psoriasis. PMID- 28814118 TI - Considerations for clinical trial design in older adults with cancer. PMID- 28814119 TI - Correction to: North American Congress of Clinical Toxicology (NACCT) Abstracts 2017. PMID- 28814120 TI - How East Germany Fabricated the Myth of HIV Being Man-Made. AB - Despite the fact that the origin of human immunodeficiency virus (HIV) being a contamination and a mutation originating from primates is well-documented alternative narratives are often being heard ofespecially in sub-Saharan Africa. One such narrative is about HIV being man-made in a military laboratory in the United States. In this article, it is shown how this narrative was fabricated by the intelligence services in East Germany (German Democratic Republic - GDR) as part of the ideological warfare during the Cold War. The purpose of this article is to put an end to a long-lasting conspiracy theory, which is still alive and may create diversion from serious research on the topic. PMID- 28814122 TI - Flibanserin toxicity in a toddler following ingestion. AB - INTRODUCTION: Flibanserin is a medication recently approved by the FDA for treatment of generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Its mechanism of action is not fully understood but is thought to modulate serotonin receptors and increase levels of norepinephrine and dopamine. While much is known about toxicity of other drugs which affect these systems, there is little information about toxicity of flibanserin at this time. CASE: We present a case of a 2-year-old boy who ingested an estimated 600 mg of his mother's flibanserin. Following ingestion, the child developed facial twitching and unresponsiveness to pain, concerning for seizure-like activity. In the emergency department (ED) he was found to have hypertension, mydriasis, slurred speech, and normal labs. He responded well to supportive care including administration of benzodiazepines. Shortly after admission to the hospital, his temperature increased to 38.4 degrees C. Toxicology testing revealed the presence of 1-(3-trifluoromethylphenyl)-piperazine (TFMPP), a flibanserin metabolite. TFMPP is a recreational drug used as an alternative to 3,4 methylenedioxymethamphetamine (more commonly known as "MDMA" or "ecstasy"). DISCUSSION: This case highlights potential toxicity associated with ingestion of flibanserin. PMID- 28814121 TI - Perceptions of Iranian Female Drug Users Toward HIV Testing: A Qualitative Content Analysis. AB - BACKGROUND: Drug-dependent women are the vulnerable population deprived of access to health services and also have particular relevance to public health perspective because they are important bridge population for driving HIV/AIDS epidemic. This qualitative study aimed to explore the perception of drug dependent women regarding HIV testing. METHODS: In this qualitative study, we approached 23 women with substance use disorders in 2 of the selected drop-in centers in the south Tehran. Focus group discussion, face-to-face semistructured interviews, and field notes were used to collect the data. Qualitative content analysis was used to extract the explanatory model of women's perceptions about HIV testing. RESULTS: Four main themes emerged from the data: forgotten health during use, having misconception, and sharing of sexual partner in secrecy and concerns. Seven subthemes were extracted, including not being sex worker, point of ruin, voluntary selection and concerns about fear of abandonment and fear of loss and death, double concern, and future of children. CONCLUSION: Beliefs and values of drug-dependent women can be positive points leading them to do an HIV test, and misconceptions of these women would be corrected by using safe behavioral skills training. PMID- 28814123 TI - Establishing the NeuroRecovery Network Community Fitness and Wellness facilities: multi-site fitness facilities provide activity-based interventions and assessments for evidence-based functional gains in neurologic disorders. AB - BACKGROUND: Physical fitness is a necessity for those living with a spinal cord injury, yet access to fitness facilities, equipment, and specially trained fitness experts are limited. METHODS: This article introduces the concept of a network of fitness facilities specially geared towards individuals with spinal cord injury and other neurological disorders. RESULTS: The Community Fitness and Wellness branch of the NeuroRecovery Network was created to provide a continuum of care after traditional rehabilitation for individuals living with a spinal cord injury and other neurological disorders. Community Fitness and Wellness facilities translate activity-based interventions performed during rehabilitation into a community setting as well as provide other fitness and wellness opportunities. Community Fitness and Wellness facilities are staffed by professionals with training on the specialized needs of individuals living with spinal cord injury or other neurological disorders. Standardized assessments evaluate functional, health, and quality of life gains at regular intervals. A national database gathers information on standardized interventions and assessment outcomes providing a mechanism for evaluation of interventions performed in the community setting. CONCLUSIONS: The establishment of Community Fitness and Wellness facilities allows for the quick translation and evaluation of novel, effective approaches from research to individuals in the community. Implications for Rehabilitation Fitness needs of individuals with spinal cord injury living in the community necessitate the use of special equipment and trained staff. Community Fitness and Wellness Programs offer specially trained staff and adaptive equipment providing a continuity of care for those with spinal cord injuries and other neurological disorders. PMID- 28814125 TI - Recreational drug use at a major music festival: trend analysis of anonymised pooled urine. AB - OBJECTIVE: The spread of new psychoactive substances (NPS) has expanded rapidly in the last decade. The complexity of the pharmacological effects of NPS challenges the traditional treatment guidelines, and information of the emergence of new arrivals is valuable. Our knowledge on the actual range of recreational drugs used and NPS available in Denmark is limited as identification is possible only when consumers become patients in the healthcare system or through drug seizures. We aimed to detect classical recreational drugs and NPS in the urine of music festival attendees and evaluate if the use of NPS could have been predicted by comparing study data with drug seizure data from the previous year published by European and Danish health authorities. METHODS: In a cross-sectional study, 44 urine samples were collected from three urinals at Roskilde Festival 2016-the largest Danish music festival. Two urinals were placed at music stages with late night concerts, and one urinal was placed at a camp site. Samples were prepared using enzymatic hydrolysis followed by cationic and anionic solid phase extraction, and analysed using ultra performance liquid chromatography-high resolution time-of-flight mass spectrometry (UPLC-HR-TOF-MS). Data were processed using an in-house library of 467 target substances, including legal and illegal drugs and metabolites. Urine drug-screening immunoassays were also evaluated and results were compared to UPLC-HR-TOF-MS results. RESULTS: In total, 77 drugs, including metabolites, were qualitatively identified in the 44 urine samples. The recreational drugs identified were amphetamine (n = 30), cocaine (n = 44), MDA (n = 40), MDMA (n = 44), THC-COOH (n = 19) and ketamine (n = 17). No NPS were identified. Sample testing using the urine drug-screening immunoassays showed presence of cocaine (n = 27), methamphetamine/MDMA (n = 4), THC (n = 7), "Spice" (n = 7) and methylphenidate (n = 1). These discrepancies might be caused by differences in cut-off values between the analytical methods, limited specificity or cross-reactivity of the urine drug-screening immunoassays compared to UPLC-HR TOFMS results. CONCLUSION: Widespread uses of classical recreational drugs were identified in pooled urine samples. The prevalence of NPS was not as comprehensive as expected based on the European and Danish health authorities reports on illegal drugs. Urine drug-screening immunoassays results are advised to be confirmed by chromatographic bioanalysis. PMID- 28814124 TI - Comparative metabolic profiling of Costus speciosus leaves and rhizomes using NMR, GC-MS and UPLC/ESI-MS/MS. AB - Costus speciosus had been used in oriental systems of medicines, to treat diverse ailments. The present study was focused on NMR, GC-MS and UPLC/ESI-MS/MS-based metabolic profiling of C. speciosus. This metabolic study resulted in the identification of 91 and quantification of 69 metabolites. Caffeic acid derivatives previously unreported in C. speciosus were also identified. High quantity of steroidal saponins namely methyl protogracillin (297.97 +/- 0.07 mg/g dried wt.) and dioscin (158.72 +/- 0.27 mg/g dried wt.) were observed in butanol fraction of rhizomes. Health care metabolites including caffeic acid (37.88 +/- 0.04 mg/g dried wt.) and trehalose (75.12 +/- 0.08 mg/g dried wt.) were also detected in ethyl acetate and aqueous fractions of rhizomes, respectively. Metabolites of nutraceutical and biological significance including eremanthine (5.14 +/- 0.68%, peak area), tocopherols (~22%), sterols (~25%) were also identified from hexane fractions of rhizomes and leaves using GC-MS. The analytical techniques used had successfully differentiated metabolites composition among leaves and rhizomes. PMID- 28814126 TI - Detection of ingested nitromethane and reliable creatinine assessment using multiple common analytical methods. AB - AIM: Nitromethane, found in fuels used for short distance racing, model cars, and model airplanes, produces a falsely elevated serum creatinine with standard creatinine analysis via the Jaffe method. Erroneous creatinine elevation often triggers extensive testing, leads to inaccurate diagnoses, and delayed or inappropriate medical interventions. Multiple reports in the literature identify "enzymatic assays" as an alternative method to detect the true value of creatinine, but this ambiguity does not help providers translate what type of enzymatic assay testing can be done in real time to determine if there is indeed false elevation. METHODS: We report seven cases of ingested nitromethane where creatinine was determined via Beckman Coulter(r) analyser using the Jaffe method, Vitros(r) analyser, or i-Stat(r) point-of-care testing. Nitromethane was detected and semi-quantified using a common clinical toxic alcohol analysis method, and quantified by headspace-gas chromatography-mass spectrometry. RESULTS: When creatinine was determined using i-Stat(r) point-of-care testing or a Vitros(r) analyser, levels were within the normal range. Comparatively, all initial creatinine levels obtained via the Jaffe method were elevated. Nitromethane concentrations ranged from 42 to 310 MUg/mL. CONCLUSIONS: These cases demonstrate reliable assessment of creatinine through other enzymatic methods using a Vitros(r) analyser or i-STAT(r). Additionally, nitromethane is detectable and quantifiable using routine alcohols gas chromatography analysis and by headspace gas chromatography-mass spectrometry. PMID- 28814129 TI - A protean disease: The phenotypic range of neuromyelitis optica spectrum disorder. PMID- 28814128 TI - Effects of telemonitoring on glycaemic control and healthcare costs in type 2 diabetes: A randomised controlled trial. AB - Introduction This study examined the effect of a telehealth intervention on the control of type 2 diabetes and subsequent potential cost-savings to the health system. Methods This prospective randomised controlled trial randomised adults with type 2 diabetes to the intervention (diabetes program) or control (usual care) arm. Key eligibility criteria included an HbA1c level of at least 58 mmol/mol (7.5%) without severe or unstable comorbidities. All participants continued their usual healthcare, but participants in the intervention arm received additional diabetes care from a diabetes care coordinator via a home monitor that captured clinical measures. Data collected included biomedical, quality of life measures and healthcare (GP, outpatient and inpatient) costs. The primary outcome was HbA1c collected at baseline and 6 months. Analysis was conducted on a complete case intention-to-treat basis. The healthcare system perspective was taken to calculate the incremental cost per percentage-point reduction in HbA1c. Results Results from 63 participants from each study arm were analysed. HbA1c in the intervention group decreased from a median 68 mmol/mol (8.4%) to 58 mmol/mol (7.5%), and remained unchanged in the control group at median 65 mmol/mol (8.1%) at the 6-month endpoint. The intervention effect on HbA1c change was statistically significant ( p = .004). Total healthcare costs in the intervention group, including the intervention costs, were lower (mean $3781 vs. $4662; p < .001) compared with usual care. Discussion There was a clinically meaningful and statistically significant benefit from the telehealth intervention at a lower cost; thus, telehealth was cost-saving and produced greater health benefits compared with usual care. PMID- 28814127 TI - Carbon nanotubes functionalized with folic acid attached via biomimetic peptide linker. AB - AIM: Anchoring folic acid (FA) with a biomimetic peptidic linker resistant to proteolytic degradation to act as a homing device on functionalized carbon nanotubes. MATERIALS & METHODS: Ethylenediamine was attached to oxidized multiwalled carbon nanotubes (MWNTs) using 4-(4,6-dimethoxy-[1,3,5]triazin-2-yl) 4-methylmorpholinium tetrafluoroborate. FA was coupled with 6-aminohexanoic acid and derivatives of beta-alanine, affording four intermediates, which connected to the MWNTs via peptidic linkers of various lengths. RESULTS: Biomimetic nanomaterials were produced with FA as a homing molecule. The structure and properties of the nanomaterials were analyzed, confirming the versatility of the peptides used as linkers. CONCLUSION: Conjugates of FA attached to MWNTs via peptide linkers prepared from beta-alanine residues are resistant to proteolytic degradation. Viability in colon cancer cells and normal colonocytes confirmed their lack of cytotoxicity. PMID- 28814130 TI - Identification and characterization of a sulfoglycosidase from Bifidobacterium bifidum implicated in mucin glycan utilization. AB - Human gut symbiont bifidobacteria possess carbohydrate-degrading enzymes that act on the O-linked glycans of intestinal mucins to utilize those carbohydrates as carbon sources. However, our knowledge about mucin type O-glycan degradation by bifidobacteria remains fragmentary, especially regarding how they decompose sulfated glycans, which are abundantly found in mucin sugar-chains. Here, we examined the abilities of several Bifidobacterium strains to degrade a sulfated glycan substrate and identified a 6-sulfo-beta-d-N-acetylglucosaminidase, also termed sulfoglycosidase, encoded by bbhII from Bifidobacterium bifidum JCM 7004. A recombinant BbhII protein showed a substrate preference toward 6-sulfated and 3,4-disulfated N-acetylglucosamines over non-sulfated and 3-sulfated N acetylglucosamines. The purified BbhII directly released 6-sulfated N acetylglucosamine from porcine gastric mucin and the expression of bbhII was moderately induced in the presence of mucin. This de-capping activity may promote utilization of sulfated glycans of mucin by other bacteria including bifidobacteria, thereby establishing the symbiotic relationship between human and gut microbes. PMID- 28814132 TI - Islet amyloid in recent-onset type 1 diabetes-the DiViD study. PMID- 28814133 TI - Behavioral and Psychosocial Characteristics Among Head Start Childcare Providers. AB - The aim of the study was twofold: (a) describe behavioral and psychosocial characteristics of Head Start childcare providers including technology use, physical activity, nutrition, depression, and quality of life and (b) examine associations among these characteristics. Using a cross-sectional design, a nonrandom sample of 80 Head Start childcare providers completed an online survey via SurveyMonkey. About 80.1% were overweight or obese. Nearly all had a computer or smartphone. About 55% met the national physical activity recommendation of 150 min/week. Approximately 56.2% did not know the recommended daily servings of fruits and vegetables, and 26.3% had >=3 servings of vegetables per day. About 38.8% had major depression or dysthymia, and 31.3% had depressive symptoms. The top two perceived health needs were weight loss and stress management. Providing a health promotion and stress management program to childcare providers may benefit both providers and children, considering the strong influence of teachers on children. PMID- 28814131 TI - What Factors Influence Women's Perceptions of their Systemic Recurrence Risk after Breast Cancer Treatment? AB - BACKGROUND: Breast cancer patients' misunderstanding of their systemic cancer recurrence risk has consequences on decision-making and quality of life. Little is known about how women derive their risk estimates. METHODS: Using Los Angeles and Georgia's SEER registries (2014-2015), a random sample of early-stage breast cancer patients was sent surveys about 2 to 3 months after surgery ( N = 3930; RR, 68%). We conducted an inductive thematic analysis of open-ended responses about why women chose their risk estimates in a uniquely large sub-sample ( N = 1,754). Clinician estimates of systemic recurrence risk were provided for patient sub-groups with DCIS and with low-, intermediate-, and high-risk invasive disease. Women's perceived risk of systemic recurrence (0% to 100%) was categorized as overestimation, reasonably accurate estimation, or underestimation (0% for invasive disease) and was compared across identified factors and by clinical presentation. RESULTS: Women identified 9 main factors related to their clinical experience (e.g., diagnosis and testing; treatment) and non-clinical beliefs (e.g., uncertainty; spirituality). Women who mentioned at least one clinical experience factor were significantly less likely to overestimate their risk (12% v. 43%, P < 0.001). Most women who were influenced by "communication with a clinician" had reasonably accurate recurrence estimates (68%). "Uncertainty" and "family and personal history" were associated with overestimation, particularly for women with DCIS (75%; 84%). "Spirituality, religion, and faith" was associated with an underestimation of risk (63% v. 20%, P < 0.001). LIMITATIONS: The quantification of our qualitative results is subject to any biases that may have occurred during the coding process despite rigorous methodology. CONCLUSIONS: Patient-clinician communication is important for breast cancer patients' understanding of their numeric risk of systemic recurrence. Clinician discussions about recurrence risk should address uncertainty and relevance of family and personal history. PMID- 28814134 TI - Demonstrating the Relationship Between School Nurse Workload and Student Outcomes. AB - This article describes how one very large, diverse school district developed a Student Acuity Tool for School Nurse Assignment and used a logic model to successfully advocate for additional school nurse positions. The logic model included three student outcomes that were evaluated: provide medications and procedures safely and accurately, increase the number of students with a medical home, and increase the number of students with chronic illness that receive case management. Pairing a staffing formula with an evaluation plan that focuses on student outcomes and the priorities of the school district provides a strong case that school nurses are essential and that they contribute to student success. PMID- 28814135 TI - Spanish Validation of the MacArthur Competence Assessment Tool for Clinical Research Interview for Assessing Patients' Mental Capacity to Consent to Clinical Research. AB - The aim of the study was to assess a Spanish adaptation of a method that determines the categorical capacity status of potential participants in research projects. The sample consisted of 120 subjects (40 general medicine inpatients, 40 psychiatric inpatients, and 40 healthy controls). The MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) interview and Mini-Mental State Examination (MMSE) were used. A feasibility study was carried out and reliability and validity calculations were made against the expert-judgment gold standard. The mean duration of the MacCAT-CR was 13 min. For the MacCAT-CR understanding, appreciation, reasoning, and expressing a choice subscales, the intraclass coefficient correlation (interrater reliability) was .93, .88, .90, and .50, respectively, and internal consistency (Cronbach's alpha) was .96, .94, and .95, respectively. Patients considered to be incompetent for expert-judgment obtained lower scores in the MacCAT-CR interview. The Spanish version of the MacCAT-CR is feasible, reliable, and valid for assessing the capacity of patients to give consent in research. PMID- 28814136 TI - Hybrid core shell nanoparticles entrapping Gd-DTPA and 18F-FDG for simultaneous PET/MRI acquisitions. AB - AIM: Although there has been an improvement in the hardware and software of the PET/MRI system, the development of the nanoprobes exploiting the simultaneous acquisition of the bimodal data is still under investigation. Moreover, few studies on biocompatible and clinically relevant probes are available. This work presents a core-shell polymeric nanocarrier with improved relaxometric properties for simultaneous PET/MRI acquisitions. MATERIALS & METHODS: Core-shell nanoparticles entrapping the Gd-DTPA and 18F-FDG are obtained by a complex coacervation. RESULTS & DISCUSSION: The boosting of r1 of the entrapped Gd-DTPA up to five-times compared with 'free Gd-DTPA', is confirmed by the PET/MRI scan. The sorption of 18F-FDG into the nanoparticles is studied and designed to be integrated downstream for the production of the tracer. PMID- 28814137 TI - PEGylated crosslinked hyaluronic acid nanoparticles designed through a microfluidic platform for nanomedicine. AB - AIM: A high versatile microfluidic platform is proposed to design, in a one-step strategy, PEGylated crosslinked hyaluronic acid nanoparticles (cHANPs) entrapping a magnetic resonance imaging contrast agent and a dye for multimodal imaging applications. MATERIALS & METHODS: Clinically relevant biomaterials were shaped in the form of spherical NPs through a microfluidic flow focusing approach. A comparison between post processing and simultaneous PEGylation is reported to evaluate the potentiality of the chemical decoration of the cHANPs in microfluidics. RESULTS: An accurate control of the NPs in terms of size, PEGylation and loading was obtained. Furthermore, in vitro cell viability is reported and their ability to boost the magnetic resonance imaging signal is also confirmed. CONCLUSION: The proposed microfluidic approach reveals its ability to overcome several limitations of the traditional processes and to become an easy to-use platform for theranostic applications. PMID- 28814138 TI - Finnish nurses' attitudes towards their role in the euthanasia process. AB - BACKGROUND: Nurses' voices remain unheard in most debates about euthanasia, although their crucial role in the euthanasia process is widely acknowledged. Moreover, in Canadian euthanasia law, nurses have a more active role, which further highlights the need for knowledge about nurses' attitudes towards their role in the euthanasia process. RESEARCH QUESTIONS: What are Finnish nurses' attitudes towards their potential role in the euthanasia process? Which characteristics are associated with those attitudes? RESEARCH DESIGN: Cross sectional web-based survey. Participants and research context: 1003 nurses, recruited via social media and the members' bulletin of the Finnish Nurses Association. Ethical considerations: Ethical approval was obtained from the Committee on Research Ethics of the university to which the first author was affiliated. FINDINGS: The great majority (85.2%) of nurses felt that their perspective should be considered in decision-making related to euthanasia. Furthermore, most of the participants (74.7%) reported willingness to participate in the euthanasia process if it were legal, and 88.6% agreed that a nurse should be present when euthanasia is performed if the patient wishes so. Furthermore, over half agreed that some of the preparatory tasks were part of their job description. However, a minority (32.9%) agreed with a possible obligation to participate based on their profession. Nurses' age, religiosity and educational level influenced their attitudes in the current results. DISCUSSION: Despite the strong agreement on decision-making concerning euthanasia and participation in the euthanasia process, obligation to participate based on the profession was rejected by most participants. Nurses regarded themselves as consultants in the decision-making process, which may indicate their unwillingness to share the responsibility for the decision itself. CONCLUSION: Specific safety mechanisms should be considered to protect nurses who refuse to be involved in the euthanasia process due to harm that involuntary participation might cause. PMID- 28814139 TI - Validation of a Brazilian version of the moral sensitivity questionnaire. AB - BACKGROUND: Moral sensitivity has been identified as a foundational component of ethical action. Diminished or absent moral sensitivity can result in deficient care. In this context, assessing moral sensitivity is imperative for designing interventions to facilitate ethical practice and ensure that nurses make appropriate decisions. OBJECTIVE: The main purpose of this study was to validate a scale for examining the moral sensitivity of Brazilian nurses. RESEARCH DESIGN: A pre-existing scale, the Moral Sensitivity Questionnaire, which was developed by Lutzen, was used after the deletion of three items. The reliability and validity of the scale were examined using Cronbach's alpha and factor analysis, respectively. Participants and research context: Overall, 316 nurses from Rio Grande do Sul, Brazil, participated in the study. Ethical considerations: This study was approved by the Ethics Committee of Research of the Nursing School of the University of Sao Paulo. FINDINGS: The Moral Sensitivity Questionnaire contained 27 items that were distributed across four dimensions: interpersonal orientation, professional knowledge, moral conflict and moral meaning. The questionnaire accounted for 55.8% of the total variance, with Cronbach's alpha of 0.82. The mean score for moral sensitivity was 4.45 (out of 7). DISCUSSION AND CONCLUSION: The results of this study were compared with studies from other countries to examine the structure and implications of the moral sensitivity of nurses in Brazil. The Moral Sensitivity Questionnaire is an appropriate tool for examining the moral sensitivity of Brazilian nurses. PMID- 28814140 TI - Ethical sensitivity, burnout, and job satisfaction in emergency nurses. AB - BACKGROUND: Rising levels of burnout and decreasing job satisfaction can inhibit healthcare professionals from providing high-quality care due to a corresponding decrease in their ethical sensitivity. AIM: This study aimed to determine the relationship between the level of ethical sensitivity in emergency service nurses and their levels of burnout and job satisfaction. RESEARCH DESIGN: This research employed a descriptive and cross-sectional design. Participants and research context: This study was conducted with a sample of 236 nurses, all of whom worked in emergency service between 24 July 2015 and 28 April 2016. Data were collected using the Moral Sensitivity Questionnaire, Maslach Burnout Inventory, and Minnesota Job Satisfaction Scale. Ethical considerations: This study was approved by the Institutional Ethics Review Board of Ondokuz Mayis University. FINDINGS: There was a weak and negative correlation (r = -0.158, p = 0.015) between Moral Sensitivity Questionnaire and Maslach Burnout Inventory scores. There was also a weak and negative correlation (r = -0.335, p < 0.001) between the Maslach Burnout Inventory and Minnesota Job Satisfaction Scale scores. DISCUSSION AND CONCLUSION: Decreased job satisfaction and increased burnout levels among emergency service nurses might result in them indulging in improper practices, frequently facing ethical problems, and a decrease in the overall quality of service in hospitals. In order for emergency service nurses to recognize ethical problems and make the most accurate decisions, a high level of ethical sensitivity is critical. In this respect, it is suggested that continuing education after graduation and training programs should be organized. PMID- 28814141 TI - Effects of calcitonin on orthodontic tooth movement and associated root resorption in rats. AB - OBJECTIVES: Our main aim was to evaluate the effects of calcitonin (CT) on orthodontic tooth movement (OTM) and orthodontic root resorption in a rat model. MATERIAL AND METHODS: Eighty male Wistar rats were randomly divided into five groups. Rats in the negative control group were not given any appliances or injections. All the remaining rats were used to establish a model of OTM. The positive control group were then injected with normal saline, while rats in the three experimental groups were injected with 0.2 IU, 1 IU or 5 IU/kg/day CT. Nickel-titanium closed-coil springs were used to deliver an initial 50 g mesial force to the left maxillary first molar for 14 days in rats in the positive control group and the experimental groups. Each group was randomly subdivided into two groups, one for analysis of tooth movement, tissue changes and tartrate resistant acid phosphatase (TRAP)-positive cells in alveolar bone, the other to examine root resorption by scanning electron microscopy. RESULTS: The OTM distance, the number of force-induced osteoclasts and root resorption areas were significantly decreased in CT-injected rats in a dose-dependent manner. CONCLUSIONS: Administration of CT reduces the root resorption area and may therefore be effective as a novel adjunctive orthodontic approach to diminish undesired tooth movement via enhancing anchorage or preventing relapse after OTM. PMID- 28814142 TI - Effect of terpenes on transdermal iontophoretic delivery of diclofenac potassium under constant voltage. AB - OBJECTIVE: The aim of the study was to enhance the transdermal delivery of diclofenac potassium (DP) from hydrogels by constant voltage iontophoresis (CVI). The other objective was to establish the safety and efficacy of CVI in rats. MATERIALS AND METHODS: Hydrogels of DP were developed using hydroxyethyl cellulose as matrix material and geraniol, l-menthol and thymol as iontophoretic efficiency enhancers (IEE). In vitro permeation of hydrogels under CVI (1.5 V) was performed in Franz diffusion cells across porcine skin. The ability of CVI to deliver therapeutic amount of DP in vivo was assessed in rat paw edema model. RESULTS: CVI significantly (p < 0.05) increased the steady state flux of DP compared to the passive. The hydrogels containing geraniol and l-menthol enhanced the iontophoretic flux of DP by ~4.75 and ~4.49 fold, respectively compared to passive control. The in vivo studies indicated that CVI in combination with IEE, significantly reduced (p < 0.05) area under the curve (AUC) of % inflammation compared to passive treatment. An excellent correlation (r = 0.996) was noted between in vitro flux values and AUC of % inflammation. CONCLUSION: The preclinical studies conclusively demonstrated that CVI in combination with IEE's such as geraniol or l-menthol has the potential to safely deliver therapeutic amounts of DP. PMID- 28814143 TI - LY3045697: Results from two randomized clinical trials of a novel inhibitor of aldosterone synthase. AB - INTRODUCTION: LY3045697 is a potent and selective aldosterone synthase (CYP11B2) inhibitor that was developed as a safer alternative to mineralocorticoid receptor antagonists. Effects of LY3045697 on aldosterone and cortisol synthesis, as well as potassium ion homeostasis, were evaluated in two clinical studies in healthy subjects. MATERIALS AND METHODS: Two incomplete, placebo-controlled crossover design clinical studies examined safety, pharmacodynamics, and pharmacokinetics under single and repeated dose conditions in healthy subjects. Pharmacodynamics was assessed following oral potassium challenge and intravenous adrenocorticotropic hormone procedures with spironolactone 25 mg/d as an active comparator. RESULTS: A total of 51 subjects participated in the two studies, which included 38 males and 13 females (of non-childbearing potential), from 18 65 years old. LY3045697 caused rapid dose and concentration-dependent unstimulated plasma aldosterone concentration reduction seen as early as 4 h after the first dose at dose levels as low as 1 mg, and reaching near complete suppression at high doses. The potency (IC50) decreased significantly upon multiple dosing. After eight days of dosing, post-adrenocorticotropic hormone challenge plasma aldosterone concentration increase was dose-dependently blunted by LY3045697 with high potency with a dose as low as 0.1 mg resulting in substantial effect, and with an overall IC50 of 0.38 ng/ml. Minor reductions in cortisol were observed only at the top dose of 300 mg. LY3045697 is generally safe and tolerated, and exhibits linear pharmacokinetics. CONCLUSIONS: LY3045697 is a potent and highly selective aldosterone synthase inhibitor with selectivity for CYP11B2, offering a substantial potential advantage over previous aldosterone synthase inhibitors evaluated in the clinic. PMID- 28814144 TI - Intrathecal administration of AYX2 DNA-decoy produces a long-term pain treatment in rat models of chronic pain by inhibiting the KLF6, KLF9 and KLF15 transcription factors. AB - Background: Nociception is maintained by genome-wide regulation of transcription in the dorsal root ganglia-spinal cord network. Hence, transcription factors constitute a promising class of targets for breakthrough pharmacological interventions to treat chronic pain. DNA decoys are oligonucleotides and specific inhibitors of transcription factor activities. A methodological series of in vivo in vitro screening cycles was performed with decoy/transcription factor couples to identify targets capable of producing a robust and long-lasting inhibition of established chronic pain. Decoys were injected intrathecally and their efficacy was tested in the spared nerve injury and chronic constriction injury models of chronic pain in rats using repetitive von Frey testing. Results: Results demonstrated that a one-time administration of decoys binding to the Kruppel-like transcription factors (KLFs) 6, 9, and 15 produces a significant and weeks-month long reduction in mechanical hypersensitivity compared to controls. In the spared nerve injury model, decoy efficacy was correlated to its capacity to bind KLF15 and KLF9 at a specific ratio, while in the chronic constriction injury model, efficacy was correlated to the combined binding capacity to KLF6 and KLF9. AYX2, an 18-bp DNA decoy binding KLF6, KLF9, and KLF15, was optimized for clinical development, and it demonstrated significant efficacy in these models. Conclusions: These data highlight KLF6, KLF9, and KLF15 as transcription factors required for the maintenance of chronic pain and illustrate the potential therapeutic benefits of AYX2 for the treatment of chronic pain. PMID- 28814145 TI - Analgesia by Deletion of Spinal Neurokinin 1 Receptor Expressing Neurons Using a Bioengineered Substance P-Pseudomonas Exotoxin Conjugate. AB - Abstract: Cell deletion approaches to pain directed at either the primary nociceptive afferents or second-order neurons are highly effective analgesic manipulations. Second-order spinal neurons expressing the neurokinin 1 (NK1) receptor are required for the perception of many types of pain. To delete NK1+ neurons for the purpose of pain control, we generated a toxin-peptide conjugate using DTNB-derivatized (Cys0) substance P (SP) and a N-terminally truncated Pseudomonas exotoxin (PE35) that retains the endosome-release and ADP ribosylation enzymatic domains but with only one free sulfhydryl side chain for conjugation. This allowed generation of a one-to-one product linked by a disulfide bond (SP-PE35). In vitro, Chinese hamster ovary cells stably transfected with the NK1 receptor exhibited specific cytotoxicity when exposed to SP-PE35 (IC50 = 5 * 10-11 M), whereas the conjugate was nontoxic to NK2 and NK3 receptor-bearing cell lines. In vivo studies showed that, after infusion into the spinal subarachnoid space, the toxin was extremely effective in deleting NK1 receptor-expressing cells from the dorsal horn of the spinal cord. The specific cell deletion robustly attenuated thermal and mechanical pain sensations and inflammatory hyperalgesia but did not affect motoric capabilities. NK1 receptor cell deletion and antinociception occurred without obvious lesion of non-receptor expressing cells or apparent reorganization of primary afferent innervation. These data demonstrate the extraordinary selectivity and broad-spectrum antinociceptive efficacy of this ligand-directed protein therapeutic acting via receptor-mediated endocytosis. The loss of multiple pain modalities including heat and mechanical pinch, transduced by different populations of primary afferents, shows that spinal NK1 receptor-expressing neurons are critical points of convergence in the nociceptive transmission circuit. We further suggest that therapeutic end points can be effectively and safely achieved when SP-PE35 is locally infused, thereby producing a regionally defined analgesia. PMID- 28814147 TI - Threshold Effect of G9a/Glp on Peripheral Nerve Injury Induced Hypersensitivity. AB - Background: Previous studies disclosed the pivotal role of methyltransferase complex G9a/Glp in the pathogenesis of neuropathic hypersensitivity induced by peripheral nerve injury. We observed that higher dose of G9a inhibitor improved nociceptive behavior, but the lower dose worsened pain. The aim of this study is to extensively observe the differential effect of various dosages of G9a/Glp inhibitors on nerve injury-induced allodynia. Materials and methods: After approval by the institutional ethical committee on pain research in conscious animals, C57BL/6 mice were used for measuring nociceptive behavior evoked with von Frey filaments after spared nerve injury. G9a/Glp inhibitor BIX01294 or UNC0638 was injected through the pre-buried intrathecal catheter. The dose response curves of behavioral changes were depicted when inhibitors were administered once in bolus at the 14th day post spared nerve injury. Withdrawal behaviors were compared during the 49 days' observation window after spared nerve injury with various dosages of inhibitors injected intrathecally for 14 days. Results: Dose-behavior curves of a single bolus of both BIX01294 and UNC0638 displayed a "V"-shaped responses of allodynia withdrawal from lower through higher dose when measured at the 14th day post spared nerve injury. A threshold dose of 10.0 ug for BIX01294 and 80.0 ug for UNC0638 significantly worsened allodynia. However, daily bolus intrathecal injection for 14 days of both inhibitors lower or higher than these threshold doses prominently improved nociceptive behavior, producing contrasting results. On the same animal, threshold dose followed by a lower or higher dose with a 14 days' interval also showed contrast effect on nociceptive behavior, and a lower or higher dose to threshold dose sequence of inhibitor administration was vice versa. Conclusions: Methyltransferase complex G9a/Glp has a threshold role in mediating peripheral nerve injury-induced hypersensitivity at its low level versus high level through inhibiting and facilitating the nociceptive behavior, respectively. PMID- 28814146 TI - Evidence that Dry Eye Represents a Chronic Overlapping Pain Condition. AB - Abstract: Recent data suggest that corneal somatosensory dysfunction may be the underlying cause of severe dry eye symptoms in the absence of ocular surface pathology seen in a subset of patients diagnosed with "dry eye syndrome." This subset of patients tends to demonstrate a unique constellation of symptoms that are persistent, more severe, and generally respond poorly to current dry eye therapies targeting inadequate or dysfunctional tears. A growing body of literature suggests that symptoms in these patients may be better characterized as neuropathic ocular pain rather than dry eye. In these patients, dry eye symptoms are often associated with numerous comorbid pain conditions and evidence of central pain processing abnormalities, where eye pain is just one of multiple overlapping peripheral manifestations. In this review, we discuss the concept and potential mechanisms of chronic overlapping pain conditions as well as evidence for considering neuropathic ocular pain as one of these overlapping pain conditions. PMID- 28814149 TI - N+ implantation induce cytocompatibility of shape-controlled three-dimensional self-assembly graphene. AB - AIM: The aim of the present research was to synthesize N+ implanted 3D self assembly graphene (N+/3D-SGHs) to overcome the weaknesses of graphene (small sizes and poor hydrophilicity) in tissue engineering scaffolds. MATERIALS & METHODS: N+/3D-SGHs was achieved by ion implantation on one-step hydrothermal synthesized 3D self-assembly graphene (3D-SGHs), and N+/3D-SGHs with different doses of nitrogen ions (1 * 1016 ions/cm2, 1 * 1018 ions/cm2 and 1 * 1020 ions/cm2), which adjusted by nitrogen ion beam intensity. RESULTS: N+/3D-SGHs, as scaffolds, provide stereo space and hydrophilic groups for mouse-fibroblast cells (L929) growth and proliferation. Notably, N+/3D-SGHs with the N+ injected quantity of 1 * 1020 ions/cm2 displayed the highest protein-adhesion strength, cell viability and proliferation, which supported its good cytocompatibility. CONCLUSION: This study demonstrated N+/3D-SGHs as a promising and effective tissue scaffold that might have applications in biomedicine. PMID- 28814150 TI - Nitrous oxide labor analgesia and pain relief memory in breastfeeding women. AB - OBJECTIVE: The use of labor pain relief medications is a controversial issue that has engendered heated discussions among health care professionals about safety, interference with birthing, and breastfeeding. METHODS: This is a case-control study with 62 puerperae treated with nitrous oxide and 124 control women (ratio 1:2), matched for age, gestational age, parity, delivery route, labor augmentation, and spinal regional analgesia. We tested anhedonia, anxiety, and depression symptoms at hospital discharge by The Edinburgh Postnatal Depression Scale (EPDS), and the intensity of nitrous oxide labor pain relief and satisfaction memory by a retrospective Visual Analog Scale (VAS, 0-10 Numeric Rating Scale) at a set cut off time of 3 months of a child's age. RESULTS: Nitrous oxide use did not influence EPDS subscales upon discharge. Its use was instead associated with a lasting positive labor pain relief experience (VAS, 7.3 +/- 2.2) in 83.5% of women, and labor satisfaction memory (VAS, 8.9 +/- 1.8) in 90% of women, respectively, and with a significantly higher breastfeeding rates from the seventh day after discharge (p < .031), to the 1st (p < .043), and the third month of life (p < .016). CONCLUSIONS: Nitrous oxide labor analgesia is associated with favorable effects on both women's psychoemotional experience of labor and breastfeeding success. PMID- 28814148 TI - Could an endoneurial endothelial crosstalk between Wnt/beta-catenin and Sonic Hedgehog pathways underlie the early disruption of the infra-orbital blood-nerve barrier following chronic constriction injury? AB - Background: Blood-nerve barrier disruption is pivotal in the development of neuroinflammation, peripheral sensitization, and neuropathic pain after peripheral nerve injury. Activation of toll-like receptor 4 and inactivation of Sonic Hedgehog signaling pathways within the endoneurial endothelial cells are key events, resulting in the infiltration of harmful molecules and immunocytes within the nerve parenchyma. However, we showed in a previous study that preemptive inactivation of toll-like receptor 4 signaling or sustained activation of Sonic Hedgehog signaling did not prevent the local alterations observed following peripheral nerve injury, suggesting the implication of another signaling pathway. Methods: Using a classical neuropathic pain model, the infraorbital nerve chronic constriction injury (IoN-CCI), we investigated the role of the Wnt/beta-catenin pathway in chronic constriction injury-mediated blood-nerve barrier disruption and in its interactions with the toll-like receptor 4 and Sonic Hedgehog pathways. In the IoN-CCI model versus control, mRNA expression levels and/or immunochemical detection of major Wnt/Sonic Hedgehog pathway (Frizzled-7, vascular endothelial-cadherin, Patched-1 and Gli-1) and/or tight junction proteins (Claudin-1, Claudin-5, and Occludin) readouts were assessed. Vascular permeability was assessed by sodium fluorescein extravasation. Results: IoN-CCI induced early alterations in the vascular endothelial cadherin/beta-catenin/Frizzled-7 complex, shown to participate in local blood nerve barrier disruption via a beta-catenin-dependent tight junction protein downregulation. Wnt pathway also mediated a crosstalk between toll-like receptor 4 and Sonic Hedgehog signaling within endoneurial endothelial cells. Nevertheless, preemptive inhibition of Wnt/beta-catenin signaling before IoN-CCI could not prevent the downregulation of key Sonic Hedgehog pathway readouts or the disruption of the infraorbital blood-nerve barrier, suggesting that Sonic Hedgehog pathway inhibition observed following IoN-CCI is an independent event responsible for blood-nerve barrier disruption. Conclusion: A crosstalk between Wnt/beta-catenin- and Sonic Hedgehog-mediated signaling pathways within endoneurial endothelial cells could mediate the chronic disruption of the blood nerve barrier following IoN-CCI, resulting in increased irreversible endoneurial vascular permeability and neuropathic pain development. PMID- 28814151 TI - Long-Term Care Service Trajectories and Their Predictors for Persons Living With Dementia: Results From a Canadian Study. AB - OBJECTIVE: We used latent transition analysis to explore common long-term care (LTC) service trajectories and their predictors for older adults with dementia. METHOD: Using linked administrative data collected over a 4-year interval (2008 2011), the study sample included 3,541 older persons with dementia who were clients of publicly funded LTC in British Columbia, Canada. RESULTS: Our results revealed relatively equal reliance on home care (HC) and facility-based residential care (RC) as starting points. HC service users were further differentiated into "intermittent HC" and "continuous HC" groups. Mortality was highest for the RC group. Age, changes in cognitive performance, and activities of daily living were important predictors of transitions into HC or RC. DISCUSSION: Reliance on HC and RC by persons with dementia raises critical questions about ensuring that an adequate range of services is available in local communities to support aging in place and to ensure appropriate timing for entry into institutions. PMID- 28814152 TI - Distant metastasis in patients with myxofibrosarcoma. AB - PURPOSE: A clinical feature of myxofibrosarcoma is local recurrence, but knowledge about distant metastasis is sparse. We evaluated the tendency of clinical and histological features of metastasis in myxofibrosarcoma patients. METHODS: Fifty-eight patients with myxofibrosarcoma were treated in our hospitals, and a total of 16 consecutive patients with distant metastases were included in this retrospective study (9 males and 7 females, with a mean age of 77 years). Because there was no patient complicated by both lung and lymph node metastases, we compared the age, sex, tumor size and location, French Federation of Cancer Centers Sarcoma Group (FNCLCC) grade, American Joint Committee on Cancer (AJCC) stage, and times of the first metastasis from the initial examination between the lung and lymph node groups. In addition, we examined factors affecting the prognosis. RESULTS: The median follow-up period was 42.9 months (range 8-142). Eleven of 16 patients developed pulmonary metastases. The sites of extra pulmonary metastases were the lymph nodes in 5 patients, bone in 1, subcutaneous in 1, intramuscular in 1, and peritoneum in 1. The median time for patients to develop distant metastases was 17.4 months (range 0-59). The time until the onset of the first metastasis in the lung metastasis group was significantly shorter than in the lymph node group (p < 0.05). Also, the survival rate in the lymph node metastasis group was better than in the lung metastasis group (p < 0.05). CONCLUSIONS: Not only lung metastasis but also lymph node metastasis occurs frequently in myxofibrosarcoma patients. Myxofibrosarcoma with lung metastasis is more aggressive than the type with lymph node metastasis. PMID- 28814153 TI - A systematic review of treatment modalities and outcomes of type Ib endoleak after endovascular abdominal aneurysm repair. AB - Objectives To collect specific literature on type Ib endoleak after aorto-iliac endografting for abdominal aortic aneurysm, reporting data on diagnosis, treatment, and follow-up results. Methods Publications about type Ib endoleak after aorto-iliac endografting for abdominal aortic or iliac aneurysm were searched in PubMed, Web of Science, and Scopus. Considered studies were in English and published until 3 November 2016. Research methods and reporting were performed according to Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) statement. Inclusion criteria were: (1) reporting on abdominal aortic or iliac aneurysm as primary diagnosis; (2) reporting on distal endoleak after aorto-iliac endografting. Patient data, data on endovascular treatment, endoleak, reintervention, and follow-up were collected by two independent authors. Results Included studies were 11 (five original articles, six case reports), corresponding to 29 patients and 30 type Ib endoleak. Excluding missing data (2/30, 6.7%), type Ib endoleak was treated intra-operatively, within six months and after six months in six cases (21.4%), eight cases (28.6%), and fourteen cases (50%), respectively. Treatment of type Ib endoleak was endovascular in 27 cases (90%) (7 embolizations + extender cuffs, 10 extender cuffs, 8 embolizations without extender cuff, 1 Palmaz stenting and 1 iliac branched endograft), hybrid in 1 case (3.3%) and surgical in 2 cases (6.6%). Buttock claudication occurred in two cases (6.7%). One-month mortality was 3.4% (2/29) without events due to type Ib endoleak. In 14 cases (46.7%), median follow up was six months (interquartile range: 2.75-14; range: 0.75-53). Type Ib endoleak persisted or reappeared in three cases (10%), all after endovascular treatment. Two of these (2/3, 66.7%) needed endovascular reintervention. No death during follow-up was reported. Conclusions Few specific data are available in literature about type Ib endoleak after aorto-iliac endografting for abdominal aortic aneurysm. About 50% of type Ib endoleak occurred after six months from the endovascular abdominal aneurysm repair procedure. Treatment is mainly endovascular and distal endograft extension is the main and effective treatment. Buttock claudication is the most frequent complication in case of exclusion of internal iliac artery. Persistent type Ib endoleak is possible, and adjunctive endovascular procedures are necessary. PMID- 28814154 TI - A low-cost three-dimensional laser surface scanning approach for defining body segment parameters. AB - Body segment parameters are used in many different applications in ergonomics as well as in dynamic modelling of the musculoskeletal system. Body segment parameters can be defined using different methods, including techniques that involve time-consuming manual measurements of the human body, used in conjunction with models or equations. In this study, a scanning technique for measuring subject-specific body segment parameters in an easy, fast, accurate and low-cost way was developed and validated. The scanner can obtain the body segment parameters in a single scanning operation, which takes between 8 and 10 s. The results obtained with the system show a standard deviation of 2.5% in volumetric measurements of the upper limb of a mannequin and 3.1% difference between scanning volume and actual volume. Finally, the maximum mean error for the moment of inertia by scanning a standard-sized homogeneous object was 2.2%. This study shows that a low-cost system can provide quick and accurate subject-specific body segment parameter estimates. PMID- 28814155 TI - Frequency of a FAS ligand gene variant associated with inherited feline autoimmune lymphoproliferative syndrome in British shorthair cats in New Zealand. AB - AIMS To determine the frequency of the FAS-ligand gene (FASLG) variant associated with feline autoimmune lymphoproliferative syndrome (FALPS) and the proportion of carriers of the variant in three British shorthair (BSH) breeding catteries in New Zealand. METHODS Buccal swabs were collected from all cats in two BSH breeding catteries from the South Island and one from the North Island of New Zealand. DNA was extracted and was tested for the presence of the FASLG variant using PCR. Cats with the FASLG variant were identified and the frequency of the FASLG variant allele calculated. Pedigree analysis was performed and inbreeding coefficients were calculated for cats with the FASLG variant. RESULTS Of 32 BSH cats successfully tested for the presence of the FASLG variant, one kitten (3%) was homozygous (FALPS-affected), and seven (22%) cats were heterozygous (carriers) for the FASLG variant allele, and 24 (75%) cats were homozygous for the wild type allele. The overall frequency of the FASLG variant allele in these 32 cats was 0.14. Cats carrying the FASLG variant were from all three breeding catteries sampled, including two catteries that had not previously reported cases of FALPS. Pedigree analysis revealed common ancestry of FALPS-affected and carrier cats within six generations, as well as frequent inbreeding, with inbreeding coefficients >0.12 for five cats with the FASLG variant. CONCLUSIONS AND CLINICAL RELEVANCE There was a high frequency of the FASLG variant allele (0.14) in this small sample of BSH cats, with 22% of healthy cats identified as carriers of the FASLG variant. For an inherited disease, lethal at a young age, in a small population in which inbreeding is common, these results are significant. To prevent future cases of disease and stop further spread of the FASLG variant allele within the BSH population in New Zealand, it is recommended that all BSH and BSH-cross cats be tested for the presence of the FASLG variant before mating. Cats identified as carriers of the variant allele should be desexed and not used for breeding. Results support the need for further investigations of the true frequency of the FASLG variant allele and occurrence of FALPS in the wider population of BSH cats in New Zealand. PMID- 28814156 TI - A method to compare the performance of two molecular diagnostic tools in the absence of a gold standard. AB - The paper is motivated by the problem of comparing the accuracy of two molecular tests in detecting genetic mutations in tumor samples when there is no gold standard test. Commonly used sequencing methods require a large number of tumor cells in the tumor sample and the proportion of tumor cells with mutation positivity to be above a threshold level whereas new tests aim to reduce the requirement for number of tumor cells and the threshold level. A new latent class model is proposed to compare these two tests in which a random variable is used to represent the unobserved proportion of mutation positivity so that these two tests are conditionally dependent; furthermore, an independent random variable is included to address measurement error associated with the reading from each test, while existing latent class models often assume conditional independence and do not allow measurement error. In addition, methods for calculating the sample size for a study that is sufficiently powered to compare the accuracy of two molecular tests are proposed and compared. The proposed methods are then applied to a study which aims to compare two molecular tests for detecting EGFR mutations in lung cancer patients. PMID- 28814158 TI - A Phase I study of the pharmacokinetics, safety and tolerability of a novel tocopheryl phosphate mixture/oxymorphone transdermal patch system. AB - AIM: Characterize the pharmacokinetic profile and tolerability of two tocopheryl phosphate mixture/oxymorphone patch formulations in healthy subjects, and the active metabolite (6-OH-oxymorphone). MATERIALS & METHODS: Fifteen participants received a single application of oxymorphone patches +/- capsaicin for 72 h and were crossed-over for another 72 h. RESULTS: Plasma oxymorphone was detected approximately 7 h and 6-OH-oxymorphone after approximately 18-19 h postapplication of both formulations, respectively. For oxymorphone, median tmax was 24 h, and Cmax/Cmin ratio was approximately 2.4. The most frequently reported treatment-related adverse event was application site reaction, mainly with capsaicin formulation. CONCLUSION: Tocopheryl phosphate mixture/oxymorphone transdermal patches can successfully deliver therapeutic amounts of oxymorphone in a sustained manner over 72 h and are well tolerated. ANZCTR registration number: ACTRN12614000613606. PMID- 28814157 TI - The role and mechanism of glutamic NMDA receptor in the mechanical hyperalgesia in diabetic rats. AB - OBJECTIVES: Some studies have shown that painful neuropathy is a common and costly complication of both type 1 and type 2 diabetes mellitus, and glutamate is involved in the process although the mechanisms are not clear. The purpose of the present study was to investigate the effect of N-methyl-D-aspartate (NMDA) receptor on mechanical hyperalgesia in diabetic rats and the possible mechanism. METHODS: Diabetic rat model was established by intraperitoneal injection of streptozotocin (STZ, 1%, 70 mg/kg) once, and evaluated by the change in the fasting blood glucose. The mechanical hyperalgesia was estimated by mechanical withdrawal threshold (MWT) using a set of calibrated Von Frey's filaments. In addition, the expressions of phosphorylated NMDA NR1 and phosphorylated cAMP response element binding protein (pCREB) in L4/L5 dorsal horns of spinal cord were observed. RESULTS: Behavioral results showed that MK-801, an antagonist of NMDA receptor, could reduce the proportion of mechanical hyperalgesia in diabetic rats from 76.67 to 20.00%. Meanwhile, the mean MWTs in STZ group or saline treated STZ group decreased significantly at 3-8 week, while, the MWTs in MK-801 treated STZ group were significant higher than those in STZ or saline-treated STZ group. In addition, the expressions of NMDA NR1 and pCREB in L4/5 dorsal horns of spinal cord were significant higher in diabetic rats, and MK-801 down-regulated their expressions partly. CONCLUSION: All these results suggested that NMDA receptor and pCREB in the spinal cord were involved in the regulation of mechanical hyperalgesia in diabetic rats. PMID- 28814159 TI - Surviving Surveillance: How Pregnant Women and Mothers Living With HIV Respond to Medical and Social Surveillance. AB - Pregnant women and mothers living with HIV are under surveillance of service providers, family members, and the community at large. Surveillance occurs throughout the medical management of their HIV during pregnancy, preventing HIV transmission to their baby, infant feeding practices, and as part of assessments related to their ability to mother. Enacted and anticipatory HIV-related stigma can exacerbate the negative impact that being under surveillance has on mothers living with HIV as they move through their pregnancy, birthing, and mothering experiences. In response, women living with HIV find ways to manage their experiences of surveillance through engaging in acts of distancing, planning, and resisting at different points in time, and sometimes enacting all three practices at once. Positioning the narratives of pregnant women and mothers living with HIV in relation to their experiences of surveillance illuminates the relationship between the surveillance of mothers living with HIV and HIV-related stigma. PMID- 28814160 TI - Elucidation of molecular mechanism of stability of the heme-regulated eIF2alpha kinase upon binding of its ligand, hemin in its catalytic kinase domain. AB - The eIF2alpha kinase activity of the heme-regulated inhibitor (HRI) is regulated by heme which makes it a unique member of the family of eIF2alpha kinases. Since heme concentrations create an equilibrium for the kinase to be active/inactive, it becomes important to study the heme binding effects upon the kinase and understanding its mechanism of functionality. In the present study, we report the thermostability achieved by the catalytic kinase domain of HRI (HRI.CKD) upon ligand (heme) binding. Our CD data demonstrates that the HRI.CKD retains its secondary structure at higher temperatures when it is in ligand bound state. HRI.CKD when incubated with hemin loses its monomeric state and attains a higher order oligomeric form resulting in its stability. The HRI.CKD fails to refold into its native conformation upon mutation of H377A/H381A, thereby confirming the necessity of these His residues for correct folding, stability, and activity of the kinase. Though our in silico study demonstrated these His being the ligand binding sites in the kinase insert region, the spectra-based study did not show significant difference in heme affinity for the wild type and His mutant HRI.CKD. PMID- 28814161 TI - Significant rates of risky sexual behaviours among HIV-infected patients failing first-line ART: A sub-study of the Europe-Africa Research Network for the Evaluation of Second-line Therapy trial. AB - There are limited data on the prevalence of risky sexual behaviours in individuals failing first-line antiretroviral therapy (ART) and changes in sexual behaviour after switch to second-line ART. We undertook a sexual behaviour sub study of Ugandan adults enrolled in the Europe-Africa Research Network for the Evaluation of Second-line Therapy trial. A standardized questionnaire was used to collect sexual behaviour data and, in particular, risky sexual behaviours (defined as additional sexual partners to main sexual partner, inconsistent use of condoms, non-disclosure to sexual partners, and exchange of money for sex). Of the 79 participants enrolled in the sub-study, 62% were female, median age (IQR) was 37 (32-42) years, median CD4 cell count (IQR) was 79 (50-153) cells/ul, and median HIV viral load log was 4.9 copies/ml (IQR: 4.5-5.3) at enrolment. The majority were in long-term stable relationships; 69.6% had a main sexual partner and 87.3% of these had been sexually active in the preceding six months. At enrolment, around 20% reported other sexual partners, but this was higher among men than women (36% versus 6.7 %, p < 0.001). In 50% there was inconsistent condom use with their main sexual partner and a similar proportion with other sexual partners, both at baseline and follow-up. Forty-three per cent of participants had not disclosed their HIV status to their main sexual partner (73% with other sexual partners) at enrolment, which was similar in men and women. Overall, there was no significant change in these sexual behaviours over the 96 weeks following switch to second-line ART, but rate of non-disclosure of HIV status declined significantly (43.6% versus 19.6%, p <0.05). Among persons failing first-line ART, risky sexual behaviours were prevalent, which has implications for potential onward transmission of drug-resistant virus. There is need to intensify sexual risk reduction counselling and promotion of partner testing and disclosure, especially at diagnosis of treatment failure and following switch to second- or third-line ART. PMID- 28814162 TI - Insights on the Intersection of Health Equity and School Nutrition Policy Implementation: An Exploratory Qualitative Secondary Analysis. AB - BACKGROUND: Recent federal policies aimed to ensure that all children have equitable access to healthy school nutrition environments. However, historically, disparities have persisted in the quality of school nutrition environments across geographic and socioeconomic groups. There is limited literature addressing if and how recent efforts to reform the school nutrition environment have influenced such disparities. The main objective of this study was to explore stakeholders' insights on how school nutrition reform intersected with issues of inequity. METHOD: Qualitative secondary analysis (QSA) offers a unique method to examine existing data with a related but distinct inquiry. This QSA analyzed three primary studies, including stakeholder interviews and focus group data with school professionals and students (total 60 transcripts). Two trained analysts iteratively coded all transcripts in Atlas.ti Version 7 and followed principles of constant comparative analysis. Measures to enhance "trustworthiness" were built into the primary studies and the QSA. RESULTS: Broadly, stakeholders' complex insights about the school food environments' ability to compensate for healthy dietary options and "whole child" education that were perceived to be lacking in home environments. Despite the majority of respondents' positive perceptions of reforms, they also noted the challenges of addressing disparities due to family home environments and complex socioeconomic conditions. Overall, respondents reported that school food reform and nutrition education had the potential for long-term impacts on students' health, including the potential to improve disparities through enhanced academic achievement for disadvantaged populations. DISCUSSION AND CONCLUSION: QSA allowed for inquiry into frontline stakeholders' understandings of how school nutrition reform may affect health inequities. Qualitative methods allowed for the examination of complex motivations and perspectives involved in policy implementation. Understanding frontline stakeholders' perspectives is key to advance school nutrition reform in a sustainable manner, especially in light of the federal local school wellness policy final rule. PMID- 28814163 TI - Protease-activated nanomaterials for targeted cancer theranostics. AB - Cancer metastasis accompanies irreversible proteolysis. Malignant cells that abnormally express extracellular proteases usually lead to a poor outcome during cancer progression. The development of protease-activated drugs is an important goal. Moreover, the specific proteolytic mechanism can be used as a diagnostic strategy. Currently, nanotechnology for use in medication has been extensively developed to exploit the physical and chemical properties of nanoparticles. For example, to improve the efficacy of cancer therapy drugs, targeted delivery has been attempted by combining a targeting ligand with a nanoparticle. Multifunctional nanoparticles have been prepared for cancer therapy and diagnosis because of their advantages such as stable physical properties, drug carrying ability and potential specific targeting ability. In this review, we present reports on protease-activated nanoparticle design for cancer theranostics. We further describe recent protease-activated metalloprotease-based and cathepsin based nanomaterials used in cancer nanotheranostics. Innovative protease activated nanomaterials have significant potential for designing personalized treatment. PMID- 28814164 TI - CPX-351 in acute myeloid leukemia: can a new formulation maximize the efficacy of old compounds? AB - INTRODUCTION: The management of Acute Myeloid Leukemia (AML) (with the exception of acute promyelocytic leukemia) has remained largely unchanged over the past 40 years. In particular, patients defined as high-risk, according to the 2017 European Leukemia Net recommendations, represent a subgroup with poor response to current therapies that are frequently associated with high-grade toxicity and potentially fatal complications. Areas covered: Preliminary results from an ongoing phase III clinical trial suggest that CPX-351 could represent an interesting treatment option in both induction and 'bridge-to-transplant' settings. In particular, 60- to 75-year-old patients with secondary AML, when treated with CPX-351, exhibit superior overall survival (HR = 0.69; P = 0.005; median OS 9.56 vs. 5.95 months), event free survival (HR = 0.74; P = 0.021), and composite response rate (47.7% vs. 33.3%; P = 0.016) as compared to standard '7 + 3' therapy. Herein, we detail the main pharmacological features of CPX-351 and review updated results of clinical trials investigating its employment in AML. Expert commentary: Novel liposome-based drugs display a high therapeutic index and represent a promising alternative to unencapsulated drugs, especially when high-risk features complicate the use of standard treatments. Further efforts in both understanding AML biology and improving nanodrug design are needed. PMID- 28814165 TI - Ag+ implantation induces mechanical properties, cell adhesion and antibacterial effects of TiN/Ag multilayers in vitro. AB - AIM: This study aims to investigate the effect of Ag+ implantation dose on the structure, hardness, adhesion strength, friction resistance, cell adhesion and antibacterial effects of TiN/Ag multilayers. METHODS: Nanoscale TiN/Ag multilayers were deposited on Ti-6Al-4V substrates using multiarc ion plating. The multilayers were then implanted by Ag ions. RESULTS: A distinct multilayer structure and large titanium nitride grains with better (111) crystallinity were proved. The hardness and elastic modulus of the multilayer reached 32.2 and 318.9 GPa, respectively. The largest critical load was 32.5 mN, and the minimum friction coefficient was 0.092. The mechanical properties, the cell proliferation and antibacterial properties of the multilayers with Ag+ implantation were better than those without Ag+ implantation. CONCLUSION: Our results indicate that a dose of 1 * 1017 ions/cm2 induced an improvement in crystallinity, mechanical properties, as well as preferable cell adhesion and antibacterial effects. PMID- 28814166 TI - Late presentation of NMOSD as rapidly progressive leukoencephalopathy with atypical clinical and radiological findings. AB - Brain abnormalities in neuromyelitis optica spectrum disorder (NMOSD) are highly heterogeneous and often non-specific. Extensive white matter involvement has been described and frequently manifests with encephalopathy requiring prompt intervention. Rarely, this may represent the only manifestation at onset without concurrent suggestive features of the disease, thus making diagnosis challenging. NMOSD may potentially occur at any age, but it seems that this disorder has distinctive clinical features in the elderly. We describe a case of NMOSD presenting as rapidly progressive leukoencephalopathy with atypical clinical and magnetic resonance imaging (MRI) findings in a 69-year-old woman. PMID- 28814167 TI - Cardio-cephalic neural crest syndrome: A novel hypothesis of vascular neurocristopathy. AB - A novel hypothesis proposes that "cardio-cephalic neural crest (NC) syndrome," i.e. cephalic NC including cardiac NC, contributes to the concurrent occurrence of vascular diseases in the cardio- and cerebrovascular regions. NC is a transient structure present in early embryogenesis. Cephalic NC provides mesenchymal cells to the vascular media in these regions. Concurrent cardio- and cerebrovascular lesions have been reported in PHACE syndrome, ACTA2 mutation syndrome, and less frequently in the spontaneous occlusion of the circle of Willis (so-called moyamoya disease). Cardiovascular lesions in these syndromes include coarctation of the aorta, persistent truncus arteriosus, patent ductus arteriosus, and coronary artery disease, and cerebrovascular lesions include agenesis and stenosis/occlusion of the internal carotid arteries, and moyamoya phenomenon. These concurrent vascular lesions both in the cardio- and cerebrovascular regions might be related to cephalic NC. This hypothesis, although not proven, may facilitate a better understanding of the above-mentioned NC-related vascular pathologies and lead to appropriate diagnostic and therapeutic approaches for clinicians and chart future direction for researchers. PMID- 28814168 TI - Deterioration of heart rate recovery index in patients after carotid artery stenting. AB - Objective Although carotid artery stenting (CAS) is an effective treatment for severe carotid stenosis, it has been associated with alterations in autonomic functions long term after the procedure. Patients with CAS have been reported to have autonomic nervous system (ANS) dysfunction. This study aimed to evaluate heart rate recovery (HRR) indices and exercise test parameters after CAS. Methods Patients (10 male, 11 female) suitable for CAS, without a history of hypertension, diabetes mellitus, severe coronary artery or valvular heart disease, were enrolled in our study. Basal electrocardiography, echocardiography, and treadmill exercise testing were performed in all patients pre- and post procedure. The HRR index was defined as the reduction in the heart rate from the rate at peak exercise to the rate first minute (HRR1), second minute (HRR2), third minute (HRR3) and fifth minute (HRR5) after the cessation of exercise stress testing. Results The exercise time, maximal heart rate, maximal blood pressure and maximal metabolic equivalents values were significantly decreased after the procedure. The first- and second-minute HRR indices of patients before procedure were significantly lower than after procedure (23.5 +/- 6.6 vs 25.8 +/- 8.3; p < 0.001 and 41.8 +/- 12.3 vs 50.2 +/- 16.3; p < 0.001, respectively). Similarly, HRR indices after the third and fifth minutes of the recovery period were significantly lower in patients before procedure, when compared with those indices after procedure (52.9 +/- 13.1 vs 60.7 +/- 14.4; p < 0.001 and 62.4 +/- 12.8 vs 71.9 +/- 14.1; p < 0.001). Conclusion We have demonstrated that HRR indices increased in the first, second, third and fifth minutes of the recovery period after maximal exercise testing in patients after the CAS procedure, which may be a reflection of parasympathetic dominance after CAS. PMID- 28814170 TI - A Novel Reverse Branch Technique for Reconstruction of a Renal Artery Perfused by the False Lumen After Thoracic Endovascular Aortic Repair. AB - PURPOSE: To describe an innovative endovascular technique that successfully reconstructs a renal artery completely perfused by the false lumen after thoracic endovascular aortic repair (TEVAR). CASE REPORT: A 65-year-old patient diagnosed with acute Stanford type B aortic dissection underwent successful TEVAR 4 years ago. Regular follow-up found that the thoracic aorta was well repaired, but the false lumen in the abdominal aorta had enlarged year by year. The left renal artery was supplied entirely by the false lumen, which caused kidney hypoperfusion. The abdominal aorta was successfully remodeled using endovascular aneurysm repair with reconstruction of the left renal artery using Viabahn stent grafts inserted through the patent false lumen. At 6 months, computed tomography showed false lumen thrombosis and patent Viabahn stent-grafts in the false lumen. CONCLUSION: The false lumen reverse branch technique was feasible in our case, which provides a new idea for dealing with distal dissection involving the renovisceral arteries after TEVAR. PMID- 28814171 TI - A Feasibility Study of Off-the-Shelf Scalloped Stent-Grafts in Acute Type B Aortic Dissection. AB - PURPOSE: To evaluate the applicability of an off-the-shelf scalloped stent-graft to preserve left subclavian artery (LSA) flow in thoracic endovascular aortic repair (TEVAR) for acute type B aortic dissection. METHODS: The computed tomography angiograms (CTA) of 70 consecutive patients (median age 64 years; 44 men) with acute Stanford type B aortic dissection were retrospectively analyzed to identify patients in whom a short proximal landing zone (<15 mm from the retrogradely dissected wall layers) would require LSA overstenting during TEVAR. A scalloped stent-graft was deemed possible in those patients with the intimal entry tear located at least 20 mm distant from the LSA ostium. RESULTS: The LSA needed to be covered in 56 (80%) patients. Of these, an off-the-shelf scalloped stent-graft would have been applicable in 23 (41%) patients. In the latter group, the median aortic diameter was 31 mm (range 26-37), the median length of the LSA ostium was 13 mm (range 10-20), and the median width of the LSA ostium was 15 mm (range 11-24). Three differently sized off-the-shelf stent-grafts with the largest scallop possible could have adequately treated 20 (36%) of the 56 patients in the acute phase. CONCLUSION: In this single-center imaging-based study, involvement of the LSA in the setting of acute type B aortic dissection was seen in 80% of patients treated with TEVAR. Three off-the-shelf stent-grafts would suffice to treat one-third of these acute type B aortic dissections and may offer a relatively simple solution to preserve LSA flow, thereby lowering the risk of malperfusion of the (posterior) cerebrum, spinal cord, and left arm in an urgent/emergent setting. PMID- 28814172 TI - Novel Endovascular Management of Proximal Type A (DeBakey II) Aortic Dissection With a Patent Foramen Ovale Occluder. AB - PURPOSE: To present a novel endovascular management option that avoids open surgery in selected patients with subacute type A aortic dissection (DeBakey II). CASE REPORT: A 75-year-old woman with previous infrarenal abdominal aortic aneurysm repaired in 2006 and multiple comorbidities (EURO score II 20.5%) was admitted with chest pain; computed tomography angiography (CTA) showed a new dissection in the ascending aorta just above the right coronary ostium. As the patient was considered unfit to undergo surgery, an endovascular solution was suggested after multidisciplinary team discussion. With a single entry identified, coils were deployed in the false lumen followed by a patent foramen ovale (PFO) occluder placed across the entry tear to seal the cavity. Intraprocedural digital subtraction angiography and transesophageal echocardiography, as well as CTA 3 days postprocedure, confirmed an entirely thrombosed false lumen. The 6-month follow-up CTA demonstrated the PFO occluder firmly in place, shrinkage of the false lumen, and remodeling of the ascending aorta. CONCLUSION: Interventional management of the false lumen in proximal (type A) dissection is feasible and sustainable. The use of coils and closure devices may present a new, efficient, minimalistic strategy to avoid open surgery in selected cases. PMID- 28814173 TI - Early diagnosis of severe combined immunodeficiency (SCID) in Turkey: a pilot study. AB - OBJECTIVE: Severe combined immunodeficiency (SCID) is a neonatal emergency. As the T-cell receptor excision circles (TREC) test is not cost effective for neonatal screening of SCID in developing countries, this pilot study's objective aimed at identifying preliminary data to enable SCID identification in the general population. METHODS: This observational study was performed in Bagcilar Training and Research Hospital, Istanbul, Turkey. Cord-blood complete blood count (CBC) was recorded in all neonates included in the study. Absolute lymphopenia was considered in cord-blood samples if the absolute lymphocyte count was less than 2500/mm3. A control blood count was performed 1-month later for cases with detected lymphopenia. RESULTS: A total of 2945 term neonates were included in the study. Absolute lymphopenia was found in nine (0.3%) neonates, while 2936 (99.7%) had an absolute lymphocytic count above 2.5 * 103/mm3. The mean counts of red blood cells (RBC), hemoglobin (HGB), hematocrit (HCT), platelets (PLT), and monocytes in the lymphopenia group were not found to significantly differ from the non-lymphopenia group. However, there were significantly lower mean white blood cell (WBC), lymphocyte, and neutrophil counts between the groups (p < .05). CONCLUSION: Absolute lymphopenia detected using CBC analysis is a simple, easier, more non-invasive, and cheaper method than the TREC method for detection of SCID neonates, and this method may prove to be a useful alternative, especially in developing countries. PMID- 28814175 TI - Exploring the Effects of Visual Frame and Matching Direction on the Vertical Horizontal Illusion. AB - The work presented here uses an adjustment method to test the vertical-horizontal illusion across four different configurations: a cross-shape, an L-shape, an inverted-T and a rotated-T. We examine the modulatory role of the variables visual frame and direction of the adjustment on the illusory effect. Two experiments were performed, one with rectangular and one with curvilinear visual frames. Our data show that in both experiments, the size of the expected illusion increases from the cross-shape to the L-shape and from the L-shape to the inverted-T, where it reaches its maximum. In the rotated-T, the illusion reverses reaching a significant effect in the opposite direction. This pattern of results appears consistently across different experimental conditions, although the variability in the amount of illusory effect seems to be modulated by the intervention of the two variables examined. A dissection of the vertical horizontal illusion has been carried out in terms of a two-factor explanation - anisotropy and bisection - interacting in different ways across configurations. PMID- 28814174 TI - The Patient-Centered Care and Receipt of Preventive Services Among Older Adults With Chronic Diseases: A Nationwide Cross-sectional Study. AB - This article investigates the associations between the patient-centered care (PCC) and receipt of preventive services among older adults with chronic diseases. Data were derived from the nationally representative Medical Expenditure Panel Survey. The full-year consolidated data files from 2009 to 2013 were pooled to yield a final analytic sample (N = 16 654). Study outcomes included the receipt of 7 types of preventive screenings and 2 types of health education services. Patients' PCC groups were categorized as PCC, partial PCC, and non-PCC, based on 9 questions classified under the 3 distinctive attributes of PCC-whole-person care, patient engagement, and enhanced access to care. Prevalence rates for each outcome variable were calculated. We estimated odds ratios from multiple logistic regressions, comparing the likelihood of outcome variables across 3 groups of patients. Adjusting for covariates, the PCC group was more likely than the non-PCC group to receive 8 types of preventive services. The partial PCC group had a greater likelihood than the non-PCC group of receiving 7 types of preventive services. Our study reveals significant associations between PCC and receipt of preventive services. PCC has demonstrated the potential to improve preventive care for older adults with chronic diseases. PMID- 28814176 TI - Changing beliefs about past public events with believable and unbelievable doctored photographs. AB - Doctored photographs can shape what people believe and remember about prominent public events, perhaps due to their apparent credibility. In three studies, subjects completed surveys about the 2012 London Olympic torch relay (Experiment 1) or the 2011 Royal Wedding of Prince William and Kate Middleton (Experiments 2 3). Some were shown a genuine photo of the event; others saw a doctored photo that depicted protesters and unrest. A third group of subjects saw a doctored photo whose inauthenticity had been made explicit, either by adding a written disclaimer (Experiment 1) or by making the digital manipulation deliberately poor (Experiments 2-3). In all three studies, doctored photos had small effects on a subset of subjects' beliefs about the events. Of central interest though, comparable effects also emerged when the photos were overtly inauthentic. These findings suggest that cognitive mechanisms other than credibility - such as familiarity misattribution and mental imagery - can rapidly influence beliefs about past events even when the low credibility of a source is overt. PMID- 28814177 TI - Flail, aneurysm, perforation: enhanced visualisation of complex mitral valve damage in enterococcal endocarditis using 3D-echocardiography. PMID- 28814178 TI - Hematologic, Biochemical, and Endocrine Parameters in Horses With Tooth Resorption and Hypercementosis. AB - BACKGROUND: Equine odontoclastic tooth resorption and hypercementosis (EOTRH) is a frequently diagnosed condition in adult horses. The underlying etiology is still unknown. Hematologic, biochemical, and endocrine values have not been reported in EOTRH-affected horses. OBJECTIVES: The main objective of the study was to describe the hematologic, biochemical, and endocrine parameters in horses with EOTRH. STUDY DESIGN: Descriptive cross-sectional study of client-owned animals with EOTRH. METHODS: A complete blood count, biochemistry panel, and endocrine profile were performed in horses diagnosed with EOTRH. Diagnosis was based on oral and radiographic examination findings and confirmed with histopathology. RESULTS: Eighteen horses with EOTRH aged 10 to 32 years from various regions of the United States were sampled. The only consistent abnormality on the complete blood cell count and chemistry panel was hypoalbuminemia (88%). Endocrine parameters demonstrated no major abnormalities in the functioning of the thyroid and pituitary pars intermedia. The parathyroid hormone concentration was increased in 7 (47%) of 15 horses with an elevated 25 hydroxy vitamin D in 3 (17%) of 17 horses. Main Limitations: The main limitations of this study are the small sample size and lack of age-matched and management matched control horses. CONCLUSIONS: The relevance of elevated parathyroid hormone in this study cannot be determined due to the lack of age-based controls and large population studies. With the small population evaluated in this study, there are no obvious hematological, biochemical, and endocrine changes evident. Further evaluation with signalment-matched controls will be necessary to evaluate some trends noted in the laboratory values. PMID- 28814180 TI - It's Like Pulling Teeth.... PMID- 28814181 TI - Full-Mouth Intraoral Radiographic Survey in Rabbits. AB - Dental pathologies are highly prevalent in pet rabbit populations, making oral radiography an essential tool in the evaluation of lagomorph dentitions. The unique anatomy of the rabbit's mouth limits the examination of the conscious animal to the rostral portion of it's mouth. In addition, the oral examination of an aradicular hypsodont tooth is restricted to the short coronal fraction of its crown. Erstwhile images obtained by the extraoral technique were once considered the most practical and informative tool in rabbit dentistry; however, limited visualization of the key structures of individual teeth became the major drawback of this technique. As new imaging technologies are becoming widely available and affordable for veterinarians, intraoral radiography offers the ability to prevent, diagnose, and treat oral pathologies in lagomorphs. This article describes a step-by-step procedure to obtain a full-mouth radiographic survey in rabbits. For this technique, a standard dental X-ray generator and intraoral storage phosphor plates are used while applying the bisecting angle technique. Among the advantages of this technique are detailed visualization of internal and external dental structures, identification of early lesions, and detection of occult pathologies. Furthermore, intraoral images offer superior resolution and higher diagnostic quality with minimal radiation exposure, making this method safer for the veterinarian, staff members, and their patients. PMID- 28814182 TI - Regenerative Endodontics. AB - Regenerative endodontics has been defined as "biologically based procedure designed to replace damaged structures, including dentin and root structures, as well as cells of the pulp-dentin complex." This is an exciting and rapidly evolving field of human endodontics for the treatment of immature permanent teeth with infected root canal systems. These procedures have shown to be able not only to resolve pain and apical periodontitis but continued root development, thus increasing the thickness and strength of the previously thin and fracture-prone roots. In the last decade, over 80 case reports, numerous animal studies, and series of regenerative endodontic cases have been published. However, even with multiple successful case reports, there are still some remaining questions regarding terminology, patient selection, and procedural details. Regenerative endodontics provides the hope of converting a nonvital tooth into vital one once again. PMID- 28814183 TI - Diagnoses and Treatment of Dental Disorders in a Research Colony of Macaca fascicularis: A Case Series. AB - During daily routine oral examinations in a research colony of nonhuman primates (NHPs, Macaca fascicularis), a variety of oral-dental lesions were identified. A dental care program was established based on these findings. Based on the presence of dental clinical signs and their severity, 31 animals were triaged to be examined and treated by a veterinarian. Clinical examination consisted of visual inspection using a periodontal probe/explorer and full or partial mouth dental radiographs. Treatment was performed during the same procedure. Some animals had a follow-up examination including radiographs months later. Four common dental diseases were diagnosed: periodontal disease, caries, tooth fracture, and tooth attrition. Less frequent were dental abscess, enamel hypomineralization, gingival hyperplasia, hypercementosis, tooth luxation, tooth dysplasia, root resorption, abrasion. Less severe periodontal disease was treated conservatively. If severely affected, teeth were extracted. Well-circumscribed caries without endodontic involvement were treated by composite restoration. Teeth with extensive caries and pulp involvement were extracted. Teeth with exposed pulp were treated via extraction or orthograde root canal treatment. In this case series, 27 (87%) of 31 NHPs exhibited at least 1 moderate to severe dental lesion that required treatment. The presumable improvement in welfare and weight of oral/dental lesions for the overall health status in research NHPs encourages us to continue this program prospectively. PMID- 28814189 TI - Association of Methylenetetrahydrofolate Reductase C677T and A1298C Gene Polymorphisms With Recurrent Pregnancy Loss in Syrian Women. AB - C677T polymorphism of the methylenetetrahydrofolate reductase ( MTHFR) gene was a risk factor for recurrent pregnancy loss (RPL), but few studies have confirmed a possible role of MTHFR A1298C polymorphism in RPL risk. This study was carried out to determine the influence of the MTHFR gene polymorphisms in RPL Syrian women. A case-control study was performed on 2 groups (106 healthy and 100 RPL women). The frequency of the MTHFR gene polymorphisms was determined by polymerase chain reaction based on restriction fragment length gene polymorphism. In the RPL group, the genotype frequencies of MTHFR C677T were CC (41%), CT (41%), and TT (18%), and in the control group, the frequencies were CC (62.2%), CT (36.7%), and TT (1%). Statistical analysis showed a homozygous TT genotype and T allele were significantly different in the RPL group ( P = .000003 and P = .000019, respectively). The genotype frequencies of MTHFR A1298C were AA (53%), AC (44%), and CC (8%) in the RPL group, whereas in the control group, these were AA (61.3%), AC (37.8%), and CC (1%). A significant difference in the CC genotype and C allelic frequencies in the RPL women was observed ( P = .014 and P = .064, respectively). The patients having compound heterozygous (677 CT/1298AC) were associated with an estimated 4.86-fold increase in risk of pregnancy loss compared to individuals with a wild type ( P = .012). Our findings indicate that RPL women with homozygous genotype for (C677T and A1298C) either alone or compound heterozygous genotypes have a high risk of pregnancy loss in Syrian women. PMID- 28814190 TI - Effects of Neonatal Exposure to Zearalenone on Puberty Timing, Hypothalamic Nuclei of AVPV and ARC, and Reproductive Functions in Female Mice. AB - It is now established that mycoestrogen zearalenone (ZEN) disrupts reproductive physiology, but the specific mechanisms by which this occurs remain unknown, especially in brain. Growing evidence suggests that populations of estradiol (E2) sensitive neurons in anteroventral periventricular (AVPV) and arcuate (ARC) nuclei, especially kisspeptin neurons, play a pivotal role in the timing of puberty onset, ovulation, and normal reproduction. The present study was conducted to find whether the ZEN can cause estrogen-like actions during the critical period of neonatal differentiation. In this study, we compared the effect of neonatal exposure to sesame oil, E2 benzoate (EB, 20 ug/kg body weight [bw]), and 3 various doses: 0.2, 1, and 2 mg/kg bw of ZEN (0.2, 1, and 2 ZEN) on the onset of puberty and estrus cyclicity as well as ovarian follicular profile, kisspeptin expression, and neuronal density in AVPV and ARC hypothalamic nuclei and E2 and luteinizing hormone (LH) levels on postnatal day 70. Control mice received no treatment. Vaginal opening was significantly advanced by EB and 2 ZEN. Disrupted estrus cycles and decreased follicular profiles were observed in EB, 1 ZEN, and 2 ZEN animals. In addition, EB, 1 ZEN, and 2 ZEN reduced the expression of kisspeptin and neuronal density of AVPV and ARC nuclei and caused a decrease in the LH and an increase in E2 plasma levels. Taken together, our observations provide physiological evidence that neonatal exposure to ZEN exerts estrogen-like actions in the estrogen-sensitive hypothalamic AVPV and ARC nuclei, controlling reproductive functions in adult female mice. PMID- 28814193 TI - Sirolimus and mirabegron interaction in a hematopoietic cell transplant patient. AB - PURPOSE: Hematopoietic cell transplant patients are exposed to numerous classes of medications. Transplant practitioners must vigilantly monitor for drug interactions especially involving immunosuppressants. We report a hematopoietic cell transplant patient receiving sirolimus who developed supratherapeutic serum concentrations after initiating mirabegron. SUMMARY: A 31-year-old, 98 kg female received a second umbilical cord blood transplant four years after the first transplant for relapsed acute myeloid leukemia. Mycophenolate mofetil and sirolimus were utilized for graft versus host disease prophylaxis. The patient was receiving sirolimus 2 mg daily and the serum concentration on day 26 post transplant (day + 26) was within therapeutic range (6.7 MUg/L, goal range 3-12 MUg/L). Her post-transplant course was complicated by BK viruria-associated cystitis for which she was started on mirabegron. Six days after starting the new medication (day + 33), the sirolimus serum concentration increased to 19.2 MUg/L. Thus mirabegron was discontinued and sirolimus was held. Sirolimus was restarted once the serum concentration was within goal and subsequently stabilized with a combination of 1 mg and 2 mg daily for a total weekly dose of 10 mg. The proposed mechanisms of interaction include: (1) sirolimus inhibition of organic anion transporting polypeptide leading to increased mirabegron in the intestinal lumen; (2) mirabegron inhibition of P-glycoprotein leading to increased absorption of sirolimus and; (3) increased sirolimus absorption leading to increased sirolimus serum concentrations. CONCLUSION: To our knowledge, this is the first report of a potential drug interaction between sirolimus and mirabegron. Transplant specialists should be aware of this potential interaction when considering the concurrent use of these medications. PMID- 28814191 TI - Maternal Overweight Disrupts the Sexual Maturation of the Offspring. AB - The aims of the present work were to study the effect of maternal overweight and obesity on the ovarian reserve, follicular development, and ovulation of the offspring and to assess whether this maternal condition alters oocyte integrity. To this end, female offspring from rats fed standard (OSD) or cafeteria (OCD) diet were used. Body weight, vaginal opening, and estrous cycle were recorded and ovaries were obtained on the day of the second estrus. In addition, ovarian weight, ovulation rate (measured by the number of oocytes within oviducts), follicular development (determined by histology), and oocyte integrity were examined. The OCD were divided into 2 groups: offspring from rats with 17% and 28% of overweight (OCD17 and OCD28, respectively). Both OCD groups showed higher body weight, but OCD28 also exhibited early vaginal opening and higher ovarian weight and glycemia at euthanasia compared with OSD. Both OCD17 and OCD28 had lower number of primordial and primary follicles, and only OCD28 exhibited lower number of antral follicles, all compared with OSD rats. In addition, both OCD17 and OCD28 had higher ovulation rate than controls, and OCD28 had lower number of healthy oocytes, which, in turn, exhibited morphological alterations such as larger perivitelline space and zona pellucida than those of control animals. These results suggest that maternal overweight may severely affect the reproductive ability of the offspring, likely as a result of altering the organogenesis. PMID- 28814194 TI - Real-world utilization of darbepoetin alfa in cancer chemotherapy patients. AB - OBJECTIVES: To provide an understanding of darbepoetin alfa dose patterns in cancer patients undergoing myelosuppressive chemotherapy starting from 2011. STUDY DESIGN: This is a retrospective cohort study using a proprietary outpatient oncology database. METHODS: Metastatic, solid tumor cancer patients receiving concomitant myelosuppressive chemotherapy and darbepoetin alfa with an associated hemoglobin <10 g/dL during 2011-2015 were identified. The analysis was restricted to the first continuous exposure to chemotherapy agents (maximum allowable gap of 90 days between consecutive exposures) with darbepoetin alfa for each eligible patient. Initial, maintenance, weekly, and cumulative doses of darbepoetin alfa were examined across all darbepoetin alfa users. Subgroup analyses were conducted by chemotherapy type, baseline hemoglobin level, year of chemotherapy, solid tumor type, and initial dosing schedule. Differences in weekly doses across subgroups were evaluated using Wilcoxon rank-sum tests. RESULTS: Among 835 eligible patients, over 90% were 50 years or older. Mean chemotherapy course duration was 248 days, and mean duration of darbepoetin alfa treatment was 106 days. The mean weekly darbepoetin alfa dose was 110 ug. Patients received a mean of 4.3 darbepoetin alfa injections in the first chemotherapy course. There were no statistically significant differences (all P values > .05) in weekly dose by chemotherapy type, baseline hemoglobin level, year of chemotherapy, or solid tumor type. CONCLUSION: The average weekly darbepoetin alfa dose among metastatic cancer patients with chemotherapy-induced anemia from this study was 110 ug, which was lower than the labeled dosage for most adults. This estimate did not differ over time, across chemotherapy regimens, baseline hemoglobin levels, or solid tumor types. PMID- 28814195 TI - Change of plasmalogen content of red blood cells in myocardial hypoxia and acidosis. AB - BACKGROUND: The contribution of hypoxic conditions to the chemical composition of membranes is not completely established. Plasmalogens, containing an alkenyl group with aldehydogenic ether linkage, are significant components of membrane lipids and their level can change in oxygen deficiency. METHODS: Analysis of plasmalogens in red blood cells was performed in patients (n = 17) with coronary heart disease, stable angina (functional class II-III) and coronary atherosclerosis. The control group consisted of 17 healthy volunteers. In addition, isolated blood samples of seven healthy volunteers were analysed before and after 180 min incubation at 37 degrees C. Fatty acid ethyl esters and diethyl acetals of fatty aldehydes, obtained during sample preparation from red blood cells, were analysed by capillary gas-liquid chromatography. Quantitative assessment of the change of the plasmalogen levels was evaluated as change of the share of fatty aldehyde diethyl acetals in the total sum of fatty aldehyde diethyl acetals and fatty acid ethyl esters. RESULTS: In comparison with the healthy volunteers, an increase in plasmalogen content of red blood cells and a reduction of the pH of the blood plasma in the group of patients with coronary heart disease were detected. In experimental hypoxia, there was an increase in the plasmalogen content of the red blood cells and a plasma pH decrease in all samples subjected to the incubation. CONCLUSIONS: The results indicate changes in the physicochemical properties of the cell membrane in hypoxia. One of the most likely reasons of the increase of plasmalogen content in the membranes may be a more significant increase in activity of calcium-dependent phospholipases in comparison with the activity of calcium-independent plasmalogen phospholipases. PMID- 28814196 TI - A Tribute to John Doull, BS, PhD, MD: Scientist, Physician, Educator, Communicator, Advisor, and, Above All, A Gentleman and Friend to Many. PMID- 28814198 TI - Introduction to the Tribute to John Doull. PMID- 28814199 TI - Editor's Note. PMID- 28814200 TI - All-atom molecular dynamics comparison of disease-associated zinc fingers. AB - An important regulatory domain of NF-[Formula: see text]B Essential Modulator (NEMO) is a ubiquitin-binding zinc finger, with a tetrahedral CYS3HIS1 zinc coordinating binding site. Two variations of NEMO's zinc finger are implicated in various disease states including ectodermal dysplasia and adult-onset glaucoma. To discern structural and dynamical differences between these disease states, we present results of 48-[Formula: see text]s of molecular dynamics simulations for three zinc finger systems each in two states, with and without zinc-bound and correspondingly appropriate cysteine thiol/thiolate configurations. The wild-type protein, often studied for its role in cancer, maintains the most rigid and conformationally stable zinc-bound configuration compared with the diseased counterparts. The glaucoma-related protein has persistent loss of secondary structure except within the dominant conformation. Conformational overlap between wild-type and glaucoma isoforms indicate a competitive binding mechanism may be substantial in the malfunctioning configuration, while the alpha-helical disruption of the ectodermal dysplasia suggests a loss of binding selectivity is responsible for aberrant function. PMID- 28814201 TI - Using temporal distancing to regulate emotion in adolescence: modulation by reactive aggression. AB - Adopting a temporally distant perspective on stressors reduces distress in adults. Here we investigate whether the extent to which individuals project themselves into the future influences distancing efficacy. We also examined modulating effects of age across adolescence and reactive aggression: factors associated with reduced future-thinking and poor emotion regulation. Participants (N = 83, aged 12-22) read scenarios and rated negative affect when adopting a distant-future perspective, near-future perspective, or when reacting naturally. Self-report data revealed significant downregulation of negative affect during the distant-future condition, with a similar though non-significant skin conductance pattern. Importantly, participants who projected further ahead showed the greatest distress reductions. While temporal distancing efficacy did not vary with age, participants reporting greater reactive aggression showed reduced distancing efficacy, and projected themselves less far into the future. Findings demonstrate the importance of temporal extent in effective temporal distancing; shedding light on a potential mechanism for poor emotional control associated with reactive aggression. PMID- 28814202 TI - Modal and Amodal Completion in the Artwork of Coles Phillips. PMID- 28814203 TI - Effect of Vertical Stretching on the Extraction of Mean Identity From Faces. AB - Observers can extract the mean identity from a set of faces and falsely recognise it as a genuine set member. The current experiment demonstrated that this 'perceptual averaging' also occurs with vertically stretched faces. On each trial, participants decided whether a target face was present in a preceding set of four faces. In the control condition, the faces were all normally proportioned; in the stretched set condition, the face sets were stretched but the targets were normal; and in the stretched target condition, the face sets were normal but the targets were stretched. In all three conditions, participants falsely identified the set mean as a face that had been presented within the set, implying that this identity-averaging effect is based on high-level identity information rather than the low-level physical characteristics of the face stimuli. PMID- 28814204 TI - Faecal microbiota transplantation for Clostridium difficile-associated diarrhoea: a systematic review of randomised controlled trials. AB - OBJECTIVES: Faecal microbiota transplantation (FMT) has emerged as a useful approach for treating Clostridium difficile-associated diarrhoea (CDAD). Randomised controlled trials (RCTs) have recently evaluated its effectiveness, but systematic reviews have focused on evidence from case series. We therefore conducted a systematic review and meta-analysis of RCTs evaluating the effectiveness of FMT for treating CDAD. STUDY DESIGN: We included RCTs that primarily recruited adults with CDAD and compared the effectiveness of FMT with that of placebo, antibiotic therapy, or autologous stool transplantation, or compared different preparations or modes of delivery of FMT. Dichotomous symptom data were pooled to calculate a relative risk (RR) of CDAD persisting after therapy, and the number needed to treat (NNT). DATA SOURCES: MEDLINE, EMBASE, and the Cochrane Controlled Trials Register and Database of Systematic Reviews were searched to 6 February 2017. DATA SYNTHESIS: We identified ten RCTs that evaluated the treatment of a total of 657 patients with CDAD. Five RCTs compared FMT with placebo (including autologous FMT) or vancomycin treatment (total of 284 patients); FMT was statistically significantly more effective (RR, 0.41; 95% CI, 0.22-0.74; NNT, 3; 95% CI, 2-7). Heterogeneity across studies was significant (I2 = 61%); this heterogeneity was attributable to the mode of delivery of FMT, and to the therapy being more successful in European than in North American trials. The other five RCTs evaluated different approaches to FMT therapy. Frozen FMT preparations were as efficacious as fresh material in one RCT, but the numbers of patients in the remaining RCTs were too small to allow definitive conclusions. CONCLUSIONS: Moderate quality evidence from RCT trials indicates that FMT is more effective in patients with CDAD than vancomycin or placebo. Further investigations are needed to determine the best route of administration and FMT preparation. PMID- 28814206 TI - Computed tomography colonography: underutilised in Australia. PMID- 28814207 TI - No smoker left behind: it's time to tackle tobacco in Australian priority populations. PMID- 28814208 TI - The doctor as an expert: apprentice, journeyman or master. PMID- 28814209 TI - An unusual pain in the gut. PMID- 28814210 TI - Advanced Paget disease of bone. PMID- 28814211 TI - Digital rectal examination: indications and technique. PMID- 28814213 TI - Comprehensive guide to biological agents. PMID- 28814212 TI - Understanding statistical hypothesis tests and power. PMID- 28814214 TI - Faecal microbiota transplantation: past, present and future. PMID- 28814215 TI - Recruiting and retaining a rural medical workforce: the value of active community participation. PMID- 28814216 TI - Opting for rural practice: the influence of medical student origin, intention and immersion experience. AB - OBJECTIVE: To compare the influence of rural background, rural intent at medical school entry, and Rural Clinical School (RCS) participation on the likelihood of later participation in rural practice. DESIGN: Analysis of linked data from the Medical School Outcomes Database Commencing Medical Students Questionnaire (CMSQ), routinely collected demographic information, and the Australian Health Practitioner Regulation Agency database on practice location. SETTING AND PARTICIPANTS: University of Western Australia medical students who completed the CMSQ during 2006-2010 and were practising medicine in 2016. MAIN OUTCOME MEASURES: Medical practice in rural areas (ASGC-RAs 2-5) during postgraduate years 2-5. RESULTS: Full data were available for 508 eligible medical graduates. Rural background (OR, 3.91; 95% CI, 2.12-7.21; P < 0.001) and experience in an RCS (OR, 1.93; 95% CI, 1.05-3.54; P = 0.034) were significant predictors of rural practice in the multivariate analysis of all potential factors. When interactions between intention, origin, and RCS experience were included, RCS participation significantly increased the likelihood of graduates with an initial rural intention practising in a rural location (OR, 3.57; 95% CI, 1.25-10.2; P = 0.017). The effect of RCS participation was not significant if there was no pre existing intention to practise rurally (OR, 1.38; 95% CI, 0.61-3.16; P = 0.44). CONCLUSION: For students who entered medical school with the intention to later work in a rural location, RCS experience was the deciding factor for realising this intention. Background, intent and RCS participation should all be considered if medical schools are to increase the proportion of graduates working rurally. PMID- 28814217 TI - Faecal microbiota transplantation for Clostridium difficile infection: a multicentre study of non-responders. PMID- 28814218 TI - Diagnosis and management of pancreatic exocrine insufficiency. AB - INTRODUCTION: In 2015, the Australasian Pancreatic Club (APC) published the Australasian guidelines for the management of pancreatic exocrine insufficiency (http://pancreas.org.au/2016/01/pancreatic-exocrine-insufficiency-guidelines). Pancreatic exocrine insufficiency (PEI) occurs when normal digestion cannot be sustained due to insufficient pancreatic digestive enzyme activity. This may be related to a breakdown, at any point, in the pancreatic digestive chain: pancreatic stimulation; synthesis, release or transportation of pancreatic enzymes; or synchronisation of secretions to mix with ingested food. Main recommendations: The guidelines provide advice on diagnosis and management of PEI, noting the following: A high prevalence of PEI is seen in certain diseases and conditions, such as cystic fibrosis, acute and chronic pancreatitis, pancreatic cancer and pancreatic surgery. The main symptoms of PEI are steatorrhoea or diarrhoea, abdominal pain, bloating and weight loss. These symptoms are non-specific and often go undetected and untreated. PEI diagnosis is predominantly based on clinical findings and the presence of underlying disease. The likelihood of PEI in suspected patients has been categorised into three groups: definite, possible and unlikely. If left untreated, PEI may lead to complications related to fat malabsorption and malnutrition, and have an impact on quality of life. Pancreatic enzyme replacement therapy (PERT) remains the mainstay of PEI treatment with the recommended adult initial enzyme dose being 25 000-40 000 units of lipase per meal, titrating up to a maximum of 75 000-80 000 units of lipase per meal. Adjunct acid-suppressing therapy may be useful when patients still experience symptoms of PEI on high dose PERT. Nutritional management by an experienced dietitian is essential. Changes in management as a result of these guidelines: These are the first guidelines to classify PEI as being definite, possible or unlikely, and provide a diagnostic algorithm to facilitate the early diagnosis of PEI and appropriate use of PERT. PMID- 28814219 TI - Coeliac disease: review of diagnosis and management. AB - Coeliac disease is an immune-mediated systemic disease triggered by exposure to gluten, and manifested by small intestinal enteropathy and gastrointestinal and extra-intestinal symptoms. Recent guidelines recommend a concerted use of clear definitions of the disease. In Australia, the most recent estimated prevalence is 1.2% in adult men (1:86) and 1.9% in adult women (1:52). Active case finding is appropriate to diagnose coeliac disease in high risk groups. Diagnosis of coeliac disease is important to prevent nutritional deficiency and long term risk of gastrointestinal malignancy. The diagnosis of coeliac disease depends on clinico pathological correlation: history, presence of antitransglutaminase antibodies, and characteristic histological features on duodenal biopsy (when the patient is on a gluten-containing diet). Human leucocyte antigen class II haplotypes DQ2 or DQ8 are found in nearly all patients with coeliac disease, but are highly prevalent in the general population at large (56% in Australia) and testing can only exclude coeliac disease for individuals with non-permissive haplotypes. Adhering to a gluten free diet allows duodenal mucosal healing and alleviates symptoms. Patients should be followed up with a yearly review of dietary adherence and a health check. Non-coeliac gluten or wheat protein sensitivity is a syndrome characterised by both gastrointestinal and extra-intestinal symptoms related to the ingestion of gluten and possibly other wheat proteins in people who do not have coeliac disease or wheat allergy recognised by diagnostic tests. PMID- 28814220 TI - Cardiovascular disease in patients with schizophrenia. PMID- 28814221 TI - Cardiovascular disease in patients with schizophrenia. PMID- 28814222 TI - Variation in outpatient consultant physician fees in Australia by specialty and state and territory. PMID- 28814223 TI - Discrepancies in genetic testing results for coeliac disease: call for standardised testing and reporting. PMID- 28814224 TI - Correction. PMID- 28814225 TI - The road less travelled. PMID- 28814226 TI - Around the universities and research institutes. PMID- 28814227 TI - Mitochondrial Aconitase in Neurodegenerative Disorders: Role of a Metabolism- related Molecule in Neurodegeneration. AB - BACKGROUND: Mitochondrial aconitase (Aco2), a member of the family of iron-sulfur [4Fe- 4S]-containing dehydratases, is involved in cellular metabolism through the tricarboxylic acid cycle. Aco2 is highly susceptible to oxidative damage in a way that exposure to the reactive species and free radicals leads to release of iron from the central [4Fe-4S] cluster resulting in the production of the inactive form of Aco2. OBJECTIVE: There is increasing evidence supporting a direct association between impaired energy metabolism and the incidence and progression of neurodegenerative disorders in neuronal cells. RESULTS: It has been shown that alteration in bioenergetic parameters is a common pathological feature of the neurodegenerative diseases leading to neuronal dysfunction. Numerous studies have demonstrated that dysfunctional Aco2, among the other bioenergetic parameters, is a key factor that could promote neurodegeneration. CONCLUSION: Increasing our knowledge about energy metabolism-related molecules including Aco2 affected by neurodegenerative disorders might be useful to find an efficient therapeutic strategy for those central nervous system-related diseases. Accordingly, in this review, we have focused on the events and processes that occur in neurodegeneration, leading to the inactivation of Aco2 in the brain. PMID- 28814228 TI - The Effects and Action Mechanisms of Phytoestrogens on Vasomotor Symptoms during Menopausal Transition: Thermoregulatory Mechanism. AB - Phytoestrogens has recently been claimed to positively influence menopausal discomforts, including hot flashes. However, little is known about the influence of phytoestrogens on core body temperature during estrogen fluctuation at menopause. With many published findings that phytoestrogens could relieve menopausal complaints, the present review was aimed at assessing the effects of phytoestrogens on thermoregulatory mechanism during menopausal transition. Thephytoestrogens of interest in relation to human health include isoflavones, lignans, coumestans and stilbenes, which are widely distributed within nature. The molecular mechanisms underlying hot flashes are complex. Estrogen fluctuations cause hypothalamic thermoregulatory centre dysfunction which lead to hot flashes during menopause. The effects of phytoestrogens on these mechanisms may help explain the beneficial effects of phytoestrogens for alleviating hot flashes and other menopausal discomforts. PMID- 28814229 TI - Cell-Mediated and Humoral Immune Responses to Bordetella pertussis Inactivated Whole-Cells Encapsulated Alginate Microspheres as a New Vaccine Candidate. AB - : Effectiveness of the whole-cell pertussis vaccine is apparent, but improvement in the quality of the vaccine is necessary to achieve strong immunogenicity with a low bacterial number content. METHOD: Inactivated Bordetella pertussis (B. pertussis) cells entrapped microspheres were prepared via an emulsification method and analyzed for morphology, size, size distribution, loading efficiency, loading capacity, release kinetic, in vivo cytokines and antigen specific antibody subclasses. RESULTS: Bordetella pertussis encapsulated microspheres exhibited a smooth surface and spherical shape, mean particle size 151.1 um, size distribution index 0.43, loading efficiency 89.6%, loading capacity 36.3% and release kinetic similar to the Korsmeyer-Peppas model. Splenocytes of animals immunized with new microsphere-based whole-cell vaccine produced greater quantities of IFN-gamma and higher amounts of IL-4 and IL-5 cytokines compared to conventional adjuvant-adsorbed vaccines. Conventional adjuvant-adsorbed vaccines produced smaller quantities of IL-4 and IL-5. Bordetella pertussis entrapped microspheres induced both cell-mediated and humoral antibody in mice, evidenced by high levels of IgG2a and IgG1. IgG2a levels in mice were enhanced using the common aluminum phosphate-adsorbed B. pertussis whole-cell vaccine, and IgG1 levels did not increase significantly. Bordetella pertussis entrapped microspheres and common B. pertussis whole-cell vaccine samples enhanced total IgG levels in mice; however, B. pertussis-entrapped microspheres produced significantly higher levels of total IgG than other test samples. CONCLUSION: Encapsulation of inactive B. pertussis cells in microspheres appears to be a suitable approach for improving the wP vaccine quality, in particular by decreasing its toxicity to obtain good cell-mediated and humoral immunogenicity with a low bacterial number content. PMID- 28814230 TI - Virtual Screening on MMP-13 Led to Discovering New Inhibitors Including a Non Zinc Binding and a Micro Molar One: A Successful Example of Receptor Selection According to Cross-Docking Results for a Flexible Enzyme. AB - AIM AND OBJECTIVE: MMP-13 belongs to a large family of proteases called matrix metalloproteinases (MMPs) that degrades type II collagen, the main structural protein of articular cartilage. The main pathologic role of MMP-13 over expression is to contribute to the development of osteoarthritis. METHODS: To find new inhibitors with possible selectivity for MMP-13 a structure based virtual screening was employed. The inhibitory activities of 11 inhibitors among 19 purchased compounds were approved by enzyme inhibition assay. RESULTS: Our results demonstrated that the CADD (computer aided drug design) could be successfully applied to find new MMP-13 inhibitors using a receptor structure (PDB code: 3O2X) which had been demonstrated a good performance in a cross docking study. CONCLUSION: We discovered inhibitors with new scaffolds for inhibition of MMP-13 and some selectivity features such as proper S1' occupancy and interactions with S1' pocket that could be subjected to a future lead optimization study. PMID- 28814231 TI - HIV Type 1 Integrase Natural Polymorphisms in Viral Variants Circulating in FSU Countries. AB - BACKGROUND: Natural variability of integrase (IN) across HIV-1 variants may influence the emergence of resistant viruses. The most apparent explanation of this fact is the IN polymorphism and the associated differences in codon usage, which in turn, influence the probability and the terms of DRMs acquisition. Possible mechanisms by which polymorphisms affect DRMs emergence remain disputed and should still be clarified because these substitutions may be associated with a reduced activity of some INSTIs and may impact on ART regimen choice depending of HIV-1 subtype. OBJECTIVE: The aim of this work was to assess the prevalence of naturally occurring polymorphisms within the HIV-1 integrase gene, which might influence the susceptibility to INSTIs, among the patients from Russia and former USSR countries, according to HIV-1 subtypes. METHOD: A study involved 506 HIV-1 IN sequences of INSTI-naive patients from Russia, Ukraine, Armenia, Kyrgyzstan, Kazakhstan, Uzbekistan, Belarus, and Georgia. Among them, 194 sequences were newly obtained in this study and 312 were downloaded from Los-Alamos database. The proviral DNA was sequenced using an in-house PCR protocol designed on the basis of a well-conserved integrase region in order to detect all HIV-1 variants. RESULTS: The phylogenetic analyses based on IN population sequencing found subtype A6 being the most prevalent (259) (51.2%) in the collection studied, followed by subtype G (36) (7.1%), AGrecombinants (148) (29.3%), subtype B (50) (9.9%), and CRF03_AB (5) (1.0%). The major INSTI resistance-associated mutations (DRMs) were found only in two A6 samples. The prevalence of minor/ accessory substitutions depended on HIV-1 variants, while the most notable findings were L74I in subtype A6 (93.1%) and E157Q in subtype B (44.0%). Most of minor DRMs and polymorphic substitutions were concentrated in the central catalytic domain of the IN molecule. Both the DDE triad and HHCC zinc binding motifs were fully conserved. CONCLUSION: The results of the study suggest a very low risk of initiating INSTI-based therapy in patients with pre-existing polymorphic mutations in Russia and FSU countries. The therapy response in dominating HIV-1 genetic variants might be further studied in the future for a better understanding of their effect on INSTI susceptibility. The INSTI TDR is absent for the moment, but the risk may increase with expanded use of INSTIs, indicating the need for ongoing surveillance. PMID- 28814232 TI - Statins in Diabetes Mellitus. AB - Statins are a group of lipid-lowering medications that have been proven to be efficient in the protection of patients with dyslipidaemia from cardiovascular disease. The beneficial role of statins in both primary and secondary prevention has been well documented in many large randomized clinical trials. This beneficial effect extends to patients with diabetes mellitus. Their safety profile is overall good with mainly mild side effects. However, data indicate that statins may promote new onset diabetes mellitus. We review the current evidence regarding the overall efficacy and safety profile of statins in patients with diabetes mellitus; further we put into a broader perspective the debated diabetogenic effect of these drugs. PMID- 28814233 TI - Statins in acute coronary syndromes. AB - BACKGROUND: Patients with acute coronary syndrome (ACS) frequently experience recurrent adverse events from the cardiovascular system comparing to either healthy individuals or individuals with stable coronary artery disease. This is attributed to the inflammatory cascade that is activated during ACS resulting in increased risk for rupture of vulnerable plaques. OBJECTIVE: Therefore, it is of great importance to avoid recurrent events with treatment aiming at secondary prevention which includes the management of lipid profile besides alteration in the lifestyle and habits. METHODS: This review will present current data concerning present status of treatment with statins, and refer to non-statin strategies as well as novel and promising agents for the secondary prevention therapy after ACS. A thorough search of PubMed and the Cochrane Database was conducted in order to identify the majority of trials, studies, current guidelines and novel articles related to the subject. RESULTS: Statins have been proved to play very significant role in the part of secondary prevention since they decrease the burden of atherosclerotic plaques, the risk of adverse events and the need for revascularization in symptomatic patients with CAD. Therefore, they were established and suggested by both European and American guidelines as first-line treatment option for lipid-lowering management. Several clinical trials, meta- analyses and randomized trials strongly recommended the application of early and intensive treatment with statins in patients with ACS. Nevertheless, a vast majority of individualsneither tolerated statins nor achieved the optimal value for LDL-C with the highest tolerated dose of statins resulting in poor clinical outcome. Furthermore, recent clinical trials indicated further benefit of combined treatment of statins with non-statins drugson the decrease of cardiovascular events as well asprogress of coronary artery plaque. Finally, novel agentsthat are still evaluated with ongoing clinical trials have been turned into a very promising treatment option. CONCLUSION: In conclusion, statins are established as the first-line treatment for the secondary prevention after acute coronary syndromes in order to avoid the recurrence of thrombotic events. However, the research field on the field of lipid-lowering therapies is still ongoing and very promising for the future. PMID- 28814234 TI - Biomarkers of Cardiovascular Risk in Haemodialysis Patients. AB - BACKGROUND: All stages of chronic kidney disease (CKD) are associated with increased risks of atherosclerosis and cardiovascular morbidity and mortality. According to studies, levels of copeptin, growth differentiation factor-15 (GDF 15) and heart fatty-acid binding protein (h-FABP) are increased in dialysis patients. MATERIALS: This study included 50 patients (19 women, 31 men) chronically undergoing haemodialysis. The concentration of markers such as: copeptin, GDF-15, h-FABP, troponin and serum creatine kinase MB (CKMB) was measured with the use of ELISA tests. Serum concentration of 10 high-density lipoprotein (HDL) subfractions and 7 low-density lipoprotein (LDL) subfractions was analysed with the use of LipoprintTM system (Quantimetrix Corp.). RESULTS: In this study, we observed higher copeptin level, lower percentage share of cholesterol HDL4 subfraction and higher percentage share of small HDL particles subfraction in HD patients with diabetes mellitus than in those without diabetes. We also found significantly lower percentage share of cholesterol HDL5 subfraction in patients with GDF-15 > 3rd quartile (Q3) compared with those with GFD-15 <= Q3. Finally, it was observed that the percentage share of cholesterol HDL5 subfraction was significantly lower in patients with h-FABP > Q3, and the share of intermediate HDL subfractions was significantly lower in haemodialysis (HD) patients with h-FABP > 75 percentile. CONCLUSION: The fact that increased level of one biomarker correlated with higher values of other markers may suggest that their concentration depends on the severity of disease. The obtained results also suggest that the measurement of copeptin may support the diagnosis of cardiovascular problems in dialysis patients. PMID- 28814235 TI - Nanotechnology in Neurosciences: An Approach. AB - The use of nanotechnology in neurosciences has been evolving since new treatments, diagnoses and biomolecule monitoring are needed to find safer treatments for central nervous system diseases (CNDs). Nanotechnology employs devices that interact with biological systems allowing molecular interactions with a high degree of specificity. This review considers concepts associated with nanotechnology and leading areas of neurosciences with nanotechnology research. PMID- 28814236 TI - Neuroglial Cell Cryopreservation in Appropriate Inductive Conditions. AB - An ability to store cells (if they cannot be used fresh) reduces cell wastage, thereby increasing the supply of transplantable material. Cell storage is also valuable in scientific research, allowing material to be archived and experiments to be repeated from the same tissue source and facilitating research collaboration by allowing stored samples to be distributed. Cryopreservation is currently considered the most promising and successful, long-term biological conservation method. Its use has led to optimizing survival, improving protocols and stem cell and neuroglia viability, thereby assuring its future use in neuroregeneration and restoration regarding cell therapy. The success of conservation processes in ensuring cell viability depends on aspects such as the characteristics, cells' cryobiological behavior, isolation methodologies, cell freezing, the use and choice of cryoprotectants and such aspects' influence on intra- and extra-cellular dynamics. This review deals with cells' cryobiological behavior, cryopreservation and cryoprotectants, emphasizing on stem cell and neuroglial populations as therapeutic target regarding nervous system diseases. PMID- 28814237 TI - Statins in Aortic Stenosis. AB - Calcific aortic stenosis (AS) is the most common form of valvular heart disease in Europe and North America. It is a progressive disease with a prolonged period of asymptomatic latency which eventually leads to critical left ventricular outflow tract obstruction necessitating surgical replacement of the valve. Statins are lipid-lowering drugs with a robust evidence base demonstrating clinical benefit in atherosclerotic coronary artery disease. There has therefore been significant interest in the potential benefit of statins in AS. Initial animal, retrospective and non-randomized prospective studies suggested a beneficial effect of statins in AS. However, the outcomes of 3 major randomized controlled clinical trials consistently failed to demonstrate any significant benefit of lipid-lowering therapy on progression or clinical outcomes in AS. Consequently, statin therapy should not be recommended if the sole purpose is prevention of AS progression and there is no other indication for lipid-lowering therapy. However, recent data have suggested that lipoprotein(a) (Lp(a)) may play a previously unknown but critical role in the progression of AS. Lp(a) is not significantly modified by statin therapy and there is therefore significant emerging interest in targeted reduction of Lp(a) with novel therapeutic agents such as PCSK9 inhibitors and antisense oligonucleotides. PMID- 28814238 TI - Structural Insights for Drugs Developed for Phospholipase D Enzymes. AB - BACKGROUND: In recent years human phospholipase D enzymes (PLD1 and PLD2 isozymes) have emerged as drug targets for various diseases such as cardiovascular disease, cancer, infectious diseases and neurodegenerative conditions such as Alzheimer's and Parkinson's disease. The interest in PLD as a drug target is due to the fact that PLD enzymes belong to a superfamily of phospholipases that are essential to intracellular and extracellular signaling. Many bioactive lipid signaling molecules are generated by these enzymes including phosphatidic and lysophosphatidic acid, arachidonic acid, and diacylglycerol (DAG). More specifically PLDs are part of one pathway that generates phosphatidic acid which is a precursor to many lipids in the intracellular de novo pathway. The lipids produced from PA regulate many cellular events considered hallmarks of pathogenesis in cells; including proliferation, migration, invasion, angiogenesis, and vesicle transport. Hence, human PLD is a valid target for a variety of drug therapies. METHODS: The focus of this review is phospholipase D inhibitory molecules. A survey of structure-based drug design studies for PLD enzymes was done by searching several literature databases. Studies that focused on the structural aspects of phospholipase D were compiled and analyzed for content. Particular attention was given to studies involving inhibitory molecules as the focus of this work. In addition, the protein data bank (PDB) was surveyed for three dimensional structures of PLD. Structural investigation via in silico docking utilizing the available three dimensional coordinates of PLD and recent potent PLD isozyme specific inhibitors was performed to gain insights into the mode of binding by drugs designed to inhibit PLDs. RESULTS: Beginning with halopemide and derivatives such as FIPI (5-fluoro-2- indoyly des chlorohalopemide) leading to PLD isozyme selective inhibitors such as novel triazaspirone-based series of PLD inhibitors, structures and IC50 values presented were found to be in the nanomolar range for either human PLD1 or PLD2. Selective oestrogen receptor modulators (SERMS), compounds used in the treatment of oestrogen-receptor-positive breast cancer, inhibited mammalian PLD enzymes in the low micromolar range. The first universal PLD inhibitor developed was devoid of the 6-OH moiety necessary for oestrogen receptor binding and anti proliferation action. The universal PLD inhibitor contains a N,N-dimethylamino moiety which is known to reduce SERM activity and was found to inhibit several PLDs in the low micromolar range. The literature analyzed revealed a systematic approach to the biochemical evaluation of modes of binding of these inhibitors to the PLD enzymes. Finally, docking studies of several of the more potent PLD inhibitors correlates with biochemical studies with two modes of inhibitor binding to PLD: active site binding and allosteric binding. CONCLUSION: PLD inhibitors from diverse backgrounds continue to be developed as research progresses to the most potent and highly selective human PLD inhibitors with low or no off target activities. Docking studies strongly suggest both competitive (active site) and allosteric binding of these inhibitors to PLD. The three dimensional structure of PLD co-crystallized with potent inhibitors will be paramount to confirm the modes of binding for these molecules to PLD. PMID- 28814239 TI - Homology Modeling and Molecular Docking Studies of Bacillomycin and Iturin Synthetases with Novel Ligands for the Production of Therapeutic Lipopeptides. AB - BACKGROUND: Lipopeptide synthetases play an important role in the production of lipopeptides. Lipopeptides are molecules made up of peptides and fatty acid moieties and have shown to have a broad range of antimicrobial activity. As infectious diseases have caused severe health problems mainly resulting from the development of antibiotic resistant strains of disease causing microorganisms there is a need of alternatives to antibiotics. The lipopeptide synthetase of the corresponding lipopeptides can be used as template to design these as drugs using computational techniques. OBJECTIVE: The objective of this study was homology modeling and molecular docking of two lipopeptide synthetases, bacillomycin D synthetase and iturin A synthetase, with their ligands as a means of drug design. METHOD: Schrodinger software was used for homology modeling and molecular docking. RESULTS: After the identification of ligands, molecular docking of these ligands with the lipopeptide (bacillomycin and iturin) synthetases was performed. The docking was tested on the parameters of docking score and glide energy. 5 out of 21 ligands were found to dock with bacillomycin D synthetase whereas 8 out of 20 ligands docked with the iturin A synthetase. CONCLUSION: The knowledge of the docking sites and docking characteristics of the lipopeptide synthetases mentioned in the paper with the ligands can provide advantages of high speed and reliability, reduced costs on chemicals and experiments and the ethical issues concerned with the use of animal models for screening of drug toxicity. PMID- 28814240 TI - Structure Properties and Mechanisms of Action of Naturally Originated Phenolic Acids and Their Derivatives against Human Viral Infections. AB - BACKGROUND: A great effort has been made to develop efficacious antiviral drugs, but many viral infections are still lack of efficient antiviral therapies so far. The related exploration of natural products to fight viruses has been raised in recent years. Natural compounds with structural diversity and complexity offer a great chance to find new antiviral agents. Particularly, phenolic acids have attracted considerable attention owing to their potent antiviral abilities and unique mechanisms. The aim of this review is to report new discoveries and updates pertaining to antiviral phenolic acids. METHODS: The relevant references on natural phenolic acids were searched. The antiviral phenolic acids were classified according to their structural properties and antiviral types. Meanwhile, the antiviral characteristics and structure-activity relationships of phenolic acids and their derivatives were summarized. RESULTS: The review finds that natural phenolic acids and their derivatives possessed potent inhibitory effects on multiple virus in humans such as human immunodeficiency virus, hepatitis C virus, hepatitis B virus, herpes simplex virus, influenza virus and respiratory syncytial virus. In particular, caffeic acid/gallic acid and their derivatives exhibited outstanding antiviral properties by a variety of modes of action. CONCLUSION: Naturally derived phenolic acids especially caffeic acid/gallic acid and their derivatives may be regarded as novel promising antiviral leads or candidates. Additionally, scarcely any of these compounds has been used as antiviral treatment in clinical practice. Therefore, these phenolic acids with diverse skeletons and mechanisms provide us an excellent resource for finding novel antiviral drugs. PMID- 28814241 TI - The Emerging Picture of CDK11: Genetic, Functional and Medicinal Aspects. AB - Cyclin-dependent kinase 11 is a relatively neglected member of the transcriptional CDKs subfamily, despite possibly being the most versatile CDK in this group. Different CDK11 variants are known to play essential roles in major cellular processes as mRNA transcription (CDK11p110), mitosis (CDK11p58), and apoptosis (CDK11p46 and CDK11p60). Each CDK11 species targets a particular set of substrates related to its functional background, but all isoforms originate from the CDC2L gene complex in human chromosome 1p36.2. CDK11p110 is synthesized through regular cap-dependent translation of CDK11 mRNA, whereas CDK11p58 translation is initiated through an IRES, and occurs only at G2 and M phases. CDK11p46 and CDK11p60, in turn, are the products of caspase cleavage of the larger isoforms during apoptosis. L-type cyclins are the main partners of CDK11, although CDK11p58 species interacts specifically with cyclin D3. The link between CDK11 dysfunction and cancer has been known for a long time, and critical roles in the proliferation of different cancer cell lines have been assigned to CDK11. This review summarizes more than 25 years of studies that unraveled CDK11 genetic and functional aspects. PMID- 28814242 TI - Antimicrobial Peptides: A Promising Therapeutic Strategy in Tackling Antimicrobial Resistance. AB - BACKGROUND: Antimicrobial resistance (AMR) has posed a serious threat to global public health and it requires immediate action, preferably long term. Current drug therapies have failed to curb this menace due to the ability of microbes to circumvent the mechanisms through which the drugs act. From the drug discovery point of view, the majority of drugs currently employed for antimicrobial therapy are small molecules. Recent trends reveal a surge in the use of peptides as drug candidates as they offer remarkable advantages over small molecules. METHODS: Newer synthetic strategies like organometalic complexes, Peptide-polymer conjugates, solid phase, liquid phase and recombinant DNA technology encouraging the use of peptides as therapeutic agents with a host of chemical functions, and tailored for specific applications. In the last decade, many peptide based drugs have been successfully approved by the Food and Drug Administration (FDA). This success can be attributed to their high specificity, selectivity and efficacy, high penetrability into the tissues, less immunogenicity and less tissue accumulation. Considering the enormity of AMR, the use of Antimicrobial Peptides (AMPs) can be a viable alternative to current therapeutics strategies. AMPs are naturally abundant allowing synthetic chemists to develop semi-synthetics peptide molecules. AMPs have a broad spectrum of activity towards microbes and they possess the ability to bypass the resistance induction mechanisms of microbes. RESULT: The present review focuses on the potential applications of AMPs against various microbial disorders and their future prospects. Several resistance mechanisms and their strategies have also been discussed to highlight the importance in the current scenario. CONCLUSION: Breakthroughs in AMP designing, peptide synthesis and biotechnology have shown promise in tackling this challenge and has revived the interest of using AMPs as an important weapon in fighting AMR. PMID- 28814243 TI - A Pharmacokinetic-Pharmacodynamic Model of Tamoxifen and Endoxifen to Predict Their Distribution and Effects on Inhibition of Tumor Growth. AB - BACKGROUND: Tamoxifen is widely used in the therapy for breast cancer and has three major metabolites, N-desmethyltamoxifen, 4-hydroxytamoxifen, and endoxifen. Endoxifen has played a major role in the inhibition of tumor growth of breast cancer and the tumor growth is related to endoxifen concentration. OBJECTIVES: The aim of this study was to develop a pharmacokinetic-pharmacodynamic model to predict the distribution of tamoxifen and endoxifen quantitatively, and to discover the anti-tumor effect patterns of tamoxifen and endoxifen. METHODS: The pharmacokinetic-pharmacodynamic model was established by integrating a four compartments pharmacokinetics model and a pharmacodynamic model, the first one include central compartment and peripheral compartment both of which contain tamoxifen and endoxifen. The parameters of the model were calculated by the values of plasma concentrations and the tumor growth data before and after the administration of tamoxifen. RESULTS: The transport rate k42 (6.0003) of endoxifen from the peripheral compartment to the central compartment and the metabolism rate k34 (0.0031) from tamoxifen to endoxifen in the peripheral compartment were proven to be significant, which showed that tamoxifen and endoxifen are mainly distributed in the central compartment. The model provided reasonable predictions of tumor growth, which was inhibited after the administration and varies with the concentration of endoxifen. CONCLUSION: We established a PK-PD model of tamoxifen and endoxifen to predict the tumor growth. The parameters of the pharmacodynamic model, which characterized the tumor growth, revealed the patterns of tamoxifen's anti-tumor functions. The PK-PD model successfully provided illustration for the pharmacokinetics of tamoxifen and endoxifen, and predicted the inhibition effect of endoxifen on the tumor growth. PMID- 28814244 TI - History, Prevalence and Assessment of Limited Joint Mobility, from Stiff Hand Syndrome to Diabetic Foot Ulcer Prevention: A Narrative Review of the Literature. AB - BACKGROUND: Limited Joint Mobility (LJM) is a dreaded complication of Diabetes Mellitus (DM). During the last half century, LJM has been studied in patients of different age because it has been considered useful for the monitoring of a patient's condition and for the prevention of vascular disease and diabetic foot. OBJECTIVES: The main aims of this review are to describe the relationship between DM and joint mobility as well as its prevalence and assessment. We have also investigated the role of LJM in the development of diabetic foot ulcers. METHODOLOGY: An in-depth literature search was conducted to identify studies that examined the prevalence and characteristics of LJM in patients with DM of different types, age, durations and chronic complications. RESULTS: Many factors (therapy improvements, population characteristics and different evaluation methods) concur to hinder an exact assessment of the prevalence of LJM. However, it has been confirmed that LJM is widespread among patients with DM and may affect more than two-thirds of them in addition to being a major risk factor for foot ulcer. Its role in the monitoring of a patient's condition is also important for the definition of risk thresholds such as in patients with diabetic foot. The efficacy of exercise therapy for the treatment of LJM, also in patients at risk of foot ulcer, has not been discussed. CONCLUSION: Difficulties encountered in the definition of the prevalence of LJM may hinder its study and the establishment of preventive interventions. However, LJM plays a key role in the monitoring of patients, especially those at risk for ulcer. PMID- 28814245 TI - Benefits of SGLT2 Inhibitors Beyond Glycemic Control - A Focus on Metabolic, Cardiovascular and Renal Outcomes. AB - BACKGROUND: Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new pharmacotherapeutic class for the treatment of Type 2 Diabetes Mellitus (T2DM). OBJECTIVE: To evaluate beneficial effects of the SGLT2 inhibitors on metabolic, cardiovascular, and renal outcomes. METHODS: A Pub-Med search (1966 to July 2017) was performed of published English articles using keywords sodium-glucose co transporter 2 inhibitors, canagliflozin, dapagliflozin, and empagliflozin. A review of literature citations provided further references. The search identified 17 clinical trials and 2 meta-analyses with outcomes of weight loss and blood pressure reduction with dapagliflozin, canagliflozin, or empagliflozin. Three randomized trials focused on either empagliflozin or canagliflozin and reduction of cardiovascular disease and progression of renal disease. RESULTS: SGLT2 inhibitors have a beneficial profile in the treatment of T2DM. They have evidence of reducing weight between 2.9 kilograms when used as monotherapy to 4.7 kilograms when used in combination with metformin, and reducing systolic blood pressure between 3 to 5 mmHg and reducing diastolic blood pressure approximately 2 mmHg. To date, reduction of cardiovascular events was seen specifically with empagliflozin in patients with T2DM and a history of cardiovascular disease. In the same population, empagliflozin was associated with slowing the progression of kidney disease. Moreover, patients with increased risk of cardiovascular disease treated with canagliflozin have decreased risk of death from cardiovascular causes, nonfatal MI, or nonfatal stroke. Data regarding these outcomes with dapagliflozin are underway. CONCLUSION: SGLT2 inhibitors demonstrate some positive metabolic effects. In addition, empagliflozin specifically has demonstrated reduction in cardiovascular events and delay in the progression of kidney disease in patients with T2DM and a history of cardiovascular disease. Further data is needed to assess if this is a class effect. PMID- 28814246 TI - Approach to Pediatric Traumatic Brain Injury in the Emergency Department. AB - BACKGROUND: Traumatic Brain Injury is a major cause of morbidity and mortality in the pediatric population affecting millions of people yearly. It is important that practitioners have the knowledge and skills to care for these complicated patients, as the initial care can significantly affect the course of the injury. We discuss the initial management of traumatic brain injury based on mild, moderate and severe presentations. RESULT AND CONCLUSION: Management strategies to address Intracranial Pressure and Cerebral perfusion pressure, the use of oxygenation and ventilation strategies, temperature, correction of metabolic abnormalities and seizure care are discussed. PMID- 28814247 TI - Fluid and Medication Considerations in the Traumatized Patient. AB - This article reviews fluid therapy and medications in pediatric trauma. For resuscitation in the setting of hemorrhagic shock, isotonic crystalloid solution is the first-line agent of choice. Colloid solutions offer no additional benefit, introduce possible increased risks and cost more than crystalloids. Blood products, starting with pRBCs, should be introduced after 20-40 ml/kg of crystalloid has been administered if there is ongoing need for volume replacement. The use of a massive transfusion protocol of 1:1:1 (if >30 kg) or 30:20:20 (if <30 kg) of pRBCs:FFP:platelets is suggested after an initial 30 ml/kg of pRBcs has been administered. Cryoprecipitate should be given for documented low fibrinogen or ongoing bleeding after administration of 1 round of all 3 blood components. For patients at risk of massive hemorrhage, early administration of tranexamic acid with an initial loading dose of 15 mg/kg (maximum 1 g) is recommended. Choice of medication for intubation of the patient with Traumatic Brain Injury (TBI) may best be guided by physiology: in the TBI patient with a high mean arterial pressure, premedication with lidocaine, fentanyl and use of etomidate may be most appropriate, whereas in the hemodynamically compromised patient, use of ketamine alone may be considered. If needed, norepinephrine has been recommended as a temporizing agent for vasopressor support in the setting of fluid-refractory shock. Although controversial, in the setting of significant spinal cord injury, the potential benefits of administering 24-48 hours of steroids (initial 30 mg/kg of methylprednisolone within 8 hours of injury) may outweigh the risks especially in previously healthy pediatric patients. PMID- 28814248 TI - Pediatric Abdominal Trauma. AB - Abdominal trauma is present in approximately 25% of pediatric patients with major trauma and is the most common cause of unrecognized fatal injury in children. Pediatric abdominal trauma is typically blunt in nature with the spleen being the most common organ injured. Nonoperative management is employed in over 95% of patients. Penetrating injuries are less common but often require operative management. Knowledge of specific mechanisms of injury aids the clinician in the diagnosis of specific injuries. Computed Tomography (CT) is the gold standard in the identification of intra-abdominal injury. Focused Assessment with Sonography for Trauma (FAST) can detect the presence of free fluid suggestive of intra abdominal injury. In children, the utility of FAST is limited because less than half of pediatric patients with abdominal injury have free fluid. Bowel perforation and pancreatic injuries may not be evident on initial CT scanning of the abdomen. Initial management of the trauma patient in shock includes fluid boluses of normal saline or Ringer's lactate with two, large-bore upper extremity catheters. Transfusion with packed red blood cells is done if the patient remains hypotensive after the second fluid bolus. Emergent laparotomy is indicated in patients with: free intraperitoneal air, hemodynamic instability despite maximal resuscitative efforts (transfusion of greater than 50% of total blood volume), gunshot wound to the abdomen or other penetrating traumas, and evisceration of intraperitoneal contents. Initial FAST followed by abdominal computed tomography is important in the evaluation of the seriously or critically injured patient. The combination of the FAST exam along with selected abdominal computed tomography can further aid in the detection of injuries that may not be clinically apparent. PMID- 28814249 TI - The Neurological Sequelae of Neonatal Hyperbilirubinemia: Definitions, Diagnosis and Treatment of the Kernicterus Spectrum Disorders (KSDs). AB - BACKGROUND: Despite its lengthy history, the study of jaundice, hyperbilirubinemia and kernicterus suffers from a lack of clarity and consistency in the key terms used to describe both the clinical and pathophysiological nature of these conditions. For example, the term Bilirubin-induced Neurological Dysfunction (BIND) has been used to refer to all neurological sequelae caused by exposure to high levels of bilirubin, to only mild neurological sequelae, or to scoring systems that quantitate the progressive stages of Acute Bilirubin Encephalopathy (ABE). OBJECTIVE: We seek to clarify and simplify terminology by introducing, defining, and proposing new terms and diagnostic criteria for kernicterus. METHODS: We propose a systematic nomenclature based on pathophysiological and clinical criteria, presenting a logical argument for each term. Acknowledging observations that kernicterus is symptomatically broad and diverse, we propose the use of the overarching term Kernicterus Spectrum Disorders (KSDs) to encompass all the neurological sequelae of bilirubin neurotoxicity including Acute Bilirubin Neurotoxicity (ABE). We further suggest subclassification of KSDs based on the principal disabling features of kernicterus (motor, auditory). Finally, we suggest the term subtle KSD to designate a child with a history of significant bilirubin neurotoxicity with mild or subtle developmental delays. RESULTS AND CONCLUSION: We conclude with a brief description of the limited treatments currently available for KSD, thereby underscoring the importance of further research. We believe that adopting a systematic nomenclature for the spectrum of clinical consequences of hyperbilirubinemia will help unify the field and promote more effective research in both prevention and treatment of KSDs. PMID- 28814250 TI - Angiotensin-Converting Enzymes (ACE and ACE2) as Potential Targets for Malignant Epithelial Neoplasia: Review and Bioinformatics Analyses Focused in Oral Squamous Cell Carcinoma. AB - INTRODUCTION: The Renin-Angiotensin System (RAS) has emerged as being related to vascular disease. Recently the RAS has been associated with obesity, diabetes, and even cancer. OBJECTIVE: This review and Bioinformatics analyses focuses on the investigation of Angiotensinconverting enzymes (ACE and ACE2) as therapeutical targets for Malignant Epithelial Neoplasia, specifically for Oral Squamous Cell Carcinoma (OSCC). CONCLUSION: The literature review and Bioinformatics analyses showed that ACE and ACE2 are interesting targets for OSCC treatment. Studies involving RAS and OSCC should be encouraged for experimental validation. PMID- 28814251 TI - The Role of Radiopharmaceuticals in Amiodarone-Induced Thyroid Pathology. AB - BACKGROUND AND OBJECTIVE: The use of amiodarone for the treatment of ventricular and supraventricular dysrhythmias brings in organism an increased amount of iodine, interfering with thyroid function. If the treatment needs to be interrupted, iodine remains at abnormal levels for months or even years. The aim of the study was to review the literature regarding the optimal tests for early diagnostic and to analyze the role of nuclear medicine tests in the differential and correct assessment of the amiodarone-induced thyroid pathology. METHODS: We made a review of available publications in PUBMED referring the amiodaroneinduced thyroid pathology, focusing on the differential diagnosis, made by nuclear medicine tests, of hypothyroidism (AIH) and hyperthyroidism expressed as: type I amiodarone induced thyrotoxicosis (AIT I), type II amiodarone induced thyrotoxicosis (AIT II), and less frequently as a mixt form, type III amiodarone induced thyrotoxicosis (AIT III). We presented cases from the database of a tertiary center in Cluj-Napoca, Romania. RESULTS: Despite the frequent complication of thyroid function, this pathology is underestimated and diagnosed. There is a limited number of studies and clear protocols, especially in the mixed forms cases. This increase in iodine uptake interferes seriously with thyroid hormone production and release. The nuclear medicine tests are essential in the correct assessment and differential diagnosis of different forms of induced thyroid dysfunction. The destruction of the follicular cells can result in the release of excessive thyroid hormone into the circulation, with potential development of atrial fibrillation, worsening the cardiac disease, so any benefic therapeutic procedure should be known; the use of radioiodine as therapy alternative, despite the known limitations induced by blockade was clear benefic in the case presented. A special attention needs to be addressed to those patients with differentiated thyroid cancer, which will be submitted to radioiodine therapy and are under chronic therapy with amiodarone. CONCLUSION: The nuclear medicine procedures are essential in the correct assessment and differential diagnosis of different forms of induced thyroid dysfunction. The radioiodine is not recommended in AIT, due to stunning effect induced by iodine excess, but in some special, lifethreatening condition, radioiodine I-131 might be a treatment option. PMID- 28814252 TI - Bone Imaging in Metastatic Castration-resistant Prostate Cancer; Where do we Stand. AB - BACKGROUND AND OBJECTIVES: We are witnessing an era of increased clinical interest in metastatic castration-resistant prostate cancer, both in terms of treatment and also in terms of imaging options. This surge of interest is attributed to the recent developments in treatments for metastatic prostate cancer that are able to confer a significant survival advantage. We are therefore, anticipating an increase in the number of patients that we need to treat at this disease stage. Imaging is undoubtedly crucial in monitoring disease response to treatment and progression. METHODS: We have reviewed the recent literature using the following search terms: "metastatic prostate cancer", "castration-resistant", "bone metastases", "bone scan", "abiraterone", "enzalutamide". RESULTS: Bone scintigraphy has evolved recently with new and more sensitive tracers that can accurately diagnose even low volume disease progression. MRI has an established role in the diagnosis of spinal cord compression. CONCLUSION: Metastatic, castration-resistant prostate cancer is a discrete and different phase of prostate cancer with newer agents that have shown great promise in controlling the disease and offering a survival benefit for patients. Recommendations regarding the choice of imaging, trigger points for repeating imaging and intervals between imaging are still under development for this phase of the disease especially for patients treated with new androgen targeted agents. PMID- 28814253 TI - PET/MR Tomographs: A Review with Technical, Radiochemical and Clinical Perspectives. AB - BACKGROUND AND OBJECTIVE: In the last decade, an increasing number of positron emission tomography / magnetic resonance (PET/MR) tomographs were installed and many clinical studies were performed in the neurological field. METHODS: Although PET/MR has many favorable properties to support the application in brain imaging, attenuation correction, and therefore accurate quantification, is a problem that still requires optimal solution. RESULTS: In this review we have summarized the three main methods that are currently used to correct attenuation in PET/MR, namely atlas- or template-based methods, segmentation-based methods, and reconstruction-based methods. There is currently active ongoing research to refine available methods and improvements are reasonably expected in the next years. Clinical studies using PET/MR focused mainly on neurodegenerative and neurooncological disorders. PET/MR hybrids tomographs provided promising scientific results and were logistically more convenient for patients. Additionally, in order to explore all potential clinical benefits of this hybrid technology, the design and development of multimodal contrast agents has constantly increased the attention of radiochemists. Many PET/MR dual probes have been already devised, particularly in the nanotechnology field, sometimes preceding the identification of a clear diagnostic application in medicine. CONCLUSION: In the near future, we predict more clinical studies as the availability of PET/MR will further increase and new tracers for neurodegenerative disorders will accept broader clinical acceptance. PMID- 28814254 TI - Bronchiolitis Care in the Hospital. AB - BACKGROUND: Viral bronchiolitis is a common cause of hospitalization in young children, but despite a variety of therapeutic options, the mainstay of treatment remains supportive care. OBJECTIVE: To examine the most recent evidence for supportive care measures and pharmacologic options in the treatment of bronchiolitis in the hospital setting. METHOD: MEDLINE search with expert medical librarian for publications on management and therapies for bronchiolitis. RESULTS: Evidence does not support the use of bronchodilators, racemic epinephrine, deep suctioning, systemic corticosteroids, or antibiotics in the absence of a concomitant bacterial infection, as these treatments do not change the course of illness or shorten length of stay (LOS). Nebulized hypertonic saline is not routinely recommended, though it may provide some benefit for patients with anticipated prolonged LOS. Continuous pulse oximetry should not be routinely used in stable patients as it may be associated with longer LOS. Supplemental oxygen should be used to maintain oxyhemoglobin concentrations ≥90%, a level lower than what many clinicians may have used previously. Current evidence suggests high-flow nasal cannula may reduce intubation rate, but its effect on LOS is unclear. Intravenous or nasogastric tube hydration should be used when oral hydration is not sufficient. CONCLUSION: Overall, bronchiolitis remains a self-limited disease whose mainstay of therapy is supportive care. PMID- 28814255 TI - Current Evidence on the Evaluation and Management of Fever Without a Source in Infants Aged 0-90 Days: A Review. AB - BACKGROUND: Despite development of risk stratification tools decades ago, the best strategy for evaluation and management of young infants with fever without a clear source remains uncertain. OBJECTIVE: To describe the variability in current practice and review recently published evidence in three key areas: inflammatory markers were used as a tool for risk stratification, impact of viral testing, and optimal observation time on antibiotics. METHOD: Articles were identified using PubMed, Scopus, and Cochrane databases and via experts. Abstracts were screened and potential articles underwent full review if they focused on febrile infants 0 90 days with fever without a source and outcomes for key topics. RESULTS: Thirty two articles were included. Recent studies show that variability exists for most aspects of evaluation and management. C reactive protein and procalcitonin (PCT) perform poorly for identification of serious bacterial infections (SBIs). However, PCT has good diagnostic accuracy for detection of invasive bacterial infections (IBIs), such as bacteremia and meningitis. When PCT is combined with urinalysis and clinical appearance in the Step-by-Step method, the sensitivity for detection of IBI is 92% for infants > 21 days of age. Infants with lab confirmed viral infection were found to have reduced risk for SBI. Blood culture yield for true pathogens was the highest in the first 12-36 hours after incubation. CONCLUSION: Recent studies suggest viral testing and inflammatory markers (specifically PCT) can help better stratify young febrile infants at risk for IBIs. Infants who are deemed low risk may benefit from shorter observation times and tailored or discontinued antibiotic therapy. PMID- 28814256 TI - Current Issues in Intravenous Fluid Use in Hospitalized Children. AB - BACKGROUND: Fluid and electrolyte therapy is an important component in the care of the hospitalized child. Previous pediatric guidelines have followed the Holliday-Segar method of calculating and delivering maintenance IV fluids, using hypotonic fluids in maintenance therapy. However, research demonstrates that hypotonic fluids can lead to iatrogenic hyponatremia and that isotonic fluid is a safer alternative. OBJECTIVE: To provide the ideal approach to intravenous (IV) fluid use in the hospitalized child and determine the safety and effectiveness of isotonic maintenance fluid therapy. METHOD: We searched PubMed, Medline, Cochrane Controlled Clinical Trials Register, and Clinical- Trials.gov for potentially relevant publications from the last five years (2011 to July 2016) with an emphasis on randomized control trials (RCTs) and contemporary evidence-based treatment guidelines. RESULTS: For maintenance IV fluids, isotonic solutions decreased risk of hyponatremia and did not increase risk of hypernatremia. Some studies demonstrate increased ADH production or hyponatremia on admission for hospitalized patients. CONCLUSION: While there is no ideal composition of maintenance IV fluids for all children, isotonic fluids are safer than hypotonic fluids for use as maintenance in hospitalized children due to the decreased risk of iatrogenic hyponatremia. This article also provides recommendations for other types of fluid management in the inpatient pediatric population. PMID- 28814257 TI - Discharge Interventions and Modifiable Risk Factors for Preventing Hospital Readmissions in Children with Medical Complexity. AB - BACKGROUND: Concerns about the costs and quality of hospital care have led to increased interest in hospital readmissions in children. Children with medical complexity account for high proportions of inpatient utilization and have a higher risk of hospital readmission. OBJECTIVE: To identify studies of discharge interventions to prevent hospital readmissions in children with medical complexity. METHODS: We conducted a search to identify studies of discharge interventions. Included studies 1) described an intervention or modifiable risk factor around the time of hospital discharge 2) included pediatric patients with chronic illness and/or medical complexity and 3) reported subsequent hospital utilization. RESULTS: We identified ten studies testing the following interventions: multi-faceted discharge bundle (including medication review, discharge education, and follow-up appointments) (s=1), post-discharge follow-up clinic visits (s=3), post-discharge phone calls (s=2), intensive follow-up interventions for very low birth weight infants (s=2), and education interventions in children hospitalized with asthma (s=2). Four studies reported reductions in readmissions. The discharge bundle correlated with an 11.1% decrease in 30-day readmission (9.9% vs. 8.8%, p<0.05). All three studies of post discharge follow-up clinic visits reported a decrease in 30-day readmission risk among children with follow-up scheduled within 30 days, though one study also reported that medically complex children with follow- up within three days had increased readmission risk. CONCLUSION: Evidence supporting discharge interventions for children with medical complexity is limited. Multi-faceted discharge interventions and post-discharge clinic visits may be effective. PMID- 28814258 TI - Management of Complicated Pneumonia in Childhood: A Review of Recent Literature. AB - BACKGROUND: Despite declining rates of community acquired pneumonia (CAP) in children, complicated pneumonia has been on the rise in the last two decades. The management of complicated pneumonia is challenging and continues to be an area of investigation. Despite recently published guidelines, many gaps exist and recent studies attempt to answer challenging questions. OBJECTIVE: The aim was to review recently published literature to inform the clinician about the most up to date management of complicated pneumonia in children. METHODS: Using Medline, a search of the medical literature was conducted in order to find relevant clinical trials and review articles published in the last 5 years. RESULTS: Narrow spectrum antibiotics including ampicillin and azithromycin remain important first line agents, but directed therapy towards causative pathogens is the ideal standard practice. Novel DNA isolation technologies hold promise for raising the diagnostic yield of pleural fluid. Surgical interventions are often required and new literature further supports the use of fibrinolytics and minimally invasive chest tube thoracostomy. Not to be overlooked is the importance of supportive measures including oxygen therapy and adequate fluid, electrolyte and nutrition support. The use of other adjunctive therapies such as steroids in pediatric complicated pneumonia remains controversial. CONCLUSION: Recent studies have shown promise in establishing best practices for evaluation and management of complicated pneumonia in children. Despite these robust efforts however, many areas are in need of future inquiry and prospective studies could help to better understand the optimal therapeutic and diagnostic options for children with this common and persistent childhood illness. PMID- 28814259 TI - May Gender or Ethnicity Affect Delta Over Baseline Values Obtained by 13-C Urea Breath Test? AB - INTRODUCTION: 13C-urea breath test (UBT) is a non-invasive test for detecting active H. pylori infection. Previous studies showed a correlation of delta over baseline (DOB) values with bacterial load, mucosal inflammation and successful eradication. Gender has been shown to affect DOB in children. Aim of our study was to verify whether gender or ethnicity affects DOB in adults. PATIENTS AND METHODS: We retrospectively analyzed data of 2922 patients (1024M/1898F mean age 47+/-15 years) that underwent UBT in our outpatient unit, from October 2015 to October 2016. Patients were divided based on gender and ethnicity; mean DOB values were then compared. RESULTS: 686 pts (23.4%, 258M/428F, mean age 45+/-17 years) of 2922 pts showed a positive UBT. Prevalence of H. pylori infection was significantly higher in males compared to females (29% vs 22%; p=0,03). Females showed a significant higher mean DOB (34+/-25 vs 27,6+/-22; p=0,008). A total of 2922 UBT were performed during the study period (F:1898, 65%; M: 1024 35%). The prevalence of H. pylori infection is 32% in those from Eastern Countries, 28% in those from South America and 40% in both those coming from Africa and Asia. We found significantly lower DOB values in Italians compared to non-Italian (mean DOB 36+/-27 vs 69+/-32; p<0.0001). CONCLUSION: Our study showed that in our geographic area, prevalence H. pylori infection is higher in males. Moreover, it demonstrates for the first time in our geographic area that adult females show a significantly higher DOB compared to males (p=0,008). Whether this effect may be due to hormonal differences, able to influence gastric emptying, bacterial load, or even the production of urease by H. pylori, merits further investigation. PMID- 28814260 TI - Neonatal Abstinence Syndrome Management: A Review of Recent Evidence. AB - BACKGROUND: The evaluation and management of infants with neonatal abstinence syndrome (NAS), the constellation of opioid withdrawal specific to newborns, have received renewed attention over the past decade during a new epidemic of opioid use, misuse, abuse, and dependence. Infants with NAS often endure long and costly hospital stays. OBJECTIVE: We aim to review recent literature on the management and outcomes of infants with, and at risk for, opioid withdrawal. METHODS: We reviewed articles indexed in PubMed over the past 5 years that examined interventions and/or outcomes related to the management of infants with NAS. Thirty-seven studies were included in our review comprising 8 categories: 1) identification of infants at risk for NAS, 2) prenatal factors, 3) evaluation of signs and symptoms, 4) non-pharmacologic care, including rooming-in and breastfeeding, 5) standardization of traditional protocols, 6) pharmacologic management, 7) alternative treatment approaches, and 8) long-term outcomes. RESULTS: Non-pharmacologic interventions, standardization of traditional protocols, and alternative treatment approaches were all associated with improved outcomes. Lengths of stay were generally lowest in the studies of non pharmacologic interventions. Patients exposed to buprenorphine in utero tended to have better short-term outcomes than those exposed to methadone. Longer-term outcomes for infants with NAS appear to be worse than those of control groups. CONCLUSION: The current epidemic necessitates both continued research, and the application of new evidence-based practices in the assessment and treatment of newborns exposed to opioids in utero. Projects focused on non-pharmacologic interventions appear to hold the most promise. PMID- 28814261 TI - Recent Studies on the Care of First Febrile Urinary Tract Infection in Infants and Children for the Pediatric Hospitalist. AB - BACKGROUND: Urinary Tract Infection (UTI) is a common cause of bacterial infection in young children, and accounts for a significant number of pediatric hospitalizations. OBJECTIVE: To review recent publications focusing on the care of children hospitalized with their first febrile UTI. METHODS: A PubMed search was performed including publications from 2011-2016 on first febrile UTI in childhood. Abstracts were reviewed for being relevant to the care of hospitalized children and their follow-up. Relevant articles underwent full review by all authors and articles excluded from results included those without novel data analysis, primary improvement-based reports and studies with poor design or analysis. Included articles were categorized as "diagnosis", "management", "imaging" or "follow-up". RESULTS: Of 406 articles initially identified, 40 studies were included. One technical report with a systematic review was also included. Major topics addressed included the role of urinalysis in screening for UTI, use of parenteral antimicrobial therapy, the role of antimicrobial prophylaxis in prevention of recurrent UTI, and ideal follow-up and imaging approach following diagnosis of febrile UTI. CONCLUSION: Recent literature on first febrile UTI addresses a broad range of areas regarding the care of hospitalized children, though some questions remain unanswered. Overall, studies support increased attention to the potential risks, expense and invasiveness of various approaches for evaluation. Proposed updates to practice included: utilization of urinalysis for screening and diagnosis, transitioning to oral antimicrobials based on clinical improvement and limiting the routine use of voiding cystourethrogram and antimicrobial prophylaxis. PMID- 28814262 TI - Update on the Evaluation and Management of Brief Resolved Unexplained Events (Previously Apparent Life-Threatening Events). AB - BACKGROUND: The thirty-year-old term "apparent life-threatening event" (ALTE) is difficult to apply in clinical practice and research. The American Academy of Pediatrics now defines these events as brief resolved unexplained events (BRUEs), stratifies infants based on the risk of recurrence or of a serious underlying condition, and offers evidence-based management recommendations for infants at lower-risk. OBJECTIVE: To review recent ALTE literature as it relates to BRUEs. METHOD: Articles were identified by searching several clinical databases. English language articles from January 2006 to August 2016 that address ALTEs or BRUEs were included. RESULTS: Significant variation exists in the evaluation and management of patients diagnosed with BRUE. Research demonstrates low utility of most diagnostic testing, including prolonged cardiorespiratory monitoring, in the well-appearing infant without an obvious etiology. Risk factors for recurrent adverse events or significant underlying pathology include young age, prematurity, and presence of multiple events. There is little evidence to provide guidance for the management of higher-risk infants. CONCLUSION: BRUE is a diagnosis of exclusion to be applied when there is no apparent etiology after performing an appropriate history and physical examination. Lower-risk infants should not undergo routine diagnostic testing and should not be admitted solely for cardiorespiratory monitoring. Higherrisk infants are more likely to benefit from diagnostic testing and admission; however, routine screening testing is unnecessary, and the history and physical should guide the clinician's approach. Prospective research is needed to understand the incidence of BRUEs, outcomes in lower and higher-risk infants, and the utility of diagnostic testing in higher risk infants. PMID- 28814263 TI - Acute Pain Management in Hospitalized Children. AB - BACKGROUND: Acute pain in hospitalized pediatric patients is prevalent. Recent shifts in the paradigm of pediatric acute pain management focus less on reliance on opioids, due to their adverse side effects and risk of dependence, and more on multimodal pain management. OBJECTIVE: We sought to review the most recent studies on acute pain management in hospitalized pediatric patients. METHOD: We searched the Cochrane Database and PubMed for articles published in the past five years regarding the treatment of acute pain in pediatric patients focusing on large randomized or quasirandomized controlled trials, cohort trials, and meta analyses. RESULTS: We categorized results into non-pharmacological, localized, non-opiate pharmacological, and opiate based therapies. Recent studies show that environmental and non-pharmacological methods of pain management are efficacious in infants. School aged children benefit from active distraction more than passive distraction. Needleless methods of introducing lidocaine locally alleviate the pain associated with many procedures to which hospitalized children are exposed. The shift towards use of nonopiate pharmacology focuses on novel means of utilizing older medications, such as intravenous parecoxib, inhaled methoxyflurane, and sublingual ketorolac or tramadol and the avoidance of codeine. CONCLUSION: Acute pediatric pain management has changed to emphasize multimodal and multidisciplinary therapy. In all children, non-pharmacological therapies should be employed routinely. Given the myriad tools available, pediatric acute pain services have developed in order to integrate more advanced treatments such as nerve blocks and infusions of centrally acting pain modulators. PMID- 28814264 TI - Left ventricular contractile reserve by stress echocardiography as a predictor of response to cardiac resynchronization therapy in heart failure: a systematic review and meta-analysis. AB - BACKGROUND: The presence of left ventricular contractile reserve (LVCR) during stress echo (SE) may provide favorable response to cardiac resynchronization therapy (CRT) in heart failure patients. The aim of the study was to perform a meta-analysis of available SE data in this set of patients. METHODS: From a Pubmed and Advance Google Scholar database web based search scan up to December 2016, we initially identified 5906 records. From this initial set, we removed that did not include SE and duplicate studies. We assessed for eligibility 71 full-text articles assessed for eligibility, and 60 of them did not meet the inclusion criteria as follow: 1) heart failure patients with NYHA class III and IV, depressed ejection fraction (EF <35%) and QRS duration >=120 ms at study entry; 2) SE with assessment of LVCR; 3) Follow-up data. LVCR during SE was identified as reduction in wall motion score index and/or an increase in EF. RESULTS: Eleven studies with 861 patients (mean age 67 +/- 9 years, ejection fraction 25 +/- 6%) were included in the meta-analysis. The type of stress was either exercise (n = 2) or dobutamine (n = 9), the latter with low-dose (10 mcg) in two, intermediate-dose (20 mcg) in five, and high-dose (40 mcg) protocol in two studies. LVCR was detected in 555 patients (63%) and CRT-response was present in 584 (66%). The overall odds ratio for LVCR to predict a favorable CRT response was 2.06 (95%, CI 1.70-2-43), Z score: 11.055, p < 0.001. CONCLUSION: The presence of LVCR during SE with either dobutamine or exercise is associated with a greater chance of response to CRT. This parameter is now ready to be tested in a prospective multicenter trial to select patients more likely to benefit from CRT. PMID- 28814265 TI - A genome-wide transcriptome map of pistachio (Pistacia vera L.) provides novel insights into salinity-related genes and marker discovery. AB - BACKGROUND: Pistachio (Pistacia vera L.) is one of the most important commercial nut crops worldwide. It is a salt-tolerant and long-lived tree, with the largest cultivation area in Iran. Climate change and subsequent increased soil salt content have adversely affected the pistachio yield in recent years. However, the lack of genomic/global transcriptomic sequences on P. vera impedes comprehensive researches at the molecular level. Hence, whole transcriptome sequencing is required to gain insight into functional genes and pathways in response to salt stress. RESULTS: RNA sequencing of a pooled sample representing 24 different tissues of two pistachio cultivars with contrasting salinity tolerance under control and salt treatment by Illumina Hiseq 2000 platform resulted in 368,953,262 clean 100 bp paired-ends reads (90 Gb). Following creating several assemblies and assessing their quality from multiple perspectives, we found that using the annotation-based metrics together with the length-based parameters allows an improved assessment of the transcriptome assembly quality, compared to the solely use of the length-based parameters. The generated assembly by Trinity was adopted for functional annotation and subsequent analyses. In total, 29,119 contigs annotated against all of five public databases, including NR, UniProt, TAIR10, KOG and InterProScan. Among 279 KEGG pathways supported by our assembly, we further examined the pathways involved in the plant hormone biosynthesis and signaling as well as those to be contributed to secondary metabolite biosynthesis due to their importance under salinity stress. In total, 11,337 SSRs were also identified, which the most abundant being dinucleotide repeats. Besides, 13,097 transcripts as candidate stress-responsive genes were identified. Expression of some of these genes experimentally validated through quantitative real-time PCR (qRT-PCR) that further confirmed the accuracy of the assembly. From this analysis, the contrasting expression pattern of NCED3 and SOS1 genes were observed between salt-sensitive and salt-tolerant cultivars. CONCLUSION: This study, as the first report on the whole transcriptome survey of P. vera, provides important resources and paves the way for functional and comparative genomic studies on this major tree to discover the salinity tolerance-related markers and stress response mechanisms for breeding of new pistachio cultivars with more salinity tolerance. PMID- 28814266 TI - Lack of satellite DNA species-specific homogenization and relationship to chromosomal rearrangements in monitor lizards (Varanidae, Squamata). AB - BACKGROUND: Satellite DNAs (stDNAs) are highly repeated sequences that constitute large portions of any genome. The evolutionary dynamics of stDNA (e.g. copy number, nucleotide sequence, location) can, therefore, provide an insight into genome organization and evolution. We investigated the evolutionary origin of VSAREP stDNA in 17 monitor lizards (seven Asian, five Australian, and five African) at molecular and cytogenetic level. RESULTS: Results revealed that VSAREP is conserved in the genome of Asian and Australian varanids, but not in African varanids, suggesting that these sequences are either differentiated or lost in the African varanids. Phylogenetic and arrangement network analyses revealed the existence of at least four VSAREP subfamilies. The similarity of each sequence unit within the same VSAREP subfamily from different species was higher than those of other VSAREP subfamilies belonging to the same species. Additionally, all VSAREP subfamilies isolated from the three Australian species (Varanus rosenbergi, V. gouldii, and V. acanthurus) were co-localized near the centromeric or pericentromeric regions of the macrochromosomes, except for chromosomes 3 and 4 in each Australian varanid. However, their chromosomal arrangements were different among species. CONCLUSIONS: The VSAREP stDNA family lack homogenized species-specific nucleotide positions in varanid lineage. Most VSAREP sequences were shared among varanids within the four VSAREP subfamilies. This suggests that nucleotide substitutions in each varanid species accumulated more slowly than homogenization rates in each VSAREP subfamily, resulting in non species-specific evolution of stDNA profiles. Moreover, changes in location of VSAREP stDNA in each Australian varanid suggests a correlation with chromosomal rearrangements, leading to karyotypic differences among these species. PMID- 28814267 TI - Sex and tissue specific gene expression patterns identified following de novo transcriptomic analysis of the Norway lobster, Nephrops norvegicus. AB - BACKGROUND: The Norway lobster, Nephrops norvegicus, is economically important in European fisheries and is a key organism in local marine ecosystems. Despite multi-faceted scientific interest in this species, our current knowledge of genetic resources in this species remains very limited. Here, we generated a reference de novo transcriptome for N. norvegicus from multiple tissues in both sexes. Bioinformatic analyses were conducted to detect transcripts that were expressed exclusively in either males or females. Patterns were validated via RT PCR. RESULTS: Sixteen N. norvegicus libraries were sequenced from immature and mature ovary, testis and vas deferens (including the masculinizing androgenic gland). In addition, eyestalk, brain, thoracic ganglia and hepatopancreas tissues were screened in males and both immature and mature females. RNA-Sequencing resulted in >600 million reads. De novo assembly that combined the current dataset with two previously published libraries from eyestalk tissue, yielded a reference transcriptome of 333,225 transcripts with an average size of 708 base pairs (bp), with an N50 of 1272 bp. Sex-specific transcripts were detected primarily in gonads followed by hepatopancreas, brain, thoracic ganglia, and eyestalk, respectively. Candidate transcripts that were expressed exclusively either in males or females were highlighted and the 10 most abundant ones were validated via RT-PCR. Among the most highly expressed genes were Serine threonine protein kinase in testis and Vitellogenin in female hepatopancreas. These results align closely with gene annotation results. Moreover, a differential expression heatmap showed that the majority of differentially expressed transcripts were identified in gonad and eyestalk tissues. Results indicate that sex-specific gene expression patterns in Norway lobster are controlled by differences in gene regulation pattern between males and females in somatic tissues. CONCLUSIONS: The current study presents the first multi-tissue reference transcriptome for the Norway lobster that can be applied to future biological, wild restocking and fisheries studies. Sex-specific markers were mainly expressed in males implying that males may experience stronger selection than females. It is apparent that differential expression is due to sex-specific gene regulatory pathways that are present in somatic tissues and not from effects of genes located on heterogametic sex chromosomes. The N. norvegicus data provide a foundation for future gene based reproductive studies. PMID- 28814268 TI - The genomic architecture of mastitis resistance in dairy sheep. AB - BACKGROUND: Mastitis is the most prevalent disease in dairy sheep with major economic, hygienic and welfare implications. The disease persists in all dairy sheep production systems despite the implementation of improved management practises. Selective breeding for enhanced mastitis resistance may provide the means to further control the disease. In the present study, we investigated the genetic architecture of four mastitis traits in dairy sheep. Individual animal records for clinical mastitis occurrence and three mastitis indicator traits (milk somatic cell count, total viable bacterial count in milk and the California mastitis test) were collected monthly throughout lactation for 609 ewes of the Greek Chios breed. All animals were genotyped with a custom-made 960-single nucleotide polymorphism (SNP) DNA array based on markers located in quantitative trait loci (QTL) regions for mastitis resistance previously detected in three other distinct dairy sheep populations. RESULTS: Heritable variation and strong positive genetic correlations were estimated for clinical mastitis occurrence and the three mastitis indicator traits. SNP markers significantly associated with these mastitis traits were confirmed on chromosomes 2, 3, 5, 16 and 19. We identified pathways, molecular interaction networks and functional gene clusters for mastitis resistance. Candidate genes within the detected regions were identified based upon analysis of an ovine transcriptional atlas and transcriptome data derived from milk somatic cells. Relevant candidate genes implicated in innate immunity included SOCS2, CTLA4, C6, C7, C9, PTGER4, DAB2, CARD6, OSMR, PLXNC1, IDH1, ICOS, FYB, and LYFR. CONCLUSIONS: The results confirmed the presence of animal genetic variability in mastitis resistance and identified genomic regions associated with specific mastitis traits in the Chios sheep. The conserved genetic architecture of mastitis resistance between distinct dairy sheep breeds suggests that across-breed selection programmes would be feasible. PMID- 28814269 TI - Applied Swarm-based medicine: collecting decision trees for patterns of algorithms analysis. AB - BACKGROUND: The objective consensus methodology has recently been applied in consensus finding in several studies on medical decision-making among clinical experts or guidelines. The main advantages of this method are an automated analysis and comparison of treatment algorithms of the participating centers which can be performed anonymously. METHODS: Based on the experience from completed consensus analyses, the main steps for the successful implementation of the objective consensus methodology were identified and discussed among the main investigators. RESULTS: The following steps for the successful collection and conversion of decision trees were identified and defined in detail: problem definition, population selection, draft input collection, tree conversion, criteria adaptation, problem re-evaluation, results distribution and refinement, tree finalisation, and analysis. CONCLUSION: This manuscript provides information on the main steps for successful collection of decision trees and summarizes important aspects at each point of the analysis. PMID- 28814271 TI - Survival analysis of increases in care needs associated with dementia and living alone among older long-term care service users in Japan. AB - BACKGROUND: Japan is known for its long life expectancy and rapidly aging society that there are various demands of older adults need to be fulfilled with, and one of them is long-term care needs. Therefore, Japan implemented the Long-Term Care Insurance in year 2000 for citizens who are above 65-year old and citizens who are above 40-year old in needs of long-term care services. This study was undertaken to longitudinally examine the influence of dementia and living alone on care needs increases among older long-term care insurance service users in Japan. METHODS: Long-term care insurance claims data were used to identify enrollees who applied for long-term care services between October 2010 and September 2011, and subjects were tracked until March 2015. A Kaplan-Meier survival analysis was conducted to examine increases in care needs over time in months. Cox regression models were used to examine the effects of dementia and living alone on care needs increases. RESULTS: The cumulative survival rates before care needs increased over the 4.5-year observation period were 17.6% in the dementia group and 31.9% in the non-dementia group. After adjusting for age, sex, care needs level, and status of living alone, the risk of care needs increases was found to be 1.5 times higher in the dementia group. Living alone was not a significant risk factor of care needs increases, but people with dementia who lived alone had a higher risk of care needs increases than those without dementia. CONCLUSION: Dementia, older age, the female sex, and lower care needs levels were associated with a higher risk of care needs increases over the study period. Among these variables, dementia had the strongest impact on care needs increases, especially in persons who lived alone. PMID- 28814270 TI - Transcriptional analysis of abdominal fat in chickens divergently selected on bodyweight at two ages reveals novel mechanisms controlling adiposity: validating visceral adipose tissue as a dynamic endocrine and metabolic organ. AB - BACKGROUND: Decades of intensive genetic selection in the domestic chicken (Gallus gallus domesticus) have enabled the remarkable rapid growth of today's broiler (meat-type) chickens. However, this enhanced growth rate was accompanied by several unfavorable traits (i.e., increased visceral fatness, leg weakness, and disorders of metabolism and reproduction). The present descriptive analysis of the abdominal fat transcriptome aimed to identify functional genes and biological pathways that likely contribute to an extreme difference in visceral fatness of divergently selected broiler chickens. METHODS: We used the Del-Mar 14 K Chicken Integrated Systems microarray to take time-course snapshots of global gene transcription in abdominal fat of juvenile [1-11 weeks of age (wk)] chickens divergently selected on bodyweight at two ages (8 and 36 wk). Further, a RNA sequencing analysis was completed on the same abdominal fat samples taken from high-growth (HG) and low-growth (LG) cockerels at 7 wk, the age with the greatest divergence in body weight (3.2-fold) and visceral fatness (19.6-fold). RESULTS: Time-course microarray analysis revealed 312 differentially expressed genes (FDR <= 0.05) as the main effect of genotype (HG versus LG), 718 genes in the interaction of age and genotype, and 2918 genes as the main effect of age. The RNA sequencing analysis identified 2410 differentially expressed genes in abdominal fat of HG versus LG chickens at 7 wk. The HG chickens are fatter and over-express numerous genes that support higher rates of visceral adipogenesis and lipogenesis. In abdominal fat of LG chickens, we found higher expression of many genes involved in hemostasis, energy catabolism and endocrine signaling, which likely contribute to their leaner phenotype and slower growth. Many transcription factors and their direct target genes identified in HG and LG chickens could be involved in their divergence in adiposity and growth rate. CONCLUSIONS: The present analyses of the visceral fat transcriptome in chickens divergently selected for a large difference in growth rate and abdominal fatness clearly demonstrate that abdominal fat is a very dynamic metabolic and endocrine organ in the chicken. The HG chickens overexpress many transcription factors and their direct target genes, which should enhance in situ lipogenesis and ultimately adiposity. Our observation of enhanced expression of hemostasis and endocrine-signaling genes in diminished abdominal fat of LG cockerels provides insight into genetic mechanisms involved in divergence of abdominal fatness and somatic growth in avian and perhaps mammalian species, including humans. PMID- 28814272 TI - Identification of new protein-coding genes with a potential role in the virulence of the plant pathogen Xanthomonas euvesicatoria. AB - BACKGROUND: Bacteria of the genus Xanthomonas are economically important plant pathogens. Pathogenicity of Xanthomonas spp. depends on the type III-secretion system and additional virulence determinants. The number of sequenced Xanthomonas genomes increases rapidly, however, accurate annotation of these genomes is difficult, because it relies on gene prediction programs. In this study, we used a mass-spectrometry (MS)-based approach to identify the proteome of Xanthomonas euvesicatoria (Xe) strain 85-10 also known as X. campestris pv. vesicatoria, a well-studied member of plant-pathogenic Xanthomonadaceae. RESULTS: Using different culture conditions, MS-datasets were searched against a six-frame translated genome database of Xe. In total, we identified 2588 proteins covering 55% of the Xe genome, including 764 hitherto hypothetical proteins. Our proteogenomic approach identified 30 new protein-coding genes and allowed correction of the N-termini of 50 protein-coding genes. For five novel and two N terminally corrected genes the corresponding proteins were confirmed by immunoblot. Furthermore, our data indicate that two putative type VI-secretion systems encoded in Xe play no role in bacterial virulence which was experimentally confirmed. CONCLUSIONS: The discovery and re-annotation of numerous genes in the genome of Xe shows that also a well-annotated genome can be improved. Additionally, our proteogenomic analyses validates "hypothetical" proteins and will improve annotation of Xanthomonadaceae genomes, providing a solid basis for further studies. PMID- 28814273 TI - Add-on neurological benefits of antiviral therapy in HCV patients with chronic kidney disease - a nationwide cohort study. AB - BACKGROUND: Hepatitis C virus (HCV)-infected patients with chronic kidney disease (CKD) have rarely been studied because they rarely accept interferon-based therapy (IBT) and have been difficult to follow up. We investigated long-term outcomes of IBT on the population. METHODS: This population-based cohort study used the Taiwan National Health Insurance Research Database as its data source. HCV patients diagnosed with CKD between Jan. 1, 2003, and Dec. 31, 2013, were selected. They were then divided into two groups based on whether they had undergone IBT. All-cause mortality, acute myocardial infarction (AMI), ischemic stroke (IS), hemorrhagic stroke, and new-onset dialysis were evaluated using a Cox proportional hazard regression analysis after propensity score matching. RESULTS: We enrolled 9872 HCV patients with CKD: 1684 patients in the treated cohort and 8188 patients in the untreated cohort. The annual incidence of all cause mortality (19.00 vs. 42.89 events per 1000 person-years; p < 0.001) and the incidences of hemorrhagic stroke (1.21 vs. 4.19 events per 1000 person-years; p = 0.006) were lower in the treated cohort. New-onset dialysis was also lower in the treated cohort (aHR: 0.31; 95% CI: 0.20-0.48; p < 0.001). CONCLUSION: Antiviral therapy might provide protective benefits on all-cause mortality, hemorrhagic stroke, and new-onset dialysis in HCV-infected patients with CKD. PMID- 28814274 TI - Association between periodontal disease and mortality in people with CKD: a meta analysis of cohort studies. AB - BACKGROUND: Periodontal disease occurs relatively prevalently in people with chronic kidney disease (CKD), but it remains indeterminate whether periodontal disease is an independent risk factor for premature death in this population. Interventions to reduce mortality in CKD population consistently yield to unsatisfactory results and new targets are necessitated. So this meta-analysis aimed to evaluate the association between periodontal disease and mortality in the CKD population. METHODS: Pubmed, Embase, Web of Science, Scopus and abstracts from recent relevant meeting were searched by two authors independently. Relative risks (RRs) with 95% confidence intervals (CIs) were calculated for overall and subgroup meta-analyses. Statistical heterogeneity was explored by chi-square test and quantified by the I2 statistic. RESULTS: Eight cohort studies comprising 5477 individuals with CKD were incorporated. The overall pooled data demonstrated that periodontal disease was associated with all-cause death in CKD population (RR, 1.254; 95% CI 1.046-1.503; P = 0.005), with a moderate heterogeneity, I2 = 52.2%. However, no evident association was observed between periodontal disease and cardiovascular mortality (RR, 1.30, 95% CI, 0.82-2.06; P = 0.259). Besides, statistical heterogeneity was substantial (I2 = 72.5%; P = 0.012). Associations for mortality were similar between subgroups, such as the different stages of CKD, adjustment for confounding factors. Specific to all-cause death, sensitivity and cumulative analyses both suggested that our results were robust. As for cardiovascular mortality, the association with periodontal disease needs to be further strengthened. CONCLUSIONS: We demonstrated that periodontal disease was associated with an increased risk of all-cause death in CKD people. Yet no adequate evidence suggested periodontal disease was also at elevated risk for cardiovascular death. PMID- 28814275 TI - Randomized study comparing full dose monotherapy (S-1 followed by irinotecan) and reduced dose combination therapy (S-1/oxaliplatin followed by S-1/irinotecan) as initial therapy for older patients with metastatic colorectal cancer: NORDIC 9. AB - BACKGROUND: Metastatic colorectal cancer (mCRC) is a disease of older age, but there is a relative lack of knowledge about effects of chemotherapy in older patients as they are under-represented in clinical trials. Little data can guide whether the strategy in older mCRC patients should be a sequential full-dose monotherapy chemotherapy approach or a dose-reduced combination chemotherapy approach. The oral 5FU prodrug S-1 seems to have less side effects than capecitabine and should be an optimal drug for older patients, but few data are available. Improved geriatric assessments are needed to select which older patients should receive therapy. METHODS: The NORDIC 9 trial is a Nordic multicenter randomized phase II study comparing full dose monotherapy (S-1 30 mg/m2 twice daily days 1-14 every 3 weeks, followed by second line irinotecan 250 350 mg/m2 iv day 1 every 3 weeks or 180-250 mg/m2 iv day 1 every 2 weeks) with reduced dose combination therapy (S-1 20 mg/m2 days 1-14 + oxaliplatin 100 mg/m2 iv day 1 every 3 weeks, followed by second line S-1 20 mg/m2 days 1-14 + irinotecan 180 mg/m2 day 1 every 3 week) for older patients (>=70 years) with mCRC who are not candidates for full-dose standard combination therapy. Additional bevacizumab (7.5 mg/kg) is optional in first-line. Blood samples and tumor tissue will be collected to investigate predictive markers. Geriatric screening tools (G-8, VES-13, Timed-Up-and-Go and Handgrip strength), Charlson Comorbidty Index and quality of life (EORTC QLQ-C30) will be evaluated as predictors of efficacy and toxicity. The target sample size is 150 patients. The primary endpoint is progression-free survival and secondary endpoints are time-to failure of strategy, overall survival, response rate, toxicity, and correlations between biomarkers, pre-treatment characteristics and geriatric assessments. DISCUSSION: The study will add knowledge on how to treat older mCRC patients who are not candidates for standard combination therapy. Furthermore it may provide understanding of efficacy and tolerability of chemotherapy in older cancer patients and thus offer a better chance for tailored treatment strategies in these patients. TRIAL REGISTRATION: EU Clinical Trial Register, EudraCT no. 2014 000394-39 . Registered 05 May 2014. PMID- 28814276 TI - Treatment outcomes of patients with multidrug-resistant and extensively drug resistant tuberculosis in Hunan Province, China. AB - BACKGROUND: The worldwide emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) has posed additional challenges for global tuberculosis (TB) control efforts, as limited treatment options are available and treatment outcomes are often sub-optimal. This study determined treatment outcomes among a cohort of MDR-TB and XDR-TB patients in Hunan Province, China, and identified factors associated with poor treatment outcomes. METHODS: We conducted a retrospective study using data obtained from medical records of TB patients in Hunan Chest Hospital, and from the internet based TB management information system managed by the Tuberculosis Control Institute of Hunan Province, for the period 2011 to 2014. Treatment outcomes were assessed for patients diagnosed with MDR-TB (TB resistant to at least isoniazid and rifampicin) and XDR-TB (MDR-TB plus resistance to any fluoroquinolone and at least 1 second-line injectable drug). Cumulative incidence functions were used to estimate time to events (i.e. poor treatment outcomes, loss to follow-up, and unfavourable treatment outcomes); and a competing-risks survival regression model was used to identify predictors of treatment outcomes. RESULT: Of 481 bacteriologically-confirmed patients, with a mean age of 40 years (standard deviation SD +/- 13 years), 10 (2%) had XDR-TB and the remainder (471; 98%) had MDR-TB. For the entire cohort, treatment success was 57% (n = 275); 58% (n = 272) for MDR-TB and 30% (n = 3) for XDR-TB. Overall, 27% were lost to follow-up (n = 130), 27% (n = 126) for MDR-TB and 40% (n = 4) for XDR-TB; and 16% had a poor treatment outcome (n = 76), 15% for MDR-TB and 30% (n = 3) for XDR-TB. Of the 10 XDR-TB patients, 3 (30%) completed treatment, 3 (30%) died and 4 (40%) were lost to follow-up. Of the 471 MDR-TB patients, 258 (57%) were cured, 16 (3%) completed treatment, 13 (3%) died, 60 (13%) experienced treatment failure, and 126 (27%) were lost to follow-up. Resistance to ofloxacin was an independent predictor of poor (AHR = 3.1; 95%CI = 1.5, 6.3), and unfavourable (AHR = 1.7; 95%CI = 1.07, 2.9) treatment outcomes. Patients who started treatment during 2011-2012 (AHR = 2.8; 95% CI = 1.5, 5.3) and 2013 (AHR = 2.1; 95% CI = 1.2, 3.9) had poorer treatment outcomes compared to patients who started treatment during 2014. CONCLUSION: Patients with MDR-TB and XDR-TB had low rates of treatment success in Hunan Province, especially among patients who started treatment during 2011 to 2013, with evidence of improved treatment outcomes in 2014. Resistance to ofloxacin was an independent predictor of poor treatment outcomes. PMID- 28814277 TI - Phenotypes, antioxidant responses, and gene expression changes accompanying a sugar-only diet in Bactrocera dorsalis (Hendel) (Diptera: Tephritidae). AB - BACKGROUND: Diet composition (yeast:carbohydrate ratio) is an important determinant of growth, development, and reproduction. Recent studies have shown that decreased yeast intake elicits numerous transcriptomic changes and enhances somatic maintenance and lifespan, which in turn reduces reproduction in various insects. However, our understanding of the responses leading to a decrease in yeast ratio to 0% is limited. RESULTS: In the present study, we investigated the effects of a sugar-only diet (SD) on the gene expression patterns of the oriental fruit fly, Bactrocera dorsalis (Hendel), one of the most economically important pests in the family Tephritidae. RNA sequencing analyses showed that flies reared on an SD induced significant changes in the expression levels of genes associated with specific metabolic as well as cell growth and death pathways. Moreover, the observed upregulated genes in energy production and downregulated genes associated with reproduction suggested that SD affects somatic maintenance and reproduction in B. dorsalis. As expected, we observed that SD altered B. dorsalis phenotypes by significantly increasing stress (starvation and desiccation) resistance, decreasing reproduction, but did not extend lifespan compared to those that received a normal diet (ND) regime. In addition, administration of an SD resulted in a reduction in antioxidant enzyme activities and an increase in MDA concentrations, thereby suggesting that antioxidants cannot keep up with the increase in oxidative damage induced by SD regime. CONCLUSIONS: The application of an SD diet induces changes in phenotypes, antioxidant responses, and gene expressions in B. dorsalis. Previous studies have associated extended lifespan with reduced fecundity. The current study did not observe a prolongation of lifespan in B. dorsalis, which instead incurred oxidative damage. The findings of the present study improve our understanding of the molecular, biochemical, and phenotypic response of B. dorsalis to an SD diet. PMID- 28814278 TI - Epidemiology and outcomes of Endophthalmitis in chronic dialysis patients: a 13 year experience in a tertiary referral center in Taiwan. AB - BACKGROUND: Endophthalmitis is a severe eye infection leading to disabling outcome. Because there were only a few case report illustrating endophthalmitis in chronic dialysis patient, we would like to investigate the epidemiology and clinical features of endophthalmitis in chronic dialysis patient in a tertiary referral center. METHODS: We searched the health information system in the study hospital with ICD9 encoding endophthalmitis during Jan. 2002 to Dec. 2015. A total of 32 episodes of endophthalmitis occurred in chronic dialysis patients. We performed an 1:2 case-control match on propensity score. The demographic features, clinical manifestation, infection focus and visual outcome were recorded. RESULTS: Of the total of 32 patients, 25 were classified as endogenous endophthalmitis and another seven were exogenous. Most patients presented with ophthalmalgia (n = 32, 100%) and periocular swelling (n = 31, 96.8%), whereas half of the patients suffered blurred vision (n = 16, 50%). Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa were the most frequent causative pathogens. Dialysis vascular infection was also a possible unique focus for bacteremia. The visual acuity of the endogenous groups were less likely to improve in the chronic dialysis patients compared with control group. CONCLUSION: This is the first and the largest case series focusing on endophthalmitis in chronic dialysis patients. Our study showed different pathogen spectrum, an unique bacterial origin and worse visual outcome in these group of patients. Prompt referral to ophthalmologists when the patients present with suspicious symptoms (blurred vision, ophthalmalgia and periocular swelling) is crucial. PMID- 28814279 TI - Musashi-1 is the candidate of the regulator of hair cell progenitors during inner ear regeneration. AB - BACKGROUND: Hair cell loss in the cochlea is caused by ototoxic drugs, aging, and environmental stresses and could potentially lead to devastating pathophysiological effects. In adult mammals, hair cell loss is irreversible and may result in hearing and balance deficits. In contrast, nonmammalian vertebrates, including birds, can regenerate hair cells through differentiation of supporting cells and restore inner ear function, suggesting that hair cell progenitors are present in the population of supporting cells. RESULTS: In the present study, we aimed to identify novel genes related to regeneration in the chicken utricle by gene expression profiling of supporting cell and hair cell populations obtained by laser capture microdissection. The volcano plot identified 408 differentially expressed genes (twofold change, p = 0.05, Benjamini-Hochberg multiple testing correction), 175 of which were well annotated. Among these genes, we focused on Musashi-1 (MSI1), a marker of neural stem cells involved in Notch signaling, and the downstream genes in the Notch pathway. Higher expression of these genes in supporting cells compared with that in hair cells was confirmed by quantitative reverse transcription polymerase chain reaction. Immunohistochemistry analysis demonstrated that MSI1 was mainly localized at the basal side of the supporting cell layer in normal chick utricles. During the regeneration period following aminoglycoside antibiotic induced damage of chicken utricles, the expression levels of MSI1, hairy and enhancer of split-5, and cyclin D1 were increased, and BrdU labeling indicated that cell proliferation was enhanced. CONCLUSIONS: The findings of this study suggested that MSI1 played an important role in the proliferation of supporting cells in the inner ear during normal and damaged conditions and could be a potential therapeutic target in the treatment of vestibular defects. PMID- 28814280 TI - Assisted clustering of gene expression data using ANCut. AB - BACKGROUND: In biomedical research, gene expression profiling studies have been extensively conducted. The analysis of gene expression data has led to a deeper understanding of human genetics as well as practically useful models. Clustering analysis has been a critical component of gene expression data analysis and can reveal the (previously unknown) interconnections among genes. With the high dimensionality of gene expression data, many of the existing clustering methods and results are not as satisfactory. Intuitively, this is caused by "a lack of information". In recent profiling studies, a prominent trend is to collect data on gene expressions as well as their regulators (copy number alteration, microRNA, methylation, etc.) on the same subjects, making it possible to borrow information from other types of omics measurements in gene expression analysis. METHODS: In this study, an ANCut approach is developed, which is built on the regularized estimation and NCut techniques. An effective R code that implements this approach is developed. RESULTS: Simulation shows that the proposed approach outperforms direct competitors. The analysis of TCGA (The Cancer Genome Atlas) data further demonstrates its satisfactory performance. CONCLUSIONS: We propose a more effective clustering analysis of gene expression data, with the assistance of information from regulators. It provides a new venue for analyzing gene expression data based on the assisted analysis strategy. PMID- 28814281 TI - Impact of new generation hormone-therapy on cognitive function in elderly patients treated for a metastatic prostate cancer: Cog-Pro trial protocol. AB - BACKGROUND: New generation hormone-therapies (NGHT) targeting the androgen signalling pathway are nowadays proposed to elderly patients with metastatic castration-resistant prostate cancer (CRPCa). The impact of these treatments on cognitive function has never been evaluated whereas cognitive impairment may have an impact on the autonomy and the treatment adherence. The aim of this study is to prospectively assess the incidence of cognitive impairment in elderly men after treatment by NGHT for a metastatic CRPCa. METHODS/DESIGN: The Cog-Pro study is a multicentre longitudinal study including CRPCa patients >=70 years old treated with NGHT (n = 134), control metastatic prostate cancer patients without castration resistance treated with first generation androgen deprivation therapy (n = 55), and healthy participants (n = 33), matched on age and education. Cognitive, geriatric and quality of life assessment and biological tests will be performed at baseline, 3, 6 and 12 months after start of the treatment (inclusion time). The primary endpoint is the proportion of elderly patients receiving a NGHT who will experience a decline in cognitive performances within 3 months after study enrollment. Secondary endpoints concern: autonomy, quality of life, anxiety, depression, cognitive reserve, adherence to hormone-therapy, comparison of the cognitive impact of 2 different NGHT (abiraterone acetate and enzalutamide), impact of co-morbidities and biological assessments. DISCUSSION: Evaluating, understanding and analyzing the incidence, severity of cognitive impairments and their impact on quality of life, autonomy and adherence in this group of patients with advanced disease is a challenge. This study should help to improve cancer care of elderly patients and secure the use of oral treatments as the risk of non-observance does exist. Our results will provide up-to date information for patients and caregivers on impact of these treatments on cognitive function in order to help the physicians in the choice of the treatment. TRIAL REGISTRATION: NCT02907372 , registered: July 26, 2016. PMID- 28814282 TI - Alterations in resting-state functional connectivity of the default mode network in amnestic mild cognitive impairment: an fMRI study. AB - BACKGROUND: Amnestic mild cognitive impairment (aMCI) is characterized by cognitive functional decline, especially in memory. Resting-state functional magnetic resonance imaging (fMRI) has been widely used in neuroimaging studies that explore alterations between patients and normal individuals to elucidate the pathological mechanisms of different diseases. The current study was performed to investigate alterations in the functional connectivity of the default mode network (DMN) in aMCI patients compared to healthy elderly controls, as well as further define the association between neurological alterations and memory function. METHODS: Twenty-five aMCI patients and 25 healthy individuals were recruited and underwent both fMRI and neuropsychological examinations. fMRI data was analyzed by independent component analysis. RESULTS: Compared to healthy individuals, aMCI patients exhibited a significant increase in functional connectivity between the DMN and right-middle and right-superior frontal gyri, left-middle occipital gyrus, and left-middle temporal gyrus, but reduced functional connectivity between the DMN and left-middle and left-inferior frontal gyri and left insula. These alterations were found to be associated with reduced memory function. CONCLUSIONS: aMCI patients exhibited abnormal functional connectivity between the DMN and certain brain regions which is associated with changes in memory function associated with aMCI. PMID- 28814283 TI - Comparative studies on tolerance of rice genotypes differing in their tolerance to moderate salt stress. AB - BACKGROUND: Moderate salt stress, which often occurs in most saline agriculture land, suppresses crop growth and reduces crop yield. Rice, as an important food crop, is sensitive to salt stress and rice genotypes differ in their tolerance to salt stress. Despite extensive studies on salt tolerance of rice, a few studies have specifically investigated the mechanism by which rice plants respond and tolerate to moderate salt stress. Two rice genotypes differing in their tolerance to saline-alkaline stress, Dongdao-4 and Jigeng-88, were used to explore physiological and molecular mechanisms underlying tolerance to moderate salt stress. RESULTS: Dongdao-4 plants displayed higher biomass, chlorophyll contents, and photosynthetic rates than Jigeng-88 under conditions of salt stress. No differences in K+ concentrations, Na+ concentrations and Na+/K+ ratio in shoots between Dongdao-4 and Jigeng-88 plants were detected when challenged by salt stress, suggesting that Na+ toxicity may not underpin the greater tolerance of Dongdao-4 to salt stress than that of Jigeng-88. We further demonstrated that Dongdao-4 plants had greater capacity to accumulate soluble sugars and proline (Pro) than Jigeng-88, thus conferring greater tolerance of Dongdao-4 to osmotic stress than Jigeng-88. Moreover, Dongdao-4 suffered from less oxidative stress than Jigeng-88 under salt stress due to higher activities of catalase (CAT) in Dongdao-4 seedlings. Finally, RNA-seq revealed that Dongdao-4 and Jigeng-88 differed in their gene expression in response to salt stress, such that salt stress changed expression of 456 and 740 genes in Dongdao-4 and Jigeng-88, respectively. CONCLUSION: Our results revealed that Dongdao-4 plants were capable of tolerating to salt stress by enhanced accumulation of Pro and soluble sugars to tolerate osmotic stress, increasing the activities of CAT to minimize oxidative stress, while Na+ toxicity is not involved in the greater tolerance of Dongdao-4 to moderate salt stress. PMID- 28814284 TI - Effect of poly-hexamethylene biguanide hydrochloride (PHMB) treated non-sterile medical gloves upon the transmission of Streptococcus pyogenes, carbapenem resistant E. coli, MRSA and Klebsiella pneumoniae from contact surfaces. AB - BACKGROUND: Reduction of accidental contamination of the near-patient environment has potential to reduce acquisition of healthcare-associated infection(s). Although medical gloves should be removed when soiled or touching the environment, compliance is variable. The use of antimicrobial-impregnated medical gloves could reduce the horizontal-transfer of bacterial contamination between surfaces. AIM: Determine the activity of antimicrobial-impregnated gloves against common hospital pathogens: Streptococcus pyogenes, carbapenem-resistant E.coli (CREC), MRSA and ESBL-producing Klebsiella pneumoniae. METHODS: Fingerpads (~1cm2) of PHMB-treated and untreated gloves were inoculated with 10 MUL (~104 colony-forming-units [cfu]) of test-bacteria prepared in heavy-soiling (0.5%BSA), blood or distilled-water (no-soiling) and sampled after 0.25, 1, 10 or 15 min contact-time. Donor surfaces (~1cm2 computer-keys) contaminated with wet/dry inoculum were touched with the fingerpad of treated/untreated gloves and subsequently pressed onto recipient (uncontaminated) computer-keys. RESULTS: Approximately 4.50log10cfu of all bacteria persisted after 15 min on untreated gloves regardless of soil-type. In the absence of soiling, PHMB-treated gloves reduced surface-contamination by ~4.5log10cfu (>99.99%) within 10 min of contact time but only ~2.5log10 (>99.9%) and ~1.0log10 reduction respectively when heavy soiling or blood was present. Gloves became highly-contaminated (~4.52log10 4.91log10cfu) when handling recently-contaminated computer-keys. Untreated gloves contaminated "recipient" surfaces (~4.5log10cfu) while PHMB-treated gloves transferred fewer bacteria (2.4-3.6log10cfu). When surface contamination was dry, PHMB gloves transferred fewer bacteria (0.3-0.6log10cfu) to "recipient" surfaces than untreated gloves (1.0-1.9log10; P < 0.05). CONCLUSIONS: Antimicrobial impregnated gloves may be useful in preventing dissemination of organisms in the near-patient environment during routine care. However they are not a substitute for appropriate hand-hygiene procedures. PMID- 28814285 TI - Quality of Midwife-provided Intrapartum Care in Amhara Regional State, Ethiopia. AB - BACKGROUND: Despite much progress recently, Ethiopia remains one of the largest contributors to the global burden of maternal and newborn deaths and stillbirths. Ethiopia's plan to meet the sustainable development goals for maternal and child health includes unprecedented emphasis on improving quality of care. The purpose of this study was to assess the quality of midwifery care during labor, delivery and immediate postpartum period. METHODS: A cross-sectional study using multiple data collection methods and a 2-stage cluster sampling technique was conducted from January 25 to February 14, 2015 in government health facilities of the Amhara National Regional State of Ethiopia. Direct observation of performance was used to determine competence of midwives in providing care during labor, delivery, and the first 6 h after childbirth. Inventory of drugs, medical equipment, supplies, and infrastructure was conducted to identify availability of resources in health facilities. Structured interview was done to assess availability of resources and performance improvement opportunities. Data analysis involved calculating percentages, means and chi-square tests. RESULTS: A total of 150 midwives and 56 health facilities were included in the study. The performance assessment showed 16.5% of midwives were incompetent, 72.4% were competent, and 11.1% were outstanding in providing routine intrapartum care. Forty five midwives were observed while managing 54 obstetric and newborn complications and 41 (91%) of them were rated competent. Inventory of resources found that the proportion of facilities with more than 75% of the items in each category was 32.6% for drugs, 73.1% for equipment, 65.4% for supplies, 47.9% for infection prevention materials, and 43.6% for records and forms. Opportunities for performance improvement were inadequate, with 31.3% reporting emergency obstetric and newborn care training, and 44.7% quarterly or more frequent supportive supervision. Health centers fared worse in provider competence, physical resources, and quality improvement practices except for supportive supervision visits and in-service training. CONCLUSIONS: Although our findings indicate most midwives are competent in giving routine and emergency intrapartum care, the major gaps in the enabling environment and the significant proportion of midwives with unsatisfactory performance suggest that the conditions for providing quality intrapartum care are not optimal. PMID- 28814286 TI - Dietary pattern and other lifestyle factors as potential contributors to hypertension prevalence in Arusha City, Tanzania: a population-based descriptive study. AB - BACKGROUND: High blood pressure is increasing worldwide, disproportionately so in developing countries. Inadequate health care systems and adoption of unhealthy lifestyles have been linked to this emergent pattern. To better understand this trend, it is imperative we measure prevalence of hypertension, and examine specific risk factors, at a local level. This study provides a cross-sectional view of urban residents of Arusha City to determine prevalence and associated risk factors. METHODS: Blood pressure was measured using a digital sphygmomanometer. Interviews were conducted using the WHO STEPwise survey questionnaire to assess lifestyle factors. Dietary intake information was collected by a standardized Food Frequency Questionnaire (FFQ). Descriptive statistics were used to analyze demographic characteristics. Means and standard deviations were calculated for continuous variables and percentages for categorical variables. Pearson's Chi Square (chi 2) tests were used to determine significant risk factors for hypertension, and multivariate log binomial regression was used to reveal potential predictors of hypertension. Dietary patterns were analyzed by principal component analysis. RESULTS: Approximately 45% of the study population was found to be hypertensive. The mean arterial blood pressure (MABP) of the sample was 102.3 mmHg (SD = 18.3). Mean systolic and diastolic blood pressure were 136.3 (SD = 30.5) and 85.3 (SD = 16.1) mmHg, respectively. Through multivariate analysis, age and body mass index were found to be independently, positively, associated with hypertension. Adherence to 'healthy' dietary pattern was negatively independently associated with hypertension. CONCLUSIONS: With nearly half of participants being hypertensive, this study suggests that hypertension is a significant health risk in Arusha, Tanzania. Obesity, healthy diet, and age were found to be positively associated with hypertension risk. This study did not establish any significant association between increased blood pressure and Western-dietary pattern, cigarette smoking, alcohol intake, and physical activities. PMID- 28814287 TI - Early onset coats' disease initially treated as unilateral ROP at 39 weeks postmenstrual age: a case report. AB - BACKGROUND: This is the youngest case of Coats' disease, in terms of postmenstrual age (PMA), to be reported in the literature. This case highlights the remarkable variations in the clinical manifestations and the very early onset of Coats' disease. This case is unusual in both the age of onset and atypical clinical features, which resemble retinopathy of prematurity (ROP). CASE PRESENTATION: We report a case of a preterm boy born at 31 5/7 weeks gestational age who presented with atypical Coats' disease and was initially diagnosed as having ROP of only one eye at 39 weeks PMA. After initial laser treatment, severe exudative retinal detachment (ERD) occurred after initial laser treatment for ROP. Fundus fluorescein angiography (FFA) showed telangiectasia and anastomosis of peripheral retinal vessels and nonperfusion areas, and the diagnosis of Coats' disease was thus established. A series of intravitreal injections of ranibizumab (IVR) and laser ablations were performed to resolve the exudation and to ablate the abnormal vessels. At the last visit, the retinopathy was under control, and useful vision was preserved. CONCLUSIONS: Coats' disease resembling stage 3 ROP can be detected before the expected date of childbirth. Therefore, asymmetric ROP should be differentiated from Coats' disease. PMID- 28814289 TI - Cohort study on living arrangements of older men and women and risk for basic activities of daily living disability: findings from the AGES project. AB - BACKGROUND: Living arrangements of older adults have changed worldwide with increasing solitary and non-spouse households, which could affect social care systems. However, the relationship between these households and disability onset has remained unclear. We examined the relationship between living arrangements and the onset of basic activities of daily living disability in older adults, with a focus on gender differences and cohabitation status of those without a spouse. METHODS: Data from 6600 men and 6868 women aged 65 years or older without disability were obtained from the Aichi Gerontological Evaluation Study Project in Japan. Onset of disability was followed for 9.4 years. Disability was assessed based on Long-term Care Insurance System registration. A hierarchical Cox proportional hazards model was conducted to examine the risk of living alone and living only with non-spousal cohabitants compared to those living with spouses. RESULTS: Men living only with non-spousal cohabitants and those living alone were significantly more likely to develop disability after controlling for health and other covariates (hazard ratio = 1.38 and 1.45, respectively), while a significant difference was found only for women living alone (hazard ratio = 1.19). The risk of living with non-spousal cohabitants was marginally stronger in men, indicated by the interaction effect model (p = .08). A series of hierarchical analyses showed that social support exchange explained 24.4% and 15.8% of the excess risk of disability onset in men living alone and those living only with non-spousal cohabitants, respectively. A subsequent analysis also showed that support provision by older adults more greatly explained such excess risk than receiving support from others. CONCLUSIONS: Older men without spouses were more likely to develop disability onset regardless of cohabitants. Health professionals should consider programs that enhance social support exchange, particularly support provision by older adults who are at risk of disability. PMID- 28814288 TI - Monoallelic characteristic-bearing heterozygous L1053X in BRCA2 gene among Sudanese women with breast cancer. AB - BACKGROUND: Breast cancer (BC) is the most common type of cancer in women. Among many risk factors of BC, mutations in BRCA2 gene were found to be the primary cause in 5-10% of cases. The majority of deleterious mutations are frameshift or nonsense mutations. Most of the reported BRCA2 mutations are protein truncating mutations. METHODS: The study aimed to describe the pattern of mutations including single nucleotide polymorphisms (SNPs) and variants of the BRCA2 (exon11) gene among Sudanese women patients diagnosed with BC. In this study a specific region of BRCA2 exon 11 was targeted using PCR and DNA sequencing. RESULTS: Early onset cases 25/45 (55.6%) were premenopausal women with a mean age of 36.6 years. Multiparity was more frequent within the study amounting to 30 cases (66.6%), with a mean parity of 4.1. Ductal type tumor was the predominant type detected in 22 cases (48.8%) among the reported histotypes. A heterozygous monoallelic nonsense mutation at nucleotide 3385 was found in four patients out of 9, where TTA codon was converted into the stop codon TGA. CONCLUSION: This study detected a monoallelic nonsense mutation in four Sudanese female patients diagnosed with early onset BC from different families. Further work is needed to demonstrate its usefulness in screening of BC. PMID- 28814290 TI - Predicted impact of lipid lowering therapy on cardiovascular and economic outcomes of Swedish atherosclerotic cardiovascular disease guideline. AB - BACKGROUND: The effects on cardiovascular disease (CVD) by treatment recommendations on prevention of atherosclerotic CVD remain to be evaluated. The objectives were to assess treatment gap for low density lipoprotein cholesterol (LDL-C) according to guidelines, potential impact on CVD outcomes, and possible avoided economic costs, in post myocardial infarction (MI) patients, if target LDL-C levels of <=1.8 mmol/L would be achieved. METHODS: All patients registered in the Swedish Secondary Prevention after Heart Intensive care Admission register, with one-year post-MI follow-up during 2013 were selected. The REACH risk prediction and a calibrated model for recurrent cardiovascular events and death were used to estimate unadjusted risk prediction based on the REACH equation henceforth called base case, and calibrated CVD outcomes based on gender specific risk factors. The predicted impact of the LDL-C reduction on the risk of CVD was based on the Cholesterol Treatment Trialists' Collaboration findings. RESULTS: A sample of n = 5904 patients (74% men) with a mean age of 64 years were included. Around 70% did not reach LDL-C target <=1.8 mmol/L. Over a 10-year period, 820-2262 events were predicted to occur in those who did not reach target corresponding to 20% - 55% risk of CVD events. To achieve LDL-C target, the mean LDL-C had to be reduced by 0.73 mmol/L (29%). If this LDL-C reduction was achieved, 195-544 life years, 132-343 CVD events, and 7.9-20.9 million Swedish crowns (MSEK) of direct costs, and 19.3-51.0 MSEK of total costs would be avoided. CONCLUSION: Lowering of LDL cholesterol to achieve target levels according to guidelines for post-MI patients may lead to fewer cardiovascular events and avoidance of event costs. PMID- 28814291 TI - Circulating tumor DNA for personalized lung cancer monitoring. AB - Advances in deep sequencing technology have led to developments in personalized medicine. Here, we describe the implications of a recent investigation that sequenced ctDNA from the plasma of non-small cell lung cancer patients to develop personalized ctDNA tests. These 'liquid biopsies' have shown promise in monitoring tumor growth and response to treatment, providing a timely overview of mutations present in the tumor. We discuss the advantages of this budding approach, as well as its challenges and drawbacks, while also providing areas for further investigation and an outlook for the future. PMID- 28814292 TI - The protective effects of Resveratrol against radiation-induced intestinal injury. AB - BACKGROUND: Intestinal injury is a potential cause of death after high-dose radiation exposure. The aim of the present study was to investigate the protective effects of resveratrol against radiation-induced small intestine injury. METHODS: C57BL/6 N mice were irradiated and treated with resveratrol and/or Ex527 (a potent Sirt1 inhibitor), and subsequent examining intestinal morphological changes, and crypt cell apoptosis. Then, the expression and enzyme activity of SOD2 in the small intestine were examined. Furthermore, Sirt1 and acetylated p53 expression was analysed. RESULTS: Compared to the vehicle control, treatment with resveratrol improved intestinal morphology, decreased apoptosis of crypt cells, maintained cell regeneration, and ameliorated SOD2 expression and activity. Resveratrol also regulated Sirt1 and acetylated p53 expression perturbed by irradiation in the small intestine. The protective effect of resveratrol against ionizing radiation induced small intestine injury was significantly inhibited by Ex527. CONCLUSION: Our results suggest that resveratrol decreases the effects of radiation on intestinal injury at least partly via activation of Sirt1. PMID- 28814294 TI - Canine intrathoracic sarcoma with ultrastructural characteristics of human synovial sarcoma - case report. AB - BACKGROUND: Canine joint sarcomas, designated synovial sarcomas, are uncommon malignant mesenchymal neoplasms that occur in the large joints of the extremities of middle-aged, large-breed dogs. We report the diagnosis of an intrathoracic sarcoma with ultrastructural characteristics reminiscent of human synovial sarcoma in a dog. CASE PRESENTATION: A 7-year-old female spayed Tibetan terrier crossbred dog was presented for acute severe labored breathing and diagnosed with an intrathoracic neoplastic mass. The neoplasm resulted in the accumulation of substantial amounts of viscous pleural fluid that led to dyspnea. The neoplastic mass consisted of interweaving bundles of large pleomorphic mesenchymal cells, supported by an alcian blue positive myxomatous matrix. The neoplastic cells were immunohistochemically negative for cytokeratin and CD18. Transmission electron microscopy indicated that the neoplastic cells had desmosome junctions, short microvilli-like structures and ample amounts of rough endoplasmic reticulum resembling type B-like synoviocytes and synovial sarcoma as reported in people. Despite complete surgical excision of the neoplastic mass, clinical signs recurred after a month and led to the euthanasia of the dog. CONCLUSION: Currently, there are no immunohistochemical markers specific for synovial sarcoma. Canine neoplasms with transmission electron microscopy characteristics resembling type B-like synoviocytes should be considered similar to the human sarcomas that carry the specific translocations between chromosomes X and 18. PMID- 28814293 TI - Regulation of human airway smooth muscle cell migration and relevance to asthma. AB - Airway remodelling is an important feature of asthma pathogenesis. A key structural change inherent in airway remodelling is increased airway smooth muscle mass. There is emerging evidence to suggest that the migration of airway smooth muscle cells may contribute to cellular hyperplasia, and thus increased airway smooth muscle mass. The precise source of these cells remains unknown. Increased airway smooth muscle mass may be collectively due to airway infiltration of myofibroblasts, neighbouring airway smooth muscle cells in the bundle, or circulating hemopoietic progenitor cells. However, the relative contribution of each cell type is not well understood. In addition, although many studies have identified pro and anti-migratory agents of airway smooth muscle cells, whether these agents can impact airway remodelling in the context of human asthma, remains to be elucidated. As such, further research is required to determine the exact mechanism behind airway smooth muscle cell migration within the airways, how much this contributes to airway smooth muscle mass in asthma, and whether attenuating this migration may provide a therapeutic avenue for asthma. In this review article, we will discuss the current evidence with respect to the regulation of airway smooth muscle cell migration in asthma. PMID- 28814296 TI - Quality assurance and best research practices for non-regulated veterinary clinical studies. AB - Veterinary clinical trials generate data that advance the transfer of knowledge from clinical research to clinical practice in human and veterinary settings. The translational success of non-regulated and regulated veterinary clinical studies is dependent upon the reliability and reproducibility of the data generated. Clinician-scientists that conduct veterinary clinical studies would benefit from a commitment to research quality assurance and best practices throughout all non regulated and regulated research environments. Good Clinical Practice (GCP) guidance documents from the FDA provides principles and procedures designed to safeguard data integrity, reliability and reproducibility. While these documents maybe excessive for clinical studies not intended for regulatory oversight it is important to remember that research builds on research. Thus, the quality and accuracy of all data and inference generated throughout the research enterprise remains vulnerable to the impact of potentially unreliable data generated by the lowest performing contributors. The purpose of this first of a series of statement papers is to outline and reference specific quality control and quality assurance procedures that should, at least in part, be incorporated into all veterinary clinical studies. PMID- 28814295 TI - The effect of facility-based antiretroviral therapy programs on outpatient services in Kenya and Uganda. AB - BACKGROUND: Considerable debate exists concerning the effects of antiretroviral therapy (ART) service scale-up on non-HIV services and overall health system performance in sub-Saharan Africa. In this study, we examined whether ART services affected trends in non-ART outpatient department (OPD) visits in Kenya and Uganda. METHODS: Using a nationally representative sample of health facilities in Kenya and Uganda, we estimated the effect of ART programs on OPD visits from 2007 to 2012. We modeled the annual percent change in non-ART OPD visits using hierarchical mixed-effects linear regressions, controlling for a range of facility characteristics. We used four different constructs of ART services to capture the different ways in which the presence, growth, overall, and relative size of ART programs may affect non-ART OPD services. RESULTS: Our final sample included 321 health facilities (140 in Kenya and 181 in Uganda). On average, OPD and ART visits increased steadily in Kenya and Uganda between 2007 and 2012. For facilities where ART services were not offered, the average annual increase in OPD visits was 4.2% in Kenya and 13.5% in Uganda. Among facilities that provided ART services, we found average annual OPD volume increases of 7.2% in Kenya and 5.6% in Uganda, with simultaneous annual increases of 13.7% and 12.5% in ART volumes. We did not find a statistically significant relationship between annual changes in OPD services and the presence, growth, overall, or relative size of ART services. However, in a subgroup analysis, we found that Ugandan hospitals that offered ART services had statistically significantly less growth in OPD visits than Ugandan hospitals that did not provide ART services. CONCLUSIONS: Our findings suggest that ART services in Kenya and Uganda did not have a statistically significant deleterious effects on OPD services between 2007 and 2012, although subgroup analyses indicate variation by facility type. Our findings are encouraging, particularly given recent recommendations for universal access to ART, demonstrating that expanding ART services is not inherently linked to declines in other health services in sub-Saharan Africa. PMID- 28814297 TI - Genotyping and comparative pathology of Spirocerca in black-backed jackals (Canis mesomelas) in South Africa. AB - BACKGROUND: The pathology of spirocercosis, a disease caused by the infestation of carnivores with the nematode Spirocerca lupi, has been extensively described in domestic dogs and coyotes. However, it has not been described in wild carnivores in South Africa. The aim of this study was to evaluate whether black backed jackals are a host for Spirocerca species and to provide a detailed description of the associated pathology. Jackals were also stratified according to age and the Spirocerca species recovered were characterized using molecular techniques. METHODS: Standard necropsies were performed on routinely culled jackals from three of the nine provinces of South Africa during the period June 2012 to February 2013. Jackals were screened for the presence of pathognomonic Spirocerca-induced lesions and for evidence of aberrant migration. Relevant samples were submitted for histopathology and collected larvae were genotyped at nine microsatellite loci. RESULTS: Spirocerca lupi-associated aortic lesions were found in 16 of 93 (17%) black-backed jackals. Of these, four (25%) were associated with S. lupi larvae. Genotyping of the larvae revealed amplification of all nine loci that amplified dog-derived S. lupi, with the same level of polymorphism in the allele size ranges. Only 1 of 93 jackals had an esophageal nodule with concurrent S. lupi-induced aortic aneurysms. The single esophageal nodule found did not contain adult nematodes, nor did it communicate with the esophageal lumen. None of the jackals that were examined had macroscopically evident spondylitis, which is frequently reported in the dog. Histopathology of the S. lupi-induced aortic lesions in the jackal revealed replacement of elastic and smooth muscle fibers by fibrous connective tissue. In cases where inflammation was present, the inflammatory infiltrate consisted predominantly of eosinophils. The single esophageal nodule histologically resembled the early inflammatory nodule described in dogs and consisted of fibrous connective tissue, multifocal accumulation of lymphocytes, plasma cells and rare hemosiderin-laden macrophages. CONCLUSIONS: These lesions suggest that the life cycle of S. lupi may not or only rarely be completed in jackals. A possible explanation might be that jackals are relatively resistant to developing significant pathology associated with S. lupi-infection. However, before any conclusions can be drawn, many more jackals, including those that die naturally will have to be investigated for evidence of S. lupi infection. PMID- 28814298 TI - Erratum to: A framework to assess patient-reported adverse outcomes arising during hospitalization. PMID- 28814299 TI - Biological function in the twilight zone of sequence conservation. AB - Strong DNA conservation among divergent species is an indicator of enduring functionality. With weaker sequence conservation we enter a vast 'twilight zone' in which sequence subject to transient or lower constraint cannot be distinguished easily from neutrally evolving, non-functional sequence. Twilight zone functional sequence is illuminated instead by principles of selective constraint and positive selection using genomic data acquired from within a species' population. Application of these principles reveals that despite being biochemically active, most twilight zone sequence is not functional. PMID- 28814300 TI - Increasing on-target cleavage efficiency for CRISPR/Cas9-induced large fragment deletion in Myxococcus xanthus. AB - BACKGROUND: The CRISPR/Cas9 system is a powerful tool for genome editing, in which the sgRNA binds and guides the Cas9 protein for the sequence-specific cleavage. The protocol is employable in different organisms, but is often limited by cell damage due to the endonuclease activity of the introduced Cas9 and the potential off-target DNA cleavage from incorrect guide by the 20 nt spacer. RESULTS: In this study, after resolving some critical limits, we have established an efficient CRISPR/Cas9 system for the deletion of large genome fragments related to the biosynthesis of secondary metabolites in Myxococcus xanthus cells. We revealed that the high expression of a codon-optimized cas9 gene in M. xanthus was cytotoxic, and developed a temporally high expression strategy to reduce the cell damage from high expressions of Cas9. We optimized the deletion protocol by using the tRNA-sgRNA-tRNA chimeric structure to ensure correct sgRNA sequence. We found that, in addition to the position-dependent nucleotide preference, the free energy of a 20 nt spacer was a key factor for the deletion efficiency. CONCLUSIONS: By using the developed protocol, we achieved the CRISPR/Cas9-induced deletion of large biosynthetic gene clusters for secondary metabolites in M. xanthus DK1622 and its epothilone-producing mutant. The findings and the proposals described in this paper were suggested to be workable in other organisms, for example, other Gram negative bacteria with high GC content. PMID- 28814301 TI - Incidence of cancer among licenced commercial pilots flying North Atlantic routes. AB - BACKGROUND: To evaluate cancer incidence among licenced commercial pilots in association with cosmic radiation. METHODS: Cohort study where ionizing radiation dose of cosmic radiation was estimated from airline data and software program and cancer incidence was obtained by record linkage with nation-wide cancer registry. All licenced commercial male airline pilots were followed from 1955 to 2015, ever or never employed at airline with international routes. Standardized incidence ratios were calculated and relative risk by Poisson regression, to examine exposure-response relation. RESULTS: Eighty three cancers were registered compared with 92 expected; standardized incidence ratios were 0.90 (95% CI 0.71 to 1.11) for all cancers, 3.31 (95% CI 1.33 to 6.81) for malignant melanoma, and 2.49 (95% CI 1.69 to 3.54), for basal cell carcinoma of skin. The risk for all cancers, malignant melanoma, prostate cancer, basal cell carcinoma of skin, and basal cell carcinoma of trunk increased with an increase in number of employment years, cumulative air hours, total cumulative radiation dose, and cumulative radiation dose sustained up to age of 40 years. The relative risk for the highest exposure categories of cumulative radiation dose were 2.42 (95% CI 1.50 to 3.92) for all cancers, 2.57 (95% CI 1.18 to 5.56) for prostate cancer, 9.88 (95% CI 1.57 to 190.78) for malignant melanoma, 3.61 (95% CI 1.64 to 8.48) for all basal cell carcinoma, and 6.65 (95% CI 1.61 to 44.64) for basal cell carcinoma of trunk. CONCLUSIONS: This study was underpowered to study brain cancer and leukaemia risk. Basal cell carcinoma of skin is radiation-related cancer, and may be attributed to cosmic radiation. Further studies are needed to clarify the risk of cancers in association with cosmic radiation, other workplace exposure, host factors, and leisure sun-exposure, as clothes, and glass in cockpit windows shield pilots from the most potent ultraviolet-radiation. PMID- 28814302 TI - OmpA protein sequence-based typing and virulence-associated gene profiles of Pasteurella multocida isolates associated with bovine haemorrhagic septicaemia and porcine pneumonic pasteurellosis in Thailand. AB - BACKGROUND: Pasteurella multocida is a Gram-negative bacterium that causes economically significant infections of a broad range of animal species. Pneumonic and septicaemic pasteurellosis caused by this bacterium remain important problems in pigs, cattle, and water buffaloes in Thailand. The aim of this study was to characterise the virulence-associated gene profiles and to develop an OmpA molecular typing scheme for classifying 191 bovine and porcine isolates of P. multocida collected between 1989 and 2012 in Thailand using polymerase chain reactions (PCRs), nucleotide sequencing, and sequence and structural bioinformatics analyses. RESULTS: PCR screening successfully characterised the profiles of 25 virulence-associated genes in all isolates. The gene profiles separated these isolates into bovine and porcine clusters based on eight genes (hgbB, hsf1, tadD, nanH, pfhA, plpE, pmHAS, and tbpA). Phylogenetic analyses of the nucleotide and protein sequences corresponding to the ompA gene, which encodes a major outer membrane surface protein, showed two major bovine and porcine clusters. Structural prediction and analysis of the dN/dS ratio revealed four hypervariable extracellular loops of the OmpA transmembrane domains. These four loops were used to develop an OmpA typing scheme. This scheme classified 186 isolates into five major loop sequence types (LST8, LST12, LST15, LST18, and LST19), consistent with the phylogenetic results. The loop regions of the bovine isolates were predicted to be more antigenic than those of the porcine isolates. Thus, molecular evolution of the OmpA proteins could be used to classify P. multocida isolates into different capsular types, host types, and, possibly, pathogenicity levels. CONCLUSIONS: Together with the virulence-associated gene profiles, the typing reported in this work provides a better understanding of P. multocida virulence. Effective monitoring and potential strain-specific subunit vaccines could be developed based on these loop oligopeptides. PMID- 28814303 TI - Data collection of patients with diabetes in family medicine: a study in north eastern Italy. AB - BACKGROUND: Studies on data collection and quality of care in Italian family medicine are lacking. The aim of this study was to assess the completeness of data collection of patients with diabetes in a large sample of family physicians in the province of Verona, Veneto region, a benchmark for the Italian National Health System. METHODS: We extracted the data on all the patients with diabetes from the electronic health records of 270 family physicians in 2006 and 2009. We reported the percentage of patients with data recorded for 12 indicators of performance derived from the National Institute for Clinical Excellence diabetes guidelines. Secondarily, we assessed quality of care using the Q-score (the lower the score, the greater the risk of cardiovascular events). RESULTS: Patients with diabetes were 18,507 in 2006 and 20,744 in 2009, and the percentage of patients registered as having diabetes was 4.9% and 5.4% of the total population, respectively (p < 0.001). Data collection improved for all the indicators between 2006 and 2009 but the performance was still low at the end of the study period: patients with no data recorded were 42% in 2006 and 32% in 2009, while patients with data recorded for >=5 indicators were 9% in 2006 and 17% in 2009. The Q score improved (mean +/- SD, 20.7 +/- 3.0 in 2006 vs 21.3 +/- 3.6 in 2009, p < 0.001) but most patients were at increased risk of cardiovascular events in both years (Q-score <= 20). CONCLUSIONS: We documented an improvement in data collection and quality of care for patients with diabetes during the study period. Nonetheless, data collection was still unsatisfactory in comparison with international benchmarks in 2009. Structural interventions in the organization of family medicine, which have not been implemented since the study period, should be prioritised in Italy. PMID- 28814304 TI - The research activities of Ontario's large community acute care hospitals: a scoping review. AB - BACKGROUND: Ontario's large community hospitals (LCHs) provide care to 65% of the province's hospitalized patients, yet we know very little about their research activities. By searching for research publications from 2013 to 2015, we will describe the extent, type and collaborative nature of Ontario's LCHs' research activities. METHODS: We conducted a scoping review by searching PubMed, Embase and the Cumulative Index to Nursing and Allied Health Literature databases from January 1, 2013 until December 31, 2015 for all publication types whose author(s) was affiliated with any of the 44 LCHs. Articles were screened and abstracted by three reviewers, independently. The data were charted and results described using summary statistics, scatter plots, and bar charts. RESULTS: We included 798 publications from 39 LCHs and 454 authors. The median number of publications was 7 (Interquartile range (IQR) 23). Observational study design was most commonly reported in over 50% of publications. Program evaluation was the focus in 40% of publications. Primary LCH authorship was observed for 535 publications. Over 25% and 65% of the publications were attributable to 24 authors and 9 LCHs, respectively. There was minimal collaboration both within (21.2%) and between (7.8%) LCHs. LCH size and geographic proximity to academic hospitals had minimal impact on research activity. CONCLUSIONS: Ontario's LCHs publish infrequently, collaborate infrequently, and their role in translational research activity is not well defined. A future survey questionnaire to LCH researchers identified through this review is planned to both validate and elicit their interpretations of our study findings and opinions about LCH involvement in research. PMID- 28814305 TI - Blood pressure-lowering effect of Shinrin-yoku (Forest bathing): a systematic review and meta-analysis. AB - BACKGROUND: Shinrin-yoku (experiencing the forest atmosphere or forest bathing) has received increasing attention from the perspective of preventive medicine in recent years. Some studies have reported that the forest environment decreases blood pressure. However, little is known about the possibility of anti hypertensive applications of Shinrin-yoku. This study aimed to evaluate preventive or therapeutic effects of the forest environment on blood pressure. METHODS: We systematically reviewed the medical literature and performed a meta analysis.Four electronic databases were systematically searched for the period before May 2016 with language restriction of English and Japanese. The review considered all published, randomized, controlled trials, cohort studies, and comparative studies that evaluated the effects of the forest environment on changes in systolic blood pressure. A subsequent meta-analysis was performed. RESULTS: Twenty trials involving 732 participants were reviewed. Systolic blood pressure of the forest environment was significantly lower than that of the non forest environment. Additionally, diastolic blood pressure of the forest environment was significantly lower than that of the non-forest environment. CONCLUSIONS: This systematic review shows a significant effect of Shinrin-yoku on reduction of blood pressure. PMID- 28814306 TI - Blood acid-base status in impala (Aepyceros melampus) immobilised and maintained under total intravenous anaesthesia using two different drug protocols. AB - BACKGROUND: In mammals, homeostasis and survival are dependent on effective trans membrane movement of ions and enzyme function, which are labile to extreme acid base changes, but operate efficiently within a narrow regulated pH range. Research in patients demonstrating a pH shifts outside the narrow regulated range decreased the cardiac output and systemic vascular resistance and altered the oxygen binding to haemoglobin. These cardiopulmonary observations may be applicable to the risks associated with anaesthesia and performance of wildlife ungulates on game farms. The aim of this study was to compare blood pH changes over time in impala immobilised and anaesthetised with two different drug protocols (P-TMP - immobilisation: thiafentanil-medetomidine; maintenance: propofol-ketamine-medetomidine; P-EME - immobilisation: etorphine-medetomidine; maintenance: etorphine-ketamine-medetomidine). Additionally, we discuss the resultant blood pH using both the Henderson-Hasselbalch and the Stewart approaches. Two data collection time points were defined, Time1 before maintenance of general anaesthesia and Time 2 at end of maintenance of general anaesthesia. We hypothesise that blood pH would not be different between drug protocols and would not change over time. RESULTS: Significant differences were detected over time but not between the two drug protocols. Overall, the blood pH decreased over time from 7.37 +/- 0.04 to 7.31 +/- 0.05 (p = 0.001). Overall, over time arterial partial pressure of carbon dioxide changed from 51.3 +/- 7.5 mmHg to 72.6 +/- 12.4 mmHg (p < 0.001); strong ion difference from 44.6 +/- 2.4 mEq/L to 46.9 +/- 3.1 mEq/L (p < 0.001); anion gap from 15.0 +/- 3.1 mEq/L to 10.9 +/- 2.2 mEq/L (p < 0.001); and total weak acids from 16.1 +/- 1.2 mmol/L to 14.0 +/- 1.1 mmol/L (p < 0.001). The bicarbonate changed from 29.6 +/- 2.7 mEq/L to 36.0 +/- 4.1 mEq/L (p < 0.001); and lactate changed from 2.9 +/- 1.5 mEq/L to 0.3 +/- 0.03 mEq/L (p < 0.001) over time. CONCLUSIONS: The profound increase in the partial pressure of carbon dioxide that worsened during the total intravenous anaesthesia in both protocols initiated a substantial metabolic compensatory response to prevent severe acidaemia. This compensation resulted in a clinically acceptable mild acidaemic state, which worsened over time but not between the protocols, in healthy impala. However, these important compensatory mechanisms require normal physiological function and therefore when immobilising ill or anorexic wild ungulates their acid-base status should be carefully assessed. PMID- 28814307 TI - Which intervention is better for malaria vector control: insecticide mixture long lasting insecticidal nets or standard pyrethroid nets combined with indoor residual spraying? AB - BACKGROUND: Malaria control today is threatened by widespread insecticide resistance in vector populations. The World Health Organization (WHO) recommends the use of a mixture of unrelated insecticides for indoor residual spraying (IRS) and long-lasting insecticidal nets (LNs) or as a combination of interventions for improved vector control and insecticide resistance management. Studies investigating the efficacy of these different strategies are necessary. METHODS: The efficacy of Interceptor(r) G2 LN, a newly developed LN treated with a mixture of chlorfenapyr (a pyrrole) and alpha-cypermethrin (a pyrethroid), was compared to a combined chlorfenapyr IRS and Interceptor(r) LN (a standard alpha cypermethrin LN) intervention in experimental huts in Cove Southern Benin, against wild, free-flying, pyrethroid-resistant Anopheles gambiae s.l. A direct comparison was also made with a pyrethroid-only net (Interceptor(r) LN) alone and chorfenapyr IRS alone. RESULTS: WHO resistance bioassays performed during the trial demonstrated a pyrethroid resistance frequency of >90% in the wild An. gambiae s.l. from the Cove hut site. Mortality in the control (untreated net) hut was 5%. Mortality with Interceptor(r) LN (24%) was lower than with chlorfenapyr IRS alone (59%, P < 0.001). The combined Interceptor(r) LN and chlorfenapyr IRS intervention and the mixture net (Interceptor(r) G2 LN) provided significantly higher mortality rates (73 and 76%, respectively) and these did not differ significantly between both treatments (P = 0.15). Interceptor LN induced 46% blood-feeding inhibition compared to the control untreated net, while chlorfenapyr IRS alone provided none. Both mixture/combination strategies also induced substantial levels of blood-feeding inhibition (38% with combined interventions and 30% with Interceptor(r) G2 LN). A similar trend of improved mortality of pyrethroid-resistant An. gambiae s.l. from Cove was observed with Interceptor(r) G2 LN (79%) compared to Interceptor LN (42%, P < 0.001) in WHO tunnel tests. CONCLUSION: The use of chlorfenapyr and alpha-cypermethrin together as a mixture on nets (Interceptor(r) G2 LN) or a combined chlorfenapyr IRS and pyrethroid LN intervention provides improved control of pyrethroid-resistant malaria vectors by inducing significantly higher levels of mortality through the chlorfenapyr component and providing personal protection through the pyrethroid component. Both strategies are comparable in their potential to improve the control of malaria transmitted by pyrethroid resistant mosquito vectors. PMID- 28814308 TI - Are we anywhere near there yet? The state of harm reduction in North America in 2017. PMID- 28814309 TI - Performance, biochemical and haematological responses, and relative organ weights of laying hens fed diets supplemented with prebiotic, probiotic and synbiotic. AB - BACKGROUND: The increasing trend of ban on the use of antibiotic growth promoters (AGPs) across the globe in the poultry industry has led to a growing need for alternatives to AGPs. Prebiotic, probiotic and their combination as a synbiotic have been considered as potential alternatives. This study aimed to investigate the effects of a prebiotic (isomaltooligosaccharide, IMO), a probiotic (PrimaLac(r)), and their combination (synbiotic) on hen performance, biochemical and haematological responses, and relative organ weights from 20 to 52 weeks of age. RESULTS: Supplementation of 1% IMO (PRE), 0.1% PrimaLac(r) (PRO) and 1% IMO + 0.1% PrimaLac(r) (SYN) improved (P < 0.05) feed intake and egg production at 20 36 weeks of age; body weight gain, feed conversion ratio and egg mass at 20-36 and 20-52 weeks of age; and egg weight at 20-36, 37-52 and 20-52 weeks of age. Compared to control-fed hens at 20-36 weeks of age, PRO- and SYN-fed hens produced less (P < 0.05) small size eggs while SYN-fed hens produced more large size eggs. From 37 to 52 weeks of age, PRE-, PRO- or SYN-fed hens produced less (P < 0.05) medium size eggs, and more large and extra-large size eggs. PRE, PRO or SYN supplementation decreased (P < 0.05) the serum total cholesterol at 36 weeks of age, and serum low-density lipoprotein (LDL) cholesterol, alanine aminotransferase (ALT) and alkaline phosphatase (ALP) at 36 and 52 weeks of age. At 36 and 52 weeks of age, supplementation of PRE, PRO or SYN increased (P < 0.05) lymphocyte percentage and decreased (P < 0.05) heterophil percentage, leading to a lower heterophil to lymphocyte (H/L) ratio. No significant differences were observed in the relative weights of the heart, liver, ovary, pancreas and spleen of all dietary treatment groups. CONCLUSIONS: Supplementation of PRE, PRO or SYN improved performance, serum total cholesterol, LDL cholesterol, ALT, ALP and H/L ratio of hens from 20 to 52 weeks of age. These results demonstrated the use of PRE, PRO and SYN as alternative feed additives to AGPs for improving the health and productivity of hens, while PRO is the best for commercial layer production to yield maximum profit. PMID- 28814310 TI - Modelling the benefits of long-acting or transmission-blocking drugs for reducing Plasmodium falciparum transmission by case management or by mass treatment. AB - BACKGROUND: Anti-malarial drugs are an important tool for malaria control and elimination. Alongside their direct benefit in the treatment of disease, drug use has a community-level effect, clearing the reservoir of infection and reducing onward transmission of the parasite. Different compounds potentially have different impacts on transmission-with some providing periods of prolonged chemoprophylaxis whilst others have greater transmission-blocking potential. The aim was to quantify the relative benefit of such properties for transmission reduction to inform target product profiles in the drug development process and choice of first-line anti-malarial treatment in different endemic settings. METHODS: A mathematical model of Plasmodium falciparum epidemiology was used to estimate the transmission reduction that can be achieved by using drugs of varying chemoprophylactic (protection for 3, 30 or 60 days) or transmission blocking activity (blocking 79, 92 or 100% of total onward transmission). Simulations were conducted at low, medium or high transmission intensity (slide prevalence in 2-10 year olds being 1, 10 or 40%, respectively), with drugs administered either via case management or mass drug administration (MDA). RESULTS: Transmission reductions depend strongly on deployment strategy, treatment coverage and endemicity level. Transmission-blocking was most effective at low endemicity, whereas chemoprophylaxis was most useful at high endemicity levels. Increasing the duration of protection as much as possible was beneficial. Increasing transmission-blocking activity from the level of ACT to a 100% transmission-blocking drug (close to the effect estimated for ACT combined with primaquine) produced moderate impact but was not as effective as increasing the duration of protection in medium-to-high transmission settings (slide prevalence 10-40%). Combining both good transmission-blocking activity (e.g. as achieved by ACT or ACT + primaquine) and a long duration of protection (30 days or more, such as provided by piperaquine or mefloquine) within a drug regimen can substantially increase impact compared with drug regimens with only one of these properties in medium to high transmission areas (slide-prevalence in 2-10 year olds ~10 to 40%). These results applied whether the anti-malarials were used for case management or for MDA. DISCUSSION: These results emphasise the importance of increasing access to treatment for routine case management, and the potential value of choosing first-line anti-malarial treatment policies according to local malaria epidemiology to maximise impact on transmission. There is no indication that the optimal drug choice should differ between delivery via case management or MDA. PMID- 28814311 TI - Social inequalities in the utilization of outpatient psychotherapy: analyses of registry data from German statutory health insurance. AB - BACKGROUND: Most studies on health disparities deal with the occurrence of disease, but little is known about inequalities in the utilization of mental health services. This paper examines social inequalities in the utilization of outpatient psychotherapy within a health care system where there are low financial barriers to health care and a lack of specific health policies to address access to psychotherapeutic services. METHODS: Registry data of German statutory health insurance for the year 2013 were used (total population: N = 746,963; 10,711 women and men with psychotherapy). Logistic regression analyses were performed to estimate the effects of three socio-economic (SES) indicators on the utilization of psychotherapy. RESULTS: Utilization of psychotherapy by SES status did not correspond to the social structure of the insured population. Social disparities that disadvantaged less privileged women and men were found; this applied to education, income and occupational position. The most pronounced differences were found for education. In contrast, effects of income were rather small. These findings must be interpreted against the backdrop of the absence of financial barriers to outpatient psychotherapy in Germany. CONCLUSIONS: A marked degree of psychotherapy under-utilization was found for lower SES groups. Psychotherapists should pay increased attention to clients with lower socio economic position. Enhancing mental health literacy, as well as reducing the stigma of mental illness, is crucial for increasing the usage of psychotherapeutic services of those who need it most. Relevant health policy is needed to reduce the barriers to, and consequently increase psychotherapy utilization. PMID- 28814312 TI - Rationale and Design of the Brigham Cohort for psoriasis and psoriatic arthritis registry (COPPAR). AB - BACKGROUND: Psoriasis (PsO) and psoriatic arthritis (PsA) are related conditions with poorly defined transition among them, risk factors for progression, complex treatment algorithms, and biomarkers for treatment response and long-term outcomes. We describe the development of a PsO/PsA registry at an academic medical center. METHODS: We developed a single-center PsO/PsA longitudinal disease registry including biorepository that captures relevant disease markers and treatment choices in a circumscribed population with a defined catchment area. We searched the electronic medical record for patients with visits in the last year for PsO or PsA. They formed the potentially eligible registry population. Baseline patient and provider questionnaires were developed using standardized measures, including demographics, comorbidities, medications, specific disease characteristics, functional status, quality of life, mental health, and resource use. An abbreviated set of items was collected every six month and at visits with treatment changes or disease flares. Biospecimens included blood (serum, plasma, DNA, RNA) and skin biopsy samples, with repeat collections of serum and plasma. Data from the EMR to augment the registry questionnaires are available on all patients. DISCUSSION: Searching the Brigham EMR system from 2013 through 2014, we found 1694 patients with PsO and 1028 with PsA. Their mean age was 55 years and 53% were female. Of these 17% had diabetes, 38% hyperlipidemia, and 45% hypertension. The median BMI was 29.6. PsA patients used more systemic prednisone, MTX, and TNF alpha inhibitors (47%, 60%, and 66%) compared to PsO patients (28%, 20% and 21%). We have collected plasma in 410 patients, DNA/RNA in 453 patients. In conclusion, we have developed a PsO/PsA registry to better define longitudinal disease characteristics, perform biomarker studies, and examine treatment trends. PMID- 28814314 TI - Erratum to: The advantages of SMRT sequencing. PMID- 28814313 TI - A mixed methods study of HIV-related services in buprenorphine treatment. AB - BACKGROUND: Opioid use disorder (OUD) is a major risk factor in the acquisition and transmission of HIV. Clinical practice guidelines call for the integration of HIV services in OUD treatment. This mixed methods study describes the integration of HIV services in buprenorphine treatment and examines whether HIV services vary by prescribers' medical specialty and across practice settings. METHODS: Data were obtained via qualitative interviews with buprenorphine experts (n = 21) and mailed surveys from US buprenorphine prescribers (n = 1174). Survey measures asked about screening for HIV risk behaviors at intake, offering HIV education, recommending all new patients receive HIV testing, and availability of on-site HIV testing. Prescribers' medical specialty, practice settings, caseload demographics, and physician demographics were measured. Multivariate models of HIV services were estimated, while accounting for the nesting of physicians within states. RESULTS: Qualitative interviews revealed that physicians often use injection behaviors as the primary indicator for whether a patient should be tested for HIV. Interviews revealed that HIV-related services were often viewed as beyond the scope of practice among general psychiatrists. Surveys indicated that prescribers screened for an average of 3.2 of 5 HIV risk behaviors (SD = 1.6) at intake. About 62.0% of prescribers delivered HIV education to patients and 53.2% recommended HIV testing to all new patients, but only 32.3% offered on site HIV testing. Addiction specialists and psychiatrists screened for significantly more HIV risk behaviors than physicians in other specialties. Addiction specialists and psychiatrists were significantly less likely than other physicians to offer on-site testing. Physicians in individual medical practice were significantly less likely to recommend HIV testing and to offer onsite testing than physicians in other settings. CONCLUSIONS: Buprenorphine treatment providers have not uniformly integrated HIV-related screening, education, and testing services for patients. Differences by medical specialty and practice setting suggest an opportunity for targeting efforts to increase implementation. PMID- 28814315 TI - Incidental detection of two adult gravid filarial worms in breast: a case report. AB - BACKGROUND: Microfilaria is a major public health problem in tropical and subtropical countries and is an endemic problem in India. Wuchereria bancrofti is the commonest filarial infection. In some lesions, microfilariae and adult filarial worm have been incidentally detected in fine-needle aspirates. CASE PRESENTATION: A 35 year old hindu female presented with lump in upper outer quadrant of left breast. Fine needle aspiration revealed two adult gravid female filarial worms. CONCLUSION: To our knowledge this is the first ever case report to demonstrate two live gravid female and embryoid forms in wet mount preparation. PMID- 28814316 TI - Evaluation of sarolaner and spinosad oral treatments to eliminate fleas, reduce dermatologic lesions and minimize pruritus in naturally infested dogs in west Central Florida, USA. AB - BACKGROUND: An in-home investigation of naturally flea infested dogs was conducted in West Central Florida, USA to evaluate and compare the effectiveness of two different oral flea adulticides to control flea infestations, minimize dermatologic lesions and reduce pruritus over an 8-week period. METHODS: Twenty nine dogs living in 19 homes and another 26 dogs residing in 16 different homes were orally administered either a sarolaner or spinosad chewable, respectively on day 0 and once between days 28-30. Products were administered by study personnel according to label directions. Flea populations on dogs were estimated using visual area counts and flea infestations in the indoor premises were assessed using intermittent-light flea traps on days 0, 7, 14, 21 and once between days 28 30, 40-45, and 56-60. Assessments of dermatologic lesions were conducted monthly during the study and severity of pruritus was evaluated throughout the study on the same schedule as flea counts were conducted. Concurrent treatments for existing skin disease were not allowed. RESULTS: The administration of sarolaner or spinosad reduced flea populations on dogs by 99.0% and 97.3%, respectively within 7 days. Flea infestations on the sarolaner- and spinosad-treated dogs were reduced by > 99% at every counting period from day 14 post-treatment through the end of the 8-week study. At the end of the study 96.4 and 92.0% of the dogs treated with sarolaner and spinosad, respectively were flea-free. Flea populations in the indoor premises were also markedly reduced the end of the study, with 100 and 99.8% reductions in flea trap counts in the sarolaner and spinosad treatment groups, respectively. FAD lesion scores, atopic dermatitis lesions scores (CADESI-4) and pruritus severity scores were also markedly improved with both formulations. CONCLUSIONS: An in-home clinical field study conducted during the summer of 2016 in subtropical Florida demonstrated that two monthly administrations of either sarolaner or spinosad chewables almost completely eliminated flea infestations on dogs and in private residences, while markedly reducing dermatology lesions and pruritus. PMID- 28814317 TI - Collaborative care for panic disorder, generalised anxiety disorder and social phobia in general practice: study protocol for three cluster-randomised, superiority trials. AB - BACKGROUND: People with anxiety disorders represent a significant part of a general practitioner's patient population. However, there are organisational obstacles for optimal treatment, such as a lack of coordination of illness management and limited access to evidence-based treatment such as cognitive behavioral therapy. A limited number of studies suggest that collaborative care has a positive effect on symptoms for people with anxiety disorders. However, most studies are carried out in the USA and none have reported results for social phobia or generalised anxiety disorder separately. Thus, there is a need for studies carried out in different settings for specific anxiety populations. A Danish model for collaborative care (the Collabri model) has been developed for people diagnosed with depression or anxiety disorders. The model is evaluated through four trials, of which three will be outlined in this protocol and focus on panic disorder, generalised anxiety disorder and social phobia. The aim is to investigate whether treatment according to the Collabri model has a better effect than usual treatment on symptoms when provided to people with anxiety disorders. METHODS: Three cluster-randomised, clinical superiority trials are set up to investigate treatment according to the Collabri model for collaborative care compared to treatment-as-usual for 364 patients diagnosed with panic disorder, generalised anxiety disorder and social phobia, respectively (total n = 1092). Patients are recruited from general practices located in the Capital Region of Denmark. For all trials, the primary outcome is anxiety symptoms (Beck Anxiety Inventory (BAI)) 6 months after baseline. Secondary outcomes include BAI after 15 months, depression symptoms (Beck Depression Inventory) after 6 months, level of psychosocial functioning (Global Assessment of Functioning) and general psychological symptoms (Symptom Checklist-90-R) after 6 and 15 months. DISCUSSION: Results will add to the limited pool of information about collaborative care for patients with anxiety disorders. To our knowledge, these will be the first carried out in a Danish context and the first to report results for generalised anxiety and social phobia separately. If the trials show positive results, they could contribute to the improvement of future treatment of anxiety disorders. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02678624 . Retrospectively registered 7 February 2016; last updated 15 August 2016. PMID- 28814318 TI - Annexin A2 could enhance multidrug resistance by regulating NF-kappaB signaling pathway in pediatric neuroblastoma. AB - BACKGROUND: Chemotherapy is one of major therapeutic regimens for neuroblastoma (NB) in children. However, recurrence and metastasis associated with poor prognosis caused by acquired multidrug resistance remains a challenge. There is a great need to achieve new insight into the molecular mechanism of drug resistance in NB. The aim of this study is to identify novel drug sensitivity-related biomarkers as well as new therapeutic targets to overcome chemoresistance. METHODS: We proteome-wide quantitatively compared protein expression of two NB cell lines with different drug sensitivities, isolated from the same patient prior to and following chemotherapy. Annexin A2 (ANXA2) emerged as a key factor contributing to drug resistance in NB. Then, we assessed the correlation of ANXA2 expression and clinical characteristics using a tissue microarray. Further, the roles of ANXA2 in chemoresistance for NB and the underlying mechanisms were studied by using short hairpin RNA (shRNA) in vitro and vivo. RESULTS: First in total, over 6000 proteins were identified, and there were about 460 significantly regulated proteins which were up- or down-regulated by greater than two folds. We screened out ANXA2 which was upregulated by more than 12-fold in the chemoresistant NB cell line, and it might be involved in the drug resistance of NB. Then, using a tissue chip containing 42 clinical NB samples, we found that strong expression of ANXA2 was closely associated with advanced stage, greater number of chemotherapy cycles, tumor metastasis and poor prognosis. Following knockdown of ANXA2 in NB cell line SK-N-BE(2) using shRNA, we demonstrate enhanced drug sensitivity for doxorubicin (2.77-fold) and etoposide (7.87-fold) compared with control. Pro-apoptotic genes such as AIF and cleaved-PARP were upregulated. Inhibiting ANXA2 expression attenuated transcriptional activity of NF-kappaB via down-regulated nuclear translocation of subunit p50. Finally, simulated chemotherapy in a xenograft NB nude mouse model suggests that ANXA2 knockdown could improve clinical results in vivo. CONCLUSION: Our profiling data provided a rich source for further study of the molecular mechanisms of acquired drug resistance in NB. Further study may determine the role of ANXA2 as a prognostic biomarker and a potential therapeutic target for patients with multidrug-resistant NB. PMID- 28814319 TI - Constipation in adults with neurofibromatosis type 1. AB - BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal-dominant disease characterised by symptoms of the skin, eyes, nervous system and bones. A previous study indicated that constipation, large rectal diameters and prolonged colorectal transit times are common in children with NF1. The aim of the present study was to investigate and compare the prevalence of gastrointestinal symptoms in adult patients with NF1 to their unaffected relatives serving as the control group. Patients with NF1 were recruited from one of two Danish National Centres of Expertise for NF1 and their unaffected relatives were invited to participate as controls. Gastrointestinal symptoms were assessed with a web-based, self administered, validated, Rome(r) III diagnostic questionnaire. Logistic regression was used to estimate the prevalence of functional dyspepsia, IBS and functional constipation in each group and the groups were compared using their odds ratios. RESULTS: The response rates for patients and controls were 66.4% and 82.4%, respectively. We compared 175 patients, median age 34.2 (IQR = 20.1) and 91 of their unaffected relatives, median age 42.0 (IQR = 12). The overall likelihood of fulfilling the diagnostic criteria for functional constipation, irritable bowel syndrome or functional dyspepsia was 33.1% among patients vs. 14.3% among controls, (odds ratio (OR): 2.97; 95% CI: 1.56-5.66) and after adjustment for age and gender (OR: 3.06; 95% CI: 1.62-5.79). The likelihood of functional constipation was higher among patients (OR: 3.80; 95% CI: 1.27-11.31), and this was still true after adjustment (OR: 3.49; 95% CI: 1.14-10.64). The likelihood of irritable bowel syndrome (OR: 2.29; 95% CI: 0.98-5.33) was evident after adjustment (OR: 2.46; 95% CI: 1.10-5.47), whereas there was no difference in the likelihood of functional dyspepsia (OR: 2.35; 95% CI: 0.67-8.32) after adjustment (OR:2.25; 95% CI: 0.70-7.17). CONCLUSIONS: Overall, having symptoms usually attributed to either functional dyspepsia, IBS or functional constipation is more common in adults with NF1 compared to unaffected relatives. Of the three, the likelihood of constipation is markedly higher. The high prevalence of constipation indicates that it is not functional but part of the NF1 disorder. PMID- 28814320 TI - Intrathecal morphine versus femoral nerve block for pain control after total knee arthroplasty: a meta-analysis. AB - BACKGROUND: This meta-analysis aims to illustrate the efficacy and safety of intrathecal morphine (ITM) versus femoral nerve block (FNB) for pain control after total knee arthroplasty (TKA). METHODS: In April 2017, a systematic computer-based search was conducted in PubMed, EMBASE, Web of Science, Cochrane Database of Systematic Reviews, Cami Info. Inc., Casalini databases, EBSCO databases, Verlag database and Google database. Data on patients prepared for TKA surgery in studies that compared ITM versus FNB for pain control after TKA were collected. The main outcomes were the visual analogue scale (VAS) at 6, 12, 24, 48 and 72 and total morphine consumption at 12, 24 and 48 h. The secondary outcomes were complications that included postoperative nausea and vomiting (PONV) and itching. Stata 12.0 was used for pooling the data. RESULTS: Five clinical studies with a total of 225 patients (ITM group = 114, FNB group = 111) were ultimately included in the meta-analysis. The results revealed that the ITM group was associated with a reduction of VAS at 6, 12, 24, 48 and 72 h and total morphine consumption at 12, 24 and 48 h. There was no significant difference between the occurrences of PONV. However, the ITM group was associated with an increased occurrence of itching after TKA. CONCLUSIONS: Some immediate analgesic efficacy and opioid-sparing effects were obtained with the administration of ITM when compared with FNB. The complications of itching in the ITM group were greater than in the FNB group. The sample size and the quality of the included studies were limited. A multi-centre RCT is needed to identify the optimal method for reaching maximum pain control after TKA. PMID- 28814321 TI - Relatives' perceived quality of palliative care: comparisons between care settings in which patients die. AB - BACKGROUND: Dying in the preferred setting is an indicator of good palliative care quality. Most people prefer to die at home. But does the quality of care as perceived by their relatives vary depending on the care setting that is the place of death? The aim is to compare (from the relatives perspective) whether there are perceived differences in the quality of palliative care between the settings in which people die. METHODS: Multivariate linear regression analyses have been carried out using an existing dataset containing information collected using the relatives' version of the Consumer Quality Index (CQ-index) Palliative Care. The dataset includes 1368 relatives of patients with a wide variety of conditions who died in various locations: at home, in hospital, in residential care for the elderly, a hospice, palliative care unit or in another institution (e.g. institutions for people with intellectual disabilities or mental healthcare institutions). The relatives were the first contacts (family members or other people close to the patient) and they received the survey between 6 weeks and 6 months after the bereavement. RESULTS: Based on the raw data, differences between locations in terms of the perceived quality of care initially appeared inconsistent. The multivariate regression analyses however showed that relatives of people who died at home were generally the most positive about the palliative care that the patient and they themselves received when the patient was dying. The care provided by hospices also received a relatively good rating. In hospitals and in residential settings for care of the elderly, the care was rated less highly by the relatives. CONCLUSIONS: The quality of palliative care as experienced from the relatives' perspective is highest when the patient dies at home or in a hospice. This is an argument for letting people die at home, if they so wish, as far as possible and feasible. PMID- 28814322 TI - Critical appraisal of arguments for the delayed-start design proposed as alternative to the parallel-group randomized clinical trial design in the field of rare disease. AB - BACKGROUND: A number of papers have proposed or evaluated the delayed-start design as an alternative to the standard two-arm parallel group randomized clinical trial (RCT) design in the field of rare disease. However the discussion is felt to lack a sufficient degree of consideration devoted to the true virtues of the delayed start design and the implications either in terms of required sample-size, overall information, or interpretation of the estimate in the context of small populations. OBJECTIVES: To evaluate whether there are real advantages of the delayed-start design particularly in terms of overall efficacy and sample size requirements as a proposed alternative to the standard parallel group RCT in the field of rare disease. METHODS: We used a real-life example to compare the delayed-start design with the standard RCT in terms of sample size requirements. Then, based on three scenarios regarding the development of the treatment effect over time, the advantages, limitations and potential costs of the delayed-start design are discussed. RESULTS: We clarify that delayed-start design is not suitable for drugs that establish an immediate treatment effect, but for drugs with effects developing over time, instead. In addition, the sample size will always increase as an implication for a reduced time on placebo resulting in a decreased treatment effect. CONCLUSIONS: A number of papers have repeated well-known arguments to justify the delayed-start design as appropriate alternative to the standard parallel group RCT in the field of rare disease and do not discuss the specific needs of research methodology in this field. The main point is that a limited time on placebo will result in an underestimated treatment effect and, in consequence, in larger sample size requirements compared to those expected under a standard parallel-group design. This also impacts on benefit-risk assessment. PMID- 28814323 TI - Efficacy of sarolaner (SimparicTM) against induced infestations of Amblyomma cajennense on dogs. AB - BACKGROUND: Amblyomma cajennense is the main vector of Rickettsia rickettsii which causes Brazilian spotted fever. This adult tick preferably infests horses and capybaras, but has low host specificity during its immature stages, thus posing a threat to humans and dogs. In this study, the efficacy of sarolaner (SimparicTM/Simparica(r), Zoetis) when administered once orally to dogs at 2 mg/kg was evaluated against induced infestations of A. cajennense nymphs for up to 35 days after treatment. METHODS: Based on pretreatment tick counts, 20 dogs were randomly allocated to treatment with sarolaner (SimparicTM) dosed at 2 mg/kg of body weight or a placebo on Day 0 of the study. Artificial infestations were performed using laboratory raised A. cajennense nymphs on study days -2, 5, 12, 19, 26 and 33. Efficacy was determined at 48 h post-treatment or post-infestation at each time point relative to the counts for dogs that received placebo. RESULTS: There were no adverse reactions to treatment. A single dose of sarolaner (SimparicTM) provided 100% efficacy on study days 2, 7 and 14; and >= 99.6% on days 21, 28 and 35. Geometric mean live tick counts for sarolaner were significantly lower than those for placebo on all days (P < 0.0001). CONCLUSIONS: Under the conditions of the present study, sarolaner (SimparicTM) administered once orally at 2 mg/kg provided 100% efficacy against existing infestations and >= 99.6% efficacy within 48 h against weekly challenges of A. cajennense for at least 35 days after treatment. PMID- 28814324 TI - Cancerouspdomains: comprehensive analysis of cancer type-specific recurrent somatic mutations in proteins and domains. AB - BACKGROUND: Discriminating driver mutations from the ones that play no role in cancer is a severe bottleneck in elucidating molecular mechanisms underlying cancer development. Since protein domains are representatives of functional regions within proteins, mutations on them may disturb the protein functionality. Therefore, studying mutations at domain level may point researchers to more accurate assessment of the functional impact of the mutations. RESULTS: This article presents a comprehensive study to map mutations from 29 cancer types to both sequence- and structure-based domains. Statistical analysis was performed to identify candidate domains in which mutations occur with high statistical significance. For each cancer type, the corresponding type-specific domains were distinguished among all candidate domains. Subsequently, cancer type-specific domains facilitated the identification of specific proteins for each cancer type. Besides, performing interactome analysis on specific proteins of each cancer type showed high levels of interconnectivity among them, which implies their functional relationship. To evaluate the role of mitochondrial genes, stem cell specific genes and DNA repair genes in cancer development, their mutation frequency was determined via further analysis. CONCLUSIONS: This study has provided researchers with a publicly available data repository for studying both CATH and Pfam domain regions on protein-coding genes. Moreover, the associations between different groups of genes/domains and various cancer types have been clarified. The work is available at http://www.cancerouspdomains.ir . PMID- 28814325 TI - Australian adolescents' beliefs and help-seeking intentions towards peers experiencing symptoms of depression and alcohol misuse. AB - BACKGROUND: Many young people are reluctant to seek professional help for mental health problems, preferring to rely on their friends for support. It is therefore important to ensure that adolescents can identify signs of psychological distress in their peers, talk to them about these, and help them access appropriate services when necessary. The current study examined adolescents' ability to recognise symptoms of depression and alcohol misuse, perceived barriers to help seeking, and their intentions to encourage a peer to seek help from a range of informal and formal help sources. METHOD: The current study used baseline data from a randomised controlled trial of a school-based intervention that teaches adolescents how to overcome barriers to accessing professional help for mental health and substance use problems (MAKINGtheLINK). Participants (n = 2456) were presented with two vignettes portraying depression and alcohol misuse, respectively, and were asked to identify the problems described. Participants provided data on their past help-seeking behaviour, confidence to help a peer, perceived barriers to help-seeking, and intentions to encourage a peer to seek help. RESULTS: Health professionals were the main source of help that participants had relied on for depressive symptoms, followed by friends and parents. In contrast, friends were the main source of help that participants had relied on for alcohol and other drug problems, followed by health professionals and parents. Just over half of the sample correctly identified the problems described in the two vignettes, although the majority of participants were confident that they could talk to a peer and help them seek professional help if needed. Most agreed that the vignettes described problems that warranted professional help, however approximately half the sample was unsure or considered it unlikely that they would seek help if they experienced similar problems. For both disorders, participants were most likely to encourage a peer to seek help from their family, followed by formal help sources and friends. CONCLUSIONS: While the results point towards a greater willingness to approach formal help sources, particularly for depression, peers remain an important source of support for young people experiencing mental health and substance use problems. PMID- 28814326 TI - Distal defect of the humerus, a possible normal variant: a case report. AB - BACKGROUND: Many normal variants of bones on plain radiographs have been reported. CASE PRESENTATION: In the current report, a 14-year-old Asian girl noticed an occasional slight elbow pain. She had no traumatic episode. Plain radiographs showed a well-defined osteolytic lesion with a sclerotic rim, which was continuous with the normal subarticular bone in the distal humerus. Magnetic resonance imaging revealed that the defect area seen on the plain radiograph showed low-signal to iso-signal intensity on T1-weighted images and slightly high signal intensity on T2-weighted fat suppression images. Bone edema was not observed. The association between her elbow pain and the lesion was not conclusive. CONCLUSIONS: The findings from the images suggested that the lesion was a normal variant rather than osteochondritis dissecans or a neoplastic lesion, and possibly an anatomical counterpart of a dorsal defect of the patella. PMID- 28814327 TI - Neocortical Sox9+ radial glia generate glutamatergic neurons for all layers, but lack discernible evidence of early laminar fate restriction. AB - Glutamatergic neurons in the cerebral cortex are derived from embryonic neural stem cells known as radial glial progenitors (RGPs). Early RGPs, present at the onset of cortical neurogenesis, are classically thought to produce columnar clones of glutamatergic neurons spanning the cortical layers. Recently, however, it has been reported that a subset of early RGPs may undergo early commitment to upper layer neuron fates, thus bypassing genesis of deep layer neurons. However, the latter mode of early RGP differentiation was not confirmed in some other studies, and remains controversial. To further investigate the clonal output from early RGPs, we employed genetic lineage tracing driven by Sox9, a transcription factor gene that is expressed in all early RGPs. We found that early RGPs produced columnar clones spanning all cortical layers, with no evidence of significant laminar fate restriction. These data support the classic progressive restriction model of cortical neurogenesis, and suggest that early RGPs do not undergo early commitment to only upper or lower layer fates. PMID- 28814328 TI - Building capacity for dissemination and implementation research: one university's experience. AB - BACKGROUND: While dissemination and implementation (D&I) science has grown rapidly, there is an ongoing need to understand how to build and sustain capacity in individuals and institutions conducting research. There are three inter related domains for capacity building: people, settings, and activities. Since 2008, Washington University in St. Louis has dedicated significant attention and resources toward building D&I research capacity. This paper describes our process, challenges, and lessons with the goal of informing others who may have similar aims at their own institution. ACTIVITIES: An informal collaborative, the Washington University Network for Dissemination and Implementation Research (WUNDIR), began with a small group and now has 49 regular members. Attendees represent a wide variety of settings and content areas and meet every 6 weeks for half-day sessions. A logic model organizes WUNDIR inputs, activities, and outcomes. A mixed-methods evaluation showed that the network has led to new professional connections and enhanced skills (e.g., grant and publication development). As one of four, ongoing, formal programs, the Dissemination and Implementation Research Core (DIRC) was our first major component of D&I infrastructure. DIRC's mission is to accelerate the public health impact of clinical and health services research by increasing the engagement of investigators in later stages of translational research. The aims of DIRC are to advance D&I science and to develop and equip researchers with tools for D&I research. As a second formal component, the Washington University Institute for Public Health has provided significant support for D&I research through pilot projects and a small grants program. In a third set of formal programs, two R25 training grants (one in mental health and one in cancer) support post-doctoral scholars for intensive training and mentoring in D&I science. Finally, our team coordinates closely with D&I functions within research centers across the university. We share a series of challenges and potential solutions. CONCLUSION: Our experience in developing D&I research at Washington University in St. Louis shows how significant capacity can be built in a relatively short period of time. Many of our ideas and ingredients for success can be replicated, tailored, and improved upon by others. PMID- 28814329 TI - Severe persistent pulmonary hypertension of the newborn and dysmorphic features in neonate with a deletion involving TWIST1 and PHF14: a case report. AB - BACKGROUND: Persistent pulmonary hypertension is a well-known disease of the newborn that in most cases responds well to treatment with nitric oxide and treatment of any underlying causes. Genetic causes of persistent pulmonary hypertension of the newborn are rare. The TWIST1 gene is involved in morphogenetics, and deletions are known to cause Saethre-Chotzen syndrome. Deletions of PHF14 have never been reported in neonates, but animal studies have shown a link between severe defects in lung development and deletions of this gene. There have not, to the best of our knowledge, been any publications of a link between the genes TWIST1 and PHF14 and persistent pulmonary hypertension of the newborn, making this a novel finding. CASE PRESENTATION: We describe a white male neonate born at term to non-consanguineous white parents; he presented with dysmorphic features and a therapy-refractory persistent pulmonary hypertension. Array-based comparative genomic hybridization revealed the presence of a 14.7 Mb interstitial deletion on chromosome 7, encompassing the genes TWIST1 and PHF14. CONCLUSIONS: The TWIST1 gene can explain our patient's dysmorphic features. His severe persistent pulmonary hypertension has, however, not been described before in conjunction with the TWIST1 gene, but could be explained by involvement of PHF14, consistent with findings in animal experiments showing lethal respiratory failure with depletion of PHF14. These findings are novel and of importance for the clinical management and diagnostic workup of neonates with severe persistent pulmonary hypertension of the newborn and dysmorphic features. PMID- 28814330 TI - Novel remote electronic medication supply model for opioid-dependent outpatients with polypharmacy--first long-term case study. AB - BACKGROUND: Patients with substance use disorders grow older thanks to effective treatments. Together with a high prevalence of comorbidities, psychological problems, and low social support, these patients are at high risk for medication non-adherence. Established treatment facilities face challenges to accommodate these complex patients within their setting. Electronic medication management aids (e-MMAs) might be appropriate to simultaneously monitor and improve adherence for these patients. CASE PRESENTATION: We report the first long-term experiences with a novel remote electronic medication supply model for two opioid dependent patients with HIV. John (beginning dementia, 52 years, 6 tablets daily at 12 am) and Mary (frequent drug holidays, 48 years, 5-6 tablets daily at 8 pm) suffered from disease progression due to non-adherence. We electronically monitored adherence and clinical outcomes during 659 (John) and 953 (Mary) days between July 2013 and April 2016. Both patients retrieved over 90% of the pouches within 75 min of the scheduled time. Technical problems occurred in 4% (John) and 7.2% (Mary) of retrievals, but on-site support was seldom required. Viral loads fell below detection limits during the entire observation period. CONCLUSIONS: Continuous medication supply and persistence with treatment of over 1.7 years, timing adherence of more than 90%, and suppressed HIV viral load are first results supporting the feasibility of the novel supply model for patients on opioid-assisted treatment and polypharmacy. PMID- 28814331 TI - Circulating levels of soluble Fas (sCD95) are associated with risk for development of a nonresolving acute kidney injury subphenotype. AB - BACKGROUND: Critically ill patients with acute kidney injury (AKI) can be divided into two subphenotypes, resolving or nonresolving, on the basis of the trajectory of serum creatinine. It is unknown if the biology underlying these two AKI recovery patterns is different. METHODS: We measured eight circulating biomarkers in plasma obtained from a cohort of patients admitted to an intensive care unit (ICU) (n = 1241) with systemic inflammatory response syndrome. The biomarkers were representative of several biologic processes: apoptosis (soluble Fas), inflammation (soluble tumor necrosis factor receptor 1, interleukin 6, interleukin 8) and endothelial dysfunction, (angiopoietin 1, angiopoietin 2, and soluble vascular cell adhesion molecule 1). We tested for associations between biomarker levels and AKI subphenotypes using relative risk regression accounting for multiple hypotheses with the Bonferroni correction. RESULTS: During the first 3 days of ICU admission, 868 (70%) subjects developed AKI; 502 (40%) had a resolving subphenotype, and 366 (29%) had a nonresolving subphenotype. Hospital mortality was 12% in the resolving subphenotype and 21% in the nonresolving subphenotype. Soluble Fas was the only biomarker associated with a nonresolving subphenotype after adjustment for age, body mass index, diabetes, and Acute Physiology and Chronic Health Evaluation III score (p = 0.005). CONCLUSIONS: Identifying modifiable targets in the Fas-mediated pathway may lead to strategies for prevention and treatment of a clinically important form of AKI. PMID- 28814332 TI - Efficacy and safety of sarolaner (Simparica(r)) in the treatment and control of naturally occurring flea infestations in dogs presented as veterinary patients in Australia. AB - BACKGROUND: The efficacy and safety of a novel isoxazoline compound, sarolaner (Simparica(r), Zoetis) and spinosad (Comfortis(r), Elanco) as a positive control were evaluated for the treatment and control of natural flea infestations on dogs in two randomised, blinded, multi-centric clinical trials conducted in 11 veterinary clinics in northeastern and southeastern states of Australia. METHODS: A total of 162 client-owned dogs (80 in northern study and 82 in southern study) from 105 households were enrolled. Each household was randomly allocated to receive either sarolaner (Simparica(r), Zoetis) or spinosad (Comfortis(r), Elanco). Dogs were dosed on Days 0, 30 and 60 and physical examinations and flea counts were conducted on Days 0, 14, 30, 60 and 90. Efficacy assessments were based on the percentage reduction in live flea counts post-treatment compared to Day 0. RESULTS: In the northern study, at enrolment, primary dogs had flea counts ranging from 5 to 772. At the first efficacy assessment on Day 14, sarolaner resulted in 99.3% mean reduction in live flea counts relative to Day 0, compared to 94.6% in the spinosad group. On Day 30, the sarolaner-treated group had mean efficacy of 99.2% compared to 95.7% in the spinosad-treated group, and on days 60 and 90, both groups had mean efficacies of >= 98.8%. In the southern study, at enrolment, primary dogs had flea counts ranging from 5 to 156. Both sarolaner and spinosad resulted in >= 96.7% mean reduction in live flea counts on Day 14. On Day 30, the sarolaner-treated group had mean efficacy of 99.5% compared to 89.7% in the spinosad-treated group, and on days 60 and 90, both groups had mean efficacies of >= 98.6%. No treatment-related adverse events were observed in either study. CONCLUSIONS: A single monthly dose of sarolaner (Simparica(r)) administered orally at 2-4 mg/kg for three consecutive months was well tolerated and provided excellent efficacy against natural infestations of fleas under a range of Australian field conditions including different climatic and housing conditions. Similar efficacy was observed with spinosad (Comfortis(r)) after the second and third monthly treatments. PMID- 28814333 TI - Rapamycin Prevents cyclophosphamide-induced Over-activation of Primordial Follicle pool through PI3K/Akt/mTOR Signaling Pathway in vivo. AB - BACKGROUND: Primordial follicular depletion has thought to be a common adverse effect of chemotherapy especially for female of reproductive age. The study aimed to evaluate the protective effect of rapamycin on the primordial follicles and its potential mechanism for patients receiving chemotherapy. METHODS: 8-week old BALB/c female mice were randomly assigned into four groups (control; rapamycin; cyclophosphamide; and rapamycin combined with cyclophosphamide). Hematoxylin staining, immunohistochemical, TUNEL, western blotting and ELISA were employed to assess inter-group differences using Student's t-test and Mann-Whitney test. RESULTS: Cyclophosphamide depleted the follicular reserve and induced the phosphorylation of the key proteins of PI3K/Akt/mTOR pathway in mice in a dose dependent manner. Co-treatment with rapamycin significantly reduced primordial follicle loss at all cyclophosphamide dose groups and prevent the follicle growth wave caused by cyclophosphamide treatment (P < 0.05). TUNEL staining showed that no apoptosis occured in the primordial follicles in all groups and fewer apoptosis in large growing follicles were observed in ovaries from rapamycin + cyclophosphamide group compared to that received cyclophosphamide alone. Serum anti-Mullerian hormone (AMH) was significantly reduced in cyclophosphamide alone group, in contrast to the normal level in rapamycin + cyclophosphamide group. Compared to p-Akt/Akt and p-mtor/mtor, p-rps6/rps6 was significantly decreased in rapamycin + cyclophosphamide group (P < 0.05), indicating that rapamycin attenuated the increased level of phosphorylation of rpS6 after cyclophosphamide treatment. CONCLUSIONS: Rapamycin can prevent the primordial follicle activation induced by cyclophosphamide through PI3K/Akt/mTOR signaling pathway and thus plays a role in preserving the follicle pool. These results suggest that rapamycin may be an effective protection for ovarian function during chemotherapy, which means a new nonsurgical application for protection of ovarian reserve and prevention of POF. PMID- 28814334 TI - Abernethy malformation associated with Caroli's syndrome in a patient with a PKHD1 mutation: a case report. AB - BACKGROUND: Abernethy malformation is a rare congenital anomaly characterised by the partial or complete absence of the portal vein and the subsequent development of an extrahepatic portosystemic shunt. Caroli's disease is a rare congenital condition characterised by non-obstructive saccular intrahepatic bile duct dilation. Caroli's disease combined with congenital hepatic fibrosis and/or renal cystic disease is referred to - Caroli's syndrome. The combination of Abernethy malformation and Caroli's syndrome has not been reported previously. CASE PRESENTATION: We present the case of a 23-year-old female who was found to have both type II Abernethy malformation and Caroli's syndrome. Radiological imaging was performed, including computed tomography with three-dimensional reconstruction and magnetic resonance imaging with (magnetic resonance cholangiopancreatography (MRCP), which revealed a side-to-side portocaval shunt, intrahepatic bile duct dilation, congenital hepatic fibrosis, and renal cysts. In addition, PKHD1 (polycystic kidney and hepatic disease 1) gene mutational analysis revealed a paternally inherited heterozygous missense mutation (c.1877A > G, p.Lys626Arg). A liver biopsy confirmed the pathological features of Caroli's syndrome. CONCLUSIONS: To our knowledge, this is the first reported case of a patient with both type II Abernethy malformation and Caroli's syndrome diagnosed using a comprehensive approach that included imaging, mutational analysis, and liver biopsy. Additionally, this is the second reported case to date of an Asian patient presenting with liver and renal disorders with the same paternally inherited PKHD1 missense mutation. PMID- 28814335 TI - Comparative transcriptome analysis of second- and third-generation merozoites of Eimeria necatrix. AB - BACKGROUND: Eimeria is a common genus of apicomplexan parasites that infect diverse vertebrates, most notably poultry, causing serious disease and economic losses. Eimeria species have complex life-cycles consisting of three developmental stages. However, the molecular basis of the Eimeria reproductive mode switch remains an enigma. METHODS: Total RNA extracted from second- (MZ-2) and third-generation merozoites (MZ-3) of Eimeria necatrix was subjected to transcriptome analysis using RNA sequencing (RNA-seq) followed by qRT-PCR validation. RESULTS: A total of 6977 and 6901 unigenes were obtained from MZ-2 and MZ-3, respectively. Approximately 2053 genes were differentially expressed genes (DEGs) between MZ-2 and MZ-3. Compared with MZ-2, 837 genes were upregulated and 1216 genes were downregulated in MZ-3. Approximately 95 genes in MZ-2 and 48 genes in MZ-3 were further identified to have stage-specific expression. Gene ontology category and KEGG analysis suggested that 216 upregulated genes in MZ-2 were annotated by 70 GO assignments, 242 upregulated genes were associated with 188 signal pathways, while 321 upregulated genes in MZ 3 were annotated by 56 GO assignments, 322 upregulated genes were associated with 168 signal pathways. The molecular functions of upregulated genes in MZ-2 were mainly enriched for protein degradation and amino acid metabolism. The molecular functions of upregulated genes in MZ-3 were mainly enriched for transcriptional activity, cell proliferation and cell differentiation. CONCLUSIONS: To the best of our knowledge, this is the first RNA-seq data study of the MZ-2 and MZ-3 stages of E. necatrix; it demonstrates a high number of differentially expressed genes between the MZ-2 and MZ-3 of E. necatrix. This study forms a basis for deciphering the molecular mechanisms underlying the shift from the second to third generation schizogony in Eimeria. It also provides valuable resources for future studies on Eimeria, and provides insight into the understanding of reproductive mode plasticity in different Eimeria species. PMID- 28814336 TI - Risk behaviour determinants among people who inject drugs in Stockholm, Sweden over a 10-year period, from 2002 to 2012. AB - BACKGROUND: People who inject drugs (PWID) frequently engage in injection risk behaviours exposing them to blood-borne infections. Understanding the underlying causes that drive various types and levels of risk behaviours is important to better target preventive interventions. METHODS: A total of 2150 PWID in Swedish remand prisons were interviewed between 2002 and 2012. Questions on socio demographic and drug-related variables were asked in relation to the following outcomes: Having shared injection drug solution and having lent out or having received already used drug injection equipment within a 12 month recall period. RESULTS: Women shared solutions more than men (odds ratio (OR) 1.51, 95% confidence interval (CI) 1.03; 2.21). Those who had begun to inject drugs before age 17 had a higher risk (OR 1.43, 95% CI 0.99; 2.08) of having received used equipment compared to 17-19 year olds. Amphetamine-injectors shared solutions more than those injecting heroin (OR 2.43, 95% CI 1.64; 3.62). A housing contract lowered the risk of unsafe injection by 37-59% compared to being homeless. CONCLUSIONS: Women, early drug debut, amphetamine users and homeless people had a significantly higher level of injection risk behaviour and need special attention and tailored prevention to successfully combat hepatitis C and HIV transmission among PWID. TRIAL REGISTRATION: ClinicalTrials.gov Identifier, NCT02234167. PMID- 28814337 TI - Validity of a Cochrane Systematic Review and meta-analysis for determining the safety of vitamin E. AB - The public safety of alpha-tocopherol has been called in question by several meta analyses which have raised concern among regulatory authorities. The objective of this study was to evaluate the Cochrane Database Systematic Review 2012 (CD007176) which concludes that alpha-tocopherol forms of vitamin E have a statistically significant effect on mortality, by assessing the trials and datasets used and determining their effect upon the primary outcome.The Alpha Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC), a factorial design study of Finnish smokers was a pivotal paper in the Cochrane Review owing to the high mortality rate observed which resulted in a substantial weighting (42.6%) in the meta-analysis. The Cochrane meta-analysis used a 3 cell analytical method comparing all vitamin E cells (vitamin E alone plus vitamin E + beta-carotene) to the placebo only cell. This had the unfortunate effect of incorrectly inflating the mortality risk attributed to vitamin E by not balancing the contribution to mortality of the beta-carotene intervention. Re-analysis of the ATBC trial using data derived from the more generally accepted 'inside the table' (2 cell - vitamin E versus placebo) or 'at the margins' (4 cell - all vitamin E versus all non-vitamin E) analytical methods demonstrates a statistically non-significant result.The data from the ATBC study has been given in 5 datasets (the trial alone and four extended post-trial follow-up time periods). Using the 3 cell analysis method only the 6 and 8-year (used in the meta-analysis) follow-up periods were statistically significant. Using the 2 or 4 cell method the outcome remains non significant over all time periods.The impartiality of excluding trials with zero mortality is also examined and questioned.This paper raises concerns overall as to the appropriateness of datasets chosen, the validity of methods and generalisability of results when using meta-analysis as a tool to determine safety. Issues raised in this paper are not unique to the Cochrane study in question. Until we have new tools, there may be a need to rely on conventional narrative systematic literature synthesis in the assessment of safety or contain our results to specific sub-populations where more conclusive results can be determined. PMID- 28814338 TI - Anti-nausea effects and pharmacokinetics of ondansetron, maropitant and metoclopramide in a low-dose cisplatin model of nausea and vomiting in the dog: a blinded crossover study. AB - BACKGROUND: Nausea is a subjective sensation which is difficult to measure in non verbal species. The aims of this study were to determine the efficacy of three classes of antiemetic drugs in a novel low dose cisplatin model of nausea and vomiting and measure change in potential nausea biomarkers arginine vasopressin (AVP) and cortisol. A four period cross-over blinded study was conducted in eight healthy beagle dogs of both genders. Dogs were administered 18 mg/m2 cisplatin intravenously, followed 45 min later by a 15 min infusion of either placebo (saline) or antiemetic treatment with ondansetron (0.5 mg/kg; 5-HT3 antagonist), maropitant (1 mg/kg; NK1 antagonist) or metoclopramide (0.5 mg/kg; D2 antagonist). The number of vomits and nausea associated behaviours, scored on a visual analogue scale, were recorded every 15 min for 8 h following cisplatin administration. Plasma samples were collected to measure AVP, cortisol and antiemetic drug concentrations. RESULTS: The placebo treated group vomited an average number of 7 times (range 2-13). None of the dogs in either the ondansetron or maropitant treated groups vomited during the observation period. The onset of nausea-like behaviour in the placebo-treated group occurred at t3.5h and peaked at t4.75h with nausea behaviour score of 58.5 +/- 4.6 mm. Ondansetron and maropitant reduced overall the area under the curve of nausea behaviour score by 90% and 25%, respectively. Metoclopramide had no effect on either vomiting or nausea. Cisplatin-induced nausea and vomiting caused concomitant increases in AVP and cortisol. In the placebo-treated group, AVP and cortisol increased from t2.5h, peaked at t5h (11.3 +/- 2.9 pmol L-1 and 334.0 +/- 46.7 nmol/L, respectively) and returned to baseline by t8h. AVP and cortisol increases were completely prevented by ondansetron and only partially by maropitant, while metoclopramide had no effect. The terminal half-lives (harmonic mean +/- pseudo SD) for ondansetron, maropitant and metoclopramide were 1.21 +/- 0.51, 5.62 +/- 0.77 and 0.87 +/- 0.17 h respectively. CONCLUSIONS: 5-HT3 receptor antagonist ondansetron demonstrates the greatest anti-emetic and anti-nausea efficacy of the three drugs. AVP and cortisol appear to be selective biomarkers of nausea rather than emesis, providing a means of objectively measuring of nausea in the dog. PMID- 28814339 TI - Social disparities in body mass index (BMI) trajectories among Chinese adults in 1991-2011. AB - BACKGROUND: Obesity is a serious public health problem in China. The relationship between obesity and socio-economic status (SES) is changing and affected by uncertainty, particularly, in developing countries. The sex-related differences in body mass index (BMI) trajectories are controversial and require substantial empirical data for updating and enriching. METHODS: This study examined the relationship between SES and BMI in Chinese adults from a dynamic perspective using longitudinal data (1991-2011) from the China Health and Nutrition Survey (CHNS). Then, sex-related differences were determined. A hierarchical linear model was used. RESULTS: SES positively affected the male BMI changes, with faster BMI growth rates in the high-SES males over the past 20 years. By contrast, female BMI was only affected by BMI baseline and residential area. Specifically, greater BMI baseline led to greater BMI growth rate and earlier BMI decline. In the past 20 years, the BMI growth rate has been greater in the urban females than in the rural females. CONCLUSIONS: The relationship between SES and obesity is complex in China, and a substantial sex-related difference exists. We argue that this large sex-related difference is due to the rapid economic and social changes that have affected national health and increased the gender inequality and social role restrictions in females. We provide insights for further research and policy recommendations. PMID- 28814340 TI - Detection and genetic characterization of canine astroviruses in pet dogs in Guangxi, China. AB - BACKGROUND: Astroviruses (AstVs) have been reported to infect and cause gastroenteritis in most animal species. Human AstVs were regarded the causative agent of viral diarrhea in children. In dogs, little is known about the epidemiology and clinical significance of AstV infection. FINDINGS: In this study, we collected and tested 253 rectal swabs from pet dogs; of which 64 samples (25.3%) tested positive for AstVs with diarrhea and 15 more samples (5.9%) also was identified as AstVs, however without any clinical signs. Phylogenetic analysis of 39 partial ORF1b sequences from these samples revealed that they are similar to AstVs, which can be subdivided into three lineages. Interestingly, out of the 39 isolates sequenced, 16 isolates are shown to be in the Mamastrovirus 5/canine astrovirus (CAstV) lineage and the remaining 23 isolates displayed higher similarities with known porcine astrovirus (PoAstV) 5 and 2. Further, analysis of 13 capsid sequences from these isolates showed that they are closely clustered with Chinese or Italy CAstV isolates. CONCLUSIONS: The findings indicate that CAstVs commonly circulate in pet dogs, and our sequencing results have shown the genomic diversity of CAstVs leading to increasing number of clusters. PMID- 28814341 TI - A review of national policies and strategies to improve quality of health care and patient safety: a case study from Lebanon and Jordan. AB - BACKGROUND: Improving quality of care and patient safety practices can strengthen health care delivery systems, improve health sector performance, and accelerate attainment of health-related Sustainability Development Goals. Although quality improvement is now prominent on the health policy agendas of governments in low- and middle-income countries (LMICs), including countries of the Eastern Mediterranean Region (EMR), progress to date has not been optimal. The objective of this study is to comprehensively review existing quality improvement and patient safety policies and strategies in two selected countries of the EMR (Lebanon and Jordan) to determine the extent to which these have been institutionalized within existing health systems. METHODS: We used a mixed methods approach that combined documentation review, stakeholder surveys and key informant interviews. Existing quality improvement and patient safety initiatives were assessed across five components of an analytical framework for assessing health care quality and patient safety: health systems context; national policies and legislation; organizations and institutions; methods, techniques and tools; and health care infrastructure and resources. RESULTS: Both Lebanon and Jordan have made important progress in terms of increased attention to quality and accreditation in national health plans and strategies, licensing requirements for health care professionals and organizations (albeit to varying extents), and investments in health information systems. A key deficiency in both countries is the absence of an explicit national policy for quality improvement and patient safety across the health system. Instead, there is a spread of several (disjointed) pieces of legal measures and national plans leading to fragmentation and lack of clear articulation of responsibilities across the entire continuum of care. Moreover, both countries lack national sets of standardized and applicable quality indicators for performance measurement and benchmarking. Importantly, incentive systems that link contractual agreement, regulations, accreditation, and performance indicators are underutilized in Lebanon and absent in Jordan. At the healthcare organizational level, there is a need to instill a culture of continuous quality improvement and promote professional training in quality improvement and patient safety. CONCLUSION: Study findings highlight the importance of aligning policies, organizations, methods, capacities and resources in order to institutionalize quality improvement and patient safety practices in health systems. Gaps and dysfunctions identified can help inform national deliberations and dialogues among key stakeholders in each study country. Findings can also inform future quality improvement efforts in the EMR and beyond, with a particular emphasis on LMICs. PMID- 28814342 TI - Septal contributions to olfactory bulb interneuron diversity in the embryonic mouse telencephalon: role of the homeobox gene Gsx2. AB - BACKGROUND: Olfactory bulb (OB) interneurons are known to represent diverse neuronal subtypes, which are thought to originate from a number of telencephalic regions including the embryonic dorsal lateral ganglionic eminence (dLGE) and septum. These cells migrate rostrally toward the OB, where they then radially migrate to populate different OB layers including the granule cell layer (GCL) and the outer glomerular layer (GL). Although previous studies have attempted to investigate regional contributions to OB interneuron diversity, few genetic tools have been used to address this question at embryonic time points when the earliest populations are specified. METHODS: In this study, we utilized Zic3-lacZ and Gsx2e-CIE transgenic mice as genetic fate-mapping tools to study OB interneuron contributions derived from septum and LGE, respectively. Moreover, to address the regional (i.e. septal) requirements of the homeobox gene Gsx2 for OB interneuron diversity, we conditionally inactivated Gsx2 in the septum, leaving it largely intact in the dLGE, by recombining the Gsx2 floxed allele using Olig2 Cre/+ mice. RESULTS: Our fate mapping studies demonstrated that the dLGE and septum gave rise to OB interneuron subtypes differently. Notably, the embryonic septum was found to give rise largely to the calretinin+ (CR+) GL subtype, while the dLGE was more diverse, generating all major GL subpopulations as well as many GCL interneurons. Moreover, Gsx2 conditional mutants (cKOs), with septum but not dLGE recombination, showed impaired generation of CR+ interneurons within the OB GL. These Gsx2 cKOs exhibited reduced proliferation within the septal subventricular zone (SVZ), which correlated well with the reduced number of CR+ interneurons observed. CONCLUSIONS: Our findings indicate that the septum and LGE contribute differently to OB interneuron diversity. While the dLGE provides a wide range of OB interneuron subtypes, the septum is more restricted in its contribution to the CR+ subtype. Gsx2 is required in septal progenitors for the correct expansion of SVZ progenitors specified toward the CR+ subtype. Finally, the septum has been suggested to be the exclusive source of CR+ interneurons in postnatal studies. Our results here demonstrate that dLGE progenitors in the embryo also contribute to this OB neuronal subtype. PMID- 28814343 TI - Stable inheritance of DNA methylation allows creation of epigenotype maps and the study of epiallele inheritance patterns in the absence of genetic variation. AB - BACKGROUND: Differences in DNA methylation can arise as epialleles, which are loci that differ in chromatin state and are inherited over generations. Epialleles offer an additional source of variation that can affect phenotypic diversity beyond changes to nucleotide sequence. Previous research has looked at the rate at which spontaneous epialleles arise but it is currently unknown how they are maintained across generations. RESULTS: We used two Arabidopsis thaliana mutation accumulation (MA) lines and determined that over 99.998% of the methylated regions in the genome are stably inherited across each generation indicating that spontaneous epialleles are rare. We also developed a novel procedure that determines genotypes for offspring of genetically identical parents using only DNA methylation data. The resulting epigenotype maps are highly accurate and strongly agree with expected allele frequency and crossover number. Using epigenotype maps, we explore the inheritance of methylation states in regions of differential methylation between the parents of genetic crosses. Over half of the regions show methylation levels consistent with cis inheritance, whereas the other half show evidence of trans-chromosomal methylation and demethylation as well as other possibilities. CONCLUSIONS: DNA methylation is stably inherited by offspring and spontaneous epialleles are rare. The epigenotyping procedure that we describe provides an important first step to epigenetic quantitative trait loci mapping in genetically identical individuals. PMID- 28814344 TI - Microbial phylogeny determines transcriptional response of resistome to dynamic composting processes. AB - BACKGROUND: Animal manure is a reservoir of antibiotic resistance genes (ARGs) that pose a potential health risk globally, especially for resistance to the antibiotics commonly used in livestock production (such as tetracycline, sulfonamide, and fluoroquinolone). Currently, the effects of biological treatment (composting) on the transcriptional response of manure ARGs and their microbial hosts are not well characterized. Composting is a dynamic process that consists of four distinct phases that are distinguished by the temperature resulting from microbial activity, namely the mesophilic, thermophilic, cooling, and maturing phases. In this study, changes of resistome expression were determined and related to active microbiome profiles during the dynamic composting process. This was achieved by integrating metagenomic and time series metatranscriptomic data for the evolving microbial community during composting. RESULTS: Composting noticeably reduced the aggregated expression level of the manure resistome, which primarily consisted of genes encoding for tetracycline, vancomycin, fluoroquinolone, beta-lactam, and aminoglycoside resistance, as well as efflux pumps. Furthermore, a varied transcriptional response of resistome to composting at the ARG levels was highlighted. The expression of tetracycline resistance genes (tetM-tetW-tetO-tetS) decreased during composting, where distinctive shifts in the four phases of composting were related to variations in antibiotic concentration. Composting had no effect on the expression of sulfonamide and fluoroquinolone resistance genes, which increased slightly during the thermophilic phase and then decreased to initial levels. As indigenous populations switched greatly throughout the dynamic composting, the core resistome persisted and their reservoir hosts' composition was significantly correlated with dynamic active microbial phylogenetic structure. Hosts for sulfonamide and fuoroquinolone resistance genes changed notably in phylognetic structure and underwent an initial increase and then a decrease in abundance. By contrast, hosts for tetracycline resistance genes (tetM-tetW-tetO-tetS) exhibited a constant decline through time. CONCLUSIONS: The transcriptional patterns of a core resistome over the course of composting were identified, and microbial phylogeny was the key determinant in defining the varied transcriptional response of resistome to this dynamic biological process. This research demonstrated the benefits of composting for manure treatment. It reduced the risk of emerging environmental contaminants such as tetracyclines, tetracycline resistance genes, and clinically relevant pathogens carrying ARGs, as well as RNA viruses and bacteriophages. PMID- 28814345 TI - Hospital characteristics related to the hospital length of stay among inpatients receiving invasive cervical discectomy due to road traffic accidents under automobile insurance in South Korea. AB - BACKGROUND: In South Korea, people injured in road traffic accidents receive compensation for medical costs through their automobile insurance. However, the automobile insurance system appears to manage health care inefficiently. This study aimed to investigate the factors associated with the hospital length of stay (LOS), which was used as an indicator of healthcare utilization, for inpatients covered by automobile insurance and undergoing invasive cervical discectomy. METHODS: Insurance claims data from 158 hospitals were used. The study included 850 inpatients who were involved in automobile accidents in 2014 and 2015 and who underwent invasive cervical discectomy. Poisson regression analysis was performed to examine the associations between the LOS and hospital level characteristics. RESULTS: The mean LOS for inpatients covered by automobile insurance was 25.75 days. A higher proportion of inpatients with automobile insurance were associated with a longer LOS (rate ratio [RR]: 1.027 per 1% increase, 95% confidence interval [CI]: 1.012-1.042). A higher hospital volume of invasive cervical discectomy (RR: 0.970 per 10 case increase, 95% CI: 0.945 0.997), bed turnover rate (RR: 0.988 per 1 increase, 95% CI: 0.979-0.997), and number of neurosurgeons or orthopedic specialists (RR: 0.930 per 1/100 beds increase, 95% CI: 0.876-0.987) were associated with a shorter LOS. CONCLUSIONS: Our findings suggest that inpatients covered by automobile insurance were associated with a longer LOS when treated at small-sized, low-provider, and low volume hospitals with high proportions of such patients. Based on these findings, policymakers and healthcare professionals ought to consider improved strategies for efficient management of automobile insurance for inpatients in small-sized hospitals. PMID- 28814346 TI - Point-of-care ultrasonography: a practical step in the path to precision in critical care. PMID- 28814348 TI - Traduction francaise de l'echelle Charcot-Marie-Tooth Disease Pediatric Scale. AB - Resume Cet article presente le processus de traduction en francais du Charcot Marie-Tooth Disease Pediatric Scale (CMTPedS), le seul outil de mesure valide evaluant la severite de la maladie chez les enfants atteints de CMT. Le processus de traduction utilise s'inspire des lignes directrices de la Food and Drug Administration (FDA). La version preliminaire francophone du CMTPedS a ete testee aupres de 14 enfants atteints. Les resultats de l'application demontrent que la passation a ete bien toleree par les enfants et s'est averee conviviale pour les cliniciens. La disponibilite de cet outil en francais semble prometteuse pour le suivi des enfants atteints et la realisation d'essais clinique. PMID- 28814347 TI - Early troponin I in critical illness and its association with hospital mortality: a cohort study. AB - BACKGROUND: Troponin I (TnI) is frequently elevated in critical illness, but its interpretation is unclear. Our primary objectives in this study were to evaluate whether TnI is associated with hospital mortality and if this association persists after adjusting for potential confounders. We also aimed to ascertain whether addition of TnI to the Acute Physiological and Chronic Health Evaluation II (APACHE II) risk prediction model improves its performance in general intensive care unit (ICU) populations. METHODS: We performed an observational cohort study with independent derivation and validation cohorts in two general level 3 ICU departments in the United Kingdom. The derivation cohort was a 4.5 year cohort (2010-2014) of general ICU index admissions (n = 1349). The validation cohort was used for secondary analysis of a prospective study dataset (2010) (n = 145). The primary exposure was plasma TnI concentration taken within 24 h of ICU admission. The primary outcome was hospital mortality. We performed multivariate regression, adjusting for components of the APACHE II model. We derived the risk prediction score from the multivariable model with TnI. RESULTS: Hospital mortality was 37.3% (n = 242) for patients with detectable TnI, compared with 14.6% (n = 102) for patients without detectable TnI. There was a significant univariate association between TnI and hospital mortality (OR per doubling TnI 1.16, 95% CI 1.13-1.20, p < 0.001). This persisted after adjustment for APACHE II model components (TnI OR 1.05, 95% CI 1.01-1.09, p = 0.003). TnI correlated most strongly with the acute physiology score (APS) component of APACHE II (r = 0.39). Addition of TnI to the APACHE II model did not improve discrimination (APACHE II concordance statistic [c-index] 0.835, 95% CI 0.811-0.858; APACHE II + TnI c index 0.837, 95% CI 0.813-0.860; p = 0.330) or other measures of model performance. CONCLUSIONS: TnI is an independent predictor of hospital mortality and correlates most highly with the APS component of APACHE II. It does not improve risk prediction. We would not advocate the adoption of routine troponin analysis on admission to ICU, and we recommend that troponin be measured only if clinically indicated. PMID- 28814349 TI - Breakfast consumption and nutrient intakes in 4-18-year-olds: UK National Diet and Nutrition Survey Rolling Programme (2008-2012). AB - Although breakfast consumption is widely considered to be an important component of a healthy lifestyle, few UK studies have examined differences in nutrient intakes between breakfast consumers and breakfast skippers among children and adolescents. We investigated associations between breakfast skipping in 4-18-year olds and their nutrient intakes using data from the UK's National Diet and Nutrition Survey Rolling Programme. Dietary data were derived from 4-d estimated food diaries of 802 children aged 4-10 years and 884 children aged 11-18 years (1686 in total). Daily nutrient intakes of children with different breakfast habits were compared by one-way ANCOVA adjusting for relevant covariates (sex, age, ethnicity, equivalised household income and BMI). Within-person analysis was carried out on children with an irregular breakfast habit (n 879) comparing nutrient intakes on breakfast days with those on non-breakfast days using repeated measures ANCOVA. We observed that the overall nutritional profile of the children in terms of fibre and micronutrient intake was superior in frequent breakfast consumers (micronutrients: folate, Ca, Fe and I (P<0.01)) and, for the 4-10 years age group, on breakfast days (micronutrients: folate, vitamin C, Ca and I (P<0.01)). Also, significantly higher proportions of breakfast-consuming children met their reference nutrient intakes of folate, vitamin C, Ca, Fe and I compared with breakfast skippers (chi 2 analysis, P<0.001). Our study adds to the body of data linking breakfast consumption with higher quality dietary intake in school-age children, supporting the promotion of breakfast as an important element of a healthy dietary pattern in children. PMID- 28814350 TI - Involvement of patients and parents in research undertaken by the Australian and New Zealand Fontan Registry. AB - Research that is closely connected with the population it is studying and in which the translational value to healthcare is high is a laudable goal, but it is not often achieved. The Australian and New Zealand Fontan Registry has developed a model for involving patients and parents of children with a Fontan circulation in its research. The model involves consumer participation in the overarching Steering Committee, and has set in place multiple channels of communication allowing the early dissemination of research findings before peer-reviewing, and consumer feedback at all levels of the research. Our focus was not only to provide information but also to give a voice to this community and include them as researchers. These communication channels are a part of a larger network involving the practitioner community, support groups, funding agencies, and health authorities. This close connection with the target research population has multiple benefits: safeguarding the project; controlling and adjusting both the messages conveyed and the investigations; building a community; raising new ideas for research; increasing our research participation rate; increasing the weight of our endeavours; and, above all, increasing our own satisfaction in our research undertakings. In conclusion, the interactions with patients and their families within Australia and New Zealand provide one potential model for the involvement of patients and parents that may result in research that is more relevant, focussed, and practically applicable in a healthcare setting. PMID- 28814351 TI - HOSPITAL-BASED HEALTH TECHNOLOGY ASSESSMENT IN IRAN. AB - BACKGROUND: Hospitals with health technology assessment (HTA) programs have reported its positive effects on the management of resources and costs. This study aimed to identify the barriers faced by hospital-based HTA (HBHTA) in Iran by inductive content analysis of stakeholders' and decision-makers' points of view. METHODS: The key individuals and organizations that could provide rich, relevant, and diverse data in response to the research question were purposively selected for the interviews and focus group discussion. RESULTS: Twelve stakeholders from seven public hospitals participated in the interviews. Another eighteen stakeholders from twelve HBHTA-related organizations took part in the focus group discussion. Most of the hospitals' senior management team did not feel the need for HBHTA and believed that in Iran a systematic process like HTA faces many challenges. CONCLUSIONS: The stakeholders participating in this study highlighted the significance of certain points that needed to be addressed before establishing HBHTA in Iran. PMID- 28814352 TI - Characteristics of drug-induced anaphylaxis in children and adolescents. AB - BACKGROUND: Although data on anaphylaxis in the general population exist for different allergens, there is still lack of detailed etiologic data on drug induced anaphylaxis (DIA), particularly in children. OBJECTIVE: To define the etiology of DIA, to determine the accuracy of drug-related anaphylaxis histories, along with the severity and culprit drug associations among individuals <18 years old. METHODS: Patients with a history of drug hypersensitivity reaction (DHR) referred to our center between January 2012 and February 2016 were included. After the collection of European Network for Drug Allergy questionnaire results, initial skin tests and/or provocation tests were performed for the offending drug. RESULTS: Among 561 children and adolescents referred due to a suspected DHR, 113 (19%) (median age [interquartile range], 9.6 years [5.4-13.8 years]; 55% boys) had anaphylaxis in their history. At the end of diagnostic evaluation of the patients, 84 (74% of the patients with a history of DIA) were actually hypersensitive to the offending drug. Major drugs that resulted in DIA were antibiotics (33%), nonsteroidal anti-inflammatory drugs (25%), and chemotherapeutics (19%). The majority of patients reported grade 2 (moderate) (45%) and grade 3 (severe) (33%) anaphylactic reactions. A history of systemic illness (41.7 versus 7.1%; p = 0.001), concomitant intake of other drugs regularly (36.9 versus 10.3%; p = 0.007), and the use of chemotherapeutics as the culprit drug (19 versus 0%; p = 0.011) were more frequent, whereas the use of antibiotics was less frequent (34.5 versus 75.9%; p < 0.001) among patients with actual DIA compared to drug tolerant patients. CONCLUSION: Three-fourths of the children and adolescents referred due to a suspected history of DIA were found to actually be drug hypersensitive. Prediagnosed systemic illness and different types of drugs would have an impact on the risk of DIA; however, atopic disease or a family history of drug hypersensitivity did not have an impact on actual DIA. PMID- 28814353 TI - Pre- and postoperative blood neutrophil-to-lymphocyte and eosinophil-to lymphocyte ratios in patients with sinonasal polyps: A preliminary investigation. AB - BACKGROUND: Identifying specific endotypes within the broad picture of chronic rhinosinusitis with nasal polyps (CRSwNP), by using biomarkers for instance, remains a challenge. The prognostic role of the neutrophil-to-lymphocyte ratio (NLR) and the eosinophil-to-lymphocyte ratio (ELR) as potential markers of inflammation has already been discussed. OBJECTIVE: The aim of the present study was to compare NLR and ELR before and after endoscopic sinus surgery (ESS) and nasal mometasone furoate for CRSwNP by stratifying patients by their clinical and histologic features. METHODS: The study included 115 consecutive patients with CRSwNP treated with ESS and nasal mometasone furoate, with a postoperative follow up of >12 months. Eosinophilic-type CRSwNP was histopathologically defined after hematoxylin and eosin tissue staining. RESULTS: In the subcohort of patients with an histologic diagnosis of eosinophilic-type CRSwNP, the mean +/- standard deviation ELR significantly decreased after surgery (0.22 +/- 0.16 versus 0.18 +/ 0.12; p = 0.04), whereas, among patients with a histologic diagnosis of noneosinophilic-type CRSwNP, the mean NLR significantly decreased after surgery (1.98 +/- 0.98 versus 1.90 +/- 0.90; p = 0.04). CONCLUSION: Different CRSwNP endotypes are characterized by different biohumoral patterns. It is reasonable to assume that surgery enables clearance of the polyps and polypoid mucosa, which reduces the load of antigens that triggers the inflammation. Consistent with the above-mentioned biologic mechanism, ESS could correspond to a reduction in blood ELR values and eosinophil count in eosinophilic-type CRSwNP. Analysis of the data did not demonstrate an added value of measuring pre- versus postoperative ELR compared with measuring the blood eosinophil count. When used after ESS, topical corticosteroids also had more significant anti-inflammatory effects. As for the subcohort of patients with noneosinophilic CRSwNP, the fact that the mean NLR dropped significantly after surgery was definitely an original finding. Unlike eosinophilic inflammation, the inflammatory patterns seen in noneosinophilic CRSwNP are still poorly understood. PMID- 28814354 TI - Primum adiuvare ... primum non nocere ... and the practice of allergy. PMID- 28814355 TI - Der p 1 and Der p 2 specific immunoglobulin E measurement for diagnosis of Dermatophagoides pteronyssinus allergy: A systematic review and meta-analysis. AB - BACKGROUND: A clinical history of allergic symptoms and a skin-prick test with house-dust mite crude extracts are standard diagnostic procedures for Dermatophagoides pteronyssinus allergy. Specific immunoglobulin E (IgE) responses to Der p 1 and Der p 2 allergens have been used for the diagnosis of D. pteronyssinus allergy; however, evaluation of the diagnostic performance of Der p 1 and Der p 2 specific IgE (sIgE) produced inconsistent findings. We sought to evaluate the diagnostic accuracy of Der p 1 sIgE and Der p 2 sIgE measurement in the diagnosis of D. pteronyssinus allergy by performing a systematic review and meta-analysis of previously published studies. METHODS: Several medical literature electronic data bases were searched for related literature published through August 1, 2016. A bivariate model was used to pool estimates of sensitivity, specificity, diagnostic odds ratio, and area under the summary receiver operating curves as the main diagnostic measures. RESULTS: Eight studies, which involved 1095 patients, were included in our analysis. The pooled estimates of sensitivity, specificity, and diagnostic odds ratio for Der p 1 were 0.84, 0.97, and 166.57, respectively. The combined results for Der p 2 were a sensitivity of 0.87, specificity of 1.00, and a diagnostic odds ratio of 17342.35. The areas under the summary receiver operating curves for Der p 1 sIgE and Der p 2 sIgE were 0.94 and 0.98, respectively. CONCLUSION: Our results supported the use of Der p 1 and Der p 2 sIgE in the diagnosis of D. pteronyssinus allergy. Both displayed good diagnostic performance and would be useful in a clinical setting in the accurate diagnosis of dust mite allergy. PMID- 28814356 TI - Pneumococcal 13-valent conjugate vaccine administration after inferior response to pneumococcal vaccine. AB - BACKGROUND: The pneumococcal vaccine, a nonconjugated vaccine, may be used to evaluate the integrity of the humoral immune system. Those patients with an inferior response to a nonconjugated vaccine may be vaccinated with a conjugated vaccine, which elicits both a B- and T-cell response. OBJECTIVE: We evaluated the immunogenicity of a conjugated vaccine in patients with inferior responses to a nonconjugated vaccine. METHODS: This was an institutional review board approved retrospective study that involved 22 patients with suspected specific antibody deficiency who received a nonconjugated vaccine, followed by a conjugated vaccine. Patients with an inferior response had <70% response in pneumococcal serotypes (1.3 MUg/mL, with at least a two to fourfold increase), whereas protective responses were those with a >70% response. These patients were subsequently administered a conjugated vaccine at various time intervals (1-36 months), and titers were evaluated 4-6 weeks later. RESULTS: A protective response was found in 6 of 22 patients (average age, 62.2 years) after conjugated vaccine administration. Half of the responders were vaccinated <12 months after nonconjugated vaccine administration. The majority of the nonresponders (n = 16) received a conjugated vaccine <12 months after a nonconjugated vaccine. Of the nonresponders, 10 received a conjugated vaccine <12 months after a nonconjugated vaccine and did not mount a protective response. Other associated immunologic findings included hypogammaglobulinemia (n = 6), low immunoglobulin G1 (IgG1) levels (n = 5), and low IgG2 levels (n = 6). CONCLUSION: The majority of the patients with an inferior response to a nonconjugated vaccine also had an inferior response to a conjugated vaccine. Conjugated vaccine administration time did not affect the response rate. Analysis of the data demonstrated that patients with suspected specific antibody deficiency may not benefit from a conjugated vaccine, which suggested a defect that may affect more than pure antibody responses. Also, the majority of patients with IgG2 deficiency mounted an inadequate response to Pneumococcal 13-valent conjugate vaccine. PMID- 28814357 TI - Association of aeroallergen sensitization and atopic disease in the Sonoran Desert. AB - BACKGROUND: Numerous aeroallergens have been associated with the development of asthma, including Alternaria, house-dust mite, and pet dander. Tucson, Arizona, is located in the Sonoran Desert, which has the highest diversity of vegetation of any desert in the world. Given the unique pollen profile in this region, we sought to identify the most common aeroallergens associated with rhinitis and asthma diagnosis in the local adult population. OBJECTIVE: To identify the prevalence of aeroallergen sensitivity in the Tucson adult population and to identify which aeroallergens are associated with a diagnosis of asthma. METHODS: We conducted a retrospective electronic chart review of 226 consecutive adult patients who underwent aeroallergen skin-prick testing for rhinitis at The University of Arizona Adult Allergy and Immunology Clinic over the course of 1 year. All the subjects were tested to a standard panel of tree, grass, weed, mold, house-dust mite, animal dander, cockroach, and feather extracts. Asthma was diagnosed by using the Expert Panel Report 3 guidelines. RESULTS: Skin testing results were most commonly positive to mesquite (54%), Bermuda (48%), palo verde (47%), olive tree (43%), and chenopodium (43%). Compared with the subjects without asthma, those subjects with asthma were more often sensitized to molds (odds ratio [OR] 2.25 [95% confidence interval {CI}, 1.22-4.14]; p = 0.005), including Alternaria alternata (OR 2.58 [95% CI, 1.23-5.39]; p = 0.011), and cat hair and/or pelt (OR 2.13 [95% CI, 1.24-3.69]; p = 0.006). CONCLUSION: Regional pollens contributed significantly to allergic disease in this unique climate. Sensitization to Alternaria and other nonregional aeroallergens were related to asthma, which supported the current practice of testing and treating patients for allergy to both locally significant and ubiquitous aeroallergens. PMID- 28814358 TI - Frequency of selective immediate responders to aminopenicillins and cephalosporins in Turkish children. AB - BACKGROUND: Beta-lactam antibiotics (BLA) are the most commonly prescribed antibiotics and are responsible for the majority of immediate hypersensitivity reactions to drugs in children. Cross-reactivity is important in hypersensitivity to BLAs because these drugs all share a common beta-lactam structure and some share similar side chains. OBJECTIVE: The aim of this study was to evaluate the clinical characteristics of patients who are diagnosed with immediate-type BLA hypersensitivity and frequency of patients with side chain hypersensitivity, "selective responders." METHODS: The study included patients who were diagnosed with immediate-type BLA hypersensitivity between January 2011 and May 2016 in a pediatric allergy outpatient clinic. The patients who had negative penicillin test (minor determinant mixture, benzylpenicilloylpoly-L-lysine, penicillin G) results and could tolerate penicillin V and/or BLAs with dissimilar side chains but had positive skin and/or provocation test results with the suspected drug were diagnosed as selective responders. RESULTS: During the study period, 357 patients (55.2% girls) were admitted to our clinic with suspected immediate-type BLA hypersensitivity. Parents of 11 patients did not give consent for an allergy workup with the suspected drug. Forty-five of the patients were diagnosed (45/346 [13%]) based on skin test or drug provocation test results. The most common susceptible agent was amoxicillin-clavulanate. Of the patients, 71.4% with a reaction to sulbactam-ampicillin /or amoxicillin-clavulanate and 93.7% with a reaction to cephalosporin were classified as selective responders. CONCLUSION: Among children with immediate BLA hypersensitivity, selective responders constituted an important group. Most of the patients with reactions to aminopenicillin and cephalosporins safely tolerated penicillin V and BLAs with dissimilar side chains after negative allergy workup results. PMID- 28814359 TI - The risk of autoimmune connective tissue diseases in patients with atopy: A nationwide population-based cohort study. AB - BACKGROUND: The relationship between autoimmune connective tissue disease (ACTD) and atopy is controversial. OBJECTIVES: To investigate the risks of ACTDs in patients with atopic triad diseases, including atopic dermatitis, allergic rhinitis, and asthma, by using a nationwide data base. METHODS: A cohort of 155,311 patients newly diagnosed with atopic dermatitis, allergic rhinitis, or asthma in 2002-2011 was obtained from the Taiwan National Health Insurance Research Database. An age- and sex-matched control group was selected from the same data base. The association between atopy and ACTD was investigated by using Cox proportional hazards regression analyses. RESULTS: Atopic dermatitis, allergic rhinitis, and asthma were present in 12.1, 78.6, and 26.3%, respectively, of the patients with atopy. The presence of atopic diseases increased the overall risk of ACTDs (incidence rate ratio 1.85 [95% confidence interval {CI}, 1.52-2.25]). The hazard ratio (HR) for ACTDs remained higher after adjusting for age, sex, urbanization level, socioeconomic status, and comorbidities. Individual risks of systemic lupus erythematosus (HR 1.58 [95% CI, 1.06-2.37]), rheumatoid arthritis (HR 1.74 [95% CI, 1.31-2.33]), and Sjogren syndrome (HR 2.49 [95% CI, 1.71-3.63]) were also higher. The coexistence of atopic triad diseases increased the risk of ACTDs from 1.80 (95% CI, 1.48-2.21) for one atopic disease to 3.29 (95% CI, 1.22-8.88) for three atopic diseases. CONCLUSION: The presence of atopic triad diseases is significantly associated with risks of systemic lupus erythematosus, rheumatoid arthritis, and Sjogren syndrome, and their coexistence exacerbates this risk. To our knowledge, this was the first study that reported an increased risk of Sjogren syndrome among patients with atopy. PMID- 28814360 TI - Skin rash in a 2-week-old infant. AB - We presented a case of a male infant with annular patchy rash on his torso since 2 weeks of age. This was initially diagnosed as tinea corporis but did not respond to oral antifungal treatment. Because of the appearance of the rash and a history of a certain disease in a maternal aunt, we suspected the most probable cause of the rash and the diagnosis was confirmed by laboratory testing. Furthermore, laboratory screening of the mother, who was asymptomatic, revealed that she was seropositive for the disease and was counseled on the importance of follow-up. The infant's rash gradually improved and completely disappeared, without any sequalae by 8 months of age. PMID- 28814361 TI - For the Patient. PMID- 28814363 TI - Fluoride Availability and Stability in Children's Toothpastes in Uruguay. AB - PURPOSE: The purpose of this study was to evaluate the availability and stability of fluoride in children's toothpastes in Uruguay. METHODS: Six commercial brands of children's toothpaste available in Uruguay were tested. Analyses were made when the dentifrices were purchased (fresh samples) and after one year of storage (aged samples). Total fluoride (TF) and total soluble fluoride (TSF) concentrations were determined using an ion specific electrode. RESULTS: Four of the children's dentifrices showed TF concentration similar to that specified on the package. Three products showed similar concentrations of TF and TSF with no variations after the one-year storage period. Two dentifrices showed an initial insoluble fluoride concentration greater than 50 percent, which increased with toothpaste aging. CONCLUSION: Most tested toothpastes showed a decrease in the soluble fluoride content with aging. The high quantity of insoluble fluoride found in two tested dentifrices may compromise their anti-caries efficacy. PMID- 28814364 TI - Effect of Cured Versus Uncured Adhesive Inclusion on the Microtensile Bond Strength of Sealants. AB - PURPOSE: To determine the impact of light curing of bonding agents on the microtensile bond strength (MTBS) of sealants on extracted teeth. METHODS: Flat enamel surfaces were created on 54 extracted, sound human molars by sequential grinding. Three different sealants- Clinpro (3M ESPE), Ultraseal XT Hydro (Ultradent), and Fluorshield VLC (Dentsply)- were placed after acid etching without a bonding agent (control) or with three different bonding agents - Adper Single Bond Plus (3M ESPE), Peak Universal Bond (Ultradent), and Prime&Bond Elect (Dentsply)- each in both light-cured and uncured form. The teeth were sectioned into bar specimens and the MTBS of each specimen was measured. The bond strength data were analyzed using two-way analysis of variance and Tukey's test (P=0.05). RESULTS: There was no significant difference between the MTBS of sealants in the thermocycled and non-thermocycled groups. The uncured adhesive had the lowest bond strength in each group, except for Clinpro after thermocycling. Teeth with uncured adhesive exhibited significantly lower bond strength in the Ultraseal (no thermocycling) and Fluroshield (with thermocycling) groups (P=0.02 and P=0.001, respectively). CONCLUSIONS: Adding bonding agents without curing before sealant placement weakened the microtensile bond strength. There was no significant difference in MTBS between the thermocycled and nonthermocycled groups. PMID- 28814365 TI - Pediatric Admissions After Dental Care Under General Anesthesia: A Retrospective Study at a Tertiary Care Center. AB - PURPOSE: The purpose of this study was to identify factors associated with planned and unplanned pediatric hospital admissions following dental treatment under general anesthesia (DGA) in a tertiary care center. METHODS: Dental and medical records of 100 subjects one to 20 years of age, with a known history of admission after DGA, were reviewed retrospectively for patient-, procedure-, and anesthesia-related factors as well as adverse events following DGA. RESULTS: During the review period (December 3, 2011 to June 30, 2015), 10,371 subjects underwent DGA, of which 100 subjects (less than one percent) required admission. A significant association was found between postoperative (PO) recovery time and unplanned admissions following DGA (P<0.001). Adverse post-operative events significantly associated with unplanned admissions included emesis (P=0.01) and hypoxia (P<0.001). CONCLUSIONS: Patients who were classified as having American Anesthesiology Association (ASA) III status were more frequently admitted following DGA. Adverse events such as emesis and hypoxia were significantly associated with patients with an unplanned admission. PMID- 28814366 TI - Porphyromonas Gingivalis and IgG1 and IgG2 Subclass Antibodies in Patients with Juvenile Idiopathic Arthritis. AB - PURPOSE: The purpose of this study was to evaluate the periodontal status and the presence and concentration of Porphyromonas gingivalis (P. gingivalis) and immunoglobulin G (IgG) subclass against P. gingivalis in juvenile idiopathic arthritis (JIA) and its association with rheumatic clinical activity parameters. METHODS: Rheumatologic conditions and periodontal status were clinically assessed in 51 patients with JIA. P. gingivalis, IgG1 and IgG2, high-sensitivity C reactive protein, erythrocyte sedimentation rate, rheumatoid factor (RF), anti citrullinated protein antibodies (ACPAs), and human leukocyte antigen B27 were also evaluated. RESULTS: Periodontitis was observed in 21.5 percent of the patients, 23.5 percent of whom were positive for P. gingivalis, which was associated with enthesitis-related arthritis (P<0.035). IgG1 against P gingivalis was associated with RF autoantibodies (P=0.05), and all patients positive for ACPAs had higher anti-P gingivalis IgG1 levels. A significant correlation was found between the presence of limited joint mobility and the plaque index in polyarticular JIA (r=0.55, P=0.028). CONCLUSIONS: An association between IgG and rheumatic disease activity markers in JIA was evident. It is important to investigate the familiar periodontal status and clinical course in JIA, especially in enthesitis-related arthritis. PMID- 28814367 TI - Relationship Between Salivary Cortisol Levels and Children's Behavior During a Dental Examination. AB - PURPOSE: To correlate the salivary cortisol levels in children attending a university dental clinic with their behavior during the dental appointment. METHODS: A prospective study was conducted with 43 seven- to 10-year-old children whose behavior during the dental appointment was assessed using the Frankl scale. Participants were divided into two groups: (1) cooperative children; and (2) uncooperative children. All children had four saliva samples collected as follows: prior to the dental examination (S1); shortly after the dental examination (S2); 30 minutes after waking up in the morning after the day of the appointment (S3); and in the afternoon, 24 hours after the dental appointment (S4). Salivary cortisol levels were measured by the chemiluminescent assay method. Statistical analysis included the Friedman and the Wilcoxon signed rank tests. RESULTS: For the cooperative group, salivary cortisol levels were significantly lower at S1 (P=0.004), S2 (P=0.006), and S4 (P=0.001) compared to S3. For the uncooperative group, salivary cortisol levels were significantly higher at S1 compared to S2 (P=0.005). CONCLUSIONS: Uncooperative children presented high levels of salivary cortisol prior to and shortly after the dental appointment. The period anticipating the consultation was considered highly stressful. PMID- 28814368 TI - Uncommon Occurrence of Lip Squamous Cell Carcinoma in a Pediatric Patient. AB - Although head and neck squamous cell carcinoma represents one of the most common cancers among adults, it is rare in pediatric patients. The purpose of this report is to discuss the case of a 15-year-old male patient referred by his dentist due to a three-month old ulcer in his lower lip. The patient denied tobacco smoking and drinking alcohol, and confirmed that he performed manual labor in a brick yard, being exposed daily to the sun without protection. Clinical examination revealed an exophytic rounded ulcer in the right lower lip, measuring 1.5 cm, with a flaky bed. An incisional biopsy was performed, and histopathologic analysis confirmed the diagnosis of squamous cell carcinoma. The treatment of choice was surgical excision. Malignancy should be included in the differential diagnosis of chronic oral ulcers in children and adolescents. Moreover, chronic sun exposure might be associated with occurrence of lip squamous cell carcinoma. PMID- 28814369 TI - Intraosseous Leiomyoma of the Jaw in an Adolescent. AB - Leiomyoma is a benign tumor of the smooth muscle that rarely occurs in the mouth as an intraosseous lesion. The purposes of this paper are to: (1) present a case of an intraosseous solid leiomyoma of the mandible in a 13-year-old child, who presented with a well-defined unilocular radiolucency in the right mandible incidentally discovered during a routine dental radiographic examination; and (2) conduct a review of the literature to describe clinicopathological features and management of intraosseous jaw leiomyoma (IJL). A total of 17 articles describing 18 cases of IJL satisfied the selection criteria; including the present patient, to date a total of 19 cases of IJL have been reported. IJL occurs mainly in young patients (36.8 percent), more often in boys (1:5:1 male-to-female ratio), and reaches a larger size in children than in adults. The treatment of choice for IJL is surgical excision, which should be as minimally invasive as possible, especially in children. PMID- 28814370 TI - Unusual Case of Graphite Tattoo in a Pediatric Patient: Clinical Presentation and Differential Diagnosis. AB - Graphite tattoo, a rare finding in children, is characterized by a localized blue grey macule of variable sizes and shapes. Intraoral graphite implantation may cause this pigmentation through accidental injury with a graphite pencil. The purpose of this paper is to report an unusual case of graphite tattoo involving the anterior palate region in a seven-year-old girl. A diagnosis was made based on clinical and radiographic examinations and histopathology features. This report also highlights the importance of differential diagnosis and management of oral benign and malignant pigmented lesions in children. PMID- 28814371 TI - Dental Management Considerations in a Pediatric Patient with Moyamoya Disease. AB - Moyamoya disease is a rare progressive cerebral arteriopathy associated with risk of ischemic and hemorrhagic brain complications. The dental care of affected individuals should be performed in a pain- and stress-free manner to decrease the chance of occurrence of episodes of hypocapnia, hypercapnia, hypotension, hypovolemia, and hypothermia. Dental treatment may be provided in an outpatient dental setting or in a hospital setting, but both venues require interdisciplinary collaboration to ensure safe delivery of patient care. In cases of general anesthesia, the perioperative management must be well-coordinated between dental clinicians and anesthesiologists to minimize the risk of adverse events. The purposes of this paper are to present the case of an eight-year-old Asian male with Moyamoya disease, and to discuss important aspects of his dental, behavioral, and medical management. PMID- 28814372 TI - Association of CYP19A1 gene polymorphisms with anoestrus in water buffaloes. AB - Cytochrome P450 aromatase (encoded by the CYP19A1 gene) regulates oestrogen biosynthesis and so plays an essential role in female fertility. We investigated the genetic association of CYP19A1 with the risk of anoestrus in Egyptian water buffaloes. A total of 651 animals (326 anoestrous and 325 cycling) were used in this case-control study. Using single-strand conformation polymorphisms and sequencing, four single nucleotide polymorphisms (SNPs) were detected; c.-135T>C SNP in the 5'UTR and three non-synonymous SNPs: c.559G>A (p. V187M) in Exon 5, c.1285C>T (p. P429S) and c.1394A>G (p. D465G) in Exon 10. Individual SNP anoestrus association analyses revealed that genotypes (CC, AA and GG) and alleles (C, A and G) of the -135T>C, c.559G>A and c.1394A>G SNPs respectively were high risk for anoestrus. A further analysis confirmed that these three SNPs were in linkage disequilibrium. Additionally, haplotypes with two (TAG/122 and CAA/221) or three (CAG/222) risk alleles were significantly associated with susceptibility to anoestrus, lower blood levels of both oestradiol and antioxidant enzymes (superoxide dismutase, glutathione peroxidase (GPX) and catalase) and downregulated expression levels of CYP19A1, oestrogen receptor alpha and Gpx3 in the ovary, as well as increased serum level of malondialdehyde. This suggests the occurrence of a high incidence of oxidative ovarian damage and subsequently ovarian inactivity in buffaloes carrying risk alleles. Therefore, with this study we suggest the selection of buffaloes with protective alleles at these SNPs to improve the reproductive efficiency of the herd. PMID- 28814373 TI - Convenience, quality and choice: Patient and service-provider perspectives for treating primary care complaints in urgent care settings. AB - AIM: To investigate why patients chose to attend two, nurse-led, minor injury units (MIUs) to access primary healthcare services rather than attend their GP practice. BACKGROUND: Since the 1980's, healthcare organisations in the UK and elsewhere have implemented an increasingly consumer-orientated model of healthcare provision. As a result, patients with non-urgent presentations are attending Emergency Departments (EDs) and other urgent care facilities in growing numbers. METHODS: A comparative case study approach was adopted and between October 2014 and May 2015 the researcher was embedded as a participant observer as part of the emergency nurse practitioner team at two, nurse-led, MIUs (site A and B). During this time, 40 patients, 17 service-providers and 1 senior manager were interviewed. RESULTS: Patients and service-providers at both sites identified convenience and quality of care as the principle reasons patients presented for primary healthcare services at MIUs rather than their GP practice. Service-providers were aware that by providing treatment, they established a precedent and a sense of expectation for future care. CONCLUSION: Patients are acting rationally and predictably in response to healthcare policy promises regarding choice, expectation created by service-providers, and local demographic factors. PMID- 28814374 TI - From bench (laboratory) to bed (hospital/home): How to explore effective natural and synthetic PAK1-blockers/longevity-promoters for cancer therapy. AB - PAK family kinases are RAC/CDC42-activated kinases that were first found in a soil amoeba 4 decades ago, and 2 decades later, were discovered in mammals as well. Since then at least 6 members of this family have been identified in mammals. One of them called PAK1 has been best studied so far, mainly because it is essential not only for malignant cell growth and metastasis, but also for many other diseases/disorders such as diabetes (type 2), AD (Alzheimer's disease), hypertension, and a variety of inflammatory or infectious diseases, which definitely shorten our lifespan. Moreover, PAK1-deficient mutant of C. elegans lives longer than the wild-type by 60%, clearly indicating that PAK1 is not only an oncogenic but also ageing kinase. Thus, in theory, both anti-oncogenic and longevity-promoting activities are among the "intrinsic" properties or criteria of "clinically useful" PAK1-blockers. There are a variety of PAK1-blocking natural products such as propolis and curcumin which indeed extend the healthy lifespan of small animals such as C. elegans by inducing the autophagy. Recently, we managed to synthesize a series of potent water-soluble and highly cell permeable triazolyl esters of COOH-bearing PAK1-blockers such as Ketorolac, ARC (artepillin C) and CA (caffeic acid) via "Click Chemistry" that boosts their anti cancer activity over 500-fold, mainly by increasing their cell-permeability, and one of them called 15K indeed extends the lifespan of C. elegans. In this mini review we shall discuss both synthetic and natural PAK1-blockers, some of which would be potentially useful for cancer therapy with least side effect (rather promoting the longevity as well). PMID- 28814375 TI - Influencers of generic drug utilization: A systematic review. AB - INTRODUCTION: With an increase in prescription drug spending and rising drug costs there is a need to encourage the use of generic prescription drugs. However, maximizing generic drug use is not possible without the public's positive perception and meeting their informational needs about generic drugs. Thus, improving the public's confidence in, and knowledge of generic drugs on the market is critical. The objective of this systematic review is to examine and evaluate the studies focusing on the nature and extent of key factors influencing generic drug use in the United States in order to help guide policy, education and practice interventions. MATERIALS AND METHODS: Using multiple search engines and key word screening criteria, empirical studies published in English between January 1, 2005 and December 31, 2015 were identified. A qualitative synthesis of the evidence identified domains of key factors that influenced generic drug use across studies. RESULTS: Over 3000 citations met the key word screening criteria; 67 of these met inclusion criteria for the systematic review. Seven domains of factors that influence generic drug utilization were identified: 1) patient related factors, 2) formulary management or cost containment, 3) healthcare policies, 4) promotional activities, 5) educational initiatives, 6) technology, and 7) physician-related factors. CONCLUSION: Patients, physicians, pharmacists, formulary managers, and policymakers play an important role in generic drug use. Understanding the factors influencing generic drug use can help guide future policy, education, and practice interventions to increase generic drug use. PMID- 28814376 TI - Cross-sectional imaging of sinus of Valsalva aneurysms: lessons learned. AB - Sinus of Valsalva aneurysm, dilatation of one or more of the aortic sinuses, is a rare but important aortic root defect, which can be a cause of some serious cardiac sequels. The purpose of this article is to review the etiopathogenesis, relevant anatomy, clinical manifestations, potential complications, multimodality imaging features, and management of this rare but important entity of sinus of Valsalva. PMID- 28814377 TI - Body Weight Misperception and Dissatisfaction Among Overweight and Obese Adult Nigerians. AB - BACKGROUND: The increase in the prevalence of overweight and obesity in low- and medium-income countries has a negative impact on overall health. Correct perception of one's body weight is a step in seeking healthy help toward weight reduction in overweight and obese individuals. OBJECTIVE: This study was carried out to assess the body weight misperception and dissatisfaction among overweight and obese adults in an urban African setting. METHODS: This study was part of a larger cross-sectional study that was designed to plan an intervention for overweight and obese adults in an urban African setting. For this study, we randomly selected only overweight and obese adults (>=18 years old) who consented to participate in the study from 15 enumeration areas in Alimosho Local Government Area of Lagos State, Nigeria. We followed the World Health Organization guidelines for conducting community surveys in recruiting overweight and obese participants. We assessed body weight perception and dissatisfaction through their responses to the following: "How do you describe your weight?" and "I feel bad about myself because of my weight." Data for this study were collected between November 2012 and March 2013. RESULTS: We recruited 567 participants, of whom more than half (n=304, 53.6%) misperceived their weight as either underweight or normal weight, and 61.2% (n=186) of whom were women. The strength of agreement between the actual body mass index and weight perception was very poor (kappa=.032, SE .015, P=.04). The strongest predictor of weight perception was sex (female) with an odds ratio of 1.63 (95% CI 1.13-2.35). About 41.1% (n=233) of the participants were dissatisfied with their weight, of whom 30.0% (n=70) were men. Age (young adult) was a predictor of weight dissatisfaction with an odds ratio of 2.37 (95% CI 1.62-3.46). CONCLUSIONS: More than half of the participants misperceived their body weight as either underweight or normal weight, and the majority of them were women. More men were not happy with their body weight, and participants in the young adult age group were more dissatisfied with their body weight. PMID- 28814378 TI - mHealth Technologies for Palliative Care Patients at the Interface of In-Patient to Outpatient Care: Protocol of Feasibility Study Aiming to Early Predict Deterioration of Patient's Health Status. AB - BACKGROUND: Palliative care patients are a particularly vulnerable population and one of the critical phases in patients' trajectories is discharge from specialized in-patient palliative care into outpatient care, where availability of a palliative care infrastructure is highly variable. A relevant number of potentially avoidable readmissions and emergency visits of palliative patients is observed due to rapid exacerbation of symptoms indicating the need for a closer patient monitoring. In the last years, different mHealth technology applications have been evaluated in many different patient groups. OBJECTIVE: The aim of our study is to test feasibility of a remote physical and social tracking system in palliative care patients. METHODS: A feasibility study with explorative, descriptive study design, comprised of 3 work packages. From the wards of the Clinic of Radiation-Oncology at the University Hospital Zurich, including the specialized palliative care ward, 30 patients will be recruited and will receive a mobile phone and a tracking bracelet before discharge. The aim of work package A is to evaluate if severely ill patients accept to be equipped with a tracking bracelet and a mobile phone (by semiquantitative questionnaires and guideline interviews). Work package B evaluates the technical feasibility and quality of the acquired electronic health data. Work package C will demonstrate whether physical activity parameters, such as step count, sleep duration, social activity patterns like making calls, and vital signs (eg, heart rate) do correlate with subjective health data and can serve as indicator to early detect and predict changes in patients' health status. Activity parameters will be extracted from the mobile phone's and wristband's sensor data using signal processing methods. Subjective health data is captured via electronic version of visual analog scale and Distress Thermometer as well as the European Organization for Research and Treatment of Cancer - Quality of Life Questionnaire C30 in paper version. RESULTS: Enrollment began in February 2017. First study results will be reported in the middle of 2018. CONCLUSIONS: Our project will deliver relevant data on patients' acceptance of activity and social tracking and test the correlation between subjective symptom assessment and objective activity in the vulnerable population of palliative care patients. The proposed study is meant to be preparatory work for an intervention study to test the effect of wireless monitoring of palliative care patients on symptom control and quality of life. PMID- 28814379 TI - Are Routine Radiographs Needed the Day After Open Reduction and Internal Fixation Surgery for Distal Radius and Ankle Fractures: Study Protocol for a Prospective, Open Label, Randomized Controlled Trial. AB - BACKGROUND: Distal radius and ankle fractures are one of the most common operatively treated fractures. To date, there is no consensus concerning the need for a standard postoperative radiograph. This leads to undesirable practice variations. A standardized radiograph in the department of radiology would theoretically be more reproducible and operator independent than an intraoperatively obtained fluoroscopic image. However, if adequate intraoperative radiographs have been obtained, it is questionable if these postoperative radiographs are necessary and will lead to changes in the treatment strategy. If standard postoperative radiographs are no longer required, this would lead to a reduction in radiation exposure and health care costs. The hypothesis is that routine standardized postoperative radiographs do not influence the quality of care for patients operated on for either a distal radius or an ankle fracture if adequate intraoperative standardized radiographs have been obtained. OBJECTIVE: The primary aim of this study is to evaluate if there is a need for routine postoperative radiographs after an osteosynthesis of a distal radius or ankle fracture. METHODS: In a prospective, randomized controlled, open label trial based on a noninferiority design, we will enroll 332 patients. Patients will be randomized either in the control or the intervention group. The control group will be treated according to our current, standard protocol in which all patients receive a standard anterior-posterior and lateral radiograph on the first postoperative day. Patients randomized to the intervention group will be treated without a standard postoperative radiograph. All patients (N=332) will have a routine clinical and radiographic control after 6 weeks in the outpatient clinic. Primary outcome is a change in treatment plan, defined as either additional imaging or a reoperation based on the postoperative imaging. Secondary outcome measures include a 36-Item Short Form Survey, Patient-Rated Wrist Hand Evaluation, Foot and Ankle Outcome Score, Visual Analogue Scale, and the range of motion. Those questionnaires will be filled out at the 6-week outpatient control. RESULTS: The trial was started in August 2016, and 104 patients have been enrolled up to this point. CONCLUSIONS: Our findings will be reported in peer reviewed publications and may lead to a strong reduction in radiation exposure and health care costs. A preliminary, conservative estimation suggests a yearly cost saving of CHF 1.3 million in Switzerland. PMID- 28814380 TI - The Effect of Integration of Self-Management Web Platforms on Health Status in Chronic Obstructive Pulmonary Disease Management in Primary Care (e-Vita Study): Interrupted Time Series Design. AB - BACKGROUND: Worldwide nearly 3 million people die from chronic obstructive pulmonary disease (COPD) every year. Integrated disease management (IDM) improves quality of life for COPD patients and can reduce hospitalization. Self-management of COPD through eHealth is an effective method to improve IDM and clinical outcomes. OBJECTIVES: The objective of this implementation study was to investigate the effect of 3 chronic obstructive pulmonary disease eHealth programs applied in primary care on health status. The e-Vita COPD study compares different levels of integration of Web-based self-management platforms in IDM in 3 primary care settings. Patient health status is examined using the Clinical COPD Questionnaire (CCQ). METHODS: The parallel cohort design includes 3 levels of integration in IDM (groups 1, 2, 3) and randomization of 2 levels of personal assistance for patients (group A, high assistance, group B, low assistance). Interrupted time series (ITS) design was used to collect CCQ data at multiple time points before and after intervention, and multilevel linear regression modeling was used to analyze CCQ data. RESULTS: Of the 702 invited patients, 215 (30.6%) registered to a platform. Of these, 82 participated in group 1 (high integration IDM), 36 in group 1A (high assistance), and 46 in group 1B (low assistance); 96 participated in group 2 (medium integration IDM), 44 in group 2A (high assistance) and 52 in group 2B (low assistance); also, 37 participated in group 3 (no integration IDM). In the total group, no significant difference was found in change in CCQ trend (P=.334) before (-0.47% per month) and after the intervention (-0.084% per month). Also, no significant difference was found in CCQ changes before versus after the intervention between the groups with high versus low personal assistance. In all subgroups, there was no significant change in the CCQ trend before and after the intervention (group 1A, P=.237; 1B, P=.991; 2A, P=.120; 2B, P=.166; 3, P=.945). CONCLUSIONS: The e-Vita eHealth-supported COPD programs had no beneficial impact on the health status of COPD patients. Also, no differences were found between the patient groups receiving different levels of personal assistance. TRIAL REGISTRATION: Netherlands Trial Registry NTR4098; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4098 (Archived by WebCite at http://www.webcitation.org/6sbM5PayG). PMID- 28814382 TI - Predictive utility of swab screening for vancomycin-resistant Enterococcus in selection of empiric antibiotics for Enterococcus sterile-site infections: a retrospective cohort study. AB - BACKGROUND: Swab screening for vancomycin-resistant Enterococcus (VRE) is used to identify VRE carriers and thus prevent transmission of this organism. We tested whether screening results could have unintended benefits in predicting the vancomycin susceptibility of subsequent Enterococcus infections experienced by these patients. METHODS: We conducted a retrospective cohort study of all patients admitted to a large tertiary care hospital between 2010 and 2015 who underwent swab screening for VRE before experiencing an Enterococcus sterile-site infection. We derived test characteristics using the screening result as the test variable predicting the presence or absence of vancomycin resistance in the sterile-site Enterococcus species. RESULTS: Culture results for sterile-site samples were positive for Enterococcus for 619 patients during the study period. Of these, 488 (79%) had previously undergone VRE screening. A total of 19 (4%) of the 488 screening results were positive for VRE, and 10 (2%) of the sterile-site Enterococcus isolates were resistant to vancomycin. The overall specificity of VRE swabs was 97% (95% confidence interval [CI] 96%-99%), sensitivity was 70% (95% CI 35%-93%), the positive likelihood ratio was 28 (95% CI 14-56), and the negative likelihood ratio was 0.31 (95% CI 0.12-0.79). The post-test probability of vancomycin resistance in a sterile-site culture, given a positive result with VRE screening swab, was 37% using study data and 83% using published aggregate prevalence data for VRE in the United States. INTERPRETATION: Prior VRE screening swab results represent a useful tool for predicting vancomycin resistance in sterile-site Enterococcus infections. Patients with a positive result for VRE screening swab and Enterococcus identified by culture of sterile-site samples should receive empiric treatment with linezolid or daptomycin until sensitivity results are available. PMID- 28814381 TI - Impact of a Tutored Theoretical-Practical Training to Develop Undergraduate Students' Skills for the Detection of Caries Lesions: Study Protocol for a Multicenter Controlled Randomized Study. AB - BACKGROUND: Tutored laboratorial activities could be a manner of improving the competency development of students. However, its impact over conventional theoretical classes has not yet been tested. Additionally, different university contexts could influence this issue and should be explored. OBJECTIVE: To assess the impact of a tutored theoretical-practical training for teaching undergraduate students to detect caries lesions as compared with theoretical teaching activities. The impact of these teaching/learning activities will be assessed in terms of efficacy, cost/benefit, retention of knowledge/acquired competences, and student acceptability. METHODS: Sixteen centers (7 centers from Brazil and 9 centers from other countries throughout the world) are involved in the inclusion of subjects for this protocol. A randomized controlled study with parallel groups will be conducted. One group (control) will be exposed to a 60- to 90-minute conventional theoretical class and the other group (test) will be exposed to the same theoretical class and also a 90-minute laboratory class, including exercises and discussions based on the evaluation of a pool of images and extracted teeth. The mentioned outcomes will be evaluated immediately after the teaching activities and also in medium- and long-term analyses. To compare the long-term outcomes, students who enrolled in the university before the participating students will be interviewed for data collection and these data will be used as a control and compared with the trained group. This stage will be a nonrandomized phase of this study, nested in the main study. Appropriate statistical analysis will be performed according to the aims of this study. Variables related to the centers will also be analyzed and used to model adjustment as possible sources of variability among results. RESULTS: This ongoing study is funded by a Brazilian national funding agency (CNPq- 400736/2014-4). We expect that the tutored theoretical-practical training will improve the undergraduate students' performance in the detection of caries lesions and subsequent treatment decisions, mainly in terms of long-term retention of knowledge. Our hypothesis is that tutored theoretical-practical training is a more cost-effective option for teaching undergraduate students to detect caries lesions. CONCLUSIONS: If our hypothesis is confirmed, the use of laboratory training in conjunction with theoretical classes could be used as an educational strategy in Cariology to improve the development of undergraduate students' skills in the detection of caries lesions and clinical decision-making. PMID- 28814383 TI - High-Resolution, Accurate-Mass (HRAM) Mass Spectrometry Urine Steroid Profiling in the Diagnosis of Adrenal Disorders. AB - BACKGROUND: Steroid profiling is a promising diagnostic tool with adrenal tumors, Cushing syndrome (CS), and disorders of steroidogenesis. Our objective was to develop a multiple-steroid assay using liquid-chromatography, high-resolution, accurate-mass mass spectrometry (HRAM LC-MS) and to validate the assay in patients with various adrenal disorders. METHODS: We collected 24-h urine samples from 114 controls and 71 patients with adrenal diseases. An HRAM LC-MS method was validated for quantitative analysis of 26 steroid metabolites in hydrolyzed urine samples. Differences in steroid excretion between patients were analyzed based on Z-score deviation from control reference intervals. RESULTS: Limits of quantification were 20 ng/mL. Dilution linearity ranged from 80% to 120% with means of 93% to 110% for all but 2 analytes. Intraassay and interassay imprecision ranged from 3% to 18% for all but 1 analyte. Control women had lower excretion of androgen and glucocorticoid precursors/metabolites than men (P < 0.001), but no difference in mineralocorticoids was seen (P = 0.06). Androgens decreased with age in both sexes (P < 0.001). Compared with patients with adrenocortical adenoma (ACA), patients with adrenocortical carcinoma (ACC) had 11 steroids with increased Z scores, especially tetrahydro-11-deoxycortisol (14 vs 0.5, P < 0.001), pregnanetriol (7.5 vs -0.4, P = 0.001), and 5-pregnenetriol (5.4 vs -0.4, P = 0.01). Steroid profiling also demonstrated metabolite abnormalities consistent with enzymatic defects in congenital adrenal hyperplasia and differences in pituitary vs adrenal CS. CONCLUSIONS: Our HRAM LC-MS assay successfully quantifies 26 steroids in urine. The statistically significant differences in steroid production of ACC vs ACA, adrenal vs pituitary CS, and in congenital adrenal hyperplasia should allow for improved diagnosis of patients with these diseases. PMID- 28814384 TI - Twenty-Four-Hour Biological Variation Profiles of Cardiac Troponin I in Individuals with or without Chronic Kidney Disease. PMID- 28814386 TI - Role of anthracycline and comprehensive geriatric assessment for elderly patients with diffuse large B-cell lymphoma. AB - Survival outcome for elderly patients with newly diagnosed diffuse large B-cell lymphoma remains suboptimal in the rituximab era. In this systematic review, we summarize available evidence relevant to the inclusion of anthracycline in upfront chemoimmunotherapy for these elderly patients and highlight the need of prospective clinical trials. With limited prospective data, we find that pretreatment comprehensive geriatric assessment accurately predicts survival and treatment-related toxicities, suggesting its potential role in guiding overall treatment decision-making. PMID- 28814387 TI - Effects of NK1 receptors on gastric motor functions and satiation in healthy humans: results from a controlled trial with the NK1 antagonist aprepitant. AB - Aprepitant, an NK1 receptor antagonist, is approved for the treatment of chemotherapy-induced or postoperative emesis by blocking NK1 receptors in the brain stem vomiting center. The effects of NK1 receptors on gastric functions and postprandial symptoms in humans are unclear; a single, crossover study did not show a significant effect of aprepitant on gastrointestinal transit. Our aim was to compare, in a randomized, double-blind, placebo-controlled, parallel-group study (12 healthy volunteers per group), the effects of aprepitant vs. placebo on gastric emptying of solids (by scintigraphy) with a 320-kcal meal, gastric volumes (GVs; fasting and accommodation by single photon emission-computed tomography ), satiation [maximum tolerated volume (MTV)], and symptoms after a dyspeptogenic meal of Ensure. Aprepitant (125 mg on day 1, followed by 80 mg on days 2-5) or placebo, one tablet daily, was administered for 5 consecutive days. Statistical analysis was by unpaired rank sum test, adjusted for sex difference and body mass index. To assess treatment effects on symptoms, we incorporated MTV in the model. Aprepitant increased fasting, postprandial, and accommodation GV and tended to increase volume to fullness and MTV by ~200 kcal. However, aprepitant increased aggregate symptoms, nausea, and pain scores after ingestion the MTV of Ensure. There was no significant effect of aprepitant on gastric half emptying time of solids. We conclude that NK1 receptors are involved in the control of GV and in determining postprandial satiation and symptoms. Further studies of the pharmacodynamics and therapeutic role of NK1 receptor antagonists in patients with gastroparesis and dyspepsia are warranted.NEW & NOTEWORTHY Aprepitant increases fasting, postprandial, and accommodation gastric volumes. Aprepitant increases volume to fullness and maximum tolerated volume during a nutrient drink test. NK1 receptors are involved in the control of gastric volume and in determining postprandial satiation and symptoms. PMID- 28814388 TI - Impact of Poxvirus Vector Priming, Protein Coadministration, and Vaccine Intervals on HIV gp120 Vaccine-Elicited Antibody Magnitude and Function in Infant Macaques. AB - Despite success in reducing vertical HIV transmission by maternal antiretroviral therapy, several obstacles limit its efficacy during breastfeeding, and breast milk transmission is now the dominant mode of mother-to-child transmission (MTCT) of HIV in infants. Thus, a pediatric vaccine is needed to eradicate oral HIV infections in newborns and infants. Utilizing the infant rhesus macaque model, we compared 3 different vaccine regimens: (i) HIV envelope (Env) protein only, (ii) poxvirus vector (modified vaccinia virus Ankara [MVA])-HIV Env prime and HIV Env boost, and (iii) coadministration of HIV Env and MVA-HIV Env at all time points. The vaccines were administered with an accelerated, 3-week-interval regimen starting at birth for early induction of highly functional HIV Env-specific antibodies. We also tested whether an extended, 6-week immunization interval using the same vaccine regimen as in the coadministration group would enhance the quality of antibody responses. We found that pediatric HIV vaccines administered at birth are effective in inducing HIV Env-specific plasma IgG. The vaccine regimen consisting of only HIV Env protein induced the highest levels of variable region 1 and 2 (V1V2)-specific antibodies and tier 1 neutralizing antibodies, whereas the extended-interval regimen induced both persistent Env-specific systemic IgG and mucosal IgA responses. Antibody-dependent cell-mediated cytotoxicity (ADCC) antibodies in plasma were elicited by all vaccine regimens. These data suggest that infant immunizations beginning at birth are effective for the induction of functional HIV Env-specific antibodies that could potentially protect against breast milk transmission of HIV and set the stage for immunity prior to sexual debut. PMID- 28814390 TI - Physiological and metabolic differences between visceral and subcutaneous adipose tissues in Nile tilapia (Oreochromis niloticus). AB - Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SCAT) have different structures and metabolic functions and play different roles in the regulation of the mammal endocrine system. However, little is known about morphology and physiological and metabolic functions between VAT and SCAT in fish. We compared the morphological, physiological, and biochemical characteristics of VAT and SCAT in Nile tilapia and measured their functions in energy intake flux, lipolytic ability, and gene expression patterns. SCAT contained more large adipocytes and nonadipocytes than VAT in Nile tilapia. VAT had higher lipid content and was the primary site for lipid deposition. Conversely, SCAT had higher hormone-induced lipolytic activity. Furthermore, SCAT had a higher percentage of monounsaturated and lower polyunsaturated fatty acids than VAT. SCAT had higher mitochondrial DNA, gene expression for fatty acid beta oxidation, adipogenesis, and brown adipose tissue characteristics, but it also had a lower gene expression for inflammation and adipocyte differentiation than VAT. SCAT and VAT have different morphological structures, as well as physiological and metabolic functions in fish. VAT is the preferable lipid deposition tissue, whereas SCAT exhibits higher lipid catabolic activity than VAT. The physiological functions of SCAT in fish are commonly overlooked. The present study indicates that SCAT has specific metabolic characteristics that differ from VAT. The differences between VAT and SCAT should be considered in future metabolism studies using fish as models, either in biomedical or aquaculture studies. PMID- 28814389 TI - Equine Arteritis Virus Elicits a Mucosal Antibody Response in the Reproductive Tract of Persistently Infected Stallions. AB - Equine arteritis virus (EAV) has the ability to establish persistent infection in the reproductive tract of the stallion (carrier) and is continuously shed in its semen. We have recently demonstrated that EAV persists within stromal cells and a subset of lymphocytes in the stallion accessory sex glands in the presence of a significant local inflammatory response. In the present study, we demonstrated that EAV elicits a mucosal antibody response in the reproductive tract during persistent infection with homing of plasma cells into accessory sex glands. The EAV-specific immunoglobulin isotypes in seminal plasma included IgA, IgG1, IgG3/5, and IgG4/7. Interestingly, seminal plasma IgG1 and IgG4/7 possessed virus neutralizing activity, while seminal plasma IgA and IgG3/5 did not. However, virus-neutralizing IgG1 and IgG4/7 in seminal plasma were not effective in preventing viral infectivity. In addition, the serological response was primarily mediated by virus-specific IgM and IgG1, while virus-specific serum IgA, IgG3/5, IgG4/7, and IgG6 isotype responses were not detected. This is the first report characterizing the immunoglobulin isotypes in equine serum and seminal plasma in response to EAV infection. The findings presented herein suggest that while a broader immunoglobulin isotype diversity is elicited in seminal plasma, EAV has the ability to persist in the reproductive tract, in spite of local mucosal antibody and inflammatory responses. This study provides further evidence that EAV employs complex immune evasion mechanisms during persistence in the reproductive tract that warrant further investigation. PMID- 28814392 TI - Temporal eating patterns: associations with nutrient intakes, diet quality, and measures of adiposity. AB - Background: Some evidence suggests that higher energy intake (EI) later in the day is associated with poor diet quality and obesity. However, EI at one eating occasion (EO) is also dependent on EI at surrounding EOs. Studies that examine the distribution of EOs across the day are rare.Objective: The aim of this study was to examine associations between temporal eating patterns, nutrient intakes, diet quality, and measures of adiposity in a representative sample of Australian adults.Design: Dietary data from two 24-h recalls collected during the cross sectional 2011-2012 Australian National Nutrition and Physical Activity Survey were analyzed (n = 4544 adults, aged >=19 y). Temporal eating patterns, based on the distribution of EOs across the day, were determined by using latent class analysis. Diet quality estimated adherence to healthy eating recommendations and was assessed by using the 2013 Dietary Guidelines Index (DGI). Multivariate regression models assessed associations between temporal eating patterns, nutrient intakes, diet quality, and adiposity (body mass index, waist circumference, weight status, and central weight status). Models were adjusted for potential confounders and energy misreporting.Results: Three patterns, labeled "conventional," "later lunch," and "grazing," were identified. Compared with a "conventional" or "later lunch" pattern, men and women with a "grazing" pattern had lower DGI scores and higher intakes of discretionary (noncore) foods (P < 0.05). Among women, the "grazing" pattern was associated with overweight or obesity (OR: 1.57; 95% CI: 1.15, 2.13) and central overweight or obesity (OR: 1.73; 95% CI: 1.19, 2.50). These associations were attenuated after the exclusion of energy misreporters and adjustment for total EI.Conclusions: This study found that a "grazing" temporal eating pattern was modestly but significantly associated with poorer diet quality and adiposity among women, after adjustment for covariates and energy misreporting. Future research should consider the impact of energy misreporting on the relation between temporal eating patterns and adiposity. This secondary analysis was registered at anzctr.org.au as ACTRN12617001029381. PMID- 28814391 TI - Filling the void: a role for exercise-induced BDNF and brain amyloid precursor protein processing. AB - Inactivity, obesity, and insulin resistance are significant risk factors for the development of Alzheimer's disease (AD). Several studies have demonstrated that diet-induced obesity, inactivity, and insulin resistance exacerbate the neuropathological hallmarks of AD. The aggregation of beta-amyloid peptides is one of these hallmarks. beta-Site amyloid precursor protein-cleaving enzyme 1 (BACE1) is the rate-limiting enzyme in amyloid precursor protein (APP) processing, leading to beta-amyloid peptide formation. Understanding how BACE1 content and activity are regulated is essential for establishing therapies aimed at reducing and/or slowing the progression of AD. Exercise training has been proven to reduce the risk of AD as well as decrease beta-amyloid production and BACE1 content and/or activity. However, these long-term interventions also result in improvements in adiposity, circulating metabolites, glucose tolerance, and insulin sensitivity making it difficult to determine the direct effects of exercise on brain APP processing. This review highlights this large void in our knowledge and discusses our current understanding of the direct of effect of exercise on beta-amyloid production. We have concentrated on the central role that brain-derived neurotrophic factor (BDNF) may play in mediating the direct effects of exercise on reducing brain BACE1 content and activity as well as beta amyloid production. Future studies should aim to generate a greater understanding of how obesity and exercise can directly alter APP processing and AD-related pathologies. This knowledge could provide evidence-based hypotheses for designing therapies to reduce the risk of AD and dementia. PMID- 28814393 TI - Soya, maize, and sorghum-based ready-to-use therapeutic food with amino acid is as efficacious as the standard milk and peanut paste-based formulation for the treatment of severe acute malnutrition in children: a noninferiority individually randomized controlled efficacy clinical trial in Malawi. AB - Background: Development of more cost-effective ready-to-use therapeutic food (RUTF) is a global public health priority. To date, previous lower-cost recipes have been less effective than the standard peanut and milk (PM)-based RUTF, particularly in children aged <24 mo.Objective: We aimed to compare the efficacy of the PM-RUTF to a milk-free soya, maize, and sorghum (FSMS)-RUTF enriched with crystalline amino acids without cow milk powder and a milk, soya, maize, and sorghum (MSMS)-RUTF containing 9.3% skim cow milk powder.Design: This nonblinded, 3-arm, parallel-group, simple randomized controlled trial enrolled Malawian children with severe acute malnutrition.Results: In intention-to-treat analyses, FSMS-RUTF showed noninferiority for recovery rates in children aged 24-59 mo (Delta: -1.9%; 95% CI: -9.5%, 5.6%) and 6-23 mo (Delta: -0.2%; 95% CI: -7.5%, 7.1%) compared with PM-RUTF. MSMS-RUTF also showed noninferiority for recovery rates in children aged 24-59 mo (Delta: 0.0%; 95% CI: -7.3%, 7.4%) and 6-23 mo (Delta: 0.6%; 95% CI: -4.3%, 5.5%). Noninferiority in recovery rates was also observed in per-protocol analyses. For length of stay in the program (time to cure), both FSMS-RUTF in children aged 24-59 mo (Delta: 2.8 d; 95% CI: -0.8, 6.5 d) and 6-23 mo (Delta: 3.4 d; 95% CI: -1.2, 8.0 d) and MSMS-RUTF in children aged 24-59 mo (Delta: 0.2 d; 95% CI: -3.1, 3.6 d) and 6-23 mo (Delta: 1.2 d; 95% CI: 3.4, 5.8 d) were not inferior to PM-RUTF. FSMS-RUTF was also significantly better than PM-RUTF at increasing hemoglobin and body iron stores in anemic children, with mean hemoglobin increases of 2.1 (95% CI: 1.6, 2.6) and 1.3 (95% CI: 0.9, 1.8) and mean body iron store increases of 2.0 (95% CI: 0.8, 3.3) and 0.1 (95% CI: -1.1, 1.3) for FSMS-RUTF and PM-RUTF, respectively.Conclusions: FSMS-RUTF without milk is efficacious in the treatment of severe acute malnutrition in children aged 6-23 and 24-59 mo. It is also better at correcting iron deficiency anemia than PM-RUTF. This trial was registered at www.pactr.org as PACTR201505001101224. PMID- 28814394 TI - Dynamics of intrapericardial and extrapericardial fat tissues during long-term, dietary-induced, moderate weight loss. AB - Background: In view of evidence linking pericardial fat accumulation with increased cardiovascular disease risk, strategies to reduce its burden are needed. Data comparing the effects of specific long-term dietary interventions on pericardial fat tissue mobilization are sparse.Objective: We sought to evaluate intrapericardial-fat (IPF) and extrapericardial-fat (EPF) changes during weight loss interventions by different dietary regimens.Design: During 18 mo of a randomized controlled trial, we compared a Mediterranean/low-carbohydrate (MED/LC) diet plus 28 g walnuts/d with a calorically equal low-fat (LF) diet among randomly assigned participants with moderate abdominal obesity. We performed whole-body MRI and volumetrically quantified IPF and EPF among 80 participants to follow the 18-mo changes.Results: The participants [mean age: 48.6 y; mean body mass index (BMI; in kg/m2); 31.7; 90% men] had baseline IPF and EPF (mean +/- SD) volumes of 172.4 +/- 53.3 mL and 194.9 +/- 71.5 mL, respectively. The 18-mo moderate weight loss of 3.7 kg was similar in both groups, but the reduction in waist circumference was higher in the MED/LC group ( 6.9 +/- 6.6 cm) than in the LF diet group (-2.3 +/- 6.5 cm; P = 0.01). After 18 mo, the IPF volume had reduced twice as much in the MED/LC group compared with the LF group [-37 +/- 26.2 mL (-22% +/- 15%) compared with -15.5 +/- 26.2 mL (-8% +/- 15%), respectively; P < 0.05, after adjustment for changes in weight or visceral adipose tissue]. The EPF volume had reduced similarly in both groups [ 41.6 +/- 30.2 mL (-23% +/- 16%) in the MED/LC group compared with -37.9 +/- 28.3 mL (-19% +/- 14%) in the LF group; P > 0.1]. After controlling for weight loss, IPF and EPF volume reduction paralleled changes in lipid profile but not with improved glycemic profile variables: the IPF relative reduction was associated with a decrease in triglycerides (TGs) (beta = 0.090; 95% CI: 0.026, 0.154; P = 0.007) and the ratio of TGs to high-density lipoprotein (HDL) cholesterol (beta = 2.689; 95% CI: 0.373, 5.003; P = 0.024), and the EPF relative reduction was associated with an increase in HDL cholesterol (beta = -0.452; 95% CI: -0.880, 0.023; P = 0.039) and a decrease in total cholesterol and HDL cholesterol (beta = 3.766; 95% CI: 1.092, 6.440; P = 0.007).Conclusions: Moderate but persistent dietary-induced weight loss substantially decreased both IPF and EPF volumes. Reduction of pericardial adipose tissues is independently associated with an improved lipid profile. The Mediterranean diet, rich in unsaturated fats and restricted carbohydrates, is superior to an LF diet in terms of the IPF burden reduction. This trial was registered at clinicaltrials.gov as NCT01530724. PMID- 28814395 TI - Fecal concentrations of bacterially derived vitamin K forms are associated with gut microbiota composition but not plasma or fecal cytokine concentrations in healthy adults. AB - Background: Emerging evidence suggests novel roles for bacterially derived vitamin K forms known as menaquinones in health and disease, which may be attributable in part to anti-inflammatory effects. However, the relevance of menaquinones produced by gut bacteria to vitamin K requirements and inflammation is undetermined.Objective: This study aimed to quantify fecal menaquinone concentrations and identify associations between fecal menaquinone concentrations and serum vitamin K concentrations, gut microbiota composition, and inflammation.Design: Fecal and serum menaquinone concentrations, fecal microbiota composition, and plasma and fecal cytokine concentrations were measured in 80 men and postmenopausal women (48 men, 32 women, age 40-65 y) enrolled in a randomized, parallel-arm, provided-food trial. After consuming a run-in diet for 2 wk, participants were randomly assigned to consume a whole grain-rich (WG) or a refined grain-based (RG) diet for 6 wk. Outcomes were measured at weeks 2 and 8.Results: The median total daily excretion of menaquinones in feces was 850 nmol/d but was highly variable (range: 64-5358 nmol/d). The total median (IQR) fecal concentrations of menaquinones decreased in the WG diet compared with the RG diet [-6.8 nmol/g (13.0 nmol/g) dry weight for WG compared with 1.8 nmol/g (12.3 nmol/g) dry weight for RG; P < 0.01)]. However, interindividual variability in fecal menaquinone concentrations partitioned individuals into 2 distinct groups based on interindividual differences in concentrations of different menaquinone forms rather than the diet group or the time point. The relative abundances of several gut bacteria taxa, Bacteroides and Prevotella in particular, differed between these groups, and 42% of identified genera were associated with >=1 menaquinone form. Menaquinones were not detected in serum, and neither fecal concentrations of individual menaquinones nor the menaquinone group was associated with any marker of inflammation.Conclusion: Menaquinone concentrations in the human gut appear highly variable and are associated with gut microbiota composition. However, the health implications remain unclear. This trial was registered at clinicaltrials.gov as NCT01902394. PMID- 28814396 TI - Consumption of galacto-oligosaccharides increases iron absorption from a micronutrient powder containing ferrous fumarate and sodium iron EDTA: a stable isotope study in Kenyan infants. AB - Background: Whether consumption of prebiotics increases iron absorption in infants is unclear.Objective: We set out to determine whether prebiotic consumption affects iron absorption from a micronutrient powder (MNP) containing a mixture of ferrous fumarate and sodium iron EDTA (FeFum+NaFeEDTA) in Kenyan infants.Design: Infants (n = 50; aged 6-14 mo) consumed maize porridge that was fortified with an MNP containing FeFum+NaFeEDTA and 7.5 g galacto oligosaccharides (GOSs) (Fe+GOS group, n = 22) or the same MNP without GOSs (Fe group, n = 28) each day for 3 wk. Then, on 2 consecutive days, we fed all infants isotopically labeled maize porridge and MNP test meals containing 5 mg Fe as 57FeFum+Na58FeEDTA or ferrous sulfate (54FeSO4). Iron absorption was measured as the erythrocyte incorporation of stable isotopes. Iron markers, fecal pH, and bacterial groups were assessed at baseline and 3 wk. Comparisons within and between groups were done with the use of mixed-effects models.Results: There was a significant group-by-compound interaction on iron absorption (P = 0.011). The median percentages of fractional iron absorption from FeFum+NaFeEDTA and from FeSO4 in the Fe group were 11.6% (IQR: 6.9-19.9%) and 20.3% (IQR: 14.2-25.7%), respectively, (P < 0.001) and, in the Fe+GOS group, were 18.8% (IQR: 8.3-37.5%) and 25.5% (IQR: 15.1-37.8%), respectively (P = 0.124). Between groups, iron absorption was greater from the FeFum+NaFeEDTA (P = 0.047) in the Fe+GOS group but not from the FeSO4 (P = 0.653). The relative iron bioavailability from FeFum+NaFeEDTA compared with FeSO4 was higher in the Fe+GOS group than in the Fe group (88% compared with 63%; P = 0.006). There was a significant time-by-group interaction on Bifidobacterium spp. (P = 0.008) and Lactobacillus/Pediococcus/Leuconostoc spp. (P = 0.018); Lactobacillus/Pediococcus/Leuconostoc spp. decreased in the Fe group (P = 0.013), and there was a nonsignificant trend toward higher Bifidobacterium spp. in the Fe+GOS group (P = 0.099). At 3 wk, iron absorption was negatively correlated with fecal pH (P < 0.001) and positively correlated with Lactobacillus/Pediococcus/Leuconostoc spp. (P = 0.001).Conclusion: GOS consumption by infants increased iron absorption by 62% from an MNP containing FeFum+NaFeEDTA, thereby possibly reflecting greater colonic iron absorption. This trial was registered at clinicaltrials.gov as NCT02666417. PMID- 28814397 TI - Association of TCN2 rs1801198 c.776G>C polymorphism with markers of one-carbon metabolism and related diseases: a systematic review and meta-analysis of genetic association studies. AB - Background: Vitamin B-12 (cobalamin) deficiency may produce severe neurologic and hematologic manifestations. Approximately 20-25% of circulating cobalamin binds to transcobalamin 2 (TCN2), which is referred to as active vitamin B-12. The G allele of the TCN2 c.776G>C (rs1801198) polymorphism has been associated with a lower plasma concentration of holotranscobalamin. However, genotype association studies on rs1801198 have led to conflicting results regarding its influence on one-carbon metabolism (OCM) markers or its association with pathologic conditions.Objective: We assessed the association of rs1801198 genotypes with OCM marker concentrations and primary risks of congenital abnormalities, cancer, and Alzheimer disease.Design: We conducted a systematic review of the literature that was published from January 1966 to February 2017 and included all studies that assessed the association between rs1801198 and OCM markers or a pathologic condition.Results: Thirty-four studies met the inclusion criteria. Subjects with the rs1801198 GG genotype had significantly lower concentrations of holotranscobalamin [standardized mean difference (SMD): -0.445 (95% CI: -0.673, 0.217; P < 0.001); I2 = 48.16% (95% CI: 0.00%, 78.10%; P = 0.07)] and higher concentrations of homocysteine (European descent only) [SMD: 0.070 (95% CI: 0.020, 0.120; P = 0.01); I2 = 0.00% (95% CI: 0.00%, 49.59%; P = 0.73)] than did subjects with the rs1801198 CC genotype. The meta-analysis on the association between rs1801198 and methylmalonic acid (MMA) lacked statistical power. No significant difference was observed regarding cobalamin, folate, and red blood cell folate. No significant association was observed between rs1801198 and primary risks of congenital abnormalities, cancer, or Alzheimer disease.Conclusions: Meta-analysis results indicate an influence of rs1801198 on holotranscobalamin and homocysteine concentrations in European-descent subjects. In addition, well-designed and -powered studies should be conducted for assessing the association between rs1801198 and MMA and clinical manifestations that are linked to a decreased availability of cobalamin. This review was registered at www.crd.york.ac.uk/prospero as CRD42017058504. PMID- 28814398 TI - Plasma lipidomic profiles and cardiovascular events in a randomized intervention trial with the Mediterranean diet. AB - Background: Lipid metabolites may partially explain the inverse association between the Mediterranean diet (MedDiet) and cardiovascular disease (CVD).Objective: We evaluated the associations between 1) lipid species and the risk of CVD (myocardial infarction, stroke, or cardiovascular death); 2) a MedDiet intervention [supplemented with extra virgin olive oil (EVOO) or nuts] and 1-y changes in these molecules; and 3) 1-y changes in lipid species and subsequent CVD.Design: With the use of a case-cohort design, we profiled 202 lipid species at baseline and after 1 y of intervention in the PREDIMED (PREvencion con DIeta MEDiterranea) trial in 983 participants [230 cases and a random subcohort of 790 participants (37 overlapping cases)].Results: Baseline concentrations of cholesterol esters (CEs) were inversely associated with CVD. A shorter chain length and higher saturation of some lipids were directly associated with CVD. After adjusting for multiple testing, direct associations remained significant for 20 lipids, and inverse associations remained significant for 6 lipids. When lipid species were weighted by the number of carbon atoms and double bonds, the strongest inverse association was found for CEs [HR: 0.39 (95% CI: 0.22, 0.68)] between extreme quintiles (P-trend = 0.002). Participants in the MedDiet + EVOO and MedDiet + nut groups experienced significant (P < 0.05) 1-y changes in 20 and 17 lipids, respectively, compared with the control group. Of these changes, only those in CE(20:3) in the MedDiet + nuts group remained significant after correcting for multiple testing. None of the 1-y changes was significantly associated with CVD risk after correcting for multiple comparisons.Conclusions: Although the MedDiet interventions induced some significant 1-y changes in the lipidome, they were not significantly associated with subsequent CVD risk. Lipid metabolites with a longer acyl chain and higher number of double bonds at baseline were significantly and inversely associated with the risk of CVD. PMID- 28814399 TI - Modeling the dose effects of soybean oil in salad dressing on carotenoid and fat soluble vitamin bioavailability in salad vegetables. AB - Background: Previously, we showed that vegetable oil is necessary for carotenoid absorption from salad vegetables. Research is needed to better define the dose effect and its interindividual variation for carotenoids and fat-soluble vitamins.Objective: The objective was to model the dose-response relation between the amount of soybean oil in salad dressing and the absorption of 1) carotenoids, phylloquinone, and tocopherols in salad vegetables and 2) retinyl palmitate formed from the provitamin A carotenoids.Design: Women (n = 12) each consumed 5 vegetable salads with salad dressings containing 0, 2, 4, 8, or 32 g soybean oil. Blood was collected at selected time points. The outcome variables were the chylomicron carotenoid and fat-soluble vitamin area under the curve (AUC) and maximum content in the plasma chylomicron fraction (Cmax). The individual specific and group-average dose-response relations were investigated by fitting linear mixed-effects random coefficient models.Results: Across the entire 0-32-g range, soybean oil was linearly related to the chylomicron AUC and Cmax values for alpha-carotene, lycopene, phylloquinone, and retinyl palmitate. Across 0-8 g of soybean oil, there was a linear increase in the chylomicron AUC and Cmax values for beta-carotene. Across a more limited 0-4-g range of soybean oil, there were minor linear increases in the chylomicron AUC for lutein and alpha- and total tocopherol. Absorption of all carotenoids and fat-soluble vitamins was highest with 32 g oil (P < 0.002). For 32 g oil, the interindividual rank order of the chylomicron AUCs was consistent across the carotenoids and fat-soluble vitamins (P < 0.0001).Conclusions: Within the linear range, the average absorption of carotenoids and fat-soluble vitamins could be largely predicted by the soybean oil effect. However, the effect varied widely, and some individuals showed a negligible response. There was a global soybean oil effect such that those who absorbed more of one carotenoid and fat-soluble vitamin also tended to absorb more of the others. This trial was registered at clinicaltrials.gov as NCT02867488. PMID- 28814400 TI - Mediation and modification of genetic susceptibility to obesity by eating behaviors. AB - Background: Many genetic variants show highly robust associations with body mass index (BMI). However, the mechanisms through which genetic susceptibility to obesity operates are not well understood. Potentially modifiable mechanisms, including eating behaviors, are of particular interest to public health.Objective: Here we explore whether eating behaviors mediate or modify genetic susceptibility to obesity.Design: Genetic risk scores for BMI (BMI-GRSs) were calculated for 3515 and 2154 adults in the Fenland and EDEN (Etude des determinants pre et postnatals de la sante et du developpement de l'enfant) population-based cohort studies, respectively. The eating behaviors-emotional eating, uncontrolled eating, and cognitive restraint-were measured through the use of a validated questionnaire. The mediating effect of each eating behavior on the association between the BMI-GRS and measured BMI was assessed by using the Sobel test. In addition, we tested for interactions between each eating behavior and the BMI-GRS on BMI.Results: The association between the BMI-GRS and BMI was mediated by both emotional eating (EDEN: P-Sobel = 0.01; Fenland: P-Sobel = 0.02) and uncontrolled eating (EDEN: P-Sobel = 0.04; Fenland: P-Sobel = 0.0006) in both sexes combined. Cognitive restraint did not mediate this association (P-Sobel > 0.10), except among EDEN women (P-Sobel = 0.0009). Cognitive restraint modified the relation between the BMI-GRS and BMI among men (EDEN: P-interaction = 0.0001; Fenland: P-interaction = 0.04) and Fenland women (P-interaction = 0.0004). By tertiles of cognitive restraint, the association between the BMI-GRS and BMI was strongest in the lowest tertile of cognitive restraint, and weakest in the highest tertile.Conclusions: Genetic susceptibility to obesity was partially mediated by the "appetitive" eating behavior traits (uncontrolled and emotional eating) and, in 3 of the 4 population groups studied, was modified by cognitive restraint. High levels of cognitive control over eating appear to attenuate the genetic susceptibility to obesity. Future research into interventions designed to support restraint may help to protect genetically susceptible individuals from weight gain. PMID- 28814402 TI - Molecular insights into the normal operation, regulation, and multisystemic roles of K+-Cl- cotransporter 3 (KCC3). AB - Long before the molecular identity of the Na+-dependent K+-Cl- cotransporters was uncovered in the mid-nineties, a Na+-independent K+-Cl- cotransport system was also known to exist. It was initially observed in sheep and goat red blood cells where it was shown to be ouabain-insensitive and to increase in the presence of N ethylmaleimide (NEM). After it was established between the early and mid nineties, the expressed sequence tag (EST) databank was found to include a sequence that was highly homologous to those of the Na+-dependent K+-Cl- cotransporters. This sequence was eventually found to code for the Na+ independent K+-Cl- cotransport function that was described in red blood cells several years before. It was termed KCC1 and led to the discovery of three isoforms called KCC2, KCC3, and KCC4. Since then, it has become obvious that each one of these isoforms exhibits unique patterns of distribution and fulfills distinct physiological roles. Among them, KCC3 has been the subject of great attention in view of its important role in the nervous system and its association with a rare hereditary sensorimotor neuropathy (called Andermann syndrome) that affects many individuals in Quebec province (Canada). It was also found to play important roles in the cardiovascular system, the organ of Corti, and circulating blood cells. As will be seen in this review, however, there are still a number of uncertainties regarding the transport properties, structural organization, and regulation of KCC3. The same is true regarding the mechanisms by which KCC3 accomplishes its numerous functions in animal cells. PMID- 28814401 TI - Effects of protein supplementation combined with resistance exercise on body composition and physical function in older adults: a systematic review and meta analysis. AB - Background: Overweight and obese older people face a high risk of muscle loss and impaired physical function, which may contribute to sarcopenic obesity. Resistance exercise training (RET) has a beneficial effect on muscle protein synthesis and can be augmented by protein supplementation (PS). However, whether body weight affects the augmentation of muscular and functional performance in response to PS in older people undergoing RET remains unclear.Objective: This study was conducted to identify the effects of PS on the body composition and physical function of older people undergoing RET.Design: We performed a comprehensive search of online databases to identify randomized controlled trials (RCTs) reporting the efficacy of PS for lean mass gain, strength gain, and physical mobility improvements in older people undergoing RET.Results: We included 17 RCTs; the overall mean +/- SD age and body mass index (BMI; in kg/m2) in these RCTs were 73.4 +/- 8.1 y and 29.7 +/- 5.5, respectively. The participants had substantially greater lean mass and leg strength gains when PS and RET were used than with RET alone, with the standard mean differences (SMDs) being 0.58 (95% CI: 0.32, 0.84) and 0.69 (95% CI: 0.39, 0.98), respectively. The subgroup of studies with a mean BMI >=30 exhibited substantially greater lean mass (SMD: 0.53; 95% CI: 0.19, 0.87) and leg strength (SMD: 0.88; 95% CI: 0.42, 1.34) gains in response to PS. The subgroup of studies with a mean BMI <30 also exhibited relevant gains in response to PS.Conclusions: Compared with RET alone, PS combined with RET may have a stronger effect in preventing aging-related muscle mass attenuation and leg strength loss in older people, which was found in studies with a mean BMI >=30 and in studies with a mean BMI <30. Clinicians could use nutrition supplement and exercise strategies, especially PS plus RET, to effectively improve the physical activity and health status of all older patients. PMID- 28814403 TI - Oxidized low-density lipoprotein-induced microparticles promote endothelial monocyte adhesion via intercellular adhesion molecule 1. AB - Oxidized low-density lipoprotein (oxLDL) accumulates early in atherosclerotic lesions and plays an important role in the progressive formation of atherosclerotic plaques. Endothelial derived microparticles (EMPs) form a heterogeneous population of <1-MUm particles that shed from endothelial membranes upon activation. While EMPs are shown to be involved in atherosclerotic pathophysiology and progression, there is no report regarding the relationship between oxLDL and EMPs. In this study, we aim to determine the influence of oxLDL on endothelial microparticle release and the subsequent regulation of the endothelial activation. EMPs were collected from the medium of human umbilical vein endothelial cells (HUVECs) treated with oxLDL or PBS as control. We find that oxLDL increases the release of EMPs containing intercellular adhesion molecule 1 (ICAM-1) but not vascular cell adhesion molecule 1 (VCAM-1). Confocal microscopy analysis further demonstrates that these EMPs interact with endothelial cells and increase the expression of ICAM-1 in HUVECs. The fact that injecting oxLDL-induced EMPs via the tail vein of ICR mice augments ICAM-1 expression on aortic endothelial cells confirms our results in vivo. Finally, oxLDL-induced EMPs from HUVECs increase the adhesion of monocytes to endothelial cells as determined by the adhesion assay. Our study suggests that oxLDL may augment the release of EMPs harboring increased levels of ICAM-1 that can be transferred to endothelial cells elsewhere. This leads to increased monocyte recruitment in other regions where oxLDL accumulation was initially more limited. EMPs may therefore serve as the mediator that propagates oxLDL-induced endothelial inflammation. PMID- 28814404 TI - Adaptive spatiotemporal changes in morphology, anatomy, and mechanics during the ontogeny of subshrubs with square-shaped stems. AB - PREMISE OF THE STUDY: Plant stems can be regarded as fiber-reinforced structures characterized by anatomical heterogeneity, mechanical anisotropy, and adaptability to changing internal and external constraints. Our study focused on adaptive spatiotemporal changes in morphology, anatomy, and mechanical properties during the ontogeny of Leonurus cardiaca L. (Lamiaceae) internodes, proving considerable functional adaptability. METHODS: Four-point bending tests and torsional tests were carried out on the same internodes to measure flexural and torsional stiffness. Axial and polar second moments of area for entire cross sections and for individual tissues were determined from transverse stem sections immediately after testing. Based on these data, additional relevant mechanical parameters such as bending elastic modulus, torsional modulus and twist to bend ratio were calculated. KEY RESULTS: Leonurus cardiaca is characterized by a square-shaped hollow stem in transverse section with an outer frame of various strengthening tissues and an inner ring of parenchyma. Statistical analyses of axial and polar second moment of area, flexural stiffness, torsional stiffness, bending elastic modulus, and torsional modulus revealed significant differences for all comparisons with respect to spatial resolution (two adjacent internodes) and temporal resolution (in June before flowering and in September after fruit formation). The twist to bend ratios of the internodes, however, always remain in the same range. CONCLUSIONS: With respect to spatiotemporal development, stems of the subshrub L. cardiaca show a marked increase in flexural and torsional stiffness during ontogeny. Strikingly, changes in stem mechanics are more influenced by variations in mechanical tissue properties than by changes in relative proportion of different tissue types. PMID- 28814406 TI - Comparative epigenetic and genetic spatial structure of the perennial herb Helleborus foetidus: Isolation by environment, isolation by distance, and functional trait divergence. AB - PREMISE OF THE STUDY: Epigenetic variation can play a role in local adaptation; thus, there should be associations among epigenetic variation, environmental variation, and functional trait variation across populations. This study examines these relationships in the perennial herb Helleborus foetidus (Ranunculaceae). METHODS: Plants from 10 subpopulations were characterized genetically (AFLP, SSR markers), epigenetically (MSAP markers), and phenotypically (20 functional traits). Habitats were characterized using six environmental variables. Isolation by-distance (IBD) and isolation-by-environment (IBE) patterns of genetic and epigenetic divergence were assessed, as was the comparative explanatory value of geographical and environmental distance as predictors of epigenetic, genetic, and functional differentiation. KEY RESULTS: Subpopulations were differentiated genetically, epigenetically, and phenotypically. Genetic differentiation was best explained by geographical distance, while epigenetic differentiation was best explained by environmental distance. Divergence in functional traits was correlated with environmental and epigenetic distances, but not with geographical and genetic distances. CONCLUSIONS: Results are compatible with the hypothesis that epigenetic IBE and functional divergence reflected responses to environmental variation. Spatial analyses simultaneously considering epigenetic, genetic, phenotypic and environmental information provide a useful tool to evaluate the role of environmental features as drivers of natural epigenetic variation between populations. PMID- 28814405 TI - Can asexuality confer a short-term advantage? Investigating apparent biogeographic success in the apomictic triploid fern Myriopteris gracilis. AB - PREMISE OF THE STUDY: Although asexual taxa are generally seen as evolutionary dead ends, asexuality appears to provide a short-term benefit in some taxa, including a wider geographic distribution compared to sexual relatives. However, this may be an illusion created by multiple, morphologically cryptic, asexual lineages, each occupying a relatively small area. In this study we investigate the role of multiple lineages in the biogeography of Myriopteris gracilis Fee (Pteridaceae), a North American apomictic triploid fern species with a particularly large range. METHODS: Range-wide asexuality was assessed by counting spores/sporangium in 606 Myriopteris gracilis specimens from across the species range, and lineage structure was assessed with both plastid DNA sequence and Genotyping By Sequencing (GBS) SNP datasets. KEY RESULTS: Spore counting of >600 specimens identified no sexual populations, establishing that Myriopteris gracilis is exclusively asexual. The plastid data estimated the crown age of M. gracilis at ca. 2.5 mya and identified two lineages, each largely confined to the eastern or western portions of the range. These groups were further subdivided by the GBS data, revealing at least seven asexual lineages of varying geographic distributions, each occupying a relatively small portion of the total range of M. gracilis. CONCLUSIONS: Although maintained exclusively through asexual reproduction, the broad distribution of Myriopteris gracilis is a compilation of numerous, independently formed asexual lineages. Since no single asexual lineage occupies the full extent of the species distribution, recurrent lineage formation should be considered when evaluating the short-term benefit of asexuality in this taxon and others. PMID- 28814407 TI - Fungal endophyte communities in the temperate fern Polystichum munitum show early colonization and extensive temporal turnover. AB - PREMISE OF THE STUDY: Fungal endophytes have been shown to colonize all land plants, yet surprisingly little attention has been given to their community composition in ferns. We examined the diversity and temporal turnover of fungal endophytes in foliar tissue of the temperate western sword fern, Polystichum munitum, comparing taxa in newly emerged leaflets and in the same fronds after 1 mo of exposure in the field. METHODS: Utilizing next-generation sequencing, we sampled pinnae from P. munitum in spring, 2-3 d after they emerged. We additionally sampled pinnae 30 d later from the same fern blades. From these samples, we sequenced fungal DNA to characterize the initial colonization and temporal turnover of endophytes in the host. KEY RESULTS: We demonstrate that P. munitum is abundantly colonized by endophytes in newly emerged foliar tissue. However, 1 mo later, the community composition undergoes a marked shift: the overall richness of endophytes increases, but the evenness of the community wanes as a single taxon, Flagellospora fusarioides, comes to dominate. CONCLUSIONS: We conclude that P. munitum hosts a variety of fungal endophyte taxa, similarly to other land plants. However, the rapid shift of the endophyte community we report is an unprecedented observation. Therefore, we further conclude that repeated sampling should be the standard in endophyte studies, because single sampling events are not sufficient to capture the dynamic nature of these cryptic microfungi. PMID- 28814409 TI - Identification of imaging features that determine quality and repeatability of retinal capillary plexus density measurements in OCT angiography. AB - PURPOSE: Optical coherence tomography angiography (OCT-A) potentially allows for rapid and non-invasive quantification of retinal capillary plexus density in various disease states. This study aims to identify the key features that influenced the repeatability of OCT-A measurements. METHODS: We obtained OCT-A images on two separate visits in 44 healthy eyes from 44 subjects, each imaged with using the Topcon DRI OCT Triton imaging system. The parafoveal vessel density within a 1.5 mm radius centred over the fovea was obtained with the built in tool for the superficial and deep retinal plexuses. Repeatability of vessel density was determined by intraclass correlation (ICC) and mean variation. We evaluated several image parameters to determine their influence on the repeatability of vessel density measurement in each of the two capillary plexuses. RESULTS: The mean age of the subjects was 70.2+/-9.2 years, with 64% males. Mean parafoveal vessel density measurements for the first and second visits were 53.3+/-11.1 and 53.3+/-10.3 for the superficial plexus and 27.3+/ 8.59 and 27.0+/-8.78 for the deep plexus. ICC analyses demonstrated that high fine vessel visibility, the absence of motion artefact and software-derived image quality score of 60 or above were necessary to obtain a good (ICC>0.6) or excellent (ICC>0.75) repeatability. CONCLUSIONS: Our study identified the imaging parameters that determined the repeatability of quantitative retinal vessel density measurements. These findings have implications in determining if OCT-A images can be used to accurately evaluate serial changes in retinal vessel density. PMID- 28814410 TI - Characteristics of primary extranodal marginal zone B-cell lymphoma in Korea: conjunctiva versus other ocular adnexa. AB - AIMS: To compare the clinical characteristics and prognosis of primary conjunctival versus other ocular adnexal extranodal marginal zone B-cell lymphoma (EMZL). METHODS: Retrospective review of clinical records for all consecutive patients with primary ocular adnexal EMZL treated from March 1995 to December 2015. RESULTS: 198 patients were evaluated including 81 with primary conjunctival and 117 with other ocular adnexal EMZL. Conjunctival EMZL was found at a younger age (40.3+/-10.3vs 54.3+/-13.4 years, p<0.0001) with a female predilection (75.3%vs35.9%, p<0.0001) and had a higher rate of bilaterality (40.7%vs11.1%, p<0.0001) and a lower rate of systemic involvement (1.2%vs9.4%, p=0.030) compared with other ocular adnexal EMZLs. Conjunctival EMZL also showed a higher rate of complete response to primary treatment (98.8%vs89.5%, p=0.016) than other ocular adnexal EMZLs; however, recurrence and lymphoma-related death rates were not different between the two groups (p>0.05). Kaplan-Meier estimates for disease specific survival at 5 and 10 years were 98.2% and 98.2% in conjunctival and 98.6%, respectively, and 95.2% in other ocular adnexal EMZLs. Univariate analysis showed that systemic involvement was negatively associated with conjunctival tumour location and positively associated with age (OR=0.35 and OR=1.05, p=0.045 and p=0.012, respectively), and treatment response was positively associated with conjunctival tumour location and negatively associated with age (OR=3.02 and OR=0.95, p=0.035 and p=0.009, respectively). CONCLUSIONS: Conjunctival EMZL shows unique demographic characteristic compared with other ocular adnexal EMZLs. Long term follow-up is required due to late recurrence in ocular adnexal EMZL. PMID- 28814408 TI - Intrinsic Maturational Neonatal Immune Deficiencies and Susceptibility to Group B Streptococcus Infection. AB - Although a normal member of the gastrointestinal and vaginal microbiota, group B Streptococcus (GBS) can also occasionally be the cause of highly invasive neonatal disease and is an emerging pathogen in both elderly and immunocompromised adults. Neonatal GBS infections are typically transmitted from mother to baby either in utero or during passage through the birth canal and can lead to pneumonia, sepsis, and meningitis within the first few months of life. Compared to the adult immune system, the neonatal immune system has a number of deficiencies, making neonates more susceptible to infection. Recognition of GBS by the host immune system triggers an inflammatory response to clear the pathogen. However, GBS has developed several mechanisms to evade the host immune response. A comprehensive understanding of this interplay between GBS and the host immune system will aid in the development of new preventative measures and therapeutics. PMID- 28814411 TI - Local synthesis of sex hormones: are there consequences for the ocular surface and dry eye? AB - Sex hormones are associated with the physiology and pathophysiology of almost all organs in the body, as well as most diseases. Interest in the associations between sex hormones and ocular tissues has increased in recent years. Androgens may have a positive effect on dry eye, whereas the effects of oestrogen on ocular conditions remain unclear. Intracrinology, the local synthesis and metabolism of hormones that is unique to humans, is of relevance to the eye and may help to explain why studies of the relationship between oestrogens and dry eye signs and symptoms are inconclusive. Knowledge of the pathways of hormone formation and metabolism is crucial to understanding the pathogenesis of ocular disease including dry eye. This review examines the mechanisms of steroidal sex hormone biosynthesis and reviews the significance of locally produced sex hormones, with a focus on ocular surface tissues. Much of the current literature is based on animal studies, which may not be transferable to humans due to the absence of intracrine production in animals. A large proportion of the human studies investigate systemic hormone levels rather than local levels. There is subsequently a need for additional studies to provide a better understanding of the local production of sex hormones within the human eye and ocular surface and to clarify the relationships between ocular levels of sex hormones and conditions including dry eye. PMID- 28814412 TI - Long-term outcomes with as-needed aflibercept in diabetic macular oedema: 2-year outcomes of the ENDURANCE extension study. AB - BACKGROUND/AIMS: To evaluate the efficacy and safety of individualised 2.0 mg intravitreal aflibercept retreatment for diabetic macular oedema (DME) through the fifth year of management. METHODS: This is a phase IV, 2-year, open-label extension study. Sixty patients completing the 3-year VISTA DME (Study of Intravitreal Aflibercept Injection in Patients With Diabetic Macular Edema) phase III trial enrolled in the ENDURANCE (Long-Term Efficacy and Safety of Intravitreal Aflibercept for the Treatment of DME in Subjects Who Completed the VISTA DME Trial) extension study. All patients received aflibercept in the presence of clinically relevant DME. Intervals between visits were prescribed according to disease activity. The main outcome measure was mean aflibercept injections given through 2 years. RESULTS: A mean of 7.7 aflibercept injections were administered through 2 years. Fifteen (25%) patients required no retreatment and 48% (n=29) of patients received five or fewer injections through 2 years. Among patients who received at least one aflibercept retreatment during ENDURANCE, the mean number of injections through 2 years was 9.5. The mean visual acuity and central retinal thickness gains achieved during VISTA DME were maintained and stable during ENDURANCE. The most notable safety signal was progression of diabetic retinopathy. Six (10%) patients converted from non proliferative to proliferative diabetic retinopathy (PDR), and a total of eight patients experienced PDR events occurring at a mean of 387 days following the previous aflibercept treatment. CONCLUSION: The need for aflibercept retreatment was substantially reduced in the fourth and fifth years of aflibercept dosing for DME following initiation of therapy in the VISTA DME trial. While vision gains achieved during the 3-year VISTA DME trial were maintained through ENDURANCE with a reduced treatment burden, clinically relevant worsening of diabetic retinopathy was observed with progression to PDR in 10% of the eyes. TRIAL REGISTRATION NUMBER: NCT02299336. PMID- 28814413 TI - Ophthalmic statistics note 12: multivariable or multivariate: what's in a name? PMID- 28814414 TI - Amblyopia and strabismus: trends in prevalence and risk factors among young adults in Israel. AB - AIMS: To estimate the prevalence of amblyopia, present strabismus and amblyopia risk factors (ARFs) among young adults in Israel and to analyse trends over time of prevalence rates. METHODS: We conducted a cross-sectional study including 107 608 pre-enlistees aged 17.4+/-0.6 years born between 1971 and 1994. Across the birth years, the following trends of prevalence rates among young adults were analysed: prevalence of amblyopia, prevalence of strabismus, severity of amblyopia and prevalence of ARFs (strabismsus, anisometropia and isoametropia). Unilateral amblyopia was defined as best corrected visual acuity (BCVA) of <0.67 (6/9) in either eye or as an interocular difference of two lines or more. Bilateral amblyopia was defined as BCVA of <0.67 (6/9) in both eyes. The severity of amblyopia was classified as mild (BCVA >=0.5 [6/12]), moderate (BCVA <0.5 [6/12] and >=0.25 [6/24]) or severe (BCVA <0.25 [6/24]). RESULTS: The prevalence of young adulthood amblyopia declined by 33%, from 1.2% to 0.8% (R2=0.87, p<0.001) across 24 birth years. This decline may be due to a drop in unilateral amblyopia from 1% to 0.6% (R2=0.93, p<0.001), while the prevalence of bilateral amblyopia remained stable (0.2%, p=0.12). The decline in amblyopia was apparent in mild and moderate amblyopia, but not in severe amblyopia. Strabismus and anisometropia were detected in 6-12% and 11-20% of subjects with unilateral amblyopia, respectively, without significant trends. Strabismic amblyopia remained constant in the entire population across years. Isoametropia was detected in 46-59% of subjects with bilateral amblyopia without a significant trend across birth years. Prevalence of strabismus in the study population decreased by 50%, from 1.2% to 0.6% (R2=0.75, p<0.001). In subjects with present strabismus, the prevalence of mild unilateral amblyopia increased, while moderate or severe unilateral amblyopia remained relatively stable. CONCLUSION: Among young adults, the prevalence of unilateral amblyopia, as well as the prevalence of present strabismus, decreased significantly over a period of a generation. The prevalence of strabismic, bilateral or severe (both unilateral and bilateral) amblyopia remained stable. The establishment of the national screening programme for children and the improved utility of treatment for amblyopia and strabismus coincide with these trends. Thus, it is possible that these early interventions resulted in modification of the 'natural history' of these conditions and their prevalence in adolescence. PMID- 28814415 TI - Optical coherence tomography angiography enhances the detection of optic nerve damage in multiple sclerosis. AB - BACKGROUND: Quantitative assessment of optic nerve damage is important in the evaluation of optic neuritis (ON) and multiple sclerosis (MS). OBJECTIVE: To detect optic nerve damage using optical coherence tomography (OCT) and OCT angiography in MS. METHODS: Peripapillary retinal nerve fibre layer (NFL) thickness, macular ganglion cell complex (GCC) thickness and Optic Nerve Head Flow Index (ONH-FI) were measured. The ONH-FI was defined as flow signal averaged over the optic disc. Diagnostic accuracy was evaluated by the area under the receiver-operating characteristics curve (AROC). RESULTS: Sixty-eight eyes of 45 MS participants and 55 eyes of 32 healthy controls (HCs) were analysed. Of MS eyes, 25 had a history of ON (MS+ON) and 43 didn't (MS-ON). MS-ON and MS+ON eyes had reductions in ONH-FI (p=0.031 and p=0.001, respectively), GCC thickness (p=0.245 and p<0.001, respectively), and NFL thickness (p=0.003 and p=0.024, respectively), compared with HCs. The highest AROC (0.940) was achieved by the logistic regression combination of all three variables, which was significantly higher than other variables (p=0.018). CONCLUSION: MS produces both retinal structural loss and decreased ONH perfusion in MS eyes with and without history of ON. The combination of perfusion and structural measurements enhances detection of optic nerve damage in MS. OCT angiography may be a useful additional retinal marker in evaluation of ON in MS. PMID- 28814416 TI - The volume of peripapillary vessels within the retinal nerve fibre layer: an optical coherence tomography angiography study of normal subjects. AB - BACKGROUND/AIMS: To investigate the contribution of vascular volume calculated by optical coherence tomography angiography (OCTA) to the measurement of peripapillary retinal nerve fibre layer (RNFL) thickness. METHODS: We used OCTA scans to build volumetric maps of the RNFL angiograms by thresholding the decorrelation images and summing the number of white pixels along the z-axis at each location. We used these maps to calculate the contribution of the vascular tissue to the RNFL thickness. RESULTS: We analysed 51 eyes from 36 subjects. The mean RNFL volume calculated on the peripapillary region was 0.607+/-0.045 mm3 and the mean vessel volume was 0.217+/-0.035 mm3, with a mean vessel/total RNFL ratio of 35.627%+/-3.942%. When evaluated in the peripapillary circular section, the total contribution of the vascular tissue to the global RNFL thickness was 29.071%+/-3.945%. The superior and inferior sectors showed the highest percentage of vascular tissue within the RNFL circular profile (31.369% and 34.788% respectively). CONCLUSIONS: We found that the vascular contribution to the RNFL thickness is 29.07+/-3.945%. This is much higher than what has been reported from calculations made on the structural OCT alone (13% reported by Hood et al and 11.3%+/-1.6% for the Cirrus OCT and 11.8%+/-1.4% for the Spectralis OCT reported by Patel et al). We conclude that evaluation of the vascular tissue contribution to the RNFL thickness with OCTA might be useful when performing precise quantification of the neuronal tissue. PMID- 28814417 TI - Intravitreal bevacizumab monotherapy in myopic choroidal neovascularisation: 5 year outcomes for the PAN-American Collaborative Retina Study Group. AB - PURPOSE: To report the long-term anatomical and visual outcomes of intravitreal bevacizumab (IVB) monotherapy in naive choroidal neovascularisation (CNV) caused by myopia. METHODS: Retrospective analysis of naive CNV secondary to myopia that underwent antivascular endothelial growth factor monotherapy was performed. Collected data included demographic details, clinical examination details including visual acuity at presentation and follow-up with imaging and treatment details. Main outcome measures were resolution of CNV activity at the last visit. Secondary outcomes included change in visual acuity, number of injections and adverse events. RESULTS: Thirty-three eyes of 31 subjects with a mean age of 51.48+/-16.4 years were included. The mean follow-up was 66.47 months. 27 eyes had type 2 CNV and the rest seven eyes had type 1 CNV. The mean number of IVB injections per eye was 4.9. Mean visual acuity at baseline reduced from 0.65+/ 0.33 logMAR units (Snellen equivalent=20/89) to 0.73+/-0.50 logMAR units (20/107) at final follow-up (p=0.003). The mean central macular thickness decreased from 309.31+/-86 um at baseline to 267.5+/-70.89 um at the last visit (p=0.03). However, visual acuity was maintained (+/-1 line of baseline) in 13 eyes (39.4%), >=2 line improvement in nine (27.3%) eyes and more than two lines worsening in 11 eyes (33.3%). Foveal atrophy was observed at baseline and last visit in 6 (12.5%) and 14 (29.1%), respectively (p=0.007). No systemic adverse events were observed. CONCLUSION: IVB monotherapy is safe and effective for long-term treatment of CNV secondary to myopia in real life. PMID- 28814420 TI - Surveying paediatricians' assessment of childhood bruising patterns. PMID- 28814421 TI - Stimulating innovation through the hackathon concept in paediatrics: our experience at the Aga Khan University. PMID- 28814418 TI - Comparing glaucomatous disc change using stereo disc viewing and the MatchedFlicker programme in glaucoma experts and trainees. AB - BACKGROUND/AIMS: The objective of this study is to evaluate the accuracy and speed of trainees and experienced glaucoma specialists using the MatchedFlicker software against the manual examination of stereoscopic disc photographs for detecting glaucomatous optic disc change. METHODS: Three experienced glaucoma specialists, two resident ophthalmologists and one glaucoma fellow from multiple institutions independently evaluated the same 140 image pairs from 100 glaucomatous/ocular hypertensive eyes using a handheld stereo viewer and the MatchedFlicker programme. Fifty had progression to glaucoma as determined by the Ocular Hypertension Treatment Study (OHTS) Optic Disc Reading Group and endpoint committee, and 50 more were negative controls for progression with photos taken a few minutes apart. Twenty photo pairs from each of the two groups were duplicated for reviewer variability analysis. The initial viewing method was randomised and then alternated for each group of 70 image pairs. Reviewer accuracy and evaluation time for each method were measured. RESULTS: Evaluators averaged 8.6 s faster per image pair (26%) with the MatchedFlicker programme than with the stereo viewer (p=0.0007). Evaluators correctly identified more image pairs when using the MatchedFlicker software over the stereo viewer (p=0.0003). There was no significant difference between the expert and trainee group in speed or overall accuracy for either method. Experts were significantly more consistent than trainees with the duplicate image pairs (p=0.029). Trainees appeared more reluctant to designate eyes as showing glaucoma progression than experts. CONCLUSIONS: Both expert glaucoma specialists and ophthalmologists in various stages of training had greater accuracy and speed with the MatchedFlicker programme than with a handheld stereoscopic viewer. PMID- 28814419 TI - Chronic cough postacute respiratory illness in children: a cohort study. AB - OBJECTIVE: Data on the aetiology of persistent cough at the transitional stage from subacute to chronic cough (>4 weeks duration) are scarce. We aimed to (1) identify the prevalence of chronic cough following acute respiratory illness (ARI) and (2) determine the diagnostic outcomes of children with chronic cough. DESIGN: Prospective cohort study. SETTING: A paediatric emergency department (ED) in Brisbane, Australia. PATIENTS: Children aged <15 years presenting with an ARI with cough. INTERVENTIONS: Children were followed weekly for 28 days;those with a persistent cough at day 28 were reviewed by a paediatric pulmonologist. MAIN OUTCOME MEASURES: Cough persistence at day 28 and pulmonologist diagnosis. RESULTS: 2586 children were screened and 776 (30%) were ineligible; 839 children (median age=2.3 years, range=0.5 months to 14.7 years, 60% male) were enrolled over 2 years. Most children (n=627, 74.8%) had cough duration of <7 days at enrolment. At day 28, 171/839 (20.4%, 95% CI 17.7 to 23.1) children had persistent cough irrespective of cough duration at enrolment. The cough was wet in 59/171 (34.5%), dry in 45/171 (26.4%) and variable in 28/171 (16.1%). Of these 117 children , 117 (68.4%) were reviewed by a paediatric pulmonologist. A new and serious chronic lung disease was diagnosed in 36/117 (30.8%) children; 55/117 (47.0%) were diagnosed with protracted bacterial bronchitis. CONCLUSIONS: When chronic cough develops post-ARI, clinical review is warranted, particularly if parents report a history of prolonged or recurrent cough. Parents of children presenting acutely to ED with cough should be counselled about the development of chronic cough, as an underlying respiratory condition is not uncommon. PMID- 28814422 TI - Mothers' knowledge and attitudes to sudden infant death syndrome risk reduction messages: results from a UK survey. AB - OBJECTIVE: To investigate mothers' knowledge of reducing the risks for sudden infant death syndrome (SIDS) and attitudes towards safer sleep practices. DESIGN AND SETTING: A cross-sectional survey was carried out in deprived areas of Bristol, UK. Recruitment took place in 2014 at local health visitor-led baby clinics. PARTICIPANTS: Of 432 mothers approached, 400 (93%) completed the face-to face survey. Participants with infants at 'higher' risk of SIDS (using an algorithm based on a previous observational study) were compared with those at 'lower' risk. MAIN OUTCOME MEASURES: The survey asked participants to recall three SIDS risk reduction strategies (unprompted), and scored responses to 14 SIDS risk-related infant sleep scenarios (prompted). RESULTS: Overall, 48/400 (12%) mothers were classified as higher risk. Mothers in the higher risk group were less likely to breast feed (multivariate OR=3.59(95% CI 1.46 to 8.86)), less likely to be able to cite two or more unprompted correct SIDS risk reduction strategies (multivariate OR=2.05(95% CI 1.02 to 4.13)) and scored lower on prompted safer sleep scenarios overall.Notably, only 206/400 (52%) of all mothers surveyed (33% in the higher risk group) from these deprived areas in Bristol identified infant sleep position as a risk reduction strategy for SIDS, despite 25 years of campaigns. CONCLUSIONS: Mothers in the higher risk group were disadvantaged when it came to some aspects of knowledge of SIDS risk reduction and attitudes to safer sleep. The initial 'Back-to Sleep' message that dramatically reduced these deaths a generation ago needs more effective promotion for today's generation of mothers. PMID- 28814423 TI - Portal hypertension and its management in children. AB - Portal hypertension (PHT), defined as raised intravascular pressure in the portal system, is a complication of chronic liver disease or liver vascular occlusion. Advances in our ability to diagnose and monitor the condition but also predict the risk of gastrointestinal bleeding have enabled us to optimise the management of children with PHT either at a surveillance or at a postbleeding stage. A consensus among paediatric centres in the classification of varices can be beneficial in streamlining future paediatric studies. New invasive (endoscopic and surgical procedures) and non-invasive (pharmacotherapy) techniques are currently used enabling clinicians to reduce mortality and morbidity in children with PHT. PMID- 28814424 TI - Hospitalisation of preterm infants with pertussis in the context of a maternal vaccination programme in England. AB - AIMS: To assess whether preterm infants are at increased risk of pertussis infection and whether this increased following introduction of a maternal pertussis vaccination in England, while examining characteristics of infants associated with more severe disease. METHODS: Infants aged <60 days admitted between 1 April 2009 and 31 March 2016 with a pertussis diagnosis code were extracted from Hospital Episode Statistics (HES) data. HES data were reconciled with existing surveillance systems to capture maternal vaccination status where available. Cases were compared preimplementation and postimplementation of the maternal programme with respect to demography, preterm or full-term birth and coinfection. Survival analysis was undertaken to assess the impact of variables on duration of hospital stay. RESULTS: The proportion of hospitalised preterm infants (138/1309, 10.6%) was higher than population estimates (7.4%), increasing from 9.8% (83/847) to 12.1% (56/462) following implementation of the maternal programme. Longer duration of hospital stay was associated with prematurity, younger age, additional respiratory illnesses and mothers unvaccinated in pregnancy. Of 13 deaths, 5 were preterm (38.5%) and 11 (84.6%) were female. A larger proportion of full-term infants' (49/188, 26.1%) mothers had been vaccinated in pregnancy than preterm infants (7/49, 14.3%), with 14.3% of mothers of full-term cases vaccinated after 35 weeks. CONCLUSIONS: Preterm infants are over-represented in hospitalised pertussis cases and have less benefit from the maternal pertussis vaccination programme in England due to reduced opportunity for maternal vaccination. PMID- 28814425 TI - Hypertension outcomes and cardiovascular status in young adults with childhood diagnosed white coat hypertension. PMID- 28814426 TI - Scheduled rituximab maintenance reduces relapse rate in eosinophilic granulomatosis with polyangiitis. PMID- 28814427 TI - Response to: 'The GRAPPA-OMERACT initiative to standardise outcomes in Psoriatic Arthritis clinical trials and longitudinal observational studies' by Tillet et al. PMID- 28814428 TI - Mortality in idiopathic inflammatory myopathy: results from a Swedish nationwide population-based cohort study. AB - : Patients with idiopathic inflammatory myopathies (IIMs) suffer an increased burden of comorbidities, but data on mortality in recently diagnosed IIM are conflicting. Also, little is known when, if ever, in relation to IIM diagnosis, mortality is increased. METHODS: A population-based IIM cohort of patients diagnosed between 2002 and 2011 and general population comparators were identified using healthcare registers. They were linked to the cause of death register for follow-up. RESULTS: 224 (31%) of the 716 patients with IIM and 870 (12%) of the 7100 general population died during follow-up. This corresponded to a mortality rate of 60/1000 person-years in IIM and 20/1000 person-years in the general population. The cumulative mortality at 1 year after diagnosis was 9% in IIM and 1% in the general population, and increased in both IIM and the general population with time. The overall hazard ratio (HR) 95%CI of death comparing IIM with the general population was 3.7 (3.2 to 4.4). When we stratified on time since diagnosis, we noted an increase in mortality already within the first year of diagnosis compared with the general population, HR 9.6 (95% CI 6.9 to 13.5). This HR then plateaued around 2 after >10 years with the disease, although the estimates were not statistically significant. Malignancies, diseases of the circulatory and respiratory system were common causes of death. CONCLUSION: Mortality is increased in patients with contemporary IIM. The increased mortality was noted within a year of diagnosis, which calls for extra vigilance during the first year of IIM diagnosis. PMID- 28814429 TI - Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis. AB - BACKGROUND: Nintedanib is an inhibitor targeting platelet-derived growth factor receptor, fibroblast growth factor receptor and vascular endothelial growth factor receptor tyrosine kinases that has recently been approved for the treatment of idiopathic pulmonary fibrosis. The aim of this study was to analyse the effects of nintedanib in the fos-related antigen-2 (Fra2) mouse model of systemic sclerosis (SSc). METHODS: The effects of nintedanib on pulmonary arterial hypertension with proliferation of pulmonary vascular smooth muscle cells (PVSMCs) and luminal occlusion, on microvascular disease with apoptosis of microvascular endothelial cells (MVECs) and on fibroblast activation with myofibroblast differentiation and accumulation of extracellular matrix were analysed. We also studied the effects of nintedanib on the levels of key mediators involved in the pathogenesis of SSc and on macrophage polarisation. RESULTS: Nintedanib inhibited proliferation of PVSMCs and prevented thickening of the vessel walls and luminal occlusion of pulmonary arteries. Treatment with nintedanib also inhibited apoptosis of MVECs and blunted the capillary rarefaction in Fra2-transgenic mice. These effects were associated with a normalisation of the serum levels of vascular endothelial growth factor in Fra2 mice on treatment with nintedanib. Nintedanib also effectively blocked myofibroblast differentiation and reduced pulmonary, dermal and myocardial fibrosis in Fra2-transgenic mice. The antifibrotic effects of nintedanib were associated with impaired M2 polarisation of monocytes and reduced numbers of M2 macrophages. CONCLUSION: Nintedanib targets core features of SSc in Fra2 transgenic mice and ameliorates histological features of pulmonary arterial hypertension, destructive microangiopathy and pulmonary and dermal fibrosis. These data might have direct implications for the ongoing phase III clinical trial with nintedanib in SSc-associated interstitial lung disease. PMID- 28814430 TI - The 2017 EULAR standardised procedures for ultrasound imaging in rheumatology. AB - BACKGROUND: In 2001, the European League Against Rheumatism developed and disseminated the first guidelines for musculoskeletal (MS) ultrasound (US) in rheumatology. Fifteen years later, the dramatic expansion of new data on MSUS in the literature coupled with technological developments in US imaging has necessitated an update of these guidelines. OBJECTIVES: To update the existing MSUS guidelines in rheumatology as well as to extend their scope to other anatomic structures relevant for rheumatology. METHODS: The project consisted of the following steps: (1) a systematic literature review of MSUS evaluable structures; (2) a Delphi survey among rheumatologist and radiologist experts in MSUS to select MS and non-MS anatomic structures evaluable by US that are relevant to rheumatology, to select abnormalities evaluable by US and to prioritise these pathologies for rheumatology and (3) a nominal group technique to achieve consensus on the US scanning procedures and to produce an electronic illustrated manual (ie, App of these procedures). RESULTS: Structures from nine MS and non-MS areas (ie, shoulder, elbow, wrist and hand, hip, knee, ankle and foot, peripheral nerves, salivary glands and vessels) were selected for MSUS in rheumatic and musculoskeletal diseases (RMD) and their detailed scanning procedures (ie, patient position, probe placement, scanning method and bony/other landmarks) were used to produce the App. In addition, US evaluable abnormalities present in RMD for each anatomic structure and their relevance for rheumatology were agreed on by the MSUS experts. CONCLUSIONS: This task force has produced a consensus-based comprehensive and practical framework on standardised procedures for MSUS imaging in rheumatology. PMID- 28814431 TI - Calprotectin as a marker of inflammation in patients with early rheumatoid arthritis. AB - OBJECTIVES: Calprotectin is an inflammatory marker of interest in rheumatoid arthritis (RA). We evaluated whether the level of calprotectin was associated with disease activity, and if it was predictive of treatment response and radiographic progression in patients with early RA. METHODS: Plasma from disease modifying antirheumatic drug (DMARD)-naive patients with RA fulfilling 2010 American College of Rheumatology/European League Against Rheumatism classification criteria with symptom duration <2 years was analysed for calprotectin at baseline, and after 1, 3 and 12 months. All patients received treat-to-target therapy, as part of a randomised controlled strategy trial (ARCTIC). The association between calprotectin, erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) and measures of disease activity were assessed by correlations. We used likelihood ratios and logistic regression models to assess the predictive value of the baseline inflammatory markers for treatment response and radiographic damage. RESULTS: 215 patients were included: 61% female, 82% anti-citrullinated peptide antibody positive, mean (SD) age 50.9 (13.7) years and median (25, 75 percentile) symptom duration 5.8 (2.8, 10.5) months. Calprotectin was significantly correlated with Clinical Disease Activity Index (r=0.32), ESR (r=0.50) and ultrasonography power Doppler (r=0.42) before treatment onset. After 12 months of treatment, calprotectin, but not ESR and CRP, was significantly correlated with power Doppler (r=0.27). Baseline levels of calprotectin, ESR and CRP were not predictive of treatment response, but high levels of calprotectin were associated with radiographic progression in multivariate models. CONCLUSIONS: Calprotectin was correlated with inflammation assessed by ultrasound before and during DMARD treatment, and was also associated with radiographic progression. The data support that calprotectin may be of interest as an inflammatory marker when assessing disease activity in different stages of RA. TRIAL REGISTRATION NUMBER: NCT01205854; Post-results. PMID- 28814432 TI - Minimal to no transfer of certolizumab pegol into breast milk: results from CRADLE, a prospective, postmarketing, multicentre, pharmacokinetic study. AB - BACKGROUND: Women with chronic inflammatory diseases face uncertainty regarding the safety of biologics during breast feeding. CRADLE was the first industry sponsored study to evaluate certolizumab pegol (CZP) concentrations in human breast milk and estimate average daily infant dose (ADID) of maternal CZP. METHODS: CRADLE (NCT02154425) was a pharmacokinetic study of lactating mothers receiving CZP. After >=3 CZP doses, breast milk samples were collected across one dosing period (14 days for 200 mg every 2 weeks [Q2W]; 28 days for 400 mg every 4 weeks [Q4W]). Optimal analytical methods were developed to determine CZP and polyethylene glycol (PEG) levels in breast milk. ADID and relative infant dose (RID) were estimated. Safety events in mothers and infants were assessed. RESULTS: 19 CZP-treated mothers were screened; 17 entered the sampling period: 16 on 200 mg Q2W, 1 on 400 mg Q4W. 77/137 (56%) breast milk samples had no measurable CZP. For 4/17 mothers, all samples were below the lower limit of quantification (LLOQ). Estimated ADID was 0-0.0104 mg/kg/day; median RID: 0.15%. PEG was undetectable in 134/137 samples (results could not be determined in three samples). Infants of CZP-exposed mothers had a safety profile consistent with that of unexposed similar-age infants. CONCLUSION: When quantifiable, CZP concentrations were <3* LLOQ (<1% plasma concentration observed with therapeutic dose), indicating no/minimal CZP transfer from plasma to breast milk. RID was 0.15% of maternal dose; <10% is considered unlikely to be of clinical concern. No PEG transfer was observed. CZP absorption by infants via breast milk is unlikely due to its low oral bioavailability and Fc--free molecular structure. These findings are reassuring and support continuation of CZP treatment during breast feeding. TRIAL REGISTRATION NUMBER: NCT02154425; Results. PMID- 28814433 TI - Personalized Medicine-Based Approach to Model Patterns of Chemoresistance and Tumor Recurrence Using Ovarian Cancer Stem Cell Spheroids. AB - Purpose: Chemoresistant ovarian cancers grow in suspension within the ascites fluid. To screen the effect of chemotherapeutics and biologics on resistant ovarian cancers with a personalized basis, we developed a 3D hanging drop spheroid platform.Experimental Design: We initiated spheroids with primary aldehyde dehydrogenase-positive (ALDH+) CD133+ ovarian cancer stem cells (OvCSC) from different patient samples and demonstrated that stem cell progeny from harvested spheroids was similar to the primary tumor. OvCSC spheroids were utilized to initiate tumors in immunodeficient mice. Drug responses to cisplatin and ALDH-targeting compound or JAK2 inhibitor determined whether the OvCSC population within the spheroids could be targeted. Cells that escaped therapy were isolated and used to initiate new spheroids and model tumor reemergence in a personalized manner.Results: OvCSC spheroids from different patients exhibited varying and personalized responses to chemotherapeutics. Xenografts were established from OvCSC spheroids, even with a single spheroid. Distinct responses to therapy were observed in distinct primary tumor xenografts similar to those observed in spheroids. Spheroids resistant to cisplatin/ALDH inhibitor therapy had persistent, albeit lower ALDH expression and complete loss of CD133 expression, whereas those resistant to cisplatin/JAK2 inhibitor therapy were enriched for ALDH+ cells.Conclusions: Our 3D hanging drop suspension platform can be used to propagate primary OvCSCs that represent individual patient tumors effectively by differentiating in vitro and initiating tumors in mice. Therefore, our platform can be used to study cancer stem cell biology and model tumor reemergence to identify new targeted therapeutics from an effective personalized medicine standpoint. Clin Cancer Res; 23(22); 6934-45. (c)2017 AACR. PMID- 28814435 TI - Adaptive Global Innovative Learning Environment for Glioblastoma: GBM AGILE. AB - Glioblastoma (GBM) is a deadly disease with few effective therapies. Although much has been learned about the molecular characteristics of the disease, this knowledge has not been translated into clinical improvements for patients. At the same time, many new therapies are being developed. Many of these therapies have potential biomarkers to identify responders. The result is an enormous amount of testable clinical questions that must be answered efficiently. The GBM Adaptive Global Innovative Learning Environment (GBM AGILE) is a novel, multi-arm, platform trial designed to address these challenges. It is the result of the collective work of over 130 oncologists, statisticians, pathologists, neurosurgeons, imagers, and translational and basic scientists from around the world. GBM AGILE is composed of two stages. The first stage is a Bayesian adaptively randomized screening stage to identify effective therapies based on impact on overall survival compared with a common control. This stage also finds the population in which the therapy shows the most promise based on clinical indication and biomarker status. Highly effective therapies transition in an inferentially seamless manner in the identified population to a second confirmatory stage. The second stage uses fixed randomization to confirm the findings from the first stage to support registration. Therapeutic arms with biomarkers may be added to the trial over time, while others complete testing. The design of GBM AGILE enables rapid clinical testing of new therapies and biomarkers to speed highly effective therapies to clinical practice. Clin Cancer Res; 24(4); 737-43. (c)2017 AACR. PMID- 28814436 TI - Mapping the drivers of overdiagnosis to potential solutions. PMID- 28814434 TI - Combined CDK4/6 and mTOR Inhibition Is Synergistic against Glioblastoma via Multiple Mechanisms. AB - Purpose: Glioblastoma (GBM) is a deadly brain tumor marked by dysregulated signaling and aberrant cell-cycle control. Molecular analyses have identified that the CDK4/6-Rb-E2F axis is dysregulated in about 80% of GBMs. Single-agent CDK4/6 inhibitors have failed to provide durable responses in GBM, suggesting a need to combine them with other agents. We investigate the efficacy of the combination of CDK4/6 inhibition and mTOR inhibition against GBM.Experimental Design: Preclinical in vitro and in vivo assays using primary GBM cell lines were performed.Results: We show that the CDK4/6 inhibitor palbociclib suppresses the activity of downstream mediators of the mTOR pathway, leading to rebound mTOR activation that can be blocked by the mTOR inhibitor everolimus. We further show that mTOR inhibition with everolimus leads to activation of the Ras mediator Erk that is reversible with palbociclib. The combined treatment strongly disrupts GBM metabolism, resulting in significant apoptosis. Further increasing the utility of the combination for brain cancers, everolimus significantly increases the brain concentration of palbociclib.Conclusions: Our findings demonstrate that the combination of CDK4/6 and mTOR inhibition has therapeutic potential against GBM and suggest it should be evaluated in a clinical trial. Clin Cancer Res; 23(22); 6958-68. (c)2017 AACR. PMID- 28814437 TI - Adaptive responses of rat descending vasa recta to ischemia. AB - tested whether rat descending vasa recta (DVR) undergo regulatory adaptations after the kidney is exposed to ischemia. Left kidneys (LK) were subjected to 30 min renal artery cross clamp. After 48 h, the postischemic LK and contralateral right kidney (RK) were harvested for study. When compared with DVR isolated from either sham-operated LK or the contralateral RK, postischemic LK DVR markedly increased their NO generation. The selective inducible NOS (iNOS) inhibitor 1400W blocked the NO response. Immunoblots from outer medullary homogenates showed a parallel 2.6-fold increase in iNOS expression ( P = 0.01). Microperfused postischemic LK DVR exposed to angiotensin II (ANG II, 10 nM), constricted less than those from the contralateral RK, and constricted more when exposed to 1400W (10 uM). Resting membrane potentials of pericytes from postischemic LK DVR pericytes were hyperpolarized relative to contralateral RK pericytes (62.0 +/- 1.6 vs. 51.8 +/- 2.2 mV, respectively, P < 0.05) or those from sham-operated LK (54.9 +/- 2.1 mV, P < 0.05). Blockade of NO generation with 1400W did not repolarize postischemic pericytes (62.5 +/- 1.4 vs. 61.1 +/- 3.4 mV); however, control pericytes were hyperpolarized by exposure to NO donation from S-nitroso- N-acetyl- dl-penicillamine (51.5 +/- 2.9 to 62.1 +/- 1.4 mV, P < 0.05). We conclude that postischemic adaptations intrinsic to the DVR wall occur after ischemia. A rise in 1400W sensitive NO generation and iNOS expression occurs that is associated with diminished contractile responses to ANG II. Pericyte hyperpolarization occurs that is not explained by the rise in ambient NO generation within the DVR wall. PMID- 28814439 TI - Stimulating bioelectronic medicine discovery for urological disorders. PMID- 28814438 TI - Collecting duct prorenin receptor knockout reduces renal function, increases sodium excretion, and mitigates renal responses in ANG II-induced hypertensive mice. AB - Augmented intratubular angiotensin (ANG) II is a key determinant of enhanced distal Na+ reabsorption via activation of epithelial Na+ channels (ENaC) and other transporters, which leads to the development of high blood pressure (BP). In ANG II-induced hypertension, there is increased expression of the prorenin receptor (PRR) in the collecting duct (CD), which has been implicated in the stimulation of the sodium transporters and resultant hypertension. The impact of PRR deletion along the nephron on BP regulation and Na+ handling remains controversial. In the present study, we investigate the role of PRR in the regulation of renal function and BP by using a mouse model with specific deletion of PRR in the CD (CDPRR-KO). At basal conditions, CDPRR-KO mice had decreased renal function and lower systolic BP associated with higher fractional Na+ excretion and lower ANG II levels in urine. After 14 days of ANG II infusion (400 ng.kg-1.min-1), the increases in systolic BP and diastolic BP were mitigated in CDPRR-KO mice. CDPRR-KO mice had lower abundance of cleaved alphaENaC and gammaENaC, as well as lower ANG II and renin content in urine compared with wild type mice. In isolated CD from CDPRR-KO mice, patch-clamp studies demonstrated that ANG II-dependent stimulation of ENaC activity was reduced because of fewer active channels and lower open probability. These data indicate that CD PRR contributes to renal function and BP responses during chronic ANG II infusion by enhancing renin activity, increasing ANG II, and activating ENaC in the distal nephron segments. PMID- 28814441 TI - Left Of Bang Interventions in Trauma: ethical implications for military medical prophylaxis. AB - Advances in medical capability should be accompanied by discussion of their ethical implications. In the military medical context there is a growing interest in developing prophylactic interventions that will mitigate the effects of trauma and improve survival. The ethics of this novel capability are currently unexplored. This paper describes the concept of trauma prophylaxis (Left Of Bang Interventions in Trauma) and outlines some of the ethical issues that need to be considered, including within concept development, research and implementation. Trauma prophylaxis can be divided into interventions that do not (type 1) and those that do (type 2) have medical enhancement as an unintended side effect of their prophylactic action. We conclude that type 1 interventions have much in common with established military medical prophylaxis, and the potentially enhancing qualities of type 2 interventions raise different issues. We welcome further debate on both interventions. PMID- 28814442 TI - Extending Antimicrobial Stewardship to All Hospitalized Children: The Time Is Now. PMID- 28814443 TI - Antibiotic Use by Pediatric Residents: Identifying Opportunities and Strategies for Antimicrobial Stewardship. AB - OBJECTIVES: To determine the antibiotic prescribing practices of pediatric residents and assess how they acquire knowledge leading to prescribing behaviors. METHODS: We performed a cross-sectional electronic survey of all pediatric residents at the Children's National Medical Center and Nicklaus Children's Hospital, assessing antibiotic prescribing patterns for common pediatric infections, use of antibiograms, and factors influencing antibiotic choice. RESULTS: Eighty-five surveys (45%) were returned complete and included in the analysis. Increased deviations from clinical guideline recommendations were observed for antibiotic treatments of sinusitis and community-acquired pneumonia as compared with otitis media and group A streptococcal pharyngitis. Only 57% of residents reported having used antibiograms. General pediatric inpatient attending physicians were identified as the most influential source for house staff antibiotic knowledge. CONCLUSIONS: Results illustrate the need for better promotion and integration of clinical guidelines with antibiograms when developing antibiotic education programs for residents in training. In addition, pediatric hospitalists should play an active role in the implementation of these programs and can provide valuable insight into the development of educational programs in conjunction with graduate medical education divisions. PMID- 28814440 TI - Mechanical, hormonal and metabolic influences on blood vessels, blood flow and bone. AB - Bone tissue is highly vascularized due to the various roles bone blood vessels play in bone and bone marrow function. For example, the vascular system is critical for bone development, maintenance and repair and provides O2, nutrients, waste elimination, systemic hormones and precursor cells for bone remodeling. Further, bone blood vessels serve as egress and ingress routes for blood and immune cells to and from the bone marrow. It is becoming increasingly clear that the vascular and skeletal systems are intimately linked in metabolic regulation and physiological and pathological processes. This review examines how agents such as mechanical loading, parathyroid hormone, estrogen, vitamin D and calcitonin, all considered anabolic for bone, have tremendous impacts on the bone vasculature. In fact, these agents influence bone blood vessels prior to influencing bone. Further, data reveal strong associations between vasodilator capacity of bone blood vessels and trabecular bone volume, and poor associations between estrogen status and uterine mass and trabecular bone volume. Additionally, this review highlights the importance of the bone microcirculation, particularly the vascular endothelium and NO-mediated signaling, in the regulation of bone blood flow, bone interstitial fluid flow and pressure and the paracrine signaling of bone cells. Finally, the vascular endothelium as a mediator of bone health and disease is considered. PMID- 28814444 TI - Implementing an Inpatient Pediatric Prospective Audit and Feedback Antimicrobial Stewardship Program Within a Larger Medical Center. AB - BACKGROUND: Pediatric antimicrobial stewardship programs (ASPs) within larger institutions have unique opportunities to develop programs specialized to the needs of the pediatric program. In January 2013, our institution established a formalized pediatric ASP utilizing the prospective audit and feedback process. In an effort to standardize therapy and improve quality of care, members of the ASP developed evidence-based guidelines for management of common inpatient pediatric infections. ASP members met periodically with faculty and house staff to discuss guidelines and ways to improve prescribing. METHODS: Provider adherence with clinical inpatient practice guidelines, frequency of interventions suggested by ASP, and acceptance of interventions by providers were elements used to measure process change. We measured outcome data by analyzing antimicrobial utilization (defined as days of therapy) and length of therapy. RESULTS: Over a period of 2 years, institutional ASP guidelines were applicable to nearly half (44%) of all antimicrobial orders. Interventions were performed on 30% of all antimicrobial orders, of which 89% were accepted. Total antimicrobial days of therapy and length of therapy decreased significantly when comparing pre- and post-ASP. Overall, the susceptibility profiles of common bacterial pathogens to antibiotics remained stable. CONCLUSIONS: Pediatric ASPs within larger institutions have opportunities to create programs specific to the needs of the population they serve. We observed high rates of adherence by providers and a subsequent reduction in antibiotic utilization when implementing an audit feedback-based process. PMID- 28814445 TI - Meeting Report on Experimental Approaches to Evolution and Ecology Using Yeast and Other Model Systems. AB - The fourth EMBO-sponsored conference on Experimental Approaches to Evolution and Ecology Using Yeast and Other Model Systems (https://www.embl.de/training/events/2016/EAE16-01/), was held at the EMBL in Heidelberg, Germany, October 19-23, 2016. The conference was organized by Judith Berman (Tel Aviv University), Maitreya Dunham (University of Washington), Jun-Yi Leu (Academia Sinica), and Lars Steinmetz (EMBL Heidelberg and Stanford University). The meeting attracted ~120 researchers from 28 countries and covered a wide range of topics in the fields of genetics, evolutionary biology, and ecology with a unifying focus on yeast as a model system. Attendees enjoyed the Keith Haring inspired yeast florescence microscopy artwork (Figure 1), a unique feature of the meeting since its inception, and the one-minute flash talks that catalyzed discussions at two vibrant poster sessions. The meeting coincided with the 20th anniversary of the publication describing the sequence of the first eukaryotic genome, Saccharomyces cerevisiae (Goffeau et al. 1996). Many of the conference talks focused on important questions about what is contained in the genome, how genomes evolve, and the architecture and behavior of communities of phenotypically and genotypically diverse microorganisms. Here, we summarize highlights of the research talks around these themes. Nearly all presentations focused on novel findings, and we refer the reader to relevant manuscripts that have subsequently been published. PMID- 28814446 TI - Communicating echocardiography results to patients: a future role for the clinical scientist? PMID- 28814447 TI - Acute myocarditis secondary to cardiac tuberculosis: a case report. AB - : Isolated myocardial involvement in tuberculosis is exceedingly rare but there are reports it can present with sudden cardiac death, atrioventricular block, ventricular arrhythmias or congestive cardiac failure. We report the case of a 33 year-old male, of South Asian descent, who presented with chest pain, shortness of breath and an abnormal ECG. The patient had no significant past medical history and coronary angiogram showed no evidence of coronary artery disease. Of note, the patient had recently been discharged from a local district hospital with an episode of myocarditis. The patient was found to be severely hypoxic with evidence of severe biventricular failure on echocardiography. Computed tomography of the chest demonstrated hilar lymphadenopathy, and the differential diagnosis was thought to be tuberculosis or sarcoidosis. A TB Quantiferon gold test performed at the district hospital was positive; however, fine needle aspiration was negative for acid-fast bacilli. Despite aggressive diuresis, the patient became increasingly hypoxic and suffered a cardiac arrest. Post-mortem confirmed a diagnosis of myocardial tuberculosis - a rare case of acute decompensated heart failure. LEARNING POINTS: Tuberculosis myocarditis is a rare diagnosis but should be considered in at risk individuals presenting with acute fulminant myocarditis.Cardiac failure can occur even in the absence of disseminated tubercular disease.TB myocarditis is not just a disease of the immunocompromised.Definitive diagnosis of cardiac tuberculosis during life requires a myocardial biopsy.Echocardiography is a vital tool for the assessment of cardiac function, filling pressures and fluid status in the critically unwell patient. PMID- 28814449 TI - Haem iron and nitrate/nitrite account for much of the mortality increase associated with red meat consumption. PMID- 28814448 TI - Carcinogen susceptibility is regulated by genome architecture and predicts cancer mutagenesis. AB - The development of many sporadic cancers is directly initiated by carcinogen exposure. Carcinogens induce malignancies by creating DNA lesions (i.e., adducts) that can result in mutations if left unrepaired. Despite this knowledge, there has been remarkably little investigation into the regulation of susceptibility to acquire DNA lesions. In this study, we present the first quantitative human genome-wide map of DNA lesions induced by ultraviolet (UV) radiation, the ubiquitous carcinogen in sunlight that causes skin cancer. Remarkably, the pattern of carcinogen susceptibility across the genome of primary cells significantly reflects mutation frequency in malignant melanoma. Surprisingly, DNase-accessible euchromatin is protected from UV, while lamina-associated heterochromatin at the nuclear periphery is vulnerable. Many cancer driver genes have an intrinsic increase in carcinogen susceptibility, including the BRAF oncogene that has the highest mutation frequency in melanoma. These findings provide a genome-wide snapshot of DNA injuries at the earliest stage of carcinogenesis. Furthermore, they identify carcinogen susceptibility as an origin of genome instability that is regulated by nuclear architecture and mirrors mutagenesis in cancer. PMID- 28814450 TI - In localised prostate cancer, radical prostatectomy was associated with more sexual dysfunction and urinary incontinence than radiation or active surveillance. PMID- 28814451 TI - Androgen deprivation and immunotherapy for the treatment of prostate cancer. AB - Prostate cancer is the most common newly diagnosed malignancy in men, and the second most common cause of cancer-related death in the United States. The primary treatment for recurrent prostate cancer is androgen deprivation, and this therapy is typically continued lifelong for patients with metastatic prostate cancer. Androgens and androgen deprivation have profound effects on the immune system, a finding that has become more appreciated in an era where immune-based treatments for cancer are being increasingly explored. Preclinical studies suggest that androgen deprivation could potentially positively or negatively affect the use of approved immunotherapies, or those that are being developed for the treatment of prostate cancer. In this review, we provide a brief overview of the different types of androgen deprivation treatments used in the management of prostate cancer, discuss their effects on prostate tumors and the immune system and how they are being explored in combination with immunotherapy. Finally, we address some of the critical questions in the field that must be answered to identify the best approaches to combine androgen deprivation with immunotherapy for the treatment of prostate cancer. PMID- 28814452 TI - Medical ovariectomy in menopausal breast cancer patients with high testosterone levels: a further step toward tailored therapy. AB - Five years of adjuvant therapy with anti-estrogens reduce the incidence of disease progression by about 50% in estrogen receptor-positive breast cancer patients, but late relapse can still occur after anti-estrogens have been discontinued. In these patients, excessive androgen production may account for renewed excessive estrogen formation and increased risks of late relapse. In the 50% of patients who do not benefit with anti-estrogens, the effect of therapy is limited by de novo or acquired resistance to treatment. Androgen receptor and epidermal growth factor receptor overexpression are recognized mechanisms of endocrine resistance suggesting the involvement of androgens as activators of the androgen receptor pathway and as stimulators of epidermal growth factor synthesis and function. Data from a series of prospective studies on operable breast cancer patients, showing high serum testosterone levels are associated to increased risk of recurrence, provide further support to a role for androgens in breast cancer progression. According to the above reported evidence, we proposed to counteract excessive androgen production in the adjuvant setting of estrogen receptor positive patients and suggested selecting postmenopausal patients with elevated levels of serum testosterone, marker of ovarian hyperandrogenemia, for adjuvant treatment with a gonadotropins-releasing hormone analogue (medical oophorectomy) in addition to standard therapy with anti-estrogens. The proposed approach provides an attempt of personalized medicine that needs to be further investigated in clinical trials. PMID- 28814454 TI - Air pollution as a catalyst for supporting tobacco control policies? Evidence from a nationwide study on Chinese medical students. AB - PURPOSE: Few studies have discussed how the increasing ambient air pollution may affect policy-related attitudes. Medical professionals constitute an important interest group who analyse and solve public issues within a medicalised framework. The current study investigates whether ambient air pollution is associated with a greater likelihood of supporting tobacco control measures among medical students. METHODS: We conducted multistage sampling among the medical students from 42 cities in China. We employed propensity-score matching to eliminate the selection bias and used multilevel logistic regressions for the main analysis (n1=9458, n2=42). RESULTS: we found that city-level air particulate matter is consistently associated with the support for tobacco control among medical students, net of other individual-level and city-level covariates. For one standard increase in air particulate matter, people are 1.21 times more likely to fully support tobacco control measures (p<0.05). This association is significantly stronger among medical students who are financially worse-off and are ethnic majority. CONCLUSIONS: Environmental pollution has a significant correlation with people's attitudes towards health policies, even when such policies are not directly concerned with the natural environment. Policy makers may use this opportunity to implement tobacco control measures against the backdrop of China's pollution crisis. PMID- 28814453 TI - Sympathetic Signaling Reactivates Quiescent Disseminated Prostate Cancer Cells in the Bone Marrow. AB - Clinical observations have identified an association between psychologic stress and cancer relapse, suggesting that the sympathetic nervous system/norepinephrine (NE) plays a role in reactivation of dormant disseminated tumor cells (DTC) in the bone marrow niche. Here, the mechanism by which NE regulates prostate cancer DTCs in the marrow is explored. NE directly stimulated prostate cancer cell proliferation through beta2-adrenergic receptors (ADRB2). NE also altered prostate cancer proliferation in the marrow niche by indirectly downregulating the secretion of the dormancy inducing molecule growth arrest specific-6 (GAS6) expressed by osteoblasts. These observations were confirmed in cocultures of prostate cancer cells expressing the fluorescent ubiquitination-based cell-cycle reporters (FUCCI) and osteoblasts isolated from GAS6-deficient (GAS6-/-) animals. A novel ex vivo model system, using femurs harvested from GAS6+/+ or GAS6-/- mice, was used to confirm these results. As in coculture, when prostate cancer cells were injected into the marrow cavities of GAS6+/+ femurs, NE altered the prostate cancer cell cycle. However, NE had less of an impact on prostate cancer cells in femur explants isolated from GAS6-/- mice. Together, this study demonstrates that NE reactivates prostate cancer cell cycling through both a direct action on prostate cancer cells and indirectly on adjacent niche cells.Implications: Identification of mechanisms that target DTCs may provide novel therapeutic approaches to prevent or treat cancer metastases more effectively. Mol Cancer Res; 15(12); 1644-55. (c)2017 AACR. PMID- 28814456 TI - Downregulation of early visual cortex excitability mediates oscillopsia suppression. AB - OBJECTIVE: To identify in an observational study the neurophysiologic mechanisms that mediate adaptation to oscillopsia in patients with bilateral vestibular failure (BVF). METHODS: We directly probe the hypothesis that adaptive changes that mediate oscillopsia suppression implicate the early visual-cortex (V1/V2). Accordingly, we investigated V1/V2 excitability using transcranial magnetic stimulation (TMS) in 12 avestibular patients and 12 healthy controls. Specifically, we assessed TMS-induced phosphene thresholds at baseline and cortical excitability changes while performing a visual motion adaptation paradigm during the following conditions: baseline measures (i.e., static), during visual motion (i.e., motion before adaptation), and during visual motion after 5 minutes of unidirectional visual motion adaptation (i.e., motion adapted). RESULTS: Patients had significantly higher baseline phosphene thresholds, reflecting an underlying adaptive mechanism. Individual thresholds were correlated with oscillopsia symptom load. During the visual motion adaptation condition, no differences in excitability at baseline were observed, but during both the motion before adaptation and motion adapted conditions, we observed significantly attenuated cortical excitability in patients. Again, this attenuation in excitability was stronger in less symptomatic patients. CONCLUSIONS: Our findings provide neurophysiologic evidence that cortically mediated adaptive mechanisms in V1/V2 play a critical role in suppressing oscillopsia in patients with BVF. PMID- 28814458 TI - Staying in service with posttraumatic headache: A retrospective cohort study of patient outcome. AB - OBJECTIVE: To predict the probability of a military outcome (medical discharge/retirement) in patients with mild traumatic brain injury from a clinical analysis of predetermined patient and headache characteristics. METHODS: This retrospective cohort study sampled all new patients referred for headache evaluation at the Brain Injury Clinic of the Womack Army Medical Center, Ft. Bragg, NC (August 2008-January 2010). Headache characteristics were extracted and analyzed. Multivariable binary logistic regressions were conducted to predict probability of medical discharge/retirement. RESULTS: Ninety-five soldiers (age 31.3 +/- 7.4 years, male 93.7%) reported 166 headaches. The most common injury cited was a blast (53.7%). Patients with a continuous headache have almost 4 times the odds of a medically related discharge/retirement compared to patients without such a headache (continuous headache regression coefficient estimate: p < 0.042, odds ratio 3.98, 95% Wald confidence interval 1.05-15.07). Results suggest that, compared to service members who did not have a continuous headache, patients with headache histories with severe holocephalic pain who medicate to keep functioning had the highest probability of medical discharge/retirement. CONCLUSIONS: Certain headache characteristics may be predictive of military outcomes after mild traumatic brain injury, and we propose a profile that may be useful in that prediction. These data could be useful in future attempts to assess and treat patients with posttraumatic headache and to advise longer-term planning for return to duty or discharge. PMID- 28814455 TI - National randomized controlled trial of virtual house calls for Parkinson disease. AB - OBJECTIVE: To determine whether providing remote neurologic care into the homes of people with Parkinson disease (PD) is feasible, beneficial, and valuable. METHODS: In a 1-year randomized controlled trial, we compared usual care to usual care supplemented by 4 virtual visits via video conferencing from a remote specialist into patients' homes. Primary outcome measures were feasibility, as measured by the proportion who completed at least one virtual visit and the proportion of virtual visits completed on time; and efficacy, as measured by the change in the Parkinson's Disease Questionnaire-39, a quality of life scale. Secondary outcomes included quality of care, caregiver burden, and time and travel savings. RESULTS: A total of 927 individuals indicated interest, 210 were enrolled, and 195 were randomized. Participants had recently seen a specialist (73%) and were largely college-educated (73%) and white (96%). Ninety-five (98% of the intervention group) completed at least one virtual visit, and 91% of 388 virtual visits were completed. Quality of life did not improve in those receiving virtual house calls (0.3 points worse on a 100-point scale; 95% confidence interval [CI] -2.0 to 2.7 points; p = 0.78) nor did quality of care or caregiver burden. Each virtual house call saved patients a median of 88 minutes (95% CI 70 120; p < 0.0001) and 38 miles per visit (95% CI 36-56; p < 0.0001). CONCLUSIONS: Providing remote neurologic care directly into the homes of people with PD was feasible and was neither more nor less efficacious than usual in-person care. Virtual house calls generated great interest and provided substantial convenience. CLINICALTRIALSGOV IDENTIFIER: NCT02038959. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with PD, virtual house calls from a neurologist are feasible and do not significantly change quality of life compared to in-person visits. The study is rated Class III because it was not possible to mask patients to visit type. PMID- 28814459 TI - The virtual house call: A 21st-century innovation in the care of patients with Parkinson disease. PMID- 28814460 TI - As the world turns, why do some people adapt to vestibular failure and others do not? PMID- 28814457 TI - Direct oral anticoagulant- vs vitamin K antagonist-related nontraumatic intracerebral hemorrhage. AB - OBJECTIVE: To compare the neuroimaging profile and clinical outcomes among patients with intracerebral hemorrhage (ICH) related to use of vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) for nonvalvular atrial fibrillation (NVAF). METHODS: We evaluated consecutive patients with NVAF with nontraumatic, anticoagulant-related ICH admitted at 13 tertiary stroke care centers over a 12-month period. We also performed a systematic review and meta analysis of eligible observational studies reporting baseline characteristics and outcomes among patients with VKA- or DOAC-related ICH. RESULTS: We prospectively evaluated 161 patients with anticoagulation-related ICH (mean age 75.6 +/- 9.8 years, 57.8% men, median admission NIH Stroke Scale [NIHSSadm] score 13 points, interquartile range 6-21). DOAC-related (n = 47) and VKA-related (n = 114) ICH did not differ in demographics, vascular risk factors, HAS-BLED and CHA2DS2-VASc scores, and antiplatelet pretreatment except for a higher prevalence of chronic kidney disease in VKA-related ICH. Patients with DOAC-related ICH had lower median NIHSSadm scores (8 [3-14] vs 15 [7-25] points, p = 0.003), median baseline hematoma volume (12.8 [4-40] vs 24.3 [11-58.8] cm3, p = 0.007), and median ICH score (1 [0-2] vs 2 [1-3] points, p = 0.049). Severe ICH (>2 points) was less prevalent in DOAC-related ICH (17.0% vs 36.8%, p = 0.013). In multivariable analyses, DOAC-related ICH was independently associated with lower baseline hematoma volume (p = 0.006), lower NIHSSadm scores (p = 0.022), and lower likelihood of severe ICH (odds ratio [OR] 0.34, 95% confidence interval [CI] 0.13 0.87, p = 0.025). In meta-analysis of eligible studies, DOAC-related ICH was associated with lower baseline hematoma volumes on admission CT (standardized mean difference = -0.57, 95% CI -1.02 to -0.12, p = 0.010) and lower in-hospital mortality rates (OR = 0.44, 95% CI 0.21-0.91, p = 0.030). CONCLUSIONS: DOAC related ICH is associated with smaller baseline hematoma volume and lesser neurologic deficit at hospital admission compared to VKA-related ICH. PMID- 28814461 TI - Subcutaneous immunoglobulin in myasthenia gravis exacerbation: A prospective, open-label trial. AB - OBJECTIVE: To investigate the efficacy, tolerability, and safety of subcutaneous immunoglobulin (SCIg) in patients with mild to moderate myasthenia gravis (MG) exacerbation. METHODS: We performed a prospective, open-label, phase 3 trial in patients with MG aged 18 years or older and mild to moderate worsening (transition from Myasthenia Gravis Foundation of America class I to II/III or class II to III), treated with SCIg (2 g/kg), self-administered over 4 weeks. The primary endpoint was change in quantitative MG (QMG) score from baseline to study end at 6 weeks. Secondary endpoints included change in manual muscle testing (MMT), MG activities of daily living (MG-ADL), and MG composite (MGC) scores, as well as occurrence of adverse events, and tolerability as assessed via Treatment Satisfaction Questionnaire for Medication (TSQM). RESULTS: Twenty-two of 23 patients completed the study. QMG score decreased from 14.9 +/- 4.1 to 9.8 +/- 5.6 (p < 0.0001), MMT score decreased from 16.8 +/- 9.5 to 5.2 +/- 4.5 (p < 0.0001), MG-ADL score decreased from 9.5 +/- 3.0 to 4.6 +/- 3.0 (p < 0.0001), and MGC score decreased from 17.4 +/- 5.0 to 5.6 +/- 4.5 (p < 0.0001). Satisfaction by TSQM was high (79.6 +/- 15.6%). Common adverse events included headache and injection site reactions. No serious adverse events occurred. CONCLUSIONS: SCIg is well-tolerated, safe, and effective in mild to moderate MG exacerbation. Comparative safety and efficacy must be established with randomized controlled trials. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients with mild to moderate MG exacerbation, SCIg is safe and effective in reducing MG disability measures. PMID- 28814462 TI - 18F-AV-1451 binds to motor-related subcortical gray and white matter in corticobasal syndrome. AB - OBJECTIVE: To investigate tau distribution in patients with corticobasal syndrome (CBS) using 18F-AV-1451 PET. METHODS: Six consecutively recruited patients with CBS and 20 age-matched healthy controls underwent 2 PET scans with 18F-AV-1451 (for tau) and 18F-florbetaben (for beta-amyloid). We compared standardized uptake value ratio maps of the 18F-AV-1451 PET images between the patients with CBS and controls. RESULTS: Compared to controls, patients with CBS exhibited asymmetrically increased 18F-AV-1451 binding in the putamen, globus pallidus, and thalamus contralateral to the clinically more affected side and in the ipsilateral globus pallidus and dentate nucleus. Voxel-based comparison additionally showed asymmetrically increased 18F-AV-1451 binding in the focal regions of the precentral gray and white matter and in the midbrain, predominantly in the contralateral side. 18F-AV-1451 binding in the precentral white matter correlated with motor severity. CONCLUSIONS: 18F-AV-1451 asymmetrically binds to motor-related subcortical gray and white matter structures in patients with CBS. This pattern corresponds to tau pathology distribution in postmortem studies, and motor deficit in patients with CBS may be associated with tau accumulation predominantly in the subcortical white matter underlying the motor cortex, leading to disruptions in motor-related networks. PMID- 28814463 TI - Neurobiological correlates of state-dependent context fear. AB - Retrieval of fear memories can be state-dependent, meaning that they are best retrieved if the brain states at encoding and retrieval are similar. Such states can be induced by activating extrasynaptic gamma-aminobutyric acid type A receptors (GABAAR) with the broad alpha-subunit activator gaboxadol. However, the circuit mechanisms and specific subunits underlying gaboxadol's effects are not well understood. Here we show that gaboxadol induces profound changes of local and network oscillatory activity, indicative of discoordinated hippocampal cortical activity, that were accompanied by robust and long-lasting state dependent conditioned fear. Episodic memories typically are hippocampus-dependent for a limited period after learning, but become cortex-dependent with the passage of time. In contrast, state-dependent memories continued to rely on hippocampal GABAergic mechanisms for memory retrieval. Pharmacological approaches with alpha subunit-specific agonists targeting the hippocampus implicated the prototypic extrasynaptic subunits (alpha4) as the mediator of state-dependent conditioned fear. Together, our findings suggest that continued dependence on hippocampal rather than cortical mechanisms could be an important feature of state-dependent memories that contributes to their conditional retrieval. PMID- 28814464 TI - On the transition from reconsolidation to extinction of contextual fear memories. AB - Retrieval of an associative memory can lead to different phenomena. Brief reexposure sessions tend to trigger reconsolidation, whereas more extended ones trigger extinction. In appetitive and fear cued Pavlovian memories, an intermediate "null point" period has been observed where neither process seems to be engaged. Here we investigated whether this phenomenon extends to contextual fear memory. Adult rats were subjected to a contextual fear conditioning paradigm, reexposed to the context 2 d later for 3, 5, 10, 20, or 30 min, with immediate injections of MK-801 or saline following reexposure, and tested on the following day. We observed a significant effect of MK-801 with the 3- and 30-min sessions, impairing reconsolidation and extinction, respectively. However, it did not have significant effects with 5-, 10-, or 20-min sessions, even though freezing decreased from reexposure to test. Further analyses indicated that this is not likely to be due to a variable transition point at the population level. In conclusion, the results show that in contextual fear memories there is a genuine "null point" between the parameters that induce reconsolidation and extinction, as defined by the effects of MK-801, although NMDA receptor independent decreases in freezing can still occur in these conditions. PMID- 28814465 TI - The ventromedial prefrontal cortex in a model of traumatic stress: fear inhibition or contextual processing? AB - The ventromedial prefrontal cortex (vmPFC) has consistently appeared altered in post-traumatic stress disorder (PTSD). Although the vmPFC is thought to support the extinction of learned fear responses, several findings support a broader role for this structure in the regulation of fear. To further characterize the relationship between vmPFC dysfunction and responses to traumatic stress, we examined the effects of pretraining vmPFC lesions on trauma reactivity and enhanced fear learning in a rodent model of PTSD. In Experiment 1, lesions did not produce differences in shock reactivity during an acute traumatic episode, nor did they alter the strength of the traumatic memory. However, when lesioned animals were subsequently given a single mild aversive stimulus in a novel context, they showed a blunting of the enhanced fear response to this context seen in traumatized animals. In order to address this counterintuitive finding, Experiment 2 assessed whether lesions also attenuated fear responses to discrete tone cues. Enhanced fear for discrete cues following trauma was preserved in lesioned animals, indicating that the deficit observed in Experiment 1 is limited to contextual stimuli. These findings further support the notion that the vmPFC contributes to the regulation of fear through its influence on context learning and contrasts the prevailing view that the vmPFC directly inhibits fear. PMID- 28814466 TI - Interaction of induced anxiety and verbal working memory: influence of trait anxiety. AB - This study examines the influence of trait anxiety on working memory (WM) in safety and threat. Interactions between experimentally induced anxiety and WM performance (on different cognitive loads) have been reported in healthy, nonanxious subjects. Differences in trait anxiety may moderate these interactions. Accordingly, these interactions may be potentiated by high trait anxiety (HTA), or show a resilient pattern that protects cognitive performance. HTA and low trait anxiety (LTA) were defined by a median split of scores on the trait component of the state-trait anxiety inventory. Sustained anxiety was evoked by a probabilistic exposure to an aversive scream, and was measured by eyeblink startle and self-report. WM was tested using an n-back task (1-, 2-, and 3-back). Results revealed that, as expected, the HTA group reported greater anxiety during the task. However, trait anxiety did not impact the modulation of WM performance by induced anxiety. Notably, HTA influenced anxiety-potentiated startle (startle during threat minus startle during safe; APS) differently as a function of memory load. Accordingly, APS decreased with increasing WM load, but HTA antagonized this reduction. The HTA group showed no impairment on the 3-back WM task despite a higher APS. The amplified APS could be associated with the increase in effort-related cognitive arousal. Furthermore, this third replication of the interaction of induced anxiety by load on WM performance testifies to the robustness of the unique interplay between anxiety and WM. PMID- 28814468 TI - Persistent effects of acute stress on fear and drug-seeking in a novel model of the comorbidity between post-traumatic stress disorder and addiction. AB - Even following long periods of abstinence, individuals with anxiety disorders have high rates of relapse to drugs of abuse. Although many current models of relapse demonstrate effects of acute stress on drug-seeking, most of these studies examine stressful experiences that occur in close temporal and physical proximity to the reinstatement test. Here, we assess the effects of a stressful experience in one context on fear and drug-seeking in a different context. We adapt the stress-enhanced fear learning procedure to examine impacts on drug seeking long after the stressful experience occurred. We find massive footshock in a distinct environment produced an acute increase in corticosterone, long-term hyper-responsivity to a single shock in different contexts with extensive histories of drug-seeking behaviors, enhancements in cocaine-induced conditioned place preference in mice, and persistent enhancements in cue-induced reinstatement of methamphetamine-seeking behavior in rats. Together, these experiments demonstrate that an acute trauma causes persistent changes in responsivity to mild stressors and drug-seeking behavior in other contexts, which mirrors aspects of the comorbidity between post-traumatic stress disorder and substance use disorders. These behavioral approaches provide novel procedures for investigating basic mechanisms underlying this comorbidity and they provide powerful tools for testing preclinical pharmacological and behavioral interventions. PMID- 28814467 TI - Input from the medial geniculate nucleus modulates amygdala encoding of fear memory discrimination. AB - Generalization of fear can involve abnormal responding to cues that signal safety and is common in people diagnosed with post-traumatic stress disorder. Differential auditory fear conditioning can be used as a tool to measure changes in fear discrimination and generalization. Most prior work in this area has focused on elevated amygdala activity as a critical component underlying generalization. The amygdala receives input from auditory cortex as well as the medial geniculate nucleus (MgN) of the thalamus, and these synapses undergo plastic changes in response to fear conditioning and are major contributors to the formation of memory related to both safe and threatening cues. The requirement for MgN protein synthesis during auditory discrimination and generalization, as well as the role of MgN plasticity in amygdala encoding of discrimination or generalization, have not been directly tested. GluR1 and GluR2 containing AMPA receptors are found at synapses throughout the amygdala and their expression is persistently up-regulated after learning. Some of these receptors are postsynaptic to terminals from MgN neurons. We found that protein synthesis dependent plasticity in MgN is necessary for elevated freezing to both aversive and safe auditory cues, and that this is accompanied by changes in the expressions of AMPA receptor and synaptic scaffolding proteins (e.g., SHANK) at amygdala synapses. This work contributes to understanding the neural mechanisms underlying increased fear to safety signals after stress. PMID- 28814469 TI - Characterization of the amplificatory effect of norepinephrine in the acquisition of Pavlovian threat associations. AB - The creation of auditory threat Pavlovian memory requires an initial learning stage in which a neutral conditioned stimulus (CS), such as a tone, is paired with an aversive one (US), such as a shock. In this phase, the CS acquires the capacity of predicting the occurrence of the US and therefore elicits conditioned defense responses. Norepinephrine (NE), through beta-adrenergic receptors in the amygdala, enhances threat memory by facilitating the acquisition of the CS-US association, but the nature of this effect has not been described. Here we show that NE release, induced by the footshock of the first conditioning trial, promotes the subsequent enhancement of learning. Consequently, blocking NE transmission disrupts multitrial but not one-trial conditioning. We further found that increasing the time between the conditioning trials eliminates the amplificatory effect of NE. Similarly, an unsignaled footshock delivered in a separate context immediately before conditioning can enhance learning. These results help define the conditions under which NE should and should not be expected to alter threat processing and fill an important gap in the understanding of the neural processes relevant to the pathophysiology of stress and anxiety disorders. PMID- 28814470 TI - A dangerous context changes the way that rats learn about and discriminate between innocuous events in sensory preconditioning. AB - Four experiments used a sensory preconditioning protocol to examine how a dangerous context influences learning about innocuous events. In Experiments 1, 2, and 3, rats were exposed to presentations of a tone followed immediately or 20 sec later by presentations of a light. These tone-light pairings occurred in a context that was either familiar and safe, or equally familiar but dangerous, that is, it was a context in which rats had been exposed to footshock. Rats were next exposed to parings of the light and shock and then tested with the tone (and light). The experiments showed that a dangerous context permits formation of a tone-light association under circumstances that preclude formation of that same association in a safe context (Experiments 1 and 2), and that this facilitative effect on associative formation depends on the content being currently dangerous rather than having been dangerous in the past (Experiment 3). Experiment 4 examined whether a dangerous context facilitates discrimination between two innocuous events. In a safe or dangerous context, rats were exposed to a tone that signaled the light and then to a white noise presented alone. Subsequent to conditioning of the light, the tests revealed that rats that had been exposed to these tone-light and white noise alone presentations in a dangerous context froze to the tone but not to the noise, whereas those exposed in a safe context froze to both the tone and the white noise. The results were related to previous evidence that the amygdala is critical for processing information about innocuous stimuli in a dangerous but not a safe context. They were attributed to an amygdala-based enhancement of arousal and/or attention in a dangerous context, hence the facilitation of associative formation and enhanced discriminability in this context. PMID- 28814471 TI - Novelty and fear conditioning induced gene expression in high and low states of anxiety. AB - Emotional states influence how stimuli are interpreted. High anxiety states in humans lead to more negative, threatening interpretations of novel information, typically accompanied by activation of the amygdala. We developed a handling protocol that induces long-lasting high and low anxiety-like states in rats to explore the role of state anxiety on brain activation during exposure to a novel environment and fear conditioning. In situ hybridization of the inducible transcription factor Egr-1 found increased gene expression in the lateral nucleus of the amygdala (LA) following exposure to a novel environment and contextual fear conditioning in high anxiety-like rats. In contrast, low state anxiety-like rats did not generate Egr-1 increases in LA when placed in a novel chamber. Egr-1 expression was also examined in the dorsal hippocampus and prefrontal cortex. In CA1 of the hippocampus and medial prefrontal cortex (mPFC), Egr-1 expression increased in response to novel context exposure and fear conditioning, independent of state anxiety level. Furthermore, in mPFC, Egr-1 in low anxiety like rats was increased more with fear conditioning than novel exposure. The current series of experiments show that brain areas involved in fear and anxiety like states do not respond uniformly to novelty during high and low states of anxiety. PMID- 28814472 TI - Neurobiology of fear and specific phobias. AB - Fear, which can be expressed innately or after conditioning, is triggered when a danger or a stimulus predicting immediate danger is perceived. Its role is to prepare the body to face this danger. However, dysfunction in fear processing can lead to psychiatric disorders in which fear outweighs the danger or possibility of harm. Although recognized as highly debilitating, pathological fear remains insufficiently treated, indicating the importance of research on fear processing. The neurobiological basis of normal and pathological fear reactions is reviewed in this article. Innate and learned fear mechanisms, particularly those involving the amygdala, are considered. These fear mechanisms are also distinguished in specific phobias, which can indeed be nonexperiential (implicating innate, learning-independent mechanisms) or experiential (implicating learning-dependent mechanisms). Poor habituation and poor extinction are presented as dysfunctional mechanisms contributing to persistence of nonexperiential and experiential phobias, respectively. PMID- 28814473 TI - Breaking boundaries: optimizing reconsolidation-based interventions for strong and old memories. AB - Recent research has demonstrated that consolidated memories can enter a temporary labile state after reactivation, requiring restabilization in order to persist. This process, known as reconsolidation, potentially allows for the modification and disruption of memory. Much interest in reconsolidation stems from the possibility that maladaptive memory traces-a core feature of several psychiatric conditions-could be tackled by disrupting their reconsolidation. However, research has indicated a range of supposed boundary conditions on the induction of reconsolidation. Stronger memories, often resulting from exposure to stressful conditions, or older memories, appear to be relatively resistant to undergoing reconsolidation. This may be taken as a potential stumbling block for reconsolidation-based interventions: in clinical practice, old and strong maladaptive memories are the norm rather than the exception. Yet, boundary conditions have been derived from limited experimental evidence, are not unique to reconsolidation-based interventions, and do not seem to be absolute. In this paper, we review a range of experimental studies that have aimed to disrupt old memories, or memories that were strengthened by stress manipulations, through reconsolidation. Such research highlights several techniques that could be used to optimize reconsolidation-based approaches and overcome putative boundary conditions. We supplement this review of experimental literature with a case study of a reconsolidation-based treatment of a strong and decades-old phobia for mice, further suggesting that age and strength of memory may not be insurmountable barriers. Translating findings from basic science, to human experiments, to clinical applications and back again, can potentially unlock powerful new treatments for the many people who suffer daily from anxiety disorders. PMID- 28814476 TI - Phase I trial of the androgen receptor modulator CR1447 in breast cancer patients. AB - CR1447 (4-hydroxytestosterone, 4-OHT) binds to the androgen receptor and has antiproliferative activity in both ER-positive and ER-negative/AR-positive breast cancer cells in preclinical studies. The objective of this first-in man trial was to evaluate the safety and to determine the dose of CR1447, administered as an ointment, for Phase II. Escalating doses (100, 200, 400 mg) of CR1447 were administered topically on a daily basis to patients with ER-positive/AR positive/HER2-negative advanced breast cancer pretreated with several lines of therapy. 14 patients have been treated for a total of 42 cycles. Two patients, one at dose level 100 mg and one at dose level 200 mg, showed early tumour progression and were replaced. Related adverse events were all <= grade 2 and included fatigue, bone and joint pain, stiffness, dry skin and mouth, nausea, sweating, urinary tract infection, rash, headache and distress. No drug-related dose-limiting toxicities (DLTs) were seen. Two patients (17%) achieved stable disease at 3 months. Pharmacokinetic analysis confirmed dose-dependent transdermal uptake of CR1447. 4-OH-androstenedione (4-OHA), a key metabolite of 4 OHT, was undetectable in most of the plasma samples. Urine metabolites of 4-OHT and 4-OHA indicate high exposure of 4-OHT after topical administration. Oestradiol serum concentrations did not increase, confirming preclinical data that CR1447 is not converted to estrogens in vivo In conclusion, CR1447 administered transdermally as an ointment is well tolerated and appears to have single-agent activity in heavily pretreated ER-positive/HER2-negative breast cancer patients. The recommended phase II dose is 400 mg/day. PMID- 28814475 TI - Developmental pathway genes and neural plasticity underlying emotional learning and stress-related disorders. AB - The manipulation of neural plasticity as a means of intervening in the onset and progression of stress-related disorders retains its appeal for many researchers, despite our limited success in translating such interventions from the laboratory to the clinic. Given the challenges of identifying individual genetic variants that confer increased risk for illnesses like depression and post-traumatic stress disorder, some have turned their attention instead to focusing on so called "master regulators" of plasticity that may provide a means of controlling these potentially impaired processes in psychiatric illnesses. The mammalian homolog of Tailless (TLX), Wnt, and the homeoprotein Otx2 have all been proposed to constitute master regulators of different forms of plasticity which have, in turn, each been implicated in learning and stress-related disorders. In the present review, we provide an overview of the changing distribution of these genes and their roles both during development and in the adult brain. We further discuss how their distinct expression profiles provide clues as to their function, and may inform their suitability as candidate drug targets in the treatment of psychiatric disorders. PMID- 28814477 TI - Iodine excess exposure during pregnancy and lactation impairs maternal thyroid function in rats. AB - Adequate maternal iodine consumption during pregnancy and lactation guarantees normal thyroid hormones (TH) production, which is crucial to the development of the fetus. Indeed, iodine deficiency is clearly related to maternal hypothyroidism and deleterious effects in the fetal development. Conversely, the effects of iodine excess (IE) consumption on maternal thyroid function are still controversial. Therefore, this study aimed to investigate the impact of IE exposure during pregnancy and lactation periods on maternal hypothalamus pituitary-thyroid axis. IE-exposed dams presented reduced serum TH concentration and increased serum thyrotropin (TSH) levels. Moreover, maternal IE exposure increased the hypothalamic expression of Trh and the pituitary expression of Trhr, Dio2, Tsha and Tshb mRNA, while reduced the Gh mRNA content. Additionally, IE-exposed dams presented thyroid morphological alterations, increased thyroid oxidative stress and decreased expression of thyroid genes/proteins involved in TH synthesis, secretion and metabolism. Furthermore, Dio1 mRNA expression and D1 activity were reduced in the liver and the kidney of IE-treated animals. Finally, the mRNA expression of Slc5a5 and Slc26a4 were reduced in the mammary gland of IE exposed rats. The latter results are in accordance with the reduction of prolactin expression and serum levels in IE-treated dams. In summary, our study indicates that the exposure to IE during pregnancy and lactation induces primary hypothyroidism in rat dams and impairs iodide transfer to the milk. PMID- 28814478 TI - Effect of patient weight on first pass success and neuromuscular blocking agent dosing for rapid sequence intubation in the emergency department. AB - OBJECTIVES: The primary objective of this study was to determine the association between patient weight and first pass success (FPS) during rapid sequence intubation (RSI) in the ED. The secondary objective was to evaluate the association between patient weight and neuromuscular blocking agent (NMBA) dosing. METHODS: This was a retrospective cohort study conducted in a tertiary care academic ED. Consecutive adult patients who underwent RSI in the ED between January 2014 and June 2016 were included. Data were collected on patient, operator and procedural characteristics. The cohort was categorised into the following weight strata: <80 kg, 80 to <100 kg, 100 to <120 kg and >=120 kg. The primary outcome of interest was FPS. A multivariable logistic regression analysis was conducted to evaluate the relationship between patient weight category and FPS. NMBA dosing was reported descriptively. RESULTS: The sample included 891 patients. FPS for each weight category was as follows: <80 kg (91%), 80 to <100 kg (90%), 100 to <120 kg (91%) and >=120 kg (76%). After adjusting for potential confounders, the heaviest weight category was associated with decreased odds of FPS (OR 0.2, 95% CI 0.1 to 0.5, p<0.001). Median doses for succinylcholine (based on total body weight) decreased as weight increased: <80 kg (1.5 mg/kg), 80 to <100 kg (1.3 mg/kg), 100 to <120 kg (1.2 mg/kg) and >=120 kg (1.0 mg/kg). Median doses for rocuronium (based on ideal body weight) were similar across weight categories: <80 kg (1.3 mg/kg), 80 to <100 kg (1.4 mg/kg), 100 to <120 kg (1.3 mg/kg) and >=120 kg (1.4 mg/kg). CONCLUSIONS: Very heavy patients (>120 kg) undergoing RSI in the ED had a reduced FPS, and succinylcholine was more commonly underdosed than rocuronium in the heavier weight group. PMID- 28814474 TI - Role of the bed nucleus of the stria terminalis in aversive learning and memory. AB - Surviving threats in the environment requires brain circuits for detecting (or anticipating) danger and for coordinating appropriate defensive responses (e.g., increased cardiac output, stress hormone release, and freezing behavior). The bed nucleus of the stria terminalis (BNST) is a critical interface between the "affective forebrain"-including the amygdala, ventral hippocampus, and medial prefrontal cortex-and the hypothalamic and brainstem areas that have been implicated in neuroendocrine, autonomic, and behavioral responses to actual or anticipated threats. However, the precise contribution of the BNST to defensive behavior is unclear, both in terms of the antecedent stimuli that mobilize BNST activity and the consequent defensive reactions. For example, it is well known that the BNST is essential for contextual fear conditioning, but dispensable for fear conditioning to discrete conditioned stimuli (CSs), at least as indexed by freezing behavior. However, recent evidence suggests that there are circumstances in which contextual freezing may persist independent of the BNST. Furthermore, the BNST is involved in the reinstatement (or relapse) of conditioned freezing to extinguished discrete CSs. As such, there are critical gaps in understanding how the BNST contributes to fundamental processes involved in Pavlovian fear conditioning. Here, we attempt to provide an integrative account of BNST function in fear conditioning. We discuss distinctions between unconditioned stress and conditioned fear and the role of BNST circuits in organizing behaviors associated with these states. We propose that the BNST mediates conditioned defensive responses-not based on the modality or duration of the antecedent threat or the duration of the behavioral response to the threat-but rather as consequence the ability of an antecedent stimulus to predict when an aversive outcome will occur (i.e., its temporal predictability). We argue that the BNST is not uniquely mobilized by sustained threats or uniquely involved in organizing sustained fear responses. In contrast, we argue that the BNST is involved in organizing fear responses to stimuli that poorly predict when danger will occur, no matter the duration, modality, or complexity of those stimuli. The concepts discussed in this review are critical to understanding the contribution of the human BNST to fear and anxiety disorders. PMID- 28814480 TI - Pharmacy preceptorship in the emergency department. PMID- 28814479 TI - Early prediction of hospital admission for emergency department patients: a comparison between patients younger or older than 70 years. AB - OBJECTIVE: The aim of this study was to develop models that predict hospital admission to ED of patients younger and older than 70 and compare their performance. METHODS: Prediction models were derived in a retrospective observational study of all patients>=18 years old visiting the ED of a university hospital during the first 6 months of 2012. Patients were stratified into two age groups (<70 years old and >=70 years old). Multivariable logistic regression analysis was used to identify predictors of hospital admission among factors available immediately after patient arrival to the ED. Validation of the prediction models was performed on patients presenting to the ED during the second half of the year 2012. RESULTS: 10 807 patients were included in the derivation and 10 480 in the validation cohorts. The strongest independent predictors of hospital admission among the 8728 patients <70 years old were age, sex, triage category, mode of arrival, performance of blood tests, chief complaint, ED revisit, type of specialist, phlebotomised blood sample and all vital signs. The area under the curve (AUC) of the validation cohort for those <70 years old was 0.86 (95% CI 0.85 to 0.87). Among the 2079 patients >=70 years, the same factors were predictive, except for gender, type of specialist and heart rate; the AUC was 0.77 (95% CI 0.75 to 0.79). The prediction models could identify a group of 10% of patients with the highest risk in whom hospital admission was predicted at ED triage, with a positive predictive value (PPV) of 71% (95% CI 68% to 74%) in younger patients and PPV of 87% (95% CI 81% to 92%) in older patients. CONCLUSION: Demographic and clinical factors readily available early in the ED visit can be useful in identifying patients who are likely to be admitted to the hospital. While the model for the younger patients had a higher AUC, the model for older patients had a higher PPV in identifying the patients at highest risk for admission. Of note, heart rate was not a useful predictor in the older patients. PMID- 28814481 TI - Plausibility criteria for putative pathophysiological mechanisms in functional gastrointestinal disorders: a consensus of experts. AB - BACKGROUND AND AIMS: The functional gastrointestinal disorders (FGIDs) are extremely common conditions associated with a considerable personal, social and health economic burden. Managing FGIDs in clinical practice is challenging because of the uncertainty of symptom-based diagnosis, the high frequency of overlap between these conditions and the limited efficacy of available therapies. It has often been argued that successful drug development and management of FGIDs requires knowledge of the underlying pathophysiology. Numerous and highly variable candidate pathophysiological mechanisms have been implicated in the generation of FGID symptoms, but there is no current consensus on how to best define the relevance of these disturbances. METHODS: A group of international experts on FGIDs developed plausibility criteria that should be fulfilled by relevant pathophysiological mechanisms in FGIDs. RESULTS: Five criteria are proposed: (1) the presence of the abnormality in a subset of patients, (2) temporal association between proposed mechanism and symptom(s), (3) correlation between the level of impairment of the mechanism and symptom(s), (4) induction of the symptom(s) by provoking the pathophysiological abnormality in healthy subjects and (5) treatment response by a therapy specifically correcting the underlying disorder or congruent natural history of symptoms and dysfunction in the absence of specific therapy. Based on strength of evidence for these five criteria according to the Grading of Recommendations Assessment, Development and Evaluation system, a plausibility score can be calculated for each mechanism. CONCLUSION: Evaluation of the strength of evidence for candidate pathophysiological abnormalities fulfilling these five plausibility criteria will help to identify the most relevant mechanisms to target for novel diagnostic approaches and for the development of new therapies. PMID- 28814482 TI - Lrig1+ gastric isthmal progenitor cells restore normal gastric lineage cells during damage recovery in adult mouse stomach. AB - OBJECTIVE: Lrig1 is a marker of proliferative and quiescent stem cells in the skin and intestine. We examined whether Lrig1-expressing cells are long-lived gastric progenitors in gastric glands in the mouse stomach. We also investigated how the Lrig1-expressing progenitor cells contribute to the regeneration of normal gastric mucosa by lineage commitment to parietal cells after acute gastric injury in mice. DESIGN: We performed lineage labelling using Lrig1-CreERT2/+;R26R YFP/+ (Lrig1/YFP) or R26R-LacZ/+ (Lrig1/LacZ) mice to examine whether the Lrig1 YFP-marked cells are gastric progenitor cells. We studied whether Lrig1-YFP marked cells give rise to normal gastric lineage cells in damaged mucosa using Lrig1/YFP mice after treatment with DMP-777 to induce acute injury. We also studied Lrig1-CreERT2/CreERT2 (Lrig1 knockout) mice to examine whether the Lrig1 protein is required for regeneration of gastric corpus mucosa after acute injury. RESULTS: Lrig1-YFP-marked cells give rise to gastric lineage epithelial cells both in the gastric corpus and antrum, in contrast to published results that Lgr5 only marks progenitor cells within the gastric antrum. Lrig1-YFP-marked cells contribute to replacement of damaged gastric oxyntic glands during the recovery phase after acute oxyntic atrophy in the gastric corpus. Lrig1 null mice recovered normally from acute gastric mucosal injury indicating that Lrig1 protein is not required for lineage differentiation. Lrig1+ isthmal progenitor cells did not contribute to transdifferentiating chief cell lineages after acute oxyntic atrophy. CONCLUSIONS: Lrig1 marks gastric corpus epithelial progenitor cells capable of repopulating the damaged oxyntic mucosa by differentiating into normal gastric lineage cells in mouse stomach. PMID- 28814483 TI - Analysis of learning curves in gastroscopy training: the need for composite measures for defining competence. PMID- 28814484 TI - Reassessment of gamma-glutamyl transpeptidase to platelet ratio (GPR): a large sample, dynamic study based on liver biopsy in a Chinese population with chronic hepatitis B virus (HBV) infection. PMID- 28814485 TI - Increased human intestinal barrier permeability plasma biomarkers zonulin and FABP2 correlated with plasma LPS and altered gut microbiome in anxiety or depression. PMID- 28814487 TI - Too hard to swallow! PMID- 28814486 TI - Serum ghrelin is associated with risk of colorectal adenocarcinomas in the ATBC study. AB - BACKGROUND: Colorectal cancers are the third most common cancers in women and men in the USA. While dietary and lifestyle factors such as Western diet, physical inactivity and obesity have been linked to an increased risk of this malignancy, the mechanisms for these associations are unclear. GI hormones, including ghrelin, are involved in energy balance by mediating appetite and metabolism; however, the association between ghrelin and colorectal cancer has not been studied. METHODS: We conducted a case-control study nested within the all-male Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish smokers (aged 50-69 years) to examine serum ghrelin concentration and colorectal cancer risk. Data from 284 colon and 239 rectal cancers and 523 controls (matched on age, date of blood draw and serum availability) were analysed. ORs and 95% CIs were calculated using multivariable (conditional) logistic regression. RESULTS: Overall, low-serum ghrelin was significantly associated with increased risk of colorectal cancer (Q1 vs Q4: OR:1.57, 95% CI 1.05 to 2.34). For individuals developing tumours within 10 years of blood draw, those in the lowest quartile of serum ghrelin concentrations were statistically significantly more likely to develop colorectal cancers than those with higher serum ghrelin concentrations (OR: 10.86, 95% CI 5.01 to 23.55). However, for individuals with tumours developing more than 20 years after blood draw, low-serum ghrelin concentrations were associated with a decreased risk of colorectal cancer relative to those with the highest serum ghrelin concentrations (OR: 0.26, 95% CI 0.11 to 0.64). CONCLUSION: Low-serum ghrelin was associated with an increased colorectal cancer risk within 10 years of blood draw with a decreased risk for developing colorectal cancer more than 20 years after blood draw. These results suggest that ghrelin concentrations may vary across the carcinogenic process. PMID- 28814488 TI - Association of cardiovascular disease risk factors with coronary artery calcium volume versus density. AB - OBJECTIVES: Recently, the density score of coronary artery calcium (CAC) has been shown to be associated with a lower risk of cardiovascular disease (CVD) events at any level of CAC volume. Whether risk factors for CAC volume and CAC density are similar or distinct is unknown. We sought to evaluate the associations of CVD risk factors with CAC volume and CAC density scores. METHODS: Baseline measurements from 6814 participants free of clinical CVD were collected for the Multi-Ethnic Study of Atherosclerosis. Participants with detectable CAC (n=3398) were evaluated for this study. Multivariable linear regression models were used to evaluate independent associations of CVD risk factors with CAC volume and CAC density scores. RESULTS: Whereas most CVD risk factors were associated with higher CAC volume scores, many risk factors were associated with lower CAC density scores. For example, diabetes was associated with a higher natural logarithm (ln) transformed CAC volume score (standardised beta=0.44 (95% CI 0.31 to 0.58) ln-units) but a lower CAC density score (beta=-0.07 (-0.12 to -0.02) density units). Chinese, African-American and Hispanic race/ethnicity were each associated with lower ln CAC volume scores (beta=-0.62 (-0.83to -0.41), -0.52 ( 0.64 to -0.39) and -0.40 (-0.55 to -0.26) ln-units, respectively) and higher CAC density scores (beta= 0.41 (0.34 to 0.47), 0.18 (0.12 to 0.23) and 0.21 (0.15 to 0.26) density units, respectively) relative to non-Hispanic White. CONCLUSIONS: In a cohort free of clinical CVD, CVD risk factors are differentially associated with CAC volume and density scores, with many CVD risk factors inversely associated with the CAC density score after controlling for the CAC volume score. These findings suggest complex associations between CVD risk factors and these components of CAC. PMID- 28814489 TI - Right ventricular outflow tract stent versus BT shunt palliation in Tetralogy of Fallot. AB - OBJECTIVE: This study sets out to compare morbidity, mortality and reintervention rates after stenting of the right ventricular outflow tract (RVOT) versus modified Blalock-Taussig shunt (mBTS) for palliation in patients with tetralogy of Fallot (ToF)-type lesions. METHODS: Retrospective case review study evaluating 101 patients (64 males) with ToF lesions who underwent palliation with either mBTS (n=41) or RVOT stent (n=60) to augment pulmonary blood flow over a 10-year period. Procedure-related morbidity, mortality and reintervention rates were assessed and compared. RESULTS: Admission rate to paediatric intensive care unit (PICU) was lower in the RVOT stent group (22% vs 100%; p<0.001). Thirty-day mortality in the RVOT stent group was (1/60 (1.7%)) compared with (2/41 (4.9%)) in the mBTS group (p=0.565). Mortality until surgical repair was comparable in both groups (5/60, 8.4%, including three non-cardiac death in the RVOT stent group vs 2/41, 4.9% (p=0.698)). Total hospital length of stay was shorter for the RVOT stent group (median 7 days vs 14 days; p<0.003). Time to surgical repair was shorter in the RVOT stent group (median 232 days, IQR 113-360) compared with the mBTS group (median 428 days, IQR 370-529; p<0.001) due to improved pulmonary arterial growth. CONCLUSION: RVOT stenting in Fallot-type lesions can be accomplished safely, with lower PICU admission rate, a shorter hospital length of stay and shorter duration of palliation until complete repair compared with mBTS palliation. PMID- 28814490 TI - Clinical features and prognosis of patients with isolated severe aortic stenosis and valve area less than 1.0 cm2. AB - OBJECTIVE: Current guidelines define severe aortic stenosis (AS) as an aortic valve area (AVA)<=1.0 cm2, but some authors have suggested that the AVA cut-off be decreased to 0.8 cm2. The aim of this study was, therefore, to better describe the clinical features and prognosis of patients with an AVA of 0.8-0.99 cm2. METHODS: Patients with isolated, severe AS and ejection fraction >=55% with an AVA of 0.8-0.99 cm2 (n=105) were compared with those with an AVA<0.8 cm2 (n=155) and 1.0-1.3 cm2 (n=81). The endpoint of this study was a combination of death from any cause or aortic valve replacement at or before 3 years. RESULTS: Patients with an AVA of 0.8-0.99 cm2 group comprised predominantly normal-flow, low-gradient (NFLG) AS, while high gradients and low flow were more often observed with an AVA<0.8 cm2. The frequency of symptoms was not significantly different between an AVA of 0.8-0.99 cm2 and 1.0-1.3 cm2. The combined endpoint was achieved in 71%, 52% and 21% of patients with an AVA of 0.8 cm2, 0.8-0.99 cm2and 1.0-1.3 cm2, respectively (p<0.001). Among patients with an AVA of 0.8 0.99 cm2, NFLG AS was associated with a lower hazard (HR=0.40, 95% CI 0.23 to 0.68, p=0.001) of achieving the combined endpoint with outcomes similar to moderate AS in the first 1.5 years of follow-up. Patients with high-gradient or low-flow AS with an AVA of 0.8-0.99 cm2 had outcomes similar to those with an AVA<0.8 cm2. The sensitivity for the combined endpoint was 61% for an AVA cut-off of 0.8 cm2 and 91% for a cut-off of 1.0 cm2. CONCLUSIONS: The outcomes of patients with AS with an AVA of 0.8-0.99 cm2 are variable and are more precisely defined by flow-gradient status. Our findings support the current AVA cut-off of 1.0 cm2. PMID- 28814491 TI - Surgical treatment of Marfan syndrome and related disorders is all about dealing with uncertainties. PMID- 28814492 TI - Influence of arterial stiffness on cardiovascular outcome in patients without high blood pressure. AB - OBJECTIVE: Although blood pressure (BP) is a major determinant of arterial stiffness, whether high pulse wave velocity (PWV) adversely influences cardiac parameters and cardiovascular (CV) outcome in patients without high BP remains unclear. METHODS: Outpatients without high BP (n=320), defined as systolic BP >=140 mm Hg, were enrolled in this retrospective study. At baseline, all patients underwent echocardiography and multidetector CT to determine the coronary artery calcification (CAC) score. Arterial stiffness was assessed based on brachial ankle PWV (baPWV), from which patients were classified into two groups: those with high (>=18 m/s, n=89) and low baPWV (<18 m/s, n=231). Cardiac parameters and CV event incidence during the follow-up period were compared between these groups. RESULTS: In multivariable linear regression analysis, baPWV was significantly associated with CAC score and serum N-terminal pro-brain natriuretic peptide hormone level, after adjustment for confounding factors. In multivariable logistic regression analysis, baPWV >=18 m/s was significantly associated with CAC score >=400 (OR 2.466, 95% CI 1.012 to 6.009, p=0.0471). Kaplan-Meier analysis showed that the high-baPWV group experienced more CV events during the 575 days of follow-up (20% vs 6%, p=0.0003). CONCLUSIONS: High baPWV was associated with greater CAC and a high risk of a future CV event, especially coronary artery disease, even in patients without high BP. PMID- 28814493 TI - What do our patients think they know about atrial fibrillation? ... Is that asking the right question? PMID- 28814494 TI - Syncope and orthostatic hypotension: early markers of cardiac disease in the general population. PMID- 28814495 TI - Right Ventricular-Pulmonary Vascular Interactions. AB - Accurate and comprehensive evaluation of right ventricular (RV)-pulmonary vascular (PV) interactions is critical to the assessment of cardiopulmonary function, dysfunction, and failure. Here, we review methods of quantifying RV-PV interactions and experimental results from clinical trials as well as large- and small-animal models based on pressure-volume analysis. We conclude by outlining critical gaps in knowledge that should drive future studies. PMID- 28814497 TI - Extracellular Acid-Base Balance and Ion Transport Between Body Fluid Compartments. AB - Clinical assessment of acid-base disorders depends on measurements made in the blood, part of the extracellular compartment. Yet much of the metabolic importance of these disorders concerns intracellular events. Intracellular and interstitial compartment acid-base balance is complex and heterogeneous. This review considers the determinants of the extracellular fluid pH related to the ion transport processes at the interface of cells and the interstitial fluid, and between epithelial cells lining the transcellular contents of the gastrointestinal and urinary tracts that open to the external environment. The generation of acid-base disorders and the associated disruption of electrolyte balance are considered in the context of these membrane transporters. This review suggests a process of internal and external balance for pH regulation, similar to that of potassium. The role of secretory gastrointestinal epithelia and renal epithelia with respect to normal pH homeostasis and clinical disorders are considered. Electroneutrality of electrolytes in the ECF is discussed in the context of reciprocal changes in Cl- or non Cl- anions and [Formula: see text]. PMID- 28814498 TI - Both Ways at Once: Keeping Small Airways Clean. AB - The small airways of the lungs are under constant assault from the pathogens and debris in the air that they must conduct to alveoli. Although hygiene is of paramount importance for respiratory health, the underlying principles of airway clearance have not been well integrated or established. Newly emerging concepts of simultaneous absorption and secretion of airway surface liquid (ASL) and the role of [Formula: see text] in the maturation of mucins have advanced from experimental evidence as well as observations from the congenital disease cystic fibrosis (CF) to present a novel model that integrates microanatomy with organ physiology to meet the constant challenge of cleaning small airways. PMID- 28814496 TI - Cardiometabolic Features of Polycystic Ovary Syndrome: Role of Androgens. AB - Polycystic ovary syndrome (PCOS) is the most common endocrine disorder that affects reproductive-age women. Hyperandrogenemia is present in a significant fraction (~80%) of women with PCOS. Increased prevalence of cardiometabolic risk factors is frequently observed in PCOS women. The present review aims to highlight the key role of androgens in mediating the negative cardiometabolic profile observed in PCOS women. PMID- 28814499 TI - Therapeutic Stimulation for Restoration of Function After Spinal Cord Injury. AB - Paralysis due to spinal cord injury can severely limit motor function and independence. This review summarizes different approaches to electrical stimulation of the spinal cord designed to restore motor function, with a brief discussion of their origins and the current understanding of their mechanisms of action. Spinal stimulation leads to impressive improvements in motor function along with some benefits to autonomic functions such as bladder control. Nonetheless, the precise mechanisms underlying these improvements and the optimal spinal stimulation approaches for restoration of motor function are largely unknown. Finally, spinal stimulation may augment other therapies that address the molecular and cellular environment of the injured spinal cord. The fact that several stimulation approaches are now leading to substantial and durable improvements in function following spinal cord injury provides a new perspectives on the previously "incurable" condition of paralysis. PMID- 28814501 TI - Knockout of the Golgi stacking proteins GRASP55 and GRASP65 impairs Golgi structure and function. AB - Golgi reassembly stacking protein of 65 kDa (GRASP65) and Golgi reassembly stacking protein of 55 kDa (GRASP55) were originally identified as Golgi stacking proteins; however, subsequent GRASP knockdown experiments yielded inconsistent results with respect to the Golgi structure, indicating a limitation of RNAi based depletion. In this study, we have applied the recently developed clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology to knock out GRASP55 and GRASP65, individually or in combination, in HeLa and HEK293 cells. We show that double knockout of GRASP proteins disperses the Golgi stack into single cisternae and tubulovesicular structures, accelerates protein trafficking, and impairs accurate glycosylation of proteins and lipids. These results demonstrate a critical role for GRASPs in maintaining the stacked structure of the Golgi, which is required for accurate posttranslational modifications in the Golgi. Additionally, the GRASP knockout cell lines developed in this study will be useful tools for studying the role of GRASP proteins in other important cellular processes. PMID- 28814500 TI - Monoubiquitination of syntaxin 3 leads to retrieval from the basolateral plasma membrane and facilitates cargo recruitment to exosomes. AB - Syntaxin 3 (Stx3), a SNARE protein located and functioning at the apical plasma membrane of epithelial cells, is required for epithelial polarity. A fraction of Stx3 is localized to late endosomes/lysosomes, although how it traffics there and its function in these organelles is unknown. Here we report that Stx3 undergoes monoubiquitination in a conserved polybasic domain. Stx3 present at the basolateral-but not the apical-plasma membrane is rapidly endocytosed, targeted to endosomes, internalized into intraluminal vesicles (ILVs), and excreted in exosomes. A nonubiquitinatable mutant of Stx3 (Stx3-5R) fails to enter this pathway and leads to the inability of the apical exosomal cargo protein GPRC5B to enter the ILV/exosomal pathway. This suggests that ubiquitination of Stx3 leads to removal from the basolateral membrane to achieve apical polarity, that Stx3 plays a role in the recruitment of cargo to exosomes, and that the Stx3-5R mutant acts as a dominant-negative inhibitor. Human cytomegalovirus (HCMV) acquires its membrane in an intracellular compartment and we show that Stx3-5R strongly reduces the number of excreted infectious viral particles. Altogether these results suggest that Stx3 functions in the transport of specific proteins to apical exosomes and that HCMV exploits this pathway for virion excretion. PMID- 28814502 TI - Selective regulation of clathrin-mediated epidermal growth factor receptor signaling and endocytosis by phospholipase C and calcium. AB - Clathrin-mediated endocytosis is a major regulator of cell-surface protein internalization. Clathrin and other proteins assemble into small invaginating structures at the plasma membrane termed clathrin-coated pits (CCPs) that mediate vesicle formation. In addition, epidermal growth factor receptor (EGFR) signaling is regulated by its accumulation within CCPs. Given the diversity of proteins regulated by clathrin-mediated endocytosis, how this process may distinctly regulate specific receptors is a key question. We examined the selective regulation of clathrin-dependent EGFR signaling and endocytosis. We find that perturbations of phospholipase Cgamma1 (PLCgamma1), Ca2+, or protein kinase C (PKC) impair clathrin-mediated endocytosis of EGFR, the formation of CCPs harboring EGFR, and EGFR signaling. Each of these manipulations was without effect on the clathrin-mediated endocytosis of transferrin receptor (TfR). EGFR and TfR were recruited to largely distinct clathrin structures. In addition to control of initiation and assembly of CCPs, EGF stimulation also elicited a Ca2+- and PKC-dependent reduction in synaptojanin1 recruitment to clathrin structures, indicating broad control of CCP assembly by Ca2+ signals. Hence EGFR elicits PLCgamma1-calcium signals to facilitate formation of a subset of CCPs, thus modulating its own signaling and endocytosis. This provides evidence for the versatility of CCPs to control diverse cellular processes. PMID- 28814503 TI - Transition of yeast Can1 transporter to the inward-facing state unveils an alpha arrestin target sequence promoting its ubiquitylation and endocytosis. AB - Substrate-transport-elicited endocytosis is a common control mechanism of membrane transporters avoiding excess uptake of external compounds, though poorly understood at the molecular level. In yeast, endocytosis of transporters is triggered by their ubiquitylation mediated by the Rsp5 ubiquitin-ligase, recruited by alpha-arrestin-family adaptors. We here report that transport elicited ubiquitylation of the arginine transporter Can1 is promoted by transition to an inward-facing state. This conformational change unveils a region of the N-terminal cytosolic tail targeted by the Art1 alpha-arrestin, which is activated via the TORC1 kinase complex upon arginine uptake. Can1 mutants altered in the arginine-binding site or a cytosolic tripeptide sequence permanently expose the alpha-arrestin-targeted region so that Art1 activation via TORC1 is sufficient to trigger their endocytosis. We also provide evidence that substrate transport elicited endocytosis of other amino acid permeases similarly involves unmasking of a cytosolic Art1-target region coupled to activation of Art1 via TORC1. Our results unravel a mechanism likely involved in regulation of many other transporters by their own substrates. They also support the emerging view that transporter ubiquitylation relies on combinatorial interaction rules such that alpha-arrestins, stimulated via signaling cascades or in their basal state, recognize transporter regions permanently facing the cytosol or unveiled during transport. PMID- 28814504 TI - Osm1 facilitates the transfer of electrons from Erv1 to fumarate in the redox regulated import pathway in the mitochondrial intermembrane space. AB - Prokaryotes have aerobic and anaerobic electron acceptors for oxidative folding of periplasmic proteins. The mitochondrial intermembrane space has an analogous pathway with the oxidoreductase Mia40 and sulfhydryl oxidase Erv1, termed the mitochondrial intermembrane space assembly (MIA) pathway. The aerobic electron acceptors include oxygen and cytochrome c, but an acceptor that can function under anaerobic conditions has not been identified. Here we show that the fumarate reductase Osm1, which facilitates electron transfer from fumarate to succinate, fills this gap as a new electron acceptor. In addition to microsomes, Osm1 localizes to the mitochondrial intermembrane space and assembles with Erv1 in a complex. In reconstitution studies with reduced Tim13, Mia40, and Erv1, the addition of Osm1 and fumarate completes the disulfide exchange pathway that results in Tim13 oxidation. From in vitro import assays, mitochondria lacking Osm1 display decreased import of MIA substrates, Cmc1 and Tim10. Comparative reconstitution assays support that the Osm1/fumarate couple accepts electrons with similar efficiency to cytochrome c and that the cell has strategies to coordinate expression of the terminal electron acceptors. Thus Osm1/fumarate is a new electron acceptor couple in the mitochondrial intermembrane space that seems to function in both aerobic and anaerobic conditions. PMID- 28814506 TI - Role of clathrin in dense core vesicle biogenesis. AB - The dense core vesicles (DCVs) of neuroendocrine cells are a rich source of bioactive molecules such as peptides, hormones, and neurotransmitters, but relatively little is known about how they are formed. Using fractionation profiling, a method that combines subcellular fractionation with mass spectrometry, we identified ~1200 proteins in PC12 cell vesicle-enriched fractions, with DCV-associated proteins showing distinct profiles from proteins associated with other types of vesicles. To investigate the role of clathrin in DCV biogenesis, we stably transduced PC12 cells with an inducible short hairpin RNA targeting clathrin heavy chain, resulting in ~85% protein loss. DCVs could still be observed in the cells by electron microscopy, but mature profiles were approximately fourfold less abundant than in mock-treated cells. By quantitative mass spectrometry, DCV-associated proteins were found to be reduced approximately twofold in clathrin-depleted cells as a whole and approximately fivefold in vesicle-enriched fractions. Our combined data sets enabled us to identify new candidate DCV components. Secretion assays revealed that clathrin depletion causes a near-complete block in secretagogue-induced exocytosis. Taken together, our data indicate that clathrin has a function in DCV biogenesis beyond its established role in removing unwanted proteins from the immature vesicle. PMID- 28814505 TI - The molecular architecture of the yeast spindle pole body core determined by Bayesian integrative modeling. AB - Microtubule-organizing centers (MTOCs) form, anchor, and stabilize the polarized network of microtubules in a cell. The central MTOC is the centrosome that duplicates during the cell cycle and assembles a bipolar spindle during mitosis to capture and segregate sister chromatids. Yet, despite their importance in cell biology, the physical structure of MTOCs is poorly understood. Here we determine the molecular architecture of the core of the yeast spindle pole body (SPB) by Bayesian integrative structure modeling based on in vivo fluorescence resonance energy transfer (FRET), small-angle x-ray scattering (SAXS), x-ray crystallography, electron microscopy, and two-hybrid analysis. The model is validated by several methods that include a genetic analysis of the conserved PACT domain that recruits Spc110, a protein related to pericentrin, to the SPB. The model suggests that calmodulin can act as a protein cross-linker and Spc29 is an extended, flexible protein. The model led to the identification of a single, essential heptad in the coiled-coil of Spc110 and a minimal PACT domain. It also led to a proposed pathway for the integration of Spc110 into the SPB. PMID- 28814507 TI - Systematic gene tagging using CRISPR/Cas9 in human stem cells to illuminate cell organization. AB - We present a CRISPR/Cas9 genome-editing strategy to systematically tag endogenous proteins with fluorescent tags in human induced pluripotent stem cells (hiPSC). To date, we have generated multiple hiPSC lines with monoallelic green fluorescent protein tags labeling 10 proteins representing major cellular structures. The tagged proteins include alpha tubulin, beta actin, desmoplakin, fibrillarin, nuclear lamin B1, nonmuscle myosin heavy chain IIB, paxillin, Sec61 beta, tight junction protein ZO1, and Tom20. Our genome-editing methodology using Cas9/crRNA ribonuclear protein and donor plasmid coelectroporation, followed by fluorescence-based enrichment of edited cells, typically resulted in <0.1-4% homology-directed repair (HDR). Twenty-five percent of clones generated from each edited population were precisely edited. Furthermore, 92% (36/39) of expanded clonal lines displayed robust morphology, genomic stability, expression and localization of the tagged protein to the appropriate subcellular structure, pluripotency-marker expression, and multilineage differentiation. It is our conclusion that, if cell lines are confirmed to harbor an appropriate gene edit, pluripotency, differentiation potential, and genomic stability are typically maintained during the clonal line-generation process. The data described here reveal general trends that emerged from this systematic gene-tagging approach. Final clonal lines corresponding to each of the 10 cellular structures are now available to the research community. PMID- 28814508 TI - Dynamic functional assembly of the Torsin AAA+ ATPase and its modulation by LAP1. AB - TorsinA is an essential AAA+ ATPase requiring LAP1 or LULL1 as cofactors. The dynamics of the Torsin/cofactor system remain poorly understood, with previous models invoking Torsin/cofactor assemblies with fixed stoichiometries. Here we demonstrate that TorsinA assembles into homotypic oligomers in the presence of ATP. Torsin variants mutated at the "back" interface disrupt homo-oligomerization but still show robust ATPase activity in the presence of its cofactors. These Torsin mutants are severely compromised in their ability to rescue nuclear envelope defects in Torsin-deficient cells, suggesting that TorsinA homo oligomers play a key role in vivo. Engagement of the oligomer by LAP1 triggers ATP hydrolysis and rapid complex disassembly. Thus the Torsin complex is a highly dynamic assembly whose oligomeric state is tightly controlled by distinctively localized cellular cofactors. Our discovery that LAP1 serves as a modulator of the oligomeric state of an AAA+ protein establishes a novel means of regulating this important class of oligomeric ATPases. PMID- 28814510 TI - A Heterologous Model of Thrombospondin Type 1 Domain-Containing 7A-Associated Membranous Nephropathy. AB - Thrombospondin type 1 domain-containing 7A (THSD7A) is a target for autoimmunity in patients with membranous nephropathy (MN). Circulating autoantibodies from patients with THSD7A-associated MN have been demonstrated to cause MN in mice. However, THSD7A-associated MN is a rare disease, preventing the use of patient antibodies for larger experimental procedures. Therefore, we generated antibodies against the human and mouse orthologs of THSD7A in rabbits by coimmunization with the respective cDNAs. Injection of these anti-THSD7A antibodies into mice induced a severe nephrotic syndrome with proteinuria, weight gain, and hyperlipidemia. Immunofluorescence analyses revealed granular antigen-antibody complexes in a subepithelial location along the glomerular filtration barrier 14 days after antibody injection, and immunohistochemistry for rabbit IgG and THSD7A as well as ultrastructural analyses showed the typical characteristics of human MN. Mice injected with purified IgG from rabbit serum that was taken before immunization failed to develop any of these changes. Notably, MN developed in the absence of detectable complement activation, and disease was strain dependent. In vitro, anti-THSD7A antibodies caused cytoskeletal rearrangement and activation of focal adhesion signaling. Knockdown of the THSD7A ortholog, thsd7aa, in zebrafish larvae resulted in altered podocyte differentiation and impaired glomerular filtration barrier function, with development of pericardial edema, suggesting an important role of THSD7A in glomerular filtration barrier integrity. In summary, our study introduces a heterologous mouse model that allows further investigation of the molecular events that underlie MN. PMID- 28814509 TI - Chemoproteomics Reveals Chemical Diversity and Dynamics of 4-Oxo-2-nonenal Modifications in Cells. AB - 4-Oxo-2-nonenal (ONE) derived from lipid peroxidation modifies nucleophiles and transduces redox signaling by its reactions with proteins. However, the molecular interactions between ONE and complex proteomes and their dynamics in situ remain largely unknown. Here we describe a quantitative chemoproteomic analysis of protein adduction by ONE in cells, in which the cellular target profile of ONE is mimicked by its alkynyl surrogate. The analyses reveal four types of ONE-derived modifications in cells, including ketoamide and Schiff-base adducts to lysine, Michael adducts to cysteine, and a novel pyrrole adduct to cysteine. ONE-derived adducts co-localize and exhibit crosstalk with many histone marks and redox sensitive sites. All four types of modifications derived from ONE can be reversed site-specifically in cells. Taken together, our study provides much-needed mechanistic insights into the cellular signaling and potential toxicities associated with this important lipid derived electrophile. PMID- 28814511 TI - Targeting Phospholipase D4 Attenuates Kidney Fibrosis. AB - Phospholipase D4 (PLD4), a single-pass transmembrane glycoprotein, is among the most highly upregulated genes in murine kidneys subjected to chronic progressive fibrosis, but the function of PLD4 in this process is unknown. Here, we found PLD4 to be overexpressed in the proximal and distal tubular epithelial cells of murine and human kidneys after fibrosis. Genetic silencing of PLD4, either globally or conditionally in proximal tubular epithelial cells, protected mice from the development of fibrosis. Mechanistically, global knockout of PLD4 modulated innate and adaptive immune responses and attenuated the upregulation of the TGF-beta signaling pathway and alpha1-antitrypsin protein (a serine protease inhibitor) expression and downregulation of neutrophil elastase (NE) expression induced by obstructive injury. In vitro, treatment with NE attenuated TGF-beta induced accumulation of fibrotic markers. Furthermore, therapeutic targeting of PLD4 using specific siRNA protected mice from folic acid-induced kidney fibrosis and inhibited the increase in TGF-beta signaling, decrease in NE expression, and upregulation of mitogen-activated protein kinase signaling. Immunoprecipitation/mass spectrometry and coimmunoprecipitation experiments confirmed that PLD4 binds three proteins that interact with neurotrophic receptor tyrosine kinase 1, a receptor also known as TrkA that upregulates mitogen activated protein kinase. PLD4 inhibition also prevented the folic acid-induced upregulation of this receptor in mouse kidneys. These results suggest inhibition of PLD4 as a novel therapeutic strategy to activate protease-mediated degradation of extracellular matrix and reverse fibrosis. PMID- 28814512 TI - Zoonotic Risk, Pathogenesis, and Transmission of Avian-Origin H3N2 Canine Influenza Virus. AB - Two subtypes of influenza A virus (IAV), avian-origin canine influenza virus (CIV) H3N2 (CIV-H3N2) and equine-origin CIV H3N8 (CIV-H3N8), are enzootic in the canine population. Dogs have been demonstrated to seroconvert in response to diverse IAVs, and naturally occurring reassortants of CIV-H3N2 and the 2009 H1N1 pandemic virus (pdmH1N1) have been isolated. We conducted a thorough phenotypic evaluation of CIV-H3N2 in order to assess its threat to human health. Using ferret-generated antiserum, we determined that CIV-H3N2 is antigenically distinct from contemporary human H3N2 IAVs, suggesting that there may be minimal herd immunity in humans. We assessed the public health risk of CIV-H3N2 * pandemic H1N1 (pdmH1N1) reassortants by characterizing their in vitro genetic compatibility and in vivo pathogenicity and transmissibility. Using a luciferase minigenome assay, we quantified the polymerase activity of all possible 16 ribonucleoprotein (RNP) complexes (PB2, PB1, PA, NP) between CIV-H3N2 and pdmH1N1, identifying some combinations that were more active than either parental virus complex. Using reverse genetics and fixing the CIV-H3N2 hemagglutinin (HA), we found that 51 of the 127 possible reassortant viruses were viable and able to be rescued. Nineteen of these reassortant viruses had high-growth phenotypes in vitro, and 13 of these replicated in mouse lungs. A single reassortant with the NP and HA gene segments from CIV-H3N2 was selected for characterization in ferrets. The reassortant was efficiently transmitted by contact but not by the airborne route and was pathogenic in ferrets. Our results suggest that CIV-H3N2 reassortants may pose a moderate risk to public health and that the canine host should be monitored for emerging IAVs.IMPORTANCE IAV pandemics are caused by the introduction of novel viruses that are capable of efficient and sustained transmission into a human population with limited herd immunity. Dogs are a a potential mixing vessel for avian and mammalian IAVs and represent a human health concern due to their susceptibility to infection, large global population, and close physical contact with humans. Our results suggest that humans are likely to have limited preexisting immunity to CIV-H3N2 and that CIV-H3N2 * pdmH1N1 reassortants have moderate genetic compatibility and are transmissible by direct contact in ferrets. Our study contributes to the increasing evidence that surveillance of the canine population for IAVs is an important component of pandemic preparedness. PMID- 28814513 TI - Escape of tick-borne flavivirus from 2' -C-methylated nucleoside antivirals is mediated by a single conservative mutation in NS5 that has a dramatic effect on viral fitness. AB - Tick-borne encephalitis virus (TBEV) causes a severe and potentially fatal neuroinfection in humans. Despite its high medical relevance, no specific antiviral therapy is currently available. Here we demonstrate that treatment with a nucleoside analog, 7-deaza-2' -C-methyladenosine (7-deaza-2' -CMA), substantially improved disease outcome, increased survival, and reduced signs of neuroinfection and viral titers in the brains of mice infected with a lethal dose of TBEV. To investigate the mechanism of action of 7-deaza-2' -CMA, two drug resistant TBEV clones were generated and characterized. The two clones shared a signature amino acid substitution, S603T, in the viral NS5 RNA-dependent RNA polymerase (RdRp) domain. This mutation conferred resistance to various 2' -C methylated nucleoside derivatives, but no cross-resistance was seen to other nucleoside analogs, such as 4' -C-azidocytidine and 2' -deoxy-2' -beta-hydroxy-4' -azidocytidine (RO-9187). All-atom molecular dynamics simulations revealed that the S603T RdRp mutant repels a water molecule that coordinates the position of a metal ion cofactor as 2' -C-methylated nucleoside analogs approach the active site. To investigate its phenotype, the S603T mutation was introduced into a recombinant TBEV (Oshima-IC) generated from an infectious cDNA clone and into a TBEV replicon that expresses a reporter luciferase gene (Oshima-REP-luc2A). The mutants were replication-impaired, showing reduced growth and small plaque size in mammalian cell culture and reduced levels of neuroinvasiveness and neurovirulence in rodent models. These results indicate that TBEV resistance to 2' -C-methylated nucleoside inhibitors is conferred by a single conservative mutation that causes a subtle atomic effect within the active site of viral NS5 RdRp and is associated with strong attenuation of the virus.Importance This study found that the nucleoside analog 7-deaza-2' -C-methyladenosine (7-deaza-2' -CMA) has high antiviral activity against tick-borne encephalitis virus (TBEV), a pathogen that causes severe human neuroinfections in large areas of Europe and Asia and for which there is currently no specific therapy. Treating mice infected with a lethal dose of TBEV with 7-deaza-2' -CMA resulted in significantly higher survival rates, reduced the severity of neurological signs of the disease. Thus, this compound shows promise for further development as an anti-TBEV drug. It is important to generate drug-resistant mutants to understand how the drug works and to develop guidelines for patient treatment. We generated TBEV mutants that were resistant not only to 7-deaza-2' -CMA but also to a broad range of other 2' -C methylated antiviral medications. Our findings suggest that combination therapy could be used to improve treatment and reduce the emergence of drug-resistant viruses during nucleoside analog therapy for TBEV infection. PMID- 28814516 TI - Baculovirus Molecular Evolution via Gene Turnover and Recurrent Positive Selection of Key Genes. AB - Hosts and viruses are locked in an evolutionary arms race. Hosts are constantly evolving to suppress virulence and replication, while viruses, which are reliant on host machinery for survival and reproduction, develop counterstrategies to escape this immune defense. Viruses must also adapt to novel conditions while establishing themselves in a host species. Both processes provide strong selection for viral adaptation. Understanding adaptive evolution in insect viruses can help us to better understand adaptive evolution in general and is important due to the use of these viruses as biocontrol agents and for protecting ecologically or economically important species from outbreaks. Here we examine the molecular evolution of baculoviruses and nudiviruses, a group of insect infecting viruses with key roles in biocontrol. We looked for signatures of selection between genomes of baculoviruses infecting a range of species and within a population of baculoviruses. Both analyses found only a few strong signatures of positive selection, primarily in replication- and transcription associated genes and several structural protein genes. In both analyses, we detected a conserved complex of genes, including the helicase gene, showing consistently high levels of adaptive evolution, suggesting that they may be key in antagonistic coevolution to escape host suppression. These genes are integral to the baculovirus life cycle and may be good focal genes for developing baculoviruses as effective biocontrol agents or for targeting baculoviruses infecting ecologically relevant species. Recombination and complex genomes make evolution in these double-stranded DNA viruses more efficient than that in smaller RNA viruses with error-prone replication, as seen via signatures of selection in specific genes within a population of baculoviruses.IMPORTANCE Most viral evolutionary studies focus on RNA viruses. While these viruses cause many human and animal diseases, such studies leave us with a lesser understanding of how DNA viruses adapt to hosts and how the host responds to these pathogens. In this paper, we focus on the evolution of baculoviruses, a group of insect infecting DNA viruses, many of which have been used in biocontrol. We find that most of the genome is under purifying selection, with only a few key genes evolving adaptively. Our results provide a glimpse into how DNA viruses differ from RNA viruses in their evolutionary dynamics and identify genes that are key to DNA virus adaptation, improving our understanding of how this group of pathogens evolves. PMID- 28814515 TI - [18F]-Fluorodeoxyglucose Uptake in Lymphoid Tissue Serves as a Predictor of Disease Outcome in the Nonhuman Primate Model of Monkeypox Virus Infection. AB - Real-time bioimaging of infectious disease processes may aid countermeasure development and lead to an improved understanding of pathogenesis. However, few studies have identified biomarkers for monitoring infections using in vivo imaging. Previously, we demonstrated that positron emission tomography/computed tomography (PET/CT) imaging with [18F]-fluorodeoxyglucose (FDG) can monitor monkeypox disease progression in vivo in nonhuman primates (NHPs). In this study, we investigated [18F]-FDG-PET/CT imaging of immune processes in lymphoid tissues to identify patterns of inflammation in the monkepox NHP model and to determine the value of [18F]-FDG-PET/CT as a biomarker for disease and treatment outcomes. Quantitative analysis of [18F]-FDG-PET/CT images revealed differences between moribund and surviving animals at two sites vital to the immune response to viral infections, bone marrow and lymph nodes (LNs). Moribund NHPs demonstrated increased [18F]-FDG uptake in bone marrow 4 days postinfection compared to surviving NHPs. In surviving, treated NHPs, increase in LN volume correlated with [18F]-FDG uptake and peaked 10 days postinfection, while minimal lymphadenopathy and higher glycolytic activity were observed in moribund NHPs early in infection. Imaging data were supported by standard virology, pathology, and immunology findings. Even with the limited number of subjects, imaging was able to differentiate the difference between disease outcomes, warranting additional studies to demonstrate whether [18F]-FDG-PET/CT can identify other, subtler effects. Visualizing altered metabolic activity at sites involved in the immune response by [18F]-FDG-PET/CT imaging is a powerful tool for identifying key disease-specific time points and locations that are most relevant for pathogenesis and treatment.IMPORTANCE Positron emission tomography and computed tomography (PET/CT) imaging is a universal tool in oncology and neuroscience. The application of this technology to infectious diseases is far less developed. We used PET/CT imaging with [18F]-labeled fluorodeoxyglucose ([18F]-FDG) in monkeys after monkeypox virus exposure to monitor the immune response in lymphoid tissues. In lymph nodes of surviving monkeys, changes in [18F]-FDG uptake positively correlated with enlargement of the lymph nodes and peaked on day 10 postinfection. In contrast, the bone marrow and lymph nodes of nonsurvivors showed increased [18F]-FDG uptake by day 4 postinfection with minimal lymph node enlargement, indicating that elevated cell metabolic activity early after infection is predictive of disease outcome. [18F]-FDG-PET/CT imaging can provide real-time snapshots of metabolic activity changes in response to viral infections and identify key time points and locations most relevant for monitoring the development of pathogenesis and for potential treatment to be effective. PMID- 28814514 TI - BA71DeltaCD2: a New Recombinant Live Attenuated African Swine Fever Virus with Cross-Protective Capabilities. AB - African swine fever is a highly contagious viral disease of mandatory declaration to the World Organization for Animal Health (OIE). The lack of available vaccines makes its control difficult; thus, African swine fever virus (ASFV) represents a major threat to the swine industry. Inactivated vaccines do not confer solid protection against ASFV. Conversely, live attenuated viruses (LAV), either naturally isolated or obtained by genetic manipulation, have demonstrated reliable protection against homologous ASFV strains, although little or no protection has been demonstrated against heterologous viruses. Safety concerns are a major issue for the use of ASFV attenuated vaccine candidates and have hampered their implementation in the field so far. While trying to develop safer and efficient ASFV vaccines, we found that the deletion of the viral CD2v (EP402R) gene highly attenuated the virulent BA71 strain in vivo Inoculation of pigs with the deletion mutant virus BA71DeltaCD2 conferred protection not only against lethal challenge with the parental BA71 but also against the heterologous E75 (both genotype I strains). The protection induced was dose dependent, and the cross-protection observed in vivo correlated with the ability of BA71DeltaCD2 to induce specific CD8+ T cells capable of recognizing both BA71 and E75 viruses in vitro Interestingly, 100% of the pigs immunized with BA71DeltaCD2 also survived lethal challenge with Georgia 2007/1, the genotype II strain of ASFV currently circulating in continental Europe. These results open new avenues to design ASFV cross-protective vaccines, essential to fight ASFV in areas where the virus is endemic and where multiple viruses are circulating.IMPORTANCE African swine fever virus (ASFV) remains enzootic in most countries of Sub-Saharan Africa, today representing a major threat for the development of their swine industry. The uncontrolled presence of ASFV has favored its periodic exportation to other countries, the last event being in Georgia in 2007. Since then, ASFV has spread toward neighboring countries, reaching the European Union's east border in 2014. The lack of available vaccines against ASFV makes its control difficult; so far, only live attenuated viruses have demonstrated solid protection against homologous experimental challenges, but they have failed at inducing solid cross protective immunity against heterologous viruses. Here we describe a new LAV candidate with unique cross-protective abilities: BA71DeltaCD2. Inoculation of BA71DeltaCD2 protected pigs not only against experimental challenge with BA71, the virulent parental strain, but also against heterologous viruses, including Georgia 2007/1, the genotype II strain of ASFV currently circulating in Eastern Europe. PMID- 28814517 TI - Zinc Salts Block Hepatitis E Virus Replication by Inhibiting the Activity of Viral RNA-Dependent RNA Polymerase. AB - Hepatitis E virus (HEV) causes an acute, self-limiting hepatitis in healthy individuals and leads to chronic disease in immunocompromised individuals. HEV infection in pregnant women results in a more severe outcome, with the mortality rate going up to 30%. Though the virus usually causes sporadic infection, epidemics have been reported in developing and resource-starved countries. No specific antiviral exists against HEV. A combination of interferon and ribavirin therapy has been used to control the disease with some success. Zinc is an essential micronutrient that plays crucial roles in multiple cellular processes. Zinc salts are known to be effective in reducing infections caused by few viruses. Here, we investigated the effect of zinc salts on HEV replication. In a human hepatoma cell (Huh7) culture model, zinc salts inhibited the replication of genotype 1 (g-1) and g-3 HEV replicons and g-1 HEV infectious genomic RNA in a dose-dependent manner. Analysis of a replication-defective mutant of g-1 HEV genomic RNA under similar conditions ruled out the possibility of zinc salts acting on replication-independent processes. An ORF4-Huh7 cell line-based infection model of g-1 HEV further confirmed the above observations. Zinc salts did not show any effect on the entry of g-1 HEV into the host cell. Furthermore, our data reveal that zinc salts directly inhibit the activity of viral RNA dependent RNA polymerase (RdRp), leading to inhibition of viral replication. Taken together, these studies unravel the ability of zinc salts in inhibiting HEV replication, suggesting their possible therapeutic value in controlling HEV infection.IMPORTANCE Hepatitis E virus (HEV) is a public health concern in resource-starved countries due to frequent outbreaks. It is also emerging as a health concern in developed countries owing to its ability to cause acute and chronic infection in organ transplant and immunocompromised individuals. Although antivirals such as ribavirin have been used to treat HEV cases, there are known side effects and limitations of such therapy. Our discovery of the ability of zinc salts to block HEV replication by virtue of their ability to inhibit the activity of viral RdRp is important because these findings pave the way to test the efficacy of zinc supplementation therapy in HEV-infected patients. Since zinc supplementation therapy is known to be safe in healthy individuals and since high dose zinc is used in the treatment of Wilson's disease, it may be possible to control HEV-associated health problems following a similar treatment regimen. PMID- 28814518 TI - A Single-Amino-Acid Substitution at Position 225 in Hemagglutinin Alters the Transmissibility of Eurasian Avian-Like H1N1 Swine Influenza Virus in Guinea Pigs. AB - Efficient transmission from human to human is the prerequisite for an influenza virus to cause a pandemic; however, the molecular determinants of influenza virus transmission are still largely unknown. In this study, we explored the molecular basis for transmission of Eurasian avian-like H1N1 (EAH1N1) swine influenza viruses by comparing two viruses that are genetically similar but differ in their transmissibility in guinea pigs: the A/swine/Guangxi/18/2011 virus (GX/18) is highly transmissible by respiratory droplet in guinea pigs, whereas the A/swine/Heilongjiang/27/2012 virus (HLJ/27) does not transmit in this animal model. We used reverse genetics to generate a series of reassortants and mutants in the GX/18 background and tested their transmissibility in guinea pigs. We found that a single-amino-acid substitution of glycine (G) for glutamic acid (E) at position 225 (E225G) in the HA1 protein completely abolished the respiratory droplet transmission of GX/18, whereas the substitution of E for G at the same position (G225E) in HA1 enabled HLJ/27 to transmit in guinea pigs. We investigated the underlying mechanism and found that viruses bearing 225E in HA1 replicated more rapidly than viruses bearing 225G due to differences in assembly and budding efficiencies. Our study indicates that the amino acid 225E in HA1 plays a key role in EAH1N1 swine influenza virus transmission and provides important information for evaluating the pandemic potential of field influenza virus strains.IMPORTANCE Efficient transmission among humans is a prerequisite for a novel influenza virus to cause a human pandemic. Transmissibility of influenza viruses is a polygenic trait, and understanding the genetic determinants for transmissibility will provide useful insights for evaluating the pandemic potential of influenza viruses in the field. Several amino acids in the hemagglutinin (HA) protein of influenza viruses have been shown to be important for transmissibility, usually by increasing virus affinity for human-type receptors. In this study, we explored the genetic basis of the transmissibility difference between two Eurasian avian-like H1N1 (EAH1N1) swine influenza viruses in guinea pigs and found that the amino acid glutamic acid at position 225 in the HA1 protein plays a critical role in the transmission of EAH1N1 virus by increasing the efficiency of viral assembly and budding. PMID- 28814520 TI - Contributions of individual domains to function of the HIV-1 Rev response element. AB - The HIV-1 Rev response element (RRE) is a 351-base element in unspliced and partially spliced viral RNA; binding of the RRE by the viral Rev protein induces nuclear export of RRE-containing RNAs, as required for virus replication. It contains one long, imperfect double helix (domain I), one branched domain (domain II) containing a high-affinity Rev-binding site, and two or three additional domains. We previously reported that the RRE assumes an "A" shape in solution and suggested that the location of the Rev binding sites in domains I and II, opposite each other on the two legs of the A, is optimal for Rev binding and explains Rev's specificity for RRE-containing RNAs. Using SAXS and a quantitative functional assay, we have now analyzed a panel of RRE mutants. All the results support the essential role of the A shape for RRE function. Moreover, they suggest that the distal portion of domain I and the three crowning domains all contribute to the maintenance of the A shape. Domains I and II are necessary and sufficient for substantial RRE function, provided they are joined by a flexible linker that allows the two domains to face each other.IMPORTANCE Retroviral replication requires that some of the viral RNAs transcribed in the cell nucleus be exported to the cytoplasm without being spliced. To achieve this, HIV-1 encodes a protein, Rev, which binds to a complex, highly structured element within viral RNA, the Rev Response Element (RRE), and escorts RRE-containing RNAs from the nucleus. We previously reported that the RRE is "A"-shaped and suggested that this architecture, with the 2 legs opposite one another, can explain the specificity of Rev for the RRE. We have analyzed the functional contributions of individual RRE domains, and now report that several domains contribute, with some redundancy, to maintenance of the overall RRE shape. The data strongly support the hypothesis that the opposed placement of the 2 legs is essential for RRE function. PMID- 28814519 TI - Extracellular Matrix Proteins Mediate HIV-1 gp120 Interactions with alpha4beta7. AB - Gut-homing alpha4beta7high CD4+ T lymphocytes have been shown to be preferentially targeted by human immunodeficiency virus type 1 (HIV-1) and are implicated in HIV-1 pathogenesis. Previous studies demonstrated that HIV-1 envelope protein gp120 binds and signals through alpha4beta7 and that this likely contributes to the infection of alpha4beta7high T cells and promotes cell-to-cell virus transmission. Structures within the second variable loop (V2) of gp120, including the tripeptide motif LDV/I, are thought to mediate gp120-alpha4beta7 binding. However, lack of alpha4beta7 binding has been reported in gp120 proteins containing LDV/I, and the precise determinants of gp120-alpha4beta7 binding are not fully defined. In this work, we report the novel finding that fibronectins mediate indirect gp120-alpha4beta7 interactions. We show that Chinese hamster ovary (CHO) cells used to express recombinant gp120 produced fibronectins and other extracellular matrix proteins that copurified with gp120. CHO cell fibronectins were able to mediate the binding of a diverse panel of gp120 proteins to alpha4beta7 in an in vitro cell binding assay. The V2 loop was not required for fibronectin-mediated binding of gp120 to alpha4beta7, nor did V2 specific antibodies block this interaction. Removal of fibronectin through anion exchange chromatography abrogated V2-independent gp120-alpha4beta7 binding. Additionally, we showed a recombinant human fibronectin fragment mediated gp120 alpha4beta7 interactions similarly to CHO cell fibronectin. These findings provide an explanation for the apparently contradictory observations regarding the gp120-alpha4beta7 interaction and offer new insights into the potential role of fibronectin and other extracellular matrix proteins in HIV-1 biology.IMPORTANCE Immune tissues within the gut are severely damaged by HIV-1, and this plays an important role in the development of AIDS. Integrin alpha4beta7 plays a major role in the trafficking of lymphocytes, including CD4+ T cells, into gut lymphoid tissues. Previous reports indicate that some HIV-1 gp120 envelope proteins bind to and signal through alpha4beta7, which may help explain the preferential infection of gut CD4+ T cells. In this study, we demonstrate that extracellular matrix proteins can mediate interactions between gp120 and alpha4beta7 This suggests that the extracellular matrix may be an important mediator of HIV-1 interaction with alpha4beta7-expressing cells. These findings provide new insight into the nature of HIV-1-alpha4beta7 interactions and how these interactions may represent targets for therapeutic intervention. PMID- 28814521 TI - HIV Fusion in Dendritic Cells Occurs Mainly at the Surface and Is Limited by Low CD4 Levels. AB - HIV-1 poorly infects monocyte-derived dendritic cells (MDDCs). This is in large part due to SAMHD1, which restricts viral reverse transcription. Pseudotyping HIV 1 with vesicular stomatitis virus G protein (VSV-G) strongly enhances infection, suggesting that earlier steps of viral replication, including fusion, are also inefficient in MDDCs. The site of HIV-1 fusion remains controversial and may depend on the cell type, with reports indicating that it occurs at the plasma membrane or, conversely, in an endocytic compartment. Here, we examined the pathways of HIV-1 entry in MDDCs. Using a combination of temperature shift and fusion inhibitors, we show that HIV-1 fusion mainly occurs at the cell surface. We then asked whether surface levels or intracellular localization of CD4 modulates HIV-1 entry. Increasing CD4 levels strongly enhanced fusion and infection with various HIV-1 isolates, including reference and transmitted/founder strains, but not with BaL, which uses low CD4 levels for entry. Overexpressing coreceptors did not facilitate viral infection. To further study the localization of fusion events, we generated CD4 mutants carrying heterologous cytoplasmic tails (LAMP1 or Toll-like receptor 7 [TLR7]) to redirect the molecule to intracellular compartments. The intracellular CD4 mutants did not facilitate HIV-1 fusion and replication in MDDCs. Fusion of an HIV-2 isolate with MDDCs was also enhanced by increasing surface CD4 levels. Our results demonstrate that MDDCs are inefficiently infected by various HIV-1 and HIV-2 strains, in part because of low CD4 levels. In these cells, viral fusion occurs mainly at the surface, and probably not after internalization.IMPORTANCE Dendritic cells (DCs) are professional antigen-presenting cells inducing innate and adaptive immune responses. DCs express the HIV receptor CD4 and are potential target cells for HIV. There is debate about the sensitivity of DCs to productive HIV-1 and HIV-2 infection. The fusion step of the viral replication cycle is inefficient in DCs, and the underlying mechanisms are poorly characterized. We show that increasing the levels of CD4 at the plasma membrane allows more HIV fusion and productive infection in DCs. We further demonstrate that HIV fusion occurs mainly at the cell surface and not in an intracellular compartment. Our results help us understand why DCs are poorly sensitive to HIV infection. PMID- 28814523 TI - Screening of FDA-Approved Drugs for Inhibitors of Japanese Encephalitis Virus Infection. AB - Japanese encephalitis virus (JEV), an arthropod-borne flavivirus, is a major cause of acute viral encephalitis in humans. No approved drug is available for the specific treatment of JEV infections, and the available vaccines are not effective against all clinical JEV isolates. In the study described here, a high throughput screening of an FDA-approved drug library for inhibitors of JEV was performed. Five hit drugs that inhibited JEV infection with a selective index of >10 were identified. The antiviral activities of these five hit drugs against other flavivirus, including Zika virus, were also validated. As three of the five hit drugs were calcium inhibitors, additional types of calcium inhibitors that confirmed that calcium is essential for JEV infection, most likely during viral replication, were utilized. Adaptive mutant analysis uncovered that replacement of Q130, located in transmembrane domain 3 of the nonstructural NS4B protein, which is relatively conserved in flaviviruses, with R or K conferred JEV resistance to manidipine, a voltage-gated Ca2+ channel (VGCC) inhibitor, without an apparent loss of the viral growth profile. Furthermore, manidipine was indicated to protect mice against JEV-induced lethality by decreasing the viral load in the brain, while it abrogated the histopathological changes associated with JEV infection. This study provides five antiflavivirus candidates and identifies cytoplasmic calcium to be a novel antiviral target for the treatment of JEV infection. The findings reported here provide therapeutic possibilities for combating infections caused by flaviviruses.IMPORTANCE No approved therapy for the treatment of Japanese encephalitis virus infection is currently available. Repurposing of approved drugs would accelerate the development of a therapeutic stratagem. In this study, we screened a library of FDA-approved drugs and identified five hit drugs, especially calcium inhibitors, exerting antiflavivirus activity that blocked viral replication. The in vivo efficacy and toxicity of manidipine were investigated with a mouse model of JEV infection, and the viral target was identified by generating an adaptive mutant. PMID- 28814522 TI - Characterization of cis-Acting RNA Elements of Zika Virus by Using a Self Splicing Ribozyme-Dependent Infectious Clone. AB - Zika virus (ZIKV) has caused significant outbreaks and epidemics in the Americas recently, raising global concern due to its ability to cause microcephaly and other neurological complications. A stable and efficient infectious clone of ZIKV is urgently needed. However, the instability and toxicity of flavivirus cDNA clones in Escherichia coli hosts has hindered the development of ZIKV infectious clones. Here, using a novel self-splicing ribozyme-based strategy, we generated a stable infectious cDNA clone of a contemporary ZIKV strain imported from Venezuela to China in 2016. The constructed clone contained a modified version of the group II self-splicing intron P.li.LSUI2 near the junction between the E and NS1 genes, which were removed from the RNA transcripts by an easy-to-establish in vitro splicing reaction. Transfection of the spliced RNAs into BHK-21 cells led to the production of infectious progeny virus that resembled the parental virus. Finally, potential cis-acting RNA elements in ZIKV genomic RNA were identified based on this novel reverse genetics system, and the critical role of 5'-SLA promoter and 5'-3' cyclization sequences were characterized by a combination of different assays. Our results provide another stable and reliable reverse genetics system for ZIKV that will help study ZIKV infection and pathogenesis, and the novel self-splicing intron-based strategy could be further expanded for the construction of infectious clones from other emerging and reemerging flaviviruses.IMPORTANCE The ongoing Zika virus (ZIKV) outbreaks have drawn global concern due to the unexpected causal link to fetus microcephaly and other severe neurological complications. The infectious cDNA clones of ZIKV are critical for the research community to study the virus, understand the disease, and inform vaccine design and antiviral screening. A panel of existing technologies have been utilized to develop ZIKV infectious clones. Here, we successfully generated a stable infectious clone of a 2016 ZIKV strain using a novel self-splicing ribozyme-based technology that abolished the potential toxicity of ZIKV cDNA clones to the E. coli host. Moreover, two crucial cis-acting replication elements (5'-SLA and 5'-CS) of ZIKV were first identified using this novel reverse genetics system. This novel self-splicing ribozyme-based reverse genetics platform will be widely utilized in future ZIKV studies and provide insight for the development of infectious clones of other emerging viruses. PMID- 28814524 TI - Mutation of the Putative Immunosuppressive Domain of the Retroviral Envelope Glycoprotein Compromises Infectivity. AB - The envelope glycoprotein of diverse endogenous and exogenous retroviruses is considered inherently immunosuppressive. Extensive work mapped the immunosuppressive activity to a highly conserved domain, termed the immunosuppressive domain (ISD), in the transmembrane (TM) subunit of the envelope glycoprotein and identified two naturally polymorphic key residues that afford immunosuppressive activity to distinct envelope glycoproteins. Concurrent mutation of these two key residues (E14R and A20F) in the envelope glycoprotein of the Friend murine leukemia virus (F-MLV) ISD has been reported to abolish its immunosuppressive activity, without affecting its fusogenicity, and to weaken the ability of the virus to replicate specifically in immunocompetent hosts. Here, we show that mutation of these key residues did, in fact, result in a substantial loss of F-MLV infectivity, independently of host immunity, challenging whether associations exist between the two. Notably, a loss of infectivity incurred by the F-MLV mutant with the E14R and A20F double ISD mutation was conditional on expression of the ecotropic envelope receptor murine cationic amino acid transporter-1 (mCAT1) in the virus-producing cell. Indeed, the F-MLV mutant retained infectivity when it was produced by human cells, which naturally lack mCAT1 expression, but not by murine cells. Furthermore, mCAT1 overexpression in human cells impaired the infectivity of both the F-MLV double mutant and the wild type F-MLV strain, suggesting a finely tuned relationship between the levels of mCAT1 in the producer cell and the infectivity of the virions produced. An adverse effect on this relationship, rather than disruption of the putative ISD, is therefore more likely to explain the loss of F-MLV infectivity incurred by mutations in key ISD residues E14 and A20.IMPORTANCE Retroviruses can interact with their hosts in ways that, although not entirely understood, can greatly influence their pathogenic potential. One such example is a putative immunosuppressive activity, which has been mapped to a conserved domain of the retroviral envelope glycoprotein of several exogenous as well as endogenous retroviruses. In this study, mutations naturally found in some envelope glycoproteins lacking immunosuppressive activity were shown to affect retrovirus infectivity only if the host cell that produced the retrovirus also expressed the cellular entry receptor. These findings shed light on a novel role for this conserved domain in providing the necessary stability to the envelope glycoprotein in order to withstand the interaction with the cellular receptor during virus formation. This function of the domain is critical for further elucidation of the mechanism of immunosuppression mediated by the retroviral envelope glycoprotein. PMID- 28814525 TI - Structure-Guided Functional Annotation of the Influenza A Virus NS1 Protein Reveals Dynamic Evolution of the p85beta-Binding Site during Circulation in Humans. AB - Rational characterization of virulence and host-adaptive markers in the multifunctional influenza A virus NS1 protein is hindered by a lack of comprehensive knowledge about NS1-host protein protein interfaces. Here, we surveyed the impact of amino acid variation in NS1 at its structurally defined binding site for host p85beta, a regulator of phosphoinositide 3-kinase (PI3K) signaling. Structure-guided alanine scanning of all viral residues at this interface defined 10 positions contributing to the interaction, with residues 89, 95, 98, 133, 145, and 162 being the most important. A bioinformatic study of >24,000 publicly available NS1 sequences derived from viruses infecting different hosts highlighted several prevalent amino acid variants at the p85beta interface that either enhanced (I95) or weakened (N135, T145, L161, Y161, S164) p85beta binding. Interestingly, analysis of viruses circulating in humans since the 1918 pandemic revealed the temporal acquisition of functionally relevant variants at this interface. I95 (which enhanced p85beta binding) quickly became prevalent in the 1940s and experimentally conferred a fitness advantage to a recombinant 1930s based H1N1 virus in human lung epithelial cells. Surprisingly, H1N1 and H3N2 viruses recently acquired T145 or N135, respectively, which diminished p85beta binding but apparently not the overall fitness in the human population. Evolutionary analyses revealed covariation of the NS1-p85beta binding phenotype in humans with functional changes at multiple residues in other viral proteins, suggesting an unexplored compensatory or synergistic interplay between phenotypes in vivo Overall, our data provide a resource to understand the consequences of the NS1-p85beta binding spectrum of different influenza viruses and highlight the dynamic evolution of this property in viruses circulating in humans.IMPORTANCE In humans, influenza A viruses are responsible for causing seasonal epidemics and occasional pandemics. These viruses also circulate and evolve in other animal species, creating a reservoir from which novel viruses with distinct properties can emerge. The viral nonstructural protein NS1 is an important host range determinant and virulence factor that exhibits strain-specific interactions with several host factors, although few have been characterized extensively. In the study described here, we comprehensively surveyed the impact of natural and unnatural NS1 variations on the binding of NS1 to host p85beta, a subunit of phosphoinositide 3-kinase that regulates intracellular metabolism and contributes to virus replication and virulence. We define the p85beta-binding site on NS1 and provide a predictive resource to assess this ability of NS1 in viruses from different hosts. Strikingly, we uncover a spectrum of p85beta binding by different NS1 proteins and reveal that viruses evolving in humans have undergone dynamic changes in this NS1 function over the last century. PMID- 28814526 TI - HIV-1 Exploits a Dynamic Multi-aminoacyl-tRNA Synthetase Complex To Enhance Viral Replication. AB - A hallmark of retroviruses such as human immunodeficiency virus type 1 (HIV-1) is reverse transcription of genomic RNA to DNA, a process that is primed by cellular tRNAs. HIV-1 recruits human tRNALys3 to serve as the reverse transcription primer via an interaction between lysyl-tRNA synthetase (LysRS) and the HIV-1 Gag polyprotein. LysRS is normally sequestered in a multi-aminoacyl-tRNA synthetase complex (MSC). Previous studies demonstrated that components of the MSC can be mobilized in response to certain cellular stimuli, but how LysRS is redirected from the MSC to viral particles for packaging is unknown. Here, we show that upon HIV-1 infection, a free pool of non-MSC-associated LysRS is observed and partially relocalized to the nucleus. Heat inactivation of HIV-1 blocks nuclear localization of LysRS, but treatment with a reverse transcriptase inhibitor does not, suggesting that the trigger for relocalization occurs prior to reverse transcription. A reduction in HIV-1 infection is observed upon treatment with an inhibitor to mitogen-activated protein kinase that prevents phosphorylation of LysRS on Ser207, release of LysRS from the MSC, and nuclear localization. A phosphomimetic mutant of LysRS (S207D) that lacked the capability to aminoacylate tRNALys3 localized to the nucleus, rescued HIV-1 infectivity, and was packaged into virions. In contrast, a phosphoablative mutant (S207A) remained cytosolic and maintained full aminoacylation activity but failed to rescue infectivity and was not packaged. These findings suggest that HIV-1 takes advantage of the dynamic nature of the MSC to redirect and coopt cellular translation factors to enhance viral replication.IMPORTANCE Human tRNALys3, the primer for reverse transcription, and LysRS are essential host factors packaged into HIV-1 virions. Previous studies found that tRNALys3 packaging depends on interactions between LysRS and HIV-1 Gag; however, many details regarding the mechanism of tRNALys3 and LysRS packaging remain unknown. LysRS is normally sequestered in a high molecular-weight multi-aminoacyl-tRNA synthetase complex (MSC), restricting the pool of free LysRS-tRNALys Mounting evidence suggests that LysRS is released under a variety of stimuli to perform alternative functions within the cell. Here, we show that HIV-1 infection results in a free pool of LysRS that is relocalized to the nucleus of target cells. Blocking this pathway in HIV-1 producing cells resulted in less infectious progeny virions. Understanding the mechanism by which LysRS is recruited into the viral assembly pathway can be exploited for the development of specific and effective therapeutics targeting this nontranslational function. PMID- 28814528 TI - Physician training protocol within the WEB Intrasaccular Therapy (WEB-IT) study. AB - INTRODUCTION: The WEB Intra-saccular Therapy (WEB-IT) trial is an investigational device exemption study to demonstrate the safety and effectiveness of the WEB device for the treatment of wide-neck bifurcation aneurysms. The neurovascular replicator (Vascular Simulations, Stony Brook, New York, USA) creates a physical environment that replicates patient-specific neurovascular anatomy and hemodynamic physiology, and allows devices to be implanted under fluoroscopic guidance. OBJECTIVE: To report the results of a unique neurovascular replicator based training program, which was incorporated into the WEB-IT study to optimize technical performance and patient safety. METHODS: US investigators participated in a new training program that incorporated full surgical rehearsals on a neurovascular replicator. No roll-in cases were permitted within the trial. Custom replicas of patient-specific neurovascular anatomy were created for the initial cases treated at each center, as well as for cases expected to be challenging. On-site surgical rehearsals were performed before these procedures. RESULTS: A total of 48 participating investigators at 25 US centers trained using the replicator. Sessions included centralized introductory training, on-site training, and patient-specific full surgical rehearsal. Fluoroscopy and procedure times in the WEB-IT study were not significantly different from those seen in two European trials where participating physicians had significant WEB procedure experience before study initiation. CONCLUSIONS: A new program of neurovascular replicator-based physician training was employed within the WEB-IT study. This represents a new methodology for education and training that may be an effective means to optimize technical success and patient safety during the introduction of a new technology. PMID- 28814529 TI - Selective HIF-1 Regulation under Nonhypoxic Conditions by the p42/p44 MAP Kinase Inhibitor PD184161. AB - Hypoxia-inducible factor-1 (HIF-1) is a key gene regulator for cellular adaptation to low oxygen. In addition to hypoxia, several nonhypoxic stimuli, including hormones and growth factors, are essential for cell-specific HIF-1 regulation. Our studies have highlighted angiotensin II (AngII), a vasoactive hormone, as a potent HIF-1 activator in vascular smooth muscle cells (VSMC). AngII increases HIF-1 transcriptional activity by modulating specific signaling pathways. In VSMC, p42/p44 mitogen-activated protein kinase (MAPK) pathway activation is essential for HIF-1-mediated transcription during AngII treatment. The present study shows that PD184161, a potent MEK1/2 inhibitor, is an HIF-1 blocker in Ang II-treated VSMC. Unlike PD98059, a widely-used MEK1/2 inhibitor, we found that PD184161 blocked AngII-driven HIF-1alpha protein induction in a dose-dependent manner. Interestingly, the effect of PD184161 was specific to nonhypoxic activators, since HIF-1alpha induction by hypoxia (1% O2) was unaffected under similar conditions. VSMC treatment with MG132, a proteasome inhibitor, indicated that PD184161 influenced HIF-1alpha protein stability. PD184161 also increased HIF-1alpha binding to von Hippel-Lindau tumor suppressor protein, an E3 ligase component and an indication of HIF-1alpha hydroxylation. Finally, we show that PD184161 blocked mitochondrial ROS (mtROS) production and cellular ATP levels, at the same time enhancing ascorbate availability in AngII treated VSMC. Taken together, our study indicates that, independently of p42/p44 MAPK activation, PD184161 blocks mtROS generation by AngII, leading to re establishment of cellular ascorbate levels, increased VHL binding, and decreased HIF-1alpha stability. Therefore, this study reveals a previously unsuspected role for PD184161 as an HIF-1 inhibitor in VSMC under nonhypoxic conditions. PMID- 28814530 TI - A High-Fat Diet Decreases Bone Mass in Growing Mice with Systemic Chronic Inflammation Induced by Low-Dose, Slow-Release Lipopolysaccharide Pellets. AB - Background: Chronic inflammation is associated with increased bone resorption and is linked to osteopenia, or low bone mass. Obesity is also associated with low grade chronic upregulation of inflammatory cytokines.Objective: This study investigated the effect of high-fat (HF) diet-induced obesity on bone structure changes in growing mice with existing systemic chronic inflammation induced by low-dose, slow-release lipopolysaccharide (LPS).Methods: Forty-eight 6-wk-old female C57BL/6 mice were randomly assigned to 4 treatment groups (n = 12/group) in a 2 * 2 factorial design-control (placebo) or LPS treatment (1.5 MUg/d)-and consumed either a normal-fat (NF, 10% of energy as fat) or an HF (45% of energy as fat) diet ad libitum for 13 wk. Bone structure, serum biomarkers of bone turnover, and osteoclast differentiation were measured.Results: No alterations were observed in final body weights, fat mass, or lean mass in response to LPS treatment. LPS treatment increased serum concentration of tartrate-resistant acid phosphatase (TRAP, a bone resorption marker) and bone marrow osteoclast differentiation and decreased femoral and lumbar vertebral bone volume (BV):total volume (TV) by 25% and 24%, respectively, compared with the placebo. Mice fed the HF diet had greater body weight at the end of the study (P < 0.01) due to increased fat mass (P < 0.01) than did mice fed the NF diet. The HF diet increased serum TRAP concentration, bone marrow osteoclast differentiation, and expression of tumor necrosis factor alpha, interleukin 1beta and interleukin 6 in adipose tissue. Compared with the NF diet, the HF diet decreased BV:TV by 10% and 8% at femur and lumbar vertebrae, respectively, and the HF diet was detrimental to femoral and lumbar vertebral bone structure with decreased trabecular number and increased trabecular separation and structure model index.Conclusion: Results suggest that HF diets and systemic chronic inflammation have independent negative effects on bone structure in mice. PMID- 28814527 TI - Effects of nicotine on homeostatic and hedonic components of food intake. AB - Chronic tobacco use leads to nicotine addiction that is characterized by exaggerated urges to use the drug despite the accompanying negative health and socioeconomic burdens. Interestingly, nicotine users are found to be leaner than the general population. Review of the existing literature revealed that nicotine affects energy homeostasis and food consumption via altering the activity of neurons containing orexigenic and anorexigenic peptides in the brain. Hypothalamus is one of the critical brain areas that regulates energy balance via the action of these neuropeptides. The equilibrium between these two groups of peptides can be shifted by nicotine leading to decreased food intake and weight loss. The aim of this article is to review the existing literature on the effect of nicotine on food intake and energy homeostasis and report on the changes that nicotine brings about in the level of these peptides and their receptors that may explain changes in food intake and body weight induced by nicotine. Furthermore, we review the effect of nicotine on the hedonic aspect of food intake. Finally, we discuss the involvement of different subtypes of nicotinic acetylcholine receptors in the regulatory action of nicotine on food intake and energy homeostasis. PMID- 28814532 TI - Developmental Process and Early Phases of Implementation for the US Interagency Committee on Human Nutrition Research National Nutrition Research Roadmap 2016 2021. AB - The Interagency Committee on Human Nutrition Research (ICHNR) is charged with improving the planning, coordination, and communication among federal agencies engaged in nutrition research and with facilitating the development and updating of plans for federal research programs to meet current and future domestic and international needs for nutrition. The ICHNR is co-chaired by the USDA Under Secretary for Research, Education, and Economics and Chief Scientist and the US Department of Health and Human Services Assistant Secretary for Health and is made up of >10 departments and agencies. Once the ICHNR was reassembled after a 10-y hiatus, the ICHNR recognized a need for a written roadmap to identify critical human nutrition research gaps and opportunities. This commentary provides an overview of the process the ICHNR undertook to develop a first-of-its kind National Nutrition Research Roadmap, which was publicly released on 4 March 2016. The primary audience for the Roadmap is federal science agency leaders, along with relevant program and policy staff who rely on federally supported human nutrition research, in addition to the broader scientific community. The Roadmap is framed around the following 3 questions: 1) How can we better understand and define eating patterns to improve and sustain health? 2) What can be done to help people choose healthy eating patterns? 3) How can we develop and engage innovative methods and systems to accelerate discoveries in human nutrition? Within these 3 questions, 11 topical areas were identified on the basis of the following criteria: population impact, feasibility given current technological capacities, and emerging scientific opportunities. This commentary highlights initial federal and some professional research society efforts to address the Roadmap's research and resource priorities. We conclude by noting examples of early collaborations and partnerships to move human nutrition research forward in the 21st century. PMID- 28814531 TI - Patients with Nonalcoholic Fatty Liver Disease Have a Low Response Rate to Vitamin D Supplementation. AB - Background: Hypovitaminosis D is associated with an increased severity of nonalcoholic fatty liver disease (NAFLD), but reports on the response to cholecalciferol (vitamin D3) supplementation are conflicting.Objective: The objective of this study was to determine if standard vitamin D3 supplementation is effective in NAFLD with hypovitaminosis D.Methods: Sixty-five well characterized adults [age (mean +/- SD): 51.6 +/- 12.3 y] with biopsy-proven NAFLD were screened. Forty-two patients (the ratio of men to women was 13:29) had hypovitaminosis D (plasma 25-hydroxyvitamin D [25(OH)D] <30 ng/mL). An observational study was performed in NAFLD patients with hypovitaminosis D treated with 2000 IU cholecalciferol (vitamin D3) daily for 6 mo per clinical practice. Plasma 25(OH)D, hepatic and metabolic panels, and metabolic syndrome components were assessed before and after cholecalciferol supplementation. Body composition was measured by using bioelectrical impedance analysis. The primary outcome measure was plasma 25(OH)D >=30 ng/mL at the end of the study. Secondary outcomes included change in serum transaminases, fasting plasma glucose, and insulin and homeostasis model assessment of insulin resistance (HOMA-IR). Chi square, Student's t tests, correlation coefficient, and multivariate analysis were performed.Results: Twenty-six (61.9%) patients had nonalcoholic steatohepatitis (NASH), and 16 (38.1%) had hepatic steatosis. After 6 mo of cholecalciferol supplementation, plasma 25(OH)D >=30 ng/mL was observed in 16 subjects (38.1%; responders) whereas the remaining 26 patients (61.9%) were nonresponders with plasma 25(OH)D <30 ng/mL. Significantly fewer (P < 0.01) patients with NASH were responders (4 of 26, 15.4%) than those with hepatic steatosis (12 of 16, 75%). Baseline fasting serum alanine aminotransferase, plasma glucose, and HOMA-IR were similar in the responders and nonresponders, but the NASH score on the liver biopsy was lower (16.5%) in the responders (P < 0.001). Nonresponders had a higher fat mass (10.5%) and lower fat-free mass (10.4%) than responders did. End-of-treatment alanine aminotransferase and HOMA IR improved only in responders. The baseline HOMA-IR and histological NASH score were independent predictors of nonresponse to cholecalciferol supplementation.Conclusions: Daily supplementation with 2000 IU cholecalciferol for 6 mo did not correct hypovitaminosis D in the majority of patients with NASH. Further studies are needed to determine if higher doses are effective. This trial was registered at clinicaltrials.gov as 13-00153. PMID- 28814534 TI - Clinician attitudes to pain and use of analgesia in cattle: where are we 10 years on? AB - Pain in cattle can arise though disease or injury or may result from veterinary or husbandry procedures. Controlling pain is important to safeguard animal welfare. Previous studies indicated that the use of analgesics in cattle has lagged behind use in companion animals. Over the last decade, more analgesic products have become available for use in cattle and there have been increased efforts to communicate the importance and benefits of analgesia. A questionnaire (based on that used in a similar study published in 2006) was sent to UK cattle practitioners asking them to score pain severity for several conditions of cattle and asking about their attitudes towards and use of analgesic medicines. A total of 242 surveys were returned. Male clinicians and those graduating before 1990 scored pain severity significantly lower and were significantly less likely to use NSAIDs. Generally, use of NSAIDs was more common for conditions assigned higher pain scores. However, uptake of NSAID use was much lower for a number of routine procedures in calves than would be expected from the pain scores they were assigned. A need remains to increase use of analgesic products, especially NSAIDs in calves, in line with best practice recommendations. PMID- 28814533 TI - Dietary Selenium Deficiency or Excess Reduces Sperm Quality and Testicular mRNA Abundance of Nuclear Glutathione Peroxidase 4 in Rats. AB - Background: Glutathione peroxidase (GPX) 4 and selenoprotein P (SELENOP) are abundant, and several variants are expressed in the testis.Objective: We determined the effects of dietary selenium deficiency or excess on sperm quality and expressions of GPX4 and SELENOP variants in rat testis and liver.Methods: After weaning, male Sprague-Dawley rats were fed a Se-deficient basal diet (BD) for 5 wk until they were 9 wk old [mean +/- SEM body weight (BW) = 256 +/- 5 g]. They were then fed the BD diet alone (deficient) or with 0.25 (adequate), 3 (excess), or 5 (excess) mg Se/kg for 4 wk. Testis, liver, blood, and semen were collected to assay for selenoprotein mRNA and protein abundances, selenium concentration, GPX activity, 8-hydroxy-deoxyguanosine concentration, and sperm quality.Results: Dietary selenium supplementations elevated (P < 0.05) tissue selenium concentrations and GPX activities. Compared with those fed BD + 0.25 mg Se/kg, rats fed BD showed lower (P < 0.05) BW gain (86%) and sperm density (57%) but higher (P < 0.05) plasma 8-hydroxy-deoxyguanosine concentrations (189%), and nonprogressive sperm motility (4.4-fold). Likewise, rats fed BD + 5 mg Se/kg had (P = 0.06) lower BW gain and higher (1.9-fold) sperm deformity rates than those in the selenium-adequate group. Compared with the selenium-adequate group, dietary selenium deficiency (BD) or excess (BD + 3 or 5 mg Se/kg) resulted in 45 77% lower (P < 0.05) nuclear Gpx4 (nGpx4) mRNA abundance in the testis. Rats fed BD had lower (P < 0.05) mRNA levels of 2 Selenop variants in both testis and liver than those in the other groups. Testicular SELENOP was 155-170% higher (P < 0.05) in rats fed BD + 5 mg Se/kg and hepatic c/mGPX4 was 13-15% lower (P < 0.05) in rats fed BD than in the other groups.Conclusions: The mRNA abundance of rat testicular nGPX4 responded to dietary selenium concentrations in similar ways to sperm parameters and may be used as a sensitive marker to assess appropriate Se status for male function. PMID- 28814536 TI - The Future of Fragile X Syndrome: CDC Stakeholder Meeting Summary. PMID- 28814538 TI - Implications of the FMR1 Premutation for Children, Adolescents, Adults, and Their Families. AB - BACKGROUND AND OBJECTIVES: Given the nature of FMR1 gene expansions, most biological mothers, and often multiple other family members of children with fragile X syndrome (FXS), will have a premutation, which may increase individual and family vulnerabilities. This article summarizes important gaps in knowledge and notes potential implications for pediatric providers with regard to developmental and medical risks for children and adolescents with an FMR1 premutation, including possible implications into adulthood. METHODS: A structured electronic literature search was conducted on FMR1 pre- and full mutations, yielding a total of 306 articles examined. Of these, 116 focused primarily on the premutation and are included in this review. RESULTS: Based on the literature review, 5 topic areas are discussed: genetics and epidemiology; phenotypic characteristics of individuals with the premutation; implications for carrier parents of children with FXS; implications for the extended family; and implications for pediatricians. CONCLUSIONS: Although the premutation phenotype is typically less severe in clinical presentation than in FXS, premutation carriers are much more common and are therefore more likely to be seen in a typical pediatric practice. In addition, there is a wide range of medical, cognitive/developmental, and psychiatric associated features that individuals with a premutation are at increased risk for having, which underscores the importance of awareness on the part of pediatricians in identifying and monitoring premutation carriers and recognizing the impact this identification may have on family members. PMID- 28814540 TI - Autism Spectrum Disorder in Fragile X Syndrome: Cooccurring Conditions and Current Treatment. AB - BACKGROUND AND OBJECTIVE: Individuals with fragile X syndrome (FXS) are frequently codiagnosed with autism spectrum disorder (ASD). Most of our current knowledge about ASD in FXS comes from family surveys and small studies. The objective of this study was to examine the impact of the ASD diagnosis in a large clinic-based FXS population to better inform the care of people with FXS. METHODS: The study employed a data set populated by data from individuals with FXS seen at specialty clinics across the country. The data were collected by clinicians at the patient visit and by parent report for nonclinical and behavioral outcomes from September 7, 2012 through August 31, 2014. Data analyses were performed by using chi2 tests for association, t tests, and multiple logistic regression to examine the association between clinical and other factors with ASD status. RESULTS: Half of the males and nearly 20% of females met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for current ASD. Relative to the FXS-only group, the FXS with ASD (FXS+ASD) group had a higher prevalence of seizures (20.7% vs 7.6%, P < .001), persistence of sleep problems later in childhood, increased behavior problems, especially aggressive/disruptive behavior, and higher use of alpha-agonists and antipsychotics. Behavioral services, including applied behavior analysis, appeared to be underused in children with FXS+ASD (only 26% and 16% in prekindergarten and school-age periods, respectively) relative to other populations with idiopathic ASD. CONCLUSIONS: These findings confirm among individuals with FXS an association of an ASD diagnosis with important cooccurring conditions and identify gaps between expected and observed treatments among individuals with FXS+ASD. PMID- 28814539 TI - FORWARD: A Registry and Longitudinal Clinical Database to Study Fragile X Syndrome. AB - BACKGROUND AND OBJECTIVE: Advances in the care of patients with fragile X syndrome (FXS) have been hampered by lack of data. This deficiency has produced fragmentary knowledge regarding the natural history of this condition, healthcare needs, and the effects of the disease on caregivers. To remedy this deficiency, the Fragile X Clinic and Research Consortium was established to facilitate research. Through a collective effort, the Fragile X Clinic and Research Consortium developed the Fragile X Online Registry With Accessible Research Database (FORWARD) to facilitate multisite data collection. This report describes FORWARD and the way it can be used to improve health and quality of life of FXS patients and their relatives and caregivers. METHODS: FORWARD collects demographic information on individuals with FXS and their family members (affected and unaffected) through a 1-time registry form. The longitudinal database collects clinician- and parent-reported data on individuals diagnosed with FXS, focused on those who are 0 to 24 years of age, although individuals of any age can participate. RESULTS: The registry includes >2300 registrants (data collected September 7, 2009 to August 31, 2014). The longitudinal database includes data on 713 individuals diagnosed with FXS (data collected September 7, 2012 to August 31, 2014). Longitudinal data continue to be collected on enrolled patients along with baseline data on new patients. CONCLUSIONS: FORWARD represents the largest resource of clinical and demographic data for the FXS population in the United States. These data can be used to advance our understanding of FXS: the impact of cooccurring conditions, the impact on the day to-day lives of individuals living with FXS and their families, and short-term and long-term outcomes. PMID- 28814537 TI - Public Health Literature Review of Fragile X Syndrome. AB - OBJECTIVES: The purpose of this systematic literature review is to describe what is known about fragile X syndrome (FXS) and to identify research gaps. The results can be used to help inform future public health research and provide pediatricians with up-to-date information about the implications of the condition for individuals and their families. METHODS: An electronic literature search was conducted, guided by a variety of key words. The search focused on 4 areas of both clinical and public health importance: (1) the full mutation phenotype, (2) developmental trajectories across the life span, (3) available interventions and treatments, and (4) impact on the family. A total of 661 articles were examined and 203 were included in the review. RESULTS: The information is presented in the following categories: developmental profile (cognition, language, functional skills, and transition to adulthood), social-emotional profile (cooccurring psychiatric conditions and behavior problems), medical profile (physical features, seizures, sleep, health problems, and physiologic features), treatment and interventions (educational/behavioral, allied health services, and pharmacologic), and impact on the family (family environment and financial impact). Research gaps also are presented. CONCLUSIONS: The identification and treatment of FXS remains an important public health and clinical concern. The information presented in this article provides a more robust understanding of FXS and the impact of this complex condition for pediatricians. Despite a wealth of information about the condition, much work remains to fully support affected individuals and their families. PMID- 28814542 TI - Fragile X Newborn Screening: Lessons Learned From a Multisite Screening Study. AB - BACKGROUND: Delays in the diagnosis of children with fragile X syndrome (FXS) suggest the possibility of newborn screening as a way to identify children earlier. However, FXS does not have a proven treatment that must be provided early, and ethical concerns have been raised about the detection of infants who are carriers. This article summarizes major findings from a multisite, prospective, longitudinal pilot screening study. METHODS: Investigators in North Carolina, California, and Illinois collaborated on a study in which voluntary screening for FXS was offered to parents in 3 birthing hospitals. FXS newborn screening was offered to >28 000 families to assess public acceptance and determine whether identification of babies resulted in any measurable harms or adverse events. Secondary goals were to determine the prevalence of FMR1 carrier gene expansions, study the consent process, and describe early development and behavior of identified children. RESULTS: A number of publications have resulted from the project. This article summarizes 10 "lessons learned" about the consent process, reasons for accepting and declining screening, development and evaluation of a decision aid, prevalence of carriers, father participation in consent, family follow-up, and maternal reactions to screening. CONCLUSIONS: The project documented public acceptance of screening as well as the challenges inherent in obtaining consent in the hospital shortly after birth. Collectively, the study provides answers to a number of questions that now set the stage for a next generation of research to determine the benefits of earlier identification for children and families. PMID- 28814541 TI - Assessing the Fragile X Syndrome Newborn Screening Landscape. AB - BACKGROUND: Fragile X syndrome (FXS) is the most common known inherited form of intellectual disability. Early identification is an important step in linking FXS individuals with appropriate and timely medical and social services. Newborn screening (NBS) is 1 approach that has been used for other conditions to facilitate early identification. METHODS: A literature review was conducted to identify issues, barriers, challenges, and approaches to addressing challenges related to NBS for FXS. Search terms included: fragile X syndrome, FMR1, newborn screening, screening, and genetic testing. To supplement the literature review, 9 key informant interviews were conducted. Information gathered through these interviews supplemented what was identified in the literature. Information from both the literature review and supplemental interviews was reviewed by 3 researchers who discussed and came to consensus on thematic areas and categorization of issues. RESULTS: The barriers and challenges related to NBS for FXS identified in the literature and by experts and stakeholders are categorized into 5 thematic areas: public health burden, treatment, timing, screening/testing methodologies, and translating results. Summaries of these issues and barriers are provided, along with potential approaches to addressing them. CONCLUSIONS: The issues and barriers described in this article highlight limited areas of knowledge that need be addressed to improve our understanding of FXS and the potential benefit of NBS. The landscape of NBS for FXS could be influenced by a series of research findings over time or a larger breakthrough that demonstrates an effective targeted treatment that has to be implemented early in life. PMID- 28814543 TI - Loss of dual leucine zipper kinase signaling is protective in animal models of neurodegenerative disease. AB - Hallmarks of chronic neurodegenerative disease include progressive synaptic loss and neuronal cell death, yet the cellular pathways that underlie these processes remain largely undefined. We provide evidence that dual leucine zipper kinase (DLK) is an essential regulator of the progressive neurodegeneration that occurs in amyotrophic lateral sclerosis and Alzheimer's disease. We demonstrate that DLK/c-Jun N-terminal kinase signaling was increased in mouse models and human patients with these disorders and that genetic deletion of DLK protected against axon degeneration, neuronal loss, and functional decline in vivo. Furthermore, pharmacological inhibition of DLK activity was sufficient to attenuate the neuronal stress response and to provide functional benefit even in the presence of ongoing disease. These findings demonstrate that pathological activation of DLK is a conserved mechanism that regulates neurodegeneration and suggest that DLK inhibition may be a potential approach to treat multiple neurodegenerative diseases. PMID- 28814544 TI - Direct detection of early-stage cancers using circulating tumor DNA. AB - Early detection and intervention are likely to be the most effective means for reducing morbidity and mortality of human cancer. However, development of methods for noninvasive detection of early-stage tumors has remained a challenge. We have developed an approach called targeted error correction sequencing (TEC-Seq) that allows ultrasensitive direct evaluation of sequence changes in circulating cell free DNA using massively parallel sequencing. We have used this approach to examine 58 cancer-related genes encompassing 81 kb. Analysis of plasma from 44 healthy individuals identified genomic changes related to clonal hematopoiesis in 16% of asymptomatic individuals but no alterations in driver genes related to solid cancers. Evaluation of 200 patients with colorectal, breast, lung, or ovarian cancer detected somatic mutations in the plasma of 71, 59, 59, and 68%, respectively, of patients with stage I or II disease. Analyses of mutations in the circulation revealed high concordance with alterations in the tumors of these patients. In patients with resectable colorectal cancers, higher amounts of preoperative circulating tumor DNA were associated with disease recurrence and decreased overall survival. These analyses provide a broadly applicable approach for noninvasive detection of early-stage tumors that may be useful for screening and management of patients with cancer. PMID- 28814545 TI - Metabolic differentiation of early Lyme disease from southern tick-associated rash illness (STARI). AB - Lyme disease, the most commonly reported vector-borne disease in the United States, results from infection with Borrelia burgdorferi. Early clinical diagnosis of this disease is largely based on the presence of an erythematous skin lesion for individuals in high-risk regions. This, however, can be confused with other illnesses including southern tick-associated rash illness (STARI), an illness that lacks a defined etiological agent or laboratory diagnostic test, and is coprevalent with Lyme disease in portions of the eastern United States. By applying an unbiased metabolomics approach with sera retrospectively obtained from well-characterized patients, we defined biochemical and diagnostic differences between early Lyme disease and STARI. Specifically, a metabolic biosignature consisting of 261 molecular features (MFs) revealed that altered N acyl ethanolamine and primary fatty acid amide metabolism discriminated early Lyme disease from STARI. Development of classification models with the 261-MF biosignature and testing against validation samples differentiated early Lyme disease from STARI with an accuracy of 85 to 98%. These findings revealed metabolic dissimilarity between early Lyme disease and STARI, and provide a powerful and new approach to inform patient management by objectively distinguishing early Lyme disease from an illness with nearly identical symptoms. PMID- 28814547 TI - Annual Summary of Vital Statistics: 2013-2014. AB - The number of births in the United States increased by 1% between 2013 and 2014, to a total of 3 988 076. The general fertility rate rose 1% to 62.9 births per 1000 women. The total fertility rate also rose 0.3% in 2014, to 1862.5 births per 1000 women. The teenage birth rate fell to another historic low in 2014, 24.2 births per 1000 women. The percentage of all births to unmarried women declined to 40.2% in 2014, from 40.6% in 2013. In 2014, the cesarean delivery rate declined to 32.2% from 32.7% in 2013. The preterm birth rate declined for the seventh straight year in 2014 to 9.57%; the low birth weight rate was unchanged at 8.00%. The infant mortality rate decreased to a historic low of 5.82 infant deaths per 1000 live births in 2014. The age-adjusted death rate for 2014 was 7.2 deaths per 1000 population, down 1% from 2013. Crude death rates for children aged 1 to 19 years did not change significantly between 2013 and 2014. Unintentional injuries and suicide were, respectively, the first and second leading causes of death in this age group. These 2 causes of death jointly accounted for 46.5% of all deaths to children and adolescents in 2014. PMID- 28814546 TI - mGlu7 potentiation rescues cognitive, social, and respiratory phenotypes in a mouse model of Rett syndrome. AB - Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene. The cognitive impairments seen in mouse models of RTT correlate with deficits in long-term potentiation (LTP) at Schaffer collateral (SC)-CA1 synapses in the hippocampus. Metabotropic glutamate receptor 7 (mGlu7) is the predominant mGlu receptor expressed presynaptically at SC-CA1 synapses in adult mice, and its activation on GABAergic interneurons is necessary for induction of LTP. We demonstrate that pathogenic mutations in MECP2 reduce mGlu7 protein expression in brain tissue from RTT patients and in MECP2 deficient mouse models. In rodents, this reduction impairs mGlu7-mediated control of synaptic transmission. We show that positive allosteric modulation of mGlu7 activity restores LTP and improves contextual fear learning, novel object recognition, and social memory. Furthermore, mGlu7 positive allosteric modulation decreases apneas in Mecp2+/- mice, suggesting that mGlu7 may be a potential therapeutic target for multiple aspects of the RTT phenotype. PMID- 28814548 TI - Chorioamnionitis in the Development of Cerebral Palsy: A Meta-analysis and Systematic Review. AB - CONTEXT: Chorioamnionitis (CA) has often been linked etiologically to cerebral palsy (CP). OBJECTIVES: To differentiate association from risk of CA in the development of CP. DATA SOURCES: PubMed, Cochrane Library, Embase, and bibliographies of original studies were searched by using the keywords (chorioamnionitis) AND ((cerebral palsy) OR brain). STUDY SELECTION: Included studies had to have: (1) controls, (2) criteria for diagnoses, and (3) neurologic follow-up. Studies were categorized based on: (1) finding incidence of CP in a CA population, or risk of CP; and (2) incidence of CA in CP or association with CP. DATA EXTRACTION: Two reviewers independently verified study inclusion and extracted data. RESULTS: Seventeen studies (125 256 CA patients and 5 994 722 controls) reported CP in CA. There was significantly increased CP inpreterm histologic chorioamnionitis (HCA; risk ratio [RR] = 1.34, P < .01), but not in clinical CA (CCA). Twenty-two studies (2513 CP patients and 8135 controls) reported CA in CP. There was increased CCA (RR = 1.43, P < .01), but no increase in HCA in preterm CP. Increased HCA was found (RR = 4.26, P < .05), as well as CCA in term/near-term CP (RR = 3.06, P < .01). CONCLUSIONS: The evidence for a causal or associative role of CA in CP is weak. Preterm HCA may be a risk factor for CP, whereas CCA is not. An association with term and preterm CP was found for CCA, but only with term CP for HCA. PMID- 28814549 TI - Cesarean Delivery and Body Mass Index at 6 Months and Into Childhood. AB - BACKGROUND AND OBJECTIVES: The prevalence of cesarean delivery (CD) is rising worldwide, and so is childhood obesity. Studies have shown associations between these factors. We examined the development of BMI from birth through childhood to determine whether CDs were associated with differences in growth and obesity. METHODS: Term children from the birth cohorts Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) and COPSAC2010 were included. Height, length, and weight measurements were collected prospectively until 5 years in COPSAC2010 and until 13 years in COPSAC2000. Dual-energy x-ray absorptiometry (DXA) scans were performed at 3.5 and 7 years. Information on relevant covariates were verified during clinical visits. Analyses were adjusted for covariates associating with CD. RESULTS: In COPSAC2010, 20% (N = 138/673) of the children were delivered by CD; 49% were girls. In COPSAC2000, 19% (N = 76/393) were delivered by CD; 51% were girls. Children delivered by CD had a higher mean BMI at 6 months compared with those delivered vaginally: COPSAC2010 beta-coefficient, .41 (95% confidence interval [CI], .12 to .69), P = .01; COPSAC2000 beta coefficient, .16 (95% CI, -.11 to .68), P = .16; and meta-analysis beta coefficient, .37 (95% CI, .14 to .60), P = .002. There were no differences in BMI trajectory between the 2 groups by 5 and 13 years, nor cross-sectional BMI at 5 and 13 years, nor in fat percentages from DXA scans. CONCLUSIONS: Children delivered by CD had a higher BMI at 6 months of age, but this difference did not track into later childhood. Our study does not support the hypothesis that CD leads to later overweight. PMID- 28814550 TI - Changing Neurodevelopment at 8 Years in Children Born Extremely Preterm Since the 1990s. AB - BACKGROUND AND OBJECTIVE: Survival of extremely preterm (EP; <28 weeks' gestation) infants has increased over the last 2 decades. Equivalent reductions in developmental morbidity in early childhood have not been consistently reported. The aim of this study was to determine trends in neurodevelopmental outcomes at 8 years of age of children born EP (22-27 completed weeks' gestation) over the past 2 decades. METHODS: Population-based cohorts of all EP survivors born in the state of Victoria, Australia in 1991-1992, 1997, and 2005 were recruited at birth. At 8 years of age, general intelligence (IQ), academic achievement, and neurosensory status were assessed. Major neurosensory disability was defined as any of moderate or severe cerebral palsy, IQ <-2 SD relative to term controls, blindness, or deafness. RESULTS: Rates of major neurosensory disability were similar in all eras (1991-1992, 18%; 1997, 15%; 2005, 18%), as were rates of IQ <-2 SD, cerebral palsy, blindness, and deafness. Mean z scores for IQ were similar across eras, but there was some evidence that scores for academic achievement were lower in 2005 than in 1997, and the odds of having academic problems were higher in 2005 than in both earlier eras. These outcomes were not explained by differences in known perinatal care or sociodemographic variables between eras. CONCLUSIONS: Contrary to expectations, rates of major neurosensory disability have not improved, and academic performance is poorer at early school age in 2005 than in earlier eras for EP children born in the state of Victoria, Australia. PMID- 28814551 TI - Follow-up of Extremely Preterm Infants; the Long and the Short of It. PMID- 28814552 TI - Larose G, Levy A, Bailey B, Cummins-McManus B, Lebel D, Gravel J. Decreasing Prescribing Errors During Pediatric Emergencies: A Randomized Simulation Trial. Pediatrics. 2017:139(3):e20163200. PMID- 28814553 TI - Mallory LA, Osorio SN, Prato BS, et al; IMPACT Pilot Study Group. Project IMPACT Pilot Report: Feasibility of Implementing a Hospital-to-Home Transition Bundle. Pediatrics. 2017;139(3):e20154626. PMID- 28814554 TI - Crawford-Jakubiak JE, Alderman EM, Leventhal JM, AAP COMMITTEE ON CHILD ABUSE AND NEGLECT, AAP COMMITTEE ON ADOLESCENCE. Care of the Adolescent After an Acute Sexual Assault. Pediatrics. 2017;139(3):e20164243. PMID- 28814555 TI - Re: Neonatal Abstinence Syndrome and High School Performance. PMID- 28814557 TI - When technology creates uncertainty: pulse oximetry and overdiagnosis of hypoxaemia in bronchiolitis. PMID- 28814558 TI - Don't forget that facial petechiae may be a sign of physical abuse. PMID- 28814559 TI - Are expanding disease definitions unnecessarily labelling women with polycystic ovary syndrome? PMID- 28814560 TI - Overdiagnosis, ethics, and trolley problems: why factors other than outcomes matter-an essay by Stacy Carter. PMID- 28814561 TI - Statistics Notes: What is a percentage difference? PMID- 28814562 TI - Elias Mossialos: The politics of R&D. PMID- 28814563 TI - Statistics Notes: Percentage differences, symmetry, and natural logarithms. PMID- 28814564 TI - What it feels like to be compulsorily detained for treatment. PMID- 28814565 TI - Trastuzumab Biosimilar on Track for Approval. AB - An FDA expert panel recommended approval of Mylan's MYL-14010, a biosimilar candidate for Genentech's trastuzumab, putting it on track to become the first approved biosimilar for cancer. Experts predict that biosimilars will lead to lower drug prices, but caution that the savings won't be as dramatic as that seen with generics. PMID- 28814567 TI - Cbfbeta2 deficiency preserves Langerhans cell precursors by lack of selective TGFbeta receptor signaling. AB - The mouse Langerhans cell (LC) network is established through the differentiation of embryonic LC precursors. BMP7 and TGFbeta1 initiate cellular signaling that is essential for inducing LC differentiation and preserving LCs in a quiescent state, respectively. Here we show that loss of Cbfbeta2, one of two RNA splice variants of the Cbfb gene, results in long-term persistence of embryonic LC precursors after their developmental arrest at the transition into the EpCAM+ stage. This phenotype is caused by selective loss of BMP7-mediated signaling essential for LC differentiation, whereas TGFbetaR signaling is intact, maintaining cells in a quiescent state. Transgenic Cbfbeta2 expression at the neonatal stage, but not at the adult stage, restored differentiation from Cbfbeta2-deficient LC precursors. Loss of developmental potential in skin residential precursor cells was accompanied by diminished BMP7-BMPR1A signaling. Collectively, our results reveal an essential requirement for the Cbfbeta2 variant in LC differentiation and provide novel insight into how the establishment and homeostasis of the LC network is regulated. PMID- 28814569 TI - The impact of urban speed reduction programmes on health system cost and utilities. AB - BACKGROUND: Vehicle speed changes impact the probability of injuring a pedestrian in ways that differ from the way that it impacts the probability of a collision or of death. Therefore, return on investment in speed reduction programmes has complex and unpredictable manifests. The objective of this study is to analyse the impact of motor vehicle speed reduction on the collision-related morbidity and mortality rates of urban pedestrians. METHODS AND FINDINGS: We created a simple way to estimate the public health impacts of traffic speed changes using a Markov model. Our outcome measures include the cost of injury, quality-adjusted life years (QALYs) gained and probability of death and injury due to a road traffic collision. Our two-way sensitivity analysis of speed, both before the implementation of a speed reduction programme and after, shows that, due to key differences in the probability of injury compared with the probability of death, speed reduction programmes may decrease the probability of death while leaving the probability of injury unchanged. The net result of this difference may lead to an increase in injury costs due to the implementation of a speed reduction programme. We find that even small investments in speed reductions have the potential to produce gains in QALYs. CONCLUSIONS: Our reported costs, effects and incremental cost-effectiveness ratios may assist urban governments and stakeholders to rethink the value of local traffic calming programmes and to implement speed limits that would shift the trade-off to become between minor injuries and no injuries, rather than severe injuries and fatalities. PMID- 28814568 TI - Fetal-type gastrointestinal adenocarcinoma: a morphologically distinct entity with unfavourable prognosis. AB - AIMS: This multi-institutional study and a re-evaluation of the TCGA cohort explores the morphological spectrum, genetics and outcome of GI (gastrointestinal) hepatoid tumours, tumours expressing alpha-fetoprotein (AFP) and fetal-type (FT) GI adenocarcinomas. METHODS: 44 tumours with evidence of hepatocellular differentiation were evaluated for morphology as well as by immunohistochemistry for AFP, HepPar1, glypican-3 and arginase-1 and by in situ hybridisation for albumin. Three categories were defined: type I (hepatoid: morphological evidence of hepatocellular differentiation), type II (FT GI adenocarcinoma: tubular profiles and subnuclear vacuolisation, resembling fetal intestine) and type III: positive for at least two hepatocyte-specific markers but lacking morphological evidence of hepatocellular differentiation. GI adenocarcinomas in the TCGA cohort were also evaluated (n=829). RESULTS: 18 cases were classified as type I, 19 as FT GI adenocarcinomas and 7 as type III (resembling conventional gastrointestinal carcinomas). Serum AFP was elevated in 92% of cases. 93% of tumours were positive for glypican-3, 90% for albumin and 89% for AFP. Arginase-1 was restricted to 35% of type 1 tumours. TCGA gastric tumours with elevated AFP expression showed morphological features of FT GI adenocarcinoma (70%) and were exclusively MSI stable. TCGA gastric adenocarcinomas with high AFP expression showed inferior survival on univariate and multivariate analysis. CONCLUSIONS: FT GI adenocarcinomas show a distinctive morphological and immunohistochemical profile. Gastric adenocarcinomas with elevated expression of AFP morphologically resemble FT GI adenocarcinomas, demonstrate aggressive behaviour, independent of grade and stage, and a distinct genetic profile. PMID- 28814566 TI - Neurodevelopmental outcome at 2 years for preterm children born at 22 to 34 weeks' gestation in France in 2011: EPIPAGE-2 cohort study. AB - Objectives To describe neurodevelopmental outcomes at 2 years corrected age for children born alive at 22-26, 27-31, and 32-34 weeks' gestation in 2011, and to evaluate changes since 1997.Design Population based cohort studies, EPIPAGE and EPIPAGE-2.Setting France.Participants 5567 neonates born alive in 2011 at 22-34 completed weeks' gestation, with 4199 survivors at 2 years corrected age included in follow-up. Comparison of outcomes reported for 3334 (1997) and 2418 (2011) neonates born alive in the nine regions participating in both studies.Main outcome measures Survival; cerebral palsy (2000 European consensus definition); scores below threshold on the neurodevelopmental Ages and Stages Questionnaire (ASQ; at least one of five domains below threshold) if completed between 22 and 26 months corrected age, in children without cerebral palsy, blindness, or deafness; and survival without severe or moderate neuromotor or sensory disabilities (cerebral palsy with Gross Motor Function Classification System levels 2-5, unilateral or bilateral blindness or deafness). Results are given as percentage of outcome measures with 95% confidence intervals.Results Among 5170 liveborn neonates with parental consent, survival at 2 years corrected age was 51.7% (95% confidence interval 48.6% to 54.7%) at 22-26 weeks' gestation, 93.1% (92.1% to 94.0%) at 27-31 weeks' gestation, and 98.6% (97.8% to 99.2%) at 32-34 weeks' gestation. Only one infant born at 22-23 weeks survived. Data on cerebral palsy were available for 3599 infants (81.0% of the eligible population). The overall rate of cerebral palsy at 24-26, 27-31, and 32-34 weeks' gestation was 6.9% (4.7% to 9.6%), 4.3% (3.5% to 5.2%), and 1.0% (0.5% to 1.9%), respectively. Responses to the ASQ were analysed for 2506 children (56.4% of the eligible population). The proportion of children with an ASQ result below threshold at 24 26, 27-31, and 32-34 weeks' gestation were 50.2% (44.5% to 55.8%), 40.7% (38.3% to 43.2%), and 36.2% (32.4% to 40.1%), respectively. Survival without severe or moderate neuromotor or sensory disabilities among live births increased between 1997 and 2011, from 45.5% (39.2% to 51.8%) to 62.3% (57.1% to 67.5%) at 25-26 weeks' gestation, but no change was observed at 22-24 weeks' gestation. At 32-34 weeks' gestation, there was a non-statistically significant increase in survival without severe or moderate neuromotor or sensory disabilities (P=0.61), but the proportion of survivors with cerebral palsy declined (P=0.01).Conclusions In this large cohort of preterm infants, rates of survival and survival without severe or moderate neuromotor or sensory disabilities have increased during the past two decades, but these children remain at high risk of developmental delay. PMID- 28814571 TI - MicroRNA-15b deteriorates hypoxia/reoxygenation-induced cardiomyocyte apoptosis by downregulating Bcl-2 and MAPK3. AB - To investigate the role of miRNA-15b in cardiomyocyte apoptosis after ischemia reperfusion injury in acute myocardial infarction (AMI), we conducted the AMI rat model by using left anterior descending ligation and performed hypoxia/reoxygenation experiments in H9c2 cells. MiRNA-15b was measured by quantitative reverse transcription PCR (qRT-PCR). Cardiomyocyte apoptosis was determined by terminal deoxynucleotide transferase dUTP nick end labeling staining. Synthesized miRNA-15b mimic and inhibitor were transfected into H9c2 cells by Lipofectamine regent. RNA expression of B cell lymphoma/leukemia-2 (Bcl 2) and mitogen-activated protein kinase 3 (MAPK3) was examined by qRT-PCR and their protein expression was determined by western blot. Ischemia reperfusion increased miRNA-15b expression in the ischemic rat heart and resulted more severe cardiomyocytes apoptosis. In H9c2 cells, hypoxia/reoxygenation induced increased miRNA-15b expression and augmented cardiomyocyte apoptosis observed at 24 hours after 24-hour hypoxia. Compared with the vehicle group, miRNA-15b mimic further raised miRNA-15b level and increased cardiomyocyte apoptosis, whereas miRNA-15b inhibitor suppressed miRNA-15b expression and protected cardiomyocytes from apoptosis. Although the mRNA expression of the target genes Bcl-2 and MAPK3 was not changed significantly, the protein expression of these two genes were markedly reduced after miRNA-15b mimic treatment and significantly increased after transfected with miRNA-15b inhibitors. In conclusion, miRNA-15b deteriorates cardiomyocyte apoptosis by post-transcriptionally downregulating the expression of Bcl-2 and MAPK3. PMID- 28814570 TI - EB1 and EB3 regulate microtubule minus end organization and Golgi morphology. AB - End-binding proteins (EBs) are the core components of microtubule plus end tracking protein complexes, but it is currently unknown whether they are essential for mammalian microtubule organization. Here, by using CRISPR/Cas9 mediated knockout technology, we generated stable cell lines lacking EB2 and EB3 and the C-terminal partner-binding half of EB1. These cell lines show only mild defects in cell division and microtubule polymerization. However, the length of CAMSAP2-decorated stretches at noncentrosomal microtubule minus ends in these cells is reduced, microtubules are detached from Golgi membranes, and the Golgi complex is more compact. Coorganization of microtubules and Golgi membranes depends on the EB1/EB3-myomegalin complex, which acts as membrane-microtubule tether and counteracts tight clustering of individual Golgi stacks. Disruption of EB1 and EB3 also perturbs cell migration, polarity, and the distribution of focal adhesions. EB1 and EB3 thus affect multiple interphase processes and have a major impact on microtubule minus end organization. PMID- 28814572 TI - Physicians and blocking: can we tear down this wall? PMID- 28814574 TI - A dinosaur missing-link? Chilesaurus and the early evolution of ornithischian dinosaurs. AB - The enigmatic dinosaur taxon Chilesaurus diegosuarezi was originally described as a tetanuran theropod, but this species possesses a highly unusual combination of features that could provide evidence of alternative phylogenetic positions within the clade. In order to test the relationships of Chilesaurus, we added it to a new dataset of early dinosaurs and other dinosauromorphs. Our analyses recover Chilesaurus in a novel position, as the earliest diverging member of Ornithischia, rather than a tetanuran theropod. The basal position of Chilesaurus within the clade and its suite of anatomical characters suggest that it might represent a 'transitional' taxon, bridging the morphological gap between Theropoda and Ornithischia, thereby offering potential insights into the earliest stages of ornithischian evolution, which were previously obscure. For example, our results suggest that pubic retroversion occurred prior to some of the craniodental and postcranial modifications that previously diagnosed the clade (e.g. the presence of a predentary bone and ossified tendons). PMID- 28814573 TI - Conserved Dynamics of Chloroplast Cytoskeletal FtsZ Proteins Across Photosynthetic Lineages. AB - The cytoskeletal Filamenting temperature-sensitive Z (FtsZ) ring is critical for cell division in bacteria and chloroplast division in photosynthetic eukaryotes. While bacterial FtsZ rings are composed of a single FtsZ, except in the basal glaucophytes, chloroplast division involves two heteropolymer-forming FtsZ isoforms: FtsZ1 and FtsZ2 in the green lineage and FtsZA and FtsZB in red algae. FtsZ1 and FtsZB probably arose by duplication of the more ancestral FtsZ2 and FtsZA, respectively. We expressed fluorescent fusions of FtsZ from diverse photosynthetic organisms in a heterologous system to compare their intrinsic assembly and dynamic properties. FtsZ2 and FtsZA filaments were morphologically distinct from FtsZ1 and FtsZB filaments. When coexpressed, FtsZ pairs from plants and algae colocalized, consistent with heteropolymerization. Fluorescence recovery after photobleaching experiments demonstrated that subunit exchange was greater from FtsZ1 and FtsZB filaments than from FtsZ2 and FtsZA filaments and that FtsZ1 and FtsZB increased turnover of FtsZ2 and FtsZA, respectively, from heteropolymers. GTPase activity was essential only for turnover of FtsZ2 and FtsZA filaments. Cyanobacterial and glaucophyte FtsZ properties mostly resembled those of FtsZ2 and FtsZA, though the glaucophyte protein exhibited some hybrid features. Our results demonstrate that the more ancestral FtsZ2 and FtsZA have retained functional attributes of their common FtsZ ancestor, while eukaryotic specific FtsZ1 and FtsZB acquired new but similar dynamic properties, possibly through convergent evolution. Our findings suggest that the evolution of a second FtsZ that could copolymerize with the more ancestral form to enhance FtsZ-ring dynamics may have been essential for plastid evolution in the green and red photosynthetic lineages. PMID- 28814575 TI - Prenatal environment affects embryonic response to song. AB - Early environmental enrichment improves postnatal cognition in animals and humans. Here, we examined the effects of the prenatal acoustic environment (parental song rate) on prenatal attention in superb fairy-wren (Malurus cyaneus) embryos, the only songbird species with evidence of prenatal discrimination of maternal calls and in ovo call learning. Because both adults also sing throughout the incubation phase, we broadcast songs to embryos and measured their heart rate response in relation to parental song rate and tutor identity (familiarity, sex). Embryos from acoustically active families (high parental song rate) had the strongest response to songs. Embryos responded (i) strongest to male songs irrespective of familiarity with the singer, and (ii) strongest if their father had a high song rate during incubation. This is the first evidence for a prenatal physiological response to particular songs (potential tutors) in the egg, in relation to the prenatal acoustic environment, and before the sensitive period for song learning. PMID- 28814576 TI - Children's Hospitals' Solutions for Patient Safety Collaborative Impact on Hospital-Acquired Harm. AB - OBJECTIVES: To determine if an improvement collaborative of 33 children's hospitals focused on reliable best practice implementation and culture of safety improvements can reduce hospital-acquired conditions (HACs) and serious safety events (SSEs). METHODS: A 3-year prospective cohort study design with a 12-month historical control population was completed by the Children's Hospitals' Solutions for Patient Safety collaborative. Identification and dissemination of best practices related to 9 HACs and SSE reduction focused on key process and culture of safety improvements. Individual hospital improvement teams leveraged the resources of a large, structured children's hospital collaborative using electronic, virtual, and in-person interactions. RESULTS: Thirty-three children's hospitals from across the United States volunteered to be part of the Children's Hospitals' Solutions for Patient Safety collaborative. Thirty-two met all the data submission eligibility requirements for the HAC improvement objective of this study, and 21 participated in the high-reliability culture work aimed at reducing SSEs. Significant harm reduction occurred in 8 of 9 common HACs (range 9%-71%; P < .005 for all). The mean monthly SSE rate decreased 32% (from 0.77 to 0.52; P < .001). The 12-month rolling average SSE rate decreased 50% (from 0.82 to 0.41; P < .001). CONCLUSIONS: Participation in a structured collaborative dedicated to implementing HAC-related best-practice prevention bundles and culture of safety interventions designed to increase the use of high-reliability organization practices resulted in significant HAC and SSE reductions. Structured collaboration and rapid sharing of evidence-based practices and tools are effective approaches to decreasing hospital-acquired harm. PMID- 28814577 TI - Physician-Nurse Interactions in Critical Care. AB - Nearly 20% of nurses leave their first job within a year of being hired. Many do so because they perceive the work environment to be unhealthy or nonsupportive. Nurse turnover is costly. When new nurses leave within 3 years of being hired, it costs the hospital $64 000, over and above salaries, to replace them. One of the hallmarks of an unhealthy work environment is poor communication between doctors and nurses. We present a case in which a nurse advocates for a young mother by questioning the doctor. She is reprimanded for doing so. We then asked 3 nurses to discuss the implications of such interactions for nurse satisfaction, patient safety, and a healthy work environment. PMID- 28814579 TI - Hepatosplenic schistosomiasis: playing hide-and-seek with an elusive parasite. AB - A 27-year-old man of Eritrean origin presented with persistent left-sided abdominal pain. Initial investigation showed signs of liver fibrosis, portal hypertension and splenomegaly. A diagnosis of hepatosplenic schistosomiasis was suspected on grounds of elevated total IgE, grey area antischistosomiasis antibodies and the high endemic status of his native country. However, repeated microscopy of faecal and urine samples, as well as rectal biopsies, failed to demonstrate schistosomal eggs. Finally, the diagnosis of hepatosplenic schistosomiasis was established through demonstration of a Schistosoma mansoni egg in a liver biopsy taken in an attempt to clarify the cause of the above findings. The patient had recently been treated for uncomplicated malaria. Lowered schistosomiasis worm/egg burden and hence reduced sensitivity of classic microscopy-based schistosomiasis testing was attributed to the antischistosomal activity of the antimalarial chemotherapy. PMID- 28814578 TI - Genetic human prion disease modelled in PrP transgenic Drosophila. AB - Inherited human prion diseases, such as fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD), are associated with autosomal dominant mutations in the human prion protein gene PRNP and accumulation of PrPSc, an abnormal isomer of the normal host protein PrPC, in the brain of affected individuals. PrPSc is the principal component of the transmissible neurotoxic prion agent. It is important to identify molecular pathways and cellular processes that regulate prion formation and prion-induced neurotoxicity. This will allow identification of possible therapeutic interventions for individuals with, or at risk from, genetic human prion disease. Increasingly, Drosophila has been used to model human neurodegenerative disease. An important unanswered question is whether genetic prion disease with concomitant spontaneous prion formation can be modelled in Drosophila We have used pUAST/PhiC31-mediated site directed mutagenesis to generate Drosophila transgenic for murine or hamster PrP (prion protein) that carry single-codon mutations associated with genetic human prion disease. Mouse or hamster PrP harbouring an FFI (D178N) or fCJD (E200K) mutation showed mild Proteinase K resistance when expressed in Drosophila Adult Drosophila transgenic for FFI or fCJD variants of mouse or hamster PrP displayed a spontaneous decline in locomotor ability that increased in severity as the flies aged. Significantly, this mutant PrP-mediated neurotoxic fly phenotype was transferable to recipient Drosophila that expressed the wild-type form of the transgene. Collectively, our novel data are indicative of the spontaneous formation of a PrP-dependent neurotoxic phenotype in FFI- or CJD-PrP transgenic Drosophila and show that inherited human prion disease can be modelled in this invertebrate host. PMID- 28814580 TI - Ventrain: from theory to practice. Bridging until re-tracheostomy. AB - Imminent upper airway obstruction due to life-threatening tracheal stenosis of any cause is challenging. A 77-year-old woman, with a history of temporal tracheostomy for prolonged mechanical ventilation, presented with life threatening tracheal stenosis to the emergency department. After failed intubation with a 5.0 mm internal diameter endotracheal tube, the patient was ventilated via a tube exchanger using Ventrain. Ventrain is a manual ventilation device that, in addition to oxygen supply during inspiration, initiates expiration by actively removing gas from the lungs by suction. Despite the nearly obstructed airway the patient was adequately ventilated with 'permissive' hypercarbia of 50 mm Hg and Saturation of peripheral Oxygen (SpO2) 95%-98% until surgical re-tracheostomy was performed. The haemodynamic stability of the patient indicated that the active expiration prevented intrapulmonary pressure build-up by air trapping and subsequent barotrauma and/or haemodynamic deterioration, which may well be observed during traditional jet ventilation especially in case of a completely obstructed airway. PMID- 28814581 TI - Hyperammonaemic encephalopathy following an uncomplicated surgery. AB - A 59-year-old woman who underwent an uncomplicated exploratory laparotomy, adhesiolysis, small bowel resection and anterolateral thigh flap had a complicated postoperative period characterised by wound dehiscence and poor nutritional intake. 29 days postoperatively, a tremor developed in her upper limbs associated with weakness. Her Glasgow Coma Scale (GCS) fell to 4 and she was transferred to the intensive care unit. The patient was reviewed by multiple specialists and multiple differentials were considered and eliminated. Eventually, investigations revealed hyperammonaemic encephalopathy, being a result of low arginine and potentially small intestinal bacterial overgrowth. Following treatment with sodium benzoate, sodium phenylbutyrate and arginine along with haemodialysis and rifaximin, GCS and hyperammonaemia rapidly improved. She was stepped down to surgical high-dependency unit, continued arginine therapy with total parenteral nutrition and percutaneous endoscopic gastrostomy feeds. She was discharged with regular follow-up from surgeons and biochemistry and continues oral arginine therapy. PMID- 28814582 TI - Adrenal myelolipoma(s) as presenting manifestation of subclinical Cushing's disease (eutopic ACTH-dependent Cushing's syndrome). AB - Primary adrenal myelolipomas, relatively rare benign tumours of the adrenal cortex are typically unilateral, hormonally inactive and asymptomatic, hence often diagnosed as 'adrenal incidentaloma'. Bilateral adrenal myelolipomas, in particular, may be associated with underlying endocrinopathies associated with elevated circulating adrenocorticotropic hormone (ACTH) concentration. Subclinical cortisol hypersecretion, irrespective of its ACTH dependency, does not manifest typical clinical phenotype of hypercortisolemia, and thus termed subclinical Cushing's syndrome. In this article, hormonal evaluation in a middle aged woman with diabetes, hypertension and incidentally discovered unilateral adrenal myelolipoma revealed underlying subclinical Cushing's disease. Abdominal CT revealed another tiny focus in the contralateral adrenal gland, probably representing incipient myelolipoma. PMID- 28814583 TI - Does use of point-of-care testing improve cost-effectiveness of the NHS Health Check programme in the primary care setting? A cost-minimisation analysis. AB - OBJECTIVE: To determine if use of point of care testing (POCT) is less costly than laboratory testing to the National Health Service (NHS) in delivering the NHS Health Check (NHSHC) programme in the primary care setting. DESIGN: Observational study and theoretical mathematical model with microcosting approach. SETTING: We collected data on NHSHC delivered at nine general practices (seven using POCT; two not using POCT). PARTICIPANTS: We recruited nine general practices offering NHSHC and a pathology services laboratory in the same area. METHODS: We conducted mathematical modelling with permutations in the following fields: provider type (healthcare assistant or nurse), type of test performed (total cholesterol with either lab fasting glucose or HbA1c), cost of consumables and variable uptake rates, including rate of non-response to invite letter and rate of missed [did not attend (DNA)] appointments. We calculated total expected cost (TEC) per 100 invites, number of NHSHC conducted per 100 invites and costs for completed NHSHC for laboratory and POCT-based pathways. A univariate and probabilistic sensitivity analysis was conducted to account for uncertainty in the input parameters. MAIN OUTCOME MEASURES: We collected data on cost, volume and type of pathology services performed at seven general practices using POCT and a pathology services laboratory. We collected data on response to the NHSHC invitation letter and DNA rates from two general practices. RESULTS: TEC of using POCT to deliver a routine NHSHC is lower than the laboratory-led pathway with savings of L29 per 100 invited patients up the point of cardiovascular disease risk score presentation. Use of POCT can deliver NHSHC in one sitting, whereas the laboratory pathway offers patients several opportunities to DNA appointment. CONCLUSIONS: TEC of using POCT to deliver an NHSHC in the primary care setting is lower than the laboratory-led pathway. Using POCT minimises DNA rates associated with laboratory testing and enables completion of NHSHC in one sitting. PMID- 28814584 TI - Examining self-reported and biological stress and near misses among Emergency Medicine residents: a single-centre cross-sectional assessment in the USA. AB - OBJECTIVES: To examine the relationship between perceived and biological stress and near misses among Emergency Medicine residents. DESIGN: Self-rated stress and stress biomarkers were assessed in residents in Emergency Medicine before and after a day shift. The supervising physicians and residents reported numbers of near misses. SETTING: The study took place in the Emergency Department of a large trauma 1 centre, located in Detroit, USA. PARTICIPANTS: Residents in Emergency Medicine volunteered to participate. The sample consisted of 32 residents, with complete data on 28 subjects. Residents' supervising physicians assessed the clinical performance of each resident. PRIMARY AND SECONDARY OUTCOME MEASURES: Participants' preshift and postshift stress, biological stress (salivary cortisol, plasma interleukin-6, tumour necrosis factor-alpha (TNF-alpha) and high sensitivity C-reactive protein), residents' and supervisors' reports of near misses, number of critically ill and patients with trauma seen during the shift. RESULTS: Residents' self-reported stress increased from an average preshift level of 2.79 of 10 (SD 1.81) to a postshift level of 5.82 (2.13) (p<0.001). Residents cared for an average of 2.32 (1.52) critically ill patients and 0.68 (1.06) patients with trauma. Residents reported a total of 7 near misses, compared with 11 reported by the supervising physicians. After controlling for baseline work related exhaustion, residents that cared for more patients with trauma and had higher levels of TNF-alpha reported a higher frequency of near misses (R2=0.72; p=0.001). Residents' preshift ratings of how stressful they expected the shift to be were related to the supervising physicians' ratings of residents' near misses during the shift. CONCLUSION: Residents' own ratings of near misses were associated with residents' TNF-alpha, a biomarker of systemic inflammation and the number of patients with trauma seen during the shift. In contrast, supervisor reports on residents' near misses were related only to the residents' preshift expectations of how stressful the shift would be. PMID- 28814585 TI - Multiplex Real-Time PCR Assay for Simultaneous Identification of Neisseria gonorrhoeae and Its Ciprofloxacin Susceptibility Status. AB - A real-time PCR (RT-PCR) assay was designed for the simultaneous identification of Neisseria gonorrhoeae and its ciprofloxacin susceptibility status. A SYBR green-based multiplex RT-PCR format was used; it comprised two different forward primers and a common reverse primer to detect single nucleotide polymorphisms (SNPs) in gyrA of N. gonorrhoeae The primer pairs were evaluated for their sensitivity and specificity using genomic DNA from 254 N. gonorrhoeae isolates (82 were ciprofloxacin susceptible and 172 were ciprofloxacin resistant) and 23 non-N. gonorrhoeae species isolates. The performance of the primers was validated using genomic DNA from 100 different N. gonorrhoeae isolates (46 were ciprofloxacin susceptible and 54 were ciprofloxacin resistant) and 52 non-N. gonorrhoeae isolates. The latter panel was revalidated by testing 99 (46 isolates were ciprofloxacin susceptible and 53 isolates were ciprofloxacin resistant) of the N. gonorrhoeae isolates and 23 non-N. gonorrhoeae isolates. These primers detected N. gonorrhoeae and its ciprofloxacin susceptibility status with over 99% sensitivity and specificity for all panels tested. This assay has the potential to be an inexpensive and rapid test for the simultaneous identification of N. gonorrhoeae and its ciprofloxacin susceptibility status. PMID- 28814587 TI - A case of cardiopulmonary arrest due to spontaneous coronary artery dissection in a pregnant woman. AB - We present the case of a young pregnant woman with cardiopulmonary arrest due to acute coronary syndrome. Emergent coronary angiography (CAG) and intravascular ultrasound (IVUS) showed extensive coronary artery dissection in the left anterior descending artery, which was treated with primary percutaneous coronary intervention. After managing the heart failure and disseminated intravascular coagulation, a dead fetus was delivered via caesarean section 4 days after admission to the hospital. Follow-up CAG and IVUS at 18 months showed persistent dissection in the non-stented site; hence, another stent was implanted. Dual antiplatelet therapy was discontinued 6 months later; however, aspirin and beta blockers were continued lifelong. PMID- 28814588 TI - Massive epidermal vulval cyst: an unusual late complication of female genital mutilation. AB - Vulval epidermal cysts are rare and infrequently described in literature. They present a difficult diagnostic dilemma and surgical challenges. They most commonly occur as a late complication of female genital mutilation (FGM) and manifest as a primary condition. We present a case of a large vulval epidermal inclusion cyst, lined by vulval squamous epithelium, in a woman with a background of FGM who was referred with suspected vulval cancer. We discuss the clinical presentation, MRI findings, surgical treatment and outcome. PMID- 28814586 TI - Molecular Diagnosis of Invasive Aspergillosis and Detection of Azole Resistance by a Newly Commercialized PCR Kit. AB - Aspergillus fumigatus is the main species responsible for aspergillosis in humans. The diagnosis of aspergillosis remains difficult, and the rapid emergence of azole resistance in A. fumigatus is worrisome. The aim of this study was to validate the new MycoGENIE A. fumigatus real-time PCR kit and to evaluate its performance on clinical samples for the detection of A. fumigatus and its azole resistance. This multiplex assay detects DNA from the A. fumigatus species complex by targeting the multicopy 28S rRNA gene and specific TR34 and L98H mutations in the single-copy-number cyp51A gene of A. fumigatus The specificity of cyp51A mutation detection was assessed by testing DNA samples from 25 wild type or mutated clinical A. fumigatus isolates. Clinical validation was performed on 88 respiratory samples obtained from 62 patients and on 69 serum samples obtained from 16 patients with proven or probable aspergillosis and 13 patients without aspergillosis. The limit of detection was <1 copy for the Aspergillus 28S rRNA gene and 6 copies for the cyp51A gene harboring the TR34 and L98H alterations. No cross-reactivity was detected with various fungi and bacteria. All isolates harboring the TR34 and L98H mutations were accurately detected by quantitative PCR (qPCR) analysis. With respiratory samples, qPCR results showed a sensitivity and specificity of 92.9% and 90.1%, respectively, while with serum samples, the sensitivity and specificity were 100% and 84.6%, respectively. Our study demonstrated that this new real-time PCR kit enables sensitive and rapid detection of A. fumigatus DNA and azole resistance due to TR34 and L98H mutations in clinical samples. PMID- 28814589 TI - Ureaplasma parvum causing life-threatening disease in a susceptible patient. AB - A 56-year-old man with lymphoma developed orchitis followed by septic arthritis of his right glenohumeral joint. Synovial fluid cultures were negative but PCR amplification test was positive forUreaplasmaparvum. The patient was treated with doxycycline. Two and a half years later, the patient presented with shortness of breath and grade III/IV diastolic murmur on auscultation. Echocardiography revealed severely dilated left heart chambers, severe aortic regurgitation and several mobile masses on the aortic valve cusps suspected to be vegetations. He underwent valve replacement; valve tissue culture was negative but the 16S rRNA gene amplification test was positive for U. parvumHe was treated again with doxycycline. In an outpatient follow-up 1 year and 3 months later, the patient was doing well. Repeated echocardiography showed normal aortic prosthesis function. PMID- 28814590 TI - Congenitally corrected transposition of great arteries. PMID- 28814591 TI - Spleno-renal artery transposition in a solitary functioning kidney for treatment resistant hypertension and acute kidney injury. AB - Renal Artery Stenosis (RAS) is an important cause of treatment-resistant hypertension. Uncontrolled hypertension with RAS can cause progressive chronic kidney disease (CKD) leading to end-stage kidney disease. Therapeutic revascularisation can be helpful in appropriate circumstances where pharmaceutical intervention has failed and significant renovascular disease contributes to resistant hypertension. We present an interesting case of a Caucasian male with peripheral vasculopathy, abdominal aortic aneurysm (AAA), single functioning kidney and ostial RAS caused by stent struts from an endovascular AAA stent graft. He had escalating medications requirement, with repeated failed attempts at percutaneous radiological intervention that led to an episode of contrast-induced acute kidney injury (AKI), before undergoing successful surgical revascularisation by a splenic artery transposition graft to the left renal artery that was performed to improve kidney function and the blood pressure. This report highlights the challenges faced with regard to the management of severe hypertension and progressive CKD. PMID- 28814592 TI - Fever and generalised lymphadenopathy in an HIV-positive patient: a diagnostic challenge. AB - Fever and generalised lymphadenopathy is a common presentation of a variety of diseases and a thorough investigation is often necessary for appropriate diagnosis.We present a 53-year-old male patient admitted with fever, weight loss of 15 kg in 3 months and abdominal discomfort. Examination was only remarkable for axillary and inguinal lymphadenopathy. Blood tests showed normocytic normochromic anaemia, cholestasis and a previously unknown HIV-1 infection with lymphocyte CD4 +count of 239 cells/mm3 and viral load 3.172.370 copies/mL. A body CT scan showed multiple axillary, mediastinal, lumbar, aortic, iliac and pelvic lymphadenopathy as well as hepatosplenomegaly. An excisional biopsy of the left axillary lymphadenopathy was performed and histology ultimately revealed multicentric Castleman's disease associated with Human Herpes Virus-8. After initiation of antiretroviral therapy, rituximab was given and progressive clinical improvement occurred. PMID- 28814593 TI - Unique case of herniated small bowel infarction within a colonic stomal prolapse. AB - The number of permanent colostomies carried out in the United Kingdom is approximately 6400 per year1. Stomal prolapse is a known complication of colostomy formation. We presented the first case of small bowel herniation into a healthy stomal prolapse with subsequent ischaemia of the herniated bowel in a 102 year-old patient. This rare sequela of a relatively common stomal complication highlights an important consideration when faced with a large prolapse presenting acutely. It also raises an important discussion point for the management of our ever-ageing patient population. PMID- 28814594 TI - Concomitant carotid aplasia and basilar artery occlusion in a child with PHACES syndrome. AB - We report a case of an 8-year-old girl with posterior fossa abnormalities, haemangioma, arterial lesions, cardiac abnormalities or coarctation of the aorta and eye abnormalities syndrome with right carotid aplasia and complete basilar occlusion. The patient initially presented at 2.5 weeks of age with a growing right facial haemangioma involving segments 1, 3 and 4. Initial MRI at 2.5 weeks of age revealed an extraconal right orbital haemangioma without posterior fossa abnormalities and MR angiography (MRA) 3 weeks later showed right internal carotid aplasia. A follow-up MRA and cerebral angiography at 8 years of age revealed a complete occlusion of the basilar artery that was not appreciated on previous imaging. Neurological function remains normal, meeting all age appropriate milestones. PMID- 28814595 TI - Bleeding ectopic duodenal varix: use of a new microvascular plug (MVP) device along with transjugular intrahepatic portosystemic shunt (TIPSS). AB - Ectopic varices (ECV) occur along the gastrointestinal (GI) tract outside the common variceal sites and represent 2%-5% of all GI variceal bleeds with mortality rates up to 40%. Management is challenging because of inaccessibility and increased risk of rebleeding. We report what is to our knowledge the first clinical use of a new microvascular plug (MVP) with transjugular intrahepatic portosystemic shunt (TIPSS) for a bleeding duodenal varix (DV). A 68-year-old man presented with melena. Endoscopy demonstrated a grade II varix in the second part of the duodenum with red wale sign. TIPSS was performed and portogram revealed a single DV. Poststent placement venogram revealed a persistent varix and hence a 5 7 mm MVP was deployed. Subsequent imaging showed cessation of blood through the DV. The patient had no further bleeding. TIPSS with embolisation is an effective treatment for ECV. This MVP offers advantages due to its size and compatibility and can be redeployed in case of suboptimal placement. PMID- 28814596 TI - The use of cardiac MRI in a rare case of primary mural endocarditis. PMID- 28814597 TI - Hydropneumothorax as an iatrogenic complication after nasogastric intubation. PMID- 28814598 TI - Migration of a Kirschner wire into the lung with shoulder dislocation. PMID- 28814599 TI - Total alimentary canal necrosis: infarction from oesophagus to anus. PMID- 28814600 TI - Fungating groin mass in a woman with a history of follicular lymphoma. PMID- 28814601 TI - IL-15 Complexes Induce Migration of Resting Memory CD8 T Cells into Mucosal Tissues. AB - IL-15 is an essential cytokine known to promote T cell survival and activate the effector function of memory phenotype CD8 T cells. Blocking IL-15 signals also significantly impacts tissue-specific effector and memory CD8 T cell formation. In this study, we demonstrate that IL-15 influences the generation of memory CD8 T cells by first promoting their accumulation into mucosal tissues and second by sustaining expression of Bcl-6 and T-bet. We show that the mechanism for this recruitment is largely dependent on mammalian target of rapamycin and its subsequent inactivation of FoxO1. Last, we show that IL-15 complexes delivered locally to mucosal tissues without reinfection is an effective strategy to enhance establishment of tissue resident memory CD8 T cells within mucosal tissues. This study provides mechanistic insight into how IL-15 controls the generation of memory CD8 T cells and influences their trafficking and ability to take up residence within peripheral tissues. PMID- 28814602 TI - Carbon Nanoparticles Inhibit the Antimicrobial Activities of the Human Cathelicidin LL-37 through Structural Alteration. AB - Host defense peptides, also known as antimicrobial peptides, are key elements of innate host defense. One host defense peptide with well-characterized antimicrobial activity is the human cathelicidin, LL-37. LL-37 has been shown to be upregulated at sites of infection and inflammation and is regarded as one of the primary innate defense molecules against bacterial and viral infection. Human exposure to combustion-derived or engineered nanoparticles is of increasing concern, and the implications of nanomaterial exposure on the human immune response is poorly understood. However, it is widely acknowledged that nanoparticles can interact strongly with several immune proteins of biological significance, with these interactions resulting in structural and functional changes of the proteins involved. This study investigated whether the potent antibacterial and antiviral functions of LL-37 were inhibited by exposure to, and interaction with, carbon nanoparticles, together with characterizing the nature of the interaction. LL-37 was exposed to carbon black nanoparticles in vitro, and the antibacterial and antiviral functions of the peptide were subsequently assessed. We demonstrate a substantial loss of antimicrobial function when the peptide was exposed to low concentrations of nanomaterials, and we further show that the nanomaterial-peptide interaction resulted in a significant change in the structure of the peptide. The human health implications of these findings are significant, as, to our knowledge, this is the first evidence that nanoparticles can alter host defense peptide structure and function, indicating a new role for nanoparticle exposure in increased disease susceptibility. PMID- 28814603 TI - Single Nucleotide Polymorphisms of the High Affinity IgG Receptor FcgammaRI Reduce Immune Complex Binding and Downstream Effector Functions. AB - Binding of IgG Abs to FcgammaRs on immune cells induces FcgammaR cross-linking that leads to cellular effector functions, such as phagocytosis, Ab-dependent cellular cytotoxicity, and cytokine release. However, polymorphisms in low affinity FcgammaRs have been associated with altered avidity toward IgG, thereby substantially impacting clinical outcomes of multimodular therapy when targeting cancer or autoimmune diseases with mAbs as well as the frequency and severity of autoimmune diseases. In this context, we investigated the consequences of three nonsynonymous single nucleotide polymorphisms (SNPs) for the high affinity receptor for IgG, FcgammaRI. Only SNP V39I, located in the extracellular domain of FcgammaRI, reduces immune-complex binding of FcgammaRI whereas monomeric IgG binding is unaffected. This leads to reduced FcgammaRI effector functions, including Fc receptor gamma-chain signaling and intracellular calcium mobilization. SNPs I301M and I338T, located in the transmembrane or intracellular domain, respectively, have no influence on monomeric IgG or immune complex binding, but FcRgamma signaling is decreased for both SNPs, especially for I338T. We also found that the frequency of these SNPs in a cohort of healthy Dutch individuals is very low within the population. To our knowledge, this study addresses for the first time the biological consequences of SNPs in the high affinity FcgammaR, and reveals reduction in several FcgammaRI functions, which have the potential to alter efficacy of therapeutic Abs. PMID- 28814604 TI - Macrophage-Restricted Shp2 Tyrosine Phosphatase Acts as a Rheostat for MMP12 through TGF-beta Activation in the Prevention of Age-Related Emphysema in Mice. AB - Persistent activation of macrophages in lungs plays a critical role in the production of matrix metalloproteinases (MMPs) that contributes to the destruction of alveolar walls, a hallmark for pulmonary emphysema. Dysregulated TGF-beta1 signaling has been an essential determinant in the elevation of MMPs during the development of emphysema. Nevertheless, the mechanism for this MMP dependent pathogenesis has yet to be clearly investigated. Recently, we identified an important role for tyrosine phosphatase Src homology domain containing protein tyrosine phosphatase 2 (Shp2) in regulating the activation of alveolar macrophages. Over a long-term observation period, mice with Shp2 deletion in macrophages (LysMCre:Shp2fl/fl ) develop spontaneous, progressive emphysema-like injury in the lungs, characterized by massive destruction of alveolar morphology, interstitial extracellular matrix degradation, and elevated levels of MMPs, particularly, significant increases of macrophage elastase (MMP12) in aged mice. Further analysis demonstrated that MMP12 suppression by TGF beta1 activation was apparently abrogated in LysMCre:Shp2fl/fl mice, whereas the TGF-beta1 concentration in the lungs was relatively the same. Mechanistically, we found that loss of Shp2 resulted in attenuated SMAD2/3 phosphorylation and nuclear translocation in response to TGF-beta activation, thereby upregulating MMP12 expression in macrophages. Together, our findings define a novel physiological function of Shp2 in TGF-beta1/MMP12-dependent emphysema, adding insights into potential etiologies for this chronic lung disorder. PMID- 28814606 TI - Their loss is our gain: regressive evolution in vertebrates provides genomic models for uncovering human disease loci. AB - Throughout Earth's history, evolution's numerous natural 'experiments' have resulted in a diverse range of phenotypes. Though de novo phenotypes receive widespread attention, degeneration of traits inherited from an ancestor is a very common, yet frequently neglected, evolutionary path. The latter phenomenon, known as regressive evolution, often results in vertebrates with phenotypes that mimic inherited disease states in humans. Regressive evolution of anatomical and/or physiological traits is typically accompanied by inactivating mutations underlying these traits, which frequently occur at loci identical to those implicated in human diseases. Here we discuss the potential utility of examining the genomes of vertebrates that have experienced regressive evolution to inform human medical genetics. This approach is low cost and high throughput, giving it the potential to rapidly improve knowledge of disease genetics. We discuss two well-described examples, rod monochromacy (congenital achromatopsia) and amelogenesis imperfecta, to demonstrate the utility of this approach, and then suggest methods to equip non-experts with the ability to corroborate candidate genes and uncover new disease loci. PMID- 28814607 TI - Early career researchers: an interview with Graham Scott. AB - Graham Scott is an Assistant Professor at McMaster University, Canada, where he studies the integrative biology of how animals cope in challenging environments. He received his Bachelor's degree in biology before completing a Master's degree with Trish Schulte and then a PhD in 2009 with Bill Milsom at the University of British Columbia, Canada. He moved on to continue his postdoc training with Ian Johnston at the University of St Andrews, UK. Scott received the Animal Section Presidents' Medal from the Society for Experimental Biology in 2012, he was an author on the Journal of Zoology Paper of the Year in 2015 and he was awarded the Robert G. Boutilier New Investigator Award by the Canadian Society of Zoologists in 2017. PMID- 28814605 TI - ADAM10-Mediated ICOS Ligand Shedding on B Cells Is Necessary for Proper T Cell ICOS Regulation and T Follicular Helper Responses. AB - The proper regulation of ICOS and ICOS ligand (ICOSL) has been shown to be essential for maintaining proper immune homeostasis. Loss of either protein results in defective humoral immunity, and overexpression of ICOS results in aberrant Ab production resembling lupus. How ICOSL is regulated in response to ICOS interaction is still unclear. We demonstrate that a disintegrin and metalloproteinase (ADAM)10 is the primary physiological sheddase of ICOSL in mice and humans. Using an in vivo system in which ADAM10 is deleted only on B cells, elevated levels of ICOSL were seen. This increase is also seen when ADAM10 is deleted from human B cell lines. Identification of the primary sheddase has allowed the characterization of a novel mechanism of ICOS regulation. In wild type mice, interaction of ICOS/ICOSL results in ADAM10-induced shedding of ICOSL on B cells and moderate ICOS internalization on T cells. When this shedding is blocked, excessive ICOS internalization occurs. This results in severe defects in T follicular helper development and TH2 polarization, as seen in a house dust mite exposure model. In addition, enhanced TH1 and TH17 immune responses are seen in experimental autoimmune encephalomyelitis. Blockade of ICOSL rescues T cell ICOS surface expression and rescues, at least in part, T follicular helper numbers and the abnormal Ab production previously reported in these mice. Overall, we propose a novel regulation of the ICOS/ICOSL axis, with ADAM10 playing a direct role in regulating ICOSL, as well as indirectly regulating ICOS, thus controlling ICOS/ICOSL-dependent responses. PMID- 28814608 TI - Parasite-altered feeding behavior in insects: integrating functional and mechanistic research frontiers. AB - Research on parasite-altered feeding behavior in insects is contributing to an emerging literature that considers possible adaptive consequences of altered feeding behavior for the host or the parasite. Several recent ecoimmunological studies show that insects can adaptively alter their foraging behavior in response to parasitism. Another body of recent work shows that infection by parasites can change the behavior of insect hosts to benefit the parasite; manipulations of host feeding behavior may be part of this phenomenon. Here, we address both the functional and the underlying physiological frontiers of parasite-altered feeding behavior in order to spur research that better integrates the two. Functional categories of parasite-altered behavior that are adaptive for the host include prophylaxis, therapy and compensation, while host manipulation is adaptive for the parasite. To better understand and distinguish prophylaxis, therapy and compensation, further study of physiological feedbacks affecting host sensory systems is especially needed. For host manipulation in particular, research on mechanisms by which parasites control host feedbacks will be important to integrate with functional approaches. We see this integration as critical to advancing the field of parasite-altered feeding behavior, which may be common in insects and consequential for human and environmental health. PMID- 28814609 TI - Tail regeneration and other phenomena of wound healing and tissue restoration in lizards. AB - Wound healing is a fundamental evolutionary adaptation with two possible outcomes: scar formation or reparative regeneration. Scars participate in re forming the barrier with the external environment and restoring homeostasis to injured tissues, but are well understood to represent dysfunctional replacements. In contrast, reparative regeneration is a tissue-specific program that near perfectly replicates that which was lost or damaged. Although regeneration is best known from salamanders (including newts and axolotls) and zebrafish, it is unexpectedly widespread among vertebrates. For example, mice and humans can replace their digit tips, while many lizards can spontaneously regenerate almost their entire tail. Whereas the phenomenon of lizard tail regeneration has long been recognized, many details of this process remain poorly understood. All of this is beginning to change. This Review provides a comparative perspective on mechanisms of wound healing and regeneration, with a focus on lizards as an emerging model. Not only are lizards able to regrow cartilage and the spinal cord following tail loss, some species can also regenerate tissues after full thickness skin wounds to the body, transections of the optic nerve and even lesions to parts of the brain. Current investigations are advancing our understanding of the biological requirements for successful tissue and organ repair, with obvious implications for biomedical sciences and regenerative medicine. PMID- 28814610 TI - Determining the behavioural dose-response relationship of marine mammals to air gun noise and source proximity. AB - The effect of various anthropogenic sources of noise (e.g. sonar, seismic surveys) on the behaviour of marine mammals is sometimes quantified as a dose response relationship, where the probability of an animal behaviourally 'responding' (e.g. avoiding the source) increases with 'dose' (or received level of noise). To do this, however, requires a definition of a 'significant' response (avoidance), which can be difficult to quantify. There is also the potential that the animal 'avoids' not only the source of noise but also the vessel operating the source, complicating the relationship. The proximity of the source is an important variable to consider in the response, yet difficult to account for given that received level and proximity are highly correlated. This study used the behavioural response of humpback whales to noise from two different air gun arrays (20 and 140 cubic inch air gun array) to determine whether a dose-response relationship existed. To do this, a measure of avoidance of the source was developed, and the magnitude (rather than probability) of this response was tested against dose. The proximity to the source, and the vessel itself, was included within the one-analysis model. Humpback whales were more likely to avoid the air gun arrays (but not the controls) within 3 km of the source at levels over 140 re. 1 uPa2 s-1, meaning that both the proximity and the received level were important factors and the relationship between dose (received level) and response is not a simple one. PMID- 28814611 TI - Homing pigeons (Columba livia) modulate wingbeat characteristics as a function of route familiarity. AB - Mechanisms of avian navigation have received considerable attention, but whether different navigational strategies are accompanied by different flight characteristics is unknown. Managing energy expenditure is critical for survival; therefore, understanding how flight characteristics, and hence energy allocation, potentially change with birds' familiarity with a navigational task could provide key insights into the costs of orientation. We addressed this question by examining changes in the wingbeat characteristics and airspeed of homing pigeons (Columba livia) as they learned a homing task. Twenty-one pigeons were released 20 times individually either 3.85 or 7.06 km from home. Birds were equipped with 5 Hz GPS trackers and 200 Hz tri-axial accelerometers. We found that, as the birds' route efficiency increased during the first six releases, their median peak-to-peak dorsal body (DB) acceleration and median DB amplitude also increased. This, in turn, led to higher airspeeds, suggesting that birds fly slower when traversing unfamiliar terrain. By contrast, after route efficiency stabilised, birds exhibited increasing wingbeat frequencies, which did not result in further increases in speed. Overall, higher wind support was also associated with lower wingbeat frequencies and increased DB amplitude. Our study suggests that the cost of early flights from an unfamiliar location may be higher than subsequent flights because of both inefficient routes (increased distance) and lower airspeeds (increased time). Furthermore, the results indicate, for the first time, that birds modulate their wingbeat characteristics as a function of navigational knowledge, and suggest that flight characteristics may be used as 'signatures' of birds' route familiarity. PMID- 28814612 TI - Effects of a social cue on reproductive development and pre-alternate molt in seasonally breeding migrant and resident female songbirds (Zonotrichia leucophrys). AB - To time reproduction optimally, birds have evolved diverse mechanisms by which they respond to environmental changes that help them anticipate and prepare for the breeding season. While residents initiate reproductive preparation and breed in the same geographic location, migrant birds simultaneously prepare for breeding and migration far from their breeding grounds. As a result, it is hypothesized that migrant and resident birds use environmental cues differently to prepare to breed and that there is adaptive specialization in mechanisms regulating reproductive preparation. Specifically, residents are expected to rely more on non-photic cues (e.g. food, temperature, social cues) than migrants. We tested this general prediction using a social cue manipulation. First, we compared the effects of subspecies-appropriate recorded male song on reproductive development in migrants and residents on a naturally increasing photoperiod. Second, we tested the sensitivity of migrant-specific life history events (fattening and pre-alternate molt) to song treatment. After 82 days, residents had higher luteinizing hormone and greater ovarian development than migrants, but song treatment had no effect on these metrics in either subspecies. Song advanced pre-alternate molt but had no effect on fattening in migrants. While our study does not support specialization in social cue use in migrants and residents, it is consistent with findings in the literature of specialization in photoperiodic response. It also demonstrates for the first time that social cues can influence molt in a migrant species. Additional findings from a pilot study looking at responses to a live male suggest it is important to test other kinds of social cues. PMID- 28814613 TI - Osteoimmunology: The Conceptual Framework Unifying the Immune and Skeletal Systems. AB - The immune and skeletal systems share a variety of molecules, including cytokines, chemokines, hormones, receptors, and transcription factors. Bone cells interact with immune cells under physiological and pathological conditions. Osteoimmunology was created as a new interdisciplinary field in large part to highlight the shared molecules and reciprocal interactions between the two systems in both heath and disease. Receptor activator of NF-kappaB ligand (RANKL) plays an essential role not only in the development of immune organs and bones, but also in autoimmune diseases affecting bone, thus effectively comprising the molecule that links the two systems. Here we review the function, gene regulation, and signal transduction of osteoimmune molecules, including RANKL, in the context of osteoclastogenesis as well as multiple other regulatory functions. Osteoimmunology has become indispensable for understanding the pathogenesis of a number of diseases such as rheumatoid arthritis (RA). We review the various osteoimmune pathologies, including the bone destruction in RA, in which pathogenic helper T cell subsets [such as IL-17-expressing helper T (Th17) cells] induce bone erosion through aberrant RANKL expression. We also focus on cellular interactions and the identification of the communication factors in the bone marrow, discussing the contribution of bone cells to the maintenance and regulation of hematopoietic stem and progenitors cells. Thus the time has come for a basic reappraisal of the framework for understanding both the immune and bone systems. The concept of a unified osteoimmune system will be absolutely indispensable for basic and translational approaches to diseases related to bone and/or the immune system. PMID- 28814614 TI - Role of Inactivity in Chronic Diseases: Evolutionary Insight and Pathophysiological Mechanisms. AB - This review proposes that physical inactivity could be considered a behavior selected by evolution for resting, and also selected to be reinforcing in life threatening situations in which exercise would be dangerous. Underlying the notion are human twin studies and animal selective breeding studies, both of which provide indirect evidence for the existence of genes for physical inactivity. Approximately 86% of the 325 million in the United States (U.S.) population achieve less than the U.S. Government and World Health Organization guidelines for daily physical activity for health. Although underappreciated, physical inactivity is an actual contributing cause to at least 35 unhealthy conditions, including the majority of the 10 leading causes of death in the U.S. First, we introduce nine physical inactivity-related themes. Next, characteristics and models of physical inactivity are presented. Following next are individual examples of phenotypes, organ systems, and diseases that are impacted by physical inactivity, including behavior, central nervous system, cardiorespiratory fitness, metabolism, adipose tissue, skeletal muscle, bone, immunity, digestion, and cancer. Importantly, physical inactivity, itself, often plays an independent role as a direct cause of speeding the losses of cardiovascular and strength fitness, shortening of healthspan, and lowering of the age for the onset of the first chronic disease, which in turn decreases quality of life, increases health care costs, and accelerates mortality risk. PMID- 28814629 TI - Modular tissue engineering for the vascularization of subcutaneously transplanted pancreatic islets. AB - : The transplantation of pancreatic islets, following the Edmonton Protocol, is a promising treatment for type I diabetics. However, the need for multiple donors to achieve insulin independence reflects the large loss of islets that occurs when islets are infused into the portal vein. Finding a less hostile transplantation site that is both minimally invasive and able to support a large transplant volume is necessary to advance this approach. Although the s.c. site satisfies both these criteria, the site is poorly vascularized, precluding its utility. To address this problem, we demonstrate that modular tissue engineering results in an s.c. vascularized bed that enables the transplantation of pancreatic islets. In streptozotocin-induced diabetic SCID/beige mice, the injection of 750 rat islet equivalents embedded in endothelialized collagen modules was sufficient to restore and maintain normoglycemia for 21 days; the same number of free islets was unable to affect glucose levels. Furthermore, using CLARITY, we showed that embedded islets became revascularized and integrated with the host's vasculature, a feature not seen in other s.c. STUDIES: Collagen-embedded islets drove a small (albeit not significant) shift toward a proangiogenic CD206+MHCII-(M2-like) macrophage response, which was a feature of module-associated vascularization. While these results open the potential for using s.c. islet delivery as a treatment option for type I diabetes, the more immediate benefit may be for the exploration of revascularized islet biology. PMID- 28814615 TI - Single-cell gene expression of the bovine blastocyst. AB - The first two differentiation events in the embryo result in three cell types - epiblast, trophectoderm (TE) and hypoblast. The purpose here was to identify molecular markers for each cell type in the bovine and evaluate the differences in gene expression among individual cells of each lineage. The cDNA from 67 individual cells of dissociated blastocysts was used to determine transcript abundance for 93 genes implicated as cell lineage markers in other species or potentially involved in developmental processes. Clustering analysis indicated that the cells belonged to two major populations (clades A and B) with two subpopulations of clade A and four of clade B. Use of lineage-specific markers from other species indicated that the two subpopulations of clade A represented epiblast and hypoblast respectively while the four subpopulations of clade B were TE. Among the genes upregulated in epiblast were AJAP1, DNMT3A, FGF4, H2AFZ, KDM2B, NANOG, POU5F1, SAV1 and SLIT2 Genes overexpressed in hypoblast included ALPL, FGFR2, FN1, GATA6, GJA1, HDAC1, MBNL3, PDGFRA and SOX17, while genes overexpressed in all four TE populations were ACTA2, CDX2, CYP11A1, GATA2, GATA3, IFNT, KRT8, RAC1 and SFN The subpopulations of TE varied among each other for multiple genes including the prototypical TE marker IFNT. New markers for each cell type in the bovine blastocyst were identified. Results also indicate heterogeneity in gene expression among TE cells. Further studies are needed to confirm whether subpopulations of TE cells represent different stages in the development of a committed TE phenotype. PMID- 28814630 TI - Inverted-region electron transfer as a mechanism for enhancing photosynthetic solar energy conversion efficiency. AB - In all photosynthetic organisms, light energy is used to drive electrons from a donor chlorophyll species via a series of acceptors across a biological membrane. These light-induced electron-transfer processes display a remarkably high quantum efficiency, indicating a near-complete inhibition of unproductive charge recombination reactions. It has been suggested that unproductive charge recombination could be inhibited if the reaction occurs in the so-called inverted region. However, inverted-region electron transfer has never been demonstrated in any native photosynthetic system. Here we demonstrate that the unproductive charge recombination in native photosystem I photosynthetic reaction centers does occur in the inverted region, at both room and cryogenic temperatures. Computational modeling of light-induced electron-transfer processes in photosystem I demonstrate a marked decrease in photosynthetic quantum efficiency, from 98% to below 72%, if the unproductive charge recombination process does not occur in the inverted region. Inverted-region electron transfer is therefore demonstrated to be an important mechanism contributing to efficient solar energy conversion in photosystem I. Inverted-region electron transfer does not appear to be an important mechanism in other photosystems; it is likely because of the highly reducing nature of photosystem I, and the energetic requirements placed on the pigments to operate in such a regime, that the inverted-region electron transfer mechanism becomes important. PMID- 28814631 TI - Face percept formation in human ventral temporal cortex. AB - Loci in ventral temporal cortex are selectively active during viewing of faces and other objects, but it remains unclear whether these areas represent accumulation of simple visual information or processing of intact percept. We measured broadband electrocorticographic changes from implanted electrodes on the ventral temporal brain surface while showing patients noise-degraded images of faces and houses. In a subset of posterior fusiform gyrus face-selective regions, cortical activity decreased parametrically with noise increase, until the perceptual threshold was surpassed. At noise levels higher than the perceptual threshold, and for house stimuli, activity remained at baseline. We propose that this convergence of proportional and thresholded response may identify active areas where face percepts are extracted from simple visual features. These loci exist within a topological structure of face percept formation in the human ventral visual stream, preceded by category-nonselective activity in pericalcarine early visual areas and in concert with all-or-nothing activity in postperceptual subregions of the ventral temporal lobe. This topological organization suggests a physiological basis for the anatomy of face perception, explaining different perceptual deficits following temporal lobe injury.NEW & NOTEWORTHY Philosophers have puzzled for millennia about how humans build abstract conceptual objects (house/face/tool) from the simple features of the world they see around them (line/patch/lighting). Understanding the biological foundation of this process requires detailed knowledge of the spatial-temporal characteristics of cerebral cortex. By examining the physiology of the human temporal lobe via implanted electrodes while showing subjects noise-degraded images, we find that face percept formation happens in specific subregions within known face-processing areas. PMID- 28814632 TI - Intermittent apnea elicits inactivity-induced phrenic motor facilitation via a retinoic acid- and protein synthesis-dependent pathway. AB - Respiratory motoneuron pools must provide rhythmic inspiratory drive that is robust and reliable, yet dynamic enough to respond to respiratory challenges. One form of plasticity that is hypothesized to contribute to motor output stability by sensing and responding to inadequate respiratory neural activity is inactivity induced phrenic motor facilitation (iPMF), an increase in inspiratory output triggered by a reduction in phrenic synaptic inputs. Evidence suggests that mechanisms giving rise to iPMF differ depending on the pattern of reduced respiratory neural activity (i.e., neural apnea). A prolonged neural apnea elicits iPMF via a spinal TNF-alpha-induced increase in atypical PKC activity, but little is known regarding mechanisms that elicit iPMF following intermittent neural apnea. We tested the hypothesis that iPMF triggered by intermittent neural apnea requires retinoic acid and protein synthesis. Phrenic nerve activity was recorded in urethane-anesthetized and -ventilated rats treated intrathecally with an inhibitor of retinoic acid synthesis (4-diethlyaminobenzaldehyde, DEAB), a protein synthesis inhibitor (emetine), or vehicle (artificial cerebrospinal fluid) before intermittent (5 episodes, ~1.25 min each) or prolonged (30 min) neural apnea. Both DEAB and emetine abolished iPMF elicited by intermittent neural apnea but had no effect on iPMF elicited by a prolonged neural apnea. Thus different patterns of reduced respiratory neural activity elicit phenotypically similar iPMF via distinct spinal mechanisms. Understanding mechanisms that allow respiratory motoneurons to dynamically tune their output may have important implications in the context of respiratory control disorders that involve varied patterns of reduced respiratory neural activity, such as central sleep apnea and spinal cord injury.NEW & NOTEWORTHY We identify spinal retinoic acid and protein synthesis as critical components in the cellular cascade whereby repetitive reductions in respiratory neural activity elicit rebound increases in phrenic inspiratory activity. PMID- 28814633 TI - Variance in exposed perturbations impairs retention of visuomotor adaptation. AB - Sensorimotor control requires an accurate estimate of the state of the body. The brain optimizes state estimation by combining sensory signals with predictions of the sensory consequences of motor commands using a forward model. Given that both sensory signals and predictions are uncertain (i.e., noisy), the brain optimally weights the relative reliance on each source of information during adaptation. In support, it is known that uncertainty in the sensory predictions influences the rate and generalization of visuomotor adaptation. We investigated whether uncertainty in the sensory predictions affects the retention of a new visuomotor relationship. This was done by exposing three separate groups to a visuomotor rotation whose mean was common at 15 degrees counterclockwise but whose variance around the mean differed (i.e., SD of 0 degrees , 3.2 degrees , or 4.5 degrees ). Retention was assessed by measuring the persistence of the adapted behavior in a no-vision phase. Results revealed that mean reach direction late in adaptation was similar across groups, suggesting it depended mainly on the mean of exposed rotations and was robust to differences in variance. However, retention differed across groups, with higher levels of variance being associated with a more rapid reversion toward nonadapted behavior. A control experiment ruled out the possibility that differences in retention were accounted for by differences in success rates. Exposure to variable rotations may have increased the uncertainty in sensory predictions, making the adapted forward model more labile and susceptible to change or decay.NEW & NOTEWORTHY The brain predicts the sensory consequences of motor commands through a forward model. These predictions are subject to uncertainty. We use visuomotor adaptation and modulate uncertainty in the sensory predictions by manipulating the variance in exposed rotations. Results reveal that variance does not influence the final extent of adaptation but selectively impairs the retention of motor memories. These results suggest that a more uncertain forward model is more susceptible to change or decay. PMID- 28814635 TI - Perception of the dynamic visual vertical during sinusoidal linear motion. AB - The vestibular system provides information for spatial orientation. However, this information is ambiguous: because the otoliths sense the gravitoinertial force, they cannot distinguish gravitational and inertial components. As a consequence, prolonged linear acceleration of the head can be interpreted as tilt, referred to as the somatogravic effect. Previous modeling work suggests that the brain disambiguates the otolith signal according to the rules of Bayesian inference, combining noisy canal cues with the a priori assumption that prolonged linear accelerations are unlikely. Within this modeling framework the noise of the vestibular signals affects the dynamic characteristics of the tilt percept during linear whole-body motion. To test this prediction, we devised a novel paradigm to psychometrically characterize the dynamic visual vertical-as a proxy for the tilt percept-during passive sinusoidal linear motion along the interaural axis (0.33 Hz motion frequency, 1.75 m/s2 peak acceleration, 80 cm displacement). While subjects (n=10) kept fixation on a central body-fixed light, a line was briefly flashed (5 ms) at different phases of the motion, the orientation of which had to be judged relative to gravity. Consistent with the model's prediction, subjects showed a phase-dependent modulation of the dynamic visual vertical, with a subject-specific phase shift with respect to the imposed acceleration signal. The magnitude of this modulation was smaller than predicted, suggesting a contribution of nonvestibular signals to the dynamic visual vertical. Despite their dampening effect, our findings may point to a link between the noise components in the vestibular system and the characteristics of dynamic visual vertical.NEW & NOTEWORTHY A fundamental question in neuroscience is how the brain processes vestibular signals to infer the orientation of the body and objects in space. We show that, under sinusoidal linear motion, systematic error patterns appear in the disambiguation of linear acceleration and spatial orientation. We discuss the dynamics of these illusory percepts in terms of a dynamic Bayesian model that combines uncertainty in the vestibular signals with priors based on the natural statistics of head motion. PMID- 28814634 TI - State-dependent sensorimotor gating in a rhythmic motor system. AB - Sensory feedback influences motor circuits and/or their projection neuron inputs to adjust ongoing motor activity, but its efficacy varies. Currently, less is known about regulation of sensory feedback onto projection neurons that control downstream motor circuits than about sensory regulation of the motor circuit neurons themselves. In this study, we tested whether sensory feedback onto projection neurons is sensitive only to activation of a motor system, or also to the modulatory state underlying that activation, using the crab Cancer borealis stomatogastric nervous system. We examined how proprioceptor neurons (gastropyloric receptors, GPRs) influence the gastric mill (chewing) circuit neurons and the projection neurons (MCN1, CPN2) that drive the gastric mill rhythm. During gastric mill rhythms triggered by the mechanosensory ventral cardiac neurons (VCNs), GPR was shown previously to influence gastric mill circuit neurons, but its excitation of MCN1/CPN2 was absent. In this study, we tested whether GPR effects on MCN1/CPN2 are also absent during gastric mill rhythms triggered by the peptidergic postoesophageal commissure (POC) neurons. The VCN and POC pathways both trigger lasting MCN1/CPN2 activation, but their distinct influence on circuit feedback to these neurons produces different gastric mill motor patterns. We show that GPR excites MCN1 and CPN2 during the POC-gastric mill rhythm, altering their firing rates and activity patterns. This action changes both phases of the POC-gastric mill rhythm, whereas GPR only alters one phase of the VCN-gastric mill rhythm. Thus sensory feedback to projection neurons can be gated as a function of the modulatory state of an active motor system, not simply switched on/off with the onset of motor activity.NEW & NOTEWORTHY Sensory feedback influences motor systems (i.e., motor circuits and their projection neuron inputs). However, whether regulation of sensory feedback to these projection neurons is consistent across different versions of the same motor pattern driven by the same motor system was not known. We found that gating of sensory feedback to projection neurons is determined by the modulatory state of the motor system, and not simply by whether the system is active or inactive. PMID- 28814636 TI - Muscle proprioceptors in adult rat: mechanosensory signaling and synapse distribution in spinal cord. AB - The characteristic signaling and intraspinal projections of muscle proprioceptors best described in the cat are often generalized across mammalian species. However, species-dependent adaptations within this system seem necessary to accommodate asymmetric scaling of length, velocity, and force information required by the physics of movement. In the present study we report mechanosensory responses and intraspinal destinations of three classes of muscle proprioceptors. Proprioceptors from triceps surae muscles in adult female Wistar rats anesthetized with isoflurane were physiologically classified as muscle spindle group Ia or II or as tendon organ group Ib afferents, studied for their firing responses to passive-muscle stretch, and in some cases labeled and imaged for axon projections and varicosities in spinal segments. Afferent projections and the laminar distributions of provisional synapses in rats closely resembled those found in the cat. Afferent signaling of muscle kinematics was also similar to reports in the cat, but rat Ib afferents fired robustly during passive-muscle stretch and Ia afferents displayed an exaggerated dynamic response, even after locomotor scaling was accounted for. These differences in mechanosensory signaling by muscle proprioceptors may represent adaptations for movement control in different animal species.NEW & NOTEWORTHY Muscle sensory neurons signal information necessary for controlling limb movements. The information encoded and transmitted by muscle proprioceptors to networks in the spinal cord is known in detail only for the cat, but differences in size and behavior of other species challenge the presumed generalizability. This report presents the first findings detailing specializations in mechanosensory signaling and intraspinal targets for functionally identified subtypes of muscle proprioceptors in the rat. PMID- 28814637 TI - Asymmetric vestibular stimulation reveals persistent disruption of motion perception in unilateral vestibular lesions. AB - Self-motion perception was studied in patients with unilateral vestibular lesions (UVL) due to acute vestibular neuritis at 1 wk and 4, 8, and 12 mo after the acute episode. We assessed vestibularly mediated self-motion perception by measuring the error in reproducing the position of a remembered visual target at the end of four cycles of asymmetric whole-body rotation. The oscillatory stimulus consists of a slow (0.09 Hz) and a fast (0.38 Hz) half cycle. A large error was present in UVL patients when the slow half cycle was delivered toward the lesion side, but minimal toward the healthy side. This asymmetry diminished over time, but it remained abnormally large at 12 mo. In contrast, vestibulo ocular reflex responses showed a large direction-dependent error only initially, then they normalized. Normalization also occurred for conventional reflex vestibular measures (caloric tests, subjective visual vertical, and head shaking nystagmus) and for perceptual function during symmetric rotation. Vestibular related handicap, measured with the Dizziness Handicap Inventory (DHI) at 12 mo correlated with self-motion perception asymmetry but not with abnormalities in vestibulo-ocular function. We conclude that 1) a persistent self-motion perceptual bias is revealed by asymmetric rotation in UVLs despite vestibulo ocular function becoming symmetric over time, 2) this dissociation is caused by differential perceptual-reflex adaptation to high- and low-frequency rotations when these are combined as with our asymmetric stimulus, 3) the findings imply differential central compensation for vestibuloperceptual and vestibulo-ocular reflex functions, and 4) self-motion perception disruption may mediate long-term vestibular-related handicap in UVL patients.NEW & NOTEWORTHY A novel vestibular stimulus, combining asymmetric slow and fast sinusoidal half cycles, revealed persistent vestibuloperceptual dysfunction in unilateral vestibular lesion (UVL) patients. The compensation of motion perception after UVL was slower than that of vestibulo-ocular reflex. Perceptual but not vestibulo-ocular reflex deficits correlated with dizziness-related handicap. PMID- 28814638 TI - Field repetition and local mapping in the hippocampus and the medial entorhinal cortex. AB - Hippocampal place cells support spatial cognition and are thought to form the neural substrate of a global "cognitive map." A widely held view is that parts of the hippocampus also underlie the ability to separate patterns or to provide different neural codes for distinct environments. However, a number of studies have shown that in environments composed of multiple, repeating compartments, place cells and other spatially modulated neurons show the same activity in each local area. This repetition of firing fields may reflect pattern completion and may make it difficult for animals to distinguish similar local environments. In this review we 1) highlight some of the navigation difficulties encountered by humans in repetitive environments, 2) summarize literature demonstrating that place and grid cells represent local and not global space, and 3) attempt to explain the origin of these phenomena. We argue that the repetition of firing fields can be a useful tool for understanding the relationship between grid cells in the entorhinal cortex and place cells in the hippocampus, the spatial inputs shared by these cells, and the propagation of spatially related signals through these structures. PMID- 28814639 TI - Deposition and hydrolysis of serine dipeptide lipids of Bacteroidetes bacteria in human arteries: relationship to atherosclerosis. AB - Multiple reaction monitoring-MS analysis of lipid extracts from human carotid endarterectomy and carotid artery samples from young individuals consistently demonstrated the presence of bacterial serine dipeptide lipid classes, including Lipid 654, an agonist for human and mouse Toll-like receptor (TLR)2, and Lipid 430, the deacylated product of Lipid 654. The relative levels of Lipid 654 and Lipid 430 were also determined in common oral and intestinal bacteria from the phylum Bacteroidetes and human serum and brain samples from healthy adults. The median Lipid 430/Lipid 654 ratio observed in carotid endarterectomy samples was significantly higher than the median ratio in lipid extracts of common oral and intestinal Bacteroidetes bacteria, and serum and brain samples from healthy subjects. More importantly, the median Lipid 430/Lipid 654 ratio was significantly elevated in carotid endarterectomies when compared with control artery samples. Our results indicate that deacylation of Lipid 654 to Lipid 430 likely occurs in diseased artery walls due to phospholipase A2 enzyme activity. These results suggest that commensal Bacteriodetes bacteria of the gut and the oral cavity may contribute to the pathogenesis of TLR2-dependent atherosclerosis through serine dipeptide lipid deposition and metabolism in artery walls. PMID- 28814640 TI - Agpat4/Lpaatdelta deficiency highlights the molecular heterogeneity of epididymal and perirenal white adipose depots. AB - Acylglycerophosphate acyltransferase 4 (AGPAT4)/lysophosphatidic acid acyltransferase delta catalyzes the formation of phosphatidic acid (PA), a precursor of triacyl-glycerol (TAG). We investigated the effect of Agpat4 gene ablation on white adipose tissue (WAT) after finding consistent expression across depots. Epididymal WAT mass was 40% larger in male Agpat4-/- mice than wild-type littermates, but unchanged in perirenal, retroperitoneal, and inguinal WAT and subscapular brown adipose tissue. Metabolic changes were identified in epididymal WAT that were not evident in perirenal WAT, which was analyzed for comparison. The total epididymal TAG content doubled, increasing adipocyte cell size without changing markers of differentiation. Enzymes involved in de novo lipogenesis and complex lipid synthesis downstream of phosphatidic acid production were also unchanged. However, total epididymal TAG hydrolase activity was reduced, and there were significant decreases in total ATGL and reduced phosphorylation of hormone-sensitive lipase at the S563 and S660 PKA-activation sites. Analysis of Agpats 1, 2, 3, and 5, as well as Gpats 1, 2, 3, and 4, demonstrated compensatory upregulation in perirenal WAT that did not occur in epididymal WAT. Our findings therefore indicate depot-specific differences in the redundancy of Agpat4 and highlight the molecular and metabolic heterogeneity of individual visceral depots. PMID- 28814641 TI - Ceramide activation of RhoA/Rho kinase impairs actin polymerization during aggregated LDL catabolism. AB - Macrophages use an extracellular, hydrolytic compartment formed by local actin polymerization to digest aggregated LDL (agLDL). Catabolism of agLDL promotes foam cell formation and creates an environment rich in LDL catabolites, including cholesterol and ceramide. Increased ceramide levels are present in lesional LDL, but the effect of ceramide on macrophage proatherogenic processes remains unknown. Here, we show that macrophages accumulate ceramide in atherosclerotic lesions. Using macrophages from sphingosine kinase 2 KO (SK2KO) mice to mimic ceramide-rich conditions of atherosclerotic lesions, we show that SK2KO macrophages display impaired actin polymerization and foam cell formation in response to contact with agLDL. C16-ceramide treatment impaired wild-type but not SK2KO macrophage actin polymerization, confirming that this effect is due to increased ceramide levels. We demonstrate that knockdown of RhoA or inhibition of Rho kinase restores agLDL-induced actin polymerization in SK2KO macrophages. Activation of RhoA in macrophages was sufficient to impair actin polymerization and foam cell formation in response to agLDL. Finally, we establish that during catabolism, macrophages take up ceramide from agLDL, and inhibition of ceramide generation modulates actin polymerization. These findings highlight a critical regulatory pathway by which ceramide impairs actin polymerization through increased RhoA/Rho kinase signaling and regulates foam cell formation. PMID- 28814643 TI - A Genome-Wide Approach to Understanding a Noncanonical ARF. PMID- 28814642 TI - An InDel in the Promoter of Al-ACTIVATED MALATE TRANSPORTER9 Selected during Tomato Domestication Determines Fruit Malate Contents and Aluminum Tolerance. AB - Deciphering the mechanism of malate accumulation in plants would contribute to a greater understanding of plant chemistry, which has implications for improving flavor quality in crop species and enhancing human health benefits. However, the regulation of malate metabolism is poorly understood in crops such as tomato (Solanum lycopersicum). Here, we integrated a metabolite-based genome-wide association study with linkage mapping and gene functional studies to characterize the genetics of malate accumulation in a global collection of tomato accessions with broad genetic diversity. We report that TFM6 (tomato fruit malate 6), which corresponds to Al-ACTIVATED MALATE TRANSPORTER9 (Sl-ALMT9 in tomato), is the major quantitative trait locus responsible for variation in fruit malate accumulation among tomato genotypes. A 3-bp indel in the promoter region of Sl ALMT9 was linked to high fruit malate content. Further analysis indicated that this indel disrupts a W-box binding site in the Sl-ALMT9 promoter, which prevents binding of the WRKY transcription repressor Sl-WRKY42, thereby alleviating the repression of Sl-ALMT9 expression and promoting high fruit malate accumulation. Evolutionary analysis revealed that this highly expressed Sl-ALMT9 allele was selected for during tomato domestication. Furthermore, vacuole membrane-localized Sl-ALMT9 increases in abundance following Al treatment, thereby elevating malate transport and enhancing Al resistance. PMID- 28814644 TI - Subgenome Dominance in an Interspecific Hybrid, Synthetic Allopolyploid, and a 140-Year-Old Naturally Established Neo-Allopolyploid Monkeyflower. AB - Recent studies have shown that one of the parental subgenomes in ancient polyploids is generally more dominant, having retained more genes and being more highly expressed, a phenomenon termed subgenome dominance. The genomic features that determine how quickly and which subgenome dominates within a newly formed polyploid remain poorly understood. To investigate the rate of emergence of subgenome dominance, we examined gene expression, gene methylation, and transposable element (TE) methylation in a natural, <140-year-old allopolyploid (Mimulus peregrinus), a resynthesized interspecies triploid hybrid (M. robertsii), a resynthesized allopolyploid (M. peregrinus), and progenitor species (M. guttatus and M. luteus). We show that subgenome expression dominance occurs instantly following the hybridization of divergent genomes and significantly increases over generations. Additionally, CHH methylation levels are reduced in regions near genes and within TEs in the first-generation hybrid, intermediate in the resynthesized allopolyploid, and are repatterned differently between the dominant and recessive subgenomes in the natural allopolyploid. Subgenome differences in levels of TE methylation mirror the increase in expression bias observed over the generations following hybridization. These findings provide important insights into genomic and epigenomic shock that occurs following hybridization and polyploid events and may also contribute to uncovering the mechanistic basis of heterosis and subgenome dominance. PMID- 28814645 TI - Zygotic Genome Activation Occurs Shortly after Fertilization in Maize. AB - The formation of a zygote via the fusion of an egg and sperm cell and its subsequent asymmetric division herald the start of the plant's life cycle. Zygotic genome activation (ZGA) is thought to occur gradually, with the initial steps of zygote and embryo development being primarily maternally controlled, and subsequent steps being governed by the zygotic genome. Here, using maize (Zea mays) as a model plant system, we determined the timing of zygote development and generated RNA-seq transcriptome profiles of gametes, zygotes, and apical and basal daughter cells. ZGA occurs shortly after fertilization and involves ~10% of the genome being activated in a highly dynamic pattern. In particular, genes encoding transcriptional regulators of various families are activated shortly after fertilization. Further analyses suggested that chromatin assembly is strongly modified after fertilization, that the egg cell is primed to activate the translational machinery, and that hormones likely play a minor role in the initial steps of early embryo development in maize. Our findings provide important insights into gamete and zygote activity in plants, and our RNA-seq transcriptome profiles represent a comprehensive, unique RNA-seq data set that can be used by the research community. PMID- 28814647 TI - Substrate-triggered position switching of TatA and TatB during Tat transport in Escherichia coli. AB - The twin-arginine protein transport (Tat) machinery mediates the translocation of folded proteins across the cytoplasmic membrane of prokaryotes and the thylakoid membrane of plant chloroplasts. The Escherichia coli Tat system comprises TatC and two additional sequence-related proteins, TatA and TatB. The active translocase is assembled on demand, with substrate-binding at a TatABC receptor complex triggering recruitment and assembly of multiple additional copies of TatA; however, the molecular interactions mediating translocase assembly are poorly understood. A 'polar cluster' site on TatC transmembrane (TM) helix 5 was previously identified as binding to TatB. Here, we use disulfide cross-linking and molecular modelling to identify a new binding site on TatC TM helix 6, adjacent to the polar cluster site. We demonstrate that TatA and TatB each have the capacity to bind at both TatC sites, however in vivo this is regulated according to the activation state of the complex. In the resting-state system, TatB binds the polar cluster site, with TatA occupying the TM helix 6 site. However when the system is activated by overproduction of a substrate, TatA and TatB switch binding sites. We propose that this substrate-triggered positional exchange is a key step in the assembly of an active Tat translocase. PMID- 28814646 TI - The Intracellular Immune Receptor Sw-5b Confers Broad-Spectrum Resistance to Tospoviruses through Recognition of a Conserved 21-Amino Acid Viral Effector Epitope. AB - Plants use both cell surface-resident pattern recognition receptors (PRRs) and intracellular nucleotide binding leucine-rich repeat (NLR) receptors to detect various pathogens. Plant PRRs typically recognize conserved pathogen-associated molecular patterns (PAMPs) to provide broad-spectrum resistance. By contrast, plant NLRs generally detect pathogen strain-specific effectors and confer race specific resistance. Here, we demonstrate that the tomato (Solanum lycopersicum) NLR Sw-5b confers broad-spectrum resistance against American-type tospoviruses by recognizing a conserved 21-amino acid peptide region within viral movement protein NSm (NSm21). Sw-5b NB-ARC-LRR domains directly associate with NSm21 in vitro and in planta. Domain swap, site-directed mutagenesis and structure modeling analyses identified four polymorphic sites in the Sw-5b LRR domain that are critical for the recognition of NSm21 Furthermore, recognition of NSm21 by Sw 5b likely disturbs the residues adjacent to R927 in the LRR domain to weaken the intramolecular interaction between LRR and NB-ARC domains, thus translating recognition of NSm21 into activation of Sw-5b. Natural variation analysis of Sw 5b homologs from wild tomato species of South America revealed that the four polymorphic sites in the Sw-5b LRR domain were positively selected during evolution and are all necessary to confer resistance to tospovirus. The results described here provide a new example of a plant NLR mediating broad-spectrum resistance through recognition of a small conserved PAMP-like region within the pathogen effector. PMID- 28814648 TI - ZC4H2 stabilizes Smads to enhance BMP signalling, which is involved in neural development in Xenopus. AB - Bone morphogenetic proteins (BMPs) play vital roles in regulating stem cell maintenance, differentiation and embryonic development. Intracellularly, BMP signalling is mediated by Smad proteins, which are regulated post transcriptionally through reversible phosphorylation and ubiquitination. ZC4H2 is a small nuclear protein associated with intellectual disability and neural development in humans. Here, we report that ZC4H2 is highly expressed in the developing neural system and is involved in neural patterning and BMP signalling in Xenopus Knockdown of ZC4H2 led to expansion of the expression of the pan neural plate marker Sox2 in Xenopus embryos. In mammalian cells, ZC4H2 promotes BMP signalling and is involved in BMP regulated myogenic and osteogenic differentiation of mouse myoblast cells. Mechanistically, ZC4H2 binds and stabilizes Smad1 and Smad5 proteins through reducing their association with the Smurf ubiquitin ligases and thus their ubiquitination. We also found that a group of ZC4H2 mutations, which have been isolated in patients with intellectual disorders, showed weaker Smad-stabilizing activity, suggesting that the ZC4H2 Smad interaction might contribute to proper neural development in humans. PMID- 28814650 TI - Failure to differentiate between divergence of species and their genes can result in over-estimation of mutation rates in recently diverged species. PMID- 28814649 TI - Wnt ligand presentation and reception: from the stem cell niche to tissue engineering. AB - Stem cells reside in niches where spatially restricted signals maintain a delicate balance between stem cell self-renewal and differentiation. Wnt family proteins are particularly suited for this role as they are modified by lipids, which constrain and spatially regulate their signalling range. In recent years, Wnt/beta-catenin signalling has been shown to be essential for the self-renewal of a variety of mammalian stem cells. In this review, we discuss Wnt-responsive stem cells in their niche, and mechanisms by which Wnt ligands are presented to responsive cells. We also highlight recent progress in molecular visualization that has allowed for the monitoring of Wnt signalling within the stem cell compartment and new approaches to recapitulate this niche signalling in vitro Indeed, new technologies that present Wnt in a localized manner and mimic the three-dimensional microenvironment of stem cells will advance our understanding of Wnt signalling in the stem cell niche. These advances will expand current horizons to exploit Wnt ligands in the rapidly evolving fields of tissue engineering and regenerative medicine. PMID- 28814651 TI - N2-fixing tropical legume evolution: a contributor to enhanced weathering through the Cenozoic? AB - Fossil and phylogenetic evidence indicates legume-rich modern tropical forests replaced Late Cretaceous palm-dominated tropical forests across four continents during the early Cenozoic (58-42 Ma). Tropical legume trees can transform ecosystems via their ability to fix dinitrogen (N2) and higher leaf N compared with non-legumes (35-65%), but it is unclear how their evolutionary rise contributed to silicate weathering, the long-term sink for atmospheric carbon dioxide (CO2). Here we hypothesize that the increasing abundance of N2-fixing legumes in tropical forests amplified silicate weathering rates by increased input of fixed nitrogen (N) to terrestrial ecosystems via interrelated mechanisms including increasing microbial respiration and soil acidification, and stimulating forest net primary productivity. We suggest the high CO2 early Cenozoic atmosphere further amplified legume weathering. Evolution of legumes with high weathering rates was probably driven by their high demand for phosphorus and micronutrients required for N2-fixation and nodule formation. PMID- 28814652 TI - Evolution of plasticity and adaptive responses to climate change along climate gradients. AB - The relative contributions of phenotypic plasticity and adaptive evolution to the responses of species to recent and future climate change are poorly understood. We combine recent (1960-2010) climate and phenotypic data with microclimate, heat balance, demographic and evolutionary models to address this issue for a montane butterfly, Colias eriphyle, along an elevational gradient. Our focal phenotype, wing solar absorptivity, responds plastically to developmental (pupal) temperatures and plays a central role in thermoregulatory adaptation in adults. Here, we show that both the phenotypic and adaptive consequences of plasticity vary with elevation. Seasonal changes in weather generate seasonal variation in phenotypic selection on mean and plasticity of absorptivity, especially at lower elevations. In response to climate change in the past 60 years, our models predict evolutionary declines in mean absorptivity (but little change in plasticity) at high elevations, and evolutionary increases in plasticity (but little change in mean) at low elevation. The importance of plasticity depends on the magnitude of seasonal variation in climate relative to interannual variation. Our results suggest that selection and evolution of both trait means and plasticity can contribute to adaptive response to climate change in this system. They also illustrate how plasticity can facilitate rather than retard adaptive evolutionary responses to directional climate change in seasonal environments. PMID- 28814653 TI - Natural selection on thermal preference, critical thermal maxima and locomotor performance. AB - Climate change is resulting in a radical transformation of the thermal quality of habitats across the globe. Whereas species have altered their distributions to cope with changing environments, the evidence for adaptation in response to rising temperatures is limited. However, to determine the potential of adaptation in response to thermal variation, we need estimates of the magnitude and direction of natural selection on traits that are assumed to increase persistence in warmer environments. Most inferences regarding physiological adaptation are based on interspecific analyses, and those of selection on thermal traits are scarce. Here, we estimate natural selection on major thermal traits used to assess the vulnerability of ectothermic organisms to altered thermal niches. We detected significant directional selection favouring lizards with higher thermal preferences and faster sprint performance at their optimal temperature. Our analyses also revealed correlational selection between thermal preference and critical thermal maxima, where individuals that preferred warmer body temperatures with cooler critical thermal maxima were favoured by selection. Recent published estimates of heritability for thermal traits suggest that, in concert with the strong selective pressures we demonstrate here, evolutionary adaptation may promote long-term persistence of ectotherms in altered thermal environments. PMID- 28814654 TI - The complex effects of demographic history on the estimation of substitution rate: concatenated gene analysis results in no more than twofold overestimation. PMID- 28814655 TI - Identifying climate drivers of infectious disease dynamics: recent advances and challenges ahead. AB - Climate change is likely to profoundly modulate the burden of infectious diseases. However, attributing health impacts to a changing climate requires being able to associate changes in infectious disease incidence with the potentially complex influences of climate. This aim is further complicated by nonlinear feedbacks inherent in the dynamics of many infections, driven by the processes of immunity and transmission. Here, we detail the mechanisms by which climate drivers can shape infectious disease incidence, from direct effects on vector life history to indirect effects on human susceptibility, and detail the scope of variation available with which to probe these mechanisms. We review approaches used to evaluate and quantify associations between climate and infectious disease incidence, discuss the array of data available to tackle this question, and detail remaining challenges in understanding the implications of climate change for infectious disease incidence. We point to areas where synthesis between approaches used in climate science and infectious disease biology provide potential for progress. PMID- 28814657 TI - Differential sperm storage by female zebra finches Taeniopygia guttata. AB - When females mate promiscuously, female sperm storage provides scope to bias the fertilization success towards particular males via the non-random acceptance and utilization of sperm. The difficulties observing post-copulatory processes within the female reproductive tract mean that the mechanisms underlying cryptic female choice remain poorly understood. Here, we use zebra finches Taeniopygia guttata, selected for divergent sperm lengths, combined with a novel technique for isolating and extracting sperm from avian sperm storage tubules (SSTs), to test the hypothesis that sperm from separate ejaculates are stored differentially by female birds. We show that sperm from different inseminations enter different SSTs in the female reproductive tract, resulting in almost complete segregation of the sperm of competing males. We propose that non-random acceptance of sperm into SSTs, reflected in this case by sperm phenotype, provides a mechanism by which long sperm enjoy enhanced fertilization success in zebra finches. PMID- 28814656 TI - Odours from marine plastic debris induce food search behaviours in a forage fish. AB - Plastic pollution is an anthropogenic stressor in marine ecosystems globally. Many species of marine fish (more than 50) ingest plastic debris. Ingested plastic has a variety of lethal and sublethal impacts and can be a route for bioaccumulation of toxic compounds throughout the food web. Despite its pervasiveness and severity, our mechanistic understanding of this maladaptive foraging behaviour is incomplete. Recent evidence suggests that the chemical signature of plastic debris may explain why certain species are predisposed to mistaking plastic for food. Anchovy (Engraulis sp.) are abundant forage fish in coastal upwelling systems and a critical prey resource for top predators. Anchovy ingest plastic in natural conditions, though the mechanism they use to misidentify plastic as prey is unknown. Here, we presented wild-caught schools of northern anchovy (Engraulis mordax) with odour solutions made of plastic debris and clean plastic to compare school-wide aggregation and rheotactic responses relative to food and food odour presentations. Anchovy schools responded to plastic debris odour with increased aggregation and reduced rheotaxis. These results were similar to the effects food and food odour presentations had on schools. Conversely, these behavioural responses were absent in clean plastic and control treatments. To our knowledge, this is the first experimental evidence that adult anchovy use odours to forage. We conclude that the chemical signature plastic debris acquires in the photic zone can induce foraging behaviours in anchovy schools. These findings provide further support for a chemosensory mechanism underlying plastic consumption by marine wildlife. Given the trophic position of forage fish, these findings have considerable implications for aquatic food webs and possibly human health. PMID- 28814658 TI - Sperm competition games when males invest in paternal care. AB - Sperm competition games investigate how males partition limited resources between pre- and post-copulatory competition. Although extensive research has explored how various aspects of mating systems affect this allocation, male allocation between mating, fertilization and parental effort has not previously been considered. Yet, paternal care can be energetically expensive and males are generally predicted to adjust their parental effort in response to expected paternity. Here, we incorporate parental effort into sperm competition games, particularly exploring how the relationship between paternal care and offspring survival affects sperm competition and the relationship between paternity and paternal care. Our results support existing expectations that (i) fertilization effort should increase with female promiscuity and (ii) paternal care should increase with expected paternity. However, our analyses also reveal that the cost of male care can drive the strength of these patterns. When paternal behaviour is energetically costly, increased allocation to parental effort constrains allocation to fertilization effort. As paternal care becomes less costly, the association between paternity and paternal care weakens and may even be absent. By explicitly considering variation in sperm competition and the cost of male care, our model provides an integrative framework for predicting the interaction between paternal care and patterns of paternity. PMID- 28814659 TI - Fluorescence Detection of Glutathione (GSH) and Oxidized Glutathione (GSSG) in Blood with a NIR-Excitable Cyanine Probe. AB - Cyanine has been widely utilized as a near infrared (NIR) fluorophore for detection of glutathione (GSH). However, the excitation of most of the reported cyanine-based probes was less than 800 nm, which inevitably induce biological background absorption and lower the sensitivity, limiting their use for detection of GSH in blood samples. To address this issue, here, a heptamethine cyanine probe (DNIR), with a NIR excitation wavelength at 804 nm and a NIR emission wavelength at 832 nm, is employed for the detection of GSH and its oxidized form (GSSG) in blood. The probe displays excellent selectivity for GSH over GSSG and other amino acids (AAs), and rapid response to GSH, in particular a good property for indirect detection of GSSG in the presence of enzyme glutathione reductase (GR) and the reducing agent nicotinamideadenine dinucleotide phosphate (NADPH), without further separation prior to fluorescent measurement. To the best of our knowledge, this is the first attempt to explore NIR fluorescent approach for the simultaneous assay of GSH and GSSG in blood. As such, we expect that our fluorescence sensors with both NIR excitation and NIR emission make this strategy suitable for the application in complex physiological systems. PMID- 28814660 TI - Sustained immune tolerance induction in enzyme replacement therapy-treated CRIM negative patients with infantile Pompe disease. AB - BACKGROUND: Cross-reactive immunological material-negative (CRIM-negative) infantile Pompe disease (IPD) patients develop an immune response against enzyme replacement therapy (ERT) with alglucosidase alfa that nullifies ERT efficacy. Prophylactic immune tolerance induction (ITI) with rituximab, methotrexate, and IVIG successfully prevents development of deleterious rhGAA IgG antibodies; however, safety, likelihood of success, and long-term efficacy of ITI in a larger cohort remain unknown. METHODS: Clinical data were analyzed for 19 CRIM-negative IPD patients who received ITI with rituximab, methotrexate, and IVIG in the ERT naive setting (ERT+ITI) and compared to a historical cohort of 10 CRIM-negative IPD patients on ERT monotherapy. RESULTS: ITI was safely tolerated, although infections were reported in 4 patients. Fourteen (74%) ERT+ITI patients were alive, with a median age of 44.2 months at their final assessment. The eldest survivor was 103.9 months old, with 100.2 months of follow-up after initiation of ERT+ITI. Death (n = 5) occurred at a median age of 29.2 months and was unrelated to the administration of ITI. Fifteen patients either did not seroconvert (n = 8) or maintained low titers (n = 7; defined as titers of <=6,400 throughout the course of ERT) following ERT+ITI. Only one patient developed high and sustained antibody titers (defined as titers of >=51,200 at or beyond 6 months on ERT). Left ventricular mass index (LVMI) decreased from a median of 248.5 g/m2 at baseline to 76.8 g/m2 at a median time from ERT+ITI initiation to 59 weeks. ERT+ITI significantly improved overall survival (P = 0.001), eliminated/reduced antibodies at values of <=6,400 at week 52 on ERT (P = 0.0004), and improved LVMI at week 52 on ERT (P = 0.02) when compared with ERT monotherapy. CONCLUSION: Evidence from this international cohort of CRIM-negative IPD patients further supports the safety, feasibility, and efficacy of ITI in the prevention of immune responses to ERT. TRIAL REGISTRATION: Clinicaltrials.gov NCT01665326. FUNDING: This research was supported in part by the Lysosomal Disease Network, a part of NIH Rare Diseases Clinical Research Network, and by a grant from Genzyme, a Sanofi company. PMID- 28814661 TI - HDAC inhibition induces HIV-1 protein and enables immune-based clearance following latency reversal. AB - Promising therapeutic approaches for eradicating HIV include transcriptional activation of provirus from latently infected cells using latency-reversing agents (LRAs) and immune-mediated clearance to purge reservoirs. Accurate detection of cells capable of producing viral antigens and virions, and the measurement of clearance of infected cells, is essential to assessing therapeutic efficacy. Here, we apply enhanced methodology extending the sensitivity limits for the rapid detection of subfemtomolar HIV gag p24 capsid protein in CD4+ T cells from ART-suppressed HIV+ individuals, and we show viral protein induction following treatment with LRAs. Importantly, we demonstrate that clinical administration of histone deacetylase inhibitors (HDACis; vorinostat and panobinostat) induced HIV gag p24, and ex vivo stimulation produced sufficient viral antigen to elicit immune-mediated cell killing using anti-gp120/CD3 bispecific antibody. These findings extend beyond classical nucleic acid endpoints, which are confounded by the predominance of mutated, defective proviruses and, of paramount importance, enable assessment of cells making HIV protein that can now be targeted by immunological approaches. PMID- 28814662 TI - Irgm1 coordinately regulates autoimmunity and host defense at select mucosal surfaces. AB - The pathogenesis of primary Sjogren's syndrome (SS), an autoimmune disease that targets the mucosa of exocrine tissues, is poorly understood. Although several mouse models have been developed that display features of SS, most of these are within the larger context of a lupus-like presentation. Immunity-related GTPase family M protein 1 (Irgm1) is an interferon-inducible cytoplasmic GTPase that is reported to regulate autophagy and mitochondrial homeostasis. Here, we report that naive Irgm1-/- mice display lymphocytic infiltration of multiple mucosal tissues including the lung in a manner reminiscent of SS, together with IgA class predominant autoantibodies including anti-Ro and anti-La. This phenotype persists in the germ-free state, but is abolished by deletion of Irgm3. Irgm1-/- mice have increased local production in the lung of TECP15-idiotype IgA, a natural antibody with dual reactivity against host and pneumococcal phosphorylcholine. Associated with this, Irgm1-/- mice display enhanced opsonization and clearance of Streptococcus pneumoniae from the lung and increased survival from pneumococcal pneumonia. Taken together, our results identify Irgm1 as a master regulator of mucosal immunity that dually modulates evolutionarily conserved self- and other directed immune responses at the interface of host with environment. PMID- 28814663 TI - Parasympathetic dysfunction and antiarrhythmic effect of vagal nerve stimulation following myocardial infarction. AB - Myocardial infarction causes sympathetic activation and parasympathetic dysfunction, which increase risk of sudden death due to ventricular arrhythmias. Mechanisms underlying parasympathetic dysfunction are unclear. The aim of this study was to delineate consequences of myocardial infarction on parasympathetic myocardial neurotransmitter levels and the function of parasympathetic cardiac ganglia neurons, and to assess electrophysiological effects of vagal nerve stimulation on ventricular arrhythmias in a chronic porcine infarct model. While norepinephrine levels decreased, cardiac acetylcholine levels remained preserved in border zones and viable myocardium of infarcted hearts. In vivo neuronal recordings demonstrated abnormalities in firing frequency of parasympathetic neurons of infarcted animals. Neurons that were activated by parasympathetic stimulation had low basal firing frequency, while neurons that were suppressed by left vagal nerve stimulation had abnormally high basal activity. Myocardial infarction increased sympathetic inputs to parasympathetic convergent neurons. However, the underlying parasympathetic cardiac neuronal network remained intact. Augmenting parasympathetic drive with vagal nerve stimulation reduced ventricular arrhythmia inducibility by decreasing ventricular excitability and heterogeneity of repolarization of infarct border zones, an area with known proarrhythmic potential. Preserved acetylcholine levels and intact parasympathetic neuronal pathways can explain the electrical stabilization of infarct border zones with vagal nerve stimulation, providing insight into its antiarrhythmic benefit. PMID- 28814664 TI - Pulmonary arterial hypertension treatment with carvedilol for heart failure: a randomized controlled trial. AB - BACKGROUND: Right-sided heart failure is the leading cause of death in pulmonary arterial hypertension (PAH). Similar to left heart failure, sympathetic overactivation and beta-adrenoreceptor (betaAR) abnormalities are found in PAH. Based on successful therapy of left heart failure with beta-blockade, the safety and benefits of the nonselective beta-blocker/vasodilator carvedilol were evaluated in PAH. METHODS: PAH Treatment with Carvedilol for Heart Failure (PAHTCH) is a single-center, double-blind, randomized, controlled trial. Following 1-week run-in, 30 participants were randomized to 1 of 3 arms for 24 weeks: placebo, low-fixed-dose, or dose-escalating carvedilol. Outcomes included clinical measures and mechanistic biomarkers. RESULTS: Decreases in heart rate and blood pressure with carvedilol were well tolerated; heart rate correlated with carvedilol dose. Carvedilol-treated groups had no decrease in exercise capacity measured by 6-minute walk, but had lower heart rates at peak and after exercise, and faster heart rate recovery. Dose-escalating carvedilol was associated with reduction in right ventricular (RV) glycolytic rate and increase in betaAR levels. There was no evidence of RV functional deterioration; rather, cardiac output was maintained. CONCLUSIONS: Carvedilol is likely safe in PAH over 6 months of therapy and has clinical and mechanistic benefits associated with improved outcomes. The data provide support for longer and larger studies to establish guidelines for use of beta-blockers in PAH. TRIAL REGISTRATION: ClinicalTrials.gov NCT01586156FUNDING. This project was supported by NIH R01HL115008 and R01HL60917 and in part by the National Center for Advancing Translational Sciences, UL1TR000439. PMID- 28814665 TI - Fatty acid oxidation by the osteoblast is required for normal bone acquisition in a sex- and diet-dependent manner. AB - Postnatal bone formation is influenced by nutritional status and compromised by disturbances in metabolism. The oxidation of dietary lipids represents a critical source of ATP for many cells but has been poorly studied in the skeleton, where the prevailing view is that glucose is the primary energy source. Here, we examined fatty acid uptake by bone and probed the requirement for fatty acid catabolism during bone formation by specifically disrupting the expression of carnitine palmitoyltransferase 2 (Cpt2), an obligate enzyme in fatty acid oxidation, in osteoblasts and osteocytes. Radiotracer studies demonstrated that the skeleton accumulates a significant fraction of postprandial fatty acids, which was equal to or in excess of that acquired by skeletal muscle or adipose tissue. Female, but not male, Cpt2 mutant mice exhibited significant impairments in postnatal bone acquisition, potentially due to an inability of osteoblasts to modify fuel selection. Intriguingly, suppression of fatty acid utilization by osteoblasts and osteocytes also resulted in the development of dyslipidemia and diet-dependent modifications in body composition. Taken together, these studies demonstrate a requirement for fatty acid oxidation during bone accrual and suggest a role for the skeleton in lipid homeostasis. PMID- 28814666 TI - Rapamycin reversal of VEGF-C-driven lymphatic anomalies in the respiratory tract. AB - Lymphatic malformations are serious but poorly understood conditions that present therapeutic challenges. The goal of this study was to compare strategies for inducing regression of abnormal lymphatics and explore underlying mechanisms. CCSP-rtTA/tetO-VEGF-C mice, in which doxycycline regulates VEGF-C expression in the airway epithelium, were used as a model of pulmonary lymphangiectasia. After doxycycline was stopped, VEGF-C expression returned to normal, but lymphangiectasia persisted for at least 9 months. Inhibition of VEGFR-2/VEGFR-3 signaling, Notch, beta-adrenergic receptors, or autophagy and antiinflammatory steroids had no noticeable effect on the amount or severity of lymphangiectasia. However, rapamycin inhibition of mTOR reduced lymphangiectasia by 76% within 7 days without affecting normal lymphatics. Efficacy of rapamycin was not increased by coadministration with the other agents. In prevention trials, rapamycin suppressed VEGF-C-driven mTOR phosphorylation and lymphatic endothelial cell sprouting and proliferation. However, in reversal trials, no lymphatic endothelial cell proliferation was present to block in established lymphangiectasia, and rapamycin did not increase caspase-dependent apoptosis. However, rapamycin potently suppressed Prox1 and VEGFR-3. These experiments revealed that lymphangiectasia is remarkably resistant to regression but is responsive to rapamycin, which rapidly reduces and normalizes the abnormal lymphatics without affecting normal lymphatics. PMID- 28814667 TI - Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens. AB - Adrenergic signaling is known to promote tumor growth and metastasis, but the effects on tumor stroma are not well understood. An unbiased bioinformatics approach analyzing tumor samples from patients with known biobehavioral profiles identified a prominent stromal signature associated with cancer-associated fibroblasts (CAFs) in those with a high biobehavioral risk profile (high Center for Epidemiologic Studies Depression Scale [CES-D] score and low social support). In several models of epithelial ovarian cancer, daily restraint stress resulted in significantly increased CAF activation and was abrogated by a nonspecific beta blocker. Adrenergic signaling-induced CAFs had significantly higher levels of collagen and extracellular matrix components than control tumors. Using a systems based approach, we found INHBA production by cancer cells to induce CAFs. Ablating inhibin beta A decreased CAF phenotype both in vitro and in vivo. In preclinical models of breast and colon cancers, there were increased CAFs and collagens following daily restraint stress. In an independent data set of renal cell carcinoma patients, there was an association between high depression (CES-D) scores and elevated expression of ACTA2, collagens, and inhibin beta A. Collectively, our findings implicate adrenergic influences on tumor stroma as important drivers of CAFs and establish inhibin beta A as an important regulator of the CAF phenotype in ovarian cancer. PMID- 28814668 TI - Injury-induced actin cytoskeleton reorganization in podocytes revealed by super resolution microscopy. AB - The architectural integrity of tissues requires complex interactions, both between cells and between cells and the extracellular matrix. Fundamental to cell and tissue homeostasis are the specific mechanical forces conveyed by the actomyosin cytoskeleton. Here we used super-resolution imaging methods to visualize the actin cytoskeleton in the kidney glomerulus, an organized collection of capillaries that filters the blood to make the primary urine. Our analysis of both mouse and human glomeruli reveals a network of myosin IIA containing contractile actin cables within podocyte cell bodies and major processes at the outer aspects of the glomerular tuft. These likely exert force on an underlying network of myosin IIA-negative, noncontractile actin fibers present within podocyte foot processes that function to both anchor the cells to the glomerular basement membrane and stabilize the slit diaphragm against the pressure of fluid flow. After injuries that disrupt the kidney filtration barrier and cause foot process effacement, the podocyte's contractile actomyosin network relocates to the basolateral surface of the cell, manifesting as sarcomere-like structures juxtaposed to the basement membrane. Our findings suggest a new model of the podocyte actin cytoskeleton in health and disease and suggest the existence of novel mechanisms that regulate podocyte architecture. PMID- 28814669 TI - Neonatal and adult recent thymic emigrants produce IL-8 and express complement receptors CR1 and CR2. AB - The maintenance of peripheral naive T lymphocytes in humans is dependent on their homeostatic division, not continuing emigration from the thymus, which undergoes involution with age. However, postthymic maintenance of naive T cells is still poorly understood. Previously we reported that recent thymic emigrants (RTEs) are contained in CD31+CD25- naive T cells as defined by their levels of signal joint T cell receptor rearrangement excision circles (sjTRECs). Here, by differential gene expression analysis followed by protein expression and functional studies, we define that the naive T cells having divided the least since thymic emigration express complement receptors (CR1 and CR2) known to bind complement C3b- and C3d decorated microbial products and, following activation, produce IL-8 (CXCL8), a major chemoattractant for neutrophils in bacterial defense. We also observed an IL-8-producing memory T cell subpopulation coexpressing CR1 and CR2 and with a gene expression signature resembling that of RTEs. The functions of CR1 and CR2 on T cells remain to be determined, but we note that CR2 is the receptor for Epstein-Barr virus, which is a cause of T cell lymphomas and a candidate environmental factor in autoimmune disease. PMID- 28814670 TI - MTG16 is a tumor suppressor in colitis-associated carcinoma. AB - MTG16 is a member of the myeloid translocation gene (MTG) family of transcriptional corepressors. While MTGs were originally identified in chromosomal translocations in acute myeloid leukemia, recent studies have uncovered a role in intestinal biology. For example, Mtg16-/- mice have increased intestinal proliferation and are more sensitive to intestinal injury in colitis models. MTG16 is also underexpressed in patients with moderate/severe ulcerative colitis. Based on these findings, we postulated that MTG16 might protect against colitis-associated carcinogenesis. MTG16 was downregulated at the protein and RNA levels in patients with inflammatory bowel disease and in those with colitis associated carcinoma. Mtg16-/- mice subjected to inflammatory carcinogenesis modeling exhibited worse colitis and increased tumor multiplicity and size. Loss of MTG16 also increased severity of dysplasia, apoptosis, proliferation, DNA damage, and WNT signaling. Moreover, transplantation of WT marrow into Mtg16-/- mice failed to rescue the Mtg16-/- protumorigenic phenotypes, indicating an epithelium-specific role for MTG16. While MTG dysfunction is widely appreciated in hematopoietic malignancies, the role of this gene family in epithelial homeostasis, and in colon cancer, was unrealized. This report identifies MTG16 as an important modulator of colitis and tumor development in inflammatory carcinogenesis. PMID- 28814671 TI - Antifibrotic role of vascular endothelial growth factor in pulmonary fibrosis. AB - The chronic progressive decline in lung function observed in idiopathic pulmonary fibrosis (IPF) appears to result from persistent nonresolving injury to the epithelium, impaired restitution of the epithelial barrier in the lung, and enhanced fibroblast activation. Thus, understanding these key mechanisms and pathways modulating both is essential to greater understanding of IPF pathogenesis. We examined the association of VEGF with the IPF disease state and preclinical models in vivo and in vitro. Tissue and circulating levels of VEGF were significantly reduced in patients with IPF, particularly in those with a rapidly progressive phenotype, compared with healthy controls. Lung-specific overexpression of VEGF significantly protected mice following intratracheal bleomycin challenge, with a decrease in fibrosis and bleomycin-induced cell death observed in the VEGF transgenic mice. In vitro, apoptotic endothelial cell derived mediators enhanced epithelial cell injury and reduced epithelial wound closure. This process was rescued by VEGF pretreatment of the endothelial cells via a mechanism involving thrombospondin-1 (TSP1). Taken together, these data indicate beneficial roles for VEGF during lung fibrosis via modulating epithelial homeostasis through a previously unrecognized mechanism involving the endothelium. PMID- 28814672 TI - VIPAR, a quantitative approach to 3D histopathology applied to lymphatic malformations. AB - BACKGROUND: Lack of investigatory and diagnostic tools has been a major contributing factor to the failure to mechanistically understand lymphedema and other lymphatic disorders in order to develop effective drug and surgical therapies. One difficulty has been understanding the true changes in lymph vessel pathology from standard 2D tissue sections. METHODS: VIPAR (volume information based histopathological analysis by 3D reconstruction and data extraction), a light-sheet microscopy-based approach for the analysis of tissue biopsies, is based on digital reconstruction and visualization of microscopic image stacks. VIPAR allows semiautomated segmentation of the vasculature and subsequent nonbiased extraction of characteristic vessel shape and connectivity parameters. We applied VIPAR to analyze biopsies from healthy lymphedematous and lymphangiomatous skin. RESULTS: Digital 3D reconstruction provided a directly visually interpretable, comprehensive representation of the lymphatic and blood vessels in the analyzed tissue volumes. The most conspicuous features were disrupted lymphatic vessels in lymphedematous skin and a hyperplasia (4.36-fold lymphatic vessel volume increase) in the lymphangiomatous skin. Both abnormalities were detected by the connectivity analysis based on extracted vessel shape and structure data. The quantitative evaluation of extracted data revealed a significant reduction of lymphatic segment length (51.3% and 54.2%) and straightness (89.2% and 83.7%) for lymphedematous and lymphangiomatous skin, respectively. Blood vessel length was significantly increased in the lymphangiomatous sample (239.3%). CONCLUSION: VIPAR is a volume-based tissue reconstruction data extraction and analysis approach that successfully distinguished healthy from lymphedematous and lymphangiomatous skin. Its application is not limited to the vascular systems or skin. FUNDING: Max Planck Society, DFG (SFB 656), and Cells-in-Motion Cluster of Excellence EXC 1003. PMID- 28814673 TI - Human lung tumor FOXP3+ Tregs upregulate four "Treg-locking" transcription factors. AB - Experimental data indicate that FOXP3+ Tregs can markedly curtail host antitumor immune responses, but the properties of human intratumoral Tregs are still largely unknown, in part due to significant methodologic problems. We studied the phenotypic, functional, epigenetic, and transcriptional features of Tregs in 92 patients with non-small-cell lung cancer, comparing the features of Tregs within tumors versus corresponding blood, lung, and lymph node samples. Intratumoral Treg numbers and suppressive function were significantly increased compared with all other sites but did not display a distinctive phenotype by flow cytometry. However, by undertaking simultaneous evaluation of mRNA and protein expression at the single-cell level, we demonstrated that tumor Tregs have a phenotype characterized by upregulated expression of FOXP3 mRNA and protein as well as significantly increased expression of EOS, IRF4, SATB1, and GATA1 transcription factor mRNAs. Expression of these "Treg-locking" transcription factors was positively correlated with levels of FOXP3 mRNA, with highest correlations for EOS and SATB1. EOS had an additional, FOXP3 mRNA-independent, positive correlation with FOXP3 protein in tumor Tregs. Our study identifies distinctive features of intratumoral Tregs and suggests that targeting Treg-locking transcription factors, especially EOS, may be of clinical importance for antitumor Treg-based therapy. PMID- 28814674 TI - Rilonacept maintains long-term inflammatory remission in patients with deficiency of the IL-1 receptor antagonist. AB - BACKGROUND: Deficiency of IL-1 receptor antagonist (DIRA) is a rare autoinflammatory disease that presents with life-threatening systemic inflammation, aseptic multifocal osteomyelitis, and pustulosis responsive to IL-1 blocking treatment. This study was performed (a) to investigate rilonacept, a long-acting IL-1 inhibitor, in maintaining anakinra-induced inflammatory remission in DIRA patients, (b) to determine doses needed to maintain remission, and (c) to evaluate the safety and pharmacokinetics of rilonacept in young children (<12 years). METHODS: Six mutation-positive DIRA patients (children, ages 3-6 years), treated with daily anakinra, were enrolled into an open-label pilot study of subcutaneous rilonacept for 24 months. Clinical symptoms and inflammatory blood parameters were measured at all visits. A loading dose (4.4 mg/kg) was administered, followed by once weekly injections (2.2 mg/kg) for 12 months. Dose escalation (4.4 mg/kg) was allowed if inflammatory remission was not maintained. Subjects in remission at 12 months continued rilonacept for an additional 12 months. RESULTS: Five of six patients required dose escalation for findings of micropustules. Following dose escalation, all patients were in remission on weekly rilonacept administration, with stable laboratory parameters for the entire study period of 24 months. All children are growing at normal rates and have normal heights and weights. Quality of life improved while on rilonacept. No serious adverse events were reported. CONCLUSION: Rilonacept was found to maintain inflammatory remission in DIRA patients. The once weekly injection was well tolerated and correlated with increased quality of life, most likely related to the lack of daily injections. TRIAL REGISTRATION: ClinicalTrials.gov NCT01801449. FUNDING: NIH, NIAMS, and NIAID. PMID- 28814676 TI - Cosmetic/Surgical Dermatology: Should it be an Integrated Part of Medical Dermatology? PMID- 28814677 TI - A Hospital Based Study of Pterygium in Tertiary Care Hospital of Nepal. AB - Background Pterygium, a triangular fibrovascular subepithelial growth of degenerative bulbar conjunctival tissue over the limbus onto the cornea, is one of the common ocular conditions that may result in discomfort, tearing, photophobia and significant visual impairment. Little is known about its epidemiology in Nepalese context. Objective The current study aims to analyze the epidemiology of pterygium in a hospital-based population in Kavre District, a mid hilly region of central Nepal. Method This was a prospective hospital based study carried out in the Department of Ophthalmology in Dhulikhel Hospital, Kathmandu University Hospital for a period of one year from January to December 2013. All the patients with pterygium, aged 21 years and above attending the outpatients department were included into the study. The epidemiological data was collected using a standard questionnaire and complete ocular examination was performed by the Ophthalmologist. Result A total of 7925 patients were seen in the Ophthalmology outpatient department during a one year period, out of which 5622 patients (age range 20-80 years) were eligible for the study. A total of 137 patients, 43(31.4%) males and 94 females (68.6%) had different grades of pterygium with mean age of 48.6+/- 12.8 years. The overall prevalence of pterygium was 2.4 %. Majority of the patients with pterygium were between 41-60 years. Fifty-eight percent of pterygium were of grade I followed by 41% of grade II. Unilateral and nasal pterygia were common. Conclusion The prevalence of pterygium is low in this hospital based population, majority of cases affecting females and old age population. PMID- 28814675 TI - Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer's disease. AB - BACKGROUND: Noninvasive detection of Alzheimer's disease (AD) with high specificity and sensitivity can greatly facilitate identification of at-risk populations for earlier, more effective intervention. AD patients exhibit a myriad of retinal pathologies, including hallmark amyloid beta-protein (Abeta) deposits. METHODS: Burden, distribution, cellular layer, and structure of retinal Abeta plaques were analyzed in flat mounts and cross sections of definite AD patients and controls (n = 37). In a proof-of-concept retinal imaging trial (n = 16), amyloid probe curcumin formulation was determined and protocol was established for retinal amyloid imaging in live patients. RESULTS: Histological examination uncovered classical and neuritic-like Abeta deposits with increased retinal Abeta42 plaques (4.7-fold; P = 0.0063) and neuronal loss (P = 0.0023) in AD patients versus matched controls. Retinal Abeta plaque mirrored brain pathology, especially in the primary visual cortex (P = 0.0097 to P = 0.0018; Pearson's r = 0.84-0.91). Retinal deposits often associated with blood vessels and occurred in hot spot peripheral regions of the superior quadrant and innermost retinal layers. Transmission electron microscopy revealed retinal Abeta assembled into protofibrils and fibrils. Moreover, the ability to image retinal amyloid deposits with solid-lipid curcumin and a modified scanning laser ophthalmoscope was demonstrated in live patients. A fully automated calculation of the retinal amyloid index (RAI), a quantitative measure of increased curcumin fluorescence, was constructed. Analysis of RAI scores showed a 2.1-fold increase in AD patients versus controls (P = 0.0031). CONCLUSION: The geometric distribution and increased burden of retinal amyloid pathology in AD, together with the feasibility to noninvasively detect discrete retinal amyloid deposits in living patients, may lead to a practical approach for large-scale AD diagnosis and monitoring. FUNDING: National Institute on Aging award (AG044897) and The Saban and The Marciano Family Foundations. PMID- 28814678 TI - Sex Determination From the Bicondylar Width of the Femur: A Nepalese Study Using Digital X-ray Images. AB - Background One of the important components of forensic identification is sex determination. The prediction of sex becomes easy with a complete skeleton. The problem arises with mutilated and incomplete skeletal remains. The skull and pelvis are preferred for sex prediction, but not uncommonly, long bones are brought for forensic examination. The femur out stands as the most dimorphic long bone. The literature on sex determination from the femur in different population groups is in abundance. The forensic anthropology literature suggests that longitudinal dimensions are often less discriminating than the breadth and circumference of long bones. Many researchers have suggested that the bicondylar width of the femur is the most dimorphic dimension. Objective To evaluate the sexing potential of the bicondylar width of the femur in the Nepalese population using digital X-ray images. Method A sample of 200 digital X-ray images of the knee belonging to 100 males and 100 females was used to measure the bicondylar width of the right femur. These digital X-ray images were those of Nepalese patients who visited the Department of Radiology at the affiliate hospital of Kathmandu University School of Medical Sciences, Dhulikhel, Nepal for diagnostic and treatment purposes. Result The resent study reveals a statistically significant difference for the bicondylar width of the femur between males and females. A regression equation was derived with sectioning point 77.84. Using the regression equation the prediction of sex was 68% with an overlapping of 32%. Having a low prediction in comparison to other studies in different populations, 95% confidence interval for the mean was used to get a range of measurements of the bicondylar width for males and females. The range stated in the present study is 79.47 mm to 82.20 mm for males and 73.75 mm to 75.93 mm for females. Conclusion The bicondylar width of the femur cannot be individually recommended for sex determination in the Nepalese population, but could be considered if analyzed along with the other morphometric traits for sex determination. PMID- 28814679 TI - Awareness on Hypertension and its Self-Management Practices Among Hypertensive Patients Attending Outreach Clinics of a Medical College in South India. AB - Background Recent data suggest that hypertension is a significant public health problem in India. The success strategies for hypertension management depend upon clients' awareness on hypertension and its self-management practices. Objective To determine awareness, self-management practices and compliance with treatment among hypertensive patients. Method This cross-sectional study was done in January 2012 at four health centres in Mangalore. All confirmed cases of hypertension attending the outpatient department were interviewed using a semi structured interview schedule. Result Majority (58.7%) of the 315 participants were of the age group 41 to 60 years and majority (53.6%) were males. Most patients (69.5%) were educated up to high school level. The awareness level about hypertension was average or good in majority (52.4%) of the participants. Self management practices were found to be average or good among 60.6% cases. Good compliance with treatment was seen in 78.7% cases and blood pressure was in control in 72.4% cases. Quality of self-management practices was found to influence control of blood pressure (p=0.021). Awareness, self-management practices and compliance were found to be significantly poor among aged (above 50 years), males, less educated, unemployed, unskilled or retired patients. Conclusion Awareness on hypertension and self-management practices were average or above among majority of the studied population. However this study identified groups who need to be better educated and further monitored to achieve universal blood pressure control among hypertensive population during the routine health care services in this settings. PMID- 28814680 TI - Safe and Feasible Time Limit for Early Appendectomy in Appendiceal Mass. AB - Background Early appendectomy in appendiceal mass is gaining popularity among some surgeons. However, it is endowed with increasing operative difficulty with time, and safe and feasible timing is not yet clear. Objective To know safe and feasible time limit for early appendectomy in appendiceal mass. Method This is a retrospective study. Between May 2009 and July 2014, 114 patients of appendiceal mass who underwent early surgical intervention by a single surgeon were studied. Group I included 98 patients operated within seven days of onset of pain and group II included 16 patients operated between 8th and 15 days of pain. Type of operative procedure, difficulties and complications were analyzed. Result There were 58 men and 56 women. Their mean age was 24.27 +/- 8.7 years. In group I, 98 (100%) patients had appendectomy and adhesiolysis was safe and feasible. In group II, 5(31.25%) patients had extra-peritoneal drainage of abscess without attempt for appendectomy. Remaining 11 patients had attempt for appendectomy, but only 3(18.75%) out of 4 patients operated on the 8th day could have appendectomy. Six (37.5%) patients had just drainage of abscess. Two (12.5%) patients, operated on the 12th and 15th days of pain had just open-closed due to dense adhesion and both resolved. One patient operated on the 10th day sustained ileal injury. Surgical site infection occurred in 16.6% (14 in 86) in group I and 33.3% (5 in 15) in group B (P= 0.001). Mean operative time was 34.4 +/- 9.23 minutes and 43.7 +/- 16.38 minutes for group I and group II respectively. Mean hospital stay after surgery was 2.9 +/- 1.1 days and 5.5 +/- 1.37 days in group I and group II respectively. Conclusion Early appendectomy in appendiceal mass seems safe and feasible up to 7th day since onset of pain in my experience. However, this limit may vary with surgeon's experience, and further studies are required to better clarify this issue. PMID- 28814681 TI - Epidemiological Study of Tobacco Smoking Behaviour amongst Residents of the Hill Region of Nepal. AB - Background Tobacco use is still a serious public health problem in the world and represents a major cause of morbidity and mortality in most parts of the world. Objective To measure the prevalence of tobacco use and to identify the factors associated with tobacco use among the residents of Dhankuta Municipality. Method The cross-sectional study was conducted among the residents of the Dhankuta Municipality where 205 households were taken as subjects. Pretested semistructured questionnaire was used for data collection and face to face interview was conducted. Univariate and multivariate logistic regression was used to see the association between various factors and tobacco use and identify the predictor variables. Result Overall prevalence of tobacco consumption in Dhankuta Municipality was found to be 57.1%. Prevalence of tobacco consumption among the male was significantly higher (67%) than female (47.1%) (p<0.05). Most of the respondents (56.4%) started consuming tobacco due to peer pressure and for recreation (24.8%). The multivariate logistic regression showed that the people with illiterate have higher chances of consuming tobacco than above School Leaving Certificate (OR 38.395, 95% CI=3.209- 459.417). The respondents below poverty line (<1.25 US$) was consuming tobacco more than above poverty line (> 1.25 US $) (OR 6.814, 95% CI= 1.255-36.986). Conclusion The aims of this study was to measure the prevalence of tobacco use and to identify the factors associated with tobacco use among the residents of the Dhankuta Municipality. We conclude that the prevalence rate of tobacco consumption in the Dhankuta Municipality was found to be moderately high. Factors like male in gender, Brahmin/Chhetri in ethnicity, lack of education, poor occupation like farmer and housewife, poor economic status were associated with tobacco use. PMID- 28814682 TI - Therapeutic Neck Dissection in Oral Squamous Cell Carcinoma: Is Selective Neck Dissection the Way Ahead? AB - Background Selective neck dissection in multimodality treatment protocols is slowly being accepted for the management of N+ neck in many centers. This is because the functional disability is lower than modified radical neck dissection. Objective This study compares the regional recurrence rates between patients who underwent selective neck dissection and patients underwent comprehensive neck dissection for node positive oral squamous cell carcinoma. Method A retrospective study comparing patients with node positive oral squamous cell carcinoma who underwent either selective neck dissection or comprehensive neck dissection between August 2011 and January 2014 was done, with a mean follow up period of 12 months. Regional failures were assessed to whether they were isolated neck failures or associated with a local or distant failure. Result A total of 131 neck dissections were performed which included 93 selective neck dissections and 38 comprehensive neck dissections. A total of 17 patients developed regional recurrence, of which 11 patients had ipsilateral neck recurrence. Of the 11 patients with ipsilateral neck recurrence one patient also had contralateral neck nodes and in two patients there was associated distant metastasis. Conclusion Selective neck dissection for management of node positive neck disease is based on sound scientific principles and a randomised controlled trial comparing it with modified radical neck dissection would probably give the answer regarding the optimal procedure for these patients. PMID- 28814683 TI - Prevalence of Attention Deficit Hyperactivity Disorder among School Children and Associated Co-morbidities - A Hospital Based Descriptive Study. AB - Attention Deficit Hyperactivity Disorder is the most common neuro- developmental disorders of childhood characterized by the core symptoms including inattentiveness and distractibility and frequently involve impairments in executive functioning, increased impulsivity, and restlessness. Objective To find out the prevalence of Attention Deficit Hyperactivity Disorder among school aged children Presented to Pediatric clinic and also to investigate associated comorbidities. Method This study was conducted at Nobel Medical College Teaching Hospital, Biratnagar during April 2014 - March 2015. Attention Deficit Hyperactivity Disorder was diagnosed by the developmental Pediatrician after taking relevant history and the clinical assessment using Attention Deficit Hyperactivity Disorder rating scale with diagnostic criteria consistent with Diagnostic Statistical Manual - IV classification. Spence anxiety scale child and parent rated version and Strength and Difficulty Questionnaire were also used. Result Result showed the yearly prevalence of Attention Deficit Hyperactivity Disorder being 41(11.7%) with male: female ratio of 4:1. The study reported that Attention Deficit Hyperactivity Disorder combined type was the commonest type that was 26(63%) cases followed by Inattentive type 9(22%) cases and 6(15%) were hyperactive type. The mean age for Attention Deficit Hyperactivity Disorder was 7 years and 5 months. The most common co-morbidities were sleep problem 12(29.3%), Learning difficulty 10(24.4%), Anxiety disorder 10(24.4), Oppositional Defiant Disorder 9(22%), Autism Spectrum Disorder 5(12%), speech delay 6(14.6%), and 4(10%) had associated tics. There was abnormal SDQ prevalence of 29.3% across the area of emotional distress. The mean abnormal SDQ score in total difficulty area 8 (20.7%), socializing with peer 9(22%), behavioral difficulty 11(26.8%), hyperactivity/inattention 23(56.1%) and impact of difficulties in young person's life being 5(12.2%). Conclusion There is high prevalence of Attention Deficit Hyperactivity Disorder in children and adolescents in Nepal. This study has also looked at co-morbidities associated with Attention Deficit Hyperactivity Disorder and the findings of the study have thrown lights on the mental health and other developmental issues associated with it. PMID- 28814684 TI - Correlation Between Oral Health and Body Mass Index among Nepalese Teachers. AB - Background Health problems like high body weight and oral diseases have the same essential risk factors as the inflammatory nature of obesity and periodontal disease are widely recognized. Body Mass Index and oral health indices are correlated and may be a confounder of disease status. Objective To assess oral health status and Body Mass Index of school teachers of Kathmandu valley and to find the correlation between them. Method A cross sectional study with purposive sampling was done on 100 Nepalese teachers to assess Body Mass Index, Community Periodontal Index and Decayed Missing Filled Teeth index. Mann-Whitney U-test, crude and adjusted odds ratio were used to analyze the difference between periodontal status based on Community Periodontal Indexscores in relation to age, Body Mass Index, Decayed Missing Filled Teeth. Result The prevalence of periodontal disease according to Community Periodontal Index score was: bleeding on probing 14%, calculus 34%, pocket depth 4-5 mm 35%, pocket depth >= 6 mm 12%. The mean Decayed Missing Filled Teeth index was 4.41, and mean number of teeth present was 29.22. According to Body Mass Index score; 10% were underweight, 38% overweight and 2% obese. There were significant differences in age, Body Mass Index and number of teeth present between the control and periodontitis groups. Logistic regression analysis revealed that the risk of periodontal disease increased with age, and there is an increased risk of periodontitis by 39% for each 1 kg/m2 Body Mass Index increase. Conclusion There is increased risk of periodontitis with gain in Body Mass Index in teachers of Kathmandu valley. PMID- 28814685 TI - Prevalence of Early Repolarization Patterns in Adults. AB - Background The finding of persistent Junction point elevation of 1 mm or more in adjacent leads in electrocardiogram is considered to be due to early repolarization. This condition was considered benign in the past but presently it is believed to be the rare cause of idiopathic ventricular fibrillation and sudden death. Objective The main objective of the study is to find out the prevalence of early repolarization pattern in subjects having electrocardiogram at Kathmandu Medical College Teaching Hospital. Method Twelve lead electrocardiograms of patients attending Kathmandu Medical College Teaching Hospital were studied. Data was collected for patient particulars. Electrocardiograms were analyzed for the type of early repolarization. Result The overall prevalence of early repolarization pattern of electrocardiogram was 2.82 %. It's prevalence in male and female was 4.95 % and 0.77 % respectively. The prevalence of different types of early repolarization electrocardiography pattern was 0.70 %, 1.25% and 0.63% of the population studied for type I, II, and III early repolarization patterns. Type IV or Brugada pattern was not detected in our study. Conclusion The commonest pattern observed was type II that is early repolarization pattern in inferior or inferolateral leads. Having knowledge of early repolarization and its type helps to counsel the physicians about the risk of arrhythmia and sudden cardiac death. PMID- 28814686 TI - Pattern of Cardiac Diseases in Children Attended at Dhulikhel Hospital, Nepal. AB - Background Congenital Heart Disease and Rheumatic Heart Disease are the most common childhood cardiac disease encountered in developing countries. Objective To study the pattern and the prevalence of cardiac diseases, its age wise distribution and to determine their risk factors for mortality in children presented to Dhulikhel Hospital, Kathmandu University Hospital. Method A study of cardiac diseases in children, since birth to 16 years of age attending the department of pediatrics in Dhulikhel Hospital, Kathmandu University Hospital was done over a period of 30 months (Jan 2014 to June 2016). The pattern of disease was studied. Detailed clinical examination of all cases was done followed by the necessary relevant investigations including electrocardiography, chest x-ray, echocardiography and supportive laboratory investigations. Result In this study period, 218 pediatric cardiac cases were encountered, among which 144 cases (66.05%) were Congenital Heart Disease, 57 cases (26.14%) were Rheumatic Heart Disease, 14 cases (6.42%) were Pericardial Disease and 3 cases (1.37%) were classified as Dilated Cardiomyopathy. Majority of Congenital Heart Disease were of isolated Ventricular Septal Defect (25%) and isolated Atrial Septal Defect (20.13%) followed by Patent Ductus Arteriosus (9.02%), Tetralogy of Fallot (6.94%) and Complex Congenital Heart Disease (6.25%). All of the Rheumatic Heart Disease primarily involved the Mitral Valve; however combined Aortic Valve involvement was seen in 26.31% of cases. All the 14 cases of pericardial disease presented with pericardial effusion and two cases presented with constrictive pericarditis. All the cases of pericardial disease were investigated to be of tubercular in origin. Conclusion Septal defects are the most common Congenital Heart Disease encountered in children. Although the prevalence of Rheumatic Heart Disease is decreasing worldwide, it is still a big burden in our community. Tubercular pericardial effusion is still not uncommon and should be suspected with a child presenting with pericardial effusion. Increased level of cardiac care and corrective surgeries are needed for children with cardiac disease in Dhulikhel Hospital, Kathmandu University Hospital. PMID- 28814687 TI - Laparoscopic Appendectomy Versus Open Appendectomy for Acute Appendicitis: A Prospective Comparative Study. AB - Background Appendicitis is the most common cause for acute abdominal pain. Laparoscopic appendectomy is an effective alternative to open appendectomy. It is a minimally invasive results in less postoperative pain, less wound infection, early return to normal work and less morbidity compared to open appendectomy. Both surgical methods are safe but there has been a controversy about which surgical procedure is the most appropriate. Objective To compare the outcomes of laparoscopic versus open appendectomy. Method In this prospective study, from January 2015 to April 2016, 212 cases of acute appendicitis were included. Diagnosis was based on Alvarado score of seven or above. Patients were distributed into two groups where every alternate patient was operated either open or laparoscopically. The groups were compared in terms of operative time, postoperative pain, postoperative wound infection, other morbidities and length of hospital stay. Result Of 212 patients, 106 underwent open and 104 underwent laparoscopic appendectomy. Other two patients, in whom laparoscopy was converted to open procedure, were excluded from the study. The mean operating time in laparoscopic appendectomy group was 44.57 +/- 6.68 minutes and in open appendectomy group, was 36.34 +/- 7.47 minutes (p < 0.05). The visual analog scale scores at 6th, 12th, 24th and 48th hours were higher in open appendectomy group compared to laparoscopic appendectomy group (p< 0.05). The hospital stay was 2.63 +/- 0.60 days in laparoscopic appendectomy group and 3.26 +/- 0.68 days in open appendectomy group (p < 0.05). Surgical site infection in laparoscopic appendectomy and open appendectomy group were 3.8% and 14 % respectively (p< 0.05). Conclusion In laparoscopic appendectomy group, there is lower incidence of wound infection, lesser postoperative analgesic requirement and shorter hospital stay in comparison to open appendectomy. Though, the operative time is more with laparoscopic appendectomy, it can be considered as the gold standard for surgical treatment of acute appendicitis. PMID- 28814688 TI - Analysis of Post Earthquake Disease Pattern in a Camp at Gyampesal Gorkha. AB - Background A major earthquake occurred in Nepal on 25th April 2015 with magnitude of 7.8 causing mass panic amongst people. Objective To analyze scenario, experience and disease pattern of Post Earthquake camp at Gyampesal, Gorkha. Method A prospective observational study done on 13th and 14th June 2015 in a population who attended the health camp at health post, Gyampesal Gorkha. Analysis was done for age, sex, and disease pattern. Medicines for their health problems was provided by Manipal Teaching Hospital, Pokhara, Nepal Pediatric Society and Children Welfare in Nepal, Kathmandu. Result Total 159 patients [80.5% children and 19.5% adults] had attended the health camp. The mean age of children was 6.18+/-4.27 SD with maximum between 2-5 years (39%) and mean age of adults was 37.87+/-14.07 SD. Among the children males were more (50.8%) than females but in adult group females (83.9%) were more. Most common complaints were earthquake related fear (Children- 60.23% / adults -71%), insect bite [children 25.8% /adults -35.5%], pain abdomen (children- 64.1% / adult -38.7%) and decreased appetite (children- 83.6% / adults - 16.1%). Pain abdomen and decreased appetite was significantly high in children with p < 0.009 and 0.001 respectively. The common disease patterns noted in children were recurrent abdominal pain (25%), acute gastroenteritis (19.5%), upper respiratory tract infections (15.6%), Impetigo (15.6%), Dental caries(10%), Pityriasis alba (10%). In adults Acid peptic disease (51.6%), Headache (32.5%), hypertension, Upper respiratory infections, scabies and Urinary tract infection (16%), Acute gastroenteritis (13%) was common. Conclusion Earthquake related fear, insect bite and Communicable diseases both airborne and water borne were the commonest findings observed. Therefore basic needs and services like safe water and sanitation, adequate shelter, primary healthcare services and vector-control campaigns are crucial and essential for these displaced populations. PMID- 28814689 TI - Correlation of Cervical Pap Smear with Biopsy in the Lesion of Cervix. AB - Background Cervical cancer can be controlled to a greater extent by screening to improve morbidity and mortality. Pap smear is important screening method, which has proven to be highly effective in reducing the number of cases and the mortality from cervical carcinoma. Any abnormality detected in pap smear has to be confirmed with cervical biopsy, which remains the reference investigation. Objective To find the changes of cervical cytology by pap smear, to classify cervical lesions into malignant and benign groups on cytological and histopathological basis and to correlate the changes observed in cervical cytology with cervical biopsy. Method This is a prospective cross sectional study done in between July 2014 and July 2015 in Dhulikhel Hospital, Kathmandu University Hospital. During the period, all the samples requested for pap smear were studied. The cases who had undergone both pap smear and cervical biopsy were compared. Clinical data were obtained from requisition submitted along with the cytology and tissue specimens received in the department. Result During the study period, total 1922 pap smears were performed and out of them 75 patients were advised to do cervical biopsy. On cytology, out of total 1922 number of cases, 67.90% were normal, 27.90% were inflammatory smears, 3.80% were unsatisfactory (inadequate) and 0.40% were high grade intraepithelial lesions. Highest numbers of patients screened for pap smear ranged from 31 to 40 years. On histopathology, 78.70% had chronic cervicitis, 8% had normal findings, 1.30% had moderate and 6.70% had severe squamous intraepithelial lesions. The frank malignancy was found in 5.30%. The mean age +/- SD for carcinoma was 52.75+/-6.29. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value of pap smear were 77.80%, 100%, 100% and 97% respectively considering cervical biopsy as the gold standard Conclusion This study revealed a good correlation of cervical cytology with cervical biopsy. Pap is a cost effective screening method for early detection of premalignant and malignant cervical lesions. However, biopsy is considered as the gold standard for the confirmation of abnormalities detected in cervical smear. PMID- 28814690 TI - Imaging in Infertile Female Patients Who Underwent Hysterosalpingography Investigation at Dhulikhel Hospital. AB - Background Fallopian tube and uterine abnormalities are the most common cause of female infertility, accounting for 30% of cases. Hysterosalpingography is the safe, minimal invasive radiographic technique for evaluation of uterine cavity and fallopian tubes defects. The purpose of the study was to assess the various uterine and tubal abnormalities leading to infertility Objective To assess the abnormalities in uterus and fallopian tubes detected on Hysterosalpingography (as causative factors of infertility in a tertiary care centre for proper decision making in treatment. Method This is the prospective cross sectional study done in department of radiology Dhulikhel hospital, Kathmandu University Hospital between January 2015 to January 2016 with complain of infertility. Hysterosalpingography was performed using ionic contrast medium (10-20 ml of 76% urograffin) under digital fluoroscopy. Radiographic films were obtained and analyzed. Demographic data and radiological findings were reviewed and the obtained data analyzed with SPSS version 16. Result Out of the total 100 patient, 75 had primary infertility while 25 had secondary infertility. The age ranged from 19 to 43 years with mean age of 27.75 years. Normal Hysterosalpingography findings were seen in 37% cases. Tubal abnormalities were seen in 34%, uterine abnormalities in 23% and both tubal and uterine abnormalities in 6% patients. The most common tubal abnormality detected on Hysterosalpingography was tubal block 75%. Out of the 30 patients who had tubal block, unilateral block was noted in 76.7% patients whereas bilateral block was noted in 23.3%. Hydrosalphinx was seen in 25% cases with tubal abnormality. Among the 29 cases with various uterine abnormalities, bicornuate uterus 9% was the most common abnormality Conclusion Hysterosalpingography is an easily available radiographic procedure that can demonstrate a wide variety of uterine and tubal abnormalities for the initial assessment of infertility which can avoid unnecessary and sometimes more aggressive procedures. PMID- 28814691 TI - Study of Depression among the Nursing Students in a University Medical College of Nepal. AB - Nursing students pass through many stressful situations during their academic course. Depression is frequently observed in this student group. Objective To quantify and compare the level of depression among the students undertaking undergraduate and graduate level nursing education in Kathmandu University School of Medical Sciences, Nepal. Method A questionnaire based cross-sectional study was carried out among all the students of Proficiency Certificate Level, Bachelor in Nursing Sciences and B.Sc. Nursing in Kathmandu University School of Medical Sciences, studying in different years during the academic year (2013-14) using Beck Depression Inventory. Descriptive statistics was used for computing scores of Beck Depression Inventory while Pearson correlation was used for analysis of association. Result Among the total 227 students consenting for the study, 212 were amenable for analysis. All of the participants were females, with mean age 20.10 (+/- 2.2). Almost 40% were found to be having depressive symptoms in variable degrees of severity (Mild-27.4%, Moderate-9%, Severe-1.4%). Frequency of depression was higher among the senior grade students. Agitation, fatigability and sadness were the items having highest mean score; (0.82 +/- 0.72), (0.76 +/- 0.63), and (0.74 +/- 0.52) respectively, while weight loss and loss of libido had the least score, (0.10 +/-0.33) and (0.19 +/-0.55) respectively. Item on suicidal ideation was significantly correlated with age (p=0.038) and BDI score (< 0.001). Conclusion Depression is common among the nursing students in Nepal; which may also be related to the multitude of stressors they experience during their studentship. PMID- 28814692 TI - Permanent Teeth Emergence Time and Sequence in Children of Kavre District, Nepal. AB - Background Population specific standards on the timing and sequence of emergence of permanent teeth are essential in planning dental care for children. There is only a single study on the emergence of permanent teeth in Nepalese children. Objective To determine the standards for permanent teeth emergence time and sequence in children of Kavre district, Nepal. Method A descriptive cross sectional study was conducted in 623 children of age 5 to 14 years from six different schools of Kavre district. The number of permanent tooth erupted except third molar was recorded along with age and gender. Data were analysed using SPSS 20.0. Descriptive statistics was used to determine the number and percentage of permanent teeth emerged at different ages and the mean age of emergence of each tooth. Student 't' test was used to determine the inter jaw differences in the mean age of emergence of each tooth. Result The study population constituted 50.7% boys and 49.3% girls of the total sample. The first tooth to emerge was mandibular first molar, whereas maxillary second molar tended to be the last to emerge in both the genders. Though in general, mandibular teeth tended to precede the corresponding maxillary teeth in emergence but significantly only mandibular central, lateral and second premolar emerged earlier than maxillary.( p <= 0.05) Conclusion This study can be used as a reference data for clinical and academic purpose especially for the children of Kavre district, Nepal. PMID- 28814693 TI - Socio Demographic Predictors in Delayed Presentation of Head and Neck Cancer. AB - Background Head and neck cancer is a major public health problem worldwide. In spite of the increase in incidence, there has been paucity of research on socio demographic factors influencing head and neck cancer. Objective To study the influence of various socio demographic factors on late presentation of head and neck cancer. Method Prospective, analytical study conducted in 69 patients with Head and neck malignancies in Department of Otorhinolaryngology and Head and Neck surgery, Kathmandu University School of Medical sciences between January 2015 to January 2016. Collected data were entered and analyzed using IBM SPSS statistical software 21.0. All the socio demographic variables were compared between the early and late presentation groups of patient using Chi-square test. A 'p' value of < 0.05 was considered statistically significant. Result Forty eight were male and 21 were female. The age of patients ranged from 34 to 70 years (mean age 52.03). Twenty patients were diagnosed in stage I, 13 in stage II, 20 in stage III and 16 in stage IV. Significant association was seen between stage of head and neck cancer and duration of illness (p=0.007), educational status of patient (p=0.003) and educational status of patient's care taker (p=0.005). However, no statistical association was seen between stage at diagnosis of head and neck cancer and gender, type of family, previous consultation, systems of alternative medicine adopted before diagnosis, smoking habit, alcohol intake, tobacco chewing habit and occupation. Conclusion The results of this study suggest that educational status may influence the presentation of head and neck cancer. PMID- 28814694 TI - Diseases in Disaster: Post-Earthquake Dermatoses, Nepal 2015. AB - Nepal experienced a devastating earthquake measuring 7.8 Richter scale on 25th April 2015. Although the heightened effects were secondary to trauma, the indirect effects were also of prime importance. We came across different dermatoses, directly or indirectly secondary to earthquake. We here present an audit of the cutaneous effects following four months of the major shock presenting to a tertiary care center of central Nepal. A total of 7326 patients presented to the dermatology department over a period of four months following the major shock. Among them a total of 3833 patients (52.32%) had direct or indirect dermatoses following earthquake. PMID- 28814695 TI - Paediatric Stroke: A Rare Presentation of Iron Deficiency Anemia in a Four Year Old Child. AB - Paediatric stroke is an uncommon syndrome with even lesser annual incidence rates of arterial ischemic stroke in infants and children. In children the diagnosis of stroke is frequently delayed or missed. This is due to subtle and nonspecific clinical presentations, a complicated differential diagnosis and a lack of awareness by physicians and also delay in the seeking of medical attention as in our case. We report you a rare case of a four year old child from remote Nepal who presented to our Out Patient Department after a long gap of around four months after the sudden onset of loss of consciousness and decreased movement of right limbs who after detailed history examination and lab investigations and imaging revealed ischemic stroke due to iron deficiency anemia. PMID- 28814696 TI - Even a Tooth Slips Sometimes. AB - While impaction of a tooth or two in dentoalveolar region is common, ectopic presence of them in non-dentate area is less commonly reported. A 45-year-old female reported to the department with pain on right back teeth region since two days. On examination, grossly decayed 46, root stump 47, missing 48, with poor periodontal status were noted. Panoramic radiograph was advised for screening, which revealed an inverted impacted 48 at the right ramus just below subcondylar region. However, it was an incidental finding and the patient was asymptomatic, she was informed about the pros and the cons of her case and kept under close monitoring. PMID- 28814697 TI - Superior Mesenteric Artery Syndrome: Diagnosis and Management. AB - Superior mesenteric artery syndrome is a life-threatening rare acquired upper gastrointestinal disorder due to mechanical compression of third part of duodenum by the acute angulation of Superior mesenteric artery, leading to obstruction. Acute loss of intervening mesenteric fat as a result of a variety of debilitating conditions is believed to be the etiologic factor causing the reduced aortomesenteric angle. Abdominal CT angiography showed the dilatation of second part of duodenum and vascular compression of the proximal third part of the duodenum between the aorta and superior mesenteric artery. We report a case of 15 year old young boy who presented with recurrent postprandial pain in the epigastric region, accompanied by epigastric fullness, nausea, postprandial bilious vomiting and weight loss. When conservative measures were ineffective, laparoscopic retrocolic duodenojejunostomy, side to side anastomosis, was performed in the patient to relieve the obstruction. This case report is unusual as it is concerned with the description of a rare disease entity and its radiological appearances for early preoperative diagnosis, better understanding and management of the disease are discussed in the pertinent light of literature. PMID- 28814698 TI - Accessory Lobe of Liver Associated with a "Bean Shaped" Gall Bladder. AB - Occurrence of accessory lobes of liver and anomalies of gall bladder is quite common. A thorough knowledge of their variation can minimise diagnostic and surgical errors. We found concurrent variations of liver and gall bladder. A small accessory liver lobe was attached to the quadrate lobe through a stalk formed by peritoneum. The gall bladder was "bean shaped" due to the presence of a constriction in the middle of its body. Since the accessory lobe was quite close to gall bladder, it could compress the gall bladder and hinder normal functioning of it. The knowledge of these variations might be of importance to radiologists and surgeons dealing with the hepatobiliary system. PMID- 28814699 TI - Teaching District Concept of BP Koirala Institute of Health Sciences: An Inter disciplinary Community Based Medical Education and Health Service Delivery Model in Rural Nepal. AB - Community based education trains health professional students to deal with the community health problems. The attitude and skills they gain as planners for health care provision are applicable in both hospital and community settings. BP Koirala Institute of Health Sciences has implemented a model of Community based education which encompasses the health institutions, organisations and the communities of the sixteen districts in eastern Nepal and refers to this concept as the 'Teaching District" concept of B P Koirala Institute of Health Sciences. This paper seeks to describe the concept and its implementation. Almost 20 years have passed since first initiated; and pending a comprehensive evaluation, this concept has gathered a great deal of experience to serve as a model for partnership between academic health sciences institutions with the district health system of Nepal. PMID- 28814700 TI - The Birth of Hospital, Asclepius cult and Early Christianity. AB - History of hospital is one of main fields of researches in medical history. Besides writing a history of an individual hospital, considerable efforts have been made to trace the origin of hospital. Those who quest for the origin of hospital are faced with an inevitable problem of defining hospital. As the different definition can lead to a different outcome, it is important to make a clear definition. In this article, the hospital was defined as an institution in which patients are housed and given medical treatments. According to the definition, the Great Basilius is regarded to have created the first hospital in 369 CE. The creation of hospital is considered to be closely related with Christian philantrophy. However, the question is raised against this explanation. As the religious philantrophy does not exclusively belong to the Christianity alone, more comprehensive and persuasive theory should be proposed to explain why the first hospital was created in the Christian World, not in the Buddhistic or other religious world. Furthermore, in spite of sharing the same Christian background, why the first hospital appeared in Byzantine Empire, not in Western Roman Empire, also should be explained. My argument is that Asclepius cult and the favorable attitude toward medicine in Greek world are responsible to the appearance of the first hospital in Byzantine Empire. The evangelic work of Jesus was heavily depended on healing activities. The healing activities of Jesus and his disciples were rivalled by Asclepius cult which had been widely spread and practiced in the Hellenistic world. The temples of Asclepius served as a model for hospital, for the temples were the institution exclusively reserved for the patients. The exclusive housing of patients alone in the temples of Asclepius is clearly contrasted with the other early forms of hospitals in which not only patients but also the poor, foreigners and pilgrims were housed altogether. Toward the healing god Asclepius, the Latin Church fathers and Greek Church fathers showed significant difference of attitudes. The Latin fathers were generally very critical on Asclepius while the Greek fathers were more favorable to the same healing god. This difference is also considered to be an important factor that can explain why the first hospital appeared in the Byzantine Empire. PMID- 28814701 TI - "Byoin" in Modern Japan: Focusing on the Terminological Introduction of "Hospital" and the Complex Formation of Its Concept. AB - This paper aims to clarify when the term of Byoin (hospital) was introduced and how its concept was developed in modern Japan. The word "Byoin" was introduced in Japan in 1787 for the first time, but it had not been in use until early 1860s. Instead, various medical institutions performing the functions of modern medical facilities, such as Yojosho (A place for preserving health), Shijuku (private school), called by traditional names as ever. Japanese intellectuals already adopted the word Byoin and the concept of western hospital in early 1860s when their national delegates were dispatched to Europe to revise the treaties forged with western powers. Japanese translations of hospital appeared in English Japanese/Japanese-English dictionaries published in the 1860s. For instance, the word Byoin (hospital in Japanese) was first published in a dictionary published in 1867 and unclearly connected to the words, hospital, infirmary. This paper will argue that the concept of Byoin was sophisticated through Meiji government's efforts to implement reforms distinguishing medical facilities based on their capacity of inpatients and quality. The first medical law (Isei) proclaimed by the Meiji government in 1874 articulated regulations for a hospital in eight different articles. The government established hospitals in various parts of the country, following its newly established modern medical care policies. However, in this process, Iin (hospital/clinic), another term for "hospital" appeared. Regional differences and financial issues made standardizing the concept of a hospital even more difficult. In response to the widely embedded confusion, the Japanese government made an effort to clarify the concept of a hospital, setting up provisions regarding the size of medical facilities. As a result, the word Byoin finally came to be used for a hospital with more than ten beds, while a clinic with beds below ten was called Shinryojo (clinic). On the other hand, Iin meant a medical facility less qualified than a hospital since 1933 when Japanese government made a harder restriction on the usage of Byoin. PMID- 28814703 TI - Becoming an International Scientist in South Korea: Ho Wang Lee's Research Activity about Epidemic Hemorrhagic Fever. AB - In the 1960-70s, South Korea was still in the position of a science latecomer. Although the scientific research environment in South Korea at that time was insufficient, there was a scientist who achieved outcomes that could be recognized internationally while acting in South Korea. He was Ho Wang Lee(1928~ ) who found Hantann Virus that causes epidemic hemorrhagic fever for the first time in the world. It became a clue to identify causative viruses of hemorrhagic diseases that were scattered here and there throughout the world. In addition, these outcomes put Ho Wang Lee on the global center of research into epidemic hemorrhagic fever. This paper examines how a Korean scientist who was in the periphery of virology could go into the central area of virology. Also this article shows the process through which the virus found by Ho Wang Lee was registered with the international academia and he proceeded with follow-up research based on this progress to reach the level at which he generalized epidemic hemorrhagic fever related studies throughout the world. While he was conducting the studies, experimental methods that he had never experienced encountered him as new difficulties. He tried to solve the new difficulties faced in his changed status through devices of cooperation and connection. Ho Wang Lee's growth as a researcher can be seen as well as a view of a researcher that grew from a regional level to an international level and could advance from the area of non-mainstream into the mainstream. This analytic tool is meaningful in that it can be another method of examining the growth process of scientists in South Korea or developing countries. PMID- 28814702 TI - Reorganizing Hospital Space: The 1894 Plague Epidemic in Hong Kong and the Germ Theory. AB - This paper examined whether the preventive measures taken by the Hong Kong's colonial authorities were legitimate during the 1894 Hong Kong plague epidemic, and illuminated the correlation between the plague epidemic and hospital space in Hong Kong in the late 19th century. The quarantine measures taken by the colonial authorities were neither a clear-cut victory for Western medicine nor for a rational quarantine based on scientific medical knowledge. Hong Kong's medical officials based on the miasma theory, and focused only on house-to-house inspections and forced quarantine or isolation, without encouraging people to wear masks and without conducting disinfection. Even after Hong Kong plague spread, the Hong Kong's colonial authorities were not interested in what plague bacilli were, but in where they were to be found and how to prevent and control an outbreak of the disease. The germ theory brought significant changes to the disease classification system. Until the 1890s, Hong Kong's colonial authority had classified cause of death mainly on the basis of symptoms, infectious diseases, parts of the body and diseases of systems. Microbiological analysis of the cause of death in Hong Kong was started by Hunter, a bacteriologist, in 1902. He used bacteriological tests with a microscope to analyze the cause of death. New disease recognition and medical recognition brought large changes to hospital space as well. In particular, from the 1880s to the early 1900s, Western medical circles witnessed shifts from miasma theory to the germ theory, thereby influencing Hong Kong's hospital spaces. As the germ theory took ground in Hong Kong in 1894, the bacteriological laboratory and isolation ward became inevitable facilities, and hospital space were reorganized accordingly. However, the colonial authorities and local elites' strategy was different. As a government bacteriologist, Hunter established a central facility to unify several laboratories and to manage urban space from ouside the hospital. On the contrary, the Tungwah Hospital tried to transform hospital space with isolation ward and Receiving Ward System as the eclectic form of Chinese and Western medicine. The 1894 Hong Kong plague promoted the introduction of germ theory and the reorganization of hospital space. PMID- 28814704 TI - [Clinical Evaluation of Urosepsis in Tane General Hospital ; Clinical Utility of Measurement of Procalcitonin]. AB - We clinicaliye valuated 355 patients with urinarytract infections (UTI), suspected of having urosepsis at Tane General Hospital, and determined the usefulness of the biomarker procalcitonin (PCT) as an aid in predicting urosepsis. Clinical and microbiological data were collected. The logistic regression analysis was used to determine the risk factors of urosepsis. Of 355 patients, 169 patients (47.6%) were diagnosed with urosepsis. C-reactive protein (CRP) (OR 2. 633, p<0. 001), PCT (OR 2. 153, p=0. 003) and clinical diagnosis (calculous pyelonephritis OR 1. 886, p=0. 019, acute prostatitis OR 3. 614, p<0. 001) were established as the independent risk factors of urosepsis. Of 169 patients with urosepsis, 43 patients (25.4%) were diagnosed with severe urosepsis. In the severe urosepsis group, 2 patients with a PCT value <2.0 ng/ml were included. The mortalityrate in patients with severe urosepsis was 4.65% (2/43) in this study. We concluded that the PCT level could be a reliable marker suggestive of urosepsis. However, patients very early in the onset of infection mayhave a normal PCT value. It is essential to use all available clinical information when interpreting the results of a PCT measurement. PMID- 28814705 TI - [Spontaneous Subcapsular Renal Hemorrhage of Papillary Renal Cell Carcinoma]. AB - A 75-year-old man with a history of chronic kidney disease (CKD) visited our emergency room after the sudden onset of severe right lower abdominal pain and nausea. Computed tomography (CT) showed right perirenal hematoma and renal tumor, which was diagnosed as a spontaneous rupture of the right renal tumor. It was difficult to correctly diagnose the tumor as benign or malignant with magnetic resonance imaging (MRI). Because of CKD, a shunt was implanted, and dynamic enhanced CT was performed. Dynamic enhanced CT showed a slightly enhanced area of the tumor, and it was diagnosed as renal cell carcinoma (RCC). Radical nephrectomy was performed, and he has not experienced recurrence within 7 months after the surgery. Pathological diagnosis was papillary renal carcinoma. Spontaneous renal hemorrhage is relatively uncommon, but the most common cause of spontaneous renal hemorrhage is renal cell carcinoma (26.1%). CT is useful for diagnosis, but it is not highly accurate. Therefore, it is necessary to discuss surgical indication carefully. PMID- 28814706 TI - [Diagnostic Impact of 3D-CT with Retrograde Pyelography for Ureteropelvic Junction Obstruction : A Case Report]. AB - A 26-year-old woman presented to our hospital with right costovertebral angle (CVA) pain. Ultrasonographyand computed tomography(CT) scan indicated right hydronephrosis, and MAG3 renogram showed an obstructed pattern in the right kidney. Enhanced CT scan revealed an ureteropelvic junction obstruction (UPJO) with an aberrant vessel. To clarifythe ureteropelvic junction (UPJ) structure in detail, we utilized 3D-CT with retrograde pyelography (RP), which further revealed the true pinhole ureteral stricture of UPJ unaffected bythe aberrant vessel. PMID- 28814707 TI - [Transurethral Injection Using Deflux for Vesicoureteral Reflux in Three Adult Women with Frequent Febrile Urinary Tract Infections]. AB - We report three patients with frequent febrile urinary tract infections (fUTI) who underwent transurethral injection therapy with Deflux for vesicoureteral reflux (VUR). The first case was in a 52-yearold woman who was initially diagnosed with right grade II and left grade I VUR at 18 years of age. She frequently experienced fUTI due to VUR. The second case was in a 29-year-old woman. At age 23,she was diagnosed with right grade III VUR when she developed fUTI. After that,she repeatedly developed fUTI. The third case was in a 40-year old woman who had frequently experienced fUTI since 25 years of age and had gradually become antibiotics-resistant. She was diagnosed with right grade III VUR when she was referred to our hospital. No visible reflux was confirmed by postoperative voiding cystourethrography after the patients underwent transurethral injection using Deflux. One patient developed fUTI once after surgery,but there were no perioperative complications and no recurrences. Transurethral injection using Deflux for VUR might therefore be safe and effective for treating VUR in adult female patients. PMID- 28814708 TI - [A Case of Pulmonary Tumor Thrombotic Microangiopathy in Castration-Resistant Prostate Cancer]. AB - A man aged 83 years under treatment with enzalutamide for castration-resistant prostate cancer presented with general malaise and exertional dyspnea. The underlying cause could not be identified by further investigations. On the 5th hospital day, he died due to a sudden exacerbation of dyspnea. The results of an autopsy indicated tumor emboli and stenosis of small pulmonary arteries with the fibrocellular intimal thickening, and therefore our final diagnosis was pulmonary tumor thrombotic microangiopathy. PMID- 28814709 TI - Spindle Cell Oncocytoma of the Anterior Pituitary Presenting with an Acute Clinical Course Due To Intraventricular Hemorrhage. A Case Report and Review of Literature. AB - BACKGROUND Spindle cell oncocytoma (SCO) is a rare nonfunctioning neoplasm of the adenohypophysis, and was first described in 2002. SCO has been categorized as a separate entity by the 2007 World Health Organization (WHO) and is classified as a Grade 1 tumor of the central nervous system (CNS). Review of the literature has shown that 33 cases of SCO have been reported to date, and most of them presented with a mass effect or with panhypopituitarism. However, all reported cases have described the tendency of SCO to be hypervascular on imaging and histology. We detail the first reported case of SCO to present with acute symptoms (pituitary apoplexy) and intraventricular hemorrhage, and review the literature on SCO. CASE REPORT We report the case of 56-year-old man who presented suddenly with a severe headache and an altered level of consciousness. Brain magnetic resonance imaging (MRI) showed a suprasellar mass with hemorrhagic areas within the tumor and bleeding into the lateral ventricle with chiasmal and hypothalamic compression. The patient underwent urgent craniotomy, tumor resection and placement of an external ventricular drain (EVD). Histology and immunohistochemistry supported a diagnosis of SCO. CONCLUSIONS SCO of the adenohypophysis should be considered in patients who present suddenly with symptoms of pituitary apoplexy and intraventricular hemorrhage which may worsen the prognosis. PMID- 28814710 TI - Left Univentricular Pacing by Rate-Adaptive Atrioventricular Delay in Treatment of Chronic Heart Failure. AB - BACKGROUND Cardiac resynchronization therapy (CRT) is efficacious in the treatment of chronic heart failure (CHF); however, because it is non physiological, some patients are unresponsive. The present study used rate adaptive atrioventricular delay (RAAVD) to track the physiological atrioventricular delay and investigated the effects of left univentricular pacing on CRT. MATERIAL AND METHODS Patients with CHF fulfilling the indication of CRT Class I were categorized into a left univentricular pacing by RAAVD group and a standard biventricular pacing group. Preoperative and postoperative electrocardiography QRS duration, echocardiographic indicators, quality of life, cardiac function, and annual treatment cost were estimated. The standard deviation (RS/R-SD5) of the S/R ratio in lead V1 at 5 heart rate segments in the left univentricular pacing by RAAVD was calculated, and the accuracy of RAAVD in tracking the physiological AV delay was evaluated. RESULTS The comparison between the left univentricular pacing by RAAVD group and the standard biventricular pacing group after operation showed a significantly reduced QRS duration (137+/ 11 vs. 144+/-11 ms, P<0.05), increased AVVTI (21.84+/-2.25 vs. 20.45+/-2.12 cm, P<0.05), reduced IVMD (64.27+/-12.29 vs. 71.39+/-13.64 ms, P<0.05), decreased MRA (3.09+/-1.12 vs. 3.73+/-1.19 cm2, P<0.05), and reduced average annual treatment cost (1.30+/-0.1 vs. 2.20+/-0.2 million Yuan, P<0.05). The RS/R-SD5 in the left univentricular pacing by RAAVD group was negatively correlated with improvements in cardiac function (r=-0.394, P=0.031). CONCLUSIONS Left univentricular pacing by RAAVD has treatment effects similar to those of standard biventricular pacing, and is an economically and physiologically effective method for biventricular systolic resynchronization in the treatment of CHF. PMID- 28814712 TI - Secondary compound hypothesis revisited: Selected plant secondary metabolites promote bacterial degradation of cis-1,2-dichloroethylene (cDCE). AB - Cis-1,2-dichloroethylene (cDCE), which is a common hazardous compound, often accumulates during incomplete reductive dechlorination of higher chlorinated ethenes (CEs) at contaminated sites. Simple monoaromatics, such as toluene and phenol, have been proven to induce biotransformation of cDCE in microbial communities incapable of cDCE degradation in the absence of other carbon sources. The goal of this microcosm-based laboratory study was to discover non-toxic natural monoaromatic secondary plant metabolites (SPMEs) that could enhance cDCE degradation in a similar manner to toluene and phenol. Eight SPMEs were selected on the basis of their monoaromatic molecular structure and widespread occurrence in nature. The suitability of the SPMEs chosen to support bacterial growth and to promote cDCE degradation was evaluated in aerobic microbial cultures enriched from cDCE-contaminated soil in the presence of each SPME tested and cDCE. Significant cDCE depletions were achieved in cultures enriched on acetophenone, phenethyl alcohol, p-hydroxybenzoic acid and trans-cinnamic acid. 16S rRNA gene sequence analysis of each microbial community revealed ubiquitous enrichment of bacteria affiliated with the genera Cupriavidus, Rhodococcus, Burkholderia, Acinetobacter and Pseudomonas. Our results provide further confirmation of the previously stated secondary compound hypothesis that plant metabolites released into the rhizosphere can trigger biodegradation of environmental pollutants, including cDCE. PMID- 28814711 TI - Reprogramming Bone Marrow Stem Cells to Functional Endothelial Cells in a Mini Pig Animal Model. AB - BACKGROUND The aims of this study were to compare the morphological, biochemical, and functional properties of reprogrammed bone marrow stem cell (BMSC)-derived arterial endothelial cells (AECs) and venous endothelial cells (VECs), following adenosine triphosphate (ATP)-stimulation in a mini pig animal model. MATERIAL AND METHODS Bone marrow aspiration was performed in six adult mini pigs. Harvested mononuclear cells were isolated, cultured, and treated with vascular endothelial growth factor (VEGF) (16 ug/ml). Transformed cells were characterized using immunofluorescence staining for CD31 and von Willebrandt factor (vWF) and expression of endothelial nitric oxide synthase (eNOS). Cell release of nitric oxide (cNO) was measured using spectrophotometry. Matrigel assays were used to investigate angiogenesis in transformed BMSCs. RESULTS Reprogrammed BMSCs in culture showed a typical cobblestone-like pattern of growth. Immunofluorescence staining was positive for CD31 and vWF expression. Expression of eNOS, using immunofluorescence staining and Western blot, showed no difference between the reprogrammed BMSCs and VECs. Spectrophotometric examination following stimulation with 10mmol/l ATP, showed comparable cNO release for reprogrammed BMSCs (10.87+/ 1.76 pmol/106 cells/min) and VECs (13.23+/-2.16 pmol/10^6 cells/min), but reduced cNO release for AECS (3.44+/-0.75 pmol/10^6 cells/min). Matrigel assay for angiogenesis showed vascular tube formation of differentiated BMSC endothelial cells (grade 3.25). BMSCs cultured without VEGF did not demonstrate vascular tube formation. CONCLUSIONS The findings of this study showed that eNOS expression and release of NO could be used to show that BMSCs can be reprogrammed to functional VECs and AECs. PMID- 28814713 TI - Gelsolin dysfunction causes photoreceptor loss in induced pluripotent cell and animal retinitis pigmentosa models. AB - Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) cause X-linked RP (XLRP), an untreatable, inherited retinal dystrophy that leads to premature blindness. RPGR localises to the photoreceptor connecting cilium where its function remains unknown. Here we show, using murine and human induced pluripotent stem cell models, that RPGR interacts with and activates the actin severing protein gelsolin, and that gelsolin regulates actin disassembly in the connecting cilium, thus facilitating rhodopsin transport to photoreceptor outer segments. Disease-causing RPGR mutations perturb this RPGR-gelsolin interaction, compromising gelsolin activation. Both RPGR and Gelsolin knockout mice show abnormalities of actin polymerisation and mislocalisation of rhodopsin in photoreceptors. These findings reveal a clinically-significant role for RPGR in the activation of gelsolin, without which abnormalities in actin polymerisation in the photoreceptor connecting cilia cause rhodopsin mislocalisation and eventual retinal degeneration in XLRP.Mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) cause retinal dystrophy, but how this arises at a molecular level is unclear. Here, the authors show in induced pluripotent stem cells and mouse knockouts that RPGR mediates actin dynamics in photoreceptors via the actin-severing protein, gelsolin. PMID- 28814714 TI - Evaluation of thermodynamics, formation energetics and electronic properties of vacancy defects in CaZrO3. AB - Using first-principles total energy calculations we have evaluated the thermodynamics and the electronic properties of intrinsic vacancy defects in orthorhombic CaZrO3. Charge density calculations and the atoms-in-molecules concept are used to elucidate the changes in electronic properties of CaZrO3 upon the introduction of vacancy defects. We explore the chemical stability and defect formation energies of charge-neutral as well as of charged intrinsic vacancies under various synthesis conditions and also present full and partial Schottky reaction energies. The calculated electronic properties indicate that hole-doped state can be achieved in charge neutral Ca vacancy containing CaZrO3 under oxidation condition, while reduction condition allows to control the electrical conductivity of CaZrO3 depending on the charge state and concentration of oxygen vacancies. The clustering of neutral oxygen vacancies in CaZrO3 is examined as well. This provides useful information for tailoring the electronic properties of this material. We show that intentional incorporation of various forms of intrinsic vacancy defects in CaZrO3 allows to considerably modify its electronic properties, making this material suitable for a wide range of applications. PMID- 28814716 TI - Lithium enrichment in intracontinental rhyolite magmas leads to Li deposits in caldera basins. AB - The omnipresence of lithium-ion batteries in mobile electronics, and hybrid and electric vehicles necessitates discovery of new lithium resources to meet rising demand and to diversify the global lithium supply chain. Here we demonstrate that lake sediments preserved within intracontinental rhyolitic calderas formed on eruption and weathering of lithium-enriched magmas have the potential to host large lithium clay deposits. We compare lithium concentrations of magmas formed in a variety of tectonic settings using in situ trace-element measurements of quartz-hosted melt inclusions to demonstrate that moderate to extreme lithium enrichment occurs in magmas that incorporate felsic continental crust. Cenozoic calderas in western North America and in other intracontinental settings that generated such magmas are promising new targets for lithium exploration because lithium leached from the eruptive products by meteoric and hydrothermal fluids becomes concentrated in clays within caldera lake sediments to potentially economically extractable levels.Lithium is increasingly being utilized for modern technology in the form of lithium-ion batteries. Here, using in situ measurements of quartz-hosted melt inclusions, the authors demonstrate that preserved lake sediments within rhyolitic calderas have the potential to host large lithium-rich clay deposits. PMID- 28814715 TI - Mast cells decrease efficacy of anti-angiogenic therapy by secreting matrix degrading granzyme B. AB - Resistance towards VEGF-centered anti-angiogenic therapy still represents a substantial clinical challenge. We report here that mast cells alter the proliferative and organizational state of endothelial cells which reduces the efficacy of anti-angiogenic therapy. Consequently, absence of mast cells sensitizes tumor vessels for anti-angiogenic therapy in different tumor models. Mechanistically, anti-angiogenic therapy only initially reduces tumor vessel proliferation, however, this treatment effect was abrogated over time as a result of mast cell-mediated restimulation of angiogenesis. We show that mast cells secrete increased amounts of granzyme b upon therapy, which mobilizes pro angiogenic laminin- and vitronectin-bound FGF-1 and GM-CSF from the tumor matrix. In addition, mast cells also diminish efficacy of anti-angiogenic therapy by secretion of FGF-2. These pro-angiogenic factors act beside the targeted VEGFA VEGFR2-axis and reinduce endothelial cell proliferation and angiogenesis despite the presence of anti-angiogenic therapy. Importantly, inhibition of mast cell degranulation with cromolyn is able to improve efficacy of anti-angiogenic therapy. Thus, concomitant mast cell-targeting might lead to improved efficacy of anti-angiogenic therapy.Resistance towards VEGF-centered anti-angiogenic therapy is an important clinical challenge. Here, the authors show that mast cells mediate resistance to anti-angiogenetic inhibitors by altering the proliferative and organizational state of endothelial cells through mobilization of FGF-1 and GM-CSF from the tumor matrix and secretion of FGF-2. PMID- 28814717 TI - Drosophila protease ClpXP specifically degrades DmLRPPRC1 controlling mitochondrial mRNA and translation. AB - ClpXP is the major protease in the mitochondrial matrix in eukaryotes, and is well conserved among species. ClpXP is composed of a proteolytic subunit, ClpP, and a chaperone-like subunit, ClpX. Although it has been proposed that ClpXP is required for the mitochondrial unfolded protein response, additional roles for ClpXP in mitochondrial biogenesis are unclear. Here, we found that Drosophila leucine-rich pentatricopeptide repeat domain-containing protein 1 (DmLRPPRC1) is a specific substrate of ClpXP. Depletion or introduction of catalytically inactive mutation of ClpP increases DmLRPPRC1 and causes non-uniform increases of mitochondrial mRNAs, accumulation of some unprocessed mitochondrial transcripts, and modest repression of mitochondrial translation in Drosophila Schneider S2 cells. Moreover, DmLRPPRC1 over-expression induces the phenotypes similar to those observed when ClpP is depleted. Taken together, ClpXP regulates mitochondrial gene expression by changing the protein level of DmLRPPRC1 in Drosophila Schneider S2 cells. PMID- 28814719 TI - Physical implementation of oblivious transfer using optical correlated randomness. AB - We demonstrate physical implementation of information-theoretic secure oblivious transfer based on bounded observability using optical correlated randomness in semiconductor lasers driven by common random light broadcast over optical fibers. We demonstrate that the scheme can achieve one-out-of-two oblivious transfer with effective key generation rate of 110 kb/s. The results show that this scheme is a promising approach to achieve information-theoretic secure oblivious transfer over long distances for future applications of secure computation such as privacy preserving database mining, auctions and electronic-voting. PMID- 28814718 TI - Adaptive and non-adaptive divergence in a common landscape. AB - Species in a common landscape often face similar selective environments. The capacity of organisms to adapt to these environments may be largely species specific. Quantifying shared and unique adaptive responses across species within landscapes may thus improve our understanding of landscape-moderated biodiversity patterns. Here we test to what extent populations of two coexisting and phylogenetically related fishes-three-spined and nine-spined stickleback-differ in the strength and nature of neutral and adaptive divergence along a salinity gradient. Phenotypic differentiation, neutral genetic differentiation and genomic signatures of adaptation are stronger in the three-spined stickleback. Yet, both species show substantial phenotypic parallelism. In contrast, genomic signatures of adaptation involve different genomic regions, and are thus non-parallel. The relative contribution of spatial and environmental drivers of population divergence in each species reflects different strategies for persistence in the same landscape. These results provide insight in the mechanisms underlying variation in evolutionary versatility and ecological success among species within landscapes.The three-spined stickleback is a model species for the study of adaptive divergence. Here, Raeymaekers et al. compare how the three-spined stickleback and its relative the nine-spined stickleback vary at the phenotypic and genomic levels in response to the same spatial and environmental drivers. PMID- 28814720 TI - Seasonal total methane depletion in limestone caves. AB - Methane concentration in caves is commonly much lower than the external atmosphere, yet the cave CH4 depletion causal mechanism is contested and dynamic links to external diurnal and seasonal temperature cycles unknown. Here, we report a continuous 3-year record of cave methane and other trace gases in Jenolan Caves, Australia which shows a seasonal cycle of extreme CH4 depletion, from ambient ~1,775 ppb to near zero during summer and to ~800 ppb in winter. Methanotrophic bacteria, some newly-discovered, rapidly consume methane on cave surfaces and in external karst soils with lifetimes in the cave of a few hours. Extreme bacterial selection due to the absence of alternate carbon sources for growth in the cave environment has resulted in an extremely high proportion 2-12% of methanotrophs in the total bacteria present. Unexpected seasonal bias in our cave CH4 depletion record is explained by a three-step process involving methanotrophy in aerobic karst soil above the cave, summer transport of soil-gas into the cave through epikarst, followed by further cave CH4 depletion. Disentangling cause and effect of cave gas variations by tracing sources and sinks has identified seasonal speleothem growth bias, with implied palaeo-climate record bias. PMID- 28814721 TI - Acceleration of osteoblast differentiation by a novel osteogenic compound, DMP PYT, through activation of both the BMP and Wnt pathways. AB - Osteoblast differentiation is regulated through the successive activation of signaling molecules by a complex interplay of extracellular signals such as bone morphogenetic protein (BMP) and Wnt ligands. Numerous studies have identified natural as well as synthetic compounds with osteogenic activity through the regulation of either BMP/SMADs or the Wnt/beta-catenin pathway. Here, we attempted to isolate small molecules that concurrently activated both SMADs and beta-catenin, which led to the discovery of a novel potent osteogenic compound, DMP-PYT. Upon BMP2 stimulation, DMP-PYT substantially increased osteoblast differentiation featured by enhanced expression of osteoblast-specific genes and accelerated calcification through activation of BMPs expression. DMP-PYT promoted BMP2-induced SMAD1/5/8 phosphorylation and beta-catenin expression, the latter in a BMP2-independent manner. DMP-PYT alone enhanced nuclear localization of beta catenin to promote the DNA-binding and transcriptional activity of T-cell factor, thereby resulting in increased osteoblast differentiation in the absence of BMP2. Most importantly, DMP-PYT advanced skeletal development and bone calcification in zebrafish larvae. Conclusively, DMP-PYT strongly stimulated osteoblast differentiation and bone formation in vitro and in vivo by potentiating BMP2 induced activation of SMADs and beta-catenin. These results suggest that DMP-PYT may have beneficial effects for preventing and for treating osteoporosis. PMID- 28814722 TI - Evidence of a reduction in cloud condensation nuclei activity of water-soluble aerosols caused by biogenic emissions in a cool-temperate forest. AB - Biogenic organic aerosols can affect cloud condensation nuclei (CCN) properties, and subsequently impact climate change. Large uncertainties exist in how the difference in the types of terrestrial biogenic sources and the abundance of organics relative to sulfate affect CCN properties. For the submicron water soluble aerosols collected for two years in a cool-temperate forest in northern Japan, we show that the hygroscopicity parameter kappaCCN (0.44 +/- 0.07) exhibited a distinct seasonal trend with a minimum in autumn (kappaCCN = 0.32 0.37); these kappaCCN values were generally larger than that of ambient particles, including water-insoluble fractions. The temporal variability of kappaCCN was controlled by the water-soluble organic matter (WSOM)-to-sulfate ratio (R2 > 0.60), where the significant reduction of kappaCCN in autumn was linked to the increased WSOM/sulfate ratio. Positive matrix factorization analysis indicates that alpha-pinene-derived secondary organic aerosol (SOA) substantially contributed to the WSOM mass (~75%) in autumn, the majority of which was attributable to emissions from litter/soil microbial activity near the forest floor. These findings suggest that WSOM, most likely alpha-pinene SOA, originated from the forest floor can significantly suppress the aerosol CCN activity in cool-temperate forests, which have implications for predicting climate effects by changes in biogenic emissions in future. PMID- 28814723 TI - The trap bag concept of afterglow luminescence. AB - This article explains the behavior of afterglow luminescence using the trap bag concept, in which a constant phosphor dose contains a presumed bag with the ability to capture or release electrons through its opening. Luminescence is emitted as the bag releases the captured electrons. The electron-holding capacity is determined by the irradiation conditions, the width of the opening, and the electron activation; these factors are inherent properties of the long persistent luminescence (PLUM) dose and are affected by the thermal status. During the afterglow stage, higher temperatures may result in a wider opening and increased activation of electrons released from the bag, thus creating a higher light intensity and leading to the quicker exhaustion of the electrons within. In contrast, the opposite phenomenon will occur at lower temperatures. This article provides a detailed explanation of the trap bag concept at various thermal statuses and provides a method for delaying the afterglow peak profile through temperature change. Experimental tests were performed to confirm the proposed concept. PMID- 28814724 TI - Pathogenic bacteria enhance dispersal through alteration of Drosophila social communication. AB - Pathogens and parasites can manipulate their hosts to optimize their own fitness. For instance, bacterial pathogens have been shown to affect their host plants' volatile and non-volatile metabolites, which results in increased attraction of insect vectors to the plant, and, hence, to increased pathogen dispersal. Behavioral manipulation by parasites has also been shown for mice, snails and zebrafish as well as for insects. Here we show that infection by pathogenic bacteria alters the social communication system of Drosophila melanogaster. More specifically, infected flies and their frass emit dramatically increased amounts of fly odors, including the aggregation pheromones methyl laurate, methyl myristate, and methyl palmitate, attracting healthy flies, which in turn become infected and further enhance pathogen dispersal. Thus, olfactory cues for attraction and aggregation are vulnerable to pathogenic manipulation, and we show that the alteration of social pheromones can be beneficial to the microbe while detrimental to the insect host.Behavioral manipulation of host by pathogens has been observed in vertebrates, invertebrates, and plants. Here the authors show that in Drosophila, infection with pathogenic bacteria leads to increased pheromone release, which attracts healthy flies. This process benefits the pathogen since it enhances bacterial dispersal, but is detrimental to the host. PMID- 28814725 TI - Micromotor-enabled active drug delivery for in vivo treatment of stomach infection. AB - Advances in bioinspired design principles and nanomaterials have led to tremendous progress in autonomously moving synthetic nano/micromotors with diverse functionalities in different environments. However, a significant gap remains in moving nano/micromotors from test tubes to living organisms for treating diseases with high efficacy. Here we present the first, to our knowledge, in vivo therapeutic micromotors application for active drug delivery to treat gastric bacterial infection in a mouse model using clarithromycin as a model antibiotic and Helicobacter pylori infection as a model disease. The propulsion of drug-loaded magnesium micromotors in gastric media enables effective antibiotic delivery, leading to significant bacteria burden reduction in the mouse stomach compared with passive drug carriers, with no apparent toxicity. Moreover, while the drug-loaded micromotors reach similar therapeutic efficacy as the positive control of free drug plus proton pump inhibitor, the micromotors can function without proton pump inhibitors because of their built-in proton depletion function associated with their locomotion.Nano- and micromotors have been demonstrated in vitro for a range of applications. Here the authors demonstrate the in-vivo therapeutic use of micromotors to treat H. pylori infection. PMID- 28814726 TI - Nitric Oxide regulates mouth development in amphioxus. AB - The development of the mouth in animals has fascinated researchers for decades, and a recent study proposed the modern view of recurrent evolution of protostomy and deuterostomy. Here we expanded our knowledge about conserved traits of mouth formation in chordates, testing the hypothesis that nitric oxide (NO) is a potential regulator of this process. In the present work we show for the first time that NO is an essential cell signaling molecule for cephalochordate mouth formation, as previously shown for vertebrates, indicating its conserved ancestral role in chordates. The experimental decrease of NO during early amphioxus Branchiostoma lanceolatum development impaired the formation of the mouth and gill slits, demonstrating that it is a prerequisite in pharyngeal morphogenesis. Our results represent the first step in the understanding of NO physiology in non-vertebrate chordates, opening new evolutionary perspectives into the ancestral importance of NO homeostasis and acquisition of novel biological roles during evolution. PMID- 28814727 TI - Disruption of the structural and functional features of surfactant protein A by acrolein in cigarette smoke. AB - The extent to which defective innate immune responses contribute to chronic obstructive pulmonary disease (COPD) is not fully understood. Pulmonary surfactant protein A (SP-A) plays an important role in regulating innate immunity in the lungs. In this study, we hypothesised that cigarette smoke (CS) and its component acrolein might influence pulmonary innate immunity by affecting the function of SP-A. Indeed, acrolein-modified SP-A was detected in the lungs of mice exposed to CS for 1 week. To further confirm this finding, recombinant human SP-A (hSP-A) was incubated with CS extract (CSE) or acrolein and then analysed by western blotting and nanoscale liquid chromatography-matrix-assisted laser desorption/ionisation time-of-flight tandem mass spectrometry. These analyses revealed that CSE and acrolein induced hSP-A oligomerisation and that acrolein induced the modification of six residues in hSP-A: His39, His116, Cys155, Lys180, Lys221, and Cys224. These modifications had significant effects on the innate immune functions of hSP-A. CSE- or acrolein-induced modification of hSP-A significantly decreased hSP-A's ability to inhibit bacterial growth and to enhance macrophage phagocytosis. These findings suggest that CS-induced structural and functional defects in SP-A contribute to the dysfunctional innate immune responses observed in the lung during cigarette smoking. PMID- 28814728 TI - Prevalence of smoking in patients with bipolar disorder, major depressive disorder and schizophrenia and their relationships with quality of life. AB - Few studies have compared the prevalence of smoking between patients with bipolar disorder, major depressive disorder (MDD) and schizophrenia. This study examined the prevalence of smoking and its relationships with demographic and clinical characteristics, and quality of life (QOL) in patients with these psychiatric disorders. A total of 1,102 inpatients were consecutively screened. Psychopathology and QOL were measured with standardized instruments. The prevalence of current smoking in the whole sample was 16.7%; 17.5% in bipolar disorder, 10.6% in MDD and 18.5% in schizophrenia. The rates of smoking in bipolar disorder (p = 0.004, OR = 2.5, 95%CI: 1.3-4.7) and schizophrenia (p = 0.03, OR = 2.0, 95%CI: 1.06-3.8) were significantly higher than in MDD, while no difference was found between bipolar disorder and schizophrenia. Smokers had a higher mental QOL than non-smokers (p = 0.007) in MDD, but no difference was found in the other two groups. Male gender, living alone, higher personal income, older age of onset, health insurance coverage, and first episode was significantly associated with smoking in one or more diagnostic groups. Smoking appears more common in bipolar disorder and schizophrenia than in MDD in China. The figures in all disorders were lower than that reported in most of other countries. PMID- 28814729 TI - Thermally induced crystallization, hole-transport, NLO and photovoltaic activity of a bis-diarylamine-based push-pull molecule. AB - The synthesis of a molecule constituted of two diarylamine-based push-pull chromophores covalently linked via their nitrogen atom is described. Comparison of the electronic properties with the parent monomer shows that dimerization has negligible influence on the electronic properties of the molecule but exerts a dramatic impact on the capacity of the material to self-reorganize. Application of thermal annealing to thin films induces the crystallization under original morphologies, a process accompanied by a partial bleaching of the absorption in the visible range and by a huge increase of hole-mobility. X-ray diffraction data on single crystals reveal the presence of pi-stacked organization with a non centrosymmetric co-facial arrangement of the dipoles which leads to intrinsic 2nd order bulk NLO properties of thin films as evidenced by second harmonic generation under 800 nm laser light. The implications of this thermally induced crystallization on the photovoltaic properties of the material are discussed on the basis of preliminary results obtained on simple bilayer organic solar cells. PMID- 28814730 TI - Quantification of lactate from various metabolic pathways and quantification issues of lactate isotopologues and isotopmers. AB - 13C-labeled glucose combined with chromatography and mass spectrometry enables us to decipher the percentage of lactate generated from various metabolic pathways. We showed that lactate derived from glycolysis, pentose phosphate pathway, Krebs cycle, and other sources accounted for 82-90%, 6.0-11%, 0.67-1.8% and 1.5-7.9%, respectively, depending on different types of cells. When using glucose isotopomers ([1-13C]-, [3-13C]-, [4-13C]-, and [6-13C]glucose) or isotopologues ([1,2-13C2]- and [1,2,3-13C3]glucose) for tracing, the ratio of lactate derived from glucose carbon 1, 2, 3 over 4, 5, 6 via glycolysis varied significantly, ranging from 1.6 (traced with [1,2-13C2]glucose) to 0.85 (traced with [6 13C]glucose), but the theoretical ratio should be 1. The odd results might be caused by intramolecular 13C, which may significantly affect lactate fragmentation under tandem mass spectrometry condition, leading to erroneous quantification. Indeed, the fragmentation efficiency of [U-13C]lactate, [2,3 13C]lactate, and [3-13C]lactate were 1.4, 1.5 and 1.2 folds higher than lactate, respectively, but [1-13C]lactate was similar to lactate, suggesting that carbon 13 at different positions could differentially influence lactate fragmentation. This observed phenomenon was inconsistent with the data based on theoretical calculation, according to which activation energies for all lactate isotopomers and isotopologues are nearly identical. The inconsistency suggested a need for further investigation. Our study suggests that calibration is required for quantifying metabolite isotopolugues and isotopomers. PMID- 28814731 TI - Spatial Regression and Prediction of Water Quality in a Watershed with Complex Pollution Sources. AB - Fast economic development, burgeoning population growth, and rapid urbanization have led to complex pollution sources contributing to water quality deterioration simultaneously in many developing countries including China. This paper explored the use of spatial regression to evaluate the impacts of watershed characteristics on ambient total nitrogen (TN) concentration in a heavily polluted watershed and make predictions across the region. Regression results have confirmed the substantial impact on TN concentration by a variety of point and non-point pollution sources. In addition, spatial regression has yielded better performance than ordinary regression in predicting TN concentrations. Due to its best performance in cross-validation, the river distance based spatial regression model was used to predict TN concentrations across the watershed. The prediction results have revealed a distinct pattern in the spatial distribution of TN concentrations and identified three critical sub-regions in priority for reducing TN loads. Our study results have indicated that spatial regression could potentially serve as an effective tool to facilitate water pollution control in watersheds under diverse physical and socio-economical conditions. PMID- 28814732 TI - Dual Contrast - Magnetic Resonance Fingerprinting (DC-MRF): A Platform for Simultaneous Quantification of Multiple MRI Contrast Agents. AB - Injectable Magnetic Resonance Imaging (MRI) contrast agents have been widely used to provide critical assessments of disease for both clinical and basic science imaging research studies. The scope of available MRI contrast agents has expanded over the years with the emergence of molecular imaging contrast agents specifically targeted to biological markers. Unfortunately, synergistic application of more than a single molecular contrast agent has been limited by MRI's ability to only dynamically measure a single agent at a time. In this study, a new Dual Contrast - Magnetic Resonance Fingerprinting (DC - MRF) methodology is described that can detect and independently quantify the local concentration of multiple MRI contrast agents following simultaneous administration. This "multi-color" MRI methodology provides the opportunity to monitor multiple molecular species simultaneously and provides a practical, quantitative imaging framework for the eventual clinical translation of molecular imaging contrast agents. PMID- 28814733 TI - Enhancing Immune Responses to Cancer Vaccines Using Multi-Site Injections. AB - For a vaccine to be effective it must induce a sufficiently robust and specific immune response. Multi-site injection protocols can increase the titers of rabies virus-neutralizing antibodies. Hypothetically, spreading a vaccine dose across multiple lymphatic drainage regions could also potentiate T cell responses. We used a replication-deficient adenovirus serotype 5-vectored cancer vaccine targeting the melanoma-associated antigen dopachrome tautomerase. Clinically, high numbers of tumor-infiltrating CD8+ T cells are a positive prognostic indicator. As such, there is interest in maximizing tumor-specific T cell responses. Our findings confirm a positive correlation between the number of tumor-specific T cells and survival. More importantly, we show for the first time that using multiple injection sites could increase the number of vaccine-induced CD8+ T cells specific for a self-tumor antigen. Further, the number of tumor antigen-specific antibodies, as well CD8+ T cells specific for a foreign antigen could also be enhanced. Our results show that multi-site vaccination induces higher magnitude immune responses than a single-bolus injection. This provides a very simple and almost cost-free strategy to potentially improve the efficacy of any current and future vaccine. Broader clinical adoption of multi-site vaccination protocols for the treatment of cancers and infectious diseases should be given serious consideration. PMID- 28814734 TI - Dipole orientation analysis without optical simulation: application to thermally activated delayed fluorescence emitters doped in host matrix. AB - The dipole orientation of guest emitters doped into host matrices is usually investigated by angular dependent photoluminescence (PL) measurements, which acquire an out-of-plane PL radiation pattern of the guest-host thin films. The PL radiation patterns generated by these methods are typically analysed by optical simulations, which require expertise to perform and interpret in the simulation. In this paper, we developed a method to calculate an orientational order parameter S without the use of full optical simulations. The PL radiation pattern showed a peak intensity (I sp) in the emission direction tilted by 40 degrees -60 degrees from the normal of the thin film surface plane, indicating an inherent dipole orientation of the emitter. Thus, we directly correlated I sp with S. The S - I sp relation was found to depend on the film thickness (d) and refractive indices of the substrate (n sub) and the organic thin film (n org). Hence, S can be simply calculated with information of I sp, d, n sub, and n org. We applied our method to thermally activated delayed fluorescence materials, which are known to be highly efficient electroluminescence emitters. We evaluated S and found that the error of this method, compared with an optical simulation, was less than 0.05. PMID- 28814735 TI - Self-assembly of ternary hollow microspheres with strong wideband microwave absorption and controllable microwave absorption properties. AB - In this study, we report a simple and efficient two-step method consisting of water-in-oil (W/O) emulsion technique and subsequent annealing process for synthesizing the hollow reduced graphene oxide microspheres embedded with Co nanoparticles (Air@rGO?Co). The microspheres showed good electromagnetic properties because of the coexistence of magnetic loss and dielectric loss to microwaves. The minimum reflection loss (RLmin) value of S1.5 reaches -68.1 dB at 13.8 GHz with a thickness of 2.2 mm, and the absorption bandwidth (lower than -10 dB) is 7.1 GHz covering from 10.9 GHz to 18.0 GHz. More interestingly, we can easily controll the microwave absorbing properties of the microspheres by changing the ratio of the two components in the composites. The excellent electromagnetic match at the corresponding resonance peaks for dielectric and magnetic loss play an important role in improving microwave absorption property. Our study provides a good potential method for preparation of lightweight microwave absorbing materials. PMID- 28814736 TI - Emotions alter muscle proprioceptive coding of movements in humans. AB - Emotions can evoke strong reactions that have profound influences, from gross changes in our internal environment to small fluctuations in facial muscles, and reveal our feelings overtly. Muscles contain proprioceptive afferents, informing us about our movements and regulating motor activities. Their firing reflects changes in muscle length, yet their sensitivity can be modified by the fusimotor system, as found in animals. In humans, the sensitivity of muscle afferents is modulated by cognitive processes, such as attention; however, it is unknown if emotional processes can modulate muscle feedback. Presently, we explored whether muscle afferent sensitivity adapts to the emotional situation. We recorded from single muscle afferents in the leg, using microneurography, and moved the ankle joint of participants, while they listened to evocative classical music to induce sad, neutral, or happy emotions, or sat passively (no music). We further monitored their physiological responses using skin conductance, heart rate, and electromyography measures. We found that muscle afferent firing was modified by the emotional context, especially for sad emotions, where the muscle spindle dynamic response increased. We suggest that this allows us to prime movements, where the emotional state prepares the body for consequent behaviour-appropriate reactions. PMID- 28814737 TI - Susceptibility of influenza A(H1N1)/pdm2009, seasonal A(H3N2) and B viruses to Oseltamivir in Guangdong, China between 2009 and 2014. AB - Nasopharyngeal swabs were collected from patients through the influenza surveillance network of the CDC of Guangdong. All specimens between 2009 and 2014 were checked for influenza virus using MDCK cells and further subtyped. Of those collected, 542 H1N1pdm09, 230 A(H3N2)and 448 B viruses selected at random were subjected to fluorescence-based NAI assays. Viral RNA was extracted from resistant isolates, and their NA genes were amplified by RT-PCR. Alignment of nucleotides and amino acids was performed. We performed structural modelling and simulations of mutants using Modeller 9.x and AutoDock and analyzed conformations and binding affinities. All tested seasonal type B and H3N2 viruses from 2009 to 2014 remained sensitive to oseltamivir. However, there were five strains (out of 198 tested isolates acquired between June and September 2013) that were resistant to oseltamivir. Another three resistant strains were identified among isolates from March to April 2014. We found that 2013/2014 oseltamivir-resistant strains and 2012/2013/2014 oseltamivir-sensitive strains had all or some of the following mutations: N44S, N200S,V241I, I321V,N369K, N386 K and K432E. MutationsV241I, N369K, N386K and K432E, alone or in conjunction with H275Y, had a significant impact on the binding pattern and affinity of oseltamivir for neuraminidase, rendering neuraminidase less susceptible. PMID- 28814738 TI - Identification of Novel Non-secosteroidal Vitamin D Receptor Agonists with Potent Cardioprotective Effects and devoid of Hypercalcemia. AB - Vitamin D regulates many biological processes, but its clinical utility is limited by its hypercalcemic effect. Using a virtual screening platform to search novel chemical probes that activate the vitamin D signaling, we report discovery of novel non-steroidal small-molecule compounds that activate the vitamin D receptor (VDR), but are devoid of hypercalcemia. A lead compound (known as VDR 4 1) demonstrated potent transcriptional activities in a VDR reporter gene assay, and significantly ameliorated cardiac hypertrophy in cell culture studies and in animal models. VDR 4-1 also effectively suppressed secondary hyperparathyroidism in 1alpha-hydroxylase knockout mice. In contrast to 1alpha,25-dihydroxyvitamin D3 (1,25-D3 or calcitriol), a naturally occurring VDR agonist, VDR 4-1 therapy even at high doses did not induce hypercalcemia. These findings were accompanied by a lack of upregulation of calcium transport genes in kidney and in the gut providing a mechanism for the lack of hypercalcemia. Furthermore, VDR 4-1 therapy significantly suppressed cardiac hypertrophy and progression to heart failure in both vitamin D deficient and normal mice without inducing significant hypercalcemia. In conclusion, we have identified a unique VDR agonist compound with beneficial effects in mouse models of hyperparathyroidism and heart failure without inducing significant hypercalcemia. PMID- 28814739 TI - Re-characterization of the Glomerulopathy in CD2AP Deficient Mice by High Resolution Helium Ion Scanning Microscopy. AB - Helium ion scanning microscopy (HIM) is a novel technology that directly visualizes the cell surface ultrastructure without surface coating. Despite its very high resolution, it has not been applied extensively to study biological or pathology samples. Here we report the application of this powerful technology to examine the three-dimensional ultrastructural characteristics of proteinuric glomerulopathy in mice with CD2-associated protein (CD2AP) deficiency. HIM revealed the serial alteration of glomerular features including effacement and disorganization of the slit diaphragm, followed by foot process disappearance, flattening and fusion of major processes, and eventual transformation into a podocyte sheet as the disease progressed. The number and size of the filtration slit pores decreased. Strikingly, numerous "bleb" shaped microprojections were observed extending from podocyte processes and cell body, indicating significant membrane dynamics accompanying CD2AP deficiency. Visualizing the glomerular endothelium and podocyte-endothelium interface revealed the presence of endothelial damage, and disrupted podocyte and endothelial integrity in 6 week old Cd2ap-KO mice. We used the HIM technology to investigate at nanometer scale resolution the ultrastructural alterations of the glomerular filtration apparatus in mice lacking the critical slit diaphragm-associated protein CD2AP, highlighting the great potential of HIM to provide new insights into the biology and (patho)physiology of glomerular diseases. PMID- 28814740 TI - A Flexible Electret Membrane with Persistent Electrostatic Effect and Resistance to Harsh Environment for Energy Harvesting. AB - A novel flexible electret membrane, exhibiting persistent electrostatic effect, distinctive temperature stability and outstanding capability of resistance to harsh environment and fatigue, is demonstrated by experiment. Its excellent electret performance is correlated to the synergy of three factors, which are space charge injection, dipole orientation and interfacial polarization according to the analysis of charge storage mechanism. This electret membrane is provided with sandwich configuration PTFE/THV/PTFE, prepared by hot pressing method and thermal charging technology. After wiped its surface with alcohol, its surface potential declines to zero from -550 V, then recovers rapidly to -310 V and finally maintains constant for 800 hours, which shows that its electret performance distinctly precedes traditional electret material such as single PTFE, FEP electret membrane. The measurement of thermal stimulating potentials displays that its surface potential reaches maximum about 5 times initial value at 125 degrees C. A micro-vibration energy harvester is assembled with this membrane. Its maximum output power reaches 4.66 MUW at tapping frequency 5 Hz and keeps stable during over 2000 tapping tests within 100 days, which indicates the long-life service and resistance to harsh environment and fatigue of this electret membrane. PMID- 28814741 TI - Twin birth changes DNA methylation of subsequent siblings. AB - We asked if twin birth influences the DNA methylation of subsequent siblings. We measured whole blood methylation using the HumanMethylation450 array for siblings from two twin and family studies in Australia and Korea. We compared the means and correlations in methylation between pairs of siblings born before a twin birth (BT siblings), born on either side of a twin birth (B/AT pairs) and born after a twin birth (AT siblings). For the genome-wide average DNA methylation, the correlation for AT pairs (rAT) was larger than the correlation for BT pairs (rBT) in both studies, and from the meta-analysis, rAT = 0.46 (95% CI: 0.26, 0.63) and rBT = -0.003 (95% CI: -0.30, 0.29) (P = 0.02). B/AT pairs were not correlated (from the meta-analysis rBAT = 0.08; 95% CI: -0.31, 0.45). Similar results were found for the average methylation of several genomic regions, e.g., CpG shelf and gene body. BT and AT pairs were differentially correlated in methylation for 15 probes (all P < 10-7), and the top 152 differentially correlated probes (at P < 10-4) were enriched in cell signalling and breast cancer regulation pathways. Our observations are consistent with a twin birth changing the intrauterine environment such that siblings both born after a twin birth are correlated in DNA methylation. PMID- 28814743 TI - Nutritional status and the influence of TV consumption on female body size ideals in populations recently exposed to the media. AB - Television consumption influences perceptions of attractive female body size. However, cross-cultural research examining media influence on body ideals is typically confounded by differences in the availability of reliable and diverse foodstuffs. 112 participants were recruited from 3 Nicaraguan villages that differed in television consumption and nutritional status, such that the contribution of both factors could be revealed. Participants completed a female figure preference task, reported their television consumption, and responded to several measures assessing nutritional status. Communities with higher television consumption and/or higher nutritional status preferred thinner female bodies than communities with lower television consumption and/or lower nutritional status. Bayesian mixed models estimated the plausible range of effects for television consumption, nutritional status, and other relevant variables on individual preferences. The model explained all meaningful differences between our low nutrition villages, and television consumption, after sex, was the most likely of these predictors to contribute to variation in preferences (probability mass >95% when modelling only variables with zero-order associations with preferences, but only 90% when modelling all possible predictors). In contrast, we found no likely link with nutritional status. We thus found evidence that where media access and nutritional status are confounded, media is the more likely predictor of body ideals. PMID- 28814742 TI - The Candida albicans HIR histone chaperone regulates the yeast-to-hyphae transition by controlling the sensitivity to morphogenesis signals. AB - Morphological plasticity such as the yeast-to-hyphae transition is a key virulence factor of the human fungal pathogen Candida albicans. Hyphal formation is controlled by a multilayer regulatory network composed of environmental sensing, signaling, transcriptional modulators as well as chromatin modifications. Here, we demonstrate a novel role for the replication-independent HIR histone chaperone complex in fungal morphogenesis. HIR operates as a crucial modulator of hyphal development, since genetic ablation of the HIR complex subunit Hir1 decreases sensitivity to morphogenetic stimuli. Strikingly, HIR1 deficient cells display altered transcriptional amplitudes upon hyphal initiation, suggesting that Hir1 affects transcription by establishing transcriptional thresholds required for driving morphogenetic cell-fate decisions. Furthermore, ectopic expression of the transcription factor Ume6, which facilitates hyphal maintenance, rescues filamentation defects of hir1Delta/Delta cells, suggesting that Hir1 impacts the early phase of hyphal initiation. Hence, chromatin chaperone-mediated fine-tuning of transcription is crucial for driving morphogenetic conversions in the fungal pathogen C. albicans. PMID- 28814744 TI - Monocyte infiltration and proliferation reestablish myeloid cell homeostasis in the mouse retina following retinal pigment epithelial cell injury. AB - Age-related macular degeneration (AMD), a leading contributor of vision loss, currently lacks comprehensive treatment. While AMD histopathology involves retinal pigment epithelium (RPE) injury associated with immune cell infiltration, the nature of immune cell responses to RPE injury remains undefined. We induced RPE injury pharmacologically and genetically in transgenic mouse models in which microglia and systemic monocytes were separately tagged, enabling a spatial and temporal dissection of the relative contributions of microglia vs. monocytes to post-injury changes. We found that myeloid cell responses to RPE injury occur in stages: (1) an early mobilization of endogenous microglia from the inner retina to the RPE layer, followed by (2) subsequent monocyte infiltration from the retinal vasculature into the inner retina that replenishes the local myeloid cell population in a CCR2-regulated manner. These altered distributions of myeloid cells post-injury were long-lived, with recruited monocytes acquiring the distribution, markers, and morphologies of neighboring endogenous microglia in a durable manner. These findings indicate the role played by infiltrating monocytes in maintaining myeloid cell homeostasis in the retina following AMD-relevant RPE injury and provide a foundation for understanding and therapeutically modulating immune aspects in retinal disease. PMID- 28814745 TI - Suppression of GRK2 expression reduces endothelial dysfunction by restoring glucose homeostasis. AB - Despite the associations between diabetic complications and vascular endothelial dysfunction, a direct therapeutic method targeting endothelial dysfunction remains poorly characterized. We have previously shown that chemical inhibition of G-protein-coupled receptor kinase 2 (GRK2) slightly enhances insulin sensitivity and reduces endothelial dysfunction in type 2 diabetic mice. In this study, we identified GRK2 as a novel therapeutic target of diabetic endothelial dysfunction and investigated the effect on diabetic endothelial dysfunction through the systemic administration of GRK2 siRNA using a hydrodynamic-based procedure, resulting in suppression of increased GRK2 protein levels in the liver. Suppressed GRK2 levels in the liver markedly improved glucose homeostasis, as well as improved the impaired endothelial Akt/eNOS-dependent signal activation (insulin-stimulated phosphorylation of Akt and eNOS) and vascular responses (clonidine-induced and insulin-induced endothelial-dependent relaxation response and phenylephrine-induced contractile response) in type 2 diabetic aortas. Interestingly, insulin-stimulated Akt/eNOS signaling was increased only by normalizing the glucose concentration in human umbilical vein endothelial cells (HUVECs) with GRK2 overexpression, suggesting of an important role of hepatic GRK2. Our results clarified the relationship among hepatic GRK2, glucose homeostasis, and vascular endothelial function. Liver-targeting GRK2 siRNA delivery represents a novel therapeutic tool to restore glucose homeostasis and reduce endothelial dysfunction. PMID- 28814747 TI - Understanding Tribofilm Formation Mechanisms in Ionic Liquid Lubrication. AB - Ionic liquids (ILs) have recently been developed as a novel class of lubricant anti-wear (AW) additives, but the formation mechanism of their wear protective tribofilms is not yet well understood. Unlike the conventional metal-containing AW additives that self-react to grow a tribofilm, the metal-free ILs require a supplier of metal cations in the tribofilm growth. The two apparent sources of metal cations are the contact surface and the wear debris, and the latter contains important 'historical' interface information but often is overlooked. We correlated the morphological and compositional characteristics of tribofilms and wear debris from an IL-lubricated steel-steel contact. A complete multi-step formation mechanism is proposed for the tribofilm of metal-free AW additives, including direct tribochemical reactions between the metallic contact surface with oxygen to form an oxide interlayer, wear debris generation and breakdown, tribofilm growth via mechanical deposition, chemical deposition, and oxygen diffusion. PMID- 28814746 TI - Rewiring of the FtsH regulatory network by a single nucleotide change in saeS of Staphylococcus aureus. AB - In the Gram-positive pathogen Staphylococcus aureus, the membrane-bound ATP dependent metalloprotease FtsH plays a critical role in resistance to various stressors. However, the molecular mechanism of the FtsH functions is not known. Here, we identified core FtsH target proteins in S. aureus. In the strains Newman and USA300, the abundance of 33 proteins were altered in both strains, of which 11 were identified as core FtsH substrate protein candidates. In the strain Newman and some other S. aureus strains, the sensor histidine kinase SaeS has an L18P (T53C in saeS) substitution, which transformed the protein into an FtsH substrate. Due to the increase of SaeS L18P in the ftsH mutant, Eap, a sae regulon protein, was also increased in abundance, causing the Newman-specific cell-aggregation phenotype. Regardless of the strain background, however, the ftsH mutants showed lower virulence and survival in a murine infection model. Our study illustrates the elasticity of the bacterial regulatory network, which can be rewired by a single substitution mutation. PMID- 28814748 TI - Functional characterization of PBP1 gene in Helicoverpa armigera (Lepidoptera: Noctuidae) by using the CRISPR/Cas9 system. AB - Pheromone binding proteins (PBPs) are thought to play crucial roles in perception of the sex pheromones particularly in noctuid moths, but this is rarely in vivo evidenced due to lacking an effective technique. Here, we reported an in vivo functional study of PBP1 in the important lepidopteran pest Helicoverpa armigera (HarmPBP1), by using the CRISPR/Cas9 system. Efficient and heritable mutagenesis was achieved by egg injection of mixture of Cas9-mRNA and HarmPBP1-sgRNA. The TA cloning and sequencing revealed various insertion and/or deletion (indel) mutations at the target site. Among those, one mutation resulted in a premature stop codon at the target site, which led to a highly truncated protein with only 10 amino acids. The HarmPBP1 with this mutation would completely loss its function, and thus was used to select the homozygous mutant insects for functional analysis. The electroantennogram recording showed that the mutant male adults displayed severely impaired responses to all three sex pheromone components (Z11-16:Ald, Z9-16:Ald and Z9-14:Ald). Our study provides the first in vivo evidence that HarmPBP1 plays important role in perception of female sex pheromones, and also an effective methodology for using CRISPR/Cas9 system in functional genetic study in H. armigera as well as other insects. PMID- 28814749 TI - Preparation of CH3NH3PbI3 thin films with tens of micrometer scale at high temperature. AB - The fabrication of high-quality organic-inorganic hybrid halide perovskite layers is the key prerequisite for the realization of high efficient photon energy harvest and electric energy conversion in their related solar cells. In this article, we report a novel fabrication technique of CH3NH3PbI3 layers based on high temperature chemical vapor reaction. CH3NH3PbI3 layers have been prepared by the reaction of PbI2 films which were deposited by pulsed laser deposition, with CH3NH3I vapor at various temperatures from 160 degrees C to 210 degrees C. X ray diffraction patterns confirm the formation of pure phase, and photoluminescence spectra show the strong peak at around 760 nm. Scanning electron microscopy images confirm the significantly increased average grain size from nearly 1 MUm at low reaction temperature of 160 degrees C to more than 10 MUm at high reaction temperature of 200 degrees C. The solar cells were fabricated, and short-circuit current density of 15.75 mA/cm2, open-circuit voltage of 0.49 V and fill factor of 71.66% have been obtained. PMID- 28814750 TI - The linear artifact in enhanced depth imaging spectral domain optical coherence tomography. AB - Optical coherence tomography (OCT) is a valuable ancillary test in the diagnosis and management of chorioretinal disease. The evaluation of choroid thickness using OCT has become the focus of clinical applications. We report a linear artifact that acts as a confounding factor in choroidal thickness measurements by enhanced depth imaging OCT. We found that the linear artifact is located stably at a depth of 485 MUm beneath the retinal pigment epithelium in 81.88% of subjects. The study suggested that the linear artifact was a confounding factor in assessing choroidal thickness and that caution should be used in the interpretation of the choroidal thickness, especially when it is approximately 485 MUm. PMID- 28814751 TI - Comparison of chronic physical and emotional social defeat stress effects on mesocorticolimbic circuit activation and voluntary consumption of morphine. AB - Chronic social defeat stress (CSDS) is a well-established rodent model of depression that induces persistent social avoidance. CSDS triggers molecular adaptations throughout the mesocorticolimbic reward circuit, including changes in the activity of dopamine neurons in the ventral tegmental area (VTA), that may also influence drug reward. One limitation of traditional, physical CSDS (PS) is that injury complicates the study of opiate drugs like morphine. Thus, we sought to characterize a variation of CSDS, termed emotional CSDS (ES), that eliminates this confound. We assessed the effect of PS and ES on mesocorticolimbic circuit activation, VTA gene expression, and morphine intake. We found that PS and ES similarly induced DeltaFosB in the hippocampus, but only PS significantly increased DeltaFosB expression in the prefrontal cortex and striatum. In contrast, cFos expression was similarly reduced by both PS and ES. Interestingly, we found that PS and ES similarly increased voluntary morphine consumption immediately following stress, despite differences in the magnitude of the depressive phenotype and striatal DeltaFosB expression at this time point. Combined, these data suggest that both stress paradigms may be useful for investigation of stress-induced changes in drug behavior. PMID- 28814752 TI - Oncofetal HMGA2 effectively curbs unconstrained (+) and (-) DNA supercoiling. AB - HMGA2 belongs to the family of the high mobility group (HMG) proteins. It binds DNA via three AT-hook domains to the minor groove of adenine-thymine (AT) rich DNA. Recently, a new function of HMGA2 as a replication fork chaperone that protects stem and cancer cells from replication fork collapse induced by chemotherapeutic agents was uncovered, suggesting a previously uncharacterized binding at replication forks. In this study, we examined HMGA2 binding to four DNA structures relevant to replication forks, namely ds DNA, ss DNA, forked DNA and supercoiled DNA plectonemes. We detected HMGA2 binding to supercoiled DNA at the lowest concentration and this binding mode transiently stabilizes the supercoiled plectonemes against relaxation by type I topoisomerase. Together, these findings suggest a plausible mechanism how fork regression and collapse are attenuated by HMGA2 during replication stress, i.e. through transient stabilization of positively supercoiled plectonemes in the parental duplex. PMID- 28814753 TI - The [PSI +] yeast prion does not wildly affect proteome composition whereas selective pressure exerted on [PSI +] cells can promote aneuploidy. AB - The yeast Sup35 protein is a subunit of the translation termination factor, and its conversion to the [PSI +] prion state leads to more translational read through. Although extensive studies have been done on [PSI +], changes at the proteomic level have not been performed exhaustively. We therefore used a SILAC based quantitative mass spectrometry approach and identified 4187 proteins from both [psi -] and [PSI +] strains. Surprisingly, there was very little difference between the two proteomes under standard growth conditions. We found however that several [PSI +] strains harbored an additional chromosome, such as chromosome I. Albeit, we found no evidence to support that [PSI +] induces chromosomal instability (CIN). Instead we hypothesized that the selective pressure applied during the establishment of [PSI +]-containing strains could lead to a supernumerary chromosome due to the presence of the ade1-14 selective marker for translational read-through. We therefore verified that there was no prevalence of disomy among newly generated [PSI +] strains in absence of strong selection pressure. We also noticed that low amounts of adenine in media could lead to higher levels of mitochondrial DNA in [PSI +] in ade1-14 cells. Our study has important significance for the establishment and manipulation of yeast strains with the Sup35 prion. PMID- 28814754 TI - Unveiling Cerebral Leishmaniasis: parasites and brain inflammation in Leishmania donovani infected mice. AB - Visceral leishmaniasis (VL) is a systemic disease with multifaceted clinical manifestations, including neurological signs, however, the involvement of the nervous system during VL is underestimated. Accordingly, we investigated both brain infection and inflammation in a mouse model of VL. Using bioluminescent Leishmania donovani and real-time 2D-3D imaging tools, we strikingly detected live parasites in the brain, where we observed a compartmentalized dual-phased inflammation pattern: an early phase during the first two weeks post-infection, with the prompt arrival of neutrophils and Ly6Chigh macrophages in an environment presenting a variety of pro-inflammatory mediators (IFN-gamma, IL-1beta, CXCL 10/CXCR-3, CCL-7/CCR-2), but with an intense anti-inflammatory response, led by IL-10; and a re-inflammation phase three months later, extremely pro inflammatory, with novel upregulation of mediators, including IL-1beta, TNF-alpha and MMP-9. These new data give support and corroborate previous studies connecting human and canine VL with neuroinflammation and blood-brain barrier disruption, and conclusively place the brain among the organs affected by this parasite. Altogether, our results provide convincing evidences that Leishmania donovani indeed infects and inflames the brain. PMID- 28814755 TI - Membrane fouling induced by AHL-mediated soluble microbial product (SMP) formation by fouling-causing bacteria co-cultured with fouling-enhancing bacteria. AB - Membrane fouling still remains a major obstacle for wider applications of membrane bioreactor (MBR), which is mainly caused by soluble microbial products (SMP). Identification of key bacteria responsible for SMP production is essential for mitigation of membrane fouling. Here, we investigated the effect of microbial interaction on membrane fouling. We measured the membrane fouling potentials of 13 bacterial strains isolated from a pilot-scale MBR treating domestic wastewater when they were cultivated as single-culture and co-culture. We found that fouling causing bacteria (FCB) displayed much higher fouling potential when co-cultured even with non-FCB and mixed population (activated sludge). In particular, the fouling potential of strain S26, one of FCB, increased 26.8 times when cultivated with strain S22 (fouling-enhancing bacteria, FEB). The secretion of N-octanoyl-L homoserine lactone (C8-HSL) was increased by co-cultivating S22 and S26 as compared with cultivating as single culture, which stimulated the production of fouling-causing SMP by S26 and consequently resulted in severe membrane fouling. This result suggests that AHL-mediated quorum-sensing (QS) regulatory system was involved in secretion of fouling-causing SMP. PMID- 28814756 TI - Giant pandas can discriminate the emotions of human facial pictures. AB - Previous studies have shown that giant pandas (Ailuropoda melanoleuca) can discriminate face-like shapes, but little is known about their cognitive ability with respect to the emotional expressions of humans. We tested whether adult giant pandas can discriminate expressions from pictures of half of a face and found that pandas can learn to discriminate between angry and happy expressions based on global information from the whole face. Young adult pandas (5-7 years old) learned to discriminate expressions more quickly than older individuals (8 16 years old), but no significant differences were found between females and males. These results suggest that young adult giant pandas are better at discriminating emotional expressions of humans. We showed for the first time that the giant panda, can discriminate the facial expressions of humans. Our results can also be valuable for the daily care and management of captive giant pandas. PMID- 28814757 TI - Top canopy nitrogen allocation linked to increased grassland carbon uptake in stands of varying species richness. AB - Models predict that vertical gradients of foliar nitrogen (N) allocation, increasing from bottom to top of plant canopies, emerge as a plastic response to optimise N utilisation for carbon assimilation. While this mechanism has been well documented in monocultures, its relevance for mixed stands of varying species richness remains poorly understood. We used 21 naturally assembled grassland communities to analyse the gradients of N in the canopy using N allocation coefficients (K N ) estimated from the distribution of N per foliar surface area (KN-F) and ground surface area (KN-G). We tested whether: 1) increasing plant species richness leads to more pronounced N gradients as indicated by higher K N -values, 2) K N is a good predictor of instantaneous net ecosystem CO2 exchange and 3) functional diversity of leaf N concentration as estimated by Rao's Q quadratic diversity metric is a good proxy of K N . Our results show a negative (for KN-G) or no relationship (for KN-F) between species richness and canopy N distribution, but emphasize a link (positive relationship) between more foliar N per ground surface area in the upper layers of the canopy (i.e. under higher KN-G) and ecosystem CO2 uptake. Rao's Q was not a good proxy for either K N . PMID- 28814758 TI - Targeted insertion of an anti-CD2 monoclonal antibody transgene into the GGTA1 locus in pigs using FokI-dCas9. AB - Xenotransplantation from pigs has been advocated as a solution to the perennial shortage of donated human organs and tissues. CRISPR/Cas9 has facilitated the silencing of genes in donor pigs that contribute to xenograft rejection. However, the generation of modified pigs using second-generation nucleases with much lower off-target mutation rates than Cas9, such as FokI-dCas9, has not been reported. Furthermore, there have been no reports on the use of CRISPR to knock protective transgenes into detrimental porcine genes. In this study, we used FokI-dCas9 with two guide RNAs to integrate a 7.1 kilobase pair transgene into exon 9 of the GGTA1 gene in porcine fetal fibroblasts. The modified cells lacked expression of the alphaGal xenoantigen, and secreted an anti-CD2 monoclonal antibody encoded by the transgene. PCR and sequencing revealed precise integration of the transgene into one allele of GGTA1, and a small deletion in the second allele. The cells were used for somatic cell nuclear transfer to generate healthy male knock-in piglets, which did not express alphaGal and which contained anti-CD2 in their serum. We have therefore developed a versatile high-fidelity system for knocking transgenes into the pig genome for xenotransplantation purposes. PMID- 28814759 TI - Influence of film mulching on soil microbial community in a rainfed region of northeastern China. AB - Information about the effect of plastic film mulching (PFM) on the soil microbial communities of rainfed regions remains scarce. In the present study, Illumina Hiseq sequencer was employed to compare the soil bacterial and fungal communities under three treatments: no mulching (NM), spring mulching (SM) and autumn mulching (AM) in two layers (0-10 and, 10-20 cm). Our results demonstrated that the plastic film mulching (PFM) application had positive effects on soil physicochemical properties as compared to no-mulching (NM): higher soil temperature (ST), greater soil moisture content (SMC) and better soil nutrients. Moreover, mulching application (especially AM) caused a significant increase of bacterial and fungal richness and diversity and played important roles in shaping microbial community composition. These effects were mainly explained by the ST and SMC induced by the PFM application. The positive effects of AM and SM on species abundances were very similar, while the AM harbored relatively more beneficial microbial taxa than the SM, e.g., taxa related to higher degrading capacity and nutrient cycling. According to the overall effects of AM application on ST, SMC, soil nutrients and microbial diversity, AM is recommended during maize cultivation in rain-fed region of northeast China. PMID- 28814760 TI - miR-181a involves in the hippocampus-dependent memory formation via targeting PRKAA1. AB - Post-transcriptional gene regulation by microRNAs (miRNAs) is involved in memory formation. However, the roles of individual miRNAs in these processes remain largely unknown. In this study, we want to clarify the role of miR-181a in hippocampus-dependent memory formation. A transient increase in miR-181a expression was observed after conditioned fear conditioning (CFC) and object location task (OLT) training. Selective overexpression or inhibition of miR-181a in the dorsal hippocampus (DH) via the injection of a miR-181a agomir or antagomir enhanced or impaired the CFC- and OLT-dependent memory formation, respectively. Using bioinformatics and luciferase assays, we identified PRKAA1 as a potential target gene of miR-181a. After CFC or OLT training, the expression and activity of PRKAA1 decreased as miR-181a expression increased and was effectively blocked by the miR-181a antagomir. Moreover, microinjection of the PRKAA1 agonist AICAR or inhibitor compound C in the DH reversed the roles of the miR-181a agomir or antagomir in CFC- and OLT-dependent memory formation. In conclusion, this work provides novel evidence describing the role and mechanism of miR-181a in hippocampus-dependent memory formation, which sheds light on the potential regulation of cognition and future treatments for cognitive disorders. PMID- 28814761 TI - Transplantation of bioengineered rat lungs recellularized with endothelial and adipose-derived stromal cells. AB - Bioengineered lungs consisting of a decellularized lung scaffold that is repopulated with a patient's own cells could provide desperately needed donor organs in the future. This approach has been tested in rats, and has been partially explored in porcine and human lungs. However, existing bioengineered lungs are fragile, in part because of their immature vascular structure. Herein, we report the application of adipose-derived stem/stromal cells (ASCs) for engineering the pulmonary vasculature in a decellularized rat lung scaffold. We found that pre-seeded ASCs differentiated into pericytes and stabilized the endothelial cell (EC) monolayer in nascent pulmonary vessels, thereby contributing to EC survival in the regenerated lungs. The ASC-mediated stabilization of the ECs clearly reduced vascular permeability and suppressed alveolar hemorrhage in an orthotopic transplant model for up to 3 h after extubation. Fibroblast growth factor 9, a mesenchyme-targeting growth factor, enhanced ASC differentiation into pericytes but overstimulated their proliferation, causing a partial obstruction of the vasculature in the regenerated lung. ASCs may therefore provide a promising cell source for vascular regeneration in bioengineered lungs, though additional work is needed to optimize the growth factor or hormone milieu for organ culture. PMID- 28814762 TI - Down-regulation of PDK4 is Critical for the Switch of Carbohydrate Catabolism during Syncytialization of Human Placental Trophoblasts. AB - Pyruvate dehydrogenase kinase (PDK) is known as a gatekeeper directing the carbon flux into glycolysis via inhibition of the pyruvate dehydrogenase complex. During syncytialization of placental trophoblasts, both ATP production and oxygen consumption are increased to meet enhanced energetic demands by syntiotrophoblasts. We hypothesized that down-regulation of PDK expression may play a central role in the switch from glycolysis to oxidative phosphorylation (OXPHOS) during syncytialization. By using primary human trophoblasts, we demonstrated that PDK4 was the dominating PDK isoform in human cytotrophoblasts, and its abundance was substantially decreased upon syncytialization, which was accompanied by decreases in lactate production and increases in ATP production. Knock-down of PDK4 expression reduced lactate production and increased ATP production, while over-expression of PDK4 increased lactate production and decreased ATP production, indicating that down-regulation of PDK4 is key to the shift from glycolysis to OXPHOS during syncytialization. Moreover, human chorionic gonadotropin (hCG)/cAMP/PKA pathway was demonstrated to be involved in the down-regulation of PDK4 expression upon syncytialization. Taken together, our findings disclosed that down-regulation of PDK4 is critical for the metabolic shift from glycolysis to OXPHOS during syncytialization, which may be a prerequisite for the proper implementation of syncytiotrophoblast functions. PMID- 28814764 TI - Percolation Phase Transition of Surface Air Temperature Networks: A new test bed for El Nino/La Nina simulations. AB - In this work, we studied the air-sea interaction over the tropical central eastern Pacific from a new perspective, climate network. The surface air temperatures over the tropical Pacific were constructed as a network, and the nodes within this network were linked if they have a similar temporal varying pattern. Using three different reanalysis datasets, we verified the percolation phase transition. That is, when the influences of El Nino/La Nina are strong enough to isolate more than 48% of the nodes, the network may abruptly be divided into many small pieces, indicating a change of the network state. This phenomenon was reproduced successfully by a coupled general circulation model, Flexible Global Ocean-Atmosphere-Land System Model Spectral Version 2, but another model, Flexible Global Ocean-Atmosphere-Land System Model Grid-point Version 2, failed. As both models have the same oceanic component, but are with different atmospheric components, the improperly used atmospheric component should be responsible for the missing of the percolation phase transition. Considering that this new phenomenon is only recently noticed, current state-of-the-art models may ignore this process and induce unrealistic simulations. Accordingly, percolation phase transition is proposed as a new test bed, which deserves more attention in the future. PMID- 28814765 TI - Electric-field-induced alignment of electrically neutral disk-like particles: modelling and calculation. AB - This work reveals a torque from electric field to electrically neutral flakes that are suspended in a higher electrical conductive matrix. The torque tends to rotate the particles toward an orientation with its long axis parallel to the electric current flow. The alignment enables the anisotropic properties of tiny particles to integrate together and generate desirable macroscale anisotropic properties. The torque was obtained from thermodynamic calculation of electric current free energy at various microstructure configurations. It is significant even when the electrical potential gradient becomes as low as 100 v/m. The changes of electrical, electroplastic and thermal properties during particles alignment were discussed. PMID- 28814766 TI - Effect of hydrogen passivation on the decoupling of graphene on SiC(0001) substrate: First-principles calculations. AB - Intercalation of hydrogen is important for understanding the decoupling of graphene from SiC(0001) substrate. Employing first-principles calculations, we have systematically studied the decoupling of graphene from SiC surface by H atoms intercalation from graphene boundary. It is found the passivation of H atoms on both graphene edge and SiC substrate is the key factor of the decoupling process. Passivation of graphene edge can weaken the interaction between graphene boundary and the substrate, which reduced the energy barrier significantly for H diffusion into the graphene-SiC interface. As more and more H atoms diffuse into the interface and saturate the Si dangling bonds around the boundary, graphene will detach from substrate. Furthermore, the energy barriers in these processes are relatively low, indicating that these processes can occur under the experimental temperature. PMID- 28814763 TI - Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing. AB - In multiple myeloma malignant plasma cells expand within the bone marrow. Since this site is well-perfused, a rapid dissemination of "fitter" clones may be anticipated. However, an imbalanced distribution of multiple myeloma is frequently observed in medical imaging. Here, we perform multi-region sequencing, including iliac crest and radiology-guided focal lesion specimens from 51 patients to gain insight into the spatial clonal architecture. We demonstrate spatial genomic heterogeneity in more than 75% of patients, including inactivation of CDKN2C and TP53, and mutations affecting mitogen-activated protein kinase genes. We show that the extent of spatial heterogeneity is positively associated with the size of biopsied focal lesions consistent with regional outgrowth of advanced clones. The results support a model for multiple myeloma progression with clonal sweeps in the early phase and regional evolution in advanced disease. We suggest that multi-region investigations are critical to understanding intra-patient heterogeneity and the evolutionary processes in multiple myeloma.In multiple myeloma, malignant cells expand within bone marrow. Here, the authors use multi-region sequencing in patient samples to analyse spatial clonal architecture and heterogeneity, providing novel insight into multiple myeloma progression and evolution. PMID- 28814767 TI - Application of the Onodera prognostic nutrition index and neutrophil-to lymphocyte ratio in risk evaluation of postoperative complications in Crohn's disease. AB - This study aimed to investigate application of Onodera prognostic nutrition index (OPNI) and neutrophil-to-lymphocyte ratio (NLR) in evaluating risk of postoperative complications in Crohn's disease (CD). Clinical data of 108 postoperative CD patients in 9 years were respectively reviewed. OPNI and NLR were within 1 week preoperatively. Average OPNI was 38.8 +/- 8.2 and significantly lower in patients with: CD type B3; lymphopenia; decreased haemoglobin, prealbumin, and albumin; and daily enteral nutrition <500 kcal/d. Average NLR was 5.9 +/- 12.1 and significantly higher in patients with: CD type B3, neutrophilia, lymphopenia, decreased prealbumin, and enteral nutrition <500 kcal/d. Youden index was maximal at OPNI 39.8 and NLR 4.1, patients were divided into two groups by OPNI 39.8 and NLR 4.1; Low OPNI (<=39.8) group had significantly greater incidence of type B3, lymphopenia, decreased haemoglobin, prealbumin and albumin, and enteral nutrition <500 kcal/day, more likely to have intra-abdominal bleeding. High NLR group (>=4.1) had significantly greater incidence of type B3, neutrophilia, and lymphopenia, more likely to develop lung infection. OPNI and NLR were significantly negatively correlated. Smoking within 1 year preoperatively, OPNI <39.8, NLR >= 4.1 were independent risk factors for postoperative complications in CD. PMID- 28814768 TI - Risk Factors For Radiation-Induced Skin Ulceration in Percutaneous Coronary Interventions of Chronic Total Occluded Lesions: A 2-Year Observational Study. AB - Relationship between radiation-induced skin ulceration (RSU) and variables in percutaneous coronary interventions (PCI) was rarely reported. RSU is a severe complication in PCIs, especially for chronic total occlusion (CTO) lesions. We investigated the RSUs and their risk factors in patients receiving CTO PCIs over a 2-year period. Data were analyzed using chi-square tests, t-tests and receiver operating characteristic (ROC) curve. Of 238 patients, 11 patients (4.6%) had RSUs all at right upper back. RSUs were significantly associated with use of left anterior oblique (LAO) views (100% vs. 47.1%, p < 0.001), retrograde techniques (36.3% vs. 7.9%, p = 0.012), or a procedure time (PT) defined as a time duration between the first and last angiograms of > 120, 180, or 240 minutes (p < 0.05). ROC analysis showed a long PT was an accurate predictor of RSUs (AUC = 0.88; p < 0.001) at a cut-off of 130 minutes (sensitivity = 0.91, specificity = 0.81). The results showed risk factors for RSUs containing use of large LAO views, retrograde techniques, and prolonged PTs. This study suggests that, to minimize RSU, interventionalists should limit PT to roughly 2 hours in fixed LAO views. PMID- 28814769 TI - Genome-wide Association Studies for Female Fertility Traits in Chinese and Nordic Holsteins. AB - Reduced female fertility could cause considerable economic loss and has become a worldwide problem in the modern dairy industry. The objective of this study was to detect quantitative trait loci (QTL) for female fertility traits in Chinese and Nordic Holsteins using various strategies. First, single-trait association analyses were performed for female fertility traits in Chinese and Nordic Holsteins. Second, the SNPs with P-value < 0.005 discovered in Chinese Holsteins were validated in Nordic Holsteins. Third, the summary statistics from single trait association analyses were combined into meta-analyses to: (1) identify common QTL for multiple fertility traits within each Holstein population; (2) detect SNPs which were associated with a female fertility trait across two Holstein populations. A large numbers of QTL were discovered or confirmed for female fertility traits. The QTL segregating at 31.4~34.1 Mb on BTA13, 48.3~51.9 Mb on BTA23 and 34.0~37.6 Mb on BTA28 shared between Chinese and Nordic Holsteins were further ascertained using a validation approach and meta-analyses. Furthermore, multiple novel variants identified in Chinese Holsteins were validated with Nordic data as well as meta-analyses. The genes IL6R, SLC39A12, CACNB2, ZEB1, ZMIZ1 and FAM213A were concluded to be strong candidate genes for female fertility in Holsteins. PMID- 28814770 TI - Rapid phenotypic individualization of bacterial sister cells. AB - A growing bacterium typically divides into two genetically identical and morphologically similar sister cells and eventually gives rise to a clonal population. Nevertheless, significant phenotypic differentiation among isogenic cells frequently occurs, with the resulting heterogeneity in cellular behavior often ensuring population level growth and survival in complex and unpredictable environments. Although several mechanisms underlying the generation of phenotypic heterogeneity have been elucidated, the speed with which identical sister cells tend to phenotypically diverge from each other has so far remained unaddressed. Using Escherichia coli as a model organism, we therefore examined the timing and dynamics of phenotypic individualization among sister cells by scrutinizing and modeling microscopically tracked clonally growing populations before and after a semi-lethal heat challenge. This analysis revealed that both survival probability and post-stress physiology of sister cells shift from highly similar to uncorrelated within the first decile of their cell cycles. This nearly-immediate post-fission randomization of sister cell fates highlights the potential of stochastic fluctuations during clonal growth to rapidly generate phenotypically independent individuals. PMID- 28814771 TI - RNA sequencing of db/db mice liver identifies lncRNA H19 as a key regulator of gluconeogenesis and hepatic glucose output. AB - Liver plays a key role in maintaining glucose homeostasis and impaired hepatic glucose metabolism is associated with type 2 diabetes. In the present study, we used RNA sequencing to profile the transcriptome of the livers of diabetic db/db mice as compared to the normal db/+ mice and identified 218 differentially expressed genes. Amongst these, there were 3 lncRNAs that were significantly downregulated and H19 was the most altered lncRNA in the livers of db/db mice. H19 expression significantly correlated with the expression of genes of the glycolysis and gluconeogenesis pathways, which suggest that altered hepatic H19 levels can directly or indirectly modulate their expression. Inhibition of H19 using specific siRNA in HepG2 cells and primary mouse hepatocytes significantly increased the levels of gluconeogenic genes. This was subsequently accompanied by increased hepatic glucose output. Further,H19 depletion in HepG2 cells impaired insulin signaling and increased nuclear localization of FoxO1, an important transcriptional regulator of gluconeogenic gene expression. Our results reveal a novel link between decreased H19 levels and impaired gluconeogenesis via regulation of FoxO1 nuclear levels. These put forth interesting observations on the regulatory role of H19 in altering hepatic physiology during diabetes. PMID- 28814772 TI - Myosin isoform expressed in metastatic prostate cancer stimulates cell invasion. AB - During metastasis, tumor cells migrate out of their original tissue to invade other organs. Secretion of exosomes and metalloproteases is essential for extracellular matrix remodeling, enabling migration through tissue barriers. Metastatic prostate cancer is differentiated by expression of the rare isoform A of the molecular motor myosin IC, however the function of this isoform remained unknown. Here we show that it contributes causatively to the invasive motility of prostate cancer cells. We found that the isoform associates with metalloprotease containing exosomes and stimulates their secretion. While the data show that myosin IC is involved in prostate cancer cell migration, migration outside extracellular matrix in vitro proves little affected specifically by isoform A. Nevertheless, this isoform stimulates invasion through extracellular matrix, pointing to a critical role in secretion. Both the secretion and invasion depend on the integrity of the motor and lipid-binding domains of the protein. Our results demonstrate how myosin IC isoform A is likely to function in metastasis, driving secretion of exosomes that enable invasion of prostate cancer cells across extracellular matrix barriers. The new data identify a molecule suitable for a mechanistically grounded development into a marker and target for prognosis, detection, and treatment of invasive prostate cancer. PMID- 28814773 TI - High-speed manufacturing of highly regular femtosecond laser-induced periodic surface structures: physical origin of regularity. AB - Highly regular laser-induced periodic surface structures (HR-LIPSS) have been fabricated on surfaces of Mo, steel alloy and Ti at a record processing speed on large areas and with a record regularity in the obtained sub-wavelength structures. The physical mechanisms governing LIPSS regularity are identified and linked with the decay length (i.e. the mean free path) of the excited surface electromagnetic waves (SEWs). The dispersion of the LIPSS orientation angle well correlates with the SEWs decay length: the shorter this length, the more regular are the LIPSS. A material dependent criterion for obtaining HR-LIPSS is proposed for a large variety of metallic materials. It has been found that decreasing the spot size close to the SEW decay length is a key for covering several cm2 of material surface by HR-LIPSS in a few seconds. Theoretical predictions suggest that reducing the laser wavelength can provide the possibility of HR-LIPSS production on principally any metal. This new achievement in the unprecedented level of control over the laser-induced periodic structure formation makes this laser-writing technology to be flexible, robust and, hence, highly competitive for advanced industrial applications based on surface nanostructuring. PMID- 28814774 TI - Molecular characterization of two novel echovirus 18 recombinants associated with hand-foot-mouth disease. AB - Human echovirus 18 (E-18) is a member of the enterovirus B species. To date, sixteen full-length genome sequences of E-18 are available in the GenBank database. In this study, we describe the complete genomic characterization of two E-18 strains isolated in Yunnan, China. Pairwise comparisons of the nucleotide sequences and the deduced amino acid sequences revealed that the two Yunnan E-18 strains had 87.5% nucleotide identity and 96.3-96.5% amino acid identity with the Chinese strain. Phylogenetic and bootscanning analyses revealed the two E-18 strains had the highest identity with other several EV-B serotypes than the other E-18 strains in the P3 coding region, especially, 3B region of the Swine Vesicular disease virus (SVDV) strain HK70, indicated that frequent intertypic recombination might have occurred in the two Yunnan strains. This study contributes the complete genome sequences of E-18 to the GenBank database and provides valuable information on the molecular epidemiology of E-18 in China. PMID- 28814776 TI - Continuously wavelength-tunable passband-flattened fiber comb filter based on polarization-diversified loop structure. AB - Continuous wavelength tuning of optical comb filters, which is an essential functionality for flexible signal processing in reconfigurable optical systems, has been challenging in high order filter structures with two birefringent elements (BEs) or more due to cumbersomeness in finding a combination of waveplates and BEs and complexity in determining their individual azimuthal orientations. Here, we propose a continuously tunable polarization-independent passband-flattened fiber comb filter with two BEs using a polarization diversified loop structure for the first time. The proposed filter consists of a polarization beam splitter and two groups of a half-wave plate, quarter-wave plate, and polarization-maintaining fiber (PMF). The azimuthal orientation of PMF in the second group is fixed as 22.5 degrees . Orientation angle sets of the four waveplates, which can induce an arbitrary phase shift from 0 to 2pi in the passband-flattened transmittance function, are found from the filter transmittance derived using Jones matrix formulation. From theoretical spectral analysis, it is confirmed that passband-flattened comb spectra can be continuously tuned. Theoretical prediction is verified by experimental demonstration. Moreover, the wavelength-dependent evolution of the output state of polarization (SOP) of each PMF is investigated on the Poincare sphere, and the relationship between wavelength tuning and SOP evolution is also discussed. PMID- 28814775 TI - Mutational profile of rare variants in inflammasome-related genes in Behcet disease: A Next Generation Sequencing approach. AB - Behcet's disease (BD) is an immune-mediated systemic disorder with a well established association with HLA class I and other genes. BD has clinical overlap with many autoinflammatory diseases (AIDs). The aim of this study was to investigate the role of rare variants in seven genes involved in AIDs: CECR1, MEFV, MVK, NLRP3, NOD2, PSTPIP1 and TNFRSF1A using a next generation sequencing (NGS) approach in 355 BD patients. To check global association of each gene, 4 tests: SKAT, CollapseBt, C(alpha) and weighted KBAC were used. Databases: 1000 Genomes Project Phase 3, Infevers, HGMD and ClinVar and algorithms: PolyPhen2 and SIFT were consulted to collect information of the 62 variants found. All the genes resulted associated using SKAT but only 3 (MVK, NOD2 and PSTPIP1) with C(alpha) and weighted KBAC. When all the genes are considered, 40 variants were associated to AIDs in clinical databases and 25 were predicted as pathogenic at least by one of the algorithms. Including only MVK, NOD2 and PSTPIP1, the associated to AIDs variants found in BD were 20 and the predicted as pathogenic, 12. The maxima contribution corresponds to NOD2. This study supports influence of rare variants in genes involved in AIDs in the pathogenesis of BD. PMID- 28814777 TI - The Microbial Ecosystem Distinguishes Chronically Diseased Tissue from Adjacent Tissue in the Sigmoid Colon of Chronic, Recurrent Diverticulitis Patients. AB - Diverticular disease is commonly associated with the older population in the United States. As individual's age, diverticulae, or herniation of the mucosa through the colonic wall, develop. In 10-25% of individuals, the diverticulae become inflamed, resulting in diverticulitis. The gut ecosystem relies on the interaction of bacteria and fungi to maintain homeostasis. Although bacterial dysbiosis has been implicated in the pathogenesis of diverticulitis, associations between the microbial ecosystem and diverticulitis remain largely unstudied. This study investigated how the cooperative network of bacteria and fungi differ between a diseased area of the sigmoid colon chronically affected by diverticulitis and adjacent non-affected tissue. To identify mucosa-associated microbes, bacterial 16S rRNA and fungal ITS sequencing were performed on chronically diseased sigmoid colon tissue (DT) and adjacent tissue (AT) from the same colonic segment. We found that Pseudomonas and Basidiomycota OTUs were associated with AT while Microbacteriaceae and Ascomycota were enriched in DT. Bipartite co-occurrence networks were constructed for each tissue type. The DT and AT networks were distinct for each tissue type, with no microbial relationships maintained after intersection merge of the groups. Our findings indicate that the microbial ecosystem distinguishes chronically diseased tissue from adjacent tissue. PMID- 28814778 TI - In vivo and in vitro sex differences in the dendritic morphology of developing murine hippocampal and cortical neurons. AB - Altered dendritic morphology is common in neurodevelopmental disorders (NDDs), many of which show sex biases in prevalence, onset and/or severity. However, whether dendritic morphology varies as a function of sex in juvenile mice or primary neuronal cell cultures is largely unknown even though both are widely used models for studying NDDs. To address this gap, we quantified dendritic morphology in CA1 pyramidal hippocampal and adjacent somatosensory pyramidal cortical neurons from male and female postnatal day (P)28 C57BL/6J mice. As determined by Sholl analysis of Golgi-stained brain sections, dendritic arbors of male hippocampal neurons are more complex than females. Conversely, dendritic morphology of female cortical neurons is more complex than males. In primary neuron-glia co-cultures from P0 mouse hippocampi, male neurons have more complex dendritic arbors than female neurons. Sex differences are less pronounced in cortical cultures. In vitro sex differences in dendritic morphology are driven in part by estrogen-dependent mechanisms, as evidenced by decreased dendritic complexity in male hippocampal neurons cultured in phenol red-free media or in the presence of an estrogen receptor antagonist. Evidence that sex influences dendritic morphogenesis in two models of neurodevelopment in a region-specific manner has significant mechanistic implications regarding sex biases in NDDs. PMID- 28814779 TI - The BEACH Protein LRBA Promotes the Localization of the Heterotrimeric G-protein Golf to Olfactory Cilia. AB - BEACH domain proteins are involved in membrane protein traffic and human diseases, but their molecular mechanisms are not understood. The BEACH protein LRBA has been implicated in immune response and cell proliferation, and human LRBA mutations cause severe immune deficiency. Here, we report a first functional and molecular phenotype outside the immune system of LRBA-knockout mice: compromised olfaction, manifesting in reduced electro-olfactogram response amplitude, impaired food-finding efficiency, and smaller olfactory bulbs. LRBA is prominently expressed in olfactory and vomeronasal chemosensory neurons of wild type mice. Olfactory impairment in the LRBA-KO is explained by markedly reduced concentrations (20-40% of wild-type levels) of all three subunits alphaolf, beta1 and gamma13 of the olfactory heterotrimeric G-protein, Golf, in the sensory cilia of olfactory neurons. In contrast, cilia morphology and the concentrations of many other proteins of olfactory cilia are not or only slightly affected. LRBA is also highly expressed in photoreceptor cells, another cell type with a specialized sensory cilium and heterotrimeric G-protein-based signalling; however, visual function appeared unimpaired by the LRBA-KO. To our knowledge, this is the first observation that a BEACH protein is required for the efficient subcellular localization of a lipid-anchored protein, and of a ciliary protein. PMID- 28814780 TI - Adaptive simulations, towards interactive protein-ligand modeling. AB - Modeling the dynamic nature of protein-ligand binding with atomistic simulations is one of the main challenges in computational biophysics, with important implications in the drug design process. Although in the past few years hardware and software advances have significantly revamped the use of molecular simulations, we still lack a fast and accurate ab initio description of the binding mechanism in complex systems, available only for up-to-date techniques and requiring several hours or days of heavy computation. Such delay is one of the main limiting factors for a larger penetration of protein dynamics modeling in the pharmaceutical industry. Here we present a game-changing technology, opening up the way for fast reliable simulations of protein dynamics by combining an adaptive reinforcement learning procedure with Monte Carlo sampling in the frame of modern multi-core computational resources. We show remarkable performance in mapping the protein-ligand energy landscape, being able to reproduce the full binding mechanism in less than half an hour, or the active site induced fit in less than 5 minutes. We exemplify our method by studying diverse complex targets, including nuclear hormone receptors and GPCRs, demonstrating the potential of using the new adaptive technique in screening and lead optimization studies. PMID- 28814782 TI - Monolithic beam steering in a mid-infrared, surface-emitting, photonic integrated circuit. AB - The mid-infrared (2.5 < lambda < 25 MUm) spectral region is utilized for many purposes, such as chemical/biological sensing, free space communications, and illuminators/countermeasures. Compared to near-infrared optical systems, however, mid-infrared component technology is still rather crude, with isolated components exhibiting limited functionality. In this manuscript, we make a significant leap forward in mid-infrared technology by developing a platform which can combine functions of multiple mid-infrared optical elements, including an integrated light source. In a single device, we demonstrate wide wavelength tuning (240 nm) and beam steering (17.9 degrees) in the mid-infrared with a significantly reduced beam divergence (down to 0.5 degrees). The architecture is also set up to be manufacturable and testable on a wafer scale, requiring no cleaved facets or special mirror coating to function. PMID- 28814781 TI - Association between LRP1 C766T polymorphism and Alzheimer's disease susceptibility: a meta-analysis. AB - Low density lipoprotein receptor-related protein 1 (LRP1) C766T polymorphism (rs1799986) has been extensively investigated for Alzheimer's disease (AD) susceptibility. However, results in different studies have been contradictory. Therefore, we conducted a meta-analysis containing 6455 AD cases and 6304 controls from 26 independent case-control studies to determine whether there was an association between the LRP1 C766T polymorphism and AD susceptibility. The combined analysis showed that there was no significant association between LRP1 C766T polymorphism and AD susceptibility (TT + CT versus CC: OR = 0.920, 95% CI = 0.817-1.037, P = 0.172). In subgroup analysis, significant decreased AD susceptibility was found among Asian population in allele model (T versus C: OR = 0.786, 95% CI = 0.635-0.974, P = 0.028) and dominant model (TT + CT versus CC: OR = 0.800, 95% CI = 0.647-0.990, P = 0.040). Moreover, T allele of LRP1 C766T was statistically associated with late onset of AD (LOAD) (T versus C: OR = 0.858, 95% CI = 0.748-0.985, P = 0.029; TT + CT versus CC: OR = 0.871, 95% CI = 0.763 0.994, P = 0.040). In conclusion, our meta-analysis suggested that LRP1 C766T polymorphism was associated with lower risk of AD in Asian, and could reduce LOAD risk especially. Considering some limitations of our meta-analysis, further large scale studies should be done to reach a more comprehensive understanding. PMID- 28814783 TI - Mycoplasma pneumoniae-Associated Bronchiolitis Obliterans Following Acute Bronchiolitis. AB - The characteristics of Mycoplasma pneumonia (M. pneumoniae)-associated bronchiolitis obliterans (BO) are not well known. We retrospectively reviewed 17 patients with M. pneumoniae-associated BO. All patients had M. pneumoniae associated acute bronchiolitis prior to the development of BO. In the acute bronchiolitis stage, all patients had fever and cough; six patients also had wheezing and dyspnoea. BO was diagnosed approximately 1.5-8 months later based on clinical manifestations and chest high-resolution computed tomography (HRCT) findings. All patients presented with wheezing and/or dyspnoea at the time of diagnosis of BO. HRCT findings included mosaic attenuation, pronounced air trapping, central bronchiectasis and emphysema, according to disease severity. Lung function tests revealed mild to severe airway obstruction. Fourteen of 17 patients had a greater than 12% increase in forced expiratory volume in 1 second values after taking salbutamol. All patients had positive allergy test results and family or personal history of atopic disease. Four patients had a history of asthma before M. pneumonia bronchiolitis. Asthma was diagnosed before, at the time of or after the diagnosis of BO in 11 cases. M. pneumoniae-associated BO may therefore develop following M. pneumonia bronchiolitis and overlap with asthma. PMID- 28814784 TI - Social isolation suppresses actin dynamics and synaptic plasticity through ADF/cofilin inactivation in the developing rat barrel cortex. AB - Exposure to a stressful environment early in life can cause psychiatric disorders by disrupting circuit formation. Actin plays central roles in regulating neuronal structure and protein trafficking. We have recently reported that neonatal isolation inactivated ADF/cofilin, the actin depolymerizing factor, resulted in a reduced actin dynamics at spines and an attenuation of synaptic alpha-amino-3 hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor delivery in the juvenile rat medial prefrontal cortex (mPFC), leading to altered social behaviours. Here, we investigated the impact of neonatal social isolation in the developing rat barrel cortex. Similar to the mPFC study, we detected an increase in stable actin fraction in spines and this resulted in a decreased synaptic AMPA receptor delivery. Thus, we conclude that early life social isolation affects multiple cortical areas with common molecular changes. PMID- 28814785 TI - Comparison between spectral analysis and symbolic dynamics for heart rate variability analysis in the rat. AB - Spectral analysis of heart rate (HR) has been widely used to assess the autonomic cardiovascular control. A nonlinear approach, known as symbolic analysis, has been reported to be very useful to assess the autonomic control of cardiovascular system in humans, but very few studies reported on the differences between these two approaches on experimental models. Two distinct approaches were used to elicit autonomic changes in conscious Wistar rats: (1) pharmacological blockade of cardiac autonomic receptors with atenolol (ATE, N = 9) or methylatropine (ATR, N = 9) and (2) mild changes in arterial pressure (AP) induced by phenylephrine (PHE, N = 9) or sodium nitroprusside (NPS, N = 9). Series of cardiac interval (CI) and systolic AP (SAP) were assessed using spectral analysis and symbolic dynamics. Results show that, for spectral analysis, the power in high frequency band of CI and the power in low frequency band of SAP are the most reliable indices of vagal and sympathetic modulation, respectively. For symbolic analysis, results point 0V% and 1V% to be related to sympathetic and 2UV% to vagal modulation. Interestingly, the incidence of 1V patterns, hitherto with unknown meaning, was revealed the best index of sympathetic modulation in the rat and should be accounted for in the future studies. PMID- 28814786 TI - New approach to arterial stiffness: BP-independent local carotid stiffness. PMID- 28814789 TI - Differential oxidation of protein-tyrosine phosphatases during zebrafish caudal fin regeneration. AB - Zebrafish have the capacity to regenerate lost tissues and organs. Amputation of the caudal fin results in a rapid, transient increase in H2O2 levels emanating from the wound margin, which is essential for regeneration, because quenching of reactive oxygen species blocks regeneration. Protein-tyrosine phosphatases (PTPs) have a central role in cell signalling and are susceptible to oxidation, which results in transient inactivation of their catalytic activity. We hypothesized that PTPs may become oxidized in response to amputation of the caudal fin. Using the oxidized PTP-specific (ox-PTP) antibody and liquid chromatography-mass spectrometry, we identified 33 PTPs in adult zebrafish fin clips of the total of 44 PTPs that can theoretically be detected based on sequence conservation. Of these 33 PTPs, 8 were significantly more oxidized 40 min after caudal fin amputation. Surprisingly, Shp2, one of the PTPs that were oxidized in response to caudal fin amputation, was required for caudal fin regeneration. In contrast, Rptpalpha, which was not oxidized upon amputation, was dispensable for caudal fin regeneration. Our results demonstrate that PTPs are differentially oxidized in response to caudal fin amputation and that there is a differential requirement for PTPs in regeneration. PMID- 28814788 TI - Synthesis of Saccharumoside-B analogue with potential of antiproliferative and pro-apoptotic activities. AB - A new series of phenolic glycoside esters, saccharumoside-B and its analogs (9b 9n, 10) have been synthesized by the Koenigs-Knorr reaction. Antiproliferative activities of the compounds (9b-9n, 10) were evaluated on various cancer cell lines including, MCF-7 breast, HL-60 leukemia, MIA PaCa-2 pancreatic, DU145 prostate, HeLa cervical and CaCo-2 colon, as well as normal human MCF10A mammary epithelial and human peripheral blood mononuclear cells (PBMC) by MTT assay. Compounds (9b-9n, 10) exhibited considerable antiproliferative effects against cancer cells with IC50 range of 4.43 +/- 0.35 to 49.63 +/- 3.59 uM, but they are less cytotoxic on normal cells (IC50 > 100 uM). Among all the compounds, 9f showed substantial antiproliferative activity against MCF-7 and HL-60 cells with IC50 of 6.13 +/- 0.64 and 4.43 +/- 0.35, respectively. Further mechanistic studies of 9f were carried out on MCF-7 and HL-60 cell lines. 9f caused arrest of cell cycle of MCF-7 and HL-60 cells at G0/G1 phase. Apoptotic population elevation, mitochondrial membrane potential loss, increase of cytosolic cytochrome c and Bax levels, decrease of Bcl-2 levels and enhanced caspases-9 and -3 activities were observed in 9f-treated MCF-7 and HL-60 cells. These results demonstrate anticancer and apoptosis-inducing potentials of 9f in MCF-7 and HL-60 cells via intrinsic pathway. PMID- 28814790 TI - In silico investigation of a KCNQ1 mutation associated with short QT syndrome. AB - Short QT syndrome (SQTS) is a rare condition characterized by abnormally 'short' QT intervals on the ECG and increased susceptibility to cardiac arrhythmias and sudden death. This simulation study investigated arrhythmia dynamics in multi scale human ventricle models associated with the SQT2-related V307L KCNQ1 'gain of-function' mutation, which increases slow-delayed rectifier potassium current (IKs). A Markov chain (MC) model recapitulating wild type (WT) and V307L mutant IKs kinetics was incorporated into a model of the human ventricular action potential (AP) for investigation of QT interval changes and arrhythmia substrates. In addition, the degree of simulated IKs inhibition necessary to normalize the QT interval and terminate re-entry in SQT2 conditions was quantified. The developed MC model accurately reproduced AP shortening and reduced effective refractory period associated with altered IKs kinetics in homozygous (V307L) and heterozygous (WT-V307L) mutation conditions, which increased the lifespan and dominant frequency of re-entry in 3D human ventricle models. IKs reductions of 58% and 65% were sufficient to terminate re-entry in WT V307L and V307L conditions, respectively. This study further substantiates a causal link between the V307L KCNQ1 mutation and pro-arrhythmia in human ventricles, and establishes partial inhibition of IKs as a potential anti arrhythmic strategy in SQT2. PMID- 28814791 TI - Molecular dynamics simulations of heterogeneous cell membranes in response to uniaxial membrane stretches at high loading rates. AB - The chemobiomechanical signatures of diseased cells are often distinctively different from that of healthy cells. This mainly arises from cellular structural/compositional alterations induced by disease development or therapeutic molecules. Therapeutic shock waves have the potential to mechanically destroy diseased cells and/or increase cell membrane permeability for drug delivery. However, the biomolecular mechanisms by which shock waves interact with diseased and healthy cellular components remain largely unknown. By integrating atomistic simulations with a novel multiscale numerical framework, this work provides new biomolecular mechanistic perspectives through which many mechanosensitive cellular processes could be quantitatively characterised. Here we examine the biomechanical responses of the chosen representative membrane complexes under rapid mechanical loadings pertinent to therapeutic shock wave conditions. We find that their rupture characteristics do not exhibit significant sensitivity to the applied strain rates. Furthermore, we show that the embedded rigid inclusions markedly facilitate stretch-induced membrane disruptions while mechanically stiffening the associated complexes under the applied membrane stretches. Our results suggest that the presence of rigid molecules in cellular membranes could serve as "mechanical catalysts" to promote the mechanical destructions of the associated complexes, which, in concert with other biochemical/medical considerations, should provide beneficial information for future biomechanical-mediated therapeutics. PMID- 28814793 TI - Resolving the central metabolism of Arabidopsis guard cells. AB - Photosynthesis and water use efficiency, key factors affecting plant growth, are directly controlled by microscopic and adjustable pores in the leaf-the stomata. The size of the pores is modulated by the guard cells, which rely on molecular mechanisms to sense and respond to environmental changes. It has been shown that the physiology of mesophyll and guard cells differs substantially. However, the implications of these differences to metabolism at a genome-scale level remain unclear. Here, we used constraint-based modeling to predict the differences in metabolic fluxes between the mesophyll and guard cells of Arabidopsis thaliana by exploring the space of fluxes that are most concordant to cell-type-specific transcript profiles. An independent 13C-labeling experiment using isolated mesophyll and guard cells was conducted and provided support for our predictions about the role of the Calvin-Benson cycle in sucrose synthesis in guard cells. The combination of in silico with in vivo analyses indicated that guard cells have higher anaplerotic CO2 fixation via phosphoenolpyruvate carboxylase, which was demonstrated to be an important source of malate. Beyond highlighting the metabolic differences between mesophyll and guard cells, our findings can be used in future integrated modeling of multi-cellular plant systems and their engineering towards improved growth. PMID- 28814792 TI - Genetic regulatory effects modified by immune activation contribute to autoimmune disease associations. AB - The immune system plays a major role in human health and disease, and understanding genetic causes of interindividual variability of immune responses is vital. Here, we isolate monocytes from 134 genotyped individuals, stimulate these cells with three defined microbe-associated molecular patterns (LPS, MDP, and 5'-ppp-dsRNA), and profile the transcriptomes at three time points. Mapping expression quantitative trait loci (eQTL), we identify 417 response eQTLs (reQTLs) with varying effects between conditions. We characterize the dynamics of genetic regulation on early and late immune response and observe an enrichment of reQTLs in distal cis-regulatory elements. In addition, reQTLs are enriched for recent positive selection with an evolutionary trend towards enhanced immune response. Finally, we uncover reQTL effects in multiple GWAS loci and show a stronger enrichment for response than constant eQTLs in GWAS signals of several autoimmune diseases. This demonstrates the importance of infectious stimuli in modifying genetic predisposition to disease.Insight into the genetic influence on the immune response is important for the understanding of interindividual variability in human pathologies. Here, the authors generate transcriptome data from human blood monocytes stimulated with various immune stimuli and provide a time-resolved response eQTL map. PMID- 28814794 TI - Increased Body Exposure to New Anti-Trypanosomal Through Nanoencapsulation. AB - Lychnopholide, a lipophilic sesquiterpene lactone, is efficacious in mice at the acute and chronic phases of Chagas disease. Conventional poly-epsilon caprolactone (PCL) and long-circulating poly(D,L-lactide)-block-polyethylene glycol (PLA-PEG) nanocapsules containing lychnopholide were developed and characterized. Lychnopholide presented high association efficiency (>90%) with the nanocapsules. A new, fast and simple HPLC-UV-based bioanalytical method was developed, validated in mouse plasma and applied to lychnopholide quantification in in vitro release kinetics and pharmacokinetics. The nanocapsules had mean hydrodynamic diameters in the range of 100-250 nm, negative zeta potentials (-30 mV to -57 mV), with good physical stability under storage. Atomic force microscopy morphological analysis revealed spherical monodispersed particles and the absence of lychnopholide crystallization or aggregation. Association of lychnopholide to PLA-PEG nanocapsules resulted in a 16-fold increase in body exposure, a 26-fold increase in plasma half-life and a dramatic reduction of the lychnopholide plasma clearance (17-fold) in comparison with free lychnopholide. The improved pharmacokinetic profile of lychnopholide in long-circulating nanocapsules is in agreement with the previously reported improved efficacy observed in Trypanosoma cruzi-infected mice. The present lychnopholide intravenous dosage form showed great potential for further pre-clinical and clinical studies in Chagas disease and cancer therapies. PMID- 28814795 TI - Direct comparison of PET/CT and MRI to predict the pathological response to neoadjuvant chemotherapy in breast cancer: a meta-analysis. AB - Both PET/CT and breast MRI are used to assess pathological complete response to neoadjuvant chemotherapy (NAC) in patients with breast cancer. The aim is to compare the utility of PET/CT and breast MRI by using head-to-head comparative studies. Literature databases were searched prior to July 2016. Eleven studies with a total of 527 patients were included. For PET/CT, the pooled SEN was 0.87 (95% confidence interval (CI): 0.71-0.95) and SPE was 0.85 (95% CI: 0.70-0.93). For MRI, the pooled SEN was 0.79 (95% CI: 0.68-0.87) and SPE was 0.82 (95% CI: 0.72-0.89). In the conventional contrast enhanced (CE)-MRI subgroup, PET/CT outperformed conventional CE-MRI with a higher pooled sensitivity (0.88 (95% CI: 0.71, 0.95) vs. 0.74 (95% CI: 0.60, 0.85), P = 0.018). In the early evaluation subgroup, PET/CT was superior to MRI with a notable higher pooled specificity (0.94 (95% CI: 0.78, 0.98) vs. 0.83 (95% CI: 0.81, 0.87), P = 0.015). The diagnostic performance of MRI is similar to that of PET/CT for the assessment of breast cancer response to NAC. However, PET/CT is more sensitive than conventional CE-MRI and more specific if the second imaging scan is performed before 3 cycles of NAC. PMID- 28814796 TI - CRISPR-Cas9 Mediated Labelling Allows for Single Molecule Imaging and Resolution. AB - Single molecule imaging approaches like dSTORM and PALM resolve structures at 10 20 nm, and allow for unique insights into protein stoichiometry and spatial relationships. However, key obstacles remain in developing highly accurate quantitative single molecule approaches. The genomic tagging of PALM fluorophores through CRISPR-Cas9 offers an excellent opportunity for generating stable cell lines expressing a defined single molecule probe at endogenous levels, without the biological disruption and variability inherent to transfection. A fundamental question is whether these comparatively low levels of expression can successfully satisfy the stringent labelling demands of super-resolution SMLM. Here we apply CRISPR-Cas9 gene editing to tag a cytoskeletal protein (alpha-tubulin) and demonstrate a relationship between expression level and the subsequent quality of PALM imaging, and that spatial resolutions comparable to dSTORM can be achieved with CRISPR-PALM. Our approach shows a relationship between choice of tag and the total expression of labelled protein, which has important implications for the development of future PALM tags. CRISPR-PALM allows for nanoscopic spatial resolution and the unique quantitative benefits of single molecule localization microscopy through endogenous expression, as well as the capacity for super resolved live cell imaging. PMID- 28814797 TI - Adjustment of the Arabidopsis circadian oscillator by sugar signalling dictates the regulation of starch metabolism. AB - Arabidopsis plants store part of the carbon fixed by photosynthesis as starch to sustain growth at night. Two competing hypotheses have been proposed to explain this diel starch turnover based on either the measurement of starch abundance with respect to circadian time, or the sensing of sugars to feedback to the circadian oscillator to dynamically adjust the timing of starch turnover. We report a phase oscillator model that permitted derivation of the ideal responses of the circadian regulation of starch breakdown to maintain sucrose homeostasis. Testing the model predictions using a sugar-unresponsive mutant of Arabidopsis demonstrated that the dynamics of starch turnover arise from the circadian clock measuring and responding to the rate of change of cellular sucrose. Our theory and experiments suggest that starch turnover is controlled by the circadian clock acting as a dynamic homeostat responding to sucrose signals to maintain carbon homeostasis. PMID- 28814798 TI - Genetic polymorphisms of lncRNA-p53 regulatory network genes are associated with concurrent chemoradiotherapy toxicities and efficacy in nasopharyngeal carcinoma patients. AB - The relevance of the transcription factor p53 in cancer is inarguable, and numerous lncRNAs are involved in the p53 regulatory network as either regulators or effectors, triggering a transcriptional response that causes either cell arrest or apoptosis following DNA damage in a p53-dependent manner. Despite the fact that the therapeutic response is improved in NPC, heterogeneity among people remains with regard to the susceptibility of adverse effects and the efficacy of treatments. Therefore, we analysed eight potentially functional SNPs of five genes in the lncRNA-p53 regulatory network in a discovery cohort of 505 NPC patients. By performing multivariate logistic regression, the impact of genetic variations on the efficacy and risk of CRT-induced toxicities was investigated. The most dramatic finding was that the MEG3 rs10132552 CC genotype had a greater than three-fold increased risk of developing grade 3-4 anaemia (OR = 3.001, 95%CI = 1.355-6.646, P = 0.007). Furthermore, the rs10132552 CT genotype had a better response to treatment (OR = 0.261, 95%CI = 0.089-0.770, P = 0.015). Individuals carrying LINC-ROR rs2027701 with one or two variant alleles had significant associations with a reduced risk of neutropaenia (OR = 0.503, 95%CI = 0.303 0.835, P = 0.008). In conclusion, our results suggested that genetic polymorphisms of the lncRNA-p53 regulatory network could play a potential role in reducing treatment-related toxicities and improving outcomes for NPC patients. PMID- 28814799 TI - On mechanism behind UV-A light enhanced antibacterial activity of gallic acid and propyl gallate against Escherichia coli O157:H7. AB - Possible mechanisms behind the enhanced antimicrobial activity of gallic acid (GA) and its ester propyl gallate (PG) in the presence of UV-A light against Escherichia coli O157:H7 were investigated. GA by itself is a mild antimicrobial and has a pro-oxidant ability. We found that the presence of UV-A light increases the uptake of GA by the bacteria. Once GA is internalized, the interaction between GA and UV-A induces intracellular ROS formation, leading to oxidative damage. Concurrently, GA + UV-A also inhibits the activity of superoxide dismutase (SOD), magnifying the imbalance of redox status of E. coli O157:H7. In addition to ROS induced damage, UV-A light and GA also cause injury to the cell membrane of E. coli O157:H7. UV-A exposed PG caused oxidative damage to the cell and significantly higher damage to the cell membrane than GA + UV-A treatment, explaining its higher effectiveness than GA + UV-A treatment. The findings presented here may be useful in developing new antimicrobial sanitation technologies for food and pharmaceutical industries. PMID- 28814800 TI - Variations in biocorona formation related to defects in the structure of single walled carbon nanotubes and the hyperlipidemic disease state. AB - Ball-milling utilizes mechanical stress to modify properties of carbon nanotubes (CNTs) including size, capping, and functionalization. Ball-milling, however, may introduce structural defects resulting in altered CNT-biomolecule interactions. Nanomaterial-biomolecule interactions result in the formation of the biocorona (BC), which alters nanomaterial properties, function, and biological responses. The formation of the BC is governed by the nanomaterial physicochemical properties and the physiological environment. Underlying disease states such as cardiovascular disease can alter the biological milieu possibly leading to unique BC identities. In this ex vivo study, we evaluated variations in the formation of the BC on single-walled CNTs (SWCNTs) due to physicochemical alterations in structure resulting from ball-milling and variations in the environment due to the high-cholesterol disease state. Increased ball-milling time of SWCNTs resulted in enhanced structural defects. Following incubation in normal mouse serum, label-free quantitative proteomics identified differences in the biomolecular content of the BC due to the ball-milling process. Further, incubation in cholesterol-rich mouse serum resulted in the formation of unique BCs compared to SWCNTs incubated in normal serum. Our study demonstrates that the BC is modified due to physicochemical modifications such as defects induced by ball-milling and physiological disease conditions, which may result in variable biological responses. PMID- 28814801 TI - Strain-dependence of the Angelman Syndrome phenotypes in Ube3a maternal deficiency mice. AB - Angelman syndrome (AS) is a genetic neurodevelopmental disorder, most commonly caused by deletion or mutation of the maternal allele of the UBE3A gene, with behavioral phenotypes and seizures as key features. Currently no treatment is available, and therapeutics are often ineffective in controlling AS-associated seizures. Previous publications using the Ube3a maternal deletion model have shown behavioral and seizure susceptibility phenotypes, however findings have been variable and merit characterization of electroencephalographic (EEG) activity. In this study, we extend previous studies comparing the effect of genetic background on the AS phenotype by investigating the behavioral profile, EEG activity, and seizure threshold. AS C57BL/6J mice displayed robust behavioral impairments, spontaneous EEG polyspikes, and increased cortical and hippocampal power primarily driven by delta and theta frequencies. AS 129 mice performed poorly on wire hang and contextual fear conditioning and exhibited a lower seizure threshold and altered spectral power. AS F1 hybrid mice (C57BL/6J * 129) showed milder behavioral impairments, infrequent EEG polyspikes, and fewer spectral power alterations. These findings indicate the effect of common genetic backgrounds on the Ube3a maternal deletion behavioral, EEG, and seizure threshold phenotypes. Our results will inform future studies on the optimal strain for evaluating therapeutics with different AS-like phenotypes. PMID- 28814802 TI - Relationship between necrotic patterns in glioblastoma and patient survival: fractal dimension and lacunarity analyses using magnetic resonance imaging. AB - Necrosis is a hallmark feature of glioblastoma (GBM). This study investigated the prognostic role of necrotic patterns in GBM using fractal dimension (FD) and lacunarity analyses of magnetic resonance imaging (MRI) data and evaluated the role of lacunarity in the biological processes leading to necrosis. We retrospectively reviewed clinical and MRI data of 95 patients with GBM. FD and lacunarity of the necrosis on MRI were calculated by fractal analysis and subjected to survival analysis. We also performed gene ontology analysis in 32 patients with available RNA-seq data. Univariate analysis revealed that FD < 1.56 and lacunarity > 0.46 significantly correlated with poor progression-free survival (p = 0.006 and p = 0.012, respectively) and overall survival (p = 0.008 and p = 0.005, respectively). Multivariate analysis revealed that both parameters were independent factors for unfavorable progression-free survival (p = 0.001 and p = 0.015, respectively) and overall survival (p = 0.002 and p = 0.007, respectively). Gene ontology analysis revealed that genes positively correlated with lacunarity were involved in the suppression of apoptosis and necrosis associated biological processes. We demonstrate that the fractal parameters of necrosis in GBM can predict patient survival and are associated with the biological processes of tumor necrosis. PMID- 28814803 TI - The bHLH transcription factor CgbHLH001 is a potential interaction partner of CDPK in halophyte Chenopodium glaucum. AB - Plants have evolved different abilities to adapt to the ever-fluctuating environments for sessility. Calcium-dependent protein kinase (CDPK) is believed to play a pivotal role in abiotic stress signaling. So far, study on the specific substrates that CDPK recognized in response to adversity is limited. In the present study, we revealed a potential interaction between CDPK and a bHLH transcription factor under salt stress in Chenopodium glaucum. First, we identified a CgCDPK, which was up-regulated under salt and drought stress; then by Y2H screening, CgCDPK was detected to be involved in interaction with a bHLH TF (named as CgbHLH001), which also positively respond to salt and drought stress. Further computational prediction and experiments including GST-pulldown and BiFC assays revealed that potential interaction existed between CgCDPK and CgbHLH001, and they might interact on the plasma membrane. In addition, CgCDPK overexpressed transgenic tobacco line could significantly accumulate transcripts of NtbHLH (a homolog of CgbHLH001 in N. tabacum), which provided another evidence of correlation between CgCDPK and CgbHLH001. Our results suggest that CgbHLH001 can interact with CgCDPK in signal transduction pathway in response to abiotic stress, which should provide new evidence for further understanding of the substrate specificity of plant CDPK signaling pathway. PMID- 28814804 TI - A unique thermo-induced gel-to-gel transition in a pH-sensitive small-molecule hydrogel. AB - For a hydrogel based on a zwitterionic dendritic surfactant, we report an apparently unprecedented reversible temperature-induced gel-to-gel phase transition below the melting point of its alkyl chains, where the supramolecular self-assembly of surfactant molecules underwent a dramatic transformation from low-temperature surfactant bilayers to high-temperature entangled surfactant worm like micelles. PMID- 28814806 TI - Enhanced wintertime greenhouse effect reinforcing Arctic amplification and initial sea-ice melting. AB - The speeds of both Arctic surface warming and sea-ice shrinking have accelerated over recent decades. However, the causes of this unprecedented phenomenon remain unclear and are subjects of considerable debate. In this study, we report strong observational evidence, for the first time from long-term (1984-2014) spatially complete satellite records, that increased cloudiness and atmospheric water vapor in winter and spring have caused an extraordinary downward longwave radiative flux to the ice surface, which may then amplify the Arctic wintertime ice-surface warming. In addition, we also provide observed evidence that it is quite likely the enhancement of the wintertime greenhouse effect caused by water vapor and cloudiness has advanced the time of onset of ice melting in mid-May through inhibiting sea-ice refreezing in the winter and accelerating the pre-melting process in the spring, and in turn triggered the positive sea-ice albedo feedback process and accelerated the sea ice melting in the summer. PMID- 28814805 TI - Intercalating and maintenance gefitinib plus chemotherapy versus chemotherapy alone in selected advanced non-small cell lung cancer with unknown EGFR status. AB - Epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKIs) are standard treatment for advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation. However, EGFR mutation testing is not attainable in approximately 20% of patients. The current study examined intercalating and maintaining gefitinib treatment in stage IIIB/IV non-squamous NSCLC, never or former light smoking patients with unknown EGFR mutation status. Briefly, 219 patients who achieved stable disease (SD) with gemcitabine (1250 mg/m2) plus carboplatin (5 AUC) were randomized at 1:1 ratio to continue chemotherapy (n = 110) or intercalating gefitinib (250 mg/day on days 15-25 of each cycle until disease progress (n = 109). Progression-free survival (PFS) was 9.7 vs. 4.2 month in the gefitinib vs. control arm (HR: 0.41, 95% CI: 0.31-0.56; P < 0.001). Overall survival (OS) was also longer in the gefitinib arm (20.1 vs. 15.4 months; HR: 0.68; 95% CI 0.48-0.97; P = 0.0323). Adverse events, including diarrhea, dermal reaction and thrombocytopenia, were more common in the gefitinib arm. In conclusion, intercalating and maintenance gefitinib treatment is a viable option for advanced NSCLC patients with unknown EGFR mutation status in subpopulations with high EFGR mutation rate. PMID- 28814807 TI - Psychological Impact of Vehicle Exhaust Exposure: Insights from an Animal Model. AB - Air pollution resulting from exhaust emissions of vehicles has risen in the recent years, reportedly causing major adverse effects on the heart, lungs and the brain. Though respiratory and cardiovascular effects of these emissions are well identified, psychological and neurobiological complications of prolonged exposure to vehicle emissions remain unknown. Pro-oxidants are considered as major constituents of vehicle emissions. This is important considering causal link between oxidative stress and behavioral and cognitive impairments. We hypothesized that prolonged exposure to pro-oxidants in vehicle emissions result in behavioral and cognitive deficits. We developed a simulated vehicle exhaust exposure model in rats. The model used a simulated mixture of vehicle exhaust that comprised of pro-oxidant constituents of exhaust, namely, carbon dioxide (13%), carbon monoxide (0.68%) and nitrogen dioxide (1000 ppm) in air. Rats were exposed either to a high (1:10 dilution) or low (~1:1000 dilution) physiologically relevant dose of simulated mixture in air for two weeks in separate experiments followed by a comprehensive behavioral and cognitive analysis. We observed that prolonged exposure to pro-oxidants in vehicle exhaust increased anxiety-and depression-like behavior as well as led to impaired memory in rats. This is important preclinical evidence, particularly relevant to human population exposed to high vehicular traffic. PMID- 28814808 TI - Direct observation of multiple rotational stacking faults coexisting in freestanding bilayer MoS2. AB - Electronic properties of two-dimensional (2D) MoS2 semiconductors can be modulated by introducing specific defects. One important type of defect in 2D layered materials is known as rotational stacking fault (RSF), but the coexistence of multiple RSFs with different rotational angles was not directly observed in freestanding 2D MoS2 before. In this report, we demonstrate the coexistence of three RSFs with three different rotational angles in a freestanding bilayer MoS2 sheet as directly observed using an aberration corrected transmission electron microscope (TEM). Our analyses show that these RSFs originate from cracks and dislocations within the bilayer MoS2. First principles calculations indicate that RSFs with different rotational angles change the electronic structures of bilayer MoS2 and produce two new symmetries in their bandgaps and offset crystal momentums. Therefore, employing RSFs and their coexistence is a promising route in defect engineering of MoS2 to fabricate suitable devices for electronics, optoelectronics, and energy conversion. PMID- 28814809 TI - Non-thermal plasma-treated solution demonstrates antitumor activity against pancreatic cancer cells in vitro and in vivo. AB - Pancreatic cancer is associated with a high mortality rate. In advanced stage, patients often experience peritoneal carcinomatosis. Using a syngeneic murine pancreatic cancer cell tumor model, the effect of non-thermal plasma (NTP) on peritoneal metastatic lesions was studied. NTP generates reactive species of several kinds which have been proven to be of relevance in cancer. In vitro, exposure to both plasma and plasma-treated solution significantly decreased cell viability and proliferation of 6606PDA cancer cells, whereas mouse fibroblasts were less affected. Repeated intraperitoneal treatment of NTP-conditioned medium decreased tumor growth in vivo as determined by magnetic resonance imaging, leading to reduced tumor mass and improved median survival (61 vs 52 days; p < 0.024). Tumor nodes treated by NTP-conditioned medium demonstrated large areas of apoptosis with strongly inhibited cell proliferation. Contemporaneously, no systemic effects were found. Apoptosis was neither present in the liver nor in the gut. Also, the concentration of different cytokines in splenocytes or blood plasma as well as the distribution of various hematological parameters remained unchanged following treatment with NTP-conditioned medium. These results suggest an anticancer role of NTP-treated solutions with little to no systemic side effects being present, making NTP-treated solutions a potential complementary therapeutic option for advanced tumors. PMID- 28814811 TI - The 3-D structure of the Somma-Vesuvius volcanic complex (Italy) inferred from new and historic gravimetric data. AB - Existing 3-D density models of the Somma-Vesuvius volcanic complex (SVVC), Italy, largely disagree. Despite the scientific and socioeconomic importance of Vesuvius, there is no reliable 3-D density model of the SVVC. A considerable uncertainty prevails concerning the presence (or absence) of a dense body underlying the Vesuvius crater (1944 eruption) that is implied from extensive seismic investigations. We have acquired relative gravity measurements at 297 stations, including measurements in difficult-to-access areas (e.g., the first ever measurements in the crater). In agreement with seismic investigations, the simultaneous inversion of these and historic data resolves a high-density body that extends from the surface of the Vesuvius crater down to depths that exceed 2 km. A 1.5-km radius horseshoe-shaped dense feature (open in the southwestern sector) enforces the existing model of groundwater circulation within the SVVC. Based on its volcano-tectonic evolution, we interpret volcanic structures that have never been imaged before. PMID- 28814810 TI - Amygdala-centred functional connectivity affects daily cortisol concentrations: a putative link with anxiety. AB - The amygdala plays a critical role in emotion. Its functional coupling with the hippocampus and ventromedial prefrontal cortex extending to a portion of the anterior cingulate cortex (ACC) is implicated in anxiogenesis and hypothalamic pituitary-adrenal (HPA) system regulation. However, it remains unclear how amygdala-centred functional connectivity (FC) affects anxiety and cortisol concentrations in everyday life. Here, we investigate the relationship between daily cortisol concentrations (dCOR) and amygdala-centred FC during emotional processing in forty-one healthy humans. FC analyses revealed that higher dCOR predicted strengthened amygdala-centred FC with the hippocampus and cerebellum, but inhibited FC with the supramarginal gyrus and a perigenual part of the ACC (pgACC) when processing fearful faces (vs. neutral faces). Notably, the strength of amygdala-hippocampus FC mediated the positive relationship between cortisol and anxiety, specifically when the effect of amygdala-pgACC FC, a presumptive neural indicator of emotional control, was taken into account. Individuals with diminished connectivity between the amygdala and pgACC during fear-related processing might be more vulnerable to anxiogenesis as it pertains to greater circulating cortisol levels in everyday life. Individual functional patterns of amygdala-hippocampal-pgACC connectivity might provide a key to understand the complicate link between cortisol and anxiety-related behaviors. PMID- 28814812 TI - Transurethral resection of the prostate (TURP) vs GreenLight photoselective vaporization of benign prostatic hyperplasia: analysis of BPH6 outcomes after 1 year of follow-up. AB - The surgical treatment of benign prostatic obstruction is changing over the time, thanks the increase evidence about the successful role of laser techniques in this surgery. We aimed to compare prostatic GreenLight photovaporization (PVP) to bipolar transurethral resection of the prostate (TURP) with regard to lower urinary tract symptoms (LUTS) improvement through the evaluation of BPH6. We enrolled 220 consecutive subjects affected by LUTS. We performed a propensity score matching using prostate volume, peak flow and International Prostate Symptoms Score (IPSS). A total of 110 (55 TURP and 55 PVP) were analyzed. We found after 1 year of follow-up that the rate of subjects resulting in greater BPH6 recovery in the PVP group vs TURP (45.6% vs 18.2%; P=0.001). The TURP treatment showed greater catheterization time (4.67 vs 1.25; P<0.01) while PVP showed greater recovery experience (82.4 vs 58.2; <0.01). Postoperative ejaculatory dysfunctions were observed in both groups, 58.8% in TURP and 34.5% in PVP group. The multivariate logistic regression analysis, adjusted for preoperative variables, showed that PVP was independently associated with BPH6 recovery end point (odds ratio=3.77; P<0.01). This study showed data in favor of PVP. Although IPSS and peak flow improvements were similar, PVP showed better clinical outcomes. PMID- 28814813 TI - Sexual dysfunction among diabetics and its impact on the SQoL of their partners. AB - Sexual dysfunction (SD) has long been known to affect a significant number of people worldwide with serious implications and limitations on sexual expression and fulfillment. This may affect the sexual quality of life (SQoL) of individuals and their partners. A cross-sectional study was conducted among diabetic patients and their partners who visited the Tema General Hospital. A total of 130 and 116 diabetic males and females and their partners were interviewed. Male and female diabetic participants and partners were evaluated using the Golombuk Rust Inventory for Sexual Satisfaction-Male (GRISS-M)/SQoL-M and GRISS-Female/SQoL-F, respectively. For the diabetic males, the mean age and duration of diabetes (DOD) was 63.04+/-10.85 and 8.38+/-6.53 years, respectively, and that of the diabetic females was 56.98+/-9.42 and 6.11+/-5.31 years, respectively. Diabetic male participants with SD were significantly older and had a longer duration of diabetes. The mean SQoL and SQoL-Partner (SQoL-P) recorded for the diabetic males and their partners was 42.29+/-30.88 and 52.86+/-15.26, respectively. The mean SQoL and SQoL-P recorded for the diabetic females and their partners was 57.73+/ 14.91 and 64.97+/-19.68, respectively. Diabetic males who had impotence had female partners with significantly lower SQoL-P scores, and similar results were recorded for those who had premature ejaculation, nonsensuality, avoidance and dissatisfaction problems. Female diabetics who had nonsensuality, avoidance and infrequency had male partners who recorded significantly lower SQoL-P scores. Female diabetics with higher perceptions of what an adequate intravaginal ejaculatory latency time (IELT) should be had male partners with significantly lower SQoL-P scores. Ageing and DOD are more likely to affect the sexual functioning of diabetic males than females. SD in diabetics with problems of impotence/vaginismus, premature ejaculation/anorgasmia, nonsensuality and avoidance has an adverse effect on the SQoL-P of their partners. Male partners of diabetic females who have a higher perception of IELT had a reduced SQoL. Ageing and longer DOD in diabetics are associated with a reduced SQoL-P of their partners. PMID- 28814814 TI - Umbilical cord extracts improve diabetic abnormalities in bone marrow-derived mesenchymal stem cells and increase their therapeutic effects on diabetic nephropathy. AB - Bone marrow-derived mesenchymal stem cells (BM-MSC) has been applied as the most valuable source of autologous cell transplantation for various diseases including diabetic complications. However, hyperglycemia may cause abnormalities in intrinsic BM-MSC which might lose sufficient therapeutic effects in diabetic patients. We demonstrated the functional abnormalities in BM-MSC derived from both type 1 and type 2 diabetes models in vitro, which resulted in loss of therapeutic effects in vivo in diabetic nephropathy (DN). Then, we developed a novel method to improve abnormalities in BM-MSC using human umbilical cord extracts, namely Wharton's jelly extract supernatant (WJs). WJs is a cocktail of growth factors, extracellular matrixes and exosomes, which ameliorates proliferative capacity, motility, mitochondrial degeneration, endoplasmic reticular functions and exosome secretions in both type 1 and type 2 diabetes derived BM-MSC (DM-MSC). Exosomes contained in WJs were a key factor for this activation, which exerted similar effects to complete WJs. DM-MSC activated by WJs ameliorated renal injury in both type 1 and type 2 DN. In this study, we developed a novel activating method using WJs to significantly increase the therapeutic effect of BM-MSC, which may allow effective autologous cell transplantation. PMID- 28814815 TI - Spondyloarthropathies: Ruminococcus on the horizon in arthritic disease. PMID- 28814816 TI - Osteoarthritis: Chondroitin sulfate - CONCEPT clear, uncertainties unchanged. PMID- 28814817 TI - Conjugated polymers mediate effective activation of the Mammalian Ion Channel Transient Receptor Potential Vanilloid 1. AB - Selective and rapid regulation of ionic channels is pivotal to the understanding of physiological processes and has a crucial impact in developing novel therapeutic strategies. Transient Receptor Potential (TRP) channels are emerging as essential cellular switches that allow animals to respond to their environment. In particular, the Vanilloid Receptor 1 (TRPV1), besides being involved in the body temperature regulation and in the response to pain, has important roles in several neuronal functions, as cytoskeleton dynamics, injured neurons regeneration, synaptic plasticity. Currently available tools to modulate TRPV1 activity suffer from limited spatial selectivity, do not allow for temporally precise control, and are usually not reversible, thus limiting their application potential. The use of optical excitation would allow for overcoming all these limitations. Here, we propose a novel strategy, based on the use of light-sensitive, conjugated polymers. We demonstrate that illumination of a polymer thin film leads to reliable, robust and temporally precise control of TRPV1 channels. Interestingly, the activation of the channel is due to the combination of two different, locally confined effects, namely the release of thermal energy from the polymer surface and the variation of the local ionic concentration at the cell/polymer interface, both mediated by the polymer photoexcitation. PMID- 28814818 TI - Multigenerational effects of copper nanomaterials (CuONMs) are different of those of CuCl2: exposure in the soil invertebrate Enchytraeus crypticus. AB - Nanomaterials (NMs) are recommended to be tested in longer term exposures. Multigenerational (MG) studies are scarce and particularly important because effects can be transferred to the next generation. The current risk assessment framework does not include MG effects and this is a caveat for persistent materials. Here, the effects of copper NMs (CuONMs) and copper salt (CuCl2) were assessed in a MG exposure (4 generations in spiked soil + 2 generations in clean soil, F1 to F7 generations in total), with the standard soil model Enchytraeus crypticus, using relevant reproduction test effect concentrations (EC10, EC50), monitoring survival and reproduction. This represented ca. 1 year continuous exposure tests. MG effects varied with effect concentration and test materials: CuONMs caused increased toxicity for EC10 exposed organisms (EC50 did not change), and transfer to clean media reset effects, whereas CuCl2 reduced toxicity for EC10 and EC50, but the transfer to clean media "revived" the initial effects, i.e. close to EC50 levels in F7. Clearly CuONMs and CuCl2 cause different mechanisms of toxicity or response in the long term, not predictable based on short term or one generation studies. The present contributes for the improvement of risk assessment, adding important information for the long term exposure and effects. PMID- 28814819 TI - Marinocyanins, cytotoxic bromo-phenazinone meroterpenoids from a marine bacterium from the streptomycete clade MAR4. AB - Six cytotoxic and antimicrobial metabolites of a new bromo-phenazinone class, the marinocyanins A-F (1-6), were isolated together with the known bacterial metabolites 2-bromo-1-hydroxyphenazine (7), lavanducyanin (8, WS-9659A) and its chlorinated analog WS-9659B (9). These metabolites were purified by bioassay guided fractionation of the extracts of our MAR4 marine actinomycete strains CNS 284 and CNY-960. The structures of the new compounds were determined by detailed spectroscopic methods and marinocyanin A (1) was confirmed by crystallographic methods. The marinocyanins represent the first bromo-phenazinones with an N isoprenoid substituent in the skeleton. Marinocyanins A-F show strong to weak cytotoxicity against HCT-116 human colon carcinoma and possess modest antimicrobial activities against Staphylococcus aureus and amphotericin-resistant Candida albicans. PMID- 28814820 TI - Flavonoid content and antioxidant activity of vegetables from Indonesia. AB - Extracts from 11 vegetables of Indonesian origin were screened for flavonoid content, total phenolics, and antioxidant activity. The flavonols myricetin, quercetin, and kaempferol and flavones luteolin and apigenin were quantified by HPLC. Flavonoid content in mg/100 g fresh weight (fw) was apparently initially reported for Cosmos caudatus H.B.K. (52.19), Polyscias pinnata (52.19), Pluchea indica Less. (6.39), Nothopanax scutellarius (Burm.f.) Merr (5.43), Talinum triangulare (Jacq.) Willd. (3.93), Pilea melastomoides (Poir.) Bl. (2.27), and Etlingera elatior (Jack) R.M.Sm (1.18). The flavonoid content of the vegetables studied were mainly quercetin and kaempferol and ranged from 0.3 to 143 mg/100 g fw, with the highest level found in Sauropus androgynus (L) Merr. C. caudatus H.B.K. had the greatest total phenols among the vegetables analysed, with 1.52 mg GAE/100 g fw. P. indica Less. and C. caudatus H.B.K. had the highest antioxidant activity as measured by ferric cyanide reducing power, DPPH (2,2-diphenyl-1 picrylhydrazyl) and ABTS (2,2'-azino-bis-(3-ethylbenzthiazoline-6-sulphonic acid) scavenging, and inhibition of linoleic acid oxidation. Therefore, S. androgynus (L) Merr, C. caudatus H.B.K., and P. pinnata were identified as potentially rich sources of dietary flavonoids and antioxidants. PMID- 28814821 TI - The influence of roasting, pasteurisation, and storage on the polyphenol content and antioxidant capacity of California almond skins. AB - Polyphenols and antioxidant activity of skins from California almonds subjected to roasting, pasteurisation, and storage were determined by LC-MS quantification, total phenols (TP), and ferric reducing antioxidant power (FRAP). Pasteurisation did not significantly change TP, FRAP, or flavonoids and phenolic acids (FP). Roasted almonds had 26% less TP and 34% less FRAP than raw, but equivalent FP (n = 12). Storing almonds at 4 and 23 degrees C for 15 mo resulted in gradual increases in FP, up to 177% and 200%, respectively (n = 13). At 4 degrees C and 15 mo, polyphenols increased 18-fold for p-hydroxybenzoic acid, whilst others were 45-200% higher compared to baseline values. Isorhamnetin-3-O-rutinoside accounted for 48% of the increase in FP. After 15 mo, FRAP and TP increased to 200% and 190% of initial values. Accelerated ageing of whole almonds increased FP content by 10% after 3 days, but TP and FRAP values were not significantly different from baseline to day 10. Thus, in almond skins, roasting decreases TP and FRAP but not FP, whilst storage for up to 15 mo doubles FP. PMID- 28814822 TI - High visibility in two-color above-threshold photoemission from tungsten nanotips in a coherent control scheme. AB - In this article, we present coherent control of above-threshold photoemission from a tungsten nanotip achieving nearly perfect modulation. Depending on the pulse delay between fundamental ([Formula: see text]) and second harmonic ([Formula: see text]) pulses of a femtosecond fiber laser at the nanotip, electron emission is significantly enhanced or depressed during temporal overlap. Electron emission is studied as a function of pulse delay, optical near-field intensities, DC bias field and final photoelectron energy. Under optimized conditions modulation amplitudes of the electron emission of 97.5% are achieved. Experimental observations are discussed in the framework of quantum-pathway interference supported by local density of states simulations. PMID- 28814823 TI - Relationship between the Antifungal Susceptibility Profile and the Production of Virulence-Related Hydrolytic Enzymes in Brazilian Clinical Strains of Candida glabrata. AB - Candida glabrata is a facultative intracellular opportunistic fungal pathogen in human infections. Several virulence-associated attributes are involved in its pathogenesis, host-pathogen interactions, modulation of host immune defenses, and regulation of antifungal drug resistance. This study evaluated the in vitro antifungal susceptibility profile to five antifungal agents, the production of seven hydrolytic enzymes related to virulence, and the relationship between these phenotypes in 91 clinical strains of C. glabrata. All C. glabrata strains were susceptible to flucytosine. However, some of these strains showed resistance to amphotericin B (9.9%), fluconazole (15.4%), itraconazole (5.5%), or micafungin (15.4%). Overall, C. glabrata strains were good producers of catalase, aspartic protease, esterase, phytase, and hemolysin. However, caseinase and phospholipase in vitro activities were not detected. Statistically significant correlations were identified between micafungin minimum inhibitory concentration (MIC) and esterase production, between fluconazole and micafungin MIC and hemolytic activity, and between amphotericin B MIC and phytase production. These results contribute to clarify some of the C. glabrata mechanisms of pathogenicity. Moreover, the association between some virulence attributes and the regulation of antifungal resistance encourage the development of new therapeutic strategies involving virulence mechanisms as potential targets for effective antifungal drug development for the treatment of C. glabrata infections. PMID- 28814824 TI - Cataract surgery in patients with pseudoex-foliation syndrome: current updates. AB - Pseudoexfoliation is a ubiquitous syndrome of multifactorial origin affecting elderly people by increasing the risk of cataract and secondary glaucoma development. Despite modern techniques and technologies for cataract surgery, pseudoexfoliation syndrome represents a challenge for surgeons because of the increased weakness of the zonular apparatus and limited pupil dilation. Due to the inherent difficulties during surgery, the risk of vitreous loss in these patients is several times higher than in cataract patients without pseudoexfoliation. Using currently available surgical devices (ophthalmic viscosurgical device, iris retractors and ring dilators, capsular tension ring, etc.), the risk of intraoperative complications may be much reduced, allowing the surgeon to handle difficult cases with greater confidence and safety. This review analyzes the methodologic approach to the patient with zonular laxity with the aim of providing useful advices to limit the risks of intraoperative and postoperative complications. From the preoperative planning, to the intraoperative management of the small pupil and phacodonesis, and to the postoperative correction of capsule phimosis and intraocular lens dislocation, a step approach to the surgical management of pseudoexfoliation patients is illustrated. PMID- 28814825 TI - Air-insufflated high-definition dacryoendoscopy yields significantly better image quality than conventional dacryoendoscopy. AB - PURPOSE: To facilitate the analysis of lacrimal conditions, we utilized high definition dacryoendoscopy (HDD) and undertook observations with a pressure controlled air-insufflation system. We report the safety and performance of HDD. METHODS: In this retrospective, non-randomized clinical trial, 46 patients (14 males and 32 females; age range 39-91 years; mean age +/- SD 70.3+/-12.0 years) who had lacrimal disorders were examined with HDD and conventional dacryoendoscopy (CD). The high-definition dacryoendoscope had 15,000 picture element image fibers and an advanced objective lens. Its outer diameter was 0.9 1.2 mm. Air insufflation was controlled at 0-20 kPa with a digital manometer based pressure-controlled air-insufflation system to evaluate the quality of the image. The HDD had an air/saline irrigation channel between the outer sheath (outer diameter =1.2 mm) and the metal inner sheath of the endoscope. We used it and the CD in air, saline, and diluted milk saline with and without manual irrigation to quantitatively evaluate the effect of air pressure and saline irrigation on image quality. RESULTS: In vivo, the most significant improvement in image quality was demonstrated with air-insufflated (5-15 kPa) HDD, as compared with saline-irrigated HDD and saline-irrigated CD. No emphysema or damage was noted under observation with HDD. In vitro, no significant difference was demonstrated between air-insufflated HDD and saline-irrigated HDD. In vitro, the image quality of air-insufflated HDD was significantly improved as compared with that of saline-irrigated CD. CONCLUSION: Pressure-controlled (5-15 kPa) air insufflated HDD is safe, and yields significantly better image quality than CD and saline-irrigated HDD. PMID- 28814826 TI - Comparison between bilateral implantation of a trifocal intraocular lens and blended implantation of two bifocal intraocular lenses. AB - PURPOSE: To compare visual outcomes and performance between bilateral implantation of a diffractive trifocal intraocular lens (IOL) Acrysof(r)PanOptix(r) TFNT00 and blended implantation of two different near add power bifocal IOLs: Acrysof(r) Restor(r) SV25T0 in dominant eye and Acrysof(r) Restor(r) SN6AD1 in the nondominant eye. METHODS: This prospective, nonrandomized, consecutive and comparative study assessed 20 patients (40 eyes) who had bilateral cataract surgery performed using the IOLs described. Patients were divided into groups, bilateral trifocal implant and blended implant. Evaluation included measurement of binocular uncorrected and corrected distance visual acuity at 4 m (UDVA, CDVA) and uncorrected intermediate (60 cm) and near (at 40 cm) visual acuity; contrast sensitivity (CS) and visual defocus curve. RESULTS: Postoperative CDVA comparison showed no statistical significance between groups. UDVA was significantly better in the trifocal groups. Under photopic conditions, the trifocal group had better CS in higher frequencies with and without glare. The binocular defocus curve demonstrated a trifocal behavior in both groups, with the bilateral trifocal group exhibiting better performance for intermediate vision. CONCLUSION: Both lens combinations were able to provide good near, intermediate and distance vision, with the trifocal group showing significantly better performance at intermediate distances and better CS under photopic conditions. PMID- 28814827 TI - Anticholinesterase constituents from the leaves of Spondias mombin L. (Anacardiaceae). AB - Spondias mombin has been used in traditional medicine for the management of several diseases, including memory loss. This study aimed to evaluate the cholinesterase inhibitory activity of the methanol extract of the leaves and its derived fractions, as well as carry out detailed phytochemical investigations leading to the isolation and characterization of bioactive compounds from the plant. The acetyl cholinesterase (AChE) and butyryl cholinesterase (BUChE) inhibitory activities were evaluated by colorimetric and thin-layer chromatography bioautographic assay techniques. The ethyl acetate fraction was most active against both enzymes, with percentage inhibition of 58.10 +/- 1.08% and 52.66 +/- 1.34% against AChE and BUChE, respectively. Three compounds, namely, botulin, campesterol and phytol, with IC50 of 0.88 MUg/mL (AChE), 4.67 MUg/mL (BuChE); 1.89 MUg/mL (AChE), 4.08 MUg/mL (BuChE) and 12.51 MUg/mL (AChE), 23.89 MUg/mL (BuChE), respectively, were isolated from the supernatant of the ethyl acetate fraction. The isolated cholinesterase inhibitory compounds correlate with the known memory-enhancing property of the plant and thus support one of its uses in ethnomedicine. PMID- 28814828 TI - Comparison of efficacy and safety of oral agents for the treatment of relapsing remitting multiple sclerosis. AB - In the therapeutic scenario of disease-modifying therapies for relapsing remitting multiple sclerosis, the introduction of oral agents, starting in 2010 with fingolimod, has been a huge step forward in therapeutic options due to the easier administration route. Three oral drugs fingolimod, teriflunomide, and dimethyl fumarate, which are clinically approved for the treatment of relapsing remitting multiple sclerosis, are reviewed in this work. Results of Phase III clinical trials and their extension studies showed that the three oral agents significantly reduced the annualized relapse rate - a superior efficacy compared to placebo. Fingolimod 0.5 mg consistently reduced clinical relapses and brain volume loss. In all Phase III studies, teriflunomide 14 mg dose showed a reduction in the risk of disability accumulation. Regarding safety profile, fingolimod had more safety issues than the other two agents. For this reason, it should be strictly monitored for risks of infections, cancers, and certain transitory effects such as irregular cardiac function, decreased lymphocyte count, and a higher level of liver enzymes. Adverse effects of teriflunomide are well characterized and can be considered manageable. The main risks marked with dimethyl fumarate were flushing and gastrointestinal events. PMID- 28814830 TI - Comparative analysis of essential oil composition of Iranian and Indian Nigella sativa L. extracted using supercritical fluid extraction and solvent extraction. AB - The objective of this study was to compare the oil extraction yield and essential oil composition of Indian and Iranian Nigella sativa L. extracted by using Supercritical Fluid Extraction (SFE) and solvent extraction methods. In this study, a gas chromatography equipped with a mass spectrophotometer detector was employed for qualitative analysis of the essential oil composition of Indian and Iranian N. sativa L. The results indicated that the main fatty acid composition identified in the essential oils extracted by using SFE and solvent extraction were linoleic acid (22.4%-61.85%) and oleic acid (1.64%-18.97%). Thymoquinone (0.72%-21.03%) was found to be the major volatile compound in the extracted N. sativa oil. It was observed that the oil extraction efficiency obtained from SFE was significantly (P<0.05) higher than that achieved by the solvent extraction technique. The present study showed that SFE can be used as a more efficient technique for extraction of N. Sativa L. essential oil, which is composed of higher linoleic acid and thymoquinone contents compared to the essential oil obtained by the solvent extraction technique. PMID- 28814829 TI - Antibiotic susceptibility, heteroresistance, and updated treatment strategies in Helicobacter pylori infection. AB - In this review, we discuss the problem of antibiotic resistance, heteroresistance, the utility of cultures and antibiotic susceptibility tests in Helicobacter pylori (Hp) eradication, as well as the updated treatment strategies for this infection. The prevalence of antibiotic resistance is increasing all over the world, especially for metronidazole and clarithromycin, because of their heavy use in some geographical areas. Heteroresistance (simultaneous presence of both susceptible and resistant strains in different sites of a single stomach) is another important issue, as an isolate could be mistakenly considered susceptible if a single biopsy is used for antimicrobial tests. We also examined literature data regarding eradication success rates of culture-guided and empiric therapies. The empiric therapy and the one based on susceptibility testing, in Hp eradication, may depend on several factors such as concomitant diseases, the number of previous antibiotic treatments, differences in bacterial virulence in individuals with positive or negative cultures, together with local antibiotic resistance patterns in real-world settings. Updated treatment strategies in Hp infection presented in the guidelines of the Toronto Consensus Group (2016) are reported. These suggest to prolong eradication therapy up to 14 days, replacing the old triple therapy with a quadruple therapy based on proton pump inhibitor (PPI), bismuth, metronidazole, and tetracycline for most of the patients, or as an alternative quadruple therapy without bismuth, based on the use of PPI, amoxicillin, metronidazole, and clarithromycin. The new drug vonoprazan, a first in-class potassium-competitive acid blocker recently approved in Japan, is also considered to be a promising solution for Hp eradication, even for clarithromycin resistant strains. Furthermore, there is growing interest in finding new therapeutic strategies, such as the development of vaccines or the use of natural resources, including probiotics, plants, or nutraceuticals. PMID- 28814831 TI - Schiff base derived from thiosemicarbazone and anthracene showed high potential in overcoming multidrug resistance in vitro with low drug resistance index. AB - Multidrug resistance (MDR) is a huge obstacle in cancer chemotherapeutics. Overcoming MDR is a great challenge for anticancer drug discovery. Here, DNA binding and cytotoxicity of Schiff base L1 and L2 were explored to assess their efficiency in fighting cancer and overcoming the MDR. L1 and L2 could treat extremely chemoresistant MCF-7/ADR cell as drug-sensitive cell, with drug resistance index (DRI) <2.13, showing high potential in overcoming the MDR. The apoptotic ratio induced by L1 and L2 was low for both MCF-7 and MCF-7/ADR cells. L1 and L2 induced an impairment of cell cycle progression of MCF-7 and MCF-7/ADR cell lines and suppressed cell growth by perturbing progress through the G0/G1 phase, with L2 causing more profound effect, which might account for lower drug resistance after L2 treatment. The molecular docking revealed weak interaction between L1/L2 and P-glycoprotein (P-gp), the most important drug efflux pump and intracellular Rhodamine 123 accumulation indicated that the activity of P-gp was not inhibited by L1 and L2. Combined with the cellular uptake results, it implied that L1 and L2 could bypass P-gp efflux to exert anticancer activity. PMID- 28814832 TI - Combinatorial and sequential delivery of gemcitabine and oseltamivir phosphate from implantable poly(d,l-lactic-co-glycolic acid) cylinders disables human pancreatic cancer cell survival. AB - Combination therapies against multiple targets are currently being developed to prevent resistance to a single chemotherapeutic agent and to extirpate pre existing resistance in heterogeneous cancer cells in tumors due to selective pressure from the single agent. Gemcitabine (GEM), a chemotherapeutic agent, is the current standard of care for patients with pancreatic cancer. Patients with pancreatic cancer receiving GEM have a low progression-free survival. Given the poor response rate to GEM, cancer cells are known to develop rapid resistance to this drug. Metronomic chemotherapy using combinatorial and sequential delivery systems are novel developmental approaches to disrupt tumor neovascularization, reduce systemic drug toxicity, and increase the sensitivity of chemotherapeutics in cancer. Here, implantable double-layered poly(d,l-lactic-co-glycolic acid) (PLGA) cylinders were engineered to sequentially release GEM in combination with oseltamivir phosphate (OP) over an extended time. Double-layered PLGA cylindrical implants loaded with these active hydrophilic drugs were fabricated with minimal loss of drugs during the formulation, enabling extensive control of drug loading and establishing uniform drug distribution throughout the polymer matrix. OP is used in the formulation because of its anticancer drug properties targeting mammalian neuraminidase 1 (Neu1) involved in multistage tumorigenesis. OP and GEM encapsulated in inner/outer GEMin/OPout or OPin/GEMout implantable double-layered PLGA cylinders displayed sustained near linear release over 30 days. OP and GEM released from the double-layered PLGA cylinders effectively reduced cell viability in pancreatic cancer cell line PANC1 and its GEM-resistant variant for up to 15 days. PMID- 28814833 TI - Markers of oxidative/nitrosative stress and inflammation in lung tissue of rats exposed to different intravenous iron compounds. AB - Iron deficiency anemia is a frequent complication in clinical conditions such as chronic kidney disease, chronic heart failure, inflammatory bowel disease, cancer, and excessive blood loss. Given the ability of iron to catalyze redox reactions, iron therapy can be associated with oxidative stress. The lung is uniquely susceptible to oxidative stress, and little is known about the effects of intravenous iron treatment in this organ. This study characterized changes in markers of oxidative/nitrosative stress and inflammation in the lung of non-iron deficient, non-anemic rats treated with five weekly doses (40 mg iron per kg body weight) of low molecular weight iron dextran (LMWID), iron sucrose (IS), ferric carboxymaltose (FCM), ferumoxytol (FMX), iron isomaltoside 1000 (IIM), or saline (control). Rats treated with LMWID, FMX, or IIM showed significant changes in most measures of oxidative/nitrosative stress, inflammation, and iron deposition compared to the saline-treated controls, with greatest changes in the LMWID treatment group. Increases in products of lipid peroxidation (thiobarbituric acid reactive substances) and protein nitrosation (nitrotyrosine) were consistent with increases in the activity of antioxidant enzymes (catalase, Cu,Zn-SOD, GPx), decreases in antioxidative capacity (reduced:oxidized GSH ratio), increased levels of transcription factors involved in the inflammatory pathway (NF-kappaB, HIF-1alpha), inflammatory cytokines (TNF-alpha, IL-6), adhesion molecules (VCAM 1), markers of macrophage infiltration (ED-1), and iron deposition (Prussian blue, ferritin). Since changes in measured parameters in FCM- or IS-treated rats were generally modest, the results suggest that FCM and IS have a low propensity to induce lung inflammation. The relevance of these findings to clinical safety profiles of the tested intravenous iron products requires further investigation. PMID- 28814834 TI - Intracellular trafficking of new anticancer therapeutics: antibody-drug conjugates. AB - Antibody-drug conjugate (ADC) is a milestone in targeted cancer therapy that comprises of monoclonal antibodies chemically linked to cytotoxic drugs. Internalization of ADC takes place via clathrin-mediated endocytosis, caveolae mediated endocytosis, and pinocytosis. Conjugation strategies, endocytosis and intracellular trafficking optimization, linkers, and drugs chemistry present a great challenge for researchers to eradicate tumor cells successfully. This inventiveness of endocytosis and intracellular trafficking has given considerable momentum recently to develop specific antibodies and ADCs to treat cancer cells. It is significantly advantageous to emphasize the endocytosis and intracellular trafficking pathways efficiently and to design potent engineered conjugates and biological entities to boost efficient therapies enormously for cancer treatment. Current studies illustrate endocytosis and intracellular trafficking of ADC, protein, and linker strategies in unloading and also concisely evaluate practically applicable ADCs. PMID- 28814836 TI - Safety of switching from brand-name to generic levetiracetam in patients with epilepsy. AB - PURPOSE: The approach to the use of generic antiepileptic drugs has recently evolved from major concern to general acceptance, but the evidence related specifically to the safety of switching from brand-name to generic levetiracetam (LEV) is scarce. The aim of the study was to assess the risk of increased frequency of seizures or other adverse events after replacement of a brand-name LEV with a generic one. PATIENTS AND METHODS: This retrospective analysis included 159 patients treated with LEV in a tertiary outpatient epilepsy clinic. We included all patients diagnosed with epilepsy who were treated with LEV as at March 1, 2013. Most patients were forced to switch to the generic LEV because of the sudden rise in cost of the branded LEV. We recorded data on age, sex, age at onset of epilepsy, type of epilepsy, and its treatment. We analyzed data from one visit before potential switching and from two visits after the potential switching. The interval between visits was typically 3 months. We registered an increase in the frequency of seizures and in the occurrence of adverse events. RESULTS: Among 151 subjects who switched to generic LEV after March 1, 2013, increased frequency of seizures was noted in 9 patients (6%) during the first follow-up visit. Patients with increased frequency of seizures did not differ from other patients regarding sex, age, age at the onset of epilepsy, and the median dose of LEV before switching or the median duration of treatment with LEV before switching. Two patients returned to brand-name LEV. Adverse events were noted in six other patients (4%) and included somnolence, irritability, or dizziness. CONCLUSION: Switching from brand-name to generic LEV is generally safe. PMID- 28814835 TI - Efficacy and tolerability of two different formulations of atorvastatin in Korean patients with hypercholesterolemia: a multicenter, prospective, randomized clinical trial. AB - PURPOSE: This study was designed to compare the efficacy and tolerability of the generic formulation (Atorva(r)) and the reference formulation (Lipitor(r)) of atorvastatin, both at a dosage of 20 mg once daily. METHODS: This study was a prospective open-label, randomized controlled study. Hypercholesterolemic patients who had not achieved low-density lipoprotein (LDL) cholesterol goals according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) guideline were randomized to generic formulation or reference formulation of atorvastatin. The primary end point was the percent change of blood LDL cholesterol at 8 weeks from the baseline. The secondary end points included the percent changes of total cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride (TG), apolipoprotein B (ApoB), and apolipoprotein A1 (ApoA1) levels, the percent changes of ApoB/ApoA1 and total cholesterol/HDL cholesterol ratios, and the change in high-sensitivity C-reactive protein (hsCRP) levels. The LDL cholesterol goal achievement rate according to the NCEP-ATP III guideline was also evaluated. RESULTS: Three hundred and seventy-six patients were randomized, and 346 patients (176 in the generic group and 170 in the reference group) completed the study. After the 8 weeks of treatment, LDL cholesterol level was significantly decreased in both the groups, and the decrement was comparable between the two groups (-43.9%+/-15.3% in the generic group, -43.3%+/-17.0% in the reference group, P=0.705). The percent changes of total cholesterol, HDL cholesterol, TG, ApoB, ApoA1, ApoB/ApoA1 ratio, total cholesterol/HDL cholesterol ratio, and hsCRP showed insignificant difference between the two groups. However, LDL cholesterol goal achievement rate was significantly higher in the generic group compared to the reference group (90.6% vs 83.0%, P=0.039) in per-protocol analysis. Adverse event rate was comparable between the two groups (12.0% vs 13.7%, P=0.804). CONCLUSION: The generic formulation of atorvastatin 20 mg was not inferior to the reference formulation of atorvastatin 20 mg in the management of hypercholesterolemia. PMID- 28814837 TI - Simulating clinical trial visits yields patient insights into study design and recruitment. AB - PURPOSE: We elicited patient experiences from clinical trial simulations to aid in future trial development and to improve patient recruitment and retention. PATIENTS AND METHODS: Two simulations of draft Phase II and Phase III anifrolumab studies for systemic lupus erythematosus (SLE)/lupus nephritis (LN) were performed involving African-American patients from Grady Hospital, an indigent care hospital in Atlanta, GA, USA, and white patients from Altoona Arthritis and Osteoporosis Center in Altoona, PA, USA. The clinical trial simulation included an informed consent procedure, a mock screening visit, a mock dosing visit, and a debriefing period for patients and staff. Patients and staff were interviewed to obtain sentiments and perceptions related to the simulated visits. RESULTS: The Atlanta study involved 6 African-American patients (5 female) aged 27-60 years with moderate to severe SLE/LN. The Altoona study involved 12 white females aged 32-75 years with mild to moderate SLE/LN. Patient experiences had an impact on four patient-centric care domains: 1) information, communication, and education; 2) responsiveness to needs; 3) access to care; and 4) coordination of care; and continuity and transition. Patients in both studies desired background material, knowledgeable staff, family and friend support, personal results, comfortable settings, shorter wait times, and greater scheduling flexibility. Compared with the Altoona study patients, Atlanta study patients reported greater preferences for information from the Internet, need for strong community and online support, difficulties in discussing SLE, emphasis on transportation and child care help during the visits, and concerns related to financial matters; and they placed greater importance on time commitment, understanding of potential personal benefit, trust, and confidentiality of patient data as factors for participation. Using these results, we present recommendations to improve study procedures to increase retention, recruitment, and compliance for clinical trials. CONCLUSION: Insights from these two studies can be applied to the development and implementation of future clinical trials to improve patient recruitment, retention, compliance, and advocacy. PMID- 28814839 TI - Acceptance and usability of a home-based monitoring tool of health indicators in children of people with dementia: a Proof of Principle (POP) study. AB - BACKGROUND: Large-scale cohort studies are needed to confirm the relation between dementia and its possible risk factors. The inclusion of people with dementia in research is a challenge, however, children of people with dementia are at risk and are highly motivated to participate in dementia research. For technologies to support home-based data collection during large-scale studies, participants should be able and willing to use technology for a longer period of time. OBJECTIVE: This study investigated acceptance and usability of iVitality, a research platform for home-based monitoring of dementia health indicators, in 151 children of people with dementia and investigated which frequency of measurements is acceptable for them. METHODS: Participants were randomized to fortnightly or monthly measurements. At baseline and after 3 months, participants completed an online questionnaire regarding the acceptance (Technology Acceptance Model; 38 items) and usability (Post-Study System Usability Questionnaire; 24 items) of iVitality. Items were rated from 1 (I totally disagree) to 7 (I totally agree). Participants were also invited to take part in an online focus group (OFG) after 3 months of follow-up. Descriptive statistics and both two-sample/independent and paired t-tests were used to analyze the online questionnaires and a directed content analysis was used to analyze the OFGs. RESULTS: Children of people with dementia accept iVitality after long-term use and evaluate iVitality as a user friendly, useful, and trusted technology, despite some suggestions for improvement. Overall, mean scores on acceptance and usability were higher than 5 (I somewhat agree), although the acceptance subscales "social influence" and "time" were rated somewhat lower. No significant differences in acceptance and usability were found between both protocol groups. Over time, "affect" significantly increased among participants measuring blood pressure fortnightly. CONCLUSION: iVitality has the potential to be used in large-scale studies for home-based monitoring of health indicators related to the development of dementia. PMID- 28814838 TI - Post-acute care for stroke - a retrospective cohort study in Taiwan. AB - BACKGROUND: Stroke often causes functional decline in patients. Therefore, after the acute phase, many patients require post-acute care (PAC) to maximize their functional progress, reduce disability, and make it possible for them to return to their home and community. PAC can be provided in different settings. Taiwan's National Health Insurance (NHI) proposed a PAC pilot program, effective since 2014, for stroke patients that allowed patients with the potential for functional improvement to receive PAC rehabilitation in regional or community hospitals. The purpose of this study was to explore the initial achievements and clinical impact of this program in Taiwan. METHODS: This was a retrospective cohort study that mainly analyzed basic hospitalization data and scores for function and quality of life, as recorded immediately after admission and before discharge, for stroke patients in the PAC program in a hospital in Taiwan. RESULTS: This study collected complete data from a total of 168 patients. After an average of 43.57 days in the program, patients showed significant improvement in the Modified Rankin Scale (MRS), the Barthel Activity Daily Living Index (B-ADL), the Lawton Brody Instrumental Activity Daily Living Scale (LB-IADL), the Functional Oral Intake Scale (FOIS), and the Mini Nutrition Assessment (MNA), in mobility, self care, and usual activity, as well as on anxiety/depression in the EuroQol Five Dimensions Questionnaire (EQ-5D) and in the Mini Mental State Examination (MMSE). After discharge, 76.8% of the patients could return to their home and community. CONCLUSION: This study showed that the pilot PAC program significantly promoted recovery of function in stroke patients and helped them to return to their home and community. Patients with the potential for functional recovery should consider receiving PAC service in a hospital after discharge from acute stroke care. PMID- 28814840 TI - Epidemiology and Synergistic Hepatopathology of Malaria and Hepatitis C Virus Coinfection. AB - Malaria and hepatitis C virus (HCV) infections are very common causes of human suffering with overlapping global geographic distributions. With the growing incidence of HCV infections in malaria-endemic zones and malaria in areas with exceptionally high HCV prevalence, coinfections and syndemism of both pathogens are likely to occur. However, studies of malaria and HCV coinfections are very rare despite the fact that liver-stage plasmodiasis and hepatitis C develop in hepatocytes which may synergistically interact. The fact that both pathogens share similar entry molecules or receptors in early invasive steps of hepatocytes further makes hepatopathologic investigations of coinfected hosts greatly important. This review sought to emphasize the public health significance of malaria/HCV coinfections and elucidate the mechanisms of pathogens' entrance and invasion of susceptible host to improve on existing or develop antiplasmodial drugs and hepatitis C therapeutics that can intervene at appropriate stages of pathogens' life cycles. PMID- 28814841 TI - Use of care and the oral health status of people aged 60 years and older in France: results from the National Health and Disability Survey. AB - OBJECTIVE: We aimed to analyze, from the data in a national survey, the use of oral care and the oral health status of patients living at home or in an institution. BACKGROUND: Patients aged 60 years and older have important oral health needs, but their oral management may differ according to their immediate environment. The fact of living at home or in an institution can influence the use of care and alter the patients' perception of their oral health status. METHODS: The data analyzed were taken from a survey on disability and health carried out in 2008-2009, which is representative of the population living in France. It consists of two sections, one centered on disability and health among home-dwellers and the other on patients living in an institution. In each of these two populations, we carried out descriptive analysis of three themes: use of care, forgoing of care, and oral health. RESULTS: Although visits to physicians and specialists were frequent, visits to dentists were lower in both populations. While a minority of patients forwent care, it was dental care that was mainly forgone by both home-dwellers and institutionalized patients. The cost factor remained the principal reason, but other factors such as fear or accessibility problems were cited. Use of a dental appliance was considerably more frequent among institutionalized patients than among home-dwellers, with just over half the institutionalized population wearing a dental appliance. Perceived state of oral health remained difficult to interpret. CONCLUSION: To improve access to oral care for the elderly, the patients, their entourage and health providers need increased awareness and information on the importance of good oral health. Better information must be associated with regular clinical examination. PMID- 28814842 TI - BFH-OSTM, a new predictive screening tool for identifying osteoporosis in elderly Han Chinese males. AB - PURPOSE: To develop and validate a new clinical screening tool to identify primary osteoporosis by dual-energy X-ray absorptiometry (DXA) in two elderly Han Chinese male populations. METHODS: A cross-sectional study was conducted, enrolling 1,870 community-dwelling and 574 hospital-checkup elderly Han Chinese males aged >=50 years. All subjects completed a structured questionnaire and had their bone mineral density (BMD) measured using DXA. Using logistic regression analysis in the 1,870 community-dwelling males, we assessed the ability of numerous potential clinical risk factors to identify male with osteoporosis. Multiple variable regression analysis and item reduction yielded a final tool named the Beijing Friendship Hospital Osteoporosis Self-assessment Tool for Elderly Male (BFH-OSTM). Receiver operating characteristic (ROC) curve was generated to compare the validation of the BFH-OSTM and Osteoporosis Self assessment Tool for Asians (OSTA) for identifying elderly male at increased the risk of primary osteoporosis in the 574 hospital-checkup males. RESULTS: In screening the 1,870 community-dwelling subjects with DXA, 14.2% (266/1,870) had osteoporosis, and a further 51.8% (969/1,870) had osteopenia. Of the items screened in the questionnaire, weight, height and previous history of fragility fracture were predictive of osteoporosis. A final tool (BFH-OSTM) was based on body weight and fragility fracture history only. The BFH-OSTM index (cutoff =70) had a sensitivity of 85% and specificity of 53% for identifying osteoporosis according to the WHO criteria, with an area under the ROC curve of 0.763. The predictive value of BFH-OSTM was validated in the 574 hospital-checkup population, which performed better than OSTA. CONCLUSION: The BFH-OSTM may perform well for identifying elderly male at increased risk for osteoporosis and applying it would result in more prudent use of BMD measurement by DXA, especially for Han Chinese male. PMID- 28814843 TI - Effects of hearing loss on speech recognition under distracting conditions and working memory in the elderly. AB - PURPOSE: The current study aimed to evaluate hearing-related changes in terms of speech-in-noise processing, fast-rate speech processing, and working memory; and to identify which of these three factors is significantly affected by age-related hearing loss. METHODS: One hundred subjects aged 65-84 years participated in the study. They were classified into four groups ranging from normal hearing to moderate-to-severe hearing loss. All the participants were tested for speech perception in quiet and noisy conditions and for speech perception with time alteration in quiet conditions. Forward- and backward-digit span tests were also conducted to measure the participants' working memory. RESULTS: 1) As the level of background noise increased, speech perception scores systematically decreased in all the groups. This pattern was more noticeable in the three hearing-impaired groups than in the normal hearing group. 2) As the speech rate increased faster, speech perception scores decreased. A significant interaction was found between speed of speech and hearing loss. In particular, 30% of compressed sentences revealed a clear differentiation between moderate hearing loss and moderate-to severe hearing loss. 3) Although all the groups showed a longer span on the forward-digit span test than the backward-digit span test, there was no significant difference as a function of hearing loss. CONCLUSION: The degree of hearing loss strongly affects the speech recognition of babble-masked and time compressed speech in the elderly but does not affect the working memory. We expect these results to be applied to appropriate rehabilitation strategies for hearing-impaired elderly who experience difficulty in communication. PMID- 28814844 TI - Comparison between parameters of muscle performance and inflammatory biomarkers of non-sarcopenic and sarcopenic elderly women. AB - BACKGROUND: Sarcopenia is a multifactorial geriatric syndrome with complex interrelationships. Increased plasma levels of inflammatory mediators increase the catabolic stimuli of the musculature, thereby causing a decrease in mass and muscular function. OBJECTIVE: The objective of this study was to compare the performance of the knee extensors test (by isokinetic dynamometer) and plasma levels of interleukin-6 (IL-6) and soluble receptors of tumor necrosis factor alpha (sTNFR1) between sarcopenics and non-sarcopenics community-dwelling elderly women residents of Brazil. MATERIAL AND METHODS: The diagnosis of sarcopenia included measurements of body composition (by densitometry with dual energy source of X-ray), handgrip strength (by Jamar(r) dynamometer), and the usual gait velocity according to the recommendations of the European Working Group on Sarcopenia in Older People. In both sarcopenics and non-sarcopenics elderly women, we evaluated the muscle function by knee extensors test (using an isokinetic dynamometer Byodex System 4 Pro(r)) at angular speeds of 60 degrees /s and 180 degrees /s) and also we evaluated the plasma concentrations of IL-6 and sTNFR1. Comparisons of muscle performance between groups were carried out using mixed factorial ANOVA with post hoc Bonferroni test; sTNFR1 and IL-6 variables were analyzed by applying Mann-Whitney U test. RESULTS: Statistical differences were observed between groups regarding muscle power (P=0.01), total work adjusted to body weight (P=0.01) at a rate of 180 degrees /s, and plasma levels of sTNFR1 (P=0.01). CONCLUSION: Sarcopenic elder women showed lower performance of the lower limbs, especially at a higher speed, predisposing these older women to greater vulnerability in functional activities that require agility and postural stability. Plasma levels of sTNFR1 were higher for non-sarcopenics elderlies. However, due to the observational nature of the study, it was impossible to infer causality among the variables surveyed. PMID- 28814846 TI - Erratum: Olmesartan vs ramipril in the treatment of hypertension and associated clinical conditions in the elderly: a reanalysis of two large double-blind, randomized studies at the light of the most recent blood pressure targets recommended by guidelines [Corrigendum]. AB - [This corrects the article on p. 1575 in vol. 10, PMID: 26491273.]. PMID- 28814845 TI - Texture-modified food and fluids in dementia and residential aged care facilities. AB - INTRODUCTION: Dysphagia is common in people living with dementia and associated with increased risk of aspiration pneumonia, dehydration, malnutrition, and death. Treatment options are limited and the use of texture-modified food and fluids (TMF) is a widespread clinical practice. This review aimed to evaluate the evidence for TMF in dementia. METHODS: A literature search using terms "dysphagia," "texture-modified food and fluids," "dementia," and "aged care" was performed by using three electronic databases from 1990 to March 2017. Studies were assessed for suitability, then reviewed with data extracted, and grouped by categories of outcome measures. RESULTS: A total of 3,722 publications were identified, and 22 studies met the inclusion criteria. Studies were heterogeneous in design and methodology. There were no publications examining dementia exclusively; however, many subjects with dementia were included in studies of residential aged care facilities. TMF reduced the risk of aspiration seen on videofluoroscopy but not clinical aspiration and pneumonia. TMF was associated with lower daily energy and fluid intake and variable adherence. CONCLUSION: There is a lack of evidence for people living with dementia and in residential care facilities that TMF improves clinical outcomes such as aspiration pneumonia, nutrition, hydration, morbidity, and mortality. Adverse effects including poorer energy and fluid intake were identified. PMID- 28814847 TI - Relationship between tongue strength, lip strength, and nutrition-related sarcopenia in older rehabilitation inpatients: a cross-sectional study. AB - OBJECTIVE: The objective of this study was to clarify the relationship between tongue strength, lip strength, and nutrition-related sarcopenia (NRS). PATIENTS AND METHODS: A total of 201 older inpatients aged >=65 years (70 men, median age: 84 years, interquartile range: 79-89 years) consecutively admitted for rehabilitation were included in this cross-sectional study. The main factors evaluated were the presence of NRS diagnosed by malnutrition using the Mini Nutrition Assessment - Short Form, sarcopenia based on the criteria of the Asian Working Group for Sarcopenia, tongue strength, and lip strength. Other factors such as age, sex, comorbidity, physical function, cognitive function, and oral intake level were also assessed. RESULTS: In all, 78 (38.8%) patients were allocated to the NRS group, and 123 (61.2%) patients were allocated to the non NRS group. The median tongue strength and lip strength (interquartile range) were significantly lower in the NRS group (tongue: 22.9 kPa [17.7-27.7 kPa] and lip: 7.2 N [5.6-9.8 N]) compared with the non-NRS group (tongue: 29.7 kPa [24.8-35.1 kPa] and lip: 9.9 N [8.4-12.3 N], P<0.001 for both). Multivariable logistic regression analysis showed that NRS was independently associated with tongue strength (odds ratio [OR] =0.93, 95% confidence interval [CI] 0.87-0.98, P=0.012) and lip strength (OR =0.76, 95% CI 0.66-0.88, P<0.001), even after adjusting for age, sex, comorbidity, physical function, cognitive function, and oral intake level. CONCLUSION: The likelihood of occurrence of NRS decreased when tongue strength or lip strength increased. Tongue strength and lip strength may be important factors for preventing and improving NRS, regardless of the presence of low oral intake level in older rehabilitation inpatients. PMID- 28814848 TI - Pathophysiological mechanism of long-term noninvasive ventilation in stable hypercapnic patients with COPD using functional respiratory imaging. AB - INTRODUCTION: Patients with severe COPD often develop chronic hypercapnic respiratory failure. Their prognosis worsens and they are more likely to develop exacerbations. This has major influence on the health-related quality of life. Currently, there is no information about the success of long-term noninvasive ventilation (NIV) among patients who receive NIV in acute settings. Also, little is known about the pathophysiological mechanism of NIV. METHODS: Ten Global Initiative for Obstructive Lung Disease stage III and IV COPD patients with respiratory failure who were hospitalized following acute exacerbation were treated with NIV using a Synchrony BiPAP device for 6 months. Arterial blood gases and lung function parameters were measured. Low-dose computed tomography of the thorax was performed and used for segmentation. Further analyses provided lobe volume, airway volume, and airway resistance, giving an overall functional description of the separate airways and lobes. Ventilation perfusion (VQ) was calculated. Patient-reported outcomes were evaluated. RESULTS: PaCO2 significantly improved from 50.03 mmHg at baseline to 44.75 mmHg after 1 month and 43.37 mmHg after 6 months (P=0.006). Subjects showed improvement in the 6 minute walk tests (6MWTs) by an average of 51 m (from 332 m at baseline to 359 m at 1 month and 383 m at 6 months). Patients demonstrated improvement in self reported anxiety (P=0.018). The improvement in image-based VQ was positively associated with the 6MWT and the anxiety domain of the Severe Respiratory Insufficiency Questionnaire. CONCLUSION: Though previous studies of long-term NIV have shown conflicting results, this study demonstrates that patients can benefit from long-term NIV treatment, resulting in improved VQ, gas exchange, and exercise tolerance. PMID- 28814849 TI - Tiotropium bromide exerts anti-inflammatory effects during resistive breathing, an experimental model of severe airway obstruction. AB - INTRODUCTION: Resistive breathing (RB), a hallmark of obstructive airway diseases, is characterized by strenuous contractions of the inspiratory muscles that impose increased mechanical stress on the lung. RB is shown to induce pulmonary inflammation in previous healthy animals. Tiotropium bromide, an anticholinergic bronchodilator, is also shown to exert anti-inflammatory effects. The effect of tiotropium on RB-induced pulmonary inflammation is unknown. METHODS: Adult rats were anesthetized, tracheostomized and breathed spontaneously through a two-way non-rebreathing valve. Resistances were connected to the inspiratory and/or expiratory port, to produce inspiratory resistive breathing (IRB) of 40% or 50% Pi/Pi,max (40% and 50% IRB), expiratory resistive breathing (ERB) of 60% Pe/Pe,max (60% ERB) or combined resistive breathing (CRB) of both 40% Pi/Pi,max and 60% Pe/Pe,max (40%/60% CRB). Tiotropium aerosol was inhaled prior to RB. After 6 h of RB, mechanical parameters of the respiratory system were measured and bronchoalveolar lavage (BAL) was performed. IL-1beta and IL-6 protein levels were measured in lung tissue. Lung injury was estimated histologically. RESULTS: In all, 40% and 50% IRB increased macrophage and neutrophil counts in BAL and raised IL-1beta and IL-6 lung levels, tissue elasticity, BAL total protein levels and lung injury score. Tiotropium attenuated BAL neutrophil number, IL-1beta, IL-6 levels and lung injury score increase at both 40% and 50% IRB. The increase in macrophage count and protein in BAL was only reversed at 40% IRB, while tissue elasticity was not affected. In all, 60% ERB raised BAL neutrophil count and total protein and reduced macrophage count. IL-1beta and IL-6 levels and lung injury score were increased. Tiotropium attenuated these alterations, except for the decrease in macrophage count and the increase in total protein level. In all, 40%/60% CRB increased macrophage and neutrophil count in BAL, IL-1beta and IL-6 levels, tissue elasticity, total protein in BAL and histological injury score. Tiotropium attenuated the aforementioned alterations. CONCLUSION: Tiotropium inhalation attenuates RB induced pulmonary inflammation. PMID- 28814850 TI - Increased parasympathetic cardiac modulation in patients with acute exacerbation of COPD: how should we interpret it? AB - BACKGROUND: Cardiac autonomic modulation (CAM) is impaired in patients with stable COPD. Exacerbation aggravates the patients' health status and functional capacity. While the clinical and functional effects of exacerbation are known, no studies investigated CAM during exacerbation and whether there is a relationship between CAM and functional capacity and dyspnea. METHODS: Thirty-two patients with moderate to severe COPD were enrolled into two groups: stable COPD (GSta, n=16) and acute exacerbation of COPD (GAE, n=16). The GAE patients were evaluated 24-48 hours after starting standard therapy for COPD exacerbation during hospitalization; the GSta patients were evaluated in an outpatient clinic and included in the study if no decompensation episodes had occurred during the previous month. The heart rate (HR) and R-wave peak detection intervals in ms (RRi) were registered using a heart rate monitor (Polar(r) system) at rest in seated position during 10 minutes. CAM was assessed by heart rate variability (HRV) linear and non-linear analysis. Functional capacity was evaluated by handgrip strength test, performed by Jamar(r) dynamometer, and dyspnea was scored using the modified scale of the Medical Research Council. RESULTS: GAE presented higher parasympathetic CAM values compared with GSta for square root of the mean squared differences of successive RRi (RMSSD; 17.8+/-5.6 ms vs 11.7+/-9.5 ms); high frequency (HF; 111.3+/-74.9 ms2 vs 45.6+/-80.7 ms2) and standard deviation measuring the dispersion of points in the plot perpendicular to the line of identity (SD1; 12.7+/-3.9 ms vs 8.3+/-6.7 ms) and higher CAM values for standard deviation of the mean of all of RRi (STD RRi; 19.3+/-6.5 ms vs 14.3+/-12.5 ms); RRi tri (5.2+/-1.7 ms vs 4.0+/-3.0 ms); triangular interpolation of NN interval histogram (TINN; 88.7+/-26.9 ms vs 70.6+/-62.2 ms); low frequency (LF; 203+/ 210.7 ms2 vs 101.8+/-169.7 ms2) and standard deviation measuring the dispersion of points along the line of identity (SD2; 30.4+/-14.8 ms vs 16.2+/-12.54 ms). Lower values were observed for the complexity indices: approximate entropy (ApEn; 0.9+/-0.07 vs 1.06+/-0.06) and sample entropy (SampEn; 1.4+/-0.3 vs 1.7+/-0.3). Significant and moderate associations were observed between HF (nu) and handgrip strength (r=-0.58; P=0.01) and between LF (ms2) and subjective perception of dyspnea (r=-0.53; P=0.03). CONCLUSION: COPD exacerbated patients have higher parasympathetic CAM than stable patients. This should be interpreted with caution since vagal influence on the airways determines a narrowing and not a better clinical condition. Additionally, functional capacity was negatively associated with parasympathetic CAM in COPD exacerbation. PMID- 28814851 TI - Effect of allergic phenotype on treatment response to inhaled bronchodilators with or without inhaled corticosteroids in patients with COPD. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder encompassing different phenotypes with different responses to treatment. The present 1-year, two-center hospital-based study investigated whether the plasma immunoglobulin E (IgE) level and/or eosinophil cell count could be used as biomarkers to stratify patients with COPD according to predicted responses to inhaled corticosteroids (ICS)-based therapy. METHODS: A hospital-data based cohort study of COPD patients treated at two territory hospital centers was conducted for 1 year. Allergic biomarkers, including blood eosinophil counts and IgE levels, were assessed at baseline. Lung function parameters, including forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and the COPD Assessment Test (CAT), were also evaluated. The frequencies of acute exacerbation (AE) and pneumonia were also measured. Eosinophilia and a high IgE level were defined as >3% and 173 IU/mL, respectively. RESULTS: A total of 304 patients were included. Among patients with eosinophilia and high IgE levels, ICS-based therapy was associated with significant improvements in FEV1, FVC, and CAT scores, compared with bronchodilator (BD) therapy (P<=0.042). ICS-based therapy was also associated with a significantly lower incidence of AE vs BD-based therapy (11.7% vs 24.1%; P<0.008). Among patients with only eosinophilia, ICS-based therapy yielded significantly better CAT score results vs BD-based treatment (7 vs 13; P=0.032). A receiver operating characteristic curve analysis found that the combination of a high plasma IgE level and eosinophilia most sensitively and specifically identified patients who would benefit from the addition of ICS to BD therapy. CONCLUSION: Our findings support the use of blood eosinophil cell counts plus IgE levels as predictive biomarkers of the ICS response in certain patients with COPD. Both biomarkers could potentially be used to stratify COPD patients regarding ICS-based therapy. PMID- 28814852 TI - Prognostic variables and scores identifying the end of life in COPD: a systematic review. AB - INTRODUCTION: COPD is a major cause of mortality, and the unpredictable trajectory of the disease can bring challenges to end-of-life care. We aimed to investigate known prognostic variables and scores that predict prognosis in COPD in a systematic literature review, specifically including variables that contribute to risk assessment of patients for death within 12 months. METHODS: We conducted a systematic review on prognostic variables, multivariate score or models for COPD. Ovid MEDLINE, EMBASE, the Cochrane database, Cochrane CENTRAL, DARE and CINAHL were searched up to May 1, 2016. RESULTS: A total of 5,276 abstracts were screened, leading to 516 full-text reviews, and 10 met the inclusion criteria. No multivariable indices were developed with the specific aim of predicting all-cause mortality in stable COPD within 12 months. Only nine indices were identified from four studies, which had been validated for this time period. Tools developed using expert knowledge were also identified, including the Gold Standards Framework Prognostic Indicator Guidance, the RADboud Indicators of Palliative Care Needs, the Supportive and Palliative Care Indicators Tool and the Necesidades Paliativas program tool. CONCLUSION: A number of variables contributing to the prediction of all-cause mortality in COPD were identified. However, there are very few studies that are designed to assess, or report, the prediction of mortality at or less than 12 months. The quality of evidence remains low, such that no single variable or multivariable score can currently be recommended. PMID- 28814853 TI - Improving adherence to alpha-1 antitrypsin deficiency screening guidelines using the pulmonary function laboratory. PMID- 28814854 TI - Platelet distribution width as a prognostic factor in patients with COPD - pilot study. AB - BACKGROUND: Platelets may actively participate in inflammation in COPD. Platelet distribution width (PDW), a measure of platelets' volume heterogeneity, may increase in platelets' activation. We hypothesized that PDW may be a marker of hypercoagulation, which plays a significant role in conditions associated with worse survival of patients with COPD, eg, acute myocardial infarction and other forms of ischemic heart disease. METHODS: Retrospective analysis of 79 patients. Variables were compared after grouping patients according to the upper normal limit of PDW, using Welch's t-tests or Mann-Whitney U, and chi-square tests. Survival in the two groups was compared using the Kaplan-Meier method and Cox proportional hazards regression. RESULTS: Ten patients presented values of PDW above 16 fL, which was the upper limit of normality for our laboratory. Compared to patients with normal PDW, they had lower forced expiratory flow between 25% and 75% of vital capacity (FEF 25-75) - 35% of reference value vs 57% (P=0.003) and peak expiratory flow - 39% vs 54% (P<0.001). The median survival of patients with elevated PDW was 743 days compared to those with normal PDW (1,305 days) (P=0.025). The adjusted HR was 4.59 (95% CI: 1.1, 19.19; P=0.04). CONCLUSION: Our analysis indicates that elevated PDW is associated with reduced survival of patients with COPD. If our data are to be confirmed, PDW may be used as an inexpensive and repeatable prognostic tool in COPD. PMID- 28814855 TI - Effect of carbocisteine on patients with COPD: a systematic review and meta analysis. AB - BACKGROUND: COPD is the fourth leading cause of death in the world. It is a common, progressive, treatable and preventable disease. The exacerbation of COPD is associated with the peripheral muscle force, forced expiratory volume in 1 second (FEV1), the quality of life and mortality. Many studies indicated that the mucoactive medicines could reduce the exacerbations of COPD. This study summarized the efficacy of carbocisteine as a treatment for COPD. METHODS: We searched the randomized controlled trials (RCTs) following electronic bibliographic databases: MedLine, Embase, Cochrane Library and Web of Science. We additionally searched gray literature database: OpenSIGLE. We also additionally searched the clinical trial registers: ClinicalTrials.gov register and International Clinical Trials Registry Platform Search Portal. We used RCTs to assess the efficacy of the treatments. We included studies of adults (older than 18 years) with COPD. We excluded studies that were published as protocol or written in non-English language (Number 42016047078). FINDINGS: Our findings included data from four studies involving 1,357 patients. There was a decrease in the risk of the rate of total number of exacerbations with carbocisteine compared with placebo (-0.43; 95% confidence interval [CI] -0.57, -0.29, P<0.01). Carbocisteine could also improve the quality of life (-6.29; 95% CI -9.30, -3.27) and reduce the number of patients with at least one exacerbation (0.86; 95% CI 0.78, 0.95) compared with placebo. There was no significant difference in the FEV1 and adverse effects and the rate of hospitalization. INTERPRETATION: Long term use of carbocisteine (500 mg TID) may be associated with lower exacerbation rates, the smaller number of patients with at least one exacerbation and higher quality of life of patients with COPD. PMID- 28814856 TI - Prognostic role of neutrophil-lymphocyte ratio and platelet-lymphocyte ratio for hospital mortality in patients with AECOPD. AB - BACKGROUND AND OBJECTIVES: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is one of the leading causes of hospitalization and is associated with considerable mortality, for which clinicians are seeking useful and easily obtained biomarkers for prognostic evaluation. This study aimed to determine the potential role of the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) as prognostic makers for hospital mortality in patients with AECOPD. METHODS: We included 303 patients with AECOPD in this retrospective study. Clinical characteristics, NLR, PLR, and serum levels of C reactive protein (CRP) and other data were collected. Relationships between NLR/PLR and CRP were evaluated by Pearson's correlation test. Receiver operating characteristics curve and the area under the curve (AUC) were used to assess the ability of NLR and PLR to predict hospital mortality in patients with AECOPD. RESULTS: Mean levels of NLR and PLR of all patients with AECOPD were 7.92+/-8.79 and 207.21+/-148.47, respectively. NLR levels correlated with serum CRP levels (r=0.281, P<0.05). The overall hospital mortality rate was 12.21% (37/303). Levels of NLR and PLR were signifi-cantly higher among non-survivors compared to survivors of AECOPD (both P<0.05). At a cut-off value of 6.24, the sensitivity and specificity of the NLR in predicting hospital mortality were 81.08% and 69.17%, respectively, with an AUC of 0.803. At a cut-off of 182.68, the corresponding sensitivity, specificity and AUC of PLR were 64.86%, 58.27%, and 0.639. The combination of NLR, PLR, and CRP increased the prognostic sensitivity. CONCLUSION: NLR and PLR levels were increased in non-survivor patients with AECOPD, and the NLR may be simple and useful prognostic marker for hospital mortality in patients with AECOPD. More studies should be carried out to confirm our findings. PMID- 28814858 TI - Spotlight on glycopyrronium/formoterol fumarate inhalation aerosol in the management of COPD: design, development, and place in therapy. AB - Long-acting bronchodilators are the mainstay of the treatment of COPD. With the advent of several combination inhalers with long-acting antimuscarinic agents (LAMAs) and long-acting beta agonists (LABAs), the choice of therapy in the treatment of COPD has been ever expanding. With the focus of COPD management shifting from FEV1-based treatment escalation to symptoms and risk-based treatment, we are seeing a paradigm shift in COPD treatment with early introduction of LAMA-LABA combination as a single inhaler. Glycopyrronium/formoterol fumarate fixed-dose combination formulated in a familiar metered-dose inhaler format using proprietary co-suspension technology is a new option on the market. We purport to discuss the evidence behind the approval of the drug combination and its place in therapy. PMID- 28814857 TI - When is dual bronchodilation indicated in COPD? AB - Inhaled bronchodilator medications are central to the management of COPD and are frequently given on a regular basis to prevent or reduce symptoms. While short acting bronchodilators are a treatment option for people with relatively few COPD symptoms and at low risk of exacerbations, for the majority of patients with significant breathlessness at the time of diagnosis, long-acting bronchodilators may be required. Dual bronchodilation with a long-acting beta2-agonist and long acting muscarinic antagonist may be more effective treatment for some of these patients, with the aim of improving symptoms. This combination may also reduce the rate of exacerbations compared with a bronchodilator-inhaled corticosteroid combination in those with a history of exacerbations. However, there is currently a lack of guidance on clinical indicators suggesting which patients should step up from mono- to dual bronchodilation. In this article, we discuss a number of clinical indicators that could prompt a patient and physician to consider treatment escalation, while being mindful of the need to avoid unnecessary polypharmacy. These indicators include insufficient symptomatic response, a sustained increased requirement for rescue medication, suboptimal 24-hour symptom control, deteriorating symptoms, the occurrence of exacerbations, COPD-related hospitalization, and reductions in lung function. Future research is required to provide a better understanding of the optimal timing and benefits of treatment escalation and to identify the appropriate tools to inform this decision. PMID- 28814859 TI - Inhibitory effect of zirconium oxide nanoparticles on Candida albicans adhesion to repaired polymethyl methacrylate denture bases and interim removable prostheses: a new approach for denture stomatitis prevention. AB - BACKGROUND: Despite drawbacks, cold-cured acrylic resin is still the most common material used in denture repair. Zirconia nanoparticles were among the reinforcements added to increase the strength of the resin. The effect on Candida due to the addition of zirconia nanoparticles to the resin has not been investigated. PURPOSE: The aim of this study was to evaluate the effect of zirconia nanoparticles added to cold-cured acrylic resin on Candida albicans adhesion. MATERIALS AND METHODS: A total of 120 acrylic resin specimens with dimensions measuring 22*10*2.5 mm3 were prepared and divided into two equal groups. One group (repair) comprised heat-polymerized specimens that were sectioned at the center and prepared to create a 2 mm repair area that was repaired with cold-cured resin reinforced with 0% wt, 2.5% wt, 5% wt, and 7.5% wt zirconia nanoparticles. The second group contained intact cold-cured acrylic resin specimens reinforced with 0% wt, 2.5% wt, 5% wt, and 7.5% wt zirconia nanoparticles. Specimens were incubated at 37 degrees C in artificial saliva containing C. albicans, and the effect of zirconia nanoparticles on C. albicans was assessed using two methods: 1) a slide count method and 2) a direct culture test. Variations in the number of living Candida were observed in relation to the different concentrations of zirconia nanoparticles. Analysis of variance (ANOVA) and post hoc Tukey's tests were performed for data analysis. If the P-value was <=0.05, then the difference was considered as statistically significant. RESULTS: It was found that C. albicans adhesion to repaired specimens was significantly decreased by the addition of zirconia nanoparticles (P<0.00001) in comparison with the control group. Intact cold-cured groups and groups repaired with cold cured resin reinforced with 7.5% wt zirconia nanoparticles showed the lowest Candida count. Tukey's test showed a significant difference between the repaired group and the intact cold-cured group, while the later demonstrated a lower Candida count. CONCLUSION: The addition of zirconia nanoparticles to cold-cured acrylic resin is an effective method for reducing Candida adhesion to repaired polymethyl methacrylate (PMMA) denture bases and cold-cured removable prosthesis. CLINICAL SIGNIFICANCE: Based on the results of the current study, zirconia nanoparticles have an antifungal effect, which could be incorporated in the repair material for repairing denture bases and in PMMA removable prostheses as a possible approach for denture stomatitis prevention. PMID- 28814860 TI - Quantum dots in imaging, drug delivery and sensor applications. AB - Quantum dots (QDs), also known as nanoscale semiconductor crystals, are nanoparticles with unique optical and electronic properties such as bright and intensive fluorescence. Since most conventional organic label dyes do not offer the near-infrared (>650 nm) emission possibility, QDs, with their tunable optical properties, have gained a lot of interest. They possess characteristics such as good chemical and photo-stability, high quantum yield and size-tunable light emission. Different types of QDs can be excited with the same light wavelength, and their narrow emission bands can be detected simultaneously for multiple assays. There is an increasing interest in the development of nano-theranostics platforms for simultaneous sensing, imaging and therapy. QDs have great potential for such applications, with notable results already published in the fields of sensors, drug delivery and biomedical imaging. This review summarizes the latest developments available in literature regarding the use of QDs for medical applications. PMID- 28814861 TI - The influence of direct laser metal sintering implants on the early stages of osseointegration in diabetic mini-pigs. AB - BACKGROUND: High failure rates of oral implants have been reported in diabetic patients due to the disruption of osseointegration. The aim of this study was to investigate whether direct laser metal sintering (DLMS) could improve osseointegration in diabetic animal models. METHODS: Surface characterizations were carried out on two types of implants. Cell morphology and the osteogenic related gene expression of MG63 cells were observed under conditions of DLMS and microarc oxidation (MAO). A diabetes model in mini-pigs was established by intravenous injection of streptozotocin (150 mg/kg), and a total of 36 implants were inserted into the mandibular region. Micro-computed tomography (micro-CT) and histologic evaluations were performed 3 and 6 months after implantation. RESULTS: The Ra (the average of the absolute height of all points) of MAO surface was 2.3+/-0.3 um while the DLMS surface showed the Ra of 27.4+/-1.1 um. The cells on DLMS implants spread out more podia than those on MAO implants through cell morphology analysis. Osteogenic-related gene expression was also dramatically increased in the DLMS group. Obvious improvement was observed in the micro-CT and Van Gieson staining analyses of DLMS implants compared with MAO at 3 months, although this difference disappeared by 6 months. DLMS implants showed a higher bone-implant contact percentage (33.2%+/-11.2%) at 3 months compared with MAO group (18.9%+/-7.3%) while similar results were showed at 6 months between DLMS group (42.8%+/-10.1%) and MAO group (38.3%+/-10.8%). CONCLUSION: The three dimensional environment of implant surfaces with highly porous and fully interconnected channel and pore architectures can improve cell spreading and accelerate the progress of osseointegration in diabetic mini-pigs. PMID- 28814863 TI - Gentamicin coating of nanotubular anodized titanium implant reduces implant related osteomyelitis and enhances bone biocompatibility in rabbits. AB - Titanium and titanium alloy are widely used as orthopedic implants for their favorable mechanical properties and satisfactory biocompatibility. The aim of the present study was to investigate the antibacterial effect and bone cell biocompatibility of a novel implant made with nanotubular anodized titanium coated with gentamicin (NTATi-G) through in vivo study in rabbits. The animals were divided into four groups, each receiving different kinds of implants, that is, NTATi-G, titanium coated with gentamicin (Ti-G), nanotubular anodized titanium uncoated with gentamicin (NTATi) and titanium uncoated with gentamicin (Ti). The results showed that NTATi-G implant prevented implant-related osteomyelitis and enhanced bone biocompatibility in vivo. Moreover, the body temperature of rabbits in NTATi-G and Ti-G groups was lower than those in Ti groups, while the weight of rabbits in NTATi-G and Ti-G groups was heavier than those in NTATi and Ti groups, respectively. White blood cell counts in NTATi-G group were lower than NTATi and Ti groups. Features of myelitis were observed by X-ray films in the NTATi and Ti groups, but not in the NTATi-G and Ti-G groups. The radiographic scores, which assessed pathology and histopathology in bone tissues, were significantly lower in the NTATi-G and Ti-G groups than those in the NTATi and Ti groups, respectively (P<0.05). Meanwhile, explants and bone tissue culture demonstrated significantly less bacterial growth in the NTATi-G and Ti-G groups than in the NTATi and Ti groups, respectively (P<0.01). The bone volume in NTATi-G group was greater than Ti-G group, and little bone formation was seen in NTATi and Ti groups. PMID- 28814862 TI - Polyethylenimine-based micro/nanoparticles as vaccine adjuvants. AB - Vaccines have shown great success in treating and preventing tumors and infections, while adjuvants are always demanded to ensure potent immune responses. Polyethylenimine (PEI), as one of the well-studied cationic polymers, has been used as a transfection reagent for decades. However, increasing evidence has shown that PEI-based particles are also capable of acting as adjuvants. In this paper, we briefly review the physicochemical properties and the broad applications of PEI in different fields, and elaborate on the intracellular processes of PEI-based vaccines. In addition, we sum up the proof of their in vivo and clinical applications. We also highlight some mechanisms proposed for the intrinsic immunoactivation function of PEI, followed by the challenges and future perspectives of the applications of PEI in the vaccines, as well as some strategies to elicit the desirable immune responses. PMID- 28814864 TI - Controlled release of lovastatin from poly(lactic-co-glycolic acid) nanoparticles for direct pulp capping in rat teeth. AB - Statin at appropriate concentrations has been shown to induce odontoblastic differentiation, dentinogenesis, and angiogenesis. However, using a carrier to control statin release might reduce toxicity and enhance its therapeutic effects. The aim of this study was to prepare poly(d,l-lactide-co-glycolide acid) (PLGA) nanoparticles that contain lovastatin for application in direct pulp capping. The PLGA-lovastatin particle size was determined using dynamic light scattering measurements and transmission electron microscopy. In addition, the release of lovastatin was quantified using a UV-Vis spectrophotometer. The cytotoxicity and alkaline phosphatase (ALP) activity of PLGA-lovastatin nanoparticles on human dental pulp cells were investigated. Moreover, a real-time polymerase chain reaction (PCR) assay, Western blot analysis, and an enzyme-linked immunosorbent assay (ELISA) were used to examine the osteogenesis gene and protein expression of dentin sialophosphoprotein (DSPP), dentin matrix acidic phosphoprotein 1 (DMP1), and osteocalcin (OCN). Finally, PLGA-lovastatin nanoparticles and mineral trioxide aggregate (MTA) were compared as direct pulp capping materials in Wistar rat teeth. The results showed that the median diameter of PLGA-lovastatin nanoparticles was 174.8 nm and the cumulative lovastatin release was 92% at the 44th day. PLGA-lovastatin nanoparticles demonstrated considerably a lower cytotoxicity than free lovastatin at 5, 9, and 13 days of culture. For ALP activity, the ALP amount of PLGA-lovastatin (100 MUg/mL) was significantly higher than that of the other groups for 9 and 13 days of culture. The real-time PCR assay, Western blot analysis, and ELISA assay showed that PLGA-lovastatin (100 MUg/mL) induced the highest mRNA and protein expression of DSPP, DMP1, and OCN in pulp cells. Histological evaluation of the animal studies revealed that MTA was superior to the PLGA-lovastatin in stimulating the formation of tubular dentin in an observation period of 2 weeks. However, in an observation period of 4 weeks, it was evident that the PLGA-lovastatin and MTA were competitive in the formation of tubular reparative dentin and a complete dentinal bridge. PMID- 28814865 TI - In vitro and in vivo evaluation of SN-38 nanocrystals with different particle sizes. AB - 7-Ethyl-10-hydroxycamptothecin (SN-38) is a potent broad-spectrum antitumor drug derived from irinotecan hydrochloride (CPT-11). Due to its poor solubility and instability of the active lactone ring, its clinical use is significantly limited. As one of the most promising formulations for poorly water-soluble drugs, nanocrystals have attracted increasing attention. In order to solve these problems and evaluate the antitumor effect of SN-38 in vitro and in vivo, two nanocrystals with markedly different particle sizes were prepared. Dynamic light scattering and transmission electron microscopy were used to investigate the two nanocrystals. The particle sizes of SN-38 nanocrystals A (SN-38/NCs-A) and SN-38 nanocrystals B (SN-38/NCs-B) were 229.5+/-1.99 and 799.2+/-14.44 nm, respectively. X-ray powder diffraction analysis showed that the crystalline state of SN-38 did not change in the size reduction process. An accelerated dissolution velocity of SN-38 was achieved by nanocrystals, and release rate of SN-38/NCs-A was significantly faster than that of SN-38/NCs-B. Cellular uptake, cellular cytotoxicity, pharmacokinetics, animal antitumor efficacy, and tissue distribution were subsequently examined. As a result, enhanced intracellular accumulation in HT1080 cells and cytotoxicity on different tumor cells were observed for SN-38/NCs-A compared to that for SN-38/NCs-B and solution. Besides, compared to the SN-38 solution, SN-38/NCs-A had a higher bioavailability after intravenous injection; while the bioavailability of SN-38/NCs-B was even lower than that of the SN-38 solution. SN-38/NCs-A exhibited a significant inhibition of tumor growth compared to SN-38 solution and SN-38/NCs-B in vivo. The antitumor effect of SN-38/NCs-B was stronger than SN-38 solution. The tissue distribution study in tumor-bearing mice showed that nanocrystals could markedly improve the drug accumulation in tumor tissue by the enhanced permeability and retention effect compared to SN-38 solution, and the amount of SN-38 in tumors of SN-38/NCs A group was much more than that of SN-38/NCs-B group. In conclusion, nanocrystals dramatically enhanced the anticancer efficacy of SN-38 in vitro and in vivo, and the particle size had a significant influence on the dissolution behavior, pharmacokinetic properties, and tumor inhibition of nanocrystals. PMID- 28814866 TI - Graphene oxide and reduced graphene oxide induced neural pheochromocytoma-derived PC12 cell lines apoptosis and cell cycle alterations via the ERK signaling pathways. AB - Given the novel applications of graphene materials in biomedical and electronics industry, the health hazards of these particles have attracted extensive worldwide attention. Although many studies have been performed on graphene material-induced toxic effects, toxicological data for the effect of graphene materials on the nervous system are lacking. In this study, we focused on the biological effects of graphene oxide (GO) and reduced graphene oxide (rGO) materials on PC12 cells, a type of traditional neural cell line. We found that GO and rGO exerted significant toxic effects on PC12 cells in a dose- and time dependent manner. Moreover, apoptosis appeared to be a response to toxicity. A potent increase in the number of PC12 cells at G0/G1 phase after GO and rGO exposure was detected by cell cycle analysis. We found that phosphorylation levels of ERK signaling molecules, which are related to cell cycle regulation and apoptosis, were significantly altered after GO and rGO exposure. In conclusion, our results show that GO has more potent toxic effects than rGO and that apoptosis and cell cycle arrest are the main toxicity responses to GO and rGO treatments, which are likely due to ERK pathway regulation. PMID- 28814867 TI - Exploring cellular uptake of iron oxide nanoparticles associated with rhodium citrate in breast cancer cells. AB - Nanocarriers have the potential to improve the therapeutic index of currently available drugs by improving their efficacy and achieving therapeutic steady state levels over an extended period. The association of maghemite-rhodium citrate (MRC) nanoparticles (NPs) has the potential to increase specificity of the cytotoxic action. However, the interaction of these NPs with cells, their uptake mechanism, and subcellular localization need to be elucidated. This work evaluates the uptake mechanism of MRC NPs in metastatic and nonmetastatic breast cancer-cell models, comparing them to a nontumor cell line. MRC NPs uptake in breast cancer cells was more effective than in normal cells, with regard to both the amount of internalized material and the achievement of more strategic intracellular distribution. Moreover, this process occurred through a clathrin dependent endocytosis pathway with different basal expression levels of this protein in the cell lines tested. PMID- 28814869 TI - The economic burden of schizophrenia in Malaysia. AB - INTRODUCTION: Schizophrenia (SCZ) is a highly debilitating disease despite its low prevalence. The economic burden associated with SCZ is substantial and mainly attributed to productivity loss. To improve the understanding of economic burden of SCZ in the low- and middle-income country regions, we aimed to determine the economic burden of SCZ in Malaysia. METHODS: A retrospective study was conducted using a prevalence-based approach from a societal perspective in Malaysia with a 1 year period from 2013. We used micro-costing technique with bottom-up method and included direct medical cost, direct non-medical cost, and indirect cost. The main data source was medical chart review which was conducted in Hospital Kuala Lumpur (HKL). The medical charts were identified electronically by matching the unique patient's identification number registered under the National Mental Health Schizophrenia Registry and the list of patients in HKL in 2013. Other data sources were government documents, literatures, and local websites. To ensure robustness of result, probabilistic sensitivity analysis was conducted. RESULTS: The total estimated number of treated SCZ cases in Malaysia in 2015 was 15,104 with the total economic burden of USD 100 million (M) which was equivalent to 0.04% of the national gross domestic product. On average, the mean cost per patient was USD 6,594. Of the total economic burden of SCZ, 72% was attributed to indirect cost, costing at USD 72M, followed by direct medical cost (26%), costing at USD 26M, and direct non-medical cost (2%), costing at USD 1.7M. CONCLUSION: This study highlights the magnitude of economic burden of SCZ and informs the policy-makers that there is an inadequate support for SCZ patients. More resources should be allocated to improve the condition of SCZ patients and to reduce the economic burden. PMID- 28814868 TI - Nano-sized cytochrome P450 3A4 inhibitors to block hepatic metabolism of docetaxel. AB - Most drugs are metabolized by hepatic cytochrome P450 3A4 (CYP3A4), resulting in their reduced bioavailability. In this study, we present the design and evaluation of bio-compatible nanocarriers trapping a natural CYP3A4-inhibiting compound. Our aim in using nanocarriers was to target the natural CYP3A4 inhibiting agent to hepatic CYP3A4 and leave drug-metabolizing enzymes in other organs undisturbed. In the design of such nanocarriers, we took advantage of the nonspecific accumulation of small nanoparticles in the liver. Specific targeting functionalization was added to direct nanocarriers toward hepatocytes. Nanocarriers were evaluated in vitro for their CYP3A4 inhibition capacity and in vivo for their biodistribution, and finally injected 24 hours prior to the drug docetaxel, for their ability to improve the efficiency of the drug docetaxel. Nanoparticles of poly(lactic-co-glycolic) acid (PLGA) with a hydrodynamic diameter of 63 nm, functionalized with galactosamine, showed efficient in vitro CYP3A4 inhibition and the highest accumulation in hepatocytes. When compared to docetaxel alone, in nude mice bearing the human breast cancer, MDA-MB-231 model, they significantly improved the delay in tumor growth (treated group versus docetaxel alone, percent treated versus control ratio [%T/C] of 32%) and demonstrated a major improvement in overall survival (survival rate of 67% versus 0% at day 55). PMID- 28814870 TI - Abnormal intrinsic functional hubs in alcohol dependence: evidence from a voxelwise degree centrality analysis. AB - OBJECTIVE: To explore the abnormal intrinsic functional hubs in alcohol dependence using voxelwise degree centrality analysis approach, and their relationships with clinical features. MATERIALS AND METHODS: Twenty-four male alcohol dependence subjects free of medicine (mean age, 50.21+/-9.62 years) and 24 age- and education-matched male healthy controls (mean age, 50.29+/-8.92 years) were recruited. The alcohol use disorders identification test and the severity of alcohol dependence questionnaire (SADQ) were administered to assess the severity of alcohol craving. Voxelwise degree centrality approach was used to assess the abnormal intrinsic functional hubs features in alcohol dependence. Simple linear regression analysis was performed to investigate the relationships between the clinical features and abnormal intrinsic functional hubs. RESULTS: Compared with healthy controls, alcohol dependence subjects exhibited significantly different degree centrality values in widespread left lateralization brain areas, including higher degree centrality values in the left precentral gyrus (BA 6), right hippocampus (BA 35, 36), and left orbitofrontal cortex (BA 11) and lower degree centrality values in the left cerebellum posterior lobe, bilateral secondary visual network (BA 18), and left precuneus (BA 7, 19). SADQ revealed a negative linear correlation with the degree centrality value in the left precentral gyrus (R2=0.296, P=0.006). CONCLUSION: The specific abnormal intrinsic functional hubs appear to be disrupted by alcohol intoxication, which implicates at least three principal neural systems: including cerebellar, executive control, and visual cortex, which may further affect the normal motor behavior such as an explicit type of impaired driving behavior. These findings expand our understanding of the functional characteristics of alcohol dependence and may provide a new insight into the understanding of the dysfunction and pathophysiology of alcohol dependence. PMID- 28814871 TI - Exploring the long-term safety of asenapine in adults with schizophrenia in a double-blind, fixed-dose, extension study. AB - PURPOSE: The primary objective of this study was to assess long-term safety with sublingual asenapine 2.5 or 5 mg twice daily (BID) in patients with schizophrenia. PATIENTS AND METHODS: Actively treated patients on asenapine 2.5 mg BID, asenapine 5 mg BID, or olanzapine 15 mg once daily (QD) who completed a 6 week randomized, double-blind, placebo- and olanzapine-controlled study continued lead-in treatment in this 26-week, multicenter, double-blind, double-dummy, olanzapine-controlled Phase IIIB extension study; placebo patients were assigned to asenapine 2.5 mg BID treatment. Safety analyses were based on the all treated set (patients who received one or more doses of extension trial medication); change from baseline analyses used the acute study baseline. Treatment-emergent adverse events (TEAEs) and changes in laboratory parameters were monitored; weight change for asenapine versus olanzapine was the key secondary objective. Descriptive statistics were used; weight change was analyzed using a mixed-model repeated-measure approach. RESULTS: Of the 120 patients in the all-treated set, 60% completed treatment (asenapine 2.5 mg BID 66.1% overall, asenapine 5 mg BID 52.4%, olanzapine 15 mg QD 56.3%). The incidence of TEAEs was higher for placebo patients from the lead-in study who switched to asenapine 2.5 mg BID for extension treatment (71.0%) versus patients continuing asenapine 2.5 mg BID (38.7%), asenapine 5 mg BID (38.1%), or olanzapine 15 mg QD (25.0%). The most common TEAE (>=5% in every group) was worsening of schizophrenia. Least squares mean change in body weight from the acute study baseline to week 26 was +0.6 kg for overall asenapine 2.5 mg BID, +0.8 kg for asenapine 5 mg BID, and +1.2 kg for olanzapine 15 mg QD. There were no clinically relevant changes in metabolic parameters; values were generally similar across treatment groups. CONCLUSION: Asenapine 2.5 mg BID and 5 mg BID were generally well tolerated in long-term treatment. Weight gain was less for overall asenapine 2.5 mg BID and 5 mg BID than for olanzapine 15 mg QD. PMID- 28814872 TI - MicroRNA expression profiles in chronic epilepsy rats and neuroprotection from seizures by targeting miR-344a. AB - MicroRNA (miRNA) is believed to play a crucial role in the cause and treatment of epilepsy by controlling gene expression. However, it is still unclear how miRNA profiles change after multiple prolonged seizures and aggravation of brain injury in chronic epilepsy (CE). To investigate the role of miRNA in epilepsy, we utilized the CE rat models with pentylenetetrazol (PTZ) and miRNA profiles in the hippocampus. miRNA profiles were characterized using miRNA microarray analysis and were compared with the rats in the sham group, which received 0.9% physiological saline treatment at the same dose. Four up-regulated miRNAs (miR 139-3p, -770-5p, -127-5p, -331-3p) and 5 down-regulated miRNAs (miR-802-5p, -380 5p, -183-5p, -547-5p, -344a/-344a-5p) were found in the CE rats (fold change >1.5, P<0.05). Three of the dysregulated miRNAs were validated by quantitative real-time polymerase chain reaction, which revealed an outcome consistent with the initial results of the miRNA microarray analyses. Then, miR-344a agomir was intracerebroventricularly injected and followed by PTZ induction of CE models to investigate the effect of miR-344a in chronic neocortical epileptogenesis. After miRNA-344a agomir and scramble treatment, results showed a restoration of seizure behavior and a reduction in neuron damage in the cortex in miRNA-334a agomir treated rats. These data suggest that miRNA-344a might have a small modulatory effect on seizure-induced apoptosis signaling pathways in the cortex. PMID- 28814873 TI - Safety and efficacy of paliperidone palmitate 1-month formulation in Chinese patients with schizophrenia: a 25-week, open-label, multicenter, Phase IV study. AB - RATIONALE: Long-acting injectable (LAI) paliperidone palmitate 1-month formulation (PP1M) has demonstrated acceptable tolerability and favorable clinical outcomes in Western and Asian patients with schizophrenia. Hence, analysis of the outcomes of long-term PP1M treatment specifically in Chinese patients is of interest. OBJECTIVE: The aim of this study is to evaluate the long term safety and efficacy of PP1M treatment in Chinese patients with schizophrenia. METHODS: In this 25-week, open-label, Phase IV study, patients (18 65 years) diagnosed with schizophrenia and having a baseline Positive and Negative Syndrome Scale (PANSS) total score of 60-120 (inclusive) were enrolled. All patients received injections of PP1M 150 mg eq. (day 1) and 100 mg eq. (day 8), followed by a flexible once-monthly maintenance dosing (75, 100, or 150 mg eq.). RESULTS: Of the 353 patients, 234 (66.3%) completed the study treatment (mean age, 31.1 years; 52.7% men). The PANSS total score (primary end point) improved significantly over the 6-month treatment period (mean [standard deviation] change from baseline to end of treatment, -27.2 [18.30]; P<0.0001). The Clinical Global Impressions-Severity and Personal and Social Performance scores (secondary end points) also improved significantly (P<0.0001). At 6 months, PP1M had a positive impact on medication satisfaction, adherence, and increased preference for LAIs. Treatment-emergent adverse events (TEAEs) were reported by 181 (51.3%) patients (TEAEs >=5%: extrapyramidal disorder [15.3%], akathisia [10.5%], blood prolactin increase [8.8%], insomnia [5.4%]). A total of 8 deaths were reported, including 4 completed suicides. CONCLUSION: Long-term treatment with PP1M was efficacious, and no new safety concerns were identified in Chinese patients with schizophrenia. Overall, the results were comparable with observations from previous studies. PMID- 28814875 TI - Suicidal and homicidal tendencies after Lyme disease: an ignored problem. PMID- 28814874 TI - La belle indifference revisited: a case report on progressive supranuclear palsy misdiagnosed as conversion disorder. AB - BACKGROUND: Since the advent of computed tomography and magnetic resonance imaging scans, neurological disorders have less often been falsely labeled as conversion disorder (CD). However, misdiagnosis of a neurological disorder as CD still occurs, especially in cases with insidious onset. Misinterpretation of la belle indifference may contribute to such misdiagnosis. Here, we describe a case of progressive supranuclear palsy/Richardson's syndrome (PSPS) misdiagnosed as a case of CD. CASE: A 62-year-old woman consulted two different neurologists in 2012 because of falling spells since 2009 and was diagnosed with CD. She was referred to the Clinical Center of Excellence for Body, Mind, and Health for treatment of CD. After neurological examination, blood tests, and psychiatric examination, in which la belle indifference and a history of incest were found, CD was confirmed. However, despite treatment for CD, the patient's physical symptoms deteriorated over a year. After repeated physical and psychiatric examinations, neurocognitive assessment, and consultation with a third neurologist because of suspicion of neurological disease, the patient was diagnosed with PSPS. CONCLUSION: La belle indifference may be a psychological sign in the context of CD, but it may also be an expression of lack of mimic due to Parkinsonism or of eye movement disorder in the context of neurological illness. A diagnosis of CD should not be considered definitive if no improvement occurs in terms of physical, mental, and cognitive symptoms despite appropriate therapy. In case of deterioration, neurological reexamination and reinterpretation of la belle indifference should be considered. PMID- 28814876 TI - Neutrophil/lymphocyte ratio and mean platelet volume in central serous chorioretinopathy. AB - PURPOSE: This study aimed to evaluate mean platelet volume (MPV) and neutrophil/lymphocyte ratio (NLR) values and their relationship with clinical findings in patients with central serous chorioretinopathy (CSCR). METHODS: Overall, 87 patients fulfilling inclusion criteria and 320 age- and sex-matched healthy individuals as controls were included in the study. The CSCR patients (n=87) were classified into 2 groups as acute CSCR (group 1, n=43) and chronic CSCR (group 2, n=44). RESULTS: It was found that NLR (P<0.05) and C-reactive protein (CRP) (P<0.05) values were higher in acute CSCR group than the other groups. MPV value was found to be higher in chronic CSCR group than the other groups (P<0.001). CONCLUSION: It seems that neutrophils play a major role in acute CSCR while platelets are involved in progression to chronic CSCR. Larger, prospective studies are needed on this topic. PMID- 28814877 TI - Mechanism and therapeutic effectiveness of nerve growth factor in osteoarthritis pain. AB - Osteoarthritis (OA) is the most common form of articular joint arthritis and a cause of significant morbidity. In this review, we present the role of nerve growth factor (NGF) in pain generation, relationship between NGF and OA pain, and pathogenic factors (interleukin-1beta, transforming growth factor-beta1, mechanical loading, and adipokines) involved in OA development. Since NGF blocking is an efficient way to inhibit OA-associated pain, we summarize four categories of drugs that target NGF/tropomyosin receptor kinase A (TrkA) signaling. In addition, we discuss the future of NGF/TrkA antagonists and underline their potential for use in OA pain relief. A better understanding of the causes and treatment of OA will facilitate the development of more effective methods of OA pain management. PMID- 28814878 TI - Heavy Drinking in University Students With and Without Attention Deficit/Hyperactivity Disorder: Contributions of Drinking Motives and Protective Behavioral Strategies. AB - This study examined rates of heavy drinking and alcohol problems in relation to drinking motives and protective behavioral strategies in university students with a documented current diagnosis of attention-deficit/hyperactivity disorder (ADHD; n = 31) compared with students with no history of ADHD (n = 146). Participants completed a Web-based questionnaire, and logistic regression models tested interactions between ADHD/comparison group membership and motives and protective strategies. Group differences in rates of heavy drinking and alcohol problems were not statistically significant, but medium-sized risk ratios showed that students without ADHD reported heavy drinking at a rate 1.44 times higher than students with ADHD and met screening criteria for problematic alcohol use at a rate of 1.54 times higher than students with ADHD. Other key findings were, first, that drinking to enhance positive affect (e.g., drinking because it is exciting), but not to cope with negative affect (e.g., drinking to forget your worries), predicted both heavy drinking and alcohol problems. Second, only protective behavioral strategies that emphasize alcohol avoidance predicted both heavy drinking and alcohol problems. Contrary to expectations, we found no ADHD related moderation of effects of motives or protective strategies on our alcohol outcomes. Results of this study are limited by the small sample of students with ADHD but highlight tentative similarities and differences in effects of motives and strategies on drinking behaviors and alcohol problems reported by students with and without ADHD. PMID- 28814879 TI - Circulating tumor cells correlate with patterns of recurrence in patients with hormone-sensitive prostate cancer. AB - The aim of this study was to evaluate the correlation between circulating tumor cells (CTCs) and patterns of recurrence in patients with hormone-sensitive prostate cancer. The study involved patients with histologically confirmed, advanced prostatic adenocarcinoma, who were tested for CTCs (Veridex(r)) when they developed recurrence after radical prostatectomy or external beam radiation between 2008 and 2014. Forty-two prostate cancer patients were evaluated. CTCs were detected in 14 out of 42 (33.3%) patients (Group A), while the remaining 28 (66.7%) showed undetectable levels of CTCs (Group B). The mean prostate-specific antigen value was higher in Group A in comparison to Group B (6.2 vs 3.3 ng/dL) (P=0.48). Presence of bone metastases alone or along with nodal metastases was more common in Group A (57.1%) in comparison to Group B (25%) (P=0.04). In a univariate analysis, the presence of CTCs at diagnosis correlated with the development of bone recurrence (OR: 4; 95% CI: 1.0-15.9; P=0.05). Even if the study enrolled only a small number of patients, the detection of CTCs in the blood appears to correlate with the pattern of progression in patients with hormone-sensitive prostate cancer, suggesting a possible role in anticipating recurrence at the bone in men with higher tumor load. Further prospective studies are warranted in this setting. PMID- 28814880 TI - CD155 expression and its correlation with clinicopathologic characteristics, angiogenesis, and prognosis in human cholangiocarcinoma. AB - BACKGROUND: CD155, an immunoglobulin-like adhesion molecule, plays an important role in carcinoma such as cells migration, proliferation, metastasis, and tumor immune. The upregulation of CD155 has been found in several human malignancies, but its expression in cholangiocarcinoma (CCA) still remains unclear. The aim of this study is to investigate CD155 expression and its correlations with clinicopathologic data, angiogenesis, and prognosis in the patients with CCA. MATERIALS AND METHODS: CD155 expression was investigated in 20 paired CCA tissues and corresponding paracancerous tissues by Western blotting and quantitative real time polymerase chain reaction assays at protein and mRNA levels. Besides, this study evaluated the correlation between the tumor CD155 expression and the level of both vascular endothelial growth factor and intratumoral microvessel density by immunohistochemistry in 90 cases of CCA. Moreover, the clinical and prognostic significance of CD155 in CCA was assessed by immunohistochemistry. RESULTS: The protein and mRNA levels of CD155 were higher in CCA tumor tissues compared with corresponding paracancerous tissues (P<0.05). Immunohistochemical staining showed that CD155 was located in the cytoplasm of carcinoma cells and overexpressed in 61.2% (55/90) CCA tissues. Obviously, CD155 expression level was significantly correlated with tumor histological grade (P=0.002), lymph node metastasis (P<0.001), and tumor-node-metastasis (P=0.03). Additionally, Spearman rank correlation test demonstrated that CD155 expression was positively associated with vascular endothelial growth factor (r=0.481, P<0.001) and microvessel density (r=0.442, P<0.001) in CCA tissues. More importantly, CCA patients with high CD155 expression had a markedly shorter overall survival (P<0.001) and disease-free survival (P<0.001) after surgical resection, and multivariate analysis showed that high CD155 expression was an independent poor prognostic predictor of overall survival and disease-free survival (P<0.001). CONCLUSION: Our results revealed that upregulated CD155 correlated with aggressive clinicopathologic characteristics, angiogenesis, and poor prognosis in CCA and may be a promising prognostic biomarker for the CCA patients. PMID- 28814881 TI - Elevated expression of neuropilin-2 associated with unfavorable prognosis in hepatocellular carcinoma. AB - Neuropilin-2 (NRP2) is a single-pass transmembrane glycoprotein and has recently been detected in several human cancer cells. However, its clinical relevance in hepatocellular carcinoma (HCC) remains unclear. This study aimed at evaluating NRP2 expression and clinicopathological significance in HCC patients. Tissue microarray of 190 HCC patients from the First Affiliated Hospital of Zhejiang University was established, and immunohistochemical staining was performed for NRP2. The Kaplan-Meier analysis and Cox proportional hazard model were used to analyze the survival rate. We found that NRP2 expression in HCC was significantly associated with tumor histological degree (P=0.023) and cirrhosis (P=0.040). Furthermore, NRP2-positive HCC patients demonstrated shorter disease-free survival (DFS) and overall survival (OS) than those of NRP2-negative patients. Then, the multivariate Cox analysis showed that hazard ratios of NRP2-positive patients with DFS and OS were 2.167 (95% CI: 1.626, 2.889) and 2.317 (95% CI: 1.548, 3.469), respectively. Our results suggested that NRP2 expression was considered as an independent factor for the prediction of unfavorable prognosis in HCC patients, and we believe that NRP2 could serve as a biomarker of poor prognosis and a novel target in treating HCC tumors. PMID- 28814882 TI - The effect of lipiodol deposition in HCC after TACE on the necrosis range of PMCT. AB - OBJECTIVE: To study the impact of lipiodol deposition in the lesion of hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE) on the necrosis area of percutaneous microwave coagulation therapy (PMCT). MATERIALS AND METHODS: A total of 44 patients with HCC with 56 nodules, with a size ranging from 1.5 to 3.5 cm, was selected in our study. About 23 patients (26 nodules) underwent PMCT treatment only as Group A and 21 patients (30 nodules) were treated by PMCT-combined TACE as Group B. All patients underwent PMCT with single electrode and one-point ablation. Paired t-test was used to analyze pre- and postoperatively the volume of tumor and the necrosis volume after PMCT. Independent t-test was used to compare the difference in the necrosis area between two groups (alpha=0.05). RESULTS: All patients underwent PMCT or PMCT combined with TACE successfully. The tumor and necrosis size of Group A was 16.29+/-19.23 cm3 and 17.98+/-18.49 cm3 (P=0.650), and 11.95+/-12.78 cm3 and 16.60+/-11.70 cm3 of Group B (P=0.017). There was no significant difference on necrosis volume between the two groups (P=0.581). The necrosis area of Group B was larger than the size of the tumor (P=0.017), but the ablation area of the two groups was smaller than the theoretic area (P=0.001). (The theoretic area means that the necrosis area of ablation should be 1.0 cm larger than the tumor in diameter.). CONCLUSION: PMCT combined with TACE could enlarge the ablation area, but will not lead to an ideal necrosis area than the PMCT alone. The lipiodol deposition in the tumor lesion may hinder the expansion of the heating field. Therefore, further research was needed. PMID- 28814883 TI - Serum exosomal miR-125b is a novel prognostic marker for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide with high mortality. Circulating miRNA has been demonstrated as a novel noninvasive biomarker for many tumors. This study aimed to investigate the potential of circulating miR-125b as a prognostic marker of HCC. Exosomes were extracted from serum samples collected from two independent cohorts: cohort 1: HCC (n=30), chronic hepatitis B (CHB, n=30), liver cirrhosis (LC, n=30); cohort 2: HCC (n=128). We found that miR-125b levels were remarkably increased in exosomes compared to those in serum from patients with CHB, LC, and HCC (P<0.01, respectively). However, miR-125b levels in exosomes and the serum from HCC patients were inferior to that of CHB (P<0.01 and P=0.06) and LC patients (P<0.01 for all). Additionally, miR-125b levels in exosomes were associated with tumor number (P=0.02), encapsulation (P<0.01), and TNM stage (P<0.01). Kaplan-Meier analysis indicated that HCC patients with lower exosomal miR-125b levels showed reduced time to recurrence (TTR) (P<0.01) and overall survival (OS) (P<0.01). Furthermore, multivariate analysis revealed that miR-125b level in exosomes, but not in serum, was an independent predictive factor for TTR (P<0.001) and OS (P=0.011). Exosomal miR-125b levels predicted the recurrence and survival of HCC patients with an area under the ROC curve of 0.739 (83.0% sensitivity and 67.9% specificity) and 0.702 (82.5% sensitivity and 53.4% specificity). In conclusion, exosomal miR-125b could serve as a promising prognostic marker for HCC. PMID- 28814884 TI - Outcomes of adding induction chemotherapy to concurrent chemoradiotherapy for stage T3N0-1 nasopharyngeal carcinoma: a propensity-matched study. AB - OBJECTIVE: Our objective was to examine whether adding induction chemotherapy to concurrent chemoradiotherapy improved survival in stage III nasopharyngeal carcinoma (NPC) patients, especially in low-risk patients at stage T3N0-1. MATERIALS AND METHODS: We retrospectively analyzed 687 patients with stage T3N0-1 NPC treated with intensity-modulated radiation therapy (IMRT) plus concurrent chemotherapy (CC) with or without induction chemotherapy (IC). Propensity score matching (PSM) method was used to select 237 pairs of patients from two cohorts. Overall survival (OS), locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and progression-free survival (PFS) were assessed by using the Kaplan-Meier method, log-rank test, and Cox regression analysis. RESULTS: No significant survival differences were observed between IC plus CC and CC cohorts with similar 4-year OS (91.7% vs 92.6%, P=0.794), LRFS, (92.7% vs 96.8%, P=0.138), DMFS (93.5% vs 94.3%, P=0.582), and PFS (87.5% vs 91.1%, P=0.223). In a univariate analysis, lower Epstein-Barr virus deoxyribonucleic acid (EBV DNA; <4,000 copies/mL) significantly improved 4-year DMFS (95.5% vs 91.6%, P=0.044) compared with higher EBV DNA (>=4,000 copies/mL). No factors were associated with 4-year OS, LRFS, DMFS, and PFS in a multivariate analysis. IC plus CC group experienced higher rates of grade 3-4 leucopenia (P<0.001) and neutropenia (P<0.001). CONCLUSION: The addition of IC to CC in stage T3N0-1 NPC patients treated with IMRT did not significantly improve their survival. The IC group experienced higher rates of grade 3-4 hematological toxicities. Therefore, further investigation is required. PMID- 28814885 TI - IGF2BP3 as a potential tissue marker for the diagnosis of esophageal high-grade intraepithelial neoplasia. AB - BACKGROUND: The clinical significance of insulin-like growth factor-II mRNA binding protein-3 (IGF2BP3) in esophageal high-grade intraepithelial neoplasia (HGIN) is not clear. This study was designed to characterize the expression of IGF2BP3 in HGIN. PATIENTS AND METHODS: IGF2BP3 expression was evaluated by Western blot analyses in 12 cases and by immunohistochemistry (IHC) in 112 cases. The associations between IGF2BP3 expression in HGIN and the clinicopathological parameters were examined. RESULTS: Moderate to strong IGF2BP3 expression was present in HGIN samples. Using IHC, it was found that IGF2BP3 was positive in 68 (60.71%) cases. Intense IHC of IGF2BP3 in HGIN was associated with a deeper lesion depth, and the lesion depth was the only predictor of the positive expression of IGF2BP3. CONCLUSION: Our results suggested that IGF2BP3 may be a supplementary tissue marker for preoperative diagnosis of HGIN. PMID- 28814886 TI - A practical guide to the handling and administration of talimogene laherparepvec in Europe. AB - Talimogene laherparepvec is a herpes simplex virus-1-based intralesional oncolytic immunotherapy and is the first oncolytic virus to be approved in Europe. It is indicated for the treatment of adults with unresectable melanoma that is regionally or distantly metastatic (stage IIIB, IIIC, and IVM1a) with no bone, brain, lung, or other visceral disease. Talimogene laherparepvec is a genetically modified viral therapy, and its handling needs special attention due to its deep freeze, cold-chain requirements, its potential for viral shedding, and its administration by direct intralesional injection. This review provides a practical overview of handling, storage, and administration procedures for this agent in Europe. Talimogene laherparepvec vials should be transported/stored frozen at a temperature of -90 degrees C to -70 degrees C, and once thawed, vials must not be refrozen. Universal precautions for preparation, administration, and handling should be followed to avoid accidental exposure. Health care providers should wear personal protective equipment, and materials that come into contact with talimogene laherparepvec should be disposed of in accordance with local institutional procedures. Individuals who are immunocompromised or pregnant should not prepare or administer this agent. Talimogene laherparepvec is administered by intralesional injection into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound. Treatment should be continued for >=6 months. As with other immunotherapies, patients may experience an increase in the size of existing lesion(s) or the appearance of new lesions (ie, progression) prior to achieving a response ("pseudo-progression"). As several health care professionals (eg, physicians [dermatologists, surgeons, oncologists, radiologists], pharmacists, nurses) are involved in different stages of the process, there is a need for good interdisciplinary collaboration when using talimogene laherparepvec. Although there are specific requirements for this agent's storage, handling, administration, and disposal, these can be effectively managed in a real-world clinical setting through the implementation of training programs and straightforward standard operating procedures. PMID- 28814887 TI - SHP2 overexpression enhances the invasion and metastasis of ovarian cancer in vitro and in vivo. AB - PURPOSE: SHP2 has roles in a variety of signal transduction pathways and in many important cellular processes, including proliferation, differentiation, movement regulation, and apoptosis. In addition, SHP2 expression is closely associated with multiple types of malignancies. In this study, we examined the role of SHP2 in epithelial ovarian cancer. PATIENTS AND METHODS: SHP2 expression in cancer and normal ovarian tissue specimens was evaluated by immunohistochemical staining and Western blot analyses. The correlation between the SHP2 expression level and clinicopathological features was analyzed. The role of SHP2 in epithelial ovarian cancer was evaluated by assessing SHP2 expression patterns in vitro and in vivo, and activation of the PI3K/AKT pathway was examined. RESULTS: SHP2 is expressed at higher levels in ovarian cancer tissues than in normal ovarian tissues and in an ovarian cancer cell line than in a normal ovarian cell line. On the basis of these findings, SHP2 is overexpressed in ovarian cancer both in vitro and in vivo. In addition, SHP2 overexpression is associated with tumor stage and differentiation, enhanced cell proliferation and invasion, and tumorigenesis and metastasis. CONCLUSION: SHP2 overexpression enhances ovarian tumor proliferation and invasion by activating the PI3K-AKT axis, indicating that SHP2 potentially plays a direct role in the pathogenesis of ovarian epithelial cell cancer. These novel findings provide key insights that are applicable to basic cancer research and to the prevention and treatment of cancer. PMID- 28814888 TI - Frequency of colistin and fosfomycin resistance in carbapenem-resistant Enterobacteriaceae from a tertiary care hospital in Karachi. AB - INTRODUCTION: Management of infections with carbapenem-resistant Enterobacteriaceae (CRE) is challenging. In recent times, agents such as colistin and fosfomycin have been used in combination with other antibiotics to treat such infections. In this study, we aim to seek frequency of colistin and fosfomycin resistance in CRE from Pakistan. METHODS: This study was conducted at clinical laboratories, Aga Khan University Hospital. In total, 251 CRE were included in the study. Colistin minimum inhibitory concentrations (MICs) were performed using broth microdilution (BMD) method and VITEK(r) 2 system, whereas fosfomycin susceptibility was performed using Kirby-Bauer method. MIC50 and MIC90 were calculated for colistin and agreement between VITEK and BMD was also calculated. RESULTS: Out of 251 strains colistin MIC of >=4 ug/mL was seen in 40 (15.9%). Of these strains 20 (50%) were Klebsiella pneumoniae. Colistin MIC50 and MIC90 were found to be 0.5 and 16 ug/mL, respectively. BMD and VITEK 2 showed 100% categorical agreement. Essential agreement was 88.5% with kappa score 0.733 indicating strong agreement between VITEK and BMD. 31 out of 251 (12.3%) CREs were resistant to fosfomycin. CONCLUSION: Study shows frequency of colistin and fosfomycin resistance to be 15.9% and 12.3%, respectively. In countries where rate of CREs is high, emerging resistance against these last resort antibiotics is alarming as it leaves clinicians with almost no options to manage such multidrug resistant and extensively drug resistant infections. PMID- 28814890 TI - Clinical and economic analysis of outcomes of dose tapering or withdrawal of tumor necrosis factor-alpha inhibitors upon achieving stable disease activity in rheumatoid arthritis patients. AB - OBJECTIVE: To compare the real-world, 5-year clinical and cost impact of maintaining treatment with the tumor necrosis factor-alpha inhibitors (anti-TNFs) adalimumab, etanercept, or infliximab vs dose tapering or withdrawal in rheumatoid arthritis (RA) patients who have achieved remission (defined as a 28 joint count Disease Activity Score [DAS28] < 2.6) or low disease activity (LDA; DAS28 < 3.2). METHODS: Using a 5-year Markov model with 1-month cycle length, we examined the clinical and cost impact of three treatment strategies: withdrawal, tapering, or maintenance of anti-TNFs among RA patients in remission or who have achieved LDA. This model assessed the time to loss of disease control, time to regaining control after treatment reinitiation, and associated medical and anti TNF costs. To determine the risk of losing disease control, 14 studies (2309 patients) were meta-analyzed, adjusted for treatment strategy, anti-TNF, RA patient type (early or established RA), and model entry criterion (remission or LDA). RESULTS: Anti-TNF withdrawal and tapering incurred comparable 5-year total costs (?37,900-?59,700 vs ?47,500-?59,200), which were lower than those incurred by anti-TNF maintenance (?67,100-?72,100). Established RA patients had higher total costs than early RA patients (?45,900-?72,100 vs ?37,900-?71,700). Maintenance was associated with the longest time to loss of disease control (range, 27.3-47.1 months), while withdrawal had the shortest (range, 6.9-30.5 months). CONCLUSION: Dose tapering or withdrawal of anti-TNFs results in similar reduction of health care costs but less time in sustained disease control compared to maintaining therapy. Future research is needed to understand the long term clinical consequences of these strategies and patient preferences for treatment withdrawal. PMID- 28814889 TI - Fluconazole resistance in Candida species: a current perspective. AB - Candida albicans and the emerging non-albicans Candida spp. have significant clinical relevance among many patient populations. Current treatment guidelines include fluconazole as a primary therapeutic option for the treatment of these infections, but it is only fungistatic against Candida spp. and both inherent and acquired resistance to fluconazole have been reported. Such mechanisms of resistance include increased drug efflux, alteration or increase in the drug target, and development of compensatory pathways for producing the target sterol, ergosterol. While many mechanisms of resistance observed in C. albicans are also found in the non-albicans species, there are also important and unexpected differences between species. Furthermore, mechanisms of fluconazole resistance in emerging Candida spp., including the global health threat Candida auris, are largely unknown. In order to preserve the utility of one of our fundamental antifungal drugs, fluconazole, it is essential that we fully appreciate the manner by which Candida spp. manifest resistance to it. PMID- 28814892 TI - Treatment of a traumatic atrophic depressed scar with hyaluronic acid fillers: a case report. AB - BACKGROUND: Hyaluronic acid filler has been documented in the treatment of atrophic depressed acne scars relatively frequently in the literature but rarely in chronic depressed traumatic atrophic facial scars. METHODS: This case report discusses the use of hyaluronic acid fillers in the correction of a post traumatic facial atrophic scar on the right cheek. RESULTS: The right cheek scar was substantially corrected with one session of two different hyaluronic acids injected in a deep and superficial plane. CONCLUSION: Relatively accurate, simple and effective correction of this atrophic traumatic scar may suggest that fillers are a suitable alternative to surgery for such scars. PMID- 28814893 TI - Presentation and outcomes of necrotizing soft tissue infections. AB - BACKGROUND: Necrotizing soft tissue infections (NSTIs) are aggressive infections associated with significant morbidity, including amputation and organ failure, and high mortality. The rapid progression and significant risk of morbidity and mortality associated with NSTIs makes quick diagnosis and treatment critical. The objective of this study was to determine the presentation of patients diagnosed with NSTIs and their in-hospital outcomes. METHODS: This was a retrospective review of adult (>17 years) patients with a discharge diagnosis of necrotizing fasciitis at London Health Sciences Centre (annual census 125,000) over a 5-year period (April 2008-March 2013). RESULTS: Sixty patients with confirmed NSTI were included in this study. Common comorbidities at presentation included immunocompromise (58.3%), diabetes mellitus (41.7%), vascular disease (45.0%), and obesity (24.6%). Initial presentations included swelling (91.7%), erythema (86.7%), bullae (28.3%), petechiae (8.3%), and bruising (45.0%). Fifty (83.3%) underwent surgery, with a median (interquartile range) time from initial emergency department presentation to surgery of 15.5 hours (7.8, 74.9). In hospital mortality among those who had surgical intervention was 14.0%, compared to 60.0% for patients who did not have surgery (Delta46.0%; 95% CI: 14.8% to 70.2%). CONCLUSION: Diabetes mellitus, immune-compromise, vascular disease, and obesity are common comorbidities of NSTIs. Survival is higher among patients who receive surgical treatment. Patients presenting with this clinical picture warrant a high degree of suspicion. PMID- 28814891 TI - Diabetes and dyslipidemia: characterizing lipoprotein metabolism. AB - Premature atherosclerosis in diabetes accounts for much of the decreased life span. New treatments have reduced this risk considerably. This review explores the relationship among the disturbances in glucose, lipid, and bile salt metabolic pathways that occur in diabetes. In particular, excess nutrient intake and starvation have major metabolic effects, which have allowed us new insights into the disturbance that occurs in diabetes. Metabolic regulators such as the forkhead transcription factors, the farnesyl X transcription factors, and the fibroblast growth factors have become important players in our understanding of the dysregulation of metabolism in diabetes and overnutrition. The disturbed regulation of lipoprotein metabolism in both the intestine and the liver has been more clearly defined over the past few years, and the atherogenicity of the triglyceride-rich lipoproteins, and - in tandem - low levels of high-density lipoproteins, is seen now as very important. New information on the apolipoproteins that control lipoprotein lipase activity has been obtained. This is an exciting time in the battle to defeat diabetic atherosclerosis. PMID- 28814894 TI - Startle modulation by heat pain with varying threat levels in chronic pain patients and pain-free controls. AB - BACKGROUND: Empirical evidence suggests that affective responses to pain are changed in chronic pain. The investigation of startle responses to pain might contribute to clarifying whether such alterations also expand to motivational defensive reactions. We aimed at comparing startle responses to tonic heat pain with high threat (HT) or low threat (LT) in patients with chronic musculoskeletal pain and controls. As pain-related anxiety and catastrophizing are typically elevated in chronic pain, we expected to find stronger startle responses in patients specifically under experimental HT. METHODS: Patients with chronic musculoskeletal, preferentially, back pain (N = 19) and matched pain-free controls (N = 19) underwent two pain-related threat conditions (high and low) in balanced order. Only, in the HT condition, 50% of the trials were announced to include a short further noxious temperature increase at the end. Startle responses to loud tones were always assessed prior to a potential temperature increase in the phase of anticipation and were recorded by surface electromyogram. RESULTS: Surprisingly, we observed no differences in startle responses and ratings of emotional and pain responses between patients and controls despite significantly higher pain-related anxiety and catastrophizing in the patients. Overall, startle was potentiated in the HT condition, but only in participants who started with this condition. CONCLUSION: Our results suggest that, in general, patients with pain are not more responsive emotionally to experimental threat manipulations despite elevated pain anxiety and catastrophizing. Instead, exaggerated responses in patients might be triggered only by individual concerns relating to pain, which are not sufficiently mirrored by our threat paradigm. PMID- 28814895 TI - Caffeine as an opioid analgesic adjuvant in fibromyalgia. AB - BACKGROUND: Caffeine's properties as an analgesic adjuvant with nonsteroidal anti inflammatory drugs/acetaminophen are well documented. However, little clinical research has explored caffeine's effects on opioid analgesia. This study assessed the effects of caffeine consumption on pain and other symptoms in opioid-using and nonusing chronic pain patients meeting the survey criteria for fibromyalgia. MATERIALS AND METHODS: Patients presenting to a university-based pain clinic completed validated self-report questionnaires assessing symptoms. Patients (N=962) meeting the fibromyalgia survey criteria were stratified by opioid use and further split into groups based on caffeine amount consumed per day (no caffeine, or low, moderate, high caffeine). Analysis of covariance with Dunnett's post hoc testing compared pain and symptom severity between the no caffeine group and the caffeine consuming groups. RESULTS: In opioid users, caffeine consumption had modest but significant effects on pain, catastrophizing, and physical function. Lower levels of pain interference were associated with low and moderate caffeine use compared to no caffeine intake. Lower pain catastrophizing and higher physical function were observed in all caffeine dose groups, relative to the no caffeine group. Lower pain severity and depression were observed only in the moderate caffeine group. In opioid nonusers, low caffeine intake was associated with higher physical function; however, no other significant effects were observed. CONCLUSION: Caffeine consumption was associated with decreased pain and symptom severity in opioid users, but not in opioid nonusers, indicating caffeine may act as an opioid adjuvant in fibromyalgia-like chronic pain patients. These data suggest that caffeine consumption concomitant with opioid analgesics could provide therapeutic benefits not seen with opioids or caffeine alone. PMID- 28814896 TI - Development of a profile scoring system for assessing the psychosocial situation of patients with chronic musculoskeletal pain. AB - Chronic pain is a manifestation of interactions among physical, psychological, and social conditions, but the latter two, that is, the nonphysical correlates of chronic pain, are only rarely measured. This study aimed to develop a profile scoring system for assessing the psychosocial situation of patients with chronic musculoskeletal pain. An expert panel chose social and psychological domains considered to be relevant to patients with chronic pain and wrote questions asking about each of those domains. The questionnaire was completed by 252 patients with chronic musculoskeletal pain. Factor analysis was used to select questionnaire items for each domain. Associations and interactions of pain severity and each domain score with pain-related quality of life (PRQOL) were examined using linear regression models. Five domains were chosen: work, family, sleep, mental health, and PRQOL. Then, a total of 17 questions were created for the work, family, and sleep domains. Using the likelihood-ratio test, we found significant interactions with PRQOL in four pairs: severity-family, severity mental, family-sleep, and work-mental. The association between pain severity and PRQOL was related to each patient's social and psychological situation. These results suggest that interventions for patients with chronic pain may be personalized to account for each individual's psychosocial situation. PMID- 28814897 TI - Discordance of the estrogen receptor and HER-2/neu in breast cancer from primary lesion to first and second metastatic site. AB - BACKGROUND: Hormone receptor and HER-2/neu discordance between the primary lesion and first metastasis has been reported. This study was performed to determine further biomarker discordance rates between the first and subsequent metastatic breast cancer lesions. METHODS: We performed a retrospective review of paired biomarkers from primary breast cancers compared to first reported and subsequent metastases from 103 patients with breast cancer. The estrogen receptor (ER), progesterone receptor (PR), and HER-2/neu status were reported at all three time points. In addition, hormone, cytotoxic, and targeted treatments were recorded for primary and metastatic disease, and survival was determined. RESULTS: Between the primary and first metastases, discordance rates for ER, PR, and HER-2/neu were 15.8%, 33.7%, and 14.3%, respectively. There was discordance between the first and second metastases for the ER receptor in 18.8%, PR receptor in 19.8%, and HER-2/neu in 10.7%. Overall, there was discordance between the primary tumor and either the first or second metastases for ER in 27.7%, PR receptor in 40.7%, and HER-2/neu in 19.6% of cases. Discordance of either ER or PR affected survival, with worse survival experienced by those patients with all three hormone receptors remaining negative, and intermediate survival reported for those with discordant tumors (ER chi2=14.27, p=0.0008; PR chi2=11.31, p=0.0035). There was no difference in survival for patients whose HER-2/neu tumors were discordant. CONCLUSION: This study demonstrated that continued metastatic disease evolution may be associated with different tumor biology and that studies of metastatic lesions appear warranted, especially if targeted therapy is an option. PMID- 28814898 TI - Reducing rectal injury in men receiving prostate cancer radiation therapy: current perspectives. AB - Dose escalation is now the standard of care for the treatment of prostate cancer with radiation therapy. However, the rectum tends to be the dose-limiting structure when treating prostate cancer, given its close proximity. Early and late toxicities can occur when the rectum receives large doses of radiation therapy. New technologies allow for prevention of these toxicities. In this review, we examine the evidence that supports various dose constraints employed to prevent these rectal injuries from occurring. We also examine the use of intensity-modulated radiation therapy and how this compares to older radiation therapy techniques that allow for further sparing of the rectum during a radiation therapy course. We then review the literature on endorectal balloons and the effects of their daily use throughout a radiation therapy course. Tissue spacers are now being investigated in greater detail; these devices are injected into the rectoprostatic fascia to physically increase the distance between the prostate and the anterior rectal wall. Last, we review the use of systemic drugs, specifically statin medications and antihypertensives, as well as their impact on rectal toxicity. PMID- 28814899 TI - Irritable bowel symptoms and the development of common mental disorders and functional somatic syndromes identified in secondary care - a long-term, population-based study. AB - OBJECTIVE: Irritable bowel syndrome (IBS) is associated with mental vulnerability, and half of patients report comorbid somatic and mental symptoms. We aimed to investigate the relationship between an IBS symptom continuum and the subsequent development of common mental disorders (CMDs) and functional somatic syndromes (FSSs). METHODS AND STUDY DESIGN: A longitudinal population-based study comprising two 5-year follow-up studies, Dan-MONICA 1 (1982-1987) and Inter99 (1999-2004), recruited from the western part of Copenhagen County. The total study population (n = 7,278) was divided into symptom groups according to the degree of IBS definition fulfillment at baseline and/or follow-up and was followed until December 2013 in Danish central registries. Cox regression was used for the analyses, adjusting for age, sex, length of education and cohort membership. In a subsequent analysis, we adjusted for mental vulnerability as a risk factor for both CMDs and FSSs, including IBS. RESULTS: Over a 5-year period, 51% patients had no IBS symptoms, 17% patients had IBS symptoms without abdominal pain, 22% patients had IBS symptoms including abdominal pain and 10% patients fulfilled the IBS definition. IBS and IBS symptoms including abdominal pain were significantly associated with the development of CMDs and other FSSs identified in secondary care. When adjusting for mental vulnerability, IBS and IBS symptoms including abdominal pain were no longer associated with CMDs, but the significant relationship to other FSSs remained. CONCLUSION: In a clinical setting, the perspective should be broadened to individuals not fulfilling the symptom cluster of IBS but who report frequent abdominal pain. Additionally, it is important to combine symptom-based criteria of IBS with psychosocial markers such as mental vulnerability, because it could guide clinicians in decisions regarding prognosis and treatment. PMID- 28814900 TI - Acidic oral moisturizers with pH below 6.7 may be harmful to teeth depending on formulation: a short report. AB - Xerostomia affects 30% of the population and manifests as a side effect of medications, systemic diseases, or cancer therapy. Oral moisturizers are prescribed to overcome the ailments of dry mouth and its symptoms. It is imperative that these products help to restore hyposalivation and that they do not present any secondary effect that can harm oral health. It has been shown in the literature that some oral moisturizers may have an erosive potential due to their acidic pH, which is below the critical pH of dentin and enamel. The purpose of this paper was to make clinicians aware of the erosive potential of these products and make recommendations to manufactures for future formulations avoiding acidic pH. For this reason, care should be taken to formulate these products with safe pH values for both enamel and root dentin which, based on specific formulation should be around 6.7 or higher. PMID- 28814902 TI - Orbital apex cyst: a rare cause of compressive optic neuropathy post-functional endoscopic sinus surgery. AB - There are various causes that can lead to compressive optic neuropathy. We present here orbital apex cyst as an unusual cause of compressive optic neuropathy in a 49-year-old male. He presented with 2 weeks painless loss of vision in the left eye with left-sided headache. He had had left functional endoscopic sinus surgery for left nasal polyps 4 years earlier. Magnetic resonance imaging of brain and orbit revealed a left discrete orbital nodule, possibly orbital cyst or mucocele, which was compressing on the left optic nerve. Left eye vision improved markedly from hand movement to 6/36 pinhole 6/18 after initiation of intravenous dexamethasone. A subsequent endoscopic endonasal left optic nerve decompression found the orbital nodule lesion to be an orbital cyst. Marsupialization was performed instead of excision, as the cyst ruptured intraoperatively. Postoperative vision improved to 6/7.5 with normal optic nerve function postoperatively. Possible cause of orbital apex cyst is discussed. PMID- 28814901 TI - Prediction of drug-related problems in diabetic outpatients in a number of hospitals, using a modeling approach. AB - OBJECTIVE: Drug-related problems (DRPs) are considered a serious, expensive, and important undesirable complication of health care. However, as current health care resources are limited, pharmacist DRP services cannot be provided to all patients. Using a modeling approach, we aimed to identify risk factors for DRPs so that patients for DRP-reduction services can be better identified. METHODS: Patients with diabetes from outpatient clinics from five key university affiliated and public hospitals in Jordan were assessed for DRPs (drug without an indication, untreated indication, and drug efficacy problems). Potential risk factors for DRPs were assessed. A logistic regression model was used to identify risk factors using a randomly selected, independent, nonoverlapping development (75%) subsample from full dataset. The remaining validation subsample (25%) was reserved to assess the discriminative ability of the model. RESULTS: A total of 1,494 patients were recruited. Of them, 81.2% had at least one DRP. Using the development subsample (n=1,085), independent risk factors for DRPs identified were male gender, number of medications, prescribed gastrointestinal medication, and nonadherence to self-care and non-pharmacological recommendations. Validation results (n=403) showed an area under the receiver operating characteristic curve of 0.679 (95% confidence interval=0.629-0.720); the model sensitivity and specificity values were 65.4% and 63.0%, respectively. CONCLUSION: Within the outpatient setting, the results of this study predicted DRPs with acceptable accuracy and validity. Such an approach will help in identifying patients needing pharmacist DRP services, which is an important first step in appropriate intervention to address DRPs. PMID- 28814903 TI - Ixeris dentata extract regulates salivary secretion through the activation of aquaporin-5 and prevents diabetes-induced xerostomia. AB - The aim of this study was to investigate the effects of Ixeris dentata (IXD) extract to improve the salivation rate in dry mouth induced by diabetes. Both control and diabetic rats were treated with a sublingual spray of either water or IXD extract to determine the effects of IXD on salivation. During the study, we observed that IXD extract treatment increased the salivary flow rate in diabetic rats. The expression of alpha-amylase was increased significantly in both saliva and glandular tissue lysates of IXD-treated diabetic rats. Aquaporin-5 protein expression was abnormally low in the salivary glands of diabetic rats, which increased hyposalivation and led to salivary dysfunction. However, a single oral spray of IXD extract drastically increased the expression of aquaporin-5 in salivary gland acinar and ductal cells in diabetic rats. Moreover, IXD extract induced expression of Na+/H+ exchangers in the salivary gland, which suggests that Na+/H+ exchangers modulate salivary secretions and aid in the fluid secretion mechanism. Furthermore, transient treatment with IXD extract increased the intracellular calcium in human salivary gland cells. Taken together, these results suggest the potential value of an IXD extract for the treatment of diabetes-induced hyposalivation and xerostomia. PMID- 28814904 TI - The journey of rheumatoid arthritis patients: a review of reported lag times from the onset of symptoms. AB - BACKGROUND: Even after achieving tremendous advances in diagnosis and treatment of rheumatoid arthritis (RA), many of the patients undergo delays in diagnosis and initiation of treatment, which leads to worsening of the condition and poor prognosis. OBJECTIVE: The objective of this study was to perform a literature review to quantify the lag times in diagnosis and treatment of RA and study the reported factors associated with it. METHODS: The authors searched literature published until September 2016 in electronic full-text and abstract databases and hand-searched the suitable articles. RESULTS: The weighted average of median lag time from symptom onset to therapy was 11.79 months (12 studies, 5,512 patients, range 3.6-24.0 months). Lag1 was 3.14 months (onset of symptoms to first physician consultant; 12 studies, 6,055 patients, range 0-5.7 months); lag2 was 2.13 months (physician visit to RA specialist referral; 13 studies, 34,767 patients, range 0.5-6.6 months); lag3 was 2.91 months (consultation with rheumatologist to diagnosis; 3 studies, 563 patients, range 0-5 months), lag4 was 2.14 months (diagnosis to initiation of disease-modifying antirheumatic drug therapy; 5 studies, 30,685 patients, range 0-2.2 months). Numerous patient-and physician-related factors like gender, ethnicity, primary care physician knowledge of the condition, availability of diagnostics, and so on were responsible for the delays. CONCLUSION: This review estimated the delay times and identified the main factors for delay in RA patients in diagnosis and initiation of treatment. A most plausible solution to this is coordinated effort by the rheumatology and primary care physicians. PMID- 28814905 TI - Conjunctival Flora of Human Immunodeficiency Virus Patients on Antiretroviral Treatment. AB - OBJECTIVES: To determine the conjunctival flora of human immunodeficiency virus (HIV) patients on antiretroviral treatment (ART). METHODOLOGY: A total of 104 conjunctival swabs from 104 HIV patients on ART underwent microbiological evaluation to describe the flora. RESULT: There were 71 (68.26%) women and 33 (31.74%) men. The mean age was 42.9 +/- 9.77 (range: 22-70) years. Negative cultures were found in 39 (37.50%) cases. Bacterial growth occurred in 65 (62.50%) cases. Coagulase-negative Staphylococcus was found in 59 eyes (90.76%), and coagulase-positive in 3 eyes (4.61%). There was a significant correlation between the duration of ART, the degrees of immunosuppression, and bacterial growth. CONCLUSIONS: Knowledge of the conjunctival flora in HIV patients may provide a better guideline in the choice of antibiotic for the management of ocular surface infections. PMID- 28814906 TI - Psychosocial challenges for patients with advanced lung cancer: interventions to improve well-being. AB - As compared to other cancers, lung malignancies are associated with high symptom burden, poorer prognosis, and stigmatization. Such factors increase psychological distress and negatively impact quality of life. Research has documented the efficacy of psychosocial interventions to alleviate psychological distress and promote well-being among patients with cancer. This article summarizes the current literature on psychosocial interventions in lung cancer. Major types of psychosocial interventions in lung cancer include cognitive-behavioral therapies, psycho-education, mind-body, exercise, and supportive or palliative care strategies. Discussion relative to the purpose, sample, research design, outcomes, and quality of the studies is presented. Findings may be useful in clinical environments as a resource to help health providers better understand mental health treatment options and care for patients facing lung cancer. The need to direct future research toward the advancement of science and improve well being and quality of life outcomes for patients with advanced lung cancer and their family members is discussed. PMID- 28814907 TI - New prognostic biomarkers and therapeutic effect of bevacizumab for patients with non-small-cell lung cancer. AB - BACKGROUND: Several biomarkers have emerged as potential prognostic and predictive markers for non-small-cell lung cancer (NSCLC). Successful inhibition of angiogenesis with the antivascular endothelial growth factor antibody, bevacizumab, has improved the efficacy seen with standard cytotoxic therapy of NSCLC. However, despite such enhanced treatment strategies, the prognosis for patients with advanced NSCLC remains poor. PATIENTS AND METHODS: We assessed potential biomarkers in 161 NSCLC patients and 42 control patients. Enzyme-linked immunosorbent assay methods were used to evaluate three biomarkers: platelet derived microparticle (PDMP), high-mobility group box-1 (HMGB1), and plasminogen activator inhibitor-1 (PAI-1). We studied the effects of bevacizumab on the expression of these markers. We also analyzed the relationship of the newly designed risk factor (NDRF) to overall survival and disease-free survival. The NDRF classification of patients was determined from the levels of PDMP, HMGB1, and PAI-1. To determine the individual prognostic power of PDMP, HMGB1, and PAI 1, we evaluated associations between their levels and patient outcomes by Kaplan Meier survival analysis in a derivation cohort. RESULTS: PDMP, HMGB1, and PAI-1 levels were higher in NSCLC patients compared with control patients. Notably, the difference in PDMP levels exhibited the strongest statistical significance (p<0.001). Multivariate analysis showed that HMGB1 and PAI-1 levels were significantly correlated with PDMP levels. Patients who received standard chemotherapy with bevacizumab exhibited significantly reduced levels of all three markers compared with patients who received standard chemotherapy. NDRF3 status (high levels of all three markers) was significantly correlated with a poor prognosis (p<0.05 for overall survival and disease-free survival). CONCLUSION: Our results demonstrate that abnormal levels of PDMP, HMGB1, and PAI-1 are related to each other in NSCLC. Moreover, our findings suggest that the vascular complications associated with these markers may contribute to a poor prognosis for NSCLC patients. PMID- 28814908 TI - Pulmonary Cryptococcosis Presenting With Lung Mass: Report of 7 Cases and Review of Literature. AB - Pulmonary cryptococcosis is commonly found in immunocompromised patients. This microorganism rarely infects immunocompetent individuals, and when it does, it causes mild symptoms. The radiological findings of this disease may involve an intrapulmonary mass that mimics lung tumor. The objective of this study was to review the clinicopathological information, radiological findings, and treatment of patients who presented with intrapulmonary mass due to cryptococcosis. This study collected data from 7 patients who were treated at Songklanagarind Hospital, Songkhla, Thailand, between 2009 and 2014. Their clinical data, radiological findings, pathological results, and treatment protocols were reviewed. The patients were 2 women and 5 men, ranging in age from 37 to 79 years old. One case was an immunocompromised host. Four cases experienced the chest symptoms of dyspnea, hemoptysis, and chronic cough. The most common location of mass was the left lower lobe (71%). Four cases had a history of bird contact. Lung lobectomy was performed in 3 cases (42%), and all of the patients were treated with oral fluconazole. An intrapulmonary mass caused by this microorganism is mainly found in immunocompetent patients. Treatment with the antifungal drug fluconazole is very effective. PMID- 28814909 TI - Increasing medical student exposure to musculoskeletal medicine: the initial impact of the Orthopaedic Surgery and Sports Medicine Interest Group. AB - PURPOSE: To investigate the impact of the Orthopaedic Surgery and Sports Medicine Interest Group (OSSMIG) on medical student interest and confidence in core musculoskeletal (MSK) concepts through supplemental education and experiences at a single tertiary, academic institution. METHODS: Medical student OSSMIG members at various levels of training were anonymously surveyed at the beginning and end of the 2014-2015 academic year. RESULTS: Eighteen (N=18) medical student interest group members completed the survey. Significant improvement in their level of training was observed with regard to respondents' self-assessed competence and confidence in MSK medicine (p<0.05). Additionally, respondents' attitudes toward exposure and support from the interest group were significantly higher than those provided by the institution (p<0.05). Members believed OSSMIG increased interest in MSK medicine, improved confidence in their ability to perform orthopedics related physical exams, strengthened mentorship with residents and attendings, and developed a connection with the Department of Orthopedic Surgery and its residents (median "Strongly Agree", interquartile range one and two scale items). CONCLUSION: Since its inception 8 years ago, OSSMIG has been well received and has positively impacted University of Washington School of Medicine students through various interventions. Surgical interest groups should target both the students interested in primary care and surgery. Medical schools can provide additional exposure to MSK medicine by leveraging interest groups that provide early clinical experiences and supplementary instruction. PMID- 28814911 TI - Four tenets of modern validity theory for medical education assessment and evaluation. AB - Validity is considered by many to be the most important criterion for evaluating a set of scores, yet few agree on what exactly the term means. Since the mid 1800s, scholars have been concerned with the notion of validity, but over time, the term has developed a variety of meanings across academic disciplines and contexts. Accordingly, when scholars with different academic backgrounds, many of whom hold deeply entrenched perspectives about validity conceptualizations, converge in the field of medical education assessment, it is a recipe for confusion. Thus, it is important to work toward a consensus about validity in the context of medical education assessment. Thus, the purpose of this work was to present four fundamental tenets of modern validity theory in an effort to establish a framework for scholars in the field of medical education assessment to follow when conceptualizing validity, interpreting validity evidence, and reporting research findings. PMID- 28814910 TI - A 15-year review of the Stanford Internal Medicine Residency Program: predictors of resident satisfaction and dissatisfaction. AB - INTRODUCTION: Satisfaction with training and with educational experiences represents important internal medicine (IM) programmatic goals. Graduates from IM residency programs are uniquely poised to provide insights into their educational and training experiences and to assess whether these experiences were satisfactory and relevant to their current employment. METHODS: We surveyed former IM residents from the training program held during the years 2000-2015 at the Department of Medicine, Stanford University. The first part of the survey reviewed the IM residency program and the second part sought identifying data regarding gender, race, ethnicity, work, relationships, and financial matters. The primary outcome was satisfaction with the residency experience. RESULTS: Of the 405 individuals who completed the Stanford IM residency program in the study period, we identified 384 (95%) former residents with a known email address. Two hundred and one (52%) former residents responded to the first part and 185 (48%) answered both the parts of the survey. The mean age of the respondents was 36.9 years; 44% were female and the mean time from IM residency was 6.1 (+/-4.3) years. Fifty-eight percent reported extreme satisfaction with their IM residency experience. Predictors associated with being less than extremely satisfied included insufficient outpatient experience, insufficient international experience, insufficient clinical research experience, and insufficient time spent with family and peers. CONCLUSION: The residents expressed an overall high satisfaction rate with their IM training. The survey results provided insights for improving satisfaction with IM residency training that includes diversifying and broadening IM training experiences. PMID- 28814912 TI - The opioid overdose epidemic: opportunities for pharmacists. PMID- 28814913 TI - Right Ventricular Remodeling and Dysfunction in Obstructive Sleep Apnea: A Systematic Review of the Literature and Meta-Analysis. AB - BACKGROUND: Recent studies have reported that obstructive sleep apnea (OSA) patients present alterations in right ventricular (RV) structure and function. However, large randomized controlled trials evaluating the impact of OSA on the right ventricle are lacking. METHODS: A comprehensive electronic database (PubMed, Web of Science, and Google Scholar) and reference search up to October 30, 2016, was performed. A systematic review and meta-analysis were performed to assess RV structure and function in OSA patients based on conventional echocardiography and tissue Doppler imaging. RESULTS: Twenty-five studies with 1,503 OSA patients and 796 controls were included in this study. OSA patients exhibited an increase in RV internal diameter (weighted mean difference (WMD) (95% confidence intervals (CIs)) 2.49 (1.62 to 3.37); p = 0.000) and RV wall thickness (WMD (95% CIs) 0.82 (0.51 to 1.13); p = 0.000). Furthermore, OSA patients had a significantly elevated RV myocardial performance index (WMD (95% CI) 0.08 (0.06 to 0.10); p = 0.000), decreased RV S' (WMD (95% CI) -0.95 (-1.59 to -0.32); p = 0.003), tricuspid annular plane systolic excursion (WMD (95% CI) 1.76 (-2.73 to -0.78); p = 0.000), and RV fractional area change (WMD (95% CI) 3.16 (-5.60 to -0.73); p = 0.011). CONCLUSION: OSA patients display RV dilatation, increased wall thickening, and altered RV function. PMID- 28814914 TI - Body Height of Children with Bronchial Asthma of Various Severities. AB - Influence of bronchial asthma (BA) severity on physical development in children patients was evaluated in comparison with healthy population. Materials and Methods. 1042 children and adolescents (768 boys) with atopic BA were evaluated. All children underwent standard examination in a clinical setting, including anthropometry. The control group included 875 healthy children of a comparable age (423 boys). Results. The fraction of patients with the normal, lower, and increased height among the whole group of patients with BA is close to the corresponding values in the healthy population (chi2 = 3.32, p = 0.65). The fraction of BA patients with the reduced physical development is increased monotonically and significantly when the BA severity increases: healthy group, 8.2% (72/875), BA intermittent, 4.2% (6/144), BA mild persistent 9% (47/520), BA moderate persistent, 11.7% (36/308), and BA severe persistent, 24.3% (17/70) (chi2 = 45.6, p = 0,0009). Conclusion. The fraction of the children with the reduced height is increased monotonically and significantly in the groups of increasing BA severities. At the same time, the fraction of such children in groups of intermittent and mild persistent BA practically does not differ from the conditionally healthy peers. PMID- 28814916 TI - Studies on the moss flora of the Bio-Bio Region of Chile: Part 3. AB - This is the final report on the moss flora of the Bio-Bio Region (Region VIII) in south-central Chile where collections were made in 2001-2003. Reported in this paper are one species new to South America, four species new to Chile and 16 species new to the Region. With these new additions the total number of taxa in the Bio-Bio Region is 343, corresponding to 331 species and 12 infraspecific taxa. A complete checklist of the mosses for all the provinces in the Region is presented. PMID- 28814915 TI - A new generic system for the pantropical Caesalpinia group (Leguminosae). AB - The Caesalpinia group is a large pantropical clade of ca. 205 species in subfamily Caesalpinioideae (Leguminosae) in which generic delimitation has been in a state of considerable flux. Here we present new phylogenetic analyses based on five plastid and one nuclear ribosomal marker, with dense taxon sampling including 172 (84%) of the species and representatives of all previously described genera in the Caesalpinia group. These analyses show that the current classification of the Caesalpinia group into 21 genera needs to be revised. Several genera (Poincianella, Erythrostemon, Cenostigma and Caesalpinia sensu Lewis, 2005) are non-monophyletic and several previously unclassified Asian species segregate into clades that merit recognition at generic rank. In addition, the near-completeness of our taxon sampling identifies three species that do not belong in any of the main clades and these are recognised as new monospecific genera. A new generic classification of the Caesalpinia group is presented including a key for the identification of genera, full generic descriptions, illustrations (drawings and photo plates of all genera), and (for most genera) the nomenclatural transfer of species to their correct genus. We recognise 26 genera, with reinstatement of two previously described genera (Biancaea Tod., Denisophytum R. Vig.), re-delimitation and expansion of several others (Moullava, Cenostigma, Libidibia and Erythrostemon), contraction of Caesalpinia s.s. and description of four new ones (Gelrebia, Paubrasilia, Hererolandia and Hultholia), and make 75 new nomenclatural combinations in this new generic system. PMID- 28814918 TI - Impatiens bokorensis (Balsaminaceae), a new species from Cambodia. AB - Impatiens bokorensis, a new species of family Balsaminaceae from Phnum Bokor National Park in southwestern Cambodia, is described and illustrated. The species is similar to Impatiens patula, but is readily distinguished by the orbicular obovate dorsal petal, shorter pedicels and larger seeds. PMID- 28814917 TI - A new species of Heliconia (Heliconiaceae) with pendent inflorescence, from Chucanti Private Nature Reserve, eastern Panama. AB - Heliconia berguidoi (Heliconiaceae), a new species from premontane forest of eastern Panama, is described, illustrated and its conservation status evaluated. Heliconia berguidoi bears pink flowers, an uncommon color in this group. It differs from the Colombian species Heliconia rhodantha and Heliconia sanctae theresae, the most similar taxa, by the combination of a petiole glabrous except for the woolly base, a very long peduncle, the perianth pubescent at the apex and staminode with cuspidate apex. Heliconia berguidoi is also similar to Heliconia pogonantha in all four of its varieties and to Heliconia ramonensis in two of its four varieties, but differs by a combination of the long peduncle, pink flowers and staminode with cuspidate apex. Fifty-six Heliconia species have been found in Panama, eighteen of them endemic. PMID- 28814919 TI - Dataset of herbarium specimens of threatened vascular plants in Catalonia. AB - This data paper describes a specimens' dataset of the Catalonian threatened vascular plants conserved in five public Catalonian herbaria (BC, BCN, HGI, HBIL and MTTE). Catalonia is an administrative region of Spain that includes large autochthon plants diversity and 199 taxa with IUCN threatened categories (EX, EW, RE, CR, EN and VU). This dataset includes 1,618 records collected from 17th century to nowadays. For each specimen, the species name, locality indication, collection date, collector, ecology and revision label are recorded. More than 94% of the taxa are represented in the herbaria, which evidence the paper of the botanical collections as an essential source of occurrence data. PMID- 28814920 TI - Garcinia hopii (Clusiaceae), a new species from Bidoup Nui Ba National Park, southern Vietnam. AB - A new species, Garcinia hopii H.Toyama & V.S.Dang is described from Bidoup Nui Ba National Park, southern Vietnam. This species is similar to Garcinia hendersoniana Whitmore but differs from that species in having larger leaves, clustered pistillate flowers, a greater number of sterile anthers and a larger stigma of young fruits. A description, preliminary conservation assessment, illustration, photographs and DNA barcodes of the new species are provided, as well as an updated key to Garcinia sect. Hebradendron in Indochina. PMID- 28814921 TI - Distribution of the invasive plant species Heracleum sosnowskyi Manden. in the Komi Republic (Russia). AB - Occurrences of the invasive plant species Heracleum sosnowskyi Manden. in the Komi Republic (northeastern part of European Russia) were recorded and published in the Global Biodiversity Information Facility (GBIF http://www.gbif.org) using the RIVR information system (http://ib.komisc.ru/add/rivr/en). RIVR stands for "Rasprostranenie Invasionnyh Vidov Rastenij" [Occurrence of Invasion Plant Species]. This citizen science project aims at collecting occurrence data about invasive plant species with the help of citizen scientists. Information can be added by any user after a simple registration (concept) process. However, the data published in GBIF are provided only by professional scientists. The total study area is approximately 19,000 km2. The GBIF resource contains 10894 Heracleum sosnowskyi occurrence points, each with their geographical coordinates and photographs of the plants in the locus of growth. The preliminary results of species distribution modelling on the territory of European North-East Russia presented. PMID- 28814922 TI - Four new synonyms and a new combination in Parnassia (Celastraceae). AB - Parnassia yunnanensis had been previously described based on mixed specimens containing materials partially belonging to Parnassia cacuminum, which makes the application of Parnassia yunnanensis ambiguous. Therefore, we lectotypified Parnassia yunnanensis and meanwhile synonymized Parnassia lanceolata var. oblongipetala under it. Parnassia yunnanensis var. longistipitata was found more similar to Parnassia cacuminum rather than Parnassia yunnanensis, thus a new combination, Parnassia cacuminum var. longistipitata comb. nov. was proposed. Furthermore, other three names (Parnassia vevusta, Parnassia degeensis and Parnassia kangdingensis) were reduced to synonyms of Parnassia cacuminum too. PMID- 28814923 TI - Nine species from Madagascar are moved from Vernonia to Distephanus (Compositae, Vernonieae). AB - The genus Distephanus is native to Madagascar, the Mauritius, central and southern Africa, Yemen (Socotra Island), and China. The majority of the diversity is found in Madagascar. Here we provide new combinations for nine species of Vernonia that belong in Distephanus, all from Madagascar. All of the species were formerly placed in the large genus Vernonia, now greatly reduced. PMID- 28814924 TI - Cousinia waldheimiana (Asteraceae) a new record from Uzbekistan (Central Asia). AB - During the study of plant specimens in the Central herbarium Academy of Sciences of Uzbekistan Institute of the gene pool of plants and animals (TASH) one new record for the flora of Uzbekistan (Cousinia waldheimiana) was identified. This species is the fourth member of Cousinia sect. Jurineopsis collected in the Uzbek part of the Northern Alay range. PMID- 28814925 TI - Morphological characteristics and genetic evidence reveals a new species of Manihot (Euphorbiaceae, Crotonoideae) from Goias, Brazil. AB - During botanical expeditions between 2010 and 2015, as part of a taxonomic study of Manihot in the Midwest region of Brazil, approximately 500 specimens of the genus were collected. Some of these specimens presented similarities to Manihot irwinii. However, after careful morphological analyses, associated with genetic evidence, we propose here Manihot pulchrifolius as a new species. The new species is described, illustrated, and compared to Manihot irwinii, its most similar species. Furthermore, geographic distribution, conservation status, and period of flowering and fruiting of the novel species are also provided. PMID- 28814926 TI - Wuchereria bancrofti infection at four primary schools and surrounding communities with no previous blood surveys in northern Uganda: the prevalence after mass drug administrations and a report on suspected non-filarial endemic elephantiasis. AB - BACKGROUND: A prevalence study of Wuchereria bancrofti infection was carried out in 2014 at 4 study sites in northern Uganda using antigen and microfilaria tests. Each study site consists of a primary school and surrounding communities. These sites are inside the filariasis endemic area and have been covered by mass drug administration under the national elimination programme. However, no prevalence study had been conducted there before the present study. Without information on past and present endemicity levels, our study was meant to be an independent third-party investigation to know the latest filariasis situation. RESULTS: A total of 982 people including 570 schoolchildren (7-19 years) and 412 community people (7-25 years) were examined, all of them for filarial antigen and 695 for microfilariae. The study revealed that all subjects were negative by both methods. CONCLUSIONS: It was considered that annual mass drug administrations together with anti-malarial activities such as indoor residual spraying had contributed to the reduction of the filarial infection. However, based on the past data obtained near our study sites, we cannot exclude the possibility that filarial prevalence rates in our study sites were very low or even zero originally. During the study, we encountered several patients with lower leg edema and pachydermic (elephant skin-like), mossy skin lesion of the foot. Judging from clinical features and bare-footed life-style of people in the area, non-filarial elephantiasis, possibly podoconiosis, was suspected. This elephantiasis has been reported in areas where filariasis is not endemic. PMID- 28814927 TI - Weight Loss Supplements: Boon or Bane? AB - Dietary health supplements for weight loss seem to be the future nowadays. However, this industry is plagued by lack of regulations and ignorance regarding the constituents of the supplements. Of all the supplements consumed, the ones for weight loss are most commonly found in the market. Reports of liver failure, kidney impairment and worsening of chronic ailments in patients who consume these supplements are surfacing recently which make us question the credibility of these products. The safety of these products lie in the clear stating of the ingredients by the manufacturer, well informed patient, knowledgeable physician and tight regulations from the regulatory board. PMID- 28814928 TI - Love as a Modulator of Pain. AB - Pain is modulated by various factors, the most notable of which is emotions. Since love is an emotion, it can also modulate pain. The answer to the question of whether it enhances or reduces pain needs to be determined. A review was conducted of animal and human studies in which this enigmatic emotion and its interaction with pain was explored. Recent advances in neuroimaging have revealed similarities in brain activation relating to love and pain. At the simplest level, this interaction can be explained by the overlapping network structure in brain functional connectivity, although the explanation is considerably more complex. The effect of love can either result in increased or decreased pain perception. An explanation of the interaction between pain and love relates to the functional connectivity of the brain and to the psychological construct of the individual, as well as to his or her ability to engage resources relating to emotion regulation. In turn, this determines how a person relates to love and reacts to pain. PMID- 28814929 TI - In Vitro Cytotoxic and Anticancer Effects of Zamzam Water in Human Lung Cancer (A594) Cell Line. AB - BACKGROUND: Zamzam water is naturally alkaline and rich in a variety of minerals which may represent a powerful tool for cancer therapy. In this research, the cytotoxic effects of Zamzam water were investigated in human lung cancer (A549) cell line and compared with human skin fibroblasts (HSF). METHODS: Two different preparations of Zamzam water were used: Z1, with pH adjusted to 7.2 and Z2, with no pH adjustment. The effects of both treatments on the morphology of the A549 and HSF cell lines were investigated. The cell viability of HSF and A549 cells was identified by the MTT assay and trypan blue exclusion. Detection of apoptotic cells and cell cycle analyses were determined using flow cytometry. Moreover, reactive oxygen species (ROS) were measured for both cell lines. RESULTS: Both Zamzam water treatments, Z1 and Z2 showed reductions in the cell viability of A549 cells. Cell death occurred via necrosis among cells treated with Z2. Cell cycle arrest occurred in the G0/G1 phases for cells treated with Z2. Cellular and mitochondrial ROS productions were not affected by either treatment. CONCLUSION: Our findings indicate that Zamzam water might have potential therapeutic efficacy for lung cancer. PMID- 28814930 TI - Comparing Lavage of the Peritoneal Cavity with Lidocaine, Bupivacaine and Normal Saline to Reduce the Formation of Abdominal Adhesion Bands in Rats. AB - BACKGROUND: Intra-abdominal adhesions are fibrous bands that develop after abdominal surgery or inflammation and cause mortality and morbidity following surgeries. This study aimed to assess the effects of bupivacaine, saline and two doses of lidocaine, after peritoneal lavage and to compare their effects in reducing abdominal adhesions in rat. METHODS: In a blinded, randomised, placebo controlled clinical trial, 50 female rats were anaesthetised and the parietal peritoneum was scratched to induce punctate bleeding. The rats were randomly assigned to five groups: saline, lidocaine 2% (3 and 6 mg/kg), bupivacaine 0.25% (2 mg/kg) and control (no irrigation). The peritoneal cavity was irrigated with the appropriate solution during laparotomy. Two weeks later, re-laparotomy was performed. The quantity, quality, severity and scores of adhesions were recorded and compared. RESULTS: The quantity and quality of adhesions were significantly higher in the control group than in the lidocaine (6 mg/kg) and bupivacaine groups. The quality of the adhesions was higher in the normal saline group than in the lidocaine (6 mg/kg) and bupivacaine groups. The severity of adhesions between the lidocaine 3 and 6 mg/kg groups and between the lidocaine 3 mg/kg and saline groups was lower than that in the control group. CONCLUSION: Using lidocaine (6 mg/kg) and bupivacaine lavage in first laparotomy reduces abdominal peritoneal obstruction because of the formation of adhesion bands. PMID- 28814931 TI - Prediction of Histological Grade and Completeness of Resection of Intracranial Meningiomas: Role of Peritumoural Brain Edema. AB - BACKGROUND: Meningioma is the commonest primary intracranial tumour in adults. Excision is curative for low grade meningioma, whereas high-grade meningioma requires adjuvant therapy following surgery. Several studies have examined the association between peritumoural brain Edema - a common feature in meningioma - and histological grading with mixed results. The present study attempted to elucidate this association and if peritumoural brain Edema affects the intra operative judgement of surgeons on the completeness of resection. METHODS: An observational study was conducted among those who underwent surgery for meningioma. Eighteen subjects were recruited each for low- and high-grades, respectively. Magnetic resonance imaging (MRI) prior to surgery was employed for interpreting the Edema index and MRI after surgery was used to determine residual tumour. RESULTS: Median age was 50 years, male to female ratio was 1:3.5, 69.4% had peritumoural brain Edema and 75% had reported gross resection. Among the reported gross total resection cases, 40.7% had residual tumour. Analysis showed statistically significant association between peritumoural brain Edema (P = 0.027) and tumour volume (P = 0.001) with high-grade meningioma, however multivariate analysis did not present any association. No association was noted between judgement of tumour resection by surgeons and peritumoural brain Edema. CONCLUSION: Odds ratio for peritumoural brain Edema remained high and the tumour volume exhibited marginal P-value marginal significance for prediction of high grade meningioma. These two factors may still contribute to the tumour grade and should be included in further studies on the prognosis of meningioma. PMID- 28814932 TI - Achievement of LDL Cholesterol Goal and Adherence to Statin by Diabetes Patients in Kelantan. AB - BACKGROUND: Statins are a class of potent drugs that can be used to reduce cholesterol, especially low-density lipoprotein cholesterol (LDL-C). However, their effectiveness is limited if adherence to treatment is poor. The objectives of the study are to estimate the proportion of diabetic patient who has achieved LDL-C goal and to determine the association of LDL-C achievement with socio demographic factors and statin therapy adherence. METHODS: This is a cross sectional study involving 234 patients with type 2 diabetes mellitus (T2DM) and dyslipidaemia attending an outpatient clinic in a hospital in Kelantan. Interviews and self-administered questionnaires were used to determine their sociodemographic and clinical characteristics. Adherence to therapy was assessed using the Medication Compliance Questionnaire (MCQ). The associations between the achievement of LDL targets and sociodemographic/clinical factors, including adherence, were analysed with simple logistic regression. RESULTS: About 37.6% of patients achieved their LDL-C target. The percentage of patients who adhered to statin use was 98.3%, and 20.5% of these patients reported full adherence. There was no significant association between achievement of LDL-C targets with adherence or any other sociodemographic factors, such as age, gender and educational or economic status (all P-value < 0.05). CONCLUSION: Despite a high level of adherence, the majority of patients failed to achieve LDL-C targets. More concerted efforts are needed to improve this. PMID- 28814933 TI - Inflammatory Biomarkers and Their Value in Predicting Survival and Outcome among Patients with Spontaneous Intracerebral Haemorrhage. AB - BACKGROUND: Spontaneous intracerebral haemorrhage (SICH) has emerged as one of the most devastating forms of stroke in recent decades. This disease is noted to carry a 30-day mortality rate of approximately 45%. An increasing number of studies have implicated a complex immune-mediated and inflammation-mediated cascade of responses in the pathophysiology of SICH and the resultant neurologic outcome. Several clinical studies have demonstrated an association between inflammatory markers and outcome in patients with SICH. However, the exact relationship between serum biomarkers and functional outcomes amongst survivors has not been clearly elucidated. This study aimed to evaluate the changes in peripheral leukocyte count (WBC count) and C-reactive protein (CRP) levels in patients with SICH and to correlate these findings with survival and functional outcome. METHODOLOGY: A prospective, descriptive and correlational study was conducted at Sarawak General Hospital (SGH) over the span of two years (April 2013-April 2015). Patients aged between 30 years and 75 years with supratentorial intracerebral bleed secondary to uncontrolled hypertension were recruited in this study. Data pertaining to the demography, clinical and radiological parameters, peripheral WBC count and CRP levels were obtained. Mortality and functional outcomes were determined at 6 months post ictus. Patients were recruited following the fulfilment of exclusion and inclusion criteria, and all obtained data were analysed with the Statistical Package for Social Sciences (SPSS) for Windows version 21.0. RESULTS: A total of 60 patients with a mean age of 56 years were recruited in this study. We found that approximately 16 patients were less than or equal to 50 years old (26.7%) and that 44 patients belonged to the older age group of above 50 years (73.3%). The Glasgow Coma Scale (GCS) score on admission ranged from 9 to 14/15 with a median value of 11/15. The mean clot volume was 20.1 cm3. The GCS score on admission and clot volume were significantly associated with the Glasgow Outcome Scale (GOS) at 6 months and overall survival (P < 0.05). The elevated WBC count and CRP level on admission and at 72 hours post admission were significantly associated with GOS at 6 months and overall survival (P < 0.05). Thus, the GCS score, clot volume, WBC count and CRP levels on admission and at 72 hours post admission can be used to predict functional outcome at 6 months and overall survival in patients with SICH. CONCLUSION: We could conclude via this study that for patients with SICH, the main determinants or predictors of functional outcome at 6 months and overall survival were noted to be the GCS score on admission, clot size, WBC count and CRP levels on admission and at 72 hours post admission. PMID- 28814934 TI - Direct Medical Costs of Dengue Fever in Vietnam: A Retrospective Study in a Tertiary Hospital. AB - BACKGROUND: In Vietnam, dengue fever is a major health concern, yet comprehensive information on its economic costs is lacking. The present study investigated treatment costs associated with dengue fever from the perspective of health care provision. METHODS: This retrospective study was conducted between January 2013 and December 2015 in Cu Chi General Hospital. The following dengue-related treatment costs were calculated: hospitalisation, diagnosis, specialised services, drug usage and medical supplies. Average cost per case and treatment cost across different age was calculated. RESULTS: In the study period, 1672 patients with dengue fever were hospitalised. The average age was 24.98 (SD = 14.10) years, and 47.5% were males (795 patients). Across age groups, the average cost per episode was USD 48.10 (SD = 3.22). The highest costs (USD 56.61, SD = 48.84) were incurred in the adult age group (> 15 years), and the lowest costs (USD 30.10, SD = 17.27) were incurred in the paediatric age group (< 15 years). CONCLUSION: The direct medical costs of dengue-related hospitalisation place a severe economic burden on patients and their families. The probable economic value of dengue management in Vietnam is significant. PMID- 28814935 TI - Knowledge and Attitude of Dental Students towards HIV/AIDS Patients in Melaka, Malaysia. AB - BACKGROUND: Cross contamination of HIV is a real threat today. Dental treatment often includes direct contact with a patient's blood and saliva, therefore dental professionals can be easily exposed to HIV microorganisms. Hence, it is essential to gain insight into dental students' knowledge and attitude towards HIV patients. METHOD: A cross-sectional survey of 186 clinical year dental students (year 3, 4 and 5) in the 2015-2016 academic session at the Faculty of Dentistry, Melaka-Manipal Medical College (MMMC), Manipal University, Melaka volunteered to participate in the study. A self-administered questionnaire was used to determine their knowledge and attitude towards HIV/AIDS patients. RESULTS: Among 137 respondents (females 74.5% and males 25.6%), 40.9% were Malay, 46.7% were Chinese, 10.2% were Indian and 2.2% were others. The majority had an excellent (41.6%) to good (56.2%) knowledge and only (18%) had a professional attitude. There was a statistically significant association of knowledge with gender (P = 0.009) and ethnicity (P = 0.024), However, no association was found between attitude and gender (P = 0.756) or ethnicity (P = 0.792), or between knowledge and attitude (P = 0.473) of dental students. CONCLUSION: Dental students' knowledge was not significantly associated with attitude. However, knowledge was associated with gender and ethnicity, but no association was found between age and knowledge and between age, gender, or ethnicity and attitude. PMID- 28814936 TI - Development and Validation of a Coping Scale for Caregivers in Malaysia. AB - INTRODUCTION: Caregivers often experience stressful situations while in the midst of the caregiving process. Thus, various methods of coping have been widely applied and studied in previous researches. The aim of this study was to develop a novel questionnaire to assess the coping strategies employed by those who provide care to patients, and to further validate it among caregivers of schizophrenia patients in Malaysia. METHODS: This study, which involved the caregivers of schizophrenia patients from a hospital in Kuala Lumpur, Malaysia, was comprised of three parts, namely in-depth interviews, a pilot study, and the validation of the developed questionnaire, known as Caregiver Cope (CgCopeTM). RESULTS: Part A originally consisted of eight themes, and it was later modified to seven themes with four items each after discussions with some experts. Part B initially had 28 items derived from the seven themes in Part A, which were then reduced to six components after a factor analysis. Part C of the questionnaire consisted of 19 items, with six components (Distraction, Caring for patient, Venting, Religion, Recreation, and Social support) having a moderate to high reliability ranging from a Cronbach's alpha coefficient of 0.54 to 0.82. A factor analysis showed that the six factors of coping accounted for 62.36% of the total variance. CONCLUSION: The CgCOPETM questionnaire is suitable for use among caregivers of schizophrenia patients. There is a need to further validate the instrument among caregivers of other patient populations. PMID- 28814937 TI - Compound Odontoma in Anterior Mandible-A Case Report. AB - Odontomas are the most common odontogenic hamartomas worldwide. Depending on the level of organisation of the tissues inside, these can be differentiated into compound type or complex type. As these are asymptomatic and do not cause any changes in the bone, they are often diagnosed during the routine dental examination. Complex odontomas are commonly found to occur in posterior mandible while compound odontomas are found in the anterior maxilla. A nine-year-old female child reported for a routine dental check-up, when a missing left permanent mandibular lateral incisor [32] was noticed. Further investigations revealed compound odontoma and unerupted 32, which is an unusual location. Early detection of these tumours is essential to avoid lengthy corrective treatments. PMID- 28814939 TI - Acute Rehabilitation in Traumatic Brain Injury. PMID- 28814938 TI - Superior Mesenteric Artery Syndrome in association with Abdominal Tuberculosis: An Eye Opener. AB - Superior Mesenteric Artery Syndrome (SMAS) is a rare clinical entity presenting as acute or chronic upper gastrointestinal obstruction. It occurs due to compression of third part of duodenum between abdominal aorta and overlying superior mesenteric artery caused by a decrease in angle between the two vessels. Rapid loss of retroperitoneal fat, in conditions leading to severe weight loss is the main factor responsible for this disorder. Superior mesenteric artery syndrome in association with abdominal tuberculosis has not been reported earlier to the best of our knowledge. Therefore, an unknown cause (SMAS) of upper gastrointestinal obstruction in a patient of abdominal tuberculosis is being presented for the first time through this case report. An imaging diagnosis of SMAS was made on contrast enhanced CT abdomen which also confirmed the clinical suspicion of abdominal tuberculosis in the patient. The patient was managed conservatively and recovered without requiring any surgical intervention for the obstructive symptoms. PMID- 28814940 TI - Cardiac health knowledge and misconceptions among nursing students: implications for nursing curriculum design. AB - BACKGROUND: Cardiac misconceptions are common among healthcare professionals. The development of professional knowledge is considered an essential component of nursing education. Nurses, regardless of their grade, skills, and experience, should be updated with information so as to be able to rectify their misconceptions, as these could affect patient health outcomes. As the literature evaluating the cardiac knowledge and misconceptions of nursing students is sparse, a study of the subject seems warranted. METHODS: A cross-sectional sample survey was used to study the cardiac knowledge and cardiac misconceptions of nursing students in Hong Kong. The study sample included 385 senior nursing students from three universities. Their level of knowledge of cardiac disease was assessed using the modified Coronary Heart Disease Knowledge Test. The York Cardiac Beliefs Questionnaire (YCBQv1) was used to examine cardiac misconceptions. RESULTS: The scores for the nursing students' level of knowledge were diverse. Their mean score in the Cardiac Knowledge Test was 12.27 out of 18 (SD 2.38), with a range of 2-17. For cardiac misconceptions, their mean score in the YCBQv1 was 6.98 out of 20 (SD 2.84), with a range of 0-14. A negative correlation, r = -0.33 was found among students with more knowledge and fewer misconceptions. (p < 0.001). The Chi-square tests found some associations between the students' experiences of caring for cardiac patients and misconceptions about stress and physiology. CONCLUSIONS: The results of our analyses indicate a diversity in levels of knowledge among the nursing students. Students with higher scores in cardiac knowledge did not necessarily have fewer misconceptions. There were associations between the students' misbeliefs and their caregiving experiences with cardiac patients. This study presents a framework for designing the contents of cardiac nursing programmes and is a starting point for promoting research on misconceptions held by undergraduate nursing students. A new paradigm of teaching should include inputs from both perspectives to help students to make critical use of theoretical knowledge to rectify their misconceptions and pursue excellence in the working world. PMID- 28814941 TI - A survey on the perception of allergy specialists about the reimbursed grass pollen tablets for seasonal allergic rhinitis in Italy. AB - BACKGROUND: Sublingual immunotherapy (SLIT) is a feasible option to classical subcutaneous immunotherapy to treat respiratory allergy and is increasingly prescribed in Europe. However, the lack of reimbursement may limit its prescription. In 2015, the 5-grass pollen tablets was authorized by the European Medicine Agency to treat grass-pollen induced rhinitis and was approved in Italy for full reimbursement. We evaluated the opinions of allergy specialists after the availability of the reimbursed 5-grass pollen tablets. METHODS: A multiple choice questionnaire composed by six questions was used to assess the specialists opinion. The questionnaire was uploaded on the free access online platform SurveyMonkey. The link to access the platform was sent to all members of the Societa Italiana di Asma, Allergologia e Immunologia Clinica (SIAAIC). The access to the questionnaire was anonymous. At survey ending, the access was closed and data were downloaded directly from SurveyMonkey website. RESULTS: The questionnaire was filled by 70 allergists. The majority of allergists felt as most important the concept of SLIT as a drug, the content of allergen extract mirroring the natural exposure, the pre-coseasonal schedule as the most patient's oriented, the very good profile of tolerability and safety, the importance of the build-up phase, and the importance of checking the patient after starting immunotherapy. CONCLUSIONS: The opinions of the Italian allergy specialists about the reimbursed 5-grass-pollen tablets are very positive and make likely an appropriate prescription of SLIT for grass-pollen induced rhinitis in the next years. PMID- 28814942 TI - Awareness of venous thromboembolism and thromboprophylaxis among hospitalized patients: a cross-sectional study. AB - BACKGROUND: Patient awareness of venous thromboembolism (VTE) and thromboprophylaxis is essential for their safety. In this study, we evaluated patients' awareness of VTE and their perceptions of thromboprophylaxis. METHODS: We administered a cross-sectional survey to patients hospitalized at the King Abdulaziz Medical City, Riyadh, Saudi Arabia. RESULTS: Of 190 patients approached, 174 completed the survey, constituting a response rate of 95%. Most participants (72%) were receiving thromboprophylaxis. However, only 32 and 15% reported knowledge of deep vein thrombosis (DVT) and pulmonary embolism (PE), respectively. Fifty-five percent of participants with knowledge of DVT identified swelling of the leg as a symptom. Risk factors for blood clot development were correctly identified by about half of participants, although most agreed that blood clots can cause death (77%). The level of awareness of DVT or PE did not significantly differ by respondents' demographics. However, awareness of DVT or PE was significantly higher among those with a personal or family history of VTE. Participants had positive perceptions of thromboprophylaxis and were satisfied with treatment (> 69%), but perceived its adverse effects less favorably and reported lower satisfaction with the information provided about DVT and PE (46%). CONCLUSION: This study demonstrates the lack of awareness of VTE, DVT, and PE among hospitalized patients. More attention must be paid to patient education to ensure safe and high-quality patient care. PMID- 28814943 TI - Comparison of different laboratory tests in the evaluation of hemorrhagic risk of patients using rivaroxaban in the critical care setting: diagnostic accuracy study. AB - BACKGROUND: Rivaroxaban is a direct oral anticoagulant designed to dispense with the necessity of laboratory monitoring. However, monitoring rivaroxaban levels is necessary in certain clinical conditions, especially in the critical care setting. METHODS: This is a diagnostic accuracy study evaluating sensitivity and specificity of prothrombin time (PT), activated partial thromboplastin time (aPTT), and Dilute Russell viper venom time (dRVVT), to evaluate the hemorrhagic risk in patients taking rivaroxaban. The study used a convenience sample of 40 clinically stable patients using rivaroxaban to treat deep vein thrombosis or atrial fibrillation admitted in a private hospital in Brazil, compared to a group of 60 healthy controls. The samples from patients were collected two hours after the use of the medication (peak) and two hours before the next dose (trough). RESULTS: The correlation with the plasmatic concentration measured by anti-FXa assay was higher for PT and dRVVTS. The PT and aPTT tests presented higher specificity, while dRVVT was 100% sensible. CONCLUSIONS: There was a strong correlation between the tests and the plasma concentration of the drug. Additionally, our results demonstrated the potential use of dRVVT as a screening test in the emergency room and the need of a second test to improve specificity. PMID- 28814944 TI - Cell Counting and Viability Assessment of 2D and 3D Cell Cultures: Expected Reliability of the Trypan Blue Assay. AB - BACKGROUND: Whatever the target of an experiment in cell biology, cell counting and viability assessment are always computed. The Trypan Blue (TB) assay was proposed about a century ago and is still the most widely used method to perform cell viability analysis. Furthermore, the combined use of TB with a haemocytometer is also considered the standard approach to estimate cell population density. There are numerous research articles reporting the use of TB assays to compute cell number and viability of 2D and 3D cultures. However, the literature still lacks studies regarding the reliability of the TB assay in terms of assessment of its repeatability and reproducibility. METHODS: We compared the TB assay's measurements obtained by two biologists who analysed 105 different samples in double-blind for a total of 210 counts performed. We measured: (a) the repeatability of the count performed by the same operator; (b) the reproducibility of counts performed by the two operators. RESULTS: There were no significant differences in the results obtained with 2D and 3D cell cultures: we estimated an approximate variability of 5% when the TB assay was used to assess the viability of the culture, and a variability of around 20% when it was used to determine the cell population density. CONCLUSIONS: The main aim of this study was to make researchers aware of potential measurement errors when TB is used with a haemocytometer for counting and viability measurements in 2D and 3D cultures. We believe that these results can help researchers to determine whether the expected reliability of the TB assay is compliant with their applications. PMID- 28814945 TI - Glomerular abundance of complement proteins characterized by proteomic analysis of laser-captured microdissected glomeruli associates with progressive disease in IgA nephropathy. AB - BACKGROUND: The clinical course of IgA nephropathy (IgAN) is variable and complement activation may predict prognosis. The present study investigated whether glomerular abundance of complement proteins associates with progression to end-stage renal disease (ESRD) in patients for whom prognosis could not be predicted based on clinical variables. METHODS: Based on data from the Norwegian Kidney Biopsy Registry and the Norwegian Renal Registry, three groups were included: IgAN patients with (n = 9) or without (n = 16) progression to ESRD during 10 years, and controls (n = 15) with a normal kidney biopsy. IgAN patients had eGFR > 45 ml/min/1.73 m2 and non-nephrotic proteinuria at time of biopsy. Using stored formalin-fixed paraffin embedded kidney biopsy tissue, about 100 glomerular cross sections were microdissected for each patient. Samples were analyzed by liquid chromatography-tandem mass spectrometry and relative abundances of complement proteins were compared between groups. RESULTS: Proteomic analyses quantified 2018 proteins, of which 28 proteins belong to the complement system. As compared to IgAN patients without progressive disease, glomeruli from patients with progressive IgAN had significantly higher abundance of components of the classical and the terminal complement pathways, and inhibitory factors such as Factor H and factor H related proteins. Abundance of complement proteins classified progressors from non-progressors with an area under ROC curve of 0.91 (p = 0.001). Clinical and morphological data were similar between the two patient groups and could not predict progressive IgAN. CONCLUSIONS: In conclusion, higher glomerular abundance of complement proteins was associated with a progressive clinical course in IgAN and are candidate biomarkers to predict prognosis. PMID- 28814947 TI - Preserving the Anti-Scientific Linear No-Threshold Myth: Authority, Agnosticism, Transparency, and the Standard of Care. AB - The linear no-threshold (LNT) assumption is over 70 years old and holds that all ionizing radiation exposure leaves cumulative effects, all of which are harmful regardless of how low the dose or dose rate is. The claimed harm centers on the risk of future radiogenic cancer. This has been shown countless times to be fallacious, and hundreds of scientific studies-both experimental and observational/epidemiological-demonstrate that at low enough doses and dose rates, ionizing radiation stimulates an evolved adaptive response and therefore is beneficial to health, lowering rather than raising the risk of cancer. Yet the myth of uncorrected lifetime cumulative risk still pervades the field of radiation science and underlies the policies of virtually all regulatory agencies around the world. This article explores some of the motivations behind, and methods used to assure, the extreme durability of the LNT myth in the face of the preponderance of contrary evidence and the manifest harms of radiophobia. These include subservience to the voice of authority, tactics such as claiming agnosticism on behalf of the entire field, transparent references to contrary evidence while dismissing the findings without refutation, and seeking shelter behind the legally protective medical standard of care. PMID- 28814946 TI - Protein signatures of molecular pathways in non-small cell lung carcinoma (NSCLC): comparison of glycoproteomics and global proteomics. AB - BACKGROUND: Non-small cell lung carcinoma (NSCLC) remains the leading cause of cancer deaths in the United States. More than half of NSCLC patients have clinical presentations with locally advanced or metastatic disease at the time of diagnosis. The large-scale genomic analysis of NSCLC has demonstrated that molecular alterations are substantially different between adenocarcinoma (ADC) and squamous cell carcinoma (SqCC). However, a comprehensive analysis of proteins and glycoproteins in different subtypes of NSCLC using advanced proteomic approaches has not yet been conducted. METHODS: We applied mass spectrometry (MS) technology featuring proteomics and glycoproteomics to analyze six primary lung SqCCs and eleven ADCs, and we compared the expression level of proteins and glycoproteins in tumors using quantitative proteomics. Glycoproteins were analyzed by enrichment using a chemoenzymatic method, solid-phase extraction of glycopeptides, and quantified by iTRAQ-LC-MS/MS. Protein quantitation was further annotated via Ingenuity Pathway Analysis. RESULTS: Over 6000 global proteins and 480 glycoproteins were quantitatively identified in both SqCC and ADC. ADC proteins (8337) consisted of enzymes (22.11%), kinases (5.11%), transcription factors (6.85%), transporters (6.79%), and peptidases (3.30%). SqCC proteins (6967) had a very similar distribution. The identified glycoproteins, in order of relative abundance, included membrane (42%) and extracellular matrix (>33%) glycoproteins. Oncogene-coded proteins (82) increased 1.5-fold among 1047 oncogenes identified in ADC, while 124 proteins from SqCC were up-regulated in tumor tissues among a total of 827 proteins. We identified 680 and 563 tumor suppressor genes from ADC and SqCC, respectively. CONCLUSION: Our systematic analysis of proteins and glycoproteins demonstrates changes of protein and glycoprotein relative abundance in SqCC (TP53, U2AF1, and RXR) and in ADC (SMARCA4, NOTCH1, PTEN, and MST1). Among them, eleven glycoproteins were upregulated in both ADC and SqCC. Two glycoproteins (ELANE and IGFBP3) were only increased in SqCC, and six glycoproteins (ACAN, LAMC2, THBS1, LTBP1, PSAP and COL1A2) were increased in ADC. Ingenuity Pathway Analysis (IPA) showed that several crucial pathways were activated in SqCC and ADC tumor tissues. PMID- 28814948 TI - Synthesis, Characterization, Cytotoxic Activity, and Interactions with CT-DNA and BSA of Cationic Ruthenium(II) Complexes Containing Dppm and Quinoline Carboxylates. AB - The complexes cis-[Ru(quin)(dppm)2]PF6 and cis-[Ru(kynu)(dppm)2]PF6 (quin = quinaldate; kynu = kynurenate; dppm = bis(diphenylphosphino)methane) were prepared and characterized by elemental analysis, electronic, FTIR, 1H, and 31P{1H} NMR spectroscopies. Characterization data were consistent with a cis arrangement for the dppm ligands and a bidentate coordination through carboxylate oxygens of the quin and kynu anions. These complexes were not able to intercalate CT-DNA as shown by circular dichroism spectroscopy. On the other hand, bovine serum albumin (BSA) binding constants and thermodynamic parameters suggest spontaneous interactions with this protein by hydrogen bonds and van der Waals forces. Cytotoxicity assays were carried out on a panel of human cancer cell lines including HepG2, MCF-7, and MO59J and one normal cell line GM07492A. In general, the new ruthenium(II) complexes displayed a moderate to high cytotoxicity in all the assayed cell lines with IC50 ranging from 10.1 to 36 uM and were more cytotoxic than the precursor cis-[RuCl2(dppm)2]. The cis [Ru(quin)(dppm)2]PF6 were two to three times more active than the reference metallodrug cisplatin in the MCF-7 and MO59J cell lines. PMID- 28814949 TI - Physicians' views on the role of smoking in smoking-related diseases: findings from cross-sectional studies from 1982-2014 in Estonia. AB - BACKGROUND: Previous reports have shown that physicians who smoke underestimate the effects of smoking on health and this influences their practice. This study was designed to investigate the views of Estonian physicians on the role of smoking in smoking-related diseases. METHODS: Cross-sectional postal surveys were sent to all practising physicians in Estonia in 1982, 2002 and 2014 providing data from 3504, 2694, and 2865 physicians respectively. Data analysis involved calculation of the prevalence of smoking with 95% confidence intervals and calculation of the prevalence of agreement with a causal role of smoking in ischaemic heart disease (IHD), lung cancer and chronic bronchitis. Logistic regression was used to analyse associations between agreement with the statements that smoking is a cause of IHD, lung cancer, chronic bronchitis and study year, smoking status, age group and ethnicity. Fully adjusted odds ratios with 95% confidence intervals were calculated. RESULTS: The age-standardized prevalence of current smoking among men decreased from 39.6% in 1982 to 14.2% in 2014, and among women from 12.4 to 5.1%, respectively. Compared with 1982, the proportion of physicians agreeing with statements that smoking is a major cause or one of the causes of IHD, lung cancer, or chronic bronchitis was significantly higher in 2002 and 2014. Past and never smokers were more likely to admit a causal role of smoking in lung cancer than smokers. Agreement with a causal role of smoking in IHD and chronic bronchitis was significantly higher among never and past smoking women only. Compared with non-Estonians, the odds ratio indicating agreement with all three statements was significantly higher among Estonians. CONCLUSION: From 1982 to 2014, physicians' attitudes towards the health risks of smoking improved in Estonia. However, their assessment of a causal role of smoking in smoking related diseases was related to their own smoking habits and ethnicity. A further decline in smoking among Estonian physicians would require special efforts targeted at physicians. Societal pressure from a national policy could support a further decline in the social acceptability of smoking in Estonia and developments in medical education could provide continuing evidence-based information about the effects of smoking to Estonian physicians. PMID- 28814951 TI - Optimal formulations of local foods to achieve nutritional adequacy for 6-23 month-old rural Tanzanian children. AB - Background: Achieving nutritional goals of infants and young children while maintaining the intake of local and culture-specific foods can be a daunting task. Diet optimisation using linear goal programming (LP) can effectively generate optimal formulations incorporating local and culturally acceptable foods. Objective: The primary objective of this study was to determine whether a realistic and affordable diet that achieves dietary recommended intakes (DRIs) for 22 selected nutrients can be formulated for rural 6-23-month-old children in Tanzania. Design: Dietary intakes of 400 children aged 6-23 months were assessed using a weighed dietary record (WDR), 24-hour dietary recalls and a 7-days food record. A market survey was also carried out to estimate the cost per 100 g of edible portion of foods that are commonly consumed in the study area. Dietary and market survey data were then used to define LP model parameters for diet optimisation. All LP analyses were done using linear program solver (LiPS) version 1.9.4 to generate optimal food formulations. Results: Optimal formulations that achieved DRIs for 20 nutrients for children aged 6-11 months and all selected nutrients for children aged 12-23 months were successfully developed at a twofold cost of the observed food purchase across age groups. Optimal formulations contained a mixture of ingredients such as wholegrain cereals, Irish potatoes, pulses and seeds, fish and poultry meat as well as fruits and vegetables that can be sourced locally. Conclusions: Our findings revealed that given the available food choices, it is possible to develop optimal formulations that can improve dietary adequacy for rural 6-23-month-old children if food budget for the child's diets is doubled. These findings suggest the need for setting alternative interventions which can help households increase access to nutrient-dense foods that can fill the identified nutrient gaps. PMID- 28814950 TI - Morinda citrifolia L. leaf extract prevent weight gain in Sprague-Dawley rats fed a high fat diet. AB - Background: Morinda citrifolia L. is widely used as a folk medicinal food plant to manage a panoply of diseases, though no concrete reports on its potential anti obesity activity. This study aimed to evaluate the potential of M. citrifolia leaf extracts (MLE60) in the prevention of weight gain in vivo and establish its phytochemical profile. Design: Male Sprague-Dawley rats were divided into groups based on a normal diet (ND) or high fat diet (HFD), with or without MLE60 supplementation (150 and 350 mg/kg body weight) and assessed for any reduction in weight gain. Plasma leptin, insulin, adiponectin, and ghrelin of all groups were determined. 1H NMR and LCMS methods were employed for phytochemical profiling of MLE60. Results: The supplementation of MLE60 did not affect food intake indicating that appetite suppression might not be the main anti-obesity mechanism involved. In the treated groups, MLE60 prevented weight gain, most likely through an inhibition of pancreatic and lipoprotein activity with a positive influence on the lipid profiles and a reduction in LDL levels . MLE60 also attenuated visceral fat deposition in treated subjects with improvement in the plasma levels of obesity-linked factors . 1Spectral analysis showed the presence of several bioactive compounds with rutin being more predominant. Conclusion: MLE60 shows promise as an anti-obesity agents and warrants further research. PMID- 28814952 TI - Regulative effects of curcumin spice administration on gut microbiota and its pharmacological implications. AB - Curcumin, the major active component of turmeric (Curcuma longa), is widely used as a spice and food-coloring agent, and also exhibits multiple biological activities. However, as curcumin has poor systemic bioavailability its pharmacology remains to be elucidated. Owing to the high concentration of curcumin in the gastrointestinal tract after oral administration, we hypothesize that it may exert regulative effects on the gut microbiota. We investigated the regulative effects of oral curcumin administration on the gut microbiota of C57BL/6 mice and found that curcumin significantly affected the abundance of several representative families in gut microbial communities, including Prevotellaceae, Bacteroidaceae, and Rikenellaceae. Considering the pathogenic associations between gut microbiota and many diseases, the present findings may help us to interpret the therapeutic benefits of curcumin. PMID- 28814954 TI - Intrinsic Osteoinductivity of Porous Titanium Scaffold for Bone Tissue Engineering. AB - Large bone defects and nonunions are serious complications that are caused by extensive trauma or tumour. As traditional therapies fail to repair these critical-sized defects, tissue engineering scaffolds can be used to regenerate the damaged tissue. Highly porous titanium scaffolds, produced by selective laser sintering with mechanical properties in range of trabecular bone (compressive strength 35 MPa and modulus 73 MPa), can be used in these orthopaedic applications, if a stable mechanical fixation is provided. Hydroxyapatite coatings are generally considered essential and/or beneficial for bone formation; however, debonding of the coatings is one of the main concerns. We hypothesised that the titanium scaffolds have an intrinsic potential to induce bone formation without the need for a hydroxyapatite coating. In this paper, titanium scaffolds coated with hydroxyapatite using electrochemical method were fabricated and osteoinductivity of coated and noncoated scaffolds was compared in vitro. Alizarin Red quantification confirmed osteogenesis independent of coating. Bone formation and ingrowth into the titanium scaffolds were evaluated in sheep stifle joints. The examinations after 3 months revealed 70% bone ingrowth into the scaffold confirming its osteoinductive capacity. It is shown that the developed titanium scaffold has an intrinsic capacity for bone formation and is a suitable scaffold for bone tissue engineering. PMID- 28814953 TI - In vitro characterization of jellyfish venom fibrin(ogen)olytic enzymes from Nemopilema nomurai. AB - BACKGROUND: Because jellyfish are capable of provoking envenomation in humans, they are considered hazardous organisms. Although the effects of their toxins are a matter of concern, information on the venom components, biological activity and pathological mechanisms are still scarce. Therefore, the aim of the present study was to investigate a serine protease component of Nemopilema nomurai jellyfish venom (NnV) and unveil its characteristics. METHODS: To determine the relationship between fibrinolytic activity of NnV and the serine protease, fibrin zymography was performed using metalloprotease and serine protease inhibitors. The biochemical characterization of serine proteases of NnV were determined by the amidolytic assay. Fractions with fibrinolytic activity were obtained by DEAE cation exchange column. RESULTS: NnV displayed fibrinolytic activities with molecular masses of approximately 70, 35, 30, and 28 kDa. The fibrinolytic activity of NnV was completely obliterated by phenylmethylsulfonyl fluoride, a prototype serine protease inhibitor. Based on amidolytic assays using chromogenic substrates specific for various kinds of serine proteases, NnV predominantly manifested a chymotrypsin-like feature. Its activity was completely eliminated at low pH (< 6) and high temperatures (> 37 degrees C). Some metal ions (Co2+, Cu2+, Zn2+ and Ni2+) strongly suppressed its fibrinolytic activity, while others (Ca2+ and Mg2+) failed to do so. Isolation of a serine protease with fibrionolytic activity from NnV revealed that only p3 showed the fibrinolytic activity, which was completely inhibited by PMSF. CONCLUSION: The present study showed that N. nomurai jellyfish venom has a chymotrypsin-like serine protease with fibrinolytic activity. Such information might be useful for developing clinical management of jellyfish envenomation and pharmacological agents with therapeutic potential for thrombotic diseases in the future. PMID- 28814955 TI - Characterization of Carbapenem-Resistant Acinetobacter baumannii Strains Isolated from Hospitalized Patients in Palestine. AB - The American Centers for Disease Control and Prevention (CDC) recognizes Acinetobacter baumannii as a source of global outbreaks and epidemics especially due to its increasing resistance to commercially available antibiotics. In this study, 69 single patient multidrug resistant isolates collected from all over Palestine, except Gaza, were studied. All the isolates were resistant to all the beta-lactam antibiotics including the carbapenems. Of the 69 isolates, 82.6% were positive for blaOXA-23, 14.5% were positive for blaOXA-24, and 3% were positive for blaOXA-58. None were positive for blaOXA-143 and blaOXA-235. In addition, 5.8% and 0% were positive for blaNDM and blaKPC, respectively. Of the 69 isolates, none were positive for the aminoglycoside aphA6 gene while 93% were positive for the aphA1 gene. The acetyltransferases aacC1 and aacA4 genes tested positive in 22% and 13% of the isolates, respectively. The ompA biofilm-producing virulence gene was detected in all isolates. Finally, Multilocus Sequence Typing (MLST) of 13 isolates revealed that more than one strain of A. baumannii was circulating in Palestinian hospitals as results revealed that 7 isolates were of ST208, 2 isolates ST218, 1 isolate ST231, 1 isolate ST348, and 2 new Sequence Types. The detection of these drug resistant pathogens is a reminder of the importance of active surveillance for resistant bacteria in order to prevent their spread in hospital settings. PMID- 28814956 TI - Rapid Rapamycin-Only Induced Osteogenic Differentiation of Blood-Derived Stem Cells and Their Adhesion to Natural and Artificial Scaffolds. AB - Stem cells are a centerpiece of regenerative medicine research, and the recent development of adult stem cell-based therapy systems has vigorously expanded the scope and depth of this scientific field. The regeneration of damaged and/or degraded bone tissue in orthopedic, dental, or maxillofacial surgery is one of the main areas where stem cells and their regenerative potential could be used successfully, requiring tissue engineering solutions incorporating an ideal stem cell type paired with the correct mechanical support. Our contribution to this ongoing research provides a new model of in vitro osteogenic differentiation using blood-derived stem cells (BDSCs) and rapamycin, visibly expressing typical osteogenic markers within ten days of treatment. In depth imaging studies allowed us to observe the adhesion, proliferation, and differentiation of BDSCs to both titanium and bone scaffolds. We demonstrate that BDSCs can differentiate towards the osteogenic lineage rapidly, while readily adhering to the scaffolds we exposed them to. Our results show that our model can be a valid tool to study the molecular mechanisms of osteogenesis while tailoring tissue engineering solutions to these new insights. PMID- 28814958 TI - Does Survival Vary for Breast Cancer Patients in the United States? A Study from Six Randomly Selected States. AB - BACKGROUND: Breast cancer is the most common cancer in women. Disparities in some characteristics of breast cancer patients and their survival data for six randomly selected states in the US were examined. MATERIALS AND METHODS: A probability random sampling method was used to select the records of 2,000 patients from each of six randomly selected states. Demographic and disease characteristics were extracted from the Surveillance Epidemiology and End Results (SEER) database. To evaluate relationships between variables, we employed a Cox Proportional Regression to compare survival times in the different states. RESULTS: Iowa had the highest mean age of diagnosis at 64.14 years (SE = 0.324) and Georgia had the lowest at 57.97 years (SE = 0.313). New Mexico had the longest mean survival time of 189.09 months (SE = 20.414) and Hawaii the shortest at 119.01 (SE = 5.394) months, a 70.08-month difference (5.84 years). Analysis of stage of diagnosis showed that the highest survival times for Whites and American Indians/Alaska Natives were for stage I cancers. The highest survival times for Blacks varied. Stage IV cancer consistently showed the lowest survival times. CONCLUSIONS: Differences in breast cancer characteristics across states highlight the need to understand differences between the states that result in variances in breast cancer survival. PMID- 28814957 TI - Induced Pluripotent Stem Cell for the Study and Treatment of Sickle Cell Anemia. AB - Sickle cell anemia (SCA) is a monogenic disease of high mortality, affecting millions of people worldwide. There is no broad, effective, and safe definitive treatment for SCA, so the palliative treatments are the most used. The establishment of an in vitro model allows better understanding of how the disease occurs, besides allowing the development of more effective tests and treatments. In this context, iPSC technology is a powerful tool for basic research and disease modeling, and a promise for finding and screening more effective and safe drugs, besides the possibility of use in regenerative medicine. This work obtained a model for study and treatment of SCA using iPSC. Then, episomal vectors were used for reprogramming peripheral blood mononuclear cells to obtain integration-free iPSC. Cells were collected from patients treated with hydroxyurea and without treatment. The iPSCP Bscd lines were characterized for pluripotent and differentiation potential. The iPSC lines were differentiated into HSC, so that we obtained a dynamic and efficient protocol of CD34+CD45+ cells production. We offer a valuable tool for a better understanding of how SCA occurs, in addition to making possible the development of more effective drugs and treatments and providing better understanding of widely used treatments, such as hydroxyurea. PMID- 28814959 TI - Poor sleep is highly associated with house dust mite allergic rhinitis in adults and children. AB - BACKGROUND: Sleep disorders are often underreported to physicians by patients with allergies. This study aimed to characterize the sleep disorders associated with respiratory allergy to house dust mites (HDM) at the time of initiation of sublingual allergen immunotherapy (SLIT) in routine clinical practice. METHODS: This prospective, cross-sectional, observational study was conducted between November 2014 and March 2015 at 189 French trial sites and included 1750 participants suffering from HDM allergy who were initiating SLIT. Participants aged less than 5 years old and those who had previously started an allergen immunotherapy (AIT) for HDM allergy were not enrolled in the study. Sleep disorders were assessed by self-administered questionnaires: the Epworth Sleepiness Scale (ESS), the Insomnia Severity Index (ISI) and a modified version of the Hotel Dieu-42 (HD-42) sleep disorder questionnaire. Logistic regression models adjusted for obesity, smoking status, asthma control and nasal obstruction were used to study the relationship between allergic rhinitis (AR) classification and sleep disorders/complaints. RESULTS: Of the 1786 participants enrolled, 1750 (907 adults and 843 children) composed the analysis population. The majority of participants (73.5% of adults and 65.8% of children) reported that their sleep disorders had prompted them to consult their physician. The most commonly observed sleep complaints were poor-quality sleep (50.3% of adults and 37.3% of children), snoring (48.1 and 41.4%, respectively) and nocturnal awakening (37.6 and 28.2%, respectively). Difficulties falling asleep were reported by 27.0% of adults and 24.7% of children. Adults and children suffering from severe persistent AR experienced sleep complaints significantly more often than participants with intermittent or mild persistent AR. CONCLUSIONS: This study highlights the high frequency of sleep disorders and their significant impact on patients with AR induced by HDM, in particular when AR is persistent and severe. Consequently, asking allergic patients about the quality of their sleep appears to be important, especially when the patient has persistent and severe AR. PMID- 28814960 TI - Corrigendum to "Antidiabetic Properties, Bioactive Constituents, and Other Therapeutic Effects of Scoparia dulcis". AB - [This corrects the article DOI: 10.1155/2016/8243215.]. PMID- 28814961 TI - Compound Schisandra-Ginseng-Notoginseng-Lycium Extract Ameliorates Scopolamine Induced Learning and Memory Disorders in Mice. AB - Schisandra, Ginseng, Notoginseng, and Lycium barbarum are traditional Chinese medicinal plants sharing cognitive-enhancing properties. To design a functional food to improve memory, we prepared a compound Schisandra-Ginseng-Notoginseng Lycium (CSGNL) extract and investigated its effect on scopolamine-induced learning and memory loss in mice. To optimize the dose ratios of the four herbal extracts in CSGNL, orthogonal experiments were performed. Mice were administered CSGNL by gavage once a day for 30 days and then mouse learning and memory were evaluated by Morris water maze and step-through tests. The mechanisms of CSGNL improving learning and memory were investigated by assaying acetylcholine (ACh) levels and choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities in the brain tissues of treated mice. The results showed that CSGNL significantly ameliorated scopolamine-induced learning and memory impairment, at least in part, by modulating ACh levels and ChAT and AChE activities in the mouse brain. Our data support the use of CSGNL as a functional food for learning and memory enhancement. PMID- 28814962 TI - Circulating zinc-alpha2-glycoprotein levels are low in newly diagnosed patients with metabolic syndrome and correlate with adiponectin. AB - BACKGROUND: Zinc-alpha2-glycoprotein (ZAG) is a novel adipokine that reduces insulin resistance, protecting against type 2 diabetes. However, past studies have been contradictory. This cross-sectional study aims to investigate the association of circulating ZAG with metabolic syndrome (MetS) in middle-aged and older Chinese adults. METHODS: Four hundred eighty nine individuals (234 healthy controls and 255 MetS patients) were examined. All individuals were screened for MetS according to the diagnostic guidelines of the United States National Cholesterol Education Program (NCEP) Expert Panel Adult Treatment Panel (ATP) III criteria. Circulating ZAG and ADI levels were measured by ELISA. Blood fat, glucose and insulin were measured with a commercial kit. Circulating ZAG levels were compared with various parameters in study subjects. RESULTS: Plasma ZAG levels were lower in MetS patients compared to those of the healthy controls (35.0 +/- 11.7 vs. 46.1 +/- 18.6 mg/L, P < 0.01). ZAG showed a positive correlation with age, HDL-C, HOMA-beta and ADI, but a negative correlation with Fat%, BMI, WHR, blood pressure, triglycerides, FFA, FBG, 2 h-BG, fasting insulin, 2 h-Ins, HbA1c and HOMA-IR (P < 0.01). When the population was divided according to tertiles of ADI, subjects in the highest tertile had the highest ZAG levels. The analysis of ROC curves revealed that the best cutoff value for plasma ZAG to predict MetS was 45.2 mg/L (sensitivity 92%, specificity 59%, and AUC 0.80). CONCLUSIONS: We found that circulating ZAG levels were decreased in patients with MetS. In fact, circulating ZAG decreased progressively with an increasing number of MetS components and associated with ADI levels, suggesting that ZAG is related to IR and MetS and may be a sensitizer. TRIAL REGISTRATION: ChiCTR-OCC-11001422. Registered 23 June 2011. PMID- 28814963 TI - Effects of a liquid high-fat meal on postprandial lipid metabolism in type 2 diabetic patients with abdominal obesity. AB - BACKGROUND: Postprandial lipemia and lipoprotein lipase (LPL) activity play crucial roles in the pathogenesis of accelerated atherosclerosis. This study aimed to evaluate the postprandial lipid metabolism after the ingestion of a liquid high-fat meal in type 2 diabetic patients with abdominal obesity, and determine if the PvuII polymorphisms of LPL influence their postprandial lipid responses. METHODS: Serum glucose, insulin, triglycerides (TG), total cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) were measured in fasting and postprandial state at 0.5, 1, 2, 4, 6 and 8 h after a liquid high-fat meal in 51 type 2 diabetic patients with abdominal obesity, 31 type 2 diabetic patients without abdominal obesity and 39 controls. Their PvuII polymorphisms of LPL were tested in fasting. RESULTS: Type 2 diabetic patients with abdominal obesity had significantly higher postprandial areas under the curve (AUC) of glucose [least square mean difference (LSMD) = 30.763, 95% confidence interval (CI) = 23.071 38.455, F = 37.346, P < 0.05] and TC (LSMD = 3.995, 95% CI = 1.043-6.947, F = 3.681, P < 0.05) than controls. Postprandial AUCs for insulin, homeostasis model assessment-insulin resistance (HOMA-IR) and TG were higher (LSMD = 86.987, 95% CI = 37.421-136.553, F = 16.739, P < 0.05; LSMD = 37.456, 95% CI = 16.312-58.600, F = 27.012, P < 0.05; LSMD = 4.684, 95% CI = 2.662-6.705, F = 26.158, P < 0.05), whereas HDL-C AUC was lower (LSMD = -1.652, 95% CI = -2.685 - -0.620, F = 8.190, P < 0.05) in type 2 diabetic subjects with abdominal obesity than those without abdominal obesity. In type 2 diabetic patients with abdominal obesity, postprandial TG AUC was lower in P-/- than in P+/- (LSMD = -4.393, 95% CI = 9.278 - -0.491, F = 4.476, P < 0.05) and P+/+ (LSMD = -7.180, 95% CI = -12.319 - 2.014, F = 4.476, P < 0.05) phenotypes. Postprandial AUCs for glucose, insulin, HOMA-IR, TC and HDL-C were not different according to PvuII phenotypes. CONCLUSIONS: Abdominal obesity exacerbates the postprandial lipid responses in type 2 diabetic patients, which partly explains the excess atherogenic risk in these patients. In addition, the presence of P+ allele could contribute to a greater postprandial TG increase in type 2 diabetic patients with abdominal obesity. TRIAL REGISTRATION: ChiCTR-IOR-16008435. Registered 8 May 2016. PMID- 28814965 TI - Convolutional Neural Network for the Detection of End-Diastole and End-Systole Frames in Free-Breathing Cardiac Magnetic Resonance Imaging. AB - Free-breathing cardiac magnetic resonance (CMR) imaging has short examination time with high reproducibility. Detection of the end-diastole and the end-systole frames of the free-breathing cardiac magnetic resonance, supplemented by visual identification, is time consuming and laborious. We propose a novel method for automatic identification of both the end-diastole and the end-systole frames, in the free-breathing CMR imaging. The proposed technique utilizes the convolutional neural network to locate the left ventricle and to obtain the end-diastole and the end-systole frames from the respiratory motion signal. The proposed procedure works successfully on our free-breathing CMR data, and the results demonstrate a high degree of accuracy and stability. Convolutional neural network improves the postprocessing efficiency greatly and facilitates the clinical application of the free-breathing CMR imaging. PMID- 28814966 TI - Computational Paradigms for Mental Health. PMID- 28814964 TI - Milk disrupts p53 and DNMT1, the guardians of the genome: implications for acne vulgaris and prostate cancer. AB - There is accumulating evidence that milk shapes the postnatal metabolic environment of the newborn infant. Based on translational research, this perspective article provides a novel mechanistic link between milk intake and milk miRNA-regulated gene expression of the transcription factor p53 and DNA methyltransferase 1 (DNMT1), two guardians of the human genome, that control transcriptional activity, cell survival, and apoptosis. Major miRNAs of milk, especially miRNA-125b, directly target TP53 and complex p53-dependent gene regulatory networks. TP53 regulates the expression of key genes involved in cell homeostasis such as FOXO1, PTEN, SESN1, SESN2, AR, IGF1R, BAK1, BIRC5, and TNFSF10. Nuclear interaction of p53 with DNMT1 controls gene silencing. The most abundant miRNA of milk and milk fat, miRNA-148a, directly targets DNMT1. Reduced DNMT1 expression further attenuates the activity of histone deacetylase 1 (HDAC1) involved in the regulation of chromatin structure and access to transcription. The presented milk-mediated miRNA-p53-DNMT1 pathway exemplified at the promoter regulation of survivin (BIRC5) provides a novel explanation for the epidemiological association between milk consumption and acne vulgaris and prostate cancer. Notably, p53- and DNMT1-targeting miRNAs of bovine and human milk survive pasteurization and share identical seed sequences, which theoretically allows the interaction of bovine miRNAs with the human genome. Persistent intake of milk-derived miRNAs that attenuate p53- and DNMT1 signaling of the human milk consumer may thus present an overlooked risk factor promoting acne vulgaris, prostate cancer, and other p53/DNMT1-related Western diseases. Therefore, bioactive miRNAs of commercial milk should be eliminated from the human food chain. PMID- 28814967 TI - Kalman Filtering for Genetic Regulatory Networks with Missing Values. AB - The filter problem with missing value for genetic regulation networks (GRNs) is addressed, in which the noises exist in both the state dynamics and measurement equations; furthermore, the correlation between process noise and measurement noise is also taken into consideration. In order to deal with the filter problem, a class of discrete-time GRNs with missing value, noise correlation, and time delays is established. Then a new observation model is proposed to decrease the adverse effect caused by the missing value and to decouple the correlation between process noise and measurement noise in theory. Finally, a Kalman filtering is used to estimate the states of GRNs. Meanwhile, a typical example is provided to verify the effectiveness of the proposed method, and it turns out to be the case that the concentrations of mRNA and protein could be estimated accurately. PMID- 28814968 TI - ASP-based method for the enumeration of attractors in non-deterministic synchronous and asynchronous multi-valued networks. AB - BACKGROUND: This paper addresses the problem of finding attractors in biological regulatory networks. We focus here on non-deterministic synchronous and asynchronous multi-valued networks, modeled using automata networks (AN). AN is a general and well-suited formalism to study complex interactions between different components (genes, proteins,...). An attractor is a minimal trap domain, that is, a part of the state-transition graph that cannot be escaped. Such structures are terminal components of the dynamics and take the form of steady states (singleton) or complex compositions of cycles (non-singleton). Studying the effect of a disease or a mutation on an organism requires finding the attractors in the model to understand the long-term behaviors. RESULTS: We present a computational logical method based on answer set programming (ASP) to identify all attractors. Performed without any network reduction, the method can be applied on any dynamical semantics. In this paper, we present the two most widespread non-deterministic semantics: the asynchronous and the synchronous updating modes. The logical approach goes through a complete enumeration of the states of the network in order to find the attractors without the necessity to construct the whole state-transition graph. We realize extensive computational experiments which show good performance and fit the expected theoretical results in the literature. CONCLUSION: The originality of our approach lies on the exhaustive enumeration of all possible (sets of) states verifying the properties of an attractor thanks to the use of ASP. Our method is applied to non deterministic semantics in two different schemes (asynchronous and synchronous). The merits of our methods are illustrated by applying them to biological examples of various sizes and comparing the results with some existing approaches. It turns out that our approach succeeds to exhaustively enumerate on a desktop computer, in a large model (100 components), all existing attractors up to a given size (20 states). This size is only limited by memory and computation time. PMID- 28814970 TI - Prevalence and characteristics of Epstein-Barr virus-associated gastric carcinomas in Portugal. AB - BACKGROUND: Gastric cancer (GC) is one of the most common malignant tumors of the digestive tract and is the third leading cause of cancer death worldwide. Epstein Barr virus (EBV) has been associated with approximately 10% of the total cases of gastric carcinomas. No previous study has analyzed the prevalence of EBV infection in gastric cancer of the Portuguese population. METHODS: In the present study, we have analyzed 82 gastric carcinoma cases and 33 healthy individuals (control group) from Coimbra region for the presence of EBV by polymerase chain reaction (PCR) and by in situ hybridization (ISH) for EBV-encoded small RNAs (EBERs). The status of H. pylori infection was assessed by serology and by PCR. RESULTS: EBV was detected by PCR in 90.2% of stomach cancer cases, whereas EBERs were detected in 11%. In our series, EBV-associated gastric carcinoma (EBVaGC) were significantly associated with gender and the majority of them presented lymph node metastasis. These cases were generally graded in more advanced pTNM stages and, non-surprisingly, showed worse survival. H. pylori infection was detected in 62.2% of the gastric cancers and 64.7% of these patients were CagA+. On the other hand, the H. pylori prevalence was higher in the EBV-negative gastric carcinomas (64.4%) than in those carcinoma cases with EBV+ (44.4%). CONCLUSIONS: The present study shows that prevalence of EBVaGC among Portuguese population is in accordance with the worldwide prevalence. EBV infection seems to be associated to poorer prognostic and no relation to H. pylori infection has been found. Conversely, the presence of H. pylori seems to have a favourable impact on patient's survival. Our results emphasize that geographic variation can contribute with new epidemiological data on the association of EBV with gastric cancer. PMID- 28814972 TI - Mental health literacy in adolescents: ability to recognise problems, helpful interventions and outcomes. AB - BACKGROUND: Although mental health literacy has been widely studied in adults, there are still relatively few studies on adolescent populations. In Sri Lanka, adolescents account for about one fifth of the population. Current evidence shows that most mental health problems diagnosed in adulthood begin in adolescence. There is also growing evidence that the trajectories of these disorders can be altered through early recognition and intervention. Although, help-seeking for mental health problems is known to be poor in adolescents, mental health literacy improves help-seeking. It is also known that adolescents may act as agents of change regarding mental health in their wider communities. Thus, mental health literacy in adolescents is an important aspect of community mental health initiatives. The objective of this study was to describe aspects of mental health literacy in terms of ability to recognise problems, helpful interventions, helpful referral options and outcomes in a target adolescent population in Sri Lanka. The association between socio economic variables and recognition of mental health problems was also examined. METHODS: This descriptive cross sectional study used a pretested questionnaire on 1002 adolescents aged between 13 and 16, where mental health literacy was assessed using 4 case vignettes. The vignettes represented depression with suicidal ideation, social phobia, psychosis and diabetes, where the last was for comparison. RESULTS: The response rates for recognition as a mental health problem was 82.2% (n = 824) for the vignette depicting depression, 68.7% (n = 689) for the psychosis vignette and 62.3% (n = 623) for the social phobia vignette. "Talking to the person", was responded to as helpful by 49.9% (n = 500), for the depression vignette followed by 49.8% (n = 499) for social phobia, 39.5% (n = 396) for psychosis and 19.5% (n = 195) for the diabetes vignette. The response rate for exercise being a helpful intervention was 25% (n = 251) for the diabetes vignette, followed by 21% (n = 210) for social phobia, 18.7% (n = 187) for psychosis vignette and 18.4% (n = 184) for the depression vignette. While 70.2% (n = 704) responded that there would be benefit in seeing a doctor for the diabetes vignette, the response rates for psychosis was 48.5% (n = 486), and for both depression and social phobia it was 48.2% (n = 483). The responses for the persons in the vignettes becoming better with treatment was 81.4% (n = 816) for the diabetes, 79.5% (n = 797) for depression, 75.6% (n = 758) for psychosis and 63.4% (n = 636) for the social phobia vignette. A statistically significant association was found between the income level of the family and appropriate recognition as mental health problems, for all the 3 mental health related vignettes. CONCLUSIONS: The ability to recognise mental health problems, helpful interventions and outcomes in this population was comparable to those of adolescent populations in other countries, with some exceptions. The main differences were in relation to the identification and interventions in response to the psychosis and social phobia vignettes. PMID- 28814971 TI - Quality of life in anxious adolescents. AB - PURPOSE: To examine associations between health-related quality of life (HRQoL) and anxiety symptoms across anxiety domains (obsessions/compulsions, social anxiety, panic disorder, agoraphobia, separation anxiety, physical injury fears, generalised anxiety, and posttraumatic stress) in a general adolescent population. Expanded knowledge about these associations can provide valuable information for improving interventions and prevention strategies for adolescent anxiety. METHODS: Cross-sectional data about anxiety were collected via a school survey from a community sample of Norwegian adolescents aged 12-17 (N = 1719). Based on scores from the Spence Children's Anxiety Scale (SCAS), each adolescent was categorized as reporting a low, medium, or high level of anxiety. Each adolescent's HRQoL was then measured using the Questionnaire for Measuring Health Related Quality of Life in Children and Adolescents Revised Version (KINDL-R). Hierarchical regression analyses were performed to determine any relationship between anxiety symptoms and HRQoL. RESULTS: Across domains of anxiety, anxiety symptoms were inversely associated with overall HRQoL. All HRQoL-dimensions were inversely associated with overall level of anxiety symptoms. In adolescents with medium and high anxiety symptoms, poor HRQoL was documented in all HRQoL dimensions with the exception of the family dimension. CONCLUSIONS: The strong association between elevated levels of anxiety symptoms and poor HRQoL demonstrate the importance of improved mental health interventions and prevention initiatives targeting anxious adolescents. PMID- 28814973 TI - Photoautotrophic production of polyhydroxyalkanoates in a synthetic mixed culture of Synechococcus elongatus cscB and Pseudomonas putida cscAB. AB - BACKGROUND: One of the major challenges for the present and future generations is to find suitable substitutes for the fossil resources we rely on today. Cyanobacterial carbohydrates have been discussed as an emerging renewable feedstock in industrial biotechnology for the production of fuels and chemicals, showing promising production rates when compared to crop-based feedstock. However, intrinsic capacities of cyanobacteria to produce biotechnological compounds are limited and yields are low. RESULTS: Here, we present an approach to circumvent these problems by employing a synthetic bacterial co-culture for the carbon-neutral production of polyhydroxyalkanoates (PHAs) from CO2. The co culture consists of two bio-modules: Bio-module I, in which the cyanobacterial strain Synechococcus elongatus cscB fixes CO2, converts it to sucrose, and exports it into the culture supernatant; and bio-module II, where this sugar serves as C-source for Pseudomonas putida cscAB and is converted to PHAs that are accumulated in the cytoplasm. By applying a nitrogen-limited process, we achieved a maximal PHA production rate of 23.8 mg/(L day) and a maximal titer of 156 mg/L. We will discuss the present shortcomings of the process and show the potential for future improvement. CONCLUSIONS: These results demonstrate the feasibility of mixed cultures of S. elongatus cscB and P. putida cscAB for PHA production, making room for the cornucopia of possible products that are described for P. putida. The construction of more efficient sucrose-utilizing P. putida phenotypes and the optimization of process conditions will increase yields and productivities and eventually close the gap in the contemporary process. In the long term, the co-culture may serve as a platform process, in which P. putida is used as a chassis for the implementation of synthetic metabolic pathways for biotechnological production of value-added products. PMID- 28814969 TI - The role of open abdomen in non-trauma patient: WSES Consensus Paper. AB - The open abdomen (OA) is defined as intentional decision to leave the fascial edges of the abdomen un-approximated after laparotomy (laparostomy). The abdominal contents are potentially exposed and therefore must be protected with a temporary coverage, which is referred to as temporal abdominal closure (TAC). OA use remains widely debated with many specific details deserving detailed assessment and clarification. To date, in patients with intra-abdominal emergencies, the OA has not been formally endorsed for routine utilization; although, utilization is seemingly increasing. Therefore, the World Society of Emergency Surgery (WSES), Abdominal Compartment Society (WSACS) and the Donegal Research Academy united a worldwide group of experts in an international consensus conference to review and thereafter propose the basis for evidence directed utilization of OA management in non-trauma emergency surgery and critically ill patients. In addition to utilization recommendations, questions with insufficient evidence urgently requiring future study were identified. PMID- 28814975 TI - The typically developing paediatric foot: how flat should it be? A systematic review. AB - BACKGROUND: All typically developing children are born with flexible flat feet, progressively developing a medial longitudinal arch during the first decade of their lives. Whilst the child's foot is expected to be flat, there is currently no consensus as to how flat this foot should be. Furthermore, whilst feet are observed to decrease in flatness with increasing age, it is not known how flat they should be at each age increment. The objective of this systematic review is to define the postural characteristics of the 'typically' developing paediatric foot. METHODS: The PRISMA protocol was applied to compare all data currently published describing the typical development of the paediatric foot. The Epidemiological Appraisal Instrument (EAI) was used to assess the risk of bias of the included studies. RESULTS: Thirty four epidemiological papers pertaining to the development of the paediatric foot were graphically compared. Sixteen different foot posture assessments were identified of which footprint based measures were the most reported outcome. CONCLUSION: Firstly, the use of the term normal in relation to foot posture is misleading in the categorisation of the paediatric foot, as indeed a flat foot posture is a normal finding at specific ages. Secondly, the foot posture of the developing child is indeed age dependent and has been shown to change over time. Thirdly, no firm conclusion could be reached as to which age the foot posture of children ceases to develop further, as no two foot measures are comparable, therefore future research needs to consider the development of consensus recommendations as to the measurement of the paediatric foot, using valid and reliable assessment tools. PMID- 28814974 TI - Time-resolved transcriptome analysis and lipid pathway reconstruction of the oleaginous green microalga Monoraphidium neglectum reveal a model for triacylglycerol and lipid hyperaccumulation. AB - BACKGROUND: Oleaginous microalgae are promising production hosts for the sustainable generation of lipid-based bioproducts and as bioenergy carriers such as biodiesel. Transcriptomics of the lipid accumulation phase, triggered efficiently by nitrogen starvation, is a valuable approach for the identification of gene targets for metabolic engineering. RESULTS: An explorative analysis of the detailed transcriptional response to different stages of nitrogen availability was performed in the oleaginous green alga Monoraphidium neglectum. Transcript data were correlated with metabolic data for cellular contents of starch and of different lipid fractions. A pronounced transcriptional down regulation of photosynthesis became apparent in response to nitrogen starvation, whereas glucose catabolism was found to be up-regulated. An in-depth reconstruction and analysis of the pathways for glycerolipid, central carbon, and starch metabolism revealed that distinct transcriptional changes were generally found only for specific steps within a metabolic pathway. In addition to pathway analyses, the transcript data were also used to refine the current genome annotation. The transcriptome data were integrated into a database and complemented with data for other microalgae which were also subjected to nitrogen starvation. It is available at https://tdbmn.cebitec.uni-bielefeld.de. CONCLUSIONS: Based on the transcriptional responses to different stages of nitrogen availability, a model for triacylglycerol and lipid hyperaccumulation is proposed, which involves transcriptional induction of thioesterases, differential regulation of lipases, and a re-routing of the central carbon metabolism. Over expression of distinct thioesterases was identified to be a potential strategy to increase the oleaginous phenotype of M. neglectum, and furthermore specific lipases were identified as potential targets for future metabolic engineering approaches. PMID- 28814976 TI - Analysis of proteomes released from in vitro cultured eight Clostridium difficile PCR ribotypes revealed specific expression in PCR ribotypes 027 and 176 confirming their genetic relatedness and clinical importance at the proteomic level. AB - BACKGROUND: Clostridium difficile is the causative agent of C. difficile infection (CDI) that could be manifested by diarrhea, pseudomembranous colitis or life-threatening toxic megacolon. The spread of certain strains represents a significant economic burden for health-care. The epidemic successful strains are also associated with severe clinical features of CDI. Therefore, a proteomic study has been conducted that comprises proteomes released from in vitro cultured panel of eight different PCR ribotypes (RTs) and employs the combination of shotgun proteomics and label-free quantification (LFQ) approach. RESULTS: The comparative semi-quantitative analyses enabled investigation of a total of 662 proteins. Both hierarchical clustering and principal component analysis (PCA) created eight distinctive groups. From these quantifiable proteins, 27 were significantly increased in functional annotations. Among them, several known factors connected with virulence were identified, such as toxin A, B, binary toxin, flagellar proteins, and proteins associated with Pro-Pro endopeptidase (PPEP-1) functional complex. Comparative analysis of protein expression showed a higher expression or unique expression of proteins linked to pathogenicity or iron metabolism in RTs 027 and 176 supporting their genetic relatedness and clinical importance at the proteomic level. Moreover, the absence of putative nitroreductase and the abundance of the Abc-type fe3+ transport system protein were observed as biomarkers for the RTs possessing binary toxin genes (027, 176 and 078). Higher expression of selected flagellar proteins clearly distinguished RTs 027, 176, 005 and 012, confirming the pathogenic role of the assembly in CDI. Finally, the histidine synthesis pathway regulating protein complex HisG/HisZ was observed only in isolates possessing the genes for toxin A and B. CONCLUSIONS: This study showed the applicability of the LFQ approach and provided the first semi-quantitative insight into the proteomes released from in vitro cultured panel of eight RTs. The observed differences pointed to a new direction for studies focused on the elucidation of the mechanisms underlining the CDI nature. PMID- 28814977 TI - Worse inflammatory profile in omnivores than in vegetarians associates with the gut microbiota composition. AB - AIMS: To describe the abundance of major phyla and some genera in the gut microbiota of individuals according to dietary habits and examine their associations with inflammatory markers, insulin resistance, and cardiovascular risk profile. METHODS: A total of 268 non-diabetic individuals were stratified into groups of dietary types (strict vegetarians, lacto-ovo-vegetarians, and omnivores). The taxonomic composition and phylogenetic structure of the microbiota were obtained through the analysis of the 16S rRNA gene. Samples were clustered into operational taxonomic units at 97% similarity using GreenGenes 13.5 database. Clinical, biochemical, and circulating inflammatory markers were compared by ANOVA or Kruskal-Wallis test. RESULTS: The sample (54.2% women, mean age 49.5 years) was composed of 66 strict vegetarians, 102 lacto-ovo-vegetarians and 100 omnivores. Considering the entire sample, the greatest abundant phyla were Firmicutes (40.7 +/- 15.9%) and Bacteroidetes (39.5 +/- 19.9%), and no difference in abundances was found between individuals with normal and excess weight. Stratifying by dietary types, the proportion of Firmicutes was lower and of Bacteroidetes was higher in strict vegetarians when compared to lacto-ovo vegetarians and omnivores. At the genus level, strict vegetarians had a higher Prevotella abundance and Prevotella/Bacteroides ratio than the other groups. They also had a lower proportion of Faecalibacterium than lacto-ovo-vegetarians, and both vegetarian groups had higher proportions than did omnivores. Succinivibrio and Halomonas from the Proteobacteria phylum were overrepresented in omnivores. The omnivorous group showed higher values of anthropometric data, insulin, HOMA IR, and a worse lipid profile. Inflammatory markers exhibited a gradual and significant increase from the vegetarians and lacto-ovo-vegetarians to the omnivorous group. CONCLUSIONS: There are differences in gut microbiota composition of individuals with distinct dietary habits, who differ according to their inflammatory and metabolic profiles. Based on the findings relative to bacteria abundances and on their recognized actions in the metabolism, we suggest that exposure to animal foods may favor an intestinal environment which could trigger systemic inflammation and insulin resistance-dependent metabolic disorders. PMID- 28814979 TI - Executive functioning in Cornelia de Lange syndrome: domain asynchrony and age related performance. AB - BACKGROUND: The aim of this study was to examine executive functioning in adolescents and adults with Cornelia de Lange syndrome (CdLS) to identify a syndrome and age-related profile of cognitive impairment. METHODS: Participants were 24 individuals with CdLS aged 13-42 years (M = 22; SD = 8.98), and a comparable contrast group of 21 individuals with Down syndrome (DS) aged 15-33 years (M = 24; SD = 5.82). Measures were selected to test verbal and visual fluency, inhibition, perseverance/flexibility, and working memory and comprised both questionnaire and performance tests. RESULTS: Individuals with CdLS showed significantly greater impairment on tasks requiring flexibility and inhibition (rule switch) and on forwards span capacity. These impairments were also reported in the parent/carer-rated questionnaire measures. Backwards Digit Span was significantly negatively correlated with chronological age in CdLS, indicating increased deficits with age. This was not identified in individuals with DS. CONCLUSIONS: The relative deficits in executive functioning task performance are important in understanding the behavioural phenotype of CdLS. Prospective longitudinal follow-up is required to examine further the changes in executive functioning with age and if these map onto observed changes in behaviour in CdLS. Links with recent research indicating heightened responses to oxidative stress in CdLS may also be important. PMID- 28814978 TI - Evolutionary history of the mariner element galluhop in avian genomes. AB - BACKGROUND: Transposable elements (TEs) are highly abundant genomic parasites in eukaryote genomes. Although several genomes have been screened for TEs, so far very limited information is available regarding avian TEs and their evolutionary histories. Taking advantage of the rich genomic data available for birds, we characterized the evolutionary history of the galluhop element, originally described in Gallus gallus, through the use of several bioinformatic analyses. RESULTS: galluhop homologous sequences were found in 6 of 72 genomes analyzed: 5 species of Galliformes (Gallus gallus, Meleagris gallopavo, Coturnix japonica, Colinus virginianus, Lyrurus tetrix) and one Buceritiformes (Buceros rhinoceros). The copy number ranged from 5 to 10,158, in the genomes of C. japonica and G. gallus respectively. All 6 species possessed short elements, suggesting the presence of Miniature Inverted repeats Transposable Elements (MITEs), which underwent an ancient massive amplification in the G. gallus and M. gallopavo genomes. Only 4 species showed potential MITE full-length partners, although no potential coding copies were detected. Phylogenetic analysis of reconstructed coding sequences showed that galluhop homolog sequences form a new mariner subfamily, which we termed Gallus. Inter-species and intragenomic galluhop distance analyses indicated a high identity between the consensus of B. rhinoceros and the other 5 related species, and different emergence ages of the element between the Galliformes species and B. rhinocerus, suggesting that horizontal transfer took place from Galliformes to a Buceritiformes ancestor, probably through an intermediate species. CONCLUSIONS: Overall, our results showed that mariner elements have amplified to high copy numbers in some avian species, and that this transposition burst probably occurred in the common ancestor of G. gallus and M. gallopavo. In addition, although no coding sequences could be found currently, they probably existed, allowing an ancient massive MITE amplification in these 2 species. The other 4 species also have MITEs, suggesting that this new mariner family is prone to give rise to such non-autonomous derivatives. Last, our results suggest that a horizontal transfer event of a galluhop element occurred between Galliformes and Buceritiformes. PMID- 28814980 TI - Cooperative effect of chidamide and chemotherapeutic drugs induce apoptosis by DNA damage accumulation and repair defects in acute myeloid leukemia stem and progenitor cells. AB - BACKGROUND: Many conventional chemotherapeutic drugs are known to be involved in DNA damage, thus ultimately leading to apoptosis of leukemic cells. However, they fail to completely eliminate leukemia stem cells (LSCs) due to their higher DNA repair capacity of cancer stem cells than that of bulk cancer cells, which becomes the root of drug resistance and leukemia recurrence. A new strategy to eliminate LSCs in acute myeloid leukemia (AML) is therefore urgently needed. RESULTS: We report that a low-dose chidamide, a novel orally active benzamide type histone deacetylase (HDAC) inhibitor, which selectively targets HDACs 1, 2, 3, and 10, could enhance the cytotoxicity of DNA-damaging agents (daunorubicin, idarubicin, and cytarabine) in CD34+CD38- KG1alpha cells, CD34+CD38- Kasumi cells, and primary refractory or relapsed AML CD34+ cells, reflected by the inhibition of cell proliferation, induction of apoptosis, and increase of cell cycle arrest in vitro. Mechanistically, these events were associated with DNA damage accumulation and repair defects. Co-treatment with chidamide and the DNA damaging agent IDA gave rise to the production of gammaH2A.X and inhibited posttranslationally but not transcriptionally the repair gene of ATM, BRCA1, and checkpoint kinase 1 (CHK1) and 2 (CHK2) phosphorylation. Finally, the combination of chidamide and IDA initiated caspase-3 and PARP cleavage, but not caspase-8 and caspase-9, and ultimately induced CD34+CD38- KG1alpha cell apoptosis. Further analysis of AML patients' clinical characteristics revealed that the ex vivo efficacy of chidamide in combination with IDA in primary CD34+ samples was significantly correlated to peripheral blood WBC counts at diagnosis, while LDH levels and karyotype status had no effect, indicating that the combination regimen of chidamide and IDA could rapidly diminish tumor burden in patients with R/R AML. CONCLUSIONS: These findings provide preclinical evidence for low-dose chidamide in combination with chemotherapeutic agents in treating recurrent/resistant AML as an alternative salvage regimen, especially those possessing stem and progenitor cells. PMID- 28814981 TI - CpG location and methylation level are crucial factors for the early detection of oral squamous cell carcinoma in brushing samples using bisulfite sequencing of a 13-gene panel. AB - BACKGROUND: Oral squamous cell carcinoma (OSCC) is usually diagnosed at an advanced stage and is commonly preceded by oral premalignant lesions. The mortality rates have remained unchanged (50% within 5 years after diagnosis), and it is related to tobacco smoking and alcohol intake. Novel molecular markers for early diagnosis are urgently needed. The purpose of this study was to evaluate the diagnostic value of methylation level in a set of 18 genes by bisulfite next generation sequencing. METHODS: With minimally invasive oral brushing, 28 consecutive OSCC, one squamous cell carcinoma with sarcomatoid features, six high grade squamous intraepithelial lesions (HGSIL), 30 normal contralateral mucosa from the same patients, and 65 healthy donors were evaluated for DNA methylation analyzing 18 target genes by quantitative bisulfite next-generation sequencing. We further evaluated an independent cohort (validation dataset) made of 20 normal donors, one oral fibroma, 14 oral lichen planus (OLP), three proliferative verrucous leukoplakia (PVL), and two OSCC. RESULTS: Comparing OSCC with normal healthy donors and contralateral mucosa in 355 CpGs, we identified the following epigenetically altered genes: ZAP70, ITGA4, KIF1A, PARP15, EPHX3, NTM, LRRTM1, FLI1, MIR193, LINC00599, PAX1, and MIR137HG showing hypermethylation and MIR296, TERT, and GP1BB showing hypomethylation. The behavior of ZAP70, GP1BB, H19, EPHX3, and MIR193 fluctuated among different interrogated CpGs. The gap between normal and OSCC samples remained mostly the same (Kruskal-Wallis P values < 0.05), but the absolute values changed conspicuously. ROC curve analysis identified the most informative CpGs, and we correctly stratified OSCC and HGSIL from normal donors using a multiclass linear discriminant analysis in a 13-gene panel (AUC 0.981). Only the OSCC with sarcomatoid features was negative. Three contralateral mucosa were positive, a sign of a possible field cancerization. Among imprinted genes, only MIR296 showed loss of imprinting. DNMT1, TERC, and H19 together with the global methylation of long interspersed element 1 were unchanged. In the validation dataset, values over the threshold were detected in 2/2 OSCC, in 3/3 PVL, and in 2/14 OLP. CONCLUSIONS: Our data highlight the importance of CpG location and correct estimation of DNA methylation level for highly accurate early diagnosis of OSCC. PMID- 28814982 TI - Cord blood DNA methylation and adiposity measures in early and mid-childhood. AB - BACKGROUND: Excess adiposity in childhood is associated with numerous adverse health outcomes. As this condition is difficult to treat once present, identification of risk early in life can help inform and implement strategies to prevent the onset of the condition. We performed an epigenome-wide association study to prospectively investigate the relationship between cord blood DNA methylation and adiposity measurements in childhood. METHODS: We measured genome wide DNA methylation from 478 children in cord blood and measured overall and central adiposity via skinfold caliper measurements in early (range 3.1-3.3 years) and mid-childhood (age range 7.3-8.3 years) and via dual X-ray absorptiometry (DXA) in mid-childhood. Final models were adjusted for maternal age at enrollment, pre-pregnancy body mass index, education, folate intake during pregnancy, smoking during pregnancy, and gestational weight gain, and child sex, race/ethnicity, current age, and cord blood cell composition. RESULTS: We identified four promoter proximal CpG sites that were associated with adiposity as measured by subscapular (SS) and triceps (TR) ratio (SS:TR) in early childhood, in the genes KPRP, SCL9A10, MYLK2, and PRLHR. We additionally identified one gene body CpG site associated with early childhood SS + TR on PPAPDC1A; this site was nominally associated with SS + TR in mid-childhood. Higher methylation at one promoter proximal CpG site in MMP25 was also associated with SS:TR in mid-childhood. In regional analyses, methylation at an exonal region of GFPT2 was positively associated with SS:TR in early childhood. Finally, we identified regions of two long, non-coding RNAs which were associated with SS:TR (LOC100049716) and fat-free mass index (LOC102723493) in mid-childhood. CONCLUSION: This analysis identified novel CpG loci associated with adiposity outcomes. However, our results suggest little consistency across the various adiposity outcomes tested, particularly among the more accurate DXA measurements of body composition. We recommend using caution when interpreting these associations. PMID- 28814984 TI - Protective Mechanisms of the Mitochondrial-Derived Peptide Humanin in Oxidative and Endoplasmic Reticulum Stress in RPE Cells. AB - Age-related macular degeneration (AMD) is the leading cause of severe and irreversible vision loss and is characterized by progressive degeneration of the retina resulting in loss of central vision. The retinal pigment epithelium (RPE) is a critical site of pathology of AMD. Mitochondria and the endoplasmic reticulum which lie in close anatomic proximity to each other are targets of oxidative stress and endoplasmic reticulum (ER) stress, respectively, and contribute to the progression of AMD. The two organelles exhibit close interactive function via various signaling mechanisms. Evidence for ER mitochondrial crosstalk in RPE under ER stress and signaling pathways of apoptotic cell death is presented. The role of humanin (HN), a prominent member of a newly discovered family of mitochondrial-derived peptides (MDPs) expressed from an open reading frame of mitochondrial 16S rRNA, in modulation of ER and oxidative stress in RPE is discussed. HN protected RPE cells from oxidative and ER stress-induced cell death by upregulation of mitochondrial GSH, inhibition of ROS generation, and caspase 3 and 4 activation. The underlying mechanisms of ER mitochondrial crosstalk and modulation by exogenous HN are discussed. The therapeutic use of HN and related MDPs could potentially prove to be a valuable approach for treatment of AMD. PMID- 28814983 TI - Honey, Propolis, and Royal Jelly: A Comprehensive Review of Their Biological Actions and Health Benefits. AB - BACKGROUND: There are several health benefits that honeybee products such as honey, propolis, and royal jelly claim toward various types of diseases in addition to being food. SCOPE AND APPROACH: In this paper, the effects of honey, propolis, and royal jelly on different metabolic diseases, cancers, and other diseases have been reviewed. The modes of actions of these products have also been illustrated for purposes of better understanding. KEY FINDINGS AND CONCLUSIONS: An overview of honey, propolis, and royal jelly and their biological potentials was highlighted. The potential health benefits of honey, such as microbial inhibition, wound healing, and its effects on other diseases, are described. Propolis has been reported to have various health benefits related to gastrointestinal disorders, allergies, and gynecological, oral, and dermatological problems. Royal jelly is well known for its protective effects on reproductive health, neurodegenerative disorders, wound healing, and aging. Nevertheless, the exact mechanisms of action of honey, propolis, and royal jelly on the abovementioned diseases and activities have not been not fully elucidated, and further research is warranted to explain their exact contributions. PMID- 28814985 TI - Activation of Endocannabinoid Receptor 2 as a Mechanism of Propofol Pretreatment Induced Cardioprotection against Ischemia-Reperfusion Injury in Rats. AB - Propofol pretreatment before reperfusion, or propofol conditioning, has been shown to be cardioprotective, while its mechanism is unclear. The current study investigated the roles of endocannabinoid signaling in propofol cardioprotection in an in vivo model of myocardial ischemia/reperfusion (I/R) injury and in in vitro primary cardiomyocyte hypoxia/reoxygenation (H/R) injury. The results showed that propofol conditioning increased both serum and cell culture media concentrations of endocannabinoids including anandamide (AEA) and 2 arachidonoylglycerol (2-AG) detected by LC-MS/MS. The reductions of myocardial infarct size in vivo and cardiomyocyte apoptosis and death in vitro were accompanied with attenuations of oxidative injuries manifested as decreased reactive oxygen species (ROS), malonaldehyde (MDA), and MPO (myeloperoxidase) and increased superoxide dismutase (SOD) production. These effects were mimicked by either URB597, a selective endocannabinoids degradation inhibitor, or VDM11, a selective endocannabinoids reuptake inhibitor. In vivo study further validated that the cardioprotective and antioxidative effects of propofol were reversed by selective CB2 receptor antagonist AM630 but not CB1 receptor antagonist AM251. We concluded that enhancing endogenous endocannabinoid release and subsequent activation of CB2 receptor signaling represent a major mechanism whereby propofol conditioning confers antioxidative and cardioprotective effects against myocardial I/R injury. PMID- 28814986 TI - 2-Deoxy-D-glucose Restore Glucocorticoid Sensitivity in Acute Lymphoblastic Leukemia via Modification of N-Linked Glycosylation in an Oxygen Tension Independent Manner. AB - In childhood acute lymphoblastic leukemia, treatment failure is associated with resistance to glucocorticoid agents. Resistance to this class of drugs represents one of the strongest indicators of poor clinical outcome. We show that leukemic cells, which are resistant to the glucocorticoid drug methylprednisolone, display a higher demand of glucose associated with a deregulation of metabolic pathways, in comparison to sensitive cells. Interestingly, a combinatorial treatment of glucocorticoid and the glucose analog 2-deoxy-D-glucose displayed a synergistic effect in methylprednisolone-resistant cells, in an oxygen tension-independent manner. Unlike solid tumors, where 2-deoxy-D-glucose promotes inhibition of glycolysis by hexokinase II exclusively under hypoxic conditions, we were able to show that the antileukemic effects of 2-deoxy-D-glucose are far more complex in leukemia. We demonstrate a hexokinase II-independent cell viability decrease and apoptosis induction of the glucose analog in leukemia. Additionally, due to the structural similarity of 2-deoxy-D-glucose with mannose, we could confirm that the mechanism by which 2-deoxy-D-glucose predominantly acts in leukemia is via modification in N-linked glycosylation, leading to endoplasmic reticulum stress and consequently induction of the unfolded protein response. PMID- 28814989 TI - Editors' Note. PMID- 28814988 TI - The draft genome of the hyperthermophilic archaeon Pyrodictium delaneyi strain hulk, an iron and nitrate reducer, reveals the capacity for sulfate reduction. AB - Pyrodictium delaneyi strain Hulk is a newly sequenced strain isolated from chimney samples collected from the Hulk sulfide mound on the main Endeavour Segment of the Juan de Fuca Ridge (47.9501 latitude, -129.0970 longitude, depth 2200 m) in the Northeast Pacific Ocean. The draft genome of strain Hulk shared 99.77% similarity with the complete genome of the type strain Su06T, which shares with strain Hulk the ability to reduce iron and nitrate for respiration. The annotation of the genome of strain Hulk identified genes for the reduction of several sulfur-containing electron acceptors, an unsuspected respiratory capability in this species that was experimentally confirmed for strain Hulk. This makes P. delaneyi strain Hulk the first hyperthermophilic archaeon known to gain energy for growth by reduction of iron, nitrate, and sulfur-containing electron acceptors. Here we present the most notable features of the genome of P. delaneyi strain Hulk and identify genes encoding proteins critical to its respiratory versatility at high temperatures. The description presented here corresponds to a draft genome sequence containing 2,042,801 bp in 9 contigs, 2019 protein-coding genes, 53 RNA genes, and 1365 hypothetical genes. PMID- 28814987 TI - Green Tea Polyphenols Ameliorate the Early Renal Damage Induced by a High-Fat Diet via Ketogenesis/SIRT3 Pathway. AB - SCOPE: Several reports in the literature have suggested the renoprotective effects of ketone bodies and green tea polyphenols (GTPs). Our previous study found that GTP consumption could elevate the renal expression of the ketogenic rate-limiting enzyme, which was decreased by a high-fat diet (HFD) in rats. Here, we investigated whether ketogenesis can mediate renoprotection by GTPs against an HFD. METHODS AND RESULTS: Wistar rats were fed a standard or HFD with or without GTPs for 18 weeks. The renal oxidative stress level, kidney function, renal expression, and activity levels of mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase 2 (HMGCS2) and sirtuin 3(SIRT3) were detected. The increased renal oxidative stress and the loss of renal function induced by the HFD were ameliorated by GTPs. Renal ketogenesis and SIRT3 expression and activity levels, which were reduced by the HFD, were restored by GTPs. In vitro, HEK293 cells were transfected with the eukaryotic expression plasmid pcDNA HMGCS2. GTP treatment could upregulate HMGCS2 and SIRT3 expression. Although SIRT3 expression was not affected by HMGCS2 transfection, the 4-hydroxy-2-nonenal (4-HNE) level and the acetyl-MnSOD (K122)/MnSOD ratio were reduced in HMGCS2-transfected cells in the context of H2O2. CONCLUSION: The ketogenesis/SIRT3 pathway mediates the renoprotection of GTPs against the oxidative stress induced by an HFD. PMID- 28814990 TI - Privacy and Security in Multi-User Health Kiosks. AB - Enforcement of the Health Insurance Portability and Accountability Act (HIPAA) and the Health Information Technology for Economic and Clinical Health Act (HITECH) has gotten stricter and penalties have become more severe in response to a significant increase in computer-related information breaches in recent years. With health information said to be worth twice as much as other forms of information on the underground market, making preservation of privacy and security an integral part of health technology development, rather than an afterthought, not only mitigates risks but also helps to ensure HIPAA and HITECH compliance. This paper provides a guide, based on the Office for Civil Rights (OCR) audit protocol, for creating and maintaining an audit checklist for multi user health kiosks. Implementation of selected audit elements for a multi-user health kiosk designed for use by community-residing older adults illustrates how the guide can be applied. PMID- 28814991 TI - Feasibility of Using Telehealth to Deliver the "Powerful Tools for Caregivers" Program. AB - Caregivers report poorer health and wellness than the general population and identify numerous barriers to their attending programs to improve health and wellness. The purpose of this study was to explore the feasibility of employing a telehealth delivery method to enhance access to caregiver wellness programs. This article presents the quantitative results of a mixed methods feasibility study of translating the Powerful Tools for Caregivers (PTC) program to a telehealth delivery format. Four unpaid family caregivers of older adults participated in a telehealth delivered PTC program, a wellness program with established outcomes in the in-person environment. The program was delivered using synchronous videoconferencing methods. High class attendance and a high median total average Telehealth Usability Questionnaire score of 5.7 indicated the telehealth delivery method was feasible. This research suggests that telehealth is a feasible delivery format for a caregiver program traditionally delivered in an in-person format. PMID- 28814992 TI - Feasibility of a Supplemental Phonological Awareness Intervention via Telepractice for Children with Hearing Loss: A Preliminary Study. AB - The goal of the current study was to examine the feasibility of a telepractice intervention to improve phonological awareness skills in children with hearing loss as compared to a conventional in-person intervention. Twenty children with hearing loss participated in this study. Two groups of ten children each received a supplemental phonological awareness intervention either via telepractice or an in-person service delivery model. Within each of the two groups, five children were enrolled in preschool or kindergarten and five children were enrolled in first or second grade. The two groups of children demonstrated similar phonological awareness, non-verbal IQ, and vocabulary skills during pre-tests. After a 12-week intervention children with hearing loss showed improved phonological awareness skills as measured by a standardized post-test. No significant differences were found between the performance of the telepractice group and in-person group. Nor was a significant interaction found between the two age groups (PreK/K vs. 1st /2nd grade) and the two types of service delivery models (in-person vs. telepractice). The results suggest that a telepractice service delivery model is feasible for young children with hearing loss, and that telepractice may be as effective as in-person intervention in improving phonological awareness skills. PMID- 28814993 TI - Exploration of the Effects of Telerehabilitation in a School-Based Setting for At Risk Youth. AB - This study explored the efficacy and feasibility of a motion-capture program that may be utilized for telerehabilitation purposes. Two children attending a school for at-risk children received 20 sessions of Timocco, with sessions lasting for 30 minutes, under the guidance of research assistants. The researchers employed a mixed methods design to analyze quantitative data and qualitative interviews. Both children improved their fine and gross motor coordination, as measured on the Bruininks-Oseretsky Test of Motor Proficiency Short Form. To explore feasibly, qualitative verbal reports of the child participants and research assistants were obtained. The children and research assistants reported positive experiences with the utilization of this platform. A collaborative, consultative telerehabilitation model may be a promising delivery mode of services for improving motor skills in children, with frequent input from the child, aide or teacher, and clinician. Further exploration is needed for telerehabilitative service delivery for at-risk children. PMID- 28814994 TI - Home Quick - Occupational Therapy Home Visits Using mHealth, to Facilitate Discharge from Acute Admission Back to the Community. AB - This article reports upon an initiative to improve the timeliness of occupational therapy home visits for discharge planning by implementing technology solutions while maintaining patient safety. A community hospital in Queensland, Australia, hosted a process evaluation that examined which aspects of home visiting could be replaced or augmented by alternative technologies. Strategies were trialled, implemented and assessed using the number of home visits completed and the time from referral to completion as outcomes. A technology-enhanced solution called "Home Quick" was developed using technology to facilitate pre-discharge home visits. The implementation of Home Quick resulted in an increase in the number of home visits conducted prior to discharge (50% increase from 145 to 223) and significantly increased the number of patients seen earlier following referral (X2=69.3; p<0.001). The substitution of direct home visits with technology enabled remote visits is suitable for a variety of home visiting scenarios traditionally performed by occupational therapists. PMID- 28814995 TI - The Efficacy of Telehealth-Delivered Speech and Language Intervention for Primary School-Age Children: A Systematic Review. AB - The purpose of this article is to determine if telehealth-delivered speech language pathology interventions are as effective as traditional in-person delivery for primary school-age children with speech and/or language difficulties. A systematic review was conducted (in accordance with PRISMA guidelines) using five databases, two journals and reference lists. Titles and abstracts were screened for inclusion, with relevant studies reviewed in full text. Initial searches identified 132 articles. Following exclusion of non relevant studies, seven articles remained for inclusion. Results revealed both telehealth and in-person participants made significant and similar improvements when treatment effects were measured through five of the six outcome measures. Findings showed there is limited but promising evidence to support telehealth for delivering speech-language pathology intervention services to school-age children. Whilst this is encouraging, particularly for rural children where in person services are limited, more rigorous study designs are required to support the efficacy of telehealth for this population. PMID- 28814996 TI - A Commentary on Telerehabilitation Services in Pakistan: Current Trends and Future Possibilities. AB - A 2014 World Health Organization (WHO) study reported that almost 27 million people with disability live in Pakistan with fewer than one allied rehabilitation professional per 10,000 people. The current study sought to determine the attitudes toward telerehabilitation via a survey administered to 329 Pakistani rehabilitation professionals. Study results indicate that rehabilitation professionals in Pakistan are knowledgeable about telerehabilitation and Information and Communication Technology (ICT), and are receptive to employing telerehabilitation programs and applications. Therefore, we can infer that the future of telerehabilitation can be bright in Pakistan but requires the attention of policy makers and non-government organizations to launch an appropriate program nationwide. The authors suggest that a range of telerehabilitation services (e.g., consultation, assessment, and therapy) could alleviate the shortage of rehabilitation personnel in Pakistan. PMID- 28814997 TI - Telehealth is Face-to-Face Service Delivery. AB - The Commentary contests the increasingly outdated and narrow use of the terminology 'face-to-face' (often abbreviated as F2F) to connote clinical interactions in which both the client and the practitioner are physically present in the same room or space. An expanded definition is necessary because when delivered synchronously via videoconferencing, telehealth also provides face-to face services (i.e., the practitioner and the client view each other's faces). Terminology that uses face-to-face to connote only in-person care is limiting and perpetuates language that is out of line with progressive US regulatory language and broad interpretation within existing regulatory language. It is this author's hope that this commentary will raise awareness of the important policy implications associated with this seemingly minor distinction in terminology and impact the lingering misapplication of the term, face-to-face. PMID- 28814998 TI - Correction To: TSAVOURELOU, A., STYLIANIDES, N., PAPADOPOULOS, A., DIKAIAKOS, M. D., NANAS, S., KYPRIANOU, T., TOKMAKIDIS, S. P. (2016). TELEREHABILITATION SOLUTION CONCEPTUAL PAPER FOR COMMUNITY-BASED EXERCISE REHABILITATION OF PATIENTS DISCHARGED AFTER CRITICAL ILLNESS. INTERNATIONAL JOURNAL OF TELEREHABILITATION, 8(2), 61-70. DOI: 10.5195/IJT.2016.6205. AB - [This corrects the article on p. 61 in vol. 8, PMID: 28775802.]. PMID- 28814999 TI - Centralization of Liver Cancer Surgery and Impact on Multidisciplinary Teams Working on Stage IV Colorectal Cancer. AB - Surgical resection is the most effective treatment approach for colorectal liver metastases but only a minority of patients is suitable for upfront surgery. The treatment strategies of stage IV colorectal cancer have shifted towards a continuum of care in which medical and surgical treatment combinations are tailored to the clinical setting of the individual patient. The optimization of treatment through appropriate decision-making and multimodal therapy for stage IV colorectal cancer require a joint multidisciplinary meeting in a centralized liver cancer unit. PMID- 28815000 TI - African tick bite fever in returning Swedish travellers. Report of two cases and aspects of diagnostics. AB - Introduction: African tick-bite fever, caused by Rickettsia africae, is endemic in rural areas of sub-Saharan Africa and a possible cause of fever in returning Swedish travellers. Two patients are presented, and the advantages and disadvantages of different diagnostic methods are discussed. Patients and methods: Two middle-aged men fell ill with fever after returning home from South Africa. Both had single eschars and one also presented with a lymph node swelling. Samples were taken for serology, general bacterial culture from the wound (Patient 1) using a swab and additionally for Patient 2 PCR of a skin biopsy from the eschar. Results and discussion: Both patients seroconverted one month after onset. Real-time PCR of the biopsy was positive, where sequencing of the gltA gene was 99-100% consistent with R. africae. A drop of fluid from the biopsy contained a sufficient number of bacteria to also allow for isolation of rickettsiae in Vero cell culture. Direct molecular detection by PCR from a swab used for bacteria culture from the eschar from Patient 1 also yielded a positive result. In conclusion, the findings highlight the usefulness of swabs for early non-invasive diagnosis of African tick-bite fever in febrile travellers. PMID- 28815001 TI - Serogrouping and seroepidemiology of North European hantaviruses using a novel broadly targeted synthetic nucleoprotein antigen array. AB - Introduction: Hantaviruses are globally distributed zoonotic pathogens. Great diversity and high antigenic cross-reactivity makes diagnosis by traditional methods cumbersome. Materials and methods: 'Megapeptides', 119-120-mers from the amino terminus of the nucleoprotein of 16 hantaviruses, representing the four major branches of the hantavirus phylogenetic tree, were utilized in a novel IgG based hantavirus suspension multiplex immunoassay (HSMIA) for detection of past hantavirus infections in 155 North European human samples. We compared HSMIA with established EIAs and focus reduction neutralization test (FRNT). Results and discussion: The Puumala hantavirus (PUUV) component in the HSMIA gave concordant results with a PUUV IgG EIA in 142 sera from Northern Sweden (of which 31 were EIA positive, 7 borderline and 104 EIA negative, sensitivity 30/31 = 97%, specificity 104/ 104 = 100%, 134/135 = 99% concordance), with another immunoassay in 40 PUUV IgG positive sera from Finland (36/40 = 90% sensitivity), and was concordant in 8 of 11 cases with PUUV and DOBV neutralization titers, respectively. Two major IgG reactivity patterns were found: (i) a PUUV-specific pattern covering phylogroup IV and its serogroups B and C; and (ii) a Dobrava virus (DOBV)-specific pattern, covering the serogroup A portion of phylogroup III. In addition, we found several minor patterns with reactivity to only one or two megapeptides indicating additional hantaviruses infecting humans in the Swedish and Finnish populations. Conclusion: The broadly reactive and rational HSMIA yielded results highly correlated with the established PUUV EIAs and the NT results. It is a sensitive and specific assay, which will be suited for efficient serosurveillance of hantaviruses in humans. Its use in animals should be further investigated. PMID- 28815002 TI - A comprehensive method for identification of suitable reference genes in extracellular vesicles. AB - Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) is one of the most sensitive, economical and widely used methods for evaluating gene expression. However, the utility of this method continues to be undermined by a number of challenges including normalization using appropriate reference genes. The need to develop tailored and effective strategies is further underscored by the burgeoning field of extracellular vesicle (EV) biology. EVs contain unique signatures of small RNAs including microRNAs (miRs). In this study we develop and validate a comprehensive strategy for identifying highly stable reference genes in a therapeutically relevant cell type, cardiosphere-derived cells. Data were analysed using the four major approaches for reference gene evaluation: NormFinder, GeNorm, BestKeeper and the Delta Ct method. The weighted geometric mean of all of these methods was obtained for the final ranking. Analysis of RNA sequencing identified miR-101-3p, miR-23a-3p and a previously identified EV reference gene, miR-26a-5p. Analysis of a chip-based method (NanoString) identified miR-23a, miR-217 and miR-379 as stable candidates. RT-qPCR validation revealed that the mean of miR-23a-3p, miR-101-3p and miR-26a-5p was the most stable normalization strategy. Here, we demonstrate that a comprehensive approach of a diverse data set of conditions using multiple algorithms reliably identifies stable reference genes which will increase the utility of gene expression evaluation of therapeutically relevant EVs. PMID- 28815004 TI - Hypersensitivity pneumonitis among wind musicians - an overlooked disease? AB - Hypersensitivity pneumonitis (HP) is a complex pulmonary disorder mediated by the immune system and caused by various inhaled antigens against which the subject has previously been sensitized. In about 50% of the cases, the antigen is not identified. Identification and removal of the eliciting antigen is important for the prognosis. We report two cases of HP caused by molds and atypical mycobacteria isolated from wind instruments. We present the first case of HP caused by bassoon playing and another case of HP caused by molds in a trombone. HP caused by fungi and bacteria in wind instruments may be much more common than previously thought. HP caused by fungi and bacteria in wind instruments is probably underdiagnosed; this calls for more clinical attention when HP is suspected. PMID- 28815003 TI - Glioblastoma stem-like cells secrete the pro-angiogenic VEGF-A factor in extracellular vesicles. AB - Glioblastoma multiforme (GBM) are mortifying brain tumours that contain a subpopulation of tumour cells with stem-like properties, termed glioblastoma stem like cells (GSCs). GSCs largely contribute to tumour initiation, propagation and resistance to current anti-cancer therapies. GSCs are situated in perivascular niches, closely associated with brain microvascular endothelial cells, thereby involved in bidirectional molecular and cellular interactions. Moreover, extracellular vesicles are suspected to carry essential information that can adapt the microenvironment to the tumour's needs, including tumour-induced angiogenesis. In GBM, extracellular vesicles produced by differentiated tumour cells and GSCs were demonstrated to disseminate locally and at distance. Here, we report that the pro-angiogenic pro-permeability factor VEGF-A is carried in extracellular vesicles secreted from ex vivo cultured patient-derived GSCs. Of note, extracellular vesicle-derived VEGF-A contributes to the in vitro elevation of permeability and angiogenic potential in human brain endothelial cells. Indeed, VEGF-A silencing in GSCs compromised in vitro extracellular vesicle mediated increase in permeability and angiogenesis. From a clinical standpoint, extracellular vesicles isolated from circulating blood of GBM patients present higher levels of VEGF-A, as compared to healthy donors. Overall, our results suggest that extracellular vesicle-harboured VEGF-A targets brain endothelial cells and might impact their ability to form new vessels. Thus, tumour-released EV cargo might emerge as an instrumental part of the tumour-induced angiogenesis and vascular permeability modus operandi in GBM. PMID- 28815005 TI - Phase I study evaluating the safety, tolerability and pharmacokinetics of a novel oral dissolvable film containing dexamethasone versus Fortecortin dexamethasone tablets. AB - Introduction: Systemic corticosteroids are anti-inflammatory agents with dexamethasone among the most potent in the class. Within (respiratory) allergy, systemic corticosteroids are usually applied in medical emergencies. In these situations, patients may experience physical or logistic problems taking tablets. To fulfil a practical unmet need for outpatients, Dexa ODF, an oral dissolvable film containing dexamethasone, was developed. Objectives: We compared the safety, tolerability and pharmacokinetics (PK) of Dexa ODF with Fortecortin tablets in healthy subjects. Methods: Thirty subjects participated in this open label, two way, cross-over study, consisting of two treatment visits separated by 5-10 days. On both treatment visits, subjects randomly received one single dose of Dexa ODF (one strip; 8 mg dexamethasone) or one single dose of Fortecortin (two 4 mg tablets). Safety evaluations and blood sampling for PK were conducted until 48 h post-dose and bioequivalence analysis was performed on AUC(0-t), AUC(0-infinity) and Cmax. Results: All subjects were dosed. Forty-five adverse events (AEs) were reported by 17 subjects and approximately 50% were deemed 'possibly treatment related' (14 on Dexa ODF; 12 on Fortecortin) with no significant difference between treatments. For all three bioequivalence parameters the 90% CIs were within the acceptance limits of bioequivalence (0.8;1.25). Conclusion: We demonstrated good tolerability and bioequivalence of Dexa ODF (8 mg dexamethasone) compared to Fortecortin tablets (2 * 4 mg dexamethasone). Dexa ODF is currently under development as an innovative treatment for use within respiratory and allergic conditions, including emergencies. PMID- 28815007 TI - Appropriate selection for omalizumab treatment in patients with severe asthma? AB - Background: Omalizumab improves asthma control in patients with uncontrolled severe allergic asthma; however, appropriate patient selection is crucial. Information in this field is sparse. Objective: We aimed to estimate whether potential omalizumab candidates were appropriately selected according to guidelines, and the clinical effect of omalizumab treatment over time. Design: We performed a retrospective observational study on adult patients with asthma treated with omalizumab during 2006-2015 at the Department of Respiratory Medicine at Odense University Hospital (OUH), Denmark. Data were obtained from the Electronic Patient Journal of OUH and Odense Pharmaco-Epidemiological Database. Guideline criteria for omalizumab treatment were used to evaluate the appropriateness of omalizumab candidate selection, and the Asthma Control Test (ACT) to assess the clinical effects of omalizumab at weeks 16 and 52 from treatment initiation. Results: During the observation period, 24 patients received omalizumab, but only 10 patients (42%) fulfilled criteria recommended by international guidelines. The main reasons for not fulfilling the criteria were inadequately reduced lung function, insufficient number of exacerbations, and asthma standard therapy below Global Initiative for Asthma (GINA) step 4-5. Seventeen and 11 patients completed treatment at weeks 16 and 52, with a statistically significant increase in ACT score of 5.1 points [95% confidence interval (CI) 3.1-7.2, p = 0.0001] and 7.7 points (95% CI 4.3-11.1, p = 0.0005), respectively. Conclusion: Only 42% of the omalizumab-treated patients were appropriately selected according to current guidelines. Still, as omalizumab showed significant improvement in asthma control over time, it is important to keep this drug in mind as an add-on to asthma therapy in well-selected patients. PMID- 28815006 TI - Biomarkers in inflammometry pediatric asthma: utility in daily clinical practice. AB - Asthma is a common disease in both high and lower income countries that starts early and persists often for life. A correct and accurate diagnosis, treatment and follow-up during childhood are essential for a better understanding of adult asthma and avoiding over- or under-treatment. Th2 inflammation in children with asthma symptoms is usually assessed by measuring with serum total IgE, blood eosinophilia and FeNO levels that may help to predict asthma, particularly in those infants and young children in whom lung function tests are difficult to perform. FeNO measurement, compared to intra-individual levels, may be useful also for ascertaining treatment adherence. Nevertheless, an isolated measurement may be insufficient and only the combination of these markers improves the diagnosis, phenotyping and follow-up of an asthmatic child. PMID- 28815008 TI - Evaluation of medication adherence in chronic disease at a federally qualified health center. AB - BACKGROUND: While medication adherence in chronic disease has been evaluated in the general population, limited data are available among Medicaid recipients, especially within federally qualified health centers (FQHCs). This study determined baseline medication adherence for Medicaid recipients receiving care in an FQHC for first-line medications used in hypertension, hyperlipidemia, and diabetes. Secondary outcomes included baseline adherence for individual patient factors. METHODS: Patients from the Salud Family Health Centers, an FQHC with a large percentage of both Spanish-speaking patients and providers, were included in this study. Using retrospective prescription claims reports from 1 January 2015 to 1 October 2015, medication possession ratios (MPRs) and proportion of days covered (PDC) were calculated for each medication group. Patients with adherence ?0.80 were considered adherent. RESULTS: From 1034 individual patients, 1788 medications were evaluated. Using MPRs, adherence rates were highest among medications for hypertension (67.2% adherent), followed by hyperlipidemia (67.0%), and lastly diabetes (58.0%); p < 0.001. Likewise, using PDC, adherence rates were highest for medications for hypertension (56.6%), followed by hyperlipidemia (52.2%), and lastly diabetes (45.0%); p = 0.010. Lower rates of adherence were seen among men, patients age 18-29 years old, African Americans, and patients with English documented as their preferred language. CONCLUSIONS: Although overall medication adherence rates within our FQHC patients were comparable with those in previous literature, differences seen among medication groups and patient individual factors suggest that there is still much to be learned in improving adherence. Future efforts will require a multifaceted approach, tailored to patient-specific needs. PMID- 28815010 TI - Development and characterisation of a low-concentration sodium dodecyl sulphate decellularised porcine dermis. AB - The aim of this study was to adapt a proprietary decellularisation process for human dermis for use with porcine skin. Porcine skin was subject to: sodium chloride (1 M) to detach the epidermis, trypsin paste to remove hair follicles, peracetic acid (0.1% v/v) disinfection, washed in hypotonic buffer and 0.1% (w/v) sodium dodecyl sulphate in the presence of proteinase inhibitors followed by nuclease treatment. Cellular porcine skin, decellularised porcine and human dermis were compared using histology, immunohistochemistry, GSL-1 lectin (alpha gal epitope) staining, biochemical assays, uniaxial tensile and in vitro cytotoxicity tests. There was no microscopic evidence of cells in decellularised porcine dermis. DNA content was reduced by 98.2% compared to cellular porcine skin. There were no significant differences in the biomechanical parameters studied or evidence of cytotoxicity. The decellularised porcine dermis retained residual alpha-gal epitope. Basement membrane collagen IV immunostaining was lost following decellularisation; however, laminin staining was retained. PMID- 28815012 TI - The 2016 Ming K Jeang Award for Excellence in Cell & Bioscience. AB - Two research groups led by Dr. Jim Hu of University of Toronto, Canada and Dr. Renping Zhou of Rutgers University, USA, respectively, won the 2016 Ming K Jeang Award for Excellence in Cell & Bioscience. PMID- 28815009 TI - Strategies for dementia prevention: latest evidence and implications. AB - Dementia is a common and debilitating syndrome with enormous impact on individuals and societies. Preventing disease onset or progression would translate to public health and societal benefits. In this review, we discuss the latest evidence on interventions that may show promise for the prevention of cognitive decline. We appraise existing evidence primarily drawn from randomized controlled trials, systematic reviews, and meta-analyses, but also highlight observational studies in humans and relevant work in model organisms. Overall, there is currently limited evidence to support a cause-effect relationship between any preventive strategy and the development or progression of dementia. However, studies to date suggest that a multifactorial intervention comprising regular exercise and healthy diet, along with the amelioration of vascular risk factors, psychosocial stress, and major depressive episodes may be most promising for the prevention of cognitive decline. We discuss the challenges, future directions, and implications of this line of research. PMID- 28815013 TI - Diabetic retinopathy: reversibility of epigenetic modifications and new therapeutic targets. AB - In recent years, considerable progress has been made in the molecular mechanisms of epigenetics in disease development and progression, the reversible characteristics of epigenetic modification provide new insights for the treatment of such diseases. The pathogenesis of diabetic retinopathy (DR) has not yet been fully understood, treatment of refractory and recurrent diabetic macular edema remains a big change in clinical practice. This review emphasizes that reversibility of epigenetic modification could provide a new strategy for the prevention and treatment of diseases. PMID- 28815014 TI - The relationship between intolerance of uncertainty in chiropractic students and their treatment intervention choices. AB - BACKGROUND: Psychological factors, such as intolerance of uncertainty (IU), have been shown to impact on the quality of medical care. However, this psychological measure has not been studied in the chiropractic profession. Our objective was to investigate if higher levels of IU in chiropractic students were related to poor choices of management in specific clinical scenarios. Also, we sought to investigate if levels of IU were related to students' intentions to adopt a prescriptive chiropractic technique system and evaluate their levels of self belief. METHOD: Between October and November of 2016, students from two Australian chiropractic programs (N = 444) answered a questionnaire on measures of IU levels, patient case scenarios for neck and low back pain, and questions about self-ratings of their future chiropractic abilities and perceived need for the adoption of a chiropractic technique system. Associations were tested by the IU score and the therapeutic choices relating to a) a neck pain case scenario, b) a low back pain scenario, c) various technique systems, and d) the self-rated competence level treating the IU score both as a continuous and a categorical variable. RESULTS: There was an overall response rate of 53%. Those students who were high in levels of IU were significantly more likely to make incorrect clinical decisions than those with normal or low levels of IU for the neck pain case scenario. No differences were found on the low back pain scenario, on preferences to use a technique system in the future, or on predicted self-rating of competence after graduation. CONCLUSIONS: Psychological factors, such as IU, may have an impact on chiropractic students' clinical decisions. However, it does not impact on all aspects of practice. This finding has implications for chiropractic educators, especially when dealing with neck pain. However, it may be relevant to continue the search for specific personality profiles in relation to various favourable and unfavourable practice patterns, as it is unknown whether these dynamics are important for other aspects of chiropractic education. PMID- 28815016 TI - Erratum to: Dog bite injuries to humans and the use of breed-specific legislation: a comparison of bites from legislated and non-legislated dog breeds. AB - [This corrects the article DOI: 10.1186/s13620-017-0101-1.]. PMID- 28815015 TI - Exploring the definition of "acute" neck pain: a prospective cohort observational study comparing the outcomes of chiropractic patients with 0-2 weeks, 2-4 weeks and 4-12 weeks of symptoms. AB - BACKGROUND: Neck pain is a common complaint in chiropractic patients. Amongst other baseline variables, numerous studies identify duration of symptoms as a strong predictor of outcome in neck pain patients. The usual time frame used for 'acute' onset of pain is between 0 and 4 weeks. However, the appropriateness of this time frame has been challenged for chiropractic low back pain patients. Therefore, the purpose of this study was to compare outcomes in neck pain patients with 0-2 vs 2-4 and 4-12 weeks of symptoms undergoing chiropractic treatment. METHODS: This is a prospective cohort observational study with 1 year follow-up including 495 patients whose data was collected between October 2009 and March 2015. Patients were divided into high-acute (0-2 weeks), mid-acute (2-4 weeks) and subacute (4-12 weeks) corresponding to duration of their symptoms at initial treatment. Patients completed the numerical pain rating scale (NRS) and Bournemouth questionnaire for neck pain (BQN) at baseline. At follow-up time points of 1 week, 1 month, 3 months, 6 months and 1 year the NRS and BQN were completed along with the Patient Global Impression of Change (PGIC) scale. The PGIC responses were dichotomized into 'improved' and 'not improved' patients and compared between the 3 subgroups. The Chi-square test was used to compare improved patients between the 3 subgroups and the unpaired Student's t-test was used for the NRS and BQN change scores. RESULTS: The proportion of patients 'improved' was only significantly higher for patients with symptoms of 0-2 weeks compared to 2-4 weeks at the 1 week outcome time point (p = 0.015). The NRS changes scores were significantly greater for patients with 2-4 weeks of symptoms compared to 4-12 weeks of symptoms only at 1 week (p = 0.035). CONCLUSIONS: The time period of 0-4 weeks of symptoms as the definition of "acute" neck pain should be maintained. Independent of the exact duration of symptoms, medium-term and long-term outcome is favourable for acute as well as subacute neck pain patients. TRIAL REGISTRATION: Not applicable for prospective cohort studies. Ethics approval prior to study EK 19/2009. PMID- 28815017 TI - Autophagy and airway fibrosis: Is there a link? AB - In the past decade, an emerging process named "autophagy" has generated intense interest in many chronic lung diseases. Tissue remodeling and fibrosis is a common feature of many airway diseases, and current therapies do not prevent or reverse these structural changes. Autophagy has evolved as a conserved process for bulk degradation and recycling of cytoplasmic components to maintain basal cellular homeostasis and healthy organelle populations in the cell. Furthermore, autophagy serves as a cell survival mechanism and can also be induced by chemical and physical stress to the cell. Accumulating evidence demonstrates that autophagy plays an essential role in vital cellular processes, including tissue remodeling. This review will discuss some of the recent advancements made in understanding the role of this fundamental process in airway fibrosis with emphasis on airway remodeling, and how autophagy can be exploited as a target for airway remodeling in asthma and chronic obstructive pulmonary disease. PMID- 28815018 TI - Serum complexed and free prostate specific antigen levels are lower in female elite athletes in comparison to control women. AB - BACKGROUND: We hypothesize that prostate specific antigen (PSA), a protein that it is under regulation by androgens, may be differentially expressed in female elite athletes in comparison to control women. METHODS: We conducted a cross sectional study of 106 female athletes and 114 sedentary age-matched controls. Serum from these women was analyzed for complexed prostate specific antigen (cPSA) and free prostate specific antigen (fPSA), by fifth generation assays with limits of detection of around 6 and 140 fg/mL, respectively. A panel of estrogens, androgens and progesterone in the same serum was also quantified by tandem mass spectrometry. Results: Both components of serum PSA (cPSA and fPSA) were lower in the elite athletes vs the control group (P=0.033 and 0.013, respectively). Furthermore, estrone (p=0.003) and estradiol (p=0.004) were significantly lower, and dehydroepiandrosterone (p=0.095) and 5-androstene 3beta, 17beta-diol (p=0.084) tended to be higher in the athletes vs controls. Oral contraceptive use was similar between groups and significantly associated with increased cPSA and fPSA in athletes (p= 0.046 and 0.009, respectively). PSA fractions were not significantly associated with progesterone changes. The Spearman correlation between cPSA and fPSA in both athletes and controls was 0.75 (P < 0.0001) and 0.64 (P < 0.0001), respectively. Conclusions: Elite athletes have lower complexed and free PSA, higher levels of androgen precursors and lower levels of estrogen in their serum than sedentary control women. ABBREVIATIONS: cPSA, complexed PSA; fPSA, free PSA; PCOS, polycystic ovarian syndrome; E1, estrone; E2, estradiol; DHEA, dehydroepiandrosterone, Testo, testosterone; DHT, dihydrotestosterone; PROG, progesterone; Delta 4, androstenedione; Delta 5, androst-5-ene-3beta, 17beta-diol; BMD, body mineral density; LLOQ, lower limit of quantification; ULOQ, upper limit of quantification; LOD, limit of detection; ACT, alpha 1-antichymotrypsin. PMID- 28815019 TI - Therapeutic potential of systemic brain rejuvenation strategies for neurodegenerative disease. AB - Neurodegenerative diseases are a devastating group of conditions that cause progressive loss of neuronal integrity, affecting cognitive and motor functioning in an ever-increasing number of older individuals. Attempts to slow neurodegenerative disease advancement have met with little success in the clinic; however, a new therapeutic approach may stem from classic interventions, such as caloric restriction, exercise, and parabiosis. For decades, researchers have reported that these systemic-level manipulations can promote major functional changes that extend organismal lifespan and healthspan. Only recently, however, have the functional effects of these interventions on the brain begun to be appreciated at a molecular and cellular level. The potential to counteract the effects of aging in the brain, in effect rejuvenating the aged brain, could offer broad therapeutic potential to combat dementia-related neurodegenerative disease in the elderly. In particular, results from heterochronic parabiosis and young plasma administration studies indicate that pro-aging and rejuvenating factors exist in the circulation that can independently promote or reverse age-related phenotypes. The recent demonstration that human umbilical cord blood similarly functions to rejuvenate the aged brain further advances this work to clinical translation. In this review, we focus on these blood-based rejuvenation strategies and their capacity to delay age-related molecular and functional decline in the aging brain. We discuss new findings that extend the beneficial effects of young blood to neurodegenerative disease models. Lastly, we explore the translational potential of blood-based interventions, highlighting current clinical trials aimed at addressing therapeutic applications for the treatment of dementia-related neurodegenerative disease in humans. PMID- 28815020 TI - Advances on minimally invasive approach for benign total hysterectomy: a systematic review. AB - Hysterectomy is one of the most commonly performed gynecologic surgeries, mainly for uterine myomas, abnormal uterine bleeding, and prolapses. It can be performed through several routes, each of which has its advantages and disadvantages. We conducted this systematic review to evaluate recent advances in surgical outcomes of benign total hysterectomies by any route: vaginal (VH), laparoscopic (LH), laparoscopically assisted vaginal (LAVH), single-port (SP), and robotic-assisted laparoscopy (RH). The search was applied to the PubMed electronic database by using keywords "hysterectomy" and "uterine benign disease", "adenomyosis", and "myoma". Prospective and randomized trials of the last 3 years were included. Nine studies were selected and showed that VH was superior to LH, LAVH, and RH in terms of hospital stay and operation time and had the same complication rate and lower costs. SP hysterectomy had no clear advantages over VH or conventional LH. PMID- 28815021 TI - Toward an understanding of the Cdc48/p97 ATPase. AB - A conserved AAA+ ATPase, called Cdc48 in yeast and p97 or VCP in metazoans, plays an essential role in many cellular processes by segregating polyubiquitinated proteins from complexes or membranes. For example, in endoplasmic reticulum (ER) associated protein degradation (ERAD), Cdc48/p97 pulls polyubiquitinated, misfolded proteins out of the ER and transfers them to the proteasome. Cdc48/p97 consists of an N-terminal domain and two ATPase domains (D1 and D2). Six Cdc48 monomers form a double-ring structure surrounding a central pore. Cdc48/p97 cooperates with a number of different cofactors, which bind either to the N terminal domain or to the C-terminal tail. The mechanism of Cdc48/p97 action is poorly understood, despite its critical role in many cellular systems. Recent in vitro experiments using yeast Cdc48 and its heterodimeric cofactor Ufd1/Npl4 (UN) have resulted in novel mechanistic insight. After interaction of the substrate attached polyubiquitin chain with UN, Cdc48 uses ATP hydrolysis in the D2 domain to move the polypeptide through its central pore, thereby unfolding the substrate. ATP hydrolysis in the D1 domain is involved in substrate release from the Cdc48 complex, which requires the cooperation of the ATPase with a deubiquitinase (DUB). Surprisingly, the DUB does not completely remove all ubiquitin molecules; the remaining oligoubiquitin chain is also translocated through the pore. Cdc48 action bears similarities to the translocation mechanisms employed by bacterial AAA ATPases and the eukaryotic 19S subunit of the proteasome, but differs significantly from that of a related type II ATPase, the NEM-sensitive fusion protein (NSF). Many questions about Cdc48/p97 remain unanswered, including how it handles well-folded substrate proteins, how it passes substrates to the proteasome, and how various cofactors modify substrates and regulate its function. PMID- 28815022 TI - Modeling of RAS complexes supports roles in cancer for less studied partners. AB - BACKGROUND: RAS protein interactions have predominantly been studied in the context of the RAF and PI3kinase oncogenic pathways. Structural modeling and X ray crystallography have demonstrated that RAS isoforms bind to canonical downstream effector proteins in these pathways using the highly conserved switch I and II regions. Other non-canonical RAS protein interactions have been experimentally identified, however it is not clear whether these proteins also interact with RAS via the switch regions. RESULTS: To address this question we constructed a RAS isoform-specific protein-protein interaction network and predicted 3D complexes involving RAS isoforms and interaction partners to identify the most probable interaction interfaces. The resulting models correctly captured the binding interfaces for well-studied effectors, and additionally implicated residues in the allosteric and hyper-variable regions of RAS proteins as the predominant binding site for non-canonical effectors. Several partners binding to this new interface (SRC, LGALS1, RABGEF1, CALM and RARRES3) have been implicated as important regulators of oncogenic RAS signaling. We further used these models to investigate competitive binding and multi-protein complexes compatible with RAS surface occupancy and the putative effects of somatic mutations on RAS protein interactions. CONCLUSIONS: We discuss our findings in the context of RAS localization to the plasma membrane versus within the cytoplasm and provide a list of RAS protein interactions with possible cancer related consequences, which could help guide future therapeutic strategies to target RAS proteins. PMID- 28815023 TI - Antibiotic resistance, ability to form biofilm and susceptibility to copper alloys of selected staphylococcal strains isolated from touch surfaces in Polish hospital wards. AB - BACKGROUND: Despite the employment of sanitary regimes, contact transmission of the aetiological agents of hospital infections is still exceedingly common. The issue of microbe transmission becomes particularly important when facing multidrug-resistant microorganisms such as methicillin-resistant staphylococci. In the case of deficiencies in cleaning and disinfection procedures, hospital equipment made of copper alloys can play an important role, complementing traditional hospital hygiene procedures. The objective of this study was to characterize staphylococcal strains isolated from touch surfaces in Polish hospital wards in terms of their drug resistance, ability to form biofilm and susceptibility to antimicrobial activity of copper alloys. METHODS: The materials for the study were 95 staphylococcal strains isolated from touch surfaces in 13 different hospital wards from Malopolska province (the south of Poland). Phenotypic and genotypic antibiotic resistance were checked for erythromycin, clindamycin, gentamycin, ciprofloxacin, trimethoprim/sulfamethoxazole and mupirocin. Biofilm formation ability for the tested strains was checked with the use of culture on Congo red agar. Susceptibility to copper, tin bronze, brass and new silver was tested using a modification of the Japanese standard. RESULTS: Over 67% of the analysed staphylococcal strains were methicillin-resistant (MR). Four strains were resistant to all of the tested antibiotics, and 14 were resistant to all except mupirocin. Strains classified as MR had significantly increased resistance to the remaining antibiotic groups. About one-third of the analysed strains revealed biofilm-forming ability. Among the majority of species, biofilm-forming and non-biofilm-forming strains were distributed evenly; in the case of S. haemolyticus only, negative strains accounted for 92.8%. Susceptibility to copper alloys was different between strains and rather lower than in the case of the SA strain selected for comparison. CONCLUSIONS: Coagulase negative staphylococci, the most commonly isolated in Polish hospital wards, should not be neglected as an infection risk factor due their high antibiotic resistance. Our experiments confirmed that touch surfaces made of copper alloys may play an important role in eliminating bacteria from the hospital environment. PMID- 28815025 TI - Oesophageal candidiasis and squamous cell cancer in patients with gain-of function STAT1 gene mutation. AB - BACKGROUND: Oesophageal candidiasis is a common, usually self-limiting opportunistic infection, but long-term infection with Candida is known to predispose to oral and oesophageal squamous cell cancer (SCC). Permissive factors that lead to immune deficiencies can underlie persistent or recurring candidiasis, called chronic mucocutaneous candidiasis (CMC). Secondary immune deficiencies are most often due to human immunodeficiency virus (HIV) infection, antibiotic use and immunosuppressive treatment (steroids, chemotherapy). Inborn errors of the immune system (primary immune deficiencies) can present with isolated CMC known as CMC disease (CMCD), which is most often found in patients with autoimmune polyendocrinopathy syndrome type 1 (APS1)/APECED or in patients with an underlying gain-of-function STAT1 mutation (GOF-STAT1). OBJECTIVE: To describe a new form of inherited/familial CMC with a high risk for developing squamous cell carcinoma of the oesophagus, due to a gain-of-function mutation in the STAT1 gene. METHODS AND RESULTS: This report describes a family of patients with CMC with confirmed GOF-STAT1 mutation. These patients usually present with CMCD in childhood, have severe oral and oesophageal candidiasis accompanied by severe difficulty swallowing, chest pain, heartburn, and are at risk of developing oral and/or oesophageal SCC. This case series describes six patients in three generations of the same family, two of whom developed and died of SCC. We recommend regular endoscopic surveillance to detect early oesophageal neoplasia in patients with CMCD as well as urgent endoscopy in symptomatic patients. CONCLUSION: CMC is not a well-recognised condition in gastroenterology practice and clinicians need to be aware of the genetics of the condition as well as the risk for oesophageal cancer so that they can counsel their patients and arrange surveillance appropriately. PMID- 28815026 TI - The diagnostic value of 24-hour ambulatory intraesophageal pH-impedance in patients with laryngopharyngeal reflux symptoms comparable with typical symptoms. AB - BACKGROUND: The diagnosis of laryngopharyngeal reflux is currently based on a combination of the patient history of multichannel intraluminal impedance and ambulatory pH (MII-pH); however, none of these findings alone is specific for the diagnosis of laryngopharyngeal reflux. We aimed to compare the baseline characteristics and esophageal baseline impedance values between patients with and without laryngopharyngeal reflux symptoms. METHODS: We retrospectively analyzed data from two groups of patients with laryngopharyngeal reflux according to their reflux finding score (RFS) as scored by ENTs. Control patients were nonerosive reflux disease patients without laryngopharyngeal reflux. All MII-pH parameters and baseline impedance were analyzed from six levels and the proximal and distal baseline impedance and the ratio of the proximal to distal baseline impedance levels was calculated. RESULTS: Altogether 123 patients with laryngopharyngeal reflux and 49 control patients were included. A total of 81 of 123 patients had RFS >= 7, and 42 of 123 patients had RFS < 7. Baseline impedance analysis showed that patients with laryngopharyngeal reflux symptoms had significantly lower proximal baseline impedance values (1997 +/- 51 vs 2245 +/- 109, p < 0.05) than the control group. Additionally, patients with laryngopharyngeal reflux symptoms had a significantly lower proximal-to-distal ratio (1.28 +/- 0.05 vs 1.53 +/- 0.09, p < 0.05). In the subgroup analysis, patients with RFS < 7 were found to have a significantly lower acid exposure time than either the patients with RFS >= 7 (3.85 +/- 0.65 vs 8.2 +/- 1.52, p < 0.05) or the control group (3.85 +/- 0.65 vs 6.1 +/- 0.81, p < 0.05). Additionally, patients with RFS >= 7 had significantly lower proximal baseline impedance levels than the control group (1970 +/- 63 vs 2245 +/- 109, p < 0.05). CONCLUSIONS: Patients with pathologic laryngopharyngeal reflux symptom scores had lower proximal baseline impedance levels and lower proximal-to-distal ratios, which may reflect the proximal mucosal noxious effect of the refluxate. These results may indicate that laryngopharyngeal reflux symptoms may be due to chronic acid exposure in the proximal segments of the esophagus, and the proximal-to-distal ratio may be used as a new metric for diagnosis. PMID- 28815024 TI - Stem cell-derived organoids to model gastrointestinal facets of cystic fibrosis. AB - Cystic fibrosis (CF) is one of the most frequently occurring inherited human diseases caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) which lead to ample defects in anion transport and epithelial fluid secretion. Existing models lack both access to early stages of CF development and a coeval focus on the gastrointestinal CF phenotypes, which become increasingly important due increased life span of the affected individuals. Here, we provide a comprehensive overview of gastrointestinal facets of CF and the opportunity to model these in various systems in an attempt to understand and treat CF. A particular focus is given on forward-leading organoid cultures, which may circumvent current limitations of existing models and thereby provide a platform for drug testing and understanding of disease pathophysiology in gastrointestinal organs. PMID- 28815027 TI - Endoscopic ultrasound in gastric cancer staging before and after neoadjuvant chemotherapy. A comparison with PET-CT in a clinical series. AB - BACKGROUND: Treatment of gastric cancer is based on accurate staging. Emerging methods, such as PET-CT, are increasingly being used for this purpose. Our aim was to analyze the results of EUS and PET-CT in staging and restaging our patients with gastric cancer, comparing both of them with the histological results. METHODS: Patients with confirmed gastric cancer were prospectively enrolled. Inclusion criteria for the final analysis included only patients who finally received a surgical resection. All patients underwent preoperative TNM staging by means of EUS and PET-CT within 21 days prior to the surgical treatment. RESULTS: A total of 256 patients were included. The overall EUS accuracy for T staging was 78% and 80.2% in restaging. EUS showed its best accuracy when distinguishing T1-T2 tumors vs. T3-T4, with an increased accuracy in restaging. Regarding N staging, the overall accuracy of EUS was 76.2%, and 72.5% for PET-CT (p = 0.02). With regards to restaging, accuracy of EUS and PET CT for N staging was 88.5% and 69%, respectively, with significant differences (p < 0.0001). CONCLUSIONS: EUS performed better than PET-CT in gastric cancer N staging and restaging. EUS accuracy in this setting is still suboptimal and probably more than one single diagnostic procedure should be used. PMID- 28815028 TI - The majority of hepatitis C patients treated with direct acting antivirals are at risk for relevant drug-drug interactions. AB - BACKGROUND: Direct-acting antivirals have improved treatment of chronic hepatitis C virus infection significantly. Direct-acting antivirals inhibit/induce and can also be substrates of drug-metabolising enzymes and transporters. This increases the risk for drug-drug interactions. OBJECTIVE: The purpose of this study was to predict drug-drug interactions with co-medication used by hepatitis C virus infected patients. METHODS: We assembled a nationwide cohort of hepatitis C patients and collected cross-sectional data on co-medication use. We compiled a list of currently available direct-acting antiviral regimens and cross-checked for potential drug-drug interactions with used co-medication. RESULTS: The cohort included 461 patients of which 77% used co-medication. We identified 260 drugs used as co-medication. Antidepressants (7.4%), proton pump inhibitors (7.1%) and benzodiazepines (7.1%) were most frequently used. Of the patients, 60% were at risk for a clinically relevant drug-drug interaction with at least one of the direct-acting antiviral regimens. Interactions were most common with paritaprevir/ritonavir/ombitasvir/dasabuvir and least interactions were predicted with grazoprevir/elbasvir. CONCLUSION: Co-medication use is rich in frequency and diversity in chronic hepatitis C patients. The majority of patients are at risk for drug-drug interactions which may affect efficacy or toxicity of direct-acting antivirals or co-medication. The most recently introduced direct-acting antivirals are associated with a lower risk of drug-drug interactions. PMID- 28815029 TI - Nodular regenerative hyperplasia rarely leads to liver transplantation: A 20-year cohort study in all Dutch liver transplant units. AB - BACKGROUND: Nodular regenerative hyperplasia is an uncommon liver condition associated with several autoimmune disorders and drugs. The clinical symptoms of nodular regenerative hyperplasia vary from asymptomatic to severe complications of portal hypertension (nodular regenerative hyperplasia-syndrome). OBJECTIVE: The purpose of this study was to identify the prognosis and optimal management, as well as the role of liver transplantation, in nodular regenerative hyperplasia. METHODS: The pathology databases of all three Dutch liver transplant units were retrospectively scrutinised for explanted livers diagnosed with nodular regenerative hyperplasia or without clear diagnosis. Pre- and post transplantation clinical, biochemical, radiological and histological information was obtained from electronic and paper records. RESULTS: In total, 1886 patients received a liver transplant. In 255 patients, nodular regenerative hyperplasia could not be excluded. After detailed chart review, the native livers of 11 patients (0.6%) (82% male, median age: 44 years) displayed nodular regenerative hyperplasia. Seven patients (64%) had underlying disorders or drug exposure which possibly caused nodular regenerative hyperplasia. Laboratory and imaging abnormalities were present in all patients but did not contribute to the diagnosis of nodular regenerative hyperplasia. Five-year survival was 73% (median follow-up: four years, range: 2-248 months). CONCLUSION: Nodular regenerative hyperplasia is a rare finding in patients, predominantly young males, transplanted for end-stage liver disease with unknown aetiology. Nonetheless, liver transplantation may have an important role in end-stage nodular regenerative hyperplasia-syndrome. PMID- 28815030 TI - A combined bile and urine proteomic test for cholangiocarcinoma diagnosis in patients with biliary strictures of unknown origin. AB - BACKGROUND: Detection of cholangiocarcinoma (CC) remains a diagnostic challenge particularly in patients with primary sclerosing cholangitis (PSC). We recently established diagnostic peptide marker models in bile and urine to detect CC. Our aim was to combine both models to reach a higher diagnostic accuracy of CC diagnosis. METHODS: Bile (BPA) and urine (UPA) proteome analysis by capillary electrophoresis mass spectrometry was performed in a case-control phase II study on 87 patients (36 CC including 13 with CC on top of PSC, 33 PSC and 18 other benign disorders). A logistic regression model with both analyses was developed and subsequently validated in a prospective cohort of 45 patients. RESULTS: In the retrospective study, single BPA and UPA showed sensitivities of 83 and 89 % and specificities of 80 and 86 % with an area under the curve (AUC) value of 0.85 and 0.93. If CC was defined as positive UPA and BPA the combination resulted in a sensitivity of 72 % and a specificity of 96 %. The logistic regression model resulted in an increase in sensitivity to 92 % at 84 % specificity with an AUC of 0.96. Applied to the prospective study cohort, the logistic regression model was superior in its sensitivity (94%) and specificity (76%) over single BPA (63% sensitivity, 69% specificity) and UPA (81% sensitivity, 72% specificity) with an AUC of 0.84. CONCLUSION: Our logistic regression model enables CC diagnosis with a higher accuracy than currently available diagnostic tools leading potentially to an earlier diagnosis. PMID- 28815031 TI - Capsule retention related to small bowel capsule endoscopy: a large European single-center 10-year clinical experience. AB - BACKGROUND: The most concerning complication of video capsule endoscopy (VCE) is capsule retention (CR) in the gastrointestinal (GI) tract although clinical outcome and management of patients with CR are still uncertain in a large single center material. OBJECTIVES: The aim of this retrospective study was to investigate incidence, causes, risk factors, management and clinical outcomes of CR in a large single center between 2001 and 2011. RESULTS: 2401 consecutive small-bowel (SB) VCEs were performed. CR was detected in 25 cases (1%). CR in patients with suspected and known Crohn's disease (CD) undergoing VCE occurred in 14/1370 (1%) including known CD 9/390 (2.3%) and suspected CD 5/980 (0.5%). CR in patients with obscure GI bleeding was observed in 11/816 (1.3%) cases. The SB was the most common site of CR with 17 cases followed by the esophagus (4 cases), colon (2 cases), and stomach (2 cases). Emergency endoscopic intervention (3 cases) and surgery (2 cases) was needed in 5 cases of CR. Elective capsule removal was performed by surgery in 6 cases and endoscopically in 8 cases. Three retained capsules dislodged after steroid treatment and another 3 cases of CR resolved without any intervention. CONCLUSION: This large clinical material demonstrates that CR is a rare complication with a favorable clinical outcome. Most patients with CR can be electively managed with non-surgical intervention. PMID- 28815032 TI - Pain may be an important factor to consider in inflammatory bowel disease patients troubled by fatigue. AB - BACKGROUND: Pain has been associated with fatigue in many chronic diseases, but data are not available for inflammatory bowel disease (IBD). The aim of this study was to investigate whether fatigue is associated with pain in IBD after adjusting for the relevant covariates. METHODS: Participants were recruited from nine hospitals in the south-eastern and western part of Norway. Socio-demographic variables were self-reported by patients. Disease activity was assessed by disease activity indices and faecal calprotectin. Patient-reported outcomes (PROs) were collected using the Fatigue Questionnaire (FQ), Brief Pain Inventory (BPI), Hospital Anxiety and Depression Scale (HADS) and Basic Nordic Sleep Questionnaire. RESULTS: From a total of 452 invited patients, 414 (91.6%) provided written informed consent. After excluding any missing data, 408 total patients were included in the analyses (ulcerative colitis = 180 and Crohn's disease = 228). In the crude analysis, substantial and chronic fatigue were associated with increased pain intensity regardless of the diagnosis. However, when controlling for relevant covariates in the ANCOVA, the differences in pain intensity among patients with and without substantial or chronic fatigue were insignificant. The Cohen's d effect size was small to moderate (>0.20) in patients with chronic fatigue. CONCLUSIONS: Despite a tendency of elevated pain intensity scores among patients with fatigue, these differences were insignificant after controlling for the relevant covariates. However, based on Cohen's effect size, these differences may be of clinical importance in a subset of patients. PMID- 28815033 TI - Early histological findings may predict the clinical phenotype in Crohn's colitis. AB - BACKGROUND AND AIMS: Predicting the clinical course of Crohn's disease (CD) is relevant for treatment selection. Currently, such diagnostic tools are lacking. In a previous pilot study, morphometric tissue image analysis showed promise in predicting the clinical phenotype and need for surgery. In this study, we aimed to validate our previous results on a larger cohort. METHODS: Colonic biopsies from CD patients with colonic or ileocolonic disease and at least five years of post-biopsy clinical follow-up were analyzed. The results were used to predict post-biopsy clinical phenotypes and outcomes. Data analysis was performed using multivariate regression models, discriminant score (DS) computations and Neural Network (NNET). RESULTS: Multivariate analysis of morphometric variables differentiated between B1 and B2 phenotypes (sensitivity 81%, specificity 74%, accuracy on cross-validation 75%; area under the curve (AUC) of 0.74 (CI 0.6 0.84; NNET model sensitivity 87%, specificity 67% on the testing population)). Differentiation between B1 and B3 phenotypes was also possible (sensitivity 69%, specificity 76%, accuracy 70.5% on cross-validation; AUC 0.78 (CI 0.68-0.89); NNET model sensitivity 78%, specificity 77% on the testing population)). Differentiating between B2 and B3 phenotypes was not possible using morphometric variables. Multivariate analysis predicted surgery (sensitivity 67%, specificity 72.5%, accuracy 69%; AUC 0.72 (CI 0.61-0.82); NNET model sensitivity 80%, specificity 91% on the testing population)). CONCLUSIONS: This study validates previous results and suggests that morphometric image analysis of early biopsies from Crohn's colitis patients may contribute to the prediction of future outcomes such as clinical phenotype and surgery. Prospective validation on larger cohorts is still needed. PMID- 28815034 TI - Compliance with the faecal calprotectin test in patients with inflammatory bowel disease. AB - BACKGROUND: We investigated, for the first time, levels of compliance with faecal calprotectin test in inflammatory bowel disease patients. METHODS: All consecutive adult inflammatory bowel disease patients having been prescribed an faecal calprotectin test between December 2014-July 2015 were included. At their next visit to the hospital, patients had to return a stool sample for the faecal calprotectin test and answer a simple questionnaire: 'Have you brought a stool sample? If not, why not? If so, did you encounter any difficulties when collecting the sample? Were you aware of faecal calprotectin before being asked to take the test?'. RESULTS: One hundred and one patients were included (50 men; 77 patients with Crohn's disease). The range age was 40 years (19-68). Eighty nine patients were being treated with infliximab, 10 were on vedolizumab, and two were not being treated with a biologic. Thirty-seven patients (35%) had performed the faecal calprotectin test. Eighty-one patients (80%) had not been aware of faecal calprotectin before being asked to take the test. Of the 64 patients who did not take the test, the prime reasons for non-compliance were forgetfulness (n = 49, 76.6%), a lack of perceived benefit for the test (n = 7, 11%), constipation (n = 5, 7.8%), refusal to handle faeces (n = 2, 3.1%), and difficulty collecting the stool sample (n = 1, 1.5%). CONCLUSION: Only one-third of the patients performed the faecal calprotectin test. The main reason for non-compliance was forgetfulness. Our present results emphasise the need for better patient education on the importance of complying with faecal calprotectin testing and the future of faecal calprotectin testing at home. PMID- 28815035 TI - Long-term follow-up reveals high incidence of colorectal cancer in Indian patients with inflammatory bowel disease. AB - BACKGROUND: As the magnitude of sporadic colorectal cancer (CRC) in India is low, magnitude of CRC in ulcerative colitis (UC) is also considered low. As a result, screening for CRC in UC although advocated may not be followed everywhere. We report our data of UC-related CRC from a low-incidence area of sporadic CRC. METHODS: A total of 1012 patients with left-sided colitis/pancolitis having more than one full-length colonoscopy performed at least a year after the onset of symptoms were included in retrospective analysis of prospectively maintained case records. In addition, 136 patients with duration of disease >10 years underwent surveillance white-light colonoscopy prospectively during the study period. RESULTS: A total of 1012 individuals were finally included (6542 person-years of follow-up, 68.5% males, disease duration: 6.4 +/- 6.8 years). Twenty (1.97%) patients developed CRC. Two (10%) patients developed CRC during the first decade, 10/20 (50%) during the second and 8/20 (40%) after the second decade of disease. The cumulative risk of developing CRC was 1.5%, 7.2% and 23.6% in the first, second and third decade, respectively. Of 136 high-risk UC cases, five (3.6%) had CRC on screening colonoscopy. Disease duration and increasing age of onset were associated with higher risk of CRC. CONCLUSIONS: Cumulative risk of CRC in Indian UC patients is as high as 23.6% at 30 years. The risk of CRC increases with increasing age of onset and increasing duration of disease. A low risk of sporadic CRC does not confer a low risk of UC-related CRC, and regular screening is warranted. PMID- 28815036 TI - Bacterial stimuli activate nitric oxide colonic mucosal production in diverticular disease. Protective effects of L. casei DG(r) (Lactobacillus paracasei CNCM I-1572). AB - BACKGROUND: Micro-inflammation and changes in gut microbiota may play a role in the pathogenesis of diverticular disease (DD). OBJECTIVE: The objective of this article is to evaluate the expression of nitric oxide (NO)-related mediators and S100B in colonic mucosa of patients with DD in an ex vivo model of bacterial infection. METHODS: Intestinal biopsies obtained from patients with diverticulosis, symptomatic uncomplicated diverticular disease (SUDD) and SUDD with previous acute diverticulitis (SUDD+AD) were stimulated with the probiotic L. casei DG(r) (LCDG) and/or the pathogen enteroinvasive Escherichia coli (EIEC). S100B, NO release and iNOS expression were then evaluated. RESULTS: Basal iNOS expression was significantly increased in SUDD and SUDD+AD patients. Basal NO expression was significantly increased in SUDD+AD. No differences in S100B release were found. In all groups, iNOS expression was significantly increased by EIEC and reduced by LCDG. In all groups, except for SUDD+AD, EIEC significantly increased NO release, whereas no increase was observed when LCDG was added to biopsies. EIEC did not induce significant changes in S100B release. CONCLUSIONS: Colonic mucosa of patients with DD is characterized by a different reactivity toward pathogenic stimuli. LCDG plays a role in counteracting the pro inflammatory effects exerted by EIEC, suggesting a beneficial role of this probiotic in DD. PMID- 28815037 TI - Elevated serum DAND5 is associated with metastasis and predicts poor prognosis in colorectal cancer. AB - BACKGROUND: The biologic and clinical significance of DAND5 remains unknown in colorectal cancer (CRC). OBJECTIVE: Herein, we investigated the function of DAND5 and evaluated its clinical significance in both serum and matched primary tumors in patients with CRC. METHODS: The role of DAND5 was explored in CRC cells and clinical significance of DAND5 was investigated in CRC patients (n = 217) and healthy controls (n = 63). RESULTS: Knockdown of DAND5 significantly decreased CRC cell proliferation, migration and invasion partly associated with epithelial mesenchymal transition phenotype. Serum DAND5 levels in CRC were significantly higher than in normal controls and accurately distinguished CRC from healthy subjects. High serum DAND5 levels were significantly correlated with tumor differentiation, large tumor size, advanced Tumor Node Metastasis (TNM) stage, lymph node and liver metastasis, high carcinoembryonic antigen level, recurrence, poor overall and disease-free survival. Serum DAND5 level, together with lymph node metastasis, were independent prognostic factors for CRC patients. High DAND5 protein expression in CRC tissues was increased according to TNM stage. A significant positive correlation existed between serum DAND5 levels and matched DAND5 expression in CRC tissues. CONCLUSION: Our data provide novel evidence for the clinical significance of DAND5 as a potential biomarker for CRC prognosis. PMID- 28815038 TI - Management of desmoid tumours: A large national database of familial adenomatous patients shows a link to colectomy modalities and low efficacy of medical treatments. AB - BACKGROUND: Desmoid tumours represent a major complication of familial adenomatous polyposis. Our aims were to study the factors associated with the development of desmoid tumours in familial adenomatous polyposis patients, and to describe presentation and management of desmoid tumours. METHODS AND PATIENTS: We reviewed all patients with familial adenomatous polyposis followed at our institution between 1965-2013, with either identified adenomatous polyposis coli gene mutation, or a personal and family history suggesting adenomatous polyposis coli-related polyposis. Response to treatment of desmoid tumours was assessed by Response Evaluation Criteria In Solid Tumor (RECIST) criteria. RESULTS: A total of 180 patients with familial adenomatous polyposis were included with a median follow-up of 19 years since diagnosis. Thirty-one (17%) patients developed 58 desmoid tumours, a median (range) 4.7 (0.8-41.6) years after their diagnosis of familial adenomatous polyposis. The only factor significantly associated with occurrence of desmoid tumours was the type of surgery: 12 (12%) desmoid tumours in 104 patients treated by colectomy, versus 19 (25%) desmoid tumours in 76 patients treated by proctocolectomy, p = 0.027. The localisation of desmoid tumours was: mesenteric (n = 25), abdominal wall (n = 30) or extra-abdominal (n = 3). Nineteen patients underwent 36 surgical procedures for desmoid tumours. Recurrence occurred in 26 (72%) cases and the recurrence-free survival was 2.6 (95% confidence interval (CI), 0.2-5.9) years. Thirteen patients received 27 medical treatments over a median 14 months. Objective response was observed in four (15%) patients and the median progression-free survival was nine (95% CI, 1.1-16.9) months. CONCLUSION: If confirmed, colectomy (versus proctocolectomy) should be performed in adenomatous polyposis coli-related familial adenomatous polyposis patients to avoid desmoid tumours. We show that there is a high prevalence of post-surgical recurrence and the low efficacy of available medical treatments for desmoid tumours. PMID- 28815039 TI - Predicting ADR from PDR and individual adenoma-to-polyp-detection-rate ratio for screening and surveillance colonoscopies: A new approach to quality assessment. AB - BACKGROUND AND AIMS: Adenoma detection rate (ADR) has been established as a quality indicator for screening colonoscopy. Because ADR is cumbersome to obtain in routine practice, polyp detection rate (PDR), polypectomy rate (PR) and adenoma-to-polyp-detection-rate-ratio (APDRR) have been proposed to estimate ADR. This study aimed to evaluate APDRR in order to estimate ADR (ADRest) in different settings. METHODS: Average risk screening and surveillance colonoscopies from a community-based private practice and a tertiary academic hospital setting were retrospectively evaluated. APDRR was calculated as averaged group APDRR for all study procedures (APDRR) and for the first half of study procedures of each gastroenterologist (APDRRag) or individually for each gastroenterologist on the basis of his or her first 25, 50 and 100 colonoscopies (APDRRind). ADRest was determined from PDR by using APDRR, APDRRag, and APDRRind, respectively. RESULTS: A total of 2717 individuals were analyzed. Using APDRR, significant correlations between ADR and ADRest were observed for the entire (0.944, p < 0.001), proximal (0.854, p < 0.001), and distal (0.977, p < 0.001) colon. These correlations were lost when APDRRag was used to estimate each gastroenterologist's ADR for the second half of his or her included colonoscopies. However, ADR and ADRest correlated significantly with a root-mean-square-error of 6.8% and 5.8% when APDRRind on the basis of each gastroenterologist's first 50 and 100 colonoscopies was used for subsequent colonoscopies. CONCLUSIONS: ADR for subsequent colonoscopies of an individual endoscopist can be reliably estimated from PDR by using an individually calculated APDRR. Prospective studies are needed to verify this promising approach in different practice settings. PMID- 28815040 TI - The organisation and needs of young sections belonging to UEG National Societies: Results of a Europe-wide survey. AB - One of the aims of the Young Talent Group (YTG) is to make United European Gastroenterology (UEG) more attractive for young fellows interested in gastroenterology, and to involve them actively in UEG activities, by collaborating with young GI sections (YGIS) across Europe. Therefore, the YTG launched a survey to collect up-to-date information on YGISs belonging to UEG National Societies. The Friends of YTG were chosen as the target population and received a web-based questionnaire concerning their personal information, the structure of YGIS in their respective country, the YGIS' support mechanisms for young trainees, and ideas on how to improve them. Overall, 24 of 29 Friends answered the survey (83%). Among the Societies surveyed, only half have a young section. Typically, YGIS are supported, but not influenced, by National Societies through several initiatives. Results of the survey suggest that a lack of funding, of harmonised education, and of active roles available within National Societies, were the concerns most prevalent among young fellows. Our survey shows that the development of YGIS is being hindered by organisational, financial, and political issues. The YTG believes that a close collaboration between National Societies, UEG, and the YTG is necessary in order to offer young fellows the most productive and professionally satisfying future possible. PMID- 28815041 TI - "UPRegulation" of CD47 by the endoplasmic reticulum stress pathway controls anti tumor immune responses. AB - We recently demonstrated that targeting the unfolded protein response (UPR) protein GRP78 down-regulates CD47 expression, resulting in increased tumor macrophage infiltration and inhibited resistance to anti-estrogen therapy. We now show new data indicating that anti-estrogen therapy regulates CD47 expression and implicates its ligand, thrombospondin-1, in regulation of tumor macrophage infiltration. Moreover, GRP78 and CD47 co-expression is associated with poor prognosis in breast cancer patients, suggesting the existence of crosstalk between UPR and immunity that regulates therapeutic responses in breast cancer. PMID- 28815050 TI - A case of azoospermia in a non-destructive testing worker exposed to radiation. AB - BACKGROUND: Interest in radiation-related health problems has been growing with the increase in the number of workers in radiation-related jobs. Although an occupational level of radiation exposure would not likely cause azoospermia, several studies have reported the relation between radiation exposure and azoospermia after accidental or therapeutic radiation exposure. We describe a case of azoospermia in a non-destructive testing (NDT) worker exposed to radiation and discuss the problems of the related monitoring system. CASE PRESENTATION: A 39-year-old man who was childless after 8 years of marriage was diagnosed with azoospermia through medical evaluations, including testicular biopsy. He did not have any abnormal findings on biochemical evaluations, other risk factors, or evidence of congenital azoospermia. He had been working in an NDT facility from 2005 to 2013, attaching and arranging gamma-ray films on the structures and inner spaces of ships. The patient's thermoluminescent dosimeter (TLD) badge recorded an exposure level of 0.01781 Gy for 80 months, whereas results of his florescence in situ hybridization (FISH) translocation assay showed an exposure level of up to 1.926 Gy of cumulative radiation, which was sufficient to cause azoospermia. Thus, we concluded that his azoospermia was caused by occupational radiation exposure. CONCLUSION: The difference between the exposure dose records measured through TLD badge and the actual exposure dose implies that the monitor used by the NDT worker did not work properly, and such a difference could threaten the health and safety of workers. Thus, to protect the safety and health of NDT workers, education of workers and strengthening of law enforcement are required to ensure that regulations are strictly followed, and if necessary, random sampling of NDT workers using a cytogenetic dosimeter, such as FISH, should be considered. PMID- 28815051 TI - The relationship between emotional labor status and workplace violence among toll collectors. AB - BACKGROUND: This study aimed to identify the emotional labor and workplace violence status among toll collectors by assessing and comparing the same with that in workers in other service occupation. It also aimed to analyze the relationship between emotional labor and workplace violence. METHODS: This study examined emotional labor and workplace violence status in 264 female toll collectors from August 20 to September 4, 2015. The emotional labor was assessed using the Korean Emotional Labor Scale (K-ELS), and a questionnaire was used to examine the presence or absence, and type and frequency of workplace violence experienced by the subjects. A linear regression analysis was also performed to analyze the relationship between workplace violence and emotional labor. RESULTS: The scores on "emotional demanding and regulation (p < 0.001)," "overload and conflict in customer service (p = 0.005)," "emotional disharmony and hurt (p < 0.001)," and "organizational surveillance and monitoring (p < 0.001)" among the sub-categories of emotional labor were significantly high and indicated "at-risk" levels of emotional labor in those who experienced workplace violence, whereas they were "normal" of emotional labor in those who did not. Even after being adjusted in the linear regression analysis, the emotional labor scores for the above 4 sub-categories were still significantly high in those who experienced workplace violence. On comparing the present scores with 13 other service occupations, it was found that toll collectors had the highest level in "emotional disharmony and hurt," "organizational surveillance and monitoring," and "organizational supportive and protective system". CONCLUSIONS: This study found that the toll collectors engaged in a high level of emotional labor. Additionally, there was a significant relationship between emotional labor and the experience of workplace violence among the toll collectors. PMID- 28815052 TI - A practical validation study of a commercial accelerometer using good and poor sleepers. AB - We validated a Fitbit sleep tracking device against typical research-use actigraphy across four nights on 38 young adults. Fitbit devices overestimated sleep and were less sensitive to differences compared to the Actiwatch, but nevertheless captured 88 (poor sleepers) to 98 percent (good sleepers) of Actiwatch estimated sleep time changes. Bland-Altman analysis shows that the average difference between device measurements can be sizable. We therefore do not recommend the Fitbit device when accurate point estimates are important. However, when qualitative impacts are of interest (e.g. the effect of an intervention), then the Fitbit device should at least correctly identify the effect's sign. PMID- 28815053 TI - Social support and social control in the context of cancer patients' exercise: A pilot study. AB - Social support is an important factor for exercise among cancer patients, but too much control might elicit reactance and lead to detrimental effects. In this pilot study, 56 dyads (cancer patient + relative) filled out a questionnaire assessing social support, social control, and reactance. After 4 weeks (T2), patients' exercise was assessed with a 7-day recall. About half of the patients did not engage in any self-reported exercise behavior. Relative-reported support was the only variable associated with exercise behavior at T2. Perceived control (r = .4) but not perceived support was significantly correlated with reactance. Male patients reported more support, but were also more prone to reactance. PMID- 28815054 TI - Global meaning in people with stroke: Content and changes. AB - After a traumatic event like a stroke, people need to find meaning and control again. This study enhances knowledge on one of the driving principles behind meaning-making processes: global meaning. Global meaning refers to individuals' general orienting systems, comprising fundamental beliefs and life goals. Little is known about global meaning in people with stroke and whether global meaning changes after stroke. In this qualitative study, five aspects of global meaning were found: core values, relationships, worldview, identity and inner posture. Continuity in all aspects was reported, but worldview, identity and inner posture were also subjected to change. PMID- 28815055 TI - Green lacewings (Neuroptera: Chrysopidae) are commonly associated with a diversity of rickettsial endosymbionts. AB - BACKGROUND: Bacterial symbionts transmitted from mothers to offspring are found in the majority of arthropods. Numerous studies have illustrated their wide impact on host biology, such as reproduction, behavior, and physiology One of the most common inherited symbionts is Rickettsia spp. (Alphaproteobacteria, Rickettsiales), which are found in about one-quarter of terrestrial arthropods, as well as in other invertebrates. In insect populations, Rickettsia spp. have been reported to cause reproductive modifications and fecundity-enhancing effects. Here, we investigated the incidence and genetic diversity of Rickettsia symbionts in green lacewings (Neuroptera, Chrysopidae), which are best known for their use as biological control agents against crop pests. RESULTS: We screened 18 species of green lacewings and allies for Rickettsia and found the symbiont in 10 species, infecting 20-100% of sampled individuals. Strain characterization based on multiple bacterial loci revealed an unprecedented diversity of Rickettsia associated with lacewings, suggesting multiple independent acquisitions. Further, the detected Rickettsia lineages are restricted to a specific lineage (i.e., species or genus) of investigated lacewings, and these associations are stable across multiple sampled locations and points in time. CONCLUSIONS: We conclude that Rickettsia-lacewing symbioses are common and evolutionarily stable. The role of these symbionts remains to be identified, but is potentially important to optimizing their use in biological pest control. PMID- 28815056 TI - Hemojuvelin regulates the innate immune response to peritoneal bacterial infection in mice. AB - Hereditary hemochromatosis and iron imbalance are associated with susceptibility to bacterial infection; however, the underlying mechanisms are poorly understood. Here, we performed in vivo bacterial infection screening using several mouse models of hemochromatosis, including Hfe (Hfe-/- ), hemojuvelin (Hjv-/- ), and macrophage-specific ferroportin-1 (Fpn1fl/fl ;LysM-Cre+ ) knockout mice. We found that Hjv-/- mice, but not Hfe-/- or Fpn1fl/fl ;LysM-Cre+ mice, are highly susceptible to peritoneal infection by both Gram-negative and Gram-positive bacteria. Interestingly, phagocytic cells in the peritoneum of Hjv-/- mice have reduced bacterial clearance, IFN-gamma secretion, and nitric oxide production; in contrast, both cell migration and phagocytosis are normal. Expressing Hjv in RAW264.7 cells increased the level of phosphorylated Stat1 and nitric oxide production. Moreover, macrophage-specific Hjv knockout mice are susceptible to bacterial infection. Finally, we found that Hjv facilitates the secretion of IFN gamma via the IL-12/Jak2/Stat4 signaling pathway. Together, these findings reveal a novel protective role of Hjv in the early stages of antimicrobial defense. PMID- 28815057 TI - Giant retinal tear after intra-arterial chemotherapy for advanced unilateral retinoblastoma. AB - BACKGROUND: Retinoblastoma is considered the most common intraocular malignancy in childhood, comprising 4% of all pediatric cancers. Management of retinoblastoma has evolved over the past two decades and intra-ophthalmic artery chemotherapy has emerged as a new modality of globe-conserving treatment with excellent results. This treatment achieves effective tumor reduction by delivering localized chemotherapy, decreases enucleation rate, and minimizes systemic and local side effects. CASE PRESENTATION: We report the case of an 8 year-old girl with a late presentation of an advanced unilateral retinoblastoma associated to diffuse exudative retinal detachment in the right eye, classified as group E by the International Classification of Retinoblastoma. The initial therapeutic proposal for the patient was five sessions of intra-ophthalmic artery chemotherapy (IAC) associated to large spot diode laser therapy. After undergoing four sessions of IAC, the fundus exam revealed a giant retinal tear associated to a total retinal detachment in the affected eye. The IAC treatment was concluded and enucleation was considered the best treatment option at that moment, since IAC was unable to control the tumor's activity and the patient's eye presented with a complex rhegmatogenous retinal detachment (RRD). However, family left for a second opinion and never returned. CONCLUSIONS: The usage of IAC for retinoblastoma management may lead to important local complications. Despite rare, RRD secondary to IAC may occur. We postulate that the giant tear observed in this case was caused by the rapid tumor necrosis using this route of treatment. PMID- 28815059 TI - Erratum: Long noncoding RNA: noncoding and not coded. AB - [This corrects the article DOI: 10.1038/cddiscovery.2016.104.]. PMID- 28815058 TI - Testicular microlithiasis is associated with ethnicity and socioeconomic status. AB - BACKGROUND: There are limited studies about testicular microlithiasis (TML) and background information such as health, lifestyle, and socioeconomic status. PURPOSE: To assess the prevalence of TML in relation to socioeconomic status and ethnicity. MATERIAL AND METHODS: From a database of scrotal ultrasound examinations in a single institution, all men who underwent routine ultrasound examinations for a variety of symptoms from 1998 to 2015 were included. Skilled observers performed all examinations, and presence of any form of intra testicular calcification, including TML, was recorded on the examination report and a representative image obtained and stored. A total of 1105 cases with TML were reviewed and random sample of 1105 controls from the same database was also reviewed. Demographics were recorded including ethnicity (white, black, and others) and socioeconomic groups (IMD Quintile). RESULTS: Black men had increased prevalence of TML (odds ratio [OR] = 2.17, 95% confidence interval [CI] = 1.72 2.75) compared with white men. Among the 1105 TML cases, 423 (38.3%) were white, 273 (24.7%) black, 152 (13.8%) had other ethnicities, and 257 (23.2%) had no ethnicity recorded. In the control group of 1105 men without TML, 560 (50.7%) were white, 171 (15.5%) black, 111 (10.0%) had other specified ethnicities, and 263 (23.8%) had no ethnicity recorded. Men from the most deprived socioeconomic groups had higher prevalence of TML than men in the most affluent groups, with a trend in OR from the least deprived to the most deprived group. CONCLUSION: Pathogenesis and clinical relevance of TML is unknown but our results point towards possible ethnic and socioeconomic variation in the underlying causes of TML. PMID- 28815061 TI - Introduction to the focused issue on esophageal cancer of the Journal of Thoracic Disease. PMID- 28815060 TI - Defective expression of ATG4D abrogates autophagy and promotes growth in human uterine fibroids. AB - Uterine fibroids (UF) are the most common pelvic tumors in women of reproductive age and they usually cause heavy menstrual bleeding, pain and infertility. Autophagy is a collection of processes that enables the cells to digest and recycle their cytoplasmic contents, such as toxic protein aggregates, defunct or disused organelles and invading microorganisms. Dysregulation in autophagy process were described in neoplasms; however, the contribution of autophagy to the pathogenesis of UF remains unknown. In this study, we demonstrate that autophagy is deregulated in human UF as evidenced by significant accumulation of autophagosome in human UF cells compared to normal myometrium cells. Analysis of the autophagy markers revealed an enhanced initiation of the autophagy in UF tissues compared to their adjacent myometrial tissues (MyoF). However, autophagosome maturation and flux was blocked in UF tissues, as marked by accumulation of LC3-B and P62 protein. This block was associated with defective expression of autophagy-related protein 4 (ATG4) in the UF tissues compared to MyoF in ~90% of patient samples. Silencing of ATG4D in normal human myometrial cells resulted in defective autophagy flux, enhanced cell proliferation and increased extracellular matrix production, which phenocopy UF cell line. This study indicates that impairment of autophagy flux secondary to defective expression of ATG4D expression is a new mechanistic aberration that contributes to UF pathogenesis. Targeting autophagy pathway could provide novel medical therapeutic approach for non-surgical treatment of UF. PMID- 28815062 TI - New insights into the surgical anatomy of the esophagus. AB - Implementation of (robot assisted) minimally invasive esophagectomy and increased knowledge of the relation between the autonomic nervous system and the immune response have led to new insights regarding the surgical anatomy of the esophagus. First, two layers of connective tissue were identified; the aorto esophageal and aorto-pleural ligaments that separate the peri-esophageal compartment, containing vagus nerves, carinal lymph nodes and trachea, from the para-aortic compartment; containing thoracic duct and azygos vein. Second the surgical anatomy of the pulmonary vagus nerve branches has been described in detail. Based on the hypothesis that sparing the vagal nerve branches may be important a method to spare the pulmonary branches of the vagus nerve during thoracoscopic esophagectomy was validated in a cadaver study. Further studies will now investigate the impact of these new insights in the surgical anatomy of the esophagus in clinical practice. PMID- 28815063 TI - The impact of flexible endoscopy in esophageal surgery. AB - Achalasia and Treatment of esophageal Adenocarcinoma are commonly associated to surgical resection. Newer technologies in interventional endoscopy gave way to a substantial paradigm shift in the management of these conditions. In the case of achalasia, endoscopic myotomy is rapidly displacing Heller's myotomy as the gold standard in many centers. Early stage neoplasia in Barrett's esophagus (BE) comprising high-grade dysplasia (HGD), intramucosal and, in some cases, submucosal carcinoma is now being treated without the need of esophagectomy. This review presents a summary of the most relevant endoscopic techniques for both achalasia and esophageal cancer. Endoscopic advances in diagnostic and therapeutic arenas allow for minimally invasive therapies and organ preservation in most settings of achalasia and early stage neoplasia of the esophagus provided that the clinical setting and physician's expertise are prepared for this approach. PMID- 28815064 TI - Endoscopic diagnosis and management of early squamous cell carcinoma of esophagus. AB - In recent years, diagnosis of early squamous cell carcinoma (SCC) of the esophagus has been increasingly emphasized. Utilization of image enhanced technology such as narrow band imaging (NBI) and magnification endoscopy allowed detailed examination of the esophageal mucosa. Different patterns of intrapapillary capillary loops (IPCL) have been proven to accurately diagnose and predict the depth of invasion of the tumors. In addition, the application of endoscopic submucosal dissection (ESD) has enabled safe en bloc resection of esophageal lesions. Promising results of ESD have been published and ESD is now the standard of therapy in early SCC of esophagus. PMID- 28815065 TI - Neoadjuvant treatment of locally advanced esophageal and junctional cancer: the evidence-base, current key questions and clinical trials. AB - Recent trials, including CROSS, MAGIC, ACCORD, and OEO2, have established neoadjuvant therapy as standard of care for locally advanced (cT2-3NanyM0) esophageal and junctional cancer compared with surgery alone. The CROSS trial in particular defines a new benchmark for outcomes from multimodal therapy, with a 5 year survival rate of 47%, a median survival of 47 months, a pathologic complete response rate (pCR) of 29% and an R0 resection rate of 92%. Several key questions remain, in particular whether CROSS-regimen chemoradiotherapy is superior to neoadjuvant chemotherapy alone for esophageal cancer, in particular adenocarcinoma. Second, with respect to neoadjuvant chemoradiation, whether an apparent complete clinical response can justify a "watch and wait" surveillance policy, with salvage surgery reserved for where relapse occurs. Third, whether with modern staging, predicted node negative cT2 tumors merit neoadjuvant therapy as standard. Finally, with the enormous interest in the application of targeted and immune-based therapies, and positive leads from other cancers, whether such approaches can improve outcomes in patients undergoing treatment with curative intent. We review herein a brief overview of the existing evidence-base and current active trials addressing these key questions. PMID- 28815066 TI - Anaesthesia during oesophagectomy. AB - In this review, we will provide an overview of the current state of the art of perioperative practices for open and laparoscopic oesophagus surgery from the anaesthetist's perspective. Morbidity and mortality after oesophagectomy is still high despite multidisciplinary and enhanced recovery pathways showing promising results. The anaesthetist has an important role in the complex care of the oesophageal cancer patient. Minimizing unnecessary fluid administration, adequate pain management, hypotension, and protective lung ventilation are examples of proven strategies that can improve outcome after this high-risk surgery. PMID- 28815067 TI - The extent of lymphadenectomy in esophageal resection for cancer should be standardized. AB - The incidence of esophageal cancer increases, with approximately 482,000 patients diagnosed with esophageal cancer each year. Despite the growing incidence of esophageal carcinoma, the extent of the lymphadenectomy is still under discussion. Lymph node status is an important prognostic parameter in esophageal cancer and an independent predictor of survival. Surgical strategy depends on the distribution pattern of nodal metastases but consensus on the extent of lymphadenectomy differs worldwide. For squamous cell cancer, Japanese surgeons have standardized the 2- or 3-field lymphadenectomy according to the location of the tumor. For adenocarcinoma, in the Western World accounting for 85% of all esophageal cancers, the type of lymphadenectomy to perform is not clear. Moreover, the use of neoadjuvant therapy may influence the mediastinal lymph nodes and the significance of the lymphadenectomy for survival. These aspects have challenged the traditional policy concerning lymphadenectomy, at least in the Western World. Furthermore, an extensive lymphadenectomy may improve survival but, on the other hand, may cause significant more morbidity. An overview of the literature on the extent of lymphadenectomy for esophageal cancer with respect to the supposed lymph node distribution patterns for squamous cell carcinoma and adenocarcinoma, the different lymph node classification systems, the commonly used surgical techniques and outcomes, and the proposal of observational cohort study to standardize the type of lymphadenectomy according to the type of tumor, location and use of neoadjuvant therapy will be provided. PMID- 28815068 TI - Pattern of lymph node metastases of squamous cell esophageal cancer based on the anatomical lymphatic drainage system: efficacy of lymph node dissection according to tumor location. AB - Knowing the anatomical lymphatic drainage of the esophagus is crucial to understanding the dissemination pattern of esophageal tumor. During the embryonal growth, the middle and lower part of the esophagus stretches as the lymphatic networks develop in the submucosal layer. The abundant submucosal lymphatics drain in a longitudinal fashion directly to their proximal and distal ends. The lymphatic route from the proximal esophagus through recurrent nerve nodes to supraclavicular nodes are a component of the mesentery of the proximal esophagus. The lower esophagus mostly drains its lymph into paracardial nodes related to celiac nodes through the mesentery of the distal esophagus. Lymphatic routes to mid and lower paraesophageal nodes usually originate from the intermuscular area of the muscularis propria. The lymphatic communication between the submucosa and intermuscular area is limited. The anatomical concept was confirmed clinically by a large series of single institution and the nationwide registry in Japan. The clinical data for the incidence of involved nodes verified the anatomical observations that long longitudinal extension of lymphatic drainage in the submucosa connected to the upper mediastinum lymphatics and paracardial lymphatics. The extent of dissection should be not tailored according to the anatomical distance from the tumor but according to the incidences of metastasis of each area, those were differed by tumor location. The areas for node dissection should be modified according to the tumor location. Although in patients with tumor limited to within the submucosal layer, even with tumors located in the mid- and lower esophagus, lymphatic metastasis was frequent in the upper mediastinum and perigastric area via the abundant submucosal lymphatics in a longitudinal fashion. When tumor invades or penetrates the muscle layer, the incidence of paraesophageal lymph node metastasis in the middle and lower mediastinum increases. PMID- 28815069 TI - Three-field lymph node dissection in esophageal cancer surgery. AB - Although multidisciplinary treatment has improved the prognosis of esophageal cancer, it is commonly associated with one of the worse prognoses. Since lymph node (LN) metastases can primarily occur from the cervical to the abdominal field, a strategy for extended LN dissection has been established. The three field LN dissection (3FD) during a transthoracic esophagectomy which is defined as a procedure for cervico-thoraco-abdominal LN dissection, was established in the 1980s' in Japan, and is currently widely accepted throughout the world. To date, various comparative trials between 3FD and two field LN dissections (2FD) have been reported and show that a transthoracic esophagectomy with 3FD is superior to 2FD for prognosis. However, in 3FD, postoperative complications, such as recurrent laryngeal nerve palsy and postoperative gastrointestinal dysfunction can be induced. Furthermore, there are few prospective trials that have compared between 2FD and 3FD. Therefore, to determine the ideal range of LN dissection, various factors (e.g., location of the primary tumor, disease progression, tumor histology, and perioperative treatment) must be considered. Recently, the efficacy of intense perioperative treatment for esophageal cancer has been reported, and the significance of minimally invasive surgical procedures are being verified. The ideal combination of perioperative treatment and feasible surgery must be established to improve the oncological outcome of esophageal cancer patients further. PMID- 28815070 TI - Supracarinal dissection of the oesophagus and lymphadenectomy by MIE. AB - Since 1995, video-assisted thoracoscopic oesophagectomy (VATS), according the same surgical principles as the Japanese open surgery, has been completed in 700 patients with oesophageal cancer. Our indication for VATS is (I) no extensive pleural adhesion; (II) no contiguous tumor spread; (III) pulmonary function capable of sustaining single-lung ventilation, and (IV) non radiated patients. We use 4 ports around a 5 cm mini-thoracotomy on 5th intercostal space. We laid emphasis on utilizing magnifying effect of video (5 to 20 magnifications), obtained by positioning the camera at close vicinity to the dissection. Magnified view facilitates recognizing the fine layer structure of the mediastinum. The dissection should be performed following this layer structure just like open the page of a book. Tearing the layer makes the dissection irrational and cause unnecessary bleeding and invasiveness. The microanatomies we recognize during upper mediastinal dissection are (I) the most outer layer below the mediastinal pleura are branches from the vagus nerve and thoracic sympathetic trunk; (II) there is no vessel flow in the nerves or out, in the field of dissection; (III) the ideal layer of dissection along the nerve is exposing the epineurium; (IV) the strongest fixing structures in the mediastinum are the vagal nerves and nerves form thoracic sympathetic trunk; (V) the stump of thoracic duct shows particular appearance because of the intramural smooth muscle; (VI) the lymphonodes in the mediastinum are fixed strongly with nerves and gently with vessels; (VII) the aorta is covered with fine fibrous membrane consisting of branches form thoracic sympathetic trunk, etc. Magnified view shows the microstructure of the lymph node such as the afferent lymphatics penetrating the capsule and the hilum structure consisting the efferent lymphatics, artery, vein and nerve. The direction of the hilum of nodes is defined in each region. Therefore, understanding the hilum direction facilitates rational dissection. The hospital mortality was four patients (0.6%). The rate of regional control was 95%. The 5-year survival rates of the patients with pStage 0, 1, 2, 3, 4 were 92%, 88%, 69%, 52% and 24%, respectively, which were favorably compared with open surgery. PMID- 28815071 TI - Gastro-esophageal junction cancers: what is the best minimally invasive approach? AB - The short-term advantages of minimally invasive esophagectomy (MIE) in terms of less morbidity and better quality of life (QoL) in comparison with open esophagectomy (OE) became visible in the last few years. There are two main MIE approaches: a transthoracic esophagectomy (TTE) (either accompanied by an intrathoracic or cervical anastomosis) or a transhiatal esophagectomy (THE) (accompanied by a cervical anastomosis). Additionally, minimally invasive gastrectomy is increasingly gaining popularity over open gastrectomy. Controversy still exists about what approach is the best for esophagogastric junction tumors (EGJ) and the choice of the approach is currently based on the surgeons' discretion. In this study, we describe the definition, staging and classification, indications for each minimally invasive approach for EGJ tumors, the surgical technique, current developments and problems regarding surgical treatment for patients with cancer of the EGJ. PMID- 28815072 TI - Hybrid and total minimally invasive esophagectomy: how I do it. AB - Esophagectomy is a major surgical procedure associated with a significant risk of morbidity and mortality. Minimally invasive esophagectomy is becoming the preferred approach because of the potential to limit surgical trauma, reduce respiratory complications, and promote earlier functional recovery. Various hybrid and total minimally invasive surgical techniques have been introduced in clinical practice over the past 20 years, and minimally invasive esophagectomy has been shown equivalent to open surgery concerning the short-term outcomes. Implementation of a minimally invasive esophagectomy program is technically demanding and requires a significant learning curve and the infrastructure of a dedicated multidisciplinary center where optimal staging, individualized therapy, and perioperative care can be provided to the patient. Both hybrid and total minimally invasive techniques of esophagectomy have proven safe and effective in expert centers. The choice of the surgical approach should be driven by preoperative staging, tumor site and histology, comorbidity, patient's anatomy and physiological status, and surgeon's experience. PMID- 28815073 TI - Predictive factors in the evaluation of treatment response to neoadjuvant chemoradiotherapy in patients with advanced esophageal squamous cell cancer. AB - Neoadjuvant therapy before esophagectomy is evidence-based, and is a standard-of care for locally advanced and operable esophageal cancer. However response to such treatment varies in individual patients, from no clinical response to pathological complete response. It has been consistently shown that a good pathological responses is of prognostic value, but perhaps in the expense of those who do not. It is important to identify suitable predictive factors for response, so that patients are not exposed to potentially harmful chemotherapy and/or radiotherapy without benefits. Alternative management strategies can be devised. Various clinical, radiological, serological and potential molecular markers have been studied. None has been shown to be sufficiently reliable to be used in daily practice. Certainly more understanding of the molecular basis for response to chemotherapy/radiotherapy is needed, so that patient treatment can be tailored and individualized. PMID- 28815074 TI - Enhanced recovery protocols after oesophagectomy. AB - The feasibility and safety of enhanced recovery protocols (ERP) have been demonstrated in a large number of surgical specialties. Several studies have shown improved post-operative outcomes and economic benefit from the use of ERPs in oesophageal cancer surgery. However, these improvements are not always translated more widely into clinical practice due to variation in protocols, poor compliance and failure to implement a robust implementation strategy. ERP implementation strategies should reflect the fact that these are complex interventions that are influenced by a wide range of social, organizational and cultural factors. PMID- 28815076 TI - Definitive chemoradiotherapy. AB - Definitive chemoradiotherapy (dCRT) is reflecting a treatment standard in oesophageal cancer. For irresectable localised tumours and for inoperable patients, dCRT can change the treatment intent from palliative to curative. In patients with squamous cell carcinoma (SCC), in particular in those of cervical location, dCRT is a proper alternative for treatment that may include radical surgery. Patients with localised locoregional recurrence after primary surgery can survive for long-term after salvage CRT. PMID- 28815075 TI - The feeding route after esophagectomy: a review of literature. AB - Enhanced recovery programs effectively optimize perioperative care and reduce postoperative morbidity. In esophagectomy, several components of the ERAS program are successfully introduced. However, timing and type of postoperative feeding remain a matter of debate. Adequate nutritional support is essential in patients undergoing an esophagectomy. These patients often present with weight loss and their eating pattern is strongly altered by the procedure and reconstruction. Total parenteral nutrition (TPN) is associated with severe septic complications and enteral nutrition (EN) does not increase major complications. Therefore, early EN after esophagectomy is favored over TPN. However, with enteral feeding tubes minor complications occur frequently (13-38%) and in some cases this can hamper recovery. Based on experience in other types of upper gastro-intestinal surgery, early start of oral feeding could improve time to functional recovery after surgery. The total length of stay was significantly shorter in four prospective studies (6-12 vs. 8-13 days). However, large randomized controlled trials are lacking and the potential benefit of early oral feeding after esophageal surgery remains elusive. EN is nowadays the optimal feeding route after esophagectomy. TPN should only be used in specific cases in which EN is contraindicated. Early initiation of oral intake is promising and could improve postoperative recovery. However, further research is needed to substantiate these results. PMID- 28815077 TI - Salvage esophagectomy: safe therapeutic strategy? AB - The objectives of this review were to assess both the short- and long-term clinical outcomes in patients managed with definitive chemoradiotherapy, and salvage esophagectomy subsequently in comparison to those neoadjuvant chemoradiotherapy followed by planned esophagectomy (NCRS) for esophageal cancer from published literature. Eleven studies comprising 1,906 patients were included, 563 in the salvage group and 1,343 in the NCRS group. Pooled analysis showed no significant difference between salvage and NCRS groups in overall survival [hazard ratio (HR) =1.17; 95% confidence interval (95% CI), 0.94-1.46, P=0.148], postoperative mortality [pooled odds ratios (POR) =1.12; 95% CI, 0.52 2.41, P=0.775], pulmonary complications (POR =1.24; 95% CI, 0.83-1.86, P=0.292) and positive resection margin incidence (POR =1.29; 95% CI, 0.94-1.76, P=0.114). However, within the salvage group there were increases in postoperative morbidity (POR =1.30; 95% CI, 1.00-1.67, P=0.046) and anastomotic leak (POR =1.88; 95% CI, 1.41-2.51, P<0.001). Herein we found that salvage esophagectomy has similar short and long-term mortality in comparison to planned esophagectomy following neoadjuvant chemoradiotherapy. However, anastomotic leak is increased following salvage esophagectomy suggesting the need for this practice to be reserved for high volume surgeons within high volume centers. PMID- 28815078 TI - Surgical anatomy of the omental bursa and the stomach based on a minimally invasive approach: different approaches and technical steps to resection and lymphadenectomy. AB - BACKGROUND: It is imperative for surgeons to have a proper knowledge of the omental bursa in order to perform an adequate dissection during minimally invasive surgery (MIS) of the upper gastrointestinal (GI) tract. This study aimed to describe (1) the various approaches which can be used to enter the bursa and to perform a complete lymphadenectomy, (2) the boundaries and anatomical landmarks of the omental bursa as seen during MIS, and (3) whether a bursectomy should be performed for oncological reasons in upper GI cancer. METHODS: In this observational study, videos of 20 patients undergoing different MIS procedures were reviewed, and the findings were verified prospectively in 5 patients undergoing a total gastrectomy and in a transversely sectioned cadaver. A systematic literature review (PubMed) was performed on the additive value of bursectomy during gastrectomy for cancer. RESULTS: The omental bursa can be surgically entered through the hepatogastric ligament, gastrocolic ligament, gastrosplenic ligament or through the transverse mesocolon. Anatomical boundaries of the omental bursa could be clearly identified, and new anatomical landmarks were described (gastro-omental folds). The cranial part of the omental bursa consists of two compartments (splenic recess and superior recess), separated by the gastropancreatic fold, communicating at the level of the pancreas, and extending distally as the inferior recess. There is no clear evidence regarding beneficial effect of a bursectomy in upper GI oncology. CONCLUSIONS: The description of the omental bursa in this study may help surgeons perform a more adequate oncological dissection during MIS. Bursectomy should not be routinely performed during oncological resections. PMID- 28815079 TI - Implementation of minimally invasive esophagectomy in a tertiary referral center for esophageal cancer. AB - BACKGROUND: Esophagectomy remains the gold standard in the curative intent treatment of resectable esophageal cancer. However, this procedure is complex and associated with high risk of complications. In an effort to reduce the postoperative morbidity associated with open esophagectomy various minimally invasive techniques have been introduced and developed during the recent years. The aim of the current study was to present our 4.5-year experience of the gradual implementation of various minimally invasive esophagectomy (MIE) techniques in our tertiary referral center. METHODS: From May 2012 a transitional period from conventional open esophagectomy to MIE was initiated. This period was preceded by fellowships and visits to expert centers abroad. Thereafter, a gradual implementation and refinement of the new techniques followed. Technique related data were collected prospectively. RESULTS: Between January 1st 2011 and December 31st 2016 a total of 249 patients underwent an esophagectomy in our unit. Seventy-six cases were performed through a conventional open esophagectomy and 173 by some type of MIE. An increasing utilization of MIE over this time period was seen and finally reached 100% of treatment intentions, during the last 2 years. Ten cases (5.7%) where converted to open approach. A decrease in leak rate, operating time, peroperative bleeding and hospital stay as well as an increasing number of harvested lymph nodes was observed during the implementation period. CONCLUSIONS: The transition from conventional open esophagectomy to MIE was successful at our center. The implementation was overall safe with good postoperative outcomes, although changes in results required technical modifications over time. PMID- 28815080 TI - McKeown or Ivor Lewis totally minimally invasive esophagectomy for cancer of the esophagus and gastroesophageal junction: systematic review and meta-analysis. AB - BACKGROUND: Minimally invasive esophagectomy (MIE) has consistently been associated with improved perioperative outcome and similar oncological safety compared to open esophagectomy. However, it is currently unclear what type of MIE is preferred for patients with resectable esophageal cancer. METHODS: Literature was searched in Medline, Embase and the Cochrane library combining relevant search terms. Articles that included patients undergoing totally minimally invasive esophagectomy (TMIE) or hybrid minimally invasive esophagectomy (HMIE) and compared McKeown with Ivor Lewis procedures were included. Studies were excluded if they included >10% of patients undergoing a procedure other than MIE McKeown or MIE Ivor Lewis (i.e., transhiatal resections). The primary outcome parameter was anastomotic leakage. Secondary outcome parameters were: other complications, reinterventions, reoperations, hospital length of stay, ICU length of stay, postoperative mortality, operative time, blood loss, R0 resection rate, lymph nodes examined, quality of life and costs. RESULTS: Five studies with a total of 1,681 patients undergoing TMIE were included. There were no studies comparing HMIE McKeown versus HMIE Ivor Lewis. There were no randomized controlled trials and all included studies were cohort studies with a moderate risk of bias. No meta-analysis could be performed for R0 resection rate, survival, quality of life and costs because there was insufficient data available for these parameters. The incidence of anastomotic leakage did not differ between the groups [relative risk (RR) =1.39, 95% confidence interval (CI) =0.90-10.38, P=0.14]. TMIE Ivor Lewis was associated with a lower incidence of recurrent laryngeal nerve (RLN) trauma (RR =6.70, 95% CI =3.09-14.55, P<0.001), a shorter hospital length of stay [standardized mean difference (SMD) =0.17, 95% CI =0.06 0.28, P=0.002] and less blood loss (SMD =0.69, 95% CI =0.25-1.12, P=0.002). CONCLUSIONS: TMIE Ivor Lewis is associated with improved outcome regarding RLN trauma, hospital length of stay and blood loss as compared to TMIE-McKeown, but the incidence of anastomotic leakage is not different. The evidence is limited, of low quality and at risk for bias. A randomized controlled trial is currently being performed in order to demonstrate whether a McKeown or Ivor Lewis procedure should be preferred in patients undergoing MIE. PMID- 28815081 TI - Robot-assisted minimally invasive thoraco-laparoscopic esophagectomy for esophageal cancer in the upper mediastinum. AB - BACKGROUND: Patients with upper third esophageal cancer or esophageal cancer with upper mediastinal paratracheal lymph node metastases are often precluded from surgery because of technical difficulties. With the aid of robotic surgery, an excellent overview and reach of the thoracic inlet can be accomplished. In this way, patients with upper mediastinal esophageal cancer are eligible for esophageal resection with curative intent. The aim of this study was to review the results of a consecutive series of patients who underwent robot-assisted minimally invasive esophagectomy (RAMIE) for tumors of the upper 1/3 of the esophagus or positive lymph nodes in the upper mediastinum. METHODS: Between 2007 2016, 31 patients who underwent RAMIE in the UMC Utrecht for proximal esophageal cancer or proximal thoracic lymphadenopathy were identified from a prospective surgical database. Perioperative characteristics and oncologic outcomes were collected. RESULTS: The majority of patients had a squamous cell carcinoma. Clinical tumor stage was cT3 or higher in 25 (81%) of patients. Clinically positive lymph nodes (cN1-3) were observed in 29 (94%) patients. Neoadjuvant treatment was administered in 27 (87%) patients. Median duration of the surgical procedure was 435 min (range 299-874 min). Pulmonary complications were most frequent and occurred in 13 (42%) patients. Median intensive care (ICU stay) was 1 day (range 1-65 days) and median overall postoperative hospital stay was 15 days (range 10-118 days). In hospital mortality was 10%. Causes of mortality were tracheo-neo-esophageal fistula, sepsis after abdominal wall drainage due to leakage of the jejunal fistula resulting in respiratory and kidney failure, after which refraining further treatment resulting in death, and irreversible ARDS in a patient with COPD Gold III needing extracorporeal life support. Radical resection was achieved in 30 (97%) of the patients. Median number of retrieved lymph nodes was 22 (range 9-57). Median time of follow up was 18 months (range 3-81 months). Median disease-free survival was 13 months (range 0-81 months) and median overall survival was 16 months (range 0-81 months). Tumor recurrence occurred in 15 patients (48%) and was locoregional only in 3 patients, systemic only in 5 patients and combined locoregional and systemic in 7 patients. CONCLUSIONS: Robot assisted thoraco-laparoscopic esophagectomy with curative intent in patients with upper mediastinal esophageal cancer is feasible, but associated with increased in hospital mortality. Short-term oncologic results are encouraging. PMID- 28815082 TI - Non responders to neoadjuvant chemoradiation for esophageal cancer: why better prediction is necessary. AB - BACKGROUND: Patients with pathologic limited or no response (pNR) to neoadjuvant chemoradiation (nCRT) are subjected to curative intended esophagectomy with subsequent perioperative morbidity and mortality, but potentially only harm from nCRT. The primary aim of this study was to compare the overall survival (OS) of patients with pNR and patients who underwent primary esophagectomy to evaluate potentially benefits of nCRT in these patients. The secondary aim was to identify predictive clinicopathologic factors for pNR and pathologic complete response (pCR) to nCRT with the goal to preselect these patients before the start of treatment. METHODS: From the period 2005 to 2016, 206 esophageal cancer (EC) patients treated with Carboplatin/Paclitaxel and radiotherapy with complementary esophagectomy were included in this cohort. OS of patients with pNR was compared with a historical cohort of primary surgically treated patients (n=218) after a propensity score matching resulting in a group of 68 patients with pNR after nCRT versus a group of 68 primary esophagectomy patients. RESULTS: The OS in the pNR group and the primary esophagectomy group was comparable (P=0.986). No predictive factors were found in this cohort for pNR. Female gender (OR 2.5, 95% CI 1.2-5.3) and squamous cell carcinoma (SCC) (OR 2.6, 95% CI 1.3-5.3) were identified as independent predictive factors for pCR. CONCLUSIONS: Patients with a pNR do not benefit from nCRT followed by resection. These patients had a similar OS as those who had a primary esophagectomy alone. Although this indicates that nCRT does not negatively impact the OS of patients with pNR, patients still have an increased morbidity because of nCRT. Hence, it is important to identify factors that predict pNR. The ability to predict pNR (and pCR) will enable tailored and personalized care preventing unnecessary nCRT with increased morbidity. PMID- 28815083 TI - Routine jejunostomy tube feeding following esophagectomy. AB - BACKGROUND: Malnutrition is an important problem following esophagectomy. A surgically placed jejunostomy secures an enteral feeding route, facilitating discharge with home-tube feeding and long-term nutritional support. However, specific complications occur, and data are lacking that support its use over other enteral feeding routes. Therefore routine jejunostomy tube feeding and discharge with home-tube feeding was evaluated, with emphasis on weight loss, length of stay and re-admissions. METHODS: Consecutive patients undergoing esophagectomy for cancer, with gastric tube reconstruction and jejunostomy creation, were analyzed. Two different regimens were compared. Before January 07, 2011 patients were discharged when oral intake was sufficient, without tube feeding. After that discharge with home-tube feeding was routinely performed. Logistic regression analysis corrected for confounders. RESULTS: Some 236 patients were included. The median duration of tube feeding was 35 days. Reoperation for a jejunostomy-related complication was needed in 2%. The median body mass index (BMI) remained stable during tube feeding. The BMI decreased significantly after stopping tube feeding: from 25.6 (1st-3rd quartile 23.0-28.6) kg/m2 to 24.4 (22.0-27.1) kg/m2 at 30 days later [median weight loss: 3.0 (1.0 5.3) kg; 3.9% (1.5-6.3%)]. Weight loss was not affected by the duration of tube feeding duration. Routine home-tube feeding did not affect weight loss, admission time or the readmission rate. CONCLUSIONS: Weight loss following esophagectomy occurs once that tube feeding is stopped, independently from the time interval after esophagectomy. Moreover routine discharge with home-tube feeding does not reduce length of stay or readmissions. These findings question the value of routine jejunostomy placement and emphasize the need for further research. PMID- 28815084 TI - Predictive factors for post-operative respiratory infections after esophagectomy for esophageal cancer: outcome of randomized trial. AB - BACKGROUND: The first and only randomized trial comparing open esophagectomy (OE) with minimally invasive esophagectomy (MIE) showed a significant lower incidence of post-operative respiratory infections in the patients who underwent MIE. In order to identify which specific factors are related to a better respiratory outcome in this trial an additional analysis was performed. METHODS: This was a prospective, multicenter, randomized controlled trial. Eligible patients, with a resectable intrathoracic esophageal carcinoma, including the gastro-esophageal (GE) junction tumors and Eastern Cooperative Oncology Group <=2, were randomized to either MIE or OE. Respiratory infection investigated was defined as a clinical manifestation of (broncho-) pneumonia confirmed by thorax X-ray and/ or Computed Tomography scan and a positive sputum culture. A logistic regression model was used. RESULTS: From 2009 to 2011, 115 patients were randomized in 5 centers. Eight patients developed metastasis during neoadjuvant therapy or had an irresectable tumor and were therefore excluded from the analysis. Fifty-two OE patients were comparable to 55 MIE patients with regard to baseline characteristics. In-hospital mortality was not significantly different [2% (open group) and 4% (MIE group)]. A body mass index (BMI) >=26 and OE were associated with a roughly threefold risk of developing a respiratory infection. CONCLUSIONS: Overweight patients and OE are independently associated with a significant higher incidence of post-operative respiratory infections, i.e., pneumonia. PMID- 28815086 TI - How minimally invasive esophagectomy was implemented at the Norfolk and Norwich University Hospital. PMID- 28815085 TI - Recurrent laryngeal nerve injury after esophagectomy for esophageal cancer: incidence, management, and impact on short- and long-term outcomes. AB - BACKGROUND: Recurrent laryngeal nerve (RLN) injury caused by esophagectomy may lead to postoperative morbidity, however data on long-term recovery are scarce. The aim of this study was to evaluate the consequences of RLN palsy (RLNP) in terms of pulmonary morbidity and long-term functional recovery. METHODS: Patients who underwent a 3-stage transthoracic (McKeown) or a transhiatal esophagectomy for esophageal carcinoma in the University Medical Center Utrecht (UMCU) between January 2004 and March 2016 were included from a prospective database. Multivariable analyses were conducted to assess the association between RLNP and pulmonary complications and hospital stay. Data regarding long-term recovery were summarized using descriptive statistics. RESULTS: Out of the 451 included patients, 47 (10%) were diagnosed with RLNP. Of the patients with RLNP, 34 (7%) had a unilateral lesion, 8 (2%) had a bilateral lesion, and in 5 (1%) the location of the lesion was unknown. The incidence of RLNP was 3/127 (2%) in the transhiatal group, and 44/324 (14%) in the McKeown group. RLNP after McKeown esophagectomy was associated with a higher incidence of pulmonary complications (OR 2.391; 95% CI 1.222-4.679; P=0.011), as well as a longer hospital stay (+4 days) (P=0.001). Of the RLNP patients with more than 6 months follow up almost half recovered fully {median follow-up of 17.5 [7-135] months}. Of the remainder, six required a surgical intervention and the others had residual symptoms. CONCLUSIONS: RLNP after McKeown esophagectomy is associated with an increased pulmonary complication rate, longer hospital stay, and a moderate long-term recovery. Further studies are necessary that examine technologies, which may reduce RLNP incidence and contribute to the early detection and treatment of RLNP. PMID- 28815087 TI - Ocular and Systemic Risk Factors of Different Morphologies of Scotoma in Patients with Normal-Tension Glaucoma. AB - THE AIM: The aim of this study was to assess general and ocular profiles of patients with single-localisation changes in visual field. MATERIAL AND METHODS: The study group consisted of 215 Caucasian patients with normal-tension glaucoma with scotoma on single localisation or with preperimetric glaucoma. During regular follow-up visits, ophthalmic examination was carried out and medical history was recorded. The results of the visual field were allocated as paracentral scotomas, arcuate scotomas, peripheral defects, or hemispheric defects. Statistical analysis was conducted with Statistica 12, and p < 0.05 was considered statistically significant. RESULTS: Risk factors such as notch, disc hemorrhage, general hypertension, migraine, and diabetes were strongly associated with specific visual field defects. Paracentral defect was significantly more frequent for women (p = 0.05) and patients with disc hemorrhage (p < 0.001). Arcuate scotoma occurred frequently in patients without disc hemorrhage (p = 0.046) or migraines (p = 0.048) but was observed in coexistence with general hypertension (p < 0.001). The hemispheric defect corresponded with notch (p = 0.0036) and migraine (p = 0.081). Initial IOP was highest in patients with arcuate scotoma and lowest in patients with preperimetric glaucoma (p = 0.0120). CONCLUSIONS: The specific morphology of scotoma in patients with normal-tension glaucoma is connected with definite general and ocular risk factors. PMID- 28815088 TI - Use of Anti-VEGF Agents in Glaucoma Surgery. AB - A number of antivascular endothelial growth factor agents are currently available to treat various ocular conditions. These agents have similar, but distinct, biologic qualities and have been explored in the management of neovascular glaucoma and in glaucoma surgery. Several different delivery methods are described, and because these medications are routinely given as intraocular injections, some benefits over traditional antifibrotic medications when used in glaucoma surgery are noted. These agents effectively induce regression of anterior segment neovascularization and facilitate initial surgical management of neovascular glaucoma, but the long-term outcome of this condition remains dependent on definitive management of the underlying process. Use in trabeculectomy or tube shunt procedures for other types of glaucoma has shown promise in modulating bleb morphology but has not yet been found to be as effective as traditional antifibrotic agents. There are reports of persistently raised intraocular pressure after repeated use of the anti-VEGF agents, possibly related to frequency of injection. These medications have wide application in the field of surgical glaucoma, but a definitive role has yet to be defined. PMID- 28815089 TI - Risk Assessment for Corneal Ectasia following Photorefractive Keratectomy. AB - PURPOSE: To analyze the risk factors associated with a series of ectasia cases following photorefractive keratectomy (PRK) and all published cases. METHODS: In a retrospective study on post-PRK ectasia patients, 9 eyes of 7 patients were included, in addition to 20 eyes of 13 patients from the literature. Risk of post PRK ectasia was calculated using the ectasia risk score system (ERSS) for laser in situ keratomileusis (LASIK) patients. The percent tissue altered (PTA) was also evaluated. RESULTS: ERSS scoring of zero for age, RSB, and spherical equivalent was found in 66%, 86%, and 86% of the eyes, respectively. Pachymetry risk score was 2 in 60% of the eyes and 3 or 4 in 16% of the eyes. Topography risk score was 3 in 41% of the eyes and 4 in 21% of the eyes. Cumulative ectasia risk score was >=4 (high risk) in 77% of the eyes and >=3 (medium and high risk) in 86% of the eyes. Average PTA was 23.2 +/- 7.0%. All eyes but one had a PTA < 40%. CONCLUSIONS: Preoperative corneal topographic abnormalities and thin corneas may be significant risk factors for developing ectasia following PRK. Post-LASIK ectasia risk scoring also has relevance in the risk for developing post-PRK ectasia. PMID- 28815090 TI - Effects of the Rho-Kinase Inhibitor Y-27632 on Extraocular Muscle Surgery in Rabbits. AB - PURPOSE: To evaluate the effect of the Rho-kinase inhibitor Y-27632 on postoperative inflammation and adhesion following extraocular muscle surgery in rabbits. METHODS: The superior rectus muscle reinsertion was performed on both eyes of 8 New Zealand white rabbits. After reinsertion, the rabbits received subconjunctival injections of the Rho-kinase inhibitor and saline on each eye. To assess acute and late inflammatory changes, Ki-67, CD11beta+, and F4/80 were evaluated and the sites of muscle reattachment were evaluated for a postoperative adhesion score and histopathologically for collagen formation. RESULTS: F4/80 antibody expression was significantly different in the Rho-kinase inhibitor injected group at both postoperative day 3 and week 4 (p = 0.038, 0.031). However, Ki-67 and CD11beta+ were not different the between two groups. The difference in the SRM/conjunctiva adhesion score between the two groups was also significant (p = 0.034). Conclusion. Intraoperative subconjunctival injection of the Rho-kinase inhibitor may be effective for adjunctive management of inflammation and fibrosis in rabbit eyes following extraocular muscle surgery. PMID- 28815091 TI - "Spice" (Synthetic Marijuana) Induced Acute Myocardial Infarction: A Case Series. AB - Marijuana is the most widely abused "recreational" substance in the United States, with highest prevalence in young adults. It is reported to cause ischemic strokes, hepatitis, anxiety, and psychosis. Although it is associated with dose dependent tachycardia and can lead to coronary vasospasm, it has not been directly related to acute myocardial infarction (AMI). Marijuana induced coronary vasospasm can result in endothelial denudation at the site of a vulnerable atherosclerotic plaque in response to hemodynamic stressors, potentially causing an AMI. Spice refers to herbal mixture with composition and effects similar to that of marijuana and therefore is referred to as "synthetic marijuana." Herein, we report 3 cases of spice induced ST-segment elevation myocardial infarction. All patients were relatively young and had few or absolutely no risk factors for cardiovascular disease. All patients underwent emergent coronary angiography, with two needing stent placement and the third requiring only aspiration thrombectomy. Our case series emphasizes the importance of suspecting and investigating synthetic marijuana use in low risk young adults presenting with AMI. PMID- 28815092 TI - Zinc Chloride Smoke Inhalation Induced Severe Acute Respiratory Distress Syndrome: First Survival in the United States with Extended Duration (Five Weeks) Therapy with High Dose Corticosteroids in Combination with Lung Protective Ventilation. AB - Zinc chloride smoke bomb exposure is frequently seen in military drills, combat exercises, metal industry works, and disaster simulations. Smoke exposure presents with variety of pulmonary damage based on the intensity of the exposure. Smoke induced severe acute respiratory distress syndrome (ARDS) is often fatal and there are no standard treatment guidelines. We report the first survival of smoke induced severe ARDS in the United States (US) with prolonged use of high dose steroids (five weeks) and lung protective ventilation alone. Previously reported surviving patients in China and Taiwan required extracorporeal membrane oxygenation (ECMO) and other invasive modalities. We suggest that an extended course of high dose corticosteroids should be considered for the treatment of smoke inhalation related ARDS and should be introduced as early as possible to minimize the morbidity and mortality. We further suggest that patients with smoke inhalation should be observed in the hospital for at least 48 to 72 hours before discharge, as ARDS can have a delayed onset. Being vigilant for infectious complications is important due to prolonged steroid treatment regimen. Patients must also be monitored for critical illness polyneuromyopathy. Additionally, upper airway injury should be suspected and early evaluation by otorhinolaryngology may be beneficial. PMID- 28815093 TI - A Case of Hyperparathyroidism due to a Large Intrathyroid Parathyroid Adenoma with Recurrent Episodes of Acute Pancreatitis. AB - We report a case of a 66-year-old woman who developed hyperparathyroidism due to a large intrathyroid parathyroid adenoma with episodes of acute pancreatitis. She had previously been treated for acute pancreatitis twice. Serum calcium was 12.4 mg/dL, and intact parathyroid hormone was 253 pg/dL. Ultrasonography and computed tomography of the neck with contrast enhancement revealed a soft tissue mass (28 mm transverse diameter) within the left lobe of the thyroid. 99mTc-MIBI scintigraphy demonstrated focal accumulation due to increased radiotracer uptake in the left thyroid lobe. Left hemithyroidectomy was performed. Histopathology showed no signs of invasion, and this is consistent with parathyroid adenoma. Immunostaining was positive for expression of chromogranin A and parathyroid hormone. The patient had no episode of pancreatitis after the operation. In a patient with recurrent episodes of pancreatitis, the possibility of complication with hyperparathyroidism should be considered. PMID- 28815094 TI - Add-On Therapy with Ertapenem in Infections with Multidrug Resistant Gram Negative Bacteria: Pediatric Experience. AB - Optimal therapy for infections with carbapenem resistant GNB is not well established due to the weakness of data. Patients presenting with bloodstream infections caused by multidrug resistant Klebsiella pneumoniae were treated with a combination treatment. Optimal therapy for infections with carbapenem resistant Gram-negative bacteria is a serious problem in pediatric patients. We presented three cases who were successfully treated with addition of ertapenem to the combination treatment for bacteremia with multidrug resistant Klebsiella pneumoniae. Dual carbapenem treatment approach is a new approach for these infections and requires more data in children. PMID- 28815095 TI - Acinetobacter lwoffii Peritonitis in a Patient on Automated Peritoneal Dialysis: A Case Report and Review of the Literature. AB - Acinetobacter lwoffii, a nonfermentative gram-negative aerobic bacillus, which presents in the normal flora of the oropharynx and skin, has recently been reported as a cause of human infection. Herein, the authors present a case report of peritonitis related to automated peritoneal dialysis caused by A. lwoffii. PMID- 28815096 TI - A Case of Congenital Brainstem Oligodendroglioma: Pathology Findings and Review of the Literature. AB - Congenital and perinatal primary brain neoplasms are extremely rare. Brainstem neoplasms in the perinatal and neonatal period are typically of high-grade nature and have poor prognoses with survival rates of less than 2 years from diagnosis. Herein, we report an unusual case of congenital anaplastic oligodendroglioma that arose in the pons and was detected as diffuse pontine glioma on in utero imaging studies during prenatal evaluation at 26 weeks' gestation. A male infant was delivered at 36.4 weeks of gestation via Cesarean section who developed progressive dyspnea shortly after birth. Magnetic resonance imaging (MRI) studies of his head showed the expansile, poorly demarcated mass in the pons with minimal heterogeneous enhancement and severe communicating hydrocephalus. Despite aggressive management, including dexamethasone treatment, the infant expired on the third day of postnatal life. On postmortem examination cut sections through the brainstem and cerebellum disclosed the neoplasm that infiltrated the entire pons, extended into the midbrain, medulla, cerebellar peduncles, and caudal diencephalon. Histological sections demonstrated an anaplastic oligodendroglioma infiltrating the pons, 4th ventricle, midbrain, medulla, cerebellar white matter, posterior thalamus, and occipital white matter. The pathological features of the lesion distinguish it from previous reports in which spontaneous regression of pontine gliomas occurred and argue in favor of establishing a tissue diagnosis to plan for aggressive versus conservative management. PMID- 28815097 TI - Pancreaticoduodenal Artery Aneurysm Associated with Celiac Trunk Stenosis: Case Illustration and Literature Review. AB - Pancreaticoduodenal artery aneurysms (PDA) are rare visceral aneurysms. Celiac trunk stenosis represents a common attributable aetiology for those aneurysms. Therefore, an alternative treatment approach, which differs from those isolated aneurysms, is recommended. We hereby present a 77-year-old male patient who was admitted with sudden onset of severe abdominal pain and significant drop in haemoglobin, occurring within a 24-hour interval. Contrast-enhanced computed tomography revealed a ruptured visceral aneurysm arising from the anterior branch of the inferior pancreaticoduodenal artery. A severe stenosis was also noted at the take-off of the celiac trunk. Selective catheterization of the supplying branch of the superior mesenteric artery, followed by coil embolization of the aneurysm, was performed, resulting in cessation of flow within the aneurysm, with preservation of the posterior branch, supplying the celiac territory. PDAs are usually asymptomatic and discovered incidentally at rupture. The risk of rupture is independent of the aneurysmal size and is associated with a 50% mortality rate. The consensus on coping with aneurysms is to treat them whenever they are discovered. Selective angiography followed by coil embolization represents a less invasive, and frequently definitive, approach than surgery. The risk for ischemia mandates that the celiac territory must not be compromised after embolization. PMID- 28815098 TI - Osteoblastic Metastases Mimickers on Contrast Enhanced CT. AB - Secondary osseous involvement in lymphoma is more common compared to primary bone lymphoma. The finding of osseous lesion can be incidentally discovered during the course of the disease. However, osseous metastases are infrequently silent. Detection of osseous metastases is crucial for accurate staging and optimal treatment planning of lymphoma. The aim of imaging is to identify the presence and extent of osseous disease and to assess for possible complications such as pathological fracture of the load-bearing bones and cord compression if the lesion is spinal. We are presenting two patients with treated lymphoma who were in complete remission. On routine follow-up contrast enhanced CT, there were new osteoblastic lesions in the spine worrisome for metastases. Additional studies were performed for further evaluation of both of them which did not demonstrate any corresponding suspicious osseous lesion. The patients have a prior history of chronic venous occlusive thrombosis that resulted in collaterals formation. Contrast enhancement of the vertebral body marrow secondary to collaterals formation and venous flow through the vertebral venous plexus can mimic the appearance of spinal osteoblastic metastases. PMID- 28815099 TI - Enabling Comprehension of Patient Subgroups and Characteristics in Large Bipartite Networks: Implications for Precision Medicine. AB - A primary goal of precision medicine is to identify patient subgroups based on their characteristics (e.g., comorbidities or genes) with the goal of designing more targeted interventions. While network visualization methods such as Fruchterman-Reingold have been used to successfully identify such patient subgroups in small to medium sized data sets, they often fail to reveal comprehensible visual patterns in large and dense networks despite having significant clustering. We therefore developed an algorithm called ExplodeLayout, which exploits the existence of significant clusters in bipartite networks to automatically "explode" a traditional network layout with the goal of separating overlapping clusters, while at the same time preserving key network topological properties that are critical for the comprehension of patient subgroups. We demonstrate the utility of ExplodeLayout by visualizing a large dataset extracted from Medicare consisting of readmitted hip-fracture patients and their comorbidities, demonstrate its statistically significant improvement over a traditional layout algorithm, and discuss how the resulting network visualization enabled clinicians to infer mechanisms precipitating hospital readmission in specific patient subgroups. PMID- 28815100 TI - Surveillance of Peripheral Arterial Disease Cases Using Natural Language Processing of Clinical Notes. AB - Peripheral arterial disease (PAD) is a chronic disease that affects millions of people worldwide and yet remains underdiagnosed and undertreated. Early detection is important, because PAD is strongly associated with an increased risk of mortality and morbidity. In this study, we built a PAD surveillance system using natural language processing (NLP) for early detection of PAD from narrative clinical notes. Our NLP algorithm had excellent positive predictive value (0.93) and identified 41% of PAD cases before the initial ankle-brachial index (ABI) test date while in 12% of cases the NLP algorithm detected PAD on the same date as the ABI (the gold standard for comparison). Hence, our system ascertains PAD patients in a timely and accurate manner. In conclusion, our PAD surveillance NLP algorithm has the potential for translation to clinical practice for use in reminding clinicians to order ABI tests in patients with suspected PAD and to reinforce the implementation of guideline recommended risk modification strategies in patients diagnosed with PAD. PMID- 28815101 TI - Characterizing the Strength of Evidence in FDA Labels for Pharmacogenomic Biomarker-Guided Medication Use. AB - There is great heterogeneity in drug treatment response that is thought to be due to individual-level allelic variation in pharmacogenomic biomarkers. FDA Drug Labels provide information to guide pharmacogenomic biomarker use. Yet, the strength of evidence for clinical validity and clinical utility is lacking. We characterized the strength of evidence and treatment recommendations contained in FDA Drug Labels as of December 2015. Pharmacogenomic biomarker information was provided for 137 drugs, involving 49 pharmacogenomic biomarkers, constituting 166 drug-biomarker pairs. Convincing/adequate evidence of clinical validity was found for 46% of pairs, of clinical utility for 29% of pairs, and of both, for 27% of pairs. Despite evidence of convincing/adequate validity/utility, no treatment recommendation was provided for 37% of pairs. Germline biomarkers represented nearly three-quarters of all drug-biomarker pairs, however, only 29% and 16% of pairs had convincing/adequate evidence for clinical validity and clinical utility, respectively. Separately, somatic biomarkers that serve as molecular targets for targeted therapies, had convincing/adequate evidence for 95% of pairs for clinical validity, and for 67% for clinical utility. The strength of evidence for pharmacogenomic biomarker use is low, underscoring the need for additional research to achieve the promise of precision medicine. PMID- 28815102 TI - Clinical Trials.Gov: A Topical Analyses. AB - ClinicalTrials.gov was established as a web-based registry for clinical trials of human participants in 2000. Mandatory registration started in 2008. Given more than a decade of registered trials, it's important to understand the "topic" areas and their evolution over time from this resource. This information may help in identifying current knowledge gaps. We use dynamic topic model (DTM) methods to discover topics and their evolution over last 17 years. Our model suggests that there are disease or organ specific trials such as 'Cardiovascular disorders', Heart & Brain conditions', or 'Breast & Prostate cancer' as well as trials registered for general health. General health trials are less likely to be FDA regulated, but both health and pain management, as well as surgical, heart, and brain trials have upward trend in recent years while advanced cancer trials have downward trended. Our model derives unique insights from metadata associated with each topic area. PMID- 28815103 TI - Search Datasets in Literature: A Case Study of GWAS. AB - One of the missions of the NIH BD2K (Big Data to Knowledge) initiative is to make data discoverable and promote the re-use of existing datasets. Our ultimate goal is to develop a scalable approach that can automatically scan millions of scientific publications and identify underlying data sets. Using Genome-Wide Association Studies (GWAS) as a use case, we conducted an initial study to identify GWAS dataset attributes in MEDLINE abstracts, by developing a hybrid approach that combines domain dictionaries and pattern-based rules. The automatic GWAS dataset attribute recognition system achieved an F-measure of 84.85%. We further applied the GWAS attribute recognition system to indexing MEDLINE abstracts and built an online GWAS dataset search engine called "GWAS Dataset Finder". Our evaluation showed that the GWAS Dataset Finder outperformed PubMed significantly in retrieving literature with desired datasets. Our study demonstrates the potential application of text mining methods in building the data discovery index. It can create a better index of literature linked with their underlying data sets, thus improving data discoverability. PMID- 28815104 TI - Electronic phenotyping with APHRODITE and the Observational Health Sciences and Informatics (OHDSI) data network. AB - The widespread usage of electronic health records (EHRs) for clinical research has produced multiple electronic phenotyping approaches. Methods for electronic phenotyping range from those needing extensive specialized medical expert supervision to those based on semi-supervised learning techniques. We present Automated PHenotype Routine for Observational Definition, Identification, Training and Evaluation (APHRODITE), an R- package phenotyping framework that combines noisy labeling and anchor learning. APHRODITE makes these cutting-edge phenotyping approaches available for use with the Observational Health Data Sciences and Informatics (OHDSI) data model for standardized and scalable deployment. APHRODITE uses EHR data available in the OHDSI Common Data Model to build classification models for electronic phenotyping. We demonstrate the utility of APHRODITE by comparing its performance versus traditional rule-based phenotyping approaches. Finally, the resulting phenotype models and model construction workflows built with APHRODITE can be shared between multiple OHDSI sites. Such sharing allows their application on large and diverse patient populations. PMID- 28815105 TI - Extracting Country-of-Origin from Electronic Health Records for Gene- Environment Studies as Part of the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) Study. AB - We describe here the extraction of country-of-origin, an acculturation variable relevant for gene-environment studies, in a biorepository linked to de-identified electronic health records (EHRs) assessed by the Epidemiologic Architecture for Genes Linked to Environment (EAGLE), a study site of the Population Architecture using Genomics and Epidemiology (PAGE) I study. We extracted country-of-origin from the unstructured clinical free text using regular expressions within the MySQL relational database system in a cohort of 15,863 subjects of mostly non European descent (including 11,519 African Americans, 1,702 Hispanics, and 1,118 Asians). We performed searches for 231 world countries (including independent sovereign states, dependent areas, and disputed territories) and common misspellings in >14 gigabytes of data including >13 billion characters of clinical text. Manual review of a fraction of the initial country-of-origin assignments established rules for data cleaning and quality control to achieve final country-of-origin status for each subject. After data cleaning, a total of 1,911/15,893 (12.02%) subjects were assigned to a country-of-origin outside of the United States. Mexico was the most commonly assigned country outside of the United States (264 subjects; 13.8% of subjects with a foreign country-of-origin assignment). The distribution of the countries assigned followed expectations based on known migration patterns to the United States with an emphasis on the southeastern region. These data suggest country-of-origin can be successfully extracted from unstructured clinical text for downstream genetic association studies. PMID- 28815106 TI - Automated Prediction of Hepatic Arterial Stenosis. AB - Several thousand life-saving liver transplants are performed each year. One of the most common causes of early transplant failure is arterial stenosis of the anastomotic junction. Early detection of transplant arterial stenosis can help prevent transplant failure and the need to re-transplant. Doppler ultrasound is the most common screening method, but it suffers from poor specificity. Positive screening cases proceed to angiography which is an invasive and expensive procedure. A more accurate test could decrease the number of normal patients who would have to undergo this invasive diagnostic procedure. We present a turnkey clinical decision support tool for automated prediction of stenosis based on Fourier spectrum analysis of Doppler sonograms to compute a Stenosis Index that has been shown to have higher accuracy than traditional measures. The results of the automated approach compare favorably with the manual approach. Software is available from the authors on request. PMID- 28815107 TI - Introducing a Comprehensive Informatics Framework to Promote Breast Cancer Risk Assessment and Chemoprevention in the Primary Care Setting. AB - Breast cancer is the most commonly diagnosed cancer among women in the United States, and current routine screening prevention methods are costly and expose patients to unnecessary risks of overtreatment. The utilization of a risk-based stratification model, genetic testing, and chemoprevention could decrease the incidence of invasive breast cancer but uptake has been low among high-risk women. The goal of this project was to implement a comprehensive informatics framework to promote breast cancer risk assessment and chemoprevention in the primary care setting that was informed by potential user feedback. The framework provides evidence-based decision support to both providers and patients. For providers we developed a novel breast cancer risk navigation (BNAV) tool which incorporates an evidence-based breast cancer risk model into the electronic health record. For patients a decision aid was designed that allows participants to experience risk through an activity and to address patient-related barriers to chemoprevention. We conducted usability testing to determine barriers and facilitators affecting the toolbox use by providers. A total of seven subjects were recruited and completed the usability testing. Using think-aloud protocols, semi-structured interviews, and subject recordings, we identified recurring themes related to the usability of BNAV. Themes specifically aligned with the content, ease of use, and navigation of the application. This feedback was used to make interface changes to the application that more appropriately tailored BNAV to engage the target population of primary care providers and thus more effectively optimizing shared decision-making associated with breast cancer risk assessment and prevention in clinical practice. A comprehensive informatics framework to increase breast cancer risk assessment and chemoprevention in the primary care setting has been successfully introduced to address this challenge. Given the proven efficacy of breast cancer chemoprevention in high-risk populations, higher uptake may significantly reduce the public health burden of this disease. PMID- 28815108 TI - Monitoring biomedical literature for post-market safety purposes by analyzing networks of text-based coded information. AB - Literature review is critical but time-consuming in the post-market surveillance of medical products. We focused on the safety signal of intussusception after the vaccination of infants with the Rotashield Vaccine in 1999 and retrieved all PubMed abstracts for rotavirus vaccines published after January 1, 1998. We used the Event-based Text-mining of Health Electronic Records system, the MetaMap tool, and the National Center for Biomedical Ontologies Annotator to process the abstracts and generate coded terms stamped with the date of publication. Data were analyzed in the Pattern-based and Advanced Network Analyzer for Clinical Evaluation and Assessment to evaluate the intussusception-related findings before and after the release of the new rotavirus vaccines in 2006. The tight connection of intussusception with the historical signal in the first period and the absence of any safety concern for the new vaccines in the second period were verified. We demonstrated the feasibility for semi-automated solutions that may assist medical reviewers in monitoring biomedical literature. PMID- 28815109 TI - Visualization of molecular structures using HoloLens-based augmented reality. AB - Biological molecules and biologically active small molecules are complex three dimensional structures. Current flat screen monitors are limited in their ability to convey the full three dimensional characteristics of these molecules. Augmented reality devices, including the Microsoft HoloLens, offer an immersive platform to change how we interact with molecular visualizations. We describe a process to incorporate the three dimensional structures of small molecules and complex proteins into the Microsoft HoloLens using aspirin and the human leukocyte antigen (HLA) as examples. Small molecular structures can be introduced into the HoloStudio application, which provides native support for rotating, resizing and performing other interactions with these molecules. Larger molecules can be imported through the Unity gaming development platform and then Microsoft Visual Developer. The processes described here can be modified to import a wide variety of molecular structures into augmented reality systems and improve our comprehension of complex structural features. PMID- 28815110 TI - Development of a Framework for Large Scale Three-Dimensional Pathology and Biomarker Imaging and Spatial Analytics. AB - With the rapid advancement in large-throughput scanning technologies, digital pathology has emerged as platform with promise for diagnostic approaches, but also for high-throughput quantitative data extraction and analysis for translational research. Digital pathology and biomarker images are rich sources of information on tissue architecture, cell diversity and morphology, and molecular pathway activation. However, the understanding of disease in three dimension (3D) has been hampered by their traditional two-dimension (2D) representations on histologic slides. In this paper, we propose a scalable image processing framework to quantitatively investigate 3D phenotypic and cell specific molecular features from digital pathology and biomarker images in information- lossless 3D tissue space. We also develop a generalized 3D spatial data management framework with multi-level parallelism and provide a sustainable infrastructure for rapid spatial queries through scalable and efficient spatial data processing. The developed framework can facilitate biomedical research by efficiently processing large-scale, 3D pathology and in-situ biomarker imaging data. PMID- 28815111 TI - Generalizable Middleware to Support Use of REDCap Dynamic Data Pull for Integrating Clinical and Research Data. AB - To support integration of clinical and research data, the makers of REDCap, a widely-used electronic data capture system, released the Dynamic Data Pull (DDP) module. Although DDP is a standard module in REDCap, institutions must develop custom middleware web services to exchange data between REDCap and local source systems. The lack of middleware is a barrier to institutional adoption and use by investigators. To overcome this gap, we developed a REDCap DDP web service middleware (accessible at https://github.com/wcmc-research-informatics/redcap ddp) that minimizes developer effort, relies on configuration by non-developers, and can generalize to other settings. Early findings suggest the approach is successful. PMID- 28815112 TI - Predicting intervention onset in the ICU with switching state space models. AB - The impact of many intensive care unit interventions has not been fully quantified, especially in heterogeneous patient populations. We train unsupervised switching state autoregressive models on vital signs from the public MIMIC-III database to capture patient movement between physiological states. We compare our learned states to static demographics and raw vital signs in the prediction of five ICU treatments: ventilation, vasopressor administra tion, and three transfusions. We show that our learned states, when combined with demographics and raw vital signs, improve prediction for most interventions even 4 or 8 hours ahead of onset. Our results are competitive with existing work while using a substantially larger and more diverse cohort of 36,050 patients. While custom classifiers can only target a specific clinical event, our model learns physiological states which can help with many interventions. Our robust patient state representations provide a path towards evidence-driven administration of clinical interventions. PMID- 28815113 TI - Towards Generation, Management, and Exploration of Combined Radiomics and Pathomics Datasets for Cancer Research. AB - Cancer is a complex multifactorial disease state and the ability to anticipate and steer treatment results will require information synthesis across multiple scales from the host to the molecular level. Radiomics and Pathomics, where image features are extracted from routine diagnostic Radiology and Pathology studies, are also evolving as valuable diagnostic and prognostic indicators in cancer. This information explosion provides new opportunities for integrated, multi-scale investigation of cancer, but also mandates a need to build systematic and integrated approaches to manage, query and mine combined Radiomics and Pathomics data. In this paper, we describe a suite of tools and web-based applications towards building a comprehensive framework to support the generation, management and interrogation of large volumes of Radiomics and Pathomics feature sets and the investigation of correlations between image features, molecular data, and clinical outcome. PMID- 28815114 TI - An Exploration of Latent Structure in Observational Huntington's Disease Studies. AB - Huntington's disease (HD) is a monogenic neurodegenerative disorder characterized by the progressive decay of motor and cognitive abilities accompanied by psychiatric episodes. Tracking and modeling the progression of the multi-faceted clinical symptoms of HD is a challenging problem that has important implications for staging of HD patients and the development of improved enrollment criteria for future HD studies and trials. In this paper, we describe the first steps towards this goal. We begin by curating data from four recent observational HD studies, each containing a diverse collection of clinical assessments. The resulting dataset is unprecedented in size and contains data from 19,269 study participants. By analyzing this large dataset, we are able to discover hidden low dimensional structure in the data that correlates well with surrogate measures of HD progression. The discovered structures are promising candidates for future consumption by downstream statistical HD progression models. PMID- 28815115 TI - Discovering adverse drug events combining spontaneous reports with electronic medical records: a case study of conventional DMARDs and biologics for rheumatoid arthritis. AB - The use of multiple data sources has been preferred in the surveillance of adverse drug events due to shortcomings of using only a single source. In this study, we proposed a framework where the ADEs associated with interested drugs are systematically discovered from the FDA's Adverse Event Reporting System (AERS), and then validated through mining unstructured clinical notes from Electronic Medical Records (EMRs). This framework has two features. First, a higher priority was given to clinical practice during signal detection and validation. Second, the normalization by NLP facilitated the interoperation between AERS-DM and the EMR. To demonstrate this methodology, we investigated potential ADEs associated with drugs (class level) for rheumatoid arthritis (RA) patients. The results demonstrated the feasibility and sufficient accuracy of the framework. The framework can serve as the interface between the informatics domain and the medical domain to facilitate ADE discovery. PMID- 28815116 TI - Reducing Clinical Noise for Body Mass Index Measures Due to Unit and Transcription Errors in the Electronic Health Record. AB - Body mass index (BMI) is an important outcome and covariate adjustment for many clinical association studies. Accurate assessment of BMI, therefore, is a critical part of many study designs. Electronic health records (EHRs) are a growing source of clinical data for research purposes, and have proven useful for identifying and replicating genetic associations. EHR-based data collected for clinical and billing purposes have several unique properties, including a high degree of heterogeneity or "clinical noise." In this work, we propose a new method for reducing the problems of transcription and recording error for height and weight and apply these methods to a subset of the Vanderbilt University Medical Center biorepository known as EAGLE BioVU (n=15,863). After processing, we show that the distribution of BMI from EAGLE BioVU closely matches population based estimates from the National Health and Nutrition Examination Surveys (NHANES), and that our approach retains far more data points than traditional outlier detection methods. PMID- 28815117 TI - Systematic Analysis of Free-Text Family History in Electronic Health Record. AB - Family history is an important component in modern clinical care especially in the era of precision medicine. Family history information in the Electronic Health Record (EHR) system is usually stored in structured format as well as in free-text format. In this study, we systematically analyzed a family history text corpus from 3 million clinical notes for the patients receiving their primary care at Mayo Clinic. Family members, medical problems, and their associations were analyzed and reported. Our findings showed a great agreement between positive/negated medical problems mentioned in the diagnosis report and the family history, as measured by observed agreement and random agreement. We also found that the family history of some medical problems existed up to 10~15 years prior to the diagnosis date of such problems. Finally two patient cases were studied to show the medical problems in the diagnosis and family history associated with the timeline. PMID- 28815118 TI - Deep Learning from EEG Reports for Inferring Underspecified Information. AB - Secondary use1of electronic health records (EHRs) often relies on the ability to automatically identify and extract information from EHRs. Unfortunately, EHRs are known to suffer from a variety of idiosyncrasies - most prevalently, they have been shown to often omit or underspecify information. Adapting traditional machine learning methods for inferring underspecified information relies on manually specifying features characterizing the specific information to recover (e.g. particular findings, test results, or physician's impressions). By contrast, in this paper, we present a method for jointly (1) automatically extracting word- and report-level features and (2) inferring underspecified information from EHRs. Our approach accomplishes these two tasks jointly by combining recent advances in deep neural learning with access to textual data in electroencephalogram (EEG) reports. We evaluate the performance of our model on the problem of inferring the neurologist's over-all impression (normal or abnormal) from electroencephalogram (EEG) reports and report an accuracy of 91.4% precision of 94.4% recall of 91.2% and F1 measure of 92.8% (a 40% improvement over the performance obtained using Doc2Vec). These promising results demonstrate the power of our approach, while error analysis reveals remaining obstacles as well as areas for future improvement. PMID- 28815120 TI - Integrating Temporal Pattern Mining in Ischemic Stroke Prediction and Treatment Pathway Discovery for Atrial Fibrillation. AB - Atrial fibrillation (AF) is associated with an increased risk of acute ischemic stroke (AIS). Accurately predicting AIS and planning effective treatment pathways for AIS prevention are crucial for AF patients. Because of the temporality of patients' disease progressions, sequential disease and treatment patterns have the potential to improve risk prediction performance and contribute to effective treatment pathways. This paper integrates temporal pattern mining into the AF study of AIS prediction and treatment pathway discovery. We combine temporal pattern mining with feature selection to identify temporal risk factors that have predictive ability, and integrate temporal pattern mining with treatment efficacy analysis to discover temporal treatment patterns that are statistically effective. Results show that our approach has identified new potential temporal risk factors for AIS that can improve the prediction performance, and has discovered treatment pathway patterns that are statistically effective to prevent AIS for AF patients. PMID- 28815119 TI - Extracting geographic locations from the literature for virus phylogeography using supervised and distant supervision methods. AB - The field of phylogeography allows researchers to model the spread and evolution of viral genetic sequences. Phylogeography plays a major role in infectious disease surveillance, viral epidemiology and vaccine design. When conducting viral phylogeographic studies, researchers require the location of the infected host of the virus, which is often present in public databases such as GenBank. However, the geographic metadata in most GenBank records is not precise enough for many phylogeographic studies; therefore, researchers often need to search the articles linked to the records for more information, which can be a tedious process. Here, we describe two approaches for automatically detecting geographic location mentions in articles pertaining to virus-related GenBank records: a supervised sequence labeling approach with innovative features and a distant supervision approach with novel noise- reduction methods. Evaluated on a manually annotated gold standard, our supervised sequence labeling and distant supervision approaches attained F-scores of 0.81 and 0.66, respectively. PMID- 28815122 TI - Incorporating Data Citation in a Biomedical Repository: An Implementation Use Case. AB - Research data is a dynamic and evolving entity and the ability to cite such data depends on recreating the same datasets utilized in the original research. Despite the availability of several existing technologies, most data repositories lack the necessary setup to recreate a point-in-time snapshot of data, let alone long-term sustainability of dynamic data without restoring an entire database. Through this project, we adopted a subset of the Research Data Alliance data citation working group recommendations to establish a robust informatics system supporting dynamic data and its use for reproducible research within our evolving clinical data repository. We implemented key recommendations: data versioning, times-stamping, query storing, query time-stamping, query PID, and data citation in one data repository, implemented entirely at the database level, and were able to successfully reproduce a previous dataset as it existed at a specific point-in time using only the PID as provided in a citation. PMID- 28815121 TI - Enhancing Electronic Health Record Data with Geospatial Information. AB - Electronic Health Record (EHR)-derived data is a valuable resource for research, and efforts are underway to overcome some of its limitations by using data from external sources to gain a fuller picture of patient characteristics, symptoms, and exposures. Our goal was to assess the utility of augmenting EHR data with geocoded patient addresses to identify geospatial variation of disease that is not explained by EHR-derived demographic factors. Using 2011-2014 encounter data from 27,604 University of Pennsylvania Hospital System asthma patients, we identified factors associated with asthma exacerbations: risk was higher in female, black, middle aged to elderly, and obese patients, as well as those with positive smoking history and with Medicare or Medicaid vs. private insurance. Significant geospatial variability of asthma exacerbations was found using generalized additive models, even after adjusting for demographic factors. Our work shows that geospatial data can be used to cost-effectively enhance EHR data. PMID- 28815123 TI - Rapid and Reusable Text Visualization and Exploration Development with DELVE. AB - We present DELVE (Document ExpLoration and Visualization Engine), a framework for developing interactive visualizations as modular Web-applications to assist researchers with exploratory literature search. The goal for web-applications driven by DELVE is to better satisfy the information needs of researchers and to help explore and understand the state of research in scientific liter ature by providing immersive visualizations that both contain facets and are driven by facets derived from the literature. We base our framework on principles from user centered design and human-computer interaction (HCI). Preliminary evaluations demon strate the usefulness of DELVE's techniques: (1) a clinical researcher immediately saw that her original query was inappropriate simply due to the frequencies displayed via generalized clouds and (2) a muscle biologist quickly learned of vocabulary differences found between two disciplines that were referencing the same idea, which we feel is critical for interdisciplinary work. We dis cuss the underlying category-theoretic model of our framework and show that it naturally encourages the development of reusable visualizations by emphasizing interoperability. PMID- 28815124 TI - PheKnow-Cloud: A Tool for Evaluating High-Throughput Phenotype Candidates using Online Medical Literature. AB - As the adoption of Electronic Healthcare Records has grown, the need to transform manual processes that extract and characterize medical data into automatic and high-throughput processes has also grown. Recently, researchers have tackled the problem of automatically extracting candidate phenotypes from EHR data. Since these phenotypes are usually generated using unsupervised or semi-supervised methods, it is necessary to examine and validate the clinical relevance of the generated "candidate" phenotypes. We present PheKnow-Cloud, a framework that uses co-occurrence analysis on the publicly available, online repository ofjournal articles, PubMed, to build sets of evidence for user-supplied candidate phenotypes. PheKnow-Cloud works in an interactive manner to present the results of the candidate phenotype analysis. This tool seeks to help researchers and clinical professionals evaluate the automatically generated phenotypes so they may tune their processes and understand the candidate phenotypes. PMID- 28815125 TI - Visualizing and Validating Metadata Traceability within the CDISC Standards. AB - The Food & Drug Administration has begun requiring that electronic submissions of regulated clinical studies utilize the Clinical Data Information Standards Consortium data standards. Within regulated clinical research, traceability is a requirement and indicates that the analysis results can be traced back to the original source data. Current solutions for clinical research data traceability are limited in terms of querying, validation and visualization capabilities. This paper describes (1) the development of metadata models to support computable traceability and traceability visualizations that are compatible with industry data standards for the regulated clinical research domain, (2) adaptation of graph traversal algorithms to make them capable of identifying traceability gaps and validating traceability across the clinical research data lifecycle, and (3) development of a traceability query capability for retrieval and visualization of traceability information. PMID- 28815126 TI - A Simple Text Mining Approach for Ranking Pairwise Associations in Biomedical Applications. AB - We present a simple text mining method that is easy to implement, requires minimal data collection and preparation, and is easy to use for proposing ranked associations between a list of target terms and a key phrase. We call this method KinderMiner, and apply it to two biomedical applications. The first application is to identify relevant transcription factors for cell reprogramming, and the second is to identify potential drugs for investigation in drug repositioning. We compare the results from our algorithm to existing data and state-of-the-art algorithms, demonstrating compelling results for both application areas. While we apply the algorithm here for biomedical applications, we argue that the method is generalizable to any available corpus of sufficient size. PMID- 28815127 TI - A Knowledge-based System for Intelligent Support in Pharmacogenomics Evidence Assessment: Ontology-driven Evidence Representation and Retrieval. AB - Pharmacogenomics holds promise as a critical component of precision medicine. Yet, the use of pharmacogenomics in routine clinical care is minimal, partly due to the lack of efficient and effective use of existing evidence. This paper describes the design, development, implementation and evaluation of a knowledge based system that fulfills three critical features: a) providing clinically relevant evidence, b) applying an evidence-based approach, and c) using semantically computable formalism, to facilitate efficient evidence assessment to support timely decisions on adoption of pharmacogenomics in clinical care. To illustrate functionality, the system was piloted in the context of clopidogrel and warfarin pharmacogenomics. In contrast to existing pharmacogenomics knowledge bases, the developed system is the first to exploit the expressivity and reasoning power of logic-based representation formalism to enable unambiguous expression and automatic retrieval of pharmacogenomics evidence to support systematic review with meta-analysis. PMID- 28815128 TI - A comparative study of different methods for automatic identification of clopidogrel-induced bleedings in electronic health records. AB - Electronic health records (EHRs) linked with biobanks have been recognized as valuable data sources for pharmacogenomic studies, which require identification of patients with certain adverse drug reactions (ADRs) from a large population. Since manual chart review is costly and time-consuming, automatic methods to accurately identify patients with ADRs have been called for. In this study, we developed and compared different informatics approaches to identify ADRs from EHRs, using clopidogrel-induced bleeding as our case study. Three different types of methods were investigated: 1) rule-based methods; 2) machine learning-based methods; and 3) scoring function-based methods. Our results show that both machine learning and scoring methods are effective and the scoring method can achieve a high precision with a reasonable recall. We also analyzed the contributions of different types of features and found that the temporality information between clopidogrel and bleeding events, as well as textual evidence from physicians' assertion of the adverse events are helpful. We believe that our findings are valuable in advancing EHR-based pharmacogenomic studies. PMID- 28815129 TI - SDT: A Tree Method for Detecting Patient Subgroups with Personalized Risk Factors. AB - Eradicating health disparity is a new focus for precision medicine research. Identifying patient subgroups is an effective approach to customized treatments for maximizing efficiency in precision medicine. Some features may be important risk factors for specific patient subgroups but not necessarily for others, resulting in a potential divergence in treatments designed for a given population. In this paper, we propose a tree-based method, called Subgroup Detection Tree (SDT), to detect patient subgroups with personalized risk factors. SDT differs from conventional CART in the splitting criterion that prioritizes the potential risk factors. Subgroups are automatically formed as leaf nodes in the tree growing procedure. We applied SDT to analyze a clinical hypertension (HTN) dataset, investigating significant risk factors for hypertensive heart disease in African-American patients, and uncovered significant correlations between vitamin D and selected subgroups of patients. Further, SDT is enhanced with ensemble learning to reduce the variance of prediction tasks. PMID- 28815130 TI - Ground Truth Creation for Complex Clinical NLP Tasks - an Iterative Vetting Approach and Lessons Learned. AB - Natural language processing (NLP) holds the promise of effectively analyzing patient record data to reduce cognitive load on physicians and clinicians in patient care, clinical research, and hospital operations management. A critical need in developing such methods is the "ground truth" dataset needed for training and testing the algorithms. Beyond localizable, relatively simple tasks, ground truth creation is a significant challenge because medical experts, just as physicians in patient care, have to assimilate vast amounts of data in EHR systems. To mitigate potential inaccuracies of the cognitive challenges, we present an iterative vetting approach for creating the ground truth for complex NLP tasks. In this paper, we present the methodology, and report on its use for an automated problem list generation task, its effect on the ground truth quality and system accuracy, and lessons learned from the effort. PMID- 28815131 TI - Integrating Medication Alert Data into a Clinical Data Repository to Enable Retrospective Study of Drug Interaction Alerts in Clinical Practice. AB - Current clinical data repositories primarily extract data from multiple administrative and electronic medical record (EMR) data resources (e.g., hospital and physician billing records) containing specific patient-level data including demographics, medications, laboratory results, diagnoses, and procedure codes. It overlooks the importance of EMR system-level data (e.g., medication alerts that are routinely used by physicians, nurses, and pharmacists for decision support) for the surveillance of EMR decision support tools. These medication alerts are a significant source of information for providers, to minimize avoidable adverse drug events. This study describes the integration of medication alert data into an i2b2-based clinical data repository to support the investigation of clinical events occurring around patients with anticoagulation treatment that triggered drug-drug interaction alerts. The integration of medication alerts allows us to repurpose the clinical and translational research infrastructure to conduct retrospective effectiveness surveillance of clinical decision support tools. PMID- 28815132 TI - Precision Diagnosis Of Melanoma And Other Skin Lesions From Digital Images. AB - Melanoma will affect an estimated 73,000 new cases this year and result in 9,000 deaths, yet precise diagnosis remains a serious problem. Without early detection and preventative care, melanoma can quickly spread to become fatal (Stage IV 5 year survival rate is 20-10%) from a once localized skin lesion (Stage IA 5- year survival rate is 97%). There is no biomarker for melanoma in clinical use, and the current diagnostic criteria for skin lesions remains subjective and imprecise. Accurate diagnosis of melanoma relies on a histopathologic gold standard; thus, aggressive excision of melanocytic skin lesions has been the mainstay of treatment. It is estimated that 36 biopsies are performed for every melanoma confirmed by pathology among excised lesions. There is significant morbidity in misdiagnosing melanoma such as progression of the disease for a false negative prediction vs the risks of unnecessary surgery for a false positive prediction. Every year, poor diagnostic precision adds an estimated $673 million in overall cost to manage the disease. Currently, manual dermatoscopic imaging is the standard of care in selecting atypical skin lesions for biopsy, and at best it achieves 90% sensitivity but only 59% specificity when performed by an expert dermatologist. Many computer vision (CV) algorithms perform better than dermatologists in classifying skin lesions although not significantly so in clinical practice. Meanwhile, open source deep learning (DL) techniques in CV have been gaining dominance since 2012 for image classification, and today DL can outperform humans in classifying millions of digital images with less than 5% error rates. Moreover, DL algorithms are readily run on commoditized hardware and have a strong online community of developers supporting their rapid adoption. In this work, we performed a successful pilot study to show proof of concept to DL skin pathology from images. However, DL algorithms must be trained on very large labelled datasets of images to achieve high accuracy. Here, we begin to assemble a large imageset of skin lesions from the UCSF and the San Francisco Veterans Affairs Medical Center (VAMC) dermatology clinics that are well characterized by their underlying pathology, on which to train DL algorithms. If trained on sufficient data, we hypothesize that our approach will significantly outperform general dermatologists in predicting skin lesion pathology. We posit that our work will allow for precision diagnosis of melanoma from widely available digital photography, which may optimize the management of the disease by decreasing unnecessary office visits and the significant morbidity and cost of melanoma misdiagnosis. PMID- 28815133 TI - Correlating Lab Test Results in Clinical Notes with Structured Lab Data: A Case Study in HbA1c and Glucose. AB - It is widely acknowledged that information extraction of unstructured clinical notes using natural language processing (NLP) and text mining is essential for secondary use of clinical data for clinical research and practice. Lab test results are currently structured in most of the electronic health record (EHR) systems. However, for referral patients or lab tests that can be done in non clinical setting, the results can be captured in unstructured clinical notes. In this study, we proposed a rule-based information extraction system to extract the lab test results with temporal information from clinical notes. The lab test results of glucose and HbA1c from 104 randomly sampled diabetes patients selected from 1996 to 2015 are extracted and further correlated with structured lab test information in the Mayo Clinic EHRs. The system has high F1-scores of 0.964, 0.967 and 0.966 in glucose, HbA1c and overall extraction, respectively. PMID- 28815135 TI - Active Deep Learning-Based Annotation of Electroencephalography Reports for Cohort Identification. AB - The annotation of a large corpus of Electroencephalography (EEG) reports is a crucial step in the development of an EEG-specific patient cohort retrieval system. The annotation of multiple types of EEG-specific medical concepts, along with their polarity and modality, is challenging, especially when automatically performed on Big Data. To address this challenge, we present a novel framework which combines the advantages of active and deep learning while producing annotations that capture a variety of attributes of medical concepts. Results obtained through our novel framework show great promise. PMID- 28815134 TI - Interrogating Patient-level Genomics and Mouse Phenomics towards Understanding Cytokines in Colorectal Cancer Metastasis. AB - Background: Colorectal cancer is the second leading cancer-related death worldwide and a majority of patients die from metastasis. Chronic intestinal inflammation plays an important role in tumor progression of colorectal cancer. However, few study works on systematically predicting colorectal cancer metastasis using inflammatory cytokine genes. Results: We developed a supervised machine learning approach to predict colorectal cancer tumor progression using patient level genomic features. To better understand the role of cytokines, we integrated the metastatic-related genes from mouse phenotypic data. In addition, pathway analysis and network visualization were also applied to top significant genes ranked by feature weights of the final prediction model. The combined model of cytokines and mouse phenotypes achieved a predictive accuracy of 75.54%, higher than the model based on mouse phenotypes independently (70.42%, p value<0.05). In additional, the combined model outperformed the model based on the existing metastatic-related epithelial-to-mesenchymal transition (EMT) genes (75.54% vs. 71.61%, p-value<0.05). We also observed that the most important cytokine gene features of the our model interact with the cancer driver genes and are highly associated with the colorectal cancer metastasis signaling pathway. Conclusion: We developed a combined model using both cytokine and mouse phenotype information to predict colorectal cancer metastasis. The results suggested that the inflammatory cytokines increase the power of predicting metastasis. We also systematically demonstrated the critical role of cytokines in progression of colorectal tumor. PMID- 28815136 TI - Design Recommendations for Pharmacogenomics Clinical Decision Support Systems. AB - The use of pharmacogenomics (PGx) in clinical practice still faces challenges to fully adopt genetic information in targeting drug therapy. To incorporate genetics into clinical practice, many support the use of Pharmacogenomics Clinical Decision Support Systems (PGx-CDS) for medication prescriptions. This support was fueled by new guidelines to incorporate genetics for optimizing drug dosage and reducing adverse events. In addition, the complexity of PGx led to exploring CDS outside the paradigm of the basic CDS tools embedded in commercial electronic health records. Therefore, designing the right CDS is key to unleashing the full potential of pharmacogenomics and making it a part of clinicians' daily workflow. In this work, we 1) identify challenges and barriers of the implementation of PGx-CDS in clinical settings, 2) develop a new design approach to CDS with functional characteristics that can improve the adoption of pharmacogenomics guidelines and thus patient safety, and 3) create design guidelines and recommendations for such PGx-CDS tools. PMID- 28815137 TI - Combining Kernel and Model Based Learning for HIV Therapy Selection. AB - We present a mixture-of-experts approach for HIV therapy selection. The heterogeneity in patient data makes it difficult for one particular model to succeed at providing suitable therapy predictions for all patients. An appropriate means for addressing this heterogeneity is through combining kernel and model-based techniques. These methods capture different kinds of information: kernel-based methods are able to identify clusters of similar patients, and work well when modelling the viral response for these groups. In contrast, model-based methods capture the sequential process of decision making, and are able to find simpler, yet accurate patterns in response for patients outside these groups. We take advantage of this information by proposing a mixture-of-experts model that automatically selects between the methods in order to assign the most appropriate therapy choice to an individual. Overall, we verify that therapy combinations proposed using this approach significantly outperform previous methods. PMID- 28815138 TI - Integrative network and transcriptomics-based approach predicts genotype- specific drug combinations for melanoma. AB - Computational methods for drug combination predictions are needed to identify effective therapies that improve durability and prevent drug resistance in an efficient manner. In this paper, we present SynGeNet, a computational method that integrates transcriptomics data characterizing disease and drug z-score profiles with network mining algorithms in order to predict synergistic drug combinations. We compare SynGeNet to other available transcriptomics-based tools to predict drug combinations validated across melanoma cell lines in three genotype groups: BRAF-mutant, NRAS-mutant and combined. We showed that SynGeNet outperforms other available tools in predicting validated drug combinations and single agents tested as part of additional drug pairs. Interestingly, we observed that the performance of SynGeNet decreased when the network construction step was removed and improved when the proportion of matched-genotype validation cell lines increased. These results suggest that delineating functional information from transcriptomics data via network mining and genomic features can improve drug combination predictions. PMID- 28815139 TI - SemanticFind: Locating What You Want in a Patient Record, Not Just What You Ask For. AB - We present a new model of patient record search, called SemanticFind, which goes beyond traditional textual and medical synonym matches by locating patient data that a clinician would want to see rather than just what they ask for. The new model is implemented by making extensive use of the UMLS semantic network, distributional semantics, and NLP, to match query terms along several dimensions in a patient record with the returned matches organized accordingly. The new approach finds all clinically related concepts without the user having to ask for them. An evaluation of the accuracy of SemanticFind shows that it found twice as many relevant matches compared to those found by literal (traditional) search alone, along with very high precision and recall. These results suggest potential uses for SemanticFind in clinical practice, retrospective chart reviews, and in automated extraction of quality metrics. PMID- 28815140 TI - D2Refine: A Platform for Clinical Research Study Data Element Harmonization and Standardization. AB - In this paper, we present a platform known as D2Refine for facilitating clinical research study data element harmonization and standardization. D2Refine is developed on top of OpenRefine (formerly Google Refine) and leverages simple interface and extensible architecture of OpenRefine. D2Refine empowers the tabular representation of clinical research study data element definitions by allowing it to be easily organized and standardized using reconciliation services. D2Refine builds on valuable built-in data transformation features of OpenRefine to bring source data sets to a finer state quickly. We implemented the reconciliation services and search capabilities based on the standard Common Terminology Services 2 (CTS2) and the serialization of clinical research study data element definitions into standard representation using clinical information modeling technology for semantic interoperability. We demonstrate that D2Refine is a useful and promising platform that would help address the emergent needs for clinical research study data element harmonization and standardization. PMID- 28815141 TI - Identifying Metastases-related Information from Pathology Reports of Lung Cancer Patients. AB - Metastatic patterns of spread at the time of cancer recurrence are one of the most important prognostic factors in estimation of clinical course and survival of the patient. This information is not easily accessible since it's rarely recorded in a structured format. This paper describes a system for categorization of pathology reports by specimen site and the detection of metastatic status within the report. A clinical NLP pipeline was developed using sentence boundary detection, tokenization, section identification, part-of-speech tagger, and chunker with some rule based methods to extract metastasis site and status in combination with five types of information related to tumor metastases: histological type, grade, specimen site, metastatic status indicators and the procedure. The system achieved a recall of 0.84 and 0.88 precision for metastatic status detection, and 0.89 recall and 0.93 precision for metastasis site detection. This study demonstrates the feasibility of applying NLP technologies to extract valuable metastases information from pathology reports and we believe that it will greatly benefit studies on cancer metastases that utilize EHRs. PMID- 28815142 TI - A Data Capture Framework for Large-scale Interventional Studies with Survey Workflow Management. AB - Capturing high-quality survey data is an arduous process for large-scale and extensive interventional studies. This paper presents the architecture, interface design, and an innovative form generation engine of a system called RE- Form: Refactorized Electronic Web Forms. REForm provides researchers the capability to design and manage surveys and the flexibility to organize them in a customizable workflow. REForm has been designed, implemented, pilot-tested and deployed for an NCI-funded interventional study IMPACT. It enables IMPACT to design and conduct a baseline survey of 95 questions with 662 options, a post-intervention survey of 82 questions with 574 options, six Ecological Momentary Assessment (EMA) surveys including four questions and 26 options each, and a follow-up survey con- taining 15 questions and 125 options. Feedback designed in the post-intervention survey showed that more than 94 percent of IMPACT participants highly endorsed the design and usability of the surveys created using REForm. PMID- 28815143 TI - Analyzing Electronic Medical Records to Predict Risk of DIT (Death, Intubation, or Transfer to ICU) in Pediatric Respiratory Failure or Related Conditions. AB - Large volumes of data are generated in hospital settings, including clinical and physiological data generated during the course of patient care. Our goal, as proof of concept, was to identify early clinical factors or traits useful for predicting the outcome, of death, intubation, or transfer to ICU, for children with pediatric respiratory failure. We implemented both supervised and unsupervised methods to extend our understanding on statistical relationships in clinical and physiological data. As a supervised learning method, we use binary logistic regression to predict the risk of developing DIT outcome. Next, we implemented unsupervised k-means algorithm on principal components of clinical and physiological data to further explore the contribution of clinical and physiological data on developing DIT outcome. Our results show that early signals of DIT can be detected in physiological data, and two risk factors, blood pressure and oxygen level, are the most important determinant of developing DIT. PMID- 28815144 TI - A Clinical Decision Support System for Monitoring Post-Colonoscopy Patient Follow Up and Scheduling. AB - This paper describes a natural language processing (NLP)-based clinical decision support (CDS) system that is geared towards colon cancer care coordinators as the end users. The system is implemented using a metadata- driven Structured Query Language (SQL) function (discriminant function). For our pilot study, we have developed a training corpus consisting of 2,085 pathology reports from the VA Connecticut Health Care System (VACHS). We categorized reports as "actionable"- requiring close follow up, or "non-actionable"- requiring standard or no follow up. We then used 600 distinct pathology reports from 6 different VA sites as our test corpus. Analysis of our test corpus shows that our NLP approach yields 98.5% accuracy in identifying cases that required close clinical follow up. By integrating this into our cancer care tracking system, our goal is to ensure that patients with worrisome pathology receive appropriate and timely follow-up and care. PMID- 28815145 TI - Evolving Research Data Sharing Networks to Clinical App Sharing Networks. AB - Research networks for data sharing are growing into a large platform for pragmatic clinical trials to generate quality evidence for shared medical decision-making. Institutions partnering in the networks have made large investments in developing the infrastructure for sharing data. We investigate whether institutions partnering on Patient-Centered Outcomes Research Institute's (PCORI) network can share clinical apps. At two different sites, we imported patient data in PCORI's clinical data model (CDM) format into i2b2 repositories, and adapted the SMART-on-FHIR cell to perform CDM-to-FHIR translation, serving demographics, laboratory results and diagnoses. We performed manual validations and tested the platform using four apps from the SMART app gallery. Our study demonstrates an approach to extend the research infrastructure to allow the partnering institutions to run shared clinical apps, and highlights the involved challenges. Our results, tooling and publically accessible data service can potentially transform research networks into clinical app sharing networks and pave the way towards a learning health system. PMID- 28815146 TI - Quantifying the relative change in physical activity after Total Knee Arthroplasty using accelerometer based measurements. AB - Osteoarthritis is amongst the top five most disabling conditions affecting Americans over 65 years of age and imposes an annual economic burden estimated at $ 89.1 billion. Nearly half of the cost of care of Osteoarthritis is attributable to hospitalizations for total knee arthroplasties (TKA) and total hip arthroplasties (THA). The current clinical practice relies predominantly on subjective assessment of physical function and pain via patient reported outcome measures (PROM) that have proven inadequate for providing a validated, reliable and responsive measure of TKA outcomes. Wearable activity monitors, which produce a trace of regularly monitored physical activity derived from accelerometer measurements, provide a novel opportunity to objectively assess physical functional status in Osteoarthritis patients. Using data from the Osteoarthritis Initiative (OAI), we demonstrate the feasibility of quantifying the relative change in physical activity patterns in Osteoarthritis subjects using accelerometer based measurements of daily physical activity. PMID- 28815147 TI - Triangulating Methodologies from Software, Medicine and Human Factors Industries to Measure Usability and Clinical Efficacy of Medication Data Visualization in an Electronic Health Record System. AB - Within the last decade, use of Electronic Health Record (EHR) systems has become intimately integrated into healthcare practice in the United States. However, large gaps remain in the study of clinical usability and require rigorous and innovative approaches for testing usability principles. In this study, validated tools from the core functions that EHRs serve-software, medicine and human factors-were combined to holistically understand and objectively measure usability of medication data displays. The first phase of this study included 132 medical trainee participants who were randomized to one of two simulated EHR environments with either a medication list or a medication timeline visualization. Within these environments human-computer interaction metrics, clinical reasoning and situation awareness tests, and usability surveys captured their multi-faceted interactions. Results showed no statistically significant differences in the two displays from software and situation awareness perspectives, though there were higher statistically significant usability scores of the medication timeline (intervention) as compared to the medication list (control). This first phase of a novel design in triangulating methodologies revealed several limitations from which future experiments will be adjusted with hopes of yielding further insight and a generalizable testing platform for evolving EHR interfaces. PMID- 28815148 TI - Spatio-temporal Analysis for New York State SPARCS Data. AB - Increased accessibility of health data provides unique opportunities to discover spatio-temporal patterns of diseases. For example, New York State SPARCS (Statewide Planning and Research Cooperative System) data collects patient level detail on patient demographics, diagnoses, services, and charges for each hospital inpatient stay and outpatient visit. Such data also provides home addresses for each patient. This paper presents our preliminary work on spatial, temporal, and spatial-temporal analysis of disease patterns for New York State using SPARCS data. We analyzed spatial distribution patterns of typical diseases at ZIP code level. We performed temporal analysis of common diseases based on 12 years' historical data. We then compared the spatial variations for diseases with different levels of clustering tendency, and studied the evolution history of such spatial patterns. Case studies based on asthma demonstrated that the discovered spatial clusters are consistent with prior studies. We visualized our spatial-temporal patterns as animations through videos. PMID- 28815149 TI - Classifying Supplement Use Status in Clinical Notes. AB - Clinical notes contain rich information about supplement use that is critical for detecting adverse interactions between supplements and prescribed medications. It is important to know the context in which supplements are mentioned in clinical notes to be able to correctly identify patients that either currently take the supplement or did so in the past. We applied text mining methods to automatically classify supplement use into four status categories: Continuing (C), Discontinued (D), Started (S), and Unclassified (U). We manually classified 1,300 sentences into these categories, which were further split as training (1000 sentences) and testing (300 sentences) sets. We evaluated the 7 types of feature sets and 5 algorithms, and the best model (SVM with unigram, bigram and indicator word within certain distance) performed F-measure of 0.906, 0.913, 0.914, 0.715 for status C, D, S, U, respectively on the testing set. This study demonstrates the feasibility of using text mining methods to classify supplement use status from clinical notes. PMID- 28815150 TI - Identifying Psychiatric Comorbidities for Obstructive Sleep Apnea in the Biomedical Literature and Electronic Health Record. AB - Obstructive sleep apnea (OSA) is one of the most common diseases among Americans, affecting between 5 and 20% of the population. While there is existing evidence of numerous comorbid conditions, such as obesity, diabetes, and high blood pressure, the vast majority of this evidence has focused explicitly on cardiovascular morbidities and excluded any mental or behavioral disorders. The goal of this study was to examine psychiatric comorbidities of OSA in two types of sources: (1) biomedical literature in the MEDLINE/PubMed database (focusing on MeSH descriptors) and Semantic MEDLINE Database (SemMedDB; for semantic predications), and (2) electronic health record data in the MIMIC-III database. Approximately 300 unique psychiatric comorbidities were identified, ranked, and compared across MEDLINE/PubMed, SemMedDB, and MIMIC-III. The preliminary results highlight the potential of this multi-angled approach for suggesting opportunities for further investigation that may contribute to improving mental health in persons afflicted with OSA. PMID- 28815151 TI - Eye-tracking for clinical decision support: A method to capture automatically what physicians are viewing in the EMR. AB - Eye-tracking is a valuable research tool that is used in laboratory and limited field environments. We take steps toward developing methods that enable widespread adoption of eye-tracking and its real-time application in clinical decision support. Eye-tracking will enhance awareness and enable intelligent views, more precise alerts, and other forms of decision support in the Electronic Medical Record (EMR). We evaluated a low-cost eye-tracking device and found the device's accuracy to be non-inferior to a more expensive device. We also developed and evaluated an automatic method for mapping eye-tracking data to interface elements in the EMR (e.g., a displayed laboratory test value). Mapping was 88% accurate across the six participants in our experiment. Finally, we piloted the use of the low-cost device and the automatic mapping method to label training data for a Learning EMR (LEMR) which is a system that highlights the EMR elements a physician is predicted to use. PMID- 28815152 TI - Populating Physician Biographical Pages Based on EMR Data. AB - The physicians' biographical pages are essential in providing information about physicians' specialties. However, physicians may not have biographical pages or the current pages are not comprehensive. We hypothesize that physicians' specialty information can be mined from Electronic Medical Records (EMRs) of their patients. We proposed an automated physician specialty populating (PSP) system that analyzes physician-ascertained diagnoses in EMRs, aggregates them to an appropriate granularity based on the current biographical pages, and populates the biographical pages accordingly. In this study, we applied the system using EMR data from Mayo Clinic and evaluated the system using the current biographical pages regarding various ranking strategies. Preliminary results demonstrated that using EMR data is a scalable and systematic way to populate physicians' biographical pages. PMID- 28815153 TI - High-Risk Drug-Drug Interactions Between Clinical Practice Guidelines for Management of Chronic Conditions. AB - Clinicians and clinical decision-support systems often follow pharmacotherapy recommendations for patients based on clinical practice guidelines (CPGs). In multimorbid patients, these recommendations can potentially have clinically significant drug-drug interactions (DDIs). In this study, we describe and validate a method for programmatically detecting DDIs among CPG recommendations. The system extracts pharmacotherapy intervention recommendations from narrative CPGs, normalizes the terms, creates a mapping of drugs and drug classes, and then identifies occurrences of DDIs between CPG pairs. We used this system to analyze 75 CPGs written by authoring entities in the United States that discuss outpatient management of common chronic diseases. Using a reference list of high risk DDIs, we identified 2198 of these DDIs in 638 CPG pairs (46 unique CPGs). Only 9 high-risk DDIs were discussed by both CPGs in a pairing. In 69 of the pairings, neither CPG had a pharmacologic reference or a warning of the possibility of a DDI. PMID- 28815155 TI - Segmentation of phase contrast microscopy images based on multi-scale local Basic Image Features histograms. AB - Phase contrast microscopy (PCM) is routinely used for the inspection of adherent cell cultures in all fields of biology and biomedicine. Key decisions for experimental protocols are often taken by an operator based on typically qualitative observations. However, automated processing and analysis of PCM images remain challenging due to the low contrast between foreground objects (cells) and background as well as various imaging artefacts. We propose a trainable pixel-wise segmentation approach whereby image structures and symmetries are encoded in the form of multi-scale Basic Image Features local histograms, and classification of them is learned by random decision trees. This approach was validated for segmentation of cell versus background, and discrimination between two different cell types. Performance close to that of state-of-the-art specialised algorithms was achieved despite the general nature of the method. The low processing time ( < 4 s per 1280 * 960 pixel images) is suitable for batch processing of experimental data as well as for interactive segmentation applications. PMID- 28815156 TI - Evolving the Metrics of Success in Spine Care: Focus on Opioids. PMID- 28815154 TI - Spin Trapping: A Review for the Study of Obesity Related Oxidative Stress and Na+/K+-ATPase. AB - Reactive oxygen species (ROS) have gained attention with mounting evidence of their importance in cell signaling and various disease states. ROS is produced continuously as a natural by-product of normal oxygen metabolism. However, high levels ROS causes oxidative stress and damage to biomolecules. This results in loss of protein function, DNA cleavage, lipid peroxidation, or ultimately cell injury or death. Obesity has become a worldwide epidemic; studies show fat accumulation is associated with increased ROS and oxidative stress. Evidence exists supporting oxidative stress as a factor driving forward insulin resistance (IR), potentially resulting in diabetes. Na+/K+-ATPase signaling is also a potential source of ROS promoting oxidative stress. The best way to observe radical species in biological systems is electron paramagnetic resonance spectroscopy with spin trapping. EPR spin trapping is an important technique to study the mechanisms driving disease states attributed to ROS. PMID- 28815157 TI - A Levering Technique Using Small Parallel Rods for Open Reduction of High-Grade Thoracolumbar Dislocation. AB - STUDY DESIGN: Technical report. OBJECTIVE: Dorsolumbar vertebral dislocations, with or without associated fractures, occur secondary to very high velocity trauma. The reduction procedures and techniques, which may be adopted in these situations, have been multifariously discussed in the literature. Our objective was to assess the outcome of a novel reduction maneuver, using parallel rods which we have employed in reduction of high-grade thoracolumbar fractures to achieve precise sagittal balance as well as accurate vertebral alignment with minimal soft tissue damage. METHODS: The study included a total of 11 cases of thoracolumbar dislocations, who had presented to our emergency spine services following high-velocity trauma. After appropriate systemic stabilization and necessary investigations, all patients were surgically treated using the described technique. RESULTS: There were no surgical complications at 2-year follow-up. Radiographs showed good reduction and maintained sagittal balance. CONCLUSION: We believe that this technique is an excellent means of achieving safer, easier, and accurate reduction for restoration of sagittal/coronal balance and alignment in high-grade thoracolumbar dislocations. It is easily reproducible and predictable. PMID- 28815158 TI - Does the Spine Surgeon's Experience Affect Fracture Classification, Assessment of Stability, and Treatment Plan in Thoracolumbar Injuries? AB - STUDY DESIGN: Prospective survey-based study. OBJECTIVES: The AO Spine thoracolumbar injury classification has been shown to have good reproducibility among clinicians. However, the influence of spine surgeons' clinical experience on fracture classification, stability assessment, and decision on management based on this classification has not been studied. Furthermore, the usefulness of varying imaging modalities including radiographs, computed tomography (CT) and magnetic resonance imaging (MRI) in the decision process was also studied. METHODS: Forty-one spine surgeons from different regions, acquainted with the AOSpine classification system, were provided with 30 thoracolumbar fractures in a 3-step assessment: first radiographs, followed by CT and MRI. Surgeons classified the fracture, evaluated stability, chose management, and identified reasons for any changes. The surgeons were divided into 2 groups based on years of clinical experience as <10 years (n = 12) and >10 years (n = 29). RESULTS: There were no significant differences between the 2 groups in correctly classifying A1, B2, and C type fractures. Surgeons with less experience had more correct diagnosis in classifying A3 (47.2% vs 38.5% in step 1, 73.6% vs 60.3% in step 2 and 77.8% vs 65.5% in step 3), A4 (16.7% vs 24.1% in step 1, 72.9% vs 57.8% in step 2 and 70.8% vs 56.0% in step3) and B1 injuries (31.9% vs 20.7% in step 1, 41.7% vs 36.8% in step 2 and 38.9% vs 33.9% in step 3). In the assessment of fracture stability and decision on treatment, the less and more experienced surgeons performed equally. The selection of a particular treatment plan varied in all subtypes except in A1 and C type injuries. CONCLUSION: Surgeons' experience did not significantly affect overall fracture classification, evaluating stability and planning the treatment. Surgeons with less experience had a higher percentage of correct classification in A3 and A4 injuries. Despite variations between them in classification, the assessment of overall stability and management decisions were similar between the 2 groups. PMID- 28815159 TI - Short Posterior Stabilization in Combination With Cement Augmentation for the Treatment of Thoracolumbar Fractures and the Effects of Implant Removal. AB - STUDY DESIGN: Retrospective case series. OBJECTIVE: Short posterior stabilization with vertebroplasty is one treatment option for thoracolumbar burst fractures (AO A3). Whether it avoids progression in segmental kyphosis, especially after implant removal, is unclear. In a retrospective case-control study, its stability and the effect on intervertebral discs with and without implant removal was studied. METHODS: Fifty-nine consecutive patients were treated with bisegmental short posterior instrumentation and additional vertebroplasty of the fractured vertebra. Twenty-nine patients (male/female 17/12; age: 41.7 +/- 15.4 years) underwent implant removal. Changes of segmental kyphosis and disc heights between both groups (with and without implant removal) were compared on lateral X-rays preoperative, postoperative, after 1 year and after implant removal. Risk factors for loss of reduction were analyzed. RESULTS: Kyphosis increased up to 12 months after implant removal. The loss of bisegmental correction was 6.0 +/- 4.2 (range 0 degrees to 16 degrees ) 12 months after implant removal. Risk factors for loss of reduction are younger patient age, fractures of the thoracolumbar junction (Th12), and degree of traumatic kyphosis. Intervertebral discs traversed by the stabilization lose height and don't recover within 1 year after implant removal. Without implant removal, disc height of the lower adjacent level is reduced after 24 months. CONCLUSIONS: Short posterior stabilization in combination with vertebroplasty is a treatment alternative for thoracic and lumbar AO A3 fractures. After implant removal kyphosis increases, predominantly in the segment above the augmented vertebra. Risk factors for loss of reduction include younger age, fractures of the thoracolumbar junction (T12), and higher fracture kyphosis. PMID- 28815160 TI - The Burden of Spine Fractures in India: A Prospective Multicenter Study. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVES: The objectives of this study were (1) to determine the characteristics of patients sustaining spinal trauma in India and (2) to explore the association between patient or injury characteristics and outcomes after spinal trauma. METHODS: In affiliation with the ongoing INternational ORthopaedic MUlticentre Study (INORMUS), 192 patients with spinal injuries were recruited during an 8-week period (November 2011 to June 2012) from 14 hospitals in India and followed for 30-days. The primary outcome was a composite of mortality, complications, and reoperation. This was regressed on a set of 13 predictors in a multiple logistic regression model. RESULTS: Most patients were middle-aged (mean age = 51.0 years; median age = 55.5 years; range = 18.0 to 72.0 years), male (60.4%), injured from falls (72.4%), and treated in a private setting (59.9%). Fractures in the lumbar region (51.0%) were most common, followed by thoracic (30.7%) and cervical (18.2%). More than 1 in 5 (21.6%) patients experienced a treatment delay greater than 24 hours, and 36.5% arrived by ambulance. Thirty-day mortality and complication rates were 2.6% and 10.0%, respectively. Care in the public hospital system (odds ratio [OR] = 6.7, 95% CI = 1.1-41.6), chest injury (OR = 11.1, 95% CI = 1.8-66.9), and surgical intervention (OR = 4.8, 95% CI = 1.2-19.6) were independent predictors of major complications. CONCLUSIONS: Treatment in the public health care system, increased severity of injury, and surgical intervention were associated with increased risk of major complications following spinal trauma. The need for a large-scale, prospective, multicenter study taking into account spinal stability and neurologic status is feasible and warranted. PMID- 28815161 TI - Trends and Cost of Posterior Cervical Fusions With and Without Recombinant Human Bone Morphogenetic Protein-2 in the US Medicare Population. AB - STUDY DESIGN: Retrospective database review. OBJECTIVE: To analyze and report the trends and cost of posterior cervical fusions (PCFs) with and without off-label recombinant human bone morphogenetic protein-2 (rhBMP-2) in the Medicare population. METHODS: Patient records from the PearlDiver database were retrospectively reviewed from January 1, 2005, to December 31, 2012, to distinguish individuals who underwent a PCF with or without rhBMP-2. Total numbers, incidence, age, gender, geographic region, reimbursement, and length of stay were analyzed and summarized. RESULTS: The combined total of non-rhBMP-2 (n = 39 479; 85.51%) and rhBMP-2 PCF (n = 6692; 14.49%) procedures performed between 2005 and 2012 was 46 171. In general, the number of PCFs without rhBMP-2 consistently increased over time, while the number of PCFs with rhBMP-2 had only a slight increase from 2005 to 2012. On average, PCFs without rhBMP-2 were associated with $1197 higher cost than those with rhBMP-2, but the average length of stay was similar (6 days). From 2005 to 2012, the average cost for procedures with and without rhBMP-2 increased by $12 605 and $7291, respectively. The percentage of rhBMP-2 use peaked in 2007 and dwindled until 2010, and declined an additional 2.84% from 2011 to 2012. Multiple age, region, and gender tendencies were observed. CONCLUSIONS: To our knowledge, this was the first study to use the PearlDiver database to report incidence and cost trends of PCF procedures. This article provides meaningful trend data on PCFs to surgeons and clinicians, researchers, and patients, as well as functions as a beacon for future research questions. PMID- 28815162 TI - Clinical Application of Ceramics in Anterior Cervical Discectomy and Fusion: A Review and Update. AB - STUDY DESIGN: Narrative review. OBJECTIVES: Anterior cervical discectomy and fusion (ACDF) is a reliable procedure, commonly used for cervical degenerative disc disease. For interbody fusions, autograft was the gold standard for decades; however, limited availability and donor site morbidities have led to a constant search for new materials. Clinically, it has been shown that calcium phosphate ceramics, including hydroxyapatite (HA) and tricalcium phosphate (TCP), are effective as osteoconductive materials and bone grafts. In this review, we present the current findings regarding the use of ceramics in ACDF. METHODS: A review of the relevant literature examining the clinical use of ceramics in anterior cervical discectomy and fusion procedures was conducted using PubMed, OVID and Cochrane. RESULT: HA, coralline HA, sandwiched HA, TCP, and biphasic calcium phosphate ceramics were used in combination with osteoinductive materials such as bone marrow aspirate and various cages composed of poly-ether-ether ketone (PEEK), fiber carbon, and titanium. Stand-alone ceramic spacers have been associated with fracture and cracks. Metallic cages such as titanium endure the risk of subsidence and migration. PEEK cages in combination with ceramics were shown to be a suitable substitute for autograft. CONCLUSION: None of the discussed options has demonstrated clear superiority over others, although direct comparisons are often difficult due to discrepancies in data collection and study methodologies. Future randomized clinical trials are warranted before definitive conclusions can be drawn. PMID- 28815163 TI - Does Operative or Nonoperative Treatment Achieve Better Results in A3 and A4 Spinal Fractures Without Neurological Deficit?: Systematic Literature Review With Meta-Analysis. AB - STUDY DESIGN: Systematic literature review with meta-analysis. OBJECTIVE: Thoracolumbar (TL) fractures can be treated conservatively or surgically. Especially, the treatment strategy for incomplete and complete TL burst fractures (A3 and A4, AOSpine classification) in neurologically intact patients remains controversial. The aim of this work was to collate the clinical evidence on the respective treatment modalities. METHODS: Searches were performed in PubMed and the Web of Science. Clinical and radiological outcome data were collected. For studies comparing operative with nonoperative treatment, the standardized mean differences (SMD) for disability and pain were calculated and methodological quality and risk of bias were assessed. RESULTS: From 1929 initial matches, 12 were eligible. Four of these compared surgical with conservative treatment. A comparative analysis of radiological results was not possible due to a lack of uniform reporting. Differences in clinical outcomes at follow-up were small, both between studies and between treatment groups. The SMD was 0.00 (95% CI -0.072, 0.72) for disability and -0.05 (95% CI -0.91, 0.81) for pain. Methodological quality was high in most studies and no evidence of publication bias was revealed. CONCLUSIONS: We did not find differences in disability or pain outcomes between operative and nonoperative treatment of A3 and A4 TL fractures in neurologically intact patients. Notwithstanding, the available scores have been developed and validated for degenerative diseases; thus, their suitability in trauma may be questionable. Specific and uniform outcome parameters need to be defined and enforced for the evaluation of TL trauma. PMID- 28815164 TI - A Meta-Analysis of Cervical Laminoplasty Techniques: Are Mini-Plates Superior? AB - STUDY DESIGN: Meta-analysis and systematic review of literature. OBJECTIVE: In the late 1990s, spinal surgeons experimented by using maxillofacial fixation plates as an alternative to sutures, anchors, and local spinous process autografts to provide a more rigid and lasting fixation for laminoplasty. This eventually led to the advent of laminoplasty mini-plates, which are currently used. The objective is to compare laminoplasty techniques with plate and without plate with regard to functional outcome results. METHODS: Qualitative and quantitative analyses were performed to evaluate the currently available studies in an attempt to justify the use of a plate in laminoplasty. RESULTS: The principal finding of this study was that there was no statistically significant difference in clinical outcome between the 2 different techniques of laminoplasty. CONCLUSION: There is not enough evidence in the literature to support one technique over the other, and hence, there is no evidence to support change in practice (using or not using the plate in laminoplasty). A randomized controlled trial will give a better comparison between the 2 groups. PMID- 28815165 TI - Editorial Perspective. PMID- 28815166 TI - Objective Functional Testing in Patients With Lumbar Degenerative Disc Disease. PMID- 28815167 TI - Response to "Objective Functional Testing in Patients With Lumbar Degenerative Disc Disease". PMID- 28815168 TI - Retro-ureteral Small Bowel Herniation After Radical Cystectomy. AB - Small bowel obstruction caused by internal herniation under ureteric bands is a rare occurrence. Only 6 previous cases have been documented. This case report reviews the case of a 79-year-old male who presented to emergency with abdominal pain requiring subsequent laparotomy and release of internal herniation of bowel under ureter. PMID- 28815169 TI - Technical efficiency of rural primary health care system for diabetes treatment in Iran: a stochastic frontier analysis. AB - BACKGROUND: Our aim was to explore the technical efficiency (TE) of the Iranian rural primary healthcare (PHC) system for diabetes treatment coverage rate using the stochastic frontier analysis (SFA) as well as to examine the strength and significance of the effect of human resources density on diabetes treatment. METHODS: In the SFA model diabetes treatment coverage rate, as a output, is a function of health system inputs (Behvarz worker density, physician density, and rural health center density) and non-health system inputs (urbanization rate, median age of population, and wealth index) as a set of covariates. Data about the rate of self-reported diabetes treatment coverage was obtained from the Non Communicable Disease Surveillance Survey, data about health system inputs were collected from the health census database and data about non-health system inputs were collected from the census data and household survey. RESULTS: In 2008, rate of diabetes treatment coverage was 67% (95% CI: 63%-71%) nationally, and at the provincial level it varied from 44% to 81%. The TE score at the national level was 87.84%, with considerable variation across provinces (from 59.65% to 98.28%).Among health system and non-health system inputs, only the Behvarz density (per 1000 population)was significantly associated with diabetes treatment coverage (beta (95%CI): 0.50 (0.29-0.70),p < 0.001). CONCLUSION: Our findings show that although the rural PHC system can considered efficient in diabetes treatment at the national level, a wide variation exists in TE at the provincial level. Because the only variable that is predictor of TE is the Behvarz density, the PHC system may extend the diabetes treatment coverage by using this group of health care workers. PMID- 28815170 TI - The Geography of Primary Hepatic Neoplasms Treatments in Canada: Changes in Latitudes and Changes in Attitudes. AB - BACKGROUND: Studies on treatment modalities for primary hepatic neoplasms (PHN) in Canada are lacking. Our primary aim was to analyze the age-standardized incidence of hepatic resection, ablation, transplantation, and embolization for PHN between 2002 and 2013. Secondary aim was to evaluate temporal trends for these treatment modalities. STUDY DESIGN: National Canadian Cancer Registries were accessed for relevant epidemiological data. Age-standardized incidence of treatment ratios (SIRs) was calculated and comparisons were performed for Atlantic Canada, Ontario, the Prairies, and British Columbia. RESULTS: British Columbia recorded the highest SIRs for ablation (1.9; 95% CI 1.8-2.0), hepatic resection (1.2; 95% CI 1.1-1.3), and transarterial locoregional therapies (2.8; 95% CI 2.4-3.2). For hepatic resection, the lowest SIR was found in Atlantic Canada (0.7; 95% CI 0.6-0.9), while the Prairies recorded the lowest estimate for transarterial therapies (0.2; 95% CI 0.1-0.4). Liver transplantation had the highest SIR in Ontario (1.5; 95% CI 1.3-1.6) and the lowest SIR in British Columbia. No significant temporal changes in SIRs were observed for any of the treatments except for transarterial therapies. CONCLUSIONS: Treatment of PHN in Canada differs by geography. Variations might be due to differences in expertise or access to therapeutic modalities. PMID- 28815171 TI - Functional analysis of Na+/H+ exchanger 9 variants identified in patients with autism and epilepsy. AB - Na+/H+ exchanger isoform 9, NHE9, finely tunes the pH within the endosomal lumen to regulate cargo trafficking and turnover. In patients with autism, genetic approaches have revealed deletions, truncations and missense mutations in the gene encoding NHE9 (SLC9A9). To help establish causality, functional evaluation is needed to distinguish pathogenic mutations from harmless polymorphisms. Here, we evaluated three previously uncharacterized NHE9 variants, P117T, D496N, and Q609K reported in patients with autism and epilepsy. We show that NHE9-DsRed localizes to recycling endosomes in HEK293 cells where it significantly alkalinizes luminal pH, and elevates accumulation of transferrin. All three NHE9 variants were expressed and localized to endosomal compartments, similar to wild type NHE9. In contrast to previously characterized NHE9 variants, we observed no loss-of-function with respect to endosomal pH homeostasis and transferrin endocytosis. These findings suggest that the three NHE9 substitutions analyzed in our study are either benign polymorphisms or may have a cell-type specific or regulatory function not detected in our cell culture model. Our findings highlight the importance of combining the use of cellular studies of function with sequencing technologies that capture genomic variation in patients. PMID- 28815172 TI - Blues clues. PMID- 28815173 TI - Mouse models and induced pluripotent stem cells in researching psychiatric disorders. AB - Psychiatric disorders are a problem for society both on a micro level involving patients and their families as well as on a macro level involving global economic costs. For years, scientists have relied on mouse models for research, but these have shortcomings that greatly hinder efforts to understand the pathophysiology and genetic factors of psychiatric disorders. Induced pluripotent stem cells (iPSCs) have shown potential to overcome obstacles that mouse models face and can provide patient-specific cells that allow for better understanding of genetic effects on psychiatric disorders. This review explores the current progress using iPSCs to model psychiatric disorders, specifically bipolar disorder and schizophrenia, while discussing remaining issues with iPSC use and how these issues can be resolved in the future. PMID- 28815174 TI - HIT the nail on the head. PMID- 28815175 TI - Platelet-rich plasma-an 'Elixir' for treatment of alopecia: personal experience on 117 patients with review of literature. AB - Platelet-rich plasma (PRP) has emerged as a new treatment modality in regenerative plastic surgery and dermatology. PRP is a simple, cost-effective and feasible treatment option with high patient satisfaction for hair loss and can be regarded as a valuable adjuvant treatment modality for androgenic alopecia and other types of non-scarring alopecias. Authors have proposed a hair model termed "Golden anchorage with 'molecular locking' of ectodermal and mesenchymal components for survival and integrity of hair follicle (HF)" in this article. Golden anchorage comprises of bulge stem cells, ectodermal basement membrane and bulge portion of APM. PRP with its autologous supply of millions of growth factors works on 'Golden anchorage' along with keratinocytes (PDGF), dermal papilla (IGF and fibroblast growth factor), vasculature (VEGF and PDGF) and neural cells (Nerve Growth Factor) in a multipronged manner serving as an 'elixir' for hair growth and improving overall environment. PMID- 28815177 TI - TLR4 in glioblastoma-when cancer stem cells ignore "danger signals". PMID- 28815176 TI - Strategies for retinal cell generation from human pluripotent stem cells. AB - Induced pluripotent stem cells (iPSCs) are specialized self-renewing cells that are generated by exogenously expressing pluripotency-associated transcription factors in somatic cells such as fibroblasts, peripheral blood mononuclear cells, or lymphoblastoid cell lines (LCLs). iPSCs are functionally similar to naturally pluripotent embryonic stem cells (ESCs) in their capacity to propagate indefinitely and potential to differentiate into all human cell types, and are devoid of the associated ethical complications of origin. iPSCs are useful for studying embryonic development, disease modeling, and drug screening. Additionally, iPSCs provide a personalized approach for pathological studies, particularly for diseases that lack appropriate animal models. Retinal cell differentiations using iPSCs have been successful in this regard. Several protocols to generate various retinal cells have been developed to maximize a specific cell type or, most recently, to mimic in vivo retinal structure and cellular environment. As differentiation protocols continue to improve we are likely to see an increase in our basic understanding of various retinal degenerative diseases and the utilization of iPSCs in clinical trials. PMID- 28815179 TI - Interleukin-17 Can Induce Osteoarthritis in Rabbit Knee Joints Similar to Hulth's Method. AB - Interleukin-17 (IL-17) is closely related to osteoarthritis (OA), but animal studies that employ IL-17 to induce OA are currently lacking. Therefore, this study evaluated the effect of IL-17 in the rabbit knee joint. The right knees served as the control group. The left knees were divided randomly into 4 groups: a Hulth group and 3 IL-17 groups (1-ng, 10-ng, and 50-ng groups). OA was induced in the Hulth group using Hulth's method. The IL-17 groups were injected with 1, 10, or 50 ng of IL-17 as indicated. Specimens were collected at 72 h, 1 week, 3 weeks, 6 weeks, and 12 weeks after surgery or the last injection. Subsequently, the following experiments were conducted: X-ray analysis, histological evaluation, and polymerase chain reaction (PCR) analysis of the mRNA expression levels of cartilage degeneration-related markers. At 12 weeks, like the Hulth group, the 10-ng and 50-ng IL-17 groups displayed typical manifestations of OA. The X-ray results, histological scores, and mRNA expression levels showed statistically significant differences between the control group and the 10-ng and 50-ng IL-17 groups. In sum, injecting 10 ng of IL-17 into the rabbit knee joint can induce OA similar to OA induced by Hulth's method. PMID- 28815178 TI - Stem cell manipulation, gene therapy and the risk of cancer stem cell emergence. AB - Stem cells (SCs) have been extensively studied in the context of regenerative medicine. Human hematopoietic stem cell (HSC)-based therapies have been applied to treat leukemic patients for decades. Handling of mesenchymal stem cells (MSCs) has also raised hopes and concerns in the field of tissue engineering. Lately, discovery of cell reprogramming by Yamanaka's team has profoundly modified research strategies and approaches in this domain. As we gain further insight into cell fate mechanisms and identification of key actors and parameters, this also raises issues as to the manipulation of SCs. These include the engraftment of manipulated cells and the potential predisposition of those cells to develop cancer. As a unique and pioneer model, the use of HSCs to provide new perspectives in the field of regenerative and curative medicine will be reviewed. We will also discuss the potential use of various SCs from embryonic to adult stem cells (ASCs), including induced pluripotent stem cells (iPSCs) as well as MSCs. Furthermore, to sensitize clinicians and researchers to unresolved issues in these new therapeutic approaches, we will highlight the risks associated with the manipulation of human SCs from embryonic or adult origins for each strategy presented. PMID- 28815180 TI - Assessing Cognitive Estimation and Its Effects on Community Integration in People with Acquired Brain Injury Undergoing Rehabilitation. AB - The purpose of the present study was to examine the convergent and divergent validity of the Biber Cognitive Estimation Test (BCET) in individuals with ABI undergoing postacute rehabilitation and to assess the measure's ability to account for unique variance in community integration following rehabilitation. Participants with ABI referred for postacute rehabilitation (N = 201) were assessed on the BCET and a number of other neuropsychological tests that have been demonstrated to rely on aspects of executive processing (Trail-Making Test, Modified Six Elements Test, and verbal fluency measures) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Internal consistency of the total BCET was good; however, interpretable solutions for existing subscales were not discerned. The BCET total score demonstrated positive associations with tests of executive functioning; however, it was also significantly associated with more general aspects of neuropsychological functioning suggesting that it does not solely assess executive processes in ABI patients undergoing rehabilitation. Hierarchical multiple regression suggested that the BCET accounted for significant additional variance in community integration after severity of disability, executive functioning, and more general aspects of neuropsychological status were statistically controlled. While the subscale structure of the BCET may be somewhat inconsistent, the total scale score accounts for some unique variance in pragmatic rehabilitation outcome and may be a useful tool in postacute rehabilitation assessment protocols. PMID- 28815181 TI - Characterization of Exopolysaccharide Produced by Streptococcus thermophilus CC30. AB - An exopolysaccharide (EPS) producing strain CC30 was isolated from raw milk and identified as Streptococcus thermophilus with morphological and 16S sequencing analysis. The strain was shown to produce 1.95 g/L of EPS when grown in skim milk lactose medium at 30 degrees C by increasing the viscosity of the medium. The EPS was isolated and purified, and it was shown to consist of glucose and galactose in 1 : 1 ratio, with molecular weights ranging from 58 to 180 kDa. FTIR spectroscopy indicated the EPS to have amide, hydroxyl, and carboxyl groups. Under Atomic Force Microscopy, EPS showed spike-like lumps of EPS. Scanning Electron Microscopy (SEM) studies showed that it had irregular lumps with a coarse surface. The EPS displayed pseudoplastic nature. Thermogravimetric analysis (TGA) reported a degradation temperature of 110.84 degrees C. The purified EPS exhibited reducing activity, hydrogen peroxide radical scavenging activity, and emulsification activity. The results of the present study indicated that EPS producing Streptococcus thermophilus could serve as a promising candidate for further exploitation in food industry. PMID- 28815182 TI - Neutrophil-to-Lymphocyte Ratio Is a Potential Prognostic Biomarker in Patients with Ovarian Cancer: A Meta-Analysis. AB - BACKGROUND AND AIMS: Plenty of studies were conducted to explore the prognostic significance of neutrophil-to-lymphocyte ratio (NLR) in ovarian cancer with contradictory results. This study aims to summarize the prognostic significance of NLR in patients with ovarian cancer. METHODS: A literature search in PubMed, Cochrane Library, and Embase was conducted. The endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: Eleven studies involving a total of 2,892 patients were identified. The results indicated that patients with high NLR had shorter PFS compared to patients with low NLR in ovarian cancer (HR = 1.55, 95% CI = 1.15-2.08, p = 0.004, and I2 = 61%). Similarly, high NLR was related to shorter OS (HR = 1.51, 95% CI = 1.03-2.23, p = 0.04, and I2 = 85%). Moreover, high NLR was significantly associated with shorter PFS when the NLR cut off was less than 3.3 (p = 0.03) or when treatment is operation (p = 0.002). In addition, high NLR was distinctly related to worse OS in Asian people (p = 0.04) or operation (p = 0.04). CONCLUSION: High NLR was associated with shorter PFS and shorter OS in ovarian cancer. NLR is potentially a promising prognostic biomarker in patients with ovarian cancer. PMID- 28815183 TI - PinX1 Is a Potential Prognostic Factor for Non-Small-Cell Lung Cancer and Inhibits Cell Proliferation and Migration. AB - PinX1 has been identified as a suppressor of telomerase enzymatic activity. However, the tumour-suppressive roles of PinX1 in different types of human cancers are unclear. PinX1 expression status and its correlation with clinicopathological features in non-small-cell lung cancer (NSCLC) have not been investigated. Accordingly, in this study, we aimed to evaluate the roles of PinX1 in NSCLC. PinX1 expression status was examined by immunohistochemistry using tissue microarray from a total of 158 patients. Correlations among PinX1 expression, clinicopathological variables, and patient survival were analysed. Furthermore, we overexpressed PinX1 in NSCLC cells and tested telomerase activity using real-time quantitative telomeric repeat amplification protocol (qTRAP) assays. Proliferation and migration of NSCLC cells were examined using the MTS method, wound healing assays, and transwell assays, respectively. Our results showed that negative PinX1 expression was associated with a poor prognosis in NSCLC. Sex, smoking status, lymph gland status, subcarinal lymph node status, pathological stage, and PinX1 expression were related to survival. PinX1 was not an independent prognostic factor in NSCLC. PinX1 overexpression inhibited proliferation and migration in NSCLC cells by suppressing telomerase activity. Our findings suggested that PinX1 could be a potential tumour suppressor in NSCLC and that loss of PinX1 promoted NSCLC progression. PMID- 28815184 TI - Evaluation of Risk Factors for Vertebral Compression Fracture after Carbon-Ion Radiotherapy for Primary Spinal and Paraspinal Sarcoma. AB - BACKGROUND AND PURPOSE: Carbon-ion radiotherapy (C-ion RT) was effective therapy for inoperable spinal and paraspinal sarcomas. However, a significant adverse event following radiotherapies is vertebral compression fractures (VCFs). In this study, we investigated the incidence of and risk factors for post-C-ion RT VCFs in patients with spinal or paraspinal sarcomas. MATERIAL AND METHODS: Thirty consecutive patients with spinal or paraspinal sarcomas treated with C-ion RT were retrospectively reviewed. Various clinical parameters and the Spinal Instability Neoplastic Score (SINS) were used to evaluate the risk factors for post-C-ion RT VCFs. RESULTS: The overall incidence of VCFs was 23% (median time: 7 months). Patients with VCFs showed a markedly higher SINS score (median value, 9 points) than those without VCF (5 points). The area under the receiver operating characteristic curve for the SINS score was 0.88, and the optimum SINS cut-off score was 8 points. The cumulative incidence of VCFs at 1 year was 9% for patients with a SINS score under 8 points, versus 80% for those with a SINS score of 8 points or higher (p < 0.0001). CONCLUSIONS: In patients with a SINS score of 8 points or higher, referral to a spine surgeon for stabilization and multidisciplinary discussion is appropriate. PMID- 28815185 TI - Saliva-Derived Host Defense Peptides Histatin1 and LL-37 Increase Secretion of Antimicrobial Skin and Oral Mucosa Chemokine CCL20 in an IL-1alpha-Independent Manner. AB - Even though skin and oral mucosae are continuously in contact with commensal and opportunistic microorganisms, they generally remain healthy and uninflamed. Host defense peptides (HDPs) make up the body's first line of defense against many invading pathogens and are involved in the orchestration of innate immunity and the inflammatory response. In this study, we investigated the effect of two salivary HDPs, LL-37 and Hst1, on the inflammatory and antimicrobial response by skin and oral mucosa (gingiva) keratinocytes and fibroblasts. The potent antimicrobial chemokine CCL20 was investigated and compared with chemokines CCL2, CXCL1, CXCL8, and CCL27 and proinflammatory cytokines IL-1alpha and IL-6. Keratinocyte-fibroblast cocultures showed a synergistic increase in CCL20 secretion upon Hst1 and LL-37 exposure compared to monocultures. These cocultures also showed increased IL-6, CXCL1, CXCL8, and CCL2 secretion, which was IL-1alpha dependent. Secretion of the antimicrobial chemokine CCL20 was clearly IL-1alpha independent. These results indicate that salivary peptides can stimulate skin as well as gingiva cells to secrete antimicrobial chemokines as part of the hosts' defense to counteract infection. PMID- 28815186 TI - Children are not little adults: blood transfusion in children with burn injury. AB - Blood transfusion in burns larger than 20% total body surface area (TBSA) are frequent due to operative procedures, blood sampling, and physiologic response to burn injury. Optimizing the use of blood transfusions requires an understanding of the physiology of burn injury, the risks and benefits of blood transfusion, and the indications for transfusion. Age also plays a role in determining blood transfusion requirements. Children in particular have a different physiology than adults, which needs to be considered prior to transfusing blood and blood products. This article describes the physiologic differences between children and adults in general and after burn injury and describes how these differences impact blood transfusion practices in children. PMID- 28815187 TI - A Rare Presentation of Fibromuscular Dysplasia: Postpartum Vascular Catastrophe and Brief Literature Review. AB - Spontaneous coronary artery dissection is a very rare cause of acute coronary syndromes and can be life threatening given the rarity of the condition. It should be part of differentials in young females presenting with acute coronary syndromes without routine risk factors for coronary artery disease, especially before, during, and after pregnancy. It is closely associated with fibromuscular dysplasia and management can be very challenging at times. We present a case of spontaneous coronary artery dissection presenting with recurrent ST segment elevation myocardial infarction in association with fibromuscular dysplasia. PMID- 28815188 TI - Painless Aortic Dissection-Diagnostic Dilemma With Fatal Outcomes: What Do We Learn? AB - Aortic dissection is the most catastrophic clinical condition that involves the aorta. It has a high mortality as well as high rate of misdiagnosis due to frequent unusual presentation. Typically, it presents with acute chest, back, and tearing abdominal pain. However, it can present atypically with minimal or no pain, making diagnosis difficult. Physicians should always suspect acute aortic dissection in patients with certain clinical conditions like difficult-to-control hypertension, giant cell arteritis, bicuspid aortic valve, intracranial aneurysms, simple renal cysts, family history of aortic disease, and Marfan syndrome, especially when a patient presents with ischemic symptoms involving multiple organ without an obvious cause. PMID- 28815189 TI - A Case of Pulmonary Vein Thrombosis Associated With Treatment of Omalizumab. AB - Pulmonary vein thrombosis (PVT) is a challenging diagnosis and has been described in association with or as a complication of pulmonary tumors, lung surgeries, atrial myxoma, and after radiofrequency catheter ablation for atrial fibrillation. There are not many reported cases of PVT associated with medication use. We present a case of a 53-year-old male with a history of severe persistent asthma on omalizumab, who presented with shortness of breath and was found to have PVT on computed tomography scan of the chest. The hypercoagulable workup was normal, and the patient did not have a history of malignancy or pulmonary surgeries. Currently, available data suggest an association between omalizumab use and increased risk of arterial thrombotic events. However, on a literature search, we could not find any reported cases of PVT with omalizumab treatment. PMID- 28815190 TI - Giant Left Atrial Myxoma Masquerading as Cough-Syncope Syndrome. AB - Left atrial myxomas are the most common type of benign primary cardiac tumor. Patients can present with generalized symptoms, such as fatigue, symptoms from obstruction of the myxoma, or even embolization of the myxoma causing distal thrombosis. We describe a case with several-month duration of syncopal episodes that occurred after coughing and with exertion. Computed tomography of the chest showed a 6.1 cm by 4.5 cm mass in the left atrium, later evaluated with an echocardiogram. Cardiothoracic surgery removed the mass, and it was determined to be an atrial myxoma. It is important for an internist to be able to diagnose an atrial myxoma because of the risks associated with embolization and even sudden death as myxoma can block blood supply from atrium to ventricle. PMID- 28815191 TI - A randomized, fellow eye, comparison of keratometry, aberrometry, tear film, axial length and the anterior chamber depth after eye rubbing in non-keratoconic eyes. AB - BACKGROUND: To investigate the effect of eye rubbing on keratometry (K), aberrometry, tear film break-up-time (TFBUT) and anterior chamber depth (ACD). METHODS: Volunteers without any corneal pathology or dry eyes were randomised to rubbing in one eye and the fellow-eye was control. Eye rubbing was performed for 2 min. Primary outcomes studied were anterior and posterior K changes. Secondary outcomes were changes in TFBUT, axial length (AL) & ACD, K changes in various zones, asphericity and aberrometry. Pre and post rubbing K, aberrometry, ACD and TFBUT were assessed in a predetermined sequence. The relationship of the above parameters to axial length (AL) was also assessed. Astigmatism was analysed using vector analysis. RESULTS: Pre versus post rubbing, anterior flatter K further flattened (42.51 +/- 1.52 D vs. 42.36 +/- 1.53 D, p = 0.003) and the changes to J0 vector in central cornea (-0.16 +/- 0.26 D vs. -0.27 +/- 0.33 D, p = 0.038) suggested change to against-the-rule (ATR) astigmatism. There was significant change in Z2+2 polynomial following rubbing. We found a positive correlation between axial length and change in posterior K (r = 0.335, p = 0.020). The TFBUT reduced following eye rubbing (15.3 s vs. 13.9 s, p = 0.0001). There was a positive correlation between AL and increase in ACD post rubbing (r = 0.300, p = 0.038). There was a positive correlation between ACD and change in mean posterior K (r = 0.305, p = 0.035). CONCLUSIONS: In healthy eyes, following eye rubbing, there is a significant change in TFBUT and central anterior K changes towards ATR astigmatism. Longer eyes had more changes in posterior K and ACD. Whereas, eyes with deeper ACD showed more steepness of posterior K. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02131740. PMID- 28815192 TI - Epileptic Negative Myoclonus as the First and Only Symptom in a Challenging Diagnosis of Benign Epilepsy With Centrotemporal Spikes. AB - OBJECTIVE: To investigate the clinical and neurophysiological characteristics of epileptic negative myoclonus as the first and only ictal symptom of benign epilepsy with centrotemporal spikes. METHODS: Electrophysiological evaluations included polygraphic recordings with simultaneous video electroencephalogram monitoring and tests performed with patient's upper limb outstretched in standing posture. Epileptic negative myoclonus manifestations, electrophysiological features, and responses to antiepileptic drugs were analyzed. RESULTS: The authors report 2 patients with benign epilepsy with centrotemporal spikes, who had epileptic negative myoclonus as the first and only seizure type. Video electroencephalogram monitoring results showed that their negative myoclonus seizures were emanating from the contralateral central and the parietal regions. Epileptic negative myoclonus was controlled by administration of valproate and levetiracetam. CONCLUSION: Epileptic negative myoclonus can be the first and only seizure type of benign epilepsy with centrotemporal spikes, and long-term follow up monitoring should be the care for the recurrence and/or presence of other types of seizures. PMID- 28815193 TI - Adoptive Transfer of Isolated Bone Marrow Neutrophils. AB - Adoptive transfer experiments of specific cell populations are widely used methods to assess the role of the injected population on an ongoing process. In the last years, new and unprecedented roles in the regulation of immune responses have been reported for neutrophils. The following protocol is to be used to isolate neutrophils from bone marrow and to inject them in an appropriate host to test the role of neutrophils during infection, inflammation or other pathological conditions. PMID- 28815194 TI - Focusing light inside dynamic scattering media with millisecond digital optical phase conjugation. AB - Wavefront shaping based on digital optical phase conjugation (DOPC) focuses light through or inside scattering media, but the low speed of DOPC prevents it from being applied to thick, living biological tissue. Although a fast DOPC approach was recently developed, the reported single-shot wavefront measurement method does not work when the goal is to focus light inside, instead of through, highly scattering media. Here, using a ferroelectric liquid crystal based spatial light modulator, we develop a simpler but faster DOPC system that focuses light not only through, but also inside scattering media. By controlling 2.6 * 105 optical degrees of freedom, our system focused light through 3 mm thick moving chicken tissue, with a system latency of 3.0 ms. Using ultrasound-guided DOPC, along with a binary wavefront measurement method, our system focused light inside a scattering medium comprising moving tissue with a latency of 6.0 ms, which is one to two orders of magnitude shorter than those of previous digital wavefront shaping systems. Since the demonstrated speed approaches tissue decorrelation rates, this work is an important step toward in vivo deep-tissue non-invasive optical imaging, manipulation, and therapy. PMID- 28815195 TI - Actigraphic sleep characteristics among older Americans. AB - OBJECTIVES: To date, there has been no evidence about objectively measured sleep characteristics from a representative national probability sample of adults in the United States. We used actigraphy to measure the sleep characteristics of older Americans. DESIGN: Cross-sectional study. SETTING: Sleep sub-study within Wave 2 (2010-2011) of the ongoing National Social Life, Health and Aging Project (NSHAP). PARTICIPANTS: Seven hundred and thirty-nine NSHAP participants aged 62 90. INTERVENTION: Not applicable. MEASUREMENTS: Study participants wore a wrist actigraph for 72 hours and sleep properties were compared across demographic, socioeconomic, and health-behavior related lines. RESULTS: Actigraph-estimated sleep time averaged 7.2 hours (SE 0.06 hr) each night; the majority of the sample (80%) slept between 5.8 and 8.6 hours/night. Average time spent awake after sleep onset (WASO) was 39 minutes (SE 1.2 min). Women had significantly more total sleep time and lower sleep fragmentation compared to men. Total sleep time increased significantly with age although sleep percentage decreased with age. Compared with White participants, African American participants had significantly more WASO (9.2 minutes, p < 0.01) and greater sleep fragmentation (2.3 percentage points, p < 0.001). WASO was significantly higher and sleep percentage significantly lower among those with less education. CONCLUSIONS: Both short sleepers and long sleepers - often conventionally defined as obtaining <6 and >9 hrs/night, respectively - are relatively rare among older Americans when sleep is estimated by actigraphy. Sleep quality is significantly poorer among men, African Americans, and those with less education. PMID- 28815197 TI - Autosomal Recessive Inheritance: Cystic Fibrosis. AB - The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040. PMID- 28815196 TI - Simultaneous Health Risk Behaviors in Adolescents Associated with Higher Economic Class in the Northeast of Brazil. AB - DESIGN: The social, cultural, and economic context can be an important variable in the perception and adoption of risk behaviors in adolescents. OBJECTIVE: The purpose of this study was to identify the prevalence of simultaneous health risk behaviors and associated socioeconomic factors in adolescents living in the metropolitan region of Aracaju, State of Sergipe, Brazil. METHODS: The sample consisted of 2,207 high school students aged 13-18 years. The risk behaviors measured were "low levels of physical activity," "excessive daily TV time," "high consumption of alcoholic beverages on a single occasion," "involvement in fights," "smoking cigarettes," "carrying firearms," and "marijuana consumption." Information was obtained through self-administered questionnaire. RESULTS: Considering the results, it was observed that female adolescents and those aged up to 16 years were less likely to have two or more health risk behaviors compared to males and those aged 17 years or more, respectively. It was also found that both high- and middle-income level adolescents had higher prevalence of having two or more health risk behaviors. CONCLUSIONS: It was concluded that male adolescents older than 16 years with better socioeconomic level were more exposed to the simultaneous presence of several health risk behaviors. PMID- 28815198 TI - Lead Poisoning. AB - The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040. PMID- 28815199 TI - Squamous Cell Carcinoma of the Lung. AB - The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040. PMID- 28815201 TI - Benign Papilloma of the Breast. AB - The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040. PMID- 28815202 TI - Genetic Mutations and Multifactorial Inheritance: Dilated Cardiomyopathy. AB - The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040. PMID- 28815203 TI - Transition to Subspecialty Sign-Out at an Academic Institution and Its Advantages. AB - Many pathology departments are introducing subspecialty sign-out in surgical pathology. In 2014, the University of Vermont Medical Center transitioned from general sign-out to partial subspecialty sign-out to include gastrointestinal and breast/cervix subspecialty benches; other specimens remained on general benches. Our experiences with the transition are described, including attending pathologist, trainee, support staff, and clinician satisfaction. A survey was e mailed to all University of Vermont Medical Center anatomic pathology attendings, pathology trainees, pathologist assistants and grossing technicians, and clinicians who send surgical pathology specimens, immediately before and 1 year after transitioning to partial subspecialty sign-out. Quality assurance metrics were obtained for the 18 months prior to and following the transition. Gastrointestinal and breast/cervix attendings were more satisfied with partial subspecialty sign-out compared to those on the general benches. Overall, trainees were more satisfied with general sign-out because of the rotation schedule but preferred partial subspecialty sign-out due to improved teaching and more focused learning while on subspecialty benches. Clinicians remained very satisfied with our department and our reports; no differences were observed. Turnaround time was unchanged. After switching to partial subspecialty sign-out, there were significantly fewer discrepancies following multidisciplinary conference review for gastrointestinal and breast/cervix cases but remained the same for general cases. Fewer formal internal consults were performed after transitioning to partial subspecialty sign-out across all areas, but more notable for gastrointestinal and breast/cervix cases. Our data show improved quality assurance metrics and trainee education in a subspecialty sign-out setting compared to general sign-out setting. PMID- 28815200 TI - The Case for Laboratory Developed Procedures: Quality and Positive Impact on Patient Care. AB - An explosion of knowledge and technology is revolutionizing medicine and patient care. Novel testing must be brought to the clinic with safety and accuracy, but also in a timely and cost-effective manner, so that patients can benefit and laboratories can offer testing consistent with current guidelines. Under the oversight provided by the Clinical Laboratory Improvement Amendments, laboratories have been able to develop and optimize laboratory procedures for use in-house. Quality improvement programs, interlaboratory comparisons, and the ability of laboratories to adjust assays as needed to improve results, utilize new sample types, or incorporate new mutations, information, or technologies are positive aspects of Clinical Laboratory Improvement Amendments oversight of laboratory-developed procedures. Laboratories have a long history of successful service to patients operating under Clinical Laboratory Improvement Amendments. A series of detailed clinical examples illustrating the quality and positive impact of laboratory-developed procedures on patient care is provided. These examples also demonstrate how Clinical Laboratory Improvement Amendments oversight ensures accurate, reliable, and reproducible testing in clinical laboratories. PMID- 28815204 TI - Pathology Competencies for Medical Education and Educational Cases. AB - Current medical school curricula predominantly facilitate early integration of basic science principles into clinical practice to strengthen diagnostic skills and the ability to make treatment decisions. In addition, they promote life-long learning and understanding of the principles of medical practice. The Pathology Competencies for Medical Education (PCME) were developed in response to a call to action by pathology course directors nationwide to teach medical students pathology principles necessary for the practice of medicine. The PCME are divided into three competencies: 1) Disease Mechanisms and Processes, 2) Organ System Pathology, and 3) Diagnostic Medicine and Therapeutic Pathology. Each of these competencies is broad and contains multiple learning goals with more specific learning objectives. The original competencies were designed to be a living document, meaning that they will be revised and updated periodically, and have undergone their first revision with this publication. The development of teaching cases, which have a classic case-based design, for the learning objectives is the next step in providing educational content that is peer-reviewed and readily accessible for pathology course directors, medical educators, and medical students. Application of the PCME and cases promotes a minimum standard of exposure of the undifferentiated medical student to pathophysiologic principles. The publication of the PCME and the educational cases will create a current educational resource and repository published through Academic Pathology. PMID- 28815205 TI - Subarachnoid Hemorrhage Related to Ruptured Berry Aneurysm. AB - The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040. PMID- 28815206 TI - Autosomal Recessive Polycystic Kidney Disease. AB - The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040. PMID- 28815207 TI - Novel AMPD2 mutation in pontocerebellar hypoplasia, dysmorphisms, and teeth abnormalities. PMID- 28815208 TI - Novel POLG variants associated with late-onset de novo status epilepticus and progressive ataxia. PMID- 28815209 TI - Pathways to Genome-targeted Therapies in Serous Ovarian Cancer. AB - Genome sequencing technologies and corresponding oncology publications have generated enormous publicly available datasets for many cancer types. While this has enabled new treatments, and in some limited cases lifetime management of the disease, the treatment options for serous ovarian cancer remain dismal. This review summarizes recent advances in our understanding of ovarian cancer, with a focus on heterogeneity, functional genomics, and actionable data. PMID- 28815210 TI - LpxK Is Essential for Growth of Acinetobacter baumannii ATCC 19606: Relationship to Toxic Accumulation of Lipid A Pathway Intermediates. AB - Acinetobacter baumannii ATCC 19606 can grow without lipid A, the major component of lipooligosaccharide. However, we previously reported that depletion of LpxH (the fourth enzyme in the lipid A biosynthetic pathway) prevented growth of this strain due to toxic accumulation of lipid A pathway intermediates. Here, we explored whether a similar phenomenon occurred with depletion of LpxK, a kinase that phosphorylates disaccharide 1-monophosphate (DSMP) at the 4' position to yield lipid IVA. An A. baumannii ATCC 19606 derivative with LpxK expression under the control of an isopropyl beta-d-1-thiogalactopyranoside (IPTG)-regulated expression system failed to grow without induction, indicating that LpxK is essential for growth. Light and electron microscopy of LpxK-depleted cells revealed morphological changes relating to the cell envelope, consistent with toxic accumulation of lipid A pathway intermediates disrupting cell membranes. Using liquid chromatography-mass spectrometry (LCMS), cellular accumulation of the detergent-like pathway intermediates DSMP and lipid X was shown. Toxic accumulation was further supported by restoration of growth upon chemical inhibition of LpxC (upstream of LpxK and the first committed step of lipid A biosynthesis) using CHIR-090. Inhibitors of fatty acid synthesis also abrogated the requirement for LpxK expression. Growth rescue with these inhibitors was possible on Mueller-Hinton agar but not on MacConkey agar. The latter contains outer membrane-impermeable bile salts, suggesting that despite growth restoration, the cell membrane permeability barrier was not restored. Therefore, LpxK is essential for growth of A. baumannii, since loss of LpxK causes accumulation of detergent-like pathway intermediates that inhibit cell growth. IMPORTANCEAcinetobacter baumannii is a Gram-negative pathogen for which new therapies are needed. The lipid A biosynthetic pathway has several potential enzyme targets for the development of anti-Gram-negative agents (e.g., LpxC). However, A. baumannii ATCC 19606 can grow in the absence of LpxC and, correspondingly, of lipid A. In contrast, we show that cellular depletion of LpxK, a kinase occurring later in the pathway, inhibits growth. Growth inhibition results from toxic accumulation of lipid A pathway intermediates, since chemical inhibition of LpxC or fatty acid biosynthesis rescues cell growth upon loss of LpxK. Overall, this suggests that targets such as LpxK can be essential for growth even in those Gram-negative bacteria that do not require lipid A biosynthesis per se. This strain provides an elegant tool to derive a better understanding of the steps in a pathway that is the focus of intense interest for the development of novel antibacterials. PMID- 28815211 TI - Phenotypic Differences between Asian and African Lineage Zika Viruses in Human Neural Progenitor Cells. AB - Recent Zika virus (ZIKV) infections have been associated with a range of neurological complications, in particular congenital microcephaly. Human neural progenitor cells (hNPCs) are thought to play an important role in the pathogenesis of microcephaly, and experimental ZIKV infection of hNPCs has been shown to induce cell death. However, the infection efficiency and rate of cell death have varied between studies, which might be related to intrinsic differences between African and Asian lineage ZIKV strains. Therefore, we determined the replication kinetics, including infection efficiency, burst size, and ability to induce cell death, of two Asian and two African ZIKV strains. African ZIKV strains replicated to higher titers in Vero cells, human glioblastoma (U87MG) cells, human neuroblastoma (SK-N-SH) cells, and hNPCs than Asian ZIKV strains. Furthermore, infection with Asian ZIKV strains did not result in significant cell death early after infection, whereas infection with African ZIKV strains resulted in high percentages of cell death in hNPCs. The differences between African and Asian lineage ZIKV strains highlight the importance of including relevant ZIKV strains to study the pathogenesis of congenital microcephaly and caution against extrapolation of experimental data obtained using historical African ZIKV strains to the current outbreak. Finally, the fact that Asian ZIKV strains infect only a minority of cells with a relatively low burst size together with the lack of early cell death induction might contribute to its ability to cause chronic infections within the central nervous system (CNS). IMPORTANCE The mechanism by which ZIKV causes a range of neurological complications, especially congenital microcephaly, is not well understood. The fact that congenital microcephaly is associated with Asian lineage ZIKV strains raises the question of why this was not discovered earlier. One possible explanation is that Asian and African ZIKV strains differ in their abilities to infect cells of the CNS and to cause neurodevelopmental problems. Here, we show that Asian ZIKV strains infect and induce cell death in human neural progenitor cells-which are important target cells in the development of congenital microcephaly-less efficiently than African ZIKV strains. These features of Asian ZIKV strains likely contribute to their ability to cause chronic infections, often observed in congenital microcephaly cases. It is therefore likely that phenotypic differences between ZIKV strains could be, at least in part, responsible for the ability of Asian ZIKV strains to cause congenital microcephaly. PMID- 28815212 TI - Variable Virulence of Biotype 3 Vibrio vulnificus due to MARTX Toxin Effector Domain Composition. AB - Vibrio vulnificus is an environmental organism that causes septic human infections characterized by high morbidity and mortality. The annual incidence and global distribution of this pathogen are increasing as ocean waters warm. Clinical strains exhibit variations in the primary virulence toxin, suggesting a potential for the emergence of new strains with altered virulence properties. A clonal outbreak of tilapia-associated wound infections in Israel serves as a natural experiment for the sudden emergence of a new V. vulnificus strain. The effector domain content of the multifunctional autoprocessing RTX (MARTX) toxin of the outbreak-associated biotype 3 (BT3) strains was previously shown to harbor a modification generated by recombination. The modification introduced an actin induced adenylate cyclase effector domain (ExoY) and an effector domain that disrupts the Golgi organelle (DmX). Here, we report that the exchange of these effector domains for a putative progenitor biotype 1 toxin arrangement produces a toxin that slows the lysis kinetics of targeted epithelial cells but increases cellular rounding phenotypes in response to bacteria. In addition, replacing the biotype 3 toxin variant with the putative progenitor biotype 1 variant renders the resulting strain significantly more virulent in mice. This suggests that the exchange of MARTX effector domains during the emergence of BT3 generated a toxin with reduced toxin potency, resulting in decreased virulence of this outbreak associated strain. We posit that selection for reduced virulence may serve as a route for this lethal infectious agent to enter the human food chain by allowing it to persist in natural hosts. IMPORTANCEVibrio vulnificus is a serious infection linked to climate change. The virulence capacity of these bacteria can vary by gene exchange, resulting in new variants of the primary virulence toxin. In this study, we tested whether the emergence of an epidemic strain of V. vulnificus with a novel toxin variant correlated with a change in virulence. We found that restoring the biotype 3 toxin variant to the putative progenitor-type toxin resulted in dramatically increased virulence, revealing that the emergence of the biotype 3 strain could be linked to virulence reduction. This reduced virulence, previously found also in the biotype 1 strain, suggests that reduced virulence may stimulate outbreaks, as strains have greater capacity to enter the human food chain through reduced impact to environmental hosts. PMID- 28815213 TI - Identification of Rab18 as an Essential Host Factor for BK Polyomavirus Infection Using a Whole-Genome RNA Interference Screen. AB - BK polyomavirus (BKPyV) is a human pathogen first isolated in 1971. BKPyV infection is ubiquitous in the human population, with over 80% of adults worldwide being seropositive for BKPyV. BKPyV infection is usually asymptomatic; however, BKPyV reactivation in immunosuppressed transplant patients causes two diseases, polyomavirus-associated nephropathy and hemorrhagic cystitis. To establish a successful infection in host cells, BKPyV must travel in retrograde transport vesicles to reach the nucleus. To make this happen, BKPyV requires the cooperation of host cell proteins. To further identify host factors associated with BKPyV entry and intracellular trafficking, we performed a whole-genome small interfering RNA screen on BKPyV infection of primary human renal proximal tubule epithelial cells. The results revealed the importance of Ras-related protein Rab18 and syntaxin 18 for BKPyV infection. Our subsequent experiments implicated additional factors that interact with this pathway and suggest a more detailed model of the intracellular trafficking process, indicating that BKPyV reaches the endoplasmic reticulum (ER) lumen through a retrograde transport pathway between the late endosome and the ER. IMPORTANCE Polyomaviruses bind to a group of specific gangliosides on the plasma membrane of the cell prior to being endocytosed. They then follow a retrograde trafficking pathway to reach the endoplasmic reticulum (ER). The viruses begin to disassemble in the ER and then exit the ER and move to the nucleus. However, the details of intracellular trafficking between the endosome and the ER are largely unknown. By implementing a whole human genome small interfering RNA screen, we identified Rab18, syntaxin 18, and the NRZ complex as key components in endosome-ER trafficking of the human polyomavirus BKPyV. These results serve to further elucidate the route BKPyV takes from outside the cell to its site of replication in the nucleus. PMID- 28815214 TI - Chlamydomonas reinhardtii LFO1 Is an IsdG Family Heme Oxygenase. AB - Heme is essential for respiration across all domains of life. However, heme accumulation can lead to toxicity if cells are unable to either degrade or export heme or its toxic by-products. Under aerobic conditions, heme degradation is performed by heme oxygenases, enzymes which utilize oxygen to cleave the tetrapyrrole ring of heme. The HO-1 family of heme oxygenases has been identified in both bacterial and eukaryotic cells, whereas the IsdG family has thus far been described only in bacteria. We identified a hypothetical protein in the eukaryotic green alga Chlamydomonas reinhardtii, which encodes a protein containing an antibiotic biosynthesis monooxygenase (ABM) domain consistent with those associated with IsdG family members. This protein, which we have named LFO1, degrades heme, contains similarities in predicted secondary structures to IsdG family members, and retains the functionally conserved catalytic residues found in all IsdG family heme oxygenases. These data establish LFO1 as an IsdG family member and extend our knowledge of the distribution of IsdG family members beyond bacteria. To gain further insight into the distribution of the IsdG family, we used the LFO1 sequence to identify 866 IsdG family members, including representatives from all domains of life. These results indicate that the distribution of IsdG family heme oxygenases is more expansive than previously appreciated, underscoring the broad relevance of this enzyme family. IMPORTANCE This work establishes a protein in the freshwater alga Chlamydomonas reinhardtii as an IsdG family heme oxygenase. This protein, LFO1, exhibits predicted secondary structure and catalytic residues conserved in IsdG family members, in addition to a chloroplast localization sequence. Additionally, the catabolite that results from the degradation of heme by LFO1 is distinct from that of other heme degradation products. Using LFO1 as a seed, we performed phylogenetic analysis, revealing that the IsdG family is conserved in all domains of life. Additionally, C. reinhardtii contains two previously identified HO-1 family heme oxygenases, making C. reinhardtii the first organism shown to contain two families of heme oxygenases. These data indicate that C. reinhardtii may have unique mechanisms for regulating iron homeostasis within the chloroplast. PMID- 28815215 TI - Structural Characterization of Acidic M17 Leucine Aminopeptidases from the TriTryps and Evaluation of Their Role in Nutrient Starvation in Trypanosoma brucei. AB - Leucine aminopeptidase (LAP) is found in all kingdoms of life and catalyzes the metal-dependent hydrolysis of the N-terminal amino acid residue of peptide or amino acyl substrates. LAPs have been shown to participate in the N-terminal processing of certain proteins in mammalian cells and in homologous recombination and transcription regulation in bacteria, while in parasites, they are involved in host cell invasion and provision of essential amino acids for growth. The enzyme is essential for survival in Plasmodium falciparum, where its drug target potential has been suggested. We report here the X-ray structures of three kinetoplastid acidic LAPs (LAP-As from Trypanosoma brucei, Trypanosoma cruzi, and Leishmania major) which were solved in the metal-free and unliganded forms, as well as in a number of ligand complexes, providing insight into ligand binding, metal ion requirements, and oligomeric state. In addition, we analyzed mutant cells defective in LAP-A in Trypanosoma brucei, strongly suggesting that the enzyme is not required for the growth of this parasite either in vitro or in vivo. In procyclic cells, LAP-A was equally distributed throughout the cytoplasm, yet upon starvation, it relocalizes in particles that concentrate in the perinuclear region. Overexpression of the enzyme conferred a growth advantage when parasites were grown in leucine-deficient medium. Overall, the results suggest that in T. brucei, LAP-A may participate in protein degradation associated with nutrient depletion. IMPORTANCE Leucine aminopeptidases (LAPs) catalyze the hydrolysis of the N-terminal amino acid of peptides and are considered potential drug targets. They are involved in multiple functions ranging from host cell invasion and provision of essential amino acids to site specific homologous recombination and transcription regulation. In kinetoplastid parasites, there are at least three distinct LAPs. The availability of the crystal structures provides important information for drug design. Here we report the structure of the acidic LAPs from three kinetoplastids in complex with different inhibitors and explore their role in Trypanosoma brucei survival under various nutrient conditions. Importantly, the acidic LAP is dispensable for growth both in vitro and in vivo, an observation that questions its use as a specific drug target. While LAP-A is not essential, leucine depletion and subcellular localization studies performed under starvation conditions suggest a possible function of LAP-A in the response to nutrient restriction. PMID- 28815217 TI - Deletion of Cytoplasmic Double-Stranded RNA Sensors Does Not Uncover Viral Small Interfering RNA Production in Human Cells. AB - Antiviral immunity in insects and plants is mediated by the RNA interference (RNAi) pathway in which viral long double-stranded RNA (dsRNA) is processed into small interfering RNAs (siRNAs) by Dicer enzymes. Although this pathway is evolutionarily conserved, its involvement in antiviral defense in mammals is the subject of debate. In vertebrates, recognition of viral RNA induces a sophisticated type I interferon (IFN)-based immune response, and it has been proposed that this response masks or inhibits antiviral RNAi. To test this hypothesis, we analyzed viral small RNA production in differentiated cells deficient in the cytoplasmic RNA sensors RIG-I and MDA5. We did not detect 22 nucleotide (nt) viral siRNAs upon infection with three different positive-sense RNA viruses. Our data suggest that the depletion of cytoplasmic RIG-I-like sensors is not sufficient to uncover viral siRNAs in differentiated cells. IMPORTANCE The contribution of the RNA interference (RNAi) pathway in antiviral immunity in vertebrates has been widely debated. It has been proposed that RNAi possesses antiviral activity in mammalian systems but that its antiviral effect is masked by the potent antiviral interferon response in differentiated mammalian cells. In this study, we show that inactivation of the interferon response is not sufficient to uncover antiviral activity of RNAi in human epithelial cells infected with three wild-type positive-sense RNA viruses. PMID- 28815216 TI - Epistatic Interactions within the Influenza A Virus Polymerase Complex Mediate Mutagen Resistance and Replication Fidelity. AB - Lethal mutagenesis is a broad-spectrum antiviral strategy that employs mutagenic nucleoside analogs to exploit the high mutation rate and low mutational tolerance of many RNA viruses. Studies of mutagen-resistant viruses have identified determinants of replicative fidelity and the importance of mutation rate to viral population dynamics. We have previously demonstrated the effective lethal mutagenesis of influenza A virus using three nucleoside analogs as well as the virus's high genetic barrier to mutagen resistance. Here, we investigate the mutagen-resistant phenotypes of mutations that were enriched in drug-treated populations. We find that PB1 T123A has higher replicative fitness than the wild type, PR8, and maintains its level of genome production during 5-fluorouracil (2,4-dihydroxy-5-fluoropyrimidine) treatment. Surprisingly, this mutagen resistant variant also has an increased baseline rate of C-to-U and G-to-A mutations. A second drug-selected mutation, PA T97I, interacts epistatically with PB1 T123A to mediate high-level mutagen resistance, predominantly by limiting the inhibitory effect of nucleosides on polymerase activity. Consistent with the importance of epistatic interactions in the influenza virus polymerase, our data suggest that nucleoside analog resistance and replication fidelity are strain dependent. Two previously identified ribavirin {1-[(2R,3R,4S,5R)-3,4-dihydroxy-5 (hydroxymethyl)oxolan-2-yl]-1H-1,2,4-triazole-3-carboxamide} resistance mutations, PB1 V43I and PB1 D27N, do not confer drug resistance in the PR8 background, and the PR8-PB1 V43I polymerase exhibits a normal baseline mutation rate. Our results highlight the genetic complexity of the influenza A virus polymerase and demonstrate that increased replicative capacity is a mechanism by which an RNA virus can counter the negative effects of elevated mutation rates. IMPORTANCE RNA viruses exist as genetically diverse populations. This standing genetic diversity gives them the potential to adapt rapidly, evolve resistance to antiviral therapeutics, and evade immune responses. Viral mutants with altered mutation rates or mutational tolerance have provided insights into how genetic diversity arises and how it affects the behavior of RNA viruses. To this end, we identified variants within the polymerase complex of influenza virus that are able to tolerate drug-mediated increases in viral mutation rates. We find that drug resistance is highly dependent on interactions among mutations in the polymerase complex. In contrast to other viruses, influenza virus counters the effect of higher mutation rates primarily by maintaining high levels of genome replication. These findings suggest the importance of maintaining large population sizes for viruses with high mutation rates and show that multiple proteins can affect both mutation rate and genome synthesis. PMID- 28815219 TI - Conventional NK cells and ILC1 are partially ablated in the livers of Ncr1 iCreTbx21 fl/fl mice. AB - Mouse liver contains both Eomes-dependent conventional natural killer (cNK) cells and Tbet-dependent liver-resident type I innate lymphoid cells (ILC1). In order to better understand the role of ILC1, we attempted to generate mice that would lack liver ILC1, while retaining cNK, by conditional deletion of Tbet in NKp46+ cells. Here we report that the Ncr1 iCreTbx21 fl/fl mouse has a roughly equivalent reduction in both the cNK and ILC1 compartments of the liver, limiting its utility for investigating the relative contributions of these two cell types in disease models. We also describe the phenotype of these mice with respect to NK cells, ILC1 and NKp46 + ILC3 in the spleen and small intestine lamina propria. PMID- 28815218 TI - Capturing the systemic immune signature of a norovirus infection: an n-of-1 case study within a clinical trial. AB - BACKGROUND: The infection of a participant with norovirus during the adaptive study of interleukin-2 dose on regulatory T cells in type 1 diabetes (DILT1D) allowed a detailed insight into the cellular and cytokine immune responses to this prevalent gastrointestinal pathogen. METHODS: Serial blood, serum and peripheral blood mononuclear cell (PBMC) samples were collected pre-, and post development of the infection. To differentiate between the immune response to norovirus and to control for the administration of a single dose of aldesleukin (recombinant interleukin-2, rIL-2) alone, samples from five non-infected participants administered similar doses were analysed in parallel. RESULTS: Norovirus infection was self-limited and resolved within 24 hours, with the subsequent development of anti-norovirus antibodies. Serum pro- and anti inflammatory cytokine levels, including IL-10, peaked during the symptomatic period of infection, coincident with increased frequencies of monocytes and neutrophils. At the same time, the frequency of regulatory CD4 + T cell (Treg), effector T cell (Teff) CD4 + and CD8 + subsets were dynamically reduced, rebounding to baseline levels or above at the next sampling point 24 hours later. NK cells and NKT cells transiently increased CD69 expression and classical monocytes expressed increased levels of CD40, HLA-DR and SIGLEC-1, biomarkers of an interferon response. We also observed activation and mobilisation of Teffs, where increased frequencies of CD69 + and Ki-67 + effector memory Teffs were followed by the emergence of memory CD8 + Teff expressing the mucosal tissue homing markers CD103 and beta7 integrin. Treg responses were coincident with the innate cell, Teff and cytokine response. Key Treg molecules FOXP3, CTLA-4, and CD25 were upregulated following infection, alongside an increase in frequency of Tregs with the capacity to home to tissues. CONCLUSIONS: The results illustrate the innate, adaptive and counter-regulatory immune responses to norovirus infection. Low-dose IL-2 administration induces many of the Treg responses observed during infection. PMID- 28815221 TI - A modified efficient purse-string stapling technique (mEST) that uses a new metal rod for intracorporeal esophagojejunostomy in laparoscopic total gastrectomy. AB - Intracorporeal esophagojejunostomy after laparoscopic total gastrectomy is technically difficult because this procedure should be performed in a narrow surgical field in the upper abdomen even when completely laparoscopic approaches are used. The placement of the anvil of a circular stapling device into the esophagus and connection the instrument to the anvil are extremely difficult steps in this surgery. Therefore, we developed a simple technique for intracorporeal esophagojejunostomy using hemi-double stapling technique; we named this technique the efficient purse-string stapling technique (EST). More recently, we have developed a modified EST (mEST) that utilizes a new stainless steel anvil rod instead of a plastic rod. Relative to the plastic rod, the steel rod is reusable and shorter; thus, it was easier to perform anvil placement into the esophagus with the steel rod. Anvil preparation for mEST: a stainless steel rod is attached to the shaft of the anvil, and the needle and thread are sutured to the tip of the rod. After complete insertion of the anvil into the esophageal cavity, the needle and thread are used to penetrate the anterior esophageal wall, and the esophagus is then clamped using a linear stapler just distal to the site penetrated by the thread. The linear stapler is fired, and anvil placement in the esophagus is simultaneously accomplished. After the rod is removed from the anvil, the instrument is intracorporeally connected to the anvil and then fired to complete the gastrojejunostomy. This technique is simple and facilitates intracorporeal reconstruction procedures in laparoscopic total gastrectomy. PMID- 28815222 TI - Twenty years after: from Milan criteria to a "blended" approach. PMID- 28815220 TI - Severity and outcomes of acute alcoholic pancreatitis in cannabis users. AB - BACKGROUND: Cannabis is the most commonly and widely used illicit drug in the world and is also the most commonly used drug of abuse in alcohol drinkers. Experimental studies have shown conflicting results of the effects of cannabis on the severity of acute pancreatitis (AP). The purpose of this study is to ascertain the clinical effects of simultaneous alcohol and cannabis use on severity at presentation and outcomes of acute alcoholic pancreatitis (AAP). METHODS: A retrospective review was conducted on the patients discharged with principle or secondary diagnosis of AP using ICD-9 & ICD-10 codes during the time period from January 2006 to December 2015 at a large community-based hospital in Central Georgia. Patients with alcoholic pancreatitis with cannabis (CB+) and without cannabis (CB-) use were identified and were matched with sex and age. RESULTS: Our study findings showed that a greater percentage of CB+ patients did not have a systemic inflammatory response syndrome (SIRS) score (P=0.043), had a lower BISAP score (P=0.031), and had a significantly lower BUN level (P=0.033), but there was no difference in the Balthazar Index and revised Atlanta classification severity between the two groups. CB+ patients tended to need less ICU care than CB- patients (P=0.059). CONCLUSIONS: Based on our findings, we found that CB+ patients had less severe presentation of AAP indicating that cannabis could modulate the inflammatory effect of alcohol on the pancreas. Further large scale prospective studies are needed to confirm our results. PMID- 28815223 TI - Hepatocellular carcinoma: when is liver transplantation oncologically futile? AB - Selection criteria of patients with hepatocellular carcinoma (HCC) for liver transplantation (LT) have been progressively expanded since the introduction of the Milan criteria. Transplanting patients with unfavourable tumor characteristics increases the risk of tumor recurrence and impacts post transplant survival. Although tumor number and size are the basis of widely accepted selection criteria and correlate with tumor grading and microvascular invasion, stronger predictors of tumor recurrence have been recently identified. These surrogates of aggressive tumor biology include non-response to pre transplant treatment, rapid recurrence within the first months after treatment, increased alpha-fetoprotein (AFP) concentrations, 18F-FDG positron emission tomography (PET) positive HCCs and poor differentiation and microvascular invasion in histology. The presence of any of these risk factors significantly increases the risk of tumor recurrence in patients within and beyond the Milan criteria. Especially the combination of two or more of these factors is associated with an inacceptably high recurrence risk and can render LT oncologically futile even in patients not exceeding the Milan criteria. In contrast, in absence of these risk factors also patients exceeding expanded selection criteria may undergo LT with low recurrence risk and favourable post transplant outcome. In selected cases this may even be applicable to patients with macrovascular invasion, who are conventionally excluded from LT. The main focus of this article is to review LT for HCC in the light of recurrence rates and to explore at what tumor stage transplantation becomes futile. PMID- 28815224 TI - A picture is worth a thousand words: Electronic cigarette content on Instagram and Pinterest. AB - INTRODUCTION: This study examined electronic cigarette (e-cig) content in visual materials posted on the social-media platforms Instagram and Pinterest. Both platforms allow users to upload pictures to the internet and share them globally. Users can search for pictures tagged with specific keywords and phrases. METHODS: Using content analysis, this study identified themes in image postings of e-cigs on social media. During five weeks of data collection, keywords were used to identify pictures related to e-cigs. These pictures were then coded into one or more categories. RESULTS: The three most popular categories for Instagram posts were marketing, customization and juices/flavors. The three most popular categories for Pinterest posts were customization, marketing and memes. CONCLUSIONS: Because of the persuasive power of visuals, it is important to examine communication on Instagram and Pinterest as well as the specific visual messages communicated. Stores and manufacturers use these and similar platforms to communicate with users and potential users; thus it seems that marketers are capitalizing on opportunities for persuasive appeal. The results highlight the popularity of e-cig content on these two social media platforms and reveal an emphasis on marketing and customization. PMID- 28815225 TI - Chronic In Vivo Interaction of Dendritic Cells Expressing the Ligand Rae-1epsilon with NK Cells Impacts NKG2D Expression and Function. AB - To investigate how dendritic cells (DCs) interact with NK cells in vivo, we developed a novel mouse model in which Rae-1epsilon, a ligand of the NKG2D receptor, is expressed in cells with high levels of CD11c. In these CD11c-Rae1 mice, expression of Rae-1 was confirmed on all subsets of DCs and a small subset of B and T cells, but not on NK cells. DC numbers and activation status were unchanged, and NK cells in these CD11c-Rae1 mice presented the same Ly49 repertoire and maturation levels as their littermate wildtype controls. Early NK cell activation after mouse CMV infection was slightly lower than in wildtype mice, but NK cell expansion and viral control were comparable. Notably, we demonstrate that chronic interaction of NK cells with NKG2D ligand-expressing DCs leads to a reversible NKG2D down-modulation, as well as impaired NKG2D-dependent NK cell functions, including tumor rejection. In addition to generating a useful mouse model, our studies reveal in vivo the functional importance of the NK cell and DC cross-talk. PMID- 28815228 TI - Inertio-elastic flow instabilities in a 90 degrees bent microchannel. AB - Biological samples having viscoelastic properties are frequently tested using microfluidic devices. In addition, viscoelastic fluids such as polymer solutions have been used as a suspending medium to spatially focus particles in microchannels. The occurrence of flow instability even at low Reynolds number is a unique property of viscoelastic fluids. In this study, we report the instability in viscoelastic flow for a channel having a 90 degrees bent geometry, which is a characteristic of many microfluidic devices. Interestingly, we observed that the flow instability in aqueous poly(ethylene oxide) (PEO) solution occurs when the concentration of PEO is as low as 50 ppm. We systematically investigated the effects of the polymer concentration, flow rate, and elasticity number on the flow instability. The results show that the flow is stabilized in shear-thinning fluids, whereas the flow instability is amplified when both elastic and inertial effects are pronounced. We believe that this study is useful to design microfluidic devices such as cell-deformability measurement devices based on viscoelastic particle focusing. PMID- 28815227 TI - Microparticle parking and isolation for highly sensitive microRNA detection. AB - Isolating small objects, such as particles, cells, and molecules, in individual aqueous droplets is useful for chemical and biological assays. We have developed a simple microfluidic platform to immobilize (park) microparticles at defined locations, and isolate particles in monodisperse droplets surrounded by immiscible oil. While conventional methods can only achieve stochastic encapsulation of objects within larger droplets, our in situ method ensures that a single particle is entrapped in a similar-sized droplet, with ~95% yield for parking and isolation. This enables time-lapse studies of reactions in confined volumes and can be used to perform enzymatic amplification of a desired signal to improve the sensitivity of diagnostic assays. To demonstrate the utility of our technique, we perform highly sensitive, multiplexed microRNA detection by isolating encoded, functional hydrogel microparticles in small aqueous droplets. Non-fouling hydrogel microparticles are attractive for microRNA detection due to favorable capture kinetics. By encapsulating these particles in droplets and employing a generalizable enzyme amplification scheme, we demonstrate an order of magnitude improvement in detection sensitivity compared to a non-amplified assay. PMID- 28815229 TI - Edge mode amplification in disordered elastic networks. AB - Understanding how mechanical systems can be designed to efficiently transport elastic information is important in a variety of fields, including in materials science and biology. Recently, it has been discovered that certain crystalline lattices present "topologically-protected" edge modes that can amplify elastic signals. Several observations suggest that edge modes are important in disordered systems as well, an effect not well understood presently. Here we build a theory of edge modes in disordered isostatic materials and compute the distribution g(kappa) of Lyapunov exponents kappa characterizing how modes penetrate in the bulk, and find good agreement with numerical results. We show that disordered isostatic materials generically act as levers with amplification of an order LL where L is the system size, whereas more connected materials amplify signals only close to free surfaces. Our approach, which is based on recent results in "free" random matrix theory, makes an analogy with electronic transport in a disordered conductor. PMID- 28815226 TI - Is Beta-Amyloid Accumulation a Cause or Consequence of Alzheimer's Disease? AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by the pathological hallmarks of extracellular beta-amyloid (Abeta) plaques and intraneuronal tau-containing neurofibrillary tangles in the brain. Intraneuronal accumulation of Abeta also plays a role to accelerate AD progression by promoting neurodegeneration. Additionally, AD is associated with the development of amyloid angiopathy (CAA), in which Abeta builds up on the walls of the cerebral arteries, which augments the development of cerebral vascular disease (CVD). Conversely, CVD promotes Abeta deposition and the development of AD by affecting the balance of Abeta production and clearance. However, it remains to be determined whether the accumulation of Abeta is a cause or consequence of AD. The interaction between AD and CVD is a topic of considerable current interest. Here, we discuss the role of CVD in Abeta accumulation and the development of AD to provide a new point of view that combination therapies that address the accompanying cerebral microvascular disease may potentiate the efficacy of emerging treatment for AD. PMID- 28815230 TI - Elastic deformation of soft coatings due to lubrication forces. AB - Elastic deformation of rigid materials with soft coatings (stratified materials) due to lubrication forces can alter the interpretation of dynamic surface forces measurements and prevent contact formation between approaching surfaces. Understanding the role of elastic deformation on the process of fluid drainage is necessary, in particular for the case where one (or both) of the interacting materials consists of a rigid substrate with a soft coating. We combine lubrication theory and solid linear elasticity to describe the dynamic of fluid drainage past a compliant stratified boundary. The analysis presented covers the full range of coating thicknesses, from an elastic foundation to a half-space for an incompressible coating. We decouple the individual contributions of the coating thickness and material properties on the elastic deformation, hydrodynamic forces, and fluid film thickness. We obtain a simple expression for the shift in contact position during force measurements that is valid for many experimental conditions. We compare directly the effect of stratification on the out-of-contact deformation to the well-known effect of stratification on indentation. We show that corrections developed for stratification in contact mechanics are not applicable to elastohydrodynamic deformation. Finally, we provide generalized contour maps that can be employed directly to estimate the elastic deformation present in most dynamic surface force measurements. PMID- 28815231 TI - Fluorescence activated cell sorting via a focused traveling surface acoustic beam. AB - Fluorescence activated cell sorting (FACS) has become an essential technique widely exploited in biological studies and clinical applications. However, current FACS systems are quite complex, expensive, bulky, and pose potential sample contamination and biosafety issues due to the generation of aerosols in an open environment. Microfluidic technology capable of precise cell manipulation has great potential to reinvent and miniaturize conventional FACS systems. In this work, we demonstrate a benchtop scale FACS system that makes use of a highly focused traveling surface acoustic wave beam to sort out micron-sized particles and biological cells upon fluorescence interrogation at ~kHz rates. The highly focused acoustic wave beam has a width of ~50 MUm that enables highly accurate sorting of individual particles and cells. We have applied our acoustic FACS system to isolate fluorescently labeled MCF-7 breast cancer cells from diluted whole blood samples with the purity of sorted MCF-7 cells higher than 86%. The cell viability before and after acoustic sorting is higher than 95%, indicating excellent biocompatibility that should enable a variety of cell sorting applications in biomedical research. PMID- 28815232 TI - Blue-shifting tuning of the selective reflection of polymer stabilized cholesteric liquid crystals. AB - We report on electrically-induced, large magnitude (>300 nm), and reversible tuning of the selective reflection in polymer stabilized cholesteric liquid crystals (PSCLCs) prepared from negative dielectric anisotropy nematic liquid crystal hosts. The electrically-induced blue shift in the selective reflection of the PSCLCs is distinguished from our prior reports of bandwidth broadening and red-shifting tuning of the selective reflection in PSCLCs. The dominant factor in delineating the electro-optic response of the PSCLCs detailed here are the preparation conditions. Specifically, long exposure to UV intensity exceeding 250 mW cm-2. Other factors are shown to contribute to the response, including the type and concentration of photoinitiator. PMID- 28815234 TI - Synthesis of mesoporous iridium nanosponge: a highly active, thermally stable and efficient olefin hydrogenation catalyst. AB - Three dimensional porous structures offer high specific surface areas and large pore volumes, which enhance substrate diffusion within the porous structures and provide a large number of surface active sites. Such types of structures find applications in catalysis. Herein, we report a simple synthetic strategy for the preparation of iridium nanosponges by the capping agent dissolution method. An Ir@BNHx nanocomposite was prepared starting from different iridium precursors by a solid state reduction method using ammonia borane wherein iridium(0) nanoparticles are embedded in a BNHx polymer. Capping agent (here, the BNHx polymer) dissolution using water under ambient conditions resulted in the formation of a mesoporous iridium nanosponge. This iridium nanosponge exhibits a surface area of 33.5 m2 g-1. The iridium nanosponge was found to be catalytically active for hydrogenation of a variety of olefinic substrates including linear and cyclic alkenes and alpha,beta-unsaturated esters under relatively mild conditions and exhibits high turnover frequencies. It was also found to exhibit much better catalytic activity as compared to other iridium based heterogeneous catalysts for olefin hydrogenation reactions. Additionally, catalyst recovery was achieved via simple filtration from the hydrogenation reaction mixture. The catalytically active surface area of iridium nanosponge was estimated using H2-temperature programmed desorption (TPD) experiments. Moreover, the catalyst was found to be thermally quite robust. The catalyst was recyclable over seven cycles of styrene hydrogenation and was found to be capable of hydrogenating 99% of styrene to ethyl benzene after seven cycles. PMID- 28815233 TI - The protective effect of acerola (Malpighia emarginata) against oxidative damage in human dermal fibroblasts through the improvement of antioxidant enzyme activity and mitochondrial functionality. AB - Acerola fruits (Malpighia emarginata DC.) from the central region of Cuba were analyzed to determine their chemical composition and protective capacity against oxidative damage using an in vitro human dermal fibroblast (HDFa) model. The chemical composition analyses showed a high content of vitamin C, total polyphenols, beta-carotene and folates in the acerola fruit. From the HPLC DAD/ESI-MSn analyses, two anthocyanins (cyanidin 3-O-rhamnoside and pelargonidin 3-O-rhamnoside), three hydroxycinnamoyl derivatives (caffeoyl hexoside, dihydrocaffeoylquinic acid and coumaroyl hexoside) and fifteen flavonols (mostly glycosylated forms of quercetin and kaempferol) were detected. HDFa were pre incubated with an acerola crude extract (ACExt) and subsequently subjected to oxidative stress induced by AAPH. Apoptosis, intracellular ROS and the biomarkers of lipid and protein oxidation significantly increased after inducing stress, while the activities of the antioxidant enzyme catalase and superoxide dismutase and mitochondrial functionality were markedly affected. However, ACExt was able to protect against oxidative damage through decreasing apoptosis, intracellular ROS levels and lipid and protein damage, besides improving antioxidant enzyme activities and mitochondrial functionality. The obtained results support acerola fruits as relevant sources of functional compounds with promising effects on human health. PMID- 28815235 TI - Growth kinetics and mechanisms of multinary copper-based metal sulfide nanocrystals. AB - Multinary copper-based metal sulfide (Cu-M-S) nanocrystals (NCs) usually have high absorption coefficients and near-optimum direct band gaps, which have been considered as novel photo-absorption materials for quantum dot-sensitized solar cells (QDSCs) and hole-transport materials for perovskite solar cells (PSCs). However, the formation and phase transformation mechanisms of Cu-M-S NCs during the solution-based preparing approaches are complicated. Herein, Cu-M-S NCs, including Cu2ZnSnS4 (CZTS), Cu2SnS3 (CTS), CuInS2 (CIS), and CuSbS2 (CAS), have been synthesized through solution-based hot-injection methods. Their formation and phase transformation mechanisms have been studied in terms of the growth kinetics. An effective method has been proposed to investigate the formation mechanisms of Cu-M-S NCs. The results suggest that CZTS, CTS, and CIS NCs are formed through an inter-reaction between metal sulfides rather than the classical cation exchange reactions, and CAS NCs are formed based on the CuxS structure; these findings provide new insights into the formation of Cu-M-S NCs. In addition, the anisotropic or isotropic growth processes during the growth stage have been found to be the key issues in the formation of a zinc blende or wurtzite structure NCs, respectively, which can be controlled by tuning the relative reactivity of metal precursors. PMID- 28815236 TI - Ring closing metathesis of unprotected peptides. AB - An efficient and expedient route to the synthesis of dicarba peptides from protecting group-free sequences is reported using Ru-alkylidene catalysed olefin metathesis. A range of cyclic peptides was prepared from linear peptides containing two Z-crotyl glycine residues. Free amine groups were masked as salts with Bronsted acids preventing in situ catalyst decomposition. Excellent RCM conversion was obtained in both DMF and methanol. PMID- 28815237 TI - Induced polarization restricts the conformational distribution of a light harvesting molecular triad in the ground state. AB - The light-harvesting molecular triad consisting of carotenoid polyene (C), diaryl porphyrin (P) and pyrrole-fullerene (C60) is a donor-acceptor molecule capable of absorbing incident light in the visible range. Its ability to convert solar energy to electrical excitation and charge separation energy suggests a great potential in real-world applications. The ensemble of its conformations under ambient conditions varies widely according to its electronic state. In previous work, we applied a non-polarizable model to study the conformational distribution of the molecular triad in the ground and charge separated states. However, due to the lack of polarization, which imparts subtle changes in the charge distribution on atoms, molecular simulations fail to produce accurate average dipole moments. We developed the first polarizable model for a molecular triad to investigate the structural and dynamic properties of a molecular triad in the ground state in an explicit organic solvent, tetrahydrofuran (THF). We performed first-principles electronic structure calculations of the individual components in the triad as well as THF and then fit the partial atomic charges to the electrostatic potential using the i-RESP methodology. We validated these force field parameters by comparing the thermodynamic and dynamic properties obtained from molecular dynamics simulations with those from experiments. We enhanced the sampling of the triad conformations with replica exchange molecular dynamics simulations. We characterized the effects of induced polarization on the structural stability of the triad by analyzing the free energy landscapes constructed with polarizable force fields. Furthermore, by using principal component analysis, we found that the molecular triad conformations adopted a small range of torsional angles with induced polarization. The triad conformation solvated in polar solvent with a polarizable force field qualitatively agrees with that obtained from nuclear magnetic resonance spectroscopy. PMID- 28815238 TI - [Effect of sintering temperature on mechanical properties of dental zirconia toughened alumina ceramics]. AB - PURPOSE: To investigate the effect of sintering temperature on mechanical properties of dental zirconia toughened alumina (ZTA) ceramics prepared by gel casting technique. METHODS: The samples prepared by gel-casting were sintered at 1100, 1200, 1250, 1300 and 1400degrees centigrade for each group. The flexural strength, fracture toughness, Vickers hardness and brittleness index were obtained and microscopic morphology of each group was observed under scanning electron microscope (SEM). The data were statistically analyzed using SPSS 19.0 software package. RESULTS: The flexural strength, fracture toughness and Vickers hardness increased with the increasing sintering temperature during 1100~1400degrees centigrade. The lowest brittleness index (0.74+/-0.16) MUm-1/2 was observed in group sintered at 1200degrees centigrade and the highest (2.76+/ 0.14) MUm-1/2 was at 1400degrees centigrade (P<0.05), while the flexural strength of these two groups was (46.89+/-3.24) MPa and (349.64+/-54.72) MPa, respectively. CONCLUSIONS: The ZTA dental ceramics exhibit good machinability with proper sintering temperature (1200degrees centigrade) and the strength meets the requirement of clinical application. PMID- 28815239 TI - [Elimination of Entercoccus faecalis with different disinfection methods in root canals in vitro]. AB - PURPOSE: To compare the elimination effect against E.faecalis in root canals with different methods. METHODS: Fifty extracted premolars with single root canal were selected. After cleaning and autoclaving, they were contaminated by E.faecalis and incubated for 28 days as models. Then the models were randomly and equally divided into 5 groups and treated as below: specimens in group A were treated with saline irrigation, specimens in group B were treated with 3% NaClO irrigation (as positive control), specimens in group C were treated with PUI, specimens in group D were treated with diode laser radiation, specimens in group E were treated with combination of PUI and diode laser radiation. The specimens from root canals were collected by paper points. The bacterial suspensions were later serially diluted and plated on tryptic soy agar plates to enumerate the CFUs after 48 hours. Statistical analysis was performed using SAS 8.02 software package. RESULTS: As with all parts of the root canal in aggregate, the CFUs of the specimens treated with PUI, diode laser radiation and the combination of them were significantly lower than the specimens treated with saline irrigation (P<0.01), but there was no significant difference among 3 groups (P>0.05). However, the specimens treated with 3% NaClO irrigation had the best effect of disinfection. The number of CFUs in the specimens treated with 3% NaClO was almost zero. There was no significant difference between this group and others in CFUs(P<0.01). CONCLUSIONS: Specimens treated with PUI, diode laser radiation and the combination of them showed great effect of elimination against biofilm of Enterococcus faecalis compared with saline irrigation. Irrigation with 3% NaClO was the most efficient method in this experiment. PMID- 28815240 TI - [Research on physical and mechanical properties, crown accuracy by using self- made FUS-invest dental investment]. AB - PURPOSE: To evaluate the physical and mechanical properties of pure titanium castings cast by self- made FUS-invest dental investment, and evaluate casting accuracy. METHODS: Seven pure titanium castings were cast by self-made FUS-invest zirconium investment and analyzed using servo hydraulic dynamic experiment system (JJG139-83 standard), scanning electron microscope and energy spectrum analysis. Thirty-eight crowns of pure titanium were cast by two different methods. One cast by FUS-invest zirconium embedding material was used for experiment and the other cast by phosphate embedding material was used as control. Casting accuracy was assessed through measuring the difference value d at the marginal marker points and distance between casting pieces of wall and working modes of casting were examined under microscope. Scanning electron microscope with energy-dispersive spectrum (EDS) was used to analyze the status of composition of the casting surface. SPSS 17.0 software package was used to investigate the difference of two groups. RESULTS: 1Qualitative analysis of servo hydraulic dynamic experiment system showed various mechanical properties: elastic modulus (123.5+/-14.2) GPa, yield strength (569.3+/-16.5) MPa, tensile strength (668.4+/-16.1) MPa, elongation (4.5+/-0.2)%. EDS analysis of the fracture was observed at different depth (13, 25, 50, 350 MUm) under the surface of pollution layer, a little Si and Fe with different atomic percentage was found but no Zr. 2No significant difference (P>0.05) was found between each group of four markers on the marginal fit, and internal fit, whereas significant difference (P<0.01) was found at different marker point. CONCLUSIONS: The mechanical properties of commercially pure titanium casting by self-made FUS-invest zirconium-based investment can meet the qualification of dental metal materials, although elongation was a little lower. Both the marginal adaptation and internal fit between the two groups had no significant difference. The mean marginal difference was 46 MUm, the mean internal difference at axial angle was 56 MUm and approximately 0 at axial wall. PMID- 28815241 TI - [Effect of estrogen on genioglossus and hypoglossal nucleus of female rats]. AB - PUEPOSE: To study the hypoglossal nucleus spontaneous discharge and genioglossus function of SD rats with different estrogen levels, and explore the possible central pathways of estrogen protecting upper airway stability. METHODS: Thirty SD rats were randomly divided into 3 groups: sham operation group (Sham), ovariectomized group (OVX) and ovariectomized + estrogen covering group (OVX+E2). The hypoglossal nucleus spontaneous discharge frequency and maximum amplitude of spontaneous discharge were measured with extracellular recording technique;BL-420 biological was used to detect the genioglossus EMG and contraction. The measurements included the average frequency, the maximum frequency, the integral amplitude, the maximum amplitude of the genioglossus, the amplitude of the evoked EMG, the critical fusion frequency, the 50% tonic contraction, and the intensity of the stimulus. SPSS 13.0 software package was used to analyze the data with One way ANOVA. RESULTS: The hypoglossal nucleus spontaneous discharge frequency and maximum amplitude of spontaneous discharge in OVX group were significantly lower than the Sham group and OVX+E2 group (P<0.05). The genioglossus EMG maximum frequency, average frequency, amplitude and integral maximum discharge magnitude, 50% tonic contraction drive of genioglossus in OVX group were significantly lower than the Sham and OVX+E2 group (P<0.05); the threshold stimulation strength and critical fusion frequency in OVX group were significantly higher than the Sham and OVX + E2 group (P<0.05); there was no significant difference between OVX+ E2 group and the Sham group (P>0.05); there was no significant difference among the three groups (P>0.05). CONCLUSIONS: Estrogen changes excitability of hypoglossal nucleus and affect contraction of genioglossus. Estrogen levels can affect genioglossus contraction function and the ability of resistance to fatigue. PMID- 28815242 TI - [Investigation of the effect of nuclear factor kappaB on inflammatory cell recruitment phenotype of oral cancer associated macrophage]. AB - PURPOSE: To explore the ability of nuclear factor kappaB (NFkappaB) in sustaining inflammatory cell recruitment phenotype of oral cancer associated macrophages, by using NFkappaB inhibitor(-Bay11-7082). METHODS: By primary culture, murine macrophages were harvested. Cal27 conditioned medium (CM) and Bay11-7082 were applied for stimulation of the macrophages. RT-PCR and ELISA were used for detecting the inflammatory cell recruitment related chemotactic factors. GraphPadPrism5 was used for statistical analysis. RESULTS: Bay11-7082 prevented the contour change into a spindle shape via Cal 27 CM. It also attenuated MCP-1, GM-CSF, MCP-5 and CCL-5 mRNA increase after Cal 27 CM stimulation (P<0.05). At protein level, impeding NFkappaB activation could significantly prevent MCP-1 and GM-CSF secretion from oral cancer associated macrophage (P<0.001). CONCLUSIONS: NFkappaB signaling may play a key role in sustaining the inflammatory cell recruitment phenotype of oral cancer associated macrophages. PMID- 28815243 TI - [Effects of EMD on relapse and root repair after orthodontic tooth movement in rats]. AB - PURPOSE: To study the effect of enamel matrix derivative(EMD) on root repair and tooth movement relapse after orthodontic tooth movement in rats. METHODS: Twenty 10-weeks old male rats were divided into experimental and control group randomly (n=10). 100 g force was exerted to the left maxillary first molars for 14 days and then removed. EMD was injected in rats in the experimental group since appliance was removed. The control group received no injection. Micro-CT was taken to analyze the changes of root resorption volume and distance of tooth movement. The differences were analyzed by SPSS19.0 software package. RESULTS: Fourteen days after device removal, the repair volume of root resorption lacunae in the experimental group and the control group were (0.0295+/-0.0052)*107 MUm3,(0.0189+/-0.0086)*107 MUm3, respectively. The relapse distance and relapse percentage after tooth movement were (0.089+/-0.005) mm, (64.76+/-3.63)%, (0.127+/-0.010) mm and (92.28+/-1.90)%, respectively. Statistical analysis showed the repair volume of root resorption lacunae, the relapse distance and relapse percentage were statistically significant 14 days after device removal (P<0.05). CONCLUSIONS: EMD can enhance the effect of root repair and decrease early relapse after orthodontic tooth movement in a certain extent. PMID- 28815244 TI - [Cytotoxicity of carboxymethyl chitosan zinc and peptide to human periodontal ligament cells]. AB - PURPOSE: The purpose of this investigation was to study the cytotoxicity of carboxymethyl chitosan zinc and peptide to human periodontal ligament cells in vitro, in order to provide a reference for understanding materials' safety. METHODS: The primary cells were obtained from human periodontal tissues and cultured. The cultured cells were identified by observing the shape under microscope and by immunocytochemical method. HPDLCs were cultured in different concentrations of the tested materials extract and the activity of cells was evaluated using CCK-8 assay. The cytotoxicity grade was determined in term of the cell relative growth rates. The concentration of the tested materials extract was 100%, 75%, 50% and 25% in group 1-4, respectively. The fifth group had no materials. All statistical analysis was performed using SPSS 17.0 software package. RESULTS: The primary cells owned fibroblasts' shape. Immunocytochemical analysis showed the cells were stained positively to antibodies against vimentin, and negatively to antibodies against cytokeratin, which indicated that they were external embryo mesenchymal cell. The cell relative growth rates were more than 100%, no matter the concentrations of materials extract were. The cytotoxicity grade of CMC-Zn+-P was 0. CONCLUSIONS: CMC-Zn+-P exhibits no cytotoxicity to HPDLCs in vitro, which meets the requirements of the national standard. PMID- 28815245 TI - [Experimental study on osteogenesis of acellular porcine pericardium in guided bone regeneration]. AB - PURPOSE: To observe the retention time and effect of acellular porcine pericardium (APP) in bone regeneration for rabbit femoral bone defects. METHODS: APP was prepared as follows: fresh porcine pericardium was chosen, high and low osmotic NaCl solution were used to soak the specimen alternately, trypsin+EDTA were used for digest, and then immersed with TritonX-100, cross-linked by using glutaraldehyde. 24 New Zealand rabbits were selected, and the area of bone defect was created 8 mm*8 mm*5 mm in size on bilateral distal femur. Stochastic method was used for grouping. One side of bone defect was covered with APP (experimental group); and the other side was covered without APP (control group). General observation, X-ray examination, histological examination, and bone mineral density (BMD) were performed 4 weeks, 8 weeks and 12 weeks after operation. SPSS18.0 software package was used for statistical analysis. RESULTS: After surgery, all wounds healed without complications. Under general observation, there were some fibrous cysts covered on the surface of APP. BMD (P<0.05) in the experimental group was significantly greater than that in the control group. On histological examination, the rate of osteogenesis in the experimental group was faster than that in the control group. CONCLUSIONS: Bone regeneration can be achieved using APP in the repair of rabbit bone defects. The retention time of APP can meet the needs of osteogenesis. PMID- 28815246 TI - [Effect of PKC inhibition on cell migration and invasion of oral squamous cell carcinoma]. AB - PURPOSE: By using HN4 cells, the correlation among protein kinase C(PKC), P120 catenin(P120ctn) and E-cadherin (E-cad) was investigated, and the role of them in migration and invasion of oral squamous-cell cancer(OSCC) was evaluated. METHODS: Plasmid pGFP-V-RS-P120ctn shRNA was used to transfect HN4 cells to significantly reduce the expression of P120ctn and PKC inhibitor staurosporine (STS) was added. mRNA and protein expression of PKC, P120ctn and E-cad were tested and Transwell cell invasion and cell migration assay was used to test the invasion and migration capacity before and after PKC inhibition. Statistical analysis was performed using SPSS 18.0 software package. RESULTS: When PKC was inhibited by STS, the expression of P120ctn and E-cad in OSCC cells were increased and the migration and invasion capacity of tumor cells decreased significantly (P<0.05). CONCLUSIONS:PKC may be involved in the process of HN4 migration and invasion by regulating cell adhesion through the effect of P120ctn and E-cad. PMID- 28815247 TI - [Changes of cementum endotoxin levels in different teeth with periodontitis treated with root conditioning]. AB - PURPOSE: To observe the changes of endotoxin levels after different teeth with periodontitis were treated with different methods. METHODS: Six healthy premolars extracted for orthodontic reasons and 36 posterior teeth extracted due to severe periodontitis were selected. Each tooth was processed from two 4 mm*4 mm*1 mm cementum pieces 2 mm under the cementum-enamel junction, each tooth with periodontitis was numbered. Healthy teeth served as negative control group, one of the two tablets from each tooth with periodontitis was selected in the periodontitis group, which was not treated with root surface treatment. The remaining 36 teeth with periodontitis were randomly divided into 6 groups: SRP group, SRP + antimicrobial peptide A group , SRP + antimicrobial peptide B group, SRP + EDTA group, SRP + Er:YAG laser group and SRP + Nd:YAG laser group. Endotoxin concentration in each tooth was determined by chromogenic substrate limulus reagent. The endotoxin concentration in each tooth was recorded according to the serial number, and the changes of endotoxin concentration were calculated before and after treatment. SPSS17.0 software package was used to analyze the data. RESULTS: Compared with the teeth with periodontitis, endotoxin concentration decreased to varying degrees, there were significant differences in each treatment group(P<0.01). Compared with SRP group, endotoxin levels in SRP + antimicrobial peptide A group, SRP + antimicrobial peptide B group, SRP + Er:YAG laser group were significantly decreased(P<0.01). No significant difference decreased was from between SRP + EDTA group and SRP + Nd:YAG laser group(P>0.05). CONCLUSIONS: Treatment of teeth with periodontitis using different methods can decrease the level of endotoxin, and the treatment of periodontitis root surface with antimicrobial peptide A + SRP may be more effective. PMID- 28815248 TI - [Differentially expressed genes between the human mandible- and ilium- derived mesenchymal cells]. AB - PURPOSE: To explore the differentially expressed genes between human mandible- and ilium- derived mesenchymal cells. METHODS: Differentially expressed genes between the human mandible- and ilium- derived mesenchymal cells were obtained from the GEO database based on the analysis of GEO2R software, then the relationship among these genes were analysed using DAVID and Gene MANIA on-line database. RESULTS: Two hundred and ninety three differentially expressed genes between the human mandible and iliac derived mesenchymal cells were obtained, and most of them were homeobox genes that related to bone development. These genes could also be enriched into different subgroups based on the analysis of DAVID database, such as "skeletal system development", "forebrain development", "limb development" and "WNT signaling pathway". After the analysis from Gene MANIA database, the molecular networks of MSX1, MSX2, HAND2, SIX1, PITX2, OSR2, PAX3 and PRRX1 were built to show that these eight genes exhibited interactions, including co-expression, co-localization, genetic interactions. CONCLUSIONS: There are different gene regulating mechanisms between the human mandible- and ilium- derived mesenchymal cells. It implies that genetic modification may be applied to get iliac derived mesenchymal cells to be more suitable for tissue engineered repair of jaw. PMID- 28815249 TI - [Effect of hemostatic agent on bonding strength of deciduous tooth dentin]. AB - PUPPOSE: To investigate the effect of hemostatic agent on bonding strength of deciduous tooth dentin. METHODS: Forty deciduous molars were used to make dentin grinding model and randomly divided into observation group and control group, 20 teeth in each group. Teeth in the observation group were covered with hemostatic agent for 30s, and then washed, followed by processing; while teeth in the control group were subjected to bonding directly. Micro tensile bond strength and micro leakage were measured and compared in the two groups. SPSS19.0 software package was used to analyze the data. RESULTS: Micro tensile bond strength of the observation group was (12.84+/-2.10) MPa, significantly lower than that of the control group (P<0.05); most resin protrusion in the observation group was > 35 MUm and long and dense, extending into the open dentinal tubules; while resin protrusion in the control group was about 7 to 35 MUm, with obvious collateral communication. There was no significant difference in the degree of micro leakage between the two groups (P>0.05). CONCIUSIONS: Hemostatic agent has certain impact on the dentin bonding strength of deciduous tooth, special attention should be paid during clinical application. PMID- 28815250 TI - [Methods and effects of injection of salvianolic acid B combined with triamcinolone acetonide in the treatment of oral submucous fibrosis]. AB - PURPOSE: To introduce the methods of triamcinolone acetonide (TA) and salvianolic acid B(SA-B) intralesional injection in the treatment of oral submucous fibrosis and evaluate the treatment effects. METHODS: TA combined with SA-B were consecutively applied intralesionally 1 time weekly for 30 times. The technique of intralesional injection was that syringe needle be emptied into submucous tissues 1 cm posterior to the corner of oral cavity running from the front to retromolar area by pushing the injection, then the syringe needle retained to the original point and upward from the front to retromolar area by pushing the injection, finally the syringe needle returned to the starting point and downward from the front to retromolar area by pushing the injection. Mouth opening, the color change of the buccal mucosa and the increase of capillary vessels as determined by degree I-IV visual analog scale were evaluated at 12, 24, and 36 month. The data were analyzed with SPSS 21.0 software package. RESULTS: One hundred and fourteen subjects fulfilled the study without obvious adverse reactions. After treatment for 36 months , the net gain in mouth opening of the early stage group,middle stage group and advanced stage group was (12.0+/-1.2) mm, (14.5+/-2.4) mm and (15.5+/-1.5) mm, respectively. The response rate of color change of the buccal mucosa and the increase of capillary vessels in early stage group, middle stage group and advanced stage group after treatment for 36 months was 100%, 94.7% and 90.7%, respectively. CONCLUSIONS: Triamcinolone acetonide and salvianolic acid B intralesional injection is effective in the treatment of oral submucous fibrosis. PMID- 28815251 TI - [Morphometric analysis of maxillofacial bone in 48 patients with ectodermal dysplasia]. AB - PURPOSE: The study was performed to analyze the maxillofacial morphology of 48 patients with ectodermal dysplasia (ED) and to provide some reference for implant treatment of ED patients. METHODS: The study collected the clinical data and lateral cephalometric radiographs of 48 patients with ED treated between June 2013 and October 2016. The patients were grouped as follows: group 1, 23 patients, at least with two kinds of ectodermal disorder, besides hypodontia; group 2, 25 patients, only with one kind of ectodermal disorder, besides hypodontia. The number of missing teeth and maxillofacial cephalometric parameters were compared between 2 groups. SPSS 17.0 software package was performed for statistical analysis. RESULTS: The number of missing teeth was significantly larger in group 1(22.3+/-5.8) than group 2 (12+/-6.6) (P<0.05). The number of retained deciduous teeth was significantly larger in group 1 (8+/-4) than in group 2 (2.4+/-2.7) in females (P<0.05). Cephalometric analysis showed a reduced maxilla length (ANS-Ptm), retrusive maxilla (S-Ptm, SNA, NA-PA), a normal size (S-Co) and length (Co-Po) of mandible, a protruding mandible (NP-FH) and chin (Y axis), skeletal Angle III malocclusion(ANB<0) and a reduced facial height (N-Me) in two groups. SNA, NA-PA, ANS-Ptm, S-Ptm and Y axis were significantly decreased and NP-FH was significantly increased in group 1 compared to group 2 in males (P<0.05). CONCLUSIONS: Maxillofacial morphology of ED patients typically presented a reduced maxilla length and retrusive maxilla, a normal size and length of mandible, a protruding mandible and chin, skeletal Angle III malocclusion and a reduced facial height. The severity of abnormalities in maxillofacial bone morphology was correlated positively with absence of permanent teeth. Furthermore, retained deciduous teeth might have positive effect on the development of maxillofacial bone. PMID- 28815252 TI - [Expression of PTPRZ1 in oral squamous cell carcinoma originated from oral submucous fibrosis and its clinical significance]. AB - PURPOSE: This study was aimed to detect the expression of PTPRZ1 in oral squamous cell carcinoma (OSCC) originated from oral submucous fibrosis (OSF), and discuss its role in the development and progression of OSCC originating from OSF as well as its clinical significance. METHODS: Immunohistochemisty (IHC) and Western blot (WB) for the expression and distribution of PTPRZ1 were carried out in 36 cases of OSF transforming into OSCC, 23 cases of OSCC and 21 cases of healthy controls. The data were analyzed by Chi-square test using SPSS 21.0 software package. RESULTS: IHC results demonstrated that the expression of PTPRZ1 in OSCC originated from the OSF was strongly positive and the rate of positive expression was 72.22%; expression of PTPRZ1 in OSCC was weakly positive, the positive rate was 43.47%; and the expression of PTPRZ1 in healthy controls was negative. The rate of PTPRZ1 positive expression was significantly higher in OSCC originated from OSF and OSCC with non-OSF than that of the healthy controls (P<0.01). The positive expression rate of OSCC originated from OSF was significantly higher than that of OSCC with non-OSF (P<0.05).WB results showed the expression of PTPRZ1 was weak in the healthy controls and in OSCC with non-OSF, but strong in OSCC originated from OSF. Correlation analysis between PTPRZ1 and clinical data showed PTPRZ1 was correlated with recurrence and metastasis positively (rk=0.642, P<0.05; rk=0.656, P<0.05). CONCLUSIONS: Differential expression of PTPRZ1 in OSCC originating from OSF and OSCC with non-OSF was significant. PTPRZ1, which plays an important role in the processes of development, invasion and metastasis of OSCC originated from OSF, can be used as a molecular marker for early diagnosis and targeted gene for treatment of OSCC originating from OSF. PMID- 28815253 TI - [A survey on knowledge, attitude and practice related to evidence-based dentistry among dental students]. AB - PURPOSE: To investigate the knowledge, attitude and practice related to evidence based dentistry among dental students, and to provide a reference for targeted evidence-based dentistry teaching and practice evidence-based dentistry in dental students. METHODS: Dental students who attended the internship in Shanghai Ninth People's Hospital and Pudong People's Hospital were invited to attend this survey. Information on knowledge, attitude and practices related evidence-based dentistry was collected through questionnaires. SPSS 21.0 software package was used for data analysis. RESULTS: A total of 62 dental students attended this survey. Evidence-based dentistry related knowledge and attitude scores were 5.5+/ 1.9 and 5.1+/-1.0, respectively. Over three quarters of students took courses on evidence-based medicine, while around half of students (56.5%) self-reported that they knew little about evidence-based medicine. 70.5% students practiced evidence based dentistry less than once in the process of clinical decision making per week. The majority of students (80.3%) used MEDLINE or other databases to search for practice-related literature less than once per week. 63.9% students used practice guideline. The top three barriers to practice evidence-based dentistry were lack of information resources, insufficient time and lack of search skills. CONCLUSIONS: Evidence-based dentistry related knowledge and practice among dental students is deficient, whereas they hold positive attitude on practice. The top three barriers to practice evidence-based dentistry are lack of information resources, insufficient time and lack of search skills. PMID- 28815254 TI - [The relationship between periodontitis and arterial sclerosis without genetic confounding]. AB - PURPOSE: The aim of this study was to evaluate periodontitis as a significant risk factor related to arterial sclerosis after eliminating genetic confounding. METHODS: Fifty two monozygotic twin pairs, 104 patients, were divided into 3 groups. group A: 24 pairs, 48 healthy people, as the blank group; group B: 28 patients with periodontitis, as the control group; group C: 28 patients with periodontitis, as the treatment group. The sample in group B and C had the same gene type. The index of CRP, IL-6, TNF-alphaand IMT were detected before treatment, 6 and 12 week after treatment. The data were analyzed using SPSS 17.0 software package. RESULTS: The index of CRP, IL-6, TNF-alpha and IMT decreased after treatment in group C, there was no significant change in group A and B at each check point. CONCLUSIONS: Periodontitis can promote the development of sclerosis without the intervening of gene. PMID- 28815255 TI - [Investigation of related risk factors of temporomandibular disorders in 109 patients]. AB - PURPOSE: To investigate the related risk factors of temporomandibular disorders(TMD), and to provide evidences for clinical prevention. METHODS: One hundred and nine TMD patients were included in the study as case group, while 109 people with no TMJ symptoms and signs were selected randomly as control group. All subjects fulfilled questionaires. Logistics regression analysis was used to analyze the data with SPSS 22.0 software package. RESULTS: Females patients were more common than males, with 20~29 age group accounting for 44%. The proportions of patients with habits of bruxism or clenching, unilateral mastication and maxillofacial injure history were significantly greater than those of control group (P<0.05). The proportions of patients with life stress and habits of stay up late, chewing hard food and orthodontic treatment history showed no significant difference compared with the control group (P>0.05). CONCLUSIONS: TMD has a higher prevalence in female than in male, with a peak incidence in 20-29 age group. Habits of bruxism or clenching, unilateral mastication and maxillofacial injury history may be risk factors of TMD, while life stress, habits of stay-up late, chewing hard food and orthodontic treatments show no significant correlation with TMD. PMID- 28815256 TI - [Comparison of the differences in pain and the effect of ibuprofen in reducing endodontic flare-up after single-visit root canal therapy between Uyghur and Han patients with chronic apical periodontitis]. AB - PURPOSE: To compare the incidence of postoperative pain of chronic periapical periodontitis patients with root canal therapy between Han and Uygur, and the effect of ibuprofen in reducing endodontic flare-up after single-visit root canal therapy between Uyghur and Han patients with chronic apical periodontitis, in order to provide a basis for clinical administration. METHODS: Two hundred and fifty Uyghur and 250 Han patients with chronic apical periodontitis in their incisor, canine and premolar were collected, and randomly divided into 2 groups: experimental group and control group. After single-visit root canal therapy, Uyghur patients in the experimental group (UEG) and Han patients in the experimental group (HEG) took ibuprofen capsules according to the drug instructions; while Uyghur patients in the control group (UCG) and Han patients in the control group(HCG) took placebo capsules. Both doctors and patient kept blind from the drug capsules and group of the patients. The incidence, degree of endodontic Flare-up at 6, 12, 24, 48, 72 hours and 1 week after root canal therapy were recorded and analyzed by chi2 test using SPSS11.0 software package. RESULTS: During the experiment, the incidence of E flare-up in Uygur patients was higher than in Han patients; the incidence of E flare-up in different groups in orders from high to low was: UCG>HCG>UEG>HEG. Chi-square test showed that there were significant differences between the two groups. In view of time distribution, most of flare-up happened between 24~48 hours after root canal therapy with the highest degree in all 4 groups. Regardless of the incidence or degree of flare-up, HEG and HCG were significantly greater than UEG and UCG. CONCLUSIONS: Ibuprofen can reduce and prevent flare-up for both Uyghur and Han patients, but it has better effect on Han patients. PMID- 28815257 TI - [Effect of functional appliance on upper airway in adolescent patients with skeletal Class II malocclusion]. AB - PURPOSE: To investigate the effect of functional appliance on upper airway in adolescent patients with skeletal Class II malocclusion based on cone-beam CT (CBCT). METHODS: Thirty adolescent patients (male:female=1:1) with skeletal Class II malocclusion and their 30 counterparts with skeletal Class I malocclusion were selected. Skeletal Class II malocclusion patients were treated with Activator for 12 months on average, meanwhile skeletal Class I malocclusion patients were treated with fixed appliance without extraction. Cone-beam CT (CBCT) films were taken before and 12 months after treatment. Films of skeletal Class II malocclusion patients were measured (items about skeletal and upper airway, and the outline of upper airway depicted with 3D reconstruction) and compared with the reference standards and the measurements of their counterpart patients with skeletal Class I malocclusion. Independent t test was performed in inter-group comparison and paired t test was performed in inner-group comparison using SAS 8.0 software package. RESULTS: Before treatment, patients with skeletal Class II malocclusion showed decreased SNB and APDI value, increased ANB, Wits, and OJ compared with standard value and value of skeletal Class I malocclusion patients. In addition, decreased MPW and PAS value, and downsized volume of upper airway and transverse diameter minimum were found in skeletal Class II malocclusion patients. After treatment with Activator, patients with skeletal Class II malocclusion showed increased MPW and PAS value, and enlarged volume of upper airway and transverse diameter minimum. All values of skeletal items of patients with skeletal Class II malocclusion showed trends to get close to the reference standards and the values of skeletal Class I malocclusion patients. There was no significant difference between different genders of the two groups. CONCLUSIONS: Patients with skeletal Class II malocclusion have constructed upper airways. Treatment with Activator can increase the MPW and PAS values and enlarge volume of upper airway and transverse diameter minimum. Functional appliance can ameliorate the narrowness of upper airway for skeletal Class II patients. PMID- 28815258 TI - [Anterolateral thigh flap for reconstruction of defects after en bloc resection of buccal cancer : a retrospective study of 23 cases]. AB - PURPOSE: This study was aimed to observe the effects of anterolateral thigh flap for reconstruction of tissue defects after en bloc resection of buccal cancer. METHODS: Twenty-three patients with soft tissue defects after en bloc resection of buccal cancer underwent simultaneous reconstruction with anterolateral thigh flap from May, 2013 to May, 2015 were observed. Anterolateral thigh flaps were designed and harvested in form of single or multiple islands to restore the defect in buccal region after surgery. The appearance and function of both the oral and maxillofacial region and the donor site were recorded and evaluated. RESULTS: All the 23 flaps survived. Only 3 of them experienced vascular crisis within 24 hours after surgery, and recovered gradually after salvage. The success rate was 100%. One to three years of follow-up showed satisfying morphology and function for both the receipt sites and the donor sites. Buccal abscess was observed in 1 patient and recovered after rinsing and drainage. Two patients died of recurrence. CONCLUSIONS: Good effects can be achieved using anterolateral thigh flap to reconstruct buccal defects after en bloc resection of cancer, which is suitable for application in clinical practice. PMID- 28815259 TI - [Safety and efficacy of ultrasound hyperthermia combined with chemotherapy and radical operation for advanced oral squamous cell carcinoma]. AB - PURPOSE: To explore the safety and efficacy of ultrasound hyperthermia combined with chemotherapy and radical operation for advanced oral squamous cell carcinoma (OSCC). METHODS: Nine patients who had definite pathological diagnosis were enrolled in this clinical trail from 2015 to 2016. All patients underwent ultrasound hyperthermia combined with chemotherapy before radical operation. The treatment regime was as follows: Docetaxel and cisplatin (75mg/m2) used on the first day, fluorouracil (750 mg/m2) infused from 1st to 5th day. All patients received 2 cycles of thermo-chemotherapy, the therapeutic temperature was set to be 40-42 degrees centigrade, ultrasound hyperthermia was performed for 40 minutes every other day for 5 times. The therapeutic outcomes were evaluated by observation of clinical tumor regression. RESULTS: Of the 9 patients, complete response(CR)was seen in 1 case, partial response (PR) was seen in 3 cases, stable disease(SD)was seen in 5 cases. Complications were not severe and tolerable. CONCLUSIONS: Ultrasound hyperthermia combined with chemotherapy (TPF) may improve the therapeutic effect in advanced OSCC without obvious adverse reactions, and the toxicity and side effects are well tolerated. PMID- 28815260 TI - [Improving the teaching quality by multiple tools and technology in oral histopathology experimental course]. AB - PURPOSES: Oral histopathology is a course which needs to be combined with theory and practice closely. Experimental course plays an important role in teaching oral histopathology. Here, we aim to explore a series of effective measures to improve the teaching quality of experimental course and tried to train observation, thinking, analysis and problem solving skills of dental students. METHODS: We re-edited and updated the experimental textbook "guidelines of experimental course of oral histopathology", and published the reference book for experimental course--"color pocket atlas of oral histopathology: experiment and diadactic teaching". The number of clinicopathological cases for presentation and class discussion was increased, and high-quality teaching slides were added and replaced the poor-quality or worn out slides. We established a variety of teaching methods based on the internet, which provided an environment of self directed learning for dental students. Instead of simple slice-reading examination, a new evaluation system based on computer was established. RESULTS: The questionnaire survey showed that the students spoke positively on the teaching reform for experimental course. They thought that the reform played a significant role in enriching the teaching content, motivating learning interest and promoting self-study. Compared with traditional examination, computer-based examination showed a great advantage on mastering professional knowledge systematically and comprehensively. CONCLUSIONS: The measures adopted in our teaching reform not only effectively improve the teaching quality of experimental course of oral histopathology, but also help the students to have a clear, logical thinking when facing complicated diseases and have the ability to apply theoretical knowledge into clinical practice. PMID- 28815261 TI - Author Impact Metrics in Communication Sciences and Disorder Research. AB - Purpose: The purpose was to examine author-level impact metrics for faculty in the communication sciences and disorder research field across a variety of databases. Method: Author-level impact metrics were collected for faculty from 257 accredited universities in the United States and Canada. Three databases (i.e., Google Scholar, ResearchGate, and Scopus) were utilized. Results: Faculty expertise was in audiology (24.4%; n = 490) and speech-language pathology (75.6%; n = 1,520). Women comprised 68.1% of faculty, and men comprised 31.9% of faculty. The percentage of faculty in the field of communication sciences and disorders identified in each database was 10.5% (n = 212), 44.0% (n = 885), and 84.4% (n = 1,696) for Google Scholar, ResearchGate, and Scopus, respectively. In general, author-level impact metrics were positively skewed. Metric values increased significantly with increasing academic rank (p < .05), were greater for men versus women (p < .05), and were greater for those in audiology versus speech language pathology (p < .05). There were statistically significant positive correlations between all author-level metrics (p < .01). Conclusions: These author-level metrics may serve as a benchmark for scholarly production of those in the field of communication sciences and disorders and may assist with professional identity management, tenure and promotion review, grant applications, and employment. PMID- 28815262 TI - Semantic and Phonological Encoding in Adults Who Stutter: Silent Responses to Pictorial Stimuli. AB - Purpose: Research on language planning in adult stuttering is relatively sparse and offers diverging arguments about a potential causative relationship between semantic and phonological encoding and fluency breakdowns. This study further investigated semantic and phonological encoding efficiency in adults who stutter (AWS) by means of silent category and phoneme identification, respectively. Method: Fifteen AWS and 15 age- and sex-matched adults who do not stutter (ANS) participated. The groups were compared on the basis of the accuracy and speed of superordinate category (animal vs. object) and initial phoneme (vowel vs. consonant) decisions, which were indicated manually during silent viewing of pictorial stimuli. Movement execution latency was accounted for, and no other cognitive, linguistic, or motor demands were posed on participants' responses. Therefore, category identification accuracy and speed were considered indirect measures of semantic encoding efficiency and phoneme identification accuracy and speed of phonological encoding efficiency. Results: For category decisions, AWS were slower but not less accurate than ANS, with objects eliciting more errors and slower responses than animals in both groups. For phoneme decisions, the groups did not differ in accuracy, with consonant errors outnumbering vowel errors in both groups, and AWS were slower than ANS in consonant but not vowel identification, with consonant response time lagging behind vowel response time in AWS only. Conclusions: AWS were less efficient than ANS in semantic encoding, and they might harbor a consonant-specific phonological encoding weakness. Future independent studies are warranted to discover if these positive findings are replicable and a marker for persistent stuttering. PMID- 28815263 TI - Disseminated Vesicular Rash in an Immunocompetent Adult Woman: A Quiz. Atypical hand, foot, and mouth disease caused by echovirus 3. PMID- 28815264 TI - Agreeableness as Predictor of Induced Scratching in Patients with Atopic Dermatitis: A Replication Study. AB - In patients with atopic dermatitis agreeableness and public self-consciousness have previously been shown to be significant predictors of induced scratching, while depression was significantly related to induced itch. This study aimed to replicate these findings. Itch and scratching were induced by videos of crawling insects or skin diseases. Induced itch was measured using a visual analogue scale. Scratching behavior was evaluated by two raters. Psychological variables were assessed using validated questionnaires. Induced scratching could be predicted significantly by agreeableness (corrected R2 = 15.5% or 38 % after exclusion of one outlier): Patients scoring low on agreeableness showed a higher increase in scratch movements than patients scoring high on this scale. No associations between induced scratching/itch and public self consciousness/depression were found. One clinical implication that arises from this study could be to offer patients scoring low on agreeableness certain psychological interventions. PMID- 28815265 TI - Human Herpesvirus-7 Papular Rash: A Comment to Brazzelli et al. AB - is missing (Correspondence). PMID- 28815266 TI - Adult Staphylococcal Scalded Skin Syndrome Successfully Treated with Multimodal Therapy Including Intravenous Immunoglobulin. PMID- 28815267 TI - Long-term Trend in Sunscreen Use among Beachgoers in Denmark. AB - This observational study examined the trend from the 1990s to 2016 of sunscreen use, sun protection factor (SPF) and quantity of sunscreen applied amongst beachgoers in Denmark. In 1997, 1998, 1999 and 2016, a total of 1,306 beachgoers were asked if they had used sunscreen on that day and, if so, which SPF. In 1992 and 2016 another 143 beachgoers had their sunscreen bottles weighed before and after application. The frequency of sunscreen use among women increased from 45% in 1997 to 78% in 2016, while the frequency of use among men increased from 39% to 49%. For both sexes the median SPF increased, on average, by one unit per year, from SPF 5 in 1997 to SPF 20 in 2016. The quantity of sunscreen applied increased from 0.48 mg/cm2 in 1992 to 0.57 mg/cm2 in 2016. Thus, the frequency of sunscreen use, the SPF, and the quantity of sunscreen applied have increased in the recent decades. PMID- 28815268 TI - Temporal Stability of the Healthy Human Skin Microbiome Following Dead Sea Climatotherapy. AB - Dead Sea climatotherapy (DSC) is a therapeutic modality for a variety of chronic skin conditions, yet there has been scarce research on the relationship between the cutaneous microbiota and disease states in response to DSC. We characterized the skin bacterial and fungal microbiome of healthy volunteers who underwent DSC. Bacterial community diversity remained similar before and after treatment, while fungal diversity was significantly reduced as a result of the treatment. Individuals showed greater inter-individual than temporal bacterial community variance, yet the opposite was true for fungal community composition. We further identified Malassezia as the genus driving temporal mycobiome variations. The results indicate that the microbiome remains stable throughout DSC, while the mycobiome undergoes dramatic community changes. The results of this study will serve as an important baseline for future investigations of microbiome and mycobiome temporal phenomena in diseased states. PMID- 28815269 TI - Enhanced conscious processing and blindsight-like detection of fear-conditioned stimuli under continuous flash suppression. AB - Emotional information, and specifically fear-related stimuli, have been shown to be preferentially processed at a nonconscious level and gain privileged access to awareness. However, recent evidence has emerged suggesting these findings are explained by low-level visual features rather than emotional salience. In this study, we tested the hypothesis that emotional salience increases both blindsight (i.e., detection with reduced awareness) and awareness of visually suppressed stimuli. We used fear conditioning to manipulate the emotional significance of neutral expressions presented under Continuous Flash Suppression. Fifty-two healthy participants were presented with perithreshold neutral faces, previously paired with an electric shock (CS+) or not (CS-), and asked to localise the quadrant wherein faces were presented and rate their level of confidence in the response. Results showed fear conditioning strength (indexed by skin conductance response to CS+ versus CS-) was positively associated with both increased "blindsight" and awareness of conditioned stimuli. These findings suggest emotional significance alone, and not merely low-level visual differences, can enhance pre-conscious and conscious processing of visual stimuli. PMID- 28815270 TI - Pre-analytic evaluation of volumetric absorptive microsampling and integration in a mass spectrometry-based metabolomics workflow. AB - Volumetric absorptive microsampling (VAMS) is a novel approach that allows single drop (10 MUL) blood collection. Integration of VAMS with mass spectrometry (MS) based untargeted metabolomics is an attractive solution for both human and animal studies. However, to boost the use of VAMS in metabolomics, key pre-analytical questions need to be addressed. Therefore, in this work, we integrated VAMS in a MS-based untargeted metabolomics workflow and investigated pre-analytical strategies such as sample extraction procedures and metabolome stability at different storage conditions. We first evaluated the best extraction procedure for the polar metabolome and found that the highest number and amount of metabolites were recovered upon extraction with acetonitrile/water (70:30). In contrast, basic conditions (pH 9) resulted in divergent metabolite profiles mainly resulting from the extraction of intracellular metabolites originating from red blood cells. In addition, the prolonged storage of blood samples at room temperature caused significant changes in metabolome composition, but once the VAMS devices were stored at - 80 degrees C, the metabolome remained stable for up to 6 months. The time used for drying the sample did also affect the metabolome. In fact, some metabolites were rapidly degraded or accumulated in the sample during the first 48 h at room temperature, indicating that a longer drying step will significantly change the concentration in the sample. Graphical abstract Volumetric absorptive microsampling (VAMS) is a novel technology that allows single-drop blood collection and, in combination with mass spectrometry (MS)-based untargeted metabolomics, represents an attractive solution for both human and animal studies. In this work, we integrated VAMS in a MS-based untargeted metabolomics workflow and investigated pre-analytical strategies such as sample extraction procedures and metabolome stability at different storage conditions. The latter revealed that prolonged storage of blood samples at room temperature caused significant changes in metabolome composition, but if VAMS devices were stored at - 80 degrees C, the metabolome remained stable for up to 6 months. PMID- 28815272 TI - Gold nanoparticle-based localized surface plasmon immunosensor for staphylococcal enterotoxin A (SEA) detection. AB - We describe the engineering of stable gold nanoparticle (AuNP) bioconjugates for the detection of staphylococcal enterotoxin A (SEA) using localized surface plasmon resonance (LSPR). Two types of AuNP bioconjugates were prepared by covalently attaching anti-SEA antibody (Ab) or SEA to AuNPs. This was achieved by reacting Traut's reagent with lysine residues of both proteins to generate thiol groups that bind to gold atoms on the AuNP surface. These bioconjugates were characterized in-depth by absorption spectroscopy, cryo-transmission electron microscopy, dynamic light scattering, and zeta potential measurements. Their stability over time was assessed after 1 year storage in the refrigerator at 4 degrees C. Two formats of homogeneous binding assays were set up on the basis of monitoring of LSPR peak shifts resulting from the immunological reaction between the (i) immobilized antibody and free SEA, the direct assay, or (ii) immobilized SEA and free antibody, the competitive assay. In both formats, a correlation between the LSPR band shift and SEA concentration could be established. Though the competitive format did not meet the expected analytical performance, the direct format, the implementation of which was very simple, afforded a specific and sensitive response within a broad dynamic range-nanogram per milliliter to microgram per milliliter. The limit of detection (LOD) of SEA was estimated to equal 5 ng/mL, which was substantially lower than the LOD obtained using a quartz crystal microbalance. Moreover, the analytical performance of AuNP-Ab bioconjugate was preserved after 1 year of storage at 4 degrees C. Finally, the LSPR biosensor was successfully applied to the detection of SEA in milk samples. The homogeneous nanoplasmonic immunosensor described herein provides an attractive alternative for stable and reliable detection of SEA in the nanogram per milliliter range and offers a promising avenue for rapid, easy to implement, and sensitive biotoxin detection. Sensitive LSPR Biosensing of SEA in buffer and milk using stable AuNP-Antibody bioconjugates Graphical abstract. PMID- 28815271 TI - The Prolidase Activity, Oxidative Stress, and Nitric Oxide Levels of Bladder Tissues with or Without Tumor in Patients with Bladder Cancer. AB - This study was designed to evaluate the malondialdehyde (MDA), glutathione (GSH) and nitric oxide (NO) levels, and also prolidase, glutathione peroxidase (GSH Px), superoxide dismutase (SOD) enzyme activities in malignant and benign cancers of bladder tissue. A total of 59 patients admitted to our clinic due to microscopic or macroscopic haematuria, were prospectively included in the study. Because of some reasons (no request to participate in the study, the inability to reach, other malignancies, alcohol consumption, metabolic disease), eight patients were excluded from study. Of the 51 patients, 25 were bladder tumor patients, and 26 were patients without cancers. The bladder tissue samples were obtained from all patients under anesthesia (spinal, epidural or general) for the measurement of MDA, GSH and NO levels, and prolidase, GSH-Px and SOD enzyme activities. Among the patients with bladder cancers, 7 patients were females and 18 patients were males, with an average age of 68.4 +/- 2.49. Among patients without tumors, 6 patients were females and 20 patients were males, with an average age of 58 +/- 2.05. In patients with bladder tumors, the oxidants (MDA, NO, prolidase) were higher, and the antioxidants (SOD, GSH, GSH-Px) were lower than those in patients without tumors. It was concluded that the oxygen free radicals play a role in the etiology of bladder cancers similar to many other tumors and inflammatory conditions. Therefore, we assume that antioxidants may provide benefits in the prevention and treatment of bladder cancer. PMID- 28815273 TI - Micro- versus nano-sized molecularly imprinted polymers in MALDI-TOF mass spectrometry analysis of peptides. AB - The integration of molecularly imprinted polymers (MIPs) with MALDI-TOF mass spectrometry (MS) combines MIP selectivity with MS sensitivity. Whether the size of the MIP material-micro versus nano-has an effect on the MS analysis was the object of the study. MIPs, targeting respectively the epitope peptide NR11 of cardiac troponin I and the peptide CK13 of human serum transferrin, were synthesized and characterized. The size-related performance of the MIP materials hyphenated with MALDI-TOF-MS analysis was studied by the incubation of the target peptide with the respective micro- or nano-MIP, followed by rinsing to remove non specific deposition of the MIP to the MALDI target plate, co-crystallization with the organic matrix, and mass analysis. The quality of the MS analysis was assessed comparing the S/N of the mass peaks of the MIP-bound peptide to that of the same quantity of free peptide. Sweet spots and lower S/N (~ 1 order of magnitude) were observed for micro-MIP materials, while in the case of nano-MIP bound peptide, the S/N was comparable to that of the free peptide, indicating higher compatibility of the nano-MIPs to MALDI-TOF-MS. The nano-MIP/MALDI-TOF-MS permitted the selective determination of the target peptide in real serum samples. Graphical abstract ?. PMID- 28815274 TI - A new metabolomics-based strategy for identification of endogenous markers of urine adulteration attempts exemplified for potassium nitrite. AB - Urine adulteration to circumvent positive drug testing represents a problem for toxicological laboratories. While creatinine is a suitable marker for dilution, detection of chemicals is often performed by dipstick tests associated with high rates of false positives. Several methods would be necessary to check for all possible adulterants. Untargeted mass spectrometry (MS) methods used in metabolomics should theoretically allow detecting concentration changes of any endogenous urinary metabolite or presence of new biomarkers produced by chemical adulteration. As a proof of concept study, urine samples from 10 volunteers were treated with KNO2 and analyzed by high-resolution MS. For statistical data evaluation, XCMSplus and MetaboAnalyst were used. Compound identification was performed by database searches using an in-house database, Chemspider, METLIN, HMDB, and NIST. Principle component analysis revealed clear separation between treated and untreated urine samples. In detail, 307 features showed significant concentration changes with fold changes greater than 2 (79 decreased; 228 increased). Mainly amino acids (e.g., histidine, methylhistidine, di- and trimethyllysine) and purines (uric acid) were detected in lower amounts. 5-HO isourate was found to be formed as a new compound from uric acid and, e.g., imidazole lactate concentrations increased due to the breakdown of histidine. This metabolomics-based strategy allowed for a broad identification range of markers of urinary adulteration. More studies will be needed to investigate routine applicability of identified potential markers exploring urinary conditions of their formation and stability. Selected markers might then be integrated into routine MS screening procedures allowing for detection of adulteration within routine MS analysis. Graphical Abstract ?. PMID- 28815275 TI - Similar failure rate in immediate post-operative weight bearing versus protected weight bearing following meniscal repair on peripheral, vertical meniscal tears. AB - PURPOSE AND HYPOTHESIS: Post-operative weight bearing after meniscal repair is a point of debate among physicians. This study sought to evaluate whether patients adhering to an immediate WBAT rehabilitation programme have a higher failure rate compared to those adhering to a more traditional, protected, NWB status following meniscal repair. The null hypothesis was that there would be no difference in failure between the two groups. METHODS: A retrospective review of meniscal repair patients greater than 5 years from surgery was performed for patients receiving meniscal repair treatment. Patients were categorized by post-surgical weight-bearing status, either NWB or WBAT, and then analysed for failure of repair. Failure was defined as re-operation on the torn meniscus. The study controlled for variables including age at surgery, sex, height, weight, and BMI, classification of tear type, acuity of the tear, repair location (medial or lateral), repair location within the meniscus, repair technique, and concomitant procedures. RESULTS: Re-operations were performed in 61 of 157 patients [38.9%]. There was no difference between weight-bearing groups for failure of meniscus repair (n.s.). The tears were acute vertical tears located in the posterior horn and body. For the 61 patients with re-operation, the average time to re-operation was 2.2 years with 10 [16%] > 5 years from surgery, 17 [28%] 2-5 years from surgery, and 34 [56%] < 2 years from surgery. In isolated meniscal repair patients (n = 62), there was no difference between weight-bearing groups for rate of re-operation (n.s.). CONCLUSION: Weight bearing as tolerated after meniscal repair for peripheral, vertical tears does not result in a higher failure rate than traditional, non-weight bearing over a five-year follow-up period. The clinical relevance is that, based on these data, it may be appropriate to allow weight bearing as tolerated following meniscal repair of peripheral, vertical tears. LEVEL OF EVIDENCE: Retrospective cohort study, Level III. PMID- 28815276 TI - Determination of 89 drugs and other micropollutants in unfiltered wastewater and freshwater by LC-MS/MS: an alternative sample preparation approach. AB - A liquid chromatography-triple quadrupole-tandem mass spectrometry (LC-qQq-MS/MS) method was developed for simultaneous determination of 89 legal neuropsychiatric pharmaceuticals and illicit drugs (both parent compounds and metabolites) and other micropollutants in unfiltered wastewater and freshwater. The target chemicals fall under the classes of amphetamine-type stimulants, cocaine compounds, opiates and opioids, benzodiazepines, lysergic compounds, antipsychotics, anesthetics, antiepileptics, antidepressants, sympathomimetics, cannabinoids, blood thinners, antihistamines, beta-blockers, caffeine derivatives, nicotine derivatives, z-drugs, new designer drugs, and Alzheimer medications. The sample preparation procedure was designed for unfiltered wastewater and freshwater without the need to separate the particulate matter (if any) from the aqueous phase prior to extraction. Samples were pre-concentrated by rotary evaporation in the presence of a solvent. Method precision (absolute values; N = 6 replicate analyses at the fortification level of 50 ng, k = 6 days) for 87 out of 89 target analytes ranged from 2.8 to 34% (RSD %). The limits of detection ranged from 0.11 to 202 ng L-1, and the matrix effects ranged from +16 to -84%. A total of 10 samples, 8 wastewater, 1 drinking water, and 1 lake water, were collected from New York State, USA, and were analyzed for the target compounds to demonstrate the applicability of the developed method. This is the first study to report the analysis of multiple classes of pharmaceuticals, illicit drugs, and other micropollutants in unfiltered wastewater. Graphical abstract Analysis of 89 micropollutants in unfiltered wastewater by LC-MS/MS. PMID- 28815277 TI - Discontinuation rate and adverse events after 1 year of vaginal pessary use in women with pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: To ascertain the rate of discontinuation after vaginal pessary use among pelvic organ prolapse patients. METHODS: We enrolled women suffering from pelvic organ prolapse who opted to use vaginal pessary as the first line of treatment and were fitted with a pessary at the urogynecological clinic in Khon Kaen University's Srinagarind Hospital (Thailand) during the period between 2010 and 2016. Patients' medical records were retrospectively reviewed. Patients were contacted by telephone if there were missing data or if more information was required. RESULTS: One hundred and forty women were included. The median age was 71.5 years (interquartile = 65.0, 77.0) and normal vaginal parity was 4.0 (interquartile =3.0, 6.0). The mean +/- SD of BMI was 23.5+/- 3.6 kg/m2. Most of the women enrolled in the study (97.9%) were postmenopausal and many were at an advanced stage of prolapse (73.6%). Support pessaries were the most common treatment (95.0%). The discontinuation rate of pessary use after 1 year was 16.1%. The most common reason for discontinuing the vaginal pessary was frequent expulsion (26.3%). Abnormal vaginal discharge was the most common adverse effect after pessary insertion (17.1%). Lower BMI and history of hysterectomy were the significant risk factors for discontinuation of pessary use (0.76 [95%CI 0.62-0.93] and 15.89 [95%CI 1.67-151.02] respectively). CONCLUSIONS: The discontinuation rate of pessary use in the case of pelvic organ prolapse was low after 1 year. Abnormal vaginal discharge was the most common adverse side effect. Lower BMI and history of hysterectomy were factors significantly associated with the discontinuation. PMID- 28815278 TI - Phenotypic, genetic and molecular characterization of 7B-1, a conditional male sterile mutant in tomato. AB - KEY MESSAGE: We characterized the photoperiod-sensitive 7B - 1 male-sterile mutant in tomato, showing its allelism with stamenless - 2 . Mapping experiments indicated SlGLO2 , a B-class MADS-box family member, as a strong candidate to underlie the 7B - 1 mutation. The interest in male sterility (MS) dates back to a long time due to its perspective use in hybrid seed production. Here, we characterize 7B-1, a photoperiod-sensitive male-sterile (ms) mutant in tomato (Solanum lycopersicum L.), in which stamens are restored to fertility by permissive growth conditions in short days (SD). This system represents a useful strategy to facilitate the maintenance of the ms line. Examination of 7B-1 and other structural mutants, vms, sl, sl-2 and tap3, showed carpellization of stamens in the third floral whorl. 7B-1 exhibits strong expressivity in long days (LD), producing 100% aberrant anthers and virtually no seed production under open pollination, whereas it recovered fertility in SD. By genetic analysis, we demonstrate that 7B-1 is not allelic to sl nor to vms; instead it shows allelism to sl-2. Because the homeotic phenotype of the mutation resembles lesions to members of the B-class MADS-box transcription factor family, that specify petal and stamen identity, we pursued a candidate gene approach towards these targets. Using an interspecific backcross mapping population and markers linked to B-class MADS-box genes, significant linkage was found between 7B-1 and the SlGLO2 gene on Chr6. This result was supported by the 7B-1 phenotype that is similar to that of SlGLO2 knock outs and by the strong downregulation of the gene in the mutant. Although the lesion underlying the mutant phenotype is still elusive, our results pave the way for the final demonstration that SlGLO2 underlies 7B-1 and further the use of 7B-1 mutant in tomato hybrid seed production schemes. PMID- 28815279 TI - Evaluation of training dose in male Sprague-Dawley rats trained to discriminate 4 methylmethcathinone. AB - RATIONALE: Although the synthetic cathinone 4-methylmethcathinone (4-MMC, mephedrone) has been a subject of intensive research investigation, the pharmacological mechanisms involved in its interoceptive stimulus effects have yet to be fully characterized. OBJECTIVE: The present study employed drug discrimination methods in rats to compare the interoceptive stimulus properties of two different training doses of 4-MMC to other substances with similar pharmacological actions. METHODS: Sixteen male Sprague-Dawley rats were trained to discriminate either 1.0 mg/kg (N = 8) or 3.0 mg/kg (N = 8) 4-MMC from saline. Substitution tests were conducted with drugs that increase extracellular monoamine levels (d-amphetamine, (+)-methamphetamine, 4-MMC, MDMA, MDPV, and (-) cocaine), a serotonin releaser (+)-fenfluramine, and a serotonergic (5-HT2A) hallucinogen (+)-LSD. RESULTS: Stimulus control was established in fewer sessions in the subjects trained with 3.0 mg/kg compared to those trained with 1.0 mg/kg 4 MMC. Cocaine, MDMA, and d-amphetamine produced full substitution in the 1.0 mg/kg 4-MMC-trained rats at doses that did not decrease response rate. However, doses of test drugs that engendered > 80% 4-MMC-lever selection concurrently produced rate-decreasing effects in rats trained to discriminate 3.0 mg/kg 4-MMC. CONCLUSIONS: These findings further characterize the interoceptive stimulus effects of 4-MMC and indicate that these effects vary little with training dose; however, qualitative differences in substitutability of test drugs were observed between training groups. This study expands existing knowledge regarding the psychopharmacology of 4-MMC and the potential neurochemical substrates contributing to its subjective effects. PMID- 28815280 TI - Overcoming challenges in single particle inductively coupled plasma mass spectrometry measurement of silver nanoparticles. AB - Single particle ICP-MS has evolved rapidly as a quantitative method for determining nanoparticle size and number concentration at environmentally relevant exposure levels. Central to the application of spICP-MS is a commonly used, but not rigorously validated, calibration approach based on the measured transport efficiency and the response of ionic standards. In this work, we present a comprehensive and systematic study of the accuracy, precision and robustness of spICP-MS using the rigorously characterized reference material (RM) 8017 (Polyvinylpyrrolidone Coated Nominal 75 nm Silver Nanoparticles), recently issued by the National Institute of Standards and Technology (NIST). We report for the first time, statistically significant differences in frequency-based and size-based measures of transport efficiency with NIST RM 8013 Gold Nanoparticles and demonstrate that the size-based measure of transport efficiency is more robust and yields accurate results for the silver nanoparticle RM relative to TEM based reference values. This finding is significant, because the frequency-based method is more widely applied. Furthermore, we demonstrate that the use of acidified ionic standards improves measurement of ICP-MS Ag response, but does not degrade the accuracy of the results for AgNP suspensions in water or various other diluents. Approaches for controlling AgNP dissolution were investigated and are shown to effectively improve particle stability in dilute suspensions required for spICP-MS analysis, while minimally affecting the measured intensity and allowing for more robust analysis. This study is an important and necessary advancement toward full validation and adoption of spICP-MS by the broader research community. Graphical abstract Measurement challenges in spICP-MS analysis. PMID- 28815281 TI - Quantitative characterization of colloidal assembly of graphene oxide-silver nanoparticle hybrids using aerosol differential mobility-coupled mass analyses. AB - In this work, we develop an aerosol-based, time-resolved ion mobility-coupled mass characterization method to investigate colloidal assembly of graphene oxide (GO)-silver nanoparticle (AgNP) hybrid nanostructure on a quantitative basis. Transmission electron microscopy (TEM) and zeta potential (ZP) analysis were used to provide visual information and elemental-based particle size distributions, respectively. Results clearly show a successful controlled assembly of GO-AgNP by electrostatic-directed heterogeneous aggregation between GO and bovine serum albumin (BSA)-functionalized AgNP under an acidic environment. Additionally, physical size, mass, and conformation (i.e., number of AgNP per nanohybrid) of GO AgNP were shown to be proportional to the number concentration ratio of AgNP to GO (R) and the selected electrical mobility diameter. An analysis of colloidal stability of GO-AgNP indicates that the stability increased with its absolute ZP, which was dependent on R and environmental pH. The work presented here provides a proof of concept for systematically synthesizing hybrid colloidal nanomaterials through the tuning of surface chemistry in aqueous phase with the ability in quantitative characterization. Graphical Abstract Colloidal assembly of graphene oxide-silver nanoparticle hybrids characterized by aerosol differential mobility coupled mass analyses. PMID- 28815282 TI - Correction of vitamin D status by calcidiol: pharmacokinetic profile, safety, and biochemical effects on bone and mineral metabolism of daily and weekly dosage regimens. AB - RATIONALE: Calcidiol can be employed to correct vitamin D deficiency. MAIN RESULTS: Calcidiol administered at daily and weekly regimens over a period of 3 months was able to successfully raise 25-hydroxyvitamin D levels without altering other markers related to bone and mineral metabolism. SIGNIFICANCE: Calcidiol supplementation is effective and safe. INTRODUCTION: The correction of vitamin D status is necessary to maintain an optimal mineral and skeletal homeostasis. Despite cholecalciferol (vitamin D3) is the most commonly used drug for vitamin D supplementation, the more hydrophilic compound calcidiol (25-hydroxyvitamin D3) can be employed at daily, weekly, and monthly regimens to reach in the short term the target levels of serum 25-hydroxyvitamin D [25(OH)D]. In the administration of different doses of calcidiol pharmacokinetic study (ADDI-D study), the efficacy and safety of daily and weekly dosages of calcidiol were tested. METHODS: A total of 87 Caucasian, community-dwelling, postmenopausal women, aged 55 years or older, with vitamin D inadequacy (serum 25(OH)D levels <30 ng/ml, with mean 25(OH)D below 20 ng/ml, namely 16.5 +/- 7.5 ng/ml) were randomized to receive three different dosages of calcidiol: 20 MUg/day, 40 MUg/day, and 125 MUg/week for 3 months. The attained level of serum 25(OH)D was selected as primary endpoint to assess efficacy, while other parameters of mineral metabolism, (serum calcium, parathyroid hormone, phosphate, FGF23, urinary calcium, and markers of bone turnover) were assessed as secondary endpoints to establish safety. RESULTS: In all the three groups, serum 25(OH)D values significantly and promptly rose and plateaued above the 30 ng/ml threshold remaining within safety interval after 14 days of treatment, with similar efficacy for the similar daily and weekly dose regimens. The different dosages were also equally effective in controlling secondary hyperparathyroidism. No significant changes in calcium and phosphate metabolism and in bone turnover markers were observed for any of the treatments, confirming the safety of this compound. CONCLUSIONS: The results of this study demonstrate the short- and mid term efficacy and safety on core parameters of mineral metabolism of different daily or weekly dosages of calcidiol when used to treat vitamin D inadequacy or deficiency in postmenopausal women. Further studies are needed to assess falls as primary outcome of calcidiol supplementation. PMID- 28815283 TI - Risk factors for recurrence after hysterectomy plus native-tissue repair as primary treatment for genital prolapse. AB - INTRODUCTION AND HYPOTHESIS: Identification of risk factors for pelvic organ prolapse (POP) recurrence is crucial to provide adequate preoperative counselling and tailor surgical treatment. The aim of this retrospective study was to identify risk factors for recurrence in a large series of patients with POP treated with primary transvaginal native-tissue repair involving high uterosacral ligament suspension. METHODS: Postoperative descent of POP-Q stage 2 or higher in any compartment was considered as recurrence. Global recurrence (GR) was defined as any recurrence in any compartment irrespective of the surgical procedures performed during primary prolapse surgery. True recurrence (TR) was defined as recurrence in a compartment repaired during primary prolapse surgery. RESULTS: Of a total of 533 eligible women, 519 were available for follow-up. Univariate analysis showed that age <=50 years, premenopausal status, obesity (BMI >30 kg/m2), history of severe macrosomia (>4,500 g), preoperative POP stage 3 or higher and absence of anterior repair at the time of POP surgery were risk factors for GR. Multivariate analysis confirmed lack of posterior repair (odds ratio, OR, 1.8), severe macrosomia (OR 2.7), premenopausal status (OR 3.9), obesity (OR 2.2) and preoperative stage 3 or higher (OR 2.6) as risk factors for GR. Univariate analysis showed that premenopausal status and preoperative POP stage 3 or higher were risk factors for TR. Multivariate analysis confirmed premenopausal status (OR 4.0) and preoperative stage 3 or higher (OR 4.5) as risk factors for TR. CONCLUSIONS: This study confirmed preoperative stage 3 or higher as a risk factor for prolapse recurrence. The study also identified additional risk factors for surgical failure including lack of posterior repair, severe macrosomia, premenopausal status and obesity. PMID- 28815284 TI - Analysis of lipophilic marine biotoxins by liquid chromatography coupled with high-resolution mass spectrometry in seawater from the Catalan Coast. AB - Marine biotoxins regularly occur along the coast, with several consequences for the environment as well as the food industry. Monitoring of these compounds in seawater is required to assure the safety of marine resources for human consumption, providing a means for forecasting shellfish contamination events. In this study, an analytical method was developed for the detection of ten lipophilic marine biotoxins in seawater: azaspiracids 1, 2, 3, 4 and 5, classified as azaspiracid shellfish poisoning toxins, and pectenotoxin 2, okadaic acid and the related dinophysistoxin 1, yessotoxin and homoyessotoxin, classified as diarrheic shellfish poisoning toxins. The method is based on the application of solid-liquid ultrasound-assisted extraction and solid-phase extraction, followed by high-performance liquid chromatography coupled with high-resolution mass spectrometry. The limits of detection of this method are in the range of nanograms per litre and picograms per litre for most of the compounds, and recoveries range from 20.5% to 97.2%. To validate the effectiveness of this method, 36 samples of surface water from open coastal areas and marinas located along the Catalan coast on the Mediterranean Sea were collected and analysed. Eighty-eight per cent of these samples exhibited okadaic acid in particulate and aqueous phases in concentrations ranging from 0.11 to 560 MUg/g and from 2.1 to 1780 ng/L respectively. Samples from open coastal areas exhibited higher concentrations of okadaic acid in particulate material, whereas in samples collected in sportive ports, the particulate material exhibited lower levels than the aqueous phase. Graphical Abstract Biotoxins investigated in seawater of the Catalan coast. PMID- 28815288 TI - Interview with Prof. Pia Sundgren, President of the 40th Annual Meeting of the ESNR, Malmo; 13th-17th of September 2017. PMID- 28815285 TI - Aggressive haematological malignancies. PMID- 28815289 TI - [Aggressive primary cutaneous B-cell lymphomas and novel EBV+ entities]. AB - Primary cutaneous large B-cell lymphomas (PCBLT), EBV-positive large B-cell lymphomas, not otherwise specified (EBV+ DLBCL, NOS), and primary cutaneous intravascular large B-cell lymphomas (PCIVLBL) are recognized as cutaneous lymphomas with intermediate to poor prognosis. Differentiation from indolent B cell lymphomas or other pathologies of the skin can be complex, both clinically and histologically, but vital for the outcome of the patient. The combination of immunotherapy and polychemotherapy regimens, such as R-CHOP, has led to significant improvements in prognosis, especially in diffuse large B-cell lymphomas. Therapeutic decisions need to be individually made for each patient, ideally within an interdisciplinary tumor conference. Immunosenescence may be an important factor in the pathogenesis of EBV+ DLBCL, NOS in elderly individuals. Their prognosis is less favorable than that of patients with EBV-negative PCBLT, whereby this has been observed particularly in elderly patients. One third of patients with PCIVLBL progress to systemic disease. The occurrence of nodal manifestation is rarely observed. Symptoms may vary depending on the organ system involved. Currently there are no evidence-based therapy recommendations due to the rarity of the disease. EBV-positive mucocutaneous ulcer is a new provisional category in the current WHO classification for lymphoid neoplasms. It has been segregated from EBV+ DLBCL, NOS due to its self-limiting course and good response to conservative therapy. PMID- 28815291 TI - Prognostic value of atherosclerotic burden and coronary vascular function in patients with suspected coronary artery disease. AB - PURPOSE: To evaluate the prognostic value of coronary atherosclerotic burden, assessed by coronary artery calcium (CAC) score, and coronary vascular function, assessed by coronary flow reserve (CFR) in patients with suspected coronary artery disease (CAD). METHODS: We studied 436 patients undergoing hybrid 82Rb positron emission tomography/computed tomography imaging. CAC score was measured according to the Agatston method, and patients were categorized into three groups (0, <400, and >=400). CFR was calculated as the ratio of hyperemic to baseline myocardial blood flow, and it was considered reduced when <2. RESULTS: Follow-up was 94% complete during a mean period of 47+/-15 months. During follow-up, 17 events occurred (4% cumulative event rate). Event-free survival decreased with worsening of CAC score category (p < 0.001) and in patients with reduced CFR (p < 0.005). At multivariable analysis, CAC score >=400 (p < 0.01) and CFR (p < 0.005) were independent predictors of events. Including CFR in the prognostic model, continuous net reclassification improvement was 0.51 (0.14 in patients with events and 0.37 in those without). At classification and regression tree analysis, the initial split was on CAC score. For patients with a CAC score < 400, no further split was performed, while patients with a CAC score >=400 were further stratified by CFR values. Decision curve analyses indicate that the model including CFR resulted in a higher net benefit across a wide range of decision threshold probabilities. CONCLUSIONS: In patients with suspected CAD, CFR provides significant incremental risk stratification over established cardiac risk factors and CAC score for prediction of adverse cardiac events. PMID- 28815292 TI - Concentrations and Exposure Evaluation of Metals in Diverse Food Items from Chengdu, China. AB - A total of 520 food samples belonging to 29 food types and 63 drinking water were collected in Chengdu market of China in 2014 to investigate the concentrations of 11 metals, and to assess the related exposure to the local consumers by estimating the hazard quotient and carcinogenic risk (CR). The results showed that metals concentrations in drinking water were below the limit values suggested by the Ministry of Health of the People's Republic of China, and FAO/WHO (Food and Agriculture Organization of the United Nations/World Health Organization). While As, Cd, and Cr were found at concentrations higher than the limit values in some of the foodstuffs. Children in Chengdu intake more metals compared to adults, with the same order of Mn > Zn > Cu > Sr > Cr > Ni > As > Cd > Pb > Co > Sb. Among all of the diverse food, rice, flour, and fish and seafood were the primary sources to intake metals for Chengdu residents. Residents in Chengdu are subjected to both carcinogenic and non-carcinogenic risks based on the calculated HI and CR values, especially for children. Finally, total daily metals intakes for both children and adults were calculated based on the current study and our previous studies, including consumption of food and drinking water and intake of outdoor and indoor dust. Dietary exposure is the predominant exposure route to metals for Chengdu residents, accounting for more than 75.8% of the total daily metals intakes for both children and adults. PMID- 28815293 TI - The novel preventive effect of Daikenchuto (TJ-100), a Japanese herbal drug, against neonatal necrotizing enterocolitis in rats. AB - PURPOSE: Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease of premature infants. Daikenchuto, a Japanese herbal drug, has several effects on the digestive system, so we investigated its preventive effects in a rat model of NEC. METHODS: NEC was induced in newborn rats via asphyxia (100% N2 for 90 s; every 4 h) + LPS (4 mg/kg/day [administered orally on days 0 and 1]). The effects of Daikenchuto were evaluated in four groups (control: 0 g/kg/day, I: 0.3 g/kg/day, II: 0.6 g/kg/day, and III: 1.0 g/kg/day). Daikenchuto was administered into the stomach through a microcatheter. The incidence and severity of NEC were pathologically assessed using the NEC grade in accordance with Dovorak's previous report. Cell positivity for inflammatory cytokine (IL-6) was also evaluated. RESULTS: Daikenchuto reduced the incidence of NEC in control, Groups I, II, and III to 68.7, 30.0, 30.7, and 13.3%, respectively. High-dose Daikenchuto significantly improved the incidence of NEC, and the rate of IL-6 positive cells in group III was significantly lower than in the control group (p = 0.04). CONCLUSION: We evaluated the effect of Daikenchuto against NEC and found that it reduced the incidence rate of NEC due to a decrease in the IL-6 production. PMID- 28815294 TI - Diallyl trisulfide inhibits proliferation, invasion and angiogenesis of glioma cells by inactivating Wnt/beta-catenin signaling. AB - Aberrant activation of Wnt/beta-catenin signaling leads to increased cell proliferation and survival and promotes the development of various human tumors, including glioma, one of the most common primary brain tumors. The treatment efficacy of many anticancer drugs remains limited or unsatisfactory and it is urgently necessary to develop effective and low-toxicity anticancer drugs or strategies, especially for glioma. Here, we report that diallyl trisulfide suppresses survival, migration, invasion and angiogenesis in glioma cells. These effects were associated with inhibition of the Wnt/beta-catenin signaling cascade, which was accompanied by decreased expression of LRP6, TRIM29 and Pygo2. A dual-luciferase reporter assay confirmed that DATS treatment decreased TCF/LEF mediated transcription. Finally, a nude mouse tumorigenicity model was used to examine the biological effect of diallyl trisulfide in vivo. Consistent with the previous results, diallyl trisulfide inhibited proliferation, invasion and angiogenesis in glioma cells by suppressing Wnt/beta-catenin signaling. PMID- 28815295 TI - Loss of Kirrel family members alters glomerular structure and synapse numbers in the accessory olfactory bulb. AB - The accessory olfactory system controls social and sexual behaviours in mice, both of which are critical for their survival. Vomeronasal sensory neuron (VSN) axons form synapses with mitral cell dendrites in glomeruli of the accessory olfactory bulb (AOB). Axons of VSNs expressing the same vomeronasal receptor (VR) converge into multiple glomeruli within spatially conserved regions of the AOB. Here, we have examined the role of the cell adhesion molecule Kirrel2 in the formation of glomeruli within the AOB. We find that Kirrel2 expression is dispensable for early axonal guidance events, such as fasciculation of the vomeronasal tract and segregation of apical and basal VSN axons into the anterior and posterior regions of the AOB, but is necessary for glomeruli formation. Specific ablation of Kirrel2 expression in VSN axons results in the disorganization of the glomerular layer of the posterior AOB and in the formation of fewer and larger glomeruli. Furthermore, simultaneous ablation of Kirrel2 and Kirrel3 expression leads to a loss of morphologically identifiable glomeruli in the AOB, reduced excitatory synapse numbers, and larger presynaptic terminals. Taken together, our results demonstrate that Kirrel2 and Kirrel3 are essential for the formation of glomeruli and suggest they contribute to synaptogenesis in the AOB. PMID- 28815297 TI - Leukocyte-reduced platelet-rich plasma increases proliferation of tenocytes treated with prednisolone: a cell cycle analysis. AB - INTRODUCTION: The purpose of this study was to evaluate the effect of allogenic leukocyte-reduced platelet-rich plasma on human tenocytes after treatment with prednisolone and to develop a standardization of its application for clinical practice. METHODS: A leukocyte-reduced PRP was produced using the Arthrex Double Syringe (Arthrex, Inc., Naples, FL, USA), in a modified single-spin separation method. Human tenocytes were isolated from discarded rotator cuff segments. Tenocytes were cultured in the presence of PRP and prednisolone, both alone and in combination. Control samples were treated in media containing 2% FCS for 72 h. After 72 h of incubation, cell cycle kinetics of tenocytes were analyzed to assess proliferation. RESULTS: Incubation of the tenocytes with PRP alone for 48 h led to high proliferation rate (10% PRP, 28.0 +/- 10.5%; 20% PRP, 40.9 +/- 3.3%). Incubation in the presence of prednisolone led to a significant decrease of the proliferation rate (5.2 +/- 3.1%; p < 0.05). Treatment with PRP for 48 h significantly increased the proliferation of tenocytes in a dose-dependent manner (10% PRP, 28.0 +/- 10.5%; 20% PRP, 40.9 +/- 3.3%; p < 0.05). The presence of prednisolone resulted in a decreased tenocyte proliferation (5.2 +/- 3.1%; p < 0.05), whereas addition of PRP for 24 and 48 h after prednisolone exposure did not show any compensating effect independent of PRPs concentration (10% PRP, 3.7 +/- 3.0%; 20% PRP, 2.5 +/- 2.5%). However, a significantly increased cell proliferation of tenocytes was evident when PRP was applied 24 h after prednisolone incubation for 48 h (31.0 +/- 3.4 and 34.3 +/- 4.7%). CONCLUSION: The use of leukocyte-reduced PRP stimulates the proliferation of tenocytes and antagonizes the negative effect of prednisolone 24 h after treatment. Addition of PRP 48 h after treatment with prednisolone has no positive effect on the proliferation rate of tenocytes. PMID- 28815296 TI - Autoantibodies against "rods and rings"-related IMPDH2 in hepatitis C genotype 1 and DAA therapy in a "real life" cohort. AB - Autoantibodies against inosine-5'-monophosphate-dehydrogenase-2 (IMPDH2; "rods and rings" pattern) develop in chronic hepatitis C (CHC) patients under treatment with peg-interferon (IFN) and ribavirin (RBV), an inhibitor of IMPDH2. We investigated the influence of the alternative therapy with direct-acting antivirals (DAA)/ribavirin on anti-IMPDH2 autoantibody generation and the use of anti-IMPDH2 development as a marker for therapy outcome (sustained virologic response, SVR). We analyzed a "real life" cohort of 104 unselected CHC genotype 1 (GT1) patients treated with IFN/first-generation DAA/RBV prospectively compared to a historic cohort of 59 IFN/RBV-treated CHC GT1 patients. First-generation DAA were boceprevir (BOC) or telaprevir (TPR). Serum autoantibodies were tested by indirect immunofluorescence (IFA) using recombinant IMPDH2 expressing HEK293 cells and native HEp2-cells as substrates. 64/163 (39%) CHC patients turned anti IMPDH2 positive during therapy, but only 43/163 (26%) showed also "rods and rings" structures. 99/163 (61%) were tested as anti-IMPDH2 negative. 53/104 (51%) CHC patients undergoing IFN/DAA/RBV therapy were anti-IMPDH2 positive and 38/104 (37%) were in parallel anti-"rods and rings" positive. HCV clearance/SVR rate after IFN/DAA/RBV therapy and anti-IMPDH2 status were not significantly dependent. CHC GT1 patients treated with IFN/first-generation DAA/RBV developed anti-IMPDH2 autoantibodies comparable to previous studies including patients under IFN/RBV therapy. Anti-IMPDH2 titers show no use as a marker for therapy outcome in CHC GT1 patients. PMID- 28815298 TI - The interaction of pupil response with the vergence system. AB - PURPOSE: A gaze shift from a target at distance to a target at near leads to pupillary constriction. The regulation of this pupillary near response is ill known. We investigated the impact of accommodation, convergence, and proximity on the pupillary diameter. METHODS: We recorded pupil size and vergence eye movements with the use of an infrared eye tracker. We determined the pupillary response in four conditions: (1) after a gaze shift from far to near without accommodation, (2) after a gaze shift from far to near with neither accommodation nor convergence, (3) after accommodation alone, and (4) after accommodation with convergence without a gaze shift to near. These responses were compared to the pupil response of a full near response and to a gaze shift from one far target to another. RESULTS: We found a reliable pupillary near response. The removal of both accommodation and convergence in gaze shift from far to near abolished the pupillary near response. Accommodation alone did not induce pupillary constriction, while convergence and accommodation together induced a pupil response similar to the full near response. CONCLUSIONS: The main trigger for the pupillary response seems to be convergence. Neither accommodation nor proximity alone induce a significant pupillary constriction. This suggests that the miosis of the near triad is closely coupled to the vergence system rather than being independently regulated. PMID- 28815299 TI - Morphological and phylogenetic analysis of a microsporidium (Nosema sp.) isolated from rice stem borer, Chilo suppressalis (Walker) (Lepidoptera: Pyralidae). AB - A new microsporidium was isolated from Chilo suppressalis (Walker) (Lepidoptera: Pyralidae), one of the most important rice pests in China. The morphology and molecular systematics of this novel microsporidium were described in this study. The spores were long oval and measured 3.17 * 1.64 MUm on fresh smears. Ultrastructure of the spores was characteristic for the genus Nosema: a diplokaryon, 10-12 polar filament coils of the same type, and posterior vacuole. Small subunit rRNA gene sequence data and phylogenetic analysis further confirmed that the microsporidian species from C. suppressalis belong to the true Nosema sub-group of the genus Nosema. Besides, the microsporidium Nosema sp. CS could cause systemic infection of Bombyx mori and infect silkworms through vertical transmission. Therefore, mulberry field pest control should be carefully monitored, and sanitation of mulberry leaves is essential to control the pebrine disease in sericulture. PMID- 28815301 TI - Keeping brains young with making music. AB - Music-making is a widespread leisure and professional activity that has garnered interest over the years due to its effect on brain and cognitive development and its potential as a rehabilitative and restorative therapy of brain dysfunctions. We investigated whether music-making has a potential age-protecting effect on the brain. For this, we studied anatomical magnetic resonance images obtained from three matched groups of subjects who differed in their lifetime dose of music making activities (i.e., professional musicians, amateur musicians, and non musicians). For each subject, we calculated a so-called BrainAGE score which corresponds to the discrepancy (in years) between chronological age and the "age of the brain", with negative values reflecting an age-decelerating brain and positive values an age-accelerating brain, respectively. The index of "brain age" was estimated using a machine-learning algorithm that was trained in a large independent sample to identify anatomical correlates of brain-aging. Compared to non-musicians, musicians overall had lower BrainAGE scores, with amateur musicians having the lowest scores suggesting that music-making has an age decelerating effect on the brain. Unlike the amateur musicians, the professional musicians showed a positive correlation between their BrainAGE scores and years of music-making, possibly indicating that engaging more intensely in just one otherwise enriching activity might not be as beneficial than if the activity is one of several that an amateur musician engages in. Intense music-making activities at a professional level could also lead to stress-related interferences and a less enriched environment than that of amateur musicians, possibly somewhat diminishing the otherwise positive effect of music-making. PMID- 28815302 TI - Reliability and validity of the German version of the Utrecht Questionnaire for Outcome Assessment in Aesthetic Rhinoplasty (D-OAR). AB - The outcome of aesthetic rhinoplasty is determined by the patient's subjective satisfaction with the nasal appearance which is difficult to assess. The Utrecht Questionnaire for Outcome Assessment in Aesthetic Rhinoplasty (OAR) is a brief and reliable instrument to assess the influence of the subjective nasal appearance on quality of life in patients undergoing aesthetic rhinoplasty. Preoperative application of this questionnaire reveals important aspects and possible disturbances of the body image which could be negative predictors concerning the result. On the other hand, it represents an appropriate tool to assess the postoperative outcome. The aim of this study was to determine the validity, reliability and responsiveness of the adapted German version of the OAR (D-OAR). The adaption of the OAR to German language was performed by a forward and backward translation process. Patients undergoing rhinoplasty were asked to complete the D-OAR preoperatively, 1, 3 and 12 months after procedure and healthy volunteers without any nasal complaints served as controls to test validity, reliability and responsiveness. An excellent internal consistency, a good test retest reliability and good inter-item and item-total correlations demonstrated a good reliability of the D-OAR. The convincing validity of the adapted version was proven by an excellent discriminant and a sufficient content validity. Significant differences between pre- and postoperative D-OAR scores revealed a good responsiveness of the instrument. Hence, with a sufficient validity, reliability and sensitivity to changes, the D-OAR is a short and helpful instrument to assess the subjective perception of the nasal appearance in German patients. PMID- 28815300 TI - Holaphyllamine, a steroid, is able to induce defense responses in Arabidopsis thaliana and increases resistance against bacterial infection. AB - MAIN CONCLUSION: A chemical screen of plant-derived compounds identified holaphyllamine, a steroid, able to trigger defense responses in Arabidopsis thaliana and improve resistance against the pathogenic bacterium Pseudomonas syringae pv tomato DC3000. A chemical screen of 1600 plant-derived compounds was conducted and allowed the identification of a steroid able to activate defense responses in A. thaliana at a concentration of 1 uM without altering growth. The identified compound is holaphyllamine (HPA) whose chemical structure is similar to steroid pregnanes of mammals. Our data show that HPA, which is not constitutively present in A. thaliana, is able to trigger the formation of reactive oxygen species, deposition of callose and expression of several pathogenesis-related genes of the salicylic and jasmonic acid pathways. In addition, the results show that pre-treatment of A. thaliana seedlings with HPA before infection with the pathogenic bacterium Pseudomonas syringae pv tomato DC3000 results in a significant reduction of symptoms (i.e., reduction of bacterial colonies). Using A. thaliana mutants, we have found that the activation of defense responses by HPA does not depend on BRI1/BAK1 receptor kinases. Finally, a structure/function study reveals that the minimal structure required for activity is a 5-pregnen-20-one steroid with an equatorial nucleophilic group in C-3. Together, these findings demonstrate that HPA can activate defense responses that lead to improved resistance against bacterial infection in A. thaliana. PMID- 28815303 TI - Effect of barley supplementation on the fecal microbiota, caecal biochemistry, and key biomarkers of obesity and inflammation in obese db/db mice. AB - PURPOSE: Barley is a low-glycemic index grain that can help diabetic and obese patients. The effect of barley intake depends on the host and the associated gut microbiota. This study investigated the effect of barley intake on the fecal microbiota, caecal biochemistry, and key biomarkers of obesity and inflammation. METHODS: Obese db/db mice were fed diets with and without barley during 8 weeks; lean mice were used as lean controls. Fecal microbiota was evaluated using 16S marker gene sequencing in a MiSeq instrument; several markers of caecal biochemistry, obesity, and inflammation were also evaluated using standard techniques. RESULTS: Bacterial richness (i.e., Operational Taxonomic Units) and Shannon diversity indexes were similar in all obese mice (with and without barley) and higher compared to lean controls. Barley intake was associated with increased abundances of Prevotella, Lactobacillus, and the fiber-degraders S24-7 (Candidatus Homeothermaceae) compared to both lean and obese controls. The analysis of unweighted UniFrac distances showed a separate clustering of samples for each experimental group, suggesting that consumption of barley contributed to a phylogenetically unique microbiota distinct from both obese and lean controls. Caecal butyrate concentrations were similar in all obese mice, while succinic acid was lower in the barley group compared to obese controls. Barley intake was also associated with lower plasma insulin and resistin levels compared to obese controls. CONCLUSIONS: This study shows that barley intake is associated with a different fecal microbiota, caecal biochemistry, and obesity biomarkers in db/db mice that tend to be more similar to lean controls. PMID- 28815304 TI - Reduced histone H3 K27 trimethylation is encountered in about 50% of atypical teratoid/rhabdoid tumors (AT/RT) but is not associated with molecular subgroup status and outcome. PMID- 28815305 TI - Predictors of early mortality after rabbit antithymocyte globulin as first-line treatment in severe aplastic anemia. AB - Despite being recommended as first-line immunosuppressive therapy in severe aplastic anemia (SAA), horse antithymocyte globulin (ATG) is still unavailable in many countries outside the USA. Rabbit ATG is more lymphocytoxic than horse ATG, and this might result in a higher incidence of severe infections and early mortality. This study was designed to identify the risk factors for early mortality and overall survival (OS) after rabbit ATG in patients with SAA. We retrospectively reviewed 185 patients with SAA who underwent rabbit ATG and cyclosporine. The incidence of death in 3 months following rabbit ATG therapy was 15.1% (28/185). Early mortality was mainly related to infectious complications, despite adequate antibiotic and/or antifungal treatment. Age > 35 years (odds ratio [OR] 5.06, P = 0.001) and baseline absolute neutrophil count (ANC) <= 0.1 * 109/L (OR 7.64, P < 0.001) were independent risk factors for early mortality after immunosuppressive therapy with this agent. Hematological response at 6 months was observed in only 29.7% of all patients. OS at 1 year after rabbit ATG was 75.3%; and age > 35 years (OR 1.88, P = 0.03), baseline ANC <= 0.1 * 109/L (OR 2.65, P < 0.001), and lack of response to rabbit ATG (OR 11.40, P < 0.001) were independently associated with mortality. Alternative strategies are needed for the treatment of SAA patients in countries were horse ATG is unavailable, particularly for those at high risk for early mortality after rabbit ATG due to a higher age and very low pre-treatment neutrophil count. PMID- 28815306 TI - The effect of helmet materials and simulated bone and tissue layers on bullet behaviour in a gelatine model of overmatch penetrating head injury. AB - The aim of this work was to simulate an overmatch ballistic event against a head wearing a helmet. The experiments were designed to understand how layers of bone (or synthetic bone), synthetic skin and currently used helmet materials influence the behaviour of full metal jacket mild steel core (FMJ MSC) 7.62 * 39 mm bullets, impacting on targets with a mean velocity of 650 m/s. Bullet behaviour within 10% (by mass) gelatine blocks was assessed by measurements made of the temporary cavity within the blocks using high-speed video and of the permanent cavity by dissecting blocks post firing. While ANOVA did not find significant difference at the 0.05 level in the mean values of most of the measurements, there was a significant difference in neck length within the gelatine blocks. The addition of material layers did produce greater variability in the temporary cavity measurements under some of the conditions. One of the synthetic bone polymers with a synthetic skin layer produced similar results within the gelatine blocks to the horse scapulae (with residual tissue) and may be suitable for future ballistic experiments. PMID- 28815307 TI - Clinical outcomes after local anesthesia with monitored anesthesia care during thyroidectomy and selective neck dissection: a randomized study. AB - Although thyroidectomy under local anesthesia with monitored anesthesia care (LA MAC) has been reported, reports of neck dissections beyond level VI under LA-MAC in patients with thyroid cancer are rare. We aimed to analyze clinical data and patient satisfaction levels during thyroidectomy and selective neck dissection by comparing LA-MAC and general anesthesia (GA) in adult patients undergoing these surgeries for thyroid cancer. The 60 enrolled patients comprised 50 patients that underwent thyroidectomy and 10 that underwent selective neck dissection; 30 underwent thyroidectomy (n = 25) or selective neck dissection (n = 5) under LA MAC and 30 (matched patients) underwent thyroidectomy (n = 25) or selective neck dissection (n = 5) under GA. Complaints of postoperative nausea, vomiting, throat discomfort, and voice changes were significantly fewer in the LA-MAC group than in the GA group. Postoperative pain, odynophagia, dyspnea, and patient satisfaction levels were not significantly different between groups. In the thyroidectomy group, postoperative nausea, vomiting, throat discomfort, and voice changes were less common with LA-MAC, whereas postoperative pain, odynophagia, dyspnea, and patient satisfaction levels were similar for both anesthesia methods. The selective neck dissection group showed no differences between the two anesthesia methods. No postoperative complications were reported in all patients. Our results suggest that LA-MAC can be routinely used for select cases of thyroidectomy and is feasible for selective neck dissection beyond level VI with regard to postoperative discomfort, patient satisfaction levels, and safety. However, further investigations are necessary to clarify these findings. PMID- 28815308 TI - Patient reported pain-related outcome measures after tonsil surgery: an analysis of 32,225 children from the National Tonsil Surgery Register in Sweden 2009-2016. AB - The objective of this study was to describe factors affecting pain after pediatric tonsil surgery, using patient reported pain-related outcome measures (pain-PROMs) from the National Tonsil Surgery Register in Sweden. In total, 32,225 tonsil surgeries on children (1 to <18 years) during 2009-2016 were included; 13,904 tonsillectomies with or without adenoidectomy (TE +/- A), and 18,321 tonsillotomies with or without adenoidectomy (TT +/- A). Adjustments were made for variables included in the register to compensate for contributable factors in the analysis. When compared to TE +/- A for surgical indication obstruction, TT +/- A resulted in lower pain-PROMs, shorter use of postoperative analgesics, earlier return to regular food intake, and lower risk for contact with health care services due to pain. Children who underwent TE +/- A because of obstruction problems stopped taking painkillers and returned to normal eating habits sooner, compared to children who underwent TE +/- A for infectious indications. In both indication groups, TE +/- A performed with hot rather than cold technique (dissection and haemostasis) generally resulted in higher pain PROMs. Older children reported more days on analgesics and a later return to regular food intake after TE +/- A than younger ones. No clinically relevant difference between sexes was found. Between 2012 and 2016 (pre-and post implementation of Swedish national guidelines for pain treatment), the mean duration of postoperative analgesic use had increased. In conclusion, TE +/- A caused considerably higher ratings of pain-related outcome measures, compared to TT +/- A. For TE +/- A, cold surgical techniques (dissection and haemostasis) were superior to hot techniques in terms of pain-PROMs. Older children reported higher pain-PROMs after TE +/- A than younger ones. PMID- 28815309 TI - Elimination of medically intractable epileptic drop attacks following endoscopic total corpus callosotomy in Rett syndrome. AB - INTRODUCTION: Rett syndrome is a neurodevelopmental genetic disorder, characterized by developmental delay, hand stereotypies, abnormal gait, and acquired microcephaly. Epilepsy is very common in Rett syndrome and can be medically intractable. It remains uncertain if a patient with epileptic drop attacks associated with this genetic disease can benefit from corpus callosotomy. CASE REPORT: We report an 8-year-old girl with Rett syndrome and medically intractable epileptic drop attacks who underwent endoscopic total corpus callosotomy without any complications that led to the successful elimination of her seizures. CONCLUSION: Total corpus callosotomy is a feasible treatment option for medically intractable epileptic drop attacks in Rett syndrome and should not be considered as a contraindication in this condition. This is the first reported case of corpus callosotomy in Rett syndrome. PMID- 28815310 TI - Innovation in neurosurgery. PMID- 28815311 TI - [Acute complications of vascular anomalies in childhood]. AB - Congenital and acquired vascular anomalies are common in childhood. In addition to predominantly harmless vascular skin alterations there are others which must be immediately treated due to the potentially threatening complications. As examples three anomalies and the typical complications are presented. Hemangiomas in infancy can make urgent treatment necessary because they can be complicated by obstruction or painful ulceration. Kaposiform hemangioendothelioma can lead to a life-threatening consumption coagulopathy. Klippel-Trenaunay syndrome can be complicated by thrombosis, localized coagulopathy, and superinfections. PMID- 28815312 TI - Trilateral retinoblastoma: A systematic review of 211 cases. AB - We conducted a systematic review of 72 studies to characterize trilateral retinoblastomas. Kaplan-Meier analysis was used to estimate survival, and statistical significance was assessed by using a log-rank test. We analyzed 211 cases of trilateral retinoblastomas. The average age of onset of retinoblastoma was 0.79 +/- 1.38 years, and the average latency period between the onset of retinoblastomas and trilateral retinoblastomas was 1.49 +/- 1.76 years. The brain tumors were found before the retinoblastoma diagnosis in 6 cases (3.1%), concurrently in 61 cases (32.1%), and after the retinoblastoma diagnosis in 123 cases (64.7%). Pineal tumors were found in 155 cases (73.4%) and sellar tumors in 46 cases (21.8%). The overall median survival was 10.3 months (95% CI, 8.5-13) and the 5-year survival rate was 15.7%. Central nervous system symptoms were variable and associated with shorter survival in univariate and multivariate analyses. The survival time in patients who received high-dose chemotherapy with stem cell transplant was significantly longer (p = 0.0067) than that of with or without conventional chemotherapy. Twelve long-term survivors were reported, and of these, six patients were treated with high-dose chemotherapy with stem cell transplant and six patients were treated with conventional chemotherapy. It is important that survivors continue to undergo regular medical surveillance in order to detect trilateral retinoblastoma at a potentially curative stage. Trilateral retinoblastoma patients with an irradiation history had shorter survival than those without irradiation history for retinoblastoma. High-dose chemotherapy should be considered as a potential treatment option for trilateral retinoblastomas. PMID- 28815313 TI - Epidemiology and cerebrovascular events related to cervical and intracranial arteries dissection: the experience of the city of Pisa. AB - Spontaneous dissection of cervical arteries (sCAD) is a major cause of ischemic stroke in young patients, with an incidence varying from 1.7 to 3/100,000/year for extracranial internal carotid artery (ICAD) and 1 to 1.9/100,000/year for extracranial vertebral artery (VAD). Reliable epidemiological data on stroke incidence related to sCAD are scarce in Italy. This study aims to evaluate the incidence, clinical features, and outcome of cerebrovascular events related to sCAD and spontaneous intracranial arteries dissections (sIAD) in the city of Pisa (Italy). We retrospectively analyzed consecutive patients admitted between December 1997 and June 2015 with a diagnosis of stroke, TIA, or Bernard-Horner syndrome due to acute cervical or intracranial artery dissection. Considering that our hospital collects presumptively all patients hospitalized with sCAD coming from the referral geographical area, data may provide a good approximation to real incidence of sCAD in our population. Clinical and radiological features, acute treatment and outcome were collected. Seventy-seven cases were included (mean age 48.1+/-10.4 years, range 23-77,72.7% males), 66 residents in the district of Pisa. Crude incidence rate of cerebrovascular events due to intra or extracranial dissection was 1.88/100,000/year. The incidence of ICAD was 0.80/100,000/year and 0.43/100,000/year for VAD. Stroke occurred in 76.6% of patients. VAD was more prone to cause ischemic stroke and present with cervical pain or focal signs (p < 0.01) than ICAD group, which had older age at onset. sIAD were more frequent in the posterior circle (p = 0.01) and more associated with ischemic lesions. A good outcome (mRS 0-2) was observed in 79% of patients. This is the first epidemiological attempt to investigate impact of sCAD and sIAD in Italy. PMID- 28815314 TI - A Comparative Study on Macro- and Microelement Bioaccumulation Properties of Leaves and Bark of Quercus petraea and Pinus sylvestris. AB - Trees are widely used for biomonitoring and filtering air in industrial, urban, and rural areas. This research was undertaken to examine accumulation capacities of macroelements (Ca, K, Mg, Na) and trace metals (As, Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, Zn) in needles and bark of Pinus sylvestris and leaves and bark of Quercus petraea growing in the vicinity of the chlor-alkali plant PCC Rokita in Brzeg Dolny (Lower Silesia, SW Poland). Because Scots pine is well studied and considered a useful bioindicator, we have used this species as a base for comparison of the accumulation ability of sessile oak that shows some features of good bioindicator, but whose biogeochemistry was scarcely studied. Results showed that for both species leaves contained more macroelements (Ca, K, Mg), whereas the bark was richer in most trace metals (Cd, Cr, Cu, Fe, and Pb). However, trees studied differed with respect to element content. Oak bark and leaves were more effective in accumulating macro- and trace elements (bark Cd, Co, Cr, Cu, K, Mg, Mn, Na, Ni, Pb and leaves Ca, Cr, Cu, Fe, K, Mg, Na, Ni) than Scots pine tissues. Nevertheless, foliar metal accumulation index of these species was similar, suggesting that their overall ability to accumulate trace metals was similar. PMID- 28815317 TI - Comparison of USDA Forest Service and Stakeholder Motivations and Experiences in Collaborative Federal Forest Governance in the Western United States. AB - In the United States, over 191 million acres of land is managed by the United States Department of Agriculture Forest Service, a federal government agency. In several western U.S. states, organized collaborative groups have become a de facto governance approach to providing sustained input on management decisions on much public land. This is most extensive in Oregon, where at least 25 "forest collaboratives" currently exist. This affords excellent opportunities for studies of many common themes in collaborative governance, including trust, shared values, and perceptions of success. We undertook a statewide survey of participants in Oregon forest collaboratives to examine differences in motivations, perceptions of success, and satisfaction among Forest Service participants ("agency participants"), who made up 31% of the sample, and other respondents ("non-agency") who represent nonfederal agencies, interest groups, citizens, and non-governmental groups. We found that agency participants differed from non-agency participants. They typically had higher annual incomes, and were primarily motivated to participate to build trust. However, a majority of all respondents were similar in not indicating any other social or economic motivations as their primary reason for collaborating. A majority also reported satisfaction with their collaborative-despite not ranking collaborative performance on a number of specific potential outcomes highly. Together, this suggests that collaboration in Oregon is currently perceived as successful despite not achieving many specific outcomes. Yet there were significant differences in socioeconomic status and motivation that could affect the ability of agency and nonagency participants to develop and achieve mutually-desired goals. PMID- 28815316 TI - Health-related quality of life associated with regorafenib treatment in refractory advanced gastric adenocarcinoma. AB - BACKGROUND: The INTEGRATE phase II multinational randomized controlled trial demonstrated the activity of regorafenib on progression-free survival (PFS) in patients with refractory advanced gastric adenocarcinoma. We sought to evaluate whether these PFS gains had the potential to be offset by quality of life (QoL) impacts from treatment side effects and to thereby determine the appropriateness of continuing development to phase III. METHODS: QoL was assessed in INTEGRATE at baseline and at each 4 weeks thereafter, until discontinuation of study treatment, using the QLQ-C30, STO22, and EQ-5D questionnaires. The patient disease and treatment assessment (PTDATA) form was also provided to English speaking participants. Randomized groups were compared on the QLQ-C30, STO22, and EQ-5D scales using a repeated-measures model; the frequency of troublesome symptoms and side effects measured by the PTDATA form; and deterioration-free survival (DFS). The prognostic value of baseline QoL information was also evaluated. RESULTS: Of the 147 eligible randomized patients, 142 consented to participate in the QoL substudy, 136 completed a baseline QoL assessment, and 95 completed at least one post-baseline QoL assessment. The DFS rate was significantly improved with regorafenib, and there was no compelling statistical evidence that regorafenib had a broad negative effect across the spectrum of QoL indices evaluated. Fatigue, anxiety, appetite loss, and pain were among the issues most commonly reported for both randomized groups. Baseline levels of pain, appetite, constipation, and physical functioning were prognostic factors for survival. CONCLUSIONS: Regorafenib improved DFS without an excessively negative effect on QoL. Progressing development to the phase III setting is warranted. PMID- 28815318 TI - [Adrenal crisis]. AB - Patients with chronic adrenal insufficiency suffer from reduced quality of life and increased mortality. An association between mortality and adrenal crisis is assumed. The frequency of adrenal crisis is about 8/100 patient years. The main causes are infectious disease. Pathophysiology is poorly understood to date. An association with an exaggerated inflammatory response due to a lack of glucocorticoid modulation as well as mineralocorticoid deficiency and diminished adrenomedullary function are discussed. The therapy of adrenal crisis includes prompt parenteral administration of hydrocortisone combined with isotonic saline. To prevent adrenal crisis, patients are equipped with an emergency card and set and educated in glucocorticoid dose adjustment. PMID- 28815319 TI - Anemia as a risk factor for all-cause mortality: obscure synergic effect of chronic kidney disease. AB - BACKGROUND: Anemia is common in chronic kidney disease (CKD) and may be associated with mortality in CKD patients. However, few studies have examined this relationship in Asian populations. METHODS: A total of 62,931 Japanese people (age 64.0 +/- 8.0 years; men 38.5%) were followed up from 2008 to 2012. Participants were divided into six groups in accordance with their estimated glomerular filtration rate (eGFR) (<45, 45-59, >=60 mL/min/1.73 m2) and by hemoglobin levels (13.0 g/dL for men; 12.0 g/dL for women). Hazard ratio and confidence interval (CI) for mortality with a combination of eGFR and anemia were calculated. After matching using propensity score (PS) for anemia, survival analysis between anemic and non-anemic people, independent from some variables, including eGFR, was performed. RESULTS: A total of 828 (1.3%) participants died (non-anemic vs. anemic, 1.2 vs. 2.3%, p < 0.01). Multivariable Cox analysis showed that, independent of eGFR levels, anemic people had significantly higher mortality. Anemic people were found to have significantly poorer survival than non-anemic people as per a log-rank test (p < 0.01) for the PS-matching cohort. Further stratified logistic analysis using PS in the overall cohort odds ratio (95% CI) showed 2.25 (1.89-2.67) with p < 0.01. CONCLUSION: The results of the present study showed that anemia was an independent risk factor of all-cause mortality. PMID- 28815320 TI - Inhibitory growth evaluation and apoptosis induction in MCF-7 cancer cells by new 5-aryl-2-butylthio-1,3,4-oxadiazole derivatives. AB - BACKGROUND: Cancer has become one of the global health issues and it is the life threatening disease characterized by unrestrained growth of cells. Despite various advances being adopted by chemotherapeutic management, the use of the current anticancer drugs such as Doxorubicin, Asparginase, Methotrexate, Vincristine remains limited due to high toxicity, side effects and developing drug resistance. Apoptosis is a crucial cellular process and improper regulation of apoptotic signaling pathways may lead to cancer formation. Subsequently, the synthesis of effective chemotherapeutic agents that can induce apoptosis in tumor cell has emerged as a significant approach in cancer drug discovery. METHODS: The goal of this work is to develop a potential antitumor agent exerting significant inhibitory effects on cancer cell and low cytotoxicity, for which we focused on the structural features of 1,3,4-oxadiazoles as it a privileged scaffold in modern medicinal chemistry and have the ability to inhibit growth factors, enzymes and kinases potentially involved in the attainment of cellular immortality and carcinogenesis. RESULT: In vitro MTT screening assay showed the compound 5-aminophenyl-2-butylthio-1,3,4-oxadiazole (5e) showing the highest inhibitory effect against MCF-7 cancer cell with IC50 value 10.05 +/- 1.08 uM while it is much safer and less toxic on normal cell line (HEK-293). The dose dependent treatment of MCF-7 cells with 5e resulted in inhibition of cell migration in the wound healing assay. The flow-cytometry analysis showed the cells arrested in G0/G1 phase of the cell cycle. Compound 5e induced apoptosis of MCF-7 cells was characterized using DAPI staining and Annexin V-PE/7-AAD dual binding assay. Reduction of NBT by compound 5e showed a reduced generation of ROS. Western blotting studies showed high activation of apoptotic protein Caspase3 and decrease in expression of anti-apoptotic protein BCL-2. CONCLUSION: Based on the results of in vitro studies, it could be concluded that compound 5e showed a significant inhibitory growth effect on MCF-7 cells and have the potential to be developed as lead molecule and further structural modifications may result in promising new anticancer agents. PMID- 28815315 TI - Emerging Gene Therapies for Genetic Hearing Loss. AB - Gene therapy, or the treatment of human disease using genetic material, for inner ear dysfunction is coming of age. Recent progress in developing gene therapy treatments for genetic hearing loss has demonstrated tantalizing proof-of principle in animal models. While successful translation of this progress into treatments for humans awaits, there is growing interest from patients, scientists, clinicians, and industry. Nonetheless, it is clear that a number of hurdles remain, and expectations for total restoration of auditory function should remain tempered until these challenges have been overcome. Here, we review progress, prospects, and challenges for gene therapy in the inner ear. We focus on technical aspects, including routes of gene delivery to the inner ear, choice of vectors, promoters, inner ear targets, therapeutic strategies, preliminary success stories, and points to consider for translating of these successes to the clinic. PMID- 28815321 TI - Fixational eye movements in Tourette syndrome. AB - Studies of saccadic eye movements in subjects with Tourette syndrome (TS) have provided additional evidence that there is a link between TS symptoms and deficits in fronto-striato-thalamic networks. These studies revealed impaired timing and inhibition of saccades. We compared fixational eye movements, such as microsaccades and ocular drifts, in subjects with TS and healthy controls.We measured horizontal and vertical eye positions with video-oculography in 14 subjects with Tourette syndrome. We found reduced microsaccade amplitude but increased time between adjacent microsaccades (intersaccadic interval). Hence, the rate of microsaccades was reduced in subjects with TS compared to controls. Measure of ocular stability during intersaccadic intervals revealed increased drift velocity and increased variance in eye position. We hypothesize that increased activity of the direct fronto-striatal pathway and the resulting reduction in basal ganglia outflow targeting the superior colliculus fixation zone affect the rate and amplitude of microsaccades in subjects with TS. The resulting impairment in frontal eye field fixation leads to increased drifts during intersaccadic interval in subjects with TS. Possible clinical implication for these results is that fixational eye movements can be objective biological markers of TS. PMID- 28815324 TI - Alcohol and head and neck cancer. AB - In this article, we reviewed the association between alcohol drinking and head and neck cancer (HNC) and its subsites, using the available literature. Alcohol drinking is an established risk factor for HNC, and this association may be stronger among cancers of the oropharynx and hypopharynx than the oral cavity or larynx. In addition, higher alcohol consumption over a shorter period was more harmful than fewer alcohol consumption over a longer period, and the most frequently consumed alcoholic beverages in a population is likely to be associated with the highest risk of HNC in that population. The risk of HNC after >= 20 years of alcohol cessation appear to be similar to the risk among never drinkers. The interaction between genetic polymorphisms related to alcohol metabolism and alcohol drinking on the risk of HNC has been noted, and the prevalence of these genetic polymorphisms in each population should be of concern. Finally, the association between alcohol drinking and the survival of individuals with HNC remains unclear, and mortality due to competing causes should be considered in future research to evaluate this association. PMID- 28815322 TI - Headache in patients with chronic subdural hematoma: analysis in 1080 patients. AB - Headache is a major symptom in chronic subdural hematoma (CSDH) patients. However, some CSDH patients do not complain headache although the hematoma is thick with definite midline shift. This clinical study was performed to identify the mechanism of headache in CSDH patients. We compiled clinical data of 1080 surgically treated CSDH patients (711 males and 369 females), and in 54 cases, the pressure of hematoma was measured during burr hole surgery using a glass stick manometer. Headache was recognized in 22.6% of patients, while nausea or vomit suggesting increased intracranial pressure was detected in only 3.0%. Ophthalmological examination was performed in 238 patients, and papilledema was identified in only one patient (0.4%). The mean age of patients with headache (59.8 +/- 16.9 years) was significantly younger than that of those without (75.7 +/- 11.2 years) (P < 0.01). In 54 cases, the mean hematoma pressure was not significantly different between patients with (17.1 +/- 6.2 mmH2O) and without (18.4 +/- 7.2 mmH2O) headache (P > 0.10). Hematoma thickness was significantly greater in patients without headache (P < 0.01), but the ratio of midline shift to hematoma thickness was significantly greater in patients with headache (P < 0.01). In our results, the status of increased intracranial pressure was rare in CSDH patients, and high hematoma pressure was not a cause of headache. Midline shift was the most influenced factor for headache in our study, and based on the results, the authors consider that the potential cause of headache in CSDH might be stretching or twisting of the pain-sensitive meninges and meningeal arteries or veins. PMID- 28815325 TI - Stumbling Blocks at the Clinic: Experiences of Seeking HIV Treatment and Care in South Africa. AB - Prompt antiretroviral therapy (ART) initiation maximises the therapeutic and prevention benefits of a treat-all strategy for HIV therapy. Using in-depth semi structured interviews with men and women 18 years and older (N = 41), who were highly motivated and seeking treatment, this study examined salient factors that were associated with delays in treatment access and initiation. Results revealed clinic-related barriers including an onerous, inefficient multi-step process to initiate ART. Participants experienced additional delays due to difficulties accessing care (e.g., being turned away from clinics and referred elsewhere) and health service challenges. Health service challenges included difficulty securing appointments, administrative mistakes (especially lost clinic folders and test results), difficulty navigating the clinic system (e.g., failure to collect a queue card or waiting for incorrect services) and negative clinic-patient interactions. Overall, there was a pervasive negative perception of clinics. Results strongly indicate the need for more patient-centred models of care and the need to reduce unnecessary patient-days at clinics. PMID- 28815326 TI - A cross-sectional study on late taste disorders in survivors of allogeneic hematopoietic cell transplantation. AB - Taste disorders are one of the most common complications in patients undergoing allogeneic hematopoietic cell transplantation (HCT). They persist in some patients as a late complication 3 months or more after HCT. Therefore, we conducted a cross-sectional study to evaluate the prevalence and predictive factors of late taste disorders, with the help of a self-reporting and closed ended questionnaire, which was distributed among 91 patients in our institute. The median age at this study was 50 (range, 25-69) years. The median follow-up period was 54 (range, 3-234) months after HCT. Taste disorders were observed in 43 patients (47%). The most frequent form of late taste disorders was reduced appetite in 18 patients (20%). The most frequent form of decline of basic taste was umami, which was observed in 12 patients (13%). Almost all taste disorders were mild in their severity. Multivariate logistic regression analyses showed that the duration of less than 1 year post HCT and the presence of oral chronic graft-versus-host disease are important risk factors for late taste disorders in survivors of HCT. These data suggested that taste disorders usually return to normal levels more than a year after HCT in most recipients. PMID- 28815327 TI - Molecular characterization and heterogeneity of circulating tumor cells in breast cancer. AB - INTRODUCTION: This study analyzes peripheral blood samples from breast cancer (BC) patients. CTCs from peripheral blood were enriched by size-based separation and were then cultivated in vitro. The primary aim of this study was to demonstrate the antigen independent CTC separation method with high CTC recovery. Subsequently, CTCs enriched several times during the treatment were characterized molecularly. METHODS: Patients with different stages of BC (N = 167) were included into the study. All patients were candidates for surgery, surgical diagnostics, or were undergoing chemotherapy. In parallel, 20 patients were monitored regularly and in addition to CTC presence, also CTC character was examined by qPCR, with special focus on HER2 and ESR status. RESULTS: CTC positivity in the cohort was 76%. There was no significant difference between the tested groups, but the highest CTC occurrence was identified in the group undergoing surgery and similarly in the group before the start of neoadjuvant treatment. On the other hand, the lowest CTC frequencies were observed in the menopausal patient group (56%), ESR+ patient group (60%), and DCIS group (44.4%). It is worth noting that after completion of neoadjuvant therapy (NACT) CTCs were present in 77.7% of cases. On the other hand, patients under hormonal treatment were CTC positive only in 52% of cases. DISCUSSIONS: Interestingly, HER2 and ESR status of CTCs differs from the status of primary tumor. In 50% of patients HER2 status on CTCs changed not only from HER2+ to HER2-, but also from HER2- to HER2+ (33%). ESR status in CTCs changed only in one direction from ESR+ to ESR-. CONCLUSIONS: Data obtained from the present study suggest that BC is a heterogeneous disease but CTCs may be detected independently of the disease characteristics in 76% of patients at any time point during the course of the disease. This relatively high CTC occurrence in BC should be considered when planning the long-term patient monitoring. PMID- 28815328 TI - Microbial diversity in acidic thermal pools in the Uzon Caldera, Kamchatka. AB - Microbial communities of four acidic thermal pools in the Uzon Caldera, Kamchatka, Russia, were studied using amplification and pyrosequencing of 16S rRNA gene fragments. The sites differed in temperature and pH: 1805 (60 degrees C, pH 3.7), 1810 (90 degrees C, pH 4.1), 1818 (80 degrees C, pH 3.5), and 1807 (86 degrees C, pH 5.6). Archaea of the order Sulfolobales were present among the dominant groups in all four pools. Acidilobales dominated in pool 1818 but were a minor fraction at the higher temperature in pool 1810. Uncultivated Archaea of the Hot Thaumarchaeota-related clade were present in significant quantities in pools 1805 and 1807, but they were not abundant in pools 1810 and 1818, where high temperatures were combined with low pH. Nanoarchaeota were present in all pools, but were more abundant in pools 1810 and 1818. A similar abundance pattern was observed for Halobacteriales. Thermophilic Bacteria were less diverse and were mostly represented by aerobic hydrogen- and sulfur-oxidizers of the phylum Aquificae and sulfur-oxidising Proteobacteria of the genus Acidithiobacillus. Thus we showed that extremely acidic hot pools contain diverse microbial communities comprising different metabolic groups of prokaryotes, including putative lithoautotrophs using energy sources of volcanic origin, and various facultative and obligate heterotrophs. PMID- 28815329 TI - Efficacy and safety of ledipasvir/sofosbuvir with ribavirin in chronic hepatitis C patients who failed daclatasvir/asunaprevir therapy: pilot study. AB - BACKGROUND: In Japan, daclatasvir (DCV) and asunaprevir (ASV) therapy was the first IFN-free treatment to be approved, and thousands of patients have since been successfully treated, with an SVR rate of around 90%. The converse, however, is that around 10% of patients fail to achieve viral eradication and must be retreated using a different approach. This study is to evaluate treatment efficacy of ledipasvir/sofosbuvir and ribavirin in patients who failed to respond to DCV and ASV therapy. METHODS: Thirty patients were treated with 12 weeks of ledipasvir/sofosbuvir and ribavirin. We evaluated the rate of sustained virological response 12 weeks after the end of treatment (SVR12) and examined the incidence of adverse events during ledipasvir/sofosbuvir and ribavirin treatment. NS5A and NS5B resistance-associated variants (RAVs) in treatment failure cases were examined. RESULTS: The overall SVR12 rate was 86.7% (26/30). Large decreases in mean log10 HCV RNA levels were observed in patients without cirrhosis, and the SVR12 rate for these patients was 100% (12/12). In cases of cirrhosis, SVR12 rate was 72.2% (13/18). The common factors in treatment failure cases were the presence of liver cirrhosis and both NS5A L31M/I and Y93H RAVs. The frequency of RAVs did not change before and after treatment among patients who relapsed. CONCLUSION: Ledipasvir/sofosbuvir with ribavirin is an effective retreatment option for patients with chronic hepatitis C who failed to respond to prior daclatasvir and asunaprevir therapy. PMID- 28815330 TI - Homer1a protein expression in schizophrenia, bipolar disorder, and major depression. AB - In recent years, there was growing interest in postsynaptic density proteins in the central nervous system. Of the most important candidates of this specialized region are proteins belonging to the Homer protein family. This family of scaffolding proteins is suspected to participate in the pathogenesis of a variety of diseases. The present study aims to compare Homer1a expression in the hippocampus and cingulate gyrus of patients with major psychiatric disorders including schizophrenia, bipolar disorder and major depression. Immunohistochemistry was used to analyze changes of Homer1a protein expression in the hippocampal formation and the cingulate gyrus from the respective disease groups. Glial cells of the cingulate gyrus gray matter showed decreased Homer1a levels in bipolar disorder when compared to controls. The same results were seen when comparing cingulate gyrus gray matter glial cells in bipolar disorder with major depression. Stratum oriens glial cells of the hippocampus showed decreased Homer1a levels in bipolar disorder when compared to controls and major depression. Stratum lacunosum glial cells showed decreased Homer1a levels in bipolar disorder when compared to major depression. In stratum oriens interneurons Homer1a levels were increased in all disease groups when compared to controls. Stratum lucidum axons showed decreased Homer1a levels in bipolar disorder when compared to controls. Our data demonstrate altered Homer1a levels in specific brain regions and cell types of patients suffering from schizophrenia, bipolar disorder and major depression. These findings support the role of Homer proteins as interesting candidates in neuropsychiatric pathophysiology and treatment. PMID- 28815331 TI - Meta-analysis of the Long-Term Treatment Effects of Psychological Interventions in Youth with PTSD Symptoms. AB - To date, the long-term effectiveness of psychological treatments in reducing post traumatic stress disorder symptoms in children and adolescents has not been investigated extensively. This meta-analysis quantifies the long-term effects of psychological interventions in children and adolescents with PTSD symptoms and examines the period-dependent follow-up (FU) effects based on 47 studies. The mean FU effect sizes (ESs) for PTSD symptoms ranged from medium (between treatment ESs for controlled studies) to large (within treatment ESs for uncontrolled studies; pooled analysis including all studies). These effects were comparable to the post-treatment ESs, which suggests that the treatment effects remained stable. ESs did not differ depending on the length of the FU period (6 months). In randomized controlled trials (RCTs), as well as trials conducted with treatment as usual or active control groups, the long-term treatment effects for the reduction of PTSD symptoms were small. These results demonstrate the long-term effectiveness of psychological interventions in the treatment of PTSD in youth. However, more studies should include a FU assessment. Further research should focus on RCTs with long-term assessments, report comorbid symptoms and investigate the influence of potential moderators. Research is also warranted to determine how to improve the long-term effects of treatments for PTSD in youth. PMID- 28815332 TI - Pilot Study of Whole Blood MicroRNAs as Potential Tools for Diffuse Low-Grade Gliomas Detection. AB - Earlier diagnosis and longitudinal monitoring of diffuse low-grade gliomas (DLGG) increase overall survival by maximizing surgery efficacy and optimizing time for an adjuvant treatment when resection is incomplete. Presently, only imaging permits the non-invasive detection and monitoring of DLGG, but it lacks sensitivity. Measure of circulating microRNAs levels could represent a non invasive alternative. We hypothesized that slow-growing DLGG induce overtime a systemic reaction impacting blood cells microRNA profiles, while the intact blood brain barrier restricts the passage of tumor microRNAs into bloodstream. In 15 DLGG patients and 15 healthy controls, expression levels of 758 microRNAs were measured by the TaqMan OpenArray RT-qPCR platform, on preoperative whole blood, containing both cell-free and blood cells microRNAs. Normalized data were computed by a Student t test with a p value threshold allowing a 10% rate of false positive. Statistical analysis retained fifteen microRNAs, all overexpressed in patients. MiR-20a, miR-106a, miR-20b, and miR-93 belong to clusters genetically related. As miR-223 and miR-let7e, they target the transcription factor STAT3. MicroRNA expression levels were not correlated to preoperative tumor volume. A signature composed of miR-93, miR-590-3p, and miR 454 enabled to nearly perfectly separate patients from controls. Our study performed on a homogeneous cohort was designed accordingly to DLGG particularities and provided the first microRNAs signature proposal. Functional convergence on STAT3 and overexpression of miR-223, factors respectively involved in myeloid-derived suppressor cells and granulocytes, argued for a systemic peripheral response. Overexpressed microRNAs and tumor volume were uncorrelated, making a tumor origin elusive. PMID- 28815333 TI - Comparison of different culture conditions for smooth muscle cell differentiation of human umbilical cord vein CD146+ perivascular cells. AB - Pericytes are CD146+ perivascular cells (PCs) that have multipotential differentiation capacity as mesenchymal stem cells. Beside their crucial roles in vascular development and blood flow regulation, they have ability to differentiate into vascular cell types in vivo. These properties make pericytes preferred cells in the field of vascular tissue engineering. Culture medium for in vitro differentiation of pericytes to vascular smooth muscle cells (SMCs) has not been defined yet. The aim of this study is to try different culture media for SMC differentiation of CD146+ PCs. For this purpose, CD146+ PCs were isolated from human umbilical cord vein. Then they were characterized by immunofluorescence staining and flow cytometric analysis. Three different culture media including; (1) Transforming growth factor beta 1 (TGF-beta1)+ bone morphogenic protein 4, (2) TGF-beta1+ L-ascorbic acid (L-AA) and (3) Horse serum, were compared for differentiation of CD146+ PCs to SMCs by IFS and real time polymerase chain reaction. As a result, in the case of SMC differentiation of CD146+ PCs, second culture medium including TGF-beta1 and L-AA was found to be more effective than other two media. These results are important for establishing proper culture conditions for in vitro SMC differentiation of CD146+ PCs. PMID- 28815334 TI - Clinical characteristics of patient selection and imaging predictors of outcome in solid tumors treated with checkpoint-inhibitors. AB - The rapidly evolving knowledge on tumor immunology and the continuous implementation of immunotherapy in cancer have recently led to the FDA and EMA approval of several checkpoint inhibitors as immunotherapic agents in clinical practice. Anti-CTLA-4, anti-PD-1, and anti-PDL-1 antibodies are becoming standard of care in advanced melanoma, as well as in relapsed or metastatic lung and kidney cancer, demonstrating higher and longer response compared to standard chemotherapy. These encouraging results have fostered the evaluation of these antibodies either alone or in combination with other therapies in several dozen clinical trials for the treatment of multiple tumor types. However, not all patients respond to immune checkpoint inhibitors, hence, specific biomarkers are necessary to guide and monitor therapy. The utility of PD-L1 expression as a biomarker has varied in different clinical trials, but, to date, no consensus has been reached on whether PD-L1 expression is an ideal marker for response and patient selection; approximately 20-25% of patients will respond to immunotherapy with checkpoint inhibitors despite a negative PD-L1 staining. On the other hand, major issues concern the evaluation of objective response in patients treated with immunotherapy. Pure morphological criteria as commonly used in solid tumors (i.e. RECIST) are not sufficient because change in size is not an early and reliable marker of tumor response to biological therapies. Thus, the scientific community has required a continuous adaptation of immune-related response criteria (irRC) to overcome the problem. In this context, metabolic information and antibody-based imaging with positron emission tomography (PET) have been investigated, providing a powerful approach for an optimal stratification of patients at staging and during the evaluation of the response to therapy. In the present review we provide an overview on the clinical characteristics of patient selection when using imaging predictors of outcome in solid tumors treated with checkpoint-inhibitors. PMID- 28815336 TI - Treatment selection in oropharyngeal cancer: a surveillance, epidemiology, and end results (SEER) patterns of care analysis. AB - PURPOSE: Treatment for oropharyngeal cancer (OPC) has changed over the past two decades under multiple influences. We provide a population-based description of the application of radiotherapy, surgery, and chemotherapy to OPC in 1997, 2004, and 2009. METHODS: The National Cancer Institute's Patterns of Care study for OPC included multiple variables not available in the public-use dataset. We identified factors correlating with selection of primary surgery versus radiotherapy with or without chemotherapy (RTC) and analyzed predictors of all cause mortality. We estimated the frequency of human papillomavirus (HPV) testing. RESULTS: RTC was more common in 2009 than in 1997, and was more commonly applied to Stage IV cases. However, RTC was not an independent risk factor for mortality compared with surgery. HPV status was known in 14% of patients in 2009. CONCLUSIONS: RTC is the most common treatment for OPC, but it may not provide the best outcomes. HPV testing was uncommon in 2009. PMID- 28815335 TI - In focus in HCB. PMID- 28815337 TI - Fluorine-18-fluorodeoxyglucose positron emission tomography as an objective substitute for CT morphologic response criteria in patients undergoing chemotherapy for colorectal liver metastases. AB - PURPOSE: The computed tomography (CT) morphologic response of colorectal liver metastases (CLM) after chemotherapy is reportedly correlated with pathologic response and survival outcomes of patients undergoing surgery. However, they are rather subjective criteria and not evaluable without adequate quality of contrast enhanced CT images. This study sought the potential use of fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) as an objective substitute for predicting pathological viability of CLM after chemotherapy. METHODS: Predictive ability of tumor viability of <=10% was compared between FDG PET/CT and contrast-enhanced CT in 34 patients who underwent curative surgical resection for CLM after chemotherapy. The CT morphology and response were defined according to the reported criteria (Chun YS, JAMA 2009). RESULTS: The mean standard uptake value (SUV-mean) in CLM was significantly lower in patients with group 1 and group 2 CT morphology (median, 2.53 and 3.00, respectively) than in group 3 (median, 3.32). The tumor SUV-mean showed moderate correlation with the tumor pathologic viability (r = 0.660, P < 0.0001). A receiver operating characteristic curve analysis revealed that both the tumor SUV-mean (area under the curve [AUC], 0.916; the cut-off value, 3.00) and the CT morphology (AUC, 0.882) have excellent predictive power for <=10% of tumor viability, while degree of tumor shrinkage showed lower predictive power (AUC, 0.692). CONCLUSIONS: FDG PET shows significant correlation with pathologic viability of CLM after chemotherapy and may offer additional objective information for estimating tumor viability when the CT morphologic response is not evaluable. PMID- 28815338 TI - Prolonged hypotension after carotid artery stenting: incidence, predictors and consequences. AB - BACKGROUND: Hemodynamic changes frequently occur after carotid artery stenting (CAS), and in some patients these changes, particularly hypotension, may be prolonged. There are discrepant results for predicting patients at high risk for these prolonged hemodynamic changes and identifying the effect on clinical outcome. In this study, we aimed to determine the frequency, predictors and consequences associated with prolonged hypotension (PH) after CAS in our center. METHODS: We retrospectively analyzed the demographics, risk factors, nature of carotid disease, degree of stenosis of both internal carotid arteries, stent diameter and site of dilatation during stenting in 137 CAS procedures. After CAS, duration of hospital stay, complications during hospital stay and major vascular events or death in a 3-month period were evaluated. PH was defined as a systolic blood pressure <90 mmHg lasting more than 1 h despite adequate treatment after CAS. RESULTS: PH occured in 23 (16.8%) patients. The presence of contralateral stenosis >=70% and absence of diabetes mellitus were significantly associated with PH. Duration of hospital stay was significantly longer in patients with PH. No patients with PH had a periprocedural complication or major vascular events in the follow-up period. CONCLUSION: PH was more prevalent in patients with contralateral high-degree carotid stenosis and patients without diabetes mellitus after CAS. PH did not cause any post-procedural complications or major vascular events at follow-up, but it resulted longer hospital stays. Further studies are needed to better define the pathophysiologic mechanisms underlying these hemodynamic alterations. PMID- 28815339 TI - Expression of large neutral amino acid transporters LAT1 and LAT2 in medulloblastoma. PMID- 28815340 TI - Intradural lumbosacral malignant extrarenal rhabdoid tumor: a case report. AB - BACKGROUND: Rhabdoid tumors are highly malignant tumors predominantly affecting the pediatric population. When these tumors occur outside of the kidneys, they are referred to as malignant extrarenal rhabdoid tumors (MERT), a rare highly aggressive subtype. Less commonly, these tumors involve the neuro-axis. OBJECTIVE: Here we present a case of a 15-year-old girl with intradural MERT of the lumbosacral spine who presented with back pain, sudden worsening of lower extremity strength, and complete loss of bowel and bladder control. RESULTS: The patient's tumor showed loss of INI-1 and negative staining for cytokeratin AE1AE3, CD99, and SOX10. CONCLUSIONS: To our knowledge, there are no previous case reports of MERT with intradural lumbosacral spinal involvement. PMID- 28815341 TI - De novo weekly and biweekly darbepoetin alfa dosing in pediatric patients with chronic kidney disease. AB - BACKGROUND: Darbepoetin alfa is a commonly prescribed erythropoiesis-stimulating agent (ESA) for correcting anemia in pediatric chronic kidney disease (CKD) patients. However, little information exists on its use in ESA-naive patients. This study evaluated the efficacy and safety of darbepoetin alfa in pediatric patients initiating ESA therapy. METHODS: One-hundred sixteen pediatric ESA-naive subjects (aged 1-18 years) with CKD stages 3-5D and hemoglobin (Hb) <10 g/dl from 43 centers in the US, Europe, and Mexico were randomized by age (three groups) and dialysis status (yes vs. no) to receive darbepoetin alfa once weekly (QW) or every 2 weeks (Q2W) subcutaneously (not on dialysis and peritoneal dialysis subjects) and intravenously (hemodialysis subjects). The drug was titrated to achieve Hb levels of 10.0-12.0 g/dl over 25 weeks. Patient- and parent-reported health-related outcomes were measured by the Pediatric Quality of Life Inventory (PedsQLTM) in children >=2 years. RESULTS: In both groups, mean Hb concentrations increased to >=11.0 g/dl over the first 3 months of treatment and remained stable within the 10.0-12.0 g/dl target range. The median time to achieve hemoglobin >=10 g/dl was slightly longer for subjects <12 years (QW and Q2W, both 28 days) vs. those >=12 years (23 and 22 days, respectively). Adverse event profiles were similar between groups, with QW, four (7%) and Q2W, five (9%). PedsQLTM scores showed modest increases. CONCLUSIONS: Darbepoetin alfa can be safely administered either QW or Q2W to ESA-naive pediatric patients with CKD-related anemia to achieve Hb targets of 10.0-12.0 g/dl. PMID- 28815342 TI - Development of a Novel Detachable Magnetic Nerve Stimulator for Intraoperative Neuromonitoring. AB - BACKGROUND: Recurrent laryngeal nerve (RLN) palsy is a serious complication of thyroid surgery. During intraoperative neuromonitoring (IONM) of the RLN in thyroid surgery, repeated shifting between surgical instruments and the nerve stimulator is cumbersome and time-consuming. Therefore, we developed a simple detachable magnetic nerve stimulator that may be connected to all metallic surgical instruments. This study aimed to investigate the feasibility and efficacy of this detachable magnetic nerve stimulator for IONM in a porcine model and humans. METHODS: Eight RLNs in four pigs and thirteen in nine patients that underwent thyroidectomy were examined. We developed a detachable nerve stimulator that combined surgical instruments with the nerve-stimulating probe. We evaluated the electromyography (EMG) amplitudes of the RLNs in pigs and patients using conventional nerve probes and surgical instruments with the novel detachable magnetic nerve stimulator attached. RESULTS: The EMG amplitudes of the eight RLNs in pigs and thirteen in patients were analyzed. The detachable magnetic nerve stimulator was feasible and safe. There was no significant difference in the EMG amplitude between instruments (P = 0.423 in animals, P = 0.446 in humans). CONCLUSIONS: The application of stimulating dissection using a detachable magnetic nerve stimulator during thyroidectomy with IONM is simple, convenient, and effective. It provides surgeons with real-time feedback of the EMG response during intermittent IONM. We propose that this novel device could be an essential guide for most surgeons, especially for less experienced head and neck surgeons. PMID- 28815343 TI - Assessment of macrophyte, heavy metal, and nutrient concentrations in the water of the Nairobi River, Kenya. AB - Nairobi River tributaries are the main source of the Athi River. The Athi River basin is the fourth largest and important drainage system in Kenya covering 650 km and with a drainage area of 70,000 km2. Its water is used downstream by about four million people not only for irrigation but also for domestic purposes. However, its industrial, raw sewer, and agricultural pollution is alarming. In order to understand distribution and concentration of heavy metals and nutrients in the water of Nairobi River, 28 water samples were collected in the rainy season (October) of 2015 and dry season (June) of 2016. Cd, Cu, Cr, Zn, As, Pb, Fe, Ni, Mn, NO3-, and TP were analyzed. Only Cr, Pb, Fe, and Mn had concentrations exceeding the WHO permissible limit for drinking water. Out of the 28 sites examined in the study, one site had Pb exceeding the WHO recommended level. Similarly, three sites exceeded the same level for Cr. Only three sites were within the WHO permissible limits for drinking water for Mn while just four sites were within USEPA limit for Fe. Industrial effluent, domestic sewerage, agricultural activities, and solid waste were the main sources of pollution. Significant spatial variation of both heavy metals and nutrients concentration was observed and emanated from point source pollution. Eleven out of 31 macrophytes species that were identified along the river and its tributaries are effective heavy metal and nutrient bioaccumulators and may be used in phytoremediation. PMID- 28815344 TI - Long-Term Survival After Hematopoietic Stem Cell Transplantation for Complete STAT1 Deficiency. AB - PURPOSE: Complete signal transducer and activator of transcription 1 (STAT1) deficiency is a rare autosomal recessive condition characterized by impairment of intracellular signaling from both type I and type II interferons (IFN). Affected patients are prone to early severe mycobacterial and viral infections, which usually result in death before 18 months of age. We previously reported a patient affected by complete STAT1 deficiency who underwent hematopoietic stem cell transplantation (HSCT). Here, we describe the transplantation procedures and long term outcomes. METHODS: The patient, who had suffered multiple life-threatening mycobacterial and viral infections in the first years of life, underwent HSCT at 4 years of age from a partially matched (HLA compatibility 8/10) unrelated donor after a myeloablative conditioning regimen consisting of busulfan, cyclophosphamide, and anti-thymocyte globulin. RESULTS: Hematological reconstitution was detected at d+15, with full donor engraftment demonstrated by molecular analysis of leukocytes. Several complications occurred in the post transplantation phase, including acute graft versus host disease, posterior reversible encephalopathy, thrombotic thrombocytopenic purpura, bilateral keratoconjunctivitis with complete loss of vision, and chronic lower limb lymphedema. Analysis of STAT1 in CD3+ cells at 90 and 120 days after HSCT by flow cytometry showed normal STAT1 phosphorylation levels in response to IFN-alpha. CONCLUSIONS: Notably, no severe infections occurred after discharge (day + 90) during a 9-year follow-up, suggesting that normal response to IFNs in hematopoietic cells is sufficient to provide protection in humans. PMID- 28815346 TI - Unilateral cancer-associated retinopathy: diagnosis, serology and treatment. AB - PURPOSE: To report a case of unilateral cancer-associated retinopathy (CAR) with clinical, serological and electroretinogram (ERG) normalization after aggressive cancer treatment combined with steroids and rituximab. METHODS: Work-up included extensive clinical and electrophysiological testing. Also, serological work-up for antiretinal antibodies and oncological screening was organized. RESULTS: A 45 year-old female presented with progressive photopsias, photophobia and relative central scotoma in the right eye since 6 weeks prior. BCVA was 1.0 in both eyes. Biomicroscopy, IOP and fundus exam were unremarkable. Also, colour vision, autofluorescence imaging, OCT and EOG were normal. Visual fields showed decreased central sensitivity in the right eye. ERG showed a unilateral, electronegative combined and ON-bipolar response. A diagnosis of CAR was suspected. After a diagnosis of an adenocarcinoma of the right ovary, radical ovariectomy and hysterectomy were performed, followed by adjuvant chemotherapy. A whole-body PET scan revealed no metastasis. Treatment with rituximab monoclonal antibodies in combination with corticosteroids was initiated. The patient tested positive for serum autoantibodies against TRPM1, a transient receptor potential cation channel expressed in ON-bipolar cells. During treatment, there was progressive improvement in symptoms and the ERG normalized. Serology confirmed complete clearance of autoantibodies. CONCLUSIONS: Although rare, unilateral CAR does occur and in cases with high clinical suspicion an oncological work-up is mandatory. Aggressive cancer treatment combined with steroids and rituximab can lead to normalization of the clinical and ERG phenotype, with clearing of antiretinal antibodies. PMID- 28815345 TI - Mosapride Stabilizes Intestinal Microbiota to Reduce Bacterial Translocation and Endotoxemia in CCl4-Induced Cirrhotic Rats. AB - BACKGROUND: Impaired intestinal motility may lead to the disruption of gut microbiota equilibrium, which in turn facilitates bacterial translocation (BT) and endotoxemia in cirrhosis. We evaluated the influence of mosapride, a prokinetic agent, on BT and DNA fingerprints of gut microbiota in cirrhotic rats. METHODS: A rat model of cirrhosis was set up via subcutaneous injection of carbon tetrachloride (CCl4). The portal pressure, liver and intestinal damage, plasma endotoxin, BT, and intestinal transit rate (ITR) of cirrhotic rats were determined. Fecal DNA fingerprints were obtained by ERIC-PCR. The expressions of tight junction proteins were evaluated by western blotting. RESULTS: Mosapride treatment to cirrhotic rats significantly reduced the plasma endotoxin level and incidence of BT, accompanied by increased ITR. Cirrhotic rats (including those treated with mosapride) suffered from BT exhibited significantly lower ITR than those who are free of BT. Pearson coefficient indicated a significant and negative correlation between the plasma endotoxin level and ITR. The genomic fingerprints of intestinal microbiota from the three groups fell into three distinctive clusters. In the mosapride-treated group, Shannon's index was remarkably increased compared to the model group. Significantly positive correlation was detected between Shannon's index and ITR. Mosapride did not improve hepatic and intestinal damages and ileal expressions of occludin and ZO 1. CONCLUSIONS: Mosapride significantly increases intestinal motility in cirrhotic rats, thus to recover the disordered intestinal microbiota, finally resulting in decreased plasma endotoxin and BT. PMID- 28815347 TI - The tumor-stromal ratio as a strong prognosticator for advanced gastric cancer patients: proposal of a new TSNM staging system. AB - BACKGROUND: Insufficient attention is paid to the underlying tumor microenvironment (TME) evolution, that resulting in tumor heterogeneity and driving differences in cancer aggressiveness and treatment outcomes. The morphological evaluation of the proportion of the stroma at the most invasive part of primary tumor (tumor-stromal ratio, TSR) in cancer is gaining momentum as evidence strengthens for the clinical relevance. METHODS: Tissue samples from the most invasive part of the primary gastric cancer (GC) of 494 patients were analyzed for their TSR, and a new TSNM (tumor-stromal node metastasis) staging system based on patho-biological behaviors was established and assessed. RESULTS: TSR is a new and strong independent prognostic factor for GC patients. The likelihood of tumor invasion is increased significantly for patients in the stromal-high subgroup compared to those in the stromal-low subgroup (P = 0.011). The discrimination ability of TSR was not less than the TNM staging system and was better in patients with stages I and II GC. We integrated the TSR parameter into the TNM staging system and proposed a new TSNM staging system creatively. There were three new subgroups (IC, IIC, IIID). There were four major groups and 10 subgroups in the TSNM system. The difference in overall survival (OS) was statistically significant among all TSNM system (P < 0.005 for all). Deep analyses revealed well predictive performance of the TSNM (P < 0.001). CONCLUSIONS: This study confirms the TSR as a TME prognostic factor for GC. TSR is a candidate TME parameter that could easily be implemented in routine pathology diagnostics, and the TSNM staging system has been established to optimize risk stratification for GC. The value of the TSNM staging system should be validated in further prospective study. PMID- 28815348 TI - Counseling Close to Home: Genetic Counselors' Experiences with their own Family Members. AB - Genetic counselors are trained to provide personalized genetic information and support to clients and their families. When requests for counseling comes from the counselor's own family member, should that counselor still provide service? There is a paucity of literature regarding genetic counselors counseling their own family members and no specific recommendations regarding how to reply to requests for genetic information from relatives. The purpose of this mixed methods study was to report genetic counselors' and genetic counseling students' perspectives and experiences providing genetic counseling to relatives. In the present study, 423 genetic counselors and genetic counseling students completed a 70-item web-based survey that explored genetic counselors' experiences counseling family members outside of a clinic setting. The majority (73%; n = 301/410) of respondents have been asked to provide genetic counseling. Over half (57%; n = 257/423) provided counseling, personalized genetic information or risk assessment to family members. Only a small fraction of respondents (11%; n = 45/420) responded that they received any formal training in their graduate education, or in any other capacity that addressed the issue of how genetic counselors should respond to genetic counseling requests made family members. Those who have were less likely to provide genetic counseling to a family member (p < 0.05). Respondents who provided genetic counseling to relatives were significantly more likely to think their colleagues would do the same. Those who never provided genetic counseling to relatives were more likely to think their colleagues would refer to an unrelated genetic counselor (p < 0.0001). We highlight how our results have clinical and professional implications and provide suggestions to generate discussion among genetic counselors on how they might respond to requests for counseling from family members. PMID- 28815349 TI - Tumor Volume Doubling Time as a Dynamic Prognostic Marker for Patients with Hepatocellular Carcinoma. AB - BACKGROUND AND AIMS: To evaluate the clinical value of tumor growth rate in hepatocellular carcinoma (HCC) patients, we investigated the growth rate of HCC by calculating the tumor volume doubling time (TVDT) and its impact on survival and recurrence. METHODS: A retrospective cohort study of 269 HCC patients who underwent two or more pretreatment imaging studies of computed tomography or magnetic resonance imaging was performed. Tumor growth rate and TVDT were calculated by comparing tumor volumes between imaging studies. Clinical parameters independently related to a TVDT of <2 months were evaluated. After dividing patients into slow-growing (159 patients with TVDT >2 months) and rapid growing (110 patients with TVDT <2 months) groups, we compared the groups in terms of their survival and recurrence outcomes. The response to transarterial chemoembolization (TACE) was evaluated according to TVDT. RESULTS: The median tumor growth rate and TVDT were 37.5%/month and 2.37 months, respectively. By logistic regression analyses, a high Child-Pugh score, small initial tumor diameter, gross vascular invasion, and tumor multiplicity were found to be independently associated with a TVDT of <2 months (P < 0.05). Patients in the rapid-growing group had lower survival rates and higher recurrence rates (P < 0.05). The response to TACE was worse in the rapid-growing group (P < 0.05). CONCLUSIONS: A fast HCC growth rate is associated with poor liver function and aggressive tumor biology. HCC patients with shorter TVDTs exhibit poorer survival and recurrence outcomes as well as a poor response to TACE. PMID- 28815350 TI - Already at the Table: Patterns of Play and Gambling Involvement Prior to Gambling Expansion. AB - During 2011, the Governor of Massachusetts signed a bill to allow casino gambling in the state (Commonwealth of Massachusetts 2011). As a result, two resort casinos will begin operations during 2018 and 2019; a smaller slots parlor began operations during June 2015. Prior to this expansion, gambling was widely available in Massachusetts, through the state lottery, off-track betting, and gambling opportunities available in neighboring states. Within this context, it is important to understand the patterns of gambling involvement in the population prior to gambling expansion. The current study examined gambling involvement, patterns of play, and gambling-related problems prior to gambling expansion among a sample of 511 Massachusetts residents who were members of a statewide Internet panel. To measure patterns of play, we asked questions about past-year games played and frequency of play. To measure breadth of involvement, we assessed the number of different games played. To measure depth of involvement, we measured time spent gambling, amount wagered, and amount won or lost. Principal component analysis revealed four play pattern components accounting for more than 50% of the variance in game play frequency. Multiple regression analyses revealed that component scores composed of casino gambling and skill-based gambling (e.g., poker, sports) variables uniquely contributed to the prediction of gambling related problems, even when depth of involvement was controlled. However, the addition of breadth of involvement to the model resulted in a model where no set of variables contributed significantly, suggesting a complex relationship among play patterns, depth, and breadth of involvement. The study established discrete and distinguishable gambling play patterns associated with gambling-related problems and identified groups of individuals potentially vulnerable to the effects of gambling expansion. PMID- 28815351 TI - An integrated model of skin cancer risk in sexual minority males. AB - Sexual minority males are an at-risk group for developing skin cancer. Elevated rates of skin cancer among this population are thought to be driven by excess indoor tanning; however, motivations to indoor tan among this population are unknown. Theoretically, appearance-based and affect regulation motives may be proximal predictors of increased indoor tanning in this population. The current study tests an integrated biopsychosocial model of indoor tanning behaviors and future intentions among a sample of sexual minority males. Participants were 231 sexual minority males, between the age of 14 and 35 years, residing in San Diego County, California, who completed a battery of self-report questionnaires online. Constructs assessed included skin tone, perceived susceptibility to skin cancer, sociocultural pressures to tan, appearance-based motives to tan, affect regulation in regard to indoor tanning, indoor tanning behaviors over the previous 3 months, and future intentions to indoor tan. The three proposed proximal predictors of indoor tanning all displayed significant pathways; however, results varied depending upon the specific outcome measure modeled. Affect regulation was significantly associated with increased odds of indoor tanning, and future intentions to indoor tan. Increased appearance reasons to tan were significantly associated with future intentions to indoor tan, while increased appearance reasons not to tan were significantly associated with fewer number of indoor tanning sessions. Results underscore the unique pathways of affect regulation and appearance-based motives in indoor tanning behaviors. Skin cancer prevention programs focusing on sexual minority males may wish to address affect and appearance concerns. PMID- 28815352 TI - Two patterns of contrast-enhanced ultrasonography with Sonazoid(r) in spontaneous rupture of hepatocellular carcinoma: a report of four cases. AB - Spontaneous rupture is a life-threatening complication of hepatocellular carcinoma (HCC). Detecting active bleeding is critical. Color Doppler and contrast-enhanced ultrasonography (CEUS) with Levovist(r) are reported to be useful for detecting active bleeding. A few reports have described using Sonazoid(r) to detect bleeding in ruptured HCC. This report describes two distinctive patterns of bleeding from ruptured HCC observed in CEUS with Sonazoid(r). Four patients with suspected HCC rupture were examined by gray-scale ultrasonography (US) and then CEUS with Sonazoid(r). Two patterns of bleeding were observed with CEUS: jet-like extravasation (n = 2) and bubble leakage (n = 2). While contrast-enhanced computed tomography and angiography revealed active bleeding in only one patient, CEUS detected active bleeding and enabled the bleeding site to be estimated in all patients. Transcatheter arterial embolization was performed based on the findings of CEUS, and hemostasis was achieved in all patients. CEUS using Sonazoid(r) could demonstrate active bleeding as two patterns, and these findings enabled us to detect the rupture site of HCC more confidently than with other modalities. PMID- 28815353 TI - Perceptions of the Inpatient Training Experience: A Nationwide Survey of Gastroenterology Program Directors and Fellows. AB - BACKGROUND: Inpatient training is a key component of gastroenterology (GI) fellowship programs nationwide, yet little is known about perceptions of the inpatient training experience. AIM: To compare the content, objectives and quality of the inpatient training experience as perceived by program directors (PD) and fellows in US ACGME-accredited GI fellowship programs. METHODS: We conducted a nationwide, online-based survey of GI PDs and fellows at the conclusion of the 2016 academic year. We queried participants about (1) the current models of inpatient training, (2) the content, objectives, and quality of the inpatient training experience, and (3) the frequency and quality of educational activities on the inpatient service. We analyzed five-point Likert items and rank assessments as continuous variables by an independent t test and compared proportions using the Chi-square test. RESULTS: Survey response rate was 48.4% (75/155) for PDs and a total of 194 fellows completed the survey, with both groups reporting the general GI consult team (>90%) as the primary model of inpatient training. PDs and fellows agreed on the ranking of all queried responsibilities of the inpatient fellow to develop during the inpatient service. However, fellows indicated that attendings spent less time teaching and provided less formal feedback than that perceived by PDs (p < 0.0001). PDs rated the overall quality of the inpatient training experience (p < 0.0001) and education on the wards (p = 0.0003) as better than overall ratings by fellows. CONCLUSION: Although GI fellows and PDs agree on the importance of specific fellow responsibilities on the inpatient service, fellows report experiencing less teaching and feedback from attendings than that perceived by PDs. Committing more time to education and assessment may improve fellows' perceptions of the inpatient training experience. PMID- 28815354 TI - NF-E2-Related Factor 2 Suppresses Intestinal Fibrosis by Inhibiting Reactive Oxygen Species-Dependent TGF-beta1/SMADs Pathway. AB - BACKGROUND AND AIMS: This study aimed to evaluate the antifibrotic effects of NF E2-Related Factor 2 (Nrf2) on intestinal fibrosis. Intestinal fibrosis is a common complication of Crohn's disease; however, its mechanism of intestinal fibrosis is largely unclear. METHODS: BALB/c mice received 2,4,6-trinitrobenzene sulfonic acid weekly via intrarectal injections to induce chronic fibrotic colitis. They also diet containing received 1% (w/w) tert-butylhydroquinone (tBHQ), which is an agonist of Nrf2. Human intestinal fibroblasts (CCD-18Co cells) were pretreated with tBHQ or si-Nrf2 followed by stimulation with transforming growth factor-beta1 (TGF-beta1), which transformed the cells into myofibroblasts. The main fibrosis markers such as alpha-smooth muscle actin, collagen I, tissue inhibitor of metalloproteinase-1, and TGF-beta1/SMADs signaling pathway were detected by quantitative real-time RT-PCR, immunohistochemical analysis, and Western blot analysis. Levels of cellular reactive oxygen species (ROS) were detected by dichlorodihydrofluorescein diacetate. RESULTS: tBHQ suppressed the intestinal fibrosis through the TGF beta1/SMADs signaling pathway in TNBS-induced colitis and CCD-18Co cells. Moreover, Nrf2 knockdown enhanced the TGF-beta1-induced differentiation of CCD 18Co cells. ROS significantly increased in TGF-beta1-stimulated CCD-18Co cells. Pretreatment with H2O2, the primary component of ROS, was demonstrated to block the effect of tBHQ on reducing the expression of TGF-beta1. Moreover, scavenging ROS by N-acetyl cysteine could inhibit the increasing expression of TGF-beta1 promoted by Nrf2 knockdown. CONCLUSIONS: The results suggested that Nrf2 suppressed intestinal fibrosis by inhibiting ROS/TGF-beta1/SMADs pathway in vivo and in vitro. PMID- 28815355 TI - Egg donation of vitrified oocytes bank produces similar pregnancy rates by blastocyst transfer when compared to fresh cycle. AB - PURPOSE: Advances in reproductive techniques, mainly the introduction of oocyte vitrification, have provided the opportunity to conceive from oocyte banks. The aim of this study was to compare the clinical outcomes of fresh and vitrified oocytes in an egg donation program following blastocyst transfer. METHODS: This retrospective observational study included 504 oocyte donation cycles. All donor women were younger than 30 years of age. The recipient cycles were divided into two groups: fresh oocytes (n = 78) or vitrified oocytes (n = 426). All oocytes were fertilized by ICSI using ejaculated sperm, followed by blastocyst transfer. Endometrium preparation was performed with estradiol valerate plus micronized progesterone according to standard protocols. RESULTS: Recipients were of similar age (fresh 42.0 +/- 4.5 years vs vitrified 41.8 +/- 4.8 years; p = 0.790). The fresh group received more mature oocytes for injection compared to the vitrified group (10.1 +/- 2.8 vs 9.2 +/- 2.2; p = 0.005). The two pronuclei (2PN) rate (74.5 vs 77.4%; p = 0.195) and blastocyst rate (48.8 vs 51.6%; 0.329) were similar between the fresh and vitrified groups, respectively. The rates of clinical pregnancy were 60.9% in the fresh and 59.0% in the vitrified groups (p = 0.771). CONCLUSIONS: Our findings suggest that vitrified oocytes result in similar pregnancy rates when compared to fresh oocytes with blastocyst transfer in an egg donation program. Moreover, vitrified oocytes may allow for a better cycle schedule, starting with a lower number of oocytes to be fertilized. Therefore, we hypothesize that egg banks with vitrified oocytes could be safely utilized in an egg donation program. PMID- 28815356 TI - Dent disease in Poland: what we have learned so far? AB - PURPOSE: Dent disease (DD) is a rare tubulopathy characterized by proximal tubular dysfunction leading to chronic kidney disease (CKD). The aim of the study was to characterize patients with DD in Poland. METHODS: A retrospective analysis of a national cohort with genetically confirmed diagnosis. RESULTS: Of 24 males, all patients except one carried mutations in the CLCN5 gene; in one patient a mutation in the OCRL gene was disclosed. Molecular diagnosis was delayed 1 year on average (range 0-21 years). The most common features were tubular proteinuria (100%), hypercalciuria (87%), and nephrocalcinosis (56%). CKD (<=stage II) and growth deficiency were found in 45 and 22% of patients, respectively. Over time, a progression of CKD and persistence of growth impairment was noted. Subnephrotic and nephrotic proteinuria (20%) was found in most patients, but tubular proteinuria was assessed in only 67% of patients. In one family steroid-resistant nephrotic syndrome prompted a genetic testing, and reverse phenotyping. Five children (20%) underwent kidney biopsy, and two of them were treated with immunosuppressants. Hydrochlorothiazide and angiotensin-converting enzyme inhibitors were prescribed for a significant proportion of patients (42 and 37.5%, respectively), while supplemental therapy with phosphate, potassium, vitamin D (12.5% each), and alkali (4.2%) was insufficient, when compared to the percentages of patients requiring repletion. CONCLUSIONS: We found CLCN5 mutations in the vast majority of Polish patients with DD. Proteinuria was the most constant finding; however, tubular proteins were not assessed commonly, likely leading to delayed molecular diagnosis and misdiagnosis in some patients. More consideration should be given to optimize the therapy. PMID- 28815357 TI - Carbon-fiber-reinforced PEEK fixation system in the treatment of spine tumors: a preliminary report. AB - BACKGROUND: Protocols including combination of surgery and radiotherapy are more and more frequent in the treatment of bone tumors of the spine. In metastatic disease, combination of surgery and radiotherapy is since long time accepted, as based on clinical evidence. In primary tumors, combination of surgery and radiotherapy can be considered in all the cases in which a satisfactory oncological margin cannot be achieved: high-grade malignancies, recurrent tumors, huge tumors expanding in an extracompartimental area, and when tumor-free margin requires unacceptable functional sacrifices. However, metal implants are an obstacle in the collaboration between surgeons and radiation oncologists. Carbon fiber-reinforced polyethil-ether-ether-ketone (CFR-PEEK) composite implants could make easier and more effective the treatment as radiolucent and not interfering with ionizing radiation and accelerated particles. The purpose of this article is to report the preliminary results from a cohort of patients treated with CFR-PEEK and to evaluate the safety and the non-inferiority of the device respect the commonly used titanium implants. MATERIALS AND METHODS: This study concerns an ambispective cohort series of 34 tumor patients (14 metastases and 20 primaries, most of them recurrent) submitted to thoracic and lumbar spine fixation with a CFR-PEEK composite implants. Oncologic surgery was palliative decompression and fixation in 9 cases, tumor excision in 21, and enbloc resection in 4. Data collected for this preliminary report were all intraoperative remarks, incidence of complications, changes in neurological status, local control, and survival. All the cases were followed 6-36 months (mean 13 months). RESULTS: Only one intraoperative screw breakage occurred out of 232 implanted screws. Pain control and neurological improvement were the early clinical results. Two sacral screws loosening were found at 9 and 12 months in multilevel constructs performed on multirecurrent tumors. Six local recurrences were early found thanks to the implant radiolucency. Radiation oncologists' opinion was favourable as concerning better treatment planning on CT and lacking of scattering effect during the treatment. CONCLUSIONS: No artifacts on imaging studies mean early local recurrence detection. For radiation oncologists, no artifacts on imaging studies mean easier planning and no scattering effect means more effective and safe radiotherapy, particularly when particles are used. Moreover, it seems that the clinical use of CFR-PEEK composite implants may be safe and at least comparable with the commonly used titanium implants in terms of intraoperative complications, stability at weight bearing and at functional recovery. Larger patient series and longer follow-up are required to confirm these data. PMID- 28815358 TI - Friendship Attachment Style Moderates the Effect of Adolescent Exposure to Violence on Emerging Adult Depression and Anxiety Trajectories. AB - Exposure to violence during adolescence is associated with increased risk behaviors and mental health problems in adulthood. Friendship attachment during adolescence may, however, mitigate the negative effects of exposure to violence on trajectories of depression and anxiety in young adulthood. In this study, we used growth curve modeling to examine associations between exposure to violence and mental health outcomes, followed by multi-group analyses with friendship attachment as the moderator. The sample was drawn from a longitudinal study (12 waves; 1994-2012) of 676 (54% female) urban high school students. We found strong positive associations between exposure to violence during adolescence and later self-reported depressive and anxiety symptoms. Notably, securely attached adolescents reported faster decreases in mental health symptoms as a function of violence relative to their insecurely attached peers as they transitioned into adulthood. PMID- 28815359 TI - Heavy metal pollution in sediments of the largest reservoir (Three Gorges Reservoir) in China: a review. AB - The Three Gorges Dam in China is the world's largest dam. Upon its completion in 2003, the Three Gorges Reservoir (TGR) became the largest reservoir in China and plays an important role in economic development and national drinking water safety. However, as a sink and source of heavy metals, there is a lack of continuous and comparative data on heavy metal pollution in sediments. This study reviewed all available literatures published on heavy metals in TGR sediments and further provided a comprehensive assessment of the pollution tendency of these heavy metals. The results showed that heavy metal concentrations in TGR sediments varied spatially and temporally. Temporal variations indicated that Hg in tributaries, as well as As, Cd, Cr, Cu, Ni, Pb, and Zn in the mainstream, exhibited a higher probability to exceed background values after the impoundment of TGR. Pollution assessments by contamination factor, geoaccumulation index, and potential ecological risk were similar. High Cd and Hg concentrations in both the mainstream and tributaries are a cause for much concern. However, sediment quality guidelines produced different results, as most previous studies adopted different sampling and measurement strategies. The data inconsistencies and lack of continuity regarding the reservoir confirm the need for a continuous monitoring network and the development of quality criteria relevant to the sediments of the TGR in the future. PMID- 28815361 TI - Factors Associated with Pre-exposure Prophylaxis in a Highly Insured Population of Urban Men Who Have Sex with Men, 2014. AB - In the United States, an estimated 25% of men who have sex with men (MSM) have indications for receiving pre-exposure prophylaxis to prevent HIV infection (PrEP), but <4% reported PrEP use in the past 12 months. We evaluate factors associated with having heard of, willingness to use, and use of PrEP in a venue based, time-spaced sample of 316 urban, highly insured Boston MSM in the 2014 NHBS. We found that 53.7% of respondents reported receiving usual medical care from a doctor's office or health maintenance organization, 57.6% had an indication for PrEP, 66.6% had heard of PrEP, 53.6% reported willingness to use PrEP, and 5.8% reported use of PrEP in the past 12 months. In multivariable analyses, an indication for PrEP was statistically associated with having heard of, willingness to use and use of PrEP in the past 12 months. Findings guide statewide efforts to evaluate and promote PrEP. PMID- 28815360 TI - Epidemiology in Germany-general development and personal experience. AB - Did you ever hear about epidemiology in Germany? Starting from an epidemiological desert the discipline has grown remarkably, especially during the last 10-15 years: research institutes have been established, research funding has improved, multiple curriculae in Epidemiology and Public Health are offered. This increase has been quite steep, and now the epidemiological infrastructure is much better. Several medium-sized and even big population cohorts are ongoing, and the number and quality of publications from German epidemiologists has reached a respectable level. My own career in epidemiology started in the field of environmental health. After German reunification I concentrated for many years on environmental problems in East Germany and observed the health benefits after improvement of the situation. Later, I concentrated on population-based cohorts in newborns (GINI/LISA) and adults (KORA, German National Cohort), and on biobanking. This Essay describes the development in Germany after worldwar 2, illustrated by examples of research results and build-up of epidemiological infractructures worth mentioning. PMID- 28815363 TI - The use of natural language processing on pediatric diagnostic radiology reports in the electronic health record to identify deep venous thrombosis in children. AB - Venous thromboembolism (VTE) is a potentially life-threatening condition that includes both deep vein thrombosis (DVT) and pulmonary embolism. We sought to improve detection and reporting of children with a new diagnosis of VTE by applying natural language processing (NLP) tools to radiologists' reports. We validated an NLP tool, Reveal NLP (Health Fidelity Inc, San Mateo, CA) and inference rules engine's performance in identifying reports with deep venous thrombosis using a curated set of ultrasound reports. We then configured the NLP tool to scan all available radiology reports on a daily basis for studies that met criteria for VTE between July 1, 2015, and March 31, 2016. The NLP tool and inference rules engine correctly identified 140 out of 144 reports with positive DVT findings and 98 out of 106 negative reports in the validation set. The tool's sensitivity was 97.2% (95% CI 93-99.2%), specificity was 92.5% (95% CI 85.7 96.7%). Subsequently, the NLP tool and inference rules engine processed 6373 radiology reports from 3371 hospital encounters. The NLP tool and inference rules engine identified 178 positive reports and 3193 negative reports with a sensitivity of 82.9% (95% CI 74.8-89.2) and specificity of 97.5% (95% CI 96.9 98). The system functions well as a safety net to screen patients for HA-VTE on a daily basis and offers value as an automated, redundant system. To our knowledge, this is the first pediatric study to apply NLP technology in a prospective manner for HA-VTE identification. PMID- 28815362 TI - Metric to quantify white matter damage on brain magnetic resonance images. AB - PURPOSE: Quantitative assessment of white matter hyperintensities (WMH) on structural Magnetic Resonance Imaging (MRI) is challenging. It is important to harmonise results from different software tools considering not only the volume but also the signal intensity. Here we propose and evaluate a metric of white matter (WM) damage that addresses this need. METHODS: We obtained WMH and normal appearing white matter (NAWM) volumes from brain structural MRI from community dwelling older individuals and stroke patients enrolled in three different studies, using two automatic methods followed by manual editing by two to four observers blind to each other. We calculated the average intensity values on brain structural fluid-attenuation inversion recovery (FLAIR) MRI for the NAWM and WMH. The white matter damage metric is calculated as the proportion of WMH in brain tissue weighted by the relative image contrast of the WMH-to-NAWM. The new metric was evaluated using tissue microstructure parameters and visual ratings of small vessel disease burden and WMH: Fazekas score for WMH burden and Prins scale for WMH change. RESULTS: The correlation between the WM damage metric and the visual rating scores (Spearman rho > =0.74, p < 0.0001) was slightly stronger than between the latter and WMH volumes (Spearman rho > =0.72, p < 0.0001). The repeatability of the WM damage metric was better than WM volume (average median difference between measurements 3.26% (IQR 2.76%) and 5.88% (IQR 5.32%) respectively). The follow-up WM damage was highly related to total Prins score even when adjusted for baseline WM damage (ANCOVA, p < 0.0001), which was not always the case for WMH volume, as total Prins was highly associated with the change in the intense WMH volume (p = 0.0079, increase of 4.42 ml per unit change in total Prins, 95%CI [1.17 7.67]), but not with the change in less-intense, subtle WMH, which determined the volumetric change. CONCLUSION: The new metric is practical and simple to calculate. It is robust to variations in image processing methods and scanning protocols, and sensitive to subtle and severe white matter damage. PMID- 28815364 TI - Long bone mesenchymal stem cells (Lb-MSCs): clinically reliable cells for osteo diseases. AB - Mesenchymal stem cells (MSCs) have been designated as the most reliable cells in clinics to treat osteo-diseases because of their versatile nature. MSCs, isolated from long bone (Lb-MSCs) are rarely reported and named as RIA-MSCs because of the reamer-irrigator-aspirator (RIA) device. The potential of these cells in the treatment of non-union bone fractures made them the ideal candidates to be studied for clinical practices. In this work, effect of cryopreservation on the proliferation and differentiation capabilities of long bone MSCs (Lb-MSCs) has been studied. For this purpose, Lb-MSCs were isolated via RIA device and characterized using flow cytometry and differentiation assays. Cells were cryopreserved for 3, 6 and 12 months and thereafter were characterized using differentiation assays and genetic markers specific for osteogenic, chondrogenic, and adipogenic potential quantitatively by qRT-PCR. Lb-MSCs were found expressing MSC characteristic markers defining their identity. The population doubling time (PDT) was about 2.5 +/- 0.5 days and colonies appeared after 7-10 days. Differentiation potential and gene expression of 3, 6 and 12 months cryopreserved Lb-MSCs were unaltered. The results show that cryopreservation did not have an effect on the differentiation potential of human Lb-MSCs. Therefore, our work offers Lb-MSCs as clinically cells for treating osteo-diseases. PMID- 28815365 TI - The effect of dichlorvos on control of drosophila and its safety evaluation under different application methods. AB - Drosophila is a common strawberry pest. In this work, toxicities of the 77.5% EC dichlorvos to 3rd instar larvae and adults of drosophila were evaluated through indoor bioassays and field bioassays, respectively. To insure the safety, dichlorvos dissipation and terminal residue in strawberry by different application methods under field conditions were determined by high-performance liquid chromatography. The decline curves of dichlorvos residues in strawberry corresponded with first-order kinetics, and dichlorvos dissipated rapidly in strawberry with half-life (t1/2) of 7.58-13.17 h. Terminal residues below the maximum residue limit of strawberry and soil in different distance were achieved after 24 h under different application methods. This article provides guidance to the proper and safe use of dichlorvos in agriculture; it is more reasonable that dichlorvos is applied by embedding on the ground near the strawberry plants covered plastic film with holes. PMID- 28815366 TI - Abiotic nitrate loss and nitrogenous trace gas emission from Chinese acidic forest soils. AB - There are an increasing number of studies, which have shown the potential importance of abiotic denitrification in nitrogen biogeochemistry through pure chemical coupling between nitrate/nitrite reduction and Fe(II) oxidation. However, there is little direct evidence showing the environmental significance of abiotic nitrate (NO3-) reduction in acidic soils. We assessed the magnitude and gaseous product stoichiometry of abiotic nitrate reduction in acidic forest soils based on sterilized anoxic soil incubations at different soil pHs and nitrate loadings. The results showed that 24.9, 53.4, and 88.7% of added nitrate (70 mg N kg-1) were lost during 15 days incubation at pHs 3.9, 4.8, and 5.6, respectively. Nitrous oxide (N2O) was found as the dominant gaseous product of abiotic nitrate reduction, accounting for 5.0, 28.9, and 47.9% of nitrate losses at three pH levels, respectively. Minor but clear NO accumulations were observed for all nitrate-amended treatments, with the maxima at intermediate pH 4.8. The percentage of NO increased significantly with soil pH decline, leading to a negative correlation between NO/N2O ratio and soil pH. Though saturations were found under excessive nitrogen loading (i.e., 140 mg N kg-1), we still pose that abiotic nitrate reduction may represent a potentially important pathway for nitrate loss from acidic forest soils receiving nitrogen deposition. Our results here highlight the importance of abiotic nitrate reduction in the soil nitrogen cycle, with special relevance to nitrate removal and nitrogenous trace gas (NO and N2O) emissions from acidic soils. PMID- 28815367 TI - Microplastic pollution, a threat to marine ecosystem and human health: a short review. AB - Human populations are using oceans as their household dustbins, and microplastic is one of the components which are not only polluting shorelines but also freshwater bodies globally. Microplastics are generally referred to particles with a size lower than 5 mm. These microplastics are tiny plastic granules and used as scrubbers in cosmetics, hand cleansers, air-blasting. These contaminants are omnipresent within almost all marine environments at present. The durability of plastics makes it highly resistant to degradation and through indiscriminate disposal they enter in the aquatic environment. Today, it is an issue of increasing scientific concern because these microparticles due to their small size are easily accessible to a wide range of aquatic organisms and ultimately transferred along food web. The chronic biological effects in marine organisms results due to accumulation of microplastics in their cells and tissues. The potential hazardous effects on humans by alternate ingestion of microparticles can cause alteration in chromosomes which lead to infertility, obesity, and cancer. Because of the recent threat of microplastics to marine biota as well as on human health, it is important to control excessive use of plastic additives and to introduce certain legislations and policies to regulate the sources of plastic litter. By setup various plastic recycling process or promoting plastic awareness programmes through different social and information media, we will be able to clean our sea dustbin in future. PMID- 28815368 TI - Proteomics analysis identified a DRT protein involved in arsenic resistance in Populus. AB - KEY MESSAGE: A DRT protein was identified and proved to be involved in the poplar arsenic resistance through comparative proteomics analysis between arsenic sensitive and resistant cultivars. Arsenic pollution in soil has been a serious problem all over the world. It is very important to dissect plants arsenic stress response mechanisms in phytoremediation. In this study, arsenate-tolerant Populus deltoides cv. 'zhonglin 2025' and arsenate-sensitive Populus * euramericana cv. 'I-45/51' were screened from 10 poplar varieties. Systematic comparisons between these two cultivars demonstrated that 'zhonglin 2025' exhibited slighter morphological and structural injury, lower ROS and MDA accumulation, and higher photosynthesis and ROS scavenging ability under arsenate stress, compared with 'I 45/51'. Through comparative proteomics analysis, we detected that most of the identified arsenate-responsive proteins were stress and defense related. Among these proteins, PdDRT102 was found to be only highly induced in 'zhonglin 2025' under arsenate stress. Heterologous over-expression of PdDRT102 in Arabidopsis conferred to enhanced tolerance to arsenate and sodium chloride. PdDRT102 localizes to the plasma membrane and the nucleus in Arabidopsis. Interestingly, the remarkably increased fluorescence protein signals in the nucleus were found during arsenate stress. Together, these results not only provided an overall understanding on poplar response to arsenate stress, but also revealed that DRT102 protein might involve in protecting poplar against this stress. PMID- 28815371 TI - [Side Effects of Modernity : Dam Building, Health Care, and the Construction of Power in the Context of the Control of Schistosomiasis in Egypt in the 1960s and early 1970s]. AB - This article analyzes the modernization campaigns in Egypt in the 1960s and early 1970s. The regulation of the Nile by the Aswan High Dam and the resulting irrigation projects caused the rate of schistosomiasis infestation in the population to rise. The result was a discourse between experts from the global north and Egyptian elites about modernization, development aid, dam building and health care. The fight against schistosomiasis was like a cipher, which combined different power-laden concepts and arguments. This article will decode the cipher and allow a deeper look into the contemporary dimensions of power bound to this subject. The text is conceived around three thematic axes. The first deals with the discursive interplay of modernization, health and development aid in and for Egypt. The second focuses on far-reaching and long-standing arguments within an international expert discourse about these concepts. Finally, the third presents an exemplary case study of West German health and development aid for fighting schistosomiasis in the Egyptian Fayoum oasis. PMID- 28815369 TI - Suspended particulate matter collection methods influence the quantification of polycyclic aromatic compounds in the river system. AB - In this study, we compared the influence of two different collection methods, filtration (FT) and continuous flow field centrifugation (CFC), on the concentration and the distribution of polycyclic aromatic compounds (PACs) in suspended particulate matter (SPM) occurring in river waters. SPM samples were collected simultaneously with FT and CFC from a river during six sampling campaigns over 2 years, covering different hydrological contexts. SPM samples were analyzed to determine the concentration of PACs including 16 polycyclic aromatic hydrocarbons (PAHs), 11 oxygenated PACs (O-PACs), and 5 nitrogen PACs (N PACs). Results showed significant differences between the two separation methods. In half of the sampling campaigns, PAC concentrations differed from a factor 2 to 30 comparing FT and CFC-collected SPMs. The PAC distributions were also affected by the separation method. FT-collected SPM were enriched in 2-3 ring PACs whereas CFC-collected SPM had PAC distributions dominated by medium to high molecular weight compounds typical of combustion processes. This could be explained by distinct cut-off threshold of the two separation methods and strongly suggested the retention of colloidal and/or fine matter on glass-fiber filters particularly enriched in low molecular PACs. These differences between FT and CFC were not systematic but rather enhanced by high water flow rates. PMID- 28815370 TI - Effects of small hydropower plants on mercury concentrations in fish. AB - Although the impacts of large dams on freshwater biota are relatively well known, the effects of small hydropower plants (SHP) are not well investigated. In this work, we studied if mercury (Hg) concentrations in fish rise in two tropical SHP reservoirs, and whether similar effects take place during impoundment. Total Hg concentrations in several fish species were determined at two SHP in the Upper Guapore River basin floodplain, Brazil. In total, 185 specimens were analysed for Hg content in dorsal muscle and none of them reported levels above the safety limit (500 MUg kg-1) for fish consumption recommended by the World Health Organisation (WHO). The highest levels of Hg (231 and 447 MUg kg-1) were found in carnivorous species in both reservoirs. Mercury increased as a function of standard length in most of the fish populations in the reservoirs, and higher Hg concentrations were found in fish at the reservoir compared with fish downstream. The high dissolved oxygen concentrations and high transparency of the water column (i.e. oligotrophic reservoir) together with the absence of thermal stratification may explain low Hg methylation and low MeHg levels found in fish after flooding. Overall, according to limnological characteristics of water, we may hypothesise that reservoir conditions are not favourable to high net Hg methylation. PMID- 28815372 TI - Do TRPV1 antagonists increase the risk for skin tumourigenesis? A collaborative in vitro and in vivo assessment. AB - A recent hypothesis suggesting that the pharmacological target TRPV1 (transient receptor potential vanilloid subfamily, member 1) may function as a tumour suppressor, which potentially impacts the development of TRPV1 antagonist therapeutics for a range of conditions. However, little is known about the long term physiologic effects of TRPV1 blockade in the skin. In vitro and in vivo studies suggested that the potent TRPV1 competitive antagonist AMG-9810 promoted proliferation in N/TERT1 cells (telomerase-immortalised primary human keratinocytes 1) and tumour development in mouse skin that was mediated through EGFR/Akt/mTOR signalling. We attempted to reproduce the reported in vitro and in vivo findings to further explore this hypothesis to understand the underlying mechanism and the risk associated with TRPV1 antagonism in the skin. In vitro proliferation studies using multiple methods and topical application with AMG 9810 and structurally similar TRPV1 antagonists such as SB-705498 and PAC-14028 were performed. Although we confirmed expression of TRPV1 in primary human epidermal keratinocytes (HEKn) and spontaneously immortalised human keratinocytes (HaCaT), we were unable to demonstrate cell proliferation in either cell type or any clear evidence of increased expression of proteins in the EGFR/Akt/mTOR signalling pathway with these molecules. We were also unable to demonstrate skin tumour promotion or underlying molecular mechanisms involved in the EGFR/Akt/mTOR signalling pathway in a single-dose and two-stage carcinogenesis mouse study treated with TRPV1 antagonists. In conclusion, our data suggest that inhibiting the pharmacological function of TRPV1 in skin by specific antagonists has not been considered to be indicative of skin tumour development. PMID- 28815375 TI - Disparities in Emergency Department Wait Time Among Patients with Mental Health and Substance-Related Disorders. AB - This study examined disparities in emergency department (ED) wait time for patients with mental health and substance-related disorders (PwMHSDs), using data from the 2009-2011 National Hospital Ambulatory Medical Care Survey (NHAMCS). Wait time was defined as the time between arrival at ED and being seen by an ED provider. Results from multivariable regression models show racial disparities, with non-Hispanic Black PwMHSDs experiencing longer ED wait time, compared to non Hispanic White PwMHSDs. A temporal decline in ED wait time was also observed over the study period. The findings of this study have implications for informing the development of policies tailored at facilitating the delivery of equitable emergency care services to all PwMHSDs. PMID- 28815374 TI - The roles of physical activity and sedentary behavior on Hispanic children's mental health: a motor skill perspective. AB - PURPOSE: Motor competence (MC) has been recognized as the foundation for life time moderate-to-vigorous physical activity (MVPA) as well as an influential factor in reducing sedentary behavior during childhood. Guided by Blair et al.'s health model, the purpose of this study was to examine the behavioral mechanism of mental health including physical, psychosocial, and cognitive health among Hispanic children related to MC and MVPA. METHODS: A prospective research design was used with two-wave assessments across one academic year. A total of 141 Hispanic kindergarteners (Meanage = 5.37, SD = 0.48) were recruited in Texas. Nearly all (94.3%) of the participants were from low-income families based on the Income Eligibility Guidelines. The study was approved by the University Research Review Board, and informed consent was obtained from parents/guardians prior to starting the study. RESULTS: Multiple regressions indicated that manipulative skill was a significant predictor of physical and psychosocial health (beta = 0.21, beta = 0.26, p < 0.05, respectively) and locomotor skill served as a significant predictor for cognitive health (beta = 0.22, p < 0.01), after controlling for BMI. Bootstrapping analyses supported the statistical significance of indirect effects of MC on mental health outcomes through MVPA (95% CI [0.031, 0.119]) and sedentary behavior (95% CI [0.054, 0.235]), respectively. CONCLUSION: The results suggest that skill-based activities/games, with instructions, should be encouraged during school-based physical activity and health promotion programs in childhood education. Better understanding of the early effects of MC may contribute to designing strategies to promote Hispanic children's well-being. PMID- 28815373 TI - Autologous nasal chondrocytes delivered by injectable hydrogel for in vivo articular cartilage regeneration. AB - Cell based tissue engineering serves as a promising strategy for articular cartilage repair, which remains a challenge both for researchers and clinicians. The aim of this research was to assess the potential of autologous nasal chondrocytes (NCs) combined with alginate hydrogel as injectable constructs for rabbit articular cartilage repair. Autologous nasal chondrocytes were isolated from rabbit nasal septum, expanded either on monolayer or in 3D alginate hydrogel. In vitro, DNA quantification revealed that NCs can proliferate stable in 3D alginate matrix, but slower than that cultured in monolayer. Further, a higher synthesis rate of glycosaminoglycans (GAGs) was detected by GAG measurement in 3D alginate culture. Gene expression analysis at different time point (day 1, 7, 14) showed that 3D culture of NCs in alginate up-regulated chondrogenic markers (Col2A1, ACAN SOX9), meanwhile down-regulated dedifferentiation related gene (Col1A1). In vivo, autologous nasal chondrocytes combined with alginate hydrogel were used for repairing rabbit knee osteochondral defect (Alg + NC group). Histological staining indicated that Alg + NC group obtained superior and more hyaline-like repaired tissue both at 3 and 6 months after surgery. Mechanical analysis showed that the repaired tissue in the Alg + NC group possessed similar mechanical properties to the native cartilage. In conclusion, nasal chondrocytes appeared to be a very promising seed cell source for cartilage tissue engineering, and alginate hydrogel can serve as suitable delivery system. PMID- 28815376 TI - Evaluation of genetic and non-genetic factors on foot and mouth disease (FMD) virus vaccine-elicited immune response in Hardhenu (Bos taurus x Bos indicus) cattle. AB - Foot and mouth disease (FMD) is the most contagious disease of mammals and a major threat to animal husbandry sector. In India, vaccination with the inactivated trivalent (O, A and Asia1) vaccine is one proven way for protecting the livestock from FMD. However, many outbreaks have been reported in different parts of the country. Therefore, present study was aimed at elucidating the effects of genetic and non-genetic factors on FMD viral vaccine-elicited immune response in Hardhenu cattle. The effect of season of vaccination was not consistent. The effect of status of animal was significant for all the pre and post AB titres except for pre AB titre of serotype O and post AB titre of Asia1.The estimates of heritability for response to vaccination were low to high ranging from 0.11 to 0.45. The highest heritability estimate was obtained for serotype O and the lowest for Asia1. The heritability estimates for pre and post AB titres ranged from 0.15 to 0.33. All the pre and post AB titres and responses to vaccination had genetic correlations ranged from high negative to high positive among them. Results of this study highlight the variation in vaccine response which needs to be further exploited on large-scale animal data for better immunization and protection against highly contagious viral vesicular disease of cloven-hoofed animals. PMID- 28815377 TI - Bacterial community structures in air conditioners installed in Japanese residential buildings. AB - The bacterial community structures in four Japanese split-type air conditioners were analyzed using a next-generation sequencer. A variety of bacteria were detected in the air filter of an air conditioner installed on the first floor. In the evaporator of this air conditioner, bacteria belonging to the genus Methylobacterium, or the family of Sphingomonadaceae, were predominantly detected. On the other hand, the majority of bacteria detected in the air filters and evaporators of air conditioners installed on the fifth and twelfth floors belonged to the family Enterobacteriaceae. The source of bacteria belonging to the family Enterobacteriaceae may have been aerosols generated by toilet flushing in the buildings. Our results suggested the possibility that the bacterial contamination in the air conditioners was affected by the floor level on which they were installed. The air conditioner installed on the lower floor, near the ground, may have been contaminated by a variety of outdoor bacteria, whereas the air conditioners installed on floors more distant from the ground may have been less contaminated by outdoor bacteria. However, these suppositions may apply only to the specific split-type air conditioners that we analyzed, because our sample size was small. PMID- 28815379 TI - A 450 Year Old Turkish Poem, Art as a Qualitative Investigation Tool, Buddhist Deathways, Karma and Eudaimonia in Death and Organ Donation: The Wonders of Truly Diverse Bioethical Inquiry! PMID- 28815378 TI - Effect of aging on mechanical stresses, deformations, and hemodynamics in human femoropopliteal artery due to limb flexion. AB - Femoropopliteal artery (FPA) reconstructions are notorious for poor clinical outcomes. Mechanical and flow conditions that occur in the FPA with limb flexion are thought to play a significant role, but are poorly characterized. FPA deformations due to acute limb flexion were quantified using a human cadaver model and used to build a finite element model that simulated surrounding tissue forces associated with limb flexion-induced deformations. Strains and intramural principal mechanical stresses were determined for seven age groups. Computational fluid dynamics analysis was performed to assess hemodynamic variables. FPA shape, stresses, and hemodynamics significantly changed with age. Younger arteries assumed straighter positions in the flexed limb with less pronounced bends and more uniform stress distribution along the length of the artery. Even in the flexed limb posture, FPAs younger than 50 years of age experienced tension, while older FPAs experienced compression. Aging resulted in localization of principal mechanical stresses to the adductor hiatus and popliteal artery below the knee that are typically prone to developing vascular pathology. Maximum principal stresses in these areas increased threefold to fivefold with age with largest increase observed at the adductor hiatus. Atheroprotective wall shear stress reduced after 35 years of age, and atheroprone and oscillatory shear stresses increased after the age of 50. These data can help better understand FPA pathophysiology and can inform the design of targeted materials and devices for peripheral arterial disease treatments. PMID- 28815381 TI - A Virtuous Death: Organ Donation and Eudaimonia. PMID- 28815380 TI - Expression of microRNAs in tumors of the central nervous system in pediatric patients in Mexico. AB - PURPOSE: MicroRNAs were identified as molecules that participate in gene regulation; alterations in their expression characterize central nervous system (CNS). Information in pediatrics is scarce, so the objective of this work was to determine and then compare the patterns of expression of microRNAs in astrocytomas, ependymomas, and medulloblastomas, as well as in non-neoplastic brain. METHODS: Low-density arrays were utilized to evaluate 756 microRNAs in three samples of each type of tumor and non-neoplastic brain. The relative expression was calculated in order to identify the three microRNAs whose expression was modified notably. This was verified using RT-qPCR in more number of tumor samples. RESULTS: The microRNAs selected for testing were miR-100-5p, miR-195-5p, and miR-770-5p. A higher expression of miR-100-5p was observed in the astrocytomas and ependymomas compared to the medulloblastomas: on average 3.8 times (p < 0.05). MiR-770-5p was expressed less in medulloblastomas compared to astrocytomas four times (p = 0.0162). MiR-195-5p had a low expression in medulloblastomas compared to non-neoplastic cerebellum (p = 0.049). In all three tumor types, expression of miR-770-5p was lower than in non-neoplastic brain (p < 0.001). CONCLUSIONS: These microRNAs may represent potential markers in these tumors. PMID- 28815382 TI - Spontaneous cross-species imitation in interactions between chimpanzees and zoo visitors. AB - Imitation is a cornerstone of human development, serving both a cognitive function (e.g. in the acquisition and transmission of skills and knowledge) and a social-communicative function, whereby the imitation of familiar actions serves to maintain social interaction and promote prosociality. In nonhuman primates, this latter function is poorly understood, or even claimed to be absent. In this observational study, we documented interactions between chimpanzees and zoo visitors and found that the two species imitated each other at a similar rate, corresponding to almost 10% of all produced actions. Imitation appeared to accomplish a social-communicative function, as cross-species interactions that contained imitative actions lasted significantly longer than interactions without imitation. In both species, physical proximity promoted cross-species imitation. Overall, imitative precision was higher among visitors than among chimpanzees, but this difference vanished in proximity contexts, i.e. in the indoor environment. Four of five chimpanzees produced imitations; three of them exhibited comparable imitation rates, despite large individual differences in level of cross-species interactivity. We also found that chimpanzees evidenced imitation recognition, yet only when visitors imitated their actions (as opposed to postures). Imitation recognition was expressed by returned imitation in 36% of the cases, and all four imitating chimpanzees engaged in so-called imitative games. Previously regarded as unique to early human socialization, such games serve to maintain social engagement. The results presented here indicate that nonhuman apes exhibit spontaneous imitation that can accomplish a communicative function. The study raises a number of novel questions for imitation research and highlights the imitation of familiar behaviours as a relevant-yet thus far understudied-research topic. PMID- 28815383 TI - A 5-Year Follow-Up Study of Laparoscopic Sleeve Gastrectomy Among Morbidly Obese Adolescents: Does It Improve Body Image and Prevent and Treat Diabetes? AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is widely used, and it is important to examine its physiologic and psychological efficacy among adolescents. We assessed LSG's efficacy for weight loss, its short- and long-term effects on resolving and improving obesity-related comorbidities, and its psychological outcomes among morbidly obese adolescents. METHODS: We retrospectively analyzed the medical records of 91 morbidly obese adolescents in Qatar who underwent LSG (2011-2014), with 1- and 5-year follow-ups. RESULTS: The mean preoperative weight and body mass index (BMI) were 132.5 +/- 25.3 kg and 48 +/- 7.5 kg/m2, respectively. Postoperatively, mean weight and BMI decreased to 101 +/- 22 kg and 36.4 +/- 7.2 kg/m2, respectively. At 1 year, the mean excess weight loss (%EWL), percent total weight loss (%TWL), and percent BMI loss (%BMIL) were 49.48 +/- 25.8, 23.1 +/- 11.9, and 23.16 +/- 11.8%, respectively. At 5 years, %EWL, %TWL, and %BML were 78 +/- 12, 35.8 +/- 11.5, and 36 +/- 12%, respectively. No patients developed postoperative leaks, and three patients had endoscopic dilatation due to stenosis. Overall, 64% of obstructive sleep apnea patients were cured, all prediabetic patients had total remission, and 50% of the diabetic patients were cured. The overall mean HBA1c level was 6 mmol/L, which significantly decreased to 5.1 mmol/L postoperatively (P = 0.0001). At 5 years, there was no relapse of diabetes, and 75% of the diabetic adolescents had complete remission. The only patient with hypertension showed complete resolution with laparoscopic sleeve gastrectomy. Postoperatively, overall body image satisfaction significantly improved (P = 0.0001). CONCLUSION: LSG significantly ameliorated short- and long-term obesity-related comorbidities and body image dissatisfaction among Qatari adolescents. PMID- 28815385 TI - Stretching the Boundaries of Parental Responsibility and New Legal Guidelines for Determination of Brain Death. PMID- 28815384 TI - Association between discordance of LDL-C and non-HDL-C and clinical outcomes in patients with stent implantation: from the FU-Registry. AB - It is not yet clear whether the discordance of low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) predicts the follow-up clinical outcome (major adverse cardiovascular events: MACEs) in patients with coronary stent implantation. Among 2015 patients with coronary stent implantation (Fukuoka University [FU]-Registry), excluding those with acute coronary syndrome or hemodialysis, we selected 801 patients who had undergone successful stent implantation with a follow-up until 18 months, and classified them into 3 groups according to baseline LDL-C and non-HDL-C levels [percentile(P)non-HDL-C more than (P)LDL-C, (P)non-HDL-C equal to (P)LDL-C, and (P)non-HDL-C less than (P) LDL-C]. We found that the discordance of (P)LDL-C and (P)non-HDL-C was not a significant predictor of MACEs. Higher LDL-C level was consistently and independently associated with higher incidences of MACEs after controlling for conventional risk factors and the type of stent used by multivariate Cox regression analyses. In conclusion, LDL-C levels are more important than non-HDL-C levels and the discordance of LDL-C and non-HDL-C levels as predictors of MACEs in patients with stable angina after stent implantation. PMID- 28815386 TI - Genomic characterization of a novel calicivirus, FHMCV-2012, from baitfish in the USA. AB - During regulatory sampling of fathead minnows (Pimephales promelas), a novel calicivirus was isolated from homogenates of kidney and spleen inoculated into bluegill fry (BF-2) cells. Infected cell cultures exhibiting cytopathic effects were screened by PCR-based methods for selected fish viral pathogens. Illumina HiSeq next generation sequencing of the total RNA revealed a novel calicivirus genome that showed limited protein sequence similarity to known homologs in a BLASTp search. The complete genome of this fathead minnow calicivirus (FHMCV) is 6564 nt long, encoding a polyprotein of 2114 aa in length. The complete polyprotein shared only 21% identity with Atlantic salmon calicivirus,followed by 11% to 14% identity with mammalian caliciviruses. A molecular detection assay (RT PCR) was designed from this sequence for screening of field samples for FHMCV in the future. This virus likely represents a prototype species of a novel genus in the family Caliciviridae, tentatively named "Minovirus". PMID- 28815387 TI - Image-Guided Surgical Robotic System for Percutaneous Reduction of Joint Fractures. AB - Complex joint fractures often require an open surgical procedure, which is associated with extensive soft tissue damages and longer hospitalization and rehabilitation time. Percutaneous techniques can potentially mitigate these risks but their application to joint fractures is limited by the current sub-optimal 2D intra-operative imaging (fluoroscopy) and by the high forces involved in the fragment manipulation (due to the presence of soft tissue, e.g., muscles) which might result in fracture malreduction. Integration of robotic assistance and 3D image guidance can potentially overcome these issues. The authors propose an image-guided surgical robotic system for the percutaneous treatment of knee joint fractures, i.e., the robot-assisted fracture surgery (RAFS) system. It allows simultaneous manipulation of two bone fragments, safer robot-bone fixation system, and a traction performing robotic manipulator. This system has led to a novel clinical workflow and has been tested both in laboratory and in clinically relevant cadaveric trials. The RAFS system was tested on 9 cadaver specimens and was able to reduce 7 out of 9 distal femur fractures (T- and Y-shape 33-C1) with acceptable accuracy (~1 mm, ~5 degrees ), demonstrating its applicability to fix knee joint fractures. This study paved the way to develop novel technologies for percutaneous treatment of complex fractures including hip, ankle, and shoulder, thus representing a step toward minimally-invasive fracture surgeries. PMID- 28815388 TI - Guiding Patients Toward the Appropriate Surgical Treatment for Obesity: Should Presurgery Psychological Correlates Influence Choice Between Roux-en-Y Gastric Bypass and Vertical Sleeve Gastrectomy? AB - BACKGROUND: Helping patients determine which type of bariatric surgery, Roux-en-Y gastric bypass (RYGB) or vertical sleeve gastrectomy (VSG), may be the best treatment can be challenging. This study investigated psychological correlates and their influence on weight loss for patients who underwent RYGB or VSG. METHODS: Four hundred twenty-two patients (RYGB = 305; VSG = 117) completed screening questionnaires presurgery and underwent surgery between August 2012 and April 2015. Associations between demographics and questionnaires with percentage weight change were evaluated using multivariable linear regression models. RESULTS: Median age was 48 years and median BMI 45.3 kg/m2 presurgery. Median percentage changes in weight from baseline to years 1 and 2 follow-up were - 31.5% (range - 52.2 to - 9.2%) and - 31.2% (range - 50.0 to - 1.2%) for RYGB and 25.3% (range - 49.8 to - 4.7%) and - 23.3% (range - 58.9 to - 1.6%) for VSG, respectively. Linear regression models revealed that younger patients lost more weight than older patients at years 1 (RYGB p < 0.0001; VSG p = 0.0001) and 2 (RYGB p = 0.005; VSG p = 0.002). No psychological correlates were significantly associated with weight loss outcomes. Post hoc analyses comparing patients who had surgery to those in the same cohort who did not have surgery revealed significantly higher rates of depression (p < 0.001), anxiety (p < 0.001), binge eating (p = 0.003), night eating (p < 0.001), food addiction (p = 0.042), and lower self-efficacy (p < 0.001) among patients who did not have surgery. DISCUSSION: Patients who are psychologically higher functioning are more likely to complete the evaluation process and undergo bariatric surgery. For patients who had surgery, psychological correlates were not associated with weight loss outcome for either RYGB or VSG. Implications for surgical choice are discussed. PMID- 28815389 TI - Spine bone mineral density increases after 6 months of exclusive lactation, even in women who keep breastfeeding. AB - : This pilot study enrolled 31 women who had breastfed exclusively for 6 months. Lumbar and thoracic BMD increased 4 and 5%, respectively. Femoral neck and total body BMD did not change. Return of menses and progestin-only pill use were two potential signals that predicted a greater increase in BMD. PURPOSE/INTRODUCTION: The skeleton is resorbed during lactation to provide much of the calcium content of milk. After lactation ceases, these deficits in skeletal mineral content are largely restored, such that lactation has a neutral or protective effect against the long-term risk of low bone mineral density (BMD), osteoporosis, and fragility fractures. We hypothesized that a large observational study may identify the factors that predict a greater increase in BMD after lactation ceases. A pilot study was first needed to test feasibility and the magnitude of expected BMD change. METHODS: We undertook Factors Affecting Bone formation after Breastfeeding Pilot (FABB Pilot), which enrolled women who had breastfed exclusively for 6 months and planned to wean soon. The main outcome was change in BMD between enrolment and 6 months later. RESULTS: Thirty-one women were recruited and completed both time points. Lumbar and thoracic spine BMD increased 4 and 5%, respectively; there was no significant change in femoral neck and total body BMD. Most women did not wean their babies as planned but continued to breastfeed multiple times per day. Despite this, a significant increase in BMD was seen in the subsequent 6 months. Return of spontaneous menses and use of a progestin-only pill at recruitment were two potential signals that predicted a greater increase in BMD during the 6 months after exclusive lactation. CONCLUSIONS: Spine BMD increased significantly during 6 months following exclusive lactation and despite continued lactation. The factors that stimulate skeletal recovery remain to be identified. PMID- 28815390 TI - Abnormal relationships between local and global brain measures in subjects at clinical high risk for psychosis: a pilot study. AB - We examined whether abnormal volumes of several brain regions as well as their mutual associations that have been observed in patients with schizophrenia, are also present in individuals at clinical high-risk (CHR) for developing psychosis. 3T magnetic resonance imaging was acquired in 19 CHR and 20 age- and handedness matched controls. Volumes were measured for the body and temporal horns of the lateral ventricles, hippocampus and amygdala as well as total brain, cortical gray matter, white matter, and subcortical gray matter volumes. Relationships between volumes as well as correlations between volumes and cognitive and clinical measures were explored. Ratios of lateral ventricular volume to total brain volume and temporal horn volume to total brain volume were calculated. Volumetric abnormalities were lateralized to the left hemisphere. Volumes of the left temporal horn, and marginally, of the body of the left lateral ventricle were larger, while left amygdala but not hippocampal volume was significantly smaller in CHR participants compared to controls. Total brain volume was also significantly smaller and the ratio of the temporal horn/total brain volume was significantly higher in CHR than in controls. White matter volume correlated positively with higher verbal fluency score while temporal horn volume correlated positively with a greater number of perseverative errors. Together with the finding of larger temporal horns and smaller amygdala volumes in the left hemisphere, these results indicate that the ratio of temporal horns volume to brain volume is abnormal in CHR compared to controls. These abnormalities present in CHR individuals may constitute the biological basis for at least some of the CHR syndrome. PMID- 28815391 TI - The Role of Epigenetics in Type 1 Diabetes. AB - PURPOSE OF REVIEW: Epigenetics is defined as mitotically heritable changes in gene expression that do not directly alter the DNA sequence. By implication, such epigenetic changes are non-genetically determined, although they can be affected by inherited genetic variation. Extensive evidence indicates that autoimmune diseases including type 1 diabetes are determined by the interaction of genetic and non-genetic factors. Much is known of the genetic causes of these diseases, but the non-genetic effects are less clear-cut. Further, it remains unclear how they interact to cause the destructive autoimmune process. This review identifies the key issues in the genetic/non-genetic interaction, examining the most recent evidence of the role of non-genetic effects in the disease process, including the impact of epigenetic effects on key pathways. RECENT FINDINGS: Recent research indicates that these pathways likely involve immune effector cells both of the innate and adaptive immune response. Specifically, there is evidence of cell type specific enrichment in altered DNA methylation, changes which were temporally stable and enriched at gene regulatory elements. Epigenomics remains in its infancy, and we anticipate further studies will define how the interaction of genetic and non-genetic effects induces tissue-specific destruction and enhances our ability to predict, and possibly even modify that process. PMID- 28815392 TI - Strategy for CYP3A Induction Risk Assessment from Preclinical Signal to Human: a Case Example of a Late-Stage Discovery Compound. AB - PURPOSE: The exposure of G2917 decreased by four-fold at oral doses of 100 mg/kg twice daily for seven days in cynomolgus monkeys. Additional investigative work was conducted to understand: (1) the causes for the significant reduction in G2917 exposure in monkeys; (2) the extrapolation of in vitro induction data to in vivo findings in monkeys, and (3) the relevance of this pre-clinical finding to humans at the projected human efficacious dose. METHODS: Pharmacokinetic and induction potency (in vitro and in vivo) of G2917 in monkeys, and the in vitro human induction potency were studied. The hepatic CYP3A biomarkers 4beta hydroxycholesterol (4beta-HC) and 6beta-hydroxycortisol/cortisol ratio (6beta OHC/C) were monitored in in vivo studies. The static mechanistic model was used to quantitatively understand the in vitro-in vivo extrapolation (IVIVE) on the magnitude of induction retrospectively. Physiologically based pharmacokinetic (PBPK) modeling was used to predict the human pharmacokinetics and induction based drug-drug interactions (DDI). RESULTS: All in vitro and in vivo data indicate that the significant reduction in exposure of G2917 in monkeys is caused by auto-induction of CYP3A. The mechanistic understanding of IVIVE of G2917 induction in monkey provides higher confidence in the induction risk prediction in human using the PBPK modeling. PBPK model analysis predicted minimum auto induction and DDI liability in humans at the predicted efficacious dose. CONCLUSIONS: The learning of this example provided a strategy to address the human CYP3A induction risk prospectively when there is an auto-induction finding in preclinical toxicology study. PMID- 28815393 TI - Pattern noise (PANO): a new automated functional glaucoma test. AB - PURPOSE: To present a newly developed visual field device (pattern noise: PANO) designed to be sensitive to glaucoma defects, cost-effective, material-practical and easy to repair and therefore particularly suited for low-income countries, where glaucoma can be highly prevalent (e.g. sub-Saharan Africa). METHODS: This is primarily a descriptive paper, but it also includes a prospective matched case control pilot study. Hardware, stimulus, target configuration, testing strategy and result sheet are described. The main outcome measure is the contrast level (range 2-64). Targets are composed of bright/dark pixels flickering with 18 Hz and have a size of 5 degrees . Pixel size is approximated to the hill of vision. Average luminance of targets is constant and equals background luminance.The study was performed in the West Region in Cameroon. Twenty eyes of 20 newly presenting patients with glaucomatous optic disc cupping on funduscopy were compared with 20 eyes of 20 normal patients matched in age and laterality of eye. RESULTS: Mean age was 32.9 +/- 18.8 years for glaucoma patients and 32.2 +/- 15.6 years for healthy subjects. Mean contrast threshold was significantly higher in eyes with abnormal disc (16.2 +/- 14.3 vs. 4.4 +/- 0.8, P = 0.002). Correlation of mean contrast thresholds and cup-to-disc ratio was significant (r = 0.59; P = 0.006). Average examination time was significantly longer for glaucoma eyes compared to healthy eyes (8.2 vs. 6.1 min, P < 0.001), whereas error rate did not differ (4.8 +/- 2.5% vs. 4.1 +/- 1.8%, P = 0.33). CONCLUSION: PANO demonstrated visual field defects in patients with glaucomatous optic disc. Defects correlated significantly with glaucomatous optic nerve head morphological alterations. Healthy eyes obtained normal results. More studies are needed to establish PANO. PMID- 28815395 TI - Identification of a novel envelope protein encoded by ORF 136 from Cyprinid herpesvirus 3. AB - Cyprinid herpesvirus 3 (CyHV-3) is the pathogenic agent of koi herpesvirus disease (KHVD) afflicting common carp and koi (Cyprinus carpio L.) populations globally. As described previously, proteomic analyses of purified CyHV-3 particles have shown that at least 46 structural proteins are incorporated into CyHV-3 virions; among these ORF136 may encode a putative envelope protein. In this study, Western blotting analysis showed that a specific band with the predicted molecular weight of 17 kDa was detected both in purified virions and envelope components using a rabbit anti-ORF136 polyclonal antibody. Indirect immunofluorescence assay with confocal laser scanning microscopy indicated that the ORF136 protein was distributed in the cytoplasm of CCB cells infected with CyHV-3 and transfected with a pVAX1-ORF136 plasmid. Furthermore, immunogold electron microscopy confirmed that ORF136 protein localized to the CyHV-3 envelope. PMID- 28815396 TI - Reconciling Spirituality and Workplace: Towards a Balanced Proposal for Occupational Health. AB - We examined the relationship between spirituality in the workplace and occupational health and explored the benefits for employees, employers and the organisation. Using a qualitative methodology, we focused on secular organisations in the service sector to analyse this question in the context of labour relations in Europe. Our results indicate that embracing spirituality in the workplace yields a number of benefits in addition to those of a health related nature. Religious beliefs and practices can be accommodated in the workplace provided that a balance is maintained between the needs of employers and employees. PMID- 28815394 TI - Shared Dysregulation of Homeostatic Brain-Body Pathways in Depression and Type 2 Diabetes. AB - PURPOSE OF REVIEW: The purpose of this review is to provide an overview of shared dysregulation of the hypothalamic-pituitary-adrenal (HPA) and brain-gut microbiome (BGM) axes associated with depression and type 2 diabetes (T2D). Clinical implications and future research are also discussed. RECENT FINDINGS: Both depression and T2D are associated with dysregulation of the HPA and BGM axes. These pathways regulate immune function, glucose metabolism, and sleep, which are altered in both illnesses. Dysregulation of homeostatic brain-body pathways may be positively influenced through different therapeutic actions, including psychotherapy, healthy eating, physical activity, sleep promotion, and certain anti-inflammatory or antidepressant medications. While the causal nature of the relationship between depression and T2D remains unclear, these conditions share dysregulation of homeostatic brain-body pathways that are central to mental and physical health. Better understanding of this dysregulation may provide opportunities for interventions that could benefit both conditions. Future research should examine the additive burden of depression and T2D on HPA and BGM dysregulation and better differentiate depression from emotional distress. PMID- 28815397 TI - Detecting and accounting for multiple sources of positional variance in peak list registration analysis and spin system grouping. AB - Peak lists derived from nuclear magnetic resonance (NMR) spectra are commonly used as input data for a variety of computer assisted and automated analyses. These include automated protein resonance assignment and protein structure calculation software tools. Prior to these analyses, peak lists must be aligned to each other and sets of related peaks must be grouped based on common chemical shift dimensions. Even when programs can perform peak grouping, they require the user to provide uniform match tolerances or use default values. However, peak grouping is further complicated by multiple sources of variance in peak position limiting the effectiveness of grouping methods that utilize uniform match tolerances. In addition, no method currently exists for deriving peak positional variances from single peak lists for grouping peaks into spin systems, i.e. spin system grouping within a single peak list. Therefore, we developed a complementary pair of peak list registration analysis and spin system grouping algorithms designed to overcome these limitations. We have implemented these algorithms into an approach that can identify multiple dimension-specific positional variances that exist in a single peak list and group peaks from a single peak list into spin systems. The resulting software tools generate a variety of useful statistics on both a single peak list and pairwise peak list alignment, especially for quality assessment of peak list datasets. We used a range of low and high quality experimental solution NMR and solid-state NMR peak lists to assess performance of our registration analysis and grouping algorithms. Analyses show that an algorithm using a single iteration and uniform match tolerances approach is only able to recover from 50 to 80% of the spin systems due to the presence of multiple sources of variance. Our algorithm recovers additional spin systems by reevaluating match tolerances in multiple iterations. To facilitate evaluation of the algorithms, we developed a peak list simulator within our nmrstarlib package that generates user-defined assigned peak lists from a given BMRB entry or database of entries. In addition, over 100,000 simulated peak lists with one or two sources of variance were generated to evaluate the performance and robustness of these new registration analysis and peak grouping algorithms. PMID- 28815398 TI - Characterization of host response, resorption, and strength properties, and performance in the presence of bacteria for fully absorbable biomaterials for soft tissue repair. AB - PURPOSE: The objective was to evaluate the host response, resorption, and strength properties, and to assess the performance in the presence of bacteria for PhasixTM Mesh (PhasixTM) and Gore(r) Bio-A(r) Tissue Reinforcement (Bio-A(r)) in preclinical models. METHODS: In a rat model, one mesh (2 * 2 cm) was implanted subcutaneously in n = 60 rats. Animals were euthanized after 2, 4, 8, 12, 16, or 24 weeks (n = 5/mesh/time point), and implant sites were assessed for host inflammatory response and overall fibrotic repair thickness. In a rabbit model, meshes (3.8 cm diameter) were bilaterally implanted in subcutaneous pockets in n = 20 rabbits (n = 10 rabbits/mesh) and inoculated with 108 CFU clinically isolated methicillin-resistant Staphylococcus aureus (MRSA). One mesh type was implanted per animal. Animals were euthanized after 7 days, and implants were assessed for abscess formation, bacterial colonization, and mechanical strength. RESULTS: In the rat study, PhasixTM and Bio-A(r) exhibited similar biocompatibility, although Bio-A(r) demonstrated a significantly greater inflammatory response at 4 weeks compared to PhasixTM (p < 0.01). Morphometric analysis demonstrated rapid resorption of Bio-A(r) implants with initially thicker repair sites at 2, 4, 8, and 12 weeks (p < 0.0001), which transitioned to significantly thinner sites compared to PhasixTM at 16 and 24 weeks (p < 0.0001). In the rabbit bacterial inoculation study, PhasixTM exhibited significantly lower abscess score (p < 0.001) and bacterial colonization (p < 0.01), with significantly greater mechanical strength than Bio-A(r) (p < 0.001). CONCLUSIONS: Host response, resorption, repair thickness, strength, and bacterial colonization suggest a more stable and favorable outcome for monofilament, macroporous devices such as PhasixTM relative to multifilament, microporous devices such as Bio-A(r) over time. PMID- 28815399 TI - An "aubergine" in the heart: huge native mitral valve endocarditis caused by Streptococcus agalactiae. PMID- 28815400 TI - Advance Directives and the Descendant Argument. AB - By issuing an advance treatment directive, an autonomous person can formally express what kinds of treatment she wishes and does not wish to receive in case she becomes ill or injured and unable to autonomously decide about her treatment. While many jurisdictions and medical associations endorse them, advance treatment directives have also been criticized. According to an important criticism, when a person irreversibly loses her autonomy what she formerly autonomously desired ceases to be of (central) importance in deciding about her treatment. The medical ethical debate regarding different possible ways of solving the problem on which the criticism is based has grown exceedingly intricate. Instead of assessing the developments made in the debate so far, I present a thought experiment-built around a suicide case-which suggests that the problem is not as intractable as it has generally been deemed to be. PMID- 28815401 TI - Abdominal infection reveals a rare disease. PMID- 28815402 TI - Covered Esophageal Stenting Is Effective for Symptomatic Gastric Lumen Narrowing and Related Complications Following Laparoscopic Sleeve Gastrectomy. AB - BACKGROUND AND STUDY AIMS: Laparoscopic sleeve gastrectomy (LSG) is gaining popularity in treating morbid obesity. Prior studies showed a 3.5% risk of gastric sleeve stenosis (GSS). There is no consensus on how to treat these patients, and the role of endoscopic therapy has been addressed in only a few studies. We aim to assess the efficacy and safety of endoscopic stenting in the management of GSS following LSG. PATIENTS AND METHODS: Retrospective data were reviewed from July 2009 to November 2013. Patients were referred for endoscopic therapy for symptoms or imaging findings suggestive of gastric leak or narrowing following LSG. Endoscopic therapy included the use of fully covered self expanding esophageal metal stents (FCSEMS) in addition to over-the-scope clip system (OTSC) when necessary. RESULTS: All 27 patients were females with mean age of 40 years; six patients were excluded from the study. Major symptom was nausea and vomiting in 57% of the patients. Five of 21 patients had concomitant leaks. All 21 patients underwent FCSEMS placement, and four out of five patients (80%) with concomitant leak had OTSC. The success rate in both groups for resolution of stricture and leak was 100%, and no surgical intervention was required. There were no immediate or delayed complications of endoscopic therapy. Median follow up of 6 months was available for 20/21 patients. Among patients with gastric leak, 80% had resolution of their symptoms compared with 93% of patients with GSS. CONCLUSIONS: Endoscopic therapy for LSG-related GSS or leaks with FCSEMS is highly effective and safe. PMID- 28815404 TI - Neurological Presentation of Zika Virus Infection Beyond the Perinatal Period. AB - PURPOSE OF REVIEW: Our purpose was to summarize the current knowledge about the neurological presentation of Zika virus infection after the perinatal period. Other Flaviviruses infections, such as West Nile virus (WNV) or Japanese encephalitis virus (JEV), can result in neuro-invasive disease such as myelitis, encephalitis, or meningitis. We aimed at describing the specificities of ZV neurological infection. RECENT FINDINGS: The recent outbreaks demonstrated clearly the neurotropism of ZV. However, by contrast with other Flaviviruses, the most frequent neurological presentation of ZV infection beyond the perinatal period was Guillain-Barre syndrome, especially the demyelination form of GBS. Encephalitis and myelitis seem to occur less frequently after ZV infection than after WNV or JEV infection. The pathophysiology of neurological ZV infections is still poorly understood and no specific treatment is available. Moreover, no data is available about long-term persisting symptoms and possible impairment of patients after the acute clinical episode. PMID- 28815405 TI - Supplemented Organic and Inorganic Selenium Affects Milk Performance and Selenium Concentration in Milk and Tissues in the Guanzhong Dairy Goat. AB - Trace amounts of selenium (Se) are essential for several organisms, and deficiencies therein have adverse effects on growth, development, and reproduction; this is particularly significant in animals raised for milk and livestock production. To study the effect of Se on Guanzhong dairy goats, their diets were supplemented with different sources (inorganic or organic) and Se concentrations (0.2 or 0.4 mg Se/kg). A non-Se-fortified basal diet served as a negative control, and a sixth treatment group received both inorganic and organic Se sources (0.2 mg Se/kg diet each). Dietary Se supplementation increased milk production, with organic Se being more effective than inorganic Se. Selenium supplementation also increased Se concentration and glutathione peroxidase activity in whole blood, with organic Se more effective than inorganic Se at the same Se concentration. With increasing Se in diets, the Se content in milk increased markedly, reaching a plateau value at day 30 in all groups, and organic Se (0.4 mg/kg diet) had the best effect. In addition, dietary Se sources and concentrations markedly affected Se concentrations in different tissues and organs. Thus, organic Se supplementation of a basal diet at 0.4 mg/kg is practically applicable for Se-enriched milk and meat production in Guanzhong dairy goats. PMID- 28815403 TI - Overexpression of Topoisomerase 2-Alpha Confers a Poor Prognosis in Pancreatic Adenocarcinoma Identified by Co-Expression Analysis. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of human cancer-related death in the developed countries. Its progression and prognosis are influenced by a complex network of gene interactions. AIMS: The purpose of this study is to explore key genes associated with pancreatic ductal adenocarcinoma and to predict the possible mechanisms. METHODS: A weighted gene co-expression network was constructed to identify gene modules associated with the progression of PDAC. RESULTS: In the significant module (R 2 = 0.30), a total of 20 network hub genes were identified, 6 of which were also hub nodes in the protein-protein interaction network of the module genes. In validation, TOP2A has a higher correlation than other hub genes. Also, in the test set (n = 118), TOP2A was more highly expressed in PDAC than normal pancreas samples (P < 0.001). What is more, gene set enrichment analysis demonstrated that eight gene sets (n = 118), "nucleotide excision repair," "P53 signaling pathway," "proteasome," "mismatch repair," "homologous recombination," "DNA replication," "cell cycle," and "base excision repair," were enriched (FDR < 0.05). In gene ontology analysis, TOP2A in the enriched set was associated with cell cycle and cell division. Furthermore, survival analysis indicated that higher expression of TOP2A resulted in the lower overall survival time as well as disease-free survival time. CONCLUSION: TOP2A was identified in association with the progression and prognosis of PDAC probably by regulating cell cycle and p53 signaling pathway. PMID- 28815406 TI - Successful management of a hydropic fetus with severe anemia and thrombocytopenia caused by anti-CD36 antibody. AB - Cases of CD36 deficiency are not rare in Asian populations, foetal and neonatal alloimmune thrombocytopenia (FNAIT) caused by anti-CD36 isoantibodies appears more frequent than other HPA alloantibodies. However, little is known about the treatment of anti-CD36 mediated FNAIT in this region. A Chinese male foetus, whose mother had a history of multiple intrauterine foetal demise and/or hydrops, was diagnosed with severe FNAIT at 27 weeks of gestational age. Immunological analysis revealed total absence of CD36 on platelets and monocytes from mother, caused by a 329-330delAC mutation of the CD36 gene. Anti-CD36 and anti-HLA class I antibodies were detected in the maternal serum, whereas only anti-CD36 isoantibodies were detectable in the foetal blood sample. Serial intrauterine transfusions with red blood cells (RBC) and platelets from a CD36null donor were performed to improve the severe anaemia and thrombocytopenia. The baby (2250 g; Apgar scores 10) was delivered vaginally at 32 weeks of gestation with normal haemoglobin (186 g/L) but low platelet count (48 * 109/L). After 2 days the platelet count rose to 121 * 109/L. This report suggests that intrauterine transfusions with compatible RBC and CD36null platelets are useful in preventing the deleterious clinical effects of anti-CD36-mediated severe FNAIT. PMID- 28815407 TI - Efficacy and safety of the early use of V2 receptor antagonists in elderly patients with decompensated heart failure. AB - We recently reported that the early initiation of tolvaptan in congestive heart failure shortened the hospital stay and reduced the rate of in-hospital death. However, whether or not these results apply to elderly patients with congestive heart failure is unclear. We performed a sub-analysis of our previous study. Among the 102 patients in that study, we retrospectively analyzed the elderly patients >75 years of age treated with tolvaptan. First, we analyzed the efficacy of early tolvaptan use in these patients. We then compared the efficacy and the safety of all tolvaptan use between elderly and younger patients. There were no significant differences in the baseline clinical parameters between the early- and late-tolvaptan-use elderly patients, except for the serum blood nitrogen urea. However, the early use of tolvaptan was also associated with the earlier initiation of ambulatory cardiac rehabilitation, a shorter hospital stay, and a lower rate of in-hospital death in elderly congestive heart failure patients. Furthermore, there were no significant differences in the occurrence of worsening renal failure and hypernatremia. The early use of tolvaptan in elderly patients was also associated with a shorter hospital stay and reduced mortality. We also confirmed the safety of tolvaptan in elderly patients. It might, therefore, be beneficial to consider administering tolvaptan early in elderly patients with heart failure, just as in younger patients. PMID- 28815408 TI - Diphenyl diselenide modulates nucleotidases, reducing inflammatory responses in the liver of Toxoplasma gondii-infected mice. AB - The aim of this study was to verify the effect of diphenyl diselenide (PhSe)2 on hepatic nucleotidases and on the concentration of purines in mice infected by Toxoplasma gondii. The animals were divided into four groups: Group A (uninfected), Group B (uninfected and treated with (PhSe)2), Group C (infected), and Group D (infected and treated with (PhSe)2). The inoculation (groups C and D) was performed with 50 cysts of T. gondii (ME-49 strain). Mice from groups B and D were treated with 5 MUmol kg-1 of (PhSe)2. Liver tissue from infected mice showed less severe inflammation, elevated ATP/ADO ratio, elevated NTPDase, 5'nucleotidase, and ADA activities compared to the uninfected group (Group A; P < 0.05). However, infected and treated mice showed decreased ATP levels and elevated ADO levels, as well as higher NTPDase and 5'nucleotidase activities and decreased ADA activity in the hepatic tissue compared to the infected group (P < 0.05). Moreover, the (PhSe)2 treatment of infected mice reduced the hepatic inflammation and showed an immunomodulatory effect on ectonucleotidases of hepatic lymphocytes, which it returned to basal levels. Therefore, chronic infection by T. gondii induces hepatic inflammation in mice, and it is possible that purine levels and nucleotidase activities in hepatic tissue are related to the pathogenesis of the infection in this tissue. The treatment with (PhSe)2 was able to reverse the hepatic inflammation in mice chronically infected, possibly due to the modulation of purinergic enzymes that produce an anti-inflammatory profile through the purinergic system in the liver tissue. PMID- 28815410 TI - Efficacy and safety of a 4-factor prothrombin complex concentrate for rapid vitamin K antagonist reversal in Japanese patients presenting with major bleeding or requiring urgent surgical or invasive procedures: a prospective, open-label, single-arm phase 3b study. AB - Rapid vitamin K antagonist (VKA) reversal is required in patients experiencing major bleeding or requiring urgent surgery. Four-factor prothrombin complex concentrate (4F-PCC; Beriplex(r)/Kcentra(r)) was shown in two large randomized controlled, international phase 3b trials to be an effective alternative to plasma for urgent VKA reversal. In the present prospective, open-label, single arm phase 3b trial, we evaluate the efficacy and safety of 4F-PCC in Japanese patients. Eleven patients [international normalized ratio (INR) >=2] requiring rapid VKA reversal owing to major bleeding (n = 6) or before urgent surgical/invasive procedures (n = 5) were administered 4F-PCC dosed based on INR and weight. INR reduction (<=1.3 0.5 h postinfusion; primary endpoint) was achieved in 81.8% of patients (major bleeding, 83.3%; surgical/invasive procedures, 80.0%). Effective hemostasis (main secondary endpoint) was met in 60.0% (major bleeding) and 100% (surgical/invasive procedure) of evaluable patients. Adverse events (AEs) and serious AEs were reported in 90.9 and 45.5% of patients, respectively. Two AEs were considered treatment-related; thromboembolic events rated mild and not clinically relevant by investigators. There were no deaths, fluid overload events, or viral transmission cases. Consistent with the previous results, 4F-PCC may be an effective and well-tolerated treatment for rapid VKA reversal in Japanese patients experiencing major bleeding or requiring urgent surgical/invasive procedures. PMID- 28815411 TI - Synthesis, characterization and molecular docking studies of thiouracil derivatives as potent thymidylate synthase inhibitors and potential anticancer agents. AB - Thymidylate synthase (TS), one of folate-dependent enzymes, is a key and well recognized target for anticancer agents. In this study, a series of 6-aryl-5 cyano thiouracil derivatives were designed and synthesized in accordance with essential pharmacophoric features of known TS inhibitors. Nineteen compounds were screened in vitro for their anti-proliferative activities toward HePG-2, MCF-7, HCT-116, and PC-3 cell lines. Compounds [Formula: see text], [Formula: see text], and 24 exhibited high anti-proliferative activity, comparable to that of 5 fluorouracil. Additionally, ten compounds with potent anti-proliferative activities were further evaluated for their ability to inhibit TS enzyme. Six compounds ([Formula: see text], [Formula: see text], [Formula: see text], 22, 23 and 24) demonstrated potent dose-related TS inhibition with [Formula: see text] values ranging from 1.57 to [Formula: see text]. The in vitro TS activity results were consistent with those of the cytotoxicity assay where the most potent anti proliferative compounds of the series showed good TS inhibitory activity comparable to that of 5-fluorouracil. Furthermore, molecular docking studies were carried out to investigate the binding pattern of the designed compounds with the prospective target, TS (PDB-code: 1JU6). PMID- 28815409 TI - Insulin-Like Growth Factor (IGF) Pathway Targeting in Cancer: Role of the IGF Axis and Opportunities for Future Combination Studies. AB - Despite a strong preclinical rationale for targeting the insulin-like growth factor (IGF) axis in cancer, clinical studies of IGF-1 receptor (IGF-1R)-targeted monotherapies have been largely disappointing, and any potential success has been limited by the lack of validated predictive biomarkers for patient enrichment. A large body of preclinical evidence suggests that the key role of the IGF axis in cancer is in driving treatment resistance, via general proliferative/survival mechanisms, interactions with other mitogenic signaling networks, and class specific mechanisms such as DNA damage repair. Consequently, combining IGF targeted agents with standard cytotoxic agents, other targeted agents, endocrine therapies, or immunotherapies represents an attractive therapeutic approach. Anti IGF-1R monoclonal antibodies (mAbs) do not inhibit IGF ligand 2 (IGF-2) activation of the insulin receptor isoform-A (INSR-A), which may limit their anti proliferative activity. In addition, due to their lack of specificity, IGF-1R tyrosine kinase inhibitors are associated with hyperglycemia as a result of interference with signaling through the classical metabolic INSR-B isoform; this may preclude their use at clinically effective doses. Conversely, IGF-1/IGF-2 ligand-neutralizing mAbs inhibit proliferative/anti-apoptotic signaling via IGF 1R and INSR-A, without compromising the metabolic function of INSR-B. Therefore, combination regimens that include these agents may be more efficacious and tolerable versus IGF-1R-targeted combinations. Herein, we review the preclinical and clinical experience with IGF-targeted therapies to-date, and discuss the rationale for future combination approaches as a means to overcome treatment resistance. PMID- 28815412 TI - Study of the removal mechanism of aquatic emergent pollutants by new bio-based chars. AB - This work is dedicated to study the potential application of char byproducts obtained in the gasification of rice husk (RG char) and rice husk blended with corn cob (RCG char) as removal agents of two emergent aquatic contaminants: tetracycline and caffeine. The chars presented high ash contents (59.5-81.5%), being their mineral content mainly composed of silicon (as silica) and potassium. The samples presented a strong basic character, which was related to its higher mineral oxides content. RCG char presented better textural properties with a higher apparent surface area (144 m2 g-1) and higher micropore content (V micro = 0.05 cm3 g-1). The alkaline character of both chars promoted high ecotoxicity levels on their aqueous eluates; however, the ecotoxic behaviour was eliminated after pH correction. Adsorption experiments showed that RG char presented higher uptake capacity for both tetracycline (12.9 mg g-1) and caffeine (8.0 mg g-1), indicating that textural properties did not play a major role in the adsorption process. For tetracycline, the underlying adsorption mechanism was complexation or ion exchange reactions with the mineral elements of chars. The higher affinity of RG char to caffeine was associated with the higher alkaline character presented by this char. PMID- 28815413 TI - Biosurfactants during in situ bioremediation: factors that influence the production and challenges in evalution. AB - Research on the influence of biosurfactants on the efficiency of in situ bioremediation of contaminated soil is continuously growing. Despite the constant progress in understanding the mechanisms involved in the effects of biosurfactants, there are still many factors that are not sufficiently elucidated. There is a lack of research on autochthonous or exogenous microbial metabolism when biostimulation or bioaugmentation is carried out to produce biosurfactants at contaminated sites. In addition, studies on the application of techniques that measure the biosurfactants produced in situ are needed. This is important because, although the positive influence of biosurfactants is often reported, there are also studies where no effect or negative effects have been observed. This review aimed to examine some studies on factors that can improve the production of biosurfactants in soils during in situ bioremediation. Moreover, this work reviews the methodologies that can be used for measuring the production of these biocomposts. We reviewed studies on the potential of biosurfactants to improve the bioremediation of hydrocarbons, as well as the limitations of methods for the production of these biomolecules by microorganisms in soil. PMID- 28815414 TI - Comparison of image quality between step-and-shoot and continuous bed motion techniques in whole-body 18F-fluorodeoxyglucose positron emission tomography with the same acquisition duration. AB - OBJECTIVE: This study aimed to compare the qualities of whole-body positron emission tomography (PET) images acquired by the step-and-shoot (SS) and continuous bed motion (CBM) techniques with approximately the same acquisition duration, through phantom and clinical studies. METHODS: A body phantom with 10 37 mm spheres was filled with 18F-fluorodeoxyglucose (FDG) solution at a sphere to-background radioactivity ratio of 4:1 and acquired by both techniques. Reconstructed images were evaluated by visual assessment, percentages of contrast (%Q H) and background variability (%N) in accordance with the Japanese guideline for oncology FDG-PET/computed tomography (CT). To evaluate the variability of the standardized uptake value (SUV), the coefficient of variation (CV) for both maximum SUV and peak SUV was examined. Both the SUV values were additionally compared with those of standard images acquired for 30 min, and their accuracy was evaluated by the %difference (%Diff). In the clinical study, whole-body 18F FDG PET/CT images of 60 patients acquired by both techniques were compared for liver signal-to-noise ratio (SNRliver), CV at end planes, and both SUV values. RESULTS: In the phantom study, the visual assessment and %Q H values of the two techniques did not differ from each other. However, the %N values of the CBM technique were significantly higher than those of the SS technique. Additionally, the CV and %Diff for both SUV values in the CBM images tended to be slightly higher than those in SS images. In the clinical study, the SNRliver values of CBM images were significantly lower than those of SS images, although the CV at the end planes in CBM images was significantly lower than those in SS images. In the Bland-Altman analysis for both SUV values, the mean differences were close to 0, and most lesions exhibited SUVs within the limits of agreement. CONCLUSIONS: The CBM technique exhibited slightly lesser uniformity in the center plane than the SS technique. Additionally, in the phantom study, the CV and %Diff of SUV values in CBM images tended to be slightly higher than those of SS images. However, since these differences were subtle, they might be negligible in clinical settings. PMID- 28815415 TI - Type 2 Diabetes with Comorbid Depression in Relation to Cognitive Impairment: an Opportunity for Prevention? AB - Studies show poor glycemic control is associated with increased risk of dementia among patients with Type 2 diabetes, indicating potential for prevention of dementia with improved glycemia. Emerging evidence suggests that a relationship between short-term glycemic control and cognitive function exists in Type 2 diabetes. However, detailed mechanisms relating diabetic dementia are lacking, as other concurrent conditions, such as depression, may also increase the risk of dementia in Type 2 diabetes. We examined the effects of glycemic control and depression on cognitive function in 88 patients (mean age, 67 +/- 4 years) whose A1c (glycosylated hemoglobin) levels, comorbid depression, mini-mental state examination (MMSE) scores were recorded at baseline. Seventeen patients had depression; 14 agreed on anti-depressants. In 6 months, 69 patients reached A1c goal of < 7% (A1c from 9.7 +/- 0.8 to 6.4 +/- 0.3) while cognition improved significantly (MMSE scored from 20.2 +/- 3.5 to 26.2 +/- 2.1, p < 0.05). Cognitive increment in controlled diabetes was more consistently observed if their underlying depression was effectively treated (n - 14). Nineteen patients did not reach A1c goal of < 7% (A1c from 9.6 +/- 0.9 to 8.9 +/- 0.9) while cognitive increment was minimal (MMSE scored from 20.6 +/- 4.9 to 21.3 +/- 5.1, p > 0.05). Cognitive decrements were observed among depressed diabetics who refused anti-depressants. Multivariate analysis adjusted for age, education, alcohol use, and other variables yielded similar results. We found controlled glycemia and depression prevent cognitive decline. Further research into mechanisms of cognitive impairment in diabetes may allow us to challenge the concept of dementia in those patients as an irremediable disease. PMID- 28815416 TI - What Is the Evidence for Paediatric/Adolescent Bariatric Surgery? AB - PURPOSE OF REVIEW: In spite of the increasing prevalence of severe and complex obesity in children, surgery as a potential management option is still not widely accepted. The purpose of this review is to examine the evidence for surgical options in the severely obese paediatric population. Increasing evidence supports early rather than later use of bariatric surgery in the treatment of extreme obesity. RECENT FINDINGS: Prior to 2007, the feasibility and safety of surgery have been reported by predominantly small, sporadic single-centre retrospective case series. Increasing long-term data is now emerging due to the formation of multi-centre prospective national consortiums with two large, prospective long term outcome studies published within the last year aiding our understanding of the efficacy and safety of bariatric surgery within the adolescent population. It is increasingly clear that adolescent bariatric surgery outcomes are comparable to adults, with similar sustainable weight loss, resolution of co-morbidities and complication rates. However, these studies are solely from dedicated specialist adolescent centres and results may not be reproducible if not performed in regulated environments with specialist multi-disciplinary teams. PMID- 28815417 TI - Cellular interactome analysis of vaccinia virus K7 protein identifies three transport machineries as binding partners for K7. AB - Identification of viral-host interacting proteins will contribute to understanding of how poxvirus exploits the host cellular machinery. The vaccinia virus gene K7R encodes a conserved protein K7 in most orthopoxviruses. To gain insight into the biology of K7, we investigated the cellular interactome of K7 by GST pulldown coupled with mass spectrometry. The top categories of identified proteins contained components of trafficking machineries. We selected key components of three transport machineries including coatomer, retromer, and CHEVI to further confirm their binding abilities to K7. Di-lysine motif of K7 is required for its interaction with coatomer, while C terminal leucines in K7 are critical for association of retromer. Our study uncovers the viral-host interactome of vaccinia K7 and reveals three host transport machineries as binding partners of K7, which might have important roles in poxvirus' life cycles. PMID- 28815418 TI - Availability of angiography and therapeutic embolization for the treatment of acute bleeding in patients with hemophilia. AB - Clotting factor replacement therapy alone is often inadequate for acute bleeding in hemophilia patients, and surgery for such patients poses significant clinical challenges. Arterial angiographic intervention is used to control bleeding in local blood vessels. In the present study, we examined the clinical course and prognosis of hemophilia patients with bleeding who had undergone angiography, and evaluated the validity of diagnostic angiography and therapeutic embolization in these patients. Angiography was performed in five hemophilia patients, who experienced bleeding that was difficult to control even after treatment with clotting factor replacement or bypassing agent therapy. Of these patients, four were confirmed to have continued bleeding, and angiographic embolization was performed using clotting factor concentrates or bypassing agents. However, one patient developed uncontrollable bleeding at the puncture site, which eventually led to the patient's death. Thus, angiography and therapeutic embolization may be the preferred procedures for the treatment of hemorrhagic complications, refractory to treatment with clotting factor concentrates or bypassing agents. Further comprehensive, multidisciplinary team studies are needed to develop effective strategies to reduce hemorrhagic complications. PMID- 28815419 TI - Effect of sertraline on complications and survival after hematopoietic stem-cell transplantation, a double-blind, placebo-controlled clinical study. AB - Previous studies have found a connection between psychiatric problems and post hematopoietic stem-cell transplantation (HSCT) complications. We sought to evaluate the effect of sertraline on engraftment time, hospitalization period, mortality, and post-transplantation complications in HSCT recipients with depression and/or anxiety. We recruited adults aged 18-60, who were candidates for autologous or allogeneic HSCT with major depression and/or anxiety disorder. They were administered 50 mg of sertraline or placebo daily for the first week, and then 100 mg for the following seven weeks. We documented occurrence and severity of early post-HSCT complications, including infection, mucositis, nausea and vomiting, diarrhea, pain, renal toxicities and liver complications, acute graft-versus-host disease, and veno-occlusive disease, as well as time to engraftment, length of hospitalization and 6-month mortality. Overall, 56 patients participated in the study (sertraline group n = 30, placebo group n = 26). Of the complications, only mortality and readmission up to 6 months post transplantation were significantly higher in the placebo group compared to sertraline group (P values = 0.040, 0.028, respectively). There were no significant differences for other complications between the groups. Mean engraftment time was significantly lower in the sertraline group (P value = 0.048). This study provides evidence that sertraline positively influences engraftment time, readmission, and mortality after HSCT. PMID- 28815421 TI - Knowledge, Beliefs and Attitudes of Somali Men in Olmsted County, Minnesota, U.S., on the Human Papillomavirus Vaccine and Cervical Cancer Screening: January 17, 2015. AB - This study explores the general knowledge of Human Papillomavirus vaccine (HPV) and cervical cancer screening (CCS) among Somali men in the U.S., who are major decision-makers in Somali households. HPV infects both men and women, and causes genital warts and cervical cancer (CC). High mortality from CC persists among minorities due to low uptake of preventive tools. Eleven questions assessed general knowledge of HPV and CCS among 30 Somali male respondents. The knowledge of HPV and CCS by education level, age, and years lived in the U.S., was assessed using the health belief model. Most respondents had no knowledge of HPV vaccine and CCS, and low perceived susceptibility to HPV infection. There is need for more research on Somali men's attitude to HPV vaccine and CCS uptake among Somali adolescents and women. PMID- 28815422 TI - Anatomy and physiology in coronary artery disease imaging. PMID- 28815420 TI - Road Map for the Structure-Based Design of Selective Covalent HCV NS3/4A Protease Inhibitors. AB - Over the last 2 decades, covalent inhibitors have gained much popularity and is living up to its reputation as a powerful tool in drug discovery. Covalent inhibitors possess many significant advantages including increased biochemical efficiency, prolonged duration and the ability to target shallow, solvent exposed substrate-binding domains. However, rapidly mounting concerns over the potential toxicity, highly reactive nature and general lack of selectivity have negatively impacted covalent inhibitor development. Recently, a great deal of emphasis by the pharmaceutical industry has been placed toward the development of novel approaches to alleviate the major challenges experienced through covalent inhibition. This has unexpectedly led to the emergence of "selective" covalent inhibitors. The purpose of this review is not only to provide an overview from literature but to introduce a technical guidance as to how to initiate a systematic "road map" for the design of selective covalent inhibitors which we believe may assist in the design and development of optimized potential selective covalent HCV NS3/4A viral protease inhibitors. PMID- 28815423 TI - Backbone and side-chain 1H, 15N, and 13C resonance assignments of a novel Staphylococcal inhibitor of myeloperoxidase. AB - The bacterium Staphylococcus aureus produces an array of anti-inflammatory molecules that prevent the innate immune system from recognizing it as a pathogen and clearing it from the host. In the acute phase of inflammation, our immune system relies on neutrophils to clear invading bacteria. Recently, novel classes of secreted proteins from S. aureus, including the Extracellular Adherence Protein (EAP) family (Stapels et al., Proc Natl Acad Sci USA 111:13187-13192, 2014) and the Staphylococcal Peroxidase Inhibitor (SPIN), (unpublished work) have been identified as highly selective inhibitors acting on Neutrophil Serine Proteases (NSPs) and myeloperoxidase (MPO) respectively. SPIN is a protein found only in Staphylococci, with no sequence homology to any known proteins. Solution NMR structural studies of SPIN are therefore expected to provide a deeper understanding of its interaction with MPO. In this study, we report the backbone and side-chain 1H, 15N, and 13C resonance assignments of SPIN. Furthermore, using the chemical shifts of these resonances, we predicted the secondary structure of SPIN in solution via the TALOS-N server. The assignment data has been deposited in the BMRB data bank under Accession No. 27069. PMID- 28815424 TI - Hexamermis popilliae n. sp. (Nematoda: Mermithidae) parasitizing the Japanese beetle Popillia japonica Newman (Coleoptera: Scarabaeidae) in Italy. AB - A new species of mermithid nematode, Hexamermis popilliae n. sp. (Nematoda: Mermithidae) is described from the Japanese beetle Popillia japonica Newman in Italy, an area of new introduction for this invasive pest. The combination of the following characters separates H. popilliae from other members of the genus Hexamermis Steiner, 1924: adult head obtuse; amphidial pouches slightly posterior to lateral head papillae in female but adjacent to lateral head papillae in males; amphidial openings large, well developed; amphidial pouches elliptical in females and oblong in males; cuticular vulvar cone well developed, vulvar lips greatly reduced or lacking, vagina curved at tip where meeting uteri, without reverse bend (not S-shaped), spicules slightly curved, with a slight bend in the basal portion, approximately equal to body width at cloaca. This is the first record of a species of Hexamermis parasitizing the Japanese beetle Popillia japonica. The only previous mention of mermithid nematodes from P. japonica was an undescribed species of Psammomermis in North America. Hexamermis popilliae will be evaluated as a potential biological control agent in an integrated control program of the Japanese beetle in Italy. PMID- 28815426 TI - Identification and red blood cell automated counting from blood smear images using computer-aided system. AB - Red blood cell count plays a vital role in identifying the overall health of the patient. Hospitals use the hemocytometer to count the blood cells. Conventional method of placing the smear under microscope and counting the cells manually lead to erroneous results, and medical laboratory technicians are put under stress. A computer-aided system will help to attain precise results in less amount of time. This research work proposes an image-processing technique for counting the number of red blood cells. It aims to examine and process the blood smear image, in order to support the counting of red blood cells and identify the number of normal and abnormal cells in the image automatically. K-medoids algorithm which is robust to external noise is used to extract the WBCs from the image. Granulometric analysis is used to separate the red blood cells from the white blood cells. The red blood cells obtained are counted using the labeling algorithm and circular Hough transform. The radius range for the circle-drawing algorithm is estimated by computing the distance of the pixels from the boundary which automates the entire algorithm. A comparison is done between the counts obtained using the labeling algorithm and circular Hough transform. Results of the work showed that circular Hough transform was more accurate in counting the red blood cells than the labeling algorithm as it was successful in identifying even the overlapping cells. The work also intends to compare the results of cell count done using the proposed methodology and manual approach. The work is designed to address all the drawbacks of the previous research work. The research work can be extended to extract various texture and shape features of abnormal cells identified so that diseases like anemia of inflammation and chronic disease can be detected at the earliest. PMID- 28815425 TI - Methodological Study of Vancomycin Dosing in Elderly Patients Using Actual Serum Creatinine Versus Rounded Serum Creatinine. AB - PURPOSE: The practice of intentional rounding up of serum creatinine (SCr) in elderly patients with low measured values can lead to an underestimation of creatinine clearance and subsequent inaccurate dosing of medications. Thus, the purpose of this study was to evaluate the accuracy of vancomycin dose calculations for patients aged >=65 years using an SCr rounded up to 1 mg/dL versus actual SCr. METHODS: This study compared the difference between measured steady-state vancomycin trough concentrations with predicted trough concentrations that have been calculated using rounded SCr and actual SCr. All non-obese patients >=65 years of age with a baseline SCr <1 mg/dL who received a vancomycin regimen based on a SCr rounded to 1 mg/dL, and had a steady-state trough drawn between June 2014 and December 2015, were evaluated. A total of 1709 patients were evaluated, of whom 56 met all the selection criteria. RESULTS: The mean difference between measured vancomycin trough concentrations and predicted trough concentrations using rounded SCr was 8.84 versus 4.54 MUg/mL using actual SCr [mean difference 4.31, 95% confidence interval (CI) 3.2-5.41; p < 0.0001]. In female patients, the mean difference between measured concentrations and predicted concentrations using rounded SCr was 9.68 versus 3.53 MUg/mL using actual SCr (mean difference 6.15, 95% CI 4.42-7.88; p < 0.0001), while in male patients the mean difference between measured concentrations and predicted concentrations using rounded SCr was 8.21 versus 5.29 MUg/mL using actual SCr (mean difference 2.92, 95% CI 1.6-4.24; p < 0.0001). CONCLUSION: Using actual SCr to perform vancomycin dosing calculations more accurately predicted measured vancomycin troughs than using an SCr rounded to 1 mg/dL. In our sex-specific analysis, using actual SCr resulted in more accurate trough projections for both males and females than using a rounded SCr. PMID- 28815427 TI - Learning About Love: A Meta-Analytic Study of Individually-Oriented Relationship Education Programs for Adolescents and Emerging Adults. AB - Despite recent policy initiatives and substantial federal funding of individually oriented relationship education programs for youth, there have been no meta analytic reviews of this growing field. This meta-analytic study draws on 17 control-group studies and 13 one-group/pre-post studies to evaluate the effectiveness of relationship education programs on adolescents' and emerging adults' relationship knowledge, attitudes, and skills. Overall, control-group studies produced a medium effect (d = .36); one-group/pre-post studies also produced a medium effect (d = .47). However, the lack of studies with long-term follow-ups of relationship behaviors in the young adult years is a serious weakness in the field, limiting what we can say about the value of these programs for helping youth achieve their aspirations for healthy romantic relationships and stable marriages. PMID- 28815429 TI - Investigation on Surface Polarization of Al2O3-capped GaN/AlGaN/GaN Heterostructure by Angle-Resolved X-ray Photoelectron Spectroscopy. AB - The surface polarization of Ga-face gallium nitride (GaN) (2 nm)/AlGaN (22 nm)/GaN channel (150 nm)/buffer/Si with Al2O3 capping layer is investigated by angle-resolved X-ray photoelectron spectroscopy (ARXPS). It is found that the energy band varies from upward bending to downward bending in the interface region, which is believed to be corresponding to the polarization variation. An interfacial layer is formed between top GaN and Al2O3 due to the occurrence of Ga N bond break and Ga-O bond forming during Al2O3 deposition via the atomic layer deposition (ALD). This interfacial layer is believed to eliminate the GaN polarization, thus reducing the polarization-induced negative charges. Furthermore, this interfacial layer plays a key role for the introduction of the positive charges which lead the energy band downward. Finally, a N2 annealing at 400 degrees C is observed to enhance the interfacial layer growth thus increasing the density of positive charges. PMID- 28815430 TI - Clinical evaluation of the antifungal effect of sertraline in the treatment of cryptococcal meningitis in HIV patients: a single Mexican center experience. AB - PURPOSE: Cryptococcal meningitis is a potentially fatal fungal infection associated with a significant attributable morbidity and mortality, especially among HIV/AIDS patients. The first-line therapy for the treatment of this clinical entity is the combinatory therapy of amphotericin B plus flucytosine. However, the high cost, toxic effects, and limited repertoire of effective antifungal drugs have led to the investigation of novel molecules. This is a prospective, double-blinded, and randomized study performed in a Mexican tertiary care center to evaluate the antifungal activity of sertraline in the treatment of cryptococcal meningitis in HIV patients. METHODS: During June 2015-December 2016, patients were recruited and included in one of two study groups: group A was given standard antifungal treatment plus sertraline 200 mg/day, while group B was given standard antifungal plus placebo. Lumbar punctures were performed on days 0, 7, and 14 of the study, and cryptococcal antigenemia and quantitative fungal culture in cerebrospinal fluid at each time point were evaluated to measure the rate of fungal clearance. RESULTS: The fungal loads and cryptococcal antigenemia titers showed a marked tendency to decrease by day 14 in both groups. Otherwise, group B exhibited a slightly higher nonstatistical rate of fungal clearance ( 0.2868 +/- 0.08275 log CFU/ml/day) than group A (-0.2496 +/- 0.08340 log CFU/ml/day). CONCLUSIONS: A statistical difference between study groups was not found. This is the first study in Latin America that reports the experience of using sertraline as an adjuvant in the antifungal management of cryptococcal meningitis in HIV patients. PMID- 28815431 TI - Central-peripheral differences in audiovisual and visuotactile event perception. AB - We examined audiovisual and visuotactile integration in the central and peripheral visual field using visual fission and fusion illusions induced by sounds or taps. The fission illusion occurs when a single flash is perceived as two flashes if paired with two beeps or taps; the fusion illusion, by contrast, occurs when two flashes are perceived as a single flash if the flashes are paired with a single beep or tap. Beeps and taps induced similar patterns of illusions: the fission illusion was larger in the periphery than in the center, whereas the fusion illusion was larger in the center than in the periphery. An analysis based on signal detection theory revealed that both a decline in discriminability and a shift in criterion were associated with the more pronounced fission induced by sounds in the periphery. In contrast, only a shift in criterion was associated with the larger fission induced by taps in the periphery, and the larger fusion induced by a sound or tap in the center. To accommodate these findings, two accounts are proposed: audiovisual signals are more likely to be integrated in peripheral than in central vision, and the interpretation of visual signals favors discontinuous percepts, especially in the periphery. PMID- 28815428 TI - The Pharmacology and Toxicology of Third-Generation Anticonvulsant Drugs. AB - Epilepsy is a neurologic disorder affecting approximately 50 million people worldwide, or about 0.7% of the population [1]. Thus, the use of anticonvulsant drugs in the treatment of epilepsy is common and widespread. There are three generations of anticonvulsant drugs, categorized by the year in which they were developed and released. The aim of this review is to discuss the pharmacokinetics, drug-drug interactions, and adverse events of the third generation of anticonvulsant drugs. Where available, overdose data will be included. The pharmacokinetic properties of third-generation anticonvulsant drugs include relatively fewer drug-drug interactions, as well as several unique and life-threatening adverse events. Overdose data are limited, so thorough review of adverse events and knowledge of drug mechanism will guide expectant management of future overdose cases. Reporting of these cases as they occur will be necessary to further clarify toxicity of these drugs. PMID- 28815432 TI - Influence of nitrogen loading and flooding on seedling emergence and recruitment from a seed bank in Chaohu Lake Basin, China. AB - Vegetation severely degraded and even disappeared in the water bodies of Chaohu Lake basin, which is the fifth largest freshwater lake in the Yangtze flood plain in China, because of water pollution and eutrophication. Vegetation restoration projects have been carried out. However, the influences of water quality and hydrology on vegetation restoration from seed banks have been rarely investigated. This experiment aimed to identify the effect of water level and nitrogen loading (ammonium and nitrate) on seedling emergence and recruitment from the riparian seed bank of the river in this basin. Most of the species in the seed bank germinated under moist conditions. Under flooding conditions, however, the growth of aquatic species, especially Vallisneria natans (Lour.) Hara, was inhibited when the nitrogen concentration increased. At 0.37 mg/L NH4+ N in the water column, the growth of V. natans was inhibited. The results suggested that flooding was a primary limiting factor of seedling emergence. The inhibitory effect of high nitrogen loading on the growth of aquatic species was one of the main driving mechanisms of macrophyte degradation under flooding conditions; nevertheless, competitive advantage might determine the community pattern in moist habitats. Therefore, water level control and water quality improvement should be the key aspects of vegetation restoration in degraded rivers or lakes. PMID- 28815434 TI - Measles Vaccination is Best for Children: The Argument for Relying on Herd Immunity Fails. AB - This article examines an argument which may negatively influence measles vaccination uptake. According to the argument, an individual child in a highly vaccinated society may be better off by being non-vaccinated; the child does not risk vaccine adverse effects and is protected against measles through herd immunity. Firstly, the conclusion of the argument is challenged by showing that herd immunity's protection is unreliable and inferior to vaccination. Secondly, the logic of the argument is challenged by showing that the argument is inherently self-defeating and therefore logically inconsistent. In practice the argument cannot be used to protect children against measles. Measles vaccination is undoubtedly best for children, even in highly vaccinated societies. Only if a medical contraindication to vaccination exists should vaccination be waived in favour of reliance on herd immunity. This places obligations on those who stand in care relationships with the child: parents, healthcare providers, and the state. PMID- 28815433 TI - New insights on the green synthesis of metallic nanoparticles using plant and waste biomaterials: current knowledge, their agricultural and environmental applications. AB - Nanotechnology is a rapidly growing scientific field and has attracted a great interest over the last few years because of its abundant applications. Green nanotechnology is a multidisciplinary field that has emerged as a rapidly developing research area, serving as an important technique that emphasize on making the procedure which are clean, non-hazardous, and especially environmentally friendly, in contrast with chemical and physical methods currently employed for nanosynthesis. The biogenic routes could be termed green as these do not involve the use of highly toxic chemicals or elevated energy inputs during the synthesis. Differences in the bio-reducing agents employed for nanosynthesis can lead to the production of nanoparticles (NPs) having distinct shapes, sizes, and bioactivity. The exquitiveness of the green fabricated NPs have capacitated their potential applications in various sectors such as biomedicine, pharmacology, food science, agriculture, and environmental engineering. The present review summarizes current knowledge on various biogenic synthesis methods, relying on plants, waste biomass, and biopolymers and their reducing and stabilizing agents to fabricate nanomaterials. The main emphasis has been given on the current status and future challenges related to the wide-scale fabrication of nanoparticles for environmental remediation, pathogenicity, and agricultural applications. PMID- 28815435 TI - Recent Trends in Sustainable Textile Waste Recycling Methods: Current Situation and Future Prospects. AB - In recent years, there have been increasing concerns in the disposal of textile waste around the globe. The growth of textile markets not only depends on population growth but also depends on economic and fashion cycles. The fast fashion cycle in the textile industry has led to a high level of consumption and waste generation. This can cause a negative environmental impact since the textile and clothing industry is one of the most polluting industries. Textile manufacturing is a chemical-intensive process and requires a high volume of water throughout its operations. Wastewater and fiber wastes are the major wastes generated during the textile production process. On the other hand, the fiber waste was mainly created from unwanted clothes in the textile supply chain. This fiber waste includes natural fiber, synthetic fiber, and natural/synthetic blends. The natural fiber is mostly comprised of cellulosic material, which can be used as a resource for producing bio-based products. The main challenge for utilization of textile waste is finding the method that is able to recover sugars as monosaccharides. This review provides an overview of valorization of textile waste to value-added products, as well as an overview of different strategies for sugar recovery from cellulosic fiber and their hindrances. PMID- 28815436 TI - Headache attributed to airplane travel: diagnosis, pathophysiology, and treatment - a systematic review. AB - BACKGROUND: Headache attributed to airplane travel, also named "airplane headache" (AH) is a headache that occurs during take-off and landing. Today, there are still uncertainties about the pathophysiology and treatment of AH. This systematic review was performed to facilitate identification of the existing literature on AH in order to discuss the current evidence and areas that remain to be investigated in AH. METHODS: The systematic literature search was performed in 3 relevant medical databases; PubMed, Scopus, and Embase. The search yielded 220 papers and the papers were sorted based on inclusion and exclusion criteria established for this study. RESULTS: This systematic review included 39 papers. Main findings revealed that AH attacks are clinically stereotyped and appear mostly during landing phases. The headache presents as a severe painful headache that often disappears within 30 min. The pain is unilateral and localized in the fronto-orbital region. Sinus barotrauma has been considered as the main cause of AH. Nonsteroidal anti-inflammatory drugs and triptans have been taken by passengers with AH, to relieve the headache. CONCLUSIONS: Based on this systematic review, further studies seem required to investigate underlying mechanisms in AH and also to investigate the biological effects of nonsteroidal anti-inflammatory drugs and triptans for alleviating of AH. These studies would advance our understanding of AH pathogenesis and potential use of treatments that are not yet established. PMID- 28815437 TI - A Rare Complication of Bariatric Surgery: Retrograde Intussusception. PMID- 28815438 TI - Basic Sciences and Psychiatry. PMID- 28815439 TI - Predatory Journals Spamming for Publications: What Should Researchers Do? AB - In the internet era spam has become a big problem. Researchers are troubled with unsolicited or bulk spam emails inviting them to publish. However, this strategy has helped predatory journals hunt their prey and earn money. These journals have grown tremendously during the past few years despite serious efforts by researchers and scholarly organizations to hinder their growth. Predatory journals and publishers are often based in developing countries, and they potentially target researchers from these counties by using different tactics identified in previous research. In response to the spread of predatory publishing, scientists are trying to develop criteria and guidelines to help avoid them-for example, the recently reported "predatory rate". This article attempts to (a) highlight the strategies used by predatory journals to convince researchers to publish with them, (b) report their article processing charges, (c) note their presence in Jeffrey Beall's List of Predatory Publishers, (d) rank them based on the predatory rate, and (e) put forward suggestions for junior researchers (especially in developing counties), who are the most likely targets of predatory journals. PMID- 28815440 TI - Peritoneal Metastases from Gastroenteropancreatic Neuroendocrine Tumors. PMID- 28815441 TI - Pluripotent Stem Cells in Adult Tissues: Struggling To Be Acknowledged Over Two Decades. AB - Stem cells have fascinated scientists for a long time and huge research efforts have been put into them as they have the potential to regenerate diseased organs. Besides embryonic stem cells (ES) and induced pluripotent stem cells (iPS), it has been postulated that pluripotent stem cells (PSCs) may also exist in various adult tissues. They are thought to be more primitive than the adult stem cells (ASCs), serve as a backup pool to give rise to ASCs and thus play a crucial role in maintaining life-long homeostasis. These PSCs could also be the embryonic stem cells in adult tissues that were proposed to initiate cancers according to the Embryonic Rest Hypothesis put forth in the nineteenth century. However, the very presence of PSCs in adult tissues is mired with controversies. This article is a sincere attempt to review research carried out by various investigators over the last two decades and various attempts to demonstrate their presence in adult tissues. Such adult PSCs could be the ideal stem cell candidates to bring about endogenous regeneration compared to ES/iPS cells grown in Petri dish and also score better over ASCs which in fact are tissue committed progenitors with limited regenerative potential that differentiate from the PSCs. PSCs in adult tissues have remained elusive until now as they possibly get unknowingly discarded due to their small size and inability to pellet at 1000-1200 rpm (250 g). They will likely prove to be a game changer in the field of stem cells biology, for regenerative medicine and for our understanding of cancer initiation. PMID- 28815442 TI - Excessive daytime sleepiness in secondary chronic headache from the general population. AB - BACKGROUND: Excessive daytime sleepiness (EDS, defined as Epworth sleepiness scale score > 10) is a common symptom, with a prevalence of 10-20% in the general population. It is associated with headache and other chronic pain disorders. However, little is known about the prevalence of EDS among people with secondary chronic headaches. FINDINGS: A total of 30,000 persons aged 30-44 from the general population was screened for headache by a questionnaire. The 633 eligible participants with self-reported chronic headache were interviewed and examined by a headache specialist who applied the International Classification of Headache Disorders with supplementary definitions for chronic rhinosinusitis and cervicogenic headache. A total of 93 participants had secondary chronic headache and completed the ESS. A total of 47 participants had chronic post-traumatic headache (CPTH) and/or cervicogenic headache (CEH), 39 participants had headache attributed to chronic rhinosinusitis (HACRS), while 7 had other secondary headaches. 23.3% of those with CPTH, CEH or HACRS reported EDS. In multivariable logistic regression analysis the odds ratios of EDS were not significantly different in people with CPTH/CEH or HACRS. CONCLUSION: Almost one out of four subjects with secondary chronic headache reported EDS with no differences between the various secondary chronic headaches. PMID- 28815443 TI - Endoscopic Ultrasound as a Pretreatment Clinical Staging Tool for Gastric Cancer: Association with Pathology and Outcome. AB - BACKGROUND: Endoscopic ultrasound (EUS) is a guideline-recommended diagnostic test to estimate pretreatment clinical stage in gastric cancer. The impact of EUS to discriminate long-term outcomes has not been established. OBJECTIVES: The objectives of our study were to (1) evaluate the association between EUS and pathologic stage; (2) evaluate the ability of EUS to predict disease-specific survival (DSS); and (3) determine how neoadjuvant chemotherapy (NCT) affects these relationships. METHODS: A prospective gastric cancer database at a tertiary care cancer center identified 734 patients who underwent curative intent resection. Patients were separated into EUS low-risk (T1-2, N0) and EUS high-risk (T3-4 Nany, or Tany N+) groups. Agreement statistics and 5-year DSS were estimated stratified by NCT. RESULTS: Between 1987 and 2015, 68% (502/734) of patients were not treated with NCT. Among these patients, percentage agreement between EUS and pathology was moderate (individual T stage: 52%; N stage: 70%; risk group: 73%). EUS accurately estimated pathologic risk group in 73% (365/502) of patients, whereas it overestimated pathologic risk group in 19% (93/502) of patients and underestimated risk in 8% (41/502) of patients. EUS in non-NCT staging was able to discriminate DSS for T stage (hazard ratio [HR] 5.07, p < 0.05), N stage (HR 3.58, p < 0.05), and risk group (HR 6.35, p < 0.05). Among patients treated with NCT, EUS was unable to discriminate DSS for T stage (HR 0.94, p > 0.05), N stage (HR 1.46, p > 0.05) and risk group (HR 0.50, p > 0.05). CONCLUSIONS: Pretreatment clinical staging based on EUS alone could lead to over- or under treatment in 27% of patients and can discriminate DSS in NCT-naive patients. EUS should be used in the context of other validated clinical risk tools. PMID- 28815444 TI - Gladius and its derivatives as potential biosorbents for marine diesel oil. AB - The demand for low cost and effective materials to remove contaminants such as residues of oil spills has encouraged studies on new biosorbents produced from wastes. Considering the overgeneration of fishing residues and the necessity to provide an alternative purpose for such materials, this study aimed to evaluate squid gladius and its derivatives (beta-chitin and chitosan) as sorbents to remove marine diesel oil (MDO) from fresh and artificial seawater. It was also executed an attempted to improve their performances through a high-intensity ultrasound treatment (UT-gladius and UT-beta-chitin). All sorbents removed MDO at both salinities. Contact surface area, salinity, and water retention seemed to play a key role in the outcomes. UT-beta-chitin's performance was significantly superior to beta-chitin's and chitosan's in MDO removal at salinity 0, as well as at salinity 30, where gladius and UT-gladius also excelled. Ultrasound treatment improved the oil removal performance of UT-beta-chitin by increasing its contact surface area. This is the first report on the efficiency of gladius and UT-beta chitin for such purpose, and brought up huge possibilities and new questions that can lead to the achievement of biosorbents of great efficiency. PMID- 28815445 TI - Identification and Treatment Optimization of Comorbid Depression in Rheumatoid Arthritis. AB - Patients with rheumatoid arthritis (RA) suffer from high rates of depression but depression often remains undiagnosed and untreated among RA patients. Because of its high prevalence and its profound impact on functional disability and health related quality of life, prompt recognition and management of comorbid depression is urgently needed in patients with RA. Rheumatologists face the challenge of addressing depression in their clinical interactions with patients. The purpose of this paper is to present the prevalence of comorbid depression in RA, to delineate the consequences of depression among RA patients, to discuss the barriers to the identification of depression among RA patients, and to outline a set of recommendations to identify and treat comorbid depression that could be implemented within the rheumatology clinic setting. A comprehensive approach to the management of both physical and mental health needs of RA patients can aid in improving patient overall quality of life. New clinical protocols should be developed to include routine depression screening as part of the rheumatology visit. Patient education to address misconceptions, knowledge gaps, and destigmatize depression is also recommended. More counseling resources, including emotional support groups, are necessary to provide treatment for those suffering from depression. Such interventions could help mitigate disability, improve quality of life, patient function, and overall satisfaction. PMID- 28815447 TI - Erratum to: Predictors of Bowel Function in Long-term Rectal Cancer Survivors with Anastomosis. PMID- 28815446 TI - A human PET study of [11C]HMS011, a potential radioligand for AMPA receptors. AB - BACKGROUND: alpha-Amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor is a primary mediator of fast glutamatergic excitatory signaling in the brain and has been implicated in diverse neuropsychiatric diseases. We recently developed a novel positron emission tomography (PET) ligand, 2-(1-(3 ([11C]methylamino)phenyl)-2-oxo-5-(pyrimidin-2-yl)-1,2-dihydropyridin-3-yl) benzonitrile ([11C]HMS011). This compound is a radiolabelled derivative of perampanel, an antiepileptic drug acting on AMPA receptors, and was demonstrated to have promising in vivo properties in the rat and monkey brains. In the current study, we performed a human PET study using [11C]HMS011 to evaluate its safety and kinetics. Four healthy male subjects underwent a 120-min PET scan after injection of [11C]HMS011. Arterial blood sampling and metabolite analysis were performed to obtain parent input functions for three of the subjects using high performance liquid chromatography. Regional distribution volumes (V Ts) were calculated based on kinetic models with and without considering radiometabolite in the brain. The binding was also quantified using a reference tissue model with white matter as reference. RESULTS: Brain uptake of [11C]HMS011 was observed quickly after the injection, followed by a rapid clearance. Three hydrophilic and one lipophilic radiometabolites appeared in the plasma, with notable individual variability. The kinetics in the brain with apparent radioactivity retention suggested that the lipophilic radiometabolite could enter the brain. A dual-input graphical model, an analytical model designed in consideration of a radiometabolite entering the brain, well described the kinetics of [11C]HMS011. A reference tissue model showed small radioligand binding potential (BP*ND) values in the cortical regions (BP*ND = 0-0.15). These data suggested specific binding component of [11C]HMS011 in the brain. CONCLUSIONS: Kinetic analyses support some specific binding of [11C]HMS011 in the human cortex. However, this ligand may not be suitable for practical AMPA receptor PET imaging due to the small dynamic range and metabolite in the brain. PMID- 28815448 TI - 1H, 15N and 13C chemical shift assignments of the C-terminal domain of TRADD. AB - The tumor necrosis factor receptor-associated death domain protein, TRADD, is a multifunctional intracellular molecule participating in divergent signaling pathways, such as NF-kappaB and apoptosis. TRADD consists of two structurally distinct domains. Its N-terminal domain displays an alpha-beta plaits fold while its C-terminal domain belongs to the death domain (DD) superfamily. TRADD DD is a central component in the tumor necrosis factor receptor 1 signaling. It interacts with other DD-containing proteins through homotypic interactions. TRADD DD is also involved in p75NTR-mediated signalling in MCF-7 human breast cancer cells. Here we report backbone and sidechain 1H, 13C and 15N chemical shift assignments of TRADD DD in pure water as a basis for further structural and functional studies. PMID- 28815449 TI - Electrodeposition of SnO2 on FTO and its Application in Planar Heterojunction Perovskite Solar Cells as an Electron Transport Layer. AB - We report the performance of perovskite solar cells (PSCs) with an electron transport layer (ETL) consisting of a SnO2 thin film obtained by electrochemical deposition. The surface morphology and thickness of the electrodeposited SnO2 films were closely related to electrochemical process conditions, i.e., the applied voltage, bath temperature, and deposition time. We investigated the performance of PSCs based on the SnO2 films. Remarkably, the experimental factors that are closely associated with the photovoltaic performance were strongly affected by the SnO2 ETLs. Finally, to enhance the photovoltaic performance, the surfaces of the SnO2 films were modified slightly by TiCl4 hydrolysis. This process improves charge extraction and suppresses charge recombination. PMID- 28815451 TI - All HER2-Positive Tumors are not Created Equal. PMID- 28815450 TI - A case of pancreatic cancer with severe vomiting treated by endoscopic ultrasound guided celiac ganglia neurolysis. AB - A 50-year-old man with advanced pancreatic cancer was admitted for intractable severe vomiting 5-6 times a day, continuing over a week. He had been treated for advanced pancreatic cancer with chemotherapy for 6 months, and had undergone self expandable metalic stent placement for obstructive jaundice due to the pancreatic cancer 4 months before admission. No abnormal findings suggesting gastrointestinal obstruction or brain metastasis were revealed on diagnostic imaging. We performed endoscopic ultrasound-guided celiac ganglia neurolysis twice by injecting ethanol into the celiac ganglion. After the treatments, the vomiting disappeared, and his eating habits gradually returned to normal. The patient died 7 months after treatment due to the advanced pancreatic cancer without recurrence of the vomiting. PMID- 28815452 TI - 18F-FDG PET radiomics approaches: comparing and clustering features in cervical cancer. AB - OBJECTIVES: The aims of our study were to find the textural features on 18F-FDG PET/CT which reflect the different histological architectures between cervical cancer subtypes and to make a visual assessment of the association between 18F FDG PET textural features in cervical cancer. METHODS: Eighty-three cervical cancer patients [62 squamous cell carcinomas (SCCs) and 21 non-SCCs (NSCCs)] who had undergone pretreatment 18F-FDG PET/CT were enrolled. A texture analysis was performed on PET/CT images, from which 18 PET radiomics features were extracted including first-order features such as standardized uptake value (SUV), metabolic tumor volume (MTV) and total lesion glycolysis (TLG), second- and high-order textural features using SUV histogram, normalized gray-level co-occurrence matrix (NGLCM), and neighborhood gray-tone difference matrix, respectively. These features were compared between SCC and NSCC using a Bonferroni adjusted P value threshold of 0.0028 (0.05/18). To assess the association between PET features, a heat map analysis with hierarchical clustering, one of the radiomics approaches, was performed. RESULTS: Among 18 PET features, correlation, a second-order textural feature derived from NGLCM, was a stable parameter and it was the only feature which showed a robust trend toward significant difference between SCC and NSCC. Cervical SCC showed a higher correlation (0.70 +/- 0.07) than NSCC (0.64 +/ 0.07, P = 0.0030). The other PET features did not show any significant differences between SCC and NSCC. A higher correlation in SCC might reflect higher structural integrity and stronger spatial/linear relationship of cancer cells compared with NSCC. A heat map with a PET feature dendrogram clearly showed 5 distinct clusters, where correlation belonged to a cluster including MTV and TLG. However, the association between correlation and MTV/TLG was not strong. Correlation was a relatively independent PET feature in cervical cancer. CONCLUSIONS: 18F-FDG PET textural features might reflect the differences in histological architecture between cervical cancer subtypes. PET radiomics approaches reveal the association between PET features and will be useful for finding a single feature or a combination of features leading to precise diagnoses, potential prognostic models, and effective therapeutic strategies. PMID- 28815453 TI - The clinical eye. PMID- 28815454 TI - Effects of Se and Cd Co-treatment on the Morphology, Oxidative Stress, and Ion Concentrations in the Ovaries of Laying Hens. AB - This study aims at revealing the effects of the combined treatment of selenium and cadmium on ovary morphology, oxidative stress, and 28 kinds of ion concentrations in laying hens. In this experiment, 128 healthy 31-week-old chickens were selected and divided into four treatment groups, three of which were separately fed the basic diets supplemented with either Se or Cd or both Se and Cd for 90 days, and the remaining group was fed the basic diet and treated as a control. The chickens were sacrificed for collecting ovarian tissues. Morphological structure and ultrastructure analysis of ovaries in the Cd-treated group revealed ovarian damage, with decreased activities of SOD and GPx, along with increased levels of MDA and H2O2. Cd treatment also resulted in disturbances in ion balance. The concentrations of Ca, Ti, Cu, Zn, and Ba were significantly reduced, while the concentrations of Fe, Mo, and Cd were significantly increased when compared with the control group. Interestingly, the damages caused by cadmium were alleviated in the Se+Cd-treated group. These results indicate that selenium can alleviate cadmium-induced ovarian damages. PMID- 28815455 TI - Using a Mcintosh blade for retromolar intubation: a comment. PMID- 28815456 TI - Recommendations for biomarker testing in epithelial ovarian cancer: a National Consensus Statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology. AB - Because of advances in the understanding of histological and molecular characteristics in ovarian cancer, it is now possible to recognize the existence of five subtypes, which in turn has allowed a more refined therapeutic approach and better design of clinical trials. Each of these five subtypes has specific histological features and a particular biomarker expression, as well as mutations in different genes, some of which have prognostic and predictive value. CA125 and HE4 are examples of ovarian cancer biomarkers used in the diagnosis and follow-up of these malignancies. Currently, somatic or germinal mutations on BRCA1 and BRCA2 genes are the most important biomarkers in epithelial ovarian cancer having prognostic and predictive value. This article will review the histological and molecular characteristics of the five subtypes of ovarian cancer, describing the most important biomarkers and mutations that can guide in diagnosis, screening and tailored treatment strategy. PMID- 28815457 TI - Overexpression of a peroxidase gene (AtPrx64) of Arabidopsis thaliana in tobacco improves plant's tolerance to aluminum stress. AB - KEY MESSAGE: AtPrx64 is one of the peroxidases gene up-regulated in Al stress and has some functions in the formation of plant second cell wall. Its overexpression may improve plant tolerance to Al by some ways. Studies on its function under Al stress may help us to understand the mechanism of plant tolerance to Al stress. In Arabidopsis thaliana, the expressions of some genes (AtPrxs) encoding class III plant peroxidases have been found to be either up-regulated or down-regulated under aluminum (Al) stress. Among 73 genes that encode AtPrxs in Arabidopsis, AtPrx64 is always up-regulated by Al stress, suggesting this gene plays protective roles in response to such stress. In this study, transgenic tobacco plants were generated to examine the effects of overexpressing of AtPrx64 gene on the tolerance to Al stress. The results showed that overexpression of AtPrx64 gene increased the root growth and reduced the accumulation of Al and ROS in the roots. Compared with wild type controls, transgenic tobaccos had much less soluble proteins and malondialdehyde in roots and much more root citrate exudation. The activity of plasma membrane (PM) H+-ATPase, the phosphorylation of PM H+-ATPase and its interaction with 14-3-3 proteins increased in transgenic tobaccos; moreover, the content of lignin in root tips also increased. Taken together, these results showed that overexpression of AtPrx64 gene might enhance the tolerance of tobacco to Al stress. PMID- 28815458 TI - Backbone and side-chain resonance assignments of (Ca2+)4-calmodulin bound to beta calcineurin A CaMBD peptide. AB - Calcineurin (CaN) is a heterodimeric and highly conserved serine/threonine phosphatase (PP2B) that plays a critical role in coupling calcium signals to physiological processes including embryonic cardiac development, NF-AT-regulated gene expression in immune responses, and apoptosis. The catalytic subunit (CaNA) has three isoforms (alpha, beta, and gamma,) in humans and seven isoforms in Paramecium. In all eukaryotes, the EF-hand protein calmodulin (CaM) regulates CaN activity in a calcium-dependent manner. The N- and C-domains of CaM (CaMN and CaMC) recognize a CaM-binding domain (CaMBD) within an intrinsically disordered region of CaNA that precedes the auto-inhibitory domain (AID) of CaNA. Here we present nearly complete 1H, 13C, and 15N resonance assignments of (Ca2+)4-CaM bound to a peptide containing the CaMBD sequence in the beta isoform of CaNA (betaCaNA-CaMBDp). Its secondary structure elements predicted from the assigned chemical shifts were in good agreement with those observed in the high-resolution structures of (Ca2+)4-CaM bound to CaMBDs of multiple enzymes. Based on the reported literature, the CaMBD of the alpha isoform of CaNA can bind to CaM in two opposing orientations which may influence the regulatory function of CaM. Because a high resolution structure of (Ca2+)4-CaM bound to betaCaNA-CaMBDp has not been reported, our studies serve as a starting point for determining the solution structure of this complex. This will demonstrate the preferred orientation of (Ca2+)4-CaM on the CaMBD as well as the orientations of CaMN and CaMC relative to each other and to the AID of betaCaNA. PMID- 28815459 TI - A Roadmap for Reducing Cardiac Device Infections: a Review of Epidemiology, Pathogenesis, and Actionable Risk Factors to Guide the Development of an Infection Prevention Program for the Electrophysiology Laboratory. AB - PURPOSE OF REVIEW: Cardiovascular implantable electronic device (CIED) infections are highly morbid, common, and costly, and rates are increasing (Sohail et al. Arch Intern Med 171(20):1821-8 2011; Voigt et al. J Am Coll Cardiol 48(3):590-1 2006). Factors that contribute to the development of CIED infections include patient factors (comorbid conditions, self-care, microbiome), procedural details (repeat procedure, contamination during procedure, appropriate pre-procedural prep, and antimicrobial use), environmental and organizational factors (patient safety culture, facility barriers, such as lack of space to store essential supplies, quality of environmental cleaning), and microbial factors (type of organism, virulence of organism). Each of these can be specifically targeted with infection prevention interventions. RECENT FINDINGS: Basic prevention practices, such as administration of systemic antimicrobials prior to incision and delaying the procedure in the setting of fever or elevated INR, are helpful for day-to-day prevention of cardiac device infections. Small single-center studies provide proof-of-concept that bundled prevention interventions can reduce infections, particularly in outbreak settings. However, data regarding which prevention strategies are the most important is limited as are data regarding the optimal prevention program for day-to-day prevention (Borer et al. Infect Control Hosp Epidemiol 25(6):492-7 2004; Ahsan et al. Europace 16(10):1482-9 2014). Evolution of infection prevention programs to include ambulatory and procedural areas is crucial as healthcare delivery is increasingly provided outside of hospitals and operating rooms. The focus on traditional operating rooms and inpatient care leaves the vast majority of healthcare delivery-including cardiac device implantations in the electrophysiology laboratory-uncovered. PMID- 28815460 TI - Developing a System for Processing Health Data of Children Using Digitalized Toys: Ethical and Privacy Concerns for the Internet of Things Paradigm. AB - EDUCERE (Ubiquitous Detection Ecosystem to Care and Early Stimulation for Children with Developmental Disorders) is a government funded research and development project. EDUCERE objectives are to investigate, develop, and evaluate innovative solutions for society to detect changes in psychomotor development through the natural interaction of children with toys and everyday objects, and perform stimulation and early attention activities in real environments such as home and school. In the EDUCERE project, an ethical impact assessment is carried out linked to a minors' data protection rights. Using a specific methodology, the project has achieved some promising results. These include use of a prototype of smart toys to detect development difficulties in children. In addition, privacy protection measures which take into account the security concerns of health data, have been proposed and applied. This latter security framework could be useful in other Internet of Things related projects. It consists of legal and technical measures. Special attention has been placed in the transformation of bulk data such as acceleration and jitter of toys into health data when patterns of atypical development are found. The article describes the different security profiles in which users are classified. PMID- 28815462 TI - A New Erice Report Considering the Safety of Medicines in the 21st Century. AB - Pharmacovogilance policy, methods and practice require transformation at all levels to create an integrated, comprehensive, continuously improving system, fulfilling the broader remit of overall healthcare vigilance. In pursuit of this vision, energetic measures, including active engagement with patients, are needed to reduce our ignorance about many aspects of patients' experience of medical therapies and their outcomes, including the benefits, but especially the extensive harm known to be caused by medical interventions. More information and communication in this domain will help set more accurate and realistic public expectations about the benefits and harm of therapy. All aspects of medicines development, regulation and use must be characterized by openness, transparency, ethical practice and a primary focus on the benefit and self-determined choices of patients. Notwithstanding, progress has been made in medicines safety information and communication but significant gaps and deficiencies remain. Promotion of the most beneficial use of medicines and the prevention of harm have not advanced sufficiently. This paper is a report from a group of experts, following previous similar decade reviews: the Erice Declaration (1996) and the Erice Manifesto (2006). PMID- 28815461 TI - Drug-Induced Kidney Injury in the Elderly. AB - The incidence of acute kidney injury in the elderly has grown over the past decade. One of the primary drivers is drug-induced nephrotoxicity, which is the result of a combination of the unique susceptibilities to kidney injury and the increased use of medications in the elderly population. Specific drug classes are associated with increased rates of kidney injury including agents that block the renin angiotensin system, antimicrobials, and chemotherapeutic agents. Mechanistically, injury may be due to hemodynamic effects, tubular or glomerular toxicity, and interstitial nephritis. Early recognition of nephrotoxicity is critical, as are preventative steps when applicable. Unfortunately, treatment for established drug-induced kidney injury is limited and supportive care is required. Limiting exposure to nephrotoxic drugs is critical in decreasing the incidence of acute kidney injury in the elderly patient. PMID- 28815463 TI - The many faces (and phases) of ceramide and sphingomyelin I - single lipids. AB - Ceramides, the simplest kind of two-chained sphingolipids, contain a single hydroxyl group in position 1 of the sphingoid base. Sphingomyelins further contain a phosphocholine group at the OH of position 1 of ceramide. Ceramides and sphingomyelins show a variety of species depending on the fatty acyl chain length, hydroxylation, and unsaturation. Because of the relatively high transition temperature of sphingomyelin compared to lecithin and, particularly, of ceramides with 16:0-18:0 saturated chains, a widespread idea on their functional importance refers to formation of rather solid domains enriched in sphingomyelin and ceramide. Frequently, and especially in the cell biology field, these are generally (and erroneously) assumed to occur irrespective on the type of N-acyl chain in these lipids. This is because most studies indicating such condensed ordered domains employed sphingolipids with acyl chains with 16 carbons while scarce attention has been focused on the influence of the N-acyl chain on their surface properties. However, abundant evidence has shown that variations of the N-acyl chain length in ceramides and sphingomyelins markedly affect their phase state, interfacial elasticity, surface topography, electrostatics and miscibility and that, even the usually conceived "condensed" sphingolipids and many of their mixtures, may exhibit liquid-like expanded states. This review is a summarized overview of our work and of related others on some facts regarding membranes composed of single molecular species of ceramide and sphingomyelin. A second part is dedicated to discuss the miscibility properties between species of sphingolipids that differ in N-acyl and oligosaccharide chains. PMID- 28815466 TI - Medical students' perceptions of a novel institutional incident reporting system : A thematic analysis. AB - BACKGROUND: Errors in healthcare are a major patient safety issue, with incident reporting a key solution. The incident reporting system has been integrated within a new medical curriculum, encouraging medical students to take part in this key safety process. The aim of this study was to describe the system and assess how students perceived the reporting system with regards to its role in enhancing safety. METHODS: Employing a thematic analysis, this study used interviews with medical students at the end of the first year. Thematic indices were developed according to the information emerging from the data. Through open, axial and then selective stages of coding, an understanding of how the system was perceived was established. RESULTS: Analysis of the interview specified five core themes: (1) Aims of the incident reporting system; (2) internalized cognition of the system; (3) the impact of the reporting system; (4) threshold for reporting; (5) feedback on the systems operation. Selective analysis revealed three overriding findings: lack of error awareness and error wisdom as underpinned by key theoretical constructs, student support of the principle of safety, and perceptions of a blame culture. CONCLUSIONS: Students did not interpret reporting as a manner to support institutional learning and safety, rather many perceived it as a tool for a blame culture. The impact reporting had on students was unexpected and may give insight into how other undergraduates and early graduates interpret such a system. Future studies should aim to produce interventions that can support a reporting culture. PMID- 28815465 TI - Non-injection Drug Use and Injection Initiation Assistance among People Who Inject Drugs in Tijuana, Mexico. AB - Although most people who inject drugs (PWID) report receiving assistance during injection initiation events, little research has focused on risk factors among PWID for providing injection initiation assistance. We therefore sought to determine the influence of non-injection drug use among PWID on their risk to initiate others. We used generalized estimating equation (GEE) models on longitudinal data among a prospective cohort of PWID in Tijuana, Mexico (Proyecto El Cuete IV), while controlling for potential confounders. At baseline, 534 participants provided data on injection initiation assistance. Overall, 14% reported ever initiating others, with 4% reporting this behavior recently (i.e., in the past 6 months). In a multivariable GEE model, recent non-injection drug use was independently associated with providing injection initiation assistance (adjusted odds ratio [AOR] = 2.42, 95% confidence interval [CI] = 1.39-4.20). Further, in subanalyses examining specific drug types, recent non-injection use of cocaine (AOR = 9.31, 95% CI = 3.98-21.78), heroin (AOR = 4.00, 95% CI = 1.88 8.54), and methamphetamine (AOR = 2.03, 95% CI = 1.16-3.55) were all significantly associated with reporting providing injection initiation assistance. Our findings may have important implications for the development of interventional approaches to reduce injection initiation and related harms. Further research is needed to validate findings and inform future approaches to preventing entry into drug injecting. PMID- 28815467 TI - A method for evaluating luminance non-uniformity of displays by use of a commercially available digital camera. AB - The luminance uniformity of liquid-crystal displays (LCDs) deteriorates with their prolonged use. In this paper, we present a method for evaluating the degree of luminance non-uniformity of LCDs with the use of a commercially available digital camera. In this study, seven monochrome LCDs, which were used during various operating times ranging from 5000 to 25,000 h, were evaluated with use of a camera. The maximum luminance deviation (MLD) was measured on the two dimensional (2D) images obtained with the camera. In addition, an index of the luminance non-uniformity was calculated as the ratio of the area exhibiting luminance non-uniformity to the area of the entire LCD screen. We determined the area with the luminance non-uniformity by setting the allowable luminance deviation as the judgment criterion to evaluate the degree of luminance non uniformity. The MLD values were less than 20% for all conditions, and they varied depending on the locations of the luminance measurement. The area ratios of the luminance non-uniformity based on 2D luminance distributions tended to increase with the duration of use of LCDs, and they indicated the degree of luminance non uniformity of the LCDs regardless of the measurement locations. Our approach of using a commercially available digital camera showed its potential usefulness for providing more detailed and consistent evaluations of the degree of luminance non uniformity of LCDs based on the 2D luminance distributions. PMID- 28815464 TI - Inherited Nonsyndromic Ichthyoses: An Update on Pathophysiology, Diagnosis and Treatment. AB - Hereditary ichthyoses are due to mutations on one or both alleles of more than 30 different genes, mainly expressed in the upper epidermis. Syndromic as well as nonsyndromic forms of ichthyosis exist. Irrespective of etiology, virtually all types of ichthyosis exhibit a defective epidermal barrier that constitutes the driving force for hyperkeratosis, skin scaling, and inflammation. In nonsyndromic forms, these features are most evident in severe autosomal recessive congenital ichthyosis (ARCI) and epidermolytic ichthyosis, but to some extent also occur in the common type of non-congenital ichthyosis. A correct diagnosis of ichthyosis essential not only for genetic counseling but also for adequate patient information about prognosis and therapeutic options-is becoming increasingly feasible thanks to recent progress in genetic knowledge and DNA sequencing methods. This paper reviews the most important aspects of nonsyndromic ichthyoses, focusing on new knowledge about the pathophysiology of the disorders, which will hopefully lead to novel ideas about therapy. PMID- 28815468 TI - A Feminist Critique of Justifications for Sex Selection. AB - This paper examines dominant arguments advocating for the procreative right to undergo sex selection for social reasons, based on gender preference. I present four of the most recognized and common justifications for sex selection: the argument from natural sex selection, the argument from procreative autonomy, the argument from family balancing, and the argument from children's well-being. Together these represent the various means by which scholars aim to defend access to sex selection for social reasons as a legitimate procreative choice. In response, I contend that these justifications are flawed and often inconsistent and therefore fail to vindicate the practice. PMID- 28815469 TI - Metagenome Analysis: a Powerful Tool for Enzyme Bioprospecting. AB - Microorganisms are found throughout every corner of nature, and vast number of microorganisms is difficult to cultivate by classical microbiological techniques. The advent of metagenomics has revolutionized the field of microbial biotechnology. Metagenomics allow the recovery of genetic material directly from environmental niches without any cultivation techniques. Currently, metagenomic tools are widely employed as powerful tools to isolate and identify enzymes with novel biocatalytic activities from the uncultivable component of microbial communities. The employment of next-generation sequencing techniques for metagenomics resulted in the generation of large sequence data sets derived from various environments, such as soil, the human body and ocean water. This review article describes the state-of-the-art techniques and tools in metagenomics and discusses the potential of metagenomic approaches for the bioprospecting of industrial enzymes from various environmental samples. We also describe the unusual novel enzymes discovered via metagenomic approaches and discuss the future prospects for metagenome technologies. PMID- 28815470 TI - Alterations in SCAI Expression during Cell Plasticity, Fibrosis and Cancer. AB - Suppressor of cancer cell invasion (SCAI) has been originally characterized as a tumor suppressor inhibiting metastasis in different human cancer cells, and it has been suggested that SCAI expression declines in tumors. The expression patterns and role of SCAI during physiological and pathophysiological processes is still poorly understood. Earlier we demonstrated that SCAI is regulating the epithelial-mesenchymal transition of proximal tubular epithelial cells, it is downregulated during renal fibrosis and it is overexpressed in Wilms' tumors. Here we bring further evidence for the involvement of SCAI during cell plasticity and we examine the prognostic value and expression patterns of SCAI in various tumors. SCAI prevented the activation of the SMA promoter induced by angiotensin II. SCAI expression decreased in a model of endothelial-mesenchymal transition and increased during iPS reprogramming of fibroblasts. During renal fibrosis SCAI expression declined, as evidenced in a rat model of renal transplant rejection and in TGF-beta1 overexpressing transgenic mice. High expression of SCAI correlated with better survival in patients with breast and lung cancers. Intriguingly, in the case of other cancers (gastric, prostate, colorectal) high SCAI expression correlated with poor survival of patients. Finally, we bring evidence for SCAI overexpression in colorectal cancer patients, irrespective of stage or metastatic status of the disease, suggesting a diverse role of SCAI in various diseases and cancer. PMID- 28815473 TI - Publication of Abstracts and Full Papers from the International Conference on the Origin of Life, San Diego, 2017. PMID- 28815471 TI - Impact of Centralizing Gastric Cancer Surgery on Treatment, Morbidity, and Mortality. AB - INTRODUCTION: Centralization of gastric cancer surgery is thought to improve outcome and has been imposed in the Netherlands since 2012. This study analyzes the effect of centralization in terms of treatment outcome and survival in the Eastern part of the Netherlands. METHODS: All gastric cancer patients without distant metastases who underwent a gastrectomy in six hospitals in the Eastern part of the Netherlands between 2008 and 2011 (pre-centralization) and 2013-2016 (post-centralization) were selected from the Netherlands Cancer Registry. Patient and tumor characteristics and treatment outcomes (duration of surgery, blood loss, resection margin, lymphadenectomy, chemotherapy, postoperative complications and hospital stay, and overall and disease-free survival) were analyzed and compared between pre- and post-centralization. RESULTS: One hundred forty-four patients were included pre-centralization and 106 patients post centralization. Patient and tumor characteristics were almost similar in the two periods. After centralization, more patients were treated with perioperative chemotherapy (25 vs. 42% p < 0.01). The proportion of patients treated with an adequate lymphadenectomy (21 vs. 93% p < 0.01) and laparoscopic surgery (6 vs. 40% p < 0.01) increased significantly (p < 0.01). The amount of cardiac complications (16 vs. 7.5% p < 0.05) decreased; however, complications needing a re-intervention were comparable (42 vs. 40% p = 0.79). Median hospital stay decreased from 10 to 8 days (p < 0.01). A 30-day mortality did not differ significantly (4.2 vs. 1.9%). A 1-year overall (78 vs. 80% p = 0.17) and disease free survival (73 vs. 74% p = 0.66) remained stable. DISCUSSION: Centralizing gastric cancer treatment in the Eastern part of the Netherlands resulted in improved lymph node harvesting and a successful introduction of laparoscopic gastrectomies. Centralization has not translated into improved mortality, and other variables may also have led to these improved outcomes. Further research using a nationwide population-based study will be needed to confirm these data. PMID- 28815472 TI - Comparison of PET/CT and whole-mount histopathology sections of the human prostate: a new strategy for voxel-wise evaluation. AB - BACKGROUND: Implementation of PET/CT in diagnosis of primary prostate cancer (PCa) requires a profound knowledge about the tracer, preferably from a quantitative evaluation. Direct visual comparison of PET/CT slices to whole prostate sections is hampered by considerable uncertainties from imperfect coregistration and fundamentally different image modalities. In the current study, we present a novel method for advanced voxel-wise comparison of histopathology from excised prostates to pre-surgical PET. Resected prostates from eight patients who underwent PSMA-PET/CT were scanned (ex vivo CT) and thoroughly pathologically prepared. In vivo and ex vivo CT including histopathology were coregistered with three different methods (manual, semi /automatic). Spatial overlap after CT-based registration was evaluated with dice similarity (DSC). Furthermore, we constructed 3D cancer distribution models from histopathologic information in various slices. Subsequent smoothing reflected the intrinsically limited spatial resolution of PSMA-PET. The resulting histoPET models were used for quantitative analysis of spatial histopathology-PET pattern agreement focusing on p values and coefficients of determination (R 2). We examined additional rigid mutual information (MI) coregistration directly based on PSMA-PET and histoPET. RESULTS: Mean DSC for the three different methods (ManReg, ScalFactReg, and DefReg) were 0.79 +/- 0.06, 0.82 +/- 0.04, and 0.90 +/- 0.02, respectively, while quantification of PET-histopathology pattern agreement after CT-based registration revealed R 2 45.7, 43.2, and 41.3% on average with p < 10-5. Subsequent PET-based MI coregistration yielded R 2 61.3, 55.9, and 55.6%, respectively, while implying anatomically plausible transformations. CONCLUSIONS: Creating 3D histoPET models based on thorough histopathological preparation allowed sophisticated quantitative analyses showing highly significant correlations between histopathology and (PSMA-)PET. We recommend manual CT-based coregistration followed by a PET-based MI algorithm to overcome limitations of purely CT-based coregistrations for meaningful voxel-wise comparisons between PET and histopathology. PMID- 28815474 TI - Influence of bio-fertilizer containing beneficial fungi and rhizospheric bacteria on health promoting compounds and antioxidant activity of Spinacia oleracea L. AB - BACKGROUND: This study evaluates the influences of bio fertilizers containing mycorrhizal fungi (Glomus fasciculatum, Glomus mosseae) individually or in combination with N-fixer (Azotobacter chroococcum), K solubilizer (Bacillus mucilaginous) and P solubilizer (Bacillus megaterium) on soil fertility and phytochemical levels of spinach. RESULTS: Root colonization by mycorrhizal fungi was increased in the presence of bacterial inoculation in comparison to individual inoculation treatments. Inoculation of bio fertilizer containing mycorrhizal fungi and bacterial species considerably augmented the concentration of total phenolic compounds, flavonoids and phenolic acid contents. The 1, 1 diphenyl-2-picrylhydrazyl (DPPH) scavenging capacity of spinach was found to be positively coincided with flavonoid contents, while partially correlated with total phenolic compounds and phenolic acids. Further, the HPLC analysis showed that significantly higher antioxidant activity of spinach was correlated with quercetin contents and chlorogenic acid. Chlorophyll contents were also increased following the bio fertilization treatments. CONCLUSION: Results revealed that these microbes are useful tool for improving health promoting compounds in spinach. PMID- 28815475 TI - Cancer Training for Frontline Healthcare Providers in Tanzania. AB - Cervical and breast cancer are responsible for the highest cancer-related mortality in Tanzania, although both are preventable or curable if diagnosed at an early stage. Limited knowledge of cervical cancer by clinic and dispensary level healthcare providers in Tanzania is a barrier for prevention and control strategies. The purpose of the study was to provide basic oncology training to frontline healthcare workers with a focus on cervical and breast cancer in order to increase knowledge. A 1-day cancer training symposium was conducted in Arusha, Tanzania, with 43 clinicians. Pre- and post-intervention surveys assessed cancer knowledge and confidence of clinicians in risk assessment. Sixty-nine percent of the participants reported never receiving any cervical cancer training in the past. A significant difference was found between the pre- and post-test in a majority of knowledge questions and in reported confidence recognizing signs and symptoms of breast and cervical cancer (p < 0.05). The 1-day community oncology training symposium was effective in delivering and increasing basic knowledge about cervical and breast cancers to these healthcare providers. The low level of baseline cancer knowledge among frontline medical providers in Tanzania illustrates the need for increased training around the country. PMID- 28815476 TI - Long-Term Safety and Effectiveness of Adalimumab for Moderate to Severe Psoriasis: Results from 7-Year Interim Analysis of the ESPRIT Registry. AB - INTRODUCTION: ESPRIT (NCT00799877) is an ongoing 10-year international prospective observational registry evaluating the long-term safety and effectiveness of originator adalimumab in routine clinical practice for adult patients with chronic plaque psoriasis. Herein, we report the long-term safety, effectiveness, and patient-reported outcomes (PROs) following adalimumab treatment over the first 7 years of the ESPRIT registry. METHODS: All treatment emergent (All-TE) adverse events (AE) since the initial (first ever) dose of adalimumab were assessed. Physician Global Assessment (PGA) and PROs (PROs for US patients only) were evaluated during registry participation. RESULTS: As of 30 November 2015, 6051 patients in the ESPRIT registry were analyzed, representing 23,660.1 patient-years (PY) of overall adalimumab exposure. The incidence rates for All-TE serious AEs, serious infections, and malignancies were 4.4, 1.0, and 1.0 events per 100 PY (E/100PY), respectively. The standardized mortality ratio for TE deaths in the registry was 0.27 (95% CI 0.18-0.38). During the registry's first 7 years, PGA "clear" or "minimal" was achieved by >50% of patients at each annual visit, and among US patients, the mean improvement from baseline in different PROs was maintained. CONCLUSION: No new safety signals were identified during the first 7 years of the registry, and safety was consistent with the known safety profile of adalimumab. The number of TE deaths was below the expected rate. During the registry's first 7 years, most of the patients remained free of All-TE cardiovascular events, serious infections, and malignancy. As observed effectiveness of adalimumab and improvements from baseline in PROs were maintained through 7 years of registry participation. FUNDING: Abbvie. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT00799877. PMID- 28815477 TI - Radiotherapy for mucosa-associated lymphoid tissue (MALT) lymphoma of the rectum: a case report. AB - Extra-nodal mucosa-associated lymphoid tissue (MALT) lymphoma is frequently involved with the upper gastrointestinal tract, but rarely involved with the rectum. We report a case of rectal MALT lymphoma treated by radiotherapy (RT) alone. A 74-year-old woman with lower abdominal pain was diagnosed with MALT lymphoma by endoscopic mucosal resection (EMR). She was diagnosed as stage IE (Ann Arbor) MALT lymphoma by diagnostic work-up and review of EMR specimens. Definitive RT was performed with curative intent, totaling 30 Gy in 15 fractions. Complete response was confirmed by colonoscopy after RT with no progression observed at 5 years. Definitive RT is effective for rectal MALT lymphoma. PMID- 28815478 TI - O-(2-[18F]fluoroethyl)-L-tyrosine PET in gliomas: influence of data processing in different centres. AB - BACKGROUND: PET using O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) is an established method for brain tumour diagnostics, but data processing varies in different centres. This study analyses the influence of methodological differences between two centres for tumour characterization with 18F-FET PET using the same PET scanner. Methodological differences between centres A and B in the evaluation of 18F-FET PET data were identified for (1) framing of PET dynamic data, (2) data reconstruction, (3) cut-off values for tumour delineation to determine tumour-to-brain ratios (TBR) and tumour volume (Tvol) and (4) ROI definition to determine time activity curves (TACs) in the tumour. Based on the 18F-FET PET data of 40 patients with untreated cerebral gliomas (20 WHO grade II, 10 WHO grade III, 10 WHO grade IV), the effect of different data processing in the two centres on TBRmean, TBRmax, Tvol, time-to-peak (TTP) and slope of the TAC was compared. Further, the effect on tumour grading was evaluated by ROC analysis. RESULTS: Significant differences between centres A and B were found especially for TBRmax (2.84 +/- 0.99 versus 3.34 +/- 1.13; p < 0.001), Tvol (1.14 +/- 1.28 versus 1.51 +/- 1.44; p < 0.001) and TTP (22.4 +/- 8.3 min versus 30.8 +/- 6.3 min; p < 0.001) and minor differences for TBRmean and slope. Tumour grading was not influenced by different data processing. CONCLUSIONS: Variable data processing of 18F-FET PET in different centres leads to significant differences especially for TBRmax and Tvol. A standardization of data processing and evaluation is needed to make 18F-FET PET comparable between different centres. PMID- 28815479 TI - Validation of the Internet Addiction Test in Students at a Pakistani Medical and Dental School. AB - Despite growing concerns over pathological internet usage, studies based on validated psychometric instruments are still lacking in Pakistan. This study aimed to examine the psychometric properties of the Internet Addiction Test (IAT) in a sample of Pakistani students. A total of 522 students of medicine and dentistry completed the questionnaire, which consisted of four sections: (a) demographics, (b) number of hours spent on the Internet per day, (c) English version of the IAT, and (d) the Defense Style Questionnaire-40. Maximum likelihood analysis and principal axis factoring were used to validate the factor structure of the IAT. Convergent and criterion validity were assessed by correlating IAT scores with number of hours spent online and defense styles. Exploratory and confirmatory factor analysis reflected the goodness of fit of a unidimensional structure of the IAT, with a high alpha coefficient. The IAT had good face and convergent validity and no floor and ceiling effects, and was judged easy to read by participants. PMID- 28815480 TI - Evaluation of Electronic Healthcare Databases for Post-Marketing Drug Safety Surveillance and Pharmacoepidemiology in China. AB - INTRODUCTION: Electronic healthcare databases (EHDs) are used increasingly for post-marketing drug safety surveillance and pharmacoepidemiology in Europe and North America. However, few studies have examined the potential of these data sources in China. METHODS: Three major types of EHDs in China (i.e., a regional community-based database, a national claims database, and an electronic medical records [EMR] database) were selected for evaluation. Forty core variables were derived based on the US Mini-Sentinel (MS) Common Data Model (CDM) as well as the data features in China that would be desirable to support drug safety surveillance. An email survey of these core variables and eight general questions as well as follow-up inquiries on additional variables was conducted. These 40 core variables across the three EHDs and all variables in each EHD along with those in the US MS CDM and Observational Medical Outcomes Partnership (OMOP) CDM were compared for availability and labeled based on specific standards. RESULTS: All of the EHDs' custodians confirmed their willingness to share their databases with academic institutions after appropriate approval was obtained. The regional community-based database contained 1.19 million people in 2015 with 85% of core variables. Resampled annually nationwide, the national claims database included 5.4 million people in 2014 with 55% of core variables, and the EMR database included 3 million inpatients from 60 hospitals in 2015 with 80% of core variables. Compared with MS CDM or OMOP CDM, the proportion of variables across the three EHDs available or able to be transformed/derived from the original sources are 24-83% or 45-73%, respectively. CONCLUSIONS: These EHDs provide potential value to post-marketing drug safety surveillance and pharmacoepidemiology in China. Future research is warranted to assess the quality and completeness of these EHDs or additional data sources in China. PMID- 28815482 TI - A quick glance at selected topics in this issue. PMID- 28815483 TI - Photocatalytic Properties of Co3O4-Coated TiO2 Powders Prepared by Plasma Enhanced Atomic Layer Deposition. AB - Co3O4-coated commercial TiO2 powders (P25) p-n junction photocatalysts were prepared by plasma-enhanced atomic layer deposition (PEALD) technique. The structure, morphology, bandgap, and photocatalytic properties under ultraviolet light were investigated systematically. Although the deposition of Co3O4 does not change the anatase structure and crystallite size of P25 powders, the ultraviolet photocatalytic activity has been improved evidently. For the Co3O4-coated P25 powders, the trace Co ions exist as Co3O4 nanoparticles attached to TiO2 powder surface instead of the occupation of Ti4+ position in TiO2 lattice. The Co3O4 coated P25 powders exhibit enhanced photocatalytic degradation efficiency of almost 100% for methylene blue in 1.5 h under ultraviolet light, compared with P25 of 80%. The Mott-Schottky plots of photocatalyst powders confirm the p-n heterojunction formation in Co3O4-TiO2 nanocomposite materials, which is beneficial to increase the efficiency of photogenerated electron-hole separation. In addition, the Co3O4 coating also promotes the adsorption of organic dyes of methylene blue on P25 powders. PMID- 28815484 TI - Diagnostic performance of a newly developed salivary cortisol and cortisone measurement using an LC-MS/MS method with simple and rapid sample preparation. AB - BACKGROUND: Late-night salivary cortisol level is one of the first-line tests recommended by the Endocrine Society for the diagnosis of endogenous hypercortisolism. Most routine laboratories measure cortisol levels using immunoassay tests which fail to determine low cortisol levels accurately due to the numerous interfering substances. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with simple and rapid sample preparation was developed for the simultaneous measurement of cortisol and cortisone and its performance in the diagnosis of endogenous hypercortisolism was evaluated. METHODS: 324 late-night saliva samples were analyzed from which 272 samples were derived from patients with a suspected diagnosis of endogenous hypercortisolism. Salivary cortisol levels were assayed using an electrochemiluminescent immunoassay (ECLIA, Cortisol II, Roche), and simultaneous measurement of cortisol and cortisone was performed using an LC-MS/MS method. RESULTS: A strong correlation between cortisol results measured using ECLIA and LC-MS/MS (r 2 = 0.892) was demonstrated. Receiver operating characteristics (ROC) analysis showed good diagnostic performance of cortisol and cortisone levels assayed using LC MS/MS method and for cortisol measured using ECLIA. CONCLUSIONS: Late-night salivary cortisol and cortisone are useful parameters for the diagnosis of hypercortisolism. Using samples obtained from patients where the diagnosis of hypercortisolism is extremely challenging cut-off values for midnight salivary cortisol and cortisone measured by LC-MS/MS method were established. PMID- 28815485 TI - Screening for Osteoporosis in Older Men: Operating Characteristics of Proposed Strategies for Selecting Men for BMD Testing. AB - BACKGROUND: The optimal approach for selecting men for bone mineral density (BMD) testing to screen for osteoporosis is uncertain. OBJECTIVE: To compare strategies for selecting older men for screening BMD testing. DESIGN: Prospective cohort study. PARTICIPANTS: A total of 4043 community-dwelling men aged >=70 years at four US sites. MAIN MEASURES: BMD at the total hip, femoral neck, and lumbar spine using dual-energy x-ray absorptiometry (DXA). Sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio, and area under the receiver operating curve (AUC) of the Osteoporosis Self-Assessment Tool (OST) and Fracture Risk Assessment Tool (FRAX) without BMD to discriminate between those with and without osteoporosis as defined by World Health Organization (WHO) diagnostic criteria, and between those recommended and not recommended for pharmacologic therapy based on the National Osteoporosis Foundation (NOF) guidelines. KEY RESULTS: Among the cohort, 216 (5.3%) had a BMD T-score <= -2.5 at the femoral neck, total hip, or lumbar spine, and 1184 (29.2%) met criteria for consideration of pharmacologic therapy according to NOF guidelines. The OST had better discrimination (AUC 0.68) than the FRAX (AUC 0.62; p = 0.004) for identifying T-score-defined osteoporosis. Use of an OST threshold of <2 resulted in sensitivity of 0.83 and specificity of 0.36 for the identification of osteoporosis, compared to sensitivity of 0.59 and specificity of 0.59 for the use of FRAX with a cutoff of 9.3% 10-year risk of major osteoporotic fracture. CONCLUSIONS: The OST performs modestly better than the more complex FRAX in selecting older men for BMD testing to screen for osteoporosis; the use of either tool substantially reduces the proportion of men referred for BMD testing compared to universal screening. Of 1000 men aged 70 and older in this community-based cohort, the use of an OST cutoff of <2 to select men for BMD testing would result in 654 men referred for BMD testing, of whom 44 would be identified as having osteoporosis, and nine with osteoporosis would be missed. PMID- 28815481 TI - Gene Delivery Approaches for Mesenchymal Stem Cell Therapy: Strategies to Increase Efficiency and Specificity. AB - A significant number of clinical trials have been undertaken to explore the use of mesenchymal stem cells (MSCs) for the treatment of several diseases such as Crohn's disease, diabetes, bone defects, myocardial infarction, stroke etc., Due to their efficiency in homing to the tissue injury sites, their differentiation potential, the capability to secrete a large amount of trophic factors and their immunomodulatory effects, MSCs are becoming increasingly popular and expected to be one of the promising therapeutic approaches. However, challenges associated with the isolation of pure MSC populations, their culture and expansion, specific phenotypic characterization, multi-potential differentiation and challenges of efficient transplantation limit their usage. The current strategies of cell-based therapies emphasize introducing beneficial genes, which will improve the therapeutic ability of MSCs and have better homing efficiency. The continuous improvement in gene transfer technologies has broad implications in stem cell biology. Although viral vectors are efficient vehicles for gene delivery, construction of viral vectors with desired genes, their safety and immunogenicity limit their use in clinical applications. We review current gene delivery approaches, including viral and plasmid vectors, for transfecting MSC with beneficial genes. The review also discusses the use of a few emerging technologies that could be used to improve the transfer/induction of desirable genes for cell therapy. PMID- 28815486 TI - Staphylococcus Aureus Carriage in French Athletes at Risk of CA-MRSA Infection: a Prospective, Cross-sectional Study. AB - BACKGROUND: Staphylococcus aureus (SA) is a leading cause of infectious diseases in sports teams. In recent decades, community-associated SA (CA-SA) strains have emerged worldwide and have been responsible for outbreaks in sports teams. There are very few data on the prevalence of these strains in France, and none on the carriage among athletes. METHODS: We conducted a cross-sectional study to determine the SA carriage proportion among athletes practicing sports at risk for CA-SA infection in a French county, and determined the methicillin-resistant and/or CA-SA proportion. We also analyzed SA carriage according to risks factors and studied the SA clonality in a sample of our population. RESULTS: We included 300 athletes; SA carriage proportion was 61% (n = 183) and one was MRSA carrier (0.33%). The MRSA strain belonged to the clonal complex ST5. None of the strain produced Panton Valentine Leucocidin, and we did not find clonal distribution within the teams. Interestingly, we found a high throat-only carriage (n = 57), 31.1% of the SA carriers. CONCLUSION: We found a high SA carriage with a local epidemiology quite different than that reported in a similar population in the USA. Further studies on SA carriage should include throat sampling. TRIAL REGISTRATION: The approved protocol was registered on ClinicalTrial.gov , NCT01148485. PMID- 28815487 TI - Benzophenone-3 Impairs Autophagy, Alters Epigenetic Status, and Disrupts Retinoid X Receptor Signaling in Apoptotic Neuronal Cells. AB - Benzophenone-3 (BP-3) is the most widely used compound among UV filters for the prevention of photodegradation. Population studies have demonstrated that it penetrates through the skin and crosses the blood-brain barrier. However, little is known about the impact of BP-3 on the nervous system and its possible adverse effects on the developing brain. We demonstrated that the neurotoxic effects of BP-3 were accompanied by the induction of apoptosis, as evidenced by apoptosis related caspase-3 activation and apoptotic body formation as well as the inhibition of autophagy, as determined by the downregulation of autophagy-related genes, decreased autophagosome formation, and reduced LC3B-to-LC3A ratio. In this study, we showed for the first time that the BP-3-induced apoptosis of neuronal cells is mediated via the stimulation of RXRalpha signaling and the attenuation of RXRbeta/RXRgamma signaling, as demonstrated using selective antagonist and specific siRNAs as well as by measuring the mRNA and protein expression levels of the receptors. This study also demonstrated that environmentally relevant concentrations of BP-3 were able to inhibit autophagy and disrupt the epigenetic status of neuronal cells, as evidenced by the inhibition of global DNA methylation as well as the reduction of histone deacetylases and histone acetyl transferases activity, which may increase the risks of neurodevelopmental abnormalities and/or neural degenerations. PMID- 28815488 TI - Exploring Vaccine Hesitancy Through an Artist-Scientist Collaboration : Visualizing Vaccine-Critical Parents' Health Beliefs. AB - This project explores vaccine hesitancy through an artist-scientist collaboration. It aims to create better understanding of vaccine hesitant parents' health beliefs and how these influence their vaccine-critical decisions. The project interviews vaccine-hesitant parents in the Netherlands and Finland and develops experimental visual-narrative means to analyse the interview data. Vaccine-hesitant parents' health beliefs are, in this study, expressed through stories, and they are paralleled with so-called illness narratives. The study explores the following four main health beliefs originating from the parents' interviews: (1) perceived benefits of illness, (2) belief in the body's intelligence and self-healing capacity, (3) beliefs about the "inside-outside" flow of substances in the body, and (4) view of death as a natural part of life. These beliefs are interpreted through arts-based diagrammatic representations. These diagrams, merging multiple aspects of the parents' narratives, are subsequently used in a collaborative meaning-making dialogue between the artist and the scientist. The resulting dialogue contrasts the health beliefs behind vaccine hesitancy with scientific knowledge, as well as the authors' personal, and differing, attitudes toward these. PMID- 28815489 TI - In reply: Using a Mcintosh blade for retromolar intubation: a comment. PMID- 28815490 TI - Generating Genetically Modified Mice: A Decision Guide. AB - The generation of a new genetically modified mouse strain is a big hurdle to take for many researchers. It is often unclear which steps and decisions have to be made prior to obtaining the desired mouse model. This review aims to help researchers by providing a decision guide that answers the essential questions that need to be asked before generating the most suitable genetically modified mouse line in the most optimal timeframe. The review includes the latest technologies in both the stem cell culture and gene editing tools, particularly CRISPR/Cas9, and provides compatibility guidelines for selecting among the different types of genetic modifications that can be introduced in the mouse genome and the various routes for introducing these modifications into the mouse germline. PMID- 28815491 TI - Direct Generation of Conditional Alleles Using CRISPR/Cas9 in Mouse Zygotes. AB - Conditional alleles in genetically modified mice allow for the deletion of a gene of interest in a target tissue when combined with a tissue-specific Cre recombinase. A conditional allele is achieved by introducing LoxP sites around a critical exon, a gene, or a cluster of genes. Previously, conditional alleles were introduced in the mouse germline by classic gene targeting in embryonic stem cells, a challenging and time-consuming procedure. Now, conditional alleles can be generated directly in fertilized mouse eggs (zygotes) using the CRISPR/Cas9 technology. This one-step generation of mice is easier in design and faster. Here, we describe our achieved success rate, the considerations in design of a conditional allele, a detailed protocol to prepare the zygote injection mix, and the screening procedure to identify the new conditional knockout mouse strain. PMID- 28815492 TI - Building Cre Knockin Rat Lines Using CRISPR/Cas9. AB - Conditional gene inactivation strategy helps researchers to study the gene functions that are critical in embryogenesis or in defined tissues of adulthood. The Cre/loxP system is widely used for conditional gene inactivation/activation in cells or organisms. Cre knockin animal lines are essential for gene expression or inactivation in a spatially and temporally restricted manner. However, to generate a Cre knockin line by traditional approach is laborious. Recently, the clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9) has been proven as a simple and efficient genome-editing tool. We have used CRISPR/Cas9 system to generate rat strains that carry Cre genes in different targeted gene loci by direct delivery of gRNAs/Cas9/donors into fertilized eggs. Here, we described a stepwise procedure for the generation of Cre knockin rat, including target site selection, RNA preparation, the construction of the template donor, pronuclear injection, and the genotyping of precise Cre insertion in F0 rats. Taken together, the establishment of Cre knockin line can be achieved within 6 weeks. PMID- 28815493 TI - Dual Recombinase-Mediated Cassette Exchange by Tyrosine Site-Specific Recombinases. AB - Recombinase-mediated cassette exchange, or RMCE, is a genome engineering tool that can be used to swap DNA fragments of interest between two DNA molecules. In a variation of RMCE, called dual RMCE, the exchange of DNA fragments is mediated by two recombinases in contrast to one recombinase in the classic RMCE reaction. Under optimal conditions, the efficiency of dual RMCE can be quite high: up to ~45% of the transfected cells depending on the recombinase pair used to mediate the replacement reaction. Here we describe protocols for preparing for, performing, and optimizing the parameters of dual RMCE. PMID- 28815494 TI - Use of the DICE (Dual Integrase Cassette Exchange) System. AB - When constructing transgenic cell lines via plasmid DNA integration, precise targeting to a desired genomic location is advantageous. It is also often advantageous to remove the bacterial backbone, since bacterial elements can lead to the epigenetic silencing of neighboring DNA. The least cumbersome method to remove the plasmid backbone is recombinase-mediated cassette exchange (RMCE). RMCE is accomplished by arranging recombinase sites in the genome and in a donor plasmid such that a recombinase can both integrate the donor plasmid and excise its bacterial backbone. When a single recombinase is used for RMCE, recombination between undesired pairings of the sites can lead to a significant number of unwanted cell lines. To reduce the frequency with which these side products occur, several variants of RMCE that increase desired outcomes have been developed. Nevertheless, an important feature lacking from these improved RMCE methods is that none have fully utilized the recombinases that have been demonstrated to be the most robust and stringent at performing genomic integration in plants and animals, i.e., the phiC31 and Bxb1 phage integrases. To address this need, we have developed an RMCE protocol using these two serine integrases that we call dual integrase cassette exchange (DICE). Our DICE system provides a means to achieve high-precision DNA integration at a desired location and is especially well suited for repeated recombination into the same locus. In this chapter, we provide our most current protocols for using DICE in feeder-free human-induced pluripotent stem cells . PMID- 28815495 TI - Ligand-Controlled Site-Specific Recombination in Zebrafish. AB - Cre-mediated site-specific recombination has emerged as an indispensable tool for the precise manipulation of genomes allowing lineage-tracing studies, temporal and spatial misexpressions, and in particular the generation of conditional knockout alleles. Previously, we and others showed that Cre and its ligand inducible variant CreERT2 are also highly efficient in the developing and adult zebrafish. The number of Cre driver and effector lines is currently still limited in zebrafish. However, the recent advent of novel genome editing tools such as TALEN and CRISPR/Cas will significantly increase interest in the conditional Cre/lox-technology in this organism. The considerations of basic transgene design and subsequent transgenesis have been addressed elsewhere. Here we outline practical experimental steps for transient functionality tests of CreERT2 driver and effector constructs. In addition, we introduce detailed protocols to elicit CreERT2-mediated recombination in vivo at embryonic as well as adult stages. PMID- 28815496 TI - Injection-Based Delivery of Cell-Permeable Peptide-Tagged Cre. AB - The technique of Cre-mediated DNA recombination at loxP sites has been used widely in manipulation of the genome in cultured cells and in living organisms. Local delivery of Cre recombinase protein tagged with a cell-penetrating (or permeable) peptide (Cre-CPP) has the advantage of additional spatial and temporal control when compared to genetic delivery methods. In this chapter, we describe protocols for injection-based intramuscular delivery of Cre-CPP dissolved in hydrogel to skeletal muscle and by ultrasound-guided injection to cardiac muscle in mice. PMID- 28815497 TI - Viral Delivery of GFP-Dependent Recombinases to the Mouse Brain. AB - Many genetic tools have been developed that use green fluorescent protein (GFP) and its derivatives for labeling specific cell populations in organisms and in cell culture. To extend the use of GFP beyond labeling purposes, we developed methods and reagents that use GFP as a driver of biological activities. We used nanobodies that bind GFP to engineer CRE-DOG and Flp-DOG, recombinases that can induce Cre/lox and Flp/FRT recombination in a GFP-dependent manner, respectively. Here, we present a protocol to deliver CRE-DOG and Flp-DOG into the mouse brain by recombinant AAV infection. This protocol enables one to manipulate gene expression specifically in GFP-expressing cells, found either in transgenic GFP reporter lines or in cells made to express GFP by other transduction methods. PMID- 28815498 TI - Recombinase-Mediated Cassette Exchange Using Adenoviral Vectors. AB - Site-specific recombinases are important tools for the modification of mammalian genomes. In conjunction with viral vectors, they can be utilized to mediate site specific gene insertions in animals and in cell lines which are difficult to transfect. Here we describe a method for the generation and analysis of an adenovirus vector supporting a recombinase-mediated cassette exchange reaction and discuss the advantages and limitations of this approach. PMID- 28815499 TI - Marker Removal in Transgenic Plants Using Cre Recombinase Delivered with Potato Virus X. AB - In this chapter we present an alternative method to develop marker-free transgenic plants. It makes use of the Cre/loxP recombination system from bacteriophage P1 and consists of two essential components. The first component is the transgenic plant containing a loxP-flanked marker gene. The second component is a cre transient expression vector based on potato virus X. The great benefit of this transient delivery method consists in the avoidance of stable integration of the cre recombinase gene into the plant genome. Upon infection of the loxP target plant with PVX-Cre, the virus spreads systemically through the plant and causes the recombinase-mediated excision of the marker gene. Marker-free transgenic loci can be transmitted to the progeny by plant regeneration from PVX Cre systemically infected leaves or self-pollination of virus-infected plants. The protocol covers generation of loxP-target transgenic plants, PVX-mediated delivery of Cre recombinase protein, phenotypic and molecular analysis of recombination events, and transmission of marker-free transgenic loci to the next generation. The transient expression system described in this chapter can be adapted for marker gene removal in other plant species that are amenable for virus infection. PMID- 28815500 TI - Nanoparticle-Mediated Recombinase Delivery into Maize. AB - We describe a non-DNA-based system for delivering Cre recombinase protein into maize tissue using gold-plated mesoporous silica nanoparticle (Au-MSN). Cre protein is first loaded into the pores of Au-MSNs and then delivered using the biolistic method to immature embryos of a maize line (Lox-corn), which harbors loxP sites flanking a selection and a reporter gene. The release of the Cre recombinase protein inside the plant cell leads to recombination at the loxP sites, eliminating both genes. Visual screening is used to identify recombination events, which can be regenerated to mature and fertile plants. Using the experimental procedures and conditions described here, as high as 20% of bombarded embryos can produce regenerable recombinant callus events. This nanomaterial-mediated, DNA-free methodology has potential to become an effective tool for plant genome editing. PMID- 28815501 TI - Immunohistochemical Procedures for Characterizing the Retinal Expression Patterns of Cre Driver Mouse Lines. AB - The retina is a thin neural tissue sitting on the backside of the eye, composed of light-sensing cells, interneurons, and output ganglion neurons. The latter send electrical signals to higher visual centers in the brain. Transgenic mouse lines are becoming one of the most valuable mammalian animal models for the study of visual signal processing within the retina. Especially, the generation of Cre recombinase transgenic mouse lines provides a powerful tool for genetic manipulation. A key step for the utilization of transgenic lines is the characterization of their transgene expression patterns in the retina. Here we describe a standard protocol for characterizing the expression pattern of the Cre recombinase or fluorescent proteins in the retina with an immunohistochemical approach. PMID- 28815503 TI - Imaging Neural Architecture in Brainbow Samples. AB - The fluorescent protein revolution has made the light microscope the most widely used tool for studying biological structure from the single-molecule to whole organism scales. However, traditional approaches are limited in their ability to resolve components in highly complex structures, such as the brain. In recent years, this limitation has been circumvented by the development of multicolor labeling methods, termed Brainbow. Brainbow tools rely on site-specific recombinases to make stochastic "choices" between different combinations of fluorescent proteins so that structures in close proximity to one another can be resolved based on their color profile. These new approaches, however, call for more refined methods of sample preparation and imaging optimized for multispectral imaging, which are presented here. The most robust approach for generating useful Brainbow data combines immunohistology with multispectral laser scanning confocal microscopy. This chapter, therefore, focuses on this particular technique, though the imaging principle discussed here is applicable to other Brainbow approaches as well. PMID- 28815502 TI - FLPing Genes On and Off in Drosophila. AB - The fruit fly, Drosophila melanogaster, has been a favorite experimental system of developmental biologists for more than a century. One of the most attractive features of this model system is the clarity by which one can analyze mutant phenotypes. Most genes are found in single copies, and loss-of-function mutants often have obvious phenotypes that can be analyzed during development and in adulthood. As with all metazoans, a significant fraction of Drosophila genes are used during both embryonic and postembryonic development, and null mutants often die during embryogenesis thereby precluding the analysis of postembryonic tissues. For several decades researchers worked around this problem by either studying gynandromorphs or irradiating chromosomes carrying mutations in the hope of inducing mitotic recombination which would then allow for the analysis of mutant phenotypes in smaller populations of cells. The former method suffers from the fact that mutations in the gene of interest are often lethal when generated in large sectors, which is a hallmark of gynandromorphs. Clonal induction with the latter method occurs at relatively low frequencies making this method laborious. The introduction of the yeast FRT System/FRT site-directed recombination system to Drosophila has made generating loss-of-function mosaic clones simple and easy. Over the years several variants of this method have allowed developmental biologists to remove genes, overexpress genes, and even express one gene in patches of cells that are mutant for a second gene. In this review we will briefly discuss some of various FRT System/FRT-based approaches that are being used to manipulate gene expression in Drosophila. The individual FRT System/FRT-based methods are described in the papers that are cited herein. We will outline the procedure that our lab uses to prepare and analyze mosaic clones in Drosophila eye-antennal imaginal discs. PMID- 28815504 TI - Purification and In Vitro Characterization of Zinc Finger Recombinases. AB - Zinc finger recombinases (ZFRs) are designer site-specific recombinases that have been adapted for a variety of genome editing purposes. Due to their modular nature, ZFRs can be customized for targeted sequence recognition and recombination. There has been substantial research on the in vivo properties and applications of ZFRs; however, in order to fully understand and customize them, it will be necessary to study their properties in vitro. Experiments in vitro can allow us to optimize catalytic activities, improve target specificity, measure and minimize off-target activity, and characterize key steps in the recombination pathway that might be modified to improve performance. Here, we present a straightforward set of protocols for the expression and purification of ZFRs, an assay system for catalytic proficiency in vitro and bandshift assays for detection of sequence-specific DNA interactions. PMID- 28815505 TI - Preparing Mate-Paired Illumina Libraries Using Cre Recombinase. AB - Large insert mate pair reads have been used in de novo assembly and discovery of structural variants. We developed a new approach, Cre-LoxP inverse PCR paired end (CLIP-PE), which exploits the advantages of (1) Cre-LoxP recombination system to efficiently circularize large DNA fragments, (2) inverse PCR to enrich for the desired products that contain both ends of the large DNA fragments, and (3) use of restriction enzymes to introduce a recognizable junction site between ligated fragment ends. We have successfully created CLIP-PE libraries of up to 22 kb jumping pairs and demonstrated their ability to improve genome assemblies. The CLIP-PE methodology can be implemented with existing and future next-generation sequencing platforms. PMID- 28815506 TI - Preparing Fosmid Mate-Paired Libraries Using Cre-LoxP Recombination. AB - Fosmid end sequencing has been widely utilized in genome sequence assemblies and genome structural variation studies. We have developed a new approach to construct fosmid paired-end libraries that is suitable for Illumina sequencing platform. This approach employs a newly modified fosmid vector (pFosClip) which contains two loxP sites with identical orientation and two inverse Illumina adaptor priming sites flanking the cloning site. DNA prepared from the fosmid library constructed with pFosClip can be treated with the Cre recombinase to remove most of the vector DNA, leaving only 107 bp of the vector sequence with insert DNA. Frequent cutting restriction enzymes and ligase are used to digest the fosmid DNA to small (less than 1 Kb) fragments and recircularize the fosmid ends and all the internal fragments. Finally an inverse PCR step with the Illumina primers is used to enrich the fosmid paired ends (PEs) for sequencing. The advantages of this approach are the following: (1) the circularization of short fragments with sticky ends is efficient; therefore the success rate is higher than other approaches that attempt to join both blunt ends of large fosmid vectors; and (2) the restriction enzyme cutting generates an identifiable junction tag for splitting the paired reads. (3) Multiple restriction enzymes can be used to overcome possible enzyme-cutting bias. Our results have shown that this approach has produced mostly fosmid size (30-40 Kb) pairs from the targeted fungi and plant genomes and has drastically increased the scaffold sizes in the assembled genomes. PMID- 28815507 TI - Using Purified Tyrosine Site-Specific Recombinases In Vitro to Rapidly Construct and Diversify Metabolic Pathways. AB - The site-specific recombinase Cre was previously reported to have in vitro activity. Here, we describe the method of purifying two new tyrosine site specific recombinases VCre and Dre along with Cre by nickel affinity chromatography. We proved the in vitro function of the VCre and Dre on their respective conditional recombination sites. We also developed a methodology to one-step construct and optimize the productivity of a biosynthetic pathway through the combinatorial integration of promoters into a plasmid-encoded pathway by simply incubating a DNA mixture with recombinase system at 37 degrees C in vitro. PMID- 28815508 TI - Multipart DNA Assembly Using Site-Specific Recombinases from the Large Serine Integrase Family. AB - Assembling multiple DNA fragments into functional plasmids is an important and often rate-limiting step in engineering new functions in living systems. Bacteriophage integrases are enzymes that carry out efficient recombination reactions between short, defined DNA sequences known as att sites. These DNA splicing reactions can be used to assemble large numbers of DNA fragments into a functional circular plasmid in a method termed serine integrase recombinational assembly (SIRA). The resulting DNA assemblies can easily be modified by further recombination reactions catalyzed by the same integrase in the presence of its recombination directionality factor (RDF). Here we present a set of protocols for the overexpression and purification of bacteriophage phiC31 and Bxb1 integrase and RDF proteins, their use in DNA assembly reactions, and subsequent modification of the resulting DNA assemblies. PMID- 28815509 TI - Production of Minicircle DNA Vectors Using Site-Specific Recombinases. AB - Minicircle DNA vectors are plasmid derivatives free of bacterial elements. These vectors are mostly provided from common plasmids via recombination by site specific recombinases in E. coli. Absence of bacterial backbone in minicircle vectors results in high-level and persistent expression of transgene in comparison with conventional plasmids and provides promising vehicles for gene therapy and vaccination. Here we describe the production of replicative minicircle DNA vectors using the PBAD/araC system expressing PhiC31 integrase in E. coli. PMID- 28815510 TI - Inhibition of gamma-Secretase Leads to an Increase in Presenilin-1. AB - gamma-Secretase inhibitors (GSIs) are potential therapeutic agents for Alzheimer's disease (AD); however, trials have proven disappointing. We addressed the possibility that gamma-secretase inhibition can provoke a rebound effect, elevating the levels of the catalytic gamma-secretase subunit, presenilin-1 (PS1). Acute treatment of SH-SY5Y cells with the GSI LY-374973 (N-[N-(3,5 difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, DAPT) augments PS1, in parallel with increases in other gamma-secretase subunits nicastrin, presenilin enhancer 2, and anterior pharynx-defective 1, yet with no increase in messenger RNA expression. Over-expression of the C-terminal fragment (CTF) of APP, C99, also triggered an increase in PS1. Similar increases in PS1 were evident in primary neurons treated repeatedly (4 days) with DAPT or with the GSI BMS-708163 (avagacestat). Likewise, rats examined after 21 days administered with avagacestat (40 mg/kg/day) had more brain PS1. Sustained gamma-secretase inhibition did not exert a long-term effect on PS1 activity, evident through the decrease in CTFs of APP and ApoER2. Prolonged avagacestat treatment of rats produced a subtle impairment in anxiety-like behavior. The rebound increase in PS1 in response to GSIs must be taken into consideration for future drug development. PMID- 28815512 TI - P2Y2 Receptor Functions in Cancer: A Perspective in the Context of Colorectal Cancer. AB - Purinergic signaling has recently emerged as a network of signaling molecules, enzymes and receptors that coordinates the action and behavior of cancerous cells. Extracellular adenosine 5' triphosphate activates a plethora of P2 nucleotide receptors that can putatively modulate cancer cell proliferation, survival and dissemination. In this context, the G protein-coupled P2Y2 receptor was identified as one of the entities coordinating the cellular and molecular events that characterize cancerous cells. In this chapter, we will look at the contribution of the P2Y2 receptor in cancer outcomes and use this information to demonstrate that the P2Y2 receptor represents a drug target of interest in the setting of colorectal cancer, for which the role and function of this receptor is poorly defined. More particularly, we will review how the P2Y2 receptor modulates cancer cell proliferation and survival, while promoting cell dissemination and formation of metastases. Finally, we will investigate how the P2Y2 receptor can contribute to the detrimental development of drug resistance that is often observed in cancerous cells. PMID- 28815511 TI - The Structure-Forming Juncture in Oxidative Protein Folding: What Happens in the ER? AB - The folding of disulfide bond containing proteins proceeds in a biphasic manner. Initially, cysteines are oxidized to form disulfide bonds. Structure is largely absent during this phase. Next, when a minimally correct number of native linkages of disulfide bonds have been acquired, the biopolymer conformationally folds into the native, or a native-like, state. Thus, at the end of this "oxidative folding" process, a stable and biologically active protein is formed. This review focuses on dissecting the "structure-forming step" in oxidative protein folding. The ability to follow this pivotal step in protein maturation in somewhat detail is uniquely facilitated in "oxidative" folding scenarios. We review this step using bovine pancreatic Ribonuclease A as a model while recognizing the impact that this step has in subcellular trafficking and protein aggregation. PMID- 28815513 TI - An Update on P2Y13 Receptor Signalling and Function. AB - The distribution of nucleotide P2Y receptors across different tissues suggests that they fulfil key roles in a number of physiological and pathological conditions. P2Y13 is one of the latest P2Y receptors identified, a novel member of the Gi-coupled P2Y receptor subfamily that responds to ADP, together with P2Y12 and P2Y14. Pharmacological studies drew attention to this new ADP receptor, with a pharmacology that overlaps that of P2Y12 receptors but with unique features and roles. The P2RY12-14 genes all reside on human chromosome 3 at 3q25.1 and their strong sequence homology supports their evolutionary origin through gene duplication. Polymorphisms of P2Y13 receptors have been reported in different human populations, yet their consequences remain unknown. The P2Y13 receptor is versatile in its signalling, extending beyond the canonical signalling of a Gi-coupled receptor. Not only can it couple to different G proteins (Gs/Gq) but the P2Y13 receptor can also trigger several intracellular pathways related to the activation of MAPKs (mitogen-activated protein kinases) and the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3 axis. Moreover, the availability of P2Y13 receptor knockout mice has highlighted the specific functions in which it is involved, mainly in the regulation of cholesterol and glucose metabolism, bone homeostasis and aspects of central nervous system function like pain transmission and neuroprotection. This review summarizes our current understanding of this elusive receptor, not only at the pharmacological and molecular level but also, in terms of its signalling properties and specific functions, helping to clarify the involvement of P2Y13 receptors in pathological situations. PMID- 28815515 TI - Assessing Communication Skills in Real Medical Encounters in Oncology: Development and Validation of the ComOn-Coaching Rating Scales. AB - One of the challenges in research on teaching physician-patient communication is how to assess communication, necessary for evaluating training, the learning process, and for feedback. Few instruments have been validated for real physician patient consultations. Real consultations involve unique contexts, different persons, and topics, and are difficult to compare. The aim of this study is to develop and validate a rating scale for assessment of such consultations. For the evaluation study of a communication skills training for physicians in oncology, real consultations were recorded in three assessment points. Based on earlier work and on current studies, a new instrument was developed for assessment of these consultations. Two psychologists were trained in using the instrument and assessed 42 consultations. For inter-rater reliability, interclass correlation (ICC) was calculated. The final version of the rating scales consists of 13 items evaluated on a 5-point scale. The items are grouped in seven areas: "Start of conversation," "assessment of the patient's perspective," "structure of conversation," "emotional issues," "end of conversation," "general communication skills," and "overall evaluation." ICC coefficients for the domains ranged from .44 to .77. An overall coefficient of all items resulted in an ICC of .66. The ComOn-Coaching Rating Scales are a short, reliable, and applicable instrument for the assessment of real physician-patient consultations in oncology. If adapted, they could be used in other areas. They were developed for research and teaching purposes and meet the required methodological criteria. Rater training should be considered more deeply by further research. PMID- 28815514 TI - Intraepithelial lymphocyte immunophenotype: a useful tool in the diagnosis of celiac disease. AB - According to new ESPGHAN guidelines, gluten challenge is considered necessary when there is doubt about the initial diagnosis of celiac disease (CD). The main aim of this study was to quantify intraepithelial lymphocyte (IEL) immunophenotype on celiac patients on gluten-containing diet (GCD) compared to those on gluten-free diet (GFD). Another aim was to evaluate the clinical utility of IELs in the CD diagnosis, especially in selected patients on GFD where diagnostic uncertainty remains. IEL immunophenotype (TCRgammadelta and NK-like IELs) were studied by flow cytometry in 111 children with CD (81 children with CD on GCD and 30 celiac patients on GFD) and a control group (10 children). Duration of GFD was 5.4 +/- 1.6 years. TCRgammadelta IELs in celiac patients receiving a GCD or GFD were significantly higher (p < 0.001) than in the control group. NK like IELs in patients receiving a GCD or GFD were significantly lower than in the control group (p < 0.001). We observed a permanent decrease of NK-like IELs and an increment of TCRgammadelta IELs after following an adequate establishment and compliance of a long-term GFD in celiac patients. Recognition of IELs changes in the intestinal mucosa on celiac patients after long-term establishment of a GFD could constitute a useful tool for CD diagnosis in various situations: in which there is doubt about the initial diagnosis and repeat biopsy is necessary (avoiding the need of gluten challenges), and in those patients with symptoms/signs suggestive of CD who maintain a low gluten diet. PMID- 28815516 TI - Gastrointestinal Epithelial Organoid Cultures from Postsurgical Tissues. AB - An organoid is a cellular structure three-dimensionally (3D) cultured from self organizing stem cells in vitro, which has a cell population, architectures, and organ specific functions like the originating organs. Recent advances in the 3D culture of isolated intestinal crypts or gastric glands have enabled the generation of human gastrointestinal epithelial organoids. Gastrointestinal organoids recapitulate the human in vivo physiology because of all the intestinal epithelial cell types that differentiated and proliferated from tissue resident stem cells. Thus far, gastrointestinal organoids have been extensively used for generating gastrointestinal disease models. This protocol describes the method of isolating a gland or crypt using stomach or colon tissue after surgery and establishing them into gastroids or colonoids. PMID- 28815517 TI - Autophagy in Adipocyte Differentiation. AB - Adipose tissue regulates metabolic homeostasis by acting as an endocrine organ and energy reservoir. Adipose tissue development and functional maintenance are dependent on adipocyte differentiation, in which autophagy plays an important role. It has been shown that autophagy deficiency dampens adipocyte differentiation, compromises adipose tissue development, dysregulates adipocytokine secretion, and even causes sudden death in young animals. Therefore, accurate assessment of autophagy in adipocyte is critical for the study of adipose biology or pathology of metabolic diseases. In this chapter, we described the procedure of autophagy analysis during adipocyte differentiation, and discussed the power of steady-state autophagy protein (e.g., beclin 1, LC3, and p62) levels versus autophagy flux to reflect autophagy activity. PMID- 28815518 TI - Organelle Communication at Membrane Contact Sites (MCS): From Curiosity to Center Stage in Cell Biology and Biomedical Research. AB - Cell biology has long recognized that organelles can communicate with each other. Initially, such communication was thought to occur primarily via vesicular trafficking between biochemically distinct organelles. However, studies starting in the 1970s on lipid metabolism have unearthed another way how organelles can communicate and have spawned the field of membrane contact sites (MCS). While, initially, MCS had been recognized as fluid entities that mediate lipid and ion transport in an ad hoc manner, more recently MCS have been found to depend on protein-protein interactions that control themselves a variety of MCS functions. As a result, the cell biological definition of an intracellular organelle as an isolated membrane compartment is now being revised. Accordingly, the organelle definition now describes organelles as dynamic membrane compartments that function in a milieu of coordinated contacts with other organelles. Through these mercurial functions, MCS dictate the function of organelles to a large extent but also play important roles in a number of diseases, including type 2 diabetes, neurodegenerative diseases, infections, and cancer. This book assembles reviews that describe our quickly evolving knowledge about organellar communication on MCS and the significance of MCS for disease. PMID- 28815519 TI - Over Six Decades of Discovery and Characterization of the Architecture at Mitochondria-Associated Membranes (MAMs). AB - The discovery of proteins regulating ER-mitochondria tethering including phosphofurin acidic cluster sorting protein 2 (PACS-2) and mitofusin-2 has pushed contact sites between the endoplasmic reticulum (ER) and mitochondria into the spotlight of cell biology. While the field is developing rapidly and controversies have come and gone multiple times during its history, it is sometimes overlooked that significant research has been done decades ago with the original discovery of these structures in the 1950s and the first characterization of their function (and coining of the term mitochondria associated membrane, MAM) in 1990. Today, an ever-increasing array of proteins localize to the MAM fraction of the endoplasmic reticulum (ER) to regulate the interaction of this organelle with mitochondria. These mitochondria-ER contacts, sometimes referred to as MERCs, regulate a multitude of biological functions, including lipid metabolism, Ca2+ signaling, bioenergetics, inflammation, autophagy, mitochondrial structure, and apoptosis. PMID- 28815520 TI - Regulation of Mitochondrial Dynamics and Autophagy by the Mitochondria-Associated Membrane. AB - Mitochondria are powerhouses and central to metabolism in cells. They are highly dynamic organelles that continuously fuse, divide, and move along the cytoskeleton to form the mitochondrial network. The fusion and fission are catalyzed by four dynamin-related GTPases in mammals that are controlled by a variety of protein-protein interactions and posttranslational modifications. Mitochondrial dynamics and metabolism are linked and regulate each other. Starvation induces mitochondrial elongation, which enables the mitochondria to produce energy more efficiently and to escape from autophagic degradation. Damaged portions of mitochondria are removed from the healthy parts by division, and subsequently degraded via a specific mode of autophagy termed mitophagy. Recent studies shed light on the contribution of the endoplasmic reticulum to mitochondrial dynamics and the cooperation of the two organelles for the progression of autophagy including mitophagy. A subdomain of the endoplasmic reticulum apposed to mitochondria is called the mitochondria-associated membrane (MAM), which comprises a unique set of proteins that interact with mitochondrial proteins. Here we review our current understanding of the molecular mechanisms of mitochondrial dynamics and mitochondria-related processes in the context of the interaction with the endoplasmic reticulum. PMID- 28815521 TI - Endoplasmic Reticulum-Mitochondria Communication Through Ca2+ Signaling: The Importance of Mitochondria-Associated Membranes (MAMs). AB - The execution of proper Ca2+ signaling requires close apposition between the endoplasmic reticulum (ER) and mitochondria. Hence, Ca2+ released from the ER is "quasi-synaptically" transferred to mitochondrial matrix, where Ca2+ stimulates mitochondrial ATP synthesis by activating the tricarboxylic acid (TCA) cycle. However, when the Ca2+ transfer is excessive and sustained, mitochondrial Ca2+ overload induces apoptosis by opening the mitochondrial permeability transition pore. A large number of regulatory proteins reside at mitochondria-associated ER membranes (MAMs) to maintain the optimal distance between the organelles and to coordinate the functionality of both ER and mitochondrial Ca2+ transporters or channels. In this chapter, we discuss the different pathways involved in the regulation of ER-mitochondria Ca2+ flux and describe the activities of the various Ca2+ players based on their primary intra-organelle localization. PMID- 28815522 TI - Ceramide Transport from the Endoplasmic Reticulum to the Trans Golgi Region at Organelle Membrane Contact Sites. AB - Lipids are the major constituents of all cell membranes and play dynamic roles in organelle structure and function. Although the spontaneous transfer of lipids between different membranes rarely occurs, lipids are appropriately transported between different organelles for their metabolism and to exert their functions in living cells. Proteins that have the biochemical capability to catalyze the intermembrane transfer of lipids are called lipid transfer proteins (LTPs). All organisms possess many types of LTPs. Recent studies revealed that LTPs are key players in the interorganelle transport of lipids at organelle membrane contact sites (MCSs). This chapter depicts how LTPs rationally operate at MCSs by using the ceramide transport protein CERT as a typical model for the LTP-mediated interorganelle transport of lipids. PMID- 28815523 TI - Endoplasmic Reticulum - Plasma Membrane Crosstalk Mediated by the Extended Synaptotagmins. AB - The endoplasmic reticulum (ER) possesses multiplicity of functions including protein synthesis, membrane lipid biogenesis, and Ca2+ storage and has broad localization throughout the cell. While the ER and most other membranous organelles are highly interconnected via vesicular traffic that relies on membrane budding and fusion reactions, the ER forms direct contacts with virtually all other membranous organelles, including the plasma membrane (PM), without membrane fusion. Growing evidence suggests that these contacts play major roles in cellular physiology, including the regulation of Ca2+ homeostasis and signaling and control of cellular lipid homeostasis. Extended synaptotagmins (E Syts) are evolutionarily conserved family of ER-anchored proteins that tether the ER to the PM in PM PI(4,5)P2-dependent and cytosolic Ca2+-regulated manner. In addition, E-Syts possess a cytosolically exposed lipid-harboring module that confers the ability to transfer/exchange glycerolipids between the ER and the PM at E-Syts-mediated ER-PM contacts. In this chapter, the functions of ER-PM contacts and their role in non-vesicular lipid transport with special emphasis on the crosstalk between the two bilayers mediated by E-Syts will be discussed. PMID- 28815524 TI - Endoplasmic Reticulum-Plasma Membrane Contacts Regulate Cellular Excitability. AB - Cells that have intrinsic electrical excitability utilize changes in membrane potential to communicate with neighboring cells and initiate cellular cascades. Excitable cells like neurons and myocytes have evolved highly specialized subcellular architectures to translate these electrical signals into cellular events. One such structural specialization is sarco-/endoplasmic reticulum-plasma membrane contact sites. These membrane contact sites are positioned by specific membrane-membrane tethering proteins and contain an ever-expanding list of additional proteins that organize information transfer across the junctional space (~ 15-25 nm distance) to shape membrane identity and control cellular excitability. In this chapter we discuss how contacts between the sarco /endoplasmic reticulum and plasma membrane are essential for regulated excitation contraction coupling in striated muscle and control of lipid-dependent ion channels. PMID- 28815525 TI - The Lipid Droplet and the Endoplasmic Reticulum. AB - Lipid droplets (LDs) are often found adjacent to the endoplasmic reticulum (ER). The ER-LD association may appear morphologically similar to the prototypical membrane contact sites found between the ER and other organelles, but the functional relationship between the ER and LDs is unique in that highly hydrophobic lipid esters are transported between them. This transportation is thought to occur through some form of membrane continuity, but its details are yet to be defined. Lipin, seipin, and FIT proteins, which are located at the ER LD interface, may be involved in the lipid ester transport and probably play important roles for functional connectivity of the two organelles. More recently, LDs in the nucleus were found to be closely adhered to the inner nuclear membrane, representing a specialized form of the ER-LD association. In this article, we will give an overview of the ER-LD association, which is still filled with many unanswered questions. PMID- 28815526 TI - Role of Intra- and Inter-mitochondrial Membrane Contact Sites in Yeast Phospholipid Biogenesis. AB - Eukaryotic cells exhibit intracellular compartments called organelles wherein various specialized enzymatic reactions occur. Despite the specificity of the characteristic functions of organelles, recent studies have shown that distinct organelles physically connect and communicate with each other to maintain the integrity of their functions. In yeast, multiple inter- and intramitochondrial membrane contact sites (MCSs) were identified to date and were proposed to be involved in phospholipid biogenesis. In the present article, we focus on inter- and intra-organellar MCSs involving mitochondria and their tethering factors, such as the ERMES (endoplasmic reticulum (ER)-mitochondria encounter structure) complex and EMC (conserved ER membrane protein complex) between mitochondria and the ER, vCLAMP (vacuole and mitochondria patch) between mitochondria and vacuoles, and the MICOS (mitochondrial contact site) complex between the mitochondrial outer and inner membranes (MOM and MIM). All of these membrane tethering factors were proposed to be involved in phospholipid biogenesis. Furthermore, the existence of functional interconnections among multiple organelle contact sites is suggested. In the present article, we summarize the latest discoveries in regard to MCSs and MCS-forming factors involving mitochondria and discuss their molecular functions, with particular focus on phospholipid metabolism in yeast. PMID- 28815528 TI - Alzheimer Disease. AB - The most widely accepted hypothesis to explain the pathogenesis of Alzheimer disease (AD) is the amyloid cascade, in which the accumulation of extraneuritic plaques and intracellular tangles plays a key role in driving the course and progression of the disease. However, there are other biochemical and morphological features of AD, including altered calcium, phospholipid, and cholesterol metabolism and altered mitochondrial dynamics and function that often appear early in the course of the disease, prior to plaque and tangle accumulation. Interestingly, these other functions are associated with a subdomain of the endoplasmic reticulum (ER) called mitochondria-associated ER membranes (MAM). MAM, which is an intracellular lipid raft-like domain, is closely apposed to mitochondria, both physically and biochemically. These MAM localized functions are, in fact, increased significantly in various cellular and animal models of AD and in cells from AD patients, which could help explain the biochemical and morphological alterations seen in the disease. Based on these and other observations, a strong argument can be made that increased ER-mitochondria connectivity and increased MAM function are fundamental to AD pathogenesis. PMID- 28815527 TI - Discovery and Roles of ER-Endolysosomal Contact Sites in Disease. AB - Inter-organelle membrane contact sites (MCSs) serve as unique microenvironments for the sensing and exchange of cellular metabolites and lipids. Though poorly defined, ER-endolysosomal contact sites are quickly becoming recognized as centers for inter-organelle lipid exchange and metabolic decision-making. Here, we review the discovery and current state of knowledge of ER-endolysosomal MCSs with particular focus on the molecular players that establish and/or utilize these contact sites in metabolism. We also discuss associations of ER endolysosomal MCS-associated proteins in human disease, as well as the therapeutic promise these contact sites hold in modulating cellular physiology. PMID- 28815529 TI - Mitochondrial-Associated Membranes in Parkinson's Disease. AB - Parkinson's disease (PD) is a common neurodegenerative disorder, with ageing being a major risk factor. Accordingly, estimates predict an increasing number of PD patients due to our expanding life span. Consequently, developing a true disease-modifying therapy is necessary. In this regard, monogenic PD offers a suitable means for determining pathogenesis. Among monogenic forms of PD, mitochondrial dysfunction may be a major cause and is also likely to be involved in sporadic PD. Thus, mitochondrial impairment may be a common pathway. Recently, mitochondria-associated membranes (MAM) were identified as dynamic sites between mitochondria and endoplasmic reticulum. Indeed, the gene product of alpha synuclein is a major component of MAM, with other gene products also involved. This review focuses on the possibility of using MAM as novel therapeutic targets. PMID- 28815530 TI - Role of Endoplasmic Reticulum-Mitochondria Communication in Type 2 Diabetes. AB - Although mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and disrupted lipid and calcium (Ca2+) homeostasis are classically associated with both insulin resistance and beta-cell dysfunction in type 2 diabetes mellitus (T2DM), the interplay between these metabolic stresses is less known. Both organelles interact through contact points known as mitochondria-associated membranes (MAM), in order to exchange both lipids and Ca2+ and regulate cellular homeostasis. Recent evidences suggest that MAM could be an important hub for hormonal and nutrient signaling in the liver and that ER-mitochondria miscommunication could participate to hepatic insulin resistance, highlighting the importance of MAM in the control of glucose homeostasis. Here, we specifically discuss the role of MAM in hormonal and nutrient-regulated signaling pathways supporting a role in the control of glucose homeostasis and analyze the evidences pointing a role of ER-mitochondria miscommunication in T2DM. Collectively, these data suggest that targeting MAM structure and function might be a novel strategy for the treatment of T2DM. PMID- 28815531 TI - Mitochondria-Endoplasmic Reticulum Contact Sites Mediate Innate Immune Responses. AB - Mitochondria and the endoplasmic reticulum (ER) are fundamental organelles that coordinate high-order cell functions. Mitochondria are centers of energy production, whereas the ER is responsible for folding, transport, and degradation of proteins. In addition to their specific functions, mitochondria and ER actively communicate with each other to promote a variety of cellular events, such as material transfer and signal transduction. Recent studies have shown the critical involvement of these organelles in regulation of the innate immune system, which functions in host defense. The innate immune system utilizes a wide range of germ-line-encoded pattern recognition receptors (PRRs) to recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and induces inflammatory and antiviral responses. Contact sites between mitochondria and the ER function in assembly of the NLR family pyrin domain containing 3 (NLRP3)-inflammasome to promote the inflammatory response. The NLRP3-inflammasome is a protein complex composed of the receptor NLRP3 on the ER side and the adaptor apoptosis-associated speck-like protein containing a CARD on the mitochondrial side; it induces caspase-1-dependent maturation of proinflammatory cytokines such as interleukin (IL)-1beta and IL-18. Furthermore, ER-mitochondria contact sites function in initiation and mediation of signal transduction pathways downstream of intracellular PRRs, such as retinoic acid inducible gene I-like receptor and cyclic GMP-AMP synthase, to promote the antiviral response. Therefore, ER-mitochondria contact sites, also known as mitochondria-associated membranes, play key roles in regulation of innate immune responses. PMID- 28815532 TI - Hepatitis C Virus Replication. AB - Viruses use synthetic mechanism and organelles of the host cells to facilitate their replication and make new viruses. Host's ATP provides necessary energy. Hepatitis C virus (HCV) is a major cause of liver disease. Like other positive strand RNA viruses, the HCV genome is thought to be synthesized by the replication complex, which consists of viral- and host cell-derived factors, in tight association with structurally rearranged vesicle-like cytoplasmic membranes. The virus-induced remodeling of subcellular membranes, which protect the viral RNA from nucleases in the cytoplasm, promotes efficient replication of HCV genome. The assembly of HCV particle involves interactions between viral structural and nonstructural proteins and pathways related to lipid metabolisms in a concerted fashion. Association of viral core protein, which forms the capsid, with lipid droplets appears to be a prerequisite for early steps of the assembly, which are closely linked with the viral genome replication. This review presents the recent progress in understanding the mechanisms for replication and assembly of HCV through its interactions with organelles or distinct organelle like structures. PMID- 28815533 TI - Hijacking of Membrane Contact Sites by Intracellular Bacterial Pathogens. AB - Intracellular bacterial pathogens have evolved sophisticated mechanisms to hijack host cellular processes to promote their survival and replication inside host cells. Over the past two decades, much attention has been given to the strategies employed by these pathogens to manipulate various vesicular trafficking pathways. But in the past 5 years, studies have brought to light that intracellular bacteria also target non-vesicular trafficking pathways. Here we review how three vacuolar pathogens, namely, Legionella, Chlamydia, and Coxiella hijack components of cellular MCS with or without the formation of stable MCS. A common theme in the manipulation of MCS by intracellular bacteria is the dependence on the secretion of bacterial effector proteins. During the early stages of the Legionella life cycle, the bacteria connects otherwise unrelated cellular pathways (i.e., components of ER-PM MCS, PI4KIIIalpha, and Sac1 and the early secretory pathway) to remodel its nascent vacuole into an ER-like compartment. Chlamydia and Coxiella vacuoles establish direct MCS with the ER and target lipid transfer proteins that contain a FFAT motif, CERT, and ORP1L, respectively, suggesting a common mechanism of VAP-dependent lipid acquisition. Chlamydia also recruits STIM1, an ER calcium sensor involved in store-operated calcium entry (SOCE) at ER-PM MCS, and elucidating the role of STIM1 at ER-Chlamydia inclusion MCS may uncover additional role for these contacts. Altogether, the manipulation of MCS by intracellular bacterial pathogens has open a new and exciting area of research to investigate the molecular mechanisms supporting pathogenesis. PMID- 28815534 TI - Alterations in Ca2+ Signalling via ER-Mitochondria Contact Site Remodelling in Cancer. AB - Inter-organellar contact sites establish microdomains for localised Ca2+ signalling events. One of these microdomains is established between the ER and the mitochondria. Importantly, the so-called mitochondria-associated ER membranes (MAMs) contain, besides structural proteins and proteins involved in lipid exchange, several Ca2+-transport systems, mediating efficient Ca2+ transfer from the ER to the mitochondria. These Ca2+ signals critically control several mitochondrial functions, thereby impacting cell metabolism, cell death and survival, proliferation and migration. Hence, the MAMs have emerged as critical signalling hubs in physiology, while their dysregulation is an important factor that drives or at least contributes to oncogenesis and tumour progression. In this book chapter, we will provide an overview of the role of the MAMs in cell function and how alterations in the MAM composition contribute to oncogenic features and behaviours. PMID- 28815535 TI - History, Discovery, and Classification of lncRNAs. AB - The RNA World Hypothesis suggests that prebiotic life revolved around RNA instead of DNA and proteins. Although modern cells have changed significantly in 4 billion years, RNA has maintained its central role in cell biology. Since the discovery of DNA at the end of the nineteenth century, RNA has been extensively studied. Many discoveries such as housekeeping RNAs (rRNA, tRNA, etc.) supported the messenger RNA model that is the pillar of the central dogma of molecular biology, which was first devised in the late 1950s. Thirty years later, the first regulatory non-coding RNAs (ncRNAs) were initially identified in bacteria and then in most eukaryotic organisms. A few long ncRNAs (lncRNAs) such as H19 and Xist were characterized in the pre-genomic era but remained exceptions until the early 2000s. Indeed, when the sequence of the human genome was published in 2001, studies showed that only about 1.2% encodes proteins, the rest being deemed "non coding." It was later shown that the genome is pervasively transcribed into many ncRNAs, but their functionality remained controversial. Since then, regulatory lncRNAs have been characterized in many species and were shown to be involved in processes such as development and pathologies, revealing a new layer of regulation in eukaryotic cells. This newly found focus on lncRNAs, together with the advent of high-throughput sequencing, was accompanied by the rapid discovery of many novel transcripts which were further characterized and classified according to specific transcript traits.In this review, we will discuss the many discoveries that led to the study of lncRNAs, from Friedrich Miescher's "nuclein" in 1869 to the elucidation of the human genome and transcriptome in the early 2000s. We will then focus on the biological relevance during lncRNA evolution and describe their basic features as genes and transcripts. Finally, we will present a non-exhaustive catalogue of lncRNA classes, thus illustrating the vast complexity of eukaryotic transcriptomes. PMID- 28815536 TI - Long Noncoding RNA: Genome Organization and Mechanism of Action. AB - For the last four decades, we have known that noncoding RNAs maintain critical housekeeping functions such as transcription, RNA processing, and translation. However, in the late 1990s and early 2000s, the advent of high-throughput sequencing technologies and computational tools to analyze these large sequencing datasets facilitated the discovery of thousands of small and long noncoding RNAs (lncRNAs) and their functional role in diverse biological functions. For example, lncRNAs have been shown to regulate dosage compensation, genomic imprinting, pluripotency, cell differentiation and development, immune response, etc. Here we review how lncRNAs bring about such copious functions by employing diverse mechanisms such as translational inhibition, mRNA degradation, RNA decoys, facilitating recruitment of chromatin modifiers, regulation of protein activity, regulating the availability of miRNAs by sponging mechanism, etc. In addition, we provide a detailed account of different mechanisms as well as general principles by which lncRNAs organize functionally different nuclear sub-compartments and their impact on nuclear architecture. PMID- 28815537 TI - From Heterochromatin to Long Noncoding RNAs in Drosophila: Expanding the Arena of Gene Function and Regulation. AB - Recent years have witnessed a remarkable interest in exploring the significance of pervasive noncoding transcripts in diverse eukaryotes. Classical cytogenetic studies using the Drosophila model system unraveled the perplexing attributes and "functions" of the "gene"-poor heterochromatin. Recent molecular studies in the fly model are likewise revealing the very diverse and significant roles played by long noncoding RNAs (lncRNAs) in development, gene regulation, chromatin organization, cell and nuclear architecture, etc. There has been a rapid increase in the number of identified lncRNAs, although a much larger number still remains unknown. The diversity of modes of actions and functions of the limited number of Drosophila lncRNAs, which have been examined, already reflects the profound roles of such RNAs in generating and sustaining the biological complexities of eukaryotes. Several of the known Drosophila lncRNAs originate as independent sense or antisense transcripts from promoter or intergenic, intronic, or 5'/3' UTR regions, while many of them are independent genes that produce only lncRNAs or coding as well as noncoding RNAs. The different lncRNAs affect chromatin organization (local or large-scale pan-chromosomal), transcription, RNA processing/stability, or translation either directly through interaction with their target DNA sequences or indirectly by acting as intermediary molecules for specific regulatory proteins or may act as decoys/sinks, or storage sites for specific proteins or groups of proteins, or may provide a structural framework for the assembly of substructures in nucleus/cytoplasm. It is interesting that many of the "functions" alluded to heterochromatin in earlier cytogenetic studies appear to find correlates with the known subtle as well as far-reaching actions of the different small and long noncoding RNAs. Further studies exploiting the very rich and powerful genetic and molecular resources available for the Drosophila model are expected to unravel the mystery underlying the long reach of ncRNAs. PMID- 28815538 TI - Long Noncoding RNAs in the Yeast S. cerevisiae. AB - Long noncoding RNAs have recently been discovered to comprise a sizeable fraction of the RNA World. The scope of their functions, physical organization, and disease relevance remain in the early stages of characterization. Although many thousands of lncRNA transcripts recently have been found to emanate from the expansive DNA between protein-coding genes in animals, there are also hundreds that have been found in simple eukaryotes. Furthermore, lncRNAs have been found in the bacterial and archaeal branches of the tree of life, suggesting they are ubiquitous. In this chapter, we focus primarily on what has been learned so far about lncRNAs from the greatly studied single-celled eukaryote, the yeast Saccharomyces cerevisiae. Most lncRNAs examined in yeast have been implicated in transcriptional regulation of protein-coding genes-often in response to forms of stress-whereas a select few have been ascribed yet other functions. Of those known to be involved in transcriptional regulation of protein-coding genes, the vast majority function in cis. There are also some yeast lncRNAs identified that are not directly involved in regulation of transcription. Examples of these include the telomerase RNA and telomere-encoded transcripts. In addition to its role as a template-encoding telomeric DNA synthesis, telomerase RNA has been shown to function as a flexible scaffold for protein subunits of the RNP holoenzyme. The flexible scaffold model provides a specific mechanistic paradigm that is likely to apply to many other lncRNAs that assemble and orchestrate large RNP complexes, even in humans. Looking to the future, it is clear that considerable fundamental knowledge remains to be obtained about the architecture and functions of lncRNAs. Using genetically tractable unicellular model organisms should facilitate lncRNA characterization. The acquired basic knowledge will ultimately translate to better understanding of the growing list of lncRNAs linked to human maladies. PMID- 28815539 TI - Long Noncoding RNAs in Plants. AB - The eukaryotic genomes are pervasively transcribed. In addition to protein-coding RNAs, thousands of long noncoding RNAs (lncRNAs) modulate key molecular and biological processes. Most lncRNAs are found in the nucleus and associate with chromatin, but lncRNAs can function in both nuclear and cytoplasmic compartments. Emerging work has found that many lncRNAs regulate gene expression and can affect genome stability and nuclear domain organization both in plant and in the animal kingdom. Here, we describe the major plant lncRNAs and how they act, with a focus on research in Arabidopsis thaliana and our emerging understanding of lncRNA functions in serving as molecular sponges and decoys, functioning in regulation of transcription and silencing, particularly in RNA-directed DNA methylation, and in epigenetic regulation of flowering time. PMID- 28815540 TI - Long Noncoding RNAs in Mammalian Development and Diseases. AB - Following analysis of sequenced genomes and transcriptome of many eukaryotes, it is evident that virtually all protein-coding genes have already been discovered. These advances have highlighted an intriguing paradox whereby the relative amount of protein-coding sequences remain constant but nonprotein-coding sequences increase consistently in parallel to increasing evolutionary complexity. It is established that differences between species map to nonprotein-coding regions of the genome that surprisingly is transcribed extensively. These transcripts regulate epigenetic processes and constitute an important layer of regulatory information essential for organismal development and play a causative role in diseases. The noncoding RNA-directed regulatory circuit controls complex characteristics. Sequence variations in noncoding RNAs influence evolution, quantitative traits, and disease susceptibility. This chapter presents an account on a class of such noncoding transcripts that are longer than 200 nucleotides (long noncoding RNA-lncRNA) in mammalian development and diseases. PMID- 28815541 TI - Long Noncoding RNAs in Cancer and Therapeutic Potential. AB - Long noncoding RNAs (lncRNAs) are the major elements of the mammalian transcriptome that is emerging as a central player controlling diverse cellular mechanisms. Most of the well-studied lncRNAs so far are found to be crucial in regulating cellular processes such as cell cycle, growth, and apoptosis that ensure homeostasis. Owing to their location and distribution in the genome, lncRNAs influence the transcription of a wide range of proteins directly or indirectly by transcriptional and posttranscriptional alterations, which opens up the "LncRNA-cancer paradigm" in a context-dependent manner, i.e., either oncogenic or tumor suppressive. Thus, this chapter is a consolidation of lncRNA association in exhibiting or suppressing the typical cancer hallmarks such as continuous proliferation, surpassing apoptosis, genomic instability, drug resistance, invasion, and metastasis studied till date. In addition, special focus has been given on the efficient application of lncRNAs as potential targets for therapeutics that holds a great promise for future cancer therapy. PMID- 28815542 TI - Long Noncoding RNAs in Pluripotency of Stem Cells and Cell Fate Specification. AB - Since the annotation of the mouse genome (FANTOM project) [Kawai J et al (2001) Functional annotation of a full-length mouse cDNA collection. Nature 409(6821):685-690] or the human genome [An integrated encyclopedia of DNA elements in the human genome. (2012) Nature 489(7414):57-74; Harrow J et al (2012) GENCODE: the reference human genome annotation for the ENCODE project. Genome Res 22(9):1760-1774], the roles of long noncoding RNAs in coordinating specific signaling pathways have been established in a wide variety of model systems. They have emerged as crucial and key regulators of stem cell maintenance and/or their differentiation into different lineages. In this chapter we have discussed the recently discovered lncRNAs that have been shown to be necessary for the maintenance of pluripotency of both mouse and human ES cells. We have also highlighted the different lncRNAs which are involved in directed differentiation of stem cells into any of the three germ layers. In recent years stem cell therapies including bone marrow transplantation are becoming an integral part of modern medicinal practices. However, there are still several challenges in making stem cell therapy more reproducible so that the success rate reaches a high percentage in the clinic. It is hoped that understanding the molecular mechanisms pertaining to the role of these newly discovered lncRNAs in the differentiation process of stem cells to specific lineages should pave the way to make stem cell therapy and regenerative medicine as a normal clinical practice in the near future. PMID- 28815544 TI - Technological Developments in lncRNA Biology. AB - It is estimated that more than 90% of the mammalian genome is transcribed as non coding RNAs. Recent evidences have established that these non-coding transcripts are not junk or just transcriptional noise, but they do serve important biological purpose. One of the rapidly expanding fields of this class of transcripts is the regulatory lncRNAs, which had been a major challenge in terms of their molecular functions and mechanisms of action. The emergence of high throughput technologies and the development in various conventional approaches have led to the expansion of the lncRNA world. The combination of multidisciplinary approaches has proven to be essential to unravel the complexity of their regulatory networks and helped establish the importance of their existence. Here, we review the current methodologies available for discovering and investigating functions of long non-coding RNAs (lncRNAs) and focus on the powerful technological advancement available to specifically address their functional importance. PMID- 28815545 TI - Concurrent melanoma and thyroid malignancy in a young woman. Is it genetic? PMID- 28815546 TI - Clusters of week-specific maternal gestational weight gain pattern and their association with birthweight: an observational cohort study. AB - INTRODUCTION: Gestational weight gain varies widely among different populations, and an inappropriate gestational weight gain is associated with adverse pregnancy outcomes. We aimed to investigate week-specific serial changes in gestational weight gain in an urban Chinese population to derive clusters of gestational weight gain patterns and explore the impact of gestational weight gain patterns on birthweight. MATERIAL AND METHODS: This was an observational cohort study of 6130 women delivered at a university hospital in Shanghai, China. Pre-pregnancy bodyweight, height, week-specific and total gestational weight gain, pregnancy outcome and birthweight were extracted using electronic medical records. The association between gestational weight gain and gestational age was tested using linear regression, and week-specific reference percentiles for gestational weight gain were calculated. Hierarchical clustering was used to derive gestational weight gain clusters. Mean birthweight among the clusters was compared using Dunnet's test. RESULTS: We found a significant linear association between gestational weight gain and gestational age (r = 0.56; p < 0.00001). Seven distinct clusters of gestational weight gain pattern were identified. The birthweight significantly correlated with gestational weight gain (r = 0.28; p < 0.00001). Compared with the cluster that had normal gestational weight gain throughout the pregnancy, the mean birthweight among the clusters that had abnormal gestational weight gain (inadequate or excessive) in the third trimester was significantly different (p < 0.001), but those who achieved normal gestational weight gain (between 5 and 95 percentile) in the third-trimester had similar mean birthweight. CONCLUSION: Women with abnormal gestational weight gain before the third-trimester still had a fair chance of delivering a normal birthweight baby if their gestational weight gain was normal in the third trimester, suggesting that interventions started even late in pregnancy may have a positive effect on fetal growth. PMID- 28815543 TI - Understanding the Role of lncRNAs in Nervous System Development. AB - The diversity of lncRNAs has expanded within mammals in tandem with the evolution of increased brain complexity, suggesting that lncRNAs play an integral role in this process. In this chapter, we will highlight the identification and characterization of lncRNAs in nervous system development. We discuss the potential role of lncRNAs in nervous system and brain evolution, along with efforts to create comprehensive catalogues that analyze spatial and temporal changes in lncRNA expression during nervous system development. Additionally, we focus on recent endeavors that attempt to assign function to lncRNAs during nervous system development. We highlight discrepancies that have been observed between in vitro and in vivo studies of lncRNA function and the challenges facing researchers in conducting mechanistic analyses of lncRNAs in the developing nervous system. Altogether, this chapter highlights the emerging role of lncRNAs in the developing brain and sheds light on novel, RNA-mediated mechanisms by which nervous system development is controlled. PMID- 28815547 TI - Adjustable mini-sling compared with conventional mid-urethral slings in women with urinary incontinence. A randomized controlled trial. AB - INTRODUCTION: The primary aim of this study was to compare the objective and subjective outcomes and short-term complication rates of an adjustable single incision mini-sling (SIMS) vs. standard mid-urethral slings (SMUS). The secondary aim was to report pain perception and complications at the one-year follow up. MATERIAL AND METHODS: The study was designed as a multicenter prospective randomized trial where women were included from eight centers in Denmark, Norway and Sweden. The trial was registered at ClinicalTrials.gov: NCT01754558. A total of 305 women less than 60 years old with verified stress urinary incontinence were included. All women were randomized to SIMS (Ajust(r) ; n = 155) or SMUS (TVT, TVT-O or TOT; n = 150) and were evaluated by stress test and bladder diary before and after surgery and symptoms related to incontinence using ICIQ-SF, PISQ 12 and PGI-S and PGI-I. Objective cure was defined as no leakage during a stress test and subjective cure defined as no leakage stated in the bladder diary or no indication of urinary leakage in the ICIQ-SF. Furthermore, mesh exposure and dyspareunia were recorded. RESULTS: In total, 280 women [141 (91%) in the SIMS and 139 (94%) in the SMUS groups] participated in the one-year follow up. No difference between the groups was observed regarding objective and subjective outcomes. VAS score disclosed a lower postoperative pain perception in the SIMS group than in the SMUS group. CONCLUSIONS: Ajust(r) appears to be as efficient as SMUS regarding objective and subjective outcomes and was associated with less pain perception during the postoperative period. PMID- 28815548 TI - Persistent increase in TNF and IL-1 markers in severe mental disorders suggests trait-related inflammation: a one year follow-up study. AB - OBJECTIVE: We evaluated if plasma levels of inflammatory markers are persistently altered in severe mental disorders with psychotic symptoms or associated with state characteristics in a longitudinal study. METHODS: Soluble tumor necrosis factor receptor 1 (sTNF-R1), interleukin-1 receptor antagonist (IL-1Ra), von Willebrand factor (VWF), and osteoprotegerin (OPG) were measured in schizophrenia (n = 69) and affective (n = 55) spectrum patients at baseline and at one-year follow-up, and compared to healthy controls (HC) (n = 92) with analysis of covariance. Association between change in symptoms and inflammatory markers was analyzed with mixed-effects models. RESULTS: sTNF-R1 was higher in the schizophrenia (P < 0.0001) and affective disorders (P = 0.02) compared to HC, while IL-1Ra was higher in schizophrenia (P = 0.01) compared to HC at one year follow-up. There were no significant differences between schizophrenia and affective groups; however, levels in the affective group were in between schizophrenia and HC for sTNF-R1 and IL-1Ra. There were no significant associations between change in symptoms and inflammatory markers. CONCLUSION: Persistently increased sTNF-R1 and IL-1Ra after one year in patients with severe mental disorders primarily reflecting data from the schizophrenia group may suggest that inflammation is a trait phenomenon, and not only the result of stress-related mechanisms associated with acute episodes. PMID- 28815549 TI - Effect of long-term treatment with tumour necrosis factor-alpha inhibitors on single-dose ultraviolet-induced changes in human skin. PMID- 28815550 TI - Fertility preservation in women with borderline ovarian tumors - how does it impact disease outcome? A cohort study. AB - INTRODUCTION: Borderline ovarian tumors are typically indolent neoplasms. Since many are diagnosed in younger women, fertility conservation is an important consideration and has been advocated based on retrospective data. The objective of this study was to identify features impacting on recurrence and survival in a series of borderline ovarian tumors, and to assess the safety of a fertility sparing approach. MATERIAL AND METHODS: A historical cohort study of consecutive borderline ovarian tumors cases treated at a single institution over 30 years (1981-2011). Data on surgical approach (fertility-sparing or otherwise), disease stage, CA125 levels, histological features, adjuvant treatment and follow-up data were collected. Recurrence and survival were assessed using the Kaplan-Meier method and associations with the variables of interest were evaluated using a multivariate Cox proportional hazards model. RESULTS: 213 patients were included. Of 132 women age 40 years and below at diagnosis, 112 (85%) had a fertility sparing procedure and 60 (46%) had conservation of an involved ovary. Fifty patients (24%) developed recurrences; fertility preservation (hazard ratio = 2.57; 95% confidence interval 1.1-6; p = 0.029) and advanced stage (hazard ratio = 4.15; 95% confidence interval 2.3-7.6; p < 0.001) were independently associated with recurrence on multivariate analysis. Eleven (5%) patients died of their disease. Fertility preservation was not associated with compromised survival. CONCLUSIONS: Borderline ovarian tumors carry a good prognosis overall. Fertility preservation is associated with a higher risk of disease relapse; however, as most relapses are localized and may be salvaged with surgical treatment, overall survival is not compromised. PMID- 28815551 TI - Atypical fibroxanthoma management: Recurrence, metastasis and disease-specific death. AB - Atypical fibroxanthoma (AFX) is a rare spindle cell neoplasm predominantly found on the head and neck of elderly individuals with sun-damaged skin, with no evidence-based guidelines for their management. A systematic retrospective review of the literature focusing on treatment modality found a recurrence and metastasis rate of 8.0% (5.6% when adjusted for incomplete excisions) and 0.5% for local excision and 4.6% and 3.2% for Mohs micrographic surgery, respectively. Our results suggest that with clear surgical margins, AFX is unlikely to recur and metastases are rare, with significantly higher rates in the immunosuppressed population. PMID- 28815553 TI - Osteoporosis in patients with erythropoietic protoporphyria. AB - BACKGROUND: Erythropoietic protoporphyria (EPP) is a rare metabolic disease with painful photosensitivity due to protoporphyrin IX accumulation. OBJECTIVES: To evaluate bone mineral density (BMD) and known osteoporosis risk factors in patients with EPP. METHODS: Patients with EPP attending the Erasmus MC outpatient clinic who had undergone BMD measurements were included. Plasma 25 hydroxy (OH) vitamin D, alkaline phosphatase, parathyroid hormone and total protoporphyrin IX levels were measured; information on lifestyle, sunlight exposure and a bone relevant physical exercise index [Bone Physical Activity Questionnaire (BPAQ) score] was obtained via questionnaires. BMD scores and the prevalence of osteopenia and osteoporosis in the EPP population were compared with a reference population. RESULTS: Forty-four patients with EPP (23 female, 21 male; mean age 37.6 years) were included. The mean SDs of the T-scores were -1.12 for the lumbar spine and -0.82 for the femoral neck (both P < 0.001). Osteopenia was present in 36%; osteoporosis in 23%. Based on the reference population the expected prevalence was 15% and 1%, respectively. Prevalence of vitamin D deficiency was 50% (defined as a 25-OH vitamin D level < 50 nmol L-1 ). Mean self-reported BPAQ score was 19.4 units (reference interval 19-24). Multiple linear regression analysis showed a significant influence of vitamin D deficiency and bone-relevant physical exercise score on BMD in patients with EPP. CONCLUSIONS: The prevalence of osteoporosis and osteopenia is greatly increased in patients with EPP. Alkaline phosphatase (related to vitamin D deficiency) and amount of weight bearing exercise are significantly correlated with low BMD in this population. PMID- 28815552 TI - Connect-Home: Transitional Care of Skilled Nursing Facility Patients and their Caregivers. AB - BACKGROUND: Older adults that transfer from skilled nursing facilities (SNF) to home have significant risk for poor outcomes. Transitional care of SNF patients (i.e., time-limited services to ensure coordination and continuity of care) is poorly understood. OBJECTIVE: To determine the feasibility and relevance of the Connect-Home transitional care intervention, and to compare preparedness for discharge between comparison and intervention dyads. DESIGN: A non-randomized, historically controlled design-enrolling dyads of SNF patients and their family caregivers. SETTING: Three SNFs in the Southeastern United States. PARTICIPANTS: Intervention dyads received Connect-Home; comparison dyads received usual discharge planning. Of 173 recruited dyads, 145 transferred to home, and 133 completed surveys within 3 days of discharge. INTERVENTION: The Connect-Home intervention consisted of tools and training for existing SNF staff to deliver transitional care of patient and caregiver dyads. MEASUREMENTS: Feasibility was assessed with a chart review. Relevance was assessed with a survey of staff experiences using the intervention. Preparedness for discharge, the primary outcome, was assessed with Care-Transitions Measure-15 (CTM-15). RESULTS: The intervention was feasible and relevant to SNF staff (i.e., 96.9% of staff recommended intervention use in the future). Intervention dyads, compared to comparison dyads, were more prepared for discharge (CTM-15 score 74.7 vs 65.3, mean ratio 1.16, 95% CI: 1.08, 1.24). CONCLUSION: Connect-Home is a promising transitional care intervention for older patients discharged from SNF care. The next step will be to test the intervention using a cluster randomized trial, with patient outcomes including re-hospitalization. PMID- 28815554 TI - Severe disruption and disorganization of dermal collagen fibrils in early striae gravidarum. AB - BACKGROUND: Striae gravidarum (SG), or stretch marks of pregnancy, begin as erythematous streaks and mature into hypopigmented atrophic bands. OBJECTIVES: In order to investigate molecular alterations that may promote atrophy of SG, we investigated dermal type I collagen fibrils, which provide human skin with support. METHODS: We obtained skin samples of recently developed, erythematous abdominal SG from pregnant women. To examine the organization of collagen fibrils, second-harmonic generation imaging was performed using multiphoton microscopy. Immunostaining was used to determine protein expression and localization of type I procollagen, the precursor of type I collagen fibrils. Real-time polymerase chain reaction was used to determine gene expression levels. RESULTS: In control (hip) and stretched normal-appearing perilesional abdominal skin, dermal collagen fibrils were organized as tightly packed, interwoven bundles. In SG, collagen bundles appeared markedly separated, especially in the mid-to-deep dermis. In the spaces separating these bundles, loosely packed wavy collagen fibrils lacking organization as bundles were present. These disorganized fibrils persisted into the postpartum period and failed to form densely packed bundles. Numerous large fibroblasts displaying type I procollagen expression were in close proximity to the disorganized fibrils, suggesting that the fibrils are newly synthesized. Supporting this possibility, immunostaining and gene expression of type I procollagen were increased throughout the dermis of SG. CONCLUSIONS: Early SG display marked separation of collagen bundles and emergence of disorganized collagen fibrils that fail to form bundles. These alterations may reflect ineffective repair of collagen bundles disrupted by intense skin stretching. Persistent disruption of the collagenous extracellular matrix likely promotes formation and atrophy of SG. PMID- 28815555 TI - Subcutaneous pigmented clear cell sarcoma as a challenging simulator of melanoma. PMID- 28815556 TI - Trends in indications, complications and outcomes for venous resection during pancreatoduodenectomy. AB - BACKGROUND: Pancreatoduodenectomy with superior mesenteric-portal vein resection has become a common procedure in pancreatic surgery. The aim of this study was to compare standard pancreatoduodenectomy with pancreatoduodenectomy plus venous resection at a high-volume centre, and to examine trends in management and outcome over a decade for the latter procedure. METHODS: This retrospective observational study included all patients undergoing pancreatoduodenectomy with or without venous resection at Oslo University Hospital between January 2006 and December 2015. Trends were evaluated by assessing preoperative clinical and radiological characteristics, as well as perioperative outcomes in three time intervals (early, intermediate and late). RESULTS: A total of 784 patients had a pancreatoduodenectomy, of whom 127 (16.2 per cent) underwent venous resection. Venous resection resulted in a longer operating time (median 422 versus 312 min; P = 0.001) and greater estimated blood loss (EBL) (median 700 versus 500 ml; P = 0.004) than standard pancreatoduodenectomy. The rate of severe complications was significantly higher for pancreatoduodenectomy with venous resection (37.0 versus 26.3 per cent; P = 0.014). The overall burden of complications, evaluated using the Comprehensive Complication Index (CCI), did not differ (median score 8.7 versus 8.7; P = 0.175). Trends in venous resection over time showed a significant reduction in EBL (median 1050 versus 375 ml; P = 0.001) and duration of hospital stay (median 14 versus 9 days; P = 0.011) between the early and late periods. However, despite an improvement in the intermediate period, severe complication rates returned to baseline in the late period (18 of 43 versus 9 of 42 versus 20 of 42 patients in early, intermediate and late periods respectively; P = 0.032), as did CCI scores (median 20.9 versus 0 versus 20.9; P = 0.041). CONCLUSION: Despite an initial improvement in severe complications for venous resection during pancreatoduodenectomy, this was not maintained over time. Every fourth patient with venous resection needed relaparotomy, most frequently for bleeding. PMID- 28815557 TI - Societal and Family Lifetime Cost of Dementia: Implications for Policy. AB - OBJECTIVES: To estimate the cost of dementia and the extra cost of caring for someone with dementia over the cost of caring for someone without dementia. DESIGN: We developed an evidence-based mathematical model to simulate disease progression for newly diagnosed individuals with dementia. Data-driven trajectories of cognition, function, and behavioral and psychological symptoms were used to model disease progression and predict costs. Using modeling, we evaluated lifetime and annual costs of individuals with dementia, compared costs of those with and without clinical features of dementia, and evaluated the effect of reducing functional decline or behavioral and psychological symptoms by 10% for 12 months (implemented when Mini-Mental State Examination score <=21). SETTING: Mathematical model. PARTICIPANTS: Representative simulated U.S. incident dementia cases. MEASUREMENTS: Value of informal care, out-of-pocket expenditures, Medicaid expenditures, and Medicare expenditures. RESULTS: From time of diagnosis (mean age 83), discounted total lifetime cost of care for a person with dementia was $321,780 (2015 dollars). Families incurred 70% of the total cost burden ($225,140), Medicaid accounted for 14% ($44,090), and Medicare accounted for 16% ($52,540). Costs for a person with dementia over a lifetime were $184,500 greater (86% incurred by families) than for someone without dementia. Total annual cost peaked at $89,000, and net cost peaked at $72,400. Reducing functional decline or behavioral and psychological symptoms by 10% resulted in $3,880 and $680 lower lifetime costs than natural disease progression. CONCLUSION: Dementia substantially increases lifetime costs of care. Long-lasting, effective interventions are needed to support families because they incur the most dementia cost. PMID- 28815558 TI - Sequence variants in ESR1 and OXTR are associated with Mayer-Rokitansky-Kuster Hauser syndrome. AB - INTRODUCTION: Mayer-Rokitansky-Kuster-Hauser syndrome (MRKHS) is characterized by congenital absence of the uterus and the upper two-thirds of the vagina in otherwise phenotypically normal females. It is found isolated or associated with renal, skeletal and other malformations. Despite ongoing research, the etiology is mainly unknown. For a long time, the hypothesis of deficient hormone receptors as the cause for MRKHS has existed, supported by previous findings of our group. The aim of the present study was to identify unknown genetic causes for MRKHS and to compare them with data banks including a review of the literature. MATERIAL AND METHODS: DNA sequence analysis of the oxytocin receptor (OXTR) and estrogen receptor-1 gene (ESR1) was performed in a group of 93 clinically well-defined patients with uterovaginal aplasia (68 with the isolated form and 25 with associated malformations). RESULTS: In total, we detected three OXTR variants in 18 MRKHS patients with one leading to a missense mutation, and six ESR1 variants in 21 MRKHS patients, two of these causing amino acid changes and therefore potentially disease. CONCLUSIONS: The identified variants on DNA level might impair receptor function through different molecular mechanisms. Mutations of ESR1 and OXTR are associated with MRKHS. Thus, we consider these genes potential candidates associated with the manifestation of MRKHS. PMID- 28815559 TI - Characteristic elevation of soluble TNF receptor II : I ratio in macrophage activation syndrome with systemic juvenile idiopathic arthritis. AB - To investigate the clinical significance of soluble tumour necrosis factor receptor (sTNF-R) II/I ratio as an indicator of the diagnosis of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (s JIA), we measured the serum sTNF-RI and II levels in 117 patients with s-JIA, including 29 patients with MAS, 15 with Epstein-Barr virus-induced haemophagocytic lymphohistiocytosis (EBV-HLH), 15 with Kawasaki disease (KD) and 28 healthy controls (HCs). We determined their correlation with measurements of disease activity and severity. Furthermore, we measured serum interleukin (IL)-18 levels in patients with EBV-HLH and compared these in levels in patients with MAS. The sTNF-RII/I ratio was elevated significantly in MAS and EBV-HLH patients compared with those in the acute phase of s-JIA and KD patients, whereas there were no significant differences between HCs and those in the acute phase of s JIA. The sTNF-RII/I ratio increased profoundly as MAS developed and correlated positively with disease activity. Serum IL-18 levels were elevated significantly in MAS patients compared with EBV-HLH patients. The monitoring of serum IL-18 and sTNF-RII/I might be useful for the diagnosis of MAS and the differentiation between MAS and EBV-HLH. PMID- 28815560 TI - Comparison of indirubin concentrations in indigo naturalis ointment for psoriasis treatment: a randomized, double-blind, dosage-controlled trial. AB - BACKGROUND: Indigo naturalis and its refined formulation, Lindioil, are effective in treating psoriatic symptoms topically. Indirubin is the active ingredient in indigo naturalis. OBJECTIVES: To determine the efficacy and safety of different concentrations of indirubin in Lindioil ointment for treating psoriasis. METHODS: In this randomized, double-blind trial, adult patients presenting with chronic plaque psoriasis for > 1 year and with < 20% of the body surface area (BSA) affected were randomized to apply Lindioil ointment containing 200, 100, 50 or 10 MUg g-1 of indirubin twice daily for 8 weeks followed by an additional 12-week safety/extension period. The primary end point was the mean percentage change in Psoriasis Area and Severity Index (PASI) score along with the proportion of participants achieving 75% and 90% reductions in PASI scores (PASI 75 and PASI 90, respectively) from baseline to week 8. RESULTS: The results from week 8 revealed that the 200 MUg g-1 group had the greatest reduction in PASI score [69.2%, 95% confidence interval (CI) 55.5-82.8], followed by the 100 MUg g-1 group (63.1%, 95% CI 52.8-73.5), the 10 MUg g-1 group (53.4%, 95% CI 42.8-64.0) and the 50 MUg g-1 group (50.3%, 95% CI 37.4-63.2), with a between-group comparison of P = 0.0445. The group with the highest proportion of the patients achieving PASI 75 (57%, P = 0.0474) and PASI 90 (30%, P = 0.0098) was the 200 MUg g-1 group. No severe treatment-related adverse events were reported during the 20 week evaluation. CONCLUSIONS: An amount of 200 MUg g-1 of indirubin in Lindioil ointment is the most effective concentration studied so far for treating psoriasis topically, and is safe. PMID- 28815561 TI - Early segregation of the adrenal cortex and gonad in chicken embryos. AB - The adrenal gland is an endocrine organ that plays essential roles in stress responses. This organ consists of two types of tissues, adrenomedulla and adrenocortex, deriving from different embryonic origins. Whereas it is well accepted that the adrenomedulla derives from neural crest cells, the origin of the adrenocortex remains elusive. In addition, the adrenocortex and gonads, two major steroid hormone-producing tissues, have been thought to share the same origin, although the experimental evidence is lacking. In this study, to identify the origin of adrenocortex and to compare it to that of gonads, we scrutinized the medial portion of the coelomic epithelium (CE) after the lateral plate mesoderm has split into two CE components with a concomitant opening of the coelomic cavity in between them. We found that early medial CE consists of a two cell layer-thick band of epithelial-like cells, the outer and inner CEs. The outer CE faces the coelomic cavity, whereas the inner CE is juxtaposed to nascent blood vessels. Combining direct cell labeling with early molecular markers, we found that outer CE was the origin of the gonad but not the adrenocortex. The adrenocortex, instead, appears to derive from inner CE. Thus, the adrenocortical and gonadal progenitors are already segregated from each other when the coelomic cavity has opened. This study provides a new basis for understanding how the adrenal gland forms and how steroid hormone-producing tissues arise during development. PMID- 28815563 TI - Bone marrow failure syndrome caused by homozygous frameshift mutation in the ERCC6L2 gene. AB - Inherited bone marrow failure syndromes (IBMFS) are group of disorders that lead to inadequate production of blood cells. Mutations in genes involved in telomere maintenance, DNA repair, and the cell cycle cause IBMFS. ERCC6L2 gene mutations have been associated with bone marrow failure that includes developmental delay and microcephaly. We report 2 cases of bone marrow failure with no extra hematopoietic manifestations in patients from unrelated families with a homozygous truncating mutation in ERCC6L2. Bone marrow failure without developmental delay or microcephaly with ERCC6L2 mutation has not been previously described. PMID- 28815562 TI - Treadmill training and body weight support for walking after stroke. AB - BACKGROUND: Treadmill training, with or without body weight support using a harness, is used in rehabilitation and might help to improve walking after stroke. This is an update of the Cochrane review first published in 2003 and updated in 2005 and 2014. OBJECTIVES: To determine if treadmill training and body weight support, individually or in combination, improve walking ability, quality of life, activities of daily living, dependency or death, and institutionalisation or death, compared with other physiotherapy gait-training interventions after stroke. The secondary objective was to determine the safety and acceptability of this method of gait training. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched 14 February 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) and the Database of Reviews of Effects (DARE) (the Cochrane Library 2017, Issue 2), MEDLINE (1966 to 14 February 2017), Embase (1980 to 14 February 2017), CINAHL (1982 to 14 February 2017), AMED (1985 to 14 February 2017) and SPORTDiscus (1949 to 14 February 2017). We also handsearched relevant conference proceedings and ongoing trials and research registers, screened reference lists, and contacted trialists to identify further trials. SELECTION CRITERIA: Randomised or quasi-randomised controlled and cross-over trials of treadmill training and body weight support, individually or in combination, for the treatment of walking after stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted data, and assessed risk of bias and methodological quality. The primary outcomes investigated were walking speed, endurance, and dependency. MAIN RESULTS: We included 56 trials with 3105 participants in this updated review. The average age of the participants was 60 years, and the studies were carried out in both inpatient and outpatient settings. All participants had at least some walking difficulties and many could not walk without assistance. Overall, the use of treadmill training did not increase the chances of walking independently compared with other physiotherapy interventions (risk difference (RD) -0.00, 95% confidence interval (CI) -0.02 to 0.02; 18 trials, 1210 participants; P = 0.94; I2 = 0%; low-quality evidence). Overall, the use of treadmill training in walking rehabilitation for people after stroke increased the walking velocity and walking endurance significantly. The pooled mean difference (MD) (random-effects model) for walking velocity was 0.06 m/s (95% CI 0.03 to 0.09; 47 trials, 2323 participants; P < 0.0001; I2 = 44%; moderate-quality evidence) and the pooled MD for walking endurance was 14.19 metres (95% CI 2.92 to 25.46; 28 trials, 1680 participants; P = 0.01; I2 = 27%; moderate-quality evidence). Overall, the use of treadmill training with body weight support in walking rehabilitation for people after stroke did not increase the walking velocity and walking endurance at the end of scheduled follow-up. The pooled MD (random-effects model) for walking velocity was 0.03 m/s (95% CI -0.05 to 0.10; 12 trials, 954 participants; P = 0.50; I2 = 55%; low-quality evidence) and the pooled MD for walking endurance was 21.64 metres (95% CI -4.70 to 47.98; 10 trials, 882 participants; P = 0.11; I2 = 47%; low-quality evidence). In 38 studies with a total of 1571 participants who were independent in walking at study onset, the use of treadmill training increased the walking velocity significantly. The pooled MD (random-effects model) for walking velocity was 0.08 m/s (95% CI 0.05 to 0.12; P < 0.00001; I2 = 49%). There were insufficient data to comment on any effects on quality of life or activities of daily living. Adverse events and dropouts did not occur more frequently in people receiving treadmill training and these were not judged to be clinically serious events. AUTHORS' CONCLUSIONS: Overall, people after stroke who receive treadmill training, with or without body weight support, are not more likely to improve their ability to walk independently compared with people after stroke not receiving treadmill training, but walking speed and walking endurance may improve slightly in the short term. Specifically, people with stroke who are able to walk (but not people who are dependent in walking at start of treatment) appear to benefit most from this type of intervention with regard to walking speed and walking endurance. This review did not find, however, that improvements in walking speed and endurance may have persisting beneficial effects. Further research should specifically investigate the effects of different frequencies, durations, or intensities (in terms of speed increments and inclination) of treadmill training, as well as the use of handrails, in ambulatory participants, but not in dependent walkers. PMID- 28815564 TI - Target temperature 34 vs. 36 degrees C after out-of-hospital cardiac arrest - a retrospective observational study. AB - BACKGROUND: Intensive care for comatose survivors of cardiac arrest includes targeted temperature management (TTM) to attenuate cerebral reperfusion injury. A recent multi-center clinical trial did not show any difference in mortality or neurological outcome between TTM targeting 33 degrees C or 36 degrees C after out of-hospital-cardiac-arrest (OHCA). In our institution, the TTM target was changed accordingly from 34 to 36 degrees C. The aim of this retrospective study was to analyze if this change had affected patient outcome. METHODS: Intensive care registry and medical record data from 79 adult patients treated for OHCA with TTM during 2010 (n = 38; 34 degrees C) and 2014 (n = 41; 36 degrees C) were analyzed for mortality and neurological outcome were assessed as cerebral performance category. Student's t-test was used for continuous data and Fischer's exact test for categorical data, and multivariable logistic regression was applied to detect influence from patient factors differing between the groups. RESULTS: Witnessed arrest was more common in 2010 (95%) vs. 2014 (76%) (P = 0.03) and coronary angiography was more common in 2014 (95%) vs. 2010 (76%) (P = 0.02). The number of patients awakening later than 72 h after the arrest did not differ. After adjusting for gender, hypertension, and witnessed arrest, neither 1-year mortality (P = 0.77), nor 1-year good neurological outcome (P = 0.85) differed between the groups. CONCLUSION: Our results, showing no difference between TTM at 34 degrees C and TTM at 36 degrees C as to mortality or neurological outcome after OHCA, are in line with the previous TTM-trial results, supporting the use of either target temperature in our institution. PMID- 28815565 TI - Generation of animal form by the Chordin/Tolloid/BMP gradient: 100 years after D'Arcy Thompson. AB - The classic book "On Growth and Form" by naturalist D'Arcy Thompson was published 100 years ago. To celebrate this landmark, we present experiments in the Xenopus embryo that provide a framework for understanding how simple, quantitative transformations of a morphogen gradient might have affected evolution and morphological diversity of organisms. D'Arcy Thompson proposed that different morphologies might be generated by modifying physical parameters in an underlying system of Cartesian coordinates that pre-existed in Nature and arose during evolutionary history. Chordin is a BMP antagonist secreted by the Spemann organizer located on the dorsal side of the gastrula. Chordin generates a morphogen gradient as first proposed by mathematician Alan Turing. The rate limiting step of this dorsal-ventral (D-V) morphogen is the degradation of Chordin by the Tolloid metalloproteinase in the ventral side. Chordin is expressed at gastrula on the dorsal side where BMP signaling is low, while at the opposite side peak levels of BMP signaling are reached. In fishes, amphibians, reptiles and birds, high BMP signaling in the ventral region induces transcription of a secreted inhibitor of Tolloid called Sizzled. By depleting Sizzled exclusively in the ventral half of the embryo we were able to expand the ventro-posterior region in an otherwise normal embryo. Conversely, ventral depletion of Tolloid, which stabilizes Chordin, decreased ventral and tail structures, phenocopying the tolloid zebrafish mutation. We explain how historical constraints recorded in the language of DNA become subject to the universal laws of physics when an ancestral reaction-diffusion morphogen gradient dictates form. PMID- 28815566 TI - Maturation promoting factor destabilization mediates human chorionic gonadotropin induced meiotic resumption in rat oocytes. AB - Human chorionic gonadotropin (hCG) mimics the action of luteinizing hormone (LH) and triggers meiotic maturation and ovulation in mammals. The mechanism by which hCG triggers meiotic resumption in mammalian oocytes remains poorly understood. We aimed to find out the impact of hCG surge on morphological changes, adenosine 3',5'-cyclic monophosphate (cAMP), guanosine 3',5'-cyclic monophosphate (cGMP), cell division cycle 25B (Cdc25B), Wee1, early mitotic inhibitor 2 (Emi2), anaphase-promoting complex/cyclosome (APC/C), meiotic arrest deficient protein 2 (MAD2), phosphorylation status of cyclin-dependent kinase 1 (Cdk1), its activity and cyclin B1 expression levels during meiotic resumption from diplotene as well as metaphase-II (M-II) arrest in cumulus oocyte complexes (COCs). Our data suggest that hCG surge increased cyclic nucleotides level in encircling granulosa cells but decreased their level in oocyte. The reduced intraoocyte cyclic nucleotides level is associated with the decrease of Cdc25B, Thr161 phosphorylated Cdk1 and Emi2 expression levels. On the other hand, hCG surge increased Wee1, Thr14/Tyr15 phosphorylated Cdk1, APC/C as well as MAD2 expression levels. The elevated APC/C activity reduced cyclin B1 level. The changes in phosphorylation status of Cdk1 and reduced cyclin B1 level might have resulted in maturation promoting factor (MPF) destabilization. The destabilized MPF finally triggered resumption of meiosis from diplotene as well as M-II arrest in rat oocytes. PMID- 28815567 TI - Diversification rates are more strongly related to microhabitat than climate in squamate reptiles (lizards and snakes). AB - Patterns of species richness among clades can be directly explained by the ages of clades or their rates of diversification. The factors that most strongly influence diversification rates remain highly uncertain, since most studies typically consider only a single predictor variable. Here, we explore the relative impacts of macroclimate (i.e., occurring in tropical vs. temperate regions) and microhabitat use (i.e., terrestrial, fossorial, arboreal, aquatic) on diversification rates of squamate reptile clades (lizards and snakes). We obtained data on microhabitat, macroclimatic distribution, and phylogeny for >4000 species. We estimated diversification rates of squamate clades (mostly families) from a time-calibrated tree, and used phylogenetic methods to test relationships between diversification rates and microhabitat and macroclimate. Across 72 squamate clades, the best-fitting model included microhabitat but not climatic distribution. Microhabitat explained ~37% of the variation in diversification rates among clades, with a generally positive impact of arboreal microhabitat use on diversification, and negative impacts of fossorial and aquatic microhabitat use. Overall, our results show that the impacts of microhabitat on diversification rates can be more important than those of climate, despite much greater emphasis on climate in previous studies. PMID- 28815568 TI - Gliptin therapy reduces hepatic and myocardial fat in type 2 diabetic patients. AB - BACKGROUND: Increased hepatic fat and cardiac fat are common in patients with type 2 diabetes mellitus (T2DM) and are associated with a greater risk of liver fibrosis and cardiovascular (CV) events. Sex-specific differences of dipeptidyl peptidase-four (DPP-4) inhibitor effects on hepatic (HCL) and myocardial fat content (MYCL) have not yet been evaluated. METHOD: Forty-one T2DM patients (20 male, 21 female) received a gliptin add-on therapy if HbA1c goals were not reached under metformin monotherapy. They underwent cardiac and liver magnetic resonance tomography and spectroscopy before and 6 months after therapy initiation. Plasma samples were analysed for the growth differentiation factor 15 (GDF-15), a novel marker for cardiovascular risk. RESULTS: Thirty-eight patients on gliptin therapy completed the study. We observed a positive correlation between MYCL and HCL before therapy (R = 0.41, P = 0.05). After 6 months of therapy, we noticed a significant weight reduction in women only (P = 0.02) whereas waist circumference decreased similarly in both sexes. HbA1c sunk significantly in both sexes (P = 0.002). HCL decreased significantly (P = 0.0004), with women featuring higher basal HCL (P < 0.05). MYCL decreased in women only (P = 0.01) and GDF-15 comparably in both sexes (P < 0.05). CONCLUSIONS: 6 months of DPP-4-therapy led to a significant overall decrease in HCL and body weight such as a reduction of MYCL only in women. This preliminary data set could implicate that gliptin may be a feasible therapy option in fatty liver patients with diabetes potentially including positive effects on cardiovascular function particularly in women. PMID- 28815569 TI - Glucose-dependent leucocyte activation in familial hypercholesterolemia. AB - BACKGROUND: Leucocyte activation is an obligatory factor in the development of atherosclerosis. The postprandial situation has been associated to increased leucocyte activation in several disorders, such as type 2 diabetes mellitus and familial combined hyperlipidaemia. Our study aim was to evaluate the effect of post-OGTT hyperglycaemia on leucocyte activation in patients with familial hypercholesterolemia (FH). MATERIALS AND METHODS: Patients who met the diagnostic criteria for heterozygous FH and healthy volunteers were asked to undergo an oral glucose tolerance test. Leucocyte activation markers CD11b and CD66b were determined by flow cytometry. Post-OGTT changes were calculated as area under the curve (AUC) and the incremental area under the curve corrected for baseline values (dAUC). The impact of being an FH patient and using statins on the time dependent profile of the leucocyte activation markers was studied with repeated measurements analysis. RESULTS: Thirteen FH patients using statins, nine FH patients without statins and 14 healthy volunteers were included. FH subjects on statins had a slightly higher HbA1c than those not using these drugs or controls. Post-OGTT glucose levels were significantly higher in patients with FH when compared to healthy controls (P = 0.001). These effects were independent from the use of statins. CONCLUSIONS: Surprisingly, our study shows impaired post-OGTT glucose excursions in patients with FH compared to healthy volunteers. Post-OGTT hyperglycaemia may be related to persistent post-OGTT activation of monocytes in FH patients compared to healthy controls, and therefore, it may contribute to the development of cardiovascular disease in patients with FH. PMID- 28815570 TI - Tat transport in Escherichia coli requires zwitterionic phosphatidylethanolamine but no specific negatively charged phospholipid. AB - Translocation of folded proteins by the Tat system of Escherichia coli is believed to rely on the presence of phosphatidylethanolamine (PE) and the negatively charged phospholipids cardiolipin (CL) and phosphatidylglycerol (PG). Here, we show that while PE is indeed essential for activity, the Tat system is fully functional in a clsA/clsB/clsC deletion strain lacking CL, and in a pgsA deletion strain lacking both PG and CL during aerobic growth on complex media. In contrast to early studies that relied on strains with reduced lipid levels, this study therefore demonstrates that PG and CL are dispensable for Tat transport. The lack of these lipids may be compensated by other anionic phospholipids such as phosphatidic acid, CDP-diacylglycerol or N-acyl-PE. PMID- 28815571 TI - Functional electrical stimulation of the ankle dorsiflexors during walking in spastic cerebral palsy: a systematic review. AB - AIM: To assess the effect of functional electrical stimulation (FES) of ankle dorsiflexors in children and adolescents with spastic cerebral palsy (CP) during walking. METHOD: A systematic review was performed using the American Academy of Cerebral Palsy and Developmental Medicine methodology and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Six databases were searched for studies applying interventions to patients aged younger than 20 years. Outcomes were classified according to the International Classification of Functioning, Disability and Health (ICF). RESULTS: Seven hundred and eighty abstracts were found, 35 articles were fully screened, and 14 articles were used for analysis. Only five articles (three studies) were of level I to III evidence. At ICF participation and activity level, there is limited evidence for a decrease in self-reported frequency of toe-drag and falls. At ICF body structure and function level, there is clear evidence (I-III) that FES increased (active) ankle dorsiflexion angle, strength, and improved selective motor control, balance, and gait kinematics, but decreased walking speed. Adverse events include skin irritation, toleration, and acceptation issues. INTERPRETATION: There are insufficient data supporting functional gain by FES on activity and participation level. However, evidence points towards a role for FES as an alternative to orthoses in children with spastic CP. WHAT THIS PAPER ADDS: Effects of functional electrical stimulation (FES) point towards a potential role as an alternative to orthoses for patients with spastic cerebral palsy (CP). Some evidence for a decrease in self-reported frequency of toe-drag and falls with the use of FES in spastic CP. Limited evidence for improvements in activity and participation in patients with spastic CP using FES. PMID- 28815572 TI - Risk of second primary cancers in women diagnosed with endometrial cancer in German and Swedish cancer registries. AB - Along with the increasing incidence and favorable prognosis, more women diagnosed with endometrial cancer may develop second primary cancers (SPCs). We aimed at investigating risk of SPCs after endometrial cancer in Germany and Sweden to provide insight into prevention strategies for SPCs. Endometrial cancer patients diagnosed at age >=15 years in Germany during 1997-2011 and in Sweden nationwide during 1997-2012 were selected. Standardized incidence ratios (SIRs), calculated as the ratio of observed to expected numbers of cases, were used to assess the risk of a specific second cancer after endometrial cancer for both German and Swedish datasets. Among 46,929 endometrial cancer survivors in Germany and 18,646 in Sweden, overall 2,897 and 1,706 SPCs were recorded, respectively. Significantly elevated SIRs were observed in Germany for ovarian (SIR = 1.3; 95%CI:1.1-1.5) and kidney cancers [1.6 (1.3-1.8)], while in Sweden the SIRs were 5.4 (4.6-6.3) and1.4 (1.0-1.9), respectively. Elevated risk for second ovarian endometrioid carcinoma was pronounced after early (<55 years) onset endometrial cancer in Germany [9.0 (4.8-15)] and Sweden [7.7 (5.1-11)]. In Germany elevated risks were found for second ovarian endometrioid carcinoma after endometrioid histology of first endometrial cancer [6.3 (4.0-9.4)] and for second kidney cancer after clear cell histology of endometrial cancer [4.9 (1.6-11)]. We found exceptionally elevated risk of second ovarian endometrioid carcinoma after endometrial cancer of the same histology or of early onset. Risk for second kidney cancer was also increased, particularly after endometrial cancer of clear cell histology. Cancer prevention strategies should focus on these cancers after endometrial cancer diagnosis. PMID- 28815573 TI - Impact of adenoma detection on the benefit of faecal testing vs. colonoscopy for colorectal cancer. AB - Colonoscopy quality, as measured by adenoma detection rates, varies widely across providers and is inversely related to patients' post-colonoscopy cancer risk. This has unknown consequences for the benefits of faecal immunochemical testing (FIT) vs. primary colonoscopy screening for colorectal cancer. Using an established microsimulation model, we predicted the lifetime colorectal cancer incidence and mortality benefits of annual FIT vs. 10-yearly colonoscopy screening at differing ADR levels (quintiles; averages 15.3-38.7%), with colonoscopy performance assumptions estimated from community-based data on physician ADRs and patients' post-colonoscopy risk of cancer. For patients receiving FIT screening with follow-up colonoscopy by physicians from the highest ADR quintile, simulated lifetime cancer incidence and mortality were 28.8 and 5.4 per 1,000, respectively, vs. 20.6 and 4.4 for primary colonoscopy screening (risk ratios, RR = 1.40; 95% probability interval (PI), 1.19-1.71 for incidence, and RR = 1.22; 95%PI, 1.02-1.54 for mortality). With every 5% point ADR decrease, lifetime cancer incidence was predicted to increase on average 9.0% for FIT vs. 12.3% for colonoscopy, and mortality increased 9.9% vs. 13.3%. In ADR quintile 1, simulated mortality was lower for FIT than colonoscopy screening (10.1 vs. 11.8; RR = 0.85; 95%PI, 0.83-0.90), while incidences were more similar. This suggests that relative cancer incidence and mortality reductions for FIT vs. colonoscopy screening may differ by ADR, with fewer predicted deaths with colonoscopy screening in higher ADR settings and fewer deaths with annual FIT screening in lower ADR settings. PMID- 28815575 TI - Validation of the Scale for Assessment and Rating of Ataxia: testing a test (and failing it). PMID- 28815574 TI - Age-related reference values for the pediatric Scale for Assessment and Rating of Ataxia: a multicentre study. AB - AIM: For reliable assessment of ataxia severity in children, the Childhood Ataxia and Cerebellar Group of the European Pediatric Neurology Society aimed to validate the Scale for Assessment and Rating of Ataxia (SARA) according to age. METHOD: Twenty-two pediatric ataxia experts from 15 international institutions scored videotaped SARA performances in 156 typically developing children (4-16y: m/f=1; 12 children per year of age; including nine different nationalities). We determined age-dependency and reliability of pediatric SARA scores by a mixed model. RESULTS: In typically developing children, age was the only variable that revealed a relationship with SARA scores (p<0.001). The youngest children revealed the highest scores and the highest variation in scores (<8y; p<0.001). After 11 years of age, pediatric scores approached adult outcomes. The interobserver agreement of total SARA scores was substantial with an intraclass correlation coefficient of 0.63 (95% confidence interval 0.56-0.69; p<0.001). INTERPRETATION: In typically developing European children, both SARA scores and interobserver agreement are age-dependent. For reliable interpretation of pediatric SARA scores, consideration of the underlying test construct appears prudent. These data will hopefully contribute to a correct and uniform interpretation of longitudinal SARA scores from childhood to adulthood. PMID- 28815576 TI - MicroRNA and mesial temporal lobe epilepsy with hippocampal sclerosis: Whole miRNome profiling of human hippocampus. AB - OBJECTIVE: Mesial temporal lobe epilepsy (mTLE) is a severe neurological disorder characterized by recurrent seizures. mTLE is frequently accompanied by neurodegeneration in the hippocampus resulting in hippocampal sclerosis (HS), the most common morphological correlate of drug resistance in mTLE patients. Incomplete knowledge of pathological changes in mTLE+HS complicates its therapy. The pathological mechanism underlying mTLE+HS may involve abnormal gene expression regulation, including posttranscriptional networks involving microRNAs (miRNAs). miRNA expression deregulation has been reported in various disorders, including epilepsy. However, the miRNA profile of mTLE+HS is not completely known and needs to be addressed. METHODS: Here, we have focused on hippocampal miRNA profiling in 33 mTLE+HS patients and nine postmortem controls to reveal abnormally expressed miRNAs. In this study, we significantly reduced technology related bias (the most common source of false positivity in miRNA profiling data) by combining two different miRNA profiling methods, namely next generation sequencing and miRNA-specific quantitative real-time polymerase chain reaction. RESULTS: These methods combined have identified and validated 20 miRNAs with altered expression in the human epileptic hippocampus; 19 miRNAs were up regulated and one down-regulated in mTLE+HS patients. Nine of these miRNAs have not been previously associated with epilepsy, and 19 aberrantly expressed miRNAs potentially regulate the targets and pathways linked with epilepsy (such as potassium channels, gamma-aminobutyric acid, neurotrophin signaling, and axon guidance). SIGNIFICANCE: This study extends current knowledge of miRNA-mediated gene expression regulation in mTLE+HS by identifying miRNAs with altered expression in mTLE+HS, including nine novel abnormally expressed miRNAs and their putative targets. These observations further encourage the potential of microRNA based biomarkers or therapies. PMID- 28815577 TI - Emerging roles of rhomboid-like pseudoproteases in inflammatory and innate immune responses. AB - Rhomboid-like pseudoproteases are a conserved superfamily of proteins related to the rhomboid intramembrane serine proteases that lack key catalytic residues. iRhom2, a member of the rhomboid-like pseudoprotease superfamily, regulates the maturation and trafficking of ADAM17 and is associated with inflammatory arthritis. Recent studies demonstrate that iRhom2 is also involved in innate immunity by regulating the trafficking and stability of MITA (also called STING), which is a central adaptor in innate antiviral signalling pathways. Here, we summarize recent progress on the roles and mechanisms of iRhom2 and its homologues in innate immunity and also discuss the links between the physiological functions of iRhoms and immunological diseases. PMID- 28815578 TI - IL-17 polarization of MAIT cells is derived from the activation of two different pathways. AB - MAIT cells are expanded in salivary glands of patients with Sjogren's syndrome and are IL-17 polarized. IL-7 and IL-23 induce IL-17 production activating two different pathways: IL-7 stimulation induces in fact a significant STAT3 and HIF1alpha upregulation, conversely, IL-23 stimulation significantly induces RORc overexpression in MAIT cells of patients with Sjogren's syndrome. PMID- 28815580 TI - Deciding to Come Out to Parents: Toward a Model of Sexual Orientation Disclosure Decisions. AB - The purpose of this study was to conduct research to understand nonheterosexual youths' decision to disclose their sexual orientation information to their parents. The sample for this study includes 22 youth between the ages of 14 and 21. Constructivist grounded theory guided the qualitative methodology and data analysis. The findings from this study posit an emerging model of sexual orientation disclosure decisions comprised of four interrelated factors that influence the decision to disclose or not disclose, as well as a description of the mechanism through which disclosure either does or does not occur. Clinical implications and recommendations for further research are provided. PMID- 28815579 TI - "Histological characteristics of HPV-associated and -independent squamous cell carcinomas of the vulva: A study of 1,594 cases". AB - There are at least two different etio-pathogenic pathways for the development of vulvar squamous cell carcinoma (VSCC): one associated with infection by human papillomavirus (HPV) and another independent of HPV. We aimed to describe the histological characteristics of HPV-associated and -independent tumors and to determine the best strategy to identify HPV in VSCC. A single paraffin block was available for review from a series of 1,594 VSCCs. In all cases HPV DNA detection was analyzed using the SPF10PCR/DEIA/LiPA25 system and p16 immunohistochemistry (IHC). A tumor was considered as unquestionably HPV-associated if both HPV DNA and p16 IHC were positive. A tumor was considered indisputably HPV-independent if both HPV DNA and p16 IHC were negative. Two groups of tumors were classified as non-conclusive: (1) HPV DNA+/p16- and (2) HPV DNA-/p16+. WHO typing and a thorough histological evaluation were conducted in all cases. Four hundred and forty-one tumors were HPV DNA+ with 367 cases (23.0%) being HPV DNA+/p16+. The latter tumors were more frequently basaloid or warty (49.8%), but 36.5% were of the keratinizing type; 1,153 tumors were HPV DNA-, with 1,060 cases (66.5%) being HPV DNA-/p16-. These HPV DNA-/p16- tumors were mostly keratinizing (81.2%) but were occasionally basaloid or warty (5.2%). The features of HPV DNA-/p16+ cases (n = 93) were similar to those of the HPV-associated VSCC, and HPV DNA+/p16- (n = 74) cases had a more diverse profile, although they were more similar to HPV independent tumors. Several histological characteristics were more frequently associated with HPV-related VSCC (koilocytotic-like change, necrosis, moderate to marked pleomorphism, invasive front in nests; p < 0.001), however, none of these characteristics allowed differentiation between HPV-associated and -independent VSCC. In conclusion, histological criteria do not allow differentiation between HPV-associated and -independent VSCC. p16 Alone is a clinically easy strategy to determine HPV status in VSCC. PMID- 28815582 TI - Activation of TWIST1 by COL11A1 promotes chemoresistance and inhibits apoptosis in ovarian cancer cells by modulating NF-kappaB-mediated IKKbeta expression. AB - We have shown that collagen type XI alpha 1 (COL11A1) promotes ovarian cancer progression and is associated with chemoresistance to cisplatin and paclitaxel in ovarian cancer cells. Here, we demonstrate how COL11A1 regulates twist family basic helix-loop-helix transcription factor 1-related protein 1 (TWIST1) to induce chemoresistance and inhibit apoptosis in ovarian cancer cells. Small interfering RNA-mediated reduction in COL11A1 protein levels increased the chemosensitivity to cisplatin and paclitaxel via downregulated TWIST1 expression. TWIST1 messenger RNA levels positively associated with COL11A1 messenger RNA expression levels in ovarian tumors. High TWIST1 expression levels were significantly associated with a progression-free interval of <= 6 months (p = 0.001) and death (p = 0.040). In addition, patients with high TWIST1 mRNA levels had significantly shorter 5-year overall-survival (p = 0.004) and progression free survival (p = 0.009) rates, compared to patients with low TWIST1 levels. Increased TWIST1 expression caused by COL11A1-induced transcription of the inhibitor of nuclear factor kappa B kinase subunit beta (IKKbeta) gene occurred via increased SP1 phosphorylation and binding to the IKKbeta promoter. COL11A1 mediated nuclear factor-kappa B activation, via transcriptional activation of IKKbeta, promoted TWIST1, Mcl-1, and GAS6 expression, which were associated with chemoresistance and anti-apoptosis in ovarian cancer cells. We suggest that IKKbeta and TWIST1 can potentially be targeted in patients with COL11A1-positive ovarian cancer. PMID- 28815583 TI - Educational and rehabilitation service utilization in adolescents born preterm or with a congenital heart defect and at high risk for disability. AB - AIM: This historical cohort study describes the use of educational and rehabilitation services in adolescents born preterm or with a congenital heart defect (CHD). METHOD: Parents of 76 young people (mean age 15y 8mo [SD 1y 8mo]) with CHD and 125 born <=29 weeks gestational age (mean age 16y [SD 2y 5mo]) completed a demographics questionnaire including educational and rehabilitation resource utilization within the previous 6 months. Rehabilitation services included occupational therapy, physical therapy, speech language pathology, psychology. Developmental (Leiter Brief IQ, Movement-ABC, Strengths and Difficulties Questionnaire) and functional (Vineland) status of the young people was assessed. Pearson chi2 tests were used to perform simple pairwise comparisons of categorical outcomes across the two groups (CHD, preterm). Univariate logistic regression was used to examine predictors of service utilization. RESULTS: Developmental profiles of the two groups (CHD/preterm) were similar (29.9%/30% IQ<80; 43.5%/50.0% motor difficulties; 23.7%/22.9% behavior problems). One-third received educational supports or attended segregated schools. Only 16% (preterm) and 26.7% (CHD) were receiving rehabilitation services. Services were provided predominantly in the school setting, typically weekly. Few received occupational therapy or physical therapy (1.3-7.6%) despite functional limitations. Leiter Brief IQ<70 was associated with receiving educational supports (CHD: OR 5.53, 95% CI 1.29-23.68; preterm: OR 14.63, 3.10-69.08) and rehabilitation services (CHD: OR 4.46, 1.06-18.88; preterm: OR 5.11, 1.41-18.49). Young people with motor deficits were more likely to require educational (CHD: OR 5.72, 1.99-16.42; preterm: OR 3.11, 1.43-6.77) and rehabilitation services (preterm: OR 3.97, 1.21 13.03). INTERPRETATION: Although young people with impairments were more likely to receive educational and rehabilitation services, many may not be adequately supported, particularly by rehabilitation specialists. Rehabilitation services at this important transition phase could be beneficial in optimizing adaptive functioning in the home, school, and community. PMID- 28815581 TI - T helper type 1 polarizing gammadelta T cells and Scavenger receptors contribute to the pathogenesis of Pemphigus vulgaris. AB - gammadelta T cells and Scavenger receptors are key parts of the innate immune machinery, playing significant roles in regulating immune homeostasis at the epithelial surface. The roles of these immune components are not yet characterized for the autoimmune skin disorder Pemphigus vulgaris (PV). Phenotyping and frequency of gammadelta T cells estimated by flow cytometry have shown increased frequency of gammadelta T cells (6.7% versus 4.4%) producing interferon- gamma (IFN-gamma; 35.2% versus 26.68%) in the circulation of patients compared with controls. Dual cytokine-secreting (IFN-gamma and interleukin-4) gammadelta T cells indicate the plasticity of these cells. The gammadelta T cells of patients with PV have shown higher cytotoxic potential and the higher frequency of gammadelta T cells producing IFN-gamma shows T helper type 1 polarization. The increased expression of Scavenger receptors expression (CD36 and CD163) could be contributing to the elevated inflammatory environment and immune imbalance in this disease. Targeting the inflammatory gammadelta T cells and Scavenger receptors may pave the way for novel therapeutics. PMID- 28815584 TI - Maintenance of CD8+ memory T lymphocytes in the spleen but not in the bone marrow is dependent on proliferation. AB - It is current belief that numbers of CD8+ memory T lymphocytes in the memory phase of an immune response are maintained by homeostatic proliferation. Here, we compare the proliferation of CD8+ memory T lymphocytes, generated by natural infections and by intentional immunization, in spleen and bone marrow (BM). Fifty percent of CD8+ memory T lymphocytes in the spleen are eliminated by cyclophosphamide within 14 days, indicating that numbers of at least 50% of splenic CD8+ memory T lymphocytes are maintained by proliferation. The numbers of CD8+ memory T lymphocytes in the BM, however, were not affected by cyclophosphamide. This stability was independent of circulating CD8+ memory T cells, blocked by FTY720, showing that BM is a privileged site for the maintenance of memory T lymphocytes, as resident cells, resting in terms of proliferation. PMID- 28815585 TI - Mammal-induced trophic cascades in invertebrate food webs are modulated by grazing intensity in subalpine grassland. AB - Even though mammalian herbivores can exert strong indirect effects on other animals by altering the vegetation, the study of trophic cascades retains a focus on apex predators and their top-down forces. Bottom-up trophic interaction chains induced by mammalian herbivores, particularly in invertebrate food webs, remain largely unexplored. We tested whether effects of mammalian herbivores on the vegetation ricochet back up several trophic levels of the invertebrate food web. We further tested two alternative hypotheses: the strength of herbivore-induced indirect interactions either increases with plant productivity because of a concurrent higher grazing intensity, or it decreases because of a higher plant tolerance to grazing. We progressively excluded large, medium and small herbivorous mammals from replicated plots of 6 m2 in productive, intensively grazed short-grass vegetation and less productive, less intensively grazed tall grass vegetation of subalpine grasslands. We measured vegetation quantity, quality, structure and composition, and determined the abundance of invertebrate herbivores, detritivores, omnivores and predators. We used structural equation modelling to test vegetation-mediated cascading effects of the different mammalian herbivores across different trophic groups of invertebrates. In the short-grass vegetation, mammals caused changes in vegetation quantity and thickness. These changes directly affected detritivorous and predatory invertebrate abundance, yet indirectly affected predatory and omnivorous invertebrates through a bottom-up trophic cascade via changes in herbivorous invertebrate abundance. In the tall-grass vegetation, mammal-induced changes in vegetation quality and composition affected detritivorous invertebrates and in turn omnivorous invertebrates, but these cascading effects were weaker than those in the short-grass vegetation. Smaller mammals were at least as important as large mammals in structuring the invertebrate food web. Our results demonstrate that differently sized mammalian herbivores can trigger trophic cascades in the local invertebrate food web. Our findings further support the hypothesis that herbivore-induced indirect interactions are stronger in more productive systems because of higher foraging intensity, as opposed to the hypothesis that a higher grazing tolerance of plants should dampen herbivore-induced indirect interactions in productive systems. PMID- 28815586 TI - Differential interference contrast-photothermal microscopy in nanospace: impacts of systematic parameters. AB - Differential interference contrast-photothermal microscopy (DIC-PTM), as a promising tool for trace analysis of nonfluorescent compounds, suffered low sensitivity in nanospace especially for aqueous samples, due to the poor thermophysical property of water and the unoptimised configuration. To improve its performance, a five-layer DIC-PTM model is built and influences of different parameters on the photothermal signal are investigated. The initial phase shift phi0 between two branches of the probe beam is found to be a key factor determining the detection sensitivity and response linearity: at a large phi0 (<=pi/2) both a high sensitivity and a good linearity can be achieved, while a high signal-to-noise ratio occurs at a small phi0 . The steady-state photothermal phase shift phidc has little impact on the linearity, which, however, is greatly influenced by the range of periodic photothermal phase shift phiac . By introducing two coatings into a nanospace to confine the photothermal effect within and around the sample, the sensitivity can be enhanced from a few times to over 100 times. On an optimised DIC-PTM configuration and chip structure, detection limit down to 10-3 cm-1 (or 40 molecules in a detection volume of 0.2 fL) was achieved in a 300-nm-thick nanospace. This work paves a way for optimising the DIC-PTM and chip structure for sensitive detection of analytes in nanospaces. PMID- 28815587 TI - Beveled posteromedial corner of the radial head: a three-dimensional micro computed tomography modeling study. AB - The posteromedial quadrant of the radial head is known to be different from the other quadrants. However, the explanation of this unique anatomical feature remains elusive. Hence, this study was designed to address this unique anatomical variance using three-dimensional MUCT (micro-computed tomography) analysis. Nine fresh cadaveric radial heads were scanned using MUCT. Three-dimensional subchondral bone and cartilage models were rendered. Both models were separated into the four quadrants at both the periphery (rim) and the articulating dish (fovea): anteromedial (AM), posteromedial (PM), posterolateral (PL), and anterolateral (AL). Each quadrant was analyzed in terms of (1) subchondral bone porosity (SBP), (2) mean subchondral bone thickness (MSBT), and (3) mean cartilage thickness (MCT). There was a significant difference between the fovea and the rim in terms of its microarchitectural features. Although within the fovea, the PM quadrant did not differ significantly from the other quadrants, a significant difference was found within the rim. In terms of SBP, PM, AM, PL and AL were calculated as 33, 37, 36 and 35%, respectively. In terms of MSBT, PM, AM, PL and AL were calculated as 0.11, 0.10, 0.09, and 0.09 mm, respectively. In terms of MCT, PM, AM, PL and AL were calculated 1.09, 0.81, 0.84 and 0.83 mm, respectively. The PM corner of the radial head between the 8 and 9 o'clock positions, was beveled. This might explain why the PM quadrant of the rim differed significantly from the other quadrants in terms of its microarchitectural features. PMID- 28815588 TI - The tooth, the whole tooth and nothing but the tooth: tooth shape and ontogenetic shift dynamics in the white shark Carcharodon carcharias. AB - Results from this study of the white shark Carcharodon carcharias include measurements obtained using a novel photographic method that reveal significant differences between the sexes in the relationship between tooth cuspidity and shark total length, and a novel ontogenetic change in male tooth shape. Males exhibit broader upper first teeth and increased distal inclination of upper third teeth with increasing length, while females do not present a consistent morphological change. Substantial individual variation, with implications for pace of life syndrome, was present in males and tooth polymorphism was suggested in females. Sexual differences and individual variation may play major roles in ontogenetic changes in tooth morphology in C. carcharias, with potential implications for their foraging biology. Such individual and sexual differences should be included in studies of ontogenetic shift dynamics in other species and systems. PMID- 28815589 TI - Tight temporal coupling between synaptic rewiring of olfactory glomeruli and the emergence of odor-guided behavior in Xenopus tadpoles. AB - Olfactory sensory neurons (OSNs) are chemoreceptors that establish excitatory synapses within glomeruli of the olfactory bulb. OSNs undergo continuous turnover throughout life, causing the constant replacement of their synaptic contacts. Using Xenopus tadpoles as an experimental system to investigate rewiring of glomerular connectivity, we show that novel OSN synapses can transfer information immediately after formation, mediating olfactory-guided behavior. Tadpoles recover the ability to detect amino acids 4 days after bilateral olfactory nerve transection. Restoration of olfactory-guided behavior depends on the efficient reinsertion of OSNs to the olfactory bulb. Presynaptic terminals of incipient synaptic contacts generate calcium transients in response to odors, triggering long lasting depolarization of olfactory glomeruli. The functionality of reconnected terminals relies on well-defined readily releasable and cytoplasmic vesicle pools. The continuous growth of non-compartmentalized axonal processes provides a vesicle reservoir to nascent release sites, which contrasts to the gradual development of cytoplasmic vesicle pools in conventional excitatory synapses. The immediate availability of fully functional synapses upon formation supports an age-independent contribution of OSNs to the generation of odor maps. PMID- 28815590 TI - Juxtanodin in retinal pigment epithelial cells: Expression and biological activities in regulating cell morphology and actin cytoskeleton organization. AB - Juxtanodin (JN, also known as ermin) was initially identified as an actin cytoskeleton-related oligodendroglial protein in the rat central nervous system. It was subsequently also found in the rat olfactory neuroepithelium, especially at the apical junctional belt of the sustentacular cells. We further examined JN expression and functional roles in the retina using fluorescence histochemistry, confocal microscopy, immuno-electron microscopy, molecular biology, and cell culture. Prominent JN expression was found in the photoreceptor-supporting retinal pigment epithelium (RPE), especially in a zone corresponding to the apices of RPE cells, at the roots of the RPE microvilli, and at the base of RPE cells next to the Bruch's membrane. Partial co-localization of JN immunoreactivity with F-actin (labeled with phalloidin) was observed at the apices and bases of RPE cells. No JN was detected in other cell types of the retina. In cultured human RPE cell line ARPE-19, expression of extrinsic JN up regulated formation of actin cytoskeleton stress fibers, caused redistribution of more F-actin fibers to the cell periphery, and promoted spreading/enlargement of transfected cells. These findings suggest possible roles of JN in RPE molecular transport, phagocytosis and formation of outer blood-retinal barrier, or possible involvement of JN expression perturbations in pathogenesis of such retinal disorders as proliferative vitreoretinopathy and age-related macular degeneration. PMID- 28815591 TI - Engineering defined membrane-embedded elements of AMPA receptor induces opposing gating modulation by cornichon 3 and stargazin. AB - KEY POINTS: The AMPA-type ionotropic glutamate receptors (AMPARs) mediate the majority of excitatory synaptic transmission and their function impacts learning, cognition and behaviour. The gating of AMPARs occurs in milliseconds, precisely controlled by a variety of auxiliary subunits that are expressed differentially in the brain, but the difference in mechanisms underlying AMPAR gating modulation by auxiliary subunits remains elusive and is investigated. The elements of the AMPAR that are functionally recruited by auxiliary subunits, stargazin and cornichon 3, are located not only in the extracellular domains but also in the lipid-accessible surface of the AMPAR. We reveal that the two auxiliary subunits require a shared surface on the transmembrane domain of the AMPAR for their function, but the gating is influenced by this surface in opposing directions for each auxiliary subunit. Our results provide new insights into the mechanistic difference of AMPAR modulation by auxiliary subunits and a conceptual framework for functional engineering of the complex. ABSTRACT: During excitatory synaptic transmission, various structurally unrelated transmembrane auxiliary subunits control the function of AMPA receptors (AMPARs), but the underlying mechanisms remain unclear. We identified lipid-exposed residues in the transmembrane domain (TMD) of the GluA2 subunit of AMPARs that are critical for the function of AMPAR auxiliary subunits, stargazin (Stg) and cornichon 3 (CNIH3). These residues are essential for stabilizing the AMPAR-CNIH3 complex in detergents and overlap with the contacts made between GluA2 TMD and Stg in the cryoEM structures. Mutating these residues had opposite effects on gating modulation and complex stability when Stg- and CNIH3-bound AMPARs were compared. Specifically, in detergent the GluA2-A793F formed an unstable complex with CNIIH3 but in the membrane the GluA2 A793F-CNIH3 complex expressed a gain of function. In contrast, the GluA2-A793F Stg complex was stable, but had diminished gating modulation. GluA2-C528L destabilized the AMPAR-CNIH3 complex but stabilized the AMPAR-Stg complex, with overall loss of function in gating modulation. Furthermore, loss-of-function mutations in this TMD region cancelled the effects of a gain-of-function Stg carrying mutation in its extracellular loop, demonstrating that both the extracellular and the TMD elements contribute independently to gating modulation. The elements of AMPAR functionally recruited by auxiliary subunits are, therefore, located not only in the extracellular domains but also in the lipid accessible surface of the AMPAR. The TMD surface we defined is a potential target for auxiliary subunit-specific compounds, because engineering of this hotspot induces opposing functional outcomes by Stg and CNIH3. The collection of mutant phenotype mapping provides a framework for engineering AMPAR gating using auxiliary subunits. PMID- 28815592 TI - Sexual selection on male body size, genital length and heterozygosity: Consistency across habitats and social settings. AB - Spatial and temporal variation in environmental factors and the social setting can help to maintain genetic variation in sexually selected traits if it affects the strength of directional selection. A key social parameter which affects the intensity of, and sometimes predicts the response to, mating competition is the operational sex ratio (OSR; ratio of receptive males to females). How the OSR affects selection for specific male traits is poorly understood. It is also unclear how sexual selection is affected by interactions between the OSR and environmental factors, such as habitat complexity, that alter key male-female interactions such as mate encounter rates. Here, we experimentally manipulated the OSR and habitat complexity and quantified sexual selection on male mosquitofish (Gambusia holbrooki) by directly measuring male reproductive success (i.e. paternity). We show that despite a more equitable sharing of paternity (i.e. higher levels of multiple paternity) under a male-biased OSR, selection on focal male traits was unaffected by the OSR or habitat complexity. Instead, sexual selection consistently, and significantly, favoured smaller bodied males, males with higher genome wide heterozygosity (based on >3,000 SNP markers) and males with a relatively long gonopodium (intromittent organ). Our results show that sexual selection on male body size, relative genital size and heterozygosity in this system is consistent across environments that vary in ecological parameters that are expected to influence mate encounter rates. PMID- 28815593 TI - Hypothalamic neurons out of control. PMID- 28815594 TI - Differential effects of changes in spectral irradiance on photoacclimation, primary productivity and growth in Rhodomonas salina (Cryptophyceae) and Skeletonema costatum (Bacillariophyceae) in simulated blackwater environments. AB - The underwater light field in blackwater environments is strongly skewed toward the red end of the electromagnetic spectrum due to blue light absorption by colored dissolved organic matter (CDOM). Exposure of phytoplankton to full spectrum irradiance occurs only when cells are mixed up to the surface. We studied the potential effects of mixing-induced changes in spectral irradiance on photoacclimation, primary productivity and growth in cultures of the cryptophyte Rhodomonas salina and the diatom Skeletonema costatum. We found that these taxa have very different photoacclimation strategies. While S. costatum showed classical complementary chromatic adaption, R. salina showed inverse chromatic adaptation, a strategy previously unknown in the cryptophytes. Transfer of R. salina to periodic full spectrum light (PFSL) significantly enhanced growth rate (MU) by 1.8 times and primary productivity from 0.88 to 1.35 mg C . (mg Chl-1 ) . h-1 . Overall, R. salina was less dependent on PFSL than was S. costatum, showing higher MU and net primary productivity rates. In the high-CDOM simulation, carbon metabolism of the diatom was impaired, leading to suppression of growth rate, short-term 14 C uptake and net primary production. Upon transfer to PFSL, MU of the diatom increased by up to 3-fold and carbon fixation from 2.4 to 6.0 mg C . (mg Chl-1 ) . h-1 . Thus, a lack of PFSL differentially impairs primarily CO2 fixation and/or carbon metabolism, which, in turn, may determine which phytoplankton dominate the community in blackwater habitats and may therefore influence the structure and function of these ecosystems. PMID- 28815595 TI - Sigma-1 receptor ligands inhibit catecholamine secretion from adrenal chromaffin cells due to block of nicotinic acetylcholine receptors. AB - Adrenal chromaffin cells (ACCs) are the neuroendocrine arm of the sympathetic nervous system and key mediators of the physiological stress response. Acetylcholine (ACh) released from preganglionic splanchnic nerves activates nicotinic acetylcholine receptors (nAChRs) on chromaffin cells causing membrane depolarization, opening voltage-gated Ca2+ channels (VGCC), and exocytosis of catecholamines and neuropeptides. The serotonin transporter is expressed in ACCs and interacts with 5-HT1A receptors to control secretion. In addition to blocking the serotonin transporter, some selective serotonin reuptake inhibitors (SSRIs) are also agonists at sigma-1 receptors which function as intracellular chaperone proteins and can translocate to the plasma membrane to modulate ion channels. Therefore, we investigated whether SSRIs and other sigma-1 receptor ligands can modulate stimulus-secretion coupling in ACCs. Escitalopram and fluvoxamine (100 nM to 1 MUM) reversibly inhibited nAChR currents. The sigma-1 receptor antagonists NE-100 and BD-1047 also blocked nAChR currents (~ 50% block at 100 nM) as did PRE-084, a sigma-1 receptor agonist. Block of nAChR currents by fluvoxamine and NE-100 was not additive suggesting a common site of action. VGCC currents were unaffected by the drugs. Neither the increase in cytosolic [Ca2+ ] nor the resulting catecholamine secretion evoked by direct membrane depolarization to bypass nAChRs was altered by fluvoxamine or NE-100. However, both Ca2+ entry and catecholamine secretion evoked by the cholinergic agonist carbachol were significantly reduced by fluvoxamine or NE-100. Together, our data suggest that sigma-1 receptors do not acutely regulate catecholamine secretion. Rather, SSRIs and other sigma-1 receptor ligands inhibit secretion evoked by cholinergic stimulation because of direct block of Ca2+ entry via nAChRs. PMID- 28815596 TI - Use of first-trimester placenta growth factor concentration to predict hypertensive disorders of pregnancy in a low-risk Asian population. AB - OBJECTIVE: To determine the value of placenta growth factor (PlGF) for predicting hypertensive disorders of pregnancy (HDP) in a low-risk population when used either alone or in combination with other markers. METHODS: A prospective observational cohort study was conducted among women with singleton pregnancy in the first trimester in New Delhi, India, between October 1, 2013, and September 30, 2016. First-trimester measures included maternal history, body mass index (BMI), mean arterial pressure (MAP), Doppler uterine artery pulsatility index, and serum levels of biomarkers (including PlGF). RESULTS: Among 1725 women, 208 (12.1%) developed HDP; 74 (35.6%) of these cases were early onset. Mean PlGF levels were significantly lower among cases than among controls (30.42 +/- 10.22 vs 37.31 +/- 13.28 pg/mL; P<0.001). As a biomarker for prediction of HDP, PlGF fared better than pregnancy-associated plasma protein A (PAPP-A): area under the curve 0.685 (95% confidence interval [CI] 0.620-0.750; P<0.001) versus 0.659 (95% CI 0.593-0.726; P<0.001). The highest odds ratio was found for MAP (8.369, 95% CI 5.752-12.215). The combination of PlGF, PAPP-A, BMI, MAP, and Doppler uterine artery pulsatility index provided an area under the receiver operating characteristic curve of 0.876 (95% CI 0.833-0.919; P<0.001). CONCLUSION: Combining PlGF concentration with biochemical and biophysical markers provided a good screening test for HDP during the first trimester. PMID- 28815598 TI - LPA1 is a key mediator of intracellular signalling and neuroprotection triggered by tetracyclic antidepressants in hippocampal neurons. AB - Both lysophosphatidic acid (LPA) and antidepressants have been shown to affect neuronal survival and differentiation, but whether LPA signalling participates in the action of antidepressants is still unknown. In this study, we examined the role of LPA receptors in the regulation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) activity and neuronal survival by the tetracyclic antidepressants, mianserin and mirtazapine in hippocampal neurons. In HT22 immortalized hippocampal cells, antidepressants and LPA induced a time- and concentration-dependent stimulation of ERK1/2 phosphorylation. This response was inhibited by either LPA1 and LPA1/3 selective antagonists or siRNA-induced LPA1 down-regulation, and enhanced by LPA1 over-expression. Conversely, the selective LPA2 antagonist H2L5186303 had no effect. Antidepressants induced cyclic AMP response element binding protein phosphorylation and this response was prevented by LPA1 blockade. ERK1/2 stimulation involved pertussis toxin-sensitive G proteins, Src tyrosine kinases and fibroblast growth factor receptor (FGF-R) activity. Tyrosine phosphorylation of FGF-R was enhanced by antidepressants through LPA1 . Serum withdrawal induced apoptotic death, as indicated by increased annexin V staining, caspase activation and cleavage of poly-ADP-ribose polymerase. Antidepressants inhibited the apoptotic cascade and this protective effect was curtailed by blockade of either LPA1 , ERK1/2 or FGF-R activity. Moreover, in primary mouse hippocampal neurons, mianserin acting through LPA1 increased phospho-ERK1/2 and protected from apoptosis induced by removal of growth supplement. These data indicate that in neurons endogenously expressed LPA1 receptors mediate intracellular signalling and neuroprotection by tetracyclic antidepressants. PMID- 28815597 TI - Cardiac action potential repolarization revisited: early repolarization shows all or-none behaviour. AB - In healthy mammalian hearts the action potential (AP) waveform initiates and modulates each contraction, or heartbeat. As a result, AP height and duration are key physiological variables. In addition, rate-dependent changes in ventricular AP duration (APD), and variations in APD at a fixed heart rate are both reliable biomarkers of electrophysiological stability. Present guidelines for the likelihood that candidate drugs will increase arrhythmias rely on small changes in APD and Q-T intervals as criteria for safety pharmacology decisions. However, both of these measurements correspond to the final repolarization of the AP. Emerging clinical evidence draws attention to the early repolarization phase of the action potential (and the J-wave of the ECG) as an additional important biomarker for arrhythmogenesis. Here we provide a mechanistic background to this early repolarization syndrome by summarizing the evidence that both the initial depolarization and repolarization phases of the cardiac action potential can exhibit distinct time- and voltage-dependent thresholds, and also demonstrating that both can show regenerative all-or-none behaviour. An important consequence of this is that not all of the dynamics of action potential repolarization in human ventricle can be captured by data from single myocytes when these results are expressed as 'repolarization reserve'. For example, the complex pattern of cell-to-cell current flow that is responsible for AP conduction (propagation) within the mammalian myocardium can change APD and the Q-T interval of the electrocardiogram alter APD stability, and modulate responsiveness to pharmacological agents (such as Class III anti-arrhythmic drugs). PMID- 28815599 TI - The reduction of intraepidermal P2X3 nerve fiber density correlates with behavioral hyperalgesia in a rat model of nerve injury-induced pain. AB - Skin biopsies from patients with neuropathic pain often show changes in epidermal innervation, although it remains to be elucidated to what extent such changes can be linked to a particular subgroup of nerve fibers and how these changes are correlated with pain intensity. Here, we investigated to what extent behavioral signs of hyperalgesia are correlated with immunohistochemical changes of peptidergic and non-peptidergic epidermal nerve fibers in a rat model of nerve injury-induced pain. Rats subjected to unilateral partial ligation of the sciatic nerve developed significant mechanical and thermal hyperalgesia as tested by the withdrawal responses of the ipsilateral footpad to von Frey hairs and hotplate stimulation. At day 14, epidermal nerve fiber density and total epidermal nerve fiber length/mm2 were significantly and consistently reduced compared to the contralateral side, following testing and re-testing by two blinded observers. The expression of calcitonin gene-related peptide, a marker for peptidergic nerve fibers, was not significantly changed on the ipsilateral side. In contrast, the expression of the P2X3 receptor, a marker for non-peptidergic nerve fibers, was not only significantly reduced but could also be correlated with behavioral hyperalgesia. When labeling both peptidergic and non-peptidergic nerve fibers with the pan-neuronal marker PGP9.5, the expression was significantly reduced, albeit without a significant correlation with behavioral hyperalgesia. In conjunction, our data suggest that the pathology of the P2X3 epidermal nerve fibers can be selectively linked to neuropathy, highlighting the possibility that it is the degeneration of these fibers that drives hyperalgesia. PMID- 28815600 TI - The many facets of mindfulness and the prediction of change following mindfulness based stress reduction (MBSR). AB - OBJECTIVES: Mindfulness-based stress reduction (MBSR) promotes numerous psychological benefits, but few studies have identified for whom MBSR is most effective. The current study tested the hypothesis that lower baseline mindfulness invites more "room to grow" and, thus, predicts greater improvement during MBSR. METHOD: We examined three facets of mindfulness (awareness, acceptance, decentering) among 131 MBSR participants prior to enrollment, to test the hypothesis that lower baseline mindfulness predicts greater improvements in perceived stress, positive affect (PA), and negative affect (NA) following MBSR. RESULTS: Lower acceptance and decentering predicted greater decreases in perceived stress. Higher awareness, acceptance, and decentering predicted greater increases in PA. Higher awareness predicted greater reductions in NA. Lower decentering predicted greater reductions in NA. CONCLUSION: Findings partly supported the hypothesis that lower baseline mindfulness predicts greater improvement following MBSR and emphasize the importance of assessing multiple mindfulness facets given their unique, contrasting relations to outcomes. PMID- 28815601 TI - Antimicrobial synergism and cytotoxic properties of Citrus limon L., Piper nigrum L. and Melaleuca alternifolia (Maiden and Betche) Cheel essential oils. AB - OBJECTIVES: The chemical composition, antimicrobial and synergistic effect, and cytotoxic activity of Citrus limon (lemon), Piper nigrum (green pepper) and Melaleuca alternifoila (tea tree) essential oils (EOs) were investigated. METHODS: Chemical analyses of essential oils were tested by GC-FID and GC-MS spectroscopy. The antimicrobial activity assay was conducted using microdilution method against several oral bacteria and Candida spp. originating from the humans with oral disorders. The synergistic antimicrobial activity was evaluated using checkerboard method. The cytotoxicity evaluation of EOs was assessed using MTT test. KEY FINDINGS: Limonene (37.5%) and beta-pinene (17.9%) were the major compounds in C. limon oil, beta-pinene (34.4%), delta-3-carene (19.7%), limonene (18.7%) and alpha-pinene (10.4%) in P. nigrum oil and terpinen-4-ol (38.6%) and gamma-terpinene (21.7%) in M. alternifolia oil. The broad-spectrum antimicrobial activity was achieved by tested three EOs, with C. limon oil being the strongest against bacteria and M. alternifolia oil strongest against fungi. The EOs demonstrated synergism; their combined application revealed an increase in antimicrobial activity. All tested essential oils showed lower cytotoxic activity in comparison with the positive control, and the obtained results confirmed a dose-dependent activity. CONCLUSIONS: The results of this study encourage use of tested EOs in development of a novel agent intended for prevention or therapy of corresponding oral disorders. PMID- 28815602 TI - Efficacy and safety of amphotericin B formulations: a network meta-analysis and a multicriteria decision analysis. AB - OBJECTIVES: Despite its broad spectrum, conventional amphotericin B (AB) is associated with serious adverse events. Lipid-based formulations may offer safer options. We aimed to synthesize the evidence of efficacy and safety of AB formulations. METHODS: We performed a systematic review and network meta-analysis (NMA) to compare all available formulations: conventional AB; lipid complex or ABLC; colloidal dispersion or ABCD; liposomal or LAB; AB in Intralipid. Randomized controlled trials were searched in four databases. Cure, fever, chills, nephrotoxicity, death and drug discontinuation were assessed. NMA was based on Bayesian methods accounting for direct and indirect comparisons. Probability ranks estimating the best formulation were built for each outcome. The relative benefit-risk of formulations was assessed with stochastic multicriteria acceptability analyses (SMAA). KEY FINDINGS: We identified 25 trials (n = 2996). No significant differences among drugs were observed for cure or death. All lipid-based formulations were safer than conventional AB for nephrotoxicity. AB-Intralipid was more tolerable than conventional AB and caused less chills than ABCD. AB-Intralipid was the best therapy (>60%) regarding nephrotoxicity, fever, chills and discontinuation. The scenario from SMAA favoured AB-Intralipid (81% acceptability). Conventional AB was secondary to all lipid-based formulations. CONCLUSIONS: Amphotericin B-Intralipid was identified as safer, cost-saving treatment in comparison with other formulations. PMID- 28815603 TI - Registration of phase-contrast images in propagation-based X-ray phase tomography. AB - X-ray phase tomography aims at reconstructing the 3D electron density distribution of an object. It offers enhanced sensitivity compared to attenuation based X-ray absorption tomography. In propagation-based methods, phase contrast is achieved by letting the beam propagate after interaction with the object. The phase shift is then retrieved at each projection angle, and subsequently used in tomographic reconstruction to obtain the refractive index decrement distribution, which is proportional to the electron density. Accurate phase retrieval is achieved by combining images at different propagation distances. For reconstructions of good quality, the phase-contrast images recorded at different distances need to be accurately aligned. In this work, we characterise the artefacts related to misalignment of the phase-contrast images, and investigate the use of different registration algorithms for aligning in-line phase-contrast images. The characterisation of artefacts is done by a simulation study and comparison with experimental data. Loss in resolution due to vibrations is found to be comparable to attenuation-based computed tomography. Further, it is shown that registration of phase-contrast images is nontrivial due to the difference in contrast between the different images, and the often periodical artefacts present in the phase-contrast images if multilayer X-ray optics are used. To address this, we compared two registration algorithms for aligning phase-contrast images acquired by magnified X-ray nanotomography: one based on cross-correlation and one based on mutual information. We found that the mutual information-based registration algorithm was more robust than a correlation-based method. PMID- 28815605 TI - Enhanced EDX images by fusion of multimodal SEM images using pansharpening techniques. AB - The goal of this paper is to explore the potential interest of image fusion in the context of multimodal scanning electron microscope (SEM) imaging. In particular, we aim at merging the backscattered electron images that usually have a high spatial resolution but do not provide enough discriminative information to physically classify the nature of the sample, with energy-dispersive X-ray spectroscopy (EDX) images that have discriminative information but a lower spatial resolution. The produced images are named enhanced EDX. To achieve this goal, we have compared the results obtained with classical pansharpening techniques for image fusion with an original approach tailored for multimodal SEM fusion of information. Quantitative assessment is obtained by means of two SEM images and a simulated dataset produced by a software based on PENELOPE. PMID- 28815604 TI - Chronic morphine reduces the readily releasable pool of GABA, a presynaptic mechanism of opioid tolerance. AB - KEY POINTS: Chronic treatment with opioids, such as morphine, leads to analgesic tolerance. While postsynaptic opioid tolerance is well documented, the involvement of presynaptic mechanisms remains unclear. We show that chronic morphine reduces the ability of periaqueductal grey (PAG) neurons to maintain GABAergic transmission. This depression of GABAergic transmission was due to a reduction in the effective size of the readily releasable pool. This also led to a reduction in opioid presynaptic inhibition; these presynaptic adaptations need to be considered in the development of strategies to reduce opioid tolerance. ABSTRACT: The midbrain periaqueductal grey (PAG) plays a critical role in tolerance to the analgesic actions of opioids such as morphine. While numerous studies have identified the postsynaptic adaptations induced by chronic morphine treatment in this and other brain regions, the presence of presynaptic adaptations remains uncertain. We examined GABAergic synaptic transmission within rat PAG brain slices from animals which underwent a low dose morphine treatment protocol which produces tolerance, but not withdrawal. Evoked GABAergic IPSCs (inhibitory postsynaptic currents) were less in morphine compared to control saline treated animals. Postsynaptic GABAA receptor mediated currents and desensitization, presynaptic release probability (Pr ), and inhibition by endogenous neurotransmitters were similar in morphine and saline treated animals. By contrast, the effective size of the readily releasable pool (RRP) was smaller in morphine treated animals. While the MU-opioid agonist DAMGO produced a reduction in Pr and RRP size in saline treated animals, it only reduced Pr in morphine treated animals. Consequently, DAMGO-induced inhibition of evoked IPSCs during short burst stimulation was less in morphine, compared to saline treated animals. These results indicate that low dose chronic morphine treatment reduces presynaptic MU-opioid inhibition by reducing the size of the pool of vesicles available for action potential dependent release. This novel presynaptic adaptation may provide important insights into the development of efficacious pain therapies that can circumvent the development of opioid tolerance. PMID- 28815606 TI - Prospective study of urinary prostaglandin E2 metabolite and pancreatic cancer risk. AB - The cyclooxygenase 2 (COX-2) pathway is upregulated in many pancreatic cancer cells, and it is believed that carcinogenetic effects of COX-2 upregulation are largely through prostaglandin E2 (PGE2) overproduction. We tested this hypothesis by evaluating the association between urinary PGE2 metabolites (PGE-M), a biomarker of in vivo PGE2 overproduction, and pancreatic cancer risk. We conducted a case-control study with 722 subjects (239 cases and 483 controls) nested within two prospective cohort studies, the Shanghai Women's Health Study (SWHS) and Shanghai Men's Health Study (SMHS). Pre-diagnosis urine samples were measured for PGE-M using a liquid chromatography/tandem mass spectrometric method. Conditional logistic regression was used to estimate odds ratio (OR) and 95% confidence intervals (95%CI), with adjustment for potential confounders. Compared to those with the lowest urine level of PGE-M (the first quartile), individuals with higher urine levels of PGE-M had an increased risk of developing pancreatic cancer, with adjusted ORs (95%CI) of 1.63 (0.98-2.73), 1.55 (0.90 2.69) and 1.94 (1.07-3.51), for the second to the fourth quartile groups, respectively (p for trend = 0.054). This dose-response positive association was more evident among those who had BMI <25 kg/m2 than overweight individuals (p for interaction = 0.058). After excluding cases diagnosed in the first year of follow up and their matched controls, this positive association persisted (p for trend = 0.037) and the interaction became statistically significant (p for interaction = 0.017). Our study adds additional evidence that the COX-2 pathway is involved in pancreatic carcinogenesis and suggests that urinary PGE-M may serve as a biomarker for predicting pancreatic cancer risk. PMID- 28815607 TI - A 3D tri-culture system reveals that activin receptor-like kinase 5 and connective tissue growth factor drive human glomerulosclerosis. AB - Glomerular scarring, known as glomerulosclerosis, occurs in many chronic kidney diseases and involves interaction between glomerular endothelial cells (GECs), podocytes, and mesangial cells (MCs), leading to signals that promote extracellular matrix deposition and endothelial cell dysfunction and loss. We describe a 3D tri-culture system to model human glomerulosclerosis. In 3D monoculture, each cell type alters its phenotype in response to TGFbeta, which has been implicated as an important mediator of glomerulosclerosis. GECs form a lumenized vascular network, which regresses in response to TGFbeta. MCs respond to TGFbeta by forming glomerulosclerotic-like nodules with matrix deposition. TGFbeta treatment of podocytes does not alter cell morphology but increases connective tissue growth factor (CTGF) expression. BMP7 prevents TGFbeta-induced GEC network regression, whereas TGFbeta-induced MC nodule formation is prevented by SMAD3 siRNA knockdown or ALK5 inhibitors but not BMP7, and increased phospho SMAD3 was observed in human glomerulosclerosis. In 3D tri-culture, GECs, podocytes, and MCs form a vascular network in which GECs and podocytes interact intimately within a matrix containing MCs. TGFbeta treatment induces formation of nodules, but combined inhibition of ALK5 and CTGF is required to prevent TGFbeta induced nodule formation in tri-cellular cultures. Identification of therapeutic targets for glomerulosclerosis depends on the 3D culture of all three glomerular cells. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28815608 TI - Factors associated with patient no-show rates in an academic otolaryngology practice. AB - OBJECTIVES/HYPOTHESIS: Factors affecting access to healthcare is an expanding area of research. This study seeks to identify factors associated with no-show rates in an academic otolaryngology practice to improve clinical efficiency and patient access to care. STUDY DESIGN: Retrospective review. METHODS: A retrospective review of scheduled clinical appointments from February 1, 2015 to January 30, 2016 at a single academic otolaryngology department was performed. Statistical analysis was completed to examine the association of no-show rates with the following: otolaryngology subspecialty, clinic location (e.g., main campus vs. satellite), patient demographic factors, attending seniority, temporal factors, insurance types, rurality, and visit type. RESULTS: There was an overall no-show rate of 20% for 22,759 scheduled clinic visits. Satellite clinics had the highest no-show rates at 25% (P < .001). New patient visits had the highest no show rate at 24% (P < .001). Among subspecialties, facial plastic surgery had the lowest no-show rate (12.6%), whereas Pediatrics had the highest (23%) (P < .001). No significant association between gender and no-show rates was observed (P = .29), but patients over 60 years old had the lowest no-show rate (12.7%, P < .0001). Patients with Medicaid (28%), Medicare (15.3%), and commercial insurance (12.9%) had significantly different overall no-show rates (P < .0001). CONCLUSIONS: Increased clinic no-show rates are associated with satellite clinics, new patient visits, younger age, and insurance type. No-show rates varied among subspecialties. Further investigation is warranted to assess barriers to appointment compliance and to develop interventions to improve access to care. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:626-631, 2018. PMID- 28815609 TI - The academic-practice gap: Strategies for an enduring problem. AB - The academic-practice gap in nursing is well documented. Academe is criticized for producing nurses insufficiently prepared to fully participate in patient care. Practice settings are criticized for having unrealistic expectations of new graduates. This article is based on a review of the literature and an exploration of contemporary practices used to bridge academic and practice partnerships. Differences in outcome expectations for new graduates between academe and practice are outlined and consequences of the gap for new graduates, patients, and employers are discussed. Five specific strategies to address the gap are discussed, with the primary realm and responsibility for two falling to education, one to practice, and two to both. Strategies discussed include increased use of simulated learning in nursing education; disruptive innovations in education that promote learner-centered active learning; extended orientation/Transition to Practice Programs for new graduates; dedicated education units; and academic service partnerships. Current literature suggests the viewpoints of academic and practice leaders continue to appear divergent. Closing the gap will require a dedicated and coordinated response from both academe and clinical practice. PMID- 28815610 TI - Growth responses to elevated temperatures and the importance of ontogenetic niche shifts in Bromeliaceae. AB - Epiphytic bromeliads represent a major component of Neotropical forests, but the potential effect of climate change on these plants is unclear. We investigated whether and how bromeliads are affected by the predicted 3 degrees C temperature rise by the end of the century. We conducted growth experiments with 17 epiphytic bromeliad species at different temperatures to determine their fundamental thermal niches. By comparing those with niches for germination, we tested whether ontogenetic niche shift or niche contraction occurs in Bromeliaceae. Applying a classical growth analysis, we assessed the relative importance of the underlying growth components on interspecific variations in growth. Members of two bromeliad subfamilies differed in their response to elevated temperatures: Tillandsioideae may be negatively affected, whereas Bromelioideae moved closer to their thermal optimum. Across different ontogenetic stages, thermal niche characteristics revealed both niche shift and niche contraction. Interspecific variation in growth was driven almost exclusively by net assimilation rate at all temperatures. We conclude that the vulnerability of tropical plants to a future increase in temperature may be more variable than suggested by previous studies. We emphasize the importance of assessing niche breadth over multiple life stages and the need for better microclimatic data to link laboratory data with field conditions. PMID- 28815611 TI - The value of frontal sinusotomy for chronic rhinosinusitis with nasal polyps-A cost utility analysis. AB - OBJECTIVES/HYPOTHESIS: The number of surgical procedures performed for frontal sinusitis and the associated costs have increased dramatically over the past decade. The purpose of this study was to evaluate the cost-effectiveness of endoscopic frontal sinusotomy (EFS) in patients with chronic rhinosinusitis with nasal polyposis (CRSwNP). STUDY DESIGN: Cohort-style Markov decision-tree economic model with a 36-year time horizon. METHODS: Matched cohorts of CRSwNP patients who underwent endoscopic sinus surgery (ESS) with (n = 139) and without (n = 49) EFS were compared to each other and to patients (n = 139) from the Medical Expenditures Survey Panel database who underwent medical management for chronic rhinosinusitis. Multi-year health utility values were calculated from responses to the EuroQol 5-Dimension instrument. The primary outcome measure was the incremental cost-effectiveness ratio (ICER). RESULTS: Decision analysis showed that ESS without EFS proved more cost-effective than ESS with EFS or medical management. ESS without EFS compared to medical management yielded an ICER of $9,004/quality-adjusted life year (QALY). ESS with EFS compared to ESS without EFS yielded an ICER of $62,310/QALY. At a willingness-to-pay (WTP) threshold of $50,000/QALY, ESS without EFS was more cost-effective than ESS with EFS with 52.1% certainty. These results were robust to one-way analysis and probabilistic sensitivity analysis. CONCLUSIONS: ESS remains a cost-effective intervention compared to medical therapy alone for patients with CRSwNP. In this study, the addition of frontal sinusotomy during ESS for patients with CRSwNP was not found to be cost-effective at a WTP threshold of $50,000/QALY, but may be cost effective at a higher threshold of $100,000/QALY. LEVEL OF EVIDENCE: 2c. Laryngoscope, 128:43-51, 2018. PMID- 28815612 TI - Network Analysis in Community Psychology: Looking Back, Looking Forward. AB - Network analysis holds promise for community psychology given the field's aim to understand the interplay between individuals and their social contexts. Indeed, because network analysis focuses explicitly on patterns of relationships between actors, its theories and methods are inherently extra-individual in nature and particularly well suited to characterizing social contexts. But, to what extent has community psychology taken advantage of this network analysis as a tool for capturing context? To answer these questions, this study provides a review of the use network analysis in articles published in American Journal of Community Psychology. Looking back, we describe and summarize the ways that network analysis has been employed in community psychology research to understand the range of ways community psychologists have found the technique helpful. Looking forward and paying particular attention to analytic issues identified in past applications, we provide some recommendations drawn from the network analysis literature to facilitate future applications of network analysis in community psychology. PMID- 28815613 TI - Switching off photoprotection of photosystem I - a novel tool for gradual PSI photoinhibition. AB - Photosystem I (PSI) has evolved in anaerobic atmospheric conditions and until today remains susceptible to oxygen. To minimize the probability of damaging side reactions, plants have evolved sophisticated mechanisms to control electron transfer, and PSI becomes inhibited only when malfunctions of these regulatory mechanisms occur. Because of the complicated induction of PSI photoinhibition, a detailed investigation into the process and following reactions are still largely missing. Here, we introduce the theoretical framework and a novel method for an easy and controlled induction of PSI photoinhibition in vivo. The method mimics the PSI damage mechanisms of fluctuating light-sensitive mutant plants (stn7, pgr5) which cannot control electron donation to PSI. Because PSII and PSI have different light absorption properties, electrons accumulate in the intersystem electron transfer chain (ETC), if PSII is preferentially excited. A saturating light pulse given upon an over-reduced ETC leads to the saturation of PSI electron acceptors, ultimately leading to the production of reactive oxygen species and photoinhibition of PSI. By adjusting the time of the light treatment, PSI can be gradually photoinhibited, providing a novel tool to holistically investigate the PSI photoinhibition phenomenon. PMID- 28815615 TI - Trans-methylation reactions in plants: focus on the activated methyl cycle. AB - Trans-methylation reactions are vital in basic metabolism, epigenetic regulation, RNA metabolism, and posttranslational control of protein function and therefore fundamental in determining the physiological processes in all living organisms. The plant kingdom is additionally characterized by the production of secondary metabolites that undergo specific hydroxylation, oxidation and methylation reactions to obtain a wide array of different chemical structures. Increasing research efforts have started to reveal the enzymatic pathways underlying the biosynthesis of complex metabolites in plants. Further engineering of these enzymatic machineries offers significant possibilities in the development of bio based technologies, but necessitates deep understanding of their potential metabolic and regulatory interactions. Trans-methylation reactions are tightly coupled with the so-called activated methyl cycle (AMC), an essential metabolic circuit that maintains the trans-methylation capacity in all living cells. Tight regulation of the AMC is crucial in ensuring accurate trans-methylation reactions in different subcellular compartments, cell types, developmental stages and environmental conditions. This review addresses the organization and posttranslational regulation of the AMC and elaborates its critical role in determining metabolic regulation through modulation of methyl utilization in stress-exposed plants. PMID- 28815614 TI - Resveratrol for Alzheimer's disease. AB - The amyloid hypothesis suggests that the progressive accumulation and deposition of central nervous system (CNS) amyloid with aging is the proximate cause of Alzheimer's disease (AD). Thus, targeting molecular mechanisms of aging may be a viable treatment approach. Caloric restriction prevents diseases of aging, including AD, in animal models, perhaps by activation of sirtuins. The sirtuins (e.g., mammalian SIRT1) are deacetylases that link energy balance (NAD+ /NADH) to regulation of gene transcription. Resveratrol is a potent activator of SIRT1, and thus may mimic caloric restriction to prevent diseases of aging. We conducted a randomized, double-blind, placebo-controlled, phase II trial of resveratrol for individuals with mild-to-moderate AD. Resveratrol (1) is detectable in cerebrospinal fluid (at low nanomolar levels), (2) is safe and well tolerated, (3) alters AD biomarker trajectories, (4) preserves blood-brain barrier integrity, and (5) modulates the CNS immune response. Further studies are needed to determine the safety and efficacy of resveratrol and the validity of this approach in the treatment and prevention of AD and other diseases of aging. PMID- 28815616 TI - Predictors of complicated airway foreign body extraction. AB - OBJECTIVES: To evaluate outcomes of foreign body aspiration (FBA) and to investigate surgeon and hospital volume as risk factors for a complicated course. STUDY DESIGN: Retrospective case series. METHODS: Children with FBA in a multihospital network were identified from January 2005 to September 2015. Demographic information, surgeon, and hospital location were reviewed. Mean operative time and hospital length of stay were recorded. Cases requiring intensive care unit admission, hospital stay greater than 24 hours, need for more than one bronchoscopy, operative time greater than 1 hour, or death were considered "complicated." RESULTS: A total of 450 cases of airway foreign body extraction were performed. Patient ages ranged from 0.6 to 18.8 years, with a median age of 1.9 years. Bronchoscopy with foreign body extraction was performed by 55 different surgeons at 11 different facilities. There were one to 24 surgeons for each facility, with an average number of 5.4 surgeons per facility. A total of 88 (19.6%) cases were considered complicated, including five (1.1%) deaths. Increased rates of complications were seen with unwitnessed aspiration (P = 0.008) and hyperlucency (P < 0.001) or infiltrates (P = 0.001) on chest radiographs. No significant association was found between surgeon type or facility as related to a complicated case. CONCLUSIONS: Unwitnessed aspiration events and abnormalities on chest radiograph may be associated with a more complicated course in children with FBA. This multihospital study identified a low number of procedures by many surgeons; however, surgeon and hospital volume did not significantly correlate with higher complication rates. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:490-495, 2018. PMID- 28815617 TI - Disparities in sinonasal squamous cell carcinoma short- and long-term outcomes: Analysis from the national cancer database. AB - OBJECTIVES/HYPOTHESIS: To examine sociodemographic, hospital-specific, and disease-related characteristics in relation to outcomes in sinonasal squamous cell carcinoma (SCC). STUDY DESIGN: The National Cancer Database was queried for location codes corresponding to the nasal cavity and paranasal sinuses and histology codes representing SCC malignancy. Multivariate analyses were performed against short- and long-term outcomes (overall survival, days to discharge, 30 day readmission, and 30- and 90-day mortality). RESULTS: The database included 5,584 sinonasal SCC patients with an overall median survival of 53.5 months (95% confidence interval [CI]: 49.7-57.8). On multivariate analysis, uninsured, Medicaid, and Medicare were independently associated with worse overall survival compared to private insurance (hazard ratio [HR]: 1.49, 95% CI: 1.22-1.82, P < .001; HR: 1.57, 95% CI: 1.34-1.85, P < .001; and HR: 1.14, 95% CI: 1.01-1.29, P = .03, respectively). Both Medicaid and Medicare were also associated with increased 30-day mortality (HR: 1.36, 95% CI: 1.76-143.29, P = .02; HR: 8.27, 95% CI: 1.66-70.88, P = .02, respectively), and Medicaid patients spent more time in the hospital following surgery (difference in days to discharge: HR: 2.09, 95% CI: 0.57-3.61, P < .01). Compared to white race, other race was associated with improved overall survival (HR: 0.79, 95% CI: 0.63-0.99, P = .04) but increased 30 day readmissions (HR: 3.85, 95% CI: 1.58-8.38, P < .01). Hispanic ethnicity was associated with increased 30-day readmissions (HR: 2.35, 95% CI: 1.08-4.75, P = .02]. The highest income bracket (>=$63,000) was associated with fewer hospital readmissions (HR: 0.33, 95% CI: 0.13-0.79, P = .01). CONCLUSIONS: Sociodemographic and economic differences in outcomes of patients with sinonasal SCC cancer exist. An understanding of these differences may help minimize disparities in oncologic treatment. LEVEL OF EVIDENCE: 2c. Laryngoscope, 128:560 567, 2018. PMID- 28815618 TI - Effect on gene expression of three allelic variants in GATA motifs of ABO, RHD, and RHCE regulatory elements. AB - BACKGROUND: Only a few genetic variants have been reported in regulatory elements of blood group genes. Most of them affect GATA motifs, binding sites for the GATA 1 transcription factor. STUDY DESIGN AND METHODS: Samples from two patients and one donor with unusual or discrepant serology for ABO, RhD, and RhCE antigens were analyzed by DNA sequencing. Analyzed regions included the coding sequence and portions of regulatory elements. The effect of some variants on gene expression was evaluated in reporter gene assays. RESULTS: Three new alleles were identified. Their key variants are located in the ABO Intron 1 enhancer, the RHD proximal promoter, and the RHCE proximal promoter. IVS1 + 5859A was found in an African American patient with a group O forward type and a group B reverse type. 5'UTR-115C was the only RHD variant sequence found in a mixed-race black and Caucasian prenatal patient showing mixed-field agglutination with anti-D. 5'UTR 83T was found in several black donors and patients in the context of the genetically related RHCE*ceBI and RHCE*ceSM alleles. Reporter assays of promoter constructs including 5'UTR-115C or 5'UTR-83T showed a significant reduction in RH gene expression. CONCLUSION: Three new alleles in the ABO, RHD, and RHCE genes consist of single-nucleotide changes within GATA motifs, emphasizing the key role of GATA transcription factors in the expression of blood group genes. PMID- 28815619 TI - Sluggish cognitive tempo in children and adolescents with higher functioning autism spectrum disorders: Social impairments and internalizing symptoms. AB - Sluggish cognitive tempo (SCT) was introduced in 1980s in the field of attention deficit hyperactivity disorder (ADHD). Studies indicate that symptoms of SCT are separate from symptoms of ADHD and independently associated with multiple domains of functioning in clinical groups and in typical development. We assessed whether similar pattern would apply to higher functioning autism spectrum disorders (ASD). Children with higher functioning ASD (N = 55; 5-15 years) were divided into the ASD+High SCT (n = 17), the ASD+Medium SCT (n = 18) and the ASD+Low SCT (n = 20) groups based on parent-rated daydreaming and slowness on the Five to Fifteen questionnaire (FTF). The groups were compared on SCT-related impairments found in previous studies: social skills, academic functioning, psychiatric symptoms, and processing speed. Assessment methods were the FTF, the Development and Well-Being Assessment, and the Coding subtest of the WISC-III. The ADHD symptoms were statistically controlled due to the overlap between SCT and ADHD. The ASD+High SCT and ASD+Medium SCT groups were significantly more likely to have the most pronounced social impairments, and the ASD+High SCT group had significantly higher rate of internalizing disorders compared to the ASD+Low SCT group. Our results suggest that children with higher functioning ASD and high or medium levels of SCT symptoms could be at higher risk for psychosocial impairments than children with higher functioning ASD with low levels of SCT symptoms. Co-occurring ADHD symptoms do not explain the finding. Recognizing SCT symptoms in higher functioning ASD would be important to targeting preventive support. PMID- 28815620 TI - One- and two-sample t tests. PMID- 28815621 TI - Red blood cell sedimentation of Apheresis Granulocytes. AB - Sedimentation of Apheresis Granulocyte components removes red blood cells. It is used to increase the blood donor pool when blood group-compatible donors cannot be recruited for a patient because of a major ABO incompatibility or incompatible red blood cell antibodies in the recipient. Because granulocytes have little ABO and few other red blood cell antigens on their membrane, such incompatibility lies mostly with the contaminating red blood cells. Video Clip S1 shows the process of red blood cell sedimentation of an Apheresis Granulocyte component. This video was filmed with a single smart phone attached to a commercial tripod and was edited on a tablet computer with free software by an amateur videographer without prior video experience. PMID- 28815622 TI - Selling Innovations Like Soap: The Interactive Systems Framework and Social Marketing. AB - Despite the popularity and noted utility of Wandersman and colleagues' (2008) Interactive Systems Framework, the literature currently provides a primary focus on delivery organizations' and supportive stakeholders' capacities and strategies to implement innovations, presenting a critical gap in understanding. Unfortunately, reflective of a larger void in community dissemination and implementation efforts, there is a more limited focus on the dissemination of innovations. This paper presents the social marketing literature as a supplement to the Prevention Synthesis and Translation System (PSTS), the system responsible for dissemination. The study and practice of innovation synthesis and translation is examined in the literature; and based on the conclusions drawn, social marketing theory is used to provide a systematic approach to improving dissemination within the Interactive Systems Framework. Specifically, three gaps related to the PSTS are identified in the literature that align with and can be filled using social marketing. Social marketing is defined and presented as a supplement by providing theory and practices, within a systems context, for effectively communicating and influencing change. By blending social marketing with the Interactive Systems Framework, the aim is to improve the understanding of strategic communication and its role in the effective dissemination, and subsequent implementation, of innovations. PMID- 28815623 TI - Housing and Child Welfare: Emerging Evidence and Implications for Scaling up Services. AB - Inadequate housing threatens family stability in communities across the United States. This study reviews emerging evidence on housing interventions in the context of scale-up for the child welfare system. In child welfare, scale-up refers to the extent to which fully implemented interventions sustainably alleviate family separations associated with housing instability. It incorporates multiple aspects beyond traditional measures of effectiveness including costs, potential reach, local capacities for implementation, and fit within broader social services. The framework further encompasses everyday circumstances faced by service providers, program administrators, and policymakers who allocate resources under conditions of scarcity and uncertainty. The review of current housing interventions reveals a number of systemic constraints for scale-up in child welfare. Reliance on rental assistance programs limits capacity to address demand, while current practices that target the most vulnerable families may inadvertently diminish effectiveness of the intervention and increase overall demand. Alternative approaches that focus on homelessness prevention and early intervention must be tested in conjunction with community initiatives to increase accessibility of affordable housing. By examining system performance over time, the scalability framework provides an opportunity for more efficient coordination of housing services within and outside of the child welfare system. PMID- 28815624 TI - Morbidity and mortality in children undergoing bronchoscopy for foreign body removal. AB - OBJECTIVES/HYPOTHESIS: Analyze morbidity and mortality among children undergoing bronchoscopy for foreign body removal. STUDY DESIGN: Multicenter retrospective review using the American College of Surgeons Pediatric National Surgical Quality Improvement Program from 2014 and 2015. METHODS: Patients were identified using Current Procedural Terminology code 31635. Demographics, time to surgery, operative times, hospitalization time, and complications were collected. Multivariate logistic regression was used to identify predictive factors for major adverse events. RESULTS: Three hundred thirty-four patients were included (mean age 3.7 years, 59.0% male). Preoperative sepsis syndrome was present in 5.7% of patients and 8.1% had asthma. Of the patients, 5.1% percent of patients had a tracheostomy. Bronchoscopy was performed by an otolaryngologist (65.4%) or a pediatric surgeon (33.1%). Mean operative time was 27.4 minutes, whereas mean total operating room time was 54.6 minutes. Airway foreign bodies were located in 269 patients (80.5%), with 62.5% being located in the mainstem bronchus. Operative time was longer when foreign bodies were in the mainstem bronchus or distal to it. Mean time to surgery from admission was 0 days, and mean duration of hospitalization was 1 day. One patient (0.3%) required reoperation for respiratory reasons, and three (0.9%) required readmission for related reasons. No patients remained hospitalized at 30 days. Two (0.6%) had a postoperative pneumonia, and two (0.6%) required reintubation. One patient death (0.3%) occurred within 2 weeks of bronchoscopy. No significant differences were identified in operative time, time to surgery, or hospitalization time based on age, gender, presence of a tracheostomy, or surgical specialty. CONCLUSIONS: Bronchoscopy for identification and removal of airway foreign bodies had minimal morbidity in this group. LEVEL OF EVIDENCE: 2b. Laryngoscope, 128:1226-1229, 2018. PMID- 28815626 TI - Preliminary quantification of the permeability, solubility and diffusion coefficients of major aroma compounds present in herbs through various plastic packaging materials. AB - BACKGROUND: Aroma permeation through packaging material is an important factor when designing a package for food products. The masses of aroma compounds permeating through films over time were measured at 25 degrees C using a quasi isostatic system. A model was proposed for estimating the permeability coefficients (P) of key aroma compounds present in fresh herbs (i.e. eucalyptol, estragole, linalool and citral) through major plastic films used by the food industry [i.e. low-density polyethylene (LDPE), polypropylene (PP), nylon (Nylon), polyethylene terephthalate (PET), metalised-polyethylene terephthalate (MPET) and poly(lactic acid) (PLA)]. Solubility coefficients (S) were estimated from the amount of aroma compound sorbed in the films. Diffusion coefficients (D) were estimated following from the relation P = D*S. RESULTS: P and D for all four aroma compounds were highest in LDPE, except for eucalyptol, which P was slightly higher in PLA. The solubility coefficients and contact angles were highest in PLA suggesting the highest affinity of PLA to these aroma compounds. The theoretical solubility parameters were correlated with the solubility coefficients for estragole and citral, but not for eucalyptol and linalool. CONCLUSION: The preliminary P, D and S of eucalyptol, estragole, linalool and citral through LDPE, PP, Nylon, PET, MPET and PLA can be useful in selecting the proper packaging material for preserving these specific aroma compounds in food products and can potentially be used for estimating the shelf life of food products based on aroma loss. (c) 2017 Society of Chemical Industry. PMID- 28815627 TI - Should infants who fail their newborn hearing screen undergo cytomegalovirus testing? PMID- 28815625 TI - Association of transcallosal motor fibres with function of both hands after unilateral neonatal arterial ischemic stroke. AB - AIM: The objective of this study was to investigate the involvement of the motor fibres of the corpus callosum after unilateral neonatal arterial ischemic stroke (NAIS) of the middle cerebral artery territory and the relationship to both ipsilesional and contralesional hand function. METHOD: Using high-resolution structural magnetic resonance imaging (MRI), functional MRI, and magnetic resonance diffusion-tractography, we compared the midsagittal area of the motor part of the corpus callosum (defined by the fibres connecting the precentral gyri) between 33 7-year-old children after unilateral NAIS and 31 typically developing 7-year-old children. Hand motor performance was assessed by the box and blocks test. RESULTS: Children after NAIS showed on average significantly smaller motor corpus callosum area compared to typically developing children (p<0.001, without differences of the non-motor corpus callosum area). In addition, there was a significant positive association between the motor part of the corpus callosum and both contralesional (Pr(>|t|)=0.034) and ipsilesional hand motor performance (Pr(>|t|)=0.006) after controlling for lesion volume and sex. In a post-hoc analysis the additional contribution of corticospinal tract damage was evaluated. INTERPRETATION: Compared to typically developing children, children after NAIS exhibited a smaller motor part of their corpus callosum associated with reduced contralesional but also ipsilesional manual dexterity. These results indicate that the affection of transcallosal motor fibres in unilateral NAIS might be of functional relevance and an important part of the involved structural network that should be elucidated in further studies. PMID- 28815628 TI - The Use of IC50 for Potency and MTD as Objective in Study BIA 10-2474. PMID- 28815629 TI - Impulsive Decision Making in Young Adult Social Drinkers and Detoxified Alcohol Dependent Patients: A Cross-Sectional and Longitudinal Study. AB - BACKGROUND: Impulsive decision making relates to problematic substance use. Specifically, altered delay discounting (DD) has been suggested as a behavioral marker for addiction, while other relevant facets of choice impulsivity such as probability discounting (PD) or loss aversion are clearly understudied. METHODS: Two studies were performed collecting behavioral data on choice impulsivity with a value-based decision-making battery providing estimates of DD, PD for gains and losses, and loss aversion. Study (1): In a sample of 198 male 18-year-old social drinkers, we analyzed impulsive choice behavior and its association with alcohol consumption and self-report measures of substance use-related personality traits on a cross-sectional level. Additionally, the predictive value of baseline choice behavior for the trajectories of alcohol consumption over a 12-month follow-up period was evaluated. Study (2): Behavioral data on choice impulsivity were collected for 114 detoxified patients with alcohol use disorder (AUD) and 98 control participants. We analyzed group differences at baseline and assessed the predictive value of choice impulsivity for relapse to heavy alcohol use in patients during a follow-up period of 48 weeks. RESULTS: Study (1): Only DD was associated with baseline alcohol use, but no measure of choice impulsivity predicted the drinking trajectories over the following 12 months. Study (2): Compared to the control group, AUD patients showed higher DD, lower risk aversion regarding probabilistic gains, lower risk seeking regarding probabilistic losses, and lower loss aversion facing mixed prospects. Further, shallow discounting of probabilistic losses at baseline was predictive for relapse in patients. CONCLUSIONS: All 4 domains of impulsive decision making were considerably altered in AUD patients though mostly not related to alcohol use in young adult social drinkers. This suggests that these facets of impulsive behavior may develop as consequences of chronic alcohol consumption. Furthermore, discounting of probabilistic losses might prove valuable in identifying patients vulnerable for relapse. PMID- 28815630 TI - CAREGIVER-CHILD INTERACTION, CAREGIVER TRANSITIONS, AND GROUP SIZE AS MEDIATORS BETWEEN INTERVENTION CONDITION AND ATTACHMENT AND PHYSICAL GROWTH OUTCOMES IN INSTITUTIONALIZED CHILDREN. AB - This report describes a secondary analysis of data from a comprehensive intervention project which included training and structural changes in three Baby Homes in St. Petersburg, Russian Federation. Multiple mediator models were tested according to the R.M. Baron and D.A. Kenny () causal-steps approach to examine whether caregiver-child interaction quality, number of caregiver transitions, and group size mediated the effects of the intervention on children's attachment behaviors and physical growth. The study utilized a subsample of 163 children from the original Russian Baby Home project, who were between 11 and 19 months at the time of assessment. Results from comparisons of the training and structural changes versus no intervention conditions are presented. Caregiver-child interaction quality and number of caregiver transitions fully mediated the association between intervention condition and attachment behavior. No other mediation was found. Results suggest that the quality of interaction between caregivers and children in institutional care is of primary importance to children's development, but relationship context may play a less direct mediational role, supporting caregiver-child interactions. PMID- 28815631 TI - Comparison and interpretability of the available urticaria activity scores. AB - The urticaria activity score (UAS) is the gold standard for assessing disease activity in patients with chronic spontaneous urticaria (CSU). Two different versions, the UAS7 and UAS7TD , are currently used in clinical trials and routine care. To compare both versions and to obtain data on their interpretability, 130 CSU patients applied both versions and globally rated their disease activity as none, mild, moderate, or severe. UAS7 and UAS7TD values correlated strongly (r = .90, P < .001). Interquartile ranges for UAS7 and UAS7TD values for mild, moderate, and severe CSU were 11-20 and 10-24, 16-30 and 16-32, and 27-37 and 28 40. UAS7 values were slightly, but significantly lower as compared to UAS7TD values (mean difference: 1.6 +/- 4.6, P < .001). This difference was driven by lower wheal subscores (2.1 +/- 3.5, P < .001) and was most pronounced in patients with severe CSU (2.5 +/- 5.6, P < .01). The UAS7/UAS7TD ratio was 0.96 +/- 0.21 and did not differ significantly between mild, moderate, and severe CSU. Since the results of both UAS versions are comparable, we recommend the use of the UAS7, which is less burdensome in administration and scoring. PMID- 28815632 TI - Uniform-sized neurosphere-mediated motoneuron differentiation in microwell arrays. AB - We developed the photocrosslinkable hydrogel microwell arrays for uniform-sized neurosphere-mediated motoneuron differentiation. Neural stem cells (NSCs) were obtained from embryonic cerebral cortex and spinal cord. To generate uniform sized neurospheres in a homogeneous manner, the dissociated cells were cultured in the hydrogel microwell arrays for 3 days. Uniform-sized neurospheres harvested from microwell arrays were replated into laminin-coated substrate. In parallel, uniform-sized neurospheres cultured in microwell arrays were encapsulated by photocrosslinkable gelatin methacrylate hydrogels in a three-dimensional manner. We demonstrated the effect of hydrogel microwell sizes (e.g., 50, 100, 150 MUm in diameter) on motoneuron differentiation, showing that the largest uniform-sized neurospheres derived from embryonic spinal cord efficiently differentiated into motoneurons. Therefore, this hydrogel microwell array could be a powerful array to regulate the uniform-sized neurosphere-mediated motoneuron differentiation. PMID- 28815633 TI - The gas that fuels the engine: Individuals' motivations for medicalisation. AB - It is well established that the drivers of medicalisation have shifted alongside changes in the institution of medicine. The process of medicalisation is no longer incited by macro processes of institutional prestige or control; rather, individual patients/consumers are pushing the process forward. The present study complicates this neat transition and examines the relationship between structure and agency using the case of assisted reproductive technology (ART), specifically the medicalisation of lesbian reproduction in the US. I explore individuals' influence on and motivations towards medicalisation through 24 in-depth interviews with women in same-sex relationships who had ever attempted to become pregnant. In centring on their experiences, I find that while individual consumers may now propel medicalisation forward, oftentimes consumers' motivations for doing so reside in the prestige and control of medicine. In other words, consumers now seek medicalisation precisely because of the process's previous institutional drivers. In exploring what fuels the engine of medicalisation, the findings reveal its nuance and complexity. PMID- 28815634 TI - Effect of trapping methods on the estimation of alpha diversity of a phlebotomine sandfly assemblage in southern Mexico. AB - The aims of the study were to (a) investigate the effect of trapping methods on alpha diversity; and (b) enhance the knowledge of the sandfly assemblage in the state of Quintana Roo. Field work was undertaken in a tropical forest of southern Mexico from August 2013 to July 2014. Sampling was conducted monthly during three consecutive nights. For each trapping night, 12 different types of trap were operated from 18.00 to 24.00 hours in four transects. Measures of alpha community diversity were based on the quantification of the number of species (Chao 2, Jackknife 2, Clench's equation, Margalef's index) and the community structure, as well as the dominance (Simpson and Berger-Parker indexes) and evenness (Shannon's entropy index, true diversity of the Jost and Pielou index). With a total sampling effort of 1728 night-traps, 16 101 phlebotomine sandflies were collected; they represented two genera and 13 species. Diversity estimates of 100% (Chao 2 and Clench's equation) and 85% (Jackknife 2) of potential species in the study area were calculated. Shannon traps and CDC light traps indicated the largest number of species, but only Shannon traps showed the greatest abundance. This inventory of sandflies is an important activity to enhance our knowledge of sandfly assemblages and guilds. The ultimate goal of studying alpha diversity in sandflies would be to have a better understanding of the population dynamics and all complex networks of interactions that may, in turn, be associated with the epidemiology of the disease. PMID- 28815636 TI - Muslims' tolerance towards outgroups: Longitudinal evidence for the role of respect. AB - We employed a longitudinal design to test two hypotheses concerning Muslims' respect for and tolerance towards disapproved outgroups. In support of the outgroup respect-tolerance hypothesis derived from the disapproval-respect model of social tolerance, our results strongly suggest that respect for disapproved outgroups is not just a correlate of tolerance towards those groups, but a causal antecedent. In support of the intergroup respect-reciprocity hypothesis, we identified respect from disapproved outgroups as an effective source of respect for disapproved outgroups and therefore also as a (distal) source of tolerance towards those groups. Normative and political implications are discussed. PMID- 28815635 TI - Associations Between Genomic Variants in Alcohol Dehydrogenase Genes and Alcohol Symptomatology in American Indians and European Americans: Distinctions and Convergence. AB - BACKGROUND: Higher rates of alcohol use disorders (AUD) have been observed in some Native American populations than other ethnic groups such as European Americans (EAs) in the United States. Previous studies have shown that variation in the alcohol dehydrogenase (ADH) genes may affect the risk for development of AUD and that the prevalence of these variants differs depending on the ancestral origins of a population. METHODS: In this study, we assessed sequencing variants in the ADH genomic region (ADH1-7) and tested for their associations with AUD phenotypes in 2 independent populations: an American Indian (AI) community sample and an EA cohort from the San Francisco Family Alcohol Study. Association tests were conducted for both common and rare variants using sequencing data for 2 phenotypes: the number of alcohol-related life events and the count of alcohol dependence drinking symptoms. A regularized regression method was used to select the best set of ADH variants associated with phenotypes. Variance component model was incorporated in all analyses to leverage the admixture and relatedness. RESULTS: Two variants near ADH4 and 2 near ADH1C exhibited significant associations with AUD in AIs; no variant was significant in EAs. Common risk variants in AIs were either absent from or much less frequent in EAs. The feature selection method selected mostly distinct yet often colocated subsets of ADH variants to be associated with AUD phenotypes between the 2 cohorts. In the rare variant analyses, the only association was observed between the whole region and the alcohol-related life events in AIs. CONCLUSIONS: Our results suggest that ADH variants, both common and rare, are more likely to impact risk for alcohol related symptomatology in this AI population than in this EA sample, and ADH variants that might affect AUD are likely different but convergent on similar regions between the 2 populations. PMID- 28815637 TI - Synergistic antibacterial and antibiofilm efficacy of nisin in combination with p coumaric acid against food-borne bacteria Bacillus cereus and Salmonella typhimurium. AB - : The aim of the study was to evaluate possible antibacterial and antibiofilm efficacy of a bacteriocin, nisin with two essential oil components linalool and p coumaric acid in combination against food-borne bacteria Bacillus cereus and Salmonella typhimurium. Their inhibition effects on planktonic cells and preformed biofilms were evaluated using microbroth dilution and checkerboard titration methods. Nisin/p-coumaric acid combination showed synergistic effects against planktonic cells of both the studied bacteria, whereas nisin/linalool combination showed synergistic activity against B. cereus and additive effect against S. typhimurium. In preformed biofilms, nisin by itself failed to show >50% antibiofilm efficacy against both the studied bacteria, but in combination with linalool and p-coumaric acid, it exerted >50% antibiofilm efficacy. On the basis of fractional inhibitory concentration indices values, nisin/p-coumaric acid combination exhibited synergistic antibiofilm activity, whereas nisin/linalool combination showed additive effects against preformed biofilms of studied bacteria. The results provide evidence that p-coumaric acid due to its synergistic interactions with nisin against planktonic cells and biofilms of both Gram-positive and Gram-negative food-borne bacteria enhanced the antibacterial spectrum of nisin, which subsequently may facilitate their use in the food industry. SIGNIFICANCE AND IMPACT OF THE STUDY: In the present work, synergistic interactions between a bacteriocin, nisin and essential oil component p-coumaric acid on planktonic cells as well as on biofilms of Gram-positive and Gram negative food-borne bacteria have been reported. The results of this study provide evidence that nisin/p-coumaric acid combination can be considered as a promising source for development of more potent broad spectrum antimicrobial blend for food preservation, which subsequently may facilitate their use in the food industry. To the best of our knowledge, this is the first report of the antibacterial and antibiofilm efficacy of nisin in combination with essential oil components against food-borne bacteria. PMID- 28815638 TI - New insights into the origin and the genetic status of the Balkan donkey from Serbia. AB - The Balkan donkey (Equus asinus L.) is commonly regarded as a large-sized, unselected, unstructured and traditionally managed donkey breed. We assessed the current genetic status of the three largest E. asinus populations in the central Balkans (Serbia) by analysing the variability of nuclear microsatellites and the mitochondrial (mtDNA) control region of 77 and 49 individuals respectively. We further analysed our mtDNA dataset along with 209 published mtDNA sequences of ancient and modern individuals from 19 European and African populations to provide new insights into the origin and the history of the Balkan donkey. Serbian donkey populations are highly genetically diverse at both the nuclear and mtDNA levels despite severe population decline. Traditional Balkan donkeys in Serbia are rather heterogeneous; we found two groups of individuals with similar phenotypic features, somewhat distinct nuclear backgrounds and different proportions of mtDNA haplotypes belonging to matrilineal Clades 1 and 2. Another group, characterized by larger body size, different coat colour, distinct nuclear gene pool and predominantly Clade 2 haplotypes, was delineated as the Banat donkey breed. The maternal landscape of the large Balkan donkey population is highly heterogeneous and more complex than previously thought. Given the two independent domestication events in donkeys, multiple waves of introductions into the Balkans from Greece are hypothesized. Clade 2 donkeys probably appeared in Greece prior to those belonging to Clade 1, whereas expansion and diversification of Clade 1 donkeys within the Balkans predated that of Clade 2 donkeys. PMID- 28815639 TI - Safety, Tolerability, and Pharmacokinetic Characteristics of a Novel Nonopioid Analgesic, VVZ-149 Injections in Healthy Volunteers: A First-in-Class, First-in Human Study. AB - VVZ-149, a dual antagonist of GlyT2 and 5HT2 A receptors, is an investigational analgesic with a novel mechanism of action that is currently under early-stage clinical development as an injectable agent for the treatment of postoperative pain. Here, the safety, tolerability, and pharmacokinetics of VVZ-149 injections in healthy male volunteers were explored in a randomized, double-blind, single- and multiple-ascending-dose (SAD and MAD, respectively), placebo-controlled clinical study. Subjects randomly received a 4-hour intravenous infusion of 0.25 8 mg/kg VVZ-149 or placebo in the SAD study (n = 46) or a 4-hour intravenous infusion of 4-7 mg/kg VVZ-149 or placebo twice daily for 3 days in the MAD study (n = 20). Serial blood and urine samples were collected for the pharmacokinetic analysis of VVZ-149 and its active metabolite (VVZ-368). Noncompartmental and compartmental pharmacokinetic analyses were performed. Various dosing scenarios were simulated to identify the adequate dosing regimen for the subsequent trials. Plasma exposure to VVZ-149 and VVZ-368 showed a dose-proportional increase. VVZ 149 did not accumulate in the plasma, whereas the plasma concentration of VVZ-368 increased by 1.23- to 2.49-fold after the fifth and sixth doses, respectively, in the MAD trial. Among the simulated dosing regimens, a loading dose followed by a maintenance dose was found to be an optimal dosing regimen, yielding the effective concentration estimated from animal studies in rat models of neuropathic or inflammatory pain. Single- or multiple-dose administration of VVZ 149 was generally well tolerated. These results showed that 0.5-8 mg/kg VVZ-149 exhibited linear pharmacokinetic characteristics and can be safely administered in further clinical studies. PMID- 28815640 TI - In vitro genotoxicity of airborne Ni-NP in air-liquid interface. AB - Studies using advanced toxicological methods enabling in vitro conditions that are more realistic are currently needed for understanding the risks of pulmonary exposure to airborne nanoparticles. Owing to the carcinogenicity of certain nickel compounds, the increased production of nickel nanoparticles (Ni-NPs) raises occupational safety concerns. The aim of this study was to investigate the genotoxicity of airborne Ni-NPs using a recently developed air-liquid interface exposure system. The wild-type Chinese hamster lung fibroblast cell line (V79) was used and cytotoxicity, DNA damage and mutagenicity were studied by testing colony forming efficiency, alkaline DNA unwinding and HPRT mutation assays, respectively. Additionally, co-exposure to a PARP-1 inhibitor was performed to test possible involvement of base excision repair (BER) in repair of Ni-induced DNA damage. The results showed that cell viability was reduced significantly (to 45% and 46%) after 48 hours Ni-NP exposure at concentrations of 0.15 and 0.32 MUg cm-2 . DNA damage was significantly increased after Ni-NP exposure in the presence of the BER inhibitor indicating that Ni-NP-induced DNA damages are subsequently repaired by BER. Furthermore, there was no increased HPRT mutation frequency following Ni-NP exposure. In conclusion, this study shows that Ni-NP treatment of lung fibroblasts in an air-liquid interface system that mimics real life exposure, results in increased DNA strand breaks and reduced cellular viability. These DNA lesions were repaired with BER in an error-free manner without resulting in mutations. This study also underlines the importance of appropriate quantification of the actual exposure concentrations during air liquid interface exposure studies. PMID- 28815641 TI - Advances in Capillary Electrophoretically Mediated Microanalysis for On-line Enzymatic and Derivatization Reactions. AB - This review summarizes recent developments, applications, and innovations of capillary electrophoretically mediated microanalysis methods. As a follow up of an earlier review, it covers the literature from early 2015 to early 2017. This article is divided into three parts. In the first part, different types of mixing procedures and applications of enzyme mediated microanalysis are discussed; the second part summarizes immobilized enzyme reactors (IMERs), while the third part deals with recent advances in on-line derivatization reactions. PMID- 28815642 TI - NOX4- and Nrf2-mediated oxidative stress induced by silver nanoparticles in vascular endothelial cells. AB - It has been widely reported that silver nanoparticles (AgNPs) induce oxidative stress in various cell lines. However, the mechanism for this effect and its consequences for cellular signaling are poorly understood. In this study, human umbilical vein endothelial cells (HUVECs) were used to assess the toxicity and investigate the associated molecular mechanisms caused by exposure to AgNPs. We demonstrated that AgNP exposure significantly and dose-dependently decreased the cell viability, induced reactive oxygen species (ROS) generation and led to early apoptosis in HUVECs. Our findings showed that AgNPs induced excess ROS production that affected the signaling pathways by a mechanism that depended on activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity through upregulation of NADPH oxidase 4 (NOX4) protein expressions. Moreover, AgNPs could disrupt the inactivation of the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant response, which is considered another important element for oxidative stress caused by AgNPs in HUVECs. The redox imbalance between NOX4 and Nrf2 was an important cause for the ROS overproduction that led to cell injury in HUVECs. The results provided insight into the mechanisms of oxidative stress induced by AgNPs in vascular endothelial cells. PMID- 28815643 TI - Early intervention with non-ablative fractional laser to improve cutaneous scarring-A randomized controlled trial on the impact of intervention time and fluence levels. AB - BACKGROUND AND OBJECTIVES: Laser treatment in the early phases of wound healing may reduce scar formation. However, little is known on when in the early wound healing phases laser exposure most optimally should be provided and at which fluence levels. This study investigates the clinical effect of non-ablative fractional-laser (NAFL) performed at three early time points at a range of fluence levels versus untreated control scars. MATERIALS AND METHODS: A randomized, controlled, intra-individual trial with erbium-glass 1,540 nm NAFL versus no laser treatment on sixteen subjects receiving 10 standardized full thickness punch-biopsy wounds. A single NAFL-exposure was applied to test-wounds 1 day before, immediately after, or 2 weeks after wounding. Three fluence levels provided deep and superficial energy depositions (range 30-70 mJ/microbeam). Primary outcome comprised the total-score of the observer part of Patient Observer-Scar-Assessment-Scale (POSAS), performed by blinded on-site assessment at 3 months follow-up. Secondary outcomes were clinical evaluation on visual analogue-scale (VAS), reflectance measurements, and histology. RESULTS: NAFL treatment applied 1 day before, immediately after or 2 weeks after wounding had the potential to offer subtle but detectable improvement in clinical scar appearance compared to untreated controls. Thus, NAFL-exposure 1 day before wounding (POSAS-total: median of 15 vs. control-median of 16, P = 0.03, VAS: median 4.1 vs. control-median 5.5, P = 0.03, medium-fluence), as well as immediately-, and 2 weeks after wounding (POSAS-total: P <= 0.05, low-fluence) induced improvement compared to untreated controls. No significant differences in dyschromia were detected between NAFL-treated and control scars. Histology showed subtle changes towards more mature interwoven bundles of collagen in NAFL-treated scars as compared to controls. CONCLUSIONS: This study indicates that a single NAFL-treatment at low to medium fluence performed 1 day prior, or in the early phases of wound healing, may have the potential to optimize scar formation in full thickness wounds. Lasers Surg. Med. 50:28-36, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28815644 TI - Role of gammadelta T cells in exacerbated airway inflammation during reinfection of neonatally primed mice in adulthood. AB - Age at primary infection with respiratory syncytial virus (RSV) is a crucial factor in determining the outcome of reinfection. However, how neonatal RSV infection affects the immune system and renders the host more susceptible to reinfection in later life is poorly understood. In the present study, by using BALB/c mice that were first infected with RSV as neonates, the role of gammadelta T cells in the development of airway inflammation during reinfection in adulthood was investigated. We found that neonatal RSV infection resulted in an aggravated infiltration of mononuclear cells in bronchoalveolar lavage (BAL) fluids, in parallel with a significant increase in the levels of type 2 cytokines in lungs on day 4 after reinfection. Since the numbers of total gammadelta T cells as well as activated gammadelta T cells, particularly IL-4-, IL-5-, and IL-13-producing gammadelta T cells, were enhanced markedly in the lungs of neonatally primed mice, we speculate that gammadelta T cells might participate in the augmented airway inflammation seen during reinfection. Indeed, depletion of gammadelta T cells attenuated the severity of lung histopathology during reinfection. Meanwhile, treatment of neonatal mice with anti-TCRdelta mAb diminished not only the numbers of neutrophils, eosinophils, and lymphocytes, but also the levels of IL-4, IL-5, and IL-13 in the lungs after reinfection in adulthood, suggesting that gammadelta T cells, particularly Th2-type gammadelta T cells might play a critical role in exacerbating the pulmonary tissue pathology during reinfection of adult mice that were first infected as neonates. PMID- 28815647 TI - Wildlife disease ecology from the individual to the population: Insights from a long-term study of a naturally infected European badger population. AB - Long-term individual-based datasets on host-pathogen systems are a rare and valuable resource for understanding the infectious disease dynamics in wildlife. A study of European badgers (Meles meles) naturally infected with bovine tuberculosis (bTB) at Woodchester Park in Gloucestershire (UK) has produced a unique dataset, facilitating investigation of a diverse range of epidemiological and ecological questions with implications for disease management. Since the 1970s, this badger population has been monitored with a systematic mark-recapture regime yielding a dataset of >15,000 captures of >3,000 individuals, providing detailed individual life-history, morphometric, genetic, reproductive and disease data. The annual prevalence of bTB in the Woodchester Park badger population exhibits no straightforward relationship with population density, and both the incidence and prevalence of Mycobacterium bovis show marked variation in space. The study has revealed phenotypic traits that are critical for understanding the social structure of badger populations along with mechanisms vital for understanding disease spread at different spatial resolutions. Woodchester-based studies have provided key insights into how host ecology can influence infection at different spatial and temporal scales. Specifically, it has revealed heterogeneity in epidemiological parameters; intrinsic and extrinsic factors affecting population dynamics; provided insights into senescence and individual life histories; and revealed consistent individual variation in foraging patterns, refuge use and social interactions. An improved understanding of ecological and epidemiological processes is imperative for effective disease management. Woodchester Park research has provided information of direct relevance to bTB management, and a better appreciation of the role of individual heterogeneity in disease transmission can contribute further in this regard. The Woodchester Park study system now offers a rare opportunity to seek a dynamic understanding of how individual-, group- and population-level processes interact. The wealth of existing data makes it possible to take a more integrative approach to examining how the consequences of individual heterogeneity scale to determine population-level pathogen dynamics and help advance our understanding of the ecological drivers of host-pathogen systems. PMID- 28815645 TI - Lenalidomide as second-line therapy for advanced hepatocellular carcinoma: exploration of biomarkers for treatment efficacy. AB - BACKGROUND: Lenalidomide has immunomodulatory and anti-angiogenic effects and showed moderate anti-tumour efficacy in patients with. advanced hepatocellular carcinoma (HCC) AIM: To explore potential biomarkers of lenalidomide efficacy as second-line therapy for HCC. METHODS: Eligible patients were diagnosed with advanced HCC, documented progression on sorafenib, and Child-Pugh class A liver function. Patients received 25 mg/day lenalidomide orally on days 1-21 every 4 weeks. The primary endpoint was 6 month progression-free survival rate. Early alpha-fetoprotein response was defined as a > 20% decline of alpha-fetoprotein levels from baseline within the first 4 weeks of treatment. Vascular response, evaluated using dynamic contrast-enhanced magnetic resonance imaging, was defined as a > 40% decline in Ktrans after 2 weeks of treatment. The percentage of peripheral blood lymphocyte subsets were also analysed. RESULTS: Fifty-five patients were enrolled. The response rate was 13%, and the disease-control rate was 53%. The 6 month progression-free survival rate was 9.1%. The median progression-free and overall survival was 1.8 months and 8.9 months respectively. Early alpha-fetoprotein response was significantly associated with higher disease control rate (76% vs 22%, P = .001) and longer progression-free survival (P = .020). Vascular response was not associated with any treatment outcomes. Patients with a high pre-treatment B cell percentage were more likely to have disease control (70% vs 36%, P = .010) and exhibited longer progression-free survival (P < .001) and overall survival (P = .042). CONCLUSIONS: Lenalidomide exhibited moderate activity as second-line therapy for advanced HCC. Its immunomodulatory effects should be further explored (www.clinicaltrials.gov NCT01545804). PMID- 28815646 TI - A novel endpoint for the assessment of chemotherapy-induced peripheral neuropathy in rodents: biomechanical properties of peripheral nerve. AB - Chemotherapy-induced peripheral neuropathy (CiPN) is a frequent adverse effect in patients and a leading safety consideration in oncology drug development. Although behavioral assessment and microscopic examination of the nerves and dorsal root ganglia can be incorporated into toxicity studies to assess CiPN risk, more sensitive and less labor-intensive endpoints are often lacking. In this study, rats and mice administered vincristine (75 MUg kg-1 day-1 , i.p., for 10 days in rats and 100 MUg kg-1 day-1 , i.p., for 11 days in mice, respectively) were employed as the CiPN models. Behavioral changes were assessed during the dosing phase. At necropsy, the sural or sciatic nerve was harvested from the rats and mice, respectively, and assessed for mechanical and histopathological endpoints. It was found that the maximal load and the load/extension ratio were significantly decreased in the nerves collected from the animals dosed with vincristine compared with the vehicle-treated animals (P < 0.05). Additionally, the gait analysis revealed that the paw print areas were significantly increased in mice (P < 0.01), but not in rats following vincristine administration. Light microscopic histopathology of the nerves and dorsal root ganglia were unaffected by vincristine administration. We concluded that ex vivo mechanical properties of the nerves is a sensitive endpoint, providing a new method to predict CiPN in rodent. Gait analysis may also be a useful tool in these pre-clinical animal models. PMID- 28815648 TI - Direct uptake of HCO3- in the marine angiosperm Posidonia oceanica (L.) Delile driven by a plasma membrane H+ economy. AB - Seagrasses access HCO3- for photosynthesis by 2 mechanisms, apoplastic carbonic anhydrase-mediated dehydration of HCO3- to CO2 and direct HCO3- uptake. Here, we have studied plasma membrane energization and the mechanism for HCO3- import in Posidonia oceanica. Classical electrophysiology and ion-selective microelectrodes were used to measure the membrane potential, cytosolic pH, and the cytosolic concentrations of Na+ and Cl- upon the addition of HCO3- . The photosynthetic response to HCO3- and to inhibitors was also measured. Results indicate that the primary pump of P. oceanica plasma membrane is a fusicoccin-sensitive H+ -ATPase. Bicarbonate depolarizes the plasma membrane voltage and transiently acidifies the cytosol, indicating that HCO3- is transported into the cells by an H+ -symport. Initial cytosolic acidification is followed by an alkalinization, suggesting an internal dehydration of HCO3- . The lack of cytosolic Na+ and Cl- responses rules out the contribution of these ions to HCO3- transport. The energetics of nH+ /HCO3- symport allows, for n = 1, an estimate of cytosolic accumulation of 0.22 mM HCO3- . Because this transporter could permit accumulation of HCO3- up to 100 times above the equilibrium concentration, it would be a significant component of a carbon-concentrating mechanism in this species. PMID- 28815650 TI - Standards or References: A Central Question for Growth Monitoring? PMID- 28815649 TI - Systematic review with meta-analysis: enteral nutrition therapy for the induction of remission in paediatric Crohn's disease. AB - BACKGROUND: Despite potential adverse-events in a paediatric population, corticosteroids are used to induce remission in paediatric Crohn's disease. Exclusive enteral nutrition also induces remission, but is infrequently used in the USA because corticosteroids are considered the superior therapy. New data have become available since the publication of the most recent meta-analysis in 2007. AIM: To see if current literature supports the use of EEN versus CS in paediatric populations. METHODS: All studies with comparator arms of exclusive enteral nutrition and an exclusive corticosteroids, with remission clearly defined were identified by searching eight online databases. RESULTS: Of 2795 identified sources, nine studies met our inclusion criteria. Eight of these (n = 451), had data that could be abstracted into our meta-analysis. Exclusive enteral nutrition was as effective as corticosteroids in inducing remission (OR = 1.26 [95% CI 0.77, 2.05]) in paediatric Crohn's disease. There was no difference between Exclusive enteral nutrition and corticosteroids efficacy when comparing newly diagnosed Crohn's (OR = 1.61 [95% CI .87, 2.98]) or relapsed (OR = 0.76 [95% CI .29-1.98]). Intestinal healing was significantly more likely among patients receiving Exclusive enteral nutrition compared to corticosteroids (OR = 4.5 [95% CI 1.64, 12.32]). There was no difference in the frequency of biomarker normalisation including CRP (OR = 0.85 [95% CI .44, 1.67]) and faecal calprotectin (OR 2.79 [95% CI .79-10.90]). CONCLUSIONS: There is no difference in efficacy between exclusive enteral nutrition and corticosteroids in induction of remission in Crohn's disease in a paediatric population. Exploratory analyses suggest that a greater proportion of patients treated with exclusive enteral nutrition achieved mucosal healing. PMID- 28815651 TI - Peptide Mimetic Drugs for Modulating Thrombosis and Hemostasis. AB - Preclinical Research Hemostasis is the complex physiological process that stems bleeding at an injury site while simultaneously maintaining unobstructed circulation in other areas of the body. This system is kept in balance with finely tuned regulation by pro- and antithrombotic agents. When this balance is thrown out of equilibrium, uncontrolled bleeding, or thrombotic complications can occur. Because of the high number of hemostatic disorders, researchers are continually searching for improved technologies for controlling coagulation. Recently, peptide mimetic strategies have been employed to target and regulate various stages of the coagulation cascade. In this review, we present an overview of the coagulation cascade and provide a summary of various peptide-mimetic approaches for its modulation. Drug Dev Res 78 : 236-244, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28815652 TI - A comparison of 20 heterogeneity variance estimators in statistical synthesis of results from studies: a simulation study. AB - When we synthesize research findings via meta-analysis, it is common to assume that the true underlying effect differs across studies. Total variability consists of the within-study and between-study variances (heterogeneity). There have been established measures, such as I2 , to quantify the proportion of the total variation attributed to heterogeneity. There is a plethora of estimation methods available for estimating heterogeneity. The widely used DerSimonian and Laird estimation method has been challenged, but knowledge of the overall performance of heterogeneity estimators is incomplete. We identified 20 heterogeneity estimators in the literature and evaluated their performance in terms of mean absolute estimation error, coverage probability, and length of the confidence interval for the summary effect via a simulation study. Although previous simulation studies have suggested the Paule-Mandel estimator, it has not been compared with all the available estimators. For dichotomous outcomes, estimating heterogeneity through Markov chain Monte Carlo is a good choice if an informative prior distribution for heterogeneity is employed (eg, by published Cochrane reviews). Nonparametric bootstrap and positive DerSimonian and Laird perform well for all assessment criteria for both dichotomous and continuous outcomes. Hartung-Makambi estimator can be the best choice when the heterogeneity values are close to 0.07 for dichotomous outcomes and medium heterogeneity values (0.01 , 0.05) for continuous outcomes. Hence, there are heterogeneity estimators (nonparametric bootstrap DerSimonian and Laird and positive DerSimonian and Laird) that perform better than the suggested Paule-Mandel. Maximum likelihood provides the best performance for both types of outcome in the absence of heterogeneity. PMID- 28815653 TI - Reply to Letter: The Use of IC50 for Potency and MTD as Objective in Study BIA 10 2474, by Mattheus van Iersel, MD. PMID- 28815654 TI - Early predictors of psychosocial functioning 5 years after paediatric stroke. AB - AIM: Little is known about psychological and social outcomes after paediatric stroke. This study aimed to evaluate psychosocial outcomes in children 5 years after paediatric stroke and explore the contribution of early presenting factors. METHOD: Thirty-one children (19 males, 12 females) with arterial ischemic stroke were involved in this prospective, longitudinal study. Children underwent intellectual assessment at 12 months poststroke and parents completed questionnaires rating their own mental health and their child's functioning at 12 months and 5 years poststroke. RESULTS: At 5-year follow-up, psychological and social function were significantly poorer than normative expectations. Exploration of early predictive factors showed poorer cognitive and psychological function at 12 months poststroke and older age at stroke onset was associated with poorer psychosocial function at 5 years. Larger lesion size was also associated with poorer psychological function at 5 years poststroke. INTERPRETATION: These early predictors of poorer psychosocial outcome suggest that screening children within the first year after stroke may identify children most at risk of later problems and facilitate early intervention. PMID- 28815655 TI - A clinical trial design using the concept of proportional time using the generalized gamma ratio distribution. AB - Traditional methods of sample size and power calculations in clinical trials with a time-to-event end point are based on the logrank test (and its variations), Cox proportional hazards (PH) assumption, or comparison of means of 2 exponential distributions. Of these, sample size calculation based on PH assumption is likely the most common and allows adjusting for the effect of one or more covariates. However, when designing a trial, there are situations when the assumption of PH may not be appropriate. Additionally, when it is known that there is a rapid decline in the survival curve for a control group, such as from previously conducted observational studies, a design based on the PH assumption may confer only a minor statistical improvement for the treatment group that is neither clinically nor practically meaningful. For such scenarios, a clinical trial design that focuses on improvement in patient longevity is proposed, based on the concept of proportional time using the generalized gamma ratio distribution. Simulations are conducted to evaluate the performance of the proportional time method and to identify the situations in which such a design will be beneficial as compared to the standard design using a PH assumption, piecewise exponential hazards assumption, and specific cases of a cure rate model. A practical example in which hemorrhagic stroke patients are randomized to 1 of 2 arms in a putative clinical trial demonstrates the usefulness of this approach by drastically reducing the number of patients needed for study enrollment. PMID- 28815656 TI - Multiple progressive annular telangiectasias: A clinicopathological variant of cutaneous collagenous vasculopathy? AB - Telangiectasias are the clinical manifestation of diverse processes affecting blood vessels. Herein we report the case of a 60-year-old man presenting long standing asymptomatic annular telangiectatic lesions with whitish centers. The histopathologic examination revealed thickened blood dermal vessel walls in the superficial dermis showing reduplication of the basement membrane resembling cutaneous collagenous vasculopathy (CCV). We suggest that this atypical clinicopathological presentation may represent either a localized annular variant of CCV or a previously unreported clinical form of multiple cutaneous telangiectasias. PMID- 28815657 TI - Celecoxib inhibits osteoblast differentiation independent of cyclooxygenase activity. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) exert their effects primarily by inhibiting the activity of cyclooxygenase (COX), thus suppressing prostaglandin synthesis. Some NSAIDs are known to perform functions other than pain control, such as suppressing tumour cell growth, independent of their COX-inhibiting activity. To identify NSAIDs with COX-independent activity, we examined various NSAIDs for their ability to inhibit osteoblastic differentiation using the mouse pre-osteoblast cell line MC3T3-E1. Only celecoxib and valdecoxib strongly inhibited osteoblastic differentiation, and this effect was not correlated with COX-inhibiting activity. Moreover, 2,5-dimethyl (DM)-celecoxib, a celecoxib analogue that does not inhibit COX activity, also inhibited osteoblastic differentiation. Celecoxib and DM-celecoxib inhibited osteoblastic differentiation induced by bone morphogenetic protein (BMP)-2 in C2C12 mouse myoblast cell line. Although celecoxib suppresses the growth of some tumour cells, the viability and proliferation of MC3T3-E1 cells were not affected by celecoxib or DM-celecoxib. Instead, celecoxib and DM-celecoxib suppressed BMP-2 induced phosphorylation of Smad1/5, a major downstream target of BMP receptor. Although it is well known that COX plays important roles in osteoblastic differentiation, these results suggest that some NSAIDs, such as celecoxib, have targets other than COX and regulate phospho-dependent intracellular signalling, thereby modifying bone remodelling. PMID- 28815658 TI - Response to Letters to the Editor Birth Defects Outcomes in Pregnancies Conceived through In Vitro Fertilization. PMID- 28815659 TI - Expanding exposure-based interventions for eating disorders. AB - Initial trials evaluating exposure-based interventions for eating disorders (EDs) in the 1980s demonstrated mixed results. Since that time, innovations in exposure therapy for anxiety disorders have yielded insights that can be used to refine and expand the approach to effectively target ED behaviors. This article provides a brief summary of relevant advances in exposure therapy for anxiety and outlines how these advances may be adapted and evaluated for use with ED samples. More specifically, we propose shifting to an inhibitory learning framework, considering treatment targets other than fear, and increasing variability in exposure techniques represent three important areas for future study. Overall, this article aims to provide professionals in the field with a framework for how to incorporate cutting-edge advances in exposure therapy into rigorous intervention research for EDs. PMID- 28815660 TI - Absorption and tolerability of taste-masked hydrocortisone granules in neonates, infants and children under 6 years of age with adrenal insufficiency. AB - OBJECTIVES: There is no licensed, dose-appropriate formulation of hydrocortisone for children with adrenal insufficiency (AI) and patients rely on compounded adult medication. The aim of this study was to evaluate the absorption, palatability and safety of Infacort(r) , an immediate-release, granule formulation of hydrocortisone with taste masking. STUDY DESIGN: Single site with satellites attended by a "flying" doctor from investigator site. Open-label, single-dose study in three consecutive child cohorts (n = 24) with AI; Cohort 1, children aged 2 to <6 years (n = 12); Cohort 2, infants aged 28 days to <2 years (n = 6); Cohort 3, neonates aged 1 to <28 days (n = 6). METHODS: Fasted children were given a single dose of Infacort(r) as dry granules administered directly from a capsule or spoon followed by a drink. The primary end-point was the maximum serum cortisol concentration up to 240 minutes after Infacort(r) administration. Secondary end-points were palatability and adverse events (AEs). RESULTS: All children showed an increase in cortisol above baseline after Infacort(r) (P < .0001), with geometric mean +/- SD cortisol concentration at 60 minutes of 575.8 +/- 299.5 nmol L-1 . There was no failure in administration of Infacort(r) , and 95.5% of parents/carers preferred Infacort(r) to their child's current medication. In 7 children who completed the palatability questionnaire, 80% of responses were very good or neutral, and 20% were adverse. No serious or severe treatment-emergent AEs were reported. CONCLUSIONS: Infacort(r) is well tolerated, easy to administer to neonates, infants and children and shows good absorption, with cortisol levels at 60 minutes after administration similar to physiological cortisol levels in healthy children. PMID- 28815661 TI - Effectiveness of oral health education on oral hygiene and dental caries in schoolchildren: Systematic review and meta-analysis. AB - OBJECTIVES: The objective of this study was to evaluate the effectiveness of oral health educational actions in the school context in improving oral hygiene and dental caries in schoolchildren through systematic review and meta-analysis. METHODS: Clinical trials with schoolchildren between 5 and 18 years old were included. Eligible studies were those which had as outcomes caries, plaque accumulation, gingivitis, toothache or tooth loss and which had been published from 1995 to 2015, in any language. The risk of bias was assessed in specific domains according to the Cochrane Handbook. A meta-analysis was carried out using fixed-effects models. RESULTS: A total of 4417 references were found, from which 93 full texts were evaluated and 12 included in this meta-analysis. Five studies showed a reduction in plaque levels, and two studies with gingivitis as the outcome found no effect. There was not enough evidence on the effectiveness of the interventions in reducing dental caries. CONCLUSIONS: Traditional oral health educational actions were effective in reducing plaque, but not gingivitis. There is no long-term evidence in respect of the effectiveness of these interventions in preventing plaque accumulation, gingivitis and dental caries in the school environment. PMID- 28815662 TI - Risks of Adverse Perinatal Outcomes after Repeat Terminations of Pregnancy by their Methods: a Nationwide Register-based Cohort Study in Finland 1996-2013. AB - BACKGROUND: Repeat terminations of pregnancy (TOPs) are associated with an increased risk of adverse outcomes in the subsequent birth. The perinatal outcomes after repeat TOPs by their methods have not yet been properly studied. This study aimed to examine perinatal outcomes in subsequent pregnancy among the women with a singleton birth and a history of TOPs. METHODS: All the first-time mothers (n = 419 879) with a singleton birth during 1996-2013 in Finland were identified from the Medical Birth Register and linked to the Abortion Register. Adjusted multivariable logistic regression analysis was used to estimate risks of adverse perinatal outcomes. RESULTS: The increased incidence of adverse perinatal outcomes was found with increasing number of surgical TOPs. After adjusting for confounders, the women with one surgical TOP had slightly increased but significant odds of 1.07 (95% CI 1.02, 1.13) for being small for gestational age compared with the women having no TOP. A significantly high risk for extremely preterm birth (OR 1.51, 95% CI 1.03, 2.23) was found among the women having had repeat surgical TOPs when compared to the women with no TOP. Non-significant risks were found for adverse perinatal outcomes after women's repeat surgical TOPs than repeat medical TOPs. CONCLUSION: Information regarding the consequences of repeat induced TOPs will be significant in sexual health education as well as counselling women after first termination. PMID- 28815663 TI - WHO 2016 Classification of gliomas. AB - Gliomas are the most frequent intrinsic tumours of the central nervous system and encompass two principle subgroups: diffuse gliomas and gliomas showing a more circumscribed growth pattern ('nondiffuse gliomas'). In the revised fourth edition of the WHO Classification of CNS tumours published in 2016, classification of especially diffuse gliomas has fundamentally changed: for the first time, a large subset of these tumours is now defined based on presence/absence of IDH mutation and 1p/19q codeletion. Following this approach, the diagnosis of (anaplastic) oligoastrocytoma can be expected to largely disappear. Furthermore, in the WHO 2016 Classification gliomatosis cerebri is not an entity anymore but is now considered as a growth pattern. The most important changes in the very diverse group of 'nondiffuse' gliomas and neuronal-glial tumours are the introduction of anaplastic pleomorphic xanthoastrocytoma, of diffuse leptomeningeal glioneuronal tumour and of RELA fusion-positive ependymoma as entities. In the last part of this review, after very briefly touching upon classification of neuronal, choroid plexus and pineal region tumours, some practical implications and challenges associated with the WHO 2016 Classification of gliomas are discussed. PMID- 28815664 TI - Simultaneous lateral bone augmentation and implant placement using a particulated synthetic bone substitute around chronic peri-implant dehiscence defects in dogs. AB - AIM: To determine the histological outcomes when using a highly porous synthetic bone substitute and a cross-linked collagen membrane for lateral bone augmentation of peri-implant dehiscence defects. METHODS: In eight dogs, three treatment groups were randomly allocated at each peri-implant dehiscence defect (mean height * depth = 3 * 1 mm) as follows: (i) synthetic bone substitute covered by a cross-linked collagen membrane (test group), (ii) deproteinized bovine bone mineral covered by a natural collagen membrane (positive control), and (iii) no treatment (negative control). Two healing periods (8 and 16 weeks) were applied. RESULTS: The differences in healing outcomes between the test and positive control groups were not significant at 8 weeks. Horizontal bone augmentation 2 mm below the implant shoulder was significantly greater in the test group (1.22 +/- 0.53 mm) than in the positive and negative controls (0.42 +/ 0.51 and 0.36 +/- 0.50 mm, respectively) at 16 weeks. Similarly, the augmented tissue thickness at 0, 1, and 2 mm apical to the implant shoulder was significantly greater in the test group than in the positive control group. CONCLUSION: The test group showed significantly better histological outcomes for lateral bone augmentation and tissue thickness at 16 weeks compared to both the positive and negative control groups. PMID- 28815666 TI - Dorsomedial prefrontal cortex repetitive transcranial magnetic stimulation treatment of posttraumatic stress disorder in eating disorders: An open-label case series. AB - Posttraumatic stress disorder (PTSD) is a common comorbid condition in anorexia nervosa (AN) and bulimia nervosa (BN), and may be associated with reduced response to treatment. We report on a case series employing repetitive transcranial magnetic stimulation (rTMS) with a novel target, the dorsomedial prefrontal cortex (DMPFC). Fourteen subjects with eating disorders and comorbid PTSD received 20-30 neuronavigated DMPFC-rTMS treatments on an open-label basis. PTSD symptoms were assessed pretreatment and posttreatment with the PTSD checklist-Civilian (PCL-C) and the Difficulties in Emotional Regulation Scale (DERS). PCL-C scores were reduced by 51.99% +/- 27.24% overall, from a mean of 54.29 +/- 19.34 pretreatment to 24.86 +/- 17.43 posttreatment (p < .001). Of the 14, 8 showed an improvement of >50%. DERS scores improved by 36.02% +/- 24.24% overall, from 140.00 +/- 22.09 at pretreatment to 89.29 +/- 38.31 at posttreatment (p < .001). OF the 14 subjects, 5 achieved >50% improvement. These data may suggest that DMPFC-rTMS could be helpful in the treatment of PTSD in some ED patients. PMID- 28815667 TI - Diagnostic performance of unenhanced computed tomography and 18 F fluorodeoxyglucose positron emission tomography in indeterminate adrenal tumours. AB - OBJECTIVE: Evidence on the diagnostic performance of adrenal imaging is limited. We aimed to assess the diagnostic performance of unenhanced computed tomography (CT) and 18 F-fluorodeoxyglucose (18 FDG) positron emission tomography (PET)/CT imaging in a high-risk population for adrenal malignancy using an optimal reference standard. DESIGN: Retrospective cohort study. METHODS: Imaging studies of patients with adrenal nodules who underwent adrenal biopsy and/or adrenalectomy between 1994 and 2014 were reviewed and compared to the reference standard of histology. Eighty % of patients presented with known or suspected extra-adrenal malignancy. RESULTS: Unenhanced abdominal CT was performed in 353 patients with adrenal lesions; median size was 3 (0.7-15) cm and median radiodensity was 33 (-21-78) Hounsfield units (HU). Radiodensity of >10 HU diagnosed malignancy with a sensitivity of 100%, specificity of 33%, positive predictive value (PPV) of 72% and negative predictive value (NPV) of 100%. 18 FDG PET/CT was performed in 89 patients; median tumour size was 2.1 (0.7-9.2) cm. Maximum standardized uptake (SUV max) was higher in malignant lesions when compared to benign lesions (median=10 [2.3-29.4] vs 3.7 [1.4-24.5], respectively, P<.0001). Similarly, median SUV max lesion to SUV max liver ratio (ALR) in malignant lesions was higher than in benign lesions (median=3 [0.74-13.4] vs 1.2 [0.5-6.6], respectively, P<.0001). 18 FDG-PET/CT ALR >1.8 diagnosed malignancy with a sensitivity of 87%, specificity of 84%, PPV of 85% and NPV of 86%. CONCLUSION: Noncontract CT radiodensity of <=10 HU excludes malignancy even in a high-risk population. For indeterminate adrenal lesions, given a superior specificity, 18 FDG-PET/CT could be considered as a second stage imaging study. PMID- 28815668 TI - Primary low-grade neuroendocrine carcinoma of the skin: An exceedingly rare entity. AB - Low-grade neuroendocrine tumors (NETs), also known as carcinoid tumor, commonly arise from the gastrointestinal (GI) and pulmonary tracts, but rarely occur in the skin. Cutaneous NET typically occurs as metastases or high-grade primary lesions, called Merkel cell carcinoma. In the few cases described in literature, primary low-grade neuroendocrine carcinomas of the skin (LGNECS) are usually indolent cutaneous nodules, presenting on the head and trunk of elderly patients. LGNECS tumors are histologically similar to its counterparts arising in other anatomic locations. As there is no NET cut-off for the skin due to their rarity, the GI scale was used instead; low-grade NETs have a Ki-67 proliferative index of less than 3%. The distinction between primary and metastatic NET, however, is not absolute and can be difficult. A primary vs metastatic NET diagnosis relies on clinical exclusion of a NET in other, more common, anatomic locations. Here, we present a case of an LGNECS on the scalp of a 72-year-old female patient. Whole body imaging failed to identify any octreotide-avid lesions elsewhere in the patient, aside from 2 positive cervical lymph nodes, which were confirmed with a node dissection and histologic evaluation. This is the 19th reported case of LGNECS and the 2nd reported case of LGNECS with nodal metastasis. PMID- 28815670 TI - Commentary on Wolfgang Loch's paper 'Drives and objects - observations on the origins of the emotional object world'. PMID- 28815665 TI - Pharmacological modulation of C-X-C motif chemokine receptor 4 influences development of acute respiratory distress syndrome after lung ischaemia reperfusion injury. AB - Activation of C-X-C motif chemokine receptor 4 (CXCR4) has been reported to result in lung protective effects in various experimental models. The effects of pharmacological CXCR4 modulation on the development of acute respiratory distress syndrome (ARDS) after lung injury, however, are unknown. Thus, we studied whether blockade and activation of CXCR4 influences development of ARDS in a unilateral lung ischaemia-reperfusion injury rat model. Anaesthetized, mechanically ventilated animals underwent right lung ischaemia (series 1, 30 minutes; series 2, 60 minutes) followed by reperfusion for 300 minutes. In series 1, animals were treated with vehicle or 0.7 MUmol/kg of AMD3100 (CXCR4 antagonist) and in series 2 with vehicle, 0.7 or 3.5 MUmol/kg ubiquitin (non-cognate CXCR4 agonist) within 5 minutes of reperfusion. AMD3100 significantly reduced PaO2 /FiO2 ratios, converted mild ARDS with vehicle treatment into moderate ARDS (PaO2 /FiO2 ratio<200) and increased histological lung injury. Ubiquitin dose-dependently increased PaO2 /FiO2 ratios, converted moderate-to-severe into mild-to-moderate ARDS and reduced protein content of bronchoalveolar lavage fluid (BALF). Measurements of cytokine levels (TNFalpha, IL-6, IL-10) in lung homogenates and BALF showed that AMD3100 reduced IL-10 levels in homogenates from post-ischaemic lungs, whereas ubiquitin dose-dependently increased IL-10 levels in BALF from post-ischaemic lungs. Our findings establish a cause-effect relationship for the effects of pharmacological CXCR4 modulation on the development of ARDS after lung ischaemia-reperfusion injury. These data further suggest CXCR4 as a new drug target to reduce the incidence and attenuate the severity of ARDS after lung injury. PMID- 28815671 TI - Drives and objects - Observations on the origins of the emotional object world. PMID- 28815672 TI - Letter to the Editor. PMID- 28815673 TI - Erratum. PMID- 28815674 TI - Wolfgang Loch and his perception of the principles of the psychoanalytic method. PMID- 28815676 TI - Reply to Dr. Najeeb. PMID- 28815675 TI - Comments on 'Who founded Buddhism? Notes on the psychological effectiveness of religious objects'. PMID- 28815677 TI - Memory: Between traumatic shock and psychic historicization. AB - 'I want to erase him from my memory,' she said, 'his eyes, his eyes staring at me ... they are there every night, his hand ... every night it hits me again and again ...'. On the basis of these few words taken from the therapeutic work with Keltoum, the author reflects theoretically and clinically on the place of memory in a traumatism: a fixed memory, a 'frozen image', the signs of a traumatic compulsion to repeat, are the expressions of a process of psychic disorganization but also of a 'symbolized and symbolizing' memory anticipating a possible historicization of this memory, of a path, therefore, towards a resolution of the trauma resulting from a process of psychic integration and reorganization. PMID- 28815678 TI - Cutaneous iridophoroma in a Green iguana ?????????????(Iguana iguana)??????????????????????????. AB - An 11-year-old intact male Green iguana (Iguana iguana) was referred for treatment of a probable iridophoroma based on previous cytopathology. A periocular mass was present near the right medial canthus. Computed tomography did not show any sign of metastasis. Clinicopathologic abnormalities included lymphopenia and hyperproteinemia. Cytologic and histologic evaluations of the mass were consistent with iridophoroma. Complete surgical excision of the mass was not possible without removal of the orbit due to local tissue involvement. Recovery and suture removal were unremarkable. Adjunctive radiation therapy was recommended, but not performed. A year later, the surgical site had healed well. To our knowledge, this is the first reported chromatophoroma cytopathology in a Green iguana. Chromatophoromas should be included in the differential diagnoses of pigmented skin tumors in reptiles. Early surgical excision is useful to limit local tissue destruction and metastatic potential. PMID- 28815679 TI - (-)-Epigallocatechin-3-gallate and atorvastatin treatment down-regulates liver fibrosis-related genes in non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) and associated advanced liver diseases have become prevalent conditions in many countries and are associated with increased mortality. Gene expression profiles in NAFLD have been examined recently but changes in expression elicited by chemical compound treatments have not been investigated. Since (-)-Epigallocatechin-3-gallate (EGCG) and atorvastatin (ATST) exhibit similar efficacy in NAFLD models, we reasoned that some common key genes might alter after treatment of EGCG and ATST. Accordingly, we applied integrated bioinformatics analyses of RNA microarray data from EGCG and ATST treatment groups compared to controls in a NAFLD phenotypic mouse model. Using differential expression (DE) analysis, Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis, Gene Set Enrichment Analysis (GSEA) and ClueGO enrichment, shared EGCG and ATST down-regulated pathways were identified which included extracellular matrix (ECM)-receptor interaction and protein processing in endoplasmic reticulum (ER). To refine key genes associated with liver fibrosis, a human NAFLD signature derived from patients of different fibrosis stages was analyzed. The results showed that fibrosis-related genes Col1a1, Col1a2, Col3a1 and Col6a3 were significantly down-regulated. These four genes were further validated as down-regulated in an independent mouse NAFLD dataset. We conclude that EGCG and ATST treatment results in the significant down regulation of genes related to liver fibrosis. PMID- 28815681 TI - Meta-analytical synthesis of regression coefficients under different categorization scheme of continuous covariates. AB - Recently, the number of clinical prediction models sharing the same regression task has increased in the medical literature. However, evidence synthesis methodologies that use the results of these regression models have not been sufficiently studied, particularly in meta-analysis settings where only regression coefficients are available. One of the difficulties lies in the differences between the categorization schemes of continuous covariates across different studies. In general, categorization methods using cutoff values are study specific across available models, even if they focus on the same covariates of interest. Differences in the categorization of covariates could lead to serious bias in the estimated regression coefficients and thus in subsequent syntheses. To tackle this issue, we developed synthesis methods for linear regression models with different categorization schemes of covariates. A 2-step approach to aggregate the regression coefficient estimates is proposed. The first step is to estimate the joint distribution of covariates by introducing a latent sampling distribution, which uses one set of individual participant data to estimate the marginal distribution of covariates with categorization. The second step is to use a nonlinear mixed-effects model with correction terms for the bias due to categorization to estimate the overall regression coefficients. Especially in terms of precision, numerical simulations show that our approach outperforms conventional methods, which only use studies with common covariates or ignore the differences between categorization schemes. The method developed in this study is also applied to a series of WHO epidemiologic studies on white blood cell counts. PMID- 28815680 TI - Study of coverage of confidence intervals for the standardized mortality ratio in studies with missing death certificates. AB - This paper assesses the coverage probability of commonly used confidence intervals for the standardized mortality ratio (SMR) when death certificates are missing. It also proposes alternative confidence interval approaches with coverage probabilities close to .95. In epidemiology, the SMR is an important measure of risk of disease mortality (or incidence) to compare a specific group to a reference population. The appropriate confidence interval for the SMR is crucial, especially when the SMR is close to 1.0 and the statistical significance of the risk needs to be determined. There are several ways to calculate confidence intervals, depending on a study characteristics (ie, studies with small number of deaths, studies with small counts, aggregate SMRs based on several countries or time periods, and studies with missing death certificates). This paper summarizes the most commonly used confidence intervals and newly applies several existing approaches not previously used for SMR confidence intervals. The coverage probability and length of the different confidence intervals are assessed using a simulation study and different scenarios. The performance of the confidence intervals for the lung cancer SMR and all other cancer SMR is also assessed using the dataset of French and Czech uranium miners. Finally, the most appropriate confidence intervals to use under different study scenarios are recommended. PMID- 28815682 TI - Molecular evidence for trans-stadial transmission of Anaplasma platys by Rhipicephalus sanguineus sensu lato under field conditions. AB - This study investigated the transmission of Anaplasma platys by Rhipicephalus sanguineus sensu lato (Ixodida: Ixodidae). Engorged nymphs (n = 404) removed from A. platys-infected dogs were incubated at 28 degrees C until moulting. Unfed adults were obtained and divided into 48 pools. Unfed ticks collected from the grounds of the dog shelter, comprising 1800 larvae (n = 18 pools), 3100 nymphs (n = 62 pools) and 85 adults (n = 10 pools, including three male and seven female pools) were sorted into 90 pools. All pools were screened by polymerase chain reaction for the 16S rRNA gene of A. platys. Of 48 pools of unfed adults obtained from engorged nymphs, 12 were positive for A. platys; the infection rate maximum likelihood estimate (MLE) was 3.36 [95% confidence interval (CI) 1.84-5.68]. Anaplasma platys was detected in five of 23 male pools (MLE 2.82, 95% CI 1.06 6.20) and seven of 25 female pools (MLE 3.83, 95% CI 1.72-7.57). Of seven pools of unfed adult females collected from the shelter grounds, one was positive for A. platys (MLE 1.74, 95% CI 0.11-8.22). Among 62 unfed nymph pools, eight were infected with A. platys (MLE 0.27, 95% CI 0.13-0.52). No A. platys DNA was detected in the larva pools. The present results reveal molecular evidence for the trans-stadial transmission of A. platys by R. sanguineus s.l. PMID- 28815683 TI - Phase imaging quality improvement by modification of AFM probes' cantilever. AB - Imaging of the surface of materials by atomic force microscopy under tapping and phase imaging mode, with use of modified probes is addressed. In this study, the circularly shaped holes located in varying distance from the probe base, were cut out by focused ion beam. Such modification was a consequence of the results of the previous experiments (probe tip sharpening and cantilever thinning) where significant improvement of image quality in tapping and phase imaging mode has been revealed. The solution proposed herein gives similar results, but is much simpler from the technological point of view. Shorter exposition time of the tip onto gallium ions during FIB processing allows to reduce material degradation. The aim of this modification was to change harmonic oscillators' properties in the simplest and fastest way, to obtain stronger signal for higher resonant frequencies, which can be advantageous for improving the quality of imaging in PI mode. Probes shaped in that way were used for AFM investigations with Bruker AFM nanoscope 8. As a testing material, titanium roughness standard sample, supplied by Bruker, was used. The results have shown that the modifications performed within these studies influence the oscillation of the probes, which in some cases may result in deterioration of the imaging quality under tapping mode for one or both self-resonant frequencies. However, phase imaging results obtained using modified probes are of higher quality. The numerical simulations performed by application of finite element method were used to explain the results obtained experimentally. Phenomenon described within this study allows to apply developed modelling methodology for prediction of effects of various modifications on the probes' tip, and as a result, to predict how proposed modifications will affect AFM imaging quality. PMID- 28815684 TI - Cognitive psychophysiological treatment of bodily-focused repetitive behaviors in adults: An open trial. AB - BACKGROUND: Body-focused repetitive behaviors (BFRBs), such as hair pulling, skin picking, and nail biting, are repetitive, destructive, and nonfunctional habits that cause significant distress. Separate BFRBs form a cohesive group and could be assessed as part of the Tourette/tic spectrum or obsessive-compulsive spectrum of disorders. The treatment of choice is either antidepressant or behavioral treatment, both of which have shown effectiveness. The cognitive psychophysiological (CoPs) model focuses on the tension and emotional build up that triggers habits by addressing cognitive-behavioral, emotional and psychophysiological processes preceding onset rather than the habit itself. The CoPs approach has already shown efficacy in treatment of tic and Tourette disorder. OBJECTIVE: The aim of the current open trial was to view whether BFRBs can be validly assessed on a standard tic scale (Tourette Symptom Global Scale; TSGS) and evaluate the efficacy of the CoPs intervention on 64 participants (54 completers) with 1 of 3 subtypes of BFRBs (hair pulling, nail biting, and skin picking) compared to a waitlist control. METHOD: Participants were assessed at baseline on an adapted TSGS and after receving 14 weeks of CoPs therapy with six months follow up. RESULTS: The TSGS was reliably and validly adapted to measure BFRBs. The CoPs intervention was effective for all BRFB subtypes with a large effect size (intention-to-treat g = 1.54; completers g = 2.04), with 74% of patients showing clinically significant improvement. Mood and self-esteem also improved posttreatment. The decrease in symptoms was maintained at the 6-month follow-up, with a further decrease in perfectionism. CONCLUSION: BFRBs can be reliably assessed as a tic spectrum disorder rather than as part of the obsessive compulsive spectrum. The CoPs model may offer a complementary treatment for BFRBs. PMID- 28815685 TI - Diagnosis of thrombotic thrombocytopenic purpura among patients with ADAMTS13 Activity 10%-20. PMID- 28815686 TI - The cost of being clean: A cost analysis of nasopharyngoscope reprocessing techniques. AB - OBJECTIVE: Nasopharyngoscopes are an essential instrument to otolaryngologists; reprocessing them in a high-value manner is paramount. Although several different techniques for reprocessing exist, all methods yield similar effectiveness. Given equivalent effectiveness outcomes, a cost analysis of four nasopharyngoscope reprocessing techniques was performed. STUDY DESIGN: Cost-minimization analysis. METHODS: Four techniques were evaluated: 1) an automated reprocessor using peracetic acid (Steris System 1; Steris Canada Inc., Mississauga, Canada), 2) an automated reprocessor using ortho-phthalaldehyde (OPA) (Cidex OPA; Advanced Sterilization Products, Johnson and Johnson Inc., Markham, Canada), 3) a manually performed accelerated hydrogen peroxide bath (Revital-Ox; Steris Canada Inc.), and 4) a chlorine dioxide wipe (Tristel Trio Wipes System; Tristel plc, Cambridgeshire, U.K.). The costing perspective was a third-party payer that was adjusted to 2014 Canadian dollars. The base-case scenario used an annual volume of 4,153 reprocessing events in a tertiary care setting, and a scenario analysis assessed the impact of volume and capital expense. RESULTS: The cost per reprocessing event for the Steris (Steris Canada Inc.) automated endoscope reprocessing, Cidex OPA (Advanced Sterilization Products), Revital-Ox (Steris Canada Inc.), and Tristel Trio Wipes (Tristel plc) were $20.58, $14.20, $9.57, and $13.14, respectively. Scenario analysis demonstrated the Tristel Trio Wipes System (Tristel plc) was the least expensive method in practices with low reprocessing volumes (a threshold of less than 6 events per day, or 22 per week), whereas the Revital-Ox (Steris Canada Inc.) system was least expensive at higher volumes and became substantially more so as volumes increased. CONCLUSION: A manual accelerated hydrogen peroxide bath offers the least costly approach to nasopharyngoscope reprocessing. The convenience and portability of the Tristel Trio (Tristel plc) system may be a good alternative for low reprocessing volumes, or when rapid turnaround is necessary. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:64-71, 2018. PMID- 28815687 TI - Disappearing subcutaneous papules and nodules: Characteristic features of muscle herniation and piezogenic pedal papules. PMID- 28815688 TI - Bone morphogenetic protein 2 controls iron homeostasis in mice independent of Bmp6. AB - Hepcidin is a key iron regulatory hormone that controls expression of the iron exporter ferroportin to increase the iron supply when needed to support erythropoiesis and other essential functions, but to prevent the toxicity of iron excess. The bone morphogenetic protein (BMP)-SMAD signaling pathway, through the ligand BMP6 and the co-receptor hemojuvelin, is a central regulator of hepcidin transcription in the liver in response to iron. Here, we show that dietary iron loading has a residual ability to induce Smad signaling and hepcidin expression in Bmp6-/- mice, effects that are blocked by a neutralizing BMP2/4 antibody. Moreover, BMP2/4 antibody inhibits hepcidin expression and induces iron loading in wildtype mice, whereas a BMP4 antibody has no effect. Bmp2 mRNA is predominantly expressed in endothelial cells of the liver, where its baseline expression is higher, but its induction by iron is less robust than Bmp6. Mice with a conditional ablation of Bmp2 in endothelial cells exhibit hepcidin deficiency, serum iron overload, and tissue iron loading in liver, pancreas and heart, with reduced spleen iron. Together, these data demonstrate that in addition to BMP6, endothelial cell BMP2 has a non-redundant role in hepcidin regulation by iron. PMID- 28815689 TI - Medication adherence in patients with apparent resistant hypertension: findings from the SYMPATHY trial. AB - AIMS: Hypertension is only controlled in approximately 35% of the patients, which could be partially due to nonadherence. Recently, bioanalytical assessment of adherence to blood pressure (BP) lowering drugs has gaining interest. Our aim was to explore possible determinants of nonadherence in treatment resistant hypertension, assessed by objective screening for antihypertensive agents in serum. The secondary aim was to study the effect of adherence on the change in BP. METHODS: This project was a substudy of SYMPATHY; an open-label randomized controlled trial to assess the effect of renal denervation on BP 6 months after treatment compared to usual care in patients with resistant hypertension. Stored serum samples were screened for antihypertensive agents to assess adherence at baseline and 6 months after intervention, using liquid chromatography-tandem mass spectrometry. Office and 24-h BP were measured on the same day as blood was sampled. Patients and physicians were unaware of adherence measurements. RESULTS: Ninety-eight baseline and 83 6-month samples were available for analysis. Sixty eight percent [95% confidence interval (CI) 59-78%] of the patients was nonadherent (n = 67). For every onw pill more prescribed, 0.785 [95%CI 0.529 0.891] prescribed pill was less detected in blood. A decrease of one pill in adherence between baseline and 6 months was associated with a significant rise in office systolic BP of 4 (95%CI 0.230-8.932) mmHg. CONCLUSION: Objective measurement of BP lowering drugs in serum, as a tool to assess adherence, showed that nonadherence was very common in patients with apparent resistant hypertension. Furthermore, the assessment results were related to (changes in) blood pressure. Our findings provide direct and objective methodology to help the physician to understand and to improve the condition of apparent resistant hypertension. PMID- 28815690 TI - Treatment of individuals who cannot receive blood products for religious or other reasons. AB - By virtue of their religious principles, Jehovah's Witnesses (JWs) generally object to receiving blood products, raising numerous ethical, legal, and medical challenges for providers who care for these patients, especially in the emergent setting. In this review, we discuss several areas relevant to the care of JWs, including the current literature on "bloodless" medical care in the setting of perioperative and intraoperative management, acute blood loss, trauma, pregnancy, and malignancy. We have found that medical and administrative efforts in the form of bloodless medicine and surgery programs can be instrumental in helping to reduce risks of morbidity and mortality in these patients. Planning prior to an anticipated event associated with blood loss or anemia (such as elective surgery, pregnancy, and chemotherapy) is critical. Specifically, bloodless medicine programs should prioritize vigilant early screening and management of anemias, early establishment of patient wishes regarding transfusion, and the incorporation of those wishes into multidisciplinary medical and surgical care. Although there are now a variety of human-based and nonhuman-based products available as transfusion alternatives, the degree and quality of evidence to support their use varies significantly between products and is also largely dependent on the clinical setting. PMID- 28815691 TI - Keratin 6b variant p.Gly499Ser reported in delayed-onset pachyonychia congenita is a non-pathogenic polymorphism. PMID- 28815692 TI - Amelioration of atopic-like skin conditions in NC/Tnd mice by topical application with distilled Alpinia intermedia Gagnep extracts. AB - Alpinia intermedia, a perennial plant that belongs to the Zingiberaceae family, has been used in folk medicine for a long time in the southern region of Japan. Because skin care is an effective approach that enables patients to manage their atopic dermatitis (AD), various herbal ingredients with few adverse effects have been evaluated for use in AD patients in recent years. In this study, we examined whether distilled extracts obtained from A. intermedia were beneficial for AD like skin conditions in NC/Tnd mice. Topical application with the A. intermedia extracts significantly reduced the severity of AD, transepidermal water loss and scratching behavior in the mice. Supplementation of the extracts to cell cultures suppressed the expression of Tslp mRNA in PAM212 keratinocytes, degranulation in bone marrow-derived cultured mast cells (BMCMC), and neurite outgrowth in PC12 cells and dorsal root ganglia. In addition, the component analysis revealed that beta-pinene was a major constituent of the A. intermedia extracts. The inhibitory effects of beta-pinene both in vivo and in vitro were also demonstrated. These results indicate that topical application with the A. intermedia extract to the skin of NC/Tnd mice improved the condition of the skin by suppressing multiple inflammatory responses. The extracts may become novel skin-care remedies for AD patients. PMID- 28815693 TI - Ibrutinib-associated Pneumocystis jirovecii pneumonia. PMID- 28815694 TI - Pemetrexed-induced lower limb pseudocellulitis. PMID- 28815696 TI - A novel method for sub-arc VMAT dose delivery verification based on portal dosimetry with an EPID. AB - PURPOSE: The EPID-based sub-arc verification of VMAT dose delivery requires synchronization of the acquired electronic portal images (EPIs) with the VMAT delivery, that is, establishment of the start- and stop-MU of the acquired images. To realize this, published synchronization methods propose the use of logging features of the linac or dedicated hardware solutions. In this study, we developed a novel, software-based synchronization method that only uses information inherently available in the acquired images. METHOD: The EPIs are continuously acquired during pretreatment VMAT delivery and converted into Portal Dose Images (PDIs). Sub-arcs of approximately 10 MU are then defined by combining groups of sequentially acquired PDIs. The start- and stop-MUs of measured sub arcs are established in a synchronization procedure, using only dosimetric information in measured and predicted PDIs. Sub-arc verification of a VMAT dose delivery is based on comparison of measured sub-arc PDIs with synchronized, predicted sub-arc PDIs, using gamma-analyses. To assess the accuracy of this new method, measured and predicted PDIs were compared for 20 clinically applied VMAT prostate cancer plans. The sensitivity of the method for detection of delivery errors was investigated using VMAT deliveries with intentionally inserted, small perturbations (25 error scenarios; leaf gap deviations <= 1.5 mm, leaf motion stops during <= 15 MU, linac output error <= 2%). RESULTS: For the 20 plans, the average failed pixel rates (FPR) for full-arc and sub-arc dose QA were 0.36% +/- 0.26% (1 SD) and 0.64% +/- 0.88%, based on 2%/2 mm and 3%/3 mm gamma-analyses, respectively. Small systematic perturbations of up to 1% output error and 1 mm leaf offset were detected using full-arc QA. Sub-arc QA was able to detect positioning errors in three leaves only during approximately 20 MU and small dose delivery errors during approximately 40 MU. In an ROC analysis, the area under the curve (AUC) for the combined full-arc/sub-arc approach was 0.90. CONCLUSIONS: A novel method for sub-arc VMAT dose delivery verification with EPIDs is proposed, using only dosimetric information in acquired EPIs for synchronization. Especially in combination with full-arc QA, the established sensitivity for detection of very small errors is high, with also a high specificity. PMID- 28815697 TI - Case-control study of chronic low-level exposure of inorganic arsenic species and non-melanoma skin cancer. AB - A significant relationship between arsenic exposure and non-melanoma skin cancer (NMSC) is well known. The toxicity of arsenics which develop NMSC is dependent on their species. Accordingly, total arsenic levels are unreliable for risk assessment of NMSC. However, there are few studies on quantitative exposure assessment of arsenic species in NMSC patients. To validate the contribution of each arsenic species to NMSC, we compared the creatinine-adjusted urinary concentration of arsenic species in NMSC patients and community controls. A total of 124 biopsy-proven NMSC cases and 125 age- and sex-matched community controls, drinking tap water with low-level arsenic concentration (<5 MUg/L), were included in the study. High-performance liquid chromatography and inductively coupled plasma mass spectrometry were used for the measurement. The NMSC group was found to have significantly higher levels of total inorganic arsenic, trivalent and pentavalent arsenic and monomethylarsonic acid than the control group. Total arsenic, organic arsenic and dimethylarsonic acid levels were lower in the NMSC group. We suggest that inorganic arsenic species, trivalent arsenic and pentavalent arsenic may influence the prevalence of NMSC, in spite of these levels being lower than the Agency for Toxic Substances and Disease Registry recommended standard or the levels reported by other highly contaminated areas and neighboring countries in East Asia. Furthermore, it also suggests that total arsenic level cannot represent the risk of NMSC. PMID- 28815695 TI - A distinctive histidine residue is essential for in vivo glycation-inactivation of human CD59 transgenically expressed in mice erythrocytes: Implications for human diabetes complications. AB - Clinical and experimental evidences support a link between the complement system and the pathogenesis of diabetes complications. CD59, an extracellular cell membrane-anchored protein, inhibits formation of the membrane attack complex (MAC), the main effector of complement-mediated tissue damage. This complement regulatory activity of human CD59 (hCD59) is inhibited by hyperglycemia-induced E amino glycation of Lys41 . Biochemical and structural analyses of glycated proteins with known three-dimensional structure revealed that glycation of E amino lysyl residues occurs predominantly at "glycation motives" that include lysyl/lysyl pairs or proximity of a histidyl residue, in which the imidazolyl moiety is ~ 5A from the E-amino group. hCD59 contains a distinctive Lys41 /His44 putative glycation motif within its active site. In a model of transgenic diabetic mice expressing in erythrocytes either the wild type or a H44Q mutant form of hCD59, we demonstrate in vivo that the His44 is required for Lys41 glycation and consequent functional inactivation of hCD59, as evidenced using a mouse erythrocytes hemolytic assay. Since (1) the His44 residue is not present in CD59 from other animal species and (2) humans are particularly prone to develop complications of diabetes, our results indicate that the Lys41 /His44 glycation motif in human CD59 may confer humans a higher risk of developing vascular disease in response to hyperglycemia. PMID- 28815698 TI - Altered regulation of TERMINAL FLOWER 1 causes the unique vernalisation response in an arctic woodland strawberry accession. AB - Vernalisation requirement is an agriculturally important trait that postpones the development of cold-sensitive floral organs until the spring. The family Rosaceae includes many agriculturally important fruit and berry crops that suffer from crop losses caused by frost injury to overwintering flower buds. Recently, a vernalisation-requiring accession of the Rosaceae model woodland strawberry (Fragaria vesca) has been identified in northern Norway. Understanding the molecular basis of the vernalisation requirement in this accession would advance the development of strawberry cultivars better adapted to temperate climate. We use gene silencing, gene expression analysis, genetic mapping and population genomics to study the genetic basis of the vernalisation requirement in woodland strawberry. Our results indicate that the woodland strawberry vernalisation requirement is endemic to northern Norwegian population, and mapping data suggest the orthologue of TERMINAL FLOWER1 (FvTFL1) as the causal floral repressor. We demonstrate that exceptionally low temperatures are needed to downregulate FvTFL1 and to make these plants competent to induce flowering at low postvernalisation temperatures in the spring. We show that altered regulation of FvTFL1 in the northern Norwegian woodland strawberry accession postpones flower induction until the spring, allowing plants to avoid winter injuries of flower buds that commonly occur in temperate regions. PMID- 28815699 TI - Application of the condensed protocol for the NIA-AA guidelines for the neuropathological assessment of Alzheimer's disease in an academic clinical practice. AB - AIMS: In response to concerns regarding resource expenditures required to implement fully the 2012 National Institute on Aging and the Alzheimer's Association (NIA-AA) Sponsored Guidelines for the neuropathological assessment of Alzheimer's disease (AD), we previously developed a sensitive and cost-reducing condensed protocol (CP) at the University of Washington (UW) Alzheimer's Disease Research Center (ADRC) that consolidated the recommended NIA-AA protocol into fewer cassettes requiring fewer immunohistochemical stains. The CP was not designed to replace NIA-AA protocols, but instead to make the NIA-AA criteria accessible to clinical and forensic neuropathology practices where resources limit full implementation of NIA-AA guidelines. METHODS AND RESULTS: In this regard, we developed practical criteria to instigate CP sampling and immunostaining, and applied these criteria in an academic clinical neuropathological practice. During the course of 1 year, 73 cases were sampled using the CP; of those, 53 (72.6%) contained histological features that prompted CP work-up. We found that the CP resulted in increased identification of AD and Lewy body disease neuropathological changes from what was expected using a clinical history-driven work-up alone, while saving approximately $900 per case. CONCLUSIONS: This study demonstrates the feasibility and cost-savings of the CP applied to a clinical autopsy practice, and highlights potentially unrecognised neurodegenerative disease processes in the general ageing community. PMID- 28815700 TI - Pseudoangiosarcomatous squamous cell carcinoma of the skin: A need for a more rigorous nomenclature for histopathological variants of squamous cell carcinoma. AB - Over the years, squamous cell carcinomas (SCC) that mimicked vascular lesions have been encompassed within different classifications and the underlying etiopathogenic mechanisms have been interpreted in different ways by different authors. Here, we present a case of SCC with pseudovascular areas in the right leg of a 96-year-old woman with chronic venous insufficiency. Histopathological examination closely resembled an angiosarcoma, but the immunohistochemical negativity for endothelial markers and the strong positivity for the pancytokeratin marker AE1/AE3 revealed the epithelial nature of the neoplasm. After a comprehensive review of all similar previously published cases, we believe that it is necessary to separate SCC with pseudoluminal structures composed of glandular-like areas (pseudoglandular or adenoid SCC) from those mimicking vascular lumina (pseudovascular and pseudoangiosarcomatous SCC). We would like to emphasize that acantholytic SCC, a definitive variant of SCC, can be further classified into the common or ordinary subtype of acantholytic SCC, that shows solid nests containing numerous acantholytic atypical keratinocytes without any mimickers for specific structures, and pseudoglandular, pseudovascular and pseudoangiosarcomatous subtypes when glandular or vascular structures are mimicked, respectively. PMID- 28815701 TI - LincRNA DYN-LRB2-2 upregulates cholesterol efflux by decreasing TLR2 expression in macrophages. AB - This study is designed to determine whether lincRNA-DYNLRB2-2 could promote cholesterol efflux through regulating the expression of TLR2. THP-1 and RAW264.7 cells were incubated with oxLDL for 48 h to induce the formation of foam cells, and ORO staining was performed and intracellular cholesterol contents were measured by HPLC assay. qRT-PCR and Western blotting were performed to detect mRNA and protein expression levels, respectively. Lentiviral vector LV-DYNLRB2-2 and lincRNA-DYNLRB2-2 siRNA was constructed to explore its potential role. The cholesterol efflux was assessed by liquid scintillation counting. The effects of TRL2 were determined in apoE-/- mice that fed a high fat diet and were randomly divided into three groups and infected with LV-Mock, LV-Sh-TRL2, or LV-TRL2. Atherosclerosis was observed in the aortic sinus and the levels of cytokines and serum biochemical parameters were measured. Ox-LDL induced foam cell formation in the THP-1 and RAW264.7 cells. LincRNA DYN-LRB2-2 was upregulated in oxLDL-treated THP-1 and Raw264.7 cells. LincRNA-DYNLRB2-2 plays important role in regulating the cholesterol efflux, ABCA1 expression level and anti-inflammatory processes in THP-1 and RAW264.7 cells. Further study indicated that lincRNA-DYNLRB2-2 negatively regulated TRL2 expression and TRL2 overexpression reversed the effects of lincRNA-DYNLRB2-2 on cholesterol efflux and ABCA1 expression level in THP-1 and RAW264.7 cells. Besides, we found TRL2 plays important role in lipid accumulation, plaque formation and regulating serum inflammatory cytokines level in apoE-/- mice with a high fat diet. LincRNA DYN-LRB2-2 upregulates cholesterol efflux by decreasing TLR2 expression in macrophages. PMID- 28815702 TI - A multicentre study of long-term follow-up and owner satisfaction following enucleation in horses. AB - BACKGROUND: Horses are reported to return to a variety of disciplines following unilateral enucleation; however, owners of horses with ocular disease are frequently reluctant to consider the procedure. There is little published information investigating owners' attitudes towards, and satisfaction following, enucleation. OBJECTIVES: To investigate the hypotheses: 1) horses return to their previous level of work following unilateral enucleation and 2) their owners are satisfied with the post-operative outcome. STUDY DESIGN: Retrospective case series with cross-sectional survey. METHODS: Clinical records from eight equine referral centres in the United Kingdom were reviewed to identify horses that underwent enucleation between August 2006 and March 2015. Owner questionnaires were completed to corroborate information provided by medical records and obtain information on client perceptions. RESULTS: A total of 170 cases were identified and 119 owner questionnaires completed. The most frequent primary uses of horses in the study were pleasure/leisure riding, showjumping and dressage, with 25.2% (n = 30) of horses used for competition. Following enucleation, 77.3% (n = 92) of horses were performing at an equivalent or higher level than prior to enucleation and 60.0% (n = 18/30) of competition horses were competing at an equivalent or higher level. Complications related to the surgical site (predominantly mild post operative swelling) were reported in 3.7% of cases and nonocular complications in 3.7% of cases. Of owners who reported being concerned or very concerned about certain factors prior to surgery, >=86.8% reported that these factors caused little or no issue post-surgery. Most owners, 90.8% (n = 108) were pleased with the outcome following surgery, with 21.3% (n = 23/108) wishing the procedure had been undertaken sooner. MAIN LIMITATIONS: Retrospective data collection from clinical records and the potential for recall bias. CONCLUSIONS: Horses can return successfully to a variety of disciplines following enucleation. Owners are satisfied with the outcome and pleased that enucleation was performed. PMID- 28815703 TI - THE EPISTEMOLOGY BEHIND THE CURTAIN: THOUGHTS ON THE SCIENCE OF PSYCHOANALYSIS. AB - This essay is concerned with the epistemological complications of the interface between psychoanalysis and "scientific" disciplines and methodologies-in particular, with respect to theories of knowledge and conceptualizations of subjectivity appropriate to psychoanalysis. The author suggests that there is in such interface the potential for an untheorized scientism in empiricist prescriptions for the reform and rescue of psychoanalysis, and revisits the notion that subjectivity as conceived psychoanalytically, grounded in lived experience, is irreducible in ways that are unique and existentially abiding. The author explores the problem through the lens of philosophical hermeneutics and cautions against merging psychoanalysis, under the guise of a salutary pluralism, with disciplines guided by a systematized empiricism and its attendant epistemological commitments. PMID- 28815704 TI - THE VIBRANT CHALLENGES OF CLINICALLY EFFECTIVE PSYCHOANALYTIC MINDEDNESS. AB - In addressing the central challenges of developing and maintaining the analyst's psychoanalytic mindedness, this paper focuses on two particularly challenging core components of clinical effectiveness not so easily developed despite the rigors of the tripartite training model. The first is the analyst's receptivity to unconscious communication, which entails the analyst's curiosity, acceptance of human nature, doubt, restraint, narcissistic balance, and integrity. A brief clinical vignette illustrates this. The second factor is recognizing and managing the inherent disappointments and narcissistic challenges in working psychoanalytically. The author maintains that the ability to lose and subsequently recover one's analytic mind entails discipline, courage, and faith that only experience can provide. PMID- 28815705 TI - ON THE BIRTH AND DEVELOPMENT OF PSYCHOANALYTIC FIELD THEORY, PART 1. AB - Defining Psychoanalysis: Achieving a Vernacular Expression, by Ian Miller. London: Karnac, 2016. 116 pp. The Pioneers of Psychoanalysis in South America: An Essential Guide, edited by Nydia Lisman-Pieczanski and Alberto Pieczanski. London/New York: Routledge, 2015. 537 pp. Reading Italian Psychoanalysis, edited by Franco Borgogno, Alberto Luchetti, and Luisa Marino Coe. London/New York: Routledge, 2016. 738 pp. PMID- 28815706 TI - REEXAMINING SCHREBER THROUGH THE LENS OF A PRESENT-DAY CASE: FANTASIES OF DEATH, REBIRTH, AND GENDER TRANSFORMATION. AB - In the history of psychoanalysis, the Schreber case has long been a source of controversy. Speculations about Schreber have abounded essentially because none of the speculators, including Freud (), has been constrained by the reality of interactive dynamics with Schreber on the couch. This author contends, however, that knowing someone analytically must involve the transference experience. He presents the case of Z, a middle-aged patient of his who described a fantasy that was uncannily similar to Schreber's, permitting a present-day reexamination of the original case, as well as ongoing speculations that include the way in which live clinical material can interact with the reading of a historical document. PMID- 28815709 TI - ATYPICAL DISCOURSES. AB - This essay outlines novel ways of communicating with patients by altering semantics, syntax, word use, or sounds. Language is viewed as a tool for coping with problems rather than a medium with which to mirror external reality or internal human nature. This view of language emerges from a pragmatic critique of truth. The broader goal of this essay is to weave together the philosophy of pragmatism, especially as it has been articulated by Richard Rorty, with the theory and practice of psychoanalysis. Clinical case examples are discussed. PMID- 28815711 TI - REBEL WITHOUT A CAUSE: A PSYCHOANALYTIC AND FAMILY-LIFE-CYCLE VIEW OF EMERGING ADULTHOOD IN THE FILM. AB - The period during which grown children leave home and establish a new, self supporting family is called emerging adulthood. This paper uses psychoanalytic concepts and family-life-cycle theory to analyze the film Rebel without a Cause () as a dramatic example of three families going through this phase. Freud's () rescue-motif of the child trying to save an endangered peer to repay his parents for having been nurtured is also characteristic of this period and is considered practice for parenting the next generation. Proximate conflict and support enable two of the film's families to continue the path to reproduce themselves. PMID- 28815713 TI - CLINICAL WINNICOTT: TRAVELING A REVOLUTIONARY ROAD. AB - The author contends that, contrary to the usual perception that Winnicott followed a linear progression "through pediatrics to psychoanalysis," Winnicott's vision was always a psychoanalytic one, even during his early pediatric work. His place in the development of psychoanalytic theory is highlighted, and the author discusses such key Winnicottian concepts as transitional space, the false self, and the use of the object. Winnicott's unique approach to the form and value of analytic interpretation is particularly emphasized, and his thoughts on the treatment of depression are also addressed, as well as his distinction between regression and withdrawal. Included is a summary of convergences and divergences between Winnicott's thinking and that of Bion. PMID- 28815714 TI - WILLIAM HAZLITT, OBSESSIVE LOVE, AND LIBER AMORIS. AB - William Hazlitt, a distinguished literary figure of the early nineteenth century and a forerunner of psychoanalytic insights, had a keen awareness of the impact of the imagination on assessing works of art. At forty-two, he became hopelessly involved in an obsessive love affair with a nineteen-year-old woman and could not extricate himself from the relationship. The affair followed the death of his father, a powerful influence on his life. Factors in his obsessive love included finding an object of idealization subject to his imaginative creation and narcissistically reexperiencing himself about to begin a new life. PMID- 28815716 TI - Characterization of H5N6 highly pathogenic avian influenza viruses isolated from wild and captive birds in the winter season of 2016-2017 in Northern Japan. AB - On 15 November 2016, a black swan that had died in a zoo in Akita prefecture, northern Japan, was strongly suspected to have highly pathogenic avian influenza (HPAI); an HPAI virus (HPAIV) belonging to the H5N6 subtype was isolated from specimens taken from the bird. After the initial report, 230 cases of HPAI caused by H5N6 viruses from wild birds, captive birds, and domestic poultry farms were reported throughout the country during the winter season. In the present study, 66 H5N6 HPAIVs isolated from northern Japan were further characterized. Phylogenetic analysis of the hemagglutinin gene showed that the H5N6 viruses isolated in northern Japan clustered into Group C of Clade 2.3.4.4 together with other isolates collected in Japan, Korea and Taiwan during the winter season of 2016-2017. The antigenicity of the Japanese H5N6 isolate differed slightly from that of HPAIVs isolated previously in Japan and China. The virus exhibited high pathogenicity and a high replication capacity in chickens, whereas virus growth was slightly lower in ducks compared with that of an H5N8 HPAIV isolate collected in Japan in 2014. Comprehensive analyses of Japanese isolates, including those from central, western, and southern Japan, as well as rapid publication of this information are essential for facilitating greater control of HPAIVs. PMID- 28815718 TI - A potential high risk for fatty liver disease was found in mice generated after assisted reproductive techniques. AB - Abnormal gametogenesis and embryonic development may lead to poor health status of the offspring. The operations involved in the assisted reproductive technologies (ARTs) occur during the key stage of gametogenesis and early embryonic development. To assess the potential risk of abnormal lipid metabolism in the liver of adult ARTs offspring, two ARTs mice models derived from preimplantation genetic diagnosis (PGD group) and in vitro cultured embryos without biopsy (IVEM group) were constructed. And control mice were from in vivo naturally conceived (Normal group). The results showed that ARTs offspring had increased body weight and body fat content comparing to normal group. An increasing volume and amount of lipid droplets as well as lipid droplet fusion were found in the hepatocytes of ARTs mice, and a significantly increased liver TG content was also shown in the ARTs mice, which due to the increased TG synthesis and decreased TG transport in the liver. All the results indicated that the manipulations involved in ARTs might play an important role in the lipid accumulation of adult offspring. By analyzing the DNA methylation profiles of 7.5dpc embryos, we proposed that methylation deregulation of the genes related to liver development in ARTs embryos might contribute to the abnormal phenotype in the offspring. The study demonstrated that ARTs procedures have adverse effect on liver development which resulted in abnormal lipid metabolism and induced the potential high risk of fatty liver in adulthood. PMID- 28815717 TI - Partial inferior turbinectomy in rhinoseptoplasty has no effect in quality-of life outcomes: A randomized clinical trial. AB - OBJECTIVE: Evaluate the impact of endoscopic partial inferior turbinectomy (EPIT) associated with primary rhinoseptoplasty on quality-of-life outcomes (QOL), complications, and surgical duration. STUDY DESIGN: Randomized clinical trial. METHODS: Individuals with nasal obstruction aged >= 16 years who were candidates for functional and aesthetics primary rhinoseptoplasty were evaluated from March 2014 through May 2015. Eligible participants were randomly allocated to rhinoseptoplasty with or without EPIT (excision of one-third of the inferior turbinates). RESULTS: Fifty patients were studied. Most were Caucasian and had moderate/severe allergic rhinitis symptoms. Mean age was 36 ( +/- 14.5) years. Rhinoseptoplasty was associated with improvement in all QOL scores irrespective of turbinate intervention (P < 0.001). Analysis of covariance was conducted to control for potential confounders. There was no difference between the groups in absolute score changes for Nasal Obstruction Symptom Evaluation-Portuguese (NOSE p) (-50.5 vs. -47.6; P = 0.723), Rhinoplasty Outcome Evaluation (ROE) (47 vs. 44.8; P = 0.742), and all World Health Organization Quality of Life Scale Abbreviated (WHOQOL-bref) score domains (P > 0.05). There were no differences between the groups regarding presence of the complications. Surgical duration was higher in the EPIT group (212 minutes +/- 7.8 vs. 159.1 +/- 5.6; P ? 0.001). CONCLUSIONS: Turbinate reduction through EPIT during primary rhinoseptoplasty did not improve short-term general and specific QOL outcomes. The use of EPIT increases surgical time considerably without improving QOL scores. There was no difference in postoperative incidence of complications, suggesting that EPIT is a safe technique. LEVEL OF EVIDENCE: 1b. Laryngoscope, 128:57-63, 2018. PMID- 28815719 TI - Cytokine profiling of MCF-7 cell line 2D, progressive 3D, and 3D revert cultures. AB - Cancer cytokines are known to mediate several complex cancer cell physiologies. Also, cancer cells themselves are known to secrete cytokines whose expressions and net inducible results are controlled by a variety of factors. We profiled a few cytokines secreted by 2D, 3D aggregates, and the 3DRs of MCF-7 cell line at various time points. Several cytokines were seen more expressed by 3D cultures on the 4th day and IL-10 peaked on the day 1 of 3D cultures while TNF-alpha level peaked on the 7th day. alpha-Defensin, SDF-7, and TGF-beta also showed markedly higher levels. There was a reduced expression of IL-6 and IL-17 by the 3DRs. TGF beta did not show much change among the 2D, progressive 3D, and 3DR cultures. Utilizing 3DRs as study material will be a significant extension of the ways cells lines can be used for research. PMID- 28815721 TI - RGD Peptide-Based Target Drug Delivery of Doxorubicin Nanomedicine. AB - Preclinical Research Doxorubicin (DOX) is commonly used for the treatment of breast cancer and lymphoma. However, its clinical use has been severely limited due to cardiotoxicity, requiring the development of safer and more efficient pharmaceutical formulations of DOX. Advances in nanotechnology have provided new ways to administer chemotherapeutic drugs like DOX are conveyed into the body and to tumor sites. These Nanotechnology approaches have aided in the selective accumulation of DOX into tumor sites via the enhanced permeability and retention. However, the absence of active targeting ligands still hinders the effective delivery of DOX. Among all active targeting ligands developed to date, RGD peptide (Arginylglycylaspartic acid) occupies a unique position owing to its inherent safety, biocompatibility, and targeting ability. Accordingly, modification of DOX with RGD ligand is anticipated to improve transport of DOX into tumor cells. In this review, we discuss using RGD peptide for improving the therapeutic efficacy of DOX nanomedicine. Drug Dev Res 78 : 283-291, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28815720 TI - Pharmacological evidence of involvement of nitric oxide pathway in anti-pruritic effects of sumatriptan in chloroquine-induced scratching in mice. AB - Chloroquine (CQ) induces histamine-independent itch in human and mice. We recently reported the role of intradermal nitric oxide (NO)/cyclic guanosine monophosphate pathway in CQ-evoked scratching in mice. Chloroquine stimulates neuronal nitric oxide synthase (nNOS) activity to over-producing NO in the skin. Sumatriptan, a 5-hydroxytryptamine 1b/1d receptors (5-HTR1b/1d) agonist, is involved in pain and used to treat migraine and cluster headaches. According to previous studies, sumatriptan inhibits NOS activity. Thus, we aimed to investigate the effect of sumatriptan on CQ-induced scratching. We used the rostral back model of itch. Chloroquine was injected intradermally into the rostral back of NMRI mice, and the scratching behavior was evaluated by measuring the number of bouts over 30 min. We evaluated the effect of sumatriptan and combination of sumatriptan and a non-selective NO synthase inhibitor, L-N-nitro arginine methyl ester (L-NAME), on the scratching behavior. Additionally, the changes of skin, hippocampus, and cortical nitrite level after different treatments were studied. Intraperitoneal and intradermal sumatriptan attenuates CQ-induced itch which reversed by GR-127935, the selective 5-HTR1b and 5-HTR1d antagonist. Co-administration of subeffective doses of sumatriptan and L-NAME significantly decreases the scratching behavior. Intradermal injection of CQ significantly increases the intradermal nitrite levels while it does not have any significant effects on hippocampal or cortical nitrite concentrations. Likewise, the effective doses of intraperitoneal and intradermal sumatriptan significantly reduce intradermal nitrite levels. We concluded that sumatriptan suppresses CQ induced itch most likely by activating 5-HT1b/1d receptors. This effect probably mediates through NO pathway. PMID- 28815722 TI - Probable allergic contact dermatitis from hydroquinone presenting as leukomelanoderma: Report of two cases. PMID- 28815723 TI - Rapid automatic creation of monodisperse emulsion droplets by microfluidic device with degassed PDMS slab as a detachable suction actuator. AB - We previously developed a technique that enabled automatic creation of monodisperse water-in-oil droplets with the use of an air-evacuated PDMS microfluidic device. Although the device generated droplets over a long-time period, the production rate was slow (~10 droplets per second). In the current study, we aimed to improve this rate, using the same fluid pumping principle described in our previous work, by remodeling our device configuration. To achieve this aim, we developed a new device with a much larger PDMS surface area to-volume ratio within the air-trapping void space (178 cm-1 ), than that of our earlier device (5.0 cm-1 ). This design approach was based on the idea that a larger PDMS surface area-to-volume ratio was likely to create a higher vacuum inside the void space, thereby contributing to faster liquid flow and an increased droplet generation rate. The new device consisting of five layers featuring a degassed PDMS slab as a detachable liquid-suction actuator, which was stacked on a lower microfluidic layer. In this device, the rate of droplet production increased during the time-course droplet formation and reached ca. 470 droplets per second immediately before completely consuming the loaded aqueous solution (20 MUL). PMID- 28815724 TI - Secreted products of Fasciola hepatica inhibit the induction of T cell responses that mediate allergy. AB - There is evidence from epidemiology studies of a negative association between infection with helminth parasites and the development of allergy and asthma. Here, we demonstrate that the excretory/secretory products of the helminth Fasciola hepatica (FHES) protected mice against ovalbumin (OVA)-induced allergic asthma when administered at time of allergen sensitization. FHES reduced the accumulation of mucus, eosinophils and lymphocytes into the airways of allergen challenged mice. Furthermore, FHES treatment suppressed Th2 responses in the airways. Interestingly, systemic administration of FHES at allergen challenge had no effect on airway inflammation, demonstrating that alum-induced Th2 response is set following initial allergen sensitization. Our findings highlight the immunomodulatory potential of molecules secreted by F. hepatica. PMID- 28815725 TI - P2Y6 regulates cytoskeleton reorganization and cell migration of C2C12 myoblasts via ROCK pathway. AB - Migration of skeletal muscle precursor cells is required for limb muscle development and skeletal muscle repair. This study aimed to examine the role of P2Y6 receptor in C2C12 myoblasts migration. C2C12 myoblasts were treated with P2Y6 agonist UDP, P2Y6 antagonist MRS2578, Ca2+ channel blocker BTP2, or ROCK inhibitor GSK269962 or Y27632, and the migration ability of C2C12 cells was assessed by wound healing assay. The cellular Ca2+ content was analyzed with fluo 4 probe and the activation of ROCK (phosphorlyation of LIMK and cofilin) was assayed by western blot. The cytoskeleton was labeled with Actin-Tracker Green and Tubulin-Tracker-Red. Silencing P2Y6 expression in C2C12 myoblasts reduced intracellular Ca2+ content and cell motility. Whereas UDP increased cellular Ca2+ content, actin filaments, and cell migration, MRS2578 had the opposite effects. The effects of UDP were abrogated by BTP2 and GSK269962 (and Y27632). Disruption of P2Y6 signaling pathway caused C2C12 myoblasts to have an elongated morphology. These results demonstrated that P2Y6 signaled through Ca2+ influx and RhoA/ROCK to reorganize cytoskeleton and promote migration in myoblasts. PMID- 28815726 TI - Differential expression profile analysis of lncRNA UCA1alpha regulated mRNAs in bladder cancer. AB - Urothelial carcinoma associated 1alpha (UCA1alpha) is a novel long non-coding RNA (lncRNA) that regulates bladder cancer proliferation, migration, and invasion. The target genes of UCA1alpha have, however, not been identified. To address this, a pCDNA3.1(+)-UCA1alpha over-expression vector was transfected into UM-UC-2 bladder cancer cells. Genes differentially expressed between pCDNA3.1(+) UCA1alpha and pCDNA3.1(+) transfected cell were then detected by microarray and bioinformatics analysis. A total of 71 differentially expressed genes were identified, including 52 up-regulated genes and 19 down-regulated genes. As expected, the lncRNA UCA1alpha expression level was significantly increased when compared to that of pCDNA3.1(+) transfected cells. The five most significantly up regulated and five most significantly down-regulated genes were selected, and their expression levels were also assessed by real time quantitative polymerase chain reaction and Western blot. The mRNA and protein expression levels of FOXI3 and GSTA3 were found to be significantly increased, and those of MED18 and TEX101 were found to be significantly decreased. Gene ontology (GO) clustering identified several significant biological processes, cellular components, and molecular functions, associated with lncRNA UCA1alpha over-expression. The differentially expressed genes were involved in several significant pathways as shown by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway clustering. Cell proliferation activity was significantly increased following overexpression of lncRNA UCA1alpha increasing over culture time. The present study identifies, for the first time, potential target genes for lncRNA UCA1alpha in bladder cancer, and provides a significant reference for studying the role of lncRNA UCA1alpha in bladder cancer. PMID- 28815727 TI - Gender disparities among patients with peripheral arterial disease treated via endovascular approach: A propensity score matched analysis. AB - BACKGROUND: Remarkable improvement in the treatment of Peripheral Arterial Disease (PAD) has led to changes in revascularization strategies from traditional open surgery to less invasive endovascular management. However, few studies are available on gender disparities in patients with PAD treated via an endovascular approach. This study was designed to analyze gender related differences with respect to in-hospital outcomes in PAD patients. METHODS: Our data was obtained from National Inpatient Sample (NIS) 2012 through 2014. We used International Classification of Diseases, 9th Revision, Clinical Modification diagnostic and procedural codes appropriate for PAD and endovascular treatment. Endovascular treatment included drug eluting stent, bare metal stent, atherectomy or angioplasty of lower extremity arteries. A propensity score matching was performed to adjust for imbalances between variables. RESULTS: Females presented late with more comorbidities and underwent more emergent/urgent procedures. After performing propensity score matched analysis, 25 758 patients were included in each group. There was no difference in in-hospital mortality between males and females in matched cohorts (2.3% vs 2.4%, P = 0.25). Acute renal failure, gangrene, infection, and composite of all complications were higher in males. Only blood transfusion was noted higher in females. CONCLUSION: This study revealed no difference in in-hospital mortality between males and females undergoing endovascular peripheral intervention. Males have a higher rate of complications compared to females which explains the higher cost of care in males. Further research with long-term follow up is needed to see if there is any difference with regards to long-term outcomes and re-admission. PMID- 28815729 TI - Infusions Are the Optimal Dosing Method in Intravenous ADME Studies Rather Than Bolus Dosing. PMID- 28815728 TI - Effects of bifenthrin exposure on the estrogenic and dopaminergic pathways in zebrafish embryos and juveniles. AB - Bifenthrin is a pyrethroid insecticide used in urban and agricultural applications. Previous studies have shown that environmentally relevant (ng/L) concentrations of bifenthrin increased plasma concentrations of 17beta-estradiol (E2) and altered the expression of dopaminergic pathway components. The dopaminergic neurons can indirectly regulate E2 biosynthesis, suggesting that bifenthrin may disrupt the hypothalamic-pituitary-gonadal (HPG) axis. Because embryos do not have a complete HPG axis, the hypothesis that bifenthrin impairs dopamine regulation was tested in embryonic and 1-mo-old juvenile zebrafish (Danio rerio) with exposure to measured concentrations of 0.34 and 3.1 ug/L bifenthrin for 96 h. Quantitative reverse transcriptase polymerase chain reaction was used to investigate transcripts of tyrosine hydroxylase (TH), dopamine receptor 1 (DR1) and 2A (DR2A), dopamine active transporter (DAT), estrogen receptor alpha (ERalpha), ERbeta1, ERbeta2, luteinizing hormone beta (LHbeta), follicle-stimulating hormone beta (FSHbeta), vitellogenin (VTG), cytochrome P450 cyp19a1a, and cyp19a1b. Levels of E2 were measured by enzyme-linked immunosorbent assay (ELISA). Dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations were measured by liquid chromatrography-tandem mass spectrometry (LC-MS/MS). Significant decreases in TH and DR1 transcripts and HVA levels, as well as ratios of HVA/dopamine and HVA+DOPAC/dopamine, in zebrafish embryos were observed after bifenthrin treatment. In juveniles, a significant increase in the expression of ERbeta1 and the DOPAC to dopamine ratio was noted. These results show a possible antiestrogenic effect of bifenthrin in embryos, and estrogenicity in juveniles, indicating life-stage-dependent toxicity in developing fish. Environ Toxicol Chem 2018;37:236-246. (c) 2017 SETAC. PMID- 28815730 TI - Loss of BMI-1 dampens migration and EMT of colorectal cancer in inflammatory microenvironment through TLR4/MD-2/MyD88-mediated NF-kappaB signaling. AB - : Increasing evidence from various clinical and experimental studies has demonstrated that the inflammatory microenvironment created by immune cells facilitates tumor migration. Epithelial-mesenchymal transition (EMT) is involved in the progression of cancer invasion and metastasis in an inflammatory microenvironment. B-lymphoma Moloney murine leukemia virus insertion region 1 (BMI-1) acts as an oncogene in various tumors. Ectopic expression of Bmi-1 have an effect on EMT and invasiveness. The purpose of this study was to investigate the efficacy of BMI-1 on inflammation-induced tumor migration and EMT and the underlying mechanism. We observed that the expression of BMI-1, TNF-alpha, and IL 1beta was significantly increased in HT29 and HCT116 cells after THP-1 Conditioned-Medium (THP-1-CM) stimulation. Additionally, inhibition of BMI-1 impeded cell invasion induced by THP-1-CM-stimulation in both HT29 and HCT116 cells. BMI-1 knockdown remarkably repressed THP-1-CM-induced EMT by regulating the expression of EMT biomarkers with an increase in E-cadherin accompanied by decrease in N-cadherin and vimentin. Furthermore, downregulation of BMI-1 dramatically impeded THP-1-CM-triggered Toll-like receptor 4(TLR4)/myeloid differentiation protein 2(MD-2)/myeloid differentiation factor 88(MyD88) activity by repressing the expression of the TLR4/MD-2 complex and MyD88. Further data demonstrated that knockout of BMI-1 also dampened NF-kappaB THP-1-CM-triggered activity. Taken all data together, our findings established that BMI-1 modulated TLR4/MD-2/MyD88 complex-mediated NF-kappaB signaling involved in inflammation induced cancer cells invasion and EMT, and therefore, could be a potential chemopreventive agent against inflammation-associated colorectal cancer. HIGHLIGHTS: Establishment of an inflammatory microenvironment. Suppression of BMI 1 reverses THP-1-CM-induced inflammatory cytokine production in CRC. Loss of BMI 1 suppressed TLR4/MD-2/MyD88 complex-mediated NF-kappaB signaling. PMID- 28815731 TI - Case report of cutaneous protothecosis caused by Prototheca wickerhamii designated as genotype 2 and current status of human protothecosis in Japan. AB - An 85-year-old Japanese woman presented with infiltrative erythema and ulceration on the extensor surface of her right forearm. Direct microscopic examination demonstrated spherical and morula-like sporangia, while histopathology revealed numerous microorganisms with a mulberry-like appearance in the dermis. Staining of the microorganisms also showed mulberry-like sporangia that resembled the spokes of a wheel. The isolated yeast-like microorganism had been identified as Prototheca wickerhamii genotype 2 in another independent study on the basis of its morphological, biochemical and genetic analysis. This case of protothecosis was recorded in Kyushu, Japan, and oral treatment with itraconazole 200 mg/day for 2 months was effective. Herein, we also summarize and analyze 39 cases of human protothecosis reported in Japan since the first record in 1983. PMID- 28815732 TI - Antibacterial and beta-Lactamase Inhibitory Activity of Monocyclic beta-Lactams. AB - Due to the widespread emergence of resistant bacterial strains, an urgent need for the development of new antibacterial agents with novel modes of action has emerged. The discovery of naturally occurring monocyclic beta-lactams in the late 1970s, mainly active against aerobic Gram-negative bacteria, has introduced a new approach in the design and development of novel antibacterial beta-lactam agents. The main goal was the derivatization of the azetidin-2-one core in order to improve their antibacterial potency, broaden their spectrum of activity, and enhance their beta-lactamase stability. In that respect, our review covers the updates in the field of monocyclic beta-lactam antibiotics during the last three decades, taking into account an extensive collection of references. An overview of the relationships between the structural features of these monocyclic beta lactams, classified according to their N-substituent, and the associated antibacterial or beta-lactamase inhibitory activities is provided. The different paragraphs disclose a number of well-established classes of compounds, such as monobactams, monosulfactams, monocarbams, monophosphams, nocardicins, as well as other known representative classes. Moreover, this review draws attention to some less common but, nevertheless, possibly important types of monocyclic beta lactams and concludes by highlighting the recent developments on siderophore conjugated classes of monocyclic beta-lactams. PMID- 28815733 TI - Comparison of the pharmacokinetic profiles of two different amphotericin B formulations in healthy dogs. AB - This study was conducted to compare the pharmacokinetic profiles of conventional (Fungizone(r) ) and liposomal amphotericin B (AmBisome(r) ) formulations in order to predict their therapeutic properties, and evaluate their potential differences in veterinary treatment. For this purpose, twelve healthy mixed breed dogs received both drugs at a dose of 0.6 mg/kg by intravenous infusion over a 4-min period in a total volume of 40 ml. Blood samples were collected at 0, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 48, 72 and 96 hr after dosing, and concentrations of drug in plasma were determined by high-performance liquid chromatography (HPLC). Pharmacokinetics was described by a two-compartment model. Although both formulations were administered at the same doses (0.6 mg/kg), the plasma pharmacokinetics of liposomal amphotericin B differed significantly from those of amphotericin B deoxycholate in healthy dogs (p < .05). Liposomal amphotericin B showed markedly higher peak plasma concentrations (approximately ninefold greater) and higher area under the plasma concentration curve values (approximately 14-fold higher) compared to conventional formulation. It is concluded that AmBisome(r) reached higher plasma concentration and lower distribution volume and had a longer half-life compared to Fungizone(r) , and therefore, AmBisome(r) is reported to be an appropriate and effective choice for the treatment of systemic mycotic infections in dogs. PMID- 28815734 TI - Mortality benefit of primary transportation to a PCI-capable center persists through an eight-year follow-up in patients with ST-segment elevation myocardial infarction. AB - BACKGROUND: The purpose of this study was to compare long-term outcomes of primary transport (PT) and secondary transport (ST) in patients with STEMI. METHOD: We assigned consecutive 869 patients referred for STEMI during a 2-year period (2008-2009). The primary endpoint was to compare long-term outcomes and mortality of PT to a catheterization laboratory and ST from regional hospitals to a catheterization laboratory. Six hundred seventy-seven patients (77.9%) were enrolled for the final evaluation, 192 (22.1%) having been excluded. RESULTS: The median DBT was 34 +/- 15.92 min for PT patients (n = 354) and 100 +/- 28.82 min for ST patients (n = 323) (P < 0.005). One-month mortality was 3.95% in the PT group versus 9.46% in the ST group (P = 0.002). One-year mortality in the PT was 7.35% and 20.51% in the ST group (P < 0.005). Eight-year mortality was in the PS 26.8% versus 32.6% in the ST group (P = 0.035). Left ventricular ejection fraction (LVEF) was 45 +/- 12.14% versus 45 +/- 12.48% (P = 0.21); creatine kinase (CK) was 22.78 +/- 78.69 ukat/L versus 23.21 +/- 82.61 ukat/L, (P = 0.58); and length of hospitalization was 4.98 +/- 4.61 days in the PT group versus 5.25 +/- 5.86 days in the ST group (P = 0.22). The air transport was used in the PT group (RR 0.85, 95% CI 0.63-1.09); and ST group (RR 1.17, 95% CI 0.91-1.40); P = 0.22). Time distribution of cardiac arrest median for PT 1432 days (n = 25) versus ST 266 (n = 31) P = 0.24. CONCLUSION: The mortality benefits of PT to a PCI capable hospital persist throughout an 8-year follow-up. PMID- 28815735 TI - Traps and transformations influencing the financial viability of tourism on private-land conservation areas. AB - The ability of private conservation organizations to remain financially viable is a key factor influencing their effectiveness. One-third of financially motivated private-land conservation areas (PLCAs) surveyed in South Africa are unprofitable, raising questions about landowners' abilities to effectively adapt their business models to the socioeconomic environment. In any complex system, options for later adaptation can be constrained by starting conditions (path dependence). We tested 3 hypothesized drivers of path dependence in PLCA ecotourism and hunting business models: (H1) the initial size of a PLCA limits the number of mammalian game and thereby predators that can be sustained; (H2) initial investments in infrastructure limit the ability to introduce predators; and (H3) rainfall limits game and predator abundance. We further assessed how managing for financial stability (optimized game stocking) or ecological sustainability (allowing game to fluctuate with environmental conditions) influenced the ability to overcome path dependence. A mechanistic PLCA model based on simple ecological and financial rules was run for different initial conditions and management strategies, simulating landowner options for adapting their business model annually. Despite attempts by simulated landowners to increase profits, adopted business models after 13 years were differentiated by initial land and infrastructural assets, supporting H1 and H2. A conservation organization's initial assets can cause it to become locked into a financially vulnerable business model. In our 50-year simulation, path dependence was overcome by fewer of the landowners who facilitated natural ecological variability than those who maintained constant hunting rates and predator numbers, but the latter experienced unsustainably high game densities in low rainfall years. Management for natural variability supported long-term ecological sustainability but not shorter term socioeconomic sustainability for PLCAs. Our findings highlight trade-offs between ecological and economic sustainability and suggest a role for governmental support of the private conservation industry. PMID- 28815736 TI - The diagnosis and management of contact lens-related microbial keratitis. AB - Contact lens-associated microbial keratitis poses a diagnostic dilemma for optometrists on two fronts. The distinction between sterile inflammation and microbial infection is often blurred. In addition, there is a requirement with nearly 50 per cent of the Australian and New Zealand optometric profession being therapeutically endorsed, to distinguish between cases of infection that can be managed in the community verses those that require escalation to public hospitals that have access to laboratory diagnostic tools and advanced imaging techniques, such as in vivo confocal microscopy. Pattern recognition and incorporation of knowledge of aetiology and risk factors assists optometrists to decide on optimal management strategies. Skilled optometrists will utilise emerging diagnostic and therapeutic technologies to ensure safe management strategies and better outcomes for these cases. PMID- 28815737 TI - Retroperitoneal gastric duplication mimicking a prenatal adrenal cyst. PMID- 28815738 TI - The Effect of Depression, Generalized Anxiety, and Selective Serotonin Reuptake Inhibitors on Change in Bone Metabolism in Adolescents and Emerging Adults. AB - The purpose of this study was to prospectively examine the independent contribution of major depressive disorder (MDD), generalized anxiety disorder (GAD), and selective serotonin reuptake inhibitors (SSRIs) use to changes in bone metabolism in older adolescents and emerging adults. Medically healthy 15- to 20 year-olds who were unmedicated or within 1 month of starting an SSRI were prospectively followed. Psychiatric functioning and medication treatment were assessed monthly. Every 4 months, trabecular and cortical volumetric bone mineral density (vBMD) at the radius and markers of bone metabolism were evaluated. Every 8 months, total body less head areal bone mineral content and lumbar spine (LS) areal BMD (aBMD) were determined. Linear mixed-effects regression analysis examined associations between bone measures on the one hand and MDD, GAD, and SSRI indices on the other. A total of 264 participants were followed for 1.51 +/- 0.76 years. After adjusting for age, sex, vitamin D concentration, physical activity, lean mass or grip strength, and time in the study, MDD severity was associated with increasing LS aBMD. Similarly, SSRI use was associated with increasing LS aBMD and bone formation in female participants. In contrast, SSRI use was associated with decreasing LS aBMD in males. After accounting for depression, GAD was independently, albeit weakly, associated with increased bone mineralization. In older adolescents and emerging adults, MDD and GAD are associated with increasing bone mass, particularly in the lumbar spine and in females, whereas SSRIs are associated with increasing bone mass in females but decreasing bone mass in males. (c) 2017 American Society for Bone and Mineral Research. PMID- 28815739 TI - Kernicterus in a boy with ornithine transcarbamylase deficiency: A case report. AB - Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle defect associated with severe and usually fatal hyperammonemia. This study describes a patient with early onset lethal OTCD due to a known pathogenic variant (c.298+1G>A), as well as the novel autopsy finding of kernicterus with relatively low blood concentration of unconjugated bilirubin (UCB) (11.55 mg/dL). The patient was a full-term male with a family history of two previous male siblings who died as newborns after acute neurologic deterioration. The patient's symptoms began at 24 h of life with lethargy that rapidly progressed to coma upon admission to the neonatal intensive care unit. Although hyperammonemia and hyperbilirubinemia were documented, hemofiltration could not be performed. OTCD diagnosis was biochemically established. Despite nutritional intervention and treatment for hyperammonemia, the patient died on the sixth day of life. At autopsy, external brain examination revealed a marked yellow pigmentation typical of kernicterus that included gray matter, particularly the thalamus and basal ganglia; dentate nuclei of the cerebellum and brain stem gray matter were also affected. Microscopic findings were consistent with the classical description of tissue damage in OTCD, including the presence of Alzheimer type II astrocytes in basal ganglia, necrosis, neuronal loss with spongiform degeneration and macrophage infiltration surrounded by astroglia. This condition may be an important comorbidity in newborns with hyperammonemia. PMID- 28815740 TI - Maternal Obesity and Male Genital Anomalies: Potential Role of Placental Insufficiency and Metabolic Syndrome. PMID- 28815741 TI - Prospective evaluation of a week one overnight metyrapone test with subsequent dynamic assessments of hypothalamic-pituitary-adrenal axis function after pituitary surgery. PMID- 28815742 TI - Look to the past for an optimistic future. PMID- 28815743 TI - Pathophysiology of nocturnal lower urinary tract symptoms in older patients with urinary incontinence. AB - OBJECTIVES: To explore the mismatch between functional bladder capacity and nocturnal urine production, and to study the pathophysiology of an increased nocturnal urine production in older patients with urinary incontinence. METHODS: The present prospective observational study included adults aged >=65 years with urinary incontinence. Participants completed questionnaires, frequency volume charts and renal function profiles. The nocturnal lower urinary tract symptom index was defined as nocturnal urine output/maximum voided volume; the nocturnal polyuria index as nocturnal/24 h urine output. RESULTS: The median age (n = 95) was 74 years (69-79), 87% were women and 73% had nocturnal lower urinary tract symptoms (nocturnal urinary incontinence or nocturia >=2). Participants with nocturnal lower urinary tract symptoms had a significantly higher nocturnal urine output (809 mL vs 650 mL; P = 0.001) and no significant difference in maximum voided volume (350 mL vs 437 mL; P = 0.079) compared with participants without nocturnal lower urinary tract symptoms. Participants (nocturnal polyuria index >33% [n = 56], nocturnal polyuria index >40% [n = 42], nocturnal lower urinary tract symptom index >1.87 [n = 51]) showed higher night-time diuresis rates, free water and sodium clearance compared with during the daytime. Controls (nocturnal polyuria index <=33% [n = 26], nocturnal polyuria index <=40% [n = 40], nocturnal lower urinary tract symptom index <=1.87 [n = 44]) had no circadian rhythm in their diuresis rate or sodium clearance, but more nocturnal free water clearance compared with during the daytime. CONCLUSIONS: The majority of older adults with urinary incontinence present nocturnal lower urinary tract symptoms. An increased nocturnal sodium diuresis seems to be the only mechanism differentiating patients with nocturnal lower urinary tract symptoms from controls. PMID- 28815744 TI - Identifying prebariatric subtypes based on temperament traits, emotion dysregulation, and disinhibited eating: A latent profile analysis. AB - OBJECTIVE: The efficacy of bariatric surgery has been proven; however, a subset of patients fails to achieve expected long-term weight loss postoperatively. As differences in surgery outcome may be influenced by heterogeneous psychological profiles in prebariatric patients, previous subtyping models differentiated patients based on temperament traits. The objective of this study was to expand these models by additionally considering emotion dysregulation and disinhibited eating behaviors for subtyping, as these factors were associated with maladaptive eating behaviors and poor postbariatric weight loss outcome. METHOD: Within a prospective multicenter registry, N = 370 prebariatric patients were examined using interview and self-report questionnaires. A latent profile analysis was performed to identify subtypes based on temperament traits, emotion dysregulation, and disinhibited eating behaviors. RESULTS: Five prebariatric subtypes were identified with specific profiles regarding self-control, emotion dysregulation, and disinhibited eating behaviors. Subtypes were associated with different levels of eating disorder psychopathology, depression, and quality of life. The expanded model increased variance explanation compared to temperament based models. CONCLUSION: By adding emotion dysregulation and disinhibited eating behaviors to previous subtyping models, specific prebariatric subtypes emerged with distinct psychological deficit patterns. Future investigations should test the predictive value of these subtypes for postbariatric weight loss and health related outcomes. PMID- 28815745 TI - Recent developments in open tubular capillary electrochromatography from 2016 to 2017. AB - Interest in open-tubular capillary electrochromatography (OT-CEC) continues to thrive because of the inherent advantage of OT-CEC combining the high efficiency of capillary electrophoresis and the high selectivity of high performance liquid chromatography. For the period 2016 to 2017, novel materials have been developed as first-time stationary phases for OT-CEC and are grouped in this review as polymer-based materials, frameworks, nanoparticles, graphene-based materials, and biomaterials. Coating and fabrication methods mostly rely on covalent coating strategies while non-covalent immobilisation strategies like electrostatic assembly are notably still being employed. The concern of overcoming phase ratio challenges in OT-CEC coatings have also generated adoption of combined coating strategies including multi-layering, layer-by-layer self-assembly and methods adapted from nanofilm fabrications like epitaxial growth, liquid phase deposition, or nucleation of crystal growth. The emergence of non-conventional coating characterisation methods such as transmission electron microscopy, X-ray diffraction or X-ray photoelectron spectroscopy is also discussed. PMID- 28815746 TI - Matthew baillie's specimens and engravings. AB - In 1799, Matthew Baillie, William Hunter's nephew, published his famous atlas of pathology. It was entitled A Series of Engravings Accompanied with Explanations which are Intended to Illustrate the Morbid Anatomy of Some of the Most Important Parts of the Human Body. The present study aims to match the illustrations to extant specimens in the collections of William and John Hunter, preserved at the University of Glasgow and at the Royal College of Surgeons of England respectively. Baillie's book contains 10 fasciculi, consisting of 73 plates and 206 figures. The specimens Baillie illustrated came from his own collection and those of ten others, including his uncles, William and John Hunter. The book was illustrated by William Clift and engraved by James Basire, William Skelton and James Heath. Excluding eight illustrations of intestinal worms where the provenance of the specimens is uncertain, a total of 98 specimens from William Hunter's collection were illustrated in 104 figures. Eight of the specimens were calculi impossible to identify specifically. Excluding worms and calculi, 72 of William Hunter's specimens illustrated by Baillie are extant in the Hunterian Collection at the University of Glasgow. All but one of the 20 specimens illustrated that had belonged to John Hunter were identified in the on-line catalog of the Royal College of Surgeons of England. Baillie's own collection was destroyed when the Royal College of Surgeons of England was bombed in 1941. Baillie is credited with being the first to produce an illustrated systematic textbook of morbid anatomy and probably the first to illustrate emphysema and transposition of the great vessels. His book, however, was not comprehensive. It did not cover a number of topics such as muscles and bones and there is little coverage of the nervous system. Baillie's book, however, was an original concept as an atlas of morbid anatomy and showed his deep insight into pathology. Clin. Anat. 31:622-631, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28815747 TI - What is your diagnosis? Erythrocyte morphology in a cow. PMID- 28815748 TI - Rubinstein-Taybi Syndrome in a Fetus: Contribution of 2- and 3-Dimensional Ultrasonography. PMID- 28815749 TI - Oestrogen receptor expression in melanoma. PMID- 28815750 TI - Learning theories and tools for the assessment of core nursing competencies in simulation: A theoretical review. AB - AIM: To identify the theories used to explain learning in simulation and to examine how these theories guided the assessment of learning outcomes related to core competencies in undergraduate nursing students. BACKGROUND: Nurse educators face the challenge of making explicit the outcomes of competency-based education, especially when competencies are conceptualized as holistic and context dependent. DESIGN: Theoretical review. DATA SOURCES: Research papers (N = 182) published between 1999-2015 describing simulation in nursing education. REVIEW METHODS: Two members of the research team extracted data from the papers, including theories used to explain how simulation could engender learning and tools used to assess simulation outcomes. Contingency tables were created to examine the associations between theories, outcomes and tools. RESULTS: Some papers (N = 79) did not provide an explicit theory. The 103 remaining papers identified one or more learning or teaching theories; the most frequent were the National League for Nursing/Jeffries Simulation Framework, Kolb's theory of experiential learning and Bandura's social cognitive theory and concept of self efficacy. Students' perceptions of simulation, knowledge and self-confidence were the most frequently assessed, mainly via scales designed for the study where they were used. Core competencies were mostly assessed with an observational approach. CONCLUSION: This review highlighted the fact that few studies examined the use of simulation in nursing education through learning theories and via assessment of core competencies. It also identified observational tools used to assess competencies in action, as holistic and context-dependent constructs. PMID- 28815751 TI - Flow cytometry in Spermatology: A bright future ahead. AB - Techniques such as mass spectrometry have led to unprecedented knowledge of the proteins that are present in the spermatozoa of humans and other mammals. However, in spite of their high-throughput and fractioning techniques, most of the techniques in use only offer average values for the entire sperm population. Yet, ejaculate is very heterogeneous, and average values may mask relevant biological information.The application of flow cytometry may overcome this disadvantage, allowing proteomic analysis at the single-cell level. Moreover, recent advances in cytometry, allowing multiple analyses within a single cell combined with powerful statistical tools, as an expanding subfield in spermatology, are described. The increased use of advanced flow cytometers in andrology laboratories will allow the rapid development of multiparametric, multicolour flow cytometry in andrology that will expand the clinical applications and research possibilities of flow cytometry-based proteomic approaches, especially in the subfields of clinical andrology and sperm biotechnology. PMID- 28815752 TI - Rapidly progressive intravascular primary effusion lymphoma in an HIV-positive renal transplant recipient. AB - We describe the clinical and post-mortem findings of a case of rapidly progressive, ultimately fatal primary effusion lymphoma (PEL) arising in an HIV positive man 2 years after renal transplantation. Disseminated multi-organ involvement associated with a peculiar intravascular pattern of growth, as seen in this case, has only been reported once previously. This is also, to our knowledge, the first detailed description of a lymphoma arising post-transplant in an HIV-positive patient. PMID- 28815753 TI - Aruncin B: Synthetic Studies, Structural Reassignment and Biological Evaluation. AB - A ring-closing alkene metathesis (RCM)/ oxyselenation-selenoxide elimination sequence was established to the sodium salts E- and Z-25 of the originally proposed structure for the recently isolated cytotoxin aruncin B (1), as well as to the sodium salt Z-34 of a related ethyl ether regioisomer; however, none of their corresponding free acids could be obtained. Their acid sensitivity, together with detailed analysis of the spectroscopic data indicated that profound structural revision was necessary. This led to reassignment of aruncin B as a Z gamma-alkylidenebutenolide Z-36. Although a related RCM/ oxyselenation-selenoxide elimination sequence was used to confirm the gamma-alkylidenebutenolide motif, a beta-iodo Morita-Baylis-Hillman reaction/ Sonogashira cross-coupling-5-exo-dig lactonisation sequence was subsequently developed, due to its brevity and flexibility for diversification. Aruncin B (36), together with 14 gamma alkylidenebutenolide analogues, were generated for biological evaluation. PMID- 28815754 TI - Pharmacokinetic interactions and dosing rationale for antiepileptic drugs in adults and children. AB - AIMS: Population pharmacokinetic modelling has been widely used across many therapeutic areas to identify sources of variability, which are incorporated into models as covariate factors. Despite numerous publications on pharmacokinetic drug-drug interactions (DDIs) between antiepileptic drugs (AEDs), such data are not used to support the dose rationale for polytherapy in the treatment of epileptic seizures. Here we assess the impact of DDIs on plasma concentrations and evaluate the need for AED dose adjustment. METHODS: Models describing the pharmacokinetics of carbamazepine, clobazam, clonazepam, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, valproic acid and zonisamide in adult and paediatric patients were collected from the published literature and implemented in NONMEM v7.2. Taking current clinical practice into account, we explore simulation scenarios to characterize AED exposure in virtual patients receiving mono- and polytherapy. Steady-state, maximum and minimum concentrations were selected as parameters of interest for this analysis. RESULTS: Our simulations show that DDIs can cause major changes in AED concentrations both in adults and children. When more than one AED is used, even larger changes are observed in the concentrations of the primary drug, leading to significant differences in steady-state concentration between mono- and polytherapy for most AEDs. These results suggest that currently recommended dosing algorithms and titration procedures do not ensure attainment of appropriate therapeutic concentrations. CONCLUSIONS: The effect of DDIs on AED exposure cannot be overlooked. Clinical guidelines must consider such covariate effects and ensure appropriate dosing recommendations for adult and paediatric patients who require combination therapy. PMID- 28815755 TI - Large-Scale Synthesis of Freestanding Layer-Structured PbI2 and MAPbI3 Nanosheets for High-Performance Photodetection. AB - Recently, due to the possibility of thinning down to the atomic thickness to achieve exotic properties, layered materials have attracted extensive research attention. In particular, PbI2 , a kind of layered material, and its perovskite derivatives, CH3 NH3 PbI3 (i.e., MAPbI3 ), have demonstrated impressive photoresponsivities for efficient photodetection. Herein, the synthesis of large scale, high-density, and freestanding PbI2 nanosheets is demonstrated by manipulating the microenvironment during physical vapor deposition. In contrast to conventional two-dimensional (2D) growth along the substrate surface, the essence here is the effective nucleation of microplanes with different angles relative to the in-plane direction of underlying rough-surfaced substrates. When configured into photodetectors, the fabricated device exhibits a photoresponsivity of 410 mA W-1 , a detectivity of 3.1 * 1011 Jones, and a fast response with the rise and decay time constants of 86 and 150 ms, respectively, under a wavelength of 405 nm. These PbI2 nanosheets can also be completely converted into MAPbI3 materials via chemical vapor deposition with an improved photoresponsivity up to 40 A W-1 . All these performance parameters are comparable to those of state-of-the-art layered-material-based photodetectors, revealing the technological potency of these freestanding nanosheets for next generation high-performance optoelectronics. PMID- 28815756 TI - Can ad hoc analyses of clinical trials help personalize treatment decisions? PMID- 28815757 TI - First-line treatment selection and early monitoring patterns in chronic phase chronic myeloid leukemia in routine clinical practice: SIMPLICITY. AB - Achieving successful outcomes in chronic phase-chronic myeloid leukemia (CP-CML) requires careful monitoring of cytogenetic/molecular responses (CyR/MR). SIMPLICITY (NCT01244750) is an observational study exploring tyrosine kinase inhibitor use and management patterns in patients with CP-CML receiving first line imatinib (n = 416), dasatinib (n = 418) or nilotinib (n = 408) in the US and 6 European countries in routine clinical practice. Twelve-month follow-up data of 1242 prospective patients (enrolled October 01 2010-September 02 2015) are reported. 81% of patients had baseline comorbidities. Treatment selection was based on perceived efficacy over patient comorbidity profile. There was a predominance of imatinib-treated patients enrolled earlier in the study, with subsequent shift toward dasatinib- and nilotinib-treated patients by 2013/2014. Monitoring for either CyR/MR improved over time and was documented for 36%, 82%, and 95% of patients by 3, 6, and 12 months, respectively; 5% had no documentation of CyR/MR monitoring during the first year of therapy. Documentation of MR/CyR testing was higher in Europe than the US (P < .001) and at academic versus community practices (P = .001). Age <65 years, patients being followed at sites within Europe, those followed at academic centers and patients no longer on first line therapy were more likely to be monitored by 12 months. SIMPLICITY demonstrates that the NCCN and ELN recommendations on response monitoring have not been consistently translated into routine clinical practice. In the absence of appropriate monitoring practices, clinical response to TKI therapy cannot be established, any needed changes to treatment strategy will thus not be implemented, and long-term patient outcomes are likely to be impacted. PMID- 28815758 TI - Detection of Cyprinid Herpesvirus 1 DNA in cutaneous squamous cell carcinoma of koi carp (Cyprinus carpio). AB - BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is an uncommon disease affecting koi carp (Cyprinus carpio). Cutaneous papilloma (carp pox) is a benign epidermal proliferation reported in koi and has been shown to be caused by Cyprinid Herpesvirus 1 (CyHV1). HYPOTHESIS/OBJECTIVES: Histological, ultrastructural and molecular investigations were carried out aiming to investigate the aetiology of cSCC within archived tissue samples. ANIMALS: Surgical samples of masses located on the integument, fins and lips of 13 koi carp belonging to different private owners were included in this retrospective study. METHODS: CyHV1 DNA and RNA presence were investigated in five cSCC formalin-fixed paraffin-embedded tissue samples to recognize CyHV1 presence and its replication activity. RESULTS: All cases were histologically diagnosed as cSCC. The ultrastructural observations confirmed the squamous differentiation of neoplastic epithelial cells, which showed abundant tonofilament bundles and desmosomes. Although no virus particles were revealed ultrastructurally, the molecular investigation detected viral DNA in five epidemiologically unrelated cSCC. Viral transcript analysis revealed no evidence for viral replication in the tested cSCC, which could be consistent with latent infection. CONCLUSIONS AND CLINICAL IMPORTANCE: These findings illustrate the frequent association of carp cSCC with CyHV1, although a direct cause-effect relationship cannot be established at this time. Therefore, surveillance programmes should take into account the suspected viral origin of cSCC to better inform prevention and control of CyHV1 in the future. PMID- 28815760 TI - Impact Microindentation: Consistency of Serial Measurements and Alterations in Patients With Paget's Disease of the Tibia. AB - Impact microindentation (IMI) is a new technique for the in vivo measurement of tissue-level properties of cortical bone in humans. To address issues related to the proper application of IMI in clinical practice and to directly examine cortical bone properties in patients with tibia pathology, we studied 11 subjects without tibia pathology and nine patients with Paget's disease of the tibia in biochemical remission after bisphosphonate treatment. Serial indentations in the tibias of both legs were performed in all subjects by a single operator until 10 adequate measurements were obtained in each tibia. In patients without Paget's disease (7 men and 4 women; mean age, 61.9 years; range, 51 to 72 years), there was no difference in mean bone material strength index (BMSi) between the dominant and nondominant leg (82.1 +/- 1.3 and 81.4 +/- 1.3, respectively; p = 0.606). In each individual subject studied, sequential indentations in both legs showed no trends for higher or lower values with time. The standard deviation of unnormalized bone material strength (BMSu) was also comparable between the dominant and nondominant tibia (5.3 and 4.5, respectively; p = 0.657). In patients with Paget's disease (4 men and 5 women; mean age, 69.5 years; range, 55 to 87 years), mean BMSi of the Pagetic tibia was lower, albeit nonsignificantly, than that of the contralateral nonaffected tibia (74.7 +/- 1.7 and 78.7 +/- 1.3, respectively; p = 0.120). In contrast to subjects without Paget's disease, the SD of adequate BMSu values was significantly larger in the Pagetic tibia compared to that of the non-Pagetic tibia (7.6 versus 5.0, respectively, p = 0.008). These results highlight the consistency of serial IMI measurements as performed by a single operator in the presence as well as absence of tibia pathology and illustrate that the method is able to capture alterations of tissue-level cortical bone properties in patients with Paget's disease of the tibia. (c) 2017 The Authors.Journal of Bone and Mineral Research Published by Wiley Periodicals Inc. PMID- 28815761 TI - "My mentor didn't speak to me for the first four weeks": Perceived Unfairness experienced by nursing students in clinical practice settings. AB - AIMS AND OBJECTIVES: To explore the perceived unfairness experienced by student nurses during their undergraduate clinical placements. BACKGROUND: It is important that student nurses feel supported by practice staff during their clinical placement education experiences. However, it has been reported that learners can feel ignored, unsupported and bullied by others in the clinical environment and this has a detrimental effect on their learning. It is important to understand the student nurse perspective and explore ways in which their feelings of belongingness might be enhanced in the clinical area. DESIGN: A descriptive narrative approach was used to explore the qualitative data generated by the survey and interviews. Limited closed-question survey data were acquired to explore a selection of quantified survey responses about placements and mentorship. METHODS: A survey was conducted with 1,425 student nurses from adult and mental health degree nursing pathways, across nine institutions in the North West of England, UK. Unstructured interviews were undertaken with 22 student nurses from across these nine institutions. The data generated from both methods (free-text survey responses and interview) were thematically analysed. RESULTS: There were times when student nurses felt that they had been treated unfairly by various members of the healthcare team during their clinical placements. Unfairness was related to being ignored and unsupported or being used as an "extra pair of hands" and having their supernumerary status ignored. Student nurses want to have feelings of belongingness in the clinical area and value enthusiasm for teaching from mentors. Certain positive mentor qualities were identified through the data in this study. These have been used to inform a tiered model of mentorship, to inform future thinking about student nurse education. CONCLUSION: Student nurses can feel like they are being treated unfairly in the clinical area in numerous ways. Identifying ways in which mentorship practice can be developed to adequately support education is important. This can lead to satisfaction and development on both sides of the student/educator relationship. RELEVANCE TO PRACTICE: Exploring student nurse perceptions of their learning is important when attempting to enhance educational practice in the clinical setting. PMID- 28815759 TI - Prediction of Reduction Potentials of Copper Proteins with Continuum Electrostatics and Density Functional Theory. AB - Blue copper proteins, such as azurin, show dramatic changes in Cu2+ /Cu+ reduction potential upon mutation over the full physiological range. Hence, they have important functions in electron transfer and oxidation chemistry and have applications in industrial biotechnology. The details of what determines these reduction potential changes upon mutation are still unclear. Moreover, it has been difficult to model and predict the reduction potential of azurin mutants and currently no unique procedure or workflow pattern exists. Furthermore, high-level computational methods can be accurate but are too time consuming for practical use. In this work, a novel approach for calculating reduction potentials of azurin mutants is shown, based on a combination of continuum electrostatics, density functional theory and empirical hydrophobicity factors. Our method accurately reproduces experimental reduction potential changes of 30 mutants with respect to wildtype within experimental error and highlights the factors contributing to the reduction potential change. Finally, reduction potentials are predicted for a series of 124 new mutants that have not yet been investigated experimentally. Several mutants are identified that are located well over 10 A from the copper center that change the reduction potential by more than 85 mV. The work shows that secondary coordination sphere mutations mostly lead to long range electrostatic changes and hence can be modeled accurately with continuum electrostatics. PMID- 28815762 TI - Examining the social construction of surveillance: A critical issue for health visitors and public health nurses working with mothers and children. AB - AIMS AND OBJECTIVES: To critically examine surveillance practices of health visitors (HV) in the UK and public health nurses (PHNs) in Canada. BACKGROUND: The practice and meaning of surveillance shifts and changes depending on the context and intent of relationships between mothers and HVs or PHNs. DESIGN: We present the context and practice of HVs in the UK and PHNs in Canada and provide a comprehensive literature review regarding surveillance of mothers within public health systems. We then present our critique of the meaning and practice of surveillance across different settings. METHODS: Concepts from Foucault and discourse analysis are used to critically examine and discuss the meaning of surveillance. RESULTS: Surveillance is a complex concept that shifts meaning and is socially and institutionally constructed through relations of power. CONCLUSIONS: Healthcare providers need to understand the different meanings and practices associated with surveillance to effectively inform practice. RELEVANCE TO CLINICAL PRACTICE: Healthcare providers should be aware of how their positions of expert and privilege within healthcare systems affect relationships with mothers. A more comprehensive understanding of personal, social and institutional aspects of surveillance will provide opportunities to reflect upon and change practices that are supportive of mothers and their families. PMID- 28815763 TI - Does low-energy collision-induced dissociation of lithiated and sodiated carbohydrates always occur at anomeric carbon of the reducing end? AB - RATIONALE: Collision-induced dissociation (CID) tandem mass spectrometry is one of the major methods in the structural determination of carbohydrates. Previous experimental studies and theoretical investigation of lithiated and sodiated underivatized carbohydrates seem to indicate that dehydration reactions and cross ring dissociation of low-energy CID mainly occur at the anomeric carbon of the reducing end. However, these studies only investigated a few carbohydrates. METHODS: ESI-MS/MS spectra of [M + Li]+ and [M + Na]+ ions of several 18 O1 labeled monosaccharides and disaccharides at O1 of the reducing end were studied using a linear ion trap mass spectrometer. RESULTS: Dissociations from the losses of both labeled and unlabeled neutral fragments were observed. The branching ratios of dissociations from the losses of unlabeled neutrals for dehydration reactions are larger than that for cross-ring dissociation; lithiated carbohydrates are larger than sodiated carbohydrates, and 1-4 linkages of disaccharides are larger than the other linkages. For some lithiated carbohydrates, dehydration reactions from the losses of unlabeled neutrals have larger branching ratios than that from the losses of labeled neutrals. The fragments from the losses of unlabeled neutrals investigated using MS3 showed that the losses of unlabeled H2 O mainly occur at the reducing monomer for sodiated carbohydrates, but the losses of unlabeled C2 H4 O2 for lithiated carbohydrates can occur at both reducing and nonreducing monomers. The ratio of B1 and Y1 ions to C1 and Z1 ions of disaccharides is related to the cis or trans configuration of the O1 and O2 atoms in the nonreducing monomer. The results are explained by the properties of transition states of dissociation channels. CONCLUSIONS: Our data shows that dehydration reactions and cross ring dissociation do not always occur at the anomeric carbon atom of the reducing monomer. PMID- 28815764 TI - Aligning digital CD8+ scoring and targeted next-generation sequencing with programmed death ligand 1 expression: a pragmatic approach in early-stage squamous cell lung carcinoma. AB - AIMS: To study programmed death ligand 1 (PD-L1) expression, tumour-infiltrating T lymphocytes (TILs) and the molecular context in patients with early-stage squamous cell lung carcinomas (SCCs). METHODS AND RESULTS: The study included samples from 40 patients (discovery cohort) and 29 patients (validation cohort) diagnosed with early-stage SCC. PD-L1 immunohistochemistry (IHC) was performed with three commercially available clones (E1L3N, SP263 and SP142). CD8+ TILs were scored with a digital algorithm. All tumours were analysed with targeted next generation sequencing (NGS). Additionally, TP53 mutations were investigated with direct sequencing. In both cohorts, we observed a significant association between CD8+ TILs density and high PD-L1 IHC expression in tumour cells (TCs). Furthermore, high SP142 PD-L1 expression in immune cells (ICs) was also associated significantly with CD8+ TILs density. Therefore, CD8+ TILs density discriminated between patients with high versus low PD-L1 IHC expression with excellent sensitivity and specificity. Interestingly, the highest percentages of PD-L1-positive TCs with the three antibodies were found in samples with cyclin dependent kinase 6 (CDK6) amplification, with high amplification of proto oncogene C-Myc (CMYC) or with cyclin D1-PI3 kinase subunit alpha (CCND1-PIK3CA) co-amplification. High SP142 PD-L1 IHC expression in ICs showed a non-significant correlation with TP53 mutations. Conversely, most cases with fibroblast growth factor receptor 1 (FGFR1) amplification were negative for all PD-L1 clones. CONCLUSIONS: Our preliminary results support the use of digital CD8+ TILs scoring and targeted NGS alongside PD-L1 expression. The approach presented herein could help define patients with SCCs candidates to immune checkpoints inhibitors. PMID- 28815765 TI - New tools and functions in data-out activities at Protein Data Bank Japan (PDBj). AB - The Protein Data Bank Japan (PDBj), a member of the worldwide Protein Data Bank (wwPDB), accepts and processes the deposited data of experimentally determined biological macromolecular structures. In addition to archiving the PDB data in collaboration with the other wwPDB partners, PDBj also provides a wide range of original and unique services and tools, which are continuously improved and updated. Here, we report the new RDB PDBj Mine 2, the WebGL molecular viewer Molmil, the ProMode-Elastic server for normal mode analysis, a virtual reality system for the eF-site protein electrostatic molecular surfaces, the extensions of the Omokage search for molecular shape similarity, and the integration of PDBj and BMRB searches. PMID- 28815766 TI - Preparation of Robust Metal-Free Magnetic Nanoemulsions Encapsulating Low Molecular-Weight Nitroxide Radicals and Hydrophobic Drugs Directed Toward MRI Visible Targeted Delivery. AB - With a view to developing a theranostic nanomedicine for targeted drug delivery systems visible by magnetic resonance (MR) imaging, robust metal-free magnetic nanoemulsions (mean particle size less than 20 nm) consisting of a biocompatible surfactant and hydrophobic, low molecular weight 2,2,5-trimethyl-5-(4 alkoxy)phenylpyrrolidine-N-oxyl radicals were prepared in pH 7.4 phosphate buffered saline (PBS). The structure of the nanoemulsions was characterized by electron paramagnetic resonance spectroscopy, and dynamic light scattering and small-angle neutron-scattering measurements. The nanoemulsions showed high colloidal stability, low cytotoxicity, enough reduction resistance to excess ascorbic acid, and sufficient contrast enhancement in the proton longitudinal relaxation time (T1 ) weighted MR images in PBS in vitro (and preliminarily in vivo). Furthermore, the hydrophobic anticancer drug paclitaxel could be encapsulated inside the nanoparticles, and the resulting paclitaxel-loaded nanoemulsions were efficiently incorporated into HeLa cells to suppress cell growth. PMID- 28815767 TI - Gut microbiota of a long-distance migrant demonstrates resistance against environmental microbe incursions. AB - Migratory animals encounter suites of novel microbes as they move between disparate sites during their migrations, and are frequently implicated in the global spread of pathogens. Although wild animals have been shown to source a proportion of their gut microbiota from their environment, the susceptibility of migrants to enteric infections may be dependent upon the capacity of their gut microbiota to resist incorporating encountered microbes. To evaluate migrants' susceptibility to microbial invasion, we determined the extent of microbial sourcing from the foraging environment and examined how this influenced gut microbiota dynamics over time and space in a migratory shorebird, the Red-necked stint Calidris ruficollis. Contrary to previous studies on wild, nonmigratory hosts, we found that stint on their nonbreeding grounds obtained very little of their microbiota from their environment, with most individuals sourcing only 0.1% of gut microbes from foraging sediment. This microbial resistance was reflected at the population level by only weak compositional differences between stint flocks occupying ecologically distinct sites, and by our finding that stint that had recently migrated 10,000 km did not differ in diversity or taxonomy from those that had inhabited the same site for a full year. However, recent migrants had much greater abundances of the genus Corynebacterium, suggesting a potential microbial response to either migration or exposure to a novel environment. We conclude that the gut microbiota of stint is largely resistant to invasion from ingested microbes and that this may have implications for their susceptibility to enteric infections during migration. PMID- 28815768 TI - Micro-vesicles derived from human Wharton's Jelly mesenchymal stromal cells mitigate renal ischemia-reperfusion injury in rats after cardiac death renal transplantation. AB - The purpose of the present study was to investigate the possible therapeutic effects of the human Wharton-Jelly mesenchymal stromal cells derived micro vesicles (hWJMSCs-MVs) on renal ischemia-reperfusion injury (IRI) after cardiac death (CD) renal transplantation in rats. MVs were injected intravenously in rats immediately after renal transplantation. The animals were sacrificed at 24 h, 48 h, 1 and 2 weeks post-transplantation. ELISA was used to determine the von Willebrand Factor (vWF), tumor necrosis factor (TNF)-alpha, and interleukin (IL) 10 levels in the serum. Tubular cell proliferation and apoptosis were identified by Ki67 immunostaining and TUNEL assay. Renal fibrosis was assessed by Masson's tri-chrome straining and alpha-smooth muscle actin (alpha-SMA) staining. The infiltration of inflammatory cells was detected by CD68+ staining. The transforming growth factor (TGF)-beta, hepatocyte growth factor (HGF), and alpha SMA expression in the kidney was measured by Western blot. After renal transplantation, the rats treated with hWJMSCs-MVs improved survival rate and renal function. Moreover, MVs mitigated renal cell apoptosis, enhanced proliferation, and alleviated inflammation at the first 48 h. In the late period, abrogation of renal fibrosis was observed in the MVs group. MVs also could decrease the number of CD68+ macrophages in the kidney. Furthermore, MVs decreased the protein expression levels of alpha-SMA and TGF-beta1 and increased the protein expression level of HGF at any point (24 h, 48 h, 1 or 2 weeks). The administration of MVs immediately after renal transplantation could ameliorate IRI in both the acute and chronic stage. PMID- 28815770 TI - Pyoderma gangrenosum-like ulcer caused by Helicobacter cinaedi in a patient with hypogammaglobulinemia. PMID- 28815769 TI - Homology modeling in a dynamical world. AB - A key concept in template-based modeling (TBM) is the high correlation between sequence and structural divergence, with the practical consequence that homologous proteins that are similar at the sequence level will also be similar at the structural level. However, conformational diversity of the native state will reduce the correlation between structural and sequence divergence, because structural variation can appear without sequence diversity. In this work, we explore the impact that conformational diversity has on the relationship between structural and sequence divergence. We find that the extent of conformational diversity can be as high as the maximum structural divergence among families. Also, as expected, conformational diversity impairs the well-established correlation between sequence and structural divergence, which is nosier than previously suggested. However, we found that this noise can be resolved using a priori information coming from the structure-function relationship. We show that protein families with low conformational diversity show a well-correlated relationship between sequence and structural divergence, which is severely reduced in proteins with larger conformational diversity. This lack of correlation could impair TBM results in highly dynamical proteins. Finally, we also find that the presence of order/disorder can provide useful beforehand information for better TBM performance. PMID- 28815771 TI - Molstack-Interactive visualization tool for presentation, interpretation, and validation of macromolecules and electron density maps. AB - Our understanding of the world of biomolecular structures is based upon the interpretation of macromolecular models, of which ~90% are an interpretation of electron density maps. This structural information guides scientific progress and exploration in many biomedical disciplines. The Protein Data Bank's web portals have made these structures available for mass scientific consumption and greatly broaden the scope of information presented in scientific publications. The portals provide numerous quality metrics; however, the portion of the structure that is most vital for interpretation of the function may have the most difficult to interpret electron density and this ambiguity is not reflected by any single metric. The possible consequences of basing research on suboptimal models make it imperative to inspect the agreement of a model with its experimental evidence. Molstack, a web-based interactive publishing platform for structural data, allows users to present density maps and structural models by displaying a collection of maps and models, including different interpretation of one's own data, re refinements, and corrections of existing structures. Molstack organizes the sharing and dissemination of these structural models along with their experimental evidence as an interactive session. Molstack was designed with three groups of users in mind; researchers can present the evidence of their interpretation, reviewers and readers can independently judge the experimental evidence of the authors' conclusions, and other researchers can present or even publish their new hypotheses in the context of prior results. The server is available at http://molstack.bioreproducibility.org. PMID- 28815772 TI - Ectropion Improvement with Topical Tazarotene in Children with Lamellar Ichthyosis. AB - BACKGROUND/OBJECTIVES: Lamellar ichthyosis (LI) is a well-described phenotypic subtype of autosomal recessive congenital ichthyosis (ARCI). The condition typically presents at birth with collodion membrane and leads to thick, plate like scaling of the skin throughout the body, alopecia, and prominent ocular manifestations. Ocular complications include bilateral cicatricial ectropion and lagophthalmos. These ocular complications can lead to chronic exposure keratitis and in some cases corneal ulceration and blindness. No cure for ichthyosis exists. Treatment of ocular complications in LI includes surgical correction, systemic retinoids, and a variety of topical therapies such as emollients, keratolytics, and retinoids. METHODS: Five children with LI cared for at our institution were identified and included. Patient age at the start of therapy ranged from 2 weeks to 9 years. Electronic medical records were reviewed and data from pediatric dermatologist and pediatric ophthalmologist visits were obtained. Data were collected before and after treatment of daily or twice-daily 0.05% to 0.1% tazarotene cream applied to the face and eyelids. RESULTS: All patients had improvement in the degree of ectropion, with complete resolution in two of the five patients. The two patients with lagophthalmos at the time of tazarotene initiation experienced complete resolution. No adverse effects were reported. CONCLUSIONS: Tazarotene cream appears to be effective in the management of ectropion and lagophthalmos in the setting of LI in children, even in the neonatal period. PMID- 28815773 TI - Overtreatment of diabetes in older people. PMID- 28815774 TI - Excitonically Coupled States in Crystalline Coordination Networks. AB - When chromophores are brought into close proximity, noncovalent interactions (pi pi/CH-pi) can lead to the formation of excitonically coupled states, which bestow new photophysical properties upon the aggregates. Because the properties of the new states not only depend on the strength of intermolecular interactions, but also on the relative orientation, supramolecular assemblies, where these parameters can be varied in a deliberate fashion, provide novel possibilities for the control of photophysical properties. This work reports that core-substituted naphthalene diimides (cNDIs) can be incorporated into surface-mounted metal- organic structures/frameworks (SURMOFs) to yield optical properties strikingly different from conventional aggregates of such molecules, for example, formed in solution or by crystallization. Organic linkers are used, based on cNDIs, well known organic chromophores with numerous applications in different optoelectronic devices, to fabricate MOF thin films on transparent substrates. A thorough characterization of the properties of these highly ordered chromophoric assemblies reveals the presence of non-emissive excited states in the crystalline material. Structural modulations provide further insights into the nature of the coupling that gives rise to an excited-state energy level in the periodic structure. PMID- 28815775 TI - Photoinduced Electron Transfer Switching Mechanism of a Naphthalimide Derivative with its Solvatochromic Behaviour: An Experimental and Theoretical Study with In Cell Investigations. AB - The sole existence of a t-bone-shaped naphthalimide derivative [2-(2-aminoethyl) 1H-benzo[de]isoquinoline-1,3(2H)dione] (NAP), which gives rise to a photoinduced electron transfer (PET) mechanism, has been established using a combination of experimental and theoretical studies. In parallel an in vitro-in cell PET mechanism has also been shown. To understand the photophysics of NAP, solvent studies have been carried out in different solvents. In addition, theoretical calculations have been conducted to explain the spectroscopic properties through optimized structures. A "turn off" PET mechanism has also been observed in the presence of specific metal ions, namely, Cr3+ , Fe3+ and Hg2+ among a series of metal ions. Theoretical studies reveal that NAP-Cr3+ , NAP-Fe3+ and NAP-Hg2+ have their HOMO energy states lying in between a HOMO-LUMO energy state of the t-bone type NAP molecule. On the contrary, the HOMO state of the other metal ion-NAP conjugate (NAP-Mn+ ) does not lie in between the HOMO-LUMO energy gap of the t bone-type NAP molecule. Coupled with in vitro studies, in cell investigations reveal an enhancement of fluorescence intensity of NAP upon cytosolic metal sensing. Furthermore, a very high cell viability of NAP treated cells as tested by MTT assay and a fast permeation of the said compound as revealed by flow cytometry suggest NAP to be a potential candidate in metal sensing and bioimaging applications. PMID- 28815776 TI - Photochemical and Electrochemical Triggered Bis(hydrazone) Switch. AB - Herein, we report the synthesis of a double hydrazone capable of undergoing photochemical E/Z isomerization through the imine double bonds. The bis(hydrazone) 1-E,E can be considered as a "two-arm" system in which the controlled movement of each arm is obtained by photo-modulation, making possible the appearance of two isolable metastable isomeric states 1-E,Z and 1-Z,Z. Such states are characterized by very specific structural, optical, and electrochemical properties. The latter allows the reversible return from either 1 E,Z or 1-Z,Z to the 1-E,E state. Our results are of great importance in the further development of molecular machines and photochemically controlled reactions by introducing for the first time double hydrazones as tunable photochemical switches. PMID- 28815777 TI - A deficiency of the link protein Bral2 affects the size of the extracellular space in the thalamus of aged mice. AB - Bral2 is a link protein stabilizing the binding between lecticans and hyaluronan in perineuronal nets and axonal coats (ACs) in specific brain regions. Using the real-time iontophoretic method and diffusion-weighted magnetic resonance, we determined the extracellular space (ECS) volume fraction (alpha), tortuosity (lambda), and apparent diffusion coefficient of water (ADCW ) in the thalamic ventral posteromedial nucleus (VPM) and sensorimotor cortex of young adult (3-6 months) and aged (14-20 months) Bral2-deficient (Bral2-/- ) mice and age-matched wild-type (wt) controls. The results were correlated with an analysis of extracellular matrix composition. In the cortex, no changes between wt and Bral2 /- were detected, either in the young or aged mice. In the VPM of aged but not in young Bral2-/- mice, we observed a significant decrease in alpha and ADCW in comparison with age-matched controls. Bral2 deficiency led to a reduction of both aggrecan- and brevican-associated perineuronal nets and a complete disruption of brevican-based ACs in young as well as aged VPM. Our data suggest that aging is a critical point that reveals the effect of Bral2 deficiency on VPM diffusion. This effect is probably mediated through the enhanced age-related damage of neurons lacking protective ACs, or the exhausting of compensatory mechanisms maintaining unchanged diffusion parameters in young Bral2-/- animals. A decreased ECS volume in aged Bral2-/- mice may influence the diffusion of neuroactive substances, and thus extrasynaptic and also indirectly synaptic transmission in this important nucleus of the somatosensory pathway. PMID- 28815778 TI - MAPK8 regulates chicken male germ cell differentiation through JNK signaling pathway. AB - The study aims to analyze the key signaling pathways in regulating the process of embryonic stem cells (ESCs) differentiation into spermatogonial stem cells (SSCs). We explored the specific regulating mechanisms of C-Jun amino-terminal kinase (JNK) signaling in this process. Interference/overexpression of MAPK8 allows the JNK signaling pathway to be blocked/activated. In Retinoic acid (RA) induced in vitro differentiation assays, the expression of germ cell marker genes, cvh, c-kit, integrin alpha6 and integrin beta1, was observed to upregulate while activating JNK signaling significantly. Fluorescence Activated Cell Sorting (FACs) analysis showed that the proportion of cvh+ and integrin alpha6+ cells in the overexpression group was significantly higher than which in the RA + shRNA MAPK8 group. In in vivo situations, shRNA-MAPK8 could stably express in chicken embryos and significantly down-regulate expression of MAPK8 and downstream genes in JNK signaling pathway. With PAS stain, we found that PGCs (primordial germ cells) was significantly decreased after inhibiting MAPK8. With real-time quantitative PCR (qRT-PCR) and Western Blot, we identified that reproductive related genes expression was significantly suppressed after inhibiting MAPK8 in vivo. We preliminarily concluded that knockdown/ overexpression of MAPK8 could affect differentiation of ESC by inhibiting/activating JNK signal. PMID- 28815779 TI - Short-Term Teriparatide and Recombinant Human Bone Morphogenetic Protein-2 for Regenerative Approach to Medication-Related Osteonecrosis of the Jaw: A Preliminary Study. AB - Our objective was to examine whether adjunct teriparatide administration and local application of recombinant human bone morphogenetic protein-2 (rhBMP-2) is beneficial for the regeneration of jaw bone in patients with medication-related osteonecrosis of the jaw (MRONJ). This study enrolled 17 patients diagnosed with MRONJ. All patients received sequestrectomy under general or local anesthesia with suspension of bisphosphonate. The bone regeneration ratio was compared on cone beam computed tomography (CBCT) scans, acquired immediately post-operation and after 6 months. The patients were divided into groups, based on their treatment regimens: teriparatide combined with rhBMP-2 (parathyroid hormone [PTH]+BMP), rhBMP-2 (BMP), and the control. Biochemical markers were also evaluated at the baseline (T0), 1 month (T1), and 3 months (T2) after surgery. Significant increase was observed in the values of the biochemical markers, serum osteocalcin, and serum C-terminal telopeptide cross-link of type I collagen, within 3 months of surgery in the PTH+BMP group, whereas the mean value in the BMP group did not show a significant change. In all groups, the MRONJ lesions were healed and new bone formation was detected in the CBCT images. The regeneration ratio was significantly greater in the group PTH+BMP than in the BMP and control groups. Significantly greater amount of bone formation was observed in the group PTH+BMP than in the BMP and control groups. Local application of rhBMP-2 alone also had a beneficial effect on bone regeneration but was not more significant than control. Based on these findings, administration of short-term teriparatide with rhBMP-2 in MRONJ patients may maximize the regeneration of bone after surgery. (c) 2017 American Society for Bone and Mineral Research. PMID- 28815780 TI - Prognostic significance of E-cadherin and beta-catenin expression in HPV-negative oropharyngeal squamous cell carcinomas. AB - BACKGROUND: The purpose of this work was to investigate the prognostic significance of E-cadherin and beta-catenin expression in surgically treated human papillomavirus (HPV)-negative patients with oropharyngeal squamous cell carcinoma (SCC). METHODS: Consecutive patients with oropharyngeal SCC who underwent surgical treatment between 1990 and 2009 were retrospectively collected. Immunohistochemical analysis of E-cadherin and beta-catenin expression was performed on tissue microarrays. RESULTS: E-cadherin and beta-catenin expression was evaluable in 232 cases. Low membranous E-cadherin, low membranous beta-catenin expression, and nuclear beta-catenin expression were associated with a poorer disease-specific and overall survival, although the differences were only significant for beta-catenin membranous expression (P = .024 and P = .016, respectively). In multivariate analysis, nodal metastasis and low membranous beta catenin expression were significant independent predictors of reduced disease specific and overall survival. CONCLUSION: Low membranous beta-catenin expression is a significant independent predictor of both reduced disease-specific and overall survival in patients with HPV-negative oropharyngeal SCC. PMID- 28815781 TI - External jugular veno-accompanying artery adipofascial flap: A novel and convenient flap for head and neck reconstruction. AB - BACKGROUND: The veno-accompanying artery adipofascial (VAF) flap is nourished by accompanying vessels near large superficial veins. We examined whether the VAF flap can be applied to the external jugular vein. METHODS: Based on anatomic and angiographic studies, we performed reconstructive surgeries using external jugular veno-accompanying artery adipofascial (EJ-VAF) flaps. A retrospective chart review was performed for all patients who underwent this surgery. RESULTS: The presence of arteries accompanying the external jugular vein was confirmed. The presence of source arteries was also confirmed. These included the occipital, facial, and superior thyroid arteries. All patients had satisfactory outcomes, except for 1 patient who had partial necrosis, which was managed using conservative treatment. CONCLUSION: Our anatomic and angiographic studies in this clinical series indicate that the EJ-VAF flap is a reliable and convenient flap. Thus, it is useful in reconstruction of small to medium head and neck defects. PMID- 28815782 TI - Influence of conjugated linoleic acids and vitamin E on milk fatty acid composition and concentrations of vitamin A and alpha-tocopherol in blood and milk of dairy cows. AB - The objective of this trial was to investigate the influences of conjugated linoleic acid (CLA) and vitamin E (Vit. E) and their interactions on fatty acid composition and vitamins in milk (alpha-tocopherol, retinol and beta-carotene) as well as on alpha-tocopherol in blood of pluriparous cows from week 6 ante partum until week 10 post-partum (p.p.). We assigned 59 pluriparous German Holstein cows to four treatment groups with the treatment factors CLA and Vit. E at two levels in a 2 * 2 factorial design. Milk fatty acid composition and milk vitamins were analysed on lactation days 7 and 28. alpha-tocopherol in blood serum was analysed on days -42, -7, 1, 7, 14, 28 and 70 relative to parturition. Milk concentration of alpha-tocopherol was influenced by Vit. E (p < .001) and CLA (p = .034). Percentage of cis-9, trans-11 CLA in total milk fat was influenced by treatment with CLA (p < .001), while for percentage of trans-10, cis-12 CLA an interaction between treatment and day (p = .019), driven by an increase in both CLA groups from day 7 to day 28, was found. Serum ratios of alpha-tocopherol to cholesterol were influenced by Vit. E (p < .001). Results suggest that treatment with CLA during late pregnancy and early lactation is suitable to enhance the proportion of trans-10, cis-12 CLA in milk and thereby influencing nutritional properties. As treatment with Vit. E did not have an impact on milk fatty acid composition, it might be possible to increase the antioxidative capacity of the dairy cow without affecting milk properties. Consequently, combined treatment with CLA and Vit. E might elicit synergistic effects on the cow and milk quality by increasing the proportion of CLA in milk fat as well as the excretion of Vit. E and the Vit. E levels in serum. PMID- 28815783 TI - Stuck in tradition-A qualitative study on barriers for implementation of evidence based nutritional care perceived by nursing staff. AB - AIMS AND OBJECTIVES: To explore the barriers for nutritional care as perceived by nursing staff at an acute orthopaedic ward, aiming to implement evidence-based nutritional care. BACKGROUND: Previous studies indicate that nurses recognise nutritional care as important, but interventions are often lacking. These studies show that a range of barriers influence the attempt to optimise nutritional care. Before the implementation of evidence-based nutritional care, we examined barriers for nutritional care among the nursing staff. DESIGN: Qualitative study. METHODS: Four focus groups with thirteen members of the nursing staff were interviewed between October 2013-June 2014. The interview guide was designed according to the Theoretical Domains Framework. The interviews were analysed using qualitative content analysis. RESULTS: Three main categories emerged: lacking common practice, failing to initiate treatment and struggling with existing resources. The nursing staff was lacking both knowledge and common practice regarding nutritional care. They felt they protected patient autonomy by accepting patient's reluctance to eat or getting a feeding tube. The lack of nutritional focus from doctors decreased the nursing staffs focus leading to nonoptimal nutritional treatment. Competing priorities, physical setting and limited nutritional supplements were believed to hinder nutritional care. CONCLUSION: The results suggest that nutritional care is in a transitional state from experience- to evidence-based practice. Barriers for nutritional care are grounded in lack of knowledge among nursing staff and insufficient collaboration between nursing staff and the doctors. There is a need for nutritional education for the nursing staff and better support from the organisation to help nursing staff provide evidence-based nutritional care. RELEVANCE TO CLINICAL PRACTICE: This study contributes with valuable knowledge before the implementation of evidence-based nutritional care. The study provides an understanding of barriers for nutritional care and presents explanations to why nutritional care has failed to become an integrated part of the daily treatment and care. PMID- 28815784 TI - Nursing care for stroke patients: A survey of current practice in 11 European countries. AB - AIMS AND OBJECTIVES: To conduct a survey of the clinical nursing practice in European countries in accordance with the European Stroke Strategies 2006 and to examine to what extent the European Stroke Strategies have been implemented in stroke care nursing in Europe. BACKGROUND: Stroke is a leading cause of death and disability globally. Optimal organisation of interdisciplinary stroke care is expected to ameliorate outcome after stroke. Consequently, universal access to stroke care based on evidence-based guidelines is a priority. DESIGN: This study is a descriptive cross-sectional survey. METHODS: A questionnaire comprising 61 questions based on the European Stroke Strategies and scientific evidence in nursing practice was distributed to representatives of the European Association of Neuroscience Nurses, who sent the questionnaire to nurses active in stroke care. The questionnaire covered the following areas of stroke care: organisation of stroke services, management of acute stroke and prevention including basic care and nursing, and secondary prevention. RESULTS: Ninety-two nurses in stroke care in 11 European countries participated in the survey. Within the first 48 hr after stroke onset, 95% monitor patients regularly, 94% start mobilisation after 24 hr when patients are stable, and 89% assess patients' ability to swallow. Change of position for immobile patients is followed by 73%, and postvoid residual urine volume is measured by 85%. Some aspects needed improvement, for example, staff education (70%), education for patients/families/carers (55%) and individual care plans in secondary prevention (62%). CONCLUSIONS: The participating European countries comply well with the European Stroke Strategies guidelines, particularly in the acute stroke care, but not all stroke units have reached optimal development in all aspects of stroke care nursing. RELEVANCE TO CLINICAL PRACTICE: Our study may provide clinical administrators and nurses in stroke care with information that may contribute to improved compliance with the European Stroke Strategies and evidence-based guidelines. PMID- 28815785 TI - Late Pleistocene origin of the entire circumarctic range of the arctic-alpine plant Kalmia procumbens. AB - The circumarctic ranges of arctic-alpine plants are thought to have been established in the late Pliocene/early Pleistocene, when the modern arctic tundra was formed in response to climate cooling. Previous findings of range-wide genetic structure in arctic-alpine plants have been thought to support this hypothesis, but few studies have explicitly addressed the temporal framework of the genetic structure. Here, we estimated the demographic history of the genetic structure in the circumarctic Kalmia procumbens using sequences of multiple nuclear loci and examined whether its genetic structure reflects prolonged isolation throughout the Pleistocene. Both Bayesian clustering and phylogenetic analyses revealed genetic distinction between alpine and arctic regions, whereas detailed groupings were somewhat discordant between the analyses. By assuming a population grouping based on the phylogenetic analyses, which likely reflects a deeper intraspecific divergence, we conducted model-based analyses and demonstrated that the intraspecific genetic divergence in K. procumbens likely originated during the last glacial period. Thus, there is no need to postulate range separation throughout the Pleistocene to explain the current genetic structure in this species. This study demonstrates that range-wide genetic structure in arctic-alpine plants does not necessarily result from the late Pliocene/early Pleistocene origin of their circumarctic ranges and emphasizes the importance of a temporal framework of the current genetic structure for understanding the biogeographic history of the arctic flora. PMID- 28815786 TI - Vitamin D intake during the first 4 years and onset of asthma by age 5: A nested case-control study. AB - BACKGROUND: Early-life vitamin D intake has been linked to asthma risk in childhood, but the role of longitudinal vitamin D exposure has not been previously evaluated. We investigated the association between vitamin D intake during the first 4 years of life and asthma risk by age 5. METHODS: Within a Finnish population-based birth cohort, 182 incident asthma cases were matched to 728 controls on sex, genetic risk for type 1 diabetes, delivery hospital, and time of birth. Vitamin D intake was assessed by age-specific 3 day food records. Parents completed a validated version of the International Study of Asthma and Allergies in Childhood questionnaire at 5 years. RESULTS: At 3 months, supplements were the main source of vitamin D intake; intake from foods increased from 3 months on, mainly from fortified milk products. Vitamin D intake at each specific age was associated with an increased risk of any asthma, atopic, and non atopic asthma, but only intake at 1 and 2 years was statistically significantly associated with asthma. Longitudinal vitamin D intake was associated with an increased risk of asthma (OR 1.24; 95%CI 1.00-1.53). CONCLUSIONS: Increased vitamin D intake in childhood, particularly intake at 1 and 2 years of age, may increase risk of childhood asthma. This might reflect a true effect or residual confounding by lifestyle or environmental factors. Repeated assessment of vitamin D intake allowed evaluation of the longitudinal and age-dependent impact of vitamin D on the risk of asthma. Further longitudinal studies are required to confirm or question these findings. PMID- 28815787 TI - Evaluation of incidence, significance, and prognostic role of circulating tumor microemboli and transforming growth factor-beta receptor I in head and neck cancer. AB - BACKGROUND: Circulating tumor microemboli (CTM) are clusters of circulating tumor cells (CTCs), involved in metastasis, as also transforming growth factor-beta (TGF-beta). The purpose of this study was to verify their role in progression free survival (PFS). METHODS: Blood from patients with locally advanced head and neck squamous cell carcinoma (HNSCC; n = 53) was analyzed in 2 moments. TGF-beta receptor I (TGF-betaRI) expression was evaluated by immunocytochemistry. RESULTS: Comparing CTM1 (baseline) with CTM2 (first follow-up), patients with CTM1 positive disease who became CTM2-negative were classified as favorable (PFS 20 months). Patients with unfavorable evolution (CTM1-negative/CTM2-positive), had PFS of 17.5 months. Patients always CTM-negative showed PFS of 22.4 months, those always positive, 4.7 months (P < .001). The TGF-betaRI expression in the first follow-up correlated with poor PFS (12 * 26 months; P = .007), being an independent prognostic factor (hazard ratio [HR] = 6.088; P = .033). CONCLUSION: CTM1/2, TGF-betaRI expression, and unfavorable CTM kinetics may represent poor prognosis in locally advanced HNSCC. PMID- 28815788 TI - Association between radioiodine treatment for thyroid cancer and risk of stroke. AB - BACKGROUND: The purpose of this study was to evaluate the association between radioiodine (I-131) therapy for thyroid cancer and the risk of stroke in Taiwan. METHODS: A total of 10 104 of the patients aged 20 years or older, who were newly diagnosed with thyroid cancer during 2000-2010, were recruited and classified into 2 cohorts according to whether they received I-131 therapy through 1:1 propensity score matching. The cumulative Kaplan-Meier curves for the incidence of stroke in the 2 cohorts were compared using the log-rank test. RESULTS: After adjustment for age, sex, and comorbidities, the I-131 therapy group showed no significantly higher risk of ischemic stroke (adjusted HR [aHR] = 1.05; 95% confidence interval [CI] = 0.82-1.34) or hemorrhagic stroke (aHR = 1.06; 95% CI = 0.58-1.93) than did the non-I-131 therapy group. CONCLUSION: The I-131 treatment for thyroid cancer did not increase the risk of stroke during 10-year follow-up. PMID- 28815789 TI - Cost-effectiveness of emergency department-initiated treatment for opioid dependence. AB - BACKGROUND AND AIMS: In a recent randomized trial, patients with opioid dependence receiving brief intervention, emergency department (ED)-initiated buprenorphine and ongoing follow-up in primary care with buprenorphine (buprenorphine) were twice as likely to be engaged in addiction treatment compared with referral to community-based treatment (referral) or brief intervention and referral (brief intervention). Our aim was to evaluate the relative cost-effectiveness of these three methods of intervening on opioid dependence in the ED. DESIGN: Measured health-care use was converted to dollar values. We considered a health-care system perspective and constructed cost effectiveness acceptability curves that indicate the probability each treatment is cost-effective under different thresholds of willingness-to-pay for outcomes studied. SETTING: An urban ED in the United States. PARTICIPANTS: Opioid dependent patients aged 18 years or older. MEASUREMENTS: Self-reported 30-day assessment data were used to construct cost-effectiveness acceptability curves for patient engagement in formal addiction treatment at 30 days and the number of days illicit opioid-free in the past week. FINDINGS: Considering only health-care system costs, cost-effectiveness acceptability curves indicate that at all positive willingness-to-pay values, ED-initiated buprenorphine treatment was more cost-effective than brief intervention or referral. For example, at a willingness to-pay threshold of $1000 for 30-day treatment engagement, we are 79% certain ED initiated buprenorphine is most cost-effective compared with other studied treatments. Similar results were found for days illicit opioid-free in the past week. Results were robust to secondary analyses that included patients with missing cost data, included crime and patient time costs in the numerator, and to changes in unit price estimates. CONCLUSION: In the United States, emergency department-initiated buprenorphine intervention for patients with opioid dependence provides high value compared with referral to community-based treatment or combined brief intervention and referral. PMID- 28815790 TI - Evaluation of wastewater treatment by ozonation for reducing the toxicity of contaminants of emerging concern to rainbow trout (Oncorhynchus mykiss). AB - Although conventional wastewater treatment technologies are effective at removing many contaminants of emerging concern (CECs) from municipal wastewater, some contaminants are not removed efficiently. Ozonation may be a treatment option for reducing the concentrations of recalcitrant CECs in wastewater, but this process may generate toxic transformation products. In the present study, we conducted semibatch experiments to ozonate municipal wastewater effluent spiked with 5 commonly detected CECs. The purpose of the present study was to evaluate whether ozonation increased or decreased biological responses indicative of sublethal toxicity in juvenile rainbow trout (Oncorhynchus mykiss) injected intraperitoneally (i.p.) with extracts prepared from ozonated and nonozonated wastewater effluent. Blood, liver, and brain tissues were collected from the fish at 72 h post injection for analysis of a battery of biomarkers. In fish i.p. injected with the extracts from nonozonated wastewater effluent, significant induction of plasma vitellogenin (VTG) was observed, but ozonation of the municipal wastewater effluent spiked with CECs significantly reduced this estrogenic response. However, in fish injected with extracts from spiked municipal wastewater effluent after ozonation, the balance of hepatic glutathione in its oxidized (glutathione disulfide [GSSG]) form was altered, indicating oxidative stress. Levels of the neurotransmitter serotonin were significantly elevated in brain tissue from trout injected with the extracts from ozonated spiked municipal wastewater effluent, a biological response that has not been previously reported in fish. Other in vivo biomarkers showed no significant changes across treatments. These results indicate that ozonation reduces the estrogenicity of wastewater, but may increase other sublethal responses. The increase in biomarker responses after ozonation may be because of the formation of biologically active products of transformation of CECs, but further work is needed to confirm this conclusion. Environ Toxicol Chem 2018;37:274-284. (c) 2017 SETAC. PMID- 28815792 TI - Understanding implications of consumer behavior for wildlife farming and sustainable wildlife trade. AB - Unsustainable wildlife trade affects biodiversity and the livelihoods of communities dependent upon those resources. Wildlife farming has been proposed to promote sustainable trade, but characterizing markets and understanding consumer behavior remain neglected but essential steps in the design and evaluation of such operations. We used sea turtle trade in the Cayman Islands, where turtles have been farm raised for human consumption for almost 50 years, as a case study to explore consumer preferences toward wild-sourced (illegal) and farmed (legal) products and potential conservation implications. Combining methods innovatively (including indirect questioning and choice experiments), we conducted a nationwide trade assessment through in-person interviews from September to December 2014. Households were randomly selected using disproportionate stratified sampling, and responses were weighted based on district population size. We approached 597 individuals, of which 37 (6.2%) refused to participate. Although 30% of households had consumed turtle in the previous 12 months, the purchase and consumption of wild products was rare (e.g., 64-742 resident households consumed wild turtle meat [i.e., 0.3-3.5% of households] but represented a large threat to wild turtles in the area due to their reduced populations). Differences among groups of consumers were marked, as identified through choice experiments, and price and source of product played important roles in their decisions. Despite the long-term practice of farming turtles, 13.5% of consumers showed a strong preference for wild products, which demonstrates the limitations of wildlife farming as a single tool for sustainable wildlife trade. By using a combination of indirect questioning, choice experiments, and sales data to investigate demand for wildlife products, we obtained insights about consumer behavior that can be used to develop conservation-demand-focused initiatives. Lack of data from long-term social ecological assessments hinders the evaluation of and learning from wildlife farming. This information is key to understanding under which conditions different interventions (e.g., bans, wildlife farming, social marketing) are likely to succeed. PMID- 28815791 TI - Risk of preeclampsia after gestational exposure to selective serotonin reuptake inhibitors and other antidepressants: A study from The Norwegian Mother and Child Cohort Study. AB - PURPOSE: To describe the risk of early- and late-onset preeclampsia across pregnancies exposed to antidepressants and to evaluate the impact of timing and length of gestational exposure to antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), on preeclampsia. METHODS: The Norwegian Mother and Child Cohort, a prospective population-based study, and the Medical Birth Registry of Norway provided information on antidepressant exposure, depression, and anxiety symptoms in pregnancy, preeclampsia diagnoses, and important covariates. Within a pregnancy cohort of depressed women, we compared the risk of late-onset preeclampsia between SSRI-exposed and nonmedicated pregnancies using marginal structural models (weighted) and modified Poisson regression models. RESULTS: Of the 5887 pregnancies included, 11.1% were exposed at any time before week 34 to SSRIs, 1.3% to serotonin-norepinephrine reuptake inhibitors, 0.4% to tricyclic antidepressants, and 0.5% to other antidepressants. The risks of early- and late-onset preeclampsia by exposure status in pregnancy were 0.3% and 3.6% (nonmedicated), 0.4% and 3.7% (SSRIs), 1.5% and 4.1% (serotonin-norepinephrine reuptake inhibitors), and 7.1% and 10.0% (tricyclic antidepressants). Compared with nonmedicated pregnancies, SSRI-exposed in mid and late gestation had adjusted relative risks for late-onset mild preeclampsia of 0.76 (95% confidence interval, 0.38-1.53) and 1.56 (0.71-3.44) (weighted models), respectively. There was no association between SSRI exposure in pregnancy and severe late-onset preeclampsia. CONCLUSIONS: We have provided evidence that SSRI use in early and midpregnancy does not substantially increase the risk of late onset preeclampsia. PMID- 28815793 TI - Responsiveness and Morphology Study of Dual Stimuli-Controlled Supramolecular Polymer. AB - The synthesis and characterization of a linear supramolecular polymer formed by dual host-guest recognitions is presented. The polymer linked by the orthogonal interactions of azobenzene with beta-cyclodextrin and methyl viologen with sulfonatocalix[4]arene is constructed, and the morphology change along with the formation and vanishment of host-guest interaction is investigated. The reversible disassembly-reassembly of the polymer induced by light and the redox process are monitored by UV-vis and cyclic voltammetry, respectively. The interesting morphology differences between the monomer guest (G), supramolecular polymer (P), and light dissembled product pseudorotaxane (D1) are observed and analyzed. G conducts self-assembly into a short rod with average width of 83 nm due to the molecular amphipathy and pi-pi interaction between naphthalene nucleuses, while P exhibits 20 nm wide line morphology. Irradiating P with 365 nm light, the corresponding aggregation D1 shows as 35 nm wide short rod. PMID- 28815794 TI - Finding the candidate sequence variants for diagnosis of hypertrophic cardiomyopathy in East Slovak patients. AB - BACKGROUND: Hypertrophic cardiomyopathy is a heterogeneous myocardial disease. Mutations appearing in several genes might be a potential cause of the disease. The aim of the study was to analyze selected exons of the sarcomeric and non sarcomeric genes, with the purpose to identify potential candidate genetic variants and to understand etiopathogenetic mechanisms of hypertrophic cardiomyopathy in East Slovak patients. METHODS: This study recruited 23 unrelated patients with hypertrophic cardiomyopathy, namely, 13 men and 10 women (mean age of 58.09+/-15.82 years) and 25 healthy controls in order to determine the candidate sequence variants, in the selected exons of six cardiomyopathy genes (MYBPC3, MYH7, NEBL, SCN5A, TNNI3, TNNT2), by conventional capillary-based Sanger sequencing method and standard protocols. RESULTS: Molecular genetic results confirmed the presence of 43 sequence variants in the selected exons of six cardiomyopathy genes, 58.14% of detected variants were novel. The majority of detected sequence variants were confirmed within exon 23 of MYH7 gene. Only 11 genetic alterations were predicted to be potentially pathogenic. CONCLUSIONS: In our study, we identified known and novel sequence variants in 23 unrelated patients with hypertrophic cardiomyopathy, but we did not observe any strong mutation hotspot. The results of our study assumed that exon 23 of MYH7 gene can be in potential affinity to hypertrophic cardiomyopathy in our cohort of patients. The sequence variants identified in this study may be further investigated in order to determine their functions in disease pathogenesis and improve management, diagnosis, and treatment in Slovak patients. PMID- 28815795 TI - Routine detection of serum antidesmocollin autoantibodies is only useful in patients with atypical pemphigus. AB - Autoantibodies against the 3 desmocollin (Dsc; Dsc1-Dsc3) isoforms have been described in different pemphigus variants. Here, we developed state-of-the-art detection systems for serum anti-Dsc1, Dsc2 and Dsc1 IgG and IgA. These assays were applied in 5 different cohorts including pemphigus vulgaris (PV) patients with compatible direct immunofluorescence (IF) microscopy but no reactivity against desmogleins 1 and 3 (n = 24) and sera from patients with autoimmune blistering diseases with positive direct IF microscopy taken at the time of diagnosis (n = 749). We found that detection of anti-Dsc serum reactivity is not helpful in the routine diagnosis of PV, pemphigus foliaceus and paraneoplastic pemphigus but may be valuable in pemphigus vegetans. PMID- 28815796 TI - New graduate nurses' preparation for recognition and prevention of failure to rescue: A qualitative study. AB - AIM AND OBJECTIVE: To explore new graduate nurses' experiences with recognition and prevention of failure to rescue. BACKGROUND: Failure to rescue is recognised as a quality-of-care indicator, a core measure of nursing care in hospitals, and a determinant for staffing in acute care facilities. Clinical reasoning is an essential component in preventing failure to rescue and should be emphasised in nursing education and new graduate orientation. Many nurses graduate without the ability to use clinical reasoning in providing patient care which can lead to adverse patient outcomes. DESIGN: A descriptive phenomenological design was used. METHODS: A purposive sample of 14 new graduate nurses from a nursing programme in the south-eastern USA, in practice for no more than eighteen months, was recruited. Individual one-on-one interviews were conducted from January-June 2016 and audio-recorded for accuracy. Data were evaluated using the consolidated criteria for reporting qualitative research (COREQ) guidelines. Recordings were professionally transcribed and reviewed. RESULTS: Using Giorgi's methods for data analysis, five main themes were discerned in the data: clinical preparation in school; experience with emergent situations; development of clinical reasoning; low confidence as a new graduate; and responding to emergencies. Within each theme, subthemes emerged. CONCLUSION: The words of the participants provided rich detail into the preparation of new graduate nurses and how nurse educators, managers and preceptors can better focus learning opportunities to prepare them for practice. Experiential learning combined with collaboration among education stakeholders will lead to a better prepared and more confident nursing work force. RELEVANCE TO CLINICAL PRACTICE: Better preparation and continued support of new graduate nurses lead to positive patient outcomes and more satisfaction with their choice of nursing as a profession. PMID- 28815797 TI - Striking the balance between primary prevention of allergic disease and optimal infant growth and nutrition. PMID- 28815798 TI - Infant spinal anesthesia: Do girls need a larger dose of local anesthetic? AB - BACKGROUND: Gender differences in absorption, distribution, and metabolism of a number of anesthetic agents have been identified in adults. Clinically, adult studies suggest women demonstrate slower onset of opioid analgesic effects, lower spinal and epidural dose requirements, and greater sensitivity to neuromuscular blocking agents. Sex-related differences in the pharmacokinetics and pharmacodynamics of local anesthetics in neonates and infants, however, have not been well documented. As a result, it is not known whether modification of the dose of local anesthetic for awake spinal anesthesia in infants is required. AIMS: Our aim was to determine whether the ED50 and ED95 of local anesthetics used for infant spinal anesthesia are different between sexes. METHODS: This was a retrospective analysis of data previously collected during dose-response studies of levobupivacaine and ropivacaine spinal anesthetics. The doses were reanalyzed using generalized linear regression analysis to determine whether there is a discernible difference in dose requirements between male and female infants. RESULTS: One hundred and twenty infant spinal anesthetics were reviewed. For levobupivacaine, the ED50 (95% CI) was 0.69 (0.49-0.88) mg vs 0.49 (0.33 0.65), whereas the ED95(95% CI) was 1.07 (0.73-1.41) vs 0.93 (0.64-1.22) for girls and boys, respectively. For ropivacaine spinal anesthesia, the ED50 (95% CI) was 0.64 (0.35-0.92) mg vs 0.30 (-0.32-0.92), whereas the ED95 (95% CI) was 1.30 (0.73-1.87) vs 1.66 (0.55-2.76) for girls and boys, respectively. CONCLUSION: There is no evidence that sex differences occur at the ED50 dose range or at the clinically relevant ED95 dose. Modification of spinal anesthetic dose is not required for infant girls. PMID- 28815799 TI - Characterization of opioid use in sickle cell disease. AB - PURPOSE: Opioid analgesics are commonly used to treat vaso-occlusive pain episodes in sickle cell disease (SCD), but comprehensive evidence characterizing opioid use in this patient population is limited. Our objective was to characterize opioid use patterns among SCD patients using a large nationwide database. METHODS: A large, US medical claims database was utilized to identify a cohort of 3882 SCD patients, and characteristics of opioid use were analyzed. Clinical variables including age, gender, medication use, health care utilization, and medical history were evaluated for correlations with opioid use. RESULTS: Forty percent of patients took opioid medications during a 12-month span, and the prevalence of any opioid use was highest for 20 to 29-year-old patients (58%). The median daily opioid dose was 1.85 mg (interquartile range: 0.62-10.68 mg) oral morphine equivalents (OME). While most opioid users took between 0 and 5 mg OME daily, 3% of pediatric patients and 23% of adult patients used more than 30-mg OME daily. High-dose opioid use was associated with older age, hydroxyurea therapy, nonsteroidal anti-inflammatory drug (NSAID) use, and frequent inpatient hospitalizations. In multivariable-adjusted analyses, patients with vaso-occlusive complications such as pain crisis (OR = 3.8, 95% CI 2.7-5.3) and avascular necrosis (AVN) (OR = 3.7, 95% CI 2.7-5.1) were associated with high dose opioid use. CONCLUSIONS: Our study showed that only 40% SCD patients were on opioid analgesics during a 12-month span. However, a non-trivial number of patients used a much higher dose of opioids despite a relatively low average daily opioid dose among SCD patients, particularly with vaso-occlusive complications. PMID- 28815800 TI - A method for data-driven exploration to pinpoint key features in medical data and facilitate expert review. AB - PURPOSE: To develop a method for data-driven exploration in pharmacovigilance and illustrate its use by identifying the key features of individual case safety reports related to medication errors. METHODS: We propose vigiPoint, a method that contrasts the relative frequency of covariate values in a data subset of interest to those within one or more comparators, utilizing odds ratios with adaptive statistical shrinkage. Nested analyses identify higher order patterns, and permutation analysis is employed to protect against chance findings. For illustration, a total of 164 000 adverse event reports related to medication errors were characterized and contrasted to the other 7 833 000 reports in VigiBase, the WHO global database of individual case safety reports, as of May 2013. The initial scope included 2000 features, such as patient age groups, reporter qualifications, and countries of origin. RESULTS: vigiPoint highlighted 109 key features of medication error reports. The most prominent were that the vast majority of medication error reports were from the United States (89% compared with 49% for other reports in VigiBase); that the majority of reports were sent by consumers (53% vs 17% for other reports); that pharmacists (12% vs 5.3%) and lawyers (2.9% vs 1.5%) were overrepresented; and that there were more medication error reports than expected for patients aged 2-11 years (10% vs 5.7%), particularly in Germany (16%). CONCLUSIONS: vigiPoint effectively identified key features of medication error reports in VigiBase. More generally, it reduces lead times for analysis and ensures reproducibility and transparency. An important next step is to evaluate its use in other data. PMID- 28815801 TI - Chronic widespread pain prevalence in the general population: A systematic review. AB - : Chronic widespread pain (CWP) is a significant burden in communities. Understanding the impact of population-dependent (e.g., age, gender) and contextual-dependent (e.g. survey method, region, inequality level) factors have on CWP prevalence may provide a foundation for population-based strategies to address CWP. Therefore, the purpose of this study was to estimate the global prevalence of CWP and evaluate the population and contextual factors associated with CWP. A systematic review of CWP prevalence studies (1990-2017) in the general population was undertaken. Meta-analyses were conducted to determine CWP prevalence, and study population data and contextual factors were evaluated using a meta-regression. Thirty-nine manuscripts met the inclusion criteria. Study CWP prevalence ranged from 1.4% to 24.0%, with CWP prevalence in men ranging from 0.8% to 15.3% and 1.7% to 22.1% in women. Estimated overall CWP prevalence was 9.6% (8.0-11.2%). Meta-regression analyses showed gender, United Nations country development status, and human development index (HDI) influenced CWP prevalence, while survey method, region, methodological and reporting quality, and inequality showed no significant effect on the CWP estimate. Globally CWP affects one in ten individuals within the general population, with women more likely to experience CWP than men. HDI was noted to be the socioeconomic factor related to CWP prevalence, with those in more developed countries having a lower CWP prevalence than those in less developed countries. Most CWP estimates were from developed countries, and CWP estimates from countries with a lower socioeconomic position is needed to further refine the global estimate of CWP. SIGNIFICANCE: This systematic review and meta-analysis updates the current global CWP prevalence by examining the population-level (e.g. age, gender) and contextual (e.g. country development status; survey style; reporting and methodologic quality) factors associated with CWP prevalence. This analyses provides evidence to support higher levels of CWP in countries with a lower socioeconomic position relative to countries with a higher socioeconomic position. PMID- 28815802 TI - Prophylactic effects of ellagic acid and rosmarinic acid on doxorubicin-induced neurotoxicity in rats. AB - Doxorubicin (DOX) is a chemotherapeutic agent widely used in human malignancies. Its long-term use cause neurobiological side effects. The aim of the present study was to investigate the prophylactic effect exerted by daily administration of ellagic acid (EA) and rosmarinic acid (RA) on DOX-induced neurotoxicity in rats. Our data showed that DOX-induced significant elevation of brain malondialdehyde, tumor necrosis factor-alpha (TNF-alpha), inducible nitric oxide synthase (iNOS), caspase-3, and cholinesterase associated with significant reduction in reduced glutathione, monoamines namely serotonin, dopamine, as well as norepinephrine. Concomitant administration of EA (10 mg/kg/day, p.o. for 14 days) and/or RA (75 mg/kg/day, p.o. for 14 days) with DOX significantly mitigated the neural changes induced by DOX. Meanwhile, treatment ameliorated pro inflammatory cytokines as TNF-alpha, iNOS, and attenuated oxidative stress biomarkers as well as brain monoamines. In conclusion, EA and RA can effectively protect against DOX-induced neurotoxicity, and the mechanisms underlying the neuroprotective effect are potentially associated with its antioxidant, anti inflammatory, and antiapoptotic properties. PMID- 28815803 TI - Validity of cancer diagnosis in the National Health Insurance database compared with the linked National Cancer Registry in Taiwan. AB - PURPOSE: We aimed to evaluate the validity of cancer diagnosis in the National Health Insurance (NHI) database, which has routinely collected the health information of almost the entire Taiwanese population since 1995, compared with the Taiwan National Cancer Registry (NCR). METHODS: There were 26,542,445 active participants registered in the NHI database between 2001 and 2012. National Cancer Registry and NHI database records were compared for cancer diagnosis; date of cancer diagnosis; and 1, 2, and 5 year survival. In addition, the 10 leading causes of cancer deaths in Taiwan were analyzed. RESULTS: There were 908,986 cancer diagnoses in NCR and NHI database and 782,775 (86.1%) in both, with 53,192 (5.9%) in the NHI database only and 73,019 (8.0%) in the NCR only. The positive predictive value of the NHI database cancer diagnoses was 94% for all cancers; the positive predictive value of the 10 specific cancers ranged from 95% (lung cancer) to 82% (cervical cancer). The date of diagnosis in the NHI database was generally delayed by a median of 15 days (interquartile range 8-18) compared with the NCR. The 1, 2, and 5 year survival rates were 71.21%, 60.85%, and 47.44% using the NHI database and were 71.18%, 60.17%, and 46.09% using NCR data. CONCLUSIONS: Recording of cancer diagnoses and survival estimates based on these diagnosis codes in the NHI database are generally consistent with the NCR. Studies using NHI database data must pay careful attention to eligibility and record linkage; use of both sources is recommended. PMID- 28815804 TI - Octadentate Picolinic Acid-Based Bispidine Ligand for Radiometal Ions. AB - The synthesis of the octadentate bispidine ligand bearing two picolinic acid pendant arms (H2 bispa2 ), and its coordination chemistry with radionuclides relevant for nuclear medicine, namely indium(III) (111 In), lutetium(III) (177 Lu), and lanthanum(III) (as surrogate for 225 Ac), are reported. The non radioactive metal complexes of the N6 O2 -type bispa ligand were characterized by 1 H and 13 C NMR spectroscopy, elemental analysis, mass spectrometry and single crystal X-ray analysis. Experimental structural data, computational analysis, complex stabilities determined by potentiometric titration, and "radiostabilities" determined by competition studies in the presence of human serum reveal complex stabilities of H2 bispa2 comparable to those of the macrocyclic "gold standard" DOTA. After an incubation time of 1 day, 86 and 87 % of [177 Lu(bispa2 )]+ and [177 Lu(DOTA)]- , respectively, remain intact. Importantly, unlike DOTA, H2 bispa2 is radiolabeled quantitatively with 111 InIII and 225 AcIII under ambient conditions, which is an essential aspect when working with heat-sensitive antibodies as targeting vectors. In the case of 111 InIII , room temperature radiolabeling of H2 bispa2 yields molar activities as high as 70 MBq nmol-1 within 10 minutes. These are promising results for radiopharmaceutical applications of H2 bispa2 . PMID- 28815805 TI - Intracellular iron overload leading to DNA damage of lymphocytes and immune dysfunction in thalassemia major patients. AB - OBJECTIVES: To investigate the cause and effects of intracellular iron overload in lymphocytes of thalassemia major patients. METHODS: Sixty-six thalassemia major patients having iron overload and 10 age-matched controls were chosen for the study. Blood sample was collected, and serum ferritin, oxidative stress; lymphocyte DNA damage were examined, and infective episodes were also counted. RESULTS: Case-control analysis revealed significant oxidative stress, iron overload, DNA damage, and rate of infections in thalassemia cases as compared to controls. For cases, oxidative stress (ROS) and iron overload (serum ferritin) showed good correlation with R2 = 0.934 and correlation between DNA damage and ROS gave R2 = 0.961. We also demonstrated that intracellular iron overload in thalassemia caused oxidative damage of lymphocyte DNA as exhibited by DNA damage assay. The inference is further confirmed by partial inhibition of such damage by chelation of iron and the concurrent lowering of the ROS level in the presence of chelator deferasirox. CONCLUSION: Therefore, intracellular iron overload caused DNA fragmentation, which may ultimately hamper lymphocyte function, and this may contribute to immune dysfunction and increased susceptibility to infections in thalassemia patients as indicated by the good correlation (R2 = 0.91) between lymphocyte DNA damage and rate of infection found in this study. PMID- 28815806 TI - Evaluation in zebrafish model of the toxicity of rhodamine B-conjugated crotamine, a peptide potentially useful for diagnostics and therapeutics. AB - Crotamine is defensin-like cationic peptide from rattlesnake venom that possesses anticancer, antimicrobial, and antifungal properties. Despite these promising biological activities, toxicity is a major concern associated with the development of venom-derived peptides as therapeutic agents. In the present study, we used zebrafish as a system model to evaluate the toxicity of rhodamine B-conjugated (RhoB) crotamine derivative. The lethal toxic concentration of RhoB crotamine was as low as 4 MUM, which effectively kill zebrafish larvae in less than 10 min. With non-lethal concentrations (<1 MUM), crotamine caused malformation in zebrafish embryos, delayed or completely halted hatching, adversely affected embryonic developmental programming, decreased the cardiac functions, and attenuated the swimming distance of zebrafish. The RhoB-crotamine translocated across vitelline membrane and accumulated in zebrafish yolk sac. These results demonstrate the sensitive responsivity of zebrafish to trial crotamine analogues for the development of novel therapeutic peptides with improved safety, bioavailability, and efficacy profiles. PMID- 28815807 TI - Molybdenum Oxides - From Fundamentals to Functionality. AB - The properties and applications of molybdenum oxides are reviewed in depth. Molybdenum is found in various oxide stoichiometries, which have been employed for different high-value research and commercial applications. The great chemical and physical characteristics of molybdenum oxides make them versatile and highly tunable for incorporation in optical, electronic, catalytic, bio, and energy systems. Variations in the oxidation states allow manipulation of the crystal structure, morphology, oxygen vacancies, and dopants, to control and engineer electronic states. Despite this overwhelming functionality and potential, a definitive resource on molybdenum oxide is still unavailable. The aim here is to provide such a resource, while presenting an insightful outlook into future prospective applications for molybdenum oxides. PMID- 28815808 TI - Intravoxel incoherent motion diffusion-weighted imaging in assessing bladder cancer invasiveness and cell proliferation. AB - BACKGROUND: Nonmuscle-invasive bladder cancer (NMIBC, Stage T1 or lower) is treated with transurethral resection (TUR), while muscle-invasive bladder cancer (MIBC, Stage T2 or more) requires neoadjuvant chemotherapy before radical cystectomy. Hence, preoperative differentiation is vital. PURPOSE: To investigate whether intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) can differentiate NMIBC from MIBC and to assess whether there were correlations between IVIM parameters and the Ki-67 labeling index (LI). STUDY TYPE: Retrospective. SUBJECTS: Thirty-six patients diagnosed with bladder cancer confirmed by histopathological findings. FIELD STRENGTH/SEQUENCE: 3.0T magnetic resonance imaging (MRI) DWI with eight b-values ranging from 0 to 1000 s/mm2 . ASSESSMENT: Molecular diffusion coefficient (D), perfusion-related diffusion coefficient (D*), perfusion fraction (f), and apparent diffusion coefficient (ADC) were calculated by biexponential and monoexponential models fits, respectively. STATISTICAL TESTS: Comparisons were made between the MIBC and NMIBC group, and differences were analyzed by comparing the areas under the receiver operating characteristic curves (AUCs). The correlations between these parameters and Ki-67 LI were assessed by Spearman's rank correlation analysis. RESULTS: The ADC and D value were significantly lower in patients with MIBC compared to those with NMIBC (P < 0.01). No significant (P > 0.05) differences were observed in D* and f. The AUC of D value (0.894) was significantly (P < 0.05) larger than the ADC value (0.786), with sensitivities and specificities of 95% and 87.5% (D) and 80% and 68.7% (ADC), respectively. In addition, the D and ADC values were significantly correlated with Ki-67 LI (r = -0.785, r = -0.643, respectively; both P < 0.01). DATA CONCLUSION: The D value obtained from IVIM exhibited better performance than conventional DWI for distinguishing NMIBC from MIBC and may serve as a potential imaging biomarker for bladder cancer invasion. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1054 1060. PMID- 28815809 TI - Response to validity of patient-reported outcome measures in atopic eczema/dermatitis. PMID- 28815810 TI - Proteome characterization of human pancreatic cyst fluid from intraductal papillary mucinous neoplasm by liquid chromatography/tandem mass spectrometry. AB - RATIONALE: In recent years, the molecular components of pancreatic cyst fluid have been used for diagnosis and prognosis. Because the protein markers that are currently used in clinical tests are unreliable, proteomic studies to find new protein markers are being conducted. However, such researches have been limited due to the complexity of pancreatic cyst fluid and the immaturity of proteomic techniques. METHODS: To overcome these limitations and provide a pancreatic cyst proteome dataset, we examined cyst fluid proteome with tandem mass spectrometry. The proteomic analysis was performed using a Orbitrap-based mass spectrometer (Q Exactive) coupled with a 50-cm-long nano-liquid chromatography column. Protein mutations were identified using mutation sequence database search. RESULTS: A total of 5850 protein groups were identified from microliters of cyst fluid. Among those, 3934 protein groups were reported for the first time in pancreatic cyst fluid. Although high-abundance proteins were not depleted in the experiment, our dataset detected almost all pancreatic tumor markers such as mucin family members, S100 proteins, and CEA-related proteins. In addition, 590 protein mutation marker candidates were discovered. CONCLUSIONS: We provide a comprehensive cyst proteome dataset that includes cystic cellular proteins and mutated proteins. Our findings would serve as a rich resource for further IPMN studies and clinical applications. The MS data have been deposited in the ProteomeXchange with identifier PXD005671 (http://proteomecentral.proteomexchange.org/dataset/PXD005671). PMID- 28815811 TI - Study of the effects of spray drying in whey-starch on the probiotic capacity of Lactobacillus rhamnosus 64 in the gut of mice. AB - AIMS: To evaluate the effects of spray drying of Lactobacillus rhamnosus 64 on its capacity to modulate the gut immune response and on the attenuation of TNBS induced colitis in mice. METHODS AND RESULTS: Lactobacillus rhamnosus 64 was spray dried in cheese whey-starch solution and administered to mice for 3, 6 or 10 consecutive days. Peritoneal macrophage phagocytic activity, secretory IgA levels in the small intestinal fluid and TNFalpha, IFNgamma, IL-10, IL-6 and IL-2 levels in homogenates of the small and large intestine were determined. The effects of spray drying were also evaluated in an acute model of Trinitrobenzenesulfonic acid (TNBS)-induced colitis. A shift in the regulation of immune parameters, particularly the cytokine profile, was observed for mice treated with the spray-dried culture, compared to the profile observed in animals that received the strain as fresh culture (FC). The spray-dried culture of L. rhamnosus 64 showed anti-inflammatory properties in murine model of TNBS-induced colitis. CONCLUSIONS: The spray-drying process of L. rhamnosus 64 in whey-starch modified its immunomodulating capacity in healthy animals and conferred enhanced protection in an in vivo model of inflammation. SIGNIFICANCE AND IMPACT OF THE STUDY: Probiotic capacity can be affected by spray drying in relation to the properties observed for the strain as an overnight FC. This fact should be taken into account when producing the culture for its application in the industry. PMID- 28815812 TI - Association of left ventricular systolic dysfunction with mortality in incident peritoneal dialysis patients. AB - AIM: Cardiovascular disease is associated with morbidity and mortality in peritoneal dialysis patients but the relationship between left ventricular ejection fraction (LVEF) and outcomes is unclear. This study aimed to explore the association between LVEF and mortality in incident continuous ambulatory peritoneal dialysis (CAPD) patients. METHODS: The patients were divided into three groups according to LVEF levels (>0.6, 0.5 to 0.6, and <0.5). Kaplan-Meier analysis and the Cox proportional hazards models were used to evaluate association of LVEF with mortality. RESULTS: Among the 594 patients, LVEF levels of >0.6, 0.5 to 0.6, and <0.5 were detected in 428 (72.0%), 127 (21.4%) and 39 (6.6%) patients, respectively. During a median follow-up of 39.6 months, 127 (21.4%) patients died, of the deaths, 57.5% were attributable to cardiovascular causes. Patients with LVEF <0.5 had worst overall rates of survival and cardiovascular death-free survival among groups. Compared with LVEF >0.6, adjusted all-cause mortality hazard ratio (HR) and 95% confidence interval (CI) for patients with LVEF 0.5 to 0.6 and <0.5 were 1.62 (1.09-2.43) and 1.93 (1.06 3.52), respectively. The corresponding adjusted cardiovascular mortality HR were 1.60 (0.94-2.47) and 2.16 (1.04-4.74), respectively. CONCLUSION: Reduced LVEF is significantly associated with increased all-cause and cardiovascular mortality in incident CAPD patients. PMID- 28815813 TI - Primary osteosarcoma of the uterine cervix: A case report. AB - Primary osteosarcoma of the uterine cervix is extremely rare. Only 20 cases have been reported, 19 of which originated in the uterine corpus. We report a case of primary uterine cervical osteosarcoma with pulmonary metastasis in a 30-year-old nulligravida woman. The initial diagnosis was carcinosarcoma of the uterine cervix, as detected by cervical cytology and biopsy analysis. We performed a total hysterectomy, bilateral salpingo-oophorectomy and colostomy without macroscopic residual tumors in the abdominal cavity, but pelvic recurrent tumors appeared 14 days postoperatively. Both recurrent and metastatic tumors were effectively reduced by combination therapy of adriamycin with ifosfamide; however, the patient died as a result of of disease progression nine months after her first visit to our department. PMID- 28815814 TI - Supporting end of life decision making: Case studies of relational closeness in supported decision making for people with severe or profound intellectual disability. AB - BACKGROUND: The United Nations Convention on the Rights of Persons with Disabilities (UNCRPD) promotes the use of supported decision making in lieu of substitute decision making. To date, there has been a lack of focus on supported decision making for people with severe or profound intellectual disability, including for end of life decisions. METHODS: Five people with severe or profound intellectual disability's experiences of supported decision making were examined. This article is particularly focused on one participant's experiences at the end of his life. RESULTS: All five case studies identified that supporters were most effective in providing decision-making support for participants when they were relationally close to the person and had knowledge of the person's life story, particularly in relation to events that demonstrated preference. CONCLUSIONS: Findings from this study provide new understandings of supported decision making for people with severe or profound intellectual disability and have particular relevance for supporting decision making at the end of life. PMID- 28815815 TI - Synthesis, Optical Properties, and DNA Interaction of New Diquats Based on Triazolopyridines and Triazoloquinolines. AB - New diquat derivatives based on [1,2,3]triazolo[1,5-a]pyridine and [1,2,3]triazolo[1,5-a]quinoline have been synthesized in excellent yields. To evaluate the effect of the alkyl bridge length, ethane and propane dibromo alkane substrates were used for their synthesis. Theoretical calculations predicted a very small energetic barrier between the two possible enantiomers P (Ra ) and M (Sa ), which makes them very difficult to resolve. Thermal denaturation studies, UV/Visible spectroscopy, and fluorescence titrations with ct-DNA evidenced the intercalation of the quinoline derivatives in DNA. PMID- 28815816 TI - Coordination Behavior of a Planar Chiral Cyclic (Amino)(Ferrocenyl)Carbene Ligand in Iridium Complexes. AB - Iridium complexes bearing a new type of chiral carbene ligand, cyclic (amino)(ferrocenyl)carbene (CAFeC), were prepared. The complexes, which are quite stable in air and moisture, were fully characterized by NMR spectroscopy and X ray diffraction analysis. The NMR spectra of the dicarbonyl complex [IrCl(CO)2 (CAFeC)] showed signals for two isomers in solution, which were assigned to diastereomeric rotamers arising from the rotation of the chiral CAFeC ligand around the axes of the Ir-Ccarbene bond. IR spectroscopy of the dicarbonyl complex revealed that the donor strength of CAFeC is much higher than those of classic N-heterocyclic carbenes (NHCs) and comparable to those of cyclic amino alkyl carbenes (CAACs). PMID- 28815817 TI - Wrong-patient incidents during medication administrations. AB - AIMS AND OBJECTIVES: To describe the factors pertaining to medication being administered to the wrong patient and to describe how patient identification is mentioned in wrong-patient incident reports. BACKGROUND: Although patient identification has been given high priority to improve patient safety, patient misidentifications occur, and wrong-patient incidents are common. DESIGN: A descriptive content analysis. METHODS: Incident reports related to medication administration (n = 1,012) were collected from two hospitals in Finland between 1 January 2013-31 December 2014. Of those, only incidents involving wrong-patient medication administration (n = 103) were included in this study. RESULTS: Wrong patient incidents occurred due for many reasons, including nurse-related factors (such as tiredness, a lack of skills or negligence) but also system-related factors (such as rushing or heavy workloads). In 77% (n = 79) of wrong-patient incident reports, the process of identifying of the patient was not described at all. CONCLUSIONS: There is need to pay more attention to and increase training in correct identification processes to prevent wrong-patient incidents, and it is important to adjust system factors to support nurses. RELEVANCE TO CLINICAL PRACTICE: Active patient identification procedures, double-checking and verification at each stage of the medication process should be implemented. More attention should also be paid to organisational factors, such as division of work, rushing and workload, as well as to correct communication. The active participation of nurses in handling incidents could increase risk awareness and facilitate useful protection actions. PMID- 28815818 TI - An Unprecedented Blue Chromophore Found in Nature using a "Chemistry First" and Molecular Networking Approach: Discovery of Dactylocyanines A-H. AB - Guided by a "chemistry first" approach using molecular networking, eight new bright-blue colored natural compounds, namely dactylocyanines A-H (3-10), were isolated from the Polynesian marine sponge Dactylospongia metachromia. Starting from ilimaquinone (1), an hemisynthetic phishing probe (2) was prepared for annotating and matching structurally related natural substances in D. metachromia crude extract network. This strategy allowed characterizing for the first time in Nature the blue zwitterionic quinonoid chromophore. The solvatochromic properties of the latter are reported. PMID- 28815819 TI - Novel consortium of Klebsiella variicola and Lactobacillus species enhances the functional potential of fermented dairy products by increasing the availability of branched-chain amino acids and the amount of distinctive volatiles. AB - AIMS: Identify novel bacterial taxa that could increase the availability of branched-chain amino acids and the amount of distinctive volatiles during skim milk fermentation. METHODS AND RESULTS: We recovered 344 bacterial isolates from stool samples of healthy and breastfed infants. Five were selected based on their ability to produce branched-chain amino acids. Three strains were identified as Escherichia coli, one as Klebsiella pneumoniae and other as Klebsiella variicola by molecular and biochemical methods. HPLC and solid-phase microextraction with GC-MS were used for the determination of free amino acids and volatile compounds respectively. The consortium formed by K. variicola and four Lactobacillus species showed the highest production of Leu and Ile in skim milk fermentation. In addition, the production of volatile compounds, such as acetoin, ethanol, 2 nonanone, and acetic, hexanoic and octanoic acids, increased in comparison to commercial yogurt, Emmental and Gouda cheese. Also, distinctive volatiles, such as 2,3-butanediol, 4-methyl-2- hexanone and octanol, were identified. CONCLUSION: The use of K. variicola in combination with probiotic Lactobacillus species enhances the availability of Leu and Ile and the amount of distinctive volatiles during skim milk fermentation. SIGNIFICANCE AND IMPACT OF THE STUDY: The identified consortium increases the functional potential of fermented dairy products. PMID- 28815820 TI - Functional analysis of the biosynthetic gene cluster required for immunity and secretion of a novel Lactococcus-specific bacteriocin, lactococcin Z. AB - AIMS: Characterization of the biosynthesis (secretion and immunity) of lactococcin Z. METHODS AND RESULTS: Lactococcin Z is produced by Lactococcus lactisQU 7. DNA sequence analysis revealed that the lactococcin Z gene cluster (c. 5.1 kb) includes four genes encoding putative biosynthetic proteins, LczB (self-immunity protein), LczC (an ABC transporter) and LczD (a transport accessory protein), besides the previously identified LczA. LczB showed 25.5% identity to LciA, the lactococcin A immunity protein, while LczC and LczD had 93.7 and 95.3% identities, respectively, to corresponding proteins of lactococcin A. Heterologous expression of various combinations of the four genes indicated that lczB confers self-immunity against lactococcin Z, and that the four genes are necessary to produce lactococcin Z. However, LczB and LciA showed no cross immunity to lactococcins A and Z respectively. CONCLUSIONS: The results verified that LczB is the lactococcin Z immunity protein, and LczC is responsible for lactococcin Z secretion in a manner dependent on LczD expression. SIGNIFICANCE AND IMPACT OF THE STUDY: The biosynthesis (secretion and immunity) of a new Lactococcus-specific bacteriocin, lactococcin Z, was characterized. Moreover, the results suggested that lactococcin Z has different immunity and action mechanisms from other Lactococcus-specific bacteriocins. PMID- 28815821 TI - Infant feeding patterns and eczema in children in the first 6 years of life. AB - BACKGROUND: Modes of infant feeding such as direct and indirect breastfeeding, and formula feeding, and their combinations may play a role in child health. OBJECTIVE: The aim was to investigate which feeding patterns in the first 6 months pose risks of eczema/skin allergy in children up to 6 years compared to direct breastfeeding for at least 3 months. METHODS: The Infant Feeding Practices Study II in the United States and its 6-year follow-up provided data on feeding modes in infancy and doctor's diagnosed eczema/skin allergy in the first 6 years of life (1387 infants), based on parental reports. Different feeding patterns were identified. Log-linear models were used to estimate prevalence ratios (PRs) of feeding patterns for doctor's diagnosed eczema/skin allergy in the first 6 years of life, adjusting for confounders. RESULTS: Compared to "direct breastfeeding for at least 3 months" (DBF3m), the combination of "direct feeding at the breast (DBF), pumping and feeding breast milk (BM), and formula (FF) in the first months" (DBF/BM/FF) showed a statistically significant higher risk of eczema/skin allergy in the first 6 years of life (PR = 1.46), adjusting for confounders. DBF combined with BM for the first 3 months followed by mixed feeding also had an increased risk (PR = 1.26), although not statistically significant. Formula feeding introduced since birth had no effect on eczema. Among the confounders, paternal eczema and race/ethnicity (Hispanic vs White) were associated with a higher risk of eczema/skin allergy. CONCLUSIONS & CLINICAL RELEVANCE: Mixed infant feeding may carry a higher risk of eczema/skin allergy compared to direct feeding at the breast. The recent epidemic of pumping and feeding in the United States and the use of mixed infant feeding modes requires additional studies to provide appropriate and renewed assessments of the risks of feeding modes for the future development of allergies. PMID- 28815823 TI - Ten years of simulation-based training in pediatric anesthesia: The inception, evolution, and dissemination of the Managing Emergencies in Pediatric Anesthesia (MEPA) course. AB - 2016 marked the 10-year anniversary of the inception of the Managing Emergencies in Paediatric Anaesthesia (MEPA) course. This simulation-based program was originally created to allow trainees in pediatric anesthesia to experience operating room emergencies which although infrequent, would be considered key competencies for any practicing anesthetist with responsibility for providing care to children. Since its original manifestation, the course has evolved in content, scope, and worldwide availability, such that it is now available at over 60 locations on five continents. The content has been modified for different learner groups and translated into several languages. This article describes the history, evolution, and dissemination of the MEPA course to share lessons learnt with educators considering the launch of similar initiatives in their field. PMID- 28815822 TI - Hepatitis C virus-related complications are increasing in women veterans: A national cohort study. AB - There are gender-specific variations in the epidemiology and clinical course of hepatitis C virus (HCV) infection. However, few long-term longitudinal studies have examined trends in the incidence and prevalence of serious liver complications among women compared with men with HCV infection. We used the Veterans Administration Corporate Data Warehouse to identify all veterans with positive HCV viraemia from January 2000 to December 2013. We calculated gender specific annual incidence and prevalence rates of cirrhosis, decompensated cirrhosis and hepatocellular cancer (HCC) adjusting for age, diabetes, HIV and alcohol use. We also calculated the average annual per cent change (AAPC) for each outcome by gender using piecewise linear regression in the Joinpoint software. We identified 264 409 HCV-infected veterans during 2000-2013, of whom 7162 (2.7%) were women. There were statistically significant increases over time in the incidence rates of cirrhosis, decompensated cirrhosis and HCC for both men and women. The annual-adjusted incidence rates of cirrhosis, decompensated cirrhosis and HCC were higher in men than women for all study years. However, these complications increased at a similar rate in both groups. Specifically, the AAPC for cirrhosis was 13.1 and 15.2, while it was 15.6 and 16.9 for decompensated cirrhosis and 21.0 and 25.3 for HCC in men and women, respectively (all test of parallelism not significant). The results were similar in the prevalence analyses, although AAPCs were slightly smaller for each outcome. In conclusion, we found an ongoing upward trend in the incidence and prevalence of HCV complications in this cohort of HCV-infected women. This increase in cirrhosis complications in women with active HCV infection is similar to those in men. With cure from HCV now becoming a reality, most of the projected burden of HCV is potentially preventable. However, benefits of HCV treatment will need to extend to all patients in order to stem the rising tide of HCV complications. PMID- 28815824 TI - Time-of-flight secondary ion mass spectrometry using a new primary ion beam generated by vacuum electrospray of a protic ionic liquid, propylammonium nitrate. AB - RATIONALE: Protic ionic liquids have the potential to be useful materials for primary ion beams in terms of protonation, since they have active protons. Selecting protic ionic liquids suitable for primary ion beams is of great importance to increase molecular secondary ion yields. Propylammonium nitrate ([C3 H7 NH3 ][NO3 ]) seems promising in view of its proton affinity. It is likely that [C3 H7 NH3 ]+ cations can act as proton donors, and [NO3 ]- anions can work as proton acceptors. METHODS: Time-of-flight secondary ion mass spectrometry (TOF SIMS) experiments have been performed to verify the usefulness of [C3 H7 NH3 ][NO3 ]. A primary propylammonium nitrate cluster ion beam was generated by vacuum electrospray, and then used to analyze amino acids (arginine, glutamic acid, aspartic acid), angiotensin II and polyethylene glycol. Positive and negative secondary ion mass spectra were obtained to study both protonation and deprotonation. RESULTS: The propylammonium nitrate cluster ion beam successfully generated protonated molecules [M + H]+ of all the analytes in positive ion mode. The primary ion beam also generated deprotonated molecules [M - H]- of glutamic acid, aspartic acid and angiotensin II in negative ion mode. Additionally, adduct ions related to [C3 H7 NH3 ][NO3 ] were detected in the case of arginine and polyethylene glycol. CONCLUSIONS: The TOF-SIMS experiments confirmed that the propylammonium nitrate cluster ion beam was useful in generating molecular secondary ions, demonstrating that it is well suited for a primary ion beam in TOF-SIMS. PMID- 28815825 TI - The prevalence and specific characteristics of hospitalised pressure ulcer patients: A multicentre cross-sectional study. AB - OBJECTIVE: To ascertain the pressure ulcer prevalence in secondary and tertiary general hospitals in different areas of Guangdong Province in China and explore the possible risk factors that are related to pressure ulcers. BACKGROUND: Few multicentre studies have been conducted on pressure ulcer prevalence in Chinese hospitals. DESIGN: A cross-sectional study design was used. METHODS: Data from a total of 25,264 patients were included in the analysis at 25 hospitals in China. The investigators were divided into two groups. The investigators in group 1 examined the patients' skin. When a pressure ulcer was found, a pressure ulcer assessment form was completed. The investigators in group 2 provided guidance to the nurses, who assessed all patients and completed another questionnaire. A multivariate logistic regression analysis was used to analyse the relationship between the possible risk factors and pressure ulcer. RESULTS: The overall prevalence rate of pressure ulcers in the 25 hospitals ranged from 0%-3.49%, with a mean of 1.26%. The most common stage of the pressure ulcers was stage II (41.4%); most common anatomical locations were sacrum (39.5%) and the feet (16.4%). Braden score (p < .001), expected length of stay (p < .001), incontinence (p < .001), care group (p = .011), hospital location (p < .001), type of hospitals (p = .004), ages of patients (p < .001) were associations of pressure ulcers from the multivariate logistic regression analysis. CONCLUSIONS: The overall prevalence rate of pressure ulcers in Chinese hospitals was lower than that reported in previous investigations. Specific characteristics of pressure ulcer patients were as follows: low Braden score, longer expected length of stay, double incontinence, an ICU and a medical ward, hospital location in the Pearl River Delta, a university hospital and an older patient. RELEVANCE TO CLINICAL PRACTICE: The survey could make managers know their prevalence level of pressure ulcers and provide priorities for clinical nurses. PMID- 28815826 TI - An interview-based study of nonattendance at screening for cardiovascular diseases and diabetes in older women: Nonattendees' perspectives. AB - AIMS AND OBJECTIVES: This study explored nonattendees' perspectives on a screening programme for cardiovascular disease and diabetes mellitus among women aged 60-77 years. BACKGROUND: Nonattendance in screening is a common concern and has been associated with increased morbidity and mortality. Whether nonattendees need targeted information to participate in screening is unknown. Thus, it is important to explore the reasons for nonattendance, particularly as nonattendees' perspectives have not been fully explored. DESIGN: An interview study. METHODS: The data were obtained through semistructured interviews with 10 women sampled from a population who declined to participate in a women's screening programme for cardiovascular disease and diabetes mellitus. Additionally, reflective notes on the interview context were documented. The data were collected in 2013. Kvale and Brinkmann's method for data analysis was applied. RESULTS: All informants found the screening offer personally irrelevant, but this belief was changeable. The informants' perceptions of screening were based on subjective health and risk beliefs, personal knowledge of diseases and the screening programme, and distrust in the healthcare system. CONCLUSION: Personal experiences, beliefs and self protective strategies influence individuals' subjective interpretations of a screening programme's relevance. The perception that screening is irrelevant seems to be rooted in nonattendees' personal health-related assessment and knowledge. Consequently, whether nonattendance is determined by an informed decision is questionable. Negative experiences with the healthcare system led to hesitation towards screening in general. RELEVANCE TO CLINICAL PRACTICE: This study is relevant to healthcare workers as well as decision-makers from a screening and preventive perspective. The findings highlight important issues that should be addressed to encourage invitees to accept screening invitations and to facilitate informed decision-making about screening participation. PMID- 28815827 TI - Outer membrane lipid homeostasis via retrograde phospholipid transport in Escherichia coli. AB - Biogenesis of the outer membrane (OM) in Gram-negative bacteria, which is essential for viability, requires the coordinated transport and assembly of proteins and lipids, including lipopolysaccharides (LPS) and phospholipids (PLs), into the membrane. While pathways for LPS and OM protein assembly are well studied, how PLs are transported to and from the OM is not clear. Mechanisms that ensure OM stability and homeostasis are also unknown. The trans-envelope Tol-Pal complex, whose physiological role has remained elusive, is important for OM stability. Here, we establish that the Tol-Pal complex is required for PL transport and OM lipid homeostasis in Escherichia coli. Cells lacking the complex exhibit defects in lipid asymmetry and accumulate excess PLs in the OM. This imbalance in OM lipids is due to defective retrograde PL transport in the absence of a functional Tol-Pal complex. Thus, cells ensure the assembly of a stable OM by maintaining an excess flux of PLs to the OM only to return the surplus to the inner membrane. Our findings also provide insights into the mechanism by which the Tol-Pal complex may promote OM invagination during cell division. PMID- 28815828 TI - Exploring Electrical Currents through Nanographenes: Visualization and Tuning of the through-Bond Transmission Paths. AB - In this work, electrical currents through nanographenes, a class of alternant hydrocarbons also known as polycyclic aromatic hydrocarbons, in molecular junctions under small bias are explored. We illustrate that when the pi-current dominates, that is, when no quantum interference takes place, the current prefers the direction of the shortest bond (the bond with the highest double bond character) upon entering the molecule from the contacts. As such, the idea of electrons propagating through double bonds from contact to contact, originating from the curly arrow drawings used in a previously established selection rule for transmission, seems to be more deeply rooted in the actual physical process of electron transport than previously anticipated. Furthermore, this work confirms that the sigma-current behaves completely differently than the pi-current. When this type of current becomes important, that is, when quantum interference takes place, the current generally prefers the shortest path from contact to contact, irrespective of the length of the bonds constituting this path, in accordance with the strong distance dependency of the sigma-current. Finally, it is demonstrated that keto groups (and cross-conjugating groups in general) can be used to seal off parts of the molecule for the current. No current flows through the sealed off part of the molecule under small bias and it does not influence the transmission spectrum of the considered system. PMID- 28815829 TI - Reagent-Free C-H/N-H Cross-Coupling: Regioselective Synthesis of N Heteroaromatics from Biaryl Aldehydes and NH3. AB - An unprecedented synthesis of N-heteroaromatics from biaryl aldehydes and NH3 through reagent-free C-H/N-H cross-coupling has been developed. The electrosynthesis uses NH3 as an inexpensive and atom-economic nitrogen donor, requires no oxidizing agents, and allows efficient and regioselective access to a wide range of phenanthridines and structurally related polycyclic N heteroaromatic products. PMID- 28815832 TI - Targeting the Genome-Stability Hub Ctf4 by Stapled-Peptide Design. AB - The exploitation of synthetic lethality by small-molecule targeting of pathways that maintain genomic stability is an attractive chemotherapeutic approach. The Ctf4/AND-1 protein hub, which links DNA replication, repair, and chromosome segregation, represents a novel target for the synthetic lethality approach. Herein, we report the design, optimization, and validation of double-click stapled peptides encoding the Ctf4-interacting peptide (CIP) of the replicative helicase subunit Sld5. By screening stapling positions in the Sld5 CIP, we identified an unorthodox i,i+6 stapled peptide with improved, submicromolar binding to Ctf4. The mode of interaction with Ctf4 was confirmed by a crystal structure of the stapled Sld5 peptide bound to Ctf4. The stapled Sld5 peptide was able to displace the Ctf4 partner DNA polymerase alpha from the replisome in yeast extracts. Our study provides proof-of-principle evidence for the development of small-molecule inhibitors of the human CTF4 orthologue AND-1. PMID- 28815831 TI - Prognostic significance of Kadish staging in esthesioneuroblastoma: An analysis of the National Cancer Database. AB - BACKGROUND: Given the rarity of esthesioneuroblastoma, it is difficult to validate a staging system. The purpose of this study was to investigate the utility of the Kadish staging system in esthesioneuroblastoma using the National Cancer Database (NCDB). METHODS: One thousand one hundred sixty-seven patients with esthesioneuroblastoma were identified from the NCDB. RESULTS: Five-year survival was 80.0% for Kadish A, 87.7% for Kadish B, 77.0% for Kadish C, and 49.5% for Kadish D. Kadish B had higher survival than Kadish A. More Kadish B patients received surgery with adjuvant therapy than Kadish A patients (41.6% vs 32.5%; P = .0038) and also had more positive margins (21.6% vs 11.3%; P = .03). There was no difference in age distribution, sex, race, or neck dissection status between the 2 groups. CONCLUSION: Kadish B had greater survival than Kadish A, but the treatment characteristics could not account for this difference. The utility of early-stage Kadish staging is uncertain and requires further study. PMID- 28815830 TI - Determinants of the Inhibition of DprE1 and CYP2C9 by Antitubercular Thiophenes. AB - Mycobacterium tuberculosis (Mtb) DprE1, an essential isomerase for the biosynthesis of the mycobacterial cell wall, is a validated target for tuberculosis (TB) drug development. Here we report the X-ray crystal structures of DprE1 and the DprE1 resistant mutant (Y314C) in complexes with TCA1 derivatives to elucidate the molecular basis of their inhibitory activities and an unconventional resistance mechanism, which enabled us to optimize the potency of the analogs. The selected lead compound showed excellent in vitro and in vivo activities, and low risk of toxicity profile except for the inhibition of CYP2C9. A crystal structure of CYP2C9 in complex with a TCA1 analog revealed the similar interaction patterns to the DprE1-TCA1 complex. Guided by the structures, an optimized molecule was generated with differential inhibitory activities against DprE1 and CYP2C9, which provides insights for development of a clinical candidate to treat TB. PMID- 28815833 TI - Solvation Accounts for the Counterintuitive Nucleophilicity Ordering of Peroxide Anions. AB - The nucleophilic reactivities (N, sN ) of peroxide anions (generated from aromatic and aliphatic peroxy acids or alkyl hydroperoxides) were investigated by following the kinetics of their reactions with a series of benzhydrylium ions (Ar2 CH+ ) in alkaline aqueous solutions at 20 degrees C. The second-order rate constants revealed that deprotonated peroxy acids (RCO3- ), although they are the considerably weaker Bronsted bases, react much faster than anions of aliphatic hydroperoxides (ROO- ). Substitution of the rate constants of their reactions with benzhydrylium ions into the linear free energy relationship lg k=sN (N+E) furnished nucleophilicity parameters (N, sN ) of peroxide anions, which were successfully applied to predict the rates of Weitz-Scheffer epoxidations. DFT calculations with inclusion of solvent effects by means of the Integral Equation Formalism version of the Polarizable Continuum Model were performed to rationalize the observed reactivities. PMID- 28815834 TI - Innervation of the human posterior cricoarytenoid muscle by the external branch of the superior laryngeal nerve. AB - BACKGROUND: The posterior cricoarytenoid muscle is the abductor muscle for the vocal cords and is innerved by the recurrent laryngeal nerve (RLN). The purpose of this study was to present our determination if the external branch of the superior laryngeal nerve (SLN) contributes to the motor innervation of the posterior cricoarytenoid muscle. METHODS: We performed electromyographies (EMGs) via needle electrodes on 47 posterior cricoarytenoid muscles from 28 patients during thyroidectomy (9 lobectomies and 19 total thyroidectomies) with intraoperative neural monitoring. The RLN, vagus nerve, and external branch of the SLN were stimulated intraoperatively and the responses were evaluated by EMG. RESULTS: Positive EMG responses were obtained from 16 (34%) of 47 posterior cricoarytenoid muscles after external branch of the SLN stimulation. The EMG of the posterior cricoarytenoid muscle was unilaterally positive in 8 of 19 patients (42%) with total thyroidectomy, and 2 of 19 patients (10.5%) were bilaterally positive. CONCLUSION: The external branch of the SLN contributes to the ipsilateral posterior cricoarytenoid muscle innervation in one-third of the cases. This contribution is usually unilateral, but is occasionally bilateral. PMID- 28815835 TI - Patient education materials assessment tool for laryngectomy health information. AB - BACKGROUND: The decision to undergo laryngectomy carries medical, social, and emotional consequences. This study evaluates the understandability and actionability of current laryngectomy information. METHODS: Laryngectomy-related educational materials from an online search were evaluated using the validated Patient Education Materials Assessment Tool (PEMAT). Reading difficulty was calculated using the Flesch-Kincaid Level, Flesch Reading Ease, Gunning-Fog Index (GFI), Coleman-Liau Index, Automated Readability Index, and Simple Measure of Gobbledygook (SMOG) score. Interrater agreement was assessed using Cohen's kappa. Pearson's correlation coefficient was used to determine the relationship among readability, understandability, and actionability. RESULTS: Forty-four articles were included. Interrater agreement was substantial (kappa = 0.71). Mean understandability was 68.3% +/- 17% and mean actionability was 66.3% +/- 24%. Average reading difficulty exceeded the ability of an average American adult. There was a negative correlation between readability and understandability (R = 0.49; P < .05). CONCLUSION: Most laryngectomy information is too difficult for the average person to read, understand, or act upon. Revisions may be warranted to benefit a larger readership. PMID- 28815836 TI - [2.2]Paracyclophanes with N-Heterocycles as Ligands for Mono- and Dinuclear Ruthenium(II) Complexes. AB - [2.2]Paracyclophane, with its unique structure, allows the design of unusual 3D structures by functionalization of this rigid and stable hydrocarbon scaffold. Therefore different mono- and homodisubstituted [2.2]paracyclophanes with pyridyl, pyrimidyl and oxazolinyl substituents were developed in order to evaluate their ability as bridging ligands for two ruthenium centres. With the successfully synthesized [2.2]paracyclophane-based N-donor functions, the cycloruthenation reaction using [RuCl2 (p-cymene)]2 as precursor was explored. Compared to 2-phenylpyridine, the [2.2]paracyclophane derivative is clearly inferior in the cycloruthenation reaction, resulting in poor yields for the neutral complexes. By addition of KPF6 , the cationic complexes can be obtained in good yields and are formed diastereoselectively in case of a pyridyl substituent, resulting in only one diastereomer for dinuclear ruthenium complexes of bispyridyl-substituted [2.2]paracyclophanes as bridging ligands. PMID- 28815837 TI - Cost of asthma in children: A nationwide, population-based, cost-of-illness study. AB - BACKGROUND: Childhood asthma is very prevalent and costs can be high, especially in severe disease. This study aimed to estimate the cost of asthma in Portuguese children and the variations by level of asthma control. METHODS: A nationwide, population- and prevalence-based cost-of-illness study with a societal perspective was conducted. We measured direct and indirect costs using a bottom up approach and a human capital method, respectively, for 208 children (<18 years), from two national repositories. Generalized linear modelling for analysis of asthma costs' determinants and sensitivity analysis to assess uncertainty were performed. RESULTS: The mean annualized asthma cost per child was ?929.35 (95% CI, 809.65-1061.11): ?698.65 (95% CI, 600.88-798.27) for direct costs and ?230.70 (95% CI, 197.36-263.81) for indirect costs. Extrapolations for the Portuguese children amounted to ?161 410 007.61 (95% CI, 140 620 769.55-184 293 968.55) for total costs. Direct costs represent 75.2% with the costliest domain (51.1% of total costs) being the healthcare service use: 20.7% for scheduled medical visits and 30.4% for acute asthma care-non-scheduled medical visits (7.9%, ?12 766 203.20), emergency department visits (11.7%, ?18 932 464.80) and hospitalizations (10.8%, ?17 406 946.00). Children with partly controlled and uncontrolled asthma had higher mean costs per year (adjusted coefficients: 1.46 [95% CI, 1.12-1.90] and 2.25 [95% CI, 1.56-3.24], respectively). CONCLUSIONS: Costs of childhood asthma are high (0.9% of the healthcare expenditures in Portugal). Direct costs represented three-fourth of total costs, mainly related to the use of healthcare services for acute asthma care. Policies and interventions to improve asthma control and reduce acute use of healthcare services have the potential to reduce asthma costs. PMID- 28815838 TI - Wacker-Type Oxidation Using an Iron Catalyst and Ambient Air: Application to Late Stage Oxidation of Complex Molecules. AB - A practical and general iron-catalyzed Wacker-type oxidation of olefins to ketones is presented, and it uses ambient air as the sole oxidant. The mild oxidation conditions enable exceptional functional-group tolerance, which has not been demonstrated for any other Wacker-type reaction to date. The inexpensive and nontoxic reagents [iron(II) chloride, polymethylhydrosiloxane, and air] can, therefore, also be employed to oxidize complex natural-product-derived and polyfunctionalized molecules. PMID- 28815839 TI - Circulating tumor cells in patients with head and neck squamous cell carcinoma: Feasibility of detection and quantitation. AB - BACKGROUND: The purpose of this study was to present our findings that because circulating tumor cells (CTCs) exist in extremely low numbers, their detection and quantification are challenging. METHODS: Peripheral blood samples were collected from 32 patients with head and neck squamous cell carcinoma (HNSCC), and were subjected to the CellSieve Microfiltration Assay using a low-pressure filtration system. The CTCs captured by the filter were stained with an antibody cocktail (anti-cytokeratin (CK) 8, 18, and 19, anti-epithelial cell adhesion molecule (EpCAM), and anti-CD45 antibodies). RESULTS: The CTCs were detected in 29 of 32 patients (90.6%). Although patients with advanced disease had a significantly higher number of CTCs, the clinical N classification was not associated with the CTC count. After treatment, the CTC count showed a significant decrease. CONCLUSION: The CTCs were successfully detected and quantified in patients with HNSCC by using a low-pressure filtration system equipped with precision microfilters. Further studies using a larger number of patient samples and/or molecular analysis of CTCs are warranted. PMID- 28815840 TI - Current status of home blood pressure monitoring in Asia: Statement from the HOPE Asia Network. AB - Hypertension represents a major burden in Asia, with a high prevalence rate but poor level of awareness and control reported in many countries in the region. Home blood pressure monitoring has been validated as an accurate and reliable measure of blood pressure that can help guide hypertension treatment as well as identify masked and white-coat hypertension. Despite its benefits, there has been limited research into home blood pressure monitoring in Asia. The authors reviewed the current evidence on home blood pressure monitoring in Asia, including but not limited to published literature, data presented at congresses, and national hypertension management guidelines to determine the current utilization of home blood pressure monitoring in clinical practice in the region. Public policies to enable greater access to home blood pressure monitoring and its use in clinical care would add considerably to improving hypertension outcomes in Asia. PMID- 28815842 TI - In Situ Investigation of Methane Dry Reforming on Metal/Ceria(111) Surfaces: Metal-Support Interactions and C-H Bond Activation at Low Temperature. AB - Studies with a series of metal/ceria(111) (metal=Co, Ni, Cu; ceria=CeO2 ) surfaces indicate that metal-oxide interactions can play a very important role for the activation of methane and its reforming with CO2 at relatively low temperatures (600-700 K). Among the systems examined, Co/CeO2 (111) exhibits the best performance and Cu/CeO2 (111) has negligible activity. Experiments using ambient pressure X-ray photoelectron spectroscopy indicate that methane dissociates on Co/CeO2 (111) at temperatures as low as 300 K-generating CHx and COx species on the catalyst surface. The results of density functional calculations show a reduction in the methane activation barrier from 1.07 eV on Co(0001) to 0.87 eV on Co2+ /CeO2 (111), and to only 0.05 eV on Co0 /CeO2-x (111). At 700 K, under methane dry reforming conditions, CO2 dissociates on the oxide surface and a catalytic cycle is established without coke deposition. A significant part of the CHx formed on the Co0 /CeO2-x (111) catalyst recombines to yield ethane or ethylene. PMID- 28815841 TI - Response assessment after induction chemotherapy for head and neck squamous cell carcinoma: From physical examination to modern imaging techniques and beyond. AB - Significant correlations between the response to induction chemotherapy and success of subsequent radiotherapy have been reported and suggest that the response to induction chemotherapy is able to predict a response to radiotherapy. Therefore, induction chemotherapy may be used to tailor the treatment plan to the individual patient with head and neck cancer: following the planned subsequent (chemo)radiation schedule, planning a radiation dose boost, or reassessing the modality of treatment (eg, upfront surgery). Findings from reported trials suggest room for improvement in clinical response assessment after induction chemotherapy, but an optimal method has yet to be identified. Historically, indices of treatment efficacy in solid tumors have been based solely on systematic assessment of tumor size. However, functional imaging (eg, fluorodeoxyglucose-positron emission tomography (FDG-PET) potentially provides an earlier indication of response to treatment than conventional imaging techniques. More advanced imaging techniques are still in an exploratory phase and are not ready for use in clinical practice. PMID- 28815843 TI - Ilizarov technique and limited surgical methods for correction of post-traumatic talipes equinovarus in children. AB - BACKGROUND: The objective of this study was to evaluate the efficacy and safety of using Ilizarov invasive distraction technique combined with limited surgical operations in the treatment of post-traumatic talipes equinovarus in children. METHODS: Eighteen cases of post-traumatic deformed feet in 15 patients who received the treatment of Ilizarov frame application, limited soft-tissue release or osteotomy were selected in this study. After removal of the frame, an ankle foot orthosis was used continuously for another 6-12 months. Pre- and post operatively, the International Clubfoot Study Group (ICFSG) score was employed to evaluate the gait and range of motion of the ankle joint. Radiographical assessment was also conducted. RESULTS: Patients were followed up for 22 (17-32) months. Ilizarov frame was applied for a mean duration of 5.5 (4-9) months. When it was removed, the gait was improved significantly in all the patients. The correction time was 6-8 weeks for patients who underwent soft-tissue release and 8-12 weeks for those with bone osteotomy. At the last follow-up assessment, the differences between pre- and post-operative plantar-flexion angle, dorsiflexion, motion of ankle joint and talocalcaneal angle were significant (all P < 0.05). The observed complications included wire-hole infection in one foot, toe contracture in one, residual deformity in three, recurrence of deformity in two and spastic ischaemia in one foot. CONCLUSION: Our findings suggest that Ilizarov technique combined with limited surgical operation can be considered as an efficient and successful method for correction of post-traumatic talipes equinovarus in children. PMID- 28815844 TI - Do adult mental health services identify child abuse and neglect? A systematic review. AB - Child abuse and neglect play a causal role in many mental health problems. Knowing whether users of mental health services were abused or neglected as children could be considered essential for developing comprehensive formulations and effective treatment plans. In the present study we report the findings of a systematic review, using independent searches of three databases designed to discover how often mental health staff find out whether their clients were abused or neglected as children. Twenty-one relevant studies were identified. Most people who use mental health services are never asked about child abuse or neglect. The majority of cases of child abuse or neglect are not identified by mental health services. Only 28% of abuse or neglect cases identified by researchers are found in the clients' files: emotional abuse, 44%; physical abuse, 33%; sexual abuse, 30%; emotional neglect, 17%; and physical neglect, 10%. Between 0% and 22% of mental health service users report being asked about child abuse. Men and people diagnosed with psychotic disorders are asked less than other people. Male staff ask less often than female staff. Some improvement over time was found. Policies compelling routine enquiry, training, and trauma informed services are required. PMID- 28815845 TI - Proceedings of the 21st Annual Conference of the European Society for Domestic Animal Reproduction (ESDAR), Bern, Switzerland, 24 - 26 August 2017. PMID- 28815846 TI - Innovative look at dairy heifer rearing: Effect of prenatal and post-natal environment on later performance. AB - As heifer rearing is a costly investment, dairy farmers have been stimulated to maximize early growth of their calves, mainly by enhanced liquid feeding. However, the long-term effects of this "accelerated growth" are largely unknown. Studies recently performed at Ghent University indicate that in dairy cattle, certain maternal factors (such as young age and high milk yield) and environmental factors (such as high ambient temperatures) create a suboptimal environment for the developing foetus, altering the phenotype of the newborn calf. According to the "thrifty phenotype hypothesis," these metabolic alterations prepare the newborn for similar ("matching") conditions after birth, enhancing its survival during periods of limited feeding. Yet, when an abundance of nutrients is available in post-natal life (e.g., during periods of enhanced feeding), the "mismatch" between pre- and post-natal environment results in an early catch-up growth, with potential negative consequences. The aim of the article was to discuss this mismatch between pre- and post-natal environment in dairy calves. Previous studies, especially in human medicine, have shown catch-up growth to be associated with obesity, fertility problems, metabolic diseases and a reduced lifespan. Hence, we hypothesize that, by applying programs of accelerated growth, our current management system accentuates the mismatch between the pre- and post-natal environment in dairy calves. We can conclude that, although more research is necessary, the current findings point towards a more individual approach when rearing dairy heifers. PMID- 28815847 TI - Mastitis treatment-Reduction in antibiotic usage in dairy cows. AB - Animal-friendly, economical, resource-saving milk production provides the basis for sustained consumer acceptance. Bovine mastitis plays a decisive role in the dairy industry-disturbing animal health and welfare and causing considerable economic losses on the other hand. Currently, antimicrobial treatment is indispensable to keep bovine udder health, animal welfare and economic aspects in balance. On the contrary, emergence and spread of antimicrobial resistance (AMR) is an urgent matter of particular public interest, and as a consequence, antimicrobial usage (AMU) in production livestock is a critically discussed subject. In urgent need of future reduction in AMU in the dairy industry, this review article describes and discusses possible approaches promising prompt implementation, including therapeutical alternatives as well as pro- and metaphylactic concepts such as the implementation of evidence-based mastitis therapy concepts and selective dry cow treatment (sDCT), in search of the most effective and contemporary methods for decreasing AMU and AMR in dairy production. PMID- 28815848 TI - Inflammation and fertility in the mare. AB - A transient uterine inflammation post-breeding is a normal physiological reaction in the mare, and it is believed that the inflammatory response is necessary to eliminate bacteria and excess spermatozoa introduced into the uterine lumen. A tight balance between multiple pro- and anti-inflammatory factors is required for resolving the breeding-induced inflammation within 24-36 hr in the reproductively healthy mare, whereas a subpopulation of mares is susceptible to development of a persistent infection that can interfere with fertility. The aetiology of persistent endometritis can be either bacterial or semen-induced and both scenarios can threaten the establishment of pregnancy. Several factors associated with susceptibility to persistent endometritis have been identified including altered innate immune response in the early inflammatory process, reduced myometrial contractions and impaired opsonization; however, the pathogenesis to susceptibility has not been fully elucidated. Current research focuses on the initial hours of uterine inflammatory responses to semen and bacteria, and potential treatments to modify this altered innate immune response. An increased understanding of the mechanisms involved in the disease progression is necessary to improve the treatment and management of these mares. This review attempts to summarize the current knowledge of the uterine inflammatory and immunological responses to breeding-induced endometritis, persistent breeding-induced endometritis (PBIE) and bacterial endometritis in the mare. PMID- 28815849 TI - Molecular aspects of uterine diseases in dogs. AB - Uterine diseases are common in dogs, particularly in countries where elective spaying is not usually performed. The associated clinical illnesses may be of varying degree ranging from merely decreased fertility to a critical pyometra requiring intensive care to survive. The diagnosis of some uterine diseases is generally uncomplicated, such as in a classic pyometra presenting with enlarged, fluid-filled uterus, purulent vaginal discharge and characteristic signs of illness or in other disorders associated with uterine enlargement. However, it can be more puzzling in diseases with normal uterine size and very mild or obscure clinical signs. It is important to recognize the uterine diseases early because of the risk of potentially life-threatening complications such as sepsis developing if treatment is delayed in cases where bacterial infection is present. In breeding bitches, an early diagnosis, that is when the disease has not developed extensively, will increase the possibility of non-surgical treatment options without increased risk and thereby also increasing chances of maintained fertility. Early diagnosis and treatment initiation are thus favourable for complete recovery, also in less severe uterine diseases and those without infection. Molecular markers are molecules in biological samples that can be measured for diagnostic purposes, outcome prediction, and for gaining more information about different physiological and pathological conditions. Examples of commonly evaluated markers include laboratory variables analysed in blood, urine, cytological or tissue biopsy samples. Regarding the genetic pre disposition for different uterine diseases in dogs, information is lacking. Recently, the global gene expression in uterine tissue in dogs has been investigated more closely, and newly developed technologies provide excellent opportunities for identifying molecular markers worth exploring further. The focus of this review article is to highlight findings on markers relevant for diagnosis, prediction of prognosis and treatment outcome in the most common uterine diseases in dogs. PMID- 28815851 TI - Basics of genome editing technology and its application in livestock species. AB - In the last decade, the research community has witnessed a blooming of targeted genome editing tools and applications. Novel programmable DNA nucleases such as zinc finger nucleases (ZFNs), transcription activator-like endonucleases (TALENs) and the clustered regularly interspaced short palindromic repeats/Cas9 system (CRISPR/Cas9) possess long recognition sites and are capable of cutting DNA in a very specific manner. These DNA nucleases mediate targeted genetic alterations by enhancing the DNA mutation rate via induction of double-strand breaks at a predetermined genomic site. Compared to conventional homologous recombination based gene targeting, DNA nucleases, also referred to as Genome Editors (GEs), can increase the targeting rate around 10,000- to 100,000-fold. The successful application of different GEs has been shown in a myriad of different organisms, including insects, amphibians, plants, nematodes and several mammalian species, including human cells and embryos. In contrast to all other DNA nucleases, that rely on protein-DNA binding, CRISPR/Cas9 uses RNA to establish a specific binding of its DNA nuclease. Besides its capability to facilitate multiplexed genomic modifications in one shot, the CRISPR/Cas is much easier to design compared to all other DNA nucleases. Current results indicate that any DNA nuclease can be successfully employed in a broad range of organisms which renders them useful for improving the understanding of complex physiological systems such as reproduction, producing transgenic animals, including creating large animal models for human diseases, creating specific cell lines, and plants, and even for treating human genetic diseases. This review provides an update on DNA nucleases, their underlying mechanism and focuses on their application to edit the genome of livestock species. PMID- 28815852 TI - Life-threatening systemic rotavirus infection after vaccination in severe combined immunodeficiency (SCID). PMID- 28815853 TI - Changes to white matter microstructure in transient ischemic attack: A longitudinal diffusion tensor imaging study. AB - Transient ischemic attack (TIA) is associated with localized ischemic changes, identifiable by diffusion-weighted imaging. Past research has not considered whether TIA is also associated with diffuse changes to white matter microstructure; further past work has not tracked changes longitudinally. Here we examine whole-brain changes in fractional anisotropy (FA) in individuals with TIA presenting with sensorimotor symptoms. Twenty individuals with a recent (within 30 days) TIA and 12 healthy older adults were recruited. Participants underwent 3.0 T diffusion MRI at baseline; scans were repeated for the TIA group 90 days post-TIA. Track-based spatial statistics (TBSS) was used to conduct a voxel-wise analysis of FA between groups. FA was significantly lower in the TIA group relative to healthy controls, primarily in anterior white matter tracts including: forceps minor, anterior thalamic radiations, cingulum, inferior fronto occipital fasciculus, and corticospinal tract. TBSS results informed an ROI-based longitudinal examination of FA in the TIA group. There were no changes to TBSS identified clusters, forceps minor, or the corticospinal tract over time. There was lower FA in the anterior thalamic radiations in the TIA-affected hemisphere at baseline, but no difference between hemispheres at 90 days. In summary, individuals with TIA presenting with sensorimotor symptoms have decreased FA in tracts that are also implicated in sensorimotor function, which outlast the clinical symptoms associated with TIA. This suggests a more profound type of brain damage associated with TIA than has been typically described in past work. Diffusion tensor imaging may have utility as a marker of TIA-associated changes to white matter pathways. Hum Brain Mapp 38:5795-5803, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28815854 TI - Expression of natural cytotoxicity receptors and cytokine production on endometrial natural killer cells in women with recurrent pregnancy loss or implantation failure, and the expression of natural cytotoxicity receptors on peripheral blood natural killer cells in pregnant women with a history of recurrent pregnancy loss. AB - AIM: Natural cytotoxicity receptors (NCR) are unique markers that regulate natural killer (NK) cell cytotoxicity and cytokine production. In this study, we investigated the expression of NCR (NKp46, NKp44, and NKp30) and cytokine production in NK cells derived from the uterine endometrium of women with recurrent pregnancy loss (RPL). We also investigated the expression of NCR in peripheral blood NK cells in pregnant women with and without a history of RPL. METHODS: The expression of NCR (NKp46, NKp44, and NKp30) in NK cells (CD56dim and CD56bright ) in the uterine endometrium was analyzed using 3-color flow cytometry. Cytokine (tumor necrosis factor-alpha and interferon-gamma) production was also analyzed. NK cells from the mid-secretory endometrium of 28 women with RPL, 34 women with implantation failure, and 74 controls were collected and mechanically dispersed using a tissue grinder. The expression of NCR in peripheral blood NK cells from pregnant women with (n = 17) and without (n = 91) a history of RPL was analyzed. RESULTS: The percentages of NKp46+ NK cells were significantly lower in both women with RPL and pregnant women with a history of RPL. The percentages of tumor necrosis factor-alpha- and/or interferon-gamma producing uterine endometrial NK cells were significantly lower in women with RPL compared with controls. CONCLUSION: The changes in NCR expression and cytokine production, especially decreased NKp46 expression in endometrial NK cells, suggests the presence of abnormal NK cell regulation in women with reproductive failures. PMID- 28815855 TI - Solid-State Step-Scan FTIR Spectroscopy of Binuclear Copper(I) Complexes. AB - The structure in the ground and excited electronic state of two binuclear CuI N heterocyclic phosphine complexes that are promising for implementation in organic light-emitting diodes is investigated by a combination of the time-resolved step scan FTIR technique and quantum chemical calculations at the DFT level of theory. In contrast to the usual application of step-scan FTIR spectroscopy in solution, the herein-presented analyses are performed in a solid phase, that is, the CuI complexes are embedded in a KBr matrix (KBr pellet). The application of solid state time-resolved step-scan FTIR spectroscopy is of great importance for transition metal complexes, since their photophysical properties often change on moving from solid to dissolved samples. The efficient applicability of the solid state step-scan technique in a KBr matrix is demonstrated on the chosen CuI reference systems on nano- and microsecond timescales with an excitation wavelength of 355 nm. By comparison with theoretical results, the structure of the complexes in the electronic ground and lowest-lying electronically excited state can be determined. PMID- 28815856 TI - Molecular Dynamics Insights into Polyamine-DNA Binding Modes: Implications for Cross-Link Selectivity. AB - Biogenic polyamines, which play a role in DNA condensation and stabilization, are ubiquitous and are found at millimolar concentration in the nucleus of eukaryotic cells. The interaction modes of three polyamines-putrescine (Put), spermine (Spm), and spermidine (Spd)-with a self-complementary 16 base pair (bp) duplex, are investigated by all-atom explicit-solvent molecular dynamics. The length of the amine aliphatic chain leads to a change of the interaction mode from minor groove binding to major groove binding. Through all-atom dynamics, noncovalent interactions that stabilize the polyamine-DNA complex and prefigure the reactivity, leading to the low-barrier formation of deleterious DNA-polyamine cross-links, after one-electron oxidation of a guanine nucleobase, are unraveled. The binding strength is quantified from the obtained trajectories by molecular mechanics generalized Born surface area post-processing (MM-GBSA). The values of binding free energies provide the same affinity order, PutA (p.Trp363*), c.1714C>T (p.Arg572*), and c.2270_2271del (p.Pro757Argfs*7). All patients shared similar clinical features as previously reported including seizures, global developmental delay, intellectual disability, variable neurologic regression, behavior issues, and dysmorphic facial features. Features including heart defects and kidney abnormalities were not reported in our patients. These findings expands the clinical spectrum of HNRNPU-related disorder and shows that HNRNPU contributes to a subset of the clinical phenotypes associated with the contiguous 1q43-q44 deletion syndrome. PMID- 28815872 TI - A multimethod computational simulation approach for investigating mitochondrial dynamics and dysfunction in degenerative aging. AB - Research in biogerontology has largely focused on the complex relationship between mitochondrial dysfunction and biological aging. In particular, the mitochondrial free radical theory of aging (MFRTA) has been well accepted. However, this theory has been challenged by recent studies showing minimal increases in reactive oxygen species (ROS) as not entirely deleterious in nature, and even beneficial under the appropriate cellular circumstances. To assess these significant and nonintuitive observations in the context of a functional system, we have taken an in silico approach to expand the focus of the MFRTA by including other key mitochondrial stress response pathways, as they have been observed in the nematode Caenorhabditis elegans. These include the mitochondrial unfolded protein response (UPRmt ), mitochondrial biogenesis and autophagy dynamics, the relevant DAF-16 and SKN-1 axes, and NAD+ -dependent deacetylase activities. To integrate these pathways, we have developed a multilevel hybrid-modeling paradigm, containing agent-based elements among stochastic system-dynamics environments of logically derived ordinary differential equations, to simulate aging mitochondrial phenotypes within a population of energetically demanding cells. The simulation experiments resulted in accurate predictions of physiological parameters over time that accompany normal aging, such as the declines in both NAD+ and ATP and an increase in ROS. Additionally, the in silico system was virtually perturbed using a variety of pharmacological (e.g., rapamycin, pterostilbene, paraquat) and genetic (e.g., skn-1, daf-16, sod-2) schemes to quantitate the temporal alterations of specific mechanistic targets, supporting insights into molecular determinants of aging as well as cytoprotective agents that may improve neurological or muscular healthspan. PMID- 28815873 TI - Critical interpretive synthesis of barriers and facilitators to TB treatment in immigrant populations. AB - OBJECTIVE: To systematically review studies of TB treatment experiences in immigrant populations, using Critical Interpretive Synthesis (CIS). METHODS: On 26 October 2014, MEDLINE, CINAHL, Embase, LILACS, and PsycINFO were systematically searched. Grey literature and reference lists were hand-searched. Initial papers included were restricted to studies of immigrant patient perspectives; after a model was developed, a second set of papers was included to test the emerging theory. RESULTS: Of 1761 studies identified in the search, a total of 29 were included in the synthesis. Using those studies, we developed a model that suggested treatment experiences were strongly related to the way both individuals and societies adjusted to immigration ('acculturation strategies'). Relationships with healthcare workers and immigration policies played particularly significant roles in TB treatment. CONCLUSIONS: This review emphasised the roles of repatriation policy and healthcare workers in forming experiences of TB treatment in immigrant populations. PMID- 28815874 TI - White matter alterations associate with onset symptom dimension in obsessive compulsive disorder. AB - AIM: The high heterogeneity of obsessive-compulsive disorder (OCD) is best described by a multidimensional model involving symptom dimensions. We aimed to investigate white matter alterations associated with OCD, focusing on the impact of long-lasting effect of symptom dimensions assessed at onset of illness. Furthermore, we investigated white matter alterations associated with this disorder, controlling for the impact of medications and for the prevailing current symptom dimension. METHODS: We studied 58 patients affected by OCD and 58 age- and sex-matched healthy controls. We divided patients according to symptom dimension at onset of illness, assessed with the five-factor model. T-tests were performed in order to investigate differences between subgroups. Similar analyses were performed considering the prevailing current symptom dimension. Analyses were conducted with tract-based spatial statistics on diffusion tensor imaging. RESULTS: Doubt/checking and rituals/superstition symptom dimensions at onset and symmetry/perfectionism current symptom dimensions were characterized by significant alterations in diffusion tensor imaging measures. An association of white matter alterations and symmetry/perfectionism current dimension was found only when controlling for the effect of doubt/checking dimension at onset. Finally, results pointed out that the observed differences between patients and healthy controls were carried by the effect of previous and current medications. CONCLUSION: Our findings evidenced that onset symptom dimensions are associated with enduring alterations of white matter microstructure. Onset symptom dimensions may reflect underlying endophenotypes. In addition, present results confirm the effect of medications on white matter in OCD, showing a large effect of current treatment on myelination. PMID- 28815875 TI - The Pathogenic A2V Mutant Exhibits Distinct Aggregation Kinetics, Metal Site Structure, and Metal Exchange of the Cu2+ -Abeta Complex. AB - A prominent current hypothesis is that impaired metal ion homeostasis may contribute to Alzheimer's disease (AD). We elucidate the interaction of Cu2+ with wild-type (WT) Abeta1-40 and the genetic variants A2T and A2V which display increasing pathogenicity as A2TT p.Arg61*) in a heterozygous state. Quantitative fluorescent multiplex PCR identified a new deletion of exons 15 and 16 in TRIM37 in one isolated patient and another deletion of exon 9 in two siblings. Breakpoints of both the deletions were localized in Alu sequences. Given the high number of Alu repeats, which predispose to gene rearrangements, one should always consider such genetic rearrangements in the molecular diagnosis of non-Finnish MULIBREY nanism patients. Early diagnosis of the disease would prompt careful cardiac follow up of such patients as cardiological complication is a characteristic feature of the MULIBREY nanism as described in this report. PMID- 28815878 TI - Prediction of energy expenditure during walking in adults with down syndrome. AB - BACKGROUND: When developing walking programmes for improving health in adults with Down syndrome (DS), physical activity professionals are in need of an equation for predicting energy expenditure. We therefore developed and cross validated an equation for predicting the rate of oxygen uptake (VO2 ; an index of energy expenditure) for adults with and without DS. METHOD: A total of 469 VO2 observations during walking across different speeds were available from 54 adults with DS and 61 adults without DS. RESULTS: Significant predictors of VO2 were speed, speed square, group and group-by-speed interaction. Separate models for each group showed that speed and its square significantly predicted VO2 . Absolute per cent error was small and did not differ between groups. CONCLUSION: Adults with DS have different VO2 response to walking speed from persons without DS. VO2 is predicted from speed with acceptable accuracy for persons with DS. PMID- 28815881 TI - Corrigendum: Photoinduced DNA Interstrand Cross-Link Formation by Naphthalene Boronates via a Carbocation. PMID- 28815880 TI - Immunogenicity, efficacy and safety of Nuwiq(r) (human-cl rhFVIII) in previously untreated patients with severe haemophilia A-Interim results from the NuProtect Study. AB - INTRODUCTION: Nuwiq(r) (Human-cl rhFVIII) is a fourth generation recombinant FVIII, produced in a human cell line, without chemical modification or protein fusion. No inhibitors developed in studies with Nuwiq(r) in 201 previously treated patients with haemophilia A (HA). The immunogenicity, efficacy and safety of Nuwiq(r) in previously untreated patients (PUPs) with severe HA are being assessed in the ongoing NuProtect study. METHODS: The study, conducted across 38 centres worldwide, is evaluating 110 true PUPs of all ages and ethnicities enrolled for study up to 100 exposure days (EDs) or 5 years maximum. The primary objective is to assess the immunogenicity of Nuwiq(r) (inhibitor activity >=0.6 BU) using the Nijmegen-modified Bethesda assay at a central laboratory. RESULTS: Data for 66 PUPs with >=20 EDs from a preplanned interim analysis were analysed. High-titre (HT) inhibitors developed in 8 of 66 patients after a median of 11.5 EDs (range 6-24). Five patients developed low-titre inhibitors (4 transient). The cumulative incidence (95% confidence interval) was 12.8% (4.5%, 21.2%) for HT inhibitors and 20.8% (10.7%, 31.0%) for all inhibitors. During inhibitor-free periods, median annualized bleeding rates during prophylaxis were 0 for spontaneous bleeds and 2.40 for all bleeds. Efficacy was rated as "excellent" or "good" in treating 91.8% of bleeds. Efficacy of surgical prophylaxis was "excellent" or "good" for 8 (89%) procedures and "moderate" for 1 (11%). No tolerability concerns were evident. CONCLUSION: These interim data show a cumulative incidence of 12.8% for HT inhibitors and convincing efficacy and tolerability in PUPs treated with Nuwiq(r) . PMID- 28815879 TI - Calibrated imaging reveals altered grey matter metabolism related to white matter microstructure and symptom severity in multiple sclerosis. AB - Multiple sclerosis (MS) involves damage to white matter microstructures. This damage has been related to grey matter function as measured by standard, physiologically-nonspecific neuroimaging indices (i.e., blood-oxygen-level dependent signal [BOLD]). Here, we used calibrated functional magnetic resonance imaging and diffusion tensor imaging to examine the extent to which specific, evoked grey matter physiological processes were associated with white matter diffusion in MS. Evoked changes in BOLD, cerebral blood flow (CBF), and oxygen metabolism (CMRO2 ) were measured in visual cortex. Individual differences in the diffusion tensor measure, radial diffusivity, within occipital tracts were strongly associated with MS patients' BOLD and CMRO2 . However, these relationships were in opposite directions, complicating the interpretation of the relationship between BOLD and white matter microstructural damage in MS. CMRO2 was strongly associated with individual differences in patients' fatigue and neurological disability, suggesting that alterations to evoked oxygen metabolic processes may be taken as a marker for primary symptoms of MS. This work demonstrates the first application of calibrated and diffusion imaging together and details the first application of calibrated functional MRI in a neurological population. Results lend support for neuroenergetic hypotheses of MS pathophysiology and provide an initial demonstration of the utility of evoked oxygen metabolism signals for neurology research. Hum Brain Mapp 38:5375-5390, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28815882 TI - Application of chitosan microparticles for mitigation of Salmonella in agricultural water. AB - AIM: The activity of chitosan microparticles (CM) was examined using a matrix of conditions in order to assess the efficacy of CM as a mitigation against various strains of Salmonella enterica in agricultural water. METHODS AND RESULTS: Different concentrations of CM (0, 0.01, 0.1, 0.2, 0.3% w/v) were examined for antimicrobial activity against log vs stationary phase cells of Salmonella and at different conditions of temperature, salinity and pH. Results showed greatest activity with 0.3% CM at pH 7, 25-37 degrees C without additional of salt. Significant reductions in Salmonella levels were also achieved in natural pond water, although decreases were reduced compared to sterile water. All serotypes were sensitive to CM, with minimal inhibitory concentrations ranging from 0.0031 to 0.0250% w/v. Phylogenic analysis of Javiana strains showed increased resistance appeared in multiple genetic lineages. CONCLUSION: Conditions demonstrating greatest CM activity were compatible with agricultural practices. Although sensitivity to CM varied among Salmonella strains, all strains were sensitive under conditions examined in this study. SIGNIFICANCE AND IMPACT OF THE STUDY: This research indicated that CM, a natural compound with minimal environmental impact, could be an effective alternative for mitigating Salmonella in agricultural water applications. PMID- 28815883 TI - WWC2 is an independent prognostic factor and prevents invasion via Hippo signalling in hepatocellular carcinoma. AB - WWC family proteins negatively regulate HEK293 cell proliferation and organ growth by suppressing the transcriptional activity of Yes-associated protein (YAP), a major effector of the Hippo pathway. The function of the scaffolding protein WWC1 (also called KIBRA) has been intensively studied in cells and animal models. However, the expression and clinicopathologic significance of WWC2 in cancer are poorly characterized. This study aimed to clarify the biological function and mechanism of action of WWC2 in hepatocellular carcinoma (HCC). Retrospective analysis revealed WWC2 was significantly down-regulated in 95 clinical HCC tissues compared to the paired adjacent non-cancerous tissues. Moreover, loss of WWC2 expression was significantly associated with advanced clinicopathological features, including venous infiltration, larger tumour size and advanced TNM stage. Positive WWC2 expression was associated with significantly better 5-year overall survival, and WWC2 was an independent prognostic factor for overall survival in HCC. Moreover, we confirmed WWC2 inhibits HCC cell invasive ability in vitro. Elevated YAP expression was also observed in the same cohort of HCC tissues. Pearson's correlation coefficient analysis indicated WWC2 expression correlated inversely with nuclear YAP protein expression in HCC. Mechanistically, we confirmed overexpression of WWC2 suppresses the invasive and metastatic potential of HCC cells by activating large tumour suppressor 1 and 2 kinases (LATS1/2), which in turn phosphorylates the transcriptional co-activator YAP. Overall, this study indicates WWC2 functions as a tumour suppressor by negatively regulating the Hippo signalling pathway and may serve as a prognostic marker in HCC. PMID- 28815884 TI - Periodontal ligament-like tissue regeneration with drilled porous decalcified dentin matrix sheet composite. AB - OBJECTIVE: In this study, we constructed a composite by combining the human dental follicle cell sheet and a manual drilled porous decalcified dentin matrix that was used to construct ectopic tissue-engineered periodontal ligament-like tissues in renal capsules of nude mice. MATERIALS AND METHODS: Human dental follicle cells were harvested from human lower third molars and then embedded into a temperature-sensitive culture dish. These cells were then placed into frozen porous decalcified dentin matrix sheets and induced by 50 g/ml ascorbic acid. This established a "sandwich structure" in vitro implant that was placed in nude mice under the renal capsule. The mice were sacrificed at 4 and 8 weeks after implantation, and the implants were assessed after haematoxylin-eosin staining, Masson staining and immunohistochemical staining. RESULTS: The experimental group showed a fibre structure between the dentin and HA-TCP after 4 weeks. After 8 weeks, the collagen fibres increased, and the direction was perpendicular to the dentin. Immunohistochemistry showed positive staining in the osteopontin and periostin. CONCLUSION: The composite can induce ectopic bone and fibre formation, and the fibre had a certain directionality. Besides, the composite can maintain the stability of the periodontal ligament width. PMID- 28815886 TI - Disentangling the role of management, vegetation structure, and plant quality for Orthoptera in lowland meadows. AB - Seminatural grasslands provide habitats for various species and are important for biodiversity conservation. The understanding of the diverse responses of species and traits to different grassland management methods is therefore urgently needed. We disentangled the role of grassland management (fertilization and irrigation), vegetation structure (biomass, sward height) and plant quality (protein and fiber content) for Orthoptera communities in lowland hay meadows in Germany. We found vegetation structure to be the most important environmental category in explaining community structure of Orthoptera (species richness, total individuals, functional diversity and species composition). Intensively used meadows (fertilized, irrigated, high plant biomass) were characterized by assemblages with few species, low functional diversity, and low conservation value. Thereby, the relatively moderate fertilizer inputs in our study system of up to ~75 kg N/ha/year reduced functional diversity of Orthoptera, while this negative effect of fertilization was not detectable when solely considering taxonomic aspects. We found strong support for a prominent role of plant quality in shaping Orthoptera communities and especially the trait composition. Our findings demonstrate the usefulness of considering both taxonomic and functional components (functional diversity) in biodiversity research and we suggest a stronger involvement of plant quality measures in Orthoptera studies. PMID- 28815885 TI - Novel landscape of HLA-G isoforms expressed in clear cell renal cell carcinoma patients. AB - Immune checkpoints are powerful inhibitory molecules that promote tumor survival. Their blockade is now recognized as providing effective therapeutic benefit against cancer. Human leukocyte antigen G (HLA-G), a recently identified immune checkpoint, has been detected in many types of primary tumors and metastases, in malignant effusions as well as on tumor-infiltrating cells, particularly in patients with clear cell renal cell carcinoma (ccRCC). Here, in order to define a possible anticancer therapy, we used a molecular approach based on an unbiased strategy that combines transcriptome determination and immunohistochemical labeling, to analyze in-depth the HLA-G isoforms expressed in these tumors. We found that the expression of HLA-G is highly variable among tumors and distinct areas of the same tumor, testifying a marked inter- and intratumor heterogeneity. Moreover, our results generate an inventory of novel HLA-G isoforms which includes spliced forms that have an extended 5'-region and lack the transmembrane and alpha-1 domains. So far, these isoforms could not be detected by any method available and their assessment may improve the procedure by which tumors are analyzed. Collectively, our approach provides the first extensive portrait of HLA G in ccRCC and reveals data that should prove suitable for the tailoring of future clinical applications. PMID- 28815887 TI - Viologens and Their Application as Functional Materials. AB - Organic materials have recently gained considerable attention for electronic applications, improving performance and sustainability to current technologies. Commercialized metal-based systems are generally expensive, toxic and difficult to recycle, however organic materials offer promising solutions. Viologens, N,N' di-quaternized bipyridyl salts, are a well-studied species exhibiting three reversible redox states, possessing valuable electrochromic and electron accepting properties. These properties can be fine-tuned through synthesis by altering the nitrogen substituents and various counteranions. Currently, viologens have become of great interest as functional materials in a wide array of applications; a few to name include electrochromic devices, molecular machines, and organic batteries. This review highlights representative recent work and advances towards utilizing viologens in practical applications that currently compete with metal-based technologies. Additionally, modified viologens that can be further fine-tuned will be discussed. PMID- 28815888 TI - Friction and Wetting Transitions of Magnetic Droplets on Micropillared Superhydrophobic Surfaces. AB - Reliable characterization of wetting properties is essential for the development and optimization of superhydrophobic surfaces. Here, the dynamics of superhydrophobicity is studied including droplet friction and wetting transitions by using droplet oscillations on micropillared surfaces. Analyzing droplet oscillations by high-speed camera makes it possible to obtain energy dissipation parameters such as contact angle hysteresis force and viscous damping coefficients, which indicate pinning and viscous losses, respectively. It is shown that the dissipative forces increase with increasing solid fraction and magnetic force. For 10 um diameter pillars, the solid fraction range within which droplet oscillations are possible is between 0.97% and 2.18%. Beyond the upper limit, the oscillations become heavily damped due to high friction force. Below the lower limit, the droplet is no longer supported by the pillar tops and undergoes a Cassie-Wenzel transition. This transition is found to occur at lower pressure for a moving droplet than for a static droplet. The findings can help to optimize micropillared surfaces for low-friction droplet transport. PMID- 28815889 TI - C-H Bond Trifluoromethylation of Arenes Enabled by a Robust, High-Valent Nickel(IV) Complex. AB - The robust, high-valent NiIV complex [(Py)2 NiIV F2 (CF3 )2 ] (Py=pyridine) was synthesized and fully characterized by NMR spectroscopy, X-ray diffraction, and elemental analysis. It reacts with aromatic compounds at 25 degrees C to form the corresponding benzotrifluorides in nearly quantitative yield. The monomeric and dimeric NiIII CF3 complexes 2?Py and 2 were identified as key intermediates, and their structures were unambiguously determined by EPR spectroscopy and X-ray diffraction. Preliminary kinetic studies in combination with the isolation of reaction intermediates confirmed that the C-H bond-breaking/C-CF3 bond-forming sequence can occur both at NiIV CF3 and NiIII CF3 centers. PMID- 28815890 TI - A Semi-Synthetic Glycoconjugate Vaccine Candidate for Carbapenem-Resistant Klebsiella pneumoniae. AB - Hospital-acquired infections are an increasingly serious health concern. Infections caused by carpabenem-resistant Klebsiella pneumoniae (CR-Kp) are especially problematic, with a 50 % average survival rate. CR-Kp are isolated from patients with ever greater frequency, 7 % within the EU but 62 % in Greece. At a time when antibiotics are becoming less effective, no vaccines to protect from this severe bacterial infection exist. Herein, we describe the convergent [3+3] synthesis of the hexasaccharide repeating unit from its capsular polysaccharide and related sequences. Immunization with the synthetic hexasaccharide 1 glycoconjugate resulted in high titers of cross-reactive antibodies against CR-Kp CPS in mice and rabbits. Whole-cell ELISA was used to establish the surface staining of CR-Kp strains. The antibodies raised were found to promote phagocytosis. Thus, this semi-synthetic glycoconjugate is a lead for the development of a vaccine against a rapidly progressing, deadly bacterium. PMID- 28815891 TI - Cystic kidneys in fetal Walker-Warburg syndrome with POMT2 mutation: Intrafamilial phenotypic variability in four siblings and review of literature. AB - Walker-Warburg syndrome (WWS) is a severe form of congenital muscular dystrophy secondary to alpha-dystroglycanopathy with muscle, brain, and eye abnormalities often leading to death in the first weeks of life. It is transmitted in an autosomal recessive pattern, and has been linked to at least 15 different genes; including protein O-mannosyltransferase 1 (POMT1), protein O-mannosyltransferase 2 (POMT2), protein O-mannose beta-1,2-N acetylglucosaminyltransferase (POMGNT1), fukutin (FKTN), isoprenoid synthase domain-containing protein (ISPD), and other genes. We report on a consanguineous family with four consecutive siblings affected by this condition with lethal outcome in three (still birth), and termination of the fourth pregnancy based on antenatal MRI identification of brain and kidney anomalies that heralded proper and deep clinical phenotyping. The diagnosis of WWS was suggested based on the unique collective phenotype comprising brain anomalies in the form of lissencephaly, subcortical/subependymal heterotopia, and cerebellar hypoplasia shared by all four siblings; microphthalmia in one sibling; and large cystic kidneys in the fetus and another sibling. Other unshared neurological abnormalities included hydrocephalus and Dandy-Walker malformation. Whole exome sequencing of the fetus revealed a highly conserved missense mutation in POMT2 that is known to cause WWS with brain and eye anomalies.In conclusion, the heterogeneous clinical presentation in the four affected conceptions with POMT2 mutation expands the current clinical spectrum of POMT2-associated WWS to include large cystic kidneys; and confirms intra-familial variability in terms of brain, kidney, and eye anomalies. PMID- 28815892 TI - Preaxial polydactyly in an individual with Wiedemann-Steiner syndrome caused by a novel nonsense mutation in KMT2A. AB - Wiedemann-Steiner syndrome (WDSTS) is an autosomal dominant disorder characterized by hypertrichosis, intellectual disability, and dysmorphic facial appearances (down-slanted vertically narrow palpebral fissures, wide nasal bridge, broad nasal tip, and thick eyebrows). In 2012, Jones and co-workers identified heterozygous mutations in KMT2A (lysine methyltransferase 2A) as the molecular cause of WDSTS. Although the phenotype of this syndrome continues to expand, the associated features are not fully understood. Here, we report WDSTS in a 12-year-old Japanese boy with a novel nonsense mutation in KMT2A. He had right preaxial polydactyly, which has not been previously reported in WDSTS. We could not identify a causal relationship between the KMT2A mutation and preaxial polydactyly, and cannot exclude the preaxial polydactyly is a simple coincidence. We summarized the clinical features of WDSTS associated with KMT2A mutation and discussed the cardinal symptoms in detail. PMID- 28815894 TI - Challenges of developing and conducting clinical trials in rare disorders. AB - Rare disease drug development is a rapidly expanding field. Clinical researchers in rare diseases face many challenges when conducting trials in small populations. Disease natural history is often poorly understood and the ability to detect clinically meaningful outcomes requires understanding of their rate of occurrence and variability, both of which contribute to difficulties in powering a study. Standard trial designs are not optimized to obtain adequate safety and efficacy data from small numbers of patients, so alternative designs (enrichment, crossover, adaptive, N-of 1) need to be considered. The affected patients can be hard to identify, especially early in the course of their disease, are generally geographically dispersed, and are often children. Trials are frequently conducted on an international scale and may be subject to complex or multiple regulatory agency oversights and may be affected by local customs, cultures, and practices. A basic understanding of the FDA programs supporting development of drugs for rare diseases is provided by this review and the role of early consultation with the FDA is emphasized. Of recent FDA New Molecular Entities (NME) approvals, 41% (17 approvals) in 2014, 47% (21 approvals) in 2015, and 41% (9 approvals) in 2016 were for rare disease indications. Through effective interactions and collaborations with physicians, institutions, and patient groups, sponsors have been successful in bringing new treatments to market for individuals affected by rare diseases. Challenges to drug development have been overcome through the focused efforts of patients/families, non-profit patient advocacy groups, drug developers, and regulatory authorities. PMID- 28815893 TI - The facial morphology in Down syndrome: A 3D comparison of patients with and without obstructive sleep apnea. AB - Obstructive sleep apnea (OSA) occurs at a high prevalence in patients with Down syndrome (DS). A polysomnogram, which is often cumbersome and challenging, remains the gold standard method of diagnosing OSA. OSA in patients with DS is often attributed to skeletal and soft-tissue structural alterations that are characteristic of the DS phenotype; as such, we hypothesized that assessing anthropometric facial measurements may be predictive of OSA in patients with DS. We used the 3dMDface sterophotography system to capture and create 3D facial images, and we subsequently identified facial landmarks using a single, experienced investigator and utilizing proprietary software to calculate inter landmark distances and angles. We compared our findings with similar data for neurotypically developing participants. We further compared the findings in participants with DS with and without OSA. Participants with DS had maxillomandibular hypoplasia with smaller ear, nose, and eye measurements compared to neurotypically developing peers. We found no statistically significant differences in 3D photogrammetric measurements between participants with DS with or without OSA. PMID- 28815895 TI - Health professional students' rural placement satisfaction and rural practice intentions: A national cross-sectional survey. AB - OBJECTIVE: The aim of this study was to profile students undertaking placements at University Departments of Rural Health (UDRHs) and investigate factors affecting students' satisfaction and intention to enter rural practice. DESIGN: Cross-sectional survey comprising 21 core questions used by all UDRHs. SETTING: Eleven UDRHs across Australia that support students' placements in regional, rural and remote locations. PARTICIPANTS: Medical, nursing and allied health students who participated in UDRH placements between July 2014 and November 2015 and completed the questionnaire. MAIN OUTCOME MEASURES: Key dependent variables were placement satisfaction and rural practice intention. Descriptive variables were age, gender, Aboriginal or Torres Strait Islander (ATSI) background, location of placement, healthcare discipline, year of study and type and length of placement. RESULTS: A total of 3328 students responded. The sample was predominantly female (79%), the mean age was 26.0 years and 1.8% identified as ATSI. Most placements (69%) were >2 but <=12 weeks, 80% were in Modified Monash 3, 4 or 5 geographical locations. Public hospitals and community health made up 63% of placements. Students satisfied with their placement had 2.33 higher odds of rural practice intention. Those satisfied with Indigenous cultural training, workplace supervision, access to education resources and accommodation had higher odds of overall satisfaction and post-placement rural practice intention. CONCLUSIONS: The majority of students were highly satisfied with their placement and the support provided by rural clinicians and the UDRHs. UDRHs are well placed to provide health professional students with highly satisfactory placements that foster rural practice intention. PMID- 28815896 TI - The signals to trigger the initiation of ovule enlargement are from the pollen tubes: The direct evidence. AB - In angiosperms, initiation of ovule enlargement represents the start of seed development, the molecular mechanism of which is not yet elucidated. It was previously reported that pollen tube contents, rather than double fertilization, can trigger ovule enlargement. However, it remains unclear whether the signal(s) to trigger the initiation of ovule enlargement are from the sperm cells or from the pollen tubes. Recently, we identified a mutant drop1- drop2-, which produces pollen tubes with no sperm cells. Taking advantage of this special genetic material, we conducted pollination assays, and found that the ovules pollinated with drop1- drop2- pollen could initiate the enlargement and exhibited significant enlarged sizes at 36 h after pollination in comparison with those unpollinated ovules. However, the sizes of the ovules pollinated with drop1- drop2- pollen are significantly smaller than those of the ovules pollinated with wild-type pollen. These results demonstrate that the pollen tube, rather than the sperm cells, release the signal to trigger the initiation of ovule enlargement, and that double fertilization is required for further enlargement of the seeds. PMID- 28815898 TI - Synthesis of Bicyclo[n.1.0]alkanes by a Cobalt-Catalyzed Multiple C(sp3 )-H Activation Strategy. AB - A cobalt-catalyzed dual C(sp3 )-H activation strategy has been developed and it provides a novel strategy for the synthesis of bicyclo[4.1.0]heptanes and bicyclo[3.1.0]hexanes. A key to the success of this reaction is the conformation induced methylene C(sp3 )-H activation of the resulting cobaltabicyclo[4.n.1] intermediate. In addition, the synthesis of bicyclo[3.1.0]hexane from pivalamide, by a triple C(sp3 )-H activation, has also been demonstrated. PMID- 28815899 TI - Deuterium- and Tritium-Labelled Compounds: Applications in the Life Sciences. AB - Hydrogen isotopes are unique tools for identifying and understanding biological and chemical processes. Hydrogen isotope labelling allows for the traceless and direct incorporation of an additional mass or radioactive tag into an organic molecule with almost no changes in its chemical structure, physical properties, or biological activity. Using deuterium-labelled isotopologues to study the unique mass-spectrometric patterns generated from mixtures of biologically relevant molecules drastically simplifies analysis. Such methods are now providing unprecedented levels of insight in a wide and continuously growing range of applications in the life sciences and beyond. Tritium (3 H), in particular, has seen an increase in utilization, especially in pharmaceutical drug discovery. The efforts and costs associated with the synthesis of labelled compounds are more than compensated for by the enhanced molecular sensitivity during analysis and the high reliability of the data obtained. In this Review, advances in the application of hydrogen isotopes in the life sciences are described. PMID- 28815900 TI - Mechanically Interlocked Molecules (MIMs)-Molecular Shuttles, Switches, and Machines (Nobel Lecture). AB - Chemistry welcomes a new bond: The mechanical bond has endowed molecules with component parts whose movements can be controlled and monitored. In his Nobel Lecture, J. F. Stoddart describes how being able to template the formation of mechanically interlocked molecules has led to the design and synthesis of shuttles, switches, and machines at the nanoscale. PMID- 28815897 TI - Multidrug-resistant Enterobacteriaceae, Pseudomonas aeruginosa, and vancomycin resistant Enterococcus: Three major threats to hematopoietic stem cell transplant recipients. AB - Hematopoietic stem cell transplant (HSCT) recipients are uniquely threatened by the emergence of multidrug-resistant (MDR) bacteria because these patients rely on immediate active antimicrobial therapy to combat bacterial infections. This review describes the epidemiology and treatment considerations for three challenging MDR bacterial pathogens in HSCT recipients: MDR Enterobacteriaceae, including extended-spectrum beta-lactamase (ESBL)-producing and carbapenem resistant Enterobacteriaceae (CRE), Pseudomonas aeruginosa, and vancomycin resistant Enterococcus (VRE). These bacteria are common causes of infection in this population and bacteremias caused by these organisms are associated with high mortality rates. Carbapenems remain the treatments of choice for serious infections due to ESBL-producing Enterobacteriaceae in HSCT recipients. Administration of beta-lactam agents as an extended infusion is associated with improved outcomes in patients with severe infections caused by P. aeruginosa. Older agents used for the treatment of CRE and MDR P. aeruginosa infections, such as polymyxins and aminoglycosides, have major limitations. Newer agents, such as ceftazidime-avibactam and ceftolozane-tazobactam have great potential for the treatment of Klebsiella pneumoniae carbapemenase-producing CRE and MDR P. aeruginosa, respectively, but more pre-clinical and clinical data are needed to better evaluate their efficacy. Daptomycin dosages >=8 mg/kg/day are recommended to treat VRE infections in this population, particularly in the setting of increasing daptomycin resistance. Strategies to prevent these infections include strict adherence to recommended infection control practices and multidisciplinary antimicrobial stewardship. Last, gastrointestinal screening to guide empirical therapy and the use of polymerase chain reaction-based rapid diagnostics may decrease the time to administration of appropriate therapy for these infections, thereby leading to improved outcomes. PMID- 28815902 TI - Response to Comment on "A Liposomal System Capable of Generating CO2 Bubbles to Induce Transient Cavitation, Lysosomal Rupturing and Cell Necrosis". PMID- 28815901 TI - A novel heterozygous mutation in FGFR2 gene causing Pfeiffer syndrome. PMID- 28815903 TI - Rhenium-Loaded TiO2 : A Highly Versatile and Chemoselective Catalyst for the Hydrogenation of Carboxylic Acid Derivatives and the N-Methylation of Amines Using H2 and CO2. AB - Herein, we report a heterogeneous TiO2 -supported Re catalyst (Re/TiO2 ) that promotes various selective hydrogenation reactions, which includes the hydrogenation of esters to alcohols, the hydrogenation of amides to amines, and the N-methylation of amines, by using H2 and CO2 . Initially, Re/TiO2 was evaluated in the context of the selective hydrogenation of 3-phenylpropionic acid methyl ester to afford 3-phenylpropanol (pH2 =5 MPa, T=180 degrees C), which revealed a superior performance over other catalysts that we tested in this study. In contrast to other typical heterogeneous catalysts, hydrogenation reactions with Re/TiO2 did not produce dearomatized byproducts. DFT studies suggested that the high selectivity for the formation of alcohols in favor of the hydrogenation of aromatic rings is ascribed to the higher affinity of Re towards the COOCH3 group than to the benzene ring. Moreover, Re/TiO2 showed a wide substrate scope for the hydrogenation reaction (19 examples). Subsequently, this Re/TiO2 catalyst was applied to the hydrogenation of amides, the N-methylation of amines, and the N-alkylation of amines with carboxylic acids or esters. PMID- 28815904 TI - Comparative in vitro study on cytotoxicity of recombinant beta-hairpin peptides. AB - Natural antimicrobial peptides (AMPs) are important components of the innate immune system with a wide spectrum of biological activity. In this study, we investigated the cytotoxic effect of three recombinant beta-hairpin cationic AMPs: arenicin-1 from the polychaeta Arenicola marina, tachyplesin I from the horseshoe crab Tachypleus tridentatus, and gomesin from the spider Acanthoscurria gomesiana. All the three beta-hairpin AMPs were overexpressed in Escherichia coli. Different cell lines were incubated with various concentrations of the investigated AMPs in order to evaluate their cytotoxic activity. Double staining with subsequent flow cytometric analysis was used to determine the predominant way of cell death mediated by each AMP. Hemolytic activity of the peptides was tested against fresh human red blood cells. Our results indicated that all the three AMPs exhibited significant cytotoxic effect against cancer cells that varied depending on the cell line type and, in most cases, on the presence of serum components. Flow cytometric analysis implicitly indicated that tachyplesin I mostly promoted late apoptosis/necrosis, while arenicin-1 and gomesin induced early apoptosis under the same conditions. Tachyplesin I proved to be the most promising therapeutic candidate as it displayed the highest specific cytotoxicity against cancer cell lines, independent of the serum presence. PMID- 28815905 TI - Degradable Vanadium Disulfide Nanostructures with Unique Optical and Magnetic Functions for Cancer Theranostics. AB - Multifunctional biodegradable inorganic theranostic nano-agents are of great interest to the field of nanomedicine. Upon lipid modification, VS2 nanosheets could be converted into ultra-small VS2 nanodots encapsulated inside polyethylene glycol (PEG) modified lipid micelles. Owing to paramagnetism, high near-infrared (NIR) absorbance, and chelator-free 99m Tc4+ labeling of VS2 , such VS2 @lipid PEG nanoparticles could be used for T1-weighted magnetic resonance (MR), photoacoustic (PA),and single photon emission computed tomography (SPECT) tri modal imaging guided photothermal ablation of tumors. Importantly, along with the gradual degradation of VS2 , our VS2 @lipid-PEG nanoparticles exhibit effective body excretion without appreciable toxicity. The unique advantages of VS2 nanostructures with highly integrated functionalities and biodegradable behaviors mean they are promising for applications in cancer theranostics. PMID- 28815906 TI - Deep gray matter iron measurement in patients with liver cirrhosis using quantitative susceptibility mapping: Relationship with pallidal T1 hyperintensity. AB - BACKGROUND: The liver is a central organ for the metabolism of iron and manganese and the places where those metals are commonly deposited overlap in the brain. PURPOSE/HYPOTHESIS: To elucidate the relationship between pallidal T1 hyperintensity and iron deposition in the deep gray matter of liver cirrhosis patients using quantitative susceptibility mapping (QSM). STUDY TYPE: Retrospective case-control study SUBJECTS: In all, 38 consecutive liver cirrhosis patients who received brain magnetic resonance imaging (MRI) as pretransplant evaluation. FIELD STRENGTH/SEQUENCE: QSM was reconstructed from 3D multi- or single-echo phase images at 3T. T1 -weighted images were used for the assessment of pallidal hyperintensity and pallidal index (PI). ASSESSMENT: Patients were divided into two groups according to the presence of pallidal hyperintensity by consensus of two radiologists. Susceptibility values were acquired for five deep gray matter structures. STATISTICAL TEST: QSM measures were compared between two groups using the t-test. We also calculated Pearson correlations between QSM measures and PI. RESULTS: In all, 26 patients showed pallidal hyperintensity (T1 h group) and 12 did not (T1 n group). The susceptibility of the globus pallidus (GP) in the T1 h group (120.6 +/- 38.1 ppb) was significantly lower than that in the T1 n group (150.0 +/- 35.2, P = 0.030). The susceptibility of the dentate nucleus (DN) in the T1 h group (88.1 +/- 31.0) was significantly lower than that in the T1 n group (125.6 +/- 30.6, P = 0.001). Negative correlation between the susceptibility of GP (r = -0.37, P = 0.022) and the PI, and between DN (r = 0.43, P < 0.001) and the PI was found. DATA CONCLUSION: Liver cirrhosis patients with pallidal T1 hyperintensity had lower susceptibility values in the GP and DN than those without it. This suggests a possible interaction between iron and manganese in the brains of liver cirrhosis patients. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1342-1349. PMID- 28815908 TI - Necrotizing Sweet's syndrome presenting as necrotizing fasciitis with a good response to immune suppressant treatment. PMID- 28815907 TI - T7 RNA polymerase-driven inducible cell lysis for DNA transfer from Escherichia coli to Bacillus subtilis. AB - The majority of the good DNA editing techniques have been developed in Escherichia coli; however, Bacillus subtilis is better host for a plethora of synthetic biology and biotechnology applications. Reliable and efficient systems for the transfer of synthetic DNA between E. coli and B. subtilis are therefore of the highest importance. Using synthetic biology approaches, such as streamlined lambda Red recombineering and Gibson Isothermal Assembly, we integrated genetic circuits pT7L123, Repr-ts-1 and pLT7pol encoding the lysis genes of bacteriophages MS2, PhiX174 and lambda, the thermosensitive repressor and the T7 RNA polymerase into the E. coli chromosome. In this system, T7 RNA polymerase regulated by the thermosensitive repressor drives the expression of the phage lysis genes. We showed that T7 RNA polymerase significantly increases efficiency of cell lysis and transfer of the plasmid and bacterial artificial chromosome-encoded DNA from the lysed E. coli into B. subtilis. The T7 RNA polymerase-driven inducible cell lysis system is suitable for the efficient cell lysis and transfer of the DNA engineered in E. coli to other naturally competent hosts, such as B. subtilis. PMID- 28815909 TI - Proximal Neuropathy and Associated Skeletal Muscle Changes Resembling Denervation Atrophy in Hindlimbs of Chronic Hypoglycaemic Rats. AB - Peripheral neuropathy is one of the most common complications of diabetic hyperglycaemia. Insulin-induced hypoglycaemia (IIH) might potentially exacerbate or contribute to neuropathy as hypoglycaemia also causes peripheral neuropathy. In rats, IIH induces neuropathy associated with skeletal muscle changes. Aims of this study were to investigate the progression and sequence of histopathologic changes caused by chronic IIH in rat peripheral nerves and skeletal muscle, and whether such changes were reversible. Chronic IIH was induced by infusion of human insulin, followed by an infusion-free recovery period in some of the animals. Sciatic, plantar nerves and thigh muscle were examined histopathologically after four or eight weeks of infusion and after the recovery period. IIH resulted in high incidence of axonal degeneration in sciatic nerves and low incidence in plantar nerves indicating proximo-distal progression of the neuropathy. The neuropathy progressed in severity (sciatic nerve) and incidence (sciatic and plantar nerve) with the duration of IIH. The myopathy consisted of groups of angular atrophic myofibres which resembled histopathologic changes classically seen after denervation of skeletal muscle, and severity of the myofibre atrophy correlated with severity of axonal degeneration in sciatic nerve. Both neuropathy and myopathy were still present after four weeks of recovery, although the neuropathy was less severe. In conclusion, the results suggest that peripheral neuropathy induced by IIH progresses proximo-distally, that severity and incidence increase with duration of the hypoglycaemia and that these changes are partially reversible within four weeks. Furthermore, IIH induced myopathy is most likely secondary to the neuropathy. PMID- 28815911 TI - Rural health service managers' perspectives on preparing rural health services for climate change. AB - OBJECTIVE: To determine health service managers' (HSMs) recommendations on strengthening the health service response to climate change. DESIGN: Self administered survey in paper or electronic format. SETTING: Rural south-west of New South Wales. PARTICIPANTS: Health service managers working in rural remote metropolitan areas 3-7. MAIN OUTCOME MEASURES: Proportion of respondents identifying preferred strategies for preparation of rural health services for climate change. RESULTS: There were 43 participants (53% response rate). Most respondents agreed that there is scepticism regarding climate change among health professionals (70%, n = 30) and community members (72%, n = 31). Over 90% thought that climate change would impact the health of rural populations in the future with regard to heat-related illnesses, mental health, skin cancer and water security. Health professionals and government were identified as having key leadership roles on climate change and health in rural communities. Over 90% of the respondents believed that staff and community in local health districts (LHDs) should be educated about the health impacts of climate change. Public health education facilitated by State or Federal Government was the preferred method of educating community members, and education facilitated by the LHD was the preferred method for educating health professionals. CONCLUSIONS: Health service managers hold important health leadership roles within rural communities and their health services. The study highlights the scepticism towards climate change among health professionals and community members in rural Australia. It identifies the important role of rural health services in education and advocacy on the health impacts of climate change and identifies recommended methods of public health education for community members and health professionals. PMID- 28815910 TI - Streptococcus pneumoniae surface protein PfbA is a versatile multidomain and multiligand-binding adhesin employing different binding mechanisms. AB - Streptococcus pneumoniae, one of the major human respiratory pathogens, uses its repertoire of surface proteins to adhere to the epithelium of the nasopharynx and lungs leading to colonization. PfbA is a conserved surface protein of S. pneumoniae and helps the bacterium to colonize the host by recognizing the extracellular matrix (ECM) molecule fibronectin, as well as blood proteins like plasminogen and human serum albumin. The crystal structure of rPfbA150-607 revealed it to possess a beta-helical region similar to those of carbohydrate active enzymes as well as a C-terminal segment that resembles the fibronectin binding regions of fibronectin-binding proteins. To get more insight into the putative carbohydrate-binding property of PfbA and its binding to various host molecules, we generated three different constructs of PfbA and characterized them by ELISA, isothermal titration calorimetry and bio-layer interferometry experiments. Importantly, the isothermal titration calorimetry experiments revealed that PfbA binds to different saccharides. Further, ELISA and bio-layer interferometry experiments identified that (a) apart from fibronectin and plasminogen, the beta helix of PfbA also binds to other ECM molecules (b) lysines are not responsible for PfbA's binding to plasminogen, (c) in comparison with native fibrinogen, deglycosylated-fibrinogen exhibits reduced binding affinity towards PfbA implying the importance of sugar molecule-PfbA interaction and (d) the C-terminal region of PfbA binds exclusively to the N-terminal F1 modules of fibronectin. Thus, the results of this study show PfbA to be a versatile multidomain and multiligand-binding protein employing different binding mechanisms. These results could be useful for structure-based designing of inhibitors against PfbA. PMID- 28815912 TI - Assembly and RNA-free annotation of highly heterozygous genomes: The case of the thick-billed murre (Uria lomvia). AB - Thanks to a dramatic reduction in sequencing costs followed by a rapid development of bioinformatics tools, genome assembly and annotation have become accessible to many researchers in recent years. Among tetrapods, birds have genomes that display many features that facilitate their assembly and annotation, such as small genome size, low number of repeats and highly conserved genomic structure. However, we found that high genomic heterozygosity could have a great impact on the quality of the genome assembly of the thick-billed murre (Uria lomvia), an arctic colonial seabird. In this study, we tested the performance of three genome assemblers, ray/sscape, soapdenovo2 and platanus, in assembling the highly heterozygous genome of the thick-billed murre. Our results show that platanus, an assembler specifically designed for heterozygous genomes, outperforms the other two approaches and produces a highly contiguous (N50 = 15.8 Mb) and complete genome assembly (93% presence of genes from the Benchmarking Universal Single Copy Ortholog [BUSCO] gene set). Additionally, we annotated the thick-billed murre genome using a homology-based approach that takes advantage of the genomic resources available for birds and other taxa. Our study will be useful for those researchers who are approaching assembly and annotation of highly heterozygous genomes, or genomes of species of conservation concern, and/or who have limited financial resources. PMID- 28815913 TI - Metastatic triple negative breast cancer: Optimizing treatment options, new and emerging targeted therapies. AB - Triple negative breast cancer (TNBC) is a heterogeneous disease, not only on the molecular level, but also on the pathologic and clinical levels. It also has a distinct epidemiology. TNBCs are frequently of high histologic grade, typically more aggressive and difficult to treat than hormone receptor-positive tumors, and they are associated with a higher risk of early relapse with visceral metastasis after surgery, chemotherapy and/or radiotherapy. The lack of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 expression precludes the use of targeted therapies in advanced stages, and the only approved systemic treatment option is chemotherapy with or without bevacizumab. In patients with advanced TNBC, responses to chemotherapy occur, but are often of short duration and it is associated with poor prognosis. The median overall survival for patients with metastatic TNBC is about 9-12 months with conventional cytotoxic agents. Given the suboptimal outcomes with chemotherapy, new targeted therapies for TNBC are urgently needed. This review summarizes the clinical efficacy, perspectives and future challenges of using new treatment options for metastatic TNBC, such as poly-ADP-ribose-polymerase inhibitors, antiandrogen therapies and immune checkpoint inhibitors (antiprogrammed death receptor-1/PD-L1 monoclonal antibodies). PMID- 28815914 TI - Authors' reply re: Inositol treatment of anovulation in women with polycystic ovary syndrome: a meta-analysis of randomised trials. PMID- 28815915 TI - Synthesis and Characterization of Iridium(V) Coordination Complexes With an N,O Donor Organic Ligand. AB - We have prepared and fully characterized two isomers of [IrIV (dpyp)2 ] (dpyp=meso-2,4-di(2-pyridinyl)-2,4-pentanediolate). These complexes can cleanly oxidize to [IrV (dpyp)2 ]+ , which to our knowledge represent the first mononuclear coordination complexes of IrV in an N,O-donor environment. One isomer has been fully characterized in the IrV state, including by X-ray crystallography, XPS, and DFT calculations, all of which confirm metal-centered oxidation. The unprecedented stability of these IrV complexes is ascribed to the exceptional donor strength of the ligands, their resistance to oxidative degradation, and the presence of four highly donor alkoxide groups in a plane, which breaks the degeneracy of the d-orbitals and favors oxidation. PMID- 28815916 TI - Compartmentalizing Supramolecular Hydrogels Using Aqueous Multi-phase Systems. AB - A generic method is used for compartmentalization of supramolecular hydrogels by using water-in-water emulsions based on aqueous multi-phase systems (AMPS). By forming the low-molecular-weight hydrogel throughout all phases of all-aqueous emulsions, distinct, micro-compartmentalized materials were created. This structuring approach offers control over the composition of each type of the compartments by directing the partitioning of objects to be encapsulated. Moreover, this method allows for barrier-less, dynamic exchange of even large hydrophilic solutes (MW~60 kDa) between separate aqueous compartments. These features are expected to find use in the fields of, for instance, micro structured catalysts, templating, and tissue engineering. PMID- 28815918 TI - A model-based approach to characterize individual inbreeding at both global and local genomic scales. AB - Inbreeding results from the mating of related individuals and may be associated with reduced fitness because it brings together deleterious variants in one individual. In general, inbreeding is estimated with respect to an arbitrary base population consisting of ancestors that are assumed unrelated. We herein propose a model-based approach to estimate and characterize individual inbreeding at both global and local genomic scales by assuming the individual genome is a mosaic of homozygous-by-descent (HBD) and non-HBD segments. The HBD segments may originate from ancestors tracing back to different periods in the past defining distinct age-related classes. The lengths of the HBD segments are exponentially distributed with class-specific parameters reflecting that inbreeding of older origin generates on average shorter stretches of observed homozygous markers. The model is implemented in a hidden Markov model framework that uses marker allele frequencies, genetic distances, genotyping error rates and the sequences of observed genotypes. Note that genotyping errors, low-fold sequencing or genotype by-sequencing data are easily accommodated under this framework. Based on simulations under the inference model, we show that the genomewide inbreeding coefficients and the parameters of the model are accurately estimated. In addition, when several inbreeding classes are simulated, the model captures them if their ages are sufficiently different. Complementary analyses, either on data sets simulated under more realistic models or on human, dog and sheep real data, illustrate the range of applications of the approach and how it can reveal recent demographic histories among populations (e.g., very recent bottlenecks or founder effects). The method also allows to clearly identify individuals resulting from extreme consanguineous matings. PMID- 28815917 TI - HIV-infected patients' beliefs about their chronic co-treatments in comparison with their combined antiretroviral therapy. AB - OBJECTIVES: Thanks to the success of combination antiretroviral therapy (cART), HIV-infected patients can have almost a normal life expectancy. This has resulted in an aging HIV-infected population with other chronic comorbidities such as cardiovascular diseases, osteoporosis, and depression. Our hypothesis is that patients' perceptions of and attitudes towards their cART, which is perceived as crucial to their survival, differ from their beliefs about their co-treatments, and this may have an impact on their medication adherence. METHODS: We used the French version of the Beliefs about Medicine Questionnaire (BMQ-f) to measure the perceptions of patients about their co-treatments and the Beliefs about Medicine Questionnaire for Highly Active Antiretroviral Therapy (BMQ-HAART) to measure their beliefs about their cART in a representative sample (n = 150) of patients enrolled in the Swiss HIV Cohort Study (SHCS) and followed at the Infectious Disease Service at the University Hospital in Lausanne, Switzerland. The survey was administered to all eligible patients by the order of their scheduled appointments at the end of their medical visit. The BMQ comprises two subscores: Specific-Necessity (5 identical items in BMQ-f and BMQ-HAART) and Specific Concerns (also 5 identical items in BMQ-f and BMQ-HAART). The subscores were standardized by dividing the score scale by the number of questions in the scale, resulting in a range of responses between 1 (low) and 5 (high). Self-reported medication adherence was measured using the SHCS Adherence Questionnaire (SHCS AQ). Adherence was defined as not missing any dose or missing one dose of the treatment in the past 4 weeks. Sociodemographic variables were retrieved by reviewing the SHCS database. RESULTS: A response rate of 73% (109 of 150) was achieved. A total of 105 patients were included in the analysis: their median age was 56 [interquartile range (IQR) 51, 63] years and 74 were male (70%). Eighty seven patients (83%) were adherent to cART and 75 (71%) were adherent to their co treatments (P = 0.0001). The standardized mean responses for the BMQ Specific Necessity subscores were 4.46 [standard deviation (SD): 0.58] and 2.86 (SD: 1.02) for cART and co-treatments, respectively (P < 0.0001). For Specific-Concerns, the standardized mean responses were 2.9 (SD: 1.02) for cART and 4.09 (SD: 1.02) (P < 0.0001) for co-treatments. cART and co-treatment concerns increased as the number of co-treatments increased (P = 0.03 and P < 0.0001, respectively). CONCLUSIONS: Patients had higher Necessity and lower Concerns scores for their cART in comparison with their co-treatments. A higher percentage of patients reported being adherent to cART compared with the co-treatments that they reported they were most likely to miss. Further research using a bigger sample size and more objective measures of adherence is needed to explore the association between adherence and patients' perceptions. PMID- 28815920 TI - Corrigenda: The regulation of uterine proinflammatory gene expression during pregnancy in the live-bearing lizard, Pseudemoia entrecasteauxii. PMID- 28815919 TI - Graphene Oxide as a Carbocatalyst for a Diels-Alder Reaction in an Aqueous Medium. AB - The Diels-Alder (DA) reaction, a [4+2] cycloaddition reaction, is highly important in synthetic organic chemistry and is frequently used in the synthesis of natural products containing six-membered rings. Herein, we report an efficient protocol for the DA reaction between 9-hydroxymethylanthracene and N-substituted maleimides using two-dimensional graphene oxide (GO) as a heterogeneous carbocatalyst in an aqueous medium at room temperature. High yields, a wide substrate scope, low temperature, excellent functional group tolerance, atom economy, and water as a green solvent are noteworthy features of this protocol. The heterogeneous GO catalyst can be easily recovered and used multiple times without any significant loss in catalytic activity. PMID- 28815921 TI - Structure Modification toward Applicability Domain of a QSAR/QSPR Model Considering Activity/Property. AB - In drug and material design, the activity and property values of the designed chemical structures can be predicted by quantitative structure-activity and structure-property relationship (QSAR/QSPR) models. When a QSAR/QSPR model is applied to chemical structures, its applicability domain (AD) must be considered. The predicted activity/property values are only reliable for chemical structures inside the AD. Chemical structures outside the AD are usually neglected, as the predicted values are unreliable. The purpose of this study is to develop a methodology for obtaining novel chemical structures with the desired activity or property based on a QSAR/QSPR model by making use of the neglected structures. We propose a structure modification strategy for the AD that considers the activity and property simultaneously. The AD is defined by a one-class support vector machine and the structure modification is guided by a partial derivative of the AD model and matched molecular pairs analysis. Three proof-of-concept case studies generate novel chemical structures inside the AD that exhibit preferable activity/property values according to the QSAR/QSPR model. PMID- 28815922 TI - The pregnancy in neurofibromatosis 1: A retrospective register-based total population study. AB - The objective of this retrospective total population study was to form a view of the pregnancies of the patients with neurofibromatosis type 1 (NF1). A cohort of 1,410 Finnish patients with NF1 was acquired by searching NF1-related inpatient and outpatient hospital visits and confirming the diagnoses by reviewing the medical records. Ten matched control persons per patient with NF1 were collected from Population Register Centre. Study persons were linked to data from Medical Birth Register and Care Register for Health Care through the personal identity code. Cesarean deliveries, hypertension/preeclampsia, and placental abruptions were more common among mothers with NF1 with adjusted odds ratios of 2.24 (95%CI 1.63-3.07), 1.96 (95%CI 1.18-3.24), and 13.40 (95%CI 4.26-42.13), respectively. The adjusted mean pregnancy duration was 0.65 (95%CI 0.42-0.88) weeks shorter among the mothers with NF1 than in the control group consisting of non-NF1 mothers giving birth to a non-NF1 child. The pregnancies of non-NF1 mothers giving birth to a NF1 child were 0.43 (95%CI 0.24-0.62) weeks shorter than in the control group. In summary, NF1 of the mother was associated with a shortened pregnancy and increased pregnancy complications. Also, the NF1 of the fetus slightly shortened pregnancy. Since mothers with NF1 are at increased risk for pregnancy complications, careful evaluation of their pregnancies is warranted. PMID- 28815923 TI - Biophysical Screening of a Focused Library for the Discovery of CYP121 Inhibitors as Novel Antimycobacterials. AB - The development of novel antimycobacterial agents against Mycobacterium tuberculosis (Mtb) is urgently required due to the appearance of multidrug resistance (MDR) combined with complicated long-term treatment. CYP121 was shown to be a promising novel target for inhibition of mycobacterial growth. In this study, we describe the rational discovery of new CYP121 inhibitors by a systematic screening based on biophysical and microbiological methods. The best hits originating from only one structural class gave initial information about molecular motifs required for binding and activity. The initial screening procedure was followed by mode-of-action studies and further biological characterizations. The results demonstrate superior antimycobacterial efficacy and a decreased toxicity profile of our frontrunner compound relative to the reference compound econazole. Due to its low molecular weight, promising biological profile, and physicochemical properties, this compound is an excellent starting point for further rational optimization. PMID- 28815924 TI - Urinary microRNAs for prostate cancer diagnosis, prognosis, and treatment response: are we there yet? AB - Prostate cancer (PCa) remains one of the leading causes of cancer-related deaths in men. Despite the tremendous progress in research over the years, a suitable minimally invasive PCa biomarker is yet to be discovered. The recent advances regarding the roles of microRNAs as biomarkers has allowed for their study in PCa as well, especially as blood-based markers. However, there are several studies that used urine as biological sample to evaluate microRNAs as biomarkers for PCa diagnosis, prognosis, and treatment response, which were reviewed herein. A high degree of inconsistency among reports has been observed, which could be due to several analytical aspects, starting with different urinary fractions used for analysis and continuing with the employment of various analytical platforms and methods of statistical analysis. However, a few microRNAs were found to be dysregulated in the urine of PCa patients, which alone or together with serum prostate-specific antigen seem to improve diagnostic power even in the gray zone of PCa. These results warrant further confirmation by larger prospective studies, preferably using a standardized protocol for analysis. WIREs RNA 2017, 8:e1438. doi: 10.1002/wrna.1438 For further resources related to this article, please visit the WIREs website. PMID- 28815925 TI - The effects of hydropeaking on riverine plants: a review. AB - Hydropeaking refers to frequent, rapid and short-term fluctuations in water flow and water levels downstream and upstream of hydropower stations. Such fluctuations are becoming increasingly common worldwide and are known to have far reaching effects on riverine vegetation. Novel hydrology caused by hydropeaking has no natural correspondence in freshwater systems, and hence few species have adaptations to all its aspects. Here, we review the literature on hydropeaking effects on riverine plants and define the state of the information on this human alteration of riverine ecosystems. We focus on riparian plants, but also draw on information from aquatic plant species, which exhibit a wide variety of adaptations to inundation and associated processes. Riparian plants face both physiological and physical constraints because of the shifts between submergence and drainage, and erosion of substrates. At the population level, hydropeaking may favour dispersal within, but not between, reservoirs, but may hamper germination, establishment, growth and reproduction. At the community level, strong filtering towards easily dispersed, flexible, flood-tolerant and amphibious plants is expected, although few species share these traits. Hence, most riparian plant species are expected to disappear or be pushed towards the upper boundaries of the regulated river margin. Future research should examine more closely global variation in hydropeaking effects, including other taxonomic groups of species and the diversity of hydropeaking regimes. There is also a need for studies focusing on identifying the boundaries within which hydropeaking could operate without impairing plant life. PMID- 28815926 TI - Catalytic Conversion of Dinitrogen into Ammonia under Ambient Reaction Conditions by Using Proton Source from Water. AB - Molybdenum-catalyzed conversion of molecular dinitrogen into ammonia under ambient reaction conditions has been achieved by using a proton source generated in situ from the ruthenium-catalyzed oxidation of water in combination with visible light and a photosensitizer. The preset reaction system is considered as a new model for the nitrogen fixation by photosynthetic bacteria. PMID- 28815927 TI - Metallofullerenol Inhibits Cellular Iron Uptake by Inducing Transferrin Tetramerization. AB - Herein, A549 tumor cell proliferation was confirmed to be positively dependent on the concentration of Fe3+ or transferrin (Tf). Gd@C82 (OH)22 or C60 (OH)22 effectively inhibited the iron uptake and the subsequent proliferation of A549 cells. The conformational changes of Tf mixed with FeCl3 , GdCl3 , C60 (OH)22 or Gd@C82 (OH)22 were obtained by SAXS. The results demonstrate that Tf homodimers can be decomposed into monomers in the presence of FeCl3 , GdCl3 or C60 (OH)22 , but associated into tetramers in the presence of Gd@C82 (OH)22 . The larger change of SAXS shapes between Tf+C60 (OH)22 and Tf+FeCl3 implies that C60 (OH)22 is bound to Tf, blocking the iron-binding site. The larger deviation of the SAXS shape from a possible crystal structure of Tf tetramer implies that Gd@C82 (OH)22 is bound to the Tf tetramer, thus disturbing iron transport. This study well explains the inhibition mechanism of Gd@C82 (OH)22 and C60 (OH)22 on the iron uptake and the proliferation of A549 tumor cells and highlights the specific interactions of a nanomedicine with the target biomolecules in cancer therapy. PMID- 28815928 TI - A splice-site variant in ANKRD11 associated with classical KBG syndrome. PMID- 28815929 TI - Aggregation of population-based genetic variation over protein domain homologues and its potential use in genetic diagnostics. AB - Whole exomes of patients with a genetic disorder are nowadays routinely sequenced but interpretation of the identified genetic variants remains a major challenge. The increased availability of population-based human genetic variation has given rise to measures of genetic tolerance that have been used, for example, to predict disease-causing genes in neurodevelopmental disorders. Here, we investigated whether combining variant information from homologous protein domains can improve variant interpretation. For this purpose, we developed a framework that maps population variation and known pathogenic mutations onto 2,750 "meta-domains." These meta-domains consist of 30,853 homologous Pfam protein domain instances that cover 36% of all human protein coding sequences. We find that genetic tolerance is consistent across protein domain homologues, and that patterns of genetic tolerance faithfully mimic patterns of evolutionary conservation. Furthermore, for a significant fraction (68%) of the meta-domains high-frequency population variation re-occurs at the same positions across domain homologues more often than expected. In addition, we observe that the presence of pathogenic missense variants at an aligned homologous domain position is often paired with the absence of population variation and vice versa. The use of these meta-domains can improve the interpretation of genetic variation. PMID- 28815930 TI - Schmallenberg virus in Culicoides Latreille (Diptera: Ceratopogonidae) populations in France during 2011-2012 outbreak. AB - Following the emergence of the Schmallenberg virus (SBV) in 2011 in Germany and its rapid spread in Europe, Culicoides (Diptera: Ceratopogonidae) collected through the French surveillance network were analysed in order to record the presence of virus genome into species diversity collected, to assess the minimum infectious rates (MIR) and the virus circulation dynamics in Culicoides populations. Two vector activity periods were selected (2011, August to October, 53 sites and 2012, June to October, 35 sites) corresponding to 704 night collections. A total of 29,285 individual midges covering at least 50 species were tested either in pools of maximum 50 females or individually (for Culicoides obsoletus/Culicoides scoticus) using real-time RT-PCR. Nine species were found SBV positive (C. obsoletus, C. scoticus, Culicoides chiopterus, Culicoides dewulfi, Culicoides imicola, Culicoides pulicaris, Culicoides newsteadi, Culicoides lupicaris and Culicoides nubeculosus) with overall MIR ranging from 0.2% to 4.2%. While the Culicoides nubeculosus laboratory strain is generally considered to have only low vector competence for viruses, interestingly, field caught C. nubeculosus specimens were found positive twice for SBV. The first SBV positive pool was recorded in August 2011 in north-eastern France, dating the virus circulation in France 5 months earlier than the first recorded congenital malformations and 2 months earlier than the former recorded date based on retrospective serological data. The MIR were maximum in October 2011, and in July 2012 according to dates of virus arrival in the studied areas. Moreover, our study also showed that virus circulation could be locally intense with infection rate (IR) reaching up to 16% for C. obsoletus/C. scoticus in July 2012 in one site of western France. This retrospective study demonstrates the importance of large-scale analysis to describe the spatio-temporal dynamics of virus circulation. PMID- 28815932 TI - Polymer Based Hybrid Nanocomposites; A Progress Toward Enhancing Interfacial Interaction and Tailoring Advanced Applications. AB - Organic/inorganic hybrid nanocomposites, in particular polymer based hybrid nanocomposites, constitute emerging advanced materials since they combine unique properties from the inorganic and organic (i. e. polymeric) components. We investigated three different hybrid nanocomposites depending on dimensions of the dispersed phase in the nanometer range,; polymer-layered silicate (PLS) nanocomposites where polymers are mixed with layered silicates, polymer/graphene oxide hybrid nanocomposites, and polymer hybrid nanocomposites with reinforcing polymers with isodimensional phases of inorganic silicas using sol-gel reactions. This Accounts reports the chronological progress of our landmark results on the polymer based hybrid nanocomposites of the three characteristic types that have been prepared in my laboratory for more than two decades, with their impacts, importance and advanced application of the related research fields for readers. PMID- 28815931 TI - Organization of the Flavivirus RNA replicase complex. AB - Flaviviruses, such as dengue, Japanese encephalitis, West Nile, yellow fever, and Zika viruses, are serious human pathogens that cause significant morbidity and mortality globally each year. Flaviviruses are single-stranded, positive-sense RNA viruses, and encode two multidomain proteins, NS3 and NS5, that possess all enzymatic activities required for genome replication and capping. NS3 and NS5 interact within virus-induced replication compartments to form the RNA genome replicase complex. Although the individual enzymatic activities of both proteins have been extensively studied and are well characterized, there are still gaps in our understanding of how they interact to efficiently coordinate their respective activities during positive-strand RNA synthesis and capping. Here, we discuss what is known about the structures and functions of the NS3 and NS5 proteins and propose a preliminary NS3:NS5:RNA interaction model based on a large body of literature about how the viral enzymes function, physical restraints between NS3 and NS5, as well as critical steps in the replication process. WIREs RNA 2017, 8:e1437. doi: 10.1002/wrna.1437 For further resources related to this article, please visit the WIREs website. PMID- 28815933 TI - An alphaIIb beta3 antagonist prevents thrombosis without causing Fc receptor gamma-chain IIa-mediated thrombocytopenia. AB - : Essentials FcgammaRIIa-mediated thrombocytopenia is associated with drug dependent antibodies (DDAbs). We investigated the correlation between alphaIIb beta3 binding epitopes and induction of DDAbs. An FcgammaRIIa-transgenic mouse model was used to evaluate thrombocytopenia among anti-thrombotics. An antithrombotic with binding motif toward alphaIIb beta-propeller domain has less bleeding tendency. SUMMARY: Background Thrombocytopenia, a common side effect of Arg-Gly-Asp-mimetic antiplatelet drugs, is associated with drug-dependent antibodies (DDAbs) that recognize conformation-altered integrin alphaIIb beta3 . Objective To explore the correlation between alphaIIb beta3 binding epitopes and induction of DDAb binding to conformation-altered alphaIIb beta3 , we examined whether two purified disintegrins, TMV-2 and TMV-7, with distinct binding motifs have different effects on induction of alphaIIb beta3 conformational change and platelet aggregation in the presence of AP2, an IgG1 inhibitory mAb raised against alphaIIb beta3 . Methods We investigated the possible mechanisms of intrinsic platelet activation of TMV-2 and TMV-7 in the presence of AP2 by examining the signal cascade, tail bleeding time and immune thrombocytopenia in Fc receptor gamma-chain IIa (FcgammaRIIa) transgenic mice. Results TMV-7 has a binding motif that recognizes the alphaIIb beta-propeller domain of alphaIIb beta3 , unlike that of TMV-2. TMV-7 neither primed the platelets to bind ligand, nor caused a conformational change of alphaIIb beta3 as identified with the ligand-induced binding site mAb AP5. In contrast to eptifibatide and TMV-2, cotreatment of TMV-7 with AP2 did not induce FcgammaRIIa-mediated platelet aggregation and the downstream activation cascade. Both TMV-2 and TMV-7 efficaciously prevented occlusive thrombosis in vivo. Notably, both eptifibatide and TMV-2 caused severe thrombocytopenia mediated by FcgammaRIIa, prolonged tail bleeding time in vivo, and repressed human whole blood coagulation indexes, whereas TMV-7 did not impair hemostatic capacity. Conclusions TMV-7 shows antiplatelet and antithrombotic activities resulting from a mechanism different from that of all other tested alphaIIb beta3 antagonists, and may offer advantages as a therapeutic agent with a better safety profile. PMID- 28815934 TI - Re: Inositol treatment of anovulation in women with polycystic ovary syndrome: a meta-analysis of randomised trials. PMID- 28815935 TI - Fatty allograft and cardiovascular outcomes after liver transplantation. PMID- 28815936 TI - Combinatorial effect of nicotine and black tea on heart rate variability: Useful or harmful? AB - The effect of nicotine on heart rate variability (HRV) is controversial. Autonomic nervous system is the main regulator of heart rhythm, and heart rate variability is an appropriate index to assessment of the effects of the autonomic system on heart. In this study, the combination effect of nicotine and black tea consumption on sympatho-vagal balance and heart rate variability was investigated in rats. Male Wistar rats were randomized into four groups as control, tea (2.5 g/100 cc, daily), nicotine (2 mg/kg/d) and tea plus nicotine groups which treated for 28 days, and in the 29th day, their electrocardiograms (lead II) were recorded. The mean of high-frequency power (HF) in tea, nicotine and tea plus nicotine groups was significantly more than control group (P < .05), and low frequency power/high-frequency power (LF/HF) ratio in the nicotine and tea + nicotine groups was significantly less than control group (P < .05). LF values did not differ significantly among groups. Mean of standard deviation of normal RR intervals (SDNN) and square root of the mean squared differences of successive RR intervals (RMSSD) increased significantly in tea, nicotine and tea + nicotine groups in comparison with control group (P < .05) Overall, 4-week administration of black tea, nicotine or their combination with dosages used in this study can increase the heart rate variability and improve the sympatho-vagal balance in rat. PMID- 28815937 TI - The airway microbiota in early cystic fibrosis lung disease. AB - Infection plays a critical role in the pathogenesis of cystic fibrosis (CF) lung disease. Over the past two decades, the application of molecular and extended culture-based techniques to microbial analysis has changed our understanding of the lungs in both health and disease. CF lung disease is a polymicrobial disorder, with obligate and facultative anaerobes recovered alongside traditional pathogens in varying proportions, with some differences observed to correlate with disease stage. While healthy lungs are not sterile, differences between the lower airway microbiota of individuals with CF and disease-controls are already apparent in childhood. Understanding the evolution of the CF airway microbiota, and its relationship with clinical treatments and outcome at each disease stage, will improve our understanding of the pathogenesis of CF lung disease and potentially inform clinical management. This review summarizes current knowledge of the early development of the respiratory microbiota in healthy children and then discusses what is known about the airway microbiota in individuals with CF, including how it evolves over time and where future research priorities lie. PMID- 28815938 TI - Optimization of recombinant beta-glucuronidase hydrolysis and quantification of eight urinary cannabinoids and metabolites by liquid chromatography tandem mass spectrometry. AB - Prolonged urinary cannabinoid excretion in chronic frequent cannabis users confounds identification of recent cannabis intake that may be important in treatment, workplace, clinical, and forensic testing programs. In addition, differentiation of synthetic Delta9-tetrahydrocannabinol (THC) intake from cannabis plant products might be an important interpretive issue. THC, 11-hydroxy THC (11-OH-THC) and 11-nor-9-carboxy-THC (THCCOOH) urine concentrations were evaluated during previous controlled cannabis administration studies following tandem alkaline/E. coli beta-glucuronidase hydrolysis. We optimized recombinant beta-glucuronidase enzymatic urinary hydrolysis before simultaneous liquid chromatography tandem mass spectrometry (LC-MS/MS) quantification of THC, 11-OH THC, THCCOOH, cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), tetrahydrocannabivarin (THCV) and 11-nor-9-carboxy-THCV (THCVCOOH) in urine. Enzyme amount, incubation time and temperature, buffer molarity and pH were optimized using pooled urine samples collected during a National Institute on Drug Abuse, Institutional Review Board-approved clinical study. Optimized cannabinoid hydrolysis with recombinant beta-glucuronidase was achieved with 2000 IU enzyme, 2 M pH 6.8 sodium phosphate buffer, and 0.2 mL urine at 37 degrees C for 16 h. The LC-MS/MS quantification method for hydrolyzed urinary cannabinoids was validated per the Scientific Working Group on Toxicology guidelines. Linear ranges were 1-250 MUg/L for THC and CBG, 2-250 MUg/L for 11-OH-THC, CBD, CBN, THCV and THCVCOOH, and 1-500 MUg/L for THCCOOH. Inter-batch analytical bias was 92.4-112.4%, imprecision 4.4-9.3% CV (n = 25), extraction efficiency 44.3-97.1% and matrix effect -29.6 to 1.8% (n = 10). The method was utilized to analyze urine specimens collected during our controlled smoked, vaporized, and edible cannabis administration study to improve interpretation of urine cannabinoid test results. PMID- 28815939 TI - Paternal transmission of a FMR1 full mutation allele. AB - Fragile X syndrome (FXS) is the most common form of inherited intellectual disability (ID) and autism. In most of cases, the molecular basis of this syndrome is a CGG repeat expansion in the 5' untranslated region of the FMR1 gene. It is inherited as an X linked dominant trait, with a reduced penetrance (80% for males and 30% for females). Full mutation (FM) expansion from premutated alleles (PM) is only acquired via maternal meiosis, while paternal transmission always remains in the PM range. We present a 16-year-old girl with a mild fragile X syndrome phenotype. FMR1 gene study showed that the patient inherited a mosaic premutation-full mutation with an unmethylated uninterrupted allele (175, >200 CGG) from her father. The father showed an 88 CGG uninterrupted unmethylated allele in blood and sperm cells. To our knowledge, this is the first case of a FMR1 mosaic premutation-full mutation allele inherited from a PM father. In our opinion, the most likely explanation could be a postzygotic somatic expansion. We can conclude that in rare cases of a child with a full mutation whose mother does not carry a premutation, the possibility of paternal transmission should be considered. PMID- 28815940 TI - Production and perception of emotional prosody by adults with autism spectrum disorder. AB - : This study examined production and perception of affective prosody by adults with autism spectrum disorder (ASD). Previous research has reported increased pitch variability in talkers with ASD compared to typically developing (TD) controls in grammatical speaking tasks (e.g., comparing interrogative vs. declarative sentences), but it is unclear whether this pattern extends to emotional speech. In this study, speech recordings in five emotion contexts (angry, happy, interested, sad, and neutral) were obtained from 15 adult males with ASD and 15 controls (Experiment 1), and were later presented to 52 listeners (22 with ASD) who were asked to identify the emotion expressed and rate the level of naturalness of the emotion in each recording (Experiment 2). Compared to the TD group, talkers with ASD produced phrases with greater intensity, longer durations, and increased pitch range for all emotions except neutral, suggesting that their greater pitch variability was specific to emotional contexts. When asked to identify emotion from speech, both groups of listeners were more accurate at identifying the emotion context from speech produced by ASD speakers compared to TD speakers, but rated ASD emotional speech as sounding less natural. Collectively, these results reveal differences in emotional speech production in talkers with ASD that provide an acoustic basis for reported perceptions of oddness in the speech presentation of adults with ASD. Autism Res 2017, 10: 1991 2001. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This study examined emotional speech communication produced and perceived by adults with autism spectrum disorder (ASD) and typically-developing (TD) controls. Compared to the TD group, talkers with ASD produced emotional phrases that were louder, longer, and more variable in pitch. Both ASD and TD listeners were more accurate at identifying emotion in speech produced by ASD speakers compared to TD speakers, but rated ASD emotional speech as sounding less natural. PMID- 28815941 TI - T3SS effector ExoY reduces inflammasome-related responses by suppressing bacterial motility and delaying activation of NF-kappaB and caspase-1. AB - Type III-secreted effectors are essential for modulating host immune responses during the pathogenesis of Pseudomonas aeruginosa infections. Little is known about the impact of one of the effectors, ExoY, on inflammasome activation, which results in IL-1beta production and pyroptotic cell death. In this study, we found that transcriptional expression of Il-1beta was induced to a lesser extent in response to an exoY-harboring strain than to a deleted mutant. This suppressive effect of ExoY was verified by complementation assay as well as by direct translocation of exoY into host cells. In addition to the production of IL-1beta, pyroptotic cell death was also diminished in response to an exoY-harboring strain. These inflammasome responses were mediated by the adenylate cyclase activity of ExoY, which plays a role in delaying the activation of NF-kappaB and caspase-1, a key component of inflammasome-mediated responses. Moreover, the negative effects of ExoY on these responses were in part conferred by the suppression of bacterial motility, which could reduce the degree of bacterial contact with cells. Together, these results demonstrate that the adenylate cyclase activity of P. aeruginosa ExoY can reduce inflammasome-related responses by influencing both the host and the bacterium itself by delaying the activation of inflammatory pathways and suppressing bacterial motility. PMID- 28815942 TI - Plasma Membrane Protein Profiling in Beta-Amyloid-Treated Microglia Cell Line. AB - In the responsiveness of microglia to toxic stimuli, plasma membrane proteins play a key role. In this study we treated with a synthetic beta amyloid peptide murine microglial cells metabolically differently labelled with stable isotope amino acids (SILAC). The plasma membrane was selectively enriched by a multi stage aqueous two-phase partition system. We were able to identify by 1D-LC-MS/MS analyses 1577 proteins, most of them are plasma membrane proteins according to the Gene Ontology annotation. An unchanged level of amyloid receptors in this data set suggests that microglia preserve their responsiveness capability to the environment even after 24-h challenge with amyloid peptides. On the other hand, 14 proteins were observed to change their plasma membrane abundance to a statistically significant extent. Among these, we proposed as reliable biomarkers of the inflammatory microglia phenotype in AD damaged tissues MAP/microtubule affinity-regulating kinase 3 (MARK3), Interferon-induced transmembrane protein 3 (IFITM3), Annexins A5 and A7 (ANXA5, ANXA7) and Neuropilin-1 (NRP1), all proteins known to be involved in the inflammation processes and in microtubule network assembly rate. PMID- 28815943 TI - Impact Response Comparison Between Parametric Human Models and Postmortem Human Subjects with a Wide Range of Obesity Levels. AB - OBJECTIVE: Field data analyses have shown that obesity significantly increases the occupant injury risks in motor vehicle crashes, but the injury assessment tools for people with obesity are largely lacking. The objectives of this study were to use a mesh morphing method to rapidly generate parametric finite element models with a wide range of obesity levels and to evaluate their biofidelity against impact tests using postmortem human subjects (PMHS). METHODS: Frontal crash tests using three PMHS seated in a vehicle rear seat compartment with body mass index (BMI) from 24 to 40 kg/m2 were selected. To develop the human models matching the PMHS geometry, statistical models of external body shape, rib cage, pelvis, and femur were applied to predict the target geometry using age, sex, stature, and BMI. A mesh morphing method based on radial basis functions was used to rapidly morph a baseline human model into the target geometry. The model predicted body excursions and injury measures were compared to the PMHS tests. RESULTS: Comparisons of occupant kinematics and injury measures between the tests and simulations showed reasonable correlations across the wide range of BMI levels. CONCLUSIONS: The parametric human models have the capability to account for the obesity effects on the occupant impact responses and injury risks. PMID- 28815945 TI - Development of a quantitative method for the analysis of cocaine analogue impregnated into textiles by Raman spectroscopy. AB - Cocaine trafficking in the form of textile impregnation is routinely encountered as a concealment method. Raman spectroscopy has been a popular and successful testing method used for in situ screening of cocaine in textiles and other matrices. Quantitative analysis of cocaine in these matrices using Raman spectroscopy has not been reported to date. This study aimed to develop a simple Raman method for quantifying cocaine using atropine as the model analogue in various types of textiles. Textiles were impregnated with solutions of atropine in methanol. The impregnated atropine was extracted using less hazardous acidified water with the addition of potassium thiocyanate (KSCN) as an internal standard for Raman analysis. Despite the presence of background matrix signals arising from the textiles, the cocaine analogue could easily be identified by its characteristic Raman bands. The successful use of KSCN normalised the analyte signal response due to different textile matrix background interferences and thus removed the need for a matrix-matched calibration. The method was linear over a concentration range of 6.25-37.5 mg/cm2 with a coefficient of determination (R2 ) at 0.975 and acceptable precision and accuracy. A simple and accurate Raman spectroscopy method for the analysis and quantification of a cocaine analogue impregnated in textiles has been developed and validated for the first time. This proof-of-concept study has demonstrated that atropine can act as an ideal model compound to study the problem of cocaine impregnation in textile. The method has the potential to be further developed and implemented in real world forensic cases. PMID- 28815944 TI - Neonatal fractures as a presenting feature of LMOD3-associated congenital myopathy. AB - Nemaline myopathy is a rare inherited disorder characterized by weakness, hypotonia, and depressed deep tendon reflexes. It is clinically and genetically heterogeneous, with the most severe phenotype presenting as perinatal akinesia, severe muscle weakness, feeding difficulties and respiratory failure, leading to early mortality. Pathogenic variants in 12 genes, encoding components of the sarcomere or factors related to myogenesis, have been reported in patients affected with the disorder. Here, we describe an early, lethal presentation of decreased fetal movements, hypotonia, muscle weakness, and neonatal respiratory failure requiring ventilator support in three siblings from a consanguineous family. All exhibited perinatal fractures, and thus, a skeletal dysplasia was considered as possibly contributing to the phenotype. However, whole exome sequencing revealed a homozygous, loss-of-function pathogenic variant in LMOD3, which has recently been associated with nemaline myopathy and, in a subset of patients, perinatal fractures. This case demonstrates the importance of considering congenital neuromuscular disorders in the differential diagnosis of perinatal fractures. PMID- 28815946 TI - Model Catalytic Studies of Novel Liquid Organic Hydrogen Carriers: Indole, Indoline and Octahydroindole on Pt(111). AB - Indole derivatives were recently proposed as potential liquid organic hydrogen carriers (LOHC) for storage of renewable energies. In this work, we have investigated the adsorption, dehydrogenation and degradation mechanisms in the indole/indoline/octahydroindole system on Pt(111). We have combined infrared reflection absorption spectroscopy (IRAS), X-ray photoelectron spectroscopy (XPS) and DFT calculations. Indole multilayers show a crystallization transition at 200 K, in which the molecules adopt a strongly tilted orientation, before the multilayer desorbs at 220 K. For indoline, a less pronounced restructuring transition occurs at 150 K and multilayer desorption is observed at 200 K. Octahydroindole multilayers desorb already at 185 K, without any indication for restructuring. Adsorbed monolayers of all three compounds are stable up to room temperature and undergo deprotonation at the NH bond above 300 K. For indoline, the reaction is followed by partial dehydrogenation at the 5-membered ring, leading to the formation of a flat-lying di-sigma-indolide in the temperature range from 330-390 K. Noteworthy, the same surface intermediate is formed from indole. In contrast, the reaction of octahydroindole with Pt(111) leads to the formation of a different intermediate, which originates from partial dehydrogenation of the 6-membered ring. Above 390 K, all three compounds again form the same strongly dehydrogenated and partially decomposed surface species. PMID- 28815948 TI - Flow cytometric analysis of viable bacteria in urine samples of febrile patients at the emergency department. AB - BACKGROUND: Fast and reliable diagnostics are important in febrile patients admitted to the emergency department. Current urine diagnostics are fast but moderately reliable or reliable but time consuming. Flow cytometry (FC) is a new promising technique in the diagnostics of complicated urinary tract infections by counting bacteria in urine samples. The aim of this study is to improve the FC method by counting only viable bacteria. METHODS: Urine was obtained from 135 consecutive febrile patients at the emergency department. According to protocol regular diagnostic urine tests were performed. In addition, FC counting of viable and non-viable bacteria was executed after staining with thiazole orange and propidium iodide. All test results were compared to the results of urine culture (>= 105 colony forming units/mL). RESULTS: At a cut-off value of 2.01 * 105 viable bacteria/mL the sensitivity was 100% and specificity was 78.4% (AUC-value 0.955 on ROC-curve). Spearman correlation test exhibited a higher correlation for flow cytometric counting of only viable bacteria than counting of all bacteria (0.59 vs. 0.37). Using ROC-curves, the AUC-values for FC counting of all bacteria, only viable bacteria and Gram staining were respectively 0.935, 0.955, and 0.968 (P > 0.05). CONCLUSION: FC counting of only viable bacteria can predict quickly and reliably positive and negative urine cultures in febrile patients admitted to the emergency department. It can help to improve the speed and accuracy of the diagnostic procedure at the emergency department. (c) 2017 Clinical Cytometry Society. PMID- 28815947 TI - Olive Oil Phenolics Prevent Oxysterol-Induced Proinflammatory Cytokine Secretion and Reactive Oxygen Species Production in Human Peripheral Blood Mononuclear Cells, Through Modulation of p38 and JNK Pathways. AB - SCOPE: The aim of the present study was to investigate the ability of extra virgin olive oil (EVOO) polyphenols to counteract the proinflammatory effects induced by dietary and endogenous oxysterols in ex vivo immune cells. METHODS AND RESULTS: Peripheral blood mononuclear cells (PBMCs), separated from the whole blood of healthy donors, were utilized and were stimulated with an oxysterols mixture, in the presence of physiologically relevant concentrations of the EVOO polyphenols, hydroxytyrosol, tyrosol, and homovanillic alcohol. Oxysterols significantly increased the production of proinflammatory cytokines, interleukin 1beta, regulated on activation, normal T-cell expressed and secreted and macrophage migration inhibitory factor in ex vivo cultured PBMCs. Increased levels of reactive oxygen species (ROS) were also detected along with increased phosphorylation of the p38 and JNK. All phenolic compounds significantly reduced cytokine secretion induced by the oxysterols and inhibited ROS production and mitogen activated protein kinase phosphorylation. CONCLUSIONS: These results suggest that extra virgin olive oil polyphenols modulate the immune response induced by dietary and endogenous cholesterol oxidation products in human immune cells and may hold benefit in controlling chronic immune and/or inflammatory processes. PMID- 28815949 TI - Microbes and RNA - Not Something to Sneeze At. PMID- 28815950 TI - Ribosome profiling: a Hi-Def monitor for protein synthesis at the genome-wide scale. PMID- 28815952 TI - Partial Sleep Deprivation Reduces the Efficacy of Orexin-A to Stimulate Physical Activity and Energy Expenditure. AB - OBJECTIVE: Sufficient sleep is required for weight maintenance. Sleep deprivation due to noise exposure stimulates weight gain by increasing hyperphagia and reducing energy expenditure (EE). Yet the mechanistic basis underlying the weight gain response is unclear. Orexin-A promotes arousal and negative energy balance, and orexin terminals project to the ventrolateral preoptic area (VLPO), which is involved in sleep-to-wake transitions. To determine whether sleep deprivation reduces orexin function in VLPO and to test the hypothesis that sleep deprivation would attenuate the orexin-A-stimulated increase in arousal, physical activity (PA), and EE. METHODS: Electroencephalogram, electromyogram, distance traveled, and EE were determined in male Sprague-Dawley rats following orexin-A injections into VLPO both before and after acute (12-h) and chronic (8 h/d, 9 d) sleep deprivation by noise exposure. RESULTS: Orexin-A in the VLPO significantly increased arousal, PA, total EE, and PA-related EE and reduced sleep and respiratory quotient before sleep deprivation. In contrast to after acute sleep deprivation in which orexin-A failed to stimulate EE during PA only, orexin-A failed to significantly increase arousal, PA, fat oxidation, total EE, and PA related EE after chronic sleep deprivation. CONCLUSIONS: Sleep deprivation may reduce sensitivity to endogenous stimuli that enhance EE due to PA and thus stimulate weight gain. PMID- 28815953 TI - Epilepsy in fragile-X-syndrome mimicking panayiotopoulos syndrome: Description of three patients. AB - Fragile-X-syndrome is the most common cause of inherited intellectual disability. Epilepsy is reported to occur in 10-20% of individuals with Fragile-X-syndrome. A frequent seizure/electroencephalogram (EEG) pattern resembles that of benign rolandic epilepsy. We describe the clinical features, EEG findings and evolution in three patients affected by Fragile-X-syndrome and epilepsy mimicking Panayiotopoulos syndrome. Age at seizure onset was between 4 and about 7 years. Seizures pattern comprised a constellation of autonomic symptoms with unilateral deviation of the eyes and ictal syncope. Duration of the seizures could be brief or lengthy. Interictal EEGs revealed functional multifocal abnormalities. The evolution was benign in all patients with seizures remission before the age of 14. This observation expands the spectrum of benign epileptic phenotypes present in Fragile-X-syndrome and may be quite helpful in guiding anticonvulsant management and counseling families as to expectations regarding seizure remission. PMID- 28815951 TI - Physics-based all-atom modeling of RNA energetics and structure. AB - The database of RNA sequences is exploding, but knowledge of energetics, structures, and dynamics lags behind. All-atom computational methods, such as molecular dynamics, hold promise for closing this gap. New algorithms and faster computers have accelerated progress in improving the reliability and accuracy of predictions. Currently, the methods can facilitate refinement of experimentally determined nuclear magnetic resonance and x-ray structures, but are 'unreliable' for predictions based only on sequence. Much remains to be discovered, however, about the many molecular interactions driving RNA folding and the best way to approximate them quantitatively. The large number of parameters required means that a wide variety of experimental results will be required to benchmark force fields and different approaches. As computational methods become more reliable and accessible, they will be used by an increasing number of biologists, much as x-ray crystallography has expanded. Thus, many fundamental physical principles underlying the computational methods are described. This review presents a summary of the current state of molecular dynamics as applied to RNA. It is designed to be helpful to students, postdoctoral fellows, and faculty who are considering or starting computational studies of RNA. WIREs RNA 2017, 8:e1422. doi: 10.1002/wrna.1422. PMID- 28815954 TI - Diaphanospondylodysostosis and ischiospinal dysostosis, evidence for one disorder with variable expression in a patient who has survived to age 9 years. AB - Diaphanospondylodysostosis (DSD) and ischiospinal dysostosis (ISD) are both rare skeletal dysplasias consisting of abnormal axial skeletal development but normal appendicular skeletal development. Both disorders recently have been found to result from mutations in the BMPER gene. We report a patient with one deletion and one mutation of the BMPER gene who has features most consistent with DSD but who has survived to age 9 years. Survival suggests that DSD and ISD reflect a spectrum of severity of one disease process. PMID- 28815956 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 35/2017. PMID- 28815957 TI - Tailoring Hierarchical Zeolites with Designed Cationic Surfactants and Their High Catalytic Performance. AB - Three hierarchical porous zeolites (H-*BEA, H-MTW, and H-*MRE) were successfully synthesized with the assistance of designed cationic surfactants under hydrothermal synthesis conditions. The as-synthesized zeolite samples can be easily regulated by changing the number of long hydrophobic n-alkyl chains. Also, we investigated the relationship between the length of the surfactant and the formation of the microporous structure of the zeolite. Furthermore, the alkylation of benzene with propene was performed as a probe reaction to evaluate the catalytic performance of the synthesized hierarchical zeolites. The resulting materials were characterized by using a complementary combination of techniques, that is, X-ray powder diffraction, N2 adsorption-desorption isotherms, scanning electron microscopy, transmission electron microscopy, Fourier transform IR spectroscopy, 28 Si and 27 Al MAS NMR spectroscopies, thermogravimetric analysis, and computer simulation. These analysis results indicated that quaternary ammonium surfactants acted as organic structure-directing agents (OSDAs) in the formation of these hierarchical zeolite samples, whether the surfactant had long hydrophobic tail groups or not. The simulation results indicated that the organic molecules with no long hydrophobic chain could lead to the synthesis of zeolite through charge control, and the hydrophobic molecules with long hydrophobic chains could form zeolites through orbital control. These hierarchical zeolites showed improved catalytic activity towards the industrially relevant alkylation of benzene with propene compared with conventional zeolites with the same frameworks. More importantly, the success of using quaternary ammonium surfactants with no hydrophobic n-alkyl tail group in the synthesis of hierarchically structured mesoporous zeolites provides a new pathway for the synthesis of hierarchical porous materials by a soft-templating method. PMID- 28815955 TI - The role of IQSEC2 in syndromic intellectual disability: Narrowing the diagnostic odyssey. AB - While X-linked intellectual disability (XLID) syndromes pose a diagnostic challenge for clinicians, an increasing number of recognized disorders and their genetic etiologies are providing answers for patients and their families. The availability of clinical exome sequencing is broadening the ability to identify mutations in genes previously unrecognized as causing XLID. In recent years, the IQSEC2 gene, located at Xp11.22, has emerged as the cause of multiple cases of both nonsyndromic and syndromic XLID. Herein we present a case series of six individuals (five males, one female) with intellectual disability and seizures found to have alterations in IQSEC2. In all cases, the diagnostic odyssey was extensive and expensive, often including invasive testing such as muscle biopsies, before ultimately reaching the diagnosis. We report these cases to demonstrate the exhaustive work-up prior to finding the changes in IQSEC2 gene, recommend that this gene be considered earlier in the diagnostic evaluation of individuals with global developmental delay, microcephaly, and severe, intractable epilepsy, and support the use of intellectual disability panels including IQSEC2 in the first-line evaluation of these patients. PMID- 28815958 TI - Arabidopsis EXO70A1 recruits Patellin3 to the cell membrane independent of its role as an exocyst subunit. AB - The exocyst is a well-known complex which tethers vesicles at the cell membrane before fusion. Whether an individual subunit can execute a unique function is largely unknown. Using yeast-two-hybrid (Y2H) analysis, we found that EXO70A1 interacted with the GOLD domain of Patellin3 (PATL3). The direct EXO70A1-PATL3 interaction was supported by in vitro and in vivo experiments. In Arabidopsis, PATL3-GFP colocalized with EXO70A1 predominantly at the cell membrane, and PATL3 localization was insensitive to BFA and TryA23. Remarkably, in the exo70a1 mutant, PATL3 proteins accumulated as punctate structures within the cytosol, which did not colocalize with several endomembrane compartment markers, and was insensitive to BFA. Furthermore, PATL3 localization was not changed in the exo70e2, PRsec6 or exo84b mutants. These data suggested that EXO70A1, but not other exocyst subunits, was responsible for PATL3 localization, which is independent of its role in secretory/recycling vesicle-tethering/fusion. Both EXO70A1 and PATL3 were shown to bind PI4P and PI(4,5)P2 in vitro. Evidence was obtained that the other four members of the PATL family bound to EXO70A1 as well, and shared a similar localization pattern as PATL3. These findings offered new insights into exocyst subunit-specific function, and provided data and tools for further characterization of PATL family proteins. PMID- 28815959 TI - Twentieth anniversary of Homo antecessor (1997-2017): a review. AB - It has been twenty years since diagnosis and publication of the species Homo antecessor.1 Since then, new human fossils recovered from the TD6 level of the Gran Dolina site (Sierra de Atapuerca, northern Spain) have helped to refine its taxonomic and phylogenetic position. In this paper, we present a synthesis of the most characteristic features of this species, as well as our interpretation derived from the latest investigations. We focus on the phylogenetic interpretation of Homo antecessor, taking into account the most recent paleogenetic analyses and a reassessment of the European Middle Pleistocene hominin record. We try to show that, twenty years after its publication, H. antecessor provides a good opportunity to address the morphology of the last common ancestor of Neandertals and modern humans. PMID- 28815960 TI - Life is a simulation of life - or is it?: What we observe is just one run of a probabilistic process. PMID- 28815961 TI - From monkeys to modeling: The 2017 meetings of the Paleoanthropology Society. PMID- 28815962 TI - A database of archeological evidence of representational behavior. PMID- 28815963 TI - How to cultivate a tree: Celebrating the career of Linda Marie Fedigan. PMID- 28815964 TI - Sex-biased dispersal of human ancestors. AB - Some anthropologists and primatologists have argued that, judging by extant chimpanzees and humans, which are female-biased dispersers, the common ancestors of humans and chimpanzees were also female-biased dispersers. It has been thought that sex-biased dispersal patterns have been genetically transmitted for millions of years. However, this character has changed many times with changes in environment and life-form during human evolution and historical times. I examined life-form and social organization of nonhuman primates, among them gatherers (foragers), hunter-gatherers, agriculturalists, industrialists, and modern and extant humans. I conclude that dispersal patterns changed in response to environmental conditions during primate and human evolution. PMID- 28815965 TI - Current approaches and new directions in lithic analysis: Defining, identifying and interpreting variability. PMID- 28815966 TI - Trifluoromethyl Oxetanes: Synthesis and Evaluation as a tert-Butyl Isostere. AB - The synthesis of a new trifluoromethyl oxetane was developed using a Corey Chaykovsky epoxidation/ring-expansion reaction of trifluoromethyl ketones. The reaction was shown to proceed under mild conditions and displays a broad substrate scope. The trifluoromethyl oxetane was also evaluated as a tert-butyl isostere in the context of the gamma-secretase modulator (GSM) program. We demonstrate that the trifluoromethyl oxetane-containing GSM has decreased lipophilicity, improved lipophilic efficiency (LipE) and metabolic stability relative to the corresponding tert-butyl GSM analogue, thus highlighting several benefits of trifluoromethyl oxetane as a more polar tert-butyl isostere. PMID- 28815967 TI - Comparative metabolomics revealing Staphylococcus aureus metabolic response to different antibiotics. AB - It is known that changes in bacterial metabolism can contribute to the modulation of bacterial susceptibility to antibiotics. Understanding how bacterial metabolism is impacted by antibiotics may improve our understanding of the antibiotic mechanism of actions from a metabolic perspective. Here, we utilized a mass spectrometry-based targeted metabolic profiling technique to characterize the metabolome of a pair of isogenic methicillin-susceptible and resistant Staphylococcus aureus (MSSA and MRSA) strains RN450 and 450M treated with the sublethal dose of three antibiotics from different classes (beta-lactams, aminoglycosides and quinolones). These treatments induced a set of metabolic alterations after 6 h of co-incubation with antibiotics. Similar and divergent metabolic perturbations were observed from different antibiotics to the tested strains. Different metabolic response from MSSA and MRSA to the same antibiotics was also detected in the study and indicated the potentially different stress response mechanism in MSSA and MRSA metabolism. This work has shown that a complex set of metabolic changes can be induced by a variety of antibiotics, and the comparative metabolomics strategy can provide a good understanding of this process from a metabolic perspective. PMID- 28815968 TI - Discovery of naphthyl-N-acylhydrazone p38alpha MAPK inhibitors with in vivo anti inflammatory and anti-TNF-alpha activity. AB - Protein kinases constitute attractive therapeutic targets for development of new prototypes to treat different chronic diseases. Several available drugs, like tinibs, are tyrosine kinase inhibitors; meanwhile, inhibitors of serine/threonine kinases, such as mitogen-activated protein kinase (MAPK), are still trying to overcome some problems in one of the steps of clinical development to become drugs. So, here we reported the synthesis, the in vitro kinase inhibitory profile, docking studies, and the evaluation of anti-inflammatory profile of new naphthyl-N-acylhydrazone derivatives using animal models. Although all tested compounds (3a-d) have been characterized as p38alpha MAPK inhibitors and have showed in vivo anti-inflammatory action, LASSBio-1824 (3b) presented the best performance as p38alpha MAPK inhibitor, with IC50 = 4.45 MUm, and also demonstrated to be the most promising anti-inflammatory prototype, with good in vivo anti-TNF-alpha profile after oral administration. PMID- 28815969 TI - -318C/T polymorphism of the CTLA-4 gene is an independent risk factor for RBC alloimmunization among sickle cell disease patients. AB - Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) molecule is expressed on T lymphocyte membrane and negatively influences the antigen-presenting process. Reduced expression of CTLA-4 due to gene polymorphisms is associated with increased risk of autoimmune disorders, whose physiopathology is similar to that of post-transfusion red blood cell (RBC) alloimmunization. Our goal was to evaluate if polymorphisms of CTLA-4 gene that affect protein expression are associated with RBC alloimmunization. This was a case-control study in which 134 sickle cell disease (SCD) patients and 253 non-SCD patients were included. All patients were genotyped for the polymorphisms 49A/G and -318C/T of CTLA-4 gene. The genotype frequency of -318C/T differed significantly between alloimmunized and nonalloimmunized SCD patients, irrespective of clinical confounders (p = .016). SCD patients heterozygous for -318T allele presented higher risk of alloantibody development (OR: 5.4, CI: 1.15-25.6). In conclusion, the polymorphism -318C/T of CTLA-4 gene is associated with RBC alloimmunization among SCD patients. This highlights the role played by CTLA-4 on post-transfusion alloantibody development. PMID- 28815970 TI - Structural insight into the recognition of acetylated histone H3K56ac mediated by the bromodomain of CREB-binding protein. AB - : The acetylation of lysine 56 of histone H3 (H3K56ac) enhances the binding affinity of histone chaperones to H3-H4 dimers. CREB-binding protein (CBP) possesses a bromodomain that recognizes H3K56 acetylation. CBP also possesses a histone acetyltransferase (HAT) domain, which has been shown to promote H3K56 acetylation of free histones to facilitate delivery of replication-dependent chaperones to acetylated histones for chromatin assembly. However, the mechanism by which the CBP bromodomain recognizes H3K56ac and the context in which such recognition occurs remain elusive. Here, we solved the crystal structure of the CBP bromodomain in complex with an H3K56ac peptide. Our data demonstrate that the CBP bromodomain recognizes H3K56ac with high affinity. Structural and affinity analyses reveal that the CBP bromodomain prefers an aromatic residue at the -2 position and an arginine at the -4 position from the acetyl-lysine, and that the CBP bromodomain selectively recognizes an extended conformation of the H3 alphaN helix that contains H3K56ac. We also demonstrate that the CBP bromodomain binds to H3K56ac in a recombinant H3-H4 dimer but not in a mono-nucleosome. Our results suggest that the CBP bromodomain selectively recognizes an extended conformation of the K56-acetylated H3 alphaN region within an H3-H4 dimer, which is expected to facilitate the HAT activity of CBP for subsequent H3K56 acetylation of free histones. DATABASES: Coordinates of the CBP bromodomain in complex with H3K56ac as described in this article have been deposited in the PDB with accession number 5GH9. PMID- 28815971 TI - Topographical and Electrical Stimulation of Neuronal Cells through Microwrinkled Conducting Polymer Biointerfaces. AB - The development of smart biointerfaces combining multiple functions is crucial for triggering a variety of cellular responses. In this work, wrinkled organic interfaces based on the conducting polymer poly(3,4-ethylene dioxythiophene) doped with poly(styrene sulfonate) are developed with the aim to simultaneously convey electrical and topographical stimuli to cultured cells. The surface wrinkling of thin films on heat-shrink polymer sheets allows for rapid patterning of self-assembled anisotropic topographies characterized by micro/sub-microscale aligned wrinkles. The developed interfaces prove to support the growth and differentiation of neural cells (SH-SY5Y, human neuroblastoma) and are remarkably effective in promoting axonal guidance, by guiding and stimulating the neurite growth in differentiating cells. Electrical stimulation with biphasic pulses delivered through the conductive wrinkled interface is found to further promote the neurite growth, demonstrating the suitability of such interfaces as platforms for conveying multiple stimuli to cells and tissues. PMID- 28815972 TI - Assessing the ideal microwave duration for disinfection of sinus irrigation bottles-A quantitative study. AB - OBJECTIVES: Saline irrigation of the nasal cavity and paranasal sinuses has a recognised role in the management of chronic rhinosinusitis. However, bacterial recontamination of irrigation bottles through backflow from the sinonasal cavity is a concern in recurrent sinus cavity infections. While patients are encouraged to clean the irrigation bottles regularly, there remains significant concern that the use of contaminated bottles may perpetuate chronic rhinosinusitis. This study assesses the optimal microwave duration to achieve decontamination for each irrigation bottle component part (reservoir, tube and nozzle) using a standard, commercially available microwave. In addition, the irrigation fluid was also tested for contamination after each microwave cycle. STUDY DESIGN: Laboratory based experimental study. PARTICIPANTS: No patients were involved in this study. MAIN OUTCOME MEASURES: The percentage in vitro decontamination of the bottles' components was determined following 30, 60, 90, 120, 150 seconds of microwave cycles. RESULTS: Complete decontamination of the bottles was not achieved at any of the tested microwave cycles. Levels of decontamination differed for the different bottle components, and the greatest degree of decontamination for all bottle components occurred at 90 seconds. Although higher levels of decontamination were observed at microwave durations exceeding 90 seconds, this was at the expense of thermal degradation and deformation of the reservoir plastic component of the irrigation bottle. Similarly, lowest contamination of irrigation fluid was observed at 120 seconds. CONCLUSIONS: This study highlights the importance of establishing precise decontamination procedures and recommends a microwave cycle of 90 seconds for optimal decontamination. PMID- 28815973 TI - Kinetic Parameters for the Selective Hydrogenation of Acetylene on GaPd2 and GaPd. AB - Intermetallic GaPd2 is a highly selective and stable catalyst for the semi hydrogenation of acetylene. Knowledge of the underlying reaction kinetics is essential to gain a deeper understanding of the selective hydrogenation on this catalytic material. To date, there has been no experimental kinetic data published for this reaction on a well-defined intermetallic catalyst possessing isolated active sites. Kinetic measurements are performed at 140-200 degrees C, revealing an apparent activation energy of 29(2) kJ mol-1 . GaPd2 is shown to be the first binary catalyst material, which shows a positive reaction order (0.89) with respect to acetylene at 200 degrees C. The influences on the extent of acetylene conversion, specific activity and selectivity to ethylene, ethane, and higher hydrocarbons are determined by a 24 factorial experiment following a design of experiments approach. Temperature and pressure have the strongest impact on these values. The results allow optimal operation for achieving high ethylene yields. A comparison of the reaction kinetics on GaPd2 with experimental results obtained for GaPd reveals different orders of reaction of H2 and C2 H2 on the two compounds. PMID- 28815974 TI - Health promotion in Fiji: Is it feasible in the emergency department? AB - OBJECTIVES: Complications of diabetes, hypertension and asthma are commonly seen in EDs in Fiji. Time spent in the ED offers an opportunity for health promotion activities. The aim of the intervention was to provide information on diabetes, hypertension and asthma to patients in the ED. The aim of the project was to determine whether such an intervention could be implemented using public health students. The aim of this paper is to document the experiences of those who delivered and supervised the intervention. METHODS: This pilot project took place in the Colonial War Memorial Hospital, Suva, in August-October 2015. Patient suitability was assessed by the supervising emergency physician. Patients were invited to receive a 10-min information session relating to asthma, hypertension or diabetes. Once the project had concluded, the students and supervisor were given a questionnaire, requiring them to reflect on their experiences of the project. Data was analysed using an inductive approach with thematic content analysis. RESULTS: Students required intensive coaching to gain the skills and confidence to deliver the intervention. The intervention was well received by patients, whose knowledge of hypertension, diabetes and asthma was poor. CONCLUSION: Health literacy among patients in Fiji is low and measures to address this must be taken. Intensive training and supervision is required for public health students to be able to deliver such activities in the ED setting. PMID- 28815975 TI - Urea-based recirculation validation of the symmetrical palindrome catheter. AB - BACKGROUND: High blood flow and low recirculation rates are central for adequate haemodialysis. A new symmetrical tip has been invented promising efficient haemodialysis even if the ports are reversed. OBJECTIVE: To evaluate access recirculation of the 'palindrome' catheter and to report initial experiences in a clinical setting. MATERIAL AND METHODS: After implantation of the new catheter in 20 patients (male: 14; female: 6; mean age 72 +/- 12.2), access recirculation was evaluated using the urea-based recirculation test. After 30 minutes of haemodialysis, ultrafiltration was stopped and arterial and venous samples were taken. Afterwards, the blood flow rate was reduced to 120 ml/min. Another systemic arterial blood sample was taken 10 seconds after the blood pump was switched off. RESULTS: All 20 interventions were performed successfully without complications. The average recirculation rate was 8.1% with a median of 2.5% ranging from 0 to 85.8%. Recirculation rates under 5% were measured in 13 patients and more than 10% recirculation were found in two patients. The median of days between catheter implantation and recirculation assessment was the day following implantation. CONCLUSION: The new symmetrical catheter presented low recirculation rates in a clinical setting. Since there is just a single tip, fluoroscopic placement in the right atrium is facilitated. PMID- 28815976 TI - Salvage lymph node dissection: if yes, robotics? PMID- 28815977 TI - The utility of microRNAs as biomarkers in predicting progression and survival in patients with clear-cell renal cell carcinoma. PMID- 28815978 TI - An important counseling tool for urologists managing patients with neurogenic detrusor overactivity. PMID- 28815979 TI - Is choline-based PET imaging still relevant in recurrent prostate cancer? PMID- 28815980 TI - Sexuality in men with exstrophy. PMID- 28815981 TI - Positive messages for bladder cancer management in negative sentinel lymph node study. PMID- 28815982 TI - Bridge the gap: The need for harmonized regulatory and ethical standards for postmarketing observational studies. AB - Drug safety issues do not respect national borders. Hence, addressing a safety question may necessitate globally coordinated efforts between regulatory authorities and market authorization holders (MAHs) to draw reliable conclusions. Regulatory authorities have shared responsibility with MAHs sponsoring postmarketing nonintervention studies in determining study goals and design. Their shared accountabilities include what will be investigated and how the data will be retrieved to ensure appropriate study quality required for regulatory decision making. The need for a harmonized framework and ethical standards for postmarketing observational studies is well recognized but has been lacking even among the United States, European Union, and Japan, which are so-called International Conference on Harmonisation (ICH) regions. A recent update of the Council for International Organizations of Medical Sciences International Ethical Guidelines for Health-Related Research Involving Humans provides further clarification on provisions for informed consent and the role of research ethics committees. However, without incorporation into legislative structures, the future impact of these guidelines is uncertain. This lack of harmonization leads to a complex and uncertain framework for ethical review and for participant informed consent, resulting in numerous inefficiencies in the regulatory postmarketing observational studies. The regulatory frameworks for postmarketing observational studies conducted under the auspices of regulatory agencies in the 3 regions are reviewed, with a focus on ethical requirements and opportunities for efficiencies. PMID- 28815983 TI - Web alert: Microbial communities in the plant-soil system: An annotated selection of World Wide Web sites relevant to the topics in environmental microbiology. PMID- 28815984 TI - Relationships between central arterial stiffness, lean body mass, and absolute and relative strength in young and older men and women. AB - Relationships between muscular strength and arterial stiffness as well as between muscle mass and arterial stiffness have been observed suggesting a link between the neuromuscular system and vascular health. However, the relationship between central arterial stiffness and absolute and relative strength along with muscle mass has not been investigated in both sexes across a broad age range. The purpose of this study was to examine the relationship between central arterial stiffness and absolute and relative strength as well as between central arterial stiffness and lean body mass (LBM) in men and women across a broad age range. LBM, central arterial stiffness and strength were measured on 36 men and 35 women between the ages of 18 and 75 years. Strength was measured on five machine resistance exercises and summed as one measure of overall strength (absolute strength). Relative strength was calculated as total strength divided by LBM (relative strength). Central arterial stiffness was inversely related to both absolute (r = -0.230; P = 0.029) and relative strength (r = -0.484; P < 0.001) but not LBM (r = 0.097; P = 0.213). The relationship between central arterial stiffness and relative strength was attenuated but still present when controlling for either age, per cent body fat, LBM or mean arterial pressure. These results suggest that, across a wide age range, the expression of relative muscular strength has a stronger relationship with central arterial stiffness compared to either LBM or absolute strength. This suggests that muscle function more than muscle mass may be coupled with vascular health. PMID- 28815985 TI - Sticking with it: Psychotherapy outcomes for adults with autism spectrum disorder in a university counseling center setting. AB - : Young adults with autism spectrum disorders (ASD) experience high rates of comorbid mental health concerns in addition to distress arising from the core symptoms of autism. Many adults with ASD seek psychological treatment in outpatient facilities in their communities that are not specifically geared toward individuals with ASD. However, few studies have looked at the effectiveness of standard psychotherapeutic care in adults with ASD. This study aimed to discover how individuals with ASD fare in psychotherapy within a college counseling setting, compared to their neurotypical peers. Clients with ASD (n = 76) or possible ASD (n = 91) were retrospectively identified from counseling center case notes. Data from the Outcome Questionnaire-45 (OQ) were retrieved for each therapy session as a measure of client distress. Clients with ASD showed no difference in level of distress at intake compared to their neurotypical peers (n = 21,546), and improved about the same amount from pre- to post-treatment. However, students with ASD stayed in treatment for significantly more sessions than neurotypical clients, and took significantly longer to achieve maximum improvement on OQ reports. Results are discussed with implications for university and other community based treatment settings. Autism Res 2017, 10: 2048-2055. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This study aimed to discover how individuals with autism spectrum disorders (ASD) fare in psychotherapy within a university counseling setting, compared to their neurotypical peers. Clients with ASD showed no difference in level of distress at intake compared to their neurotypical peers, and improved about the same amount from pre- to post-treatment. However, students with ASD stayed in treatment for significantly more sessions than neurotypical clients, and took significantly longer to achieve maximum improvement on Outcome Questionnaire-45 reports. PMID- 28815986 TI - Modulatory Functionalization of Gold Nanorods Using Supramolecular Assemblies. AB - Supramolecular-assembly-mediated functionalization of gold nanorods (GNRs) has been developed by reversible phase transfer between water and oils, which offers a facile method for fabricating robust GNRs with surface-charge tunability. In this regard, trimethylammonium (TMA) GNRs were initially prepared from conventional cetyltrimethylammonium bromide (CTAB) GNRs by means of a ligand exchange reaction in the presence of an excess amount of TMA ligands. To further expand their functionality and potential applications, electrostatic assemblies of positively charged TMA-GNRs with negatively charged oleate ions were prepared. These assemblies (OA-GNRs) can undergo facile phase transfer from water to hexane. Interestingly, the reversible electrostatic assembly between the TMA and OA ions fabricated onto GNRs can be easily disrupted by treatment with HCl, which removes the OA ions from the GNRs to re-form the TMA-GNRs, which can be made soluble in aqueous media again. In addition, OA-GNRs can be further used for the synthesis of negatively charged GNRs such as 11-mercaptoundecanoic acid (MUA) GNRs, which are hard to prepare directly from CTAB-GNRs. This versatile method for phase transfer and functionalization on GNRs is expected to broaden the scope of their applications in sensing, biomedical imaging, photothermal therapies, and drug delivery systems. PMID- 28815987 TI - Health-related quality of life in randomized controlled trials of lorcaserin for obesity management: what mediates improvement? AB - Lorcaserin, plus diet and exercise, has demonstrated significant weight loss and improved cardiometabolic parameters vs. placebo in patients with overweight/obesity in three randomized, placebo-controlled trials. We examined whether lorcaserin is also associated with greater improvements in health-related quality of life (HRQOL) and whether these improvements are wholly attributable to weight loss. Pooled data from Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM), Behavioral Modification and Lorcaserin Second Study for Obesity Management (BLOSSOM) and BLOOM-Diabetes Mellitus (BLOOM DM) trials were analysed (n = 5624). HRQOL was assessed at baseline and 52 weeks using the Impact of Weight on Quality of Life-Lite (IWQOL-Lite) questionnaire. Multiple mediation analyses were conducted to evaluate the mechanisms underlying improved HRQOL. Greater HRQOL improvements were observed at 52 weeks in lorcaserin vs. placebo (P < 0.0001). A greater percentage of lorcaserin patients (54.1%) experienced meaningful improvements in IWQOL-Lite total score than placebo patients (48.2%) (P < 0.001). Body mass index (BMI) reduction was the primary driver of improved HRQOL (P < 0.0001), with depressive symptoms and total cholesterol also playing a role (P < 0.05). Improved HRQOL varied by gender, age, race and presence of diabetes and other comorbidities. Lorcaserin treatment significantly improves HRQOL compared with placebo. Although BMI reduction accounts for the majority of these improvements, improvement in depressive symptoms and total cholesterol are contributing factors. PMID- 28815988 TI - The Effects of Ethnic Minority Adolescents' Ethnic Self-Identification on Friendship Selection. AB - This study investigated the effects of ethnic minority adolescents' ethnic self identification (host country, dual, or heritage country) on friendship choices among ethnic majority and minority peers. Hypotheses were derived from similarity attraction and social identity theory and tested using longitudinal social network data from 1,004 middle school students (five schools) in Germany. Results showed that ethnic minority adolescents' ethnic self-identification affected friendship selection beyond ethnic homophily. While host country and dual identification was beneficial with respect to friendships with both ethnic majority and minority peers, heritage country identification was detrimental to relations with both of them. PMID- 28815989 TI - Can we improve risk communication about non-invasive prenatal testing? PMID- 28815991 TI - Functional response and multiple predator effects of two generalist predators preying on Tuta absoluta eggs. AB - BACKROUND: Interactions among invertebrate predators could affect a pest suppression. The hemipteran species Macrolophus pygmaeus (Rambur) and Nesidiocoris tenuis (Reuter) (Hemiptera: Miridae) are natural enemies of several pests in agroecosystems and coexist in tomato crops in Mediterranean countries. By using the multiplicative risk model (MRM) and the substitutive model, the multiple predator effects (MPEs) on prey suppression were calculated when two individuals of the predators foraged at the same densities on South American tomato pinworm, Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae), eggs. RESULTS: Egg consumption increased with increasing egg density and the two predators exhibited a type III functional response. Predation rates were strongly affected by prey density. Using the MRM, we found risk reduction at intraspecific treatments at high prey density. Applying the substitutive model, we detect risk enhancement at interspecific treatments at high egg density. CONCLUSIONS: At low prey densities, most of the interactions were independent, whereas at high densities most interactions were not independent and resulted in prey risk reduction, indicating antagonism between the individuals involved. We also showed that N. tenuis is a more competitive predator species for T. absoluta eggs than M. pygmaeus; however, combination of the two predator species will lead to better pest suppression at high T. absoluta population densities. (c) 2017 Society of Chemical Industry. PMID- 28815990 TI - Trade patterns facilitating highly pathogenic avian influenza virus dissemination in the free-grazing layer duck system in Vietnam. AB - Highly pathogenic avian influenza (HPAI) viruses continue to threaten smallholder poultry producers in several South-east Asian countries, including Vietnam. In particular, the free-grazing duck system has been repeatedly highlighted as a major risk factor for HPAI outbreaks. Free-grazing ducks, which scavenge on rice paddies after the harvest, account for a large proportion of the duck population in Vietnam and the wider South-east Asian region. However, the structure and dynamics of the free-grazing duck production from farm to consumption has not been described for Vietnam. In this study, we used a value chain approach to provide a complete picture of the actors involved in the production and marketing of free-grazing duck eggs and spent layer ducks, as well as to investigate the governance structure of this food system. Group interviews and key informant interviews were conducted in two provinces located in the Mekong River Delta (MRD) and the Red River Delta (RRD). The results presented here highlight similarities and differences in farming and trade practices between the two provinces. The trade of spent layer ducks involved large volumes of live ducks being sent to China and Cambodia for consumption, generating a substantial risk of transboundary spread of pathogens, including HPAI viruses. We describe the major role of "duck yards", which act as hubs in the northbound trade of spent layer ducks. These yards should be considered as essential links in the value chain of spent layer ducks when considering HPAI surveillance and control. The veterinary authorities are only marginally involved in the value chain activities, and their influence could be strengthened by increasing surveillance activities for instance in duck yards. Last, we discuss the dynamics of the duck value chain and further implications for future HPAI management policies. PMID- 28815992 TI - The spatial distribution of soil organic carbon in tidal wetland soils of the continental United States. AB - Tidal wetlands contain large reservoirs of carbon in their soils and can sequester carbon dioxide (CO2 ) at a greater rate per unit area than nearly any other ecosystem. The spatial distribution of this carbon influences climate and wetland policy. To assist with international accords such as the Paris Climate Agreement, national-level assessments such as the United States (U.S.) National Greenhouse Gas Inventory, and regional, state, local, and project-level evaluation of CO2 sequestration credits, we developed a geodatabase (CoBluCarb) and high-resolution maps of soil organic carbon (SOC) distribution by linking National Wetlands Inventory data with the U.S. Soil Survey Geographic Database. For over 600,000 wetlands, the total carbon stock and organic carbon density was calculated at 5-cm vertical resolution from 0 to 300 cm of depth. Across the continental United States, there are 1,153-1,359 Tg of SOC in the upper 0-100 cm of soils across a total of 24 945.9 km2 of tidal wetland area, twice as much carbon as the most recent national estimate. Approximately 75% of this carbon was found in estuarine emergent wetlands with freshwater tidal wetlands holding about 19%. The greatest pool of SOC was found within the Atchafalaya/Vermilion Bay complex in Louisiana, containing about 10% of the U.S. total. The average density across all tidal wetlands was 0.071 g cm-3 across 0-15 cm, 0.055 g cm-3 across 0 100 cm, and 0.040 g cm-3 at the 100 cm depth. There is inherent variability between and within individual wetlands; however, we conclude that it is possible to use standardized values at a range of 0-100 cm of the soil profile, to provide first-order quantification and to evaluate future changes in carbon stocks in response to environmental perturbations. This Tier 2-oriented carbon stock assessment provides a scientific method that can be copied by other nations in support of international requirements. PMID- 28815993 TI - Advances in hypothermic perfusion. PMID- 28815994 TI - IMRT QA using machine learning: A multi-institutional validation. AB - PURPOSE: To validate a machine learning approach to Virtual intensity-modulated radiation therapy (IMRT) quality assurance (QA) for accurately predicting gamma passing rates using different measurement approaches at different institutions. METHODS: A Virtual IMRT QA framework was previously developed using a machine learning algorithm based on 498 IMRT plans, in which QA measurements were performed using diode-array detectors and a 3%local/3 mm with 10% threshold at Institution 1. An independent set of 139 IMRT measurements from a different institution, Institution 2, with QA data based on portal dosimetry using the same gamma index, was used to test the mathematical framework. Only pixels with >=10% of the maximum calibrated units (CU) or dose were included in the comparison. Plans were characterized by 90 different complexity metrics. A weighted poison regression with Lasso regularization was trained to predict passing rates using the complexity metrics as input. RESULTS: The methodology predicted passing rates within 3% accuracy for all composite plans measured using diode-array detectors at Institution 1, and within 3.5% for 120 of 139 plans using portal dosimetry measurements performed on a per-beam basis at Institution 2. The remaining measurements (19) had large areas of low CU, where portal dosimetry has a larger disagreement with the calculated dose and as such, the failure was expected. These beams need further modeling in the treatment planning system to correct the under-response in low-dose regions. Important features selected by Lasso to predict gamma passing rates were as follows: complete irradiated area outline (CIAO), jaw position, fraction of MLC leafs with gaps smaller than 20 or 5 mm, fraction of area receiving less than 50% of the total CU, fraction of the area receiving dose from penumbra, weighted average irregularity factor, and duty cycle. CONCLUSIONS: We have demonstrated that Virtual IMRT QA can predict passing rates using different measurement techniques and across multiple institutions. Prediction of QA passing rates can have profound implications on the current IMRT process. PMID- 28815995 TI - Progressive macrothrombocytopenia and hearing loss in a large family with DIAPH1 related disease. AB - In this study, we describe a Japanese family with progressive hearing loss and macrothrombocytopenia. Using next-generation and Sanger sequencing analyses, we identified a heterozygous variant in exon 27 of the DIAPH1 gene (NM_005219), c.3637C>T, p.R1213X. All patients in the family had sensorineural hearing loss and macrothrombocytopenia. None of the patients exhibited a tendency to bleed. No pathogenic variants were found in the MYH9 gene. Hearing loss began with high frequency loss during early childhood and progressed to severe hearing loss involving all frequencies. Analyses of the mean platelet volume and platelet distribution width indicated that the macrothrombocytopenia is progressive in patients with DIAPH1 related disease.There are no reports describing progressive macrothrombocytopenia in patients with pathogenic variants of DIAPH1. Thus, progressive macrothrombocytopenia may be a novel feature of deafness patients with pathogenic variants in DIAPH1. PMID- 28815996 TI - Age-related changes in childhood wheezing characteristics: A whole population study. AB - BACKGROUND: Wheezing illnesses are characterized by phenotypic variability, which changes with age, but few studies report on a wide age range of children. We studied how prevalence, severity, and triggers of wheeze vary throughout childhood. METHODS: We analyzed data from a large population-based cohort of children from Leicestershire, UK, who were followed from infancy through late adolescence using postal questionnaires. We used generalized estimating equations to describe age-related changes in prevalence of any wheeze: episodic viral and multiple trigger wheeze; wheeze triggered by exercise, aeroallergens, food/drinks, laughing/crying; and of severe wheeze (frequent attacks, shortness of breath, sleep disturbance, disturbance of daily activities) from age 1-18 years. We analyzed this in the entire cohort (absolute prevalence) and separately among children with wheeze (relative prevalence). RESULTS: This study included 7670 children. Current wheeze was most common in 1-year-olds (36%) and then decreased in prevalence to reach 17% in children aged 14-17 years. Absolute prevalence of episodic viral wheeze (EVW) decreased with age (from 24% to 7%), while multiple trigger wheeze (MTW) remained relatively constant throughout childhood (8-12%). Among children with wheeze, the proportion with EVW decreased, and the proportion with MTW increased with age. In older children, wheeze triggered by exercise or aeroallergens, and wheeze accompanied by shortness of breath became more frequent, while wheeze triggered by food or laughter, and sleep disturbance decreased in prevalence. CONCLUSION: Knowledge of these age related changes in wheezing illness is informative for health care planning and the design of future research projects and questionnaires. PMID- 28815997 TI - Bioequivalence and Safety of Twice-Daily Sustained-Release Paracetamol (Acetaminophen) Compared With 3- and 4-Times-Daily Paracetamol: A Repeat-Dose, Crossover Pharmacokinetic Study in Healthy Volunteers. AB - Twice-daily sustained-release (SR) paracetamol (acetaminophen) offers convenient administration to chronic users. This study investigated at steady state (during the last 24 hours of a 3-day dosing period) the pharmacokinetics, bioequivalence, and safety of twice-daily SR paracetamol compared with extended-release (ER) and immediate-release (IR) paracetamol. In this open-label, randomized, multidose, 3 way crossover study, 28 healthy subjects received paracetamol SR (2 * 1000 mg twice daily), ER (2 * 665 mg 3 times daily), and IR (2 * 500 mg 4 times daily). At steady state, twice-daily SR paracetamol was bioequivalent to ER and IR paracetamol. The 90% confidence intervals for the ratios of geometric means were within the acceptance interval for SR/ER paracetamol (AUC0-t , 0.973-1.033; AUC0 24 , 0.974-1.034; AUC0-infinity , 0.948-1.011; Cmax , 1.082-1.212; Cav , 1.011 1.106) and SR/IR paracetamol (AUC0-t , 0.969-1.029; AUC0-24 , 0.968-1.027; AUC0 infinity , 0.963-1.026; Cmax , 0.902-1.010; Cav , 1.004-1.098). Given twice daily, the SR formulation demonstrated SR properties as expected. Mean time at or above a 4 MUg/mL plasma concentration of paracetamol from 2 daily doses of the SR formulation was significantly longer than that from 4 daily doses of IR paracetamol. SR formulation also had a greater Tmax , a longer half-life, and lower Cmin compared with ER and IR paracetamol. All formulations were well tolerated. PMID- 28816000 TI - Investigating facial phenotype in autism spectrum conditions: The importance of a hypothesis driven approach. AB - : Atypical facial characteristics have been observed in many disorders associated with developmental disability. While autism spectrum conditions (ASC) have not previously been thought to be associated with a distinct facial phenotype, an emerging research literature is casting doubt on this assumption. The identification of differences in the facial phenotype of individuals with ASC may contribute to efforts to promote early identification of the condition and help elucidate etiological pathways. With the aim of identifying facial phenotypes associated with ASC, this commentary evaluated facial features purported to distinguish ASC from typical development. Although there is little consensus across the reviewed studies for the majority of facial characteristics described, preliminary evidence suggests increased facial asymmetry may be more common in ASC. There is also evidence to suggest that there are morphologically distinct subgroups within ASC that correspond with different cognitive and behavioral symptomatology. However, in light of the various inconsistencies in the reported literature, and based on an accumulating understanding of etiological pathways proposed to be associated with ASC, we propose an alternative paradigm for investigating facial phenotypes in ASC. A series of studies are outlined to demonstrate the promise of a research program that has taken a hypothesis-driven approach to examine facial phenotypes associated with increased exposure to prenatal testosterone and to ASC. Autism Res 2017, 10: 1910-1918. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This commentary reviewed studies that found differences in the facial features of individuals with autism spectrum conditions (ASC) compared to typically developing individuals. While there is little agreement between studies, there is some support for asymmetrical facial features associated with ASC, and preliminary evidence that particular facial features relate to specific patterns of cognitive and behavioral symptoms. However, in light of inconsistencies between studies and based on accumulating understanding of etiological pathways, we propose an alternative approach to investigating facial differences in ASC. PMID- 28815999 TI - Incident Stenotrophomonas maltophilia infection and lung function decline in cystic fibrosis. AB - OBJECTIVES: To determine whether incident detection of Stenotrophomonas maltophilia (SM) in patients with cystic fibrosis (CF) is associated with accelerated lung function decline and increased hospitalizations and to determine whether this effect is more pronounced in individuals with subsequent chronic infection. METHODS: We performed a longitudinal, retrospective single-center, pre post study of 88 patients with CF, ages 6-51 years, with first positive respiratory culture for SM between 2008 and 2014. Rate of decline in FEV1 and hospitalization rates prior to and following incident SM infection were analyzed using segmented regression analysis of interrupted time series. RESULTS: Mean (SD) age was 17.4 (9.2) years and the mean (SD) FEV1 % predicted at acquisition was 90.0% (25.2). A total of 44% developed chronic SM infection. In regression analysis adjusted for clinical and demographic factors, there was worsening of the mean annual decline in FEV1 % predicted from -1.79 (95%CI: -2.43, -1.15) pre acquisition to -2.14 (95%CI: -2.61, -1.67) post-acquisition (P = 0.005). A significant change was observed in those with either subsequent intermittent or chronic infection. The mean annual hospitalization rate increased significantly in the subgroup with chronic infection from 0.46 (95%CI: 0.33, 0.60) to 0.88 (95%CI: 0.68, 1.07) (P = 0.007). CONCLUSIONS: In this single-center cohort, acquisition of SM in CF was associated with an acceleration in lung function decline. Among those with chronic colonization, acquisition was also associated with increased hospitalization rates. PMID- 28815998 TI - Architects of nature: growing buildings with bacterial biofilms. AB - In his text 'On Architecture', Vitruvius suggested that architecture is an imitation of nature. Here we discuss what happens when we begin using nature in architecture. We describe recent developments in the study of biofilm structure, and propose combining modern architecture and synthetic microbiology to develop sustainable construction approaches. Recently, Kolodkin-Gal laboratory and others revealed a role for precipitation of calcium carbonate in the maturation and assembly of bacterial communities with complex structures. Importantly, they demonstrated that different secreted organic materials shape the calcium carbonate crystals formed by the bacterial cells. This provides a proof-of concept for a potential use of bacteria in designing rigid construction materials and altering crystal morphology and function. In this study, we discuss how these recent discoveries may change the current strategies of architecture and construction. We believe that biofilm communities enhanced by synthetic circuits may be used to construct buildings and to sequester carbon dioxide in the process. PMID- 28816001 TI - Plasma and cerebrospinal fluid tau and neurofilament concentrations in rapidly progressive neurological syndromes: a neuropathology-based cohort. AB - BACKGROUND AND PURPOSE: Cerebrospinal fluid (CSF) tau and neurofilament light chain (NF-L) proteins have proved to be reliable biomarkers for neuronal damage; however, there is a strong need for blood-based tests. METHODS: The present study included 132 autopsy cases with rapidly progressive neurological syndromes, including Alzheimer disease (AD) (21), sporadic (65) and genetic (21) Creutzfeldt Jakob disease (CJD), 25 cases with vascular, neoplastic and inflammatory alterations, and additionally 18 healthy control individuals. CSF tau and NF-L concentrations were measured by enzyme-linked immunosorbent assay. Plasma tau and NF-L concentrations were measured using ultra-sensitive single molecule array technology. RESULTS: Plasma and CSF tau (R = 0.59, P < 0.001) and NF-L (R = 0.69, P < 0.001) levels correlated significantly (Spearman test). Plasma tau and NF-L levels were significantly higher in all disease groups compared to healthy controls (P < 0.001). Receiver operating characteristic curves were used and area under the curve values for comparisons with controls were 0.82 (AD), 0.94 (sporadic CJD), 0.92 (genetic CJD) and 0.83 (other neurological disorders) for plasma tau and 0.99, 0.99, 1.00 and 0.96 for plasma NF-L, respectively. Molecular subtyping of sporadic CJD showed a strong effect (linear logistic regression) on plasma tau (P < 0.001) but not NF-L levels (P = 0.19). CONCLUSION: Plasma tau and NF-L concentrations are strongly increased in CJD and show similar diagnostic performance to the corresponding CSF measure. Molecular subtypes of sporadic CJD show different levels of plasma tau. Although not disease-specific, these findings support the use of plasma tau and NF-L as tools to identify, or to rule out, neurodegeneration. PMID- 28816005 TI - Partnership with patients and their families. PMID- 28816002 TI - Maternal body mass index: Relation with infant respiratory symptoms and infections. AB - BACKGROUND: Maternal obesity is increasingly prevalent in many westernized countries. Many studies report associations between maternal obesity and childhood wheeze or asthma but few have considered maternal obesity in relation to respiratory infections or symptoms other than wheeze during infancy. This study assesses the relationship between maternal BMI and reported wheeze, cough and respiratory infections during the first year of life. METHODS: In 2799 mother child pairs, we examined the relations between maternal pre-pregnancy BMI and pregnancy weight gain and reported offspring wheeze, prolonged cough, lower respiratory tract infection, croup, and ear infection before age 1 year, along with reported diarrhea or vomiting. Maternally reported paternal BMI was included in the models as a proxy for unmeasured confounding by shared familial factors. RESULTS: Higher maternal BMI was associated with increased risks of offspring wheeze, prolonged cough and lower respiratory tract infection (relative risks (95%CI) per 5 kg/m2 1.09 (1.05-1.13), 1.09 (1.03-1.14), and 1.13 (1.07-1.20), respectively). These associations remained after adjusting for maternally reported paternal BMI. No associations were found with croup, ear infection, or diarrhea or vomiting. Pregnancy weight gain was not associated with any of the offspring symptoms or illnesses. DISCUSSION: Higher maternal BMI is associated with increased risk of wheeze, cough, and maternally reported lower respiratory tract infection in infancy. These associations were independent of maternally reported paternal BMI. These observations might be explained by intrauterine effects of maternal obesity upon respiratory or immune development. PMID- 28816003 TI - Prevalence of gastrointestinal symptoms in Angelman syndrome. AB - Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability, expressive speech impairment, movement disorder, epilepsy, and a happy demeanor. Children with AS are frequently reported to be poor feeders during infancy and as having gastrointestinal issues such as constipation, reflux, and abnormal food related behaviors throughout their lifetime. To assess the prevalence of gastrointestinal disorders in individuals with AS, we retrospectively analyzed medical records of 120 individuals seen at the Angelman Syndrome Clinic at Massachusetts General Hospital and 43 individuals seen at the University of North Carolina Comprehensive Angelman Clinic. The majority of patients' medical records indicated at least one symptom of gastrointestinal dysfunction, with constipation and gastroesophageal reflux disease (GERD) the most common. Other gastrointestinal issues reported were cyclic vomiting episodes, difficulty swallowing, excessive swallowing, and eosinophilic esophagitis. Upper gastrointestinal symptoms such as GERD, swallowing difficulties, cyclic vomiting, and eosinophilic esophagitis were more common in those with deletions and uniparental disomy, likely related to the involvement of multiple genes and subsequent hypotonia. The frequency of constipation is consistent among all genetic subtypes while early feeding issues appear to mainly affect those with deletions. Caregivers and healthcare providers should be aware of the high prevalence of these issues, as proper treatment may improve not only gastrointestinal dysfunction but also sleep and behavioral issues. PMID- 28816006 TI - CD38 deficiency suppresses adipogenesis and lipogenesis in adipose tissues through activating Sirt1/PPARgamma signaling pathway. AB - It has been recently reported that CD38 was highly expressed in adipose tissues from obese people and CD38-deficient mice were resistant to high-fat diet (HFD) induced obesity. However, the role of CD38 in the regulation of adipogenesis and lipogenesis is unknown. In this study, to explore the roles of CD38 in adipogenesis and lipogenesis in vivo and in vitro, obesity models were generated with male CD38-/- and WT mice fed with HFD. The adipocyte differentiations were induced with MEFs from WT and CD38-/- mice, 3T3-L1 and C3H10T1/2 cells in vitro. The lipid accumulations and the alternations of CD38 and the genes involved in adipogenesis and lipogenesis were determined with the adipose tissues from the HFD-fed mice or the MEFs, 3T3-L1 and C3H10T1/2 cells during induction of adipocyte differentiation. The results showed that CD38-/- male mice were significantly resistant to HFD-induced obesity. CD38 expressions in adipocytes were significantly increased in WT mice fed with HFD, and the similar results were obtained from WT MEFs, 3T3-L1 and C3H10T1/2 during induction of adipocyte differentiation. The expressions of PPARgamma, AP2 and C/EBPalpha were markedly attenuated in adipocytes from HFD-fed CD38-/- mice and CD38-/- MEFs at late stage of adipocyte differentiation. Moreover, the expressions of SREBP1 and FASN were also significantly decreased in CD38-/- MEFs. Finally, the CD38 deficiency mediated activations of Sirt1 signalling were up-regulated or down-regulated by resveratrol and nicotinamide, respectively. These results suggest that CD38 deficiency impairs adipogenesis and lipogenesis through activating Sirt1/PPARgamma-FASN signalling pathway during the development of obesity. PMID- 28816007 TI - Fluorous Phase-Directed Peptide Assembly Affords Nano-Peptisomes Capable of Ultrasound-Triggered Cellular Delivery. AB - Here, we report the design, synthesis and efficacy of a new class of ultrasound (US)-sensitive self-assembled peptide-based nanoparticle. Peptisomes are prepared via templated assembly of a de novo designed peptide at the interface of fluorinated nanodroplets. Utilizing peptide assembly allows for facile particle synthesis, direct incorporation of bioactive sequences displayed from the particle corona, and the ability to easily encapsulate biologics during particle preparation using a mild solvent exchange procedure. Further, nano-peptisome size can be precisely controlled by simply modulating the starting peptide and fluorinated solvent concentrations during synthesis. Biomolecular cargo encapsulated within the particle core can be directly delivered to the cytoplasm of cells upon US-mediated rupture of the carrier. Thus, nano-peptisomes represent a novel class of US-activated carriers that can shuttle cell-impermeable biomacromolecules into cells with spatial and temporal precision. PMID- 28816008 TI - Lactuca capensis reverses memory deficits in Abeta1-42-induced an animal model of Alzheimer's disease. AB - We investigated the neuropharmacological effects of the methanolic extract from Lactuca capensis Thunb. leaves (100 and 200 mg/kg) for 21 days on memory impairment in an Alzheimer's disease (AD) rat model produced by direct intraventricular delivery of amyloid-beta1-42 (Abeta1-42). Behavioural assays such as Y-maze and radial arm maze test were used for assessing memory performance. Abeta1-42 decreased cognitive performance in the behavioural tests which were ameliorated by pre-treatment with the methanolic extract. Acetylcholinesterase activity and oxidant-antioxidant balance in the rat hippocampus were abnormally altered by Abeta1-42 treatment while these deficits were recovered by pre-treatment with the methanolic extract. In addition, rats were given Abeta1-42 exhibited in the hippocampus decreased brain-derived neurotrophic factor (BDNF) mRNA copy number and increased IL-1beta mRNA copy number which was reversed by the methanolic extract administration. These findings suggest that the methanolic extract could be a potent neuropharmacological agent against dementia via modulating cholinergic activity, increasing of BDNF levels and promoting antioxidant action in the rat hippocampus. PMID- 28816009 TI - Protective Effect of Atazanavir Sulphate Against Pulmonary Fibrosis In Vivo and In Vitro. AB - Atazanavir sulphate, an antiretroviral protease inhibitor, has been used to treat HIV/AIDS, but its ability to serve as an antipulmonary fibrosis (PF) agent remains unknown. In this study, the effects of atazanavir sulphate on various aspects of PF were examined and CoCl2 was used to induce the hypoxia-mimicking condition in vitro, including epithelial-mesenchymal transition (EMT) in A549 cells, endothelial-mesenchymal transition (EndMT) in human pulmonary microvascular endothelial cells (HPMECs), proliferation in human lung fibroblasts (HLF-1) and potential protective effects in human type I alveolar epithelial cells (AT I). Additionally, the effects of atazanavir sulphate were examined using a bleomycin (BLM)-induced pulmonary fibrosis model. After atazanavir sulphate treatment, in A549 cells and HPMECs, the expression of vimentin, HMGB1, Toll-like receptor 4 (TLR-4) and p-NF-kappaB decreased, while the expression of E cadherin and VE-cadherin increased. In AT I cells, the expression of aquaporin 5 and RAGE were increased after atazanavir treatment. Proliferation of HLF-1 was reduced after atazanavir treatment, meanwhile the expression of hypoxia-inducible factor-1alpha (HIF-1alpha), prolyl hydroxylase domain protein 2 (PHD-2), HMGB1, TLR-9, p-NF-kappaB, collagen I and collagen III was decreased. In the BLM-induced pulmonary fibrosis rat model, atazanavir sulphate ameliorated PF by reducing pathological score, collagen deposition and the expression of alpha-SMA, HIF 1alpha, PHD-2, HMGB1, TLR-4, TLR-9 and p-NF-kappaB. In summary, our study supports the proposal that atazanavir sulphate may have a therapeutic potential in reducing the progression of pulmonary fibrosis by suppressing HMGB1/TLR signalling. PMID- 28816010 TI - Robotic ventral mesh rectopexy technique for rectal intussusception with rectocele - a video vignette. PMID- 28816011 TI - Lessons learnt from incidents involving the airway and breathing reported from Australasian emergency departments. AB - OBJECTIVE: To review incident reports relating to problems encountered during the ED management of patients with 'airway or breathing' problems, with the aim of finding and highlighting common themes within these rare events, and making recommendations to further improve patient safety in the areas in which deficiencies have been identified. METHODS: Thematic analysis of 36 incidents reported from Australasian EDs, which were related to problems with airway and breathing. RESULTS: In all, 51 problems were identified among the 36 incidents related to airway and/or breathing. Fourteen involved clinical decision-making, 11 equipment, nine communication, seven intubation, five surgical access and five pneumothorax. Eight incidents involved children and there were nine deaths within hours or days. CONCLUSIONS: Recommendations for improving preparedness of ED staff and facilities have been made for each of the problem areas identified with respect to clinical practice, equipment, communication and clinical process. Analysis of incidents from the Australasian Emergency Medicine Events Register allows clusters of like-events to be identified and characterised, providing the possibility of getting a better idea of how problems present and progress, with some information about contributing factors, characteristics and context. This will pave the way for earlier and better detection of life-threatening problems and the development and reinforcement of preventive and corrective strategies. PMID- 28816012 TI - Periodic Mesoporous Organosilica Films with a Tunable Steady-State Mesophase. AB - The mesophase formation in spin-coated periodic mesoporous organosilica (PMO) films aged at a controlled ambient humidity is investigated by time-resolved grazing-incidence small-angle X-ray scattering (GISAXS). The investigation demonstrates the existence of a tunable steady state in PMO spin-coated films. Thus, a film deposited at a relative humidity of 20 % has a lamellar mesophase, whereas a subsequent increase to 70 % leads to a phase transformation resulting in a P63 /mmc space group. On the other hand, an increase of the surfactant to organosilica molar ratio of between 0.26 and 0.31 results in films which at 70 % humidity form a mix of 2D and 3D hexagonal phases. A further increase of the surfactant amount leads to films with a 2D hexagonal phase. Finally, the different mesophases observed as a function of the solution aging emphasize the importance of the degree of polycondensation of the organosilica oligomers. PMID- 28816013 TI - New neurotensin analogue radiolabeled by 99m-technetium as a potential agent for tumor identification. AB - It has been shown that more than 75% of ductal pancreatic adenocarcinomas overexpressed neurotensin (NT) receptors. Overexpression of NT receptors has been reported in various human tumor types. Hence, a non-invasive diagnosis and staging method could be very beneficial. In this work, we describe radiolabeling and evaluation of new neurotensin analogues to target neurotensin receptor positive tumors such as pancreatic carcinoma. Radiolabeling was performed at 95 degrees C for 10 min using 99m Tc in the presence of tricine/EDDA exchange labeling. Radiochemical yield analysis involved ITLC and HPLC methods. A binding assay test was carried out in nine different concentrations of labeled neurotensin analogues in HT-29 cells. Radiopeptide-specific binding and internalization were studied in NT receptors expressing HT-29 cells. Biodistribution studies were performed in tumor-free BALB/c mice and HT-29 xenografted tumor-bearing nude mice. The peptide was efficiently labeled by 99m Tc with high radiochemical yields (>98%). The radioconjugate was thoroughly stable in the solution and human serum even for 24 hr. The radiolabeled peptide showed high affinity (32.66 +/- 4.01 nm) and specificity internalization (>%18 after 4 hr) to HT-29 cells. The radiopeptide efficiently showed tumor size and location in tumor-bearing nude mice. In biodistribution, a receptor-specific uptake of radiopeptide was observed in neurotensin receptor-positive organs such as intestine. Uptake in the tumor was 4.59 +/- 0.23% ID/g after 2 hr. Owing to excellent stability, high affinity, rapid blood clearance, low accumulation in non-target organs, and high uptake in tumor, the 99m Tc-HYNIC-peptide is a potential agent for targeting of NTR-overexpressing tumor cells in clinical surroundings. When successfully executed in the clinical surrounding, non invasive imaging of NTR-positive tumors with 99m Tc-labeled new neurotensin analogues could facilitate therapy procedure and monitoring. PMID- 28816014 TI - Brucellosis in a Clymene dolphin (Stenella clymene) stranded in Brazil. PMID- 28816015 TI - Liver transplantation in adult cystic fibrosis: Clinical, imaging, and pathological evidence of obliterative portal venopathy. PMID- 28816016 TI - The discovery of new and more potent chloropyramine (C4) analogues for the potential treatment of invasive breast cancer. AB - Breast cancer is the second most common cancer worldwide, accounting for 25% of all female cancers. Although the survival rate has increased significantly in the past few decades, patients who develop secondary site metastasis as well as those diagnosed with triple negative breast cancer still represent a real unmet medical challenge. Previous studies have shown that chloropyramine (C4) inhibits FAK VEGFR3 signalling. More recently, C4 is reported to have SASH1 inducing properties. However, C4 exerts its antitumour and antiangiogenic effects at high micromolar concentrations (>100 MUm) that would not be compatible with further drug development against invasive breast cancer driven by FAK signalling. In this study, molecular modelling guided structural modifications have been introduced to the chloropyramine C4 scaffold to improve its activity in breast cancer cell lines. Seventeen compounds were designed and synthesized, and their antiproliferative activity was evaluated against three human breast cancer lines (MDA-MB-231, BT474 and T47D). Compound 5c was identified to display an average activity of IC50 = 23.5-31.3 MUm, which represents a significant improvement of C4 activity in the same assay model. Molecular modelling and pharmacokinetic studies provided more promising insights into the mechanistic features of this new series. PMID- 28816017 TI - Iron-Cobalt Phosphomolybdate with High Electrocatalytic Activity for Oxygen Evolution Reaction. AB - Iron-cobalt phosphomolybdate (FeCoPM12 ) nanoparticles, which are highly efficient catalytic materials for the oxygen evolution reaction (OER), were fabricated through a coprecipitation route. Compared with iron-cobalt hydroxide and state-of-the-art RuO2 electrocatalysts, the as-prepared FeCoPM12 sample exhibited robust OER catalytic activity with a low overpotential of 258 mV at a current density of 10 mA cm-2 and a small Tafel slope of 33 mV dec-1 . Moreover, the as-synthesized sample presented preferable stability and after 10 h at 1.52 V the current density degraded by merely 8.3 %. This is ascribed to the high electrochemical stability and small porous structure of FeCoPM12 , which provide effective electron transmission and improve the catalytic performance for OER in alkaline media. PMID- 28816018 TI - A comparison of nasal nitric oxide measurement modes. PMID- 28816019 TI - iTRAQ-Based Quantitative Proteomic Analyses of High Grade Esophageal Squamous Intraepithelial Neoplasia. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide and is the fourth most lethal cancer in China. Little is known about the proteome of high grade esophageal squamous intraepithelial neoplasia (HGN), which is a premalignant lesion of ESCC. A quantitative proteomic analysis using an isobaric tag for relative and absolute quantification (iTRAQ) approach is used to characterize the protein expression profiles in HGN. Among the 3156 identified proteins, a total of 236 proteins are discovered to be differentially expressed. Compared with paired normal esophageal epithelial tissues, 138 proteins are upregulated and 98 proteins are downregulated in HGN. Bioinformatics analyses are performed according to gene ontology, clusters of orthologous groups, and kyoto encyclopedia of genes and genomes enrichment analyses. Six differentially expressed proteins are chosen and validated by Western blotting. The results of the study increase our understanding of early tumorigenesis during ESCC, and provide insights into the proteome at the initial stages of the disease that can be used to identify potential biomarkers for early diagnosis and for therapeutic targets. PMID- 28816020 TI - Real-world efficacy and safety of ombitasvir, paritaprevir/r+dasabuvir+ribavirin in genotype 1b patients with hepatitis C virus cirrhosis. AB - BACKGROUND: Direct antiviral agents (DAA) showed very good results in terms of efficacy and safety in clinical trials, but real-life data are still needed in order to confirm this profile. MATERIAL AND METHODS: In Romania, through a nationwide government-funded programme in 2015-2016, approx.5800 patients with virus C cirrhosis received fully reimbursed DAA therapy with OBV/PTV/r+DSV+RBV for 12 weeks. We analysed a national prospective cohort enrolling the first 2070 patients, all with genotype 1b. The only key inclusion criteria was advanced fibrosis (Metavir stage F4) confirmed by Fibromax testing (or liver biopsy/Fibroscan). Efficacy was assessed by the percentage of patients achieving SVR 12 weeks post-treatment (SVR12). RESULTS: Forty patients stopped the treatment because of hepatic decompensation (1.9%), 21 stopped because of other adverse events and one was lost to follow-up. This cohort was 51% females, mean age 60 years (25/82), 67% pretreated, 70% associated NASH, 67% with severe necro inflammation (severity score 3-Fibromax), 37% with comorbidities, 10.4% with Child Pugh A6, 0.5% B7. The median MELD score was 8.09 (6 / 22). SVR by intention to-treat was reported in 1999/2070(96.6%), 55/2070 failed to respond. Liver decompensation was statistically associated in multivariate analysis with platelets< 105 /mm3 (P = .03), increased total bilirubin (P < .001), prolonged INR (P = .02), and albumin<3.5 g/dL (P = .03). CONCLUSIONS: OBV/PTV/r+DSV+RBV proved to be highly efficient in our population of cirrhotics with a 96.6% SVR. Serious adverse events related to therapy were reported in 61/2070(2.9%), most of them liver decompensation (1.9%), related to hepatic dysfunction, and lower platelet count. PMID- 28816022 TI - Assessing human risk of illness with West Nile virus mosquito surveillance data to improve public health preparedness. AB - Surveillance for West Nile virus (WNV) and other mosquito-borne pathogens involves costly and time-consuming collection and testing of mosquito samples. One difficulty faced by public health personnel is how to interpret mosquito data relative to human risk, thus leading to a failure to fully exploit the information from mosquito testing. The objective of our study was to use the information gained from historic West Nile virus mosquito testing to determine human risk relative to mosquito infection and to assess the usefulness of our mosquito infection forecasting models to give advance warning. We compared weekly mosquito infection rates from 2004 to 2013 to WNV case numbers in Illinois. We then developed a weather-based forecasting model to estimate the WNV mosquito infection rate one to 3 weeks ahead of mosquito testing both statewide and for nine regions of Illinois. We further evaluated human illness risk relative to both the measured and the model-estimated infection rates to provide guidelines for public health messages. We determined that across 10 years, over half of human WNV cases occurred following the 29 (of 210) weeks with the highest mosquito infection rates. The values forecasted by the models can identify those time periods, but model results and data availability varied by region with much stronger results obtained from regions with more mosquito data. The differences among the regions may be related to the amount of surveillance or may be due to diverse landscape characteristics across Illinois. We set the stage for better use of all surveillance options available for WNV and described an approach to modelling that can be expanded to other mosquito-borne illnesses. PMID- 28816021 TI - CD155 knockdown promotes apoptosis via AKT/Bcl-2/Bax in colon cancer cells. AB - CD155, one of the nectin-like molecule family members, is involved in cell adhesion and motility. CD155 is overexpressed in several human cancers, but its role in proliferation and apoptosis of colorectal cancer remains unclear. We found that CD155 was up-regulated in colorectal cancer tissues. CD155 knockdown via shRNA lentiviruses inhibited colon cancers cell migration and invasion, with a reduction in the expression of FAK, Src and MMP-2. CD155 down-regulation also suppressed colon cancer cell proliferation, accompanied by changing expressions of some molecules related to cell cycle. Finally, CD155 knockdown increased the expression ratio between Bax and Bcl-2, resulting in a significant increase in colon cancer cell apoptosis. Taken together, these results demonstrate that CD155 is involved in not only migration and invasion but also proliferation and survival abilities of colon cancer cells, suggesting that CD155 is one of key molecules promoting the growth and metastasis of colorectal cancer. PMID- 28816023 TI - Community sensitization and decision-making for trial participation: a mixed methods study from The Gambia. AB - BACKGROUND: Ensuring individual free and informed decision-making for research participation is challenging. It is thought that preliminarily informing communities through 'community sensitization' procedures may improve individual decision-making. This study set out to assess the relevance of community sensitization for individual decision-making in research participation in rural Gambia. METHODS: This anthropological mixed-methods study triangulated qualitative methods and quantitative survey methods in the context of an observational study and a clinical trial on malaria carried out by the Medical Research Council Unit Gambia. RESULTS/DISCUSSION: Although 38.7% of the respondents were present during sensitization sessions, 91.1% of the respondents were inclined to participate in the trial when surveyed after the sensitization and prior to the informed consent process. This difference can be explained by the informal transmission of information within the community after the community sensitization, expectations such as the benefits of participation based on previous research experiences, and the positive reputation of the research institute. Commonly mentioned barriers to participation were blood sampling and the potential disapproval of the household head. CONCLUSION: Community sensitization is effective in providing first-hand, reliable information to communities as the information is cascaded to those who could not attend the sessions. However, further research is needed to assess how the informal spread of information further shapes people's expectations, how the process engages with existing social relations and hierarchies (e.g. local political power structures; permissions of heads of households) and how this influences or changes individual consent. PMID- 28816024 TI - Continuous hypomethylation of the KCNQ1OT1:TSS-DMR in monochorionic twins discordant for Beckwith-Wiedemann syndrome. PMID- 28816026 TI - Evaluation of a 12-Hour Sustained-Release Acetaminophen (Paracetamol) Formulation: A Randomized, 3-Way Crossover Pharmacokinetic and Safety Study in Healthy Volunteers. AB - Acetaminophen (paracetamol) is a first-line treatment for mild and moderate pain. A twice-daily sustained-release (SR) formulation may be more convenient for chronic users than standard immediate-release (IR) acetaminophen. This randomized, 3-way crossover study evaluated pharmacokinetics and safety of single dose 1500- and 2000-mg SR acetaminophen formulations and 2 doses of IR acetaminophen 1000 mg given 6 hours apart in healthy adults (n = 14). Primary outcome was time that plasma acetaminophen concentration was >=4 MUg/mL (TC>=4MUg/mL ). Key secondary outcomes were area under the plasma concentration time curve (AUC) from time 0 to time t, when plasma acetaminophen was detectable (AUC0-t ), AUC from 0 to infinity (AUC0-inf ), and maximum plasma acetaminophen concentration (Cmax ). TC>=4MUg/mL from 2000-mg SR acetaminophen was similar to that from 2 doses of IR acetaminophen, whereas TC>=4MUg/mL for 1500-mg SR acetaminophen was significantly shorter than that for IR acetaminophen (P = .004). The extent of acetaminophen absorption from 2000-mg SR and 2 doses of the IR formulation was similar and within bioequivalence limits with regard to AUC0 12 , AUC0-t , and AUC0-inf . The extent of acetaminophen absorption from 1500-mg SR was significantly lower than that from IR acetaminophen. The 2000-mg SR represents a potential candidate formulation for 12-hour dosing with acetaminophen. PMID- 28816025 TI - Aromatic interactions at the ligand-protein interface: Implications for the development of docking scoring functions. AB - The ability to design and fine-tune non-covalent interactions between organic ligands and proteins is indispensable to rational drug development. Aromatic stacking has long been recognized as one of the key constituents of ligand protein interfaces. In this communication, we employ a two-parameter geometric model to conduct a large-scale statistical analysis of aromatic contacts in the experimental and computer-generated structures of ligand-protein complexes, considering various combinations of aromatic amino acid residues and ligand rings. The geometry of interfacial pi-pi stacking in crystal structures accords with experimental and theoretical data collected for simple systems, such as the benzene dimer. Many contemporary ligand docking programs implicitly treat aromatic stacking with van der Waals and Coulombic potentials. Although this approach generally provides a sufficient specificity to model aromatic interactions, the geometry of pi-pi contacts in high-scoring docking conformations could still be improved. The comprehensive analysis of aromatic geometries at ligand-protein interfaces lies the foundation for the development of type-specific statistical potentials to more accurately describe aromatic interactions in molecular docking. A Perl script to detect and calculate the geometric parameters of aromatic interactions in ligand-protein complexes is available at https://github.com/michal-brylinski/earomatic. The dataset comprising experimental complex structures and computer-generated models is available at https://osf.io/rztha/. PMID- 28816027 TI - Estimation of live birth and population prevalence of Down syndrome in nine U.S. states. AB - For all of the U.S. states with sufficient data, we estimated live birth and population prevalences for Down syndrome (DS). As social service resources vary between states, such data are important for public policy discussions and state planning. We predicted the actual and nonselective live birth prevalence, and population prevalence, for DS in nine U.S. states based on publicly available datasets from the Centers for Disease Control and Prevention and the Integrated Public Use Microdata Series. As of 2010, we estimated a population size for people with DS of 4,554 in MA (population prevalence 1 in 1,440), 6,101 in NJ (1 in 1,443), 14,315 in NY (1 in 1,355), 9,739 in IL (1 in 1,319), 4,354 in IN (1 in 1,491), 7,295 in MI (1 in 1,354), 9,099 in FL (1 in 2,071), 3,014 in KY (1 in 1,442), and 3,596 in AZ (1 in 1,784). The number of people living with DS has steadily increased from 1950 until 2010 in these nine U.S. states. Population prevalence would have been higher absent DS-related elective terminations. Racial and ethnic groups, other than non-Hispanic whites, comprise a growing proportion within these DS communities, particularly among younger-aged persons. PMID- 28816028 TI - Epidemiology of head and neck cancer in Thailand. AB - Cancer is the most common cause of death in Thailand, with the mortality almost doubled during 1998-2011 (from 48.4 to 95.2 per 100 000). The estimated number of new cancer cases in 2011 was 112 392. Our review provides baseline data on the current epidemiological situation with head and neck (HN) cancer in Thailand based on reports of the National Cancer Registry and findings from local and international publications. Collectively, HN cancer approaches age-standardized rate (ASR) incidence of 15.7 and 10.7 per 100 000 males and females, respectively, and is ranked among the top five dominant cancers in Thailand. The leading HN malignancies in men are oral (ASR incidence 4.6 per 100 000), nasopharyngeal (ASR 2.8) and laryngeal (ASR 2.7) cancers, while the most common cancers in women are thyroid (ASR 5.1) and oral (ASR 3.2) carcinomas. Some local habits (betel quid chewing, traditional cigarette smoking and alcohol intake) are associated with the high incidence of oral cancer in Northeast Thailand. Despite important prognostic significance, the role of human papillomavirus infection in various HN cancers from Thailand has been scarcely addressed. There is a growing incidence of thyroid cancer over the last two decades. The Thai population overall, compared to worldwide rates of HN malignancies, has a lower incidence of laryngeal and thyroid cancers but higher incidence of nasopharyngeal cancer. PMID- 28816030 TI - Marking excellence in contributions to the gerontological nursing literature. PMID- 28816029 TI - Development of a 3-dimensional tissue lung phantom of a preterm infant for optical measurements of oxygen-Laser-detector position considerations. AB - There is a need to further improve the clinical care of our most vulnerable patients-preterm infants. Novel diagnostic and treatment tools facilitate such advances. Here, we evaluate a potential percutaneous optical monitoring tool to assess the oxygen and water vapor content in the lungs of preterm babies. The aim is to prepare for further clinical studies by gaining a detailed understanding of how the measured light intensity and gas absorption signal behave for different possible geometries of light delivery and receiver. Such an experimental evaluation is conducted for the first time utilizing a specially developed 3 dimensional-printed optical phantom based on a geometry model obtained from computer tomography images of the thorax (chest) of a 1700-g premature infant. The measurements yield reliable signals for source-detector distances up to about 50 mm, with stronger gas absorption signals at long separations and positions related to the lower part of the lung, consistent with a larger relative volume of this. The limitations of this study include the omission of scattering tissue within the lungs and that similar optical properties are used for the wavelengths employed for the 2 gases, yielding no indication on the optimal wavelength pair to use. PMID- 28816031 TI - Do you see what I see: A mother's plea. AB - There is sometimes dissonance between the medical services that the general public expects an ED to provide and the acute critical care that emergency clinicians hope to provide. One explanation for this is that the ED is both a territory and a meeting place for a cornucopia of clinicians, some of whom are not ED clinicians themselves. Roles are sometimes ambiguous and location specific. Recently, one Queensland mother believed that her son's suicide could have been prevented had emergency staff been better educated. This perspective aims to reflect on several pertinent questions: Should suicide risk be treated as a medical emergency? Is suicide prevention everyone's business? Is suicide risk assessment and management a core component of ED? How common, precise and non stigmatising is the language around suicide? To what extent is that language underpinned by mythology rather than fact? For some, these will be inconvenient questions. How they are answered is undoubtedly framed within the language used when discussing suicide. PMID- 28816032 TI - High Order in a Self-Assembled Iridium(III) Complex Gelator Towards Nanostructured IrO2 Thin Films. AB - The preparation and characterization of a new metallogelator based on the IrIII discrete cyclometalated complex [(ppy)2 Ir(bpy)](CH3 CH2 OCH2 CO2 ) are reported, where H(ppy) is 2-phenylpiridine and bpy is 2,2'-bipyridine, which is used as an ancillary ligand. The compound is able to self-assemble in water in a range of concentrations between 3 % and 6 % w/w, creating a luminescent ordered supramolecular gel. The gel and xerogel architectures were investigated through polarized optical microscopy (POM), SEM and TEM microscopies coupled with powder X-ray diffraction. The gel supramolecular organization is characterized by columnar tetragonal strands, already present at high dilution conditions, of cations surrounded by counteranions. These strands, in turn, are self-assembled in an oblique columnar cell upon gelification. The xerogel thin films obtained upon complete dehydration maintained the gel supramolecular order and can be used as a precursor for the preparation of nanostructured IrO2 thin films. PMID- 28816033 TI - Selection of 12-Hour Sustained-Release Acetaminophen (Paracetamol) Formulation Through Comparison of Pharmacokinetic Profiles of 4 Sustained-Release Prototype Formulations and Standard Acetaminophen Formulation: An Open-Label, Randomized, Proof-of-Principle Pharmacokinetic Study. AB - Acetaminophen (APAP; paracetamol), a widely used analgesic and antipyretic, is available in modified-release and immediate-release (IR) formulations requiring 3 or 4-times-daily dosing. This phase 1 open-label crossover study compared pharmacokinetic profiles of single 2000-mg doses of 4 different sustained-release (SR) formulations of APAP (designed to allow twice-daily dosing) against two 1000 mg doses (taken 6 hours apart) of standard IR APAP in 14 healthy volunteers. The primary end point was duration of time that plasma APAP concentration exceeded a plasma concentration (TC ) of 4 MUg/mL. Of the 4 SR APAP formulations studied, a single 2000-mg dose of a bilayer SR formulation had the longest mean TC>4MUg/mL (8.1 hours), similar to that of 2 doses of IR APAP (8.3 hours). Mean TC>4MUg/mL was 7.3 hours with a single-layer SR APAP, 7.5 hours with another single-layer SR APAP formulation using a different excipient, and 7.1 hours with an enteric coated SR APAP coupled with a fast-dissolving IR APAP. Secondary pharmacokinetic analyses showed a similar extent of absorption and lower peak concentration for the bilayer SR formulation compared with IR APAP. Adverse events were all mild. Based on these results, the bilayer SR APAP formulation was selected for further development. PMID- 28816034 TI - Cerebrospinal fluid cytology in nonmalignant aseptic meningeal disorders. AB - Cerebrospinal fluid cytology examination is a common and reliable primary and/or complementary procedure for the diagnosis of central nervous system (CNS) disorders. This review provides an update of aseptic meningeal disorders that may be encountered in cytopathology practice. The article covers the cytological findings and helpful ancillary studies needed of nonmalignant aseptic CNS disorders such as viral, bacterial, fungal and parasitic infections, and other noninfectious diseases, such as Mollaret's meningitis (recurrent benign lymphocytic meningitis), Guillain-Barre syndrome, multiple Sclerosis, subarachnoid haemorrhage, and drug-induced disorders. PMID- 28816035 TI - Surface Modification with ECM-Inspired SDF-1alpha/Laminin-Loaded Nanocoating for Vascular Wound Healing. AB - Surface biomimetic modification with extra-cellular matrix (ECM)-derived biomolecules is an emerging potential method of accelerating the healing of vascular stent lesions. However, insufficient capacity of the constructed biofunctional layer in maintaining its long-term efficiency and preventing thrombus and neointimal hyperplasia continue to be major limitations in clinical application. On the basis of the structure and function of ECM, in this study, we constructed a novel stromal cell-derived factor-1alpha (SDF-1alpha)/laminin loaded nanocoating on the 316L stainless steel (SS) surface to provide improved function in modulation of vascular remodeling. The modified surface was found to control delivery of biomolecules and exhibit promising potential to provide stage adjusted treatment after injury. An in vitro biocompatibility study suggested that the constructed layer may effectively prevent thrombosis formation by inhibiting platelet adhesion and activation, while accelerating endothelium regeneration by inducing endothelial cell (EC) migration and endothelial progenitor cell (EPC) aggregation. An in vivo animal test further demonstrated that the nanocoating may prevent thrombus and neointimal hyperplasia after implantation for 3 months. Therefore, the ECM-inspired nanocoating described in this study is a promising novel approach for vascular stent surface modification. PMID- 28816037 TI - Catalytic Asymmetric Oxygenations with the Environmentally Benign Oxidants H2O2 and O2. AB - The discovery of simple and efficient catalyst systems for the asymmetric oxofunctionalization of hydrocarbons is a challenging task of catalytic chemistry. In this paper, we give an overview of catalyst systems capable of conducting asymmetric oxygenative transformations of organic molecules and, in line with the major trend to sustainability, relying on green oxidants H2O2 and O2 as the ultimate oxygen source. The full historical period of asymmetric oxidation catalysis (1970 to the present day) is covered; both transition-metal based and organocatalytic systems are considered. The focus of this review is the catalytic properties of the existing catalyst systems, in particular stereoselectivity, activity, efficiency, and synthetic outlook. At the same time, mechanistic peculiarities of stereoselective oxygen transfer are given attention. PMID- 28816036 TI - Surface/Interface Carrier-Transport Modulation for Constructing Photon Alternative Ultraviolet Detectors Based on Self-Bending-Assembled ZnO Nanowires. AB - Surface/interface charge-carrier generation, diffusion, and recombination/transport modulation are especially important in the construction of photodetectors with high efficiency in the field of nanoscience. In the paper, a kind of ultraviolet (UV) detector is designed based on ZnO nanostructures considering photon-trapping, surface plasmonic resonance (SPR), piezophototronic effects, interface carrier-trapping/transport control, and collection. Through carefully optimized surface/interface carrier-transport modulation, a designed device with detectivity as high as 1.69 * 1016/1.71 * 1016 cm.Hz1/2/W irradiating with 380 nm photons under ultralow bias of 0.2 V is realized by alternating nanoparticle/nanowire active layers, respectively, and the designed UV photodetectors show fast and slow recovery processes of 0.27 and 4.52 ms, respectively, which well-satisfy practical needs. Further, it is observed that UV photodetection could be performed within an alternative response by varying correlated key parameters, through efficient surface/interface carrier-transport modulation, spectrally resolved photoresponse of the detector revealing controlled detection in the UV region based on the ZnO nanomaterial, photodetection allowed or limited by varying the active layers, irradiation distance from one of the electrodes, standing states, or electric field. The detailed carrier generation, diffusion, and recombination/transport processes are well illustrated to explain charge-carrier dynamics contributing to the photoresponse behavior. PMID- 28816038 TI - Estimating Grass-Soil Bioconcentration of Munitions Compounds from Molecular Structure. AB - A partitioning-based model is presented to estimate the bioconcentration of five munitions compounds and two munition-like compounds in grasses. The model uses polyparameter linear free energy relationships (pp-LFERs) to estimate the partition coefficients between soil organic carbon and interstitial water and between interstitial water and the plant cuticle, a lipid-like plant component. Inputs for the pp-LFERs are a set of numerical descriptors computed from molecular structure only that characterize the molecular properties that determine the interaction with soil organic carbon, interstitial water, and plant cuticle. The model is validated by predicting concentrations measured in the whole plant during independent uptake experiments with a root-mean-square error (log predicted plant concentration-log observed plant concentration) of 0.429. This highlights the dominant role of partitioning between the exposure medium and the plant cuticle in the bioconcentration of these compounds. The pp-LFERs can be used to assess the environmental risk of munitions compounds and munition-like compounds using only their molecular structure as input. PMID- 28816039 TI - Approaches and Challenges for Analysis of Flavor and Fragrance Volatiles. PMID- 28816040 TI - Carbon Nanotube Thread Electrochemical Cell: Detection of Heavy Metals. AB - In this work, all three electrodes in an electrochemical cell were fabricated based on carbon nanotube (CNT) thread. CNT thread partially insulated with a thin polystyrene coating to define the microelectrode area was used as the working electrode; bare CNT thread was used as the auxiliary electrode; and a micro quasi reference electrode was fabricated by electroplating CNT thread with Ag and then anodizing it in chloride solution to form a layer of AgCl. The Ag|AgCl coated CNT thread electrode provided a stable potential comparable to the conventional liquid-junction type Ag|AgCl reference electrode. The CNT thread auxiliary electrode provided a stable current, which is comparable to a Pt wire auxiliary electrode. This all-CNT thread three electrode cell has been evaluated as a microsensor for the simultaneous determination of trace levels of heavy metal ions by anodic stripping voltammetry (ASV). Hg2+, Cu2+, and Pb2+ were used as a representative system for this study. The calculated detection limits (based on the 3sigma method) with a 120 s deposition time are 1.05, 0.53, and 0.57 nM for Hg2+, Cu2+, and Pb2+, respectively. These electrodes significantly reduce the dimensions of the conventional three electrode electrochemical cell to the microscale. PMID- 28816041 TI - Contact Engineering of Molybdenum Ditelluride Field Effect Transistors through Rapid Thermal Annealing. AB - Understanding and engineering the interface between metal and two-dimensional materials are of great importance to the research and development of nanoelectronics. In many cases the interface of metal and 2D materials can dominate the transport behavior of the devices. In this study, we focus on the metal contacts of MoTe2 (molybdenum ditelluride) FETs (field effect transistors) and demonstrate how to use post-annealing treatment to modulate their transport behaviors in a controlled manner. We have also carried out low temperature and transmission electron microscopy studies to understand the mechanisms behind the prominent effect of the annealing process. Changes in transport properties are presumably due to anti-site defects formed at the metal-MoTe2 interface under elevated temperature. The study provides more insights into MoTe2 field effect devices and suggests guidelines for future optimizations. PMID- 28816042 TI - Rapid and Reliable Detection of Alkaline Phosphatase by a Hot Spots Amplification Strategy Based on Well-Controlled Assembly on Single Nanoparticle. AB - The first appeal of clinical assay is always accurate and rapid. For alkaline phosphatase (ALP) monitoring in medical treatment, a rapid, reliable surface enhanced Raman scattering (SERS) test kit is designed based on a "hot spots" amplification strategy. Consisting of alkyne-tagged Au nanoparticles (NPs), Ag+, and enzyme substrate, the packaged test kit can achieve one-step clinical assay of ALP in human serum within several minutes, while the operation is simple as it directly inputs the sample into the test kit. Here, Ag+ ions are adsorbed onto the surface of Au core due to electrostatic interaction between Ag+ and the negatively charged donor surface, then enzymatic biocatalysis of ALP triggers the reduction of Ag+ and subsequently silver growth occurs on every Au core surface in a controllable manner, forming "hot spots" between the Au core and Ag shell, in which the SERS signal of alkyne Raman reporters would be highly amplified. Meanwhile, ALP mediates a redox reaction of Ag+ as well as the dynamic silver coating process so the increase of SERS intensity is well-controlled and can be recognized with increasing amounts of the targets. Instead of conventional NP aggregation, this leads to a more reproducible result. In particular, the distinct Raman emission from our self-synthesized alkyne reporter is narrow and stable with zero background in the Raman silent region, suffering no optical fluctuation from biosystem inputs and the detection results are therefore reliable with a limit of detection of 0.01 U/L (2.3 pg/mL). Along with ultrahigh stability, this SERS test kit therefore is an important point-of-care candidate for a reliable, efficacious, and highly sensitive detection method for ALP, which potentially decreases the need for time-consuming clinical trials. PMID- 28816043 TI - Electronic Muscles and Skins: A Review of Soft Sensors and Actuators. AB - This article reviews several classes of compliant materials that can be utilized to fabricate electronic muscles and skins. Different classes of materials range from compliant conductors, semiconductors, to dielectrics, all of which play a vital and cohesive role in the development of next generation electronics. This paper covers recent advances in the development of new materials, as well as the engineering of well-characterized materials for the repurposing in applications of flexible and stretchable electronics. In addition to compliant materials, this article further discusses the use of these materials for integrated systems to develop soft sensors and actuators. These new materials and new devices pave the way for a new generation of electronics that will change the way we see and interact with our devices for decades to come. PMID- 28816044 TI - Action of Gold Nanospikes-Based Nanoradiosensitizers: Cellular Internalization, Radiotherapy, and Autophagy. AB - A major challenge to achieve effective X-ray radiation therapy is to use a relatively low and safe radiation dose. Various radiosensitizers, which can significantly enhance the radiotherapeutic performance, have been developed. Gold based nanomaterials, as a new type of nanoparticle-based radiosensitizers, have been extensively used in researches involving cancer radiotherapy. However, the cancer therapeutic effect using the gold nanoparticle-based radiotherapy is usually not significant because of the low cellular uptake efficiency and the autophagy-inducing ability of these gold nanomaterials. Herein, using gold nanospikes (GNSs) as an example, we prepared a series of thiol-poly(ethylene glycol)-modified GNSs terminated with methoxyl (GNSs), amine (NH2-GNSs), folic acid (FA) (FA-GNSs), and the cell-penetrating peptide TAT (TAT-GNSs), and evaluated their effects on X-ray radiotherapy. For the in vitro study, it was found that the ionizing radiation effects of these GNSs were well correlated with their cellular uptake amounts, with the same order of GNSs < NH2-GNSs < FA-GNSs < TAT-GNSs. The sensitization enhancement ratio (SER), which is commonly used to evaluate how effectively radiosensitizers decrease cell proliferation, reaches 2.30 for TAT-GNSs. The extremely high SER value for TAT-GNSs indicates the superior radiosensitization effect of this nanomaterial. The radiation enhancement mechanisms of these GNSs involved the increased reactive oxygen species (ROS), mitochondrial depolarization, and cell cycle redistribution. Western blotting assays confirmed that the surface-modified GNSs could induce the up-regulation of autophagy-related protein (LC3-II) and apoptosis-related protein (active caspase-3) in cancer cells. By monitoring the degradation of the autophagy substrate p62 protein, GNSs caused impairment of autolysosome degradation capacity and autophagosome accumulation. Our data demonstrated that autophagy played a protective role against caner radiotherapy, and the inhibition of protective autophagy with inhibitors would result in the increase of cell apoptosis. Besides the above in vitro experiments, the in vivo tumor growth study also indicated that X-ray + TAT-GNSs treatment had the best tumor growth inhibitory effect, which confirmed the highest radiation sensitizing effect of TAT-GNSs. This work furthered our understanding on the interaction mechanism between gold nanomaterials and cancer cells and should be able to promote the development of nanoradiosensitizers for clinical applications. PMID- 28816045 TI - Efficient Inorganic Perovskite Light-Emitting Diodes with Polyethylene Glycol Passivated Ultrathin CsPbBr3 Films. AB - Efficient inorganic perovskite light-emitting diodes (PeLEDs) with an ultrathin perovskite emission layer (~30 nm) were realized by doping Lewis base polyethylene glycol (PEG) into CsPbBr3 films. PEG in the perovskite films not only physically fills the crystal boundaries but also interacts with the perovskite crystals to passivate the crystal grains, reduce nonradiative recombination, and ensure efficient luminance and high efficiency. As a result, promoted brightness, current efficiency (CE), and external quantum efficiency (EQE) were achieved. The nonradiative decay rate of the PEG:CsPbBr3 composite film is 1 order of magnitude less than that of the neat CsPbBr3 film. After further optimization of the molar ratio between CsBr and PbBr2, a peak CE of 19 cd/A, a maximum EQE of 5.34%, and a maximum brightness of 36600 cd/m2 were achieved, demonstrating the interaction between PEG and the precursors. The results are expected to offer some helpful implications in optimizing the polymer assisted PeLEDs with ultrathin emission layers, which might have potential application in see-through displays. PMID- 28816046 TI - Rhodium(III)-Catalyzed C-H Activation of Nitrones and Annulative Coupling with Nitroalkenes. AB - Rh(III)-catalyzed synthesis of nitro-functionalized indenes has been realized via C-H activation of arylnitrones and annulation with nitroolefins. The reaction proceeded in moderate to high yields with good functional group tolerance under ambient atmosphere. PMID- 28816047 TI - Light-Independent Ionic Transport in Inorganic Perovskite and Ultrastable Cs Based Perovskite Solar Cells. AB - Due to light-induced effects in CH3NH3-based perovskites, such as ion migration, defects formation, and halide segregation, the degradation of CH3NH3-based perovskite solar cells under maximum power point is generally implicated. Here we demonstrated that the effect of light-enhanced ion migration in CH3NH3PbI3 can be eliminated by inorganic Cs substitution, leading to an ultrastable perovskite solar cell. Quantitatively, the ion migration barrier for CH3NH3PbI3 is 0.62 eV under dark conditions, larger than that of CsPbI2Br (0.45 eV); however, it reduces to 0.07 eV for CH3NH3PbI3 under illumination, smaller than that for CsPbI2Br (0.43 eV). Meanwhile, photoinduced halide segregation is also suppressed in Cs-based perovskites. Cs-based perovskite solar cells retained >99% of the initial efficiency (10.3%) after 1500 h of maximum power point tracking under AM1.5G illumination, while CH3NH3PbI3 solar cells degraded severely after 50 h of operation. Our work reveals an uncovered mechanism for stability improvement by inorganic cation substitution in perovskite-based optoelectronic devices. PMID- 28816048 TI - Bile Salt-like Dienones Having a Novel Skeleton or a Rare Substitution Pattern Function as Chemical Cues in Adult Sea Lamprey. AB - Two novel sulfated bile salt-like dienones, featuring either a unique, rearranged side chain or a rare cis-11,12-diol on the steroidal C-ring, herein named petromyzene A (1) and B (2), respectively, were isolated from water conditioned with spawning male sea lamprey (Petromyzon marinus; a jawless vertebrate animal). The structures of these natural products were elucidated by mass spectrometry and NMR spectroscopy. Petromyzenes A and B exhibited high olfactory potency for adult sea lamprey and strong behavioral attraction for spawning females. PMID- 28816049 TI - Trifluoromethylthiolation-Based Bifunctionalization of Diazocarbonyl Compounds by Rhodium Catalysis. AB - A new Rh-catalyzed, three-component reaction for the oxytrifluoromethylthiolation of alpha-diazoketones was developed. The SCF3 functionality was introduced using a stable dibenzenesulfonimide reagent under mild conditions. Alcohols, acetals, and ethers were used as the alkoxy sources. Cyclic ethers underwent a trifunctionalization reaction through the introduction of SCF3, OR, and N(SO2Ph)2 substituents in a single step. PMID- 28816050 TI - Coarse-Grained Model of the Dynamics of Electrolyte Solutions. AB - Ion-specific solvation has fundamental implications in biochemistry, and the thermodynamics and dynamics of aqueous salt solutions have correspondingly been investigated intensively. Nonetheless, there are fundamental unresolved issues in modeling the dynamics of aqueous salt solutions and the related problem of polymers dissolved in these solutions. In particular, experiments show that the self-diffusion coefficient, D, of water molecules in electrolyte solutions can be either enhanced or suppressed by particular salts having the same valence where the observed changes correlate with the Hofmeister series governing the relative solubility of proteins and water-soluble polymers in the same salt solutions. Recent studies have demonstrated that common atomistic models of aqueous electrolyte solutions completely fail to reproduce this basic phenomenon. Drawing on similar trends observed in the field of polymer nanocomposites, we propose a coarse-grained model of aqueous electrolyte solutions that captures the observed trends and that offers physical insight into the influence of salt on the thermodynamic and dynamic properties of electrolyte solutions. PMID- 28816051 TI - Lipid-Stabilized Water-Oil Interfaces Studied by Microfocusing Small-Angle X-ray Scattering. AB - Water-in-oil (w/o) simple emulsions are dispersed microconfined systems that find applications in many areas of advanced materials and biotechnology, such as the food industry, drug delivery, and cosmetics, to name but a few. In these systems, the structural and chemical properties of the boundary layer at the w/o interface are of paramount importance in determining functionality and stability. Recently, microfluidic methods have emerged as a valuable tool for fabricating monodisperse emulsion droplets. Because of the intrinsic flexibility of microfluidics, different interfaces can be obtained, and general principles governing their stability are needed to guide the experimental approach. Herein, we investigate the structural characteristics of the region encompassing the liquid/liquid (L/L) interface of w/o emulsions generated by a microfluidic device in the presence of phospholipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and other intercalating amphiphiles (dopants) using microfocused small-angle X-rays scattering (MU-SAXS). We show that phospholipids provide a stable and versatile boundary film of ~100 MUm whose basic units are swollen and uncorrelated DMPC bilayers. The internal arrangement of this interfacial film can be tuned by adding molecules with a different packing parameter, such as cholesterol, which is able to increase the stiffness of the lipid membranes and trigger interbilayer correlation. PMID- 28816052 TI - Animal experiments and the right to ask questions about them. PMID- 28816053 TI - In vitro exposure systems and dosimetry assessment tools for inhaled tobacco products: Workshop proceedings, conclusions and paths forward for in vitro model use. AB - In 2009, the passing of the Family Smoking Prevention and Tobacco Control Act facilitated the establishment of the FDA Center for Tobacco Products (CTP), and gave it regulatory authority over the marketing, manufacture and distribution of tobacco products, including those termed 'modified risk'. On 4-6 April 2016, the Institute for In Vitro Sciences, Inc. (IIVS) convened a workshop conference entitled, In Vitro Exposure Systems and Dosimetry Assessment Tools for Inhaled Tobacco Products, to bring together stakeholders representing regulatory agencies, academia and industry to address the research priorities articulated by the FDA CTP. Specific topics were covered to assess the status of current in vitro smoke and aerosol/vapour exposure systems, as well as the various approaches and challenges to quantifying the complex exposures in in vitro pulmonary models developed for evaluating adverse pulmonary events resulting from tobacco product exposures. The four core topics covered were: a) Tobacco Smoke and E-Cigarette Aerosols; b) Air-Liquid Interface-In Vitro Exposure Systems; c) Dosimetry Approaches for Particles and Vapours/In Vitro Dosimetry Determinations; and d) Exposure Microenvironment/Physiology of Cells. The 2.5-day workshop included presentations from 20 expert speakers, poster sessions, networking discussions, and breakout sessions which identified key findings and provided recommendations to advance these technologies. Here, we will report on the proceedings, recommendations, and outcome of the April 2016 technical workshop, including paths forward for developing and validating non-animal test methods for tobacco product smoke and next generation tobacco product aerosol/vapour exposures. With the recent FDA publication of the final deeming rule for the governance of tobacco products, there is an unprecedented necessity to evaluate a very large number of tobacco-based products and ingredients. The questionable relevance, high cost, and ethical considerations for the use of in vivo testing methods highlight the necessity of robust in vitro approaches to elucidate tobacco-based exposures and how they may lead to pulmonary diseases that contribute to lung exposure-induced mortality worldwide. PMID- 28816054 TI - Animal 'models': How a mechanistic approach can reduce suffering and improve translatability. AB - Poorly predictive animal models of disease cause avoidable suffering and hamper the discovery of new treatments for patients. A focus on mechanistic modelling has the potential to reduce animal suffering as well as improving translation from the bench to the bedside. PMID- 28816055 TI - Pain in laboratory animals: A possible confounding factor? AB - Reducing pain in animals is an ethical and sometimes legal requirement, but how do we assess pain and does it confound data collection? PMID- 28816056 TI - Letter to the Editor. PMID- 28816058 TI - TSCC and TSCYC Screening Forms in a Clinical Sample: Reliability, Validity, and Creating Local Clinical Norms. AB - Clinical norms were developed for two screening tools recently developed by Briere and published by Psychological Assessment Resources. The screening measures were derived from the most predictive items of the Trauma Symptom Checklist for Children (TSCC) and the Trauma Symptom Checklist for Young Children (TSCYC). Both screening measures (TSCC-Screening Form and TSCYC-Screening Form) have a total of 20 items measuring general trauma (12 items) and sexual concerns (8 items). Briere and Wherry report on the reliability and validity of the instrument when used with a normative group of children who are not identified as abused. This clinical sample of abused children seeking services from a child advocacy center was comprised of 86.1% females and 55.4% Hispanic children. Data were collected for 177 TSCYCs and 261 TSCCs. Internal consistencies ranged from an alpha of .74 to .85, and correlation coefficients indicating validity with the longer scales ranging from an r = .563 to .807. T score norms were calculated for this clinical sample. The measure has promise as a tool for screening multiple domains with child and caregiver informants; and in addition to its psychometric properties, it assesses sexualized behavior, suicidal thoughts, and trauma. PMID- 28816057 TI - Mitochondrial Complex I Reversible S-Nitrosation Improves Bioenergetics and Is Protective in Parkinson's Disease. AB - AIMS: This study was designed to explore the neuroprotective potential of inorganic nitrite as a new therapeutic avenue in Parkinson's disease (PD). RESULTS: Administration of inorganic nitrite ameliorates neuropathology in phylogenetically distinct animal models of PD. Beneficial effects are not confined to prophylactic treatment and also occur if nitrite is administered when the pathogenic cascade is already active. Mechanistically, the effect is mediated by both complex I S-nitrosation, which under nitrite administration is favored over formation of other forms of oxidation, and down-stream activation of the antioxidant Nrf2 pathway. Nitrite also rescues respiratory reserve capacity and increases proton leakage in LRRK2 PD patients' dermal fibroblasts. INNOVATION: The study proposes an unprecedented approach based on the administration of the nitrosonium donor nitrite to contrast complex I and redox anomalies in PD. Dysfunctional mitochondrial complex I propagates oxidative stress in PD, and treatments mitigating this defect may, therefore, limit disease progression. Therapeutic complex I targeting has been successfully achieved in ischemia/reperfusion by using nitrosonium donors such as nitrite to reversibly modify its subunits and protect from oxidative damage after reperfusion. This evidence led to the innovative hypothesis that nitrite could exert protective effects also in pathological conditions where complex I dysfunction occurs in normoxia, such as in PD. CONCLUSIONS: Overall, these results demonstrate that administration of inorganic nitrite improves mitochondrial function in PD, and it, therefore, represents an amenable intervention to hamper disease progression. Antioxid. Redox Signal. 28, 44-61. PMID- 28816059 TI - Atherothrombosis and Oxidative Stress: Mechanisms and Management in Elderly. AB - SIGNIFICANCE: The incidence of cardiovascular events (CVEs) increases with age, representing the main cause of death in an elderly population. Aging is associated with overproduction of reactive oxygen species (ROS), which may affect clotting and platelet activation, and impair endothelial function, thus predisposing elderly patients to thrombotic complications. Recent Advances: There is increasing evidence to suggest that aging is associated with an imbalance between oxidative stress and antioxidant status. Thus, upregulation of ROS producing enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and myeloperoxidase, along with downregulation of antioxidant enzymes, such as superoxide dismutase and glutathione peroxidase, occurs during aging. This imbalance may predispose to thrombosis by enhancing platelet and clotting activation and eliciting endothelial dysfunction. Recently, gut-derived products, such as trimethylamine N-oxide (TMAO) and lipopolysaccharide, are emerging as novel atherosclerotic risk factors, and gut microbiota composition has been shown to change by aging, and may concur with the increased cardiovascular risk in the elderly. CRITICAL ISSUES: Antioxidant treatment is ineffective in patients at risk or with cardiovascular disease. Further, anti-thrombotic treatment seems to work less in the elderly population. FUTURE DIRECTIONS: Interventional trials with antioxidants targeting enzymes implicated in aging-related atherothrombosis are warranted to explore whether modulation of redox status is effective in lowering CVEs in the elderly. Antioxid. Redox Signal. 27, 1083-1124. PMID- 28816061 TI - Redox Regulation and Noncoding RNAs. AB - SIGNIFICANCE: RNA is a heterogeneous class of molecules with the minority being protein coding. Noncoding RNAs (ncRNAs) are involved in translation and epigenetic control mechanisms of gene expression. Recent Advances: In recent years, the number of identified ncRNAs has dramatically increased and it is now clear that ncRNAs provide a complex layer of differential gene expression control. CRITICAL ISSUES: NcRNAs exhibit interplay with redox regulation. Redox regulation alters the expression of ncRNAs; conversely, ncRNAs alter the expression of generator and effector systems of redox regulation in a complex manner, which will be the focus of this review article. FUTURE DIRECTIONS: Understanding the role of ncRNA in redox control will lead to the development of new strategies to alter redox programs. Given that many ncRNAs (particularly microRNAs [miRNAs]) change large gene sets, these molecules are attractive drug candidates; already, now miRNAs can be targeted in patients. Therefore, the development of ncRNA therapies focusing on these molecules is an attractive future strategy. Antioxid. Redox Signal. 29, 793-812. PMID- 28816062 TI - Corrigendum. PMID- 28816060 TI - The Broad-Spectrum Antimicrobial Potential of [Mn(CO)4(S2CNMe(CH2CO2H))], a Water Soluble CO-Releasing Molecule (CORM-401): Intracellular Accumulation, Transcriptomic and Statistical Analyses, and Membrane Polarization. AB - AIMS: Carbon monoxide (CO)-releasing molecules (CORMs) are candidates for animal and antimicrobial therapeutics. We aimed to probe the antimicrobial potential of a novel manganese CORM. RESULTS: [Mn(CO)4S2CNMe(CH2CO2H)], CORM-401, inhibits growth of Escherichia coli and several antibiotic-resistant clinical pathogens. CORM-401 releases CO that binds oxidases in vivo, but is an ineffective respiratory inhibitor. Extensive CORM accumulation (assayed as intracellular manganese) accompanies antimicrobial activity. CORM-401 stimulates respiration, polarizes the cytoplasmic membrane in an uncoupler-like manner, and elicits loss of intracellular potassium and zinc. Transcriptomics and mathematical modeling of transcription factor activities reveal a multifaceted response characterized by elevated expression of genes encoding potassium uptake, efflux pumps, and envelope stress responses. Regulators implicated in stress responses (CpxR), respiration (Arc, Fnr), methionine biosynthesis (MetJ), and iron homeostasis (Fur) are significantly disturbed. Although CORM-401 reduces bacterial growth in combination with cefotaxime and trimethoprim, fractional inhibition studies reveal no interaction. INNOVATION: We present the most detailed microbiological analysis yet of a CORM that is not a ruthenium carbonyl. We demonstrate CO independent striking effects on the bacterial membrane and global transcriptomic responses. CONCLUSIONS: CORM-401, contrary to our expectations of a CO delivery vehicle, does not inhibit respiration. It accumulates in the cytoplasm, acts like an uncoupler in disrupting cytoplasmic ion balance, and triggers multiple effects, including osmotic stress and futile respiration. Rebound Track: This work was rejected during standard peer review and rescued by rebound peer review (Antioxid Redox Signal 16: 293-296, 2012) with the following serving as open reviewers: Miguel Aon, Giancarlo Biagini, James Imlay, and Nigel Robinson. Antioxid. Redox Signal. 28, 1286-1308. PMID- 28816064 TI - Re: Meta-analysis of Australian Indigenous psychiatric treatment, critiqued. PMID- 28816063 TI - Editor's Choice - Acute Cardiovascular Care Association Position Paper on Intensive Cardiovascular Care Units: An update on their definition, structure, organisation and function. AB - Acute cardiovascular care has progressed considerably since the last position paper was published 10 years ago. It is now a well-defined, complex field with demanding multidisciplinary teamworking. The Acute Cardiovascular Care Association has provided this update of the 2005 position paper on acute cardiovascular care organisation, using a multinational working group. The patient population has changed, and intensive cardiovascular care units now manage a large range of conditions from those simply requiring specialised monitoring, to critical cardiovascular diseases with associated multi-organ failure. To describe better intensive cardiovascular care units case mix, acuity of care has been divided into three levels, and then defining intensive cardiovascular care unit functional organisation. For each level of intensive cardiovascular care unit, this document presents the aims of the units, the recommended management structure, the optimal number of staff, the need for specially trained cardiologists and cardiovascular nurses, the desired equipment and architecture, and the interaction with other departments in the hospital and other intensive cardiovascular care units in the region/area. This update emphasises cardiologist training, referring to the recently updated Acute Cardiovascular Care Association core curriculum on acute cardiovascular care. The training of nurses in acute cardiovascular care is additionally addressed. Intensive cardiovascular care unit expertise is not limited to within the unit's geographical boundaries, extending to different specialties and subspecialties of cardiology and other specialties in order to optimally manage the wide scope of acute cardiovascular conditions in frequently highly complex patients. This position paper therefore addresses the need for the inclusion of acute cardiac care and intensive cardiovascular care units within a hospital network, linking university medical centres, large community hospitals, and smaller hospitals with more limited capabilities. PMID- 28816065 TI - Improved Hematopoietic Gene Therapy in a Mouse Model of Fanconi Anemia Mediated by Mesenchymal Stromal Cells. AB - In this study we propose a novel approach based on the use of mesenchymal stromal cells (MSCs), aiming at limiting risks of graft failure in gene therapy protocols associated with low conditioning regimens. Because the engraftment of corrected hematopoietic stem cells (HSCs) is particularly challenging in Fanconi anemia (FA), we have investigated the relevance of MSCs in an experimental model of FA gene therapy. Our results showed, first, that risks of graft failure in recipients conditioned with a moderate dose of 5 Gy and infused with limited numbers of wild-type HSCs are significantly higher in Fanca-/- recipients as compared with wild-type recipients. However, when wild-type HSC numbers inducing 30-50% of graft failures in Fanca-/- recipients were coinfused with MSCs, no graft failures were observed. Moreover, graft failures associated with the infusion of low numbers of gene-corrected Fanca-/- HSCs were also significantly overcome by MSC coinfusion. Our study shows for the first time that MSC coinfusion constitutes a simple and nontoxic approach to minimize risks of graft failure in gene therapy applications associated with low conditioning regimens and infusion of limited numbers of corrected HSCs. PMID- 28816066 TI - Stressing the (Epi)Genome: Dealing with Reactive Oxygen Species in Cancer. AB - SIGNIFICANCE: Growing evidence indicates cross-talk between reactive oxygen species (ROS) and several key epigenetic processes such as DNA methylation, histone modifications, and miRNAs in normal physiology and human pathologies including cancer. This review focuses on how ROS-induced oxidative stress, metabolic intermediates, and epigenetic processes influence each other in various cancers. Recent Advances: ROS alter chromatin structure and metabolism that impact the epigenetic landscape in cancer cells. Several site-specific DNA methylation changes have been identified in different cancers and are discussed in the review. We also discuss the interplay of epigenetic enzymes and miRNAs in influencing malignant transformation in an ROS-dependent manner. CRITICAL ISSUES: Loss of ROS-mediated signaling mostly by epigenetic regulation may promote tumorigenesis. In contrast, augmented oxidative stress because of high ROS levels may precipitate epigenetic alterations to effect various phases of carcinogenesis. We address both aspects in the review. FUTURE DIRECTIONS: Several drugs targeting ROS are under various stages of clinical development. Recent analysis of human cancers has revealed pervasive deregulation of the epigenetic machinery. Thus, a better understanding of the cross-talk between ROS and epigenetic alterations in cancer could lead to the identification of new drug targets and more effective treatment modalities. PMID- 28816067 TI - Post-acquisition data mining techniques for LC-MS/MS-acquired data in drug metabolite identification. AB - Metabolite identification is a crucial part of the drug discovery process. LC MS/MS-based metabolite identification has gained widespread use, but the data acquired by the LC-MS/MS instrument is complex, and thus the interpretation of data becomes troublesome. Fortunately, advancements in data mining techniques have simplified the process of data interpretation with improved mass accuracy and provide a potentially selective, sensitive, accurate and comprehensive way for metabolite identification. In this review, we have discussed the targeted (extracted ion chromatogram, mass defect filter, product ion filter, neutral loss filter and isotope pattern filter) and untargeted (control sample comparison, background subtraction and metabolomic approaches) post-acquisition data mining techniques, which facilitate the drug metabolite identification. We have also discussed the importance of integrated data mining strategy. PMID- 28816068 TI - Survey of Diplomates of the American Board of Veterinary Toxicology Regarding Perceptions of the Value of This Certification. AB - An anonymous, online questionnaire was sent to active diplomates of the American Board of Veterinary Toxicology (DABVTs; n = 95) to determine the attitudes of veterinary toxicologists toward their ABVT certification and the adequacy of the training programs in this discipline. We gathered information related to demographics, educational and work history, and other specialty board membership. Ten questions sought the respondent's opinion related to the economic value of the specialty, whether workforce shortages for DABVT exist, and whether DABVTs should complete a residency or graduate program. Fifty-one (54%) DABVTs responded. Their mean age was 58 and most (88%) held a graduate degree. When respondents were asked to rate their level of agreement (strongly disagree = 1; strongly agree = 5), most (73%) agreed or strongly agreed (median = 4) that there was a shortage of DABVTs. Fourteen (27%) participants strongly disagreed that the ABVT certification was required for their position, while 15 (29%) strongly agreed with this statement (median = 3). Most respondents agreed that the ABVT certification has been critical to their career (median = 4), in addition to a financial benefit to being a DABVT (median = 4). Most (67%) participants strongly or somewhat disagreed that current training programs are adequate to meet the shortage of DABVT (median = 2). Our findings indicate there is concern about the number of DABVTs and the adequacy of training programs to meet this perceived need. These findings improve our understanding of current attitudes of DABVTs toward their specialty. PMID- 28816070 TI - Correction to: Rossi E, et al., "It's a gut feeling" - Escherichia coli biofilm formation in the gastrointestinal tract environment. PMID- 28816069 TI - Risk of nephrotoxicity among patients who received vancomycin. PMID- 28816071 TI - Do the physiological aging of the placenta and the changes in angiogenesis marker sFlt-1 and PlGF concentrations predispose patients to late-onset preeclampsia? AB - OBJECTIVE: Aging of the placenta is associated with natural processes that impair its functions. The processes are related to both oxidative stress exacerbation and the occurrence of higher concentrations of disordered angiogenesis markers. Both these types of processes are known to play roles in the development of preeclampsia. We attempted to show that natural ageing of the placenta can be one of the cofactors contributing to the development of late-onset preeclampsia. PATIENTS, MATERIALS AND METHODS: 159 pregnant patients were divided into four groups: Two of preeclampsia patients and two of patients with physiological pregnancies, depending on the gestational age. For each group, disordered angiogenesis markers sFlt-1 and PlGF before and after 34 weeks of gestation and in particular stages of gestation were analyzed. RESULTS: Lower PlGF and sFlt 1/PlGF ratio values were found in cases of late-onset preeclampsia. In physiological pregnancies, sFlt-1 values were observed to increase and PlGF values to decrease with gestational age. An association was shown to exist between disordered angiogenesis markers and gestational age both in preeclampsia and physiological pregnancies. CONCLUSIONS: (1) Analyses of disordered angiogenesis markers in early- and late-onset preeclampsia patients and patients with physiological pregnancies allow for a suggestion that natural "ageing of the placenta" and placental hypoperfusion lesions exacerbating with the advancing gestational age are some of the causes of late-onset preeclampsia. (2) Cases of early-onset preeclampsia are associated with more severe changes of disordered angiogenesis marker concentrations, which may be indicative of a more considerable impairment of placental perfusion in such patients. (3) In the course of the physiological pregnancy, there is a gradual increase in sFlt-1 and decrease in PlGF, which implies an elevated angiogenesis disorder that progresses with the gestational age. PMID- 28816072 TI - Calcium electroporation for treatment of cutaneous metastases; a randomized double-blinded phase II study, comparing the effect of calcium electroporation with electrochemotherapy. AB - BACKGROUND: Calcium electroporation is a novel anticancer treatment, which utilizes high voltage pulses to permeabilize cell membranes and expose the cell to supraphysiological doses of calcium. Preclinical studies on calcium electroporation have shown strikingly high tumor response with cell necrosis. Calcium electroporation builds on the treatment electrochemotherapy, where chemotherapeutic drugs, mostly bleomycin, are internalized by electroporation. This double-blinded randomized study compared calcium electroporation to electrochemotherapy in terms of objective response measured 6 months after treatment. METHODS: Seven patients with a total of 47 cutaneous metastases from breast cancer and malignant melanoma were included in the protocol. A total of 37 metastases were randomized and evaluated for response, another 10 metastases were used for biopsy. This was a non-inferiority trial and metastases were randomized individually in each patient to either intratumoral calcium or bleomycin followed by application of electric pulses to tumor site. All metastases were treated once, and after 6-months of follow-up, the randomization code was revealed. RESULTS: Objective response of calcium electroporation was 72% (13/18) with complete response in 66% (12/18). For electrochemotherapy, objective response was 84% (16/19) with complete response in 68% (13/19). There was no statistically significant difference between the two treatments (p = 0.5). After 1 year, only three out of 25 metastases had relapsed. Ulceration, itching and exudation were reported slightly more frequently in metastases treated with bleomycin, and hyperpigmentation was only seen in metastases treated with bleomycin. CONCLUSION: This study shows that calcium electroporation is feasible and effective in patients with cutaneous metastases. PMID- 28816073 TI - Overactive bladder treatment: application of methylene blue to improve the injection technique of onabotulinum toxin A. AB - OBJECTIVE: The aim of this study was to test the addition of methylene blue (MB) to onabotulinum toxin A (BTX-A) solution in overactive bladder (OAB) treatment, as a means of facilitating observation of the injection site and assessing the distribution of the drug under the bladder mucosa during injection. Pharmacological interactions between BTX-A and MB were also evaluated. MATERIALS AND METHODS: The study was conducted between December 2014 and April 2016 on 30 patients: six males and 24 females (median age 57.7, range 23-80 years) diagnosed with OAB, who qualified for intravesical BTX-A injection. Each received 100 IU of BTX-A (Botox(r); Allergan), dissolved in 9.5 ml of 0.9% NaCl with the addition of 0.5 ml of MB. Cystoscopy with submucosal injection of the solution was performed systematically, including the bladder triangle. For pharmacological evaluation, quantitative determination of MB was performed on a capillary electrophoresis system with diode array detection. RESULTS: In the course of 600 injections, the addition of MB facilitated the observation of the procedure; the exact distribution of the solution could not be observed in only 43 injections in seven patients. The range of distribution of the drug varied from 1 to 2.5 cm. Pharmacological evaluation based on visual observations and experiments showed that pharmaceutical interactions do not occur between MB and this commercially available formulation of BTX-A. CONCLUSIONS: Applying a coloured solution of BTX A significantly facilitates observation of the procedure and assessment of drug distribution. There are no pharmaceutical interactions between MB and BTX-A. PMID- 28816074 TI - Prostate-specific antigen after salvage radiotherapy for postprostatectomy biochemical recurrence predicts long-term outcome including overall survival. AB - BACKGROUND: For patients with recurrent prostate cancer after radical prostatectomy (RP), salvage radiotherapy (SRT) is a second chance of cure. However, depending on risk factors, 40-70% of the patients experience further progression. With a focus on the pre- and post-SRT serum level of the prostate specific antigen (PSA), we assessed the determinants of the long-term outcome after SRT. PATIENT AND METHODS: Between 1997 and 2011, 464 patients received 3D conformal SRT with median 66.6 Gy. The median PSA level before SRT was 0.31 ng/ml. In our retrospective analysis, post-SRT progression was defined as either a rising PSA >0.2 ng/ml above the nadir, or the application of anti-androgens or clinical recurrence. A PSA <0.1 ng/ml was termed undetectable. We analyzed the data with the Kaplan-Meier method (Logrank test) and multivariable Cox regression. RESULTS: The median follow-up was 5.9 years. Overall, 178 patients had recurrence, 13 developed distant metastases and 30 died. Univariate, a pre-RP PSA <10 ng/ml, pathological stage pT <3, Gleason score <8, positive surgical margins, a pre-SRT PSA <0.2 ng/ml and a post-SRT PSA nadir <0.1 ng/ml correlated with fewer and later second recurrences. In a multivariable Cox model, pT, Gleason score, margin status and pre-SRT PSA were significant covariates of progression. If the post-SRT PSA response was included in the regression analysis, then a nadir >=0.1 ng/ml was the strongest risk factor. Initiating SRT at a PSA <0.2 ng/ml correlated with a post-SRT PSA <0.1 ng/ml. Men who achieved an undetectable post-SRT PSA nadir also had lower rates of metastases and a better overall survival. However, there were too few events for Cox regression analysis of these two endpoints. CONCLUSIONS: Early SRT at a PSA <0.2 ng/ml correlates with re-achieving an undetectable PSA, which predicts improved freedom from progression and metastases and better overall survival. PMID- 28816075 TI - Psychological impact of female genital mutilation among adolescent Egyptian girls: a cross-sectional study. AB - OBJECTIVES: Worldwide, at least 200 million women and girls have undergone female genital mutilation (FGM). The medical and sexual consequences have been documented, but the psychological impact has not been studied to the same extent. The aim of this study was to explore the relationship between FGM and psychiatric problems among adolescent girls. METHODS: A total of 204 girls, aged 14-19 years, were included in a cross-sectional study conducted at Suez Canal University Hospitals. All participants completed an Arabic-validated, structured questionnaire covering nine symptom scales. Sociodemographic data were also collected. Main outcome measures were the prevalence of psychiatric problems among adolescent girls who had undergone FGM. RESULTS: Overall, 66.2% of girls had undergone FGM. The percentage in rural areas was 91.8%, compared with 43.0% in urban areas. There were no significant differences between the FGM and non-FGM groups as regards religion, educational and socioeconomic levels. FGM girls had a significantly higher level of psychological problems with regard to somatisation, depression, anxiety, phobic anxiety and hostility compared with non-FGM girls (p < .0001). CONCLUSIONS: FGM is a traumatic experience that may leave a lasting psychological mark and a negative impact on the psychological status of affected girls. PMID- 28816076 TI - Current drug and molecular therapies for the treatment of atrophic age-related macular degeneration: phase I to phase III clinical development. AB - INTRODUCTION: Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly. Atrophic AMD, including early, intermediate and geographic atrophy (GA), accounts for ~90% of all cases. It is a multifactorial degeneration characterized by chronic inflammation, oxidative stress and aging components. Although no FDA-approved treatment yet exists for the late stage of atrophic AMD, multiple pathological mechanisms are partially known and several promising therapies are in various stages of development. Areas covered: Underlying mechanisms that define atrophic AMD will help provide novel therapeutic targets that will address this largely unmet clinical need. The purpose of this paper is to review current promising drugs that are being evaluated in clinical trials. Because no pharmacological treatments are currently available for late stage of atrophic AMD, any new therapy would have extensive market potential. Expert opinion: The number of AMD patients is predicted to increase to ~30 million worldwide by 2020. In response to this enormous unmet clinical need, new promising therapies are being developed and evaluated in clinical trials. We propose that the assessment of novel interventions will also need to consider the genotypes of participants, as the benefit may be determined by polymorphisms in an individual's genetic background. PMID- 28816077 TI - In Vitro Evaluation of the Occlusive Properties of the ArtVentive Endoluminal Occlusion System Occlusion Device for Transrenal Ureteral Occlusion. AB - PURPOSE: Current techniques for percutaneous ureteral occlusion are either technically difficult or not satisfactory because of frequent ureteral recanalization. The purpose of this in vitro study was to evaluate the occlusive properties of an "off the shelf" solution (Endoluminal Occlusion System [EOSTM]; ArtVentive Medical Group, Inc., Carlsbad, CA) for transrenal ureteral occlusion. MATERIALS AND METHODS: Both 8 and 11 mm expanded polytetrafluoroethylene-covered ArtVentive EOS devices were used in 10 porcine models. Experiments were performed in explanted porcine ureters to simulate physiologic conditions. EOS devices were deployed in a midureteral position using a transrenal approach. Contrast agent (Iopamidol 300) diluted in saline solution was infused into the renal pelvis under continuous fluoroscopic guidance. Intrapelvic pressure measurements were performed until leakage, plug dislocation, or until pelvic blow out occurred. RESULTS: All EOS devices were deployed effectively and achieved prompt total ureteral occlusion. Ureteral leakage occurred with intraureteral pressures between 60 to 109 cm H2O (8 mm EOS) and between 65 and 125 cm H2O (11 mm EOS). Before leakage, tubular reflux was seen in all cases, pelvic blowout occurred in half of the cases. CONCLUSIONS: The ArtVentive EOS occlusive device is an effective tool for "off the shelf" ureteral occlusion. Both the 8 mm and the 11 mm devices fully occluded ureters at pressure levels that are to be expected in vivo. PMID- 28816078 TI - Pathobiology of Lp(a) in calcific aortic valve disease. AB - INTRODUCTION: Calcific aortic valve disease (CAVD) is the most prevalent heart valve disorder. Gene variant in the LPA gene, which encodes for apolipoprotein(a), has been associated at the genome-wide level with CAVD. The process whereby Lp(a) promotes the development of CAVD is under intensive investigation and recent data have shed important insights into disease biology. In this regard, autotaxin (ATX), a lysophospholipase D, interacts with Lp(a) and promotes the mineralization of the aortic valve. Areas covered: In this paper, we are reviewing the biology of Lp(a) and the latest discoveries about the molecular processes that link this lipoprotein with the development of CAVD including the role of ATX. Expert commentary: Elevated Lp(a) levels are genetically determined and considered as an important risk factor for CAVD. Understanding how Lp(a) promotes the development/progression of CAVD is crucial as it may hold promise for the development of new therapies. PMID- 28816079 TI - The applicability of the translated Edmonton Symptom Assessment System: revised [ESAS-r] in Swedish palliative care. PMID- 28816080 TI - An Australian survey of parent involvement in intervention for childhood speech sound disorders. AB - PURPOSE: To investigate how speech-language pathologists (SLPs) report involving parents in intervention for phonology-based speech sound disorders (SSDs), and to describe the home practice that they recommend. Further aims were to describe the training SLPs report providing to parents, to explore SLPs' beliefs and motivations for involving parents in intervention, and to determine whether SLPs' characteristics are associated with their self-reported practice. METHOD: An online survey of 288 SLPs working with SSD in Australia was conducted. RESULT: The majority of SLPs (96.4%) reported involving parents in intervention, most commonly in providing home practice. On average, these tasks were recommended to be completed five times per week for 10 min. SLPs reported training parents using a range of training methods, most commonly providing opportunities for parents to observe the SLP conduct the intervention. SLPs' place of work and years of experience were associated with how they involved and trained parents in intervention. Most (95.8%) SLPs agreed or strongly agreed that family involvement is essential for intervention to be effective. CONCLUSION: Parent involvement and home practice appear to be intricately linked within intervention for phonology based SSDs in Australia. More high-quality research is needed to understand how to best involve parents within clinical practice. PMID- 28816081 TI - Correlates of poor treatment outcomes in patients with multi-drug resistant tuberculosis in a tertiary centre in Rivers State. PMID- 28816082 TI - Zeaxanthin dipalmitate alleviates hepatic injury induced by superimposed chronic hepatitis B and non-alcoholic steatohepatitis in non-obese mice. AB - A hepatitis B virus (HBV) transgenic mice model was used to establish the fatty liver superimposed model by feeding the methionine choline-deficient (MCD) diet for 8 weeks, with or without the gavage of 2 mg/kg zeaxanthin dipalmitate (ZD) three times per week. Both wild-type and HBV transgenic mice, with MCD diet, gained typical non-obese non-alcoholic steatohepatitis (NASH) and HBV symptoms. Coadministration with ZD exhibited evident therapeutic effects through alleviating those pathological events. Moreover, long-term vehicle-ZD treatment was found to be safe. Thus, ZD is a promising and safe hepato-protective agent against hepatic injury induced by superimposed HBV and NASH in non-obese mice. PMID- 28816083 TI - Screening for adverse perinatal outcomes: uterine artery Doppler, cerebroplacental ratio and estimated fetal weight in low-risk women at term. AB - OBJECTIVE: To stratify apparently low-risk pregnant women into those who are at risk of adverse perinatal outcomes. Appropriate stratification would allow targeted prenatal and intrapartum management. METHODS: This prospective, observational study included normotensive women with appropriately grown, non anomalous, singleton pregnancies. Participants underwent fortnightly ultrasounds from 36 weeks' gestation and intrapartum and neonatal outcomes were recorded. The association between uterine artery pulsatility index (UtA-PI), the cerebroplacental ratio (CPR) and estimated fetal weight (EFW) were explored along with their screening performance for CS-IFC and CNM. RESULTS: The final cohort included 429 women. As continuous variables, UtA-PI and the CPR were not correlated (rho = -0.05, p = .33). UtA-PI >95th centile and the CPR <10th centile were predictive of CS-IFC and CNM, with the highest sensitivity achieved by their combination (33.3%, 95% CI 11.6-55.1) for a false positive rate (FPR) of 15.8% (12.3-19.3). For CNM, the highest sensitivity (28.4%, 95% CI 18.6-38.2) and corresponding FPR (17.0%, 95% CI 13.0-20.9) was achieved by combining UtA-PI 95th centile, the CPR 10th centile and EFW 10th centile. EFW was the weakest of the three predictors. CONCLUSION: In this population, UtA-PI 95th centile and the CPR 10th centile have modest screening performance for CS-IFC and CNM. PMID- 28816085 TI - Dynamics of a vertical-flow windrow vermicomposting system. AB - Large-scale vermicomposting under outdoor conditions may differ from small-scale procedures in the laboratory. The present study evaluated changes in selected properties of a large-scale vertical-flow windrow vermicomposting system with continuous feeding with household biowaste. The windrow profile was divided into five layers of differing thickness and age after more than 12 months of vermicomposting. The top layer (0-30 cm, age <3 months) was characterised by partially decomposed organic matter with a high pH value and an elevated carbon/nitrogen (C/N) ratio. The earthworm biomass was 15 g kg-1 with a population density of 125 earthworms per kilogram predominantly found in clusters. The greatest amount of fungi (3.5 ug g-1 dw) and bacteria (62 ug g-1 dw) (expressed as phospholipid fatty acid analysis) was found in this layer. Thus, the top layer could be used for an additional cycle of windrow vermicomposting and for the preparation of aqueous extracts to protect plants against diseases. The lower layers (graduated by 30 cm and by 3 months of age) were mature as reflected by the low content of ammonia nitrogen, ratio of ammonia to nitrate nitrogen and dissolved organic carbon, and high ion-exchange capacity and its ratio to carbon. These layers were characterised by elevated values for electrical conductivity, total content of nutrients, available magnesium content, and a relatively large bacterial/fungal ratio. On the basis of the observed properties, the bottom layers were predetermined as effective fertilisers. PMID- 28816084 TI - Adenoviral Type 35 and 26 Vectors with a Bidirectional Expression Cassette in the E1 Region Show an Improved Genetic Stability Profile and Potent Transgene Specific Immune Response. AB - Genetic vaccines based on replication-incompetent adenoviral (AdV) vectors are currently in clinical development. Monovalent AdV vectors express one antigen from an expression cassette placed in most cases in the E1 region. For many vaccines, inclusion of several antigens is necessary in order to raise protective immunity and/or target more than one pathogen or pathogen strain. On the basis of the current technology, a mix of several monovalent vectors can be employed. However, a mix of the standard monovalent AdV vectors may not be optimal with respect to manufacturing costs and the final dose per vector in humans. Alternatively, a variety of bivalent recombinant AdV vector approaches is described in the literature. It remains unclear whether all strategies are equally suitable for clinical development while preserving all the beneficial properties of the monovalent AdV (e.g., immunogenic potency). Therefore, a thorough assessment of different bivalent AdV strategies was performed in a head to-head fashion compared with the monovalent benchmark. The vectors were tested for rescue efficiency, genetic stability, transgene expression, and potency to induce transgene-specific immune responses. We report that the vector expressing multiple antigens from a bidirectional expression cassette in E1 shows a better genetic stability profile and a potent transgene-specific immune response compared with the other tested bivalent vectors. PMID- 28816086 TI - Inducible Knockout of Mouse Zfhx3 Emphasizes Its Key Role in Setting the Pace and Amplitude of the Adult Circadian Clock. AB - The transcription factor zinc finger homeobox 3 (ZFHX3) plays a key role in coupling intracellular transcriptional-translational oscillations with intercellular synchrony in mouse suprachiasmatic nucleus (SCN). However, like many key players in central nervous system function, ZFHX3 serves an important role in neurulation and neuronal terminal differentiation while retaining discrete additional functions in the adult SCN. Recently, using a dominant missense mutation in mouse Zfhx3, we established that this gene can modify circadian period and sleep in adult animals. Nevertheless, we were still concerned that the neurodevelopmental consequences of ZFHX3 dysfunction in this mutant may interfere with, or confound, its critical adult-specific roles in SCN circadian function. To circumvent the developmental consequences of Zfhx3 deletion, we crossed a conditional null Zfhx3 mutant to an inducible, ubiquitously expressed Cre line (B6.Cg-Tg(UBC-cre/ERT2)1Ejb/J). This enabled us to assess circadian behavior in the same adult animals both before and after Cre mediated excision of the critical Zfhx3 exons using tamoxifen treatment. Remarkably, we found a strong and significant alteration in circadian behavior in tamoxifen-treated homozygous animals with no phenotypic changes in heterozygous or control animals. Cre-mediated excision of Zfhx3 critical exons in adult animals resulted in shortening of the period of wheel-running in constant darkness by more than 1 h in the majority of homozygotes while, in 30% of animals, excision resulted in complete behavioral arrhythmicity. In addition, we found that homozygous animals reentrain almost immediately to 6-h phase advances in the light-dark cycle. No additional overt phenotypic changes were evident in treated homozygous animals. These findings confirm a sustained and significant role for ZFHX3 in maintaining rhythmicity in the adult mammalian circadian system. PMID- 28816087 TI - Small diameter vascular graft with fibroblast cells and electrospun poly (L lactide-co-epsilon-caprolactone) scaffolds: Cell Matrix Engineering. AB - Electrospun scaffolds have been widely used in tissue engineering due to their similar structure to native extracellular matrices (ECM). However, one of the obstacles limiting the application of electrospun scaffolds for tissue engineering is the nano-sized pores, which inhibit cell infiltration into the scaffolds. To overcome this limitation, we approached to make layers which are consisted of cells onto the electrospun sheet and then tubular structure was constructed by rolling. We called this as 'Cell Matrix Engineering' because the electrospun sheets were combined with the cells to form one matrix. They maintained 3-D tubular structures well and their diameters were 4.1 mm (+/-0.1 mm). We compared the mechanical and biological properties of various vascular grafts with the electrospun PLCL sheets of different thickness. In these experiments, the vascular graft made with thin sheets showed a better cell proliferation and attachment than the grafts made with thick sheets because the thin layer allowed for more efficient mass transfer and better permeability than the thick layer. Culturing under physiological pulsatile flow condition was demonstrated in this work. These dynamic conditions provided the improved mass transport and aerobic cell metabolism. Therefore, the Cell Matrix Engineered vascular graft holds a great promise for clinical applications by overcoming the limitations associated with conventional scaffolds. PMID- 28816088 TI - New biomarker stars for traumatic brain injury. PMID- 28816089 TI - Medusa's Head: The Complement System in Traumatic Brain and Spinal Cord Injury. AB - Traumatic brain injury (TBI) and spinal cord injury (SCI) are critical medical conditions and a public health problem for which limited therapeutic options are available. The complement cascade is activated after TBI and SCI, and the resulting effects have been investigated in gene-knockout and pharmacological models. Multiple experimental studies support a net detrimental role of C3 and C5 activation in the early stages of TBI and SCI. Less firm experimental evidence suggests that, downstream of C3/C5, effector mechanisms, including the generation of membrane-activated complex and direct damage to membranes and neutrophils infiltration, may bring about the direct damage of central nervous system tissue and enhancement of neuroinflammation. The role of upstream classical, alternative, or extrinsic complement activation cascades remains unclear. Although several issues remain to be investigated, current evidence supports the investigation of a number of complement-targeting agents targeting C3 or C5, such as eculizumab, for repurposing in TBI and SCI treatment. PMID- 28816090 TI - Hypoglycemic episodes in cats with diabetes mellitus: 30 cases (2013-2015). AB - Objectives The purpose of this study was to review the characteristics of diabetic cats presenting to a specialty and emergency center for signs attributed to hypoglycemia and to identify the factors that may have contributed to the hypoglycemic episode, the patient's clinical signs and laboratory findings, and the response of hypoglycemic cats to therapy. Methods Twenty-eight cats were presented a total of 30 times for symptomatic hypoglycemia. Data were collected from cat owners at the time of presentation and from subsequent patient records. Results The majority of cats presented for neurologic signs attributed to the reduced ingestion or subsequent vomiting of a meal after insulin had been administered or the accidental double-dosing of insulin. Concurrent illnesses that may have affected insulin requirements were also common. Conclusions and relevance Cats that demonstrated clinical improvement within 12 h of treatment were more likely to recover despite their mental status and glucose level on presentation. PMID- 28816091 TI - Mobile three-dimensional visualisation technologies for clinician-led fall prevention assessments. AB - The assistive equipment provision process is routinely carried out with patients to mitigate fall risk factors via the fitment of assistive equipment within the home. However, currently, over 50% of assistive equipment is abandoned by the patients due to poor fit between the patient and the assistive equipment. This paper explores clinician perceptions of an early stage three-dimensional measurement aid prototype, which provides enhanced assistive equipment provision process guidance to clinicians. Ten occupational therapists trialled the three dimensional measurement aid prototype application; think-aloud and semi structured interview data was collected. Usability was measured with the System Usability Scale. Participants scored three-dimensional measurement aid prototype as 'excellent' and agreed strongly with items relating to the usability and learnability of the application. The qualitative analysis identified opportunities for improving existing practice, including, improved interpretation/recording measurements; enhanced collaborative practice within the assistive equipment provision process. Future research is needed to determine the clinical utility of this application compared with two-dimensional counterpart paper-based guidance leaflets. PMID- 28816092 TI - Attitudes towards science among Spanish citizens: The case of critical engagers. AB - Using data obtained from Spanish surveys on the public perception of science, this article presents a critical review of current practices of population profile segmentation, including the one-dimensional representation of perceived risks and benefits and of the systematic underestimation of critical attitudes to the social impact of science and technology. We use discriminant analysis to detect a somewhat hidden cluster in the Spanish population which we call 'critical engagers'. These individuals are critically and socially responsible and are not reticent about expressing concern regarding scientific-technological change. While they hold an overall positive attitude towards change of this kind, they are at the same time well aware of the risks posed by particular fields of application. We highlight the academic interest and political value of these individuals, attributing to this population a mature and intelligent stance which may well be employed in enhancing the relationship between science and society. PMID- 28816093 TI - Vascular complications following intra-aortic balloon pump implantation: an updated review. AB - BACKGROUND: The use of the intra-aortic balloon pump (IABP) as a support device remains controversial due to the fact that a number of studies have shown no benefit in end mortality whilst using this device. One of the reasons for this could be the increase in vascular complications when using the pump. Therefore, the aim of the present review was to assess the current literature available with regards to IABP vascular complications during the clinical situation. METHODS: A literature search was performed, searching for IABP complications in adult human studies between 1990 and 2016. RESULTS: A total of 20 reports were identified as fitting the criteria of this study. The majority of vascular complications were limb ischemia, bleeding or mesenteric ischemia. The overall incidence of vascular complications ranged from 0.94% to 31.1%. Diabetes, peripheral vascular disease and hypertension, as well as smoking were all identified as risk factors for complications following IABP. Furthermore, studies supported the use of sheathless balloon insertion to reduce the risk of complications. CONCLUSION: Major vascular complications, including limb and mesenteric ischemia as well as bleeding and hemorrhage, have been associated with IABP. However, the incidence of these complications was generally low. Further studies are still required to truly understand the risk/benefit associated with the use of IABP. PMID- 28816094 TI - Theories of Health Care Decision Making at the End of Life: A Meta-Ethnography. AB - The aim of this meta-ethnography is to appraise the types and uses of theories relative to end-of-life decision making and to develop a conceptual framework to describe end-of-life decision making among patients with advanced cancers, heart failure, and amyotrophic lateral sclerosis (ALS) and their caregivers or providers. We used PubMed, Embase, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases to extract English-language articles published between January 2002 and April 2015. Forty-three articles were included. The most common theories included decision-making models ( n = 14) followed by family-centered ( n = 11) and behavioral change models ( n = 7). A conceptual framework was developed using themes including context of decision making, communication and negotiation of decision making, characteristics of decision makers, goals of decision making, options and alternatives, and outcomes. Future research should enhance and apply these theories to guide research to develop patient-centered decision-making programs that facilitate informed and shared decision making at the end of life among patients with advanced illness and their caregivers. PMID- 28816096 TI - Management of severe pulmonary hemorrhage in a neonate on veno-arterial ECMO by the temporary clamping of the endotracheal tube - a case report. AB - Severe pulmonary hemorrhage in the newborn is an infrequent, but life threatening, event. A newborn with persistent pulmonary hypertension and a large persistent ductus arteriosus and open foramen ovale presented with hypoxemia and progressive right heart failure shortly after birth, requiring veno-arterial extracorporeal membrane oxygenation (ECMO) support. Twenty minutes after the initiation of ECMO, the patient developed severe pulmonary hemorrhage refractory to conventional treatment. As a last resort, the endotracheal tube was clamped. After transport to the ECMO center, repeated attempts to open the endotracheal tube resulted in continued blood loss and the endotracheal tube was clamped for a total of 63 hours without any mechanical ventilation. On the third postnatal day, the endotracheal tube was reopened, large amounts of clot were removed by bronchoscopy and mechanical ventilation was resumed followed by improved general condition and favorable outcome. PMID- 28816098 TI - Global fluctuations of cerebral blood flow indicate a global brain network independent of systemic factors. AB - Global synchronization across specialized brain networks is a common feature of network models and in-vivo electrical measurements. Although the imaging of specialized brain networks with blood oxygenation sensitive resting state functional magnetic resonance imaging (rsfMRI) has enabled detailed study of regional networks, the study of globally correlated fluctuations with rsfMRI is confounded by spurious contributions to the global signal from systemic physiologic factors and other noise sources. Here we use an alternative rsfMRI method, arterial spin labeled perfusion MRI, to characterize global correlations and their relationship to correlations and anti-correlations between regional networks. Global fluctuations that cannot be explained by systemic factors dominate the fluctuations in cerebral blood flow. Power spectra of these fluctuations are band limited to below 0.05 Hz, similar to prior measurements of regional network fluctuations in the brain. Removal of these global fluctuations prior to measurement of regional networks reduces all regional network fluctuation amplitudes to below the global fluctuation amplitude and changes the strength and sign of inter network correlations. Our findings support large amplitude, globally synchronized activity across networks that require a reassessment of regional network amplitude and correlation measures. PMID- 28816097 TI - * Meltblown Polymer Fabrics as Candidate Scaffolds for Rotator Cuff Tendon Tissue Engineering. AB - Various biomaterial technologies are promising for tissue engineering, including electrospinning, but commercial scale-up of throughput is difficult. The goal of the study was to evaluate meltblown fabrics as candidate scaffolds for rotator cuff tendon tissue engineering. Meltblown poly(lactic acid) fabrics were produced with several polymer crystallinities and airflow velocities [500(low), 900(medium) or 1400(high) m3air/h/m fabric]. Fiber diameter, alignment, and baseline bidirectional tensile mechanical properties were evaluated. Attachment and spreading of human adipose-derived stem cells (hASCs) were evaluated over 3 days immediately following seeding. After initial screening, the fabric with the greatest Young's modulus and yield stress was selected for 28-day in vitro culture and for evaluation of tendon-like extracellular matrix production and development of mechanical properties. As expected, airflow velocity of the polymer during meltblowing demonstrated an inverse relationship with fiber diameter. All fabrics exhibited fiber alignment parallel to the direction of collector rotation. All fabrics demonstrated mechanical anisotropy at baseline. Cells attached, proliferated, and spread on all fabrics over the initial three day culture period. Consistent with the observed loss of integrity of the unseeded biomaterial, hASC-seeded scaffolds demonstrated a significant decrease in Young's modulus over 28 days of culture. However, dsDNA, sulfated glycosaminoglycan, and collagen content increased significantly over 28 days. Histology and polarized light microscopy demonstrated collagen deposition and alignment throughout the thickness of the scaffolds. While fiber diameters approximated an order of magnitude greater than those previously reported for electrospun scaffolds intended for tendon tissue engineering, they were still within the range of collagen fiber diameters found in healthy tendon. The extent of matrix production and alignment was similar to that previously observed for multilayered electrospun scaffolds. While the Young's modulus of scaffolds after 28 days of culture was lower than native rotator cuff tendon, it approximated that reported previously following culture of electrospun scaffolds and was on the same order of magnitude as of current Food and Drug Administration-approved patches for rotator cuff augmentation. Together, these data suggest that with minor polymer and parameter modifications, meltblown scaffolds could provide an economical, high-throughput production alternative method to electrospinning for use in rotator cuff tendon tissue engineering. PMID- 28816099 TI - Sex differences of steroid receptor coactivator-1 expression after spinal cord injury in mice. AB - OBJECTIVE: The neural functional recovery of female is often better than that of male after spinal cord injury (SCI). Evidences show that estrogen can attenuate inflammation and promote the neural survival and regeneration after SCI. SRC-1 is an essential initiation factor for the estrogen-regulated target gene transcription and plays a key role in regulating estrogen activity. However, it is not known whether and how SRC-1 mediates the neural regeneration promoted by estrogen after SCI. Study of the sex differences and changes of SRC-1 expression after SCI will be helpful to understand the above questions. METHODS: In this study, the sex differences of expressions of SRC-1 and cytoskeleton-associated protein Profilin-1 in normal and SCI mice were detected by immunohistochemistry at 1-, 3-, and 7 days after injury, respectively. RESULTS: Although the SRC-1 expression in female mice was lower than that in males under normal conditions, its expression in females was more dominant after SCI. The expression of Profilin 1 in both sexes increased first, and then decreased at 3 days after injury. However, there was a second increase in females at 7 days after injury. CONCLUSION: Our study suggests that the more SRC-1 expression in females after SCI may play a role in improving the efficiency of estrogen function and thus, promote regeneration better. SRC-1 may also participate in the regulation of Profilin-1 in spinal cord, which is important in the assembly and extension of the axonal cytoskeleton during regeneration after SCI. PMID- 28816095 TI - New astroglial injury-defined biomarkers for neurotrauma assessment. AB - Traumatic brain injury (TBI) is an expanding public health epidemic with pathophysiology that is difficult to diagnose and thus treat. TBI biomarkers should assess patients across severities and reveal pathophysiology, but currently, their kinetics and specificity are unclear. No single ideal TBI biomarker exists. We identified new candidates from a TBI CSF proteome by selecting trauma-released, astrocyte-enriched proteins including aldolase C (ALDOC), its 38kD breakdown product (BDP), brain lipid binding protein (BLBP), astrocytic phosphoprotein (PEA15), glutamine synthetase (GS) and new 18-25kD-GFAP BDPs. Their levels increased over four orders of magnitude in severe TBI CSF. First post-injury week, ALDOC levels were markedly high and stable. Short-lived BLBP and PEA15 related to injury progression. ALDOC, BLBP and PEA15 appeared hyper-acutely and were similarly robust in severe and mild TBI blood; 25kD-GFAP BDP appeared overnight after TBI and was rarely present after mild TBI. Using a human culture trauma model, we investigated biomarker kinetics. Wounded (mechanoporated) astrocytes released ALDOC, BLBP and PEA15 acutely. Delayed cell death corresponded with GFAP release and proteolysis into small GFAP-BDPs. Associating biomarkers with cellular injury stages produced astroglial injury defined (AID) biomarkers that facilitate TBI assessment, as neurological deficits are rooted not only in death of CNS cells, but also in their functional compromise. PMID- 28816100 TI - Young people's attitudes towards illicit drugs: A population-based study. AB - AIMS: Previous studies indicate that young people who have positive attitudes towards illicit drugs are more inclined to experiment with them. The first aim of our study was to identify the sociodemographic and risk behaviour characteristics of young people (16-24 years) with positive attitudes towards illicit drug use. The second aim was to identify the characteristics of young people with positive attitudes towards illicit drugs among those who had never tried drugs, those who had tried cannabis but no other illicit drugs, and those who regularly used cannabis and/or had tried other illicit drugs. METHODS: The analysis was based on a population-based survey from 2013 ( N = 3812). Multiple logistic regression was used to analyse the association between sociodemographic and risk behaviour characteristics and positive attitudes towards illicit drugs. RESULTS: Young men had twice the odds of having positive attitudes towards illicit drug use compared with young women (AOR = 2.1). Also, young age, being single, being employed, smoking tobacco, practising unprotected sex, and experimental cannabis use were associated with positive attitudes towards illicit drug use. Finally, use of cannabis at least 10 times during the previous year and/or use of other illicit drugs had the strongest association with positive attitudes to illicit drug use (AOR = 6.0). CONCLUSIONS: Young people who have positive attitudes towards illicit drug use are characterized by a broad range of risky behaviours. These findings may help to identify young people at risk of initiating illicit drug use and thereby support the development and implementation of prevention programmes. PMID- 28816101 TI - Measurement of total hemoglobin reduces red cell transfusion in hospitalized patients undergoing cardiac surgery: a retrospective database analysis. AB - INTRODUCTION: Historically, perioperative hemoglobin monitoring has relied on calculated saturation, using blood gas devices that measure plasma hematocrit (Hct). Co-oximetry, which measures total hemoglobin (tHb), yields a more comprehensive assessment of hemodilution. The purpose of this study was to examine the association of tHb measurement by co-oximetry and Hct, using conductivity with red blood cell (RBC) transfusion, length of stay (LOS) and inpatient costs in patients having major cardiac surgery. METHODS: A retrospective study was conducted on patients who underwent coronary artery bypass graft (CABG) and/or valve replacement (VR) procedures from January 2014 to June 2016, using MedAssets discharge data. The patient population was sub-divided by the measurement modality (tHb and Hct), using detailed billing records and Current Procedural Terminology coding. Cost was calculated using hospital specific cost-to-charge ratios. Multivariable logistic regression was performed to identify significant drivers of RBC transfusion and resource utilization. RESULTS: The study population included 18,169 cardiovascular surgery patients. Hct-monitored patients accounted for 66% of the population and were more likely to have dual CABG and VR procedures (10.4% vs 8.9%, p=0.0069). After controlling for patient and hospital characteristics, as well as patient comorbidities, Hct monitored patients had significantly higher RBC transfusion risk (OR=1.26, CI 1.15-1.38, p<0.0001), longer LOS (IRR=1.08, p<0.0001) and higher costs (IRR=1.15, p<0.0001) than tHb-monitored patients. RBC transfusions were a significant driver of LOS (IRR=1.25, p<0.0001) and cost (IRR=1.22, p<0.0001). CONCLUSIONS: tHb monitoring during cardiovascular surgery could offer a significant reduction in RBC transfusion, length of stay and hospital cost compared to Hct monitoring. PMID- 28816102 TI - Hydrodenticity to enhance relaxivity of gadolinium-DTPA within crosslinked hyaluronic acid nanoparticles. AB - AIM: The efficacy of gadolinium (Gd) chelates as contrast agents for magnetic resonance imaging remains limited owing to poor relaxivity and toxic effects. Here, the effect of the hydration of the hydrogel structure on the relaxometric properties of Gd-DTPA is explained for the first time and called Hydrodenticity. RESULTS: The ability to tune the hydrogel structure is proved through a microfluidic flow-focusing approach able to produce crosslinked hyaluronic acid nanoparticles, analyzed regarding the crosslink density and mesh size, and connected to the characteristic correlation times of the Gd-DTPA. CONCLUSION: Hydrodenticity explains the boosting (12-times) of the Gd-DTPA relaxivity by tuning hydrogel structural parameters, potentially enabling the reduction of the administration dosage as approved for clinical use. [Formula: see text]. PMID- 28816103 TI - Assessment of work-related accidents associated with waste handling in Belo Horizonte (Brazil). AB - As more urban solid waste is generated, managing it becomes ever more challenging and the potential impacts on the environment and human health also become greater. Handling waste - including collection, treatment and final disposal - entails risks of work accidents. This article assesses the perception of waste management workers regarding work-related accidents in domestic and health service contexts in Belo Horizonte, Brazil. These perceptions are compared with national data from the Ministry of Social Security on accidents involving workers in solid waste management. A high proportion of accidents involves cuts and puncture injuries; 53.9% among workers exposed to domestic waste and 75% among those exposed to health service waste. Muscular lesions and fractures accounted for 25.7% and 12.5% of accidents, respectively. Data from the Ministry of Social Security diverge from the local survey results, presumably owing to under reporting, which is frequent in this sector. Greater commitment is needed from managers and supervisory entities to ensure that effective measures are taken to protect workers' health and quality of life. Moreover, workers should defend their right to demand an accurate registry of accidents to complement monitoring performed by health professionals trained in risk identification. This would contribute to the improved recovery of injured workers and would require managers in waste management to prepare effective preventive action. PMID- 28816104 TI - The Immune Response to Allogeneic Differentiated Mesenchymal Stem Cells in the Context of Bone Tissue Engineering. AB - The use of allogeneic differentiated mesenchymal stem cells (MSCs) to mediate bone formation may be a potential alternative to the current gold standards of bone repair. Although it is known that undifferentiated MSCs are immunomodulatory and weakly immunogenic, the host immune reaction to differentiated MSCs is less known. Implantation of allogeneic osteogenic or chondrogenically differentiated MSC pellets may be a promising route to induce bone repair via the processes of intramembranous and endochondral ossification. This review summarizes the current literature surrounding the immune response to these allogeneic differentiated stem cells in the context of bone repair and replacement. Although there have been great developments in researching the effects of allogeneic differentiated cells on the host immune system, lack of standardized preclinical assays has limited their progression to the clinics. Future investigations are required to identify the host immune cells having a positive or negative effect on bone formation mediated by these allogeneic differentiated MSCs to move the use of these cells toward future clinical bone repair therapies. PMID- 28816105 TI - Thiazolidinedione drugs in the treatment of type 2 diabetes mellitus: past, present and future. AB - Thiazolidinedione (TZD) drugs used in the treatment of type 2 diabetes mellitus (T2DM) have proven effective in improving insulin sensitivity, hyperglycemia, and lipid metabolism. Though well tolerated by some patients, their mechanism of action as ligands of peroxisome proliferator-activated receptors (PPARs) results in the activation of several pathways in addition to those responsible for glycemic control and lipid homeostasis. These pathways, which include those related to inflammation, bone formation, and cell proliferation, may lead to adverse health outcomes. As treatment with TZDs has been associated with adverse hepatic, cardiovascular, osteological, and carcinogenic events in some studies, the role of TZDs in the treatment of T2DM continues to be debated. At the same time, new therapeutic roles for TZDs are being investigated, with new forms and isoforms currently in the pre-clinical phase for use in the prevention and treatment of some cancers, inflammatory diseases, and other conditions. The aims of this review are to provide an overview of the mechanism(s) of action of TZDs, a review of their safety for use in the treatment of T2DM, and a perspective on their current and future therapeutic roles. PMID- 28816106 TI - Winner of the Annals of Science Prize for 2016. PMID- 28816108 TI - EDITORIAL: Radiopharmaceuticals for Cancer Therapy and Diagnosis. PMID- 28816107 TI - Fishing Anti-Inflammatories from Known Drugs: In Silico Repurposing, Design, Synthesis and Biological Evaluation of Bisacodyl Analogues. AB - Herein is described in silico repositioning, design, synthesis, biological evaluation and structure-activity relationship (SAR) of an original class of anti inflammatory agents based on a polyaromatic pharmacophore structurally related to bisacodyl (BSL) drug used in therapeutic as laxative. We describe the potential of TOMOCOMD-CARDD methods to find out new anti-inflammatory drug-like agents from a diverse series of compounds using the total and local atom based bilinear indices as molecular descriptors. The models obtained were validated by biological studies, identifying BSL as the first anti-inflammatory lead-like using in silico repurposing from commercially available drugs. Several biological in vitro and in vivo assays were performed in order to understand its mechanism of action. A set of analogues of BSL was prepared using low-cost synthetic procedures and further biologically investigated in zebrafish models. Compound 5c and 7e exhibited the best antiinflammatory activities and represent new promising anti-inflammatory agents for further preclinical development. PMID- 28816109 TI - Assessing the validity of commercial and municipal food environment data sets in Vancouver, Canada. AB - OBJECTIVE: The present study assessed systematic bias and the effects of data set error on the validity of food environment measures in two municipal and two commercial secondary data sets. DESIGN: Sensitivity, positive predictive value (PPV) and concordance were calculated by comparing two municipal and two commercial secondary data sets with ground-truthed data collected within 800 m buffers surrounding twenty-six schools. Logistic regression examined associations of sensitivity and PPV with commercial density and neighbourhood socio-economic deprivation. Kendall's tau estimated correlations between density and proximity of food outlets near schools constructed with secondary data sets v. ground truthed data. SETTING: Vancouver, Canada. SUBJECTS: Food retailers located within 800 m of twenty-six schools RESULTS: All data sets scored relatively poorly across validity measures, although, overall, municipal data sets had higher levels of validity than did commercial data sets. Food outlets were more likely to be missing from municipal health inspections lists and commercial data sets in neighbourhoods with higher commercial density. Still, both proximity and density measures constructed from all secondary data sets were highly correlated (Kendall's tau>0.70) with measures constructed from ground-truthed data. CONCLUSIONS: Despite relatively low levels of validity in all secondary data sets examined, food environment measures constructed from secondary data sets remained highly correlated with ground-truthed data. Findings suggest that secondary data sets can be used to measure the food environment, although estimates should be treated with caution in areas with high commercial density. PMID- 28816110 TI - Reduced beta-amyloid sensitivity for platelet-monocyte aggregates in EDTA blood of alzheimer patients. AB - Alzheimer's disease (AD) is a severe neurodegenerative brain disorder characterized by beta-amyloid plaques, Tau pathology, inflammation, neurodegeneration, and cerebrovascular dysfunction. Besides that, alterations in monocytes and platelets have been reported in the blood of Alzheimer patients. In the present study, we measured circulating levels of platelet-monocyte aggregates in EDTA blood of cognitively healthy participants and 40 AD patients, and examined their changes induced by stimulation with beta-amyloid peptides. We measured CD14, CD62P, and CD42a using fluorescence-activated cell scanning (FACS) analysis. Our data show that the levels of circulating monocyte-platelet aggregates were not different between healthy controls and AD patients. However, incubation with beta-amyloid-40, -42, and pyroglutamate-beta-amyloid increased the platelet-monocyte aggregation in healthy subjects, but not AD patients. Our data conclude that the interaction between monocytes and platelets is not altered in whole blood of AD patients, but their sensitivity toward beta-amyloid peptides is decreased. There might be a critical link between the interaction of platelets and monocytes in AD, which has to be explored in further studies. PMID- 28816111 TI - Updated 2014 STOPP criteria to identify potentially inappropriate prescribing in community-dwelling elderly patients?. AB - OBJECTIVE: To analyze potentially inappropriate prescribing (PIP) using the 2014 version of STOPP criteria. MATERIALS AND METHODS: Prescriptions were analyzed by using invoicing data and electronic medical records. RESULTS: At least one STOPP criterion was observed in 9 out of every 10 patients. The most common STOPP criteria found were: "any drug prescribed without an evidence-based clinical indication" and "any drug prescribed beyond the recommended duration, where treatment duration is well defined". CONCLUSION: The high prevalence of PIP found seems to be due to the inclusion of new criteria related to indication of medication and duration of treatments.?. PMID- 28816112 TI - Toxoplasmosis of the pituitary gland. PMID- 28816113 TI - Pointing the way to primary prevention of dementia. PMID- 28816114 TI - Low risk of ischaemic stroke in hyperhomocysteinaemia. PMID- 28816115 TI - Corrections. PMID- 28816116 TI - Seth Oliveria. PMID- 28816117 TI - The first report of Alzheimer's disease. PMID- 28816118 TI - Paroxysmal sympathetic hyperactivity: the storm after acute brain injury. AB - A substantial minority of patients who survive an acquired brain injury develop a state of sympathetic hyperactivity that can persist for weeks or months, consisting of periodic episodes of increased heart rate and blood pressure, sweating, hyperthermia, and motor posturing, often in response to external stimuli. The unifying term for the syndrome-paroxysmal sympathetic hyperactivity (PSH)-and clear diagnostic criteria defined by expert consensus were only recently established. PSH has predominantly been described after traumatic brain injury (TBI), in which it is associated with worse outcomes. The pathophysiology of the condition is not completely understood, although most researchers consider it to be a disconnection syndrome with paroxysms driven by a loss of inhibitory control over excitatory autonomic centres. Although therapeutic strategies to alleviate sympathetic outbursts have been proposed, their effects on PSH are inconsistent between patients and their influence on outcome is unknown. Combinations of drugs are frequently used and are chosen on the basis of local custom, rather than on objective evidence. New rigorous tools for diagnosis could allow better characterisation of PSH to enable stratification of patients for future therapeutic trials. PMID- 28816119 TI - Clinical presentation and management of dyskinetic cerebral palsy. AB - Cerebral palsy is the most frequent cause of severe physical disability in childhood. Dyskinetic cerebral palsy (DCP) is the second most common type of cerebral palsy after spastic forms. DCP is typically caused by non-progressive lesions to the basal ganglia or thalamus, or both, and is characterised by abnormal postures or movements associated with impaired tone regulation or movement coordination. In DCP, two major movement disorders, dystonia and choreoathetosis, are present together most of the time. Dystonia is often more pronounced and severe than choreoathetosis, with a major effect on daily activity, quality of life, and societal participation. The pathophysiology of both movement disorders is largely unknown. Some emerging hypotheses are an imbalance between indirect and direct basal ganglia pathways, disturbed sensory processing, and impaired plasticity in the basal ganglia. Rehabilitation strategies are typically multidisciplinary. Use of oral drugs to provide symptomatic relief of the movement disorders is limited by adverse effects and the scarcity of evidence that the drugs are effective. Neuromodulation interventions, such as intrathecal baclofen and deep brain stimulation, are promising options. PMID- 28816120 TI - B vitamins in stroke prevention: time to reconsider. AB - B vitamin therapy lowers plasma total homocysteine concentrations, and might be a beneficial intervention for stroke prevention; however, cyanocobalamin (a form of vitamin B12) can accelerate decline in renal function and increase the risk of cardiovascular events in patients with impaired renal function. Although early trials did not show benefit in reduction of stroke, these results might have been due to harm in participants with impaired renal function. In patients with diabetic nephropathy, cyanocobalamin is harmful, whereas B vitamins appear to reduce cardiovascular events in study participants with normal renal function. Our meta-analysis of individual patient data from two large trials of B vitamin therapy (VISP and VITATOPS) indicates that patients with impaired renal function who are exposed to high-dose cyanocobalamin do not benefit from therapy with B vitamins for the prevention of stroke (risk ratio 1.04, 95% CI 0.84-1.27), however, patients with normal renal function who are not exposed to high-dose cyanocobalamin benefit significantly from this treatment (0.78, 0.67-0.90; interaction p=0.03). The potential benefits of B vitamin therapy with folic acid and methylcobalamin or hydroxycobalamin, instead of cyanocobalamin, to lower homocysteine concentrations in people at high risk of stroke warrant further investigation. PMID- 28816122 TI - Intellectual disability and the law in Texas, USA. PMID- 28816123 TI - Genome editing: science, ethics, and public engagement. PMID- 28816124 TI - Yemen and cholera: a modern humanity test. PMID- 28816125 TI - Losing the fight against HIV in the Philippines. PMID- 28816126 TI - Building virtual communities of practice for health. PMID- 28816127 TI - Born to run: our future depends on it. PMID- 28816128 TI - Treating and preventing cholera in Bangladesh. PMID- 28816129 TI - Preventing stolen childhood. PMID- 28816130 TI - George Gershwin's death and Duret haemorrhage. PMID- 28816131 TI - Can post-mortem CT and angiography provide all the answers? PMID- 28816132 TI - Aggregate health spending. PMID- 28816133 TI - False and real, but avoidable, dichotomies. PMID- 28816134 TI - False and real, but avoidable, dichotomies - Authors' reply. PMID- 28816136 TI - The Impact of Music Therapy on Anxiety in Cancer Patients Undergoing Simulation for Radiation Therapy. AB - PURPOSE: Radiation therapy (RT) is associated with high stress levels. The role of music therapy (MT) for patients receiving RT is not well described. This study evaluates the impact of MT on anxiety and distress during simulation in patients with newly diagnosed head and neck or breast cancer. METHODS AND MATERIALS: This institutional review board-approved randomized trial of MT versus no MT at the time of simulation included the pre-State-Trait Anxiety Inventory (STAI-S Anxiety) questionnaire and Symptom Distress Thermometer (SDT). Patients randomized to MT received a consultation with a music therapist, during which music of the patients' choice to be played during simulation was selected. The no MT patients did not receive the MT consultation, nor did they hear prerecorded music during simulation. Subsequent to the simulation, all patients repeated the STAI-S Anxiety questionnaire and the SDT. RESULTS: Of the 78 patients enrolled (39 in MT group and 39 in no-MT group), 38 had breast cancer and 40 had head and neck cancer. The male-female ratio was 27:51. The overall mean pre- and post simulation STAI-S scores were 38.7 (range, 20-60) and 35.2 (range, 20-72), respectively. The overall mean pre- and post-simulation SDT scores were 3.2 (range, 0-10) and 2.5 (range, 0-10), respectively. The MT group had mean pre- and post-simulation STAI-S scores of 39.1 and 31.0, respectively (P<.0001), and the mean SDT scores before and after simulation were 3.2 and 1.7, respectively (P<.0001). The no-MT group's mean pre- and post-simulation STAI-S scores were 38.3 and 39.5, respectively (P=.46), and the mean SDT scores were 3 and 3.2, respectively (P=.51). CONCLUSIONS: MT significantly lowered patient anxiety and distress during the simulation procedure on the basis of the STAI-S questionnaire and SDT. Incorporating culturally centered individualized MT may be an effective intervention to reduce stressors. Continued research defining the role of MT intervention in improving the patient experience by reducing anxiety is warranted. PMID- 28816137 TI - High-Dose-Rate Brachytherapy in the Management of Operable Rectal Cancer: A Systematic Review. AB - PURPOSE: To evaluate the role of high-dose-rate endorectal brachytherapy (HDREBT) in the preoperative and definitive management of operable rectal cancer in terms of clinical outcomes and toxicities using a systematic review. METHODS AND MATERIALS: A review of published articles from January 1990 to December 2016 was conducted using the PubMed, Embase, and Scopus databases using the search terms "rectal" or "rectum" in combination with "brachytherapy," "high dose rate," "HDR," and "endorectal." Additional publications were identified by scanning references. Only studies published in English reporting clinical outcomes with >=30 patients treated with HDREBT were included. RESULTS: The search identified 1688 articles, of which 22 met our inclusion criteria. Twelve studies were included in this systematic review. Following preoperative HDREBT with chemoradiation therapy (CRT), the pathologic complete response (pCR) rate ranged between 18% and 31% (weighted mean rate, 22.2%); R0 resection rate, between 80% and 99% (weighted mean rate, 95.5%); and sphincter-preservation rate, between 29% and 54% (weighted mean rate, 46.4%). The weighted mean 2-year progression-free survival and overall survival (OS) rates were 68.1% and 81.5%, respectively. After preoperative HDREBT alone, the pCR rate ranged between 10.4% and 27% (weighted mean rate, 23.8%), the R0 rate was 96.5% (1 study), and the sphincter preservation rate ranged between 53.8% and 75.8% (weighted mean rate, 59.4%). The weighted mean 5-year progression-free survival and OS rates were 66.6% and 70.8%, respectively. There was only 1 study of HDREBT for nonsurgical management of rectal cancer, which reported a 2-year OS rate of 100%. CONCLUSIONS: Preoperative HDREBT either alone or in combination with CRT may result in a better pCR but may not necessarily translate into better survival, which is similar to outcomes seen following preoperative CRT alone. There were significant variations across studies in terms of patient selection, treatment approaches, and evaluation of clinical outcomes, suggesting the need for an international consensus on the dosimetric parameters and techniques of HDREBT, timing and methods of response assessment, definitions and assessment of toxicities, and optimal timing of surgery before further prospective studies. Future studies should include evaluation of the role of HDREBT in the nonsurgical curative treatment of screen detected early cancers and organ preservation in lower rectal cancers. PMID- 28816138 TI - Lymphocyte Nadir and Esophageal Cancer Survival Outcomes After Chemoradiation Therapy. AB - PURPOSE: Host immunity may affect the outcome in patients with esophageal cancer. We sought to identify factors that influenced absolute lymphocyte count (ALC) nadir during chemoradiation therapy (CRT) for esophageal cancer (EC) and looked for clinically relevant associations with survival. METHODS AND MATERIALS: 504 patients with stage I-III EC (2007-2013) treated with neoadjuvant or definitive CRT with weekly ALC determinations made during treatment were analyzed. Grade of lymphopenia from ALC nadir during CRT was based on Common Terminology Criteria for Adverse Events version 4.0. Associations of ALC nadir with survival were examined using multivariate Cox proportional hazards analysis (MVA) and competing risks regression analysis. RESULTS: The median follow-up time was 36 months. The incidences of grade 1, 2, 3, and 4 ALC nadir during CRT were 2%, 12%, 59%, and 27%, respectively. The impact was lymphocyte-specific because this was not seen for monocyte or neutrophil count. On MVA, grade 4 ALC nadir (G4 nadir) was significantly associated with worse overall and disease-specific survival outcomes. Predictors of G4 nadir included distal tumor location, definitive CRT, taxane/5-fluorouracil chemotherapy, and photon-based radiation type (vs proton based). Radiation type strongly influenced the mean body dose exposure, which was a strong predictor for G4 nadir (odds ratio 1.22 per Gray, P<.001). CONCLUSIONS: G4 nadir during CRT for EC was associated with poor outcomes, suggesting a role of host immunity in disease control. This observation provides a rationale to prospectively test chemotherapeutic and radiation treatment strategies that may have a lower impact on host immunity. PMID- 28816139 TI - Total Mesorectal Excision Versus Local Excision After Favorable Response to Preoperative Chemoradiotherapy in "Early" Clinical T3 Rectal Cancer: A Propensity Score Analysis. AB - PURPOSE: To compare oncological outcomes of total mesorectal excision (TME) and local excision (LE) in patients with "early" clinical T3 rectal cancer who received preoperative chemoradiotherapy (PCRT). METHODS AND MATERIALS: "Early" clinical T3 rectal cancer was radiologically defined as tumors with extramural extension of <5 mm without mesorectal fascia involvement and lateral lymph node metastasis. Patients with "early" clinical T3 rectal cancer who received PCRT followed by TME or LE between January 2007 and December 2013 were retrospectively analyzed. Propensity scores were generated using patient and tumor characteristics, and a one-to-one case-matched analysis was conducted. Local recurrence-free survival (LRFS), disease-free survival (DFS), and overall survival (OS) were compared between the TME and LE groups. RESULTS: Of the 406 enrolled patients, 351 received TME and 55 received LE. The median follow-up period was 45 months. Following propensity score matching, each group contained 55 patients. Among 103 patients evaluable for pathologic tumor response, 82 patients (79.6%) showed complete response or near-complete response. No significant differences were observed between the TME and LE groups in LRFS (3 year LRFS 98.1% vs 94.4%, P=.312), DFS (3-year DFS 92.1% vs 90.8%, P=.683), and OS (3-year OS 98.2% vs 100.0%, P=.895). CONCLUSIONS: In "early" clinical T3 rectal cancer, PCRT followed by LE showed comparable oncologic outcomes to TME. Because most of the matched cohort consisted of good responders to PCRT, the present results should be applied to a limited population. PMID- 28816140 TI - Comparison Between Child-Turcotte-Pugh and Albumin-Bilirubin Scores in Assessing the Prognosis of Hepatocellular Carcinoma After Stereotactic Ablative Radiation Therapy. AB - PURPOSE: To evaluate the prognostic performance of the Child-Turcotte-Pugh (CTP) score and the albumin-bilirubin (ALBI) score in hepatocellular carcinoma (HCC) patients treated using stereotactic ablative radiation therapy (SABR). METHODS AND MATERIALS: This retrospective study evaluated the data of patients with HCC who underwent SABR between December 2007 and June 2015. We collected pretreatment CTP and ALBI scores and analyzed their correlation with survival and liver toxicity. RESULTS: This study included 152 HCC patients: 78.3% of CTP class A and 21.7% of CTP class B. The median ALBI score was -2.49 (range, -3.67 to -0.84) with 39.5% of grade 1, 56.6% of grade 2, and 3.9% of grade 3. The CTP classification and ALBI grade were significantly associated with overall survival (P<.001). Albumin-bilirubin grade (1 vs 2) had a trend to stratify CTP class A patients into 2 risk groups of mortality (P=.061). Combined CTP class and ALBI score could predict development of radiation-induced liver disease (2.4% in CTP A ALBI < -2.76, 15.1% in CTP A-ALBI >= -2.76, and 25.8% in CTP B). CONCLUSION: Albumin-bilirubin score is a potential predictor for both survival and liver toxicity. Complementary use of CTP and ALBI score could predict the risk of post SABR liver toxicity. Further prospective studies are necessary before use of the ALBI score can become part of daily practice. PMID- 28816141 TI - Combined Radiation Therapy and Immune Checkpoint Blockade Therapy for Breast Cancer. AB - PURPOSE: Treatment with checkpoint inhibitors has shown durable responses in a number of solid tumors, including melanoma, lung, and renal cell carcinoma. However, most breast cancers are resistant to monotherapy with checkpoint inhibitors. Radiation therapy (RT) has been shown to have a number of immunostimulatory effects, including priming the immune system, recruiting immune cells to the tumor environment, and altering the immunosuppressive effects of the tumor microenvironment. RT therefore represents a promising adjuvant therapy to checkpoint blockade in breast cancer. METHODS AND MATERIALS: We review the data from the checkpoint blockade studies on breast cancer reported to date, the mechanisms by which RT potentiates immune responses, the preclinical and clinical data of checkpoint blockade and RT combinations, and the landscape of current clinical trials of RT and immune checkpoint inhibitor combinations in breast cancer. RESULTS: Clinical trials with checkpoint blockade therapy have demonstrated response rates of up to 19% in breast cancer, and many of the responses are durable. Preclinical data indicate that RT combined with checkpoint inhibition synergizes not only to enhance antitumor efficacy but also to induce responses outside of the radiation field. Thus multiple clinical trials are currently investigating the combination of checkpoint inhibition with RT. CONCLUSIONS: The use of combination strategies that incorporate chemotherapy and/or local strategies such as RT may be needed to augment responses to immune therapy in breast cancer. Preclinical and clinical results show that RT in combination with checkpoint blockade may be a promising therapeutic option in breast cancer. PMID- 28816142 TI - Vorinostat and Concurrent Stereotactic Radiosurgery for Non-Small Cell Lung Cancer Brain Metastases: A Phase 1 Dose Escalation Trial. AB - PURPOSE: To determine the maximum tolerated dose (MTD) of vorinostat, a histone deacetylase inhibitor, given concurrently with stereotactic radiosurgery (SRS) to treat non-small cell lung cancer (NSCLC) brain metastases. Secondary objectives were to determine toxicity, local failure, distant intracranial failure, and overall survival rates. MATERIALS AND METHODS: In this multicenter study, patients with 1 to 4 NSCLC brain metastases, each <=2 cm, were enrolled in a phase 1, 3 + 3 dose escalation trial. Vorinostat dose levels were 200, 300, and 400 mg orally once daily for 14 days. Single-fraction SRS was delivered on day 3. A dose-limiting toxicity (DLT) was defined as any Common Terminology Criteria for Adverse Events version 3.0 grade 3 to 5 acute nonhematologic adverse event related to vorinostat or SRS occurring within 30 days. RESULTS: From 2009 to 2014, 17 patients were enrolled and 12 patients completed study treatment. Because no DLTs were observed, the MTD was established as 400 mg. Acute adverse events were reported by 10 patients (59%). Five patients discontinued vorinostat early and withdrew from the study. The most common reasons for withdrawal were dyspnea (n=2), nausea (n=1), and fatigue (n=2). With a median follow-up of 12 months (range, 1-64 months), Kaplan-Meier overall survival was 13 months. There were no local failures. One patient (8%) at the 400-mg dose level with a 2.0-cm metastasis developed histologically confirmed grade 4 radiation necrosis 2 months after SRS. CONCLUSIONS: The MTD of vorinostat with concurrent SRS was established as 400 mg. Although no DLTs were observed, 5 patients withdrew before completing the treatment course, a result that emphasizes the need for supportive care during vorinostat administration. There were no local failures. A larger, randomized trial may evaluate both the tolerability and potential local control benefit of vorinostat concurrent with SRS for brain metastases. PMID- 28816143 TI - Radiation Therapy Versus No Radiation Therapy to the Neo-breast Following Skin Sparing Mastectomy and Immediate Autologous Free Flap Reconstruction for Breast Cancer: Patient-Reported and Surgical Outcomes at 1 Year-A Mastectomy Reconstruction Outcomes Consortium (MROC) Substudy. AB - PURPOSE: To determine whether adjuvant radiation therapy (RT) is associated with adverse patient-reported outcomes and surgical complications 1 year after skin sparing mastectomy and immediate autologous free flap reconstruction for breast cancer. METHODS AND MATERIALS: We compared 24 domains of patient-reported outcome measures 1 year after autologous reconstruction between patients who received adjuvant RT and those who did not. A total of 125 patients who underwent surgery between 2012 and 2015 at our institution were included from the Mastectomy Reconstruction Outcomes Consortium study database. Adjusted multivariate models were created incorporating RT technical data, age, cancer stage, estrogen receptor, chemotherapy, breast size, body mass index, and income to determine whether RT was associated with outcomes. RESULTS: At 1 year after surgery, European Organisation for Research and Treatment of Cancer (EORTC) Breast Cancer Specific Quality of Life Questionnaire breast symptoms were significantly greater in 64 patients who received RT (8-point difference on 100-point ordinal scale, P<.0001) versus 61 who did not receive RT in univariate and multivariate models. EORTC arm symptoms (20-point difference on 100-point ordinal scale, P=.0200) differed on univariate analysis but not on multivariate analysis. All other outcomes-including Numerical Pain Rating Scale, BREAST-Q (Post-operative Reconstruction Module), Patient-Report Outcomes Measurement Information System Profile 29, McGill Pain Questionnaire-Short Form (MPQ-SF) score, Generalized Anxiety Disorder Scale, and Patient Health Questionnaire-were not statistically different between groups. Surgical complications were uncommon and did not differ by treatment. CONCLUSIONS: RT to the neo-breast compared with no RT following immediate autologous free flap reconstruction for breast cancer is well tolerated at 1 year following surgery despite patients undergoing RT also having a higher cancer stage and more intensive surgical and systemic treatment. Neo-breast symptoms are more common in patients receiving RT by the EORTC Breast Cancer Specific Quality of Life Questionnaire but not by the BREAST-Q. Patient-reported results at 1 year after surgery suggest RT following immediate autologous free flap breast reconstruction is well tolerated. PMID- 28816144 TI - Comparison of Treatment Outcome Between Invasive Lobular and Ductal Carcinomas in Patients Receiving Partial Breast Irradiation With Intraoperative Electrons. AB - PURPOSE: To investigate the local outcome of patients after accelerated partial breast irradiation with intraoperative electrons (IORT) for invasive lobular carcinoma (ILC) compared with invasive ductal carcinoma (IDC). METHODS AND MATERIALS: From 1999 to 2007, 2173 patients were treated with breast-conserving surgery and IORT (21 Gy/1 fraction) as the sole local treatment: 252 patients with ILC (11.6%) were compared with 1921 patients with IDC in terms of local control. RESULTS: Compared with the IDC subgroup, patients with ILC had a low risk profile and were more hormone responsive. The 5- and 10-year in-breast tumor reappearance (IBTR) rates were 5.5% and 14.4%, respectively, for the IDC group and 7.5% and 21.8%, respectively, for the ILC group (log-rank P=.03). The excess risk of IBTR associated with ILC was particularly high for small tumors (<=1 cm: hazard ratio [HR], 2.24; 95% confidence interval [CI], 1.03-4.85), elderly patients (60-69 years: HR, 2.27; 95% CI, 1.11-4.63; >=70 years: HR, 3.28; 95% CI, 1.08-10.0), low-grade tumors (grade 1: HR, 3.50; 95% CI, 1.05-11.7), and luminal A molecular subtype (HR, 3.18; 95% CI, 1.49-6.77). Among the ILC histologic variants, no difference between classic and nonclassic subgroups was observed, although the signet ring cell and solid variants had the worst local control. CONCLUSIONS: Despite a favorable tumor profile, accelerated partial breast irradiation with IORT led to a higher incidence of IBTRs in patients with ILC compared with those with IDC. Our institutional experience emphasized the importance of the size of the irradiation field, pointing to the use of larger collimators, even when dealing with small tumors, to improve local control. PMID- 28816145 TI - Strain Imaging Detects Dose-Dependent Segmental Cardiac Dysfunction in the Acute Phase After Breast Irradiation. AB - PURPOSE: We examined the utility of echocardiographic 2-dimensional speckle tracking strain imaging (SI) for the evaluation of segmental myocardial dysfunction before and after radiation therapy (RT) and the relationship to dose exposure. METHODS AND MATERIALS: We prospectively recruited 40 women with left sided breast cancer, undergoing only adjuvant RT to the left chest. Comparisons of traditional echocardiographic parameters and SI parameters at baseline and 6 weeks after RT were analyzed. Regional strain and strain rate (SR) parameters were obtained from all 18 left ventricular segments. The correlation of change in strain parameters with segmental radiation dose was examined. RESULTS: We observed a significant reduction in global and segmental systolic strain parameters at 6 weeks after RT compared with baseline, with the largest decrement in the apical segments; this corresponded with the segments receiving the highest radiation dose exposure (apical peak systolic strain of -21.21% +/- 3.49% before RT vs -18.69% +/- 3.34% after RT, percentage change of 11.88%, P=.002; apical peak systolic SR of -1.17 +/- 0.24 s-1 before RT vs -1.04 +/- 0.19 s-1 after RT, percentage change of 11.11%, P=.008). There was a modest correlation between the apical segment systolic strain reduction and radiation dose exposure (apical segment Delta change and apical radiation dose, r=0.345, P=.031; apical segment percentage change and apical radiation dose, r=0.346, P=.031). A significant reduction in early diastolic SR was observed in the apical segments after treatment compared with baseline (apical early diastolic SR, 1.54 +/- 0.45 s-1 before RT vs 1.35 +/- 0.33 after RT s-1; percentage change, 12.34%; P=.034). CONCLUSIONS: Two-dimensional SI detected dose-related regional myocardial dysfunction in the acute phase after RT in chemotherapy-naive left-sided breast cancer patients. Although the long-term effects remain unknown, this imaging modality may have a potential role in the evaluation of irradiation-related cardiotoxicity. PMID- 28816146 TI - Quality Assessment of Stereotactic Radiosurgery of a Melanoma Brain Metastases Model Using a Mouselike Phantom and the Small Animal Radiation Research Platform. AB - PURPOSE: To establish a novel preclinical model for stereotactic radiosurgery (SRS) with combined mouselike phantom quality assurance in the setting of brain metastases. METHODS AND MATERIALS: C57B6 mice underwent intracranial injection of B16-F10 melanoma cells. T1-weighted postcontrast magnetic resonance imaging (MRI) was performed on day 11 after injection. The MRI images were fused with cone beam computed tomography (CBCT) images using the Small Animal Radiation Research Platform (SARRP). The gross tumor volume (GTV) was contoured using the MRI. A single sagittal arc using the 3 * 3 mm2 collimator was used to deliver 18 Gy prescribed to the isocenter. MRI was performed 7 days after radiation treatment, and the dose delivered to the mice was confirmed using 2 mouselike anthropomorphic phantoms: 1 in the axial orientation and the other in the sagittal orientation. The SARRP output was measured using a PTW Farmer type ionization chamber as per the American Association of Physicists in Medicine Task Group report 61, and the H-D curve was generated up to a maximum dose of 30 Gy. Irradiated films were analyzed based on optical density distribution and H-D curve. RESULTS: The tumor volume on day 11, before intervention, was 2.48 +/- 1.37 mm3 in the no-SRS arm versus 3.75 +/- 1.19 mm3 in the SRS arm (NS). In the SRS arm, GTV maximum dose (Dmax) and mean dose were 2048 +/- 207 and 1785 +/- 14 cGy. Using the mouselike phantoms, the radiochromic film showed close precision in comparison with projected isodose lines, with a Dmax of 1903.4 and 1972.7 cGy, the axial and sagittal phantoms, respectively. Tumor volume 7 days after treatment was 7.34 +/- 8.24 mm3 in the SRS arm and 60.20 +/- 40.4 mm3 in the no SRS arm (P=.009). No mice in the control group survived more than 22 days after implantation, with a median overall survival (mOS) of 19 days; mOS was not reached in the SRS group, with 1 death noted. CONCLUSIONS: Single-fraction SRS of 18 Gy delivered in a single arc can be delivered accurately with MRI T1-weighted postcontrast-based treatment planning. The mouse like phantom allows for verification of dose delivery and accuracy. PMID- 28816147 TI - Evaluating Which Dose-Function Metrics Are Most Critical for Functional-Guided Radiation Therapy. AB - PURPOSE: Four-dimensional (4D) computed tomography (CT) ventilation imaging is increasingly being used to calculate lung ventilation and implement functional guided radiation therapy in clinical trials. There has been little exhaustive work evaluating which dose-function metrics should be used for treatment planning and plan evaluation. The purpose of our study was to evaluate which dose-function metrics best predict for radiation pneumonitis (RP). METHODS AND MATERIALS: Seventy lung cancer patients who underwent 4D CT imaging and pneumonitis grading were assessed. Pretreatment 4D CT scans of each patient were used to calculate ventilation images. We evaluated 3 types of dose-function metrics that combined the patient's 4D CT ventilation image and treatment planning dose distribution: (1) structure-based approaches; (2) image-based approaches using the dose function histogram; and (3) nonlinear weighting schemes. Log-likelihood methods were used to generate normal tissue complication probability models predicting grade 3 or higher (ie, grade 3+) pneumonitis for all dose-function schemes. The area under the curve (AUC) was used to assess the predictive power of the models. All techniques were compared with normal tissue complication probability models based on traditional, total lung dose metrics. RESULTS: The most predictive models were structure-based approaches that focused on the volume of functional lung receiving >=20 Gy (AUC, 0.70). Probabilities of grade 3+ RP of 20% and 10% correspond to V20 (percentage of volume receiving >=20 Gy) to the functional subvolumes of 26.8% and 9.3%, respectively. Imaging-based analysis with the dose function histogram and nonlinear weighted ventilation values yielded AUCs of 0.66 and 0.67, respectively, when we evaluated the percentage of functionality receiving >=20 Gy. All dose-function metrics outperformed the traditional dose metrics (mean lung dose, AUC of 0.55). CONCLUSIONS: A full range of dose-function metrics and functional thresholds was examined. The calculated AUC values for the most predictive functional models occupied a narrow range (0.66-0.70), and all showed notable improvements over AUC from traditional lung dose metrics (0.55). Identifying the combinations most predictive of grade 3+ RP provides valuable data to inform the functional-guided radiation therapy process. PMID- 28816148 TI - Prompt Gamma Imaging for In Vivo Range Verification of Pencil Beam Scanning Proton Therapy. AB - PURPOSE: To report the first clinical results and value assessment of prompt gamma imaging for in vivo proton range verification in pencil beam scanning mode. METHODS AND MATERIALS: A stand-alone, trolley-mounted, prototype prompt gamma camera utilizing a knife-edge slit collimator design was used to record the prompt gamma signal emitted along the proton tracks during delivery of proton therapy for a brain cancer patient. The recorded prompt gamma depth detection profiles of individual pencil beam spots were compared with the expected profiles simulated from the treatment plan. RESULTS: In 6 treatment fractions recorded over 3 weeks, the mean (+/- standard deviation) range shifts aggregated over all spots in 9 energy layers were -0.8 +/- 1.3 mm for the lateral field, 1.7 +/- 0.7 mm for the right-superior-oblique field, and -0.4 +/- 0.9 mm for the vertex field. CONCLUSIONS: This study demonstrates the feasibility and illustrates the distinctive benefits of prompt gamma imaging in pencil beam scanning treatment mode. Accuracy in range verification was found in this first clinical case to be better than the range uncertainty margin applied in the treatment plan. These first results lay the foundation for additional work toward tighter integration of the system for in vivo proton range verification and quantification of range uncertainties. PMID- 28816149 TI - A Multi-institution, Retrospective Analysis of Cervix Intracavitary Brachytherapy Treatments. Part 1: Is EQD2 Good Enough for Reporting Radiobiological Effects? AB - PURPOSE: When brachytherapy doses are reported or added, biologically effective dose (BED) minimum dose covering 90% of the volume (D90) is used as if dose is delivered uniformly to the target. Unlike BED(D90), equivalent uniform BED (EUBED) and generalized biologically equivalent uniform dose (gBEUD) are quantities that integrate dose inhomogeneity. Here we compared BED(D90) and equivalent uniform BED (EUBED)/gBEUD in 3 settings: (1) 2 sites using tandem and ovoid (T&O) but different styles of implants; (2) 2 sites using different devices T&O and tandem and ring (T&R)-and different styles; and (3) the same site using T&O and T&R with the same style. METHODS AND MATERIALS: EUBED and gBEUD were calculated for 260 fractions from 3 institutions using BED(alpha/beta = 10 Gy). EUBED uses an extra parameter alpha with smaller values associated with radioresistant tumors. Similarly, gBEUD uses a, which places variable emphasis on hot/cold spots. Distributions were compared using the Kolmogorov-Smirnoff test at 5% significance. RESULTS: For the 2 sites using T&O, the distribution of EUBED BED(D90) was not different for values of alpha = 0.5 to 0.3 Gy-1 but was statistically different for values of alpha = 0.15 to 0.05 Gy-1 (P=.01, .002). The mean percentage differences between EUBED and BED(D90) ranged from 20% to 100% for alpha = 0.5 Gy-1 to 0.05 Gy-1. Using gBEUD-BED(D90), the P values indicate the distributions to be similar for a = -10 but to be significantly different for other values of a (-5, -1, 1). Between sites and at the same site using T&O versus T&R, the distributions were statistically different with EUBED/gBEUD irrespective of parameter values at which these quantities were computed. These differences indicate that EUBED/gBEUD capture differences between the techniques and applicators that are not detected by the BED(D90). CONCLUSIONS: BED(D90) is unable to distinguish between plans created by different devices or optimized differently. EUBED/gBEUD distinguish between dose distributions created by different devices and styles of implant and planning. This discrepancy is particularly important with the increased use of magnetic resonance imaging and hybrid devices, whereby one has the ability to create dose distributions that are significant departures from the classic pear. PMID- 28816150 TI - Phase 1 Study of Ipilimumab Combined With Whole Brain Radiation Therapy or Radiosurgery for Melanoma Patients With Brain Metastases. AB - PURPOSE: We performed a phase 1 study to determine the maximum tolerable dose and safety of ipilimumab with stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT) in patients with brain metastases from melanoma. METHODS AND MATERIALS: Based on the intracranial disease burden, patients underwent WBRT (arm A) or SRS (arm B). The ipilimumab starting dose was 3 mg/kg every 3 weeks, starting on day 3 of WBRT or 2 days after SRS. The ipilimumab dose was escalated to 10 mg/kg using a 2-stage, 3+3 design. The primary endpoint was to determine the maximum tolerable dose of ipilimumab combined with radiation therapy. The secondary endpoints were overall survival, intracranial and extracranial control, progression-free survival, and toxicity. The ClinicalTrials.gov registration number is NCT01703507. RESULTS: The characteristics of the 16 patients enrolled between 2011 and 2014 were mean age, 60 years; median number of brain metastases, 2 (range 1->10); and number with EC disease, 13 (81%). Treatment included WBRT (n=5), SRS (n=11), and ipilimumab 3 mg/kg (n=7) or 10 mg/kg (n=9). The median follow-up was 8 months (arm A) and 10.5 months (arm B). A total of 21 grade 1 to 2 neurotoxic effects occurred, with no dose-limiting toxicities. One patient experienced grade 3 neurotoxicity before ipilimumab administration. Ten additional grade 3 toxicities were reported, with gastrointestinal toxicities (n=5; 31%) the most common. No patient developed grade 4 or 5 toxicity. The median progression-free survival and overall survival in arm A was 2.5 months and 8 months and in arm B was 2.1 months and not reached, respectively. CONCLUSIONS: Concurrent ipilimumab 10 mg/kg with SRS is safe. The WBRT arm was closed early because of slow accrual but demonstrated safety with ipilimumab 3 mg/kg. No patient experienced dose-limiting toxicity. Larger studies, including those with combination checkpoint inhibitor therapy and SRS, are warranted. PMID- 28816151 TI - Quantification of Pediatric Abdominal Organ Motion With a 4-Dimensional Magnetic Resonance Imaging Method. AB - PURPOSE: To characterize respiration-induced abdominal organ motion in children receiving radiation treatment with a 4-dimensional (4D) magnetic resonance imaging (MRI) method. METHODS AND MATERIALS: We analyzed free-breathing coronal 4D MRI datasets acquired from 35 patients (aged 1-20 years) with abdominal tumors. A deformable image registration of the 4D MRI datasets was performed to derive motion trajectories of selected anatomic landmarks, from which organ motions were quantified. The association between organ motion and patient characteristics was investigated and compared with previous studies. The relation between patient height and organ motion was further investigated to predict organ motion in prospective patients. RESULTS: Organ motion and its individual variation were reduced in younger patients (eg, kidney peak-to-peak motion <5 mm for all but 1 patient aged <=8 years), although special motion management may be warranted in some adolescents. The liver and spleen exhibited greater motion than did the kidneys, while intraorgan variation was present. The motions in the liver and kidneys agreed with those reported by the previous 4D computed tomography studies. Individual variations of organ motion in younger patients were due, in part, to changes in respiration rate, which ostensibly reflected the effect of anesthesia. The prediction of organ motion was limited by large individual variations, particularly for older patients. CONCLUSIONS: The 4D MRI acquisition method and motion analysis described in this study provide a nonionizing approach to understand age-associated organ motion, which aids in the planning of abdominal radiation therapy for pediatric patients. Use of 4D MRI facilitates monitoring of changes in target motion patterns during treatment courses and in various studies of the effect of organ motion on radiation treatment. PMID- 28816152 TI - In Regard to Redmond et al. PMID- 28816153 TI - In Reply to Belderbos et al. PMID- 28816154 TI - In Regard to Ciezki et al. PMID- 28816155 TI - In Reply to Morris and Tyldesley. PMID- 28816156 TI - Erratum to Ringash J, Fisher R, Peters L, et al. Effect of p16 status on the quality-of-life experience during chemoradiation for locally advanced oropharyngeal cancer: a substudy of randomized trial trans-Tasman radiation oncology group (TROG) 02.02 (HeadSTART). Int J Radiat Oncol Biol Phys 2017;97:678 686. PMID- 28816157 TI - Prophylactic Cranial Irradiation for Small Cell Lung Cancer: New Insights. PMID- 28816158 TI - A Multi-institutional Prospective Observational Study of Stereotactic Radiosurgery for Patients With Multiple Brain Metastases (JLGK0901 Study Update): Irradiation-related Complications and Long-term Maintenance of Mini-Mental State Examination Scores. AB - PURPOSE: The JLGK0901 study showed the noninferiority of stereotactic radiosurgery (SRS) alone as initial treatment of 5 to 10 brain metastases (BMs) compared with 2 to 4 BMs in terms of overall survival and most secondary endpoints (Lancet Oncol 2014;15:387-95). However, observation periods were not long enough to allow confirmation of the long-term safety of SRS alone in patients with 5 to 10 BMs. METHODS AND MATERIALS: This was a prospective observational study of Gamma Knife SRS-treated patients with 1 to 10 newly diagnosed BMs enrolled at 23 facilities between March 1, 2009, and February 15, 2012. RESULTS: The 1194 eligible patients were categorized into the following groups: group A, 1 tumor (n=455); group B, 2 to 4 tumors (n=531); and group C, 5 to 10 tumors (n=208). Cumulative rates of Mini-Mental State Examination (MMSE) score maintenance (MMSE score decrease <3 from baseline) determined with a competing risk analysis of groups A, B, and C were 93%, 91%, and 92%, respectively, at the 12th month after SRS; 91%, 89%, and 91%, respectively, at the 24th month; 89%, 88%, and 89%, respectively, at the 36th month; and 87%, 86%, and 89%, respectively, at the 48th month (hazard ratio [HR] of group A vs group B, 0.719; 95% confidence interval [CI], 0.437-1.172; P=.18; HR of group B vs group C, 1.280; 95% CI, 0.696-2.508; P=.43). During observations ranging from 0.3 to 67.5 months (median, 12.0 months; interquartile range, 5.8-26.5 months), as of December 2014, 145 patients (12.1%) had SRS-induced complications. Cumulative complication incidences by competing risk analysis for groups A, B, and C were 7%, 8%, and 6%, respectively, at the 12th month after SRS; 10%, 11%, and 11%, respectively, at the 24th month; 11%, 11%, and 12%, respectively, at the 36th month; and 12%, 12%, and 13%, respectively, at the 48th month (HR of group A vs group B, 0.850; 95% CI, 0.592-1.220; P=.38; HR of group B vs group C, 1.052; 95% CI, 0.666-1.662, P=.83). Leukoencephalopathy occurred in 12 of the 1074 patients (1.1%) with follow-up magnetic resonance imaging and was detected after salvage whole-brain radiation therapy in 11 of these 12 patients. In these 11 patients, leukoencephalopathy was detected by magnetic resonance imaging 5.2 to 21.2 months (median, 11.0 months; interquartile range, 7.0-14.4 months) after whole-brain radiation therapy. CONCLUSIONS: Neither MMSE score maintenance nor post-SRS complication incidence differed among groups A, B, and C. This longer-term follow up study further supports the already-reported noninferiority hypothesis of SRS alone for patients with 5 to 10 BMs versus 2 to 4 BMs. PMID- 28816159 TI - Consensus Guidelines for Implementing Pencil-Beam Scanning Proton Therapy for Thoracic Malignancies on Behalf of the PTCOG Thoracic and Lymphoma Subcommittee. AB - Pencil-beam scanning (PBS) proton therapy (PT), particularly intensity modulated PT, represents the latest advanced PT technology for treating cancers, including thoracic malignancies. On the basis of virtual clinical studies, PBS-PT appears to have great potential in its ability to tightly tailor the dose to the target while sparing critical structures, thereby reducing treatment-related toxicities, particularly for tumors in areas with complicated anatomy. However, implementing PBS-PT for moving targets has several additional technical challenges compared with intensity modulated photon radiation therapy or passive scattering PT. Four dimensional computed tomography-based motion management and robust optimization and evaluation are crucial for minimizing uncertainties associated with beam range and organ motion. Rigorous quality assurance is required to validate dose delivery both before and during the course of treatment. Active motion management (eg, breath hold), beam gating, rescanning, tracking, or adaptive planning may be needed for cases involving significant motion or changes in motion or anatomy over the course of treatment. PMID- 28816161 TI - The Folie a Trois. PMID- 28816160 TI - The Impact of Cardiac Radiation Dosimetry on Survival After Radiation Therapy for Non-Small Cell Lung Cancer. AB - PURPOSE: The heart receives high radiation doses during radiation therapy of advanced-stage lung cancer. We have explored associations between overall survival, cardiac radiation doses, and electrocardiographic (ECG) changes in patients treated in IDEAL-CRT, a trial of isotoxically escalated concurrent chemoradiation delivering tumor doses of 63 to 73 Gy. METHODS AND MATERIALS: Dosimetric and survival data were analyzed for 78 patients. The whole heart, pericardium, AV node, and walls of left and right atria (LA/RA-Wall) and ventricles (LV/RV-Wall) were outlined on radiation therapy planning scans, and differential dose-volume histograms (dDVHs) were calculated. For each structure, dDVHs were approximated using the average dDVH and the 10 highest-ranked structure-specific principal components (PCs). ECGs at baseline and 6 months after radiation therapy were analyzed for 53 patients, dichotomizing patients according to presence or absence of "any ECG change" (conduction or ischemic/pericarditis-like change). All-cause death rate (DR) was analyzed from the start of treatment using Cox regression. RESULTS: 38% of patients had ECG changes at 6 months. On univariable analysis, higher scores for LA-Wall-PC6, Heart-PC6, "any ECG change," and larger planning target volume (PTV) were significantly associated with higher DR (P=.003, .009, .029, and .037, respectively). Heart-PC6 and LA-Wall-PC6 represent larger volumes of whole heart and left atrial wall receiving 63 to 69 Gy. Cardiac doses >=63 Gy were concentrated in the LA-Wall, and consequently Heart-PC6 was highly correlated with LA-Wall-PC6. "Any ECG change," LA-Wall-PC6 scores, and PTV size were retained in the multivariable model. CONCLUSIONS: We found associations between higher DR and conduction or ischemic/pericarditis-like changes on ECG at 6 months, and between higher DR and higher Heart-PC6 or LA-Wall-PC6 scores, which are closely related to heart or left atrial wall volumes receiving 63 to 69 Gy in this small cohort of patients. PMID- 28816162 TI - Heart Dosimetry is Correlated With Risk of Radiation Pneumonitis After Lung Sparing Hemithoracic Pleural Intensity Modulated Radiation Therapy for Malignant Pleural Mesothelioma. AB - PURPOSE: To determine clinically helpful dose-volume and clinical metrics correlating with symptomatic radiation pneumonitis (RP) in malignant pleural mesothelioma (MPM) patients with 2 lungs treated with hemithoracic intensity modulated pleural radiation therapy (IMPRINT). METHODS AND MATERIALS: Treatment plans and resulting normal organ dose-volume histograms of 103 consecutive MPM patients treated with IMPRINT (February 2005 to January 2015) to the highest dose <=50.4 Gy satisfying departmental normal tissue constraints were uniformly recalculated. Patient records provided maximum RP grade (Common Terminology Criteria for Toxicity and Adverse Event version 4.0) and clinical and demographic information. Correlations analyzed with the Cox model were grade >=2 RP (RP2+) and grade >=3 RP (RP3+) with clinical variables, with volumes of planning target volume (PTV) and PTV-lung overlap and with mean dose, percent volume receiving dose D (VD), highest dose encompassing % volume V, (DV), and heart, total, ipsilateral, and contralateral lung volumes. RESULTS: Twenty-seven patients had RP2+ (14 with RP3+). The median prescription dose was 46.8 Gy (39.6-50.4 Gy, 1.8 Gy/fraction). The median age was 67.6 years (range, 42-83 years). There were 79 men, 40 never-smokers, and 44 with left-sided MPM. There were no significant (P<=.05) correlations with clinical variables, prescription dose, total lung dose volume metrics, and PTV-lung overlap volume. Dose-volume correlations for heart were RP2+ with VD (35 <= D <= 47 Gy, V43 strongest at P=.003), RP3+ with VD (31 <= D <= 45 Gy), RP2+ with DV (5 <= V <= 30%), RP3+ with DV (15 <= V <= 35%), and mean dose. Significant for ipsilateral lung were RP2+ with VD (38 <= D <= 44 Gy), RP3+ with V41, RP2+ and RP3+ with minimum dose, and for contralateral lung, RP2+ with maximum dose. Correlation of PTV with RP2+ was strong (P<.001) and also significant with RP3+. CONCLUSIONS: Heart dose correlated strongly with symptomatic RP in this large cohort of MPM patients with 2 lungs treated with IMPRINT. Planning constraints to reduce future heart doses are suggested. PMID- 28816163 TI - Don't Bet Against the Elderly. PMID- 28816164 TI - Less Is More. PMID- 28816166 TI - The "Dirty Harry" Approach. PMID- 28816165 TI - Incidence and Predictors of Pericardial Effusion After Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer. AB - PURPOSE: Findings from Radiation Therapy Oncology Group (RTOG) 0617 suggested that collateral radiation to the heart may contribute to early death in patients receiving chemoradiation therapy for non-small cell lung cancer (NSCLC); however, reports of cardiac toxicity after thoracic radiation therapy (RT) remain limited. Because pericardial disease is the most common cardiac complication of thoracic RT, we investigated the incidence of and risk factors for pericardial effusion (PCE) in patients enrolled in a phase 2 prospective randomized study of intensity modulated RT versus proton therapy for locally advanced NSCLC. METHODS AND MATERIALS: From July 2009 through April 2014, 201 patients were prospectively treated with proton beam therapy or intensity modulated RT to 60 to 74 Gy with concurrent chemotherapy. The primary endpoint (grade >=2 PCE) was diagnosed on review of follow-up images. Clinical characteristics and cardiac dose-volume parameters associated with PCE were identified via Cox proportional hazards modeling and recursive partitioning analysis of null Martingale residuals. Reproducibility was evaluated in a separate retrospective cohort of 301 patients. RESULTS: The cumulative incidence rates of PCE among patients in the trial were 31.4% at 1 year and 45.4% at 2 years, with a median time to PCE of 8.9 months. Several cardiac dose-volume parameters (eg, V20 [volume receiving >=20 Gy] to V65 [volume receiving >=65 Gy]) predicted PCE, but heart volume receiving >=35 Gy (HV35) was the most strongly associated, with a cutoff volume of 10%. On multivariate analysis, HV35 >10% independently predicted PCE (hazard ratio [HR], 2.14; P=.002), a finding that maintained reproducibility in the retrospective validation cohort. Other factors associated with PCE included receipt of adjuvant chemotherapy (HR, 2.82; P<.001) and prior cardiac disease (HR, 1.68; P=.020). CONCLUSIONS: PCE was common after RT for NSCLC, occurring in nearly half of patients even after moderate radiation doses to the heart. Adjuvant chemotherapy may increase the risk of PCE, and HV35 >10% may identify patients at risk of development of this cardiac toxicity. PMID- 28816167 TI - Variabilities of Magnetic Resonance Imaging-, Computed Tomography-, and Positron Emission Tomography-Computed Tomography-Based Tumor and Lymph Node Delineations for Lung Cancer Radiation Therapy Planning. AB - PURPOSE: To investigate interobserver delineation variability for gross tumor volumes of primary lung tumors and associated pathologic lymph nodes using magnetic resonance imaging (MRI), and to compare the results with computed tomography (CT) alone- and positron emission tomography (PET)-CT-based delineations. METHODS AND MATERIALS: Seven physicians delineated the tumor volumes of 10 patients for the following scenarios: (1) CT only, (2) PET-CT fusion images registered to CT ("clinical standard"), and (3) postcontrast T1 weighted MRI registered with diffusion-weighted MRI. To compute interobserver variability, the median surface was generated from all observers' contours and used as the reference surface. A physician labeled the interface types (tumor to lung, atelectasis (collapsed lung), hilum, mediastinum, or chest wall) on the median surface. Contoured volumes and bidirectional local distances between individual observers' contours and the reference contour were analyzed. RESULTS: Computed tomography- and MRI-based tumor volumes normalized relative to PET-CT based volumes were 1.62 +/- 0.76 (mean +/- standard deviation) and 1.38 +/- 0.44, respectively. Volume differences between the imaging modalities were not significant. Between observers, the mean normalized volumes per patient averaged over all patients varied significantly by a factor of 1.6 (MRI) and 2.0 (CT and PET-CT) (P=4.10 * 10-5 to 3.82 * 10-9). The tumor-atelectasis interface had a significantly higher variability than other interfaces for all modalities combined (P=.0006). The interfaces with the smallest uncertainties were tumor lung (on CT) and tumor-mediastinum (on PET-CT and MRI). CONCLUSIONS: Although MRI based contouring showed overall larger variability than PET-CT, contouring variability depended on the interface type and was not significantly different between modalities, despite the limited observer experience with MRI. Multimodality imaging and combining different imaging characteristics might be the best approach to define the tumor volume most accurately. PMID- 28816168 TI - Domestic Job Shortage or Job Maldistribution? A Geographic Analysis of the Current Radiation Oncology Job Market. AB - PURPOSE: To examine whether permanent radiation oncologist (RO) employment opportunities vary based on geography. METHODS AND MATERIALS: A database of full time RO jobs was created by use of American Society for Radiation Oncology (ASTRO) Career Center website posts between March 28, 2016, and March 31, 2017. Jobs were first classified by region based on US Census Bureau data. Jobs were further categorized as academic or nonacademic depending on the employer. The prevalence of job openings per 10 million population was calculated to account for regional population differences. The chi2 test was implemented to compare position type across regions. The number and locations of graduating RO during our study period was calculated using National Resident Matching Program data. The chi2 goodness-of-fit test was then used to compare a set of observed proportions of jobs with a corresponding set of hypothesized proportions of jobs based on the proportions of graduates per region. RESULTS: A total of 211 unique jobs were recorded. The highest and lowest percentages of jobs were seen in the South (31.8%) and Northeast (18.5%), respectively. Of the total jobs, 82 (38.9%) were academic; the South had the highest percentage of overall academic jobs (35.4%), while the West had the lowest (14.6%). Regionally, the Northeast had the highest percentage of academic jobs (56.4%), while the West had the lowest (26.7%). A statistically significant difference was noted between regional academic and nonacademic job availability (P=.021). After we accounted for unit population, the Midwest had the highest number of total jobs per 10 million (9.0) while the South had the lowest (5.9). A significant difference was also observed in the proportion of RO graduates versus actual jobs per region (P=.003), with a surplus of trainees seen in the Northeast. CONCLUSIONS: This study presents a quantitative analysis of the RO job market. We found a disproportionately small number of opportunities compared with graduates trained in the Northeast, as well as a significant regional imbalance of academic versus nonacademic jobs. Long term monitoring is required to confirm these results. PMID- 28816169 TI - Long-Term Results of a Randomized Trial Comparing Iridium Implant Plus External Beam Radiation Therapy With External Beam Radiation Therapy Alone in Node Negative Locally Advanced Cancer of the Prostate. AB - PURPOSE: To determine the impact on long-term survival from the addition of brachytherapy to external beam radiation therapy (EBRT) in patients with prostate cancer. METHODS AND MATERIALS: Between 1992 and 1997, 104 men with cT2-3, surgically staged node-negative prostate cancer were randomized to receive either EBRT (40 Gy/20 fractions) with iridium implant (35 Gy/48 hours) or EBRT alone (66 Gy/33 fractions) to the prostate. According to T stage, Gleason score, and prostate-specific antigen level, 60% of patients had high-risk disease. Substantial improvements in biochemical control at 8 years have previously been reported. Additional follow-up was collected on deaths and metastases. RESULTS: Median follow-up was 14 years. Five patients were lost to follow-up. All other patients have been followed a minimum of 13 years. There have been 75 deaths, including 21 from prostate cancer and 25 from second cancers. No patients developing a second cancer have died from prostate cancer. There was no difference in overall survival between the 2 treatment groups: 34 deaths (67%) in the implant arm and 41 (77%) in the EBRT arm (hazard ratio [HR] 1.00, 95% confidence interval [CI] 0.63-1.59). Similarly, there was no difference in prostate cancer-specific deaths: 9 (18%) patients in the implant arm compared with 12 (23%) in the EBRT arm (HR 0.79, 95% CI 0.34-1.87). There was no statistically significant difference in the number of patients developing metastatic disease: 10 (20%) in the implant arm and 15 (28%) in the EBRT arm (HR 0.70, 95% CI 0.32-1.57). Improvements in biochemical control were maintained (HR 0.53, 95% CI 0.31-0.88). CONCLUSIONS: Despite a dramatic reduction of biochemical recurrence rates, the addition of iridium implant to EBRT did not translate into improved overall survival or prostate cancer-specific survival. PMID- 28816171 TI - Effect of magnesium supplementation on muscular damage markers in basketball players during a full season. AB - Although it has been widely accepted that Mg has a positive effect on muscle function, studies on the efficacy of Mg supplementation in young athletes have generated contrasting results. The aim of this work was to examine the effect of Mg supplementation on muscular damage markers and the association between serum Mg levels with these muscular markers. Twelve elite male basketball players (PB) from a team of Spanish Professional Basketball League and a control group (CG) comprising twelve university students who practiced regularly recreational basketball and competed in minor university leagues participated in this study. The athletes were supplemented with 400 mg/day of Mg, in the form of Mg lactate. Blood samples were taken four times during the season, each separated by eight weeks: T1: October, T2: December, T3: March, and T4: April. Serum Mg concentrations showed a significant decrease in T3 (1.56 +/- 0.03 mg/dL), with respect to T1 (1.69 +/- 0.04 mg/dL) and T2 (1.69 +/- 0.04 mg/L). At the end of the study, serum Mg concentration was significantly higher (T4: 1.79 +/- 0.06 mg/dL) than at T3. Levels of muscle damage parameters remained the same during the entire season (P > 0.05), except for creatinine, which significantly decreased after T2, and then increased significantly in T3 and T4 compared to T2. In conclusion, these results suggest that the supplementation with Mg during the season of competition may prevent associated tissue damage. PMID- 28816172 TI - [Dawn of a New Era[Editorial]]. PMID- 28816170 TI - Role of Consolidative Radiation Therapy After Autologous Hematopoietic Cell Transplantation for the Treatment of Relapsed or Refractory Hodgkin Lymphoma. AB - PURPOSE: To evaluate the role of the addition of consolidative radiation therapy after high-dose chemotherapy and autologous hematopoietic cell transplantation (AHCT) for relapsed or refractory Hodgkin lymphoma (HL). METHODS AND MATERIALS: Medical records were reviewed from a total of 80 consecutive patients who underwent high-dose chemotherapy with AHCT treated under a single protocol at University of Minnesota between November 2005 and January 2014. Of these, 32 patients received radiation therapy after AHCT as planned consolidation. RESULTS: At a median follow-up of 25 months, the 2-year overall survival (OS) and progression-free survival (PFS) for the entire cohort was 96% and 52%, respectively. Consolidative radiation therapy was found to significantly improve the 2-year PFS (67% vs 42%, P<.01) without a significant change in OS (100% vs 93%, P=.15). On subgroup analysis, consolidative radiation therapy was shown to improve PFS in patients with bulky disease (62% vs 39%, P=.02), B-symptoms (48% vs 28%, P=.05), primary refractory disease (47% vs 32%, P=.02), and those with a partial response on pretransplant imaging (47% vs 32%, P=.02). The improvement seen on 2-year PFS with consolidative radiation therapy remained significant on multivariate analysis (hazard ratio 4.64, 95% confidence interval 1.98-10.88). Minimal toxicity was observed among the patients receiving radiation therapy. CONCLUSIONS: The addition of consolidative radiation therapy after high-dose chemotherapy and AHCT demonstrated a significant improvement in 2-year PFS and no impact on OS. Radiation therapy was well tolerated, with minimal toxicity. Our study supports a role of consolidative radiation therapy in patients with HL treated with AHCT. PMID- 28816173 TI - [Considerable demands on the medical profession[Editorial]]. PMID- 28816174 TI - [Adverse drug reaction reports in Iceland from 2013 to 2016. A comparison with other Nordic countries]. AB - INTRODUCTION: Information regarding adverse drug reactions (ADRs) of new medications is based on clinical studies of selected populations. The reporting of ADRs from real-life use following the marketing of new active substances is instrumental for the continuous evaluation of their benefit-risk balance. The aim of this study was to determine the number and nature of ADR reports in Iceland and compare with other Nordic countries. MATERIALS AND METHODS: Reports of ADRs from 2013 to 2016 were examined using the Icelandic Medicines Agency's database. The total number and seriousness of ADRs by ATC-classification of drugs were compared with data published in the 2013 to 2015 annual reports from the Swedish, Danish and Norwegian Medicines Agencies. Comparison of sales between countries was examined. RESULTS: The number of ADR reports in Iceland was between 36 to 104 per 100 thousand inhabitants/year, with less than 10% defined as serious. This compares to 58 to 133 ADR reports per 100 thousand inhabitants in the other Nordic countries, with 38% to 64% of ADRs classified as serious. In Iceland, ADR reports were more common for medications in ATC-class A and less common for classes B, J and L compared to the other Nordic countries. Sales of medications were comparable between these nations. CONCLUSION: There is great variability in the number of ADRs reported annually in Iceland. The drugs reported are within different ATC-classes and the proportion of serious ADRs is low compared to the other Nordic countries. This is not explained by different sales volumes. Key words: adverse drug reaction, pharmacovigilance, ADR reporting, side effects. Correspondence: Hrefna Gudmundsdottir, Hrefna.Gudmundsdottir@lyfjastofnun.is. PMID- 28816175 TI - [Medical evaluation for suspected sexual violence against girls]. AB - INTRODUCTION: Sexual violence against children is a hidden problem. Medical examination and evaluation is needed to search for possible injuries, exclude infections, procure legal evidence and ensure the child's welfare. We assessed medical evaluations done at Landspitali University Hospital and in the Reykjavik Children's House, a specialized clinic for childhood abuse cases. MATERIAL AND METHODS: Retrospective descriptive analysis was performed on the standardized medical examinations. Age, sex, waiting time from reported violence until examination and recorded aberrant external genitalia findings were noted, and classified by the medically--oriented Adams system. Offence severity stages were assigned. RESULTS: Medical examination cases numbered 224 for 220 girls aged 1-17 years. Records were available on 218 standarized examinations among girls; 201 were adequate (92%). Most were conducted within a month (medium waiting-time 28 days; range 1-166). Hymenal changes were in 24 cases possibly associated with sexual violence, including 21 in a girl not sexually active. Two girls had human papillomavirus warts (1%) and one chlamydial infection (0.5%). Medical examination was normal in 85% (165/193) of girls who were not sexually active; 24 had possibly experienced sexual violence and four results were uncertain/controversial. For 71 offence severity was serious. CONCLUSION: Most examinations were conducted on prepubertal girls, were not a matter of urgency and showed normal results. Possible relation to sexual violence was described for one in eight. Infections were rare. When child sexual abuse is suspected, care with methodology and procedures is needed, both for elective and acute medical examinations. Key words: Violence, child sexual abuse, children, external genitalia, injuries, severity grading. Correspondence: Ebba Margret Magnusdottir, ebbamag@landspitali.is. PMID- 28816176 TI - [Severely increased serum lipid levels in diabetic ketoacidosis - case report]. AB - Severe hypertriglyceridemia is a known, but uncommon complication of diabetic ketoacidosis. We discuss the case of a 23-year-old, previously healthy, woman who initially presented to the emergency department with abdominal pain. Grossly lipemic serum due to extremely high triglyceride (38.6 mmol/L) and cholesterol (23.2 mmol/L) levels were observed with a high blood glucose (23 mmol/L) and a low pH of 7.06 on a venous blood gas. She was treated successfully with fluids and insulin and had no sequale of pancreatitis or cerebral edema. Her triglycerides and cholesterol was normalized in three days and she was discharged home on insulin therapy after five days. Further history revealed a recent change in diet with no meat, fish or poultry consumption in the last 12 months and concomitantly an increase in carbohydrate intake which might have contributed to her extremely high serum lipid levels. This case demonstrates that clinicians should be mindful of the different presentations of diabetic ketoacidosis. Key words: diabetic ketoacidosis, hypertriglyceridemia, hyperlipidemia, vegan diet, carbohydrate diet. Correspondence: Hrafnkell Stefansson, hrafnkell.stefans@gmail.com. PMID- 28816178 TI - Plasmon modes of bilayer molybdenum disulfide: a density functional study. AB - We explore the collective electronic excitations of bilayer molybdenum disulfide (MoS2) using density functional theory together with random phase approximation. The many-body dielectric function and electron energy-loss spectra are calculated using an ab initio based model involving material-realistic physical properties. The electron energy-loss function of the bilayer MoS2 system is found to be sensitive to either electron or hole doping and this is due to the fact that the Kohn-Sham band dispersions are not symmetric for energies above and below the zero Fermi level. Three plasmon modes are predicted, a damped high-energy mode, one optical mode (in-phase mode) for which the plasmon dispersion exhibits [Formula: see text] in the long wavelength limit originating from low-energy electron scattering and finally a highly damped acoustic mode (out-of-phase mode). PMID- 28816177 TI - Electrical stimulation of gut motility guided by an in silico model. AB - OBJECTIVE: Neuromodulation of the central and peripheral nervous systems is becoming increasingly important for treating a diverse set of diseases-ranging from Parkinson's Disease and epilepsy to chronic pain. However, neuromodulation of the gastrointestinal (GI) tract has achieved relatively limited success in treating functional GI disorders, which affect a significant population, because the effects of stimulation on the enteric nervous system (ENS) and gut motility are not well understood. Here we develop an integrated neuromechanical model of the ENS and assess neurostimulation strategies for enhancing gut motility, validated by in vivo experiments. APPROACH: The computational model included a network of enteric neurons, smooth muscle fibers, and interstitial cells of Cajal, which regulated propulsion of a virtual pellet in a model of gut motility. MAIN RESULTS: Simulated extracellular stimulation of ENS-mediated motility revealed that sinusoidal current at 0.5 Hz was more effective at increasing intrinsic peristalsis and reducing colon transit time than conventional higher frequency rectangular current pulses, as commonly used for neuromodulation therapy. Further analysis of the model revealed that the 0.5 Hz sinusoidal currents were more effective at modulating the pacemaker frequency of interstitial cells of Cajal. To test the predictions of the model, we conducted in vivo electrical stimulation of the distal colon while measuring bead propulsion in awake rats. Experimental results confirmed that 0.5 Hz sinusoidal currents were more effective than higher frequency pulses at enhancing gut motility. SIGNIFICANCE: This work demonstrates an in silico GI neuromuscular model to enable GI neuromodulation parameter optimization and suggests that low frequency sinusoidal currents may improve the efficacy of GI pacing. PMID- 28816179 TI - Embedded-atom method potential for modeling hydrogen and hydrogen-defect interaction in tungsten. AB - An embedded-atom method potential has been developed for modeling hydrogen in body-centered-cubic (bcc) tungsten by fitting to an extensive database of density functional theory (DFT) calculations. Comprehensive evaluations of the new potential are conducted by comparing various hydrogen properties with DFT calculations and available experimental data, as well as all the other tungsten hydrogen potentials. The new potential accurately reproduces the point defect properties of hydrogen, the interaction among hydrogen atoms, the interplay between hydrogen and a monovacancy, and the thermal diffusion of hydrogen in tungsten. The successful validation of the new potential confirms its good reliability and transferability, which enables large-scale atomistic simulations of tungsten-hydrogen system. The new potential is afterward employed to investigate the interplay between hydrogen and other defects, including [1 1 1] self-interstitial atoms (SIAs) and vacancy clusters in tungsten. It is found that both the [1 1 1] SIAs and the vacancy clusters exhibit considerable attraction for hydrogen. Hydrogen solution and diffusion in strained tungsten are also studied using the present potential, which demonstrates that tensile (compressive) stress facilitates (impedes) hydrogen solution, and isotropic tensile (compressive) stress impedes (facilitates) hydrogen diffusion while anisotropic tensile (compressive) stress facilitates (impedes) hydrogen diffusion. PMID- 28816180 TI - P-hacking. AB - Due to increasing rate of research articles getting published in recent times, medical science is evolving very fast. Open access policies of the journals make information easily available to the stakeholders for building future research proposal. Blindly having faith in whatever is published in the literature is detrimental for science; however, it is hard to find out the correctness of the data analysis. PMID- 28816181 TI - Antimicrobial and Antiproliferative Activity of Bauhinia forficata Link and Cnidoscolus quercifolius Extracts commonly Used in Folk Medicine. AB - BACKGROUND: Bauhinia forficata and Cnidoscolus quercifolius plants are commonly used in folk medicine. However, few studies have investigated their therapeutic potential. AIM: Herein, we evaluated the antimicrobial activity of B. forficata and C. quercifolius extracts against microorganisms of clinical relevance and their antiproliferative potential against tumor cells. MATERIALS AND METHODS: The following tests were performed: Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC)/minimum fungicidal concentration (MFC), inhibition of biofilm adhesion, and effects on cell morphology. Antiproliferative tests were carried out with human keratinocytes and six tumor lines. RESULTS: Bauhinia forficata showed antimicrobial activity only against C. albicans with MIC of 15.62 ug/mL and MFC higher than 2000 ug/mL. It also inhibited biofilm adhesion and caused alterations in cell morphology. Cnidoscolus quercifolius showed no significant activity (MIC > 2.0 mg/mL) against the strains. Bauhinia forficata and C. quercifolius extracts showed cytostatic activity against the tumor cells. CONCLUSION: Bauhinia forficata has promising anti-Cand/da activity and should be further investigated for its therapeutic potential. CLINICAL SIGNIFICANCE: The use of medicinal plants in the treatment of infectious processes has an important function nowadays, due to the limitations of the use of synthetic antibiotics available, related specifically to the microbial resistance emergence. PMID- 28816182 TI - A Survey of Endodontic Practices among Dentists in Burkina Faso. AB - AIM: Dental surgeons must be aware of the most appropriate endodontic treatments and how to properly conduct them. The aim of this study was to evaluate the knowledge of dental surgeons in Burkina Faso in terms of endodontic treatment procedures. MATERIALS AND METHODS: This descriptive, cross-sectional study was performed during the regular annual conference of the National Board of Dental Surgeons of Burkina Faso, held on February 27 and 28, 2015 in Ouagadougou, through a questionnaire. RESULTS: A total of 33 practitioners took part (52.4% of the dental surgeons of Burkina Faso) in the study. The majority of them (90.9%) used sodium hypochlorite as their preferred irrigation solution. Nearly half of the dental surgeons (48.5%) did not know how to use a permeabilization file, and most did not make use of nickel-titanium (NiTi) mechanized instruments (78.8%) or rubber dams (93.9%). Approximately two-thirds of participants did not perform file-in-place radiography (66.7%) or control radiography of the canal obturation (63.6%). The adjusted single-cone technique was the most commonly used (87.9%). CONCLUSION: This study highlights that the majority of dental surgeons in Burkina Faso are not using the currently recommended endodontic procedures to perform obturations. CLINICAL SIGNIFICANCE: Dental surgeons in Burkina Faso must commit to regularly upgrading their knowledge and techniques. Key words: Burkina faso, Cross-sectional study, Dental surgeons, Endodontic treatments, Protocol adherence. PMID- 28816183 TI - Impact of Polishing Systems on the Surface Roughness and Microhardness of Nanocomposites. AB - AIM: The aim of this article is to evaluate the influence of finishing and polishing techniques on the surface roughness and microhardness of two composite resins with two different types of polishing systems. MATERIALS AND METHODS: A total of 30 disk-shaped specimens of nanocomposite FiltekTM Z350 and Ceram-X(r) were prepared. They were divided into three groups. The control group (n = 10) received no finishing and polishing. The remaining specimens were divided into two groups, and they received polishing and finishing either with PoGo or Sof-Lex system. After the polishing procedures, average surface roughness (Ra) was assessed with a surface profilometer. The microhardness was determined using a Vickers hardness test. The data were tabulated and analyzed. RESULTS: The smoothest surfaces were noticed with the control group (Mylar strips) in both composite materials tested. The PoGo one-step polishing system showed significantly better surface roughness compared with the Sof-Lex polishing system. The microhardness did not show any significant variations after finishing and polishing. CONCLUSION: It can be concluded that the use of PoGo(r) one-step polishing system resulted in smoother surface with both composite materials studied compared with the Sof-Lex system. The finishing and polishing system had little influence on the surface microhardness. CLINICAL SIGNIFICANCE: The finishing procedure and polishing system can affect the physical properties and performance of resin composites. PMID- 28816184 TI - Early Screening of Diabetes and Hypertension in Primary Care Dental Clinics at King Saud University in Riyadh, Kingdom of Saudi Arabia. AB - INTRODUCTION: Diabetes mellitus and hypertension are the leading chronic diseases in Saudi Arabia; 23.1% of the Saudi population are diabetic and 25.5% are hypertensive. This cross-sectional study was made on dental setting to determine the effectiveness of screening of diabetes and hypertension in dental clinics. MATERIALS AND METHODS: This study was carried out in the primary care dental clinics at the Dental College in King Saud University in Riyadh, Saudi Arabia. Before starting any treatment, a face-to-face interview was administered to collect a brief medical history and personal data followed by measurement of body mass index (BMI). After that, blood pressure level reading was obtained using electrical sphygmomanometer. Finally, a glucose level reading was obtained from capillary blood from the patient's third fingertip using glucose reader. RESULTS: Our study included 283 participants, 118 of whom were females (41.7%). Our study showed that a significant amount of the participants are at risk of having hypertension (44.8%). In addition, a significant number (10.2%) of the participants are at risk of having diabetes. Furthermore, 35.7% of the sample had obesity as a risk factor for diabetes and hypertension. CONCLUSION: The dental team can play an important role in screening of diabetes, hypertension, and other chronic diseases. In Saudi Arabia, public awareness of the chronic diseases is still critically insufficient. CLINICAL SIGNIFICANCE: Our study showed the importance of the screening even for patients with negative history of diabetes or hypertension. PMID- 28816185 TI - An in vitro Evaluation of Friction Characteristics of Conventional Stainless Steel and Self-ligating Stainless Steel Brackets with different Dimensions of Archwires in Various Bracket-archwire Combination. AB - AIM: The purpose of this research is to compare the frictional attributes of stainless steel conventional brackets and self-ligating stainless steel brackets with different dimensions of archwires. MATERIALS AND METHODS: The test was carried with two sets of maxillary brackets: (1) Conventional stainless steel (Victory Series), (2) stainless steel self-ligating (SmartClip) without first premolar brackets. Stainless steel, nickel-titanium (NiTi), and beta-Ti which are the types of orthodontic wire alloys were tested in this study. To monitor the frictional force, a universal testing machine (Instron 33R 4467) that comprises 10 kg tension load cell was assigned on a range of 1 kg and determined from 0 to 2 kg, which allows moving of an archwire along the brackets. One-way analysis of variance was used to test the difference between groups. To analyze the statistical difference between the two groups, Student's t-test was used. RESULTS: For Victory Series in static friction, p-value was 0.946 and for kinetic friction it was 0.944; at the same time for SmartClip, the p value for static and kinetic frictional resistance was 0.497 and 0.518 respectively. Hence, there was no statistically significant difference between the NiTi and stainless steel archwires. CONCLUSION: It is concluded that when compared with conventional brackets with stainless steel ligatures, self-ligating brackets can produce significantly less friction during sliding. Beta-Ti archwires expressed high amount of frictional resistance and the stainless steel archwires comprise low frictional resistance among all the archwire materials. CLINICAL SIGNIFICANCE: In orthodontics, frictional resistance has always had a major role. Its ability to impair tooth movement leads to the need for higher forces to move the teeth and it extends the treatment time which results in loss of posterior anchorage. Friction in orthodontics is related with sliding mechanics when a wire is moving through one or a series of bracket slots. PMID- 28816186 TI - Reliability of Orthopantomography and Cone-beam Computed Tomography in Presurgical Implant Planning: A Clinical Study. AB - BACKGROUND: Preoperative diagnosis and treatment planning are fundamental requirements to ensure success rate of implant. Cone-beam computed tomography (CBCT) provides all three dimensions and has been proved as a tool for radiology, especially in the success of implant. This study was conducted to evaluate the reliability of orthopantomography (OPG) and CBCT in presurgical implant planning. MATERIALS AND METHODS: The study was conducted on 110 partially or completely edentulous adult patients (male 50 and female 60). Patient information regarding name, age, gender, and so forth was recorded. Thorough clinical examination was done to locate the edentulous site for the placement of implant. All patients were subjected to OPG and CBCT. The OPG was taken with digital panoramic unit (Planmeca) operating at 120 kVp, 2 mA, and exposure time of 17 seconds. The CBCT was taken using NewTom machine with field of view 11 * 8 cm and resolution of 0.3 * 0.3 * 0.3 mm operating at 120 kVp at 5 mA. NNT software with slice thickness of 0.1 mm was used in this study. Measurement of bone height and distance from anatomical structures was done on OPG, whereas bone height and bone width were measured on CBCT scan in all three planes, such as coronal plane, sagittal plane, and axial plane. The measurement was done by two experienced observers. RESULTS: The present study comprised 110 patients (male 50 and female 60). About 102 (16.7%) implants were placed in anterior region, and 508 (83.3%) implants were placed in posterior region. Implant site was incisor region (55), canine (30), premolar (250), and molar (275). The difference was significant (p < 0.01). Variations are usually observed in presurgical planning with CBCT and OPG. The length and width of implant remained unchanged in 90 and 85% of the cases respectively. In 8% of cases, OPG revealed more length of implant than CBCT, whereas only in 2% cases CBCT revealed more length of implant than OPG. The difference was significant (p < 0.05). When we compared the diameter, OPG revealed more diameter in 10% of cases, whereas CBCT only revealed 5% of cases. The difference was significant (p < 0.05). Observer found CBCT as effective in 95% of cases and ineffective in only 5% of cases, whereas OPG was effective in 78% of cases and ineffective in 22% of cases. The different was significant (p < 0.05). CONCLUSION: The CBCT being three-dimensional provides detailed information that two-dimensional radiographs cannot offer, which aids in precision to further improve the entire implant process. CLINICAL SIGNIFICANCE: In recent times, implant has become the treatment of choice for edentulous patients. The CBCT has increased the success rate of implant due to its high resolution, ability to demonstrate anatomical structures more effectively than other radiographic diagnostic tools. PMID- 28816187 TI - Comparison of Film Thickness of Two Commercial Brands of Glass lonomer Cement and One Dual-cured Composite: An in vitro Study. AB - AIM: The present study is undertaken to examine the film thickness of three most commonly used luting cements and to determine their usage as a luting agent. MATERIALS AND METHODS: This study was carried out strictly according to the guidelines of American Dental Association (ADS) specification no. 8. Two glass slabs of 5 cm in length and 2 cm in width were used. One glass slab was kept over the other glass slab and the space between the two glass slabs was measured using metallurgical microscope at the power of 10*. Two brands of glass ionomer cement (GIC) and one dual-cured resin cement were used in this study. The test cement is sandwiched between two glass slabs. A static load of 15 kg was applied using universal testing machine on the glass slabs for 1 hour and the space present between the two glass slabs was measured using metallurgical microscope at the power of 10*. RESULTS: Greatest film thickness was found in group III (Paracore) followed by group II (micron) and lowest in group I (GC luting and lining cement). All the tested samples can be used for luting purposes. CONCLUSION: Greatest film thickness was observed in Paracore followed by micron and lowest in GC luting and lining cement. This suggests that the 25 to 27 degrees C is ideal for mixing of the cement when used for luting consistency. The cement with film thickness more than 30 urn should never be used for luting purposes. CLINICAL SIGNIFICANCE: The dentist should choose the luting cement with utmost care noting the film thickness and bond strength of the cement. The cement with low exothermic heat production and good bond strength should be encouraged. PMID- 28816188 TI - Assessment of Changes in Nickel and Chromium Levels in the Gingival Crevicular Fluid during Fixed Orthodontic Treatment. AB - BACKGROUND: Various components of appliances used in fixed orthodontic treatment are fabricated from materials that are highly resistant in nature and have high strength and biocompatibility. Corrosion of materials occurs inside the oral cavity due to numerous environmental or oral factors that act on them. These factors include temperature, pH variation, salivary conditions, mechanical loads, microbiological and enzymatic activity, and various food components. Gingival crevicular fluid (GCF) is the material obtained from the gingival sulcus and might act as a potential source for various biomarkers in the orthodontic setup because inflammatory-induced response is directly related to orthodontic forces in GCF. In the light of above-mentioned data, we planned this study to assess and evaluate the changes occurring in nickel and chromium levels in the GCF during fixed orthodontic treatment. MATERIALS AND METHODS: This study included assessment of 30 patients who underwent fixed orthodontic treatment. Three samples were taken from the GCF of the patients giving a total of 90 samples. The samples were collected at the following time intervals: At baseline (pretreatment time), 1 month after the start of orthodontic treatment, and at 6 months after the commencement of orthodontic treatment. Cellulose strips were used for isolation of the tooth region. For GCF collection, a standardized cellulose acetate absorbent strip was used. Placement of the strips was done in the sulcus for 60 seconds for the collection of the samples. Refrigeration of the specimen bottles was done for a minimum of 7 days and was then sent to a laboratory where specimens were transferred for atomic absorption spectrophotometry. All the results were analyzed by Statistical Package for the Social Sciences software. RESULTS: At 1 month, the mean value of nickel and chromium in GCF was found to be 4.5 and 4.9 ug/gm of GCF respectively. While comparing the mean nickel levels between 1 and 6 months and between baseline and 6 months, significant results were obtained. Significant results were also obtained while comparing the mean values of chromium in GCF between baseline and 6 months and between 1 and 6 months. Gingival health index of the patients was found to be associated with increased inflammation with the progression of time of orthodontic treatment. CONCLUSION: Levels of nickel and chromium might show considerable elevation in the GCF with time along with an increase in the severity of inflammation in the gingival health in patients undergoing fixed orthodontic treatment. CLINICAL SIGNIFICANCE: Regular oral prophylaxis of the patients undergoing orthodontic treatment should be done to avoid tox-icities caused by the release of nickel and chromium and for maintenance of good oral hygiene and oral health. PMID- 28816189 TI - Effect of Different Dentifrices on the Surface Roughness of Acrylic Resins: An in vitro Study. AB - AIM: This study was undertaken to study the effect of three most commonly used dentifrices for denture cleaning and to find out any positive association between number of strokes by toothbrush and surface roughness of acrylic resin. MATERIALS AND METHODS: About 40 acrylic rectangular blocks with high finish were polished until surface roughness was calculated as 0 pirn. The materials tested were distilled water as a control group, Patanjali Dant Kanti, Colgate Total Cream, and Cleansodent as dentifrices. Stroking was done with dentifrices, and surface roughness readings were recorded at 1,000, 9,000, and 18,000 strokes. RESULTS: Patanjali Dant Kanti was found to have maximum abrasive potential followed by Colgate Total Cream, followed by Cleansodent and least by distilled water. CONCLUSION: Surface roughness was found to be directly proportional to the type, size, and fineness of the abrasive component used; the professional denture cleanser (Cleansodent) has less abrasive potential than the regular toothpastes. Among those tested, the highest abrasive potential was found in Patanjali Dant Kanti and lowest by Cleansodent (denture cleanser). CLINICAL SIGNIFICANCE: The patient as well as dentist should choose the dentifrice with utmost care noting the size and type of abrasives used. Washing the dentures normally with water without toothbrush daily and cleaning of dentures once in 10 to 15 days with a soft toothbrush and professional denture cleanser should be the line of maintenance of dentures. PMID- 28816190 TI - Comparison between Color Spaces of Vita Lumin Shade Guide with Natural Teeth in Bengaluru Population using Spectrocolorimeter: An in vivo Study. AB - AIM: The aim of this study is to compare the color space of Vita Lumin shade guide (SG) with the natural teeth of the local population. MATERIALS AND METHODS: A total of 100 maxillary central incisors (100 patients) were subjected to color measurement with a spectrocolorimeter. For each tooth, L*, a*, b* values were recorded. All the shade tabs of Vita Lumin SG were analyzed with a spectrocolorimeter to define the color space covered by the Vita Lumin SG. The L*a*b* values of natural teeth were plotted on separate scattered diagrams and compared. RESULTS: About two out of three attributes (luminance and blue spectrum) of the local population of Bengaluru displayed a broader range than those available in Vita Lumin SG. CONCLUSION: The local population requires an SG with an extended range, covering a higher luminance spectrum and broader blue spectrum. CLINICAL SIGNIFICANCE: Esthetic restorations require accurate shade matching with the adjacent natural teeth, SGs being the mean of shade selection and communication should be comparable to the natural teeth. PMID- 28816191 TI - Histologic Variants of Calcifying Odontogenic Cyst: A Study of 52 Cases. AB - AIM: This study aimed at evaluating histological features of 52 cases of calcifying odontogenic cyst (COC), which is an uncommon benign odontogenic lesion. The World Health Organization (WHO) classified COC as a neoplasm and used the term calcifying cystic odontogenic tumor (CCOT) for benign cystic type and the dentinogenic ghost cell tumor (DGCT) for the benign solid-type lesions. There is no agreement regarding COC classification. MATERIALS AND METHODS: A total of 52 cases of COC were selected and reviewed from the archive of the Pathology Department of Taleghani Educational Hospital, Tehran, Iran. To better understand the pathogenesis of COC, the cases were classified. RESULTS: There were 52 cases (31 males and 21 females). The lesion was found in all age groups, and patients' age from 8 to 61 years. Nineteen cases affected the maxilla, and 33 cases affected the mandible. Except two cases, all were intraosseous lesions. Radiographically, 30 cases showed a unilocular radiolucent area, and 22 cases showed a mixed radiolucent/ radiopaque region. Histopathologically, 43 cases were cystic type and 9 cases were neoplastic. CONCLUSION: There are two different histopathological entities. In view of these findings, it is very difficult to determine every lesion that has a cystic architecture is truly cystic or is a neoplastic one in nature. It is believed that the solid variants may be neoplastic. CLINICAL SIGNIFICANCE: A better understanding of the histological type of the lesion can provide a classification across patients. This can help in treatment planning to improve patient outcomes. PMID- 28816192 TI - Tobacco Abuse and Associated Oral Lesions among Interstate Migrant Construction Workers. AB - AIM: The present study was conducted to assess the prevalence of tobacco use and associated oral mucosal lesions among construction workers of Cochin, Kerala, India. MATERIALS AND METHODS: A cross-sectional study was carried at various construction sites of Cochin and 2,163 workers were selected using multistage sampling method and were interviewed and examined. Information regarding demographic details, form, type, frequency of tobacco use, earlier attempt to quit, and willingness to quit tobacco use was obtained using predesigned questionnaire. The oral health status was recorded on the World Health Organization oral health assessment form 1997, and the examination was carried out under natural light using mouth mirrors and probe. Data thus collected were analyzed using Statistical Package for the Social Sciences version 17 (Chicago, Illinois, USA) statistical software package. Chi-square test was applied. RESULTS: Among the 2,163 workers, 1,952 were tobacco users and 211 were nonusers. Among the users, 1,021 use smokeless form, 372 use smoked form, and 559 use both. Premalignant lesions/conditions were more commonly seen with tobacco habit, with leukoplakia (14.75%) being the most common followed by oral submucous fibrosis in 201 (9.3%), candidiasis in 123 (5.7%), ulceration in 131 (6.05%), abscess in 59 (2.73%), smokers palate in 58 (2.68%), lichen planus in 21 (0.97%), and malignant tumor in 2 (0.1%). CONCLUSION: Commonness of abusive habits and oral premalig nant lesions or conditions was considerable among the workers. Control and early diagnosis through workplace screening are the major backbones for the control of oral cancer. CLINICAL SIGNIFICANCE: Building workers are unprotected from various health hazards at workplace. Lack of access to health services makes the situation unsatisfactory. Poor literacy and low socioeconomic status have resulted in practice of tobacco, smoking, and chewing in the majority of them. Hence, it is our responsibility to find and guide them with a proper oral health education. PMID- 28816193 TI - Gingival Zenith Positions and Levels of Maxillary Anterior Dentition in Cases of Bimaxillary Protrusion: A Morphometric Analysis. AB - AIM: To investigate the two clinical parameters, such as gingival zenith positions (GZPs) and gingival zenith levels (GZLs), of maxillary anterior dentition in bimaxillary protrusion cases and collate it with severiety of crown inclination. MATERIALS AND METHODS: Gingival zenith position and GZL in 40 healthy patients (29 females and 11 males) with an average age of 21.5 years were assessed. Inclusion criteria involved absence of periodontal diseases, Angle's class I molar relationship, and upper anterior proclination within 25 to 45 degrees based on Steiner's analysis; exclusion criteria included spacing, crowding, anterior restoration and teeth with incisor attrition or rotation. The GZP was evaluated using digital calipers from voxel-based morphometry (VBM), and GZL was assessed from the tangent drawn from GZP of central incisor and canines to the linear vertical distance of GZP of lateral incisor. RESULTS: All the central incisors showed a GZP distal to VBM with a mean average of 1 mm. Severe proclination between 40 and 45 degrees showed a statistically significant variation. Lateral incisors displayed a mean of 0.5 mm deviation of GZP from the vertically bisected midline. In 80% of canine population, GZP was centralized. CONCLUSION: We conclude that the degree of proclination of maxillary anterior dentition was correlated to the gingival contour in bimaxillary cases. The investigation revealed that there is a variation in the location of GZP as the severity of proclination increases. CLINICAL SIGNIFICANCE: This study highlights the importance of microesthetics in fixed orthodontic treatment. The gingival contour should be unaltered while retraction during management of bimaxillary protrusion. PMID- 28816194 TI - Risk Factors associated with Dental Implant Failure: A Study of 302 Implants placed in a Regional Center. AB - AIM: The aim of this research is to determine which risk factors are associated with dental implant failure and survival. MATERIALS AND METHODS: Data pertaining to patients who received one or more dental implants from 2011 to 2013 in a regional center were retrospectively reviewed. This included a total of 302 Biomet 3i NanoTite Tapered Certain implants placed in 177 patients. All patients were followed up until the end of 2015. RESULTS: This study found an overall success rate of 95%. Statistically significant factors that were found to affect implant survival were implant length, surgical technique, and presence of diabetes mellitus DM. Age, gender, body mass index (BMI), implant site, smoking, and variable operators were not found to have any significant implant on implant survival. CONCLUSION: This study has demonstrated that the incidence of implant failure and its complications is affected by a number of important factors that clinicians should consider when assessing patients. A follow-up study with a larger sample size, longer follow-up period, and details of the type of prosthetic rehabilitation would be beneficial in producing more definitive conclusions which may improve clinical practice. CLINICAL SIGNIFICANCE: Dental implants play an important role in modern-day dental rehabilitation. It is vital that clinicians understand the impact of variable risk factors on implant survival. This study will add to the growing literature on the subject. PMID- 28816195 TI - Pentraxin-3 Levels in Gingival Crevicular Fluid during Canine Retraction with Nickel-Titanium Coil Spring and Active Tieback. AB - AIM: Orthodontic treatment is routinely carried out in patients with the purpose of correcting various forms of dental malocclusions. Retraction of the canines can be achieved either individually or along with incisor. Pentraxin-3 (PTX-3) is regarded as the true independent indicator of disease activity. Hence, we undertook the present study to assess and compare the level of PTX-3 in patients undergoing canine retraction with active tieback and Nickel-Titanium (NiTi) coil spring. MATERIALS AND METHODS: The present study included assessment of 25 patients that underwent canine retraction as a part of fixed orthodontic treatment. In the maxillary right and left quadrant, active tieback and NiTi coil spring were used respectively. Gingival crevicular fluid samples were collected 1 hour prior to the commencement of orthodontic canine retraction procedure followed by collection at following time intervals: 1 hour, 1, 7, and 14 days after the start of canine retraction procedure. Enzyme-linked immunosorbent assay kit was used for analysis of the samples as per manufacturer's instructions. All the data were recorded and compiled. All the results were analyzed by Statistical Package for the Social Sciences software. RESULTS: Nonsignificant difference was observed in the values of PTX-3 at baseline and 1 hour. While comparing the mean PTX-3 values between different time intervals in both the study groups, significant difference was observed. CONCLUSION: In comparison to the active tieback, NiTi coil exhibited faster space closure rate. CLINICAL SIGNIFICANCE: In patients undergoing orthodontic treatment, PTX-3 is associated with periodontal remodeling under the effect of orthodontic forces. PMID- 28816196 TI - Denture Hygiene Knowledge and Practices among Complete Denture Wearers attending a Postgraduate Dental Institute. AB - AIMS: The aim of this study was to assess the denture hygiene knowledge and practices among patients using complete dentures attending a postgraduate dental hospital in Jabalpur city. The objective of this study was to assess the relationship between hygiene knowledge and practices to the denture wearer's gender, education, and income. MATERIALS AND METHODS: A descriptive, cross sectional survey was conducted using a self-administered questionnaire involving the complete denture patients attending the Department of Prosthodontics. The study subjects were randomly selected by recruiting old dentures wearers visiting the Department of Prosthodontics for a recall visit or for new dentures on the odd dates of the month. All subjects signed an informed consent before filling the questionnaire. The institutional review committee approved the study. Descriptive statistics included computation of frequencies and percentages. Nonparametric test, namely, chi-square test, was used for further data analysis; p-value <0.05 was considered statistically significant. RESULTS: A total of 530 individuals were approached for participation in our survey, 30 (5.66%) subjects declined to participate. The results showed that 195 (39%) subjects were wearing the same dentures for more than 5 years. In this study, 51 (10.2%) subjects reported never having been advised by their dentists as to how to clean their dentures. Among all the subjects interviewed, 264 (52.8%) reported to clean the oral tissues daily. This study disclosed that 66 (13.2%) of the subjects usually slept with their dentures. Maximum subjects in illiterate group had experienced bad breath sometimes when compared with subjects in postgraduate group (chi2 = 47.452, p < 0.001). There was a significant difference for method of denture cleaning according to gender (chi2 = 101.076, p < 0.001). CONCLUSION: The majority of the denture wearers have limited knowledge of denture cleansing and oral hygiene practices. Hygiene habits and practices may not always present a positive correlation with the gender, educational level, and income of the subjects. CLINICAL SIGNIFICANCE: Periodic recall for evaluation of denture and mucosal surfaces along with reinforcement of denture hygiene instructions will go a long way in helping the patients reap maximum benefits out of their prostheses. PMID- 28816197 TI - Cytological Changes in Normal Oral Mucosa of Individuals with Tobacco Habits: A Cytomorphometric Study. AB - INTRODUCTION: Oral cancer is one of the six most common cancers in the world, and globally more than 50% of head and neck cancers occur in Asia, remarkably in India. Overall, 200,000 cases of head and neck cancers occur each year in India, among which 80,000 are oral cancers. Epidemiological and clinical studies suggest a causative role of tobacco use in the evolution of oral potentially malignant and malignant disorders. AIMS AND OBJECTIVES: The aim of the study is to evaluate independently and compare the cytological effects of smoking, tobacco chewing, and smoking in conjunction with tobacco chewing on oral mucosa by cytomorphometric analysis. MATERIALS AND METHODS: The study included a total of 120 individuals subdivided into four groups, each group with 30 individuals. Group I was tobacco smokers, group II tobacco chewers, and group III both tobacco smokers and chewers. Group IV comprised 30 individuals without tobacco habit. Smears were prepared from buccal mucosa of both the study and control groups using a cytobrush and stained using Papanicolaou staining. The cells were quantified using image analysis software. RESULTS: The results of the study showed alterations in the nuclear and cellular parameters in the study groups when compared with control groups and were statistically significant (p < 0.05). CONCLUSION: The present study explains the significance of early identification of cellular changes in individuals with tobacco habits who require early intercession even without any visible oral mucosal changes. The study emphasizes that exfoliative cytology and cytomorphometry aid as a valuable tool to evaluate the effect of tobacco on oral mucosa. CLINICAL SIGNIFICANCE: Simple noninvasive techniques like exfoliative cytology can be employed as a chairside technique and in mass screening programs for identification of cellular changes in oral mucosa of individuals with tobacco habits. Thereby, it can be used as an early diagnostic tool for identification of potentially cancerous and cancerous lesions. PMID- 28816198 TI - Lingual Frenectomy in Joubert Syndrome. AB - AIM: Our aim is to present a case of a rare disorder, such as Joubert syndrome (JS) which required oral surgical intervention under general anesthesia at a very young age to help in achieving normal developmental milestones. BACKGROUND: Ciliopathies are an emerging class of diseases of which JS is a significant member. There have been very few cases of JS with its distinguishing features which have been reported in recent literature. CASE REPORT: We herewith present a case of JS who reported to our unit with a complaint of speech abnormality. Intraoral examination revealed a tongue-tie which was planned for surgical release. As any drugs that interfere with respiratory depression have to be used with utmost care, adequate precautions were taken in this case and the patient was treated under general anesthesia. The tongue-tie was released and associated ham-artomatous outgrowths from the floor of the mouth were also excised. Appropriate postoperative care was taken and the patient was discharged. CONCLUSION: The patient treated by us did not reveal any significant intraoperative or postoperative complications. Treatment of cases of JS required a team effort of multiple dental and medical specialists. Long-term follow-up of such patients is required so that they achieve normal chronological development. CLINICAL SIGNIFICANCE: Joubert syndrome being a rare disorder requires special anesthetic care during any surgical procedure, especially that involving the oral cavity. The need and timing of surgical intervention in such cases should be carefully assessed and appropriate precautions should be taken. PMID- 28816199 TI - Early Childhood Caries: A Review. AB - AIM: To review and update the current knowledge about early childhood caries (ECC) and its etiology, prevalence, risk factors, management, and preventive strategies. BACKGROUND: Early childhood caries is a disease affecting significantly both well-developed and industrial nations. The ECC can significantly affect the child's quality of life, as it may lead to infection, swelling, pain, and other symptoms. The ECC affects children after eruption of primary teeth until age of around 5 years. REVIEW RESULTS: The ECC affects all parts of the tooth including the smooth surface. Upper anterior teeth and primary molars are usually affected. The lower anterior teeth are less likely affected. The risk factors for ECC are diet, bacteria, and host susceptibility. The additional factors, such as presence of enamel defect and the feeding practices also contribute to the initiation and progress of ECC. CONCLUSION: Dentists must focus on utilizing existing techniques to distinguish indications of right on time and propelled caries and give guidance on the best way to counteract and control caries in children. Approaches should be directed to preventive caries control strategies among children. CLINICAL SIGNIFICANCE: Preventing and controlling the development of ECC among children is important to maintain effective eating, speech development, and formation of a positive self-image. PMID- 28816200 TI - Institutional Ethics Committee Regulations and Current Updates in India. AB - AIM: The aim of the review is to provide current updates on regulations for ethics committees and researchers in India. BACKGROUND: Ethical dilemmas in research since time immemorial have been a major concern for researchers worldwide. The question "what makes clinical research ethical" is significant and difficult to answer as multiple factors are involved. REVIEW RESULTS: The research involving human participants in clinical trials should follow the required rules, regulations, and guidelines in one's own country. It is a dynamic process, and updates have to be learned by researcher and committee members. The review highlights the ethical regulation from the Drug Controller General of India, Clinical Trial Registry of India, and Indian Council of Medical Research guidelines. CONCLUSION: In this article, the updates on Indian scenario of the Ethical Committee and guidelines are compiled. CLINICAL SIGNIFICANCE: The review comes handy for clinical researchers and ethics committee members in academic institutions to check on the current updates and keep abreast with the knowledge on regulations of ethics in India. PMID- 28816201 TI - Risk factors and the prognosis of sexual dysfunction in male patients with pituitary adenomas: a multivariate analysis. AB - The impact of sexual dysfunction (SD) is distressing to many male patients with pituitary adenomas which affect both physical and psychological health. The research explored to identify risk factors affecting sexual function and the prognosis of male patients with pituitary adenomas. Two hundred and fifty-four male patients, who aged between 18 and 60 (mean +/- s.d.: 44.16 +/- 10.14) years and diagnosed with pituitary adenomas, were retrospectively analyzed. One hundred and fifty-nine patients (62.6%) complained of SD prior to surgery. The mean International Index of Erectile Function (IIEF-5) in patients with giant adenomas was 16.13 +/- 2.51, much smaller than those with microadenomas or macroadenomas (P < 0.05). All the patients showed significant improvement in terms of erectile dysfunction (ED) following surgery (P < 0.05). In addition, complete resection achieved a higher degree of SD relief than partial resection. The incidence of SD in functioning pituitary adenomas (FPAs) was much higher than that in nonfunctioning pituitary adenomas (NFPAs) (P < 0.05). In addition, compared with NFPAs, males with prolactinomas (82.8%) had the higher prevalence of SD and significantly improvement following surgical intervention (P < 0.05). An inverse relationship was identified between decreasing testosterone levels and increasing incidence of SD before surgery (P < 0.05). There was no significant difference between 6 months and 12 months after surgery in serum testosterone level (P > 0.05). Our results indicated that surgical therapy could be optimized for improvements in SD and that testosterone levels can be used as a sensitive indicator to predict the recovery rate of sexual function in patients with pituitary adenomas following surgery and the serum testosterone level will stay stable in 6 months after surgery. PMID- 28816202 TI - Testosterone treatment and cardiovascular events in prescription database studies. AB - Over the past decade, there has been a substantial increase in the number of men who are treated with testosterone. Despite this increase in the use of testosterone, the risks of adverse cardiovascular events are unclear as meta analyses have reported conflicting findings and no clinical studies have been large enough or long enough to adequately assess for cardiovascular risks. The goal of this paper is to review large prescription database studies of testosterone treatment and adverse cardiovascular events and mortality with the aim of providing some guidance for clinicians and researchers in this controversial area. PMID- 28816203 TI - Using mindfulness to reduce the health effects of community reaction to aircraft noise. AB - AIM: This paper investigates whether mindfulness-based interventions might ameliorate the detrimental health effects of aircraft noise on residential communities. REVIEW: Numerous empirical studies over the past 50 years have demonstrated the increasing negative impact of aircraft noise on residents worldwide. However, extensive database searches have revealed no published studies on psychological interventions that reduce residents' reactivity to environmental noise. By contrast, there has been extensive research over several decades confirming the effectiveness of mindfulness-based stress reduction training in lowering people's stress from work and life. Considering that stress is a major component of aircraft noise reaction, it would seem worth assessing whether mindfulness-based interventions might be effective in reducing the health effects of aircraft noise. It appears that no existing conceptualization of mindfulness specifically accounts for noise as a stressor. Conceptual Analysis: A new conceptual model is presented here which explains how mindfulness can reduce noise reactivity. Two types of mindfulness are distinguished: an active form (meta-mindfulness) and a passive form (supra-mindfulness). It is posited that meta-mindfulness can facilitate "cognitive defusion" which research has confirmed as enabling people to disconnect from their own dysfunctional thoughts. In the case of aircraft noise, negative thinking associated with residents' reactive experiences can exacerbate the health effects they suffer. The present model further proposes that supra-mindfulness can enable an individual to disengage their own sense of identity from the often overwhelming negative thoughts which can define their existence when they are consumed by extreme noise annoyance. CONCLUSION: The mindfulness processes of defusion and disidentification are postulated to be the key efficacy mechanisms potentially responsible for reducing reactivity to aircraft noise. This approach can be evaluated by extending previous research on the health benefits of mindfulness training. PMID- 28816204 TI - Deep band modulated phrase perception in quiet and noise in individuals with auditory neuropathy spectrum disorder and sensorineural hearing loss. AB - CONTEXT: Deep band modulation (DBM) improves speech perception in individuals with learning disability and older adults, who had temporal impairment in them. However, it is unclear on perception of DBM phrases at quiet and noise conditions in individuals with auditory neuropathy spectrum disorder (ANSD) and sensorineural hearing loss (SNHL), as these individuals suffer from temporal impairment. AIM: The aim is to study the effect of DBM and noise on phrase perception in individuals with normal hearing, SNHL, and ANSD. SETTINGS AND DESIGN: A factorial design was used to study deep-band-modulated phrase perception in quiet and at noise. MATERIALS AND METHODS: Twenty participants in each group (normal, SNHL, and ANSD) were included to assess phrase perception on four lists of each unprocessed (UP) and DBM phrases at different signal-to-noise ratios (SNRs) (-1, -3, and -5 dB SNR), which were presented at most comfortable level. In addition, a temporal processing was determined by gap detection threshold test. STATISTICAL ANALYSIS: A mixed analysis of variance was used to investigate main and interaction effects of conditions, noise, and groups. Further, a Pearson product moment correlation was used to document relationship between phrase perception and temporal processing among study participants in each experimental condition. RESULTS: In each group, a significant improvement was observed in DBM phrase perception over UP phrase recognition in quiet and noise conditions. Although a significant improvement was observed, the benefit of recognition from DBM over UP is negligible at -5 dB SNR in both SNHL and ANSD groups. In addition, as expected, a significant improvement in phrase perception in each condition was found in normal hearing than SNHL followed by ANSD. Further, in both atypical groups, a strong negative correlation was found between phrase perception and gap detection threshold in each of the experimental condition. CONCLUSION: This is to conclude that temporal envelope cues from DBM were made available for phrase perception in those individuals who have temporal impairment. PMID- 28816205 TI - On-site and laboratory evaluations of soundscape quality in recreational urban spaces. AB - CONTEXT: Regulations for quiet urban areas are typically based on sound level limits alone. However, the nonacoustic context may be crucial for subjective soundscape quality. AIMS: This study aimed at comparing the role of sound level and nonacoustic context for subjective urban soundscape assessment in the presence of the full on-site context, the visual context only, and without context. MATERIALS AND METHODS: Soundscape quality was evaluated for three recreational urban spaces by using four subjective attributes: loudness, acceptance, stressfulness, and comfort. The sound level was measured at each site and simultaneous sound recordings were obtained. Participants answered questionnaires either on site or during laboratory listening tests, in which the sound recordings were presented with or without each site's visual context consisting of two pictures. They rated the four subjective attributes along with their preference toward eight sound sources. RESULTS: The sound level was found to be a good predictor of all subjective parameters in the laboratory, but not on site. Although all attributes were significantly correlated in the laboratory setting, they did not necessarily covary on site. Moreover, the availability of the visual context in the listening experiment had no significant effect on the ratings. The participants were overall more positive toward natural sound sources on site. CONCLUSION: The full immersion in the on-site nonacoustic context may be important when evaluating overall soundscape quality in urban recreational areas. Laboratory evaluations may not fully reflect how subjective loudness, acceptance, stressfulness, and comfort are affected by sound level. PMID- 28816206 TI - Measurement properties of the chinese weinstein noise sensitivity scale. AB - CONTEXT: Noise sensitivity may mediate or moderate the influences of noise exposure on health, and it needs to be reliably evaluated. The 21-item Weinstein's noise sensitivity scale (WNSS) has been the most popular scale for assessing noise sensitivity, but it is not yet available in traditional Chinese. AIMS: This study aimed to conduct linguistic and psychometric performance of WNSS in Hong Kong (HK) Chinese. SETTINGS AND DESIGN: A population-based telephone survey with 1-week follow-up. MATERIALS AND METHODS: The HK Chinese WNSS was obtained after forward-backward translation from the original English version and cognitive debriefing in five Chinese adults. Its measurement properties were assessed in 569 Chinese adults aged 18 years or above. STATISTICAL ANALYSIS USED: The sample was randomly split into two halves. The first half was used to explore a scale structure of the WNSS by exploratory factor analysis (EFA) with the number of factors determined by the optimal comparison data technique and tested for being artifactual. The second half was used for confirmatory factor analysis. Convergent validity and test-retest validity were also assessed. RESULTS: EFA identified two unipolar factors and removed three items poorly associated with the factors. The factors were likely artifactual and a unidimensional structure was assessed in CFA, which showed a satisfactory fit (root mean square error of approximation = 0.055; comparative fit index = 0.904; standardized root mean square residual = 0.061). The HK Chinese WNSS had good internal consistency (Cronbach's alpha = 0.83) and test-retest reliability (intraclass correlation coefficient = 0.87). Furthermore, it confirmed the expected association with extraversion (r = -0.14, P < 0.001) and neuroticism (r = 0.28, P < 0.001). CONCLUSION: The 18-item HK Chinese WNSS was reliable and valid for assessing noise sensitivity in the Chinese population. PMID- 28816207 TI - Evaluation of the effects of various sound pressure levels on the level of serum aldosterone concentration in rats. AB - INTRODUCTION: Noise exposure may have anatomical, nonauditory, and auditory influences. Considering nonauditory impacts, noise exposure can cause alterations in the automatic nervous system, including increased pulse rates, heightened blood pressure, and abnormal secretion of hormones. The present study aimed at examining the effect of various sound pressure levels (SPLs) on the serum aldosterone level among rats. MATERIALS AND METHODS: A total of 45 adult male rats with an age range of 3 to 4 months and a weight of 200 +/- 50 g were randomly divided into 15 groups of three. Three groups were considered as the control groups and the rest (i.e., 12 groups) as the case groups. Rats of the case groups were exposed to SPLs of 85, 95, and 105 dBA. White noise was used as the noise to which the rats were exposed. To measure the level of rats' serum aldosterone, 3 mL of each rat's sample blood was directly taken from the heart of anesthetized animals by using syringes. The taken blood samples were put in labeled test tubes that contained anticoagulant Ethylenediaminetetraacetic acid. In the laboratory, the level of aldosterone was assessed through Enzyme-linked immunosorbent assay protocol. The collected data were analyzed by the use of Statistical Package for Social Sciences (SPSS) version 18. RESULTS: The results revealed that there was no significant change in the level of rats' serum aldosterone as a result of exposure to SPLs of 65, 85, and 95 dBA. However, the level of serum aldosterone experienced a remarkable increase after exposure to the SPL of 105 dBA (P < 0.001). Thus, the SPL had a significant impact on the serum aldosterone level (P < 0.001). In contrast, the exposure time and the level of potassium in the used water did not have any measurable influence on the level of serum aldosterone (P = 0.25 and 0.39). CONCLUSION: The findings of this study demonstrated that serum aldosterone can be used as a biomarker in the face of sound exposure. PMID- 28816209 TI - Hepatitis C Virus: Discovery to epitaph in a life-time. PMID- 28816210 TI - Dietary deficiency of vitamin A among rural children: A community-based survey using a food-frequency questionnaire. AB - BACKGROUND: Overt vitamin A deficiency has been controlled in most parts of India, but prevalence of subclinical deficiency may still be high, which may enhance susceptibility to infections, reduce growth potential and also lead to higher mortality. We aimed to: (i) assess the consumption pattern of vitamin A rich foods in children 1-5 years of age in rural Jammu; and (ii) estimate the dietary deficiency of vitamin A leading to risk of subclinical vitamin A deficiency in cluster- villages of the study area. METHODS: In 2011, we conducted a survey of 750 children by selecting 50 from each of the 1 5 clusters. The Helen Keller International's Food-Frequency Questionnaire (HKI-FFQ) modified to the local context was used to assess past week's intake for 28 food-items, including vitamin A-rich foods. RESULTS: The study revealed that plant sources such as amaranth, carrots, etc. and animal sources such as eggs and butter were the major sources of vitamin A in the study population. Consumption of amaranth (2.7 days/week) and carrots (1.7 days/week) was moderate but that of animal foods rich in vitamin A was low to negligible (1.1 day/week for eggs and 0.2 day/week for liver and fish combined). The majority (80%) of the cluster-villages manifested inadequate intake of vitamin A-rich foods, thereby making subclinical vitamin A deficiency a public health problem for the whole area. Faulty diets, improper breastfeeding practices, low coverage of vitamin A supplementation and high prevalence of undernutrition could be related to the observed subclinical deficiency. CONCLUSION: Dietary diversification by including both plant and animal sources of vitamin A in adequate amounts along with improved breastfeeding, better implementation of mega-dose vitamin A supplementation and minimizing undernutrition may help in lowering subclinical vitamin A deficiency. The HKI-FFQ may be used as a proxy indicator of vitamin A intake/status for identifying pockets at risk of subclinical vitamin A deficiency in resource constrained settings. PMID- 28816208 TI - PM2.5 Exposure Elicits Oxidative Stress Responses and Mitochondrial Apoptosis Pathway Activation in HaCaT Keratinocytes. AB - Background:: PM2.5 (aerodynamic diameter <= 2.5 MUm) is a dominant and ubiquitous air pollutant that has become a global concern as PM2.5 exposure has been linked to many adverse health effects including cardiovascular and pulmonary diseases. Emerging evidence supports a correlation between increased air PM2.5 levels and skin disorders although reports on the underlying pathophysiological mechanisms are limited. Oxidative stress is the most common mechanism of PM2.5-induced adverse health effects. This study aimed to investigate PM2.5-induced oxidative damage and apoptosis in immortalized human keratinocyte (HaCaT) cells. Methods:: HaCaT cells were exposed to 0, 25, 50, 100, or 200 MUg/ml PM2.5 for 24 h. Reactive oxygen species (ROS) generation, lipid peroxidation products, antioxidant activity, DNA damage, apoptotic protein expression, and cell apoptosis were measured. Results:: PM2.5 exposure (0-200 MUg/ml) for 24 h resulted in increased ROS levels (arbitrary unit: 201.00 +/- 19.28, 264.50 +/- 17.91, 305.05 +/- 19.57, 427.95 +/- 18.32, and 436.70 +/- 17.77) and malondialdehyde production (0.54 +/- 0.05 nmol/mg prot, 0.61 +/- 0.06 nmol/mg prot, 0.68 +/- 0.05 nmol/mg prot, 0.70 +/- 0.05 nmol/mg prot, and 0.76 +/- 0.05 nmol/mg prot), diminished superoxide dismutase activity (6.47 +/- 0.28 NU/mg prot, 5.97 +/- 0.30 NU/mg prot, 5.15 +/- 0.42 NU/mg prot, 4.08 +/- 0.20 NU/mg prot, and 3.76 +/- 0.37 NU/mg prot), and increased DNA damage and apoptosis in a dose-dependent manner in HaCaT cells. Moreover, cytochrome-c, caspase-3, and caspase-9 expression also increased proportionately with PM2.5 dosing. Conclusion:: PM2.5 might elicit oxidative stress and mitochondria-dependent apoptosis that likely manifests as skin irritation and damage. PMID- 28816211 TI - A study of events between the onset of symptoms and hospital admission in patients with acute abdomen. AB - BACKGROUND: Acute abdomen is a common surgical emergency. Prompt investigation and treatment, including surgical intervention, is critical in reducing morbidity and mortality. METHODS: We carried out a prospective observational study at a large urban secondary healthcare centre in India. Patients with surgical acute abdomen were consecutively enrolled in the study over a period of 2 years. Data were collected regarding the onset of symptoms, time of presentation to the hospital and events in the intervening period. RESULTS: Analysis showed that misdiagnosis by medical personnel was significantly associated with delay in admission to the hospital. Unfamiliarity with the medical facilities, ignorance, low education and illiteracy and public holiday were the contributing factors for delayed presentation. Even though we detected some trends, the delay was not significantly associated with age, sex, educational level or socioeconomic status of the patient. The delay resulted in an increased mortality and morbidity especially in patients who needed emergency operative management. CONCLUSION: Delayed presentation of acute abdomen is often not due to a single reason. The causes are distributed over various levels starting from the patient, family, medical personnel, administrative deficiencies, socioeconomic and sociocultural status of the country. PMID- 28816212 TI - Scrub typhus: A prospective, observational study during an outbreak in Rajasthan, India. AB - BACKGROUND: Scrub typhus, a potentially fatal rickettsial infection, is common in India. It usually presents with acute febrile illness along with multi-organ involvement caused by Orientia tsutsugamushi. As there was an outbreak of scrub typhus in the Hadoti region of Rajasthan and there is a paucity of data from this region, we studied this entity to describe the diverse epidemiological, clinico radiological, laboratory parameters and outcome profile of patients with scrub typhus in a tertiary care hospital. METHODS: In this descriptive study, we included all patients with an acute febrile illness diagnosed as scrub typhus by positive IgM antibodies against O. tsutsugamushi, over a period of 4 months (July to October 2014). All relevant data were recorded and analysed. RESULTS: A total of 66 (24 males/42 females) patients were enrolled. Fever was the most common presenting symptom (100%), and in 67% its duration was for 7-14 days. Other symptoms were breathlessness (66.7%), haemoptysis (63.6%), oliguria (51.5%) and altered mental status (39.4%). The pathognomonic features such as eschar (12%) and lymphadenopathy (18%) were not so common. The commonest radiological observation was consistent with acute respiratory distress syndrome. Complications noted were respiratory (69.7%), renal (51.5%) and hepatic dysfunction (48.5%). The overall mortality rate was 21.2%. CONCLUSIONS: Scrub typhus has emerged as an important cause of febrile illness in the Hadoti region and can present with varying clinical manifestations with or without eschar. A high index of suspicion, early diagnosis and prompt intervention may help in reducing the mortality. PMID- 28816213 TI - Association of presenile cataract with galactose-1-phosphate uridyl transferase gene mutations. AB - BACKGROUND: Presenile cataract is commonly idiopathic in origin. However, patients with presenile cataract could have an underlying genetic abnormality of galactose metabolism. We studied the association, if any, between idiopathic presenile cataract and galactose-1 -phosphate uridyl transferase (GALT) gene mutation. METHODS: We selected 50 patients with idiopathic presenile cataract, <45 years of age, and 50 age- and sex-matched controls for the study. Mutations in the GALT gene were determined by polymerase chain reaction restriction fragment length polymorphism. The classical galactosaemia was characterized by Q188R and K285N mutations, whereas Duarte galactosaemia by N314D mutations (Duarte-2: N314D with IVS5-24G >A and Duarte-1: N314D without IVS5- 24G>A). RESULTS: The most common mutation observed was the N314D (Duarte) mutation. The frequencies of classical and N31 4D alleles in patients with presenile cataract (16%) and controls (26%) were not statistically different (p=0.32, OR 0.54, 95% CI 0.20-1.45). Similarly, there was no statistically significant difference in the frequency distribution of Duarte-1 (p=0.77, OR 0.77, 95% CI 0.23-0.24) and Duarte-2 (p=0.44, OR 0.38, 95% CI 0.07-2.03) galactosaemia mutations in patients and controls. CONCLUSION: Duarte galactosaemia, a milder form of the disease, is more common than classical galactosaemia in the Indian population. Duarte galactosaemia is unlikely to be a causative factor in presenile cataract. PMID- 28816214 TI - Synchronous malignancies of thyroglossal duct cyst and thyroid gland. AB - Malignant involvement of thyroglossal duct cyst is rare, still rarer is the synchronous malignant involvement of the thyroid gland. Although the Sistrunk procedure is often regarded as adequate, controversy exists of the need for an additional total thyroidectomy and radioiodine ablative therapy, the decision of which depends upon the presence of (i) suspicious thyroid gland nodule; (ii) presence of lymphadenopathy; or (iii) a previous history of neck irradiation. We report a 47-year-old woman diagnosed with papillary carcinoma within a recurrent thyroglossal duct cyst with infiltration into surrounding soft tissues and a suspicious thyroid nodule of the left thyroid lobe with no regional lymph node involvement. On final histopathology, the left thyroid nodule had a follicular variant of papillary carcinoma thyroid without regional nodal involvement. The patient underwent total thyroidectomy with radioactive iodine postoperatively. PMID- 28816215 TI - Treatment of primary angle-closure glaucoma: Does early lens extraction help? PMID- 28816216 TI - The promise and challenges of buprenorphine implant for treatment of opioid dependence. PMID- 28816217 TI - Multispecialty consensus statement for primary care management of diabetic foot disease in India. PMID- 28816218 TI - Continuing professional development of doctors. AB - After graduating from medical school, all doctors need to undertake some training activities lifelong to maintain, update or develop their knowledge, skills and attitudes towards their professional practice. Continuing professional development (CPD) refers to continuing development of medical and non- medical competencies including professionalism, and interpersonal, managerial and communication skills. There is no single correct way of doing CPD. Most learning in CPD is self-directed and based on one's own learning needs. Effective CPD is characterized by the presence of three factors: a clear reason why a particular CPD needs to be undertaken, learning activities appropriate to identified needs and follow- up on learning. There are several models for CPD. However, the onus is on doctors to show that they continue to maintain appropriate professional standards after training. Here, regulation becomes essential for revalidation, monitoring and to provide the necessary impetus to make CPD mandatory. In India, the credit point system is followed by some states, but the policy to link credit hours with renewal of registration thereafter is not uniform. While the present system is able to monitor time devoted to CPD, it encourages people to gather certificates of attendance at sessions without relevance to or real interest in the subject. The quality and relevance of CPD activities matter more than the quantity of hours. Eventually, we need to move away from credit point counting towards a process of self-accreditation and reflection. Each individual will have to find appropriate methods, learn, document and present evidence that learning has happened, and show that it has been applied in practice. As a profession, we need to encourage a culture where doctors do not view CPD and recertification as a threat. Doctors will need to understand that they are accountable to their patients, and should prioritize and build CPD into their practice. PMID- 28816219 TI - Primary or specialist medical care: Which is more equitable? A policy brief. AB - BACKGROUND: Equity in health and equitable access to healthcare has been at the core of health policy in India. The key policy challenge has been how to make that possible? Various health insurance schemes such as the Rashtriya Swasthya Bima Yojana and Arogyasri seek to improve poor people's access to specialist medical care in the public and private sectors. On the other hand, access to primary medical care has been left to the supply side interventions. METHODS: We did a focused review of evidence on equity aspects of primary medical care versus specialist medical care. We selected relevant publications from the Cochrane Library, PubMed and Google Scholar searches and articles snowballing out of them. RESULTS: Higher primary care physician-to-population ratio is invariably associated with better health outcomes. Primary care may partly protect the poor from adverse effects of income inequality on health status. On the other hand, populations do not necessarily benefit from an overabundance of specialists in a geographical area. CONCLUSIONS: Three key policy lessons emerge from this review. First, states should strengthen primary medical care by upgrading health centres. Second, a family health protection plan should be introduced as a demand side intervention to deliver primary care through health centres, non-profit and for profit clinics. Third, postgraduate courses in family medicine should be introduced for a balanced development of the specialty of primary care pari passu other specialties. PMID- 28816221 TI - Why India needs video-assisted thoracic surgery (VATS). PMID- 28816222 TI - An outlier in public health history in India: A.T.W. Simeons's scheme for rural medical relief, Kolhapur, 1943-47. AB - It is customary to date provision of health services in rural India to the Report of the Bhore Committee (1946) and its descendants. It is presumed that in pre Bhore India (the last half-century of the British era) the rural public health scenario was devoid of discerning commentators and practical effort. The presumption is misleading. Historical material shows that attempts, official and non-official, to improve rural environments and attend to the health problems of villagers were not wanting. Such efforts followed two main, sometimes intersecting, streams, namely sanitation and medical relief. I examine a little known, yet noteworthy effort in the latter category, connected with Bombay Province, which incorporated in fledgling form modern practice in rural healthcare delivery. The central character was a medical expatriate of German ancestry (but contested nationality), whose connection with Bombay spanned almost two decades including the period of the Second World War. Albert Theodore William Simeons (1900-70) was a specialist in tropical medicine whose intellectual interests and facile pen ranged wide. Providence and the paranoia of the war-time Government of British India saw him in 1943 as Director of Public Health in the princely state of Kolhapur. Here he set up and supervised a novel scheme for 'Rural Medical Relief' centred on trained villagers as first-line providers of medical treatment. The scheme endured after Simeons's departure from India, and worked well enough to be remembered post-1947 by senior medical personnel of the time and also (but without crediting him) in official publications. The Kolhapur experience also inspired a first-of-its kind fictional work by this multi-faceted personality. Archival material available in India relating to Simeons's years at Kolhapur is trifling. Other primary sources have therefore been utilized to rescue the history. PMID- 28816220 TI - Incidents of violence against doctors in India: Can these be prevented? AB - Violence against doctors is on the rise all over the world. However, India has a unique problem. Meagre government spending on healthcare has resulted in poor infrastructure and human resource crunch in government hospitals. Hence, people are forced to seek private healthcare. Small and medium private healthcare establishments, which provide the bulk of healthcare services, are isolated, disorganized and vulnerable to violence. Violence against health service providers is only a manifestation of this malady. The Prevention of Violence Against Medicare Persons and Institutions Acts, which have been notified in 19 states in the past 10 years, have failed to address the issue. To prevent violence against doctors, government spending on healthcare must be increased and the Indian Penal Code should be changed to provide for a tougher penalty that could act as a deterrent to violence against doctors. PMID- 28816223 TI - Thomas Earl Starzl (11 March 1926-4 March 2017). PMID- 28816224 TI - Letter from Chennai. PMID- 28816225 TI - Letter from Glasgow. PMID- 28816226 TI - Late presentation of retinal detachment in India: A comparison between developing nations. PMID- 28816228 TI - Association of adiposity, telomere length and mortality: data from the NHANES 1999-2002. AB - BACKGROUND/OBJECTIVES: Telomere shortening is associated with age and risk of medical comorbidity. We assessed the relationship between measures of adiposity, leukocyte telomere length, and mortality and whether it is modified by age. SUBJECTS/METHODS: Subjects with dual-energy X-ray absorptiometry measures were identified using the National Health and Nutrition Examination Survey 1999-2002. Obesity was categorized using two body fat definitions (BF1%: men ?25%; females ?35%; BF2% ?28% and ?38%, respectively), body mass index (BMI) and waist circumference (WC; men ?102 cm; females ?88 cm). Telomere length relative to standard reference DNA (T/S ratio) was assessed using quantitative PCR. Weighted multivariable regression models evaluated the association of telomere length with adiposity, both continuously and categorically (low/normal BF%, low/high WC and standard BMI categories). Differences in telomere length by age and adiposity were ascertained and subsequent models were stratified by age. Proportional hazard models assessed the risk of mortality by adiposity status. A telomere by adiposity interaction was tested in the entire cohort and by age category (<60 vs ?60 years; <70 vs ?70 years). RESULTS: We identified 7827 subjects. Mean age was 46.1 years. Overall telomere length was 1.05+/-0.01 (s.e.) that differed by BF1% (low/high: 1.12+/-0.02 vs 1.03+/-0.02; P<0.001), BF2% (1.02+/-0.02 vs 1.11+/ 0.02; P<0.001), BMI (underweight 1.08+/-0.03; normal 1.09+/-0.02; overweight 1.04+/-0.02; and obese 1.03+/-0.02;P<0.001) and WC (low/high 1.09+/-0.02 vs 1.02+/-0.02; P<0.001). Adjusted beta-coefficients evaluating the relationship between telomere length and adiposity (measured continuously) were as follows: BF1% (beta=-0.0033+/-0.0008; P<0.001), BF2% (-0.041+/-0.008; P<0.001), BMI (beta= 0.025+/-0.0008; P=0.005) and WC (beta=-0.0011+/-0.0004; P=0.007). High BF% (BF1%: beta=-0.035+/-0.011; P=0.002; BF2%: beta=-0.041+/-0.008; P<0.001) and WC (beta= 0.035+/-0.011; P=0.008) were inversely related to telomere length (TL). Stratifying by age, high BF1% (-0.061+/-0.013), BF2% (-0.065+/-0.01), BMI-obesity (-0.07+/-0.015) and high WC (-0.048+/-0.013) were significant (all P<0.001). This association diminished with increasing age. In older participants, TL was inversely related to mortality (hazard ratio 0.36 (0.27, 0.49)), as were those classified by BF1% (0.68 (0.56, 0.81)), BF2% (0.75 (0.65, 0.80)), BMI (0.50 (0.42, 0.60)) and WC (0.72 (0.63, 0.83)). No interaction was observed between adiposity status, telomere length and mortality. CONCLUSIONS: Obesity is associated with shorter telomere length in young participants, a relationship that diminishes with increasing age. It does not moderate the relationship with mortality. PMID- 28816229 TI - Plasma expression level of miRNA let-7 is positively correlated with carotid intima-media thickness in patients with essential hypertension. AB - MicroRNAs (miRNA, miR) play vital part in the pathophysiology of arterial remodeling in hypertension patients, and are increasingly becoming novel biomarkers in cardiovascular disease. The study was designed to evaluate the correlation between let-7 expression level and subclinical atherosclerosis in untreated patients with newly diagnosed essential hypertension. We assessed 240 participants including 60 healthy volunteers with normal carotid intima-media thickness (nCIMT), 60 healthy volunteers with increased CIMT (iCIMT), 60 hypertension patients with nCIMT and 60 hypertension patients with iCIMT. All patients underwent measurements of CIMT and ambulatory blood pressure (BP) monitoring. The level of let-7 was quantified using real-time reverse transcription polymerase chain reaction. Correlations of let-7 expression with BP parameters and CIMT were assessed using multiple linear regression analysis. We observed the lowest miRNA let-7 expression (21.70+/-1.45 vs 29.33+/-2.58 vs 31.50+/-1.80 vs 35.49+/-2.33; P<0.001) in healthy controls with nCIMT, followed by healthy controls with iCIMT, then hypertension patients with nCIMT and highest expression in hypertension patients with iCIMT. Let-7 was independently correlated with CIMT(r=0.587, P<0.001), and multiple linear regression analysis showed that let-7 was independently correlated with CIMT (beta=0.031, P<0.001). Our findings provide significant evidence that plasma let-7 could represent a non invasive marker for atherosclerosis in hypertensive patients and herald the emergence of a potential indicator to monitor end-organ damage in hypertension. PMID- 28816230 TI - Plasma PCSK9 levels are unrelated to arterial stiffness in a community-based, 4.8 year prospective study. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important circulating serine protease in low-density lipoprotein cholesterol (LDL-C) metabolism. Increased plasma PCSK9 levels lead to increased plasma levels of LDL-C and an increased risk of cardiovascular disease (CVD). LDL-C is positively correlated with arterial stiffness, a surrogate endpoint of CVD. However, whether plasma levels of PCSK9 could influence arterial stiffness is still unclear. Our study examined the relationship between plasma levels of PCSK9 and arterial stiffness (carotid-femoral pulse wave velocity (cf-PWV)) in a community-based population. We analysed the measurements of baseline plasma PCSK9 levels and both baseline and follow-up cf-PWV in 1447 subjects in a 4.8-year longitudinal study. Pearson's correlation analyses revealed that plasma levels of PCSK9 were not correlated with cf-PWV. Additionally, multiple linear regression analyses using cf-PWV as the dependent variable and adjusting for several potential confounders showed that plasma PCSK9 levels were not significantly correlated with cf-PWV. Thus, our study could not prove an independent relationship between plasma levels of PCSK9 and arterial stiffness. PMID- 28816231 TI - Molecular mechanisms of the analgesic action of Wu-tou Decoction on neuropathic pain in mice revealed using microarray and network analysis. AB - Wu-tou Decoction (WTD) is a classic herbal formula in traditional Chinese medicine for the treatment of joint diseases, neuropathic pain (NP) and inflammatory pain. In this study we investigated whether WTD produced analgesic action in a mouse spinal nerve ligation (SNL) model and elucidated the underlying molecular mechanisms. Mice were subjected to SNL and orally treated with WTD (3.15, 6.30 or 12.60 g.kg-1.d-1) for 21 d. SNL induced mechanical hyperalgesia and heat hyperalgesia characterized by rapid and persistent pain hypersensitivity. In addition, the expression levels of IL-1beta, TNF-alpha, CCL2 and CXCL1 in the spinal cord dorsal horn were dramatically increased on the 10th d post-surgery. Oral administration of WTD dose-dependently suppressed both mechanical and heat hyperalgesia as well as the expression levels of inflammatory cytokines in the spinal cord dorsal horn on the 21st d post-surgery. Then whole genome microarray analyses were conducted to detect the gene expression profiles of spinal cord dorsal horn in SNL mice with or without WTD treatment. After construction of the WTD-SNL-network and topological analysis, a list of candidate target genes of WTD acting on SNL-induced NP was identified and found to be functionally enriched in several glial cell activation-related pathways and neuroinflammatory pathways. Our data have clarified the gene expression patterns in the mouse spinal cord under the NP condition. We also demonstrate the analgesic action of WTD through suppression of glial cell activation and neuroinflammation, which suggest the potential of WTD as a promising candidate for the treatment of NP. PMID- 28816232 TI - Dual roles of QOA-8a in antiosteoporosis: a combination of bone anabolic and anti resorptive effects. AB - Osteoporotic treatments have largely depended on antiresorptive or anabolic drugs; but the former also suppresses new bone formation, and the latter only includes human parathyroid hormone. There is no drug that has a dual effect to inhibit bone resorption and to stimulate bone formation simultaneously. Here, we report a small molecule, a quinoxaline derivative of oleanolic acid (QOA-8a) that plays such dual roles in osteoblasts and osteoclasts in the treatment of osteoporosis. Osteoclast differentiation was induced by incubation of primary mouse bone marrow-derived macrophages in the presence of RANKL and M-CSF, treatment with QOA-8a dose-dependently inhibited the osteoclast formation with an IC50 value of 0.098 MUmol/L. QOA-8a also directly acted on osteoblasts, and stimulated new bone formation in murine calvarial bones in vitro and in vivo. In an OVX rat model, administration of QOA-8a (1, 5 mg.kg-1.d-1, po) for 16 weeks effectively prevented OVX-induced bone loss, accompanied by decreased serum levels of the bone resorption marker CTX-1 and increased serum levels of osteoblast marker N-MID-OT. Meaningfully, our preliminary study revealed that QOA 8a down-regulated the ERK1/2 signal in osteoclasts and up-regulated the signal in osteoblasts. QOA-8a showed dual functions in both animal and human osteoclastogenesis and osteoblastogenesis. Our results demonstrate that QOA-8a might serve as a lead compound with a dual function of bone anabolic and anti resorptive effects in the development of anti-osteoporosis agents. PMID- 28816233 TI - Shikonin induces glioma cell necroptosis in vitro by ROS overproduction and promoting RIP1/RIP3 necrosome formation. AB - Necroptosis is a type of programmed necrosis regulated by receptor interacting protein kinase 1 (RIP1) and RIP3. Necroptosis is found to be accompanied by an overproduction of reactive oxygen species (ROS), but the role of ROS in regulation of necroptosis remains elusive. In this study, we investigated how shikonin, a necroptosis inducer for cancer cells, regulated the signaling leading to necroptosis in glinoma cells in vitro. Treatment with shikonin (2-10 MUmol/L) dose-dependently triggered necrosis and induced overproduction of intracellular ROS in rat C6 and human SHG-44, U87 and U251 glioma cell lines. Moreover, shikonin treatment dose-dependently upregulated the levels of RIP1 and RIP3 and reinforced their interaction in the glioma cells. Pretreatment with the specific RIP1 inhibitor Nec-1 (100 MUmol/L) or the specific RIP3 inhibitor GSK-872 (5 MUmol/L) not only prevented shikonin-induced glioma cell necrosis but also significantly mitigated the levels of intracellular ROS and mitochondrial superoxide. Mitigation of ROS with MnTBAP (40 MUmol/L), which was a cleaner of mitochondrial superoxide, attenuated shikonin-induced glioma cell necrosis, whereas increasing ROS levels with rotenone, which improved the mitochondrial generation of superoxide, significantly augmented shikonin-caused glioma cell necrosis. Furthermore, pretreatment with MnTBAP prevented the shikonin-induced upregulation of RIP1 and RIP3 expression and their interaction while pretreatment with rotenone reinforced these effects. These findings suggest that ROS is not only an executioner of shikonin-induced glioma cell necrosis but also a regulator of RIP1 and RIP3 expression and necrosome assembly. PMID- 28816234 TI - Novel mutations of TCIRG1 cause a malignant and mild phenotype of autosomal recessive osteopetrosis (ARO) in four Chinese families. AB - Human autosomal recessive osteopetrosis (ARO), also known as infantile malignant osteopetrosis, is a rare genetic bone disorder that often causes death. Mutations in T-cell immune regulator 1 (TCIRG1) are a frequent cause of human ARO. Six additional genes (TNFSF11, TNFRSF11A, CLCN7, OSTM1, SNX10, PLEKHM1) were also found to be associated with human ARO. In order to expand the mutation spectrum and clinical diversity for a better understanding of the ARO phenotype and to further investigate the clinical characteristics of benign subjects with ARO, we here report five individuals with ARO from four unrelated Chinese families. X-ray examination was conducted and bone turnover markers were assayed. The gene of T cell immune regulator 1 (TCIRG1) was screened and analyzed. Monocyte-induced osteoclasts were prepared and their resorption ability was studied in vitro. We identified five novel mutations (c.66delC, c.1020+1_1020+5dup, c.2181C>A, c.2236+6T>G, c.692delA) in these patients. Four patients displayed a malignant phenotype, three of them died, and one who received bone marrow transplantation survived. The remaining one, a 24-year-old male from a consanguineous family, was diagnosed based on radiological findings but presented no neurological or hematological defects. He was homozygous for c.2236+6T>G in intron 18; this mutation influenced the splicing process. An in vitro functional study of this novel splicing defect showed no resorption pits on dentine slices. TCIRG1 dependent osteopetrosis with a mild clinical course was observed for the first time in Chinese population. The present findings add to the wide range of phenotypes of Chinese patients with TCIRG1-dependent ARO and enrich the database of TCIRG1 mutations. PMID- 28816235 TI - G3BP2 is involved in isoproterenol-induced cardiac hypertrophy through activating the NF-kappaB signaling pathway. AB - The RasGAP SH3 domain-binding proteins (G3BPs) are a family of RNA-binding proteins that can co-ordinate signal transduction and post-transcriptional gene regulation. G3BPs have been shown to be involved in mediating a great diversity of cellular processes such as cell survival, growth, proliferation and apoptosis. But the potential roles of G3BPs in the pathogenesis and progression of cardiovascular diseases remain to be clarified. In the present study, we provide the first evidence that suggests the participation of G3BP2 in cardiac hypertrophy. In cultured neonatal rat cardiomyocytes (NRCMs), treatment with isoproterenol (ISO, 0.1-100 MUmol/L) significantly elevated the mRNA and protein levels of G3BP2. Similar results were observed in the hearts of rats subjected to 7D-injection of ISO, accompanied by obvious heart hypertrophy and elevated the expression of hypertrophy marker genes ANF, BNP and beta-MHC in heart tissues. Overexpression of G3BP2 in NRCMs led to hypertrophic responses evidenced by increased cellular surface area and the expression of hypertrophy marker genes, whereas knockdown of G3BP2 significantly attenuated ISO-induced hypertrophy of NRCMs. We further showed that G3BP2 directly interacted with IkappaBalpha and promoted the aggregation of the NF-kappaB subunit p65 in the nucleus and increased NF-kappaB-dependent transcriptional activity. NF-kappaB inhibition with PDTC (50 MUmol/L) or p65 knockdown significantly decreased the hypertrophic responses in NRCMs induced by ISO or G3BP2 overexpression. These results give new insight into the functions of G3BP2 and may help further elucidate the molecular mechanisms underlying cardiac hypertrophy. PMID- 28816236 TI - MicroRNA-132 suppresses cell proliferation in human breast cancer by directly targeting FOXA1. AB - Dysregulation of microRNAs (miRNAs) has been implicated in cancer. Recently, miR 132 has been reported to be downregulated in the tissues of patients with breast cancer. In this study, we investigated the functional role of miR-132 and its direct target FOXA1 in breast cancer cells. In 30 human breast cancer tissues, FOXA1 was significantly overexpressed and negatively correlated with miR-132 expression. A bioinformatics analysis suggested that FOXA1 was a potential target of miR-132. Furthermore, dual luciferase reporter assays revealed that miR-132 dose-dependently inhibited the luciferase activity of the wt 3'UTR of FOXA1 rather than the mut 3'UTR of FOXA1 in human MDA-MB-468 and SK-BR3 breast cancer cells. Moreover, ectopic miR-132 expression significantly inhibited FOXA1 protein expression, whereas miR-132 knockdown promoted FOXA1 expression in the breast cancer cells. Ectopic miR-132 expression also suppressed proliferation of the breast cancer cells, whereas miR-132 knockdown promoted proliferation of the breast cancer cells, which was reversed by knockdown of FOXA1 expression. We conclude that MiR-132 suppresses proliferation of breast cancer cells at least partially though inhibition of FOXA1. These results suggest that miR-132 and FOXA1 may be potential biomarkers or therapeutic targets in breast cancer. PMID- 28816237 TI - Genetics: Human genome editing in heart disease. PMID- 28816239 TI - Hippocampal Protein Kinase C Signaling Mediates the Short-Term Memory Impairment Induced by Delta9-Tetrahydrocannabinol. AB - Cannabis affects cognitive performance through the activation of the endocannabinoid system, and the molecular mechanisms involved in this process are poorly understood. Using the novel object-recognition memory test in mice, we found that the main psychoactive component of cannabis, delta9 tetrahydrocannabinol (THC), alters short-term object-recognition memory specifically involving protein kinase C (PKC)-dependent signaling. Indeed, the systemic or intra-hippocampal pre-treatment with the PKC inhibitors prevented the short-term, but not the long-term, memory impairment induced by THC. In contrast, systemic pre-treatment with mammalian target of rapamycin complex 1 inhibitors, known to block the amnesic-like effects of THC on long-term memory, did not modify such a short-term cognitive deficit. Immunoblot analysis revealed a transient increase in PKC signaling activity in the hippocampus after THC treatment. Thus, THC administration induced the phosphorylation of a specific Ser residue in the hydrophobic-motif at the C-terminal tail of several PKC isoforms. This significant immunoreactive band that paralleled cognitive performance did not match in size with the major PKC isoforms expressed in the hippocampus except for PKCtheta. Moreover, THC transiently enhanced the phosphorylation of the postsynaptic calmodulin-binding protein neurogranin in a PKC dependent manner. These data demonstrate that THC alters short-term object-recognition memory through hippocampal PKC/neurogranin signaling. PMID- 28816238 TI - Acute myeloid leukemia transforms the bone marrow niche into a leukemia permissive microenvironment through exosome secretion. AB - Little is known about how leukemia cells alter the bone marrow (BM) niche to facilitate their own growth and evade chemotherapy. Here, we provide evidence that acute myeloid leukemia (AML) blasts remodel the BM niche into a leukemia growth-permissive and normal hematopoiesis-suppressive microenvironment through exosome secretion. Either engrafted AML cells or AML-derived exosomes increased mesenchymal stromal progenitors and blocked osteolineage development and bone formation in vivo. Preconditioning with AML-derived exosomes 'primed' the animals for accelerated AML growth. Conversely, disruption of exosome secretion in AML cells through targeting Rab27a, an important regulator involved in exosome release, significantly delayed leukemia development. In BM stromal cells, AML derived exosomes induced the expression of DKK1, a suppressor of normal hematopoiesis and osteogenesis, thereby contributing to osteoblast loss. Conversely, treatment with a DKK1 inhibitor delayed AML progression and prolonged survival in AML-engrafted mice. In addition, AML-derived exosomes induced a broad downregulation of hematopoietic stem cell-supporting factors (for example, CXCL12, KITL and IGF1) in BM stromal cells and reduced their ability to support normal hematopoiesis. Altogether, this study uncovers novel features of AML pathogenesis and unveils how AML cells create a self-strengthening leukemic niche that promotes leukemic cell proliferation and survival, while suppressing normal hematopoiesis through exosome secretion. PMID- 28816241 TI - Combinatorial Psycho-Pharmacological Approaches for the Treatment of Abnormal Aggression. PMID- 28816240 TI - Rodent Mismatch Negativity/theta Neuro-Oscillatory Response as a Translational Neurophysiological Biomarker for N-Methyl-D-Aspartate Receptor-Based New Treatment Development in Schizophrenia. AB - Deficits in the generation of auditory mismatch negativity (MMN) generation are among the most widely replicated neurophysiological abnormalities in schizophrenia and are linked to underlying dysfunction of N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission. Here, we evaluate physiological properties of rodent MMN, along with sensitivity to NMDAR agonist and antagonist treatments, relative to known patterns of dysfunction in schizophrenia. Epidural neurophysiological responses to frequency and duration deviants, along with responses to standard stimuli, were obtained at baseline and following 2 and 4 weeks' treatment in rats treated with saline, phencyclidine (PCP, 15 mg/kg/d by osmotic minipump), or PCP+glycine (16% by weight diet) interventions. Responses were analyzed using both event-related potential (ERP) and neuro-oscillatory (evoked power) approaches. At baseline, rodent duration MMN was associated with increased theta (theta)-frequency response similar to that observed in humans. PCP significantly reduced rodent duration MMN (p<0.001) and theta-band (p<0.01) response. PCP effects were prevented by concurrent glycine treatment (p<0.01 vs PCP alone). Effects related to stimulus-specific adaptation (SSA) were observed primarily in the alpha (alpha) and beta (beta) frequency ranges. PCP treatment also significantly reduced alpha-frequency response to standard stimuli while increasing theta-band response, reproducing the pattern of deficit observed in schizophrenia. Overall, we demonstrate that rodent duration MMN shows neuro oscillatory signature similar to human MMN, along with sensitivity to the NMDAR antagonist and agonist administration. These findings reinforce recent human studies linking MMN deficits to theta-band neuro-oscillatory dysfunction and support utility of rodent duration MMN as a translational biomarker for investigation of mechanisms underlying impaired local circuit function in schizophrenia. PMID- 28816242 TI - Effect of the mGluR5-NAM Basimglurant on Behavior in Adolescents and Adults with Fragile X Syndrome in a Randomized, Double-Blind, Placebo-Controlled Trial: FragXis Phase 2 Results. AB - Preclinical data suggest that inhibition of the metabotropic glutamate receptor 5 (mGluR5) receptor might hold therapeutic benefits in Fragile X syndrome (FXS). Treatment of Fmr1 knockout mice with mGluR5-negative allosteric modulators (NAMs) has been reported to correct a broad range of phenotypes related to FXS. The early short-term clinical trials with mGluR5 NAMs, including basimglurant, assessing the effects in individuals with FXS, were supportive of further exploration in larger, well-controlled trials. We evaluated basimglurant, a potent and selective mGluR5 NAM, in a 12-week, double-blind, parallel-group study of 183 adults and adolescents (aged 14-50, mean 23.4 years) with FXS. Individuals with an FMR1 full mutation were randomized to placebo or one of two doses of basimglurant. The primary efficacy endpoint was the change from baseline in behavioral symptoms using the Anxiety Depression and Mood Scale (ADAMS) total score. All treatment arms showed marked behavioral improvements from baseline to week 12 with less improvement in the basimglurant 1.5 mg arm than placebo; however, basimglurant 0.5 mg was inferior to placebo in the ADAMs total score. Treatment with basimglurant was overall well-tolerated. A higher incidence of adverse events classified as psychiatric disorders were reported in patients treated with basimglurant, including three patients with hallucinations or psychosis. In this phase 2 clinical trial, basimglurant did not demonstrate improvement over placebo. Evaluation of the overall risk-benefit in younger patient populations is an important consideration for the design of potential further investigations of efficacy with this class of medications. PMID- 28816244 TI - Data sharing: guard the privacy of donors. PMID- 28816245 TI - Ram-pressure feeding of supermassive black holes. AB - When a supermassive black hole at the centre of a galaxy accretes matter, it gives rise to a highly energetic phenomenon: an active galactic nucleus. Numerous physical processes have been proposed to account for the funnelling of gas towards the galactic centre to feed the black hole. There are also several physical processes that can remove gas from a galaxy, one of which is ram pressure stripping by the hot gas that fills the space between galaxies in galaxy clusters. Here we report that six out of a sample of seven 'jellyfish' galaxies galaxies with long 'tentacles' of material that extend for dozens of kiloparsecs beyond the galactic disks-host an active nucleus, and two of them also have galactic-scale ionization cones. The high incidence of nuclear activity among heavily stripped jellyfish galaxies may be due to ram pressure causing gas to flow towards the centre and triggering the activity, or to an enhancement of the stripping caused by energy injection from the active nucleus, or both. Our analysis of the galactic position and velocity relative to the cluster strongly supports the first hypothesis, and puts forward ram pressure as another possible mechanism for feeding the central supermassive black hole with gas. PMID- 28816246 TI - Climate adaptation: Past US floods give lessons in retreat. PMID- 28816243 TI - Dopamine Synthesis Capacity is Associated with D2/3 Receptor Binding but Not Dopamine Release. AB - Positron Emission Tomography (PET) imaging allows the estimation of multiple aspects of dopamine function including dopamine synthesis capacity, dopamine release, and D2/3 receptor binding. Though dopaminergic dysregulation characterizes a number of neuropsychiatric disorders including schizophrenia and addiction, there has been relatively little investigation into the nature of relationships across dopamine markers within healthy individuals. Here we used PET imaging in 40 healthy adults to compare, within individuals, the estimates of dopamine synthesis capacity (Ki) using 6-[18F]fluoro-l-m-tyrosine ([18F]FMT; a substrate for aromatic amino acid decarboxylase), baseline D2/3 receptor-binding potential using [11C]raclopride (a weak competitive D2/3 receptor antagonist), and dopamine release using [11C]raclopride paired with oral methylphenidate administration. Methylphenidate increases synaptic dopamine by blocking the dopamine transporter. We estimated dopamine release by contrasting baseline D2/3 receptor binding and D2/3 receptor binding following methylphenidate. Analysis of relationships among the three measurements within striatal regions of interest revealed a positive correlation between [18F]FMT Ki and the baseline (placebo) [11C]raclopride measure, such that participants with greater synthesis capacity showed higher D2/3 receptor-binding potential. In contrast, there was no relationship between [18F]FMT and methylphenidate-induced [11C]raclopride displacement. These findings shed light on the nature of regulation between pre- and postsynaptic dopamine function in healthy adults, which may serve as a template from which to identify and describe alteration with disease. PMID- 28816247 TI - Seismology: Quake news from America. PMID- 28816248 TI - Vigorous atmospheric motion in the red supergiant star Antares. AB - Red supergiant stars represent a late stage of the evolution of stars more massive than about nine solar masses, in which they develop complex, multi component atmospheres. Bright spots have been detected in the atmosphere of red supergiants using interferometric imaging. Above the photosphere of a red supergiant, the molecular outer atmosphere extends up to about two stellar radii. Furthermore, the hot chromosphere (5,000 to 8,000 kelvin) and cool gas (less than 3,500 kelvin) of a red supergiant coexist at about three stellar radii. The dynamics of such complex atmospheres has been probed by ultraviolet and optical spectroscopy. The most direct approach, however, is to measure the velocity of gas at each position over the image of stars as in observations of the Sun. Here we report the mapping of the velocity field over the surface and atmosphere of the nearby red supergiant Antares. The two-dimensional velocity field map obtained from our near-infrared spectro-interferometric imaging reveals vigorous upwelling and downdrafting motions of several huge gas clumps at velocities ranging from about -20 to +20 kilometres per second in the atmosphere, which extends out to about 1.7 stellar radii. Convection alone cannot explain the observed turbulent motions and atmospheric extension, suggesting that an unidentified process is operating in the extended atmosphere. PMID- 28816249 TI - Carbon emissions: More nuclear power can speed CO2 cuts. PMID- 28816250 TI - Data sharing: do scientists know best? PMID- 28816252 TI - Astronomy: A turbulent stellar atmosphere in full view. PMID- 28816254 TI - History: Ingenious solutions sparked by a crisis. PMID- 28816255 TI - Massive El Nino sent greenhouse-gas emissions soaring. PMID- 28816256 TI - Budget cuts fuel frustration among Japan's academics. PMID- 28816257 TI - Thousands across India march in support of science. PMID- 28816258 TI - China launches brain-imaging factory. PMID- 28816259 TI - Why 14 ecology labs teamed up to watch grass grow. PMID- 28816260 TI - California scientists push to create massive climate-research programme. PMID- 28816261 TI - US biomedical-research facilities unprepared for attacks and natural disasters. PMID- 28816262 TI - Revitalize the world's countryside. PMID- 28816263 TI - Opioid emergency, climate language and a frozen fruit cake. PMID- 28816264 TI - Against discrimination. PMID- 28816265 TI - China's embrace of embryo selection raises thorny questions. PMID- 28816266 TI - A little democracy could go a long way. PMID- 28816267 TI - [Nuclear export signal of androgen receptor regulated of androgen receptor stability in prostate cancer]. AB - OBJECTIVE: To investigate the mechanisms of nuclear export signal of androgen receptor (NESAR) in the regulation of androgen receptor (AR) protein expression and stability in prostate cancer. METHODS: The green fluorescent protein fusion protein expression vectors pEGFP-AR(1-918aa), pEGFP-NESAR (743-817aa), pEGFP-NAR (1-665aa) and pEGFP-NAR-NESAR, and lysine mutants of NESAR pEGFP-NESAR K776R, pEGFP-NESAR K807R and pEGFP-NESAR K776R/K807R, were transiently transfected into prostate cancer cell line PC3. Fluorescence microscopy, Western blot and immunoprecipitation were used to detect NESAR regulation of androgen receptor stability. RESULTS: Under the fluorescence microscope, NESAR-containing fusion proteins were cytoplasmic localization, and their fluorescence intensities were much weaker than those without NESAR. The expression levels of NESAR-containing fusion proteins were significantly lower than those without NESAR. The half-lives of GFP-NESAR and GFP-NAR-NESAR were less than 6 h, while the expression of GFP and GFP-NAR was relatively stable and the half-life was more than 24 h in the presence of cycloheximide. The expression levels of GFP-NESAR were significantly increased by proteasome inhibitor MG132 treatment in a dose-dependent manner; in contrast, MG132 did not show any significant effect on the protein levels of GFP. When new protein synthesis was blocked, MG132 could also prevent the degradation of GFP-NESAR in the transfected cells in the presence of cycloheximide, while it had no significant effect on GFP protein stability in the parallel experiment. GFP immunoprecipitation showed that the ubiquitination level of GFP-NESAR fusion protein was significantly higher than that of the GFP control. The mutations of lysine sites K776 and K807 in NESAR significantly reduced the level of ubiquitination, and showed increased protein stability, indicating that they were the key amino acid residues of NESAR ubiquitination. CONCLUSION: NESAR was unstable and decreased the stability of its fusion proteins. NESAR was the target of polyubiquitination and mediated the degradation of its fusion proteins through the ubiquitin-proteasome pathway in prostate cancer cells. Our research provides a new way to regulate the level and/or activity of AR proteins, thus helping us understand the molecular mechanisms of AR degradation and strict control of AR in the progression to castration-resistance. PMID- 28816268 TI - [Expression and localization of transmembrane protein CMTM2 in human testis and sperm]. AB - OBJECTIVE: To study the expression of transmembrane protein CMTM2 in the testis and sperm of adult males and to approach the potential function of the protein in the male reproductive system. METHODS: The expression of CMTM2 in human testis and sperm was confirmed by Western blot. Immunohistochemical staining was used for detecting CMTM2 localization in the testis tissue, TRITC-CMTM2 and FITC Hoechst double immunofluorescence staining was performed to examine the subcellular localization of CMTM2 in the human sperm before and after acrosome reaction, that is, immunofluorescent staining was used for detecting CMTM2 localization in both the testis and sperm before and after the acrosome reaction. RESULTS: CMTM2 was presented in both human testis and sperm. In the testis, CMTM2 immunoreactive particles were observed mainly in the membrane of the different stages of spermatogenic cells. In the human sperm, its immunoreactivity was restrictively localized to the posterior head where sperm-egg fusion occurred, and the CMTM2 localization was not affected by sperm acrosome reaction. CMTM2 was widely expressed in seminiferous tubules of the human testis, mainly in the cell membranes of spermatogenic cells, which was consistent with the previous reports. The immunofluorescence performed on frozen human testis slides showed similar findings with immunohistochemistry, which gave weight to the localization of CMTM2 in the cell membranes of spermatogenic cells at different stages. TRITC CMTM2 and FITC-Hoechst double immunofluorescence staining was performed to examine the subcellular localization of CMTM2 in the human sperm before and after acrosome reaction. CMTM2 was localized at the posterior head of sperm before and after acrosome reaction. The localization and expression of CMTM2 were not affected by sperm acrosome reaction. CONCLUSION: Expression of CMTM2 in the male reproductive system of the adult human exhibits cell- and region-specific patterns, which suggests that they may play an important role in spermatogenesis and sperm-egg fusion. The expression of CMTM2 in the male reproductive system of the adult human exhibits cell- and region-specific patterns, which suggests that they may play an important role in spermatogenesis and sperm-egg fusion. However, it still remains to be further elucidated about the definite role of CMTM2 in male reproductive system and the process of spermatogenesis. And in vitro fertilization experiments are needed to confirm the role of CMTM2 in fertilization in future. PMID- 28816269 TI - [MicroRNA differential expression profile in tuberous sclerosis complex cell line TSC2-/- MEFs and normal cell line TSC2+/+ MEFs]. AB - OBJECTIVE: Tuberous sclerosis complex (TSC) is a multisystem genetic disorder caused by mutations in the TSC1 and TSC2 genes, but the molecular events contributing to TSC are not well understood. However, little is known about the role of microRNAs in TSC. To explore the microRNA differential expression profile between tuberous sclerosis complex cell line TSC2-/- MEFs and normal type cell line TSC2+/+ MEFs, and to provide new clues to study the mechanism of microRNA function in tuberous sclerosis complex. METHODS: TSC2-/- MEFs and TSC2+/+ MEFs cell lines were cultured in vitro, each with three samples chosen as the experimental group and the control group respectively. Total RNA was isolated using TRizol and purified with RNeasy mini kit according to manufacturer's instructions. RNA quality and quantity were measured by using nanodrop spectrophotometer and RNA integrity was determined by gel electrophoresis. Total RNAs were extracted by TRizol, followed by RNA quantification and quality control. MicroRNA profiles were analyzed by microarray and the threshold value used to screen up-regulated more than 2-fold change or down-regulated less than 0.5-fold change compared with controls. Real-time PCR was used to validate the reliability of microarray. Cell counting kit-8 (CCK-8) assay was performed to evaluate the proliferation. RESULTS: Fourteen microRNAs, including miR-18a-5p, miR-376c-3p, miR-136-5p, miR-467c-5p, miR-467b-5p, miR-5104, miR-3098-3p, miR-30a 3p, miR-302b-3p, miR-18a-3p, miR-19b-1-5p, miR-19a-5p, miR-20a-5p, miR-155-5p, were up-regulated, while twenty-six microRNAs, including miR-200b-3p, miR-450a-1 3p, miR-542-5p, miR-199b-5p, miR-10a-5p, miR-466c-5p, miR-450a-5p, miR-450b-5p, miR-542-3p, miR-351-5p, miR-322-3p, miR-199a-3p, miR-335-5p, miR-10b-5p, miR-351 3p, miR-155-3p, miR-497a-5p, miR-503-5p, miR-148a-3p, miR-1843a-5p, miR-199a-5p, miR-490-5p, miR-450a-2-3p, miR-322-5p, miR-214-3p, miR-450b-3p, were down regulated in tuberous sclerosis complex cell line TSC2-/- MEFs compared with normal type cell line TSC2+/+ MEFs (P<0.05). Real-time PCR confirmed the expressions of miR-136-5p, miR-30a-3p, miR-302b-3p, miR-10b-5p, miR-148a-3p, miR 199a-5p consistent with the microarray data (P<0.05). Furthermore, the overexpression of miR-199a-5p significantly inhibited cell proliferation (P<0.05). CONCLUSION: There are differences in the expression of miRNA between the tuberous sclerosis complex cell line TSC2-/- MEFs and normal cell line TSC2+/+ MEFs. MiRNA-199a-5p plays an important role in tuberous sclerosis complex, which may be developed as an important molecular target for the treatment of tuberous sclerosis complex. PMID- 28816270 TI - [Clinical value of fluorescence in situ hybridization positive of exfoliated urothelial cells in urothelial carcinoma]. AB - OBJECTIVE: To analyze the clinical pathologic characteristics of cases with fluorescence in situ hybridization (FISH) positive of exfoliated urothelial cells, so as to evaluate the clinical utility of FISH in the diagnosis of urothelial carcinoma (UC). METHODS: A total of 271 cases of FISH positive in Department of Urology of Peking University First Hospital from Apr. 2012 to Sep. 2015 were recruited in this study. Retrospective analysis was made on their clinical data. For FISH analysis, labeled probes specific for chromosomes 3, 7, 17, and the p16 (9p21) gene were used to assess chromosomal abnormalities indicative of malignancy. The positive predict values (PPV) of all the techniques were analyzed. RESULTS: Of the 271 patients, 207 cases were UC, 7 cases were non UC, and 57 cases were benign diseases. The PPV of FISH in detecting UC was 76.4%, while the 95% confidence interval (CI) 71.3% to 81.5%. In the cohort of FISH positive, this value was similar to that of urinary cytology (PPV 86.8%, 95% CI: 78.5%-95.0%). The PPV of FISH was lower than that of cystoscopy and ureteroscopy (PPV 96.1%, 95% CI: 91.7%-100.0%). There were significant differences between this study and the PPV of FISH reported abroad (PPV 53.9%, chi2=33.048, P<0.001). Of all the UC with FISH positive, bladder cancer showed an earlier pathological stage versus renal pelvic carcinoma and ureteral carcinoma, with significance (chi2=5.894, P=0.015, and chi2=13.601, P<0.001, respectively). However, no difference was found in the size, pathological stage and pathological grade of tumors between the urinary cytology positive group and the urinary cytology negative group. The rate of high-grade UC in ureteral carcinoma of FISH positive was 92.3%, much higher than that of ureteral carcinoma reported domestically. CONCLUSION: The PPV of FISH in detecting UC is higher relatively, with a better clinic value for Chinese patients. The ureteral carcinoma with FISH positive obtains a higher pathological grade, which is of great guiding significance for UC. PMID- 28816271 TI - [Construction and improvement of animal models with different positional osseous metastasis of prostate cancer in vivo]. AB - OBJECTIVE: To provide an important tool for the study of diagnose and treatment of prostate cancer (PCa) osseous metastasis and change of bone stress force on prostate cancer (PCa) osseous metastasis and a platform, which is more congruous to clinical process, for prevention and cure of neoplastic bone metastases, and to carry out the construction and improvement of animal models of PCa with different positional osseous metastasis in vivo. METHODS: Different gradient concentrations of RM-1 cells were inoculated into the cavity of left femoral bone or lumbar vertebra of mice (C57BL/6) respectively. The change of mouse activity, tumor formation, tumor size and survival time were observed respectively. And the femur tissue and spinal tissue were obtained from the mice after death. The gray value of iconography were measured by imageological examination of femur tissue, and the final histopathological examination were taken to determine the tumor type in both femur and spinal tissue. RESULTS: The tumor growth could be touched at the puncture site in all the mice after inoculated for 7 days. There were no obvious differences in the time of tumorigenesis, the rate of tumor growth and tumor size among the mice in the same group (P>0.05). As the result, the construction femoral bone and lumbar vertebra metastatic models of PCa had been confirmed by iconography and pathology detection. At the same time, the survival time of the mice inoculated with low concentrations of PCa cells was obviously longer than that of high concentrations of PCa cells ( at least 2 weeks longer). CONCLUSION: The animal models with different positional osseous metastasis (limbs and axial skeleton) of PCa using the same PCa cells (RM-1) had been first constructed successfully in our study. At the same time, a high success rate of construction of PCa animal model with bone metastasis was obtained by femoral bone marrow cavity injection of PCa cells. The rate of tumor growth was rapid, animal survival time was appropriate, and the PCa animal model with bone metastasis can be stably reproduced by our method. These animal models can be used to explore the pathogenesis of different positional PCa bone metastasis and provide a new platform, which were more congruous to clinical process, for prevention and cure of neoplastic bone metastases. PMID- 28816272 TI - [Radical nephrectomy and thrombectomy for Mayo clinic stage III tumor thrombus: a surgical technique and clinical experience]. AB - OBJECTIVE: To evaluate the effectiveness and safety of radical nephrectomy and inferior vena cava thrombectomy in the treatment of patients with Mayo III tumor thrombus, and to introduce our experience and surgical technique. METHODS: The clinical data of 8 patients with Mayo III tumor thrombus from October 2014 to September 2016 were analyzed retrospectively. Of the 8 patients, 3 were male and 5 were female. The average age was (50.8+/-18.7) years (18 to 77 years). The average body mass index (BMI) was (22.7+/-4.4) kg/m2 (15.2 to 30.8 kg/m2). Imaging suggested the right renal tumor in all the 8 cases. The average tumor size was (7.9+/-2.5) cm. Open radical nephrectomy and inferior vena cava thrombectomy was conducted in 5 cases and laparoscopic surgery in 3 cases, and 1 case was converted to open surgery. RESULTS: All the 8 surgeries were completed successfully with no death case. The average surgery time was (370.3+/-101.6) min, ranging from 272-567 min. The average vena cava blocked time was (41.0+/ 12.1) min, ranging from 17-55 min. The blood loss volume was (1 181.3+/-915.7) mL, ranging from 200-3 000 mL. During the operation, 5 cases were infused with suspended red blood cells, the amount of blood transfusion was 800-2 000 mL. 3 cases were infused of plasma with 400-1 000 mL. The average hospital stay was 9 23 d, with an average of (14.1+/-4.0) d. In the 8 patients, 4 cases underwent inferior vena cava wall resection because of invasion by tumor thrombus. Preoperative serum creatinine was 60-101 MUmol/L, with an average of (76.4+/ 15.3) MUmol/L. Serum creatinine 1 week after the operation was 74-127 MUmol/L, with an average of (100.8+/-21.1) MUmol/L. Pathological diagnosis showed 6 cases of clear cell carcinoma, 1 case of papillary carcinoma type II, and 1 case of Ewing's sarcoma. Among the 8 patients, early postoperative complications occurred in 5 cases. Postoperative complications were graded as level II, according to the Clavien classifications. The 8 cases were followed up for 2 to 24 months with an average of 11.3 months. There was 1 patient who suffered from lung metastasis. CONCLUSION: Our initial clinical results show that radical nephrectomy and inferior vena cava thrombectomy is safe and effective for patients with Mayo III tumor thrombus. The wide extension of grade III vein tumor thrombus leads to the difficulty of operation technique. Sufficient preoperative preparation, rich operative experience and skills can improve the safety of operation. PMID- 28816273 TI - [Prognostic factors of patients with T2N0M0 upper tract urothelial carcinoma: a single-center retrospective study of 235 patients]. AB - OBJECTIVE: To evaluate the impacts of the prognostic factors of T2N0M0 upper tract urothelial carcinoma (UTUC) for Chinese patients. METHODS: A retrospective study was conducted including 235 patients who were diagnosed with T2N0M0 UTUC in our hospital and received radical nephroureterectomy (RNU) or partial ureterectomy during January 2000 and December 2013. The 3 and 5-year cancer specific survival rates and bladder recurrence-free survival rates of all the patients were valued using Kaplan-Meier method, and the survival curves with statistical significance between the two were compared using the Log-rank test. Variables with significant differences in the univariate analysis were subjected to the multivariate analysis by Cox regression model. RESULTS: A total of 235 patients were included in this study, including 95 (40.4%) male patients and 140 (59.6%) female patients. The mean age was 66.73+/-10.49 years.The median follow up time was 53 (rang: 3-142) months, and during the follow-up, 74 (31.5%) patients died of UTUC after a median of 35 months,and 96 (40.9%) patients developed intravesical recurrence after a median of 19.5 months. The 3 and 5-year cancer-specific survival rates of all the patients were 89.1% and 85.9%, respectively; the bladder recurrence-free survival rates were 85.5% and 80.2%, respectively. The independent prognostic factors of cancer-specific mortality were tumor age elder than 55 years (HR=3.138, 95%CI: 1.348-7.306, P=0.008) and diameter larger than 5 cm (HR=3.320, 95%CI: 1.882-5.857, P<0.001). The independent prognostic factors of bladder recurrence-free survival were ureter tumor (HR=1.757, 95%CI: 1.159-2.664, P=0.008) and lower tumor grade (HR=1.760, 95% CI: 1.151-2.692, P=0.009). CONCLUSION: T2N0M0 UTUC has a better cancer specific survival. The intravesical recurrence was equivalent to non-muscle invasive UTUC but earlier. The tumor diameter larger than 5 cm and the patient age elder than 55 years were independently associated with cancer-specific mortality; the primary tumor located in ureter and lower tumor grade were more likely to develop intravesical recurrence. PMID- 28816274 TI - [Retroperitoneal laparoscopic with renal pedicle rotation for partial nephrectomy of ventro-renal tumor]. AB - OBJECTIVE: Retro-laparoscopic partial nephrectomy is a challenge for ventro-renal tumors, especially hilar tumors. The tumors are partial or entirely out of operative field and there is blind space for operation. To solve this problem, a set of techniques including renal pedicle rotation is developed. METHODS: A set of techniques including renal pedicle rotation, double-layer suture, early artery unclamping for retro-laparoscopic nephrectomy for ventro-renal tumors, especially hilar tumors were developed. Hilar tumors were located anteriorly to the angle of the renal and renal arteries and in contact with the anterior surface of the renal artery. The evaluation of the outcomes included the operation time, warm ischemia time, estimated haemorrhage, surgical margin, renal function after operation, and complications. This study reviewed the data of 28 patients with ventro-renal tumor, including 15 patients with complex hilar tumors. RESULTS: The average tumor size was (3.8+/-0.5) cm. The average R.E.N.A.L score was 8 (ranging from 7 to 9). The average warm ischemia time was (23.8+/-4.7) min, and suture time was (26.2+/-6.5) min, and operation time was (124.1+/-12.1) min. The median hospital stay was 4 days and the average estimated haemorrhage was (139.1+/-54.0) mL. All the surgeries were operated under laparoscope and no surgery switched to open surgery. Seven patients developed Clavien Dindo I-II complications after operation. Three patients (10.7%) developed collective system damage and received repair of collective system in time and three patients (10.7%) developed slightly gross hematuria (Clavien-Dindo I). Two patients developed wound infection (Clavien-Dind II). Three patients (10.7%) got renal vein clamped because of capillary hemorrhage from basilar part of tumors. There were 14 patients received early unclamping of renal artery, and no obvious renal vessel damage was found. There were statistically significant differences between the serum creatinine levels (P<0.05) and the estimated glomerular filtration rates (P=0.02) before and after surgery. All the patients' serum creatinine levels were in normal range and no patient needed regular dialysis. There was no positive surgical margin and the median follow-up was 7 months without local recurrence or distant metastasis. CONCLUSION: It is safe and effective to apply renal pedicle rotation technique in retro-laparoscopic partial nephrectomy for ventro-renal tumors. The short-term follow-up results are optimistic, but long follow-up is required. PMID- 28816275 TI - [Clinical application of retroperitoneal laparoscopic surgery combined with mini flank incision "hybrid surgery" for partial nephrectomy of complex renal tumors]. AB - OBJECTIVE: To evaluate the clinical effect and safety of retroperitoneal laparoscopic surgery combined with mini-flank incision "hybrid surgery" for partial nephrectomy of complex renal tumors. METHODS: Between April 2015 and December 2016, the clinical data from 16 patients with complex renal tumors who underwent the "hybrid surgery", including 10 males and 6 females, were retrospectively reviewed. The average age was (50.2+/-10.7) years, 9 cases were located in the left side and 7 cases in the right side, the mean tumor size was (6.1+/-1.0) cm, and the mean R.E.N.A.L. nephrometry score was 9.3+/-1.3. All the patients received the "hybrid surgery", the first step was to adequately mobilize the kidney and tumor, prepared the renal artery by retroperitoneal laparoscopy, and then the incision about 10-12 cm was done under the twelve rib to convert to open surgery. After the renal artery was clamped, the tumor was removed and the wound was closed under direct vision. The operative time, ischemia time, estimated blood loss, intraoperative and postoperative complications and short term renal function were recorded. RESULTS: All the 16 patients' "hybrid surgeries" were successfully performed. The mean operative time was (164.9+/ 23.6) min, mean ischemia time was (32.4+/-6.2) min, and mean estimated blood loss was (204.0+/-125.1) mL. The mean drainage tube removal time was (4.1+/-1.0) d, and the mean postoperatively hospital stay was (6.9+/-1.5) d. There were 2 patients with Clavien III grade complications. One patient was injured with collecting system, and 1 patient received a second emergency surgery for acute postoperative bleeding. The mean 1 day postoperative serum creatinine level was (126.3+/-26.4) MUmol/L, which was statistically significant (P<0.05) compared with the preoperative serum creatinine level(74.3+/-16.9)MUmol/L. There were no significant differences (P>0.05) in comparing the 1 month postoperative serum creatinine level (92.6+/-18.2) MUmol/L, 3 months postoperative serum creatinine level (80.8+/-18.4) MUmol/L with the preoperative serum creatinine level. During 3 to 20 months follow-up periods, no local recurrence or distant metastasis occurred. CONCLUSION: This "hybrid surgery" combined retroperitoneal laparoscopic surgery with mini-flank incision for partial nephrectomy is safe and effective. It could decrease the operative difficulty and be worthy of further application for some selected complex renal tumor patients. PMID- 28816276 TI - [Percutaneous biopsy of the renal masses under ultrasound: a single-center 14 years experience]. AB - OBJECTIVE: To assess the diagnostic rate, safety and clinical application of percutaneous renal masses biopsy for advanced renal cell carcinoma patients. METHODS: In this retrospective study, we collected the data of renal masses from the patients who underwent renal masses biopsy under ultrasound from April 2001 to December 2014 in Peking University First Hospital. A total of 75 patients who were undiagnosed or diagnosed with advanced renal cell carcinoma by the imageological method were enrolled in this study. The patient and lesion characteristics such as tumor size, pathology of tumor, histologic subtype, pathological grade, biopsied location and biopsied cores were recorded and analyzed. RESULTS: Among all the 75 patients, biopsy was diagnostic in 64 cases (85.3%) and non-diagnostic in 11 cases (14.7%). Of the 64 diagnostic biopsies, 60 were malignant, including 37 (61.7%) renal cell carcinoma (RCC), 13 (21.7%) urothelial carcinoma and 10 (16.7%) other malignant masses. Of all the RCC subjects, 24 suffered from clear cell RCC, 5 papillary RCC, 3 collecting duct carcinomas, 1 unclassified RCC and 4 unknown subtypes. The 11 non-diagnostic biopsied samplings included inflammatory, blood and extrarenal tissue and normal renal tissue. The proportion of collecting duct carcinoma in RCC was 10.8% and the proportion of squamous carcinoma in urothelial carcinoma was 23.1%, which were both higher than the previous research findings. For the male and female groups, non-diagnostic yields were 6.5% and 30.4%, respectively (P=0.022). Of all the 75 patients, 13 renal cell carcinoma patients underwent the surgical treatment and got the results of postoperative pathology. Comparing preoperative biopsy pathological diagnosis with postoperative pathological diagnosis, we found the diagnostic correct rates for benign and malignant lesions, pathological subtype and pathological grade were 100%, 81.8% and 60%, respectively. Mild macroscopic hematuria occurred in 1 case after RMB and there were no serious complications in all the cases. CONCLUSION: Percutaneous renal masses biopsy under ultrasound with a high diagnostic rate which can define the histologic subtype of renal cell carcinoma. With targeted therapy, more and more patients whose evaluation suggests local advanced disease or metastatic tumors adopt renal tumor biopsy to define the histologic subtype, which could avoid unnecessary surgical treatment. PMID- 28816277 TI - [Characteristics of ureteral stone position and dilatation of ureter in patients before treated with endourologic lithotripsy]. AB - OBJECTIVE: To investigate the position and the size of ureteral stone in patients before treated with ureteroscopic lithotripsy or percutaneous nephrolithotomy (PCNL), as well as the dilatation of ureter caused by stone, which may be helpful for better understanding of pathogenesis of ureteral stone and improvement of the diagnosis and treatment in clinic. METHODS: A total of 129 cases with ureteral stone for endourologic lithotripsy in Peking University People's Hospital from Aug. 2016 to Mar. 2017 were included for the retrospective review. The CT data of the ureteral stones and the ureteral dilatation were collected, including the position of stone, the transverse and longitudinal diameter of stone, and the transverse diameter of dilated upper ureter and ureteropelvic junction (UPJ). The distribution of ureteral stones and dilatation in different parts of ureter were compared and analyzed. RESULTS: All of the 129 cases of ureteral stone, stones were located at UPJ in 9 cases (7.0%), proximal ureter in 75 (58.0%), ureter crossing external iliac vessel (UEIV) in 6 (4.7%), distal ureter in 26 (20.2%), and ureterovesical junction (UVJ) in 13 (10.1%). The mean transverse diameter of proximal ureteral stones was greater than that of distal ureteral stones [(8.47+/ 2.36) mm vs. (6.74+/-1.99) mm, P<0.001], as the same as the mean longitudinal diameter [(11.00+/-4.41) mm vs. (7.50+/-4.28) mm, P<0.001]. In 114 cases of dilated ureter for stone, the UPJ had a greater transverse diameter compared with the upper ureter [(14.39+/-6.09) mm vs. (11.45+/-3.85) mm, P<0.001]. CONCLUSION: The most common location of stone is the proximal ureter in patients for endourologic lithotripsy, as the location in UEIV is rare. Both transverse and longitudinal diameters of stone in proximal ureter are greater than those in distal ureter. For dilated ureter, it is more severe in UPJ than in upper ureter. Traditionally, it is accepted that the stones lodge at 3 sites of natural narrowing in ureter, which may be questioned. PMID- 28816278 TI - [Analysis of development, safety and efficacy of percutaneous nephrolithotomy for management of upper urinary tract calculi in pediatric patients]. AB - OBJECTIVE: To evaluate the development, safety and efficacy of percutaneous nephrolithotomy(PNL) for management of upper urinary tract calculi in pediatric patients. METHODS: In the study, 77 pediatric patients undergoing 87 PNLs through mini or standard tract for upper urinary tract calculi between January 2005 and December 2016 in Peking University People's hospital were reviewed, including 69 renal calculi, 6 upper ureteral calculi, 12 renal and upper ureteral calculi, 35 single calculi, 43 multiple calculi and 9 staghorn calculi. The development and efficacy of PNL in pediatric patients were studied by analyzing the characteristics and clinical indexes, and by reviewing the associated literature. The Clavien classification system was used to evaluate the complications after PNL. RESULTS: A total of 87 PNLs were performed in 77 pediatric patients. Eighty one upper urinary tract calculi were managed through a single tract(93.1%), 5 pediatric patients were managed through 2 tracts(5.7%), and 1 pediatric patient was managed through 3 tracts(1.2%). The mean operating time was (77.0+/-29.8) min. The stone-free rate after one session was 100% for single calculi and 71.2% for multiple or staghorn calculi, 5(5.8%) children underwent auxiliary procedure to remove the residual calculi and the final stone-free rate of PNL was 88.5%. One of the main complications of pediatric PNL was fever. Sixteen (18.4%) had moderate fever(38-39 degrees C), 5 (5.7%) had high fever (39-40 degrees C) and there were no severe complications of infection, such as sepsis or septic shock. The mean hemoglobin loss was (10.3+/-16.1) g/L and the serum creatinine rise was (7.0+/-13.3) MUmol/L. One(1.2%) pediatric patient suffered ureteroscopic lithotripsy because of the obstruction by the residual stone in ureter. No injury of organs or retroperitoneal urinary extravasation occurred. General assessment of the complications showed Clavien grade I complications in 14 (16.1%) pediatric patients, grade II in 7(8.0%) children and grade III in 1(1.2%) children. There was no grade IV or V complications. The overall complication rate was 25.3%. CONCLUSION: PNL for management of upper urinary tract calculi in pediatric patients is effective. Complications after PNL, as assessed with Clavien classification system, are mild and PNL in pediatric patients is safe. PMID- 28816279 TI - [Ureteroscope can assist risk stratification in upper tract urothelial carcinoma]. AB - OBJECTIVE: To analyze the efficiency of ureteroscope and biopsy in the diagnosis of tumor grade, muscle-invasiveness and multifocality in suspected upper tract urinary carcinoma (UTUC) patients in order to find out whether it can be used in the risk stratification of UTUC patients. METHODS: A retrospective study of 76 UTUC patients who underwent preoperative ureteroscope and/or biopsy and received radical nephroureterectomy in Peking University Third Hospital during January 2014 to December 2016 was undertaken. RESULTS: In this study, 76 patients were included. There were 31 males (40.8%), and 45 females (59.2%). The median age was 64.5 years (31-88), and 51 patients had the symptom of hematuresis. The tumor was located in renal pelvis in 39 patients, and in ureter in 37 patients. Post operative pathology confirmed that all the 76 patients included in this study suffered from UTUC, of whom 21 (21.6%) were of low-grade, 51 (67.1%) were of high grade, 4 (5.3%) were undetermined, and 47 (61.9%) patients were muscle-invasive, and 27 (35.5%) were not, and 2 (2.6%) were undetermined. Among the 50 patients, in whom the grade of the tumor could be diagnosed by biopsy, the sensitivity, specificity, accuracy, positive predictive value and negative predictive value for low-grade tumor was 88.2%, 69.7%, 76.0%, 60.0% and 92.0%, respectively. Among the 27 patients, in whom the muscle-invasiveness could be diagnosed by biopsy, 5 patients were diagnosed with muscle-invasiveness, all confirmed by pathology after surgery and 22 patients were diagnosed with none muscle-invasiveness, turned out to be 50% muscle-invasive and 50% none-muscle invasive after surgery. The accuracy was 59.3%. The accuracy of ureteroscopic biopsy to diagnosis multifocality was 61.0%. On univariate analysis, biopsy grade was associated with postoperative pathology (P=0.001), while gender, age, side, body mass index (BMI), hematuresis, preoperative estimated glomerular filtration rate (eGFR), hydronephrosis, tumor size, location, multifocality and sessile were not associated with postoperative pathology grade. Biopsy grade (P=0.02), preoperative eGFR<90 mL/(min*1.73 m2)(P=0.025) and tumor located in pelvis (P=0.049) were associated with muscle invasiveness. Gender, age, side, BMI, hematuresis, hydronephrosis, tumor size, multifocality and sessile were not significantly associated with muscle invasiveness. CONCLUSION: Ureteroscope and biopsy can assist risk stratification in upper tract urothelial carcinoma patients. PMID- 28816280 TI - [Analysis of outcomes of tension-free mid-urethral sling procedure in women with mixed urinary incontinence]. AB - OBJECTIVE: To evaluate the medium and long term outcomes of tension-free mid urethral sling in the treatment of female patients with mixed urinary incontinence (MUI). METHODS: Twenty-six patients who underwent the tension-free mid-urethral sling procedure for MUI from April, 2010 to September, 2016, were followed up. Four of the 26 patients underwent retropubic tension free mid urethral sling (TVT), and 22 of them underwent transurethral middle obturator sling (TOT). Scales were used in the follow-up, such as urinary incontinence severity score (UISS), detrusor instability score (DIS), incontinence quality of life scale evaluation (I-QOL), Urogenital Distress Inventory short form (UDI-6), and the outcomes before and after the procedure were compared. RESULTS: The mean age was 62 years, with a range of 42-80 years. The mean body mass index (BMI) was 26.82 kg/m2, with a range of 21.48-31.14 kg/m2. The mean follow-up time was 26 months, with a range of 8-69 months. Twelve patients never took M-blockers and the rest 14 patients took M-blockers within two weeks. None of the patients had complications, including dysuria, injury of bladder, urethra, obturator vessel or nerve during the surgery. After pulling out the catheter, no one suffered moderate or severe pain or difficulty of urination. The overall cure rate for stress urinary incontinence (SUI) was 96.15% with 25 patients cured, and for urge urinary incontinence (UUI) was 76.92% with 20 patients cured. The patients' life quality also improved significantly (P<0.05). CONCLUSION: Ten of the 26 patients showed an overactive bladder according to urodynamic study, from whom all of the six failed patient were. And 16 patients didn't show an overactive bladder, which may due to two reasons. One is that their sense of urge is not so serious, the other one is that their sense of urge is from urethra. Proximal urethra is full of nerve, which plays a role in sense and urine control. The sense of urge may come from urethra instead of bladder. tension-free mid-urethral sling procedure is an effective treatment for women with mixed urinary incontinence. Even without taking the M-blockers, the cure rate for urge incontinence reached 76.92%. The efficacy of surgery remained stable in medium and long term, and the patients' quality of life improved significantly. PMID- 28816281 TI - [Application of flurbiprofen axetil in pain management associated during transrectal ultrasound-guided prostate biopsy]. AB - OBJECTIVE: To examine the effects of perioperative intravenous administration of flurbiprofen axetil (FA) on pain associated with transrectal ultrasound-guided prostate biopsy. METHODS: This was a randomized,controlled study. Eighty-one patients who underwent 12 core prostate biopsy were included in the study. The patients were randomly assigned to one of three groups (n=27 in each) by type of procedure during prostate biopsy. Group intrarectal local anesthesia (IRLA) received intrarectal 5% (0.05 g/L) lidocaine gel 60 mg, 5 minutes before the procedure alone; Group FA received intravenous flurbiprofen axetil (1 mg/kg) 1 hour before the procedure; Group IRLA+FA received intrarectal 5% lidocaine gel 60 mg, 5 minutes before the procedure and intravenous flurbiprofen axetil (1 mg/kg) 1 hour before the procedure. The patients were asked to score the pain by using visual analogue scale (VAS) in 4 situations,including when the probe was inserted (VASI),during anesthesia (VAS II),during biopsy (VAS III) and 20 minutes after biopsy (VAS IV). The findings were evaluated with analysis of variance,and the Tukey post hoc test was followed with an overall 2-tailed significance level at alpha =0.05. P1, P value between Group IRLA and Group FA; P2, P value between Group FA and Group IRLA +FA, P3, P value between Group IRLA and Group IRLA +FA. The bonferroni method was used to adjust the test level, alpha=0.017,a P value of less than 0.017 was accepted as the threshold for statistical significance. RESULTS: No major complications,including sepsis and severe rectal bleeding,were noted in any patient. There were no differences in general condition of the patients before procedure among the 3 groups. There were statistically significant differences in VAS scores among the 3 groups in VAS II (5.7+/-2.2, 3.0+/-1.5,3.3+/-1.9,respectively,P=0.012) and VAS III (6.7+/-2.3,3.0+/-2.1,2.9+/ 1.6,respectively,P=0.001). There were no differences in the pain scores among the 3 groups during probe insertion (VAS I, 3.2+/-1.0,4.1+/-2.1,4.2+/-1.7, respectively,P=5.752) and 20 minutes after biopsy (VAS IV, 1.4+/-2.1,1.0+/ 0.9,1.1+/-0.7,respectively,P=3.772). Between-column differences among the 3 groups were VAS II (P1=0.007,P2=5.655,P3=0.001,respectively) and VAS III(P1=0.008,P2=7.517,P3=0.001,respectively),the differences between Group IRLA and Group FA,Group IRLA and Group IRLA +FA in VAS II and VAS III were statistically significant. CONCLUSION: The intravenous flurbiprofen axetil was found to be more effective than intrarectal lidocaine gel alone. PMID- 28816282 TI - [Long-term follow up experience of comprehensive treatment of testicular mixed germ cell tumors]. AB - OBJECTIVE: Testicular mixed germ cell tumor is mixed with embryonal carcinoma, choriocarcinoma, yolk sac tumor, teratoma, seminoma and other two or more components of the testicular tumor, the clinical is relatively rare and high degree of malignancy, this article will summarize its clinical features and optimize its treatment. METHODS: A retrospective analysis of the clinical data of 22 patients with testicular tumor mixed germ cell in Peking University Third Hospital from May 1994 to November 2016 was conducted using a combination of statistical analysis and discussion of the relevant literature. RESULTS: The mean age of the 22 patients was (30.8+/-10.4) years and the rate of cryptorchidism was 13.6%. The maximum diameter of the tumor was (5.1+/-2.7 ) cm. The pathological results suggested that 12 cases (54.5%) contained two different germ cell tumor components, 7 cases (31.8%) contained 3 different tumor components, 2 cases (9.2%) contained 4 different tumor components, and 1 case (4.5%) contained 5 different tumor components. Tumor constituent analysis included yolk sac tumors(16 cases, 72.7%), mature teratoma (7 cases, 31.8%), immature teratoma (5 cases, 22.7%), embryonal carcinoma (17 cases, 77.3%) , choriocarcinoma (4 cases, 18.1%) and seminoma (6 cases, 27.3%). American Joint Committee of Cancer tumor staging indicated 19 cases of stage I a tumor, 2 cases of stage IIa tumor and 1 case of stage IIIa tumor. The mean values of human chorionic gonadotropin, alpha fetoprotein and lactate dehydrogenase were 414.50 MIU/mL, 242.95 MUg/L, 196.95 U/L (preoperative) and 17.20 MIU /mL, 90.20 MUg/L, 183.70 U/L (postoperative within a year), and the comparison of the P values between the preoperative and the postoperative within a year were 0.079, 0.043 and 0.624. Fourteen patients underwent retroperitoneal lymph nodes dissection. Most patients lived with long term survival (94.4%) after operation. CONCLUSION: Comprehensive treatment of radical orchiectomy with retroperitoneal lymphadenectomy combined with necessary radiotherapy or chemotherapy might help to control the tumor and achieve long term survival for most patients with testicular mixed germ cell tumor. PMID- 28816283 TI - [Surgery treatment of ectopic adrenocorticotrophic hormone syndrome]. AB - OBJECTIVE: To investigation the diagnosis and treatment of ectopic adrenocorticotrophic hormone (ACTH) syndrome. METHODS: The clinical characters of 57 cases of ecotopic ACTH syndrome from Jan. 1996 to Dec. 2016 were collected and analyzed. The 57 cases included 32 males and 25 females. The age ranged from 11 to 68 years (average 32 years). ACTH levels significantly increased from 16.5 to 365.6 pmol/L, with average 77.6 pmol/L (normal range <10.1 pmol/L). The pituitary MRI did not found lesions. The CT showed that their bilateral adrenal glands diffused small nodular changes or nodular hyperplasia. The 57 cases were divided into 3 groups according to different treatment options. In the study, 25 ectopic ACTH syndrome cases (44%) were group A, without identified source of ectopic hormone, were treated with bilateral or unilateral adrenalectomy due to the severity of the disease and difficulty of operation. Group B was composed of 16 cases (28%) diagnosed as ectopic ACTH syndrome by finding ectopic ACTH tumors and surgical resection. Group C included 16 cases (28%) with nonsurgical therapy. Different treatment results and prognosis were analyzed. RESULTS: In the study, 40 cases of the 57 had been followed up for 6 months to 10 years. In group A, of the 25 cases with bilateral or unilateral adrenalectomy, 4 died of diabetes and severe pulmonary infection, 18 survived, and 3 were lost to the follow-up, and the survival rate was 81% (18/22). In group B, of the 16 cases with radical tumor resection, 5 died of tumor recurrence 0.5-6.0 years after operation, 3 survived, and 8 were lost to the follow-up, and the survival rate was 37.5% (3/8). In group C, of the 16 non-operation patients, 4 with radiotherapy and chemotherapy died of metastases, diabetes or pulmonary infection, 6 with chemotherapy died of pulmonary infection within 1 year and the others were lost to the follow-up, and the survival rate was 0. CONCLUSION: Ectopic ACTH syndrome is difficult to treat. Adrenalectomy is effective for the management of ectopic ACTH syndrome, especially for those patients with severe Cushing's syndrome, but the primary tumor can not be located. PMID- 28816284 TI - [Predictive factor analysis of time to progression of castration-resistant prostate cancer after androgen deprivation therapy]. AB - OBJECTIVE: To explore risk factors including prostate-specific antigen (PSA) kinetics for the prediction of castration-resistant prostate cancer (CRPC), and to build a practical model for predicting the progression to CRPC after androgen deprivation therapy (ADT) so as to facilitate clinicians in decision-making for prostate cancer patients receiving ADT. METHODS: A total of 185 patients with prostate cancer who had received ADT as the primary therapy in Department of Urology of Peking University First Hospital from 2003 to 2014 were enrolled retrospectively. All the patients were diagnosed with prostate cancer via prostate biopsy and followed up every four weeks from the initiation of ADT. All the patients received ADT with luteinizing hormone-releasing hormone agonists (LHRH-A) or surgical castration accompanied with an antiandrogen (bicalutamide or flutamide, combined androgen blockade). The clinical information of the patients were collected including age, clinical TNM stage, Gleason score (GS), risk groups of prostate cancer, PSA at the initiation of ADT, PSA nadir after ADT, PSA decline velocity, and the time to PSA nadir. The end point of this study was the diagnosis of CRPC, which was based on the European Association of Urology (EAU) Guideline 2016. Cox proportional hazards regression models were established to analyze and estimate their effects on the time of progression to CRPC. RESULTS: In this study, 185 patients with prostate cancer who had received ADT as the primary therapy were included. The mean age was (71.02+/-8.67) years. The median time to progression to CRPC in this cohort was 38 months (ranging from 4 to 158 months). On univariate analysis, we found clinical T stage, N stage, the metastasis state before ADT, risk groups of prostate cancer, PSA decline velocity, and PSA nadir were all related to the time to CRPC progression, P<0.01 for all the above variables. And on multivariate analysis, the presence of distant metastasis before ADT (HR=6.030, 95% CI: 3.229-11.263, P=0.001), higher PSA nadir (HR=1.185, 95% CI: 1.080-1.301, P=0.001), higher PSA decline velocity>11 MUg/(L*month) (HR=2.124, 95% CI: 1.195-3.750, P=0.001), and time to PSA nadir <=9 months (HR=3.623, 95% CI: 1.640-4.817, P=0.004) were found to be significantly associated with an increased risk of progression to CRPC. CONCLUSION: Patients with rapid decreasing of PSA in the initial ADT were more likely to progress to CRPC. PMID- 28816285 TI - [Expression of CXCL16/CXCR6 in fibroblast-like synoviocytes in rheumatoid arthritis and its role in synoviocyte proliferation]. AB - OBJECTIVE: It has been found that serum CXCL16 concentration in rheumatoid arthritis (RA) patients are significantly higher than those in osteoarthritis (OA) and normal subjects, and are positively correlated with disease activity and bone erosion. However, how is CXCL16 involved in the pathogenesis of RA is unclear. To evaluate the expression of CXCL16 and its receptor CXCR6 in fibroblast-like synoviocytes (FLS) of rheumatoid arthritis (RA) patients, and to explore the role of CXCL16 in the proliferation of RA-FLS. METHODS: FLS were isolated from knee synovial tissues obtained from 8 patients of RA, 7 osteoarthritis (OA) and 3 normal controls. The diagnosis of RA was in line with the 1987 American Rheumatology Association (ACR) RA classification criteria, osteoarthritis met the 1996 ACR revised knee osteoarthritis classification criteria. Control synovium were obtained from trauma caused knee joint injury in healthy individuals who required surgery. Human knee FLS were cultured by tissue explants adherent method.FLS between passages 3 and 5 were used in the experiment. Expression of CXCL16 and its receptor CXCR6 were performed in Western blot analysis. FLS proliferation following stimulation with TNF-alpha and different concentrations of CXCL16 was examined by cell counting kit-8 (CCK-8). Expression of phosphorylated AKT (pAKT) in RA-FLS stimulated by CXCL16 was quantified by Western blot. Different concentrations of recombinant human CXCL16 were added to the culture medium of RA-FLS. After 48 h culture, supernantants were collected, and TNF-alpha, IL-6, RANKL and MMP3 in culture supernatants of RA FLS were determined by enzyme-linked immunosorbent assays (ELISA) operated following the kit instructions. RESULTS: Expression of CXCL16 and CXCR6 in RA-FLS was significantly higher than that of OA and controls (P<0.05), but no significant difference was found between OA-FLS and control FLS. Proliferation of RA-FLS was markedly up-regulated after stimulation of CXCL16 (P <0.05). In the case of the CXCL16 stimulated OA-FLS and control FLS, the FLS proliferation remained basically unchanged. Expression of phosphorylated AKT in RA-FLS increased remarkably in condition of CXCL16 (50,100, 200 MUg/L) stimulation. The levels of IL-6 and RANKL in culture supernatants of RA-FLS were obviously increased under CXCL16 (200 MU g/L) stimulation, while TNF-alpha and MMP-3 levels in the culture supernatants remained unchanged after CXCL16 (200 MUg/L) stimulation. CONCLUSION: This study shows that the expression of CXCL16 and its receptor was highly elevated in RA-FLS. Recombinant CXCL16 promoted RA-FLS proliferation and activation in vitro. All these indicate that CXCL16 play an important role in the pathogenesis of RA, anti-CXCL16 treatment may help to relieve inflammation and bone damage of RA patients. However, due to the limitations of this study, the role of CXCL16 and its receptors in RA-FLS remains to be elucidated by further research. PMID- 28816286 TI - [Prognostic value of chemotherapy-induced neutropenia in metastatic colon cancer patients undergoing first-line chemotherapy with FOLFOX]. AB - OBJECTIVE: To evaluate the prognostic value of chemotherapy-induced neutropenia (CIN) in metastatic colon cancer undergoing first-line chemotherapy with FOLFOX. METHODS: Data were collected from a retrospective survey of 158 consecutive metastatic colon cancer patients who had undergone FOLFOX chemotherapy. The clinicopathological characteristics and chemotherapy features of the patients were analyzed as potential prognostic factors. The patients were stratified by the decreased level of CIN to three groups: large decreased level (the number of neutrophil decreased more than 1.0*109 compared with that before chemotherapy), small decreased level (the number of neutrophil decreased less than 1.0*109 compared with that before chemotherapy) and the absence of neutropenia. RESULTS: According to a multivariate COX model, decreased level of CIN was a independent prognostic factor of colon cancer patients. Hazard ratios of death were 0.687 (95% CI: 0.381-0.812, P=0.016) for patients with large decreased level of CIN and 0.817 (95% CI: 0.527-0.939, P=0.027) for those with small decreased level of CIN compared with those of absent neutropenia patients. Median overall survival was 12.9 months (95% CI: 10.4-15.4) for patients without neutropenia (A) compared with 20.8 months (95% CI: 18.3-23.1) for patients with large-decreased level of CIN (L) and with 17.3 months (95% CI: 16.2-18.8) for those with small-decreased level of CIN (S vs. L, P=0.018; L vs. A, P=0.009; S vs. A, P=0.011). CONCLUSION: Our results demonstrate that the decreased level of CIN is a predictor of prognosis in patients with metastatic colon cancer undergoing FOLFOX chemotherapy. Patients who have experienced large decreased level of CIN haave longer survival time than small decreased level of CIN or absent patients. To monitor CIN decreased level timely and adjust chemotherapy drug dose may help improve the prognosis. PMID- 28816287 TI - [Diagnostic value of CT scan for AO B3 fracture of distal radius]. AB - OBJECTIVE: To determine whether 3-dimentional CT scans is able to effectively improve the detection rate of AO B3 distal radius fractures in clinics. METHODS: From Jan 2013 to Jan 2014, 30 patients with distal radius fractures were retrospectively enrolled in this study, all the patients directly visited the skeletal trauma emergency department in Beijing Jishuitan Hospital post injury and all of them accepted open reduction and internal fixation of distal radius fractures at last. All the radiographic data including X ray films and 3 dimentional CT scans of these patients were collected. Two independent observers were required to make primary AO classifications for each fracture by X rays at first, then to make final AO classifications by 3-dimentional CT scans. Finally, the detection rates of CT scans and plain films for AO B3 distal radius fractures and B3.3 distal radius fractures were compared, the agreements of the two methods for diagnosing AO B3 and B3.3 fractures were calculated by Cohen's Kappa calculations. RESULTS: All the 30 fractures were confirmed to be AO B3 distal radius fractures intraoperatively, and 10 of them were B3.3 fractures. The results were completely consistent with the results of 3-dimensional CT scans. However, only 80%(24/30) AO B3 distal radius fractures and 60%(6/10) B3.3 distal radius fractures could be diagnosed only by X rays. The detection rate of CT scans was proved to be significantly higher than X rays for diagnosing B3 distal radius fractures(100% vs. 80%,P<0.05), the detection rate of CT scans was also proved to be significantly higher than that of plain films for detecting B3.3 distal radius fractures (100% vs. 60%,P<0.05). The agreement of 3-dimentional CT scans and X ray was poor for detecting both the AO B3 distal radius fracture and B3.3 distal radius fracture (kappa=0). Most importantly, in the study process, two special kinds of B3 distal radius fracture were initially found and described by us. One was named as radial B3 fracture, and the other was named as ulna B3 fracture. CONCLUSION: 3-dimentional CT scans can effectively improve the detection rate of B3 and B 3.3 distal radius fractures, and also help find two special kinds of B3 fractures. PMID- 28816288 TI - [Recombinant human transforming growth factor beta1 promotes dental pulp stem cells proliferation and mineralization]. AB - OBJECTIVE: To explore suitable concentration of recombinant human transforming growth factor beta1 (rhTGF-beta1) usage and study the effect of rhTGF-beta1 on differentiation of dental pulp stem cells (DPSCs). METHODS: DPSCs were isolated from the undiseased third molars of people aged 18-25 years and cultured according to instructions in vitro. Different concentrations (1 , 6 , 10 MUg/L) of rhTGF-beta1 were added to the culture medium to examine DPSCs proliferation by CCK-8 (cell counting kit-8) assay.The suitable concentration was then selected. For differentiation, the DPSCs were incubated for 7 or 14 days with rhTGF-beta1 supplemented with osteo/odontoblastic induction medium containing 10 nmol/L dexamethasone, 10 mmol/L b-glycerophosphate, 50 g/L ascorbate phosphate, 10 nmol/L 1,25-dihydroxyvitamin D3 and 10% fetal bovine serum. The cells were then washed 3 times with phosphate-buffered saline and sonicated with 1%Triton X-100 for 30 minutes on ice. Cellular alkaline phosphatase (ALP) activity was assayed with p-nitrophenyl phosphate as the substrate. The enzyme activity was expressed as p-nitrophenyl produced per milligram of protein [bicinchoninic acid (BCA) protein assay kit]. To examine mineral nodule formation, the cultured cells were fixed in 4% paraformaldehyde and washed in water, and the mineralization of the extracellular matrix was assayed by 1% alizarin red S staining and elution of staining was examined as optical density (D) under microplate reader. The mean difference was considered significant at 0.05 and 95% confidence interval. RESULTS: The DPSCs had typical fibroblast morphology and could form mineral nodules after being cultured with osteo/odontoblstic induction medium for 14 days. 6 MUg/L rhTGF-beta1 significantly promoted the DPSCs proliferation on the 3rd and 5th days. After the incubation of osteo/odontoblastic induction medium, the DPSCs with the 6 MUg/L rhTGF-beta1 increased ALP activities compared with the control; D values in the 6 MUg/L rhTGF-beta1 group was 0.31+/-0.03, while the control group was 0.02+/-0.01 (P<0.05). The total protein content in the 6 MUg/L rhTGF-beta1 group was (2 775.46+/-83.54) mg/L, and the control group was (1 432.20+/-110.83) mg/L (P<0.05). To eliminate the cells proliferation influence, relative ALP activities, which was defined as the total ALP divided by the total protein content, the 6MUg/L rhTGF-beta1 group was 6 times higher than the control group. Alizarin red S staining showed increased mineral nodule formation in the rhTGF-beta1 group. The elution of staining under microplate reader also showed more optical density in the 6 MUg/L rhTGF-beta1-treated cells (0.83+/-0.02) than that in the control groups (0.55+/-0.05, P<0.05). CONCLUSION: 6 MUg/L rhTGF-beta1 could significantly promote DPSCs proliferation and odontoblastic differentiation in vitro. PMID- 28816289 TI - [Evaluation of cone-beam computed tomography on upper airway changes after alternating rapid palatal expansion and constriction]. AB - OBJECTIVE: To evaluate the changes of different parts of upper airway after alternating rapid palatal expansion and constriction via three dimensional measurement, compared with the protocol of rapid palatal expansion alone. METHODS: In the study, 36 patients with retrognathic maxilla were selected and randomized to either group A or group B. The patients in group A were treated with rapid palatal expansion alone. The patients in group B were treated with alternating rapid palatal expansion and constriction. Three dimensional analyses were performed on all pre- and post-treatment cone-beam computed tomography (CBCT) images with the software Dolphin. RESULTS: Two subjects in group B were lost to follow up during the treatment. The gender distributions, ages and all measuring items before treatment had no significant difference between group A and group B (P>0.05). Nasal floor width, nasal lateral width, nasal volume, and nasopharynx volume increased significantly in each group after rapid palatal expansion alone or rapid palatal expansion and constriction (P<0.05). The variations of oropharyngeal volume and hypopharyngeal volume had no significant difference (P>0.05). No significant difference was observed in the nasal floor width and nasal lateral width increment among the anterior, median and posterior parts in each group either (P>0.05). No significant difference in all the measuring items was observed between the two groups (P>0.05). CONCLUSION: Alternating rapid palatal expansion and constriction could increase the volume of nasal and naopharynx cavities by the similar way of rapid palatal expansion alone, and had no obvious effect on oropharynx and hypopharynx cavities. PMID- 28816290 TI - [Treatment outcome evaluation of different mandibular advancements using oral appliance to treat obstructive sleep apnea and hyponea syndrome: a systematic review]. AB - OBJECTIVE: To evaluate the polysomnology results along with mandibular titrated advancement using oral appliance to treat obstructive sleep apnea and hyponea syndrome (OSAHS). METHODS: Several electronic databases (PubMed, Embase, Cochrane Library, CNKI, VIP, and Wanfang) were systematically searched up to September 2015. There was no restriction of language or source of information. All randomized clinical trials (RCT) and before-after trials (BAT) comparing at least two different mandibular advancements were included. Two independent reviewers selected the studies, extracted data and evaluated risk of bias by quality assessment. Data were pooled using a fixed-effects model, and the summary effect measure was calculated by risk ratio (RR) and 95%CI. Meta-analysis was performed using RevMan 5.3 software. RESULTS: Two RCTs and five BATs were included in the review. Among the five BATs, two of them were randomized, while the other three were not. Outcomes including apnea hypopnea index (AHI), oxygen desaturation index (ODI), success rate (reduction of AHI or ODI >50%), normalization rate (AHI or ODI<10/h) were assessed in this review. Based on the trial design and quality assessment, four studies were included for meta-analysis. No significant difference in the success rate was found between the group with 50% of the maximal mandibular advancement (MMA) and the group with 75% of MMA [I2=0%, RR=0.93, with 95%CI (0.80, 1.09)]. No significant difference in the normalization rate was found between the 50% of MMA and 75% of MMA groups [I2=45%, RR=0.85, with 95%CI (0.68, 1.06)]. Subgroup analysis displayed that the severity of OSAHS before treatment was a potential factor affecting the normalization rate. CONCLUSION: Based on current available evidence, the success rate and normalization rate for treating OSAHS in the patients with 75% MMA were not found to be significantly higher than those with 50% MMA. Due to small simple size in this meta-analysis, the results of the present study should be interpreted with caution. Further prospective studies are needed to strengthen the evidence. PMID- 28816291 TI - [Influence of the interforaminal arch form of edentulous mandibles on design of "All-on-4": preliminary research based on conebeam computed tomography]. AB - OBJECTIVE: To classify the interforaminal arch form of edentulous mandibles by measuring the anterior-posterior distance (A-P distance) of implants planned to be inserted in "All-on-4" protocol using conebeam computed tomography (CBCT) data, and to investigate the influence of the arch form on the "All-on-4" distally tilted implants. METHODS: Seventy-four CBCT images of edentulous mandibles were collected, including 35 males and 39 females respectively. "All-on 4"implant supported fixed prostheses were designed for these patients based on the CBCT data. The A-P distance was measured in the plane which crossed bilateral mental foramens and was parallel to the occlusal plane. The interforaminal arch form of edentulous mandibles were classified according to the A-P distance. The radian of the jaw arch 7.5 mm mesially to the mental foramen was measured bilaterally, and its correlation with the A-P distance was studied. RESULTS: The average A-P distance of implant supported fixed prostheses planned in the interforaminal region was (8.5+/-1.5) mm (minimum 4.5 mm, maximum 11.8 mm). In the study, 12.2% of the subjects' mandibles were classified as square arch form with A-P distances <=7 mm, 54.0% were classified as ovoid with A-P distances >7 mm and <=9 mm, 33.8% were classified as tapered with A-P distances >9 mm. Bilaterally, 148 results of the radian of the jaw arch 7.5 mm mesially to the mental foramen were obtained, and the average radian was 15.9 degrees +/-5.5 degrees (minimum 5.6 degrees , maximum 35.2 degrees ). The radian and the A-P distance showed a negative correlation with statistical significance. CONCLUSION: In this research, the ovoid arch form was the most common type in edentulous mandibles, followed by tapered arch form. The square arch form showed the lowest percentage. As the arch form went squarer, the A-P distance became shorter, the radian of the jaw arch mesially to the mental foramen went greater, and the bone width that distally tilted implants need became bigger. The interforaminal arch form of the edentulous mandible should be analyzed before an implant supported fixed restoration is designed in the interforaminal region. The angle of inclination of distal implants should be reasonable. The bone width of the distal implant site must be adequate. The square arch form contributes negatively to the structure of implant supported fixed prostheses with distal cantilever design. PMID- 28816292 TI - [Precision of three-dimensional printed brackets]. AB - OBJECTIVE: This study was based on digital orthodontic diagnosis work flow for indirect bonding transfer tray model design and three-dimensional (3D) printing, and the aim of this paper was to inspect the dimensional accuracyof 3D printed brackets, which is the foundation of the follow up work and hoped that will illuminate the clinical application of the digital orthodontics work flow. METHODS: The samples which consisted of 14 cases of patients with malocclusion from Department of Orthodontics Peking University were selected, including 8 cases with tooth extraction and 6 cases without tooth extraction. All the 14 patients were taken intra-oral scan (Trios 3Shape, Denmark) and cone-beam computed tomography (CBCT, NewTom 3G volumetric scanner, Aperio Service,Italy)shooting after periodontal treatment. STL data and DICOM data were obtained from intraoral scans and CBCT images.Data segmentation, registration, fusion, automatic tooth arrangement, virtual positioning of orthodontic appliance and conversion the coordinates of malocclusion model were all done with self programming software. The data of 3D printing model with brackets on it were output finally and printed out with EDEN260V (Objet Geometries, Israel) to make indirect bonding transfer tray. Digital vernier caliper was used to measure the length and width of upper and lower left brackets and buccal tubes on those 3D models after removal of surrounding supporting material by ultrasonic vibration and water-spray. Intra-examiner reliability was assessed by using intra-class correlation coefficients (ICC), and one-sample T test was used to compare the measurements with the standard dimensional data of the brackets. RESULTS: There were significant differences which range in 0.04-0.17 mm between the 13 items out of the 19 measurement items. Except for the length of the lower left premolars'brackets, mean values of the other items were greater than the test value. CONCLUSION: Although the measurement results in the width of brackets and the width and length of the buccal tubes obtained experimentally were slightly larger than the test value,this may not reduce the accuracy of indirect bonding procedure in clinic necessarily. Whether the differences which range in 0.04-0.17 mm would actually affect the retention and positioning of brackets needs to be confirmed by further studies. PMID- 28816293 TI - [Effects of bioactive glass on reducing the hypersensitivity after full crown preparation]. AB - OBJECTIVE: To evaluate the efficacy of the 45S5 bioactive glass on the reduction of hypersensitivity of teeth prepared for full coverage crowns. METHODS: In the study, 31 prepared abutment teeth with vital pulp from 18 patients satisfied the inclusion criteria and exclusion criteria. The patients were informed consent and recruited into the study. This was a before and after self-control, single blind clinical trial. The severity of tooth hypersensitivity at baseline was evaluated, after application of the placebo, which was the powder of zinc oxide, and after application of the 45S5 bioactive glass on the same tooth. Tooth hypersensitivity was evaluated by Yeaple probe and visual analogue scale (VAS) when the tooth was stimulated by a fixed value of mechanical pressure and a blast of cold air respectively. And the dentist gave the subjective score, and the Schiff score at the same time. The three methods of measurement were repeated at baseline, after application of placebo and after application of the powder of 45S5 bioactive glass. Student's t test and nonparametric test were used for statistical analysis. RESULTS: The indexes measured at baseline, after the application of the placebo and after the application of the 45S5 bioactive glass were as follows, respectively: Tactile value (29.03+/-9.44) g, (29.68+/-9.48) g and (44.19+/ 11.19) g, VAS value (50.79+/-22.92) mm, (46.63+/-22.06) mm and (30.90+/-20.30) mm, Schiff score 2.13+/-0.67, 1.97+/-0.66 and 1.42+/-0.56. After the application of bioactive glass, the values of Tactile, the VAS, and the Schiff score were statistically different from those at baseline or after application of the placebo (P<0.05). The data measured at baseline and after application of the placebo were of no statistical difference (P>0.05). Statistical differences between the Schiff scores of the groups were associated with gender, tooth position, primary or secondary tooth preparation. CONCLUSION: RESULTS of the clinical trial showed that the powders of 45S5 bioactive glass were significantly effective on reducing the hypersensitivity of teeth with vital pulp after the full crown preparation. PMID- 28816294 TI - [Optimization of alkaline hydrolysis based on the side chain of diethyl ester 4 amino-N5-formyl-N8, N10-dideazatetrahydrofolic acid]. AB - OBJECTIVE: To optimize and establish the best hydrolysis method of diethyl ester 4-amino-N5-formyl-N8, N10-dideazatetrahydrofolate through the optimization of simple compound of diethyl N-(4-aminobenzoyl)-L-glutamate. METHODS: To increase the low yield of hydrolysis reaction of diethyl ester 4-amino-N5-formyl-N8, N10 dideazatetrahydrofolate due to the by-products and difficult purification, we studied the effect of NaOH and KOH, two kinds of alkalis, three concentrations between 0.175-1 mol/L and five types of reaction time involved in 20, 30, 60, 120 and 180 min on the common side chain diethyl N-(4-aminobenzoyl)-L-glutamate. A high performance liquid chromatography was established for measuring the target product and the by-products in reaction liquid in different reaction conditions. Finally, on the basis of the best hydrolysis method of diethyl ester 4-amino-N5 formyl-N8, N10-dideazatetrahydrofolate, we completed the optimization of the hydrolysis reaction conditions of diethyl ester 4-amino-N5-formyl-N8, N10 dideazatetrahydrofolate. RESULTS: We developed the best reaction condition for the hydrolysis of diethyl ester 4-amino-N5-formyl-N8, N10 dideazatetrahydrofolate, which could be carried out easily and efficiently. The results indicated that treated with the optimized condition of 0.3 mol/L KOH in 60 min at the room temperature, diethyl ester 4-amino-N5-formyl-N8, N10 dideazatetrahydrofolate was converted into its diacid derivative in 95.6 % yield, which turned to be a better reaction condition compared with the previous reaction condition. The structures of those compounds were identified to be correct by 1H nuclear magnetic resonance(1H NMR), 13C nuclear magnetic resonance(13C NMR) and electrospray ionization time of flight mass spectrometry (ESI-MS). The purity of the diacid derivative of the compound was determined to be 96% by high performance liquid chromatography(HPLC).The new hydrolysis reaction condition could not only avoid the formation of single ester hydrolysis product and amide bond hydrolysis product, but also improve the yield of the hydrolysis reaction. CONCLUSION: We have developed an efficient reaction for the hydrolysis of diethyl ester 4-amino-N5-formyl-N8, N10-dideazatetrahydro. Since the final step of the synthesis of classical folic acid antagonists is always the catalyzed hydrolysis of the side chain glutamate, the reaction also has great significance for anti-folic acid anti-tumor inhibitors synthesis. PMID- 28816295 TI - [Three-dimensional data fusion method for tooth crown and root based on curvature continuity algorithm]. AB - OBJECTIVE: To explore a three-dimensional (3D) data fusion and integration method of optical scanning tooth crowns and cone beam CT (CBCT) reconstructing tooth roots for their natural transition in the 3D profile. METHODS: One mild dental crowding case was chosen from orthodontics clinics with full denture. The CBCT data were acquired to reconstruct the dental model with tooth roots by Mimics 17.0 medical imaging software, and the optical impression was taken to obtain the dentition model with high precision physiological contour of crowns by Smart Optics dental scanner. The two models were doing 3D registration based on their common part of the crowns' shape in Geomagic Studio 2012 reverse engineering software. The model coordinate system was established by defining the occlusal plane. crown-gingiva boundary was extracted from optical scanning model manually, then crown-root boundary was generated by offsetting and projecting crown-gingiva boundary to the root model. After trimming the crown and root models, the 3D fusion model with physiological contour crown and nature root was formed by curvature continuity filling algorithm finally. In the study, 10 patients with dentition mild crowded from the oral clinics were followed up with this method to obtain 3D crown and root fusion models, and 10 high qualification doctors were invited to do subjective evaluation of these fusion models. RESULTS: This study based on commercial software platform, preliminarily realized the 3D data fusion and integration method of optical scanning tooth crowns and CBCT tooth roots with a curvature continuous shape transition. The 10 patients' 3D crown and root fusion models were constructed successfully by the method, and the average score of the doctors' subjective evaluation for these 10 models was 8.6 points (0-10 points). which meant that all the fusion models could basically meet the need of the oral clinics, and also showed the method in our study was feasible and efficient in orthodontics study and clinics. CONCLUSION: The method of this study for 3D crown and root data fusion could obtain an integrate tooth or dental model more close to the nature shape. CBCT model calibration may probably improve the precision of the fusion model. The adaptation of this method for severe dentition crowding and micromaxillary deformity needs further research. PMID- 28816296 TI - [Complete androgen insensitivity syndrome associated with vesical fistula: a case report and literature review]. AB - Androgen insensitivity syndrome (AIS) is a very uncommon genetic disorder that results from the resistance of androgen receptor (AR) to androgen, which influences the formation of the male genitalia and in turn presents with female phenotype. Surgical resection of undesceaded testicle and different kinds of genitoplasty are crucial methods to correct the deformity of reproductive system, as well as hormone replacement therapy, which is an essential therapy for postoperational rehabilitation in AIS patients. A 43-year-old patient, who was socially female, was first admitted to gastroenterology department due to recurrent ascites and occasional abdominal pain with unknown origin. Taking physical examination, ultrasonography, karyotype analysis and sex hormone levels into consideration, the overall manifestations revealed the typical clinical features of complete androgen insensitivity syndrome. After that she was transferred to urology department for laparoscopic gonadectomy. During the surgery, doctors found that there was a vesical fistula on the upper wall near the conjunction between the bladder and ligamenta umbilicale medium, which explained the recurrent ascites for more than 4 years. After resecting the testicles and the tissues around the vesical fistula for histopathology, the result suggested Sertoli cell adenoma, hyperplastic Leydig cells and urothelium atypical hyperplasia. Hormone replacement therapy was given right after discharge. The hormone levels of follicle-stimulating hormone, luteinizing hormone, estradiol and progesterone were modulated by the dysfunction of androgen production after gonadectomy and hormone replacement therapy together with psychotherapy could stabilize her hormone levels and improve the quality of her life. The patient was suspicious of AIS family history and the pedigree was made to analyze her family which was possibly X-linked recessive pattern. We propose three possible hypotheses of the fistula, which are direct surgical injury, recurrence of bladder cancer and congenital urachal anomalies. But whether it is relevant between urachal anomalies and AIS is yet to be discovered. PMID- 28816297 TI - [Perirenal cystic lymphangioma in an adult: a case report and literature review]. AB - Lymphangioma is a rare, benign mesenchymal neoplasm, which is characterized by numerous intercommunicating cystic spaces containing lymphatic fluid. It is considered a congenital disease resulting from the obstruction of regional lymph drainage during the developmental period. Lymphangioma frequently occurs in the cervical neck and axilla, also in the retroperitoneum, mediastinum, mesentery, omentum, colon, and pelvis, rarely in the perirenal space. These tumors usually present in childhood, but infrequently, these also present in adults. Patients often complain of hematuria, flank pain, or abdominal pain. Complications of lymphangioma have been reported to include infection, ruputure, or hemorrhage. There are three types of lymphangioma commonly identified: capillary, cavernous, and cystic. Cystic type is the one commonly found intra-abdominally or retroperitoneally, and may be uniloculated or multiloculated. All these perirenal tumors have a very low incidence, make it difficult to diagnose. Differential diagnosis must be performed with the primary renal lymphoma, urinoma, polycystic kidney, teratoma, both benign and malignant tumors, etc. Endoscopic ultrasound guided fine needle aspiration is recommended in some literatures, which may help make diagnosis and further guide subsequent therapeutic strategy. Regarding treatment, surgical excision can be performed via either laparotomy or laparoscopy. And injection of sclerosants into lympahgioma has been described in the literature in nonsurgical candidates. The optimal definitive treatment is total surgical excision. Despite being rare, the tumor has an excellent prognosis. Here, we report a case of a 48-year-old woman with a left renal mass found in an abdominal ultrasonography during a health checkup. In the case presented, abdominal ultrasonography and magnetic resonance urography (MRU) revealed an approximately 11.3 cm*10.6 cm*12.8 cm multilocular cystic mass in the left perirenal space. There was no history of bowel or bladder complaint, either previous illness episodes. Full blood count and kidney function tests were within normal limits. Laparoscopic surgical removal of the cyst was accomplished without incident. A benign cystic perirenal lymphangioma was diagnosed on histology and confirmed with immunohistochemical stains. One month after the surgery the ureteral stent was removed. The patient was free of disease after a 3-month follow-up period. We report the case and discuss the management of perirenal lymphangiomatosis with a literature review. PMID- 28816298 TI - [Multiple endoscopy for the treatment of upper urinary tract calculi following ileal conduit: a case report and literature review]. AB - Upper urinary tract calculi with infection is a quite difficult acute urologic emergency. And what is more, upper urinary tract obstruction after radical cystectomy following urinary diversion may be fatal in the vulnerable patients with this kind of situation. Postoperative anatomy and other factors affect the upper urinary tract calculi, and urinary tract infection greatly increased the risk. But it is particularly difficult to handle with patients with poor general condition and septic shock treatment, so how to optimize the selection program is worth further studying. A 65-year-old man was admitted to hospital for combining with renal and ureteral calculi after radical cystectomy (Bricker) in March 2017. The patient underwent transurethral resection of bladder tumor in the outer court because of the discovery of bladder tumor one year before, The postoperative pathology was high-grade papillary urothelial carcinoma and he underwent regular irrigation of the bladder. Because of tumor recurrence, he came to Peking University Third Hospital for further treatment in August 2016, and the examination of urinary tract CT indicated bladder cancer; for bilateral multiple renal pelvis and renal calices calculi, he was given laparoscopic radical cystectomy. After four months, due to sudden chill fever, he was hospitalized. After definite diagnosis, anti-inflammatory treatment combined with left nephrostomy was given. The two-stage lithotripsy was performed. After expansion of the original left renal fistula to 24 F(1 F=0.33 mm), 24 F sheath was inducted into the kidney. We introduced a flexible ureteroscopy into the channel down to the ureteral obstruction, where we found a 1 cm oval black brown stone obstructed. A guide wire was inducted through the stones down to ileal conduit in the right lower quadrant. Through the ureteroscopy, we made ureteral calculi broken into powder, and replaced the residual stones into the renal pelvis. Then we used the nephroscopy for lithotropsy in the pelvis, and finally we introduced a flexible cystoscopy for the residual stone. The operation was successful, the operation time was 181 min, and intraoperative bleeding was 10 mL. After operation, no residual stones were found in kidney, ureter, bladder (KUB) plain films. No operation complications were related to the urinary tract. Therefore, multiple endoscopy with combination therapy of upper urinary tract calculi following urinary diversion is safe and effective, and the reasonable choice with the advantages of each instrument can improve the stone clearance rate and shorten the operation time. This can be used as a useful complement to traditional treatment. PMID- 28816299 TI - [Application of intraoperative cell salvage combined with leukocyte depletion filter on radical nephrectomy for renal carcinoma with inferior vena cava tumor thrombus: 2 case reports]. AB - Intraoperative cell salvage (IOCS) has been widely used to reduce allogeneic blood transfusion and prevent blood transfusion related complications during surgery. However, due to the risk of transfusion related reaction, contamination, and immunological reaction, its use for tumor patients has been controversial and limited. To explore the feasibility of the application of IOCS in cancer patients, we reported 2 cases of renal cell carcinoma (RCC) with tumor embolism in IVC that underwent radical nephrectomy,and inferior caval venous thrombectomy receiving IOCS combined with leukocyte depletion filter (LDF) from August 2016 to November 2016 in our hospital. The cell saver blood salvage (Haemonetics, 5+) was used for these 2 cases. The salvaged blood was filtered through the LDF before infusion. For case 1 (male 45-year-old) the total operation time was 505 min, and the estimated blood loss was 4 500 ml. A total of 1 000 mL autologous blood, 12 u allogeneic packed red blood cells (PRBC), 1 200 mL fresh frozen plasma (FFP) were infused during the procedure. The patient was discharged from hospital after 75 days without complications. The postoperative follow-up for 3 months showed no tumor recurrence or metastasis. For case 2 (a male patient, aged 51 years), the total operation time was 490 min, and the estimated (blood loss was 7 000 mL. the patient received 2 700 mL autologous blood transfusion, 12 u allogeneic packed red blood cells (PRBC), and 2 400 mL fresh frozen plasma (FFP). The patient was discharged from hospital after 86 days without severe complications. the postoperative follow-up for 6 months showed no tumor recurrence or metastasis for this patient. Other relevant retrospective studies with this technique showed that cell salvage could be used safely in many kinds of cancer patients, for example, bladder cancer, liver cancer and kidney cancer. Furthermore,numerous researches have proved the safety and efficacy of the combination of these two techniques, the intraoperative cell salvage technique and leucocyte depletion filter in cancer patients. Here we only reported two cases using IOCS and LDF. Further work is needed to determine whether the use of intraoperative cell salvage combined with leukocyte depletion filter can be used safely for patients with HCC. PMID- 28816300 TI - [Combination of periodontal, orthodontic and endodontic therapy in upper anterior teeth with hopeless prognosis and long-time follow-up: a case report]. AB - It is complicated to decide the treatment plan of hopeless anterior teeth in esthetic zone due to severe periodontitis, periodontal-endodontic combined lesion or teeth trauma. The optional treatment plan for this kind of teeth includes retention after periodontal treatment, extraction and implant treatment, extraction and prosthodontic treatment and so on. To make an appropriate treatment plan, patients' periodontal conditions, periodontal biotype, local anatomy, esthetic demand, economic condition and social psychological status should be comprehensively considered. A combine of periodontal, endodontic and orthodontic therapy may achieve a good treatment effect in hopeless anterior teeth with severe periodontal destruction, tooth extrusion and occlusal trauma. In this case, a 20-year-old female who presented with symptoms of bleeding on brushing and upper incisors loosening for 1 month came to the Department of Periodontology, Peking University School and Hospital of Stomatology. The clinical examinations revealed that the patient's right upper incisor had signs of mobility (III degrees ), intrusion of 1-2 mm, and probing depth (PD) of 9-10 mm. The periapical radiograph showed that the alveolar bone of right upper incisor absorbed horizontally to the apex. And the patients showed Angle II degrees malocclusion with II degrees overbite in anterior teeth and maxillary protrusion. A diagnosis of aggressive periodontitis and Angle II degrees malocclusion was made. The treatment of this patient lasts for 5 years which include periodontal initial therapy, orthodontic therapy, guided tissue regeneration (GTR) of right upper incisor and supportive periodontal therapy and the clinical result is fine. A hopeless upper incisor was successfully retained and the longtime clinical condition was stable. The strategy of retention of hopeless upper anterior teeth, the relationship of periodontal treatment and orthodontic treatment, and the indications of periodontal and orthodontic combined therapy were also discussed on the basis of this case. Generally, the positive factors in retention of hopeless teeth includes young age, absence of systemic conditions, strong motivation for maintaining the tooth, single root anatomy, integrated dentition, good response to cause-related therapy, intrabony alveolar bone defect, thick periodontal biotype, and regular supportive periodontal therapy. And in the progress of orthodontic therapy, regular supportive periodontal therapy and good plaque control is extremely important. PMID- 28816301 TI - A new ferrocenyl bisphosphorus ligand for the asymmetric hydrogenation of alpha methylene-gamma-keto-carboxylic acids. AB - Upon incorporation of a noncovalent ion pair interaction, a new chiral ferrocenyl bisphosphorus ligand t-Bu-Wudaphos was developed. t-Bu-Wudaphos can be easily synthesized with very high diastereoselectivity as a highly air stable solid. The new ligand exhibited excellent reactivities and enantioselectivities in the asymmetric hydrogenation of alpha-methylene-gamma-keto-carboxylic acids via an ion pair noncovalent interaction (up to >99% conversion, >99% ee). PMID- 28816302 TI - Functional nanonetwork-structured polymers and carbons with silver nanoparticle yolks for antibacterial application. AB - Functional nanonetwork-structured polymers and carbons with silver nanoparticle yolks (~20 nm) were successfully fabricated via hypercrosslinking chemistry. Benefiting from the hierarchical porous nanonetwork structure and high surface areas (up to 566 m2 g-1), the as-prepared nanocomposites demonstrated superior long-term antibacterial performances (e.g., 6 days). PMID- 28816303 TI - Reversible surface functionalisation of emulsion-templated porous polymers using dithiophenol maleimide functional macromolecules. AB - A new facile and efficient route for the chemical functionalisation of thiol acrylate polyHIPE materials with responsive macromolecules using the highly emissive dithiomaleimide (DTM) linker is demonstrated. Functionalisation is found to be reversible upon addition of a thiol-containing compound, glutathione, resulting in switchable surface properties including fluorescence and wettability, hence broadening the scope of applications. PMID- 28816304 TI - Iodoarene-catalyzed oxidative transformations using molecular oxygen. AB - Molecular oxygen serves as a useful oxidant for the glycol scission of 1,2-diols and the Hofmann rearrangement of primary amides using pentamethyliodobenzene as a catalyst. The use of isobutyraldehyde and Lewis basic nitriles under O2 enabled the iodine(i)/(iii) catalytic cycle, where in situ-generated peracid acts as a terminal oxidant. PMID- 28816305 TI - Real-time atomic scale observation of void formation and anisotropic growth in II VI semiconducting ribbons. AB - Void formation in semiconductors is generally considered to be deteriorating. However, for some systems, void formation and evolution are beneficial and can be used for the fabrication of novel nanostructures. In either scenario, the understanding of void formation and evolution is of both scientific and technical high importance. Herein, using ZnS ribbons as an example, we report real-time observations of void formation and the kinetics of growth at the nano- and atomic scales upon heating. Direct imaging reveals that voids, created by a focused electron beam in wurtzite (WZ) ribbons, have a rectangular shape elongated along the <0001> direction. The voids are enclosed by low-surface-energy planes including {01-10} and {2-1-10}, with minor contribution from the higher-energy {0001} planes. Driven by thermodynamics to minimize surface energy, the voids grow straight along the [000+/-1] directions, exhibiting a strong anisotropy. Occasionally, we observe oscillatory kinetics involving periodic void growth and shrinkage, likely due to the fluctuation of the local chemical potential leading to a transitional kinetic state. We also reveal that the morphology and growth kinetics of voids are highly structure-dependent. Real-time observation during void growth through the complex WZ-zinc blende (ZB)-WZ structure shows that the void, with an initial elongated rectangular morphology in the WZ domain, transforms into a different shape, dominated by the {110} surfaces, after migrating to a domain of the ZB structure. However, when the void moves from the ZB to the WZ domain, it transforms back into a rectangular shape followed by fast growth along the [0001] direction. Our experimental results, together with density functional theory (DFT) calculations, provide valuable insights into the mechanistic understanding of void formation and evolution in semiconductors. More importantly, our study may shed light on new pathways for the morphological modulation of nanostructures by utilizing the intrinsic anisotropy of void evolution in WZ semiconductors. PMID- 28816306 TI - Comment on "Towards a personalized approach to aromatase inhibitor therapy: a digital microfluidic platform for rapid analysis of estradiol in core-needle biopsies" by S. Abdulwahab, A. H. C. Ng, M. D. Chamberlain, H. Ahmado, L.-A. Behan, H. Gomaa, R. F. Casper and A. R. Wheeler, Lab Chip, 2017, 17, 1594. AB - This comment on an article that appeared in Lab on a Chip (Abdulwahab et al., Lab Chip, 2017, 17, 1594) highlights the need for further validation of the proposed method. PMID- 28816307 TI - Quantum cascade lasers (QCLs) in biomedical spectroscopy. AB - Quantum cascade lasers (QCL) are the first room temperature semiconductor laser source for the mid-IR spectral region, triggering substantial development for the advancement of mid-IR spectroscopy. Mid-IR spectroscopy in general provides rapid, label-free and objective analysis, particularly important in the field of biomedical analysis. Due to their unique properties, QCLs offer new possibilities for development of analytical methods to enable quantification of clinically relevant concentration levels and to support medical diagnostics. Compared to FTIR spectroscopy, novel and elaborated measurement techniques can be implemented that allow miniaturized and portable instrumentation. This review illustrates the characteristics of QCLs with a particular focus on their benefits for biomedical analysis. Recent applications of QCL-based spectroscopy for analysis of a variety of clinically relevant samples including breath, urine, blood, interstitial fluid, and biopsy samples are summarized. Further potential for technical advancements is discussed in combination with future prospects for employment of QCL-based devices in routine and point-of-care diagnostics. PMID- 28816308 TI - Ln(iii) complexes (Ln = Eu, Gd, Tb, Dy) with a chiral ligand containing 1,10 phenanthroline and (-)-menthol fragments: synthesis, structure, magnetic properties and photoluminescence. AB - A series of lanthanide(iii) complexes based on the new chiral ligand L, which contains 1,10-phenanthroline and (-)-menthol fragments, namely [LnL2(NO3)3] (Ln = Eu (1), Gd (2), Tb (3), Dy (4)), have been synthesized and structurally characterized. Complexes 1-4 are isostructural and crystallize in the non centrosymmetric space group P41212. The mononuclear complexes comprise a 10 coordinate Ln3+ ion with two bidentate N,N-donor ligands (L) and three bidentate chelating nitrate groups. The magnetic properties of complexes 1-4 are determined mainly by the Ln3+ ions. In the case of complexes 3 and 4, significant anisotropy results in nonlinear field dependences of magnetization at low temperature. Complexes 1, 3 and 4 exhibit metal-centered red (Eu3+), green (Tb3+) and yellow (Dy3+) luminescence, respectively, whereas complex 2 displays blue ligand-based luminescence in the solid state at room temperature. The luminescence quantum yield for the solid samples increases in the order 4 < 2 ~ 3 < 1. The europium(iii) complex shows long luminescence lifetimes (up to 1750 MUs) and a very high quantum yield (phif = 0.87); these make this compound promising for application in sensing and optoelectronics. PMID- 28816309 TI - Reply to the 'Comment on "Towards a personalized approach to aromatase inhibitor therapy: a digital microfluidic platform for rapid analysis of estradiol in core needle-biopsies"' by P. E. Lonning, Lab Chip, 2017, 17, DOI: 10.1039/C7LC00617A. AB - This article provides our response to a comment on our article that appeared in Lab on a Chip (S. Abdulwahab, A. H. C. Ng, M. D. Chamberlain, H. Ahmado, L.-A. Behan, H. Gomaa, R. F. Casper and A. R. Wheeler, Lab Chip, 2017, 17, 1594). PMID- 28816310 TI - Role of intrinsic hydrogen bonds in the assembly of perylene imide derivatives in solution and at the liquid-solid interface. AB - The impact of hydrogen bond formation on the supramolecular assembly of two perylene imide derivatives (PMAMI and PDINH) was systematically investigated in solution and at the liquid-solid interface. PDINH has intrinsic hydrogen bond sites, but this is not the case for PMAMI. The solution assembly was explored by morphological methods (SEM, AFM, TEM and cryo-TEM) and spectral characterization (UV-vis, FL, XRD, and FTIR spectra). The surface assembly at the liquid-solid interface was detected by scanning tunneling microscopy (STM). It was found that in a mixed solution (THF/MeOH, 10 v%/90 v%), PMAMI formed nanofibers together with large sheet structures and PDINH assembled into uniform nanosheets, suggesting different molecular packing routes. The assembled structures could be adjusted by varying the solvent polarity for both molecules. At the liquid-solid interface, clearly distinguished surface nanostructures from PMAMI and PDINH were easily observed. Based on all spectral and morphological characterizations, it was suggested that in solution the assembly of PMAMI was mainly derived by pi-pi stacking interactions; on the other hand, the synergetic interaction of hydrogen bonds and pi-pi stacking was the reason for the hierarchical assembly of PDINH. Hydrogen bonds could be formed both for PMAMI and PDINH and stabilized nanostructures at the liquid-solid interface. This investigation could be useful in designing perylene imide-based building blocks for fabricating supramolecular assemblies with predetermined nanostructures and properties. PMID- 28816311 TI - Hierarchical core-shell SiO2@PDA@BiOBr microspheres with enhanced visible-light driven photocatalytic performance. AB - To explore catalysts combining highly accessible specific surface areas with low recombination of the photo-induced electron-hole pairs, a novel SiO2@PDA@BiOBr composite photocatalyst with a hierarchical core-shell structure was prepared by a facile solvothermal method. The catalyst shows a superior performance on photodegradation of Rhodamine B under visible light irradiation, especially for SiO2@PDA-2@BiOBr with the reactant kinetics constant (k = 0.0487 min-1). The enhanced photocatalytic performance of SiO2@PDA-2@BiOBr was ascribed to the decreased band-gap, higher surface area, and effectively photo-generated electron hole pairs by the introduction of polydopamine (PDA). In addition, the photocatalytic degradation is initiated by O2- derived from dye photosensitization and h+ from the BiOBr. Cyclic experiments also indicate that the SiO2@PDA-2@BiOBr is reusable during the photodegradation process. The hierarchical core-shell SiO2@PDA@BiOBr photocatalyst will provide a theoretical model for the development of physical chemistry and structural properties of BiOBr-based composites to enhance the photocatalytic performances. PMID- 28816312 TI - Palladium-catalyzed tandem cyclization/sulfonylation of homoallenyl amides with sodium sulfinates. AB - A palladium-catalyzed cyclizative sulfonylation of homoallenyl amides using sodium sulfinates as the sulfonylation reagent and PhI(O2CCF3)2 as the oxidant has been realized. The reaction proceeds at room temperature and produces structurally diverse 2-amino-5-sulfonylmethylfurans in good to excellent yields. A Pd(ii)/Pd(iv) catalytic cycle has been proposed for the formation of sulfonylated furans. The concurrent formation of a furan moiety and a C(sp3) sulfur bond in a single operation makes it a very attractive method for organic synthesis. PMID- 28816313 TI - 2,4-Diamino-1,3,5-triazine-enabled Cu-catalyzed direct sulfonamidation of aromatic C-H bonds. AB - An efficient copper acetate catalyzed sulfonamidation of arenes via C-H bond activation directed by a 2,4-diamino-1,3,5-triazine chelating group under oxygen as a terminal oxidant has been developed. The reaction shows good regioselectivity and functional group tolerance, as well as providing a straightforward methodology for the preparation of ortho-monosulfonamidated arene derivatives in moderate to high yields. The sulfonamidation at the gram scale can be performed with a good yield. PMID- 28816314 TI - Pt supraparticles with controllable DNA valences for programmed nanoassembly. AB - Supraparticles are self-limiting nanoparticle ensembles with attractive properties from their unique hierarchical (primary and secondary) structures. Aiming at relieving the bottleneck of the very limited material building blocks in DNA nanotechnology, we herein demonstrate Pt-based supraparticles as catalytic materials for valence-controllable and high density DNA functionalizations toward DNA-programmed nanoassembly. PMID- 28816315 TI - A highly selective and sensitive fluorescent nanosensor for dopamine based on formate bridged Tb(iii) complex and silver nanoparticles. AB - Highly selective determination of dopamine (DA) over other catecholamines is an urgent need for the precise diagnosis and therapy of DA related diseases. Herein, a new formate-bridged Tb(iii)-complex and silver nanoparticles (AgNPs) enhanced fluorescent nanosensor was constructed. HCOO- acted as a co-ligand of Tb(iii) and also as a linker between the Tb(iii) complex and AgNPs and more readily combined with the primary amine of DA than with epinephrine (EP). The formate-bridged action strengthened AgNPs-based surface enhanced fluorescence of the Tb3+-DA complex and improved the selectivity towards DA. Under neutral buffer conditions, the detection limit for the assay of DA was down to 0.15 nM (S/N = 3) with a linear range from 0.5 nM to 100 nM (R2 = 0.9978). Furthermore, the nanosensor could successfully distinguish DA from EP. PMID- 28816316 TI - Hydrogel scaffolds for differentiation of adipose-derived stem cells. AB - Natural extracellular matrices (ECMs) have been widely used as a support for the adhesion, migration, differentiation, and proliferation of adipose-derived stem cells (ADSCs). However, poor mechanical behavior and unpredictable biodegradation properties of natural ECMs considerably limit their potential for bioapplications and raise the need for different, synthetic scaffolds. Hydrogels are regarded as the most promising alternative materials as a consequence of their excellent swelling properties and their resemblance to soft tissues. A variety of strategies have been applied to create synthetic biomimetic hydrogels, and their biophysical and biochemical properties have been modulated to be suitable for cell differentiation. In this review, we first give an overview of common methods for hydrogel preparation with a focus on those strategies that provide potential advantages for ADSC encapsulation, before summarizing the physical properties of hydrogel scaffolds that can act as biological cues. Finally, the challenges in the preparation and application of hydrogels with ADSCs are explored and the perspectives are proposed for the next generation of scaffolds. PMID- 28816317 TI - Evaluation of mapping schemes for systematic coarse graining of higher alkanes. AB - A model is introduced to explore the influence of different coarse-grained (CG) resolutions on the structural and thermodynamic properties of higher alkanes. Four different mapping schemes are considered, for which the potentials are derived using the conditional reversible work (CRW) method. The CRW method is a bottom-up coarse-graining procedure, which derives effective pair potentials between nonbonded chemical groups defined by the mapping scheme from the underlying molecular interactions in a quick, inexpensive way. We consider the applicability of CRW for mapping sites including up to four heavy atoms and study the properties of n-dodecane and n-tetracosane in the liquid state. Both chemical and thermodynamic transferability are achieved for high resolution representations. However, the ability of the coarse-grained model to effectively describe the system deteriorates as the size of the mapping is increased and sampling issues arise. By looking at the configuration distributions of the dihedrals in the atomistic sampling runs (gas phase), it is shown that the gauche population is underrepresented. Here we address the problem and propose a viable solution to recover the agreement between atomistic and low resolution coarse grained representation. All the CRW potentials presented in the paper are reported in tabulated and analytical form. PMID- 28816318 TI - A soluble star-shaped silsesquioxane-cored polymer-towards novel stabilization of pH-dependent high internal phase emulsions. AB - A well-defined pH-responsive star-shaped polymer containing poly(N,N dimethylaminoethyl methacrylate) (PDMA) arms and a cage-like methacryloxypropyl silsesquioxane (CMSQ-T10) core was used as an interfacial stabilizer for emulsions consisting of m-xylene and water. We explored the properties of the CMSQ/PDMA star-shaped polymer using the characteristic results of nuclear magnetic resonance (NMR) spectroscopy, size exclusion chromatography (SEC), dynamic light scattering (DLS), and zeta potential and conductivity measurements. The interfacial tension results showed that the CMSQ/PDMA star-shaped polymer reduced the interfacial tension between water and oil in a pH-dependent manner. Gelled high internal phase emulsions (HIPEs) including o/w and w/o types were formed in the pH ranges of 1.2-5.8 and 9.1-12.3 with the CMSQ/PDMA star-shaped polymer as a stabilizer, when the oil fractions were 80-90 vol% and 10-20 vol%, respectively. The soluble star-shaped polymer aggregated spontaneously to form a microgel that adsorbed to the two immiscible phases. Images of the fluorescently labeled polymers demonstrated that there was a star-shaped polymer in the continuous phase, and the non-Pickering stabilization based on the percolating network of the star-shaped polymer also contributed to the stabilization of the HIPE. This pH-dependent HIPE was prepared with a novel stabilization mechanism consisting of microgel adsorption and non-Pickering stabilization. Moreover, the preparation of HIPEs provided the possibility of their application in porous materials and responsive materials. PMID- 28816319 TI - Novel multiple phosphorescence in nanostructured zinc oxide and calculations of correlated colour temperature. AB - The design and development of novel and high quantum efficiency luminescent materials, such as phosphors, having tuneability in properties, have received tremendous interest among scientists. In this paper, we have achieved for the first-time multiple phosphorescence (blue and green) having a life-time of ~10 MUs in nanostructured zinc oxide that was synthesized using an easy and facile sol-gel method. Importantly, the photoluminescence (PL) intensity and the phosphorescence life-time could be tuned by controlling the annealing temperature under a reducing atmosphere. Temperature and atmosphere dependent variation of [VO] and has been interpreted by the detailed thermodynamic analysis of defect chemistry, for the first time. These nanostructured zinc oxide particles being sufficiently large in size (around 160 nm) are extremely stable and expected to show photoluminescence for a longer period of time than nanorods and quantum dots. The quantum yield was found to be as high as 13-15% which is comparable to the order of magnitude of that of quantum dots. The calculated correlated colour temperature is found to be suitable for cool lighting applications. PMID- 28816320 TI - Formation of titanium dioxide core-shell microcapsules through a binary-phase spray technique. AB - Core-shell microcapsules consisting of a titanium dioxide shell and a hydrophobic solvent core have been prepared with diameters of a few micrometers and a narrow size distribution using a simple and fast airbrush technique. These microcapsules were prepared at room temperature in a single-step process in which an oil with a dissolved titanium alkoxide precursor was forced together with an aqueous solution, containing a surface-active polymer, through a narrow spray nozzle using a nitrogen gas propellant. Several different parameters of chemical, physical, and processing origin were investigated to find an optimal recipe. Two different alkanes, one ketone, and four alcohols were tested and evaluated as core materials, alone or together with the antifungal biocide 2-n-octyl-4 isothiazolin-3-one (OIT). Long-chain alcohols were found suitable as core oil due to their low solubility in water and surface activity. The addition of the surface-active polymers in the water phase was important in aiding the formation and stabilization of the titanium dioxide shell. An impressive loading of 50 wt% of the semi-hydrophobic OIT was possible to encapsulate using this simple and applicable procedure. PMID- 28816321 TI - Transport properties and ionicity of phosphonium ionic liquids. AB - Ionic liquids (ILs) are promising electrolytes and many efforts have been made in basic scientific research as well as in applied research. In this contribution, we synthesised a variety of partly novel phosphonium ILs with different anions as well as with different compositions and lengths of the side chains of the cations. We measured a variety of their important transport properties such as viscosity, conductivity and diffusivity by means of stress-controlled rheology, impedance spectroscopy and PFGSTE NMR diffusometry. The results are analysed with respect to different models for derivation from ideal behaviours such as the ionicity and the (fractional) Walden rule depending on their molecular structure. These models are well established in the literature and are herein applied to rarely investigated but promising phosphonium ILs, with a particular emphasis placed on the effect of ether side chains. In comparison, the models show a qualitative correlation but distinct deviation in the quantification especially in the temperature dependent values and with other IL systems. These results aim to facilitate a better understanding of the IL properties depending on the molecular composition and by this way help to choose the ILs with optimal properties for practical applications. PMID- 28816322 TI - Ultrasonication-enhanced gelation properties of a versatile amphiphilic formamidine-based gelator exhibiting both organogelation and hydrogelation abilities. AB - We describe the preparation of a novel amphiphilic gelator built from a formamidine core, which is able to form a variety of physical organogels and hydrogels at concentrations ranging from 15 to 150 mg mL-1. Interestingly, ultrasound treatment of isotropic solutions (i.e., gel-precursor) resulted in a remarkable enhancement of the gelation kinetics as well as the gelation scope and characteristic gel properties (e.g., critical gelation concentration, gel-to-sol transition temperature, viscoelastic moduli) in comparison to the heating-cooling protocol typically used to obtain supramolecular gels. Thermoreversibility, thixotropy, injectability and multistimuli responsiveness are some of the most relevant functionalities of these gels. Electron microscopy imaging revealed the formation of entangled networks made of fibers of nanometer diameters and micrometer lengths, with different morphological features depending on the solvent. Insights into the driving forces for molecular aggregations were obtained from FTIR, NMR, PXRD and computational studies. The results suggest a major stabilization of the fibers through additive N-HO hydrogen bonds, in combination with hydrophobic interactions, over pi-pi stacking interactions. PMID- 28816323 TI - Indirect dynamics in SN2@N: insight into the influence of central atoms. AB - Central atoms have a significant influence on the reaction kinetics and dynamics of nucleophilic substitution (SN2). Herein, atomistic dynamics of a prototype SN2@N reaction F- + NH2Cl is uncovered employing direct dynamics simulations that show strikingly distinct features from those determined for a SN2@C congener F- + CH3Cl. Indirect scattering is found to prevail, which proceeds predominantly through a hydrogen-bonded F--HNHCl complex in the reactant entrance channel. This unexpected finding of a pronounced contribution of indirect reaction dynamics, even at a high collision energy, is in strong contrast to a general evolution from indirect to direct dynamics with enhanced energy that characterizes SN2@C. This result suggests that the relative importance of different atomic-level mechanisms may depend essentially on the interaction potential of reactive encounters and the coupling between inter- and intramolecular modes of the pre reaction complex. For F- + NH2Cl the proton transfer pathway is less competitive than SN2. A remarkable finding is that the more favorable energetics for NH2Cl proton transfer, as compared to that for CH3Cl, does not manifest itself in the reaction dynamics. The present work sheds light on the underlying reaction dynamics of SN2@N, which remain largely unclear compared to well-studied SN2@C. PMID- 28816324 TI - The generalized maximum hardness principle revisited and applied to atoms and molecules. AB - In this perspective contribution, we revisit the Maximum Hardness Principle (MHP), formulated by Pearson in 1987, and an equivalent Minimum Polarizability Principle (MPP) from Chattaraj and Parr, with particular emphasis on the cases where nuclear potential acting on electrons does not remain constant, and where substantial modifications of the nuclear geometry take place (Generalized MHP, GMHP). We first bring basic concepts related to electronic hardness, and then we present an overview of important manifestations of the GMHP for molecular systems such as (i) the tendency of two free radicals to couple, (ii) reduced reactivity of noble gases, (iii) symmetry-breaking distortions related to the Jahn-Teller effect, and/or these connected with (anti)aromatic character of certain organic molecules, (iv) enhanced reactivity of excited states, (v) high-low spin transitions, etc. GMHP is an important qualitative indicator in studies of molecular isomerism and reactivity. Quantitative aspects, traditionally measured by changes of electronic plus nuclear energy, are readily explained by changes of hardness (or polarizability) of a molecular system. Several important exceptions from (G)MHP are discussed. PMID- 28816328 TI - Palladium-catalyzed allylic amination: a powerful tool for the enantioselective synthesis of acyclic nucleoside phosphonates. AB - Acyclic nucleoside phosphonates have been prepared in a straightforward manner and in high yields by an enantioselective palladium-catalyzed allylic substitution involving nucleic bases as nucleophiles followed by cross-metathesis reaction with diethyl allylphosphonate. PMID- 28816329 TI - Highly regio- and stereoselective trans-iodofluorination of ynamides enabling the synthesis of (E)-alpha-fluoro-beta-iodoenamides. AB - A highly regio- and stereoselective trans-iodofluorination reaction of ynamides with NIS and Et3N.3HF has been achieved, affording (E)-alpha-fluoro-beta iodoenamides in moderate to good yields. The reaction proceeds under mild reaction conditions and exhibits good functional group compatibility. PMID- 28816332 TI - Phosphine-catalyzed intramolecular Rauhut-Currier reaction: enantioselective synthesis of hydro-2H-indole derivatives. AB - A highly enantioselective intramolecular Rauhut-Currier reaction catalyzed by a multifunctional chiral aminophosphine catalyst was reported. A series of hydro-2H indole derivatives that bear an all-carbon quaternary center were obtained in high yields (up to 94%), and excellent diastereo- and enantioselectivities (up to >20 : 1 dr and >99% ee). And this reaction could be performed on a gram scale using 2 mol% catalyst loading. PMID- 28816337 TI - A Bag of Concepts Approach for Biomedical Document Classification Using Wikipedia Knowledge*. Spanish-English Cross-language Case Study. AB - OBJECTIVES: The ability to efficiently review the existing literature is essential for the rapid progress of research. This paper describes a classifier of text documents, represented as vectors in spaces of Wikipedia concepts, and analyses its suitability for classification of Spanish biomedical documents when only English documents are available for training. We propose the cross-language concept matching (CLCM) technique, which relies on Wikipedia interlanguage links to convert concept vectors from the Spanish to the English space. METHODS: The performance of the classifier is compared to several baselines: a classifier based on machine translation, a classifier that represents documents after performing Explicit Semantic Analysis (ESA), and a classifier that uses a domain specific semantic annotator (MetaMap). The corpus used for the experiments (Cross Language UVigoMED) was purpose-built for this study, and it is composed of 12,832 English and 2,184 Spanish MEDLINE abstracts. RESULTS: The performance of our approach is superior to any other state-of-the art classifier in the benchmark, with performance increases up to: 124% over classical machine translation, 332% over MetaMap, and 60 times over the classifier based on ESA. The results have statistical significance, showing p-values < 0.0001. CONCLUSION: Using knowledge mined from Wikipedia to represent documents as vectors in a space of Wikipedia concepts and translating vectors between language-specific concept spaces, a cross-language classifier can be built, and it performs better than several state of-the-art classifiers. PMID- 28816338 TI - Prediction of Emergency Department Hospital Admission Based on Natural Language Processing and Neural Networks. AB - OBJECTIVE: To describe and compare logistic regression and neural network modeling strategies to predict hospital admission or transfer following initial presentation to Emergency Department (ED) triage with and without the addition of natural language processing elements. METHODS: Using data from the National Hospital Ambulatory Medical Care Survey (NHAMCS), a cross-sectional probability sample of United States EDs from 2012 and 2013 survey years, we developed several predictive models with the outcome being admission to the hospital or transfer vs. discharge home. We included patient characteristics immediately available after the patient has presented to the ED and undergone a triage process. We used this information to construct logistic regression (LR) and multilayer neural network models (MLNN) which included natural language processing (NLP) and principal component analysis from the patient's reason for visit. Ten-fold cross validation was used to test the predictive capacity of each model and receiver operating curves (AUC) were then calculated for each model. RESULTS: Of the 47,200 ED visits from 642 hospitals, 6,335 (13.42%) resulted in hospital admission (or transfer). A total of 48 principal components were extracted by NLP from the reason for visit fields, which explained 75% of the overall variance for hospitalization. In the model including only structured variables, the AUC was 0.824 (95% CI 0.818-0.830) for logistic regression and 0.823 (95% CI 0.817-0.829) for MLNN. Models including only free-text information generated AUC of 0.742 (95% CI 0.731- 0.753) for logistic regression and 0.753 (95% CI 0.742-0.764) for MLNN. When both structured variables and free text variables were included, the AUC reached 0.846 (95% CI 0.839-0.853) for logistic regression and 0.844 (95% CI 0.836-0.852) for MLNN. CONCLUSIONS: The predictive accuracy of hospital admission or transfer for patients who presented to ED triage overall was good, and was improved with the inclusion of free text data from a patient's reason for visit regardless of modeling approach. Natural language processing and neural networks that incorporate patient-reported outcome free text may increase predictive accuracy for hospital admission. PMID- 28816339 TI - Characterization and diagnostic work-up of a patient with functionally impaired platelet GP6. PMID- 28816340 TI - Coagulation factor XII regulates inflammatory responses in human lungs. AB - Increased procoagulant activity in the alveolar compartment and uncontrolled inflammation are hallmarks of the acute respiratory distress syndrome (ARDS). Here, we investigated whether the contact phase system of coagulation is activated and may regulate inflammatory responses in human lungs. Components of the contact phase system were characterized in bronchoalveolar lavage fluids (BALF) from 54 ARDS patients and 43 controls, and their impact on cytokine/chemokine expression in human precision cut lung slices (PCLS) was assessed by a PCR array. Activation of the contact system, associated with high levels of coagulation factor XIIa (Hageman factor, FXIIa), plasma kallikrein and bradykinin, occurred rapidly in ARDS lungs after the onset of the disease and virtually normalized within one week from time of diagnosis. FXII levels in BALF were higher in ARDS non-survivors than survivors and were positively correlated with tumor necrosis factor (TNF)-alpha concentration. FXII induced the production and release of interleukin (IL)-8, IL-1beta, IL-6, leukemia inhibitory factor (LIF), CXCL5 and TNF-alpha in human PCLS in a kallikrein-kinin-independent manner. In conclusion, accumulation of FXII in ARDS lungs may contribute to the release of pro-inflammatory mediators and is associated with clinical outcome. FXII inhibition may thus offer a novel and promising therapeutic approach to antagonize overwhelming inflammatory responses in ARDS lungs without interfering with vital haemostasis. PMID- 28816342 TI - Hypofibrinogenaemia associated with novel Aalpha126Val->Asp mutation in the fibrinogen coiled coil. PMID- 28816341 TI - Clinical impact of major bleeding in patients with venous thromboembolism treated with factor Xa inhibitors or vitamin K antagonists. An individual patient data meta-analysis. AB - Factor Xa (fXa)-inhibitors are as effective and safer than vitamin-K-antagonists (VKA) in the treatment of venous thromboembolism (VTE). We previously classified the severity of clinical presentation and course of all major bleeding events from the EINSTEIN, AMPLIFY and HOKUSAI-VTE trials separately. The current aim was to combine these findings in order to increase precision, assess a class effect and analyse presentation and course for different types of bleeding, i. e. intracranial, gastro-intestinal, and other. We classified the clinical presentation and course of all major bleeding events using pre-defined criteria. Both classifications comprised four categories; one being the mildest, and four the most severe. Odds ratios (OR) were calculated for all events classified as category three or four between fXa-inhibitors and VKA recipients. Also, ORs were computed for different types of bleeding. Major bleeding occurred in 111 fXa inhibitor recipients and in 187 LMWH/VKA recipients. The clinical presentation was classified as category three or four in 35 % and 48 % of the major bleeds in fXa inhibitor and VKA recipients, respectively (OR 0.59, 95 % CI 0.36-0.97). For intracranial, gastro-intestinal and other bleeding a trend towards a less severe presentation was observed for patients treated with fXa inhibitors. Clinical course was classified as severe in 22 % of the fXa inhibitor and 25 % of the VKA associated bleeds (OR 0.83, 95 % CI 0.47-1.46). In conclusion, FXa inhibitor associated major bleeding events had a significantly less severe presentation and a similar course compared to VKA. This finding was consistent for different types of bleeding. PMID- 28816343 TI - Application of N-of-1 Experiments to Test the Efficacy of Inactivity Alert Features in Fitness Trackers to Increase Breaks from Sitting in Older Adults. AB - BACKGROUND: Frequent breaks from sitting could improve health. Many commercially available fitness trackers deliver vibration alerts that could be used to cue sitting breaks. As a potentially pragmatic approach to promote frequent breaks from sitting, we tested the efficacy of inactivity alerts among obese older adults, a highly sedentary population. METHODS: We conducted 10 sequential N-of-1 (single-case) experimental ABA trials. Participants (mean age = 68, mean BMI = 35) were monitored for a baseline phase ("A1") followed by an intervention phase ("B"). The intervention was then removed and participants were monitored to test an experimental effect (reversal "A2" phase). Total time in the study was limited to 25 days. During the intervention phase ("B"), participants used fitness trackers to stand up or move every time they received an alert (every 15 or 20 minutes of inactivity). Participants wore activPAL devices to measure breaks from sitting each day. Randomization tests were used to determine whether the number of breaks was significantly higher during the "B" phase than the two "A" phases. RESULTS: Breaks were higher by 7.2 breaks per day during the "B" phase compared to the mean of the "A" phases. Seven out of 10 participants had more sitting breaks during the intervention phase which subsequently decreased during the reversal "A2" phase (combined p-value < .05). CONCLUSION: Inactivity alert features within commercially available devices are efficacious for promoting modest improvements in breaks from sitting among older adults with obesity and could be a simple health-promoting strategy in this population. PMID- 28816344 TI - An Investigation of Two Finite Element Modeling Solutions for Biomechanical Simulation Using a Case Study of a Mandibular Bone. AB - The method used in biomechanical modeling for finite element method (FEM) analysis needs to deliver accurate results. There are currently two solutions used in FEM modeling for biomedical model of human bone from computerized tomography (CT) images: one is based on a triangular mesh and the other is based on the parametric surface model and is more popular in practice. The outline and modeling procedures for the two solutions are compared and analyzed. Using a mandibular bone as an example, several key modeling steps are then discussed in detail, and the FEM calculation was conducted. Numerical calculation results based on the models derived from the two methods, including stress, strain, and displacement, are compared and evaluated in relation to accuracy and validity. Moreover, a comprehensive comparison of the two solutions is listed. The parametric surface based method is more helpful when using powerful design tools in computer-aided design (CAD) software, but the triangular mesh based method is more robust and efficient. PMID- 28816345 TI - Errors in Calculating Anterior-Posterior Tibial Contact Locations in Total Knee Arthroplasty Using Three-Dimensional Model to Two-Dimensional Image Registration in Radiographs: An In Vitro Study of Two Methods. AB - Knowledge of anterior-posterior (A-P) tibial contact locations provides an objective assessment of the relative motion of the tibia on the femur following total knee arthroplasty (TKA), which can be used to compare the effects of different components, surgical techniques, and alignment goals on knee function in vivo. Both the lowest point method and the penetration method have been used to calculate A-P tibial contact locations using three-dimensional (3D) model to two-dimensional (2D) image registration. The primary objective of this study was to quantify errors in calculating the A-P tibial contact location using the lowest point and penetration methods because the errors in calculating the A-P tibial contact locations using these two methods are unknown. The A-P tibial contact locations were calculated with the two methods and simultaneously measured with a tibial force sensor in ten fresh-frozen cadaveric knee specimens with a TKA. Single-plane radiographs of the knee specimens were acquired at 0 deg, 30 deg, 60 deg, and 90 deg of flexion in neutrally, internally, and externally rotated orientations. While the radiographs were exposed, reference A P tibial contact locations were simultaneously collected using the tibial force sensor to be compared to the calculated A-P tibial contact locations. The overall root-mean-squared-errors (RMSEs) in the A-P tibial contact location calculated with the lowest point method, the penetration method with penetration, and penetration method without penetration were 5.5 mm, 3.6 mm, and 8.9 mm, respectively. The overall RMSE was lowest for the penetration method with penetration, making it the superior method for calculating A-P tibial contact locations. PMID- 28816346 TI - Homocysteine-lowering interventions for preventing cardiovascular events. AB - BACKGROUND: Cardiovascular disease, which includes coronary artery disease, stroke and peripheral vascular disease, is a leading cause of death worldwide. Homocysteine is an amino acid with biological functions in methionine metabolism. A postulated risk factor for cardiovascular disease is an elevated circulating total homocysteine level. The impact of homocysteine-lowering interventions, given to patients in the form of vitamins B6, B9 or B12 supplements, on cardiovascular events has been investigated. This is an update of a review previously published in 2009, 2013, and 2015. OBJECTIVES: To determine whether homocysteine-lowering interventions, provided to patients with and without pre existing cardiovascular disease are effective in preventing cardiovascular events, as well as reducing all-cause mortality, and to evaluate their safety. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 5), MEDLINE (1946 to 1 June 2017), Embase (1980 to 2017 week 22) and LILACS (1986 to 1 June 2017). We also searched Web of Science (1970 to 1 June 2017). We handsearched the reference lists of included papers. We also contacted researchers in the field. There was no language restriction in the search. SELECTION CRITERIA: We included randomised controlled trials assessing the effects of homocysteine-lowering interventions for preventing cardiovascular events with a follow-up period of one year or longer. We considered myocardial infarction and stroke as the primary outcomes. We excluded studies in patients with end-stage renal disease. DATA COLLECTION AND ANALYSIS: We performed study selection, 'Risk of bias' assessment and data extraction in duplicate. We estimated risk ratios (RR) for dichotomous outcomes. We calculated the number needed to treat for an additional beneficial outcome (NNTB). We measured statistical heterogeneity using the I2 statistic. We used a random-effects model. We conducted trial sequential analyses, Bayes factor, and fragility indices where appropriate. MAIN RESULTS: In this third update, we identified three new randomised controlled trials, for a total of 15 randomised controlled trials involving 71,422 participants. Nine trials (60%) had low risk of bias, length of follow-up ranged from one to 7.3 years. Compared with placebo, there were no differences in effects of homocysteine-lowering interventions on myocardial infarction (homocysteine-lowering = 7.1% versus placebo = 6.0%; RR 1.02, 95% confidence interval (CI) 0.95 to 1.10, I2 = 0%, 12 trials; N = 46,699; Bayes factor 1.04, high-quality evidence), death from any cause (homocysteine-lowering = 11.7% versus placebo = 12.3%, RR 1.01, 95% CI 0.96 to 1.06, I2 = 0%, 11 trials, N = 44,817; Bayes factor = 1.05, high-quality evidence), or serious adverse events (homocysteine-lowering = 8.3% versus comparator = 8.5%, RR 1.07, 95% CI 1.00 to 1.14, I2 = 0%, eight trials, N = 35,788; high-quality evidence). Compared with placebo, homocysteine-lowering interventions were associated with reduced stroke outcome (homocysteine-lowering = 4.3% versus comparator = 5.1%, RR 0.90, 95% CI 0.82 to 0.99, I2 = 8%, 10 trials, N = 44,224; high-quality evidence). Compared with low doses, there were uncertain effects of high doses of homocysteine-lowering interventions on stroke (high = 10.8% versus low = 11.2%, RR 0.90, 95% CI 0.66 to 1.22, I2 = 72%, two trials, N = 3929; very low-quality evidence).We found no evidence of publication bias. AUTHORS' CONCLUSIONS: In this third update of the Cochrane review, there were no differences in effects of homocysteine-lowering interventions in the form of supplements of vitamins B6, B9 or B12 given alone or in combination comparing with placebo on myocardial infarction, death from any cause or adverse events. In terms of stroke, this review found a small difference in effect favouring to homocysteine-lowering interventions in the form of supplements of vitamins B6, B9 or B12 given alone or in combination comparing with placebo.There were uncertain effects of enalapril plus folic acid compared with enalapril on stroke; approximately 143 (95% CI 85 to 428) people would need to be treated for 5.4 years to prevent 1 stroke, this evidence emerged from one mega-trial.Trial sequential analyses showed that additional trials are unlikely to increase the certainty about the findings of this issue regarding homocysteine-lowering interventions versus placebo. There is a need for additional trials comparing homocysteine-lowering interventions combined with antihypertensive medication versus antihypertensive medication, and homocysteine-lowering interventions at high doses versus homocysteine-lowering interventions at low doses. Potential trials should be large and co-operative. PMID- 28816347 TI - The silent enemy: Celiac disease goes viral. AB - Celiac disease is a multifactorial autoimmune chronic inflammatory disorder affecting approximately one percent of the worldwide population. In such patients, ingestion of gluten proteins from cereals like wheat, barley, and rye causes damage of the small intestine mucosa, with potentially severe consequences. Onset of the disease in predisposed individuals is believed to require a still not clearly identified external trigger, such as viral infections. A very recent study has begun to shed light on a possible mechanistic basis for this hypothesis, and surprisingly linked intestinal infections caused by common reoviruses to the onset of celiac disease. PMID- 28816348 TI - Transition metal dependent regulation of the signal transduction cascade driving oocyte meiosis. AB - The G2-M transition of the cell cycle requires the activation of members of the Cdc25 dual specificity phosphatase family. Using Xenopus oocyte maturation as a model system, we have previously shown that chelation of transition metals blocks meiosis progression by inhibiting Cdc25C activation. Here, using approaches that allow for the isolation of very pure and active recombinant Cdc25C, we show that Cdc25C does not bind zinc as previously reported. Additionally, we show that mutants in the disordered C-terminal end of Cdc25C are poor initiators of meiosis, likely due to their inability to localize to the proper sub-cellular location. We further demonstrate that the transition metal chelator, TPEN, acts on or upstream of polo-like kinases in the oocyte to block meiosis progression. Together our results provide novel insights into Cdc25C structure-function relationship and the role of transition metals in regulating meiosis. PMID- 28816349 TI - Effects of intergroup exclusion on individual needs threat and behavior tendencies. AB - This study explores the effects of intergroup exclusion on need-threat and the behavioral tendencies of excluded individuals. Results show that those excluded by in-group members perceived more threat to relational needs, while participants excluded by out-group members perceived more threat to efficacy needs. In addition, participants excluded by out-group members displayed significantly more aggression intention and less helping intention than those who were excluded by in-group members. This study indicates that the group relationship between excluders and the excluded will directly affect threat perception and behavioral responses. PMID- 28816350 TI - Characteristics and functionality of appetite-reducing thylakoid powders produced by three different drying processes. AB - BACKGROUND: Thylakoids, a chloroplast membrane extracted from green leaves, are a promising functional ingredient with appetite-reducing properties via their lipase-inhibiting effect. Thylakoids in powder form have been evaluated in animal and human models, but no comprehensive study has been conducted on powder characteristics. The aim was to investigate the effects of different isolation methods and drying techniques (drum-drying, spray-drying, freeze-drying) on thylakoids' physicochemical and functional properties. RESULTS: Freeze-drying yielded thylakoid powders with the highest lipase-inhibiting capacity. We hypothesize that the specific macromolecular structures involved in lipase inhibition were degraded to different degrees by exposure to heat during spray drying and drum-drying. We identified lightness (Hunter's L-value), greenness (Hunter's a-value), chlorophyll content and emulsifying capacity to be correlated to lipase-inhibiting capacity. Thus, to optimize the thylakoids functional properties, the internal membrane structure indicated by retained green colour should be preserved. This opens possibilities to use chlorophyll content as a marker for thylakoid functionality in screening processes during process optimization. CONCLUSION: Thylakoids are heat sensitive, and a mild drying technique should be used in industrial production. Strong links between physicochemical parameters and lipase inhibition capacity were found that can be used to predict functionality. The approach from this study can be applied towards production of standardized high-quality functional food ingredients. (c) 2017 Society of Chemical Industry. PMID- 28816351 TI - Recent advances in genomic profiling of adenosquamous carcinoma of the pancreas. AB - Adenosquamous carcinoma of the pancreas (ASCP) is a mixed tumor type which contains squamous cell carcinoma and also ductal adenocarcinoma components. Due to the rarity of this malignancy, only very limited genomic profiling has been performed. A recent paper by Fang et al. published in The Journal of Pathology contributed to our knowledge of genomic alterations by performing whole-genome and -exome sequencing of 17 ASCP tumors. They found major genomic similarities to pancreatic ductal adenocarcinoma; however, the p53 pathway was altered in a greater proportion of cases, while a high frequency of 3p loss was a distinct copy number alteration pattern observed in ASCP. Laser capture microdissection revealed that adenocarcinoma and squamous carcinoma components of ASCP harbor similar genomic variations, indicating that the origin of tumor components is the same or similar. Although the study published by Fang et al. increases our knowledge of this rare mixed tumor type, further investigation, including RNA sequencing, will be needed to fully characterize this malignancy and to aid the development of novel treatment approaches. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28816353 TI - Definition of a Medical Physicist and the Role of the Medical Physicist. PMID- 28816355 TI - Polynomial and power law of central axis backscatter factors for external and gamma-ray sources. AB - A third-degree polynomial and power-law analysis with the method of least-squares fit are computed for backscatter factor with a continuous variation of field size and different beam quality of radiation from 1.0-mm Al external x ray to 60 Co gamma ray. Three coefficients are required for a third-degree polynomial and two coefficients for power law method of each beam quality. PMID- 28816352 TI - Pulmonary artery wave propagation and reservoir function in conscious man: impact of pulmonary vascular disease, respiration and dynamic stress tests. AB - KEY POINTS: Wave travel plays an important role in cardiovascular physiology. However, many aspects of pulmonary arterial wave behaviour remain unclear. Wave intensity and reservoir-excess pressure analyses were applied in the pulmonary artery in subjects with and without pulmonary hypertension during spontaneous respiration and dynamic stress tests. Arterial wave energy decreased during expiration and Valsalva manoeuvre due to decreased ventricular preload. Wave energy also decreased during handgrip exercise due to increased heart rate. In pulmonary hypertension patients, the asymptotic pressure at which the microvascular flow ceases, the reservoir pressure related to arterial compliance and the excess pressure caused by waves increased. The reservoir and excess pressures decreased during Valsalva manoeuvre but remained unchanged during handgrip exercise. This study provides insights into the influence of pulmonary vascular disease, spontaneous respiration and dynamic stress tests on pulmonary artery wave propagation and reservoir function. ABSTRACT: Detailed haemodynamic analysis may provide novel insights into the pulmonary circulation. Therefore, wave intensity and reservoir-excess pressure analyses were applied in the pulmonary artery to characterize changes in wave propagation and reservoir function during spontaneous respiration and dynamic stress tests. Right heart catheterization was performed using a pressure and Doppler flow sensor tipped guidewire to obtain simultaneous pressure and flow velocity measurements in the pulmonary artery in control subjects and patients with pulmonary arterial hypertension (PAH) at rest. In controls, recordings were also obtained during Valsalva manoeuvre and handgrip exercise. The asymptotic pressure at which the flow through the microcirculation ceases, the reservoir pressure related to arterial compliance and the excess pressure caused by arterial waves increased in PAH patients compared to controls. The systolic and diastolic rate constants also increased, while the diastolic time constant decreased. The forward compression wave energy decreased by ~8% in controls and ~6% in PAH patients during expiration compared to inspiration, while the wave speed remained unchanged throughout the respiratory cycle. Wave energy decreased during Valsalva manoeuvre (by ~45%) and handgrip exercise (by ~27%) with unaffected wave speed. Moreover, the reservoir and excess pressures decreased during Valsalva manoeuvre but remained unaltered during handgrip exercise. In conclusion, reservoir-excess pressure analysis applied to the pulmonary artery revealed distinctive differences between controls and PAH patients. Variations in the ventricular preload and afterload influence pulmonary arterial wave propagation as demonstrated by changes in wave energy during spontaneous respiration and dynamic stress tests. PMID- 28816356 TI - A 5-Year Research and Development Agendum for Ultrasonic Imaging Diagnostic Instrumentation. AB - At most scientific meetings, the emphasis is on the results of research, not on the means by which those results were achieved. However, it was the intent of the Alliance for Engineering in Medicine and Biology in the symposium organized at the 1975 AAPM meeting to describe the instrumentation now available to researchers and practicing physicians in the field of ultrasonic diagnostic imaging. We feel that this is an appropriate and useful presentation, especially because it concerns a rapidly changing field. The papers that follow summarize the current state-of-the-art of, first, single-transducer imaging and, second, two-dimensional transducer array technology. (A third paper, summarizing the state-of-the-art of ultrasonic tissue signatures, was presented by Dennis H. Le Croissette, Jet Propulsion Laboratory, Pasadena, California 91103, but is not included here because it is to be published this spring in Ultrasonic Tissue Characterization, the proceedings of a seminar held by the National Bureau of Standards 28-30 May 1975.) These papers together offer a very broad picture of where ultrasonic diagnostic imaging instrumentation stands today, and what may be expected in the near future. PMID- 28816357 TI - Modified transit dosemeter system for 60 Co rotational therapy. AB - The transit dosemeter has been used in obtaining inhomogeneity corrections for 60 Co rotational therapy. A modified approach is presented which features a rapid electronic system for determining the average tissue-air ratio (TAR) for a 360 degrees rotation. Experimental results and early clinical experience show that this system is capable of providing a TAR value directly, and more rapidly. It can be readily incorporated in a therapy system which already includes a transit dosemeter. PMID- 28816358 TI - TRPC3-mediated Ca2+ signals as a promising strategy to boost therapeutic angiogenesis in failing hearts: The role of autologous endothelial colony forming cells. AB - Endothelial progenitor cells (EPCs) are a sub-population of bone marrow-derived mononuclear cells that are released in circulation to restore damaged endothelium during its physiological turnover or rescue blood perfusion after an ischemic insult. Additionally, they may be mobilized from perivascular niches located within larger arteries' wall in response to hypoxic conditions. For this reason, EPCs have been regarded as an effective tool to promote revascularization and functional recovery of ischemic hearts, but clinical application failed to exploit the full potential of patients-derived cells. Indeed, the frequency and biological activity of EPCs are compromised in aging individuals or in subjects suffering from severe cardiovascular risk factors. Rejuvenating the reparative phenotype of autologous EPCs through a gene transfer approach has, therefore, been put forward as an alternative approach to enhance their therapeutic potential in cardiovascular patients. An increase in intracellular Ca2+ concentration constitutes a pivotal signal for the activation of the so-called endothelial colony forming cells (ECFCs), the only known truly endothelial EPC subset. Studies from our group showed that the Ca2+ toolkit differs between peripheral blood- and umbilical cord blood (UCB)-derived ECFCs. In the present article, we first discuss how VEGF uses repetitive Ca2+ spikes to regulate angiogenesis in ECFCs and outline how VEGF-induced intracellular Ca2+ oscillations differ between the two ECFC subtypes. We then hypothesize about the possibility to rejuvenate the biological activity of autologous ECFCs by transfecting the cell with the Ca2+ -permeable channel Transient Receptor Potential Canonical 3, which selectively drives the Ca2+ response to VEGF in UCB derived ECFCs. PMID- 28816359 TI - Chrysin attenuates progression of ovarian cancer cells by regulating signaling cascades and mitochondrial dysfunction. AB - Chrysin is mainly found in passion flowers, honey, and propolis acts as a potential therapeutic and preventive agent to inhibit proliferation and invasion of various human cancer cells. Although chrysin has anti-carcinogenic effects in several cancers, little is known about its functional roles in ovarian cancer which shows poor prognosis and chemoresistance to traditional therapeutic agents. In the present study, we investigated functional roles of chrysin in progression of ovarian cancer cells using ES2 and OV90 (clear cell and serous carcinoma, respectively) cell lines. Results of the current study demonstrated that chrysin inhibited ovarian cancer cell proliferation and induced cell death by increasing reactive oxygen species (ROS) production and cytoplasmic Ca2+ levels as well as inducing loss of mitochondrial membrane potential (MMP). Moreover, chrysin activated mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT pathways in ES2 and OV90 cells in concentration-response experiments. Collectively, our results led us to propose that chrysin-induced apoptotic events are mediated by the activation of PI3K and MAPK pathways in human ovarian cancer cells. PMID- 28816360 TI - C-C motif chemokine ligand 2 regulates lps-induced inflammation and ER stress to enhance proliferation of bovine endometrial epithelial cells. AB - Chemokines play an important role in regulating the complex immune system at the maternal-fetal interface during pregnancy. Among various chemokines, C?C motif chemokine ligand 2 (CCL2) plays a role in the recruitment of immune regulatory cells to implantation sites within the endometrium. In cattle, CCL2 is abundantly expressed in the uterine endometrium. However, its intracellular signaling has not been identified. In this study, we examined the effects of CCL2 on bovine endometrial (BEND) cell proliferation. CCL2 stimulated BEND cell proliferation by abundant expression of PCNA, accumulation of cells in the G2/M phase, and activation of the PI3 K/AKT and MAPK signaling pathways. Moreover, CCL2 reduced endoplasmic reticulum stress and restored the inflammation-induced reduction in BEND cell proliferation by regulating the unfolded protein response genes and cytokines. Collectively, these results demonstrated that CCL2 plays a pivotal role in reproductive tissues and may support maternal-fetal interface to improve efficiency of pregnancy. PMID- 28816361 TI - mSEL-1L deficiency affects vasculogenesis and neural stem cell lineage commitment. AB - mSEL-1L is a highly conserved ER-resident type I protein, involved in the degradation of misfolded peptides through the ubiquitin-proteasome system (UPS), a pathway known to control the plasticity of the vascular smooth muscle cells (VSMC) phenotype and survival. In this article, we demonstrate that mSEL-1L deficiency interferes with the murine embryonic vascular network, showing particular irregularities in the intracranic and intersomitic neurovascular units and in the cerebral capillary microcirculation. During murine embryogenesis, mSEL 1L is expressed in cerebral areas known to harbor progenitor neural cells, while in the adult brain the protein is specifically restricted to the stem cell niches, co-localizing with Sox2 and Nestin. Null mice are characterized by important defects in the development of telenchephalic regions, revealing conspicuous aberration in neural stem cell lineage commitment. Moreover, mSEL-1L depletion in vitro and in vivo appears to affect the harmonic differentiation of the NSCs, by negatively influencing the corticogenesis processes. Overall, the data presented suggests that the drastic phenotypic characteristics exhibited in mSEL-1L null mice can, in part, be explained by the negative influence it plays on Notch1 signaling pathway. PMID- 28816362 TI - Social space and cultural class divisions: the forms of capital and contemporary lifestyle differentiation. AB - In this article, we address whether and how contemporary social classes are marked by distinct lifestyles. We assess the model of the social space, a novel approach to class analysis pioneered by Bourdieu's Distinction. Although pivotal in Bourdieu's work, this model is too often overlooked in later research, making its contemporary relevance difficult to assess. We redress this by using the social space as a framework through which to study the cultural manifestation of class divisions in lifestyle differences in contemporary Norwegian society. Through a Multiple Correspondence Analysis (MCA) of unusually rich survey data, we reveal a structure strikingly similar to the model in Distinction, with a primary dimension of the volume of capital, and a secondary dimension of the composition of capital. While avoiding the substantialist fallacy of predefined notions of 'highbrow' and 'lowbrow' tastes, we explore how 168 lifestyle items map onto this social space. This reveals distinct classed lifestyles according to both dimensions of the social space. The lifestyles of the upper classes are distinctly demanding in terms of resources. Among those rich in economic capital, this manifests itself in a lifestyle which involves a quest for excitement, and which is bodily oriented and expensive. For their counterparts rich in cultural capital, a more ascetic and intellectually oriented lifestyle manifests itself, demanding of resources in the sense of requiring symbolic mastery, combining a taste for canonized, legitimate culture with more cosmopolitan and 'popular' items. In contrast to many studies' descriptions of the lower classes as 'disengaged' and 'inactive', we find evidence of distinct tastes on their part. Our analysis thus affirms the validity of Bourdieu's model of social class and the contention that classes tend to take the form of status groups. We challenge dominant positions in cultural stratification research, while questioning the aptness of the metaphor of the 'omnivore', as well as recent analyses of 'emerging cultural capital'. PMID- 28816363 TI - The Suicidal Inmate: A Comparison of Inmates Who Attempt Versus Complete Suicide. AB - The aim of this study was to identify risk factors distinguishing inmates who attempt suicide from inmates who complete suicide. Compared with attempters, completers tended to be older, male, more educated, and married or separated/divorced; pretrial, committed for a violent crime, incarcerated in jail, housed in an inpatient mental health unit or protective custody setting, living in a single cell, not on suicide precautions, not previously under close observation; and more likely to act during overnight hours and die by hanging/self-strangulation. Targeted assessment of a broad range of risk factors is necessary to inform suicide prevention efforts in correctional facilities. PMID- 28816364 TI - Balancing competing needs mediates the association of caregiving demand with caregiver role strain and depressive symptoms of dementia caregivers: A cross sectional study. AB - AIMS: To examine the role of balancing competing needs in the relationship between caregiving demand and caregiving outcomes (caregivers' role strain and depressive symptoms). BACKGROUND: Caregivers who do not balance competing needs are more likely to experience negative caregiving outcomes, suggesting that balance mediates between caregiving demand and caregiving outcomes. Identifying a mediator of negative caregiving effects may help in developing tailored interventions for family caregivers of persons with dementia. DESIGN: A cross sectional, correlational design. METHODS: Data were collected from family caregivers' self-completed questionnaires between March 2013 - April 2014. A convenience sample of 120 family caregivers and care receivers with dementia was enrolled. We examined whether balance mediated the relationship between caregiving demand and caregiving outcomes (caregivers' role strain and depressive symptoms) by multiple regression analysis. To evaluate the significance of the indirect effect of caregiver balance, we used the Sobel test and Monte Carlo method, an alternative approach to testing mediation. RESULTS: Balancing competing needs completely mediated the association of caregiving demand with depressive symptoms and partially mediated the association of caregiving demand with role strain. CONCLUSION: Assessing caregivers' self-perceived sense of balance may help to identify caregivers at high risk for role strain and depressive symptoms. Interventions to enhance caregivers' perceived sense of balance between competing needs may provide a strategy for reducing the negative effects of caregiving. PMID- 28816365 TI - Hypertensive Disorders in Pregnancy and the Risk of Subsequent Cardiovascular Disease. AB - BACKGROUND: Hypertensive disorders in pregnancy (HDP) have been shown to predict later risk of cardiovascular disease (CVD). However, previous studies have not accounted for subsequent pregnancies and their complications, which are potential confounders and intermediates of this association. METHODS: A cohort of 146 748 women with a first pregnancy was constructed using the Clinical Practice Research Datalink. HDP was defined using diagnostic codes, elevated blood pressure readings, or new use of an anti-hypertensive drug between 18 weeks' gestation and 6 weeks post-partum. The study outcomes were incident CVD and hypertension. Marginal structural Cox models (MSM) were used to account for time-varying confounders and intermediates. Time-fixed exposure defined at the first pregnancy was used in secondary analyses. RESULTS: A total of 997 women were diagnosed with incident CVD, and 6812 women were diagnosed with hypertension or received a new anti-hypertensive medication during the follow-up period. Compared with women without HDP, those with HDP had a substantially higher rate of CVD (hazard ratio (HR) 2.2, 95% confidence interval (CI) 1.7, 2.7). In women with HDP, the rate of hypertension was five times that of women without a HDP (HR 5.6, 95% CI 5.1, 6.3). With overlapping 95% CIs, the time-fixed analysis and the MSM produced consistent results for both outcomes. CONCLUSIONS: Women with HDP are at increased risk of developing subsequent CVD and hypertension. Similar estimates obtained with the MSM and the time-fixed analysis suggests that subsequent pregnancies do not confound a first episode of HDP and later CVD. PMID- 28816366 TI - Modification of The Paris System for urinary tract washing specimens using diagnostic cytological features. AB - OBJECTIVE: The Paris System (TPS), which was recently introduced, emphasised the key features of malignant urine cytology: a high nuclear to cytoplasmic ratio, nuclear hyperchromasia, irregular nuclear membranes and coarse chromatin. Although other diagnostic features have been described, the diagnostic significance of such features and their application to TPS have not been fully defined for urinary tract washing specimens. METHODS: A total of 142 cases of urinary tract washing specimens with corresponding surgical pathology samples were examined for the key features of TPS and 13 previously described features. The diagnostic performance of TPS and our proposed modification of TPS was compared with that of the current system. RESULTS: In addition to the key features of TPS, in the present study, high-grade urothelial carcinoma (HGUC) frequently exhibited tumour diathesis, a ragged edge of urothelial cell groups, anisonucleosis, India ink nuclei, apoptotic bodies and pleomorphism. As anisonucleosis and India ink nuclei remained independent predictors of HGUC for the multivariate analysis, they were used to modify TPS. The reporting rate of the atypical urothelial cell (AUC) category decreased from 25.3% in the current system to 14.8% in TPS and 11.3% in our proposed modification of TPS. The sensitivity increased from 59.4% in the current system to 70.8% in TPS and 90.0% in this study. The diagnostic accuracy increased from 0.786 in the current system and 0.754 in TPS to 0.859 in this study. CONCLUSIONS: TPS is a useful diagnostic system for urinary tract washing specimens by decreasing the number of AUC cases and increasing sensitivity. In this study, anisonucleosis and India ink nuclei improved the diagnostic accuracy of HGUC. PMID- 28816368 TI - One-Pot Self-Assembly of Peptide-Based Cage-Type Nanostructures Using Orthogonal Ligations. AB - The designed arrangement of biomolecular entities within monodisperse nanostructures is an important challenge toward functional biomaterials. We report herein a method for the formation of water-soluble peptide-based cages using orthogonal ligation reactions-acylhydrazone condensation and thiol maleimide addition. The results show that using preorganized cyclic peptides and heterobifunctional spacers as building blocks and a set of orthogonal and chemoselective ligation reactions enable cage formation in one pot from six components and through eight reactions. Molecular modelling simulations reveal the structural dynamics of these structures. Finally, we exploited the reactional dynamics of the acylhydrazone by demonstrating the controlled dissociation of the cage through directed component exchange. PMID- 28816367 TI - The In Vitro and In Vivo Antiangiogenic Effects of Flavokawain B. AB - Angiogenesis is implicated in the development of a variety of pathological processes, most commonly cancer. It is essential for tumor growth and metastasis, making it an important cancer therapeutic target. Naturally occurring substances have led to the discovery of anticancer agents. Flavokawain B (FKB), a chalcone isolated from the root extracts of kava-kava plant, inhibits proliferation and causes apoptosis in vitro and in vivo of various cancer cell lines. The antimetastatic potential of FKB has also been suggested. In our study, we confirm the antiangiogenic action of FKB in vitro and, for the first time, demonstrate its strong antiangiogenic activity in vivo, using a zebrafish model. Our data show that FKB inhibits human brain endothelial cell (HUVEC) migration and tube formation even at very low and non-toxic concentrations. Moreover, FKB blocks angiogenesis process in zebrafish, with a dramatic reduction of subintestinal vein formation in a dose-dependent manner. Flavokawain B at the concentration of 2.5 MUg/mL did not exhibit any toxic effects in zebrafish larvae and caused a markedly or complete obliteration of subintestinal vein formation. Our findings along with previously published data confirm that FKB may form the basis for creating an additional tool in the treatment of cancer and other neovascularization-related diseases. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28816369 TI - In vitro Study of Five Herbs Used Against Microbial Infections in Burundi. AB - The emergence of antimicrobial resistant infectious diseases remains a major threat to worldwide public health, in developed and in developing countries. Therefore, new antimicrobial agents acting by new mechanisms of action are urgently needed. As plants used in traditional medicine may help to overcome these problems, Justicia subsessilis, Platostoma rotundifolium, Pavetta ternifolia, Stomatanthes africanus, and Virectaria major (plants highly cited to be used against microbial infections in traditional Burundian medicine) were studied to assess their traditional use efficacy. We conducted a preliminary phytochemical screening of the extracts, as well as their direct and indirect (effect on antibiotic resistance) antibacterial activity on four bacterial strains (Staphylococcus sp. and Escherichia coli) by broth microdilution methods. All five medicinal plants investigated in this work were found to have direct antibacterial activity against all tested bacterial strains (minimum inhibitory concentration = 62.5-1000 MUg/mL) that may support the use of these species in traditional Burundian medicine. Extracts (with no direct antibacterial activity), tested at 200 MUg/mL, decreased the MIC values of beta-lactams and aminoglycoside antibiotics by a factor of 2 to 64-fold. These interactions between plant extracts and antibiotics could open an avenue of research against antibiotic resistance. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28816370 TI - Does depression decrease the moderating effect of self-efficacy in the relationship between illness perception and fear of progression in breast cancer? AB - OBJECTIVE: Fear of progression (FOP) is a prevalent concern among breast cancer patients that affect their adjustment to disease. This study examined whether self-efficacy moderates the effect of illness perception (IP) on FOP and whether the moderating effect of self-efficacy depends on the level of depressive symptoms. METHODS: A cross-sectional survey including brief illness perception questionnaire (BIPQ), FOP short form, general self-efficacy scale, and the center for epidemiologic studies depression scale were administered to 245 patients with breast cancer in Korea. RESULTS: Self-efficacy moderated the negative impact of the patients' perception of chronic timeline and a greater emotional impact of the illness on FOP. However, the moderating effect of self-efficacy of the BIPQ timeline and emotions on FOP depended on level of depressive symptoms. CONCLUSIONS: The findings underscore the importance of considering the IP as determinants of FOP, as well as of self-efficacy and depression as the moderating factors in the relationship between IP and FOP, suggesting the need to enhance self-efficacy and depressive symptoms in order to compensate the negative impact of IP on FOP in breast cancer patients. PMID- 28816371 TI - Transition-Metal-Free Cleavage of CO. AB - Tertiary silane 1H , 2-[(diphenylsilyl)methyl]-6-methylpyridine, reacts with tris(pentafluorophenyl)borane (BCF) to form the intramolecular pyridine stabilized silylium 1+ -HBCF. The corresponding 2 [(diphenylsilyl)methyl]pyridine, lacking the methyl-group on the pyridine ring, forms classic N(py)->B adduct 2H -BCF featuring an intact silane Si-H fragment. Complex 1+ -HBCF promotes cleavage of the C=O triple bond in carbon monoxide with double C-Csp2 bond formation, leading to complex 3 featuring a B-(diarylmethyl)-B aryl-boryloxysilane fragment. Reaction with pinacol generates bis(pentafluorophenyl)methane 4 as isolable product, proving the transition-metal free deoxygenation of carbon monoxide by this main-group system. Experimental data and DFT calculations support the existence of an equilibrium between the silylium-hydroborate ion pair and the silane-borane mixture that is responsible for the observed reactivity. PMID- 28816372 TI - In vitro Antitubercular Activity of 3-Deoxysappanchalcone Isolated From the Heartwood of Caesalpinia sappan Linn. AB - Responsible for nearly 1.5 million deaths every year, the infectious disease tuberculosis remains one of the most serious challenges to global health. The emergence of multidrug-resistant tuberculosis and, more recently, extensively drug-resistant tuberculosis poses a significant threat in our effort to control this epidemic. New drugs are urgently needed to combat the growing threat of antimicrobial resistance. To achieve this goal, we screened approximately 500 species of medicinal plant methanol extracts and their solvent partitioned fractions for potential inhibitors of Mycobacterium tuberculosis growth. Using microdilution screening, the ethyl acetate solvent partitioned fraction from the heartwood of Caesalpinia sappan exhibited strong antitubercular activity. We isolated the active compound and identified it as 3-deoxysappanchalcone. The extracted 3-deoxysappanchalcone possessed activity against both drug-susceptible and drug-resistant strains of M. tuberculosis at MIC50 s of 3.125-12.5 MUg/mL in culture broth and MIC50 s of 6.25-12.5 MUg/mL inside macrophages and pneumocytes. 3-Deoxysappanchalcone was also found to act in partial synergy with streptomycin/ethambutol against M. tuberculosis H37Rv. 3-Deoxysappanchalcone had no cytotoxicity against the A549 cell line up to a concentration of 100 MUg/mL (selectivity index > 8-32). Further studies are warranted to establish the in vivo effect and therapeutic potential of 3-deoxysappanchalcone. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28816373 TI - Efficacy and safety of using premedication with simethicone/Pronase during upper gastrointestinal endoscopy examination with sedation: A single center, prospective, single blinded, randomized controlled trial. AB - BACKGROUND AND AIM: To investigate the efficacy and safety of premedication with simethicone/Pronase during esophagogastroduodenoscopy (EGD) with sedation. METHODS: Six hundred and ten patients were randomly allocated to two groups based on type of premedication given. Premedication used in the control group was 10 mL lidocaine hydrochloride mucilage (LHM, N = 314) and premedication used in the intervention group was 80 mL simethicone/Pronase solution plus 10 mL lidocaine hydrochloride mucilage (SP/LHM, N = 296). EGD was done under sedation. Visibility scores, number of mucosal areas that needed cleansing, water consumption for cleansing, time taken for examination, diminutive lesions, pathological diagnosis, patients' gag reflex and oxygenation (pulse oximetry) were recorded. RESULTS: SP/LHM has significantly lower total visibility score than LHM (7.978 +/ 1.526 vs 6.348 +/- 1.097, P < 0.01). During the procedure, number of intragastric areas that needed cleansing and amount of water consumed were significantly less in the SP/LHM than in the LHM group (P < 0.01). In SP/LHM (P = 0.01), endoscopy procedure duration was significantly longer. Although there was no significant difference in rate of detection of diminutive lesions between LHM and SP/LHM, the endoscopist carried out more biopsies in SP/LHM. This led to a higher rate of diagnosis of atrophic gastritis (P = 0.014) and intestinal metaplasia (P = 0.024). There was no significant difference in gag reflex (P = 0.604) and oxygenation during the endoscopy procedure for either group of patients. CONCLUSION: Routine use of premedication with simethicone/Pronase should be recommended during EGD with sedation. PMID- 28816374 TI - No change in energy efficiency in lactation: Insights from a longitudinal study. AB - OBJECTIVES: Lactation is the most energy-demanding phase of reproduction for human females, but it is still unclear how women in different environments are able to meet this additional energy demand. Previous studies have investigated whether changes in metabolism could have an energy-sparing effect in lactation, with conflicting results. Here, we asked whether increased energy efficiency in physical activity serves as an energy-sparing mechanism in lactation. METHODS: We used a longitudinal design with a control group. Participants were 33 well nourished, exclusively breastfeeding women and 29 non-pregnant, non-lactating (NPNL) controls aged 32 +/- 4 years. Lactating women were measured at peak- and post-lactation. NPNL controls completed a baseline measurement and a follow-up visit. Energy efficiency in physical activity was assessed using a graded submaximal exercise test and calculated as delta efficiency (change in work accomplished over change in energy expended) and gross efficiency (work accomplished over energy expended). RESULTS: There was no significant change in either delta efficiency or gross efficiency from peak to post lactation in lactating women, and no significant difference in delta efficiency between lactating women and NPNL controls at any time period. However, lactating women showed greater between-visit variation in delta efficiency than the NPNL controls. Additionally, 79% of lactating participants lost weight between visits (mean weight loss -3.6 +/- 2.3kg), consistent with a mobilization of body tissues to support lactation. CONCLUSION: We found no support for the idea that lactating women undergo an increase in energy efficiency to support the energy costs of lactation. PMID- 28816375 TI - Adenocarcinoma of the colon presenting as a submucosal tumor. PMID- 28816376 TI - Acetic acid-indigocarmine mixture for evaluating the margins of sessile serrated adenomas/polyps. PMID- 28816377 TI - Controlled Growth of Metal-Organic Frameworks on Polymer Brushes. AB - Polymer brushes are for the first time used to induce the synthesis of metal organic frameworks (MOFs). The semi-fixed polymer chains provide a confined environment, which allows a mild growth of MOFs in between polymer chains to give surface-attached spherical MOF nanoparticles, in contrast to the larger MOF cubes/plates formed simultaneously in solution. Polymer brushes bearing carboxylate acid functionalities are indispensable for the formation of surface bound MOFs, while no MOF nanoparticles are observed on neutral polymer brushes. Characterization of the resultant MOF/polymer brushes hybrid film indicates the formation of crystalline MOF structure. The dimension of surface-attached MOFs can be fine-tuned from 20 nm to 1.4 MUm simply by varying the structural parameter of polymer brushes and the nucleation duration. The method is not only applicable to the synthesis of MOF-5 and MIL-125, but shows great potential for the preparation of other surface-attached MOFs. PMID- 28816378 TI - Correlation of the expressions of IGF1R-RACK1-STAT3 and Bcl-xl in nasopharyngeal carcinoma with the clinicopathological features and prognosis of nasopharyngeal carcinoma. AB - The aim of this study was to investigate the correlation of expression of IGF1R RACK1-STAT3 and Bcl-xl in nasopharyngeal carcinoma (NPC) with the clinicopathological features and the prognosis of NPC. Our study selected 215 NPC tissues and 178 chronic nasopharyngitis tissues (control group). Positive expression rates of IGF1R, RACK1, STAT3, and Bcl-xl were tested by immunohistochemical method, and expression of IGF1R, RACK1, STAT3, Bcl-xl, Bcl-2, and Bax by western blotting. Correlation of IGF1R, RACK1, STAT3, and Bcl-xl with the clinicopathological features of NPC was analyzed. The correlation among those four expression was analyzed by Spearman. The survival of NPC and independent factors of prognosis were tested by Kaplan-Meier and COX proportional hazards model respectively. The NPC group had higher positive expression rates of IGF1R, RACK1, STAT3, and Bcl-xl, and elevated expression of IGF1R, RACK1, STAT3, Bcl-xl, Bcl-2, and Bax. The lymph node metastasis (LNM) group had higher positive expression rates of IGF1R and RACK1 when compared with the non-LNM group. Patients with stage III and IV had higher positive expression rates of IGF1R, RACK1, STAT3, and Bcl-xl. There was positive correlation between expression of IGF1R and RACK1, STAT3. Such correlation was found between RACK1 and STAT3. Patients with negative expression of IGF1R, RACK1, STAT3, and Bcl-xl had higher survival rates. The risky factors of poor prognosis of NPC were positive expression of IGF1R, RACK1, STAT3 and Bcl-xl, and LNM. IGF1R-RACK1-STAT3 and Bcl xl expression correlated with the clinicopathological features and poor prognosis of NPC. PMID- 28816379 TI - From Enzymes to Functional Materials-Towards Activation of Small Molecules. AB - The design of non-noble metal-containing heterogeneous catalysts for the activation of small molecules is of utmost importance for our society. While nature possesses very sophisticated machineries to perform such conversions, rationally designed catalytic materials are rare. Herein, we aim to raise the awareness of the overall common design and working principles of catalysts incorporating aspects of biology, chemistry, and material sciences. PMID- 28816380 TI - A daily diary study of posttraumatic stress, experiential avoidance, and emotional lability among inpatient nurses. PMID- 28816381 TI - Non-exposed endoscopic wall-inversion surgery for submucosal tumor of the duodenum: Novel case report. PMID- 28816382 TI - Endoscopic diagnosis and treatment of superficial pharyngeal cancer. PMID- 28816383 TI - The structure and ultrastructure of the egg capsules of stoneflies of the genus Isoperla (Insecta, Plecoptera, Perlodidae). AB - The egg capsules of five systellognathan stoneflies species representing the genus Isoperla (Plecoptera, Perlodidae) have been investigated using light and electron microscopes (SEM and TEM). We consider the structural modifications of egg coverings (egg capsules, eggshells) like: a shape of a capsule, presence of structures fixing an egg to the substratum under water, intrachorionic aeropylar system facilitating gas exchange as a factor adapting an egg/embryo to the environment. The structures protecting eggs against desiccation during a female flight before oviposition into water as well as against the dangers of external mechanical injury caused by turbulences in rapid water currents of mountain streams are described and discussed. The ground plan of the egg capsule in arctoperlarian stoneflies is also discussed. PMID- 28816384 TI - Intracellular Delivery of Functional Native Antibodies under Hypoxic Conditions by Using a Biodegradable Silica Nanoquencher. AB - Antibodies are important biopharmaceuticals, but almost all existing antibody based drugs are limited to targeting antigens located at the cell exterior because of the inability of antibodies to enter the cell interior. Available methods for intracellular delivery of antibodies have major shortcomings. Herein, we report an approach to encapsulate native antibodies in a biodegradable silica nanoquencher (BS-qNP), which could undergo efficient cellular uptake and intracellular degradation to release antibodies only under hypoxic conditions. By coating the surface of BS-qNP with cell-penetrating poly(disulfide)s (CPD), the delivered antibodies (or other proteins) avoided endolysosomal trapping. Doping of the silica coating with a fluorescent dye and a dark hole quencher further endowed BS-qNP with hypoxia-responsive fluorescence turn-on property. Our antibody delivery system thus provides the first platform capable of stable encapsulation, efficient uptake, on-demand antibody release, and imaging of release/cell state. PMID- 28816385 TI - Contrasting physiological responses to future ocean acidification among Arctic copepod populations. AB - Widespread ocean acidification (OA) is modifying the chemistry of the global ocean, and the Arctic is recognized as the region where the changes will progress at the fastest rate. Moreover, Arctic species show lower capacity for cellular homeostasis and acid-base regulation rendering them particularly vulnerable to OA. In the present study, we found physiological differences in OA response across geographically separated populations of the keystone Arctic copepod Calanus glacialis. In copepodites stage CIV, measured reaction norms of ingestion rate and metabolic rate showed severe reductions in ingestion and increased metabolic expenses in two populations from Svalbard (Kongsfjord and Billefjord) whereas no effects were observed in a population from the Disko Bay, West Greenland. At pHT 7.87, which has been predicted for the Svalbard west coast by year 2100, these changes resulted in reductions in scope for growth of 19% in the Kongsfjord and a staggering 50% in the Billefjord. Interestingly, these effects were not observed in stage CV copepodites from any of the three locations. It seems that CVs may be more tolerant to OA perhaps due to a general physiological reorganization to meet low intracellular pH during hibernation. Needless to say, the observed changes in the CIV stage will have serious implications for the C. glacialis population health status and growth around Svalbard. However, OA tolerant populations such as the one in the Disko Bay could help to alleviate severe effects in C. glacialis as a species. PMID- 28816386 TI - Chemotaxis-Guided Hybrid Neutrophil Micromotors for Targeted Drug Transport. AB - Engineering self-propelled micromotors with good biocompatibility and biodegradability for actively seeking disease sites and targeted drug transport remains a huge challenge. In this study, neutrophils with intrinsic chemotaxis capability were transformed into self-guided hybrid micromotors by integrating mesoporous silica nanoparticles (MSNs) with high loading capability. To ensure the compatibility of neutrophil cells with drug-loaded MSNs, bacteria membranes derived from E. coli were coated on MSNs in advance by a camouflaging strategy. The resulting biohybrid micromotors inherited the characteristic chemotaxis capability of native neutrophils and could effectively move along the chemoattractant gradients produced by E. coli. Our studies suggest that this camouflaging approach, which favors the uptake of MSNs into neutrophils without loss of cellular activity and motility, could be used to construct synthetic nanoparticle-loaded biohybrid micromotors for advanced biomedical applications. PMID- 28816387 TI - Getting your paper past the Editors. PMID- 28816388 TI - The Hydrophobic Gap at High Hydrostatic Pressures. AB - We have gained new insight into the so-called hydrophobic gap, a molecularly thin region of decreased electron density at the interface between water and a solid hydrophobic surface, by X-ray reflectivity experiments and molecular dynamics simulations at different hydrostatic pressures. Pressure variations show that the hydrophobic gap persists up to a pressure of 5 kbar. The electron depletion in the interfacial region strongly decreases with an increase in pressure, indicating that the interfacial region is compressed more strongly than bulk water. The decrease is most significant up to 2 kbar; beyond that, the pressure response of the depletion is less pronounced. PMID- 28816389 TI - Clinical indications for hysteroscopic removal of uterine masses: Time, age at diagnosis, and mass size. AB - AIM: The aim of this study was to investigate clinical factors associated with abnormal pathologies of uterine masses resected via hysteroscopy. METHODS: Women who underwent hysteroscopic surgery for presumptive diagnoses of abnormal endometrial or endocervical masses, such as polyps or leiomyomas on ultrasonography, between January 2012 and April 2015, were enrolled. Clinical and pathologic data were retrospectively reviewed. RESULTS: Among 189 patients, pathologic diagnoses of the uterine mass were abnormal in 172 (91.0%) cases, including polyps in 119 (63.0%), leiomyomas in 49 (26.0%), endometrial hyperplasia in two (1.0%), and endometrial cancer in two (1.0%). Seventeen (9.0%) women who underwent hysteroscopic removal showed unremarkable results on pathology, and the most common finding among them was the proliferative phase of the normal endometrium. Women aged over 40 years with uterine masses and a time since last menstrual period of over 15 days are four times more likely to be diagnosed with neoplastic masses than others (odds ratio [OR], 4.39, 95% confidence interval [CI], 1.33-14.48 and OR, 4.22, 95%CI, 1.35-13.21, respectively); those with masses over 1.5 cm in size are three times more likely to be neoplastic than others (OR, 3.08, 95%CI, 1.04-9.12). CONCLUSION: Large mass size, longer time after last menstrual period, and older age are risk factors for abnormal histologies of uterine masses resected via hysteroscopy. Clinicians should take particular care when contemplating hysteroscopic removal for women younger than 40 years, and those with masses of <1.5 cm in size in the proliferative phase of the endometrium to avoid an unnecessary surgery. PMID- 28816390 TI - Differential expression and androgen regulation of microRNAs and metalloprotease 13 in breast cancer cells. AB - MicroRNA molecules (miRNAs) play important roles in regulating cell behavior. The expression of certain miRNAs has been shown to be regulated by the androgen receptor (AR), which seems to have a critical role in the tumorigenic process of breast cancer. The differential expression of 84 miRNAs was first examined in three breast cancer cell lines: the luminal MCF-7 and T47D cells and the molecular apocrine MDA-MB-453 cells. Analysis of basal expression of miRNAs revealed that each cell line had distinct miRNA expression where let-7a and -7b were markers of MDA-MB-453 cells, whereas miR-205 was a marker for the luminal cell lines. Treating the cells with the AR agonist, CI-4AS-1, resulted in unique alterations in the expression of specific miRNA among the three cell lines. Particularly, the expression of miR-100 and miR-125 was reduced in MDA-MB-453 cells by five and three folds, respectively. This effect was simultaneous with AR induced increase in the expression and extracellular release of metalloprotease 13 (MMP13). Transfection of cells with either miR-100 or miR-125b negated the induction of MMP13 release. Additionally, AR activation induced a morphological alteration of MDA-MB-453 cells, which was blocked by miR-125b only. Collectively, these data indicate that AR may control the biological behavior of breast cancer cells and protein expression via miRNAs. PMID- 28816391 TI - Cytoskeleton and nucleoskeleton involvement in processes of cytomixis in plants. AB - Cytomixis is a form of cell-to-cell nuclear migration that involves the interaction of dynamic cytoskeletal components with the nucleus through signalling systems and linker complexes. In cytomixis two known mechanisms can be involved: actomyosin and/or microtubules and their associated motors. Perinuclear actin anchors and determines the direction of nuclear movement. In microsporogenesis cytomixis is probably initiated by a cascade of signals that trigger prophase reorganization of nucleus and cytoskeleton, and is a result of cytoskeletal protein activation, as well as a weakening of mechanisms responsible for anchoring the nucleus. The interactions between nuclei and the cytoskeleton are mediated by linker complexes that play a major role in nuclear positioning and shape, chromatin-nuclear envelope interactions, nucleoskeleton organization, gene expression and genome organization. Other contributing factors include changes in the protein composition and post-translational modifications that alter protein conformation. Cytomixis appears also to have relevance to higher order structuring, influencing tissue and organ architecture, causing collective forms of cell interactions and information exchange within a single continuum. In this review we summarize our current understanding of the cytoskeleton dynamic function in cytomictic nuclear migration. PMID- 28816392 TI - Enantioselective Phosphine-Catalyzed Formal [4+4] Annulation of alpha,beta Unsaturated Imines and Allene Ketones: Construction of Eight-Membered Rings. AB - The first highly enantioselective phosphine-catalyzed formal [4+4] annulation has been developed. In the presence of amino-acid-derived phosphines, the unprecedented [4+4] annulations between benzofuran/indole-derived alpha,beta unsaturated imines and allene ketones proceeded smoothly, thus affording azocines, bearing either a benzofuran or an indole moiety, in excellent yields and with nearly perfect enantioselectivities (>=98 % ee in most cases). This work marks the first efficient asymmetric construction of optically enriched eight membered rings by phosphine catalysis. PMID- 28816393 TI - Sperm donation perinatal outcomes in an Australian population cohort. AB - AIM: To compare perinatal outcomes for neonates conceived with donated sperm with those for neonates conceived spontaneously in an Australian population cohort. METHODS: Perinatal outcomes for all births in South Australia for the period January 1986-December 2002 were linked with assisted reproductive treatment records to determine those conceived from donated sperm. Birth outcome measures were analyzed using Student's t-test and logistic regression using generalized estimating equations to determine statistical significance. RESULTS: Donor sperm neonates were not significantly different from their spontaneously conceived counterparts in terms of mean birthweight, low birthweight, preterm delivery, small for gestational age, or large for gestational age. They were, however, significantly more likely to be born at lower mean gestational age (P = 0.012), and to have preterm delivery with low birthweight (P = 0.008), when controlling for maternal age, parity, ethnicity, socioeconomic quartile and baby's sex. These associations were not apparent when singletons and twins were considered separately. CONCLUSION: There was some evidence of compromised perinatal outcomes for donor sperm neonates compared with their spontaneously conceived counterparts, which appeared to be partly attributable to multiplicity. PMID- 28816394 TI - A review of inflammatory idiopathic myopathy focusing on polymyositis. AB - Inflammatory idiopathic myopathies are a group of autoimmune diseases affecting predominantly the proximal skeletal muscles, with raised muscle enzymes, with or without skin involvement and extramuscular organ involvement. Autoantibodies help to characterize patients into different clinical phenotypes. Successful treatment necessitates controlling inflammation early with corticosteroids and invariably requires additional immunosuppressive therapy. This review focuses on the aetiology, pathogenesis, clinical presentation, investigations and management of patients presenting with inflammatory idiopathic myopathies, predominantly focusing on polymyositis and antisynthetase syndrome. PMID- 28816395 TI - Cultural adaptation and validation of the Caring Behaviors Assessment tool in Chile. AB - This study reports the process of cultural adaptation of the Caring Behaviors Assessment tool for the Spanish language, and determine its validity and reliability. We used a mixed-methods approach with a sample of adult participants after translation and adjustment, correlations and multiple regressions were used to explain differences in perception. Internal consistency and reliability were determined by using Cronbach's alpha. While slight modifications to syntax, language, and the interval scale were necessary to enable better comprehension, all items had high average scores as did the seven subscales. Additionally, similarities with previous literature suggest cultural suitability of the instrument across countries. This version of the tool was judged to be valid and reliable, and will facilitate care measurability and theoretical sensitivity in Spanish-speaking countries. PMID- 28816396 TI - Identification of Novel Site-Specific Alterations in the Modification Level of Myelin Basic Protein Isolated from Mouse Brain at Different Ages Using Capillary Electrophoresis-Mass Spectrometry. AB - Myelin basic protein (MBP) is a multifunctional protein involved in maintaining the stability and integrity of the myelin sheath by a variety of interactions with membranes and other proteins. MBP is subjected to extensive posttranslational modifications (PTMs) that are known to be crucial for the regulation of these interactions. Here, we report capillary electrophoresis-mass spectrometric (CE-MS) analysis for the separation and identification of MBP peptides that incorporate the same PTM at different sites, creating multiple localization variants, and the ability to analyze challenging modifications such as asparagine and glutamine deamidation, isomerization, and arginine citrullination. Moreover, we observed site-specific alterations in the modification level of MBP purified from brain of mice of different age. In total, we identified 40 modifications at 33 different sites, which include both previously reported and seven novel modifications. The identified modifications include Nalpha-terminal acetylation, mono- and dimethylation, phosphorylation, oxidation, deamidation, and citrullination. Notably, some new sites of arginine methylation overlap with the sites of citrullination. Our results highlight the need for sensitive and efficient techniques for a comprehensive analysis of PTMs. PMID- 28816397 TI - A flow-through column electrolytic cell for supercritical fluid chromatography. AB - A novel flow-through column electrolytic cell was proposed as a detector to obtain current signals for supercritical fluid chromatography. The electrochemical cell consisted of two electrodes and its holder, and a working and a counter electrode were fabricated from 192 carbon strings, which were composed of 400 carbon fibers of 10 MUm in diameter filled into a heat-shrinkable tube. These electrodes were placed in the center of a holder made from polyether ether ketone blocks and they were separated by polytetrafluoroethylene membrane filters. To evaluate the sensitivity of this cell, a standard solution of ferrocene was injected into the supercritical fluid chromatography system connected to the electrolytic cell. The ferrocene was eluted through a silica gel column using a mixture of a mobile phase of supercritical CO2 and a modifier of methanol containing ammonium acetate. The current peak area of ferrocene correlated to the ferrocene concentration in the range of 10-400 MUmol/L (r = 0.999). Moreover, the limit of detection on the column estimated from a signal-to noise ratio of 3 was 9.8 * 10-13 mol. PMID- 28816398 TI - Optical properties of mice's stool in 550 to 1000 nm wavelength range. AB - The aim of this work was to measure optical properties of stool of mice to provide this relevant wavelength-dependent behavior for optical imaging modalities such as fluorescent molecular tomography and near-infrared optical tomography. BALB/c nude female mice were studied and optical properties of the stool were determined by employing the inverse adding-doubling approach. The animals were kept on chlorophyll-free diet. Nine stool samples were measured. The wavelength-dependent behavior of absorption and scattering in 550 to 1000 nm range is presented. The reduced scattering spectrum is fitted to the Mie scattering approximation in the near-infrared (NIR) wavelength range and to the Mie + Rayleigh approximation in visible/NIR range with the fitting coefficients presented. The study revealed that the absorption spectrum of stool can lead to crosstalk with the spectrum of hemoglobin in the NIR range. PMID- 28816399 TI - Preliminary results on the photoluminescence and optically stimulated luminescence in Cu-doped and Ag-doped ZnB2 X4 (B = Li, Na, K: X = Cl, Br) compounds. AB - Photoluminescence, and optically stimulated luminescence in ZnB2 X4 (B; Li,Na,K: X; Cl,Br) compounds doped with Cu+ or Ag+ were studied. Double humped emission bands attributable to the activators were observed in all the samples. The observed photoluminescence of Cu+ and Ag+ could be identified with 3d9 4s1 < >3d10 and 4d9 5s1 <->5d10 transitions respectively. The longer wavelength band (400-500 nm range) could be attributed to the Cu+ or Ag+ ion replacing alkali ion at the octahedral alkali site whereas short wavelength band (340-400 nm range) is attributed to a Cu or Ag ion at tetrahedral zinc site. The short wavelength band was found to be intense compared with long wavelength and gave an indication that most of the Cu or Ag ions prefered a tetrahedral Zn site compared with the octahedral alkali site. All the samples exhibit optically stimulated luminescence (OSL). The sensitivity was found to be lattice dependent. The lowest sensitivity of about 1% compared with Al2 O3 :C was observed in lithium lattices whereas highest the sensitivity of about 290% was observed in the case of Cu-doped ZnNa2 Br4 . PMID- 28816400 TI - Silica-modified luminescent LaPO4 :Eu@LaPO4 @SiO2 core/shell nanorods: Synthesis, structural and luminescent properties. AB - Monoclinic-type tetragonal LaPO4 :Eu (core) and LaPO4 :Eu@LaPO4 (core/shell) nanorods (NRs) were successfully prepared using a urea-based co-precipitation process under ambient conditions. An amorphous silica layer was coated around the luminescent core/shell NRs via the sol-gel process to improve their solubility and colloidal stability in aqueous and non-aqueous media. The prepared nano products were systematically characterized by X-ray diffraction pattern, transmission electron microscopy, energy dispersive X-ray analysis, and FTIR, UV/Vis, and photoluminescence spectroscopy to examine their phase purity, crystal phase, surface chemistry, solubility and luminescence characteristics. The length and diameter of the nano-products were in the range 80-120 nm and 10-15 nm, respectively. High solubility of the silica-modified core/shell/Si NRs was found for the aqueous medium. The luminescent core NRs exhibited characteristic excitation and emission transitions in the visible region that were greatly affected by surface growth of insulating LaPO4 and silica layers due to the multiphonon relaxation rate. Our luminescence spectral results clearly show a distinct difference in intensities for core, core/shell, and core/shell/Si NRs. Highly luminescent NRs with good solubility could be useful candidates for a variety of photonic-based biomedical applications. PMID- 28816401 TI - Study of organic acids in Schisandrae Chinensis Fructus after vinegar processing. AB - The ripened fruit of Schisandrae Chinensis Fructus has unique medical properties in Chinese medicine. It is commonly used after vinegar steaming. Vinegar steaming changes the color of Schisandrae Chinensis Fructus from red to black and enhances its acidic and astringent properties. Lignans are the well-investigated components in this herb. However, Schisandrae Chinensis Fructus is acidic in the theory of Chinese medicine, and whether vinegar processing changes its organic acid components remains largely unknown. In this study, the organic acids in this herb were derived by the method of methyl esterification, and further analyzed by gas chromatography with mass spectrometry. A total of 39 organic acid compounds were identified. Interestingly, Schisandrae Chinensis Fructus after vinegar processing showed a significant increase in the content of levulinic acid as compared to the unprocessed ones. Pharmacological experiments demonstrated that levulinic acid inhibited the contractility of isolated intestine and had an inhibitory effect on the excessive hyperfunction of small intestinal propulsion. Moreover, the extracts of vinegar-processed Schisandrae Chinensis Fructus had a stronger inhibitory on the excessive hyperfunction of small intestinal propulsion than that of unprocessed ones. Taken together, this study offers novel insight into the effect of Schisandrae Chinensis Fructus after vinegar processing. PMID- 28816402 TI - Blocking the ERK1/2 signal pathway can inhibit S100A12 induced human aortic smooth muscle cells damage. AB - Increased levels of S100A12 and activated matrix metalloproteinase 2/9 (MMP-2/9) produced by human aortic smooth muscle cells (HASMCs) have recently implicated in the development of thoracic aortic disease. In the present study, we investigated the effect of S100A12 on HASMCs and identified the intracellular signal pathways involved by Western blot. The results were shown that up-expression of S100A12 in HASMCs induced cell apoptosis and inhibited cell proliferation. Additionally, S100A12 significantly increased the expression of MMP-2, MMP-9, and VCAM-1 in HASMCs at translational levels. Furthermore, our results also showed that S100A12 induced HASMCs damage by increased related proteins expression was mediated by the activation of ERK1/2 signal pathway, whereas p38 MAPK had no effect on those processes. Blocked the activation of ERK1/2 could decrease S100A12 induced the apoptosis and inhibited cell proliferation of HASMCs. In conclusion, these results indicated that S100A12 could increase the expression of MMP-2, MMP-9, and vascular cell adhesion molecule 1 (VCAM-1) in HASMCs via activation of ERK1/2 signal pathway, which leads to injury of HASMCs. Therefore, antagonists of ERK1/2 may be useful for treating thoracic aortic dissection. PMID- 28816403 TI - Predictors of distant relapse in patients with FIGO stage IIB-IVA cervical cancer treated with definitive radiotherapy. AB - AIM: To investigate the predictors of distant relapse in International Federation of Gynecology and Obstetrics (FIGO) stage IIB-IVA cervical cancer patients treated with definitive radiotherapy (RT). METHODS: The clinical data of 219 patients with FIGO stage IIB-IVA cervical cancer treated with definitive RT between January 1997 and December 2011 were retrospectively reviewed. The cumulative distant relapse, progression-free survival (PFS) and overall survival (OS) rates were calculated using the Kaplan-Meier method and compared using the log-rank test. A Cox proportional hazards regression model was used to investigate the predictors of distant relapse in patients. RESULTS: Following treatment with definitive RT, 61 of the 219 (27.9%) patients developed distant relapse with median PFS and OS rates of 9.9 and 32.8 months, and estimated five year PFS and OS rates of 4.9% and 21.3%, respectively. Multivariate analysis revealed that pelvic node metastasis, pretreatment leukocytosis and pretreatment neutrophilia were significant predictors of distant relapse. The risk of developing distant relapse was found to be associated with the number of predictors that the patients displayed: the estimated five-year distant relapse rates of the patients with no predictors, one predictor and two predictors were 20.3%, 35.5% and 88.9%, respectively. CONCLUSIONS: Roughly 28% of patients with FIGO stage IIB-IVA cervical cancer developed distant relapse after definitive RT. Pelvic lymph node metastasis and pretreatment leukocytosis/neutrophilia are independent predictors of distant relapse. PMID- 28816405 TI - Synthesis, density functional theory calculations and luminescence of lanthanide complexes with 2,6-bis[(3-methoxybenzylidene)hydrazinocarbonyl] pyridine Schiff base ligand. AB - A pyridine-diacylhydrazone Schiff base ligand, L = 2,6-bis[(3-methoxy benzylidene)hydrazinocarbonyl]pyridine was prepared and characterized by single crystal X-ray diffraction. Lanthanide complexes, Ln-L, {[LnL(NO3 )2 ]NO3 .xH2 O (Ln = La, Pr, Nd, Sm, Eu, Gd, Tb, Dy and Er)} were prepared and characterized by elemental analysis, molar conductance, thermal analysis (TGA/DTGA), mass spectrometry (MS), Fourier transform infra-red (FT-IR) and nuclear magnetic resonance (NMR) spectroscopy. Ln-L complexes are isostructural with four binding sites provided by two nitro groups along with four coordination sites for L. Density functional theory (DFT) calculations on L and its cationic [LnL(NO3 )2 ]+ complexes were carried out at the B3LYP/6-31G(d) level of theory. The FT-IR vibrational wavenumbers were computed and compared with the experimentally values. The luminescence investigations of L and Ln-L indicated that Tb-L and Eu L complexes showed the characteristic luminescence of Tb(III) and Eu(III) ions. Ln-L complexes show higher antioxidant activity than the parent L ligand. PMID- 28816404 TI - Multivalency Increases the Binding Strength of RGD Peptidomimetic-Paclitaxel Conjugates to Integrin alphaV beta3. AB - This work reports the synthesis of three multimeric RGD peptidomimetic-paclitaxel conjugates featuring a number of alphaV beta3 integrin ligands ranging from 2 to 4. These constructs were assembled by conjugation of the integrin alphaV beta3 ligand cyclo[DKP-RGD]-CH2 NH2 with paclitaxel via a 2'-carbamate with a self immolative spacer, the lysosomally cleavable Val-Ala dipeptide linker, a multimeric scaffold, a triazole linkage, and finally a PEG spacer. Two monomeric conjugates were also synthesized as reference compounds. Remarkably, the new multimeric conjugates showed a binding affinity for the purified integrin alphaV beta3 receptor that increased with the number of integrin ligands (reaching a minimum IC50 value of 1.2 nm for the trimeric), thus demonstrating that multivalency is an effective strategy to strengthen the ligand-target interactions. PMID- 28816406 TI - Phosphinous Acid-Assisted Hydration of Nitriles: Understanding the Controversial Reactivity of Osmium and Ruthenium Catalysts. AB - The synthesis and catalytic behavior of the osmium(II) complexes [OsCl2 (eta6 -p cymene)(PR2 OH)] [R=Me (2 a), Ph (2 b), OMe (2 c), OPh (2 d)] in nitrile hydration reactions is presented. Among them, the best catalytic results were obtained with the phosphinous acid derivative [OsCl2 (eta6 -p-cymene)(PMe2 OH)] (2 a), which selectively provided the desired primary amides in excellent yields and short times at 80 degrees C, employing directly water as solvent, and without the assistance of any basic additive (TOF values up to 200 h-1 ). The process was successful with aromatic, heteroaromatic, aliphatic, and alpha,beta unsaturated organonitriles, and showed a high functional group tolerance. Indeed, complex 2 a represents the most active and versatile osmium-based catalyst for the hydration of nitriles reported so far in the literature. In addition, it exhibits a catalytic performance similar to that of its ruthenium analogue [RuCl2 (eta6 -p-cymene)(PMe2 OH)] (4). However, when compared to 4, the osmium complex 2 a turned out to be faster in the hydration of less-reactive aliphatic nitriles, whereas the opposite trend was generally observed with aromatic substrates. DFT calculations suggest that these differences in reactivity are mainly related to the ring strain associated with the key intermediate in the catalytic cycle, that is, a five-membered metallacyclic species generated by intramolecular addition of the hydroxyl group of the phosphinous acid ligand to the metal-coordinated nitrile. PMID- 28816407 TI - Direct and Stereospecific [3+2] Synthesis of Pyrrolidines from Simple Unactivated Alkenes. AB - Pyrrolidines are important heterocyclic compounds with endless applications in organic synthesis, metal catalysis, and organocatalysis. Their potential as ligands for first-row transition-metal catalysts inspired a new method to access complex poly-heterocyclic pyrrolidines in one step from available materials. This fundamental step forward is based on the discovery of an essential organoaluminum promoter that engages unactivated and electron-rich olefins in intermolecular [3+2] cycloadditions. PMID- 28816408 TI - Endoscopic treatment of Barrett's esophagus: What can we learn from the Western perspective? AB - The incidence of Barrett's esophagus (BE)-related neoplasia in Western countries has increased in the past several decades and, even in Eastern countries, it appears to be increasing. Endoscopic therapies are the first-line treatment for BE-related neoplasia; however, there is still no standardized treatment strategy. Most of the data have been published from Western countries where the ultimate goal of treatment is complete eradication of BE mucosa removing subtle synchronous lesions and preventing metachronous neoplasia. A multimodality approach that combines endoscopic resection and radiofrequency ablation (RFA) has been widely accepted in the West. In contrast, the lack of access to RFA treatment in the East has meant that endoscopic resection is the only feasible option. There is a wide divergence in treatment strategies for BE-related neoplasia between the East and the West. It is very important to consider these basic differences in the context of the currently available evidence to date. Therefore, the purpose of this article is to review the recent literature and to provide an overview of the endoscopic treatment options for BE. PMID- 28816409 TI - Genistein represses PEPCK-C expression in an insulin-independent manner in HepG2 cells and in alloxan-induced diabetic mice. AB - Genistein has been reported to exert beneficial effects on type 2 diabetes mellitus (T2DM); however, the underlying molecular mechanisms involved therein have not been clearly elucidated. To address this question, the effect of genistein on the expression of phosphoenolpyruvate carboxykinase (PEPCK), and glucose production in HepG2 cells and in alloxan-induced diabetic mice was investigated. HepG2 cells were exposed to different concentration of genistein in presence or absence of modulators, and the expression of cytosolic PEPCK (PEPCK C) and the signaling pathways was studied. Further, the biological relevance of the in vitro study was tested in alloxan-induced diabetic mice. Genistein lowered PEPCK-C expression and glucose production in HepG2 cells accompanied with increased in phosphorylation states of AMPK, MEK1/2, ERK1/2, and CRTC2. Treatment with the AMPK inhibitor (compound C) enhanced genistein-induced MEK1/2 and ERK1/2 activity indicating a potential cross-talk between the two signaling pathways. In vivo, genistein also reduced fasting glucose levels accompanied with reduced PEPCK-C expression and increased in AMPK and ERK1/2 phosphorylation states in the liver of genistein-treated alloxan-induced diabetic mice. Genistein fulfills the criteria of a suitable anti-diabetic agent by reducing glucose production and inhibiting PEPCK-C expression in HepG2 cells and also in alloxan-induced diabetic mice. These results indicate that genistein is an effective candidate for preventing T2DM through the modulation of AMPK-CRTC2 and MEK/ERK signaling pathways, which may allow a novel approach to modulate dysfunction in hepatic gluconeogenesis in T2DM. PMID- 28816411 TI - A stereovision model applied in bio-micromanipulation system based on stereo light microscope. AB - A bio-micromanipulation system is designed for manipulating micro-objects with a length scale of tens or hundreds of microns based on stereo light microscope. The world coordinate reconstruction of points on the surface of micro-objects is an important goal for the micromanipulation. Traditional pinhole camera model is applied widely in macrocomputer vision. However, this model will output bad data with remarkable error if it is directly used to reconstruct three-dimensional world coordinates for stereo light microscope. Therefore, a novel and improved pinhole camera model applied in bio-micromanipulation system is proposed in this article. The new model is composed of binocular-pinhole model and error correction model. The binocular-pinhole model is used to output the basic world coordinates. The error-correction model is used to correct the errors from the basic world coordinates and outputs the final high-precision world coordinates. The results show that the new model achieves a precision of 0.01 mm in the X direction, 0.01 mm in the Y direction, and 0.015 mm in the Z direction within a maximum reconstruction distance of 4.1 mm in the X direction, 2.9 mm in the Y direction, and 2.25 mm in the Z direction, and that traditional pinhole camera model achieves a lower and unsatisfactory precision of about 0.1 mm. PMID- 28816410 TI - New insights into the cellular makeup and progenitor potential of palatal connective tissues. AB - The present study investigated the regenerative potential of connective tissues harvested from two palatal areas widely used as donor sites for muco-gingival surgical approaches. Connective tissue grafts (CTGs) were obtained by de epithelialisation of a free gingival graft (deCTG) and by a split flap approach from a previous donor site (reCTG). Two types of mesenchymal stem cell (MSCs) were isolated and were named de-epithelialised MSCs (deMSCs) and re-entry MSCs (reMSCs). The cells were characterised and cellular functionality was investigated. CTGs were evaluated using immunohistochemical and ultrastructural approaches. No significant differences were observed regarding the frequency of colony-forming unit- fibroblasts, migration potential, and population doubling time between the two cell lines (p > 0.05). Both cell lines showed positivity for CD105, CD73, CD90, and CD44 and negative expression for CD34/45, CD14, CD79a, and HLA-DR. MSCs from both cell lines successfully differentiated into osteogenic, adipogenic, and chondrogenic lineages. Cells expressing antigens characteristic of CD34+ stromal cells (CD34+, alphaSMA-, CD31-) were traced in both CTGs. Ultrastructural analysis highlighted the presence of putative progenitors, namely fibroblasts,-in the pericapillary regions and in remote regions of the lamina propria- and pericytes-surrounding the capillaries. This study provides supplementary arguments for the use of CTG grafts in clinical practice due to the presence of putative progenitor cell. However, results were inconclusive regarding clinical decision-making to determine optimal harvesting area. Prior harvesting in the donor area did not appear to alter the regenerative capabilities of the connective tissue. PMID- 28816412 TI - Motivational interviewing to enhance treatment attendance in mental health settings: A systematic review and meta-analysis. AB - : WHAT IS KNOWN ON THE SUBJECT?: Despite differences between samples, some literature reviews have suggested that MI is effective in enhancing treatment attendance for individuals with mental health issues. Little is known regarding the effects of MI as a pre-treatment on individuals who are not seeking treatment for mental health issues. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: This systematic review of the literature and meta-analysis demonstrates that MI is most beneficial for individuals who are not seeking mental health treatment. MI represents an opportunity for health promotion when patients are unmotivated but may otherwise be amenable to an intervention. MI is effective as a pre-treatment intervention to motivate individuals to attend further post-MI treatment and counselling. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: MI is a process and a useful tool for clinicians in all therapeutic interactions, to motivate their patients to seek further assistance for mental heath issues. Health promotion and encouragement to attend further treatment sessions can be facilitated through telephone contact. ABSTRACT: Introduction The stages of change model suggests that individuals seeking treatment are in the "preparation" or the "action" stage of change, which is the desired outcome of successful Motivational Interviewing (MI) interventions. MI is known to enhance treatment attendance among individuals with mental health problems. Aim This study examined the published research on MI as a pre-treatment to enhance attendance among individuals treatment-seeking and non-treatment-seeking for mental health issues. Methods Fourteen randomized controlled trials were identified, and MI efficacy was examined dichotomously: attendance or non-attendance for post-MI therapy. Subgroup analysis investigated treatment-seeking and non-treatment-seeking groups. Results Despite wide variations in sample sizes, blinding and monitoring, intervention fidelity was absent in the majority of published studies. Meta-analysis revealed that MI pre treatment improved attendance relative to comparison groups. Conclusions Individuals not seeking treatment for mental health issues benefited the most from MI. Despite differences in MI treatment intensity, short interventions were as effective as longer interventions, whereas two MI sessions for as little as 15 min were effective in enhancing treatment attendance. Implications for Practice Motivational interviewing is a useful tool for clinicians in all therapeutic interactions to help motivate patients to seek assistance for mental health issues. PMID- 28816413 TI - Porcine spermatogonial stem cells self-renew effectively in a three dimensional culture microenvironment. AB - Generally, self-renewal of spermatogonial stem cells (SSCs) is maintained in vivo in a three-dimensional (3D) microenvironment consisting of the seminiferous tubule basement membrane, indicating the importance of the 3D microenvironment for in vitro culture of SSCs. Here, we report a 3D culture microenvironment that effectively maintains porcine SSC self-renewal during culture. Porcine SSCs were cultured in an agarose-based 3D hydrogel and in 2D culture plates either with or without feeder cells. Subsequently, the effects of 3D culture on the maintenance of undifferentiated SSCs were identified by analyzing cell colony formation and morphology, AP activity, and transcriptional and translational regulation of self renewal-related genes and the effects on proliferation by analyzing cell viability and single cell-derived colony number. The 3D culture microenvironment constructed using a 0.2% (w/v) agarose-based 3D hydrogel showed the strongest maintenance of porcine SSC self-renewal and induced significant improvements in proliferation compared with 2D culture microenvironments. These results demonstrate that self-renewal of porcine SSCs can be maintained more effectively in a 3D than in a 2D culture microenvironment. Moreover, this will play a significant role in developing novel culture systems for SSCs derived from diverse species in the future, which will contribute to SSC-related research. PMID- 28816416 TI - Offsetting global warming-induced elevated greenhouse gas emissions from an arable soil by biochar application. AB - Global warming will likely enhance greenhouse gas (GHG) emissions from soils. Due to its slow decomposability, biochar is widely recognized as effective in long term soil carbon (C) sequestration and in mitigation of soil GHG emissions. In a long-term soil warming experiment (+2.5 degrees C, since July 2008) we studied the effect of applying high-temperature Miscanthus biochar (0, 30 t/ha, since August 2013) on GHG emissions and their global warming potential (GWP) during 2 years in a temperate agroecosystem. Crop growth, physical and chemical soil properties, temperature sensitivity of soil respiration (Rs ), and metabolic quotient (qCO2 ) were investigated to yield further information about single effects of soil warming and biochar as well as on their interactions. Soil warming increased total CO2 emissions by 28% over 2 years. The effect of warming on soil respiration did not level off as has often been observed in less intensively managed ecosystems. However, the temperature sensitivity of soil respiration was not affected by warming. Overall, biochar had no effect on most of the measured parameters, suggesting its high degradation stability and its low influence on microbial C cycling even under elevated soil temperatures. In contrast, biochar * warming interactions led to higher total N2 O emissions, possibly due to accelerated N-cycling at elevated soil temperature and to biochar induced changes in soil properties and environmental conditions. Methane uptake was not affected by soil warming or biochar. The incorporation of biochar-C into soil was estimated to offset warming-induced elevated GHG emissions for 25 years. Our results highlight the suitability of biochar for C sequestration in cultivated temperate agricultural soil under a future elevated temperature. However, the increased N2 O emissions under warming limit the GHG mitigation potential of biochar. PMID- 28816417 TI - Docking field-based QSAR and pharmacophore studies on the substituted pyrimidine derivatives targeting HIV-1 reverse transcriptase. AB - HIV-1 reverse transcriptase (RT) is one of the most important enzymes required for viral replication, thus acting as an attractive target for antiretroviral therapy. Pyrimidine analogues reportedly have selective inhibition on HIV-1 RT with favorable antiviral activities in our previous study. To further explore the relationship between inhibitory activity and pharmacophoric characteristics, field-based QSAR models were generated and validated using Schrodinger Suite (correlation coefficient of .8078, cross-validated value of 0.5397 for training set and Q2 of 0.4669, Pearson's r of .7357 for test set). Docking, pocket surfaces, and pharmacophore study were also investigated to define the binding pattern and pharmacophoric features, including (i) pi-pi interaction with residue Tyr181, Tyr188, and Trp229 and p-pi interaction with His235 and (ii) hydrogen bond with residue Lys101 and halogen bond with residue Tyr188. The pharmacophore features of six-point hypothesis AADRRR.184, AAADRR.38, and AADRRR.26 further complimented to the docking and QSAR results. We also found that the protein ligand complex exhibited high relative binding free energy. These observations could be potentially utilized to guide the rational design and optimization of novel HIV-1 RT inhibitors. PMID- 28816414 TI - Accuracy and utility of an epigenetic biomarker for smoking in populations with varying rates of false self-report. AB - Better biomarkers to detect smoking are needed given the tremendous public health burden caused by smoking. Current biomarkers to detect smoking have significant limitations, notably a short half-life for detection and lack of sensitivity for light smokers. These limitations may be particularly problematic in populations with less accurate self-reporting. Prior epigenome-wide association studies indicate that methylation status at cg05575921, a CpG residue located in the aryl hydrocarbon receptor repressor (AHRR) gene, may be a robust indicator of smoking status in individuals with as little as half of a pack-year of smoking. In this study, we show that a novel droplet digital PCR assay for measuring methylation at cg05575921 can reliably detect smoking status, as confirmed by serum cotinine, in populations with different demographic characteristics, smoking histories, and rates of false-negative self-report of smoking behavior. Using logistic regression models, we show that obtaining maximum accuracy in predicting smoking status depends on appropriately weighting self-report and cg05575921 methylation according to the characteristics of the sample being tested. Furthermore, models using only cg05575921 methylation to predict smoking perform nearly as well as those also including self-report across populations. In conclusion, cg05575921 has significant potential as a clinical biomarker to detect smoking in populations with varying rates of accuracy in self-report of smoking behavior. PMID- 28816418 TI - Hypoxia-induced microRNA-26b inhibition contributes to hypoxic pulmonary hypertension via CTGF. AB - The objective of this study was to explore the role of miRNAs in the control of HPH as well as molecular mechanism underlying. Computational analysis and luciferase assay were carried out to search the target gene of miR-26b. Luciferase assay, RT-PCR and western-blot analysis was performed to test interaction among hypoxia, miR-26b, SRF and CTGF. MiR-26b was significantly downregulated; meanwhile, CTGF and SRF were significantly upregulated in HPH rat model. Using computational analysis, CTGF was found to be a virtual target gene of miR-26b, and only cell transfected with vectors containing wild-type CTGF 3'UTR and miR-26b showed a lower luciferase activity than scramble control. Hypoxia significantly inhibited miR-26b promoter, and promoted SRF promoter. Meanwhile, hypoxia had no effect on CTGF promoter. In addition, SRF promoted the promoter of CTGF. MiR-26b was significantly downregulated; meanwhile, CTGF and SRF were upregulated in PASMCs exposed to hypoxia. In addition, miR-26b and SRF siRNA, but not CTGF siRNA, significantly inhibited SRF expression. Meanwhile, miR 26b, SRF siRNA, and CTGF siRNA significantly inhibited CTGF expression in hypoxia treated cell. PASMCs treated with hypoxia showed higher cell viability and higher percentage cells in S phase than the control, which could be reversed by miR-26b, SRF siRNA, and CTGF siRNA transfection. These findings suggested that hypoxia induced miR-26b inhibition and SRF and CTGF upregulation in HPH rat model. CTGF mediated hypoxia-induced regulation of miR-26b and SRF in proliferation of PASMCs, which indicated that hypoxia-induced miR-26b inhibition contributed to the pathogenesis of HPH via CTGF. PMID- 28816419 TI - Tubulin acetylation accompanies autophagy development induced by different abiotic stimuli in Arabidopsis thaliana. AB - Microtubules (MTs) play an important role in the regulation of autophagy development in yeast and animal as well as in plant cells. MTs participate in maturation and traffic of autophagosomes through their dynamic state changes and post-translational modifications of tubulin, namely acetylation. We subjected Arabidopsis thaliana seedlings to metabolic-, salt-, osmotic stresses as well as irradiation of ultraviolet B and investigated the involvement of plant MTs in the development of stress-induced autophagy via tubulin acetylation. For this purpose Arabidopsis thaliana line expressing autophagy-related protein 8 h (atg8h)-GFP was generated to investigate autophagy, applying the level of free GFP as an indicator of autophagy development. Using autophagosome confocal imaging and Western blot analysis of Atg8 post-translational lipidation and synchronous GFP release it was shown that all examined stressful stimuli led to pronounced development of autophagy, particularly in different root tissues. Moreover, autophagy development was accompanied by alpha-tubulin acetylation under all stressful conditions. Presented data indicate the possible role of the post translational acetylation of alpha-tubulin in the mediation of plant stress induced autophagy. PMID- 28816421 TI - Few direct-to-consumer test users receive genetic counseling: More consumers discuss results with primary care physicians. PMID- 28816420 TI - Two patients with the heterozygous R189H mutation in ACTA2 and Complex congenital heart defects expands the cardiac phenotype of multisystemic smooth muscle dysfunction syndrome. PMID- 28816422 TI - Dolichol kinase deficiency (DOLK-CDG): Two new cases and expansion of phenotype. AB - Congenital disorders of glycosylation (CDGs) are a group of genetic diseases caused by mutations in genes that are necessary for the addition of oligosaccharides to acceptor proteins or lipids. An early step in this process requires dolichol kinase (DK) to catalyze the formation of dolichyl phosphate, which acts as a membrane anchor for initial attachment of sugar residues that are subsequently built up to oligosaccharides and transferred to acceptor proteins and lipids for further processing. Biallelic mutations in DOLK, the gene for DK, result in human in a CDG with variable symptoms, ranging from nonsyndromic dilated cardiomypopathy to severe multiorgan involvement. We report two female siblings with novel compound heterozygous mutations in DOLK: c.951C>A (p.Tyr317Ter) and c.1558A>G (p.Thr520Ala). Both patients presented in the neonatal period with severe ichthyosis, unusual distal digital constrictions and dilated cardiomyopathy which resulted in death. Histology of the skin showed lipid droplet accumulation in the stratum corneum and keratinocytes, which suggests defective epidermal lipid metabolism. These patients represent an earlier and more severe form of DOLK-CDG (CDG-1m) with a striking presentation at birth that expands the known phenotypic spectrum. PMID- 28816423 TI - Infants with cystic fibrosis still lag on some growth measures: Babies' weight on par with healthy peers, but growth is still stunted. PMID- 28816426 TI - Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. PMID- 28816424 TI - Cover Image, Volume 173A, Number 9, September 2017. AB - The cover image, by Paul Kruszka et al., is based on the Original Article Noonan Syndrome in Diverse Populations, DOI: 10.1002/ajmg.a.38362. Design Credit: Darryl Leja. PMID- 28816427 TI - Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy. PMID- 28816428 TI - Aqueous Exfoliation of Graphite into Graphene Assisted by Sulfonyl Graphene Quantum Dots for Photonic Crystal Applications. AB - We investigate the pi-pi stacking of polyaromatic hydrocarbons (PAHs) with graphene surfaces, showing that such interactions are general across a wide range of PAH sizes and species, including graphene quantum dots. We synthesized a series of graphene quantum dots with sulfonyl, amino, and carboxylic functional groups and employed them to exfoliate and disperse pristine graphene in water. We observed that sulfonyl-functionalized graphene quantum dots were able to stabilize the highest concentration of graphene in comparison to other functional groups; this is consistent with prior findings by pyrene. The graphene nanosheets prepared showed excellent colloidal stability, indicating great potential for applications in electronics, solar cells, and photonic displays which was demonstrated in this work. PMID- 28816429 TI - Smart Cellulose Nanofluids Produced by Tunable Hydrophobic Association of Polymer Grafted Cellulose Nanocrystals. AB - Cellulose fibrils, unique plant-derived semicrystalline nanomaterials with exceptional mechanical properties, have significant potential for rheology modification of complex fluids due to their ability to form a physically associated semiflexible fibrillary network. Here, we report new associative cellulose nanocrystals (ACNCs) with stress-responsive rheological behaviors in an aqueous solution. The surface-mediated living radical polymerization was employed to graft poly(stearyl methacrylate-co-2-methacryloxyethyl phosphorylcholine) brushes onto the nanofibrils, and then 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO)-mediated oxidation was conducted to produce nanoscale ACNCs in the aqueous solution. The ACNCs displayed interfibril association driven by the hydrophobic interaction that resulted in the formation of a nanofibrillar crystalline gel phase. We observed that the viscosity of the ACNC fluid showed reversible shear thinning and temperature-induced thickening in response to applied shear stress and thermal shock. Moreover, thanks to generation of a mechanically robust nanofibrillar crystalline gel network, the ACNC suspension showed extraordinary stability to changes in salinity and pH. These results highlighted that the interfibril hydrophobic association of ACNCs was vital and played an essential role in regulation of stimuli-responsive sol-gel transitions. PMID- 28816430 TI - Dual Colorimetric and Fluorescent Authentication Based on Semiconducting Polymer Dots for Anticounterfeiting Applications. AB - Semiconducting polymer dots (Pdots) have recently emerged as a novel type of ultrabright fluorescent probes that can be widely used in analytical sensing and material science. Here, we developed a dual visual reagent based on Pdots for anticounterfeiting applications. We first designed and synthesized two types of photoswitchable Pdots by incorporating photochromic dyes with multicolor semiconducting polymers to modulate their emission intensities and wavelengths. The resulting full-color Pdot assays showed that the colorimetric and fluorescent dual-readout abilities enabled the Pdots to serve as an anticounterfeiting reagent with low background interference. We also doped these Pdots into flexible substrates and prepared these Pdots as inks for pen handwriting as well as inkjet printing. We further applied this reagent in printing paper and checks for high security anticounterfeiting purposes. We believe that this dual-readout method based on Pdots will create a new avenue for developing new generations of anticounterfeiting technologies. PMID- 28816431 TI - Carbon Nanotubes Arranged As Smart Interfaces in Lipid Langmuir-Blodgett Films Enhancing the Enzymatic Properties of Penicillinase for Biosensing Applications. AB - In this paper, carbon nanotubes (CNTs) were incorporated in penicillinase phospholipid Langmuir and Langmuir-Blodgett (LB) films to enhance the enzyme catalytic properties. Adsorption of the penicillinase and CNTs at dimyristoylphosphatidic acid (DMPA) monolayers at the air-water interface was investigated by surface pressure-area isotherms, vibrational spectroscopy, and Brewster angle microscopy. The floating monolayers were transferred to solid supports through the LB technique, forming mixed DMPA-CNTs-PEN films, which were investigated by quartz crystal microbalance, vibrational spectroscopy, and atomic force microscopy. Enzyme activity was studied with UV-vis spectroscopy and the feasibility of the supramolecular device nanostructured as ultrathin films were essayed in a capacitive electrolyte-insulator-semiconductor (EIS) sensor device. The presence of CNTs in the enzyme-lipid LB film not only tuned the catalytic activity of penicillinase but also helped conserve its enzyme activity after weeks, showing increased values of activity. Viability as penicillin sensor was demonstrated with capacitance/voltage and constant capacitance measurements, exhibiting regular and distinctive output signals over all concentrations used in this work. These results may be related not only to the nanostructured system provided by the film, but also to the synergism between the compounds on the active layer, leading to a surface morphology that allowed a fast analyte diffusion because of an adequate molecular accommodation, which also preserved the penicillinase activity. This work therefore demonstrates the feasibility of employing LB films composed of lipids, CNTs, and enzymes as EIS devices for biosensing applications. PMID- 28816432 TI - An Integrated Microsystem for Real-Time Detection and Threshold-Activated Treatment of Bacterial Biofilms. AB - Bacterial biofilms are the primary cause of infections in medical implants and catheters. Delayed detection of biofilm infections contributes to the widespread use of high doses of antibiotics, leading to the emergence of antibiotic resistant bacterial strains. Accordingly, there is an urgent need for systems that can rapidly detect and treat biofilm infections in situ. As a step toward this goal, in this work we have developed for the first time a threshold activated feedback-based impedance sensor-treatment system for combined real-time detection and treatment of biofilms. Specifically, we demonstrate the use of impedimetric sensing to accurately monitor the growth of Escherichia coli biofilms in microfluidic flow cells by measuring the fractional relative change (FRC) in absolute impedance. Furthermore, we demonstrate the use of growth measurements as a threshold-activated trigger mechanism to initiate successful treatment of biofilms using bioelectric effect (BE), applied through the same sensing electrode array. This was made possible through a custom program that (a) monitored the growth and removal of biofilms within the microfluidic channels in real-time and (b) enabled the threshold-based activation of BE treatment. Such BE treatment resulted in a ~74.8 % reduction in average biofilm surface coverage as compared to the untreated negative control. We believe that this smart microsystem for integrated biofilm sensing and treatment will enable future development of autonomous biosensors optimized for accurate real-time detection of the onset of biofilms and their in situ treatment, directly on the surfaces of medical implants. PMID- 28816433 TI - Syndiotactic Polystyrene-Based Ionogel Membranes for High Temperature Electrochemical Applications. AB - This work focuses on ionogel membranes for use in Li-ion batteries fabricated from syndiotactic polystyrene (sPS) gels filled with ionic liquids (ILs). The aim is to increase the operating temperature of Li-ion batteries. Thermal stability and safe operation of Li-ion batteries are two key attributes for their success in hybrid vehicles and other high-temperature applications. The volatility of the liquid electrolytes in current lithium-ion battery technology causes thermal runaway leading to fire, explosion, and swelling of the cell. The approach followed in this work combines the thermal stability and ruggedness of sPS and the extremely low volatility of ILs. The performances of lithium metal/graphite half-cells fabricated with ionogel membranes and those with Celgard-3501 membranes are evaluated at both room temperature and at elevated temperatures of 100 degrees C. Our data show that the cells with ionogel membranes can be operated continuously at 100 degrees C without failure. In addition, better charge-discharge capacity is obtained due to high ionic conductivity and high electrolyte retention both derived from high porosity of sPS gels and better wetting of sPS by the ILs. PMID- 28816434 TI - Bifacial Perovskite Solar Cells Featuring Semitransparent Electrodes. AB - Inorganic-organic hybrid perovskite solar cells (PSCs) are promising devices for providing future clean energy because of their low cost, ease of fabrication, and high efficiencies, similar to those of silicon solar cells. These materials have been investigated for their potential use in bifacial PSCs, which can absorb light from both sides of the electrodes. Here, we fabricated bifacial PSCs featuring transparent BCP/Ag/MoO3 rear electrodes, which we formed through low temperature processing using thermal evaporation methods. We employed a comprehensive optical distribution program to calculate the distributions of the optical field intensities with constant thicknesses of the absorbing layer in the top electrode configuration. The best PSC having a transparent BCP/Ag/MoO3 electrode achieved PCEs of 13.49% and 9.61% when illuminated from the sides of the indium tin oxide and BCP/Ag/MoO3 electrodes, respectively. We observed significant power enhancement when operating this PSC using mirror reflectors and bifacial light illumination from both sides of the electrodes. PMID- 28816435 TI - Fiber-Based, Double-Sided, Reduced Graphene Oxide Films for Efficient Solar Vapor Generation. AB - Solar vapor generation is a promising and whole new branch of photothermal conversion for harvesting solar energy. Various materials and devices for solar thermal conversion were successively produced and reported for higher solar energy utilization in the past few years. Herein, a compact device of reduced graphene oxides (rGO) and paper fibers was designed and assembled for efficient solar steam generation under light illumination, and it consists of water supply pipelines (WSP), a thermal insulator (TI) and a double-sided absorbing film (DSF). Heat localization is enabled by the black DSF due to its broad absorption of sunlight. More importantly, the heat transfer, from the hot DSF to the cold base fluid (water), was suppressed by TI with a low thermal conductivity. Meanwhile, bulk water was continuously transported to the DSF by WSP through TI, which was driven by the surface energy and surface tension based on the capillary effect. The effects of reduction degrees of rGO on the photothermal conversion were explored, and the evaporation efficiency reached 89.2% under one sun with 60 mg rGO. This new microdevice provided a basic technical support for distillation, desalination, sewage treatment, and related technologies. PMID- 28816436 TI - Integrated Distance-Based Origami Paper Analytical Device for One-Step Visualized Analysis. AB - An integrated distance-based origami paper analytical device (ID-oPAD) is developed for simple, user friendly and visual detection of targets of interest. The platform enables complete integration of target recognition, signal amplification, and visual signal output based on aptamer/invertase-functionalized sepharose beads, cascaded enzymatic reactions, and a 3D microfluidic paper-based analytical device with distance-based readout, respectively. The invertase-DNA conjugate is released upon target addition, after which it permeates through the cellulose and flows down into the bottom detection zone, whereas sepharose beads with larger size are excluded and stay in the upper zone. Finally, the released conjugate initiates cascaded enzymatic reactions and translates the target signal into a brown bar chart reading. By simply closing the device, the ID-oPAD enables a sample-in-answer-out assay within 30 min with visual and quantitative readout. Importantly, bound/free probe separation is achieved by taking advantage of the size difference between sepharose beads and cellulose pores, and the downstream enzymatic amplification is realized based on the compatibility of multiple enzymes with corresponding substrates. Overall, with the advantages of low-cost, disposability, simple operation, and visual quantitative readout, the ID-oPAD offers an ideal platform for point-of-care testing, especially in resource limited areas. PMID- 28816438 TI - Interfacial Mechanisms of Water Vapor Sorption into Cellulose Nanofibril Films as Revealed by Quantitative Models. AB - Humidity is an efficient instrument for facilitating changes in local architectures of two-dimensional surfaces assembled from nanoscaled biomaterials. Here, complementary surface-sensitive methods are used to collect explicit and precise experimental evidence on the water vapor sorption into (2,2,6,6 tetramethylpiperidin-1-yl)oxyl (TEMPO) oxidized cellulose nanofibril (CNF) thin film over the relative humidity (RH) range from 0 to 97%. Changes in thickness and mass of the film due to water vapor uptake are tracked using spectroscopic ellipsometry and quartz crystal microbalance with dissipation monitoring, respectively. Experimental data is evaluated by the quantitative Langmuir/Flory Huggins/clustering model and the Brunauer-Emmett-Teller model. The isotherms coupled with the quantitative models unveil distinct regions of predominant sorption modes: specific sorption of water molecules below 10% RH, multilayer build-up between 10 to 75% RH, and clustering of water molecules above 75% RH. The study reveals the sorption mechanisms underlying the well-known water uptake behavior of TEMPO oxidized CNF directly at the gas-solid interface. PMID- 28816437 TI - Selective Targeting by a Mechanism-Based Inactivator against Pyridoxal 5' Phosphate-Dependent Enzymes: Mechanisms of Inactivation and Alternative Turnover. AB - Potent mechanism-based inactivators can be rationally designed against pyridoxal 5'-phosphate (PLP)-dependent drug targets, such as ornithine aminotransferase (OAT) or gamma-aminobutyric acid aminotransferase (GABA-AT). An important challenge, however, is the lack of selectivity toward other PLP-dependent, off target enzymes, because of similarities in mechanisms of all PLP-dependent aminotransferase reactions. On the basis of complex crystal structures, we investigate the inactivation mechanism of OAT, a hepatocellular carcinoma target, by (1R,3S,4S)-3-amino-4-fluorocyclopentane-1-carboxylic acid (FCP), a known inactivator of GABA-AT. A crystal structure of OAT and FCP showed the formation of a ternary adduct. This adduct can be rationalized as occurring via an enamine mechanism of inactivation, similar to that reported for GABA-AT. However, the crystal structure of an off-target, PLP-dependent enzyme, aspartate aminotransferase (Asp-AT), in complex with FCP, along with the results of attempted inhibition assays, suggests that FCP is not an inactivator of Asp-AT, but rather an alternate substrate. Turnover of FCP by Asp-AT is also supported by high-resolution mass spectrometry. Amid existing difficulties in achieving selectivity of inactivation among a large number of PLP-dependent enzymes, the obtained results provide evidence that a desirable selectivity could be achieved, taking advantage of subtle structural and mechanistic differences between a drug target enzyme and an off-target enzyme, despite their largely similar substrate binding sites and catalytic mechanisms. PMID- 28816439 TI - 1,3-Dipolar Cycloaddition Reactions for the Synthesis of Novel Oxindole Derivatives and Their Cytotoxic Properties. AB - The multicomponent reaction between isatin, amino acid, but-2-ynedioates, and phenacyl bromide has been developed using microwave irradiation under catalyst and base-free conditions in aqueous medium. This synthetic protocol is useful for the synthesis of various functionalized spirooxindole derivatives. This MCR exhibits a broad substrate scope with excellent yields and shorter reaction time. Additionally the synthesized spirooxindole derivatives were evaluated for their anticancer activity against three human cancer cell lines: MCF-7 (breast), A549 (lung), and HeLa cervical. Most of the compounds showed moderate to potent cytotoxic activity against the tested cell lines. PMID- 28816440 TI - High Quantities of Microplastic in Arctic Deep-Sea Sediments from the HAUSGARTEN Observatory. AB - Although mounting evidence suggests the ubiquity of microplastic in aquatic ecosystems worldwide, our knowledge of its distribution in remote environments such as Polar Regions and the deep sea is scarce. Here, we analyzed nine sediment samples taken at the HAUSGARTEN observatory in the Arctic at 2340-5570 m depth. Density separation by MicroPlastic Sediment Separator and treatment with Fenton's reagent enabled analysis via Attenuated Total Reflection FTIR and MUFTIR spectroscopy. Our analyses indicate the wide spread of high numbers of microplastics (42-6595 microplastics kg-1). The northernmost stations harbored the highest quantities, indicating sea ice as a possible transport vehicle. A positive correlation between microplastic abundance and chlorophyll a content suggests vertical export via incorporation in sinking (ice-) algal aggregates. Overall, 18 different polymers were detected. Chlorinated polyethylene accounted for the largest proportion (38%), followed by polyamide (22%) and polypropylene (16%). Almost 80% of the microplastics were <=25 MUm. The microplastic quantities are among the highest recorded from benthic sediments. This corroborates the deep sea as a major sink for microplastics and the presence of accumulation areas in this remote part of the world, fed by plastics transported to the North via the Thermohaline Circulation. PMID- 28816441 TI - An Integrated Design, Material, and Fabrication Platform for Engineering Biomechanically and Biologically Functional Soft Tissues. AB - We present a design rationale for stretchable soft network composites for engineering tissues that predominantly function under high tensile loads. The convergence of 3D-printed fibers selected from a design library and biodegradable interpenetrating polymer networks (IPNs) result in biomimetic tissue engineered constructs (bTECs) with fully tunable properties that can match specific tissue requirements. We present our technology platform using an exemplary soft network composite model that is characterized to be flexible, yet ~125 times stronger (E = 3.19 MPa) and ~100 times tougher (WExt = ~2000 kJ m-3) than its hydrogel counterpart. PMID- 28816442 TI - Characterization of Primary Organic Aerosol from Domestic Wood, Peat, and Coal Burning in Ireland. AB - An aerosol chemical speciation monitor (ACSM) was deployed to study the primary nonrefractory submicron particulate matter emissions from the burning of commercially available solid fuels (peat, coal, and wood) typically used in European domestic fuel stoves. Organic mass spectra (MS) from burning wood, peat, and coal were characterized and intercompared for factor analysis against ambient data. The reference profiles characterized in this study were used to estimate the contribution of solid fuel sources, along with oil combustion, to ambient pollution in Galway, Ireland using the multilinear engine (ME-2). During periods influenced by marine air masses, local source contribution had dominant impact and nonsea-spray primary organic emissions comprised 88% of total organic aerosol mass, with peat burning found to be the greatest contributor (39%), followed by oil (21%), coal (17%), and wood (11%). In contrast, the resolved oxygenated organic aerosol (OOA) dominated the aerosol composition in continental air masses, with contributions of 50%, compared to 12% in marine air masses. The source apportionment results suggest that the use of domestic solid fuels (peat, wood, and coal) for home heating is the major source of evening and night-time particulate pollution events despite their small use. PMID- 28816443 TI - Characterization of Ciprofloxacin Permeation Pathways across the Porin OmpC Using Metadynamics and a String Method. AB - The rapid spreading of antimicrobial resistance in Gram-negative bacteria has become a major threat for humans as well as animals. As one of the main factors involved, the permeability of the outer membrane has attracted a great deal of attention recently. However, the knowledge regarding the translocation mechanisms for most available antibiotics is so far rather limited. Here, a theoretical study concerning the diffusion route of ciprofloxacin across the outer membrane porin OmpC from E. coli is presented. To this end, we establish a protocol to characterize meaningful permeation pathways by combining metadynamics with the zero-temperature string method. It was found that the lowest-energy pathway requires a reorientation of ciprofloxacin in the extracellular side of the porin before reaching the constriction region with its carboxyl group ahead. Several affinity sites have been identified, and their metastability has been evaluated using unbiased simulations. Such a detailed understanding is potentially very helpful in guiding the development of next generation antibiotics. PMID- 28816444 TI - Mapping the Intricate Reactivity of Nanojars toward Molecules of Varying Acidity and Their Conjugate Bases Leading To Exchange of Pyrazolate Ligands. AB - A comprehensive reactivity study of nanojars toward 18 different acidic compounds with varying pKa, including 12 different carboxylic acids (both aliphatic and aromatic mono- and dicarboxylic acids), p-toluenesulfonic acid, hydrogen sulfate, hydrogen carbonate, carbonic acid, 1-decanethiol, and methanol, as well as four different conjugate bases (formate, acetate, benzoate, 2-bromoethanesulfonate) is carried out with the aid of electrospray-ionization mass spectrometry. Thus, the effect on nanojar substitution and breakdown pattern of a number of variables, such as concentration of reagent (acid or conjugate base), acidity of reagent (pKa), effect of acid vs conjugate base, steric effects, aromaticity, incarcerated anion and size of the nanojar, is evaluated. Of the substitution and breakdown products identified by mass spectrometry, acetate-substituted nanojars (Bu4N)2[CO3?{Cu27(MU-OH)27(MU-pz)27-x(MU-CH3COO)x}] (x = 1 and 2), as well as dimeric complexes (Bu4N)2[Cu2(MU-pz)2A2] (A = CO32- and SO42-) have been isolated and characterized by single-crystal X-ray diffraction. This study offers a detailed understanding of the behavior of nanojars of various sizes and with different incarcerated anions in the presence of the above-mentioned compounds at varying concentrations and tests the limits of the pyrazolate/carboxylate structural analogy in multinuclear metal complexes. The results point to the possibility of obtaining functionalized nanojars via pyrazolate/carboxylate ligand exchange, an aid in the design of anion extraction processes using nanojars or similar complexes as extracting agents. PMID- 28816445 TI - Tracking the Progress and Mechanism Study of a Solvothermal in Situ Domino N Alkylation Reaction of Triethylamine and Ammonia Assisted by Ferrous Sulfate. AB - Atom economic in situ domino N-alkylation reactions of triethylamine/ammonia with 2-(hydroxymethyl)quinolin-8-ol (HL-OH) assisted by FeSO4.7H2O were realized under mild solvothermal conditions at 120 degrees C in acetonitrile. The resulting tripodal 2,2',2"-[nitrilotris(methylene)]tris(quinolin-8-ol) (H3L3-N) forms a linear trimer [Fe3(L3-N)2] (1). Electrospray ionization mass spectrometry of the reaction solution provides evidence for the intermediates of three steps, while crystallography and X-ray photoelectron spectroscopy characterize the trimer. Shortening the time of the reaction allowed for the organic intermediates to be isolated, which led to a proposed mechanism. The method provides a facile way to produce symmetric tertiary amine from widely used NEt3 and NH3. The results represent an example of the in situ Fe2+-catalyzed domino reaction in which Fe2+ is coordinated by the generated ligands and is involved in each step until the final cluster 1. PMID- 28816446 TI - Room Temperature Dissolution of Bulk Elemental Ni and Se for Solution Deposition of a NiSe2 HER Electrocatalyst. AB - With hydrogen fuel becoming a more viable alternative to fossil fuels comes the need for inexpensive, low-energy hydrogen production. Here, a low-temperature direct solution-processing method is presented for the deposition of earth abundant pyrite-type NiSe2 as an efficient hydrogen evolution reaction (HER) catalyst. Thin films of phase-pure NiSe2 are deposited from a precursor ink prepared by room-temperature dissolution of bulk elemental Ni and Se in a binary thiolamine solvent mixture. The nanostructured NiSe2 thin films demonstrate high HER catalytic activity with 100% Faradaic efficiency. PMID- 28816447 TI - Sequential Functionalizations of Carbohydrates Enabled by Boronic Esters as Switchable Protective/Activating Groups. AB - Processes for site-selective, sequential functionalizations of carbohydrate derivatives are described. In these processes, a tricoordinate boronic ester initially serves as a protective group for a sugar-derived 1,2- or 1,3-diol motif, permitting functionalization of free OH groups. In a second step, addition of a Lewis base generates a tetracoordinate adduct, which serves as an activating group, enabling functionalization of one of the boron-bound oxygen atoms by a second electrophile. By combining an initial acylation, alkylation, or glycosylation step with an amine-mediated glycosylation of the boronic ester, a variety of selectively protected di- and trisaccharide derivatives can be accessed in an operationally simple fashion without purification of intermediates. This Lewis base-triggered switching of behavior from "latent" to "active" nucleophile is a unique feature of boronic esters relative to other protective groups for diol moieties in carbohydrate chemistry. PMID- 28816448 TI - Metal-Free Oxidative C-C Coupling of Arylamines Using a Quinone-Based Organic Oxidant. AB - A variety of arylamines are shown to undergo oxidative C-C bond formation using quinone-based chloranil/H+ reagent as the recyclable organic (metal-free) oxidant system to afford benzidines/naphthidines. Arylamines (3 degrees /2 degrees ) designed with various substituents were employed to understand the steric as well as electronic preferences of oxidative dimerization, and a mechanism involving amine radical cation has been proposed. The tetraphenylbenzidine derivative obtained via oxidative C-C coupling has been further converted to blue-emissive hole-transporting material via a simple chemical transformation. This study highlights the preparation of novel HTMs in a simple, economic, and efficient manner. PMID- 28816450 TI - Facile Synthesis, Magnetic and Electric Characterization of Mixed Valence La0.75K0.25AMnTiO6 (A = Sr and Ba) Perovskites. AB - A new series of mixed valence perovskites, La0.75K0.25AMnTiO6 (A = Sr and Ba) nanocubes, have been synthesized by a mild hydrothermal route. From powder X-ray diffraction (XRD) analysis, the crystal structure of La0.75K0.25AMnTiO6 was solved as the orthorhombic symmetry (space group Pbnm) with a random A-site or B site arrangement. The phase purity of the products was confirmed by ICP, SEM, and EDS analyses, and the oxidation states of the B-site metal atoms were determined to be +4 for Ti and +3/+4 for Mn from XPS results. The soft ferromagnetic behavior is present in both samples. The Curie point TC has been detected as high as 309 K in La0.75K0.25SrMnTiO6 and 217 K in La0.75K0.25BaMnTiO6. A Griffiths phase can be observed at the high temperature region, which is related to the magnetic inhomogeneity induced by the existence of short-range ferromagnetic clusters. The resistivity measurements indicate that the semiconducting properties of the samples can be depicted better by variable range hopping (VRH) due to a diluted double-exchange interaction of Mn3+-O-Mn4+ with Ti4+ doping. PMID- 28816449 TI - Paralog Specificity Determines Subcellular Distribution, Action Mechanism, and Anticancer Activity of TRAP1 Inhibitors. AB - Although Hsp90 inhibitors can inhibit multiple tumorigenic pathways in cancer cells, their anticancer activity has been disappointingly modest. However, by forcing Hsp90 inhibitors into the mitochondria with mitochondrial delivery vehicles, they were converted into potent drugs targeting the mitochondrial Hsp90 paralog TRAP1. Here, to improve mitochondrial drug accumulation without using the mitochondrial delivery vehicle, we increased freely available drug concentrations in the cytoplasm by reducing the binding of the drugs to the abundant cytoplasmic Hsp90. After analyzing X-ray cocrystal structures, the purine ring of the Hsp90 inhibitor 2 (BIIB021) was modified to pyrazolopyrimidine scaffolds. One pyrazolopyrimidine, 12b (DN401), bound better to TRAP1 than to Hsp90, inactivated the mitochondrial TRAP1 in vivo, and it exhibited potent anticancer activity. Therefore, the rationale and feasible guidelines for developing 12b can potentially be exploited to design a potent TRAP1 inhibitor. PMID- 28816451 TI - Palladium-Catalyzed Cascade Assembly of Tricyclic Spiroethers from Diene-Alcohol Precursors. AB - Palladium-catalyzed carboetherification-Heck reactions to form tricyclic spiroethers, which are frequently observed as scaffold segments of various biochemical compounds, from simple diene-alcohols have been carried out in a cascade fashion. This is the first attempt to link simple alcohols with diverse, medium-sized spiroether architectures. The reported synthetic strategy is short and robust and offers rapid delivery of a broad spectrum of tricyclic spiranoid ethers. PMID- 28816452 TI - Active sp3 C-H Bond Oxidation Initiated sp3-sp2 Consecutive C-H Functionalization of N-Arylglycine Amides: Construction of Isatins. AB - In the presence of catalytic triarylamine radical cation, an sp3-sp2 consecutive C-H functionalization of N-arylglycine amides was achieved, providing a series of isatin derivatives in high yields. In this transformation, the initial aerobic oxidation of the relatively active sp3 C-H bonds triggered the following intramolecular cyclization, in which the aniline group was employed as a removable auxiliary group to enable the consecutive process. PMID- 28816453 TI - Modeling of Oligosaccharides within Glycoproteins from Free-Energy Landscapes. AB - In spite of the abundance of glycoproteins in biological processes, relatively little three-dimensional structural data is available for glycan structures. Here, we study the structure and flexibility of the vast majority of mammalian oligosaccharides appearing in N- and O-glycosylated proteins using a bottom up approach. We report the conformational free-energy landscapes of all relevant glycosidic linkages as obtained from local elevation simulations and subsequent umbrella sampling. To the best of our knowledge, this represents the first complete conformational library for the construction of N- and O-glycan structures. Next, we systematically study the effect of neighboring residues, by extensively simulating all relevant trisaccharides and one tetrasaccharide. This allows for an unprecedented comparison of disaccharide linkages in large oligosaccharides. With a small number of exceptions, the conformational preferences in the larger structures are very similar as in the disaccharides. This, finally, allows us to suggest several efficient approaches to construct complete N- and O-glycans on glycoproteins, as exemplified on two relevant examples. PMID- 28816454 TI - Syntheses of 4-(Heteroaryl)cyclohexanones via Palladium-Catalyzed Ester alpha Arylation and Decarboxylation. AB - An alternative synthesis of 4-(heteroaryl)cyclohexanones is described featuring a palladium-catalyzed ester alpha-arylation followed by decarboxylation. The substrate scope is broad with a wide range of heteroaryl halides. In particular, the reaction robustness is demonstrated by the synthesis of >10 g of 4-(pyrazin-2 yl)cyclohexanone with 85% overall yield. PMID- 28816455 TI - A Palladium-Catalyzed Monodearoylative Dimerization Approach for the Synthesis of [3]Dendralenes. AB - On treatment with Pd(OAc)2 and K2CO3, a variety of 3-aryl-2-(2-bromoallyl)-1,3 dicarbonyl compounds went through a monodearoylative dimerization reaction to provide polysubstituted [3]dendralenes in moderate to good isolated yields. PMID- 28816456 TI - The Elusive Paal-Knorr Intermediates in the Trofimov Synthesis of Pyrroles: Experimental and Theoretical Studies. AB - We have used isoxazolo[3,4-b]pyridin-3(1H)-one and isoxazolo[3,4-b]quinolin-3(1H) one as "masked" heterocyclic hydroxylamines to generate Paal-Knorr intermediates of the Trofimov pyrrole synthesis. The previously inaccessible intermediates, trapped by ethyl propiolate, were obtained by reacting corresponding isoxazolones with 4-fold excess of ethyl propiolate under basic conditions at ambient temperature, and characterized by means of IR and NMR spectroscopic data as well as by single crystal X-ray analysis. Quantum chemical calculations of a [3,3]sigmatropic rearrangement of the N,O-divinyl hydroxylamines to corresponding imino-aldehydes (Paal-Knorr intermediates) revealed that this reaction proceeds via chairlike transition state and is exothermic. PMID- 28816457 TI - A Coupled Cluster Investigation of SNO Radical Isomers and Their Reactions with Hydrogen Atom: Insight into Structures, Conformers, Barriers, and Energetics. AB - High-level coupled cluster theory with single and double excitation, and including a perturbative triples correction (CCSD(T)) method and a series of Dunning's augmented correlation consistent basis sets, aug-cc-pVXZ (X = D, T, Q, and 5) was applied to examine the conformational landscape of SNO radical system. The basis set has an important effect on the relative stability of SNO radical isomers; that is, at the CCSD(T)/aug-cc-pV5Z level of theory, the NSO radical is the most stable member of SNO radical family. This is in contrast to previous density functional theory prediction suggesting SNO radical is the most stable isomer. The CCSD(T)/aug-cc-pV5Z//CCSD(T)/aug-cc-pVTZ results suggest that the reaction between SNO radical isomers and hydrogen atom result in the formation of their [H,N,S,O] hydrides with HNSO hydrides being the most stable ones. Subsequently, these hydrides could decompose either into SH and NO radicals or into SN and OH radicals. The former pathway is preferred due to relatively lower barriers and favorable reaction energies. The results from our calculations support the role of S-nitrosothiols as NO shuttling agent in signaling-pathways and as a new source of HS and NO radicals in the lower atmosphere of Venus. Overall, these high-level calculations will play an important role in improving our understanding about the chemistry of S-nitrosothiols that has recently become a topic of interest because of their involvement in biochemical pathways and planetary processes. PMID- 28816458 TI - Pressure-Induced Emission Enhancement of Carbazole: The Restriction of Intramolecular Vibration. AB - Pressure-induced emission enhancement (PIEE), a novel phenomenon in the enhancement of the solid-state emission efficiency of fluorophores, has been arousing wide attention in recent years. However, research on PIEE is still in the early stage. To further pursue more enhanced efficiency, discovering and designing more PIEE systems would be urgently desirable and of great importance. In this Letter, we found that carbazole presented a conspicuous emission enhancement under high pressure up to 1.0 GPa. In situ high-pressure infrared spectroscopy and angle-dispersive X-ray diffraction analysis combined with Hirshfeld surface theory calculation indicated that the PIEE of carbazole was attributed to the decrease of the nonradiation vibration process. This phenomenon mainly resulted from restriction of the N-H stretching vibration by increased N H...pi interactions under high pressure. Our study puts forward a mechanism of PIEE related to the restriction of intramolecular vibration, which provided deep insight into the essential role of intermolecular interaction in fluorescence emission properties. PMID- 28816459 TI - Observation and Characterization of CH3CH2-MH, (CH2)2-MH2, CH2?CH-MH3, and CH3 C=MH3- Produced by Reactions of Group 5 Metal Atoms with Ethane. AB - The primary products in reactions of laser-ablated group 5 metal atoms with ethane were identified in argon matrix IR spectra and characterized via density functional theory computations. The second- and third-row transition metals Nb and Ta produced insertion, metallacyclopropane, vinyl trihydrido, and anionic ethylidyne complexes (CH3CH2-MH, (CH2)2-MH2, CH2?CH-MH3, and CH3C=MH3-), while the first-row transition metal V yielded only the insertion and metallacyclopropane products. The energetically higher ethylidenes and neutral ethylidynes (CH3CH?MH2 and CH3C[Formula: see text]MH3) were not detected. The unique anionic ethylidynes are the most stable anionic species in the Nb and Ta systems. Evidently back-donation from the metal center to the C-C pi* orbital is stronger than that in the group 6 metal analogue but weaker than that in the corresponding group 4 metal complex. The C-M bond for the Nb and Ta ethylidyne anions is a true triple bond. PMID- 28816460 TI - Coexistence of Pinning and Moving on a Contact Line. AB - Textured surfaces are instrumental in water repellency or fluid wicking applications, where the pinning and depinning of the liquid-gas interface plays an important role. Previous work showed that a contact line can exhibit nonuniform behavior due to heterogeneities in surface chemistry or roughness. We demonstrate that such nonuniformities can be achieved even without varying the local energy barrier. Around a cylindrical pillar, an interface can reside in an intermediate state where segments of the contact line are pinned to the pillar top while the rest of the contact line moves along the sidewall. This partially pinned mode is due to the global nonaxisymmetric pattern of the surface features and exists for all textured surfaces, especially when superhydrophobic surfaces are about to be flooded or when capillary wicks are close to dryout. PMID- 28816461 TI - Access to Cyclobutadienes via an Organocatalytic Dienamine-Iminium-Allenamine Cascade Approach. AB - A new organocatalytic route to cyclobutadienes from alpha,beta-unsaturated aldehydes and ynals is described. This protocol allows a broad substrate scope and mild conditions. Furthermore, a proposed mechanism of a dienamine-iminium allenamine cascade process is discussed. PMID- 28816462 TI - 1H-Detected REDOR with Fast Magic-Angle Spinning of a Deuterated Protein. AB - Rotational echo double resonance (REDOR) is a highly successful method for heteronuclear distance determination in biological solid-state NMR, and 1H detection methods have emerged in recent years as a powerful approach to improving sensitivity and resolution for small sample quantities by utilizing fast magic-angle spinning (>30 kHz) and deuteration strategies. In theory, involving 1H as one of the spins for measuring REDOR effects can greatly increase the distance measurement range, but few experiments of this type have been reported. Here we introduce a pulse sequence that combines frequency-selective REDOR (FSR) with 1H detection. We demonstrate this method with applications to samples of uniformly 13C,15N,2H-labeled alanine and uniformly 13C,2H,15N-labeled GB1 protein, back-exchanged with 30% H2O and 70% D2O, employing a variety of frequency-selective 13C pulses to highlight unique spectral features. The resulting, robust REDOR effects provide (1) tools for resonance assignment, (2) restraints of secondary structure, (3) probes of tertiary structure, and (4) approaches to determine the preferred orientation of aromatic rings in the protein core. PMID- 28816463 TI - Signaling-Related Mobility Changes in Bacterial Chemotaxis Receptors Revealed by Solid-State NMR. AB - Bacteria employ remarkable membrane-bound nanoarrays to sense their environment and direct their swimming. Arrays consist of chemotaxis receptor trimers of dimers that are bridged at their membrane-distal tips by rings of two cytoplasmic proteins, a kinase CheA and a coupling protein CheW. It is not clear how ligand binding to the periplasmic domain of the receptor deactivates the CheA kinase bound to the cytoplasmic tip ~300 A away, but the mechanism is thought to involve changes in dynamics within the cytoplasmic domain. To test these proposals, we applied solid-state NMR mobility-filtered experiments to functional complexes of the receptor cytoplasmic fragment (U-13C,15N-CF), CheA, and CheW. Assembly of these proteins into native-like, homogeneous arrays is mediated by either vesicle binding or molecular crowding agents, and paramagnetic relaxation enhancement is used to overcome sensitivity challenges in these large complexes. INEPT spectra reveal that a significant fraction of the receptor is dynamic on the nanosecond or shorter time scale, and these dynamics change with signaling state. The mobile regions are identified through a combination of biochemical and NMR approaches (protein truncations and unique chemical shifts). The INEPT spectra are consistent with an asymmetric mobility in the methylation region (N-helix mobility ? C-helix mobility) and reveal an increase in the mobility of the N helix in the kinase-off state. This finding identifies functionally relevant dynamics in the receptor, and suggests that this N-helix segment plays a key role in propagating the signal. PMID- 28816464 TI - Influence of father-infant relationship on infant development: A father involvement intervention in Vietnam. AB - We examined the extent to which fathers can be taught and encouraged to develop positive relationships with their children, especially in infancy, and the effects of this fathering intervention on infant development. A multifaceted relationally focused intervention was used to assist fathers in Vietnam to engage in responsive direct and indirect involvement with their infants and work together with the mother as part of a parenting team. Fathers and mothers from 13 communes in a rural and semiurban district were recruited to the intervention group. Intervention fathers received group and individual counseling before and after birth, an interactive print resource, community messages about fathering, and the opportunity to participate in a Fathers Club. Couples from 12 comparable communes in a noncontiguous district were recruited to the control group. Fathers and mothers completed questionnaires at the prebirth recruitment and at 1-, 4-, and 9-months postbirth. Intervention fathers demonstrated greater increase in knowledge and attitudes regarding father-infant relationships. Both fathers and mothers reported that fathers engaged in more affection, care-taking, and play in the early months of their infants' lives and fathers felt more attached to their infants right from birth. A developmental assessment at 9 months showed that intervention infants demonstrated higher levels of motor, language, and personal/social development. This study demonstrated that fathers can be taught to interact more sensitively, responsively, and effectively with their newborn infants. Their increased interaction and emotional attachment appears to lay the foundation for enhanced infant development. (PsycINFO Database Record PMID- 28816465 TI - On informing jurors of potential sanctions. AB - Two experiments tested (a) whether jurors make assumptions about the potential punishment that would follow from a guilty verdict, (b) whether those assumptions influence jurors' implicit threshold for reasonable doubt, and (c) whether informing jurors of the potential punishment additionally influences their implicit threshold. Experiment 1 manipulated the alleged crime (grand theft vs. manslaughter) holding all other factors constant, and found that mock jurors (n = 102, recruited via Amazon Mechanical Turk) had different expectations about the relative punishments but that these expectations did not affect their implicit threshold for reasonable doubt. Experiment 2 manipulated the alleged crime as well as a judicial description of the potential punishment (e.g., term of incarceration of 2-6 vs. 7-20 years). Again, mock jurors (n = 297) were sensitive to the relative punishments, yet their implicit threshold did not differ on this basis. These findings call into question whether jurors should be informed of the potential punishment if the defendant is convicted, an argument advanced by several legal scholars. (PsycINFO Database Record PMID- 28816466 TI - A comparison of psychopathology and reoffending in female and male convicted firesetters. AB - Little is known about the psychopathological or criminal history characteristics of female firesetters, or how often women reoffend by firesetting. The current study is one of the few large-scale longitudinal investigations to compare key psychiatric and offending variables in female and male firesetters who are not incarcerated or known to be mentally disordered. In addition, the study aimed to identify the base rate of recidivism for female firesetters compared with males. The study compared all 143 female and 909 male firesetters convicted of arson and fire-related offenses between 2000 and 2009 in Victoria, Australia. The study employed a data linkage approach to compare the psychiatric and criminal histories of participants and reoffending in the sample. Firesetters of both sexes reoffended by firesetting at similar rates (males 5.1%, females 7.0%), and reoffenders shared many characteristics. Compared with male firesetters, female firesetters were found to be less criminally versatile, to have offended less overall, and were less likely to have violent offenses. Females were more often diagnosed with depression, substance misuse, and personality disorder than men. The findings indicate that female firesetters might be suitable for assessment approaches and treatment programs offered to men, but tailored to take account of the personality and psychopathological characteristics seen more often in this group. (PsycINFO Database Record PMID- 28816467 TI - How sure are you that this is the man you saw? Child witnesses can use confidence judgments to identify a target. AB - We tested whether an alternative lineup procedure designed to minimize problematic influences (e.g., metacognitive development) on decision criteria could be effectively used by children and improve child eyewitness identification performance relative to a standard identification task. Five hundred sixteen children (6- to 13-year-olds) watched a video of a target reading word lists and, the next day, made confidence ratings for each lineup member or standard categorical decisions for 8 lineup members presented sequentially. Two algorithms were applied to classify confidence ratings into categorical decisions and facilitate comparisons across conditions. The classification algorithms produced accuracy rates for the confidence rating procedure that were comparable to the categorical procedure. These findings demonstrate that children can use a ratings based procedure to discriminate between previously seen and unseen faces. In turn, this invites more nuanced and empirical consideration of ratings-based identification evidence as a probabilistic index of guilt that may attenuate problematic social influences on child witnesses' decision criteria. (PsycINFO Database Record PMID- 28816468 TI - Student threat assessment as a standard school safety practice: Results from a statewide implementation study. AB - Threat assessment has been widely endorsed as a school safety practice, but there is little research on its implementation. In 2013, Virginia became the first state to mandate student threat assessment in its public schools. The purpose of this study was to examine the statewide implementation of threat assessment and to identify how threat assessment teams distinguish serious from nonserious threats. The sample consisted of 1,865 threat assessment cases reported by 785 elementary, middle, and high schools. Students ranged from pre-K to Grade 12, including 74.4% male, 34.6% receiving special education services, 51.2% White, 30.2% Black, 6.8% Hispanic, and 2.7% Asian. Survey data were collected from school-based teams to measure student demographics, threat characteristics, and assessment results. Logistic regression indicated that threat assessment teams were more likely to identify a threat as serious if it was made by a student above the elementary grades (odds ratio 0.57; 95% lower and upper bound 0.42 0.78), a student receiving special education services (1.27; 1.00-1.60), involved battery (1.61; 1.20-2.15), homicide (1.40; 1.07-1.82), or weapon possession (4.41; 2.80-6.96), or targeted an administrator (3.55; 1.73-7.30). Student race and gender were not significantly associated with a serious threat determination. The odds ratio that a student would attempt to carry out a threat classified as serious was 12.48 (5.15-30.22). These results provide new information on the nature and prevalence of threats in schools using threat assessment that can guide further work to develop this emerging school safety practice. (PsycINFO Database Record PMID- 28816469 TI - Evaluating suggestibility to additive and contradictory misinformation following explicit error detection in younger and older adults. AB - In 2 experiments, we assessed age-related suggestibility to additive and contradictory misinformation (i.e., remembering of false details from an external source). After reading a fictional story, participants answered questions containing misleading details that were either additive (misleading details that supplemented an original event) or contradictory (errors that changed original details). On a final test, suggestibility was greater for additive than contradictory misinformation, and older adults endorsed fewer false contradictory details than younger adults. To mitigate suggestibility in Experiment 2, participants were warned about potential errors, instructed to detect errors, or instructed to detect errors after exposure to examples of additive and contradictory details. Again, suggestibility to additive misinformation was greater than contradictory, and older adults endorsed less contradictory misinformation. Only after detection instructions with misinformation examples were younger adults able to reduce contradictory misinformation effects and reduced these effects to the level of older adults. Additive misinformation however, was immune to all warning and detection instructions. Thus, older adults were less susceptible to contradictory misinformation errors, and younger adults could match this misinformation rate when warning/detection instructions were strong. (PsycINFO Database Record PMID- 28816470 TI - Effects of postwarning specificity on memory performance and confidence in the eyewitness misinformation paradigm. AB - The influence of postevent misinformation on memory is typically constrained by postwarnings, but little is known about the effectiveness of particular features of postwarnings, such as their specificity. Experiment 1 compared 2 levels of postwarning specificity: A general postwarning just stated the presence of misinformation, whereas a specific postwarning identified the test items for which misinformation had been presented earlier. The specific postwarning, but not the general postwarning, eliminated both the misinformation effect and its deleterious impact on memory monitoring (using a classic 2-alternative forced choice recognition procedure). Experiment 2 ruled out an alternative interpretation of these findings and replicated this postwarning specificity pattern using a cued-recall test. We observed, in addition to the moderating influence of task representations on misinformation acceptance, 2 unexpected facilitative effects on event memory caused by misinformation. Misinformation facilitated event memory during narrative encoding if discrepancies between the event and the narrative were detected (Experiment 1) and during retrieval if a specific postwarning was combined with cued recall (Experiment 2). We interpret the facilitative effect of discrepancy detection within a recursive-remindings framework on noticing and recollecting change. (PsycINFO Database Record PMID- 28816471 TI - How much will the sea level rise? Outcome selection and subjective probability in climate change predictions. AB - We tested whether people focus on extreme outcomes to predict climate change and assessed the gap between the frequency of the predicted outcome and its perceived probability while controlling for climate change beliefs. We also tested 2 cost effective interventions to reduce the preference for extreme outcomes and the frequency-probability gap by manipulating the probabilistic format: numerical or dual-verbal-numerical. In 4 experiments, participants read a scenario featuring a distribution of sea level rises, selected a sea rise to complete a prediction (e.g., "It is 'unlikely' that the sea level will rise . . . inches") and judged the likelihood of this sea rise occurring. Results showed that people have a preference for predicting extreme climate change outcomes in verbal predictions (59% in Experiments 1-4) and that this preference was not predicted by climate change beliefs. Results also showed an important gap between the predicted outcome frequency and participants' perception of the probability that it would occur. The dual-format reduced the preference for extreme outcomes for low and medium probability predictions but not for high ones, and none of the formats consistently reduced the frequency-probability gap. (PsycINFO Database Record PMID- 28816472 TI - How should exemplars be sequenced in inductive learning? Empirical evidence versus learners' opinions. AB - The sequencing of exemplars during study can have a large effect on category or concept induction. Counter to learners' intuitions, interleaving exemplars from different categories is often more effective for learning the different underlying categories than is blocking all the exemplars by category (e.g., Kornell & Bjork, 2008). Prior research suggests that blocking and interleaving each support different aspects of induction: Interleaving appears to enhance between-category discrimination, whereas blocking appears to promote the learning of within-category commonalities. In Experiments 1 and 2, participants studied paintings by 12 artists and were asked to induce the different artists' painting styles. We explored whether hybrid schedules can leverage the benefits of both types of schedules, comparing blocked, interleaved, and 3 hybrid schedules blocked-to-interleaved, interleaved-to-blocked, and miniblocks. The miniblocks and blocked-to-interleaved schedules were as effective, statistically, but not better than pure interleaving. The blocked schedule led to the worst performance. In Experiments 3 and 4, we explored participants' a priori beliefs by having them self-schedule hypothetical future category-learning tasks. Although participants demonstrated some metacognitive sophistication with respect to the relative benefits of blocked and interleaved study, pure interleaving was the least popular schedule, despite its being one of the most, effective schedules for learning. (PsycINFO Database Record PMID- 28816473 TI - The effects of context on processing words during sentence reading among adults varying in age and literacy skill. AB - The facilitation of word processing by sentence context reflects the interaction between the build-up of message-level semantics and lexical processing. Yet, little is known about how this effect varies through adulthood as a function of reading skill. In this study, Participants 18-64 years old with a range of literacy competence read simple sentences as their eye movements were monitored. We manipulated the predictability of a sentence-final target word, operationalized as cloze probability. First fixation durations showed an interaction between age and literacy skill, decreasing with age among more skilled readers but increasing among less skilled readers. This pattern suggests that age-related slowing may impact reading when not buffered by skill, but with continued practice, automatization of reading can continue to develop in adulthood. In absolute terms, readers were sensitive to predictability, regardless of age or literacy, in both early and later measures. Older readers showed differential contextual sensitivity in regression patterns, effects not moderated by literacy skill. Finally, comprehension performance increased with age and literacy skill, but performance among less skilled readers was especially reduced when predictability was low, suggesting that low-literacy adults (regardless of age) struggle when creating mental representations under weaker semantic constraints. Collectively, these findings suggest that aging readers (regardless of reading skill) are more sensitive to context for meaning integration processes; that less skilled adult readers (regardless of age) depend more on a constrained semantic representation for comprehension; and that the capacity for literacy engagement enables continued development of efficient lexical processing in adult reading development. (PsycINFO Database Record PMID- 28816474 TI - Deficits in category learning in older adults: Rule-based versus clustering accounts. AB - Memory research has long been one of the key areas of investigation for cognitive aging researchers but only in the last decade or so has categorization been used to understand age differences in cognition. Categorization tasks focus more heavily on the grouping and organization of items in memory, and often on the process of learning relationships through trial and error. Categorization studies allow researchers to more accurately characterize age differences in cognition: whether older adults show declines in the way in which they represent categories with simple rules or declines in representing categories by similarity to past examples. In the current study, young and older adults participated in a set of classic category learning problems, which allowed us to distinguish between three hypotheses: (a) rule-complexity: categories were represented exclusively with rules and older adults had differential difficulty when more complex rules were required, (b) rule-specific: categories could be represented either by rules or by similarity, and there were age deficits in using rules, and (c) clustering: similarity was mainly used and older adults constructed a less-detailed representation by lumping more items into fewer clusters. The ordinal levels of performance across different conditions argued against rule-complexity, as older adults showed greater deficits on less complex categories. The data also provided evidence against rule-specificity, as single-dimensional rules could not explain age declines. Instead, computational modeling of the data indicated that older adults utilized fewer conceptual clusters of items in memory than did young adults. (PsycINFO Database Record PMID- 28816477 TI - Transition from feature-search to singleton-detection strategies in visual search: The role of number of target-defining options. AB - When searching for a uniquely colored target in an RSVP stream of homogeneously colored nontarget items, observers can use singleton-detection and/or feature search modes. Using an attentional-capture paradigm, we varied systematically (a) the number of possible target colors from 1 to 4 and (b) the presence or absence of a colored ring surrounding the nontarget item displayed 200 ms before the target. When present, the ring was either the same color as 1 of the possible targets (color-match), or an irrelevant color (color-mismatch). Capture was measured as the impairment in target identification accuracy when the ring was present relative to when it was absent. Greater capture in the color-match than in the color-mismatch condition was regarded as evidence of feature-search mode. Capture in the color-mismatch condition was regarded as evidence for singleton detection mode. We show that, as the number of target colors is increased, the relative prominence of feature-search mode decreases, and that of singleton detection mode increases correspondingly. This novel finding shows that, when both feature-search and singleton-detection modes are possible, at least some degree of feature-search mode is used until the number of possible target defining colors reaches about 4. This suggests that the weight assigned to singleton-detection mode increases, and that assigned to feature-search mode decreases correspondingly, as the difficulty of maintaining the target-defining features in mind is increased. (PsycINFO Database Record PMID- 28816475 TI - The role of stimulus complexity and salience in memory for face-name associations in healthy adults: Friend or foe? AB - The associative deficit hypothesis (ADH) posits that age-related differences in recognition of associations are disproportionately larger than age differences in item recognition because of age-related difficulty in binding and retrieval of two or more pieces of information in a memory episode. This proposition rests on the observation of disproportionately greater age differences in memory for associations than in recognition of individual items. Although ADH has been supported in experiments with verbal and nonverbal stimuli, the effects of task or stimulus characteristics on its generalizability remain unclear. In a series of experiments, we examined how salience and variability of face stimuli presented in face-name pairs affect age differences in recognition of items and associations. We found that a disproportionate age-related deficit in the recognition of face-name associations emerges when face stimuli are more complex, salient, variable, and distinctive, but not when standardized faces appear within minimal visual context. These findings indicate that age-related associative memory deficits may stem at least in part from age differences in use of stimulus characteristics for contextual support. (PsycINFO Database Record PMID- 28816476 TI - Benefits of flexible prioritization in working memory can arise without costs. AB - Most recent models conceptualize working memory (WM) as a continuous resource, divided up according to task demands. When an increasing number of items need to be remembered, each item receives a smaller chunk of the memory resource. These models predict that the allocation of attention to high-priority WM items during the retention interval should be a zero-sum game: improvements in remembering cued items come at the expense of uncued items because resources are dynamically transferred from uncued to cued representations. The current study provides empirical data challenging this model. Four precision retrocueing WM experiments assessed cued and uncued items on every trial. This permitted a test for trade off of the memory resource. We found no evidence for trade-offs in memory across trials. Moreover, robust improvements in WM performance for cued items came at little or no cost to uncued items that were probed afterward, thereby increasing the net capacity of WM relative to neutral cueing conditions. An alternative mechanism of prioritization proposes that cued items are transferred into a privileged state within a response-gating bottleneck, in which an item uniquely controls upcoming behavior. We found evidence consistent with this alternative. When an uncued item was probed first, report of its orientation was biased away from the cued orientation to be subsequently reported. We interpret this bias as competition for behavioral control in the output-driving bottleneck. Other items in WM did not bias each other, making this result difficult to explain with a shared resource model. (PsycINFO Database Record PMID- 28816478 TI - Towards a unified model of vision and attention: Effects of visual landmarks and identity cues on covert and overt attention movements. AB - To what extent are shifts of attention driven by encoding of visual-spatial landmarks, associated with useful locations, or by encoding of environmental cues that act as symbolic representations, providing information about where to look next? In Experiment 1 we found that when cues were presented with a long exposure time (300 ms) attention shifts were driven by the symbolic identity of cue stimuli, independently of their visual-spatial (landmark) features; but when cues were exposed very briefly, (66 ms), attention shifts were independent of symbolic information, and were driven instead by visual landmark features. This unexpected finding was interpreted in terms of the transient and sustained response characteristics of the M-cell and P-cell inputs to the dorsal and ventral visual streams, respectively, and informed our theoretical proposal that attentional effects elicited by visual-spatial landmarks may be driven by dorsal stream ("where pathway") encoding; while attentional effects driven by the symbolic identity of cues may be driven by ventral stream ("what pathway") encoding. Detailed predictions derived from this proposal, and based on distinct physiological properties of the 2 visual streams were tested and confirmed in Experiments 2-6. Our results suggest that a 2-process view of attention shifting can be integrated with dual-stream models of vision. According to this unified theory: (a) Landmarks associated with visually useful locations elicit rapid, nonconscious shifts of attention, via nonsemantic, dorsal visual stream encoding of their features and spatial relationships; (b) Slower, endogenous shifts of attention are elicited by ventral visual stream encoding of symbolic-semantic information. (PsycINFO Database Record PMID- 28816479 TI - Alternation blindness in the representation of binary sequences. AB - Binary information is prevalent in the environment and contains 2 distinct outcomes. Binary sequences consist of a mixture of alternation and repetition. Understanding how people perceive such sequences would contribute to a general theory of information processing. In this study, we examined how people process alternation and repetition in binary sequences. Across 4 paradigms involving estimation, working memory, change detection, and visual search, we found that the number of alternations is underestimated compared with repetitions (Experiment 1). Moreover, recall for binary sequences deteriorates as the sequence alternates more (Experiment 2). Changes in bits are also harder to detect as the sequence alternates more (Experiment 3). Finally, visual targets superimposed on bits of a binary sequence take longer to process as alternation increases (Experiment 4). Overall, our results indicate that compared with repetition, alternation in a binary sequence is less salient in the sense of requiring more attention for successful encoding. The current study thus reveals the cognitive constraints in the representation of alternation and provides a new explanation for the overalternation bias in randomness perception. (PsycINFO Database Record PMID- 28816480 TI - Superior olfactory language and cognition in odor-color synaesthesia. AB - Olfaction is often considered a vestigial sense in humans, demoted throughout evolution to make way for the dominant sense of vision. This perspective on olfaction is reflected in how we think and talk about smells in the West, with odor imagery and odor language reported to be difficult. In the present study we demonstrate odor cognition is superior in odor-color synaesthesia, where there are additional sensory connections to odor concepts. Synaesthesia is a neurological phenomenon in which input in 1 modality leads to involuntary perceptual associations. Semantic accounts of synaesthesia posit synaesthetic associations are mediated by activation of inducing concepts. Therefore, synaesthetic associations may strengthen conceptual representations. To test this idea, we ran 6 odor-color synaesthetes and 17 matched controls on a battery of tasks exploring odor and color cognition. We found synaesthetes outperformed controls on tests of both odor and color discrimination, demonstrating for the first time enhanced perception in both the inducer (odor) and concurrent (color) modality. So, not only do synaesthetes have additional perceptual experiences in comparison to controls, their primary perceptual experience is also different. Finally, synaesthetes were more consistent and accurate at naming odors. We propose synaesthetic associations to odors strengthen odor concepts, making them more differentiated (facilitating odor discrimination) and easier to link with lexical representations (facilitating odor naming). In summary, we show for the first time that both odor language and perception is enhanced in people with synaesthetic associations to odors. (PsycINFO Database Record PMID- 28816481 TI - Individuals' eye movements in reading are highly consistent across time and trial. AB - Eye movements are used to study a variety of cognitive phenomena, including attention, perception, memory, language, reading, decision making, and many others, as well as cognitive impairments and individual differences in cognition. These studies assume, with little evidence, that eye movements are stable across time and trials. Eye movement stability must be better characterized to understand the full theoretical and clinical implications of individual differences in eye movement behavior. The present study examined eye movement reliability in normal individuals during reading. Thirty-nine participants completed 2 sessions of a reading task separated by 1 month. Means and standard deviations of fixation duration, saccade amplitude, first fixation duration, gaze duration, total time, go-past time, skipping, refixation and regression probabilities were compared both between sessions and across trials within sessions. All correlations were highly significant, indicating that eye movement behaviors are stable within individuals across several weeks and highly stable across trials within each individual. The different components of the ex-Gaussian distribution of fixation durations were also highly stable over time. Differences in sensitivity to lexical variables (frequency, predictability, length) were also compared, and were also observed to be highly stable across time. Eye movements in reading are therefore suitable for studying cognition and its neural underpinnings, as well as cognitive development and longitudinal change. Theoretical and clinical implications of these findings are discussed. (PsycINFO Database Record PMID- 28816482 TI - Same-location costs in peripheral cueing: The role of cue awareness and feature changes. AB - Prior studies using the peripheral cueing paradigm have shown that singleton cues that do not match to the top-down search settings of the observer can impair performance in visual search when the cue appears at the target location (in valid conditions) compared with when the cue appears at a location away from the target (in invalid conditions). This pattern, the same-location cost (SLC), has recently been suggested to originate from an awareness-dependent updating of object files in working memory. It has also been argued that the processes underlying the SLC could have obscured results of prior studies by masking attentional capture effects by peripheral cues under certain conditions. Here, we investigated to which extent the object-file updating hypothesis can be generalized and delineate necessary side conditions for object-file updating to produce the SLC. In Experiments 1 to 3, we show that during search for spatial frequencies, SLCs emerged that are at odds with the object-file updating hypothesis. SLCs were not dependent on cue awareness and were, unlike SLCs with color cues and targets (Experiment 4), not entirely eliminated where feature updating was necessary in valid and invalid conditions. We conclude that some instances of the SLC can be explained by object-file updating, but, as the present study shows, other instances of the SLC are at odds with this explanation and are therefore more likely of an attentional origin. We end with a discussion of which side conditions might favor the emergence of SLCs as a result of object file updating. (PsycINFO Database Record PMID- 28816483 TI - Effect of travel speed on the visual control of steering toward a goal. AB - Previous studies have proposed that people can use visual cues such as the instantaneous direction (i.e., heading) or future path trajectory of travel specified by optic flow or target visual direction in egocentric space to steer or walk toward a goal. In the current study, we examined what visual cues people use to guide their goal-oriented locomotion and whether their reliance on such visual cues changes as travel speed increases. We presented participants with optic flow displays that simulated their self-motion toward a target at various travel speeds under two viewing conditions in which we made target egocentric direction available or unavailable for steering. We found that for both viewing conditions, participants did not steer along a curved path toward the target such that the actual and the required path curvature to reach the target would converge when approaching the target. At higher travel speeds, participants showed a faster and larger reduction in target-heading angle and more accurate and precise steady-state control of aligning their heading specified by optic flow with the target. These findings support the claim that people use heading and target egocentric direction but not path for goal-oriented locomotion control, and their reliance on heading increases at higher travel speeds. The increased reliance on heading for goal-oriented locomotion control could be due to an increased reliability in perceiving heading from optic flow as the magnitude of flow increases with travel speed. (PsycINFO Database Record PMID- 28816484 TI - Implementation and evaluation of a parenting program to prevent child maltreatment in Suriname. AB - The prevention of child maltreatment has become a global health concern because child maltreatment is a violation of children's rights. Across the world, a variety of parenting programs have been developed to address this problem. However, no such parenting program currently exists in Suriname. This pilot study aimed to implement Lobi Mi Pikin (LMP) parenting program in Suriname and to evaluate its effects on corporal punishment (CP) and child behavioral problems. Parents-caregivers (N = 70) of children (ages 3-12 years) with externalizing behavioral problems participated in a protocoled parenting program. The child's behavioral problems and the parenting style of the parent-caregiver were assessed using the Strengths and Difficulties Questionnaire and the Parental Behavior Scale, pretreatment and posttreatment. Five-week follow-up measures revealed significant positive effects of LMP on all outcome measures. Follow-up comparisons demonstrated (a) a large reduction of total child difficulties and conduct problems, (b) a moderate reduction of hyperactivity and emotional problems, (c) a moderate to large increase in the self-reported positive behavior of the parent, and (d) a small decrease in the use of CP. This study provides preliminary evidence that LMP may be an effective model of parent training in Suriname. Moreover, it can help guide efforts to reduce the use of CP and encourage positive parenting, thereby preventing child maltreatment. (PsycINFO Database Record PMID- 28816485 TI - Risks, resources, and depressive symptomatology among Marshallese adolescents. AB - This study examined risks and resources to assess depressive symptom variation among a sample of Marshallese adolescents attending a Northwest Arkansas high school. A self-administered questionnaire was completed by 10th-12th-grade students (N = 1,493). With a general response rate in excess of 78%, the subsample (n = 208) represented 75% of all Marshallese students attending the high school and approximately 9% of the total K-12 Marshallese population. Average depressive symptom (CES-D) scores for Marshallese adolescents were 17.3; high enough to exceed the clinical caseness cut-off (16+) typically used as an evaluative criteria. Regression results found females and students who self identified in lower social class categories reported more depressive symptoms than males and self-identified higher-class students. Marshallese students with poorer grades, higher exposure to school risks, and higher exposure to gangs reported more depressive symptoms; social (friends) and psychological (self esteem) resources were both significant and negative in their association with depressive symptoms. These results represented the first comprehensive examination of depressive symptomatology among Marshallese adolescents living anywhere in the continental United States. Findings were discussed in the context of significance for clinical interventions at school and community levels. (PsycINFO Database Record PMID- 28816486 TI - Father support and adjustment difficulties among youth in residential care: The moderating role of peer victimization and gender. AB - Father support of young people living in out-of-home settings is a neglected area of research. The study examines the moderating role of peer victimization in the association between father support and adjustment difficulties among male and female adolescents in residential care settings. Using random cluster sampling, the study includes the reports of 1,409 young people, in Grades 8 to 12, residing in 16 Israeli educational residential care settings designed for youth from underprivileged backgrounds. The findings show that, on average, fathers are highly involved in these young people's lives. They also show that male adolescents, adolescents whose parents are married, Israeli-born adolescents, and those whose fathers have higher education levels have higher levels of father support. Father support is negatively associated with adjustment difficulties. A significant interaction was found between peer victimization, father support, and gender in predicting adjustment difficulties. Among boys who had experienced peer victimization at any point during their lives, the findings show a significant negative association between father support and adjustment difficulties. For boys who had never experienced peer victimization, the association was statistically insignificant. For girls, the picture revealed is different; for those who had experienced peer victimization, the level of father support was insignificantly linked with adjustment difficulties. For girls who had never experienced peer victimization, there was a significant association between increased father support and reduced adjustment difficulties. These findings shed light on ways in which father support is beneficial to young people in residential care, with implications for child welfare and education professionals. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 28816487 TI - Associations between bullying involvement, protective factors, and mental health among American Indian youth. AB - Bullying involvement as a victim or perpetrator is associated with depression and suicidality, and American Indian (AI) youth experience a disproportionately high rate of these mental health issues. This study assessed whether AI young people involved in bullying were more likely to experience negative mental health problems than AI youth who were not involved in bullying, and identified protective factors that might support this particularly vulnerable population. Data come from 1,409 8th, 9th, and 11th Grade AI students who completed the 2013 Minnesota Student Survey. Logistic regression models estimated associations between bullying involvement and internalizing symptoms and suicidality. Selected protective factors (internal assets, empowerment, positive student-teacher relationships, and feeling safe at school) were also examined as independent variables. All forms of bullying perpetration and victimization were associated with increased risk for mental health problems (odds ratio [OR]: 1.57-2.87). AI youth who reported higher levels of protective factors were less likely to report internalizing symptoms and suicidality even in the presence of bullying involvement. For example, AI youth who reported high levels of internal assets had half the odds of reporting internalizing symptoms compared with those with low levels of internal assets (OR = 0.53, confidence interval [CI] 0.38, 0.74). Findings suggest that, similar to a general sample of students, bullying-involved AI students are significantly more likely to experience mental health problems. Promoting school as a safe place and incorporating culturally relevant programming to promote internal assets such as positive identity, social competence, and empowerment among AI students could help reduce the negative effects of bullying involvement. (PsycINFO Database Record PMID- 28816489 TI - The path to an autism spectrum disorders diagnosis in Ethiopia: Parent perspective. AB - This study explores the common characteristics of children with autism spectrum disorders (ASDs) and the available diagnostic and intervention currently practiced for children with ASDs in Ethiopia based on parents' experience. Data gathered from 100 parents in Ethiopia detail the difficulties families face when they suspect their child has an autism spectrum disorder (ASD). The data indicate Ethiopian parents pursued a diagnosis of ASD after noting common ASD behaviors such as hand flapping and unusual attachments to objects. Poor social interactions were the least likely to symptoms to prompt an ASD evaluation. The large majority of parents indicated they were unaware of the services provided to their children and indicated poor parent-agency coordination. Parents noted very limited formal support systems to help cope with the stigma of having a child with ASD. Implication for future research and intervention are discussed. (PsycINFO Database Record PMID- 28816488 TI - Direct and indirect effects of child abuse and environmental stress: A lifecourse perspective on adversity and depressive symptoms. AB - There is a great deal of evidence about the mental health implications of physical child abuse and environmental stressors, or hardships that people experience at the household and neighborhood level (e.g., neighborhood violence; economic hardship, substance abuse, or conflict among family members). Yet, studies often focus on either abuse or environmental stress, not both, or examine abuse and environmental stressors as a combined set of experiences. Less is known, therefore, about how child abuse and environmental stress might work as either distinct or interrelated risks to diminish mental health over time. In this longitudinal study, we used path analyses to examine the cumulative effects of physical child abuse and environmental stressors on adult depressive symptoms among a sample of children followed into adulthood (N = 356). The goal was to assess whether chronic physical child abuse remains an independent predictor of adult outcomes once we accounted for the cumulative effects of household and neighborhood stressors across the lifecourse. Cumulative measures of physical child abuse and environmental stress each independently predicted a higher likelihood of adult depressive symptoms (beta = .122, p < .01 and beta = .283, p < .001, respectively). After accounting for adolescent depressive symptoms, only cumulative environmental stressors independently predicted depressive symptoms (beta = .202, p < .001). Tests of the indirect effect of cumulative environmental stress on the relationship between cumulative physical abuse and adult depressive symptoms were marginally statistically significant. Results add to literature that examines child abuse, adversity, and lifecourse perspectives on health. (PsycINFO Database Record PMID- 28816490 TI - Evaluation of the effects of receiving trauma-informed practices on domestic violence shelter residents. AB - Domestic violence is a potentially traumatizing experience that has devastating psychological and physical consequences. In response, domestic violence shelter programs have focused increasing attention on helping adult and child survivors understand and heal from this trauma. What have come to be called trauma-informed practices include (a) reflecting an understanding of trauma and its many effects on health and behavior, (b) addressing both physical and psychological safety concerns, (c) using a culturally informed strengths-based approach, (d) helping to illuminate the nature and effects of abuse on survivors' everyday experience; and (e) providing opportunities for clients to regain control over their lives. Despite the proliferation of these practices, little is known about their effects on survivors. In response, the current study explored the extent to which trauma informed practices, as experienced by shelter residents, related to changes in their levels of self-efficacy, safety-related empowerment, and depressive symptoms over the course of approximately 30 days in shelter. Fifty-seven shelter residents from 4 programs in Ohio completed surveys shortly after arriving in shelter and again before exit. Their perception of the degree to which they received trauma-informed services was associated with significant improvement in their self-efficacy and safety-related empowerment, but had no impact on depressive symptoms. Depressive symptoms decreased over time, regardless of receipt of trauma-informed practice. Implications for policy and practice are discussed. (PsycINFO Database Record PMID- 28816491 TI - Promoting justice or perpetuating prejudice? Interrupting external motivation in multicultural training. AB - The effects of responding to social pressure (external motivation) are short lived. Multicultural training, however, seeks to promote change in students and trainees that will be transformative and long-lasting. To this end, understanding the motivational factors that inform training is key. The present study was an investigation of the factors underlying external motivation to respond without prejudice for White individuals from the perspective of Higgins's regulatory focus (promotion and prevention) and regulatory mode (assessment and locomotion) theories. The results indicate that locomotion was negatively associated with external motivation to respond without prejudice, while assessment and prevention were positively associated with external motivation. Taken together, findings highlight the importance of cultivating locomotion (action oriented) motivation and inhibiting prevention (loss oriented) and assessment (preoccupation with finding the correct answer) motivations in multicultural training. Implications for training, effective action for justice, and future research are discussed. (PsycINFO Database Record PMID- 28816493 TI - Consequences, norms, and generalized inaction in moral dilemmas: The CNI model of moral decision-making. AB - Research on moral dilemma judgments has been fundamentally shaped by the distinction between utilitarianism and deontology. According to the principle of utilitarianism, the moral status of behavioral options depends on their consequences; the principle of deontology states that the moral status of behavioral options depends on their consistency with moral norms. To identify the processes underlying utilitarian and deontological judgments, researchers have investigated responses to moral dilemmas that pit one principle against the other (e.g., trolley problem). However, the conceptual meaning of responses in this paradigm is ambiguous, because the central aspects of utilitarianism and deontology-consequences and norms-are not manipulated. We illustrate how this shortcoming undermines theoretical interpretations of empirical findings and describe an alternative approach that resolves the ambiguities of the traditional paradigm. Expanding on this approach, we present a multinomial model that allows researchers to quantify sensitivity to consequences (C), sensitivity to moral norms (N), and general preference for inaction versus action irrespective of consequences and norms (I) in responses to moral dilemmas. We present 8 studies that used this model to investigate the effects of gender, cognitive load, question framing, and psychopathy on moral dilemma judgments. The findings obtained with the proposed CNI model offer more nuanced insights into the determinants of moral dilemma judgments, calling for a reassessment of dominant theoretical assumptions. (PsycINFO Database Record PMID- 28816492 TI - Discrimination and symptoms of obsessive-compulsive disorder among African Americans. AB - This study examined symptoms of obsessive-compulsive disorder (OCD) in a nationally representative sample of African American adults (n = 3,570) and correlations between OCD symptom dimensions and experiences of discrimination. Two categories of discrimination were examined, everyday racial discrimination and everyday nonracial discrimination (e.g., because of gender, age, and weight), to determine if racial discrimination had a unique impact on OCD symptoms. Results indicated that everyday racial discrimination was related to both categories of obsessions and all 4 categories of compulsions. Everyday nonracial discrimination, however, was not related to any of the categories of obsessions or compulsions. This indicates that racial discrimination is uniquely related to obsessions and compulsions for African Americans. The implications of these findings are discussed. (PsycINFO Database Record PMID- 28816495 TI - Inclusion of Gaming Disorder in ICD has more advantages than disadvantages. AB - This paper is a response to a recent debate paper in which Aarseth et al. argue that the inclusion of a formal diagnosis and categories for problematic video gaming or Gaming Disorder (GD) in the World Health Organization's 11th Revision of the International Classification of Diseases (ICD-11) is premature and therefore the proposal should be removed. The present authors systematically address all the six main arguments presented by Aarseth et al. and argue that, even though some of the concerns presented in the debate paper are legitimate, the inclusion of GD in ICD-11 has more advantages than disadvantages. Furthermore, the present authors also argue that the two GD subtypes ("GD, predominantly online" and "GD, predominantly offline") are unnecessary and rather problematic; the main category for GD would be perfectly sufficient. PMID- 28816494 TI - Gaming disorder: Its delineation as an important condition for diagnosis, management, and prevention. AB - Online gaming has greatly increased in popularity in recent years, and with this has come a multiplicity of problems due to excessive involvement in gaming. Gaming disorder, both online and offline, has been defined for the first time in the draft of 11th revision of the International Classification of Diseases (ICD 11). National surveys have shown prevalence rates of gaming disorder/addiction of 10%-15% among young people in several Asian countries and of 1%-10% in their counterparts in some Western countries. Several diseases related to excessive gaming are now recognized, and clinics are being established to respond to individual, family, and community concerns, but many cases remain hidden. Gaming disorder shares many features with addictions due to psychoactive substances and with gambling disorder, and functional neuroimaging shows that similar areas of the brain are activated. Governments and health agencies worldwide are seeking for the effects of online gaming to be addressed, and for preventive approaches to be developed. Central to this effort is a need to delineate the nature of the problem, which is the purpose of the definitions in the draft of ICD-11. PMID- 28816496 TI - ICD-11 Gaming Disorder: Needed and just in time or dangerous and much too early? AB - In their debate contribution, Aarseth et al. (2016) strongly argue against the proposal of WHO ICD-11 (International Classification of Diseases, 11th revision) to include Gaming Disorder as a new diagnostic category emphasizing the fact that no consensus exists on the definition and the risk that gaming will be demonized and gamers stigmatized resulting in a tsunami of false positive referrals to treatment. In this commentary, it is argued that gaming is indeed just another relatively innocent recreational activity with only a small minority losing control resulting in gaming-related problems. It is also argued that - despite a lack of full consensus on the diagnostic criteria - there are clear indications that Gaming Disorder is a relevant clinical entity worldwide and that official recognition as a mental disorder is urgently needed to facilitate the further development, accessibility, and reimbursement of the treatment. PMID- 28816497 TI - Inclusion of gaming disorder criteria in ICD-11: A clinical perspective in favor. AB - Data from a specialist treatment facility for Internet addiction (IA) in Japan showed that (a) the vast majority of treatment seekers are addicted to online games, (b) their symptoms are often quite severe, and (c) there is a significant demand for IA treatment. In addition, systemic obstacles to the delivery of medical services in Japan exist due to the exclusion of IA criteria from ICD-10. Consequently, the inclusion of GD criteria in ICD-11 will almost certainly increase the capacity and quality of treatment through advances in research and possible changes in national medical systems to meet treatment demand. PMID- 28816498 TI - The relationship between gaming disorder and addiction requires a behavioral analysis. AB - In their position paper, Aarseth et al. (2016) bring to light several timely issues concerning the categorization of gaming disorder as a form of addiction and as a discrete mental disorder. In our commentary, we welcome their caution toward this move and their discussion of the equivocal scientific data in its support and the potential negative consequences for gamers. We suggest that a more heterogeneous approach is required for understanding any behavioral addiction, as concepts from gambling appear to be more relevant for aspects of mobile gaming than for video games more generally. In addition to a greater need for clinical research, we argue that studying gaming at a different level of analysis than the epidemiological study is required to gain a meaningful understanding of the harm video games may or may not entail. PMID- 28816499 TI - Inclusion of gaming disorder in the diagnostic classifications and promotion of public health response. AB - There are ongoing controversies regarding the upcoming ICD-11 concept of gaming disorder. Recently, Aarseth et al. have put this diagnostic entity into scrutiny. Although we, a group of Iranian researchers and clinicians, acknowledge some of Aarseth et al.'s concerns, believe that the inclusion of gaming disorder in the upcoming ICD-11 would facilitate necessary steps to raise public awareness, enhance development of proper diagnostic approaches and treatment interventions, and improve health and non-health policies. PMID- 28816500 TI - Research Challenges in Financial Data Modeling and Analysis. AB - Significant research challenges must be addressed in the cleaning, transformation, integration, modeling, and analytics of Big Data sources for finance. This article surveys the progress made so far in this direction and obstacles yet to be overcome. These are issues that are of interest to data driven financial institutions in both corporate finance and consumer finance. These challenges are also of interest to the legal profession as well as to regulators. The discussion is relevant to technology firms that support the growing field of FinTech. PMID- 28816501 TI - Problematic gaming exists and is an example of disordered gaming. AB - Background The recent paper by Aarseth et al. (2016) questioned whether problematic gaming should be considered a new disorder particularly because "Gaming Disorder" (GD) has been identified as a disorder to be included in the next (11th) revision of the World Health Organization's International Classification of Diseases (ICD-11). Methods This study uses contemporary literature to argue why GD should be included in the ICD-11. Results Aarseth and colleagues acknowledge that there is much literature (including papers by some of the authors themselves) that some individuals experience serious problems with video gaming. How can such an activity be seriously problematic yet not disordered? Similar to other addictions, gaming addiction is relatively rare and is in essence a syndrome (i.e., a condition or disorder characterized by a set of associated symptoms that tend to occur under specific circumstances). Consequently, not everyone will exhibit exactly the same set of symptoms and consequences, and this partly explains why those working in the problematic gaming field often disagree on symptomatology. Conclusions Research into gaming is not about pathologizing healthy entertainment, but about pathologizing excessive and problematic behaviors that cause significant psychological distress and impairment in an individual's life. These are two related, but (ultimately) very distinct phenomena. While being aware that gaming is a pastime activity which is enjoyed non-problematically by many millions of individuals worldwide, it is concluded that problematic gaming exists and that it is an example of disordered gaming. PMID- 28816502 TI - Cost of malingering mild traumatic brain injury-related cognitive deficits during compensation and pension evaluations in the veterans benefits administration. AB - Given the high rates of exaggeration in those claiming long-term cognitive deficits as a result of mild traumatic brain injury (mTBI), the aim of this study was to evaluate the rates of malingering in those seeking disability through the Veterans Benefits Administration and estimate the financial burden of disability payments for those receiving compensation despite exaggerated mTBI-related cognitive deficits. Retrospective review included 74 veterans seen for Compensation and Pension evaluations for mTBI. Rates of malingering were based on failure of the Medical Symptom Validity Test (MSVT) and/or the Test of Memory Malingering (TOMM) trial 1 <= 40. Total estimated compensation was based on the level of disability awarded and the number of individuals found to be malingering cognitive deficits. Overall, 33-52% of the sample was found to be malingering mTBI-related cognitive deficits. The malingering groups were receiving approximately $71,000-$121,000/year ($6,390-$7,063 per year, per veteran on average). Estimated nationwide disability payments for those possibly malingering mTBI-related cognitive deficits would be $136-$235 million/year (projected costs from 2015-2020 = $700 million-$1.2 billion). It is critical that providers and administrative officials identify those exaggerating disability claims attributed to mTBI. The cost of malingering impacts society in general as well as veterans themselves, as it diverts needed funds/resources away from those legitimately impaired by their military service. PMID- 28816503 TI - Pubertal development of body size and soccer-specific functional capacities in adolescent players. AB - Pubertal growth in body size and functional capacities were examined in adolescent soccer players (n = 33). The average age at baseline was 10.9 (9.8 11.8 years). Peak height velocity (PHV) and growth curves for body mass and functional performance (countermovement jump, 15-m sprint, agility and Yo-Yo intermittent recovery test - level 1) were determined with Bayesian multilevel models. Estimates for PHV and age at PHV were 8.1 cm/year (95% credible interval: 4.2-18.5 cm/year) and 12.9 years (95% credible interval: 11.8-15.5 years), respectively. Peak body mass velocity occurred 0.48 year after PHV. Jump performance maximum velocity occurred about 2 years after PHV and peak sprint performance maximum velocity was coincident with PHV. Agility and intermittent endurance run performance showed a quadratic trend of improvement of performance, starting to level off at about 3-4 years after PHV. The modelling procedures were efficient to determine pubertal growth curves aligned for chronological age and age at PHV, considering individual differences in maturation when interpreting the development of performance in youth soccer. PMID- 28816504 TI - Validity and reliability of the 3-min all-out running test to measure critical velocity in hot environments. AB - This study's aim was to investigate the test-retest reliability of the 3-min all out running test (3MRT) in hot environments. Twelve male sprinters (age 21.2 +/- 1.8 years; height 1.78 +/- 0.01 m; weight 71.0 +/- 1.6 kg; [Formula: see text] 55.0 +/- 1.0 mL kg-1 min-1) performed an incremental exercise test in a laboratory, during which the first and second ventilatory thresholds (VT1 and VT2) and [Formula: see text] were determined. In addition, they performed two 3MRTs on an outdoor track in a hot environment, during which the critical velocity (CV) and anaerobic capacity (D') were estimated. Significant reproducibility was found in CV and D' (ICC = 0.74 and 0.61, P < 0.05). The average CV in 3MRTs (3.09 +/- 0.13 m s-1) correlated significantly with VT1 (3.13 +/- 0.07 m s-1, P < 0.05). The 3MRT is a reliable tool for measuring CV and D', while CV from 3MRT in a hot environment was identical to VT1. PMID- 28816505 TI - Pre-attack signs and symptoms in cluster headache: Characteristics and time profile. AB - Introduction In contrast to the premonitory phase of migraine, little is known about the pre-attack (prodromal) phase of a cluster headache. We aimed to describe the nature, prevalence, and duration of pre-attack symptoms in cluster headache. Methods Eighty patients with episodic cluster headache or chronic cluster headache, according to ICHD-3 beta criteria, were invited to participate. In this observational study, patients underwent a semi-structured interview where they were asked about the presence of 31 symptoms/signs in relation to a typical cluster headache attack. Symptoms included previously reported cluster headache pre-attack symptoms, premonitory migraine symptoms and accompanying symptoms of migraine and cluster headache. Results Pre-attack symptoms were reported by 83.3% of patients, with an average of 4.25 (SD 3.9) per patient. Local and painful symptoms, occurring with a median of 10 minutes before attack, were reported by 70%. Local and painless symptoms and signs, occurring with a median of 10 minutes before attack, were reported by 43.8% and general symptoms, occurring with a median of 20 minutes before attack, were reported by 62.5% of patients. Apart from a dull/aching sensation in the attack area being significantly ( p < 0.05) more frequent among men and episodic patients, compared with women and chronic patients respectively, no other differences in the prevalence of pre-attack symptoms were identified between groups. Conclusion Pre-attack symptoms are frequent in cluster headache. Since the origin of cluster headache attacks is still unresolved, studies of pre-attack symptoms could contribute to the understanding of cluster headache pathophysiology. Furthermore, identification and recognition of pre-attack symptoms could potentially allow earlier abortive treatment. PMID- 28816506 TI - Inhibition of monoacylglycerol lipase: Another signalling pathway for potential therapeutic targets in migraine? AB - Background Drugs that modulate endocannabinoid signalling are effective in reducing nociception in animal models of pain and may be of value in the treatment of migraine. Methods We investigated the anti-nociceptive effects of inhibition of monoacylglycerol lipase (MGL), a key enzyme in the hydrolysis of the 2-arachidonoylglycerol, in a rat model of migraine based on nitroglycerin (NTG) administration. We evaluated c-fos expression in specific brain areas and nociceptive behavior in trigeminal and extra-trigeminal body areas. Results URB602, a reversible MGL inhibitor, did not show any analgesic effect in the tail flick test, but it inhibited NTG-induced hyperalgesia in both the tail flick test and the formalin test applied to the hind paw or to the orofacial area. Quite unexpectedly, URB602 potentiated formalin-induced hyperalgesia in the trigeminal area when used alone. The latter result was also confirmed using a structurally distinct, irreversible MGL inhibitor, JZL184. URB602 did not induce neuronal activation in the area of interest, but significantly reduced the NTG-induced neuronal activation in the ventrolateral column of the periaqueductal grey and the nucleus trigeminalis caudalis. Conclusions These findings support the hypothesis that modulation of the endocannabinoid system may be a valuable approach for the treatment of migraine. The topographically segregated effect of MGL inhibition in trigeminal/extra-trigeminal areas calls for further mechanistic research. PMID- 28816507 TI - Arthroscopic Harvest of Adipose-Derived Mesenchymal Stem Cells From the Infrapatellar Fat Pad. AB - BACKGROUND: The successful isolation of adipose-derived mesenchymal stem cells (ADSCs) from the arthroscopically harvested infrapatellar fat pad (IFP) would provide orthopaedic surgeons with an autologous solution for regenerative procedures. PURPOSE: To demonstrate the quantity and viability of the mesenchymal stem cell population arthroscopically harvested from the IFP as well as the surrounding synovium. STUDY DESIGN: Descriptive laboratory study. METHODS: The posterior border of the IFP, including the surrounding synovial tissue, was harvested arthroscopically from patients undergoing anterior cruciate ligament reconstruction. Tissue was then collected in an AquaVage adipose canister, followed by fat fractionization using syringe emulsification and concentration with an AdiPrep device. In the laboratory, the layers of tissue were separated and then digested with 0.3% type I collagenase. The pelleted stromal vascular fraction (SVF) cells were then immediately analyzed for viability, mesenchymal cell surface markers by fluorescence-activated cell sorting, and clonogenic capacity. After culture expansion, the metabolic activity of the ADSCs was assessed by an AlamarBlue assay, and the multilineage differentiation capability was tested. The transition of surface antigens from the SVF toward expanded ADSCs at passage 2 was further evaluated. RESULTS: SVF cells were successfully harvested with a mean yield of 4.86 +/- 2.64 * 105 cells/g of tissue and a mean viability of 69.03% +/- 10.75%, with ages ranging from 17 to 52 years (mean, 35.14 +/- 13.70 years; n = 7). The cultured ADSCs composed a mean 5.85% +/- 5.89% of SVF cells with a mean yield of 0.33 +/- 0.42 * 105 cells/g of tissue. The nonhematopoietic cells (CD45-) displayed the following surface antigens as a percentage of the viable population: CD44+ (52.21% +/- 4.50%), CD73+CD90+CD105+ (19.20% +/- 17.04%), and CD44+CD73+CD90+CD105+ (15.32% +/- 15.23%). There was also a significant increase in the expression of ADSC markers CD73 (96.97% +/- 1.72%; P < .01), CD10 (84.47% +/- 15.46%; P < .05), and CD166 (11.63% +/- 7.84%; P < .005) starting at passage 2 compared with freshly harvested SVF cells. The clonogenic efficiency of SVF cells was determined at a mean 3.21% +/- 1.52% for layer 1 and 1.51% +/- 0.55% for layer 2. Differentiation into cartilage, fat, and bone tissue was demonstrated by tissue-specific staining and quantitative polymerase chain reaction. CONCLUSION: SVF cells from the IFP and adjacent synovial tissue were successfully harvested using an arthroscopic technique and produced ADSCs with surface markers that meet criteria for defined mesenchymal stem cells. CLINICAL RELEVANCE: An autologous source of stem cells can now be harvested using a simple arthroscopic technique that will allow orthopaedic surgeons easier access to progenitor cells for regenerative procedures. PMID- 28816508 TI - Stability and Predictive Validity of the Parent-Child Sleep Interactions Scale: A Longitudinal Study Among Preschoolers. AB - Little research has examined the processes underlying children's persistent sleep problems and links with later psychopathology. The current study examined the stability of parent-child sleep interactions as assessed with the parent-reported Parent-Child Sleep Interactions Scale (PSIS) and examined whether sleep interactions in preschool-age children predict sleep problems and psychiatric symptoms later in childhood. Participants included 108 preschool-age children (50% female) and their parents. Parents completed the PSIS when children were 3-5 years (T1) and again when they were 6-9 years (T2). The PSIS includes three subscales-Sleep Reinforcement (reassurance of child sleep behaviors), Sleep Conflict (parent-child conflict at bedtime), Sleep Dependence (difficulty going to sleep without parent)-and a total score. Higher scores indicate more problematic bedtime interactions. Children's sleep problems and psychiatric symptoms at T1 and T2 were assessed with a clinical interview. PSIS scores were moderately stable from T1 to T2, and the factor structure of the PSIS remained relatively consistent over time. Higher total PSIS scores at T1 predicted increases in children's sleep problems at T2. Higher PSIS Sleep Conflict scores at T1 predicted increases in oppositional defiant disorder symptoms at T2. Children with more sleep problems and higher PSIS Sleep Reinforcement scores at T1 showed increases in attention deficit/hyperactivity disorder, depressive, and anxiety symptoms at T2. These findings provide evidence for the predictive validity of the PSIS and highlight the importance of early parent-child sleep interactions in the development of sleep and psychiatric symptoms in childhood. Parent-child sleep interactions may serve as a useful target for interventions. PMID- 28816509 TI - SHP465 Mixed Amphetamine Salts in the Treatment of Attention Deficit/Hyperactivity Disorder in Children and Adolescents: Results of a Randomized, Double-Blind Placebo-Controlled Study. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy, safety, and tolerability of SHP465 mixed amphetamine salts (MAS) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). METHODS: This randomized, double-blind dose-optimization study enrolled children and adolescents (6-17 years) meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision ADHD criteria and having baseline ADHD Rating Scale IV (ADHD-RS-IV) total scores >=28. Participants were randomized 1:1 to placebo or dose-optimized SHP465 MAS (12.5-25 mg) for 4 weeks. Total score change (baseline to week 4) on the ADHD-RS-IV (primary endpoint) and the Clinical Global Impressions-Improvement (CGI-I) scale score at week 4 (key secondary endpoint) were assessed using linear mixed-effects models for repeated measures. Safety and tolerability assessments (secondary endpoints) included treatment-emergent adverse events (TEAEs) and vital sign changes. RESULTS: Of 264 randomized participants (placebo, n = 132; SHP465 MAS, n = 132), 234 (placebo, n = 118; SHP465 MAS, n = 116) completed the study. The least squares mean (95% confidence interval) treatment difference significantly favored SHP465 MAS over placebo for ADHD-RS-IV total score change from baseline to week 4 (-9.9 [-13.0, -6.8]; p < 0.001; effect size = 0.80) and CGI-I score at week 4 (-0.8 [-1.1, -0.5]; p < 0.001; effect size = 0.65). TEAE frequency was 46.6% (61/131) with placebo and 67.4% (89/132) with SHP465 MAS; no serious TEAEs were reported. TEAEs reported at a frequency of >=5% and >=2 times the placebo rate were decreased appetite, insomnia, irritability, nausea, and decreased weight. Mean +/- standard deviation increases (baseline to final on-treatment assessment) were higher with SHP465 MAS than placebo for pulse (5.7 +/- 11.78 vs. 0.7 +/- 10.79), systolic blood pressure (3.8 +/- 9.15 vs. 2.1 +/- 8.72), and diastolic blood pressure (4.0 +/- 8.23 vs. 0.5 +/- 7.45). CONCLUSIONS: SHP465 MAS demonstrated superiority over placebo in improving ADHD symptoms and global functioning in children and adolescents with ADHD. The safety and tolerability profile of SHP465 MAS was consistent with that of SHP465 MAS in adults and other long-acting psychostimulants in children and adolescents. PMID- 28816510 TI - Treatment Recommendations as Actions. AB - From the earliest studies of doctor-patient interaction (Byrne & Long, 1976), it has been recognized that treatment recommendations may be expressed in more or less authoritative ways, based on their design and delivery. There are clear differences between I'm going to start you on X and We can give you X to try and Would you like me to give you X? Yet little is known about this variation, its contexts, or its consequences. In this paper, we develop a basic taxonomy of treatment recommendations in primary care as a first step toward a more comprehensive investigation. We take as our point of departure the observation that treatment recommendations such as those above represent not only different formulations but also different social actions. We distinguish five main treatment recommendation actions: pronouncements, suggestions, proposals, offers, and assertions. We ask: what are the main dimensions on which these recommendations vary and to what end? And what sorts of factors shape a clinician's use of one action type over another with respect to recommending a medication in the primary care context? PMID- 28816511 TI - Virtual Reality and Active Videogame-Based Practice, Learning Needs, and Preferences: A Cross-Canada Survey of Physical Therapists and Occupational Therapists. AB - OBJECTIVE: Describe the clinical use of virtual reality (VR)/active videogaming (AVG) by physical therapists (PTs) and occupational therapists (OTs) in Canada, identify usage barriers and facilitators, evaluate factors that predict intention to use VR/AVGs, and determine therapists' learning needs. DESIGN: Cross-sectional survey. MATERIALS AND METHODS: Online survey of therapists in Canada who were members of 1 of 26 professional PT or OT colleges or associations using the Assessing Determinants Of Prospective Take-up of Virtual Reality (ADOPT-VR2) Instrument. RESULTS: We received 1071 (506 PTs, 562 OTs, 3 dual-trained) responses. Forty-six percent had clinical VR/AVG experience; only 12% reported current use, with the Wii being the most clinically accessible (41%) system. Therapists used VR/AVGs primarily in rehabilitation (32%) and hospital (29%) settings, preferentially targeting balance (39.3%) and physical activity (19.8%) outcomes. Stroke (25.8%), brain injury (15.3%), musculoskeletal (14.9%), and cerebral palsy (10.5%) populations were most frequently treated. Therapists with VR/AVG experience rated all ADOPT-VR2 constructs more highly than did those without experience (P < 0.001). Factors predictive of intention to use VR included the technology's perceived usefulness and therapist self-efficacy in VR/AVG use (P < 0.001). Highest-rated barriers to VR/AVG use were lack of funds, space, time, support staff, and appropriate clients, whereas facilitators included client motivation, therapist knowledge, and management support. Most (76%) respondents were interested in learning more. CONCLUSION: Understanding use, predictors of use, and learning needs is essential for developing knowledge translation initiatives to support clinical integration of VR/AVGs. Results of this first national survey will inform the creation of resources to support therapists in this field. PMID- 28816512 TI - The Effects of Active Videogame Feedback and Practicing Experience on Children's Physical Activity Intensity and Enjoyment. AB - OBJECTIVE: The study aims to explore the effects of receiving active videogame (AVG) feedback and playing experience on individuals' moderate-to-vigorous physical activity (MVPA) and perceived enjoyment. MATERIALS AND METHODS: This was a within-subject design study. The participants included 36 (n = 15 and 21 for boys and girls, respectively) fourth graders enrolled in a rural elementary school in southern Georgia area. The experiment lasted for 6 weeks with each week including three sessions. The participants were assigned in either front row (sensor feedback) or back row (no sensor feedback) during practice, which was alternated in different sessions. Two different dance games were played during the study with each game implemented for 3 weeks. The MVPA was measured with GT3X+ accelerometers. Physical activity (PA) enjoyment was assessed after the completion of the first two and last two sessions of each game. A repeated one way ANOVA (analysis of variance) was used to examine the effects of AVG feedback and game on MVPA. A repeated one-way MANOVA (multivariate analysis of variance) was conducted for each game to examine the effects of experience and AVG feedback on enjoyment and MVPA. RESULTS: No effects of AVG feedback were found for MVPA or enjoyment (P > 0.05). The effects of experience on MVPA were found for Just Dance Kids 2014 with experience decreased MVPA (P < 0.05). CONCLUSION: Students who practiced dance AVG without receiving feedback still demonstrated positive affection and accumulated similar MVPA than when practicing while receiving feedback. Experience for certain dance games tends to decrease PA intensity. PMID- 28816513 TI - Iterative Design and Testing for the Development of a Game-Based Chlamydia Awareness Intervention: A Pilot Study. AB - OBJECTIVES: Herein we describe a methodology for developing a game-based intervention to raise awareness of Chlamydia and other sexually transmitted infections among youth in Boston's underserved communities. MATERIALS AND METHODS: We engaged in three design-based experiments. These utilized mixed methods, including playtesting and assessment methods, to examine the overall effectiveness of the game. In this case, effectiveness is defined as (1) engaging the target group, (2) increasing knowledge about Chlamydia, and (3) changing attitudes toward Chlamydia testing. These three experiments were performed using participants from different communities and with slightly different versions of the game, as we iterated through the design/feedback process. RESULTS: Overall, participants who played the game showed a significant increase in participants' knowledge of Chlamydia compared with those in the control group (P = 0.0002). The version of the game, including elements specifically targeting systemic thinking, showed significant improvement in participants' intent to get tested compared with the version of the game without such elements (Stage 2: P > 0.05; Stage 3: P = 0.0045). Furthermore, during both Stage 2 and Stage 3, participants showed high levels of enjoyment, mood, and participation and moderate levels of game engagement and social engagement. During Stage 3, however, participants' game engagement (P = 0.0003), social engagement (P = 0.0003), and participation (P = 0.0003) were significantly higher compared with those of Stage 2. Thus, we believe that motivation improvements from Stage 2 to 3 were also effective. Finally, participants' overall learning effectiveness was correlated with their prepositive affect (r = 0.52) and their postproblem hierarchy (r = -0.54). CONCLUSION: The game improved considerably from its initial conception through three stages of iterative design and feedback. Our assessment methods for each stage targeted and integrated learning, health, and engagement outcomes. Lessons learned through this iterative design process are a great contribution to the games for health community, especially in targeting the development of health and learning goals through game design. PMID- 28816514 TI - Functional impairment matters in the screening and diagnosis of gaming disorder. AB - This commentary responds to Aarseth et al.'s (in press) criticisms that the ICD 11 Gaming Disorder proposal would result in "moral panics around the harm of video gaming" and "the treatment of abundant false-positive cases." The ICD-11 Gaming Disorder avoids potential "overpathologizing" with its explicit reference to functional impairment caused by gaming and therefore improves upon a number of flawed previous approaches to identifying cases with suspected gaming-related harms. We contend that moral panics are more likely to occur and be exacerbated by misinformation and lack of understanding, rather than proceed from having a clear diagnostic system. PMID- 28816515 TI - How Should We Secure Our Transplanted Meniscus? A Meta-analysis. AB - BACKGROUND: Meniscal allograft transplant (MAT) is a salvage procedure for young patients with symptomatic meniscal deficiency. Although many studies report good outcomes, MAT remains controversial, and an optimal fixation technique for the meniscus roots is debated. PURPOSE: To assess the overall outcome of MAT and compare the results of different meniscal root fixation techniques. STUDY DESIGN: Meta-analysis. METHODS: Following specific guidelines, we systematically evaluated all current literature for studies reporting on the outcomes of patients who underwent MAT. Using random effect models of proportions, we determined the tear and failure rates. Standardized mean differences (SMDs) were calculated to determine the improvement in clinical outcomes and pain level. Data were then stratified by root fixation method into 2 groups: fixation that preserved the graft's root insertions on the allograft bone (bone fixation group) and suture fixation of the root soft tissue without the allograft bone (soft tissue suture group). RESULTS: A total of 38 studies (1637 MATs, 81% men) involving subjects with a mean age of 34 years (range, 20-48 years) and a mean follow-up of 60 months (range, 25-168 months) met inclusion criteria. This overall cohort had significant improvements in Lysholm scores (from 57.8 to 81.4 points; SMD 1.5, P < .001) and pain level (visual analog scale [VAS], from 56 to 21 points; SMD 1.8, P < .001). The cohort had a tear rate of 9% and a failure rate of 12.6%. No significant differences were found between the soft tissue suture (485 MATs) and bone fixation (489 MATs) groups in terms of meniscal allograft tear rates (13.4% vs 14.9%), failure rates (17.6% vs 18.8%), Lysholm scores (from 52.3 to 82.4, SMD 2.0, and from 60.7 to 82.9, SMD 1.7; respectively), and VAS scores (from 65 points to 18 points, SMD 2.6, and from 63 points to 13 points, SMD 3.1; both P < .001). Meniscal extrusion was similar, with a weighted mean percentage of extrusion of 40.2% in the soft tissue suture group and 43.1% in the bone fixation group. CONCLUSION: This meta-analysis demonstrated significant improvements in clinical outcomes for MAT patients with low tear and failure rates. The data do not demonstrate a difference between soft tissue suture and bone fixation for MAT root fixation. This suggests that the technique of root fixation may not have an appreciable influence on clinical outcome, pain reduction, extrusion, or MAT longevity. Further prospective trials are needed. PMID- 28816516 TI - Vibrio vulnificus VvhA induces Th1 and Tfh cells to proliferate against Vibrio vulnificus in a mouse model of infection. AB - AIM: To characterize the roles of VvhA in host's acquired immune response to Vibrio vulnificus infection. MATERIALS & METHODS: The recombinant VvhA fusion protein was used to immunize mice and the anti-VvhA polyclonal antibody was produced in vivo for prophylactic and therapeutic efficacy assay. The roles of VvhA in T helper (Th) cells differentiation were analyzed by vvhA-deleted mutant during the early phase of infection, while the ratio of Th2 and T follicular helper (Tfh) cells were examined in VvhA immunization. RESULTS: Anti-VvhA antibody exhibited neutralization activity against V. vulnificus. Wild-type strain induced higher level of Th1 cells than the mutant, and the concentrations of IgG2a and IFN-gamma were increased during the early phase of infection. The spontaneous development of Tfh was observed in immunized model, and the serum IL 21 was increased. CONCLUSION: V. vulnificus VvhA elicited cellular and humoral immune responses by Th1 and Tfh cells to provide protection against VvhA. PMID- 28816517 TI - Targeted areas for improving health literacy after traumatic brain injury. AB - OBJECTIVE: To develop a framework to identify targeted areas for improving health literacy for caregivers after traumatic brain injury (TBI). METHOD: Qualitative study using inductive and deductive qualitative content analysis was conducted in a large, urban, level I trauma centre. Interviews were conducted with 23 caregivers of persons with TBI. Participants' perspectives on communication and preparation for discharge were explored and understanding of commonly used words and discharge instructions were assessed. RESULTS: Four types of communication patterns were identified: formal, informal, indirect and caregiver-initiated. Informal and caregiver-initiated communication were the most common. All caregivers reported confusion about their family member's condition, care plan or discharge plan. Caregivers were not able to define commonly used terms in discharge instructions, and were confused by formatting and medical language. Caregivers were not aware of expected caregiving roles upon discharge. Conceptualizing findings within a family-centred care model, we offer specific strategies to improve health communication and caregiver capacity building to enhance health literacy. CONCLUSIONS: Health literacy and caregiver capacity to care for loved ones with TBI after hospital discharge is low. We offer specific target areas for improvement in verbal and written communication and capacity building that take into account provider, patient and family characteristics. PMID- 28816518 TI - Balancing between prejudice and fact for Gaming Disorder: Does the existence of alcohol use disorder stigmatize healthy drinkers or impede scientific research? AB - The inclusion of Gaming Disorder (GD) criteria in the 11th Revision of the International Classification of Diseases (ICD-11) beta draft was recently criticized, and an argument was made for its removal to "avoid a waste of public resources." However, these misleading statements are believed to be based on under estimation of this ever-growing problem. Such claims may endanger public health and the psychosocial well-being of affected individuals. Thus, the seriousness of the problem was briefly emphasized in our response paper. We provided an overview of how debates of this kind were developed in our region. In addition, we addressed the arguments made on research and children's rights. The accusation that GD exerts negative impacts on children's freedom and stigmatizes healthy gamers may arise from a false belief that this new digital media is benign or not addictive. Such statements could be true in some, but not all, cases. Unwillingness to recognize the addictive potential of gaming, as well as insistence on treating GD simply as an individual problem, are reminiscent of the era in which alcoholism was viewed as a personality problem. These dangerous views place affected individuals at greater health risk and further stigmatize them. Formalization of the disorder is also expected to help in standardization of research and treatment in the field. The inclusion of GD in the upcoming ICD 11 is a responsible step in the right direction. PMID- 28816519 TI - The effects of exercise on a choice reaction time task in individuals with post concussion syndrome. AB - PURPOSE: To assess cognitive performance differences pre- and post-exercise in individuals without concussion (non-concussed, NC) and individuals with post concussion syndrome (PCS). METHODS: A total of 30 participants completed a choice reaction time (CRT) task in the form of an iPad application, measuring each individual's decision-making capabilities, while wearing a head-mounted eye tracker system. Participants completed four blocks of testing; the time interval between the first two blocks of trials and the last two blocks of trials was 10 minutes. Between the completion of block 2 and the start of block 3, the participants completed a 15-minute bout of exercise. RESULTS: Individuals with PCS at rest and following exercise displayed greater average reaction time (RT) (p<.01), lower overall accuracy (p<.01) and shorter final fixation durations (p<.05) than NC. Combined influence of learning and exercise resulted in a significant difference (p<.05) in RT from block 1 to block 3 and block 1 to block 4. CONCLUSION: Persistent concussion-based symptoms may be indicative of deficits in higher-level cognitive processing, as indicated by both decreased CRT performance and differences in gaze behaviours between groups. Therefore, individuals with PCS may not elicit appropriate decisions when navigating through an environment, potentially leading to further risk of injury. PMID- 28816520 TI - Emergence of two distinct subpopulations from Klebsiella pneumoniae grown in the stimulated microgravity environment. AB - AIM: To isolate and characterize the two phenotypically distinct subpopulations from Klebsiella pneumoniae clonal cultures grown in the simulate microgravity environment. MATERIALS & METHODS: Here clonal culture of K. pneumoniae strain ATCC BAA-1705 was grown within a vertically rotating wall vessel bioreactor. Microscopic, colony staining, biofilm assays and quantitative proteomics were used to define the features of subpopulations. RESULTS: Two subpopulations were isolated based on colony appearance and bacterial morphology and indicated the different capability of biofilm formation and antibiotics resistance. CONCLUSION: These findings would raise a possibility of understanding the adaptive roles of bacterial subpopulations formed under certain conditions from the viewpoint of population variation. PMID- 28816521 TI - Plume Activity and Tidal Deformation on Enceladus Influenced by Faults and Variable Ice Shell Thickness. AB - We investigated the effect of variations in ice shell thickness and of the tiger stripe fractures crossing Enceladus' south polar terrain on the moon's tidal deformation by performing finite element calculations in three-dimensional geometry. The combination of thinning in the polar region and the presence of faults has a synergistic effect that leads to an increase of both the displacement and stress in the south polar terrain by an order of magnitude compared to that of the traditional model with a uniform shell thickness and without faults. Assuming a simplified conductive heat transfer and neglecting the heat sources below the ice shell, we computed the global heat budget of the ice shell. For the inelastic properties of the shell described by a Maxwell viscoelastic model, we show that unrealistically low average viscosity of the order of 1013 Pa s is necessary for preserving the volume of the ocean, suggesting the important role of the heat sources in the deep interior. Similarly, low viscosity is required to predict the observed delay of the plume activity, which hints at other delaying mechanisms than just the viscoelasticity of the ice shell. The presence of faults results in large spatial and temporal heterogeneity of geysering activity compared to the traditional models without faults. Our model contributes to understanding the physical mechanisms that control the fault activity, and it provides potentially useful information for future missions that will sample the plume for evidence of life. Key Words: Enceladus-Tidal deformation-Faults-Variable ice shell thickness-Tidal heating Plume activity and timing. Astrobiology 17, 941-954. PMID- 28816522 TI - The intertwined relationship between patient education, hospital waiting times and hospital utilization. AB - Background Hospital waiting times are established instruments to ration healthcare when resources are scarce. However, higher educated patients may be better able to influence access to, and exit from, hospital care when waiting times are long. Methods Based on a representative sample of 11 European countries from the Survey of Health, Ageing and Retirement in Europe (SHARE) collected in 2004/2005, this paper investigates whether the relationship between individual educational background and hospital utilization depends on the prevalent hospital waiting times in a country. Logistic regression with interaction effects between individual education and average waiting times per country are conducted. Results Primary education is significantly associated with a lower probability of visiting a hospital overnight (OR = 0.88) compared to secondary and tertiary education. Patients in countries with long waiting times had shorter stays (OR = 0.92), and the significant interaction effect indicates that lower educated patients have longer hospital stays than higher educated patients in countries where waiting times tend to be long (OR = 1.06). Conclusions While the findings imply that educational differences exist with regard to hospital care, future research should investigate potential underlying mechanisms, i.e. patients' perceived access barriers and the perceived quality of hospital treatment. PMID- 28816523 TI - Measures to assess the performance of an Australian non-government charitable non acute health service: A Delphi Survey of Organisational Stakeholders. AB - Organisation performance measurement is relevant for non-profit charitable organisations as they strive for security in an increasingly competitive funding environment. This study aimed to identify the priority measures and indicators of organisational performance of an Australian non-government charitable organisation that delivers non-acute health services. Seventy-seven and 59 participants across nine stakeholder groups responded to a two-staged Delphi technique study of a case study organisation. The stage one questionnaire was developed using information garnered through a detailed review of literature. Data from the first round were aggregated and analysed for the stage two survey. The final data represented a group consensus. Quality of care was ranked the most important of six organisational performance measures. Service user satisfaction was ranked second followed by financial performance, internal processes, employee learning and growth and community engagement. Thirteen priority indicators were determined across the six measures. Consensus was reached on the priority organisational performance measures and indicators. Stakeholders of the case study organisation value evidence-based practice, technical strength of services and service user satisfaction over more commercially orientated indicators. PMID- 28816524 TI - From the abstract to the concrete - Implementation of an innovative tool in home care. AB - Background The implementation of innovations in practice is a critical factor for change and development processes in health and home care. We therefore analyze how an innovative tool - a mobility agreement to maintain physical mobility of home care clients - was implemented in Finnish home care. Methods Our study involves ethnographic research of 13 home care visits, two years after the mobility agreement was implemented. We analyze the emergence of contradictions, the motives of the actors and the use of artifacts supporting or inhibiting the implementation. Two in-depth cases illustrate the implementation of the mobility agreement in home care visits. Findings Our findings show that, first, to achieve practice change and development, the innovation implementation requires the overcoming of contradictions in the implementation process. Second, it calls for the emergence of a shared motive between the actors to transform the abstract concept of an innovation into a concrete practice. Third, artifacts, customary to the clients are important in supporting the implementation process. Fourth, the implementation brings about a modification of the innovation and the adopting social system. Conclusions Innovation implementation should be seen as a transformation process of an abstract concept into a concrete practice, enabled by the actors involved. Concept design and implementation should be closely linked. In health/home care innovation management, the implementation of innovations needs to be understood as a complex collective learning process. Results can be far reaching - in our case leading to change of home care workers' professional understanding and elderly clients' mobility habits. PMID- 28816525 TI - Global Side Effects: Counter-Clinics in Mental Health Care. PMID- 28816526 TI - Echocardiographic Assessment of Right Ventricle Dimensions and Function After Exposure to Extreme Altitude: Is an Expedition to 8000 m Hazardous for Right Ventricular Function? AB - Kurdziel, Marta, Jaroslaw Wasilewski, Karolina Gierszewska, Anna Kazik, Gracjan Pytel, Jacek Waclawski, Adam Krajewski, Anna Kurek, Lech Polonski, and Mariusz Gasior. Echocardiographic assessment of right ventricle dimensions and function after exposure to extreme altitude: Is an expedition to 8000 m hazardous for right ventricular function? High Alt Med Biol 18:330-337, 2017.-Although the right ventricle (RV) is under great hypoxic stress at altitude, still little is known what happens to the RV after descent. The aim of this study was to evaluate RV dimensions and function after exposure to extreme altitude. Therefore, echocardiographic examination was performed according to a protocol that focused on the RV in 11 healthy subjects participating in an expedition to K2 (8611 m) or Broad Peak (BP, 8051 m). In comparison to measurements before the expedition, after 7-8 weeks of sojourn above 2300 meters with the aim of climbing K2 and BP, the RV Tei index increased (0.5 +/- 0.1 vs. 0.4 +/- 0.1; p = 0.028), and RV free wall longitudinal systolic strain (RVFWLSS) decreased (-23.1% +/- 2.7% vs. -25.9% +/- 2.4%; p = 0.043). Decrease in peak systolic strain and strain rate was observed in the basal and mid segments of the RV free wall (respectively: -24.4% +/- 4.4% vs. -30.9% +/- 6.5%; -1.4 +/- 0.3 s-1 vs. -1.8 +/- 0.3 s-1; -28.7% +/- 3.9% vs. -34% +/- 3.3%; -1.5 +/- 0.2 s-1 vs. -1.9 +/- 0.3 s-1; p for all <0.05). The linear RV dimensions, the proximal and distal RV outflow tracks, increased (respectively: 31.3 +/- 4 mm vs. 29.2 +/- 3 mm, p = 0.025; 27 +/- 2.7 mm vs. 24.8 +/- 3 mm, p = 0.012). We found that exposure to extreme altitude may cause RV dilatation and a decrease in RV performance. The Tei index and RVFWLSS are sensitive performance indices to detect changes in RV function after the exposure to hypoxic stress. The observed alterations seem to be a manifestation of physiological adaptation to high-altitude condition in healthy individuals. PMID- 28816527 TI - Use of whey as a culture medium for Bacillus clausii for the production of protein hydrolysates with antimicrobial and antioxidant activity. AB - The use of whey as a natural culture medium to produce hydrolysates with antimicrobial from Bacillus clausii is the objective of this research. The fermentation process was carried out at 25 C for five days, where proteolytic activity, soluble peptides quantification, and antimicrobial activity using the disc diffusion method were determined every day. The fermented whey reached values of proteolytic activity between 90 and 260 U ml-1 and a production of soluble peptides between 100 and 2070 ug ml-1. The maximum values were reached after three days of fermentation to all determinations. In addition, the inhibition zone of fermented whey against Salmonella Typhimurium, Escherichia coli, Shigella flexneri, Staphylococcus aureus, Listeria monocytogenes, and Enterococcus faecalis strains were 13.7, 13.2, 14.4, 14.6, 9.8, 15.7 mm, respectively. The hydrolysates inhibited the 2, 2'-azinobis (3 ethylbenzothiazoline- 6-sulfonic acid) (ABTS) and 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radicals by 85 and 80%, respectively. The whey was used to allow the growth of B. clausii and to generate peptides with antioxidant and antimicrobial activity through the hydrolysis of proteins present in the natural culture medium. This process could be used for the development of new dairy products added with probiotics. PMID- 28816528 TI - THE INTERPLAY BETWEEN ENDOCRINOLOGY AND ONCOLOGY: THE NEW ROLE OF THE ENDOCRINOLOGIST. PMID- 28816529 TI - ART AND THE ENDOCRINOLOGY TRAINEE. PMID- 28816530 TI - HEMOGLOBIN A1C, BLOOD PRESSURE, AND LDL-CHOLESTEROL CONTROL AMONG HISPANIC/LATINO ADULTS WITH DIABETES: RESULTS FROM THE HISPANIC COMMUNITY HEALTH STUDY/STUDY OF LATINOS (HCHS/SOL). AB - OBJECTIVE: To determine the prevalence of Hispanic/Latino adults with diabetes who meet target hemoglobin A1c, blood pressure (BP), and low-density-lipoprotein cholesterol (LDL-C) recommendations, and angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blocker (ARB) and statin medication use by heritage and sociodemographic and diabetes-related characteristics. METHODS: Data were cross-sectional, collected between 2008 and 2011, and included adults age 18 to 74 years who reported a physician diagnosis of diabetes in the Hispanic Community Health Study/Study of Latinos (N = 2,148). Chi-square tests compared the prevalence of hemoglobin A1c, BP, and LDL-C targets and ACE/ARB and statin use across participant characteristics. Predictive margins regression was used to determine the prevalence adjusted for sociodemographic characteristics. RESULTS: The overall prevalence of A1c <7.0% (53 mmol/mol), BP <130/80 mm Hg, and LDL-C <100 mg/dL was 43.0, 48.7, and 36.6%, respectively, with 8.4% meeting all three targets. Younger adults aged 18 to 39 years with diabetes were less likely to have A1c <7.0% (53 mmol/mol) or LDL-C <100 mg/dL compared to those aged 65 to 74 years; younger adults were more likely to have BP <130/80 mm Hg (P<.05 for all). Individuals of Mexican heritage were significantly less likely to have A1c <7.0% (53 mmol/mol) compared to those with Cuban heritage, but they were more likely to have BP <130/80 mm Hg compared to those with Dominican, Cuban, or Puerto Rican heritage (P<.05 for all); there was no difference in LDL-C by heritage. Overall, 38.2% of adults with diabetes were taking a statin, and 50.5% were taking ACE/ARB medications. CONCLUSION: Hemoglobin A1c, BP, and LDL-C control are suboptimal among Hispanic/Latinos with diabetes living in the U.S. With 8.4% meeting all three recommendations, substantial opportunity exists to improve diabetes control in this population. ABBREVIATIONS: A1c = hemoglobin A1c; ABC = hemoglobin A1c, blood pressure, low-density-lipoprotein cholesterol; ACE = angiotensin-converting enzyme; ADA = American Diabetes Association; ARB = angiotensin receptor blocker; BMI = body mass index; BP = blood pressure; CHD = coronary heart disease; CVD = cardiovascular disease; HCHS/SOL = Hispanic Community Health Study/Study of Latinos; LDL-C = low-density-lipoprotein cholesterol; NHANES = National Health and Nutrition Examination Survey; PAD = peripheral artery disease. PMID- 28816531 TI - PREVALENCE AND PREDICTORS OF PRIMARY HYPERPARATHYROIDISM AMONG PATIENTS WITH UROLITHIASIS. AB - OBJECTIVE: Urolithiasis may be the only presenting manifestation of primary hyperparathyroidism (PHPT), and early detection of PHPT in such patients may prevent future urolithiasis and other PHPT complications. This study was performed to study the prevalence and predictors of PHPT in patients presenting with urolithiasis. METHODS: Consecutive patients presenting with urolithiasis were evaluated for clinical and biochemical manifestations of PHPT with serum and urine calcium (Ca), serum intact parathyroid hormone and 25 (OH) vitamin D. We then compared the clinical and biochemical characteristics of PHPT patients presenting with urolithiasis (group A) and without (group B). RESULTS: During the 3-year study period, 381 patients with urolithiasis were seen with a mean age of 38.5 +/- 13.9 years. Nineteen of the 381 (5%) patients had histologically proven PHPT (group A). Four patients in group A (21%) and 8 in group B (2%) had nephrocalcinosis (P<.0001), multiple stones (>=3), calcific pancreatitis, and neuropsychiatric manifestations were more common in group A (P<.0001). Presence of multiple or bilateral stones, and recurrent stone episodes predicted PHPT (odds ratio [OR]: 3.06, confidence interval [CI]: 0.87, 0.7). CONCLUSION: One out of every 20 patients with urolithiasis had PHPT, which is higher than the prevalence of PHPT in general population. The presence of nephrocalcinosis and multiple, bilateral, and recurrent stone disease increased the risk of PHPT among stone formers. ABBREVIATIONS: Ca = calcium; CI = confidence interval; iPTH = intact parathyroid hormone; nPHPT = normocalcemic PHPT; OR = odds ratio; PHPT = primary hyperparathyroidism. PMID- 28816532 TI - COMPARING CLINICAL OUTCOMES AND COSTS FOR DIFFERENT TREATMENT INTENSIFICATION APPROACHES IN PATIENTS WITH TYPE 2 DIABETES UNCONTROLLED ON BASAL INSULIN: ADDING GLUCAGON-LIKE PEPTIDE 1 RECEPTOR AGONISTS VERSUS ADDING RAPID-ACTING INSULIN OR INCREASING BASAL INSULIN DOSE. AB - OBJECTIVE: Not all patients with type 2 diabetes achieve recommended glycated hemoglobin A1c (A1C) levels after adequate titration of basal insulin (BI). Current intensification approaches include addition of rapid-acting insulin (RAI) or a glucagon-like peptide 1 receptor agonist (GLP-1 RA), but it is not clear which strategy results in better long-term outcomes. METHODS: This retrospective analysis of health insurance claims data in the U.S. MarketScan database compared glycemic control and healthcare resource utilization and costs 12 months after adding a GLP-1 RA to BI versus adding a RAI or increasing BI doses. Propensity score matching was used in the comparative effectiveness analysis. RESULTS: A total of 8,034 patients underwent treatment intensification within 6 months of showing poor glycemic control; 4,134 patients had their BI dose adjusted, and 2,076 and 331 received RAI and GLP-1 RA, respectively. A1C changes were similar for the GLP-1 RA and RAI cohorts but higher for the GLP-1 RA versus the dose adjustment group. The hypoglycemia rate was lower after adding GLP-1 RA versus RAI or increasing BI dose. No overall changes in utilization of healthcare resources or diabetes-related costs were observed between intensification strategies, although prescription costs were higher for the GLP-1 RA cohort. CONCLUSION: BI in combination with GLP-1 RAs appears to be an effective intensification strategy, further reducing A1C levels and hypoglycemia frequency compared to increasing BI doses. GLP-1 RA addition also decreases hypoglycemia frequency versus BI dose increases and RAI addition, without raising overall healthcare costs. ABBREVIATIONS: A1C = hemoglobin A1c; BI = basal insulin; CAD = coronary artery disease; ED = emergency department; FPG = fasting plasma glucose; GLP-1 RA = glucagon-like peptide 1 receptor agonist; ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification; NPH = neutral protamine Hagedorn; OAD = oral antidiabetes drug; PSM = propensity score matching; RAI = rapid-acting insulin; T2D = type 2 diabetes. PMID- 28816533 TI - HIGH PREVALENCE OF HYPOTHYROIDISM IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS WITHOUT AN INCREASE IN CIRCULATING ANTI-THYROID ANTIBODIES. AB - OBJECTIVE: Because routine investigations are necessary for the early detection of thyroid disease, this study aimed to assess the prevalence of autoimmune thyroid disease (ATD) and thyroid dysfunction (TD) in patients with systemic lupus erythematosus (SLE). METHODS: Seventy-nine SLE patients (American College of Rheumatology criteria) and 159 control patients with no diagnosis of autoimmune diseases (except for ATD) were consecutively evaluated regarding changes in laboratory assessments of thyroid function and the presence of ATD. RESULTS: ATD was detected in 11.4% of the SLE patients and 13.8% of the control patients (P = .747), whereas TD was detected in 25.3 and 9.4% (P = .002), hypothyroidism was detected in 21.5 and 6.9% (P = .002), and hyperthyroidism was detected in 3.8 and 2.5% (P = .426) of the SLE and control patients, respectively. The mean duration of SLE was longer in patients with TD (P = .036). Mild hypothyroidism was more frequent in the SLE patients with anti-Smith antibodies (P = .029). CONCLUSION: Because hypothyroidism was more frequent in SLE patients and the frequency of ATD was high in both groups, the authors suggest that TSH and anti-thyroid antibody levels be assessed in SLE patients. ABBREVIATIONS: ACA = anti-cardiolipin antibodies; ANF = anti-nuclear factor; anti CCP = anti-cyclic citrullinated peptide; anti-dsDNA = anti-double-stranded DNA; anti-RNP = anti-ribonucleoprotein; anti-Scl70 = anti-topoisomerase I antibodies; anti-SM = anti-Smith antigen antibodies; anti-SS-A/Ro = anti-Sjogren syndrome related antigen A (Ro); anti-SS-B/La = anti-Sjogren syndrome-related antigen B (La); anti-Tg = anti-thyroglobulin; anti-TPO = anti-thyroid peroxidase; ATD = autoimmune thyroid disease; ENA = extractable nuclear antigen; fT4 = free thyroxine; OR = odds ratio; RF = rheumatoid factor; SLE = systemic lupus erythematosus; SLEDAI = SLE Disease Activity Index; TD = thyroid dysfunction; TSH = thyroid-stimulating hormone; TT3 = total triiodothyronine. PMID- 28816534 TI - SEVEN FAMILIAL DYSALBUMINEMIC HYPERTHYROXINEMIA CASES IN THREE UNRELATED JAPANESE FAMILIES AND HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY ANALYSIS OF THE THYROXINE BINDING PROFILE. AB - OBJECTIVE: Familial dysalbuminemic hyperthyroxinemia (FDH) is caused by abnormal human serum albumin (HSA) with an increased thyroxine (T4) affinity leading to euthyroid hyperthyroxinemia. One- and 2-step immunoassays of serum samples from FDH patients (e.g., Japanese patients) with the HSA R218P mutation can yield false-positive free thyroxine (FT4) results. Therefore, it is difficult to distinguish FDH from syndrome of inappropriate secretion of thyroid-stimulating hormone (TSH) (e.g., syndrome of resistance to thyroid hormone, TSH-producing pituitary adenoma), even when multiple assays are used. To investigate T4 to HSA binding, we examined serum samples from 7 patients from 3 Japanese families with FDH. Clinically, abnormal thyroid function tests were noted in pregnant Patient 1. Patients 2 and 3 had histories of inappropriate treatment with antithyroid drugs and surgery. METHODS: All patients and affected family members were diagnosed with FDH using direct sequencing analysis. Gel filtration high performance liquid chromatography was used for the biochemical analyses. RESULTS: The genomic analysis revealed a heterozygous missense mutation in HSA (R218P). In FDH patient sera, the albumin effluent corresponded to the peaks for total T4 (TT4); approximately 60% of the T4 in the effluent was detected as FT4. The results for the albumin effluent from healthy volunteer and TSHoma patient sera showed no corresponding TT4 peak. CONCLUSION: In the FDH patients, a relatively larger quantity of T4 was bound to abnormal HSA. This bound T4 was measured as FT4 during the analysis. ABBREVIATIONS: F = free; FDH = familial dysalbuminemic hyperthyroxinemia; HPLC = high-performance liquid chromatography; HSA = human serum albumin; PCR = polymerase chain reaction; SITSH = syndrome of inappropriate secretion of TSH; T = total; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid stimulating hormone; WT = wild-type. PMID- 28816535 TI - PROFESSIONAL FLASH CONTINUOUS GLUCOSE MONITORING WITH AMBULATORY GLUCOSE PROFILE REPORTING TO SUPPLEMENT A1C: RATIONALE AND PRACTICAL IMPLEMENTATION. AB - OBJECTIVE: Recent consensus statements strongly advocate downloading and interpreting continuous glucose data for diabetes management in patients with type 1 or 2 diabetes. Supplementing periodic glycated hemoglobin (A1C) testing with intermittent continuous glucose monitoring (CGM) using a standardized report form known as the ambulatory glucose profile (AGP) is an evolving standard of care. The rationale for this approach and its implementation with a recently approved novel monitoring technology are explored. METHODS: Search of the medical literature, professional guidelines, and real-world evidence guided this introduction of an integrative practice framework that uses AGP in conjunction with intermittent flash continuous glucose monitoring (FCGM) as a supplement to A1C testing. RESULTS: The combination of intermittent continuous glucose pattern analysis, standardized glucose metrics, and a readily interpretable data report has the potential to practically extend the recognized benefits of CGM to more patients and clarify the relationship between A1C and average glucose levels in individual cases. CONCLUSION: Novel FCGM technologies portend greater use of continuous forms of glucose monitoring and wider adoption of AGP report analysis. Additional formal and empirical evidence is needed to more fully characterize best practice. ABBREVIATIONS: A1C = glycated hemoglobin; AGP = ambulatory glucose profile; CGM = continuous glucose monitoring; FCGM = flash continuous glucose monitoring; IQR = interquartile range; SMBG = self-monitoring of blood glucose. PMID- 28816536 TI - OPTIMIZING LENVATINIB THERAPY IN PATIENTS WITH METASTATIC RADIOACTIVE IODINE RESISTANT DIFFERENTIATED THYROID CANCERS. AB - OBJECTIVE: Lenvatinib is approved for use in advanced radioactive iodine resistant differentiated thyroid cancers (RAIR-DTCs). Its efficacy is indisputable, but toxicities are great, creating daunting challenges for patients and providers. Few data regarding early adverse events and impact on quality of life (QOL) exist; we sought to clarify these issues by analyzing our initial postapproval lenvatinib experience. METHODS: Standardized patient education was implemented, providing detailed instructions and expert provider contacts to facilitate timely reporting of toxicities and guide responsive actions. Early adverse events, QOL outcomes, and response data from 25 consecutively treated DTC patients (02/2015 and 05/2016) were retrospectively analyzed. RESULTS: The median age was 55 years (range 27-81); 52% were female. Fourteen (56%) were on antihypertensive medication(s) at baseline. Most patients (21/25, 84%) developed adverse events during the first month of therapy. Hypertension arose in 16/25 (64%), requiring antihypertensive dose adjustment/addition in 6 (24%)/12 (48%) patients, respectively, during the first month of therapy. Dose reduction was required in 11 (44%) due to multiple adverse events; the median time to first dose reduction was 33 days (range 11-84); 8 (32%) required multiple dose reductions. Therapy interruption >3 weeks occurred in 4 (16%). The median change in patient-reported fatigue score was +2 (worsening, range -2 to +10, P<.007; 0 10 scales), but the median QOL change was 0 (range +4 to -9, P = .57). The mean duration of lenvatinib therapy was 6.5 months (range 1-12); median overall and progression-free survival have not yet been reached. Lenvatinib was discontinued in 7 (28%) patients; among 20 patients with available RECIST (Response Evaluation Criteria In Solid Tumors) measurements, 10 (50%) achieved partial response. CONCLUSION: Lenvatinib has promising efficacy in RAIR-DTC, but toxicities require frequent early interventions. QOL can be maintained on lenvatinib therapy. ABBREVIATIONS: DTC = differentiated thyroid cancer; LASA = linear analog self assessment; PR = partial response; QOL = quality of life; RAI = radioactive iodine; RAIR = RAI-resistant; RECIST = Response Evaluation Criteria In Solid Tumors; Tg = thyroglobulin; VEGFR = vascular endothelial growth factor receptor. PMID- 28816537 TI - EVALUATING THE PRESCRIPTION OF ANGIOTENSIN-CONVERTING ENZYME INHIBITORS OR RECEPTOR BLOCKERS IN PATIENTS WITH DIABETES IN JORDAN. AB - OBJECTIVE: The angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are guideline-recommended agents to prevent development and progression of nephropathy and cardiovascular diseases in diabetes mellitus (DM). The aim of this study was to evaluate the prescription of ACEIs/ARBs in DM patients with guideline indications. METHODS: Electronic data files for diabetes patients were retrospectively reviewed at a primary care setting northern Jordan. Patient's characteristics and data on ACEIs/ARBs were collected. The primary outcome measure was ACEI/ARB persistence of prescription in DM patients with guideline indications. RESULTS: Data for 859 DM patients were reviewed. The mean age (+/- SEM) was 60.75 +/- 0.41 years. Most of patients (97.4%) had type 2 DM. A total of 780 patients (90.8%) had at least one clinical indication to use ACEIs/ARBs. Hypertension followed by coronary artery disease (CAD) and albuminuria were the most common indications for ACEI/ARB prescriptions. A total of 686 (87.9%) of the eligible patients were on ACEIs/ARBs. As the number of indications increased, ACEI/ARB use has also increased. ACEIs/ARBs were prescribed regularly in about 59% of patients, whereas 40.9% were ex-users. Most of the patients received ACEIs/ARBs after the onset of first indication. By multivariate analysis, hypertension, CAD, and albuminuria were significant independent predictors of ACEI/ARB prescriptions. CONCLUSION: Indications for ACEI/ARB use are highly prevalent, and the rate of receipt is relatively high but with significant lack of persistence of prescriptions. Management of DM should enforce healthcare professional/patient interactions and education to improve prescription of medications. ABBREVIATIONS: ACEI = angiotensin-converting enzyme inhibitors; ADA = American Diabetes Association; ARB = angiotensin-receptor blocker; CAD = coronary artery disease; Cr = creatinine; CVD = cardiovascular disease; DM = diabetes mellitus; HF = heart failure; HT = hypertension; JNC = Joint National Committee; KAUH = King Abdullah University Hospital; LV = left ventricular; PAD = peripheral artery disease; RAAS = renin-angiotensin-aldosterone system; TIA = transient ischemic attack. PMID- 28816538 TI - THYROID AND AGING. AB - OBJECTIVE: Review physiologic thyroid function changes with aging and emphasize careful interpretation of tests in the aging population. METHODS: Literature review. RESULTS: Using age-specific thyroid-stimulating hormone (TSH) reference ranges should minimize or avoid the unnecessary diagnosis of thyroid disease in elderly patients. Subclinical thyroid dysfunction and abnormal TSH with normal thyroid levels may improve with time, so careful monitoring of thyroid function is recommended. Overt thyroid disease should always be treated. CONCLUSION: Clinical judgement is always warranted to decide how and when to treat subclinical thyroid disease in the elderly. ABBREVIATIONS: FT4 = free thyroxine; rT3 = reverse triiodothyronine; T3 = triiodothyronine; T4 = thyroxine; TFT = thyroid function test; TSH = thyroid-stimulating hormone. PMID- 28816539 TI - NONOPERATIVE MANAGEMENT OF DIFFERENTIATED THYROID CANCER IN CALIFORNIA: A POPULATION-LEVEL ANALYSIS OF 29,978 PATIENTS. AB - OBJECTIVE: There has been increasing interest in active surveillance of papillary thyroid microcarcinoma. The objective of this study was to characterize the incidence and outcomes of nonoperatively managed differentiated thyroid cancers (DTCs) in California. METHODS: Biopsy-proven DTCs from the California Cancer Registry were linked to data from the California Office of Statewide Health Planning and Development (2004-2012). Low-risk tumors were defined as localized disease measuring <4 cm without extrathyroidal extension, nodal involvement, or distant metastasis. RESULTS: Of 29,978 patients with DTC, 318 (1.1%) were managed nonoperatively. Compared to operatively managed patients, patients managed nonoperatively were older with more comorbidities, larger tumors (mean size, 2.9 cm vs. 2.0 cm), and an increased rate of distant metastasis (20.4% vs. 3.4%). Independent predictors of nonoperative management included increasing age, larger tumor size, papillary histology, and distant metastases. Of 10,795 patients with low-risk tumors, 161 (1.5%) were managed nonoperatively, with tumor size as follows: <1 cm (15.5%), 1 to 2 cm (50.3%), >2 to 3 cm (24.3%), and >3 to 4 cm (9.9%). There were no disease-specific deaths in the low-risk, nonoperative group (median follow-up [interquar-tile range], 21.3 [5.7 to 51.1] months). The proportion of patients managed nonoperatively remained relatively stable over the study period (mean increase 0.1% per year, P = .09). All P values were <.05 unless otherwise stated. CONCLUSION: The vast majority of patients with DTCs are treated surgically, suggesting active surveillance is rarely practiced in California. Although follow-up was limited, no disease-specific mortality in nonoperatively managed, low-risk DTCs was observed. ABBREVIATIONS: CCI = Charlson Comorbidity Index; CCR = California Cancer Registry; CI = confidence interval; DTC = differentiated thyroid cancer; FTC = follicular thyroid carcinoma; HCC = Hurthle cell carcinoma; IQR = interquartile range; mPTC = papillary thyroid micro carcinoma; OR = odds ratio; OSPHD = Office of Statewide Health Planning and Development; PTC = papillary thyroid carcinoma. PMID- 28816540 TI - A COMPARISON OF PATIENT AND HEALTHCARE PROFESSIONAL VIEWS WHEN ASSESSING QUALITY OF INFORMATION ON PITUITARY ADENOMA AVAILABLE ON THE INTERNET. AB - OBJECTIVE: Patients are increasingly turning to the internet to seek reliable sources of health information and desire guidance in assessing the quality of information as healthcare becomes progressively more complex. Pituitary adenomas are a rare, diverse group of tumors associated with increased mortality and morbidity whose management requires a multidisciplinary approach. As such, patients with this disorder are often searching for additional sources of healthcare information. We undertook a study to assess the quality of information available on the internet for patients with pituitary adenoma. METHODS: After exclusion, 42 websites were identified based on a search engine query with various search terms. Each website was assessed in triplicate: once by a health professional, once by a simulated patient, and once by a patient who had a pituitary adenoma and underwent medical and surgical treatment. The assessment tools included a content-specific questionnaire, the DISCERN tool, and the Ensuring Quality Information for Patients tool. The readability of the information was assessed with the Flesch-Kincaid grade level. RESULTS: We found that the overall quality of information on pituitary adenoma on the internet was variable and written at a high grade level. Correlation between the different assessors was poor, indicating that there may be differences in how healthcare professionals and patients view healthcare information. CONCLUSION: Our findings highlight the importance of assessment of the health information by groups of the intended user to ensure the needs of that population are met. Abbreviation: EQIP = Ensuring Quality Information for Patients. PMID- 28816541 TI - VARIABILITY IN THYROID CANCER MANAGEMENT AND PROGNOSIS AMONG HISPANIC VERSUS NON HISPANIC PATIENTS : 17 YEARS DATA FROM UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AND UNIVERSITY HEALTH SYSTEM AT SAN ANTONIO. AB - : Abstracts: Objective : Given the increase in the incidence of thyroid cancer in the United States, and it's potential public health implications, patient studies assessing ethnic, disparity and health care access are important. In this study, we retrospectively examined the variability in stage of thyroid cancer at presentation and final outcome among Hispanic vs non-Hispanic patients. METHOD: After obtaining IRB approval, we retrospectively reviewed the medical records of 220 adult patients with papillary thyroid carcinoma(PTC) who were treated at UT Health Science Center San Antonio between1996 and 2013. At disease presentation, patients were staged and risk stratified according to the 2009 American Thyroid Association (ATA) and TNM staging system. Clinical data obtained during the first 6-18 months was used to identify the initial response to therapy and clinical data from the last follow up visit was used to identify the "final" outcome. We examined the effect of insurance and ethnicity on initial response to therapy and final outcome using Chi-square test and one way ANOVA. RESULT: Our patient population's ATA risk at diagnosis, initial response to therapy and final outcome did not differ by ethnicity (P=0.5, 0.3 &0.4) and insurance coverage(P=0.7, 0.3 & 0.4) . CONCLUSION: Insurance coverage and ethnicity may not be independent factors since ethnic minority individuals are more likely to be uninsured. PMID- 28816542 TI - The fate of asymptomatic severe carotid stenosis in the era of best medical therapy. AB - BACKGROUND: Medical therapy for asymptomatic carotid artery stenosis (ACAS) may obviate the carotid revascularization, according to recent literature reports, but many studies also considered moderate carotid artery stenosis (50-69% NASCET). This study reviews the most recent series of ACAS focusing on ipsilateral transient ischemic attack (TIA) stroke and annual risk of stroke in patients with ACAS >=70%, thereby also evaluating the adherence to best medical therapy (BMT). METHODS: A systematic review consisting of all the series of patients with ACAS being treated medically was performed, which was published after 2005. The annual pooled risk of ipsilateral TIA-stroke and stroke in patients with ACAS >=70% was calculated. A subgroup of studies with BMT defined as >=90% of the patients in antiplatelet and statin therapy was performed. RESULTS: Eleven studies, with the enrolling period from 1996 to 2009, were reviewed. Overall, 2185 patients were considered, with a follow-up from 2 to 13 years, for a total of 6834 patients/year. The pooled risk was 3.4%/year for ipsilateral TIA-stroke and 1.6%/year for stroke. Five studies, published from 2014, had BMT adherence, for a total of 1665 patients/year. The pooled risk was 3.5%/year for ipsilateral TIA-stroke and for stroke. CONCLUSION: The most recent series of ACAS >=70% and BMT had an overall stroke rate which is relatively low; however, the risk of developing symptoms is still relevant (3.4%/year). PMID- 28816543 TI - MiR-541-5p regulates lung fibrosis by targeting cyclic nucleotide phosphodiesterase 1A. AB - AIM OF THE STUDY: Idiopathic pulmonary fibrosis (IPF) is a lethal human disease with short survival time and few treatment options. In this study, we aim to demonstrate that cyclic nucleotide phosphodiesterase 1A (PDE1A), a Ca2+/calmodulin-stimulating PDE family member, plays a critical role in the induction of fibrosis and angiogenesis in the lung. MATERIALS AND METHODS: To induce pulmonary damage, adult male SD rats were treated with bleomycin in a dose of 6 mg/kg body weight by a single intratracheal instillation. For in vivo silencing of PDE1A in rat lung, a nonspecific control siRNA or PDE1A-specific siRNA was used to treat rat through nasal instillation. Human normal pulmonary fibroblasts MRC-5 and hFL1 and rat lung fibroblasts were used as in vitro model. Immunohistochemistry and immunoflurescence staining were performed to detect PDE1A and alpha-SMA expression. Reverse transcription-qPCR was performed to detect microRNA and mRNA expression. In vitro wound healing assay was performed to detect pulmonary fibroblasts'mortality ability. RESULTS: In vitro studies showed that PDE1A can stimulate lung fibroblasts to undergo myofibroblastic changes. This led to the identification of miR-541-5p as one of the miRNA candidates associated with bleomycin response. We found that miR-541-5p expression is downregulated in TGF-beta-treated lung fibroblasts and the rat pulmonary fibrosis model. Overexpression of miR-541-5p in lung fibroblasts inhibited mortality of human lung fibroblasts. CONCLUSIONS: MiR-541-5p is a key effector in lung fibroblastsby by regulating PDE1A expression at protein translation level and its overexpression is protective against bleomycin-induced lung fibrosis. PMID- 28816544 TI - Animal inflammation-based models of depression and their application to drug discovery. AB - INTRODUCTION: Depression, anxiety and other affective disorders are globally widespread and severely debilitating human brain diseases. Despite their high prevalence and mental health impact, affective pathogenesis is poorly understood, and often remains recurrent and resistant to treatment. The lack of efficient antidepressants and presently limited conceptual innovation necessitate novel approaches and new drug targets in the field of antidepressant therapy. Areas covered: Herein, the authors discuss the emerging role of neuro-immune interactions in affective pathogenesis, which can become useful targets for CNS drug discovery, including modulating neuroinflammatory pathways to alleviate affective pathogenesis. Expert opinion: Mounting evidence implicates microglia, polyunsaturated fatty acids (PUFAs), glucocorticoids and gut microbiota in both inflammation and depression. It is suggested that novel antidepressants can be developed based on targeting microglia-, PUFAs-, glucocorticoid- and gut microbiota-mediated cellular pathways. In addition, the authors call for a wider application of novel model organisms, such as zebrafish, in studying shared, evolutionarily conserved (and therefore, core) neuro-immune mechanisms of depression. PMID- 28816545 TI - Role of diffusion tensor imaging in the diagnosis and management of post traumatic anosmia. AB - INTRODUCTION: Anosmia is a possible complication of Traumatic Brain Injury (TBI). Psychometric and electrophysiological methods of olfaction measure and Magnetic Resonance Imaging (MRI) are the tools to evaluate the post-traumatic olfactory loss. Diffusion Tensor Imaging (DTI) provides useful data for a better understanding of etiopathogenesis TBI-related anosmia, in particular the loss of neural connections and their eventual recovery over time. MATERIALS AND METHODS: This study describes a case of TBI-related anosmia. The olfactory function was evaluated by Sniffin' Sticks Test (SST), Olfactory Event-Related Potentials (OERPs), MRI and DTI at baseline (T0) and after one year (T1). RESULTS: At baseline, SST highlighted a functional anosmia. The OERPs showed the presence of a small N1-P2 complex. MRI confirmed the presence of a scarring involved in the right orbitofrontal cortex (OFC). DTI detected a reduction in the average length and the number of neuronal fibre pathways of right OFC. At T1, a recovery of olfactory function was confirmed by SST and OERPs. CONCLUSION: While MRI images are unchanged from T0, DTI showed an increase in average length and number of fibre tracts in the right OFC. DTI could be a valid tool to display a post traumatic loss of neural connections and to better understand TBI-recovery mechanisms. PMID- 28816546 TI - Determination of Topographic Variations in Inner Retinal Blood Flow Areas in Young Chinese Subjects Using Optical Coherence Tomography Angiography. AB - PURPOSE: To investigate (i) topographic variations in, and (ii) establish references for, inner retinal blood flow areas of the macular region of young Chinese subjects by means of optical coherence tomography (OCT) angiography. METHODS: To measure inner retinal blood flow areas, we scanned an 8 * 8 mm2 area and centered on the fovea of 336 eyes from 170 subjects using OCT angiography. Blood flow area measurements were made from a 1-mm radius circle, centered on the fovea, and 3 mm to the fovea superiorly, inferiorly, temporally, and nasally. RESULTS: Mean inner retinal blood flow areas in the parafoveal, superior, inferior, nasal, and temporal macular regions were 1.78 +/- 0.28, 1.76 +/- 0.30, 1.69 +/- 0.31, 1.91 +/- 0.31, and 1.71 +/- 0.28 mm,2 respectively. Nasal inner retinal blood flow areas were significantly larger than other macular regions (p < 0.001). Gender was significantly associated with inner retinal blood flow areas of all macular regions studied. A gender-based subgroup analysis showed that inner retinal blood flow areas in superior, inferior, nasal, and temporal macular regions were significantly larger in women than men (all p < 0.05). CONCLUSIONS: Nasal blood flow areas were larger than parafoveal blood flow areas, which were larger than superior blood flow areas, which were larger than temporal blood flow areas, which were larger than inferior blood flow areas in the macular regions studied. Gender was significantly associated with inner retinal blood flow areas in all macular regions studied. PMID- 28816547 TI - Drug utilization among hypertensive patients in the outpatient department of medicine in a tertiary care hospital: A cross-sectional study. AB - BACKGROUND: Hypertension is one of the leading risk factors for cardiovascular, cerebrovascular, and renal disease. Its increasing prevalence and treatment costs influence the prescribing pattern among physicians. Drug utilization studies provide insights into the current prescribing practices and help us facilitate the rational use of drugs. We carried out the present study to assess the pattern of drug utilization in hypertensive patients. METHOD: Adults seeking treatment for hypertension were recruited. Prescriptions were studied for demographic and drug-use details. The World Health Organization indices for drug utilization were evaluated. The percentage of prescriptions adhering to the recent guidelines was determined. RESULTS: Enalapril was the most commonly prescribed drug. Monotherapy was used in 71.8% of the cases. However, 42% of the cases were newly diagnosed. The ratio of prescribed daily dose and defined daily dose showed underutilization of enalapril and atenolol and overutilization of amlodipine. About 87.5% of the prescriptions adhered to Eighth Joint National Committee guidelines. Most of the medications were available at the hospital pharmacy store and were prescribed by their generic names. Total 65.3% of the concomitant medications were not listed in the World Health Organization essential list of medicines. The average number of drugs prescribed was six. A median cost of 14.6 and 94.5 rupees was spent, respectively, on anti-hypertensive and concomitant medications per encounter. CONCLUSION: The adherence to the guideline was good. Polypharmacy can be reduced by avoiding the prescription of unnecessary medications and promoting the use of fixed-dose combinations. PMID- 28816548 TI - Dietary Supplementation with Virgin Coconut Oil Improves Lipid Profile and Hepatic Antioxidant Status and Has Potential Benefits on Cardiovascular Risk Indices in Normal Rats. AB - Research findings that suggest beneficial health effects of dietary supplementation with virgin coconut oil (VCO) are limited in the published literature. This study investigated the in vivo effects of a 5-week VCO supplemented diet on lipid profile, hepatic antioxidant status, hepatorenal function, and cardiovascular risk indices in normal rats. Rats were randomly divided into 3 groups: 1 control and 2 treatment groups (10% and 15% VCO supplemented diets) for 5 weeks. Serum and homogenate samples were used to analyze lipid profile, hepatorenal function markers, hepatic activities of antioxidant enzymes, and malondialdehyde level. Lipid profile of animals fed VCO diets showed significant reduction in total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) levels; high-density lipoprotein (HDL) level increased significantly (p < .05) compared to control; and there were beneficial effects on cardiovascular risk indices. The level of malondialdehyde (MDA), a lipid peroxidation marker, remarkably reduced and activities of hepatic antioxidant enzymes-superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx)-were markedly increased in VCO diet-fed rats. The VCO diet significantly modulated creatinine, sodium (Na+), potassium (K+), chloride (Cl-), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) compared to control. The findings suggest a beneficial effect of VCO on lipid profile, renal status, hepatic antioxidant defense system, and cardiovascular risk indices in rats. PMID- 28816549 TI - Implications of Bcl-2 and its interplay with other molecules and signaling pathways in prostate cancer progression. AB - INTRODUCTION: Among several genetic alterations involved in the progression of prostate cancer, B cell lymphoma gene number 2 (BCL-2) is an important target molecule in the progression of androgen-independent prostate cancer (AIPC) after androgen ablation or castration. Nevertheless, the molecular mechanism of BCL-2 in prostate cancer progression remains elusive and controversial. In the current review, we discuss the critical role of BCL-2 in the carcinogenesis of prostate cancer with experimental evidences on the BCL-2 molecular networks in AIPC and androgen-dependent prostate cancer (ADPC) and subsequently suggest perspective research targeting BCL-2. Areas covered: This review focused on the molecular implications of BCL-2 in association with other molecules and signaling pathways involved in the progression and carcinogenesis of prostate cancer. Expert opinion: BCL-2 plays a pivotal role in the progression of AIPC than in ADPC since androgen represses BCL-2. BCL-2 acts as a pro-survival molecule in association with androgen-related signaling in the progression of ADPC, while BCL-2 upregulation, PTEN loss, PI3K/AKT phosphorylation and receptor tyrosine kinase (RTK) activation are primarily involved in AIPC. To identify more effective prostate cancer therapy, further mechanistic studies are required with BCL-2 inhibitors in AIPC and ADPC, considering a multi-target therapy against BCL-2 and its related signaling. PMID- 28816550 TI - A Review on Biosynthesis, Analytical Techniques, and Pharmacological Activities of Trigonelline as a Plant Alkaloid. AB - Trigonelline (TRG) as a polar hydrophilic alkaloid is extracted from many plant species, for example, Trigonella foenum-graecum, Allium sepapea, Coffea sp, Pissum sativum, Glycine max, and Lycopersicon esculentum. Numerous biological activities have been reported for TRG such as protection of heart and liver and treatment of hyperglycemia, hypercholesterolemia, nervous and hormonal disorders, and cancers. Thus, the aim of this review is to summarize some information about TRG's biosynthesis pathway, pharmacological activity, pharmacokinetics, and analytical techniques to introduce TRG as an alternative choice to treat the various diseases. However, current evidence is still inadequate for introducing TRG as a novel drug, and it is necessary to examine more clinical trials to determine its acute and chronic side effects, bioavailability, pharmacokinetic parameters, and mechanisms of action. PMID- 28816551 TI - 1alpha,25-Dihydroxyvitamin D3 up-regulates IL-34 expression in SH-SY5Y neural cells. AB - Vitamin D supplementation is regarded as a novel approach to treat Alzheimer's disease, but the underlying mechanism remains elusive. The cytokine IL-34 provides strong neuroprotective and survival signals in brain injury and neurodegeneration and could be an immunological mediator for the vitamin D induced protection. The aim of this study was to investigate whether human IL-34 is up-regulated in neuronal cells by the hormonally active form of vitamin D, 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3]. We found that IL-34 was detectable in a variety of cell lines and its expression was strongly induced in SH-SY5Y neural cells in a dose- and time-dependent manner by 1alpha,25(OH)2D3 through the vitamin D receptor (VDR). Furthermore, we identified the core promoter of IL-34 gene and a VDR binding site (CGCCCT) that was required for 1alpha,25(OH)2D3-induced IL-34 expression. These findings suggest that the induction of IL-34 expression by 1alpha,25(OH)2D3 may constitute a mechanism that explains the protective function of vitamin D in Alzheimer's disease. PMID- 28816552 TI - The role of biopsy in lacrimal gland inflammation: A clinicopathologic study. AB - PURPOSE: To determine the causes of lacrimal gland inflammation based on histopathology and systemic evaluation. METHODS: This is a retrospective case series study. From the University of British Columbia Orbit Clinic between January 1976 and December 2008, we reviewed the medical records of 60 patients who presented with inflammatory features of the lacrimal gland (i.e., erythema, edema, or tenderness) in which the diagnoses were not possible clinically and on imaging alone. As was our routine practice, all these patients underwent lacrimal gland biopsy before starting any treatment. RESULTS: The histopathologic findings of the 60 patients showed that 37 (61.7%) had identifiable types of lacrimal inflammation including 10 with Sjogren's syndrome, seven with sarcoidal reaction, six with feature of granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis), five with lymphoma, two with sclerosing inflammation, two with IgG4-related dacryoadenitis, and one patient each with infectious dacryoadenitis, myoepithelial carcinoma, xanthogranuloma, eosinophilic angiocentric fibrosis, and eosinophilic allergic granulomatous nodule. The histopathologic findings of the remaining 23 (38.3%) patients showed nonspecific inflammation of the lacrimal gland. 23 patients (38.3%) had associated systemic diseases. 48 patients (80%) were treated successfully and 10 (16.7%) had recurrence of inflammation. CONCLUSIONS: We recommend that in patients presenting with lacrimal gland inflammation (i.e., erythema, edema, tenderness) in which the specific diagnosis cannot be made clinically and on imaging, biopsy is warranted for accurate diagnosis and appropriate treatment. We found that the majority of these patients (61.7%) had specific histopathology, and 38% had systemic diseases. PMID- 28816553 TI - A rare case of giant multicystic solitary fibrous tumor of the orbit. AB - Solitary fibrous tumor (SFT) is a rare spindle cell tumor of the orbit of mesenchymal origin. Though these tumors are mostly solid, partial or complete cystic changes can rarely occur. Only six such previous cases of cystic fibrous tumor of the orbit have been mentioned in the literature. We report a case of an elderly male who presented with a huge left sided medial orbital mass. Magnetic resonance imaging showed a predominant cystic orbital mass separated by septae and suggested a diagnosis of Hydatid cyst. The patient underwent complete excision of the mass and histopathology and immunohistochemistry were suggestive of cystic SFT. Cystic degeneration in SFT is extremely rare and can be a harbinger of malignancy, and pose risk of recurrence. Close follow up and monitoring is required for all such cases. PMID- 28816554 TI - Vaginal axis on MRI after unilateral and bilateral sacral hysteropexy: a controlled study. AB - The objective of this study was to evaluate the vaginal position on magnetic resonance imaging (MRI) after bilateral abdominal sacral hysteropexy (BASH) and classical abdominal sacral hysteropexy (ASH) and to investigate which method keeps the vagina the most proximate to its original anatomical position. Ten patients, with 10 having BASH, 10 ASH and 10 being nulliparous, were compared. The angle between the vagina and the pubococcygeal plate, the angle between the upper and lower vaginal segments, the distance between the posterior fornix and the 2nd vertebra and the distances between the lateral fornices and spina ischiadica were measured on MRI. A p value less than .05 was considered statistically significant. The distance between the vaginal axis and the left spina ischiadica was greater in the ASH group compared to the control and the BASH group (p = .011, .047), while it was similar between the BASH group and the control individuals (p = .473). The angle between the upper and lower vaginal segments was greater in the ASH group compared to the control group (p = .004), while no significant difference was found between the BASH and control groups (p = .112). BASH keeps the vaginal axis at a more proximate location to its original anatomical position. IMPACT STATEMENT What is already known on this subject: In pelvic reconstructive surgery; the anatomic correction serves the functional results. What the results of this study add: On MRI examination bilateral abdominal sacral hysteropexy (mimicking uterosacral ligament), keeps the vagina closer to the original anatomic position than classical abdominal sacral hysteropexy. Hence functional outcomes could be better, especially in the long term. What the implications are of these findings for clinical practice and/or further research: This study may be of interest for clinicians in terms of different methods for pelvic floor surgery and may be of interest for researchers to investigate the relationship between anatomic position and functional outcomes especially in younger patients. PMID- 28816555 TI - Chemical Utilization of Albizia lebbeck Leaves for Developing Protein Concentrates as a Dietary Supplement. AB - In search of nonconventional sources of protein to combat widespread malnutrition, the possibility of developing a protein concentrate as an alternative dietary supplement from abundantly available yet poorly valorized leaves of Albizia lebbeck (siris) was examined. A process for recovery of leaf protein concentrate (LPC) from these leaves was optimized and applied for isolation of LPCs from lower, middle, and upper canopies of the tree. The optimized conditions (leaves to water 1:9, coagulation at pH 4.0 using 1 N citric acid at 90 degrees C for 11 minutes) afforded LPCs containing protein 37.15%, 37.57%, and 37.76% in 5.99%, 5.97%, and 6.07% yield, respectively. The proximate nutritional composition, pigments, minerals, in vitro digestibility, and antinutritional factors of these LPCs were determined. Analysis of variance of these data revealed no significant difference with respect to canopy. Use of Albizia lebbeck leaves for development of LPC as a food/feed supplement was revealed. PMID- 28816556 TI - Maternal mortality in the last triennium of the Millennium Development Goal Era at the Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria. AB - : The maternal mortality ratio (MMR) of Nigeria remains high. This retrospective study aims to suggest evidence-based strategies towards achieving the sustainable development goal target 3.1 at the Obafemi Awolowo University Teaching Hospital (OAUTHC), Nigeria by providing contemporary data on MMR between October 2012 and September 2015. There were 86 maternal deaths and 5243 live births over the triennium, with annual MMRs of 1744, 1622 and 1512/100,000 live births, respectively. Fifty-six (65.2%) were postpartum deaths, while 44 (51.2%) occurred within 12 hours of admission. Using the WHO ICD-10 system, the causes of mortality were pregnancy-related infections; 26 (30.2%), haemorrhage; 20 (23.3%), hypertension; 13 (15.2%) and pregnancies with abortive outcomes; 11 (12.7%). Financial constraints, misdiagnosis and delayed referrals constituted the predominant contributors. The MMR at OAUTHC, Nigeria in the last triennium of the MDG was 'Extremely High'. Improved aseptic techniques, blood transfusion services, antimicrobial sensitivity evaluation, Universal Health Coverage, training-retraining of skilled birth-attendants and effective referral systems are advocated. IMPACT STATEMENT What is already known on the subject of the paper: Nigeria now contributes the largest proportion (19%) of the burden of maternal mortality worldwide, despite constituting just 2% of the global population. Reversing this adverse trend during the sustainable development goal (SDG) period demands effective strategies, which can only be predicated on reliable data at the hospital, regional and national levels. WHAT THIS STUDY ADDS: This article provides the contemporary maternal mortality data of the Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria, during the last triennium of the Millennium Development Goal era. The findings from the study revealed that the average maternal mortality ratio (MMR) of the Hospital over the three years was 1640/100,000 live births, and that pregnancy-related infection is now the leading cause of maternal death, followed by obstetric haemorrhage. What the implications are for clinical practice: Improvement in aseptic techniques, evaluation of antimicrobial sensitivity patterns and efficient blood transfusion services, as well as Universal Health Insurance coverage and Skilled Birth Attendants will improve the maternal health indices of the hospital, and ultimately the country during the SDG execution period. PMID- 28816557 TI - CD44 as a cancer stem cell marker and its prognostic value in patients with ovarian carcinoma. AB - : The aim of our study was to clarify whether the CD44 adhesion molecule as a cancer stem cell marker could also serve as a prognostic factor in patients with epithelial ovarian cancer (EOC). A retrospective study was performed on 87 patients with histologically verified EOC. Specimens of both primary tumour and implantation metastases were tested from 48 of them. CD44 expression was detected by immunohistochemistry. We looked for the cut-off levels of CD44 expression using the Cox regression model. We confirmed statistically significant prognostic factors for overall survival (OS) and disease-free interval (DFI) to be: stage of the disease, postoperative residual tumour and papillary serous histological type. We demonstrated a statistically significant correlation between low CD44 expression and serous papillary carcinoma histotype, tumour recurrence and chemoresistance at a value below 2%. CD44 was neither a prognostic factor of OS nor of DFI. IMPACT STATEMENT What is already known about this subject: Epithelial ovarian cancer is the second most common gynaecological cancer in developed countries. Despite great efforts devoted to ovarian cancer research during past decades, levels of patient mortality have changed very little. Cancer stem cells (CSCs) are subpopulations of cells with typical characteristics of stem cells - i.e. the ability to self-renew and differentiate in a variety of cell types. The main surface marker typical for CSCs is CD44. The aim of our study was to clarify whether the CD44 as a CSCs marker could serve as a prognostic factor in patients with epithelial ovarian cancer. Previous studies published on this topic revealed controversial results. The novelty of our study lies in looking for the cut-off using the Cox regression model. WHAT THIS STUDY ADDS: We demonstrated a statistically significant correlation between low CD44 expression and serous papillary carcinoma histotype, tumour recurrence and chemoresistance at a value below 2%, however, CD44 was neither a prognostic factor of overall survival nor of disease-free interval. We propose to investigate other markers including other CSCs as a prognostic factors or potential aims for targeted therapy in ovarian cancer. PMID- 28816558 TI - Effect of feedback from a socially interactive humanoid robot on reaching kinematics in children with and without cerebral palsy: A pilot study. AB - PURPOSE: To examine whether children with or without cerebral palsy (CP) would follow a humanoid robot's (i.e., Darwin) feedback to move their arm faster when playing virtual reality (VR) games. METHODS: Seven children with mild CP and 10 able-bodied children participated. Real-time reaching was evaluated by playing the Super Pop VRTM system, including 2-game baseline, 3-game acquisition, and another 2-game extinction. During acquisition, Darwin provided verbal feedback to direct the child to reach a kinematically defined target goal (i.e., 80% of average movement time in baseline). Outcome variables included the percentage of successful reaches ("% successful reaches"), movement time (MT), average speed, path, and number of movement units. RESULTS: All games during acquisition and extinction had larger "%successful reaches," faster speeds, and faster MTs than the 2 games during baseline (p < .05). CONCLUSION: Children with and without CP could follow the robot's feedback for changing their reaching kinematics when playing VR games. PMID- 28816559 TI - The role of the lectin-like oxLDL receptor (LOX-1) in traffic-generated air pollution exposure-mediated alteration of the brain microvasculature in Apolipoprotein (Apo) E knockout mice. AB - Recent studies have shown a strong correlation between air pollution-exposure and detrimental outcomes in the central nervous system, including alterations in blood brain barrier (BBB) integrity, neuroinflammation, and neurodegeneration. However, the mechanisms mediating these pathologies have not yet been fully elucidated. We have previously reported that exposure to traffic-generated air pollution results in increased circulating oxidized low-density lipoprotein (oxLDL), associated with alterations in BBB integrity, in atherosclerotic Apolipoprotein E null (ApoE-/-) mice. Thus, we investigated the role of the lectin-like oxLDL receptor (LOX)-1 in mediating these deleterious effects in ApoE /- mice exposed to a mixture of gasoline and diesel engine exhaust (MVE: 100 PM ug/m3) for 6 h/d, 7d/week, for 30 d by inhalation. Concurrent with exposures, a subset of mice were treated with neutralizing antibodies to LOX-1 (LOX-1 Ab) i.p., or IgG (control) i.p., every other day during exposures. Resulting brain microvascular integrity, tight junction (TJ) protein expression, matrix metalloproteinase (MMP)-9/-2 activity, ROS, and markers of cellular adhesion and monocyte/macrophage sequestration were assessed. MVE-exposure resulted in decreased BBB integrity and alterations in microvascular TJ protein expression, associated with increased LOX-1 expression, MMP-9/-2 activities, and lipid peroxidation, each of which was attenuated with LOX-1 Ab treatment. Furthermore, MVE-exposure induced cerebral microvascular ROS and adhesion molecules, expression of which was not normalized through LOX-1 Ab-treatment. Such findings suggest that alterations in brain microvascular structure and integrity observed with MVE-exposure may be mediated, at least in part, via LOX-1 signaling. PMID- 28816561 TI - Editorial. PMID- 28816560 TI - Gastroprotective and Antiulcer Effects of Celastrus paniculatus Seed Oil Against Several Gastric Ulcer Models in Rats. AB - Peptic ulcer is a recurrent chronic illness and has become almost a hallmark of the so-called civilized life. In folk medicine, the Celastrus paniculatus plant has been used for the prevention and treatment of various diseases and gastrointestinal disturbances, including dyspepsia and stomach ulcers. The aim of this study is to evaluate the gastroprotective and antiulcer effects of Celastrus paniculatus seed oil (CPO) against several gastric ulcer models in rats. The gastroprotective and antiulcer effects of CPO were evaluated using pylorus ligated ulcer ethanol- and indomethacin-induced ulcers using rantidine (40 mg/kg per os [PO]) as standard. Gastrointestinal motility was determined by gastric emptying time and gastrointestinal transit ratio. The results of the pharmacological studies of CPO (200 mg/kg, 400 mg/kg) demonstrated effective gastroprotection against ethanol- and indomethacin-induced ulcer models. In pylorus-ligated rats, the seed oil showed gastroprotective activity by decreasing total gastric juice volume and gastric acidity while increasing the gastric pH. The gastroprotection against ethanol and indomethacin is partially attributed to effective inhibition of proinflammatory cytokines, TNF-alpha and IL-6, and increase in the levels of IL-10. Treatment with CPO in ethanol-induced ulcer rats significantly (p < .05) decreased MDA (malondialdehyde) levels, which were accompanied by an increase in the activities of SOD (superoxide dismutase) and catalase. CPO reduced the rate of gastric emptying but had no effect on gastrointestinal transit. The present findings indicate that CPO has potent gastroprotective effects and support the folkloric usage of the seed oil to treat various gastrointestinal disturbances. PMID- 28816562 TI - Behcet's disease and pregnancy: what to expect? AB - The relationship between Behcet's disease (BD) and pregnancy is only reported in limited number of studies. We retrospectively collected data of 26 women with BD diagnosis and their 66 pregnancies. We analysed patients according to disease activity, age at BD diagnosis, age at first/last pregnancy, obstetric history, obstetric complications, neonatal birthweight, associated foetal abnormalities and pregnancy-related complications. Sixteen miscarriages (24.2%), two intrauterine deaths (3%) and 48 live births (72.8%) were identified. Preterm labour was observed in 12 (24%) of 50 deliveries. Colchicine was used in six pregnancies, however, there was no drug treatment for BD in the remaining 59. There was a higher rate of preterm labour and low birthweight in patients using colchicine. BD was in remission in 60 (90.9%) of 66 pregnancies, and disease flared up only in six cases. In conclusion, BD patients with altered symptoms during pregnancy carry an increased risk of obstetric complications. IMPACT STATEMENT What is already known on this subject: There are limited and conflicting data about the interaction between BD and gestation. What the results of this study add: Our findings indicated that patients who were in an active symptomatic phase of BD and were being treated with colchicine had an increased risk of preterm delivery and low birthweight. What the implications are of these findings for clinical practice and/or further research: Clinicians should consider increased obstetric complication risk among patients with active BD. PMID- 28816563 TI - Highlighting the differences in post-traumatic symptoms between patients with complicated and uncomplicated mild traumatic brain injury and injured controls. AB - OBJECTIVE: The goal of the current study is to explore the difference in acute post-concussive symptoms (PCS), headaches, sleep and mood complaints between groups of patients with complicated and uncomplicated mild traumatic brain injuries (mTBIs) and a comparable group of injured controls. Interactions among the following four factors were studied: presence of (1) PCS; (2) headaches; (3) sleep disorders; and (4) psychological status. METHODS: A total of 198 patients, followed at the outpatient mTBI clinic of the MUHC-MGH, completed questionnaires and a brief neurological assessment two weeks post-trauma. RESULTS: Whether they had a TBI or not, all patients presented PCS, headaches, sleep and mood complaints. No significant differences between groups in terms of reported symptoms were found. Variables such as depression and anxiety symptoms, as well as sleep difficulties and headaches were found to correlate with PCS. The high rate of PCS in trauma patients was observed independently of traumatic brain injury status. This study has also shown that patients with complicated mTBI were more likely to have vestibular impairment after their injury. CONCLUSION: The vestibular function should be assessed systematically after a complicated mTBI. Furthermore, the mTBI diagnosis should be based on operational criteria, and not on reported symptoms. PMID- 28816564 TI - Cytotoxicity screening and cytokine profiling of nineteen nanomaterials enables hazard ranking and grouping based on inflammogenic potential. AB - Engineered nanomaterials (ENMs) are being produced for an increasing number of applications. Therefore, it is important to assess and categorize ENMs on the basis of their hazard potential. The immune system is the foremost defence against foreign bodies. Here we performed cytokine profiling of a panel of nineteen representative ENMs procured from the Joint Research Centre (JRC) and commercial sources. Physicochemical characterization was performed using dynamic light scattering. The ENMs were all shown to be endotoxin content free. The human macrophage-differentiated THP.1 cell line was employed for cytotoxicity screening and based on the calculated IC50 values, the multi-walled carbon nanotubes (MWCNTs), ZnO, Ag and SiO2 NMs were found to be the most cytotoxic while single walled carbon nanotubes (SWCNTs), TiO2, BaSO4 and CeO2 NMs, as well as the nanocellulose materials, were non-cytotoxic (at doses up to 100 ug/mL). Multiplex profiling of cytokine and chemokine secretion indicated that the TiO2, SiO2, BaSO4, CeO2 and nanocellulose materials induced potent inflammatory responses at sub-cytotoxic doses. Hierarchical clustering of cytokine responses coupled with pathway analysis demonstrated that the panel of ENMs could be segregated into two distinct groups characterized by activation and deactivation, respectively, of PPAR (peroxisome proliferator-activated receptor)/LXR (liver X receptor/retinoid X receptor) nuclear receptor pathways (NRPs). Furthermore, using rosiglitazone, a selective PPAR-gamma agonist, we could show that PPAR-gamma played an important role in the activation of inflammatory responses in cells exposed to TiO2 and SiO2 NMs. These studies show that ENMs of diverse chemical compositions can be grouped according to their inflammatory potential. PMID- 28816565 TI - Dacryocystectomy as a treatment of chronic dacryocystitis in the elderly. AB - To evaluate the dacryocystectomy (DCT) outcomes for chronic dacryocystitis in an elderly population over 70 years old. A retrospective chart review was performed for patients over 70 years old who were diagnosed with chronic dacryocystitis and underwent DCT at the Botucatu School of Medicine, UNESP, Brazil, from 2007 to July 2014. Data were collected about patient demographics, age, gender, previous nasal, or ophthalmic diseases, symptoms related to the lacrimal drainage system preoperatively and postoperatively, signs of enlargement of the lacrimal sac (regurgitation of secretion), and histopathologic evaluation. The study sample was comprised of 17 patients with an average age of 76.5 +/- 8.5 years. The major complaint for all patients was tearing and 17.6% patients had an additional complaint of discharge. Regurgitation of secretion with lacrimal sac expression was present in 76.5% of patients. Postoperatively, 76.5% of the patients reported improvement of the initial complaint, likely due to the total excision of the lacrimal sac which removed the focal site of chronic infection. Epiphora persisted in 23.5% of patients, of whom 11.7% underwent successful lacrimal stent intubation. DCT for chronic dacryocystitis should be considered a primary procedure in individuals over 70 years old. This procedure has a much lower risk to these patients who often have associated comorbidities. PMID- 28816566 TI - Five-year motor functional outcome in children with acquired brain injury. Yet to the end of the story? AB - PURPOSE: The description of motor changes and clinical evolution of a pediatric cohort with acquired brain injury (ABI) over 5 years by the functional independence measure for children (WeeFIM). METHODS: We analyzed retrospective data from 496 patients (aged 0-18 years) with severe ABI admitted for rehabilitation. WeeFIM scores and disability rating scale (reference scale) were collected at admission, discharge and yearly, up to year 5. RESULTS: Functional limitations gradually reduced after ABI, but children still had residual disabilities at the endpoint. Seventeen percent of patients demonstrated no improvement at WeeFIM. Gait analysis showed that decreased WeeFIM scores in the mobility domain are associated with slower and shorter steps, and increased step width, compensating for imbalance. CONCLUSIONS: Five years after ABI, improvement is still found in the mobility domain of WeeFIM. This work adds evidence that margin still exists at least until year 5 after injury for profitably continuing the rehabilitation effort. PMID- 28816567 TI - How close are we to implementing a genetic risk score for coronary heart disease? AB - INTRODUCTION: Genome-wide association meta-analysis have now identified more than 150 loci where common variants (SNPs) are significantly associated with coronary heart disease (CHD) and CHD end points. Areas covered: The authors review publications from their own laboratory and published recently where identified CHD risk SNPs are used in combination, and 'scaled' by their effect size, to create a 'weighted' Genetic risk Score (GRS), which, in combination with an individual's classical CHD risk factors, can be used to identify those at overall low, intermediate and high future risk. Those at highest risk can be offered life style and therapeutic options to reduce their risk and those at intermediate levels can be monitored. Expert commentary: The authors discuss the selection of the best variants to be included in the GRS, and the potential utility of such scores in different clinical settings. The limitations of the current data sets and the way forward in the next 5 years is discussed. PMID- 28816568 TI - CUL4B mutations are uncommon in Japanese patients with Sertoli-cell-only syndrome and azoospermia. PMID- 28816569 TI - Effect of cyclic uniaxial compressive stress on human dental pulp cells in vitro. AB - PURPOSE: Teeth are exposed to various forces during functional and parafunctional movements. These processes inevitably affect the dental pulp, and the mechanism of these influences has been the subject of many previous studies using different apparatuses and obtaining different results. In this study, we aimed to investigate the effects of compressive stress on the proliferation and differentiation of human dental pulp cells (hDPCs). MATERIALS AND METHODS: A four point bending strain system was adopted to apply low-density cyclic uniaxial compressive stress (2000 microstrain, 0.5 Hz) to hDPCs for 1.5, 3, 6, 12, and 24 h. The cell cycle progression and mRNA expression of differentiation-related genes (BMP2, ALP, DMP1, DSPP, COL I) were then examined to investigate the proliferation and differentiation of hDPCs. RESULTS: The results showed that cyclic compressive stress changed the morphology of hDPCs after 12 and 24 h of mechanical loading; cell cycle progression was promoted, especially in the 24-h group (p < 0.05). The expression of BMP2 was significantly upregulated after 3 and 6 h of mechanical loading but declined in the 12- and 24-h groups, whereas the expression levels of DMP1 and DSPP were significantly upregulated in the 12- and 24-h loading groups (p < 0.05). CONCLUSIONS: Dental pulp cells were sensitive to compressive stress, especially after 12 and 24 h of applied force. Proliferation and odontogenic differentiation were significantly promoted in this in vitro model. PMID- 28816570 TI - Cardiovascular pre-participation screening in the young athlete: addressing concerns. PMID- 28816571 TI - Effects of flow changes on radiotracer binding: Simultaneous measurement of neuroreceptor binding and cerebral blood flow modulation. AB - The potential effects of changes in blood flow on the delivery and washout of radiotracers has been an ongoing question in PET bolus injection studies. This study provides practical insight into this topic by experimentally measuring cerebral blood flow (CBF) and neuroreceptor binding using simultaneous PET/MRI. Hypercapnic challenges (7% CO2) were administered to non-human primates in order to induce controlled increases in CBF, measured with pseudo-continuous arterial spin labeling. Simultaneously, dopamine D2/D3 receptor binding of [11C]raclopride or [18F]fallypride was monitored with dynamic PET. Experiments showed that neither time activity curves nor quantification of binding through binding potentials ( BPND) were measurably affected by CBF increases, which were larger than two-fold. Simulations of experimental procedures showed that even large changes in CBF should have little effect on the time activity curves of radiotracers, given a set of realistic assumptions. The proposed method can be applied to experimentally assess the flow sensitivity of other radiotracers. Results demonstrate that CBF changes, which often occur due to behavioral tasks or pharmacological challenges, do not affect PET [11C]raclopride or [18F]fallypride binding studies and their quantification. The results from this study suggest flow effects may have limited impact on many PET neuroreceptor tracers with similar properties. PMID- 28816572 TI - Effects on Alcohol Consumption and Alcohol Related Harm of a Community-Based Prevention Intervention With National Support in Sweden. AB - BACKGROUND: In order to strengthen local alcohol prevention work in Sweden the Swedish government has for the past almost 15 years commissioned the Public Health Agency of Sweden to initiate a series of community-based alcohol prevention projects. The latest of these, labeled local development with ambitions (LUMA), included 25 municipalities in Sweden. OBJECTIVES: Aim of this study is to examine if LUMA municipalities that received financial support, with requirements, increased local alcohol prevention and if alcohol consumption and harm declined. METHODS: Twenty-five Swedish municipalities that received financial support aiming to strengthen local alcohol preventing activities (intervention group) were compared to municipalities that did not receive such support (control group, N = 224), before, during, and after the intervention period. Two composite measures of policy and activity were created and used. The composite activity measure includes seven activity indicators and the composite policy measure includes six policy indicators. Harm measures have been selected based on several recommended indicators for monitoring alcohol, tobacco, and other drugs in Sweden. A fixed effects model was used to analyze data. RESULTS: The results reveal that prevention activities increased and several alcohol related harm indicators were reduced in intervention municipalities (LUMA) compared with in control municipalities. CONCLUSIONS: It seems as if financial support, combined with specific requirements and support from the regional and national level, can stimulate local alcohol prevention activities and have a significant effect on alcohol consumption and alcohol-related harm. Similar evaluations in other countries would be of great value for assessing the generalizability of findings. PMID- 28816573 TI - A longitudinal study investigating how stroke severity, disability, and physical function the first week post-stroke are associated with walking speed six months post-stroke. AB - OBJECTIVES: To investigate to which degree stroke severity, disability, and physical function the first week post-stroke are associated with preferred walking speed (PWS) at 6 months. DESIGN: Longitudinal observational study. METHOD: Participants were recruited from a stroke unit and tested within the first week (baseline) and at 6 months post-stroke. Outcome measures were the National Institutes of Health Stroke Scale (NIHSS), the Barthel Index (BI), modified Rankin Scale (mRS), PWS, Postural Assessment Scale for Stroke (PASS), and the Trunk Impairment Scale modified-Norwegian version. Multiple regression models were used to explore which variables best predict PWS at 6 months, and the Receiver Operating Characteristics (ROC) curves to determine the cutoffs. RESULTS: A total of 132 participants post-stroke were included and subdivided into two groups based on the ability to produce PWS at baseline. For the participants that could produce PWS at baseline (WSB group), PASS, PWS, and age at baseline predicted PWS at 6 months with an explained variance of 0.77. For the participants that could not produce a PWS at baseline (NoWSB group), only PASS predicted PWS at 6 months with an explained variance of 0.49. For the Walking speed at baseline (WSB) group, cutoffs at baseline for walking faster than 0.8 m/s at 6 months were 30.5 points on the PASS, PWS 0.75 m/s, and age 73.5 years. For the NoWSB group, the cutoff for PASS was 20.5 points. CONCLUSION: PASS, PWS, and age the first week predicted PWS at 6 months post-stroke for participants with the best walking ability, and PASS alone predicted PWS at 6 months post stroke for participants with the poorest walking ability. PMID- 28816575 TI - Cross-cultural translation, validity, and reliability of the French version of the Neurophysiology of Pain Questionnaire. AB - Pain physiology education is an important component in the management of patients with chronic musculoskeletal pain. The Neurophysiology of Pain Questionnaire (NPQ) was developed in English to assess pain physiology knowledge in patients. This study aimed to translate the NPQ into French (NPQ-Fr) and to investigate the main psychometric properties of the NPQ-Fr. The translation was performed using the best practice translation guidelines. One hundred and one French-speaking patients with chronic non-specific spinal pain completed the NPQ-Fr to assess its acceptability and presence of floor/ceiling effects and test its dimensionality. The construct validity was tested by comparing the patients' NPQ-Fr scores to those of 17 physiotherapists and investigating its correlation with subscales of the Short Form-36 questionnaire. The reliability (i.e., internal consistency and test-retest reliability) was also investigated. To test the test-retest reliability, 70 patients were asked to complete the NPQ-Fr twice with one week in between. Regarding the NPQ-Fr psychometric properties: 1) acceptability was good; 2) internal consistency reached a Cronbach alpha-coefficient of 0.44; 3) no floor and ceiling effects were observed in patients; 4) a principal factor analysis generated three major factors; 5) construct validity was good; and 6) reliability was acceptable (intraclass correlation coefficient = 0.644; standard error of measurement = 1.5). The NPQ-Fr has satisfactory basic psychometric properties in patients with chronic spinal pain. PMID- 28816574 TI - SGT1-HSP90 complex is required for CENP-A deposition at centromeres. AB - The centromere plays an essential role in accurate chromosome segregation, and defects in its function lead to aneuploidy and thus cancer. The centromere specific histone H3 variant CENP-A is proposed to be the epigenetic mark of the centromere, as active centromeres require CENP-A-containing nucleosomes to direct the recruitment of multiple kinetochore proteins. CENP-A K124 ubiquitylation, mediated by CUL4A-RBX1-COPS8 E3 ligase activity, is required for CENP-A deposition at the centromere. However, the mechanism that controls the E3 ligase activity of the CUL4A-RBX1-COPS8 complex remains obscure. We have discovered that the SGT1-HSP90 complex is required for recognition of CENP-A by COPS8. Thus, the SGT1-HSP90 complex contributes to the E3 ligase activity of the CUL4A complex that is necessary for CENP-A ubiquitylation and CENP-A deposition at the centromere. PMID- 28816576 TI - A demethylation deficient isoform of the lysine demethylase KDM2A interacts with pericentromeric heterochromatin in an HP1a-dependent manner. AB - Histone modifications have a profound impact on the chromatin structure and gene expression and their correct establishment and recognition is essential for correct cell functioning. Malfunction of histone modifying proteins is associated with developmental defects and diseases and detailed characterization of these proteins is therefore very important. The lysine specific demethylase KDM2A is a CpG island binding protein that has been studied predominantly for its ability to regulate CpG island-associated gene promoters by demethylating their H3K36me2. However, very little attention has been paid to the alternative KDM2A isoform that lacks the N-terminal demethylation domain, KDM2A-SF. Here we characterized KDM2A-SF more in detail and we found that, unlike the canonical full length KDM2A LF isoform, KDM2A-SF forms distinct nuclear heterochromatic bodies in an HP1a dependent manner. Our chromatin immunoprecipitation experiments further showed that KDM2A binds to transcriptionally silent pericentromeric regions that exhibit high levels of H3K36me2. H3K36me2 is the substrate of the KDM2A demethylation activity and the high levels of this histone modification in the KDM2A-bound pericentromeric regions imply that these regions are occupied by the demethylation deficient KDM2A-SF isoform. PMID- 28816577 TI - Coenzyme Q10 Inhibits Th17 and STAT3 Signaling Pathways to Ameliorate Colitis in Mice. AB - Coenzyme Q10 (CoQ10) is a powerful antioxidant substance synthesized in the body. The current study aimed to determine whether CoQ10 suppresses inflammation and inhibits p-STAT3 expression in an experimental colitis mouse model. The mice were orally fed with CoQ10 once a day for 13 days. Histological analysis of the colons was performed by immunohistochemistry. Expression of IL-17, FOXP3, p53, AMPK, and mTOR and activation of p-STAT3 and p-STAT5 in lymph node and spleen tissues were detected by confocal microscopy of stained tissue sections. The relative mRNA expression was measured with real-time PCR, and protein levels were examined by western blot. CoQ10 reduced the disease activity index score and the colon histological score. It also reduced inflammatory mediators in the colon and increased the colon length. The expression of IL-17 and p-STAT3 was decreased with CoQ10 treatment. In contrast, CoQ10 treatment increased the expression of p AMPK and FOXP3. Expression of anti-inflammatory cytokines was shown to increase in colitis mice treated with CoQ10. These results suggested that CoQ10 may reduce the severity of colitis and suppress inflammation through the inhibition of p STAT3 and IL-17. These results support the use of CoQ10 as a potential targeted therapy for the treatment of colitis. PMID- 28816578 TI - Cost analysis of telerehabilitation after arthroscopic subacromial decompression. AB - Background Subacromial impingement syndrome poses a substantial socioeconomic burden, leading to significant consumption of healthcare. Health systems are calling for greater evidence of economic impacts of particular healthcare services. Telerehabilitation programmes have the potential to reduce costs and improve patient access as an alternative to traditional care. Cost analysis has been traditionally included in study protocols and results, although the reliability and research methodology have frequently been under debate. The aim of this study was to compare costs related to a telerehabilitation programme versus conventional physiotherapy following subacromial decompression surgery (ASD). Methods The study was embedded in a randomised controlled trial. The economic analysis was based on the perspective of the health sector and the human capital method. Only the costs associated with the provision of physiotherapy services were taken into account. Costs were measured during the intervention period between baseline and 12 weeks for both groups. Student's t-test was used to compare independent variables between the two groups, with a 95% confidence interval for the estimates and real costs. Results The estimated total cost analysis shows a preliminary cost differential in favour of the telerehabilitation group, meaning that for each participant's total intervention, telerehabilitation saves 29.8% of the costs. Real cost analysis, only for received treatments, shows a cost differential in favour of telerehabilitation, meaning that for each participant's total intervention, telerehabilitation saves 22.15% of the costs incurred for conventional rehabilitation. Conclusions Our study provides direct and meaningful information about telerehabilitation opportunities and can be an essential component in further cost evaluations for different strategies after surgical procedures. This study demonstrates that there was a trend towards lower healthcare costs after ASD. Managers now have the responsibility to decide whether to implement telerehabilitation based on clinical and economic data. PMID- 28816579 TI - Application of the distance-based F test in an mGWAS investigating beta diversity of intestinal microbiota identifies variants in SLC9A8 (NHE8) and 3 other loci. AB - Factors shaping the human intestinal microbiota range from environmental influences, like smoking and exercise, over dietary patterns and disease to the host's genetic variation. Recently, we could show in a microbiome genome-wide association study (mGWAS) targeting genetic variation influencing the beta diversity of gut microbial communities, that approximately 10% of the overall gut microbiome variation can be explained by host genetics. Here, we report on the application of a new method for genotype-beta-diversity association testing, the distance-based F (DBF) test. With this we identified 4 loci with genome-wide significant associations, harboring the genes CBEP4, SLC9A8, TNFSF4, and SP140, respectively. Our findings highlight the utility of the high-performance DBF test in beta diversity GWAS and emphasize the important role of host genetics and immunity in shaping the human intestinal microbiota. PMID- 28816580 TI - Cardioprotective Effects of a Phlorotannin Extract Against Doxorubicin-Induced Cardiotoxicity in a Rat Model. AB - Long-term therapy with doxorubicin (DOX) is associated with high incidence of cumulative and irreversible dilated cardiomyopathy. The goal of this study was to evaluate the cardioprotective effects and safety of a phlorotannin extract from a brown algae Ecklonia cava (SeapolynolTM, SPN) against DOX-induced cardiotoxicity in a rat model. A total of 42 rats were divided into six groups: control, low dose SPN (LDS), high-dose SPN (HDS), DOX, DOX with low-dose SPN (DOX+LDS), and DOX with high-dose SPN (DOX+HDS). Echocardiography was performed at baseline and after 6 weeks. In left ventricular (LV) ejection fraction, DOX and DOX+LDS groups showed significant decreases (P < .001), while LDS, HDS, and DOX+HDS groups showed no significant change compared with control group. In LV mass index, DOX and DOX+LDS groups showed significant increases (P < .001 and P = .013), while LDS, HDS, and DOX+HDS groups showed no significant change compared with control group. In electron microscopy of the LV wall tissue, DOX+HDS group showed markedly less impaired myofibrils and mitochondria compared with both DOX and DOX+LDS groups. On the findings in echocardiography and electron microscopy, 6 week oral administration of SPN was safe and cardioprotective in a DOX-induced rat cardiotoxicity model in a dose-dependent manner. PMID- 28816581 TI - Novel functions for chromatin dynamics in mRNA biogenesis beyond transcription. AB - The first step of gene expression results in the production of mRNA ribonucleoparticles (mRNPs) that are exported to the cytoplasm via the NPC for translation into the cytoplasm. During this process, the mRNA molecule synthesized by RNA polymerase II (Pol II) undergoes extensive maturation, folding and packaging events that are intimately coupled to its synthesis. All these events take place in a chromatin context and it is therefore not surprising that a growing number of studies recently reported specific contributions of chromatin dynamics to various steps of mRNP biogenesis. In this extra view, we replace our recent findings highlighting the contribution of the yeast chromatin remodeling complex ISW1 to nuclear mRNA quality control in the context of the recent literature. PMID- 28816582 TI - Effects of a conductive education course in young children with cerebral palsy:A randomized controlled trial. AB - PURPOSE: To evaluate the effects of a conductive education (CE) course followed by conventional practice, on gross motor function, other functional skills, quality of life, and parents' experiences of family-centered services in young children with cerebral palsy (CP). METHODS: Twenty-one children with CP, 3-6 years old, were randomized to one 3-week CE course followed by conventional practice or conventional practice on a waiting list. Outcomes were measured 4 months after baseline. A web-based log collected data on the conventional practice. RESULTS: No additional improvements in the children's outcome were found. However, parents in the CE group reported that they received more information than parents in the waiting list group (p = 0.01). Children in both groups performed high amount of conventional practice at home. CONCLUSIONS: A 3 week CE course did not add any improvements in the children's functioning, possibly explained by the large amount of conventional practice reported of both groups. PMID- 28816584 TI - How DELLAs contribute to control potassium uptake under conditions of potassium scarcity? Hypotheses and uncertainties. AB - Maintenance of the inward transport of potassium (K) by roots is a critical step to ensure K-nutrition for all plant tissues. When plants are grown at low external K concentrations a strong enhancement of the activity of the AtHAK5 transporter takes place. In a recent work, we observed that the gai-1 mutant of Arabidopsis thaliana, which bears an altered function version of a DELLA regulatory protein, displays reduced accumulation of AtHAK5 transcripts and reduced uptake of Rubidium, an analog for K. In this Addendum we discuss some hypotheses and uncertainties regarding how DELLAs could contribute to the control of K uptake under those conditions. We advance the idea that, following K restriction, there is a zone and tissue specific regulation of DELLAs by gibberellins through a pathway that likely involves ethylene. According to this model in the epidermis of non-apical zones, DELLAs repress transcription factors that promote AtHAK5 accumulation. PMID- 28816583 TI - Mammalian cell surface display for monoclonal antibody-based FACS selection of viral envelope proteins. AB - The elicitation of broadly and efficiently neutralizing antibodies in humans by active immunization is still a major obstacle in the development of vaccines against pathogens such as the human immunodeficiency virus (HIV), influenza virus, hepatitis C virus or cytomegalovirus. Here, we describe a mammalian cell surface display and monoclonal antibody (mAb)-mediated panning technology that allows affinity-based selection of envelope (Env) variants from libraries. To this end, we established an experimental setup featuring: 1) single and site specific integration of Env to link genotype and phenotype, 2) inducible Env expression to avoid cytotoxicity effects, 3) translational coupling of Env and enhanced green fluorescent protein expression to normalize for Env protein levels, and 4) display on HEK cells to ensure native folding and mammalian glycosylation. For proof of concept, we applied our method to a chimeric HIV-1 Env model library comprising variants with differential binding affinities to the V3-loop-directed mAbs 447-52D and HGN194. Fluorescence-activated cell sorting selectively enriched a high affinity variant up to 56- and 55-fold for 447-52D and HGN194, respectively, after only a single round of panning. Similarly, the low affinity variants for each antibody could be selectively enriched up to 237 fold. The binding profiles of membrane-bound gp145 and soluble gp140 chimeras showed identical affinity ranking, suggesting that the technology can guide the identification of Env variants with optimized antigenic properties for subsequent use as vaccine candidates. Finally, our mAb-based cellular display and selection strategy may also prove useful for the development of prophylactic vaccines against pathogens other than HIV. PMID- 28816585 TI - Antioxidative and Anti-Inflammatory Activities of Akebia quinata Extracts in an In Vitro Model of Acute Alcohol-Induced Hepatotoxicity. AB - This study investigated the effects of Akebia quinata (AQ) leaf and fruit extract on acute alcohol-induced hepatotoxicity in AML12 cells. Different concentrations of AQ extracts (250 and 2500 MUg/mL) were used to treat the AML12 cells with or without ethanol for 24 h for inducing acute alcohol cytotoxicity. AQ extract treated AML12 cells showed enhanced expression of GSH-synthesizing enzymes and suppressed expression of oxidative stress makers such as NOX4, and decreased expression of tumor necrosis factor-alpha, inflammatory marker, in acute alcohol induced hepatotoxicity. Furthermore, it was observed that 100 mM ethanol treatment of AML12 cells resulted in global change of mRNA expression in microarray, but AQ leaf extract treatment reversed the global change of mRNA expression pattern into normal condition. In conclusion, AQ extract or functional component from AQ can be useful therapeutic agent in acute alcohol-induced hepatotoxicity by reducing oxidative stress and inflammation responses. PMID- 28816586 TI - Oxidative Stress in the Visceral Fat Is Elevated in Postmenopausal Women with Gynecologic Cancer. AB - OBJECTIVES: This study aimed to evaluate differences in oxidative stress of visceral fat between premenopausal and postmenopausal women and clarify the antioxidant effect of estrogen on adipocytes. MATERIALS AND METHODS: Abdominal subcutaneous and omental visceral adipose tissues were obtained from 38 patients who underwent gynecological surgery. We measured the sizes of the adipocytes and evaluated the lipid peroxidation levels in the adipose tissues. We investigated whether estrogen inhibited the intracellular reactive oxygen species (ROS) production that was induced by hydrogen peroxide (H2O2) in 3T3-L1 adipocytes. RESULTS: The visceral adipocytes were 1162.4 MUm2 and 1881.9 MUm2 in premenopausal and postmenopausal women, respectively; hence they were significantly larger in the latter (p < 0.05). The lipid peroxidation levels were 46.7 nmoL/mg protein in premenopausal women and 99.6 nmoL/mg protein in postmenopausal women; hence the lipid peroxidation levels were significantly higher in the latter (p < 0.05). Estradiol (E2) significantly reduced the intracellular ROS levels that were induced by H2O2 in 3T3-L1 adipocytes (p < 0.01). We determined that E2 significantly increased the expression of nuclear factor erythroid 2-related factor 2 (NRF2)-dependent antioxidant genes, heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), and the glutamate cysteine ligase (GCL) modifier subunit genes, in 3T3-L1 adipocytes (p < 0.01). CONCLUSION: Oxidative stress in the visceral fat is higher in postmenopausal women. The expression of the antioxidant genes HO-1, NQO1, and GCL was upregulated by estrogen in 3T3-L1 adipocytes. Hence, estrogen may act as an antioxidant in the adipose tissues of premenopausal women. PMID- 28816588 TI - Providers' Familiarity with Guidelines for Weight Gain During Pregnancy Impacts Counseling and Compliance in Obese Women. PMID- 28816587 TI - DNA methylation-independent growth restriction and altered developmental programming in a mouse model of preconception male alcohol exposure. AB - The preconception environment is a significant modifier of dysgenesis and the development of environmentally-induced disease. To date, fetal alcohol spectrum disorders (FASDs) have been exclusively associated with maternal exposures, yet emerging evidence suggests male-inherited alterations in the developmental program of sperm may be relevant to the growth-restriction phenotypes of this condition. Using a mouse model of voluntary consumption, we find chronic preconception male ethanol exposure associates with fetal growth restriction, decreased placental efficiency, abnormalities in cholesterol trafficking, sex specific alterations in the genetic pathways regulating hepatic fibrosis, and disruptions in the regulation of imprinted genes. Alterations in the DNA methylation profiles of imprinted loci have been identified in clinical studies of alcoholic sperm, suggesting the legacy of paternal drinking may transmit via heritable disruptions in the regulation of imprinted genes. However, the capacity of sperm-inherited changes in DNA methylation to broadly transmit environmentally induced phenotypes remains unconfirmed. Using bisulphite mutagenesis and second generation deep sequencing, we find no evidence to suggest that these phenotypes or any of the associated transcriptional changes are linked to alterations in the sperm-inherited DNA methylation profile. These observations are consistent with recent studies examining the male transmission of diet-induced phenotypes and emphasize the importance of epigenetic mechanisms of paternal inheritance beyond DNA methylation. This study challenges the singular importance of maternal alcohol exposures and suggests paternal alcohol abuse is a significant, yet overlooked epidemiological factor complicit in the genesis of alcohol-induced growth defects, and may provide mechanistic insight into the failure of FASD children to thrive postnatally. PMID- 28816589 TI - Acculturation Influences Postpartum Eating, Activity, and Weight Retention in Low Income Hispanic Women. AB - BACKGROUND: Low-income Hispanic women experience elevated rates of high postpartum weight retention (PPWR), which is an independent risk factor for lifetime obesity. Sociocultural factors might play an important role among Hispanic women; however, very few studies have examined this association. OBJECTIVE: The purpose of our study was to examine the associations between acculturation and maternal diet, physical activity, and PPWR. DESIGN: This is a cross-sectional study of baseline data from 282 Hispanic women participating in the FitMoms/Mamas Activas study, a randomized controlled trial examining the impact of primarily an internet-based weight control program, in reducing PPWR among low-income women. We performed multivariable linear regression to examine the association of acculturation with diet quality, physical activity, and PPWR at study entry. RESULTS: A total of 213 (76%) women had acculturation scores reflecting Mexican orientation or bicultural orientation, whereas 69 (24%) had scores that represented assimilation to Anglo culture. Women who were more acculturated had lower intakes of fruits and vegetables, lower HEI scores, and lower physical activity levels than women who were less acculturated (p < 0.05). We found an association between acculturation and PPWR in that for every 1-unit increase in acculturation score, PPWR increased, on average, by 0.80 kg. CONCLUSION: Higher acculturation was associated with poorer diet and physical activity behaviors and greater PPWR. PMID- 28816590 TI - Physical Activity and Sedentary Behaviors Among Lesbian, Bisexual, and Heterosexual Women: Findings from the Nurses' Health Study II. AB - INTRODUCTION: Lesbian and bisexual (LB) women are at greater risk of obesity than heterosexuals. However, few studies have examined sexual orientation differences in physical activity (PA) and even fewer have examined differences in sedentary behaviors. This study assessed PA more comprehensively than previous research by including aerobic PA, strengthening PA, and sitting time, to explore sexual orientation differences among adult women. METHODS: Nearly 100,000 women from Nurses' Health Study II were included in multivariable-adjusted repeated measures analyses. PA and sedentary behaviors were assessed in 1989, 1991, 1997, 2001, 2005, and 2009 (age range: 24-64 years). Aerobic PA was converted to metabolic equivalent task (MET)-hours/week, whereas strengthening PA and sedentary behaviors were measured in hours/week. About 1.3% of the sample identified as lesbian (n = 926) or bisexual (n = 415). RESULTS: On average over repeated measures, LB women reported engaging in 2-3 MET-hours/week more of total aerobic PA (beta [95% confidence interval, CI]: lesbian: 2.0 MET-hours/week [0.6-3.4]; bisexual: 2.8 MET-hours/week [0.7-4.7]) than heterosexual women. Bisexual women reported engaging in 0.2 hours/week more of strengthening PA (95% CI: 0.06-0.42) than heterosexuals; there were no differences between lesbians and heterosexuals in strengthening PA. LB women reported sitting an average of 4-5 hours/week more than heterosexuals (lesbian: 4.1 hours/week [3.1-5.2]; bisexual: 5.1 hours/week [3.6-6.7]). CONCLUSIONS: Interventions promoting less sitting time among LB women may be warranted. Additionally, findings highlight need for more research into other modifiable factors besides PA, such as minority stress or disordered eating behaviors that may contribute to greater obesity among LB women. PMID- 28816591 TI - Final year physiotherapy student's reliability in chest X-ray interpretation. AB - BACKGROUND: Newly qualified physiotherapists may be required to interpret an unreported chest X-ray (CXR) as part of their physiotherapy assessment in "on call" situations. Their interpretation may influence the patient management strategies they adopt. There is no research published which have tested the reliability of final year physiotherapy students in CXR interpretation. METHODS: Twenty-five final year physiotherapy students were asked to view and interpret the findings of six CXRs, together with a brief vignette, typical of a single commonly encountered diagnosis. Students were also asked if they had received additional CXR training on placement or had a desire to specialize in respiratory care. RESULTS: The CXR interpretations were scored as incorrect 0, partially correct 1 (abnormality detected but not able to diagnose or missed some detail) and 2 correct. Scores for each of the six CXRs were added to give a total score (out of 12). The median score was 3 out of 12, (range 0-9). Median scores were slightly higher at 4 out of 12 in those students with additional training or a desire to specialize (range 1-7), but this was not statistically significant (p = 0.43). CONCLUSIONS: Final year physiotherapy students were not able to reliably interpret CXRs. These findings were consistent with previous published research involving medical students. Therefore on graduation before starting "on call" duties it is recommended newly qualified physiotherapists receive additional training in CXR interpretation. PMID- 28816592 TI - Two-faced Fcab prevents polymerization with VEGF and reveals thermodynamics and the 2.15 A crystal structure of the complex. AB - Fcabs (Fc domain with antigen-binding sites) are promising novel therapeutics. By engineering of the C-terminal loops of the CH3 domains, 2 antigen binding sites can be inserted in close proximity. To elucidate the binding mode(s) between homodimeric Fcabs and small homodimeric antigens, the interaction between the Fcabs 448 and CT6 (having the AB, CD and EF loops and the C-termini engineered) with homodimeric VEGF was investigated. The crystal structures of these Fcabs, which form polymers with the antigen VEGF in solution, were determined. However, construction of heterodimeric Fcabs (JanusFcabs: one chain Fc-wt, one chain VEGF binding) results in formation of distinct JanusFcab-VEGF complexes (2:1), which allowed elucidation of the crystal structure of the JanusCT6-VEGF complex at 2.15 A resolution. VEGF binding to Janus448 and JanusCT6 is shown to be entropically unfavorable, but enthalpically favorable. Structure-function relationships are discussed with respect to Fcab design and engineering strategies. PMID- 28816593 TI - Elucidating the role of WRKY27 in male sterility in Arabidopsis. AB - The WRKY proteins belong to a superfamily of TFs that play pivotal roles in responses to a wide range of biotic, abiotic, developmental and physiologic cues. Here, we assayed the accumulation of basal WRKY27 transcripts in diverse tissue including root, shoot, leaf and flowers. We demonstrated that plants over expressing WRKY27 transcript levels exhibit growth aberrations and fertility defects. Scanning electron microscopic data suggest that WRKY27 overexpressor plants exhibit pollen dehiscence defects. Our fluorescein diacetate hydrolysis assay showed that flowers of plants overexpressing WRKY27 display significantly decreased pollen viability. These sterility-related phenotypes were not rescued by the exogenous applications of different phytohormones. Our results indicate the involvement of WRKY27 in particular for proper plant biomass accumulation and male fertility. PMID- 28816595 TI - Corrigendum. AB - Carlton JA, Maxwell AW, Bauer LB, McElroy SM, Layfield LJ, Ahsan H and Agarwal A. Computed tomography detection of extracapsular spread of squamous cell carcinoma of the head and neck in metastatic cervical lymph nodes. Neuroradiol J 2017; 30: 222-229. (DOI: 10.1177/1971400917694048). The name of the third co-author on page 1 of this article is incorrectly stated as Lyndsey B Bauer. The name has since been corrected on this page to Lindsey B Bauer in the e-only version of the article in the XML. (DOI: 10.1177/1971400917694048). PMID- 28816596 TI - Expression profiling of development related genes in rice plants ectopically expressing AtTOR. AB - Expression analysis of genes associated with development at different growth stages such as shoot apical meristem (SAM), root apical meristem (RAM), shoot and root tissues 10 DAG, flowers and grains of 2 high expression transgenic lines of rice ectopically expressing AtTOR revealed the involvement of AtTOR in transcriptional regulation of these genes. We have observed that in the SAM of these 2 selected lines, TR-2.24 and TR-15.1, OsFON1 and OsFON4 (orthologs of AtCLV1 and AtCLV3, respectively), OsKNOX2, OsKNOX3 and OsWOX3 became upregulated. The upregulation of OsFON1 and OsFON4 is likely to be involved in the maintenance of effective meristem size of the inflorescence and phyllotaxis. The grains and spikes of transgenic plants exhibited enhanced transcript levels of OsMADS1, OsMADS6, and OsMADS29 further implicating the role of TOR in modulating the expression of the genes in rice grain formation and development. Moreover, the upregulation of auxin transporter, PIN1c in RAM and roots derived from seedlings 10 DAG showed the involvement of TOR in root development. The seeds of 2 high expression lines also showed increased expression of OSE2 and GAMYB transcription factors involved in seed development. In summary, the present study, by heterologous expression of AtTOR in rice, demonstrated the involvement of TOR in regulating genes involved in various growth and developmental stages of rice plant and also in photosynthesis, productivity related functions and water-use efficiency. PMID- 28816597 TI - The ULK complex initiates autophagosome formation at phosphatidylinositol synthase-enriched ER subdomains. AB - In our recent paper, we biochemically analyzed autophagosome-related membranes at the initiation stage of macroautophagy/autophagy using atg knockout (KO) cells and demonstrated that the ULK complex is recruited to 2 distinct membranes: the ER membrane and ATG9A-positive autophagosome precursors. We have also identified phosphatidylinositol synthase (PIS)-enriched ER subdomains as the initiation site of autophagosome formation. Based on these findings, we propose that the ULK complex, the PIS-enriched ER subdomain, and ATG9A vesicles together initiate autophagosome formation. PMID- 28816598 TI - Short versus long double-stranded RNA activation of a post-transcriptional gene knockdown pathway. AB - RNA interference (RNAi) utilizes a conserved cellular autoimmune defense mechanism involving the internalization of dsRNA into cells and the activation of a set of RNAi related genes. Using RNAi, complete sex reversal is achievable in males of the prawn Macrobrachium rosenbergii by knocking down the transcript level of an insulin-like androgenic gland hormone (Mr-IAG) through injections of dsRNA of the entire Mr-IAG ORF sequence (dsMr-IAG - 518bp). Interestingly, in vivo knockdown success and dsMr-IAG lengths seemed to correlate, with long dsRNA being the most effective and short dsRNA fragments showing no effect. However, little is known about the RNAi machinery in M. rosenbergii. We discovered the Mr Dicer and Mr-Argonaute gene families, associated with the major knockdown pathways, in our M. rosenbergii transcriptomic library. In response to dsMr-IAG administration, only post-transcriptional pathway-related gene transcript levels were upregulated. In addition, a passive dsRNA channel (a SID1 gene ortholog) that allows external dsRNA to enter cells was found. Its function was validated by observing Mr-SID1 specific upregulation dependent on dsRNA lengths, while attempted loss-of-function experiments were lethal. Our results, which suggest differential systemic responses to dsRNA lengths, provide evidence that the above RNAi-based manipulation occurs via the post-transcriptional pathway. The temporal nature of the latter pathway supports the safety of using such RNAi-based biotechnologies in aquaculture and environmental applications. Unlike reports of RNAi driven by the administration of small dsRNA fragments in-vitro, the case presented here demonstrates length dependency in-vivo, suggesting further complexity in the context of the entire organism. PMID- 28816599 TI - Adolescent Marijuana Use and Perceived Ease of Access Before and After Recreational Marijuana Implementation in Colorado. AB - BACKGROUND: As of January 1, 2017, eight states have approved laws for recreational marijuana use. While the social impacts of these changes remain under debate, the influence on adolescent marijuana use is a key policy and health issue across the U.S. OBJECTIVE: To examine changes in adolescent marijuana-use behaviors in the first year after recreational marijuana implementation in Colorado, and to analyze the effect of retail marijuana store proximity on youth use and perceptions. METHOD: Secondary analysis of Healthy Kids Colorado Survey data from 40 schools surveyed before and after recreational marijuana sales were implemented (2013 student n = 12,240; 2014 student n = 11,931). Self-reported marijuana use, ease of access, and perceived harms were compared between years and by proximity of recreational marijuana stores to surveyed schools. RESULTS: Adolescent marijuana use behaviors, wrongness of use, and perceptions of risk of harm were unchanged from baseline to one-year follow up. Perceived ease of access to marijuana increased (from 46% to 52%). Proximity of recreational marijuana stores was not significantly associated with perceived ease of access to marijuana. Conclusions/Importance: In the first study of adolescent marijuana use and perceptions after state retail implementation of recreational marijuana, there was little change in adolescent marijuana use but a significant change in perception of ease of access. Public health workers and policymakers should continue to monitor these changes as essential for evaluating the impact of liberalization of marijuana policies. PMID- 28816594 TI - Consensus statement on current and emerging methods for the diagnosis and evaluation of cerebrovascular disease. AB - Cerebrovascular disease (CVD) remains a leading cause of death and the leading cause of adult disability in most developed countries. This work summarizes state of-the-art, and possible future, diagnostic and evaluation approaches in multiple stages of CVD, including (i) visualization of sub-clinical disease processes, (ii) acute stroke theranostics, and (iii) characterization of post-stroke recovery mechanisms. Underlying pathophysiology as it relates to large vessel steno-occlusive disease and the impact of this macrovascular disease on tissue level viability, hemodynamics (cerebral blood flow, cerebral blood volume, and mean transit time), and metabolism (cerebral metabolic rate of oxygen consumption and pH) are also discussed in the context of emerging neuroimaging protocols with sensitivity to these factors. The overall purpose is to highlight advancements in stroke care and diagnostics and to provide a general overview of emerging research topics that have potential for reducing morbidity in multiple areas of CVD. PMID- 28816601 TI - Stomate-based defense and environmental cues. AB - Environmental conditions play crucial roles in modulating immunity and disease in plants. For instance, many bacterial disease outbreaks occur after periods of high humidity and rain. A critical step in bacterial infection is entry into the plant interior through wounds or natural openings, such as stomata. Bacterium triggered stomatal closure is an integral part of the plant immune response to reduce pathogen invasion. Recently, we found that high humidity compromises stomatal defense, which is accompanied by regulation of the salicylic acid and jasmonic acid pathways in guard cells. Periods of darkness, when most stomata are closed, are effective in decreasing pathogen penetration into leaves. However, coronatine produced by Pseudomonas syringae pv. tomato (Pst) DC3000 cells can open dark-closed stomata facilitating infection. Thus, a well-known disease promoting environmental condition (high humidity) acts in part by suppressing stomatal defense, whereas an anti-stomatal defense factor such as coronatine, may provide epidemiological advantages to ensure bacterial infection when environmental conditions (darkness and insufficient humidity) favor stomatal defense. PMID- 28816602 TI - Synthesis and in vitro antimicrobial and antioxidant activities of quaternary ammonium chitosan modified with nisin. AB - Nisin had been grafted onto quaternary ammonium chitosan (QCS) through an enzyme catalyzed reaction to enhance its limited antimicrobial activity. QCS was synthesized by incorporating N-(3-chloro-2-hydroxypropyl) trimethyl ammonium chloride (CHPTAC) onto chitosan's primary amine group. The modification had been confirmed by FT-IR and 1H NMR spectroscopy. Degree of substitution (DS) of QCS nisin could be controlled by adjusting the reaction conditions. The synthesized compounds were screened in vitro to evaluate their antimicrobial and antioxidant activities. The results suggested that QCS-nisin significantly suppressed the growth of both gram-positive bacteria and gram-negative bacteria; The antioxidant effects on 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, hydroxyl radical and hydrogen peroxide (H2O2) proved to be enhanced with increasing DS and concentration. In addition, QCS-nisin showed excellent moisture absorption and retention properties; MTT assay exhibited that QCS-nisin revealed low cytotoxicity effects on cultured NIH-3T3 fibroblasts. These results suggest that QCS-nisin would appear to be a promising candidate for wound dressing application. PMID- 28816600 TI - Deciphering the tRNA-dependent lipid aminoacylation systems in bacteria: Novel components and structural advances. AB - tRNA-dependent addition of amino acids to lipids on the outer surface of the bacterial membrane results in decreased effectiveness of antimicrobials such as cationic antimicrobial peptides (CAMPs) that target the membrane, and increased virulence of several pathogenic species. After a brief introduction to CAMPs and the various bacterial resistance mechanisms used to counteract these compounds, this review focuses on recent advances in tRNA-dependent pathways for lipid modification in bacteria. Phenotypes associated with amino acid lipid modifications and regulation of their expression will also be discussed. PMID- 28816604 TI - Posttraumatic Growth Among Family Members With Missing Persons From War in Kosovo: Association With Social Support and Community Involvement. AB - There is almost no data on the role of social support and in general on posttraumatic growth among people who have missing family member(s) as result of war and who experience ambiguous loss. This study explores relationship between reported posttraumatic growth and perceived social support and social activism in community-based organizations dealing directly with issues of missing persons. Family members who reported higher levels of social support from family, friends, and important others reported significant higher levels of posttraumatic growth. Family members that reported being active in community-based organizations reported significant higher averages in posttraumatic growth scores in total and its subscales. Regression analyses indicates that factors associated posttraumatic growth were as follows: being active in community organization dealing with missing person's issues and higher levels of social support from friends and family. Findings provide insight for clinicians working with this population and psycho social experts working in postconflict contexts. PMID- 28816605 TI - End-of-Life in Disney and Pixar Films: An opportunity for Engaging in Difficult Conversation. AB - This study expanded upon previous scholarship by examining end-of-life (EOL) depictions and messages of death within Disney and Pixar animated films. We argue Disney and Pixar depictions of EOL and death can provide critical opportunities for discussing death and dying processes with children and adults alike. A content analysis of 57 movies resulted in a total of 71 character deaths. These instances of death became the discourse used for analysis. The EOL discourse was coded based on five categories (character status, depiction of death, death status, emotional reaction, and causality). After quantitative analysis, the films were qualitatively analyzed. Four themes emerged from analysis, unrealistic moments, managing EOL, intentions to kill, and transformation and spiritual connection. Discussion of results, limitations, and directions for future research are included. PMID- 28816603 TI - Analysis of the small non-protein-coding RNA profile of mouse spermatozoa reveals specific enrichment of piRNAs within mature spermatozoa. AB - Post-testicular sperm maturation and storage within the epididymis is a key determinant of gamete quality and fertilization competence. Here we demonstrate that mouse spermatozoa possess a complex small non-protein-coding RNA (sRNA) profile, the composition of which is markedly influenced by their epididymal transit. Thus, although microRNAs (miRNAs) are highly represented in the spermatozoa of the proximal epididymis, this sRNA class is largely diminished in mature spermatozoa of the distal epididymis. Coincident with this, a substantial enrichment in Piwi-interacting RNA (piRNA) abundance in cauda spermatozoa was detected. Further, features of cauda piRNAs, including; predominantly 29-31 nts in length; preference for uracil at their 5' terminus; no adenine enrichment at piRNA nt 10, and; predominantly mapping to intergenic regions of the mouse genome, indicate that these piRNAs are generated by the PIWIL1-directed primary piRNA production pathway. Accordingly, PIWIL1 was detected via immunoblotting and mass spectrometry in epididymal spermatozoa. These data provide insight into the complexity and dynamic nature of the sRNA profile of spermatozoa and raise the intriguing prospect that piRNAs are generated in situ in maturing spermatozoa. Such information is of particular interest in view of the potential role for paternal sRNAs in influencing conception, embryo development and intergenerational inheritance. PMID- 28816606 TI - Scale-up of PUF-immobilized fungal chitosanase-lipase preparation production. AB - Mucor circinelloides IBT-83 mycelium that exhibits both lipolytic (AL) and chitosanolytic (ACH) activities was immobilized into polyurethane foam in a 30 L laboratory fermenter. The process of immobilization was investigated in terms of the carrier porosity, its type, amount, and shape, location inside the fermenter, mixing, and aeration parameters during the culture, as well as downstream processing operations. The selected conditions allowed for immobilization of approximately 7 g of defatted and dried mycelium in 1 g of carrier, i.e., seven times more than achievable in 1 L shake-flasks. Enzymatic preparation obtained by this method exhibited both the chitosanolytic (ACH 432.5 +/- 6.8 unit/g) and lipolytic (AL 150.0 +/- 9.3 U/g) activities. The immobilized preparation was successfully used in chitosan hydrolysis to produce chitooligosaccharides and low molecular weight chitosan, as well as in waste fats degradation and in esters synthesis in nonaqueous media. It was found that the half-life of immobilized preparations stored at room temperature is on average of 200 days. PMID- 28816607 TI - Investigation of a green process for the polymerization of catechin. AB - Flavonoids are polyphenolic secondary plant metabolites which possess antioxidant and anti-inflammatory properties. Besides, they have been shown to exhibit increased antioxidant properties in their polymerized form. Catechins are one of the attractive class of flavonoids which belong to the group of flavan-3-ols. Polymerization of catechins have been investigated in numerous studies indicating the requirement of certain amount of organic solvent to provide the solubility of the monomer. However, many research projects have been conducted recently to replace toxic organic contaminants of the processes with environmentally friendly solvents. In this aspect, deep eutectic solvents (DESs) that are regarded as "green solvents" have been studied extensively in various enzyme catalyzed reactions. In the present study, we focused on establishing a green pathway for laccase catalyzed polycatechin synthesis by replacing organic solvent content with DESs as green solvents. For this aim, various parameters were investigated, such as DES types and concentrations laccase amount and reaction time. Consequently, the highest molecular weight polycatechin was obtained using 5% (v/v) B-M, 125 U laccase in 1 hr of reaction time, at 30 degrees C, as 4,354 +/- 678 g mol-1. Corresponding X/XO inhibitory activity and superoxide radical scavenging activities were achieved as, 59 and 50%, respectively. PMID- 28816608 TI - Function of plasma membrane microdomain-associated proteins during legume nodulation. AB - Plasma membrane microdomains are plasma membrane sub-compartments enriched in sphingolipids and sterols, and composed by a specific set of proteins. They are involved in recognizing signal molecules, transducing these signals, and controlling endocytosis and exocytosis processes. In a recent study, applying biochemical and microscopic methods, we characterized the soybean GmFWL1 protein, a major regulator of soybean nodulation, as a new membrane microdomain-associated protein. Interestingly, upon rhizobia inoculation of the soybean root system, GmFWL1 and one of its interacting partners, GmFLOT2/4, both translocate to the root hair cell tip, the primary site of interaction and infection between soybean and Rhizobium. The role of GmFWL1 as a plasma membrane microdomain-associated protein is also supported by immunoprecipitation assays performed on soybean nodules, which revealed 178 GmFWL1 protein partners including a large number of microdomain-associated proteins such as GmFLOT2/4. In this addendum, we provide additional information about the identity of the soybean proteins repetitively identified as GmFWL1 protein partners. Their function is discussed especially in regard to plant-microbe interactions and microbial symbiosis. This addendum will provide new insights in the role of plasma membrane microdomains in regulating legume nodulation. PMID- 28816609 TI - Evidence of Diversity, Site, and Host Specificity of Sea Turtle Blood Flukes (Digenea: Schistosomatoidea: "Spirorchiidae"): A Molecular Prospecting Study. AB - Neospirorchis (Digenea: "Spirorchiidae") are blood flukes of sea turtles. Trematodes tentatively identified as Neospirorchis sp. infect various sites within sea turtles inhabiting waters of the southeastern United States, but efforts to obtain specimens adequate for morphologic study has proven difficult. Two genetic targets, the internal transcribed spacer region of the ribosomal RNA gene and the partial mitochondrial cytochrome c oxidase subunit I gene, were used to investigate potential diversity among parasite specimens collected from stranded sea turtles. Sequence data were obtained from 215 trematode and egg specimens collected from 92 individual free-ranging cheloniid sea turtles comprising 4 host species. Molecular analysis yielded more than 20 different genotypes. We were able to assign 1 genotype to 1 of the 2 recognized species, Neospirorchis pricei Manter and Larson, 1950 . In many examples, genotypes exhibited host and site specificity. Our findings indicate considerable diversity of parasites resembling Neospirorchis with evidence of a number of uncharacterized blood flukes that require additional study. PMID- 28816610 TI - Tobacco control law implementation in a middle-income country: Transnational tobacco control network overcoming tobacco industry opposition in Colombia. AB - The objective of this paper is to examine the implementation of Colombia's tobacco control law. Methods involved are triangulated government legislation, news sources, and interviews with policy-makers and health advocates in Colombia. Colombia, a middle-income country, passed a tobacco control law in 2009 that included a prohibition on tobacco advertising, promotion, and sponsorship; and required pictorial health warning labels, ingredients disclosure, and a prohibition on individual cigarette sales. Tobacco companies challenged the implementation through litigation, tested government enforcement of advertising provisions and regulations on ingredients disclosure, and lobbied local governments to deprioritise policy responses to single cigarette sales. A transnational network including international health groups and funders helped strengthen domestic capacity to implement the law by; promoting public awareness of Ley [Law] 1335; training local health department staff on enforcement; facilitating health agencies' sharing of educational strategies; and providing legal defence assistance. This network included vigilant efforts by local health groups, which continuously monitored and alerted the media to noncompliance, engaged government officials and policy-makers on implementation, and raised public awareness. Support from international health NGOs and funders and continuous engagement by local health groups enhanced implementation capacities to counter continued tobacco industry interference and ensure effective tobacco control implementation. PMID- 28816611 TI - Biosynthesis regulation of natamycin production from Streptomyces natalensis HDMNTE-01 enhanced by response surface methodology. AB - Natamycin has been widely applied in medical treatments and food protection widely due to its effective inhibition to the growth of yeast and mold. As polyene macrolide antibiotic, the biosynthesis pathway of natamycin is relatively clear. To regulate the biosynthesis of natamycin, additions of precursors affecting cell growth and natamycin production were investigated. The results showed that 0.003% (w/v) potassium ferrocyanide and sodium propionate: n-butanol at a ratio of 4:1 was added into the broth at 0 and 24 hr, respectively, and they contributed to yield natamycin, reaching 1.62 g L-1 (174.6% higher than control). Furthermore, response surface methodology was undertaken to enhance natamycin production by Streptomyces natalensis HDMNTE-01 (a wild strain). The optimum conditions determined were: glucose 3.97%; soya peptone 2%; yeast extract 0.5%; original pH 7.0; inoculum volume 6%; growth in a 250-mL flask containing 24.68 mL of medium; shaken (220 rpm) at 28 degrees C for 4 days. Under the optimized conditions, the yield was 2.81 g L-1 natamycin in 5-L fermentor when the fermentation was processed. PMID- 28816612 TI - Protecting Pregnant Workers while Fighting Sexism: Work-Pregnancy Balance and Pregnant Nurses' Resistance in Quebec Hospitals: Proteger les travailleuses enceintes en luttant contre le sexisme: equilibre travail-grossesse et resistance d'infirmieres enceintes dans des hopitaux quebecois. AB - Women's workplaces should guarantee healthy pregnancies while supporting pregnant women as workers. In Quebec (Canada), a pregnant worker exposed to a "danger" for herself or her fetus may ask her employer to be reassigned to other work appropriate to her skills. This approach differs from other regulatory contexts in North America in that protection of fetal and maternal health is embedded in the health and safety legislation. The advantage is that the pregnant worker is guaranteed access to her full salary, but some may question whether specific provisions for pregnant women single out such women and produce risks for their careers or, conversely, pregnancy should receive even more special consideration. These questions are discussed using the results of a qualitative analysis of interviews with pregnant nurses, their supervisors, and their union representatives in ten hospitals in Quebec. We think that the management of pregnancy under this legislation generally protects health, but that, in the absence of true employer commitment to the health of all workers, undue burdens may be placed upon other members of the work team. Resume Les lieux de travail des femmes devraient garantir des grossesses saines tout en soutenant les femmes enceintes en tant que travailleurs. Au Quebec (Canada), une travailleuse enceinte exposee a un danger pour elle-meme ou son f?tus peut demander a son employeur d'etre reaffectee a d'autres taches sans danger et adapteches a ses competences. Cette approche differe des autres contextes reglementaires en Amerique du Nord en ce sens que la protection de la sante foetale et maternelle est integree dans la legislation sur la sante et la securite. Certains peuvent se demander si des dispositions specifiques pour les femmes enceintes singularisent ces travailleuses et contribuent a la precarisation de leur emploi. Ou, a l'inverse, si la grossesse devrait recevoir une consideration encore plus speciale. Ces questions sont discutees a la lumiere du recit d infirmieres enceintes, de gestionnaires et de representants syndicaux responsables des dossiers de conciliation travail-grossesse dans dix hopitaux du Quebec. Nous constatons que la gestion de la grossesse en vertu de cette legislation est generalement protectrice de la sante, mais qu'en l'absence d'un veritable engagement de l'employeur envers la sante de tous les travailleurs, des charges excessives peuvent etre imposees aux autres membres de l'equipe de travail. PMID- 28816613 TI - Smoking habits and type 2 diabetes mellitus in women. AB - The purpose of this case-control study was to evaluate the relationship between smoking and type 2 diabetes mellitus (T2DM) in adult females. A total of 168 women in Kaunas, Lithuania with newly diagnosed T2DM during the year 2001 and 336 controls who were women without diabetes were recruited. Participants were asked about their duration of smoking, the number of cigarettes smoked per day, pack years, and smoking cessation. Odds ratios (OR), 95 percent confidence intervals (CI) for T2DM were calculated using conditional logistic regression. After adjustment for possible confounders, women with T2DM had a nearly threefold higher odds for smoking 10 or more cigarettes per day compared with controls and using never smokers as the referent category (OR = 2.8; 95 percent CI 1.0-7.7). Women with T2DM had over fourfold odds for having smoked for 40 years or more compared to controls (OR = 4.6; 95 percent CI 1.1-18.6). Compared to controls, women with T2DM had over a sixfold higher odds for stopping smoking for 19 or fewer years with never smokers as the referent category (OR = 6.4; 95 percent CI 1.5-27.3). The findings of our study suggest a possible relationship between smoking and T2DM in women. Also, despite smoking cessation, the association with T2DM remained for a long time. PMID- 28816615 TI - In-stent hypodense area at two weeks following carotid artery stenting predicts neointimal hyperplasia after two years. AB - Introduction It has not been reported how long the follow-up study after carotid artery stenting (CAS) should be continued. The purpose of the present study is to clarify the dynamic change of the in-stent neointimal layer and residual arterial lumen by two years following CAS using three-dimensional computed tomography angiography (3D CTA) with volume rendering. Methods Thirty-six stented carotid arteries in 34 consecutive patients were examined by 3D CTA with volume rendering at two weeks and 3, 6, 12, 24 months of follow-up. Results An in-stent hypodense area could be detected in 10 of 36 (27.8%) carotid arteries at two weeks after CAS. In-stent hypodense areas gradually declined thereafter by three months. In the course of longer follow-up, the layer of the in-stent hypodense area (neointimal hyperplasia) continued to grow in size for up to 24 months. Patients with an in-stent hypodense area at two weeks have a thicker layer of neointimal hyperplasia at 24 months than patients without in-stent hypodense area at two weeks' follow-up. The predictive factors for growing neointimal hyperplasia at 24 months in multiple regression analysis are ulcer formation in pretreatment stenosis and the thickness of in-stent hypodense area at two weeks following CAS. Conclusion Our results suggest that follow-up study should be continued for a longer period even if in-stent restenosis could not be detected at one year following CAS. Especially in cases with ulcer formation in pretreatment stenosis and with a subacute in-stent hypodense area after CAS, longer follow-up is strongly recommended. PMID- 28816617 TI - The Norwegian police and victims of elder abuse in close and familial relationships. AB - Over recent decades, domestic violence or family violence, violence against women and child abuse has received much attention in the media, in political discourse and in social research. However, abuse of older adults arouses limited interest. In government action against domestic violence and in police guidance manuals, the elderly receive little attention. The aim of this article is primarily to demonstrate how the police attempt to prevent elder abuse in close relationships, especially in parent-child relationships. This article highlights some contradictions between the need of the police to produce criminal cases (often contrary to the interests of the victims) on the one hand, and the police's duty to prevent further abuse on the other. Research has documented that help and prevention measures in question make the situation even worse for the victims they are meant to help. PMID- 28816616 TI - Transfer-RNA-mediated enhancement of ribosomal proteins S6 kinases signaling for cell proliferation. AB - While transfer-RNAs (tRNAs) are known to transport amino acids to ribosome, new functions are being unveiled from tRNAs and their fragments beyond protein synthesis. Here we show that phosphorylation of 90-kDa RPS6K (ribosomal proteins S6 kinase) was enhanced by tRNALeu overexpression under amino acids starvation condition. The phosphorylation of 90-kDa RPS6K was decreased by siRNA specific to tRNALeu and was independent to mTOR (mammalian target of rapamycin) signaling. Among the 90-kDa RPS6K family, RSK1 (ribosomal S6 kinase 1) and MSK2 (mitogen-and stress-activated protein kinase 2) were the major kinases phosphorylated by tRNALeu overexpression. Through SILAC (stable isotope labeling by/with amino acids in cell culture) and combined mass spectrometry analysis, we identified EBP1 (ErbB3-binding protein 1) as the tRNALeu-binding protein. We suspected that the overexpression of free tRNALeu would reinforce ErbB2/ErbB3 signaling pathway by disturbing the interaction between ErbB3 and EBP1, resulting in RSK1/MSK2 phosphorylation, improving cell proliferation and resistance to death. Analysis of samples from patients with breast cancer also indicated an association between tRNALeu overexpression and the ErbB2-positive population. Our results suggested a possible link between tRNALeu overexpression and RSK1/MSK2 activation and ErbB2/ErbB3 signaling. PMID- 28816618 TI - Ground reaction forces produced by two different hockey skating arm swing techniques. AB - The arm swing in hockey skating can have a positive effect on the forces produced by each skate, and the resulting velocity from each push off. The main purpose of this study was to measure the differences in ground reaction forces (GRFs) produced from an anteroposterior versus a mediolateral style hockey skating arm swing. Twenty-four elite-level female hockey players performed each technique while standing on a ground-mounted force platform, and all trials were filmed using two video cameras. Force data was assessed for peak scaled GRFs in the frontal and sagittal planes, and resultant GRF magnitude and direction. Upper limb kinematics were assessed from the video using Dartfish video analysis software, confirming that the subjects successfully performed two distinct arm swing techniques. The mediolateral arm swing used a mean of 18.38 degrees of glenohumeral flexion/extension and 183.68 degrees of glenohumeral abduction/adduction while the anteroposterior technique used 214.17 degrees and 28.97 degrees respectively. The results of this study confirmed that the mediolateral arm swing produced 37% greater frontal plane and 33% less sagittal plane GRFs than the anteroposterior arm swing. The magnitudes of the resultant GRFs were not significantly different between the two techniques; however, the mediolateral technique produced a resultant GRF with a significantly larger angle from the direction of travel (44.44 degrees ) as compared to the anteroposterior technique (31.60 degrees ). The results of this study suggest that the direction of GRFs produced by the mediolateral arm swing more closely mimic the direction of lower limb propulsion during the skating stride. PMID- 28816619 TI - A survey of the pyrabactin resistance-like abscisic acid receptor gene family in poplar. AB - The conserved PYR/PYL/RCAR family acts as abscisic acid (ABA) receptors for land plants to adapt to terrestrial environments. Our recent study reported that the exogenous overexpression of poplar PtPYRL1 and PtPYRL5, the PYR/PYL/RCAR orthologs, promoted the sensitivity of transgenic Arabidopsis to ABA responses. Here, we surveyed the PtPYRL family in poplar, and revealed that although the sequence and structure are relatively conserved among these receptors, PtPYRL members have differential expression patterns and the sensitivity to ABA or drought treatment, suggesting that PtPYRLs might be good candidates to a future biotechnological use to enhance poplar resistance to water-stress environments. PMID- 28816620 TI - Childhood bereavement: The role of the surviving parent and the continuing bond with the deceased. AB - This study investigated the relationship between the role of the surviving parent in the child's grieving process, the continuing bond with the deceased parent and biopsychosocial functioning and active grief in adulthood. A survey of 135 adults, parentally bereaved in childhood, indicated that the surviving parent's role in facilitating the grieving process promoted a positive continuing bond with the deceased in childhood as well as general functioning in adulthood. The continuing bond with the deceased had a weak association with both better general functioning and relational active grief. PMID- 28816623 TI - IgG Endopeptidase in Highly Sensitized Patients Undergoing Transplantation. PMID- 28816621 TI - Use/disuse paradigms are ubiquitous concepts in characterizing the process of inheritance. AB - In recent years, a Lamarckian theme has found its way back into academic discourse on evolution and inheritance. Especially the emerging field of transgenerational small RNAs has provided at least a proof of concept for the inheritance of acquired traits. Yet it remains unclear whether the Lamarckian concept of inheritance will in fact have its rennaisance or whether it will remain the rallying cry for the outlaws, heretics and enfants terribles of molecular biology. As unclear as the future of Lamarckian theory is its content and reference. Since the formulation of the Philosophie Zoologique, Lamarckian thought has been de- and reconfiguring in and out of the scientific literature and become an umbrella-term for all kinds of unconventional modes of inheritance. This essay will argue that heritable small RNAs might in fact provide a case of genuine Lamarckian inheritance. Moreover, it will be claimed that not only the very broad concept of "inheritance of acquired traits" applies, but also that Lamarck's mechanistic insight into a use/disuse relation might help to explain a specific mode of transgenerational inheritance. PMID- 28816622 TI - Obtention and characterization of the recombinant simian Interleukin-15 in Escherichia coli for the preclinical assessment of an IL-15-based therapeutic vaccine. AB - Recombinant simian IL-15 (siIL-15) was obtained for the preclinical assessment of an anti-human IL-15 vaccine. For this purpose, the cDNA from peripheral blood mononuclear cells of a Macaca fascicularis monkey was cloned into a pIL-2 vector. The siIL-15 was expressed in Escherichia coli strain W3110 as an insoluble protein which accounted for 13% of the total cellular proteins. Inclusion bodies were solubilized in an 8 M urea solution, which was purified by ion exchange and reverse phase chromatography up to 92% purity. The protein identity was validated by electrospray ionization-mass spectrometry, confirming the presence of the amino acids which distinguish the siIL-15 from human IL-15. The purified siIL-15 stimulates the proliferation of cytotoxic T-lymphocytes line (CTLL)-2 and Kit 225 cells with EC50 values of 3.1 and 32.5 ng/mL, respectively. Antisera from modified human IL-15-immunized macaques were reactive to human and simian IL-15 in enzyme-linked immunosorbent assays. Moreover, the anti-human IL-15 antibodies from immune sera inhibited siIL-15 activity in CTLL-2 and Kit 225 cells, supporting the activity and purity of recombinant siIL-15. These results indicate that the recombinant siIL-15 is biologically active in two IL-15-dependent cell lines, and it is also suitable for the preclinical evaluation of an IL-15-based therapeutic vaccine. PMID- 28816624 TI - Comparison of Two Rabbit Models with Deficiency of Corneal Epithelium and Limbal Stem Cells Established by Different Methods. AB - Limbal stem cell defect model is an important animal model that provides a basis for the study of ocular surface diseases. The rabbit cornea is of moderate size and is widely used in such studies as an experimental animal model. At present, the main modeling methods are alkali burns, and corneal limbus girdling and corneal epithelium doctoring. Each method has its own characteristics. In this study, we observed rabbit models with severe ocular surface defect established by the two methods and changes after amniotic membrane transplantation. In the first, second, third, and fourth week after operation, the clinical manifestations, corneal transparency, and new vessels were observed according to the standard rating scale of ocular surface, compared between the two methods, and then statistically analyzed. In the fourth week after operation, the rabbits were sacrificed and their corneas and corneal limbus were extracted from sclera, embedded by optimum cutting temperature compound, frozen, and sliced for hematoxylin and eosin staining and pathological examination. There were two groups in this study. Group 1 (alkali burns) had more severe complications, such as, conjunctiva, nubecula, new vessel hyperplasia, and so on, compared to group 2 (corneal limbus girdling and corneal epithelium doctoring). In addition, there were striking differences in corneal transparency and new vessels between the two groups (p < 0.05). Corneal transparency in group 1 was lower than in group 2. New vessels in group 1 were less in the first 2 weeks, but obviously increased compared to group 2 in the subsequent weeks. Alkaline burn could be used to study new vessel hyperplasia, while corneal limbus girdling and corneal epithelium doctoring are more suitable for studying stem cell transdifferentiation, interactive roles of stem cells and microenvironment, and so on. PMID- 28816625 TI - Possible roles of sigma-dependent RNA polymerase pausing in transcription regulation. AB - The sigma subunit of bacterial RNA polymerase is required for promoter recognition during transcription initiation but may also regulate transcription elongation. The principal sigma70 subunit of Escherichia coli was shown to travel with RNA polymerase and induce transcriptional pausing at promoter-like motifs, with potential regulatory output. We recently demonstrated that an alternative sigma38 subunit can also induce RNA polymerase pausing. Here, we outline proposed regulatory roles of sigma-dependent pausing in bacteria and discuss possible interplay between alternative sigma variants and regulatory factors during transcription elongation. PMID- 28816626 TI - Comparison of the elution characteristics of individual forms of lovastatin in both isocratic and gradient modes and HPLC-PDA method development for pure and fermentation-derived lovastatin. AB - The elution characteristics of lovastatin were studied by varying the composition of mobile phase in both isocratic and gradient elution modes to comprehend the role of organic modifier and acidifier on the overall analysis time and retention time of individual forms of lovastatin. Acetonitrile has influenced on the overall analysis time, whereas the acidifier determines the retention time of hydroxy acid form of lovastatin and the retention time gap between the individual forms. A combination of acetonitrile and 0.1% trifluoroacetic acid (TFA) (60:40, v/v) in isocratic elution mode eluted both hydroxy acid and lactone forms of lovastatin at 4.5 and 5.4 min, respectively. This appears to be a better approach for the separation of pharmaceutical and clinical lovastatin samples. At isocratic elution mode, a mixture of acetonitrile and either 0.05% TFA or 0.1% H3PO4 of 60:40 (v/v) has eluted both hydroxy acid and lactone forms of lovastatin at 10 +/- 0.5 and 17 +/- 0.5 min, respectively. This is suitable for the fermentation-derived samples or for the complex mixtures of structural analogs. The fermentation broth (pH not adjusted) extracted with ethyl acetate at a ratio of 1:1 (v/v) at 60 degrees C for 30 min was the optimal extraction condition for lovastatin. PMID- 28816627 TI - Transfiguring desire: Divining the origin of species. AB - In this piece, we combine autoethnographic and poetic methods/genres to examine intimate and social experiences we have had as two transmasculine queers with complex sexual and gender histories in an intergenerational relationship. If queerness/transness is a "species," our title, playing on Darwin, promises an answer to oft-asked problematic questions of queer/trans origins. Refusing to address this question, we instead turn Darwin on himself and examine intimate moments in our lives to show how we have experienced the constant formation and personal evolution of desire and identity. Tracing memories reaching back 28 years for one of us and 58 years for the other, we describe our shifting desire and embodiment and locate ourselves in lesbian, gay, trans, and queer histories. We next investigate how illness, disability, and age difference inflect and shape the ways we understand and relate to each other and intersubjectively make meaning in our present relationship. Our inquiry illustrates our complex positionalities, examines how "dyke legacies" are embodied in our affection and interdependence, and challenges biologized, cisnormative assumptions. Thus, a knowledge formation starting from embodied trans-trans intimate lives can challenge the naturalness and intransigence assumptions in dominant notions of gender, heterosexuality, bodies, relationality, identity, and kinship. PMID- 28816628 TI - Outbreak and Cocirculation of Three Different Usutu Virus Strains in Eastern Germany. AB - Usutu virus (USUV) is a mosquito-borne flavivirus accounting for large-scale deaths in resident bird populations. In this study, we show the introduction of USUV to Eastern Germany resulting in massive death of birds, particularly blackbirds (Turdus merula). We found that three diverse USUV lineages ("Europe 3," "Africa 2," and "Africa 3-like") circulated simultaneously. Moreover, we detected USUV in Culex pipiens in a region where no dead birds were reported, strengthening the need for mosquito monitoring to uncover the spread of arboviruses. Furthermore, phylogenetic analyses revealed that mutations accumulated, in particular, in the NS3 region within short time periods. In addition, comparison of whole-genome sequences showed that diverse isolates of the cluster "Africa 3-like" are cocirculating in Germany due to independent introduction events. PMID- 28816630 TI - Glycoproteins and Polysaccharides are the Main Class of Active Constituents Required for Lymphocyte Stimulation and Antigen-Specific Immune Response Induction by Traditional Medicinal Herbal Plants. AB - Traditional herbal remedies stimulate and modulate the immune system, and it is thought that their glycoproteins and polysaccharides are responsible for this activity. We prepared crude water, protein, and polysaccharide extracts from Atractylodes macrocephala Koidz, Helianthus annuus L., Scutellaria barbata D. Don, and Hedyotis diffusa Willd, respectively, and compared their immune stimulating activities in vitro and in vivo. All protein and polysaccharide samples of the plants led to greater lymphocyte proliferation and TNF-alpha and IL-6 production in cultured splenocytes than did the crude water extracts at the same concentrations tested. In addition, the protein and polysaccharide samples did not contain lectin- or lipopolysaccharide-like molecules, so glycoproteins were deduced to be responsible for the lymphocyte stimulation. Oral administration with each of the samples enhanced the hen egg-white lysozyme (HEL) specific humoral immune and lymphocyte proliferative responses in HEL low responder C57BL/6 mice. Splenocytes from the mice fed the samples showed significantly greater increases in the level of IFN-gamma, but not IL-4, after stimulation with HEL compared with that from the untreated control. However, higher increases in HEL-specific IgG1, IgG2b, and IgG3 rather than IgG2a were found in the mice fed the samples. These results indicate that the sample mediated enhancement of anti-HEL-specific humoral immune responses was due to the stimulation of B lymphocytes rather than a selective priming of helper T cell populations. Collectively, we suggest that glycoproteins and/or polysaccharides of traditional herbal remedies enhance cellular and humoral immune response induction and thus could be useful for patients who need enhanced immune function. PMID- 28816631 TI - Platypnea-orthodeoxia syndrome: an unusual presentation of a complex disease. AB - BACKGROUND: Platypnea-orthodeoxia syndrome (POS) is an uncommon disorder characterized by dyspnea (=platypnea) and desaturation (=orthodeoxia) in upright position and improvement of symptoms and blood oxygenation in supine position. Clinical presentation is heterogeneous and often confuses the clinician. OBJECTIVES: The present case report illustrates a complicated presentation of the underlying syndrome. METHODS: Description of a POS case in a 73-year-old female with thorough workup and tailored treatment. RESULTS: In this case report, we describe a rather unusual presentation of POS, with posture-dependent hypoxemic induced psychiatric symptoms. Further investigations revealed the presence of a patent foramen ovale with atrial septum aneurysm, an aortic root dilatation up to 41 mm and bilateral lower lobe lung emboli. The ventilation-perfusion mismatch aggravated the desaturation in upright position. Since the patient remained symptomatic after treatment of the functional trigger, we choose for the percutaneous closure of the anatomical defect. We used an Occlutech Figulla Flex II UNI 33/33 mm occluder resulting in a perfect closure of the defect. CONCLUSION: Abnormal shunting in upright position may be the result of different underlying conditions, requiring a thorough workup and a tailored treatment. In case of serious co-morbid conditions, an endovascular procedure to close a patent foramen ovale, after unsuccessful treatment of precipitating conditions, should be considered. PMID- 28816629 TI - A cascade model of mentorship for frontline health workers in rural health facilities in Eastern Uganda: processes, achievements and lessons. AB - BACKGROUND: There is increasing demand for trainers to shift from traditional didactic training to innovative approaches that are more results-oriented. Mentorship is one such approach that could bridge the clinical knowledge gap among health workers. OBJECTIVES: This paper describes the experiences of an attempt to improve health-worker performance in maternal and newborn health in three rural districts through a mentoring process using the cascade model. The paper further highlights achievements and lessons learnt during implementation of the cascade model. METHODS: The cascade model started with initial training of health workers from three districts of Pallisa, Kibuku and Kamuli from where potential local mentors were selected for further training and mentorship by central mentors. These local mentors then went on to conduct mentorship visits supported by the external mentors. The mentorship process concentrated on partograph use, newborn resuscitation, prevention and management of Post-Partum Haemorrhage (PPH), including active management of third stage of labour, preeclampsia management and management of the sick newborn. Data for this paper was obtained from key informant interviews with district-level managers and local mentors. RESULTS: Mentorship improved several aspects of health-care delivery, ranging from improved competencies and responsiveness to emergencies and health worker professionalism. In addition, due to better district leadership for Maternal and Newborn Health (MNH), there were improved supplies/medicine availability, team work and innovative local problem-solving approaches. Health workers were ultimately empowered to perform better. CONCLUSIONS: The study demonstrated that it is possible to improve the competencies of frontline health workers through performance enhancement for MNH services using locally built capacity in clinical mentorship for Emergency Obstetric and Newborn Care (EmONC). The cascade mentoring process needed strong external mentorship support at the start to ensure improved capacity among local mentors to provide mentorship among local district staff. PMID- 28816634 TI - Disability benefits as an incentive for hysterectomy: Uterine fibroid patients in Taiwan. AB - Worker compensation insurance in Taiwan ensures that a woman under the age of 45 years who has her uterus removed can receive disability compensation benefits. The present study investigated whether such a compensation policy was related to a woman's inclination to have a hysterectomy. We extracted the records of 16,030 women diagnosed with uterine fibroids (UF) between 2000 and 2010 from the Longitudinal Taiwan Health Insurance Database. Each younger and older age group had a significantly lower hysterectomy rate compared to that of the 44-year-old age group. Moreover, significantly more patients with lower monthly wages had had hysterectomies than those with higher monthly wages. Policy makers should be aware that worker compensation regulations in Taiwan might encourage women with economic need to undergo hysterectomy surgery when approaching the age of 45 years. PMID- 28816633 TI - Restoration and loss after disaster: Applying the dual-process model of coping in bereavement. AB - The article asks whether disasters that destroy life but leave the material infrastructure relatively intact tend to prompt communal coping focusing on loss, while disasters that destroy significant material infrastructure tend to prompt coping through restoration/rebuilding. After comparing memorials to New Zealand's Christchurch earthquake and Pike River mine disasters, we outline circumstances in which collective restorative endeavor may be grassroots, organized from above, or manipulated, along with limits to effective restoration. We conclude that bereavement literature may need to take restoration more seriously, while disaster literature may need to take loss more seriously. PMID- 28816632 TI - The Liver Circadian Clock Modulates Biochemical and Physiological Responses to Metformin. AB - Metformin is widely used in the treatment of type 2 diabetes to lower blood glucose. Although metformin is a relatively safe and effective drug, its clinical efficacy is variable and under certain circumstances it may contribute to life threatening lactic acidosis. Thus, additional understanding of metformin pharmacokinetics and pharmacodynamics could provide important information regarding therapeutic use of this widely prescribed drug. Here we report a significant effect of time of day on acute blood glucose reduction in response to metformin administration and on blood lactate levels in healthy mice. Furthermore, we demonstrate that while metformin transport into hepatocytes is unaltered by time of day, the kinetics of metformin-induced activation of AMP activated protein kinase (AMPK) in the liver are remarkably altered with circadian time. Liver-specific ablation of Bmal1 expression alters metformin induction of AMPK and blood glucose response but does not completely abolish time of day differences. Together, these data demonstrate that circadian rhythms affect the biological responses to metformin in a complex manner. PMID- 28816635 TI - Dignity Therapy: Final Words for Final Days. PMID- 28816636 TI - The distress thermometer predicts subjective, but not objective, cognitive complaints six months after treatment initiation in cancer patients. AB - OBJECTIVES: Research has indicated that cancer-related cognitive impairments (CRCI) may be influenced by psychosocial factors such as distress, worry and fatigue. Therefore, we aimed to validate the distress thermometer (DT) as a screening tool to detect CRCI six months post-treatment-initiation in a group of general cancer patients. METHODS: Patients (>=18 years, n = 125) with a histologically confirmed diagnosis of a solid cancer or hematological malignancy, scheduled for a curative treatment, were evaluated at baseline (T0) and six months post-treatment-initiation (T1) for CRCI by a neuropsychological assessment, including patient-reported outcome measures (PROMs). Assessed cognitive domains included premorbid intelligence, attention, processing speed, flexibility, verbal and visual episodic memory and verbal fluency. PROMs entailed distress (DT, cut-off >=4, range 0-10), anxiety and depression, fatigue (FACIT fatigue scale) and subjective cognitive complaints. RESULTS: At T0, 60.4% of patients showed a DT score of >=4, whereas 50% met this criterion at T1. According to the definition of the International Cognition and Cancer Task Force, 25.5% and 28.3% of patients presented with a CRCI at T0 and T1, respectively. When evaluating the DT as a screening tool for CRCI at T1, data showed an inverse relationship between the DT and CRCI. ROC-curve analysis revealed an AUC <0.5. ROC-curve analyses evaluating the DT and FACIT-fatigue scale as screening tools for subjective cognitive complaints showed an AUC +/- SE of, respectively, 0.642 +/- 0.067 and 0.794 +/- 0.057. CONCLUSIONS: The DT at T0 cannot be used to screen for objective CRCI at T1, but both the DT and FACIT-fatigue scale at T0 showed potential as screening tools for subjective cognitive complaints at T1. PMID- 28816637 TI - The Impact of Exceeding TANF Time Limits on the Access to Healthcare of Low Income Mothers. AB - The objective of this article is to estimate the relationship of exceeding Temporary Assistance for Needy Families (TANF) time limits, with health insurance, healthcare, and health outcomes. The authors use Heckman selection models that exploit variability in state time-limit duration and timing of policy implementation as identifying exclusion restrictions to adjust the effect estimates of exceeding time limits for possible correlations between the probability of exceeding time limits and unobservable factors influencing the outcomes. The authors find that exceeding time limits decreases the predicted probability of Medicaid coverage, increases the predicted probability of being uninsured, and decreases the predicted probability of annual medical provider contact. PMID- 28816638 TI - High Prevalence of Multidrug-Resistant Community-Acquired Methicillin-Resistant Staphylococcus aureus at the Largest Veterinary Teaching Hospital in Costa Rica. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a pathogen associated with severe infections in companion animals present in the community, and it is diagnosed in animals admitted to veterinary hospitals. However, reports that describe the circulation of MRSA in animal populations and veterinary settings in Latin America are scarce. Therefore, the objective of this study was to determine the prevalence and investigate the molecular epidemiology of MRSA in the environment of the largest veterinary teaching hospital in Costa Rica. Preselected contact surfaces were sampled twice within a 6-week period. Antimicrobial resistance, SCCmec type, Panton-Valentine leukocidin screening, USA type, and clonality were assessed in all recovered isolates. Overall, MRSA was isolated from 26.5% (27/102) of the surfaces sampled, with doors, desks, and examination tables most frequently contaminated. Molecular analysis demonstrated a variety of surfaces from different sections of the hospital contaminated by three highly related clones/pulsotypes. All, but one of the isolates were characterized as multidrug-resistant SCCmec type IV-USA700, a strain sporadically described in other countries and often classified as community acquired. The detection and frequency of this unique strain in this veterinary setting suggest Costa Rica has a distinctive MRSA ecology when compared with other countries/regions. The high level of environmental contamination highlights the necessity to establish and enforce standard cleaning and disinfection protocols to minimize further spread of this pathogen and reduce the risk of nosocomial and/or occupational transmission of MRSA. PMID- 28816639 TI - Posttraumatic growth among childhood cancer survivors: Associations with ethnicity, acculturation, and religious service attendance. AB - This study assessed the association between ethnicity, religious service attendance (RSA), and acculturation with posttraumatic growth (PTG) in a diverse sample of 235 childhood cancer survivors (CCS). PTG scores were estimated for each ethnicity, and by level of RSA and acculturation. There was a significant curvilinear relationship (inverted U) between RSA and PTG, such that moderate levels of RSA were associated with the highest PTG scores. Hispanics reported the highest PTG, and both Hispanic and Anglo cultural orientation were significantly positively associated with PTG. CCS with high or low frequency of RSA as well as Hispanic CCS who lack a strong sense of cultural identity may benefit from targeted efforts to promote psychosocial adaptation in the aftermath of cancer. PMID- 28816641 TI - Preparation of recombinant human thymic stromal lymphopoietin protein. AB - Human thymic stromal lymphopoietin (hTSLP) protein plays a central role in inflammation. Characterizing properties of hTSLP requires a recombinant overexpression system that produces correctly folded, active hTSLP. In this report, an efficient overexpression system for the production of hTSLP was developed. We constructed expression plasmids of the full-length hTslp gene with or without the signal peptide and transformed the plasmids into Escherichia coli. The design of the recombinant proteins included an N-terminal His-tag, which facilitated purification. An affinity gradient elution method was used to improve recovery and concentration levels of denatured hTSLP, with 90% purity observed following affinity chromatography. Refolding of the denatured hTSLP was tested using four different protein refolding approaches. The optimal refolding conditions involved stepwise buffer exchanges to reduce the urea concentration from 4 to 0 M in 50 mM Tris (pH 8.0), 1 mM EDTA, 50 mM NaCl, 10% glycerol, 400 mM L-Arg, 0.2 mM oxidized glutathione, and 2 mM reduced glutathione. The activity of the refolded recombinant hTSLP protein was measured by an ELISA assay. Interestingly, the presence of N-terminal signal peptide inhibited the overexpression of hTSLP in E. coli. The amount of recombinant hTSLP protein purified reached a level of 2.52 * 10-3 mg/L. PMID- 28816640 TI - Exosomal microRNA communication between tissues during organogenesis. AB - Epithelial-mesenchymal interactions are required to coordinate cell proliferation, patterning, and functional differentiation of multiple cell types in a developing organ. This exquisite coordination is dependent on various secreted molecules that provide developmental signals to mediate these tissue interactions. Recently, it was reported that mature mesenchymal-derived microRNAs (miRNAs) in the fetal mouse salivary gland are loaded into exosomes, and transported to the epithelium where they influence progenitor cell proliferation. The exosomal miRNAs regulated epithelial expression of genes involved in DNA methylation in progenitor cells to influence morphogenesis. Thus, exosomal miRNAs are mobile genetic signals that cross tissue boundaries within an organ. These findings raise many questions about how miRNA signals are initiated to coordinate organogenesis and whether they are master regulators of epithelial-mesenchymal interactions. The development of therapeutic applications using exosomal miRNAs for the regeneration of damaged adult organs is a promising area of research. PMID- 28816642 TI - Proteomic Analysis of the Human Olfactory Bulb. AB - The importance of olfaction to human health and disease is often underappreciated. Olfactory dysfunction has been reported in association with a host of common complex diseases, including neurological diseases such as Alzheimer's disease and Parkinson's disease. For health, olfaction or the sense of smell is also important for most mammals, for optimal engagement with their environment. Indeed, animals have developed sophisticated olfactory systems to detect and interpret the rich information presented to them to assist in day-to day activities such as locating food sources, differentiating food from poisons, identifying mates, promoting reproduction, avoiding predators, and averting death. In this context, the olfactory bulb is a vital component of the olfactory system receiving sensory information from the axons of the olfactory receptor neurons located in the nasal cavity and the first place that processes the olfactory information. We report in this study original observations on the human olfactory bulb proteome in healthy subjects, using a high-resolution mass spectrometry-based proteomic approach. We identified 7750 nonredundant proteins from human olfactory bulbs. Bioinformatics analysis of these proteins showed their involvement in biological processes associated with signal transduction, metabolism, transport, and olfaction. These new observations provide a crucial baseline molecular profile of the human olfactory bulb proteome, and should assist the future discovery of biomarker proteins and novel diagnostics associated with diseases characterized by olfactory dysfunction. PMID- 28816643 TI - Pharmacometabolomics Informs Quantitative Radiomics for Glioblastoma Diagnostic Innovation. AB - Applications of omics systems biology technologies have enormous promise for radiology and diagnostics in surgical fields. In this context, the emerging fields of radiomics (a systems scale approach to radiology using a host of technologies, including omics) and pharmacometabolomics (use of metabolomics for patient and disease stratification and guiding precision medicine) offer much synergy for diagnostic innovation in surgery, particularly in neurosurgery. This synthesis of omics fields and applications is timely because diagnostic accuracy in central nervous system tumors still challenges decision-making. Considering the vast heterogeneity in brain tumors, disease phenotypes, and interindividual variability in surgical and chemotherapy outcomes, we believe that diagnostic accuracy can be markedly improved by quantitative radiomics coupled to pharmacometabolomics and related health information technologies while optimizing economic costs of traditional diagnostics. In this expert review, we present an innovation analysis on a systems-level multi-omics approach toward diagnostic accuracy in central nervous system tumors. For this, we suggest that glioblastomas serve as a useful application paradigm. We performed a literature search on PubMed for articles published in English between 2006 and 2016. We used the search terms "radiomics," "glioblastoma," "biomarkers," "pharmacogenomics," "pharmacometabolomics," "pharmacometabonomics/pharmacometabolomics," "collaborative informatics," and "precision medicine." A list of the top 4 insights we derived from this literature analysis is presented in this study. For example, we found that (i) tumor grading needs to be better refined, (ii) diagnostic precision should be improved, (iii) standardization in radiomics is lacking, and (iv) quantitative radiomics needs to prove clinical implementation. We conclude with an interdisciplinary call to the metabolomics, pharmacy/pharmacology, radiology, and surgery communities that pharmacometabolomics coupled to information technologies (chemoinformatics tools, databases, collaborative systems) can inform quantitative radiomics, thus translating Big Data and information growth to knowledge growth, rational drug development and diagnostics innovation for glioblastomas, and possibly in other brain tumors. PMID- 28816644 TI - CYP2B6 Haplotype Predicts Efavirenz Plasma Concentration in Black South African HIV-1-Infected Children: A Longitudinal Pediatric Pharmacogenomic Study. AB - South Africa has the highest burden of the human immunodeficiency virus (HIV) infection globally. Efavirenz (EFV), a frequently used drug against HIV infection, displays a relationship between drug concentration and pharmacodynamics effects clinically. However, haplotype-based genetic variation in drug metabolism in a pediatric sample has been little considered in a longitudinal long-term context. CYP2B6 plays a key role in variation of EFV plasma concentration through altered drug metabolism. We report here on a prospective clinical pharmacogenomics/pharmacokinetic study of Bantu-speaking children, importantly, over a period of 24 months post-initiation of EFV-based treatment in South Africa. We characterized the HIV-1-infected children (n = 60) for the CYP2B6 c.516G>T, c.785A>G, c.983T>C, and c.1459C>T single nucleotide polymorphisms (SNPs). These SNPs were determined using polymerase chain reaction/restricted fragment length polymorphism and SNaPshot genotyping. Longitudinal mid-dose EFV plasma concentrations were determined by LC-MS/MS and association analyses with genotypes and haplotypes at 1, 3, and 24 months were performed. The CYP2B6 c.516T/T genotype showed significantly higher EFV plasma concentrations (p < 0.001) compared to non 516T-allele carriers at all three time points. The minor allele frequencies (MAF) for CYP2B6 c.516T, c.785G, c.983C, and c.1459T were 0.410, 0.408, 0.110, and 0.000 respectively. Haplotypes were constructed using CYP2B6 c.516G>T,-c.785A>G and c.983T>C. The haplotype T-G-T presented with significantly increased EFV plasma concentrations compared to the reference G-A-T haplotype at 1, 3, and 24 months (p = 0.009; p = 0.003; p = 0.001), suggesting that the T-G-T haplotype predisposes a risk of EFV plasma concentrations >4 MUg/mL. The clinical implications of these pharmacogenomics observations for EFV toxicity and treatment resistance warrant further future research. PMID- 28816645 TI - A Systems Model of Parkinson's Disease Using Biochemical Systems Theory. AB - Parkinson's disease (PD), a neurodegenerative disorder, affects millions of people and has gained attention because of its clinical roles affecting behaviors related to motor and nonmotor symptoms. Although studies on PD from various aspects are becoming popular, few rely on predictive systems modeling approaches. Using Biochemical Systems Theory (BST), this article attempts to model and characterize dopaminergic cell death and understand pathophysiology of progression of PD. PD pathways were modeled using stochastic differential equations incorporating law of mass action, and initial concentrations for the modeled proteins were obtained from literature. Simulations suggest that dopamine levels were reduced significantly due to an increase in dopaminergic quinones and 3,4-dihydroxyphenylacetaldehyde (DOPAL) relating to imbalances compared to control during PD progression. Associating to clinically observed PD-related cell death, simulations show abnormal parkin and reactive oxygen species levels with an increase in neurofibrillary tangles. While relating molecular mechanistic roles, the BST modeling helps predicting dopaminergic cell death processes involved in the progression of PD and provides a predictive understanding of neuronal dysfunction for translational neuroscience. PMID- 28816647 TI - An Examination of the Holism Paradigm: A View of Social Work. AB - This article examines the holism paradigm, implications on social work practice in healthcare, and how social work practice can help promote the value of social justice. Examining the holistic health paradigm fosters a critical reflection that assists to better understand beliefs and assumptions that guide social work practice, thus leading to critical action. PMID- 28816648 TI - Attributes, behaviors, or experiences? Lessons from research on trauma regarding gender differences. PMID- 28816646 TI - Chronic Cigarette Smoke Mediated Global Changes in Lung Mucoepidermoid Cells: A Phosphoproteomic Analysis. AB - Proteomics analysis of chronic cigarette smoke exposure is a rapidly emerging postgenomics research field. While smoking is a major cause of lung cancer, functional studies using proteomics approaches could enrich our mechanistic understanding of the elusive lung cancer global molecular signaling and cigarette smoke relationship. We report in this study on a stable isotope labeling by amino acids in cell culture-based quantitative phosphoproteomic analysis of a human lung mucoepidermoid carcinoma cell line, H292 cells, chronically exposed to cigarette smoke. Using high resolution Orbitrap Velos mass spectrometer, we identified the hyperphosphorylation of 493 sites, which corresponds to 341 proteins and 195 hypophosphorylated sites, mapping to 142 proteins upon smoke exposure (2.0-fold change). We report differential phosphorylation of multiple kinases, including PAK6, EPHA4, LYN, mitogen-activated protein kinase, and phosphatases, including TMEM55B, PTPN14, TIGAR, among others, in response to chronic cigarette smoke exposure. Bioinformatics analysis revealed that the molecules differentially phosphorylated upon chronic exposure of cigarette smoke are associated with PI3K/AKT/mTOR and CDC42-PAK signaling pathways. These signaling networks are involved in multiple cellular processes, including cell polarity, cytoskeletal remodeling, cellular migration, protein synthesis, autophagy, and apoptosis. The present study contributes to emerging proteomics insights on cigarette smoke mediated global signaling in lung cells, which in turn may aid in development of precision medicine therapeutics and postgenomics biomarkers. PMID- 28816649 TI - Improving regional influenza surveillance through a combination of automated outbreak detection methods: the 2015/16 season in France. AB - The 2014/15 influenza epidemic caused a work overload for healthcare facilities in France. The French national public health agency announced the start of the epidemic - based on indicators aggregated at the national level - too late for many hospitals to prepare. It was therefore decided to improve the influenza alert procedure through (i) the introduction of a pre-epidemic alert level to better anticipate future outbreaks, (ii) the regionalisation of surveillance so that healthcare structures can be informed of the arrival of epidemics in their region, (iii) the standardised use of data sources and statistical methods across regions. A web application was developed to deliver statistical results of three outbreak detection methods applied to three surveillance data sources: emergency departments, emergency general practitioners and sentinel general practitioners. This application was used throughout the 2015/16 influenza season by the epidemiologists of the headquarters and regional units of the French national public health agency. It allowed them to signal the first influenza epidemic alert in week 2016-W03, in Brittany, with 11 other regions in pre-epidemic alert. This application received positive feedback from users and was pivotal for coordinating surveillance across the agency's regional units. PMID- 28816650 TI - Evidence for more cost-effective surveillance options for bovine spongiform encephalopathy (BSE) and scrapie in Great Britain. AB - Transmissible spongiform encephalopathies (TSEs) are an important public health concern. Since the emergence of bovine spongiform encephalopathy (BSE) during the 1980s and its link with human Creutzfeldt-Jakob disease, active surveillance has been a key element of the European Union's TSE control strategy. Success of this strategy means that now, very few cases are detected compared with the number of animals tested. Refining surveillance strategies would enable resources to be redirected towards other public health priorities. Cost-effectiveness analysis was performed on several alternative strategies involving reducing the number of animals tested for BSE and scrapie in Great Britain and, for scrapie, varying the ratio of sheep sampled in the abattoir to fallen stock (which died on the farm). The most cost-effective strategy modelled for BSE involved reducing the proportion of fallen stock tested from 100% to 75%, producing a cost saving of ca GBP 700,000 per annum. If 50% of fallen stock were tested, a saving of ca GBP 1.4 million per annum could be achieved. However, these reductions are predicted to increase the period before surveillance can detect an outbreak. For scrapie, reducing the proportion of abattoir samples was the most cost-effective strategy modelled, with limited impact on surveillance effectiveness. PMID- 28816651 TI - Cyclosporiasis in travellers returning to the United Kingdom from Mexico in summer 2017: lessons from the recent past to inform the future. AB - During the summers of 2015 and 2016, the United Kingdom experienced large outbreaks of cyclosporiasis in travellers returning from Mexico. As the source of the outbreaks was not identified, there is the potential for a similar outbreak to occur in 2017; indeed 78 cases had already been reported as at 27 July 2017. Early communication and international collaboration is essential to provide a better understanding of the source and extent of this recurring situation. PMID- 28816652 TI - Reoccurrence of botulinum neurotoxin subtype A3 inducing food-borne botulism, Slovakia, 2015. AB - A case of food-borne botulism occurred in Slovakia in 2015. Clostridium botulinum type A was isolated from three nearly empty commercial hummus tubes. The product, which was sold in Slovakia and the Czech Republic, was withdrawn from the market and a warning was issued immediately through the European Commission's Rapid Alert System for Food and Feed (RASFF). Further investigation revealed the presence of botulinum neurotoxin (BoNT) subtype BoNT/A3, a very rare subtype implicated in only one previous outbreak (Loch Maree in Scotland, 1922). It is the most divergent subtype of BoNT/A with 15.4% difference at the amino acid level compared with the prototype BoNT/A1. This makes it more prone to evading immunological and PCR-based detection. It is recommended that testing laboratories are advised that this subtype has been associated with food-borne botulism for the second time since the first outbreak almost 100 years ago, and to validate their immunological or PCR-based methods against this divergent subtype. PMID- 28816654 TI - Instantaneous Transfer Entropy for the Study of Cardiovascular and Cardiorespiratory Nonstationary Dynamics. AB - OBJECTIVE: Measures of transfer entropy (TE) quantify the direction and strength of coupling between two complex systems. Standard approaches assume stationarity of the observations, and therefore are unable to track time-varying changes in nonlinear information transfer with high temporal resolution. In this study, we aim to define and validate novel instantaneous measures of TE to provide an improved assessment of complex nonstationary cardiorespiratory interactions. METHODS: We here propose a novel instantaneous point-process TE (ipTE) and validate its assessment as applied to cardiovascular and cardiorespiratory dynamics. In particular, heartbeat and respiratory dynamics are characterized through discrete time series, and modeled with probability density functions predicting the time of the next physiological event as a function of the past history. Likewise, nonstationary interactions between heartbeat and blood pressure dynamics are characterized as well. Furthermore, we propose a new measure of information transfer, the instantaneous point-process information transfer (ipInfTr), which is directly derived from point-process-based definitions of the Kolmogorov-Smirnov distance. RESULTS AND CONCLUSION: Analysis on synthetic data, as well as on experimental data gathered from healthy subjects undergoing postural changes confirms that ipTE, as well as ipInfTr measures are able to dynamically track changes in physiological systems coupling. SIGNIFICANCE: This novel approach opens new avenues in the study of hidden, transient, nonstationary physiological states involving multivariate autonomic dynamics in cardiovascular health and disease. The proposed method can also be tailored for the study of complex multisystem physiology (e.g., brain-heart or, more in general, brain-body interactions). PMID- 28816655 TI - Gaussian Process Morphable Models. AB - Models of shape variations have become a central component for the automated analysis of images. An important class of shape models are point distribution models (PDMs). These models represent a class of shapes as a normal distribution of point variations, whose parameters are estimated from example shapes. Principal component analysis (PCA) is applied to obtain a low-dimensional representation of the shape variation in terms of the leading principal components. In this paper, we propose a generalization of PDMs, which we refer to as Gaussian Process Morphable Models (GPMMs). We model the shape variations with a Gaussian process, which we represent using the leading components of its Karhunen-Loeve expansion. To compute the expansion, we make use of an approximation scheme based on the Nystrom method. The resulting model can be seen as a continuous analog of a standard PDM. However, while for PDMs the shape variation is restricted to the linear span of the example data, with GPMMs we can define the shape variation using any Gaussian process. For example, we can build shape models that correspond to classical spline models and thus do not require any example data. Furthermore, Gaussian processes make it possible to combine different models. For example, a PDM can be extended with a spline model, to obtain a model that incorporates learned shape characteristics but is flexible enough to explain shapes that cannot be represented by the PDM. We introduce a simple algorithm for fitting a GPMM to a surface or image. This results in a non rigid registration approach whose regularization properties are defined by a GPMM. We show how we can obtain different registration schemes, including methods for multi-scale or hybrid registration, by constructing an appropriate GPMM. As our approach strictly separates modeling from the fitting process, this is all achieved without changes to the fitting algorithm. To demonstrate the applicability and versatility of GPMMs, we perform a set of experiments in typical usage scenarios in medical image analysis and computer vision: The model based segmentation of 3D forearm images and the building of a statistical model of the face. To complement the paper, we have made all our methods available as open source. PMID- 28816653 TI - Assembly rules for GABAA receptor complexes in the brain. AB - GABAA receptor (GABAAR) pentamers are assembled from a pool of 19 subunits, and variety in subunit combinations diversifies GABAAR functions to tune brain activity. Pentamers with distinct subunit compositions localize differentially at synaptic and non-synaptic sites to mediate phasic and tonic inhibition, respectively. Despite multitudes of theoretical permutations, limited subunit combinations have been identified in the brain. Currently, no molecular model exists for combinatorial GABAAR assembly in vivo. Here, we reveal assembly rules of native GABAAR complexes that explain GABAAR subunit subcellular distributions using mice and Xenopus laevis oocytes. First, alpha subunits possess intrinsic signals to segregate into distinct pentamers. Second, gamma2 is essential for GABAAR assembly with Neuroligin-2 (NL2) and GARLHs, which localize GABAARs at synapses. Third, delta suppresses alpha6 synaptic localization by preventing assembly with GARLHs/NL2. These findings establish the first molecular model for combinatorial GABAAR assembly in vivo and reveal an assembly pathway regulating GABAAR synaptic localization. PMID- 28816656 TI - Tracking-by-Detection of 3D Human Shapes: From Surfaces to Volumes. AB - 3D Human shape tracking consists in fitting a template model to temporal sequences of visual observations. It usually comprises an association step, that finds correspondences between the model and the input data, and a deformation step, that fits the model to the observations given correspondences. Most current approaches follow the Iterative-Closest-Point (ICP) paradigm, where the association step is carried out by searching for the nearest neighbors. It fails when large deformations occur and errors in the association tend to propagate over time. In this paper, we propose a discriminative alternative for the association, that leverages random forests to infer correspondences in one shot. Regardless the choice of shape parameterizations, being surface or volumetric meshes, we convert 3D shapes to volumetric distance fields and thereby design features to train the forest. We investigate two ways to draw volumetric samples: voxels of regular grids and cells from Centroidal Voronoi Tessellation (CVT). While the former consumes considerable memory and in turn limits us to learn only subject-specific correspondences, the latter yields much less memory footprint by compactly tessellating the interior space of a shape with optimal discretization. This facilitates the use of larger cross-subject training databases, generalizes to different human subjects and hence results in less overfitting and better detection. The discriminative correspondences are successfully integrated to both surface and volumetric deformation frameworks that recover human shape poses, which we refer to as 'tracking-by-detection of 3D human shapes.' It allows for large deformations and prevents tracking errors from being accumulated. When combined with ICP for refinement, it proves to yield better accuracy in registration and more stability when tracking over time. Evaluations on existing datasets demonstrate the benefits with respect to the state-of-the-art. PMID- 28816657 TI - A Dynamic Regression Approach for Frequency-Domain Partial Coherence and Causality Analysis of Functional Brain Networks. AB - Coherence and causality measures are often used to analyze the influence of one region on another during analysis of functional brain networks. The analysis methods usually involve a regression problem, where the signal of interest is decomposed into a mixture of regressor and a residual signal. In this paper, we revisit this basic problem and present solutions that provide the minimal-entropy residuals for different types of regression filters, such as causal, instantaneously causal, and noncausal filters. Using optimal prediction theory, we derive several novel frequency-domain expressions for partial coherence, causality, and conditional causality analysis. In particular, our solution provides a more accurate estimation of the frequency-domain causality compared with the classical Geweke causality measure. Using synthetic examples and in vivo resting-state functional magnetic resonance imaging data from the human connectome project, we show that the proposed solution is more accurate at revealing frequency-domain linear dependence among high-dimensional signals. PMID- 28816658 TI - Discriminative Feature Representation to Improve Projection Data Inconsistency for Low Dose CT Imaging. AB - In low dose computed tomography (LDCT) imaging, the data inconsistency of measured noisy projections can significantly deteriorate reconstruction images. To deal with this problem, we propose here a new sinogram restoration approach, the sinogram- discriminative feature representation (S-DFR) method. Different from other sinogram restoration methods, the proposed method works through a 3-D representation-based feature decomposition of the projected attenuation component and the noise component using a well-designed composite dictionary containing atoms with discriminative features. This method can be easily implemented with good robustness in parameter setting. Its comparison to other competing methods through experiments on simulated and real data demonstrated that the S-DFR method offers a sound alternative in LDCT. PMID- 28816659 TI - Low-Frequency and Broadband Vibration Energy Harvesting Using Base-Mounted Piezoelectric Transducers. AB - Piezoelectric vibration energy harvesters often consist of a cantilevered beam composed of a support layer and one or two piezoelectric layers with a tip mass. While this configuration is advantageous for maximizing electromechanical coupling, the mechanical properties of the piezoelectric material can place limitations on harvester size and resonant frequency. Here, we present numerical and experimental results from a new type of piezoelectric energy harvester in which the mechanical properties and the resonant frequency of the cantilever beam resonator are effectively decoupled from the piezoelectric component. Referred to as a base-mounted piezoelectric (BMP) harvester in this paper, this new design features a piezoelectric transducer mounted beneath the base of the cantilevered beam resonator. The flexibility in the material choice for the cantilever beam resonator means that the resonant frequency and the beam dimensions are essentially free parameters. A prototype made with a 1.6 mm mm mm polyurethane beam, a PZT-5H piezoelectric transducer, and an 8.36-g tip mass is shown to produce an average power of 8.75 and at 45 Hz across a 13.0- load under harmonic base excitations of constant peak acceleration at 0.25 and 1.0-g, respectively. We also show an increase in full-width half-maximum bandwidth approximately from 1.5 to 5.6 Hz using an array of four individual BMP harvesters of similar dimensions with peak power generation of at 37.6 Hz across a 1.934- load at 0.25 g peak base excitation. Finite elements-based numerical simulations are shown to be in reasonable agreement with experimental results, indicating that the harvester behaves like a damped mass-spring system as proposed in this paper. Fabricated using casting and laser machining techniques, this harvester shows potential as a low-cost option for powering small, low-power wireless sensor nodes and other low-power devices. PMID- 28816660 TI - Erratum to "A 200-1380 kHz Quadrifrequency Focused Ultrasound Transducer for Neurostimulation in Rodents and Primates: Transcranial In Vitro Calibration and Numerical Study of the Influence of Skull Cavity". AB - In the above paper [1], one maximum pressure listed in Table I, page 719, should be corrected. This error occurred when reporting the maximum pressure estimated in the rat brain at 1380 kHz (line 4, last column). The right value (7 MPa) does not change the discussion, and is in line with the 83% estimated pressure gain that was initially reported in rat brain (line 7, last column). Here we provide the correct table. PMID- 28816661 TI - A 3D Reconstruction Strategy of Vehicle Outline Based on Single-Pass Single Polarization CSAR Data. AB - In the last few years, interest in circular synthetic aperture radar (CSAR) acquisitions has arisen as a consequence of the potential achievement of 3D reconstructions over 360 degrees azimuth angle variation. In real-world scenarios, full 3D reconstructions of arbitrary targets need multi-pass data, which makes the processing complex, money-consuming, and time expending. In this paper, we propose a processing strategy for the 3D reconstruction of vehicle, which can avoid using multi-pass data by introducing a priori information of vehicle's shape. Besides, the proposed strategy just needs the single-pass single polarization CSAR data to perform vehicle's 3D reconstruction, which makes the processing much more economic and efficient. First, an analysis of the distribution of attributed scattering centers from vehicle facet model is presented. And the analysis results show that a smooth and continuous basic outline of vehicle could be extracted from the peak curve of a noncoherent processing image. Second, the 3D location of vehicle roofline is inferred from layover with empirical insets of the basic outline. At last, the basic line and roofline of the vehicle are used to estimate the vehicle's 3D information and constitute the vehicle's 3D outline. The simulated and measured data processing results prove the correctness and effectiveness of our proposed strategy. PMID- 28816662 TI - Distortion-Aware Correlation Tracking. AB - Recently, correlation filter (CF)-based tracking methods have attracted considerable attention because of their high-speed performance. However, distortion, which refers to the phenomenon that the correlation outputs of CF based trackers are distorted, remains a major obstacle for these methods. In this paper, we propose a distortion-aware correlation filter framework, which can detect distortions and recover from tracking failures. Our framework employs a simple yet effective feature termed normed correlation response to detect distortions. Meanwhile, we introduce a competition mechanism to handle distortions, in which we build a specialized graph to formulate and handle tracking under distortion as a maximum multi clique problem. Furthermore, a global-local context model is exploited to alleviate underlying distortions during the tracking process. Extensive experiments on the Online Tracking Benchmark show that our tracker can find the optimal target trajectory during the distortion period and retrieve the possibly missing target, consequently outperforms the state-of-the-art methods and improves the performance of CF-based trackers favorably. PMID- 28816663 TI - Specificity and Latent Correlation Learning for Action Recognition Using Synthetic Multi-View Data From Depth Maps. AB - This paper presents a novel approach to action recognition using synthetic multi view data from depth maps. Specifically, multiple views are first generated by rotating 3D point clouds from depth maps. A pyramid multi-view depth motion template is then adopted for multi-view action representation, characterizing the multi-scale motion and shape patterns in 3D. Empirically, despite the view specific information, the latent information between multiple views often provides important cues for action recognition. Concentrating on this observation and motivated by the success of the dictionary learning framework, this paper proposes to explicitly learn a view-specific dictionary (called specificity) for each view, and simultaneously learn a latent dictionary (called latent correlation) across multiple views. Thus, a novel method, specificity and latent correlation learning, is put forward to learn the specificity that captures the most discriminative features of each view, and learn the latent correlation that contributes the inherent 3D information to multiple views. In this way, a compact and discriminative dictionary is constructed by specificity and latent correlation for feature representation of actions. The proposed method is evaluated on the MSR Action3D, the MSR Gesture3D, the MSR Action Pairs, and the ChaLearn multi-modal data sets, consistently achieving promising results compared with the state-of-the-art methods based on depth data. PMID- 28816664 TI - Gradient-Based Tone Mapping for Rate-Distortion Optimized Backward-Compatible High Dynamic Range Compression. AB - This paper addresses the problem of designing a global tone mapping operator for rate distortion optimized backward compatible compression of high dynamic range (HDR) images. We address the problem of tone mapping design for two different use cases leading to two different minimization problems. The first problem considered is the minimization of the distortion on the reconstructed HDR signal under a rate constraint on the standard dynamic range (SDR) layer. The second problem remains the same minimization with an additional constraint to preserve a good quality for the SDR signal. Both the distortion and rate are expressed as a function of the spatial gradient in HDR images. Experiments show that the proposed rate and distortion models based on the HDR image gradient accurately predict the real image rate and distortion measures. Experimental results show that for the first minimization, the optimal rate-distortion performances are achieved, and that the second optimization yields the best tradeoff between rate distortion performance and quality preservation of the SDR signal. PMID- 28816665 TI - Body Structure Aware Deep Crowd Counting. AB - Crowd counting is a challenging task, mainly due to the severe occlusions among dense crowds. This paper aims to take a broader view to address crowd counting from the perspective of semantic modeling. In essence, crowd counting is a task of pedestrian semantic analysis involving three key factors: pedestrians, heads, and their context structure. The information of different body parts is an important cue to help us judge whether there exists a person at a certain position. Existing methods usually perform crowd counting from the perspective of directly modeling the visual properties of either the whole body or the heads only, without explicitly capturing the composite body-part semantic structure information that is crucial for crowd counting. In our approach, we first formulate the key factors of crowd counting as semantic scene models. Then, we convert the crowd counting problem into a multi-task learning problem, such that the semantic scene models are turned into different sub-tasks. Finally, the deep convolutional neural networks are used to learn the sub-tasks in a unified scheme. Our approach encodes the semantic nature of crowd counting and provides a novel solution in terms of pedestrian semantic analysis. In experiments, our approach outperforms the state-of-the-art methods on four benchmark crowd counting data sets. The semantic structure information is demonstrated to be an effective cue in scene of crowd counting. PMID- 28816666 TI - Efficient Multi-Strategy Intra Prediction for Quality Scalable High Efficiency Video Coding. AB - As an extension of High Efficiency Video Coding (HEVC), the Scalable High Efficiency Video Coding (SHVC) introduces multiple layers with inter-layer predictions, which greatly increases the complexity on top of the already complicated HEVC encoder. In Intra prediction for Quality SHVC, Coding Tree Unit (CTU) allows recursive splitting into four depth levels, which considers 35 Intra prediction modes and interlayer reference (ILR) mode to determine the best possible mode at each depth level. This achieves the highest coding efficiency but incurs a substantially high computational complexity. In this paper, we propose a novel Intra prediction scheme to effectively speed up the enhancement layer Intra-coding in Quality SHVC. The new features of the proposed framework include: First, spatial correlation and its correlation degree are combined to predict most probable depth level candidates. Second, for a given depth candidate, based on the probabilities of the ILR mode, we check the ILR mode by examining the residual distribution based on skewness and kurtosis to determine whether the residuals follow a Gaussian distribution. In that case, the Intra prediction comparisons, which require a high complexity, are skipped. Third, during Intra prediction selection from 35 Intra prediction modes, spatial and inter-layer correlations are combined with the local monotonicity of the Hadamard costs associated with the modes in a small neighborhood, to examine only a portion of Intra prediction modes. Finally, a hypothesis testing on the currently selected depth level is performed to examine whether the residuals present significant differences within their block to early terminate depth selection. The proposed multi-step multistrategy scheme aims to minimize the number of depth selections while greatly reducing the mode decision complexity for a depth candidate in a hierarchical fashion. Our experimental results demonstrate that the proposed scheme can achieve a speedup gain of more than 75% in average on the test video sequences, while maintaining almost the same coding efficiency. . PMID- 28816667 TI - Comments on "Iterative Re-Constrained Group Sparse Face Recognition With Adaptive Weights Learning". AB - In the above paper [1] the authors designed an IRGSC architecture for face recognition with pixel corruption and occlusion. We have discovered that the calculation of the weights vector s in the original paper is flawed. In this comment we demonstrate the correct calculations, and further analysed some of the results in the paper. PMID- 28816668 TI - Fast Open-World Person Re-Identification. AB - Existing person re-identification (re-id) methods typically assume that: 1) any probe person is guaranteed to appear in the gallery target population during deployment (i.e., closed-world) and 2) the probe set contains only a limited number of people (i.e., small search scale). Both assumptions are artificial and breached in real-world applications, since the probe population in target people search can be extremely vast in practice due to the ambiguity of probe search space boundary. Therefore, it is unrealistic that any probe person is assumed as one target people, and a large-scale search in person images is inherently demanded. In this paper, we introduce a new person re-id search setting, called large scale open-world (LSOW) re-id, characterized by huge size probe images and open person population in search thus more close to practical deployments. Under LSOW, the under-studied problem of person re-id efficiency is essential in addition to that of commonly studied re-id accuracy. We, therefore, develop a novel fast person re-id method, called Cross-view Identity Correlation and vErification (X-ICE) hashing, for joint learning of cross-view identity representation binarisation and discrimination in a unified manner. Extensive comparative experiments on three large-scale benchmarks have been conducted to validate the superiority and advantages of the proposed X-ICE method over a wide range of the state-of-the-art hashing models, person re-id methods, and their combinations. PMID- 28816669 TI - Nonlocaly Multi-Morphological Representation for Image Reconstruction From Compressive Measurements. AB - A novel multi-morphological representation model for solving the nonlocal similarity-based image reconstruction from compressed measurements is introduced in this paper. Under the probabilistic framework, the proposed approach provides the nonlocal similarity clustering for image patches by using the Gaussian mixture models, and endows a multi-morphological representation for image patches in each cluster by using the Gaussians that represent the different features to model the morphological components. Using the simple alternating iteration, the developed piecewise morphological diversity estimation (PMDE) algorithm can effectively estimate the MAP of morphological components, thus resulting in the nonlinear estimation for image patches. We extend the PMDE to a piecewise morphological diversity sparse estimation by using the constrained Gaussians with the low-rank covariance matrices, to gain the performance improvements. We report the experimental results on image compressed sensing in the case of sensing nonoverlapping patches with Gaussian random matrices. The results demonstrate that our algorithms can suppress undesirable block artifacts efficiently, and delivers reconstructed images with higher qualities than other state-of-the-art methods. PMID- 28816670 TI - Colorization Using Neural Network Ensemble. AB - This paper investigates into the colorization problem, which converts a grayscale image to a colorful version. This is a difficult problem and normally requires manual adjustment to achieve artifact-free quality. For instance, it normally requires human-labeled color scribbles on the grayscale target image or a careful selection of colorful reference images. The recent learning-based colorization techniques automatically colorize a grayscale image using a single neural network. Since different scenes usually have distinct color styles, it is difficult to accurately capture the color characteristics using a single neural network. We propose a mixture learning model representing the presence of sub color-style within an overall image data set. We, therefore, ensemble multiple neural networks to obtain better color estimation performance than could be obtained from any of the constituent neural network alone. A two-step colorization strategy is utilized as an adaptive color style clustering followed by a neural network ensemble. To ensure artifact-free quality, a joint bilateral filtering-based post-processing step is proposed. Numerous experiments demonstrate that our method generates high-quality results comparable with state of-the-art algorithms. PMID- 28816671 TI - Matched Shrunken Cone Detector (MSCD): Bayesian Derivations and Case Studies for Hyperspectral Target Detection. AB - Hyperspectral images (HSIs) possess non-negative properties for both hyperspectral signatures and abundance coefficients, which can be naturally modeled using cone-based representation. However, in hyperspectral target detection, cone-based methods are barely studied. In this paper, we propose a new regularized cone-based representation approach to hyperspectral target detection, as well as its two working models by incorporating into the cone representation l2-norm and l1-norm regularizations, respectively. We call the new approach the matched shrunken cone detector (MSCD). Also important, we provide principled derivations of the proposed MSCD from the Bayesian perspective: we show that MSCD can be derived by assuming a multivariate half-Gaussian distribution or a multivariate half-Laplace distribution as the prior distribution of the coefficients of the models. In the experimental studies, we compare the proposed MSCD with the subspace methods and the sparse representation-based methods for HSI target detection. Two real hyperspectral data sets are used for evaluating the detection performances on sub-pixel targets and full-pixel targets, respectively. Results show that the proposed MSCD can outperform other methods in both cases, demonstrating the competitiveness of the regularized cone-based representation. PMID- 28816672 TI - Templateless Non-Rigid Reconstruction and Motion Tracking With a Single RGB-D Camera. AB - We present a novel templateless approach for nonrigid reconstruction and motion tracking using a single RGB-D camera. Without any template prior, our system achieves accurate reconstruction and tracking for considerably deformable objects. To robustly register the input sequence of partial depth scans with dynamic motion, we propose an efficient local-to-global hierarchical optimization framework inspired by the idea of traditional structure-from-motion. Our proposed framework mainly consists of two stages, local nonrigid bundle adjustment and global optimization. To eliminate error accumulation during the nonrigid registration of loop motion sequences, we split the full sequence into several segments and apply local nonrigid bundle adjustment to align each segment locally. Global optimization is then adopted to combine all segments and handle the drift problem through loop-closure constraint. By fitting to the input partial data, a deforming 3D model sequence of dynamic objects is finally generated. Experiments on both synthetic and real test data sets and comparisons with state of the art demonstrate that our approach can handle considerable motions robustly and efficiently, and reconstruct high-quality 3D model sequences without drift. PMID- 28816673 TI - Generating Arm-Swing Trajectories in Real-Time Using a Data-Driven Model for Gait Rehabilitation With Self-Selected Speed. AB - Gait rehabilitation is often focused on the legs and overlooks the role of the upper limbs. However, a variety of studies have demonstrated the importance of proper arm swing both during healthy walking and during rehabilitation. In this paper, we describe a method for generating proper arm-swing trajectories in real time using only measurements of the angular velocity of a person's thighs, to be used during gait rehabilitation with self-selected walking speed. A data-driven linear time-invariant transfer function is developed, using frequency-response methods, which captures the frequency-dependent magnitude and phase relationship between the thighs' angular velocities and the arm angles (measured at the shoulder, in the sagittal plane), using a data set of 30 healthy adult subjects. We show that the proposed method generates smooth trajectories for both healthy individuals and patients with mild to moderate Parkinson disease. The proposed method can be used in future robotic devices that integrate arm swing in gait rehabilitation of patients with walking impairments to improve the efficacy of their rehabilitation. PMID- 28816674 TI - Advances in Monte Carlo Simulation for Light Propagation in Tissue. AB - Monte Carlo (MC) simulation for light propagation in tissue is the gold standard for studying the light propagation in biological tissue and has been used for years. Interaction of photons with a medium is simulated based on its optical properties. New simulation geometries, tissue-light interaction methods, and recording techniques recently have been designed. Applications, such as whole mouse body simulations for fluorescence imaging, eye modeling for blood vessel imaging, skin modeling for terahertz imaging, and human head modeling for sinus imaging, have emerged. Here, we review the technical advances and recent applications of MC simulation. PMID- 28816675 TI - Adaboost-LLP: A Boosting Method for Learning With Label Proportions. AB - How to solve the classification problem with only label proportions has recently drawn increasing attention in the machine learning field. In this paper, we propose an ensemble learning strategy to deal with the learning problem with label proportions (LLP). In detail, we first give a loss function based on different weights for LLP, and then construct the corresponding weak classifier, at the same time, estimate its conditional probabilities by a standard logistic function. At last, by introducing the maximum likelihood estimation, we propose a new anyboost learning system for LLP (called Adaboost-LLP). Unlike traditional methods, our method does not make any restrictive assumptions on training set; at the same time, compared with alter- SVM, Adaboost-LLP exploits more extra weight information and uses multiple weak classifiers that can be solved efficiently to combine a strong classifier. All experiments show that our method outperforms the existing methods in both accuracy and training time. PMID- 28816676 TI - A Novel Consistent Random Forest Framework: Bernoulli Random Forests. AB - Random forests (RFs) are recognized as one type of ensemble learning method and are effective for the most classification and regression tasks. Despite their impressive empirical performance, the theory of RFs has yet been fully proved. Several theoretically guaranteed RF variants have been presented, but their poor practical performance has been criticized. In this paper, a novel RF framework is proposed, named Bernoulli RFs (BRFs), with the aim of solving the RF dilemma between theoretical consistency and empirical performance. BRF uses two independent Bernoulli distributions to simplify the tree construction, in contrast to the RFs proposed by Breiman. The two Bernoulli distributions are separately used to control the splitting feature and splitting point selection processes of tree construction. Consequently, theoretical consistency is ensured in BRF, i.e., the convergence of learning performance to optimum will be guaranteed when infinite data are given. Importantly, our proposed BRF is consistent for both classification and regression. The best empirical performance is achieved by BRF when it is compared with state-of-the-art theoretical/consistent RFs. This advance in RF research toward closing the gap between theory and practice is verified by the theoretical and experimental studies in this paper. PMID- 28816677 TI - Prototype-Incorporated Emotional Neural Network. AB - Artificial neural networks (ANNs) aim to simulate the biological neural activities. Interestingly, many "engineering" prospects in ANN have relied on motivations from cognition and psychology studies. So far, two important learning theories that have been subject of active research are the prototype and adaptive learning theories. The learning rules employed for ANNs can be related to adaptive learning theory, where several examples of the different classes in a task are supplied to the network for adjusting internal parameters. Conversely, the prototype-learning theory uses prototypes (representative examples); usually, one prototype per class of the different classes contained in the task. These prototypes are supplied for systematic matching with new examples so that class association can be achieved. In this paper, we propose and implement a novel neural network algorithm based on modifying the emotional neural network (EmNN) model to unify the prototype- and adaptive-learning theories. We refer to our new model as "prototype-incorporated EmNN". Furthermore, we apply the proposed model to two real-life challenging tasks, namely, static hand-gesture recognition and face recognition, and compare the result to those obtained using the popular back propagation neural network (BPNN), emotional BPNN (EmNN), deep networks, an exemplar classification model, and k-nearest neighbor. PMID- 28816678 TI - Adaptive Consensus Control of Nonlinear Multiagent Systems With Unknown Control Directions Under Stochastic Topologies. AB - The consensus problem over high-order nonlinear multiagent systems with the Brunovsky-type model is studied. The model parameters and control directions of agents are supposed to be unknown. Hence, based on Nussbaum-type functions, an adaptive protocol is proposed, which guarantees achieving consensus in the network when the parameters and control directions of the agents are unknown and unidentical. The main contribution of this paper (compared with the existing similar results in the literature) is to guarantee achieving consensus in networks of agents when the communication topology is not connected constantly, and communication links stochastically switch over time. It is shown that if the probability of the network connectivity is not zero, under some conditions, almost sure consensus can be achieved. Illustrative examples verify the accuracy of the proposed consensus protocol. PMID- 28816679 TI - Adaptive Unknown Input Estimation by Sliding Modes and Differential Neural Network Observer. AB - In this paper, a differential neural network (DNN) implemented as a robust observer estimates the dynamics of perturbed uncertain nonlinear systems affected by exogenous unknown inputs. In the first stage, the identification error converges into a neighborhood around the origin. Then, the second-order sliding mode supertwisting algorithm implemented as a robust exact differentiator reconstructed the unknown inputs. The approach proposed in this paper can be applied in the case of full access to the state vector (identification problem) and in the case of partial access to the state vector (estimation problem). In the second case, the nonlinear system under study must have well-defined full relative degree with respect to the unknown input. Numerical examples showed the effectiveness of the proposed algorithm. The first example tested the DNN working as an identifier into a mathematical model describing the dynamics of a spatial minisatellite. The second example (with a DNN implemented as an observer) tested the methodology of this paper over a single link flexible robot manipulator represented in a canonical (Brunovsky) form. In both examples, the mathematical models served as data generators in the testing of the neural networks. Even when not exact mathematical description of both models was used in the input estimation, the accuracy obtained with the DNN is comparable with the case of applying a high-order differentiator with complete knowledge of the plant. PMID- 28816680 TI - ADMM-Based Algorithm for Training Fault Tolerant RBF Networks and Selecting Centers. AB - In the training stage of radial basis function (RBF) networks, we need to select some suitable RBF centers first. However, many existing center selection algorithms were designed for the fault-free situation. This brief develops a fault tolerant algorithm that trains an RBF network and selects the RBF centers simultaneously. We first select all the input vectors from the training set as the RBF centers. Afterward, we define the corresponding fault tolerant objective function. We then add an -norm term into the objective function. As the -norm term is able to force some unimportant weights to zero, center selection can be achieved at the training stage. Since the -norm term is nondifferentiable, we formulate the original problem as a constrained optimization problem. Based on the alternating direction method of multipliers framework, we then develop an algorithm to solve the constrained optimization problem. The convergence proof of the proposed algorithm is provided. Simulation results show that the proposed algorithm is superior to many existing center selection algorithms. PMID- 28816681 TI - Augmented Lagrange Programming Neural Network for Localization Using Time Difference-of-Arrival Measurements. AB - A commonly used measurement model for locating a mobile source is time-difference of-arrival (TDOA). As each TDOA measurement defines a hyperbola, it is not straightforward to compute the mobile source position due to the nonlinear relationship in the measurements. This brief exploits the Lagrange programming neural network (LPNN), which provides a general framework to solve nonlinear constrained optimization problems, for the TDOA-based localization. The local stability of the proposed LPNN solution is also analyzed. Simulation results are included to evaluate the localization accuracy of the LPNN scheme by comparing with the state-of-the-art methods and the optimality benchmark of Cramer-Rao lower bound. PMID- 28816682 TI - Rank- 2-D Multinomial Logistic Regression for Matrix Data Classification. AB - The amount of matrix data has increased rapidly nowadays. How to classify matrix data efficiently is an important issue. In this paper, by discovering the shortages of 2-D linear discriminant analysis and 2-D logistic regression, a novel 2-D framework named rank- 2-D multinomial logistic regression (2DMLR-RK) is proposed. The 2DMLR-RK is designed for a multiclass matrix classification problem. In the proposed framework, each category is modeled by a left projection matrix and a right projection matrix with rank . The left projection matrices capture the row information of matrix data, and the right projection matrices acquire the column information. We identify the parameter plays the role of balancing the capacity of learning and generalization of the 2DMLR-RK. In addition, we develop an effective framework for solving the proposed nonconvex optimization problem. The convergence, initialization, and computational complexity are discussed. Extensive experiments on various types of data sets are conducted. Comparing with 1-D methods, 2DMLR-RK not only achieves a better classification accuracy, but also costs less computation time. Comparing with other state-of-the-art 2-D methods, the 2DMLR-RK achieves a better performance for matrix data classification. PMID- 28816683 TI - Cardiorespiratory Model-Based Data-Driven Approach for Sleep Apnea Detection. AB - Obstructive sleep apnea (OSA) is a chronic sleep disorder affecting millions of people worldwide. Individuals with OSA are rarely aware of the condition and are often left untreated, which can lead to some serious health problems. Nowadays, several low-cost wearable health sensors are available that can be used to conveniently and noninvasively collect a wide range of physiological signals. In this paper, we propose a new framework for OSA detection in which we combine the wearable sensor measurement signals with the mathematical models of the cardiorespiratory system. Vector-valued Gaussian processes (GPs) are adopted to model the physiological variations among different individuals. The GP covariance is constructed using the sum of separable kernel functions, and the GP hyperparameters are estimated by maximizing the marginal likelihood function. A likelihood ratio test is proposed to detect OSA using the widely available heart rate and peripheral oxygen saturation (SpO ) measurement signals. We conduct experiments on both synthetic and real data to show the effectiveness of the proposed OSA detection framework compared to purely data-driven approaches. PMID- 28816684 TI - A Multiobjective Evolutionary Algorithm Based on Structural and Attribute Similarities for Community Detection in Attributed Networks. AB - Most of the existing community detection algorithms are based on vertex connectivity. While in many real networks, each vertex usually has one or more attributes describing its properties which are often homogeneous in a cluster. Such networks can be modeled as attributed graphs, whose attributes sometimes are equally important to topological structure in graph clustering. One important challenge is to detect communities considering both topological structure and vertex properties simultaneously. To this propose, a multiobjective evolutionary algorithm based on structural and attribute similarities (MOEA-SA) is first proposed to solve the attributed graph clustering problems in this paper. In MOEA SA, a new objective named as attribute similarity is proposed and another objective employed is the modularity . A hybrid representation is used and a neighborhood correction strategy is designed to repair the wrongly assigned genes through making balance between structural and attribute information. Moreover, an effective multi-individual-based mutation operator is designed to guide the evolution toward the good direction. The performance of MOEA-SA is validated on several real Facebook attributed graphs and several ego-networks with multiattribute. Two measurements, namely density and entropy , are used to evaluate the quality of communities obtained. Experimental results demonstrate the effectiveness of MOEA-SA and the systematic comparisons with existing methods show that MOEA-SA can get better values of and in each graph and find more relevant communities with practical meanings. Knee points corresponding to the best compromise solutions are calculated to guide decision makers to make convenient choices. PMID- 28816685 TI - Editorial. PMID- 28816686 TI - Vestibular Response to Electrical Stimulation of the Otolith Organs. Implications in the Development of A Vestibular Implant for the Improvement of the Sensation of Gravitoinertial Accelerations. AB - OBJECTIVE: Electrical stimulation of the utricular and saccular portions of the vestibular nerve improves stability in patients suffering from vestibular dysfunction. The main objective of this study was to evaluate a new technique, vestibular response telemetry (VRT), for measuring the electrically evoked vestibular compound action potential (saccular and utricular) after stimulating the otolith organ (saccular and utricular) in adults. This study used evidence that the otolith organ can be electrically stimulated in order to develop a new vestibular implant design to improve the sensation of gravitoinertial acceleration. MATERIALS AND METHODS: Four adult patients were evaluated by using a variety of measurement procedures with novel VRT software. VRT values were obtained by stimulating with three full-band Nucleus CI24RE (ST) electrodes. Specific stimuli were used. Simultaneously, electrical ocular vestibular evoked myogenic potentials (eoVEMPs) were recorded in the contralateral side. RESULTS: Electrically evoked compound action potentials were obtained in 10 of the 12 electrodes tested, and eoVEMPs were recorded when VRT was present. In addition to the validation of this technique, a set of default clinical test parameters was established. The VRT response morphology consisted of a biphasic waveform with an initial negative peak (N1) followed by a positive peak (P1), and latencies were typically 400 MUs for N1 and 800 MUs for P1. The consequences for the development of a vestibular implant for the improvement of gravitoinertial acceleration sensation are also presented. CONCLUSION: The VRT measurement technique has been shown to be a useful tool to record neural response on the otolith organ, and thus it is a convenient tool to evaluate whether the implanted electrodes provide a neural response or not. This can be used for the early development of vestibular implants to improve gravitoinertial acceleration sensation. PMID- 28816687 TI - Hearing and Otoacoustic Emissions Outcome of Stapedotomy: Does the Prosthesis Diameter Matter? AB - OBJECTIVE: To compare the hearing and otoacoustic emissions (OAE) outcome of stapedotomy employing 0.4 and 0.6 mm diameter prostheses. MATERIALS AND METHODS: In total, 18 patients with otosclerosis participated in a prospective, double armed, randomized cohort study. All the patients underwent small fenestra drill stapedotomy employing the Causse fluroplastic large loop piston prostheses. The patients were randomly assigned to groups of 0.4 mm (n=9) and 0.6 mm (n=9) diameter prostheses. The results of pure tone air and bone audiometries, speech audiometry, and OAE conducted 12 months post operatively were compared within and between the groups. RESULTS: The within-group analysis showed significant post stapedotomy improvements in the average air conduction pure tone thresholds in both groups (52.9+/-9.6 vs. 25.6+/-5.2 dB HL; p<0.0001 and 54.6+/-10.4 vs. 22.2+/ 8.2 dB HL; p<0.0001 for the 0.4 and 0.6 mm groups, respectively) and average air bone gap (ABG; 37.1+/-8.5 vs. 8.1+/-3.9 dB HL; p<0.0001 and 38.3+/-7.5 vs. 9.9+/ 4.5 dB HL; p<0.0001 in the 0.4 and 0.6 mm groups, respectively). No significant differences were found between the groups in these outcome measures, as well as in the rate of ABG closure within 10 dB HL and the word recognition scores. Favorable outcome in the post-stapedotomy bone conduction (BC) was found for the 0.6 mm prosthesis group, reflecting superior cancellation of the Carhart phenomenon for the 500-3000 Hz pure tone thresholds average (-1.7+/-3.7 vs. 3.9+/ 6.2 dB HL for the 0.4 and 0.6 mm groups, respectively; p<0.04) and 1000, 2000, and 4000 Hz average (-2.6+/-4.33 vs. 3.9+/-7.8 dB HL for the 0.4 and 0.6 mm groups, respectively; p<0.05). Small signal-to-noise ratio (SNR) values of the transient-evoked OAE (TEOAE) and distortion product OAE (DPOAE) were found at baseline and follow-up evaluation with no consistent changes post stapedotomy. CONCLUSION: Similar post-stapedotomy hearing results were found for the 0.4 and 0.6 mm prostheses with small but statistically significant advantage in BC gain and the overclosure parameter for the 0.6 mm prosthesis. OAE testing was not found to be of clinical value in the evaluation of stapedotomy hearing outcome. PMID- 28816688 TI - Cartilage Ossiculoplasty from Stapes to Tympanic Membrane in One-Stage Intact Canal Wall Tympanoplasty for Cholesteatoma. AB - OBJECTIVE: To report hearing results of cartilage interposition ossiculoplasty in one-stage intact canal wall (ICW) tympanoplasty for cholesteatoma with intact stapes. MATERIALS AND METHODS: A retrospective study of pre and postoperative hearing status was conducted at a tertiary referral otologic center in a series of 61 patients having undergone one-stage ICW tympanoplasty for cholesteatoma with intact stapes and cartilage ossiculoplasty during the same procedure. RESULTS: In the preoperative period, the mean air conduction thresholds (AC), air bone gap (ABG), and speech reception thresholds (SRT) were 35.3, 20.14, and 35.6 dB, respectively. Postoperatively, with a mean follow-up of 29 months, AC, ABG, and SRT were 27.8, 13.34, and 28.8 dB, respectively. Mean hearing gain was 6.8 dB and mean SRT improvement was 6.8 dB. Mean bone conduction thresholds for 1, 2, and 4 kHz remained stable after surgery (17.6 dB preoperatively vs. 18 dB postoperatively). CONCLUSION: Cartilage ossiculoplasty from stapes to tympanic membrane in one-stage ICW tympanoplasty for cholesteatoma is a safe, reliable, easy, and effective procedure, with no additional cost. PMID- 28816689 TI - Single Stage Canal Wall Down Mastoidectomy with Reconstruction of the Canal Wall: 5 Years' Experience in Fayoum Province, Egypt. AB - OBJECTIVE: Removing the posterior canal wall or canal wall down mastoidectomy (CWDM) for the management of cholesteatoma remains controversial. We advocate partial removal of the posterior canal wall for complete eradication, followed by canal wall defect reconstruction to restore the normal anatomy and avoid the complications of CWDM. MATERIALS AND METHODS: Sixty-four patients with cholesteatoma (71 ears) were included. This study was conducted between 2009 and 2012. Single-stage mastoidectomy was performed by drilling the upper third of the posterior canal wall together with the attic, leaving the remaining lower two thirds intact. Conchal cartilage was used to reconstruct the upper third of the posterior canal wall. RESULTS: The mean+/-SD healing time was 7.5+/-2.3 (range, 4 14) weeks. The mean+/-SD preoperative and postoperative air bone gaps were 35.8+/ 6.2 dB and 22.9+/-6.8 dB, respectively. Nearly 84.2% of the patients were followed up for at least 3 years and had dry healthy ears. Complications were noted and statistically examined. CONCLUSION: Single-stage CWDM with reconstruction of the posterior canal wall, ossicular chain, and tympanic membrane is a safe and reliable technique with the advantages of Canal wall up Mastoidectomy (CWUM). Its recurrence rate is 4.2%. Longer follow-up durations are required. PMID- 28816690 TI - Complications of the Middle Cranial Fossa Approach for Acoustic Neuroma Removal. AB - OBJECTIVE: To analyze postoperative complications after microsurgery for acoustic neuroma (AN) via the middle fossa approach (MFA). MATERIALS AND METHODS: In total, 203 consecutive patients of a tertiary skull base referral center at a university hospital were included in this retrospective chart and database analysis. All patients had undergone primary microsurgery at the Otorhinolaryngology department via MFA between December 2005 and October 2014. Postoperative complications were documented during the inpatient stay and outpatient follow-up. RESULTS: Overall, 41 complications were registered in 35 patients. The most common was cerebrospinal fluid (CSF) leakage in 13% of the patients. Bleeding complications were documented in seven patients: two cerebellar bleedings, one subdural and one epidural hematoma, two hematomas of the skin, and one bleeding through the closed wound. Two patients experienced meningitis and one patient had a transient ischemic attack. Furthermore, three cases of deep vein thrombosis occurred, which led to a lethal pulmonary embolism in one case. One patient sustained temporary palsy of the vocal fold and another reported antibiotic-associated diarrhea. CONCLUSION: Acoustic neuroma surgery via the MFA can be conducted with low morbidity and mortality. The most common complication is CSF leakage, which can be treated in most cases in a stepwise conservative manner. Severe adverse events that may require revision surgery are very scarce (1%). PMID- 28816691 TI - Eustachian Tube Obliteration and its Effect on Rhinoliquorrhea in Translabyrinthine Vestibular Schwannoma Excision. AB - OBJECTIVE: Rhinoliquorrhea is defined as a cerebrospinal fluid leakage from the nose. Our objective in this study is to determine the reduction of rhinoliquorrhea rates by Eustachian tube (ET) obliteration in the context of a translabyrinthine approach performed following vestibular schwannoma (VS) excision. MATERIALS AND METHODS: This is a prospective study achieved in a tertiary-care center where the chart review revealed 94 VS operated by the translabyrinthine approach between 2009 and 2015. There were 40 males and 54 females aged from 28-76 years. The only exclusion criterion was a previous history of cranial surgery. ET obliteration was systematically executed when the petrous apex pneumatization level was at least 2 of 4. Our main outcome measure was the development of rhinoliquorrhea. RESULTS: Eighty-eight patients underwent ET obliteration and were followed for an average of 2.6+/-1.2 years. Rhinoliquorrhea was reported in 1.14% of the patients having had an ET obliteration. When compared to our previous sample of patients operated with a translabyrinthine approach, it represents a reduction of 84%. CONCLUSION: Obliteration of the ET is a fast and simple procedure that reduces the rate of rhinoliquorrhea. We therefore recommend its use, specifically in cases of petrous apex pneumatization levels 2-4. PMID- 28816692 TI - Questionnaires in Patients with Unilateral Sudden Sensorineural Hearing Loss. AB - OBJECTIVE: In this study, we evaluated the prognostic value of the Dizziness Handicap Inventory (DHI) and the Tinnitus Handicap Inventory (THI) in patients with unilateral sudden sensorineural hearing loss (SSNHL). MATERIALS AND METHODS: In total, 101 patients with unilateral SSNHL (44 women, 57 men), who were admitted and treated at our institution between December 2012 and June 2014, were included in the study. All patients completed the questionnaires for DHI and THI during their admission and were treated with bed rest and oral methylprednisolone (1 mg/kg, which was eventually tapered). Of these, 83 patients received intratympanic dexamethasone 4 times over a 2-week period. Demographic data, accompanying symptoms, and DHI and THI subscales were compared between the non recovery group (Siegel's criteria type 4, n=63) and the recovery group (Siegel's criteria type 1-3, n=38). RESULTS: There were no significant differences between the two groups with regard to gender, hypertension, diabetes mellitus, cerebrovascular attack, and tinnitus. Patients in the non-recovery group were significantly older (51.53 vs. 50.24 years, p<0.05) and had a higher incidence of chronic kidney disease (10.53% vs. 1.59%, p<0.05) than those in the recovery group. Although more patients in the non-recovery group complained of dizziness (47.37% vs. 25.40%, p<0.05), DHI subscales were not significantly different between the groups. THI subscales were also not significantly different between the two groups. CONCLUSION: DHI and THI questionnaires may have limited prognostic value for patients with unilateral SSNHL. PMID- 28816693 TI - Multiple-Frequency Matching Treatment Strategy for Tinnitus. AB - OBJECTIVE: The first aim was to integrate commonly used tinnitus measures into a comprehensive questionnaire. Second, the effectiveness of a masking therapy based on multiple-frequency matching was verified in a clinical study. This study investigated the feasibility of a new treatment strategy for tinnitus, with two main foci. MATERIALS AND METHODS: Compare multiple-frequency matching with traditional masking therapy (Single-frequency matching) through clinical trials. The analysis indicated that the reliability and construct validity of the comprehensive questionnaire need to be improved, and the feasibility of the integration attempt remains uncertain. RESULTS: The clinical results showed that the multiple-frequency matching method was more effective than single-frequency matching for tinnitus treatment. CONCLUSION: The multiple-frequency approach should be used more often with tinnitus masking to promote the patients' recovery. PMID- 28816694 TI - Evaluation of Hearing Handicap in Adults with Auditory Neuropathy Spectrum Disorder. AB - OBJECTIVE: The present study attempted to evaluate hearing handicap in adults with auditory neuropathy spectrum disorder (ANSD). The study also attempted to determine if gender, pure tone average, speech identification scores (SIS), and reported duration of hearing loss could predict the hearing handicap in adults with ANSD. MATERIALS AND METHODS: Hearing Handicap Inventory for Adults and Hearing Handicap Questionnaire were administered to 50 adults with ANSD. RESULTS: Using both the scales, there was a significant hearing handicap in both the social and emotional domains in adults with ANSD. SIS was a good predictor of hearing handicap compared to other variables. The poor SIS can affect communication skills leading to higher degree of social handicap. CONCLUSION: The ignorance regarding the exact cause for their hearing problems and lack of appropriate management strategies could lead to emotional problems in individuals with ANSD. However, further studies are essential for determining hearing handicap with the use of hearing aids and cochlear implants. PMID- 28816695 TI - Audiological and Radiological Characteristics in Incomplete Partition Malformations. AB - OBJECTIVE: To compare the audiological and radiological findings of patients with incomplete partition malformations (IPs) and analyze the relationship between the audiological and radiological findings. MATERIALS AND METHODS: The study included 84 patients (168 ears) with IPs as follows: 26 patients with Type I;IP-I (41 ears), 54 patients with Type II;IP-II (108 ears), and 4 patients with Type III;IP III (8 ears). Remaining 11 ears were diagnosed with other inner ear malformations. Air and bone conduction thresholds were determined with pure tone audiometry, and the air bone gap was recorded in all patients with IPs. Magnetic resonance imaging studies and computerized tomography scans of the temporal bones were analyzed using the PACS system of our university. RESULTS: It was found that all the ears with IP-I were diagnosed with severe to profound hearing loss. The degree of the hearing loss varied from mild to severe/profound in patients with IP-II. Severe to profound mixed hearing loss (MHL) was determined in all ears with IP-III. The air bone gap was larger in the lower frequencies in the IP-II cases diagnosed with MHL. There was not a significant difference between the air bone gap and the size of the vestibular aqueduct in ears with IP-II (p>0.05). CONCLUSION: Each type of IP has different audiological findings. Depending on the type and degree of the hearing loss, it is possible to choose the appropriate audiological intervention. Patients with IP should be evaluated according to the type of malformation. PMID- 28816696 TI - Subjective Visual Vertical and Horizontal in Vestibular Migraine. AB - OBJECTIVE: To assess the functional status of the otolithic pathway in vestibular migraine by comparing the results of static and dynamic subjective visual vertical and horizontal [subjective visual vertical (SVV) and subjective visual horizontal (SVH)] testing in patients with vestibular migraine with that of normal individuals. MATERIALS AND METHODS: This hospital-based prospective study was conducted in 82 normal adults and 66 adults with vestibular migraine. The SVV and SVH angles were measured under static and dynamic conditions using a software based test protocol. The arithmetic mean of six readings in each situation was considered. The results were further analyzed by stratifying cases and controls into two age groups 20-40 years and 41-60 years and into gender. RESULTS: The clinical profile of the patients with vestibular migraine was comparable to the available literature. The dynamic SVV and SVH in both age groups and the static SVH in the 41-60 years age group were significantly higher compared to normal individuals (p<0.05). The dynamic SVV and SVH were significantly higher in the cases compared to controls among both males and females (p<0.05). CONCLUSION: There is evidence of otolithic pathway abnormalities in individuals with vestibular migraine. The inclusion of SVV and SVH testing for the evaluation of patients with vestibular migraine may be useful in the interpretation and rehabilitation of symptoms in these patients. PMID- 28816697 TI - Sub-Galeal Pneumocele 20 Years after Cochlear Implantation. AB - This case report documents a rare case of a subgaleal pneumocele occurring more than 20 years after cochlear implantation. On presentation, the presence of air under the scalp followed vigorous nose blowing was observed. The patient was treated conservatively with a pressure dressing, which resulted in complete resolution of the surgical emphysema. Only a handful of such cases have been reported in the literature. Most of these cases occur early after cochlear implantation. Our case is even more unique as it occurred 24 years following implantation and presented with a painless swelling associated with deterioration in cochlear implant performance. A review of the current literature is included in the discussion. PMID- 28816698 TI - Intralabyrinthine Vestibular Schwannoma Responsive to Intratympanic Gentamicin Treatment. AB - Intralabyrinthine schwannoma (ILS) is a rare benign tumor that affects the ends of cochlear and vestibular nerves. In a majority of the cases, it occurs with unilateral progressive sensorineural hearing loss. Less frequent symptoms include tinnitus, imbalance, vertigo, or fullness. The advent of magnetic resonance imaging allows early diagnosis and enables an appropriate therapeutic protocol. This report describes a case of intravestibular schwannoma, with fluctuating hearing loss and intractable vertigo, treated with intratympanic gentamicin. The patient was a 28-year-old woman with intractable vertigo and fluctuating left side hearing loss caused by left intravestibular schwannoma. Because surgery was temporarily rejected by the patient, a single dose of intratympanic gentamicin was administered. Following this, the patient showed a significant improvement in the symptoms. However, moderate to flat sensorineural hearing loss was also observed. Intratympanic gentamicin infiltration is a valid therapeutic option for patients with ILS, affected by intractable vertigo, when the patient refuses surgery. PMID- 28816699 TI - Ceruminous Adenoid Cystic Carcinoma of External Auditory Canal. AB - An adenoid cystic carcinoma (AdCC) of the ceruminous glands is very rare; its diagnosis is most often challenging, and simple biopsies may be misleading. Our paper describes a case of a circumferential mass of the left ear canal that was initially reported as a basal cell carcinoma on biopsies in the clinic and on frozen sections intraoperatively. The final pathology was an AdCC of the ceruminous glands of the external auditory canal. Our case reflects the difficulty in the diagnosis of an AdCC of the ceruminous gland and the importance of keeping broad differential diagnoses in mind when counseling patients with masses in the ear canals until final pathology is obtained. PMID- 28816701 TI - Erratum. PMID- 28816700 TI - Recovery of Tinnitus and Sensorineural Hearing Loss Due to Lysis of Arachnoid Adhesions in the Posterior Cranial Fossa: Is There a Novel Etiology in Neurotological Disorders? AB - We reported the recovery of sensorineural hearing loss and tinnitus in a 22-year old man after complete removal of intracranial portion of jugular foramen schwannoma via the retrosigmoid approach. The aim of this case report was to present the excision of a large jugular foramen schwannoma via the retrosigmoid approach and to describe the improvement of sensorineural hearing loss related to arachnoid inflammations due to chronic arachnoiditis after suboccipital craniectomy. The recovery of sensorineural hearing loss and tinnitus after release of arachnoid adhesions may indicate the clinical significance of these adhesions or arachnoiditis, which should also be considered and investigated in the etiology of other neurotological diseases. PMID- 28816702 TI - As above, so below? Towards understanding inverse models in BCI. AB - OBJECTIVE: In brain-computer interfaces (BCI), measurements of the user's brain activity are classified into commands for the computer. With EEG-based BCIs, the origins of the classified phenomena are often considered to be spatially localized in the cortical volume and mixed in the EEG. We investigate if more accurate BCIs can be obtained by reconstructing the source activities in the volume. APPROACH: We contrast the physiology-driven source reconstruction with data-driven representations obtained by statistical machine learning. We explain these approaches in a common linear dictionary framework and review the different ways to obtain the dictionary parameters. We consider the effect of source reconstruction on some major difficulties in BCI classification, namely information loss, feature selection and nonstationarity of the EEG. MAIN RESULTS: Our analysis suggests that the approaches differ mainly in their parameter estimation. Physiological source reconstruction may thus be expected to improve BCI accuracy if machine learning is not used or where it produces less optimal parameters. We argue that the considered difficulties of surface EEG classification can remain in the reconstructed volume and that data-driven techniques are still necessary. Finally, we provide some suggestions for comparing approaches. SIGNIFICANCE: The present work illustrates the relationships between source reconstruction and machine learning-based approaches for EEG data representation. The provided analysis and discussion should help in understanding, applying, comparing and improving such techniques in the future. PMID- 28816703 TI - An electromechanical, patient positioning system for head and neck radiotherapy. AB - In cancer treatment with radiation, accurate patient setup is critical for proper dose delivery. Improper arrangement can lead to disease recurrence, permanent organ damage, or lack of disease control. While current immobilization equipment often helps for patient positioning, manual adjustment is required, involving iterative, time-consuming steps. Here, we present an electromechanical robotic system for improving patient setup in radiotherapy, specifically targeting head and neck cancer. This positioning system offers six degrees of freedom for a variety of applications in radiation oncology. An analytical calculation of inverse kinematics serves as fundamental criteria to design the system. Computational mechanical modeling and experimental study of radiotherapy compatibility and x-ray-based imaging demonstrates the device feasibility and reliability to be used in radiotherapy. An absolute positioning accuracy test in a clinical treatment room supports the clinical feasibility of the system. PMID- 28816704 TI - Comparison Between Corticosteroid and Lidocaine Injection in the Treatment of Tennis Elbow: A Randomized, Double-Blinded, Controlled Trial. AB - OBJECTIVE: The aim of the study was to compare the effects of corticosteroid injection with lidocaine injection in treating tennis elbow. DESIGN: It is a prospective, double-blinded, randomized controlled trial. Patients with tennis elbow for more than 1 mo were recruited from a hospital-based rehabilitation outpatient clinic. A total of 70 patients were recruited, and 61 patients completed the study. Patients received an injection of either 10 mg (1 ml) of triamcinolone (corticosteroid group, n = 30) or 1 ml of 1% lidocaine (lidocaine group, n = 31). All of the outcome measures were evaluated before the intervention and at 2 wks and 2 mos after treatment. RESULTS: No significant group differences were observed between the corticosteroid and lidocaine groups regarding Patient-Rated Tennis Elbow Evaluation, Disability of the Arm, Shoulder, and Hand, visual analog scale for pain, and grip strength at baseline and at 2 wks and 2 mos after treatment (P > 0.05). However, within-group comparison showed significant improvement after injection with regard to Patient-Rated Tennis Elbow Evaluation, Disability of the Arm, Shoulder, and Hand, visual analog scale for pain, and grip strength in both groups (P > 0.05). CONCLUSIONS: No differences in the short-term outcomes were found between lidocaine and corticosteroid injection in a small sample of people with tennis elbow with mean duration of 3.8 mos. PMID- 28816706 TI - Prognostic Factors for Recurrence After Fertility-Preserving Surgery in Patients With Borderline Ovarian Tumors: A Systematic Review and Meta-analysis of Observational Studies. AB - OBJECTIVE: The aim of this study was to find the unfavorable prognostic factors for recurrence after fertility-preserving surgery (FPS) in patients with borderline ovarian tumors (BOTs). METHODS: To perform a meta-analysis to compare the recurrence rates of BOT patients after FPS according to different prognostic factors, we searched PubMed, EMBASE, and Cochrane for observational studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated with a fixed effects model. RESULTS: We analyzed 32 studies that included 2691 BOT patients who underwent FPS, 383 patients of whom had a relapse in the follow-up. In meta analysis, risks associated with recurrence in patients with unilateral cystectomy (OR, 2.49; 95% CI, 1.86-3.33) or serous borderline ovarian tumors (OR, 3.15; 95% CI, 1.97-5.02) were significantly increased, and there was no significantly increased OR for patients with laparoscopy compared with those with laparotomy (OR, 0.96; 95% CI, 0.57-1.60). CONCLUSIONS: Unilateral cystectomy (19.4%) and serous BOTs (19.2%) are significantly associated with higher recurrence rates, and no negative impact of laparoscopy on recurrence can be demonstrated when compared with laparotomy in the meta-analysis. PMID- 28816705 TI - Microvascular Vasodilator Plasticity After Acute Exercise. AB - Endothelium-dependent vasodilation is reduced after acute exercise or after high intraluminal pressure in isolated arterioles from sedentary adults but not in arterioles from regular exercisers. The preserved vasodilation in arterioles from exercisers is hydrogen peroxide (H2O2) dependent, whereas resting dilation is nitric oxide (NO) dependent. We hypothesize chronic exercise elicits adaptations allowing for maintained vasodilation when NO bioavailability is reduced. PMID- 28816707 TI - Effect of Group Exercising and Adjusting the Brace at Shorter Intervals on Cobb Angle and Quality of Life of Patients With Idiopathic Scoliosis. AB - OBJECTIVE: The aim of the study was to evaluate the effect of group exercise with brace adjustment at shorter intervals than used in routine practice in late-onset idiopathic scoliosis patients. DESIGN: This was a quasi-experimental study. Thirty patients with progressive scoliosis curves of 15-50 degrees and a prescription for a brace were divided into experimental and control groups, both of which participated in an 11-wk treatment program. Those in the experimental group underwent brace adjustment twice per week and performed group exercise, whereas those in the control group received a routine protocol. The quality of life and Cobb angle of patients in both groups were evaluated based on baseline and final results of the 22-item Scoliosis Research Society questionnaire and primary and secondary radiographs. RESULTS: In the experimental group, the improvement in Cobb angle and patient satisfaction was greater than that in the control group (P < 0.05). Moreover, in patients with Cobb angles of less than 30 degrees, the self-image and satisfaction domains and the total scores of patients in the experimental group were significantly different from those in the control group at the final assessment (P < 0.05). CONCLUSIONS: Brace adjustment at shorter intervals combined with group exercise increases patient satisfaction and reduces scoliosis Cobb angles. PMID- 28816708 TI - Single-Incision Approach to Implantation of the Pulse Generator and Leads for Dorsal Root Ganglion Stimulation: A Case Report. AB - Dorsal root ganglion (DRG) stimulation has recently emerged as a treatment for persistent neuropathic pain, but the permanent implantation of stimulator leads and the pulse generator can be difficult and is sometimes associated with complications. We used a single-incision approach to tunnel and implant the leads and pulse generator for DRG stimulation treatment in a patient suffering from intractable foot pain. At long-term follow-up, the patient experienced a decrease in pain intensity and improvement in function, without any complications. A single-incision implantation technique for DRG stimulator implantation may simplify implantation and decrease the risk of complications. PMID- 28816709 TI - On a Square-Root Transformation of the Odds Ratio for a Common Outcome. PMID- 28816710 TI - Establishment of Primary Cell Culture From Ascitic Fluid and Solid Tumor Obtained From Epithelial Ovarian Carcinoma Patients. AB - OBJECTIVE: Ovarian cancer is the seventh leading cause of cancer death worldwide. This is mainly due to late diagnosis and high rate of relapse and resistance following chemotherapy. In the present study, we describe simple and cost effective method to establish primary culture from ascitic fluid and solid tumor obtained from epithelial ovarian carcinoma patient, which may provide a better tool for in vitro testing of drug sensitivity and designing individualized treatment protocol. METHODS: Complete Dulbecco modified Eagle medium (DMEM) was prepared by supplementing DMEM with 10% fetal bovine serum and antibiotics (ciprofloxacin and amphotericin B). Establishment of primary culture of ovarian cancer cells from ascites fluid and solid tumor was done by using complete DMEM media. RESULTS: Primary cultures of ovarian cancer cells were established from ascitic fluid and solid tumor tissue. Of the 7 ascitic fluid samples, we were able to establish 5 primary cultures of ovarian cancer cells. All the 7 samples were diagnosed as serous papillary adenocarcinoma. Some fibroblasts were also attached to culture flask on day 4; they were removed by exposing them to trypsin for a brief period. On day 7, grape-like clusters were visualized under inverted microscope. The cells became confluent on the 10th and 11th day and showed cobblestone appearance, which is a hallmark of ovarian cancer cells. Senescent irregularly shaped cells that have ceased dividing were seen after 8 to 10 passages. CONCLUSION: This study highlights the fact that establishing primary cultures from ascitic fluid or solid tumor tissue may help us to understand the molecular profile of the cancer cells, which allow us to select the best chemotherapeutic agent for ovarian cancer patients and thus take a step toward patient-tailored therapy so that patients are not exposed to drugs to which they are not likely to respond. PMID- 28816711 TI - Multiple Drug-Intolerant Hypertension. AB - CLINICAL FEATURES: The term multiple drug intolerance (MDI) is attributed to patients who experience adverse drug reactions to more than 3 different classes of medication without a known immunological mechanism. A special attention should be given to multiple drug-intolerant hypertension (MDI-HTN) that is a cause of drop out from treatment and consequent poor blood pressure control. Patients with MDIs account for 2%-5% of all population. The patient we present is a 63-year-old man with third-degree hypertension identified with intolerance to drugs from 4 major classes of antihypertensive medication. THERAPEUTIC CHALLENGE: Patients with MDIs are difficult to treat. They frequently also have numerous comorbidities and high cardiovascular risk. It is recognized that guidelines for the management of hypertension do not include an algorithm of action in situations of MDIs to medication. SOLUTION: We chose to use a recently proposed four-step algorithm for the management of MDI-HTN. A 1-month follow-up program was established. Weekly visits were scheduled to elicit about side effects and measure blood pressure . Ambulatory blood pressure monitoring was performed after a month. The strategy was first to reuse medication from classes the patient was intolerant to, but in smaller doses and in combinations. Among same class members, we have chosen those with less adverse effects. Not all steps within the algorithm were followed since our patient did not need alternative formulation as liquid or transdermal ones. Anxiety medication was prescribed as nonlicensed antihypertensive medication. At the end of the follow-up month, blood pressure control was satisfactory, 24-hour ambulatory blood pressure monitoring was 135.5/83.0 mm Hg, and the patient did not claim any adverse drug reactions. PMID- 28816712 TI - Nurses' Knowledge and Teaching of Possible Postpartum Complications. AB - PURPOSE: The purpose of this study was to assess postpartum nurses' knowledge of maternal morbidity and mortality, and information they shared with women before discharge about identifying potential warning signs of postpartum complications. STUDY DESIGN & METHODS: Registered nurses (RNs) who care for women during postpartum (N = 372) completed an electronic survey. Descriptive statistics and bivariate analyses were used for data analysis. RESULTS: Fifty-four percent of nurse participants were aware of the rising rates of maternal mortality in the United States and 12% accurately reported the correct percentage of deaths that occurred during the postpartum period. Ninety-three percent of nurses were more likely to identify hemorrhage as a leading cause of maternal mortality. On the day of discharge, 67% of RNs spent less than 10 minutes focusing on potential warning signs. Ninety-five percent of RNs reported a correlation between postpartum education and mortality; however, only 72% strongly agreed it was their responsibility to provide this education. Nurse respondents who were over the age of 40 were significantly more likely to report feeling very competent when providing education on all of the postpartum complication variables measured (p values <0.001-0.003). CLINICAL IMPLICATIONS: The majority of nurses in this study were not up-to-date on the rates and timing of maternal mortality during the postpartum period in the United States. They did not always provide comprehensive education to all women prior to discharge from the hospital after childbirth. There is a need for nurses to provide consistent messages about potential warning signs that may ultimately reduce maternal death and severity of maternal complications. PMID- 28816713 TI - Radiation therapy to the primary in metastatic prostate cancer: palliation only or altering tumor biology? AB - PURPOSE OF REVIEW: Despite improvement in systemic treatment, the prognosis of men with de novo metastatic prostate cancer remains poor. Treating the local disease may not only reduce the occurrence of local urologic symptoms, but also slow the metastatic process, either by reducing the seeding from the primary tumor or by altering the microenvironment and thus minimizing the formation of new metastatic sites. RECENT FINDINGS: Retrospective and population-based studies have suggested that the addition of local treatment to systemic therapy may improve survival in this patient group. The aim of this review is to discuss the biologic rationale of such an approach, present and discuss the current available evidence, with a focus on radiation-based treatments. It is key to also address the issue of patient selection as not all patients with metastatic prostate cancer will benefit from the treatment of the primary tumor. SUMMARY: Retrospective and population-based research suggests a survival benefit of prostatectomy or radiotherapy in metastatic prostate cancer patients. Clinical trials evaluating the role of prostate radiotherapy in the metastatic setting are ongoing. PMID- 28816714 TI - Radiotherapy as metastasis-directed therapy for oligometastatic prostate cancer. AB - PURPOSE OF REVIEW: To summarize the available literature regarding radiotherapy as a metastasis-directed therapy (MDT) in the treatment of oligometastatic prostate cancer (PCa). RECENT FINDINGS: Three different clinical scenarios of oligometastatic PCa exist in which MDT can be applied: de novo oligometastatic PCa, oligorecurrent PCa, and oligoprogressive PCa. A cut off of three to five metastatic lesions is most often used in these settings. Data from retrospective studies, treating over 1000 patients in total, have been reported. The median progression-free survival ranges between 1 and 3 years, but is influenced by a heterogeneous use of androgen deprivation therapy. For lymph node metastases, a propensity scored matched analysis suggests that cancer specific and overall survival is improved with MDT over standard of care. MDT treatment regimens vary with different radiotherapy techniques, doses, and volumes. Adverse events are limited to grade 1-2 and only rarely grade 3 events are reported. SUMMARY: Based on data from retrospective studies, progression-free survival following MDT for oligometastatic PCa is promising with few adverse events. Comparative prospective studies are under way and will shed light on the future of MDT. PMID- 28816715 TI - Testosterone therapy improves erectile function and libido in hypogonadal men. AB - PURPOSE OF REVIEW: Erectile dysfunction and decreased libido are common complaints in the older male population. Recent studies have elucidated the role testosterone therapy (TTh) can play in men with low testosterone levels. The aim of this review is to provide an overview of these findings and the utility of TTh. We specifically examine the role of TTh on erectile function, coadministration with phosphodiesterase type 5 inhibitors, and libido. RECENT FINDINGS: Recent publications suggest that TTh improves mild erectile dysfunction, though may be less useful in men with more severe erectile dysfunction. In men unresponsive to phosphodiesterase type 5 inhibitors and with mild erectile dysfunction, TTh can further improve erectile function. TTh has also shown consistent benefit in improving libido in men with low testosterone levels at baseline, with no additional improvements once testosterone levels are normalized. SUMMARY: The available literature supports a role for TTh in men with low testosterone levels, erectile dysfunction, and low libido, with symptomatic improvement in these men. PMID- 28816717 TI - Comparison of Negative Pressure Wound Therapy and Conventional Therapy for Cranial Bone-exposed Wounds in Rabbits. AB - BACKGROUND: Bone-exposed wounds with intact or defected periosteum are difficult to heal. To provide relevant experimental evidence for guidance of clinical therapy, we established a rabbit model to compare the efficacies of negative pressure wound therapy (NPWT) and conventional guaze dressing therapy on the healing of cranial bone-exposed wounds. METHODS: Full-thickness excisional circular wounds of 2.0 cm in diameter with exposed bones covered with or without periosteum were created at the parietal regions in 88 rabbits that were further randomly divided into the following treatment groups: periosteum-intact wounds treated with conventional vaseline gauze dressings (P + Control group), periosteum-intact wounds treated with NPWT (P + NPWT group), periosteum-lacking wounds treated with conventional vaseline gauze dressings (P-Control group), and periosteum-lacking wounds treated with NPWT (P-NPWT group). The wounds of NPWT groups were treated using a negative pressure therapy assembly that was set at a continuous pressure of -125 mm Hg for 7 days, then covered with vaseline gauze. The wound healing rates, wound infection rates, hydroxyproline content, and wound tissue histology were determined and evaluated. RESULTS: The NPWT shortened the wound healing time by approximately 5 days when compared with the conventional gauze therapy. The histological characterization of wound tissues showed that NPWT decreased the inflammatory cells infiltration, accelerated reepithelialization and facilitated the organization of collagen fibers into neat layers on postoperative day (POD) 10. The NPWT enhanced bacterial clearances, reduced infection rates and increased the hydroxyproline contents in both types of wounds on PODs 10 and 15. The immunohistochemical staining of CD31 showed the NPWT treatment resulted in a significantly increased and persistent angiogenesis, and the wounds treated with NPWT showed well developed and more functional vessels at POD 7 compared with control. CONCLUSIONS: The NPWT is a more effective therapy for bone-exposed wounds than conventional guaze dressing therapy. The NPWT can promote bone-exposed wounds healing by increasing collagen contents and vessels densities while reducing inflammatory cells infiltration, reducing wound infection rates, and inducing an ordered collagen arrangement. PMID- 28816716 TI - Novel androgen axis systemic therapies for metastatic hormone-sensitive prostate cancer. AB - PURPOSE OF REVIEW: Upfront docetaxel and androgen deprivation therapy (ADT) has improved outcomes over ADT alone in men with metastatic hormone-sensitive prostate cancer (mHSPC). Here in, we review the emerging role of novel androgen axis inhibitors in the treatment of men with mHSPC. RECENT FINDINGS: Recently two studies, LATITUDE and STAMPEDE arm G, showed improved survival with addition of abiraterone acetate with prednisone or prednisolone to ADT in men with hormone naive advanced prostate cancer. SUMMARY: Upfront docetaxel in addition to ADT has been shown to improve survival outcomes in men with high-volume mHSPC. Recently, abiraterone acetate and prednisone or prednisolone and ADT have been shown to improve survival outcomes compared with ADT alone in men with mHSPC. Multiple other novel androgen axis inhibitors are being investigated in this setting, and expected to garner regulatory approval in the near future. Biomarkers predicting response to these agents are urgently needed to optimize treatment selection, not only to improve outcomes but to also minimize cost and toxicities. PMID- 28816718 TI - Double Composite Tissue Z-plasty Technique for Anatomical Restoration of Severe Nasal Deformity in Secondary Unilateral Cleft Lip. AB - BACKGROUND: Patients with secondary unilateral cleft lip are regularly affected by serious nasal deformities especially of the alar and nasal floor. A large number of techniques for correction have been published, but symmetrical restoration of severe nasal deformation is difficult to achieve. We propose an innovative approach for anatomical restoration for this entity of nasal deformities to achieve long-term symmetrical appearance and muscular function. METHODS: A total of 68 patients with severe nasal deformity due to secondary unilateral cleft lip underwent reconstructive surgery using a double composite tissue Z-plasty technique for anatomical restoration of cartilage, muscle, and soft tissue layers. Patient pictures were taken preoperatively and postoperatively to evaluate appearance and incisional wound healing. The surgical outcome was assessed based on a postoperative patient satisfaction survey. All occurring adverse effects were recorded. RESULTS: All patients were followed up for at least 7 months up to 8 years; mean follow-up period was 14.6 months. Patients were highly satisfied with the aesthetic result and improved facial profile (97.1%) and healing of the incision site (94.1%). There were 4 cases of implant deviation and 2 cases of impaired ventilation due to hypertrophic scarring of the upper lip (2 patients) and relatively decreased nostril size after augmentation rhinoplasty (1 patient), respectively, requiring surgical revision 1 year postoperatively. No other complications such as bleeding, infection, flap necrosis, and sensory dysfunction were recorded. CONCLUSIONS: The double composite tissue Z-plasty technique allows for thorough anatomical restoration of cartilage, muscle, and skin layers in unilateral cleft lip nasal deformities. This single-step approach is a safe and technically easy therapeutic option that is associated with high patient satisfaction and acceptance. PMID- 28816719 TI - The Limitations of Implantable Mesh in Mastopexy. PMID- 28816721 TI - Brief Report: Drop in CD4+ Counts Below 200 Cells/MUL After Reaching (or Starting From) Values Higher than 350 Cells/MUL in HIV-Infected Patients With Virological Suppression. AB - BACKGROUND: The aim of the study was to quantify the risk of a drop in CD4 counts below 200 cells/MUL after reaching values >350 cells/MUL on antiretroviral therapy (ART) (or after starting ART with CD4 count >350 cells/MUL) in the absence of virological failure. SETTING: Ambulatory care services, Italy. METHODS: Prospective cohort study of patients enrolled in the ICONA Foundation Study cohort who started ART with >350 CD4/MUL or with <=350 CD4/MUL and reached values >350 cells/MUL after virological suppression (VS, defined by 2 consecutive viral loads <=50 copies/mL). The date of CD4 count >350 was the baseline for the analysis and those with >=1 viral load and CD4 count after baseline were included. The primary end point was the cumulative risk (estimated using the Kaplan-Meier method) of a CD4 drop below 200 cells/MUL over follow-up, which was censored at the date of virological failure (confirmed HIV-RNA >50 copies/mL), death, or last visit. RESULTS: Six thousand six hundred sixty-three patients were included. A confirmed CD4 drop below 200 cells/MUL was never observed over a median follow-up of 45 (Q1: 21, Q3: 89) months, as long as VS was maintained. Upper limits of the 97.5% confidence interval of rates of confirmed CD4 drop below 200 cells/MUL were 0.28 and 0.38/1000 person-years of follow-up for patients with <=350 and >350 CD4 cells/MUL at starting ART. CONCLUSIONS: In patients who started ART in Italy with >350 CD4 cells/MUL or reached >350 CD4 cells/MUL after VS, the risk of a CD4 drop below 200 cells/MUL in those maintaining VS was negligible. PMID- 28816720 TI - Racial Inequities in HIV Prevalence and Composition of Risk Networks Among People Who Inject Drugs in HIV Prevention Trial Network 037. AB - BACKGROUND: HIV prevention interventions in the United States have failed to eliminate racial inequities. Here, we evaluate factors associated with racial inequities in HIV prevalence among people who inject drugs using HIV Prevention Trial Network 037 data. METHODS: We measured racial homophily (ie, all members share the same race), being in an HIV+ network (network with >=1 HIV+ member), and drug and sex risk behaviors. A 2-level logistic regression with a random intercept evaluated the association between being in an HIV+ network and race adjusting for individual-level and network-level factors. RESULTS: Data from 232 index participants and 464 network members were included in the analysis. Racial homophily was high among blacks (79%) and whites (70%); 27% of all-black, 14% of all-white, and 23% of racially mixed networks included HIV+ members. Sex risk was similar across networks, but needle sharing was significantly lower in all-black (23%) compared with all-white (48%) and racially mixed (46%) networks. All-black [adjusted odds ratio (AOR), 3.6; 95% confidence interval (CI), 1.4 to 9.5] and racially mixed (AOR, 2.0; 95% CI: 1.1 to 3.7) networks were more likely to include HIV+ network members; other factors associated with being in HIV+ network included homelessness (AOR, 2.0; 95% CI, 1.2 to 3.2), recent incarceration (AOR, 0.4; 95% CI, 0.2 to 0.7), and cocaine injection (AOR, 1.7; 95% CI, 1.0 to 2.7). Risk behaviors were not associated with being in an HIV+ network. CONCLUSION: Despite having lower drug risk behavior, all-black networks disproportionately included HIV+ members. HIV prevention interventions for people who inject drugs need to go beyond individual risk and consider the composition of risk networks. PMID- 28816723 TI - Melphalan-Induced Atrial Fibrillation. PMID- 28816722 TI - Omega-3 Fatty Acids in Rheumatic Diseases: A Critical Review. AB - Many clinical trials of omega-3 fatty acids, supplied as fish oil supplements, have been carried out in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), lupus nephritis, and osteoarthritis (OA) over the past 3 decades. This review attempts to summarize the highlights of these studies to evaluate the clinical efficacy for omega-3 fatty acids to be added alongside existing treatment regimens. A total of 20 clinical trials have been carried out in RA, of which 16 exhibited significant improvements in multiple disease clinical outcomes. Nine clinical trials have been completed in SLE and lupus nephritis, of which 6 exhibited significant improvements in 1 or more clinical outcomes. A total of 4 clinical trials have been conducted in OA, of which 3 exhibited significant improvements in at least 1 clinical parameter. Multiple mechanisms for the clinical effects of omega-3 fatty acids have been implicated, including the modulation of eicosanoid synthesis toward a more anti-inflammatory profile and suppressed production of proinflammatory cytokines. Overall, fish oil supplements appear to be a safe and effective agent that could be added to the current treatment regimens in RA. Longer-term trials with larger patient cohort sizes are warranted to establish any long-term benefits of fish oil supplements in SLE, lupus nephritis, and OA. PMID- 28816724 TI - Radiation Recall Dermatitis Consecutive to Cabozantinib Use. PMID- 28816725 TI - Effect of Citalopram for the Treatment of Neurocardiogenic Syncope. AB - BACKGROUND: Neurocardiogenic syncope (NCS) is a common form of syncope. Although selective serotonin reuptake inhibitors and other medications have been used to treat NCS with variable success, there is no consensus regarding a first-line therapy. STUDY QUESTION: To assess the effects of citalopram in NCS and to examine the effect of diagnostic use of the head-up tilt table (HUTT) versus empirical diagnosis on patient outcome. STUDY DESIGN: A retrospective case series of 1000 consecutive patients who were diagnosed with NCS and treated with citalopram. MEASURES AND OUTCOMES: The primary outcome measure was well-being score (WS) recorded at each outpatient visit. RESULTS: After excluding patients who had other comorbidities, were taking daily medication, or did not attend a follow-up visit within 1 month after treatment initiation, data from 186 patients were included. Thirty-five patients were diagnosed empirically, and 151 patients were diagnosed with the HUTT. All 186 patients were followed up within 1 month (early follow-up); of these, 92 patients attended a second follow-up after 1 month (late follow-up). The early follow-up group showed a significant improvement in mean WS (7.35 vs. 4.46, P < 0.001) and only 5 patients discontinued therapy because of intolerability. The late follow-up group also showed significant improvements in mean WS at the early follow-up (7.42 vs. 4.43, P < 0.001) and late follow-up (7.42 vs. 4.26, P < 0.001). Of 186 patients who were treated with citalopram, only 11 reported the development of undesirable side effects. There was no significant difference in the outcome of patients who were diagnosed empirically versus those who were diagnosed with the HUTT. CONCLUSIONS: Citalopram seems to have desirable effects on NCS and patient well being. Diagnostic use of the HUTT is useful for confirming diagnoses of NCS but is not likely to improve patient outcome. PMID- 28816726 TI - Acute Inflammatory Demyelinating Polyradiculoneuropathy Secondary to Ifosfamide. PMID- 28816727 TI - Effect of Time on Scleral Lens Settling and Change in Corneal Clearance. AB - SIGNIFICANCE: With the increase in the use of scleral contact lenses among practitioners, questions regarding lens settling are gradually gaining attention. This is because current studies support the notion that scleral lenses settle back over time. More research is needed to understand the exact cause and the factors that underpin such phenomenon. PURPOSE: The present study aims to assess the effect of time on topographic corneal clearance of three scleral contact lenses of varying sagittal depths. METHODS: Three scleral contact lenses were fitted to 20 subjects with previous diagnosis of keratoconus (n = 18) or pellucid marginal degeneration (n = 2). The fit was based on corneal sagittal height measured with the Visante optical coherence tomographer (OCT) at 15 mm along the horizontal meridian. To select an appropriate lens from the diagnostic lens set, values of 325 MUm (lens 1), 375 MUm (lens 2), and 425 MUm (lens 3) were randomly added in sequence to the corneal sagittal height. Subjects wore each lens for 1 hour. Corneal clearance was measured at 10-minute intervals for 1 hour using a custom ultra-long OCT. To assess change in clearance, central point and two mid peripheral points (+3 mm and -3 mm) along an 8-mm chord were measured by taking differences at each time point up to 1 hour. Measurements were repeated for the two other lenses. RESULTS: Mean central corneal clearance loss for all three lenses was 33.83 +/- 48.40 MUm. This was 26 +/- 27 MUm (13 +/- 14 MUm, +3 mm; 34 +/- 37 MUm, -3 mm), lens 1; 35 +/- 59 MUm (38 +/- 61 MUm, +3 mm; 52 +/- 69 MUm, 3 mm), lens 2; and 41 +/- 54 MUm (33 +/- 26 MUm, +3 mm; 52 +/- 48 MUm, -3 mm), lens 3, respectively. There was no significant difference (P = 0.06) at central and other locations for lens 1 (location and over time). There were significant differences for both lenses 2 and 3 (P < .001, P = .01, respectively) for all three locations and over time. CONCLUSIONS: There is a likelihood of clearance loss after 1 hour of lens wear. This varies between subjects, initial lens-fit relationship, and over time. PMID- 28816728 TI - Lipid Deposition on Contact Lenses when Using Contemporary Care Solutions. AB - SIGNIFICANCE: There remains only a small amount of data from human studies demonstrating the effect of contact lens/lens care solution combinations on the deposition of lipids. Therefore, information on the degree to which modern materials deposit lipids when used with contemporary care solutions would be valuable. PURPOSE: The present study aims to determine the effect of lens care system combinations on levels of total lipid, cholesterol, and cholesteryl esters extracted from three different contact lenses (CLs) when used with four contemporary care systems. METHODS: Experienced CL wearers were recruited to participate in this study. Combinations of three CLs (etafilcon A [ETA], galyfilcon A [GALY], and senofilcon A [SENO]) and four CL care solutions (Biotrue, ClearCare, OPTI-FREE PureMoist, and RevitaLens Ocutec) were investigated. A total of 791 CLs were analyzed. Subjects were randomized to one lens type and then used all four lens care solutions in random sequence for 10-14 days before the CLs were collected and analyzed for the amount of cholesterol, cholesteryl esters, and total lipids. RESULTS: The mean range of cholesterol recovered across the different care solutions was 0.34-2.77 MUg/lens, 3.48-4.29 MUg/lens, and 4.75-6.20 MUg/lens for ETA, SENO, and GALY lenses, respectively. Use of OPTI-FREE PureMoist with ETA lenses led to a significantly greater amount of cholesterol being recovered when compared to the use of the other solutions with ETA lenses (P < .05). The mean range of cholesteryl esters recovered across different care solutions was 1.31-2.02 MUg/lens, 6.43-7.19 MUg/lens, and 7.96 10.13 MUg/lens for ETA, SENO, and GALY lenses, respectively. There were no differences in the amount of cholesteryl esters and total lipids extracted for a given lens type when used with any of the four care solutions (P > .05). CONCLUSIONS: This study did not demonstrate conclusively that any of the solution/CL combinations were superior to any of the other combinations when the amounts of lipid deposition were compared among the tested lenses. PMID- 28816729 TI - RETINA EXPANSION TECHNIQUE FOR MACULAR HOLE APPOSITION REPORT 2: Efficacy, Closure Rate, and Risks of a Macular Detachment Technique to Close Large Full Thickness Macular Holes. AB - PURPOSE: To describe the safety and efficacy of a technique to close large thickness macular holes. METHODS: A consecutive retrospective interventional case series of 16 patients with macular holes greater than 650 microns in "aperture" diameter were included. The technique involves vitrectomy, followed by internal limiting membrane peeling. The macula is detached using subretinal injection of saline. Fluid-air exchange is performed to promote detachment and stretch of the retina. After this, the standard fluid-air exchange is performed and perfluoropropane gas is injected. Face-down posturing is advised. Adverse effects, preoperative, and postoperative visual acuities were recorded. Optical coherence tomography scans were also taken. RESULTS: The mean hole size was 739 microns (SD: 62 microns; mean base diameter: 1,311 microns). Eighty-three percent (14 of 16) of eyes had successful hole closure after the procedure. At 12-month follow-up, no worsening in visual acuity was reported, and improvement in visual acuity was noted in 14 of 16 eyes. No patients lost vision because of the procedure. CONCLUSION: It is possible to achieve anatomical closure of large macular holes using RETMA. No patients experienced visual loss. The level of visual improvement is likely limited because of the size and chronicity of these holes. PMID- 28816730 TI - INTRAVITREAL INJECTION OF AFLIBERCEPT IN PATIENTS WITH POLYPOIDAL CHOROIDAL VASCULOPATHY: A 3-YEAR FOLLOW-UP. AB - PURPOSE: To compare the 3-year follow-up results of intravitreal injections of aflibercept between fixed dosing (FD) regimen and a pro re nata (PRN) regimen after three initial monthly doses for the treatment of polypoidal choroidal vasculopathy and to analyze factors influencing improvement in visual acuity. METHODS: We retrospectively studied all treatment-naive patients with polypoidal choroidal vasculopathy who were scheduled to receive intravitreal aflibercept injections FD or PRN after induction treatment between March 2013 and May 2014. Best-corrected visual acuity was evaluated before treatment and at 4, 12, 24, and 36 months after initial treatment. Factors that influence improvement in visual acuity were also investigated. RESULTS: Thirty-three eyes were assessed at the 3 year follow-up examination. Twenty-three eyes were treated with intravitreal aflibercept injections every 2 months for at least 1 year after three initial monthly doses (FD group), and 10 eyes were treated PRN after loading doses (PRN group). In the FD group, during the follow-up period from 1 to 3 years, quarterly dosing with capped PRN or a treat and extend regimen were selected. The mean number of administered intravitreal aflibercept was 15.3 +/- 4.6 in the FD group and 9.0 +/- 8.9 in the PRN group, with a significant difference between the two groups (P = 0.004). Significant improvement of the mean logarithm of the minimum angle of resolution values for best-corrected visual acuity was shown at 36 months, as compared to baseline values (P = 0.019). No significant difference in the improvement of best-corrected visual acuity between the two groups was observed at baseline or at 4, 12, 24, and 36 months after treatment (all P > 0.05), although there was a trend toward better results in the FD group. Multiple regression analysis showed that the FD group had better visual acuity at 36 months and greater improvement in visual acuity than the PRN group (P = 0.031 for both comparisons). CONCLUSION: Intravitreal aflibercept was effective in improving the vision of patients with polypoidal choroidal vasculopathy, as evaluated at the 3-year follow-up. Fixed treatment might be an important factor influencing improvement in visual acuity. PMID- 28816731 TI - The "write" thing. PMID- 28816732 TI - Standout nurse leaders...What's in the research? PMID- 28816733 TI - On-Duty Nonfatal Injury that Lead to Work Absences Among Police Officers and Level of Perceived Stress. AB - OBJECTIVE: We examined prevalence, frequency, duration, and recency of injury leave and the association of duty-related injury with perceived stress in U.S. police officers. METHODS: This cross-sectional study contained 422 active duty police officers from a mid-sized urban police department. For each participating officer, work history records were used to assess on-duty injuries that lead to work absences. Linear regression analyses were used for analyses. RESULTS: Most participants had experienced at least one injury (62%), and among those injured, 67% experienced more than one duty-related injury. The average number of injuries per officer was three (range 1 to 12). There was a significant linear trend in mean perceived stress across injury count even after adjusting for age, rank, and sex (P = 0.025). CONCLUSION: Findings suggest that work-related injury is common and repeated work-related injuries are psychologically distressing in U.S. police officers. PMID- 28816734 TI - The Introduction of an Active Rest Program by Workplace Units Improved the Workplace Vigor and Presenteeism Among Workers: A Randomized Controlled Trial. AB - OBJECTIVE: The present study was designed to examine the effects of active rest by workplace units on not only workers' individual vigor but also workplace vigor and presenteeism. METHODS: A total of 130 workers performed our active rest (short-time exercise) program for 10 minutes per day during their lunch breaks, three to four times per week for 8 weeks. Subjects from a workplace unit were randomly allocated to the intervention (n = 66) or control (n = 64) groups. The participants' work engagement and Work Functioning Impairment Scale (WFun) were examined at the baseline and after the 8-week intervention period. RESULTS: After 8 weeks, the intervention group showed improved "vigor" values in work engagement and WFun (P < 0.05). CONCLUSION: These results suggest that the introduction of active rest program by workplace units provides a viable means for improving workplace vigor and presenteeism. PMID- 28816735 TI - Effects of an Intervention to Reduce Sitting at Work on Arousal, Fatigue, and Mood Among Sedentary Female Employees: A Parallel-Group Randomized Trial. AB - OBJECTIVE: The aim of this study was to determine whether individuals who participated in an intervention to reduce sitting at work would report changes in arousal, fatigue, and mood. METHODS: Inactive females with full-time sedentary occupations (N = 49) were randomly assigned to take short, frequent breaks (SBs) or longer, planned breaks (LBs) from sitting each workday for 8 weeks. At baseline and postintervention, participants completed measures of arousal, fatigue, and mood. Within- and between-group changes were examined. RESULTS: SB participants reduced sitting and reported moderate to large improvements in all affective outcomes except calmness (d = -0.44 to -0.82), whereas effect sizes were small for the LB group (d = 0.01 to -0.28). Only changes in negative affect differed between groups (P = 0.045). CONCLUSION: This study suggests that taking short, frequent breaks from sitting may be an effective strategy for improving affective outcomes among sedentary female employees. PMID- 28816736 TI - Distance Traveled for an Abortion and Source of Care After Abortion. AB - OBJECTIVE: To examine the association between distance traveled for an abortion and site of postabortion care among low-income women. METHODS: We conducted a retrospective cohort study using claims data from 39,747 abortions covered by California's Medicaid program in 2011-2012. Primary outcomes were the odds of abortion-related visits to an emergency department (ED) and the original abortion site, and the secondary outcome was total abortion care costs. We used mixed effects logistic regression adjusting for patient and abortion characteristics to examine the associations between distance traveled and subsequent abortion related care at each location. RESULTS: Among all abortions (N=39,747), 3% (95% CI 2.9-3.3, n=1,232) were followed by an ED visit (3% first-trimester aspirations, 2% second trimester or later, and 4% medication abortions) and 25% (95% CI 24.1-24.9, n=9,745) were followed by a visit to the original abortion site (4% first-trimester aspirations, 3% second-trimester or later, and 77% medication abortions). Women traveling farther for their abortions had higher odds of visiting an ED (100 or more miles compared with less than 25 miles, first trimester aspirations: adjusted odds ratio [OR] 2.29, 95% CI 1.50-3.49; medication abortions: adjusted OR 2.30, 95% CI 1.34-3.93) and lower odds of returning to their abortion site for follow-up (100 or more miles compared with less than 25 miles, first-trimester aspirations: adjusted OR 0.36, 95% CI 0.18 0.70; second trimester or later: adjusted OR 0.52, 95% CI 0.31-0.88; and medication abortions: adjusted OR 0.33, 95% CI 0.23-0.50). Costs were consistently higher when subsequent care occurred at an ED rather than the abortion site (median cost $941 compared with $536, P<.001). CONCLUSION: For most patients, greater distance traveled for abortion was associated with increased likelihood of seeking subsequent care at an ED. Increasing the number of rural Medicaid abortion providers and reimbursing providers for telemedicine and alternatives to routine follow-up would likely improve continuity of care and reduce state costs by shifting the location of follow-up from EDs back to abortion providers. PMID- 28816737 TI - Necrotizing Infundibular Crystalline Folliculitis: An Unusual Clinical Presentation and Demonstration of the Presence of Calcium Palmitate. AB - Necrotizing infundibular crystalline folliculitis (NICF) is a rare disorder, which was described for the first time by Lucke et al in 1999. NICF is characterized by multiple folliculocentric papules with a predilection for occurring in seborrheic areas in adults and corresponding dilated follicular ostia containing crystalline material. The precise pathogenesis and nature of this crystalline material are currently unknown. Here, we report an unusual case of NICF presented as an uncommon generalized skin rash in an adolescent. In addition, we present analysis using infrared microscopy for improved characterization of this crystalline material. Similar to previous cases, a biopsy revealed a dilated follicular ostium with the appearance of containing crystalline material associated with parakeratosis. Infrared microscopy analysis produced specific spectral features of calcium palmitate. PMID- 28816738 TI - Progressive, Painful Erosions of the Face, Neck, and Lips: Challenge. PMID- 28816739 TI - Nicolau Syndrome (Embolia Cutis Medicamentosa): A Rare and Poorly Recognized Iatrogenic Cause of Cutaneous Thrombotic Vasculopathy. AB - Nicolau syndrome is a rare form of iatrogenic cutaneous necrosis which affects injection sites. Although classically associated with intramuscular injections, it may develop after subcutaneous or other routes of parenteral drug administration. Clinically, it manifests as necrotic ulcers that often develop in a background of erythematous and livedoid reticular patches. The histopathologic characteristics of Nicolau syndrome are poorly documented in the dermatopathology literature and features only rarely as one of the obscure causes of cutaneous thrombotic vasculopathy. We report a case of Nicolau syndrome developing secondary to subcutaneous injection of cyclizine to familiarize the clinicians and pathologists to this unusual condition. Given that it is potentially avoidable, pathologists should alert the clinicians to the possibility of Nicolau syndrome when a skin biopsy from an injection site shows signs of extensive thrombotic vasculopathy. PMID- 28816740 TI - The Value of Direct Immunofluorescence on Proteinase-Digested Formalin-Fixed Paraffin-Embedded Skin Biopsies. AB - Direct immunofluorescence (DIF) on frozen tissue (DIF-F) is the method of choice for the identification of immune deposits present in skin and other tissues. DIF can also be performed on formalin-fixed paraffin-embedded tissue (DIF-P) after antigen retrieval with proteases and has proven to be of value in renal pathology. However, its utility in skin biopsies has not been fully examined. In this study, we performed DIF-P on 60 skin biopsies that comprised of bullous pemphigoid (n = 18), pemphigoid gestationis (n = 1), pemphigus (n = 7), linear IgA disease (n = 7), vasculitis (n = 20), lupus erythematosus (n = 3), and dermatitis herpetiformis (n = 4) cases. We compared the results of DIF-P with those of DIF-F from the same patients. The diagnostic features were found in 15 of 19 (79%) pemphigoid (bullous pemphigoid and pemphigoid gestationis), 3 of 7 (43%) pemphigus, 3 of 7 (43%) linear IgA disease, 14 of 20 (70%) vasculitis, 1 of 3 (33%) lupus erythematosus, and none (0%) of the dermatitis herpetiformis cases tested. Overall, DIF-P is less sensitive than DIF-F but seems to be a valuable technique that could aid in the diagnosis of vasculitides, immunobullous, and connective tissue disorders when fresh tissue is unavailable. PMID- 28816741 TI - Reflectance Confocal Microscopy Criteria of Pigmented Squamous Cell Carcinoma In Situ. AB - Pigmented squamous cell carcinoma in situ (pSCCis) is difficult to diagnose based on clinical and dermoscopic examination. Reflectance confocal microscopy (RCM) allows noninvasive differentiation between malignant and benign pigmented skin lesions. We determined the frequency of key RCM features of pSCCis and correlated the RCM criteria with the corresponding dermoscopic and histopathologic criteria. The study included 28 lesions with biopsy-proven diagnosis of pSCCis derived from 28 patients. Clinical, dermoscopic, and RCM images of these lesions were retrospectively analyzed by 3 independent observers. Assessment for the presence of RCM criteria revealed scale or parakeratosis (20/28; 71%); irregular honeycomb pattern in the spinous-granular layer (28/28; 100%); spindle-shaped cells with dendritic branches infiltrating the epidermis (12/28; 43%); edged papillae (24/28; 86%), and dilated looped blood vessels within the papillae (18/28; 64%). Fifty-three percent of the cases displayed at least 4 RCM criteria and 96% of cases displayed at least 3 RCM criteria. We propose that the diagnosis of pSCCis could be established based on 1 major criterion-irregular honeycomb pattern-and 2 of the following minor criteria-scale or parakeratosis, spindle-shaped cells with dendritic branches infiltrating the epidermis, edged papillae, and dilated looped blood vessels within the papillae. PMID- 28816742 TI - Congenital Lesion on the Hand of a Child. PMID- 28816743 TI - Elastic Staining in Differentiating Between Follicular Streamers and Follicular Scars in Horizontal Scalp Biopsy Sections. AB - BACKGROUND: Accurate identification of follicular streamers versus follicular scars on horizontal scalp biopsy sections is important to differentiate between cicatricial and noncicatricial alopecias. However, distinguishing between them can be difficult especially in nonoptimal specimens. The utility of elastic Verhoeff-Van Gieson (EVG) stain in cicatricial alopecias has been described on vertical sections, but its evaluation on horizontal sections has not been performed. METHODS: Sixty-four cicatricial alopecias (25 lichen planopilaris, 29 central centrifugal cicatricial alopecias, and 10 discoid lupus erythematosus) and 53 noncicatricial alopecias (34 androgenic alopecia, 8 telogen effluvium, and 11 alopecia areata) were identified, and EVG staining was performed on horizontal sections. RESULTS: In follicular streamers, EVG highlighted an intact elastic network composed of delicate and thin elastic fibers circumferentially surrounding the angiofibrotic streamer without elastic network attenuation, loss, clumping, thickening, or recoil. In follicular scars, EVG demonstrated central attenuation and loss of the elastic network with peripheral clumping and recoil of elastic fibers. CONCLUSIONS: In cases where distinguishing between follicular streamers and scars is difficult, EVG may be a helpful adjunctive tool in this regard and aid in allowing better discrimination between cicatricial and noncicatricial alopecias. PMID- 28816744 TI - Eruptive Keratoacanthoma-Like Discoid Lupus Erythematosus. AB - Hypertrophic discoid lupus erythematosus can resemble keratoacanthoma histomorphologically. We describe a unique case of eruptive keratoacanthomatous scaly papules in a 56-year-old woman with discoid lupus erythematosus. We review the literature and conclude by discussing important histologic features and useful immunostains to consider when attempting to discern the underlying identity and pathogenicity of such lesions. PMID- 28816745 TI - Restoration of normal sympathetic neural function in heart failure following baroreflex activation therapy: final 43-month study report. AB - BACKGROUND: Baroreflex activation therapy (BAT) exerts in severe heart failure sympathoinhibitory effects, improving clinical variables and reducing hospitalization rate. The current follow-up study was aimed at determining the long-term effects of BAT, assessing whether BAT in heart failure allows to restore physiological levels of sympathetic function. METHODS: Seven patients out of the 11 heart failure patients aged 66.5 +/- 3 years (mean +/- SEM) in New York Heart Association Class III with left ventricular ejection fraction 40% or less and impaired functional capacity recruited in the study survived at the final follow-up (43.5 +/- 2.1 months). Measurements included muscle sympathetic nerve activity (MSNA, microneurography) and spontaneous baroreflex-MSNA sensitivity together with hospitalization rate, echocardiography, Minnesota score, New York Heart Association class and standard clinical data. Measurements were collected before and at 6, 21 and 43 months following BAT. Data were compared with those collected in 17 age-matched healthy controls. All assessments were made with the heart failure patient on optimal active therapy. RESULTS: In the seven patients, BAT maintained its beneficial effects over 43.5 +/- 2.1 months of follow-up. MSNA values underwent a progressive significant reduction from baseline to 21 and 43 months follow-up following BAT (from 46.2 +/- 2.4 to 31.3 +/- 3.0 e 26.6 +/- 2.0 bursts/min, P < 0.05 at least), becoming almost superimposable to the ones seen in healthy controls (25.5 +/- 0.8 bursts/min). Baroreflex-MSNA sensitivity improved, without achieving, however, a full normalization. Blood pressure and heart rate did not change. Left ventricular ejection fraction improved significantly from 32.3 +/- 2 to 36.7 +/- 3% (P < 0.05). Hospitalization rate decreased substantially when measured as days/year/patients it decreased from 10.3 +/- 2.5 preimplant to 1.01 +/- 1.4 at the 43.5th month follow-up (P < 0.02). No side effects were reported in the long-term period. CONCLUSION: The current study provides evidence that BAT in heart failure with reduced ejection fraction allows not only to improve hemodynamic and clinical profile but also to exert profound sympathoinhibitory effects, allowing an almost complete restoration of physiological levels of the sympathetic neural function. PMID- 28816754 TI - Health Care Services in IBD: Factors Associated with Service Utilization and Preferences for Service Options for Routine and Urgent Care. AB - BACKGROUND: We aimed to explore factors associated with health service utilization and preference for services, including alternatives to attending the emergency department (ED) when experiencing mild to moderate or severe symptoms. METHODS: A total of 1143 persons (46% response rate) aged 18 to 65 years in the population-based University of Manitoba IBD Research Registry participated in the survey. RESULTS: Although 61% had a gastroenterologist, when experiencing active symptoms, only 29% felt they could call their gastroenterologist for an urgent appointment, and 42% could call their gastroenterologist for telephone advice. Nine percent of the respondents visited the ED in the previous year. If having severe symptoms, 48% said that they would attend the ED. Visits to the ED were related to higher bowel symptom severity and high health anxiety. When experiencing severe symptoms, women, persons with Crohn's disease and those with high health anxiety, indicated that they would be more likely to use the ED. Considering services which could be available in the future respondents indicated that if acutely symptomatic they would be very likely or likely to use the following services: phone contact with inflammatory bowel disease nurse (77%), phone contact with a gastroenterologist (75%), and going to a walk-in gastroenterology clinic (71%). CONCLUSIONS: Persons with inflammatory bowel disease are receptive to options other than the ED when experiencing inflammatory bowel disease symptoms; however, attending the ED remains a prominent choice. Improved access to specialized care may improve timeliness of care and reduce ED attendance. Future research should include the impact of health anxiety on health care utilization. PMID- 28816755 TI - Opening Doors for Urgent IBD Access: Harder than It Looks. PMID- 28816756 TI - Characterizing the Posttransfer Period Among Patients with Pediatric Onset IBD: The Impact of Academic Versus Community Adult Care on Emergent Health Resource Utilization. AB - BACKGROUND: Patients diagnosed with inflammatory bowel disease (IBD) during childhood require transfer to an adult gastroenterologist, in Ontario usually just before their 18th birthday. Pediatric onset IBD is a complex phenotype with demonstrated noncompliance risk that may require targeted measures to optimize health care outcomes in the adult care setting. PURPOSE: The purpose of this study was to determine the impact of posttransfer health care setting (academic versus community gastroenterologist) on emergent health resource utilization. METHODS: This was a population-based retrospective cohort study using health care administrative data from Ontario, Canada. A cohort of patients with Pediatric onset IBD was identified and health resource utilization during a 2-year pretransfer period, transfer of care period and 2-year posttransfer period was analyzed. Posttransfer health care setting was defined as academic (i.e., gastroenterologists providing care in a university affiliated tertiary care center) versus community. A third comparator group, loss to follow-up, was also identified. The primary outcome of this study comprised emergency department utilization. Secondary outcomes included hospitalizations, surgeries, ambulatory visits, endoscopic investigations, and radiological investigations. RESULTS: Overall, there were no significant differences found in emergency department use, ambulatory care visits (aside from the expected drop in the lost to follow-up group), hospitalizations, endoscopic procedures, or radiological procedures between exposure groups. CONCLUSIONS: Posttransfer health care setting does not seem to significantly impact emergent health resource utilization in the posttransfer period. PMID- 28816757 TI - Therapeutic Drug Monitoring During Induction of Anti-Tumor Necrosis Factor Therapy in Inflammatory Bowel Disease: Defining a Therapeutic Drug Window. AB - Anti-tumor necrosis factor (TNF) therapy has revolutionized the treatment of inflammatory bowel disease (IBD). However, up to 30% of patients with IBD show no clinical benefit and are defined as having a primary nonresponse. Primary nonresponse to a biologic can be attributed to either pharmacokinetic or pharmacodynamic issues, such as those involved in secondary loss of response. Pharmacokinetic issues are linked to undetectable or subtherapeutic drug concentrations because of either an accelerated non-immune-mediated clearance or immunogenicity and the development of antidrug antibodies, whereas pharmacodynamic issues are likely related to "non-TNF driven" disease. Therapeutic drug monitoring (TDM), defined as the evaluation of drug concentrations and antidrug antibodies, has been proven effective for optimizing anti-TNF therapy in IBD. Nevertheless, most of the data for TDM relate to patients losing response during maintenance therapy, whereas much less is known about the therapeutic drug window and use of TDM during anti-TNF induction therapy. Recent exposure-response relationship studies, though, demonstrate that high serum anti-TNF drug concentrations during and early after induction therapy are associated with favorable therapeutic outcomes in IBD. This suggests that early optimization of anti-TNF therapy may prevent some of the primary nonresponse related to pharmacokinetic issues (low drug concentrations) and lead to better short- and long-term outcomes. This review will focus on the role of TDM during the induction phase of anti-TNF therapy. PMID- 28816758 TI - IBD HINTS for Preventive Care. PMID- 28816759 TI - Useful Trick for Discovering Granuloma in Gastric Crohn's Disease. PMID- 28816760 TI - Colon Capsule Endoscopy: Looking Beyond the Colon in Crohn's Disease. PMID- 28816761 TI - Clinical Utility of Fecal Calprotectin Monitoring in Asymptomatic Patients with Inflammatory Bowel Disease. PMID- 28816762 TI - Standardizing Fecal Calprotectin Monitoring in Asymptomatic Patients with Inflammatory Bowel Disease. PMID- 28816764 TI - Monoarticular Joint Pain as a First Presentation of a Metastatic Squamous Cell Cancer. PMID- 28816763 TI - Mammography Findings of Breast Calcinosis in a Patient With Dermatomyositis. PMID- 28816765 TI - The Needle or Knife: Pegloticase for Refractory Crippling Gout in a Nonagenarian. PMID- 28816766 TI - Comparison of Spot Urine Protein to Creatinine Ratio to 24-Hour Proteinuria to Identify Important Change Over Time in Proteinuria in Lupus. AB - OBJECTIVES: The aim of this study was to determine whether spot urine protein-to creatinine ratio (PCR) accurately measures the change in proteinuria compared with 24-hour proteinuria (24H-P). METHODS: This was a retrospective analysis on patients' paired visits and paired urine samples for PCR and 24H-P. Patients with both abnormal 24H-P (>0.5 g/d) and PCR (>0.05 g/mmol) or both normal 24H-P (<=0.5 g/d) and PCR (<=0.05 g/mmol) at baseline visit were identified.The first follow up visit with partial recovery (50% decrease in proteinuria) or complete recovery (<=0.5 g/d) was identified for those with abnormal baseline 24H-P, and new proteinuria (>0.5 g/d) was identified for those with normal 24H-P. Twenty-four hour urine collection and PCR end-point frequencies were compared. Twenty-four hour urine collection results were converted to 24H-PCR. Twenty-four-hour PCR and PCR were utilized to measure the magnitude of change (by standardized response mean [SRM]) in patients who achieved the end points. RESULTS: Of 230 patients, at baseline, 95 patients had abnormal and 109 had normal 24H-P and PCR. On follow up, 57 achieved partial recovery, and 53 achieved complete recovery by 24H-P. Standardized response mean was -1.03 and -1.10 for 24H-PCR and PCR, respectively. By PCR, 53 patients had partial recovery, and 27 had complete recovery. Standardized response mean was -1.25 and -0.86 by 24H-PCR and PCR, respectively.For new proteinuria, 28 patients were identified by 24H-P and 21 by PCR. Twenty-four-hour PCR SRM was 0.80, and PCR SRM was 0.68. CONCLUSIONS: Protein-to-creatinine ratio does not have sufficient accuracy compared with 24H-P for improvement and worsening to be used in lieu of 24H-P. PMID- 28816767 TI - Allopurinol Medication Adherence as a Mediator of Optimal Outcomes in Gout Management. AB - BACKGROUND: Patient and provider factors, including allopurinol medication adherence, affect gout treatment outcomes. OBJECTIVES: The aim of this study was to examine associations of patient and provider factors with optimal gout management. METHODS: Linking longitudinal health and pharmacy dispensing records to questionnaire data, we assessed patient and provider factors among 612 patients with gout receiving allopurinol during a recent 1-year period. Associations of patient (medication adherence and patient activation) and provider factors (dose escalation, low-dose initiation, and anti-inflammatory prophylaxis) with serum urate (SU) goal achievement of less than 6.0 mg/dL were examined using multivariable logistic regression. Medication adherence was assessed as a mediator of these factors with goal achievement. RESULTS: A majority of patients (63%) were adherent, whereas a minority received dose escalation (31%). Medication adherence was associated with initiation of daily allopurinol doses of 100 mg/d or less (odds ratio [OR], 1.82; 95% confidence interval [CI], 1.20-2.76). In adjusted models, adherence (OR, 2.35; 95% CI, 1.50 3.68) and dose escalation (OR, 2.48; 95% CI, 2.48-4.25) were strongly associated with SU goal attainment. Low starting allopurinol dose was positively associated with SU goal attainment (OR, 1.11; 95% CI, 1.02-1.20) indirectly through early adherence, but also had a negative direct association with SU goal attainment (OR, 0.21; 95% CI, 0.12-0.37). CONCLUSIONS: Medication adherence and low starting dose combined with dose escalation represent promising targets for future gout quality improvement efforts. Low starting dose is associated with better SU goal attainment through increased medication adherence, but may be beneficial only in settings where appropriate dose escalation is implemented. PMID- 28816768 TI - Superior Displacement of the Dens in a Patient With Rheumatoid Arthritis. PMID- 28816769 TI - Do Psychosocial Factors Predict Muscle Strength, Pain, or Physical Performance in Patients With Knee Osteoarthritis? AB - OBJECTIVE: The aim of this study was to examine the relationship of psychosocial factors, namely, pain catastrophizing, kinesiophobia, and maladaptive coping strategies, with muscle strength, pain, and physical performance in patients with knee osteoarthritis (OA)-related symptoms. METHODS: A total of 109 women (64 with knee OA-related symptoms) with a mean age of 65.4 years (49-81 years) were recruited for this study. Psychosocial factors were quantified by the Pain Catastrophizing Scale, Tampa Scale for Kinesiophobia, and Pain Coping Inventory. Clinical features were assessed using isometric and isokinetic knee muscle strength measurements, visual analog scale, Western Ontario and McMaster Universities Osteoarthritis Index, and functional tests. Associations were examined using correlation and regression analysis. RESULTS: In knee OA patients, pain catastrophizing, kinesiophobia, and coping strategy explained a significant proportion of the variability in isometric knee extension and flexion strength (6.3%-9.2%), accounting for more overall variability than some demographic and medical status variables combined. Psychosocial factors were not significant independent predictors of isokinetic strength, knee pain, or physical performance. CONCLUSIONS: In understanding clinical features related to knee OA, such as muscle weakness, pain catastrophizing, kinesiophobia, and coping strategy might offer something additional beyond what might be explained by traditional factors, underscoring the importance of a biopsychosocial approach in knee OA management. Further research on individual patient characteristics that mediate the effects of psychosocial factors is, however, required in order to create opportunities for more targeted, personalized treatment for knee OA. PMID- 28816770 TI - Prevalence of Disability in Patients With Musculoskeletal Pain and Rheumatic Diseases in a Population From Cuenca, Ecuador. AB - OBJECTIVE: The aim of this study was to determine the prevalence of disability in patients with musculoskeletal pain and rheumatic diseases in Cuenca, Ecuador. METHODS: We performed a cross-sectional analytical study with randomized sampling in 4877 subjects, from urban and rural areas. COPCORD (Community Oriented Program for Control of Rheumatic Diseases)-validated questionnaire was administered house to-house to identify subjects with nontraumatic musculoskeletal pain and rheumatic diseases. The subjects were assessed by rheumatologists for diagnostic accuracy, and the Health Assessment Questionnaire Disability Index was administered to assess functional capacity. A logistic regression analysis was conducted to determine the association of rheumatic diseases with functional disability. RESULTS: Functional disability was found in 221 subjects (73.1% women), with mean age 62 (SD, 18.2) years, residing in rural areas (201 [66.5%]), with education of 6.9 (SD, 5.3) years, and of low income (77 [47.2%]). The value of HAQ-DI was a mean of 0.2 (0-2.9). The real prevalence of physical disability was 9.5%. Moderate and severe disability predominated in activities such as kneeling (4.9% and 3.3%), squatting (4.8% and 2.7%), and leaning to pick up objects (3.7% and 0.9%), respectively. Rheumatic diseases associated with physical disabilities were knee osteoarthritis (95 [31.4%]) and hand osteoarthritis (69 [22.8%]), mechanical low-back pain (43 [14.2%]), fibromyalgia (27 [9.5%]), and rheumatoid arthritis (11 [3.6%]; P < 0.001). CONCLUSIONS: Physical disability was associated with older age, female sex, rural residence, lower education, and lower income. Moderate and severe disability predominated in the dimensions of kneeling, squatting, and picking up objects. Rheumatic diseases associated with disability were hand and knee osteoarthritis, back pain, fibromyalgia, and rheumatoid arthritis. TAKE HOME MESSAGE: PMID- 28816771 TI - Primary Omental Torsion in a Pediatric Patient: Case Report and Review of the Literature. AB - Primary omental torsion is a rare cause of acute abdominal pain with a clinical presentation resembling acute appendicitis. Here, we report the case of a 7-year old child presenting with right lower quadrant pain. Primary omental torsion was discovered upon laparoscopy, and the torsed omentum was excised without postoperative complications. Potential causes, contributing factors, diagnosis, and treatment are discussed. PMID- 28816772 TI - A Case of Lenticulostriate Stroke Due to Minor Closed Head Injury in a 2-Year-Old Child: Role of Mineralizing Angiopathy. AB - OBJECTIVE: Cerebral infarction due to minor head injury is rare. Mineralizing angiopathy is considered a predisposing factor for lenticulostriate stroke after minor closed head injury. This entity is characterized by infarction of the basal ganglia and most often occurs in young children, from infancy to 2 years of age. Symptoms usually occur immediately after the injury. METHODS AND RESULTS: We present the case of a previously healthy 2-year-old female child presenting with right facial hemiparesis and aphasia, along with right arm and leg weakness that occurred immediately after a fall from the couch onto a carpeted floor. A brain computed tomography scan revealed small and linear calcifications of the basal ganglia and subcortical frontoparietal area, in the absence of signs of intracranial hemorrhage. Brain magnetic resonance imaging with stroke protocol revealed restriction of water diffusion in the left basal ganglia on diffusion weighted imaging sequences as well as apparent diffusion coefficient sequences, suggesting an acute infarct of the left basal ganglia within the distribution of the lenticulostriate vessels. The patient was treated with aspirin and conservative management and had gradual improvement over the next few days, with full recovery of the aphasia, facial nerve function, and arm and leg mobility, within 2 months. CONCLUSIONS: Some infants can present with the onset of stroke like symptoms after minor head injuries. Presence of linear calcifications of the basal ganglia noticed on brain computed tomography in many of these patients suggests that mineralizing angiopathy may be a predisposing factor for lenticulostriate stroke after minor closed head injury in infants. Brain magnetic resonance imaging to further delineate possible cerebral infarction is indicated. PMID- 28816773 TI - Synergistic antitumor effect of 3-bromopyruvate and 5-fluorouracil against human colorectal cancer through cell cycle arrest and induction of apoptosis. AB - 3-Bromopyruvic acid (3-BP) is a well-known inhibitor of energy metabolism. It has been proposed as an anticancer agent as well as a chemosensitizer for use in combination with anticancer drugs. 5-Fluorouracil (5-FU) is the first-line chemotherapeutic agent for colorectal cancer; however, most patients develop resistance to 5-FU through various mechanisms. The aim of this study was to investigate whether 3-BP has a synergistic antitumor effect with 5-FU on human colorectal cancer cells. In our study, combined 3-BP and 5-FU treatment upregulated p53 and p21, whereas cyclin-dependent kinase CDK4 and CDK2 were downregulated, which led to G0/G1 phase arrest. Furthermore, there was an increase in reactive oxygen species levels and a decrease in adenosine triphosphate levels. It was also observed that Bax expression increased, whereas Bcl-2 expression reduced, which were indicative of mitochondria-dependent apoptosis. In addition, the combination of 3-BP and 5-FU significantly suppressed tumor growth in the BALB/c mice in vivo. Therefore, 3-BP inhibits tumor proliferation and induces S and G2/M phase arrest. It also exerts a synergistic antitumor effect with 5-FU on SW480 cells. PMID- 28816783 TI - Association of Testosterone Replacement Therapy and the Incidence of a Composite of Postoperative In-hospital Mortality and Cardiovascular Events in Men Undergoing Noncardiac Surgery. AB - BACKGROUND: Whether patients on testosterone replacement therapy undergoing noncardiac surgery have an increased risk of postoperative in-hospital mortality and cardiovascular events remains unknown. We therefore sought to identify the impact of testosterone replacement on the incidence of a composite of postoperative in-hospital mortality and cardiovascular events in men undergoing noncardiac surgery. METHODS: Data from male American Society of Anesthesiologists I through IV patients 40 yr or older who underwent noncardiac surgery between May 2005 and December 2015 at the Cleveland Clinic (Cleveland, Ohio) main campus were included. The primary exposure was preoperative testosterone use. The primary outcome was a composite of postoperative in-hospital mortality and cardiovascular events. We compared patients who received testosterone and those who did not using propensity score matching within surgical procedure matches. RESULTS: Among 49,273 patients who met inclusion and exclusion criteria, 947 patients on testosterone were matched to 4,598 nontestosterone patients. The incidence of in hospital mortality was 1.3% in the testosterone group and 1.1% in the nontestosterone group, giving an odds ratio of 1.17 (99% CI, 0.51 to 2.68; P = 0.63). The incidence of myocardial infarction was 0.2% in the testosterone group and 0.6% in the nontestosterone group (odds ratio = 0.34; 99% CI, 0.05 to 2.28; P = 0.15). Similarly, no significant difference was found in stroke (testosterone vs. nontestosterone: 2.0% vs. 2.1%), pulmonary embolism (0.5% vs. 0.7%), or deep venous thrombosis (2.0% vs. 1.7%). CONCLUSIONS: Preoperative testosterone is not associated with an increased incidence of a composite of postoperative in hospital mortality and cardiovascular events. PMID- 28816774 TI - Practitioner Gender and Quality of Care in Ambulatory Cardiology Practices: A Report From the National Cardiovascular Data Practice Innovation and Clinical Excellence (PINNACLE) Registry. AB - BACKGROUND: Some studies suggest that female practitioners are more likely to provide guideline-concordant care than male practitioners; however, little is known about the role of practitioner gender in cardiology. OBJECTIVE: The aim of the study was to measure the association between practitioner gender and adherence to the cardiovascular performance measures in the American College of Cardiology's ambulatory Practice Innovation and Clinical Excellence Registry. METHODS: Patients with at least 1 outpatient visit with a unique practitioner were included. Among eligible patients, adherence to 7 guideline-supported performance measures for coronary artery disease, heart failure, and atrial fibrillation over 12 months after registry entry was compared by practitioner gender using hierarchical models adjusting for practitioner type (physicians vs advance practice practitioners) and number of visits. RESULTS: The study cohort included 1493 individual practitioners who saw 769 139 patients; 80% of practitioners were men. Male practitioners were more often physicians compared with female practitioners (98.2% vs 43.7%, P < .01). Accounting for practitioner category and visit frequency, guideline adherence rates were similar by practitioner gender for all measures with the exception of marginally higher rates for coronary artery disease performance measures for male practitioners compared with female practitioners (antiplatelet: rate ratio [RR] = 1.06; 95% confidence interval [CI], 1.03-1.09; beta-blockers: RR = 1.06; 95% CI, 1.01-1.10; and lipid-lowering drug: RR = 1.07; 95% CI, 1.04-1.10) and atrial fibrillation (oral anticoagulants: RR = 1.05; 95% CI, 1.01-1.09). CONCLUSION: Male practitioners marginally outperformed their female counterparts in ambulatory practices enrolled in a voluntary cardiovascular performance improvement registry program. Overall low adherence to some performance measures suggests room for improvement among all practitioners. PMID- 28816784 TI - Images in Anesthesiology: Ultrasound-guided Intraarticular Knee Injection. PMID- 28816786 TI - Acute Traumatic Coagulopathy: Thrombin Is the Driver! PMID- 28816787 TI - In Reply. PMID- 28816788 TI - Dealing with Ophthalmic Chemosurgery Complications. PMID- 28816789 TI - In Reply. PMID- 28816792 TI - Development of Secondary Acute Myeloid Leukemia in a Pediatric Patient Concurrently Receiving Primary Therapy for Ewing Sarcoma. AB - Ewing sarcoma is a pediatric bone and soft tissue sarcoma that requires intensive therapy, which can cause secondary malignancies. We present a rare case of early, treatment-related AML in a pediatric patient concurrently receiving primary therapy for Ewing sarcoma. Despite AML-directed therapy, our patient died secondary to complications of hyperleukocytosis. Cytogenetic and mutation profiling of the leukemia cells revealed the DNA-topoisomerase-II-inhibitor associated t(9;11)(p22;q23) translocation and clonal KRAS and BRAF mutations. This report highlights the importance of monitoring for treatment-related effects in cancer therapy, as well as the need for novel, less toxic approaches in Ewing sarcoma therapy. PMID- 28816793 TI - Unexpected Effect of Propranolol and Prednisolone on Infantile Facial Rhabdomyosarcoma. AB - A 14-month-old Nepalese infant had developed a rapidly growing facial tumor originating from a dark spot on her upper eyelid. A cavernous hemangioma was suspected and treated with high doses of propranolol and prednisolone. Remission was dramatic. Histology confirmed alveolar rhabdomyosarcoma. Chemotherapy was planned but not carried out due to complicated logistics. The girl died at the age of 3. We present this case for discussion as to whether propranolol and prednisolone might be effective in rapidly growing rhabdomyosarcomas. PMID- 28816791 TI - Resting-State Functional Connectivity in the Human Connectome Project: Current Status and Relevance to Understanding Psychopathology. AB - A key tenet of modern psychiatry is that psychiatric disorders arise from abnormalities in brain circuits that support human behavior. Our ability to examine hypotheses around circuit-level abnormalities in psychiatric disorders has been made possible by advances in human neuroimaging technologies. These advances have provided the basis for recent efforts to develop a more complex understanding of the function of brain circuits in health and of their relationship to behavior-providing, in turn, a foundation for our understanding of how disruptions in such circuits contribute to the development of psychiatric disorders. This review focuses on the use of resting-state functional connectivity MRI to assess brain circuits, on the advances generated by the Human Connectome Project, and on how these advances potentially contribute to understanding neural circuit dysfunction in psychopathology. The review gives particular attention to the methods developed by the Human Connectome Project that may be especially relevant to studies of psychopathology; it outlines some of the key findings about what constitutes a brain region; and it highlights new information about the nature and stability of brain circuits. Some of the Human Connectome Project's new findings particularly relevant to psychopathology-about neural circuits and their relationships to behavior-are also presented. The review ends by discussing the extension of Human Connectome Project methods across the lifespan and into manifest illness. Potential treatment implications are also considered. PMID- 28816794 TI - X-linked Lymphoproliferative Disease Type 1 in a Patient With the p.Gly93Asp SH2D1A Gene Mutation and Hemophagocytic Lymphohistiocytosis. AB - Hemophagocytic lymphohistiocytosis is characterized by uncontrolled activation of the immune system that leads to systemic hyperinflammation. Lymphoproliferative syndrome linked to the X chromosome is a hereditary immunodeficiency characterized by an inability to mount an adequate immune response to an Epstein Barr virus infection. Hemophagocytic lymphohistiocytosis is one of the main clinical features of X-linked lymphoproliferative syndrome. We report the case of a patient who presented with primary hemophagocytic lymphohistiocytosis associated with Epstein-Barr virus infection without a familial history of immunodeficiency. A mutation in the SH2D1A gene was identified, which confirmed the diagnosis of type 1 X-linked lymphoproliferative syndrome. PMID- 28816795 TI - Voriconazole Antifungal Prophylaxis in Children With Malignancies: A Nationwide Study. AB - BACKGROUND: Antifungal prophylaxis (AFP) is recommended in at-risk hematology oncology patients. We evaluated the safety of AFP with voriconazole (VRC) in pediatric hematology/oncology patients. MATERIALS AND METHODS: A retrospective study of VRC AFP in children with malignancies hospitalized in all 7 Greek pediatric hematology/oncology centers during 2008 to 2012 was conducted. Patients' demographics, outcome, and adverse event (AE) data were recorded. RESULTS: Four hundred twenty-nine VRC AFP courses in 249 patients (median age 6 y, 55% boys) were studied. The most common underlying diseases were acute lymphoblastic leukemia (51%), non Hodgkin lymphoma (8.6%), and acute myeloid leukemia (7.7%). The median number of VRC courses per patient was 1.7, whereas the median VRC dose was 7 mg/kg (range, 5 to 7 mg/kg) every 12 hours. During the last 2 weeks before AFP, 51% of the patients had received corticosteroids, 43% suffered from severe neutropenia, and 17.3% from mucositis. The median duration of VRC AFP was 17 days (range, 1 to 31 d). A single breakthrough fungemia due to Candida glabrata was recorded. Only 1 patient died due to the underlying disease. The most common AEs reported in 70/429 (16.3%) courses with >=1 AE were elevated liver enzymes (50%), hypokalemia (24.3%), and ophthalmological disorders (14.3%). The median time of AE onset was 5 days (range, 1 to 21 d). Among 70 AEs reported, 38.5%, 48.4%, and 12.8% were of grade I, II, and III, respectively. CONCLUSIONS: VRC prophylaxis in pediatric hematology/oncology patients appears to be well tolerated. PMID- 28816796 TI - Intrathecal Infusion of Haploidentical Nondonor Lymphocytes for Central Nervous System Leukemic Relapse After Haploidentical Hematopoietic Stem Cell Transplantation. AB - Leukemic relapse in the central nervous system (CNS) after conventional treatment is associated with a poor prognosis. The effectiveness and safety of IV infusion of human leukocyte antigen (HLA)-mismatched lymphocytes for leukemia, and intrathecal (IT) infusion of HLA-mismatched lymphocytes for cerebrospinal fluid (CSF) dissemination of medulloblastoma have been reported. A 13-year-old girl (HLA-A31) was diagnosed as relapsing from Philadelphia chromosome-positive acute leukemia in the CNS after receiving chemotherapy, tyrosine kinase inhibitors, haploidentical hematopoietic stem cell transplantation (HSCT) from her father (HLA-A31), and craniospinal irradiation. We performed an IT infusion of haploidentical lymphocytes from her mother. Peripheral blood mononuclear cells obtained from her mother (HLA-A31) were administered by IT infusion weekly. Examination of CSF 1 week after first IT showed that lymphocyte counts had increased markedly and the breakpoint cluster region/abelson-bearing cells had disappeared. Furthermore, CD3 T cells in the CSF were negative for HLA-A31, and expressed high HLA-DR. These results indicate the infused non-HSCT-donor lymphocytes did not survive, and that the HSCT donor(father)-derived lymphocytes migrated to the CSF and were activated. The patient showed partial remission for 2 months following this therapy. Serious adverse reactions and graft versus host disease were not observed. To control leukemic CNS dissemination, haploidentical nondonor lymphocytes might contribute to a graft versus leukemia effect. PMID- 28816797 TI - Microscopic Infiltration of Cryopreserved Ovarian Tissue in 2 Patients With Ewing Sarcoma. AB - We report the clinical history of 2 female patients with Ewing sarcoma and microscopic ovarian infiltration. In both cases, the initial workup found no metastasis. However, the examination of cryopreserved ovarian tissues revealed the presence of CD99 positive tumor cells with rearrangement of EWS gene confirmed by FISH. Both children were treated as patients with localized tumor and are currently in remission. These reports underline that, in Ewing sarcoma patients, retransplantation of cryopreserved ovarian tissue is not harmless and could lead to cancer relapse. These observations question also on the significance of ovarian dissemination on Ewing sarcoma prognosis and therapy. PMID- 28816798 TI - Solid Liver Lesions in an Infant With Neonatal Cholestasis: Is it Always Malignant? AB - In this report we describe a patient with neonatal cholestasis who was found to have a liver lesion with suspicious imaging features, although ultimately it was histologically proved to be a pseudotumor. We discuss the characteristic features and imaging findings of macroregenerative nodules of the liver. PMID- 28816799 TI - Successful Extracorporeal Life Support in a Pediatric Hematopoietic Stem Cell Transplant Recipient With Periengraftment Respiratory Failure. AB - The use of extracorporeal life support (ECLS) as ultimate salvage therapy for hematopoietic stem cell transplant recipients remains controversial among oncologists and critical care specialists. Prognosis is poor, particularly after allogeneic transplantation, and literature to guide clinical decision-making is scarce. Our report describes successful ECLS in a pediatric patient undergoing allogeneic hematopoietic stem cell transplantation, who developed acute respiratory failure during severe neutropenia, followed by immediate neutrophil engraftment. This unique case highlights periengraftment respiratory failure as a possible patient subgroup that could benefit from ECLS; and illustrates that the distinct etiologies of respiratory failure and the patients' immune status deserve closer consideration in future studies evaluating ECLS in this high-risk population. PMID- 28816800 TI - Acute Sickle Cell Orbitopathy Masquerading as Orbital Cellulitis. AB - Sickle cell orbitopathy is a rare manifestation of a sickle cell crisis and can closely mimic orbital cellulitis, both clinically and radiologically. We present a case where a child presented with what was thought to be orbital cellulitis and was treated accordingly. Subtle radiologic features of sickle cell orbitopathy were initially overlooked, resulting in an incorrect diagnosis and a treatment delay for the patient. Correctly treated most cases resolve with no adverse affects, highlighting how important it is to consider acute sickle cell orbitopathy in the differential diagnosis of acute periorbital swelling in children with sickle disease. PMID- 28816802 TI - Carotid Body Tumor. AB - A 17 year old girl presented with a progressively increasing swelling in her neck since 9 months. On examination a2*3 cm, firm, pulsatile swelling was felt in the left anterior triangle. The CT scan of the mass was suggestive of a carotid body tumor and urinary cathecholamines were negative. The mass was excised completely. PMID- 28816801 TI - Bevacizumab-associated Bowel Microperforation in a Patient With Neuroblastoma. AB - The antivascular endothelial growth factor antibody, bevacizumab, is effective against several malignancies in adults but unproven in pediatric oncology. In early phase pediatric studies toxicities were similar to those in adults. Bowel perforation in adults is a rare but serious toxicity, but has not been hitherto reported in children. A 5-year-old boy with chemoresistant neuroblastoma treated with bevacizumab plus radioimmunotherapy developed acute abdominal pain. Computed tomography scan showed free abdominal air and pneumatosis coli. Emergency laparotomy and bowel diversion were performed leading to complete recovery and timely continuation of antineuroblastoma therapy. Early recognition and rapid intervention can prevent a catastrophic outcome in bevacizumab-related bowel perforation. PMID- 28816804 TI - Smart Phone Apps and Maternal Child Nursing. PMID- 28816803 TI - Induction Methotrexate, Cisplatin, and 5-Fluorouracil Versus Cisplatin and 5 Fluorouracil Followed by Radiotherapy in Pediatric Nasopharyngeal Carcinoma: A Retrospective Analysis in a Tertiary Cancer Center. AB - PURPOSE: The purpose of this study is to compare treatment outcomes of methotrexate, cisplatin, and 5-fluorouracil (MPF) or cisplatin and 5-fluorouracil (PF) in pediatric NPC patients treated with sequential chemoradiotherapy. PATIENTS AND METHODS: A total of 25 patients aged 18 years or below with stage II IV NPC treated with IC using PF (n=16) or MPF (n=9) followed by radiotherapy between 2003 and 2009 were retrospectively reviewed. Radiotherapy dose was 61.2 to 66.6 Gy to the gross disease. Age, stage, radiation dose, and chemotherapy regimen were tested as prognostic factors for event-free survival (EFS) and overall survival (OS) on univariate and multivariate analyses. RESULTS: The median age at diagnosis was 13.3 years. All patients completed planned chemotherapy. All patients who received MPF achieved PR whereas 15 patients (93.8%) who received PF achieved PR (P=1). There were no differences in EFS (68.75% vs. 66.67%; P=0.84) and OS (81.25% vs. 66.67%; P=0.39) at 5 years between PF and MPF, respectively. On multivariate analysis, only tumor stage (IV vs. II III) predicted worse OS (hazard ratio, 10.3; 95% confidence interval, 1.197 88.974) but not EFS (hazard ratio, 4.805; 95% confidence interval, 0.95-24.336). Distant metastases was the predominant site of failure, seen in 5 patients (20%). CONCLUSIONS: Omission of methotrexate from the induction chemotherapy regimen did not affect treatment outcome. PMID- 28816805 TI - Development of a Mobile App for Family Planning Providers. AB - PURPOSE: To provide an overview of lessons learned during the development process of an app for iOS and Android based on national recommendations for providing quality family planning services. STUDY AND DESIGN: After a review of existing apps was conducted to determine whether an app of clinical recommendations for family planning existed, a team of clinicians, training specialists, and app developers created a resource app by first drafting a comprehensive content map. A prototype of the app was then pilot tested using smart tablets by a volunteer convenience sample of women's healthcare professionals. Outcomes measured included usability, acceptability, download analytics, and satisfaction by clinicians as reported through an investigator-developed tool. RESULTS: Sixty nine professionals tested a prototype of the app, and completed a user satisfaction tool. Overall, user feedback was positive, and a zoom function was added to the final version as a result of the pilot test. Within 3 months of being publicly available, the app was downloaded 677 times, with 97% of downloads occurring on smart phones, 76% downloads occurring on iOS devices, and 24% on Android devices. This trend persisted throughout the following 3 months. CLINICAL IMPLICATIONS: Clinicians with an interest in developing an app should consider a team approach to development, pilot test the app prior to wider distribution, and develop a web-based version of the app to be used by clinicians who are unable to access smart devices in their practice setting. PMID- 28816806 TI - Autologous Blood Transfusion for Postpartum Hemorrhage. AB - Postpartum hemorrhage (PPH) is a leading contributor to maternal morbidity and mortality in the United States and globally. Although the rate of PPH is generally decreasing nationally, severity of PPH appears to be increasing, potentially related to the various comorbidities associated with women of childbearing age. There is increasing evidence of risks associated with allogeneic blood transfusion, which has historically been the classic therapeutic approach for treatment to PPH. Pregnant women are particularly susceptible to the implications of sensitization to red cell antigens, a common sequela to allogenic blood transfusion. Autologous blood transfusion eliminates the potential of communicable disease transmission as well as the conceivable threat of a blood transfusion reaction. Recent technological advances allow cell salvage coupled with the use of a leukocyte filter to be used as an alternative approach for improving the outcome for women experiencing a PPH. Modest changes in standard operating procedure and continued training in use and application of cell salvaged blood may assist in minimizing negative outcomes from PPH. Salvaged blood has been demonstrated to be at least equal and often superior to banked blood. We discuss nursing implications for application of this technology for women with PPH. Continued research is warranted to evaluate the impact that application of cell salvage with filtration has on the patient experiencing a PPH. PMID- 28816807 TI - A Whooping Cough Education Module for WIC Clients in Utah. AB - BACKGROUND: Clients in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) are required to complete education modules quarterly to maintain eligibility. The purposes of this project were to: (1) create a whooping cough vaccination education module for WIC clients; (2) evaluate baseline perceptions of WIC clients on the whooping cough vaccine and disease; and (3) evaluate whooping cough knowledge following completion of the module. PROBLEM: A decline in vaccination rates among infants and children using WIC services was reported by a local WIC program director who requested whooping cough vaccination education materials. This quality improvement project included development of a whooping cough education module and evaluation of learning. METHODS: Learning was evaluated using a pre- and posttest design. Client feedback was solicited via open-ended questions. Quantitative analysis was performed on visual analog-type questions with paired t-tests and a Cohen's d. Content analysis was conducted on open-ended items. INTERVENTIONS: The module was designed by a team of vaccination experts and included general definitions, signs and symptoms during the three stages of disease, recommendations to prevent whooping cough, and vaccination recommendations. Learning of users of the module was then evaluated. RESULTS: After using the module, clients indicated they were significantly more likely to vaccinate themselves and their child against whooping cough, and to recommend the vaccination to their family members. The greatest concern of participants about whooping cough was how it affected infants. Participants reported they learned new information on disease seriousness, recognition of symptoms, and treatment options but still requested additional information on the whooping cough disease and vaccine. CONCLUSIONS: A whooping cough education module is an effective strategy to improve whooping cough knowledge and promote the whooping cough vaccine. PMID- 28816808 TI - Influences on Infant Feeding: Perceptions of Mother-Father Parent Dyads. AB - PURPOSE: The purpose of this study was to examine interrelational-, organizational-, and community-level influences on how coparents collaborate about infant and toddler feeding. STUDY DESIGN AND SAMPLE: Using qualitative methods, we interviewed mother-father parent dyads to explore the potential influences on infant and toddler feeding. Participants were purposively recruited from two Midwest, rural, university-system pediatric clinics. Thematic analysis was used to code the data. MEASURES: Mother-father dyadic interviews were conducted using a semistructured interview schedule. Twenty-four mother-father dyads who had a child between the ages of 6 and 36 months were interviewed together. RESULTS: Major themes include interpersonal factors (peer behavior reinforcement, dyad and important others infant feeding conflict, conflict resolution proactiveness), organizational factors (healthcare provider infant feeding support, workplace flexibility), and community factors (public perception on breastfeeding and social media influence). CLINICAL IMPLICATIONS: Community based collaboration can be a platform for mother-father dyads, researchers, public health nurses, and other healthcare providers to proactively create interventions that include opportunity for building coparenting skills and infant feeding knowledge that promote team management of common early childhood feeding challenges. PMID- 28816809 TI - Screening and Response to Maternal Mental Health Problems. PMID- 28816810 TI - Healthcare for Transgender Youth: Still Inadequate...Still at Risk. PMID- 28816811 TI - Vegetarian Diet During Pregnancy: Assessment and Support. PMID- 28816812 TI - Caring for Childbearing Women in Crisis: Midwife Pilgrim. PMID- 28816814 TI - Safe Nurse Staffing is More than Numbers and Ratios. PMID- 28816815 TI - Parent Education is Changing: A Review of Smartphone Apps. PMID- 28816816 TI - Autologous Blood Transfusion for Postpartum Hemorrhage. PMID- 28816817 TI - A Novel Surgical Technique for Ahmed Valves in Refractory Glaucoma With Silicone Oil Endotamponade. AB - PURPOSE: The purpose of the study is to describe a novel technique to implant Ahmed valves in patients with refractory glaucoma because of silicone oil (SO) endotamponade PATIENTS:: Three patients with glaucoma without SO removal were used as an example for this technique. METHODS: Technique report. RESULTS AND CONCLUSIONS: We introduce a standard technique modification for Ahmed valves in patients with SO. This modification consists on locating the Ahmed valve more tangential to the limbus curvature instead of the usual perpendicular position and inserting the tube in the posterior chamber. The tube can be longer and run parallel to pupil. This technique allows use superotemporal quadrant (fewer complications), avoid corneal touch and decrease SO loss through the tube to subconjunctival space. PMID- 28816819 TI - Medium-term Outcomes of Unsutured Scleral Flap Trabeculectomies: Comment. PMID- 28816818 TI - Reproducibility of Central Corneal Thickness Measurements in Healthy and Glaucomatous Eyes. AB - PURPOSE: The purpose of this study is to characterize intraday and interday variation in central corneal thickness (CCT) in healthy and glaucomatous subjects. METHODS: In this prospective cohort study, 40 healthy subjects and 42 subjects with primary open-angle glaucoma underwent CCT measurements by ultrasonic pachymetry on 5 days over 1 year: first at baseline, then at 1 week and 1, 6, and 12 months after baseline. On 1visit, CCT was measured every 2 hours from 08:00 to 20:00. Intraday CCT variance was compared with interday CCT variance. RESULTS: Mean CCT at all visits and time points ranged from 561 to 574 um in healthy eyes and from 548 to 563 um in glaucomatous eyes. The mean intraday CCT range (highest minus lowest readings) was 21+/-10 um in healthy participants and 21+/-10 um in glaucoma patients. The mean interday CCT range was 27+/-13 um in healthy participants and 24+/-14 um in glaucoma patients. Within-subject variance was significantly larger among the interday CCT measurements than the intraday CCT measurements in both healthy subjects and glaucoma patients (P<0.0001 for both) demonstrating that measurements taken on separate days are more different than measurements taken on the same day. Interday CCT differences of >=30 um were seen in 27.7% of normal subjects and 30% of glaucoma patients. CONCLUSIONS: CCT measurements exhibit intraday and interday variation, with the latter being significantly greater than the former. A single CCT assessment inadequately characterizes CCT and may impact risk assessment in patients with suspect and/or diagnosed glaucoma. PMID- 28816820 TI - Factors That Influence of Trabectome Surgery for Glaucoma Patients. AB - BACKGROUND: The aim of this study was to investigate the factors that influence the outcome of trabectome surgery. METHODS: This was a retrospective nonrandomized study. Seventy-eight glaucoma patients (86 eyes) who underwent trabectome surgeries and were followed up for more than 12 months were included. We classified the subtypes of glaucoma as: primary open-angle glaucoma (23 eyes), pseudo-exfoliation glaucoma (58 eyes), and secondary glaucoma (5 eyes). Forty seven eyes underwent cataract and trabectome surgeries simultaneously, and 39 underwent only trabectome surgery. We evaluated the possible influencing factors including age, sex, glaucoma index, preoperative intraocular pressure (IOP), number of medications, visual field status, central corneal thickness, type of glaucoma and operation method (trabectome only or simultaneous cataract surgeries as well). RESULTS: Trabectome surgeries significantly decreased the IOP from 23.0+/-6.7 to 12.5+/-3.0 mm Hg after 12 months (P<0.001). The success rate at 12 months was 73.3%. The results showed that a low preoperative IOP, thin central corneal thickness, prior non-selective laser trabeculoplasty history, and simultaneous cataract and trabectome surgeries were factors that contributed to the success rate. CONCLUSIONS: The success rate of trabectome surgery was higher for low-IOP glaucoma than high-IOP glaucoma. Trabectome could be a useful treatment for low-IOP glaucoma. PMID- 28816821 TI - Adjacent Segment Disease After Cervical Spine Fusion: Evaluation of a 70 Patient Long-Term Follow-Up. AB - STUDY DESIGN: A retrospective study of 70 patients undergoing surgical treatment for adjacent segment disease (ASD) after anterior cervical decompression and fusion (ACDF). OBJECTIVE: To analyze the risk factors for the development of ASD in patients who underwent ACDF. SUMMARY OF BACKGROUND DATA: ACDF has provided a high rate of clinical success for the cervical degenerative disc disease; nevertheless, adjacent segment degeneration has been reported as a complication at the adjacent level secondary to the rigid fixation. METHODS: Between January 2005 and December 2012, 70 consecutive patients underwent surgery for ASD after ACDF in our institution. In all patients thorough clinical and radiological examination was performed preoperatively, postoperatively, and at the final follow-up. The clinical data included the Neck Disability Index (NDI) and the Visual Analogue Scale (VAS). The radiological evaluation included x-rays and magnetic resonance imaging (MRI) for all patients. The duration of follow up after the adjacent segment operation ranged from 3 to 10 years. RESULTS: Surgery for ASD was performed after a mean period of 32 months from the primary ACDF. ASD occurred after single level ACDF in 54% of cases, most commonly after C5/6 fusion (28%). Risk factors for ASD were found to be preexisting radiological signs of degeneration at the primary surgery (74%) and bad sagittal profile after the primary ACDF (90%). CONCLUSION: ASD occurred predominantly in the middle cervical region (C4-6); especially in patients with preexisting evidence of radiological degeneration in the adjacent segment at the time of primary cervical fusion, notably when this surgery failed to restore or maintain the cervical lordosis. LEVEL OF EVIDENCE: 4. PMID- 28816822 TI - Selecting the LSTV as the Lower Instrumented Vertebra in the Treatment of Lenke Types 1A and 2A Adolescent Idiopathic Scoliosis: A Minimal 3-year Follow-up. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: The purpose of this study was to verify the last substantially touched vertebra (LSTV) as the ideal lower instrumented vertebra (LIV) and to identify predictive factors of adding-on in patients with Lenke type 1A and 2A curve patterns when LSTV was chosen as the LIV. SUMMARY OF BACKGROUND DATA: Although several studies have indicated that the use of the LSTV as the LIV can obtain favorable outcomes in Lenke 1A and 2A curves, the factors identifying patients with Lenke 1A and 2A curve patterns who should undergo a fusion extending beyond the LSTV have not been identified. METHODS: A total of 120 patients with Lenke 1 and 2 curves after posterior instrumentation and fusion to the LSTV were evaluated. All patients had a minimum 3-year follow-up. Patients were grouped based on the occurrence of the distal adding-on phenomenon: an adding-on group and a no adding-on group. We analyzed the significant independent factors associated with adding-on via univariate analysis and then via stepwise logistic regression analysis. RESULTS: Distal adding-on was observed in 16 patients (13.33%). Binary logistic regression analysis showed that the Risser sign (OR = 0.592, P = 0.033), preoperative distance between the LIV and the center sacral vertical line (CSVL) (LIV-CSVL) (OR = 1.286, P = 0.002), and postoperative thoracic kyphosis (T5-T12) (OR = 0.784, P = 0.002) were primary factors for distal adding-on. CONCLUSION: Selecting the LSTV as the LIV simplifies the selection of the LIV and is an effective operation strategy in patients with Lenke 1A and 2A curve types. Patients with lower Risser sign, larger preoperative LIV-CSVL, and postoperative thoracic hypokyphosis are more likely to develop distal adding-on at 3-year follow-up. LEVEL OF EVIDENCE: 4. PMID- 28816823 TI - Postoperative Changes in Presepsin Level and Values Predictive of Surgical Site Infection After Spinal Surgery: A Single-Center, Prospective Observational Study. AB - STUDY DESIGN: Single-institutional, prospective observational study. OBJECTIVE: To elucidate the perioperative kinetics of presepsin (PSEP) in patients undergoing spinal surgery, and to evaluate the possibility of PSEP in the early diagnosis of surgical site infection (SSI). SUMMARY OF BACKGROUND DATA: Early diagnosis of SSI after spinal surgery is important. Although several biomarkers have been used as early indicators of SSI, the specificity of these markers in SSI diagnosis was not high. PSEP was found as a novel diagnostic marker for bacterial sepsis in 2004. However, its kinetics after spinal surgery and its usefulness in early diagnosis of SSI have never been evaluated. METHODS: A total of 118 patients who underwent elective spinal surgery were enrolled. PSEP was measured before, immediately after, 1 day after, and 1 week after surgery. In patients without postoperative infection, perioperative kinetics of PSEP were analyzed. PSEP levels in patients with postoperative infection were also recorded separately, and their utility in SSI diagnosis was evaluated. RESULTS: In the 115 patients without postoperative infection, the median PSEP value was 126, 171, 194, and 147 pg/mL before, immediately after, 1 day after, and 1 week after surgery, respectively. Compared with the preoperative value, PSEP was significantly higher immediately after surgery and the next day, and return to the preoperative level 1 week after surgery. The estimated reference value for 95 percentile in patients without postoperative infection was 297 pg/mL 1 week after surgery. In three patients with postoperative infection, higher levels (>300 pg/mL) were observed 1 week after surgery. CONCLUSION: In patients after spinal surgery without infectious complications, blood levels of PSEP may immediately increase and return to preoperative levels 1 week after surgery. The PSEP value of 300 pg/mL 1 week after surgery might be used as a novel indicator for suspected SSI. LEVEL OF EVIDENCE: 4. PMID- 28816824 TI - Analysis of the Relationship Between the Epidural Spinal Cord Compression (ESCC) Scale and Paralysis Caused by Metastatic Spine Tumors. AB - STUDY DESIGN: A retrospective, single-institute, and radiographic study. OBJECTIVE: To evaluate the relationship between the epidural spinal cord compression (ESCC) scale and the severity of metastatic spine tumor-induced paralysis. SUMMARY OF BACKGROUND DATA: The ESCC scale is used to evaluate the grade of spinal cord compression on T2-weighted magnetic resonance imaging (MRI). However, few studies have investigated the relationship between such MRI findings and paralysis. METHODS: The subjects were 467 patients with metastatic spine tumors and grade 1b or worse spinal cord compression according to the ESCC scale. Evaluations using this scale were performed by three spine surgeons, and results that were obtained by two or more surgeons were adopted. We also examined patients whose spinal cord compression deteriorated by one grade or more to American Spinal Injury Association (ASIA) grade C or worse within the first 3 weeks after MRI. RESULTS: The kappa coefficients for inter- and intraexaminer variability were 0.90 and 0.95, respectively. ASIA grade D or worse paralysis developed in at least 50% of the patients with ESCC grade 1b or worse spinal cord compression at the C1-T2 and at least 50% of those with ESCC grade 1c or worse spinal cord compression at the T3-L5. The frequency of ASIA grade C or worse paralysis was high among the patients with ESCC grade 2 or worse spinal cord compression at the C7-L1. Nineteen patients experienced rapid deterioration of one grade or more to ASIA grade C or worse paralysis within the first 3 weeks after MRI. Of these, paralysis occurred in at least 30% of the patients with anterolateral or circumferential cord compression combined with ESCC grade 2 or 3 compression at the C7-L1. CONCLUSION: The severity of paralysis was not correlated with the ESCC scale. Patients with anterolateral or circumferential ESCC grade 2 or 3 cord compression at the C7-L1 are at high risk of rapidly progressive paralysis. LEVEL OF EVIDENCE: 4. PMID- 28816825 TI - Is Two-level Cervical Disc Replacement More Cost-effective Than Anterior Cervical Discectomy and Fusion at 7 Years? AB - STUDY DESIGN: Cost-effectiveness analysis. OBJECTIVE: To investigate 7-years cost effectiveness of two-level cervical disc replacement (CDR) and anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: CDR and ACDF are both effective treatment strategies for managing degenerative conditions of the cervical spine. CDR has been shown to be a more-cost effective intervention in the short term, but the long-term cost-effectiveness has not been established. METHODS: We analyzed 7-years follow-up data from the two-level Medtronic Prestige LP investigational device exemption study. Short-form 36 (SF-36) data were converted into health utility scores using the SF-6D algorithm. Costs were based on direct costs from the payer perspective, and effectiveness was measured as quality-adjusted life years (QALYs). The willingness-to-pay (WTP) threshold was set to $50,000/QALY. A probabilistic sensitivity analysis was conducted via Monte Carlo simulation. RESULTS: Two-level CDR had a 7-year cost of $176,654.19, generated 4.65 QALYs, and had a cost-effectiveness ratio of $37,993.53/QALY. Two level ACDF had a 7-year cost of $158,373.48, generated 4.44 QALYs, and had a cost effectiveness ratio of $35,635.72. CDR was associated with an incremental cost of $18,280.71 and an incremental effectiveness of 0.21 QALYs, resulting in an incremental cost-effectiveness ratio (ICER) of $89,021.04, above the WTP threshold. Our Monte Carlo simulation demonstrated CDR would be chosen 46% of the time based on 10,000 simulations. CONCLUSION: Two-level CDR and ACDF are both cost-effective procedures at 7-year follow up for treating degenerative conditions of the cervical spine. Based on an ICER of $89,021.04/QALY, we cannot conclude which treatment is the more cost-effective option at 7-years. CDR would be chosen 46% of the time based on 10,000 iterations of our Monte Carlo probabilistic sensitivity analysis. LEVEL OF EVIDENCE: 3. PMID- 28816827 TI - The Relationship Between Fear-Avoidance and Objective Biomechanical Measures of Function in Patients With Adult Degenerative Scoliosis. AB - STUDY DESIGN: A prospective cohort study. OBJECTIVE: The current study utilized quantitative gait analysis to examine the relationship of fear-avoidance beliefs to gait patterns in patients with adult degenerative scoliosis (ADS). SUMMARY OF BACKGROUND DATA: Among patients with chronic spine pain, fear-avoidance beliefs are predictive of behavioral deficiencies, poor work, and surgery outcomes. The impact of such beliefs on patients with major spinal deformity has yet to be investigated. Patients with ADS have previously been shown to have an altered gait pattern. Utilizing quantified gait analysis, this study aims to examine correlations between fear-avoidance and various aspects of gait in patients with ADS. METHODS: Twenty-five ADS patients completed the Tampa Scale for Kinesiophobia (TSK) questionnaire and the Fear Avoidance Beliefs Questionnaire (FABQ). Each patient performed a series of overground gait trials at a self selected comfortable speed. Pearson product correlation analysis was used to determine the relationship between the self-reported fear of movement measures and the objective gait analysis biomechanical data. RESULTS: TSK score correlated strongly with gait speed, stride, step, double support times, and step length, and correlated moderately with cadence, and stride length. The FABQ physical portion strongly correlated with stride length and step length. The FABQ physical portion was moderately correlated with gait speed and single support time. The FABQ work portion was correlated with stride length and step length. CONCLUSION: This study demonstrates a strong correlation between biomechanical gait parameters, as measured with gait analysis, and fear-avoidance of movement, as measured with the TSK and FABQ. Further, it demonstrates that quantified gait analysis can be a useful tool to evaluate patients with spine deformity and to assess the outcomes of treatments in this group of patients. This study extends previous research on the role of fear-avoidance to include patients with spinal deformity. LEVEL OF EVIDENCE: 3. PMID- 28816826 TI - Tissue Engineered Bone Differentiated From Human Adipose Derived Stem Cells Inhibit Posterolateral Fusion in an Athymic Rat Model. AB - STUDY DESIGN: Biological augmentation spinal arthrodesis trial in athymic rats. OBJECTIVE: To assess the efficacy of tissue-engineered bone to promote L4-L5 intertransverse process fusion in an athymic rat model. SUMMARY OF BACKGROUND DATA: Each year in the United States, over 400,000 spinal fusion surgeries are performed requiring bone graft. The current gold standard for posterolateral lumbar fusion is autogenous iliac crest bone graft (ICBG), but the harvesting of ICBG is associated with increased operative time and significant complications. This being the case, an alternative cost-effective bone graft source is needed. METHODS: Bovine bone cores were sterilized and decellularized for scaffold production. Human adipose derived mesenchymal stem cells (ADSC) were obtained and verified by tridifferentiation testing and seeded onto dried scaffolds. The seeded cores were cultured for 5 weeks in culture medium designed to mimic endochondral ossification and produce hypertrophic chondrocytes. Single-level intertransverse process fusions were performed at the L4-L5 level of 31 athymic rats. Fifteen rats were implanted with the hypertrophic chondrocyte seeded scaffold and 16 had scaffold alone. Half of the study rats were sacrificed at 3 weeks and the other half at 6 weeks. Spinal fusion was assessed using 2D and 3D micro computed tomography (MUCT) analysis and tissue histology. RESULTS: At 3 weeks, none of the tissue engineered rats had partial or complete fusion, whereas 62.5% of the decellularized rats fused and another 12.5% had partial fusions (P = 0.013). At 6 weeks, none of the tissue engineered rats fused and 50% had partial fusions, whereas 87.5% of the decellularized rats fused (P = 0.002). CONCLUSION: Tissue engineered bone composed of hypertrophic chondrocytes inhibits posterolateral fusion in an athymic rat model and therefore does not represent a promising cost-effective bone graft substitute. LEVEL OF EVIDENCE: N/A. PMID- 28816828 TI - Coronal Decompensation After Posterior-only Thoracolumbar Hemivertebra Resection and Short Fusion in Young Children With Congenital Scoliosis. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: To determine the incidence and risk factors of coronal decompensation after posterior-only thoracolumbar hemivertebra (HV) resection and short fusion in patients younger than 5-years old. SUMMARY OF BACKGROUND DATA: Postoperative coronal decompensation may occur in operated patients during the follow up. However, there is a paucity of valid data regarding this complication in very young patients with thoracolumbar HV. METHODS: This study reviewed a consecutive series of patients (younger than 5 years) who had undergone posterior-only hemivertebrectomy and short fusion from January 2006 to December 2014. They had a minimum follow-up of 24 months. According to the coronal compensation behavior, they were divided into two groups: Group P (progressed, curve decompensated beyond twenty degrees) and Group NP (nonprogressed, curve well compensated). RESULTS: There were 179 patients included in this study. Mean age at surgery was 38 +/- 11 months. Mean follow-up was 41 +/- 11 months. Postoperative coronal decompensation was identified in 18 patients (rate, 10.1%) who constituted Group P. The remaining 161 patients had a well-compensated pattern. In contrast to Group NP, the patients in Group P had greater preoperative lowest instrumented vertebra (LIV) translation (18.5 mm +/- 6.4 mm vs. 10.5 mm +/- 4.9 mm, P < 0.01), and higher postoperative LIV disc angle (7.0 degrees +/- 3.1 degrees vs. 3.1 degrees +/- 3.3 degrees , P < 0.01) after surgery. During the follow up, LIV translation and LIV disc experienced continuous aggravation until initiation of bracing. Preoperative LIV translation (>=15.1 mm) and postoperative LIV disc angle (>=5.5 degrees ) were identified as two independent risk factors of coronal decompensation after surgery. CONCLUSION: After thoracolumbar hemivertebrectomy in children younger than 5 years, the overall rate of coronal decompensation is approximately 10.1%. As two independent risk factors of postoperative coronal decompensation, preoperative LIV translation (>=15.1 mm) and postoperative LIV disc angle (>=5.5 degrees ) should on all accounts be the major causes for concern. LEVEL OF EVIDENCE: 4. PMID- 28816829 TI - Treatment Outcome of Metastatic Spine Tumor in Lung Cancer Patients: Did the Treatments Improve Their Outcomes? AB - STUDY DESIGN: A retrospective, single-center study. OBJECTIVE: Investigation of the changes in the treatment outcomes of patients with lung cancer derived metastatic spine tumors. SUMMARY OF BACKGROUND DATA: Metastatic spine tumors derived from lung cancer had been progressive, and their prognosis is poor. It has recently been reported that the use of molecularly targeted drugs and bone modifying agents (BMAs) improved the treatment outcomes of patients with lung cancer, but no detailed information about the treatment of metastatic spine tumors has been reported. METHODS: Two hundred seven patients with lung cancer derived metastatic spine tumors who were examined after 2000 were analyzed. They were divided into 54 patients who were treated in or before 2005 (surgical treatment: 25 patients, conservative treatment: 29 patients) (group B) and 153 patients who were treated from 2006 onwards, when a molecularly targeted drug and BMA were introduced (surgical treatment: 24, conservative treatment: 129) (group A), and the treatment outcomes of the two groups were compared. RESULTS: Significant differences in age and the affected vertebral level, paralysis grade, and Tokuhashi score (general condition, the number of vertebral metastases, and the total score) were detected between the groups. Regarding treatment outcomes, the mean duration of the post-treatment survival period was 5.1 and 9.3 months in groups B and A, respectively, that is, it was significantly longer in group A (P < 0.05). No significant intergroup difference in pain improvement was noted, and no significant post-treatment improvement in paralysis was achieved in either group. The post-treatment discharge-to-home eligibility rate did not differ significantly between the groups, but the Barthel Index improved significantly after treatment in group A (P < 0.05). CONCLUSION: After molecularly targeted drugs and BMA were introduced as treatments for lung cancer derived metastatic spine tumors, the survival periods of patients with such tumors increased, and their activity of daily living after treatment improved. LEVEL OF EVIDENCE: 4. PMID- 28816830 TI - Fatal Cerebral Edema, Seizures, and Hyponatremia After Trazodone Overdose. AB - Trazodone is a serotonin antagonist and reuptake inhibitor that is widely used for the treatment of depression and insomnia. Fatal overdose is rare and usually occurs when combined with other drugs or alcohol. Only a few lethal cases of pure trazodone overdose have been reported, all attributed to cardiotoxicity. We reported a 37-year-old woman who presented after ingesting 6.45 g of trazodone in a suicidal attempt. She was hyponatremic because of the syndrome of inappropriate antidiuretic hormone secretion and, shortly after, had a seizure and developed fatal cerebral edema. Others have described seizures and hyponatremia after pure trazodone overdose, but this is the first report of cerebral edema and death from a neurological complication. Careful monitoring and correction of sodium levels may be necessary in these patients. PMID- 28816831 TI - School Refusal Successfully Treated With Divalproex. AB - Divalproex was successfully used in a 7-year-old boy suffering from treatment refractory school refusal complicated with a mood disturbance and anxiety. Divalproex had demonstrated a rapid effect in reducing school anxiety and improving school attendance after multiple failures of other agents. Divalproex may be an effective agent for treating school refusal in children with emotional and/or behavior disturbances. PMID- 28816832 TI - Reversible Splenial Lesion Syndrome After Intravenous Immunoglobulin Treatment for Guillain-Barre Syndrome. AB - Reversible corpus callosum splenial (CCS) lesions have been described in patients with varied etiologies. The most common causes of previously reported reversible focal lesions of the CCS are viral encephalitis, antiepileptic drug toxicity/withdrawal, and metabolic disorders. Intravenous immunoglobulin (IVIG) therapy is used for different immune-mediated diseases. It is generally safe, and serious adverse reactions are uncommon. We presented a rare case of disturbed consciousness with reversible CCS lesions after IVIG therapy for Guillain-Barre syndrome in an adult woman. In this case, we believe that IVIG therapy caused reversible CCS lesions with encephalopathy and probably result of cytotoxic edema and/or cerebral arterial vasospasm. PMID- 28816833 TI - Perioperative Use of Erythromycin Reduces Cognitive Decline After Coronary Artery Bypass Grafting Surgery: A Pilot Study. AB - OBJECTIVES: Adverse neurologic outcome can be a debilitating complication after cardiac surgery. The aim of this study was to investigate the potential neuroprotective action of erythromycin, a well known antibiotic agent, regarding postoperative cognitive decline in patients undergoing cardiac surgery. METHODS: Forty patients scheduled for elective coronary artery bypass grafting surgery were prospectively randomly assigned in 2 groups: the erythromycin group (n = 19) who received erythromycin at a dose of 25 mg/kg before and after surgery and the control group (n = 21) who did not receive it. All patients were monitored with near-infrared spectroscopy during the operation. Interleukin (IL) 1 and IL-6 as inflammatory markers and tau protein as a marker of brain injury were measured before and after surgery. Neurocognitive assessment was performed before surgery, on the day of discharge, and at 3 months postoperatively. RESULTS: Both groups were comparable in terms of demographic and clinical data. Patients who took erythromycin presented with significantly better cognitive performance before discharge and 3 months after surgery. No significant differences between the 2 groups referring to IL-1 and IL-6 values were detected. Tau serum values were lower in the erythromycin group after surgery. CONCLUSIONS: Erythromycin administration attenuates cerebral damage and postoperative cognitive decline after coronary artery bypass grafting surgery. TRIAL REGISTRATION: The study was retrospectively registered at ClinicalTrials.gov (NCT01274754). Study start day: November 2008. PMID- 28816834 TI - Effect of Amantadine on Agitation in Critically Ill Patients With Traumatic Brain Injury. AB - OBJECTIVE: This study aimed to compare the presence of agitation in traumatic brain injury patients treated with amantadine with those not treated with amantadine in the intensive care unit (ICU). METHODS: This was a retrospective cohort study conduced in a trauma ICU of a tertiary care institution in the United States. Patients who received amantadine were compared with patients who did not receive amantadine. The primary outcome measure was the presence of agitation, defined as the Richmond Agitation Sedation Scale score of +2 or higher. Secondary comparisons included haloperidol use, benzodiazepine use, opioid use, and ICU length of stay. RESULTS: A total of 139 patients were included in the study cohort (70 patients in the amantadine group, 69 patients in the no-amantadine group). There were more patients who had agitation in the amantadine group (38% vs 14%, P = 0.018). Patients who received amantadine received more opioids in fentanyl equivalents (10.3 [interquartile range {IQR}, 6.3-20.4] MUg/kg vs 7.4 [IQR, 2.1-12.6] MUg/kg, P = 0.009) and had a longer ICU length of stay (4.5 [IQR, 3-10] days vs 3 [IQR, 2-5] days, P = 0.010). Haloperidol use and benzodiazepine use were similar between groups. CONCLUSIONS: The early use of amantadine after traumatic brain injury may increase the risk of agitation. This could increase opioid consumption and ICU length of stay. PMID- 28816835 TI - Acute Worsening of Tics on Varenicline. AB - OBJECTIVE: The aim of this study was to report worsening of Tourette syndrome (TS) in 2 patients treated with varenicline. BACKGROUND: Abnormal dopaminergic signaling is likely involved in the pathophysiology of TS. Varenicline is a partial alpha4beta2 nicotinic acetylcholine agonist that enhances dopamine release. Therefore, the use of varenicline may influence tics in patients with TS. METHOD: We analyzed and described 2 case studies on patients with significant worsening of tics after treatment with varenicline. RESULTS: Patient 1 had motor tics in childhood, which completely resolved by the age of 20 years. At the age of 25 years, he started varenicline and stopped smoking. Within 2 weeks, he developed motor followed by vocal tics that persisted despite stopping varenicline and restarting smoking. The tics were complex, medically refractory, and caused severe disability at work and school (Yale Global Tic Severity Scale score, 86). Patient 2 developed motor and vocal tics in adolescence that persisted into her 20s and caused significant disability in association with psychiatric comorbidities. At the age of 31 years, she started varenicline to quit smoking, which led to a marked increase in tic frequency and severity. Varenicline was discontinued after 3 weeks with improvement to baseline tic severity (Yale Global Tic Severity Scale score, 94). Ultimately, both patients successfully underwent deep brain stimulation to bilateral centromedian/parafascicular complex thalamic nuclei for medically refractory TS. CONCLUSIONS: We report 2 patients with motor and/or vocal tics that had severe worsening of tics after varenicline use. This may be due to varenicline-induced increased striatal dopamine in conjunction with nicotine cessation, influencing dopamine receptor sensitivity in TS. Providers should be cautious in prescribing varenicline to patients with TS. PMID- 28816836 TI - Reversal of Dropped Head Syndrome After the Cessation of Dopaminergic Agonist Treatment in Parkinson Disease. AB - Dropped head (DH) syndrome is a phenomenon of disproportionate neck anteflexion that has been reported in patients with Parkinson disease (PD). Antiparkinsonian medications such as dopaminergic agonists (DAs) have been implicated in the onset of DH episodes. Deep brain stimulation (DBS) is an important therapeutic option after the failure of conventional treatments such as DA therapy in patients with PD. Here, we report the case of a patient with rigid-akinetic parkinsonism who developed DH syndrome after the initiation of DA treatment. Dopaminergic agonist treatment was required to stabilize motor dysfunction during a period of 5 years; yet, the patient experienced no improvements in DH during this time. Thus, we initiated DBS as an alternative therapy and gradually withdrew DA therapy. The patient recovered from long-term DH after the discontinuation of rotigotine treatment. Accordingly, this case highlights DA treatment as a possible cause of DH and the use of DBS to allow the discontinuation of DA treatment while preserving motor function in patients with PD. PMID- 28816838 TI - Executive Summary: Clinical Practice Guideline: Safe Medication Use in the ICU. PMID- 28816839 TI - Benzodiazepines and Delirium in the Young and Old: Truth Be Told or Still Not Sold? PMID- 28816837 TI - Individualizing Thresholds of Cerebral Perfusion Pressure Using Estimated Limits of Autoregulation. AB - OBJECTIVES: In severe traumatic brain injury, cerebral perfusion pressure management based on cerebrovascular pressure reactivity index has the potential to provide a personalized treatment target to improve patient outcomes. So far, the methods have focused on identifying "one" autoregulation-guided cerebral perfusion pressure target-called "cerebral perfusion pressure optimal". We investigated whether a cerebral perfusion pressure autoregulation range-which uses a continuous estimation of the "lower" and "upper" cerebral perfusion pressure limits of cerebrovascular pressure autoregulation (assessed with pressure reactivity index)-has prognostic value. DESIGN: Single-center retrospective analysis of prospectively collected data. SETTING: The neurocritical care unit at a tertiary academic medical center. PATIENTS: Data from 729 severe traumatic brain injury patients admitted between 1996 and 2016 were used. Treatment was guided by controlling intracranial pressure and cerebral perfusion pressure according to a local protocol. INTERVENTIONS: None. METHODS AND MAIN RESULTS: Cerebral perfusion pressure-pressure reactivity index curves were fitted automatically using a previously published curve-fitting heuristic from the relationship between pressure reactivity index and cerebral perfusion pressure. The cerebral perfusion pressure values at which this "U-shaped curve" crossed the fixed threshold from intact to impaired pressure reactivity (pressure reactivity index = 0.3) were denoted automatically the "lower" and "upper" cerebral perfusion pressure limits of reactivity, respectively. The percentage of time with cerebral perfusion pressure below (%cerebral perfusion pressure < lower limit of reactivity), above (%cerebral perfusion pressure > upper limit of reactivity), or within these reactivity limits (%cerebral perfusion pressure within limits of reactivity) was calculated for each patient and compared across dichotomized Glasgow Outcome Scores. After adjusting for age, initial Glasgow Coma Scale, and mean intracranial pressure, percentage of time with cerebral perfusion pressure less than lower limit of reactivity was associated with unfavorable outcome (odds ratio %cerebral perfusion pressure < lower limit of reactivity, 1.04; 95% CI, 1.02-1.06; p < 0.001) and mortality (odds ratio, 1.06; 95% CI, 1.04-1.08; p < 0.001). CONCLUSIONS: Individualized autoregulation-guided cerebral perfusion pressure management may be a plausible alternative to fixed cerebral perfusion pressure threshold management in severe traumatic brain injury patients. Prospective randomized research will help define which autoregulation guided method is beneficial, safe, and most practical. PMID- 28816840 TI - What Definition Should We Use for Sepsis and Septic Shock? PMID- 28816841 TI - Sepsis-3: Seeing the Entire Picture. PMID- 28816842 TI - What Is the National Burden of Sepsis in U.S. Emergency Departments? It Depends on the Definition. PMID- 28816843 TI - Better Late Than Never? Deferred Consent for Minimal Risk Research in the ICU. PMID- 28816844 TI - Organizing Intensive Care for Patients Undergoing Cardiac Surgery. PMID- 28816845 TI - The Evidence Clash Between Statins and Delirium: Should They Stay, Should They Go, or Should They Be Started? PMID- 28816846 TI - Deep Immune Profiling in Trauma and Sepsis: Flow Is the Way to Go! PMID- 28816847 TI - Death Is Death: Isn't It? PMID- 28816848 TI - Turning of the Page. PMID- 28816849 TI - Steroids Redux: Targeting the Mineralocorticoid Axis in Sepsis. PMID- 28816850 TI - In-Hospital Cardiac Arrest: An Ounce of Prevention Is Worth a Pound of Cure. PMID- 28816852 TI - Assessing Nutrition Delivery in ICUs-A Difficult Problem to Digest. PMID- 28816851 TI - Clinical Practice Guideline: Safe Medication Use in the ICU. AB - OBJECTIVE: To provide ICU clinicians with evidence-based guidance on safe medication use practices for the critically ill. DATA SOURCES: PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, CINAHL, Scopus, and ISI Web of Science for relevant material to December 2015. STUDY SELECTION: Based on three key components: 1) environment and patients, 2) the medication use process, and 3) the patient safety surveillance system. The committee collectively developed Population, Intervention, Comparator, Outcome questions and quality of evidence statements pertaining to medication errors and adverse drug events addressing the key components. A total of 34 Population, Intervention, Comparator, Outcome questions, five quality of evidence statements, and one commentary on disclosure was developed. DATA EXTRACTION: Subcommittee members were assigned selected Population, Intervention, Comparator, Outcome questions or quality of evidence statements. Subcommittee members completed their Grading of Recommendations Assessment, Development, and Evaluation of the question with his/her quality of evidence assessment and proposed strength of recommendation, then the draft was reviewed by the relevant subcommittee. The subcommittee collectively reviewed the evidence profiles for each question they developed. After the draft was discussed and approved by the entire committee, then the document was circulated among all members for voting on the quality of evidence and strength of recommendation. DATA SYNTHESIS: The committee followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation system to determine quality of evidence and strength of recommendations. CONCLUSIONS: This guideline evaluates the ICU environment as a risk for medication-related events and the environmental changes that are possible to improve safe medication use. Prevention strategies for medication related events are reviewed by medication use process node (prescribing, distribution, administration, monitoring). Detailed considerations to an active surveillance system that includes reporting, identification, and evaluation are discussed. Also, highlighted is the need for future research for safe medication practices that is specific to critically ill patients. PMID- 28816853 TI - The authors reply. PMID- 28816854 TI - Caution Warranted Regarding Transfusion for Subarachnoid Hemorrhage. PMID- 28816855 TI - The authors reply. PMID- 28816856 TI - Antimicrobials and Progression to Septic Shock in Severe Sepsis Patients: Is Delay the Only Thing That Matters? PMID- 28816857 TI - The authors reply. PMID- 28816858 TI - Meta-Analysis of Bowel Protocols in Critical Care Patients: A Word of Caution. PMID- 28816859 TI - The authors reply. PMID- 28816860 TI - Management of Chronic Hepatitis B in Pregnancy. AB - Chronic hepatitis B virus (HBV) infection due to mother-to-child transmission during the perinatal period remains an important global health problem. Despite standard passive-active immunoprophylaxis with hepatitis B immunoglobulin and hepatitis B vaccine in neonates, up to 8.5% of newborns still acquire HBV infection. Thus, management of chronic HBV during pregnancy and strategies to prevent mother-to-child transmission are important steps in eradicating or reducing the global burden of chronic HBV infection. To date, the management of HBV infection in pregnancy still needs careful attention because of some controversial aspects, including the influence of pregnancy on the course of HBV replication, safety of antiviral prophylaxis with nucleus(t)ide analogs, postpartum flares of hepatitis after delivery, and the safety of breastfeeding. In this review, we highlight these important issues of preventive strategies in the perinatal period. PMID- 28816861 TI - EN FACE VERSUS 12-LINE RADIAL OPTICAL COHERENCE TOMOGRAPHY SCAN PATTERNS FOR DETECTION OF MACULAR FLUID IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION. AB - PURPOSE: To compare fluid detection of autosegmented en face to 12-line radial spectral domain optical coherence tomography scan patterns in neovascular age related macular degeneration. METHODS: Retrospective observational case series. Sixty-seven patients (94 eyes) with neovascular age-related macular degeneration underwent autosegmented en face optical coherence tomography (with associated 304 line raster scan) and 12-line radial scan patterns. Sensitivity and specificity of fluid detection for en face scan and 12-line radial scans were determined by combining radial and 304-line raster scans as a gold standard. RESULTS: Two hundred and fifty-eight en face and 12-line radial spectral domain optical coherence tomography scans were interpreted. Seventy-five scans (58.1%) had fluid, whereas 54 scans (41.9%) did not. En face scan pattern fluid detection sensitivity and specificity was 89.3% and 61.1%, respectively. Twelve-line radial scan pattern fluid detection sensitivity and specificity was 97.3% and 100%, respectively. The difference in fluid detection between scan patterns was statistically significant (P = 0.01). Decreased central macular thickness was associated with false-positive (P = 0.035) and false-negative (P = 0.01) fluid detection on en face scans. CONCLUSION: En face optical coherence tomography alone is not as sensitive or specific as the 12-line radial scan pattern in detecting fluid in neovascular age-related macular degeneration. En face scans should be corroborated with other optical coherence tomography protocols to guide clinical decision making. PMID- 28816862 TI - UNILATERAL OPTIC NEURITIS AND CENTRAL RETINAL VASCULITIS DUE TO OCULAR SYPHILIS. AB - PURPOSE: Report a case of concurrent unilateral optic neuritis and central retinal artery occlusion as the presenting signs of syphilis. METHODS: A case report of a 22-year-old man with progressive unilateral vision loss. RESULTS: With no known previous history of syphilis, genital lesions, or other extraocular manifestations, the patient presented with pain with eye movements and decreased color vision. His vision dramatically worsened after a course of oral steroids. Examination was remarkable for severe right optic disk edema with a macular cherry-red spot and mild posterior uveitis. Magnetic resonance imaging of the orbits with contrast revealed enhancement and enlargement of the distal right optic nerve. Fluorescein angiography demonstrated delayed filling of the right central retinal artery, suggestive of impending central retinal artery occlusion. Syphilis serologies were positive from the serum, and cerebrospinal fluid Venereal Disease Research Laboratory test was reactive, consistent with neurosyphilis. Oral steroids were discontinued and vision improved with 2 weeks of intravenous penicillin. CONCLUSION: This unusual case highlights one of the possible initial presentations of syphilis: unilateral optic neuritis and central retinal artery vasculitis with mild posterior uveitis. The worsening of vision after administration of oral steroids also highlights a potential complication of oral steroid use in the absence of a known etiology of vision loss. A thorough history and examination may be helpful in identifying risk factors for infectious causes, including syphilis, and should prompt additional evaluation. PMID- 28816863 TI - MANAGEMENT OF RETINOBLASTOMA WITH HIV SEROPOSITIVITY. AB - PURPOSE: To report a case of retinoblastoma with concomitant association with HIV seropositivity and its management. METHODS: A retrospective case report of a 3 year-old male child presenting with right eye Group B and left eye Group E retinoblastoma with simultaneous positivity for HIV1 antibody. The parents were also tested positive for HIV and were referred for initiating antiretroviral therapy. RESULTS: The child was managed with focal laser therapy for the right eye and six cycles of systemic chemotherapy, and the left eye was planned for enucleation with ball implant. CONCLUSION: This case poses an outlook into a dilemma as to whether or not systemic chemotherapy should be started along with antiretroviral therapy for treating retinoblastoma, as there are no cited case reports in the literature of retinoblastoma coexisting with HIV and its related management regime and future considerations to be taken for management. PMID- 28816864 TI - INCREASED PHOTORECEPTOR OUTER SEGMENT VOLUME FOLLOWING SYSTEMIC TREATMENT OF BIRDSHOT CHORIORETINOPATHY. AB - PURPOSE: Retinal degeneration in birdshot chorioretinopathy can be quantified using spectral domain optical coherence tomography by measuring the photoreceptor outer segment (PROS) volume. The purpose of this study was to determine if the PROS volume in BSCR responds to systemic immunomodulatory therapy (IMT). METHODS: Retrospective chart review with analysis of PROS volume derived from spectral domain optical coherence tomography. RESULTS: We identified a total of three patients who met our inclusion criteria. At baseline, all patients had abnormal PROS and/or ellipsoid layer findings on spectral domain optical coherence tomography. After systemic immunomodulatory therapy, these abnormalities improved, and PROS volume increased, in all patients (P < 0.05). CONCLUSION: PROS volume can increase after systemic treatment of birdshot chorioretinopathy. This SD-OCT parameter may serve as a useful marker of retinal degeneration in BSCR, and may be a useful outcome measure in monitoring treatment response in birdshot chorioretinopathy. PMID- 28816865 TI - Liquid Crystal Spatial Light Modulators for Simulating Zonal Multifocal Lenses. AB - SIGNIFICANCE: To maximize efficiency of the normally lengthy and costly multizone lens design and testing process, it is advantageous to evaluate the potential efficacy of a design as thoroughly as possible prior to lens fabrication and on eye testing. The current work describes an ex vivo approach of optical design testing. PURPOSE: The aim of this study was to describe a system capable of examining the optical characteristics of multizone bifocal and multifocal optics by subaperture stitching using liquid crystal technologies. METHODS: A liquid crystal spatial light modulator (SLM) was incorporated in each of two channels to generate complementary subapertures by amplitude modulation. Additional trial lenses and phase plates were placed in pupil conjugate planes of either channel to integrate the desired bifocal and multifocal optics once the two optical paths were recombined. A high-resolution Shack-Hartmann aberrometer was integrated to measure the optics of the dual-channel system. Power and wavefront error maps as well as point spread functions were measured and computed for each of three multizone multifocal designs. RESULTS: High transmission modulation was achieved by introducing half-wavelength optical path differences to create two- and five zone bifocal apertures. Dual-channel stitching revealed classic annular rings in the point spread functions generated from two-zone designs when the outer annular optic was defocused. However, low efficiency of the SLM prevented us from simultaneously measuring the eye + simulator aberrations, and the higher-order diffraction patterns generated by the cellular structure of the liquid crystal arrays limited the visual field to +/-0.45 degrees. CONCLUSIONS: The system successfully simulated bifocal and multifocal simultaneous lenses allowing for future evaluation of both objective and subjective evaluation of complex optical designs. However, low efficiency and diffraction phenomena of the SLM limit the utility of this technology for simulating multizone and multifocal optics. PMID- 28816866 TI - Differences in Tear Film Biochemistry of Symptomatic and Asymptomatic Lens Wearers. AB - SIGNIFICANCE: The concentration of selected proteins and inflammatory mediators in tears of symptomatic and asymptomatic contact lens wearers were quantified. The level of leukotriene B4 was higher in the symptomatic group. This may suggest that inflammation can be the cause of discomfort sensation at the end of day. PURPOSE: The present study aims to quantify the concentration of selected tear lipids and proteins in symptomatic and asymptomatic contact lens wearers. METHODS: Unstimulated evening tears were collected using glass capillary tubes from 45 healthy, adapted contact lens wearers. Twenty-two had self-described symptoms of dryness and discomfort with contact lenses and 23 were asymptomatic. Tear proteins were assayed using selected reaction monitoring mass spectrometry. Enzyme immunoassay kits were used to measure prostaglandins, leukotriene B4, and cysteinyl leukotrienes. Ocular comfort was rated on a scale of 1 to 100 at the time of tear collection. RESULTS: The average evening comfort level was above 70 for the asymptomatic (83.96 +/- 9.51, mean +/- SE) and equal or below 70 for the symptomatic group (57.28 +/- 12.38) (P < .001). LTB4 was significantly higher in symptomatic than asymptomatic contact lens wearers (0.32 +/- 0.06 ng/MUL vs. 0.17 +/- 0.04 ng/MUL, respectively; P = .03). Lysozyme was slightly but not significantly lower in symptomatic subjects (symptomatic 0.58 +/- 0.10 mg/mL vs. asymptomatic 1.73 +/- 0.46 mg/mL; P = .10). The levels of lactoferrin, lipocalin 1, proline-rich 4, prolactin-induced protein, prostaglandins, and cysteinyl leukotrienes were unchanged (P > .1) between symptomatic and asymptomatic subjects. CONCLUSIONS: The LTB4 concentration was significantly higher in symptomatic contact lens wearers compared to the asymptomatic group, and this may partly mediate the discomfort response during lens wear in the symptomatic lens wearers. No other differences were found in the level of tear factors of interest between the two groups. PMID- 28816867 TI - Peripheral Refraction and Aberration Profiles with Multifocal Lenses. AB - SIGNIFICANCE: The amount of central or peripheral myopic shift, as induced by different multifocal contact lenses when viewing objects at distance or near, may provide insights on the potential efficacy for slowing eye growth. PURPOSE: The present study aims to compare peripheral refraction and higher-order aberration profiles of four multifocal contact lenses with a single vision control lens. METHODS: Thirty-five myopes (age 21.2 +/- 2.1 years) completed the trial, of whom 16 wore Air Optix Aqua and Proclear Multifocal Distance and Near (Group 1, spherical equivalent: -2.90 +/- 0.95D), whereas 19 wore Air Optix Aqua, Air Optix Multifocal, and PureVision Multifocal (Group 2, spherical equivalent: -2.95 +/- 0.78D). Refraction and aberration profiles with lenses were measured using the BHVI-EyeMapper with (-2.00 to -5.00D in 1.00D steps) and without (+1.00D fogging) accommodation. Data were quantified using M2/4 (2nd and 2nd + 4th order), J0, J45, and higher-order aberration coefficients coma C[3, 1] and spherical aberration C[4, 0]. RESULTS: The center-distance lens exhibited a relative peripheral myopic shift in M2/4 and J0, positive on-axis C[4, 0], negative on axis C[3, 1] and on-axis M4 was less negative for accommodative demands <=-3.00D (P < .05). Inversely, the center-near lenses showed a relative peripheral hyperopic shift in M2/4 and J0, negative on-axis C[4, 0], positive on-axis C[3, 1] and on-axis M4 was more negative for demands of -2.00 and -3.00D (P < .05). Independent of lens type, relative peripheral M4 significantly decreased during accommodation. Accounting for C[4, 0], a greater change in relative M profiles and accommodative responses was found for multifocal lenses. CONCLUSIONS: Based on the hypothesis that myopic retinal defocus counters eye growth, center-near multifocal lenses exhibited the preferred on-axis features, i.e., producing a central myopic shift at near compared to the control. The center-distance lens exhibited preferred off-axis features, producing relative peripheral myopia, which increased further during accommodation. PMID- 28816868 TI - Comparison of Refractive Measures of Three Autorefractors in Children and Adolescents. AB - SIGNIFICANCE: Our study found a good agreement between three autorefractors. Not only will readers benefit as they can now compare data measured with either device in different studies but the three devices can be used in the same study to generate one pool of data, which can be analyzed together. PURPOSE: The present study aims to evaluate the agreement of three commonly used autorefractors in children and adolescents, and the potential for their interchangeable application in a large-scale study. METHODS: Participants from seven schools were enrolled using cluster sampling. Refractive errors were measured using the following three autorefractors under cycloplegic conditions in random sequence: Topcon KR-8900, Nidek ARK-510A, and Huvitz HRK-7000A. Refractive errors were compared in terms of spherical equivalent refraction (SER), cylinder power, and the J0 and J45 by repeated-measures analysis of variance (RM-ANOVA) and Bland-Altman 95% limits of agreement (95% LoA). RESULTS: A total of 2072 participants aged from 4 to 18 years were included. The mean +/- SD and 95% LoA of the differences in SER between Topcon and Nidek, Topcon and Huvitz, and Nidek and Huvitz were 0.01 +/- 0.24D (-0.46 to 0.48), -0.06 +/- 0.31D (-0.66 to 0.54), and -0.07 +/- 0.26D (-0.58 to 0.44), and those for the differences in cylinder power were -0.07 +/- 0.26D (-0.57 to 0.44), 0.01 +/- 0.32D (-0.63 to 0.64), and 0.07 +/- 0.28D (-0.48 to 0.62), respectively (RM-ANOVA, P < .001). Further, the mean differences in J0 and J45 between each refractor pair ranged from -0.03 to 0.01, and the 95% LoA were -0.78 to 0.74, -0.79 to 0.74, and -0.73 to 0.72 for J0 and -0.86 to 0.87, -0.86 to 0.88, and -0.83 to 0.84 for J45, respectively. CONCLUSIONS: Our study will allow for use of these three autorefractors interchangeably in large screening studies. PMID- 28816869 TI - Spine Trauma-What Are the Current Controversies? AB - Although less common than other musculoskeletal injuries, spinal trauma may lead to significantly more disability and costs. During the last 2 decades there was substantial improvement in our understanding of the basic patterns of spinal fractures leading to more reliable classification and injury severity assessment systems but also rapid developments in surgical techniques. Despite these advancements, there remain unresolved issues concerning the management of these injuries. At this moment there is persistent controversy within the spinal trauma community, which can be grouped under 6 headings. First of all there is still no unanimity on the role and timing of medical and surgical interventions for patients with associated neurologic injury. The same is also true for type and timing of surgical intervention in multiply injured patients. In some common injury types like odontoid fractures and burst type (A3-A4) fractures in thoracolumbar spine, there is wide variation in practice between operative versus nonoperative management without clear reasons. Also, the role of different surgical approaches and techniques in certain injury types are not clarified yet. Methods of nonoperative management and care of elderly patients with concurrent complex disorders are also areas where there is no consensus. In this overview article the main reasons for these controversies are reviewed and the possible ways for resolutions are discussed. PMID- 28816870 TI - Spinal Cord Injury-What Are the Controversies? AB - Traumatic spinal cord injuries have a tremendous impact on individuals, families, and society as a whole. Substantial heterogeneity in the patient population, their presentation and underlying pathophysiology has sparked debates along the care spectrum from initial assessment to definitive treatment. This article reviews spinal cord injury (SCI) management followed by a discussion of the salient controversies in the field. Current care practices modeled on the American Association of Neurological Surgeons/Congress of Neurological Surgeons joint section guidelines are highlighted including key recommendations regarding immobilization, avoidance of hypotension, early International Standards for Neurological Classification of SCI examination and intensive care unit treatment. From a diagnostic perspective, the evolving roles of CT, MRI, and leading-edge microstructural MRI techniques are discussed with descriptions of the relevant clinical literature for each. Controversies in management relevant to clinicians including the timing of surgical decompression, methylprednisolone administration, blood pressure augmentation, intraoperative electrophysiological monitoring, and the role of surgery in central cord syndrome and pediatric SCI are also covered in detail. Finally, the article concludes with a reflection on clinical trial design tailored to the heterogeneous population of individuals with SCI. PMID- 28816871 TI - AOSpine Classification Systems (Subaxial, Thoracolumbar). AB - Numerous classification systems for subaxial and thoracolumbar spine injuries were proposed in the past with the attempt to facilitate communication between physicians. The AO-Magerl, thoracolumbar system, and Subaxial Cervical Spine Injury Classification systems are all well known, but did not achieve universal international adoption. A group of international experienced spine trauma surgeons were brought together by AOSpine with the goal to develop a comprehensive yet simple classification system for spinal trauma. This article is a synopsis of the proposed subaxial and thoracolumbar classification systems. In several studies, this classification system was developed using an iterative consensus process among the clinical experts in sufficient number and quality of DICOM images of real cases searching for meaningful and reproducible patterns. Both systems are based on 3 injury morphology types: compression injuries (A), tension band injuries (B), and translational injuries (C) with a total of 9 subgroups. In the subaxial cervical spine 4 additional subtypes for facet injuries exist. Patient-specific modifiers and neurologic status were also included to aid surgeons in therapeutic decision making. The proposed classification systems for subaxial and thoracolumbar injuries showed substantial intraobserver and interobserver reliability (kappa = 0.64-0.85) for grading fracture type. Grading for the subtypes varied considerably due to the low frequency of certain injury subtypes among other reasons. In summary, the AOSpine thoracolumbar and subaxial cervical spine injury systems show substantial reliability, thus being valuable tools for clinical and research purposes. PMID- 28816872 TI - Application of AOSpine Subaxial Cervical Spine Injury Classification in Simple and Complex Cases. AB - INTRODUCTION: Cervical spine injury classification systems should be simple, easy to relate and remember, reliable guide for surgical planning, and predictor of outcome in clinical settings. We investigated whether the AOSpine subaxial cervical spine classification system predicted injury severity and neurologic outcome. MATERIAL AND METHODS: We analyzed the relevant clinical, imaging, management, and American Spinal Injury Association (ASIA) impairment scale (AIS) grade conversion of 92 AIS grades A-C patients with cervical spine injury. We correlated morphology class with age, injury severity score (ISS), follow-up ASIA motor score (AMS), intramedullary lesion length (IMLL), and AIS grade conversion at 6 months after injury. RESULTS: The mean age of patients was 39.3 years, 83 were men, and 69 were injured during an automobile accident or after a fall. The AOSpine class was A4 in 8, B2 in 5, B2A4 in 16, B3 in 19, and C in 44 patients. The mean ISS was 29.7 and AMS was 17.1. AIS grade was A in 48, B in 25, and C in 19 patients. Mean IMLL on postoperative magnetic resonance imaging was 72 mm: A4 = 68.1; B2A4 = 86.5; B2 = 59.3; B3 = 46.8; and C = 79.9. At a mean follow-up of 6 months, the mean AMS was 39.6. Compared to patients with class B3 injuries, those with class C injuries were significantly younger (P < 0.0001), had longer IMLL (P < 0.002), and were less likely to have AIS grade conversion to a better grade (P < 0.02). CONCLUSIONS: The AOSpine subaxial cervical spine injury classification system successfully predicted injury severity (longer IMLL) and chances of neurologic recovery (AIS grade conversion) across different class subtypes. PMID- 28816873 TI - The Need of Validated Disease-Specific Outcome Instruments for Spine Trauma. AB - This article focuses on patient-reported and clinician-reported outcome measures in spine trauma care. The measurement of the quality of care and functional and health-related quality of life outcomes of spine trauma patients has become increasingly important. However, no outcome instrument is specifically designed, validated, or universally adapted for this specific patient population. Issues specific to spinal trauma patients may not be adequately addressed by the instruments that are currently used in the literature and the daily clinical practice. The AOSpine Knowledge Forum Trauma initiated a project to develop and validate such instruments for spine trauma patients. To reflect the different perspectives of patients and the treating surgeons, 2 separate tools are being developed: the Patient Reported Outcome Spine Trauma (AOSpine PROST) and Clinician Reported Outcome Spine Trauma (AOSpine CROST). These tools hold promise, as useful instruments to measure the outcomes of spine trauma patients with and without neurological deficit, making it more feasible for clinical use as well. Treating surgeons around the world are encouraged to use the AOSpine PROST and AOSpine CROST in daily clinical practice and for research purposes to create and contribute to evidence-based and patient-centered care. Using the same outcome measures that are specifically developed and validated for traumatic spine injuries will allow us to compare the outcomes of various treatments in a valid and reproducible fashion. This contributes to a reduction of the ongoing controversies and providing the best treatments for our patients. PMID- 28816874 TI - Does Surgical Intervention or Timing of Surgery Have an Effect on Neurological Recovery in the Setting of a Thoracolumbar Burst Fracture? AB - Traumatic thoracolumbar burst fractures are one of the most common forms of spinal trauma with the majority occurring at the junctional area where mechanical load is maximal (AOSpine Thoracolumbar Spine Injury Classification System Subtype A3 or A4). Burst fractures entail the involvement of the middle column, and therefore, they are typically associated with bone fragment in the spinal canal, which may cause compression of the spinal cord, conus medullaris, cauda equina, or a combination of these. Fortunately, approximately half of the patients with thoracolumbar burst fractures are neurologically intact due to the wide canal diameter. Recent evidences have revealed that functional outcomes in the long term may be equivalent between operative and nonoperative management for neurologically intact thoracolumbar burst fractures. Nevertheless, consensus has not been met regarding the optimal treatment strategy for those with neurological deficits. The present review article summarizes the contemporary evidences to discuss the role of nonoperative management in the presence of neurological deficits and the optimal timing of decompression surgery for neurological recovery. In summary, although operative management is generally recommended for thoracolumbar fracture with significant neurological deficits, the evidence is weak, and nonoperative management can also be an option for those with solitary radicular symptoms. With regards to timing of operative management, high-quality studies comparing early and delayed intervention are lacking. Extrapolating from the evidence in cervical spine injury leads to an assumption that early intervention would also be beneficial for neurological recovery, but further studies are warranted to answer these questions. PMID- 28816875 TI - Controversies in the Management of Geriatric Odontoid Fractures. AB - Fractures of the odontoid process of C2 have become increasingly prevalent in the aging population and are typically associated with a high incidence of morbidity. Dens fractures comprise the majority of all cervical fractures in patients older than 80 years and remain the most common cervical fracture pattern in all geriatric patients. Type II odontoid fractures have been associated with limited healing potential, and both nonoperative and operative management are associated with high mortality rates. Historically, there has been some debate in the literature with regards to optimal management strategies to maximize outcomes in geriatric patients. Recent, high-quality evidence has indicated that surgical treatment of type II odontoid fractures in elderly patients is associated with improvements in both short- and long-term mortality. Additionally, surgical intervention has been shown to improve functional outcomes when compared with nonsurgical treatment. Factors to consider before surgery for geriatric type II odontoid fractures include associated comorbidities and the safety of general anesthesia administration. With appropriate measures of patient selection, surgery can provide an efficacious option for geriatric patients with type II odontoid fractures. We recommend surgical intervention via a posterior C1-C2 arthrodesis for geriatric type II odontoid fractures, provided that the surgery itself does not represent an unreasonable risk for mortality. PMID- 28816876 TI - Osteoporotic Thoracolumbar Fractures-How Are They Different?-Classification and Treatment Algorithm. AB - Osteoporotic vertebral fractures constitute at least 50% of the osteoporotic fractures that happen worldwide. Occurrence of osteoporotic fractures make the elderly patient susceptible for further fractures and increases the morbidity due to kyphosis and pain; the mortality risk is also increased in these patients. Most fractures occur in the thoracic and thoracolumbar region and are often stable. Different descriptive and prognostic classification systems have been described, but none are universally accepted. Radiographs, computed tomography, and magnetic resonance imaging are useful in imaging the fracture and evaluating the bone density. In acute stages, the fractures are well treated with conservative measures including short bed rest, analgesics, bracing, and exercises. Although most fractures heal well, up to 30% of fractures can develop painful nonunion, progressive kyphosis, and neurological deficit. For patients who develop severe pain not responding to nonoperative measures and painful nonunion, percutaneous cement augmentation procedures including vertebroplasty or kyphoplasty have been suggested. For fractures with severe collapse and that lead to neurological deficit and increasing kyphosis, instrumented stabilization is advised. Prevention and management of osteoporosis is the key element in the management of osteoporotic fractures in the elderly. Guidelines for essential adequate dietary and supplemental calcium and vitamin D, and antiosteoporotic medications have been described. PMID- 28816877 TI - Fractures in Spinal Ankylosing Disorders: A Narrative Review of Disease and Injury Types, Treatment Techniques, and Outcomes. AB - INTRODUCTION: Spinal ankylosing disorders encompass ankylosing spondylitis (AS), disseminated hyperostosis of the spine, and end-stage spondylosis. All these result in a stiffened and frequently deformed spinal column. This makes the spinal column highly susceptible to severe injuries that are commonly associated with unfavorable outcomes. Improved understanding of the underlying disease processes and clinical comorbidities may alter the poor injury related morbidity and mortality outcomes. METHODS: A systematic review of the MEDLINE and PubMed databases was performed using the following key words to identify articles published between 2001 and 2016: "ankylosing spondylitis," "epidemiology," "DISH," "treatment," "outcome," and/or "fracture." Articles were read for data on methodology (retrospective vs. prospective), type of treatment, number of patients, mean patient age, and mean follow-up. RESULTS: Twenty-one identified articles were analyzed. Average age was 63.4 years. Most patients were men. Ground level fall or low energy trauma caused most injuries. Diagnosis was delayed in 15%-41% cases. Hyperextension fracture patterns were most common. Cervical spine fractures were more common than thoracolumbar fractures, with the highest prevalence between C5 and C7. Neurologic deficits were encountered in 21% 100% of patients. Operative fixation and fusion were performed in 40%-100% of patients. Mortality was reported between 0% and 32% at 1 year postinjury. Complications were encountered in 84% of patients, mostly in the form of pneumonia, respiratory failure, and pseudoarthrosis. Neurologic deterioration has been reported in 16% of patients. Fusion was successful in 87%-100% of patients. Neurologic deficits improved in function in 6%-66% at the final follow-up. CONCLUSIONS: Because of the stiffening of the spinal column, patients with spinal ankylosing disorders are preferably evaluated for spinal fractures and ligamentous injuries after even trivial trauma. Spinal injuries in patients with AS are difficult to diagnose on plain radiographs; computed tomography and magnetic resonance imaging are recommended instead. The entire spine should be scanned for multilevel involvement. Although osteoporosis makes fixation of spine implants a significant concern, the literature has reported that most patients with AS treated surgically had good outcomes. Numerous studies have reported risks associated with conservative management. PMID- 28816878 TI - Do Formal Laminectomy and Timing of Decompression for Patients With Sacral Fracture and Neurologic Deficit Affect Outcome? AB - OBJECTIVES: To identify whether formal sacral decompression provides improvement in outcome for patients with neurologic deficit after sacral fracture compared with patients treated with indirect decompression and whether the timing of surgical decompression influences neurologic outcome? DATA SOURCES: MEDLINE was searched via PubMed using combinations of the following search terms: "Sacral fracture," "Traumatic Sacral fracture," "Sacral fracture decompression," "Sacral fracture time to decompression," "Sacral Decompression." Only clinical studies on human subjects and in the English language were included. STUDY SELECTION: Studies that did not provide sufficient detail to confirm the nature of the sacral injury, treatment rendered, and neurologic outcome were excluded. Studies using subjects less than 18 years of age, cadavers, nonhuman subjects, or laboratory simulations were excluded. All other relevant studies were reviewed in detail. DATA EXTRACTION: All studies were assigned a level of evidence using the grading tool described by the Centre for Evidence-Based Medicine and all studies were analyzed for bias. Both cohorts in articles comparing 2 groups of patients treated differently were included in the appropriate group. Early decompression was defined as before 72 hours. DATA SYNTHESIS: The effect of decompression technique and timing of decompression surgery on partial and complete neurologic recovery was estimated using a generalized linear mixed model to implement a logistic regression with a study-level random effect. CONCLUSIONS: There was no benefit to early decompression within 72 hours and no difference between formal laminectomy and indirect decompression with respect to neurologic recovery. PMID- 28816879 TI - Atlas Fractures and Atlas Osteosynthesis: A Comprehensive Narrative Review. AB - Most atlas fractures are the result of compression forces. They are often combined with fractures of the axis and especially with the odontoid process. Multiple classification systems for atlas fractures have been described. For an adequate diagnosis, a computed tomography is mandatory. To distinguish between stable and unstable atlas injury, it is necessary to evaluate the integrity of the transverse atlantal ligament (TAL) by magnetic resonance imaging and to classify the TAL lesion. Studies comparing conservative and operative management of unstable atlas fractures are unfortunately not available in the literature; neither are studies comparing different operative treatment strategies. Hence all treatment recommendations are based on low level evidence. Most of atlas fractures are stable and will be successfully managed by immobilization in a soft/hard collar. Unstable atlas fractures may be treated conservatively by halo fixation, but nowadays more and more surgeons prefer surgery because of the potential discomfort and complications of halo-traction. Atlas fractures with a midsubstance ligamentous disruption of TAL or severe bony ligamentous avulsion can be treated by a C1/2 fusion. Unstable atlas fractures with moderate bony ligamentous avulsion may be treated by atlas osteosynthesis. Although the evidence for the different treatment strategies of atlas fractures is low, atlas osteosynthesis has the potential to change treatment philosophies. The reasons for this are described in this review. PMID- 28816880 TI - Management of Hangman's Fractures: A Systematic Review. AB - BACKGROUND: Traumatic spondylolisthesis of the axis, is a common cervical spine fracture; however, to date there is limited data available to guide the treatment of these injuries. The purpose of this review is to provide an evidence-based analysis of the literature and clinical outcomes associated with the surgical and nonsurgical management of hangman's fractures. METHODS: A systematic literature search was conducted using PubMed (MEDLINE) and Scopus (EMBASE, MEDLINE, COMPENDEX) for all articles describing the treatment of hangman's fractures in 2 or more patients. Risk of nonunion, mortality, complications, and treatment failure (defined as the need for surgery in the nonsurgically managed patients and the need for revision surgery for any reason in the surgically managed patients) was compared for operative and nonoperative treatment methods using a generalized linear mixed model and odds ratio analysis. RESULTS: Overall, 25 studies met the inclusion criteria and were included in our quantitative analysis. Bony union was the principal outcome measure used to assess successful treatment. All studies included documented fracture union and were included in statistical analyses. The overall union rate for 131 fractures treated nonsurgically was 94.14% [95% confidence interval (CI), 76.15-98.78]. The overall union rate for 417 fractures treated surgically was 99.35% (95% CI, 96.81-99.87). Chance of nonunion was lower in those patients treated surgically (odds ratio, 0.12; 95% CI, 0.02-0.71). There was not a significant difference in mortality between patients treated surgically (0.16%; 95% CI, 0.01%-2.89%) and nonsurgically (1.04%; 95% CI, 0.08%-11.4%) (odds ratio, 0.15; 95% CI, 0.01-2.11). Treatment failure was less likely in the surgical treatment group (0.12%; 95% CI, 0.01%-2.45%) than the nonsurgical treatment group (0.71%; 95% CI, 0.28%-15.75%) (odds ratio 0.07; 95% CI, 0.01-0.56). CONCLUSION: Hangman's fractures are common injuries, and surgical treatment leads to an increase in the rate of osteosynthesis/fusion without significantly increasing the rate of complication. Both an anterior and a posterior approach result in a high rate of fusion, and neither approach seems to be superior. PMID- 28816881 TI - The Shikani Optical Stylet as an Alternative to Awake Fiberoptic Intubation in Patients at Risk of Secondary Cervical Spine Injury: A Randomized Controlled Trial. AB - BACKGROUND: Conventional intubation of the trachea and consequent prone positioning of anesthetized patients with cervical spine instability may result in secondary neurological injury. Historically, flexible fiberoptics used to be the chief choice for patients presenting with cervical spine instability surgery with difficult airway. Recently, the rigid optical stylets have shown promise in assisting difficult intubations. PURPOSE: The aim of the present study was to compare the efficacy of Shikani optical stylet (SOS) with the flexible fiberscope for awake intubation in patients with cervical spine instability. PATIENTS AND METHODS: In total, 60 adult patients diagnosed with cervical instability or at risk of secondary cervical injury, who were planned for awake intubation and/or self-positioning prone, were registered in this study and were randomly categorized into 2 equal groups (30 patients each), a fiberoptic group and an SOS group, followed by assessment of coughing and gagging during intubation, time to successful intubation, number of attempts for successful intubation, and hemodynamic parameters. RESULTS: As regards time to successful intubation, statistically significant differences were detected between the 2 studied groups, with the fiberoptic group having significantly longer intubation time than the Shikani group, whereas no statistically significant differences were recorded between the 2 groups with regard to the first-attempt success, the mean heart rate value, the mean arterial blood pressure, coughing, and occurrence of complications. CONCLUSION: This study validates the efficacy of both SOS and flexible fiberoptic bronchoscope for awake oral intubation in patients with cervical spine instability. SOS has been found to be more effective in reducing time to intubation. PMID- 28816882 TI - A Narrative Review of Adherence to Subarachnoid Hemorrhage Guidelines. AB - Over the past 2 decades, a large number of guidelines for aneurysmal subarachnoid hemorrhage (aSAH) management have been proposed. The primary aim of these "evidence-based" guidelines is to improve the care of aSAH patients by summarizing and making current knowledge readily available to clinicians. However, an investigation into aSAH guidelines, their changes along time and their successful translation into clinical practice is still lacking.We performed a literature search of historical events and subarachnoid hemorrhage guidelines using the Entrez PubMed NIH, Embase, and Cochrane databases for articles published up to November of 2016. Data were summarized for guidelines on aSAH management and cross-sectional studies of their application. A total of 11 guidelines and 10 cross-sectional studies on aSAH management were analyzed. The use of nimodipine for the treatment of SAH is the only recommendation that remained consistent across guidelines over time (r=0.82; P<0.05). A shift in the definitive treatment for aneurysms from open surgical clipping to endovascular coiling was also noted (r=-0.91; r=0.96; P<0.005). In addition, definitive treatment for aneurysm is being performed earlier. The use of triple-H therapy and the long-term administration of anticonvulsive therapy has decreased. Finally, written protocols for aSAH management were not consistently used across tertiary care institutions (r=-0.46; P=0.43; confidence interval, -0.95 to 0.70).We conclude that guidelines related to the management of patients with SAH have evolved from a consensus-based approach into an evidence-based approach. Nevertheless, the translation into clinical practice is limited, suggesting that personalized approaches to care is inherent, and perhaps necessary for aSAH management. PMID- 28816883 TI - Cerebral Oxygen Saturation During Electroconvulsive Therapy: A Secondary Analysis of a Randomized Crossover Trial. AB - BACKGROUND: Electroconvulsive therapy (ECT) causes acute changes in cerebral perfusion and oxygenation. Near-infrared spectroscopy is a novel, noninvasive technique to assess cerebral oxygen saturation (cSO2). We hypothesized that cSO2 increases during ECT and more so with atropine premedication and decreases when systemic desaturation (peripheral oxygen saturation <90%) occurs during ECT. METHODS: We performed a secondary analysis of a randomized trial of patients undergoing ECT for psychiatric illness during a 6-month period. During the second ECT session, patients were randomly assigned to receive either 0.01 mg/kg IV atropine or no atropine. During the third ECT session, patients were crossed over. Standard anesthetic management was performed. Data with regard to heart rate, blood pressure, peripheral oxygen saturation, and cSO2 were collected at baseline and continuously examined for 5 minutes from delivery of ECT stimulus. RESULTS: Forty-one patients underwent 82 ECT sessions. ECT resulted in significant increase in cSO2 during both the atropine and the no-atropine sessions (P<0.001 for both) but no between-session difference was observed (mean difference, 1.9+/-2.0; 95% confidence interval, -2.0, 5.9; P=0.337). The cSO2 values were lower in patients who developed systemic desaturation when compared with the cSO2 values in those who did not (mean difference, 5.0+/-2.6; 95% confidence interval -0.1, 10.2; P=0.054). However, the mean cSO2 was >60% at any measured time point, even in those with systemic desaturation. CONCLUSIONS: ECT increased cSO2 irrespective of atropine premedication. cSO2 was lower when systemic desaturation occurred. Future studies should explore the effect of cerebral oxygenation changes during ECT on outcome of psychiatric conditions. PMID- 28816884 TI - Paraplegia in Subarachnoid Hemorrhage Complicated With Coarctation of Aorta: An Unusual Complication. PMID- 28816885 TI - Adding ketamine to an opioid in a patient-controlled analgesia device: is it really relevant in the pediatric population? PMID- 28816886 TI - Reply. PMID- 28816887 TI - Statin-related musculoskeletal pain in Parkinson's disease. PMID- 28816888 TI - Reply. PMID- 28816890 TI - Improving Timeliness of beta-Agonist and Corticosteroid Administration in Patients With Acute Wheezing. AB - OBJECTIVE: Timely delivery of beta-agonists and steroids to patients with acute recurrent wheezing is a key component of the National Heart, Lung, and Blood Institute recommended emergency department (ED) asthma care. We conducted an ED improvement initiative to standardize asthma care and improve time to treatments. METHODS: Our multidisciplinary team identified key contributing factors to timeliness, developed key driver diagrams, implemented and refined a management pathway, designed and executed rapid cycle improvements, and implemented interventions. A time series design was used to analyze outcomes with baseline data and continuous monitoring during active intervention steps. The primary outcomes analyzed were the times to first beta-agonist and steroid administration. Secondary outcomes included admission rate, ED length of stay, and ED revisits. RESULTS: Assignment of the Pediatric Asthma Score, our initial pathway step, occurred in most patients within the first several months. Time to first beta-agonist administration decreased from the baseline mean of 76 minutes to 27 minutes. Time to steroid administration decreased from the baseline mean of 108 minutes to 49 minutes. Mean monthly admission rate remained at 22% with no special cause variation identified. The ED revisit rate was not negatively impacted and, in most months, was 0%. CONCLUSIONS: By standardizing asthma care in our ED and redesigning care delivery processes, care variation decreased and significant improvements in timeliness of beta-agonist and steroid administration occurred. PMID- 28816891 TI - Computed Tomography Use Plateaus Among Children With Emergency Visits for Abdominal Pain. AB - OBJECTIVES: Abdominal pain is a common pediatric complaint to emergency departments (EDs), and clinicians often rely on imaging for diagnosis. Studies have demonstrated an increase in computed tomography (CT) in this population. Following emphasis on radiation reduction by researchers and organizations, this study evaluates recent national trends in CT use among pediatric patients presenting to EDs with abdominal pain. METHODS: This is a cross-sectional analysis of ED patients 18 years or younger with chief complaint of abdominal pain in the National Hospital Ambulatory Medical Care Survey from 2008 to 2011. Outcomes include annual proportions of visits with x-ray, ultrasound, or CT, as well as diagnosis of appendicitis and hospital admission. RESULTS: Of 32,304 ED visits, 2120 (6.6%) were for abdominal pain. Proportions of visits using CT, ultrasound, and plain x-ray were 16.0%, 10.5%, and 23.4%, respectively. For all outcome measures, including imaging, hospital admission, and diagnosis of appendicitis, there was no change from 2008 to 2011. Considering previous data, there was a significant rise in ultrasound use from 5.4% (95% confidence interval, 2.4%-8.4%) in 1998 to 12.1% (95% confidence interval, 9.4%-13.7%) in 2011. Multivariate analysis of CT use found the strongest predictor to be increasing age. Females, black children, and those with Medicaid insurance had lower odds of having a CT. CONCLUSIONS: In contrast to the earlier dramatic increase in CT use for pediatric patients with abdominal pain, CT remained constant between 2008 and 2011. There was no associated change in the rate of diagnosis of appendicitis or hospitalization; however, ultrasound is increasing. PMID- 28816892 TI - Use of a Tourniquet in Total Knee Arthroplasty Causes a Paradoxical Increase in Total Blood Loss. AB - BACKGROUND: A tourniquet in total knee arthroplasty has been used in an attempt to decrease perioperative blood loss; however, questions exist regarding safety and efficacy. Tranexamic acid has also been used to decrease blood loss by stabilizing clot formation. Because of these concerns, routine tourniquet use for total knee arthroplasty was discontinued by the senior author and routine tranexamic acid administration was commenced. The purpose of this study was to examine total perioperative blood loss with tourniquet use, with tourniquet use and routine use of tranexamic acid, and with tranexamic acid use alone without tourniquet. METHODS: A retrospective cohort study of 132 patients in 3 groups was performed. The first group underwent total knee arthroplasty with limited tourniquet use only during cementing, the second group had the same protocol but with tranexamic acid administered, and the third group had tranexamic acid but no tourniquet used. Perioperative blood loss was calculated using the Gross formula. RESULTS: The mean calculated blood loss was highest in the tourniquet-only group at 1,591.39 mL (95% confidence interval [CI], 1,064.97 to 2,117.81 mL), decreased in the second group using tranexamic acid and tourniquet at 1,215.34 mL (95% CI, 1,104.93 to 1,325.75 mL), and was lowest in the third group with tranexamic acid and no tourniquet at 1,007.22 mL (95% CI, 878.78 to 1,135.66 mL). CONCLUSIONS: Use of a limited tourniquet protocol during total knee arthroplasty resulted in a paradoxical increase in blood loss. Surgeons should consider omitting routine tourniquet use in total knee arthroplasty. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28816893 TI - Periarticular Liposomal Bupivacaine Injection Versus Intra-Articular Bupivacaine Infusion Catheter for Analgesia After Total Knee Arthroplasty: A Double-Blinded, Randomized Controlled Trial. AB - BACKGROUND: Intra-articular bupivacaine hydrochloride (HCl) infusion catheters and periarticular injections of liposomal bupivacaine are often used as postoperative local anesthetics. The purpose of this study was to compare the efficacies of these local anesthetics following total knee arthroplasty. METHODS: This study was a superiority trial with a randomized, controlled, double-blinded design. Patients were randomly assigned to either delivery of bupivacaine HCl by the ON-Q* Pain Relief System pump (n = 96) or by an injection of Exparel (liposomal bupivacaine) (n = 104). The primary outcome of this study was cumulative narcotic consumption on postoperative days 0 through 3. Narcotic consumption data were collected retrospectively from in-hospital records while patients were in the hospital. Following discharge, narcotic consumption data were gathered from patient surveys, as were secondary outcomes measures. RESULTS: We did not identify greater narcotic use in the ON-Q* group compared with the Exparel group (p = 0.641). The mean difference between the groups was 0.5 morphine equivalent (95% confidence interval [CI] = -1.7 to +2.8), with the ON-Q* group consuming an average 10.4 morphine equivalents (95% CI = 8.7 to 12.0) compared with 10.9 (95% CI = 9.3 to 12.5) in the Exparel group. There were no significant differences between groups with regard to any of the secondary measures of pain with the exception of pain while walking and pain with physical therapy (p = 0.019 and p = 0.010, respectively), both of which showed an approximately 1-point difference in favor of the ON-Q* group on a visual analog scale (VAS). There were also no differences in the postoperative side effects, including nausea, constipation, or vomiting, or in the rates of study-related complications, patient satisfaction, or length of hospital stay. CONCLUSIONS: Exparel did not have superior efficacy compared with the ON-Q* Pain Relief System as reflected by narcotic consumption, our primary outcome. There were small significant differences, in favor of the ON-Q* group, in 2 secondary measures of pain during activity, but these approximately 1-point VAS differences are unlikely to be clinically relevant. The choice of a local anesthetic modality should be based on a combination of safety, convenience, and cost considerations. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 28816894 TI - The Clavicle Trial: A Multicenter Randomized Controlled Trial Comparing Operative with Nonoperative Treatment of Displaced Midshaft Clavicle Fractures. AB - BACKGROUND: The treatment of displaced midshaft clavicle fractures remains controversial. METHODS: We undertook a multicenter randomized controlled trial to compare effectiveness and safety between nonoperative management and ORIF (open reduction and internal fixation) for displaced midshaft clavicle fractures in adults. Three hundred and one eligible adult patients were randomized to 1 of the 2 treatment groups and followed at 6 weeks, 3 months, and 9 months after recruitment. The primary outcome was the rate of radiographically evident nonunion at 3 months following treatment. Secondary outcomes were the rate of radiographically evident nonunion at 9 months, limb function measured using the Constant-Murley Score and DASH (Disabilities of the Arm, Shoulder and Hand) score, and patient satisfaction. RESULTS: There was no difference in the proportion of patients with radiographic evidence of nonunion at 3 months between the operative (28%) and nonoperative (27%) groups, whereas at 9 months the proportion with nonunion was significantly lower (p < 0.001) in the operative group (0.8%) than in the nonoperative group (11%). The DASH and Constant-Murley scores and patient satisfaction were all significantly better in the operative group than in the nonoperative group at 6 weeks and 3 months. CONCLUSIONS: Although at 3 months there was no evidence that surgery had reduced the rate of nonunion of displaced midshaft clavicle fractures, at 9 months nonoperative treatment had led to a significantly higher nonunion rate (11% compared with <1%). The rate of secondary surgical intervention during the trial period was 12 (11%) of the 147 patients in the nonoperative group. ORIF is a safe and reliable intervention with superior early functional outcomes and should be considered for patients who sustain this common injury. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 28816895 TI - Ten-Year Multicenter Clinical and MRI Evaluation of Isolated Supraspinatus Repairs. AB - BACKGROUND: Early repair of isolated supraspinatus tears could prevent further deterioration of the rotator cuff; however, there is no consensus on the management of such tears because of a lack of long-term outcome studies. The purposes of this study were to report the 10-year outcomes of isolated supraspinatus repairs and to investigate the factors that favor healing and recovery. METHODS: We retrieved the records of all 511 patients who, in 2003, underwent repair of full-thickness isolated supraspinatus tears, performed by 15 surgeons at 15 centers. In 2014, the patients were asked to return for evaluation at a minimum follow-up of 10 years. One hundred and eighty-eight patients could not be reached, and 35 were excluded because they had a reoperation (17 had a retear, 7 had conversion to an arthroplasty, and 11 had other causes). A total of 288 patients (50% were men) who had a mean age (and standard deviation) at index surgery of 56.5 +/- 8.3 years (range, 32 to 77 years) were evaluated clinically, and 210 of them were also evaluated using magnetic resonance imaging (MRI). RESULTS: Thirty shoulders (10.4%) had complications, including stiffness (20 shoulders), infection (1 shoulder), and other complications (9 shoulders). The total Constant score improved from a mean of 51.8 +/- 13.6 points (range, 19 to 87 points) preoperatively to 77.7 +/- 12.1 points (range, 37 to 100 points) at 10 years. At the 10-year follow-up evaluation, the mean Subjective Shoulder Value (SSV) was 84.9 +/- 14.8 (range, 20 to 100), and the mean Simple Shoulder Test (SST) was 10.1 +/- 2.2 (range, 3 to 12). Of the 210 shoulders evaluated using MRI, the repair integrity was Sugaya type I in 26 shoulders (12%), type II in 85 (41%), type III in 59 (28%), type IV in 27 (13%), and type V in 13 (6%). The total Constant score at the final follow-up was significantly associated with tendon healing (p < 0.005) and was inversely associated with preoperative fatty infiltration (p < 0.001). Neither the surgical approach nor the preoperative retraction influenced the outcomes. CONCLUSIONS: Repairs of isolated supraspinatus tears maintained considerable improvement in clinical and radiographic outcomes at 10 years. Preoperative fatty infiltration and postoperative retear have a significantly detrimental effect on the long-term functional outcome of rotator cuff repair. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28816896 TI - Factors Associated with Adverse Events in Inpatient Elective Spine, Knee, and Hip Orthopaedic Surgery. AB - BACKGROUND: Orthopaedic procedures for degenerative musculoskeletal conditions (predominantly osteoarthritis and spinal stenosis) represent an increasing burden on the health-care system. These procedures are also associated with adverse event rates and related cost. The objective of this study was to identify risk factors for adverse events associated with orthopaedic surgeries as captured within a common clinical point-of-care system for documenting adverse events (Orthopaedic Surgical AdVerse Events Severity [OrthoSAVES] system). METHODS: In hospital adverse events were recorded at the point of care over a 2-year period for inpatient elective knee, hip, and spine orthopaedic procedures for degenerative musculoskeletal conditions. Multivariable logistic regression was employed to investigate the association between various factors (age, sex, surgical site, body mass index, surgical risk classification, operative duration, length of stay, and medical comorbidities) and the occurrence of adverse events. RESULTS: The sample included 2,146 patients. The overall adverse event rate was 27% (571 of 2,146), and by surgical site, the rates were 29% (130 of 442) for spine; 27% (266 of 998) for knee; and 25% (175 of 706) for hip. The most common adverse events had a low severity grade, but spinal procedures demonstrated more adverse events with a severity grade of >=3. Increasing age (odds ratio [OR] = 1.21, 95% confidence interval [CI] =1.05 to 1.41, per 15-year interval), male sex (OR = 1.43, 95% CI =1.16 to 1.77), increasing operative duration (OR = 1.13, 95% CI = 1.03 to 1.23, per 30-minute increase), length of stay (OR = 1.13, 95% CI = 1.10 to 1.17, per day), and undergoing revision surgery (OR = 2.23, 95% CI = 1.35 to 3.70) were independently associated with a greater likelihood of the occurrence of an adverse event. Spine surgery demonstrated decreased odds of an adverse event compared with knee surgery (OR = 0.38, 95% CI = 0.23 to 0.61) when operative duration and length of stay were taken into account. CONCLUSIONS: On the basis of our adjusted analysis, we found increasing age, male sex, revision surgery, length of stay, and increasing operative duration to be common independent risk factors for an adverse event across the population studied. The first 3 risk factors are not modifiable. The association between increasing operative duration and the risk of an adverse event across all anatomical regions and surgical procedures is a unique finding. However, modification of procedural efficiency is multifactorial and warrants further investigation. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28816897 TI - Surgical Correction of Cam Deformity in Association with Femoroacetabular Impingement and Its Impact on the Degenerative Process within the Hip Joint. AB - BACKGROUND: Cam morphology in association with femoroacetabular impingement (FAI) is a recognized cause of hip pain and cartilage damage and proposed as a leading cause of arthritis. The purpose of this study was to analyze the functional and biomechanical effects of the surgical correction of the cam deformity on the degenerative process associated with FAI. METHODS: Ten male patients with a mean age of 34.3 years (range, 23.1 to 46.5 years) and a mean body mass index (and standard deviation) of 26.66 +/- 4.79 kg/m underwent corrective surgery for cam deformity in association with FAI. Each patient underwent a computed tomography (CT) scan to assess acetabular bone mineral density (BMD), high-resolution T1rho magnetic resonance imaging (MRI) of the hips to assess proteoglycan content, and squatting motion analysis as well as completed self-administered functional questionnaires (Hip disability and Osteoarthritis Outcome Score [HOOS]) both preoperatively and 2 years postoperatively. RESULTS: At a mean follow-up of 24.5 months, improvements in functional scores and squat performance were seen. Regarding the zone of impingement in the anterosuperior quadrant of the acetabular rim, the mean change in BMD at the time of follow-up was -31.8 mg/cc (95% confidence interval [CI], -11 to -53 mg/cc) (p = 0.008), representing a 5% decrease in BMD. The anterosuperior quadrant also demonstrated a significant decrease in T1rho values, reflecting a stabilization of the cartilage degeneration. Significant correlations were noted between changes in clinical functional scores and changes in T1rho values (r = -0.86; p = 0.003) as well as between the BMD and maximum vertical force (r = 0.878; p = 0.021). CONCLUSIONS: Surgical correction of a cam deformity in patients with symptomatic FAI not only improved clinical function but was also associated with decreases in T1rho values and BMD. These findings are the first, to our knowledge, to show that alteration of the hip biomechanics through surgical intervention improves the overall health of the hip joint. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28816898 TI - Timing of Postoperative Mechanical Loading Affects Healing Following Anterior Cruciate Ligament Reconstruction: Analysis in a Murine Model. AB - BACKGROUND: Following anterior cruciate ligament (ACL) reconstruction, the mechanical loading of the tissues has a significant impact on tendon-to-bone healing. The purpose of this study was to determine the effect of the timing of the initiation of mechanical loading on healing of a tendon graft in a bone tunnel. METHODS: ACL reconstruction using a flexor tendon autograft was performed in 56 mice randomized to 4 groups with differing times to initiation of postoperative mechanical loading: (1) immediate, (2) 5 days, (3) 10 days, or (4) 21 days following surgery. An external fixator was placed across the knee at the time of surgery and removed when mechanical loading was scheduled to commence. Following removal of the external fixator, animals were permitted free, unrestricted cage activity. All mice were killed on postoperative day 28, and tendon-to-bone healing was assessed by biomechanical testing, microcomputed tomography (micro-CT), and histological analysis. RESULTS: The mean failure force (and standard deviation) of the reconstructed ACL at the time of sacrifice was highest for Group 2 (3.29 +/- 0.68 N) compared with Groups 1, 3, and 4 (p = 0.008). Micro-CT bone volume fraction was greatest for Group 2 in the femoral tunnel (p = 0.001), tibial tunnel (p = 0.063), and both bones (p < 0.001). Similarly, histological analysis demonstrated a narrower scar tissue interface and increased direct contact at the tendon-bone interface (p = 0.012) for Group 2. CONCLUSIONS: Following ACL reconstruction, a defined period of immobilization without weight-bearing appears to improve biomechanical strength of the healing tendon-bone interface, while prolonged periods without mechanical load and motion decrease the ultimate load to failure in this murine model. CLINICAL RELEVANCE: The ideal period of restricted weight-bearing and motion following ACL reconstruction remains undefined. In a murine model, improved healing was noted for animals immobilized for a brief period of 5 days. This work may serve as an initial step in determining the ideal time period in a clinical population. PMID- 28816899 TI - In Patients Having Hip or Knee Arthroplasty, Intravenous and Oral Acetaminophen Did Not Differ for 24-Hour Pain or Narcotic Use. PMID- 28816900 TI - Immediate and Delayed Passive Range of Motion After Total Shoulder Arthroplasty Did Not Differ for Function or Range of Motion at 1 Year. PMID- 28816901 TI - In Patients with a Tibial Fracture, Low-Intensity Pulsed Ultrasound After Intramedullary Nail Fixation Did Not Accelerate Radiographic Healing or Improve Functional Recovery. PMID- 28816902 TI - Ankle Arthroscopy: An Update. PMID- 28816903 TI - What's New in Limb Lengthening and Deformity Correction. PMID- 28816904 TI - The Relationship Between OREF Grants and Future NIH Funding Success. AB - BACKGROUND: The Orthopaedic Research and Education Foundation (OREF) is the leading specialty-specific nongovernmental organization providing orthopaedic funding in the United States. As extramural research funding has become increasingly difficult to acquire, one mission of the OREF is to support investigators to generate data needed to secure larger extramural funding from agencies such as the National Institutes of Health (NIH). The objectives of this study were to evaluate the rate of translating OREF faculty-level grants into subsequent NIH funding and to determine if there are identifiable factors that increase the rate of converting an OREF grant into NIH funding. METHODS: This is a retrospective review of OREF grants awarded to full-time faculty orthopaedic surgeons between 1994 and 2014. Grants were analyzed on the basis of award type and were categorized as basic science, clinical, or epidemiological. Sex, individual scholarly productivity, and publication experience were evaluated. All awardees were assessed for subsequent NIH funding using the NIH RePORTER web site. RESULTS: One hundred and twenty-six faculty-level OREF grants were awarded to 121 individuals. Twenty-seven OREF grant awardees (22%) received NIH funding at a mean of 6.3 years after OREF funding. Nineteen (46%) of 41 Career Development Grant winners later received NIH funding compared with 10 (12%) of 85 other award winners. OREF grants for basic science projects were awarded more often (58%) and were more than 4 times as likely to result in NIH funding than non-basic science projects (odds ratio, 4.70 [95% confidence interval, 1.66 to 13.33]; p = 0.0036). Faculty who later received NIH funding had higher scholarly productivity and publication experience (p < 0.05). CONCLUSIONS: The OREF grant awardee conversion rate of 22% and, particularly, the 46% for Career Development Grant winners compares favorably with the overall NIH funding success rate (18% in 2014). Faculty-level OREF grants appear to achieve their purpose of identifying and supporting researchers who aim to secure subsequent federal funding. CLINICAL RELEVANCE: The goal of this study is to examine how successful faculty who have obtained OREF grants have been in securing NIH funding later in their careers. Although subsequent accrual of NIH funding is not the only goal of OREF funding, it can be used as an important benchmark to assess the development of orthopaedic clinician-scientists. PMID- 28816905 TI - Workplace Violence and Active Shooter Considerations for Health-Care Workers: AOA Critical Issues. PMID- 28816906 TI - Comparison of Liposomal Bupivacaine with Bupivicaine Pain Pump in TKA Patients: Commentary on an article by Eric B. Smith, MD, et al.: "Periarticular Liposomal Bupivacaine Injection Versus Intra-Articular Bupivacaine Infusion Catheter for Analgesia After Total Knee Arthroplasty. A Double-Blinded, Randomized Controlled Trial". PMID- 28816907 TI - A Little Bit (of Immobilization) Goes a Long Way: Commentary on an article by Christopher L. Camp, MD, et al.: "Timing of Postoperative Mechanical Loading Affects Healing Following Anterior Cruciate Ligament Reconstruction. Analysis in a Murine Model". PMID- 28816908 TI - Use of emergency surgery score to predict the occurrence of complications after emergency surgery. PMID- 28816911 TI - Resilience in Adolescents with Cancer: Association of Coping with Positive and Negative Affect. AB - OBJECTIVE: To examine the prospective association between adolescents' coping with cancer-related stress and observed positive and negative affect during a mother-adolescent interaction task involving discussion of cancer-related stressors. METHODS: Adolescents (age 10-15 years) self-reported about their coping and affect approximately 2 months after cancer diagnosis. Approximately 3 months later, adolescents and mothers were video recorded having a discussion about cancer, and adolescents were coded for expression of positive affect (positive mood) and negative affect (sadness and anxiety). RESULTS: Adolescents' use of secondary control coping (i.e., acceptance, cognitive reappraisal, and distraction) in response to cancer-related stress predicted higher levels of observed positive affect, but not negative affect, over time. CONCLUSION: Findings provide support for the importance of coping in the regulation of positive emotions. The potential role of coping in preventive interventions to enhance resilience in adolescents facing cancer-related stress is highlighted. PMID- 28816910 TI - Acceptability of Group Visits for Attention-Deficit Hyperactivity Disorder in Pediatric Clinics. AB - OBJECTIVE: Children with attention-deficit hyperactivity disorder (ADHD) have ongoing needs that impair home and school functioning. Group visit models are a promising way to deliver timely parenting support but family and provider acceptance has not previously been examined. The objective was to describe the acceptability of ADHD group visits in busy pediatric clinics based on caregivers, child participants and facilitators. METHODS: Data were analyzed from school-age children and caregivers who participated in one of two 12-month long randomized controlled studies of the ADHD group visit model from 2012 to 2013 or 2014 to 2015. Feedback was obtained using semi-structured questions at each study end, by telephone or at the last group visit. Sessions were audio-recorded, transcribed and themes were extracted by participant type. RESULTS: A total of 34 caregivers, 41 children and 9 facilitators offered feedback. Caregivers enjoyed the "support group" aspect and learning new things from others. Caregivers reported improved understanding of ADHD and positive changes in the relationship with their child. Children were able to recall specific skills learned including how skills helped at home or school. Facilitators acknowledged systems-level challenges to offering group visits but felt the group format helped increase understanding of families' needs, improved overall care, and provided innovative ways to engage with families. CONCLUSION: The majority of comments from families and facilitators highlighted a variety of benefits of the use of a group visit model for ADHD chronic care. Despite systems-level barriers to implementation, families and facilitators felt the benefits outweighed the challenges. PMID- 28816913 TI - Influence of Written Informed Consent for Methylphenidate on Medicine Persistence Rates in Children with Attention-Deficit Hyperactivity Disorder. AB - OBJECTIVE: To assess the influence of written informed consent on nonpersistence with methylphenidate treatment in children with attention-deficit hyperactivity disorder (ADHD). METHODS: We undertook a cohort study including 141 children with ADHD who started treatment with methylphenidate, with a follow-up of 6 months. The main outcome variable was nonpersistence, defined as discontinuation of treatment by the patient. Two groups were analyzed with and without written informed consent. Use of this consent was the decision of the prescribing physician because the law allows its use on a voluntary basis. The homogeneity of both groups was verified by evaluating sex, type of ADHD, methylphenidate dosage, age, severity, and other psychiatric disorders. To assess the influence of consent on nonpersistence, bootstrapping was used to determine relative risk reduction (RRR) and number needed to treat (NNT). RESULTS: Among the participants who completed follow-up, 67 provided written informed consent and 63 did not. We found the following nonpersistence frequencies in each group: (1) with written informed consent: 5 (7.5%) and (2) without written informed consent: 15 (23.8%). The clinically significant results were RRR, 0.67 +/- 0.17; NNT, 7 (5-9). CONCLUSION: The use of written informed consent yielded higher persistence rates. Further studies are needed to determine whether we can use this procedure routinely in clinical practice. PMID- 28816912 TI - Distance-Learning, ADHD Quality Improvement in Primary Care: A Cluster-Randomized Trial. AB - OBJECTIVE: To evaluate a distance-learning, quality improvement intervention to improve pediatric primary care provider use of attention-deficit/hyperactivity disorder (ADHD) rating scales. METHODS: Primary care practices were cluster randomized to a 3-part distance-learning, quality improvement intervention (web based education, collaborative consultation with ADHD experts, and performance feedback reports/calls), qualifying for Maintenance of Certification (MOC) Part IV credit, or wait-list control. We compared changes relative to a baseline period in rating scale use by study arm using logistic regression clustered by practice (primary analysis) and examined effect modification by level of clinician participation. An electronic health record-linked system for gathering ADHD rating scales from parents and teachers was implemented before the intervention period at all sites. Rating scale use was ascertained by manual chart review. RESULTS: One hundred five clinicians at 19 sites participated. Differences between arms were not significant. From the baseline to intervention period and after implementation of the electronic system, clinicians in both study arms were significantly more likely to administer and receive parent and teacher rating scales. Among intervention clinicians, those who participated in at least 1 feedback call or qualified for MOC credit were more likely to give parents rating scales with differences of 14.2 (95% confidence interval [CI], 0.6 27.7) and 18.8 (95% CI, 1.9-35.7) percentage points, respectively. CONCLUSION: A 3-part clinician-focused distance-learning, quality improvement intervention did not improve rating scale use. Complementary strategies that support workflows and more fully engage clinicians may be needed to bolster care. Electronic systems that gather rating scales may help achieve this goal. Index terms: ADHD, primary care, quality improvement, clinical decision support. PMID- 28816914 TI - Congenital Hypotonia in Toddlerhood. AB - CASE: David is a 22-month-old boy who is new to your practice. He recently moved from a rural area in the Midwest. His father is in the United States Air Force, and his mother works as a full-time homemaker. Their household includes 5 older siblings. The family moves every year because of the father's Air Force placement.David was born full-term in Virginia, with no reported pregnancy complications and no alcohol, tobacco, or drug exposure. He was delivered vaginally, with Apgar scores of 7 and 9, respectively and no respiratory issues. In the newborn nursery, his nurse noted that he was floppy, with generalized low muscle tone. Laboratory work performed included normal thyroid studies and a chromosomal microarray.Because of persistent hypotonia, he was seen by a pediatric neurologist at 9 months of age. A magnetic resonance imaging was performed and was normal, with no structural deficits noted. He was referred to Early Intervention at 6 months, when he was not yet rolling over. He received physical therapy for a few months before the family moved again for his father's next placement.David presents in your office as a sweet nondysmorphic toddler who maintains steady eye contact and smiles responsively. His height, head circumference, and weight are at the 50th percentile. His physical examination is notable for generalized hypotonia, with intact upper and lower deep tendon reflexes. He spontaneously says about 20 words. He turns his head when his name is called and can follow a simple command, such as "clap, clap." He reaches his whole hand toward desired objects and will look at his parents if they are out of reach. He can grasp a block, bang, and transfer objects. He demonstrates an immature pincer grasp. He can roll over and sit independently and is just beginning to pull to a stand. His parents report he has recently restarted Early Intervention, where he is receiving physical, speech, and occupational therapy. His audiology examination is normal.His parents' primary concern today is regarding feeding. David is a picky eater. He has difficulty with new foods and textures. The parents noticed a regression in his tolerance for new foods around the recent move. He eats baby puffs, stage 2 to 3 baby foods, and fruit and vegetable pouches. He does not like soft, sticky foods. He is also reported to have other sensory sensitivities. He does not tolerate loud noises and is bothered by tags in his clothing. You wonder, what further work-up would be helpful for David? How can his feeding issues be addressed? PMID- 28816915 TI - Physician Awareness of Developmental Screening and Referral in the State of Kuwait. AB - OBJECTIVE: In the State of Kuwait, family physicians and pediatricians are responsible for identifying and referring children at risk of disability. The aims of this study were to better understand physician (1) use of developmental screening instruments, (2) referral practices for children at risk of developmental disability, (3) interpretation of screening results, and (4) anticipatory guidance topics prioritized over child screening. METHODS: A nonprobability volunteer, self-selection sample of family physicians, general practitioners, and pediatricians (n = 398) completed a 60-item paper questionnaire. Items assessed included: (1) practitioner familiarity with, belief in, and use of screening instruments; (2) familiarity with early childhood intervention services; (3) perceived barriers to screening implementation; and (4) anticipatory topics prioritized over screening. Logistic regression was used to test a priori hypotheses. RESULTS: In general, family doctors and pediatricians practicing in public hospitals and primary health care centers in the State of Kuwait do not use or know how to use a developmental screening instrument, while over half prioritized immunization counseling over child screening. Screening confidence and training on using screening instruments increased the likelihood of tool use. Staff shortages, time constraints, and a perceived lack of Arabic screening instruments were barriers to tool use. CONCLUSION: Raising health care providers' awareness of standardized developmental screening instruments and establishment of an early identification system in the State of Kuwait are needed. Standardization and adaptation of technically sound Arabic-language screening tools for use in the State of Kuwait and physician training programs on screening are recommended. PMID- 28816916 TI - Developmental Screening in Pediatric Sickle Cell Disease: Disease-Related Risk and Screening Outcomes in 4 Year Olds. AB - OBJECTIVE: Studies of early child development in sickle cell disease (SCD) have found modest associations between disease-related risks and developmental status in infants and toddlers, but such associations are evident by early elementary school. We screened 4-year-old children with SCD using 2 screening strategies to assess if biomedical risk factors for neurologic disease are related to developmental screening outcomes at this intermediate age. METHODS: Seventy-seven 4-year-old children with SCD (M = 4.5 yrs, SD = 0.3 yrs) completed developmental screenings at routine hematology visits using child testing (Fluharty Preschool Speech and Language Screenings Test, 2nd edition) and parent-report (Ages and Stages Questionnaire, 2nd edition) procedures. Genotype and other biomedical variables were coded from medical records. RESULTS: Children with higher-risk SCD genotypes (n = 52) showed lower performance than children with lower-risk genotypes (n = 25) on a measure related to neurologic disease risk in older children (syntactic processing); genotype risk was also related to rates of positive screenings on parent-reported developmental milestones (52% positive screenings in high-risk genotypes vs 12% in low-risk genotypes). Screening outcomes were also related to transcranial Doppler ultrasound findings assessing cerebral blood flow. CONCLUSION: Developmental screening at age 4 may be a useful target age for identifying preschoolers with sickle cell-related neurodevelopmental concerns. Parent report of developmental milestones and behavioral testing each may have a role in screening for children in need of follow-up services to address potential neurodevelopmental effects from SCD. PMID- 28816917 TI - Factors Associated with Developmental Behavioral Pediatricians Prescribing Psychotropic Medication to Children with Autism Spectrum Disorder: A Study of Three DBPNet Sites. AB - OBJECTIVE: Psychotropic medications are frequently prescribed to children with autism spectrum disorder (ASD), but little is known about the prescribing practices of developmental-behavioral pediatricians (DBPs). Our objective was to determine whether clinical site, age, insurance, or comorbidities influenced DBPs prescribing psychotropic medication for children with ASD. METHODS: A retrospective analysis was performed using electronic health record data of all patients with ASD seen at 3 academic developmental-behavioral pediatrics (DBP) clinical programs from January 2010 to December 2011. Data included age, diagnoses, primary insurance, and medications prescribed. Factors associated with prescribing psychotropic medication were examined using generalized estimating equations. RESULTS: Sites varied in the frequency with which they prescribed psychotropic medication for children with ASD (site 1: 33.1%, site 2: 49.3%, site 3: 4.0%; p < .001). We found that the following factors predicted prescribing of psychotropic medications: comorbidities (odds ratio [OR]: 2.87; 95% confidence interval [CI], 2.58-3.18), age, and primary insurance. However, the impact of insurance depended on age. For 3- to 5-year-old children, those on Medicaid were more likely to be prescribed psychotropic medications than those with private insurance (OR: 1.65; 95% CI, 1.29-2.12). This was particularly true for alpha-2 adrenergic agonists (OR: 2.48; 95% CI, 1.56-3.92) and atypical antipsychotics (OR: 2.57; 95% CI, 1.46-4.55). CONCLUSION: There are large variations in prescribing psychotropic medication to children with ASD at 3 academic DBP programs. Further research is needed to understand factors that contribute to higher use of psychotropic medication in young children with Medicaid. PMID- 28816918 TI - The Impact of Negative Life Events on Attempted Suicide in Rural China. AB - This study aims to explore the impact of negative life events (NLEs) on attempted suicide in a Chinese cultural setting. The sample comprised 791 suicide attempters and an equal number of controls matched on age, sex, and location from selected rural counties in China. Conditional logistic regression model was used to examine the association between NLEs and suicide risk. The impact of NLEs on attempted suicide was further examined using regression-based method to explore its mediation effect. The types of NLEs that were most likely to precede a suicide attempt in rural sample included the events in marriage/love, family/home, and friend/relationship. Rural women were more likely to experience more interpersonal conflicts than rural men. Approximately 75.6% of suicide attempters had experienced at least one NLE, and NLEs were strongly associated with attempted suicide. Total effect (0.676), direct effect (0.501), and the total indirect effect (0.301) of NLEs on suicide attempts were significantly mediated by hopelessness and depression. NLEs play a crucial role in predicting suicidal attempt in rural China, and they are mediated by depression and hopelessness. PMID- 28816919 TI - Enteral Nutrition Practices in Critically Ill Children Requiring Noninvasive Positive Pressure Ventilation. AB - OBJECTIVES: Evaluate the practice of providing enteral nutrition in critically ill children requiring noninvasive positive pressure ventilation. DESIGN: Retrospective cohort study. SETTING: PICU within a quaternary care children's hospital. PATIENTS: PICU patients older than 30 days requiring noninvasive positive pressure ventilation for greater than or equal to 24 hours from August 2014 to June 2015. Invasive mechanical ventilation prior to noninvasive positive pressure ventilation and inability to receive enteral nutrition at baseline were additional exclusionary criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was enteral nutrition initiation within 24 hours of admission. Secondary outcomes included time to goal enteral nutrition rate, adequacy of nutrition, adverse events (pneumonia not present at admission, intubation after enteral nutrition initiation, feeding tube misplacement), and lengths of noninvasive positive pressure ventilation and PICU stay. Among those included (n = 562), the median age was 2 years (interquartile range, 39 d to 6.8 yr), 54% had at least one chronic condition, and 43% had malnutrition at baseline. The most common primary diagnosis was bronchiolitis/viral pneumonia. The median length of time on noninvasive positive pressure ventilation was 2 days (interquartile range, 2.0-4.0). Most (83%) required continuous positive airway pressure or bi-level support during their PICU course. Sixty-four percent started enteral nutrition within 24 hours, with 72% achieving goal enteral nutrition rate within 72 hours. Forty-nine percent and 44% received an adequate cumulative calorie and protein intake, respectively, during their PICU admission. Oral feeding was the most common delivery method. On multivariable analysis, use of bi level noninvasive positive pressure ventilation (odds ratio, 0.40; 95% CI, 0.25 0.63) and continuous dexmedetomidine (odds ratio, 0.59; 95% CI, 0.35-0.97) were independently associated with decreased likelihood of early enteral nutrition. Twelve percent of patients had at least one adverse event. CONCLUSIONS: A majority of patients requiring noninvasive positive pressure ventilation received enteral nutrition within 24 hours. However, less than half achieved caloric and protein goals during their PICU admission. Further investigation is warranted to determine the safety and effectiveness of early enteral nutrition in this population. PMID- 28816920 TI - Similar Metabolic, Innate Immunity, and Adipokine Profiles in Adult and Pediatric Sepsis Versus Systemic Inflammatory Response Syndrome-A Pilot Study. AB - OBJECTIVES: To examine whether the septic profiles of heat shock protein 72, heat shock protein 90alpha, resistin, adiponectin, oxygen consumption, CO2 production, energy expenditure, and metabolic pattern, along with illness severity, nutritional, and inflammatory indices, differ between adult and pediatric patients compared with systemic inflammatory response syndrome and healthy controls. To evaluate whether these biomolecules may discriminate sepsis from systemic inflammatory response syndrome in adult and pediatric patients. DESIGN: Prospective cohort study. SETTING: University ICU and PICU. PATIENTS: Seventy eight adults (sepsis/23; systemic inflammatory response syndrome/23; healthy controls/33), 67 children (sepsis/18; systemic inflammatory response syndrome/23; controls/27), mechanically ventilated. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Flow cytometry determined mean fluorescence intensity for monocyte or neutrophil heat shock protein expression. Resistin, adiponectin, and extracellular heat shock proteins were measured using enzyme-linked immunosorbent assay; energy expenditure by E-COVX (GE Healthcare). Genomic DNA was extracted with PureLink Genomic DNA kit (Invitrogen, Carlsbad, CA) to detect heat shock protein 72 single nucleotide polymorphisms. Similarly, in adult and pediatric patients, Acute Physiology and Chronic Evaluation-II/Acute Physiology and Pediatric Risk of Mortality-III, Simplified Acute Physiology Score-III, C reactive protein, lactate, and resistin were higher and myocardial contractility, monocyte heat shock protein 72, oxygen consumption, CO2 production, energy expenditure, metabolic pattern, glucose, and albumin lower in sepsis compared with systemic inflammatory response syndrome or controls (p < 0.05). For discriminating sepsis from systemic inflammatory response syndrome, resistin, extracellular heat shock protein 90alpha, and lactate achieved a receiver operating characteristic curve greater than 0.80 in children and greater than 0.75 in adults (p < 0.05). In both, adults and children, genotype heat shock protein 72 analysis did not disclose any diagnosis or mortality group differences regarding either rs6457452 or rs1061581 haplotypes. CONCLUSIONS: Sepsis presents with similar profiles in adult and pediatric patients, characterized by enhanced inflammatory hormonal response and by repressed innate immunity, metabolism, and myocardial contractility. These features early distinguish sepsis from systemic inflammatory response syndrome across all age groups. PMID- 28816921 TI - Validity, Reliability, and Inertia of Four Different Temperature Capsule Systems. AB - PURPOSE: Telemetric temperature capsule systems are wireless, relatively noninvasive, and easily applicable in field conditions and have therefore great advantages for monitoring core body temperature. However, the accuracy and responsiveness of available capsule systems have not been compared previously. Therefore, the aim of this study was to examine the validity, reliability, and inertia characteristics of four ingestible temperature capsule systems (i.e., CorTemp, e-Celsius, myTemp, and VitalSense). METHODS: Ten temperature capsules were examined for each system in a temperature-controlled water bath during three trials. The water bath temperature gradually increased from 33 degrees C to 44 degrees C in trials 1 and 2 to assess the validity and reliability, and from 36 degrees C to 42 degrees C in trial 3 to assess the inertia characteristics of the temperature capsules. RESULTS: A systematic difference between capsule and water bath temperature was found for CorTemp (0.077 degrees C +/- 0.040 degrees C), e Celsius (-0.081 degrees C +/- 0.055 degrees C), myTemp (-0.003 degrees C +/- 0.006 degrees C), and VitalSense (-0.017 degrees C +/- 0.023 degrees C; P < 0.010), with the lowest bias for the myTemp system (P < 0.001). A systematic difference was found between trial 1 and trial 2 for CorTemp (0.017 degrees C +/- 0.083 degrees C; P = 0.030) and e-Celsius (-0.007 degrees C +/- 0.033 degrees C; P = 0.019), whereas temperature values of myTemp (0.001 degrees C +/- 0.008 degrees C) and VitalSense (0.002 degrees C +/- 0.014 degrees C) did not differ (P > 0.05). Comparable inertia characteristics were found for CorTemp (25 +/- 4 s), e-Celsius (21 +/- 13 s), and myTemp (19 +/- 2 s), whereas the VitalSense system responded more slowly (39 +/- 6 s) to changes in water bath temperature (P < 0.001). CONCLUSIONS: Although differences in temperature and inertia were observed between capsule systems, an excellent validity, test-retest reliability, and inertia was found for each system between 36 degrees C and 44 degrees C after removal of outliers. PMID- 28816922 TI - Nil Whey Protein Effect on Glycaemic Control after Intense Mixed-Mode Training in T2D. AB - : While intense endurance and resistance exercise training and whey protein supplementation have both been shown to independently improve glycaemic control, no known studies have examined the effect of high-intensity mixed-mode interval training (MMIT) and whey supplementation in adults with Type-2 diabetes (T2D). PURPOSE: To determine if peri-training whey protein supplementation combined with MMIT can improve glycaemic control. METHODS: In a double-blind randomised controlled trial, 24 men (55.7+/-5.6 y) with T2D performed MMIT with whey (20 grams) or placebo control for 10 weeks. Glycaemic control was assessed via glucose disposal rate (GDR) during a euglycaemic insulin clamp, fasting blood glucose concentration (FBG), and HOMA-IR. Changes in peak oxygen consumption (VO2peak), 1-repetition maximum strength (1RM), Vastus lateralis (VL) muscle and subcutaneous adipose thicknesses (SAT), and waist circumference (WC) were also assessed. RESULTS: 10-weeks of MMIT substantially improved GDR by 27.5% (90%CI 1.2%, 60.7%) and 24.8% (-5.4%, 64.8%) in the whey and control groups, respectively. There were likely and possible reductions in FBG by -17.4% (-30.6%, -1.6) and HOMA-IR by -14.1% (-25.3%, 1.08%) in the whey group, however, whey effects were not clearly beneficial to glycaemic outcomes, relative to control. MMIT also clearly substantially improved 1RM by 20.6% (16.3%, 24.9%) and 22.7% (18.4%, 27.2%), VO2peak by 22.6% (12.0%, 26.2%) and 18.5% (10.5%, 27.4%), VL muscle thickness by 18.9% (12.0%, 26.2%) and 18.6% (10.5%, 27.4%) and possibly reduced WC by -2.1% (-3.1%, -1.0%) and -1.9% (-3.7%, -0.1%) in the control and whey groups respectively, but the whey-control outcome was trivial or unclear. CONCLUSION: A clinically-meaningful enhancement in glycaemic control following 10 weeks of MMIT was not clearly advanced with peri-training whey protein supplementation in middle-aged men with Type-2 diabetes. PMID- 28816923 TI - Evaluation of Concurrent Oral and Long-Acting Injectable Antipsychotic Prescribing at the Minneapolis Veterans Affairs Health Care System. AB - BACKGROUND: Antipsychotic polypharmacy is defined as the concomitant prescribing of more than 1 antipsychotic medication for an individual patient. Despite clinical guideline recommendations, long-acting injectable antipsychotics (LAIAs) are often used together with oral antipsychotics (OAPs) to treat a variety of psychiatric illnesses. Little research exists to address this form of antipsychotic polypharmacy, and its role in therapy is poorly understood. The purpose of this evaluation was to determine the prevalence of this prescribing pattern at our facility, identify provider rationale for polypharmacy, and analyze trends. To our knowledge, this study is the first to describe the prevalence of and rationale for concomitant LAIA and OAP prescribing in the veteran population. METHODS: All patients receiving an LAIA at the time of study initiation were included. Long-acting injectable antipsychotics/oral antipsychotics polypharmacy was defined as the use of both agents outside the manufacturer's recommendations for titration and overlap. Statistical analysis was performed to further evaluate prescribing patterns by agent, dose, and indication. RESULTS: Long-acting injectable antipsychotics/oral antipsychotics polypharmacy occurred in 28% (22/79) of subjects. Of these, 50% (11/22) were prescribed the same antipsychotic in both dosage forms, of which 73% (8/11) were risperidone. Patients on LAIA/OAP polypharmacy were half as likely to be on a maximum dose LAIA compared with those on monotherapy (13% vs. 26%). CONCLUSIONS: Although LAIA/OAP polypharmacy occurred less frequently than reported in previous literature, this study highlights the need for further research to better understand this prescribing practice. PMID- 28816924 TI - Treatment of Premenstrual Breakthrough of Depression With Adjunctive Oral Contraceptive Pills Compared With Placebo. AB - PURPOSE/BACKGROUND: Two-thirds of women with depressive disorders report reemergence of depression premenstrually, or premenstrual exacerbation (PME), despite effective treatment of the underlying mood disorder during the remainder of the cycle. There is a paucity of studies that rigorously assess treatments targeting PME. Open-label data suggest that augmentation of antidepressants with the oral contraceptive pill (OCP) drospirenone and ethinyl estradiol (DRSP/EE) improves depressive symptoms that break through treatment premenstrually. We now report results of a randomized placebo-controlled OCP augmentation trial. METHODS: Women with unipolar depressive disorders in remission on stable antidepressant doses with a 30% increase in Montgomery-Asberg Depression Rating Scale (MADRS) scores from the follicular to luteal phase were randomized to double-blind augmentation of antidepressant with either DRSP/EE or placebo for 2 months. The MADRS and Daily Record of Severity of Problems (DRSP) measures were anchored to the menstrual cycle phase. FINDINGS/RESULTS: Of 32 women randomized, 25 (n = 12 DRSP/EE, n = 13 placebo) completed the trial. Premenstrual MADRS scores declined by a median of 43.6% and 38.9% (P = 0.59), and premenstrual DRSP scores declined by a median of 23.5% and 20.9% (P = 0.62) in the DRSP/EE and placebo groups, respectively. There was a trend toward greater improvement in premenstrual DRSP scores for women with fewer lifetime depressive episodes (r = 0.40, P = 0.06). IMPLICATIONS/CONCLUSIONS: Findings from this small randomized trial suggest that OCP augmentation of antidepressants may not be effective for treating premenstrual breakthrough of depression. Future studies should target women established to have hormonal sensitivity prior to antidepressant therapy and those with fewer lifetime depressive episodes. PMID- 28816925 TI - Treatment of Diabetic Ketoacidosis Associated With Antipsychotic Medication: Literature Review. AB - BACKGROUND: The second-generation antipsychotics (SGAs) are associated with metabolic disturbances. Diabetic ketoacidosis (DKA) is a rare, but potentially fatal sign of acute glucose metabolism dysregulation, which may be associated with the use of SGAs. This study aims to review published reports of patients with schizophrenia and antipsychotic drug-associated DKA, focusing on the effective management of both conditions. METHODS: Using a predefined search strategy, we searched PubMed and EMBASE from their inception to July 2016. The search terms were related to "diabetic ketoacidosis" and "antipsychotic medication." Case reports, case series, and reviews of case series written in English language were included in the review. RESULTS: Sixty-five reports were analyzed. In most patients who developed antipsychotic-associated DKA, 1 or more suspected antipsychotic medications were discontinued. In 5 cases, a rechallenge test was trialed, and in only 1 case, it resulted in the elevation of blood glucose. The majority was subsequently treated with a different SGA in combination with insulin/oral hypoglycemic agents; although approximately a third of patients had a complete resolution of symptoms or could control diabetes with diet only at the point of discharge. CONCLUSIONS: Patients taking antipsychotic medications should be regularly screened for insulin resistance and educated about potential complications of antipsychotic medications. This will allow clinicians to individualize treatment decisions and reduce iatrogenic contribution to morbidity and mortality. To achieve best treatment outcomes, antipsychotic-induced DKA should be treated jointly by psychiatry and endocrinology teams. PMID- 28816926 TI - Feasibility and Relevance of Antipsychotic Safety Monitoring in Children With Tourette Syndrome: A Prospective Longitudinal Study. AB - PURPOSE/BACKGROUND: Antipsychotics are efficacious for tics and are increasingly prescribed to children with behavioral disorders. Antipsychotics have important adverse effects, and systematic monitoring of drug safety is infrequently performed. The objectives of this study were to determine the feasibility of antipsychotic safety monitoring in children with Tourette Syndrome using a defined protocol and to evaluate the risk of adverse effects with chronic use. METHODS/PROCEDURES: A prospective longitudinal study of children prescribed antipsychotics was performed. Children were monitored for extrapyramidal, metabolic, and hormonal adverse effects using the Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotic Medications guidelines. This included the measurement of height, weight, waist circumference, the Extrapyramidal Symptom Rating Scale, and laboratory tests of lipids, glucose, insulin, and prolactin at prespecified time points. FINDINGS/RESULTS: Fifty-seven children who started on risperidone or aripiprazole were monitored for a mean of 10 months 3 days. Significant increases in body mass index (BMI) and waist circumference percentiles occurred with time. There was a significant time by drug interaction, with children on aripiprazole having smaller changes in BMI initially, followed by a faster rate of increase than with risperidone. There was a significant difference between Extrapyramidal Symptom Rating Scale scores on versus before starting antipsychotics and significant increases in insulin and prolactin. Change from a healthy to overweight or obese BMI percentile occurred in 26%. Extrapyramidal symptoms occurred in 35%. Medication was discontinued because of metabolic effects in 19%, and extrapyramidal symptoms in 7%. IMPLICATIONS/CONCLUSIONS: Monitoring of antipsychotic safety in children is feasible and recommended to inform treatment decisions. PMID- 28816927 TI - Use of Selective Serotonin Reuptake Inhibitors and Bone Mineral Density Change: A Population-Based Longitudinal Study in Middle-Aged and Elderly Individuals. AB - BACKGROUND: Longitudinal studies showed conflicting results regarding the association between use of selective serotonin reuptake inhibitors (SSRIs) and bone mineral density (BMD). Therefore, we investigate the association between duration of-SSRI use and BMD, and change in BMD ([INCREMENT]BMD). METHODS: Data from the population-based Rotterdam Study cohort (1991-2008) were used. In total, 4915 men and 5831 postmenopausal women, aged 45 years and older, were included, having measurement visits at 4- to 5-year intervals. Multivariable linear mixed models were applied to examine the association between SSRI use, based on pharmacy records, duration of SSRI use, and repeated measures of BMD, and changes in BMD, compared with nonuse. Femoral neck BMD (grams per centimeters squared) was measured at 4 visits, comprising 19,861 BMD measurements. Three [INCREMENT]BMD periods were examined, comprising 7897 [INCREMENT]BMD values. Change in BMD was expressed in the annual percentage [INCREMENT]BMD between 2 consecutive visits. RESULTS: In men and women, we observed no association between SSRI and BMD when compared with nonuse (women: mean difference, 0.007 g/cm; 95% confidence interval, -0.002 to 0.017; P = 0.123). We did not find an association between duration of SSRI use and [INCREMENT]BMD (women: annual percentage change, -0.081; 95% confidence interval, -0.196 to 0.033; P = 0.164). CONCLUSIONS: In conclusion, use of SSRIs is not associated with BMD or [INCREMENT]BMD, after taking duration of treatment into account, in middle-aged and elderly individuals. Therefore, our results question previously raised concerns on the adverse effects of SSRIs on BMD. PMID- 28816928 TI - Psychotic Symptoms Associated With Varenicline in a Patient With Alcohol and Nicotine Dependence: A Case Report. PMID- 28816930 TI - Associations among circulating colony-stimulating factor-1, estrogen, and bone mineral density in postmenopausal women: results from a randomized placebo controlled trial. AB - OBJECTIVE: This study addresses the relationship between circulating levels of colony-stimulating factor 1 (CSF-1) and rates of postmenopausal bone loss. The purpose was to test the hypothesis that CSF-1 levels would correlate with the rate of bone loss in estrogen-deficient woman. We further hypothesized that estrogen replacement would eliminate this association. METHODS: This was an ancillary study to the parent Kronos Early Estrogen Prevention Study (KEEPS)-a 4 year randomized placebo-controlled study that evaluated the effects of estrogen therapy on cardiovascular endpoints. Women between of the ages of 42 and 58, who had been amenorrheic for >=6 months and <=36 months, were enrolled in KEEPS. Participants were randomized to conjugated equine estrogen 0.45 mg daily, transdermal estradiol 50 micrograms weekly, or placebo. RESULTS: There was no correlation between serum levels of CSF-1 and bone mineral density at the spine, hip, or femoral neck in estrogen-deficient women (correlation 0.0017, P = 0.99 for spine; correlation 0.0010, P = 0.0079 for hip, and correlation 0.0019, P = 0.99 for femoral neck). There was also no significant correlation in the treatment group (correlation 0.0015, P = 0.99; correlation -0.00024, P = 0.99; correlation 0.0011, P = 0.99 at spine, hip, and femoral neck respectively). CONCLUSIONS: This study did not demonstrate a meaningful relationship between circulating levels of CSF-1 and bone mineral density in either the placebo group or estrogen-treated group. Although CSF-1 is required for osteoclastic bone resorption, our data suggest that circulating levels of the cytokine may not reflect this process. PMID- 28816929 TI - Effectiveness and Value of Prophylactic 5-Layer Foam Sacral Dressings to Prevent Hospital-Acquired Pressure Injuries in Acute Care Hospitals: An Observational Cohort Study. AB - PURPOSE: The purpose of this study was to examine the effectiveness and value of prophylactic 5-layer foam sacral dressings to prevent hospital-acquired pressure injury rates in acute care settings. DESIGN: Retrospective observational cohort. SAMPLE AND SETTING: We reviewed records of adult patients 18 years or older who were hospitalized at least 5 days across 38 acute care hospitals of the University Health System Consortium (UHC) and had a pressure injury as identified by Patient Safety Indicator #3 (PSI-03). All facilities are located in the United States. METHODS: We collected longitudinal data pertaining to prophylactic 5 layer foam sacral dressings purchased by hospital-quarter for 38 academic medical centers between 2010 and 2015. Longitudinal data on acute care, hospital-level patient outcomes (eg, admissions and PSI-03 and pressure injury rate) were queried through the UHC clinical database/resource manager from the Johns Hopkins Medicine portal. Data on volumes of dressings purchased per UHC hospital were merged with UHC data. Mixed-effects negative binomial regression was used to test the longitudinal association of prophylactic foam sacral dressings on pressure injury rates, adjusted for hospital case-mix and Medicare payments rules. RESULTS: Significant pressure injury rate reductions in US acute care hospitals between 2010 and 2015 were associated with the adoption of prophylactic 5-layer foam sacral dressings within a prevention protocol (-1.0 cases/quarter; P = .002) and changes to Medicare payment rules in 2014 (-1.13 cases/quarter; P = .035). CONCLUSIONS: Prophylactic 5-layer foam sacral dressings are an effective component of a pressure injury prevention protocol. Hospitals adopting these technologies should expect good value for use of these products. PMID- 28816931 TI - Effects of multicomponent training on lean and bone mass in postmenopausal and older women: a systematic review. AB - OBJECTIVE: The purpose of this systematic review was to update and examine to what extent multicomponent training interventions could improve lean and bone mass at different anatomical regions of the body in postmenopausal and older women. METHODS: A computerized literature search was performed in the following online databases: PubMed MEDLINE, Cochrane, and Web of Knowledge. The search was performed to include articles up until February 2017. The methodological quality of selected studies was evaluated using the Cochrane risk of bias tool. RESULTS: Fifteen studies met the inclusion criteria. Studies examining the effects of combined training methods in postmenopausal and older women showed contrasting results, possibly due to the wide range of the participants' age, the evaluation of different regions, and the varying characteristics of the training methods between studies. Overall, it appears that exercise modes that combine resistance, weight-bearing training, and impact-aerobic activities can increase or prevent muscle and skeletal mass loss during the ageing process in women. CONCLUSIONS: Further studies are needed to identify the optimal multicomponent training protocols, specifically the training loads that will improve lean and bone mass at different anatomical locations, in postmenopausal and older women. PMID- 28816932 TI - Postmenopausal choriocarcinoma: a rare case report and review of the literature. AB - OBJECTIVE: Choriocarcinoma is rare in postmenopausal women, and an early diagnosis contributes to a potential cure. METHODS: We report a rare case of a postmenopausal woman with choriocarcinoma. The 61-year-old patient presented with irregular vaginal bleeding, 11 years after menopause and 30 years after the birth of the last child. RESULTS: Radiological investigation found a 3-cm mass on the lower left part of the vaginal wall, and also bilateral lung nodules. Gynecological examination found 3-4 cm blue and purple nodules in the lower left part of the vaginal wall. Her serum CA125 and serum beta-hCG levels were 10.2 and 9273.9 mIU/mL, respectively. The early diagnosis was a choriocarcinoma, and combination chemotherapy (etoposide, kengshengmycin, methotrexate, leucovorin, vincristine, and cyclophosphamide [EMACO]) was administered. After the sixth chemotherapy session, her serum beta-hCG level was <2 mIU/mL, and two additional consolidation chemotherapy sessions were performed. She achieved serological remission, but 4 months after completion of the chemotherapy, a rise in serum beta-hCG level was observed. Therefore, she was subjected to a second treatment with EMACO and fluorouracil (5-Fu) local injection chemotherapy. After nine chemotherapy sessions and three local 5-Fu injections, she showed a normal beta hCG level, with negative radiological results, and negative pigmentation in the lower left part of the vaginal wall. After a 4-year follow-up period, no local recurrence or distant metastases was found. CONCLUSIONS: This patient has shown a mild response to chemotherapy when compared with patients in reproductive age, and the combination of standard chemotherapy with local injection chemotherapy may be helpful for treating similar clinical cases. PMID- 28816934 TI - Midterm outcomes of intracranial aneurysms with bleb formation with densely coiling of the aneurismal neck or entire aneurysm. AB - To evaluate whether the efficacy and safety of embolization of the aneurysmal neck were better than those of embolization of the entire aneurysm. Previous studies found that embolization of the aneurysmal neck can be used for treating ruptured intracranial aneurysm with bleb formation.In all, 163 patients with ruptured aneurysms with bleb formation who underwent endovascular embolization at the Shanghai Municipal Jing'an District Central Hospital from January 2014 to August 2015 were divided into the embolization of aneurysmal neck group (neck group; 87 cases) and embolization of entire aneurysm group (aneurysm group; 76 cases). A retrospective analysis of clinical data, follow-up Glasgow Outcome Scale (GOS) score, and occurrence of complications was performed. The impacts of different embolisms on the prognosis were compared.The median follow-up time in the neck and aneurysm groups was 17 months (9.62) and 16.5 months (9.54), respectively (P = .799). No differences were found in recurrence, postoperative GOS score, and GOS score at the last follow-up between the 2 groups. The numbers of coils and surgical complications in the neck group were smaller than those in the aneurysm group (P < .001 and P < .030, respectively). After adjusting for age and sex, the embolization method was found to be an independent predictor for surgery-related complications (odds ratio 2.419, 95% confidence interval 1.111 5.269, P = .026).The numbers of coils and surgery-related complications were smaller when embolizing the aneurysmal neck than the entire aneurysm, showing potential advantages of embolization of the aneurysmal neck. PMID- 28816933 TI - Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the Women's Health Initiative Observational Study. AB - OBJECTIVE: To determine the association between use of vaginal estrogen and risk of a global index event (GIE), defined as time to first occurrence of coronary heart disease (CHD), invasive breast cancer, stroke, pulmonary embolism, hip fracture, colorectal cancer, endometrial cancer, or death from any cause. METHODS: For this prospective observational cohort study, we used data from participants of the Women's Health Initiative Observational Study, who were recruited at 40 US clinical centers, aged 50 to 79 years at baseline and did not use systemic estrogen therapy during follow-up (n = 45,663, median follow-up 7.2 years). We collected data regarding incident CHD, invasive breast cancer, stroke, pulmonary embolism, hip fracture, colorectal cancer, endometrial cancer, death, and self-reported use of vaginal estrogen (cream, tablet). We used Cox proportional-hazards regression models to adjust for covariates. RESULTS: Among women with an intact uterus, the risks of stroke, invasive breast cancer, colorectal cancer, endometrial cancer, and pulmonary embolism/deep vein thrombosis were not significantly different between vaginal estrogen users and nonusers, whereas the risks of CHD, fracture, all-cause mortality, and GIE were lower in users than in nonusers (GIE adjusted hazard ratio 0.68, 95% confidence interval 0.55-0.86). Among hysterectomized women, the risks of each of the individual GIE components and of the overall GIE were not significantly different in users versus nonusers of vaginal estrogen (GIE adjusted hazard ratio 0.94, 95% confidence interval 0.70-1.26). CONCLUSIONS: The risks of cardiovascular disease and cancer were not elevated among postmenopausal women using vaginal estrogens, providing reassurance about the safety of treatment. PMID- 28816935 TI - Perimesencephalic nonaneurysmal subarachnoid hemorrhage caused by transverse sinus thrombosis: A case report and review of literature. AB - RATIONALE: Perimesencephalic nonaneurysmal subarachnoid hemorrhage (PNSAH) is characterized by a pattern of extravasated blood restricted to the perimesencephalic cisterns, normal angiographic findings, and an excellent prognosis with an uneventful course and low risks of complication. The precise etiology of bleeding in patients with PNSAH has not yet been established. The most common hypothesis is that PNSAH is venous in origin. Intracranial venous hypertension has been considered as the pivotal factor in the pathogenesis of PNSAH. The underlying venous pathology such as straight sinus stenosis, jugular vein occlusion may contribute to PNSAH. We describe a patient in whom transverse sinus thrombosis preceded intracranial venous hypertension and PNSAH. These findings supported that the source of the subarachnoid hemorrhage is venous in origin. PATIENT CONCERNS AND DIAGNOSES: A 45-year-old right-handed man was admitted to the hospital with a sudden onset of severe headache associated with nausea, vomiting, and mild photophobia for 6 hours. The patient was fully conscious and totally alert. An emergency brain computed tomography (CT) revealed an acute subarachnoid hemorrhage restricted to the perimesencephalic cisterns. CT angiography revealed no evidence of an intracranial aneurysm or underlying vascular malformation. Digital subtraction angiography of arterial and capillary phases confirmed the CT angiographic findings. Assessment of the venous phase demonstrated right transverse sinus thrombosis. Magnetic resonance imaging confirmed the diagnosis of cerebral venous sinus thrombosis (CVST). Lumbar puncture revealed an opening pressure of 360 mmH2O, suggestive of intracranial venous hypertension. Grave disease was diagnosed by endocrinological investigation. INTERVENTIONS: Low-molecular-weight heparin, followed by oral warfarin, was initiated immediately as the treatment for cerebral venous sinus thrombosis and PNSAH. OUTCOMES: The patient discharged without any neurologic defect after 3 weeks of hospital stay. MR venography revealed recanalization of right transverse sinus at the 6-month follow-up. No clinical or neuroimaging evidence of relapse was detected at 12 months follow-up. LESSONS: Hyperthyroidism may contribute to the development of CVST. The presence of acute transverse sinus thrombosis, as a cause of PNSAH, provides further support for the hypothesis that the source of PNSAH is venous in origin and intracranial venous hypertension plays a critical role in the pathogenesis of PNSAH. PMID- 28816936 TI - Adjuvant transarterial chemoembolization after radical resection contributed to the outcomes of hepatocellular carcinoma patients with high-risk factors. AB - We aim to investigate the effects of postoperative adjuvant transarterial chemoembolization (TACE) on survival and recurrence in hepatocellular carcinoma (HCC) patients after radical resection. A total of 320 HCC patients underwent radical resection between January 2010 and January 2014 in Qilu Hospital, Shandong University were divided into 4 groups according to the frequency of postoperative adjuvant TACE. Patients were further stratified into subgroups (tumor diameter <=5 or >5 cm) with low or high risk factors for recurrence or death. A low risk factor for recurrence or death was defined as Edmondson grade I/II without microvascular invasion (MiVI), while a high risk factor was defined as Edmondson grade III/IV or with MiVI. Survival data and recurrence rates were compared using the Kaplan-Meier method. Uni- and multivariate analyses were based on the Cox proportional analysis. Compared to those received no TACE, patients underwent 2 (log-rank, chi = 9.054, P = .003) or 3 (log-rank, chi = 4.228, P = .04) TACE showed delayed recurrence. Patients received 2 or 3 TACE showed extended overall survival (OS) compared with the other patients. No statistical differences were found between all the disease-free survival (DFS) and OS in low risk subgroups. In the patients of the high-risk subgroup with a tumor diameter of <=5, those received 2 TACE showed delayed recurrence compared with those received no TACE, and TACE (twice or thrice) can improve OS. For those of the high-risk subgroup with a tumor diameter of >5, TACE (twice or thrice) can delay recurrence and improve OS. Adjuvant TACE (twice or thrice) after radical resection is beneficial for HCC patients with poor differentiation and MiVI, especially for those with a tumor diameter of >5 cm. PMID- 28816937 TI - Effect of perioperative oral care on prevention of postoperative pneumonia associated with esophageal cancer surgery: A multicenter case-control study with propensity score matching analysis. AB - The aim of this study was to investigate the effectiveness of oral care in prevention of postoperative pneumonia associated with esophageal cancer surgery.Postoperative pneumonia is a severe adverse event associated with esophageal cancer surgery. It is thought to be caused by aspiration of oropharyngeal fluid containing pathogens. However, the relationship between oral health status and postoperative pneumonia has not been well investigated.This study included 539 patients with esophageal cancer undergoing surgery at 1 of 7 university hospitals. While 306 patients received perioperative oral care, 233 did not. Various clinical factors as well as occurrence of postoperative pneumonia were retrospectively evaluated. Propensity-score matching was performed to minimize selection biases associated with comparison of retrospective data between the oral care and control groups. Factors related to postoperative pneumonia were analyzed by logistic regression analysis.Of the original 539 patients, 103 (19.1%) experienced postoperative pneumonia. The results of multivariate analysis of the 420 propensity score-matched patients revealed longer operation time, postoperative dysphagia, and lack of oral care intervention to be significantly correlated with postoperative pneumonia.The present findings demonstrate that perioperative oral care can reduce the risk of postoperative pneumonia in patients undergoing esophageal cancer surgery. PMID- 28816938 TI - Advanced glycation end products promote ChREBP expression and cell proliferation in liver cancer cells by increasing reactive oxygen species. AB - The aim of the study was to elucidate the mechanism by which advanced glycation end products (AGEs) promote cell proliferation in liver cancer cells.We treated liver cancer HepG2 cells with 200 mg/L AGEs or bovine serum albumin (BSA) and assayed for cell viability, cell cycle, and apoptosis. We performed real-time PCR and Western blot analysis for RNA and protein levels of carbohydrate responsive element-binding protein (ChREBP) in AGEs- or BSA-treated HepG2 cells. We analyzed the level of reactive oxygen species (ROS) in HepG2 cells treated with AGEs or BSA.We found that increased S-phase cell percentage and decreased apoptosis contributed to AGEs-induced liver cancer cell proliferation. Real-time PCR and Western blot analysis showed that AGEs stimulated RNA and protein levels of ChREBP, a transcription factor promoting glycolysis and maintaining cell proliferation in liver cancer cells. Intriguingly, the level of ROS was higher in AGEs-treated liver cancer cells. Treating liver cancer cells with antioxidant N acetyl cystein (NAC) partly blocked AGEs-induced ChREBP expression and cell proliferation.Our results suggest that the AGEs-ROS-ChREBP pathway plays a critical role in promoting ChREBP expression and liver cancer cell proliferation. PMID- 28816939 TI - Correlations of ICAM-1 gene polymorphisms with susceptibility and multidrug resistance in colorectal cancer in a Chinese population. AB - BACKGROUND: Colorectal cancer (CRC) is a malignant gastrointestinal tumor with a high mortality rate, including both colon and rectal cancer. In order to provide clinical guidance for the treatment of CRC, this study is conducted to investigate the correlations of intercellular adhesion molecule 1 (ICAM-1) gene polymorphisms with susceptibility and multidrug resistance (MDR) of colorectal cancer (CRC). METHODS: A total of 195 patients with CRC were selected as the observation group and 188 healthy people enrolled as the control group. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) was used to test ICAM-1 A13848G and K469E polymorphisms. The expressions of MDR associated protein topoisomerase II (Topo II) and P-glycoprotein (P-gp) in CRC tissues were detected by immunohistochemistry. The analysis on association of clinical indexes of CRC patients with ICAM-1 gene polymorphisms was performed. RESULTS: The frequencies of KK genotype and K allele of K469E in the observation group were significantly higher than that in the control group. KE + EE genotype and E allele might be protective factors for CRC. The distribution of genotypes, K469E KK and KE+EE, was highly correlated with histologic grade of tumor differentiation. Compared with adjacent normal tissues, positive rates of Topo II and P-gp expression were significantly increased in CRC tissues. Topo II expression in CRC patients was positively associated with lymph node metastasis and depth of tumor invasion, whereas P-gp expression was only associated with depth of tumor invasion. Higher positive rates of Topo II and P-gp expression were observed in ICAM-1 K469E KK genotype carriers, indicating that ICAM-1 K469E KK genotype might be related to MDR in CRC. CONCLUSION: These findings in the current study suggested that ICAM-1 K469E polymorphism is highly correlated with susceptibility and MDR in CRC. PMID- 28816940 TI - Signet ring cell carcinoma of early gastric cancer, is endoscopic treatment really risky? AB - Signet ring cell carcinoma (SRC) is a poorly differentiated cancer of the stomach. Generally, poorly differentiated cancer is believed to show poor prognosis and aggressive behavior. Recently, however, there is debate on the aggressiveness of SRC in early gastric cancer (EGC). We therefore studied postoperation biopsies to investigate the aggressiveness of SRC in EGC.We reviewed medical records of patients with EGC who had surgery from January 2011 to December 2015 in a tertiary hospital in Daejeon, South Korea. We evaluated the histologic type, invasion depth, lymphovascular invasion (LVI), and lymph node (LN) metastasis.A total of 822 EGC lesions from 789 patients were studied. Approximately 498 differentiated cancer, 65 poorly differentiated cancer, 91 SRC, 26 poorly differentiated with SRC, 41 mixed type, 10 medullary carcinoma, and 91 poorly cohesive carcinoma other than SRC were included. LN metastasis was associated with the histologic type of EGC (P = .000). Nine percent of differentiated cancer, 21.5% of poorly differentiated cancer, 5.5% of SRC, 11.5% of poor differentiation with SRC, 26.8% of mixed type, 20% of medullary type, and 15.4% of poorly cohesive carcinoma other than SRC showed LN metastasis. The risk of SRC was not higher than well to moderated differentiated cancer (odds ratio [OR] = 0.842, P = .768). Risk of LVI was also similar with LN metastasis. Compared with differentiated cancer, OR of SRC was 1.969 (P = .172).Our results show that SRC is not more aggressive than differentiated cancer. SRC may be considered a candidate for endoscopic treatment. PMID- 28816941 TI - Single-center experience with intra-abdominal liposarcoma: Optimal minimum duration for postoperative remnant tumor screening. AB - This study sought to identify factors related to the prognosis of intra-abdominal liposarcoma and to determine the optimal minimum duration for remnant tumor screening. Intra-abdominal liposarcoma is associated with high rates of incomplete resection and recurrence requiring a sophisticated follow-up strategy.Patients who underwent surgery for intra-abdominal liposarcoma were included. Cox analyses were used to analyze factors related to recurrence and survival. To determine the optimal minimum duration for remnant tumor screening, patients with recurrence after surgery despite gross complete resection were grouped by a postoperative detection time of 1, 3, or 6 months. Their survivals were compared to the gross incomplete resection group.A total of 168 patients were included. Kaplan-Meier 5-year disease-free survival was 35.9% and overall survival was 66.5%. Multiplicity (HR=2.528, CI=1.585-4.033, P < .001), organ invasion (HR = 1.628, CI = 1.020-2.598, P = .041), and FNCLCC grades (G2,HR = 1.730, CI = 1.000-2.994; G3, HR = 3.812, CI = 2.112-6.880, P < .001) were related to recurrence. Multiplicity (HR = 2.131, CI = 1.050-4.329, P = .036), organ resection >=3 (HR = 2.857, CI = 1.322-6.174, P = .008), gross incomplete resection (HR = 4.368, CI = 1.890-10.097, P = .001), positive margin (HR = 2.766, CI = 1.367-5.600, P = .005), FNCLCC grade (G2,HR = 2.044, CI = 0.937-4.459; G3,HR = 4.470, CI = 1.893-10.557; P = .003), and RT (HR = 0.322, CI = 0.160-0.648, P = .001) were related to overall survival. Dividing patients into 1 month (P = .097) and 3 months (P = 0.063) did not yield significant differences in univariate analyses, whereas 6 months showed significant difference (P = .015) compared to the gross incomplete resection group. Patients with tumors detected within 6 months showed similar survival to the gross incomplete resection group (HR = 0.552, CI = 0.241-1.260, P = .158), whereas patients with tumor detection after 6 months showed better survival (HR = 0.325, CI = 0.149-0.708, P = .005).In conclusion, minimum duration of 6 months for remnant tumor screening using CT seems optimal. PMID- 28816943 TI - Spinal cord compression syndrome caused by intraspinal epidural fibrous cord: Three case reports. AB - RATIONALE: The spinal cord compression caused by intraspinal epidural fibrous cord. PATIENT CONCERNS: All patients in this study had spinal cord compression syndrome caused by an intraspinal epidural fibrous cord, manifested as abnormally increased epidural adipose tissue by imaging. DIAGNOSE: These abnormal fibrous connective tissue strips were not identical to the known pathological tissue such as "meningovertebral ligament." Instead, it might be a novel pathogenic cause for the spinal cord compression. INTERVENTIONS: The intraspinal exploratory operation. OUTCOMES: the first case has expected effect, the remaining two need further test. LESSONS SUBSECTIONS: The disease could be easily misdiagnosed as spinal epidural lipoma or lipomatosis before the operation. However, the overt intraoperative finding was the indefinite starting and ending points of the epidural adipose mass in addition to the increased amount of adipose tissue. The obvious compression on the spinal cord could be found as the extraordinarily large and broad hypertrophic fibrous connective tissue strips.Further studies are needed to elucidate whether it is different from, or associated with, lipoma and epidural lipomatosis, which is a serious issue to be considered by both clinicians and radiologists. Therefore, early discovery,diagnosis, and treatment should be the prerequisites to achieve a satisfactory effect. PMID- 28816942 TI - Surgical interventions for cervical spondylosis due to ossification of posterior longitudinal ligament: A meta-analysis. AB - BACKGROUND: Aim of this study was to evaluate the effectiveness of various surgical interventions for the management of cervical spondylosis due to the ossification of posterior longitudinal ligament (OPLL). METHODS: After a comprehensive literature search in electronic databases, studies were selected by following pre-determined eligibility criteria. Random effects meta-analyses were performed to estimate the effect sizes of various surgical approaches in improving Japanese Orthopedic Association (JOA) scores at latest follow-up and meta-regression analyses were carried out to examine the factors affecting the change in JOA score. RESULTS: Twenty-three studies [1576 patients; 57.83 (95% confidence interval, 95% CI: 55.98-59.68] years of age; and 73 (70-76) % males; follow-up 55.4 +/- 25.7 (range 12-170) months] were included in the meta analysis. All surgical interventions significantly (P < .00001) improved JOA score. Anterior surgical approaches had an effect size of 4.80 [4.10-5.50] and posterior approaches with laminectomy and laminoplasty improved JOA score by 3.57 [2.39-4.75] and 3.99 [3.65-4.32], respectively. Improvement in JOA score was significantly inversely related to the preoperative JOA score (P < .00001). Surgical interventions did not significantly affect cervical lordosis at the latest follow-up. CONCLUSION: Surgical interventions for cervical spondylosis due to OPLL significantly improve JOA score as observed at the latest follow-up and this is found to be significantly inversely associated with preoperative JOA score. PMID- 28816944 TI - Acute changes in neuromuscular activity in vertical jump and flexibility after exposure to whole body vibration. AB - This study was aimed to investigate the neuromuscular activity after 10 minutes of exposure to a whole body vibration (WBV) session.Twenty male young adults (24.8 +/- 2.5 year olds) were randomized and divided into 2 groups: the vibration group (VG) was exposed to 10 minutes of WBV at 35 Hz; performed 10 minutes of WBV at 35 Hz (displacement = 5 mm; magnitude = 5 g); the nonvibrated group (NVG) was the placebo group that maintained the same position on the plate but without exposure to any type of vibration. Subjects were evaluated with counter movement jump (CMJ) and muscular flexibility by means of electromyographic (EMG) analysis recorded on the vastus lateralis (VL), vastus medialis (VM), biceps femoris (BF), and gastrocnemius lateralis (LG).The 10 minutes of WBV showed an increase in muscular flexibility, associated with a decrease of EMG activity in BF (P < .01) and jump height. The latter was associated with a reduction of EMGs activity in BF (P < .01). The control group did not show any significant difference in all considered parameters.These results support the hypothesis that 10 minutes of WBV had effects on flexibility and explosive strength performance influencing neuromuscular behavior through inhibitor effects on antagonist muscles more than the stretch reflex activity on agonist muscles. PMID- 28816945 TI - 99mTc-pertechnetate-avid metastases from differentiated thyroid cancer are prone to benefit from 131I therapy: A prospective observational study. AB - The aim of this study is to determine the contribution of neck and chest Tc pertechnetate scan to the management of postoperative patients with suspicious metastatic differentiated thyroid cancer (DTC), particularly to the prediction of response to radioiodine (I) therapy. Just before I administration, a total of 184 postoperative DTC patients with stimulated serum thyroglobulin (ssTg) >10 ng/mL were enrolled to undergo neck and chest Tc-pertechnetate scan, which were directly compared with post-therapeutic I scan to determine the concordance of site and number of metastatic lesions. The percentage changes in ssTg between Tc pertechnetate-avid group and Tc-pertechnetate-nonavid group were compared, and the response to I in both groups was analyzed according to the nature of Tc pertechnetate avidity as well. The percentages of concordance between Tc pertechnetate and I scan in detecting metastases were 65.7% and 26.0% in per patient and per-site analyses with low unweighted kappa, respectively. Tc pertechnetate scan led to a change in therapeutic decision making in 19/184 (10.3%) patients. In 72 patients with I-avid metastases, the ssTg in Tc pertechnetate-avid group (n = 13) decreased significantly compared with that in Tc-pertechnetate-nonavid group (n = 59) (median: -81.56% vs -48.14%; Z = -4.276, P = .000). The difference of therapeutic response between Tc-pertechnetate-avid group and Tc-pertechnetate-nonavid group was statistically significant (chi = 8.4; P = .03). Although the consistency between Tc-pertechnetate scan before I administration and post-therapy I scan in detecting metastases is low, identifying metastases in postoperative DTC patients with elevated ssTg via Tc pertechnetate scan prior to I therapy provides incremental value for therapeutic decision making. Notably, patients with Tc-pertechnetate-avid metastases may be more prone to benefit from I therapy than those with Tc-pertechnetate-nonavid metastases. PMID- 28816947 TI - Kinematic analysis of the relationship between Modic changes and sagittal balance parameters in the cervical spine. AB - The aim of this study is to investigate the relationship between the Modic changes (MCs) and sagittal parameters of the cervical spine.We conducted a retrospective review of 100 outpatients with magnetic resonance imaging (MRI) scans of the cervical spine (50 male and 50 female). MRI parameters were measured, including neck tilt, T1 slope (T1 ), thoracic inlet angle (TIA), and cervical lordosis (CL: Cobb C2-7). Patients were divided into 4 groups according to the presence or absence of MC and T1s, respectively: MC(+) and MC(-) groups, as well as H-T1s (T1s >=25 degrees ) and L-T1s subgroups (T1s <25 degrees ). Relationships between the MC and sagittal alignment in the cervical spine and other parameters were evaluated via Spearman correlation coefficient. Radiologic parameters were compared between the MC(+) group and MC(-) group, and the prevalences of MC were compared between the H-T1s and L-T1s groups.T1s was significantly correlated with TIA and CL, with correlation coefficients of 0.562 and 0.725, respectively. T1 slope was significantly higher in patients with MC than those without MC (P = .041), and the prevalence of MC was higher in the H T1s group than the L-T1s group (37.5% and 17.1%, respectively). However, the relationship between the parameters of sagittal balance and MC was not significant.The present study demonstrated that high T1 slope is a potential risk factor for the development of MC due to impaired sagittal balance, especially in the C5-6 cervical segment. PMID- 28816946 TI - Prognostic factors of clinical endpoints in elderly patients with atrial fibrillation during a 2-year follow-up in China: An observational cohort study. AB - : This study aimed to reveal the incidence of clinical endpoints in elderly patients with atrial fibrillation (AF) during a 2-year follow-up and evaluate the related prognostic factors of these endpoints.In total, 200 elderly patients with AF and 400 age- and sex-matched patients without AF were enrolled in this prospective observational cohort study. The incidence of clinical endpoints, including thromboembolism, hemorrhage, and all-cause death, during the 2-year follow-up was analyzed. Other follow-up data, including disease history, laboratory examinations, medication status, and other clinical endpoints, were collected. The prognostic factors of these clinical endpoints were then evaluated by Cox-survival analysis. In addition, the predicative role of C-reactive protein (CRP) and platelet-activating factor (PAF) on these clinical endpoints was analyzed.The incidence of clinical endpoints, including thromboembolism, hemorrhage, and all-cause death, was significantly higher in patients with AF than in those without AF (27.8% vs 9.8%, 29.4% vs 12.7%, and 28.7% vs 11.6%, respectively; all P < .001). Antithrombotic therapy significantly reduced the incidences of all-cause deaths (P < .05). Body mass index (BMI) and digoxin were prognostic risk factors of thromboembolism; age, massive hemorrhage history, and digoxin were prognostic risk factors of hemorrhage and age, renal insufficiency history, massive hemorrhage history, and digoxin were prognostic risk factors of all-cause death (P < .05). Further, both CRP and PAF were prognostic risk factors of thromboembolism and massive hemorrhage (P < .05).Age, BMI, massive hemorrhage history, and digoxin appear to be prognostic risk factors of clinical endpoints in elderly patients with AF. Appropriate drug use during follow-up may be beneficial in preventing the occurrence of clinical endpoints in elderly patients with AF. TRIAL REGISTRATION NUMBER: ChiCTR-OCH-13003479. PMID- 28816948 TI - Medial medullary infarction caused by antineutrophil cytoplasmic antibody-related vasculitis: Case report and review of the literature. AB - RATIONALE: Medial medullary infarction accounts for less than 1% of brain infarctions, and medial medullary infarctions is very rarely caused by antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. PATIENT CONCERNS: We report the case of a 76-year-old man at low risk of arteriosclerosis who presented with disorders on the left side including gaze-evoked nystagmus, paralysis of the extremities, pyramidal signs, sensory disturbance, and dysesthesia. Brain magnetic resonance imaging also showed right medial medullary infarction. DIAGNOSES: Medial medullary infarction caused by ANCA-related vasculitis was diagnosed based on mild renal dysfunction and high levels of blood leukocytes, C-reactive protein (CRP), and myeloperoxidase (MPO)-ANCA. INTERVENTIONS AND OUTCOMES: He underwent two 3-day courses of steroid pulse therapy involving daily 1000 mg doses of methylpredonine. He then received 30 mg/day (0.5 mg/kg/day) of prednisolone (PSL) without other immunosuppressants. Levels of MPO-ANCA and the inflammatory marker CRP decreased rapidly a month after admission. Once MPO-ANCA became undetectable, the PSL dose was carefully reduced to 10 mg/day. To treat his paralysis, we provided rehabilitation with a Hybrid Assistive Limb five times starting at a month post-onset. His Barthel index score rose from 45 to 70 points. LESSONS: Medullary infarction is mostly caused by arteriosclerosis and vertebral arterial dissection. When systemic inflammatory findings are obtained, ANCA-associated vasculitis should be considered a potential cause, and steroid pulse therapy should be promptly administered. PMID- 28816949 TI - Whole exome sequencing identifies a KCNJ12 mutation as a cause of familial dilated cardiomyopathy. AB - Dilated cardiomyopathy (DCM) is characterized by left ventricular dilation, and is associated with systolic dysfunction and increased action potential duration. Approximately 50% of DCM cases are caused by inherited gene mutations with genetic and phenotypic heterogeneity. Next generation sequencing may be useful in screening unknown mutations in such cases.A family was identified with DCM, in which the affected family members developed heart failure, arrhythmia, and sudden death. Probands and 4 affected family members underwent whole exome sequencing (WES), bioinformatics methods, and gene annotation to identify potentially causative variants. The Sanger sequencing method was used to verify the candidate mutation.WES yielded 2,238,831 variations. KCNJ12 (p.Glu334del) was identified as a candidate mutation, and the heterozygous mutation was verified by Sanger sequencing.Our study emphasizes the application of WES in identifying causative mutations in DCM. This report is the first to describe the KCNJ12 gene as a cause of DCM in patients. PMID- 28816950 TI - Pemetrexed-carboplatin with intercalated icotinib in the treatment of patient with advanced EGFR wild-type lung adenocarcinoma: A case report. AB - RATIONALE: Tyrosine kinase inhibitors (TKIs) are known to have greater efficacy in epidermal growth factor receptor (EGFR) mutation nonsmall cell lung cancer (NSCLC). However, about 10% of EGFR wild-type (wt) patients respond to TKIs. PATIENT CONCERNS: Several strategies to increase the efficacy of TKIs in wt NSCLC are the subjects of ongoing investigations. One of them is combining EGFR TKI with intercalated chemotherapy. DIAGNOSES: We describe a patient with EGFR wt NSCLC, who was found with ovarian and lung metastasis, was treated with pemetrexed and intercalated icotinib. INTERVENTIONS: In this case, we reported the successful long-term maintenance treatment of a patient with EGFR wt NSCLC with pemetrexed and Icotinib. The patient (40-year-old female) was found with ovarian masses and lung masses. Pathological, immunohistochemical, and amplification refractory mutation system (ARMS) assay examinations of ovarian specimen suggested the expression of metastatic lung adenocarcinoma with wt EGFR. After failure treatment with paclitaxel-carboplatin, the patient received 4 cycles of pemetrexed plus platinum with intercalated icotinib and then remained on pemetrexed and icotinib. OUTCOMES: A partial response was achieved after the treatment. The patient's condition had remained stable on pemetrexed and icotinib for more than 20 months, with no evidence of progression. LESSONS: To our knowledge, this is the first report using the long-term maintenance treatment with pemetrexed and intercalated icotinib in EGFR wt patient. The therapeutic strategies warrant further exploration in selected populations of NSCLC. PMID- 28816951 TI - Effect of therapeutic care for treating fatigue in patients with breast cancer receiving chemotherapy. AB - BACKGROUND: This study aimed to evaluate the effect of therapeutic care (TC) for fatigue in breast cancer patients receiving chemotherapy. METHODS: A total of 48 breast cancer patients receiving chemotherapy were randomly divided into the intervention group and the control group, with 24 patients in each group. The patients in the intervention group were treated with TC, while the participants in the control group received the sham intervention. The interventions in both groups were for 30 min/d, 3 days weekly for 12 weeks. The primary outcome of fatigue was measured by the multidimensional fatigue inventory (MFI). The secondary outcomes were measured by the Hospital Anxiety and Depression Scale (HADS) and Pittsburgh Sleep Quality Index (PSQI). All outcomes were assessed before and after 6 and 12 weeks of the intervention. RESULTS: The intervention with TC showed greater efficacy than sham TC in decreasing the MFI score after week 6 (P < .05) and week 12 (P < .01) of treatment. Significant differences were also found in the HADS and PSQI between the 2 groups after 12 weeks of treatment (P < .01). CONCLUSION: This study demonstrated that TC might decrease fatigue and relieve the anxiety and depression of breast cancer patients receiving chemotherapy. PMID- 28816952 TI - Prediction of microvascular invasion of hepatocellular carcinoma with preoperative diffusion-weighted imaging: A comparison of mean and minimum apparent diffusion coefficient values. AB - The aim of the study was to investigate the value of preoperative diffusion weighted imaging (DWI) in predicting microvascular invasion (MVI) of hepatocellular carcinoma (HCC), using and comparing mean and minimum apparent diffusion coefficient (ADC) values.Preoperative MR images of 318 patients with HCC confirmed by surgical pathology were retrospectively analyzed. All patients underwent preoperative DWI on a 1.5 Tesla MRI scanner. The mean and minimum ADC values of the tumors were measured. Interobserver agreements were assessed by the intraclass correlation coefficient (ICC). The ADC values were compared in HCCs between with and without MVI. ROC curves of ADC values were obtained and then compared in distinguishing HCCs with MVI from those without MVI.There were 211 HCCs with MVI and 107 HCCs without MVI. ICC for the measurements of the mean and minimum ADC values between both observers was 0.88 (95% CI 0.85 - 0.90) and 0.88 (95% CI 0.85 - 0.90), respectively. The mean and minimum ADC values of HCCs with MVI were lower than those of HCCs without MVI (P = .00, .00, respectively). With a cut-off value of 0.98 * 10 mm/s, the minimum ADC (MinADC) showed a sensitivity of 62.56% and a specificity of 65.42% in predicting MVI, whereas the mean ADC provided a sensitivity of 79.15% and a specificity of 50.47% with a cut-off value of 1.19 * 10 mm/s. No significant difference existed between MinADC and mean ADC for their diagnostic performances in the prediction of MVI (P = .48).DWI could preoperatively provide quantitative parameters for predicting MVI of HCC. PMID- 28816953 TI - Peritumoral decreased uptake area of gadoxetic acid enhanced magnetic resonance imaging and tumor recurrence after surgical resection in hepatocellular carcinoma: A STROBE-compliant article. AB - Recently, it has been suggested that peritumoral decreased uptake area (PDUA) in the hepatobiliary phase (HBP) of gadoxetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) was associated with vascular invasion in hepatocellular carcinoma (HCC). We aimed to investigate correlations between microvascular invasion and PDUA, and elucidate the predictability of PDUA for tumor recurrence after resection.We retrospectively analyzed clinicopathological and radiological data from 126 consecutive patients with single HCC <=5 cm without macrovascular invasion who underwent preoperative Gd-EOB-DTPA-enhanced MRI and surgical resection. The presence of a faint and hypointense area around the tumor in the HBP was defined as PDUA.Among 126 patients with HCCs, microvascular invasion was observed in 29 (23.0%) patients and PDUA was observed in 15 (11.9%) patients. PDUA [odds ratio (OR) 20.06, confidence interval (CI) 4.74-84.96, P < .001] was an independent risk factor for microvascular invasion. In multivariate survival analysis using Cox regression, PDUA [hazard ratio (HR) 4.51, CI 2.17-9.38, P < .001], pathologically confirmed satellite nodules (HR 5.18, CI 1.50-17.88, P = .009), and AFP (>=100 ng/mL, HR 2.28, CI 1.04-5.01, P = .040) were independent risk factors for recurrence after resection. Recurrence-free survival in the group with PDUA was significantly lower than that in the group without PDUA according to analysis using the Kaplan-Meier method with the log-rank test (P < .001).PDUA in the HBP of Gd-EOB-DTPA-enhanced MRI could be a useful preoperative predictor of microvascular invasion and independent prognostic factor after surgical resection in patients with single HCC <=5 cm without macrovascular invasion. PMID- 28816954 TI - Tranexamic acid decreases blood loss in shoulder arthroplasty: A meta-analysis. AB - BACKGROUND: The objective of this meta-analysis was to evaluate the efficacy and safety of tranexamic acid (TXA) in shoulder arthroplasty (SA). METHODS: Academic articles were identified from the Cochrane Library, Medline (1966-2017.2), PubMed (1966-2017.2), Embase (1980-2017.2), and ScienceDirect (1966-2017.2). Randomized controlled trials (RCTs) and non-RCTs studying TXA in SA were included. Two independent reviewers conducted independent data abstraction. The I statistic was used to assess heterogeneity. Fixed- or random-effects models were used for meta analysis. RESULTS: Two RCTs and 2 non-RCTs met the inclusion criteria. This meta analysis found significant differences in postoperative hemoglobin reduction (MD = -0.71 g/dL), drainage volume (MD = -133.21 mL), and total blood loss (MD = 226.82 mL) between TXA groups and controls. There were no significant differences in blood transfusion requirements, operation time, or length of hospital stay. CONCLUSIONS: The use of TXA in SA decreases postoperative hemoglobin reduction, drainage volume, and total blood loss and does not increase the risk of complications. Because of the limited high-quality evidence currently available, additional randomized controlled trials are required. PMID- 28816955 TI - Serum HBeAg and HBV DNA levels are not always proportional and only high levels of HBeAg most likely correlate with high levels of HBV DNA: A community-based study. AB - This study aimed to investigate the correlation between quantitative hepatitis B e antigen (HBeAg) and hepatitis B virus (HBV) DNA levels, and to determine whether semiquantitative measurement of HBeAg can indicate the extent of HBV replication in HBeAg-positive subjects in the immune tolerant phase.A cross sectional, community-based survey was carried out in 12 communities of 2 counties in Zhejiang Province, China. A panel of 788 HBeAg-positive subjects was divided into 4 groups according to HBV DNA level.Groups I (n = 111), II (n = 91), III (n = 124), and IV (n = 462) had HBV DNA levels below 10 copies/mL (PCR undetectable), between 10 and 10 copies/mL (PCR detectable), between 10 and 2 * 10 copies/mL (hybridization detectable), and >2 * 10 copies/mL, respectively. The HBeAg level correlated well with the HBV DNA level (R = 0.658; P < .01) on a log scale. The average HBeAg level in group IV was significantly higher than those in the other 3 groups, and the best HBeAg cut-off value for differentiating group IV from the other 3 groups was 768 S/CO, with a sensitivity of 94.4% and specificity of 91.1%.Semiquantification of HBeAg could indicate a relative HBV DNA level in HBeAg-positive subjects in the immune tolerant phase. PMID- 28816956 TI - Differential diagnosis of posterior fossa brain tumors: Multiple discriminant analysis of Tl-SPECT and FDG-PET. AB - This study investigated the combined capability of thallium-201 (Tl)-SPECT and fluorine-18-fluoro-deoxy-glucose (FDG)-PET for differential diagnosis of posterior fossa brain tumors using multiple discriminant analysis.This retrospective study was conducted under approval of the institutional review board. In the hospital information system, 27 patients with posterior fossa intra axial tumor between January 2009 and June 2015 were enrolled and grouped as the following 7 entities: low grade glioma (LGG) 6, anaplastic astrocytoma (AA) 2, glioblastoma (GBM) 3, medulloblastoma (MB) 3, hemangioblastoma (HB) 6, metastatic tumor (Mets) 3, and malignant lymphoma (ML) 4. Tl and FDG uptakes were measured at the tumors and control areas, and several indexes were derived. Using indexes selected by the stepwise method, discriminant analysis was conducted with leave one-out cross-validation.The predicted accuracy for tumor classification was 70.4% at initial analysis and 55.6% at cross-validation to differentiate 7 tumor entities. HB, LGG, and ML were well-discriminated, but AA was located next to LGG. GBM, MB, and Mets largely overlapped and could not be well distinguished even applying multiple discriminant analysis. Correct classification in the original and cross-validation analyses was 44.4% and 33.3% for Tl-SPECT and 55.6% and 48.1% for FDG-PET. PMID- 28816957 TI - Value and impact factors of multidetector computed tomography in diagnosis of preoperative lymph node metastasis in gastric cancer: A PRISMA-compliant systematic review and meta-analysis. AB - BACKGROUND: Multidetector computed tomography (MDCT) exhibited wide ranges of sensitivities and specificities for lymph node assessment of gastric cancer (GC) in several individual studies. This present meta-analysis was carried out to evaluate the value of MDCT in diagnosis of preoperative lymph node metastasis (LNM) and to explore the impact factors that might explain the heterogeneity of its diagnostic accuracy in GC. METHODS: A comprehensive search was conducted to collect all the relevant studies about the value of MDCT in assessing LNM of GC within the PubMed, Cochrane library and Embase databases up to Feb 2, 2016. Two investigators independently screened the studies, extracted data, and evaluated the quality of included studies. The sensitivity, specificity, and area under ROC curve (AUC) were pooled to estimate the overall accuracy of MDCT. Meta-regression and subgroup analysis were carried out to identify the possible factors influencing the heterogeneity of the accuracy. RESULTS: A total of 27 studies with 6519 subjects were finally included. Overall, the pooled sensitivity, specificity, and AUC were 0.67 (95% CI: 0.56-0.77), 0.86 (95% CI: 0.81-0.90), and 0.86 (95% CI: 0.83-0.89), respectively. Meta-regression revealed that MDCT section thickness, proportion of serosal invasion, and publication year were the main significant impact factors in sensitivity, and MDCT section thickness, multiplanar reformation (MPR), and reference standard were the main significant impact factors in specificity. After the included studies were divided into 2 groups (Group A: studies with proportion of serosa-invasive GC subjects >=50%; Group B: studies with proportion of serosa-invasive GC subjects <50%), the pooled sensitivity in Group A was significantly higher than in Group B (0.84 [95% CI: 0.75-0.90] vs 0.55 [95% CI: 0.41-0.68], P < .01). For early gastric cancer (EGC), the pooled sensitivity, specificity, and AUC were 0.34 (95% CI: 0.15-0.61), 0.91 (95% CI: 0.84-0.95), and 0.83 (95% CI: 0.80-0.86), respectively. CONCLUSION: To summarize, MDCT tends to be adequate to assess preoperative LNM in serosa invasive GC, but insufficient for non-serosa-invasive GC (particularly for EGC) owing to its low sensitivity. Proportion of serosa-invasive GC subjects, MDCT section thickness, MPR, and reference standard are the main factors influencing its diagnostic accuracy. PMID- 28816958 TI - Effective apatinib treatment of pleomorphic liposarcoma: A case report. AB - RATIONALE: Pleomorphic liposarcoma (PLS) is a rare and aggressive malignant tumor, and both radiation and conventional cytotoxic chemotherapy remain controversial for metastatic or unresectable disease. PATIENT CONCERNS: We presented an 81-year-old Chinese woman with advanced PLS who received apatinib after failure chemotherapy. DIAGNOSES: The patient was diagnosed as having PLS by biopsy. INTERVENTIONS: After a failed chemotherapy, apatinib started to be taken orally 425 mg per day. OUTCOMES: This patient achieved 3-month progression-free survival (PFS) and a higher quality of life. Meanwhile, this patient suffered grade 2 hypertension and grade 3 hand-foot syndrome (HFS). LESSONS: In this case, apatinib presented good efficacy and safety to treat PLS. Randomized clinical studies are required to confirm the efficacy and safety of apatinib in the treatment of PLS. PMID- 28816959 TI - Estimation of physiologic ability and surgical stress (E-PASS) scoring system could provide preoperative advice on whether to undergo laparoscopic surgery for colorectal cancer patients with a high physiological risk. AB - Laparoscopic colorectal surgery had been widely used for colorectal cancer patient and showed a favorable outcome on the postoperative morbidity rate. We attempted to evaluate physiological status of patients by mean of Estimation of physiologic ability and surgical stress (E-PASS) system and to analyze the difference variation of postoperative morbidity rate of open and laparoscopic colorectal cancer surgery in patients with different physiological status.In total 550 colorectal cancer patients who underwent surgery treatment were included. E-PASS and some conventional scoring systems were reviewed to examine their mortality prediction ability. The preoperative risk score (PRS) in the E PASS system was used to evaluate the physiological status of patients. The difference of postoperative morbidity rate between open and laparoscopic colorectal cancer surgeries was analyzed respectively in patients with different physiological status.E-PASS had better prediction ability than other conventional scoring systems in colorectal cancer surgeries. Postoperative morbidities were developed in 143 patients. The parameters in the E-PASS system had positive correlations with postoperative morbidity. The overall postoperative morbidity rate of laparoscopic surgeries was lower than open surgeries (19.61% and 28.46%), but the postoperative morbidity rate of laparoscopic surgeries increased more significantly than in open surgery as PRS increased. When PRS was more than 0.7, the postoperative morbidity rate of laparoscopic surgeries would exceed the postoperative morbidity rate of open surgeries.The E-PASS system was capable to evaluate the physiological and surgical risk of colorectal cancer surgery. PRS could assist preoperative decision-making on the surgical method. Colorectal cancer patients who were assessed with a low physiological risk by PRS would be safe to undergo laparoscopic surgery. On the contrary, surgeons should make decisions prudently on the operation method for patient with a high physiological risk. PMID- 28816960 TI - Successful open reduction and internal fixation for displaced femoral fracture in a patient with osteopetrosis: Case report and lessons learned. AB - RATIONALE: Osteopetrosis is a rare disease that predominantly occurs in descendants of inbreeding families. In the case of fractures happen in patients with osteopetrosis, the choice between operative or conservative treatment is still controversial. Open reduction and internal fixation (ORIF) is a conventional treatment for fractures, and it possesses more applicability than conservative treatment. During this surgical treatment, ensure that bone union in the right way is pivotal to success and simultaneously prevents refracture and displacement after the operation. Herein, we present a case of femoral fracture of a patient with osteopetrosis via open reduction and internal fixation. To illustrate successful factors during the treatment process, we discuss experience combined with literature review following case report. PATIENT CONCERNS: A 67 year-old man who has diagnosed with osteopetrosis over 20 years ago suffered from pain in the left hip last for more than 1 month and he was incapable of walking recently. Before this incident, he had sustained 4 femoral fractures that treated insufficiently by open reduction surgery. DIAGNOSIS: Physical, radiological, and biological examinations indicated a femoral subtrochanteric fracture that was overlapping displacement between fracture ends. INTERVENTIONS AND OUTCOMES: Treated with surgery by open reduction with internal fixation and osteotomy, the fracture united in 12 months, and he returned to walk with full weight bearing, during which no complication occurred. LESSONS: Open reduction and internal fixation is also suitable for the patient with osteopetrosis, and they have similar union ability to the normal. To guarantee successful treatment, specific strategies of operation and rehabilitation program are necessary. PMID- 28816961 TI - Estimating of hepatic fat amount using MRI proton density fat fraction in a real practice setting. AB - The recently developed magnetic resonance imaging (MRI) proton density fat fraction (PDFF) allows measurement of the fat in all segments of hepatic tissue. However, it is time consuming and inconvenient to measure each segment repeatedly. Moreover, volume of each segment also should be adjusted with arithmetic mean of the selected segments when total amount of liver fat is estimated. Therefore, we try to develop a clinically-relevant and applicable method of estimating hepatic fat in PDFF image.A total of 164 adults were enrolled. We addressed the measurement frequency and segment selection to determine the optimal method of measuring intrahepatic fat. Total hepatic fat was estimated by the weighted mean of each segment reflecting their respective segmental volumes. We designed 2 models. In Model 1, we determined the segment order by which the mean was closest to the whole weighted mean. In Model 2, we determined the segment order by which the arithmetic mean of the selected segments was closest to the whole weighted mean.Fat fraction (FF) was most important risk factor of hepatic heterogeneity in multivariable analysis (beta = 0.534, P < .001). In severe fatty liver (FF > 22.1%), intrahepatic fat variability was 2.47% (1.16-6.26%). The arithmetic mean total intrahepatic FF was 12.66%. But the weighted mean that applied to each segmental volume was 12.90%. In Model 1, arithmetic mean of segments 4 and 5 was closest to the total estimated hepatic fat amount. However, when we added segment 8, the mean of segments 4, 5, and 8 was significantly different from the estimated total hepatic fat amount (P = .0021). In Model 2, arithmetic mean of segments 4 and 5 was closest to the total estimated hepatic fat amount. There was a significant reduction in variability between segment 4 and segments 4 and 5 (P < .0001).Averaging the mean hepatic FF of segments 4 and 5 was the most reasonable method for estimating total intrahepatic fat in practice. PMID- 28816962 TI - Relationships of capsule endoscopy Lewis score with clinical disease activity indices, C-reactive protein, and small bowel transit time in pediatric and adult patients with small bowel Crohn's disease. AB - Relationships between the capsule endoscopy Lewis score (LS) and clinical disease activity indices and C-reactive protein (CRP) are controversial in adult patients with Crohn's disease (CD). Also, data on pediatric patients are relatively less. However, correlation between LS and small bowel transit time (SBTT) remains investigational. The aim of the present study was to explore the correlations between LS and clinical disease activity indices, CRP, SBTT in pediatric, and adult patients with small bowel CD.Retrospective, single-center study on consecutive inpatients with established small bowel CD was conducted. The clinical disease activity index was determined using the abbreviated Pediatric Crohn's Disease Activity Index (aPCDAI) in patients aged <18 years and the Harvey Bradshaw Simple Index (HBI) in adults. Spearman's rank correlation coefficient was used to assess the correlations of LS with aPCDAI, HBI, CRP, and SBTT, respectively.150 patients were enrolled (30 children and adolescents). In pediatric patients, correlations between LS and aPCDAI, CRP were moderate (r1 = 0.413; r2 = 0.379; P1 = .023; P2 = .044). There was no correlation between LS and SBTT (r = -0.029; P = .88). In adults, weak correlations were found between LS and HBI, SBTT (r1 = 0.213; r2 = 0.237; P1 = .019; P2 = .009). Correlation between LS and CRP was moderate (r = 0.326; P < .001). Strong correlations were found between CRP and HBI, aPCDAI (r1 = 0.522; r2 = 0.650; P < .001). The follow-up patients were all in clinical remission after treatment within 4 months, whereas only a minority reached mucosal healing. HBI, aPCDAI, CRP, and LS in all patients were reduced after treatment, whereas difference in CRP in pediatric patients and difference in LS in adults between baseline and follow-up were not found to be statistically significant. Also, the average SBTT at baseline was not found to be different from that at follow-up in all patients.The role of capsule endoscopy should be emphasized both in pediatric and adult patients with small bowel CD. Furthermore, the small bowel transit time may not be affected by the grade of small intestinal inflammation. PMID- 28816963 TI - Efficacy and safety evaluation of fludarabine-based chemotherapy regimen for patients with non-Hodgkin lymphoma: A meta-analysis. AB - This meta-analysis was performed to evaluate the efficacy and safety of fludarabine (F)-based regimen for the treatment of non-Hodgkin lymphoma (NHL) compared with other regimens with no F contained.PubMed, Embase, Cochrane Library, Wanfang, VIP, and CNKI databases were searched to identify eligible literatures. R software version 3.12 was used for statistical analysis. Odds ratio (OR) with 95% confidence interval (CI) were utilized to express the complete response, overall response and adverse events outcomes. Egger test was carried out to examine the publication bias and sensitivity analysis was performed to evaluate the stability of our results.Twelve eligible literatures consisting of 1587 patients were included in this study. Greater complete response (OR = 1.66, 95% CI: 0.98-2.80) and overall response (OR = 1.38, 95% CI: 0.85-2.24) were found for patients who received F-based regimen than those received other regimens, although the results were not statistically significant. In addition, F-based regimen was associated with significantly lower risk of adverse events compared with other regimens (OR = 0.46, 95% CI: 0.28-0.74). Results of subgroup analysis showed that significantly lower incidence was presented only for constipation among the 7 specific adverse events (OR = 0.03, 95% CI: 0.01-0.14).F-based chemotherapy regimen was an effective and well tolerated treatment for patients with NHL. PMID- 28816964 TI - The rare Axenfeld-Rieger syndrome with systemic anomalies: A case report and brief review of literature. AB - RATIONALE: Axenfeld-Rieger syndrome (ARS) is a rare autosomal dominant disorder with ocular anterior segment dysgenesis and systemic anomalies. PATIENT CONCERNS: A 28-year-old Chinese Han female was referred to Beijing Tongren Eye Center for progressive decrease of the visual acuity on her right eye in the past month. DIAGNOSES: The patient was diagnosed as ARS with retinal detachment based on series of ophthalmic examinations performed. INTERVENTIONS: A pars plana vitrectomy was performed to manage the retinal detachment. OUTCOMES: Her best corrected visual acuity was slightly improved after surgery. LESSONS: ARS is a developmental defect of ocular anterior segment with various clinical manifestations which might cause misdiagnosis. PMID- 28816965 TI - Blue rubber bleb nevus syndrome: our experience and new endoscopic management. AB - The aim of our study is to enhance the awareness of blue rubber bleb nevus syndrome (BRBNS) through the patients in our hospital and introduced a new measure of endoscopic intervention.A retrospective review of 5 patients, who were diagnosed as BRBNS in our hospital from January 2013 to January 2017, was conducted. Data were collected with regard to demographics, clinical presentation, endoscopic and imaging findings, management, and follow-up data.In total of 5 patients, the mean age was 28.8 years, range 16 to 44 years (male/female, 1/4) with the average initial age of onset 15.4 years. No family history was identified in our group. Physical examination showed multiple cutaneous lesions in 2 patients (40%, 2/5). All the 5 patients had gastrointestinal tract vascular malformations; stomach involved in 2 cases, large intestine in 2 cases, and small intestine involved in 3 cases. Lesions in the visceral organs and tissue were found in 1 patient. Gastrointestinal bleeding was its main symptom (3/5, 60%). Laboratory investigations revealed anemia in 4 patients and abnormality of coagulopathy in 2 patients with severe anemia. Conservative approach was recommended in 3 cases that included iron supplementation, drug hemostasis, and/or blood transfusion. An innovatively therapeutic approach with endoscopic submucosal dissection (ESD) procedure was used successfully in 1 patient with 2 polypoid BRBNS lesions in rectum.BRBNS is a very rare vascular malformation syndrome with unclear etiopathogenesis and noncurative treatments. ESD procedure was a feasible approach to remove the partial gastrointestinal lesions. PMID- 28816966 TI - Causes of hematochezia and hemorrhagic antibiotic-associated colitis in children and adolescents. AB - Diseases causing hematochezia range from benign to potentially life-threatening. Systematic pediatric data on the causes of hematochezia are scarce. We studied the underlying causes and long-term outcome of hematochezia in children. We further investigated the relevance of antibiotic-associated hemorrhagic colitis in children, especially if caused by Klebsiella oxytoca.Infants, children, and adolescents with hematochezia were recruited prospectively. Patients were grouped according to age (<1 year, 1-5 years, 6-13 years, >14 years). In addition to routine diagnostics, K oxytoca stool culture and toxin analysis was performed. We collected data on history, laboratory findings, microbiological diagnostic, imaging, final diagnosis, and long-term outcome.We included 221 patients (female 46%; age 0-19 years). In 98 (44%), hematochezia was caused by infectious diseases. Endoscopy was performed in 30 patients (13.6%). No patient died due to the underlying cause of hematochezia. The most common diagnoses according to age were food protein-induced proctocolitis in infants, bacterial colitis in young children, and inflammatory bowel disease in children and adolescents. Seventeen (7.7%) had a positive stool culture for K oxytoca. Antibiotic-associated colitis was diagnosed in 12 (5%) patients: 2 caused by K oxytoca and 2 by Clostridium difficile; in the remaining 8 patients, no known pathobiont was identified.Infections were the most common cause of hematochezia in this study. In most patients, invasive diagnostic procedures were not necessary. Antibiotic associated hemorrhagic colitis caused by K oxytoca was an uncommon diagnosis in our cohort. Antibiotic-associated colitis with hematochezia might be caused by pathobionts other than C difficile or K oxytoca. PMID- 28816967 TI - Hand-assisted laparoscopic surgery versus conventional open surgery in intraoperative and postoperative outcomes for colorectal cancer: An updated systematic review and meta-analysis. AB - AIM: This meta-analysis aims to compare hand-assisted laparoscopic surgery (HALS) and conventional open surgery (OS) for colorectal cancer (CRC) in terms of intraoperative and postoperative outcomes, and to explore the safety, feasibility of HALS for CRC surgery. METHODS: A systematic literature search with no limits was performed in PubMed, Embase, and Medline. The last search was performed on April 23, 2017. The outcomes of interests included intraoperative outcomes (operative time, blood loss, length of incision, transfusion, and lymph nodes harvested), postoperative outcomes (length of hospital stay, length of postoperative hospital stay, time to first flatus, time to first liquid diet, time to first soft diet, time to first bowel movement, postoperative complications, reoperation, ileus, anastomotic leakage, wound infection, urinary complication, pulmonary infection, and mortality). RESULTS: Fifteen articles published between 2007 and 2017 with a total of 1962 patients with CRC were included in our meta-analysis. HALS was associated with longer operative time, less blood loss, smaller length of incision, shorter hospital days and postoperative hospital days, less time to first flatus, less wound infection, and less postoperative complications. There was no difference in blood transfusion, lymph node harvested, time to first liquid or soft diet, time to first bowel movement, reoperation, ileus, anastomotic leakage, pulmonary infection, urinary complications, or mortality. CONCLUSIONS: Our meta-analysis suggests that HALS in CRC surgery improves cosmesis and results in better postoperative recovery outcomes by reducing postoperative complications and hospital days. Furthermore, a large randomized control study is warranted to compare the short-term and long term outcomes of those 2 techniques for CRC treatment. PMID- 28816968 TI - Two-portal versus three-port video-assist thoracoscopic surgery for early stage nonsmall cell lung cancer: A retrospective study. AB - This study was conducted to compare the perioperative outcomes of two-portal and three-port video-assist thoracoscopic surgery (VATS) for early stage nonsmall cell lung cancer.In this retrospective analysis, 279 cases of two-port VATS with a single utility port and 152 cases of three-port VATS performed by our department from October 2010 to December 2014 were collected. The operative time, volume of intraoperative blood loss, number of dissected lymph nodes, volume of postoperative pleural drainage, postoperative extubation time, and duration of postoperative hospitalization were compared between these 2 groups.No statistically significant differences on the operative time, volume of postoperative bleed, and the number of dissected lymph nodes was noted between two-port and three-port video-assist thoracoscopic surgery. Less postoperative pleural drainage, shorter extubation time, and postoperative hospitalization were observed in the two-port VATS group when compared with those of three-port VTAS groupTwo-port VATS decreased operative postoperative pleural drainage and resulted in shorter extubation time and postoperative hospitalization compared with three-port VATS. Two-port VATS is a safe and feasible approach for early stage nonsmall cell lung cancer. PMID- 28816969 TI - Immediate breast reconstruction with omental flap for luminal breast cancer patients: Ten clinical case reports. AB - RATIONALE: Luminal subtype breast cancer, accounting for 70 to 80% of all breast cancers, has been reported to be associated with good prognosis. However, for the patients with large mass or worse mass position, omental flap transplantation may provide a new option for breast reconstruction. PATIENT CONCERNS: Ten patients (6 luminal B1, 2 luminal B2, 2 luminal A), were enrolled into the study, between January 23, 2015 and August 22, 2016. The mean age was 34.6 +/- 6.96 (24-44) years old. Immunohistochemistry demonstrated that the tumor cells were positive for estrogen receptor and progestrone receptor. DIAGNOSES: According to the clinicopathological features, diagnosis of breast cancer patients were made. INTERVENTIONS: Breast-conserving surgery, laparoscopic greater omentum harvest and vascular anas-tomosis were carried out orderly. Postoperative operative results, cosmetic outcomes, complications, as well as blood supply were investigated for surgery evaluation. Reasonable chemotherapy and irradia-tion were adopted to patients according to the pathological condition. OUTCOMES: We successfully accomplished breast reconstruction by omental flap transplantation, ex-cept one failed case because of the necrosis of omentum and changed to fat transplantation. The volumes and symmetry of breasts were all satisfied. The blood supply was detected to be fluent. Only one case of slight hematoma and another case of one distant metastasis were observed during fol-low-up period. No arm mordities or arm movement restriction occurred after surgery. Moreover, radia tion therapy and chemotherapy had no clear effects on the reconstructed breast. LESSONS: Immediate breast reconstruction surgery by transplanting omental flap for luminal breast cancer patients can be considered successful based on the excellent clinic outcome. PMID- 28816970 TI - Skin metastases in epithelial ovarian and fallopian tube carcinoma. AB - This study aimed to investigate the clinical features and outcomes of skin metastasis in ovarian and fallopian tube carcinomas.We studied patients with epithelial ovarian or fallopian tube carcinoma who developed skin metastasis from 2001 through 2012, and were also treated with chemotherapy and/or surgery.Skin metastases were classified as umbilical metastasis (Sister Joseph nodule [SJN]) and nonumbilical metastasis. Patients who developed skin metastases at paracentesis sites were excluded.Of the 206 patients treated, 12 (5.8%) developed skin metastasis: 7 developed SJN, and 5 developed nonumbilical metastasis. Six patients had serous carcinoma, 3 had clear cell carcinoma, 2 had endometrioid carcinoma, and 1 had adenocarcinoma. Four patients out of the 7 who developed SJN had skin metastasis at initial diagnosis, and all 4 patients had SJN with concomitant peritoneal dissemination. Of the 4 patients, 3 received chemotherapy, and their survival ranged from 22 to 42 months. Of the 7 patients who developed SJN, 3 patients with stage IIIC disease developed an SJN at recurrence and were treated with surgery and/or chemotherapy. Their survival duration after recurrence ranged from 26 to 43+ months. Five patients developed nonumbilical metastases 3 to 53 months (median 34 months) after initial diagnosis: 3 cases occurred in incisional scars of primary surgery, and 2 in subcutaneous metastasis in the other sites. Survival after recurrence ranged from 56 to 140+ months in 3 patients with incisional scar recurrence, and it was 5 months in 2 other patients.Sister Joseph nodule developed only in patients with peritoneal dissemination, and most patients with SJN survived for >24 months. Nonumbilical metastases occurring in incisional scars of primary surgery may carry a favorable prognosis. PMID- 28816971 TI - Combining of serial embolization and denosumab for large sacropelvic giant cell tumor: Case report of 3 cases. AB - RATIONALE: Both serial arterial embolization (SAE) and denosumab have been proved to be effective in treatment for giant cell tumor (GCT). There is potential synergic effect of combining two methods. The purpose of current study is to justify a new treatment strategy of combination of SAE and denosumab as neoadjuvant or stand-alone treatment for large sacropelvic giant cell tumor. PATIENT CONCERNS: Pelvic and sacral GCTs tend to be very large size and vascular. The concerns of surgical treatment were invasiveness of extensive surgery, intraoperative hemorrhage, nerve function jeopardized and local recurrence. However, SAE alone may not be adequate for complete removal of the tumor. DIAGNOSES: All the three cases were proved to be GCT by core-needle biopsy. Post treatment pathological change was confirmed by further biopsy. INTERVENTIONS: The patient in Case 1 diagnosed of large recurrent sacral GCT received 6 times of endovascular embolizations with 2-month interval and started on denosumab simultaneously after first session of embolization. The second case was a 22-year old female presented with a massive iliosacral tumor. SAE was performed for 3 sessions and the denosumab was started simultaneously. The patients was on treatment for half year. Both patients experienced a dramatic decrease in symptoms and concomitant improvement in function after the first embolization and weekly injection of denosumab. Tumor removal was performed on patient in case 2. The last case was a pelvic GCT and the patient received SAE and denosumab for half year. The tumor was then removed with purpose of complete cure. OUTCOMES: The first patient was still on denosumab with stable tumor. The other two patients were both free of recurrence after surgical removal of the tumors. No denosumab was used postoperatively. LESSONS: We reported the first three cases treated by combination of SAE and denosumab in the literature and aim to raise an alternative method for large GCT at challenging anatomical locations, for which surgery would carry significant risk. SAE and denosumab can synergically promote sclerosis and result in significant decrease in pain. It is reasonable to consider using SAE combined with denosumab neoadjuvantly to reduce the extensiveness and morbidity of surgery, however further investigation is warranted. PMID- 28816972 TI - Low second to fourth digit ratio in Dupuytren disease. AB - The ratio of the lengths of the second and fourth digits (2D:4D) has been described as reflecting endogenous prenatal androgen exposure. In general, 2D:4D is lower in men than in women and has potential as a biomarker or predictor for various diseases, athletic ability, and academic performance. Dupuytren disease has digital flexion contractures and is known to predominate in men, but the pathogenesis of the disease remains unclear. To clarify the relationships between Dupuytren disease and endogenous androgens, we performed a retrospective analysis of hand radiographs to investigate 2D:4D in Dupuytren disease. The study included male patients with Dupuytren disease (n = 22) and a control group (n = 18) of male patients with carpal tunnel syndrome. Only unaffected hands, without contractures or osteoarthritis, were evaluated for the purpose of radiographic assessment. The lengths of the phalanx and metacarpal bones in the second and fourth digits were measured by 2 independent observers who each performed 2 sets of measurements separated by a minimum 1-week interval. The 2D:4D was calculated separately for the phalanges and metacarpals, and a combined (phalanx + metacarpal) 2D:4D was also calculated. The reliability of the observer measurements was established using the intraclass correlation coefficient, and both the intra- and interobserver reliability showed excellent agreement. We found that compared with control group, the Dupuytren disease group had significantly lower phalanx and combined 2D:4D. These findings suggest that endogenous prenatal androgens could contribute to the development of Dupuytren disease, leading to its characteristic clinical presentation predominantly in men and affecting the ulnar rays. PMID- 28816973 TI - Soy food intake and risk of gastric cancer: A dose-response meta-analysis of prospective studies. AB - Epidemiological studies were inconsistent on the association between soy food intake and risk of gastric cancer (GC). This study aimed to determine the role of soy food intake in the development of GC.A systematic search was conducted in PubMed and Web of Science to identify all relevant studies. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were pooled using a random-effects model, and the dose-response relationship between soy food intake and GC risk was also assessed.Thirteen prospective studies were identified with a total of 517,106 participants and 5800 cases. Among 11 types of soy food, high intake of total soy food (the highest vs the lowest category: RR: 0.78, 95% CI: 0.62-0.98) and nonfermented soy food (RR: 0.63, 95% CI: 0.50-0.79) were inversely associated with GC risk, while high intake of miso soup was associated with the risk in male (RR: 1.17, 95% CI: 1.02-1.36). In dose-response meta-analysis, total soy food intake (0-150 g/day) showed no significant association with GC risk, while high intake of nonfermented soy food was inversely related, especially an intake of more than 100 g/day. In male, miso soup intake (1-5 cups/day) was significantly associated with GC risk.High intake of nonfermented soy food might reduce the risk of GC, while miso soup intake might increase the risk in male. PMID- 28816974 TI - Efficacy of cortico/cancellous composite allograft in treatment of cervical spondylosis. AB - This was a prospective comparative study.The aim of this study was to compare the clinical and radiologic outcomes of patients treated with cortico/cancellous composite allograft or autoiliac bone graft in anterior cervical discectomy and fusion.Several methods have been developed to fuse the cervical spine for treatment of cervical spondylosis. Cortico/cancellous composite allograft might be another alternative.A total of 46 patients who underwent surgery for treatment of cervical spondylosis were evaluated between September 2010 and January 2015. The duration of operation, blood loss, perioperative complications, neck disability index (NDI), visual analogue scale (VAS), and fusion rates were compared between the 2 groups.There were no significant differences in clinical or radiologic outcomes between the patients treated with cortico/cancellous composite allograft and those treated with autoiliac bone graft. The 2 groups showed similar improvements in clinical symptoms and fusion rates. Although not statistically significant, the subsidence rate was lower in the cortico/cancellous composite group.Cortico/cancellous composite allograft is an effective alternative to conventional allograft or autograft in anterior cervical discectomy and fusion. PMID- 28816975 TI - Incidence and risk factors of posterior cage migration following decompression and instrumented fusion for degenerative lumbar disorders. AB - The aim of this study was to explore the incidence and risk factors for posterior cage migration (PCM) following decompression and instrumented fusion for degenerative lumbar disorders, and hope to provide references in decision making and surgical planning for spine surgeons.By retrieving the medical records from January 2011 to December 2015, 286 patients were retrospectively reviewed. According to the occurrence of PCM, patients were divided into 2 groups: PCM group and non-PCM (N-PCM). To investigate risk values for PCM, 3 categorized factors were analyzed statistically: patient characteristics: age, sex, body mass index, bone mineral density, duration of disease, diagnosis, comorbidity, smoke; surgical variables: surgery time, blood loss, surgical strategy, cage morphology, cage size, surgical segment, fusion number, source of bone graft, surgeon experience; radiographic parameters: preoperative lumbar lordosis, correction of lumbar lordosis, preoperative lumbar mobility, preoperative intervertebral height, change of intervertebral height, Modic changes, paraspinal muscle degeneration.PCM was detected in 18 of 286 patients (6.3%) at follow-up. There was no statistically significant difference between the 2 groups in patient characteristics, except diagnosis, as lumbar spondylolisthesis was more prevalent in PCM group than that in N-PCM group. There was no difference between the 2 groups in surgical variables, except cage size and surgeon experience, as size of cage was smaller in PCM group than that in N-PCM group, and the surgeons with less experience (less than 3 years) were more prevalent in PCM group than that in N-PCM group. There was no statistically significant difference between 2 groups in radiographic parameters. Logistic regression model revealed that less than 3 years of surgeons' experience, small cage size, and lumbar spondylolisthesis were independently associated with PCM.For patients with lumbar spondylolisthesis, they should be fully informed about the risk of PCM before operation. While for spinal surgeons, large cage should be preferred, and careful manipulation should be adopted, especially for new learners with less than 3-year experience of fusion surgery. PMID- 28816976 TI - Comparison of ambulatory blood pressure and clinic blood pressure in relation to cardiovascular diseases in diabetic patients. AB - The aim of this study was to evaluate prognostic values of ambulatory blood pressure (ABP) and clinic blood pressure (CBP) in diabetic patients with hypertension. A total of 450 diabetic hypertensive patients without established cardiovascular diseases were enrolled and 416 patients who had finished 12months' follow-up were included in final analysis. Baseline data were collected and Cox proportional hazards regression analysis was used to evaluate prognostic value of ABP and CBP. Compared to those without study endpoints (n = 370), those experienced study endpoints (n = 46) were more elderly and more likely to be male, and had longer hypertension duration (7.0 +/- 3.0 years vs. 6.4 +/- 2.1 years, P < .05). No significant between-group differences in CBP indices were observed. However, those with study endpoints had significantly higher 24-hour systolic BP (SBP) (134 +/- 10 mmHg vs. 128 +/- 7 mmHg), nighttime SBP (130 +/- 7 mmHg vs. 120 +/- 5 mmHg), night/day SBP ratio (0.97 +/- 0.09 vs. 0.94 +/- 0.08), higher proportion of non-dipping BP pattern (39.1% vs. 31.4%) and higher 24-hour SBP variability. After extensively adjusted for traditional risk factors, nondipping BP pattern and 24-hourSBP, only 24-hour SBP and nighttime SBP remained independently related with cardiovascular outcomes, with hazard ratios and associated 95% confidence interval as 1.53 (1.28-2.03) and 1.50 (1.26-1.89), respectively. Although no independent relationship between BP pattern and cardiovascular outcomes was observed. In summary, in diabetic hypertensive patients without established cardiovascular diseases, baseline 24-hour SBP and nighttime SBP are useful markers for predicting short-term cardiovascular outcomes. PMID- 28816977 TI - Helicobacter pylori infection, atrophic gastritis, and pancreatic cancer risk: A meta-analysis of prospective epidemiologic studies. AB - BACKGROUND: To investigate the associations of Helicobacter pylori (Hp) infection and atrophic gastritis (AG) with pancreatic cancer risk. METHODS: A literature search in PubMed was performed up to July 2017. Only prospective cohort and nested case-control studies enrolling cancer-free participants were eligible. Incident pancreatic cancer cases were ascertained during the follow-up. The risks of pancreatic cancer were compared between persons infected and noninfected with Hp, or between those with and without AG status at baseline. Odds ratios (ORs) or hazard ratios were combined. Subgroup and sensitivity analyses were performed, and publication bias was estimated. RESULTS: Three cohort studies and 6 nested case-control studies, including 65,155 observations, were analyzed. The meta analyses did not confirm the association between pancreatic cancer risk and Hp infection (OR = 1.09, 95% confidence interval [CI] = 0.81-1.47) or AG status (OR = 1.18, 95% CI = 0.80-1.72). However, particular subpopulations potentially had increased risks of pancreatic cancer. Cytotoxin-associated gene A (CagA)-negative strains of Hp might be a causative factor of pancreatic cancer (OR = 1.30, 95% CI = 1.05-1.62), but a sensitivity analysis by leave-one-out method did not fully warrant it (OR = 1.20, 95% CI = 0.93-1.56). In 1 nested case-control study, AG at stomach corpus in Hp-negative subpopulation might have increased risk of pancreatic cancer, but with a poor test power = 0.56. Publication biases were nonsignificant in the present meta-analysis. CONCLUSION: Based on current prospective epidemiologic studies, the linkage of pancreatic cancer to Hp infection or AG status was not warranted on the whole. Nevertheless, prospective studies only focusing on those specific subpopulations are further required to obtain better power. PMID- 28816978 TI - Prognostic value of 18F-FDG-PET/CT parameters in patients with pancreatic carcinoma: A systematic review and meta-analysis. AB - BACKGROUND: The identification of pancreatic carcinoma (PC) patients with poor prognosis is a priority in clinical oncology because of their high 5-year mortality. However, the prognostic value of pretreatment F-fluorodeoxyglucose (F FDG)- positron emission tomography (PET)/computed tomography (CT) parameters in PC patients is controversial and no consensus exists as to its predictive capability. This meta-analysis was performed to comprehensively explore the prognostic significance of F-FDG-PET/CT parameters in patients with pancreatic carcinoma. METHODS: Extensive literature searches of the PubMed, Embase, Web of Science, and Cochrane Library databases were conducted to identify literature published until March 5, 2017. Comparative analyses of the pooled hazard ratios (HRs) for event-free survival (EFS) and overall survival (OS) were performed to assess their correlations with pretreatment maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Either the fixed- or the random-effects model was adopted, depending on the heterogeneity observed across studies. Subgroup and sensitivity analyses were performed to assess the robustness of the results. RESULTS: Sixteen studies including 1146 patients were identified. The pooled HRs for the probability of EFS were 1.90 (95% confidential interval (CI): 1.48-2.45) for SUVmax, 1.76 (95% CI: 1.20-2.58) for MTV, and 1.81 (95% CI: 1.27-2.58) for TLG. The pooled HRs for the probability of OS were 1.21 (95% CI: 1.12-1.31) for SUVmax, 1.56 (95% CI: 1.13-2.16) for MTV, and 1.70 (95% CI: 1.25-2.30) for TLG. A slight publication bias was detected using Begg test. After adjustment using the trim and fill procedure, the corrected HRs were not significantly different. The results of the subgroup analyses by SUVmax, MTV, and TLG showed that these factors may have similar prognostic significance. CONCLUSION: F-FDG-PET/CT parameters, such as SUVmax, MTV, and TLG, may be significant prognostic factors in patients with pancreatic carcinoma. F-FDG-PET/CT imaging could be a promising tool to provide prognostic information for these patients. PMID- 28816979 TI - A new method for locating the proximal lacerated bicanalicular ends in Chinese preschoolers and long-term outcomes after surgical repair. AB - This report is to explore the long-term outcomes of surgical repair of bicanalicular lacerations in Chinese preschool patients. In this report, 12 patients with bicanalicular lacerations were studied between September 2010 and September 2015. The distance from the punctum to the distal canalicular lacerated end was recorded before surgery to classify different types of trauma. All patients underwent surgical repair of the lacerated canaliculi by 1 surgeon within 48 hours after the trauma occurred. After treatment, the lesions were divided into 3 types according to the distance from the punctum to the distal lacerated canalicular end as follows: lateral, medial, and the central. Based on this classification, each lacerated canaliculus was successfully repaired. Nearly half of the lesions (46%) were lateral, 42% were central, and 12% were medial. The average time for locating the proximal lacerated end of the canaliculus was 3.33 +/- 1.52 minutes (range, 1.0-7.0 minutes). The follow-up time ranged from 6.0 months to 4.5 year (median, 25 months). Our study showed that 96% (23) of the canaliculi were completely patent. One lateral lesion presented with residual outdoor epiphora in cold weather secondary to left lower canalicular stenosis. All 12 patients had excellent cosmetic results. Our study displayed a surgical management based on the 3 types of lesions helped to find the proximal lacerated end of the canaliculus, and provided excellent long-term outcomes of drainage function. PMID- 28816980 TI - Two-stage hepatectomy for multiple giant alveolar echinococcosis. AB - Alveolar echinococcosis is a chronically progressive and potentially fatal disease. Patients with multiple giant alveolar echinococcosis have a poor prognosis when radical resection cannot be achieved, but curative resection can be limited by low future remnant liver volumes. In these cases, 2-stage liver resection may be a better choice: after a first-stage hepatectomy with partial resection, liver regeneration is allowed in the residual liver before proceeding to the second-stage hepatectomy. In this study, we therefore retrospectively reviewed and evaluated the safety and feasibility of two-stage hepatectomy in patients with multiple giant alveolar echinococcosis.We reviewed the data for all patients who underwent 2-stage hepatectomy for multiple giant alveolar echinococcosis between August 2013 and December 2015 at either the West China Hospital of Sichuan University or the Hospital of Ganzi Tibetan Autonomous Prefecture.We identified 7 patients in whom 2-stage hepatectomy was completed. During the first-stage hepatectomy, 4 patients underwent right-sided hepatectomy and the other 3 underwent left-sided hepatectomy. The second-stage hepatectomies were successfully performed 3 months after the first-stage procedures. All patients had follow-up durations of >1 year; there were no cases of operation related mortality, and no patients experienced disease recurrence.Two-stage hepatectomy is safe and feasible for patients with multiple giant alveolar echinococcosis. PMID- 28816981 TI - Changes of platelet times neutrophil to lymphocyte ratio predict BCLC stage A hepatocellular carcinoma survival. AB - Platelet, neutrophil, and lymphocyte ratio (PNLR) has its own unique role in influencing postoperative recurrence for patients with hepatocellular carcinoma (HCC). Surgical stress can change systemic inflammatory response of patients. Thus the aim of this study was to identify the prognostic value of changes of platelet times neutrophil to lymphocyte ratio in hepatitis B related HCC within Barcelona clinical liver cancer (BCLC) stage A.Data of patients with HCC within BCLC stage A were reviewed. Pre-, intra- and postoperative variables were retrospectively and statistically analyzed. The postoperative variable was calculated based on the data obtained on the first postoperative month following liver resection.A total of 556 patients were included in present study. During the follow-up period, 257 patients experienced recurrence and 150 patients died. Multivariate analyses suggested multiple tumors (hazard ratio [HR] = 2.409; 95% confidence interval [CI] = 1.649-3.518; P < .001), microvascular invasion (MVI) (HR = 1.585; 95% CI = 1.219-2.061; P = .001), and increased postoperative PNLR (HR = 1.900; 95% CI = 1.468-2.457; P < .001) independently associated with postoperative recurrence, whereas MVI (HR = 1.834; 95% CI = 1.324-2.542; P < .001), postoperative neutrophil to lymphocyte ratio (NLR) (HR = 1.151; 95% CI = 1.025-1.294; P = .018) and increased postoperative PNLR (HR = 2.433; 95% CI = 1.667-3.550; P < .001) contributed to postoperative mortality. The 5-year recurrence-free survival and overall survival rates of patients with increased postoperative PNLR (N = 285) versus those with decreased postoperative PNLR (N = 271) were 36.8% versus 61.5% and 47.6% versus 76.4% respectively (P < .001).Changes of PNLR was a powerful prognostic indicator of poor outcomes in patients with HCC within BCLC stage A. PNLR should be monitored in our postoperative follow-up. PMID- 28816983 TI - Characteristics of Turkish patients with elderly onset psoriatic arthritis: A retrospective cohort study. AB - Psoriatic arthritis (PsA) is a chronic inflamatory disease characterized with axial and peripheral joints involvement. It rarely affects patients older than 65 years old.The purpose of this study is to compare and evaluate the demographic, clinical and laboratory features of elderly-onset psoriatic arthritis (EOPsA) and young-onset (YOPsA) patients.A total of 180 patients diagnosed with PsA according to CASPAR criteria and followed-up in single center were included in this study. The patients with initial symptoms started after age 65 were accepted as EOPsA. Demographic, clinic, and laboratory data and the medications which the patients received were recorded and retrospectively evaluated.Nineteen (10.5%) of 180 patients were diagnosed as EOPsA, and 161 (89.5%) patients were evaluated as YOPsA. The mean patient age was 42.1years for the YOPsA group and 68.3 years for the elderly onset group. Mean duration of disease was 5.6 years for the early onset group and 1.3 years for the elderly onset group (P = .001). Fourteen (73.3%) of 19 EOPsA patients were female and 5 of them were male. Higher rates of fatique, pain scores, comorbid diseases, and acute phase reactants elevation were detected in EOPsA patients comparing to YOPsA (P = .000, P = .000, P = .001, and P = .001, respectively). YOPsA patients have more dactilitis, nail involvement, elevated PASI scores, and smoking habitus when compared with EOPsA patients (P = .019, P = .03, P = .005, P = .004, respectively). In terms of the treatment options chosen, there was no significant difference in the use of nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids (CS), methotrexate (MTX), and sulfasalazine (SSL), but there was a more frequent use of anti-tumor necrosis factor-alpha in the YOPsA group.YOPsA and EOPsA patients may presented with different clinical and laboratory features. EOPsA patients are characterized with higher rates of fatigue, pain scores, comorbid diseases, and acute phase reactants and less dactilitis, nail involvement, and anti-TNF-alpha usage. PMID- 28816982 TI - Performance of procalcitonin in diagnosing parapneumonic pleural effusions: A clinical study and meta-analysis. AB - BACKGROUND: Parapneumonic pleural effusion (PPE) is a common complication of pneumonia. The accurate diagnosis of PPE remains a challenge. Recent studies suggest that procalcitonin (PCT) emerges as a potential biomarker for PPE. Our study aimed to determine the diagnostic value of PCT for PPE by a clinical study and summarize the overall diagnostic performance of PCT through a meta-analysis. METHODS: Demographic and clinical data of the patients with PPE and controls were collected in our clinical study. The diagnostic performances of serum PCT (s-PCT) were analyzed via receiver operating characteristic (ROC) curve analysis, using area under the curve (AUC) as a measure of accuracy. Literature databases were systematically searched for the studies examining the accuracy of PCT for diagnosing PPE. Data on sensitivity, specificity, positive/negative likelihood ratio (PLR/NLR), and diagnostic odds ratio (DOR) were pooled. Summary ROC curves and AUC were used to evaluate overall test performance. RESULTS: In our clinical study, 47 patients with PPE and 101 controls were included. The s-PCT levels were significantly increased in the setting of PPE (5.44 +/- 9.82 ng/mL) compared with malignant PE (0.15 +/- 0.19 ng/mL), tuberculous PE (0.18 +/- 0.16 ng/mL), and transudates (0.09 +/- 0.03 ng/mL) (P < .001). Using a cutoff value of 0.195 ng/mL, the sensitivity and specificity of s-PCT in diagnosing PPE were 0.83 and 0.80, respectively, and AUC was 0.89. In addition, 11 studies were included in our meta-analysis. Summary performance estimates for s-PCT in diagnosing PPE were as follows: sensitivity, 0.78 (95% CI: 0.71-0.84); specificity, 0.74 (95% CI: 0.69-0.78); PLR, 3.46 (95% CI: 2.09-5.74); NLR, 0.27 (95% CI: 0.14-0.54); DOR, 12.37 (95% CI: 4.34-41.17); and AUC, 0.84. The corresponding estimates for p-PCT were as follows: sensitivity, 0.62 (95% CI: 0.57-0.67); specificity, 0.71 (95% CI: 0.68-0.75); PLR 2.31 (95% CI: 1.81-2.95); NLR, 0.47 (95% CI: 0.35-0.63); DOR, 5.48 (95% CI: 3.07-9.77); and AUC, 0.80. CONCLUSION: Both s-PCT and p-PCT might have modest performance in diagnosing PPE. However, more studies on a large scale should be performed to confirm our findings. PMID- 28816984 TI - Age threshold for moderate and severe periodontitis among Korean adults without diabetes mellitus, hypertension, metabolic syndrome, and/or obesity. AB - The purpose of this study is to determine an appropriate age threshold at which to recommend the evaluation of moderate and severe periodontitis among Korean adults.This study involved a cross-sectional analysis using data from the Korean National Health and Nutrition Examination Survey from 2012 to 2014. Incidence rates of periodontitis with the 95% confidence interval (CI) were evaluated. The predictive accuracy of age for periodontitis was determined by calculating the area under curve (AUC) on the basis of the receiver operating characteristic (ROC) curve.The cutoff value of age was 43 years in men having periodontitis with an AUC of 0.70 with 95% CI of 0.69 to 0.72. The AUC was 0.72 (95% CI: 0.70-0.73), and the cutoff value of age (49 years) was identified for the moderate periodontitis in women. The cutoff values for age with AUCs and 95% CI for individuals with periodontitis were 46 years (0.72 [0.71-0.73]), 43 years (0.73 [0.72, 0.74]), 45 years (0.71 [0.70,0.72]), 43 years (0.73 [0.72, 0.74]), and 45 years (0.74 [0.72, 0.75]) for no obesity, no abdominal obesity, no diabetes mellitus, no hypertension, and no metabolic syndrome groups, respectively.This study proposed the guideline for the appropriate age threshold at which to recommend the evaluation of moderate and severe periodontitis for the general population and additionally added the guideline for the individuals without systemic disease including diabetes mellitus, hypertension, metabolic syndrome, and obesity. This study suggests that the participants with certain age may be recommended for the regular periodontal evaluation. PMID- 28816985 TI - The curative effect of liposuction curettage in the treatment of bromhidrosis: A meta-analysis. AB - BACKGROUND: We aimed to understand the curative effect of liposuction curettage (LC) in the treatment of bromhidrosis. METHODS: Relevant studies published before January 2017were searched from the PubMed, Embase, Cochrane Library, Wanfang, VIP, and China National Knowledge Infrastructure databases. Parameters including recurrence, complications, complete response, and overall response were assessed. Meta-analysis was performed using the R 3.12 statistical package. Odds ratio (OR) and 95% confidence interval (95% CI) were used for dichotomous data. Heterogeneity was assessed using Cochran's Q-statistic and I test. In addition, Egger's test was conducted to detect publication bias. RESULTS: Ten studies with a total of 1124 participants (545 cases and 579 controls) were included. There was no statistical difference in recurrence (OR = 1.19, 95% CI: 0.51-2.74), complete response (OR = 0.66, 95% CI: 0.25-1.74), or overall response (OR = 0.63, 95% CI: 0.21-1.87) between the case and control groups. The incidence of complications in the case group was lower than that in the control group (OR = 0.24, 95% CI: 0.08-0.67) and open excision group (OR = 0.11, 95% CI: 0.07-0.19). Publication bias existed for the recurrence index in the open excision group (t = 3.3979, P = .04), but no publication bias was found in other subgroups, indicating stable results. CONCLUSIONS: LC, which has fewer complications, can be considered the primary choice in the treatment of patients with bromhidrosis compared with other surgical procedures. PMID- 28816987 TI - Analysis of background parenchymal echogenicity on breast ultrasound: Correlation with mammographic breast density and background parenchymal enhancement on magnetic resonance imaging. AB - The purpose of this study was to analyze the background parenchymal echotexture (BP echo) on breast ultrasound in detail and to evaluate the relation BP echo with menopausal status. In addition, we correlated BP echo with mammographic breast density (MGD) and background parenchymal enhancement (BPE) on magnetic resonance imaging (MRI).The institutional review board of our hospital approved this retrospective study, and the requirement of informed consent was waived. We studied 138 women (mean age 51.6 years, range from 26 to 79 years) with newly diagnosed invasive breast cancer, who had performed preoperative mammography, ultrasound, and MR from June 2013 to June 2015. BP echo was classified as homogeneous and heterogeneous according to the BI-RADS US lexicon. MGD was described into fatty, scattered, heterogeneously dense, and extremely dense. BPE was categorized as minimal, mild, moderate, and marked. The relationship between the BP echo and menopausal status was investigated. Associations between the degree of BP echo with MGD grades and BPE grades were also evaluated.Of the 138 women, 74 (54%) were premenopausal and 64 (46%) were postmenopausal. Premenopausal women were more likely to have heterogeneous BP echo (60/74, 81%) compared with postmenopausal women (10/64, 16%) (P = .000). BP echo showed significant correlation with BPE in both premenopausal and postmenopausal women (P = .000). However, MGD showed no significant correlation with BP echo or BPE, regardless of menopausal states. In the postmenopausal group, 70% women (21/30) with dense MGD showed homogeneous BP echo and 77% women (23/30) with dense MGD showed nondense BPE.In conclusion, we demonstrated that the BP echo was influenced by menopausal status. Our data support the concept that BP echo is influenced by breast hormonal changes. Because there was a significant association between BP echo and BPE in pre- and post-menopausal women, the BP echo might be a good predictor for BPE. PMID- 28816986 TI - Efficacy and safety of endocrine monotherapy as first-line treatment for hormone sensitive advanced breast cancer: A network meta-analysis. AB - BACKGROUND: Endocrine therapy was recommended as the preferred first-line treatment for hormone receptor-positive (HR+, i.e., ER+ and/or PgR+), human epidermal growth factor receptor-2-negative (HER2-) postmenopausal advanced breast cancer (ABC), but which endocrine monotherapy is optimal lacks consensus. We aimed to identify the optimal endocrine monotherapy with a network meta analysis. METHODS: We performed a network meta-analysis for a comprehensive analysis of 6 first-line endocrine monotherapies (letrozole, anastrozole, exemestane, tamoxifen, fulvestrant 250 mg and 500 mg) for HR+ HER2- metastatic or locally advanced breast cancer in postmenopausal patients. The main outcomes were objective response rate (ORR), time to progression (TTP), and progression-free survival (PFS). Secondary outcomes were adverse events. RESULTS: We identified 27 articles of 8 randomized controlled trials including 3492 patients in the network meta-analysis. For ORR, the treatments ranked in descending order of effectiveness were letrozole > exemestane > anastrozole > fulvestrant 500 mg > tamoxifen > fulvestrant 250 mg. For TTP/PFS, the order was fulvestrant 500 mg > letrozole > anastrozole > exemestane > tamoxifen > fulvestrant 250 mg. We directly compared adverse events and found that tamoxifen produced more hot flash events than fulvestrant 250 mg. CONCLUSIONS: Fulvestrant 500 mg and letrozole might be optimal first-line endocrine monotherapy choices for HR+ HER2- ABC because of efficacious ORR and TTP/PFS, with a favorable tolerability profile. However, direct comparisons among endocrine monotherapies in the first-line therapy setting are still required to robustly demonstrate any differences among these endocrine agents. Clinical choices should also depend on the specific disease situation and duration of endocrine therapy. PMID- 28816988 TI - Relationship between serum adipokine levels and radiographic progression in patients with ankylosing spondylitis: A preliminary 2-year longitudinal study. AB - The immunomodulatory effects of adipokines have been extensively studied in rheumatic diseases, and there is a paucity of information regarding their effects on bone metabolism.The aim of this study was to investigate the relationships between serum adipokines levels and radiographic progression over 2 years in patients with ankylosing spondylitis (AS).In this preliminary longitudinal study, we prospectively recruited 20 consecutive male patients with AS and 11 gender- and age-matched healthy subjects. At the baseline and 2-year follow-up, serum adiponectin, leptin, resistin, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and Dickkopf-1(DKK-1) levels were measured in AS patients using enzyme-linked immunosorbent assays; these measurements were only performed at the baseline for healthy controls. Radiographic progression was determined as the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) progression of >=2 by comparing the baseline and 2-year follow-up radiographs.All AS patients were naive to TNF-alpha blockers at the enrollment and during the 2-year follow-up period and their median disease duration was 51.5 months. At the baseline, the serum resistin, TNF-alpha, and IL-6 levels were significantly higher in AS patients than in controls. At the 2-year follow-up, the median mSASSS of AS patients was found to be significantly increased from the baseline (8-10.5, P = .001) and 7 (35%) AS patients showed radiographic progression. In AS patients, the leptin and resistin levels were significantly higher at the 2-year follow-up than at the baseline. The baseline resistin levels and changes in leptin levels from the baseline to the 2-year follow-up were significantly higher in AS patients with radiographic progression than in those without radiographic progression (P = .002 and .024, respectively). The baseline resistin levels and the increase in leptin levels during the follow-up period significantly correlated with changes in mSASSS (rho = 0.528 and 0.559, P = .017 and .01, respectively). No association between changes in serum adipokine levels and disease activity in AS patients was observed.Our findings suggest that leptin and resistin may contribute to the pathogenesis of new bone formation rather than to inflammatory processes and have the potential to be used as biomarkers of the structural outcome of AS. PMID- 28816990 TI - A randomized controlled trial of botulinum toxin A for treating neuropathic pain in patients with spinal cord injury: Retraction. PMID- 28816989 TI - Disease duration of rheumatoid arthritis is a predictor of vascular stiffness: a cross-sectional study in patients without known cardiovascular comorbidities: A STROBE-compliant article. AB - The aim of this study was to analyze the impact of disease duration on carotid to femoral pulse wave velocity (cfPWV) in rheumatoid arthritis (RA) patients without either known traditional cardiovascular risk factors or previous comorbidities.Patients with RA diagnosis attending the rheumatology outpatient clinic of Hospital Civil Juan I. Menchaca, Guadalajara, Mexico, were analyzed. A total of 106 RA patients without known traditional cardiovascular risk factors were selected. All subjects were evaluated for RA disease duration, RA disease activity score on 28 joints (DAS28), serum lipids, rheumatoid factor and anti cyclic citrullinated peptide (anti-CCP) antibodies. Arterial stiffness was measured as cfPWV by noninvasive tonometry. A multivariate regression model was used to analyze the contribution of RA disease duration and age on cfPWV. cfPWV was positively correlated with age (r = 0.450, P < .001), RA disease duration (r = 0.340, P < .001), total cholesterol (r = 0.312, P = .002), and low density lipoprotein (LDL-c) cholesterol (r = 0.268, P = .012). Patients with a RA disease duration >=10 years exhibited significantly increased cfPWV compared with patients with disease duration <2 years (8.4 +/- 1.8 vs 7.0 +/- 0.8) and >=2 to <10 years (8.4 +/- 1.8 vs 7.8 +/- 1.3), respectively. Age, RA disease duration, and triglycerides were predictors of cfPWV in multivariate analyses. According to the beta-coefficients, each year of disease duration (beta = 0.072) had a greater impact on cfPWV than age (beta = 0.054).Each year of life with RA contributes to a higher rate of vascular aging or stiffening than a year of life without RA. The cumulative damage provided by RA was most pronounced in patients with disease duration >=10 years. PMID- 28816991 TI - A case report of tracheal inflammatory myofibroblastic tumor in a 34-week pregnant woman misdiagnosed with asthma. AB - RATIONALE: Inflammatory myofibroblastic tumor (IMT) is an uncommon neoplastic entity with a tendency of local recurrence and a low risk of distant metastasis. Involvement of trachea is extremely rare. PATIENT CONCERNS: A 34-week pregnant woman previously diagnosed with asthma for 2 months was admitted with persistent wheezing and hemoptysis. A computed tomography scan and bronchoscopy revealed a gigantic polyp in the trachea. DIAGNOSES: Tracheal inflammatory myofibroblastic tumor. INTERVENTIONS: The mass was removed with an electrocautery snare and identified histologically as an IMT. Further immunochemical staining showed strong positive staining for smooth muscle actin and platelet-derived growth factor receptor alpha (PDGFRA), weak positive staining for caldesmon, and negative staining for anaplastic lymphoma kinase (ALK)1, desmin, S-100, and CD34. The tracheal IMT strongly expressed estrogen receptor-alpha (ER-alpha), which indicated that the development of this rare IMT might have been associated with hormone fluctuations that occurred during the pregnancy. OUTCOMES: Follow-up and histological analyses revealed no evidence of recurrence and metastasis. LESSONS: This report describes an extremely rare case of a tracheal IMT that presented a diagnostic dilemma for the clinician and the pathologist. Tracheal IMT is a challenge for the clinician in diagnosis due to the nonspecific clinical presentation. Histology and immunohistochemistry are required to reach an accurate diagnosis of IMT. PMID- 28816992 TI - Are Physician Assistants Needed in Guatemala? A Survey of Potential Urban and Rural Users. AB - PURPOSE: The shortage of trained health care personnel has been increasing worldwide. With the physician assistant (PA) profession, created in the United States in the 1960s, expanding globally, this study sought to ascertain whether PAs can be an innovative solution to this crisis. METHODS: We conducted a convenience sample survey to assess the need for and acceptability of future PA professionals in Guatemala. Eighty-nine doctors, nurses, and community members from rural and urban areas of Guatemala participated in the survey. RESULTS: More urban (70%) than rural (58%) respondents found it difficult to access a doctor, with cost being the major reason (34%). Access in rural areas was reportedly limited by lack of doctors and inaccessible office hours. CONCLUSIONS: Most survey respondents considered PAs to be suitable and potentially helpful providers for Guatemala, with a preference for competencies in the diagnosis of serious illnesses, drug prescription, labor and delivery attendance, and care for injuries and fractures, especially in rural locations. Belonging to the community was deemed very important for a PA who would practice in the country. PMID- 28816993 TI - Parental Guidance Required: How Parents Could Help Reduce the Shortage of Minority Physician Assistants. AB - Physician assistants (PAs) are essential to the health care system, and there are not nearly enough of them to meet the needs of our ethnically diverse population. Factors contributing to a lack of minorities in PA schools are related to academic performance, commitments outside work/school, and social and economic deprivation. From 2014 to 2016, the Texas Area Health Education Center East worked with the University of Texas Medical Branch at Galveston to implement Physician Assistant Learner Support programming. This program, targeting minority high school students, promoted and educated both students and parents about PA careers with the objective of alleviating one of the main barriers to minority higher education-lack of understanding of educational and career opportunities. This study found that parental knowledge about PA application requirements, PA degree requirements, financial aid, and career prospects at the high school level is essential to securing parental support of student selection of PA careers. PMID- 28816994 TI - Global Health Tracks in Physician Assistant Education: Making the Case. PMID- 28816995 TI - Synthesis, Crystal Structure and Luminescent Property of Mg(II) Complex with N Benzenesulphonyl-L-Leucine and 1,10-Phenanthroline. AB - A new complex [Mg(L)2(phen)(H2O)2](phen)(H2O)2 [L= N-benzenesulphonyl-L-leucine] was synthesized by the reaction of magnesium chloride hexahydrate with N benzenesulphonyl-L-leucine and 1,10-phenanthroline in the CH3CH2OH/H2O (v:v = 5:1). It was characterized by elemental analysis, IR and X-ray single crystal diffraction analysis. The crystal of the title complex [Mg(L)2(phen)(H2O)2](phen)(H2O)2 belongs to triclinic, space group P-1 with a = 0.72772(15) nm, b = 1.4279(3) nm, c = 1.4418(3) nm, alpha = 63.53(3) degrees , beta = 79.75(3) degrees , gamma = 81.83(3) degrees , V = 1.3163(5) nm3, Z =1, Dc= 1.258 MUg.m-3, MU = 0.177 mm-1, F(000) = 526, and final R1 = 0.0506, omegaR2 = 0.1328. The complex comprises a six-coordinated magnesium(II) center, with a N2O4 distorted octahedron coordination environment. The molecules are connected by hydrogen bonds and pi-pi stacking to form one dimensional chain structure. The luminescent property of the Mg(II) complex has been investigated in solid. PMID- 28816996 TI - Chemical Bonding of AlH3 Hydride by Al-L2,3 Electron Energy-Loss Spectra and First-Principles Calculations. AB - In a previous study, we used transmission electron microscopy and electron energy loss (EEL) spectroscopy to investigate dehydrogenation of AlH3 particles. In the present study, we systematically examine differences in the chemical bonding states of Al-containing compounds (including AlH3) by comparing their Al-L2,3 EEL spectra. The spectral chemical shift and the fine peak structure of the spectra were consistent with the degree of covalent bonding of Al. This finding will be useful for future nanoscale analysis of AlH3 dehydrogenation toward the cell. PMID- 28816997 TI - Sputtered Modified Barium Titanate for Thin-Film Capacitor Applications. AB - New apparatus and a new process for the sputter deposition of modified barium titanate thin-films were developed. Films were deposited at temperatures up to 900 degrees C from a Ba0.96Ca0.04Ti0.82Zr0.18O3 (BCZTO) target directly onto Si, Ni and Pt surfaces and characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). Film texture and crystallinity were found to depend on both deposition temperature and substrate: above 600 degrees C, the as-deposited films consisted of well facetted crystallites with the cubic perovskite structure. A strongly textured Pt (111) underlayer enhanced the (001) orientation of BCZTO films deposited at 900 degrees C, 10 mtorr pressure and 10% oxygen in argon. Similar films deposited onto a Pt (111) textured film at 700 degrees C and directly onto (100) Si wafers showed relatively larger (011) and diminished intensity (00l) diffraction peaks. Sputter ambients containing oxygen caused the Ni underlayers to oxidize even at 700 degrees C: Raising the process temperature produced more diffraction peaks of NiO with increased intensities. Thin-film capacitors were fabricated using ~500 nm thick BCZTO dielectrics and both Pt and Ni top and bottom electrodes. Small signal capacitance measurements were carried out to determine capacitance and parallel resistance at low frequencies and from these data, the relative permittivity (er) and resistivity (r) of the dielectric films were calculated; values ranged from ~50 to >2,000, and from ~104 to ~1010 Omega?cm, respectively. PMID- 28816998 TI - Magnetic Resonance Characterization of Porous Media Using Diffusion through Internal Magnetic Fields. AB - When a porous material is inserted into a uniform magnetic field, spatially varying fields typically arise inside the pore space due to susceptibility contrast between the solid matrix and the surrounding fluid. As a result, direct measurement of the field variation may provide a unique opportunity to characterize the pore geometry. The sensitivity of nuclear magnetic resonance (NMR) to inhomogeneous field variations through their dephasing effects on diffusing spins is unique and powerful. Recent theoretical and experimental research sheds new light on how to utilize susceptibility-induced internal field gradients to quantitatively probe the microstructure of porous materials. This article reviews ongoing developments based on the stimulated echo-pulse sequence to extend the characterization of porous media using both spatially resolved and unresolved susceptibility-induced internal gradients that operate on a diffusing spin ensemble. PMID- 28816999 TI - X-Nuclei NMR Self-Diffusion Studies in Mesoporous Silica Foam and Microporous MOF CuBTC. AB - A standard X-observe NMR probe was equipped with a z-gradient coil to enable high sensitivity pulsed field gradient NMR diffusion studies of Li+ and Cs+ cations of aqueous salt solutions in a high-porosity mesocellular silica foam (MCF) and of CO2 adsorbed in metal-organic frameworks (MOF). The coil design and the necessary probe modifications, which yield pulsed field gradients of up to +/-16.2Tm-1, are introduced. The system was calibrated at 2H resonance frequency and successfully applied for diffusion studies at 7Li, 23Na, 13C and 133Cs frequencies. Significant reductions of the diffusivities of the cations in LiClac and CsClac solution introduced into MCFs are observed. By comparison of the diffusion behavior with the bulk solutions, a tortuosity of the silica foam of 4.5 +/- 0.6 was derived. Single component self-diffusion of CO2 and CH4 (measured by 1H NMR) as well as self-diffusion of the individual components in CO2/CH4 mixtures was studied in the MOF CuBTC. The experimental results confirm high mobilities of the adsorbed gases and trends for diffusion separation factors predicted by MD simulations. PMID- 28817000 TI - A Gold Nanoparticle and Aflatoxin B1-BSA Conjugates Based Lateral Flow Assay Method for the Analysis of Aflatoxin B1. AB - A rapid and simple immuno-chromatographic assay was developed to detect aflatoxin B1 (AFB1). The assay was based on a modified competitive binding format using colloidal gold and polyclonal antibody (Pab) conjugates. The anti-AFB1 Pab was immobilized to a defined detection zone on a porous nitrocellulose membrane and colloidal gold particles were conjugated to AFB1-BSA which served as a detection reagent. The AFB1-containing sample was added to the membrane and allowed to move with AFB1-BSA-coated particles dried on the conjugation pad. The mixture was then passed along the porous membrane by capillary action past the Pab in the detection zone, which captured AFB1 or AFB1-BSA. AFB1 in the sample inhibits binding of AFB1-BSA conjugated gold particles to the Pab and prevents formation of a red color dot. In the absence of AFB1, AFB1-BSA conjugated gold particles bound to the Pab, give a red color within this detection zone. With this method, 10 MUg/mL of AFB1 was detected in less than 10 min. The developed AFB1 assay also showed no cross reaction to Ochratoxin A (OTA). PMID- 28817001 TI - Electrical Properties of Thin-Film Capacitors Fabricated Using High Temperature Sputtered Modified Barium Titanate. AB - Simple thin-film capacitor stacks were fabricated from sputter-deposited doped barium titanate dielectric films with sputtered Pt and/or Ni electrodes and characterized electrically. Here, we report small signal, low frequency capacitance and parallel resistance data measured as a function of applied DC bias, polarization versus applied electric field strength and DC load/unload experiments. These capacitors exhibited significant leakage (in the range 8-210 MUA/cm2) and dielectric loss. Measured breakdown strength for the sputtered doped barium titanate films was in the range 200 kV/cm -2 MV/cm. For all devices tested, we observed clear evidence for dielectric saturation at applied electric field strengths above 100 kV/cm: saturated polarization was in the range 8-15 MUC/cm2. When cycled under DC conditions, the maximum energy density measured for any of the capacitors tested here was ~4.7 * 10-2 W-h/liter based on the volume of the dielectric material only. This corresponds to a specific energy of ~8 * 10 3 W-h/kg, again calculated on a dielectric-only basis. These results are compared to those reported by other authors and a simple theoretical treatment provided that quantifies the maximum energy that can be stored in these and similar devices as a function of dielectric strength and saturation polarization. Finally, a predictive model is developed to provide guidance on how to tailor the relative permittivities of high-k dielectrics in order to optimize their energy storage capacities. PMID- 28817002 TI - Transparent Conducting Oxides-An Up-To-Date Overview. AB - Transparent conducting oxides (TCOs) are electrical conductive materials with comparably low absorption of electromagnetic waves within the visible region of the spectrum. They are usually prepared with thin film technologies and used in opto-electrical apparatus such as solar cells, displays, opto-electrical interfaces and circuitries. Here, based on a modern database-system, aspects of up-to-date material selections and applications for transparent conducting oxides are sketched, and references for detailed information are given. As n-type TCOs are of special importance for thin film solar cell production, indium-tin oxide (ITO) and the reasonably priced aluminum-doped zinc oxide (ZnO:Al), are discussed with view on preparation, characterization and special occurrences. For completion, the recently frequently mentioned typical p-type delafossite TCOs are described as well, providing a variety of references, as a detailed discussion is not reasonable within an overview publication. PMID- 28817003 TI - Release of Ciprofloxacin-HCl and Dexamethasone Phosphate by Hyaluronic Acid Containing Silicone Polymers. AB - The purpose of this study was to determine the effect of the covalent incorporation of hyaluronic acid (HA) into conventional hydrogel and hydrogels containing silicone as models for contact lens materials on the uptake and release of the fluoroquinolone antibiotic ciprofloxacin and the anti-inflammatory steroid dexamethasone phosphate. A 3 mg/mL ciprofloxacin solution (0.3% w/v) and a 1 mg/mL dexamethasone phosphate solution (0.1%) was prepared in borate buffered saline. Three hydrogel material samples (pHEMA; pHEMA TRIS; DMAA TRIS) were prepared with and without the covalent incorporation of HA of molecular weight (MW) 35 or 132 kDa. Hydrogel discs were punched from a sheet of material with a uniform diameter of 5 mm. Uptake kinetics were evaluated at room temperature by soaking the discs for 24 h. Release kinetics were evaluated by placing the drug loaded discs in saline at 34 degrees C in a shaking water bath. At various time points over 6-7 days, aliquots of the release medium were assayed for drug amounts. The majority of the materials tested released sufficient drug to be clinically relevant in an ophthalmic application, reaching desired concentrations for antibiotic or anti-inflammatory activity in solution. Overall, the silicone based hydrogels (pHEMA TRIS and DMAA TRIS), released lower amounts of drug than the conventional pHEMA material (p < 0.001). Materials with HA MW132 released more ciprofloxacin compared to materials with HA MW35 and lenses without HA (p < 0.02). Some HA-based materials were still releasing the drug after 6 days. PMID- 28817004 TI - Exploring Mass Transfer in Mesoporous Zeolites by NMR Diffusometry. AB - With the advent of mesoporous zeolites, the exploration of their transport properties has become a task of primary importance for the auspicious application of such materials in separation technology and heterogeneous catalysis. After reviewing the potential of the pulsed field gradient method of NMR (PFG NMR) for this purpose in general, in a case study using a specially prepared mesoporous zeolite NaCaA as a host system and propane as a guest molecule, examples of the attainable information are provided. PMID- 28817005 TI - Micro-Imaging by Interference Microscopy: A Case Study of Orientation-Dependent Guest Diffusion in MFI-Type Zeolite Host Crystals. AB - Because of the small particle size, orientation-dependent diffusion measurements in microporous materials remains a challenging task. We highlight here the potential of micro-imaging by interference microscopy in a case study with MFI type crystals in which, although with different accuracies, transient concentration profiles in all three directions can be observed. The measurements, which were performed with "rounded-boat" shaped crystals, reproduce the evolution patterns of the guest profiles recorded in previous studies with the more common "coffin-shaped" MFI crystals. The uptake and release patterns through the four principal faces (which in the coffin-shaped crystals extend in the longitudinal direction) are essentially coincident and there is no perceptible mass transfer in the direction of the long axis. The surface resistances of the four crystal faces through which mass transfer occurs are relatively small and have only a minor effect on the mass transfer rate. As a result of the pore structure, diffusion in the crystallographic c direction (which corresponds to the direction of the long axis) is expected to be much slower than in the transverse directions. This could explain the very low rate of mass transfer observed in the direction of the long axis, but it is also possible that the small end faces of the crystal may have high surface resistance. It is not possible to distinguish unequivocally between these two possibilities. All guest molecules studied (methyl-butane, benzene and 4-methyl-2-pentyne) show the same orientation dependence of mass transfer. The long 4-methyl-2-pentyne molecules would be expected to propagate at very different rates through the straight and sinusoidal channels. The coinciding patterns for uptake through the mutually perpendicular crystal faces therefore provide clear evidence that both the coffin shaped crystals and the rounded-boat-shaped crystals considered in this study, must be intergrowths rather than pure single crystals. PMID- 28817006 TI - Kinetics of Holographic Recording and Spontaneous Erasure Processes in Light Sensitive Liquid Crystal Elastomers. AB - The optical mechanism for imprinting one-dimensional grating structures into thin films of a light-sensitive monodomain liquid crystal elastomer is investigated by analyzing the time dependence of optical diffraction properties. The recording kinetics shows an irregular oscillatory behavior, which is most expressed at small grating spacings and at temperatures close to the nematic-isotropic phase transition. The oscillations are attributed to the opto-mechanical response of the film, i.e., to contraction of the film during the recording process. At temperatures far below the nematic-isotropic phase transition, the spontaneous erasure kinetics exhibits exponential relaxation with relaxation time following the Arrhenius activation law. However, at temperatures close to the nematic isotropic phase transition, the erasure process shows an interesting nonmonotonic behavior that we attribute to the non-linear relation between the concentration of the photo-transformed chemical groups and the nematic order parameter. PMID- 28817007 TI - Photonic Crystal Structure and Coloration of Wing Scales of Butterflies Exhibiting Selective Wavelength Iridescence. AB - The coloration of butterflies that exhibit human visible iridescence from violet to green has been elucidated. Highly tilted multilayers of cuticle on the ridges, which were found in the scales of male S. charonda and E. mulciber butterflies, produce a limited-view, selective wavelength iridescence (ultraviolet (UV)~green) as a result of multiple interference between the cuticle-air layers. The iridescence from C. ataxus originates from multilayers in the groove plates between the ridges and ribs. The interference takes place between the top and bottom surfaces of each layer and incoherently between different layers. Consequently, the male with the layers that are ~270 nm thick reflects light of UV~560 nm (green) and the female with the layers that are ~191 nm thick reflects light of UV~400 nm (violet). T. aeacus does not produce the iridescent sheen which T. magellanus does. No iridescent sheen is ascribed to microrib layers, which are perpendicular to the scale plane, so that they cannot reflect any backscattering. The structures of these butterflies would provide us helpful hints to manipulate light in photoelectric devices, such as blue or UV LEDs. PMID- 28817008 TI - Biophotopol: A Sustainable Photopolymer for Holographic Data Storage Applications. AB - Photopolymers have proved to be useful for different holographic applications such as holographic data storage or holographic optical elements. However, most photopolymers have certain undesirable features, such as the toxicity of some of their components or their low environmental compatibility. For this reason, the Holography and Optical Processing Group at the University of Alicante developed a new dry photopolymer with low toxicity and high thickness called biophotopol, which is very adequate for holographic data storage applications. In this paper we describe our recent studies on biophotopol and the main characteristics of this material. PMID- 28817009 TI - Semiconductor CdF2:Ga and CdF2:In Crystals as Media for Real-Time Holography. AB - Monocrystalline cadmium fluoride is a dielectric solid that can be converted into a semiconductor by doping with donor impurities and subsequent heating in the reduction atmosphere. For two donor elements, Ga and In, the donor ("shallow") state is a metastable one separated from the ground ("deep") state by a barrier. Photoinduced deep-to-shallow state transition underlies the photochromism of CdF2:Ga and CdF2:In. Real-time phase holograms are recorded in these crystals capable of following up optical processes in a wide frequency range. The features of photochromic transformations in CdF2:Ga and CdF2:In crystals as well as holographic characteristics of these media are discussed. Exemplary applications of CdF2-based holographic elements are given. PMID- 28817010 TI - Investigating the Defect Structures in Transparent Conducting Oxides Using X-ray and Neutron Scattering Techniques. AB - Transparent conducting oxide (TCO) materials are implemented into a wide variety of commercial devices because they possess a unique combination of high optical transparency and high electrical conductivity. Created during the processing of the TCOs, defects within the atomic-scale structure are responsible for their desirable optical and electrical properties. Therefore, studying the defect structure is essential to a better understanding of the behavior of transparent conductors. X-ray and neutron scattering techniques are powerful tools to investigate the atomic lattice structural defects in these materials. This review paper presents some of the current developments in the study of structural defects in n-type TCOs using x-ray diffraction (XRD), neutron diffraction, extended x-ray absorption fine structure (EXAFS), pair distribution functions (PDFs), and x-ray fluorescence (XRF). PMID- 28817011 TI - Diamond-Structured Photonic Crystals with Graded Air Spheres Radii. AB - A diamond-structured photonic crystal (PC) with graded air spheres radii was fabricated successfully by stereolithography (SL) and gel-casting process. The graded radii in photonic crystal were formed by uniting different radii in photonic crystals with a uniform radius together along the G-X direction. The stop band was observed between 26.1 GHz and 34.3 GHz by reflection and transmission measurements in the direction. The result agreed well with the simulation attained by the Finite Integration Technique (FIT). The stop band width was 8.2 GHz and the resulting gap/midgap ratio was 27.2%, which became respectively 141.4% and 161.9% of the perfect PC. The results indicate that the stop band width of the diamond-structured PC can be expanded by graded air spheres radii along the G-X direction, which is beneficial to develop a multi bandpass filter. PMID- 28817012 TI - Optical Isolator Utilizing Surface Plasmons. AB - Feasibility of usage of surface plasmons in a new design of an integrated optical isolator has been studied. In the case of surface plasmons propagating at a boundary between a transition metal and a double-layer dielectric, there is a significant difference of optical loss for surface plasmons propagating in opposite directions. Utilizing this structure, it is feasible to fabricate a competitive plasmonic isolator, which benefits from a broad wavelength operational bandwidth and a good technological compatibility for integration into the Photonic Integrated Circuits (PIC). The linear dispersion relation was derived for plasmons propagating in a multilayer magneto-optical slab. PMID- 28817013 TI - Alkylation of Benzene with Propylene in a Flow-Through Membrane Reactor and Fixed Bed Reactor: Preliminary Results. AB - Benzene alkylation with propylene was studied in the gas phase using a catalytic membrane reactor and a fixed-bed reactor in the temperature range of 200-300 degrees C and with a weight hourly space velocity (WHSV) of 51 h-1. beta-zeolite was prepared by hydrothermal synthesis using silica, aluminum metal and TEAOH as precursors. The membrane's XRD patterns showed good crystallinity for the beta zeolite film, while scanning electron microscopy SEM results indicated that its random polycrystalline film was approximately 1 MUm thick. The powders' specific area was determined to be 400 m2*g-1 by N2 adsorption/desorption, and the TPD results indicated an overall acidity of 3.4 mmol NH3*g-1. Relative to the powdered catalyst, the catalytic membrane showed good activity and product selectivity for cumene. PMID- 28817014 TI - Flux Dynamics in Y358 Superconductors. AB - Thermally activated flux motion and specific electric resistance in Y358 were studied under different magnetic fields ranging from 0 to 15 kOe. Through investigating the broadening of normal-superconducting transition, we found that the thermally-activated-flux-motion model can describe the electronic effect near the superconducting transition temperature. By modifying this model, specific electric resistance at different magnetic fields was calculated. PMID- 28817015 TI - Strained Silicon Photonics. AB - A review of recent progress in the field of strained silicon photonics is presented. The application of strain to waveguide and photonic crystal structures can be used to alter the linear and nonlinear optical properties of these devices. Here, methods for the fabrication of strained devices are summarized and recent examples of linear and nonlinear optical devices are discussed. Furthermore, the relation between strain and the enhancement of the second order nonlinear susceptibility is investigated, which may enable the construction of optically active photonic devices made of silicon. PMID- 28817016 TI - Transformation-Induced Creep and Creep Recovery of Shape Memory Alloy. AB - If the shape memory alloy is subjected to the subloop loading under the stress controlled condition, creep and creep recovery can appear based on the martensitic transformation. In the design of shape memory alloy elements, these deformation properties are important since the deflection of shape memory alloy elements can change under constant stress. The conditions for the progress of the martensitic transformation are discussed based on the kinetics of the martensitic transformation for the shape memory alloy. During loading under constant stress rate, temperature increases due to the stress-induced martensitic transformation. If stress is held constant during the martensitic transformation stage in the loading process, temperature decreases and the condition for the progress of the martensitic transformation is satisfied, resulting in the transformation-induced creep deformation. If stress is held constant during the reverse transformation stage in the unloading process, creep recovery appears due to the reverse transformation. The details for these thermomechanical properties are investigated experimentally for TiNi shape memory alloy, which is most widely used in practical applications. The volume fraction of the martensitic phase increases in proportion to an increase in creep strain. PMID- 28817017 TI - Surface Fractal Analysis for Estimating the Fracture Energy Absorption of Nanoparticle Reinforced Composites. AB - In this study, the fractal dimensions of failure surfaces of vinyl ester based nanocomposites are estimated using two classical methods, Vertical Section Method (VSM) and Slit Island Method (SIM), based on the processing of 3D digital microscopic images. Self-affine fractal geometry has been observed in the experimentally obtained failure surfaces of graphite platelet reinforced nanocomposites subjected to quasi-static uniaxial tensile and low velocity punch shear loading. Fracture energy and fracture toughness are estimated analytically from the surface fractal dimensionality. Sensitivity studies show an exponential dependency of fracture energy and fracture toughness on the fractal dimensionality. Contribution of fracture energy to the total energy absorption of these nanoparticle reinforced composites is demonstrated. For the graphite platelet reinforced nanocomposites investigated, surface fractal analysis has depicted the probable ductile or brittle fracture propagation mechanism, depending upon the rate of loading. PMID- 28817018 TI - In-Line Phase-Contrast X-ray Imaging and Tomography for Materials Science. AB - X-ray phase-contrast imaging and tomography make use of the refraction of X-rays by the sample in image formation. This provides considerable additional information in the image compared to conventional X-ray imaging methods, which rely solely on X-ray absorption by the sample. Phase-contrast imaging highlights edges and internal boundaries of a sample and is thus complementary to absorption contrast, which is more sensitive to the bulk of the sample. Phase-contrast can also be used to image low-density materials, which do not absorb X-rays sufficiently to form a conventional X-ray image. In the context of materials science, X-ray phase-contrast imaging and tomography have particular value in the 2D and 3D characterization of low-density materials, the detection of cracks and voids and the analysis of composites and multiphase materials where the different components have similar X-ray attenuation coefficients. Here we review the use of phase-contrast imaging and tomography for a wide variety of materials science characterization problems using both synchrotron and laboratory sources and further demonstrate the particular benefits of phase contrast in the laboratory setting with a series of case studies. PMID- 28817019 TI - "Pore-Like" Effects of Super-Molecular Self-Assembly on Molecular Diffusion of Poly(Ethylene Oxide)-Poly(Propylene Oxide)-Poly(Ethylene Oxide) in Water. AB - Molecular diffusion of triblock copolymers poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) in water was studied with the help of Pulsed Field Gradient NMR in the broad range of polymer weight fractions from 0.09 to 0.8. Owing to amphiphilic nature of the molecules, these block copolymers exhibit rich self-organization properties when mixed with water. In particular, at ambient temperatures they form micelles and three liquid crystalline mesophases: cubic, hexagonal, and lamellar. The corresponding super-molecular structure formations were studied with the same block copolymer and at the same temperature. Self assembly of molecules was shown to produce "pore-like" effects on their self diffusion properties by imposing severe constraints on the dimensionality of propagation. Diffusion in the hexagonal phase was shown to be quasi one dimensional in the direction parallel to the long axis of the ordered molecular rods. In the lamellar phase, diffusion was found to be quasi two-dimensional, in the plane of the lamellar structures. The observed diffusion anisotropy was attributed to the effects of the specific molecular ordering on the mesoscopic length scale. PMID- 28817020 TI - Direct Wafer Bonding and Its Application to Waveguide Optical Isolators. AB - This paper reviews the direct bonding technique focusing on the waveguide optical isolator application. A surface activated direct bonding technique is a powerful tool to realize a tight contact between dissimilar materials. This technique has the potential advantage that dissimilar materials are bonded at low temperature, which enables one to avoid the issue associated with the difference in thermal expansion. Using this technique, a magneto-optic garnet is successfully bonded on silicon, III-V compound semiconductors and LiNbO3. As an application of this technique, waveguide optical isolators are investigated including an interferometric waveguide optical isolator and a semileaky waveguide optical isolator. The interferometric waveguide optical isolator that uses nonreciprocal phase shift is applicable to a variety of waveguide platforms. The low refractive index of buried oxide layer in a silicon-on-insulator (SOI) waveguide enhances the magneto-optic phase shift, which contributes to the size reduction of the isolator. A semileaky waveguide optical isolator has the advantage of large fabrication-tolerance as well as a wide operation wavelength range. PMID- 28817022 TI - Influences of Sample Preparation on Nanoindentation Behavior of a Zr-Based Bulk Metallic Glass. AB - Influences of two different sample preparation methods, mechanical polishing and plunge cutting, on nanoindentation behavior of a Zr-based bulk metallic glass were studied. Mechanical polishing suppresses the serrated flow but promotes the creep. In contrast, plunge cutting promotes the serrated flow but suppresses the creep. However, hardness and elastic modulus obtained from these two methods are nearly the same. PMID- 28817021 TI - Extrinsic and Intrinsic Frequency Dispersion of High-k Materials in Capacitance Voltage Measurements. AB - In capacitance-voltage (C-V) measurements, frequency dispersion in high-k dielectrics is often observed. The frequency dependence of the dielectric constant (k-value), that is the intrinsic frequency dispersion, could not be assessed before suppressing the effects of extrinsic frequency dispersion, such as the effects of the lossy interfacial layer (between the high-k thin film and silicon substrate) and the parasitic effects. The effect of the lossy interfacial layer on frequency dispersion was investigated and modeled based on a dual frequency technique. The significance of parasitic effects (including series resistance and the back metal contact of the metal-oxide-semiconductor (MOS) capacitor) on frequency dispersion was also studied. The effect of surface roughness on frequency dispersion is also discussed. After taking extrinsic frequency dispersion into account, the relaxation behavior can be modeled using the Curie-von Schweidler (CS) law, the Kohlrausch-Williams-Watts (KWW) relationship and the Havriliak-Negami (HN) relationship. Dielectric relaxation mechanisms are also discussed. PMID- 28817023 TI - Atomistic Modeling of the Negative Thermal Expansion in delta- Plutonium Based on the Two-State Description. AB - The delta phase of plutonium with the fcc structure exhibits an unusual negative thermal expansion (NTE) over its narrow temperature range of stability, 593-736 K. An accurate description of the anomalous high-temperature volume effect of plutonium goes beyond the current capability of electronic-structure calculations. We propose an atomistic scheme to model the thermodynamic properties of delta-Pu based on the two-state model of Weiss for the Invar alloys, inspired by the simple free-energy analysis previously conducted by Lawson et al. The two-state mechanism is incorporated into the atomistic description of a many-body interacting system. Two modified embedded atom method potentials are employed to represent the binding energies of two competing electronic states in delta-Pu. We demonstrate how the NTE takes place in delta-Pu by means of Monte Carlo simulations implemented with the two-state mechanism. PMID- 28817025 TI - Glass Fiber Reinforced Polypropylene Mechanical Properties Enhancement by Adhesion Improvement. AB - Glass fibers (GF) are the reinforcement agent most used in polypropylene (PP) based composites, as they have good balance between properties and costs. However, their final properties are mainly determined by the strength and stability of the polymer-fiber interphase. Fibers do not act as an effective reinforcing material when the adhesion is weak. Also, the adhesion between phases can be easily degraded in aggressive environmental conditions such as high temperatures and/or elevated moisture, and by the stress fields to which the material may be exposed. Many efforts have been done to improve polymer-glass fiber adhesion by compatibility enhancement. The most used techniques include modifications in glass surface, polymer matrix and/or both. However, the results obtained do not show a good costs/properties improvement relationship. The aim of this work is to perform an accurate analysis regarding methods for GF/PP adhesion improvement and to propose a new route based on PP in-situ polymerization onto fibers. This route involves the modification of fibers with an aluminum alkyl and hydroxy-alpha-olefin and from there to enable the growth of the PP chains using direct metallocenic copolymerization. The adhesion improvements were further proved by fragmentation test, as well as by mechanical properties measurements. The strength and toughness increases three times and the interfacial strength duplicates in PP/GF composites prepared with in-situ polymerized fibers. PMID- 28817024 TI - Formation of Degenerate Band Gaps in Layered Systems. AB - In the review, peculiarities of spectra of one-dimensional photonic crystals made of anisotropic and/or magnetooptic materials are considered. The attention is focused on band gaps of a special type-the so called degenerate band gaps which are degenerate with respect to polarization. Mechanisms of formation and properties of these band gaps are analyzed. Peculiarities of spectra of photonic crystals that arise due to the linkage between band gaps are discussed. Particularly, it is shown that formation of a frozen mode is caused by linkage between Brillouin and degenerate band gaps. Also, existence of the optical Borrmann effect at the boundaries of degenerate band gaps and optical Tamm states at the frequencies of degenerate band gaps are analyzed. PMID- 28817026 TI - Strain Measurements within Fiber Boards. Part I: Inhomogeneous Strain Distribution within Medium Density Fiberboards (MDF) Loaded Perpendicularly to the Plane of the Board. AB - Internal bond strength testing is a widely used approach for testing quality traits of wood based panels. Generally, failure of internal bond specimens is due to adhesion and/or wood failure in the specimen. It has been reported that a composite product with a large variation in the vertical density profile fails in the center part of the board which is either the middle of the core layer or the transition zone between core layer and face layer. The density in the failure zone is typically 50% lower than the maximum density in the face layers. The aim of this study was to analyze the strain distribution in a specimen under tension perpendicular to the panel plane. The results showed that a high variety of strain magnitude occurred in the specimen. The strain is either aligned with the tension direction or a tension zone is built in one of the edge zones leading to failure. Vector graphics of the specimen show the problematic test setup of internal bond strength measurement. Strain spots in the edges lead to the assumption of an uneven stress distribution due to the momentum which results from non-perfect alignment or irregularities in the test setup. PMID- 28817027 TI - Two Decades of Negative Thermal Expansion Research: Where Do We Stand? AB - Negative thermal expansion (NTE) materials have become a rapidly growing area of research over the past two decades. The initial discovery of materials displaying NTE over a large temperature range, combined with elucidation of the mechanism behind this unusual property, was followed by predictions that these materials will find use in various applications through controlled thermal expansion composites. While some patents have been filed and devices built, a number of obstacles have prevented the widespread implementation of NTE materials to date. This paper reviews NTE materials that contract due to transverse atomic vibrations, their potential for use in controlled thermal expansion composites, and known problems that could interfere with such applications. PMID- 28817028 TI - Transition Metal Compounds Towards Holography. AB - We have successfully proposed the application of transition metal compounds in holographic recording media. Such compounds feature an ultra-fast light-induced linkage isomerization of the transition-metal-ligand bond with switching times in the sub-picosecond regime and lifetimes from microseconds up to hours at room temperature. This article highlights the photofunctionality of two of the most promising transition metal compounds and the photophysical mechanisms that are underlying the hologram recording. We present the latest progress with respect to the key measures of holographic media assembled from transition metal compounds, the molecular embedding in a dielectric matrix and their impressive potential for modern holographic applications. PMID- 28817029 TI - Structural and Mechanical Characterization of Zr58.5Ti8.2Cu14.2Ni11.4Al7.7 Bulk Metallic Glass. AB - Thermal stability, structure and mechanical properties of the multi-component Zr58.5Ti8.2Cu14.2Ni11.4Al7.7 bulk metallic glass have been studied in detail. The glassy material displays good thermal stability against crystallization and a fairly large supercooled liquid region of 52 K. During heating, the alloy transforms into a metastable icosahedral quasicrystalline phase in the first stage of crystallization. At high temperatures, the quasicrystalline phase undergoes a transformation to form tetragonal and cubic NiZr2-type phases. Room temperature compression tests of the as-cast sample show good mechanical properties, namely, high compressive strength of about 1,630 MPa and fracture strain of 3.3%. This is combined with a density of 6.32 g/cm3 and values of Poisson's ratio and Young's modulus of 0.377 and 77 GPa, respectively. The mechanical properties of the glass can be further improved by cold rolling. The compressive strength rises to 1,780 MPa and the fracture strain increases to 8.3% for the material cold-rolled to a diameter reduction of 10%. PMID- 28817030 TI - Statistical and Graphical Assessment of Circumferential and Radial Hardness Variation of AISI 4140, AISI 1020 and AA 6082 Aluminum Alloy. AB - Hardness homogeneity of the commonly used structural ferrous and nonferrous engineering materials is of vital importance in the design stage, therefore, reliable information regarding material properties homogeneity should be validated and any deviation should be addressed. In the current study the hardness variation, over wide spectrum radial locations of some ferrous and nonferrous structural engineering materials, was investigated. Measurements were performed over both faces (cross-section) of each stock bar according to a pre specified stratified design, ensuring the coverage of the entire area both in radial and circumferential directions. Additionally the credibility of the apparatus and measuring procedures were examined through a statistically based calibration process of the hardness reference block. Statistical and response surface graphical analysis are used to examine the nature, adequacy and significance of the measured hardness values. Calibration of the apparatus reference block proved the reliability of the measuring system, where no strong evidence was found against the stochastic nature of hardness measures over the various stratified locations. Also, outlier elimination procedures were proved to be beneficial only at fewer measured points. Hardness measurements showed a dispersion domain that is within the acceptable confidence interval. For AISI 4140 and AISI 1020 steels, hardness is found to have a slight decrease trend as the diameter is reduced, while an opposite behavior is observed for AA 6082 aluminum alloy. However, no definite significant behavior was noticed regarding the effect of the sector sequence (circumferential direction). PMID- 28817031 TI - A Series of Supramolecular Complexes for Solar Energy Conversion via Water Reduction to Produce Hydrogen: An Excited State Kinetic Analysis of Ru(II),Rh(III),Ru(II) Photoinitiated Electron Collectors. AB - Mixed-metal supramolecular complexes have been designed that photochemically absorb solar light, undergo photoinitiated electron collection and reduce water to produce hydrogen fuel using low energy visible light. This manuscript describes these systems with an analysis of the photophysics of a series of six supramolecular complexes, [{(TL)2Ru(dpp)}2RhX2](PF6)5 with TL = bpy, phen or Ph2phen with X = Cl or Br. The process of light conversion to a fuel requires a system to perform a number of complicated steps including the absorption of light, the generation of charge separation on a molecular level, the reduction by one and then two electrons and the interaction with the water substrate to produce hydrogen. The manuscript explores the rate of intramolecular electron transfer, rate of quenching of the supramolecules by the DMA electron donor, rate of reduction of the complex by DMA from the 3MLCT excited state, as well as overall rate of reduction of the complex via visible light excitation. Probing a series of complexes in detail exploring the variation of rates of important reactions as a function of sub-unit modification provides insight into the role of each process in the overall efficiency of water reduction to produce hydrogen. The kinetic analysis shows that the complexes display different rates of excited state reactions that vary with TL and halide. The role of the MLCT excited state is elucidated by this kinetic study which shows that the 3MLCT state and not the 3MMCT is likely that key contributor to the photoreduction of these complexes. The kinetic analysis of the excited state dynamics and reactions of the complexes are important as this class of supramolecules behaves as photoinitiated electron collectors and photocatalysts for the reduction of water to hydrogen. PMID- 28817032 TI - Buckling of Carbon Nanotubes: A State of the Art Review. AB - The nonlinear mechanical response of carbon nanotubes, referred to as their "buckling" behavior, is a major topic in the nanotube research community. Buckling means a deformation process in which a large strain beyond a threshold causes an abrupt change in the strain energy vs. deformation profile. Thus far, much effort has been devoted to analysis of the buckling of nanotubes under various loading conditions: compression, bending, torsion, and their certain combinations. Such extensive studies have been motivated by (i) the structural resilience of nanotubes against buckling, and (ii) the substantial influence of buckling on their physical properties. In this contribution, I review the dramatic progress in nanotube buckling research during the past few years. PMID- 28817033 TI - Acetic and Acrylic Acid Molecular Imprinted Model Silicone Hydrogel Materials for Ciprofloxacin-HCl Delivery. AB - Contact lenses, as an alternative drug delivery vehicle for the eye compared to eye drops, are desirable due to potential advantages in dosing regimen, bioavailability and patient tolerance/compliance. The challenge has been to engineer and develop these materials to sustain drug delivery to the eye for a long period of time. In this study, model silicone hydrogel materials were created using a molecular imprinting strategy to deliver the antibiotic ciprofloxacin. Acetic and acrylic acid were used as the functional monomers, to interact with the ciprofloxacin template to efficiently create recognition cavities within the final polymerized material. Synthesized materials were loaded with 9.06 mM, 0.10 mM and 0.025 mM solutions of ciprofloxacin, and the release of ciprofloxacin into an artificial tear solution was monitored over time. The materials were shown to release for periods varying from 3 to 14 days, dependent on the loading solution, functional monomer concentration and functional monomer:template ratio, with materials with greater monomer:template ratio (8:1 and 16:1 imprinted) tending to release for longer periods of time. Materials with a lower monomer:template ratio (4:1 imprinted) tended to release comparatively greater amounts of ciprofloxacin into solution, but the release was somewhat shorter. The total amount of drug released from the imprinted materials was sufficient to reach levels relevant to inhibit the growth of common ocular isolates of bacteria. This work is one of the first to demonstrate the feasibility of molecular imprinting in model silicone hydrogel-type materials. PMID- 28817035 TI - Metal-Exchanged beta Zeolites as Catalysts for the Conversion of Acetone to Hydrocarbons. AB - Various metal-beta zeolites have been synthesized under similar ion-exchange conditions. During the exchange process, the nature and acid strength of the used cations modified the composition and textural properties as well as the Bronsted and Lewis acidity of the final materials. Zeolites exchanged with divalent cations showed a clear decrease of their surface Bronsted acidity and an increase of their Lewis acidity. All materials were active as catalysts for the transformation of acetone into hydrocarbons. Although the protonic zeolite was the most active in the acetone conversion (96.8% conversion), the metal-exchanged zeolites showed varied selectivities towards different products of the reaction. In particular, we found the Cu-beta to have a considerable selectivity towards the production of isobutene from acetone (over 31% yield compared to 7.5% of the protonic zeolite). We propose different reactions mechanisms in order to explain the final product distributions. PMID- 28817034 TI - Advances in Retinal Tissue Engineering. AB - Retinal degenerations cause permanent visual loss and affect millions world-wide. Current treatment strategies, such as gene therapy and anti-angiogenic drugs, merely delay disease progression. Research is underway which aims to regenerate the diseased retina by transplanting a variety of cell types, including embryonic stem cells, fetal cells, progenitor cells and induced pluripotent stem cells. Initial retinal transplantation studies injected stem and progenitor cells into the vitreous or subretinal space with the hope that these donor cells would migrate to the site of retinal degeneration, integrate within the host retina and restore functional vision. Despite promising outcomes, these studies showed that the bolus injection technique gave rise to poorly localized tissue grafts. Subsequently, retinal tissue engineers have drawn upon the success of bone, cartilage and vasculature tissue engineering by employing a polymeric tissue engineering approach. This review will describe the evolution of retinal tissue engineering to date, with particular emphasis on the types of polymers that have routinely been used in recent investigations. Further, this review will show that the field of retinal tissue engineering will require new types of materials and fabrication techniques that optimize the survival, differentiation and delivery of retinal transplant cells. PMID- 28817036 TI - Biodegradable Orthopedic Magnesium-Calcium (MgCa) Alloys, Processing, and Corrosion Performance. AB - Magnesium-Calcium (Mg-Ca) alloy has received considerable attention as an emerging biodegradable implant material in orthopedic fixation applications. The biodegradable Mg-Ca alloys avoid stress shielding and secondary surgery inherent with permanent metallic implant materials. They also provide sufficient mechanical strength in load carrying applications as opposed to biopolymers. However, the key issue facing a biodegradable Mg-Ca implant is the fast corrosion in the human body environment. The ability to adjust degradation rate of Mg-Ca alloys is critical for the successful development of biodegradable orthopedic implants. This paper focuses on the functions and requirements of bone implants and critical issues of current implant biomaterials. Microstructures and mechanical properties of Mg-Ca alloys, and the unique properties of novel magnesium-calcium implant materials have been reviewed. Various manufacturing techniques to process Mg-Ca based alloys have been analyzed regarding their impacts on implant performance. Corrosion performance of Mg-Ca alloys processed by different manufacturing techniques was compared. In addition, the societal and economical impacts of developing biodegradable orthopedic implants have been emphasized. PMID- 28817037 TI - Preparation and Thermal Characterization of Annealed Gold Coated Porous Silicon. AB - Porous silicon (PSi) layers were formed on a p-type Si wafer. Six samples were anodised electrically with a 30 mA/cm2 fixed current density for different etching times. The samples were coated with a 50-60 nm gold layer and annealed at different temperatures under Ar flow. The morphology of the layers, before and after annealing, formed by this method was investigated by scanning electron microscopy (SEM). Photoacoustic spectroscopy (PAS) measurements were carried out to measure the thermal diffusivity (TD) of the PSi and Au/PSi samples. For the Au/PSi samples, the thermal diffusivity was measured before and after annealing to study the effect of annealing. Also to study the aging effect, a comparison was made between freshly annealed samples and samples 30 days after annealing. PMID- 28817038 TI - Generalized Fractional Derivative Anisotropic Viscoelastic Characterization. AB - Isotropic linear and nonlinear fractional derivative constitutive relations are formulated and examined in terms of many parameter generalized Kelvin models and are analytically extended to cover general anisotropic homogeneous or non homogeneous as well as functionally graded viscoelastic material behavior. Equivalent integral constitutive relations, which are computationally more powerful, are derived from fractional differential ones and the associated anisotropic temperature-moisture-degree-of-cure shift functions and reduced times are established. Approximate Fourier transform inversions for fractional derivative relations are formulated and their accuracy is evaluated. The efficacy of integer and fractional derivative constitutive relations is compared and the preferential use of either characterization in analyzing isotropic and anisotropic real materials must be examined on a case-by-case basis. Approximate protocols for curve fitting analytical fractional derivative results to experimental data are formulated and evaluated. PMID- 28817039 TI - Effective Heat and Mass Transport Properties of Anisotropic Porous Ceria for Solar Thermochemical Fuel Generation. AB - High-resolution X-ray computed tomography is employed to obtain the exact 3D geometrical configuration of porous anisotropic ceria applied in solar-driven thermochemical cycles for splitting H2O and CO2. The tomography data are, in turn, used in direct pore-level numerical simulations for determining the morphological and effective heat/mass transport properties of porous ceria, namely: porosity, specific surface area, pore size distribution, extinction coefficient, thermal conductivity, convective heat transfer coefficient, permeability, Dupuit-Forchheimer coefficient, and tortuosity and residence time distributions. Tailored foam designs for enhanced transport properties are examined by means of adjusting morphologies of artificial ceria samples composed of bimodal distributed overlapping transparent spheres in an opaque medium. PMID- 28817040 TI - Stresses and Displacements in Functionally Graded Materials of Semi-Infinite Extent Induced by Rectangular Loadings. AB - This paper presents the stress and displacement fields in a functionally graded material (FGM) caused by a load. The FGM is a graded material of Si3N4-based ceramics and is assumed to be of semi-infinite extent. The load is a distributed loading over a rectangular area that is parallel to the external surface of the FGM and either on its external surface or within its interior space. The point load analytical solutions or so-called Yue's solutions are used for the numerical integration over the distributed loaded area. The loaded area is discretized into 200 small equal-sized rectangular elements. The numerical integration is carried out with the regular Gaussian quadrature. Weak and strong singular integrations encountered when the field points are located on the loaded plane, are resolved with the classical methods in boundary element analysis. The numerical integration results have high accuracy. PMID- 28817041 TI - Optical Properties of Mg, Fe, Co-Doped Near-Stoichiometric LiTaO3 Single Crystals. AB - Mg, Fe co-doped near-stoichiometric lithium tantalite (SLT) single crystals were grown by employing the zone-leveling Czochralski (ZLCz) technique. The optical properties, holographic parameters, as well as the composition of the grown crystals were measured. It was found that the Li/Ta ratio decreased with the doping of Mg and Fe ions. A red shift was observed in absorption spectrum for the Mg, Fe co-doped crystals compared to the undoped and Mg-doped ones. The effect of the iron ions (Fe2+ and Fe3+) was further discussed based on the specified absorption bands. Moreover, the occupation mechanism for the defects was discussed by using the IR absorption spectrum, which was attributed to the FeTa3- defects in the highly Fe-doped crystal. In addition, the holographic parameters were also found to be improved with a higher Fe/Ta ratio in the crystals. PMID- 28817042 TI - Aligned Layers of Silver Nano-Fibers. AB - We describe a new dichroic polarizers made by ordering silver nano-fibers to aligned layers. The aligned layers consist of nano-fibers and self-assembled molecular aggregates of lyotropic liquid crystals. Unidirectional alignment of the layers is achieved by means of mechanical shearing. Aligned layers of silver nano-fibers are partially transparent to a linearly polarized electromagnetic radiation. The unidirectional alignment and density of the silver nano-fibers determine degree of polarization of transmitted light. The aligned layers of silver nano-fibers might be used in optics, microwave applications, and organic electronics. PMID- 28817043 TI - Molecular Beam-Thermal Desorption Spectrometry (MB-TDS) Monitoring of Hydrogen Desorbed from Storage Fuel Cell Anodes. AB - Different types of experimental studies are performed using the hydrogen storage alloy (HSA) MlNi3.6Co0.85Al0.3Mn0.3 (Ml: La-rich mischmetal), chemically surface treated, as the anode active material for application in a proton exchange membrane fuel cell (PEMFC). The recently developed molecular beam-thermal desorption spectrometry (MB-TDS) technique is here reported for detecting the electrochemical hydrogen uptake and release by the treated HSA. The MB-TDS allows an accurate determination of the hydrogen mass absorbed into the hydrogen storage alloy (HSA), and has significant advantages in comparison with the conventional TDS method. Experimental data has revealed that the membrane electrode assembly (MEA) using such chemically treated alloy presents an enhanced surface capability for hydrogen adsorption. PMID- 28817044 TI - Ceramic Laser Materials. AB - Ceramic laser materials have come a long way since the first demonstration of lasing in 1964. Improvements in powder synthesis and ceramic sintering as well as novel ideas have led to notable achievements. These include the first Nd:yttrium aluminum garnet (YAG) ceramic laser in 1995, breaking the 1 KW mark in 2002 and then the remarkable demonstration of more than 100 KW output power from a YAG ceramic laser system in 2009. Additional developments have included highly doped microchip lasers, ultrashort pulse lasers, novel materials such as sesquioxides, fluoride ceramic lasers, selenide ceramic lasers in the 2 to 3 MUm region, composite ceramic lasers for better thermal management, and single crystal lasers derived from polycrystalline ceramics. This paper highlights some of these notable achievements. PMID- 28817045 TI - Carbon Nanotubes: Solution for the Therapeutic Delivery of siRNA? AB - Carbon nanotubes have many unique physical and chemical properties that are being widely explored for potential applications in biomedicine especially as transporters of drugs, proteins, DNA and RNA into cells. Specifically, single walled carbon nanotubes (SWCNT) have been shown to deliver siRNA to tumors in vivo. The low toxicity, the excellent membrane penetration ability, the protection afforded against blood breakdown of the siRNA payload and the good biological activity seen in vivo suggests that SWCNT may become universal transfection vehicles for siRNA and other RNAs for therapeutic applications. This paper will introduce a short review of a number of therapeutic applications for carbon nanotubes and provide recent data suggesting SWCNT are an excellent option for the delivery of siRNA clinically. PMID- 28817046 TI - Sorbate Transport in Carbon Molecular Sieve Membranes and FAU/EMT Intergrowth by Diffusion NMR. AB - In this paper we present and discuss selected results of our recent studies of sorbate self-diffusion in microporous materials. The main focus is given to transport properties of carbon molecular sieve (CMS) membranes as well as of the intergrowth of FAU-type and EMT-type zeolites. CMS membranes show promise for applications in separations of mixtures of small gas molecules, while FAU/EMT intergrowth can be used as an active and selective cracking catalyst. For both types of applications diffusion of guest molecules in the micropore networks of these materials is expected to play an important role. Diffusion studies were performed by a pulsed field gradient (PFG) NMR technique that combines advantages of high field (17.6 T) NMR and high magnetic field gradients (up to 30 T/m). This technique has been recently introduced at the University of Florida in collaboration with the National Magnet Lab. In addition to a more conventional proton PFG NMR, also carbon-13 PFG NMR was used. PMID- 28817047 TI - Synthesis and Properties of Poly(Isothianaphthene Methine)s with Chiral Alkyl Chain. AB - We synthesized poly(isothianaphthene methine)s with chiral alkyl chains in the substituent. Resultant polymers are soluble in THF and CHCl3. Structure of the polymers was characterized with FT-IR, FT-Raman, and UV-Vis-NIR optical absorption spectroscopy. They showed low-bandgap both in solution and in a form of film. Optical activity of the polymers was confirmed with optical rotatory dispersion. Doping effects on the polymer were also examined with UV-Vis-NIR spectroscopy and ESR measurement. PMID- 28817048 TI - Influence of Carbon Nanotubes on Thermal Stability of Water-Dispersible Nanofibrillar Polyaniline/Nanotube Composite. AB - Significant influence on the thermal stability of polyaniline (PANI) in the presence of multi-walled carbon nanotubes (MWCNTs) is reported. By means of in situ rapid mixing approach, water-dispersible nanofibrillar PANI and composites, consisting of MWCNTs uniformly coated with PANI in the state of emeraldine salt, with a well-defined core-shell heterogeneous structure, were prepared. The de protonation process in PANI occurs at a lower temperature under the presence of MWCNTs on the polyaniline composite upon thermal treatment. However, it is found that the presence of MWCNTs significantly enhances the thermal stability of PANI's backbone upon exposure to laser irradiation, which can be ascribed to the core-shell heterogeneous structure of the composite of MWCNTs and PANI, and the high thermal conductivity of MWCNTs. PMID- 28817049 TI - Challenges and Strategies in the Synthesis of Mesoporous Alumina Powders and Hierarchical Alumina Monoliths. AB - A new rapid, very simple and one-step sol-gel strategy for the large-scale preparation of highly porous gamma-Al2O3 is presented. The resulting mesoporous alumina materials feature high surface areas (400 m2 g-1), large pore volumes (0.8 mL g-1) and the gamma-Al2O3 phase is obtained at low temperature (500 degrees C). The main advantages and drawbacks of different preparations of mesoporous alumina materials exhibiting high specific surface areas and large pore volumes such as surfactant-nanostructured alumina, sol-gel methods and hierarchically macro-/mesoporous alumina monoliths have been analyzed and compared. The most reproducible synthesis of mesoporous alumina are given. Evaporation-Induced Self-Assembly (EISA) is the sole method to lead to nanostructured mesoporous alumina by direct templating, but it is a difficult method to scale-up. Alumina featuring macro- and mesoporosity in monolithic shape is a very promising material for in flow applications; an optimized synthesis is described. PMID- 28817051 TI - X-ray Photoelectron Spectroscopy (XPS) Depth Profiling for Evaluation of La2Zr2O7 Buffer Layer Capacity. AB - Lanthanum zirconate (LZO) films from water-based precursors were deposited on Ni 5%W tape by chemical solution deposition. The buffer capacity of these layers includes the prevention of Ni oxidation of the substrate and Ni penetration towards the YBCO film which is detrimental for the superconducting properties. X ray Photoelectron Spectroscopy depth profiling was used to study the barrier efficiency before and after an additional oxygen annealing step, which simulates the thermal treatment for YBCO thin film synthesis. Measurements revealed that the thermal treatment in presence of oxygen could severely increase Ni diffusion. Nonetheless it was shown that from the water-based precursors' buffer layers with sufficient barrier capacity towards Ni penetration could be synthesized if the layers meet a certain critical thickness and density. PMID- 28817052 TI - A Study of Trimethylsilane (3MS) and Tetramethylsilane (4MS) Based alpha SiCN:H/alpha-SiCO:H Diffusion Barrier Films. AB - Amorphous nitrogen-doped silicon carbide (alpha-SiCN:H) films have been used as a Cu penetration diffusion barrier and interconnect etch stop layer in the below 90 nanometer ultra-large scale integration (ULSI) manufacturing technology. In this study, the etching stop layers were deposited by using trimethylsilane (3MS) or tetramethylsilane (4MS) with ammonia by plasma-enhanced chemical vapor deposition (PECVD) followed by a procedure for tetra-ethoxyl silane (TEOS) oxide. The depth profile of Cu distribution examined by second ion mass spectroscopy (SIMs) showed that 3MS alpha-SiCN:H exhibited a better barrier performance than the 4MS film, which was revealed by the Cu signal. The FTIR spectra also showed the intensity of Si-CH3 stretch mode in the alpha-SiCN:H film deposited by 3MS was higher than that deposited by 4MS. A novel multi structure of oxygen-doped silicon carbide (SiC:O) substituted TEOS oxide capped on 4MS alpha-SiC:N film was also examined. In addition to this, the new multi etch stop layers can be deposited together with the same tool which can thus eliminate the effect of the vacuum break and accompanying environmental contamination. PMID- 28817050 TI - Carbon Nanomaterials: Efficacy and Safety for Nanomedicine. AB - Carbon nanomaterials, including fullerenes, carbon nanohorns, and carbon nanotubes, are increasingly being used in various fields owing to these materials' unique, size-dependent functions and physicochemical properties. Recently, because of their high variability and stability, carbon nanomaterials have been explored as a novel tool for the delivery of therapeutic molecules including peptide and nucleic acid cancer drugs. However, insufficient information is available regarding the safety of carbon nanomaterials for human health, even though such information is vital for the development of safe and effective nanomedicine technologies. In this review, we discuss currently available information regarding the safety of carbon nanomaterials in nanomedicine applications, including information obtained from our own studies; and we discuss types of carbon nanomaterials that demonstrate particular promise for safe nanomedicine technologies. PMID- 28817053 TI - Elaboration of Prussian Blue Analogue/Silica Nanocomposites: Towards Tailor-Made Nano-Scale Electronic Devices. AB - The research of new molecular materials able to replace classical solid materials in electronics has attracted growing attention over the past decade. Among these compounds photoswitchable Prussian blue analogues (PBA) are particularly interesting for the elaboration of new optical memories. However these coordination polymers are generally synthesised as insoluble powders that cannot be integrated into a real device. Hence their successful integration into real applications depends on an additional processing step. Nanostructured oxides elaborated by sol-gel chemistry combined with surfactant micelle templating can be used as nanoreactors to confine PBA precipitation and organize the functional nano-objects in the three dimensions of space. In this work we present the elaboration of different CoFe PBA/silica nanocomposites. Our synthetic procedure fully controls the synthesis of PBA in the porosity of the silica matrix from the insertion of the precursors up to the formation of the photomagnetic compound. We present results on systems from the simplest to the most elaborate: from disordered xerogels to ordered nanostructured films passing through mesoporous monoliths. PMID- 28817054 TI - Initial Processes of Atomic Layer Deposition of Al2O3 on InGaAs: Interface Formation Mechanisms and Impact on Metal-Insulator-Semiconductor Device Performance. AB - Interface-formation processes in atomic layer deposition (ALD) of Al2O3 on InGaAs surfaces were investigated using on-line Auger electron spectroscopy. Al2O3 ALD was carried out by repeating a cycle of Al(CH3)3 (trimethylaluminum, TMA) adsorption and oxidation by H2O. The first two ALD cycles increased the Al KLL signal, whereas they did not increase the O KLL signal. Al2O3 bulk-film growth started from the third cycle. These observations indicated that the Al2O3/InGaAs interface was formed by reduction of the surface oxides with TMA. In order to investigate the effect of surface-oxide reduction on metal-insulator semiconductor (MIS) properties, capacitors and field-effect transistors (FETs) were fabricated by changing the TMA dosage during the interface formation stage. The frequency dispersion of the capacitance-voltage characteristics was reduced by employing a high TMA dosage. The high TMA dosage, however, induced fixed negative charges at the MIS interface and degraded channel mobility. PMID- 28817055 TI - Template-Based Geometric Simulation of Flexible Frameworks. AB - Specialised modelling and simulation methods implementing simplified physical models are valuable generators of insight. Template-based geometric simulation is a specialised method for modelling flexible framework structures made up of rigid units. We review the background, development and implementation of the method, and its applications to the study of framework materials such as zeolites and perovskites. The "flexibility window" property of zeolite frameworks is a particularly significant discovery made using geometric simulation. Software implementing geometric simulation of framework materials, "GASP", is freely available to researchers. PMID- 28817056 TI - Formation of Indium-Doped Zinc Oxide Thin Films Using Ultrasonic Spray Pyrolysis: The Importance of the Water Content in the Aerosol Solution and the Substrate Temperature for Enhancing Electrical Transport. AB - Indium doped zinc oxide [ZnO:In] thin films have been deposited at 430 degrees C on soda-lime glass substrates by the chemical spray technique, starting from zinc acetate and indium acetate. Pulverization of the solution was done by ultrasonic excitation. The variations in the electrical, structural, optical, and morphological characteristics of ZnO:In thin films, as a function of both the water content in the starting solution and the substrate temperature, were studied. The electrical resistivity of ZnO:In thin films is not significantly affected with the increase in the water content, up to 200 mL/L; further increase in water content causes an increase in the resistivity of the films. All films show a polycrystalline character, fitting well with the hexagonal ZnO wurtzite type structure. No preferential growth in samples deposited with the lowest water content was observed, whereas an increase in water content gave rise to a (002) growth. The surface morphology of the films shows a consistency with structure results, as non-geometrical shaped round grains were observed in the case of films deposited with the lowest water content, whereas hexagonal slices, with a wide size distribution were observed in the other cases. In addition, films deposited with the highest water content show a narrow size distribution. PMID- 28817057 TI - Comprehensive Study of Lanthanum Aluminate High-Dielectric-Constant Gate Oxides for Advanced CMOS Devices. AB - A comprehensive study of the electrical and physical characteristics of Lanthanum Aluminate (LaAlO3) high-dielectric-constant gate oxides for advanced CMOS devices was performed. The most distinctive feature of LaAlO3 as compared with Hf-based high-k materials is the thermal stability at the interface with Si, which suppresses the formation of a low-permittivity Si oxide interfacial layer. Careful selection of the film deposition conditions has enabled successful deposition of an LaAlO3 gate dielectric film with an equivalent oxide thickness (EOT) of 0.31 nm. Direct contact with Si has been revealed to cause significant tensile strain to the Si in the interface region. The high stability of the effective work function with respect to the annealing conditions has been demonstrated through comparison with Hf-based dielectrics. It has also been shown that the effective work function can be tuned over a wide range by controlling the La/(La + Al) atomic ratio. In addition, gate-first n-MOSFETs with ultrathin EOT that use sulfur-implanted Schottky source/drain technology have been fabricated using a low-temperature process. PMID- 28817058 TI - Ultimate Scaling of High-kappa Gate Dielectrics: Higher-kappa or Interfacial Layer Scavenging? AB - Current status and challenges of aggressive equivalent-oxide-thickness (EOT) scaling of high-kappa gate dielectrics via higher-kappa ( > 20) materials and interfacial layer (IL) scavenging techniques are reviewed. La-based higher-kappa materials show aggressive EOT scaling (0.5-0.8 nm), but with effective workfunction (EWF) values suitable only for n-type field-effect-transistor (FET). Further exploration for p-type FET-compatible higher-kappa materials is needed. Meanwhile, IL scavenging is a promising approach to extend Hf-based high-kappa dielectrics to future nodes. Remote IL scavenging techniques enable EOT scaling below 0.5 nm. Mobility-EOT trends in the literature suggest that short-channel performance improvement is attainable with aggressive EOT scaling via IL scavenging or La-silicate formation. However, extreme IL scaling (e.g., zero-IL) is accompanied by loss of EWF control and with severe penalty in reliability. Therefore, highly precise IL thickness control in an ultra-thin IL regime ( < 0.5 nm) will be the key technology to satisfy both performance and reliability requirements for future CMOS devices. PMID- 28817060 TI - Study of Direct-Contact HfO2/Si Interfaces. AB - Controlling monolayer Si oxide at the HfO2/Si interface is a challenging issue in scaling the equivalent oxide thickness of HfO2/Si gate stack structures. A concept that the author proposes to control the Si oxide interface by using ultra high vacuum electron-beam HfO2 deposition is described in this review paper, which enables the so-called direct-contact HfO2/Si structures to be prepared. The electrical characteristics of the HfO2/Si metal-oxide-semiconductor capacitors are reviewed, which suggest a sufficiently low interface state density for the operation of metal-oxide-semiconductor field-effect-transistors (MOSFETs) but reveal the formation of an unexpected strong interface dipole. Kelvin probe measurements of the HfO2/Si structures provide obvious evidence for the formation of dipoles at the HfO2/Si interfaces. The author proposes that one-monolayer Si-O bonds at the HfO2/Si interface naturally lead to a large potential difference, mainly due to the large dielectric constant of the HfO2. Dipole scattering is demonstrated to not be a major concern in the channel mobility of MOSFETs. PMID- 28817059 TI - Oriented Collagen Scaffolds for Tissue Engineering. AB - Oriented collagen scaffolds were developed in the form of sheet, mesh and tube by arraying flow-oriented collagen string gels and dehydrating the arrayed gels. The developed collagen scaffolds can be any practical size with any direction of orientation for tissue engineering applications. The birefringence of the collagen scaffolds was quantitatively analyzed by parallel Nicols method. Since native collagen in the human body has orientations such as bone, cartilage, tendon and cornea, and the orientation has a special role for the function of human organs, the developed various types of three-dimensional oriented collagen scaffolds are expected to be useful biomaterials for tissue engineering and regenerative medicines. PMID- 28817061 TI - Exact Solution of a Constraint Optimization Problem for the Thermoelectric Figure of Merit. AB - In the classical theory of thermoelectricity, the performance integrals for a fully self-compatible material depend on the dimensionless figure of merit zT. Usually these integrals are evaluated for constraints z = const. and zT = const., respectively. In this paper we discuss the question from a mathematical point of view whether there is an optimal temperature characteristics of the figure of merit. We solve this isoperimetric variational problem for the best envelope of a family of curves z(T)T. PMID- 28817062 TI - Novel Textile Scaffolds Generated by Flock Technology for Tissue Engineering of Bone and Cartilage. AB - Textile scaffolds can be found in a variety of application areas in regenerative medicine and tissue engineering. In the present study we used electrostatic flocking-a well-known textile technology-to produce scaffolds for tissue engineering of bone. Flock scaffolds stand out due to their unique structure: parallel arranged fibers that are aligned perpendicularly to a substrate, resulting in mechanically stable structures with a high porosity. In compression tests we demonstrated good mechanical properties of such scaffolds and in cell culture experiments we showed that flock scaffolds allow attachment and proliferation of human mesenchymal stem cells and support their osteogenic differentiation. These matrices represent promising scaffolds for tissue engineering. PMID- 28817063 TI - Changes in Lipids and Inflammatory Markers after Consuming Diets High in Red Meat or Dairy for Four Weeks. AB - There is a body of evidence linking inflammation, altered lipid metabolism, and insulin resistance. Our previous research found that insulin sensitivity decreased after a four-week diet high in dairy compared to a control diet and to one high in red meat. Our aim was to determine whether a relationship exists between changes in insulin sensitivity and inflammatory biomarkers, or with lipid species. Fasting Tumor Necrosis Factor alpha (TNF-alpha), Tumor Necrosis Factor Receptor II (sTNF-RII), C-reactive protein (CRP), and lipids were measured at the end of each diet. TNF-alpha and the ratio TNF-alpha/sTNF-RII were not different between diets and TNF-alpha, sTNF-RII, or the ratio TNF-alpha/sTNF-RII showed no association with homeostasis model assessment-estimated insulin resistance (HOMA IR). A number of phosphatidylethanolamine (PE) and phosphatidylinositol (PI) species differed between dairy and red meat and dairy and control diets, as did many phosphatidylcholine (PC) species and cholesteryl ester (CE) 14:0, CE15:0, lysophosphatidylcholine (LPC) 14:0, and LPC15:0. None had a significant relationship (p = 0.001 or better) with log homeostasis model assessment estimated insulin resistance (HOMA-IR), although LPC14:0 had the strongest relationship (p = 0.004) and may be the main mediator of the effect of dairy on insulin sensitivity. LPC14:0 and the whole LPC class were correlated with CRP. The correlations between dietary change and the minor plasma phospholipids PI32:1 and PE32:1 are novel and may reflect significant changes in membrane composition. Inflammatory markers were not altered by changes in protein source while the correlation of LPC with CRP confirms a relationship between changes in lipid profile and inflammation. PMID- 28817064 TI - Attenuation of Multiple Organ Damage by Continuous Low-Dose Solvent-Free Infusions of Resveratrol after Severe Hemorrhagic Shock in Rats. AB - Therapeutic effects of continuous intravenous infusions of solvent-free low doses of resveratrol on organ injury and systemic consequences resulting from severe hemorrhagic shock in rats were studied. Hemorrhagic shock was induced by withdrawing arterial blood until a mean arterial blood pressure (MAP) of 25-30 mmHg was reached. Following a shock phase of 60 min, rats were resuscitated with the withdrawn blood plus lactated Ringer's. Resveratrol (20 or 60 MUg/kg * h) was continuously infused intravenously starting with the resuscitation phase (30 min) and continued until the end of the experiment (total treatment time 180 min). Animals of the shock control group received 0.9% NaCl solution. After the observation phase (150 min), rats were sacrificed. Resveratrol significantly stabilized the MAP and peripheral oxygen saturation after hemorrhagic shock, decreased the macroscopic injury of the small intestine, significantly attenuated the shock-induced increase in tissue myeloperoxidase activity in the small intestine, liver, kidney and lung, and diminished tissue hemorrhages (particularly in the small intestine and liver) as well as the rate of hemolysis. Already very low doses of resveratrol, continuously infused during resuscitation after severe hemorrhagic shock, can significantly improve impaired systemic parameters and attenuate multiple organ damage in rats. PMID- 28817065 TI - Evaluation and Treatment of Mild Traumatic Brain Injury: The Role of Neuropsychology. AB - Awareness of mild traumatic brain injury (mTBI) and persisting post-concussive syndrome (PCS) has increased substantially in the past few decades, with a corresponding increase in research on diagnosis, management, and treatment of patients with mTBI. The purpose of this article is to provide a narrative review of the current literature on behavioral assessment and management of patients presenting with mTBI/PCS, and to detail the potential role of neuropsychologists and rehabilitation psychologists in interdisciplinary care for this population during the acute, subacute, and chronic phases of recovery. PMID- 28817066 TI - Consistency of Eating Rate, Oral Processing Behaviours and Energy Intake across Meals. AB - Faster eating has been identified as a risk factor for obesity and the current study tested whether eating rate is consistent within an individual and linked to energy intake across multiple meals. Measures of ad libitum intake, eating rate, and oral processing at the same or similar test meal were recorded on four non consecutive days for 146 participants (117 male, 29 female) recruited across four separate studies. All the meals were video recorded, and oral processing behaviours were derived through behavioural coding. Eating behaviours showed good to excellent consistency across the meals (intra-class correlation coefficients > 0.76, p < 0.001) and participants who ate faster took larger bites (beta >= 0.39, p < 0.001) and consistently consumed more energy, independent of meal palatability, sex, body composition and reported appetite (beta >= 0.17, p <= 0.025). Importantly, eating faster at one meal predicted faster eating and increased energy intake at subsequent meals (beta > 0.20, p < 0.05). Faster eating is relatively consistent within individuals and is predictive of faster eating and increased energy intake at subsequent similar meals consumed in a laboratory context, independent of individual differences in body composition. PMID- 28817067 TI - Effects of Fullerenols on Mouse Brain Microvascular Endothelial Cells. AB - Fullerenols, water-soluble C60-fullerene derivatives, have been shown to exert neuroprotective effects in vitro and in vivo, most likely due to their capability to scavenge free radicals. However, little is known about the effects of fullerenols on the blood-brain barrier (BBB), especially on cerebral endothelial cells under inflammatory conditions. Here, we investigated whether the treatment of primary mouse brain microvascular endothelial cells with fullerenols impacts basal and inflammatory blood-brain barrier (BBB) properties in vitro. While fullerenols (1, 10, and 100 ug/mL) did not change transendothelial electrical resistance under basal and inflammatory conditions, 100 ug/mL of fullerenol significantly reduced erk1/2 activation and resulted in an activation of NFkappaB in an inflammatory milieu. Our findings suggest that fullerenols might counteract oxidative stress via the erk1/2 and NFkappaB pathways, and thus are able to protect microvascular endothelial cells under inflammatory conditions. PMID- 28817068 TI - A Critical Review on the Effect of Docosahexaenoic Acid (DHA) on Cancer Cell Cycle Progression. AB - Globally, there were 14.1 million new cancer diagnoses and 8.2 million cancer deaths in 2012. For many cancers, conventional therapies are limited in their successes and an improved understanding of disease progression is needed in conjunction with exploration of alternative therapies. The long chain polyunsaturated fatty acid, docosahexaenoic acid (DHA), has been shown to enhance many cellular responses that reduce cancer cell viability and decrease proliferation both in vitro and in vivo. A small number of studies suggest that DHA improves chemotherapy outcomes in cancer patients. It is readily incorporated into cancer cell membranes and, as a result there has been considerable research regarding cell membrane initiated events. For example, DHA has been shown to mediate the induction of apoptosis/reduction of proliferation in vitro and in vivo. However, there is limited research into the effect of DHA on cell cycle regulation in cancer cells and the mechanism(s) by which DHA acts are not fully understood. The purpose of the current review is to provide a critical examination of the literature investigating the ability of DHA to stall progression during different cell cycle phases in cancer cells, as well as the consequences that these changes may have on tumour growth, independently and in conjunction with chemotherapy. PMID- 28817069 TI - Detecting Traversable Area and Water Hazards for the Visually Impaired with a pRGB-D Sensor. AB - The use of RGB-Depth (RGB-D) sensors for assisting visually impaired people (VIP) has been widely reported as they offer portability, function-diversity and cost effectiveness. However, polarization cues to assist traversability awareness without precautions against stepping into water areas are weak. In this paper, a polarized RGB-Depth (pRGB-D) framework is proposed to detect traversable area and water hazards simultaneously with polarization-color-depth-attitude information to enhance safety during navigation. The approach has been tested on a pRGB-D dataset, which is built for tuning parameters and evaluating the performance. Moreover, the approach has been integrated into a wearable prototype which generates a stereo sound feedback to guide visually impaired people (VIP) follow the prioritized direction to avoid obstacles and water hazards. Furthermore, a preliminary study with ten blindfolded participants suggests its effectivity and reliability. PMID- 28817070 TI - Influence of the Distribution of Tag IDs on RFID Memoryless Anti-Collision Protocols. AB - In recent years, Radio Frequency Identification (RFID) has become very popular. The main feature of this technology is that RFID tags do not require close handling and no line of sight is required between the reader and the tags. RFID is a technology that uses radio frequencies in order to identify tags, which do not need to be positioned accurately relative to the reader. Tags share the communication channel, increasing the likelihood of causing a problem, viz., a message collision. Tree based protocols can resolve these collisions, but require a uniform tag ID distribution. This means they are very dependent of the distribution of the IDs of the tags. Tag IDs are written in the tag and contain a predefined bit string of data. A study of the influence of the tag ID distribution on the protocols' behaviour is proposed here. A new protocol, called the Flexible Query window Tree (FQwT) is presented to estimate the tag ID distribution, taking into consideration the type of distribution. The aim is to create a flexible anti-collision protocol in order to identify a set of tags that constitute an ID distribution. As a result, the reader classifies tags into groups determined by using a distribution estimator. Simulations show that the FQwT protocol contributes to significant reductions in identification time and energy consumption regardless of the type of ID distribution. PMID- 28817071 TI - Topological Interference Management for K-User Downlink Massive MIMO Relay Network Channel. AB - In this paper, we study the emergence of topological interference alignment and the characterizing features of a multi-user broadcast interference relay channel. We propose an alternative transmission strategy named the relay space-time interference alignment (R-STIA) technique, in which a K -user multiple-input multiple-output (MIMO) interference channel has massive antennas at the transmitter and relay. Severe interference from unknown transmitters affects the downlink relay network channel and degrades the system performance. An additional (unintended) receiver is introduced in the proposed R-STIA technique to overcome the above problem, since it has the ability to decode the desired signals for the intended receiver by considering cooperation between the receivers. The additional receiver also helps in recovering and reconstructing the interference signals with limited channel state information at the relay (CSIR). The Alamouti space-time transmission technique and minimum mean square error (MMSE) linear precoder are also used in the proposed scheme to detect the presence of interference signals. Numerical results show that the proposed R-STIA technique achieves a better performance in terms of the bit error rate (BER) and sum-rate compared to the existing broadcast channel schemes. PMID- 28817072 TI - Efficient Transdermal Delivery of Alendronate, a Nitrogen-Containing Bisphosphonate, Using Tip-Loaded Self-Dissolving Microneedle Arrays for the Treatment of Osteoporosis. AB - To improve the transdermal bioavailability and safety of alendronate (ALN), a nitrogen-containing bisphosphonate, we developed self-dissolving microneedle arrays (MNs), in which ALN is loaded only at the tip portion of micron-scale needles by a dip-coating method (ALN(TIP)-MN). We observed micron-scale pores in rat skin just after application of ALN(TIP)-MN, indicating that transdermal pathways for ALN were created by MN. ALN was rapidly released from the tip of MNs as observed in an in vitro release study. The tip portions of MNs completely dissolved in the rat skin within 5 min after application in vivo. After application of ALN(TIP)-MN in mice, the plasma concentration of ALN rapidly increased, and the bioavailability of ALN was approximately 96%. In addition, the decrease in growth plate was effectively suppressed by this efficient delivery of ALN in a rat model of osteoporosis. Furthermore, no skin irritation was observed after application of ALN(TIP)-MN and subcutaneous injection of ALN, while mild skin irritation was induced by whole-ALN-loaded MN (ALN-MN)-in which ALN is contained in the whole of the micron-scale needles fabricated from hyaluronic acid-and intradermal injection of ALN. These findings indicate that ALN(TIP)-MN is a promising transdermal formulation for the treatment of osteoporosis without skin irritation. PMID- 28817073 TI - Extended Physicochemical Characterization of the Synthetic Anticoagulant Pentasaccharide Fondaparinux Sodium by Quantitative NMR and Single Crystal X-ray Analysis. AB - Fondaparinux sodium is a synthetic pentasaccharide representing the high affinity antithrombin III binding site in heparin. It is the active pharmaceutical ingredient of the anticoagulant drug Arixtra(r). The single crystal X-ray structure of Fondaparinux sodium is reported, unequivocally confirming both structure and absolute configuration. The iduronic acid adopts a somewhat distorted chair conformation. Due to the presence of many sulfur atoms in the highly sulfated pentasaccharide, anomalous dispersion could be applied to determine the absolute configuration. A comparison with the conformation of Fondaparinux in solution, as well as complexed with proteins is presented. The content of the solution reference standard was determined by quantitative NMR using an internal standard both in 1999 and in 2016. A comparison of the results allows the conclusion that this method shows remarkable precision over time, instrumentation and analysts. PMID- 28817074 TI - Familial Resemblance in Dietary Intakes of Children, Adolescents, and Parents: Does Dietary Quality Play a Role? AB - Information on familial resemblance is important for the design of effective family-based interventions. We aimed to quantify familial correlations and estimate the proportion of variation attributable to genetic and shared environmental effects (i.e., familiality) for dietary intake variables and determine whether they vary by generation, sex, dietary quality, or by the age of the children. The study sample consisted of 1435 families (1007 mothers, 438 fathers, 1035 daughters, and 1080 sons) from the multi-center I.Family study. Dietary intake was assessed in parents and their 2-19 years old children using repeated 24-h dietary recalls, from which the usual energy and food intakes were estimated with the U.S. National Cancer Institute Method. Food items were categorized as healthy or unhealthy based on their sugar, fat, and fiber content. Interclass and intraclass correlations were calculated for relative pairs. Familiality was estimated using variance component methods. Parent-offspring (r = 0.11-0.33), sibling (r = 0.21-0.43), and spouse (r = 0.15-0.33) correlations were modest. Parent-offspring correlations were stronger for the intake of healthy (r = 0.33) than unhealthy (r = 0.10) foods. Familiality estimates were 61% (95% CI: 54-68%) for the intake of fruit and vegetables and the sum of healthy foods and only 30% (95% CI: 23-38%) for the sum of unhealthy foods. Familial factors explained a larger proportion of the variance in healthy food intake (71%; 95% CI: 62-81%) in younger children below the age of 11 than in older children equal or above the age of 11 (48%; 95% CI: 38-58%). Factors shared by family members such as genetics and/or the shared home environment play a stronger role in shaping children's intake of healthy foods than unhealthy foods. This suggests that family-based interventions are likely to have greater effects when targeting healthy food choices and families with younger children, and that other sorts of intervention are needed to address the intake of unhealthy foods by children. PMID- 28817075 TI - Discrimination of Transgenic Maize Kernel Using NIR Hyperspectral Imaging and Multivariate Data Analysis. AB - There are possible environmental risks related to gene flow from genetically engineered organisms. It is important to find accurate, fast, and inexpensive methods to detect and monitor the presence of genetically modified (GM) organisms in crops and derived crop products. In the present study, GM maize kernels containing both cry1Ab/cry2Aj-G10evo proteins and their non-GM parents were examined by using hyperspectral imaging in the near-infrared (NIR) range (874.41 1733.91 nm) combined with chemometric data analysis. The hypercubes data were analyzed by applying principal component analysis (PCA) for exploratory purposes, and support vector machine (SVM) and partial least squares discriminant analysis (PLS-DA) to build the discriminant models to class the GM maize kernels from their contrast. The results indicate that clear differences between GM and non-GM maize kernels can be easily visualized with a nondestructive determination method developed in this study, and excellent classification could be achieved, with calculation and prediction accuracy of almost 100%. This study also demonstrates that SVM and PLS-DA models can obtain good performance with 54 wavelengths, selected by the competitive adaptive reweighted sampling method (CARS), making the classification processing for online application more rapid. Finally, GM maize kernels were visually identified on the prediction maps by predicting the features of each pixel on individual hyperspectral images. It was concluded that hyperspectral imaging together with chemometric data analysis is a promising technique to identify GM maize kernels, since it overcomes some disadvantages of the traditional analytical methods, such as complex and monotonous sampling. PMID- 28817077 TI - Secure Localization in the Presence of Colluders in WSNs. AB - We address the challenge of correctly estimating the position of wireless sensor network (WSN) nodes in the presence of malicious adversaries. We consider adversarial situations during the execution of node localization under three classes of colluding adversaries. We describe a decentralized algorithm that aims at determining the position of nodes in the presence of such colluders. Colluders are assumed to either forge or manipulate the information they exchange with the other nodes of the WSN. This algorithm allows location-unknown nodes to successfully detect adversaries within their communication range. Numeric simulation is reported to validate the approach. Results show the validity of the proposal, both in terms of localization and adversary detection. PMID- 28817076 TI - Spirulina maxima Extract Prevents Neurotoxicity via Promoting Activation of BDNF/CREB Signaling Pathways in Neuronal Cells and Mice. AB - Spirulina maxima is a microalgae which contains flavonoids and other polyphenols. Although Spirulina maxima 70% ethanol extract (SM70EE) has diverse beneficial effects, its effects on neurotoxicity have not been fully understood. In this study, we investigated the neuroprotective effects of SM70EE against trimethyltin (TMT)-induced neurotoxicity in HT-22 cells. SM70EE inhibited the cleavage of poly ADP ribose polymerase (PARP). Besides, ROS production was decreased by down regulating oxidative stress-associated enzymes. SM70EE increased the factors of brain-derived neurotrophic factor (BDNF)/cyclic AMPresponsive elementbinding protein (CREB) signalling pathways. Additionally, acetylcholinesterase (AChE) was suppressed by SM70EE. Furthermore, we investigated whether SM70EE prevents cognitive deficits against scopolamine-induced neurotoxicity in mice by applying behavioral tests. SM70EE increased step-through latency time and decreased the escape latency time. Therefore, our data suggest that SM70EE may prevent TMT neurotoxicity through promoting activation of BDNF/CREB neuroprotective signaling pathways in neuronal cells. In vivo study, SM70EE would prevent cognitive deficits against scopolamine-induced neurotoxicity in mice. PMID- 28817078 TI - Measurement of the Verdet Constant of Polarization-Maintaining Air-Core Photonic Bandgap Fiber. AB - We propose a method based on the white-light interference technique for measuring the Verdet constant of a polarization-maintaining air-core photonic bandgap fiber (PM-PBF). The experimental results show that the Verdet constant of the PM-PBF is ~3.3 mrad/T/m for the broadband light with a spectral width of ~38 nm and a mean wavelength of ~1550 nm, which is ~124 times less than that of a conventional stress-induced birefringent fibers called PANDA fibers (~0.41 rad/T/m for the same broad-spectrum light). The results indicate that the nonreciprocal error induced by the Faraday effect in a fiber optic gyroscope (FOG) made of the PM-PBF is theoretically ~25 times less than that of a conventional FOG made of the PANDA fiber when other conditions, such as the fiber twist, fiber coil area, and so on, are the same. PMID- 28817079 TI - Insight into the Mechanism of CO Oxidation on WO3(001) Surfaces for Gas Sensing: A DFT Study. AB - The mechanism of CO oxidation on the WO3(001) surface for gas sensing performance has been systematically investigated by means of first principles density functional theory (DFT) calculations. Our results show that the oxidation of CO molecule on the perfect WO3(001) surface induces the formation of surface oxygen vacancies, which results in an increase of the surface conductance. This defective WO3(001) surface can be re-oxidized by the O2 molecules in the atmosphere. During this step, the active O2- species is generated, accompanied with the obvious charge transfer from the surface to O2 molecule, and correspondingly, the surface conductivity is reduced. The O2- species tends to take part in the subsequent reaction with the CO molecule, and after releasing CO2 molecule, the perfect WO3(001) surface is finally reproduced. The activation energy barriers and the reaction energies associated with above surface reactions are determined, and from the kinetics viewpoint, the oxidation of CO molecule on the perfect WO3(001) surface is the rate-limiting step with an activation barrier of about 0.91 eV. PMID- 28817080 TI - Feasibility Study of an Optical Caustic Plasmonic Light Scattering Sensor for Human Serum Anti-Dengue Protein E Antibody Detection. AB - Antibody detection and accurate diagnosis of tropical diseases is essential to help prevent the spread of disease. However, most detection methods lack cost effectiveness and field portability, which are essential features for achieving diagnosis in a timely manner. To address this, 3D-printed oblate spheroid sample chambers were fabricated to measure green light scattering of gold nanoparticles using an optical caustic focus to detect antibodies. Scattering signals of 20-200 nm gold nanoparticles using a green laser were compared to green light emitting diode (LED) light source signals and to Mie theory. The change in signal from 60 to 120 nm decreased in the order of Mie Theory > optical caustic scattering > 90 degrees scattering. These results suggested that conjugating 60 nm gold nanoparticles and using an optical caustic system to detect plasmonic light scattering, would result in a sensitive test for detecting human antibodies in serum. Therefore, we studied the light scattering response of conjugated gold nanoparticles exposed to different concentrations of anti-protein E antibody, and a feasibility study of 10 human serum samples using dot blot and a handheld optical caustic-based sensor device. The overall agreement between detection methods suggests that the new sensor concept shows promise to detect gold nanoparticle aggregation in a homogeneous assay. Further testing and protocol optimization is needed to draw conclusions on the positive and negative predictive values for this new testing system. PMID- 28817081 TI - Multiphysics Simulation of Low-Amplitude Acoustic Wave Detection by Piezoelectric Wafer Active Sensors Validated by In-Situ AE-Fatigue Experiment. AB - Piezoelectric wafer active sensors (PWAS) are commonly used for detecting Lamb waves for structural health monitoring application. However, in most applications of active sensing, the signals are of high-amplitude and easy to detect. In this article, we have shown a new avenue of using the PWAS transducer for detecting the low-amplitude fatigue-crack related acoustic emission (AE) signals. Multiphysics finite element (FE) simulations were performed with two PWAS transducers bonded to the structure. Various configurations of the sensors were studied by using the simulations. One PWAS was placed near to the fatigue-crack and the other one was placed at a certain distance from the crack. The simulated AE event was generated at the crack tip. The simulation results showed that both PWAS transducers were capable of sensing the AE signals. To validate the multiphysics simulation results, an in-situ AE-fatigue experiment was performed. Two PWAS transducers were bonded to the thin aerospace test coupon. The fatigue crack was generated in the test coupon which had produced low-amplitude acoustic waves. The low-amplitude fatigue-crack related AE signals were successfully captured by the PWAS transducers. The distance effect on the captured AE signals was also studied. It has been shown that some high-frequency contents of the AE signal have developed as they travel away from the crack. PMID- 28817082 TI - Omega-3 Long-Chain Fatty Acids in the Heart, Kidney, Liver and Plasma Metabolite Profiles of Australian Prime Lambs Supplemented with Pelleted Canola and Flaxseed Oils. AB - The objective of the study was to ascertain whether human health beneficial omega 3 long-chain (>=C20) polyunsaturated fatty acid (n-3 LC-PUFA) content in heart, kidney and liver can be enhanced by supplementing prime lambs with graded levels of canola and flaxseed oil. Health status of the lambs, as a consequence of the supplementation, was also investigated by examining their plasma metabolites. Sixty purebred and first-cross lambs were allocated to one of five treatments of lucerne hay basal diet supplemented with isocaloric and isonitrogenous wheat based pellets without oil inclusion (Control) or graded levels of canola oil at 2.5% (2.5C), 5% (5C), flaxseed oil at 2.5% (2.5F) and 5% (5F) in a completely randomised design. Pre-slaughter blood, post-slaughter kidney, liver and heart samples were analysed for plasma metabolite and fatty acid profiles. Summations of docosapentaenoic acid and docosahexaenoic acid, and total n-3 LC-PUFA were enhanced in the liver and kidney of 5F supplemented lambs with a marked decrease in n-6/n-3 ratio and significant breed differences detected. There were generally no deleterious impacts on animal health status. A combination of 5% oil supplementation and lamb genetics is an effective and strategic management tool for enhancing n-3 LC-PUFA contents of heart, kidney and liver without compromising lamb health. PMID- 28817084 TI - Permalloy-Based Thin Film Structures: Magnetic Properties and the Giant Magnetoimpedance Effect in the Temperature Range Important for Biomedical Applications. AB - Permalloy-based thin film structures are excellent materials for sensor applications. Temperature dependencies of the magnetic properties and giant magneto-impedance (GMI) were studied for Fe19Ni81-based multilayered structures obtained by the ion-plasma sputtering technique. Selected temperature interval of 25 degrees C to 50 degrees C corresponds to the temperature range of functionality of many devices, including magnetic biosensors. A (Cu/FeNi)5/Cu/(Cu/FeNi)5 multilayered structure with well-defined traverse magnetic anisotropy showed an increase in the GMI ratio for the total impedance and its real part with temperature increased. The maximum of the GMI of the total impedance ratio DeltaZ/Z = 56% was observed at a frequency of 80 MHz, with a sensitivity of 18%/Oe, and the maximum GMI of the real part DeltaR/R = 170% at a frequency of 10 MHz, with a sensitivity of 46%/Oe. As the magnetization and direct current electrical resistance vary very little with the temperature, the most probable mechanism of the unexpected increase of the GMI sensitivity is the stress relaxation mechanism associated with magnetoelastic anisotropy. PMID- 28817083 TI - Comparison of Australian Recommended Food Score (ARFS) and Plasma Carotenoid Concentrations: A Validation Study in Adults. AB - Diet quality indices can predict nutritional adequacy of usual intake, but validity should be determined. The aim was to assess the validity of total and sub-scale score within the Australian Recommended Food Score (ARFS), in relation to fasting plasma carotenoid concentrations. Diet quality and fasting plasma carotenoid concentrations were assessed in 99 overweight and obese adults (49.5% female, aged 44.6 +/- 9.9 years) at baseline and after three months (198 paired observations). Associations were assessed using Spearman's correlation coefficients and regression analysis, and agreement using weighted kappa (Kw). Small, significantly positive correlations were found between total ARFS and plasma concentrations of total carotenoids (r = 0.17, p < 0.05), beta cryptoxanthin (r = 0.18, p < 0.05), beta-carotene (r = 0.20, p < 0.01), and alpha carotene (r = 0.19, p < 0.01). Significant agreement between ARFS categories and plasma carotenoid concentrations was found for total carotenoids (Kw 0.12, p = 0.02), beta-carotene (Kw 0.14, p < 0.01), and alpha-carotene (Kw 0.13, p < 0.01). In fully-adjusted regression models the only signification association with ARFS total score was for alpha-carotene (beta = 0.19, p < 0.01), while ARFS meat and fruit sub-scales demonstrated significant relationships with alpha-carotene, beta carotene, and total carotenoids (p < 0.05). The weak associations highlight the issues with self-reporting dietary intakes in overweight and obese populations. Further research is required to evaluate the use of the ARFS in more diverse populations. PMID- 28817085 TI - Long-Term Coffee Consumption Is Associated with Decreased Incidence of New-Onset Hypertension: A Dose-Response Meta-Analysis. AB - OBJECTIVE: To perform a dose-response meta-analysis of prospective cohort studies investigating the association between long-term coffee intake and risk of hypertension. METHODS: An online systematic search of studies published up to November 2016 was performed. Linear and non-linear dose-response meta-analyses were conducted; potential evidence of heterogeneity, publication bias, and confounding effect of selected variables were investigated through sensitivity and meta-regression analyses. RESULTS: Seven cohorts including 205,349 individuals and 44,120 cases of hypertension were included. In the non-linear analysis, there was a 9% significant decreased risk of hypertension per seven cups of coffee a day, while, in the linear dose-response association, there was a 1% decreased risk of hypertension for each additional cup of coffee per day. Among subgroups, there were significant inverse associations for females, caffeinated coffee, and studies conducted in the US with longer follow-up. Analysis of potential confounders revealed that smoking-related variables weakened the strength of association between coffee consumption and risk of hypertension. CONCLUSIONS: Increased coffee consumption is associated with a modest decrease in risk of hypertension in prospective cohort studies. Smoking status is a potential effect modifier on the association between coffee consumption and risk of hypertension. PMID- 28817086 TI - Non-Destructive Analysis of the Internal Anatomical Structures of Mosquito Specimens Using Optical Coherence Tomography. AB - The study of mosquitoes and analysis of their behavior are of crucial importance in the on-going efforts to control the alarming increase in mosquito-borne diseases. Furthermore, a non-destructive and real-time imaging technique to study the anatomical features of mosquito specimens can greatly aid the study of mosquitoes. In this study, we demonstrate the three-dimensional imaging capabilities of optical coherence tomography (OCT) for structural analysis of Anopheles sinensis mosquitoes. The anatomical features of An. sinensis head, thorax, and abdominal regions, along with the morphology of internal structures, such as foregut, midgut, and hindgut, were studied using OCT imaging. Two dimensional and three-dimensional OCT images, used in conjunction with histological images, proved useful for anatomical analysis of mosquito specimens. By presenting this work as an initial study, we demonstrate the applicability of OCT for future mosquito-related entomological research, and also in identifying changes in mosquito anatomical structure. PMID- 28817087 TI - The Preparation and Identification of a Monoclonal Antibody against Domoic Acid and Establishment of Detection by Indirect Competitive ELISA. AB - Domoic acid (DA) is a potent toxin, marine biotoxin, and primarily produced by Pseudo-nitzschia. The DA hapten was coupled with bovine serum albumin (BSA), and ovalbumin (OVA) as carrier proteins. DA-BSA conjugate was used as immunogen and DA-OVA as coating antigen. Cell fusion between spleen cells and sp2/0 myeloma cells developed 1C3 hybridoma clone producing 1C3 monoclonal antibody (mAb). Hybridoma was injected into the mice to produce ascites, and further purified by caprylic acid/ammonium sulfate method. The mAb was of IgG3 subclass, and was specific to DA with high affinity (2.5 * 108 L/mol). Moreover, western blot exhibited significant specificity to the DA antigens. Indirect competitive enzyme linked immunosorbent assay (ic-ELISA) showed DA working range of 0.006-0.2 ng/mL. The IC50 was 0.03 ng/mL with low limit of detection (LOD) of 0.006 ng/mL. Average DA recovery from spiked shellfish extract was 100.56% +/- 2.8% with the coefficient variation of 0.01-0.1%. Hence, mAb producing 1C3 hybridoma was successfully developed and could be used to detect DA in contaminated samples. PMID- 28817089 TI - Measurement Techniques of the Magneto-Electric Coupling in Multiferroics. AB - The current surge of interest in multiferroic materials demands specialized measurement techniques to support multiferroics research. In this review article we detail well-established measurement techniques of the magneto-electric coupling coefficient in multiferroic materials, together with newly proposed ones. This work is intended to serve as a reference document for anyone willing to develop experimental measurement techniques of multiferroic materials. PMID- 28817090 TI - Insights on the Optical Properties of Poly(3,4 Ethylenedioxythiophene):Poly(styrenesulfonate) Formulations by Optical Metrology. AB - Poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) is among the most widely used polymers that are used as printed transparent electrodes for flexible Organic Electronic (OE) devices, such as Organic Photovoltaics (OPVs). The understanding of their optical properties and the correlation of the optical properties with their electronic properties and metallic-like behavior can lead to the optimization of their functionality as transparent electrodes in multilayer OE device architectures. In this work, we study the optical properties of different PEDOT:PSS formulations by non-destructive Spectroscopic Ellipsometry (SE), from the infrared to the far ultraviolet spectral regions. The optical response of PEDOT:PSS includes an intense optical absorption originated from the conductive part (PEDOT) at lower photon energies, whereas the electronic transition energies of the non-conductive PSS part have been measured at higher photon energies. Based on the different PEDOT:PSS formulations, the optical investigation revealed significant information on the relative contribution of conductive PEDOT and insulating PSS parts of the PEDOT:PSS formulation in the overall optical response, which can strongly impact the final device functionality and its optical transparency. PMID- 28817091 TI - Production of Synthetic Phosphoanhydrite and Its Use as a Binder in Self-Leveling Underlayments (SLU). AB - An experimental study was conducted to investigate the potential use of phosphogypsum (PG) to produce self-leveling underlayments. The study was designed in two stages. Initially a phosphoanhydrite (PA) was produced by heating phosphogypsum at temperatures of 350 degrees C, 450 degrees C, 550 degrees C, and 650 degrees C. Two periods of heating were applied (2 and 4 h). The formation of anhydrite was determined by thermogravimetric analysis (DTA-TG) and confirmed by X-ray diffraction (XRD). The results show that anhydrite II was obtained at temperatures above 450 degrees C, and at higher calcination temperatures the PA solubility was lower. In the second stage of this research, the PA was used in self-leveling underlayments as the main binder in the ternary system comprised of calcium sulfate, calcium aluminate cement, and Portland cement. Self-leveling mortar screeds produced using PA (550 degrees C/4 h) and PA (650 degrees C/4 h) showed the best performance in terms of mechanical strength and no degradation was observed after immersion and immersion-drying tests. The formation of ettringite, identified by scanning electron microscopy (SEM), may have contributed to these results. Morphological changes were studied using the scanning electron microscopy (SEM) technique. PMID- 28817088 TI - The Role of Neurogenic Inflammation in Blood-Brain Barrier Disruption and Development of Cerebral Oedema Following Acute Central Nervous System (CNS) Injury. AB - Acute central nervous system (CNS) injury, encompassing traumatic brain injury (TBI) and stroke, accounts for a significant burden of morbidity and mortality worldwide, largely attributable to the development of cerebral oedema and elevated intracranial pressure (ICP). Despite this, clinical treatments are limited and new therapies are urgently required to improve patient outcomes and survival. Originally characterised in peripheral tissues, such as the skin and lungs as a neurally-elicited inflammatory process that contributes to increased microvascular permeability and tissue swelling, neurogenic inflammation has now been described in acute injury to the brain where it may play a key role in the secondary injury cascades that evolve following both TBI and stroke. In particular, release of the neuropeptides substance P (SP) and calcitonin gene related peptide (CGRP) appear to be critically involved. In particular, increased SP expression is observed in perivascular tissue following acute CNS injury, with the magnitude of SP release being related to both the frequency and degree of the insult. SP release is associated with profound blood-brain barrier disruption and the subsequent development of vasogenic oedema, as well as neuronal injury and poor functional outcomes. Inhibition of SP through use of a neurokinin 1 (NK1) antagonist is highly beneficial following both TBI and ischaemic stroke in pre clinical models. The role of CGRP is more unclear, especially with respect to TBI, with both elevations and reductions in CGRP levels reported following trauma. However, a beneficial role has been delineated in stroke, given its potent vasodilatory effects. Thus, modulating neuropeptides represents a novel therapeutic target in the treatment of cerebral oedema following acute CNS injury. PMID- 28817092 TI - Biochemical and Comparative Transcriptomic Analyses Identify Candidate Genes Related to Variegation Formation in Paeonia rockii. AB - Paeonia rockii is a wild tree peony species with large and dark purple variegations at the base of its petals. It is the genetic resource for various variegation patterns in tree peony cultivars, which is in contrast to the pure white petals of Paeonia ostii. However, the molecular mechanism underlying the formation of variegation in this plant is still unknown. Here, we conducted Illumina transcriptome sequencing for P. rockii, P. ostii (with pure white petals) and their F1 individuals (with purple-red variegation). A total of 181,866 unigenes were generated, including a variety of unigenes involved in anthocyanin biosynthesis and sequestration and the regulation of anthocyanin biosynthesis. The dark purple or purple-red variegation patterns mainly occurred due to the proportions of cyanidin (Cy)- and peonidin (Pn)-based anthocyanins. The variegations of P. rockii exhibited a "Cy > Pn" phenotype, whereas the F1 progeny showed a "Pn > Cy" phenotype. The CHS, DFR, ANS, and GST genes might play key roles in variegation pigmentation in P. rockii according to gene expression and interaction network analysis. Two R2R3-MYB transcription factors (c131300.graph_c0 and c133735.graph_c0) regulated variegation formation by controlling CHS, ANS and GST genes. Our results indicated that the various variegation patterns were caused by transcriptional regulation of anthocyanin biosynthesis genes, and the transcription profiles of the R2R3-MYBs provided clues to elucidate the mechanisms underlying this trait. The petal transcriptome data produced in this study will provide a valuable resource for future association investigations of the genetic regulation of various variegation patterns in tree peonies. PMID- 28817093 TI - Quality of Vegetables Based on Total Phenolic Concentration Is Lower in More Rural Consumer Food Environments in a Rural American State. AB - While daily consumption of fruits and vegetables (FVs) is widely recognized to be associated with supporting nutrition and health, disparities exist in consumer food environments regarding access to high-quality produce based on location. The purpose of this study was to evaluate FV quality using total phenolic (TP) scores (a phytochemical measure for health-promoting attributes, flavor, appearance, and shelf-life) in consumer food environments along a rural to urban continuum in the rural state of Montana, United States. Significant differences were found in the means of the FV TP scores (p < 0.0001) and vegetable TP scores (p < 0.0001) on the basis of rurality, while no significant difference was found for fruit TP scores by rurality (p < 0.2158). Specifically, FV TP scores and vegetable TP scores were highest for the least rural stores and lowest for the most rural stores. Results indicate an access gap to high-quality vegetables in more rural and more health-disparate consumer food environments of Montana compared to urban food environments. Findings highlight that food and nutrition interventions should aim to increase vegetable quality in rural consumer food environments in the state of Montana towards enhancing dietary quality and food choices. Future studies are called for that examine TP scores of a wide range of FVs in diverse food environments globally. Studies are further needed that examine linkages between FV quality, food choices, diets, and health outcomes towards enhancing food environments for public health. PMID- 28817094 TI - Combined Dynamic Time Warping with Multiple Sensors for 3D Gesture Recognition. AB - Cyber-physical systems, which closely integrate physical systems and humans, can be applied to a wider range of applications through user movement analysis. In three-dimensional (3D) gesture recognition, multiple sensors are required to recognize various natural gestures. Several studies have been undertaken in the field of gesture recognition; however, gesture recognition was conducted based on data captured from various independent sensors, which rendered the capture and combination of real-time data complicated. In this study, a 3D gesture recognition method using combined information obtained from multiple sensors is proposed. The proposed method can robustly perform gesture recognition regardless of a user's location and movement directions by providing viewpoint-weighted values and/or motion-weighted values. In the proposed method, the viewpoint weighted dynamic time warping with multiple sensors has enhanced performance by preventing joint measurement errors and noise due to sensor measurement tolerance, which has resulted in the enhancement of recognition performance by comparing multiple joint sequences effectively. PMID- 28817096 TI - Time-Resolved Study of Nanomorphology and Nanomechanic Change of Early-Stage Mineralized Electrospun Poly(lactic acid) Fiber by Scanning Electron Microscopy, Raman Spectroscopy and Atomic Force Microscopy. AB - In this study, scanning electron microscopy (SEM), Raman spectroscopy and high resolution atomic force microscopy (AFM) were used to reveal the early-stage change of nanomorphology and nanomechanical properties of poly(lactic acid) (PLA) fibers in a time-resolved manner during the mineralization process. Electrospun PLA nanofibers were soaked in simulated body fluid (SBF) for different periods of time (0, 1, 3, 5, 7 and 21 days) at 10 degrees C, much lower than the conventional 37 degrees C, to simulate the slow biomineralization process. Time resolved Raman spectroscopy analysis can confirm that apatites were deposited on PLA nanofibers after 21 days of mineralization. However, there is no significant signal change among several Raman spectra before 21 days. SEM images can reveal the mineral deposit on PLA nanofibers during the process of mineralization. In this work, for the first time, time-resolved AFM was used to monitor early-stage nanomorphology and nanomechanical changes of PLA nanofibers. The Surface Roughness and Young's Modulus of the PLA nanofiber quantitatively increased with the time of mineralization. The electrospun PLA nanofibers with delicate porous structure could mimic the extracellular matrix (ECM) and serve as a model to study the early-stage mineralization. Tested by the mode of PLA nanofibers, we demonstrated that AFM technique could be developed as a potential diagnostic tool to monitor the early onset of pathologic mineralization of soft tissues. PMID- 28817097 TI - Bloch Surface Waves Biosensors for High Sensitivity Detection of Soluble ERBB2 in a Complex Biological Environment. AB - We report on the use of one-dimensional photonic crystals to detect clinically relevant concentrations of the cancer biomarker ERBB2 in cell lysates. Overexpression of the ERBB2 protein is associated with aggressive breast cancer subtypes. To detect soluble ERBB2, we developed an optical set-up which operates in both label-free and fluorescence modes. The detection approach makes use of a sandwich assay, in which the one-dimensional photonic crystals sustaining Bloch surface waves are modified with monoclonal antibodies, in order to guarantee high specificity during the biological recognition. We present the results of exemplary protein G based label-free assays in complex biological matrices, reaching an estimated limit of detection of 0.5 ng/mL. On-chip and chip-to-chip variability of the results is addressed too, providing repeatability rates. Moreover, results on fluorescence operation demonstrate the capability to perform high sensitive cancer biomarker assays reaching a resolution of 0.6 ng/mL, without protein G assistance. The resolution obtained in both modes meets international guidelines and recommendations (15 ng/mL) for ERBB2 quantification assays, providing an alternative tool to phenotype and diagnose molecular cancer subtypes. PMID- 28817098 TI - Estimation of the Vertical Distribution of Radiocesium in Soil on the Basis of the Characteristics of Gamma-Ray Spectra Obtained via Aerial Radiation Monitoring Using an Unmanned Helicopter. AB - After the Fukushima Daiichi Nuclear Power Plant accident, the vertical distribution of radiocesium in soil has been investigated to better understand the behavior of radiocesium in the environment. The typical method used for measuring the vertical distribution of radiocesium is troublesome because it requires collection and measurement of the activity of soil samples. In this study, we established a method of estimating the vertical distribution of radiocesium by focusing on the characteristics of gamma-ray spectra obtained via aerial radiation monitoring using an unmanned helicopter. The estimates are based on actual measurement data collected at an extended farm. In this method, the change in the ratio of direct gamma rays to scattered gamma rays at various depths in the soil was utilized to quantify the vertical distribution of radiocesium. The results show a positive correlation between the abovementioned and the actual vertical distributions of radiocesium measured in the soil samples. A vertical distribution map was created on the basis of this ratio using a simple equation derived from the abovementioned correlation. This technique can provide a novel approach for effective selection of high-priority areas that require decontamination. PMID- 28817099 TI - Sintering Inhibition of Silver Nanoparticle Films via AgCl Nanocrystal Formation. AB - Electrically conductive films are key components in most printed and flexible electronics applications. For the solution processing of conductive films, inks containing silver nanoparticles (AgNPs) remain important because of their relatively easy processing and generally low resistivity after a sintering procedure. Because the commonly used, moderate sintering temperatures of 150-300 degrees C are still too high for most low-cost flexible substrates, expanding the knowledge of surface-ink interactions that affect the sintering temperature is desirable. It is known that chloride ions can assist the sintering of AgNP films by displacing capping agents on the surfaces of AgNPs. However, very little is known about other possible Cl-AgNP interactions that affect the resistivity and no interaction having the opposite effect (sintering inhibition) has been identified before. Here we identify such a Cl-AgNP interaction giving sintering inhibition and find that the mechanism involves the formation of AgCl nanocrystals within the AgNP film. The AgCl formation was observed after inkjet printing of AgNP inks with polyvinylpyrrolidone (PVP) as the capping agent onto papers with quick-absorbing coatings containing 0.3 wt % KCl. Our findings show that chloride can have opposite roles during sintering, either assisting or inhibiting the sintering depending on the prevalence of AgCl formation. The prevalence of AgCl formation depends on the absorption properties and the capping agent. PMID- 28817100 TI - Modulatory Effects of Exogenously Applied Polyamines on Postharvest Physiology, Antioxidant System and Shelf Life of Fruits: A Review. AB - Polyamines (PAs) are natural compounds involved in many growth and developmental processes in plants, and, specifically in fruits, play a vital role regulating its development, ripening and senescence processes. Putrescine (PUT), spermine (SPE), and spermidine (SPD) are prominent PAs applied exogenously to extend shelf life of fruits. They also originate endogenously during developmental phases of horticultural crops and simultaneously affect the quality attributes and shelf life. Their anti-ethylene nature is being exploited to enhance the shelf life when exogenously applied on fruits. In growth and development of fruits, PA levels generally fall, which marks the beginning of senescence at postharvest phase. PUT, SPE and SPD treatments are being applied during postharvest phase to prolong the shelf life. They enhance the shelf life of fruits by reducing respiration rate, ethylene release and enhance firmness and quality attributes in fruits. PAs have a mitigating impact on biotic and abiotic stresses including chilling injury (CI) in tropical and sub-tropical fruits. PAs are environment friendly in nature and are biodegradable without showing any negative effect on environment. Biotechnological interventions by using chimeric gene constructs of PA encoding genes has boosted the research to develop transgenic fruits and vegetables which would possess inherent or in situ mechanism of enhanced biosynthesis of PAs at different stages of development and thereby will enhance the shelf life and quality in fruits. Internal and external quality attributes of fruits are improved by modulation of antioxidant system and by strengthening biophysical morphology of fruits by electrostatic interaction between PAs and phospholipids in the cell wall. PMID- 28817101 TI - Forecasting the Incidence of Mumps in Zibo City Based on a SARIMA Model. AB - This study aimed to predict the incidence of mumps using a seasonal autoregressive integrated moving average (SARIMA) model, and provide theoretical evidence for early warning prevention and control in Zibo City, Shandong Province, China. Monthly mumps data from Zibo City gathered between 2005 and 2013 were used as a training set to construct a SARIMA model, and the monthly mumps in 2014 were defined as a test set for the model. From 2005 to 2014, a total of 8722 cases of mumps were reported in Zibo City; the male-to-female ratio of cases was 1.85:1, the age group of 1-20 years old accounted for 94.05% of all reported cases, and students made up the largest proportion (65.89%). The main serious endemic areas of mumps were located in Huantai County, Linzi District, and Boshan District of Zibo City. There were two epidemic peaks from April to July and from October to January in next year. The fitted model SARIMA (0, 1, 1) (0, 1, 1)12 was established (AIC = 157.528), which has high validity and reasonability. The SARIMA model fitted dynamic changes of mumps in Zibo City well. It can be used for short-term forecasting and early warning of mumps. PMID- 28817095 TI - Human Milk and Allergic Diseases: An Unsolved Puzzle. AB - There is conflicting evidence on the protective role of breastfeeding in relation to the development of allergic sensitisation and allergic disease. Studies vary in methodology and definition of outcomes, which lead to considerable heterogeneity. Human milk composition varies both within and between individuals, which may partially explain conflicting data. It is known that human milk composition is very complex and contains variable levels of immune active molecules, oligosaccharides, metabolites, vitamins and other nutrients and microbial content. Existing evidence suggests that modulation of human breast milk composition has potential for preventing allergic diseases in early life. In this review, we discuss associations between breastfeeding/human milk composition and allergy development. PMID- 28817102 TI - Anticancer Activity of Ramalin, a Secondary Metabolite from the Antarctic Lichen Ramalina terebrata, against Colorectal Cancer Cells. AB - Colorectal cancer is a leading cause of death worldwide and occurs through the highly complex coordination of multiple cellular pathways, resulting in carcinogenesis. Recent studies have increasingly revealed that constituents of lichen extracts exhibit potent pharmaceutical activities, including anticancer activity against various cancer cells, making them promising candidates for new anticancer therapeutic drugs. The main objective of this study was to evaluate the anticancer capacities of ramalin, a secondary metabolite from the Antarctic lichen Ramalina terebrata, in the human colorectal cancer cell line HCT116. In this study, ramalin displayed concentration-dependent anticancer activity against HCT116 cells, significantly suppressing proliferation and inducing apoptosis. Furthermore, ramalin induced cell cycle arrest in the gap 2/mitosis (G2/M) phase through the modulation of hallmark genes involved in the G2/M phase transition, such as tumour protein p53 (TP53), cyclin-dependent kinase inhibitor 1A (CDKN1A), cyclin-dependent kinase 1 (CDK1) and cyclin B1 (CCNB1). At both the transcriptional and translational level, ramalin caused a gradual increase in the expression of TP53 and its downstream gene CDKN1A, while decreasing the expression of CDK1 and CCNB1 in a concentration-dependent manner. In addition, ramalin significantly inhibited the migration and invasion of colorectal cancer cells in a concentration-dependent manner. Taken together, these data suggest that ramalin may be a therapeutic candidate for the targeted therapy of colorectal cancer. PMID- 28817104 TI - National and Subnational Population-Based Incidence of Cancer in Thailand: Assessing Cancers with the Highest Burdens. AB - In Thailand, five cancer types-breast, cervical, colorectal, liver and lung cancer-contribute to over half of the cancer burden. The magnitude of these cancers must be quantified over time to assess previous health policies and highlight future trajectories for targeted prevention efforts. We provide a comprehensive assessment of these five cancers nationally and subnationally, with trend analysis, projections, and number of cases expected for the year 2025 using cancer registry data. We found that breast (average annual percent change (AAPC): 3.1%) and colorectal cancer (female AAPC: 3.3%, male AAPC: 4.1%) are increasing while cervical cancer (AAPC: -4.4%) is decreasing nationwide. However, liver and lung cancers exhibit disproportionately higher burdens in the northeast and north regions, respectively. Lung cancer increased significantly in northeastern and southern women, despite low smoking rates. Liver cancers are expected to increase in the northern males and females. Liver cancer increased in the south, despite the absence of the liver fluke, a known factor, in this region. Our findings are presented in the context of health policy, population dynamics and serve to provide evidence for future prevention strategies. Our subnational estimates provide a basis for understanding variations in region-specific risk factor profiles that contribute to incidence trends over time. PMID- 28817106 TI - Ag-Coated Heterostructures of ZnO-TiO2/Delaminated Montmorillonite as Solar Photocatalysts. AB - Heterostructures based on ZnO-TiO2/delaminated montmorillonite coated with Ag have been prepared by sol-gel and photoreduction procedures, varying the Ag and ZnO contents. They have been thoroughly characterized by XRD, WDXRF, UV-Vis, and XPS spectroscopies, and N2 adsorption, SEM, and TEM. In all cases, the montmorillonite was effectively delaminated with the formation of TiO2 anatase particles anchored on the clay layer's surface, yielding porous materials with high surface areas. The structural and textural properties of the heterostructures synthesized were unaffected by the ZnO incorporated. The photoreduction led to solids with Ag nanoparticles decorating the surface. These materials were tested as photocatalysts for the degradation of several emerging contaminants with different nitrogen-bearing chemical structures under solar light. The catalysts yielded high rates of disappearance of the starting pollutants and showed quite stable performance upon successive applications. PMID- 28817105 TI - Bioactive Compounds from Mexican Varieties of the Common Bean (Phaseolus vulgaris): Implications for Health. AB - As Mexico is located within Mesoamerica, it is considered the site where the bean plant originated and where it was domesticated. Beans have been an integral part of the Mexican diet for thousands of years. Within the country, there are a number of genotypes possessing highly diverse physical and chemical properties. This review describes the major bioactive compounds contained on the Mexican varieties of the common bean. A brief analysis is carried out regarding the benefits they have on health. The effect of seed coat color on the nutraceutical compounds content is distinguished, where black bean stands out because it is high content of anthocyanins, polyphenols and flavonoids such as quercetin. This confers black bean with an elevated antioxidant capacity. The most prominent genotypes within this group are the "Negro San Luis", "Negro 8025" and "Negro Jamapa" varieties. Conversely, the analyzed evidence shows that more studies are needed in order to expand our knowledge on the nutraceutical quality of the Mexican bean genotypes, either grown or wild-type, as well as their impact on health in order to be used in genetic improvement programs or as a strategy to encourage their consumption. The latter is based on the high potential it has for health preservation and disease prevention. PMID- 28817103 TI - A Review of Anti-Angiogenic Targets for Monoclonal Antibody Cancer Therapy. AB - Tumor angiogenesis is a key event that governs tumor progression and metastasis. It is controlled by the complicated and coordinated actions of pro-angiogenic factors and their receptors that become upregulated during tumorigenesis. Over the past several decades, vascular endothelial growth factor (VEGF) signaling has been identified as a central axis in tumor angiogenesis. The remarkable advent of recombinant antibody technology has led to the development of bevacizumab, a humanized antibody that targets VEGF and is a leading clinical therapy to suppress tumor angiogenesis. However, despite the clinical efficacy of bevacizumab, its significant side effects and drug resistance have raised concerns necessitating the identification of novel drug targets and development of novel therapeutics to combat tumor angiogenesis. This review will highlight the role and relevance of VEGF and other potential therapeutic targets and their receptors in angiogenesis. Simultaneously, we will also cover the current status of monoclonal antibodies being developed to target these candidates for cancer therapy. PMID- 28817107 TI - Ag Nanorods-Oxide Hybrid Array Substrates: Synthesis, Characterization, and Applications in Surface-Enhanced Raman Scattering. AB - Over the last few decades, benefitting from the sufficient sensitivity, high specificity, nondestructive, and rapid detection capability of the surface enhanced Raman scattering (SERS) technique, numerous nanostructures have been elaborately designed and successfully synthesized as high-performance SERS substrates, which have been extensively exploited for the identification of chemical and biological analytes. Among these, Ag nanorods coated with thin metal oxide layers (AgNRs-oxide hybrid array substrates) featuring many outstanding advantages have been proposed as fascinating SERS substrates, and are of particular research interest. The present review provides a systematic overview towards the representative achievements of AgNRs-oxide hybrid array substrates for SERS applications from diverse perspectives, so as to promote the realization of real-world SERS sensors. First, various fabrication approaches of AgNRs-oxide nanostructures are introduced, which are followed by a discussion on the novel merits of AgNRs-oxide arrays, such as superior SERS sensitivity and reproducibility, high thermal stability, long-term activity in air, corrosion resistivity, and intense chemisorption of target molecules. Next, we present recent advances of AgNRs-oxide substrates in terms of practical applications. Intriguingly, the recyclability, qualitative and quantitative analyses, as well as vapor-phase molecule sensing have been achieved on these nanocomposites. We further discuss the major challenges and prospects of AgNRs-oxide substrates for future SERS developments, aiming to expand the versatility of SERS technique. PMID- 28817108 TI - A Novel Approach to Eliminate the Effect of External Stress on Interdiffusivity Measurement. AB - In this paper, the interdiffusivities in fcc Co-Ni alloys at 1373 K due to different types of diffusion couple experiments were firstly re-calculated via the unified Wagner method based on the measured composition profiles. Their maximum difference due to different approaches for diffusion couple preparation was found to be larger than one order of magnitude. Then, a comprehensive analysis on the effect of different preparation methods was performed. After that, a two-step diffusion couple technique in combination with the pragmatic numerical inverse method was proposed to determine the accurate interdiffusivities by eliminating the effect of external stress. Such a novel approach was successfully applied in the binary fcc Co-Ni alloys for demonstration purposes. Moreover, it is anticipated that such novel approach can be utilized as the standard method for accurate interdiffusivity measurement, and the resultant accurate interdiffusivities in different alloys may serve as a benchmark for the later experimental and theoretical studies. PMID- 28817110 TI - Extractive Spectrophotometric Determination of Nortriptyline Hydrochloride Using Sudan II, IV and Black B. AB - A simple spectrophotometric methods has been developed for the determination of nortriptyline hydrochloride in pure and in pharmaceuticalformulations based on the formation of ion-pair complexes with sudun II (SII), sudan (IV) (SIV) and sudan black B (SBB). The selectivity of the method was improved through extraction with chloroform. The optimum conditions for complete extracted colour development were assessed. The absorbance measurements were made at 534, 596 and 649 nm for SII, SIV and SBB complexes, respectively. The calibration graph was linear in the ranges 0.5- 280. 0.5- 37.5 and 0.5 - 31.0 MUg ml-1 of the drug usiny the same reagents, respectively. The precision of the procedure was checked by calculating the relative standard deviation of ten replicate determinations on 15 MUg ml-1 of nortriptyline HCI and was found to be 1.7, 1.3 and 1.55% using SII, SIV, and SBB complexes, respectively. The molar absorptivity and Sandell sensitivity for each ion-pair were calculated. The proposed methods were successfully applied to the deterniination of pure nortriptyline HCI and in pharmaceutical formulations, and the results demonstrated that the method is equally accurate, precise and reproducible as the official method. PMID- 28817109 TI - Dysfunctional Natural Killer Cells in the Aftermath of Cancer Surgery. AB - The physiological changes that occur immediately following cancer surgeries initiate a chain of events that ultimately result in a short pro-, followed by a prolonged anti-, inflammatory period. Natural Killer (NK) cells are severely affected during this period in the recovering cancer patient. NK cells play a crucial role in anti-tumour immunity because of their innate ability to differentiate between malignant versus normal cells. Therefore, an opportunity arises in the aftermath of cancer surgery for residual cancer cells, including distant metastases, to gain a foothold in the absence of NK cell surveillance. Here, we describe the post-operative environment and how the release of sympathetic stress-related factors (e.g., cortisol, prostaglandins, catecholamines), anti-inflammatory cytokines (e.g., IL-6, TGF-beta), and myeloid derived suppressor cells, mediate NK cell dysfunction. A snapshot of current and recently completed clinical trials specifically addressing NK cell dysfunction post-surgery is also discussed. In collecting and summarizing results from these different aspects of the surgical stress response, a comprehensive view of the NK cell suppressive effects of surgery is presented. Peri-operative therapies to mitigate NK cell suppression in the post-operative period could improve curative outcomes following cancer surgery. PMID- 28817111 TI - Prospective cohort study for identification of underlying genetic causes in neonatal encephalopathy using whole-exome sequencing. AB - PurposeNeonatal encephalopathy, which is characterized by a decreased level of consciousness, occurs in 1-7/1,000 live-term births. In more than half of term newborns, there is no identifiable etiological factor. To identify underlying genetic defects, we applied whole-exome sequencing (WES) in term newborns with neonatal encephalopathy as a prospective cohort study.MethodsTerm newborns with neonatal encephalopathy and no history of perinatal asphyxia were included. WES was performed using patient and both parents' DNA.ResultsNineteen patients fulfilling inclusion criteria were enrolled. Five patients were excluded owing to withdrawal of consent, no parental DNA samples, or a genetic diagnosis prior to WES. Fourteen patients underwent WES. We confirmed a genetic diagnosis in five patients (36%): epileptic encephalopathy associated with autosomal dominant de novo variants in SCN2A (p.Met1545Val), KCNQ2 (p.Asp212Tyr), and GNAO1 (p.Gly40Arg); lipoic acid synthetase deficiency due to compound heterozygous variants in LIAS (p.Ala253Pro and p.His236Gln); and encephalopathy associated with an X-linked variant in CUL4B (p.Asn211Ser).ConclusionWES is helpful at arriving genetic diagnoses in neonatal encephalopathy and/or seizures and brain damage. It will increase our understanding and probably enable us to develop targeted neuroprotective treatment strategies. PMID- 28817112 TI - Monoallelic and biallelic CREB3L1 variant causes mild and severe osteogenesis imperfecta, respectively. AB - PurposeOsteogenesis imperfecta (OI) is a heritable skeletal dysplasia. Dominant pathogenic variants in COL1A1 and COL1A2 explain the majority of OI cases. At least 15 additional genes have been identified, but those still do not account for all OI phenotypes that present. We sought the genetic cause of mild and lethal OI phenotypes in an unsolved family.MethodsWe performed exome sequencing on seven members of the family, both affected and unaffected.ResultsWe identified a variant in cyclic AMP responsive element binding protein 3-like 1 (CREB3L1) in a consanguineous family. The variant caused a prenatal/perinatal lethal OI in homozygotes, similar to that seen in OI type II as a result of mutations in type I collagen genes, and a mild phenotype (fractures, blue sclerae) in multiple heterozygous family members. CREB3L1 encodes old astrocyte specifically induced substance (OASIS), an endoplasmic reticulum stress transducer. The variant disrupts a DNA-binding site and prevents OASIS from acting on its transcriptional targets including SEC24D, which encodes a component of the coat protein II complex.ConclusionThis report confirms that CREB3L1 is an OI-related gene and suggests the pathogenic mechanism of CREB3L1-associated OI involves the altered regulation of proteins involved in cellular secretion. PMID- 28817113 TI - Clinical and Histologic Mimickers of Celiac Disease. AB - Celiac disease is an autoimmune disorder of the small bowel, classically associated with diarrhea, abdominal pain, and malabsorption. The diagnosis of celiac disease is made when there are compatible clinical features, supportive serologic markers, representative histology from the small bowel, and response to a gluten-free diet. Histologic findings associated with celiac disease include intraepithelial lymphocytosis, crypt hyperplasia, villous atrophy, and a chronic inflammatory cell infiltrate in the lamina propria. It is important to recognize and diagnose celiac disease, as strict adherence to a gluten-free diet can lead to resolution of clinical and histologic manifestations of the disease. However, many other entities can present with clinical and/or histologic features of celiac disease. In this review article, we highlight key clinical and histologic mimickers of celiac disease. The evaluation of a patient with serologically negative enteropathy necessitates a carefully elicited history and detailed review by a pathologist. Medications can mimic celiac disease and should be considered in all patients with a serologically negative enteropathy. Many mimickers of celiac disease have clues to the underlying diagnosis, and many have a targeted therapy. It is necessary to provide patients with a correct diagnosis rather than subject them to a lifetime of an unnecessary gluten-free diet. PMID- 28817114 TI - Trauma-informed care in the newborn intensive care unit: promoting safety, security and connectedness. AB - Both babies and their parents may experience a stay in the newborn intensive care unit (NICU) as a traumatic or a 'toxic stress,' which can lead to dysregulation of the hypothalamic-pituitary-adrenal axis and ultimately to poorly controlled cortisol secretion. Toxic stresses in childhood or adverse childhood experiences (ACEs) are strongly linked to poor health outcomes across the lifespan and trauma informed care is an approach to caregiving based on the recognition of this relationship. Practitioners of trauma-informed care seek to understand clients' or patients' behaviors in light of previous traumas they have experienced, including ACEs. Practitioners also provide supportive care that enhances the client's or patient's feelings of safety and security, to prevent their re traumatization in a current situation that may potentially overwhelm their coping skills. This review will apply the principles of trauma-informed care, within the framework of the Polyvagal Theory as described by Porges, to care for the NICU baby, the baby's family and their professional caregivers, emphasizing the importance of social connectedness among all. The Polyvagal Theory explains how one's unconscious awareness of safety, danger or life threat (neuroception) is linked through the autonomic nervous system to their behavioral responses. A phylogenetic hierarchy of behaviors evolved over time, leveraging the mammalian ventral or 'smart' vagal nucleus into a repertoire of responses promoting mother baby co-regulation and the sense of safety and security that supports health and well-being for both members of the dyad. Fostering social connectedness that is mutual and reciprocal among parents, their baby and the NICU staff creates a critical buffer to mitigate stress and improve outcomes of both baby and parents. Using techniques of trauma-informed care, as explained by the Polyvagal Theory, with both babies and their parents in the NICU setting will help to cement a secure relationship between the parent-infant dyad, redirecting the developmental trajectory toward long-term health and well-being of the baby and all family members. PMID- 28817115 TI - Administration of follicle-stimulating hormone induces autophagy via upregulation of HIF-1alpha in mouse granulosa cells. AB - Recent studies reported the important role of autophagy in follicular development. However, the underlying molecular mechanisms remain elusive. In this study, we investigated the effect of follicle-stimulating hormone (FSH) on mouse granulosa cells (MGCs). Results indicated that autophagy was induced by FSH, which is known to be the dominant hormone regulating follicular development and granulosa cell (GC) proliferation. The activation of mammalian target of rapamycin (mTOR), a master regulator of autophagy, was inhibited during the process of MGC autophagy. Moreover, MHY1485 (an agonist of mTOR) significantly suppressed autophagy signaling by activating mTOR. The expression of hypoxia inducible factor 1-alpha (HIF-1alpha) was increased after FSH treatment. Blocking hypoxia-inducible factor 1-alpha attenuated autophagy signaling. In vitro, CoCl2 induced hypoxia enhanced cell autophagy and affected the expression of beclin1 and BCL2/adenovirus E1B interacting protein 3 (Bnip3) in the presence of FSH. Knockdown of beclin1 and Bnip3 suppressed autophagy signaling in MGCs. Furthermore, our in vivo study demonstrated that the FSH-induced increase in weight was significantly reduced after effectively inhibiting autophagy with chloroquine, which was correlated with incomplete mitophagy process through the PINK1-Parkin pathway, delayed cell cycle, and reduced cell proliferation rate. In addition, chloroquine treatment decreased inhibin alpha subunit, but enhanced the expression of 3 beta-hydroxysteroid dehydrogenase. Blocking autophagy resulted in a significantly lower percentage of antral and preovulatory follicles after FSH stimulation. In conclusion, our results indicate that FSH induces autophagy signaling in MGCs via HIF-1alpha. In addition, our results provide evidence that autophagy induced by FSH is related to follicle development and atresia. PMID- 28817116 TI - Total tanshinones exhibits anti-inflammatory effects through blocking TLR4 dimerization via the MyD88 pathway. AB - Tanshinones belong to a group of lipophilic constituents of Salvia miltiorrhiza Bunge (Danshen), which is widely used in traditional Chinese medicine. A deluge of studies demonstrated that tanshinones exert anti-inflammatory effects, but the underlying mechanisms remain unclear to date. This study investigated the anti inflammatory effects and mechanisms of total tanshinones (TTN). TTN suppressed the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) and the secretion of TNF-alpha, IL-6, and IL-1beta in RAW264.7 cells, bone marrow-derived macrophages, and THP-1 cells. TTN attenuated the LPS-induced transcriptional activity of NF-kappaB and decreased IkappaB-alpha and IKK phosphorylation and NF-kappaB/p65 nuclear translocation. Furthermore, TTN inhibited the LPS-induced transcriptional activity of AP-1, which was induced by the reduction of JNK1/2, ERK1/2, and p38MAPK phosphorylation. TTN blocked LPS induced Toll-like receptor 4 (TLR4) dimerization, which consequently decreased MyD88 recruitment and TAK1 phosphorylation. In addition, TTN pretreatment effectively inhibited xylene-induced ear edema and LPS-induced septic death and improved LPS-induced acute kidney injury in mice. TTN exerts anti-inflammatory effects in vitro and in vivo by blocking TLR4 dimerization to activate MyD88-TAK1 NF-kappaB/MAPK signaling cascades, which provide the molecular basis of the anti inflammatory effect of Danshen and suggest that TTN is a potential agent for the treatment of inflammatory diseases. PMID- 28817117 TI - Increased tumor-infiltrating CD45RA-CCR7- regulatory T-cell subset with immunosuppressive properties foster gastric cancer progress. AB - Regulatory T cells (Tregs) are major components of tumor-infiltrating immune cells with potent immunosuppressive properties in gastric cancer (GC) microenvironment. However, different subsets of the Tregs and their relevance to GC are unknown. Here, we found that patients with GC showed a significantly higher Tregs infiltration in tumors, and CD45RA-CCR7- Treg subset constituted most tumor-infiltrating Tregs. Tumor-infiltrating CD45RA-CCR7- Treg subset with an effector/memory phenotype accumulated in tumors and expressed low level of HLA DR. Gastric tumor-derived TNF-alpha induced CD45RA-CCR7- Treg subset with similar phenotype to their status in tumors and inhibited their HLA-DR expression via activating STAT3 phosphorylation. These tumor-associated CD45RA-CCR7- Treg subset exerted superior immunosuppressive properties to effectively suppress CD8+ T cells' anti-tumor function including CD8+ T-cell IFN-gamma and granzyme B (GrB) production as well as CD8+ T-cell proliferation in vitro, and also contributed to the growth and progression of human gastric tumors in vivo, via IL-10 secretion and cell-cell contact mechanisms. Moreover, increased tumor-infiltrating CD45RA CCR7- Treg subset as well as higher intratumoral CD45RA-CCR7- Treg/CD8+ T-cell ratio was associated with advanced disease progression and reduced GC patient survival. This study therefore identifies a novel immunosuppressive pathway involving CD45RA-CCR7- Treg subset development within the GC microenvironment. Efforts to inhibit this pathway may therefore prove a valuable strategy to prevent, and to treat this immune suppressive of GC. PMID- 28817118 TI - Altered marginal zone and innate-like B cells in aged senescence-accelerated SAMP8 mice with defective IgG1 responses. AB - Aging has a strong impact on the activity of the immune system, enhancing susceptibility to pathogens and provoking a predominant pre-inflammatory status, whereas dampening responses to vaccines in humans and mice. Here, we demonstrate a loss of marginal zone B lymphocytes (MZ, CD19+CD45R+CD21++CD23lo) and a decrease of naive B cells (CD19+IgD+), whereas there is an enhancement of a CD19+CD45Rlo innate-like B cell population (B1REL) and the so-called aged B cell compartment (ABC, CD45R+CD21loCD23loCD5-CD11b-) in aged senescence-accelerated (SAMP8) mice but not in aged senescence-resistant (SAMR1) mice. These changes in aged SAMP8 mice were associated with lower IgG isotype levels, displaying low variable gene usage repertoires of the immunoglobulin heavy chain (VH) diversity, with a diminution on IgG1-memory B cells (CD11b-Gr1-CD138-IgM-IgD CD19+CD38+IgG1+), an increase in T follicular helper (TFH, CD4+CXCR5+PD1+) cell numbers, and an altered MOMA-1 (metallophilic macrophages) band in primary follicles. LPS-mediated IgG1 responses were impaired in the B1REL and ABC cell compartments, both in vitro and in vivo. These data demonstrate the prominent changes to different B cell populations and in structural follicle organization that occur upon aging in SAMP8 mice. These novel results raise new questions regarding the importance of the cellular distribution in the B cell layers, and their effector functions needed to mount a coordinated and effective humoral response. PMID- 28817119 TI - miR-1301 inhibits hepatocellular carcinoma cell migration, invasion, and angiogenesis by decreasing Wnt/beta-catenin signaling through targeting BCL9. AB - Metastasis is the major cause of the poor prognosis of hepatocellular carcinoma (HCC), and increasing evidence supports the contribution of miRNAs to cancer progression. However, the exact relationship between the level of miR-1301 expression and HCC cell migration, invasion, and angiogenesis remains largely unknown. Quantitative PCR was used to evaluate the level of miR-1301 expression in HCC tissues and cell lines. Transwell and tube-formation assays were used to measure the effects of miR-1301 on HCC cell migration and invasion, and angiogenesis, respectively. Luciferase reporter assays and western blotting were used to confirm the miR-1301 target genes. We found that miR-1301 was significantly downregulated in HCC tissues and cell lines. Low miR-1301 expression was associated with tumor vascular invasion and Edmondson grade. Gain- and loss-of-function assays demonstrated that miR-1301 inhibited the migration, invasion, epithelial-mesenchymal transition, and angiogenesis of HCC cells in vitro and in vivo. BCL9, upregulated in HCC tissues compared with matched adjacent normal tissues, was inversely correlated to miR-1301 levels in HCC tissues. Through reporter gene and western blot assays, BCL9 was shown to be a direct miR-1301 target. BCL9 overexpression could partially reverse the effects of miR-1301 on HCC cell migration and invasion. Most importantly, miR-1301 overexpression markedly suppressed the death of xenograft mouse models of cancer by reducing tumor load, metastasis, and host angiogenesis by downregulating BCL9, beta-catenin, and vascular endothelial growth factor expression in tumor cells. Our observations suggested that miR-1301 inhibits HCC migration, invasion, and angiogenesis via decreasing Wnt/beta-catenin signaling through targeting BCL9, and might be a therapeutic target for HCC. PMID- 28817120 TI - The erythropoietin-derived peptide MK-X and erythropoietin have neuroprotective effects against ischemic brain damage. AB - Erythropoietin (EPO) has been well known as a hematopoietic cytokine over the past decades. However, recent reports have demonstrated that EPO plays a neuroprotective role in the central nervous system, and EPO has been considered as a therapeutic target in neurodegenerative diseases such as ischemic stroke. Despite the neuroprotective effect of EPO, clinical trials have shown its unexpected side effects, including undesirable proliferative effects such as erythropoiesis and tumor growth. Therefore, the development of EPO analogs that would confer neuroprotection without adverse effects has been attempted. In this study, we examined the potential of a novel EPO-based short peptide, MK-X, as a novel drug for stroke treatment in comparison with EPO. We found that MK-X administration with reperfusion dramatically reduced brain injury in an in vivo mouse model of ischemic stroke induced by middle cerebral artery occlusion, whereas EPO had little effect. Similar to EPO, MK-X efficiently ameliorated mitochondrial dysfunction followed by neuronal death caused by glutamate-induced oxidative stress in cultured neurons. Consistent with this effect, MK-X significantly decreased caspase-3 cleavage and nuclear translocation of apoptosis inducing factor induced by glutamate. MK-X completely mimicked the effect of EPO on multiple activation of JAK2 and its downstream PI3K/AKT and ERK1/2 signaling pathways, and this signaling process was involved in the neuroprotective effect of MK-X. Furthermore, MK-X and EPO induced similar changes in the gene expression patterns under glutamate-induced excitotoxicity. Interestingly, the most significant difference between MK-X and EPO was that MK-X better penetrated into the brain across the brain-blood barrier than did EPO. In conclusion, we suggest that MK-X might be used as a novel drug for protection from brain injury caused by ischemic stroke, which penetrates into the brain faster in comparison with EPO, even though MK-X and EPO have similar protective effects against excitotoxicity. PMID- 28817121 TI - Meganuclease-assisted generation of stable transgenics in the sea anemone Nematostella vectensis. AB - The sea anemone Nematostella vectensis is a model system used by a rapidly growing research community for comparative genomics, developmental biology and ecology. Here, we describe a microinjection procedure for creating stable transgenic lines in Nematostella based on meganuclease (I-SceI)-assisted integration of a transgenic cassette into the genome. The procedure describes the preparation of the reagents, microinjection of the transgenesis vector and the husbandry of transgenic animals. The microinjection setup differs from those of previously published protocols by the use of a holding capillary mounted on an inverted fluorescence microscope. In one session of injections, a single researcher can microinject up to 1,300 zygotes with a reporter construct digested with the meganuclease I-SceI. Under optimal conditions, fully transgenic heterozygous F1 animals can be obtained within 4-5 months of the injections, with a germ-line transmission efficiency of ~3%. The method is versatile and, after a short training phase, can be carried out by any researcher with basic training in molecular biology. Flexibility of construct design enables this method to be used for numerous applications, including the functional dissection of cis-regulatory elements, subcellular localization of proteins, detection of protein-binding partners, ectopic expression of genes of interest, lineage tracing and cell-type specific reporter gene expression. PMID- 28817125 TI - Long-Term Retrospective Evaluation of Success of Narrow-Diameter Implants in Esthetic Areas: A Consecutive Case Series with 3 to 14 Years Follow-up. AB - This retrospective study reports on the outcome of 19 narrow-diameter implants (NDIs) placed in 14 consecutively treated patients 3 to 14 years postloading. Peri-implant bone remodeling, bone loss, esthetic outcomes, and patient satisfaction with the final restoration were evaluated. No implant failures or prosthetic complications were reported, yielding a 100% survival rate and a 84.2% success rate. All 14 patients reported that they were very satisfied with the esthetic results. The average mesial and distal bone remodeling was 1.99 mm and 1.84 mm, respectively. This represents physiologic bone loss post-implant placement. Only 5 implants presented with bone loss, producing an average mesial and distal bone loss of 0.14 mm and 0.17 mm, respectively. Bone loss was measured on the threads of the implant from the time of restoration to the time of follow up. The bone loss did not exceed 0.2 mm per year on any implant. These screw retained NDIs present a cost-effective, esthetically acceptable alternative for restoring limited spaces in the anterior esthetic zone. PMID- 28817124 TI - Directed differentiation and long-term maintenance of epicardial cells derived from human pluripotent stem cells under fully defined conditions. AB - Here, we describe how to efficiently direct human pluripotent stem cells (hPSCs) differentiation into self-renewing epicardial cells in a completely defined, xeno free system by temporal modulation of regulators of canonical Wnt signaling. Appropriate differentiation-stage-specific application of Gsk3 inhibitor, Wnt inhibitor, and Gsk3 inhibitor (GiWiGi) is sufficient to produce cells expressing epicardial markers and exhibiting epicardial phenotypes with a high yield and purity from multiple hPSC lines in 16 d. Characterization of differentiated cells is performed via flow cytometry and immunostaining to assess quantitative expression and localization of epicardial cell-specific proteins. In vitro differentiation into fibroblasts and smooth muscle cells (SMCs) is also described. In addition, culture in the presence of transforming growth factor (TGF)-beta inhibitors allows long-term expansion of hPSC-derived epicardial cells (for at least 25 population doublings). Functional human epicardial cells differentiated via this protocol may constitute a potential cell source for heart disease modeling, drug screening, and cell-based therapeutic applications. PMID- 28817123 TI - Evaluation of telomere length in human cardiac tissues using cardiac quantitative FISH. AB - Telomere length has been correlated with various diseases, including cardiovascular disease and cancer. The use of currently available telomere-length measurement techniques is often restricted by the requirement of a large amount of cells (Southern-based techniques) or the lack of information on individual cells or telomeres (PCR-based methods). Although several methods have been used to measure telomere length in tissues as a whole, the assessment of cell-type specific telomere length provides valuable information on individual cell types. The development of fluorescence in situ hybridization (FISH) technologies enables the quantification of telomeres in individual chromosomes, but the use of these methods is dependent on the availability of isolated cells, which prevents their use with fixed archival samples. Here we describe an optimized quantitative FISH (Q-FISH) protocol for measuring telomere length that bypasses the previous limitations by avoiding contributions from undesired cell types. We have used this protocol on small paraffin-embedded cardiac-tissue samples. This protocol describes step-by-step procedures for tissue preparation, permeabilization, cardiac-tissue pretreatment and hybridization with a Cy3-labeled telomeric repeat complementing (CCCTAA)3 peptide nucleic acid (PNA) probe coupled with cardiac specific antibody staining. We also describe how to quantify telomere length by means of the fluorescence intensity and area of each telomere within individual nuclei. This protocol provides comparative cell-type-specific telomere-length measurements in relatively small human cardiac samples and offers an attractive technique to test hypotheses implicating telomere length in various cardiac pathologies. The current protocol (from tissue collection to image procurement) takes ~28 h along with three overnight incubations. We anticipate that the protocol could be easily adapted for use on different tissue types. PMID- 28817122 TI - Single-cell mechanogenetics using monovalent magnetoplasmonic nanoparticles. AB - Spatiotemporal interrogation of signal transduction at the single-cell level is necessary to answer a host of important biological questions. This protocol describes a nanotechnology-based single-cell and single-molecule perturbation tool, termed mechanogenetics, that enables precise spatial and mechanical control over genetically encoded cell-surface receptors in live cells. The key components of this tool are a magnetoplasmonic nanoparticle (MPN) actuator that delivers defined spatial and mechanical cues to receptors through target-specific one-to one engagement and a micromagnetic tweezers (MUMT) that remotely controls the magnitude of force exerted on a single MPN. In our approach, a SNAP-tagged cell surface receptor of interest is conjugated with a single-stranded DNA oligonucleotide, which hybridizes to its complementary oligonucleotide on the MPN. This protocol consists of four major stages: (i) chemical synthesis of MPNs, (ii) conjugation with DNA and purification of monovalent MPNs, (iii) modular targeting of MPNs to cell-surface receptors, and (iv) control of spatial and mechanical properties of targeted mechanosensitive receptors in live cells by adjusting the MUMT-to-MPN distance. Using benzylguanine (BG)-functionalized MPNs and model cell lines expressing either SNAP-tagged Notch or vascular endothelial cadherin (VE-cadherin), we provide stepwise instructions for mechanogenetic control of receptor clustering and for mechanical receptor activation. The ability of this method to differentially control spatial and mechanical inputs to targeted receptors makes it particularly useful for interrogating the differential contributions of each individual cue to cell signaling. The entire procedure takes up to 1 week. PMID- 28817126 TI - Principles for Vertical Ridge Augmentation in the Atrophic Posterior Mandible: A Technical Review. AB - Guided bone regeneration has become more predictable due to advances in material sciences. Nevertheless, vertical ridge augmentation (VRA) remains a potential challenge due to the complexity of soft tissue management. This becomes more complicated in the posterior atrophic mandible due to limited access and poorer blood supply. As such, a number of critical elements must be taken into consideration in treatment planning. Anatomical structures potentially jeopardize intraoperative adverse events such as bleeding or neurosensory disturbances. The attachment of the mylohyoid often compromises lingual flap advancement. This technical review summarizes the critical factors to be assessed prior to VRA for the posterior mandible and provides a sequenced approach to bone grafting and to attaining a tension-free flap for successful bone regeneration and long-term peri implant tissue stability. PMID- 28817127 TI - Ten-Year Nonsurgical Periodontal Treatment Protocol with Adjunctive Use of Diode Laser Monitoring Clinical Outcomes in >= 6 mm Pockets: A Retrospective Controlled Case Series. AB - The clinical effects of treatment with 808- and 980-nm diode lasers as an adjunct to a uniform and consistent nonsurgical periodontal treatment protocol (NSPTP) for initial probing pockets >= 6 mm with a 10-year follow-up were evaluated. In total, 24 patients (16 test cases and 8 control cases) were treated with the NSPTP. The control group (CG) was treated only with nonsurgical conventional therapy, while the test group (TG) received treatment with thermal diode lasers (wavelength of 808 or 980 nm). All patients had recall visits every 3 months and were reevaluated at 1 year after NSPTP. Following the 1-year follow-up, patients were monitored at 4-month intervals for the remaining 9 years. In total, 646 teeth (433 in TG [124 multirooted teeth and 309 single-rooted teeth] and 213 in CG [64 multirooted teeth and 149 single-rooted teeth]) were included. The initial probing pocket depth (PPD) in single-rooted teeth from TG patients decreased from an average of 6.7 mm to 3.3 mm after 1 year, and to 2.3 mm after 10 years. The mean increase in clinical attachment level (CAL) was 3.8 mm. The initial PPD of single-rooted teeth in CG patients decreased from an average of 6.4 mm at baseline to 4 mm after 1 year and 3.3 mm after 10 years. The mean increase in CAL was 2.5 mm in CG. In the TG, the PPDs of multirooted teeth decreased from 6.2 mm to 3.3 mm after 1 year, where they remained stable for 10 years. The mean increase in CAL was 2.2 mm in this group. In the CG, the PPDs for multirooted teeth decreased from 7 mm to 5.8 mm after 1 year and were 5.1 mm after 10 years. The mean increase in CAL was 1.9 mm. The TG had significantly better clinical parameters than the CG, including reduced tooth loss. Compared to conventional debridement alone, the use of thermal diode lasers with NSPTP improves PPD and increases CAL in periodontal pockets >= 6 mm over the long term. PMID- 28817128 TI - Epithelial Inclusions Following a Bilaminar Root Coverage Procedure with a Subepithelial Connective Tissue Graft: A Histologic and Clinical Study. AB - The aim of this study was to histologically examine any epithelial cell inclusions in submerged subepithelial connective tissue graft (SCTG) after clinical healing was achieved. A total of 16 patients with Miller Class I or II gingival recessions were consecutively treated with a bilaminar procedure. At 2 months after surgery, a gingival tissue specimen was harvested from all SCTG treated sites and stained with hematoxylin-eosin. The histologic evaluation revealed connective tissue in active reorganization without epithelial inclusions in 14 of the 16 tissue specimens. In the remaining 2 specimens, epithelial islands were observed deep in the connective tissue. In one case they developed in a solid cystic space, while in the second case they were strictly integrated in the lamina propria. Complete recession coverage was obtained in 14 of the 16 treated defects, with a mean root coverage of 95.1% +/- 14.2% at 12 months. PMID- 28817129 TI - Interproximal Papilla Stability Around CAD/CAM and Stock Abutments in Anterior Regions: A 2-Year Prospective Multicenter Cohort Study. AB - : The aim of this study was to compare the interproximal papilla stability of restorations supported by computer-aided design/computer-assisted manufacture (CAD/CAM) abutments to those supported by prefabricated stock abutments in anterior areas over a 2-year follow-up. Abutments were selected depending on implant inclination and thickness of buccal peri-implant soft tissues from the following: zirconia stock, titanium stock, zirconia CAD/CAM and titanium CAD/CAM. Differences between the height of the papilla tip were measured (REC). RESULTS: REC values of titanium and zirconia CAD/CAM abutments were significantly lower than those of titanium and zirconia stock. The use of titanium and zirconia CAD/CAM abutments is related to better interproximal papillae stability. PMID- 28817130 TI - The Use of Autogenous Gingival Graft for Treatment of Lingual Recession on Mandibular Anterior Teeth. AB - The goal of this article is to demonstrate the practicality and results of increasing the zone of keratinized tissue on the lingual surface of mandibular anterior teeth via case reports. Calculus is most commonly found on the lingual surface of these teeth, so they are subjected to inflammatory elements resulting in tissue deformation and destruction. Significant attention has been paid to grafting the buccal surface, but there is a paucity of information addressing the lingual surface of mandibular anterior teeth. Gingival augmentation procedures are essential before fixed restorative dentistry to prevent further recession and facilitate plaque control. PMID- 28817131 TI - Connective Tissue Graft Wall Technique and Enamel Matrix Derivative for the Treatment of Infrabony Defects: Case Reports. AB - The present case report describes a modification of the connective tissue graft wall technique with enamel matrix derivative applied to treat deep vertical bony defects. The technique presented uses a palatal incision to gain access to the bony defect. Deep infrabony defects affecting two maxillary central incisors associated with interdental and buccal gingival recession were treated. At 1 year after surgery, 9 and 6 mm of interdental clinical attachment level gain were seen in cases 1 and 2, respectively. The position of the interdental papilla was improved, and complete root coverage was achieved. Radiographs demonstrated bone fill of the infrabony components of the defects. This report encourages the possibility to improve, in one surgical session, regenerative and esthetic parameters in the treatment of deep infrabony defects. PMID- 28817132 TI - Plasma of Argon Cleaning Treatment on Implant Abutments in Periodontally Healthy Patients: Six Years Postloading Results of a Randomized Controlled Trial. AB - The aim of this randomized, match-paired, triple-blinded, controlled clinical trial was to assess the 6-year radiographic changes around customized platform switched abutments placed according to the one abutment-one time concept, with and without plasma of argon cleaning treatment. A total of 20 periodontally healthy patients received one maxillary implant between the premolars. Immediately before stage 2 surgery and abutment connection, patients were randomly assigned to the control (cleaning protocol by steam) or test group (plasma of argon treatment). Periapical standardized digital radiographs were taken at the time of crown connection (T0) and at 12 (T1), 24 (T2), 48 (T4), 60 (T5), and 72 months (T6) after the final restoration delivery. Primary outcome measures were the success rates of the implants and prostheses and the occurrence of any technical and biologic complications during the follow-up period. Secondary outcome measures were peri-implant marginal bone level changes, bleeding on probing, and plaque score. Two patients (one in test and one in control group) dropped out at the last follow-up. Neither implant nor prosthetic complications were detected in the analyzed patients of both groups during the 6 year follow-up examinations. Radiographic analysis revealed a statistically significant higher mean bone loss in the control group than in the test group at T2 (0.4 +/- 0.28 mm; P = .018), T4 (0.52 +/- 0.63 mm; P = .037), T5 (0.61 +/- 0.70 mm; P = .038), and T6 (0.71 +/- 0.66 mm; P = .011), but not at T1 (P = .131). From baseline to the 6-year follow-up, intragroup comparisons showed an absence of statistically significant difference in the test group (P = .08). Conversely, significant differences were found in the control group (P = .01). All implants demonstrated successful periodontal parameters, with no significant differences between groups. The results of this present study indicate that contaminant and bacterial removal from abutments in two-stage implants using plasma of argon could represent a positive strategy to minimize peri-implant bone resorption and longitudinally stabilize esthetic outcomes. PMID- 28817133 TI - Identification and Efficacy Ranking of Allograft and Xenograft for Extraction and Ridge Preservation Procedures. AB - The objective of this network meta-analysis was to identify and rank different ridge preservation procedures using allograft, xenograft, or extraction only by dimensional changes in ridge width and height after tooth extraction. Electronic and hand searches of several databases were performed in September 2016 to identify randomized controlled trials on extraction and ridge preservation with 3 to 7 months of follow-up. Eight studies were included in the network meta analysis. The total number of teeth included in these trials was 466, which were randomly assigned to treatment groups. The effect sizes of ridge width ranged from -2.01 (credibility interval [CrI]: -2.92 to -1.04) for the least efficacious treatment (extraction only) to -0.21 (CrI: -2.09 to 1.67) for the most efficacious treatment (xenograft with barrier). For height, they ranged from 0.35 (CrI: -3.82 to 3.17) for the most efficacious treatment (freeze-dried bone allograft with barrier) to -1.11 (CrI: -6.21 to 3.88) for the least efficacious treatment (extraction). No significant difference was detected between treatments nor inconsistency between the direct and indirect estimates. None of the selected interventions were statistically significant compared with any other treatment. All treatment options resulted in minimal bone loss in alveolar ridge width and height. PMID- 28817134 TI - Dimensional Change and Microstructure of Intraoral Bone Block Grafts Covered with Platelet-Rich Fibrin and a Barrier Membrane in Ridge Augmentation: A Pilot Investigation. AB - This study investigated the dimensional change and microstructure of intraoral bone block grafts covered with platelet-rich fibrin (PRF) and a barrier membrane in ridge augmentation. Seven patients were included, with 18 implant sites (10 ramus and 8 symphysis). The average final ridge width gains in the ramus from cast-based measurement (3.86 +/- 0.87 mm) and cone beam computed tomography measurements (3.63 +/- 1.38 mm) were not different from the symphysis (3.36 +/- 2.26 mm and 3.44 +/- 1.52 mm, respectively). Ridge width reduction of the ramus ( 10.46 +/- 10.55%) was higher than the symphysis (-5.04 +/- 2.08%). The ramus showed bone volume fractions from the microcomputed tomography (84.66 +/- 8.36%) and percentage of bone area from histomorphometry (80.29 +/- 12.03%) that were comparable to those for the symphysis (83.13 +/- 8.1% and 84.98 +/- 14.50%, respectively). The dimensional change of the intraoral block graft covered with PRF and a resorbable membrane was minimal, and the symphysis graft was less resorbed than the ramus graft. Nevertheless, their microstructures were comparable. PMID- 28817135 TI - Using MicroCT to Assess Periodontal Regeneration Outcomes-Comparison of Image Based and Histologic Results: A Case Report. AB - The purpose of this study was to compare microcomputed tomography (microCT) and histologic analysis outcomes of a periodontal regeneration of a human defect treated with a polylactic- and polyglycolic-acid copolymer. At 11 months following the grafting procedure, the root with the surrounding periodontal tissues was removed and analyzed using microCT and histologic techniques. The results suggest that microCT three-dimensional analysis may be used in synergy with two-dimensional histologic sections to provide additional information for studying the regeneration outcomes normally reported by histologic biopsies in humans. Additional data is needed to validate these findings. PMID- 28817136 TI - Prognosis of Dental Implants Immediately Placed in Sockets Affected by Peri implantitis: A Retrospective Pilot Study. AB - The aim of this study was to describe a protocol and analyze the outcomes of immediate replacement of failed implants due to peri-implantitis. A total of 17 patients (mean age: 58 +/- 10 years) had 22 failed implants that were immediately replaced. One implant failed 16 months after insertion, resulting in an implant survival rate of 94.7%. The mean follow-up time was 40 +/- 16 months (range: 9-52 months) after insertion. Mesial and distal bone loss were 0.89 +/- 0.62 mm and 0.97 +/- 0.66 mm, respectively. Immediate implant replacement could be considered in the management of implant failure due to peri-implantitis. PMID- 28817137 TI - Immediately Loaded, Implant-Supported Overdentures Retained by a Milled Bar: An Up-to-5-Year Retrospective Clinical Study. AB - This study was conducted as an up-to-5-year retrospective investigation estimating survival rate, marginal bone loss (MBL), patient satisfaction, complications, and required prosthodontic maintenance for immediately loaded, milled bar-retained, implant-supported overdentures (ISOs). A total of 60 patients, 69 overdentures, and 179 implants were examined. The implant survival rate was 96.65%, and the mean MBL was 0.57 mm (SD 0.52). High subjective satisfaction ratings, ranging from 3 to 5 with a mean of 4.3 (SD 0.6), were observed. The incidence of complications and prosthetic maintenance was low and required short standard appointments. The present findings encourage the use of immediately loaded, milled bar-retained ISOs. PMID- 28817138 TI - Influence of Abutment Height on Maintenance of Peri-implant Crestal Bone at Bone Level Implants: A 3-Year Follow-up Study. AB - In this 3-year follow-up study, peri-implant bone loss at bone-level implants was evaluated with two definitive abutment heights: 1 mm and 2.5 mm. Peri-implant bone loss was defined as the distance between the implant shoulder and the first bone-to-implant contact from the time of loading to the 36-month follow-up, estimated using periapical radiographs. The bone loss was increased at the time of follow-up, to 1.30 mm (95% confidence interval [CI]: 0.70-1.89 mm; SD = 1.89) and 0.33 mm (95% CI: 0.11-0.55; SD = 0.59) at 36 months in short and long abutments, respectively. Placement of short abutments induced higher peri-implant bone loss at bone-level implants during a peri-implant recall program. PMID- 28817139 TI - Immediate One-Time Low-Profile Abutment to Enhance Peri-implant Soft and Hard Tissue Stability in the Esthetic Zone. AB - Reductions in peri-implant bone height have been acknowledged as a normal consequence of implant therapy. Various restorative factors contribute to this phenomenon. One is repeated abutment retightening, which causes a mechanical disruption at the implant-abutment interface, leading to soft tissue recession. Several investigators proposed placement of the definitive abutment after implant placement as a solution to the problem. The definitive use of an intermediate abutment after implant placement seems to positively affect the soft tissue response. This article aims to present a prosthetic sequence for achieving peri implant tissue stability in the esthetic zone. PMID- 28817140 TI - Relationship Between Clinical and Histologic Periodontal Biotypes in Humans. AB - Histologic and histomorphometric evaluations of gingival biopsy samples of patients presenting either a thick or a thin gingival biotype were performed. Full-thickness gingival biopsy samples were obtained and processed for histologic and histometric evaluations. Thickness of the keratinized mucosa or gingiva was found to be increased in the thick biotype. Specifically, the connective tissue layer was thicker with no change in epithelial thickness. In conclusion, gingival transparency appears to be an adequate, clinically useful method to classify the gingival biotype. The thin gingival biotype is manifested by reduced connective tissue thickness; therefore, biotype conversion or enhancement may be based on augmentation of the connective tissue portion of the gingival tissues. PMID- 28817141 TI - Effects of Platelet-Rich Fibrin on Palatal Wound Healing After Free Gingival Graft Harvesting: A Comparative Randomized Controlled Clinical Trial. AB - This study was conducted to evaluate the effects of platelet-rich fibrin (PRF) on palatal wound healing after free gingival graft (FGG) harvesting. A total of 125 patients were randomized after FGG: PRF with butyl-cyanoacrylate (BC) adhesive (PRF group; n = 42), BC adhesive alone (BC group; n = 42), and sterile wet gauze compression (WG group; n = 41). Bleeding, pain, epithelialization, feeding habits, and sensation scores were recorded for different time points. Statistically significant differences were found for all parameters in favor of the PRF group (P = .0001). PRF may provide significant benefits for wound healing parameters and patients' postoperative course after palatal graft harvesting. PMID- 28817142 TI - Morphologic Patterns of the Atrophic Posterior Maxilla and Clinical Implications for Bone Regenerative Therapy. AB - Regenerative therapies are commonly needed prior to implant placement in the posterior maxilla following tooth extraction. The aim of this study was to investigate the anatomical features of the atrophic posterior maxilla that might affect surgical approach selection and technique and risk of intra- and postoperative complications. Cone beam computed tomography files were screened to identify pristine atrophic maxillary ridges in need of bone augmentation (ridge height < 10 mm). Ridge height and width and lateral wall thickness (LWT) were measured at different levels, and palatonasal recess and lateral wall morphology were calculated. The influence of site was assessed using generalized estimation equations. The linear correlation between parameters was estimated with Pearson coefficient, and principal component analysis (PCA) was performed to establish patterns of multiple correlations. In the 433 edentulous sites and 6,062 measurements analyzed, the strongest correlations corresponded to LWT measurements at the different levels. Most of the parameters examined presented linearity (P < .001), allowing establishment of four main morphologic patterns according to anatomical features. The anatomical structures of the atrophic posterior maxilla follow linear patterns that might predict complications due to an anatomical feature and thus success in regenerative therapy. PMID- 28817143 TI - Clinical Outcomes of Socket Preservation Using Bovine-Derived Xenograft Collagen and Collagen Membrane Post-Tooth Extraction: A 6-Month Randomized Controlled Clinical Trial. AB - The aim of this study was to evaluate the clinical remodeling of the alveolar socket following the application of bovine-derived xenograft collagen and collagen membrane compared to natural spontaneous healing during the first 6 months following tooth extraction. A total of 20 patients with 20 fresh alveolar sockets were randomly allocated into a test or control group. After a 6-month follow-up period, surgical reentry was performed and implants were placed. Significant statistical differences were recorded in terms of vertical and horizontal bone changes between the test and control groups. Within the limitations of this study, socket preservation procedures may provide more favorable conditions for subsequent implant placement. PMID- 28817144 TI - Resonant silicon nanoparticles for enhancement of light absorption and photoluminescence from hybrid perovskite films and metasurfaces. AB - Recently, hybrid halide perovskites have emerged as one of the most promising types of materials for thin-film photovoltaic and light-emitting devices because of their low-cost and potential for high efficiency. Further boosting their performance without detrimentally increasing the complexity of the architecture is critically important for commercialization. Despite a number of plasmonic nanoparticle based designs having been proposed for solar cell improvement, inherent optical losses of the nanoparticles reduce photoluminescence from perovskites. Here we use low-loss high-refractive-index dielectric (silicon) nanoparticles for improving the optical properties of organo-metallic perovskite (MAPbI3) films and metasurfaces to achieve strong enhancement of photoluminescence as well as useful light absorption. As a result, we observed experimentally a 50% enhancement of photoluminescence intensity from a perovskite layer with silicon nanoparticles and 200% enhancement for a nanoimprinted metasurface with silicon nanoparticles on top. Strong increase in light absorption is also demonstrated and described by theoretical calculations. Since both silicon nanoparticle fabrication/deposition and metasurface nanoimprinting techniques are low-cost, we believe that the developed all-dielectric approach paves the way to novel scalable and highly effective designs of perovskite based metadevices. PMID- 28817145 TI - Coherent electronic and nuclear dynamics in a rhodamine heterodimer-DNA supramolecular complex. AB - Elucidating the role of quantum coherences in energy migration within biological and artificial multichromophoric antenna systems is the subject of an intense debate. It is also a practical matter because of the decisive implications for understanding the biological processes and engineering artificial materials for solar energy harvesting. A supramolecular rhodamine heterodimer on a DNA scaffold was suitably engineered to mimic the basic donor-acceptor unit of light harvesting antennas. Ultrafast 2D electronic spectroscopic measurements allowed identifying clear features attributable to a coherent superposition of dimer electronic and vibrational states contributing to the coherent electronic charge beating between the donor and the acceptor. The frequency of electronic charge beating is found to be 970 cm-1 (34 fs) and can be observed for 150 fs. Through the support of high level ab initio TD-DFT computations of the entire dimer, we established that the vibrational modes preferentially optically accessed do not drive subsequent coupling between the electronic states on the 600 fs of the experiment. It was thereby possible to characterize the time scales of the early time femtosecond dynamics of the electronic coherence built by the optical excitation in a large rigid supramolecular system at a room temperature in solution. PMID- 28817146 TI - Controlled deposition of palladium nanodendrites on the tips of gold nanorods and their enhanced catalytic activity. AB - Plasmonic Au-Pd nanostructures have drawn significant attention for use in heterogeneous catalysis. In this study, palladium nanodendrite-tipped gold nanorods (PdND-T-AuNRs) were subjected to a facile fabrication under mild reaction conditions. The palladium amounts on the two tips were tunable. In the preparation of PdND-T-AuNRs, dense capped AuNRs, a low reaction temperature, and suitable stabilizing agents were identified as critical reaction parameters for controlling palladium nanodendrites deposited on both ends of AuNRs. After overgrowth with palladium nanodendrites, the longitudinal surface plasmonic resonance peaks of PdND-T-AuNRs were red-shifted from 810 nm to 980 nm. The electrocatalytic activity of PdND-T-AuNRs for ethanol oxidation was examined, which was a bit weaker than that of cuboid core-shell Au-Pd nanodendrites; however, PdND-T-AuNRs were more stable in ethanol electrooxidation. Moreover, the photocatalytic activity of PdND-T-AuNRs for Suzuki cross-coupling reactions was investigated. At room temperature, nearly 100% yield was obtained under laser irradiation. The results can further enhance our capability of fine-tuning the optical, electronic, and catalytic properties of the bimetallic Au-Pd nanostructures. PMID- 28817147 TI - Supramolecular core-glycoshell polythiophene nanodots for targeted imaging and photodynamic therapy. AB - Supramolecular self-assembly between poly(3-hexylthiophene-2,5-diyl) (P3HT), a polymeric material extensively used for optoelectronic devices, and fluorescent glycoprobes produces core-glycoshell theranostic nanodots (glyco-dots) capable of targeted imaging and photodynamic therapy of liver and triple-negative breast cancer cells. PMID- 28817148 TI - Effect of the solvation state of electron in dissociative electron attachment reaction in aqueous solutions. AB - It is generally considered that the pre-solvated electron and the solvated electron reacting with a solute yield the same product. Silver cyanide complex, Ag(CN)2-, is used as a simple probe to demonstrate unambiguously the existence of a different reduction mechanism for pre-hydrated electrons. Using systematic multichannel transient absorption measurements at different solute concentrations from millimolar to decimolar, global data analysis and theoretical calculations, we present the dissociative electron attachment on Ag(CN)2-. The short-lived silver complex, Ag0(CN)22-, formed by hydrated electron with nanosecond pulse radiolysis, can be observed at room temperature. However, at higher temperatures only the free silver atom, Ag0, is detected, suggesting that Ag0(CN)22- dissociation is fast. Surprisingly, pulse radiolysis measurements on Ag(CN)2- reduction, performed by a 7 ps electron pulse at room temperature, show clearly that a new reduced form of silver complex, AgCN-, is produced within the pulse. This species, absorbing at 560 nm, is not formed by the hydrated electron but exclusively by its precursor. DFT calculations show that the different reactivity of the hydrated and pre-hydrated electrons can be due to the formation of different electronic states of Ag0(CN)22-: the prehydrated electron can form an excited state of this complex, which mainly dissociates into Ag0CN- + CN-. PMID- 28817149 TI - Impact of phenylalanines outside the dimer interface on phosphotriesterase stability and function. AB - We explore the significance of phenylalanine outside of the phosphotriesterase (PTE) dimer interface through mutagenesis studies and computational modeling. Previous studies have demonstrated that the residue-specific incorporation of para-fluorophenylalanine (pFF) into PTE improves stability, suggesting the importance of phenylalanines in stabilization of the dimer. However, this comes at a cost of decreased solubility due to pFF incorporation into other parts of the protein. Motivated by this, eight single solvent-exposed phenylalanine mutants are evaluated viarosetta and good correspondence between experiments and these predictions is observed. Three residues, F304, F327, and F335, appear to be important for PTE activity and stability, even though they do not reside in the dimer interface region or active site. While the remaining mutants do not significantly affect structure or activity, one variant, F306L, reveals improved activity at ambient and elevated temperatures. These studies provide further insight into role of these residues on PTE function and stability. PMID- 28817151 TI - Comprehensive analysis of long noncoding RNA-mRNA co-expression patterns in thyroid cancer. AB - Novel molecular-targeted treatments show great prospects for radioiodine refractory and surgically inoperable thyroid carcinomas. While aberrations in protein-coding genes are a focus in molecular thyroid cancer medicine, the impact of oncogenes on the expression of long noncoding RNAs (lncRNAs) has been largely uncharacterized. We aimed to identify the expression patterns of lncRNAs and mRNAs in high-throughput molecular profiles of 18 papillary thyroid cancer (PTC) patients. We identified 452 mRNAs and 240 unannotated lncRNAs that were differentially expressed in PTC. Significantly enriched GO terms and pathways were identified, many of which were linked to cancer. By integrating the predicted lncRNA target genes with differentially expressed mRNAs, we identified 20 candidate lncRNAs in 45 PTC patients. Five lncRNAs (CTD-3193O13.11, RP5 1024C24.1, AC007255.8, HOXD-AS1, and RP11-402L6.1) were verified to be differentially expressed in PTC and to exhibit specific topological characteristics in the lncRNA-mRNA co-expression network. LncRNA CTD-3193O13.11 was determined to comprise a node of co-regulation with the other lncRNAs in PTC tumorigenesis. LncRNA RP5-1024C24.1, AC007255.8, and HOXD-AS1 expression was significantly related to clinical stage, lncRNA RP11-402L6.1 expression was associated with lymph node metastasis, lncRNA CTD-3193O13.11 expression was proportional to tumor size, and lncRNA AC007255.8 expression was proportional to patient age. Therefore, our study provides a genome-wide screening and analysis of lncRNA expression in PTC, which brings novel insights into the roles of lncRNAs in PTC progression. PMID- 28817150 TI - Beryllium-based fluorenes as efficient anion sponges. AB - The F-, Cl-, CN-, NO2-, NO3-, and SO42- anion affinities of 4,5-bis(BeX)-fluorene (X = H, F, Cl, CN, NC, and OCH3) derivatives have been calculated at the B3LYP/6 311+G(3df,2p)//B3LYP/6-31+G(d,p) level of theory. The reliability of this approach was assessed using, for some suitable cases, the accurate G4MP2 ab initio composite method as a reference. The values obtained indicate that these derivatives exhibit anion affinities which are among the largest ones reported for single neutral molecules, and therefore these compounds behave as anion sponges, very much as their 1,8-diBeX-naphthalene analogues. This finding seems to confirm that both molecular frameworks, when adequately substituted at positions 1,8 in the case of naphthalene and 4,5 in the case of fluorene, may behave either as proton sponges, when the substituents are good electron donors, such as alkylamino groups, or as anion sponges, when the substituents are BeX groups, which are excellent electron acceptors. The behavior of these compounds in aqueous solution was also investigated. The interaction with water decreases the anion affinities, but still they are very large. More importantly the trends observed do not differ significantly from those found in the gas phase, in particular when monoanions are considered. PMID- 28817152 TI - Gradient-free determination of isoelectric points of proteins on chip. AB - The isoelectric point (pI) of a protein is a key characteristic that influences its overall electrostatic behaviour. The majority of conventional methods for the determination of the isoelectric point of a molecule rely on the use of spatial gradients in pH, although significant practical challenges are associated with such techniques, notably the difficulty in generating a stable and well controlled pH gradient. Here, we introduce a gradient-free approach, exploiting a microfluidic platform which allows us to perform rapid pH change on chip and probe the electrophoretic mobility of species in a controlled field. In particular, in this approach, the pH of the electrolyte solution is modulated in time rather than in space, as in the case for conventional determinations of the isoelectric point. To demonstrate the general approachability of this platform, we have measured the isoelectric points of representative set of seven proteins, bovine serum albumin, beta-lactoglobulin, ribonuclease A, ovalbumin, human transferrin, ubiquitin and myoglobin in microlitre sample volumes. The ability to conduct measurements in free solution thus provides the basis for the rapid determination of isoelectric points of proteins under a wide variety of solution conditions and in small volumes. PMID- 28817153 TI - A comparative study on the cardiac morphology and vertical jump height of adolescent black South African male and female amateur competitive footballers. AB - OBJECTIVE: The aim of this comparative study was to determine the gender differences in cardiac morphology and performance in adolescent black South African footballers. METHODS: Anthropometry, electrocardiography and echocardiography data were measured in 167 (85 males and 82 females) adolescent black South African footballers (mean age: 14.8 +/- 1.3 years). Vertical jump height was used as a performance measure of explosive lower-limb power. RESULTS: The males had less body fat compared with the females (12.1 +/- 3.6 vs 16.8 +/- 4.1%, p < 0.05), while females had higher left ventricular end-diastolic diameters compared with males (48.7 +/- 3.7 vs 40.7 +/- 8.1, p < 0.05). Vertical jump height was higher in males (37.2 +/- 10.3) compared with females (31.2 +/- 8) and was inversely associated with body fat (beta = -0.2, p < 0.05) and positively associated with lean mass (beta = 0.5, p < 0.05). CONCLUSION: The findings showed that adolescent black South African male footballers had a performance advantage over females for explosive lower-limb power, which was explained by differences in body composition and not cardiac morphology. PMID- 28817154 TI - The gold nun: a case of a gold ligature from the 15th century and the origins of restorative dentistry in Europe. AB - ABSTRACT: We here report the discovery of a gold dental ligature from the late 15th century, at the Convent of Santa Clara-a-Velha, in the city of Coimbra, Portugal. A medieval Clare's nun presented the left upper lateral incisor splinted to the canine, since the others three incisors were lost, most probably due to an aggressive periodontal disease. The convent is associated with the medieval upper class, which was well known for its consumption of high levels of sugar. There is a higher prevalence of caries in comparison to other Portuguese skeletal samples of the same time period, as well as a high prevalence of periodontal disease. Thus far, this is one of the earliest findings of dental treatment in Europe. PMID- 28817156 TI - A possible "grinder" from Tell Arbid, Syria. AB - ABSTRACT: Cereal grinding has been practiced in Mesopotamia since the Upper Palaeolithic. While evidence of cereal grinding is clear from the archaeological and textual records, what remains unclear is whether the activity leaves signs on the skeleton in the form of markers of occupational stress (MOS). A particular constellation of MOS (e.g., osteoarthritis, traumatic injuries, and accessory articular facets) has previously been used to infer the habitual grinding of grain. These same MOS were recently observed in the skeleton of a female discovered in the Middle Bronze Age cemetery at Tell Arbid, NE Syria. Through differential diagnosis our results suggest that it remains problematic to identify grain-processing activities from the skeleton, even when a bioarchaeological approach is carried out. PMID- 28817155 TI - Genetic variation of 15 autosomal STRs in a population sample of Bedouins residing in the area of the Fourth Nile Cataract, Sudan. AB - ABSTRACT: The purpose of the paper was to report allelic frequencies of 15 autosomal STR markers (AmpFlSTR NGM PCR Amplification Kit) for Bedouin inhabitants in the area of the Fourth Nile Cataract in Sudan, and compute commonly used population and forensic biostatistical parameters. Buccal swabs were collected from 117 unrelated individuals. DNA was extracted using DNA QIAamp(r) DNA Mini Kit, and quantitated with Quantifiler Human Quantification Kit in a 7500 Real-Time PCR System. Amplification of 15 AmpFlSTR NGM PCR Kit loci was performed in PCR System 9700. Electrophoresis and typing were performed in 3130 Genetic Analyzer. Arlequin v3.5 software and PowerStats v1.2 spreadsheet were used for statistical calculations. The STR frequency distributions showed no deviations from HWE. The combined values of Matching Probability and Power of Exclusion are 1.77 * 10-18 and 0.9999996, respectively. The average observed heterozygosity over 15 loci is 0.8069. Five different allelic microvariants were found. A significant linkage disequilibrium was observed in five pairs of loci. A 15 STR population database has been established for Sudanese Bedouins. The systems studied have been shown to be useful tool for personal identification in this population. PMID- 28817157 TI - Extent and Morbidity of Lateralization of a Trochanteric Fixation Nail Blade. AB - This study examined the incidence and risk factors associated with lateral helical blade migration and trochanteric pain with the trochanteric fixation nail. A retrospective review was performed of 141 cases of pertrochanteric femur fracture treated with a trochanteric fixation nail at a level I trauma center over a period of 42 months. Exclusion criteria included follow-up of less than 60 days, preexisting osteonecrosis of the femoral head, and prophylactic trochanteric fixation nail treatment. Patient demographics, operative findings, and radiographic findings were recorded. Medical records were reviewed to identify symptomatic hardware. Overall, 27 patients (19.1%) were symptomatic, and 3 (2.1%) required revision surgery for blade prominence. Of the patients, 42 (30%) had lateralization of greater than 1 cm, and 16 of these (38.1%) were symptomatic (P<.02). A risk factor for lateralization was AO classification, with 46.1% of type A2 fractures showing lateralization of greater than 1 cm. The quality of calcar reduction nearly reached statistical significance, and 44.8% of patients who had inadequate reduction had lateralization of greater than 1 cm compared with 26.4% of patients who had adequate reduction (P=.054). Lateralization of greater than 1 cm was directly associated with the presence of symptoms (P<.001) and removal of hardware because of trochanteric pain (P=.007). Multivariate analysis showed that increasing tip-apex distance, inadequate calcar reduction, and greater fracture severity were predictive of excessive lateralization of greater than 1 cm. Nearly 20% of patients had lateral hip pain associated with cephalomedullary fixation. Final lateralization of the helical blade of greater than 1 cm was a very strong predictor of symptoms. During preoperative counseling, surgeons should caution patients about this relatively frequent and likely underreported complication. [Orthopedics. 2017; 40(5):e886 e891.]. PMID- 28817158 TI - Characteristics and Efficacy of a New 3-Dimensional Printed Mesh Structure Titanium Alloy Spacer for Posterior Lumbar Interbody Fusion. AB - This study evaluated the characteristics of a newly developed 3-dimensional printed mesh structure titanium spacer and its efficacy for posterior lumbar interbody fusion. Posterior lumbar interbody fusion with this spacer was performed at 53 segments (40 patients; mean age, 64 years; range, 51-73 years). Data were collected prospectively. Radiographic characteristics were analyzed with changes in interbody height, instability of the segments, formation of bone bridges around the implants, and pseudarthrosis, as determined by dynamic radiographs and postoperative computed tomography scans. Clinical outcomes were evaluated with the visual analog scale for the low back and extremities, the Oswestry Disability Index, and the 36-Item Short Form Survey. Radiographically, preoperative anterior and posterior interbody height was significantly increased immediately postoperatively (P<.05), and this increase was maintained until the last follow-up. No segmental motion of 3 degrees or greater was noted at the last follow-up. Sagittal computed tomography images showed complete anterior bone bridges for 94.3% of cases and complete posterior bone bridges for 86.7% of cases. Coronal computed tomography images showed bilateral complete bone bridges for 94.3% of cases and unilateral bone bridges for 5.7% of cases without incomplete bilateral bone bridges. No pseudarthrosis or revision, particularly including posterior lumbar interbody fusion at L5-S1, was noted. Compared with preoperative values, the visual analog scale score for the low back and extremities, the Oswestry Disability Index, and the 36-Item Short Form Survey score showed significant improvement at the last follow-up (P<.05). Posterior lumbar interbody fusion with a newly developed 3-dimensional printed mesh structure titanium spacer showed satisfactory radiographic and clinical results, with no cases of pseudarthrosis or revision, including posterior lumbar interbody fusion at L5-S1. [Orthopedics. 2017; 40(5):e880-e885.]. PMID- 28817159 TI - Treatment of Unicameral Bone Cysts of the Proximal Femur With Internal Fixation Lessens the Risk of Additional Surgery. AB - Little data exist to guide the treatment of unicameral bone cysts in the proximal femur. Methods of treatment include corticosteroid injections, curettage and bone grafting, and internal fixation. The authors completed a multi-institutional, retrospective review to evaluate their experience with proximal femoral unicameral bone cysts. They posed the following questions: (1) Does internal fixation reduce the risk of further procedures for the treatment of a unicameral bone cyst? (2) Is radiographic healing faster with internal fixation? Following institutional review board approval, the authors conducted a retrospective review of 36 patients treated for a unicameral bone cyst of the proximal femur at their institutions between 1974 and 2014. Medical records and radiographs were reviewed to identify patient demographics and treatment outcomes. Tumor locations included femoral neck (n=13), intertrochanteric (n=16), and subtrochanteric (n=7). Initial treatment included steroid injection (n=2), curettage and bone grafting (n=9), and internal fixation with curettage and bone grafting (n=25). Mean time was 9 months to radiographic healing and 15 months to return to full activity. The number of patients requiring additional surgeries was increased among those who did not undergo internal fixation. There was no difference in time to radiographic healing. However, time to return to normal activities was reduced if patients had received internal fixation. A significant reduction in additional procedures was observed when patients had been treated with internal fixation. Although this did not influence time to radiographic healing, patients did return to normal activities sooner. Internal fixation should be considered in the treatment of proximal femoral unicameral bone cysts. [Orthopedics. 2017; 40(5):e862-e867.]. PMID- 28817160 TI - Extensor Mechanism Reconstruction for Chronic Patellar Fracture. AB - Patients with displaced patellar fractures typically present with disruption to the extensor mechanism requiring acute surgical intervention. Chronic patellar fractures with disruption of the extensor mechanism are uncommon, and few surgical options are available. The authors present a patient who sustained a fracture to the inferior pole of the patella in Africa 5 years prior that was managed conservatively with bands and a brace. He decided to pursue surgical intervention because of difficulties with leg extension, weakness, and ambulation. The patient underwent a novel reconstruction of his chronic extensor mechanism loss with a combination of inferior pole patellar fracture excision, z plasty and lengthening of the quadriceps tendon, and Achilles tendon reconstruction of the patellar tendon with both hamstring autograft and acellular human dermal matrix allograft augmentation of the entire reconstruction construct. At the final 2-year follow-up, the patient had restored active extension with no extensor lag and had returned to his preinjury activities, including running and playing soccer. [Orthopedics. 2018; 41(1):e145-e150.]. PMID- 28817161 TI - Biomechanical Evaluation of Unicortical Stress Risers of the Proximal Humerus Associated With Pectoralis Major Repair. AB - Proximal humerus fracture after pectoralis major tendon repair has been recently reported. Although this complication is rare, it may be possible to decrease such risk using newer techniques for myotenodesis. This study was designed to evaluate various unicortical stress risers created at the proximal humeral metadiaphysis during myotenodesis for repair of pectoralis major ruptures. A simulated pectoralis major myotenodesis was performed using fourth-generation Sawbones (N=30). Using previously described anatomic landmarks for the tendinous insertion, 3 repair techniques were compared: bone trough, tenodesis screws, and suture anchors (N=10 each). Combined compression and torsional load was sequentially increased until failure. Linear and rotational displacement data were collected. The average number of cycles before reaching terminal failure was 383 for the bone trough group, 658 for the tenodesis group, and 832 for the suture anchor group. Both the tenodesis and the suture anchor groups were significantly more resistant to fracture than the bone trough group (P<.001). The suture anchor group was significantly more resistant to fracture than the tenodesis group (P<.001). All test constructs failed in rotational stability, producing spiral fractures, which incorporated the unicortical defects in all cases. When tested under physiologic parameters of axial compression and torsion, failure occurred from rotational force, producing spiral fractures, which incorporated the unicortical stress risers in all cases. The intramedullary suture anchor configuration proved to be the most stable construct under combined axial and torsional loading. Using a bone trough technique for proximal humerus myotenodesis may increase postoperative fracture risk. [Orthopedics. 2017; 40(5):e801-e805.]. PMID- 28817162 TI - Determining When It Is Safe to Remove the External Fixator: Results From a Survey of the Limb Lengthening and Reconstruction Society. AB - Thousands of external fixators are applied for distraction osteogenesis each year. Determining when it is safe to remove the fixator can be difficult. The purpose of this study was to survey an international group of external fixation surgeons to determine their current practice patterns surrounding external fixator removal. A 10-question, open-ended survey was emailed to members of the Limb Lengthening and Reconstruction Society. Responses were recorded, and statistical analysis was performed. Pearson's chi-square test and likelihood ratio were used when indicated. A total of 124 surveys were sent, and 44 responses were received (35% response rate). The top 5 responses for determining when it is safe to remove a fixator were full weight bearing (75%), 3 cortices (71%), no pain (55%), after dynamization (55%), and duration of time (30%). Forty eight percent of respondents routinely dynamized the frame prior to removal. Significantly fewer surgeons who dynamized the frame protected the limb after removal (P=.046). Physicians who dynamized the frame tended to use a less constricting device for protection (boot or brace vs cast) than those who did not dynamize (P=.016). This study showed that most surgeons used radiographs and clinical evaluation to determine timing of fixator removal. Only 23% reported using computed tomography. Most surgeons dynamized the fixator prior to removal. Those who dynamized the frame were more confident in the regenerate healing. Although this study offers insight into what experienced surgeons do in their daily practice, it reveals many areas for improvement in the literature. [Orthopedics. 2017; 40(5):e876-e879.]. PMID- 28817163 TI - Provider-Initiated Patient Satisfaction Reporting Yields Improved Physician Ratings Relative to Online Rating Websites. AB - Recently, providers have begun to publicly report the results of patient satisfaction surveys from their practices. However, these outcomes have never been compared with the findings of commercial online physician rating websites. The goals of the current study were to (1) compare overall patient satisfaction ratings for orthopedic surgeons derived from provider-based third-party surveys with existing commercial physician rating websites and (2) determine the association between patient ratings and provider characteristics. The authors identified 12 institutions that provided publicly available patient satisfaction outcomes derived from third-party surveys for their orthopedic surgeons as of August 2016. Orthopedic surgeons at these institutions were eligible for inclusion (N=340 surgeons). Provider characteristics were recorded from publicly available data. Four high-traffic commercial online physician rating websites were identified: Healthgrades.com, UCompareHealthCare.com, Vitals.com, and RateMDs.com. For each surgeon, overall ratings (on a scale of 1-5), total number of ratings, and percentage of negative ratings were compared between provider initiated internal ratings and each commercial online website. Associations between baseline factors and overall physician ratings and negative ratings were assessed. Provider-initiated internal patient satisfaction ratings showed a greater number of overall patient ratings, higher overall patient satisfaction ratings, and a lower percentage of negative comments compared with commercial online physician rating websites. A greater number of years in practice had a weak association with lower internal ratings, and an academic practice setting and a location in the Northeast were protective factors for negative physician ratings. Compared with commercial online physician rating websites, provider initiated patient satisfaction ratings of orthopedic surgeons appear to be more favorable, with greater numbers of responses. [Orthopedics. 2017; 40(5):304 310.]. PMID- 28817164 TI - Prediction of acute inhalation toxicity using in vitro lung surfactant inhibition. AB - Private consumers and professionals may experience acute inhalation toxicity after inhaling aerosolized impregnation products. The distinction between toxic and non-toxic products is difficult to make for producers and product users alike, as there is no clearly described relationship between the chemical composition of the products and induction of toxicity. The currently accepted method for determination of acute inhalation toxicity is based on experiments on animals; it is time-consuming, expensive and causes stress for the animals. Impregnation products are present on the market in large numbers and amounts and exhibit great variety. Therefore, an alternative method to screen for acute inhalation toxicity is needed. The aim of our study was to determine if inhibition of lung surfactant by impregnation products in vitro could accurately predict toxicity in vivo in mice. We tested 21 impregnation products using the constant flow through set-up of the constrained drop surfactometer to determine if the products inhibited surfactant function or not. The same products were tested in a mouse inhalation bioassay to determine their toxicity in vivo. The sensitivity was 100%, i.e., the in vitro method predicted all the products that were toxic for mice to inhale. The specificity of the in vitro test was 63%, i.e., the in vitro method found three false positives in the 21 tested products. Six of the products had been involved in accidental human inhalation where they caused acute inhalation toxicity. All of these six products inhibited lung surfactant function in vitro and were toxic to mice. PMID- 28817165 TI - Contraception After Surgical and Medical Abortion: A Review. AB - Importance: To prevent subsequent unintended pregnancy, contraception should be initiated soon after surgical and medical abortion. Evidence regarding the safety of postabortion contraception, especially for longacting reversible methods, has accumulated in recent years. Objective: This review seeks to provide up-to-date recommendations about the provision and timing of contraception after surgical and medical abortion. Evidence Acquisition: Recommendations are based on the US Medical Eligibility Criteria (MEC) or on the authors' review of the current literature for topics that the MEC does not address. Results: Contraceptive counseling at the time of abortion should be collaborative. All reversible contraceptive methods are safe to begin immediately after surgical abortion, barring concern for surgical complications or underlying medical contraindications. After medical abortion, the implant may be initiated immediately, combined hormonal contraception may be initiated shortly thereafter, and the intrauterine device may be placed once the abortion is complete. Further research is needed to determine the optimal timing of depot medroxyprogesterone acetate initiation after medical abortion. Conclusions and Relevance: Abortion is an important opportunity for contraceptive counseling and provision. Clinic policies and insurance coverage should maximize access to all contraceptive methods, including long-acting reversible methods. PMID- 28817166 TI - Pregnancy Outcomes Following Cervical Conization or Loop Electrosurgical Excision Procedures. AB - Background: Conservative excisional measures used to manage cervical dysplasia are often cited as risk factors for preterm labor in subsequent pregnancies. Objective: We performed an evidence-based review of the obstetric complications following excisional procedures for cervical dysplasia in women of reproductive age. Evidence Acquisition: Between 1993 and 2016, there were 7 published meta analyses of cohort studies that consistently demonstrated an association between excisional cervical procedures and preterm labor. However, controversy remains as to whether the increased risk is due to the cervical amputation or to the risk factors that underlie the dysplasia. Results: Although data suggest an association between excisional procedures and preterm labor, the choice of the control group may either overestimate or underestimate the relative risk. In addition, recent data suggest that depth of excision greater than 10 to 12 mm is associated with increases in risk of preterm birth. Conclusions: Women with cervical dysplasia are at an increased baseline risk of preterm birth, and surgical excision confers additional risk. Pregnant patients with advanced cervical dysplasia or a history of surgical excision should be considered high risk pregnancies. PMID- 28817167 TI - Body Mass Index 50 kg/m2 and Beyond: Perioperative Care of Pregnant Women With Superobesity Undergoing Cesarean Delivery. AB - Importance: Superobesity, defined as body mass index 50 kg/m2 or greater, is the fastest-growing obesity group in the United States. Currently, 2% of pregnant women in the United States are superobese, and 50% will deliver via cesarean delivery. Objective: To review evidence of perioperative care during cesarean delivery among superobese women. Evidence Acquisition: We performed an evidence based review of maternal and neonatal risks of cesarean delivery and of intraoperative management and immediate postpartum care of superobese pregnant women. We also reviewed bariatric and general literature surgery on perioperative care of superobese patients. Results: There is limited information to direct evidence-based care of superobese women who undergo cesarean delivery. Superobese women have a 30% to 50% risk of wound complications, a 20% risk of neonatal intensive care unit admission, and a 1% to 2% risk of maternal intensive care unit admission. Preoperative discussion with superobese women should include a review of maternal and fetal risks associated with cesarean delivery, as well as operative options including skin incision. Preoperative cefazolin with a 3-g dose, chlorhexidine skin preparation, and availability of adequate personnel for patient transfers are important evidence-directed approaches to reducing maternal and personnel morbidity. Postoperatively, early ambulation and chemical prophylaxis are reasonable, although there is a lack of evidence as to whether these measures prevent thromboembolic complications. Conclusions: Superobese women are at increased risk of cesarean delivery and resultant complications. Most evidence-directed recommendations for perioperative care are extrapolated from studies of obese women undergoing bariatric surgery. As the prevalence of reproductive-age women with superobesity increases, studies directed at this high risk population are urgently need. PMID- 28817168 TI - Infection with a novel derogenid trematode in a Flap-necked chameleon (Chamaeleo dilepis). AB - A 2-year-old female Flap-necked chameleon (Chamaeleo dilepis) was presented with a history of anorexia. On physical examination, three 11*4*2 mm, light tan-pink, raised, gelatinous, freely movable, poorly demarcated, raised nodules were identified within the oral cavity. An impression smear contained multiple, light blue to green structures exhibiting an 18*35 MUm, elliptical-shaped anterior portion and a single 1*150 MUm filament with a tapered end. Initial differential etiologies included trematode ova, flagellate protozoa, fungal sporangia, plant material, and sperm. Fungal culture yielded no growth. The structures described above did not stain with Gomori methenamine silver stain. A calcofluor white stain yielded positive fluorescence. The DNA was extracted from the impression smears and pan-trematode PCR was performed; products were directly sequenced and phylogenetic analysis revealed maximum similarity with a digenean trematode in the family Derogenidae that was distinct from other trematodes for which a reference sequence was available. To our knowledge, this is the first description of cytologic features of trematode ova from an oral lesion in a chameleon. PMID- 28817169 TI - Studies on the conformation of protonated DNA. AB - Experiments were made to demonstrate the predominant protonation effects and structural changes of the ordered double helical DNA structure and denatured state of DNA. Spectrophotometric titrations performed at different wavelengths indicate that cytosine can be protonated in the DNA double helical molecule to a high extent without breakdown of the secondary structure. With DNA heat-denatured under severe conditions the protonation of cytosine can be measured at 280, 295, and 300 mMU: the apparent pK value obtained was ~4.6. The protonated double helical conformation of the DNA molecule differs from the unprotonated state, which follows from the decrease of the thermal stability and from changes in the ORD curves. The ORD of a GC-rich DNA indicates a novel Cotton effect with positive rotations at ~260 mMU in 0.02M KCl below pH 4.0 to pH 3.3. The occurrence of the new peak parallels the extent of protonated cytosine measured by the spectrophotometric titrations. It is concluded that the protonated cytosine in the double helical structure is responsible for the difference between the protonated DNA conformation and the native state at neutral pH. PMID- 28817170 TI - Possible formation of the left-handed alpha-helix of poly-L-serine. AB - A conformational study of poly-L-serine has shown that it can exist in the left handed alpha-helical form. A study of a pair of peptide units with the serine sidegroup attached to the alpha carbon atom linking the two units showed that O?H ?O hydrogen bonds between the OH group of the side chain and a carbonyl oxygen of the first peptide group in the backbone can occur in two regions of phi, namely, phi = 15 degrees -30 degrees for chi1 = 300 degrees and for phi = 225 degrees 230 degrees for phi = 60 degrees . The latter is close to a possible left-handed helix of poly-L-serine, stabilized by N?H ?O hydrogen bonds. From a study of contact criteria, the best conformation for this helix is found to be phi = 227 degrees , Psi = 238 degrees , chi1 = 65 degrees which has n = 3.65, h = 1.51 A. The N?H ?O hydrogen bond has a length of 2.90 A. (6 degrees ) and the O?H ?O hydrogen bond is of length 2.60 A. (0 degrees ). There are no other bad short contacts in the structure. The cylindrical coordinates of the atoms, as well as a perspective view of the structure arc given in this paper. PMID- 28817172 TI - Molecular weight of onuphic acid. PMID- 28817171 TI - Biopolymer News. PMID- 28817173 TI - Calculation of binding isotherms for heterogeneous polymers. AB - The matrix method of statistical mechanics is used to calculate equilibria for the binding of small molecules to polymers. When there is only one kind of binding site the problem is simple; some examples are given for illustrative purposes. If, however, the binding sites are not all equivalent and the bound molecules interact or interfere with each other, the problem is no longer trivial, being formally analogous with calculation of the helix-coil transition equilibrium in a heterogeneous polypeptide. Particular difficulties arise when the sequence of binding sites is aperiodic; most naturally occurring materials fall in this class. The purpose of this paper is to point out that problems of this type are readily solved with good accuracy by use of random-number methods on a high-speed digital computer. One such calculation is presented for illustration. The methods developed are applicable to such systems as the binding of actinomycin, Hg- , and acridine dyes to DNA. PMID- 28817174 TI - Epitaxial crystallization of poly (gamma-benzyl L-glutamate) on alkali halide single crystals. AB - Single crystals of poly(gamma-benzyl L-glutamate) were formed by epitaxial crystallization from solution in mesitylene on NaCl, KI, and KCl (001) cleavage faces. From electron microscopy and diffraction studies, the structure of these overgrowths was determined to be that of lamellae containing chain-folded alpha helical macromolecules. The usual type of crystal perfection, that of ordered helix axes and disordered side groups, was exhibited by this synthetic polypeptide. Unique orientation regimes were observed with each substrate. PMID- 28817175 TI - Drug development for breast, colorectal, and non-small cell lung cancers from 1979 to 2014. AB - BACKGROUND: Understanding the drug development pathway is critical for streamlining the development of effective cancer treatments. The objective of the current study was to delineate the drug development timeline and attrition rate of different drug classes for common cancer disease sites. METHODS: Drugs entering clinical trials for breast, colorectal, and non-small cell lung cancer were identified using a pharmaceutical business intelligence database. Data regarding drug characteristics, clinical trials, and approval dates were obtained from the database, clinical trial registries, PubMed, and regulatory Web sites. RESULTS: A total of 411 drugs met the inclusion criteria for breast cancer, 246 drugs met the inclusion criteria for colorectal cancer, and 315 drugs met the inclusion criteria for non-small cell lung cancer. Attrition rates were 83.9% for breast cancer, 87.0% for colorectal cancer, and 92.0% for non-small cell lung cancer drugs. In the case of non-small cell lung cancer, there was a trend toward higher attrition rates for targeted monoclonal antibodies compared with other agents. No tumor site-specific differences were noted with regard to cytotoxic chemotherapy, immunomodulatory, or small molecule kinase inhibitor drugs. Drugs classified as "others" in breast cancer had lower attrition rates, primarily due to the higher success of hormonal medications. Mean drug development times were 8.9 years for breast cancer, 6.7 years for colorectal cancer, and 6.6 years for non-small cell lung cancer. CONCLUSIONS: Overall oncologic drug attrition rates remain high, and drugs are more likely to fail in later-stage clinical trials. The refinement of early-phase trial design may permit the selection of drugs that are more likely to succeed in the phase 3 setting. Cancer 2017;123:4672-4679. (c) 2017 American Cancer Society. PMID- 28817176 TI - The intersection of class origin and immigration background in structuring social capital: the role of transnational ties. AB - The study investigates inequalities in access to social capital based on social class origin and immigration background and examines the role of transnational ties in explaining these differences. Social capital is measured with a position generator methodology that separates between national and transnational contacts in a sample of young adults in Sweden with three parental backgrounds: at least one parent born in Iran or Yugoslavia, or two Sweden-born parents. The results show that having socioeconomically advantaged parents is associated with higher levels of social capital. Children of immigrants are found to have a greater access to social capital compared to individuals with native background, and the study shows that this is related to transnational contacts, parents' education and social class in their country of origin. Children of immigrants tend to have more contacts abroad, while there is little difference in the amount of contacts living in Sweden across the three groups. It is concluded that knowledge about immigration group resources help us predict its member's social capital, but that the analysis also needs to consider how social class trajectories and migration jointly structure national and transnational contacts. PMID- 28817177 TI - The N-terminal ubiquitin-associated domain of Cezanne is crucial for its function to suppress NF-kappaB pathway. AB - Cezanne, a deubiquitinating cysteine protease (DUB) belonging to A20 subgroup of ovarian tumor (OTU) protein superfamily, functions as a negative regulator of NF kappaB to attenuate NF-kappaB activation and to restrain pro-inflammatory transcription in response to TNF receptor (TNFR) signaling. It is the first documented OTU DUB that preferably disassembles Lys11-linked polyubiquitin chains and has been shown to regulate multiple cellular events including immune signaling, cell survival and tumor progression. Previous studies showed that in response to TNF stimulation, Cezanne is recruited to the activated TNFR complex to suppress the build-up of polyubiquitinated RIP1 signal by removing Lys63 polyubiquitin from RIP1. However, how is Cezanne recognized and recruited to TNFR complex is not clear yet. In this study, we characterized a ubiquitin-associated (UBA) domain in the N-terminal region of Cezanne and proved its activity to bind Lys63 polyubiquitin chain. By constructing a series of truncated and site specific point mutants, we further localized the crucial binding sites for Lys63 polyubiquitin chains at Leu9 and Ser10 sites of Cezanne UBA domain. Mutation at these sites disrupted the recruitment of Cezanne to activated TNFR complex and dramatically reduced the inhibition of NF-kappaB activation by Cezanne. Our study demonstrated that the N-terminal UBA domain is crucial for the function of Cezanne during NF-kappaB activation. Cezanne is recognized and recruited into activated TNFR complex by specifically binding to polyubiquitinated signaling proteins after TNF stimulation through its N-terminal polyubiquitin binding site. This study sheds light on the molecular mechanism of negative regulation of NF kappaB activation by Cezanne. PMID- 28817178 TI - Re-making the global economy of knowledge: do new fields of research change the structure of North-South relations? AB - How is global-North predominance in the making of organized knowledge affected by the rise of new domains of research? This question is examined empirically in three interdisciplinary areas - climate change, HIV-AIDS, and gender studies - through interviews with 70 researchers in Southern-tier countries Brazil, South Africa and Australia. The study found that the centrality of the North was reinstituted as these domains came into existence, through resource inequalities, workforce mechanisms, and intellectual framing. Yet there are tensions in the global economy of knowledge, around workforce formation, hierarchies of disciplines, neoliberal management strategies, and mismatches with social need. Intellectual workers in the Southern tier have built significant research centres, workforces and some distinctive knowledge projects. These create wider possibilities of change in the global structure of organized knowledge production. PMID- 28817179 TI - Autophagy induction plays a protective role against hypoxic stress in human dental pulp cells. AB - Human dental pulp exposed to hypoxic conditions induces cell death accompanied by autophagy. However, the role of hypoxia-induced autophagy in human dental pulp cells (HDPCs) is unclear. The present study aimed to investigate the role of autophagy in hypoxia-induced apoptosis of HDPCs. Cobalt chloride (CoCl2 ) treated HDPCs, to mimic hypoxic conditions, decreased cell viability. Also, apoptosis related signal molecules, cleaved caspase-3 and PARP levels, were enhanced in CoCl2 -treated HDPCs. HDPCs exposed to CoCl2 also promoted autophagy, showing upregulated p62 and microtubule-associated protein 1 light chain 3 (LC3)-II levels, typical autophagic markers, and increased acidic autophagolysosomal vacuoles. Autophagy inhibition by 3 methyladenine (3MA) or RNA interference of LC3B resulted in increased levels of cleaved PARP and caspase-3, and the release of cytochrome c from mitochondria into cytosol in the CoCl2 -treated HDPCs. However, autophagy activation by rapamycin enhanced the p62 and LC3-II levels, whereas it reduced PARP and caspase-3 cleavage induced by CoCl2. These results revealed that CoCl2 -activated autophagy showed survival effects against CoCl2 induced apoptosis in the HDPCs. CoCl2 upregulated HIF-1alpha and decreased the phosphorylation of mTOR/p70S6K. HIF-1alpha inhibitor, YC-1 decreased p62 and LC3 II levels, whereas it augmented PARP and caspase-3 cleavage in response to CoCl2 . Also, YC-1 enhanced the phosphorylation of mTOR and p70S6K suppressed by CoCl2 , demonstrating that CoCl2 -induced autophagy via mTOR/p70S6K is mediated by HIF 1alpha. Taken together, these finding suggest that CoCl2 -induced autophagy mediated by the mTOR/p70S6K pathway plays a protective role against hypoxic stress in HDPCs. PMID- 28817180 TI - Preventable and mitigable adverse events in cancer care: Measuring risk and harm across the continuum. AB - BACKGROUND: Patient safety is a critical concern in clinical oncology, but the ability to measure adverse events (AEs) across cancer care is limited by a narrow focus on treatment-related toxicities. The objective of this study was to assess the nature and extent of AEs among cancer patients across inpatient and outpatient settings. METHODS: This was a retrospective cohort study of 400 adult patients selected by stratified random sampling who had breast (n = 128), colorectal (n = 136), or lung cancer (n = 136) treated at a comprehensive cancer center in 2012. Candidate AEs, or injuries due to medical care, were identified by trained nurse reviewers over the course of 1 year from medical records and safety-reporting databases. Physicians determined the AE harm severity and the likelihood of preventability and harm mitigation. RESULTS: The 400-patient sample represented 133,358 days of follow-up. Three hundred four AEs were identified for an overall rate of 2.3 events per 1000 patient days (91.2 per 1000 inpatient days and 0.9 per 1000 outpatient days). Thirty-four percent of the patients had 1 or more AEs (95% confidence interval, 29%-39%), and 16% of the patients had 1 or more preventable or mitigable AEs (95% confidence interval, 13%-20%). The AE rate for patients with breast cancer was lower than the rate for patients with colorectal or lung cancer (P <= .001). The preventable or mitigable AE rate was 0.9 per 1000 patient days. Six percent of AEs and 4% of preventable AEs resulted in serious harm. Examples included lymphedema, abscess, and renal failure. CONCLUSIONS: A heavy burden of AEs, including preventable or mitigable events, has been identified. Future research should examine risk factors and improvement strategies for reducing their burden. Cancer 2017;123:4728-4736. (c) 2017 American Cancer Society. PMID- 28817181 TI - Introduction of hsa-miR-103a and hsa-miR-1827 and hsa-miR-137 as new regulators of Wnt signaling pathway and their relation to colorectal carcinoma. AB - Wnt signaling is hyper-activated in most of human cancers including colorectal carcinoma (CRC). Therefore, the introduction of new regulators for Wnt pathway possesses promising diagnostic and therapeutic applications in cancer medicine. Bioinformatics analysis introduced hsa-miR-103a, hsa-miR-1827, and hsa-miR-137 as potential regulators of Wnt signaling pathway. Here, we intended to examine the effect of these human miRNAs on Wnt signaling pathway components, on the cell cycle progression in CRC originated cell lines and their expression in CRC tissues. RT-qPCR results indicated upregulation of hsa-miR-103a, hsa-miR-1827, and downregulation of hsa-miR-137 in CRC tissues. Overexpression of hsa-miR-103a and hsa-miR-1827 in SW480 cells resulted in elevated Wnt activity, detected by both Top/Flash assay and RT-qPCR analysis. Inhibition of Wnt signaling by using PNU-74654 or IWP-2 small molecules suggested that these miRNAs exerts their effect at the beta-catenin degradation complex level. Then, RT-qPCR, dual luciferase assay, and western blotting analysis indicated that APC and APC2 transcripts were targeted by hsa-miR-103a, hsa-miR-1827 while, Wnt3a and beta catenin genes were upregulated. However, hsa-miR-137 downregulated Wnt3a and beta catenin genes. Further, hsa-miR-103a and hsa-miR-1827 overexpression resulted in cell cycle progression and reduced apoptotic rate in SW480 cells, unlike hsa-miR 137 overexpression which resulted in cell cycle suppression, detected by flowcytometry and Anexin analysis. Overall, our data introduced hsa-miR-103a, hsa miR-1827 as onco-miRNAs and hsa-miR-137 as tumor suppressor which exert their effect through regulation of Wnt signaling pathway in CRC and introduced them as potential target for therapy. PMID- 28817182 TI - Centralized patient-reported outcome data collection in transplantation is feasible and clinically meaningful. AB - BACKGROUND: Allogeneic hematopoietic cell transplantation (HCT) cures many patients, but often with the risk of late effects and impaired quality of life. The value of quantifying patient-reported outcomes (PROs) is increasingly being recognized, but the routine collection of PROs is uncommon. This study evaluated the feasibility of prospective PRO collection by an outcome registry at multiple time points from unselected HCT patients undergoing transplantation at centers contributing clinical data to the Center for International Blood and Marrow Transplant Research (CIBMTR), and then it correlated the PRO data with clinical and demographic data. METHODS: The Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), 36-Item Short Form Health Survey (SF-36), and Pediatric Quality of Life Inventory measures were administered before HCT, on day 100, and at 6 and 12 months. Patients were recruited by the transplant center, but posttransplant PRO collection was managed centrally by the CIBMTR. RESULTS: There were 580 eligible patients, and 390 (67%) enrolled. Feasibility was shown by high time-specific retention rates (176 of 238 at 1 year or 74%) and participant satisfaction. Factors associated with higher response rates were an age > 50 years (odds ratio [OR], 1.58; 95% confidence interval [CI], 1.03-2.41; P = .0355), white race (OR, 4.61; 95% CI, 2.66-7.99; P < .0001), and being married (OR, 2.28; 95% CI, 1.42-3.65; P = .0006) for adults and a higher family income for children (OR, 4.99; 95% CI, 2.12-11.75; P = .0002). Importantly, pre-HCT PRO scores independently predicted survival after adjustments for patient-, disease-, and transplant-related factors. The adjusted probabilities of 1-year survival were 56%, 67%, 75%, and 76% by increasing quartiles of the pre-HCT FACT-BMT score and 58%, 72%, 62%, and 82% by increasing quartiles of the pre-HCT SF-36 physical component score. CONCLUSIONS: A hybrid model of local consent for centralized PRO collection is feasible, and pretransplant PROs provide critical prognostic information for HCT outcomes. Cancer 2017;123:4687-4700. (c) 2017 American Cancer Society. PMID- 28817184 TI - The Influence of Cytomegalovirus on Expression of HLA-G and its Ligand KIR2DL4 by Human Peripheral Blood Leucocyte Subsets. AB - HLA-G is a non-classical class I HLA antigen, normally expressed in high levels only on extravillous cytotrophoblast. It has immunosuppressive properties in pregnancy and has also been found to be upregulated on leucocytes in viral infection. In this study, proportions of all leucocyte subsets expressing HLA-G were found to be low in healthy subjects positive or negative for cytomegalovirus (CMV). Significantly greater proportions of CD4+ CD69+ and CD56+ T cells expressed HLA-G compared to other T cells. However, following stimulation with CMV antigens or intact CMV, proportions of CD4+, CD8+, CD69+ and CD56+ T cells, and also B cells expressing HLA-G, were significantly increased in CMV+ subjects. Despite some subjects having alleles of HLA-G associated with high levels of expression, no relationship was found between HLA-G genotype and expression levels. Purified B cells from CMV+ subjects stimulated in mixed culture with CMV antigens showed significantly increased HLA-G mRNA expression by real-time polymerase chain reaction. Serum levels of soluble HLA-G were similar in CMV- and CMV+ subjects but levels in culture supernatants were significantly higher in cells from CMV+ than from CMV- subjects stimulated with CMV antigens. The HLA-G ligand KIR2DL4 was mainly expressed on NK cells and CD56+ T cells with no differences between CMV+ and CMV- subjects. Following stimulation with IL-2, an increase in the proportion of CD56+ T cells positive for KIR2DL4 was found, together with a significant decrease in CD56dimCD16+ NK cells. The results show that CMV influences HLA-G expression in healthy subjects and may contribute to viral immune evasion. PMID- 28817183 TI - Combined high-intensity local treatment and systemic therapy in metastatic head and neck squamous cell carcinoma: An analysis of the National Cancer Data Base. AB - BACKGROUND: There is increasing evidence that primary tumor ablation can improve survival for some cancer patients with distant metastases. This may be particularly applicable to head and neck squamous cell carcinoma (HNSCC) because of its tropism for locoregional progression. METHODS: This study included patients with metastatic HNSCC undergoing systemic therapy identified in the National Cancer Data Base. High-intensity local treatment was defined as radiation doses >= 60 Gy or oncologic resection of the primary tumor. Multivariate Cox regression, propensity score matching, landmark analysis, and subgroup analysis were performed to account for imbalances in covariates, including adjustments for the number and location of metastatic sites in the subset of patients with this information available. RESULTS: In all, 3269 patients were included (median follow-up, 51.5 months). Patients undergoing systemic therapy with local treatment had improved survival in comparison with patients receiving systemic therapy alone in propensity score-matched cohorts (2 year overall survival, 34.2% vs 20.6%; P < .001). Improved survival was associated only with patients receiving high-intensity local treatment, whereas those receiving lower-intensity local treatment had survival similar to that of patients receiving systemic therapy without local treatment. The impact of high intensity local therapy was time-dependent, with a stronger impact within the first 6 months after the diagnosis (adjusted hazard ratio [AHR], 0.255; 95% confidence interval [CI], 0.210-0.309; P < .001) in comparison with more than 6 months after the diagnosis (AHR, 0.622; 95% CI, 0.561-0.689; P < .001) in the multivariate analysis. A benefit was seen in all subgroups, in landmark analyses of 1-, 2-, and 3-year survivors, and when adjusting for the number and location of metastatic sites. CONCLUSIONS: Aggressive local treatment warrants prospective evaluation for select patients with metastatic HNSCC. Cancer 2017;123:4583-4593. (c) 2017 American Cancer Society. PMID- 28817185 TI - Setting the stage for universal financial distress screening in routine cancer care. AB - Financial burden from cancer treatment is increasingly being recognized as a threat to optimal access, quality, and outcomes of cancer care for patients. Although research in the area is moving at a fast pace, multiple questions remain unanswered, such as how to practically integrate the assessment and management of financial burden into routine health care delivery for patients with cancer. Although psychological distress screening for patients undergoing cancer treatment now is commonplace, the authors raise the provocative idea of universal screening for financial distress to identify and assist vulnerable groups of patients. Herein, the authors outline the arguments to support screening for financial burden in addition to psychological distress, examining it as an independent patient-reported outcome for all patients with cancer at various time points during their treatment. The authors describe the proximal and downstream impact of such a strategy and reflect on some challenges and potential solutions to help integrate this concept into routine cancer care delivery. Cancer 2017;123:4092-4096. (c) 2017 American Cancer Society. PMID- 28817186 TI - A prognostic 11 genes expression model for ovarian cancer. AB - The symptoms of ovarian cancer at early stages are usually absent which makes the diagnosis in its early stages exceedingly difficult. Previous research has proven that ovarian cancer is a genetic disease, which depends on the alteration of multi-cancer related genes and anti-cancer genes, multi-stages and multi pathways, involving a variety of oncogene activation and anti-oncogene inactivation. For a better understanding of the prognostic classification of ovarian cancer, gene expression profiles were used to analyze the prognostic factors of ovarian cancer, and the prognostic model was used to classify the ovarian cancer samples. The ovarian cancer samples data were downloaded from TCGA dataset. Rebust likelihood-based survival model was built to find the key genes that could function as prognostic markers. The samples were classified by unsupervised hierarchical clustering. Furthermore, Kaplan-Meier survival analysis was used to analyze the differences in the prognosis of the samples. The prognostic model was used to classify the samples, and then the best classification model was selected as the prognostic model of ovarian cancer. Finally, GEO datasets were used for external data validation. A total of 886 genes with influence on prognosis was obtained. Then genomic combinations of 11 genes were screened out by random sampling. Then the active number of influential factors was counted based on the expression level of featured genes. When the number of influencing factors is >=7, the prognosis difference among these genes is the largest (P-value = 0.000775); and this was chosen as the final Classification model. To summary, a prognostic 11genes expression model was preliminarily built to classify the ovarian cancer samples. PMID- 28817187 TI - Second-line treatment in patients with pancreatic ductal adenocarcinoma: A meta analysis. AB - BACKGROUND: There are limited therapeutic options for treatment-refractory pancreatic ductal adenocarcinoma (PDAC), with a paucity of data to support the best option after progression on gemcitabine-based regimens. The authors performed a meta-analysis to determine the effectiveness of adding oxaliplatin (OX) or various irinotecan formulations to a fluoropyrimidine (FP) after first line treatment progression in patients with PDAC. METHODS: Different databases, including PubMed, EMBASE, and Cochrane, were searched to identify randomized controlled trials comparing FP monotherapy versus FP combination therapy that included either oxaliplatin (FPOX) or various irinotecan formulations (FPIRI) in patients with PDAC who progressed after first-line treatment. Secondary analyses were planned to assess the effectiveness of FPOX and FPIRI compared with FP. Outcomes of interest included overall survival (OS) and progression-free survival (PFS). RESULTS: Five studies with 895 patients were identified. Patients randomized to receive FPIRI/FPOX had a significantly improved PFS and a trend toward improved OS compared with those who received FP monotherapy. When comparing FPIRI with FP, there was an improvement in both PFS (hazard ratio, 0.64; 95% confidence interval, 0.47-0.87; P = .005) and OS (hazard ratio, 0.70; 95% confidence interval, 0.55-0.89; P = .004) in patients who received the combination. Conversely, FPOX produced only a modest improvement in PFS with no improvement in OS. CONCLUSIONS: Combination chemotherapy with OX or various IRI formulations appears to improve PFS compared with single-agent FP. FPIRI, but not FPOX, appears to confer an OS advantage. The combination of FP with irinotecan formulations appears to be the appropriate next line of treatment upon progression after gemcitabine-based chemotherapy regimens. Cancer 2017;123:4680 4686. (c) 2017 American Cancer Society. PMID- 28817189 TI - From preparedness to risk: from the singular risk of nuclear war to the plurality of all hazards. AB - Debates on risk have largely assumed risk to be the outcome of calculative practices. There is a related assumption that risk objects come only in one form, and that the reason not everything can be transformed into a risk is because of the difficulties in calculating and creating universal quantitative comparisons. In this article, building on recent studies of preparedness that have broadened understandings of risk, we provide an analysis of how preparedness measures might themselves produce risk, in particular through risk's durable instantiation, or what we call 'concretization'. Our empirical focus is on how government agencies in two countries shifted their attention from the risk of nuclear attack during the Cold War to an all hazards approach to preparedness. Comparing the mid- to late-twentieth century histories of the UK and Switzerland, we show that both countries shifted from focusing from a single risk to plural risks. This shift cannot be explained by a change in prevailing calculative practices, or by the fact that the risks changed historically. Instead, it is driven by historically specific changes in how risks are produced and reproduced in relation to how materializations of risk operate over time. PMID- 28817188 TI - Changes in standardized mortality rates from thyroid cancer in Korea between 1985 and 2015: Analysis of Korean national data. AB - BACKGROUND: The incidence of thyroid cancer has increased very rapidly in Korea; however, most previous studies suggested that the mortality rate for thyroid cancer remained stable. The objective of the current study was to evaluate recent changes in standardized thyroid cancer mortality using data from Statistics Korea. METHODS: Population and mortality data from 1985 through 2015 were obtained from Statistics Korea. Age-standardized mortality rates (ASMRs) from thyroid cancer per 100,000 population were calculated based on the World Health Organization standard population. RESULTS: In Korea, the ASMRs from thyroid cancer increased from 0.17 (95% confidence interval [CI], 0.17-0.18) per 100,000 in 1985 to 0.85 (95% CI, 0.83-0.86) per 100,000 in 2004, which was the highest among all countries. Subsequently, the ASMRs continuously decreased to 0.42 (95% CI, 0.41-0.43) per 100,000 between 2004 and 2015. The estimated annual percent change (APC) from 1985 to 2004 was 7.94 (95% CI, 6.43-9.46), and the corresponding value from 2004 to 2015 was -4.10 (95% CI, -5.76 to -2.40). Changes in the ASMRs reflected similar patterns in men (1985-2003: APC, 8.51; 2003-2015: APC, -4.32) and women (1985-2004: APC, 7.62; 2004-2015: APC, -4.38) and were also observed in older patients (aged >= 55 years). CONCLUSIONS: Thyroid cancer mortality in Korea increased until 2004 and then continuously decreased until 2015. Increases in the early diagnosis of thyroid cancer, changes in exposure to risk factors, and standardization in diagnosis and treatment may be associated with the decrease in thyroid cancer mortality in Korea. Cancer 2017; 123:4808-14. (c) 2017 American Cancer Society. PMID- 28817191 TI - Pullout strength of 2.0 mm cancellous and cortical screws in synthetic bone. AB - OBJECTIVE: To determine whether 2.0 mm cancellous screws are superior to 2.0 mm cortical screws when inserted into cancellous and bicortical bone. STUDY DESIGN: Biomechanical study. METHODS: The 2.0 mm cancellous screws and 2.0 mm cortical screws were inserted according to the recommended guidelines in synthetic cancellous and bicortical blocks. Fifteen screw-block constructs per group were tested to failure in axial pullout. Axial pullout strength and yield strength were calculated. Data were analyzed using a one-way ANOVA. RESULTS: The 2.0 mm cortical screws achieved lower axial pullout strength than 2.0 mm cancellous screws in cancellous blocks. The 2.0 mm cortical screws achieved greater pullout strength than 2.0 mm cancellous screws in bicortical blocks. CONCLUSION: The 2.0 mm cancellous screws may offer a biomechanical advantage in bone with thin cortices (<1 mm thick), whereas 2.0 mm cortical screws may be preferred in cortical bone with cortices measuring at least 1 mm in thickness. PMID- 28817190 TI - A Phase 1 and 2 study of Filanesib alone and in combination with low-dose dexamethasone in relapsed/refractory multiple myeloma. AB - BACKGROUND: Filanesib (ARRY-520) is a highly selective inhibitor of kinesin spindle protein, which has demonstrated preclinical antimyeloma activity. METHODS: This open-label Phase 1/2 study determined the maximum tolerated dose of Filanesib administered on Days 1 and 2 of 14-Day Cycles in patients with multiple myeloma (MM) and included expansion cohorts with and without dexamethasone (40 mg/week). Patients in the dose-escalation (N = 31) and Phase 2 single-agent (N = 32) cohorts had received prior bortezomib as well as prior thalidomide and/or lenalidomide. Patients in the Phase 2 Filanesib plus dexamethasone cohort (N = 55) had received prior alkylator therapy and had disease refractory to lenalidomide, bortezomib, and dexamethasone. Prophylactic filgrastim was incorporated during dose escalation and was used throughout Phase 2. RESULTS: Patients in each cohort had received a median of >=6 prior therapies. The most common dose-limiting toxicities were febrile neutropenia and mucosal inflammation. In Phase 2, Grade 3 and 4 cytopenias were reported in approximately 50% of patients. Nonhematologic toxicities were infrequent. Phase 2 response rates (partial responses or better) were 16% (single agent) and 15% (Filanesib plus dexamethasone). All responding patients had low baseline levels of alpha1 acid glycoprotein, a potential selective biomarker. CONCLUSIONS: Filanesib 1.50 mg/m2 /day administered with prophylactic filgrastim has a manageable safety profile and encouraging activity in heavily pretreated patients This study is registered at www.clinicaltrials.gov as NCT00821249. Cancer 2017;123:4617-4630. (c) 2017 American Cancer Society. PMID- 28817193 TI - Response-reinforcer dependency and resistance to change. AB - The effects of the response-reinforcer dependency on resistance to change were studied in three experiments with rats. In Experiment 1, lever pressing produced reinforcers at similar rates after variable interreinforcer intervals in each component of a two-component multiple schedule. Across conditions, in the fixed component, all reinforcers were response-dependent; in the alternative component, the percentage of response-dependent reinforcers was 100, 50 (i.e., 50% response dependent and 50% response-independent) or 10% (i.e., 10% response-dependent and 90% response-independent). Resistance to extinction was greater in the alternative than in the fixed component when the dependency in the former was 10%, but was similar between components when this dependency was 100 or 50%. In Experiment 2, a three-component multiple schedule was used. The dependency was 100% in one component and 10% in the other two. The 10% components differed on how reinforcers were programmed. In one component, as in Experiment 1, a reinforcer had to be collected before the scheduling of other response-dependent or independent reinforcers. In the other component, response-dependent and independent reinforcers were programmed by superimposing a variable-time schedule on an independent variable-interval schedule. Regardless of the procedure used to program the dependency, resistance to extinction was greater in the 10% components than in the 100% component. These results were replicated in Experiment 3 in which, instead of extinction, VT schedules replaced the baseline schedules in each multiple-schedule component during the test. We argue that the relative change in dependency from Baseline to Test, which is greater when baseline dependencies are high rather than low, could account for the differential resistance to change in the present experiments. The inconsistencies in results across the present and previous experiments suggest that the effects of dependency on resistance to change are not well understood. Additional systematic analyses are important to further understand the effects of the response-reinforcer relation on resistance to change and to the development of a more comprehensive theory of behavioral persistence. PMID- 28817192 TI - TssA: The cap protein of the Type VI secretion system tail. AB - The Type VI secretion system (T6SS) is a multiprotein and mosaic apparatus that delivers protein effectors into prokaryotic or eukaryotic cells. Recent data on the enteroaggregative Escherichia coli (EAEC) T6SS have provided evidence that the TssA protein is a key component during T6SS biogenesis. The T6SS comprises a trans-envelope complex that docks the baseplate, a cytoplasmic complex that represents the assembly platform for the tail. The T6SS tail is structurally, evolutionarily and functionally similar to the contractile tails of bacteriophages. We have shown that TssA docks to the membrane complex, recruits the baseplate complex and initiates and coordinates the polymerization of the inner tube with that of the sheath. Here, we review these recent findings, discuss the variations within TssA-like proteins, speculate on the role of EAEC TssA in T6SS biogenesis and propose future research perspectives. PMID- 28817194 TI - Prediction and prognosis of ventricular tachycardia recurrence after catheter ablation with remote magnetic navigation for electrical storm in patients with ischemic cardiomyopathy. AB - BACKGROUND: Ventricular tachycardia (VT) recurrence after catheter ablation for electrical storm is commonly seen in patients with ischemic cardiomyopathy (ICM). HYPOTHESIS: We hypothesized that VT recurrence can be predicted and be related to the all-cause death after VT storm ablation guided by remote magnetic navigation (RMN) in patients with ICM. METHODS: A total of 54 ICM patients (87% male; mean age, 65 +/- 7.1 years) presenting with VT storm undergoing acute ablation using RMN were enrolled. Acute complete ablation success was defined as noninducibility of any sustained monomorphic VT at the end of the procedure. Early VT recurrence was defined as the occurrence of sustained VT within 1 month after the first ablation. RESULTS: After a mean follow-up of 17.1 months, 27 patients (50%) had freedom from VT recurrence. Sustained VT recurred in 12 patients (22%) within 1 month following the first ablation. In univariate analysis, VT recurrence was associated with incomplete procedural success (hazard ratio [HR]: 6.25, 95% confidence interval [CI]: 1.20-32.47, P = 0.029), lack of amiodarone usage before ablation (HR: 4.71, 95% CI: 1.12-19.7, P = 0.034), and a longer procedural time (HR: 1.023, 95% CI: 1.00-1.05, P = 0.05). The mortality of patients with early VT recurrence was higher than that of patients without recurrence (P < 0.01). CONCLUSIONS: Inducibility of any VT at the end of procedure for VT storm guided by RMN is the strongest predictor of VT recurrence. ICM patients who have early recurrences after VT storm ablation are at high risk of all-cause death. PMID- 28817195 TI - Vertical off-centering affects organ dose in chest CT: Evidence from Monte Carlo simulations in anthropomorphic phantoms. AB - PURPOSE: The objective of our study was to assess the effect of patient vertical off-centering on organ dose in chest CT with tube current modulation. METHODS: For this purpose, anthropomorphic phantoms representing adult male, female, and overweight male were scanned on 192-slice CT scanner at 11 different vertical positions (maximal off-centering +/- 5 cm). Monte Carlo simulations were performed for each of the investigated setup, using tube current values extracted from the raw data, in order to obtain 3D dose distributions. Organ doses were calculated as a function of vertical off-centering and compared with the reference values, calculated for the phantoms positioned in the gantry isocenter. Image noise was also calculated as a function of phantoms vertical position using few circular regions of interest. Pearson statistical analysis was used to determine the correlation coefficient between image noise and organ dose values with vertical off-centering. RESULTS: Results of our study showed a significant difference in tube currents applied by the CT scanner when the phantom was scanned in off-centered vertical positions compared to those obtained when the phantom was positioned in the gantry isocenter (P < 0.005). For all investigated phantom configurations the vertical off-centering below 20 mm in both directions resulted in relative organ dose differences below 7%, while the off-centering above 40 mm was associated with higher organ dose changes of about 20%. The highest relative dose difference of 38% was observed for the thyroid gland at the lowest table positions. A significant correlation between organ doses for breasts, heart, lungs, thyroid, and liver, and vertical off-centering (R2 = 0.909 0.998, P < 0.005) was found. The relative dose increase associated with lower table position was more pronounced in peripheral organs: breast and thyroid gland. Image noise behaved opposite to the tube current and organ doses and increased at higher table positions. CONCLUSION: Strong vertical off-centering in chest CT with tube current modulation results in misoperation of the TCM function affecting both radiation dose and image noise. Therefore, special attention must be paid to a correct patient positioning in order to optimize organ doses and image quality of the respective CT examination. PMID- 28817196 TI - Quantitative Analysis of Intravoxel Incoherent Motion (IVIM) Diffusion MRI using Total Variation and Huber Penalty Function. AB - PURPOSE: Quantitative analysis in intravoxel incoherent motion (IVIM) imaging commonly uses voxel-wise estimation of the bi-exponential model, which might not be reliable for clinical interpretation. Improving model fitting performance and qualitative and quantitative parametric estimation, two novel methodologies are proposed here. METHODS: Five IVIM analyses methodologies: (a) Bi-exponential (BE) model, (b) Segmented BE method with two-parameter fitting (BEseg-2), (c) Segmented BE method with one-parameter fitting (BEseg-1), (d) BE with adaptive Total Variation penalty function (BE+TV) and (e) BE with adaptive Huber penalty function (BE+HPF) were evaluated. Relative root-mean-square error (RRMSE), relative bias (RB) and relative parameters (Drel,Drel*,&frel) were calculated to estimate the accuracy of methods in simulations. Empirical datasets from 14 patients with bone tumor were analyzed using these methodologies. Coefficient of variation (CV) were estimated for each IVIM parameter in tumor volume to measure the precision of the estimation methods in vivo. RESULTS: Both BE+TV and BE+HPF showed consistently lower RRMSE (~10-42%) and lower RB (-4 to 8%) at all noise levels, compared to BE, BEseg-2 and BEseg-1 (RRMSE: ~15-120% and RB: -20 to 62%). Estimated Drel,Drel*&frel for both BE+TV and BE+HPF methods were ~1 (0.96-1.08), whereas BE, BEseg-2 and BEseg-1 showed sub-optimal parameter estimation (0.80 1.62). For clinical data BE+TV and BE+HPF showed 30-50% improved CV in estimating D, D*, and f than BE and improved CV in estimating D* (7-23%) and f (26-30%) than BEseg-2 and BEseg-1. CONCLUSIONS: Bi-exponential model with penalty function showed quantitatively and qualitatively improved IVIM parameter estimation for both simulated and clinical dataset of bone tumors, thus potentially making this approach suitable for clinical applications in future. PMID- 28817198 TI - Valuable antibody detection method for classifying hepatitis E virus genotypes. AB - Nucleotide-based methods are conventionally used to classify the hepatitis E virus (HEV) genotypes. A serological enzyme immunoassay (EIA) using open reading frame 3 (ORF3) C-terminal peptides was developed to conveniently and accurately classify and evaluate the genotypes of HEV. The sera of mice immunized with HEV genotype 1, 3, and 4 reacted highly specifically to the peptides of the corresponding genotypes. Most (84.2%) clinical sera infected with HEV genotype 4 were positive for anti-HEV antibodies when tested with the ORF3 peptides of genotype 4, but were negative for genotypes 1 and 3. Monkey and clinical serial sera infected with HEV reacted strongly to the homologous genotype ORF3 peptides. The indirect EIAs were more sensitive, with stronger reactivity, than commercial anti-HEV immunoglobulin G assays when serial sera from monkeys infected with HEV genotype 1 or 4 were tested. All our results indicate that the serological typing EIA assays described in this study are more effective and convenient for the classification of HEV genotypes than molecular approaches, and can be used to screen large numbers of serum samples and differentiate genotypes for the diagnosis of HEV infections. PMID- 28817197 TI - Estimating seroprevalence of herpes simplex virus type 1 among different Middle East and North African male populations residing in Qatar. AB - HSV-1 epidemiology in the Middle East and North Africa (MENA) remains poorly understood. Our study aimed to measure HSV-1 antibody prevalence (seroprevalence) and its age-distribution among select MENA populations residing in Qatar. Sera were collected from male blood donors attending Hamad Medical Corporation 2013 2015. A total of 2,077 sera were tested for anti-HSV-1 antibodies using HerpeSelect(r) 1 ELISA IgG kits (Focus Diagnostics, Cypress, CA). Robust Poisson regression was conducted to estimate adjusted infection prevalence ratios. Country-specific HSV-1 seroprevalence was estimated for 10 national populations: 97.5% among Egyptians, 92.6% among Yemenis, 90.7% among Sudanese, 88.5% among Syrians, 86.5% among Jordanians, 82.3% among Qataris, 81.4% among Iranians, 81.4% among Lebanese, 80.5% among Palestinians, and 77.0% among Pakistanis. Age specific HSV-1 seroprevalence was estimated for Egypt, the Fertile Crescent (Iraq, Jordan, Lebanon, Palestine, and Syria), and Qatar. Seroprevalence increased with age among Fertile Crescent and Qatari nationals. Seroprevalence increased from 70.0% among those aged <= 24 years up to 98.0% among those aged >=55 years among Fertile Crescent nationals. Seroprevalence was consistently above 90% for all ages among Egyptians. HSV-1 seroprevalence is high in MENA, though with some variation across countries. The seroprevalence appears to have declined among current young age cohorts compared to its levels a few decades ago. PMID- 28817200 TI - Erratum. PMID- 28817199 TI - Exposure-Response Modeling and Power Analysis of Components of ACR Response Criteria in Rheumatoid Arthritis (Part 1: Binary Model). AB - American College of Rheumatology (ACR) response criteria is used to assess improvement in tender and swollen joint counts and in 3 of the 5 core measures (acute-phase reactant, physician global assessment, patient global assessment, pain, and physical function). From the clinical trial data on 5 approved biological products for the treatment of rheumatoid arthritis, population pharmacokinetic/pharmacodynamic models were developed to quantitatively describe the relationship between exposure and response rates of 3 individual components of ACR response criteria. The models were then used to simulate the clinical outcomes at various time points following different treatment regimens. The relative sensitivity of these criteria components was assessed using power analysis. As compared to the composite endpoints (ACR20/ACR50/ACR70), the individual ACR criteria components had adequate power and higher sensitivity in distinguishing treatment effects over placebo/methotrexate control. The 3 individual ACR criteria components appeared to have similar powers at different dose levels after long-term treatment. This research provides a unique approach to assess the relative sensitivity of the 3 binary components of ACR response criteria which would be useful to support future dose selection and trial design in the treatment of rheumatoid arthritis. PMID- 28817201 TI - Exposure-Response Modeling and Power Analysis of Components of ACR Response Criteria in Rheumatoid Arthritis (Part 2: Continuous Model). AB - Population pharmacokinetic/pharmacodynamic (PK/PD) models were developed to quantitate the exposure-response relationships using continuous longitudinal data on American College of Rheumatology (ACR) subcomponents, that is, tender-joint count (TJC), swollen-joint count (SJC), C-reactive protein, patient's assessment of pain, patient's global assessment of disease activity, physician's global assessment of disease activity, and patient's assessment of physical function for 5 biologics approved for use in rheumatoid arthritis. The models were then used to simulate the time courses of clinical outcomes following different treatment regimens. The relative sensitivity of the 7 subcomponents was assessed using Monte Carlo simulation-based power analysis. The developed population PK/PD models adequately described the relationship between serum concentrations and changes in ACR subcomponents. The trial simulation and subsequent power analysis showed that SJC and TJC appeared to be more sensitive than the other 5 ACR subcomponents to detect treatment effect over placebo/methotrexate. These 7 ACR subcomponents had similar power in detecting the treatment difference between different doses. In addition, the continuous measures of ACR subcomponents did not appear to be more sensitive than binary measures. PMID- 28817202 TI - Perinatal mortality in Japanese women diagnosed with gestational diabetes mellitus and diabetes mellitus. AB - AIMS: The objective of this study was to determine how many pregnant Japanese women with diabetes mellitus (DM)/gestational diabetes mellitus (GDM) experience perinatal mortality in the presence of fetal anomalies. METHODS: Our investigation included data from 205 secondary/tertiary obstetric facilities located widely in Japan. The Japan Ministry of Health, Labour and Welfare Vital Statistics of Japan was used for comparison. RESULTS: Of 237 941 women giving birth at 205 hospitals, 1796 (0.8%) and 13 037 (5.5%) had DM and GDM, respectively. The perinatal mortality rates (per 1000 births) were 10.6 (19/1796) for women with DM, 5.2 (68/13037) for women with GDM, and 3.7 (7612/2039504) for the general Japanese population. Detailed information was available for 63 (72%) of the 87 perinatal deaths occurring in women with diabetes including DM and GDM; fetal anomalies were associated with 40% (25/63) of perinatal deaths, exceeding 16% (1211/7612) in the general Japanese population (P < 0.0001). The leading four fetal anomalies associated with perinatal mortality in women with diabetes were fetal trisomy (6 cases: 1 of trisomy-13 and 5 of trisomy-18), non-immune hydrops fetalis (5 cases), cardiac deformities (3 cases) and holoprosencephaly (2 cases). CONCLUSIONS: Perinatal mortality was more likely to occur in women with glucose intolerance. In the Japanese infants that succumbed to perinatal mortality, fetal anomaly was more prevalent in those born to women with a glucose intolerance than in those born to the general population. PMID- 28817203 TI - The combination of digoxin and GSK2606414 exerts synergistic anticancer activity against leukemia in vitro and in vivo. AB - Digoxin is a member of cardiac glycosides and recent studies show that digoxin plays anticancer role in several types of cancer. However, the anticancer effects and mechanism of digoxin in leukemia is largely unknown. Her, our data show that digoxin treatment significantly inhibits leukemia cell viability. In addition, digoxin treatment significantly induced apoptosis and G2/M cell cycle arrest in leukemia cells. Furthermore, we demonstrated that digoxin treatment inactivate that oncogenic pathway Akt/mTOR signaling in leukemia cells. In addition, our data show that digoxin treatment induces activation of unfolded protein response (UPR) signaling in leukemia cells. Interestingly, our in vitro and in vivo experiments show that combination treatment of digoxin and UPR inhibitor can synergistically suppress leukemia growth and induces apoptosis and cell cycle arrest compared to single drug treatment. In summary, our findings indicate that digoxin has potential anticancer effects on leukemia. The combination of digoxin and UPR signaling inhibitor can exerts synergistic anticancer activity against leukemia. (c) 2017 BioFactors, 43(6):812-820, 2017. PMID- 28817204 TI - New insight into the control of peptic ulcer by targeting the histamine H2 receptor. AB - Peptic ulcer disease is one of the major challenges in public health globally and new evidence shows that it can be controlled by targeting the histamine H2 receptor (H2 R). Recently, a number of H2 R antagonists have been synthesized and used to block the action of histamine on the parietal cells in the stomach and decrease the acid production. In this study, we modeled the H2 R by homology modeling using the 3-D crystal structure and this model was validated based on free energy and amino acid residues present in the allowed regions of a Ramachandran plot. We used this 3-D model for screening of highly potent drugs using molecular docking. We found cimetidine, cimetex, and famotidine as the most potent drugs based on the binding affinity of drug-protein interactions. We also generated a cellular network for H2 R that could be useful for better understanding of cellular mechanism and drug targets. These findings provide a new insight into the development of suitable, specific, and effective anti-ulcer drugs for a most effective treatment of ulcerous diseases. PMID- 28817205 TI - Amniotic fluid embolism mortality rate. AB - AIM: The objective of this study was to determine the mortality rate of amniotic fluid embolism (AFE) using population-based studies and case series. METHODS: A literature search was conducted using the two key words: 'amniotic fluid embolism (AFE)' AND 'mortality rate'. Thirteen population-based studies were evaluated, as well as 36 case series including at least two patients. RESULTS: The mortality rate from population-based studies varied from 11% to 44%. When nine population based studies with over 17 000 000 live births were aggregated, the maternal mortality rate was 20.4%. In contrast, the mortality rate of AFE in case series varies from 0% to 100% with numerous rates in between. CONCLUSION: The AFE mortality rate in population-based studies varied from 11% to 44% with the best available evidence supporting an overall mortality rate of 20.4%. Data from case series should no longer be used as a basis for describing the lethality of AFE. PMID- 28817206 TI - Loureirin B promotes insulin secretion through inhibition of KATP channel and influx of intracellular calcium. AB - The development of new diabetes drugs continues to be explored. Loureirin B, a flavonoid, extracted from Dracaena cochinchinensis, has been confirmed to increase insulin secretion and decrease blood glucose levels. For searching the promotion of insulin secretion with the treatment of loureirin B, experiments were employed based on cell experiments and computational methods. First, promotion of insulin secretion was dependent on extracellular glucose concentration. At the genetic level, loureirin B enhanced the relative mRNA level of Pdx-1 and MafA. Meanwhile the intracellular level of ATP increased due to the continuous absorption of glucose. Further experiments showed that the currents of KATP channel on Ins-1 cells were inhibited and the voltage-dependent calcium channels were subsequently activated. The increase of Cx43 protein expression might mediate the Ca2+ to the intracellular. Through computational simulation, we hypothesized that loureirin B might interact with KATP channels to promote insulin secretion. In conclusion, it could be concluded that loureirin B promoted insulin secretion mainly through increasing mRNA level of Pdx-1, MafA, intracellular ATP level, inhibiting the KATP current, influx of Ca2+ to the intracellular. PMID- 28817207 TI - Reviewing the ICS 2002 terminology report: The ongoing debate. PMID- 28817208 TI - Regio- and Stereoselective Chlorocyanation of Alkynes. AB - A variety of terminal and internal alkynes were converted regio- and stereoselectively into (Z)-3-chloroacrylonitriles by treatment with BCl3 in the presence of stoichiometric amounts of imidazolium thiocyanates. These products could be readily functionalized to provide useful building blocks, thus demonstrating the synthetic value of the method. Preliminary mechanistic studies suggest initial activation of the cationic thiocyanate by the Lewis acid, followed by electrophilic attack of the alkyne. The syn addition of a chloride to the vinyl cation intermediate and final elimination of the thiourea unit afford the desired chloroacrylonitriles. PMID- 28817209 TI - Huntington's disease: a clinical review. AB - Huntington's disease (HD) is a fully penetrant neurodegenerative disease caused by a dominantly inherited CAG trinucleotide repeat expansion in the huntingtin gene on chromosome 4. In Western populations HD has a prevalence of 10.6-13.7 individuals per 100 000. It is characterized by cognitive, motor and psychiatric disturbance. At the cellular level mutant huntingtin results in neuronal dysfunction and death through a number of mechanisms, including disruption of proteostasis, transcription and mitochondrial function and direct toxicity of the mutant protein. Early macroscopic changes are seen in the striatum with involvement of the cortex as the disease progresses. There are currently no disease modifying treatments; therefore supportive and symptomatic management is the mainstay of treatment. In recent years there have been significant advances in understanding both the cellular pathology and the macroscopic structural brain changes that occur as the disease progresses. In the last decade there has been a large growth in potential therapeutic targets and clinical trials. Perhaps the most promising of these are the emerging therapies aimed at lowering levels of mutant huntingtin. Antisense oligonucleotide therapy is one such approach with clinical trials currently under way. This may bring us one step closer to treating and potentially preventing this devastating condition. PMID- 28817210 TI - Varus knee osteoarthritis: Elevated synovial CD15 counts correlate with inferior biomechanical properties of lateral-compartment cartilage. AB - The study analyzed the influence of synovitis on the histological and biomechanical properties of lateral-compartment cartilage. In a prospective cohort study, 84 patients (100 knees) with varus deformity of the knee were included. Osteochondral samples from the distal lateral femur underwent biomechanical and histologic analysis. Synovial tissue was sampled for histological (chronic synovitis score) and immunohistochemical evaluation of the degree of synovitis. CD15 (neutrophils), Ki-67 (dividing cells), and CD68 (macrophages) were tested in all synovial samples. While the histological synovitis score did not correlate with the degree of cartilage degeneration (histological OARSI grades), both CD15 (rs = 0.297, p = 0.006) and Ki-67 (rs = 0.249, p = 0.023) correlated with histological OARSI grades. There was a weak negative correlation of CD15 with biomechanical properties of cartilage of the distal lateral femur (aggregate modulus (Ha): rs = -0.125; p = 0.257; dynamic modulus (DM): rs = -0.216; p = 0.048). No correlations were observed for Ki-67 and CD68. In addition, biomechanical properties were inferior in knees with a CD15 of >8/high power field compared to knees with a CD15 of <=8/high power field (Ha: p = 0.031, d = 0.46; DM: p = 0.005, d = 0.68). The study demonstrates an association of increased inflammatory activity with advanced cartilage degeneration. Lateral-compartment cartilage in knees with elevated synovial CD15 counts has a reduced ability to withstand compressive loads. CD15 might serve as an indicator for inferior biomechanical cartilage properties. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:841-846, 2018. PMID- 28817211 TI - Reviewing the ICS 2002 terminology report: The ongoing debate. PMID- 28817212 TI - Fingolimod against endotoxin-induced fetal brain injury in a rat model. AB - AIM: Fingolimod is a sphingosine-1-phosphate receptor modulator used for multiple sclerosis treatment and acts on cellular processes such as apoptosis, endothelial permeability, and inflammation. We hypothesized that fingolimod has a positive effect on alleviating preterm fetal brain injury. METHODS: Sixteen pregnant rats were divided into four groups of four rats each. On gestational day 17, i.p. endotoxin was injected to induce fetal brain injury, followed by i.p. fingolimod (4 mg/kg maternal weight). Hysterotomy for preterm delivery was performed 6 h after fingolimod. The study groups included (i) vehicle controls (i.p. normal saline only); (ii) positive controls (endotoxin plus saline); (iii) saline plus fingolimod; and (iv) endotoxin plus fingolimod treatment. Brain tissues of the pups were dissected for evaluation of interleukin (IL)-6, caspase-3, and S100beta on immunohistochemistry. RESULTS: Maternal fingolimod treatment attenuated endotoxin-related fetal brain injury and led to lower immunoreactions for IL-6, caspase-3, and S100beta compared with endotoxin controls (P < 0.0001 for all comparisons). CONCLUSION: Antenatal maternal fingolimod therapy had fetal neuroprotective effects by alleviating preterm birth-related fetal brain injury with inhibitory effects on inflammation and apoptosis. PMID- 28817213 TI - Bismuthanes as Hemilabile Donors in an O2 -Activating Palladium(0) Complex. AB - A xanthene-based bismuthane/phosphane chelating ligand has been accessed that has enabled the synthesis of a palladium(0) bismuthane complex. The bismuthane donor proved to be hemilabile as it switched to a dangling position upon addition of O2 that gave a palladium(II) peroxide complex. Unlike the corresponding 4,5 bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) palladium peroxide, the bismuth analogue could be employed for catalytic phosphane oxidation and oxidative phenol coupling. PMID- 28817214 TI - Editorial. PMID- 28817215 TI - Unexpected collective larval dispersal but little support for sweepstakes reproductive success in the highly dispersive brooding mollusc Crepidula fornicata. AB - In many marine invertebrates, long-distance dispersal is achieved during an extended pelagic larval phase. Although such dispersal should result in high gene flow over broad spatial scales, fine-scale genetic structure has often been reported, a pattern attributed to interfamilial variance in reproductive success and limited homogenization during dispersal. To examine this hypothesis, the genetic diversity of dispersing larvae must be compared with the postdispersal stages, that is benthic recruits and adults. Such data remain, however, scarce due to the difficulty to sample and analyse larvae of minute size. Here, we carried out such an investigation using the marine gastropod Crepidula fornicata. Field sampling of three to four larval pools was conducted over the reproductive season and repeated over 3 years. The genetic composition of larval pools, obtained with 16 microsatellite loci, was compared with that of recruits and adults sampled from the same site and years. In contrast to samples of juveniles and adults, large genetic temporal variations between larval pools produced at different times of the same reproductive season were observed. In addition, full- and half-sibs were detected in early larvae and postdispersal juveniles, pointing to correlated dispersal paths between several pairs of individuals. Inbred larvae were also identified. Such collective larval dispersal was unexpected given the long larval duration of the study species. Our results suggest that each larval pool is produced by a small effective number of reproducers but that, over a reproductive season, the whole larval pool is produced by large numbers of reproducers across space and time. PMID- 28817216 TI - Functional neuroimaging after severe anoxic brain injury in children may reveal preserved, yet covert, cognitive function. AB - A growing body of evidence has confirmed that, after severe brain injury in adults, motoric and task-dependent factors that are essential for reliable communication, frequently interfere with an accurate assessment of cognitive status. In the current study, resting state functional magnetic resonance imaging (fMRI) in children who have sustained an anoxic brain injury following a near drowning incident suggests a similar pattern; preserved cognition amidst severe motoric impairment that effectively precludes accurate clinical diagnosis at the bedside. Hum Brain Mapp 38:4832-4833, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28817217 TI - Mind the cell: Seasonal variation in telomere length mirrors changes in leucocyte profile. AB - Leucocytes are typically considered as a whole in studies examining telomere dynamics in mammals. Such an approach may be precarious, as leucocytes represent the only nucleated blood cells in mammals, their composition varies temporally, and telomere length differs between leucocyte types. To highlight this limitation, we examined here whether seasonal variation in leucocyte composition was related to variation in telomere length in free-ranging mandrills (Mandrilllus sphinx). We found that the leucocyte profile of mandrills varied seasonally, with lower lymphocyte proportion being observed during the long dry season presumably because of the combined effects of high nematode infection and stress at that time of the year. Interestingly, this low lymphocyte proportion during the long dry season was associated with shorter telomeres. Accordingly, based on longitudinal data, we found that seasonal changes in lymphocyte proportion were reflected by corresponding seasonal variation in telomere length. Overall, these results suggest that variation in lymphocyte proportion in blood can significantly affect telomere measurements in mammals. However, lymphocyte proportion did not entirely explain variation in telomere length. For instance, a lower lymphocyte proportion with age could not fully explain shorter telomeres in older individuals. Overall, our results show that telomere length and leucocyte profile are strongly although imperfectly intertwined, which may obscure the relationship between telomere dynamics and ageing processes in mammals. PMID- 28817218 TI - BMI, nephroangiosclerosis and glomerulonephritis: Is there any meeting point? AB - AIM: Overweight has been related to renal arteriolosclerosis and is able to modify intrarenal haemodynamics. Increasing evidence suggests an association between weight in excess and primary glomerulonephritis (GN). The aim of this study was to evaluate the relationship between nutritional status and intrarenal arterial stiffness in primary GN associated to arteriolosclerosis. We have considered the glomerular diameter (GD) as morphological parameter in overweight and obese patients. METHODS: Clinical, laboratory, anthropometric data and renal Doppler ultrasound were performed immediately before kidney biopsy. RESULTS: Primary GN was diagnosed in 92 patients. Mild arteriolosclerosis was found in 19.6% of patients, moderate in the 20.6%, severe in the 10.9% while nephroangiosclerosis was diagnosed in 8.7% of patients. A positive correlation was found between body mass index (BMI) and renal resistive index (RRI) (P < 0.01, r = 0.34). RRI were significantly higher in patients with severe arteriolosclerosis at kidney biopsy (P < 0.05). Furthermore, higher BMI (P < 0.01) was found in patients with renal arteriolosclerosis than patients without renal arteriolosclerosis (26.1 +/- 4.4 kg/m2 vs. 24.4 +/- 4.5 kg/m2 ). Finally, in overweight and obesity patients we found a positive correlation between maximal GD and BMI (P < 0.01) and maximal GD and RRI (P < 0.01). CONCLUSION: In overweight and obese patients affected by primary GN, it might be found not only glomerular but also renal vascular lesions. Finally, we believe that nephroangiosclerosis, in combination with weight in excess, is able to modify intrarenal haemodynamic parameters. Moreover, in response to these changes, the renal tissue morphologically promotes a GD increase regardless of the underlying GN. PMID- 28817219 TI - Lycium barbarum polysaccharide attenuates chemotherapy-induced ovarian injury by reducing oxidative stress. AB - AIM: We aimed to examine the effects of Lycium barbarum polysaccharide (LBP) on ovarian damage induced by cyclophosphamide (CTX) and to investigate the underlying mechanism. METHODS: A total of 240 female Sprague-Dawley rats were randomly divided into five groups: the control group, the CTX-induced ovarian injury (OI) group, and three LBP groups. Different concentrations of LBP solution were administered to the LBP groups by gastric infusion for 15 days, and the OI group and LBP groups were then subjected to CTX treatment for another 15 days. On days 7, 14, and 28 after CTX injection, femoral vein blood and ovarian tissues were collected for the measurements of antioxidant enzymes and oxidation products. Serum indicators were measured by enzyme-linked immunosorbent assay; and Nrf2, heme oxygenase-1, and quinone oxidoreductase 1 protein levels were detected by Western blot analysis. RESULTS: LBP attenuated CTX-induced ovarian damage and reversed associated adverse effects. LBP reduced oxidative stress by enhancing the potency of antioxidant enzymes and attenuating elevated levels of oxidation products following CTX injection. Furthermore, LBP upregulated Nrf2, heme oxygenase-1, and quinone oxidoreductase 1 protein expression. CONCLUSION: LBP exerts protective effects against CTX-induced ovarian injury by reducing oxidative stress and activating the Nrf2/ARE-signaling pathway. PMID- 28817220 TI - KLK14 interactions with HAI-1 and HAI-2 serine protease inhibitors: A molecular dynamics and relative free-energy calculations study. AB - Kallikrein 14 (KLK14) is a serine protease linked to several pathologies including prostate cancer and positively correlates with Gleason score. Though KLK14 functioning in cancer is poorly understood, it has been implicated in HGF/Met signaling, given that KLK14 proteolytically inhibits HGF activator inhibitor 1 (HAI-1), which strongly inhibits pro-HGF activators, thereby contributing to tumor progression. In this work, KLK14 binding to either hepatocyte growth factor activator inhibitor type-1 (HAI-1) or type-2 (HAI-2) was essayed using homology modeling, molecular dynamic simulations and free-energy calculations through MM/PBSA and MM/GBSA. KLK14 was successfully modeled. Calculated free energies suggested higher binding affinity for the KLK14/HAI-1 interaction than for KLK14/HAI-2. This difference in binding affinity is largely explained by the higher stability of the hydrogen-bond networks in KLK14/HAI-1 along the simulation trajectory. A key arginine residue in both HAI-1 and HAI-2 is responsible for their interaction with the S1 pocket in KLK14. Additionally, MM/GBSA free-energy decomposition postulates that KLK14 Asp174 and Trp196 are hotspots for binding HAI-1 and HAI-2. PMID- 28817222 TI - Heavily Substituted Atropisomeric Diarylamines by Unactivated Smiles Rearrangement of N-Aryl Anthranilamides. AB - Diarylamines find use as metal ligands and as structural components of drug molecules, and are commonly made by metal-catalyzed C-N coupling. However, the limited tolerance to steric hindrance of these couplings restricts the synthetic availability of more substituted diarylamines. Here we report a remarkable variant of the Smiles rearrangement that employs readily accessible N-aryl anthranilamides as precursors to diarylamines. Conformational predisposition of the anthranilamide starting material brings the aryl rings into proximity and allows the rearrangement to take place despite the absence of electron withdrawing substituents, and even with sterically encumbered doubly ortho substituted substrates. Some of the diarylamine products are resolvable into atropisomeric enantiomers, and are the first simple diarylamines to display atropisomerism. PMID- 28817221 TI - Neuroprotective effects of honokiol: from chemistry to medicine. AB - The incidence of neurological disorders is growing in developed countries together with increased lifespan. Nowadays, there are still no effective treatments for neurodegenerative pathologies, which make necessary to search for new therapeutic agents. Natural products, most of them used in traditional medicine, are considered promising alternatives for the treatment of neurodegenerative diseases. Honokiol is a natural bioactive phenylpropanoid compound, belonging to the class of neolignan, found in notable amounts in the bark of Magnolia tree, and has been reported to exert diverse pharmacological properties including neuroprotective activities. Honokiol can permeate the blood brain barrier and the blood-cerebrospinal fluid to increase its bioavailability in neurological tissues. Diverse studies have provided evidence on the neuroprotective effect of honokiol in the central nervous system, due to its potent antioxidant activity, and amelioration of the excitotoxicity mainly related to the blockade of glutamate receptors and reduction in neuroinflammation. In addition, recent studies suggest that honokiol can attenuate neurotoxicity exerted by abnormally aggregated Abeta in Alzheimer's disease. The present work summarizes what is currently known concerning the neuroprotective effects of honokiol and its potential molecular mechanisms of action, which make it considered as a promising agent in the treatment and management of neurodegenerative diseases. (c) 2017 BioFactors, 43(6):760-769, 2017. PMID- 28817223 TI - Single-dose euglycaemic clamp studies demonstrating pharmacokinetic and pharmacodynamic similarity between MK-1293 insulin glargine and originator insulin glargine (Lantus) in subjects with type 1 diabetes and healthy subjects. AB - AIMS: MK-1293 is an insulin glargine that has an amino acid sequence identical to that of Lantus, the originator insulin glargine. Two euglycaemic clamp studies, 1 in subjects with type 1 diabetes (T1D) and 1 in healthy subjects, were conducted to demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) similarity between MK-1293 and Lantus commercially procured in both the European Union (EU-Lantus) and the USA (US-Lantus). MATERIALS AND METHODS: Both studies were single-dose, randomized, double-blind, single-centre, crossover studies with >=7 days between dosing periods. A 2-treatment, 4-period replicate crossover study in T1D subjects (N = 76) compared the PK and PD of MK-1293 to EU-Lantus for 30 hours after dosing. A 3-period crossover study in healthy subjects (N = 109) compared the PK and PD of MK-1293, EU-Lantus and US-Lantus for 24 hours after dosing. In both studies, all subjects received single 0.4 units/kg subcutaneous doses of MK-1293 or Lantus in all dosing periods. Pharmacokinetic assessment was based on LC-MS/MS based measurement of the major insulin glargine metabolite (M1) and PD was characterized using the euglycaemic clamp platform. RESULTS: In both studies, pre specified similarity criteria were met between MK-1293 and Lantus for comparison of PK (AUC0-24 and Cmax of M1) and PD (GIR-AUC0-24 , GIR-AUC0-12 , GIR-AUC12-24 , and GIRmax ) primary endpoints. All treatments were well tolerated. CONCLUSION: Based on comparative assessment in both T1D and healthy subjects, it can be concluded that the PK and PD properties of MK-1293 are highly similar to those of Lantus. (ClinicalTrials.gov: NCT02059174). PMID- 28817225 TI - Anionic Palladium(0) and Palladium(II) Ate Complexes. AB - Palladium ate complexes are frequently invoked as important intermediates in Heck and cross-coupling reactions, but so far have largely eluded characterization at the molecular level. Here, we use electrospray-ionization mass spectrometry, electrical conductivity measurements, and NMR spectroscopy to show that the electron-poor catalyst [L3 Pd] (L=tris[3,5-bis(trifluoromethyl)phenyl]phosphine) readily reacts with Br- ions to afford the anionic, zero-valent ate complex [L3 PdBr]- . In contrast, more-electron-rich Pd catalysts display lower tendencies toward the formation of ate complexes. Combining [L3 Pd] with LiI and an aryl iodide substrate (ArI) results in the observation of the PdII ate complex [L2 Pd(Ar)I2 ]- . PMID- 28817224 TI - A novel post hoc method for detecting index switching finds no evidence for increased switching on the Illumina HiSeq X. AB - High-throughput sequencing using the Illumina HiSeq platform is a pervasive and critical molecular ecology resource, and has provided the data underlying many recent advances. A recent study has suggested that "index switching," where reads are misattributed to the wrong sample, may be higher in new versions of the HiSeq platform. This has the potential to invalidate both published and in-progress work across the field. Here, we test for evidence of index switching in an exemplar whole-genome shotgun data set sequenced on both the Illumina HiSeq 2500, which should not have the problem, and the Illumina HiSeq X, which may. We leverage unbalanced heterozygotes, which may be produced by index switching, and ask whether the undersequenced allele is more likely to be found in other samples in the same lane than expected based on the allele frequency. Although we validate the sensitivity of this method using simulations, we find that neither the HiSeq 2500 nor the HiSeq X has evidence of index switching. This suggests that, thankfully, index switching may not be a ubiquitous problem in HiSeq X sequence data. Lastly, we provide scripts for applying our method so that index switching can be tested for in other data sets. PMID- 28817226 TI - The stochastic resonance algorithm with the direct current signal as external force and its application to the detection of weak chromatographic peaks. AB - As a potential tool for amplifying weak chromatographic peaks, the stochastic resonance algorithm was developed based upon a counterintuitive physical phenomenon. Therefore, the essential step, parameter optimization, was perplexing and difficult for analysts. In order to avoid optimizing the system parameters on a case-by-case basis, an improved algorithm was proposed by introducing a constant or direct current signal into the signal to be measured as the external force. The weak chromatographic peak can be amplified and detected by the new algorithm using the same set of parameters. Two sets of our previous experimental data were reanalyzed by using the developed algorithm and the results were satisfactory. A generalized solution was expected to come into being on account of the new algorithm. PMID- 28817227 TI - Patterns of glycaemic control in patients with type 2 diabetes mellitus initiating second-line therapy after metformin monotherapy: Retrospective data for 10 256 individuals from the United Kingdom and Germany. AB - AIM: To investigate determinants of change in glycated haemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM) at 6 months after initiating uninterrupted second-line glucose-lowering therapies. MATERIALS AND METHODS: This cohort study utilized retrospective data from 10 256 patients with T2DM who initiated second-line glucose-lowering therapy (switch from or add-on to metformin) between 2011 and 2014 in Germany and the UK. Effects of pre-specified patient characteristics on 6-month HbA1c changes were assessed using analysis of covariance. RESULTS: Patients had a mean (standard error [SE]) baseline HbA1c of 8.68% (0.02); 28.5% of patients discontinued metformin and switched to an alternative therapy and the remainder initiated add-on therapy. Mean (SE) unadjusted 6-month HbA1c change was -1.27% (0.02). When adjusted for baseline HbA1c, 6-month changes depended markedly on the magnitude of the baseline HbA1c (HbA1c <9%, -0.45% per unit increase in HbA1c; HbA1c >=9%, -0.87% per unit increase in HbA1c). Adjusted mean 6-month HbA1c reductions showed slight treatment differences (range, 0.92-1.09%; P < .001). Greater reductions in HbA1c were associated with second-line treatment initiation within 6 months of T2DM diagnosis (1.36% vs 1.03% [P < .001]) and advanced age (>=70 years, 1.13%; <70 years, 1.02% [P < .001]). CONCLUSIONS: Many patients with T2DM have very high HbA1c levels when initiating second-line therapy, indicating the need for earlier treatment intensification. Patient-specific factors merit consideration when making treatment decisions. PMID- 28817228 TI - Isolation of the New Antiplasmodial Butanolide, Malleastrumolide A, from Malleastrum sp. (Meliaceae) from Madagascar. AB - An extract of Malleastrum sp. (Meliaceae) collected in Madagascar by the Madagascar International Cooperative Biodiversity Group was found to have antimalarial activity, with an IC50 value between 2.5 and 5 MUg ml-1 . After purification by liquid-liquid partition, chromatography on a Diaion open column, C18 SPE and C18 reversed phase HPLC, the new butanolide, malleastrumolide A, was isolated. The structure of malleastrumolide A was determined by mass spectrometry, NMR, and ECD. The double bond position was determined by cross metathesis and mass spectrometry. The compound has antiproliferative activity against the A2780 ovarian cancer cell line with an IC50 value of 17.4 MUm and antiplasmodial activity against the drug-resistant Dd2 strain of Plasmodium falciparum with an IC50 value of 2.74 MUm. PMID- 28817229 TI - Performance equivalency between computer-based and traditional pen-and-paper assessment: A case study in clinical anatomy. AB - The time, material, and staff-consuming nature of anatomy's traditional pen-and paper assessment system, the increase in the number of students enrolling in medical schools and the ever-escalating workload of academic staff have made the use of computer-based assessment (CBA) an attractive proposition. To understand the impact of such shift in the assessment method, an experimental study evaluating its effect on students' performance was designed. Additionally, students' opinions toward CBA were gathered. Second-year medical students attending a Clinical Anatomy course were randomized by clusters in two groups. The pen-and-paper group attended two sessions, each consisting of a traditional sectional anatomy steeplechase followed by a theoretical examination, while the computer group was involved in two similar sessions conducted in a computerized environment. At the end of each of the computer sessions, students in this group filled an anonymous questionnaire. In the first session, pen-and-paper group students scored significantly better than computer-group students in both the steeplechase (mean +/- standard deviation: 66.00 +/- 14.15% vs. 43.50 +/- 19.10%; P < 0.001) and the theoretical examination (52.50 +/- 12.70% vs. 39.00 +/- 21.10%; P < 0.001). In the second session, no statistically significant differences were found for both the steeplechase (59.50 +/- 17.30% vs. 54.50 +/- 17.00%; P = 0.085) and the theoretical examination (57.50 +/- 13.70% vs. 54.00 +/ 14.30%; P = 0.161). Besides, an intersession improvement in students' perceptions toward CBA was registered. These results suggest that, after a familiarization period, CBA might be a performance equivalent and student accepted alternative to clinical anatomy pen-and-paper theoretical and practical examinations. Anat Sci Educ 11: 124-136. (c) 2017 American Association of Anatomists. PMID- 28817230 TI - Recent findings on fulminant type 1 diabetes. AB - Fulminant type 1 diabetes (fT1D) is a new subtype of type 1 diabetes proposed by Imagawa in 2000. It is a clinical syndrome characterized by a markedly rapid and almost complete destruction of pancreatic beta cells. Metabolic derangement is more severe in this subtype than in autoimmune type 1 diabetes. The incidence of fT1D is associated with HLA DRB1*04:05DQB1*04:01; both innate and acquired immune disorders might contribute to the development of fT1D. The presence of specific innate immune responses to enterovirus infection connected with enhanced adaptive immune pathways responsible for aggressive beta cell toxicity in fT1D. The process of beta cell destruction is extremely rapid in fT1D, and the insulin secretary capacity rarely recovers after the onset. The serum glycated albumin to glycated haemoglobin ratio is significantly higher in fT1D; a cut-off value of 3.2 for serum glycated albumin to glycated haemoglobin ratio yielded 97% sensitivity and 98% specificity for differentiating fT1D from type 2 diabetes. Fulminant type 1 diabetes is associated with pregnancy. This article also updates the diagnostic criteria for fT1D by the Japanese Diabetes Association in 2012. PMID- 28817231 TI - Effect of once-weekly dulaglutide on glycated haemoglobin (HbA1c) and fasting blood glucose in patient subpopulations by gender, duration of diabetes and baseline HbA1c. AB - AIMS: To evaluate the efficacy and safety of dulaglutide 1.5 and 0.75 mg in patients with type 2 diabetes by subgroups of gender, duration of diabetes and baseline glycated haemoglobin (HbA1c) in the dulaglutide clinical development programme (AWARD-1 to -6 and -8 clinical trials). METHODS: Change in HbA1c was analysed by gender, duration of diabetes (<5, >=5 years and <10, >=10 years), and baseline HbA1c (<8.5%, >=8.5%) in pooled and individual studies. Changes from baseline in weight, hypoglycaemia and gastrointestinal adverse events were evaluated for individual trials. RESULTS: In the pooled analysis of patients treated with dulaglutide 1.5 mg at 6 months, the reductions in HbA1c from baseline were similar across gender (men: least squares [LS] mean -1.26% [95% confidence interval {CI} -1.36, -1.16]; women: LS mean -1.33% [95% CI -1.43, 1.24]) and among duration of diabetes subgroups (<5 years: LS mean -1.32% [95% CI -1.43, -1.22]; >=5 and <10 years: LS mean -1.33% [95% CI -1.43, -1.22]; >=10 years: -1.24% [95% CI -1.35, -1.14]). Patients with baseline HbA1c >=8.5% had greater HbA1c reductions than patients with baseline HbA1c <8.5%, (>=8.5%: LS mean -1.86% [95% CI -1.97, -1.75]; <8.5%: LS mean -1.02% [95% CI -1.12, -0.93]). Reductions in fasting blood glucose (FBG) were consistent with HbA1c changes. Similar results were observed with dulaglutide 0.75 mg. In general, body weight changes were similar among duration of diabetes and in baseline HbA1c subgroups, respectively; women had a numerically greater weight loss or less weight gain than men with both dulaglutide doses. There was no clinically meaningful difference in hypoglycaemia trends by gender or duration of diabetes. Hypoglycaemia incidence and rate were generally lower in patients with baseline HbA1c >=8.5% than in those with <8.5%, except for the AWARD-4 study (combination with mealtime insulin). CONCLUSIONS: Across the AWARD studies, dulaglutide demonstrated significant improvements in glycaemic control irrespective of gender, duration of diabetes, or baseline HbA1c, with greater HbA1c and FBG reductions in patients with a higher baseline HbA1c. Dulaglutide was well tolerated, with a safety profile similar to other glucagon-like peptide-1 receptor agonists. PMID- 28817232 TI - Crystal structure of the Melampsora lini effector AvrP reveals insights into a possible nuclear function and recognition by the flax disease resistance protein P. AB - The effector protein AvrP is secreted by the flax rust fungal pathogen (Melampsora lini) and recognized specifically by the flax (Linum usitatissimum) P disease resistance protein, leading to effector-triggered immunity. To investigate the biological function of this effector and the mechanisms of specific recognition by the P resistance protein, we determined the crystal structure of AvrP. The structure reveals an elongated zinc-finger-like structure with a novel interleaved zinc-binding topology. The residues responsible for zinc binding are conserved in AvrP effector variants and mutations of these motifs result in a loss of P-mediated recognition. The first zinc-coordinating region of the structure displays a positively charged surface and shows some limited similarities to nucleic acid-binding and chromatin-associated proteins. We show that the majority of the AvrP protein accumulates in the plant nucleus when transiently expressed in Nicotiana benthamiana cells, suggesting a nuclear pathogenic function. Polymorphic residues in AvrP and its allelic variants map to the protein surface and could be associated with differences in recognition specificity. Several point mutations of residues on the non-conserved surface patch result in a loss of recognition by P, suggesting that these residues are required for recognition. PMID- 28817233 TI - Evaluation and quantitative analysis of 11 compounds in Morinda officinalis using ultra-high performance liquid chromatography and photodiode array detection coupled with chemometrics. AB - Morinda officinalis (Rubiaceae) is a traditional Chinese medicine widely used for the treatment of impotence and osteoporosis in clinical therapy. In the present study, a rapid and simple ultra-high performance liquid chromatography with photodiode array detection method was developed and validated for the simultaneous determination of 11 bioactive compounds in M. officinalis. This assay method was validated with respect to linearity (R2 > 0.9991), precision, repeatability, limit of detection, limit of quantification, and accuracy (with observed recovery rates between 94.21 and 100.38%). The quantitative results revealed significant differences in the concentrations of the selected compounds. Additionally, chemometric methods, including hierarchical clustering analysis, principal component analysis, and partial least-squares discriminate analysis, were applied to compare and sort the 25 batches of M. officinalis samples based on the quantitative data of the analytes. All of the samples were clearly divided into two groups: the Hainan samples were successfully discriminated from the samples from other origins. Simultaneous determination of multiple compounds using the proposed method combined with chemometrics could be a viable strategy to compare and evaluate the quality of M. officinalis. PMID- 28817234 TI - Osmium-Mediated Transformation of 4-Thiouridine to Cytidine as Key To Study RNA Dynamics by Sequencing. AB - To understand the functional roles of RNA in the cell, it is essential to elucidate the dynamics of their production, processing and decay. A recent method for assessing mRNA dynamics is metabolic labeling with 4-thiouridine (4sU), followed by thio-selective attachment of affinity tags. Detection of labeled transcripts by affinity purification and hybridization to microarrays or by deep sequencing then reveals RNA expression levels. Here, we present a novel sequencing method (TUC-seq) that eliminates affinity purification and allows for direct assessment of 4sU-labeled RNA. It employs an OsO4 -mediated transformation to convert 4sU into cytosine. We exemplify the utility of the new method for verification of endogenous 4sU in tRNAs and for the detection of pulse-labeled mRNA of seven selected genes in mammalian cells to determine the relative abundance of the new transcripts. The results prove TUC-seq as a straight-forward and highly versatile method for studies of cellular RNA dynamics. PMID- 28817235 TI - Discrepant HPV/cytology cotesting results: Are there differences between cytology negative versus HPV-negative cervical intraepithelial neoplasia? AB - BACKGROUND: The objective of this study was to compare cervical high-grade squamous intraepithelial lesions subcategorized as cervical intraepithelial neoplasia-3 (CIN-3)-positive after a negative cytology result but positive for high-risk human papillomavirus (HR-HPV) testing to those with a negative HR-HPV test but positive cytology (atypical squamous cells of undetermined significance [ASCUS]-positive/HPV-negative) and to assess reasons for discrepancies. METHODS: The authors retrospectively analyzed women who underwent screening with cytology and HPV testing from 2010 through 2013. After a review of surgical specimens and cytology, discrepancies were classified as sampling or interpretation error. Clinical and pathologic findings were compared. RESULTS: In total, 15,173 women (age range, 25-95 years; 7.1% were aged < 30 years) underwent both HPV and cytologic testing, and 1184 (8.4%) underwent biopsy. Cytology was positive in 19.4% of specimens, and HPV was positive in 14.5%. Eighty-four CIN-3-positive specimens were detected, including 55 that tested ASCUS-positive/HPV-positive, 11 that tested negative for intraepithelial lesion or malignancy (NILM)/HPV positive, 10 that tested ASCUS-positive/HPV-negative, 3 that tested NILM/HPV negative, and 5 tests that were unsatisfactory. There was no significant difference between NILM/HPV-positive and ASCUS-positive/HPV-negative CIN-3 in terms of size, time to occurrence, the presence of a cytopathic effect, screening history, race, or age. Six of 11 NILM/HPV-positive cases were reclassified as ASCUS, indicating an interpreting error of 55% and a sampling error of 45%. No ASCUS-positive/HPV-negative cases were reclassified. Seven cases of CIN-3 with positive cytology were HPV-negative. CONCLUSIONS: There are no significant clinical or pathologic differences between NILM/HPV-positive and ASCUS positive/HPV-negative CIN-3-positive specimens. Cytologic sampling or interpretation remains the main reason for discrepancies. However, HPV-negative CIN-3 with positive cytology exists and may be missed by primary HPV screening. Cancer Cytopathol 2017;125:795-805. (c) 2017 American Cancer Society. PMID- 28817236 TI - A new CUL4B variant associated with a mild phenotype and an exceptional pattern of leukoencephalopathy. AB - Cabezas type of X-linked syndromic intellectual disability (MRXSC; MIM300354) is a rare X-linked recessive intellectual disability characterized primarily by intellectual disability, short stature, hypogonadism, and gait abnormalities. It is caused by a wide spectrum of hemizygous variants in CUL4B. In a 10-year-old boy with an exceptional leukoencephalopathy pattern, we identified a new missense variant p.Leu329Gln in CUL4B using "Mendeliome" sequencing. However, his phenotype does not include the severe characteristics currently known for MRXSC. We discuss the divergent phenotype and propose a potential connection between the different CUL4B variants and corresponding phenotypes in the context of the current literature as well as 3D homology modeling. PMID- 28817237 TI - Dysregulation of wound healing mechanisms in diabetes and the importance of negative pressure wound therapy (NPWT). AB - Diabetes is a serious disease with severe side effects and comorbidities. Diabetic foot with its chronic nonhealing ulcers, or diabetic foot ulcers, as they are commonly called, can be devastating, even leading to amputation. Many therapies exist to assist and improve wound healing. One exciting discovery is the use of negative pressure wound therapy (NPWT) as an adjunct to standard treatment. Few studies have substantively explored the molecular mechanisms of NPWT and why we see improved wound healing, a concept that demands more research. The following commentary summarizes the current literature regarding NPWT as well as some of the vast body of work that focuses on the physiologic mechanisms of wound healing in diabetics in general. PMID- 28817239 TI - Novel dissection of the central nervous system to bridge gross anatomy and neuroscience for an integrated medical curriculum. AB - Medical schools in the United States continue to undergo curricular change, reorganization, and reformation as more schools transition to an integrated curriculum. Anatomy educators must find novel approaches to teach in a way that will bridge multiple disciplines. The cadaveric extraction of the central nervous system (CNS) provides an opportunity to bridge gross anatomy, neuroanatomy, and clinical neurology. In this dissection, the brain, brainstem, spinal cord, cauda equina, optic nerve/tract, and eyes are removed in one piece so that the entire CNS and its gateway to the periphery through the spinal roots can be appreciated. However, this dissection is rarely, if ever, performed likely due to time constraints, perceived difficulty, and lack of instructions. The goals of this project were (i) to provide a comprehensive, step-by-step guide for an en bloc CNS extraction and (ii) to determine effective strategies to implement this dissection/prosection within modern curricula. Optimal dissection methods were determined after comparison of various approaches/tools, which reduced dissection time from approximately 10 to 4 hours. The CNS prosections were piloted in small group sessions with two types of learners in two different settings: graduate students studied wet CNS prosections within the dissection laboratory and medical students used plastinated CNS prosections to review clinical neuroanatomy and solve lesion localization cases during their neurology clerkship. In both cases, the CNS was highly rated as a teaching tool and 98% recommended it for future students. Notably, 90% of medical students surveyed suggested that the CNS prosection be introduced prior to clinical rotations. Anat Sci Educ 11: 185-195. (c) 2017 American Association of Anatomists. PMID- 28817238 TI - Stakeholders in psychiatry and their attitudes toward receiving pertinent and incident findings in genomic research. AB - Increasingly more psychiatric research studies use whole genome sequencing or whole exome sequencing. Consequently, researchers face difficult questions, such as which genomic findings to return to research participants and how. This study aims to gain more knowledge on the attitudes among potential research participants and health professionals toward receiving pertinent and incidental findings. A cross-sectional online survey was developed to investigate the attitudes among research participants toward receiving genomic findings. A total of 2,637 stakeholders responded: 241 persons with mental disorders, 671 relatives, 1,623 blood donors, 74 psychiatrists, and 28 clinical geneticists. Stakeholders wanted both pertinent findings (95%) and incidental findings (91%) to be made available for research participants. The majority (77%) stated that researchers should not actively search for incidental findings. Persons with mental disorders and relatives were generally more positive about receiving any kind of findings than clinical geneticists and psychiatrists. Compared with blood donors, persons with mental disorders reported to be more positive about receiving raw genomic data and information that is not of serious health importance. Psychiatrists and clinical geneticists were less positive about receiving genomic findings compared with blood donors. The attitudes toward receiving findings were very positive. Stakeholders were willing to refrain from receiving incidental information if it could compromise the research. Our results suggest that research participants consider themselves as altruistic participants. This study offers valuable insight, which may inform future programs aiming to develop new strategies to target issues relating to the return of findings in genomic research. PMID- 28817240 TI - Prenatal presentation of Mabry syndrome with congenital diaphragmatic hernia and phenotypic overlap with Fryns syndrome. AB - We report on a family in which initial features were compatible with Fryns syndrome. The first sibling was a stillborn female with a left diaphragmatic hernia (DH). Her clinical features overlapped with Fryns syndrome. The second pregnancy, a male fetus, was followed for polyhydramnios, hypoplastic mandible, mild enlargement of the fetal bladder, hydronephrosis, and rocker bottom foot deformities. He had facial features similar to his sibling and a large cleft of the secondary palate, small jaw, and secundum atrial septal defect. He underwent surgical repair of imperforate anus, intestinal malrotation, and placement of mucous fistula for biopsy positive Hirschsprung disease. An elevated alkaline phosphatase level of 1569 U/L was reported. Whole exome sequencing performed on the second child demonstrated compound heterozygosity for the PIGV gene with the p.A341E and p.A418D variants in trans. Hyperphosphatasia with mental retardation syndrome (HPMRS) is caused by mutations in PIGV and includes hyperphosphatasia as a diagnostic hallmark. Our patient exhibited hyperphosphatasia but without any storage material in his skin cells. His features remain similar to his sister's, but includes seizures and lacks diaphragmatic hernia. Until now, HPMRS and Fryns syndrome, despite overlapping features, were considered mutually exclusive as HPMRS involves hyperphosphatasia and Fryns typically exhibits DH. Recent identification of PIGN mutations associated with several cases of Fryns syndrome point to a common pathogenetic etiology involving inborn errors of the glycosylphosphatidylinositiol anchor biosynthetic pathway. A diagnosis of HPMRS should be considered when DH is encountered on prenatal ultrasound. PMID- 28817243 TI - What the neighbors say. PMID- 28817241 TI - Association between vitamin D deficiency and heart failure risk in the elderly. AB - AIMS: The aim of this study was to evaluate the association between vitamin D deficiency and risk of heart failure in elderly patients of cardiology outpatient clinics. METHODS AND RESULTS: A cross-sectional study with an analytical approach was employed. Clinical data were collected from the elderly from August 2015 to February 2016. The dependent variable was the risk of heart failure; the independent variable was vitamin D deficiency; and intervening factors were age, gender, education, ethnicity, hypertension, diabetes mellitus, hypothyroidism, renal failure, dementia, stroke, dyslipidaemia, depression, smoking, alcoholism, obesity, andropause, and cardiac arrhythmia. To analyse the association between vitamin D deficiency and risk of heart failure, we used the bivariate logistic analysis, followed by analysis through the multivariate logistic regression model. Of the 137 elderly, the study found the following: women (75.9%); overweight (48.2%); obese (30.6%); increase in the index waist/hip (88.3%); dyslipidaemia (94.2%) and hypertension (91.2%); coronary artery disease (35.0%); and 27.7% with cardiac arrhythmia or left ventricular hypertrophy. Sixty-five per cent of the elderly were deficient in vitamin D. The risk of heart failure was significantly associated with vitamin D deficiency [odds ratio (OR): 12.19; 95% confidence interval (CI) = 4.23-35.16; P = 0.000], male gender (OR: 15.32; 95% CI = 3.39-69.20, P = 0.000), obesity (OR: 4.17; 95% CI = 1.36-12.81; P = 0.012), and cardiac arrhythmia (OR: 3.69; 95% CI = 1.23-11.11; P = 0.020). CONCLUSIONS: There was a high prevalence of vitamin D deficiency in the elderly, and the evidence shows a strong association between vitamin D deficiency and increased risk of heart failure in this population. PMID- 28817242 TI - Improved medical student perception of ultrasound using a paired anatomy teaching assistant and clinician teaching model. AB - This study describes a new teaching model for ultrasound (US) training, and evaluates its effect on medical student attitudes toward US. First year medical students participated in hands-on US during human gross anatomy (2014 N = 183; 2015 N = 182). The sessions were facilitated by clinicians alone in 2014, and by anatomy teaching assistant (TA)-clinician pairs in 2015. Both cohorts completed course evaluations which included five US-related items on a four-point scale; cohort responses were compared using Mann-Whitney U tests with significance threshold set at 0.05. The 2015 survey also evaluated the TAs (three items, five point scale). With the adoption of the TA-clinician teaching model, student ratings increased significantly for four out of five US-items: "US advanced my ability to learn anatomy" increased from 2.91 +/- 0.77 to 3.35 +/- 0.68 (P < 0.0001), "Incorporating US increased my interest in anatomy" from 3.05 +/- 0.84 to 3.50 +/- 0.71 (P < 0.0001), "US is relevant to my current educational needs" from 3.36 +/- 0.63 to 3.54 +/- 0.53 (P = 0.015), and "US training should start in Phase I" from 3.36 +/- 0.71 to 3.56 +/- 0.59 (P = 0.010). Moreover, more than 84% of students reported that TAs enhanced their understanding of anatomy (mean 4.18 +/- 0.86), were a valuable part of US training (mean 4.23 +/- 0.89), and deemed the TAs proficient in US (mean 4.24 +/- 0.86). By using an anatomy TA-clinician teaching team, this study demonstrated significant improvements in student perceptions of the impact of US on anatomy education and the relevancy of US training to the early stages of medical education. Anat Sci Educ 11: 175-184. (c) 2017 American Association of Anatomists. PMID- 28817244 TI - Key developments that impacted the field of mechanobiology and mechanotransduction. AB - Advances in mechanobiology have evolved through insights from multiple disciplines including structural engineering, biomechanics, vascular biology, and orthopaedics. In this paper, we reviewed the impact of key reports related to the study of applied loads on tissues and cells and the resulting signal transduction pathways. We addressed how technology has helped advance the burgeoning field of mechanobiology (over 33,600 publications from 1970 to 2016). We analyzed the impact of critical ideas and then determined how these concepts influenced the mechanobiology field by looking at the citation frequency of these reports as well as tracking how the overall number of citations within the field changed over time. These data allowed us to understand how a key publication, idea, or technology guided or enabled the field. Initial observations of how forces acted on bone and soft tissues stimulated the development of computational solutions defining how forces affect tissue modeling and remodeling. Enabling technologies, such as cell and tissue stretching, compression, and shear stress devices, allowed more researchers to explore how deformation and fluid flow affect cells. Observation of the cell as a tensegrity structure and advanced methods to study genetic regulation in cells further advanced knowledge of specific mechanisms of mechanotransduction. The future of the field will involve developing gene and drug therapies to simulate or augment beneficial load regimens in patients and in mechanically conditioning organs for implantation. Here, we addressed a history of the field, but we limited our discussions to advances in musculoskeletal mechanobiology, primarily in bone, tendon, and ligament tissues. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:605-619, 2018. PMID- 28817246 TI - Novel ID gene CSNK2B: The crossover from molecular diagnosis to research continues. PMID- 28817245 TI - Reports from CAGI: The Critical Assessment of Genome Interpretation. PMID- 28817249 TI - Primary sulphonylurea therapy in a newborn with transient neonatal diabetes attributable to a paternal uniparental disomy 6q24 (UPD6). PMID- 28817247 TI - Assessing predictions of fitness effects of missense mutations in SUMO conjugating enzyme UBE2I. AB - The exponential growth of genomic variants uncovered by next-generation sequencing necessitates efficient and accurate computational analyses to predict their functional effects. A number of computational methods have been developed for the task, but few unbiased comparisons of their performance are available. To fill the gap, The Critical Assessment of Genome Interpretation (CAGI) comprehensively assesses phenotypic predictions on newly collected experimental datasets. Here, we present the results of the SUMO conjugase challenge where participants were predicting functional effects of missense mutations in human SUMO-conjugating enzyme UBE2I. The performance of the predictors is similar to each other and is far from perfection. Evolutionary information from sequence alignments dominates the success: deleterious mutations at conserved positions and benign mutations at variable positions are accurately predicted. Prediction accuracy of other mutations remains unsatisfactory, and this fast-growing field of research is yet to learn the use of spatial structure information to improve the predictions significantly. PMID- 28817248 TI - Attenuated suppression of lipolysis explains the increases in triglyceride secretion and concentration associated with basal insulin peglispro relative to insulin glargine treatment in patients with type 1 diabetes. AB - AIMS: To test the hypothesis that, as well as lowering weight and increasing plasma triglyceride (TG) levels and hepatic fat compared with insulin glargine (GL) in patients with type 1 diabetes, the attenuated peripheral effects of basal insulin peglispro (BIL) may include increased free fatty acid flux to the liver, causing increased very-low-density lipoprotein (VLDL)-TG secretion and lipid oxidation, and decreased TG adipose tissue deposition. METHODS: In this open label, randomized, 2-period crossover study, 14 patients with type 1 diabetes received once-daily, individualized, stable BIL or GL doses for 3 weeks. Palmitate flux was assessed using [9,10-3 H]palmitate infusion. VLDL-TG secretion, clearance and oxidation rate were assessed using primed-constant infusion of ex vivo labelled [1-14 C]VLDL-TG, while VLDL-TG storage rate was assessed using [9,10-3 H]VLDL-TG bolus injection. RESULTS: The VLDL-TG concentration and secretion rate, and palmitate flux were statistically significantly higher during BIL than during GL treatment (58%, 51% and 35%, respectively). The ratios of least squares (LS) geometric means for VLDL-TG clearance and oxidation were 0.92 (95% confidence interval [CI] 0.72, 1.17) and 1.31 (95% CI 0.91, 1.90), respectively. The difference in LS means for VLDL-TG storage rate was -0.36 (95% CI -0.83, 0.12). CONCLUSIONS: BIL-treated patients had higher effective lipolysis, VLDL-TG secretion and VLDL-TG concentration compared with GL-treated patients, explaining the increased plasma TG concentrations reported previously. Data support attenuated effects of BIL on lipolysis, in addition to the recently described hepato-preferential glucodynamic effects. PMID- 28817251 TI - Dual Core-Shell-Structured S@C@MnO2 Nanocomposite for Highly Stable Lithium Sulfur Batteries. AB - Lithium-sulfur (Li-S) batteries have currently excited worldwide academic and industrial interest as a next-generation high-power energy storage system (EES) because of their high energy density and low cost of sulfur. However, the commercialization application is being hindered by capacity decay, mainly attributed to the polysulfide shuttle and poor conductivity of sulfur. Here, we have designed a novel dual core-shell nanostructure of S@C@MnO2 nanosphere hybrid as the sulfur host. The S@C@MnO2 nanosphere is successfully prepared using mesoporous carbon hollow spheres (MCHS) as the template and then in situ MnO2 growth on the surface of MCHS. In comparison with polar bare sulfur hosts materials, the as-prepared robust S@C@MnO2 composite cathode delivers significantly improved electrochemical performances in terms of high specific capacity (1345 mAh g-1 at 0.1 C), remarkable rate capability (465 mA h g-1 at 5.0 C) and excellent cycling stability (capacity decay rate of 0.052% per cycle after 1000 cycles at 3.0 C). Such a structure as cathode in Li-S batteries can not only store sulfur via inner mesoporous carbon layer and outer MnO2 shell, which physically/chemically confine the polysulfides shuttle effect, but also ensure overall good electrical conductivity. Therefore, these synergistic effects are achieved by unique structural characteristics of S@C@MnO2 nanospheres. PMID- 28817253 TI - Cuts Guided Deterministic Buckling in Arrays of Soft Parallel Plates for Multifunctionality. AB - Harnessing buckling instability in soft materials offers an effective strategy to achieve multifunctionality. Despite great efforts in controlling the wrinkling behaviors of film-based systems and buckling of periodic structures, the benefits of classical plate buckling in soft materials remain largely unexplored. The challenge lies in the intrinsic indeterminate characteristics of buckling, leading to geometric frustration and random orientations. Here, we report the controllable global order in constrained buckling of arrays of parallel plates made of hydrogels and elastomers on rigid substrates. By introducing patterned cuts on the plates, the randomly phase-shifted buckling in the array of parallel plates transits to a prescribed and ordered buckling with controllable phases. The design principle for cut-directed deterministic buckling in plates is validated by both mechanics model and finite element simulation. By controlling the contacts and interactions between the buckled parallel plates, we demonstrate on-demand reconfigurable electrical and optical pathways, and the potential application in design of mechanical logic gates. By varying the local stimulus within the plates, we demonstrate that microscopic pathways can be written, visualized, erased, and rewritten macroscopically into a completely new one for potential applications such as soft reconfigurable circuits and logic devices. PMID- 28817254 TI - Highly (001)-Textured Tetragonal BiFeO3 Film and Its Photoelectrochemical Behaviors Tuned by Magnetic Field. AB - Highly (001)-textured BiFeO3 film in tetragonal phase (T-BFO) with a giant c/a ratio was first obtained on quartz/polycrystalline ITO substrate. Our results indicate that the polycrystalline ITO layer with small surface roughness is a critical point to control the growth of T-BFO structure. It should be ascribed to the fact that a Bi-rich phase interlayer (~5 nm) could be formed on ITO, which acted as a crystal seed layer and thus induced the growth of (001)-textured T-BFO structure. The observed weak room temperature ferromagnetism should be attributed to Fe valence change. Open circuit potential measurements under 360 MUW/cm2 full spectra irradiation show that the open circuit potential and the lifetime of photo-induced carriers increased under applied magnetic field, which reveals that the applied magnetic field can manipulate the photo electrochemical behaviors of BFO film. Our findings offer a simple way to fabricate highly (001)-textured T BFO film, which make it desirable to obtain extensive applications for these oriented BFO films. PMID- 28817252 TI - Experimental and Theoretical Insights into the Inhibition Mechanism of Prion Fibrillation by Resveratrol and its Derivatives. AB - Resveratrol and its derivatives have been shown to display beneficial effects to neurodegenerative diseases. However, the molecular mechanism of resveratrol and its derivatives on prion conformational conversion is poorly understood. In this work, the interaction mechanism between prion and resveratrol as well as its derivatives was investigated using steady-state fluorescence quenching, Thioflavin T binding assay, Western blotting, and molecular dynamics simulation. Protein fluorescence quenching method and Thioflavin T assay revealed that resveratrol and its derivatives could interact with prion and interrupt prion fibril formation. Molecular dynamics simulation results indicated that resveratrol can stabilize the PrP127-147 peptide mainly through pi-pi stacking interactions between resveratrol and Tyr128. The hydrogen bonds interactions between resveratrol and the PrP127-147 peptide could further reduce the flexibility and the propensity to aggregate. The results of this study not only can provide useful information about the interaction mechanism between resveratrol and prion, but also can provide useful clues for further design of new inhibitors inhibiting prion aggregation. PMID- 28817255 TI - Nonacene Generated by On-Surface Dehydrogenation. AB - The on-surface synthesis of nonacene has been accomplished by dehydrogenation of an air-stable partially saturated precursor, which could be aromatized by using a combined scanning tunneling and atomic force microscope as well as by on-surface annealing. This transformation allowed the in-detail analysis of the electronic properties of nonacene molecules physisorbed on Au(111) by scanning tunneling spectroscopy measurements. The spatial mapping of molecular orbitals was corroborated by density functional theory calculations. Furthermore, the thermally induced dehydrogenation uncovered the isomerization of intermediate dihydrononacene species, which allowed for their in-depth structural and electronic characterization. PMID- 28817256 TI - Tailorable Exciton Transport in Doped Peptide-Amphiphile Assemblies. AB - Light-harvesting biomaterials are an attractive target in photovoltaics, photocatalysis, and artificial photosynthesis. Through peptide self-assembly, complex nanostructures can be engineered to study the role of chromophore organization during light absorption and energy transport. To this end, we demonstrate the one-dimensional transport of excitons along naturally occurring, light-harvesting, Zn-protoporphyrin IX chromophores within self-assembled peptide amphiphile nanofibers. The internal structure of the nanofibers induces packing of the porphyrins into linear chains. We find that this peptide assembly can enable long-range exciton diffusion, yet it also induces the formation of excimers between adjacent molecules, which serve as exciton traps. Electronic coupling between neighboring porphyrin molecules is confirmed by various spectroscopic methods. The exciton diffusion process is then probed through transient photoluminescence and absorption measurements and fit to a model for one-dimensional hopping. Because excimer formation impedes exciton hopping, increasing the interchromophore spacing allows for improved diffusivity, which we control through porphyrin doping levels. We show that diffusion lengths of over 60 nm are possible at low porphyrin doping, representing an order of magnitude improvement over the highest doping fractions. PMID- 28817257 TI - Cation-Anion Arrangement Patterns in Self-Assembled Pd2L4 and Pd4L8 Coordination Cages. AB - Compounds featuring one-dimensional regular arrangements of stacked metal complexes and alternating [cation-anion]infinity sequences have raised considerable interest owing to their peculiar electronic and optical properties as well as guest inclusion capabilities. While traditional ways to realize these structural motifs rely on crystalline compounds, exclusively existing in the solid state, recent progress in the area of metal-mediated supramolecular self assembly allows for the rational synthesis of structurally well-defined short stretches of stacked metal complexes and cation-anion arrangements. Therefore, metal cations, counteranions, and suitably designed organic bridges are allowed to self-assemble in solution. While the bridges can be designed as cross-linkers to yield extended two- or three-dimensional networks such as layered materials, metal-organic frameworks (MOFs), or porous coordination polymers (PCPs), they can also be tailored to lead to discrete nanoscopic objects. Supramolecular helicates, grids, and knots belong to this class of compounds, and a particularly interesting subfamily are coordination cages and capsules, which possess nanosized cavities with the ability to encapsulate guest molecules. Here, we focus on coordination cages consisting of two or more square-planar Pd(II) or Pt(II) metal cations, bridged by banana-shaped bis-monodentate pyridyl ligands that encapsulate various guest molecules, usually anions, in their cavities. Monoanions as well as dianions with localized or delocalized charges can be bound with remarkable complementarity between cage and guest in terms of size and shape. We show how dimerization of the prototypical [Pd2L4] cages into their interpenetrated dimers [Pd4L8] leads to an increase in cavity number from one to three while the cavity volume decreases. Usually, all three pockets of these double cages are filled with monoanions such as BF4- or Cl-, thus leading to well defined linear [Pd-anion]3Pd stacks, as observed by X-ray studies. The ligand based mechanical coupling of the linearly aligned cavities leads to interesting effects concerning guest encapsulation cooperativity, such as allosteric binding and triggered sequential uptake. While most of the so far reported coordination cages consist of only a single type of ligand, recent advances in rational assembly strategies allow for high-yielding syntheses of structurally defined multicomponent architectures by integrative self-sorting mechanisms. One family of heteroleptic [Pd2L2L'2] cages whose formation is based on shape complementarity between two different ligands, L and L', is introduced. Furthermore, the implementation of ligand-based functions such as redox activity, photochromic behavior, specific binding sites, chirality, and catalytic activity allows us to study systems with properties far beyond basic structural features. We showcase selected examples of self-assembled cages whose guest uptake or even overall structural integrity is reversibly switched by light or small molecules with potential application in stimuli responsive materials (e.g., for sequestration of pollutants or stabilization of reactive compounds) up to functional nanosystems (e.g., diagnostic devices or supramolecular catalysts) and molecular machines. PMID- 28817258 TI - Synthesis of Complex Glycolates by Enantioconvergent Addition Reactions. AB - The unique role that stereochemistry plays in molecular recognition events continues to provide a driving force for synthesizing organic compounds in enantioenriched form. The tendency of enantioenriched organic compounds to revert to an entropically favored racemic state in the presence of viable racemization pathways (e.g., the enolization of stereogenic carbonyl derivatives) can sometimes interfere with this objective; however, beginning with Noyori's foundational disclosure of a dynamic kinetic transfer hydrogenation, the ability to channel racemic, configurationally labile starting materials through stereoconvergent reaction pathways has been recognized as a powerful strategy in asymmetric synthesis. Proton transfer, retro-aldol, retro-Michael, reversible redox events, and other processes that can be deleterious to asymmetric synthesis are exploitable in enantioconvergent reactions using chiral small molecules and enzymes as asymmetric catalysts. Enantioselective reduction of configurationally labile carbonyl derivatives bearing a C-H acidic chiral center are particularly common. Because facile racemization is vital to stereocontrol in these transformations, hydrogenations of beta-dicarbonyls are commonplace, while less activated substrates have been used less commonly. Our entry into enantioconvergent catalysis evolved from a long-standing interest in the synthesis of complex glycolates and began with the development of a general Noyori-type transfer hydrogenation of alpha-keto esters. Key innovations in this work include the identification of a new terphenylsulfonamide-Ru(II) complex, which displays unusual preference toward reduction of alpha-keto esters, and the observation that alpha-keto esters racemize under mildly basic conditions. This work was extended to the dynamic kinetic hydrogenation of racemic acyl phosphonates. Moreover, the recent recognition that the mechanistic paradigm underlying enantioconvergent hydrogenation chemistry can be extended to diverse carbon-centered nucleophiles has led to advances in the art. Our lab has developed a number of enantioconvergent tertiary alcohol syntheses. In the context of carbon-centered nucleophiles, we have focused on the use of alpha-keto esters; however, in the latter part of this Account, we will briefly describe our nascent efforts to develop dynamic kinetic additions of carbon-centered nucleophiles to beta-oxo acid derivatives. While the enantioconvergent hydrogenation of beta-keto acid derivatives is carried out on 100-ton scale annually, non-hydrogenative transformations of these compounds constitute an underexplored subclass of enantioconvergent reactions. With regard to future prospects, a trend toward transformations that afford increasing levels of molecular complexity is apparent. It can be expected that the burgeoning field of asymmetric 1,2-addition chemistry will further drive this chemistry to encompass a wider array of enantioconvergent additions. Additionally, the continued exploration of these chemistries in the context of less conventional electrophiles, as well as identifying novel or overlooked modes of racemization, holds considerable potential. PMID- 28817260 TI - Current-Use Flame Retardants in the Water of Lake Michigan Tributaries. AB - In this study, we measured the concentrations of 65 flame retardants in water samples from five Lake Michigan tributaries. These flame retardants included organophosphate esters (OPEs), brominated flame retardants (BFRs), and Dechlorane related compounds. A total of 59 samples, including both the particulate and the dissolved phases, were collected from the Grand, Kalamazoo, Saint Joseph, and Lower Fox rivers and from the Indiana Harbor and Ship Canal (IHSC) in 2015. OPEs were the most abundant among the targeted compounds with geometric mean concentrations ranging from 20 to 54 ng/L; OPE concentrations were comparable among the five tributaries. BFR concentrations were about 1 ng/L, and the most abundant compounds were bis(2-ethylhexyl) tetrabromophthalate, 2-ethylhexyl 2,3,4,5-tetrabromobenzoate, and decabromodiphenyl ether. The highest BFR concentrations were measured in either the IHSC or the Saint Joseph River. The dechlorane-related compounds were detected at low concentrations (<1 pg/L). The fraction of target compounds in the particulate phase relative to the dissolved phase varied by chemical and tended to increase with their octanol-water partition coefficient. The chemical loading from all the five tributaries into Lake Michigan were <10 kg/year for the BFRs and about 500 kg/year for the OPEs. PMID- 28817259 TI - Sub-20 nm Stable Micelles Based on a Mixture of Coiled-Coils: A Platform for Controlled Ligand Presentation. AB - Ligand-functionalized, multivalent nanoparticles have been extensively studied for biomedical applications from imaging agents to drug delivery vehicles. However, the ligand cluster size is usually heterogeneous and the local valency is ill-defined. Here, we present a mixed micelle platform hierarchically self assembled from a mixture of two amphiphilic 3-helix and 4-helix peptide polyethylene glycol (PEG)-lipid hybrid conjugates. We demonstrate that the local multivalent ligand cluster size on the micelle surface can be controlled based on the coiled-coil oligomeric state. The oligomeric states of mixed peptide bundles were found to be in their individual native states. Similarly, mixed micelles indicate the orthogonal self-association of coiled-coil amphiphiles. Using differential scanning calorimetry, fluorescence recovery spectroscopy, and coarse grained molecular dynamics simulation, we studied the distribution of coiled-coil bundles within the mixed micelles and observed migration of coiled-coils into nanodomains within the sub-20 nm mixed micelle. This report provides important insights into the assembly and formation of nanophase-separated micelles with precise control over the local multivalent state of ligands on the micelle surface. PMID- 28817261 TI - Effect of Particulate Matter Mineral Composition on Environmentally Persistent Free Radical (EPFR) Formation. AB - Environmentally Persistent Free Radicals (EPFRs) are newly discovered, long-lived surface bound radicals that form on particulate matter and combustion borne particulates, such as fly ash. Human exposure to such particulates lead to translocation into the lungs and heart resulting in cardio-vascular and respiratory disease through the production of reactive oxygen species. Analysis of some waste incinerator fly ashes revealed a significant difference between their EPFR contents. Although EPFR formation occurs on the metal domains, these differences were correlated with the altering concentration of calcium and sulfur. To analyze these phenomena, surrogate fly ashes were synthesized to mimic the presence of their major mineral components, including metal oxides, calcium, and sulfur. The results of this study led to the conclusion that the presence of sulfates limits formation of EPFRs due to inhibition or poisoning of the transition metal active sites necessary for their formation. These findings provide a pathway toward understanding differences in EPFR presence on particulate matter and uncover the possibility of remediating EPFRs from incineration and hazardous waste sites. PMID- 28817262 TI - Electrical and Structural Characterization of Ba3Mo1-xNb1+xO8.5-x/2: The Relationship between Mixed Coordination, Polyhedral Distortion and the Ionic Conductivity of Ba3MoNbO8.5. AB - The electrical and structural properties of the series Ba3Mo1-xNb1+xO8.5-x/2 (x = 0.0, 0.1, 0.2, 0.3) have been determined. Ba3Mo1-xNb1+xO8.5-x/2 crystallizes in a hybrid of the 9R hexagonal perovskite and palmierite structures, in which (Mo/Nb)O4 and (Mo/Nb)O6 units coexist within the structure. Nb substitutes preferentially at the octahedral site so that the ratio of (Mo/Nb)O4 tetrahedra to (Mo/Nb)O6 octahedra decreases with increasing x resulting in a reduction in the magnitude of the ionic conductivity from 1.3 * 10-6 S cm-1 for x = 0.0 to 1.1 * 10-7 S cm-1 for x = 0.3 at 300 degrees C. However, upon heating the conductivities of the solid solution converge, which suggests that the unusual thermal structural rearrangement previously reported for Ba3MoNbO8 preserves the high temperature conductivity. The results demonstrate that the presence of (Mo/Nb)O4 tetrahedra with nonbridging apical oxygen atoms is an important prerequisite for the ionic conduction observed in the Ba3MoNbO8.5 system. PMID- 28817263 TI - Responses of Periphyton to Fe2O3 Nanoparticles: A Physiological and Ecological Basis for Defending Nanotoxicity. AB - The toxic effects of nanoparticles on individual organisms have been widely investigated, while few studies have investigated the effects of nanoparticles on ubiquitous multicommunity microbial aggregates. Here, periphyton as a model of microbial aggregates, was employed to investigate the responses of microbial aggregates exposed continuously to Fe2O3 nanoparticles (5.0 mg L-1) for 30 days. The exposure to Fe2O3 nanoparticles results in the chlorophyll (a, b, and c) contents of periphyton increasing and the total antioxidant capacity decreasing. The composition of the periphyton markedly changes in the presence of Fe2O3 nanoparticles and the species diversity significantly increases. The changes in the periphyton composition and diversity were due to allelochemicals, such as 3 methylpentane, released by members of the periphyton which inhibit their competitors. The functions of the periphyton represented by metabolic capability and contaminant (organic matter, nitrogen, phosphorus and copper) removal were able to acclimate to the Fe2O3 nanoparticles exposure via self-regulation of morphology, species composition and diversity. These findings highlight the importance of both physiological and ecological factors in evaluating the long term responses of microbial aggregates exposed to nanoparticles. PMID- 28817264 TI - Structural Diversities in Heterometallic Mn-Ca Cluster Chemistry from the Use of Salicylhydroxamic Acid: {MnIII4Ca2}, {MnII/III6Ca2}, {MnIII/IV8Ca}, and {MnIII8Ca2} Complexes with Relevance to Both High- and Low-Valent States of the Oxygen-Evolving Complex. AB - One-pot reactions between the [Mn3O(O2CPh)6(py)x]+/0 triangular precursors and either CaBr2.xH2O or CaCl2.6H2O, in the presence of salicylhydroxamic acid (shaH2), have afforded the heterometallic complexes [MnIII4Ca2(O2CPh)4(shi)4(H2O)3(Me2CO)] (1) and (pyH)[MnII2MnIII4Ca2Cl2(O2CPh)7(shi)4(py)4] (2), respectively, in good yields. Further reactions but using a more flexible synthetic scheme comprising the Mn(NO3)2.4H2O/Ca(NO3)2.4H2O and Mn(O2CPh)2.2H2O/Ca(ClO4)2.4H2O "metal blends" and shaH2, in the presence of external base NEt3, led to the new complexes (NHEt3)2[MnIII4MnIV4Ca(OEt)2(shi)10(EtOH)2] (3) and (NHEt3)4[MnIII8Ca2(CO3)4(shi)8] (4), respectively. In all reported compounds, the anion of the tetradentate (N,O,O,O)-chelating/bridging ligand salicylhydroxime (shi3-), resulting from the in situ metal-ion-assisted amide-iminol tautomerism of shaH2, was found to bridge both Mn and Ca atoms. Complexes 1-4 exhibit a variety of different structures, metal stoichiometries, and Mn oxidation-state descriptions; 1 possesses an overall octahedral metal arrangement, 2 can be described as a Mn4Ca2 octahedron bound to an additional Mn2 unit, 3 consists of a Mn8 "ring" surrounding a CaII atom, and 4 adopts a rectangular cuboidal motif of eight Mn atoms accommodating two CaII atoms. Solid-state direct-current magnetic susceptibility studies revealed the presence of predominant antiferromagnetic exchange interactions between the Mn centers, leading to S = 0 spin ground-state values for all complexes. From a bioinorganic chemistry perspective, the reported compounds may demonstrate some relevance to both high-valent scheme (3) and lower oxidation-level species (1, 2, and 4) of the catalytic cycle of the oxygen evolving complex. PMID- 28817265 TI - Highly Efficient Performance and Conversion Pathway of Photocatalytic NO Oxidation on SrO-Clusters@Amorphous Carbon Nitride. AB - This work demonstrates the first molecular-level conversion pathway of NO oxidation over a novel SrO-clusters@amorphous carbon nitride (SCO-ACN) photocatalyst, which is synthesized via copyrolysis of urea and SrCO3. The inclusion of SrCO3 is crucial in the formation of the amorphous carbon nitride (ACN) and SrO clusters by attacking the intralayer hydrogen bonds at the edge sites of graphitic carbon nitride (CN). The amorphous nature of ACN can promote the transportation, migration, and transformation of charge carriers on SCO-ACN. And the SrO clusters are identified as the newly formed active centers to facilitate the activation of NO via the formation of Sr-NOdelta(+), which essentially promotes the conversion of NO to the final products. The combined effects of the amorphous structure and SrO clusters impart outstanding photocatalytic NO removal efficiency to the SCO-ACN under visible-light irradiation. To reveal the photocatalytic mechanism, the adsorption and photocatalytic oxidation of NO over CN and SCO-ACN are analyzed by in situ DRIFTS, and the intermediates and conversion pathways are elucidated and compared. This work presents a novel in situ DRIFTS-based strategy to explore the photocatalytic reaction pathway of NO oxidation, which is quite beneficial to understand the mechanism underlying the photocatalytic reaction and advance the development of photocatalytic technology for environmental remediation. PMID- 28817266 TI - Engineering Multifunctionality in Hybrid Polyoxometalates: Aromatic Sulfonium Octamolybdates as Excellent Photochromic Materials and Self-Separating Catalysts for Epoxidation. AB - Engineering multifunctionality in hybrid polyoxometalates (hybrid POMs) is an interesting but scarcely explored topic. Herein, we set about engineering two important materials properties, viz., photochromism and self-separating catalysis, in a hybrid POM by modulating the counterion motif. A series of six aromatic sulfonium counterions have been developed on the basis of an aromatic sulfonium counterion motif that allows structural and electronic fine-tuning by changing substituents at multiple locations. Using the aromatic sulfonium counterions and sodium molybdate, six new aromatic sulfonium octamolybdate hybrids (1-6) having formulas (HPDS)4[Mo8O26] (1), (HMPDS)4[Mo8O26] (2), (MPDS)4[Mo8O26] (3), (APDS)4[Mo8O26] (4), (AMPDS)4[Mo8O26] (5), and (MAPDS)4[Mo8O26] (6) (where HPDS = (4-hydroxyphenyl)dimethylsulfonium, HMPDS = (4 hydroxy-2-methylphenyl)dimethylsulfonium, MPDS = (4 methoxyphenyl)dimethylsulfonium, APDS = (4-(allyloxy)phenyl)dimethylsulfonium, AMPDS = (4-(allyloxy)-2-methylphenyl)dimethylsulfonium and MAPDS = (4(methacryloyloxy)phenyl)dimethylsulfonium) have been synthesized, and their structures were confirmed by single crystal X-ray diffraction and ESI-MS analyses. Hybrids 1-6 acted as good solid-state photochromic materials exhibiting color change from white to purple under UV illumination (350 nm), and we show here that the photochromic properties of hybrids 1-6 could be modulated by changing the substitutions on the counterion motif. A coloration kinetic half life (t1/2) of 0.33 min was achieved with this class of hybrid POMs. Hybrids 1-6 exhibited excellent self-separating catalytic properties toward the epoxidation of olefins, yielding up to 99% epoxide product with good selectivity in short time. The substituents on the aromatic sulfonium counterions helps to fine-tune the electronic, lipophilic, and solubility properties of the hybrids and thereby their catalytic properties. Moreover, we used ESI-MS analyses to understand the mechanism of catalysis exhibited by octamolybdates 1-6 in the presence of H2O2, and we succeeded in identifying a hitherto undetected intermediate, tetraperoxo octamolybdates, shedding more light on the epoxidation mechanism. PMID- 28817267 TI - Flavoring Chemicals and Aldehydes in E-Cigarette Emissions. AB - Regulations on e-cigarettes in the U.S. do not provide guidelines on the chemical content of e-cigarette liquids. We evaluated emissions of aldehydes and flavoring chemicals in e-cigarette vapor under typical usage conditions. We selected 24 e cigarette flavors from the top selling disposable e-cigarette brands. E cigarettes were connected to a pump drawing air for two second puffs with sixty second intervals between puffs. The vapor was analyzed for the presence of aldehydes using high-performance liquid chromatography-ultraviolet detector and for the presence of flavoring chemicals with gas chromatography and an electron capture detector. All e-cigarette emissions tested contained at least one aldehyde and/or flavoring chemical on either the FEMA "High Priority Chemicals" or FDA Harmful and Potentially Harmful Constituents lists when sampled at typical usage conditions. Diacetyl, a known respiratory hazard, along with acetoin, were the most prevalent of the flavoring chemicals in e-cigarette vapor, being found in more than 60% of samples. The presence of propionaldehyde, acetaldehyde and formaldehyde were correlated, corroborating previous work suggesting thermal degradation as a pathway for aldehyde generation in e-cigarette vapors. Median formaldehyde concentrations of 626 MUg/m3 in e-cigarette vapor exceed the ACGIH maximum concentrations allowable for workers of 370 MUg/m3. PMID- 28817268 TI - Natural Organic Matter Concentration Impacts the Interaction of Functionalized Diamond Nanoparticles with Model and Actual Bacterial Membranes. AB - Changes to nanoparticle surface charge, colloidal stability, and hydrodynamic properties induced by interaction with natural organic matter (NOM) warrant consideration in assessing the potential for these materials to adversely impact organisms in the environment. Here, we show that acquisition of a coating, or "corona", of NOM alters the hydrodynamic and electrokinetic properties of diamond nanoparticles (DNPs) functionalized with the polycation poly(allylamine HCl) in a manner that depends on the NOM-to-DNP concentration ratio. The NOM-induced changes to DNP properties alter subsequent interactions with model biological membranes and the Gram-negative bacterium Shewanella oneidensis MR-1. Suwannee River NOM induces changes to DNP hydrodynamic diameter and apparent zeta potential in a concentration-dependent manner. At low NOM-to-DNP ratios, DNPs aggregate to a limited extent but retain a positive zeta-potential apparently due to nonuniform adsorption of NOM molecules leading to attractive electrostatic interactions between oppositely charged regions on adjacent DNP surfaces. Diamond nanoparticles at low NOM-to-DNP ratios attach to model membranes to a larger extent than in the absence of NOM (including those incorporating lipopolysaccharide, a major bacterial outer membrane component) and induce a comparable degree of membrane damage and toxicity to S. oneidensis. At higher NOM to-DNP ratios, DNP charge is reversed, and DNP aggregates remain stable in suspension. This charge reversal eliminates DNP attachment to model membranes containing the highest LPS contents studied due to electrostatic repulsion and abolishes membrane damage to S. oneidensis. Our results demonstrate that the effects of NOM coronas on nanoparticle properties and interactions with biological surfaces can depend on the relative amounts of NOM and nanoparticles. PMID- 28817269 TI - The Chemistry of CO2 Capture in an Amine-Functionalized Metal-Organic Framework under Dry and Humid Conditions. AB - The use of two primary alkylamine functionalities covalently tethered to the linkers of IRMOF-74-III results in a material that can uptake CO2 at low pressures through a chemisorption mechanism. In contrast to other primary amine functionalized solid adsorbents that uptake CO2 primarily as ammonium carbamates, we observe using solid state NMR that the major chemisorption product for this material is carbamic acid. The equilibrium of reaction products also shifts to ammonium carbamate when water vapor is present; a new finding that has impact on control of the chemistry of CO2 capture in MOF materials and one that highlights the importance of geometric constraints and the mediating role of water within the pores of MOFs. PMID- 28817270 TI - Magnetic Field-Activated Sensing of mRNA in Living Cells. AB - Detection of specific mRNA in living cells has attracted significant attention in the past decade. Probes that can be easily delivered into cells and activated at the desired time can contribute to understanding translation, trafficking and degradation of mRNA. Here we report a new strategy termed magnetic field activated binary deoxyribozyme (MaBiDZ) sensor that enables both efficient delivery and temporal control of mRNA sensing by magnetic field. MaBiDZ uses two species of magnetic beads conjugated with different components of a multicomponent deoxyribozyme (DZ) sensor. The DZ sensor is activated only in the presence of a specific target mRNA and when a magnetic field is applied. Here we demonstrate that MaBiDZ sensor can be internalized in live MCF-7 breast cancer cells and activated by a magnetic field to fluorescently report the presence of specific mRNA, which are cancer biomarkers. PMID- 28817271 TI - Poly(2-oxazoline)-Antibiotic Conjugates with Penicillins. AB - The conjugation of antibiotics with polymers is rarely done, but it might be a promising alternative to low-molecular-weight derivatization. The two penicillins penicillin G (PenG) and penicillin V (PenV) were attached to the end groups of different water-soluble poly(2-oxazoline)s (POx) via their carboxylic acid function. This ester group was shown to be more stable against hydrolysis than the beta-lactam ring of the penicillins. The conjugates are still antimicrobially active and up to 20 times more stable against penicillinase catalyzed hydrolysis. The antibiotic activity of the conjugates against Staphylococcus aureus in the presence of penicillinase is up to 350 times higher compared with the free antibiotics. Conjugates with a second antimicrobial function, a dodecyltrimethylammonium group (DDA-X), at the starting end of the PenG and PenV POx conjugates are more antimicrobially active than the conjugates without DDA-X and show high activity in the presence of penicillinase. For example, the conjugates DDA-X-PEtOx-PenG and DDA-X-PEtOx-PenV are 200 to 350 times more active against S. aureus in the presence of penicillinase and almost as effective as the penicillinase stable cloxacollin (Clox) under these conditions. These conjugates show even greater activity compared to cloxacollin without this enzyme present. Further, both conjugates kill Escherichia coli more effectively than PenG and Clox. PMID- 28817273 TI - Single-Step Synthesis of Iodinated Oxazoles from N-Propargyl Amides Mediated by I2/Iodosylbenzene/Trimethylsilyl Trifluoromethanesulfonate Systems. AB - A combination of I2, iodosylbenzene, and trimethylsilyl trifluoromethanesulfonate (TMSOTf) is effective for single-step synthesis of iodinated oxazoles from N propargyl amides via the aromatization of the iodocyclized intermediates, which has difficulty proceeding through conventional iodocyclization methods. Compared to the former method consisting of the metal-catalyzed cyclization of N-propargyl amides followed by halogenation of alkylideneoxazolines, the present reaction provides a facile and metal-free procedure. PMID- 28817272 TI - Cysteine Isocyanide in Multicomponent Reaction: Synthesis of Peptido-Mimetic 1,3 Azoles. AB - An alternative approach toward the simple and robust synthesis of highly substituted peptidic thiazole derivatives using Ugi-multicomponent reaction (U MCR) is described. Thus, we introduced the enantiopure (R)-2-methyl-2-isocyano-3 (tritylthio)propanoate as a novel class of isocyanide in MCR. This bifunctional isocyanide was found to undergo mild cyclodehydration to afford thiazole containing peptidomimetics in a short synthetic sequence. Several examples of bis heterocyclic rings were also synthesized through the proper choice of the aldehyde component in the U-4CR. The method opens a wide range of applications toward the synthesis of nonribosomal natural products and other bioactive compounds. PMID- 28817274 TI - Notch Inhibitors from Calotropis gigantea That Induce Neuronal Differentiation of Neural Stem Cells. AB - Neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease occur due to loss of the structure and function of neurons. For the potential treatment of neurodegenerative diseases, accelerators of neuronal differentiation of neural stem cells (NSCs) have been focused on and a cell-based assay system for measuring Notch signaling pathway activity was constructed. Using this assay system, eight compounds isolated from Calotropis gigantea were identified as inhibitors of the Notch signaling pathway. Hes1 and Hes5 are target genes of the Notch signaling pathway, and compound 1, called uscharin, decreased the protein levels of Hes1 and Hes5 in assay cells and MEB5 cells (mouse NSCs). Furthermore, uscharin (1) enhanced the differentiation of MEB5 cells into neurons. The mechanism of uscharin (1) for the Notch signaling inhibitory activity would be acceleration of the degradation of the Notch intracellular domain (NICD) in the MEB5 cells. PMID- 28817275 TI - Influence of Sodium Chloride on the Formation and Dissociation Behavior of CO2 Gas Hydrates. AB - We present an experimental study on the formation and dissociation characteristics of carbon dioxide (CO2) gas hydrates using Raman spectroscopy. The CO2 hydrates were formed from sodium chloride/water solutions with salinities of 0-10 wt %, which were pressurized with liquid CO2 in a stirred vessel at 6 MPa and a subcooling of 9.5 K. The formation of the CO2 hydrate resulted in a hydrate gel where the solid hydrate can be considered as the continuous phase that includes small amounts of a dispersed liquid water-rich phase that has not been converted to hydrate. During the hydrate formation process we quantified the fraction of solid hydrate, xH, and the fraction of the dispersed liquid water rich phase, xL, from the signature of the hydroxyl (OH)-stretching vibration of the hydrate gel. We found that the fraction of hydrate xH contained in the hydrate gel linearly depends on the salinity of the initial liquid water-rich phase. In addition, the ratio of CO2 and water was analyzed in the liquid water rich phase before hydrate formation, in the hydrate gel during growth and dissociation, and after its complete dissociation again in the liquid water-rich phase. We observed a supersaturation of CO2 in the water-rich phase after complete dissociation of the hydrate gel and were able to show that the excess CO2 exists as dispersed micro- or nanoscale liquid droplets in the liquid water rich phase. These residual nano- and microdroplets could be a possible explanation for the so-called memory effect. PMID- 28817276 TI - Selectfluor-Triggered Tandem Cyclization of o-Hydroxyarylenaminones To Access Difluorinated 2-Amino-Substituted Chromanones. AB - A practical and straightforward synthetic route through a Selectfluor-triggered tandem cyclization of o-hydroxyarylenaminone was developed to construct a variety of difluorinated 2-amino-substituted chromanones. This novel protocol features mild reaction conditions, operational simplicity, and broad substrate scope. The enamine moiety in o-hydroxyarylenaminone played dual roles to enable high efficiency in the difluorination and intramolecular cyclization, leading to the accomplishment of a new class of difluorinated 2-amino-substituted chromanones for pharmaceutical studies. PMID- 28817278 TI - Unveiling the Aggregation of Lycopene in Vitro and in Vivo: UV-Vis, Resonance Raman, and Raman Imaging Studies. AB - The present study investigates the structure of lycopene aggregates both in vitro and in vivo using ultraviolet-visible (UV-vis) and Raman spectroscopies. The electronic absorption bands of the J- and H-aggregates in vitro shift to lower and higher energies, respectively, compared to that of the lycopene monomer. Along with these results, the frequencies of the nu1 Raman bands were shifted to lower and higher frequencies, respectively. By plotting the frequencies of the nu1 Raman band against the S0 -> S2 transition energy, a linear relationship between the data set with different aggregation conformations can be obtained. Therefore, the band positions depending on the different conformations can be explained based on the idea that the effective conjugated C?C chain lengths within lycopene molecules are different due to the environmental effect (site shift effect) caused by the aggregation conformation. Applying this knowledge to the in vivo measurement of a tomato fruit sample, the relationship between the aggregation conformation of lycopene and the spectral patterns observed in the UV vis as well as Raman spectra in different parts of tomato fruits was discussed in detail. The results showed that the concentration of lycopene (particularly that of the J-aggregate) specifically increased, whereas that of chlorophyll decreased, with ripening. Furthermore, Raman imaging indicated that lycopene with different aggregate conformations was distributed inhomogeneously, even within one sample. The layer formation in tomato tissues with high concentrations of J- and H-aggregates was successfully visualized. In this manner, the presence of lycopene distributions with different aggregate conformations was unveiled in vivo. PMID- 28817279 TI - Soft Chemical Fabrication of Iron-Based Thin Film Electrocatalyst for Water Oxidation under Neutral pH and Structure-Activity Tuning by Cerium Incorporation. AB - Design of electrocatalysts for the fundamentally important oxygen evolution reaction can be greatly aided by systematic structure-activity tuning via composition variation. We have explored the iron-cerium system as they are the most abundant transition and rare earth metals, and also due to the mutualistic impact of their size and electronic attributes that can induce critical changes in the structure and electrochemical activity. Submicrometer thick films of a series of Fe(III)-Ce(III) phosphate(oxyhydroxide) (FeCePH) are fabricated using a soft chemical strategy involving surfactant-aided assembly, spin-coating, and mild thermal annealing. FT-IR, Raman, and X-ray photoelectron spectroscopies, chemical analysis, X-ray diffraction, and electron microscopy reveal the systematic structural, electronic, and morphological variation, on tuning the iron-cerium composition. Nitrogen adsorption-desorption studies show the surface area increasing and pore size distribution shrinking with the cerium content, indicating its structure-directing role. The electrocatalysis of water oxidation by FeCePH films on FTO-coated glass is studied in neutral pH conditions. The overpotential and Tafel slope decrease with increasing cerium content, reaching minima at the optimal Fe:Ce ratio of 1:0.5; the turnover frequency shows a corresponding increase and maximum. The trends are explained on the basis of the structural changes in the films, and the coupling of Ce3+/Ce4+ with Fe3+/Fe4+ that leads to active state regeneration. This study presents a rational strategy to tune the efficiency of easily fabricated transition metal-based electrocatalyst thin films through rare earth metal incorporation; it should prove useful in the design of cost-effective catalysts for water oxidation. PMID- 28817277 TI - Discovery and Characterization of (R)-6-Neopentyl-2-(pyridin-2-ylmethoxy)-6,7 dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894), an Alkyne-Lacking Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator Profiled in both Rat and Nonhuman Primates. AB - We previously observed a cutaneous type IV immune response in nonhuman primates (NHP) with the mGlu5 negative allosteric modulator (NAM) 7. To determine if this adverse event was chemotype- or mechanism-based, we evaluated a distinct series of mGlu5 NAMs. Increasing the sp3 character of high-throughput screening hit 40 afforded a novel morpholinopyrimidone mGlu5 NAM series. Its prototype, (R)-6 neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894, 8), possessed favorable properties and a predicted low clinical dose (2 mg twice daily). Compound 8 did not show any evidence of immune activation in a mouse drug allergy model. Additionally, plasma samples from toxicology studies confirmed that 8 did not form any reactive metabolites. However, 8 caused the identical microscopic skin lesions in NHPs found with 7, albeit with lower severity. Holistically, this work supports the hypothesis that this unique toxicity may be mechanism-based although additional work is required to confirm this and determine clinical relevance. PMID- 28817280 TI - X-ray Spectroscopy Uncovering the Effects of Cu Based Nanoparticle Concentration and Structure on Phaseolus vulgaris Germination and Seedling Development. AB - Nanoparticles properties such as solubility, tunable surface charges, and singular reactivity might be explored to improve the performance of fertilizers. Nevertheless, these unique properties may also bring risks to the environment since the fate of nanoparticles is poorly understood. This study investigated the impact of a range of CuO nanoparticles sizes and concentrations on the germination and seedling development of Phaseolus vulgaris L. Nanoparticles did not affect seed germination, but seedling weight gain was promoted by 100 mg Cu L 1 and inhibited by 1 000 mg Cu L-1 of 25 nm CuO and CuSO4. Most of the Cu taken up remained in the seed coat with Cu hotspots in the hilum. X-ray absorption spectroscopy unraveled that most of the Cu remained in its pristine form. The higher surface reactivity of the 25 nm CuO nanoparticles might be responsible for its deleterious effects. The present study therefore highlights the importance of the nanoparticle structure for its physiological impacts. PMID- 28817281 TI - Linking Solution Structures and Energetics: Thorium Nitrate Complexes. AB - Seeking predictive insights into how metal-ion speciation impacts solution chemistry as well as the composition and structure of solid-precipitates, thorium correlations, with both solvent and other solute ions, were quantitatively probed in a series of acidic, nitrate/perchlorate solutions held at constant ionic strength. Difference pair-distribution functions (dPDF), obtained from high energy X-ray scattering (HEXS) data, provide unprecedented structural information on the number of Th ligating ions in solution and how they change with increasing nitrate concentration. A fit of the end member solution, Th (4 m perchloric acid and no nitrate), reveals a homoleptic Th aqua ion with 10 waters in its first coordination shell. Analyses of the acidic solutions containing nitrate reveal exclusively bidentate NO3- complexation with Th, consistent with published solid state MIV nitrate structures, where MIV = Ce, Th, U, Np, Pu. Metrical fits of Th coordination as a function of nitrate concentration are used to calculate Th-NO3 stability constants, information important to a molecular-scale description of reaction energetics. The coordination environments of Th in solution were compared with single-crystal structures obtained from their precipitates, Th(NO3)4(H2O)4 and Th(NO3)4(H2O)3.(H2O)2. Relative stabilities of the solid-state compounds, assessed based on the results of molecular quantum chemical calculations, reveal the importance of including an accurate description of complexed waters when predicting relative energetics of dissolved ions in aqueous solution. PMID- 28817282 TI - TNF Induced Switching of Columnar Rectangular to Hexagonal Assemblies in a New Class of Triphenylene-Based Room Temperature Discotic Liquid Crystals. AB - A straightforward synthesis of triphenylene-based oligomeric systems that self organize into room temperature columnar structures is presented. The compounds with longer spacer length (m = 10 and 12) exhibit columnar rectangular (Colr) mesophase whereas the compound with m = 8 exists in glassy Colr state. Interestingly, the Colr self-assembly of these compounds switches to columnar hexagonal (Colh) on doping the compounds with 2,4,7-trinitrofluorenone (TNF). For the dopant concentration of 1:1 with respect to native compound, an intermediate transition state between Colr and Colh phase was observed which completely transformed into the hexagonal phase on increasing the concentration to 1:2 (compound: TNF) and afterward. Both the Colr and Colh self-assemblies have been well resolved by detailed X-ray analysis. These kind of oligomeric compounds generally possess a combination of desirable alignment properties analogous to monomeric compounds and long-lived glassy states similar to that of polymeric mesogens. In addition, charge hopping behavior is expected to increase in these compounds due to donor-acceptor interactions. Overall, these compounds can find possible potential applications in semiconductor devices. PMID- 28817283 TI - The Effects of A21G Mutation on Transmembrane Amyloid Beta (11-40) Trimer: An In Silico Study. AB - Familial Alzheimer's disease (FAD) is passed down in family, which account for 2 3% of about 40 million AD cases worldwide. The Flemish (A21G) mutant of amyloid beta (Abeta) exhibits unique properties among all hereditary mutants of FAD, including the lowest aggregation rate. Recent studies showed that Abeta oligomers play a key role in Alzheimer's disease (AD) pathogenesis. They could insert themselves in brain cell membrane, disrupting the membrane integrity and ion homeostasis. However, experimental studies of transmembrane Abeta oligomers have been limited due to their intrinsic heterogeneity. In this work, we extensively studied the A21G mutant of the transmembrane 3Abeta11-40 (A21G 3Abeta11-40) using temperature replica exchange molecular dynamics (REMD) simulations. Results provide detailed information on the conformational distribution and dynamics of transmembrane A21G 3Abeta11-40. Minimal local change from A to G leads to significant conformational changes and wider free energy holes on the free energy surface as well as altered surface charges that lead to weaker affinity to the dipalmitoylphosphatidylcholine (DPPC) lipid bilayers. These results are consistent with experimental data that showed that A21G mutants of Abeta peptides have lower aggregation rates and membrane binding rates. PMID- 28817284 TI - Fabrication of Mesoporous Polystyrene Films with Controlled Porosity and Pore Size by Solvent Annealing for Templated Syntheses. AB - Herein, we aim to develop a facile method for the fabrication of mesoporous polystyrene (PS) films with controlled porosity and pore size by solvent annealing. A PS polymer film is solvent-annealed using N,N-dimethyl formamide (DMF) vapor for the development of phase separation, followed by rapidly cooling to the preset cryogenic temperature. Subsequently, a nonsolvent (methanol) is introduced to extract the crystalline DMF from the DMF-swollen PS, giving mesoporous PS with a network structure after the removal of DMF. The porosity of the mesoporous PS films can be controlled by the degree of swelling. Most interestingly, the phase separation between PS and DMF at the thin-film state under solvent annealing can be regulated by the annealing time through the spinodal decomposition, giving the development of nanonetwork structure with controlled structural features (i.e., framework size and interframework spacing) at invariant porosity. Consequently, after the removal of DMF, mesoporous PS films with controlled porosity and pore size can be obtained and then used as a template for the fabrication of a variety of nanoporous inorganics by templated syntheses, such as nanoporous SiO2, TiO2, and Ni, providing a cost-effective way to fabricate a range of nanoporous materials with controlled porosity and pore size as well as large specific surface area for aimed applications. PMID- 28817285 TI - Inorganic-Organic Coating via Molecular Layer Deposition Enables Long Life Sodium Metal Anode. AB - Metallic Na anode is considered as a promising alternative candidate for Na ion batteries (NIBs) and Na metal batteries (NMBs) due to its high specific capacity, and low potential. However, the unstable solid electrolyte interphase layer caused by serious corrosion and reaction in electrolyte will lead to big challenges, including dendrite growth, low Coulombic efficiency and even safety issues. In this paper, we first demonstrate the inorganic-organic coating via advanced molecular layer deposition (alucone) as a protective layer for metallic Na anode. By protecting Na anode with controllable alucone layer, the dendrites and mossy Na formation have been effectively suppressed and the lifetime has been significantly improved. Moreover, the molecular layer deposition alucone coating shows better performances than the atomic layer deposition Al2O3 coating. The novel design of molecular layer deposition protected Na metal anode may bring in new opportunities to the realization of the next-generation high energy-density NIBs and NMBs. PMID- 28817286 TI - Intermolecular Aryne Ene Reaction of Hantzsch Esters: Stable Covalent Ene Adducts from a 1,4-Dihydropyridine Reaction. AB - The reaction of arynes with 1,4-dihydropyridines affords 2-aryl-1,2 dihydropyridines or 2-methylene-3-aryl-1,2,3,4-tetrahydropyridines via a regioselective C-2 or C-3 arylation. These compounds are the first series of isolable and bench-stable covalent ene adducts formed between dihydropyridines and unsaturated substrates. Experimental studies and DFT calculations provide mechanistic support for a concerted intermolecular aryne ene process, which may have implications for NAD(P)H model reactions. PMID- 28817287 TI - Visible Light-Induced Oxidative Chlorination of Alkyl sp3 C-H Bonds with NaCl/Oxone at Room Temperature. AB - A visible light-induced monochlorination of cyclohexane with sodium chloride (5:1) has been successfully accomplished to afford chlorocyclohexane in excellent yield by using Oxone as the oxidant in H2O/CF3CH2OH at room temperature. Other secondary and primary alkyl sp3 C-H bonds of cycloalkanes and functional branch/linear alkanes can also be chlorinated, respectively, under similar conditions. The selection of a suitable organic solvent is crucial in these efficient radical chlorinations of alkanes in two-phase solutions. It is studied further by the achievement of high chemoselectivity in the chlorination of the benzyl sp3 C-H bond or the aryl sp2 C-H bond of toluene. PMID- 28817288 TI - In Silico Modeling Approach for the Evaluation of Gastrointestinal Dissolution, Supersaturation, and Precipitation of Posaconazole. AB - The aim of this study was to evaluate gastrointestinal (GI) dissolution, supersaturation, and precipitation of posaconazole, formulated as an acidified (pH 1.6) and neutral (pH 7.1) suspension. A physiologically based pharmacokinetic (PBPK) modeling and simulation tool was applied to simulate GI and systemic concentration-time profiles of posaconazole, which were directly compared with intraluminal and systemic data measured in humans. The Advanced Dissolution Absorption and Metabolism (ADAM) model of the Simcyp Simulator correctly simulated incomplete gastric dissolution and saturated duodenal concentrations of posaconazole in the duodenal fluids following administration of the neutral suspension. In contrast, gastric dissolution was approximately 2-fold higher after administration of the acidified suspension, which resulted in supersaturated concentrations of posaconazole upon transfer to the upper small intestine. The precipitation kinetics of posaconazole were described by two precipitation rate constants, extracted by semimechanistic modeling of a two stage medium change in vitro dissolution test. The 2-fold difference in exposure in the duodenal compartment for the two formulations corresponded with a 2-fold difference in systemic exposure. This study demonstrated for the first time predictive in silico simulations of GI dissolution, supersaturation, and precipitation for a weakly basic compound in part informed by modeling of in vitro dissolution experiments and validated via clinical measurements in both GI fluids and plasma. Sensitivity analysis with the PBPK model indicated that the critical supersaturation ratio (CSR) and second precipitation rate constant (sPRC) are important parameters of the model. Due to the limitations of the two stage medium change experiment the CSR was extracted directly from the clinical data. However, in vitro experiments with the BioGIT transfer system performed after completion of the in silico modeling provided an almost identical CSR to the clinical study value; this had no significant impact on the PBPK model predictions. PMID- 28817289 TI - How To Drive a Flashing Electron Ratchet To Maximize Current. AB - Biological systems utilize a combination of asymmetry, noise, and chemical energy to produce motion in the highly damped environment of the cell with molecular motors, many of which are "ratchets", nonequilibrium devices for producing directed transport using nondirectional perturbations without a net bias. The underlying ratchet principle has been implemented in man-made micro- and nanodevices to transport charged particles by oscillating an electric potential with repeating asymmetric features. In this experimental study, the ratcheting of electrons in an organic semiconductor is optimized by tuning the temporal modulation of the oscillating potential, applied using nanostructured electrodes. An analytical model of steady-state carrier dynamics is used to determine that symmetry-breaking motion of carriers through the thickness of the polymer layer enables even temporally unbiased waveforms (e.g., sine) to produce current, an advance that could allow the future use of electromagnetic radiation to power ratchets. The analysis maps the optimal operating frequency of the ratchet to the mobility of the transport layer and the spatial periodicity of the potential, and relates the dependence on the temporal waveform to the dielectric characteristics and thickness of the layer. PMID- 28817290 TI - Air-Stable Porous Fe2N Encapsulated in Carbon Microboxes with High Volumetric Lithium Storage Capacity and a Long Cycle Life. AB - The development of inexpensive electrode materials with a high volumetric capacity and long cycle-life is a central issue for large-scale lithium-ion batteries. Here, we report a nanostructured porous Fe2N anode fully encapsulated in carbon microboxes (Fe2N@C) prepared through a facile confined anion conversion from polymer coated Fe2O3 microcubes. The resulting carbon microboxes could not only protect the air-sensitive Fe2N from oxidation but also retain thin and stable SEI layer. The appropriate internal voids in the Fe2N cubes help to release the volume expansion during lithiation/delithiation processes, and Fe2N is kept inside the carbon microboxes without breaking the shell, resulting in a very low electrode volume expansion (the electrode thickness variation upon lithiation is ~9%). Therefore, the Fe2N@C electrodes maintain high volumetric capacity (1030 mA h cm-3 based on the lithiation-state electrode volume) comparable to silicon anodes, stable cycling performance (a capacity retention of over 91% for 2500 cycles), and excellent rate performance. Kinetic analysis reveals that the Fe2N@C shows an enhanced contribution of capacitive charge mechanism and displays typical pseudocapacitive behavior. This work provides a new direction on designing and constructing nanostructured electrodes and protective layer for air unstable conversion materials for potential applications as a lithium-ion battery/capacitor electrode. PMID- 28817291 TI - Assembly of 2-Arylbenzothiazoles through Three-Component Oxidative Annulation under Transition-Metal-Free Conditions. AB - Highly efficient methods for the synthesis of 2-arylbenzothiazoles and 2 arylnaphtho[2,1-d]thiazoles have been developed. Readily available aromatic amines, benzaldehydes, and elemental sulfur were directly assembled through oxidative annulation and C-H functionalization under transition-metal-free conditions, where DMSO or oxygen served as the oxidant. NH4I or KI as the catalyst was found to be effective to promote the transformations to give the annulation products in good to excellent yields with wide functional group tolerance. PMID- 28817292 TI - Theoretical Analysis of the Retro-Diels-Alder Reactivity of Oxanorbornadiene Thiol and Amine Adducts. AB - Additions of amines or thiols to 7-oxanorbornadienes promote retro-[4 + 2] reactions to yield furans. Substitution at the bridgehead position also greatly influences the stability of the oxanorbornene adducts. Activation and reaction energies were computed with the M06-2X density functional, the origins of amine and thiol promoted fragmentation, and how substituent effects control fragmentation rates and reaction energetics are reported. PMID- 28817293 TI - A comparison of retrospective attribution rules. AB - OBJECTIVES: To compare the performance of methods to retrospectively attribute patients to provider systems by comparing the fraction attributed and the stability of assignment over time. STUDY DESIGN: Retrospective cross-sectional study. METHODS: Descriptive statistics are used to measure the fraction of patients attributed and stability of attribution from year to year. This study uses a panel of administrative claims data (2010-2011). Attribution rules were defined by unit of measure (count of physician visits, dollars paid), type of providers (primary care physicians [PCPs], all physicians), type of encounters (all visits, evaluation and management visits only), and level of concentration of care (majority, plurality). We created 32 retrospective attribution rules, spanning PCP-only rules, all-physician rules, hierarchical rules based on PCPs then all physicians, and lookback rules based on current-year PCP visits then prior-year experience. RESULTS: All methods exhibit a tradeoff between stability of attribution and fraction of the population attributed. This tradeoff is minimized when PCP-based rules are supplemented by a 1-year lookback when the current-year experience does not result in attribution. CONCLUSIONS: We recommend using this lookback method when multiple years of data are available. In absence of multiple years of data, PCP-based rules maximize stability; hierarchical rules result in a greater fraction attributed with less loss of stability than simple all-provider rules. PMID- 28817294 TI - Heterogeneity of nonadherent buprenorphine patients: subgroup characteristics and outcomes. AB - OBJECTIVES: To examine patient characteristics and outcomes associated with nonadherence to buprenorphine and to identify specific patterns of nonadherent behavior. STUDY DESIGN: Cross-sectional, retrospective analysis of health claims data. METHODS: Aetna's administrative claims data were used to categorize incident opioid use disorder (OUD) patients based on buprenorphine medication possession ratio (MPR) into adherent (n = 172) and nonadherent (n = 305) groups. Adherent groups were then divided into 5 subgroups based on level of MPR, as well as 2 a priori-defined groups: intermittent adherent (IA) and early treatment discontinuation-no consequences (ETDNC). Groups were compared on patient characteristics and outcomes. RESULTS: Nonadherent members incurred significantly greater healthcare costs and were more likely to relapse (P <.05). The use of high-cost healthcare services increased as a function of decreasing MPR (P <.05). Assessment of the a priori groups revealed IA members to have outcomes similar to nonadherent patients, while ETDNC members exhibited outcomes similar to adherent members. CONCLUSIONS: Administrative claims can be used to define subgroups of buprenorphine-medication assisted treatment (B-MAT) patients. Nonadherence was related to an increased likelihood of relapse, and there is an inverse relationship between MPR and cost. The heterogeneity observed within this sample indicates that treatment regimens effective for 1 subgroup may not be appropriate for all OUD patients. Increased understanding of B-MAT nonadherent subgroups may facilitate development of new interventions and medications specifically designed for nonadherent B-MAT patients, potentially leading to improved outcomes and reduced costs of care. PMID- 28817295 TI - Does the offer of free prescriptions increase generic prescribing? AB - OBJECTIVES: To test if offering zero generic co-pays for oral antidiabetic drugs (OADs) and statins increases generic dispensing for low-income subsidy (LIS) recipients with diabetes enrolled in Medicare Part D. STUDY DESIGN: We analyzed a natural experiment in which LIS recipients were randomized to Part D plans in 2008. Some plans placed selected generic OADs and statins on zero co-pay tiers whereas others did not. Randomization eliminated selection effects which could bias the study findings. METHODS: We analyzed a 5% random sample of Medicare beneficiaries with diabetes from the Chronic Condition Data Warehouse using Part D claims, formulary provisions, and co-pay tiers together with a special file prepared by CMS that identified all randomly assigned LIS recipients in 2008. We calculated proportions using generic drugs in the 2 classes and annual days' supply among users in plans with and without zero co-pay tiers for the country as a whole and California (where zero co-pay plans were particularly popular). RESULTS: We found that the demand for generic OADs was not significantly different in plans with and without zero co-pay tiers. By contrast, a large difference was observed in the percent of LIS recipients using generic statins in plans with zero co-pay tiers (61.4% vs 54.6%; P <.01). However, the difference disappeared once we controlled for formulary restrictions on the most popular brand statin at the time (Lipitor). CONCLUSIONS: This cautionary tale suggests that policy makers should give greater consideration to formulary provisions when evaluating the effects of free generics in value-based insurance designs. PMID- 28817296 TI - Patients' views on price shopping and price transparency. AB - OBJECTIVES: Driven by the growth of high deductibles and price transparency initiatives, patients are being encouraged to search for prices before seeking care, yet few do so. To understand why this is the case, we interviewed individuals who were offered access to a widely used price transparency website through their employer. STUDY DESIGN: Qualitative interviews. METHODS: We interviewed individuals enrolled in a preferred provider organization product through their health plan about their experience using the price transparency tool (if they had done so), their past medical experiences, and their opinions on shopping for care. All interviews were transcribed and manually coded using a thematic coding guide. RESULTS: In general, respondents expressed frustration with healthcare costs and had a positive opinion of the idea of price shopping in theory, but 2 sets of barriers limited their ability to do so in reality. The first was the salience of searching for price information. For example, respondents recognized that due to their health plan benefits design, they would not save money by switching to a lower-cost provider. Second, other factors were more important than price for respondents when choosing a provider, including quality and loyalty to current providers. CONCLUSIONS: We found a disconnect between respondents' enthusiasm for price shopping and their reported use of a price transparency tool to shop for care. However, many did find the tool useful for other purposes, including checking their claims history. Addressing the barriers to price shopping identified by respondents can help inform ongoing and future price transparency initiatives. PMID- 28817297 TI - Using "roll-up" measures in healthcare quality reports: perspectives of report sponsors and national alliances. AB - OBJECTIVES: To understand the views of prominent organizations in the field of healthcare quality on the topic of reporting roll-up measures that combine indicators of multiple, often disparate, dimensions of care to consumers. STUDY DESIGN: This study used a semi-structured, qualitative interview design. METHODS: We conducted 30- to 60-minute semi-structured telephone interviews with representatives of 10 organizations that sponsor public healthcare quality reports and 3 national alliances representing multiple stakeholder groups. We conducted a thematic analysis of interview transcriptions to identify common issues and concerns related to reporting roll-up measures. RESULTS: Among sponsors reporting roll-up measures, current practices for calculating and reporting these measures are diverse. The main perceived benefit of reporting roll-up measures is that they simplify large amounts of complex information for consumers. The main concern is the potential for consumers to misunderstand the measures and what associated roll-up scores communicate about provider performance. Report sponsors and national alliances feel that more guidance and research on the methods for producing and reporting scores for roll-up measures are needed. CONCLUSIONS: The results of the interviews elucidate the need for research focused on construction and reporting of roll-up measures. Studies are needed to determine if roll-up measures are indeed perceived by consumers as being less complex and easier to understand. PMID- 28817298 TI - Radical prostatectomy innovation and outcomes at military and civilian institutions. AB - OBJECTIVES: Limited data are available regarding the impact of the type of healthcare delivery system on technology diffusion and associated clinical outcomes. We assessed the adoption of minimally invasive radical prostatectomy (MIRP), a recent clinical innovation, and whether this adoption altered surgical morbidity for prostate cancer surgery. STUDY DESIGN: Retrospective review of administrative data from TRICARE, the healthcare program of the United States Military Health System. Surgery occurred at military hospitals, supported by federal appropriations, or civilian hospitals, supported by hospital revenue. METHODS: We evaluated TRICARE beneficiaries with prostate cancer (International Classification of Disease, 9th Revision, Clinical Modification [ICD-9-CM] code: 185) who received a radical prostatectomy (60.5) between 2005 and 2009. MIRP was identified based on minimally invasive surgery codes (54.21, 17.42). We assessed yearly MIRP utilization, 30-day postoperative complications (Clavien classification system), length of stay, blood transfusion, and long-term urinary incontinence and erectile dysfunction. RESULTS: A total of 3366 men underwent radical prostatectomy at military hospitals compared with 1716 at civilian hospitals, with minimal clinic-demographic differences. MIRP adoption was 30% greater at civilian hospitals. There were fewer blood transfusions (odds ratio, 0.44; P <.0001) and shorter lengths of stay (incidence risk ratio, 0.85; P <.0001) among civilian hospitals, while 30-day postoperative complications, as well as long-term urinary incontinence and erectile dysfunction rates, were comparable. CONCLUSIONS: Compared with military hospitals, civilian hospitals had a greater MIRP adoption during this timeframe, but had comparable surgical morbidity. PMID- 28817299 TI - How do Medicare Advantage beneficiary payments vary with tenure? AB - OBJECTIVES: To compare how premiums and expected out-of-pocket medical costs (OOPC) vary with the length of time Medicare Advantage (MA) beneficiaries have been enrolled in their plans. STUDY DESIGN: Descriptive and fixed effects regression analyses. METHODS: Using linked administrative enrollment and plan data, we compared the costs of the MA plans that beneficiaries chose with the costs of other plans available to them. We show predicted values adjusted for age, gender, race/ethnicity, disability, individual health risk, presence of mental health diagnoses, health plan quality, relative size of the plan's provider network, and the number of years continuously enrolled in the same plan. To further address the possibility of bias, we included county-level fixed effects and compared results to a beneficiary-level fixed effects model. RESULTS: We found average spending on premiums and OOPC in enrolled plans exceeded such costs in the lowest-cost plan by $697 in 2013. Beneficiaries who remained in their plans for 6 or more years were most at risk of spending these higher amounts, paying $786 more than they would have spent in the lowest-cost plan compared with $552 for beneficiaries in their first year of enrollment. For each year a beneficiary remained in their same plan, their additional spending in excess of the minimum cost choice increased by roughly $50. CONCLUSIONS: MA beneficiaries could reduce their exposure to healthcare spending by switching to plans with lower premiums, although there may well be rational reasons for paying costs in excess of those of the lowest-cost plan. PMID- 28817300 TI - Patient ratings of Veterans Affairs and affiliated hospitals. AB - OBJECTIVES: Hospital Compare, a website maintained by CMS, allows comparisons of outcomes and processes of care but not of patient satisfaction for hospitals within the Veteran Affairs (VA) Healthcare System. Therefore, we sought to compare online hospital ratings between VA hospitals and their local affiliated hospitals. STUDY DESIGN: Observational analysis. METHODS: We identified 39 VA hospitals and a non-VA affiliated hospital with at least 2 online Yelp ratings. We determined the difference in the mean rating (VA-affiliate rating) with weighting by the number of ratings for each hospital. We used multivariate regression to compare mean Yelp ratings between VA and non-VA affiliate hospitals, adjusting for hospital characteristics (bed size, teaching status, and accreditation). RESULTS: The mean patient rating for VA hospitals (+/- standard deviation) was higher (3.64 +/- 1.0) than the rating for affiliated hospitals (3.09 +/- 0.8; P = .0036). There was no significant correlation in rating between a VA hospital and its affiliate (r = 0.07; P = .59). After adjustment for hospital characteristics, the adjusted rating difference (VA-affiliate hospitals) was 0.65 (95% confidence interval, 0.18-1.12). CONCLUSIONS: VA hospitals had higher patient ratings than their non-VA affiliated hospitals, a finding not explained by bed size or teaching status. PMID- 28817301 TI - Patients' views of a behavioral intervention including financial incentives. AB - OBJECTIVES: Clinical trials are increasingly testing the effectiveness of paying patients' financial incentives for achieving desired clinical outcomes. Some researchers and providers are concerned that patient financial incentives will harm the doctor-patient relationship. How patients feel about these approaches, and these trials, is largely unknown. This study examined patients' perceptions of a compound behavioral and financial incentive intervention used in a large multicenter trial to lower low-density lipoprotein cholesterol (LDL-C), including their perceptions of benefits and challenges and the study's effect on patients' relationship with their primary care physicians (PCPs). STUDY DESIGN: Semi structured telephone interviews with patients post intervention. METHODS: PCPs from 3 primary care practices in the northeastern United States were randomized to 1 of 4 arms: physician financial incentives, patient financial incentives, shared incentives between physicians and patients, and a control arm. Within each arm, 10 high, 10 medium, and 10 low performers in LDL-C reduction were interviewed. Interviews targeted reasons for enrolling in the study, the specific intervention elements that helped them reach the goal (incentives, engagement, monitoring), challenges faced in reducing cholesterol, and the impact of study participation on their relationship with their PCP. RESULTS: Patients reported positive experiences with the study: 65% described personal changes to improve health and 61% reported increased awareness. Views about financial incentives varied: 71% clearly found them motivating and 36% claimed they made no difference. Patients noted that changing lifestyle (36%) and diet (65%) was difficult. Patients who substantially lowered their LDL-C revealed themes similar to those who did not. CONCLUSIONS: Overall, behavioral interventions with financial incentives appear to be socially acceptable to patients who participate in them. Both adherence monitoring and financial incentives were well received, with little effect on the physician-patient relationship. PMID- 28817302 TI - Comparative effectiveness and costs of insulin pump therapy for diabetes. AB - OBJECTIVES: Continuous subcutaneous insulin infusion (CSII), or "insulin pump" therapy, is an alternative to multiple daily insulin injections (MDII) for management of diabetes. This study evaluates patterns of healthcare utilization, costs, and blood glucose control for patients with diabetes who initiate CSII. STUDY DESIGN: Pre-post with propensity-matched comparison design involving commercially insured US adults (aged 18-64 years) with insulin-requiring diabetes who transitioned from MDII to CSII between July 1, 2009, and June 30, 2012 ("CSII initiators"; n = 2539), or who continued using MDI (n = 2539). METHODS: Medical claims and laboratory results files obtained from a large US-wide health payer were used to construct direct medical expenditures, hospital use, healthcare encounters for hypoglycemia, and mean concentration of glycated hemoglobin (A1C). We fit difference-in-differences regression models to compare healthcare expenditures for 3 years following the switch to CSII. Stratified analyses were performed for prespecified patient subgroups. RESULTS: Over 3 years, mean per person total healthcare expenditures were $1714 (95% confidence interval [CI], $1184-$2244) higher per quarter for CSII initiators compared with matched MDII patients (total mean 3-year difference of $20,565). Compared with matched controls, mean A1C concentrations became lower for CSII initiators by 0.46% in year 2 (P = .0003) and by 0.32% in year 3 (P = .047). CSII initiators also had a higher rate of hypoglycemia encounters in year 1 (P = .002). CONCLUSIONS: For adults with insulin-requiring diabetes, transitioning from MDII to CSII was associated with modest improvements in A1C but more hypoglycemia encounters and increased healthcare expenditures, without significant improvement in other potentially offsetting areas of healthcare consumption. PMID- 28817303 TI - CHRNA7 Deletions are Enriched in Risperidone-Treated Children and Adolescents. AB - OBJECTIVE: Aggression is among the most common indications for referral to child and adolescent mental health services and is often challenging to treat. Understanding the biological underpinnings of aggression could help optimize treatment efficacy. Neuronal nicotinic acetylcholine receptors (nAChRs), specifically the alpha7 nAChR, encoded by the gene CHRNA7, have been implicated in aggressive behaviors in animal models as well as humans. Copy number variants (CNVs) of CHRNA7 are found in individuals with neuropsychiatric disorders, often with comorbid aggression. In this study, we aimed to determine the prevalence of CHRNA7 CNVs among individuals treated with risperidone, predominantly for irritability and aggression. METHODS: Risperidone-treated children and adolescents were assessed for CHRNA7 copy number state using droplet digital PCR and genomic quantitative PCR. Demographic, anthropometric, and clinical data, including the Child Behavior Checklist (CBCL), were collected and compared across individuals with and without the CHRNA7 deletion. RESULTS: Of 218 individuals (90% males, mean age: 12.3 +/- 2.3 years), 7 (3.2%) were found to carry a CHRNA7 deletion and one proband carried a CHRNA7 duplication (0.46%). T-scores for rule breaking, aggression, and externalizing behavior factors of the CBCL were higher in the deletion group, despite taking 58% higher dose of risperidone. CONCLUSIONS: CHRNA7 loss may contribute to a phenotype of severe aggression. Given the high prevalence of the deletion among risperidone-treated youth, future studies should examine the therapeutic potential of alpha7 nAChR-targeting drugs to target aggression associated with CHRNA7 deletions. PMID- 28817304 TI - Medical Education and Leadership in Breastfeeding Medicine. AB - Physicians' experience with high quality training in breastfeeding during their medical education is historically varied. The process of becoming a board certified physician entails more than 20 years of education, and although medical school and residency training timelines and courses are relatively standardized across the United States and even internationally, breastfeeding education varies greatly across schools and programs. The Academy of Breastfeeding Medicine (ABM) exists, in part, because historically, physicians have received too little clinical training in breastfeeding and infant nutrition. An overarching goal of ABM, which is a multispecialty organization of doctors around the world, is to educate all maternal-child healthcare professionals, not just physicians, about breastfeeding. Within the field of medicine, family doctors, pediatricians, and obstetrician/gynecologists are considered the most logical source of breastfeeding expertise. However, the need for breastfeeding education goes beyond those providers who have obvious interactions with mothers and babies. We must educate anesthesiologists, surgeons, internists, and psychiatrists, among others. Building pipelines of physicians who are well educated in breastfeeding medicine allows more effective collaboration and care of mothers and infants among providers in various medical and surgical specialties as well as between doctors and other healthcare providers. This evidence-based education needs to be multifaceted, with didactic curricula for a strong knowledge base complemented by clinical experiences for skill development and application. Clinical knowledge and skills can also be reinforced during nonclinical opportunities in teaching, research, advocacy, and professional development. In this article, we describe a foundational framework for physician education in breastfeeding medicine as well as several creative noncurricular opportunities to develop breastfeeding expertise in future physician leaders. We conclude with a case study. PMID- 28817305 TI - Foot Massage, Touch, and Presence in Decreasing Anxiety during a Magnetic Resonance Imaging: A Feasibility Study. AB - OBJECTIVES: The purpose of the study was to determine (1) recruitment feasibility; (2) intervention adherence; (3) intervention acceptability; and (4) the preliminary effects of touch or foot massage interventions on anxiety during a magnetic resonance imaging (MRI). DESIGN: A quasi-experimental design was used. INTERVENTION: Foot massage and touch were the intervention groups and "presence" was the control group. SETTING: The study was conducted at the Center for Neurosciences, a freestanding facility, in southern Arizona. PARTICIPANTS: The sample (N = 60) was predominantly Caucasian (58.3%), married (55%), and college educated (43.3%). There were 39 females and 21 males. Fifty-three percent of the participants had an MRI head scan. OUTCOME MEASURES: Recruitment feasibility was the percentage of participants enrolled out of those screened. Adherence to foot massage and touch interventions was measured by the researcher's ability to apply full intervention for 20 min. Four factors measured participants' acceptance of the interventions as follows: (1) comfort; (2) acceptability of the length of the treatment; (3) perception of effectiveness; and (4) recommendation of treatment as part of routine MRI care. The MRI technologists' acceptability was measured by whether the intervention: (1) disrupted the workflow and (2) affected the length of the scan. State anxiety was assessed verbally by a single 10-point Likert type item. RESULTS: Recruitment feasibility was 78.2%. There were no barriers to the intervention protocol for 91.6% participants. The overall mean value of perceived effectiveness was 8.53, SD = 2.4 on a 10-point Likert type question. There was a significant difference among the three groups in terms of perceived effectiveness of the intervention F(2, 57) = 15.19, p < 0.001. Multilevel modeling documented that the foot massage intervention was a significant predictor of decreasing anxiety (beta = -1.35, SE = 0.63, p < 0.01). CONCLUSION: The use of foot massage or touch is feasible, acceptable by patients and technologists, and the use of foot massage was associated with lower state anxiety. PMID- 28817306 TI - A New Federal Task Force on Research Specific to Pregnant Women and Lactating Women: From Idea to Implementation. PMID- 28817308 TI - A 2017 Update: Centers for Disease Control and Prevention's Contributions and Investments in Breastfeeding. AB - Given that breastfeeding is important to the health of infants and their mothers, the Centers for Disease Control and Prevention's (CDC) goal is to ensure that new mothers understand the benefits of breastfeeding and, when they choose to breastfeed, have the supports they need to successfully initiate and continue breastfeeding until they reach their goals. This report summarizes CDC's current contributions and investments in breastfeeding. PMID- 28817307 TI - Geographic Distribution of Nontuberculous Mycobacterial Species Identified among Clinical Isolates in the United States, 2009-2013. AB - RATIONALE: Nontuberculous mycobacteria are an important cause of morbidity in the United States, although patient outcomes vary greatly by species. Currently, nationally representative data on the distribution of mycobacterial species from clinical isolates are limited. OBJECTIVES: Using a national hospitalization database capturing microbiologic data for nearly 6 million patient encounters, we describe the geographic distribution of, and patient demographic features associated with, clinical mycobacterial isolates in the United States. METHODS: Linked demographic and microbiologic data from the Premier Healthcare Database were extracted for all patient encounters from 2009 to 2013. Patients with at least one positive potentially pathogenic nontuberculous mycobacterial culture were identified as cases. The period prevalence was calculated, and patient-, encounter-, and hospital-level factors were analyzed. Regional differences in species distribution were analyzed; a subanalysis was conducted among patients with International Classification of Diseases, Ninth Revision, codes for pulmonary nontuberculous mycobacterial disease. Significant differences were assessed (P < 0.05). RESULTS: Of 5,928,830 unique patients included during the 5 year study period, 7,812 (0.13%) had at least one positive nontuberculous mycobacterial culture. The mean age of cases was 64 years (range, <1-89 yr), and most were female (52%) and white (70%). Hospitals with cases were more often labeled "urban" (96%), "teaching" (56%), and had at least 500 beds (78%). Species distribution differed significantly by geographic area. Mycobacterium avium complex ranged from 61 to 91% of isolates and were most frequent in the South and Northeast regions; M. abscessus/M. chelonae ranged from 2 to 18% of isolates and were most frequent in the West; and other species, including M. fortuitum and M. kansasii, ranged from 7 to 26% and were also most frequent in the West. CONCLUSIONS: Significant geographic variation exists in the distribution of nontuberculous mycobacterial species in the United States. Whereas M. avium complex was the most common species isolated in the South, M. abscessus/M. chelonae was proportionately higher in the West. Greater clinical awareness in regions with increased levels of harder-to-treat mycobacteria are needed, given differences in treatment options and implications for patient outcomes. PMID- 28817309 TI - Weight, Height, and Body Mass Index in Patients with Attention Deficit/Hyperactivity Disorder Treated with Methylphenidate. AB - OBJECTIVE: To describe the methylphenidate (MPH) effects on weight, height, and body mass index (BMI) in a Spanish sample diagnosed with attention deficit/hyperactivity disorder (ADHD). METHODS: Patients (6-18 years) diagnosed with ADHD treated at our Unit with MPH in the last 10 years were included in an observational longitudinal study. Weight, height, and BMI Z scores were measured at baseline and at last follow-up. RESULTS: Three hundred forty-two patients (mean [standard deviation] age: 10.7 [3.8] years, 80% males) were included. Mean dose was 1.25 (0.40) mg/(kg.d). After 27 (14-41) months taking MPH, weight and BMI standard deviation score (SDS) were reduced by treatment (baseline weight SDS: 0.34 [1.22], follow-up weight-SDS: -0.06 [1.38], t-test p < 0.001; baseline BMI-SDS: 0.35 [1.10], and follow-up BMI-SDS [SDS]: -0.23 [1.08], t-test p < 0.001). In the whole sample, no differences in height before and after treatment were observed. However, considering only the group of patients who were children 6-12 years (68.6%) when starting treatment, height was slightly affected (baseline height-SDS: 0.04 [1.14], follow-up: -0.10 [1.11], p < 0.001). This effect was not observed if treatment was started during adolescence. Linear regression analysis showed that age starting MPH (B = 0.07, p = 0.003), dose (B = -0.50, p = 0.001), and duration of treatment (B = 0.07, p = 0.031) affect follow up height. CONCLUSION: MPH slightly decreased weight and BMI in this group of ADHD patients followed naturalistically over 2.2 years, and slightly affected height only if treatment was started before the age of 12. Girls, children who started treatment being younger or children on higher MPH doses, showed greater impact in height. PMID- 28817310 TI - Semaphorins and Their Roles in Airway Biology: Potential as Therapeutic Targets. AB - Semaphorins are a large family of proteins originally identified as axon guidance cues that play a crucial role in neural development. They are also ubiquitously expressed beyond the nervous system and contribute to regulation of essential cell functions, such as cell migration, proliferation, and adhesion. Binding of semaphorins to their receptors, including plexins and neuropilins, triggers diverse signaling pathways, which are involved in the pathogenesis of various diseases, from cancer to autoimmune and allergic disorders. Despite emerging evidence suggestive of nonredundant roles of semaphorins in cellular and molecular mechanisms of the airway biology, their precise expression and function have not been fully addressed. Here, we first provide an overview about the semaphorin family, their receptors, signaling pathways, and their cellular functions. Then, we highlight the novel findings on the role of semaphorins in airway biology under developmental, homeostatic, and pathological conditions. In particular, we discuss the dual roles of semaphorins in respiratory disorders where they can up- or downregulate processes underlying the pathophysiology of the airway diseases. Next, our recent findings on the expression and function of semaphorin 3E in allergic asthma are further emphasized, and its potential mechanism of action in allergic airway inflammation and remodeling is discussed. Finally, we raise some unanswered questions aiming to develop future research directions. PMID- 28817311 TI - Beta-secretase inhibitors in phase I and phase II clinical trials for Alzheimer's disease. AB - INTRODUCTION: BACE 1 is a protease that cleaves the transmembrane amyloid precursor protein and generates amyloid-beta peptides that accumulate in AD brains. No known mutations are identified in the gene encoding BACE1 in AD. However, enzyme levels are elevated in AD and a single residue mutation in amyloid precursor protein protects against protein cleavage by BACE1, suggesting BACE involvement in disease pathogenesis. Drugs that can inhibit BACE1 would theoretically prevent Abeta accumulation and halt AD onset and progression. Areas covered: This review discusses clinical developments of BACE1 inhibitors and focuses on what is learned about these inhibitors as a potential treatment. Expert opinion: BACE1 inhibition as a therapeutic strategy to improve cognition in AD has been challening. Brain-penetrant BACE1 inhibitors have been developed and clinical trials are underway, both safety and efficacy are questionable. Several clinical trials suggest that BACE1 inhibition and other immunotherapies to reduce brain Abeta are insufficient to improve cognition in AD. This may be due to the emphasis on the amyloid hypothesis despite big failures. We may have to seriously consider shifting attention to therapeutic strategies other than BACE1 inhibition or reduction of Abeta alone and pay more attention to simultaneous clearance of tau and Abeta. PMID- 28817312 TI - DIsulfide Mapping PLanner Software Tool. AB - Disulfide bridges are side-chain-mediated covalent bonds between cysteines that stabilize many protein structures. Disulfide mapping experiments to resolve these linkages typically involve proteolytic cleavage of the protein of interest followed by mass spectroscopy to identify fragments corresponding to linked peptides. Here we report the sequence-based "DIMPL" web tool to facilitate the planning and analysis steps of experimental mapping studies. The software tests permutations of user-selected proteases to determine an optimal peptic digest that produces cleavage between cysteine residues, thus separating each to an individual peptide fragment. The webserver returns fragment sequence and mass data that can be dynamically ordered to enable straightforward comparative analysis with mass spectroscopy results, facilitating dipeptide identification. PMID- 28817313 TI - CCR7 Mediates TGF-beta1-Induced Human Malignant Glioma Invasion, Migration, and Epithelial-Mesenchymal Transition by Activating MMP2/9 Through the Nuclear Factor KappaB Signaling Pathway. AB - Chemokine receptor 7 (CCR7) has emerged as an inducer of invasion, migration, and epithelial-mesenchymal transition (EMT) in cancer. In this research, human malignant glioma cells were stimulated with transforming growth factor beta 1 (TGF-beta1) and siCCR7. The data show that CCR7 mediates TGF-beta1-induced EMT, migration, and invasion in U251 and U87 cells and that these effects of TGF-beta1 were reversed by treatment with siCCR7 or a CCR7 neutralizing antibody. Importantly, the TGF-beta1-mediated increase in nuclear factor kappaB (NF-kappaB) activity in human glioma cells was reduced by treatment with siCCR7 or a CCR7 neutralizing antibody. Furthermore, CCR7 was shown to mediate TGF-beta1-induced glioma cancer cell migration by activating matrix metalloproteinase 2 (MMP2)/9. Our results indicate that CCR7 mediates TGF-beta1-induced MMP2/9 expression through NF-kappaB signaling, thus facilitating glioma cell migration, invasion, and EMT, all of which progressively increase with glioblastoma progression. These findings indicate that CCR7 is a potential therapeutic target for malignant glioma. PMID- 28817315 TI - Experience of menopause in women with inflammatory bowel disease: pilot study. AB - OBJECTIVE: Inflammatory bowel diseases (IBD) are debilitating chronic intestinal diseases requiring extensive medical intervention. Little is known how IBD symptoms and treatments affect menopause experience and quality of life. The study's goal was to investigate the relationship between IBD and menopause. METHOD: Women with IBD, between the ages of 30 and 65 years, were recruited from an outpatient IBD clinic. They completed surveys on obstetric, medical, and IBD history and clinical disease activity. Quality of life was assessed using the validated menopause-specific quality of life (MENQOL) questionnaire. RESULTS: Seventy-one women (47 Crohn's disease, 22 ulcerative colitis, and two indeterminate colitis, median age 45 years) enrolled into the study. Younger age of IBD diagnosis was correlated with younger age of last menstrual period (r = 0.697). IBD severity affected menopause-related quality of life in three MENQOL domains (psychosocial, physical, and sexual); the fourth domain (vasomotor) did not appear to be affected by the severity of IBD clinical disease. CONCLUSION: Women with IBD may experience additional challenges when going through the menopause transition. Our findings support the need for further studies to better inform patients and clinicians on the relationship between IBD and menopause to optimize patient care. PMID- 28817314 TI - Role of geraniol against lead acetate-mediated hepatic damage and their interaction with liver carboxylesterase activity in rats. AB - In this study, the effect of geraniol (50 mg/kg for 30 d), a natural antioxidant and repellent/antifeedant monoterpene, in a rat model of lead acetate-induced (500 ppm for 30 d) liver damage was evaluated. Hepatic malondialdehyde increased in the lead acetate group. Reduced glutathione unchanged, but glutathione S transferase, glutathione reductase, as well as carboxylesterase activities decreased in geraniol, lead acetate and geraniol + lead acetate groups. 8-OhDG immunoreactivity, mononuclear cell infiltrations and hepatic lead concentration were lower in the geraniol + lead acetate group than the lead acetate group. Serum aspartate aminotransferase and alanine aminotransferase activities increased in the Pb acetate group. In conclusion, lead acetate causes oxidative and toxic damage in the liver and this effect can reduce with geraniol treatment. However, we first observed that lead acetate, as well as geraniol, can affect liver carboxylesterase activity. PMID- 28817316 TI - Filling quality of the reports of adverse drug reactions received at the Pharmacovigilance Centre of Sao Paulo (Brazil): missing information hinders the analysis of suspected associations. AB - BACKGROUND: The completeness and accuracy of the reports of suspected adverse drug reactions is important in pharmacovigilance. The aim of the present study was to analyze the quality of the information included in the reports sent to the Pharmacovigilance Centre of Sao Paulo (Brazil). RESEARCH DESIGN AND METHODS: A sample of 999 reports received from January 2013 to December 2014 was selected. The quality of the filled information was evaluated according to a 'sufficiency' criterion to apply the Karch-Lasagna causality algorithm. RESULTS: There were 820 reports from manufacturers and 179 from health centres. Only 4.4% (44) were fully filled, thus allowing the adequate analysis of the causal relationship between the suspected medication and the adverse event. In 30% of the reports from manufacturers, the information about the critical variables was lacking or incomplete, preventing the adequate evaluation of the report. It was also noted that the reports' poor filling quality was not related with less severity or with old and well-known medicines. CONCLUSIONS: The poor quality of the information included in the reports received by this centre, especially those sent by pharmaceutical manufacturers, hampers the identification of potential safety signals. Measures to improve the quality of the reports must be urgently adopted. PMID- 28817317 TI - Living Outside the Gender Box in Mexico: Testimony of Transgender Mexican Asylum Seekers. AB - OBJECTIVES: To explore preimmigration experiences of violence and postimmigration health status in male-to-female transgender individuals (n = 45) from Mexico applying for asylum in the United States. METHODS: We used a document review process to examine asylum declarations and psychological evaluations of transgender Mexican asylum seekers in the United States from 2012. We coded documents in 2013 and 2014 using NVivo, a multidisciplinary team reviewed them, and then we analyzed them for themes. RESULTS: Mexican transgender asylum applicants experienced pervasive verbal, physical, and sexual abuse from multiple sources, including family, school, community, and police. Applicants also experienced discrimination in school and in the workplace. Applicants immigrated to the United States to escape persistent assaults and threats to their life. Applicants suffered health and psychological effects from their experiences in Mexico that affected opportunities in the United States for employment, education, and social inclusion. CONCLUSIONS: Additional social protections for transgender individuals and antidiscrimination measures in Mexican schools and workplaces are warranted as are increased mental health assessment and treatment, job training, and education services for asylum seekers in the United States. PMID- 28817318 TI - A Way Forward for Bipartisan Health Reform? Democrat and Republican State Legislator Priorities for the Goals of Health Policy. PMID- 28817319 TI - Medicaid Reimbursement for the Female Condom. AB - OBJECTIVES: To examine state-level female condom use through Medicaid from 2004 to 2014, because in 2010, the Patient Protection and Affordable Care Act (ACA) allowed for expanded Medicaid coverage in many states, extending requirements for contraceptive care to more of the poorest women in the United States and to most women with private insurance. METHODS: We collected data via brief survey of Medicaid offices in all 50 states between March 2015 and March 2016. RESULTS: The number of states providing Medicaid reimbursement for the female condom increased 33% (from 25 to 36) since 2007. Twenty-nine states provided data showing low numbers of claims for female condoms but high rates of reimbursement. CONCLUSIONS: This period of heightened access demands that the public health community seize the moment to increase awareness about and promote the female condom among health care professionals and consumers. The pending repeal of the ACA may thwart important gains in access; policies promoting women's reproductive health must be implemented immediately. PMID- 28817320 TI - Tobacco Industry Research on Nicotine Replacement Therapy: "If Anyone Is Going to Take Away Our Business It Should Be Us". AB - Nicotine replacement therapy (NRT) is recommended for tobacco cessation on the basis of pharmaceutical industry research showing its effectiveness when combined with counseling. The tobacco industry opposed NRT when it first appeared in the 1980s but by 2016 was marketing its own NRT products. We used internal tobacco industry documents dated 1960 through 2010 to identify the industry's perceptions of NRT. As early as the 1950s, tobacco companies developed nonsmoked nicotine replacements for cigarettes, but they stopped out of concern that marketing such products would trigger Food and Drug Administration regulation of cigarettes. In the 1990s, after pharmaceutical companies began selling prescription NRT, tobacco companies found that many smokers used NRT to supplement smoking rather than to quit. In 2009, once the Food and Drug Administration began regulating tobacco, tobacco companies restarted their plans to capture the nicotine market. Although the tobacco industry initially viewed NRT as a threat, it found that smokers often combined NRT with smoking rather than using it as a replacement and began marketing their own NRT products. PMID- 28817322 TI - Diverging Life Expectancies and Voting Patterns in the 2016 US Presidential Election. AB - OBJECTIVES: To assess whether voting patterns in the 2016 US presidential election were correlated with long-run trends in county life expectancy. METHODS: I examined county-level voting data from the 2008 and 2016 presidential elections and assessed Donald Trump's share of the 2016 vote, change in the Republican vote share between 2008 and 2016, and changes in absolute numbers of Democratic and Republican votes. County-level estimates of life expectancy at birth were obtained for 1980 and 2014 from the Institute for Health Metrics and Evaluation. RESULTS: Changes in county life expectancy from 1980 to 2014 were strongly negatively associated with Trump's vote share, with less support for Trump in counties experiencing greater survival gains. Counties in which life expectancy stagnated or declined saw a 10-percentage-point increase in the Republican vote share between 2008 and 2016. CONCLUSIONS: Residents of counties left out from broader life expectancy gains abandoned the Democratic Party in the 2016 presidential election. Since coming to power, the Trump administration has proposed cuts to health insurance for the poor, social programs, health research, and environmental and worker protections, which are key determinants of population health. Health gaps likely will continue to widen without significant public investment in population health. PMID- 28817321 TI - Community Health Worker Impact on Chronic Disease Outcomes Within Primary Care Examined Using Electronic Health Records. AB - OBJECTIVES: To investigate community health worker (CHW) effects on chronic disease outcomes using electronic health records (EHRs). METHODS: We examined EHRs of 32 147 patients at risk for chronic disease during 2012 to 2015. Variables included contact with clinic-based CHWs, vitals, and laboratory tests. We estimated a mixed model for all outcomes. RESULTS: Within-group findings showed statistically significant improvements in chronic disease indicators after exposure to CHWs. In health center 1, HbA1c (glycated hemoglobin) decreased 0.15 millimoles per mole (95% confidence interval [CI] = -0.24, -0.06), body mass index decreased 0.29 kilograms per meter squared (CI = -0.39, -0.20), and total cholesterol decreased 11.9 milligrams per deciliter (CI = -13.5, -10.2). In health center 2, HbA1c decreased 0.43 millimoles per mole (CI = -0.7, -0.17), body mass index decreased by 0.08 kilograms per meter squared (CI = -0.14, 0.02), and triglycerides decreased by 22.50 milligrams per deciliter (CI = -39.0, -6.0). Total cholesterol of 3.62 milligrams per deciliter (CI = -6.6, -0.6) in health center 1 was the only improvement tied to CHW contact. CONCLUSIONS: Although patients' chronic disease indicators consistently improved, between group models provided no additional evidence of impact. EHRs' evolution may elucidate CHW contributions moving forward. PMID- 28817323 TI - Rural Versus Urban Use of Traditional and Emerging Tobacco Products in the United States, 2013-2014. AB - OBJECTIVES: To examine urban-rural differences in US prevalences of traditional and emerging tobacco product use as well as dual or polytobacco use of these products. METHODS: Our data were derived from wave 1 (2013-2014) of the Population Assessment of Tobacco and Health (PATH) Study. We estimated weighted prevalences of adult tobacco use across urban-rural geographies and examined prevalences classified by gender, poverty level, and region of the country. RESULTS: Nationally, cigarette use and smokeless tobacco use, as well as dual or polytobacco use of traditional products, were more prevalent in rural than in urban areas. Conversely, cigarillo and hookah use and dual or polytobacco use of emerging products were higher in urban areas. There was no significant urban rural difference in use of e-cigarettes. Gender, poverty, and region of the country did not seem to be driving most urban-rural differences, although differences related to cigarillo use and dual or polytobacco use of emerging products became nonsignificant after control for covariates. CONCLUSIONS: Our findings highlight important urban-rural differences in tobacco use. Whether the changing tobacco product landscape will contribute to a continuation of rural health disparities remains to be seen. PMID- 28817324 TI - Legal, Practical, and Ethical Considerations for Making Online Patient Portals Accessible for All. AB - Largely driven by the financial incentives of the HITECH Act's Meaningful Use program as part of federal US health care reform, access to portal Web sites has rapidly expanded, allowing many patients to view their medical record information online. Despite this expansion, there is little attention paid to the accessibility of portals for more vulnerable patient populations-especially patients with limited health literacy or limited English proficiency, and individuals with disabilities. We argue that there are potential legal mandates for improving portal accessibility (e.g., the Civil Rights and the Rehabilitation Acts), as well as ethical considerations to prevent the exacerbation of existing health and health care disparities. To address these legal, practical, and ethical considerations, we present standards and broad recommendations that could greatly improve the reach and impact of portal Web sites. PMID- 28817325 TI - HIV Preexposure Prophylaxis and Condomless Sex: Disentangling Personal Values From Public Health Priorities. AB - Daily HIV preexposure prophylaxis (PrEP) is an effective form of HIV protection that remains unknown and inaccessible for many people in the United States despite receiving federal approval over five years ago. PrEP is supported by the public health community, but forgoing condoms while taking PrEP has proven controversial; this controversy may be contributing to the lag in PrEP uptake. We argue that limiting PrEP access based on anticipated or actual sexual behavior contradicts the goals of public health research and practice and is not scientifically justified. As evidence for the effectiveness of novel forms of biomedical HIV protection emerges, public health professionals need to accept new definitions of "protected sex" and ensure that their personal values do not override empirical evidence when determining public health priorities. PMID- 28817326 TI - Standard Period Life Table Used to Compute the Life Expectancy of Diseased Subpopulations: More Confusing Than Helpful. AB - Life expectancy (LE) based on a period life table (PLT) traditionally serves as a general population summary metric. It is, however, becoming more frequently reported for chronically afflicted subpopulations. In general populations, there is always an obvious real cohort sharing the hypothetical PLT cohort characteristics, and the LE estimate is intuitively understood as that real cohort mean survival time, assuming constancy of death risks. In diseased subpopulations, the correspondence between the hypothetical cohort and a real cohort is not straightforward. Furthermore, the excess mortality of chronic diseases usually changes according to age at onset and time since onset. The standard PLT method does not allow for proper control of these issues, so the LE estimate can only be deemed valid under specific assumptions. Without clear statements about the real cohort to whom the estimate is intended and the assumptions allowing disregard of the effect of age at onset and time since onset, LEs of afflicted subpopulations computed with the PLT are only abstract numbers summarizing mortality rates. If called "life expectancy," they can be seriously misleading. The same applies to health-adjusted LE. PMID- 28817327 TI - Violent Death Reporting in Maryland: Demographic Variability in Data Completeness. AB - OBJECTIVES: To analyze the completeness of precipitating circumstance information recorded in the Maryland Violent Death Reporting System and identify limitations that could affect the system's utility. METHODS: We reviewed all violent deaths among Maryland residents for the years 2003 through 2014 (n = 19 161). We assessed the presence of precipitating circumstance data (abstracted from medical examiner and police reports) by manner of death and demographic characteristics. We further evaluated homicide records with multivariable regression. RESULTS: Demographic variation in circumstance reporting was most pronounced for homicide. Circumstances were known for 53.2% of homicide cases, and this percentage was lower among non-Latino Blacks (48.2%), males (50.7%), those aged 18 to 25 years (47.9%), those residing in jurisdictions with higher-than-average homicide rates (46.1%), and those who died outside in a public place (43.4%) or in a correctional facility (48.9%). With the exception of male gender, these factors were significantly associated with circumstance reporting when we controlled for demographic and situational variables. CONCLUSIONS: Circumstance reporting was least likely among groups most at risk for homicide in Maryland. Collection of circumstance data for the most affected groups should be strengthened to help develop better prevention strategies. PMID- 28817328 TI - Lead Content of Sindoor, a Hindu Religious Powder and Cosmetic: New Jersey and India, 2014-2015. AB - OBJECTIVES: To assess the extent of lead content of sindoor, a powder used by Hindus for religious and cultural purposes, which has been linked to childhood lead poisoning when inadvertently ingested. METHODS: We purchased 95 samples of sindoor from 66 South Asian stores in New Jersey and 23 samples from India and analyzed samples with atomic absorption spectrophotometry methods for lead. RESULTS: Analysis determined that 79 (83.2%) sindoor samples purchased in the United States and 18 (78.3%) samples purchased in India contained 1.0 or more micrograms of lead per gram of powder. For US samples, geometric mean concentration was 5.4 micrograms per gram compared with 28.1 micrograms per gram for India samples. The maximum lead content detected in both US and India samples was more than 300 000 micrograms per gram. Of the examined US sindoor samples, 19% contained more than 20 micrograms per gram of lead (US Food and Drug Administration [FDA] limit); 43% of the India samples exceeded this limit. CONCLUSIONS: Results suggested continued need for lead monitoring in sindoor in the United States and in sindoor carried into the United States by travelers from India, despite FDA warnings. PMID- 28817329 TI - Assessing Years of Life Lost Versus Number of Deaths in the United States, 1995 2015. AB - OBJECTIVES: To assess years of life lost to each cause of death in the United States between 1995 and 2015, and compare it with the number of deaths. METHODS: We used Vital Statistics mortality data and defined "life-years lost" as remaining life expectancy for each decedent's age, sex, and race. We calculated the share of life-years lost to each cause of death in each year, and examined reasons for changes. RESULTS: In 2015, heart disease caused the most deaths, but cancer caused 23% more life-years lost. Life-years lost to heart disease declined 6% since 1995, whereas life-years lost to cancer increased 16%. The increase for cancer was entirely attributable to population growth and longer life expectancy; had these factors remained constant, life-years lost to heart disease and cancer would have fallen 56% and 38%, respectively. Accidents (including overdoses), suicides, and homicides each caused twice the share of life-years lost as deaths. Measuring life-years lost highlighted racial disparities in heart disease, homicides, and perinatal conditions. CONCLUSIONS: Life-years lost may provide additional context for understanding long-term mortality trends. PMID- 28817330 TI - Readiness to Vaccinate Critical Personnel During an Influenza Pandemic, United States, 2015. AB - OBJECTIVES: To assess the readiness to vaccinate critical infrastructure personnel (CIP) involved in managing public works, emergency services, transportation, or any other system or asset that would have an immediate debilitating impact on the community if not maintained. METHODS: We analyzed self reported planning to vaccinate CIP during an influenza pandemic with data from 2 surveys: (1) the Program Annual Progress Assessment of immunization programs and (2) the Pandemic Influenza Readiness Assessment of public health emergency preparedness programs. Both surveys were conducted in 2015. RESULTS: Twenty-six (43.3%) of 60 responding public health emergency preparedness programs reported having an operational plan to identify and vaccinate CIP, and 16 (26.2%) of 61 responding immunization programs reported knowing the number of CIP in their program's jurisdictions. CONCLUSIONS: Many programs may not be ready to identify and vaccinate CIP during an influenza pandemic. Additional efforts are needed to ensure operational readiness to vaccinate CIP during the next influenza pandemic. PMID- 28817331 TI - Urban-Rural Differences in Suicide in the State of Maryland: The Role of Firearms. AB - OBJECTIVES: To assess whether the use of firearms explains rural-urban differences in suicide rates. METHODS: We performed a retrospective analysis on all 6196 well-characterized adult suicides in Maryland from 2003 through 2015. We computed rate ratios by using census data and then stratified by sex, with adjustment for age and race. RESULTS: Suicide rates were higher in rural compared with urban counties. However, the higher rural suicide rates were limited to firearm suicides (incident rate ratio [IRR] = 1.66; 95% confidence interval [CI] = 1.20, 2.31). Nonfirearm suicide rates were not significantly higher in rural settings. Furthermore, 89% of firearm suicides occurred in men and the higher rural firearm suicide rate was limited to men (IRR = 1.36; 95% CI = 1.09, 1.69). Women were significantly less likely to complete suicide in rural areas (IRR = 0.63; 95% CI = 0.43, 0.94), regardless of method. CONCLUSIONS: Male firearm use drives the increased rate of suicide in rural areas. The opposite associations between urbanicity and suicide in men and women may be driven by the male preference for firearms as a method for committing suicide. PMID- 28817332 TI - Individual Versus Community-Level Risk Compensation Following Preexposure Prophylaxis of HIV. AB - We analyzed the concept of risk compensation and how it has been applied in HIV prevention, paying particular attention to the strategy of HIV preexposure prophylaxis (PrEP). In risk compensation, reduced perceptions of risk after the introduction of a preventative intervention lead to more frequent risk-taking behavior. Such a change may undermine the intervention's protective benefits. We found that many studies purporting to investigate risk compensation do not assess or report changes in perceptions of risk, instead relying on behavioral measures. Our analysis suggests a complex and sometimes counterintuitive relationship between the introduction of a new prevention intervention, perceptions of HIV risk, and subsequent changes in behavior. As PrEP is introduced, we believe comprehensive assessment of community-level risk compensation-that is, changes in risk perceptions and behavior as a result of increased optimism about avoiding HIV among people not directly protected by PrEP-should not be omitted. We therefore suggest ways to assess prevention optimism and community-level risk compensation. PMID- 28817333 TI - The Epidemic of Despair Among White Americans: Trends in the Leading Causes of Premature Death, 1999-2015. AB - OBJECTIVES: To evaluate trends in premature death rates by cause of death, age, race, and urbanization level in the United States. METHODS: We calculated cause specific death rates using the Compressed Mortality File, National Center for Health Statistics data for adults aged 25 to 64 years in 2 time periods: 1999 to 2001 and 2013 to 2015. We defined 48 subpopulations by 10-year age groups, race/ethnicity, and county urbanization level (large urban, suburban, small or medium metropolitan, and rural). RESULTS: The age-adjusted premature death rates for all adults declined by 8% between 1999 to 2001 and 2013 to 2015, with decreases in 39 of the 48 subpopulations. Most decreases in death rates were attributable to HIV, cardiovascular disease, and cancer. All 9 subpopulations with increased death rates were non-Hispanic Whites, largely outside large urban areas. Most increases in death rates were attributable to suicide, poisoning, and liver disease. CONCLUSIONS: The unfavorable recent trends in premature death rate among non-Hispanic Whites outside large urban areas were primarily caused by self destructive health behaviors likely related to underlying social and economic factors in these communities. PMID- 28817335 TI - Killed by Police: Validity of Media-Based Data and Misclassification of Death Certificates in Massachusetts, 2004-2016. AB - OBJECTIVES: To assess the validity of demographic data reported in news media based data sets for persons killed by police in Massachusetts (2004-2016) and to evaluate misclassification of these deaths in vital statistics mortality data. METHODS: We identified 84 deaths resulting from police intervention in 4 news media-based data sources (WGBH News, Fatal Encounters, The Guardian, and The Washington Post) and, via record linkage, conducted matched-pair analyses with the Massachusetts mortality data. RESULTS: Compared with death certificates, there was near-perfect correlation for age in all sources (Pearson r > 0.99) and perfect concordance for gender. Agreement for race/ethnicity ranged from perfect (The Counted and The Washington Post) to high (Fatal Encounters Cohen's kappa = 0.92). Among the 78 decedents for whom finalized International Classification of Diseases, 10th Revision (ICD-10), codes were available, 59 (75.6%) were properly classified as "deaths due to legal intervention." CONCLUSIONS: In Massachusetts, the 4 media-based sources on persons killed by police provide valid demographic data. Misclassification of deaths due to legal intervention in the mortality data does, however, remain a problem. Replication of the study in other states and nationally is warranted. PMID- 28817336 TI - Children's Access to Dental Care Affected by Reimbursement Rates, Dentist Density, and Dentist Participation in Medicaid. AB - OBJECTIVES: To assess the relation between Medicaid reimbursement rates and access to dental care services in the context of dentist density and dentist participation in Medicaid in each state. METHODS: Data were from Early and Periodic Screening, Diagnostic, and Treatment reports for 2014, Medicaid reimbursement rate in 2013, dentist density in 2014, and dentist participation in Medicaid in 2014. We assessed patterns of mediation or moderation. RESULTS: Reimbursement rates and access to dental care were directly related at the state level, but no evidence indicated that higher reimbursement rates resulted in overuse of dental services for those who had access. The relation between reimbursement rates and access to care was moderated by dentist density and dentist participation in Medicaid. We estimate that more than 1.8 million additional children would have had access to dental care if reimbursement rates were higher in states with low rates. CONCLUSIONS: Children who access the dental care system receive care, but reimbursement may significantly affect access. States with low dentist density and low dentist participation in Medicaid may be able to improve access to dental services significantly by increasing reimbursement rates. PMID- 28817334 TI - Community Health Worker Support for Disadvantaged Patients With Multiple Chronic Diseases: A Randomized Clinical Trial. AB - OBJECTIVES: To determine whether a community health worker (CHW) intervention improved outcomes in a low-income population with multiple chronic conditions. METHODS: We conducted a single-blind, randomized clinical trial in Philadelphia, Pennsylvania (2013-2014). Participants (n = 302) were high-poverty neighborhood residents, uninsured or publicly insured, and diagnosed with 2 or more chronic diseases (diabetes, obesity, tobacco dependence, hypertension). All patients set a disease-management goal. Patients randomly assigned to CHWs also received 6 months of support tailored to their goals and preferences. RESULTS: Support from CHWs (vs goal-setting alone) led to improvements in several chronic diseases (changes in glycosylated hemoglobin: -0.4 vs 0.0; body mass index: -0.3 vs -0.1; cigarettes per day: -5.5 vs -1.3; systolic blood pressure: -1.8 vs -11.2; overall P = .08), self-rated mental health (12-item Short Form survey; 2.3 vs -0.2; P = .008), and quality of care (Consumer Assessment of Healthcare Providers and Systems; 62.9% vs 38%; P < .001), while reducing hospitalization at 1 year by 28% (P = .11). There were no differences in patient activation or self-rated physical health. CONCLUSIONS: A standardized CHW intervention improved chronic disease control, mental health, quality of care, and hospitalizations and could be a useful population health management tool for health care systems. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01900470. PMID- 28817337 TI - Oral Health Integration Into a Pediatric Practice and Coordination of Referrals to a Colocated Dental Home at a Federally Qualified Health Center. AB - We have integrated preventive oral health measures into preventive care visits for children at a federally qualified health center in Boston, Massachusetts. The program, started in 2015, covers 3400 children and has increased universal caries risk screening in primary care to 85%, fluoride varnish application rates to 80%, and referrals to a dental home to 35%. We accomplished this by minimizing pressures on providers' workflow, empowering medical assistants to lead the initiative, and utilizing data-driven improvement strategies, alongside colocated coordinated care. PMID- 28817338 TI - Supporting Breastfeeding Moms at Work: How a Doctor's Note Can Make the Difference. AB - One of the most critical junctures for community support of breastfeeding is the mother's return to work. When breastfeeding workers have access to both time and space for expressing breast milk, they are more likely to breastfeed for the recommended term, yet many mothers still struggle to access these simple accommodations in their workplace. Healthcare providers can and should aid nursing mothers in accessing these accommodations. One tangible way to offer support for continued breastfeeding upon return to work is to provide notes for lactation accommodation in the workplace. PMID- 28817339 TI - Changing of the Guard at GTMB. PMID- 28817340 TI - The Half-Life of Serum Thymidine Kinase 1 Concentration Is an Important Tool for Monitoring Surgical Response in Patients with Lung Cancer: A Meta-Analysis. AB - AIMS: In this meta-analysis, we evaluated the usefulness of serum thymidine kinase 1 concentration (STK1c) for monitoring the outcome of extensive open surgery in patients with lung cancer. We also compared STK1c between a healthy population and patients with benign and malignant lung tumors to assess its potential value for early detection of lung cancer and for distinguishing between benign lung disease and malignant cancer. MATERIALS AND METHODS: Related studies were retrieved from publications in PubMed, Cochrane, China National Knowledge Infrastructure, Wanfang databases, and Internet searches. Correlation was evaluated using weighted mean difference. Fixed or random effect models were selected for data analyses based on heterogeneity tested with the chi-square test. Publication bias was assessed using a funnel plot and Egger's test. RESULTS: Twenty studies were selected for analysis, which showed that STK1c was significantly (p < 0.00001) reduced by 41.7% 1 month after extensive open surgery, approximately corresponding to an STK1c half-life of 1 month. STK1c levels were significantly higher in lung cancer patients than in healthy persons (p < 0.00001) or in patients with benign lung disease (p < 0.00001). There was also a significant difference in STK1c between patients with benign and malignant lung disease (p < 0.0001). CONCLUSIONS: The half-life of STK1c may be an important tool in the clinical evaluation of surgical response in patients with lung cancer. STK1c may also be beneficial in the early detection of lung cancer. PMID- 28817341 TI - Assessment of Interday Glucose Variability in Type 2 Diabetes. PMID- 28817342 TI - Hypoglycemia Risk Related to Double Dose Is Markedly Reduced with Basal Insulin Peglispro Versus Insulin Glargine in Patients with Type 2 Diabetes Mellitus in a Randomized Trial: IMAGINE 8. AB - BACKGROUND: Basal insulin peglispro (BIL) has a peripheral-to-hepatic distribution of action that resembles endogenous insulin and a prolonged duration of action with a flat pharmacokinetic/pharmacodynamic profile at steady state, characteristics that tend to reduce hypoglycemia risk compared to insulin glargine (GL). The primary objective was to demonstrate that clinically significant hypoglycemia (blood glucose <=54 mg/dL [3.0 mmol/L] or symptoms of severe hypoglycemia) occurred less frequently within 84 h after a double dose (DD) of BIL than a DD of GL. METHODS: This was a randomized, double-blind, two period crossover study in patients with type 2 diabetes (T2D) previously treated with insulin (N = 68). For the first 3 weeks of each of the two crossover periods, patients received an individualized dose of BIL or GL once nightly (stable dose for 2 weeks/period). Then, during a 7-day inpatient stay with frequent blood glucose monitoring and standardized meals, one DD of study insulin was given. Glucose was infused if blood glucose was <=54 mg/dL (3.0 mmol/L) or for symptoms of severe hypoglycemia. RESULTS: Within 84 h after the DD, a significantly smaller proportion of patients experienced clinically significant hypoglycemia with BIL compared to GL (BIL, 6.6%; GL, 35.5%; odds ratio for BIL/GL 0.13 [95% confidence interval 0.04-0.39]; P < 0.001). Adverse event profiles were similar for the two insulins. Serum alanine aminotransferase and triglyceride levels were significantly higher with BIL versus GL. CONCLUSIONS: BIL has a markedly lower risk of hypoglycemia than GL when replicating a double-dose error in patients with T2D. PMID- 28817343 TI - Suppression of Choroidal Neovascularization in Mice by Subretinal Delivery of Multigenic Lentiviral Vectors Encoding Anti-Angiogenic MicroRNAs. AB - Lentivirus-based vectors have been used for the development of potent gene therapies. Here, application of a multigenic lentiviral vector (LV) producing multiple anti-angiogenic microRNAs following subretinal delivery in a laser induced choroidal neovascularization (CNV) mouse model is presented. This versatile LV, carrying back-to-back RNApolII-driven expression cassettes, enables combined expression of microRNAs targeting vascular endothelial growth factor A (Vegfa) mRNA and fluorescent reporters. In addition, by including a vitelliform macular dystrophy 2 (VMD2) promoter, expression of microRNAs is restricted to the retinal pigment epithelial (RPE) cells. Six days post injection (PI), robust and widespread fluorescent signals of eGFP are already observed in the retina by funduscopy. The eGFP expression peaks at day 21 PI and persists with stable expression for at least 9 months. In parallel, prominent AsRED co-expression, encoded from the VMD2-driven microRNA expression cassette, is evident in retinal sections and flat-mounts, revealing RPE-specific expression of microRNAs. Furthermore, LV-delivered microRNAs targeting the Vegfa gene in RPE cells reduced the size of laser-induced CNV in mice 28 days PI, as a consequence of diminished VEGF levels, suggesting that LVs delivered locally are powerful tools in the development of gene therapy-based strategies for treatment of age-related macular degeneration. PMID- 28817346 TI - Performances on simulator and da Vinci robot on subjects with and without surgical background. AB - OBJECTIVE: To assess whether previous training in surgery influences performance on da Vinci Skills Simulator and da Vinci robot. MATERIAL AND METHODS: In this prospective study, thirty-seven participants (11 medical students, 17 residents, and 9 attending surgeons) without previous experience in laparoscopy and robotic surgery performed 26 exercises at da Vinci Skills Simulator. Thirty-five then executed a suture using a da Vinci robot. RESULTS: The overall scores on the exercises at the da Vinci Skills Simulator show a similar performance among the groups with no statistically significant pair-wise differences (p < .05). The quality of the suturing based on the unedited videos of the test run was similar for the intermediate (7 (4, 10)) and expert group (6.5 (4.5, 10)), and poor for the untrained groups (5 (3.5, 9)), without statistically significant difference (p < .05). CONCLUSION: This study showed, for subjects new to laparoscopy and robotic surgery, insignificant differences in the scores at the da Vinci Skills Simulator and at the da Vinci robot on inanimate models. PMID- 28817344 TI - A Guide to Approaching Regulatory Considerations for Lentiviral-Mediated Gene Therapies. AB - Lentiviral vectors are increasingly the gene transfer tool of choice for gene or cell therapies, with multiple clinical investigations showing promise for this viral vector in terms of both safety and efficacy. The third-generation vector system is well characterized, effectively delivers genetic material and maintains long-term stable expression in target cells, delivers larger amounts of genetic material than other methods, is nonpathogenic, and does not cause an inflammatory response in the recipient. This report aims to help academic scientists and regulatory managers negotiate the governance framework to achieve successful translation of a lentiviral vector-based gene therapy. The focus is on European regulations and how they are administered in the United Kingdom, although many of the principles will be similar for other regions, including the United States. The report justifies the rationale for using third-generation lentiviral vectors to achieve gene delivery for in vivo and ex vivo applications; briefly summarizes the extant regulatory guidance for gene therapies, categorized as advanced therapeutic medicinal products (ATMPs); provides guidance on specific regulatory issues regarding gene therapies; presents an overview of the key stakeholders to be approached when pursuing clinical trials authorization for an ATMP; and includes a brief catalogue of the documentation required to submit an application for regulatory approval of a new gene therapy. PMID- 28817345 TI - Reverse Transcription Quantitative Polymerase Chain Reaction for Detection of and Differentiation Between RNA and DNA of HIV-1-Based Lentiviral Vectors. AB - The purpose of the described method is the detection of and differentiation between RNA and DNA of human immunodeficiency virus (HIV)-derived lentiviral vectors (LV) in cell culture supernatants and swab samples. For the analytical surveillance of genetic engineering, operations methods for the detection of the HIV-1-based LV generations are required. Furthermore, for research issues, it is important to prove the absence of LV particles for downgrading experimental settings in terms of the biosafety level. Here, a quantitative polymerase chain reaction method targeting the long terminal repeat U5 subunit and the start sequence of the packaging signal psi is described. Numerous controls are included in order to monitor the technical procedure. PMID- 28817347 TI - Introduction of Dr. Gerald W. Esch, The 2016-2017 President of ASP. PMID- 28817348 TI - Palliative Care Consults in U.S. Nursing Homes: Not Just for the Dying. AB - BACKGROUND: Little is known about nursing home (NH) residents who receive palliative care (PC) consults in the United States. OBJECTIVE: Separately by short versus long (>=90 days) stays, to describe NH residents with PC consults compared to a prevalent NH sample. DESIGN: Descriptive longitudinal study. SETTING/SUBJECTS: NH residents in 2008-2010 in 54 NHs. MEASUREMENTS: Resident characteristics came from merged Medicare and NH data from the Centers for Medicare and Medicaid Services and consult information from two PC organizations that were the sole PC consult providers in the study NHs. RESULTS: Four percent of all NH residents received a PC consult during the study period. Two-thirds had short NH stays, and 81% of short- and 27% of long-stay consult recipients were on the Medicare skilled nursing facility (SNF) benefit at the time of initial consult. Short- and long-stay NH residents with PC consults differed not only, in many respects, from NH residents generally but also from each other. Despite these differences, half of short-stay and 57% of long-stay residents were alive six months after initial consults. Residents dead at six months died at 33.5 and 34.5 median days (respectively) after initial consults. At six months, 65% of surviving short-stay consult recipients were in the community without hospice, while 59% of long-stay residents were in the NH without hospice or Medicare SNF care. CONCLUSION: The high rates of SNF care and six-month survival among NH recipients of PC consults demonstrate the utility of these consults before Medicare hospice eligibility or use. PMID- 28817349 TI - Response to the Letter to the Editor by Cullinane & Amir. PMID- 28817350 TI - American Society of Parasitologists Ninety-Second Annual Business Meeting 1 July 2017 Hilton Palacio del Rio, San Antonio, Texas. PMID- 28817351 TI - Response to: Preparing medical students for the e-patient: Is a theoretical grounding required? PMID- 28817353 TI - Measuring mental workload with the NASA-TLX needs to examine each dimension rather than relying on the global score: an example with driving. AB - The distinction between several components of mental workload is often made in the ergonomics literature. However, measurements used are often established from a global score, notably with several questionnaires that originally reflect several dimensions. The present study tested the effect of driving situation complexity, experience and subjective levels of tension and alertness on each dimension of the NASA-TLX questionnaire of workload, in order to highlight the potential influence of intrinsic, extraneous and germane load factors. The results showed that, in complex situation, mental, temporal and physical demand (load dimensions) increased, and that novice drivers presented high physical demand when subjective tension was low on performance. Moreover, increase of mental and physical demand increased effort. It thus, appears essential to distinguish the different components of mental workload used in the NASA-TLX questionnaire. Practitioner Summary: Currently, global score of NASA-TLX questionnaire is used to measure mental workload. Here, we considered independently each dimension of NASA-TLX, and results showed that mental load factors (driving situation complexity, experience, subjective tension and alertness) had a different effect on dimensions, questioning global score use to evaluate workload. PMID- 28817352 TI - ARHGAP29 Mutation Is Associated with Abnormal Oral Epithelial Adhesions. AB - Nonsyndromic cleft lip and/or palate (NSCL/P) is a prevalent birth defect of complex etiology. Previous studies identified mutations in ARHGAP29 associated with an increased risk for NSCL/P. To investigate the effects of ARHGAP29 in vivo, we generated a novel murine allele by inserting a point mutation identified in a patient with NSCL/P. This single-nucleotide variation of ARHGAP29 translates to an early nonsense mutation (K326X), presumably resulting in loss-of-function (LoF). Embryos from Arhgap29K326X/+ intercrosses were harvested at various time points. No homozygous Arhgap29K326X animals were found in the 45 analyzed litters, assessed as early as embryonic day 8.5 (e8.5). Coronal sectioning of e13.5 and e14.5 heads revealed that 59% of Arhgap29K326X/+ mice ( n = 37) exhibited improper epithelial contact between developing oral structures, while none were observed in wild types ( n = 10). In addition, Arhgap29K326X/+ embryos exhibited a significantly higher percentage of maxillary epithelium in contact with mandibular epithelium. Immunofluorescent analyses of the periderm and oral adhesions revealed the presence of Arhgap29 in periderm cells. These cells were p63 negative, keratin 17 positive, and keratin 6 positive and present at sites of adhesion, although occasionally disorganized. Oral adhesions did not appear to impair palatogenesis, as all analyzed Arhgap29K326X/+ embryos showed confluent palatal mesenchyme and epithelium at e18.5 ( n = 16), and no mice were found with a cleft at birth. Collectively, our data demonstrate that ARHGAP29 is required for embryonic survival and that heterozygosity for LoF variants of Arhgap29 increases the incidence and length of oral adhesions at a critical time point during orofacial development. In conclusion, we validate the LoF nature of the human K326X mutation in vivo and reveal a previously unknown effect of Arhgap29 in murine craniofacial development. PMID- 28817354 TI - Response to: Further evidence for curricular influence on student connectedness. PMID- 28817355 TI - Total training load may explain similar strength gains and muscle hypertrophy seen in aged rats submitted to resistance training and anabolic steroids. AB - This study aimed to quantify training parameters and analyze the morphological response of aged muscles submitted to resistance training and anabolic steroids. Aged Wistar rats were divided into groups: C - initial control; CF - final control; CAS - control with anabolic steroid, RT - resistance training, and RTA - resistance training with anabolic steroid. Maximum carried load, absolute and relative loads increased significantly in RT and RTA. RTA demonstrated greater relative load than RT. Average total volume, total climbing volume, relative total volume, relative total climbing volume, and mean climbing volume were similar between groups RT and RTA. For soleus, CAS, RT, and RTA enlarged cross sectional area of type I fibers and nuclear ratio. As for type II fibers, RTA was higher than C and CF. For plantaris, RT and RTA showed significant increases in myofibers type I compared to C and CF. For type II fibers, RTA showed a significant increase compared to C and CF. Regarding the nuclear ratio, RT and RTA showed a higher ratio than C, CF, and CAS. Our results demonstrated that both RT and RTA were not different among the analyzed morphological parameters. This fact can be explained by the absence of differences found in the training variables analyzed. PMID- 28817356 TI - American Society of Parasitologists One Hundred and Seventh Annual Council Meeting 28 June 2017 The Hilton Palacio del Rio, San Antonio, Texas. PMID- 28817357 TI - Reading Qualitative Research. PMID- 28817358 TI - Evaluation of Gastric Conduit Perfusion During Esophagectomy with Indocyanine Green Fluorescence Imaging. AB - BACKGROUND: Anastomotic leakage is a determining factor of morbidity and mortality after an esophagectomy. An adequate blood supply of the gastric conduit is vital to prevent this complication. We aimed to determine the feasibility and usefulness of indocyanine green (ICG) fluorescence imaging to evaluate the gastric conduit perfusion during an esophagectomy. METHODS: Patients with distal esophageal cancer or esophagogastric junction cancer scheduled for esophagectomy were enrolled in this study. After pulling up the gastric conduit into the chest and before performing the anastomosis, 5 mg of ICG was injected as a bolus. Visual assessment of the blood supply of the gastric conduit was compared with the ICG fluorescence imaging pattern of perfusion. RESULTS: Five patients were included in this study. Hybrid Ivor Lewis esophagectomy (laparoscopic abdomen and right thoracotomy) was performed in all cases. In all patients, visual assessment of the perfusion of the stomach determined that the conduit was well perfused. In two patients (40%), ICG fluorescence showed an inadequate blood supply of the conduit's tip. Resection of the devitalized portion of the conduit was performed in these two patients. No anastomotic leaks were recorded, and all patients had an uneventful postoperative course. CONCLUSIONS: Visual assessment of the gastric conduit may underestimate perfusion and inadequate blood supply. ICG fluorescence imaging is a promising tool to determine the gastric conduit perfusion during an esophagectomy. Prospective studies with larger series are warranted to confirm the usefulness of ICG fluorescence imaging during an esophagectomy. PMID- 28817359 TI - Developing the Storyline for an Advance Care Planning Video for Surgery Patients: Patient-Centered Outcomes Research Engagement from Stakeholder Summit to State Fair. AB - BACKGROUND: Patient-centered outcomes research (PCOR) methods and social learning theory (SLT) require intensive interaction between researchers and stakeholders. Advance care planning (ACP) is valuable before major surgery, but a systematic review found no extant perioperative ACP tools. Consequently, PCOR methods and SLT can inform the development of an ACP educational video for patients and families preparing for major surgery. OBJECTIVE: The objective is to develop and test acceptability of an ACP video storyline. DESIGN: The design is a stakeholder guided development of the ACP video storyline. Design-thinking methods explored and prioritized stakeholder perspectives. Patients and family members evaluated storyboards containing the proposed storyline. SETTING/SUBJECTS: The study was conducted at hospital outpatient surgical clinics, in-person stakeholder summit, and the 2014 Maryland State Fair. MEASUREMENTS: Measurements are done through stakeholder engagement and deidentified survey. RESULTS: Stakeholders evaluated and prioritized evidence from an environmental scan. A surgeon, family member, and palliative care physician team iteratively developed a script featuring 12 core themes and worked with a medical graphic designer to translate the script into storyboards. For 10 days, 359 attendees of the 2014 Maryland State Fair evaluated the storyboards and 87% noted that they would be "very comfortable" or "comfortable" seeing the storyboard before major surgery, 89% considered the storyboards "very helpful" or "helpful," and 89% would "definitely recommend" or "recommend" this story to others preparing for major surgery. CONCLUSIONS: Through an iterative process utilizing diverse PCOR engagement methods and informed by SLT, storyboards were developed for an ACP video. Field testing revealed the storyline to be highly meaningful for surgery patients and family members. PMID- 28817362 TI - In Response to "Microbial Diversity in Milk of Women With Mastitis: Potential Role of Coagulase-Negative Staphylococci, Viridans Group Streptococci, and Corynebacteria". PMID- 28817361 TI - Twelve tips for creating an academic teaching portfolio. AB - An academic teaching portfolio is not only a requirement at many academic teaching institutions, but it is also important in a medical educator's growth and development through documentation, reflection, evaluation, and change. Creating an academic portfolio may appear daunting at first but with careful advanced preparation, organized evidence collection of your educational work, proof of scholarship, and thorough documentation of self-reflection and change, you can produce a successful product that accurately represents your educational beliefs, accomplishments, and growth throughout your career. This article provides medical educators with twelve steps for creating a successful academic teaching portfolio. PMID- 28817360 TI - Closing the Gap: Mouse Models to Study Adhesion in Secondary Palatogenesis. AB - Secondary palatogenesis occurs when the bilateral palatal shelves (PS), arising from maxillary prominences, fuse at the midline, forming the hard and soft palate. This embryonic phenomenon involves a complex array of morphogenetic events that require coordinated proliferation, apoptosis, migration, and adhesion in the PS epithelia and underlying mesenchyme. When the delicate process of craniofacial morphogenesis is disrupted, the result is orofacial clefting, including cleft lip and cleft palate (CL/P). Through human genetic and animal studies, there are now hundreds of known genetic alternations associated with orofacial clefts; so, it is not surprising that CL/P is among the most common of all birth defects. In recent years, in vitro cell-based assays, ex vivo palate cultures, and genetically engineered animal models have advanced our understanding of the developmental and cell biological pathways that contribute to palate closure. This is particularly true for the areas of PS patterning and growth as well as medial epithelial seam dissolution during palatal fusion. Here, we focus on epithelial cell-cell adhesion, a critical but understudied process in secondary palatogenesis, and provide a review of the available tools and mouse models to better understand this phenomenon. PMID- 28817363 TI - Linking Positive Affect to Blood Lipids: A Cultural Perspective. AB - Higher levels of positive affect have been associated with better physical health. While positive affect is seen as highly desirable among Westerners, East Asians tend to deemphasize positive affect. Using large probability samples of Japanese and U.S. adult populations, the present study examined the relations of positive affect with serum lipid profiles, known to be strongly predictive of risk for cardiovascular disease, and tested whether their associations depend on cultural contexts. As predicted, positive affect was associated with healthier lipid profiles for Americans but not for Japanese. Further analyses showed that this cultural moderation was mediated by body mass index. This study highlights the role of culture in the link between positive emotions and key biological risk factors of cardiovascular disease. PMID- 28817364 TI - Association between dietary phytoestrogens intakes and prostate cancer risk in Sicily. AB - OBJECTIVE: In this study we aimed to investigate the association between dietary phytoestrogen consumption and prostate cancer in a sample of southern Italian individuals. METHODS: A population-based case-control study on the association between prostate cancer and dietary factors was conducted from January 2015 to December 2016 in a single institution of the municipality of Catania, southern Italy (Registration number: 41/2015). A total of 118 histopathological-verified prostate cancer (PCa) cases and a total of 222 controls were collected. Dietary data was collected by using two food frequency questionnaires. RESULTS: Patients with PCa consumed significantly higher levels of phytoestrogens. Multivariate logistic regression showed that lignans (Q[quartile]4 vs. Q1, OR [odds ratio] = 4.72; p < .05) and specifically, lariciresinol (Q4 vs. Q1, OR = 4.60; p < .05), pinoresinol (Q4 vs. Q1, OR = 5.62; p < .05), matairesinol (Q4 vs. Q1, OR = 3.63; p < .05), secoisolariciresinol (Q4 vs. Q1, OR = 4.10; p < .05) were associated with increased risk of PCa. Furthermore, we found that isoflavones (Q3 vs. Q1, OR = 0.28; p < .05) and specifically, genistein (Q4 vs. Q1, OR = 0.40; p < .05) were associated with reduced risk of PCa. CONCLUSION: We found of an inverse association between dietary isoflavone intake and PCa, while a positive association was found with lignans intake. PMID- 28817365 TI - Effect of Flibanserin Treatment on Body Weight in Premenopausal and Postmenopausal Women with Hypoactive Sexual Desire Disorder: A Post Hoc Analysis. AB - BACKGROUND: Flibanserin, a 5-HT1A agonist and 5-HT2A antagonist, is indicated for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. This post hoc analysis evaluated the effect of flibanserin treatment on body weight in premenopausal and postmenopausal women with HSDD. MATERIALS AND METHODS: This analysis included three 24-week, double blind, placebo-controlled studies of flibanserin 100 mg each bedtime (qhs) in premenopausal women, a similarly designed study in postmenopausal women, and a 52 week, open-label extension study in premenopausal women. RESULTS: In a pooled analysis of premenopausal women, mean baseline body mass index (BMI) was 27.0 kg/m2 in the flibanserin group (n = 1227) and 26.8 kg/m2 in the placebo group (n = 1238). Among patients who completed 24 weeks of treatment, least squares (LS) mean weight change was -1.4 kg in the flibanserin group (n = 1010) and -0.1 kg in the placebo group (n = 1066; p < 0.0001). Weight loss >=5% from baseline was reported in 21.0% of patients who received flibanserin and 7.8% of patients who received placebo; weight loss >=10% was reported in 3.8% and 2.0% of patients, respectively. In postmenopausal women, mean baseline BMI was 27.7 kg/m2 in the flibanserin group (n = 467) and 27.3 kg/m2 in the placebo group (n = 480). LS mean weight change at week 24 was -1.8 kg in the flibanserin group (n = 385) and 0.1 kg in the placebo group (n = 425; p < 0.0001), with weight loss >=5% reported in 24.7% and 7.3% of patients, respectively, and weight loss >=10% reported in 5.2% and 1.7%, respectively. In HSDD patients with >12 months (n = 880) and >18 months (n = 637) of exposure to flibanserin, mean weight change was -1.0 and -1.2 kg, respectively; 25.4% and 26.9% of patients, respectively, experienced weight loss >=5% from baseline, and 7.8% and 8.4%, respectively, experienced weight loss >=10%. CONCLUSIONS: Women treated with flibanserin for HSDD may experience weight loss. PMID- 28817366 TI - Trajectory of Dyspnea and Respiratory Distress among Patients in the Last Month of Life. AB - BACKGROUND: The trajectory of dyspnea has been reported among patients approaching the end of life. However, patients near death have been dropped from longitudinal studies or excluded altogether because of an inability to self report; proxy estimates have been reported. It is not known whether dyspnea or respiratory distress remains stable, escalates, or abates as patients reach last days. OBJECTIVE: Determine trajectory of dyspnea (self-reported) and respiratory distress (observed) among patients who were approaching death. DESIGN: A prospective, repeated-measures study of dyspnea/respiratory distress among a sample of hospice patients was done. Measures were collected at each patient encounter from hospice enrollment until patient death. MEASUREMENTS: Dyspnea was measured in response to "Are you short of breath?" and using the numeric rating scale anchored at 0 and 10. Nurses measured respiratory distress with the Respiratory Distress Observation Scale (RDOS). Patient consciousness (Reaction Level Scale), nearness to death (Palliative Performance Scale), diagnoses, and demographics were recorded. Data for the 30-day interval before death were analyzed. RESULTS: The sample was 91 patients who were female (58%) and Caucasian (83%) with dementia (32%), heart failure (26%), and cancer (13%). RDOS increased significantly from mild distress 30 days before death to moderate/severe distress on the day of death (F = 10.8, p < 0.0001). Distress was strongly correlated with nearness to death (r = -0.97, p < 0.0001) and consciousness (r = 0.97, p < 0.0001). CONCLUSIONS: Respiratory distress escalated in the last days. Inability to self-report raises care concerns about under-recognition and under-treatment of respiratory distress. PMID- 28817368 TI - Models of Palliative Care Team Composition: Nurse Practitioner-Only versus Interdisciplinary Teams that Include Specialist Physicians. PMID- 28817367 TI - Nutrition Implications for Long-Term Survivors of Pancreatic Cancer Surgery [Formula: see text]. AB - With slowly increasing survival rates in pancreatic cancer and international consensus guidelines recommending surgical resection of premalignant lesions, survival post-pancreatic resection is increasing. With longer survival time, the significant comorbidities of such major surgery have far-reaching effects on the nutrition status of the survivor of pancreatic cancer. This review describes the many nutrition-related side effects of pancreatic surgery, including the development of pancreatic enzyme insufficiency, micronutrient deficiencies, diabetes, fatty liver, and metabolic bone disease. Beyond causing additional medical problems, each of these can have significant effects on quality of life and functional status. The potential mechanisms, diagnosis criteria, and potential treatments of these conditions are described. Overall, little literature exists to fully describe the effects of these comorbidities, and even less is able to guide effective treatments for this population. Clinicians caring for these patients should begin incorporating goals for promotion of long-term health and reduction of these known and reported comorbidities in patients who have undergone pancreatic surgery. Treatment plans in this population remain understudied, and clinicians may need to consider recommendations for similar disease states when developing interventions for these patients. PMID- 28817369 TI - Is the Evidence Sufficient to Recommend Statins for All Men With Prostate Cancer? PMID- 28817370 TI - CONKO-005: Adjuvant Chemotherapy With Gemcitabine Plus Erlotinib Versus Gemcitabine Alone in Patients After R0 Resection of Pancreatic Cancer: A Multicenter Randomized Phase III Trial. AB - Purpose Gemcitabine is standard of care in the adjuvant treatment of resectable pancreatic ductal adenocarcinoma (PDAC). The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in combination with gemcitabine has shown efficacy in the treatment of advanced PDAC and was considered to improve survival in patients with primarily resectable PDAC after R0 resection. Patients and Methods In an open-label, multicenter trial, patients were randomly assigned to one of two study arms: gemcitabine 1,000 mg/m2 days 1, 8, 15, every 4 weeks plus erlotinib 100 mg once per day (GemErlo) or gemcitabine (Gem) alone for six cycles. The primary end point of the study was to improve disease-free survival (DFS) from 14 to 18 months by adding erlotinib to gemcitabine. Results In all, 436 patients were randomly assigned at 57 study centers between April 2008 and July 2013. A total of 361 instances (83%) of disease recurrence were observed after a median follow-up of 54 months. Median treatment duration was 22 weeks in both arms. There was no difference in median DFS (GemErlo 11.4 months; Gem 11.4 months) or median overall survival (GemErlo 24.5 months; Gem 26.5 months). There was a trend toward long-term survival in favor of GemErlo (estimated survival after 1, 2, and 5 years for GemErlo was 77%, 53%, and 25% v 79%, 54%, and 20% for Gem, respectively). The occurrence or the grade of rash was not associated with a better survival in the GemErlo arm. Conclusion To the best of our knowledge, CONKO-005 is the first study to investigate the combination of chemotherapy and a targeted therapy in the adjuvant treatment of PDAC. GemErlo for 24 weeks did not improve DFS or overall survival over Gem. PMID- 28817371 TI - Phase I/II Trial of Labetuzumab Govitecan (Anti-CEACAM5/SN-38 Antibody-Drug Conjugate) in Patients With Refractory or Relapsing Metastatic Colorectal Cancer. AB - Purpose The objectives were to evaluate dosing schedules of labetuzumab govitecan, an antibody-drug conjugate targeting carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) for tumor delivery of 7-ethyl-10 hydroxycamptothecin (SN-38), in an expanded phase II trial of patients with relapsed or refractory metastatic colorectal cancer. Patients and Methods Eligible patients with at least one prior irinotecan-containing therapy received labetuzumab govitecan once weekly at 8 and 10 mg/kg, or two times per week at 4 and 6 mg/km on weeks 1 and 2 of 3-week repeated cycles. End points were safety, response, pharmacokinetics, and immunogenicity. Results Eighty-six patients who had undergone a median of five prior therapies (range, one to 13) were each enrolled into one of the four cohorts. On the basis of Response Evaluation Criteria in Solid Tumors 1.1, 38% of these patients had a tumor as well as plasma carcinoembryonic antigen reduction from baseline after labetuzumab govitecan treatment; one patient achieved a partial response with a sustained response spanning > 2 years, whereas 42 patients had stable disease as the best overall response. Median progression-free survival and overall survival were 3.6 and 6.9 months, respectively. The major toxicities (grade >= 3) among all cohorts were neutropenia (16%), leukopenia (11%), anemia (9%), and diarrhea (7%). The antibody drug conjugate's mean half-life was 16.5 hours for the four cohorts. Anti drug/anti-antibody antibodies were not detected. The two once-weekly dose schedules, showing comparable toxicity and efficacy, were chosen for further study. Conclusion Monotherapy with labetuzumab govitecan demonstrated a manageable safety profile and therapeutic activity in heavily pretreated patients with metastatic colorectal cancer, all with prior irinotecan therapy. Further studies of labetuzumab govitecan treatment alone or in combination with other therapies in earlier settings are indicated. PMID- 28817372 TI - Financial Burden in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study. AB - Purpose Survivors of childhood cancer may experience financial burden as a result of health care costs, particularly because these patients often require long-term medical care. We sought to evaluate the prevalence of financial burden and identify associations between a higher percentage of income spent on out-of pocket medical costs (>= 10% of annual income) and issues related to financial burden (jeopardizing care or changing lifestyle) among survivors of childhood cancer and a sibling comparison group. Methods Between May 2011 and April 2012, we surveyed an age-stratified, random sample of survivors of childhood cancer and a sibling comparison group who were enrolled in the Childhood Cancer Survivor Study. Participants reported their household income, out-of-pocket medical costs, and issues related to financial burden (questions were adapted from national surveys on financial burden). Logistic regression identified associations between participant characteristics, a higher percentage of income spent on out-of-pocket medical costs, and financial burden, adjusting for potential confounders. Results Among 580 survivors of childhood cancer and 173 siblings, survivors of childhood cancer were more likely to have out-of-pocket medical costs >= 10% of annual income (10.0% v 2.9%; P < .001). Characteristics of the survivors of childhood cancer that were associated with a higher percentage of income spent on out-of pocket costs included hospitalization in the past year (odds ratio [OR], 2.3; 95% CI, 1.1 to 4.9) and household income < $50,000 (OR, 5.5; 95% CI, 2.4 to 12.8). Among survivors of childhood cancer, a higher percentage of income spent on out of-pocket medical costs was significantly associated with problems paying medical bills (OR, 8.9; 95% CI, 4.4 to 18.0); deferring care for a medical problem (OR, 3.0; 95% CI, 1.6 to 5.9); skipping a test, treatment, or follow-up (OR, 2.1; 95% CI, 1.1 to 4.0); and thoughts of filing for bankruptcy (OR, 6.6; 95% CI, 3.0 to 14.3). Conclusion Survivors of childhood cancer are more likely to report spending a higher percentage of their income on out-of-pocket medical costs, which may influence their health-seeking behavior and potentially affect health outcomes. Our findings highlight the need to address financial burden in this population with long-term health care needs. PMID- 28817373 TI - Cabozantinib As Salvage Therapy for Patients With Tyrosine Kinase Inhibitor Refractory Differentiated Thyroid Cancer: Results of a Multicenter Phase II International Thyroid Oncology Group Trial. AB - Purpose Sorafenib and lenvatinib are oral multikinase inhibitors targeting vascular endothelial growth factor receptor (VEGFR) and approved for radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). However, there are no approved second- or third-line therapies. MET is implicated in resistance to VEGFR inhibitors. Cabozantinib is an oral multikinase inhibitor targeting MET in addition to VEGFR and is approved for medullary thyroid cancer. In a phase I study of cabozantinib, five of eight patients with DTC previously treated with a VEGFR-targeted therapy had an objective response to cabozantinib. Patients and Methods Patients with RAI-refractory disease with Response Evaluation Criteria in Solid Tumor (RECIST) measurable disease and evidence of progression on prior VEGFR-targeted therapy were enrolled in this single-arm phase II study. The cabozantinib starting dose was 60 mg/day orally but could be escalated to 80 mg if the patient did not experience a response. Patients underwent tumor assessment according to RECIST v1.1 every 8 weeks. In this study, if at least five of 25 response-evaluable patients had an objective response, cabozantinib would be considered a promising agent in this patient population. Results Twenty-five patients were enrolled. The median age was 64 years, and 64% of patients were men. Twenty-one patients had received only one prior VEGFR-targeted therapy (sorafenib, pazopanib, or cediranib), and four patients had received two such therapies. The most common treatment-related adverse events were fatigue, weight loss, diarrhea, palmar-plantar erythrodysesthesia, and hypertension. One drug related death was noted. Of the 25 patients, 10 (40%) had a partial response, 13 (52%) had stable disease, and two (8%) had nonevaluable disease. The median progression-free survival and overall survival were 12.7 months and 34.7 months, respectively. Conclusion Cabozantinib demonstrated clinically significant, durable objective response activity in patients with RAI-refractory DTC who experienced disease progression while taking prior VEGFR-targeted therapy. PMID- 28817374 TI - Long-Term Survival Outcomes of Cancer-Directed Surgery for Malignant Pleural Mesothelioma: Propensity Score Matching Analysis. AB - Purpose Small observational studies have shown a survival advantage to undergoing cancer-directed surgery for malignant pleural mesothelioma (MPM); however, it is unclear if these results are generalizable. Our purpose was to evaluate survival after treatment of MPM with cancer-directed surgery and to explore the effect surgery interaction with chemotherapy or radiation therapy on survival by using the National Cancer Database. Patients and Methods Patients with microscopically proven MPM were identified within the National Cancer Database (2004 to 2014). Propensity score matching was performed 1:2 and among this cohort, a Cox proportional hazards regression model was used to identify predictors of survival. Median survival was calculated by using the Kaplan-Meier method. Results Of 20,561 patients with MPM, 6,645 were identified in the matched cohort, among whom 2,166 underwent no therapy, 2,015 underwent chemotherapy alone, 850 underwent cancer-directed surgery alone, 988 underwent surgery with chemotherapy, and 274 underwent trimodality therapy. The remaining 352 patients underwent another combination of surgery, radiation, or chemotherapy. Thirty-day and 90-day mortality rates were 6.3% and 15.5%. Cancer-directed surgery, chemotherapy, and radiation therapy were independently associated with improved survival (hazard ratio, 0.77, 0.74, and 0.88, respectively). Stratified analysis revealed that surgery-based multimodality therapy demonstrated an improved survival compared with surgery alone, with no significant difference between surgery-based multimodality therapies; however, the largest estimated effect was when cancer directed surgery, chemotherapy, and radiation therapy were combined (hazard ratio, 0.52). For patients with the epithelial subtype who underwent trimodality therapy, median survival was extended from 14.5 months to 23.4 months. Conclusion MPM is an aggressive and rapidly fatal disease. Surgery-based multimodality therapy was associated with improved survival and may offer therapeutic benefit among carefully selected patients. PMID- 28817375 TI - Effect of Maternal Antibody Transfer on Antibody Dynamics and Control of Porcine Circovirus Type 2 Infection in Offspring. AB - Sow immunity plays an important role in preventing viral infection and disease in newborn piglets. Vertical transmission of porcine circovirus type 2 (PCV2) may perpetuate porcine circovirus associated disease (PCVAD) in newborn and growing pigs. Hence, the immunological effects of maternal immunoglobulin transfer of PCV2-specific antibodies on PCV2 viremia and immune response in piglets in commercial swine herds were evaluated. Sow vaccination has been shown to reduce viral shedding and viremia, and increases the neutralizing antibody (NA) titers. Since NAs are important for control of PCVAD and mammary secretions may contain high anti-PCV2 NA levels, we examined the PCV2 NA levels in colostrum, milk, sow serum, and piglet serum over time to investigate an association between NA levels and protection against infection. NA titers were remarkably high (up to 10-6 50% neutralizing titer) in sow serum and colostrum on all farms regardless of viremia levels. In piglets vaccinated at 3 weeks of age, NA titers peaked at 10 weeks of age and continued to maintain high viral neutralizing titers to slaughter. The impact of maternally derived neutralizing activity was most evident during the suckling period. Although PCV2 was transmitted from sows to piglets in colostrum, piglets were largely nonviremic at weaning. Thus, NAs appear to control or suppress initial infection even though they are unable to clear or prevent infection later in life. PMID- 28817376 TI - Association between Hospice Spending on Patient Care and Rates of Hospitalization and Medicare Expenditures of Hospice Enrollees. AB - BACKGROUND: Care at the end of life is increasingly fragmented and is characterized by multiple hospitalizations, even among patients enrolled with hospice. OBJECTIVE: To determine whether hospice spending on direct patient care (including the cost of home visits, drugs, equipment, and counseling) is associated with hospital utilization and Medicare expenditures of hospice enrollees. DESIGN: Longitudinal, observational cohort study (2008-2010). SETTING/SUBJECTS: Medicare beneficiaries (N = 101,261) enrolled in a national random sample of freestanding hospices (N = 355). MEASUREMENTS: We used Medicare Hospice Cost reports to estimate hospice spending on direct patient care and Medicare claim data to estimate rates of hospitalization and Medicare expenditures. RESULTS: Hospice mean direct patient care costs were $86 per patient day, the largest component being patient visits by hospice staff (e.g., nurse, physician, and counselor visits). After case-mix adjustment, hospices spending the most on direct patient care had patients with 5.2% fewer hospital admissions, 6.3% fewer emergency department visits, 1.6% fewer intensive care unit stays, and $1,700 less in nonhospice Medicare expenditures per patient compared with hospices spending the least on direct patient care (p < 0.01 for each comparison). Ninety percent of hospices with the lowest spending on direct patient care and highest rates of hospital use were for-profit hospices. CONCLUSIONS: Patients cared for by hospices with lower direct patient care costs had higher hospitalization rates and were overrepresented by for-profit hospices. Greater investment by hospices in direct patient care may help Centers for Medicare and Medicaid Services avoid high-cost hospital care for patients at the end of life. PMID- 28817377 TI - The sustainable professor. AB - Responsible agricultural practices provide a useful lens through which to consider the lives and careers of researchers. PMID- 28817378 TI - Health policy making for street children: challenges and strategies. AB - Background The phenomenon of street children is a bio-psychological and social issue that not only harms children, but also endangers the health of a society. In line with the national programs for the development and promotion of street children's health in Iran, health policy making and essential strategies for this group of children will be presented in this paper. This paper will discuss the main issues and challenges of street children's health and, also, health policy and guidelines for this population. Methods In this review study, the keywords; street children, health, challenges, policy, and health policy making were searched through PubMed, SID, Iranmedex, World Health Organization (WHO), Emro, the Cochran Library, Medline and Google scholar to collect data. The search resulted in 84 related resources from which 48 cases that were more relevant to this research and covered the issue more comprehensively, were used. All data published during 2002-2015 have been included in this paper. Results Key concepts including street children and their health, health policy, strategies to improve the health of street children, health policy approaches for street children, the WHO's strategies, and social support program for street children must be considered in the health policy making processes for street children, as precise identification of the relevant information makes planning more effective in health policy making for this group of children. Conclusion The phenomenon of street children is a growing problem in the world and it has turned into a serious concern in many countries including Iran. The findings of this study can be used for identifying necessary measures in order to use research outcomes more effectively in policy making processes and reforming street children's health policies in Iran. PMID- 28817379 TI - Improving medical leadership education through the Feagin leadership program. PMID- 28817380 TI - Perceptions of preclinical medical students towards extracurricular activities. AB - Objectives: To determine the percentage of students involved in extracurricular activities (EAs), explore relationships between participation in EAs and students' characteristics, and investigate students' perceptions (i.e., motives and barriers) towards participation in EAs. Methods: An online, anonymous, random, cross-sectional, self-rating survey was administered during spring 2015 2016 to second-year and third-year students (n=340). Chi-square test was used to explore relationships between participation in EAs and students' characteristics. Mann-Whitney U-test was used to compare the mean 5-point Likert scale responses according to students' characteristics. Statistical significance was determined as p<0.05. Results: Two hundred thirty-seven students participated in the survey (n=237/340, response rate: 69.7%). Only 143 students (60.3%, n=140/237) participated in EAs, and this percentage significantly differed by gender (chi2(1, N=237)=4.3205, p<0.037), nationality (chi2(1, N=237)=18.7069, p<0.000) and cumulative grade point average (cGPA, chi2(1, N=237)=17.8296, p<0.000). The top three motives towards participation in EAs were: "improve resume" (83.5%, n=198), "improve networking skills" (82.7%, n=196) and "improve teamwork skills" (76.8%, n=182). The top three barriers towards participation in EAs were: "lack of time" (61.2%, n=145), "lack of equal opportunities in EAs" (57.8%, n=137) and "lack of curricular emphasis of EAs" (52.7%, n=125). There was a statistically significant difference of means between male (mean=2.8) and female (mean=3.2) students regarding the following barrier: "affect academic performance negatively" (U=5389.5, p<0.002). Conclusions: The participation rate in EAs was satisfactory, and positively related to students' characteristics of male gender, non-Saudi nationality and high cGPA. Medical schools should facilitate all potential motives and resolve all associated barriers towards participation in EAs. PMID- 28817381 TI - Advanced Radiation DOSimetry phantom (ARDOS): a versatile breathing phantom for 4D radiation therapy and medical imaging. AB - A novel breathing phantom was designed for being used in conventional and ion beam radiotherapy as well as for medical imaging. Accurate dose delivery and patient safety are aimed to be verified for four-dimensional (4D) treatment techniques compensating for breathing-induced tumor motion. The phantom includes anthropomorphic components representing an average human thorax. It consists of real tissue equivalent materials to fulfill the requirements for dosimetric experiments and imaging purposes. The different parts of the torso (lungs, chest wall, and ribs) and the tumor can move independently. Simple regular movements, as well as more advanced patient-specific breathing cycles are feasible while a reproducible setup can be guaranteed. The phantom provides the flexibility to use different types of dosimetric devices and was designed in a way that it is robust, transportable and easy to handle. Tolerance levels and the reliability of the phantom setup were determined in combination with tests on motion accuracy and reproducibility by using infrared optical tracking technology. Different imaging was performed including positron emission tomography imaging, 4D computed tomography as well as real-time in-room imaging. The initial dosimetric benchmarking studies were performed in a photon beam where dose parameters are predictable and the dosimetric procedures well established. PMID- 28817383 TI - Combined influence of CT random noise and HU-RSP calibration curve nonlinearities on proton range systematic errors. AB - Proton range random and systematic uncertainties are the major factors undermining the advantages of proton therapy, namely, a sharp dose falloff and a better dose conformality for lower doses in normal tissues. The influence of CT artifacts such as beam hardening or scatter can easily be understood and estimated due to their large-scale effects on the CT image, like cupping and streaks. In comparison, the effects of weakly-correlated stochastic noise are more insidious and less attention is drawn on them partly due to the common belief that they only contribute to proton range uncertainties and not to systematic errors thanks to some averaging effects. A new source of systematic errors on the range and relative stopping powers (RSP) has been highlighted and proved not to be negligible compared to the 3.5% uncertainty reference value used for safety margin design. Hence, we demonstrate that the angular points in the HU to-RSP calibration curve are an intrinsic source of proton range systematic error for typical levels of zero-mean stochastic CT noise. Systematic errors on RSP of up to 1% have been computed for these levels. We also show that the range uncertainty does not generally vary linearly with the noise standard deviation. We define a noise-dependent effective calibration curve that better describes, for a given material, the RSP value that is actually used. The statistics of the RSP and the range continuous slowing down approximation (CSDA) have been analytically derived for the general case of a calibration curve obtained by the stoichiometric calibration procedure. These models have been validated against actual CSDA simulations for homogeneous and heterogeneous synthetical objects as well as on actual patient CTs for prostate and head-and-neck treatment planning situations. PMID- 28817384 TI - Engineering the mechanical and biological properties of nanofibrous vascular grafts for in situ vascular tissue engineering. AB - Synthetic small diameter vascular grafts have a high failure rate, and endothelialization is critical for preventing thrombosis and graft occlusion. A promising approach is in situ tissue engineering, whereby an acellular scaffold is implanted and provides stimulatory cues to guide the in situ remodeling into a functional blood vessel. An ideal scaffold should have sufficient binding sites for biomolecule immobilization and a mechanical property similar to native tissue. Here we developed a novel method to blend low molecular weight (LMW) elastic polymer during electrospinning process to increase conjugation sites and to improve the mechanical property of vascular grafts. LMW elastic polymer improved the elasticity of the scaffolds, and significantly increased the amount of heparin conjugated to the micro/nanofibrous scaffolds, which in turn increased the loading capacity of vascular endothelial growth factor (VEGF) and prolonged the release of VEGF. Vascular grafts were implanted into the carotid artery of rats to evaluate the in vivo performance. VEGF treatment significantly enhanced endothelium formation and the overall patency of vascular grafts. Heparin coating also increased cell infiltration into the electrospun grafts, thus increasing the production of collagen and elastin within the graft wall. This work demonstrates that LMW elastic polymer blending is an approach to engineer the mechanical and biological property of micro/nanofibrous vascular grafts for in situ vascular tissue engineering. PMID- 28817382 TI - Quantum mechanical force fields for condensed phase molecular simulations. AB - Molecular simulations are powerful tools for providing atomic-level details into complex chemical and physical processes that occur in the condensed phase. For strongly interacting systems where quantum many-body effects are known to play an important role, density-functional methods are often used to provide the model with the potential energy used to drive dynamics. These methods, however, suffer from two major drawbacks. First, they are often too computationally intensive to practically apply to large systems over long time scales, limiting their scope of application. Second, there remain challenges for these models to obtain the necessary level of accuracy for weak non-bonded interactions to obtain quantitative accuracy for a wide range of condensed phase properties. Quantum mechanical force fields (QMFFs) provide a potential solution to both of these limitations. In this review, we address recent advances in the development of QMFFs for condensed phase simulations. In particular, we examine the development of QMFF models using both approximate and ab initio density-functional models, the treatment of short-ranged non-bonded and long-ranged electrostatic interactions, and stability issues in molecular dynamics calculations. Example calculations are provided for crystalline systems, liquid water, and ionic liquids. We conclude with a perspective for emerging challenges and future research directions. PMID- 28817385 TI - Novel molecular defects associated with very early-onset inflammatory bowel. AB - PURPOSE OF REVIEW: Immune dysregulation disorders present with common clinical features of multiorgan autoimmunity. Gastrointestinal involvement is the hallmark of an impaired immune homeostasis. This review will give an overview on the novel phenotypes, highlighting the major points that will help to enable early diagnosis and treatment. RECENT FINDINGS: The rapid progress on DNA sequencing technologies have led to the identification of monogenic defects that adversely impact the control of immune homeostasis. Lymphocytes may be present but dysfunctional, allowing for the development of excessive autoreactivity and resultant autoimmune disease. Regulatory T cells (Tregs) play an essential role in enforcing immune tolerance. Here we illustrate disorders caused by impairment of mechanisms ensuring Tregs function (Tregs related) in which autoimmunity is a hallmark of the clinical disease presentation and other disorders, affecting molecules more broadly involved in immune responses and indirectly causing immune dysregulation (Tregs unrelated). Clinical presentation is sometime mischievous and often symptoms are analogous in different diseases and can mislead diagnosis. SUMMARY: The increasing comprehension of immunological concepts behind immune dysregulation diseases will allow better and in some cases possibly even targeted treatment. A genetic diagnosis therefore becomes important information in this group of patients, especially as some patients might require hematopoietic stem cell transplantation. PMID- 28817386 TI - CXCR4 blockade with AMD3100 enhances Taxol chemotherapy to limit ovarian cancer cell growth. AB - The standard of care for ovarian cancer includes initial treatment with chemotherapy. Despite initial efficacy, over 70% of patients develop recurrence; thus, there is a need to identify novel approaches that can improve therapeutic outcomes. We evaluated AMD3100 (Plerixafor), an FDA-approved CXCR4 inhibitor, as a potential adjunctive therapy for low-dose Taxol (Paclitaxel) by assessing the impact on in-vitro ovarian cancer cell proliferation. Proliferation was a measure for both human TOV-112D and murine ID8 ovarian cancer cells incubated with AMD3100 and Taxol, either individually or in combination. Impact of treatment was first determined for the simultaneous administration of AMD3100 and Taxol. We next assessed a sequential application of AMD3100 pretreatment, followed by AMD3100, Taxol, or a combination to test for sensitization to Taxol. In addition, we measured the impact of AMD3100 and Taxol, individually and in combination, on colony formation, an in-vitro model assay of tumor growth. Expression data, as measured by flow cytometry, show that both ID8 and TOV-112D cells are positive for CXCR4, CXCR7, and CXCL12. Combination treatment with AMD3100 (<=10 MUmol/l) sensitized both ID8 and TOV-112D cells to low concentrations of Taxol (<=5 nmol/l), limiting cell proliferation and colony formation in vitro. Pretreatment with AMD3100 significantly increased the sensitivity of human ovarian cancer to low-dose Taxol or the combination of AMD3100 and Taxol, although this effect was not evident in murine cells. Importantly, for both human and murine cells, incubation with a combination of AMD3100 and Taxol had the largest impact on limiting cell proliferation. AMD3100 in combination with low-dose Taxol offers improved efficacy and the potential of reduced toxicity for the treatment of ovarian cancer. PMID- 28817387 TI - Response of an ovarian granulosa cell tumor with everolimus and exemestane after initial response to letrozole. AB - Granulosa cell tumors of the ovaries (GCTO), the most common sex cord tumors of the female genitalia, are characterized by a remarkably favorable prognosis but tend to recur even after several years of follow-up. Standard approach to manage these relapsing tumors is almost inexistent and physicians' choice is most commonly based on his/her personal expertise. Recently, the use of hormone therapy in GCTO has induced prolonged response and survival. In this case report, we report the first successful use of everolimus in the combination of exemestane to reverse the resistance to hormonal therapy with letrozole in a 53-year-old woman with GCTO. PMID- 28817388 TI - Ophthalmologic manifestations of systemic vasculitis. AB - PURPOSE OF REVIEW: To review the systemic vasculitides and associated ocular manifestations with emphasis on publications within the last 12 months. RECENT FINDINGS: There are multiple case reports demonstrating atypical ocular manifestations of systemic vasculitis. Often the eye findings are the initial presentation of the disorder and require a high degree of clinical suspicion to evaluate further as these conditions can compromise vision but some may also be life threatening. SUMMARY: The systemic vasculitides are a heterogenous group of rare disorders with inflammation of blood vessels as a common feature. This review will provide a synopsis of the diseases with associated ocular manifestations. The implication for clinicians is to highlight recent case reports/series demonstrating the pathology. PMID- 28817389 TI - Congenital anomalies of the optic disc: insights from optical coherence tomography imaging. AB - PURPOSE OF REVIEW: Congenital anomalies of the optic nerve are rare but significant causes of visual dysfunction in children and adults. Accurate diagnosis is dependent on a thorough funduscopic examination, but can be enhanced by imaging information garnered from optical coherence tomography (OCT). We review common congenital optic nerve anomalies, including optic disc pit, optic nerve coloboma, morning glory disc anomaly, and hypoplasia of the optic nerve, review their systemic associations, and discuss insights from OCT imaging. RECENT FINDINGS: Optic disc pits are a result of a defect in the lamina cribrosa and abnormal vitreomacular adhesions have been shown to cause maculopathy. In patients with optic nerve colobomas, OCT can be instrumental in diagnosing choroidal neovascularization, a rare but visually devastating complication. The pathogenesis of morning glory disc anomaly has been more clearly elucidated by OCT as occurring from a secondary postnatal mesenchymal abnormality rather than only the initial neuroectodermal dysgenesis of the terminal optic stalk in isolation. OCT studies of optic nerve hypoplasia have demonstrated significant thinning of the inner and outer retinal layers of the perifoveal region and thicker layers in the fovea itself, resulting in a foveal hypoplasia-like pathology, that is, significantly correlated to poorer visual outcomes. SUMMARY: OCT provides detailed in-vivo analysis of these anatomic anomalies and their resulting pathologies, shedding new insights on the pathogenesis, diagnosis, and potential visual outcomes of these conditions in children. Further study employing OCT to elucidate structure-function relationships of congenital optic nerve anomalies will help expand the role of OCT in clinical practice related to diagnosis, prognosis, and management of these entities. PMID- 28817390 TI - Hypoalbuminemia is a Predictive Factor for Fistula Formation in Recurrent Cervical Cancer. AB - OBJECTIVE: Antivascular endothelial growth factor monoclonal antibodies inhibit tumor angiogenesis, consequently impeding the recruitment of new vasculature to existing and new tumor lesions. We sought to evaluate toxicities in women with recurrent cervical cancer after receiving bevacizumab combination chemotherapy. METHODS: A review was conducted of women with recurrent and metastatic cervical cancer who were treated with salvage chemotherapy with or without bevacizumab between 2005 and 2015. Clinicopathologic data and reasons for treatment discontinuation were recorded. Patients that were excluded had other histology than squamous or adenocarcinoma, received 1 cycle of salvage chemotherapy, single agent bevacizumab, currently on treatment, or noncompliant. Statistical analysis was performed using the Fishers Exact Test, logistic regression, and Kaplan-Meier Survival Analysis. RESULTS: A total of 74 patients were included in analysis. Twenty-six patients were treated with bevacizumab (BEV) and chemotherapy and 48 patients with chemotherapy alone (chemotherapy). The progression free survival was significant with median 12 months versus 7 months for the BEV cohort (P<0.01) and the overall survival was a median 74 months versus 23 months for the BEV cohort (P=0.06). Cessation of treatment secondary to severe toxicities was seen in 46% (n=12) of BEV cohort versus 15% (n=7) of chemotherapy cohort (P<0.01). Twenty-seven percent (n=7) of patients in the BEV cohort stopped secondary because of fistula formations. Lower albumin levels and use of bevacizumab were identified as an independent predictor factors for fistula formation (P=0.004 and 0.024, respectively). CONCLUSIONS: Hypoalbuminemia and bevacizumab treatments are significant predictive factors of fistula formation in patients treated for recurrent cervical cancer. PMID- 28817391 TI - Tacrolimus Eye Drops as Adjunct Therapy in Severe Corneal Endothelial Rejection Refractory to Corticosteroids. AB - PURPOSE: To evaluate the safety and efficacy of tacrolimus eye drops as adjunctive therapy in the treatment of severe corneal endothelial rejection after penetrating keratoplasty refractory to corticosteroids. METHODS: In this prospective interventional case series, 11 eyes of 11 patients assessed for severe corneal endothelial rejection, with an inadequate response to topical, local, and systemic corticosteroids, were treated with either 0.01% or 0.05% tacrolimus eye drops 4 times daily. Improvement in signs of rejection, visual function, and development of complications were monitored. RESULTS: The duration of steroid treatment before intervention was 8.1 +/- 1.4 days (range = 7-11). Patients were subsequently administered topical tacrolimus 0.01% or 0.05% qid. The time to clinical improvement was 10.3 +/- 3.4 days (range = 3-17). The time to rejection reversal was 27.8 +/- 16.3 days (range = 7-52). After 3 months, 10 patients (90.8%) demonstrated clinical improvement, and complete restoration of graft clarity was achieved in 5 patients (45.4%). In responsive cases, steroid therapy was successfully tapered off after 60.2 +/- 19.7 days (range = 36-93). The best spectacle-corrected visual acuity improved from 1.7 +/- 0.9 to 0.8 +/- 0.5 logMAR (P = 0.0016). Reported side effects included stinging on drop instillation and punctate epithelial keratopathy. CONCLUSIONS: Tacrolimus eye drops may be able to play an adjunctive therapeutic role in patients with severe corneal endothelial rejection refractory to conventional steroid treatment. Controlled studies are needed to further investigate the role of tacrolimus in this setting. PMID- 28817392 TI - Minimum operational standards for 24/7 available emergency departments in the Netherlands: a first step taken by emergency physicians using an e-Delphi approach. AB - OBJECTIVE: The objective of this study was to effectuate a consensus of emergency physicians on minimum requirements for facility, diagnostic, and medical specialist availability as a first step toward minimum operational standards for 24/7 available emergency departments (EDs) in the Netherlands. PATIENTS AND METHODS: A two-part e-Delphi through online survey was performed between January 2015 and May 2016, using a panel of 20 experts in emergency medicine. The aim of part I was to reach an agreement on a list of possible ED elements and their definitions. The second part addressed the actual study objective to reach consensus on operational standards. Successive rounds were submitted to the members of the panel online using SurveyMonkey. Results of each survey round were discussed and interpreted in agreement with all authors in preparation for the next round. Reaching consensus, defined as 70% or more agreement or disagreement among the panel, on the level of all items was the endpoint of this study. RESULTS: Both parts I and II required five rounds. The dropout rate of the expert panel remained zero. The availability of 52 facilities and diagnostic functionalities and the manner in which 17 medical specialties should be available to every 24/7 ED were agreed upon by the expert panel. CONCLUSION: An expert panel agreed upon minimum operational standards for EDs in the Netherlands. These results are helpful as a first step toward a more widely supported standard for future 24/7 available EDs in the Netherlands and in addition to this other urgent care facilities. PMID- 28817393 TI - Increased Expiratory Computed Tomography Density Reveals Possible Abnormalities in Radiologically Preserved Lung Parenchyma in Idiopathic Pulmonary Fibrosis. AB - OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is a progressive lethal chronic lung disease with unclear pathogenesis. Radiological hallmark is the pattern of usual interstitial pneumonia accentuated in peripheral and basal areas with otherwise preserved lung structure. One hypothesis is that alveolar collapse and consequent induration lead to fibrotic transformation of lung tissue. The aim of the study was to investigate normal-appearing tissue during expiration for signs of collapsibility and differences from other diseases or controls. MATERIALS AND METHODS: We retrospectively assessed a total of 43 patients (15 IPFs, 13 chronic obstructive pulmonary diseases, and 15 controls) with nonenhanced computed tomography (CT) in inspiration and expiration, performed for routine clinical workup. Densitometry of visually unaffected lung tissue was conducted in all lung lobes with a region of interest of 15-mm in diameter on soft tissue kernel reconstruction (slice thickness, 1 mm) during inspiration and expiration. RESULTS: One-factor analysis of variance analysis yielded significant difference in attenuation changes between inspiration and expiration of unaffected lung parenchyma among all subject groups in all lung lobes. For IPF patients, the highest differences in densities were observed in the lower lobes, which is the predominantly affected site of usual interstitial pneumonia. In the chronic obstructive pulmonary disease group, the density remained rather equal in the entire lung. CONCLUSIONS: High CT attenuation changes between inspiration and expiration in IPF patients might suggest altered lung parenchyma in normal appearing tissue on CT. Density changes during the respiratory cycle might be explained by alveolar collapse of radiologically unaffected lung tissue possibly preceding fibrosis. These results support the concept of alveolar collapse preceding lung fibrosis in IPF. PMID- 28817394 TI - Drivers of Continuing Education Learning Preferences for Veterans Affairs Women's Health Primary Care Providers. AB - INTRODUCTION: Documented gaps in health professionals' training in women's health are a special concern for continuing education (CE). In the Veterans Affairs (VA) health care system, women veterans are a numerical minority, preferably assigned to designated women's health primary care providers (DWHPs). DWHPs need to maintain their knowledge and skills in women's health topics, in addition to general internal medicine topics. We explored drivers of VA DWHPs' learning preferences for women's health topics-ie, factors which influence greater and lesser learning interest. METHODS: We conducted semistructured telephone interviews with DWHPs across six VA health care systems. Interviews were audio recorded, transcribed, and coded in ATLAS.ti. We synthesized results by grouping relevant coded sections of text to form emergent themes. RESULTS: Among the 31 DWHPs interviewed, reported drivers of learning interests among women's health topics were (1) high frequency of clinical incidence of particular issues; (2) perceived appropriateness of particular issues for management in primary care settings; and (3) perceived appropriateness of particular issues for partial management in primary care. Lower interest in particular women's health topics was associated with (1) perceived existing competency or recent training in an issue and (2) perceived need for specialty care management of an issue. DISCUSSION: Understanding drivers of DWHPs' CE learning priorities lays a foundation for developing CE programming that will be of interest to women's health primary care providers. Attention to drivers of learning interests may have applicability beyond women's health, suggesting a general approach for CE programming that prioritizes high-volume topics within the practice scope of target providers. PMID- 28817395 TI - ECHO Pain Curriculum: Balancing Mandated Continuing Education With the Needs of Rural Health Care Practitioners. AB - Chronic pain is a common problem in the United States. Health care professions training at the undergraduate and graduate levels in managing chronic pain is insufficient. The Chronic Pain and Headache Management TeleECHO Clinic (ECHO Pain) is a telehealth approach at Project ECHO (Extension for Community Healthcare Outcomes), which supports clinicians interested in improving their knowledge and confidence in treating patients with chronic pain and safe opioid management. It is a vehicle for educating practicing clinicians (at the "spoke") based on work-place learning with cases selected by participants from their patient panels combined with short lectures by experts (at the "hub"). ECHO Pain has designed an innovative, interprofessional longitudinal curriculum appropriate for individual and team-based clinicians which includes relevant basic and advanced pain topics. The specific design and delivery of the curriculum enhances its relevance and accessibility to busy clinicians in practice, yet also satisfies statutory requirements for CME in New Mexico. Specific features which balance hub-and-spoke needs are presented in this descriptive article, which is intended to serve as a guide to other clinician educators interested in developing or implementing similar telehealth curricula. PMID- 28817396 TI - New Editorial Leadership for JCEHP. PMID- 28817397 TI - Real-world data on paliperidone palmitate for the treatment of schizophrenia and other psychotic disorders: a systematic review of randomized and nonrandomized studies. AB - The aim of this study was to perform a systematic review of the effects of 1 month paliperidone palmitate (PP1M) for the treatment of schizophrenia and related psychotic disorders in terms of outcomes reported in real-world evidence studies. A systematic review of real-world randomized and nonrandomized studies with PP1M was performed and is reported according to PRISMA guidelines. Comparative effectiveness data with oral antipsychotics indicate that PP1M has a lower likelihood of relapse-related events, including rehospitalization, and these differences are clinically relevant. A randomized, double-blind study showed that PP1M has no advantage over haloperidol decanoate in the time to treatment failure. Although there was a marked variability across studies, PP1M was not superior to other antipsychotics in terms of study completion rates. Pharmacoeconomic data show that, during a follow-up period of 12 months, the mean total healthcare cost was not significantly different in patients treated with PP1M compared with those receiving oral antipsychotics. The mean maximum prolactin levels were significantly higher with PP1M than with haloperidol decanoate; however, neither drug differs in the frequency of prolactin-related adverse events. Results on prolactin-related adverse events were inconsistent in two randomized comparisons with oral antipsychotics and were not reported in a randomized comparison with aripiprazole. There were no significant differences between haloperidol decanoate and PP1M in the severity of abnormal involuntary movements and parkinsonism, or in the incidence of tardive dyskinesia; however, patients treated with haloperidol decanoate showed greater worsening of akathisia and required treatment for parkinsonism and akathisia significantly more frequently than patients who received PP1M. In conclusion, real-world data that originate from both pragmatic randomized clinical trials and observational studies indicate that PP1M is superior to oral antipsychotics in delaying the time to relapse or treatment failure. Furthermore, the pharmacoeconomic data reviewed for this article suggest that the advantages of PP1M compared with oral antipsychotics are not associated with an increased total cost for healthcare providers. PMID- 28817398 TI - Three-dimensional echocardiography diagnosis of double perforation of bicuspid aortic valve. PMID- 28817399 TI - Chemotherapy for oligometastatic prostate cancer. AB - PURPOSE OF REVIEW: To analyze recent trials of upfront chemotherapy to determine how this paradigm can be applied to oligometastatic prostate cancer patients. RECENT FINDINGS: Upfront chemotherapy prolongs survival in metastatic prostate cancer, according to the ChemoHormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer and STAMPEDE docetaxel trials. However, the benefit is driven by the high volume subset and may not apply to low-volume/oligometastatic patients. SUMMARY: Oligometastatic patients may not all share the same biology. Advanced imaging techniques may help to more accurately identify truly oligometastatic patients. Molecular markers will be necessary to distinguish oligometastatic patients who fare well enough with androgen deprivation therapy alone as opposed to those for whom upfront chemotherapy may be beneficial. Emerging molecular markers of docetaxel sensitivity, such as loss of lysine-specific demethylase 5d, warrant prospective validation with one goal of identifying oligometastatic patients with greatest likelihood of benefit from this strategy. PMID- 28817400 TI - Liver xenotransplantation. AB - PURPOSE OF REVIEW: There continues to be an inadequate organ supply and lack of effective temporary support, for patients with liver failure. The purpose of this review is to discuss recent progress in the field of orthotopic pig-to-nonhuman primate (NHP) liver xenotransplantation (LXT). RECENT FINDINGS: From 1968 to 2012, survival in pig-to-NHP LXT was limited to 9 days, initially due to hyperacute rejection which has been ameliorated through use of genetically engineered donor organs, but ultimately because of profound thrombocytopenia, thrombotic microangiopathy, and bleeding. Most recently, however, demise secondary to lethal coagulopathy has been avoided with LXT of alpha(1,3) galactosyltransferase knockouts and cytomegalovirus-negative porcine xenografts into baboons receiving exogenous administration of coagulation factors and co stimulation blockade, establishing that a porcine liver is capable of supporting NHP life for nearly a month. SUMMARY: Continued consistent achievement of pig-to NHP LXT survival beyond 2 weeks justifies consideration of a clinical application as a bridge to allotransplantation for patients with acute hepatic failure. Further genetic modifications to the donor, as well as additional studies, are required in order to apply LXT as destination therapy. PMID- 28817401 TI - Challenges in the anesthetic management of ambulatory patients in the MRI suites. AB - PURPOSE OF REVIEW: MRI is becoming an indispensable diagnostic tool. The need for prolonged motion-free periods has substantially increased the need for deep sedation or anesthesia in a challenging environment. This review summarises recent literature with respect to pharmacological sedative strategies, nonpharmacological alternative approaches, airway management and safety issues in the ambulatory setting. RECENT FINDINGS: Most literature researches the pediatric patient population. The American Society of Pediatrics published guidelines for monitoring and management of pediatric patients during sedation for diagnostic procedures. Dexmedetomidine is the most researched agent for sedation. It remains uncertain what the clinical implications are of the potential neurotoxicity of repeat sedation or anesthesia in young children. Airway strategies highlight the use of end-tidal carbon dioxide monitoring. Technical imaging advancement and nonpharmacological sedation alternatives allow for shorter procedures with a lower need for sedation. SUMMARY: The anesthetic management of ambulatory patients in the MRI environment has its specific challenges and safety issues. However, the implementation of safety guidelines, new pharmacological and alternative nonpharmacological sedation strategies offer interesting perspectives to tackle these challenges. PMID- 28817402 TI - The importance of natural killer cell killer immunoglobulin-like receptor mismatch in transplant outcomes. AB - PURPOSE OF REVIEW: In recent years, the rules of engagement between natural killer (NK) cells and their targets have become better defined with the identification of an array of NK surface molecules, notably the killer immunoglobulin-like (KIR) receptors and their ligands on target cells through which signals of activation or suppression of NK function are mediated. After allogeneic stem cell transplantation (SCT), the opportunity for NK cell activation can occur both in human leucocyte antigen (HLA) matched and HLA mismatched pairs. Although less well explored in HLA identical transplants, many studies confirm the importance of NK KIR mismatching in the graft-versus-leukemia effect in haploidentical (haplo) SCT and this has stimulated recent research to better define the role of NK mismatching on transplant outcome. In this review, we describe recent progress in identifying favorable and unfavorable NK matching in SCT. RECENT FINDINGS: Recent studies focus less on KIR-HLA mismatching and more on KIR genes as tools to predict alloreactivity via NK licensing and activating KIR. SUMMARY: Current results show that transplant outcomes could be improved by judicious selection of favorable donors. PMID- 28817403 TI - Primary Bone Lymphoma Exhibits a Favorable Prognosis and Distinct Gene Expression Signatures Resembling Diffuse Large B-Cell Lymphoma Derived From Centrocytes in the Germinal Center. AB - Primary bone (PB) diffuse large B-cell lymphoma (DLBCL) is rare and has a favorable prognosis, but the underlying biological mechanisms remain unknown. In this study we analyzed the clinicopathologic features of 160 patients with PB DLBCL in comparison with 499 nonosseous DLBCL. Compared with patients with nonosseous DLBCL and secondary involvement of bone by DLBCL, PB-DLBCL patients less frequently had elderly age, B-symptoms, elevated serum lactate dehydrogenase levels, and high International Prognostic Index at diagnosis, more frequently had germinal center (GC) subtype (approximately 90%) and complete remission, and had significantly better survival. The 5-year progression-free and overall survival rates of PB-DLBCL patients were 80% and 93%, respectively, superior to both GC B cell-like (GCB) and activated B cell-like subtypes of DLBCL. Further stratifying nonosseous DLBCL cell-of-origin subtypes by clinical factors showed that PB-DLBCL had similar survival rates as the centrocyte-origin (CC) subtype of DLBCL-GCB classified by the B-cell-associated gene signature algorithm. To better understand the favorable outcome of PB-DLBCL patients, gene expression profiling and microRNA profiling were performed in a small subset of PB-DLBCL. The gene expression profiles of PB-DLBCL resembled those of nonosseous DLBCL-GCB-CC, but were distinct from other DLBCL cell-of-origin especially the centroblast-origin (CB) subtype. Compared with DLBCL-GCB-CB, PB-DLBCL and DLBCL-GCB-CC also had much higher levels of miR-125a-3p, miR-34-3p, and miR-155-5p, and significantly lower levels of miR-17-5p and miR-17-3p. These results demonstrated that PB-DLBCL is clinically distinct, and the cell-of-origin of PB-DLBCL stems from centrocytes in the GC, that are biologically attributed for the favorable prognosis of PB-DLBCL. PMID- 28817404 TI - Primary Renal Sarcomas With BCOR-CCNB3 Gene Fusion: A Report of 2 Cases Showing Histologic Overlap With Clear Cell Sarcoma of Kidney, Suggesting Further Link Between BCOR-related Sarcomas of the Kidney and Soft Tissues. AB - We report 2 primary renal sarcomas demonstrating BCOR-CCNB3 gene fusions that have recently been identified in undifferentiated round cell sarcomas of bone and soft tissue. These neoplasms occurred in male children aged 11 and 12 years, and both were cystic as a result of entrapment and dilatation of native renal tubules. Both cases were composed of variably cellular bland spindle cells with fine chromatin set in myxoid stroma and separated by a branching capillary vasculature. Both neoplasms demonstrated immunoreactivity for BCOR, cyclin D1, TLE1, and SATB2 in the spindle neoplastic cells and negativity in the prominent capillary vasculature. One case was extensively cystic and had hypocellular areas that simulated cystic nephroma; this neoplasm recurred 3 years later as a solid, highly cellular spindle cell sarcoma in the abdominal cavity. The morphology and immunoprofile of these renal neoplasms was compared with a control group of other sarcomas with BCOR genetic abnormalities, including clear cell sarcoma of the kidney (CCSK), infantile undifferentiated round cell sarcomas of soft tissue/primitive myxoid mesenchymal tumor of infancy, and bone/soft tissue sarcomas with BCOR-CCNB3 gene fusion; along with primary renal synovial sarcoma. Our findings show that the renal sarcomas with BCOR-CCNB3 gene fusion overlap with CCSK. These results are in keeping with a "BCOR-alteration family" of renal and extrarenal neoplasms which includes CCSK and undifferentiated round cell sarcomas of soft tissue/primitive myxoid mesenchymal tumor of infancy (which typically harbor BCOR internal tandem duplication), and BCOR-CCNB3 sarcomas, all of which are primarily driven by BCOR overexpression and have overlapping (but not identical) clinicopathologic features. PMID- 28817406 TI - Idiopathic Myointimal Hyperplasia of Mesenteric Veins: An Uncommon Cause of Ischemic Colitis With Distinct Mucosal Features. AB - Idiopathic myointimal hyperplasia of mesenteric veins causes chronic ischemic mucosal injury with segmental strictures that mimic inflammatory bowel disease and nonocclusive ischemic colitis. It is characterized by myointimal proliferative changes that narrow the lumina of veins combined with ischemic injury and ulcers. Most cases reported to date have been diagnosed following surgical resection. The aim of this study was to determine whether mucosal changes of idiopathic myointimal hyperplasia of mesenteric veins are sufficiently sensitive and specific to allow its recognition in biopsy material. The study group consisted of 10 patients with idiopathic myointimal hyperplasia of mesenteric veins who underwent surgical resection of the affected colon, 7 of whom had available prior endoscopic biopsies. The control group included 10 patients each with radiation, nonocclusive ischemia, Crohn disease, diverticulitis, and mucosal amyloidosis, and 5 cases of small vessel (leukocytoclastic) vasculitis. Study patients were mostly older men with distal colorectal disease. All resection specimens showed mucosal ischemia with numerous thick-walled (arteriolized) capillaries and glassy subendothelial fibrin deposits; numerous hyalinized, eosinophilic thrombi were detected in 90% of colectomy specimens. Biopsies showed arteriolized capillaries (100%), subendothelial fibrin deposits (86%), fibrin thrombi (43%), and perivascular hyalinization (43%). Fibrin thrombi were observed in only one case each of ischemic colitis and small vessel vasculitis, and none of the other abovementioned features were seen in any of the controls. We conclude that arteriolized capillaries, subendothelial fibrin deposits, and perivascular hyalinization are frequent and specific features that can facilitate recognition of idiopathic myointimal hyperplasia of mesenteric veins in biopsy samples. PMID- 28817405 TI - Cutaneous Eruptions in Patients Receiving Immune Checkpoint Blockade: Clinicopathologic Analysis of the Nonlichenoid Histologic Pattern. AB - Cutaneous eruptions are among the most common immune-related adverse events (irAEs) associated with anti-programmed cell death protein 1/programmed cell death ligand 1 therapy, and are often clinically and histologically characterized as lichenoid. Nonlichenoid patterns may also occur and are likely to be encountered by surgical pathologists, given the increasing clinical use of these agents. The purpose of this study is to describe the histopathologic features of nonlichenoid cutaneous irAEs from patients receiving anti-programmed cell death protein 1/programmed cell death ligand 1 therapies for a variety of underlying advanced malignancies. Sixteen patients with 17 biopsied eruptions were included from 2 academic institutions with extensive experience administering and monitoring responses to immune checkpoint blockade as well as treating the potential side effects. Eruptions occurred a median of 10 days (range, 1 d to 11.4 mo) after treatment initiation. Nearly half of specimens demonstrated either a psoriasiform/spongiotic or an urticarial-type reaction pattern on histologic review. Patterns consistent with Grover disease, bullous pemphigoid, and granulomatous dermatitis were also observed. Nearly two-thirds of patients required systemic corticosteroids for treatment of the cutaneous irAE, and 19% of patients discontinued immunotherapy due to their skin eruptions. 75% of patients showed an objective antitumor response. The diverse array of nonlichenoid cutaneous irAE presented here should reflect and inform the scope of histologic patterns encountered by the practicing surgical pathologist. Such eruptions are seen in patients with a variety of underlying tumor types, many of whom ultimately demonstrate a favorable response to immune checkpoint blockade. PMID- 28817407 TI - Nonoperative Management of Labral Tears of the Hip in Adolescent Athletes: Description of Sports Participation, Interventions, Comorbidity, and Outcomes. AB - CONTEXT: Hip injury among young athletes is increasing, especially hip labral tears. Some tears may require surgical intervention, especially if they are associated with boney pathology such as femoroacetabular impingement (FAI). A protocol for nonoperative treatment of the hip labral tears is not well established. OBJECTIVE: To identify current nonoperative treatment options, comorbidities, sports participation, and outcomes of adolescent athletes who were diagnosed with hip labral tears. STUDY DESIGN: Retrospective chart review. SETTING: A regional tertiary level medical and academic institution. PARTICIPANTS: Physically active 8- to 20-year-old males and females who were diagnosed with hip labral tears in 2010 to 2013. MAIN OUTCOME MEASURES: Nonoperative treatment interventions including physical therapy (PT), intraarticular injection (IAI), the type of sports participation, and comorbidity were extracted. STATISTICAL ANALYSIS: Descriptive statistics and chi tests were used with a priori alpha level <0.05. RESULTS: Among 76 adolescent athletes who were diagnosed with hip labral tear, 52 (68.4%) had PT, 55 (72.4%) received IAI, and 43 (56.6%) experienced both PT and IAI interventions. Top 3 sports participated were dance (18.4%), soccer (14.5%), and gymnastics (7.9%). The most common comorbidity was FAI, which was observed in 46 individuals (60.5%). Although there was no difference in a proportion of FAI cases between sexes, a greater proportion of surgical cases were observed among hip labrum-injured athletes with FAI compared with those without FAI (P = 0.032). CONCLUSIONS: Adolescent athletes with hip labral tears often receive PT, IAI, and a combination of both, as nonoperative treatment options in this study cohort. The adolescent athletes who sustained hip labral tears with comorbidity of FAI had significantly greater proportion of surgical cases after nonoperative treatments. PMID- 28817408 TI - Reactive Osteochondromatous Lesion of the Femoral Neck in a Highly Active Preadolescent Patient: Is This the Pathogenesis of a Cam Deformity? AB - Here, we present a rare case of a preadolescent boy with a prominent bony bump on the femoral neck. The main histological feature was concordant with a reactive osteochondromatous lesion possibly induced by repetitive microtrauma, probably because of overtraining as a soccer goalkeeper. The nature of this pathological change is consistent with the growth of a cam deformity. Especially in the preadolescent age group, we should note that repetitive use of the same joint kinematics may induce a prominent cam deformity. PMID- 28817409 TI - TRest as a New Diagnostic Variable for Chronic Exertional Compartment Syndrome of the Forearm: A Prospective Cohort Analysis of 124 Athletes. AB - OBJECTIVES: To measure the accuracy of currently used intracompartmental pressure (ICP) diagnostic variables for forearm chronic exertional compartment syndrome (CECS) and a new ICP diagnostic variable, TRest, the recovery time between the maximum ICP and return to resting pressure. DESIGN: Retrospective cohort. Level evidence IV. SETTING: University-affiliated tertiary hospital. PARTICIPANTS: Patients with suspected forearm CECS, 1990 to 2014. INTERVENTIONS: All patients underwent physical examination and exertional stress test, preceded and followed by measuring ICP in all suspicious CECS. Surgery was proposed when indicated. Minimum follow-up was 18 months. Final diagnosis was established at the final follow-up. MAIN OUTCOME MEASURES: Intracompartmental pressure measurements: PRest (baseline/pre-exercise pressure), P1 min (pressure 1 minute after exercise), P5 min (pressure 5 minutes after exercise), and TRest. Patients rated their pain and completed Quick-DASH in all follow-ups. Patients ultimately were classified into 4 groups (true positives, true negatives, false positives, and false negatives) for each ICP measurement relative to the final diagnosis. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. RESULTS: A total of 124 male athletes were diagnosed with CECS, 27 bilateral. Accuracy with standard ICP diagnostic variables was lower (sensitivity 73.5%, specificity 84.2%, positive predictive value 97%, and negative predictive value 31.4%) than with TRest (SN 100%, SP 94.7%, PPV 99.3%, and NPV 100%); 23% of patients would have been missed following the standard ICP diagnostic criteria. CONCLUSIONS: Diagnostic thresholds for current standard ICP measurements should be lowered. TRest, a new measure, might be more accurate. PMID- 28817410 TI - Fatty Infiltrate of the Lumbar Multifidus Muscles Predicts Return to Play in Young Athletes With Extension-Based Low Back Pain. AB - OBJECTIVE: To evaluate the predictive value of fatty infiltrate of the lumbar multifidus muscles (LMM) for return to play in young athletes with extension based low back pain (EB LBP). DESIGN: Retrospective cohort study. SETTING: Hospital-based sports medicine practice. PATIENTS: Sixty-two athletes, 61.3% female, and 38.7% male, mean age 14.8 years, with a primary complaint of EB LBP who underwent magnetic resonance imaging (MRI); 46.8% had a pars interarticularis stress reaction or fracture and 53.2% were MRI negative. INTERVENTIONS: A musculoskeletal fellowship-trained radiologist reviewed MRI for all subjects and graded the degree of fatty infiltrate of the LMM, using the Goutallier classification system (GCS), at the L4/L5 and L5/S1 levels. MAIN OUTCOME MEASURE: Days to return to play after first MD visit were correlated with the amount of fatty infiltrate in the LMM measured on MRI for each subject. RESULTS: When the level of fatty infiltrate increased to a 2 or 3 on the GCS (greater than fatty streaks in the muscle), the predicted probability of return to sport decreased significantly. CONCLUSION: Our study demonstrated that athletes with EB LBP and fatty infiltrate in the LMM had lower odds of return to sport compared with athletes with normal muscle. LEVEL OF EVIDENCE: II B. CLINICAL RELEVANCE: This study provides sports medicine clinicians with a prognostic tool to help manage young athletes with EB LBP. Clinicians can make decisions regarding rehabilitation and return to play based on MRI findings. PMID- 28817411 TI - Effects of Recent Concussion and Injury History on Instantaneous Relative Risk of Lower Extremity Injury in Division I Collegiate Athletes. AB - BACKGROUND: Growing evidence suggests that concussion increases the risk of lower extremity (LE) musculoskeletal injury. However, it is unclear to how the effect of concussion on LE injury risk may be influenced by previous injuries. This study sought to examine the association between concussion, previous LE injuries, and the risk LE injury to the same previously injured limb (ipsilateral) or the opposite limb (contralateral). METHODS: This retrospective study examined medical records from 110 concussed athletes and 110 matched controls for LE injuries in the 365 days before and after the concussion event. The effect of concussion on time to injury was assessed with a Cox proportional hazard model after adjusting for injury history. Fine and Gray subdistribution models assessed the cumulative risk of ipsilateral and contralateral injury by group. RESULTS: Concussion was associated with an increased instantaneous relative risk of LE injury when adjusting for LE injury history [hazard ratio (HR) = 1.67, 95% confidence interval (CI) = 1.11-2.53], agreeing with previous results. Among individuals who had a history of LE injuries before the concussion event, a nonsignificant yet moderate effect of concussion on the instantaneous relative risk of ipsilateral injuries was found after adjusting for the competing risk of contralateral injuries and censored values (HR = 1.85, 95% CI = 0.76-4.46). CONCLUSIONS: This study provides independent confirmation of previous studies, reporting an association between concussion and LE injury risk. Furthermore, this study suggests that future large-scale studies should consider the competing risk of ipsilateral, contralateral, and new injuries in populations with an injury history. PMID- 28817412 TI - Effect of Physical Methods of Lymphatic Drainage on Postexercise Recovery of Mixed Martial Arts Athletes. AB - OBJECTIVE: Physical methods are reported to be important for accelerating skeletal muscle regeneration, decreasing muscle soreness, and shortening of the recovery time. The aim of the study was to assess the effect of the physical methods of lymphatic drainage (PMLD) such as manual lymphatic drainage (MLD), the Bodyflow (BF) therapy, and lymphatic drainage by deep oscillation (DO) on postexercise regeneration of the forearm muscles of mixed martial arts (MMA) athletes. DESIGN AND METHODS: Eighty MMA athletes aged 27.5 +/- 6.4 years were allocated to 4 groups: MLD, the BF device, DO therapy, and the control group. Blood flow velocity in the cephalic vein was measured with the ultrasound Doppler velocity meter. Maximal strength of the forearm muscles (Fmax), muscle tissue tension, pain threshold, blood lactate concentration (LA), and activity of creatine kinase were measured in all groups at rest, after the muscle fatigue test (post-ex) and then 20 minutes, 24, and 48 hours after the application of PMLD. RESULTS: The muscle fatigue test reduced Fmax in all subjects, but in the groups receiving MLD, DO, and BF significantly higher Fmax was observed at recovery compared with post-ex values. The application of MDL reduced the postexercise blood LA and postexercise muscle tension. CONCLUSIONS: The lymphatic drainage methods, whether manual or using electro-stimulation and DO, improve postexercise regeneration of the forearm muscles of MMA athletes. The methods can be an important element of therapeutic management focused on optimizing training effects and reducing the risk of injuries of the combat sports athletes. PMID- 28817413 TI - ACTN3 R577X Polymorphism Is Associated With the Incidence and Severity of Injuries in Professional Football Players. AB - OBJECTIVE: The ACTN3 R577X gene variant results in the absence of the alpha actinin-3 protein in ~18% of humans worldwide and has been associated with athletic performance and increased susceptibility to eccentric muscle damage. The aim of this study was to investigate the association between ACTN3 R577X variant and indirect muscle disorders/injuries in professional football players. DESIGN: A case-control, genotype-phenotype association study. INTERVENTION: Two hundred fifty-seven male professional Italian football players (from Serie A, Primavera, Allievi, and Giovanissimi; age = 21.2 +/- 5.3 years) and 265 nonathletic controls were recruited for the study. Genomic DNA was extracted using a buccal swab, and the ACTN3 R577X genotype was performed using a PCR method. Structural-mechanical injuries and functional muscle disorders were collected from a subgroup of 169 football players during the period of 2009 to 2014. MAIN OUTCOME MEASURE: We hypothesized that the 577XX genotype would be associated with higher predisposition to muscle injuries (compared with the other genotypes). RESULTS: ACTN3 XX (alpha-actinin-3 deficiency) players had 2.66 higher odds for an injury incidence than their ACTN3 RR counterparts (95% confidence interval [CI]: 1.09 6.63, P = 0.02), whereas RX and RR players had similar injury incidence. Furthermore, ACTN3 XX players had 2.13 higher odds for having a severe injury compared with their RR counterparts (95% CI: 1.25-3.74, P = 0.0054), whereas RX individuals had 1.63 higher odds for having a severe injury compared with the RR players (95% CI: 1.10-2.40, P = 0.015). CONCLUSIONS: The ACTN3 R577X polymorphism is associated with the incidence and severity of muscle injuries in professional football players; players with the ACTN3 577XX genotype have higher odds of having muscle injuries than their RR counterparts. CLINICAL RELEVANCE: Discovering the complex relationship between gene variants and muscle injuries may assist coaches, physiologists, and the medical community to development tailored injury prevention program for football players, which could provide a new edge for successful competition. PMID- 28817414 TI - Systematic Selection of Key Logistic Regression Variables for Risk Prediction Analyses: A Five-Factor Maximum Model. AB - GENERAL AND CRITICAL REVIEW FORMAT: The evolution of clinical practice and medical technology has yielded an increasing number of clinical measures and tests to assess a patient's progression and return to sport readiness after injury. The plethora of available tests may be burdensome to clinicians in the absence of evidence that demonstrates the utility of a given measurement. OBJECTIVE: Thus, there is a critical need to identify a discrete number of metrics to capture during clinical assessment to effectively and concisely guide patient care. DATA SOURCES: The data sources included Pubmed and PMC Pubmed Central articles on the topic. Therefore, we present a systematic approach to injury risk analyses and how this concept may be used in algorithms for risk analyses for primary anterior cruciate ligament (ACL) injury in healthy athletes and patients after ACL reconstruction. MAIN RESULTS: In this article, we present the five-factor maximum model, which states that in any predictive model, a maximum of 5 variables will contribute in a meaningful manner to any risk factor analysis. CONCLUSIONS: We demonstrate how this model already exists for prevention of primary ACL injury, how this model may guide development of the second ACL injury risk analysis, and how the five-factor maximum model may be applied across the injury spectrum for development of the injury risk analysis. PMID- 28817415 TI - New model of vincristine-induced neuropathic pain in children: a first step towards prediction and prevention. PMID- 28817417 TI - Brain processing of the temporal dimension of acute pain in short-term memory. AB - The dynamics of noxious sensation shapes pain perception, yet the memory of the temporal dimension of pain remains almost completely unexplored. Here, brain activity during the memory of pain duration was contrasted with that associated with the memory of pain intensity using functional magnetic resonance imaging and a delayed reproduction task. Participants encoded, maintained during a short delay, and reproduced (1) the "duration" of pain (ie, onset-to-offset), (2) the "dynamics" of pain (ie, evolution of pain over time), or (3) the intensity of pain (ie, control with no explicit temporal processing required). Results show that the inferior frontal gyrus/insula and adjacent striatal structures as well as the supramarginal and middle temporal gyri are activated in the duration task compared to the control intensity task. Specific examination of the memory delay of the duration task further revealed activation in the supramarginal gyrus extending to the parietal operculum (possibly SII) and primary somatosensory cortex (SI). In contrast, the memory delay of the dynamic task involved the bilateral supplementary motor area and the frontoparietal attentional network. Although SI, SII, and insula may contribute to the memory trace of pain sensation, other areas less commonly reported in pain studies are associated with time processing and may therefore contribute to the processing of temporal aspects of pain. Results further suggest a differential role of core timing regions of the brain depending on specific task instructions and attentional allocations to the single dimension of time, as compared to the joint processing of both time and intensity. PMID- 28817418 TI - Neuromodulation and neurofeedback treatments in eating disorders and obesity. AB - PURPOSE OF REVIEW: Psychological interventions are the treatment of choice for most eating disorders; however, significant proportions of patients do not recover with these. Advances in understanding of the neurobiology of eating disorders have led to the development of targeted treatments, such as deep brain stimulation (DBS), noninvasive brain stimulation (NIBS), and neurofeedback. We review the emerging clinical evidence for the use of these interventions in eating disorders and obesity, together with their theoretical rationale. Finally, we reflect on future developments. RECENT FINDINGS: During the last 20 months, seven case studies/series and seven randomized controlled trials (RCTs) of NIBS or neurofeedback in different eating disorders, obesity, or food craving have appeared. These have largely had promising results. One NIBS trial, using a multisession protocol, was negative. A case series of subcallosal DBS in anorexia nervosa has also shown promise. A search of trial registries identified a further 21 neuromodulation/feedback studies in progress, indicating that neuromodulation/feedback is an area of growing interest. SUMMARY: At present, neuromodulation and neurofeedback are largely experimental interventions; however, growing understanding of the mechanisms involved, together with the rising number of studies in this area, means that the clinical utility of these interventions is likely to become clearer soon. PMID- 28817416 TI - Nicotinic modulation of descending pain control circuitry. AB - Along with the well-known rewarding effects, activation of nicotinic acetylcholine receptors (nAChRs) can also relieve pain, and some nicotinic agonists have analgesic efficacy similar to opioids. A major target of analgesic drugs is the descending pain modulatory pathway, including the ventrolateral periaqueductal gray (vlPAG) and the rostral ventromedial medulla (RVM). Although activating nAChRs within this circuitry can be analgesic, little is known about the subunit composition and cellular effects of these receptors, particularly within the vlPAG. Using electrophysiology in brain slices from adult male rats, we examined nAChR effects on vlPAG neurons that project to the RVM. We found that 63% of PAG-RVM projection neurons expressed functional nAChRs, which were exclusively of the alpha7-subtype. Interestingly, the neurons that express alpha7 nAChRs were largely nonoverlapping with those expressing MU-opioid receptors (MOR). As nAChRs are excitatory and MORs are inhibitory, these data suggest distinct roles for these neuronal classes in pain modulation. Along with direct excitation, we also found that presynaptic nAChRs enhanced GABAergic release preferentially onto neurons that lacked alpha7 nAChRs. In addition, presynaptic nAChRs enhanced glutamatergic inputs onto all PAG-RVM projection neuron classes to a similar extent. In behavioral testing, both systemic and intra-vlPAG administration of the alpha7 nAChR-selective agonist, PHA-543,613, was antinociceptive in the formalin assay. Furthermore, intra-vlPAG alpha7 antagonist pretreatment blocked PHA-543,613-induced antinociception via either administration method. Systemic administration of submaximal doses of the alpha7 agonist and morphine produced additive antinociceptive effects. Together, our findings indicate that the vlPAG is a key site of action for alpha7 nAChR mediated antinociception. PMID- 28817420 TI - OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY FOR THE DETECTION OF SECONDARY CHOROIDAL NEOVASCULARIZATION IN VITELLIFORM MACULAR DYSTROPHY. AB - PURPOSE: Optical coherence tomography angiography (OCTA) is used to assess vascular abnormality in advanced stage vitelliform macular dystrophy (VMD2). METHODS: Multimodal imaging including spectral domain (SD) OCT, autofluorescence (AF), fluorescein (FA) and indocyanine green angiography (ICGA) as well as optical coherence tomography angiography were performed. PATIENTS: Two eyes in one young patient with diagnosed vitelliform macular dystrophy were investigated for progressive visual dysfunction. RESULTS: Optical coherence tomography angiography identified neovascular formation within the outer retina and the choriocapillaris respectively while all other imaging methods were inconclusive. CONCLUSION: Optical coherence tomography angiography was superior to conventional angiography in the detection of choroidal neovascularization (CNV) in advanced retinal disorders like vitelliform macular dystrophy. PMID- 28817419 TI - The Association of Fat and Lean Tissue With Whole Body and Spine Bone Mineral Density Is Modified by HIV Status and Sex in Children and Youth. AB - BACKGROUND: HIV-infected (HIV-pos) male children/youth showed lower bone mineral density at sexual maturity than HIV-uninfected (HIV-neg) females. It is not known whether complications of HIV disease, including abnormal body fat distribution, contribute to lower bone accrual in male HIV-pos adolescents. METHODS: In a cross sectional study, we evaluated the relationship between body composition (fat and lean mass) and bone mass in HIV-pos and HIV-neg children/youth and determined if it is modified by HIV status and sex. We used generalized estimating equations to simultaneously model the effect of fat/lean mass on multiple bone outcomes, including total body bone mineral density and bone mineral content and spine bone mineral density. We evaluated effect modification by HIV and sex. RESULTS: The analysis cohort consisted of 143 HIV-neg and 236 HIV-pos, of whom 55% were black non-Hispanic and 53% were male. Ages ranged from 7 to < 25 years. Half of the children/youth were at Tanner stage 1 and 20% at Tanner 5. Fat mass was more strongly positively correlated with bone mass in HIV-neg than HIV-pos children/youth and these relationships were more evident for total body bone than spine outcomes. Within HIV strata, fat mass and bone were more correlated in female than male children/youth. The relationship between lean mass and bone varied by sex, but not by HIV status. CONCLUSIONS: HIV disease diminishes the positive relationship of greater fat mass on bone mass in children/youth. Disruptions in body fat distribution, which are common in HIV disease, may have an impact on bone accretion during pubertal development. PMID- 28817423 TI - Boring Is Beautiful in Preoperative Assessment. PMID- 28817421 TI - Association of STOP-Bang Questionnaire as a Screening Tool for Sleep Apnea and Postoperative Complications: A Systematic Review and Bayesian Meta-analysis of Prospective and Retrospective Cohort Studies. AB - BACKGROUND: The risk of postoperative complications increases with undiagnosed obstructive sleep apnea (OSA). The high-risk OSA (HR-OSA) patients can be easily identified using the STOP-Bang screening tool. The aim of this systematic review and meta-analysis is to determine the association of postoperative complications in patients screened as HR-OSA versus low-risk OSA (LR-OSA). METHODS: The following data bases were searched from January 1, 2008, to October 31, 2016, to identify the eligible articles: Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Cochrane Databases of Systematic Reviews, Medline-in-Process & other nonindexed citations, Google Scholar, Embase, Web of Sciences and Scopus. The search included studies with adult surgical patients screened for OSA with STOP-Bang questionnaire that reported at least 1 cardiopulmonary or any other complication requiring intensive care unit admission as diagnosis of outcome. We used a Bayesian random-effects analysis to evaluate the existing evidence of STOP Bang in relation to OSA and to assess the association of postoperative complications with the identified HR-OSA patients by study design and methodologies. RESULTS: This systematic review and meta-analysis was conducted using 10 cohort studies: 23,609 patients (HR-OSA, 7877; LR-OSA, 15,732). The pooled odds of perioperative complications were higher in the HR-OSA versus LR OSA patients (odds ratio 3.93, 95% credible interval, 1.85-7.77, P= .003; 6.86% vs 4.62%). The length of hospital stay was longer in HR-OSA by 2 days when compared with LR-OSA (5.0 +/- 4.2 vs 3.4 +/- 2.8 days; mean difference 2.01; 95% credible interval, 0.77-3.24; P= .005). Meta-regression to adjust for baseline confounding factors and subgroup analysis did not materially change the results. CONCLUSIONS: This systematic review and meta-analysis suggests that HR-OSA is related with higher risk of postoperative adverse events and longer length of hospital stay when compared with LR-OSA patients. Our findings support the implementation of the STOP-Bang screening tool for perioperative risk stratification. PMID- 28817424 TI - Impact of Simulator-Based Training in Focused Transesophageal Echocardiography: A Randomized Controlled Trial. AB - BACKGROUND: The aim of the study was to determine if training in transesophageal echocardiography (TEE) using a TEE simulator improves the ability of novice operators to perform and interpret a focused critical care TEE. METHODS: In this prospective, randomized, controlled study with blinded outcome assessment, 44 intensive care unit trainees were randomly assigned to a control group receiving 4 hours of lecture-based training only, or an intervention group which was additionally trained for 4 hours using a TEE simulator. After the training intervention, each participant performed 2 TEEs in intensive care unit patients which were evaluated by blinded assessors. The imaging quality of TEEs was measured using a predefined examination quality score ranging from 0 to 100 points. The correct quantification of pathologies and the interpretation of the TEEs were evaluated by blinded assessors using focused and comprehensive expert TEEs as comparators. RESULTS: A total of 114 TEEs were assessed. The mean examination quality score was 55.9 (95% confidence interval [CI], 50.3-61.5) for TEEs of the control group, 75.6 (95% CI, 70.1-81.0) for TEEs of the intervention group, and 88.5 (95% CI, 79.3-97.7) for TEEs in the expert group. The multiple comparisons revealed significant differences between all groups (19.7 [95% CI, 12.8-26.6], P < .001 for intervention versus control; 32.6 [95% CI, 23.0-42.3], P < .001 for expert versus control; 12.9 [95% CI, 3.4-22.5], P = .008 for expert versus intervention). Substantial agreement of the quantification and interpretation ratings of basic TEEs by the intervention (86.7% for quantification and 97.1% for interpretation) or expert group (93.2% for quantification and 98.4% for interpretation) with blinded assessors was detected. The control groups TEEs agreed less (75.6% for quantification and 91.8% for interpretation). CONCLUSIONS: Simulation-based TEE training improves the ability of novice operators to perform a focused critical care TEE in comparison to lecture-based education only. After 8 hours of simulator and lecture-based training, the majority of TEEs of novices are of sufficient quality for clinical use. Furthermore, a substantial skill level in correct quantification and interpretation of imaging is achieved. PMID- 28817425 TI - Hypothermia Risk With Intraoperative Continuous Renal Replacement Therapy. PMID- 28817427 TI - What Predicts Ongoing Nonsuicidal Self-Injury?: A Comparison Between Persistent and Ceased Self-Injury in Emerging Adults. AB - Although nonsuicidal self-injury (NSSI) peaks in adolescence, a significant proportion of young people continue to self-injure into emerging adulthood. Yet, little is known about factors prospectively associated with persistent NSSI. Using data from a 3-year longitudinal study (n = 1466), we compared 51 emerging adults (67.3% female; average age, 20.0 years) who continued to self-injure from adolescence and 50 emerging adults (83.7% female; average age, 20.3 years) who had ceased NSSI, on a broad range of psychosocial factors. More frequent NSSI, use of a greater number of methods, specific NSSI functions, academic and emotional distress, and lack of perceived emotion regulatory capability differentiated emerging adults who continued with NSSI and those who had ceased the behavior. Further, the relationships between social support, life satisfaction, and NSSI were mediated by perceived ability to regulate emotion. Findings from this study point to the role of personal belief in the ability to effectively regulate emotion in the cessation of NSSI. Future research directions and clinical implications are discussed. PMID- 28817428 TI - Interprofessional QI Training Enhances Competency and QI Productivity Among Graduates: Findings From Nationwide Children's Hospital. AB - PURPOSE: Significant resources are expended on quality improvement (QI) training courses. The authors sought to determine whether education provided in QI course training improves self-assessed QI content competence and QI-related productivity among course graduates. METHOD: "Quality Improvement Essentials" is a four-month didactic and experiential course designed to prepare multidisciplinary professionals to participate in and lead QI efforts at Nationwide Children's Hospital (NCH). This study used a milestone-based self-assessment survey of graduates from 2012 to 2014 to gauge change in participants' self-assessed QI competency after course completion. Four competency domains were evaluated: QI knowledge; testing and implementing change using teams; data management and analysis; and spreading and sustaining science. Metrics for assessing individual QI productivity were presentation or publication of QI work outside NCH; local, regional, or national QI teaching; serving on a local, regional, or national QI committee; appointment as a QI leader; involvement in an internal or external QI collaborative; and leading a maintenance of certification Part IV project approved by NCH. RESULTS: Course participation more than doubled participants' self-assessed QI competence across all four domains. Gains continued after the course, increasing with time rather than degrading. Self-assessed competency increase was significantly associated with increased QI productivity. CONCLUSIONS: Self-assessed QI competence dramatically improved after participation in an educational course and continued to increase over time. Increased self-assessed QI competency correlated with increased individual QI productivity. Further studies are necessary to fully evaluate "return on investment" for this type of course. PMID- 28817429 TI - The Rising Challenge of Training Physician-Scientists: Recommendations From a Canadian National Consensus Conference. AB - Physician-scientists are individuals who actively participate in patient care, have undergone additional research training, and devote the majority of their time to research. Physician-scientists are traditionally the primary catalysts in bridging the translational gap-that is, the failure to link fundamental new knowledge in the pathobiology of disease with advances in health care and health policy in a timely manner. However, there has been a shift away from training physician-scientists, and financial support for the physician-scientist is diminishing globally, causing the translational gap to grow. Given its socialized health care system and cultural and geographic diversity, Canada can serve as a unique case study in understanding how to address this phenomenon as a national priority. To this end, a Canadian national consensus conference was convened to develop recommendations for training programs and early-career supports for physician-scientists. Five recommendations were generated: (1) Establish an independent, national council whose mandate is to provide pan-Canadian oversight of physician-scientist training programs; (2) develop capacity for funding and mentorship support for physician-scientists; (3) develop coherent networks across a broad range of clinician-scientists, including physician-scientists, to reflect the unique cultural and geographic diversity of Canada and to reflect the interdisciplinarity of health research; (4) ensure that medical school curricula integrate, as a core curriculum feature, an understanding of the scientific basis of health care, including research methodologies; and (5) ensure that the funding of the physician-scientist trainee is viewed as portable and distinct from the operational funding provided to the training program itself. PMID- 28817430 TI - Beyond Citation Rates: A Real-Time Impact Analysis of Health Professions Education Research Using Altmetrics. AB - PURPOSE: To complement traditional citation-based metrics, which take years to accrue and indicate only academic attention, academia has begun considering altmetrics or alternative metrics, which provide timely feedback on an article's impact by tracking its dissemination via nontraditional outlets, such as blogs and social media, across audiences. This article describes altmetrics and examines altmetrics attention, outlets used, and top article characteristics for health professions education (HPE) research. METHOD: Using Altmetric Explorer, a tool to search altmetrics activity, the authors searched for HPE articles that had at least one altmetrics event (e.g., an article was tweeted or featured in a news story) between 2011 and 2015. Retrieved articles were analyzed using descriptive statistics. In addition, the 10 articles with the highest Altmetric Attention Scores were identified and their key characteristics extracted. RESULTS: The authors analyzed 6,265 articles with at least one altmetrics event from 13 journals. Articles appeared in 14 altmetrics outlets. Mendeley (161,470 saves), Twitter (37,537 tweets), and Facebook (1,650 posts) were most popular. The number of HPE articles with altmetrics attention increased 145%, from 539 published in 2011 to 1,321 in 2015. In 2015, 50% or more of the articles in 5 journals received altmetrics attention. Themes for articles with the most altmetrics attention included social media or social networking; three such articles were written as tips or guides. CONCLUSIONS: Increasing altmetrics attention signals interest in HPE research and the need for further investigation. Knowledge of popular and underused outlets may help investigators strategically share research for broader dissemination. PMID- 28817431 TI - Challenges in Health Care Simulation: Are We Learning Anything New? AB - The growth of health care simulation in schools of medicine and nursing is noteworthy, as is the increasingly sophisticated simulation technology, support from funding agencies and foundations for research, well-attended annual conferences, and continued interest of accreditation and certification groups. Yet there are concerns preventing the full value of health care simulation to be realized when examined from a patient safety perspective. Basic questions are asked by funders of patient safety research when assessing past simulation projects undertaken to advance patient safety: Are the safety and quality of care to patients actually improved, and is something new being learned regarding the optimal use of simulation? Concerns focus on pursuing the right research questions to learn something new about the most effective use of simulation; doing more with simulation than simply providing an interesting, stand-alone educational experience; attending more seriously to how skill acquisition, maintenance, and progression get managed; and encouraging investigators, funders, and reviewers to expand their vision regarding what constitutes important inquiry and evidence in health care simulation. Patient safety remains a multifaceted challenge in the United States, requiring multifaceted approaches. Simulation training is considered a promising approach for improving the safety and quality of health services delivery. While it takes time for any new approach to gain momentum and learn from past efforts, it also will require addressing a systematic range of essential questions to improve existing knowledge on the optimal use of simulation, and to realize similar gains in safety that other high risk industries have made. PMID- 28817432 TI - The Problems With Burnout Research. AB - Burnout among physicians and physicians-in-training is well established as a potential threat to the health and well-being of health care providers and patients. However, there are myriad problems with current burnout research and its ongoing measurement that threaten the validity of the conclusions. For example, researchers have used differing ways of defining and measuring burnout. Those who have used the Maslach Burnout Inventory vary in recommended use of the instrument and cutoff scores. As a result, the authors suggest that the term "burnout" may be misused and recommend some reconsideration of the meaning of burnout. The measurement and discussion of burnout have strong implications for interventions and policy alike. In this article, the authors review the problems with burnout research and ask important questions about the future directions of research efforts. The authors recommend a consistent measurement approach and perhaps moving toward a focus on physician wellness from a positive psychology perspective. PMID- 28817433 TI - Class-Wide Access to a Commercial Step 1 Question Bank During Preclinical Organ Based Modules: A Pilot Project. AB - PURPOSE: The authors examined the usefulness of a commercially available Step 1 question bank as a formative academic support tool throughout organ-based modules in an integrated preclinical medical curriculum. The authors also determined the extent to which correlation between question bank utilization and academic metrics varied with Medical College Admission Test (MCAT) scores. METHOD: In 2015, a cohort of 185 first-year medical students at University of Alabama School of Medicine were provided with 18-month full access to a commercially available Step 1 question bank of over 2,100 items throughout organ-based modules, although there were no requirements for use. Data on student use of the question bank were collected via an online administrative portal. Relationships between question bank utilization and academic outcomes including exams, module grades, and United States Medical Licensing Examination (USMLE) Step 1 were determined using multiple linear regression. RESULTS: MCAT scores and number of items attempted in the question bank significantly predicted all academic measures, with question bank utilization as the stronger predictor. The association between question bank utilization and academic outcome was stronger for individuals with lower MCAT scores. CONCLUSIONS: The findings elucidate a novel academic support mechanism that, for some programs, may help bridge the gap between holistic and mission based admissions practices and a residency match process that places a premium on USMLE exam scores. Distributed formative use of USMLE Step 1 practice questions may be of value as an academic support tool that benefits all students, but particularly those entering with lower MCAT scores. PMID- 28817436 TI - Why Do General Surgeons Decide to Retire?: A Population-level Survey. AB - : Limited recent data exist regarding intended retirement plans for general surgeons (GS). We sought to understand when and why surgeons decide to stop operating as primary surgeon and stop all clinical work.A paper-based survey of practicing GS in the province of Ontario, Canada, was conducted. A questionnaire was developed using a systematic approach of item generation and reduction. Face and content validity were tested. The survey was administered via mail, with a planned reminder.Overall response rate was 33.5% (242/723). The median age at which respondents planned to/did stop operating was 65 (interquartile range 60 67.5). The median age at which respondents planned to/did retire from all clinical work was 70 (interquartile range 65-72.5). Career satisfaction (97%), sense of identity (90%), and financial need (69%) were factors that influenced the decision to continue operating. Enjoyment of work (79%), camaraderie with surgical colleagues (66%), and financial need (45%) were reasons to continue working after ceasing to operate as the primary surgeon. On multivariate analysis, younger respondents (36-50 years old) perceived they were less likely to continue operating past age 65 (odds ratio 0.13), and academic surgeons were more likely to stop operating after age 65 (odds ratio 2.39). Call coverage by nonstaff surgeons was not associated with retirement age.Overall, GS plan to stop operating at age 65, and to cease all clinical activities at age 70. Younger, nonacademic surgeons plan to stop operating earlier. Career satisfaction, sense of identity, and financial need are the principal reported motivations to continue operating. PMID- 28817437 TI - Surgicopathological Quality Control and Protocol Adherence to Lymphadenectomy in the CRITICS Gastric Cancer Trial. AB - OBJECTIVE: The purpose of this study was to evaluate surgicopathological quality and protocol adherence for lymphadenectomy in the CRITICS trial. SUMMARY OF BACKGROUND DATA: Surgical quality assurance is a key element in multimodal studies for gastric cancer. In the multicenter CRITICS trial (ChemoRadiotherapy after Induction chemotherapy In Cancer of the Stomach), patients with resectable gastric cancer were randomized for preoperative chemotherapy, followed by gastrectomy with a D1+ lymphadenectomy (removal of stations 1 to 9 and 11), followed by either chemotherapy or chemoradiotherapy. METHODS: Surgicopathological compliance was defined as removal of >=15 lymph nodes. Surgical compliance was defined as removal of the indicated lymph node stations. Surgical contamination was defined as removal of lymph node stations that should be left in situ. The Maruyama Index (MI, lower is better), which has proven to be an indicator of surgical quality and is strongly associated with survival, was analyzed. RESULTS: Between 2007 and 2015, 788 patients were randomized, of whom 636 patients underwent a gastrectomy with curative intent. Surgicopathological compliance occurred in 72.8% (n = 460) of the patients and improved from 55.0% (2007) to 90.0% (2015). Surgical compliance occurred in 41.1% (n = 256). Surgical contamination occurred in 59.6% (n = 371). Median MI was 1 (range 0 to 136). CONCLUSION: Surgical quality in the CRITICS trial was excellent, with a MI of 1. Surgicopathological compliance improved over the years. This might be explained by the quality assurance program within the study and centralization of gastric cancer surgery in the Netherlands. PMID- 28817434 TI - Everolimus Is Associated With Less Weight Gain Than Tacrolimus 2 Years After Liver Transplantation: Results of a Randomized Multicenter Study. AB - BACKGROUND: Weight gain early after transplant is a risk factor for posttransplant metabolic syndrome (PTMS), cardiovascular events, and renal insufficiency. The impact of mammalian target of rapamycin inhibition on posttransplant weight gain and the development of PTMS components postliver transplantation were examined in a randomized, controlled study. METHODS: After a run-in period, patients (N = 719) were randomized at 30 +/- 5 days posttransplant in a 1:1:1 ratio to 3 treatment groups: (i) everolimus (EVR) + reduced tacrolimus (TAC) (n = 245); (ii) TAC control (n = 243) or (iii) TAC elimination (n = 231). In this post hoc analysis, weight change at 12 and 24 months was compared between groups. Vital signs, lipids, and laboratory parameters at 12 and 24 months and rates of PTMS were assessed. RESULTS: Mean increase in weight from baseline was higher at month 12 in the TAC control arm (8.15 +/- 9.27 kg) than in the EVR + reduced TAC (5.88 +/- 12.60 kg, P = 0.056) and the TAC elimination arms (4.76 +/- 9.94 kg, P = 0.007). At month 24, the TAC control arm displayed a significantly greater weight increase (9.54 +/- 10.21 kg) than either the EVR + reduced TAC (6.69 +/- 8.37 kg, P = 0.011) or the TAC elimination groups (6.01 +/- 9.98 kg, P = 0.024). Rates of PTMS were similar for the EVR + reduced TAC (71.8%), TAC elimination (70.3%) and TAC control (67.4%) arms (P = NS). CONCLUSIONS: EVR with reduced-exposure TAC attenuated weight gain at 1 and 2 years posttransplant compared with a standard TAC immunosuppression regimen. Rates of PTMS were comparable between EVR-containing and TAC control regimens. PMID- 28817438 TI - Alternatively Activated Macrophages Drive Browning of White Adipose Tissue in Burns. AB - OBJECTIVE: The aim of this study was to uncover the mediators and mechanistic events that facilitate the browning of white adipose tissue (WAT) in response to burns. BACKGROUND: In hypermetabolic patients (eg, burns, cancer), the browning of WAT has presented substantial clinical challenges related to cachexia, atherosclerosis, and poor clinical outcomes. Browning of the adipose tissue has recently been found to induce and sustain hypermetabolism. Although browning appears central in trauma-, burn-, or cancer-induced hypermetabolic catabolism, the mediators are essentially unknown. METHODS: WAT and blood samples were collected from patients admitted to the Ross Tilley Burn Centre at Sunnybrook Hospital. Wild type, CCR2 KO, and interleukin (IL)-6 KO male mice were purchased from Jax laboratories and subjected to a 30% total body surface area burn injury. WAT and serum collected were analyzed for browning markers, macrophages, and metabolic state via histology, gene expression, and mitochondrial respiration. RESULTS: In the present study, we show that burn-induced browning is associated with an increased macrophage infiltration, with a greater type 2 macrophage profile in the fat of burn patients. Similar to our clinical findings in burn patients, both an increase in macrophage recruitment and a type 2 macrophage profile were also observed in post burn mice. Genetic loss of the chemokine CCR2 responsible for macrophage migration to the adipose impairs burn-induced browning. Mechanistically, we show that macrophages recruited to burn-stressed subcutaneous WAT (sWAT) undergo alternative activation to induce tyrosine hydroxylase expression and catecholamine production mediated by IL-6, factors required for browning of sWAT. CONCLUSION: Together, our findings uncover macrophages as the key instigators and missing link in trauma-induced browning. PMID- 28817439 TI - Faculty Development for the Operating Room: An Examination of the Effectiveness of an Intraoperative Teaching Course for Surgeons. AB - OBJECTIVE: We describe a half-day faculty development course designed to equip surgical educators with evidence-based teaching frameworks shown to promote learning in the operating room (OR). We hypothesize that participating faculty will deliver improved instruction as perceived by residents. METHODS: Residents anonymously rated faculty teaching behaviors among whom they had recently worked in the OR (minimum 3 cases in preceding 6 months) using the Briefing - Intraoperative teaching - Debriefing Assessment Tool (BIDAT; 1 = never, 5 = always). Faculty then attended a half-day course. The curriculum was based on the "briefing-intraoperative teaching-debriefing" framework. Discussion and practice centered on goal setting, performance-enhancing instruction, dual task interference, and feedback. After the course, residents again evaluated the faculty. Paired-samples and independent-samples t tests were used to analyze pre and post course changes and differences between groups, respectively. RESULTS: Nineteen faculty completed the course. Associate professors (N = 4) demonstrated improved briefing (4.32 +/- 0.48 -> 4.76 +/- 0.45, P < 0.01), debriefing (4.30 +/ 0.29 -> 4.77 +/- 0.43, P < 0.01), and total teaching (4.38 +/- 0.78 -> 4.79 +/- 0.39, P < 0.05). No significant changes were observed among assistant (N = 9) or full professors (N = 6). All 3 faculty members who served as course co instructors, regardless of rank, improved significantly in briefing (4.42 +/- 0.22 -> 4.98 +/- 0.29, P < 0.05), debriefing (4.27 +/- 0.23 -> 4.98 +/- 0.29, P < 0.04), and total teaching (4.37 +/- 0.21 -> 4.99 +/- 0.02, P < 0.05). Faculty with baseline teaching scores in the bottom quartile improved teaching behaviors in all phases of instruction (P < 0.05). Teaching scores over the same period did not change among faculty who did not attend. CONCLUSIONS: A half-day course aimed at enhancing intraoperative instruction can contribute to resident-perceived improvement in structured teaching behavior among participating faculty. Initiatives directed at intraoperative instruction might be best targeted towards midlevel faculty with established technical expertise who are motivated to expand teaching efforts and those who have low levels of baseline teaching scores. PMID- 28817440 TI - Reply to the Editor. PMID- 28817441 TI - Response: Health Insurance Coverage Is Critical to the Financial Wellbeing of Trauma Patients and Trauma Centers. PMID- 28817442 TI - Aspirin Therapy on Blood Transfusion in Noncardiac Surgery: Evidence From Quality Effect Model. PMID- 28817443 TI - Impact of Different Surgical Techniques on Outcomes in Laparoscopic Sleeve Gastrectomies: First Report From the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP). PMID- 28817444 TI - Strategies for Reducing Population Surgical Costs in Medicare: Local Referrals to Low-cost Hospitals. AB - OBJECTIVE: We sought to assess hospital cost variation for elective inpatient surgical procedures within small geographic areas. SUMMARY BACKGROUND DATA: Previous studies have documented cost variation for inpatient surgical procedures on a national basis, suggesting opportunities for savings. Cost variation within small geographic areas is more relevant to policymakers, providers, and patients, but it has not been studied. METHODS: Using Medicare payment data, we identified elderly patients undergoing 1 of 7 elective inpatient surgical procedures during 2010-2012. We calculated 30-day surgical episode costs including payments for the index hospitalization, readmission, physician services, and post-acute care. Using hierarchical regression models, we identified hospitals with significantly higher average costs than the least expensive hospitals in their metropolitan statistical areas. RESULTS: The proportion of patients undergoing surgery at the lowest-cost hospitals in their metropolitan statistical areas ranged from 10% for hip replacement to 25% for coronary artery bypass grafting. In contrast, the proportion of patients undergoing surgery at significantly higher-cost hospitals ranged from 5.0% for bariatric surgery to 64% for hip replacement. These high cost hospitals had higher complication and readmission rates than their lowest cost peers. Surgery at high-cost hospitals resulted in Medicare expenditures that were $4427 to $10,417 higher than those at the lowest-cost hospitals, increasing episode costs by 25% to 47% per case. CONCLUSIONS: Significant excess expenditures are incurred due to care at hospitals with substantially higher average costs than their nearby peers. This finding highlights the potential for substantial savings without the need to refer patients over long distances. Some of the procedures studied may represent appropriate targets for future Medicare bundled payment initiatives. PMID- 28817445 TI - The safety of pembrolizumab in metastatic melanoma and rheumatoid arthritis. AB - Immunotherapy has been in use for the treatment of melanoma since a very long time, but only recently have the cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody ipilimumab and programmed cell death-1 inhibitors such as nivolimumab and pembrolizumab been shown to induce marked improvements in survival in patients with metastatic melanoma. An important concern arises in terms of the safety of the use of these agents in patients with autoimmune diseases, solid organ transplant recipients on immunosuppression, patients with a history of previous hepatitis B or C, and patients with HIV infections as these patients were excluded from pivotal immunotherapy studies. Here, we report on the safety and efficacy of pembrolizumab in a melanoma patient with multiple medical problems including poorly controlled rheumatoid arthritis and we review the available literature on the use of immunotherapy and autoimmune diseases. The weight of evidence suggests that these patients should be offered the opportunity to benefit from immune check point inhibitors, with drugs targeting programmed cell death-1 being preferred. More research is required to study the long-term effects of immunotherapy on patients with autoimmune diseases. PMID- 28817446 TI - Bevacizumab as an effective treatment for radiation necrosis after radiotherapy for melanoma brain metastases. AB - Radiation necrosis (RN) is a potential late complication of radiotherapy for intracranial malignancy, which is often associated with significant neurological morbidity. Prolonged treatment with high-dose corticosteroids or surgical resection has been the standard care for RN, but protracted steroid use can lead to significant side effects and surgical resection is not always feasible. The antivascular endothelial growth factor monoclonal antibody bevacizumab induces clinical and radiographic improvements in RN, with overall good tolerance. However, evidence supporting its use for RN in melanoma brain metastases is minimal, likely secondary to concern for intracranial bleeding. Immunotherapy is now one of the most commonly used and effective therapies for metastatic melanoma. A higher risk of RN has been reported with immunotherapy, making alternative treatment for RN in this population a priority, especially as prolonged use of steroids may counteract the treatment efficacy of immunotherapy. We report on seven melanoma patients who developed RN after stereotactic radiosurgery with or without whole-brain radiation therapy who were treated with 2-6 doses of bevacizumab. All patients experienced improvements in symptoms and quality of life, with a concurrent improvement in imaging in six patients. Furthermore, bevacizumab was well tolerated and none of the seven patients experienced intracranial or extracranial bleeding. Our series suggests that in selected melanoma brain metastases patients, bevacizumab may be a safe and effective treatment for RN, especially for those who are undergoing immunotherapy, and should be further evaluated in a prospective setting. PMID- 28817447 TI - A Stress Coping App for Hospitalized Pregnant Women at Risk for Preterm Birth. AB - BACKGROUND: Pregnant women hospitalized with preterm labor (PTL) complications experience increased stress. Prior researchers have attempted to provide stress management strategies with use of various media players to deliver stress coping interventions. PURPOSE: The purpose of this study was to examine the efficacy of a mobile device delivered stress coping app designed to reduce stress in a sample of high-risk pregnant women hospitalized with complications of PTL. METHODS: A descriptive study using a prospective mixed methods one-group pre/posttest design. Fifteen pregnant women used the mobile device app for 8 consecutive days. The app included study measures, educational overview of concepts, four guided imagery audio files to be listened to daily, and a stress self-assessment scale to be used before and after each use. Measures included: Perceived Stress Scale (PSS), Visual Analog Stress Scale (VASS), Coping Self-Efficacy Scale (CSES), and semistructured interviews. RESULTS: There was a significant drop in VASS scores when comparing scores before and after listening to the app (p < 0.0001). There were no significant differences between the baseline and Day 8 scores of PSS or CSES. All participants reported benefits from using the app and provided suggestions for improvement. CLINICAL IMPLICATIONS: The intervention reduced immediate stress and provided a respite from the stress response in this population. Maternal child nurses may consider incorporating stress coping interventions as standard care practice. PMID- 28817448 TI - The Modification of Disease Nomenclature. PMID- 28817449 TI - Classifying Skin Failure. PMID- 28817450 TI - Have You Read the Revised Surgical Dressing Local Coverage Determination and Article? PMID- 28817451 TI - Relative Temperature Maximum in Wound Infection and Inflammation as Compared with a Control Subject Using Long-Wave Infrared Thermography. AB - OBJECTIVE: The purpose of this retrospective case series was to determine whether a long-wave infrared thermography (LWIT, or thermal imaging) camera can detect specific temperature changes that are associated with wound infection and inflammation as compared with normal control subjects with similar anatomical wound locations. DESIGN: A retrospective, observational, collective, multiple case series of patients who underwent digital and thermal imaging of wounds in various states. SETTING: The subjects were selected from multiple sites including an outpatient wound care clinic, a wound care physician's office, a rehabilitation hospital, and a home healthcare organization. PATIENTS: Six subjects were selected for inclusion, including 2 each for the infection, inflammation, and normal control groups. MAIN OUTCOME MEASURE: The study collected relative temperature maximums as obtained and recorded by LWIT and digital imaging. MAIN RESULTS: In this case series, the authors demonstrate the use of an FDA-approved Scout (WoundVision, Indianapolis, Indiana) dual-imaging long-wave infrared and digital cameras to analyze images of wounds. In the 2 cases with clinically diagnosed wound infection, LWIT showed an elevation of temperature as evidenced by a maximum temperature differential between the wound and healthy skin of +4 degrees C to 5 degrees C. Also, LWIT was able to identify relative thermal changes of +1.5 degrees C to 2.2 degrees C in subjects presenting with clinical signs of inflammation. In addition, LWIT was able to show that the normal control subjects without diagnosis of infection or signs of inflammation had relative temperature differentials of +1.1 degrees C to 1.2 degrees C. Finally, LWIT could detect adequate treatment of infected wounds with antibiotics as evidenced by a return to normal temperature differences gradient of +0.8 degrees C to 1.1 degrees C, as compared with normal control subjects with wounds in the same anatomical location. CONCLUSIONS: Long-wave infrared thermography can collect and record objective data, including relative temperature maximums associated with infection, inflammation, and normal healing wounds. PMID- 28817452 TI - CMS MDS 3.0 Section M Skin Conditions in Long-term Care: Pressure Ulcers, Skin Tears, and Moisture-Associated Skin Damage Data Update. AB - GENERAL PURPOSE: The purpose of this learning activity is to provide information about the updates to the Centers for Medicare & Medicaid Services (CMS) MDS 3.0 Section M, Skin Conditions documentation in long-term care. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant should be better able to:1. Explain the use of the CMS MDS 3.0 tool for documenting skin problems in long-term care.2. Demonstrate examples of proper documentation for specific skin problems. ABSTRACT: This manuscript reviews some of the key parts of the October 2016 revised Long-term Care Resident Assessment Instrument manual for Minimum Data Set (MDS) 3.0 Section M Skin Conditions. It also reports the Centers for Medicare & Medicaid's publicly reported frequency data in long-term care for selected items on the MDS 3.0 Section M Skin Conditions. Percentages and trends of pressure ulcers/injuries, skin tears, and moisture-associated skin damage are assessed. PMID- 28817453 TI - 2017 Merit-based Incentive Payment System Data Validation and Auditing. PMID- 28817454 TI - CMS MDS 3.0 Section M Skin Conditions in Long-term Care: Pressure Ulcers, Skin Tears, and Moisture-Associated Skin Damage Data Update. PMID- 28817455 TI - Jak kinase 3 signaling in microgliogenesis from the spinal nestin+ progenitors in both development and response to injury. AB - During spinal cord development, endogenous progenitors expressing nestin can migrate into the target and differentiate into neurons and other glial cells. Microglial cells can also be derived from nestin progenitor cells, even in the adult brain. Knockdown of Jak kinase 3 (Jak3) signaling can increase neurogenesis with longer neurite outgrowth in cortical progenitor cells. This study investigated the effect of Jak3 signaling on differentiation from nestin progenitor cells using E13.5 spinal progenitor cell cultures. In growth factors enriched culture, developing neurons could not survive after several days and also a significant proportion of nestin-expressing cells transformed into ameboid Iba1 microglial cells, which increased exponentially after 5 days. This microgliogenesis was predominantly regulated by Jak3 signaling, which was confirmed by transcription factors responsible for microgliogenesis, and microglial migration and phagocytosis, such as Pu.1, Irf8, and Runx1. Jak3 inhibition also significantly increased the Tuj1 growing neurites with little microglial activation. These results indicated that neuronal and microglial cell differentiation was regulated primarily by Jak3 signaling and the developing neurons and neurite outgrowth might also be regulated by Jak3-dependent microglial activity. PMID- 28817456 TI - Role of various semiquantitative parameters of 18F-FDG PET/CT studies for interim treatment response evaluation in non-small-cell lung cancer. AB - PURPOSE: The aim of this study was to prospectively evaluate the role of various semiquantitative parameters obtained from fluorine-18 fluorodeoxyglucose (F-FDG) PET/CT in interim treatment response assessment in biopsy-proven non-small-cell lung cancer (NSCLC) and to find the best parameter, if any. MATERIALS AND METHODS: Totally, 32 patients (male/female: 25/7) with biopsy proven NSCLC and a mean age of 54.71+/-12.65 years were enrolled in the study. Each patient underwent whole-body F-FDG PET/CT scan after injecting 5.18-7.77 MBq/kg of F-FDG intravenously at baseline and after four cycles of chemotherapy. Five parameters that is, target-to-background ratio (TBR), maximum standardized uptake value (SUVmax), average standardized uptake value (SUVavg), whole-body metabolic tumor volume (MTVwb), and whole-body total lesion glycolysis (TLGwb) - were evaluated for both scans along with their percentage changes ([INCREMENT]). Patients were divided into two response groups as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria: responders and nonresponders. All parameters were compared among the two response groups using appropriate statistical methods; P value of less than 0.05 was considered significant. RESULTS: All postchemotherapy parameters were found to have a significant role in the prediction of two response groups. Post-TBR had highest area under the receiver operating characteristic curve of 0.83 with a sensitivity and specificity of 75 and 82%, respectively, at a cutoff value of 4. The [INCREMENT]s, [INCREMENT]MTVwb, [INCREMENT]TLGwb, and [INCREMENT]SUVmax were significant with cutoffs of -56, 75, and -32%, respectively. [INCREMENT]MTVwb had the highest area under the receiver operating characteristic curve of 0.83 with sensitivity and specificity of 81.25%. In multivariate analysis, post-TBR and [INCREMENT]MTVwb were found to be the independent variables for prediction of interim treatment response. CONCLUSION: Our study proves that a multitude of semiquantitative parameters as documented above differ significantly between two response groups in patients with advanced stage NSCLC receiving chemotherapy. Moreover, parameters in combination (DeltaMTV and post-TBR) with appropriate cutoffs can predict response groups with acceptable reliability. PMID- 28817457 TI - A Comparison by Meta-Analysis of Papillary Early Gastric Carcinoma to Its Tubular Counterpart for the Risk of Lymph Node Metastasis and Submucosal Invasion. AB - BACKGROUND AND AIM: At present, the decision to perform endoscopic resection for treating either papillary early gastric cancer (EGC) or tubular EGC is made according to identical criteria. However, there is controversy in the literature whether the risk of lymph node metastasis (LNM) and submucosal invasion for both disease modalities is equal, and this prompts investigation to clarify this issue. METHODS: The PubMed and Web of Science databases were searched for relevant studies published up to January 2017. Data were extracted, and the pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using a random-effects or a fixed-effects model, according to heterogeneity. RESULTS: A total of 13 studies were included in this analysis. Papillary EGC had a significantly higher LNM risk (OR, 1.97; 95% CI, 1.38-2.82) and submucosal invasion risk (OR, 1.44; 95% CI, 1.08-1.93), compared with tubular EGC. Stratified by geographic location, a significantly increased risk of LNM (OR, 2.28; 95% CI, 1.57-3.30) and submucosal invasion (OR, 1.52; 95% CI, 1.13-2.04) associated with papillary EGC was found in Asian studies. In addition, papillary EGC exhibited significantly more frequent elevated/flat growth patterns (OR, 7.54, 95% CI, 4.76-11.96). CONCLUSIONS: Our study identifies an increased risk for submucosal invasion and LNM in papillary EGC compared with tubular EGC, indicating that papillary EGC requires more careful clinical management compared with tubular EGC. PMID- 28817458 TI - Noninvasive Derivation of Fractional Flow Reserve From Coronary Computed Tomographic Angiography: A Review. AB - Coronary computed tomographic angiography (CCTA) has evolved as a rapid and highly sensitive method for the exclusion of obstructive coronary artery disease. Unfortunately, as it pertains to moderate and severe lesions, the ability to discriminate between those that are hemodynamically significant and those that are nonobstructive is lacking. Consequently, this deficiency can result in a significant number of unnecessary referrals for invasive angiography that yields nonobstructive results. Fractional flow reserve (FFR), which assesses the hemodynamic significance of a specific lesion, when performed during invasive angiography, results in improved patient outcomes compared with visual stenosis assessment alone. Through the application of computational analytic methods to CT derived anatomic coronary models, noninvasive calculation of FFR has become possible. This allows for the improved ability to differentiate between nonobstructive coronary lesions and those that are truly hemodynamically significant. Currently, HeartFlow FFRCT is the only FDA-approved and commercially available CCTA-derived FFR (CT-FFR) platform. By reducing the number of invasive procedures performed for nonobstructive disease, CT-derived FFR has the ability to lower health care expenditures and become the true gatekeeper to invasive angiography. PMID- 28817459 TI - Relation Between Epicardial Fat and Subclinical Atherosclerosis in Asymptomatic Individuals. AB - PURPOSE: Excessive quantity of epicardial adipose tissue (EAT) is considered a risk factor for coronary artery disease (CAD). There are limited data, however, on the relationship between the quality of EAT and CAD. We investigated the association between the density and volume of EAT and subclinical CAD defined by positive coronary artery calcification (CAC), using computed tomography (CT). MATERIALS AND METHODS: We reviewed 609 consecutive CT scans of patients with a mild to moderate risk for CAD to assess the EAT volume, which was measured manually by tracing the parietal pericardial sac on axial images. Fat density was recorded in mean Hounsfield units (HU), and CAC was measured using the Agatston method. RESULTS: The mean patients' age was 50+/-11 years, and 393 (64.5%) were men. Overall, CAC was present in 135 (22%) patients, of whom 97 (72%) were men and 38 (28%) were women. The mean EAT volume and density were 65+/-27 cm and 87.0+/-3.4 HU, respectively. Patients with CAC had significantly higher EAT volume (74+/-27 vs. 62+/-26 cm, P<0.001) and lower EAT density (-88+/-3 vs. -87+/ 3.4 HU, P<0.001) compared with patients without CAC. Multivariate regression analysis showed that both EAT density (hazard ratio, 0.879; 95% confidence interval, 0.817-0.946; P=0.001) and EAT volume >100 cm (hazard ratio, 1.693; 95% confidence interval, 1.256-2.999; P=0.029) predicted the presence of CAC. CONCLUSIONS: Both the quality and quantity of EAT derived from noncontrast CT scan predict subclinical CAD, with lower density and higher volume of epicardial fat associated with higher CACs. PMID- 28817460 TI - High Demand for Psychotherapy in Patients with Inflammatory Bowel Disease. AB - BACKGROUND: The relative contribution of psychological factors to the onset and course of inflammatory bowel diseases (IBD) is a matter of constant debate since its beginning, as is the clinical need and the efficacy of psychotherapeutic interventions. However, the perspective of patients with IBD has largely been ignored in this debate. METHODS: Psychometric tests including the Short-Form IBD Questionnaire (SIBDQ), the ADAP test measuring demand for psychotherapy, and the Fear-of-Progression Questionnaire Short Form as well as disease-related questions were positioned on the internet between December 2014 and January 2016. The study was advertised through DCCV (German branch of the European Federation of Crohn's and Ulcerative Colitis Associations). RESULTS: n = 631 patients responded, and complete data from n = 578 (356 Crohn's disease, 219 ulcerative colitis, 3 unclear) were available for analysis. n = 296 had previous experiences with psychotherapy, whereas n = 282 had not. This distribution clearly determined the factor "demand for psychotherapy" (chi-square = 23.7, P < 0.001). When all available data were entered into a (stepwise-forward) regression model, psychotherapy demand was dependent on previous experience (P < 0.001), fear of progression (P < 0.001), quality of life (P = 0.001), smoking (P = 0.003), and previous surgery (P = 0.005) with the total model explaining 29.7% of the variance. The total explained variance of this model was higher in ulcerative colitis (37.6%) than in Crohn's disease alone (25.4%). CONCLUSIONS: The demand for psychotherapy as additional therapy in IBD depends on previous experience with psychotherapy, fear for disease progression but also other disease or social characteristics and quality of life. PMID- 28817461 TI - Risk Factors and Outcomes of Thalidomide-induced Peripheral Neuropathy in a Pediatric Inflammatory Bowel Disease Cohort. AB - BACKGROUND: Thalidomide is an effective therapy in children with inflammatory bowel disease refractory to standard treatments, but thalidomide-induced peripheral neuropathy (TiPN) limits its long-term use. We aimed to investigate the risk factors and the outcome of TiPN in children with inflammatory bowel disease. METHODS: Within a retrospective multicenter cohort study, we evaluated prevalence and evolution of TiPN. Clinical data and candidate genetic profiles of patients with and without TiPN were compared with detect predisposing factors. RESULTS: One hundred forty-two patients were identified. TiPN was found in 72.5% of patients (38.7% clinical and instrumental alterations, 26.8% exclusive electrophysiological anomalies, and 7.0% exclusive neurological symptoms). Median TiPN-free period of treatment was 16.5 months; percentage of TiPN-free patients was 70.0% and 35.6% at 12 and 24 months of treatment, respectively. The risk of TiPN increased depending on the mean daily dose (50-99 mg/d adjusted hazard ratio 2.62; 95% confidence interval [CI], 1.31-5.21; 100-149 mg/d adjusted hazard ratio 6.16; 95% CI, 20.9-13.06; >150 mg/d adjusted hazard ratio 9.57; 95% CI, 2.6 35.2). Single nucleotide polymorphisms in ICAM1 (rs1799969) and SERPINB2 (rs6103) genes were found to be protective against TiPN (odds ratio 0.15; 95% CI, 0.03 0.82 and 0.36; 95% CI, 0.14-0.88, respectively). TiPN was the cause of drug suspension in 41.8% of patients. Clinical symptoms resolved in 89.2% of cases, whereas instrumental alteration persisted in more than half of the patients during a short follow-up. CONCLUSIONS: In children with inflammatory bowel disease, TiPN is common but mild and generally reversible. Cumulative dose seems to be the most relevant risk factor, whereas polymorphisms in genes involved in neuronal inflammation may be protective. PMID- 28817462 TI - Fecal Calprotectin More Accurately Predicts Endoscopic Remission of Crohn's Disease than Serological Biomarkers Evaluated Using Balloon-assisted Enteroscopy. AB - BACKGROUND: Fecal calprotectin (FC) has emerged as a reliable surrogate marker of endoscopic remission in Crohn's disease (CD), which has been mainly evaluated using ileocolonoscopy. We conducted this study to clarify the predictability of FC level for predicting endoscopic remission using balloon-assisted enteroscopy (BAE) findings in patients with CD and compare with that of conventional serological biomarkers. METHODS: Patients with CD scheduled to undergo BAE were prospectively enrolled, and fecal and blood samples collected before the procedures. We used a modified simple endoscopic score for CD, in which the parameter "presence of narrowing" was removed from conventional simple endoscopic score for CD. Endoscopic remission was defined as modified simple endoscopic score for CD 0 to 2. RESULTS: Seventy BAE procedures were performed in 53 patients with CD and evaluated. The area under the curve in receiver operating characteristic curve analysis of FC to predict endoscopic remission was 0.93, with an optimal cut-off value of 252.9 MUg/g, and 96% sensitivity and 83% specificity, which was higher than that for C-reactive protein, albumin, white blood cell count, and platelet count (0.76, 0.66, 0.39, and 0.65, respectively). The area under the curve of FC for predicting endoscopic remission was high in patients with ileal and ileocolonic disease location (0.86 and 0.96, cut-off values 204.2 and 253.7 MUg/g, respectively), and also higher than the area under the curve values of serological markers. CONCLUSIONS: BAE findings showed that FC was more accurate for predicting endoscopic remission in CD than C-reactive protein, albumin, white blood cell count, and platelet count. Even in small-bowel CD, FC may be a more reliable surrogate marker of endoscopic remission than serological biomarkers. PMID- 28817463 TI - Delivering High Value Inflammatory Bowel Disease Care Through Telemedicine Visits. AB - BACKGROUND: Patients with inflammatory bowel disease (IBD) require regular follow up to manage their care, which requires significant amount of time and out-of pocket costs. Telemedicine in the form of video virtual visits could serve as an alternative to in-office visits. The aim of this project was to understand if telemedicine can provide high value care (defined as quality/cost) to outpatients with IBD. METHODS: Patients who participated in the IBD telemedicine clinic in the second half of 2015 were included. Patient-reported survey data before and after the virtual visit were collected. A retrospective review was performed on the study cohort for quality outcome measures a year before and after starting the telemedicine clinic. Outcomes were analyzed using simple descriptive statistics. Differences in quality outcomes were compared using odds ratios. RESULTS: Forty-eight patients were included in the analysis. Most patients travel more than 25 miles each way, take half a day off, and on average incur an additional out-of-pocket cost of $62 for an in-office visit. Most patients (98%) agreed that there was enough time spent with their physician, 91% agreed that they felt like the physician understood their disease state, and 78% reported that they clearly understood the follow-up plan after the visit. Analysis of quality outcome measures did not show any drop in the overall quality of care, after initiating the telemedicine program. CONCLUSIONS: Telemedicine offers a low cost and convenient alternative for patients with IBD without compromising quality of care. PMID- 28817464 TI - Biologics for idiopathic inflammatory myopathies. AB - PURPOSE OF REVIEW: As treatment of refractory cases of idiopathic inflammatory myopathies (IIMs) has been challenging, there is growing interest in assessing novel biologics that target various pathways implicated in the pathogenesis of IIM. RECENT FINDINGS: In the largest clinical trial in adult and juvenile IIM assessing the effectiveness of rituximab, the primary outcome was not met but 83% of this refractory group of IIM patients met a predefined definition of improvement and rituximab demonstrated a significant glucocorticoid-sparing effect. Antitumor necrosis factor utility in IIM is generally limited by uncertain efficacy data along with recent reports suggesting their potential for inducing systemic autoimmune disease including IIM. SUMMARY: Further research is required to evaluate the role of newer therapies such as tocilizumab (anti interleukin-6), abatacept (inhibition of T-cell costimulation), sifalimumab (anti interferonalpha) and ruxolitinib, (Janus kinase inhibitor) given their biological plausibility and encouraging recent small case series results. Future clinical trials should consider the targeting of biomarkers implicated in the etiopathogenesis of IIM, predictive factors of treatment response, recent revisions in IIM classification criteria, as well as newly developed data-driven response criteria which employ validated core set measures. PMID- 28817465 TI - New insights into the recognition, classification and management of systemic sclerosis-associated pulmonary hypertension. AB - PURPOSE OF REVIEW: Pulmonary hypertension is a common complication of systemic sclerosis (SSc), and remains a leading cause of morbidity and mortality. We will review recent developments in the recognition, classification and treatment of pulmonary hypertension in SSc. RECENT FINDINGS: Advances in screening for pulmonary arterial hypertension (PAH) and use of exercise haemodynamics may help to identify pulmonary vascular disease earlier in SSc. Recent studies have led to changes in recommendations for adjunct therapy and selection of pulmonary vasodilators for the treatment of SSc-associated PAH. SUMMARY: Recent advances in the diagnosis, classification and management of pulmonary hypertension in SSc have continued to improve our understanding of this challenging disease. Ongoing investigation in the pathogenesis of this disease will afford the opportunity to develop targeted therapies to improve outcomes for SSc patients with pulmonary hypertension. PMID- 28817466 TI - Mitochondrial DNA in Acute Kidney Injury: Chicken or Egg? PMID- 28817467 TI - On Two Approaches to Weighting in Causal Inference. PMID- 28817469 TI - The Right Tool for the Job: Choosing Between Covariate-balancing and Generalized Boosted Model Propensity Scores. AB - Estimating the causal effect of an exposure (vs. some control) on an outcome using observational data often requires addressing the fact that exposed and control groups differ on pre-exposure characteristics that may be related to the outcome (confounders). Propensity score methods have long been used as a tool for adjusting for observed confounders in order to produce more valid causal effect estimates under the strong ignorability assumption. In this article, we compare two promising propensity score estimation methods (for time-invariant binary exposures) when assessing the average treatment effect on the treated: the generalized boosted models and covariate-balancing propensity scores, with the main objective to provide analysts with some rules-of-thumb when choosing between these two methods. We compare the methods across different dimensions including the presence of extraneous variables, the complexity of the relationship between exposure or outcome and covariates, and the residual variance in outcome and exposure. We found that when noncomplex relationships exist between outcome or exposure and covariates, the covariate-balancing method outperformed the boosted method, but under complex relationships, the boosted method performed better. We lay out criteria for when one method should be expected to outperform the other with no blanket statement on whether one method is always better than the other. PMID- 28817470 TI - The Use of Pharmacologic Cognitive Enhancers in Competitive Chess. PMID- 28817468 TI - Longitudinal Associations of Local Cigarette Prices and Smoking Bans with Smoking Behavior in the Multi-Ethnic Study of Atherosclerosis. AB - BACKGROUND: Few studies have examined associations of geographically proximal cigarette prices with within-person changes in smoking outcomes or assessed interactions between cigarette prices and smoking bans. METHODS: We linked neighborhood cigarette prices (inflation-adjusted) at chain supermarkets and drug stores and bar/restaurant smoking ban policies to cohort participants (632 smokers from the Multi-Ethnic Study of Atherosclerosis, 2001-2012, baseline mean age 58 years) using geocoded retailer and participant addresses. We used fixed effects models to investigate associations of within-person changes in price and ban exposures with within-person changes in five smoking outcomes: current smoking, heavy (>=10 cigarettes) smoking, cessation, relapse, and intensity (average number of cigarettes smoked per day, natural log transformed). We assessed intensity associations among all smokers, and heavy (>=10 cigarettes per day) and light (<10) baseline smokers. Finally, we tested interactions between cigarette price and bans. RESULTS: A $1 increase in price was associated with a 3% reduction in risk of current smoking (adjusted risk ratio [aRR]: 0.97; 95% confidence interval [CI] = 0.93, 1.0), a 7% reduction in risk of heavy smoking (aRR: 0.93; CI = 0.87, 0.99), a 20% increase in risk of smoking cessation (aRR: 1.2; CI = 0.99, 1.4), and a 35% reduction in the average number of cigarettes smoked per day by heavy baseline smokers (ratio of geometric means: 0.65; CI = 0.45, 0.93). We found no association between smoking bans and outcomes, and no evidence that price effects were modified by the presence of bans. CONCLUSIONS: Results underscore the importance of local prices, but not hospitality smoking bans, in influencing older adults' smoking behaviors. PMID- 28817471 TI - Bayesian Piecewise Linear Mixed Models With a Random Change Point: An Application to BMI Rebound in Childhood. AB - BACKGROUND: Body mass index (BMI) rebound refers to the beginning of the second rise in BMI during childhood. Accurate estimation of an individual's timing of BMI rebound is important because it is associated with health outcomes in later life. METHODS: We estimated BMI trajectories for 6545 children from the Avon Longitudinal Study of Parents and Children. We used a novel Bayesian two-phase piecewise linear mixed model where the "change point" was an individual-level random effect corresponding to the individual-specific timing of BMI rebound. The model's individual-level random effects (intercept, prechange slope, postchange slope, change point) were multivariate normally distributed with an unstructured variance-covariance matrix, thereby, allowing for correlation between all random effects. RESULTS: Average age at BMI rebound (mean change point) was 6.5 (95% credible interval: 6.4 to 6.6) years. The standard deviation of the individual specific timing of BMI rebound (random effects) was 2.0 years for females and 1.6 years for males. Correlation between the prechange slope and change point was 0.57, suggesting that faster rates of decline in BMI prior to rebound were associated with rebound occurring at an earlier age. Simulations showed that estimates from the model were less biased than those from models, assuming a common change point for all individuals or a nonlinear trajectory based on fractional polynomials. CONCLUSIONS: Our model flexibly estimated the individual specific timing of BMI rebound, while retaining parameters that are meaningful and easy to interpret. It is applicable in any situation where one wishes to estimate a change-point process which varies between individuals. PMID- 28817472 TI - Current State of Test Development, Administration, and Analysis: A Study of Faculty Practices. AB - Developing valid and reliable test items is a critical skill for nursing faculty. This research analyzed the test item writing practice of 674 nursing faculty. Relationships between faculty characteristics and their test item writing practices were analyzed. Findings reveal variability in practice and a gap in implementation of evidence-based standards when developing and evaluating teacher made examinations. PMID- 28817473 TI - Scaffolding Interprofessional Education: Unfolding Case Studies, Virtual World Simulations, and Patient-Centered Care. AB - Fragmentation of health care negatively impacts quality; one of the contributing factors may be ineffective collaboration among health care professionals. This article describes the implementation of an interprofessional education curriculum for graduate students enrolled in nursing, psychology, and speech-language pathology programs. Over 3 semesters, students engaged in interprofessional collaboration modules, unfolding case studies, virtual simulation, and shared case planning experiences. The curriculum's impact on students' attitudes and values toward interprofessional collaborative practice was measured. PMID- 28817474 TI - Evaluation of Clinical Judgment in Prelicensure Nursing Students. AB - Clinical judgment is an essential end-of-program outcome for prelicensure nursing students. Evaluating progression of clinical judgment when students participate in simulated patient experiences is essential in ensuring that end-of-program and course outcomes are achieved. The purpose of this study was to identify if progression in clinical judgment is evident after students participate in 4 simulated patient experiences as measured by the Lasater Clinical Judgment Rubric. PMID- 28817475 TI - Replacing Smartphones With Mini Tablet Technology: An Evaluation. AB - Handheld technology allows students to access point-of-care resources throughout the clinical experience. To assess the viability of replacing student smartphones with tablets, an evaluation project was undertaken. Overall, students were equally dissatisfied with the 2 types of tablets that were evaluated. Students saw the potential usefulness of tablets to manage clinical assignments, interact with the learning management system, and communicate with faculty, but not for retrieving information currently accessible on their phones. PMID- 28817476 TI - Gamification of Nursing Education With Digital Badges. AB - Digital badges (DBs) serve as an innovative approach to gamifying nursing education by engaging socially connected, technologically savvy nursing students in learning. Because assessment and credentialing mechanisms are housed and managed online, DBs are designed as visible indicators of accomplishment and skill. This article describes important considerations for faculty when incorporating game-based pedagogies such as DB into nursing education and identifies potential pitfalls with DB use that faculty should consider. PMID- 28817477 TI - Transitioning to the DNP: Ensuring Integrity of the Curriculum Through Curriculum Mapping. PMID- 28817478 TI - More Than 1 Million Potential Second Victims: How Many Could Nursing Education Prevent? AB - Any error made in health care can cause the health care provider to become a second victim. There are many initiatives, tools, and instruments designed to support second victims after an error has been made. The role that nursing education can play in preventing nurses from becoming second victims has not been well explored. This article presents a study designed to investigate perceptions of recent BSN graduates about preparation for medication administration, medication error, and their personal experience with error making and second victimhood. PMID- 28817479 TI - Comparison of Instructional Methods for Screening, Brief Intervention, and Referral to Treatment for Substance Use in Nursing Education. AB - Most nursing programs lack curriculum on substance use. This project evaluated 3 didactic instructional methods for teaching baccalaureate nursing students about screening, brief intervention, and referral to treatment for substance use. In person, asynchronous narrated slides and interactive online instructional methods were all effective in developing students' competency; however, active learning methods (in-person and interactive online course) were more effective in changing students' attitudes about their role in screening and intervening for drug use. PMID- 28817480 TI - Revised National Estimates of Emergency Department Visits for Sepsis in the United States. AB - OBJECTIVES: The emergency department is an important venue for initial sepsis recognition and care. We sought to determine contemporary estimates of the epidemiology of U.S. emergency department visits for sepsis. DESIGN: Analysis of data from the National Hospital Ambulatory Medical Care Survey. SETTING: U.S. emergency department visits, 2009-2011. PATIENTS: Adult (age, >= 18 yr) emergency department sepsis patients. We defined serious infection as an emergency department diagnosis of a serious infection or a triage temperature greater than 38 degrees C or less than 36 degrees C. We defined three emergency department sepsis classifications: 1) original emergency department sepsis-serious infection plus emergency department diagnosis of organ dysfunction, endotracheal intubation, or systolic blood pressure less than or equal to 90 mm Hg or explicit sepsis emergency department diagnoses; 2) quick Sequential Organ Failure Assessment emergency department sepsis-serious infection plus presence of at least two "quick" Sequential Organ Failure Assessment criteria (Glasgow Coma Scale <= 14, respiratory rate >= 22 breaths/min, or systolic blood pressure <= 100 mm Hg); and 3) revised emergency department sepsis-original or quick Sequential Organ Failure Assessment emergency department sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used survey design and weighting variables to produce national estimates of annual adult emergency department visits using updated sepsis classifications. Over 2009-2011, there were 103,257,516 annual adult emergency department visits. The estimated number of emergency department sepsis visits were as follows: 1) original emergency department sepsis 665,319 (0.64%; 95% CI, 0.57-0.73); 2) quick Sequential Organ Failure Assessment emergency department sepsis 318,832 (0.31%; 95% CI, 0.26 0.37); and 3) revised emergency department sepsis 847,868 (0.82%; 95% CI, 0.74 0.91). CONCLUSIONS: Sepsis continues to present a major burden to U.S. emergency departments, affecting up to nearly 850,000 emergency department visits annually. Updated sepsis classifications may impact national estimates of emergency department sepsis epidemiology. PMID- 28817482 TI - American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock: Erratum. PMID- 28817481 TI - Incorporating Dynamic Assessment of Fluid Responsiveness Into Goal-Directed Therapy: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: Dynamic tests of fluid responsiveness have been developed and investigated in clinical trials of goal-directed therapy. The impact of this approach on clinically relevant outcomes is unknown. We performed a systematic review and meta-analysis to evaluate whether fluid therapy guided by dynamic assessment of fluid responsiveness compared with standard care improves clinically relevant outcomes in adults admitted to the ICU. DATA SOURCES: Randomized controlled trials from MEDLINE, EMBASE, CENTRAL, clinicaltrials.gov, and the International Clinical Trials Registry Platform from inception to December 2016, conference proceedings, and reference lists of relevant articles. STUDY SELECTION: Two reviewers independently identified randomized controlled trials comparing dynamic assessment of fluid responsiveness with standard care for acute volume resuscitation in adults admitted to the ICU. DATA EXTRACTION: Two reviewers independently abstracted trial-level data including population characteristics, interventions, clinical outcomes, and source of funding. Our primary outcome was mortality at longest duration of follow-up. Our secondary outcomes were ICU and hospital length of stay, duration of mechanical ventilation, and frequency of renal complications. The internal validity of trials was assessed in duplicate using the Cochrane Collaboration's Risk of Bias tool. DATA SYNTHESIS: We included 13 trials enrolling 1,652 patients. Methods used to assess fluid responsiveness included stroke volume variation (nine trials), pulse pressure variation (one trial), and stroke volume change with passive leg raise/fluid challenge (three trials). In 12 trials reporting mortality, the risk ratio for death associated with dynamic assessment of fluid responsiveness was 0.59 (95% CI, 0.42-0.83; I = 0%; n = 1,586). The absolute risk reduction in mortality associated with dynamic assessment of fluid responsiveness was -2.9% (95% CI, -5.6% to -0.2%). Dynamic assessment of fluid responsiveness was associated with reduced duration of ICU length of stay (weighted mean difference, -1.16 d [95% CI, -1.97 to -0.36]; I = 74%; n = 394, six trials) and mechanical ventilation (weighted mean difference, -2.98 hr [95% CI, -5.08 to 0.89]; I = 34%; n = 334, five trials). Three trials were adjudicated at unclear risk of bias; the remaining trials were at high risk of bias. CONCLUSIONS: In adult patients admitted to intensive care who required acute volume resuscitation, goal-directed therapy guided by assessment of fluid responsiveness appears to be associated with reduced mortality, ICU length of stay, and duration of mechanical ventilation. High-quality clinical trials in both medical and surgical ICU populations are warranted to inform routine care. PMID- 28817483 TI - Time-course Study on Left Ventricular Function in a Rabbit Model of Ischemia reperfusion Injury With Morphine Preconditioning. AB - AIMS: To analyze the left ventricular longitudinal function in a rabbit model of myocardial ischemia reperfusion with morphine preconditioning through strain rate imaging and to evaluate the effect of morphine preconditioning. METHODS: A myocardial ischemia-reperfusion model was induced by occlusion and recanalization of the coronary artery in 40 male New Zealand white rabbits, which were divided into a sham group, morphine group, and vehicle control group. Routine echocardiography data were recorded 1 day before and within 28 days after the operation. Dynamic images were also collected and analyzed off-line using Doppler tissue imaging software. RESULTS: On the first day after the operation, the global and regional systolic functions of the left ventricle in the morphine and vehicle control groups were lower than those in the sham group. After ischemia reperfusion, some of the values of the above-mentioned parameters decreased over time, which was more obvious in the vehicle control group at each examined time point. CONCLUSIONS: The current study revealed that detection of changes in regional myocardial function after myocardial ischemia reperfusion by strain rate imaging is objective and accurate. In addition, our results indicated that morphine preconditioning significantly attenuates myocardial ischemia-reperfusion injury in rabbits. PMID- 28817484 TI - Levosimendan in Acute and Advanced Heart Failure: An Appraisal of the Clinical Database and Evaluation of Its Therapeutic Applications. AB - The use of inotropes for correcting hemodynamic dysfunction in patients with congestive heart failure has been described over many decades. However, negative or insufficient data have been collected regarding the effects of cardiac glycosides, catecholamines, and phosphodiesterase inhibitors on quality of life and survival. More recently, the calcium sensitizer and potassium channel-opener levosimendan has been proposed as a safer inodilator than traditional agents in some heart failure settings, such as advanced heart failure. At the 2017 annual congress of the Heart Failure Association of the European Society of Cardiology (Paris, April 30-May 2), a series of tutorials delivered by lecturers from 8 European countries examined how to use levosimendan safely and effectively in acute and advanced heart failure. The proceedings of those tutorials have been collated in this review to provide an expert perspective on the optimized use of levosimendan in those settings. PMID- 28817485 TI - Antidiabetic Drug Alogliptin Protects the Heart Against Ischemia-reperfusion Injury Through GLP-1 Receptor-dependent and Receptor-independent Pathways Involving Nitric Oxide Production in Rabbits. AB - GLP-1 has been reported to be cardioprotective against ischemia-reperfusion injury. We aimed to examine the effect of alogliptin, which may produce GLP-1, on ischemia-reperfusion injury and its mechanisms. Rabbits were fed a normal chow (control group) and a chow containing alogliptin (2 mg.kg.d: alogliptin-L group and 20 mg.kg.d: alogliptin-H group) for 7 days. The rabbits underwent 30 minutes of coronary occlusion and 48 hours of reperfusion. Exendin (9-39) [5 or 50 MUg/kg, i.v., alogliptin-H+exendin (9-39)-L group and alogliptin-H+exendin (9-39) H group] or L-NAME (10 mg/kg, i.v., alogliptin-H+L-NAME group) was administered to the alogliptin-H group. Alogliptin dose-dependently reduced the infarct size, which was partially blocked by exendin (9-39), but completely blocked by L-NAME. Exendin (9-39) or L-NAME alone did not affect the infarct size for themselves. The left ventricular ejection fraction and +/-dP/dt were higher in the alogliptin L group and alogliptin-H group than in the control group. Alogliptin increased the serum NOx and plasma GLP-1 levels, and those levels inversely correlated with the infarct size. Alogliptin upregulated the expressions of phosphorylated (p) Akt and p-eNOS, which were inhibited by exendin (9-39) and L-NAME, respectively. In conclusion, alogliptin protects the heart against ischemia-reperfusion injury through GLP-1 receptor-dependent and receptor-independent pathways which involve nitric oxide production in rabbits. PMID- 28817486 TI - Overcoming Clopidogrel Resistance: Three Promising Novel Antiplatelet Drugs Developed in China. AB - Clopidogrel is one of the most frequently prescribed drugs worldwide; however, the presence of clopidogrel resistance and high susceptibility to genetic variations and drug interactions are facilitating the development of other antiplatelet drugs. To overcome clopidogrel resistance, several promising clopidogrel analogues have been developed in China, such as vicagrel (and its deuterated analogues), PLD-301, and W1. These novel chemical analogues are all characterized by much faster and more efficient bioconversion to clopidogrel thiolactone (or 2-oxo-clopidogrel, the precursor of clopidogrel active metabolite) in the intestine than clopidogrel itself through bypassing the first step P450-mediated oxidation of clopidogrel in the liver. Of them, metabolic conversion of vicagrel and PLD-301 to 2-oxo-clopidogrel is catalyzed by intestinal carboxylesterase 2 and alkaline phosphatase, respectively. In this review article, we summarized all evidence on highly efficient bioconversion to their shared precursor of clopidogrel active metabolite and the mechanisms underlying such a pronounced improvement. These drugs in the pipeline would be promising antiplatelet drugs that could be superior to clopidogrel in future patient care. PMID- 28817487 TI - Inhibiting Protein Tyrosine Phosphatase 1B to Improve Regenerative Functions of Endothelial Cells. AB - Protein tyrosine phosphatase-1B (PTP1B) is an important negative regulator of insulin receptor- and vascular endothelial growth factor receptor-dependent signalings in endothelial cells. Genetic or pharmacological inhibition of PTP1B has been shown to enhance endothelial cell proliferation and migration and increase nitric oxide production. In vivo, inhibiting PTP1B can reverse endothelial dysfunction, promote angiogenesis, and accelerate wound healing. Intense research is currently continuing in an effort to discover novel selective PTP1B inhibitors, primarily for treating insulin resistance. We propose that these drugs may also represent a new horizon for boosting the regenerative capacities of endothelial cells. PMID- 28817488 TI - Risk Management of Hospitalized Psychiatric Patients Taking Multiple QTc Prolonging Drugs. AB - PURPOSE/BACKGROUND: Drug-related QTc prolongation has been linked with Torsade de Pointes and sudden cardiac death. The objective of this study was to investigate the impact of starting an additional QTc-prolonging drug on the QTc interval of psychiatric inpatients. METHODS: An observational study was performed between May 2011 and December 2014 in 6 Belgian psychiatric hospitals. Inpatients who were already taking 1 QTc-prolonging drug or more could be included in the study when an additional QTc-prolonging drug was started. Electrocardiograms were performed at baseline and follow-up. Demographic, medical, medication, and laboratory data were collected. A risk score was used to estimate the risk of QTc prolongation based on patient-specific risk factors. A cutoff value of 8 points was set as high risk for QTc prolongation. RESULTS: One hundred fifty-two patients (44.7% women; mean age, 44 [SD, 17] years) were included who received a prescription for an additional QTc-prolonging drug. There was a small but significant difference (P = 0.032) in mean QTc interval between baseline (409.1 [SD, 21.8] milliseconds) and follow-up (411.8 [SD, 21.7] milliseconds). Three patients developed a prolonged QTc interval in the follow-up electrocardiogram (QTc, >=450 [men]/470 [women] milliseconds); 8 patients had a delta QTc of 30 milliseconds or longer. No cases of torsade de pointes or sudden cardiac death were identified. Fifty eight patients (38.2%) had a risk score of 8 or higher; these patients had a significantly longer QTc interval at follow-up than did patients with a risk score of lower than 8 (P < 0.001). IMPLICATIONS/CONCLUSIONS: Only a limited number of patients developed a prolonged QTc interval after the start of an additional QTc-prolonging drug. Nevertheless, it is still important to screen for high-risk patients at baseline. A risk score can help to select high-risk patients and to stimulate an appropriate and feasible risk management of QTc prolongation in psychiatry. PMID- 28817489 TI - The Use of Granulocyte Colony-Stimulating Factor in Clozapine Rechallenge: A Systematic Review. AB - PURPOSE/BACKGROUND: Clozapine is associated with hematological abnormalities, with neutropenia and agranulocytosis of most concern. Granulocyte colony stimulating factor (G-CSF) has been used to support clozapine rechallenge after neutropenia with the aim of maintaining the neutrophil count. This study aims to explore the practice, use, safety, and efficacy of G-CSF in this context. METHODS/PROCEDURES: We conducted a systematic review to identify all studies investigating or describing G-CSF as a prophylaxis to enable continued clozapine treatment during a rechallenge. FINDINGS/RESULTS: We identified 32 reports of patients who received G-CSF either regularly (n = 23) or as required (n = 9) to support clozapine rechallenge after an episode of neutropenia necessitating discontinuation of clozapine. Seventy-five percent (n = 24) of published cases remained on clozapine with the use of continual prophylactic G-CSF or after single G-CSF administrations (n = 8). Seventy percent (n = 16) of patients in receipt of continual prophylactic G-CSF were successfully maintained on clozapine. However, 1 of the 3 episodes of rechallenge in those with a history of severe agranulocytosis (absolute neutrophil count <0.1 * 10/L) had a recurrence of agranulocytosis at week 9. IMPLICATIONS/CONCLUSIONS: Our findings suggest that G-CSF can sometimes be safely used to support the maintenance of normal neutrophil counts and clozapine use after neutropenia. Publication bias is an important limitation, however. Also, few reports clearly documented the presence or absence of an independent nonclozapine cause of the index neutropenia, which may have increased success rates. Furthermore, adverse events were not systematically recorded. Prospective studies are needed to determine safety because if agranulocytosis occurs on clozapine while supported by G-CSF, there is no obvious alternate rescue therapy to promote granulopoiesis. From the available data, it is not possible to recommend this course of action for someone with a true clozapine agranulocytosis. PMID- 28817490 TI - An Open Trial of Iloperidone for Mixed Episodes in Bipolar Disorder. AB - BACKGROUND: Mixed mood states in bipolar disorder are difficult to treat and when present indicate worse illness trajectories. Several medications are US Food and Drug Administration approved to treat mixed episodes; however, the clinical trials have been short term and rarely reported depression response. METHODS: We conducted a 5-month open-label trial examining the tolerability and efficacy of iloperidone for bipolar disorder mixed episodes. RESULTS: Mania and depression scores significantly improved over the course of the study for study completers (ie, 60%-68% improvement for manic symptoms and 41%-49% for depression symptoms). Improvements were observed early in the trial and after adjusting for concomitant medication effects. The average daily dose in completers was 15 mg. Thirty-nine percent (12/31) of the eligible sample discontinued early because of adverse effects. The adverse events most commonly associated with withdrawal were increased heart rate/palpitations (n = 5 of 12) and urinary incontinence/intense urge to urinate (n = 3 of 12). CONCLUSIONS: In a subset of patients, iloperidone provides relief for classic manic, depression, and irritability symptoms associated with mixed episodes in a long-term trial. Adverse effect profiles are likely to be a major factor contributing to individualized medication use. PMID- 28817491 TI - Speed of Improvement in Symptoms of Depression With Desvenlafaxine 50 mg and 100 mg Compared With Placebo in Patients With Major Depressive Disorder. AB - PURPOSE/BACKGROUND: This post hoc analysis examined the time point at which clinically significant improvement in major depressive disorder (MDD) symptoms occurs with desvenlafaxine versus placebo. METHODS: Data were pooled from 9 short term, double-blind, placebo-controlled studies in adults with MDD randomly assigned to desvenlafaxine 50 mg/d, 100 mg/d, or placebo. A mixed-effects model for repeated-measures analysis of change from baseline score was used to determine the time point at which desvenlafaxine treatment groups separated from placebo on the 17-item Hamilton Rating Scale for Depression and psychosocial outcomes. The association between early improvement and week 8 outcomes was examined using logistic regression analyses. Time to remission for patients with early improvement versus without early improvement was assessed using Kaplan Meier techniques. Comparisons between groups were performed with log-rank tests. RESULTS: In the intent-to-treat population (N = 4279 patients: desvenlafaxine 50 mg/d, n = 1714; desvenlafaxine 100 mg/d, n = 870; placebo, n = 1695), a statistically significant improvement on the 17-item Hamilton Rating Scale for Depression was observed with desvenlafaxine 50 mg/d at week 1 (P = 0.0129) and with desvenlafaxine 100 mg/d at week 2 (P = 0.0002) versus placebo. Early improvement was a significant predictor of later remission. Treatment assignment, baseline depression scale scores, and race were significantly associated with probability of early improvement. On several measures of depressive symptoms and function, desvenlafaxine 50 mg/d and 100 mg/d separated from placebo as early as week 1 and no later than week 4 in patients with MDD. IMPLICATIONS/CONCLUSIONS: These findings suggest that clinicians may be able to use depression rating scale scores early in treatment as a guide to inform treatment optimization. PMID- 28817492 TI - Should renal color Doppler ultrasonography be a routine test in newly diagnosed hypertensive patient? AB - : European Society of Hypertension/European Society of Cardiology guidelines recommend calculation of estimated glomerular filtration rate and evaluation of urinary albumin excretion rate as routine tests in the initial evaluation and during the follow-up of all hypertensive patients. However, from a clinical point of view, renal ultrasound - a noninvasive, readily available and cheap imaging modality - could contribute to the better evaluation of a hypertensive patient by identifying common causes of secondary hypertension (HTN) originating from the kidney and more recently by detecting renal injury in severe or long-standing essential HTN by measuring renal resistive indexes. The purpose of this review is to summarize the actual evidence which could support a larger use of renal ultrasound in the work-up of patients with newly diagnosed HTN. PMID- 28817493 TI - DNA methylation of the glucocorticoid receptor gene promoter in the placenta is associated with blood pressure regulation in human pregnancy. AB - BACKGROUND: Blood pressure (BP) regulation during pregnancy is influenced by hormones of placental origin. It was shown that the glucocorticoid system is altered in hypertensive pregnancy disorders such as preeclampsia. Epigenetic mechanism might influence the activity of genes involved in placental hormone/hormone receptor synthesis/action during pregnancy. METHOD: In the current study, we analyzed the association of 5'-C-phosphate-G-3' (CpG) site methylation of different glucocorticoid receptor gene (NR3C1) promoter regions with BP during pregnancy. The study was performed as a nested case-control study (n = 80) out of 1045 mother/child pairs from the Berlin Birth Cohort. Placental DNA was extracted and bisulfite converted. Nested PCR products from six NR3C1 proximal promoter regions [glucocorticoid receptor gene promotor region B (GR 1B), C (GR-1C), D (GR-1D), E (GR-1E), F (GR-1F), and H (GR-1H)] were analyzed by next generation sequencing. RESULTS: NR3C1 promoter regions GR-1D and GR-1E had a much higher degree of DNA methylation as compared to GR-1B, GR-1F or GR-1H when analyzing the entire study population. Comparison of placental NR3C1 CpG site methylation among hypotensive, normotensive and hypertensive mothers revealed several differently methylated CpG sites in the GR-1F promoter region only. Both hypertension and hypotension were associated with increased DNA methylation of GR 1F CpG sites. These associations were independent of confounding factors, such as family history of hypertension, smoking status before pregnancy and prepregnancy BMI. Assessment of placental glucocorticoid receptor expression by western blot showed that observed DNA methylation differences were not associated with altered levels of placental glucocorticoid receptor expression. However, correlation matrices of all NR3C1 proximal promoter regions demonstrated different correlation patterns of intraregional and interregional DNA methylation in the three BP groups, putatively indicating altered transcriptional control of glucocorticoid receptor isoforms. CONCLUSION: Our study provides evidence of an independent association between placental NR3C1 proximal promoter methylation and maternal BP. Furthermore, we observed different patterns of NR3C1 promoter methylation in normotensive, hypertensive and hypotensive pregnancy. PMID- 28817494 TI - Nocturnal hypertension and right heart remodeling. AB - BACKGROUND: We sought to investigate right ventricular (RV) and right atrial mechanics in patients with daytime, night-time and daytime-night-time hypertension. METHODS: This cross-sectional study included 256 untreated patients who underwent 24-h ambulatory blood pressure monitoring and complete echocardiographic examination including strain analysis. Night-time hypertension was defined as nocturnal SBP at least 120 mmHg and/or DBP at least 70 mmHg and daytime hypertension as SBP at least 135 mmHg and/or DBP at least 85 mmHg. RESULTS: RV structure, diastolic function and global longitudinal RV strain in patients with nocturnal hypertension are intermediate between daytime and daytime night-time hypertension. On the other side, RV systolic and diastolic strain rates referring to the RV free wall are significantly deteriorated in the patients with nocturnal and daytime-night-time hypertension in comparison with normotension and daytime hypertension. Right atrial conduit function is significantly reduced in the patients with nocturnal and day-night-time hypertension comparing with other two groups, whereas right atrial reservoir and pump functions are intermediate between daytime and daytime-night-time hypertension. A 24-h SBP is independently of other clinical and echocardiographic parameters associated with RV and right atrial global strain. CONCLUSION: RV mechanics is worse in night-time and daytime-night-time hypertensive patients than in normotensive controls and isolated daytime hypertensive patients. A 24-h SBP is independently associated with right heart mechanics. PMID- 28817495 TI - Nursing Management of the Patient Undergoing Focused Ultrasound: A New Treatment Option for Essential Tremor. AB - Essential tremor (ET) is among the most common neurological movement disorders that causes postural or action tremors, with an estimated prevalence nationwide of less than 3% of the population. The incidence of ET increases with age but often affects younger adults and has a familial trait association. Depending on disease progression, ET can cause significant limitations for individuals, in many cases, significantly limiting their ability to perform activities of daily living and occupational responsibilities. Until recently, treatment of ET heavily relied on medication management and invasive surgery, such as deep brain stimulation. With advances in the use of focused ultrasound (FUS) for treatment of various medical conditions, recent clinical trials have revealed positive outcomes with the use of FUS as a less invasive approach to treat patients with medication-refractory ET. In a large academic medical center in the mid-Atlantic region, the Department of Neurosurgery conducted a continued access study, recently approved by the Food and Drug Administration, to evaluate the effectiveness of transcranial FUS thalamotomy for the treatment of medication refractory ET. One patient's experience will be introduced, including discussion of evidence-based treatment options for ET and information on the nursing management of the patient undergoing FUS thalamotomy. PMID- 28817496 TI - Lived Experiences of Muscle Tightness Symptoms From Patients' Perspectives. AB - The aims of this study were to understand symptoms of chronic muscle tightness from the patient's perspective and explore symptom management strategies used by them. Muscle tightness, a common symptom, is a challenge to manage in clinical practice because it is commingled with other orthopedic conditions. Nurses may not be aware of the negative impact of tight muscles because this symptom is presumed to be self-limiting; however, if not treated appropriately, muscle tightness can become chronic. The focus of this study is the lived experience of patients with chronic muscle tightness. The researchers used a qualitative descriptive design in which patients provided insights into the experiences and self-management of chronic muscle tightness. Sixteen adult subjects experiencing physical impairments who were managed by physical therapists in a specialty clinic participated in the study. The subjects participated in 45- to 60-minute semistructured interviews to provide understanding of chronic muscle tightness. The interviews were recorded and transcribed for content analysis. Results indicate that patients identify day-to-day experiences of chronic muscle tightness as unresolving; these patients experience myriads of sensations and live with life restrictions that negatively affect their quality of life. Uses of complementary therapies are commonplace in managing this symptom. The symptom of chronic muscle tightness may linger, and patients use workarounds to manage their lives. Nurses must understand patients' perspectives to assist them in achieving an acceptable quality of life. PMID- 28817497 TI - Self-care in People With Motor Neuron Disease: An Integrative Review. AB - INTRODUCTION: Self-care is a crucial aspect in the management of chronic diseases. People with motor neuron disease (MND) live with a chronic degenerative condition in rapid evolution, which leads them to high dependencies. During their illness, they must apply several behaviors including adherence to ventilation and nutritional therapy. OBJECTIVE: The purpose of this review is to systematically explore the concept of self-care for people with MND. METHOD: An integrative review of the literature has been conducted. The electronic databases CINAHL, PubMed, and SCOPUS were searched. RESULTS: Fifteen articles met the inclusion criteria and were reviewed; 7 of them discuss decision-making process and adherence to ventilation and nutritional therapy. Five of them discuss strategies used by people with MND to optimize living with this illness. Four of them discuss care and monitoring behaviors performed and recommended to people with MND. No studies focused on self-care in people with MND was identified in the literature. CONCLUSIONS: The concept of self-care in people with MND is related to inventiveness, to adaptability, and to dependence. Further studies seem to be needed to understand the concept of self-care in this population. PMID- 28817498 TI - An Interprofessional Approach to Amyotrophic Lateral Sclerosis Care. AB - Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease that is characterized by the death of motor neurons in the spinal cord, brain stem, and motor cortex that are responsible for voluntary movement. For unknown reasons, military veterans are approximately twice as likely as the public to be given a diagnosis of ALS. Currently, there is no cure for ALS. The only US Food and Drug Administration-approved disease-modifying medication is riluzole (Rilutek), which may slow ALS progression but only minimally increases survival time. Multidisciplinary care in ALS has been shown to improve survival time and improve quality of life. The purpose of this article is to describe the development of an innovative evidence-based interprofessional healthcare program in a Veterans Administration medical center to address the needs of this vulnerable veteran population. PMID- 28817499 TI - Nurse Practitioner Lead Pediatric Baclofen Pump Program: Impact on Safety and Quality of Care. AB - Children with cerebral palsy experience spasticity that can be debilitating and cause significant pain and contractures. Intrathecal baclofen (ITB) therapy can help relieve this spasticity and improve the quality of life for these patients, but it comes with risk. Withdrawal from the medication in case of abrupt discontinuation of delivery can be life-threatening. Regular maintenance of the system is mandatory. Having a program in place to manage the device and support patients helps to ensure their safety. Toward this end, we developed a program with a nurse practitioner (NP) leader to secure the safety and quality of care for patients using ITB therapy. As the program grew, the NP role as an expert in the care and management of ITB pumps became essential to the safety and care of these patients. In addition to the basic outpatient and inpatient management of the baclofen pump, the NP developed a detailed educational program for the patients and leads the quality and safety initiative for the program. The NP is also in a unique position to have intimate knowledge of the patient's condition and build a strong relationship with the patient/family. The NP is able to use this knowledge and relationship as concerns arise that could be related to the ITB therapy. This has greatly improved the safety and quality of care for patients using ITB therapy at our institution. PMID- 28817500 TI - Disease-Specific Care: Spine Surgery Program Development. AB - Minimal literature exists describing the process for development of a Joint Commission comprehensive spine surgery program within a community hospital health system. Components of a comprehensive program include structured communication across care settings, preoperative education, quality outcomes tracking, and patient follow-up. Organizations obtaining disease-specific certification must have clear knowledge of the planning, time, and overall commitment, essential to developing a successful program. Health systems benefit from disease-specific certification because of their commitment to a higher standard of service. Certification standards establish a framework for organizational structure and management and provide institutions a competitive edge in the marketplace. A framework for the development of a spine surgery program is described to help guide organizations seeking disease-specific certification. In developing a comprehensive program, it is critical to define the program's mission and vision, identify key stakeholders, implement clinical practice guidelines, and evaluate program outcomes. PMID- 28817501 TI - Nurses Perceptions of a Novel Protocol Addressing Uniform Periods of Minimum Assessment Times. AB - AIMS AND OBJECTIVES: This quality improvement project aimed to understand the impact of a quiet time protocol on nurses and patients in the neurocritical care unit (NCCU) by comparing pretest and posttest outcomes, taking decibel readings, and abstracting chart information. BACKGROUND: Sleep is essential for maintaining a healthy life. Patients in the NCCU often do not get adequate amounts of sleep. Quiet time studies have focused on implementing periods of reduced noise levels to improve patient sleep. However, the perceptions of the caregivers about the protocols have not been taken into consideration, leading to difficulty in implementing these protocols if it impedes with the routine work of the caregivers. METHODS: This was a prospective quality improvement project, with a quiet time protocol in the novel setting of the NCCU with caregiver feedback on the protocol. The quiet protocol involved decreasing light, noise, and patient interactions between 11:30 PM and 2:30 AM. There were 16 nurses who consented to the study and provided feedback via self-report questionnaires. RESULTS: Implementation of this protocol did not suggest a decrease in nurse enjoyment with their job (P = .51). There were significant improvements in patient sleep quality and quantity (P < .0001). In addition, there was some evidence of decrease in the noise level and number of patient disruptions. CONCLUSIONS: The results of this single-site project suggest that, by implementing a quiet time protocol in the NCCU, patients obtained higher levels of sleep quality and quantity. The implementation of this protocol did not impact nurses' job satisfaction, suggesting that the quiet time protocol is possible, improves patients care, and does not hinder nurses' job satisfaction. PMID- 28817502 TI - Stroke-Related Disease Comorbidity and Secondary Stroke Prevention Practices Among Young Stroke Survivors. AB - BACKGROUND: Although ischemic stroke incidence has been in decline over the past 60 years, the same has not been observed among individuals younger than 55 years. Recent reports have shown a substantial increase in young stroke incidence, yet little is known about young stroke survivors. OBJECTIVE: The aim of this study was to examine the disease comorbidity profile and secondary prevention practices in stroke survivors younger than 50 years. METHODS: This study used a retrospective data analysis of secondary stroke prevention practices among young stroke survivors using data from the 2015 National Health Interview Survey. RESULTS: Approximately 57% of the sample reported having hypertension; 33%, high cholesterol; 13%, diabetes; and 7%, heart disease. In the past 12 months, more than 60% had seen a general doctor, neurologist, or specialist, and more than 75% were following low-dose aspirin advice or taking prescribed medications for blood pressure or cholesterol. Similarly, 84% had their blood pressure checked, and 66% had their cholesterol checked, but only 50% had a fasting test for their blood sugar in the past 12 months. CONCLUSIONS: Many young stroke survivors exhibit comorbid disease conditions that are similar to older stroke survivors. A large percentage are engaged in general chronic disease and secondary stroke prevention practices, yet less than two-thirds had seen a general doctor in the past 12 months. Primary care doctors and other health professionals are critical to the implementation of disease management strategies that consider their age, secondary stroke risk, expected life spans, and other issues that differ from older adult stroke survivors. PMID- 28817503 TI - Interprovider Communication Using a Scheduled Provider Alert-Response Communication System in 3 Inpatient Neurology Units. AB - BACKGROUND: Nonemergent communications between nursing staff and residents often occur randomly throughout the workday at teaching institutions, resulting in inefficiency and interruptions of scheduled resident educational conferences or periods of overnight rest. OBJECTIVE: The aim of this study was to determine whether a quality improvement communication strategy can reduce interruptive notifications during scheduled resident didactic sessions. METHODS: We conducted a prospective, mixed-methods trial of a communication strategy between nurses and residents in 3 neurology units of an academic institution. We measured content and volume of notifications from nurses to residents during scheduled conferences and overnight and categorized these notifications according to levels of urgency. We implemented an intervention requiring multidisciplinary evening work rounds between the on-call resident and charge nurse and batching of nonemergent communications. Survey data were collected. RESULTS: The total census during the 6-month study period was 728 patients. Of the 704 resident-reported nursing notifications, 50% could be safely deferred until change of shift. After the intervention, there was a 52% decrement of notifications (0.52 vs 0.25 notifications per patient, P < .01). The preintervention survey response rate was 65% for nurses (46/71) and 100% for residents (26/26), whereas postintervention response rates were 51% for nurses (36/71) and 96% for residents (24/25). Both nurses and residents responded more favorable in the postintervention period across multiple items that addressed patient safety, utility, and satisfaction (P < .01 for comparisons). CONCLUSIONS: A scheduled nurse-resident communication system reduced interruptive calls during educational conferences and overnight by half. This intervention was perceived as safe and effective and resulted in higher satisfaction among participants. PMID- 28817504 TI - Movement Demands and Perceived Wellness Associated With Preseason Training Camp in NCAA Division I College Football Players. AB - The aims of this study were to examine the movement demands of preseason practice in National Collegiate Athletic Association Division I college football players using portable global positioning system (GPS) technology and to assess perceived wellness associated with preseason practice to determine whether GPS-derived variables from the preceding day influence perceived wellness the following day. Twenty-nine players were monitored using GPS receivers (Catapult Innovations, Melbourne, Australia) during 20 preseason practices. Individual observations (n = 550) were divided into offensive and defensive position groups. Movement variables including low-, medium-, high-intensity, and sprint distance, player load, and acceleration and deceleration distance were assessed. Perceived wellness ratings (n = 469) were examined using a questionnaire which assessed fatigue, soreness, sleep quality, sleep quantity, stress, and mood. A 1-way analysis of variance for positional movement demands and multilevel regressions for wellness measures were used, followed by post hoc testing to evaluate the relational significance between categorical outcomes of perceived wellness scores and movement variables. Results demonstrated significantly (p <= 0.05) greater total, high-intensity, and sprint distance, along with greater acceleration and deceleration distances for the defensive back and wide receiver position groups compared with their respective offensive and defensive counterparts. Significant (p <= 0.05) differences in movement variables were demonstrated for individuals who responded more or less favorably on each of the 6 factors of perceived wellness. Data from this study provide novel quantification of the position specific physical demands and perceived wellness associated with college football preseason practice. Results support the use of position-specific training and individual monitoring of college football players. PMID- 28817505 TI - Effects of the Gaelic Athletic Association 15 on Lower Extremity Injury Incidence and Neuromuscular Functional Outcomes in Collegiate Gaelic Games. AB - Schlingermann, BE, Lodge, CA, Gissane, C, and Rankin, PM. Effects of the Gaelic Athletic Association 15 on lower extremity injury incidence and neuromuscular functional outcomes in collegiate Gaelic games. J Strength Cond Res 32(7): 1993 2001, 2018-The purpose of this observational analytical cohort study was to assess the effectiveness of an injury prevention program (IPP)-Gaelic Athletic Association 15 (GAA15)-on the incidence of injury in collegiate Gaelic games. One hundred and thirty-one Gaelic games players (mean age 20.5 years +/- SD 3.0) were used for analysis in this study. Participants completed preseason and postseason testing which involved performance of the Y-Balance Test. The GAA15 was used for the intervention group; coaches were instructed to implement the program before every training session and match throughout the collegiate Gaelic Athletic Association (GAA) season. The control group adopted their normal warm-up procedures for the season. The players' injuries were documented on a weekly basis by allied health care professionals working with the teams using an online database system. Results showed significant improvements in composite Y-Balance scores in favor of the intervention group (adjusted mean difference Right: 1.8 % normalized mean reach distance (%NMRD) [p = 0.007]/Left: 2.3 %NMRD [p = 0.001]). Injury rates in the intervention group (2.62 injuries per 1,000 hours) were reduced by 66% (p = 0.001) in comparison with an age-matched control group (7.62 per 1,000 hour). Training injuries, hamstring injuries, noncontact injuries, and severe injuries were also reduced as a result of the implementation of the GAA15 (injury rate ratio: 0.20, 0.59, 0.39, and 0.45, respectively). Implementation of an IPP such as the GAA15 can reduce the risk of injury in Gaelic games and influence players' neuromuscular performance assessed through the Y-Balance Test. PMID- 28817506 TI - Maximum Distance and High-Speed Distance Demands by Position in NCAA Division I Collegiate Football Games. AB - The purpose of the study was to quantify the average and maximum distances traveled by National Collegiate Athletic Association division I football athletes during competitive games. Using global positioning system devices (Catapult Sports), total and low-, moderate-, and high-speed distances were quantified by each position. Understanding maximal workloads can enhance conditioning practice periodization protocols. A total of 40 football athletes were included in the analysis. For the data to be included, athletes were required to participate in >=75% of the offensive or defensive snaps for any given game. There was a total of 286 data downloads from 13 different games for 8 different football positions. Data were calculated and compared by offensive and defensive position to establish the mean, SD, and maximum distances (in meters) traveled during competitive games. A total maximum distance range (Max Range) was established to account for athletes who accumulated in-game total distances greater than the M + 1SD for each position. A percent was also calculated to highlight how often athletes accumulated distance workloads in the Max Range. One-way analysis of variance revealed there was a main effect of football position for all distance variables (p <= 0.001). Regardless of position, 12.0-16.7% of the time athletes accumulated in-game total distances in the Max Range. Conditioning and practice periodization protocols for distance should be position specific or individualized to avoid under or over conditioning. In addition, using a Max Range for distance can help ensure athletes are achieving distance workloads that are similar to the demands of a competitive game. PMID- 28817507 TI - Comparison of Consent Models in a Randomized Trial of Corticosteroids in Pediatric Septic Shock. AB - OBJECTIVES: To describe the use of deferred and prior informed consent models in the context of a low additional risk to standard of care, placebo-controlled randomized controlled trial of corticosteroids in pediatric septic shock. DESIGN: An observational substudy of consent processes in a randomized controlled trial of hydrocortisone versus placebo. SETTING: Seven tertiary level PICUs in Canada. PATIENTS: Children newborn to 17 years inclusive admitted to PICU with suspected septic shock between July 2014 and March 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Information on the number of families approached, consent rates obtained, and spontaneously volunteered reasons for nonparticipation were collected for both deferred and informed consent. The research ethics board of five of seven centers approved a deferred consent model; however, implementation criteria for use of this model varied across sites. The consent rate using deferred versus prior informed consent was significantly higher (83%; 35/42 vs 58%; 15/26; p = 0.02). The mean times from meeting inclusion criteria to randomization (1.8 +/- 1.8 vs 3.6 +/- 2.1 hr; p = 0.007) and study drug administration (3.4 +/- 2.7 hr vs 4.8 +/- 2.1 hr; p = 0.05) were significantly shorter with the use of deferred consent versus prior informed consent. No family member or research ethics board expressed concern following use of deferred consent. CONCLUSIONS: Deferred consent was acceptable in time-sensitive critical care research to most research ethics boards, families, and healthcare providers and resulted in higher consent rates and more efficient recruitment. Larger studies on deferred consent and consistency interpreting jurisdictional guidelines are needed to advance pediatric acute care. PMID- 28817508 TI - End-Tidal CO2-Guided Chest Compression Delivery Improves Survival in a Neonatal Asphyxial Cardiac Arrest Model. AB - OBJECTIVES: To determine whether end-tidal CO2-guided chest compression delivery improves survival over standard cardiopulmonary resuscitation after prolonged asphyxial arrest. DESIGN: Preclinical randomized controlled study. SETTING: University animal research laboratory. SUBJECTS: 1-2-week-old swine. INTERVENTIONS: After undergoing a 20-minute asphyxial arrest, animals received either standard or end-tidal CO2-guided cardiopulmonary resuscitation. In the standard group, chest compression delivery was optimized by video and verbal feedback to maintain the rate, depth, and release within published guidelines. In the end-tidal CO2-guided group, chest compression rate and depth were adjusted to obtain a maximal end-tidal CO2 level without other feedback. Cardiopulmonary resuscitation included 10 minutes of basic life support followed by advanced life support for 10 minutes or until return of spontaneous circulation. MEASUREMENTS AND MAIN RESULTS: Mean end-tidal CO2 at 10 minutes of cardiopulmonary resuscitation was 34 +/- 8 torr in the end-tidal CO2 group (n = 14) and 19 +/- 9 torr in the standard group (n = 14; p = 0.0001). The return of spontaneous circulation rate was 7 of 14 (50%) in the end-tidal CO2 group and 2 of 14 (14%) in the standard group (p = 0.04). The chest compression rate averaged 143 +/- 10/min in the end-tidal CO2 group and 102 +/- 2/min in the standard group (p < 0.0001). Neither asphyxia-related hypercarbia nor epinephrine administration confounded the use of end-tidal CO2-guided chest compression delivery. The response of the relaxation arterial pressure and cerebral perfusion pressure to the initial epinephrine administration was greater in the end-tidal CO2 group than in the standard group (p = 0.01 and p = 0.03, respectively). The prevalence of resuscitation-related injuries was similar between groups. CONCLUSIONS: End tidal CO2-guided chest compression delivery is an effective resuscitation method that improves early survival after prolonged asphyxial arrest in this neonatal piglet model. Optimizing end-tidal CO2 levels during cardiopulmonary resuscitation required that chest compression delivery rate exceed current guidelines. The use of physiologic feedback during cardiopulmonary resuscitation has the potential to provide optimized and individualized resuscitative efforts. PMID- 28817511 TI - Bringing the International Council of Nurses to Our Nursing Programs. PMID- 28817510 TI - Elite Distance Runners: A 45-Year Follow-up. AB - PURPOSE: The present longitudinal study assessed cardiorespiratory capacity and running economy of Olympic athletes over several decades to measure changes in fitness in an elite group during aging. METHODS: Twenty-six male runners training for the 1968 Olympics were recruited. HR, VO2max, ventilation, and running economy were measured in 1968, 1993, and 2013. In 2013, 22 of the original runners participated: three passed away between 1993 and 2013 and one declined to participate. RESULTS: The mean +/- SD HRmax values (bpm) were 178 +/- 10.6 in 1968, 176 +/- 13.1 in 1993, and 168 +/- 16.4 in 2013 with a difference from the predicted HRmax values in 1968 and 2013 (both P < 0.001). The mean +/- SD VO2max values (mL.min.kg) were 78 +/- 3.1 in 1968, 57 +/- 6.7 in 1993, and 42 +/- 8.9 in 2013. VO2max values based on the original body weight (mL.min.kg) in 1993 and 2013 were 65 +/- 6.0 and 47 +/- 8.1, respectively, which were higher than the measured VO2max values at those times (both P < 0.001). VEmax values (L.min) were 177 +/- 13.1 in 1968, 150 +/- 24.9 in 1993, and 118 +/- 22.5 in 2013 and declined at each time (all P < 0.001). The decline in VEmax predicted (P < 0.001) the decline in VO2max (R for 1993 = 0.500; R for 2013 = 0.567). Running economy values (mL.kg.km) were 196 +/- 7.0 in 1968, 205 +/- 16.5 in 1993, and 240 +/- 27.0 in 2013 and was greater in 2013 than those in 1993 and 1968 (both P <= 0.001). CONCLUSION: Our data suggest that higher initial fitness in younger years contributed to higher fitness with aging despite an expected age-related drop in fitness. Also, older adults could maintain high levels of cardiorespiratory fitness as they age. Expectations for fitness during aging should be more robust, especially because higher fitness could bolster quality of life. PMID- 28817509 TI - High-Intensity Exercise Enhances Conduit Artery Vascular Function in Older Adults. AB - PURPOSE: Modulation of vascular function follows an exercise intensity-dependent pattern in young adults. This study aimed to investigate the potential intensity dependent effects of an acute bout of exercise on conduit and resistance artery function in healthy older adults. METHODS: Eleven healthy older adults (five males/six females, 66 +/- 1 yr) completed 30 min of recumbent cycling at 50%-55% (low intensity) and 75%-80% (high intensity) of their age-predicted HRmax on two separate study visits. Doppler ultrasound measures of brachial artery flow mediated dilation (FMD) and reactive hyperemia were taken at baseline, 10 min postexercise, and 1 h postexercise. In addition, cardiovascular hemodynamics and brachial shear rate were measured every 5 min during exercise. RESULTS: Brachial artery FMD was enhanced 10 min after high-intensity exercise (4.8% +/- 0.2% to 9.1% +/- 0.3%, P < 0.01), but not low-intensity (4.7% +/- 0.2% to 6.2% +/- 0.3%, P = 0.54) exercise. Peak and total (area under the curve) blood flow during reactive hyperemia (measures of resistance artery function) were enhanced 10 min postexercise for both intensities (peak low intensity, 372 +/- 31 to 444 +/- 37 mL.min; peak high intensity, 391 +/- 30 to 455 +/- 28 mL.min; total low intensity, 142 +/- 16 to 205 +/- 20 mL; total high intensity, 158 +/- 14 to 240 +/- 25 mL; main effect of time for both, P < 0.05). However, the magnitude of change in peak and the total blood flow were not different between exercise intensities (interaction effect; P = 0.56 and P = 0.97, respectively). Independent of exercise intensity, FMD returned to baseline 1 h after exercise (high, 5.9% +/- 0.3%; low, 5.1% +/- 0.1%; both P > 0.05). CONCLUSION: Our data indicate that high-intensity exercise acutely enhances conduit artery function in healthy older adults. In addition, an acute bout of exercise enhances resistance artery function independent of intensity. PMID- 28817512 TI - Preparing the Nurse of the Future. PMID- 28817513 TI - From Start-up to Sustainability: A Decade of Collaboration to Shape the Future of Nursing. AB - AIM: This article describes progress the Oregon Consortium for Nursing Education has made toward addressing the academic progression goals provided by the 2011 Institute of Medicine's Future of Nursing: Leading Change, Advancing Health report. BACKGROUND: The history of the consortium's development is described, emphasizing the creation of an efficient and sustainable organization infrastructure that supports a shared curriculum provided through a community college/university partnership. METHOD: Data and analysis describing progress and challenges related to supporting a shared curriculum and increasing access and affordability for nursing education across the state are presented. RESULTS: We identified four crucial attributes of maintaining collaborative community that have been cultivated to assure the consortium continues to make progress toward reaching the Institute of Medicine's Future of Nursing goals. CONCLUSION: Oregon Consortium for Nursing Education provides important lessons learned for other statewide consortiums to consider when developing plans for sustainability. PMID- 28817514 TI - Continuing the Creativity and Connections: The Massachusetts Initiative to Update the Nurse of the Future Nursing Core Competencies. AB - AIM: This article describes the collaborative effort of nursing education and practice to update the Massachusetts Nurse of the Future Nursing Core Competencies. BACKGROUND: The Nurse of the Future Nursing Core Competencies were published in 2010. With the establishment of the Massachusetts Action Coalition, a primary goal was to continue to promote the integration of these competencies into all education and practice settings throughout Massachusetts and share this process with other states. METHOD: Through an updated literature review and consultation with subject matter experts, the Nurse of the Future Competency Committee developed a process to ensure that significant practice advances were reflected in each of the competencies. RESULTS: The updated Nurse of the Future Nursing Core Competencies were published in March 2016. CONCLUSION: The updated competencies capture the knowledge, attitudes, and skills needed for all nurses to create a culture of health across the continuum of health care. PMID- 28817515 TI - The Competency/Outcomes Model: Advancing Academic Progression. AB - AIM: This article describes the Competency Model (CM) as a promising curriculum framework to foster academic progression from the associate to the baccalaureate degree in nursing. BACKGROUND: The CM was identified by the Center to Champion Nursing in America as one of four seamless nursing academic progression models to streamline nursing academic progression. It is built on a foundation of authentic collaboration between education and practice partners to develop and maintain explicit, current, practice-relevant nursing education outcomes. METHOD: Salient features and exemplars were collected from a convenience sample of education practice partnerships across the country that have implemented the CM. RESULTS: Characteristics, trends, and variations in the CM from different state, regional, and local approaches are described and contrasted. CONCLUSION: A comparison of varied approaches in CM design and implementation demonstrates its versatility to support seamless academic progression and fortify education and practice collaboration. PMID- 28817516 TI - After the Gap Analysis: Education and Practice Changes to Prepare Nurses of the Future. AB - AIM: The purpose of the study was to describe the Connecticut Nursing Collaborative-Action Coalition's work in identifying and addressing gaps between nursing education and practice based on the Institute of Medicine's Future of Nursing report. BACKGROUND: Massachusetts Nurse of the Future (NOF) Competencies highlight the knowledge, skills, and attitudes/behaviors required for professional nurses. Integrating these concepts into the educational system will prepare the nursing workforce to respond to current/future health care needs and population health issues. METHOD: Education and practice partners in four regions conducted a gap analysis of the education to practice transition for new graduate nurses using NOF as a framework for assessment. RESULTS: Gaps in competencies were similar across regions. However, each organization uniquely addressed curricular gaps to best prepare nurses of the future. CONCLUSION: Curriculum improvements will provide students the advantage of being prepared for the rapid changes happening in health care. PMID- 28817517 TI - The Nurses on Boards Coalition: The Goal Is to Have 10,000 Nurses on Boards by 2020. PMID- 28817518 TI - Continuing the Creativity and Connections: The Massachusetts Initiative to Update the Nurse of the Future Nursing Core Competencies. PMID- 28817519 TI - Maryland Action Coalition: Academic Progression Takes Several Pathways. AB - AIM: The purpose of this article is to provide an overview of the Maryland Action Coalition academic progression activities. BACKGROUND: Maryland is predicted to be one of four states that will experience a shortage of 10,000 or more registered nurses in 2025. The Maryland Action Coalition has committed to the Institute of Medicine's Future of Nursing recommendation that 80 percent of nurses be educated at the baccalaureate (or higher) level. METHOD: Various approaches to seamless academic progression are described. The Maryland articulation model was revised to reflect new academic models. RESULTS: More BS and BSN degrees have been awarded, and more employers have advertised a preference for RNs who have completed a baccalaureate degree. CONCLUSION: Maryland is developing a solid foundation to ensure that the state has a well educated nursing workforce to meet the complex health needs of all residents. PMID- 28817520 TI - ReNEW: Wyoming's Answer to Academic Progression in Nursing. AB - AIM: The aim of the study was to describe Wyoming's approach to academic progression and its projected impact. The collaborative process used to develop the shared statewide BSN curriculum is described along with recommendations. BACKGROUND: Successful educational models that address the Institute of Medicine's recommendation that 80 percent of RNs have a baccalaureate degree by 2020 face numerous challenges, especially in rural states. METHOD: ReNEW (Revolutionizing Nursing Education in Wyoming) is a creative solution designed to decrease barriers to BSN education and increase motivation through a streamlined shared curriculum building on a strong community college system and the state's one BSN program. CONCLUSION: Guiding principles, especially addressing the value of both ADN and BSN education, broad-based coalition development and maintenance, statewide structure, and ongoing funding, were keys to success. PMID- 28817521 TI - Supporting Doctoral Students and Faculty: The Development of an Annual Doctoral Symposium. AB - AIM: The aim of the study was to develop a sustainable annual symposium to support doctoral students in nursing across the state of Georgia. BACKGROUND: A goal of the nursing profession, highlighted in the Institute of Medicine Future of Nursing report of 2011, is to increase the number of nurses with doctorates. They are needed to fill faculty positions as professors retire and to step into leadership positions as health care systems become more complex. METHOD: The Georgia Nursing Leadership Coalition developed a Doctoral Symposium in 2014 that has been repeated annually. RESULTS: The Doctoral Symposium gives doctoral students and faculty the opportunity to network, discuss current issues, advance their skills, and (for students) share their work. Approximately 100 people attend each year; costs and attendance fees have been kept low. Lessons learned are provided. CONCLUSION: The Doctoral Symposium is a sustainable, valuable activity for supporting doctoral students and faculty. PMID- 28817522 TI - A Graphical Guide to the REBOA: Five Life-Saving Steps. PMID- 28817523 TI - Lysosomal Storage Diseases: Past, Present, and Future. PMID- 28817524 TI - Perioperative Hypotension in Infants: Insights From the GAS Study. PMID- 28817525 TI - No Surprise-For Long-term Opioid Avoidance, Do We Reap What We Sow? PMID- 28817526 TI - The Anesthesiologist's Dream: "Wireless" Vital Sign Monitoring? PMID- 28817527 TI - Studies on Postoperative Analgesic Efficacy: Focusing the Statistical Methods and Broadening Outcome Measures and Measurement Tools. PMID- 28817528 TI - Resuscitative Endovascular Balloon Occlusion of the Aorta: A New Weapon to Combat Exsanguinating Hemorrhage. PMID- 28817529 TI - Do Institution-Level Blood Utilization and Blood Management Initiatives Meaningfully Impact Transfusion Practices in Cardiac Surgery? PMID- 28817530 TI - Human Resources in Anesthesia: The Road to 2030. PMID- 28817531 TI - Bias, Confounding, and Interaction: Lions and Tigers, and Bears, Oh My! AB - Epidemiologists seek to make a valid inference about the causal effect between an exposure and a disease in a specific population, using representative sample data from a specific population. Clinical researchers likewise seek to make a valid inference about the association between an intervention and outcome(s) in a specific population, based upon their randomly collected, representative sample data. Both do so by using the available data about the sample variable to make a valid estimate about its corresponding or underlying, but unknown population parameter. Random error in an experiment can be due to the natural, periodic fluctuation or variation in the accuracy or precision of virtually any data sampling technique or health measurement tool or scale. In a clinical research study, random error can be due to not only innate human variability but also purely chance. Systematic error in an experiment arises from an innate flaw in the data sampling technique or measurement instrument. In the clinical research setting, systematic error is more commonly referred to as systematic bias. The most commonly encountered types of bias in anesthesia, perioperative, critical care, and pain medicine research include recall bias, observational bias (Hawthorne effect), attrition bias, misclassification or informational bias, and selection bias. A confounding variable is a factor associated with both the exposure of interest and the outcome of interest. A confounding variable (confounding factor or confounder) is a variable that correlates (positively or negatively) with both the exposure and outcome. Confounding is typically not an issue in a randomized trial because the randomized groups are sufficiently balanced on all potential confounding variables, both observed and nonobserved. However, confounding can be a major problem with any observational (nonrandomized) study. Ignoring confounding in an observational study will often result in a "distorted" or incorrect estimate of the association or treatment effect. Interaction among variables, also known as effect modification, exists when the effect of 1 explanatory variable on the outcome depends on the particular level or value of another explanatory variable. Bias and confounding are common potential explanations for statistically significant associations between exposure and outcome when the true relationship is noncausal. Understanding interactions is vital to proper interpretation of treatment effects. These complex concepts should be consistently and appropriately considered whenever one is not only designing but also analyzing and interpreting data from a randomized trial or observational study. PMID- 28817532 TI - Letter Concerning SCAI/CCAS/SPA Expert Consensus Statement for Anesthesia and Sedation Practice in the Cardiac Catheterization Laboratory. PMID- 28817533 TI - In Response. PMID- 28817534 TI - Radius regeneration after open fracture and extrusion: a case report. AB - : A pediatric patient presenting with an open forearm fracture with segmental defect is rare, and the pediatric orthopedic literature to guide treatment is sparse. There are several described methods to treat the defect, including bone grafting and bone transport techniques. In addition, there are reports of fibular regeneration after resection if the periosteum is left intact. We present a case report of complete regeneration of over half of a pediatric radial shaft with an intact periosteum, after traumatic extrusion from an open fracture. A 6-year-old girl presented with a Gustilo Grade-IIIB open fracture with extrusion and loss of 7 cm of her radial shaft. Initially, the arm was stabilized using a monoplanar external fixator. She developed a compartment syndrome and underwent volar forearm fasciotomies. We found her periosteum grossly intact and decided to allow its natural biology to provide healing potential for the radial defect. She was placed into a circular external fixator, leaving her wrist and elbow free, and her ulna was stabilized with a flexible intramedullary nail. Soft tissue coverage was obtained with a split thickness skin graft. The patient's skin graft healed uneventfully and there were radiographic signs of bone regeneration by 2 weeks postoperatively. She maintained most of her elbow and wrist motion while in her external fixator. She developed a small pin site infection that resolved with oral antibiotics. By 10 weeks postoperatively, radiographs showed adequate corticalization and the fixator was removed. By 8 months postoperatively, the patient was released to full activity with nearly full function and range of motion. Our patient sustained a severe and rare injury but had an excellent outcome with minimal complications. This report represents a method of treatment for large bony defects in children if the periosteum is grossly intact, as opposed to more complex procedures. The intact periosteum can regenerate bony defects in the forearm if stabilized appropriately. LEVEL OF EVIDENCE: Level 4; case report. PMID- 28817535 TI - Can prasugrel decrease the extent of periprocedural myocardial injury during elective percutaneous coronary intervention? AB - INTRODUCTION Periprocedural myocardial injury may be associated with an increased risk of cardiovascular events. There is limited evidence on the safety and efficacy of more potent P2Y12 antagonists in the reduction of the incidence of periprocedural myocardial injury among patients undergoing elective percutaneous coronary intervention (PCI) with inadequate response to clopidogrel. OBJECTIVES The aim of the study was to evaluate the impact of prasugrel on the incidence of periprocedural myocardial injury among patients undergoing elective PCI with inadequate response to clopidogrel, diagnosed by point-of-care genotyping and platelet function testing (PFT). PATIENTS AND METHODS This was a prespecified interim analysis of the randomized, open-label ONSIDE TEST study. Patients with stable coronary artery disease (CAD) scheduled for PCI were randomized to one of the following study arms: 1) genotyping, 2) PFT, or 3) control, and evaluated by the CYP2C19 allele genotyping and PFT with the P2Y12 assay. Patients with poor response to clopidogrel by genotyping or PFT were loaded with 60 mg of prasugrel before PCI. The incidence of periprocedural myocardial injury was analyzed. RESULTS A total of 94 patients (genotyping, 34; PFT, 34; control, 26) were analyzed. Of the 25 patients (26.6%) with inadequate response to clopidogrel, 13 were switched to prasugrel while 12 continued dual antiplatelet therapy with clopidogrel. While similar rates of any periprocedural myocardial injury were found in the genotyping, PFG, and control arms (76.5%, 73.5%, and 73.1%, respectively), the incidence of periprocedural myocardial injury tended to be lower in the subset of patients with poor response to clopidogrel who were treated with prasugrel (61.5% vs 91.7%, P = 0.078). CONCLUSIONS Guided early prasugrel administration may decrease the extent of periprocedural myocardial injury during PCI in patients with stable CAD. PMID- 28817536 TI - Uncovering the genetic background of natural anticoagulant deficiencies: time to look behind the scenes. PMID- 28817537 TI - Echocardiography in patients undergoing cardioversion for atrial fibrillation and inadequate anticoagulation: a step beyond towards maximum safety! PMID- 28817538 TI - Too much stress for enterocytes in celiac disease? On the way to better control of treatment outcome. PMID- 28817539 TI - Does the issue of stored blood get old: is all blood equal? PMID- 28817540 TI - Association of olfactory function with the intensity of self-reported physical activity in adults with type 1 diabetes. AB - INTRODUCTION Olfactory function is impaired in patients with type 1 diabetes and can be recognized as a form of diabetic neuropathy. Physical activity has various beneficial effects on type 1 diabetes. OBJECTIVES The aim of this study was to assess a relation between physical activity and olfactory function in patients with type 1 diabetes. PATIENTS AND METHODS We enrolled 120 patients with type 1 diabetes referred to an outpatient diabetes clinic. Patients with diabetes duration of less than 5 years, age above 65 years, concomitant diabetic ketoacidosis, and those using drugs affecting nasal mucosa were excluded. The final study sample included 90 patients. A control group comprised 22 healthy participants. Olfactory function was assessed using 12 odor-emitting apens called Sniffin' Sticks. Physical activity was measured using the short version of the International Physical Activity Questionnaire (IPAQ-SF). RESULTS There was a significant difference in the occurrence of hyposmia between diabetic patients and healthy controls (70.0% vs 45.5%, respectively; P = 0.03). There were no significant differences in IPAQ-SF results between the groups. Moreover, IPAQ-SF results correlated positively with olfactory test scores (r = 0.25; P = 0.02) and negatively with age. Additionally, patients with retinopathy and autonomic neuropathy obtained lower IPAQ-SF scores than patients without those complications. A stepwise multivariable linear regression analysis indicated IPAQ scores, body mass index, and peripheral neuropathy as predictors of the olfactory test score (R = 0.2). CONCLUSIONS Our study confirms the beneficial role of physical activity in type 1 diabetes within the structures of the central nervous system. PMID- 28817541 TI - Titers of antibodies to the surface antigen of hepatitis B virus after vaccination in relation to immunity-related gene variants. A prospective study among hemodialysis patients. AB - INTRODUCTION Hemodialysis (HD) patients show a weaker response to hepatitis B virus (HBV) vaccination than the healthy population. Several gene variants were reported to be associated with the levels of antibodies to HBV surface antigen (anti-HBs) after HBV vaccination among healthy individuals. OBJECTIVES The aim of the study was to determine the effect of immunity-related genes on the maximum anti-HBs antibody levels after vaccination among HD subjects. PATIENTS AND METHODS This 6-year prospective study included HD patients who were not infected with HBV and underwent HBV vaccination. Before the study, patients were classified as responders (anti-HBs >=10 IU/l, n = 356) or nonresponders (anti-HBs <10 IU/l, n = 48) to HBV vaccination. Patients were tested for the following gene variants: GC rs7041, rs1155563, rs2298849; RXRA rs10881578, rs10776909, rs749759; VDR rs1544410, rs2228570; IFNL3 rs8099917, rs12979860; IL12A rs568408; IL12B r3212227; IL4R rs1805015; IL13 rs20541; IL18 rs360719; and CCL2 rs1024611. Anti HBs titers were checked every 6 to 12 months and the individual maximum values were used in the analysis. RESULTS There was a significant difference in peak anti-HBs levels between patients with 2 major alleles of IL12A rs568408 (median, 180 IU/l; range, 0-4.105 IU/l) and those carrying 1 or 2 minor alleles (median, 451 IU/l; range, 0-5.342 IU/l; P = 0.004). In a multivariate analysis, a positive correlate of the maximum anti-HBs antibody titers was dialysis duration, while the negative ones included the GG genotype of IL12A rs568408, age, and time elapsed from dialysis onset to peak anti-HBs antibody titers. CONCLUSIONS In HD patients, peak anti-HBs levels following vaccination are independently associated with the IL12A rs568408 variant. PMID- 28817542 TI - Safety of transesophageal echocardiography-guided electrical cardioversion in patients with atrial fibrillation and inadequate anticoagulation. AB - INTRODUCTION Restoring sinus rhythm in patients with atrial fibrillation (AF)/atrial flutter (AFl) requires adequate oral anticoagulation prior to direct current cardioversion (DCC). Some patients eligible for DCC are not properly anticoagulated. OBJECTIVES The aim of the study was to assess risk factors for thrombus and spontaneous echo contrast (SEC) in the left atrium (LA) as well as the safety profile of transesophageal echocardiography (TEE)-guided DCC in patients with inadequate anticoagulation. PATIENTS AND METHODS From the cohort of 316 patients admitted for DCC, 139 patients (mean [SD] age, 63.4 [11.5] years) had inadequate anticoagulation; 91 patients were admitted urgently for acute coronary syndrome, heart failure (HF), or poor tolerance of arrhythmia. The mean (SD) CHA2DS2-VASc score was 3.0 (1.7). RESULTS TEE revealed a left atrial appendage (LAA) thrombus in 16 patients (11.5%), and SEC in the LA in 63 patients (45.3%). In a univariate analysis, LAA thrombus was more common in patients after myocardial infarction (odds ratio [OR], 3.92; 95% CI, 1.34-11.48; P = 0.009), while SEC in the LA was more common in patients with HF (OR, 2.23; 95% CI, 1.1 4.53; P = 0.02) and left ventricular ejection fraction of less than 40% (OR, 3.65; 95% CI, 1.66-8.06; P = 0.001). In a multivariate model, the most powerful SEC-predicting factor was the LA size exceeding 45 mm (OR, 3.08; 95% CI, 1.3 7.29). DCC was performed in 105 patients. No complications of TEE or DCC were observed. CONCLUSIONS AF/AFl inadequately treated with oral anticoagulation predisposes to thrombus formation and SEC in the LA. Once thrombus is excluded, DCC is a safe procedure. There were no predictors of LAA thrombus; therefore, TEE before DCC should be performed in all patients with AF/AFl in accordance with the guidelines. PMID- 28817543 TI - Plasma levels of the A subunit of factor XIII in patients undergoing off-pump coronary artery bypass surgery. PMID- 28817544 TI - Left ventricular noncompaction cardiomyopathy with severe coronary artery disease in a young patient with familial hypercholesterolemia. PMID- 28817545 TI - Are you a rich guy with a diagonal earlobe crease? PMID- 28817546 TI - Remarkable remission of an invasive giant prolactinoma under high-dose bromocriptine monotherapy. PMID- 28817547 TI - Massive saddle pulmonary embolism during radiochemotherapy of head and neck cancer. PMID- 28817548 TI - Conclusions from the analysis of adverse events in the Polish health care system in judicial decisions of civil courts between 2011 and 2013. PMID- 28817549 TI - "ECMO for Greater Poland": a unique regional program for extracorporeal life support. PMID- 28817550 TI - Role of MicroRNA-93 I in Pathogenesis of Left Ventricular Remodeling via Targeting Cyclin-D1. AB - BACKGROUND The objective of this study was to identify the pathway responsible for ventricular remodeling. MATERIAL AND METHODS We collected remodeling myocardium tissue (n=18) and control myocardium tissue (n=22), and detected the expression of 4 miRNAs in these 2 groups using real-time PCR. We then searched the miRNA database online to find the candidate genes of miR-93. Real-time PCR and Western blot analysis were used to confirm the regulatory relationship. RESULTS We found that only miR-93 was decreased in remodeling myocardium tissue, and validated CCND1 to be the direct target gene of miR-93, with the "seed sequence" located within the 3'-UTR of the target gene via luciferase reporter assay system. Furthermore, we established the negative regulatory relationship between miR-93 and CCND1 by determining the relative luciferase activity of cells transfected with wild-type or mutant 3'-UTR of CCND1. We also found that The CCND1 protein and mRNA expression level of HL-1 cells treated with 50 nM miR-93 mimics were apparently lower than the scramble control, and those of the cells treated with 100 nM miR-93 mimics and CCND1 siRNA (100 nM) were even lower than those in the 50 nM treatment group. Meanwhile, cells transfected with miR-93 mimics (50 nM) showed evidently downregulated viability when compared with the scramble controls, while cells transfected with (100 nM) and CCND1 siRNA (100nM) showed even lower viability. CONCLUSIONS We showed that CCND1 is a direct target of miR-93, and the dysregulation of the miR-93/CCND1 signaling pathway is responsible for the development of ventricular remodeling. PMID- 28817551 TI - Progress Toward Poliomyelitis Eradication - Afghanistan, January 2016-June 2017. AB - Afghanistan, Pakistan, and Nigeria remain the only countries where the transmission of endemic wild poliovirus type 1 (WPV1) continues (1). This report describes polio eradication activities, progress, and challenges in Afghanistan during January 2016-June 2017 and updates previous reports (2,3). Thirteen WPV1 cases were confirmed in Afghanistan in 2016, a decrease of seven from the 20 cases reported in 2015. From January to June 2017, five WPV1 cases were reported, compared with six during the same period in 2016. The number of affected districts declined from 23 (including WPV1-positive acute flaccid paralysis [AFP] cases and positive environmental sewage samples) in 2015 to six in 2016. To achieve WPV1 eradication, it is important that Afghanistan's polio program continue to collaborate with that of neighboring Pakistan to track and vaccinate groups of high-risk mobile populations and strengthen efforts to reach children in security-compromised areas. PMID- 28817552 TI - Effects of Antiretroviral Therapy to Prevent HIV Transmission to Women in Couples Attempting Conception When the Man Has HIV Infection - United States, 2017. AB - Existing U.S. guidelines recommend that men with human immunodeficiency virus (HIV) infection should achieve virologic suppression* with effective antiretroviral therapy (ART) before attempting conception (1). Clinical studies have demonstrated that effective ART profoundly reduces the risk for HIV transmission (2-4). This information might be useful for counseling couples planning a pregnancy in which the man has HIV infection and the woman does not (i.e., a mixed HIV-status couple, often referred to as a serodiscordant couple). PMID- 28817553 TI - Hypertension Prevalence, Awareness, Treatment, and Control Among Adults Aged >=18 Years - Los Angeles County, 1999-2006 and 2007-2014. AB - Hypertension is an important and common risk factor for heart disease and stroke, two of the leading causes of death in adults in the United States. Despite considerable improvement in increasing the awareness, treatment, and control of hypertension, undiagnosed and uncontrolled hypertension remain public health challenges (1). Data from the National Health and Nutrition Examination Survey (NHANES) were used to estimate the prevalence of hypertension, as well as awareness, treatment, and control of hypertension among adults aged >=18 years in Los Angeles County compared with adults aged >=18 years in the United States during 1999-2006 and 2007-2014. During 2007-2014, the prevalence of hypertension was 23.1% among adults in Los Angeles County, lower than the prevalence of 29.6% among all U.S. adults. Among adults with hypertension in Los Angeles County, substantial improvements from 1999-2006 to 2007-2014 were found in hypertension awareness (increase from 73.8% to 84.6%), treatment (61.3% to 77.2%), and control (28.5% to 48.3%). Similar improvements were also seen among all U.S. adults. Although the prevalence of hypertension among adults in Los Angeles County meets the Healthy People 2020 (https://www.healthypeople.gov/) goal of <=26.9%, continued progress is needed to meet the Healthy People 2020 goal of >=61.2% for control of hypertension. PMID- 28817554 TI - Occupational Distribution of Campylobacteriosis and Salmonellosis Cases - Maryland, Ohio, and Virginia, 2014. AB - Campylobacter and Salmonella are leading causes of bacterial gastroenteritis in the United States and are estimated to cause >1 million episodes of domestically acquired illness annually (1). Campylobacter and Salmonella are primarily transmitted through contaminated food, but animal-to-human and human-to-human transmission can also occur (2,3). Although occupationally acquired infections have been reported, occupational risk factors have rarely been studied. In 2015, the Occupational Safety and Health Administration (OSHA) identified 63 suspected or confirmed cases of Campylobacter infection over 3.5 years at a poultry processing plant (Kathleen Fagan, OSHA, personal communication, December 2015); most involved new workers handling chickens in the "live hang" area where bacterial contamination is likely to be the highest. These findings were similar to those of a previous study of Campylobacter infections among workers at another poultry-processing plant (4). The investigation led to discussions among OSHA, state health departments, and CDC's National Institute for Occupational Safety and Health (NIOSH); and a surveillance study was initiated to further explore the disease incidence in poultry-processing plant workers and identify any additional occupations at increased risk for common enteric infections. Deidentified reports of campylobacteriosis and salmonellosis among Maryland, Ohio, and Virginia residents aged >=16 years were obtained and reviewed. Each employed patient was classified into one of 23 major occupational groups using the 2010 Standard Occupational Classification (SOC) system.* Risk ratios (RR) and 95% confidence intervals (CI) for associations between each occupational group and each disease were calculated to identify occupations potentially at increased risk, contrasting each group with all other occupations. In 2014, a total of 2,977 campylobacteriosis and 2,259 salmonellosis cases were reported. Among the 1,772 (60%) campylobacteriosis and 1,516 (67%) salmonellosis cases in patients for whom occupational information was available, 1,064 (60%) and 847 (56%), respectively, were employed. Persons in farming, fishing, and forestry as well as health care and technical occupations were at significantly increased risk for both campylobacteriosis and salmonellosis compared with all other occupations. Targeting education and prevention strategies could help reduce disease, and improving the systematic collection of occupational information in disease surveillance systems could provide a better understanding of the extent of occupationally acquired diseases. PMID- 28817555 TI - Notes from the Field: Death of a Farm Worker After Exposure to Manure Gas in an Open Air Environment - Wisconsin, August 2016. PMID- 28817556 TI - Risk Behaviors for Contact Lens-Related Eye Infections Among Adults and Adolescents - United States, 2016. AB - Contact lens-related eye infections, which can lead to serious outcomes, including blindness, are associated with several risk factors, including sleeping in lenses, exposing lenses to water, not adhering to replacement schedules, and reusing disinfecting solution (1). In some studies, adolescent and young adult contact lens wearers have been reported to be more likely than older adult contact lens wearers to develop eye infections (2,3) and more likely to have poor contact lens hygiene practices (2). In 2015, CDC reported the number and demographics of adult contact lens wearers in the United States to define the population at risk for contact lens-related eye infections (4); however, this estimate did not include adolescents. To better understand this group of younger contact lens wearers and guide prevention efforts, a population-based survey was used to assess contact lens wear, care behaviors, risk factors, and demographics among persons aged 12-17 years (referred to as adolescents in this report), young adults aged 18-24 years, and older adults aged >=25 years in the United States. In 2016, an estimated 3.6 million adolescents (14.5%) wore contact lenses. Of the adolescents who wore contact lenses, 85% reported at least one behavior that put them at risk for a contact lens-related eye infection, compared with 81% of young adults, and 88% of older adults. These findings can inform the creation of age specific targeted prevention messages aimed at contact lens wearers and establish a baseline for evaluating trends in contact lens wear, care habits, and contact lens-related risk behaviors. PMID- 28817557 TI - Erratum: Vol. 66, No. 27. AB - In the report "Pneumococcal Vaccination Among Medicare Beneficiaries Occurring After the Advisory Committee on Immunization Practices Recommendation for Routine Use Of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine for Adults Aged >=65 Years," on page 732, the second sentence of the discussion should have read "However, approximately 20%-25% of IPD cases and 10% of community-acquired pneumonia cases in adults aged >=65 years are caused by PCV13 serotypes." PMID- 28817558 TI - QuickStats: Percentage* of Currently Employed Adults? with No Health Insurance,S by Type of Work Arrangement - National Health Interview Survey, 2010 and 2015*. PMID- 28817559 TI - Acute kidney injury occurs only rarely in patients with Kawasaki disease. PMID- 28817560 TI - Fruit weight is controlled by Cell Size Regulator encoding a novel protein that is expressed in maturing tomato fruits. AB - Increases in fruit weight of cultivated vegetables and fruits accompanied the domestication of these crops. Here we report on the positional cloning of a quantitative trait locus (QTL) controlling fruit weight in tomato. The derived allele of Cell Size Regulator (CSR-D) increases fruit weight predominantly through enlargement of the pericarp areas. The expanded pericarp tissues result from increased mesocarp cell size and not from increased number of cell layers. The effect of CSR on fruit weight and cell size is found across different genetic backgrounds implying a consistent impact of the locus on the trait. In fruits, CSR expression is undetectable early in development from floral meristems to the rapid cell proliferation stage after anthesis. Expression is low but detectable in growing fruit tissues and in or around vascular bundles coinciding with the cell enlargement stage of the fruit maturation process. CSR encodes an uncharacterized protein whose clade has expanded in the Solanaceae family. The mutant allele is predicted to encode a shorter protein due to a 1.4 kb deletion resulting in a 194 amino-acid truncation. Co-expression analyses and GO term enrichment analyses suggest association of CSR with cell differentiation in fruit tissues and vascular bundles. The derived allele arose in Solanum lycopersicum var cerasiforme and appears completely fixed in many cultivated tomato's market classes. This finding suggests that the selection of this allele was critical to the full domestication of tomato from its intermediate ancestors. PMID- 28817562 TI - Antimicrobial resistance: The complex challenge of measurement to inform policy and the public. AB - Didier Wernli and colleagues discuss the role of monitoring in countering antimicrobial resistance. PMID- 28817561 TI - Comparing efficacies of moxifloxacin, levofloxacin and gatifloxacin in tuberculosis granulomas using a multi-scale systems pharmacology approach. AB - Granulomas are complex lung lesions that are the hallmark of tuberculosis (TB). Understanding antibiotic dynamics within lung granulomas will be vital to improving and shortening the long course of TB treatment. Three fluoroquinolones (FQs) are commonly prescribed as part of multi-drug resistant TB therapy: moxifloxacin (MXF), levofloxacin (LVX) or gatifloxacin (GFX). To date, insufficient data are available to support selection of one FQ over another, or to show that these drugs are clinically equivalent. To predict the efficacy of MXF, LVX and GFX at a single granuloma level, we integrate computational modeling with experimental datasets into a single mechanistic framework, GranSim. GranSim is a hybrid agent-based computational model that simulates granuloma formation and function, FQ plasma and tissue pharmacokinetics and pharmacodynamics and is based on extensive in vitro and in vivo data. We treat in silico granulomas with recommended daily doses of each FQ and compare efficacy by multiple metrics: bacterial load, sterilization rates, early bactericidal activity and efficacy under non-compliance and treatment interruption. GranSim reproduces in vivo plasma pharmacokinetics, spatial and temporal tissue pharmacokinetics and in vitro pharmacodynamics of these FQs. We predict that MXF kills intracellular bacteria more quickly than LVX and GFX due in part to a higher cellular accumulation ratio. We also show that all three FQs struggle to sterilize non replicating bacteria residing in caseum. This is due to modest drug concentrations inside caseum and high inhibitory concentrations for this bacterial subpopulation. MXF and LVX have higher granuloma sterilization rates compared to GFX; and MXF performs better in a simulated non-compliance or treatment interruption scenario. We conclude that MXF has a small but potentially clinically significant advantage over LVX, as well as LVX over GFX. We illustrate how a systems pharmacology approach combining experimental and computational methods can guide antibiotic selection for TB. PMID- 28817563 TI - Assessment of risk of dengue and yellow fever virus transmission in three major Kenyan cities based on Stegomyia indices. AB - Dengue (DEN) and yellow fever (YF) are re-emerging in East Africa, with contributing drivers to this trend being unplanned urbanization and increasingly adaptable anthropophilic Aedes (Stegomyia) vectors. Entomological risk assessment of these diseases remains scarce for much of East Africa and Kenya even in the dengue fever-prone urban coastal areas. Focusing on major cities of Kenya, we compared DEN and YF risk in Kilifi County (DEN-outbreak-prone), and Kisumu and Nairobi Counties (no documented DEN outbreaks). We surveyed water-holding containers for mosquito immature (larvae/pupae) indoors and outdoors from selected houses during the long rains, short rains and dry seasons (100 houses/season) in each County from October 2014-June 2016. House index (HI), Breteau index (BI) and Container index (CI) estimates based on Aedes (Stegomyia) immature infestations were compared by city and season. Aedes aegypti and Aedes bromeliae were the main Stegomyia species with significantly more positive houses outdoors (212) than indoors (88) (n = 900) (chi2 = 60.52, P < 0.0001). Overall, Ae. aegypti estimates of HI (17.3 vs 11.3) and BI (81.6 vs 87.7) were higher in Kilifi and Kisumu, respectively, than in Nairobi (HI, 0.3; BI,13). However, CI was highest in Kisumu (33.1), followed by Kilifi (15.1) then Nairobi (5.1). Aedes bromeliae indices were highest in Kilifi, followed by Kisumu, then Nairobi with HI (4.3, 0.3, 0); BI (21.3, 7, 0.7) and CI (3.3, 3.3, 0.3), at the respective sites. HI and BI for both species were highest in the long rains, compared to the short rains and dry seasons. We found strong positive correlations between the BI and CI, and BI and HI for Ae. aegypti, with the most productive container types being jerricans, drums, used/discarded containers and tyres. On the basis of established vector index thresholds, our findings suggest low-to-medium risk levels for urban YF and high DEN risk for Kilifi and Kisumu, whereas for Nairobi YF risk was low while DEN risk levels were low-to-medium. The study provides a baseline for future vector studies needed to further characterise the observed differential risk patterns by vector potential evaluation. Identified productive containers should be made the focus of community-based targeted vector control programs. PMID- 28817564 TI - Cell Cycle-Related Kinase (CCRK) regulates ciliogenesis and Hedgehog signaling in mice. AB - The Hedgehog (Hh) signaling pathway plays a key role in cell fate specification, proliferation, and survival during mammalian development. Cells require a small organelle, the primary cilium, to respond properly to Hh signals and the key regulators of Hh signal transduction exhibit dynamic localization to this organelle when the pathway is activated. Here, we investigate the role of Cell Cycle Related kinase (CCRK) in regulation of cilium-dependent Hh signaling in the mouse. Mice mutant for Ccrk exhibit a variety of developmental defects indicative of inappropriate regulation of this pathway. Cell biological, biochemical and genetic analyses indicate that CCRK is required to control the Hedgehog pathway at the level or downstream of Smoothened and upstream of the Gli transcription factors, Gli2 and Gli3. In vitro experiments indicate that Ccrk mutant cells show a greater deficit in response to signaling over long time periods than over short ones. Similar to Chlamydomonas mutants lacking the CCRK homolog, LF2, mouse Ccrk mutant cells show defective regulation of ciliary length and morphology. Ccrk mutant cells exhibit defects in intraflagellar transport (the transport mechanism used to assemble cilia), as well as slowed kinetics of ciliary enrichment of key Hh pathway regulators. Collectively, the data suggest that CCRK positively regulates the kinetics by which ciliary proteins such as Smoothened and Gli2 are imported into the cilium, and that the efficiency of ciliary recruitment allows for potent responses to Hedgehog signaling over long time periods. PMID- 28817565 TI - Peer violence perpetration and victimization: Prevalence, associated factors and pathways among 1752 sixth grade boys and girls in schools in Pakistan. AB - BACKGROUND: Child peer violence is a global problem and seriously impacts health and education. There are few research studies available in Pakistan, or South Asia. We describe the prevalence of peer violence, associations, and pathways between socio-economic status, school performance, gender attitudes and violence at home. METHODS: 1752 children were recruited into a cluster randomized controlled trial conducted on 40 fairly homogeneous public schools (20 for girls and 20 for boys), in Hyderabad, Pakistan. This was ranging from 20-65 children per school. All children were interviewed with questionnaires at baseline. RESULTS: Few children had no experience of peer violence in the previous 4 weeks (21.7% of girls vs.7% of boys). Some were victims (28.6%, of girls vs. 17.9% of boys), some only perpetrated (3.3% of girls vs. 2.5%) but mostly they perpetrated and were victims (46.4%.of girls vs 72.6%. of boys). The girls' multivariable models showed that missing the last school day due to work, witnessing her father fight a man in the last month and having more patriarchal gender attitudes were associated with both experiencing violence and perpetration, while, hunger was associated with perpetration only. For boys, missing two or more days of school in the last month, poorer school performance and more patriarchal attitudes were associated with both victimization and perpetration. Witnessing father fight, was associated with peer violence perpetration for boys. These findings are additionally confirmed with structural models. DISCUSSION: Peer violence in Pakistan is rooted in poverty and socialization of children, especially at home. A critical question is whether a school-based intervention can empower children to reduce their violence engagement in the context of poverty and social norms supportive of violence. In the political context of Pakistan, reducing all violence is essential and understanding the potential of schools as a platform for intervention is key. PMID- 28817567 TI - Accounting for biotic spatial variability in fields: Case of resistance screening against sunflower Verticillium wilt. AB - In breeding for disease resistance, the magnitude of the genetic response is difficult to appreciate because of environmental stresses that interact with the plant genotype. We discuss herein the fundamental problems in breeding for disease resistance with the aim being to better understand the interactions between plant, pathogen, and spatial patterns. The goal of this study is to fine tune breeding decisions by incorporating spatial patterns of such biotic factors into the definition of disease-occurrence probability. We use a preexisting statistics method based on geostatistics for a descriptive analysis of biotic factors for trial quality control. The plant-population structure used for spatial-pattern analysis consists of two F1-hybrid cultivars, defined as symptomatic and asymptomatic controls with respect to the studied pathogen. The controls are inserted at specific locations to establish a grid arrangement over the field that include the F1-hybrid cultivars under evaluation. We characterize the spatial structure of the pathogen population and of the general plant environment-with undetermined but present abiotic constraints-not by using direct notation such as flower time or rainfall but by using plant behavior (i.e., leaf symptom severity, indirect notation). The analysis indicates areas with higher or lower risk of disease and reveals a correlation between the symptomatic control and the effective level of disease for sunflowers. This result suggests that the pathogen and/or abiotic components are major factors in determining the probability that a plant develops the disease, which could lead to a misinterpretation of plant resistance. PMID- 28817566 TI - Inhibition of mutagenic translesion synthesis: A possible strategy for improving chemotherapy? PMID- 28817568 TI - An optimal strategy for epilepsy surgery: Disruption of the rich-club? AB - Surgery is a therapeutic option for people with epilepsy whose seizures are not controlled by anti-epilepsy drugs. In pre-surgical planning, an array of data modalities, often including intra-cranial EEG, is used in an attempt to map regions of the brain thought to be crucial for the generation of seizures. These regions are then resected with the hope that the individual is rendered seizure free as a consequence. However, post-operative seizure freedom is currently sub optimal, suggesting that the pre-surgical assessment may be improved by taking advantage of a mechanistic understanding of seizure generation in large brain networks. Herein we use mathematical models to uncover the relative contribution of regions of the brain to seizure generation and consequently which brain regions should be considered for resection. A critical advantage of this modeling approach is that the effect of different surgical strategies can be predicted and quantitatively compared in advance of surgery. Herein we seek to understand seizure generation in networks with different topologies and study how the removal of different nodes in these networks reduces the occurrence of seizures. Since this a computationally demanding problem, a first step for this aim is to facilitate tractability of this approach for large networks. To do this, we demonstrate that predictions arising from a neural mass model are preserved in a lower dimensional, canonical model that is quicker to simulate. We then use this simpler model to study the emergence of seizures in artificial networks with different topologies, and calculate which nodes should be removed to render the network seizure free. We find that for scale-free and rich-club networks there exist specific nodes that are critical for seizure generation and should therefore be removed, whereas for small-world networks the strategy should instead focus on removing sufficient brain tissue. We demonstrate the validity of our approach by analysing intra-cranial EEG recordings from a database comprising 16 patients who have undergone epilepsy surgery, revealing rich-club structures within the obtained functional networks. We show that the postsurgical outcome for these patients was better when a greater proportion of the rich club was removed, in agreement with our theoretical predictions. PMID- 28817569 TI - Long-term assessment of whale shark population demography and connectivity using photo-identification in the Western Atlantic Ocean. AB - The predictable occurrence of whale sharks, Rhincodon typus, has been well documented in several areas. However, information relating to their migratory patterns, residency times and connectivity across broad spatial scales is limited. In the present study photo-identification data is used to describe whale shark population structure and connectivity among known aggregation sites within the Western Central Atlantic Ocean (WCA). From 1999 to 2015, 1,361 individuals were identified from four distinct areas: the Yucatan Peninsula, Mexico (n = 1,115); Honduras (n = 146); northern Gulf of Mexico, United States (n = 112), and Belize (n = 49). Seasonal patterns in whale shark occurrence were evident with encounters occurring in the western Caribbean Sea earlier in the year than in the GOM. There was also a significant sex bias with 2.6 times more males present than females. Seventy sharks were observed in more than one area and the highest degree of connectivity occurred among three aggregation sites along the Mesoamerican Reef. Despite this, the majority of resightings occurred in the area where the respective sharks were first identified. This was true for the WCA as a whole, with the exception of Belize. Site fidelity was highest in Mexico. Maximum likelihood modelling resulted in a population estimate of 2,167 (95% c.i. 1585.21 2909.86) sharks throughout the entire region. This study is the first attempt to provide a broad, regional population estimate using photo-identification data from multiple whale shark aggregations. Our aim is to provide population metrics, along with the description of region-scale connectivity, that will help guide conservation action in the WCA. At a global level, rapidly growing photographic databases are allowing for researchers to look beyond the description of single aggregation sites and into the ocean-scale ecology of this pelagic species. PMID- 28817570 TI - Increased hepatotoxicity among HIV-infected adults co-infected with Schistosoma mansoni in Tanzania: A cross-sectional study. AB - INTRODUCTION: Little is known about hepatotoxicity in patients with schistosome and HIV co-infections. Several studies have reported increased liver enzymes and bilirubin levels associated with schistosome infection. We investigated whether HIV-infected adults on antiretroviral therapy who had S. mansoni co-infection had a higher prevalence of hepatotoxicity than those without. METHODOLOGY/PRINCIPAL FINDINGS: We determined the presence and grade of hepatotoxicity among 305 HIV infected outpatients who had been on medium-term (3-6 months) and long-term (>36 months) antiretroviral therapy in a region of northwest Tanzania where S. mansoni is hyperendemic. We used the AIDS Clinical Trial Group definition to define mild to moderate hepatotoxicity as alanine aminotransferase, alanine aminotransferase, and/or bilirubin elevations of grade 1 or 2, and severe hepatotoxicity as any elevation of grade 3 or 4. We determined schistosome infection status using the serum circulating cathodic antigen rapid test and used logistic regression to determine factors associated with hepatotoxicity. The prevalence of mild-moderate and severe hepatotoxicity was 29.6% (45/152) and 2.0% (3/152) in patients on medium-term antiretroviral therapy and 19.6% (30/153) and 3.3% (5/153) in the patients on long-term antiretroviral therapy. S. mansoni infection was significantly associated with hepatotoxicity on univariable analysis and after controlling for other factors associated with hepatotoxicity including hepatitis B or C and anti-tuberculosis medication use (adjusted odds ratio = 3.0 [1.6-5.8], p = 0.001). CONCLUSIONS/SIGNIFICANCE: Our work demonstrates a strong association between S. mansoni infection and hepatotoxicity among HIV-infected patients on antiretroviral therapy. Our study highlights the importance of schistosome screening and treatment for patients starting antiretroviral therapy in schistosome-endemic settings. Additional studies to determine the effects of schistosome-HIV co-infections are warranted. PMID- 28817571 TI - Automated segmentation of mouse OCT volumes (ASiMOV): Validation & clinical study of a light damage model. AB - The use of spectral-domain optical coherence tomography (SD-OCT) is becoming commonplace for the in vivo longitudinal study of murine models of ophthalmic disease. Longitudinal studies, however, generate large quantities of data, the manual analysis of which is very challenging due to the time-consuming nature of generating delineations. Thus, it is of importance that automated algorithms be developed to facilitate accurate and timely analysis of these large datasets. Furthermore, as the models target a variety of diseases, the associated structural changes can also be extremely disparate. For instance, in the light damage (LD) model, which is frequently used to study photoreceptor degeneration, the outer retina appears dramatically different from the normal retina. To address these concerns, we have developed a flexible graph-based algorithm for the automated segmentation of mouse OCT volumes (ASiMOV). This approach incorporates a machine-learning component that can be easily trained for different disease models. To validate ASiMOV, the automated results were compared to manual delineations obtained from three raters on healthy and BALB/cJ mice post LD. It was also used to study a longitudinal LD model, where five control and five LD mice were imaged at four timepoints post LD. The total retinal thickness and the outer retina (comprising the outer nuclear layer, and inner and outer segments of the photoreceptors) were unchanged the day after the LD, but subsequently thinned significantly (p < 0.01). The retinal nerve fiber-ganglion cell complex and the inner plexiform layers, however, remained unchanged for the duration of the study. PMID- 28817572 TI - Tissue-specific insulin signaling mediates female sexual attractiveness. AB - Individuals choose their mates so as to maximize reproductive success, and one important component of this choice is assessment of traits reflecting mate quality. Little is known about why specific traits are used for mate quality assessment nor about how they reflect it. We have previously shown that global manipulation of insulin signaling, a nutrient-sensing pathway governing investment in survival versus reproduction, affects female sexual attractiveness in the fruit fly, Drosophila melanogaster. Here we demonstrate that these effects on attractiveness derive from insulin signaling in the fat body and ovarian follicle cells, whose signals are integrated by pheromone-producing cells called oenocytes. Functional ovaries were required for global insulin signaling effects on attractiveness, and manipulations of insulin signaling specifically in late follicle cells recapitulated effects of global manipulations. Interestingly, modulation of insulin signaling in the fat body produced opposite effects on attractiveness, suggesting a competitive relationship with the ovary. Furthermore, all investigated tissue-specific insulin signaling manipulations that changed attractiveness also changed fecundity in the corresponding direction, pointing to insulin pathway activity as a reliable link between fecundity and attractiveness cues. The cues themselves, cuticular hydrocarbons, responded distinctly to fat body and follicle cell manipulations, indicating independent readouts of the pathway activity from these two tissues. Thus, here we describe a system in which female attractiveness results from an apparent connection between attractiveness cues and an organismal state of high fecundity, both of which are created by lowered insulin signaling in the fat body and increased insulin signaling in late follicle cells. PMID- 28817573 TI - Network representations of angular regions for electromagnetic scattering. AB - Network modeling in electromagnetics is an effective technique in treating scattering problems by canonical and complex structures. Geometries constituted of angular regions (wedges) together with planar layers can now be approached with the Generalized Wiener-Hopf Technique supported by network representation in spectral domain. Even if the network representations in spectral planes are of great importance by themselves, the aim of this paper is to present a theoretical base and a general procedure for the formulation of complex scattering problems using network representation for the Generalized Wiener Hopf Technique starting basically from the wave equation. In particular while the spectral network representations are relatively well known for planar layers, the network modelling for an angular region requires a new theory that will be developed in this paper. With this theory we complete the formulation of a network methodology whose effectiveness is demonstrated by the application to a complex scattering problem with practical solutions given in terms of GTD/UTD diffraction coefficients and total far fields for engineering applications. The methodology can be applied to other physics fields. PMID- 28817574 TI - Diffusion tensor imaging profiles reveal specific neural tract distortion in normal pressure hydrocephalus. AB - BACKGROUND: The pathogenesis of normal pressure hydrocephalus (NPH) remains unclear which limits both early diagnosis and prognostication. The responsiveness to intervention of differing, complex and concurrent injury patterns on imaging have not been well-characterized. We used diffusion tensor imaging (DTI) to explore the topography and reversibility of white matter injury in NPH pre- and early after shunting. METHODS: Twenty-five participants (sixteen NPH patients and nine healthy controls) underwent DTI, pre-operatively and at two weeks post intervention in patients. We interrogated 40 datasets to generate a full panel of DTI measures and corroborated findings with plots of isotropy (p) vs. anisotropy (q). RESULTS: Concurrent examination of DTI measures revealed distinct profiles for NPH patients vs. controls. PQ plots demonstrated that patterns of injury occupied discrete white matter districts. DTI profiles for different white matter tracts showed changes consistent with i) predominant transependymal diffusion with stretch/ compression, ii) oedema with or without stretch/ compression and iii) predominant stretch/ compression. Findings were specific to individual tracts and dependent upon their proximity to the ventricles. At two weeks post intervention, there was a 6.7% drop in axial diffusivity (p = 0.022) in the posterior limb of the internal capsule, compatible with improvement in stretch/ compression, that preceded any discernible changes in clinical outcome. On PQ plots, the trajectories of the posterior limb of the internal capsule and inferior longitudinal fasciculus suggested attempted 'round trips'. i.e. return to normality. CONCLUSION: DTI profiling with p:q correlation may offer a non invasive biomarker of the characteristics of potentially reversible white matter injury. PMID- 28817575 TI - MCK1 is a novel regulator of myo-inositol phosphate synthase (MIPS) that is required for inhibition of inositol synthesis by the mood stabilizer valproate. AB - Myo-inositol, the precursor of all inositol compounds, is essential for the viability of eukaryotes. Identifying the factors that regulate inositol homeostasis is of obvious importance to understanding cell function and the pathologies underlying neurological and metabolic resulting from perturbation of inositol metabolism. The current study identifies Mck1, a GSK3 homolog, as a novel positive regulator of inositol de novo synthesis in yeast. Mck1 was required for normal activity of myo-inositol phosphate synthase (MIPS), which catalyzes the rate-limiting step of inositol synthesis. mck1Delta cells exhibited a 50% decrease in MIPS activity and a decreased rate of incorporation of [13C6]glucose into [13C6]-inositol-3-phosphate and [13C6]-inositol compared to WT cells. mck1Delta cells also exhibited decreased growth in the presence of the inositol depleting drug valproate (VPA), which was rescued by supplementation of inositol. However, in contrast to wild type cells, which exhibited more than a 40% decrease in MIPS activity in the presence of VPA, the drug did not significantly decrease MIPS activity in mck1Delta cells. These findings indicate that VPA-induced MIPS inhibition is Mck1-dependent, and suggest a model that unifies two current hypotheses of the mechanism of action of VPA-inositol depletion and GSK3 inhibition. PMID- 28817576 TI - Gestational diabetes mellitus is associated with increased pro-migratory activation of vascular endothelial growth factor receptor 2 and reduced expression of vascular endothelial growth factor receptor 1. AB - Placentas from gestational diabetes mellitus (GDM) are often hypervascularized; however, participation of vascular endothelial growth factor (VEGF) and its receptors in this placental adaptation is unclear. We aimed to test whether changes in phosphorylation of tyrosine 951 or tyrosine 1175 (pY951 or pY1175) of the vascular endothelial growth factor receptor 2 (KDR) are associated with the proangiogenic state observed in placentas from GDM. We obtained placental samples from women with normal pregnancies (n = 24) or GDM (n = 18). We measured the relative expression of markers for endothelial cell number (CD31, CD34), VEGF, vascular endothelial growth factor receptor 1 (Flt-1), KDR, pY951 and pY1175 of KDR in placental homogenate. Immunohistochemistry of placental blood vessels were performed using CD34. Proliferation and migration of human umbilical vein endothelial cells (HUVEC) obtained from normal pregnancy and GDM were determined in absence or presence of conditioned medium (CM) harvested from GDM or normoglycemic HUVEC cultures. GDM was associated with more CD31 and CD34 protein compared to normal pregnancy. High number, but reduced area of placental blood vessels was found in GDM. Reduced Flt-1 levels (mRNA and protein) are associated with reduced KDR mRNA, but higher KDR protein levels in placentas from GDM. No significant changes in Y951-or Y1175-phosphorylation of KDR in placentas from GDM were found. GDM did not alter proliferation of HUVECs, but enhanced migration. Conditioned medium harvested from GDM HUVEC cultures enhanced KDR protein amount, tube formation capacity and cell migration in HUVEC isolated from normoglycemic pregnancies. The data indicate that GDM is associated with reduced expression of Flt-1 but high pro-migratory activation of KDR reflecting a proangiogenic state in GDM. PMID- 28817577 TI - Detailing neuroanatomical development in late childhood and early adolescence using NODDI. AB - Diffusion tensor imaging (DTI) studies have provided much evidence of white and subcortical gray matter changes during late childhood and early adolescence that suggest increasing myelination, axon density, and/or fiber coherence. Neurite orientation dispersion and density imaging (NODDI) can be used to further characterize development in white and subcortical grey matter regions in the brain by improving specificity of the MRI signal compared to conventional DTI. We used measures from NODDI and DTI to examine white and subcortical gray matter development in a group of 27 healthy participants aged 8-13 years. Neurite density index (NDI) was strongly correlated with age in nearly all regions, and was more strongly associated with age than fractional anisotropy (FA). No significant correlations were observed between orientation dispersion index (ODI) and age. This suggests that white matter and subcortical gray matter changes during late childhood and adolescence are dominated by changes in neurite density (i.e., axon density and myelination), rather than increasing coherence of axons. Within brain regions, FA was correlated with both ODI and NDI while mean diffusivity was only related to neurite density, providing further information about the structural variation across individuals. Data-driven clustering of the NODDI parameters showed that microstructural profiles varied along layers of white matter, but that that much of the white and subcortical gray matter matured in a similar manner. Clustering highlighted isolated brain regions with decreasing NDI values that were not apparent in region-of-interest analysis. Overall, these results help to more specifically understand patterns of white and gray matter development during late childhood and early adolescence. PMID- 28817579 TI - The link between bond forfeiture and pretrial release mechanism: The case of Dallas County, Texas. AB - PURPOSE: The goal of this study was to evaluate the efficacy of four pretrial jail release mechanisms (i.e., bond types) commonly used during the pretrial phase of the criminal justice process in terms of their ability to discriminate between defendants failing to appear in court (i.e., bond forfeiture). These include attorney bonds, cash bonds, commercial bail bonds, and release via a pretrial services agency. METHODS: A multi-treatment propensity score matching protocol was employed to assess between-release-mechanism differences in the conditional probability of failure to appear/bond forfeiture. Data were culled from archival state justice records comprising all defendants booked into the Dallas County, Texas jail during 2008 (n = 29,416). RESULTS: The results suggest that defendants released via commercial bail bonds were less likely to experience failure to appear leading to the bond forfeiture process compared to equivalent defendants released via cash, attorney, and pretrial services bonds. This finding held across different offense categories. The study frames these differences within a discussion encompassing procedural variation within and between each release mechanism, thereby setting the stage for further research and dialog regarding potential justice reform. PMID- 28817578 TI - Deliberate self-harm behavior among young violent offenders. AB - Deliberate self-harm behavior (DSH) can have profound effects on a person's quality of life, and challenges the health care system. Even though DSH has been associated with aggressive interpersonal behaviors, the knowledge on DSH in persons exhibiting such behaviors is scarce. This study aims to (1) specify the prevalence and character of DSH, (2) identify clinical, neurocognitive, psychosocial, and criminological characteristics associated with DSH, and (3) determine predictors of DSH among young violent offenders. Data were collected from a nationally representative cohort of 270 male violent offenders, 18-25 years old, imprisoned in Sweden. Participants were interviewed and investigated neuropsychologically, and their files were reviewed for psychosocial background, criminal history, mental disorders, lifetime aggressive antisocial behaviors, and DSH. A total of 62 offenders (23%) had engaged in DSH at some point during their lifetime, many on repeated occasions, yet without suicidal intent. DSH was significantly associated with attention deficit hyperactivity disorder, mood disorders, anxiety disorders, various substance use disorders, being bullied at school, and repeated exposure to violence at home during childhood. Mood disorders, anxiety disorders, and being bullied at school remained significant predictors of DSH in a total regression model. Violent offenders direct aggressive behaviors not only toward other people, but also toward themselves. Thus, DSH must be assessed and prevented in correctional institutions as early as possible, and more knowledge is needed of the function of DSH among offenders. PMID- 28817580 TI - Criticality predicts maximum irregularity in recurrent networks of excitatory nodes. AB - A rigorous understanding of brain dynamics and function requires a conceptual bridge between multiple levels of organization, including neural spiking and network-level population activity. Mounting evidence suggests that neural networks of cerebral cortex operate at a critical regime, which is defined as a transition point between two phases of short lasting and chaotic activity. However, despite the fact that criticality brings about certain functional advantages for information processing, its supporting evidence is still far from conclusive, as it has been mostly based on power law scaling of size and durations of cascades of activity. Moreover, to what degree such hypothesis could explain some fundamental features of neural activity is still largely unknown. One of the most prevalent features of cortical activity in vivo is known to be spike irregularity of spike trains, which is measured in terms of the coefficient of variation (CV) larger than one. Here, using a minimal computational model of excitatory nodes, we show that irregular spiking (CV > 1) naturally emerges in a recurrent network operating at criticality. More importantly, we show that even at the presence of other sources of spike irregularity, being at criticality maximizes the mean coefficient of variation of neurons, thereby maximizing their spike irregularity. Furthermore, we also show that such a maximized irregularity results in maximum correlation between neuronal firing rates and their corresponding spike irregularity (measured in terms of CV). On the one hand, using a model in the universality class of directed percolation, we propose new hallmarks of criticality at single-unit level, which could be applicable to any network of excitable nodes. On the other hand, given the controversy of the neural criticality hypothesis, we discuss the limitation of this approach to neural systems and to what degree they support the criticality hypothesis in real neural networks. Finally, we discuss the limitations of applying our results to real networks and to what degree they support the criticality hypothesis. PMID- 28817582 TI - An enduring legacy of discovery: Margaret Stirewalt. PMID- 28817581 TI - Population activity structure of excitatory and inhibitory neurons. AB - Many studies use population analysis approaches, such as dimensionality reduction, to characterize the activity of large groups of neurons. To date, these methods have treated each neuron equally, without taking into account whether neurons are excitatory or inhibitory. We studied population activity structure as a function of neuron type by applying factor analysis to spontaneous activity from spiking networks with balanced excitation and inhibition. Throughout the study, we characterized population activity structure by measuring its dimensionality and the percentage of overall activity variance that is shared among neurons. First, by sampling only excitatory or only inhibitory neurons, we found that the activity structures of these two populations in balanced networks are measurably different. We also found that the population activity structure is dependent on the ratio of excitatory to inhibitory neurons sampled. Finally we classified neurons from extracellular recordings in the primary visual cortex of anesthetized macaques as putative excitatory or inhibitory using waveform classification, and found similarities with the neuron type-specific population activity structure of a balanced network with excitatory clustering. These results imply that knowledge of neuron type is important, and allows for stronger statistical tests, when interpreting population activity structure. PMID- 28817584 TI - The application of project-based learning in bioinformatics training. PMID- 28817583 TI - Dextran sodium sulfate (DSS) induces necrotizing enterocolitis-like lesions in neonatal mice. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is an inflammatory bowel disease of preterm human newborns with yet unresolved etiology. An established neonatal murine model for NEC employs oral administration of lipopolysaccharides (LPS) combined with hypoxia/hypothermia. In adult mice, feeding dextran sodium sulfate (DSS) represents a well-established model for experimental inflammatory bowel disease. Here we investigated the effect of DSS administration on the neonatal murine intestine in comparison with the established NEC model. METHODS: 3-day-old C57BL/6J mice were either fed formula containing DSS or LPS. LPS treated animals were additionally stressed by hypoxia/hypothermia twice daily. After 72 h, mice were euthanized, their intestinal tissue harvested and analyzed by histology, qRT PCR and flow cytometry. For comparison, adult C57BL/6J mice were fed with DSS for 8 days and examined likewise. Untreated, age matched animals served as controls. RESULTS: Adult mice treated with DSS exhibited colonic inflammation with significantly increased Cxcl2 mRNA expression. In contrast, tissue inflammation in neonatal mice treated with DSS or LPS plus hypoxia/hypothermia was present in colon and small intestine as well. Comparative analysis of neonatal mice revealed a significantly increased lesion size and intestinal Cxcl2 mRNA expression after DSS exposure. Whereas LPS administration mainly induced local neutrophil recruitment, DSS treated animals displayed increased monocytes/macrophages infiltration. CONCLUSIONS: Our study demonstrates the potential of DSS to induce NEC-like lesions accompanied by a significant humoral and cellular immune response in the small and large intestine of neonatal mice. The new model therefore represents a good alternative to LPS plus hypoxia/hypothermia administration requiring no additional physical stress. PMID- 28817586 TI - Ten simple rules to initiate and run a postdoctoral association. PMID- 28817585 TI - Selecting targets for the diagnosis of Schistosoma mansoni infection: An integrative approach using multi-omic and immunoinformatics data. AB - In order to effectively control and monitor schistosomiasis, new diagnostic methods are essential. Taking advantage of computational approaches provided by immunoinformatics and considering the availability of Schistosoma mansoni predicted proteome information, candidate antigens of schistosomiasis were selected and used in immunodiagnosis tests based on Enzime-linked Immunosorbent Assay (ELISA). The computational selection strategy was based on signal peptide prediction; low similarity to human proteins; B- and T-cell epitope prediction; location and expression in different parasite life stages within definitive host. Results of the above-mentioned analysis were parsed to extract meaningful biological information and loaded into a relational database developed to integrate them. In the end, seven proteins were selected and one B-cell linear epitope from each one of them was selected using B-cell epitope score and the presence of intrinsically disordered regions (IDRs). These predicted epitopes generated synthetic peptides that were used in ELISA assays to validate the rational strategy of in silico selection. ELISA was performed using sera from residents of areas of low endemicity for S. mansoni infection and also from healthy donors (HD), not living in an endemic area for schistosomiasis. Discrimination of negative (NEG) and positive (INF) individuals from endemic areas was performed using parasitological and molecular methods. All infected individuals were treated with praziquantel, and serum samples were obtained from them 30 and 180 days post-treatment (30DPT and 180DPT). Results revealed higher IgG levels in INF group than in HD and NEG groups when peptides 1, 3, 4, 5 and 7 were used. Moreover, using peptide 5, ELISA achieved the best performance, since it could discriminate between individuals living in an endemic area that were actively infected from those that were not (NEG, 30DPT, 180DPT groups). Our experimental results also indicate that the computational prediction approach developed is feasible for identifying promising candidates for the diagnosis of schistosomiasis and other diseases. PMID- 28817587 TI - Network characteristics and patent value-Evidence from the Light-Emitting Diode industry. AB - This study proposes a different angle to social network analysis that evaluates patent value and explores its influencing factors using the network centrality and network position. This study utilizes a logistic regression model to explore the relationships in the LED industry between patent value and network centrality as measured from out-degree centrality, in-degree centrality, in-closeness centrality, and network position, which is measured from effect size. The empirical result shows that out-degree centrality and in-degree centrality have significant positive effects on patent value and that effect size has a significant negative effect on patent value. PMID- 28817588 TI - Phylogeography of the reticulated python (Malayopython reticulatus ssp.): Conservation implications for the worlds' most traded snake species. AB - As an important economic natural resource in Southeast Asia, reticulated pythons (Malayopython reticulatus ssp.) are primarily harvested from the wild for their skins-which are prized in the luxury leather goods industry. Trade dynamics of this CITES Appendix II listed species are complex and management approaches on the country or regional level appear obscure. Little is known about the actual geographic point-of-harvest of snakes, how genetic diversity is partitioned across the species range, how current harvest levels may affect the genetic viability of populations, and whether genetic structure could (or should) be accounted for when managing harvest quotas. As an initial survey, we use mitochondrial sequence data to define the broad-scale geographic structure of genetic diversity across a significant portion of the reticulated python's native range. Preliminary results reveal: (1) prominent phylogenetic structure across populations east and west of Huxley's modification of Wallace's line. Thirty-four haplotypes were apportioned across two geographically distinct groups, estimated to be moderately (5.2%); (2) Philippine, Bornean and Sulawesian populations appear to cluster distinctly; (3) individuals from Ambon Island suggest recent human introduction. Malayopython reticulatus is currently managed as a single taxonomic unit across Southeast Asia yet these initial results may justify special management considerations of the Philippine populations as a phylogenetically distinct unit, that warrants further examination. In Indonesia, genetic structure does not conform tightly to political boundaries and therefore we advocate the precautionary designation and use of Evolutionary Significant Units within Malayopython reticulatus, to inform and guide regional adaptive management plans. PMID- 28817589 TI - Relationship between atherosclerosis and occlusal support of natural teeth with mediating effect of atheroprotective nutrients: From the SONIC study. AB - Whereas most of studies investigating relationship between oral health and atherosclerosis have focused on periodontitis, very few of them were examined about occlusal status of natural teeth which possibly influence dietary habit. The primary aim of this cross-sectional study was to investigate the association between the occlusal support of posterior teeth and the prevalence of atherosclerosis in community-dwelling septuagenarians. Also, the second aim was to test the hypothesis that the intake of key nutrients for atherosclerosis prevention would have a mediating effect on the relationship between the occlusal status and atherosclerosis. The study population included 468 community-dwelling dentate persons aged 69-71 years recruited from the local residential registration in Japan. Participants were divided into three groups, according to the number of occlusal support zones (OSZ) in the posterior area: Complete (four OSZ), Moderate (three or two OSZ), and Collapsed (one or no OSZ). Dietary intakes were assessed using a brief-type self-administered diet history questionnaire. Atherosclerosis was defined as carotid intima-media thickness ?1.10 mm by using carotid ultrasonography test. The logistic or linear regression model was used in multivariate analysis to assess relationship between occlusal status and atherosclerosis, and the mediating effect of key nutrients within the relationship. Multivariable analysis showed a significant association between occlusal status and atherosclerosis (odds ratio for Collapsed group to Complete group: 1.87; 95% CI: 1.45-2.41), independent of periodontal status (odds ratio: 2.01, 95%CI: 1.46-2.78). Fish and shellfish, vitamin B6 and n-3PUFAs were significantly related to both of occlusal status and atherosclerosis, and also was indicated a mediating effect on the association between occlusal status and atherosclerosis. This study implied that, within the limitation of the cross sectional study design, the reduced posterior occlusion was related to the increased prevalence of atherosclerosis via the decline of key dietary intakes among Japanese community-dwelling dentate individuals. PMID- 28817590 TI - Reconstructing Asian faunal introductions to eastern Africa from multi-proxy biomolecular and archaeological datasets. AB - Human-mediated biological exchange has had global social and ecological impacts. In sub-Saharan Africa, several domestic and commensal animals were introduced from Asia in the pre-modern period; however, the timing and nature of these introductions remain contentious. One model supports introduction to the eastern African coast after the mid-first millennium CE, while another posits introduction dating back to 3000 BCE. These distinct scenarios have implications for understanding the emergence of long-distance maritime connectivity, and the ecological and economic impacts of introduced species. Resolution of this longstanding debate requires new efforts, given the lack of well-dated fauna from high-precision excavations, and ambiguous osteomorphological identifications. We analysed faunal remains from 22 eastern African sites spanning a wide geographic and chronological range, and applied biomolecular techniques to confirm identifications of two Asian taxa: domestic chicken (Gallus gallus) and black rat (Rattus rattus). Our approach included ancient DNA (aDNA) analysis aided by BLAST based bioinformatics, Zooarchaeology by Mass Spectrometry (ZooMS) collagen fingerprinting, and direct AMS (accelerator mass spectrometry) radiocarbon dating. Our results support a late, mid-first millennium CE introduction of these species. We discuss the implications of our findings for models of biological exchange, and emphasize the applicability of our approach to tropical areas with poor bone preservation. PMID- 28817591 TI - Susceptibility of bovine dental enamel with initial erosion lesion to new erosive challenges. AB - This in vitro study evaluated the impact of initial erosion on the susceptibility of enamel to further erosive challenge. Thirty bovine enamel blocks were selected by surface hardness and randomized into two groups (n = 15): GC- group composed by enamel blocks without erosion lesion and GT- group composed by enamel blocks with initial erosion lesion. The baseline profile of each block was determined using the profilometer. The initial erosion was produced by immersing the blocks into HCl 0.01 M, pH 2.3 for 30 seconds, under stirring. The erosive cycling consisted of blocks immersion in hydrochloric acid (0.01 M, pH 2.3) for 2 minutes, followed by immersion in artificial saliva for 120 minutes. This procedure was repeated 4 times a day for 5 days, and the blocks were kept in artificial saliva overnight. After erosive cycling, final profile measurement was performed. Profilometry measured the enamel loss by the superposition of initial and final profiles. Data were analyzed by t-test (p<0.05). The result showed no statistically significant difference between groups (GS = 14.60+/-2.86 and GE = .14.69+/-2.21 MUm). The presence of initial erosion on bovine dental enamel does not enhance its susceptibility to new erosive challenges. PMID- 28817592 TI - Using k-dependence causal forest to mine the most significant dependency relationships among clinical variables for thyroid disease diagnosis. AB - Numerous data mining models have been proposed to construct computer-aided medical expert systems. Bayesian network classifiers (BNCs) are more distinct and understandable than other models. To graphically describe the dependency relationships among clinical variables for thyroid disease diagnosis and ensure the rationality of the diagnosis results, the proposed k-dependence causal forest (KCF) model generates a series of submodels in the framework of maximum spanning tree (MST) and demonstrates stronger dependence representation. Friedman test on 12 UCI datasets shows that KCF has classification accuracy advantage over the other state-of-the-art BNCs, such as Naive Bayes, tree augmented Naive Bayes, and k-dependence Bayesian classifier. Our extensive experimental comparison on 4 medical datasets also proves the feasibility and effectiveness of KCF in terms of sensitivity and specificity. PMID- 28817593 TI - A systematic review of context bias in invasion biology. AB - The language that scientists use to frame biological invasions may reveal inherent bias-including how data are interpreted. A frequent critique of invasion biology is the use of value-laden language that may indicate context bias. Here we use a systematic study of language and interpretation in papers drawn from invasion biology to evaluate whether there is a link between the framing of papers and the interpretation of results. We also examine any trends in context bias in biological invasion research. We examined 651 peer-reviewed invasive species competition studies and implemented a rigorous systematic review to examine bias in the presentation and interpretation of native and invasive competition in invasion biology. We predicted that bias in the presentation of invasive species is increasing, as suggested by several authors, and that bias against invasive species would result in misinterpreting their competitive dominance in correlational observational studies compared to causative experimental studies. We indeed found evidence of bias in the presentation and interpretation of invasive species research; authors often introduced research with invasive species in a negative context and study results were interpreted against invasive species more in correlational studies. However, we also found a distinct decrease in those biases since the mid-2000s. Given that there have been several waves of criticism from scientists both inside and outside invasion biology, our evidence suggests that the subdiscipline has somewhat self-corrected apparent biases. PMID- 28817594 TI - Soil pathogen-aphid interactions under differences in soil organic matter and mineral fertilizer. AB - There is increasing evidence showing that microbes can influence plant-insect interactions. In addition, various studies have shown that aboveground pathogens can alter the interactions between plants and insects. However, little is known about the role of soil-borne pathogens in plant-insect interactions. It is also not known how environmental conditions, that steer the performance of soil-borne pathogens, might influence these microbe-plant-insect interactions. Here, we studied effects of the soil-borne pathogen Rhizoctonia solani on aphids (Sitobion avenae) using wheat (Triticum aestivum) as a host. In a greenhouse experiment, we tested how different levels of soil organic matter (SOM) and fertilizer addition influence the interactions between plants and aphids. To examine the influence of the existing soil microbiome on the pathogen effects, we used both unsterilized field soil and sterilized field soil. In unsterilized soil with low SOM content, R. solani addition had a negative effect on aphid biomass, whereas it enhanced aphid biomass in soil with high SOM content. In sterilized soil, however, aphid biomass was enhanced by R. solani addition and by high SOM content. Plant biomass was enhanced by fertilizer addition, but only when SOM content was low, or in the absence of R. solani. We conclude that belowground pathogens influence aphid performance and that the effect of soil pathogens on aphids can be more positive in the absence of a soil microbiome. This implies that experiments studying the effect of pathogens under sterile conditions might not represent realistic interactions. Moreover, pathogen-plant-aphid interactions can be more positive for aphids under high SOM conditions. We recommend that soil conditions should be taken into account in the study of microbe-plant-insect interactions. PMID- 28817595 TI - Predictive factors of the dimensions and location of mental foramen using cone beam computed tomography. AB - OBJECTIVE: The mental foramen (MF) hosts main neurovascular structures, making it of crucial importance for surgical procedures. This study aimed to analyze the factors influencing the dimensions and location of the MF. MATERIALS AND METHODS: Cone beam computed tomography (CBCT) scans of 344 patients were examined for MF dimensions, as well as for the distances from the MF to the alveolar crest (MF MSB), and to the inferior mandibular border (MF-MIB). RESULTS: Gender, mandibular side and presence of accessory mental foramina (AMF) significantly influence MF area. Males, left hemimandibles, and hemimandibles with no AMF had a higher rate of large MF areas (B = - 0.60; p = 0.003, females; B = 0.55; p = 0.005; B = 0.85; p = 0.038). Age, gender and dental status significantly influence MF-MSB distance. The distance decreased as age increased (B = -0.054; p = 0.001), females showed a lower rate of long MF-MSB distances (B = -0.94, p = 0.001), and dentate patients showed a higher rate of long MF-MSB distances (B = 2.27; p = 0.001). Age, gender and emerging angle significantly influenced MF-MIB distance. The distance decreased as age and emerging angle increased (B = -0.01; p = 0.001; B = -0.03; p = 0.001), and females had a lower rate of long MF-MIB distances (B = -1.94, p = 0.001). CONCLUSIONS: General and local factors influence the dimensions and location of MF. MF dimensions are influenced by gender, mandibular side, anteroposterior position, and the presence of AMF. Distance from MF to alveolar crest is influenced by gender, age and dental status, while the relative MF position is influenced by age and dental status. CBCT images make it possible to analyze the MF in order to avoid complications during surgical procedures. PMID- 28817596 TI - Potential effects of climate change on members of the Palaeotropical pitcher plant family Nepenthaceae. AB - Anthropogenic climate change is predicted to have profound effects on species distributions over the coming decades. In this paper, we used maximum entropy modelling (Maxent) to estimate the effects of projected changes in climate on extent of climatically-suitable habitat for two Nepenthes pitcher plant species in Borneo. The model results predicted an increase in area of climatically suitable habitat for the lowland species Nepenthes rafflesiana by 2100; in contrast, the highland species Nepenthes tentaculata was predicted to undergo significant loss of climatically-suitable habitat over the same period. Based on the results of the models, we recommend that research be undertaken into practical mitigation strategies, as approximately two-thirds of Nepenthes are restricted to montane habitats. Highland species with narrow elevational ranges will be at particularly high risk, and investigation into possible mitigation strategies should be focused on them. PMID- 28817597 TI - A unified censored normal regression model for qPCR differential gene expression analysis. AB - Reverse transcription quantitative polymerase chain reaction (RT-qPCR) is considered as the gold standard for accurate, sensitive, and fast measurement of gene expression. Prior to downstream statistical analysis, RT-qPCR fluorescence amplification curves are summarized into one single value, the quantification cycle (Cq). When RT-qPCR does not reach the limit of detection, the Cq is labeled as "undetermined". Current state of the art qPCR data analysis pipelines acknowledge the importance of normalization for removing non-biological sample to sample variation in the Cq values. However, their strategies for handling undetermined Cq values are very ad hoc. We show that popular methods for handling undetermined values can have a severe impact on the downstream differential expression analysis. They introduce a considerable bias and suffer from a lower precision. We propose a novel method that unites preprocessing and differential expression analysis in a single statistical model that provides a rigorous way for handling undetermined Cq values. We compare our method with existing approaches in a simulation study and on published microRNA and mRNA gene expression datasets. We show that our method outperforms traditional RT-qPCR differential expression analysis pipelines in the presence of undetermined values, both in terms of accuracy and precision. PMID- 28817598 TI - Taxonomic review of Copella (Characiformes: Lebiasinidae) with an identification key for the species. AB - A taxonomic review of Copella is presented based on the analysis of the type material of all nominal species and extensive material from South American drainages. Six out of ten nominal species are recognized as valid: Copella arnoldi, C. callolepis, C. compta, C. eigenmanni, C. nattereri, and C. vilmae. Copella carsevennensis is a junior synonym of C. arnoldi, C. nigrofasciata and 'Nannostomus' stigmasemion are junior synonyms of C. callolepis, C. metae is junior synonym of C. eigenmanni, and C. meinkeni is junior synonym of C. nattereri. Species of Copella occur in the rio Amazonas and Orinoco basins, and coastal drainages of Guyana, French Guiana, Surinam, and Venezuela. An identification key is provided. PMID- 28817599 TI - Anguillicola crassus infection affects mRNA expression levels in gas gland tissue of European yellow and silver eel. AB - Using Illumina sequencing, we investigated transcriptional changes caused by the nematode Anguillicola crassus within yellow and silver eels by comparing swimbladder samples of uninfected yellow with infected yellow eels, and uninfected silver with infected silver eels, respectively. In yellow eel gas gland, the infection caused a modification of steady state mRNA levels of 1675 genes, most of them being upregulated. Functional annotation analysis based on GO terms was used to categorize identified genes with regard to swimbladder metabolism or response to the infection. In yellow eels, the most prominent category was 'immune response', including various inflammatory components, complement proteins, and immunoglobulins. The elevated expression of several glucose and monocarboxylate transporters indicated an attempt to maintain the level of glucose metabolism, even in due to the infection thickened swimbladder tissue. In silver eel swimbladder tissue, on the contrary, the mRNA levels of only 291 genes were affected. Genes in the categories 'glucose metabolism' and 'ROS metabolism' barely responded to the infection and even the reaction of the immune system was much less pronounced compared to infected yellow eels. However, in the category 'extracellular matrix', the mRNA levels of several mucin genes were strongly elevated, suggesting increased mucus production as a defense reaction against the parasite. The present study revealed a strong reaction to an Anguillicola crassus infection on mRNA expression levels in swimbladder tissue of yellow eels, whereas in silver eels the changes ware almost negligible. A possible explanation for this difference is that the silvering process requires so much energy that there is not much scope to cope with the additional challenge of a nematode infection. Another possible explanation could be that gas-secreting activity of the silver eel swimbladder was largely reduced, which could coincide with a reduced responsiveness to other challenges, like a nematode infection. PMID- 28817600 TI - Development and evaluation of height diameter at breast models for native Chinese Metasequoia. AB - Accurate tree height and diameter at breast height (dbh) are important input variables for growth and yield models. A total of 5503 Chinese Metasequoia trees were used in this study. We studied 53 fitted models, of which 7 were linear models and 46 were non-linear models. These models were divided into two groups of single models and multivariate models according to the number of independent variables. The results show that the allometry equation of tree height which has diameter at breast height as independent variable can better reflect the change of tree height; in addition the prediction accuracy of the multivariate composite models is higher than that of the single variable models. Although tree age is not the most important variable in the study of the relationship between tree height and dbh, the consideration of tree age when choosing models and parameters in model selection can make the prediction of tree height more accurate. The amount of data is also an important parameter what can improve the reliability of models. Other variables such as tree height, main dbh and altitude, etc can also affect models. In this study, the method of developing the recommended models for predicting the tree height of native Metasequoias aged 50-485 years is statistically reliable and can be used for reference in predicting the growth and production of mature native Metasequoia. PMID- 28817601 TI - Bortezomib initiates endoplasmic reticulum stress, elicits autophagy and death in Echinococcus granulosus larval stage. AB - Cystic echinococcosis (CE) is a worldwide distributed helminthic zoonosis caused by Echinococcus granulosus. Benzimidazole derivatives are currently the only drugs for chemotherapeutic treatment of CE. However, their low efficacy and the adverse effects encourage the search for new therapeutic targets. We evaluated the in vitro efficacy of Bortezomib (Bz), a proteasome inhibitor, in the larval stage of the parasite. After 96 h, Bz showed potent deleterious effects at a concentration of 5 MUM and 0.5 MUM in protoscoleces and metacestodes, respectively (P < 0.05). After 48 h of exposure to this drug, it was triggered a mRNA overexpression of chaperones (Eg-grp78 and Eg-calnexin) and of Eg-ire2/Eg xbp1 (the conserved UPR pathway branch) in protoscoleces. No changes were detected in the transcriptional expression of chaperones in Bz-treated metacestodes, thus allowing ER stress to be evident and viability to highly decrease in comparison with protoscoleces. We also found that Bz treatment activated the autophagic process in both larval forms. These facts were evidenced by the increase in the amount of transcripts of the autophagy related genes (Eg atg6, Eg-atg8, Eg-atg12, Eg-atg16) together with the increase in Eg-Atg8-II detected by western blot and by in toto immunofluorescence labeling. It was further confirmed by direct observation of autophagic structures by electronic microscopy. Finally, in order to determine the impact of autophagy induction on Echinococcus cell viability, we evaluated the efficacy of Bz in combination with rapamycin and a synergistic cytotoxic effect on protoscolex viability was observed when both drugs were used together. In conclusion, our findings demonstrated that Bz induced endoplasmic reticulum stress, autophagy and subsequent death allowing to identify unstudied parasite-host pathways that could provide a new insight for control of parasitic diseases. PMID- 28817602 TI - Exploring the potential of a structural alphabet-based tool for mining multiple target conformations and target flexibility insight. AB - Protein flexibility is often implied in binding with different partners and is essential for protein function. The growing number of macromolecular structures in the Protein Data Bank entries and their redundancy has become a major source of structural knowledge of the protein universe. The analysis of structural variability through available redundant structures of a target, called multiple target conformations (MTC), obtained using experimental or modeling methods and under different biological conditions or different sources is one way to explore protein flexibility. This analysis is essential to improve the understanding of various mechanisms associated with protein target function and flexibility. In this study, we explored structural variability of three biological targets by analyzing different MTC sets associated with these targets. To facilitate the study of these MTC sets, we have developed an efficient tool, SA-conf, dedicated to capturing and linking the amino acid and local structure variability and analyzing the target structural variability space. The advantage of SA-conf is that it could be applied to divers sets composed of MTCs available in the PDB obtained using NMR and crystallography or homology models. This tool could also be applied to analyze MTC sets obtained by dynamics approaches. Our results showed that SA-conf tool is effective to quantify the structural variability of a MTC set and to localize the structural variable positions and regions of the target. By selecting adapted MTC subsets and comparing their variability detected by SA-conf, we highlighted different sources of target flexibility such as induced by binding partner, by mutation and intrinsic flexibility. Our results support the interest to mine available structures associated with a target using to offer valuable insight into target flexibility and interaction mechanisms. The SA-conf executable script, with a set of pre-compiled binaries are available at http://www.mti.univ-paris-diderot.fr/recherche/plateformes/logiciels. PMID- 28817603 TI - Expression of the MHC class II in triple-negative breast cancer is associated with tumor-infiltrating lymphocytes and interferon signaling. AB - Tumor-infiltrating lymphocytes (TILs) have been known for their strong prognostic and predictive significance in triple-negative breast cancer (TNBC). Several mechanisms for TIL influx in TNBC have been elucidated. Major histocompatibility complex class II (MHC-II) is an essential component of the adaptive immune system and is generally restricted to the surface of antigen-presenting cells. However, it has been reported that interferon-gamma signaling may induce MHC-II in almost all cell types, including those derived from cancer. We aimed to examine the relationship between MHC-II expression in tumor cells and the amount of TILs in 681 patients with TNBC. Further, the prognostic significance of MHC-II and the association of MHC-II with a couple of molecules involved in the interferon signaling pathway were investigated using immunohistochemical staining. Higher MHC-II expression in tumor cells was associated with the absence of lymphovascular invasion (p = 0.042); larger amounts of TILs (p < 0.001); frequent formations of tertiary lymphoid structures (p < 0.001); higher expression of myxovirus resistance gene A, one of the main mediators of the interferon signaling pathway (p < 0.001); and higher expression of double-stranded RNA activated protein kinase, which can be induced by interferons (p = 0.008). Moreover, tumors that showed high MHC class I expression and any positivity for MHC-II had larger amounts of CD4- and CD8-positive T lymphocytes (p < 0.001). Positive MHC-II expression in tumor cells was associated with better disease-free survival in patients who had lymph node metastasis (p = 0.009). In conclusion, MHC-II expression in tumor cells was closely associated with an increase in TIL number and interferon signaling in TNBC. Further studies are warranted to improve our understanding regarding TIL influx, as well as patients' responses to immunotherapy. PMID- 28817604 TI - Therapeutic flexible airway endoscopy of small children in a tertiary referral center-11 years' experience. AB - OBJECTIVES: Use of therapeutic flexible airway endoscopy (TFAE) is very limited in pediatrics. We report our clinical experiences and long term outcomes of TFAE in small children from a single tertiary referral center. METHODS: This is a retrospective cohort study. Small children with their body weight no more than 5.0 kg who had received TFAE between 2005 and 2015 were enrolled. Demographic information and outcomes were reviewed and analyzed from medical charts and TFAE videos. RESULTS: A total of 313 TFAE were performed in 225 children. The mean age was 3.50 +/- 0.24 (0.01-19.2) months old; the mean body weight was 3.52 +/- 0.65 (0.57-5.0) kg. A noninvasive ventilation technique, without mask or artificial airway, was applied to support all the procedures. TFAE included laser therapy (39.6%), balloon dilatation plasty (25.6%), tracheal intubation (24.3%) and metallic stent placement (6.4%). Short-length endoscopes of 30-35 cm were used in 96%. All TFAE were successfully completed without serious adverse events or mortality. Mean procedural time was 27.6 +/- 16.1 minutes. TFAE resulted in successful extubation immediately in 67.2% (45/67) and 62.8% (118/188) were able to wean off their positive pressure ventilation support in 7 days after procedures. By the end of this study, these TFAE averted the originally suggested airway surgeries in 93.8% (61/65), as benefited from laser therapy, stent implantation, and balloon dilatation plasty. CONCLUSIONS: The TFAE modality of using short-length endoscopes as supported with this noninvasive ventilation and ICU support is a viable, instant and effective management in small children. It has resulted in rapid weaning of respiratory supports and averted more invasive rigid endoscopy or airway surgeries. PMID- 28817605 TI - All-trans retinoic acid suppresses malignant characteristics of CD133-positive thyroid cancer stem cells and induces apoptosis. AB - Recently, diagnoses of radioiodine-refractory differentiated thyroid cancer (RAI R DTC) have become more common; prognosis is poor. It has been suggested that cancer stem cells account for radiotherapy resistance. By flow cytometry, different expression percents of CD133 and OCT4 in thyroid cancer cell lines were detected. By real-time quantitative PCR, different mRNA expression of CD133, OCT4, GLUT1, thyroglobulin (TG), thyroperoxidase (TPO) and sodium iodine symporter (NIS) was analyzed; the localization of CD133, OCT4, and NIS expression was examined using immunofluorescence confocal microscopy. Different expression of CD133, OCT4, and NIS in 21 human thyroid cancer and nodule tissues was investigated using immunohistochemistry. CD133-positive cells were isolated by magnetic sorting. Stronger colony formation ability of CD133-positive and weaker ability of CD133-negative cells in vivo were examined by colony formation. The effects of all-trans retinoic acid (ATRA) on CD133-positive cells in vivo were explored with Cell Counting Kit-8, colony formation, apoptosis, cell cycle, and ethynyl deoxyuridine assays. The ARO cell line and RAI-R DTC tissue specimens had more CD133-positive cells. NIS expression was significantly lower in RAI-R DTC tissue compared to radioiodine-sensitive DTC (RAI-DTC) tissue and specimens from patients with thyroid nodule. ATRA inhibited the stem cell characteristics of CD133-positive cells and induced CD133-positive cell differentiation to CD133 negative cells, and promoted CD133-positive cell apoptosis. PMID- 28817606 TI - Distribution and associations of intraocular pressure in 7- and 12-year-old Chinese children: The Anyang Childhood Eye Study. AB - PURPOSE: To report the intraocular pressure (IOP) and its association with myopia and other factors in 7 and 12-year-old Chinese children. METHODS: All children participating in the Anyang Childhood Eye Study underwent non-contact tonometry as well as measurement of central corneal thickness (CCT), axial length, cycloplegic auto-refraction, blood pressure, height and weight. A questionnaire was used to collect other relevant information. Univariable and multivariable analysis were performed to determine the associations of IOP. RESULTS: A total of 2760 7-year-old children (95.4%) and 2198 12-year-old children (97.0%) were included. The mean IOP was 13.5+/-3.1 mmHg in the younger cohort and 15.8+/-3.5 mmHg in older children (P<0.0001). On multivariable analysis, higher IOP in the younger cohort was associated with female gender (standardized regression coefficient [SRC], 0.11, P<0.0001), increasing central corneal thickness (SRC, 0.39, P<0.0001), myopia (SRC, 0.05, P = 0.03), deep anterior chamber (SRC, 0.07, P<0.01), smaller waist (SRC, 0.07, P<0.01) and increasing mean arterial pressure (SRC, 0.13, P<0.0001). In the older cohort, higher IOP was again associated with female gender (SRC, 0.16, P<0.0001), increasing central corneal thickness (SRC, 0.43, P<0.0001), deep anterior chamber (SRC, 0.09, P<0.01), higher body mass index (SRC, 0.07, P = 0.04) and with increasing mean arterial pressure (SRC, 0.09, P = 0.01), age at which reading commenced (SRC, 0.10, P<0.01) and birth method (SRC, 0.09, P = 0.01), but not with myopia (SRC, 0.09, P = 0.20). CONCLUSION: In Chinese children, higher IOP was associated with female gender, older age, thicker central cornea, deeper anterior chamber and higher mean arterial pressure. Higher body mass index, younger age at commencement of reading and being born of a caesarean section was also associated with higher IOP in adolescence. PMID- 28817607 TI - Computer-aided position planning of miniplates to treat facial bone defects. AB - In this contribution, a software system for computer-aided position planning of miniplates to treat facial bone defects is proposed. The intra-operatively used bone plates have to be passively adapted on the underlying bone contours for adequate bone fragment stabilization. However, this procedure can lead to frequent intra-operatively performed material readjustments especially in complex surgical cases. Our approach is able to fit a selection of common implant models on the surgeon's desired position in a 3D computer model. This happens with respect to the surrounding anatomical structures, always including the possibility of adjusting both the direction and the position of the used osteosynthesis material. By using the proposed software, surgeons are able to pre plan the out coming implant in its form and morphology with the aid of a computer visualized model within a few minutes. Further, the resulting model can be stored in STL file format, the commonly used format for 3D printing. Using this technology, surgeons are able to print the virtual generated implant, or create an individually designed bending tool. This method leads to adapted osteosynthesis materials according to the surrounding anatomy and requires further a minimum amount of money and time. PMID- 28817608 TI - Data-driven coarse graining of large biomolecular structures. AB - Advances in experimental and computational techniques allow us to study the structure and dynamics of large biomolecular assemblies at increasingly higher resolution. However, with increasing structural detail it can be challenging to unravel the mechanism underlying the function of molecular machines. One reason is that atomistic simulations become computationally prohibitive. Moreover it is difficult to rationalize the functional mechanism of systems composed of tens of thousands to millions of atoms by following each atom's movements. Coarse graining (CG) allows us to understand biological structures from a hierarchical perspective and to gradually zoom into the adequate level of structural detail. This article introduces a Bayesian approach for coarse graining biomolecular structures. We develop a probabilistic model that aims to represent the shape of an experimental structure as a cloud of bead particles. The particles interact via a pairwise potential whose parameters are estimated along with the bead positions and the CG mapping between atoms and beads. Our model can also be applied to density maps obtained by cryo-electron microscopy. We illustrate our approach on various test systems. PMID- 28817609 TI - Corneal confocal microscopy is a rapid reproducible ophthalmic technique for quantifying corneal nerve abnormalities. AB - PURPOSE: To assess the effect of applying a protocol for image selection and the number of images required for adequate quantification of corneal nerve pathology using in vivo corneal confocal microscopy (IVCCM). METHODS: IVCCM was performed in 35 participants by a single examiner. For each participant, 4 observers used a standardized protocol to select 6 central corneal nerve images to assess the inter-observer variability. Furthermore, images were selected by a single observer on two occasions to assess intra-observer variability and the effect of sample size was assessed by comparing 6 with 12 images. Corneal nerve fiber density (CNFD), branch density (CNBD) and length (CNFL) were quantified using fully automated software. The data were compared using the intra class correlation coefficient (ICC) and Bland-Altman agreement plots for all experiments. RESULTS: The ICC values for CNFD, CNBD and CNFL were 0.93 (P<0.0001), 0.96 (P<0.0001) and 0.95 (P<0.0001) for inter-observer variability and 0.95 (P<0.0001), 0.97 (P<0.001) and 0.97 (P<0.0001) for intra-observer variability. For sample size variability, ICC values were 0.94 (P<0.0001), 0.95 (P<0.0001), and 0.96 (P<0.0001) for CNFD, CNBD and CNFL. Bland-Altman plots showed excellent agreement for all parameters. CONCLUSIONS: This study shows that implementing a standardized protocol to select IVCCM images results in high intra and inter-observer reproducibility for all corneal nerve parameters and 6 images are adequate for analysis. IVCCM could therefore be deployed in large multicenter clinical trials with confidence. PMID- 28817610 TI - An overview of financial sources being utilized to support Zika Virus published research. AB - BACKGROUND: Since its initial detection in Brazil in 2015, Zika Virus (ZIKV) has spread rapidly throughout most of the Caribbean and South, Central and North America. An upsurge in congenital syndrome associated with ZIKV and Guillain Barre Syndrome (GBS) has been associated with the increase in ZIKV. This amplification in numbers led to the need for funded research initiatives focusing on various countries globally and on specific experimental types. OBJECTIVES: To determine the financial institutions involved in the production of primary research into the ZIKV epidemic. This research also intends to draw attention to the investigative areas that are dominating, experimental types being conducted and the geographical areas that are producing the bulk of the research utilizing available funds. METHODS: A cross sectional search of published primary research was conducted using Pan American Health Organization (PAHO) Zika platform and PubMed between January 2007 and October 2016. Titles, abstract and full articles were assed and one researcher extracted data. Information was crossed checked by a second researcher to ensure accuracy. FINDINGS: 268 articles were included and investigations occurred across 48 countries with Brazil and USA dominating the research. Applied Research and Laboratory based studies were most frequently utilized. 38.1% of articles did not report financial sources. Public institutions were the major known contributors. Other financiers included private, non-profits and mixed funders exclusive of public sources. 156 individual financial bodies assisted with National Institute of Health being most frequently mentioned followed by The National Council for Scientific and Technological Development (CNPq) and the Institut Pasteur. Virus, vectors and reservoirs was most frequently used (99/268, 36.9%) followed by clinical management (70/268, 26.1%) and epidemiology (46/268, 17.2%). INTERPRETATION: The evidence suggests international efforts to fund ZIKV research and a need to foster collaborative and synchronized priority setting for resource allocation. PMID- 28817612 TI - Expression and functional implications of the renal apelinergic system in rodents. AB - Apelin binds to the G protein-coupled apelin receptor (APJ; gene name aplnr) to modulate diverse physiological systems including cardiovascular function, and hydromineral and metabolic balance. Recently a second endogenous ligand for APJ, named apela, has been discovered. We confirm that apela activates signal transduction pathways (ERK activation) in cells expressing the cloned rat APJ. Previous studies suggest that exogenous apela is diuretic, attributable wholly or in part to an action on renal APJ. Thus far the cellular distribution of apela in the kidney has not been reported. We have utilized in situ hybridization histochemistry to reveal strong apela labelling in the inner medulla (IM), with lower levels observed in the inner stripe of the outer medulla (ISOM), of rat and mouse kidneys. This contrasts with renal aplnr expression where the converse is apparent, with intense labelling in the ISOM (consistent with vasa recta labelling) and low-moderate hybridization in the IM, in addition to labelling of glomeruli. Apelin is found in sparsely distributed cells amongst more prevalent aplnr-labelled cells in extra-tubular regions of the medulla. This expression profile is supported by RNA-Seq data that shows that apela, but not apelin or aplnr, is highly expressed in microdissected rat kidney tubules. If endogenous tubular apela promotes diuresis in the kidney it could conceivably do this by interacting with APJ in vasculature, or via an unknown receptor in the tubules. The comparative distribution of apela, apelin and aplnr in the rodent kidney lays the foundation for future work on how the renal apelinergic system interacts. PMID- 28817611 TI - The directed migration of gonadal distal tip cells in Caenorhabditis elegans requires NGAT-1, a beta1,4-N-acetylgalactosaminyltransferase enzyme. AB - Glycoproteins such as growth factor receptors and extracellular matrix have well known functions in development and cancer progression, however, the glycans at sites of modification are often heterogeneous molecular populations which makes their functional characterization challenging. Here we provide evidence for a specific, discrete, well-defined glycan modification and regulation of a stage specific cell migration in Caenorhabditis elegans. We show that a chain terminating, putative null mutation in the gene encoding a predicted beta1,4-N acetylgalactosaminyltransferase, named ngat-1, causes a maternally rescued temperature sensitive (ts) defect in the second phase of the three phase migration pattern of the posterior, but not the anterior, hermaphrodite Distal Tip Cell (DTC). An amino-terminal partial deletion of ngat-1 causes a similar but lower penetrance ts phenotype. The existence of multiple ts alleles with distinctly different molecular DNA lesions, neither of which is likely to encode a ts protein, indicates that NGAT-1 normally prevents innate temperature sensitivity for phase 2 DTC pathfinding. Temperature shift analyses indicate that the ts period for the ngat-1 mutant defect ends by the beginning of post embryonic development-nearly 3 full larval stages prior to the defective phase 2 migration affected by ngat-1 mutations. NGAT-1 homologs generate glycan-terminal GalNAc-beta1-4GlcNAc, referred to as LacdiNAc modifications, on glycoproteins and glycolipids. We also found that the absence of the GnT1/Mgat1 activity [UDP-N acetyl-D-glucosamine:alpha-3-D-mannoside beta-1,2-N-acetylglucosaminyltransferase 1 (encoded by C. elegans gly-12, gly-13, and gly-14 and homologous to vertebrate GnT1/Mgat1)], causes a similar spectrum of DTC phenotypes as ngat-1 mutations primarily affecting posterior DTC phase 2 migration and preventing manifestation of the same innate ts period as ngat-1. GnT1/Mgat1 is a medial Golgi enzyme known to modify mannose residues and initiate N-glycan branching, an essential step in the biosynthesis of hybrid, paucimannose and complex-type N-glycans. Quadruple mutant animals bearing putative null mutations in ngat-1 and the three GnT genes (gly-12, gly-13, gly-14) were not enhanced for DTC migration defects, suggesting NGAT-1 and GnT1 act in the same pathway. These findings suggest that GnTI generates an N-glycan substrate for NGAT-1 modification, which is required at restrictive temperature (25 degrees C) to prevent, stabilize, reverse or compensate a perinatal thermo-labile process (or structure) causing late larval stage DTC phase 2 migration errors. PMID- 28817613 TI - Diflunisal inhibits prestin by chloride-dependent mechanism. AB - The motor protein prestin is a member of the SLC26 family of anion antiporters and is essential to the electromotility of cochlear outer hair cells and for hearing. The only direct inhibitor of electromotility and the associated charge transfer is salicylate, possibly through direct interaction with an anion-binding site on prestin. In a screen to identify other inhibitors of prestin activity, we explored the effect of the non-steroid anti-inflammatory drug diflunisal, which is a derivative of salicylate. We recorded prestin activity by whole-cell patch clamping HEK cells transiently expressing prestin and mouse outer hair cells. We monitored the impact of diflunisal on the prestin-dependent non-linear capacitance and electromotility. We found that diflunisal triggers two prestin associated effects: a chloride independent increase in the surface area and the specific capacitance of the membrane, and a chloride dependent inhibition of the charge transfer and the electromotility in outer hair cells. We conclude that diflunisal affects the cell membrane organization and inhibits prestin-associated charge transfer and electromotility at physiological chloride concentrations. The inhibitory effects on hair cell function are noteworthy given the proposed use of diflunisal to treat neurodegenerative diseases. PMID- 28817614 TI - Development of a technique for psyllium husk mucilage purification with simultaneous microencapsulation of curcumin. AB - This study focused on evaluating a technique for the psyllium husk mucilage (PHM) purification with simultaneous microencapsulation of curcumin. PHM was extracted with water and purified with ethanol. For the mucilage purification and simultaneous microencapsulation, an ethanolic solution of curcumin was used. After dehydration, the samples were analysed by instrumental techniques and evaluated for thermal stability. The presence of curcumin in the solution did not impair the yield of precipitated polysaccharide. Interactions of the dye and carbohydrates were confirmed by displacement of peaks in FT-IR and FT-Raman spectroscopy. The onset temperature of degradation of microcapsules was superior to that of curcumin. Thermal stability in solution at 90 degrees C also improved. After 300 minutes of heating, the microcapsules had a remnant curcumin content exceeding 70%, while, in standard sample, the remaining curcumin content was 4.46%. Thus, the developed technique was successful on purification of PHM and microencapsulation of curcumin. PMID- 28817615 TI - Genotoxic effects of Roundup Full II(r) on lymphocytes of Chaetophractus villosus (Xenarthra, Mammalia): In vitro studies. AB - In Argentina, Chaetophractus villosus has a wide distribution that overlaps with agricultural areas where soybean is the predominant crop. In such areas the pesticide Roundup Full II(r) (RU) is widely applied. The genotoxic effect of its active ingredient glyphosate (RU is 66.2% glyphosate) on the peripheral blood lymphocytes of C. villosus was tested over a range of concentrations (280, 420, 560, 1120 MUmol/L). Culture medium without glyphosate served as negative control, while medium containing mitomycin C served as positive control. Genetic damage was characterized in terms of the percentage of cells with chromosome aberrations (CA), the mean number of sister chromatid exchanges (SCE) per cell, and the modification of cell proliferation kinetics via the calculation of the replication index. Significant increases (p < 0.0001) were seen in the CA frequency and the mean number of SCEs per cell compared to negative controls at all the RU concentrations tested. Chromatid breaks, the only form of CA observed, under the 560 MUmol/L RU conditions and in presence of mitomycin C were four to five times more common than at lower concentrations, while no viable cells were seen in the 1120 MUmol/L treatment. The mean number of SCEs per cell was significantly higher under the 280 MUmol/L RU conditions than the 420 or 560 MUmol/L RU conditions; cells cultivated in the presence of MMC also showed significantly more SCEs. All the RU concentrations tested (except in the 1120 MUmol/L RU treatment [no viable cells]) induced a significant reduction in the replication index (p < 0.0001). The present results confirm the genotoxic effects of RU on C. villosus lymphocytes in vitro, strongly suggesting that exposure to RU could induce DNA damage in C. villosus wildlife. PMID- 28817617 TI - Comparison of lingual mucosa and buccal mucosa grafts used in inlay urethroplasty in failed hypospadias of pre-pubertal boys in a Chinese group. AB - OBJECTIVE: The purpose of this study was to compare the outcomes of the buccal mucosa and lingual mucosa used in children who received multiple failed hypospadias surgeries. METHOD: We conducted a retrospective study of 62 children who received buccal or lingual mucosa graft urethroplasty in our hospital between 2012 and 2015. The ages ranged from 3.5-11 y. All cases included multiple failed hypospadias procedures, and the subjects received previous operations 2-3 times. All patients underwent one-stage operations. Thirty-three cases were treated with lingual mucosa grafts. The patient ages ranged from 3.5 to 11 y (median 7.5 y), and they had previous operations 2-3 times (mean 2.8+/-0.7). Grafts ranged from lengths of 2-6 cm (mean 5.1+/-0.46 cm) and widths of 0.5-1.5 cm (mean 1.2+/- 0.16 cm). Our follow-up was 5 to 12 m (mean 8.3+/-1.2 m). Twenty-nine cases were treated with buccal mucosa grafts. The patient ages ranged from 4 to 9.2 y (median 7.0 y), and they had previous operations 2-3 times (mean 2.5+/-0.2). Grafts ranged from lengths of 2-5.3 cm (mean 4.9+/- 0.28 cm) and widths of 0.5 1.5 cm (mean 1.0+/-0.11 cm). Our follow-up was 5 to 12 m (mean 7.9+/-0.5 m). The results were tested with SPSS 18.0. The rates of complications were compared by a chi-square test, and pre-operative conditions were compared by t test. RESULTS: For the outcomes of the two groups, there was no significant difference between the groups in terms of age, preoperative surgery time, and the length and width of the grafts (p>0.05). For the lingual mucosa graft group, fistula: 2/33 (6.0%), stricture: 1/33(3.0%), ventral curvature: 2/33(6.0%), complications: 5/33(15.0%), success rate: 28/33(84.8%), Hose score: 14.34+/-0.95, peak flow: 6.5 ml/s-12.0 ml/s, and mean peak flow: 9.3+/-0.4 ml/s. For the buccal mucosa graft group, fistula: 2/29(6.8%), stricture: 2/29(6.8%), ventral curvature: 1/29 (3.4%), complication rate: 5/29(17.0%), success rate: 24/29 (83.0%), Hose score: 14.28+/ 1.03, peak flow: 6.5 ml/s-12.0 ml/s, and mean peak flow: 9.2+/-0.2 ml/s. There were no differences between the two groups for overall success, complication rates, peak flow, and the Hose scores(P>0.05). CONCLUSION: The lingual mucosal graft and the buccal mucosa graft both achieved good outcomes, and the lingual mucosa graft made up for the shortcomings of the buccal mucosa graft, which provided a reliable way to treat the multiple failed hypospadias surgeries in pre pubertal boys. PMID- 28817616 TI - Patterns of statin non-prescription in patients with established coronary artery disease: A report from a contemporary multicenter Japanese PCI registry. AB - Statin therapy is regarded as an effective medication to reduce cardiovascular events in patients at higher risk for future incidence of coronary artery disease. However, very few studies have been conducted to examine its implementation in non-Western real-world practice. In this study, we sought to describe statin prescription patterns in relation to patient characteristics in a Japanese multicenter percutaneous coronary intervention (PCI) registry as a foundation for quality improvement. We studied 15,024 patients that were prospectively enrolled in the Japan Cardiovascular Database-Keio interhospital Cardiovascular Study Registry from January 2009 to August 2014. The overall discharge statin non-prescription rate was 15.2%, without significant interhospital (MOR = 1.01) or annual differences (MOR = 1.13) observed. Hierarchical multivariable logistic regression analysis accounting for regional differences revealed that the presence of chronic kidney disease was associated with higher rates of statin non-prescription (OR 1.87, 95% confidence interval, 1.69-2.08, p value <0.001), and higher age (per 1-year increase) showed a trend for prescription of low-intensity statin (OR 1.00, 95% confidence interval, 1.00 1.01, p value = 0.045) within the subset of PCI patients (N = 4,853) enrolled after the year 2011. Our study indicates that patients with chronic kidney disease and elderlies may be the primary targets for maximizing the beneficial effect of statin therapy in post PCI patients. PMID- 28817618 TI - National-scale cropland mapping based on spectral-temporal features and outdated land cover information. AB - The lack of sufficient ground truth data has always constrained supervised learning, thereby hindering the generation of up-to-date satellite-derived thematic maps. This is all the more true for those applications requiring frequent updates over large areas such as cropland mapping. Therefore, we present a method enabling the automated production of spatially consistent cropland maps at the national scale, based on spectral-temporal features and outdated land cover information. Following an unsupervised approach, this method extracts reliable calibration pixels based on their labels in the outdated map and their spectral signatures. To ensure spatial consistency and coherence in the map, we first propose to generate seamless input images by normalizing the time series and deriving spectral-temporal features that target salient cropland characteristics. Second, we reduce the spatial variability of the class signatures by stratifying the country and by classifying each stratum independently. Finally, we remove speckle with a weighted majority filter accounting for per-pixel classification confidence. Capitalizing on a wall-to wall validation data set, the method was tested in South Africa using a 16-year old land cover map and multi-sensor Landsat time series. The overall accuracy of the resulting cropland map reached 92%. A spatially explicit validation revealed large variations across the country and suggests that intensive grain-growing areas were better characterized than smallholder farming systems. Informative features in the classification process vary from one stratum to another but features targeting the minimum of vegetation as well as short-wave infrared features were consistently important throughout the country. Overall, the approach showed potential for routinely delivering consistent cropland maps over large areas as required for operational crop monitoring. PMID- 28817619 TI - Sequential effects in preference decision: Prior preference assimilates current preference. AB - An important factor affecting preference formation is the context in which that preference decision takes place. The current research examined whether one's preference formed for a previously presented stimulus influences the processing of a subsequent preference decision, henceforth referred to as the preference sequence effect. Using a novel sequential rating/judgment paradigm, the present study demonstrated the presence of a preference sequence effect using artistic photographs and face stimuli: A neutral stimulus was preferred more following a preferable stimulus than a less preferable stimulus. Furthermore, a similar trend was found even when the potential influence of response bias was controlled. These results suggest that an assimilative sequential effect exists even when sequential judgments are made solely based on one's subjective feeling; preference formed for a preceding stimulus modulates preference for a subsequent stimulus. This implies the need for a consideration of trial sequence as a factor creating a psychological context affecting the subsequent preference decisions. PMID- 28817620 TI - GTSP1 expression in non-smoker and non-drinker patients with squamous cell carcinoma of the head and neck. AB - INTRODUCTION: The main risk factors for head and neck squamous cell carcinoma (HNSCC) are tobacco and alcohol consumption and human papillomavirus (HPV) infection. However, in a subset of patients, no risk factors can be identified. Glutathione S-transferase pi (GTSP1) is a carcinogen-detoxifying enzyme that is activated by exposure to carcinogens, and it is associated with a reduction in response to toxic therapies. We studied the expression of GTSP1 in tumor and non tumor tissue samples from patients with and without these risks to identify whether GTSP1 expression differs according to exposure to carcinogens. MATERIALS AND METHODS: Non-smoker/non-drinker (NSND) and smoker/drinker (SD) patients were matched according to age, gender, tumor site, TNM stage, grade and histological variants to establish 47 pairs of patients who have been previously tested for HPV. GTSP1 immunostaining was analyzed using a semi-quantitative method with scores ranging from 0 to 3 according to the area of immunostaining. RESULTS: GTSP1 expression was detected in the tumors of both groups. GTSP1 expression was higher in the non-tumor margins of SD patients (p = 0.004). There was no association between GTSP1 expression and positivity for HPV. No differences in survival were observed according to GTSP1 staining in tumors and non-tumor margins. CONCLUSION: This study showed that GTSP1 was expressed in tumors of HNSCC patients regardless of smoking, drinking or HPV infection status. The difference in GTSP1 expression in non-tumor margins between the two groups may have been due to two possible reasons. First, elevated GTSP1 expression in SD patients might be the result of activation of GTSP1 in response to exposure to carcinogens. Second, alternatively, impairment in the detoxifying system of GTSP1, as observed by the reduced expression of GTSP1, might make patients susceptible to carcinogens other than tobacco and alcohol, which may be the underlying mechanism of carcinogenesis in the absence of risk factors. PMID- 28817621 TI - Re-evaluation of the cost-effectiveness and effects of childhood rotavirus vaccination in Norway. AB - BACKGROUND: Rotavirus vaccination was included into the Norwegian childhood immunisation programme in 2014. Before implementation, rotavirus vaccination was found to be cost-effective from a societal perspective, but not from a healthcare perspective. Since introduction, new data on the incidence and economic effects of rotavirus disease have become available. We assessed early epidemiological effects of the rotavirus vaccination programme and re-evaluated its cost effectiveness in Norway for the years 2015-2019. METHODS: Using a dynamic transmission model, we compared the epidemiological effects of the ongoing two dose vaccination programme with Rotarix(r), and a hypothetical 3-dose programme with RotaTeq(r) with no vaccination. A baseline cost of ? 54 per fully vaccinated child was used. Cost-effectiveness was computed from a healthcare and societal perspective, using a decision analytical model. Data on healthcare use and costs, productivity losses and health utilities were based on published and own estimates. Uncertainty was accounted for in one-way, multi-way, and probabilistic sensitivity analyses. RESULTS: During 2015-2019, 114,658 home care cases, 34,571 primary care cases, 7,381 severe cases, and 2 deaths associated with rotavirus disease were avoided due to vaccination. Under baseline assumptions vaccination was cost-effective from a healthcare perspective with a cost per QALY of ? 47,447 for Rotarix(r) and ? 52,709 for RotaTeq(r). The break-even price was ? 70 for Rotarix(r) and ? 67 for RotaTeq(r). Vaccination was cost-saving from the societal perspective, and also from a healthcare perspective for vaccine prices below ? 25 and ? 22 per vaccinated child for Rotarix(r) and RotaTeq(r), respectively. CONCLUSION: Ongoing childhood rotavirus vaccination in Norway has reduced the rotavirus disease burden substantially, and is cost-effective compared with no vaccination. PMID- 28817622 TI - Ten simple rules for getting the most out of a summer laboratory internship. PMID- 28817623 TI - Metformin attenuates myocardial ischemia-reperfusion injury via up-regulation of antioxidant enzymes. AB - The objective was to examine the protective effect of metformin (Met) on myocardial ischemia-reperfusion (IR) injury and whether the mechanism was related to the AMPK/ antioxidant enzymes signaling pathway. Rat Langendorff test and H2O2 treated rat cardiomyocytes (H9c2) were used in this study. Met treatment significantly improved left ventricular (LV) function, reduced infarct size and CK-MB release in comparison with IR group. Decreased TUNEL staining positive cells were also observed in IR+Met group ex vivo. Met treatment markedly inhibited IR inducing cell death and significantly decreased apoptosis with few generations of reactive oxygen species (ROS) in H9c2 cells in comparison with IR group. Up-regulated expressions of phosphorylated LKB1/AMPK/ACC, as well as down regulated expressions of apoptotic proteins (Bax and cleaved caspase 3) were found in IR+Met group when compared to the IR group. Importantly, Met significantly up-regulated the expression of antioxidant enzymes (MnSOD and catalase) during IR procedure either ex vivo or in vitro. Compound C, a conventional inhibitor of AMPK, abolished the promoting effect of Met on antioxidant enzymes, and then attenuated the protective effect of Met on IR injury in vitro. In conclusion, Met exerted protective effect on myocardial IR injury, and this effect was AMPK/ antioxidant enzymes dependent. PMID- 28817624 TI - EphB4/EphrinB2 therapeutics in Rhabdomyosarcoma. AB - Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma affecting children and is often diagnosed with concurrent metastases. Unfortunately, few effective therapies have been discovered that improve the long-term survival rate for children with metastatic disease. Here we determined effectiveness of targeting the receptor tyrosine kinase, EphB4, in both alveolar and embryonal RMS either directly through the inhibitory antibody, VasG3, or indirectly by blocking both forward and reverse signaling of EphB4 binding to EphrinB2, cognate ligand of EphB4. Clinically, EphB4 expression in eRMS was correlated with longer survival. Experimentally, inhibition of EphB4 with VasG3 in both aRMS and eRMS orthotopic xenograft and allograft models failed to alter tumor progression. Inhibition of EphB4 forward signaling using soluble EphB4 protein fused with murine serum albumin failed to affect eRMS model tumor progression, but did moderately slow progression in murine aRMS. We conclude that inhibition of EphB4 signaling with these agents is not a viable monotherapy for rhabdomyosarcoma. PMID- 28817625 TI - Disentangling the relationship between children's motor ability, executive function and academic achievement. AB - Even though positive relations between children's motor ability and their academic achievement are frequently reported, the underlying mechanisms are still unclear. Executive function has indeed been proposed, but hardly tested as a potential mediator. The aim of the present study was therefore to examine the mediating role of executive function in the relationship between motor ability and academic achievement, also investigating the individual contribution of specific motor abilities to the hypothesized mediated linkage to academic achievement. At intervals of ten weeks, 236 children aged between 10 and 12 years were tested in terms of their motor ability (t1: cardiovascular endurance, muscular strength, motor coordination), core executive functions (t2: updating, inhibition, shifting), and academic achievement (t3: mathematics, reading, spelling). Structural equation modelling revealed executive function to be a mediator in the relation between motor ability and academic achievement, represented by a significant indirect effect. In separate analyses, each of the three motor abilities were positively related to children's academic achievement. However, only in the case of children's motor coordination, the mediation by executive function accounted for a significance percentage of variance of academic achievement data. The results provide evidence in support of models that conceive executive function as a mechanism explaining the relationship that links children's physical activity-related outcomes to academic achievement and strengthen the advocacy for quality physical activity not merely focused on health-related physical fitness outcomes, but also on motor skill development and learning. PMID- 28817627 TI - Analysing researchers' outreach efforts and the association with publication metrics: A case study of Kudos. AB - With the growth of scholarly collaboration networks and social communication platforms, members of the scholarly community are experimenting with their approach to disseminating research outputs, in an effort to increase their audience and outreach. However, from a researcher's point of view, it is difficult to determine whether efforts to make work more visible are worthwhile (in terms of the association with publication metrics) and within that, difficult to assess which platform or network is most effective for sharing work and connecting to a wider audience. We undertook a case study of Kudos (https://www.growkudos.com), a web-based service that claims to help researchers increase the outreach of their publications, to examine the most effective tools for sharing publications online, and to investigate which actions are associated with improved metrics. We extracted a dataset from Kudos of 830,565 unique publications claimed by authors, for which 20,775 had actions taken to explain or share via Kudos, and for 4,867 of these full text download data from publishers was available. Findings show that researchers are most likely to share their work on Facebook, but links shared on Twitter are more likely to be clicked on. A Mann Whitney U test revealed that a treatment group (publications having actions in Kudos) had a significantly higher median average of 149 full text downloads (23.1% more) per publication as compared to a control group (having no actions in Kudos) with a median average of 121 full text downloads per publication. These findings suggest that performing actions on publications, such as sharing, explaining, or enriching, could help to increase the number of full text downloads of a publication. PMID- 28817626 TI - Acting within an increasingly confined space: A qualitative study of sexual behaviours and healthcare needs among men who have sex with men in a provincial Tanzanian city. AB - OBJECTIVE: To explore risk perceptions, sexual practices and healthcare needs among men who have sex with men in the provincial city of Tanga in northern Tanzania. Previous research suggests that HIV/STIs are increasing problems for this population. Yet, few studies have been conducted outside the urban area of Dar es Salaam, which has limited our knowledge about the HIV/STI risk factors and healthcare needs among men who have sex with men who live outside major metropolitan areas. METHOD: During three months in 2013, 10 in-depth interviews with men who have sex with men were conducted in Tanga. Data were interpreted through qualitative content analysis. RESULTS: The theme that emerged was labelled "Acting within an increasingly confined space". The theme reflects the interference of stigma in men's lives, and in the face of potential discrimination, men perceived their sexual and healthcare choices as limited. This created obstacles for forming romantic and sexual relationships, insisting on consistent condom use with sexual partners, maintaining open and conducive relationships with family, and accessing healthcare services when required. CONCLUSIONS: Sexual stigma is a concern as it contributes to HIV/STI risk-related behaviours among men who have sex with men. Priority should be given to programmes that support same-sex practicing men in their efforts to make informed choices regarding their sexual health. Creating safe cyber networks provides an opportunity to reach this population with targeted sexual health education messages. Such programmes might be even more urgent in smaller towns and rural areas where gay specific initiatives are more limited than in urban areas. PMID- 28817628 TI - Effectiveness of Helicobacter pylori eradication in the prevention of primary gastric cancer in healthy asymptomatic people: A systematic review and meta analysis comparing risk ratio with risk difference. AB - BACKGROUND: Helicobacter pylori infection is strongly associated with gastric cancer occurrence. However, it is unclear whether eradication therapy reduces the risk of gastric cancer occurrence. We evaluated whether H. pylori eradication reduces the risk of primary gastric cancer by using both risk ratio (RR) and risk difference (RD). METHODS: Searches of PubMed, EMBASE, Google scholar, the Cochrane Library, and the Japan Medical Abstracts Society as well as those registered in databases of the Cochrane Central Register of Controlled Trials, metaRegister of Controlled Trials, ClinicalTrials.gov, controlled-trials.com, UMIN-CTR, JMACCT-CTR, and JAPIC-CTI between January 1965 and March 2017, supplemented with manual screening. Randomized controlled trials (RCTs) in which eradication therapy were implemented for the interventional group but not for the control group, and assessed the subsequent occurrence of primary gastric cancer as the main outcome. Two authors independently reviewed articles and extracted data. Integrated results for all data were presented as RR and RD. RESULTS: Seven studies met inclusion criteria. The reductions in risk of primary gastric cancer occurrence in terms of overall RR and RD were 0.67 (95% CI: 0.48 to 0.95) and 0.00 ([95% CI: -0.01 to 0.00]; number needed to treat: 125.5 [95% CI: 70.0 to 800.9]), respectively. CONCLUSIONS: The effectiveness of H. pylori eradication therapy in suppressing the occurrence of primary gastric cancer was significant and comparable to that of previous studies in terms of the estimated RR. However, the estimated RD was slight and not statistically significant. PMID- 28817629 TI - MALDI-TOF MS identification of Anopheles gambiae Giles blood meal crushed on Whatman filter papers. AB - BACKGROUND: Identification of the source of mosquito blood meals is an important component for disease control and surveillance. Recently, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) profiling has emerged as an effective tool for mosquito blood meal identification, using the abdomens of freshly engorged mosquitoes. In the field, mosquito abdomens are crushed on Whatman filter papers to determine the host feeding patterns by identifying the origin of their blood meals. The aim of this study was to test whether crushing engorged mosquito abdomens on Whatman filter papers was compatible with MALDI-TOF MS for mosquito blood meal identification. Both laboratory reared and field collected mosquitoes were tested. MATERIAL AND METHODS: Sixty Anopheles gambiae Giles were experimentally engorged on the blood of six distinct vertebrate hosts (human, sheep, rabbit, dog, chicken and rat). The engorged mosquito abdomens were crushed on Whatman filter papers for MALDI TOF MS analysis. 150 Whatman filter papers, with mosquitoes engorged on cow and goat blood, were preserved. A total of 77 engorged mosquito abdomens collected in the Comoros Islands and crushed on Whatman filter papers were tested with MALDI TOF MS. RESULTS: The MS profiles generated from mosquito engorged abdomens crushed on Whatman filter papers exhibited high reproducibility according to the original host blood. The blood meal host was correctly identified from mosquito abdomens crushed on Whatman filter papers by MALDI-TOF MS. The MS spectra obtained after storage were stable regardless of the room temperature and whether or not they were frozen. The MS profiles were reproducible for up to three months. For the Comoros samples, 70/77 quality MS spectra were obtained and matched with human blood spectra. This was confirmed by molecular tools. CONCLUSION: The results demonstrated that MALDI-TOF MS could identify mosquito blood meals from Whatman filter papers collected in the field during entomological surveys. The application of MALDI-TOF MS has proved to be rapid and successful, making it a new and efficient tool for mosquito-borne disease surveillance. PMID- 28817630 TI - Pet snakes illegally marketed in Brazil: Climatic viability and establishment risk. AB - Invasive species are one among many threats to biodiversity. Brazil has been spared, generically, of several destructive invasive species. Reports of invasive snakes' populations are nonexistent, but the illegal pet trade might change this scenario. Despite the Brazilian laws forbid to import most animals, illegal trade is frequently observed and propagules are found in the wild. The high species richness within Brazilian biomes and accelerated fragmentation of natural reserves are a critical factors facilitating successful invasion. An efficient way to ease damages caused by invasive species is identifying potential invaders and consequent prevention of introductions. For the identification of potential invaders many factors need to be considered, including estimates of climate matching between areas (native vs. invaded). Ecological niche modelling has been widely used to predict potential areas for invasion and is an important tool for conservation biology. This study evaluates the potential geographical distribution and establishment risk of Lampropeltis getula (Linnaeus, 1766), Lampropeltis triangulum (Lacepede, 1789), Pantherophis guttatus (Linnaeus, 1766), Python bivittatus Kuhl, 1820 and Python regius (Shaw, 1802) through the Maximum Entropy modelling approach to estimate the potential distribution of the species within Brazil and qualitative evaluation of specific biological attributes. Our results suggest that the North and Midwest regions harbor major suitable areas. Furthermore, P. bivittatus and P. guttatus were suggested to have the highest invasive potential among the analyzed species. Potentially suitable areas for these species were predicted within areas which are highly relevant for Brazilian biodiversity, including several conservation units. Therefore, these areas require special attention and preventive measures should be adopted. PMID- 28817631 TI - A computational model for biosonar echoes from foliage. AB - Since many bat species thrive in densely vegetated habitats, echoes from foliage are likely to be of prime importance to the animals' sensory ecology, be it as clutter that masks prey echoes or as sources of information about the environment. To better understand the characteristics of foliage echoes, a new model for the process that generates these signals has been developed. This model takes leaf size and orientation into account by representing the leaves as circular disks of varying diameter. The two added leaf parameters are of potential importance to the sensory ecology of bats, e.g., with respect to landmark recognition and flight guidance along vegetation contours. The full model is specified by a total of three parameters: leaf density, average leaf size, and average leaf orientation. It assumes that all leaf parameters are independently and identically distributed. Leaf positions were drawn from a uniform probability density function, sizes and orientations each from a Gaussian probability function. The model was found to reproduce the first-order amplitude statistics of measured example echoes and showed time-variant echo properties that depended on foliage parameters. Parameter estimation experiments using lasso regression have demonstrated that a single foliage parameter can be estimated with high accuracy if the other two parameters are known a priori. If only one parameter is known a priori, the other two can still be estimated, but with a reduced accuracy. Lasso regression did not support simultaneous estimation of all three parameters. Nevertheless, these results demonstrate that foliage echoes contain accessible information on foliage type and orientation that could play a role in supporting sensory tasks such as landmark identification and contour following in echolocating bats. PMID- 28817632 TI - Interdependency and phosphorylation of KIF4 and condensin I are essential for organization of chromosome scaffold. AB - Kinesin family member 4 (KIF4) and condensins I and II are essential chromosomal proteins for chromosome organization by locating primarily to the chromosome scaffold. However, the mechanism of how KIF4 and condensins localize to the chromosome scaffold is poorly understood. Here, we demonstrate a close relationship between the chromosome localization of KIF4 and condensin I, but not condensin II, and show that KIF4 and condensin I assist each other for stable scaffold formation by forming a stable complex. Moreover, phosphorylation of KIF4 and condensin I by Aurora B and polo-like kinase 1 (Plk1) is important for KIF4 and condensin I localization to the chromosome. Aurora B activity facilitates the targeting of KIF4 and condensin I to the chromosome, whereas Plk1 activity promotes the dissociation of these proteins from the chromosome. Thus, the interdependency between KIF4 and condensin I, and their phosphorylation states play important roles in chromosome scaffold organization during mitosis. PMID- 28817634 TI - Cross-reactivity between apical membrane antgen 1 and rhoptry neck protein 2 in P. vivax and P. falciparum: A structural and binding study. AB - Malaria, a disease endemic in many tropical and subtropical regions, is caused by infection of the erythrocyte by the apicomplexan parasite Plasmodium. Host-cell invasion is a complex process but two Plasmodium proteins, Apical Membrane Antigen 1 (AMA1) and the Rhoptry Neck protein complex (RON), play a key role. AMA1, present on the surface of the parasite, binds tightly to the RON2 component of the RON protein complex, which is inserted into the erythrocyte membrane during invasion. Blocking the AMA1-RON2 interaction with antibodies or peptides inhibits invasion, underlining its importance in the Plasmodium life cycle and as a target for therapeutic strategies. We describe the crystal structure of the complex formed between AMA1 from P. vivax (PvAMA1) and a peptide derived from the externally exposed region of P. vivax RON2 (PvRON2sp1), and of the heterocomplex formed between P. falciparum AMA1 (PfAMA1) and PvRON2sp1. Binding studies show that the affinity of PvRON2sp1 for PvAMA1 is weaker than that previously reported for the PfRON2sp1-PfAMA1 association. Moreover, while PvRON2sp1 shows strong cross-reactivity with PfAMA1, PfRON2sp1 displays no detectable interaction with PvAMA1. The structures show that the equivalent residues PvRON2-Thr2055 and PfRON2-Arg2041 largely account for this pattern of reactivity. PMID- 28817633 TI - Fat storage in Drosophila suzukii is influenced by different dietary sugars in relation to their palatability. AB - The peripheral sensitivity and palatability of different carbohydrates was evaluated and their nutritional value assessed in adult females of D. suzukii by means of an electrophysiological, behavioural and metabolic approach. The electrophysiological responses were recorded from the labellar "l" type sensilla stimulated with metabolizable mono- and disaccharides (glucose and maltose) and a non-metabolizable sugar (sucralose); the response rating and the palatability to the same sugars, evaluated by recording the proboscis extension reflex (PER), was maltose>glucose>sucralose. The nutritional value of carbohydrates was assessed by means of survival trials and fatty acids profile. Flies fed on a diet containing maltose had a longer lifespan than flies on monosaccharides, while flies fed on a diet containing sucralose had a shorter one. In addition, the ability to store fat seems to be influenced by the different sugars in the diet and is in relationship with their palatability. In fact, data showed a higher synthesis of palmitic and palmitoleic acids, most likely derived from de-novo lipogenesis with glucose as precursor, in flies fed with maltose and glucose than with non metabolizable sucralose. In conclusion, these results suggest that the ability to select different sugars on the basis of their palatability may favour the storage of energy reserves such as fat by de-novo lipogenesis, determining a longer survival capability during prolonged periods of fasting. PMID- 28817635 TI - Contractile actomyosin arcs promote the activation of primary mouse T cells in a ligand-dependent manner. AB - Mechano-transduction is an emerging but still poorly understood component of T cell activation. Here we investigated the ligand-dependent contribution made by contractile actomyosin arcs populating the peripheral supramolecular activation cluster (pSMAC) region of the immunological synapse (IS) to T cell receptor (TCR) microcluster transport and proximal signaling in primary mouse T cells. Using super resolution microscopy, OT1-CD8+ mouse T cells, and two ovalbumin (OVA) peptides with different affinities for the TCR, we show that the generation of organized actomyosin arcs depends on ligand potency and the ability of myosin 2 to contract actin filaments. While weak ligands induce disorganized actomyosin arcs, strong ligands result in organized actomyosin arcs that correlate well with tension-sensitive CasL phosphorylation and the accumulation of ligands at the IS center. Blocking myosin 2 contractility greatly reduces the difference in the extent of Src and LAT phosphorylation observed between the strong and the weak ligand, arguing that myosin 2-dependent force generation within actin arcs contributes to ligand discrimination. Together, our data are consistent with the idea that actomyosin arcs in the pSMAC region of the IS promote a mechano chemical feedback mechanism that amplifies the accumulation of critical signaling molecules at the IS. PMID- 28817636 TI - Uncovering robust patterns of microRNA co-expression across cancers using Bayesian Relevance Networks. AB - Co-expression networks have long been used as a tool for investigating the molecular circuitry governing biological systems. However, most algorithms for constructing co-expression networks were developed in the microarray era, before high-throughput sequencing-with its unique statistical properties-became the norm for expression measurement. Here we develop Bayesian Relevance Networks, an algorithm that uses Bayesian reasoning about expression levels to account for the differing levels of uncertainty in expression measurements between highly- and lowly-expressed entities, and between samples with different sequencing depths. It combines data from groups of samples (e.g., replicates) to estimate group expression levels and confidence ranges. It then computes uncertainty-moderated estimates of cross-group correlations between entities, and uses permutation testing to assess their statistical significance. Using large scale miRNA data from The Cancer Genome Atlas, we show that our Bayesian update of the classical Relevance Networks algorithm provides improved reproducibility in co-expression estimates and lower false discovery rates in the resulting co-expression networks. Software is available at www.perkinslab.ca. PMID- 28817637 TI - Genetic diversity of the O antigens of Proteus species and the development of a suspension array for molecular serotyping. AB - Proteus species are well-known opportunistic pathogens frequently associated with skin wound and urinary tract infections in humans and animals. O antigen diversity is important for bacteria to adapt to different hosts and environments, and has been used to identify serotypes of Proteus isolates. At present, 80 Proteus O-serotypes have been reported. Although the O antigen structures of most Proteus serotypes have been identified, the genetic features of these O antigens have not been well characterized. The O antigen gene clusters of Proteus species are located between the cpxA and secB genes. In this study, we identified 55 O antigen gene clusters of different Proteus serotypes. All clusters contain both the wzx and wzy genes and exhibit a high degree of heterogeneity. Potential functions of O antigen-related genes were proposed based on their similarity to genes in available databases. The O antigen gene clusters and structures were compared, and a number of glycosyltransferases were assigned to glycosidic linkages. In addition, an O serotype-specific suspension array was developed for detecting 31 Proteus serotypes frequently isolated from clinical specimens. To our knowledge, this is the first comprehensive report to describe the genetic features of Proteus O antigens and to develop a molecular technique to identify different Proteus serotypes. PMID- 28817638 TI - The transcriptional profiling of human in vivo-generated plasma cells identifies selective imbalances in monoclonal gammopathies. AB - Plasma cells (PC) represent the heterogeneous final stage of the B cells (BC) differentiation process. To characterize the transition of BC into PC, transcriptomes from human naive BC were compared to those of three functionally different subsets of human in vivo-generated PC: i) tonsil PC, mainly consisting of early PC; ii) PC released to the blood after a potent booster-immunization (mostly cycling plasmablasts); and, iii) bone marrow CD138+ PC that represent highly mature PC and include the long-lived PC compartment. This transcriptional transition involves subsets of genes related to key processes for PC maturation: the already known protein processing, apoptosis and homeostasis, and of new discovery including histones, macromolecule assembly, zinc-finger transcription factors and neuromodulation. This human PC signature is partially reproduced in vitro and is conserved in mouse. Moreover, the present study identifies genes that define PC subtypes (e.g., proliferation-associated genes for circulating PC and transcriptional-related genes for tonsil and bone marrow PC) and proposes some putative transcriptional regulators of the human PC signatures (e.g., OCT/POU, XBP1/CREB, E2F, among others). Finally, we also identified a restricted imbalance of the present PC transcriptional program in monoclonal gammopathies that correlated with PC malignancy. PMID- 28817639 TI - Impacts of forest restoration on water yield: A systematic review. AB - BACKGROUND: Enhancing water provision services is a common target in forest restoration projects worldwide due to growing concerns over freshwater scarcity. However, whether or not forest cover expansion or restoration can improve water provision services is still unclear and highly disputed. PURPOSE: The goal of this review is to provide a balanced and impartial assessment of the impacts of forest restoration and forest cover expansion on water yields as informed by the scientific literature. Potential sources of bias on the results of papers published are also examined. DATA SOURCES: English, Spanish and Portuguese peer review articles in Agricola, CAB Abstracts, ISI Web of Science, JSTOR, Google Scholar, and SciELO. Databases were searched through 2015. SEARCH TERMS: Intervention terms included forest restoration, regeneration/regrowth, forest second-growth, forestation/afforestation, and forestry. Target terms included water yield/quantity, streamflow, discharge, channel runoff, and annual flow. STUDY SELECTION AND ELIGIBILITY CRITERIA: Articles were pre-selected based on key words in the title, abstract or text. Eligible articles addressed relevant interventions and targets and included quantitative information. RESULTS: Most studies reported decreases in water yields following the intervention, while other hydrological benefits have been observed. However, relatively few studies focused specifically on forest restoration, especially with native species, and/or on projects done at large spatial or temporal scales. Information is especially limited for the humid tropics and subtropics. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: While most studies reported a decrease in water yields, meta-analyses from a sub-set of studies suggest the potential influence of temporal and/or spatial scales on the outcomes of forest cover expansion or restoration projects. Given the many other benefits of forest restoration, improving our understanding of when and why forest restoration can lead to recovery of water yields is crucial to help improve positive outcomes and prevent unintended consequences. Our study identifies the critical types of studies and associated measurements needed. PMID- 28817640 TI - Evaluation of multilocus marker efficacy for delineating mangrove species of West Coast India. AB - The plant DNA barcoding is a complex and requires more than one marker(s) as compared to animal barcoding. Mangroves are diverse estuarine ecosystem prevalent in the tropical and subtropical zone, but anthropogenic activity turned them into the vulnerable ecosystem. There is a need to build a molecular reference library of mangrove plant species based on molecular barcode marker along with morphological characteristics. In this study, we tested the core plant barcode (rbcL and matK) and four promising complementary barcodes (ITS2, psbK-psbI, rpoC1 and atpF-atpH) in 14 mangroves species belonging to 5 families from West Coast India. Data analysis was performed based on barcode gap analysis, intra- and inter-specific genetic distance, Automated Barcode Gap Discovery (ABGD), TaxonDNA (BM, BCM), Poisson Tree Processes (PTP) and General Mixed Yule-coalescent (GMYC). matK+ITS2 marker based on GMYC method resolved 57.14% of mangroves species and TaxonDNA, ABGD, and PTP discriminated 42.85% of mangrove species. With a single locus analysis, ITS2 exhibited the higher discriminatory power (87.82%) and combinations of matK + ITS2 provided the highest discrimination success (89.74%) rate except for Avicennia genus. Further, we explored 3 additional markers (psbK psbI, rpoC1, and atpF-atpH) for Avicennia genera (A. alba, A. officinalis and A. marina) and atpF-atpH locus was able to discriminate three species of Avicennia genera. Our analysis underscored the efficacy of matK + ITS2 markers along with atpF-atpH as the best combination for mangrove identification in West Coast India regions. PMID- 28817641 TI - Honey bee (Apis mellifera) colony health and pathogen composition in migratory beekeeping operations involved in California almond pollination. AB - Honey bees are important pollinators of agricultural crops. Pathogens and other factors have been implicated in high annual losses of honey bee colonies in North America and some European countries. To further investigate the relationship between multiple factors, including pathogen prevalence and abundance and colony health, we monitored commercially managed migratory honey bee colonies involved in California almond pollination in 2014. At each sampling event, honey bee colony health was assessed, using colony population size as a proxy for health, and the prevalence and abundance of seven honey bee pathogens was evaluated using PCR and quantitative PCR, respectively. In this sample cohort, pathogen prevalence and abundance did not correlate with colony health, but did correlate with the date of sampling. In general, pathogen prevalence (i.e., the number of specific pathogens harbored within a colony) was lower early in the year (January March) and was greater in the summer, with peak prevalence occurring in June. Pathogen abundance in individual honey bee colonies varied throughout the year and was strongly associated with the sampling date, and was influenced by beekeeping operation, colony health, and mite infestation level. Together, data from this and other observational cohort studies that monitor individual honey bee colonies and precisely account for sampling date (i.e., day of year) will lead to a better understanding of the influence of pathogens on colony mortality and the effects of other factors on these associations. PMID- 28817642 TI - Data sharing as social dilemma: Influence of the researcher's personality. AB - It is widely acknowledged that data sharing has great potential for scientific progress. However, so far making data available has little impact on a researcher's reputation. Thus, data sharing can be conceptualized as a social dilemma. In the presented study we investigated the influence of the researcher's personality within the social dilemma of data sharing. The theoretical background was the appropriateness framework. We conducted a survey among 1564 researchers about data sharing, which also included standardized questions on selected personality factors, namely the so-called Big Five, Machiavellianism and social desirability. Using regression analysis, we investigated how these personality domains relate to four groups of dependent variables: attitudes towards data sharing, the importance of factors that might foster or hinder data sharing, the willingness to share data, and actual data sharing. Our analyses showed the predictive value of personality for all four groups of dependent variables. However, there was not a global consistent pattern of influence, but rather different compositions of effects. Our results indicate that the implications of data sharing are dependent on age, gender, and personality. In order to foster data sharing, it seems advantageous to provide more personal incentives and to address the researchers' individual responsibility. PMID- 28817643 TI - Peripheral clinic versus centralized laboratory-based Xpert MTB/RIF performance: Experience gained from a pragmatic, stepped-wedge trial in Botswana. AB - BACKGROUND: In 2011, the Botswana National Tuberculosis Program adopted World Health Organization guidelines and introduced Xpert MTB/RIF (Xpert) assay to support intensified case finding among people living with HIV enrolling in care. An evaluation was designed to assess performance under operational conditions to inform the national Xpert scale-up. METHODS: Xpert was implemented from August 2012 through November 2014 with 13 GeneXpert instruments (GeneXpert) deployed in a phased approach over nine months: nine centralized laboratory and four point-of care (POC) peripheral clinics. Clinicians and laboratorians were trained on the four-symptom tuberculosis screening algorithm and Xpert testing. We documented our experience with staff training and GeneXpert performance. Test results were extracted from GeneXpert software; unsuccessful tests were analysed in relation to testing sites and trends over time. RESULTS: During 276 instrument-months of operation a total of 3,630 tests were performed, of which 3,102 (85%) were successful with interpretable results. Mycobacterium tuberculosis complex was detected for 447 (14%); of these, 36 (8%) were rifampicin resistant. Of all 3,630 Xpert tests, 528 (15%) were unsuccessful; of these 361 (68%) were classified as "error", 119 (23%) as "invalid" and 48 (9%) as "no result". The total number of recorded error codes was 385 and the most common reasons were related to sample processing (211; 55%) followed by power supply (77; 20%) and cartridge/module related (54; 14%). Cumulative incidence of unsuccessful test was similar between POC (17%, 95% CI: 11-25%) and centralized laboratory-based GeneXpert instruments (14%, 95% CI: 11-17%; p = 0.140). CONCLUSIONS: Xpert introduction was successful in the Botswana setting. The incidence of unsuccessful test was similar by GeneXpert location (POC vs. centralized laboratory). However, unsuccessful test incidence (15%) in our settings was higher than previously reported and was mostly related to improper sample processing. Ensuring adequate training among Xpert testing staff is essential to minimize errors. PMID- 28817644 TI - Cheek tooth morphology and ancient mitochondrial DNA of late Pleistocene horses from the western interior of North America: Implications for the taxonomy of North American Late Pleistocene Equus. AB - Horses were a dominant component of North American Pleistocene land mammal communities and their remains are well represented in the fossil record. Despite the abundant material available for study, there is still considerable disagreement over the number of species of Equus that inhabited the different regions of the continent and on their taxonomic nomenclature. In this study, we investigated cheek tooth morphology and ancient mtDNA of late Pleistocene Equus specimens from the Western Interior of North America, with the objective of clarifying the species that lived in this region prior to the end-Pleistocene extinction. Based on the morphological and molecular data analyzed, a caballine (Equus ferus) and a non-caballine (E. conversidens) species were identified from different localities across most of the Western Interior. A second non-caballine species (E. cedralensis) was recognized from southern localities based exclusively on the morphological analyses of the cheek teeth. Notably the separation into caballine and non-caballine species was observed in the Bayesian phylogenetic analysis of ancient mtDNA as well as in the geometric morphometric analyses of the upper and lower premolars. Teeth morphologically identified as E. conversidens that yielded ancient mtDNA fall within the New World stilt-legged clade recognized in previous studies and this is the name we apply to this group. Geographic variation in morphology in the caballine species is indicated by statistically different occlusal enamel patterns in the specimens from Bluefish Caves, Yukon Territory, relative to the specimens from the other geographic regions. Whether this represents ecomorphological variation and/or a certain degree of geographic and genetic isolation of these Arctic populations requires further study. PMID- 28817645 TI - Translation, cultural adaptation and validation of simplified Chinese version of the anterior cruciate ligament return to sport after injury (ACL-RSI) scale. AB - PURPOSE: To translate and cross-culturally adapt the anterior cruciate ligament return to sport after injury (ACL-RSI) into simplified Chinese [ACL-RSI (Cn)]. METHOD: In this diagnostic study, the translation, cross-culturally adaptation, and validation of the ACL-RSI was performed according to international guidelines. A total of 112 patients with ACL reconstruction participated in this study. All were capable of competitive sports before the injury and completed the Knee Injury and Osteoarthritis Outcome (KOOS), the International Knee Documentation Committee (IKDC), the Tampa Scale of Kinesiophobia (TSK), and the Tegner activity score. Forty-eight patients completed the ACL-RSI (Cn) twice within two weeks. The validity was tested using seven premade hypotheses. Internal consistency, reliability, and measurement error was assessed. RESULT: At meanly 15.6 months postoperative, 81 (72.3%) patients returned to sport, with 57 (50.9%) to competitive sport and 24 (21.4%) to recreational sport. Thirty-one (27.7%) patients didn't return to any sport, with 19 (17.0%) still had planned to return, and 12 (10.7%) gave up sport. The ACL-RSI (Cn) demonstrated excellent validity with all hypotheses confirmed. The outcome of ACL-RSI (Cn) was strongly correlated the KOOS subscale quality of life (r = 0.66, p<0.001), the TSK (r = 0.678, p<0.001), the Tegner score (r = 0.695, p<0.001). There was statistic difference between cases returned (68.6 +/- 10.1) and didn't return to sport (41.3 +/- 17.7), p<0.001; between cases returned to competitive (71.1 +/- 8.9) and recreational sport (62.9 +/- 10.5), (P = 0.002); between cases who planned to return (50.7 +/- 14.1) and gave up sport (26.5 +/- 11.7), (P<0.001). The internal consistency (Cronbach's alpha = 0.96) and test-retest reliability [intra-class correlation coefficient (ICC) = 0.90] was excellent. The measurement error, floor and ceiling effect was satisfactory. Administration time was 3.2 minutes, and no item was missed. CONCLUSIONS: The ACL-RSI (Cn) scale was confirmed as a valid, reliable, and feasible tool for evaluating psychological factors influencing return to sport. PMID- 28817646 TI - Genetic dissection of endothelial transcriptional activity of zebrafish aryl hydrocarbon receptors (AHRs). AB - The aryl hydrocarbon receptor (AHR) is a basic helix-loop-helix transcription factor conserved across phyla from flies to humans. Activated by a number of endogenous ligands and environmental toxins, studies on AHR function and gene regulation have largely focused on a toxicological perspective relating to aromatic hydrocarbons generated by human activities and the often-deleterious effects of exposure on vertebrates mediated by AHR activation. A growing body of work has highlighted the importance of AHR in physiologic processes, including immune cell differentiation and vascular patterning. Here we dissect the contribution of the 3 zebrafish AHRs, ahr1a, ahr1b and ahr2, to endothelial cyp1a1/b1 gene regulation under physiologic conditions and upon exposure to the AHR ligand Beta-naphthoflavone. We show that in fish multiple AHRs are functional in the vasculature, with vessel-specific differences in the ability of ahr1b to compensate for the loss of ahr2 to maintain AHR signaling. We further provide evidence that AHR can regulate the expression of the chemokine receptor cxcr4a in endothelial cells, a regulatory mechanism that may provide insight into AHR function in the endothelium. PMID- 28817647 TI - Caprine brucellosis: A historically neglected disease with significant impact on public health. AB - Caprine brucellosis is a chronic infectious disease caused by the gram-negative cocci-bacillus Brucella melitensis. Middle- to late-term abortion, stillbirths, and the delivery of weak offspring are the characteristic clinical signs of the disease that is associated with an extensive negative impact in a flock's productivity. B. melitensis is also the most virulent Brucella species for humans, responsible for a severely debilitating and disabling illness that results in high morbidity with intermittent fever, chills, sweats, weakness, myalgia, abortion, osteoarticular complications, endocarditis, depression, anorexia, and low mortality. Historical observations indicate that goats have been the hosts of B. melitensis for centuries; but around 1905, the Greek physician Themistokles Zammit was able to build the epidemiological link between "Malta fever" and the consumption of goat milk. While the disease has been successfully managed in most industrialized countries, it remains a significant burden on goat and human health in the Mediterranean region, the Middle East, Central and Southeast Asia (including India and China), sub-Saharan Africa, and certain areas in Latin America, where approximately 3.5 billion people live at risk. In this review, we describe a historical evolution of the disease, highlight the current worldwide distribution, and estimate (by simple formula) the approximate costs of brucellosis outbreaks to meat- and milk-producing farms and the economic losses associated with the disease in humans. Successful control leading to eradication of caprine brucellosis in the developing world will require a coordinated Global One Health approach involving active involvement of human and animal health efforts to enhance public health and improve livestock productivity. PMID- 28817648 TI - Screening for Chikungunya virus infection in aged people: Development and internal validation of a new score. AB - BACKGROUND: This study aimed to derive and validate a score for Chikungunya virus (CHIKV) infection screening in old people admitted to acute care units. METHODS: This study was performed in the Martinique University Hospitals from retrospective cases. Patients were aged 65+, admitted to acute care units for suspected CHIKV infection in 2014, with biological testing using Reverse Transcription Polymerase Chain Reaction (RT-PCR). RT-PCR was used as the gold standard. A screening score was created using adjusted odds ratios of factors associated with positive RT-PCR derived from a multivariable logistic regression model. A ROC curve was used to determine the best cut-off of the score. Bootstrap analysis was used to evaluate its internal validity. RESULTS: In all, 687 patients were included, 68% with confirmed CHIKV infection, and 32% with laboratory-unconfirmed CHIKV infection. Mean age was 80+/-8 years, 51% were women. Four variables were found to be independently associated with positive RT PCR (fever: 3 points; arthralgia of the ankle: 2 points; lymphopenia: 6 points; absence of neutrophil leucocytosis: 10 points). The best cut-off was score >=12; sensitivity was 87% (83%-90%) and specificity was 70% (63%-76%). CONCLUSION: This score shows good diagnostic performance and good internal validation and could be helpful to screen aged people for CHIKV infection. PMID- 28817649 TI - Point-of-care wound visioning technology: Reproducibility and accuracy of a wound measurement app. AB - BACKGROUND: Current wound assessment practices are lacking on several measures. For example, the most common method for measuring wound size is using a ruler, which has been demonstrated to be crude and inaccurate. An increase in periwound temperature is a classic sign of infection but skin temperature is not always measured during wound assessments. To address this, we have developed a smartphone application that enables non-contact wound surface area and temperature measurements. Here we evaluate the inter-rater reliability and accuracy of this novel point-of-care wound assessment tool. METHODS AND FINDINGS: The wounds of 87 patients were measured using the Swift Wound app and a ruler. The skin surface temperature of 37 patients was also measured using an infrared FLIRTM camera integrated with the Swift Wound app and using the clinically accepted reference thermometer Exergen DermaTemp 1001. Accuracy measurements were determined by assessing differences in surface area measurements of 15 plastic wounds between a digital planimeter of known accuracy and the Swift Wound app. To evaluate the impact of training on the reproducibility of the Swift Wound app measurements, three novice raters with no wound care training, measured the length, width and area of 12 plastic model wounds using the app. High inter-rater reliabilities (ICC = 0.97-1.00) and high accuracies were obtained using the Swift Wound app across raters of different levels of training in wound care. The ruler method also yielded reliable wound measurements (ICC = 0.92-0.97), albeit lower than that of the Swift Wound app. Furthermore, there was no statistical difference between the temperature differences measured using the infrared camera and the clinically tested reference thermometer. CONCLUSIONS: The Swift Wound app provides highly reliable and accurate wound measurements. The FLIRTM infrared camera integrated into the Swift Wound app provides skin temperature readings equivalent to the clinically tested reference thermometer. Thus, the Swift Wound app has the advantage of being a non-contact, easy-to-use wound measurement tool that allows clinicians to image, measure, and track wound size and temperature from one visit to the next. In addition, this tool may also be used by patients and their caregivers for home monitoring. PMID- 28817650 TI - snoRNA and piRNA expression levels modified by tobacco use in women with lung adenocarcinoma. AB - Lung cancer is one of the most frequent types of cancer worldwide. Most patients are diagnosed at advanced stage and thus have poor prognosis. Smoking is a risk factor for lung cancer, however most smokers do not develop lung cancer while 20% of women with lung adenocarcinoma are non-smokers. Therefore, it is possible that these two groups present differences besides the smoking status, including differences in their gene expression signature. The altered expression patterns of non-coding RNAs in complex diseases make them potential biomarkers for diagnosis and treatment. We analyzed data from differentially and constitutively expressed PIWI-interacting RNAs and small nucleolar RNAs from publicly available small RNA high-throughput sequencing data in search of an expression pattern of non-coding RNA that could differentiate these two groups. Here, we report two sets of differentially expressed small non-coding RNAs identified in normal and tumoral tissues of women with lung adenocarcinoma, that discriminate between smokers and non-smokers. Our findings may offer new insights on metabolic alterations caused by tobacco and may be used for early diagnosis of lung cancer. PMID- 28817651 TI - Comparative genetic analysis of the 45S rDNA intergenic spacers from three Saccharum species. AB - The 45S ribosomal DNA (rDNA) units are separated by an intergenic spacer (IGS) containing the signals for transcription and processing of rRNAs. For the first time, we sequenced and analyzed the entire IGS region from three original species within the genus Saccharum, including S. spontaneum, S. robustum, and S. officinarum in this study. We have compared the IGS organization within three original species of the genus Saccharum. The IGS of these three original species showed similar overall organizations comprised of putative functional elements needed for rRNA gene activity as well as a non-transcribed spacer (NTS), a promoter region, and an external transcribed spacer (ETS). The variability in length of the IGS sequences was assessed at the individual, intraspecies, and interspecies levels of the genus Saccharum, including S. spontaneum, S. robustum, and S. officinarum. The ETS had greater similarity than the NTS across species, but nevertheless exhibited variation in length. Within the IGS of the Saccharum species, base substitutions and copy number variation of sub-repeat were causes of the divergence in IGS sequences. We also identified a significant number of methylation sites. Furthermore, fluorescent in situ hybridization (FISH) co localization of IGS and pTa71 probes was detected on all representative species of the genus Saccharum tested. Taken together, the results of this study provide a better insight into the structure and organization of the IGS in the genus Saccharum. PMID- 28817652 TI - Metabolomics reveals an entanglement of fasting leptin concentrations with fatty acid oxidation and gluconeogenesis in healthy children. AB - BACKGROUND: Leptin and adiponectin communicate with organ systems in order to regulate energetic and metabolic homeostasis. Their different points of action have been well characterized; however, no study has investigated their interrelationship with the metabolism at the molecular level in vivo. OBJECTIVE: To examine the associations of leptin and adiponectin with the metabolic profile reflecting the intercellular and interorgan communication as well as activated metabolic pathways. PATIENTS/METHODS: We measured plasma concentrations of leptin, adiponectin, and insulin along with concentrations of 196 metabolites in 400 healthy, fasting 8-years old German children who participated in the German Ulm Birth Cohort Study (UBCS). Using multiple linear mixed models, we evaluated the associations between hormones and metabolites. RESULTS: Leptin levels increased exponentially with increasing BMI. Leptin was furthermore strongly associated with alanine and aspartate (Bonferroni corrected P[PBF] = 5.7*10-8 and 1.7*10-6, respectively), and negatively associated to the sum of the non esterified fatty acids (NEFA) and the sum of the long-chain acylcarnitines C12 C18 (PBF = 0.009 and 0.0001, respectively). Insulin showed a similar association pattern, although the associations were less strong than for leptin. Adiponectin was neither related to BMI nor to any metabolite. CONCLUSION: Although children were presumably metabolically similar, we found strong associations of insulin and leptin with the metabolite profile. High alanine concentrations and the lower concentrations of NEFA in children with high fasting leptin concentrations might arise from an increased gluconeogenesis and from the disinhibiting effect of leptin on the carnitine-palmitoyltransferase-1, respectively. As insulin had the same trend towards these associations, both hormones seem to be related to processes that provide the body with energy in fasting state. PMID- 28817653 TI - Perilymph pharmacokinetics of marker applied through a cochlear implant in guinea pigs. AB - Patients undergoing cochlear implantation could benefit from a simultaneous application of drugs into the ear, helping preserve residual low-frequency hearing and afferent nerve fiber populations. One way to apply drugs is to incorporate a cannula into the implant, through which drug solution is driven. For such an approach, perilymph concentrations achieved and the distribution in the ear over time have not previously been documented. We used FITC-labeled dextran as a marker, delivering it into perilymph of guinea pigs at 10 or 100 nL/min though a cannula incorporated into a cochlear implant with the outlet in the mid basal turn. After injections of varying duration (2 hours, 1 day or 7 days) perilymph was collected from the cochlear apex using a sequential sampling technique, allowing dextran levels and gradients along scala tympani to be quantified. Data were interpreted quantitatively using computer simulations of the experiments. For injections of 2 hours duration, dextran levels were critically influenced by the presence or absence of fluid leakage at the cochleostomy site. When the cochleostomy was fluid-tight, substantially higher perilymph levels were achieved at the injection site, with concentration declining along scala tympani towards the apex. Contrary to expectations, large dextran gradients along scala tympani persisted after 24 hours of sustained injection and were still present in some animals after 7 days injection. Functional changes associated with implantation and dextran delivery, and the histological state of the implant and cannula were also documented. The persistent longitudinal gradients of dextan along the ear were not readily explained by computer simulations of the experiments based on prior pharmacokinetic data. One explanation is that inner ear pharmacokinetics are altered in the period after cochlear implantation, possibly by a permeabilization of the blood-labyrinth barrier as part of the immune response to the implant. PMID- 28817654 TI - Investigating spousal concordance of diabetes through statistical analysis and data mining. AB - OBJECTIVE: Spousal clustering of diabetes merits attention. Whether old-age vulnerability or a shared family environment determines the concordance of diabetes is also uncertain. This study investigated the spousal concordance of diabetes and compared the risk of diabetes concordance between couples and noncouples by using nationally representative data. METHODS: A total of 22,572 individuals identified from the 2002-2013 National Health Insurance Research Database of Taiwan constituted 5,643 couples and 5,643 noncouples through 1:1 dual propensity score matching (PSM). Factors associated with concordance in both spouses with diabetes were analyzed at the individual level. The risk of diabetes concordance between couples and noncouples was compared at the couple level. Logistic regression was the main statistical method. Statistical data were analyzed using SAS 9.4. C&RT and Apriori of data mining conducted in IBM SPSS Modeler 13 served as a supplement to statistics. RESULTS: High odds of the spousal concordance of diabetes were associated with old age, middle levels of urbanization, and high comorbidities (all P < 0.05). The dual PSM analysis revealed that the risk of diabetes concordance was significantly higher in couples (5.19%) than in noncouples (0.09%; OR = 61.743, P < 0.0001). CONCLUSIONS: A high concordance rate of diabetes in couples may indicate the influences of assortative mating and shared environment. Diabetes in a spouse implicates its risk in the partner. Family-based diabetes care that emphasizes the screening of couples at risk of diabetes by using the identified risk factors is suggested in prospective clinical practice interventions. PMID- 28817655 TI - Assessing experience in the deliberate practice of running using a fuzzy decision support system. AB - The judgement of skill experience and its levels is ambiguous though it is crucial for decision-making in sport sciences studies. We developed a fuzzy decision support system to classify experience of non-elite distance runners. Two Mamdani subsystems were developed based on expert running coaches' knowledge. In the first subsystem, the linguistic variables of training frequency and volume were combined and the output defined the quality of running practice. The second subsystem yielded the level of running experience from the combination of the first subsystem output with the number of competitions and practice time. The model results were highly consistent with the judgment of three expert running coaches (r>0.88, p<0.001) and also with five other expert running coaches (r>0.86, p<0.001). From the expert's knowledge and the fuzzy model, running experience is beyond the so-called "10-year rule" and depends not only on practice time, but on the quality of practice (training volume and frequency) and participation in competitions. The fuzzy rule-based model was very reliable, valid, deals with the marked ambiguities inherent in the judgment of experience and has potential applications in research, sports training, and clinical settings. PMID- 28817656 TI - Investigation of the halo-artifact in 68Ga-PSMA-11-PET/MRI. AB - OBJECTIVES: Combined positron emission tomography (PET) and magnetic resonance imaging (MRI) targeting the prostate-specific membrane antigen (PSMA) with a 68Ga labelled PSMA-analog (68Ga-PSMA-11) is discussed as a promising diagnostic method for patients with suspicion or history of prostate cancer. One potential drawback of this method are severe photopenic (halo-) artifacts surrounding the bladder and the kidneys in the scatter-corrected PET images, which have been reported to occur frequently in clinical practice. The goal of this work was to investigate the occurrence and impact of these artifacts and, secondly, to evaluate variants of the standard scatter correction method with regard to halo-artifact suppression. METHODS: Experiments using a dedicated pelvis phantom were conducted to investigate whether the halo-artifact is modality-, tracer-, and/or concentration-dependent. Furthermore, 31 patients with history of prostate cancer were selected from an ongoing 68Ga-PSMA-11-PET/MRI study. For each patient, PET raw data were reconstructed employing six different variants of PET scatter correction: absolute scatter scaling, relative scatter scaling, and relative scatter scaling combined with prompt gamma correction, each of which was combined with a maximum scatter fraction (MaxSF) of MaxSF = 75% or MaxSF = 40%. Evaluation of the reconstructed images with regard to halo-artifact suppression was performed both quantitatively using statistical analysis and qualitatively by two independent readers. RESULTS: The phantom experiments did not reveal any modality dependency (PET/MRI vs. PET/CT) or tracer-dependency (68Ga vs. 18F-FDG). Patient- and phantom-based data indicated that halo-artifacts derive from high organ-to background activity ratios (OBR) between bladder/kidneys and surrounding soft tissue, with a positive correlation between OBR and halo size. Comparing different variants of scatter correction, reducing the maximum scatter fraction from the default value MaxSF = 75% to MaxSF = 40% was found to efficiently suppress halo-artifacts in both phantom and patient data. In 1 of 31 patients, reducing the maximum scatter fraction provided new PET-based information changing the patient's diagnosis. CONCLUSION: Halo-artifacts are particularly observed for 68Ga-PSMA-11-PET/MRI due to 1) the biodistribution of the PSMA-11-tracer resulting in large OBRs for bladder and kidneys and 2) inaccurate scatter correction methods currently used in clinical routine, which tend to overestimate the scatter contribution. If not compensated for, 68Ga-PSMA-11 uptake pathologies may be masked by halo-artifacts leading to false-negative diagnoses. Reducing the maximum scatter fraction was found to efficiently suppress halo-artifacts. PMID- 28817657 TI - Metaproteomics analysis of the functional insights into microbial communities of combined hydrogen and methane production by anaerobic fermentation from reed straw. AB - A metaproteomic approach was used to analyse the proteins expressed and provide functional evidence of key metabolic pathways in the combined production of hydrogen and methane by anaerobic fermentation (CHMP-AF) for reed straw utilisation. The functions and structures of bacteria and archaea populations show significant succession in the CHMP-AF process. There are many kinds of bacterial functional proteins, mainly belonging to phyla Firmicutes, Proteobacteria, Actinobacteria and Bacteroidetes, that are involved in carbohydrate metabolism, energy metabolism, lipid metabolism, and amino acid metabolism. Ferredoxin-NADP reductase, present in bacteria in genus Azotobacter, is an important enzyme for NADH/NAD+ equilibrium regulation in hydrogen production. The archaeal functional proteins are mainly involved in methane metabolism in energy metabolism, such as acetyl-CoA decarboxylase, and methyl coenzyme M reductase, and the acetic acid pathway exhibited the highest proportion of the total. The archaea of genus Methanosarcina in phylum Euryarchaeota can produce methane under the effect of multi-functional proteins through acetic acid, CO2 reduction, and methyl nutrient pathways. The study demonstrates metaproteomics as a new way of uncovering community functional and metabolic activity. The combined information was used to identify the metabolic pathways and organisms crucial for lignocellulosic biomass degradation and biogas production. This also regulates the process from its protein levels and improves the efficiency of biogas production using reed straw biomass. PMID- 28817658 TI - Hyperspectral prediction of leaf area index of winter wheat in irrigated and rainfed fields. AB - The growth status of winter wheat in irrigated field and rainfed field are obviously different and the field types may have an effect on the predictive accuracy of hyperspectral model. The objectives of the present study were to understand the difference of spectral sensitive wavelengths for leaf area index (LAI) in two field types and realize its hyperspectral prediction. In study, a total of 31 and 28 sample sites in irrigated fields and rainfed fields respectively were selected from Wenxi County, and the LAI and canopy spectra were also collected at the main grow stage of winter wheat. The method of successive projections algorithm (SPA) was applied by selecting the important wavelengths, and the multiple linear regression (MLR) and partial least squares regression (PLSR) were used to construct the predictive model based on the important wavelengths and full wavelengths, respectively. Moreover, the parameters of variable importance project (VIP) and B-coefficient derived from PLSR analysis were implemented to validate the evaluated wavelengths using the SPA method. The sensitive wavelengths of LAI for irrigated field and rainfed field were 404, 407, 413, 417, 450, 677, 715, 735, 816, 1127 and 404, 406, 432, 501, 540, 679, 727, 779, 1120, 1290 nm, respectively, and these wavelengths proved to be highly correlated with LAI. Compared with the model performance based on the SPA-MLR and PLSR methods, the method of SPA-MLR was proved to be better (rainfed field: R2 = 0.736, RMSE = 1.169, RPD = 1.6245; irrigated field: R2 = 0.716, RMSE = 1.059, RPD = 1.538). Moreover, the predictive model of LAI in rainfed fields had a better accuracy than the model in irrigated fields. The results from this study indicated that it was necessary to classify the field type while monitoring the winter wheat using the remote sensing technology. This study also demonstrated that the multivariate method of SPA-MLR could accurately evaluate the sensitive wavelengths and construct the predictive model of LAI. PMID- 28817659 TI - Resveratrol improves alcoholic fatty liver disease by downregulating HIF-1alpha expression and mitochondrial ROS production. AB - Oxidative stress has been demonstrated to be involved in the etiology of alcoholic fatty liver disease (AFLD). Previous studies had demonstrated that resveratrol (RES) could reduce oxidative stress by different mechanisms. However, the effect of RES on alcohol-induced fatty liver remains unclear. In the present study, a total of 48 male SD rats were divided into three groups: Control, AFLD, and RES groups. Rats were administered with either nothing or 65% vol/vol alcohol (5 ml/kg/day in the first three days, and then 10 ml/kg/day in the following days) with or without RES supplementation (250 mg/kg/day) for 4 weeks. Blood and liver tissue samples were collected and subjected to biochemical assays, histological examination, Western blot, and mitochondrial radical oxygen species (ROS) assays. In RES group, significant decreases in serum ALT and AST concentrations, fat deposition, triglyceride (TG) content, HIF-1alpha protein expression as well as mitochondrial ROS production in liver were observed when compared with AFLD group (all p <0.05). These results indicated that RES could alleviate the liver injury induced by alcohol and prevent the progression of AFLD. Down regulation of HIF-1alpha protein expression and mitochondrial ROS production in liver might be, at least part of, the underlying mechanisms. PMID- 28817660 TI - Cited4 is related to cardiogenic induction and maintenance of proliferation capacity of embryonic stem cell-derived cardiomyocytes during in vitro cardiogenesis. AB - Cardiac progenitor cells have a limited proliferative capacity. The CREB-binding protein/p300-interacting transactivator, with the Glu/Asp-rich carboxy-terminal domain (Cited) gene family, regulates gene transcription. Increased expression of the Cited4 gene in an adult mouse is associated with exercise-induced cardiomyocyte hypertrophy and proliferation. However, the expression patterns and functional roles of the Cited4 gene during cardiogenesis are largely unknown. Therefore, in the present study, we investigated the expression patterns and functional roles of the Cited4 gene during in vitro cardiogenesis. Using embryoid bodies formed from mouse embryonic stem cells, we evaluated the expression patterns of the Cited4 gene by quantitative reverse transcriptase-polymerase chain reaction. Cited4 gene expression levels increased and decreased during the early and late phases of cardiogenesis, respectively. Moreover, Cited4 gene levels were significantly high in the cardiac progenitor cell population. A functional assay of the Cited4 gene in cardiac progenitor cells using flow cytometry indicated that overexpression of the Cited4 gene significantly increased the cardiac progenitor cell population compared with the control and knockdown groups. A cell proliferation assay, with 5-ethynyl-2'-deoxyuridine incorporation and Ki67 expression during the late phase of cardiogenesis, indicated that the number of troponin T-positive embryonic stem cell-direived cardiomyocytes with proliferative capacity was significantly greater in the overexpression group than in the control and knockdown groups. Our study results suggest that the Cited4 gene is related to cardiac differentiation and maintenance of proliferation capacity of embryonic stem cell-derived cardiomyocytes during in vitro cardiogenesis. Therefore, manipulation of Cited4 gene expression may be of great interest for cardiac regeneration. PMID- 28817661 TI - Ouabain affects cell migration via Na,K-ATPase-p130cas and via nucleus-centrosome association. AB - Na,K-ATPase is a membrane protein that catalyzes ATP to maintain transmembrane sodium and potassium gradients. In addition, Na,K-ATPase also acts as a signal transducing receptor for cardiotonic steroids such as ouabain and activates a number of signalling pathways. Several studies report that ouabain affects cell migration. Here we used ouabain at concentrations far below those required to block Na,K-ATPase pump activity and show that it significantly reduced RPE cell migration through two mechanisms. It causes dephosphorylation of a 130 kD protein, which we identify as p130cas. Src is involved, because Src inhibitors, but not inhibitors of other kinases tested, caused a similar reduction in p130cas phosphorylation and ouabain increased the association of Na,K-ATPase and Src. Knockdown of p130cas by siRNA reduced cell migration. Unexpectedly, ouabain induced separation of nucleus and centrosome, also leading to a block in cell migration. Inhibitor and siRNA experiments show that this effect is mediated by ERK1,2. This is the first report showing that ouabain can regulate cell migration by affecting nucleus-centrosome association. PMID- 28817662 TI - Single-scan rest/stress imaging with 99mTc-Sestamibi and cadmium zinc telluride based SPECT for hyperemic flow quantification: A feasibility study evaluated with cardiac magnetic resonance imaging. AB - INTRODUCTION: We aimed to evaluate whether the hyperemic myocardial blood flow (MBF) can be estimated using cadmium zinc telluride (CZT)-based single-photon emission computed tomography (SPECT) cameras with a single, rapid rest/stress dynamic scan. Dynamic contrast-enhanced (DCE) cardiac magnetic resonance imaging (MRI) was used as a reference modality for flow measurement. MATERIALS AND METHODS: The proposed protocol included both the rest and stress acquisitions within a 24-min scan. Patients were first injected with 99mTc-Sestamibi at the resting state. Sixty minutes after the first injection, the subject was positioned via scintigraphy, after which the list-mode data acquisition was initiated and continued for 24 minutes. Five minutes after data acquisition was initiated, a stressed state was induced via dipyridamole infusion, after which a second dose of 99mTc-Sestamibi was injected. Dynamic SPECT images were reconstructed for all subjects, who also underwent T1-weighted cardiac DCE-MRI performed on days other than those of the SPECT studies. MBF values were estimated for the rest and stress MRI studies, and for the stress portion of the SPECT study. The SPECT-measured hyperemic MBF was compared with the MR-measured hyperemic MBF and coronary flow reserve (CFR), based on the regions of interest. RESULTS: A total of 30 subjects were included in this study. The hyperemic MBF estimated from SPECT showed a strong correlation with the MR-measured hyperemic MBF (r2 = 0.76) and a modest correlation with the MR-measured CFR (r2 = 0.56). Using MR-measured CFR <1.3 as a cutoff for coronary stenosis, we found that the SPECT-measured hyperemic MBF served as a useful clinical index with 94% sensitivity, 90% specificity, and 93% accuracy. CONCLUSIONS: Hyperemic MBF can be measured with a rapid, single-scan rest/stress study with CZT-based SPECT cameras. PMID- 28817663 TI - Discordance in the diagnosis of diabetes: Comparison between HbA1c and fasting plasma glucose. AB - OBJECTIVE: HbA1c has been introduced as a complementary diagnostic test for diabetes, but its impact on disease prevalence is unknown. This study evaluated the concordance between HbA1c and fasting plasma glucose (FPG) in the diagnosis of diabetes in the general population. MATERIALS AND METHODS: The study was designed as a population based investigation, with participants being sampled from the Ho Chi Minh City, Vietnam. Blood samples were collected after overnight fasting and analyzed within 4 hours after collection. HbA1c was measured with high pressure liquid chromatography (Arkray Adams, Japan). FPG was measured by the hexokinase method (Advia Autoanalyzer; Bayer Diagnostics, Germany). Diabetes was defined as HbA1c >= 6.5% or FPG >= 7.0 mmol/L. Prediabetes was classified as HbA1c between 5.7% and 6.4%. RESULTS: The study included 3523 individuals (2356 women) aged 30 years and above. Based on the HbA1c test, the prevalence of diabetes and prediabetes was 9.7% (95%CI, 8.7-10.7%; n = 342) and 34.6% (33.0 36.2; n = 1219), respectively. Based on the FPG test, the prevalence of diabetes and prediabetes was 6.3% (95%CI, 5.5-7.2%; n = 223) and 12.1% (11.1-13.2; n = 427). Among the 427 individuals identified by FPG as "pre-diabetes", 28.6% were classified as diabetes by HbA1c test. The weighted kappa statistic of concordance between HbA1c and FPG was 0.55, with most of the discordance being in the prediabetes group. CONCLUSION: These data indicate that there is a significant discordance in the diagnosis of diabetes between FPG and HbA1c measurements, and the discordance could have significant impact on clinical practice. FPG appears to underestimate the burden of undiagnosed diabetes. PMID- 28817664 TI - Gold nanoparticles partition to and increase the activity of glucose-6 phosphatase in a synthetic phospholipid membrane system. AB - Engineered nanomaterials can alter the structure and/or function of biological membranes and membrane proteins but the underlying mechanisms remain unclear. We addressed this using a Langmuir phospholipid monolayer containing an active transmembrane protein, glucose-6-phosphatase (G6Pase). Gold nanoparticles (nAu) with varying ligand shell composition and hydrophobicity were synthesized, and their partitioning in the membrane and effects on protein activity characterized. nAu incorporation did not alter the macroscopic properties of the membrane. Atomic force microscopy showed that when co-spread with other components prior to membrane compression, nAu preferentially interacted with G6Pase and each other in a functional group-dependent manner. Under these conditions, all nAu formulations reduced G6Pase aggregation in the membrane, enhancing catalytic activity 5-6 fold. When injected into the subphase beneath pre-compressed monolayers, nAu did not affect G6Pase activity over 60 minutes, implying they were unable to interact with the protein under these conditions. A small but significant quenching of tryptophan fluorescence showed that nAu interacted with G6Pase in aqueous suspension. nAu also significantly reduced the hydrodynamic diameter of G6Pase in aqueous suspension and promoted catalytic activity, likely via a similar mechanism to that observed in co-spread monolayers. Overall, our results show that nAu can incorporate into membranes and associate preferentially with membrane proteins under certain conditions and that partitioning is dependent upon ligand shell chemistry and composition. Once incorporated, nAu can alter the distribution of membrane proteins and indirectly affect their function by improving active site accessibility, or potentially by changing their native structure and distribution in the membrane. PMID- 28817665 TI - Concentrations of trace elements in human milk: Comparisons among women in Argentina, Namibia, Poland, and the United States. AB - Human milk contains essential micronutrients for growth and development during early life. Environmental pollutants, such as potentially toxic metals, can also be transferred to the infant through human milk. These elements have been well studied, but changing diets and environments and advances in laboratory technology require re-examining these elements in a variety of settings. The aim of this study was to characterize the concentrations of essential and toxic metals in human milk from four diverse populations. Human milk samples (n = 70) were collected in Argentina (n = 21), Namibia (n = 6), Poland (n = 23), and the United States (n = 20) using a standardized mid-feed collection procedure. Milk concentrations of calcium, zinc, iron, copper, manganese, lead, arsenic, and cadmium were determined using inductively coupled plasma mass spectrometry (ICP MS). We used standard multiple linear regression models to evaluate differences among populations, while including infant age, infant sex, and maternal parity status (multiparous or primiparous) as covariates. Concentrations of all elements, except zinc, varied across populations after controlling for infant age, infant sex, and maternal parity. Calcium and magnesium showed more differences across populations than iron or copper. There were no significant differences among population in zinc concentrations. Mean concentrations of lead, but not arsenic, were low compared to recently published values from other populations. The concentrations of trace elements in human milk are variable among populations. Limitations due to small sample sizes and environmental contamination of some samples prevent us from drawing robust conclusions about the causes of these differences. PMID- 28817666 TI - Assessing the sustainable development and intensification potential of beef cattle production in Sumbawa, Indonesia, using a system dynamics approach. AB - The intensification of beef cattle production in dryland areas of East Indonesia has the potential to substantially raise the incomes of smallholder farmers that dominate the sector. In this study we assess the potential for intensifying beef production on Sumbawa Island, by introducing a household feedlot production system (2-20 animals) based on the Leucaena leucocephala (leucanea) tree legume as an improved source of feed. We used a system dynamics approach to model the entire value chain, accounting for herd dynamics, demand dynamics and seasonality. Our findings complement the growing body of biophysical evidence about the potential success of this intervention, by simulating improvements in the annual profitability for beef farmers in the project area of up to 415% by 2023. Increases in farm profit were shown to depend near equally on the higher productivity of the leucaena feeding system and an associated price premium, demonstrating the importance of supporting improved agricultural production with better marketing practices. The intervention was also shown to generate positive or neutral benefits for the main post-farm value chain actors. Importantly, it also reduced the GHG emission intensity of outputs from the beef herd by 16% by 2020. We explored number of scale-out pathways, including a relatively moderate pace of autonomous adoption for our main analysis, resulting in the accumulation of 3,444 hectares of leucaena 20-years after the initial project phase, which could sustain the fattening of 37,124 male cattle per year. More ambitious rates of scale-out were found to be possible without exceeding the animal and land resources of the island. PMID- 28817667 TI - Glycoprotein Ib activation by thrombin stimulates the energy metabolism in human platelets. AB - Thrombin-induced platelet activation requires substantial amounts of ATP. However, the specific contribution of each ATP-generating pathway i.e., oxidative phosphorylation (OxPhos) versus glycolysis and the biochemical mechanisms involved in the thrombin-induced activation of energy metabolism remain unclear. Here we report an integral analysis on the role of both energy pathways in human platelets activated by several agonists, and the signal transducing mechanisms associated with such activation. We found that thrombin, Trap-6, arachidonic acid, collagen, A23187, epinephrine and ADP significantly increased glycolytic flux (3-38 times vs. non-activated platelets) whereas ristocetin was ineffective. OxPhos (33 times) and mitochondrial transmembrane potential (88%) were increased only by thrombin. OxPhos was the main source of ATP in thrombin-activated platelets, whereas in platelets activated by any of the other agonists, glycolysis was the principal ATP supplier. In order to establish the biochemical mechanisms involved in the thrombin-induced OxPhos activation in platelets, several signaling pathways associated with mitochondrial activation were analyzed. Wortmannin and LY294002 (PI3K/Akt pathway inhibitors), ristocetin and heparin (GPIb inhibitors) as well as resveratrol, ATP (calcium-release inhibitors) and PP1 (Tyr-phosphorylation inhibitor) prevented the thrombin induced platelet activation. These results suggest that thrombin activates OxPhos and glycolysis through GPIb-dependent signaling involving PI3K and Akt activation, calcium mobilization and protein phosphorylation. PMID- 28817668 TI - Titanium biomaterials with complex surfaces induced aberrant peripheral circadian rhythms in bone marrow mesenchymal stromal cells. AB - Circadian rhythms maintain a high level of homeostasis through internal feed forward and -backward regulation by core molecules. In this study, we report the highly unusual peripheral circadian rhythm of bone marrow mesenchymal stromal cells (BMSCs) induced by titanium-based biomaterials with complex surface modifications (Ti biomaterial) commonly used for dental and orthopedic implants. When cultured on Ti biomaterials, human BMSCs suppressed circadian PER1 expression patterns, while NPAS2 was uniquely upregulated. The Ti biomaterials, which reduced Per1 expression and upregulated Npas2, were further examined with BMSCs harvested from Per1::luc transgenic rats. Next, we addressed the regulatory relationship between Per1 and Npas2 using BMSCs from Npas2 knockout mice. The Npas2 knockout mutation did not rescue the Ti biomaterial-induced Per1 suppression and did not affect Per2, Per3, Bmal1 and Clock expression, suggesting that the Ti biomaterial-induced Npas2 overexpression was likely an independent phenomenon. Previously, vitamin D deficiency was reported to interfere with Ti biomaterial osseointegration. The present study demonstrated that vitamin D supplementation significantly increased Per1::luc expression in BMSCs, though the presence of Ti biomaterials only moderately affected the suppressed Per1::luc expression. Available in vivo microarray data from femurs exposed to Ti biomaterials in vitamin D-deficient rats were evaluated by weighted gene co expression network analysis. A large co-expression network containing Npas2, Bmal1, and Vdr was observed to form with the Ti biomaterials, which was disintegrated by vitamin D deficiency. Thus, the aberrant BMSC peripheral circadian rhythm may be essential for the integration of Ti biomaterials into bone. PMID- 28817669 TI - The association between renal recovery after acute kidney injury and long-term mortality after transcatheter aortic valve replacement. AB - BACKGROUND: This study aimed to examine the association between renal recovery status at hospital discharge after acute kidney injury (AKI) and long-term mortality following transcatheter aortic valve replacement (TAVR). METHODS: We screened all adult patients who survived to hospital discharge after TAVR for aortic stenosis at a quaternary referral medical center from January 1, 2008, through June 30, 2014. An AKI was defined as an increase in serum creatinine level of 0.3 mg/dL or a relative increase of 50% from baseline. Renal outcome at the time of discharge was evaluated by comparing the discharge serum creatinine level to the baseline level. Complete renal recovery was defined as no AKI at discharge, whereas partial renal recovery was defined as AKI without a need for renal replacement therapy at discharge. No renal recovery was defined as a need for renal replacement therapy at discharge. RESULTS: The study included 374 patients. Ninty-eight (26%) patients developed AKI during hospitalization: 55 (56%) had complete recovery; 39 (40%), partial recovery; and 4 (4%), no recovery. AKI development was significantly associated with increased risk of 2-year mortality (hazard ratio [HR], 2.20 [95% CI, 1.37-3.49]). For patients with AKI, the 2-year mortality rate for complete recovery was 34%; for partial recovery, 43%; and for no recovery, 75%; compared with 20% for patients without AKI (P < .001). In adjusted analysis, complete recovery (HR, 1.87 [95% CI, 1.03-3.23]); partial recovery (HR, 2.65 [95% CI, 1.40-4.71]) and no recovery (HR, 10.95 [95% CI, 2.59-31.49]) after AKI vs no AKI were significantly associated with increased risk of 2-year mortality. CONCLUSION: The mortality rate increased for all patients with AKI undergoing TAVR. A reverse correlation existed for progressively higher risk of death and the extent of AKI recovery. PMID- 28817670 TI - Synthesis, radiosynthesis and in vitro evaluation of 18F-Bodipy-C16/triglyceride as a dual modal imaging agent for brown adipose tissue. AB - BACKGROUND: Brown adipose tissue research is in the focus in the field of endocrinology. We designed a dual-modal fluorescent/PET fatty acid based tracer on commercially available Bodipy-C16, which can be synthesized to its corresponding triglyceride and which combines the benefits of fluorescent and PET imaging. METHODS: Bodipy-C16 was coupled to 1,3-diolein resulting in Bodipy triglyceride. Bodipy-C16 and Bodipy-triglyceride compounds were radiolabeled with 18F using an 18F/19F exchange reaction to yield a dual-modal imaging molecule. Uptake of radiolabeled and non-labeled Bodipy-C16 and Bodipy-triglyceride was analyzed by fluorescence imaging and radioactive uptake in cultured adipocytes derived from human brown adipose tissue and white adipose tissue. RESULTS: Bodipy C16 and Bodipy-triglyceride were successfully radiolabeled and Bodipy-C16 showed high shelf life and blood plasma stability (99% from 0-4 h). The uptake of Bodipy C16 increased over time in cultured adipocytes, which was further enhanced after beta-adrenergic stimulation with norepinephrine. The uptake of Bodipy-C16 was inhibited by oleic acid and CD36 inhibitor sulfosuccinimidyl-oleate. The poor solubility of Bodipy-triglyceride did not allow stability or in vitro experiments. CONCLUSION: The new developed dual modal fatty acid based tracers Bodipy-C16 and Bodipy-triglyceride showed promising results to stimulate further in vivo evaluation and will help to understand brown adipose tissues role in whole body energy expenditure. PMID- 28817671 TI - Immunohistochemical analysis reveals variations in proteasome tissue expression in C. elegans. AB - The ubiquitin-proteasome system (UPS) plays a crucial part in normal cell function by mediating intracellular protein clearance. We have previously shown that UPS-mediated protein degradation varies in a cell type-specific manner in C. elegans. Here, we use formalin-fixed, paraffin-embedded C. elegans sections to enable studies on endogenous proteasome tissue expression. We show that the proteasome immunoreactivity pattern differs between cell types and within subcellular compartments in adult wild-type (N2) C. elegans. Interestingly, widespread knockdown of proteasome subunits by RNAi results in tissue-specific changes in proteasome expression instead of a uniform response. In addition, long lived daf-2(e1370) mutants with impaired insulin/IGF-1 signaling (IIS) display similar proteasome tissue expression as aged-matched wild-type animals. Our study emphasizes the importance of alternate approaches to the commonly used whole animal lysate-based methods to detect changes in proteasome expression occurring at the sub-cellular, cell or tissue resolution level in a multicellular organism. PMID- 28817672 TI - Estimated future incidence of malignant mesothelioma in South Korea: Projection from 2014 to 2033. AB - Malignant mesothelioma is a malignant tumor on the pleura or the peritoneum caused mostly by asbestos. Although asbestos is not currently used in South Korea, the incidence of mesothelioma is increasing due to its long latent period. This study predicted the incidence of malignant mesothelioma in South Korea over the next 20 years using an age-period-cohort (APC) model. Data regarding mesothelioma incidence from 1994-2013 were acquired from the Korea Central Cancer Registry (KCCR). Demographic data, including prospective resident data, were acquired from the Korean Statistical Information Service (KOSIS) for 1994-2033. An APC model with Moller's power-link function was utilized to predict the incidence of mesothelioma. It was predicted that 2,380 and 1,199 new cases of mesothelioma in men and women, respectively, would occur over the next 20 years. For both sexes, the mesothelioma incidence rate was predicted to be greater in 2029-2033 compared to that in 2009-2013 (men, 0.282 vs 0.563; women, 0.155 vs 0.217). For men, the age-standardized incidence rate was predicted to be slightly greater in 2029-2033 relative to the rate in 2009-2013 (0.228 vs 0.235), while the age-standardized incidence rate in women decreased within the same timeframe (0.113 vs 0.109). The changes in mesothelioma incidence were mostly caused by changes in the population structure due to aging and not by changes in the mesothelioma risk ratio. The results of this study project a continuous increase in mesothelioma incidence in South Korea over the next 20 years. Although the projected increase in mesothelioma incidence was not related to an increase in the mesothelioma risk ratio, continuous preventive efforts are necessary to reduce the exposure to asbestos and prevent the trend from worsening. PMID- 28817673 TI - The plasmid-encoded Ipf and Klf fimbriae display different expression and varying roles in the virulence of Salmonella enterica serovar Infantis in mouse vs. avian hosts. AB - Salmonella enterica serovar Infantis is one of the prevalent Salmonella serovars worldwide. Different emergent clones of S. Infantis were shown to acquire the pESI virulence-resistance megaplasmid affecting its ecology and pathogenicity. Here, we studied two previously uncharacterized pESI-encoded chaperone-usher fimbriae, named Ipf and Klf. While Ipf homologs are rare and were found only in S. enterica subspecies diarizonae and subspecies VII, Klf is related to the known K88-Fae fimbria and klf clusters were identified in seven S. enterica subspecies I serovars, harboring interchanging alleles of the fimbria major subunit, KlfG. Regulation studies showed that the klf genes expression is negatively and positively controlled by the pESI-encoded regulators KlfL and KlfB, respectively, and are activated by the ancestral leucine-responsive regulator (Lrp). ipf genes are negatively regulated by Fur and activated by OmpR. Furthermore, induced expression of both klf and ipf clusters occurs under microaerobic conditions and at 41 degrees C compared to 37 degrees C, in-vitro. Consistent with these results, we demonstrate higher expression of ipf and klf in chicks compared to mice, characterized by physiological temperature of 41.2 degrees C and 37 degrees C, respectively. Interestingly, while Klf was dispensable for S. Infantis colonization in the mouse, Ipf was required for maximal colonization in the murine ileum. In contrast to these phenotypes in mice, both Klf and Ipf contributed to a restrained infection in chicks, where the absence of these fimbriae has led to moderately higher bacterial burden in the avian host. Taken together, these data suggest that physiological differences between host species, such as the body temperature, can confer differences in fimbriome expression, affecting Salmonella colonization and other host-pathogen interplays. PMID- 28817674 TI - New insights into the distribution, protein abundance and subcellular localisation of the endogenous peroxisomal biogenesis proteins PEX3 and PEX19 in different organs and cell types of the adult mouse. AB - Peroxisomes are ubiquitous organelles mainly involved in ROS and lipid metabolism. Their abundance, protein composition and metabolic function vary depending on the cell type and adjust to different intracellular and environmental factors such as oxidative stress or nutrition. The biogenesis and proliferation of these important organelles are regulated by proteins belonging to the peroxin (PEX) family. PEX3, an integral peroxisomal membrane protein, and the cytosolic shuttling receptor PEX19 are thought to be responsible for the early steps of peroxisome biogenesis and assembly of their matrix protein import machinery. Recently, both peroxins were suggested to be also involved in the autophagy of peroxisomes (pexophagy). Despite the fact that distribution and intracellular abundance of these proteins might regulate the turnover of the peroxisomal compartment in a cell type-specific manner, a comprehensive analysis of the endogenous PEX3 and PEX19 distribution in different organs is still missing. In this study, we have therefore generated antibodies against endogenous mouse PEX3 and PEX19 and analysed their abundance and subcellular localisation in various mouse organs, tissues and cell types and compared it to the one of three commonly used peroxisomal markers (PEX14, ABCD3 and catalase). Our results revealed that the abundance of PEX3, PEX19, PEX14, ABCD3 and catalase strongly varies in the analysed organs and cell types, suggesting that peroxisome abundance, biogenesis and matrix protein import are independently regulated. We further found that in some organs, such as heart and skeletal muscle, the majority of the shuttling receptor PEX19 is bound to the peroxisomal membrane and that a strong variability exists in the cell type-specific ratio of cytosol- and peroxisome-associated PEX19. In conclusion, our results indicate that peroxisomes in various cell types are heterogeneous with regards to their matrix, membrane and biogenesis proteins. PMID- 28817675 TI - Deaths during tuberculosis treatment among paediatric patients in a large tertiary hospital in Nigeria. AB - BACKGROUND: Despite availability of effective cure, tuberculosis (TB) remains a leading cause of death in children. In many high-burden countries, childhood TB is underdiagnosed and underreported, and care is often accessed too late, resulting in adverse treatment outcomes. In this study, we examined the time to death and its associated factors among a cohort of children that commenced TB treatment in a large treatment centre in northern Nigeria. METHODS: This is a retrospective cohort study of children that started TB treatment between 2010 and 2014. We determined mortality rates per 100 person-months of treatment, as well as across treatment and calendar periods. We used Cox proportional hazards regression to determine adjusted hazard ratios (aHR) for factors associated with mortality. RESULTS: Among 299 children with a median age 4 years and HIV prevalence of 33.4%; 85 (28.4%) died after 1,383 months of follow-up. Overall mortality rate was 6.1 per 100 person-months. Deaths occurred early during treatment and declined from 42.4 per 100 person-months in the 1st week of treatment to 2.2 per 100 person-months after at the 3rd month of treatment. Mortality was highest between October to December period (9.1 per 100 pm) and lowest between July and September (2.8 per 100 pm). Risk factors for mortality included previous TB treatment (aHR 2.04:95%CI;1.09-3.84); HIV infection (aHR 1.66:95%CI;1.02-2.71), having either extra-pulmonary disease (aHR 2.21:95%CI;1.26 3.89) or both pulmonary and extrapulmonary disease (aHR 3.03:95%CI;1.70-5.40). CONCLUSIONS: Mortality was high and occurred early during treatment in this cohort, likely indicative of poor access to prompt TB diagnosis and treatment. A redoubling of efforts at improving universal health coverage are required to achieve the End TB Strategy target of zero deaths from TB. PMID- 28817677 TI - Abnormal expression of Nrf2 may play an important role in the pathogenesis and development of adenomyosis. AB - OBJECTIVE: To explore the expression level of Nrf2 in adenomyosis and study the mechanism of abnormal expression of Nrf2 in the pathogenesis of adenomyosis. METHODS: Western blot, immunohistochemistry(IHC) and real time PCR were used to measure Nrf2 expression levels in tissue and cell samples. Knockdown and overexpression of Nrf2 were used to investigate the variation of migration ability of endometrial glandular cells as well as the regulatory mechanism. RESULTS: Nrf2 protein levels were significantly higher in the eutopic and ectopic endometrial glands when compared with control cases using IHC and western blot methods. (p< 0.05). However, there was no statistical difference in Nrf2 mRNA expression levels between the adenomyosis and control groups. Using an agonist and Nrf2 siRNA, we regulated the Nrf2 protein levels of primary cultured endometrial glandular cells. With increased expression of Nrf2, cell scratch assay showed that the agonist-treated group migrated significantly faster than the control group, with MMP9 protein level markedly elevated. In contrast, Nrf2 siRNA-treated group migrated slower than the control group, with decreased expression of MMP9 protein. All of the scratching healing spaces and protein levels between the treated and control groups were statistically significant (p< 0.05). CONCLUSIONS: Abnormal expression of Nrf2 may play an important role in the pathogenesis and development of adenomyosis. Specified reduction of Nrf2 expression could prove to be a new therapeutic target in the clinical treatment of adenomyosis. PMID- 28817676 TI - Psychological determinants of physical activity across the life course: A "DEterminants of DIet and Physical ACtivity" (DEDIPAC) umbrella systematic literature review. AB - Low levels of physical activity (PA) are reported to contribute to the occurrence of non-communicable diseases over the life course. Although psychological factors have been identified as an important category concerning PA behavior, knowledge on psychological determinants of PA is still inconclusive. Therefore, the aim of this umbrella systematic literature review (SLR) was to summarize and synthesize the scientific evidence on psychological determinants of PA behavior across the life course. A systematic online search was conducted on MEDLINE, ISI Web of Science, Scopus, and SPORTDiscus databases. The search was limited to studies published in English from January 2004 to April 2016. SLRs and meta-analyses (MAs) of observational studies investigating the association of psychological variables and PA were considered eligible. Extracted data were evaluated based on importance of determinants, strength of evidence, and methodological quality. The full protocol is available from PROSPERO (Record ID: CRD42015010616). Twenty reviews (14 SLRs and 6 MAs), mostly of moderate methodological quality, were found eligible. Convincing evidence was found for self-efficacy (positive association with PA) in children and adolescents, and stress (negative association with PA) regardless of age. Most of the evidence revealing an association between psychological determinants and PA is probable and limited, mainly due to differences in the definition of PA and of psychological determinants across reviews. Thus, scholars are urged to reach a consensus on clear definitions of relevant psychological determinants of PA, subsuming cultural biases and allowing the possibility to obtain clear interpretations and generalizability of findings. Finally, most psychological determinants should be considered within a larger framework of other multi-level determinants that may interact or mediate some of the effects. PMID- 28817678 TI - Family-based exome-wide association study of childhood acute lymphoblastic leukemia among Hispanics confirms role of ARID5B in susceptibility. AB - We conducted an exome-wide association study of childhood acute lymphoblastic leukemia (ALL) among Hispanics to confirm and identify novel variants associated with disease risk in this population. We used a case-parent trio study design; unlike more commonly used case-control studies, this study design is ideal for avoiding issues with population stratification bias among this at-risk ethnic group. Using 710 individuals from 323 Guatemalan and US Hispanic families, two inherited SNPs in ARID5B reached genome-wide level significance: rs10821936, RR = 2.31, 95% CI = 1.70-3.14, p = 1.7*10-8 and rs7089424, RR = 2.22, 95% CI = 1.64 3.01, p = 5.2*10-8. Similar results were observed when restricting our analyses to those with the B-ALL subtype: ARID5B rs10821936 RR = 2.22, 95% CI = 1.63-3.02, p = 9.63*10-8 and ARID5B rs7089424 RR = 2.13, 95% CI = 1.57-2.88, p = 2.81*10-7. Notably, effect sizes observed for rs7089424 and rs10821936 in our study were >20% higher than those reported among non-Hispanic white populations in previous genetic association studies. Our results confirmed the role of ARID5B in childhood ALL susceptibility among Hispanics; however, our assessment did not reveal any strong novel inherited genetic risks for acute lymphoblastic leukemia among this ethnic group. PMID- 28817679 TI - Increased half-life and enhanced potency of Fc-modified human PCSK9 monoclonal antibodies in primates. AB - Blocking proprotein convertase subtilisin kexin type 9 (PCSK9) binding to low density lipoprotein receptor (LDLR) can profoundly lower plasma LDL levels. Two anti-PCKS9 monoclonal antibodies (mAbs), alirocumab and evolocumab, were approved by the FDA in 2015. The recommended dose is 75 mg to 150 mg every two weeks for alirocumab and 140mg every two weeks or 420 mg once a month for evolocumab. This study attempted to improve the pharmacokinetic properties of F0016A, an IgG1 anti PCKS9 mAb, to generate biologically superior molecules. We engineered several variants with two or three amino acid substitutions in the Fc fragment based on prior knowledge. The Fc-modified mAbs exhibited increased binding to FcRn, resulting in prolonged serum half-life and enhanced efficacy in vivo. These results demonstrate that Fc-modified anti-PCKS9 antibodies may enable less frequent or lower dosing of antibodies by improved recycling into the blood. PMID- 28817681 TI - Pressure in isochoric systems containing aqueous solutions at subzero Centigrade temperatures. AB - OBJECTIVE: Preservation of biological materials at subzero Centigrade temperatures, cryopreservation, is important for the field of tissue engineering and organ transplantation. Our group is studying the use of isochoric (constant volume) systems of aqueous solution for cryopreservation. Previous studies measured the pressure-temperature relations in aqueous isochoric systems in the temperature range from 0 degrees C to - 20 degrees C. The goal of this study is to expand the pressure-temperature measurement beyond the range reported in previous publications. MATERIALS AND METHODS: To expand the pressure-temperature measurements beyond the previous range, we have developed a new isochoric device capable of withstanding liquid nitrogen temperatures and pressures of up to 413 MPa. The device is instrumented with a pressure transducer than can monitor and record the pressures in the isochoric chamber in real time. Measurements were made in a temperature range from - 5 degrees C to liquid nitrogen temperatures for various solutions of pure water and Me2SO (a chemical additive used for protection of biological materials in a frozen state and for vitrification (glass formation) of biological matter). Undissolved gaseous are is carefully removed from the system. RESULTS: Temperature-pressure data from - 5 degrees C to liquid nitrogen temperature for pure water and other solutions are presented in this study. Following are examples of some, temperature-pressure values, that were measured in an isochoric system containing pure water: (- 20 degrees C, 187 MPa); (-25 degrees C, 216 MPa); (- 30 degrees C, 242.3 MPa); (-180 degrees C, 124 MPa). The data is consistent with the literature, which reports that the pressure and temperature at the triple point, between ice I, ice III and water is, - 21.993 degrees C and 209.9 MPa, respectively. It was surprising to find that the pressure in the isochoric system increases at temperatures below the triple point and remains high to liquid nitrogen temperatures. Measurements of pressure temperature relations in solutions of pure water and Me2SO in different concentrations show that, for concentrations in which vitrification is predicted, no increase in pressure was measured during rapid cooling to liquid nitrogen temperatures. However, ice formation either during cooling or warming to and from liquid nitrogen temperatures produced an increase in pressure. CONCLUSIONS: The data obtained in this study can be used to aid in the design of isochoric cryopreservation protocols. The results suggest that the pressure measurement is important in the design of "constant volume" systems and can provide a simple means to gain information on the occurrence of vitrification and devitrification during cryopreservation processes of aqueous solutions in an isochoric system. PMID- 28817680 TI - Human alpha defensin 5 is a candidate biomarker to delineate inflammatory bowel disease. AB - Inability to distinguish Crohn's colitis from ulcerative colitis leads to the diagnosis of indeterminate colitis. This greatly effects medical and surgical care of the patient because treatments for the two diseases vary. Approximately 30 percent of inflammatory bowel disease patients cannot be accurately diagnosed, increasing their risk of inappropriate treatment. We sought to determine whether transcriptomic patterns could be used to develop diagnostic biomarker(s) to delineate inflammatory bowel disease more accurately. Four patients groups were assessed via whole-transcriptome microarray, qPCR, Western blot, and immunohistochemistry for differential expression of Human alpha-Defensin-5. In addition, immunohistochemistry for Paneth cells and Lysozyme, a Paneth cell marker, was also performed. Aberrant expression of Human alpha-Defensin-5 levels using transcript, Western blot, and immunohistochemistry staining levels was significantly upregulated in Crohn's colitis, p< 0.0001. Among patients with indeterminate colitis, Human alpha-Defensin-5 is a reliable differentiator with a positive predictive value of 96 percent. We also observed abundant ectopic crypt Paneth cells in all colectomy tissue samples of Crohn's colitis patients. In a retrospective study, we show that Human alpha-Defensin-5 could be used in indeterminate colitis patients to determine if they have either ulcerative colitis (low levels of Human alpha-Defensin-5) or Crohn's colitis (high levels of Human alpha-Defensin-5). Twenty of 67 patients (30 percent) who underwent restorative proctocolectomy for definitive ulcerative colitis were clinically changed to de novo Crohn's disease. These patients were profiled by Human alpha Defensin-5 immunohistochemistry. All patients tested strongly positive. In addition, we observed by both hematoxylin and eosin and Lysozyme staining, a large number of ectopic Paneth cells in the colonic crypt of Crohn's colitis patient samples. Our experiments are the first to show that Human alpha-Defensin 5 is a potential candidate biomarker to molecularly differentiate Crohn's colitis from ulcerative colitis, to our knowledge. These data give us both a potential diagnostic marker in Human alpha-Defensin-5 and insight to develop future mechanistic studies to better understand crypt biology in Crohn's colitis. PMID- 28817682 TI - Experimental study of tuberculosis: From animal models to complex cell systems and organoids. AB - Tuberculosis (TB) is a devastating disease to mankind that has killed more people than any other infectious disease. Despite many efforts and successes from the scientific and health communities, the prospect of TB elimination remains distant. On the one hand, sustainable public health programs with affordable and broad implementation of anti-TB measures are needed. On the other hand, achieving TB elimination requires critical advances in three areas: vaccination, diagnosis, and treatment. It is also well accepted that succeeding in advancing these areas requires a deeper knowledge of host-pathogen interactions during infection, and for that, better experimental models are needed. Here, we review the potential and limitations of different experimental approaches used in TB research, focusing on animal and human-based cell culture models. We highlight the most recent advances in developing in vitro 3D models and introduce the potential of lung organoids as a new tool to study Mycobacterium tuberculosis infection. PMID- 28817683 TI - Genome wide association analysis of cold tolerance at germination in temperate japonica rice (Oryza sativa L.) varieties. AB - A pool of 200 traditional, landraces and modern elite and old cultivars of rice, mainly japonica varieties adapted to temperate regions, have been used to perform a genome wide association study to detect chromosome regions associated to low temperature germination (LTG) regulation using a panel of 1672 SNP markers. Phenotyping was performed by determining growth rates when seeds were germinated at 25 degrees and 15 degrees C in order to separate the germination vigorousness from cold tolerance effects. As expected, the ability to produce viable seedlings varied widely among rice cultivars and also depended greatly on temperature. Furthermore, we observed a differential response during seed germination and in coleoptile elongation. Faster development at 15 degrees C was observed in seeds from varieties traditionally used as cold tolerant parents by breeders, along with other potentially useful cultivars, mainly of Italian origin. When phenotypic data were combined with the panel of SNPs for japonica rice cultivars, significant associations were detected for 31 markers: 7 were related to growth rate at 25 degrees C and 24 to growth rates at 15 degrees . Among the latter, some chromosome regions were associated to LTG while others were related to coleoptile elongation. Individual effects of the associated markers were low, but by combining favourable alleles in a linear regression model we estimated that 27 loci significantly explained the observed phenotypic variation. From these, a core panel of 13 markers was selected and, furthermore, two wide regions of chromosomes 3 and 6 were consistently associated to rice LTG. Varieties with higher numbers of favourable alleles for the panels of associated markers significantly correlated with increased phenotypic values at both temperatures, thus corroborating the utility of the tagged markers for marker assisted selection (MAS) when breeding japonica rice for LTG. PMID- 28817684 TI - Correction: The learning curve of endoscopic total mastectomy in Taiwan: A multi center study. AB - [This corrects the article DOI: 10.1371/journal.pone.0178251.]. PMID- 28817685 TI - Clinical implications of carcinoembryonic antigen distribution in serum exosomal fraction-Measurement by ELISA. AB - BACKGROUND: Serum exosomal proteins have great potential as indicators of disease status in cancer, inflammatory or metabolic diseases. The association of a fraction of various serum proteins such as carcinoembryonic antigen (CEA) with circulating exosomes has been debated. The establishment of a method to measure the exosomal fraction of such proteins might help resolve this controversy. The use of enzyme-linked immunosorbent assays (ELISAs) to measure serum exosomal molecules, for example CEA, is rare in research laboratories and totally absent in clinical biology. In this study, we optimized a method for assessment of serum exosomal molecules combining a treatment by volume-excluding polymers to isolate the exosomes, their subsequent solubilization in an assay buffer and ELISA. METHODS: One hundred sixteen consecutive patients with colorectal cancer were enrolled for this study between June 2015 and June 2016 at Wakayama Medical University Hospital (WMUH). Whole blood samples were collected from patients during surgery. Exosomes were isolated using the ExoQuick reagent, solubilized in an assay buffer and subjected to CEA detection by ELISA. The procedure of serum exosome isolation and the formulation of the assay buffer used for the ELISA were optimized in order to improve the sensitivity and specificity of the assay. RESULTS: A five-fold increase in the concentration of the exosomes in the assay buffer (using initial serum volume as a reference) and the addition of bovine serum albumin (BSA) resulted in more accurate measurements of the serum exosomal CEA. The thawing temperature of frozen serum samples before exosome extraction was also optimized. A validation study that included one hundred sixteen patients with colorectal cancer demonstrated that serum exosomal CEA from samples thawed at 25 degrees C exhibited a better AUC value, sensitivity, and specificity as well as a more correct classification than serum CEA. CONCLUSIONS: We optimized an easy and rapid detection method for assessment of serum exosomal CEA. The thawing temperature of frozen serum prior to exosome extraction, the formulation of the assay buffer used for exosome solubilization and the concentration of the exosomes in this buffer were fine-tuned to enable the appropriate and accurate measurement of serum exosomal CEA. PMID- 28817686 TI - Use of phosphodiesterase inhibitors and prevalence of self-reported glaucoma in the United States. AB - OBJECTIVE: While decreased ocular blood flow is thought to be a possible contributor to glaucoma pathogenesis, it is unclear what role systemic phosphodiesterase inhibitors (PDEi) play. We performed a cross-sectional study of a nationally representative sample of the U.S. population to investigate the relationship between the most commonly used PDEi, sildenafil and theophylline, and self-reported glaucoma. METHODS: We used the National Health and Nutrition Examination Survey 2005-2008 cycles for this observational study. 7,042 participants, aged 40 years and over, responded to a survey item on glaucoma status and were included in the analysis. Multivariable logistic regression models were constructed to evaluate the association between at least 1 year of self-reported PDEi use and prevalent glaucoma. Regressions were adjusted for potential confounding variables, including demographics, socioeconomic status, and general health conditions, and accounted for the complex design of the survey. Sample weights were constructed and used to ensure the generalizability of results. RESULTS: 482 respondents self-reported a diagnosis of glaucoma, of which 11 used sildenafil and 20 used theophylline for at least 1 year. Covariates significantly associated with higher odds of glaucoma prevalence in univariable analyses included older age, black race, former smoking status, diabetes, hyperlipidemia, myocardial infarction, and stroke. Conversely, higher education and income were significantly associated with lower odds of glaucoma prevalence. In regression analyses adjusted for demographic and socioeconomic variables, sildenafil (OR = 4.90, CI: 1.24-19.27, p = 0.025) and theophylline (OR = 3.15, CI: 1.46-6.80, p = 0.005) were significantly associated with higher odds of self reported glaucoma. These associations held after further adjustment with general health behaviors and conditions for both sildenafil and theophylline. CONCLUSIONS: Use of sildenafil and theophylline for one or more years was associated with greater prevalence of self-reported glaucoma, a finding which requires further prospective study to assess causality and possible mechanisms of action. PMID- 28817688 TI - The extremely divergent maternally- and paternally-transmitted mitochondrial genomes are co-expressed in somatic tissues of two freshwater mussel species with doubly uniparental inheritance of mtDNA. AB - Freshwater mussel species with doubly uniparental inheritance (DUI) of mtDNA are unique because they are naturally heteroplasmic for two extremely divergent mtDNAs with ~50% amino acid differences for protein-coding genes. The paternally transmitted mtDNA (or M mtDNA) clearly functions in sperm in these species, but it is still unknown whether it is transcribed when present in male or female soma. In the present study, we used PCR and RT-PCR to detect the presence and expression of the M mtDNA in male and female somatic and gonadal tissues of the freshwater mussel species Venustaconcha ellipsiformis and Utterbackia peninsularis (Unionidae). This is the first study demonstrating that the M mtDNA is transcribed not only in male gonads, but also in male and female soma in freshwater mussels with DUI. Because of the potentially deleterious nature of heteroplasmy, we suggest the existence of different mechanisms in DUI species to deal with this possibly harmful situation, such as silencing mechanisms for the M mtDNA at the transcriptional, post-transcriptional and/or post-translational levels. These hypotheses will necessitate additional studies in distantly-related DUI species that could possess different mechanisms of action to deal with heteroplasmy. PMID- 28817689 TI - Characterization and formulation into solid dosage forms of a novel bacteriophage lytic against Klebsiella oxytoca. AB - AIM: To isolate and characterize bacteriophage lytic for the opportunistic pathogen Klebsiella oxytoca and their formulation into a range of solid dosage forms for in-vitro testing. METHODS AND RESULTS: We report the isolation, genomic and functional characterization of a novel bacteriophage lytic for Klebsiella oxytoca, which does not infect the closely related Klebsiella pneumoniae. This bacteriophage was formulated into suppositories and troches and shown to be released and lyse underlying Klebsiella oxytoca bacteria in an in-vitro model. These bacteriophage formulations were stable for at least 49 days at 4 degrees C. CONCLUSIONS: The successful in-vitro assay of these formulations here suggests that they could potentially be tested in-vivo to determine whether such a therapeutic approach could modulate the gut microbiome, and control Klebsiella oxytoca overgrowth, during antibiotic therapy regimes. SIGNIFICANCE AND IMPACT OF THE STUDY: This study reports a novel bacteriophage specific for Klebsiella oxytoca which can be formulated into solid dosage forms appropriate for potential delivery in testing as a therapy to modulate gut microbiome during antibiotic therapies. PMID- 28817687 TI - Morphologic, phenotypic, and transcriptomic characterization of classically and alternatively activated canine blood-derived macrophages in vitro. AB - Macrophages are a heterogeneous cell population playing a pivotal role in tissue homeostasis and inflammation, and their phenotype strongly depends on the micromilieu. Despite its increasing importance as a translational animal model for human diseases, there is a considerable gap of knowledge with respect to macrophage polarization in dogs. The present study comprehensively investigated the morphologic, phenotypic, and transcriptomic characteristics of unstimulated (M0), M1- (GM-CSF, LPS, IFNgamma-stimulated) and M2- (M-CSF, IL-4-stimulated) polarized canine blood-derived macrophages in vitro. Scanning electron microscopy revealed distinct morphologies of polarized macrophages with formation of multinucleated cells in M2-macrophages, while immunofluorescence employing literature-based prototype-antibodies against CD16, CD32, iNOS, MHC class II (M1 markers), CD163, CD206, and arginase-1 (M2-markers) demonstrated that only CD206 was able to discriminate M2-macrophages from both other phenotypes, highlighting this molecule as a promising marker for canine M2-macrophages. Global microarray analysis revealed profound changes in the transcriptome of polarized canine macrophages. Functional analysis pointed out that M1-polarization was associated with biological processes such as "respiratory burst", whereas M2-polarization was associated with processes such as "mitosis". Literature-based marker gene selection revealed only minor overlaps in the gene sets of the dog compared to prototype markers of murine and human macrophages. Biomarker selection using supervised clustering suggested latexin (LXN) and membrane-spanning 4-domains, subfamily A, member 2 (MS4A2) to be the most powerful predicting biomarkers for canine M1- and M2-macrophages, respectively. Immunofluorescence for both markers demonstrated expression of both proteins by macrophages in vitro but failed to reveal differences between canine M1 and M2-macrophages. The present study provides a solid basis for future studies upon the role of macrophage polarization in spontaneous diseases of the dog, a species that has emerging importance for translational research. PMID- 28817690 TI - Resveratrol and caloric restriction prevent hepatic steatosis by regulating SIRT1 autophagy pathway and alleviating endoplasmic reticulum stress in high-fat diet fed rats. AB - BACKGROUND: Studies have demonstrated that resveratrol (a natural polyphenol) and caloric restriction activate Sirtuin-1 (SIRT1) and induce autophagy. Furthermore, autophagy is induced by the SIRT1-FoxO signaling pathway and was recently shown to be a critical protective mechanism against non-alcoholic fatty liver disease (NAFLD) development. We aimed to compare the effects of resveratrol and caloric restriction on hepatic lipid metabolism and elucidate the mechanism by which resveratrol supplementation and caloric restriction alleviate hepatosteatosis by examining the molecular interplay between SIRT1 and autophagy. METHODS AND RESULTS: Eight-week-old male Wistar rats (40) were divided into four groups: the STD group, which was fed a standard chow diet; the HFD group, which was fed a high-fat diet; HFD-RES group, which was fed a high-fat diet plus resveratrol (200 mg/kg.bw); and the HFD-CR group, which was fed a high-fat diet in portions containing 70% of the mean intake of the HFD group rats. The groups were maintained for 18 weeks. Metabolic parameters, Oil Red O and hematoxylin-eosin staining of the liver, and the mRNA and protein expression of SIRT1, autophagy markers and endoplasmic reticulum(ER) stress-associated genes in the liver were assessed after the 18-week treatment. We found that resveratrol (200 mg/kg bw) and caloric restriction (30%) partially prevented hepatic steatosis and hepatocyte ballooning, increased the expression of SIRT1 and autophagy markers while decreasing ER stress markers in the liver and alleviated lipid metabolism disorder. Moreover, caloric restriction provided superior protection against HFD induced hepatic fatty accumulation compared with resveratrol and the effects were associated with decreased total energy intake and body weight. CONCLUSION: We conclude that the SIRT1-autophagy pathway and decreased ER stress are universally required for the protective effects of moderate caloric restriction (30%) and resveratrol (a pharmacological SIRT1 activator) supplementation against HFD induced hepatic steatosis. PMID- 28817692 TI - Integrating Triangle and Jaccard similarities for recommendation. AB - This paper proposes a new measure for recommendation through integrating Triangle and Jaccard similarities. The Triangle similarity considers both the length and the angle of rating vectors between them, while the Jaccard similarity considers non co-rating users. We compare the new similarity measure with eight state-of the-art ones on four popular datasets under the leave-one-out scenario. Results show that the new measure outperforms all the counterparts in terms of the mean absolute error and the root mean square error. PMID- 28817691 TI - Rac2 is required for alternative macrophage activation and bleomycin induced pulmonary fibrosis; a macrophage autonomous phenotype. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by cellular phenotype alterations and deposition of extracellular matrix proteins. The alternative activation of macrophages in the lungs has been associated as a major factor promoting pulmonary fibrosis, however the mechanisms underlying this phenomenon are poorly understood. In the present study, we have defined a molecular mechanism by which signals transmitted from the extracellular matrix via the alpha4beta1 integrin lead to the activation of Rac2 which regulates alternative macrophage differentiation, a signaling axis within the pulmonary macrophage compartment required for bleomycin induced pulmonary fibrosis. Mice deficient in Rac2 were protected against bleomycin-induced fibrosis and displayed diminished collagen deposition in association with lower expression of alternatively activated profibrotic macrophage markers. We have demonstrated a macrophage autonomous process by which the injection of M2 and not M1 macrophages restored the bleomycin induced pulmonary fibrosis susceptibility in Rac2-/- mice, establishing a critical role for a macrophage Rac2 signaling axis in the regulation of macrophage differentiation and lung fibrosis in vivo. We also demonstrate that markers of alternative macrophage activation are increased in patients with IPF. Taken together, these studies define an important role for an integrin-driven Rac2 signaling axis in macrophages, and reveal that Rac2 activation is required for polarization of macrophages towards a profibrotic phenotype and progression of pulmonary fibrosis in vivo. PMID- 28817693 TI - Clinical signs, profound acidemia, hypoglycemia, and hypernatremia are predictive of mortality in 1,400 critically ill neonatal calves with diarrhea. AB - Profound acidemia impairs cellular and organ function and consequently should be associated with an increased risk of mortality in critically ill humans and animals. Neonatal diarrhea in calves can result in potentially serious metabolic derangements including profound acidemia due to strong ion (metabolic) acidosis, hyper-D-lactatemia, hyper-L-lactatemia, azotemia, hypoglycemia, hyperkalemia and hyponatremia. The aim of this retrospective study was to assess the prognostic relevance of clinical and laboratory findings in 1,400 critically ill neonatal calves with diarrhea admitted to a veterinary teaching hospital. The mortality rate was 22%. Classification tree analysis indicated that mortality was associated with clinical signs of neurologic disease, abdominal emergencies, cachexia, orthopedic problems such as septic arthritis, and profound acidemia (jugular venous blood pH < 6.85). When exclusively considering laboratory parameters, classification tree analysis identified plasma glucose concentrations < 3.2 mmol/L, plasma sodium concentrations >= 151 mmol/L, serum GGT activity < 31 U/L and a thrombocyte count < 535 G/L as predictors of mortality. However, multivariable logistic regression models based on these laboratory parameters did not have a sufficiently high enough sensitivity (59%) and specificity (79%) to reliably predict treatment outcome. The sensitivity and specificity of jugular venous blood pH < 6.85 were 11% and 97%, respectively, for predicting non survival in this study population. We conclude that laboratory values (except jugular venous blood pH < 6.85) are of limited value for predicting outcome in critically ill neonatal calves with diarrhea. In contrast, the presence of specific clinical abnormalities provides valuable prognostic information. PMID- 28817695 TI - Correction: O-GlcNAcylation mediates the control of cytosolic phosphoenolpyruvate carboxykinase activity via Pgc1alpha. AB - [This corrects the article DOI: 10.1371/journal.pone.0179988.]. PMID- 28817694 TI - A new holistic 3D non-invasive analysis of cellular distribution and motility on fibroin-alginate microcarriers using light sheet fluorescent microscopy. AB - Cell interaction with biomaterials is one of the keystones to developing medical devices for tissue engineering applications. Biomaterials are the scaffolds that give three-dimensional support to the cells, and are vectors that deliver the cells to the injured tissue requiring repair. Features of biomaterials can influence the behaviour of the cells and consequently the efficacy of the tissue engineered product. The adhesion, distribution and motility of the seeded cells onto the scaffold represent key aspects, and must be evaluated in vitro during the product development, especially when the efficacy of a specific tissue engineered product depends on viable and functional cell loading. In this work, we propose a non-invasive and non-destructive imaging analysis for investigating motility, viability and distribution of Mesenchymal Stem Cells (MSCs) on silk fibroin-based alginate microcarriers, to test the adhesion capacity of the fibroin coating onto alginate which is known to be unsuitable for cell adhesion. However, in depth characterization of the biomaterial is beyond the scope of this paper. Scaffold-loaded MSCs were stained with Calcein-AM and Ethidium homodimer-1 to detect live and dead cells, respectively, and counterstained with Hoechst to label cell nuclei. Time-lapse Light Sheet Fluorescent Microscopy (LSFM) was then used to produce three-dimensional images of the entire cells-loaded fibroin/alginate microcarriers. In order to quantitatively track the cell motility over time, we also developed an open source user friendly software tool called Fluorescent Cell Tracker in Three-Dimensions (F-Tracker3D). Combining LSFM with F-Tracker3D we were able for the first time to assess the distribution and motility of stem cells in a non-invasive, non-destructive, quantitative, and three-dimensional analysis of the entire surface of the cell-loaded scaffold. We therefore propose this imaging technique as an innovative holistic tool for monitoring cell-biomaterial interactions, and as a tool for the design, fabrication and functionalization of a scaffold as a medical device. PMID- 28817696 TI - Phenotypic and molecular characterization of sweet sorghum accessions for bioenergy production. AB - Sweet sorghum [Sorghum bicolor (L.) Moench] is a type of cultivated sorghum characterized by the accumulation of high levels of sugar in the stems and high biomass accumulation, making this crop an important feedstock for bioenergy production. Sweet sorghum breeding programs that focus on bioenergy have two main goals: to improve quantity and quality of sugars in the juicy stem and to increase fresh biomass productivity. Genetic diversity studies are very important for the success of a breeding program, especially in the early stages, where understanding the genetic relationship between accessions is essential to identify superior parents for the development of improved breeding lines. The objectives of this study were: to perform phenotypic and molecular characterization of 100 sweet sorghum accessions from the germplasm bank of the Embrapa Maize and Sorghum breeding program; to examine the relationship between the phenotypic and the molecular diversity matrices; and to infer about the population structure in the sweet sorghum accessions. Morphological and agro industrial traits related to sugar and biomass production were used for phenotypic characterization, and single nucleotide polymorphisms (SNPs) were used for molecular diversity analysis. Both phenotypic and molecular characterizations revealed the existence of considerable genetic diversity among the 100 sweet sorghum accessions. The correlation between the phenotypic and the molecular diversity matrices was low (0.35), which is in agreement with the inconsistencies observed between the clusters formed by the phenotypic and the molecular diversity analyses. Furthermore, the clusters obtained by the molecular diversity analysis were more consistent with the genealogy and the historic background of the sweet sorghum accessions than the clusters obtained through the phenotypic diversity analysis. The low correlation observed between the molecular and the phenotypic diversity matrices highlights the complementarity between the molecular and the phenotypic characterization to assist a breeding program. PMID- 28817697 TI - Correction: Field-Evolved Resistance in Corn Earworm to Cry Proteins Expressed by Transgenic Sweet Corn. AB - [This corrects the article DOI: 10.1371/journal.pone.0169115.]. PMID- 28817698 TI - Correction: Enhanced Hepatogenic Transdifferentiation of Human Adipose Tissue Mesenchymal Stem Cells by Gene Engineering with Oct4 and Sox2. AB - [This corrects the article DOI: 10.1371/journal.pone.0108874.]. PMID- 28817699 TI - Cooperative dynamics of neighborhood economic status in cities. AB - We significantly extend our earlier variant of the Schelling model, incorporating a neighborhood Potential function as well as an agent wealth gain function to study the long term evolution of the economic status of neighborhoods in cities. We find that the long term patterns of neighborhood relative economic status (RES) simulated by this model reasonably replicate the empirically observed patterns from American cities. Specifically, we find that larger fractions of rich and poor neighborhoods tend to, on average, retain status for longer than lower- and upper-middle wealth neighborhoods. The use of a Potential function that measures the relative wealth of neighborhoods as the basis for agent wealth gain and agent movement appears critical to explaining these emergent patterns of neighborhood RES. This also suggests that the empirically observed RES patterns could indeed be universal and that we would expect to see these patterns repeated for cities around the world. Observing RES behavior over even longer periods of time, the model predicts that the fraction of poor neighborhoods retaining status remains almost constant over extended periods of time, while the fraction of middle-wealth and rich neighborhoods retaining status reduces significantly over time, tending to zero. PMID- 28817700 TI - The loss and recovery of vertebrate vision examined in microplates. AB - Regenerative medicine offers potentially ground-breaking treatments of blindness and low vision. However, as new methodologies are developed, a critical question will need to be addressed: how do we monitor in vivo for functional success? In the present study, we developed novel behavioral assays to examine vision in a vertebrate model system. In the assays, zebrafish larvae are imaged in multiwell or multilane plates while various red, green, blue, yellow or cyan objects are presented to the larvae on a computer screen. The assays were used to examine a loss of vision at 4 or 5 days post-fertilization and a gradual recovery of vision in subsequent days. The developed assays are the first to measure the loss and recovery of vertebrate vision in microplates and provide an efficient platform to evaluate novel treatments of visual impairment. PMID- 28817701 TI - Effect of exoskeletal joint constraint and passive resistance on metabolic energy expenditure: Implications for walking in paraplegia. AB - An important consideration in the design of a practical system to restore walking in individuals with spinal cord injury is to minimize metabolic energy demand on the user. In this study, the effects of exoskeletal constraints on metabolic energy expenditure were evaluated in able-bodied volunteers to gain insight into the demands of walking with a hybrid neuroprosthesis after paralysis. The exoskeleton had a hydraulic mechanism to reciprocally couple hip flexion and extension, unlocked hydraulic stance controlled knee mechanisms, and ankles fixed at neutral by ankle-foot orthoses. These mechanisms added passive resistance to the hip (15 Nm) and knee (6 Nm) joints while the exoskeleton constrained joint motion to the sagittal plane. The average oxygen consumption when walking with the exoskeleton was 22.5 +/- 3.4 ml O2/min/kg as compared to 11.7 +/- 2.0 ml O2/min/kg when walking without the exoskeleton at a comparable speed. The heart rate and physiological cost index with the exoskeleton were at least 30% and 4.3 times higher, respectively, than walking without it. The maximum average speed achieved with the exoskeleton was 1.2 +/- 0.2 m/s, at a cadence of 104 +/- 11 steps/min, and step length of 70 +/- 7 cm. Average peak hip joint angles (25 +/- 7 degrees ) were within normal range, while average peak knee joint angles (40 +/ 8 degrees ) were less than normal. Both hip and knee angular velocities were reduced with the exoskeleton as compared to normal. While the walking speed achieved with the exoskeleton could be sufficient for community ambulation, metabolic energy expenditure was significantly increased and unsustainable for such activities. This suggests that passive resistance, constraining leg motion to the sagittal plane, reciprocally coupling the hip joints, and weight of exoskeleton place considerable limitations on the utility of the device and need to be minimized in future designs of practical hybrid neuroprostheses for walking after paraplegia. PMID- 28817702 TI - Global gene expression analysis of the response of physic nut (Jatropha curcas L.) to medium- and long-term nitrogen deficiency. AB - Jatropha curcas L. is an important biofuel plant with excellent tolerance of barren environments. However, studies on the regulatory mechanisms that operate in this plant in response to nitrogen (N) shortage are scarce. In this study, genome-wide transcriptional profiles of the roots and leaves of 8-week old physic nut seedlings were analyzed after 2 and 16 days of N starvation. Enrichment results showed that genes associated with N metabolism, processing and regulation of RNA, and transport predominated among those showing alterations in expression. Genes encoding transporter families underwent major changes in expression in both roots and leaves; in particular, those with roles in ammonia, amino acid and peptide transport were generally up-regulated after long-term starvation, while AQUAPORIN genes, whose products function in osmoregulation, were down-regulated. We also found that ASPARA-GINASE B1 and SARCOSINE OXIDASE genes were up-regulated in roots and leaves after 2 and 16 d N starvation. Genes associated with ubiquitination-mediated protein degradation were significantly up-regulated. In addition, genes in the JA biosynthesis pathway were strongly activated while expression of those in GA signaling was inhibited in leaves. We showed that four major classes of genes, those with roles in N uptake, N reutilization, C/N ratio balance, and cell structure and synthesis, were particularly influenced by long term N limitation. Our discoveries may offer clues to the molecular mechanisms that regulate N reallocation and reutilization so as to maintain or increase plant performance even under adverse environmental conditions. PMID- 28817703 TI - Quality of life of inguinal hernia patients in Taiwan: The application of the hernia-specific quality of life assessment instrument. AB - BACKGROUND: With the development of prosthetic mesh and tension free techniques, the recurrence rate following inguinal hernia repair has been reduced, and hernia outcomes research should focus on post-operative quality of life and potential complications. STUDY DESIGN: A novel hernia quality of life assessment instrument, HERQL, was developed. The HERQL questionnaire comprises a 4-item summative pain score measuring pain and discomfort resulting from various strenuous activities. Symptomatic and functional domains, as well as post operative satisfaction are evaluated as well. RESULTS: A total of 386 HERQL surveys were completed by 183 patients with inguinal hernias. Internal consistency reliability of the summative pain score was satisfactory, with a Cronbach's alpha of 0.85. Criterion validity was examined by concomitant assessment of the pain/discomfort and health impact subscales of the EQ-5D questionnaire, with substantial to moderate correlations. Pre-operative patients reported more severe hernia protrusion, more pain during mild to heavy exercise, and worse activity restriction and health impairment than the follow-up patients, indicating clinical validity. The conceptual structure of the HERQL demostrated the causal relationship between the formative symptomatic subscales and the reflective functional status indicators. Repeated measurement of the summative pain scores revealed an estimated time effect of -1.63, which was the rate of change in the summative pain score across the pre-operative, immediately post operative, and follow-up 3-month periods suggesting the clinical responsiveness of the HERQL. CONCLUSIONS: This study will facilitate inguinal hernia outcomes research and enhance the quality of care for this common disease by providing a validated HERQL instrument with enhanced sensitivity. PMID- 28817704 TI - Analysis of multidrug resistant group B streptococci with reduced penicillin susceptibility forming small, less hemolytic colonies. AB - Group B streptococci (GBS; Streptococcus agalactiae) are the leading cause of neonatal invasive diseases and are also important pathogens for elderly adults. Until now, nearly all GBS with reduced penicillin susceptibility (PRGBS) have shown beta-hemolytic activity and grow on sheep blood agar. However, we have previously reported three PRGBS clinical isolates harboring a CylK deletion that form small less hemolytic colonies. In this study, we examined the causes of small, less hemolytic colony formation in these clinical isolates. Isogenic strains were sequenced to identify the mutation related to a small colony size. We identified a 276_277insG nucleic acid insertion in the thiamin pyrophosphokinase (tpk) gene, resulting in premature termination at amino acid 103 in TPK, as a candidate mutation responsible for small colony formation. The recombinant strain Deltatpk, which harbored the 276_277insG insertion in the tpk gene, showed small colony formation. The recombinant strain DeltacylK, which harbored the G379T substitution in cylK, showed a reduction in hemolytic activity. The phenotypes of both recombinant strains were complemented by the expression of intact TPK or CylK, respectively. Moreover, the use of Rapid ID 32 API and VITEK MS to identify strains as GBS was evaluated clinical isolates and recombinant strains. VITEK MS, but not Rapid ID 32 API, was able to accurately identify the strains as GBS. In conclusion, we determined that mutations in tpk and cylK caused small colonies and reduced hemolytic activity, respectively, and characterized the clinical isolates in detail. PMID- 28817705 TI - Cell surface dynamics and cellular distribution of endogenous FcRn. AB - A major role for FcRn is the salvage of pinocytosed IgG and albumin from a degradative fate in lysosomes. FcRn achieves this by binding IgG in a pH dependent manner in acidic endosomes and recycling it to the plasma membrane to be released at neutral pH. This is important in maintaining high serum IgG and albumin levels and has the potential to be exploited to modulate the pharmacokinetics of antibody-based therapeutics. Although FcRn is responsible for the recycling of IgG, the dynamic behaviour of endogenous FcRn is not well understood. Our data shows that the majority of endogenous receptor is distributed throughout the endosomal system and is present only at a low percentage on the plasma membrane at steady state. A significant fraction of FcRn at the cell surface appears to be endocytosis resistant while the remainder can undergo rapid endocytosis. To maintain surface levels of the receptor, endocytosed FcRn is replaced with FcRn from the internal pool. This unexpected complexity in FcRn cell surface dynamics has led us to propose a model for FcRn trafficking that should be taken into account when targeting FcRn at the cell surface for therapeutic purposes. PMID- 28817706 TI - HIV infection, antiretroviral therapy, and measures of endothelial function, inflammation, metabolism, and oxidative stress. AB - BACKGROUND: HIV-infected patients have an increased risk of cardiovascular disease (CVD). Impaired endothelial function is an early risk factor for CVD in the general population. It is presumed that HIV infection is associated with impaired endothelial function, but results have been inconsistent. OBJECTIVES: Our objectives were to determine the relationships between HIV infection, virologic suppression with antiretroviral therapy (ART), in vivo measures of conduit artery and microvascular endothelial function, and circulating biomarkers of pathways associated with CVD. METHODS: We performed a cross-sectional analysis of three prospectively enrolled groups from a single center: 28 were HIV-infected and virologically-suppressed on a regimen of FTC/TDF/EFV (HIV+ART+), 44 were HIV infected but not on ART (HIV+ART-), and 39 were HIV-uninfected healthy volunteers (HIV-) matched to the HIV+ART- group for age, sex, smoking status, and height. None had diabetes, uncontrolled hypertension, known CVD, or other pro inflammatory condition. Flow mediated dilation (FMD), nitroglycerin-mediated dilation (NTGMD), reactive hyperemia velocity time integral (RHVTI), and FMD/RHVTI of the brachial artery were measured, as well as circulating biomarkers of systemic inflammation, metabolism, oxidative stress, and endothelial activation. RESULTS: No significant differences were found amongst the three groups in FMD (P = 0.46), NTGMD (P = 0.42), RHVTI (P = 0.17), and FMD/RHVTI (P = 0.22) in unadjusted comparisons. Adjusted ANOVA models which included brachial artery diameter, demographics, and conventional CVD risk factors did not appreciably change these findings. In pairwise comparisons, the HIV+ART- group had significantly higher soluble tumor necrosis factor receptor II, soluble CD163, beta-2 microglobulin, interferon-gamma- induced protein-10, tissue inhibitor of metalloproteinase-1, and vascular cell adhesion molecule-1 compared to the other two groups (all p<0.05). Correlates of endothelial function differed between study groups. CONCLUSION: Although untreated HIV infection was associated with elevated levels of several biomarkers of inflammation and endothelial activation, we were unable to demonstrate differences in measures of conduit artery and microvascular endothelial function in this study population. PMID- 28817708 TI - Timing and extent of finger force enslaving during a dynamic force task cannot be explained by EMG activity patterns. AB - Finger enslaving is defined as the inability of the fingers to move or to produce force independently. Such finger enslaving has predominantly been investigated for isometric force tasks. The aim of this study was to assess whether the extent of force enslaving is dependent on relative finger movements. Ten right-handed subjects (22-30 years) flexed the index finger while counteracting constant resistance forces (4, 6 and 8 N) orthogonal to the fingertip. The other, non instructed fingers were held in extension. EMG activities of the mm. flexor digitorum superficialis (FDS) and extensor digitorum (ED) in the regions corresponding to the index, middle and ring fingers were measured. Forces exerted by the non-instructed fingers increased substantially (by 0.2 to 1.4 N) with flexion of the index finger, increasing the enslaving effect with respect to the static, pre-movement phase. Such changes in force were found 260-370 ms after the initiation of index flexion. The estimated MCP joint angle of the index finger at which forces exerted by the non-instructed fingers started to increase varied between 4 degrees and 6 degrees . In contrast to the finger forces, no significant changes in EMG activity of the FDS regions corresponding to the non instructed fingers upon index finger flexion were found. This mismatch between forces and EMG of the non-instructed fingers, as well as the delay in force development are in agreement with connective tissue linkages being slack when the positions of the fingers are similar, but pulled taut when one finger moves relative to the others. Although neural factors cannot be excluded, our results suggest that mechanical connections between muscle-tendon structures were (at least partly) responsible for the observed increase in force enslaving during index finger flexion. PMID- 28817707 TI - Microbiome-mediated neutrophil recruitment via CXCR2 and protection from amebic colitis. AB - The disease severity of Entamoeba histolytica infection ranges from asymptomatic to life-threatening. Recent human and animal data implicate the gut microbiome as a modifier of E. histolytica virulence. Here we have explored the association of the microbiome with susceptibility to amebiasis in infants and in the mouse model of amebic colitis. Dysbiosis occurred symptomatic E. histolytica infection in children, as evidenced by a lower Shannon diversity index of the gut microbiota. To test if dysbiosis was a cause of susceptibility, wild type C57BL/6 mice (which are innately resistant to E. histiolytica infection) were treated with antibiotics prior to cecal challenge with E. histolytica. Compared with untreated mice, antibiotic pre-treated mice had more severe colitis and delayed clearance of E. histolytica. Gut IL-25 and mucus protein Muc2, both shown to provide innate immunity in the mouse model of amebic colitis, were lower in antibiotic pre treated mice. Moreover, dysbiotic mice had fewer cecal neutrophils and myeloperoxidase activity. Paradoxically, the neutrophil chemoattractant chemokines CXCL1 and CXCL2, as well as IL-1beta, were higher in the colon of mice with antibiotic-induced dysbiosis. Neutrophils from antibiotic pre-treated mice had diminished surface expression of the chemokine receptor CXCR2, potentially explaining their inability to migrate to the site of infection. Blockade of CXCR2 increased susceptibility of control non-antibiotic treated mice to amebiasis. In conclusion, dysbiosis increased the severity of amebic colitis due to decreased neutrophil recruitment to the gut, which was due in part to decreased surface expression on neutrophils of CXCR2. PMID- 28817709 TI - Assessment of physicians' awareness and knowledge of familial hypercholesterolemia in Saudi Arabia: Is there a gap? AB - BACKGROUND: The scarcity of familial hypercholesterolemia (FH) cases reported in Saudi Arabia might be indicative of a lack of awareness of this common genetic disease among physicians. OBJECTIVE: To assess physicians' awareness, practice, and knowledge of FH in Saudi Arabia. METHODS: This is a cross-sectional study conducted among physicians at four tertiary hospitals in Riyadh, Saudi Arabia between March 2016 and May 2016 using a self-administered questionnaire. RESULTS: A total of 294 physicians completed the survey (response rate 90.1%). Overall, 92.9% of the participants have poor knowledge of FH while only 7.1% have acceptable knowledge. The majority (68.7%) of physicians rated their familiarity with FH as average or above average, and these had higher mean knowledge scores than participants with self-reported below average familiarity (mean 3.4 versus 2.6) (P < 0.001). Consultant physicians were 4.2 times more likely to be familiar with FH than residents or registrars (OR = 4.2, 95% CI = 1.9-9.1, P < 0.001). Physicians who currently managed FH patients had higher mean knowledge scores compared to those without FH patients in their care (3.5 versus 2.9) (P = 0.006). In addition, there were statistically significant differences between physicians' mean knowledge scores and their ages, levels of training, and years in practice. Moreover, a substantial deficit was identified in the awareness of various clinical algorithms to diagnose patients with FH, cascade screening, specialist lipid services, and the existence of statin alternatives, such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. CONCLUSION: A substantial deficit was found in the awareness, knowledge, practice, and detection of FH among physicians in Saudi Arabia. Extensive educational programs are required to raise physician awareness and implement best practices; only then can the impact of these interventions on FH management and patient outcome be assessed. PMID- 28817710 TI - Excessive use of WeChat, social interaction and locus of control among college students in China. AB - In China, the number of college students using mobile phone based messaging and social networking applications like WeChat is increasing rapidly. However, there has been minimal research into the addictive nature of these applications and the psychological characteristics associate with their excessive use. There is also no published scale available for assessing excessive use of WeChat and similar applications. In the current study, we collected data from 1,245 college students in China (715 females) and developed the WeChat Excessive Use Scale (WEUS). We then assessed the relationship between excessive use of WeChat and excessive use of a social networking application-Weibo, problematic use of mobile phones, external locus of control, and social interaction skills. Our 10-item scale featured three factors, namely- "mood modification," "salience" and ''conflict"- critical factors in assessing different forms of addiction. The WEUS was found to be a reliable instrument in assessing excessive use of WeChat as it showed good internal consistency and correlated with other measures of problematic use social networking and mobile phone addiction. Our results showed that excessive users of WeChat are more likely to excessively use Weibo than they are to problematically use mobile phones. Our study also showed that greater excessive use of WeChat is associated with higher external locus of control and greater online social interaction skills. These results reveal that WeChat has unique and strong appeal among college students in China. Further, practitioners should consider dealing with malleable factors like locus of control and real life social skills in treating people with problematic messaging and social networking. PMID- 28817711 TI - On-chip detection of gel transition temperature using a novel micro thermomechanical method. AB - We present a new thermomechanical method and a platform to measure the phase transition temperature at microscale. A thin film metal sensor on a membrane simultaneously measures both temperature and mechanical strain of the sample during heating and cooling cycles. This thermomechanical principle of operation is described in detail. Physical hydrogel samples are prepared as a disc-shaped gels (200 MUm thick and 1 mm diameter) and placed between an on-chip heater and sensor devices. The sol-gel transition temperature of gelatin solution at various concentrations, used as a model physical hydrogel, shows less than 3% deviation from in-depth rheological results. The developed thermomechanical methodology is promising for precise characterization of phase transition temperature of thermogels at microscale. PMID- 28817712 TI - Study of the cross-market effects of Brexit based on the improved symbolic transfer entropy GARCH model-An empirical analysis of stock-bond correlations. AB - In this paper, we study the cross-market effects of Brexit on the stock and bond markets of nine major countries in the world. By incorporating information theory, we introduce the time-varying impact weights based on symbolic transfer entropy to improve the traditional GARCH model. The empirical results show that under the influence of Brexit, flight-to-quality not only commonly occurs between the stocks and bonds of each country but also simultaneously occurs among different countries. We also find that the accuracy of the time-varying symbolic transfer entropy GARCH model proposed in this paper has been improved compared to the traditional GARCH model, which indicates that it has a certain practical application value. PMID- 28817713 TI - L-type lectin receptor kinases: New forces in plant immunity. PMID- 28817714 TI - Insights into secular trends of respiratory tuberculosis: The 20th century Maltese experience. AB - Over half a century ago, McKeown and colleagues proposed that economics was a major contributor to the decline of infectious diseases, including respiratory tuberculosis, during the 19th and 20th centuries. Since then, there is no consensus among researchers as to the factors responsible for the mortality decline. Using the case study of the islands of Malta and Gozo, we examine the relationship of economics, in particular, the cost of living (Fisher index) and its relationship to the secular trends of tuberculosis mortality. Notwithstanding the criticism that has been directed at McKeown, we present results that improvement in economics is the most parsimonious explanation for the decline of tuberculosis mortality. We reaffirmed that the reproductively aged individuals were most at risk of dying of tuberculosis, seeing that 70 to 90% of all deaths due to tuberculosis occurred between the ages of 15 and 45. There was a clear sex differential in deaths in that, prior to 1930, rates in females were generally higher than males. During times of extreme hardship, the sex differential was exacerbated. Over the course of World War I, the sex gap in tuberculosis rates increased until peaking in 1918 when there was also the influenza pandemic. The heightened differential was most likely a result of gendered roles as opposed to biological differences since female tuberculosis rates again surpassed male rates in 1945 during World War II. Respiratory tuberculosis in both urban and rural settlements (in Malta proper) was significantly influenced by the Fisher index, which explains approximately 61% of the variation in TB death rates (R = 0.78; p<0.0001). In Gozo, there was no significant impact on respiratory tuberculosis (R = 0.23; p = 0.25), most likely a consequence of the island's isolation, a self sufficient economy and limited exposure to tuberculosis. PMID- 28817715 TI - Longitudinal sequencing in intramuscular coordination: A new hypothesis of dynamic functions in the human rectus femoris muscle. AB - The punctum fixum-punctum mobile model has been introduced in previous publications. It describes general principles of intersegmental neuromuscular succession patterns to most efficiently generate specific movement intentions. The general hypothesis of this study is that these principles-if they really do indicate a fundamental basis for efficient movement generation-should also be found in intramuscular coordination and should be indicated by "longitudinal sequencing" between fibers according to the principles of the punctum fixum punctum mobile model. Based on this general hypothesis an operationalized model was developed for the rectus femoris muscle (RF), to exemplarily scrutinize this hypothesis for the RF. Electromyography was performed for 14 healthy male participants by using two intramuscular fine wire electrodes in the RF (placed proximal and distal), three surface electrodes over the RF (placed proximal, middle, and distal), and two surface electrodes over the antagonists (m. biceps femoris and m. semitendinosus). Three movement tasks were measured: kicking movements; deceleration after sprints; and passively induced backward accelerations of the leg. The results suggest that proximal fibers can be activated independently from distal fibers within the RF. Further, it was shown that the hypothesized function of "intramuscular longitudinal sequencing" does exist during dynamic movements. According to the punctum fixum-punctum mobile model, the activation succession between fibers changes direction (from proximal to distal or inversely) depending on the intentional context. Thus, the results seem to support the general hypothesis for the RF and could be principally in line with the operationalized "inter-fiber to tendon interaction model". PMID- 28817716 TI - Endothelial dysfunction in renal arcuate arteries of obese Zucker rats: The roles of nitric oxide, endothelium-derived hyperpolarizing factors, and calcium activated K+ channels. AB - The roles of nitric oxide (NO), endothelium-derived hyperpolarizing factors (EDHF), and calcium-activated K+ (KCa) channels in diabetes-associated endothelial dysfunction of small renal arteries are not clear. The present study investigated acetylcholine (ACh)-induced vasorelaxation of renal arcuate arteries from obese Zucker (OZ) rats at different diabetes durations, and the relative contribution of NO, EDHF, and KCa channels to the endothelial dysfunction. OZ rats of 7 weeks (prediabetic stage), 12 weeks (early diabetic stage), and 20 weeks (late diabetic stage), and time-matched lean control rats, were studied. Segments of arcuate arteries (130 to 180 MUm) were isolated, cannulated and pressurized. Vascular endothelial functions were tested using ACh-induced vasodilation. Our experiments demonstrated: (1) ACh-elicited vasodilation was impaired in OZ rats of 20 weeks, but not in rats of 7 and 12 weeks; (2) inhibition of NO or EDHF (contributed by epoxyeicosatrienoic acids [EETs]) production significantly decreased ACh-induced vasodilation in both lean and OZ rats of 20 weeks. The reduction of ACh-induced vasodilation by inhibition of NO or EDHF formation was less in OZ rats, as compared to lean rats; and (3) inhibition of KCa channels markedly reduced ACh-induced vasodilation in lean control rats, but not in OZ rats of 20 weeks. Our observations indicated that endothelium-dependent vasodilation in renal arcuate arteries is impaired in diabetes mellitus; NO and EDHF, mainly EETs, dominate the ACh-induced vasodilation in renal arcuate arteries; the contribution of NO and EETs is impaired in diabetic rats; KCa channels are involved in ACh-induced vasodilation; and the activity of KCa channels is downregulated in diabetes mellitus. PMID- 28817717 TI - Short Report: TRPV1-polymorphism 1911 A>G alters capsaicin-induced sensory changes in healthy subjects. AB - BACKGROUND: C-fibers express transient receptor potential (TRP) channels. These high-voltage gated channels function as integrators of different physical stresses (e.g. heat, protons, ATP). Additionally channel activation can be induced by capsaicin. Topically applied, capsaicin elicits burning pain, heat and mechanical hyperalgesia and serves as a human surrogate model for pain. It was suggested that the TRPV1-variant rs8065080 (1911A>G) plays a pivotal role in patients with neuropathic pain syndromes. We investigated the effect of this TRPV1-SNP on thermal sensitivity and superficial skin perfusion in 25 healthy subjects. METHODS AND FINDINGS: Nine subjects being homozygous TRPV1 wild type (AA), 8 heterozygous (AG) and 8 homozygous variant (GG) carriers were selected out of a pool of genotyped healthy individuals. Under physiological conditions (no capsaicin application), there was no statistical significant difference in thermal thresholds or skin perfusion between carriers of different TRPV1 1199A>G genotypes. However, intra-individual calculations (Delta% pre vs. post capsaicin) revealed (1) less warm-detection in AA/AG (-82.1%) compared to GG (-13.1%) and (2) a gain of heat pain sensitivity in AA/AG (+22.2%) compared to GG carriers (+15.6%) after adjustment for perfusion measurements ((1)p = 0.009, (2)p = 0.021). CONCLUSION: Presence of homozygous variant TRPV1 genotype (GG) demonstrated less capsaicin-induced warm hypoesthesia in warm-detection and less capsaicin-induced heat pain sensitivity suggesting an altered channel function. This demonstrates not only the functional influence of TRPV1 rs8065080 polymorphism itself; it further more underpins the relevance of genotyping-based approaches in both patients and surrogate models of neuropathic pain in healthy volunteers. PMID- 28817718 TI - Elevated carboxylesterase activity contributes to the lambda-cyhalothrin insensitivity in quercetin fed Helicoverpa armigera (Hubner). AB - Quercetin as one of the key plant secondary metabolite flavonol is ubiquitous in terrestrial plants. In this study, the decrease in sensitivity to lambda cyhalothrin was observed in quercetin-fed Helicoverpa armigera larvae. In order to figure out the mechanisms underlying the decreased sensitivity of H. armigera larvae to lambda-cyhalothrin by quercetin induction, the changes in carboxylesterase activity and in-vitro hydrolytic metabolic capacity to lambda cyhalothrin were examined. The LC50 value of quercetin-fed H. armigera larvae to lambda-cyhalothrin showed 2.41-fold higher than that of the control. S, S, S Tributyl phosphorotrithioate (DEF) treatment showed a synergism effect on lambda cyhalothrin toxicity to quercetin-fed H. armigera. Moreover, the activity of carboxylesterase was significantly higher in quercetin-fed H. armigera larvae after fed on quercetin for 48 h. The in-vitro hydrolytic metabolic capacity to lambda-cyhalothrin in quercetin-fed H. armigera larvae midgut was 289.82 nmol 3 PBA/mg protein/min, which is significant higher than that in the control group (149.60 nmol 3-PBA/mg protein/min). The elevated CarE enzyme activity and corresponding increased hydrolytic metabolic capacity to lambda-cyhalothrin in quercetin-fed H. armigera contributed to the enhanced tolerance to lambda cyhalothrin. PMID- 28817719 TI - T cell expression of IL-18R and DR3 is essential for non-cognate stimulation of Th1 cells and optimal clearance of intracellular bacteria. AB - Th1 cells can be activated by TCR-independent stimuli, but the importance of this pathway in vivo and the precise mechanisms involved require further investigation. Here, we used a simple model of non-cognate Th1 cell stimulation in Salmonella-infected mice to examine these issues. CD4 Th1 cell expression of both IL-18R and DR3 was required for optimal IFN-gamma induction in response to non-cognate stimulation, while IL-15R expression was dispensable. Interestingly, effector Th1 cells generated by immunization rather than live infection had lower non-cognate activity despite comparable IL-18R and DR3 expression. Mice lacking T cell intrinsic expression of MyD88, an important adapter molecule in non-cognate T cell stimulation, exhibited higher bacterial burdens upon infection with Salmonella, Chlamydia or Brucella, suggesting that non-cognate Th1 stimulation is a critical element of efficient bacterial clearance. Thus, IL-18R and DR3 are critical players in non-cognate stimulation of Th1 cells and this response plays an important role in protection against intracellular bacteria. PMID- 28817721 TI - Stable isotopes in tissues discriminate the diet of free-living wild boar from different areas of central Italy. AB - The use of isotopic signatures in animal tissues provides information on the environment where they are living and, notably, on their diet. Carbon and, whenever possible, nitrogen stable isotope analyses were performed in animal hairs, muscles and fat. Particularly, we analyzed both carbon and nitrogen isotopic compositions (delta13C and delta15N) on wild boar samples across three different areas of central Italy (Latium region): Tyrrhenian Coast (TC), Maremma (MA) and Central Plains (CP). The agricultural habits of these areas imply that, in winter, no crops are available for wild boars, which feed mainly on acorns and natural feeds (tubers, earthworms etc.). In addition, the three areas were influenced by oak masting. One of these areas (CP) was characterised by the spreading of corn during the hunting season to attract the animals. For each area, we sampled 10 animals aged between 12 and 24 months and balanced by gender. Anenrichment of delta13C in CP area, where corn was used, was observed in all the analysed tissues in comparison to other areas (MA and TC). In CP area, enriched values of delta15N were also observed in all the tissues. The research demonstrates that both delta13C anddelta15N in free-living wild boar tissues are influenced by sampling area. According to feeding habits of the species and wildlife management (feed supplementation), the differences observed in delta13C and delta15Nare based on the specific feeding regime; particularly the use of corn in wintertime. Furthermore, the research highlights and discusses diversities and relationships among delta13C and delta15N in the hair, fat and muscles of free-living wild boar. PMID- 28817720 TI - Targeting of CDK9 with indirubin 3'-monoxime safely and durably reduces HIV viremia in chronically infected humanized mice. AB - Successful propagation of HIV in the human host requires entry into a permissive cell, reverse transcription of viral RNA, integration into the human genome, transcription of the integrated provirus, and assembly/release of new virus particles. Currently, there are antiretrovirals against each of these viral steps, except for provirus transcription. An inhibitor of HIV transcription could both increase potency of treatment and suppress drug-resistant strains. Cellular cyclin-dependent kinase 9 (CDK9) serves as a cofactor for the HIV Tat protein and is required for effective transcription of the provirus. Previous studies have shown that the CDK9 inhibitor Indirubin 3'-monoxime (IM) inhibits HIV transcription in vitro and in short-term in vivo studies of HIV acute infection in humanized mice (PBMC-NSG model), suggesting a therapeutic potential. The objective of this study is to evaluate the toxicity, pharmacokinetics and long term antiviral activity of IM during chronic HIV infection in humanized mice (HSC NSG model). We show that IM concentrations above EC50 values are rapidly achieved and sustained for > 3 h in plasma, and that non-toxic concentrations durably reduce HIV RNA levels. In addition, IM enhanced the antiviral activity of antiretrovirals from the reverse transcriptase, protease and integrase inhibitor classes in in vitro infectivity assays. In summary, IM may enhance current antiretroviral treatments and could help achieve a "functional cure" in HIV patients by preventing expression of proviruses. PMID- 28817722 TI - Nicotinamide alone accelerates the conversion of mouse embryonic stem cells into mature neuronal populations. AB - INTRODUCTION: Vitamin B3 has been shown to play an important role during embryogenesis. Specifically, there is growing evidence that nicotinamide, the biologically active form of vitamin B3, plays a critical role as a morphogen in the differentiation of stem cells to mature cell phenotypes, including those of the central nervous system (CNS). Detailed knowledge of the action of small molecules during neuronal differentiation is not only critical for uncovering mechanisms underlying lineage-specification, but also to establish more effective differentiation protocols to obtain clinically relevant cells for regenerative therapies for neurodegenerative conditions such as Huntington's disease (HD). Thus, this study aimed to investigate the potential of nicotinamide to promote the conversion of stem cells to mature CNS neurons. METHODS: Nicotinamide was applied to differentiating mouse embryonic stem cells (mESC; Sox1GFP knock-in 46C cell line) during their conversion towards a neural fate. Cells were assessed for changes in their proliferation, differentiation and maturation; using immunocytochemistry and morphometric analysis methods. RESULTS: Results presented indicate that 10 mM nicotinamide, when added at the initial stages of differentiation, promoted accelerated progression of ESCs to a neural lineage in adherent monolayer cultures. By 14 days in vitro (DIV), early exposure to nicotinamide was shown to increase the numbers of differentiated betaIII-tubulin positive neurons. Nicotinamide decreased the proportion of pluripotent stem cells, concomitantly increasing numbers of neural progenitors at 4 DIV. These progenitors then underwent rapid conversion to neurons, observed by a reduction in Sox 1 expression and decreased numbers of neural progenitors in the cultures at 14 DIV. Furthermore, GABAergic neurons generated in the presence of nicotinamide showed increased maturity and complexity of neurites at 14 DIV. Therefore, addition of nicotinamide alone caused an accelerated passage of pluripotent cells through lineage specification and further to non-dividing mature neurons. CONCLUSIONS: Our results show that, within an optimal dose range, nicotinamide is able to singly and selectively direct the conversion of embryonic stem cells to mature neurons, and therefore may be a critical factor for normal brain development, thus supporting previous evidence of the fundamental role of vitamins and their metabolites during early CNS development. In addition, nicotinamide may offer a simple effective supplement to enhance the conversion of stem cells to clinically relevant neurons. PMID- 28817723 TI - Sequence analysis of the rifampicin resistance determining region (RRDR) of rpoB gene in multidrug resistance confirmed and newly diagnosed tuberculosis patients of Punjab, Pakistan. AB - Molecular screening of new patients suspected for TB could help in the effective control of TB in Pakistan as it is a high TB burden country. It will be informative to understand the prevalence of multi drug resistance for a better drug regimen management in this geographical area. The Rifampicin resistance determining region (RRDR) sequencing was used to identify mutations associated with drug resistance in DNA extracts from 130 known multidrug resistant (MDR) cultured strains and compared with mutations observed in DNA extracts directly from 86 sputum samples from consecutive newly diagnosed cases in Lahore, Pakistan. These newly diagnosed samples were positive for smear microscopy, chest X-ray and presumed sensitive to first line drugs. In the known MDR group the most frequent mutations conferring resistance were found in rpoB531 (n = 51, 39.2%). In the newly diagnosed tuberculosis group with no history of MDR, mutations in rpoB531 were seen in 10 of the samples (11.6%). Collectively, all mutations in the RRDR region studied were observed in 80 (61.5%) of known MDR cases and in 14 (16.3%) of the newly diagnosed cases. Using the RRDR as a surrogate marker for MDR, sequences for the newly diagnosed (presumed sensitive) group indicate much higher levels of MDR than the 3.9% WHO 2015 global estimate and suggests that molecular screening directly from sputum is urgently required to effectively address the detection and treatment gaps to combat MDR in this high burden country. PMID- 28817724 TI - From the animal house to the field: Are there consistent individual differences in immunological profile in wild populations of field voles (Microtus agrestis)? AB - Inbred mouse strains, living in simple laboratory environments far removed from nature, have been shown to vary consistently in their immune response. However, wildlife populations are typically outbreeding and face a multiplicity of challenges, parasitological and otherwise. In this study we seek evidence of consistent difference in immunological profile amongst individuals in the wild. We apply a novel method in this context, using longitudinal (repeated capture) data from natural populations of field voles, Microtus agrestis, on a range of life history and infection metrics, and on gene expression levels. We focus on three immune genes, IFN-gamma, Gata3, and IL-10, representing respectively the Th1, Th2 and regulatory elements of the immune response. Our results show that there was clear evidence of consistent differences between individuals in their typical level of expression of at least one immune gene, and at most all three immune genes, after other measured sources of variation had been taken into account. Furthermore, individuals that responded to changing circumstances by increasing expression levels of Gata3 had a correlated increase in expression levels of IFN-gamma. Our work stresses the importance of acknowledging immunological variation amongst individuals in studies of parasitological and infectious disease risk in wildlife populations. PMID- 28817725 TI - Development of a psychological intervention for fatigue after stroke. AB - BACKGROUND AND AIM: Post-stroke fatigue (PSF) is common and distressing, but there is insufficient evidence to recommend any effective treatment for it. Psychological interventions are effective in treating fatigue in other conditions. This paper describes the development and evaluation of the feasibility of a psychological intervention for PSF. METHODS: Based on psychological correlates of PSF and evidence-based psychological interventions for fatigue in other medical conditions, we developed a manualised psychological intervention for PSF, with input from stroke clinicians, psychological therapists, and stroke survivors. The intervention was delivered by a clinical psychologist to 12 participants with PSF to test its acceptability and feasibility. According to the feedback from participants and therapists, the intervention was refined for future use. RESULTS: The intervention consisted of six individual, face-to-face treatment sessions, and one follow-up, telephone delivered booster session. It included psycho-education and discussion of strategies to promote physical and social activities and to challenge unhelpful thoughts. Four participants dropped out and the remaining eight participants completed the intervention. These eight participants also completed all assessments and feedback and reported fatigue levels as lower at the end of the study than at the baseline. All participants reported favourable opinions on the intervention and suggested that the last two treatment sessions be combined and the booster session be delivered in person as opposed to telephone. CONCLUSIONS: This psychological intervention was acceptable to stroke patients and was feasible in the local health service. These findings suggest that a randomised controlled trial to test efficacy is warranted. PMID- 28817726 TI - Evaluation of peptide designing strategy against subunit reassociation in mucin 1: A steered molecular dynamics approach. AB - Subunit reassociation in mucin 1, a breast cancer tumor marker, is reported as one of the critical factors for its cytoplasmic activation. Inhibition of its heterodimeric association would therefore result in loss of its function and alter disease progression. The present study aimed at evaluating peptide inhibitor designing strategies that may serve as antagonist against this receptor ligand alliance. Several peptides and their derivatives were designed based on native residues, subunit interface, hydrogen bonding and secondary structure. Docking studies with the peptides were carried on the receptor subunit and their binding affinities were evaluated using steered molecular dynamics simulation and umbrella sampling. Our results showed that among all the different classes of peptides evaluated, the receptor based peptide showed the highest binding affinity. This result was concurrent with the experimental observation that the receptor-ligand alliance in mucin 1 is highly specific. Our results also show that peptide ligand against this subunit association is only stabilized through native residue inter-protein interaction irrespective of the peptide structure, peptide length and number of hydrogen bonds. Consistency in binding affinity, pull force and free energy barrier was observed with only the receptor derived peptides which resulted in favorable interprotein interactions at the interface. Several observations were made and discussed which will eventually lead to designing efficient peptide inhibitors against mucin 1 heterodimeric subunit reassociation. PMID- 28817727 TI - Pilot study of lithium to restore intestinal barrier function in severe graft versus-host disease. AB - : Severe intestinal graft-vs-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) causes mucosal ulceration and induces innate and adaptive immune responses that amplify and perpetuate GVHD and the associated barrier dysfunction. Pharmacological agents to target mucosal barrier dysfunction in GVHD are needed. We hypothesized that induction of Wnt signaling by lithium, an inhibitor of glycogen synthase kinase (GSK3), would potentiate intestinal crypt proliferation and mucosal repair and that inhibition of GSK3 in inflammatory cells would attenuate the deregulated inflammatory response to mucosal injury. We conducted an observational pilot study to provide data for the potential design of a randomized study of lithium. Twenty patients with steroid refractory intestinal GVHD meeting enrollment criteria were given oral lithium carbonate. GVHD was otherwise treated per current practice, including 2 mg/kg per day of prednisone equivalent. Seventeen patients had extensive mucosal denudation (extreme endoscopic grade 3) in the duodenum or colon. We observed that 8 of 12 patients (67%) had a complete remission (CR) of GVHD and survived more than 1 year (median 5 years) when lithium administration was started promptly within 3 days of endoscopic diagnosis of denuded mucosa. When lithium was started promptly and less than 7 days from salvage therapy for refractory GVHD, 8 of 10 patients (80%) had a CR and survived more than 1 year. In perspective, a review of 1447 consecutive adult HCT patients in the preceding 6 years at our cancer center showed 0% one-year survival in 27 patients with stage 3-4 intestinal GVHD and grade 3 endoscopic appearance in the duodenum or colon. Toxicities included fatigue, somnolence, confusion or blunted affect in 50% of the patients. The favorable outcomes in patients who received prompt lithium therapy appear to support the future conduct of a randomized study of lithium for management of severe GVHD with extensive mucosal injury. TRIAL REGISTRATION: ClinicalTrials.gov NCT00408681. PMID- 28817728 TI - Evaluation of reference genes for reverse transcription quantitative real-time PCR (RT-qPCR) studies in Silene vulgaris considering the method of cDNA preparation. AB - Accurate gene expression measurements are essential in studies of both crop and wild plants. Reverse transcription quantitative real-time PCR (RT-qPCR) has become a preferred tool for gene expression estimation. A selection of suitable reference genes for the normalization of transcript levels is an essential prerequisite of accurate RT-qPCR results. We evaluated the expression stability of eight candidate reference genes across roots, leaves, flower buds and pollen of Silene vulgaris (bladder campion), a model plant for the study of gynodioecy. As random priming of cDNA is recommended for the study of organellar transcripts and poly(A) selection is indicated for nuclear transcripts, we estimated gene expression with both random-primed and oligo(dT)-primed cDNA. Accordingly, we determined reference genes that perform well with oligo(dT)- and random-primed cDNA, making it possible to estimate levels of nucleus-derived transcripts in the same cDNA samples as used for organellar transcripts, a key benefit in studies of cyto-nuclear interactions. Gene expression variance was estimated by RefFinder, which integrates four different analytical tools. The SvACT and SvGAPDH genes were the most stable candidates across various organs of S. vulgaris, regardless of whether pollen was included or not. PMID- 28817729 TI - Comparison of bioimpedance spectroscopy and X-Ray micro-computed tomography for total fat volume measurement in mice. AB - Obesity and the metabolic syndrome are two pathologies whose prevalence are in a constant increase. Evaluation of the total fat mass but also of the distribution between visceral and subcutaneous adipose tissue are important factors while assessing the pathophysiology of these two pathologies. Computed tomography (CT) and bioimpedance (BIS) are the translational methods the most frequently used in human beings as well as in rodent models in longitudinal studies on adiposity and obesity. Surprisingly, no direct comparison of micro-CT and BIS was reported yet in mice. Therefore, the present study was carried out to evaluate and compare the accuracy and the uncertainty of measurement of micro-CT and BIS in this species. The proportion of fat mass was measured with BIS, micro-CT and direct post-mortem tissue weight, and correlations between the data were established to evaluate the accuracy of the methods but also the uncertainty of BIS and micro-CT. There were significant correlations between weights of fat tissues on scale and proportion of total fat mass determined by BIS or micro-CT (r = 0.81 and 0.86 respectively) but both methods overestimated the total fat mass, especially in the smallest animals; overestimation of fat mass was amplified with BIS compared to micro-CT. In addition BIS and micro-CT were highly correlated (r = 0.94). Test-test reliability showed a greater variability of the BIS with respect to the micro-CT (coefficient of variation = 17.2 vs 5.6% respectively). Hence, as far as subtle differences between groups or changes within one group are awaited, micro-CT may appear as the most reliable method for determination of fat mass in mice. Micro CT, unlike BIS, will also allow to qualitatively and quantitatively differentiate between subcutaneous and visceral adipose tissues, which is of major importance in studies on adiposity and its complications. PMID- 28817731 TI - Wave energy resource of Brazil: An analysis from 35 years of ERA-Interim reanalysis data. AB - This paper presents a characterization of the wave power resource and an analysis of the wave power output for three (AquaBuoy, Pelamis and Wave Dragon) different wave energy converters (WEC) over the Brazilian offshore. To do so it used a 35 years reanalysis database from the ERA-Interim project. Annual and seasonal statistical analyzes of significant height and energy period were performed, and the directional variability of the incident waves were evaluated. The wave power resource was characterized in terms of the statistical parameters of mean, maximum, 95th percentile and standard deviation, and in terms of the temporal variability coefficients COV, SV e MV. From these analyses, the total annual wave power resource available over the Brazilian offshore was estimated in 89.97 GW, with largest mean wave power of 20.63 kW/m in the southernmost part of the study area. The analysis of the three WEC was based in the annual wave energy output and in the capacity factor. The higher capacity factor was 21.85% for Pelamis device at the southern region of the study area. PMID- 28817730 TI - New approach to generating insights for aging research based on literature mining and knowledge integration. AB - The proportion of the elderly population in most countries worldwide is increasing dramatically. Therefore, social interest in the fields of health, longevity, and anti-aging has been increasing as well. However, the basic research results obtained from a reductionist approach in biology and a bioinformatic approach in genome science have limited usefulness for generating insights on future health, longevity, and anti-aging-related research on a case by case basis. We propose a new approach that uses our literature mining technique and bioinformatics, which lead to a better perspective on research trends by providing an expanded knowledge base to work from. We demonstrate that our approach provides useful information that deepens insights on future trends which differs from data obtained conventionally, and this methodology is already paving the way for a new field in aging-related research based on literature mining. One compelling example of this is how our new approach can be a useful tool in drug repositioning. PMID- 28817732 TI - Enhanced inflammation in New Zealand white rabbits when MERS-CoV reinfection occurs in the absence of neutralizing antibody. AB - The Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic betacoronavirus that was first detected in humans in 2012 as a cause of severe acute respiratory disease. As of July 28, 2017, there have been 2,040 confirmed cases with 712 reported deaths. While many infections have been fatal, there have also been a large number of mild or asymptomatic cases discovered through monitoring and contact tracing. New Zealand white rabbits are a possible model for asymptomatic infection with MERS-CoV. In order to discover more about non lethal infections and to learn whether a single infection with MERS-CoV would protect against reinfection, we inoculated rabbits with MERS-CoV and monitored the antibody and inflammatory response. Following intranasal infection, rabbits developed a transient dose-dependent pulmonary infection with moderately high levels of viral RNA, viral antigen, and perivascular inflammation in multiple lung lobes that was not associated with clinical signs. The rabbits developed antibodies against viral proteins that lacked neutralizing activity and the animals were not protected from reinfection. In fact, reinfection resulted in enhanced pulmonary inflammation, without an associated increase in viral RNA titers. Interestingly, passive transfer of serum from previously infected rabbits to naive rabbits was associated with enhanced inflammation upon infection. We further found this inflammation was accompanied by increased recruitment of complement proteins compared to primary infection. However, reinfection elicited neutralizing antibodies that protected rabbits from subsequent viral challenge. Our data from the rabbit model suggests that people exposed to MERS-CoV who fail to develop a neutralizing antibody response, or persons whose neutralizing antibody titers have waned, may be at risk for severe lung disease on re-exposure to MERS-CoV. PMID- 28817733 TI - Changing patterns of cataract services in North-West Nigeria: 2005-2016. AB - PURPOSE: This study was conducted to assess the impact of the eye care programme on cataract blindness and cataract surgical services in Sokoto, Nigeria over a 12 year period 2005-2016. METHODS: Data from the 2005 population based cross sectional study of blindness in Sokoto state was re-analysed to obtain baseline estimates of the prevalence of cataract blindness and cataract surgical coverage for persons 50 years and over in Wurno health zone. A population based survey of a representative sample of persons 50 years and over in Wurno health zone was conducted in July 2016. Data on eye health workforce, infrastructure and cataract surgical services between 2005 and 2016 were analysed from relevant documents. RESULTS: In 2005 the unadjusted prevalence of bilateral cataract blindness (<3/60) in people 50 years and over in Wurno health zone was 5.6% (95% CI: 3.1, 10.1). By 2016 this had fallen to 2.1% (95% CI 1.5%, 2.7%), with the age-sex adjusted prevalence being 1.9% (95% CI 1.3%, 2.5%). The CSC for persons with visual acuity <3/60, <6/60, <6/18 for Wurno health zone was 9.1%, 7.1% and 5.5% respectively in 2005 and this had increased to 67.3%, 62.1% and 34.7% respectively in 2016. The CSR in Sokoto state increased from 272 (1005 operations) in 2006, to 596 (2799 operations) in 2014. In the 2005 survey, couching (a procedure used by traditional practitioners to dislocate the lens into the vitreous cavity) accounted for 87.5% of all cataract interventions, compared to 45.8% in the 2016 survey participants. In 2016 18% of eyes having a cataract operation with IOL implantation had a presenting visual acuity of <6/60 (poor outcome) with the main causes being postoperative complications (53%) and uncorrected refractive error (29%). CONCLUSION: Between 2005 and 2016 there was a doubling in cataract surgical rate, a 7 times increase in cataract surgical coverage (<3/60), and a decrease in cataract blindness and the proportion of eyes being couched. However, there remains a high prevalence of un-operated cataract in 2016 indicating a need to further improve access to affordable and good quality cataract surgical services. PMID- 28817734 TI - Treatment gap and barriers for mental health care: A cross-sectional community survey in Nepal. AB - CONTEXT: There is limited research on the gap between the burden of mental disorders and treatment use in low- and middle-income countries. OBJECTIVES: The aim of this study was to assess the treatment gap among adults with depressive disorder (DD) and alcohol use disorder (AUD) and to examine possible barriers to initiation and continuation of mental health treatment in Nepal. METHODS: A three stage sampling technique was used in the study to select 1,983 adults from 10 Village Development Committees (VDCs) of Chitwan district. Presence of DD and AUD were identified with validated versions of the Patient Health Questionnaire (PHQ 9) and Alcohol Use Disorder Identification Test (AUDIT). Barriers to care were assessed with the Barriers to Access to Care Evaluation (BACE). RESULTS: In this sample, 11.2% (N = 228) and 5.0% (N = 96) screened positive for DD and AUD respectively. Among those scoring above clinical cut-off thresholds, few had received treatment from any providers; 8.1% for DD and 5.1% for AUD in the past 12 months, and only 1.8% (DD) and 1.3% (AUD) sought treatment from primary health care facilities. The major reported barriers to treatment were lacking financial means to afford care, fear of being perceived as "weak" for having mental health problems, fear of being perceived as "crazy" and being too unwell to ask for help. Barriers to care did not differ based on demographic characteristics such as age, sex, marital status, education, or caste/ethnicity. CONCLUSIONS: With more than 90% of the respondents with DD or AUD not participating in treatment, it is crucial to identify avenues to promote help seeking and uptake of treatment. Given that demographic characteristics did not influence barriers to care, it may be possible to pursue general population-wide approaches to promoting service use. PMID- 28817735 TI - Association of gene expression with biomass content and composition in sugarcane. AB - About 64% of the total aboveground biomass in sugarcane production is from the culm, of which ~90% is present in fiber and sugars. Understanding the transcriptome in the sugarcane culm, and the transcripts that are associated with the accumulation of the sugar and fiber components would facilitate the modification of biomass composition for enhanced biofuel and biomaterial production. The Sugarcane Iso-Seq Transcriptome (SUGIT) database was used as a reference for RNA-Seq analysis of variation in gene expression between young and mature tissues, and between 10 genotypes with varying fiber content. Global expression analysis suggests that each genotype displayed a unique expression pattern, possibly due to different chromosome combinations and maturation amongst these genotypes. Apart from direct sugar- and fiber-related transcripts, the differentially expressed (DE) transcripts in this study belonged to various supporting pathways that are not obviously involved in the accumulation of these major biomass components. The analysis revealed 1,649 DE transcripts between the young and mature tissues, while 555 DE transcripts were found between the low and high fiber genotypes. Of these, 151 and 23 transcripts respectively, were directly involved in sugar and fiber accumulation. Most of the transcripts identified were up-regulated in the young tissues (2 to 22-fold, FDR adjusted p value <0.05), which could be explained by the more active metabolism in the young tissues compared to the mature tissues in the sugarcane culm. The results of analysis of the contrasting genotypes suggests that due to the large number of genes contributing to these traits, some of the critical DE transcripts could display less than 2-fold differences in expression and might not be easily identified. However, this transcript profiling analysis identified full-length candidate transcripts and pathways that were likely to determine the differences in sugar and fiber accumulation between tissue types and contrasting genotypes. PMID- 28817736 TI - Performance of Class I composite restorations when polished immediately or after one-day water storage. AB - This study investigated the effects on gap formation in Class I restorations (observed by vertical and horizontal forms of inspection) and on the mechanical properties of nine resin composite filling materials when the restorations were subject to finishing immediately after setting or after one-day water storage. Class I restorations with resin composite fillings were polished either immediately (3 min) after setting or after one-day water storage. Interfacial gap formation (observed by vertical inspection) was assessed using 14 gap measurement points along the interface between the restoration and cavity walls and floor (n = 10 per resin composite; total points measured per time point = 140). For marginal gaps formed at cavosurface margins in Class I cavities and in Teflon molds, marginal gap formation (observed by horizontal inspection) was assessed by measuring the maximum gap-width and opposing width (if any). Effects on mechanical properties were assessed by measuring shear bond strengths to enamel and dentin, flexural strength and modulus. After one-day storage, marginal gap widths in Class I restorations were significantly decreased for all composites, alongside a significant increase in shear bond strengths to enamel and dentin, flexural strength and modulus. Resin composite-filled Class I restorations which were polished after one-day delay presented lower gap formation compared with finishing immediately after setting. PMID- 28817737 TI - Myc mediates cancer stem-like cells and EMT changes in triple negative breast cancers cells. AB - Women with triple negative breast cancer (TNBC) have poor prognosis compared to other breast cancer subtypes. There were several reports indicating racial disparity in breast cancer outcomes between African American (AA) and European American (EA) women. For example, the mortality rates of AA breast cancer patients were three times higher than of EA patients, even though, the incidence is lower in AA women. Our in vitro studies indicate that cancer stem-like cells (CSCs) derived from AA TNBC cell lines have significantly higher self-renewal potential (mammosphere formation) than CSCs derived from EA cell lines. TNBC tumors express high levels of Myc compared to luminal A or HER2 expressing breast cancers. We studied the effects of c-Myc overexpression on CSCs and chemotherapy in AA, and EA derived TNBC cell line(s). Overexpression of c-Myc in AA derived MDA-MB-468 (Myc/MDA-468) cells resulted in a significant increase in CSCs and with minimal changes in epithelial-to-mesenchymal transition (EMT) compared to the control group. In contrast, overexpression of c-Myc in EA derived MDA-MB 231(Myc/MDA-231) cells led to increased epithelial-to-mesenchymal transition (EMT), with a minimal increase in CSCs compared to the control group. Myc/MDA-468 cells were resistant to standard chemotherapeutic treatments such as iniparib (PARP inhibitor) plus cisplatin, / iniparib, cisplatin, paclitaxel and docetaxel. However, Myc/MDA-231 cells, which showed EMT changes responded to iniparib with cisplatin, but were resistant to other drugs, such as iniparib, cisplatin, paclitaxel and docetaxel. Collectively, our results indicate that intrinsic differences in the tumor biology may contribute to the breast cancer disparities. PMID- 28817738 TI - Compliance with Supportive Periodontal Treatment in Patients with Dental Implants. AB - PURPOSE: The need for dental implants is increasing, and supportive periodontal treatment can achieve long-term success and prevent peri-implantitis. Contributing factors to noncompliance with long-term scheduled supportive periodontal treatment remain unclear. To investigate whether demographic and clinical characteristics are associated with noncompliance, the authors analyzed data for patients who had received dental implants. MATERIALS AND METHODS: The authors recruited patients participating in a supportive periodontal treatment program after receiving permanent prostheses on implants placed from 2005 to 2013. Demographic data and dental treatment histories were collected. Compliance was defined as a record of participation in a standard supportive periodontal treatment program for at least 1 year. The chi-square test, log-rank test, Kaplan Meier survival curve, and Cox proportional hazards model were used for statistical analysis. RESULTS: The study included 120 patients (259 implants, 60% compliance). The two groups (compliant and noncompliant) differed significantly in frequency distributions for sex (P = .0017), educational level (P = .0325), and histories of substance use (P = .0016), periodontitis (P = .0005), and root planing or flap surgery (P = .0002). The Kaplan-Meier survival curves and log rank test showed that increases in cumulative continuation rates were significantly associated with male sex (P = .0025); body mass index >= 24 kg/m2 (P = .0093); and a history of periodontitis (P < .0001), root planing or flap surgery (P < .0001), and substance use (P = .0026). Multivariate Cox proportional hazards model for supportive periodontal treatment noncompliance showed significantly higher compliance in patients who had received root planing or flap surgery (hazard ratio = 0.26, 95% confidence interval = 0.12 to 0.53, P = .0002). CONCLUSION: These results suggest that in patients who received a permanent prosthesis on implant placement, root planing or flap surgery was the crucial factor in determining compliance with supportive periodontal treatment. However, well-designed large-scale studies with a larger sample size are needed to confirm the findings of this study. PMID- 28817739 TI - Three-Dimensional Volumetric Changes in Severely Resorbed Alveolar Sockets After Ridge Augmentation with Bovine-Derived Xenograft and Resorbable Barrier: A Preliminary Study on CBCT Imaging. AB - PURPOSE: The primary aim of the study was to describe a novel technique to evaluate volumetric hard tissue dimensional changes after ridge augmentation procedures. The secondary aim was to apply this newly developed measuring method to compromised alveolar sockets grafted with a slowly resorbing biomaterial covered with a collagen membrane. MATERIALS AND METHODS: Eleven patients (6 men and 5 women, mean age 52.7 +/- 8.3 years) requiring extraction of one hopeless tooth for severe periodontitis in the maxillary anterior area were consecutively treated with a ridge augmentation procedure. All experimental sockets showed advanced buccal bone plate deficiency and were grafted with deproteinized bovine bone mineral with 10% collagen covered with a collagen membrane. Sockets healed by secondary intention. Three-dimensional volumetric alveolar bone changes were calculated by superimposing cone beam computed tomography scans obtained before and 12 months after the augmentation procedure. RESULTS: After 12 months, the alveolar mineralized tissue filled 91.20% +/- 7.96% of the maximum volume for regeneration. The augmentation procedure appeared not only to compensate for bone remodeling in most alveolar regions but also to repair a significant portion of the buccal wall. The most significant ridge width changes occurred 1 mm apical to the bone crest (2.33 +/- 1.46 mm, P < .001). CONCLUSION: Within present limitations, this radiographic measuring methodology can be a useful tool to evaluate changes in socket volume. A ridge preservation technique performed with collagenated bovine bone and a collagen membrane was able to improve ridge shape and dimensions in compromised alveolar sockets. PMID- 28817740 TI - Influence of Microtextured Implant Surfaces on Peri-implantitis and Its Treatment: A Preclinical Trial. AB - PURPOSE: The prevalence of peri-implantitis has increased significantly, forcing clinicians to search for ways to prevent it. Laser-microtextured surfaces promote soft tissue attachment and provide a tight seal around implants. Hence, the aim of this study was to examine the clinical, radiographic, and histologic features of ligature-induced peri-implantitis, as well as the effect of surgical treatment of these induced peri-implantitis lesions on laser-microtextured implants in a controlled animal model. MATERIALS AND METHODS: Six mini-pigs (three males/three females) received 6 implants each (3 resorbable blast textured [RBT] implants and 3 laser-microtextured [LM] implants) in mandibular premolar sites, for a total of 36 implants. Two groups were identified based on the time point of sample analysis. After osseointegration was achieved, metal wire ligatures were placed and left for 12 weeks. Group 1 samples were then obtained, and group 2 samples received rescue therapy following a guided bone regeneration (GBR) protocol. Sample collection in group 2 was completed 12 weeks after the samples were submerged and treated. All samples were analyzed histologically and measurements were taken. RESULTS: Four implants (three RBT, one LM) were lost at early time points because of implant instability. Interimplant distances and soft tissue thicknesses varied subtly between groups. More notable was the mean (+/- standard error of the mean) crestal bone loss (group 1: 1.860 +/- 1.618 mm [LM] and 2.440 +/- 2.691 mm [RBT]; group 2: 2.04 +/- 1.613 mm [LM] and 3.00 +/- 2.196 mm [RBT]) (P < .05), as demonstrated by a paired t test. Histologic pocket depth was also greater at RBT sites than at LM sites (4.448 +/- 2.839 mm and 4.121 +/- 2.251 mm, respectively, in group 1; and 3.537 +/- 2.719 mm and 2.339 +/- 1.852 mm, respectively [P < .005] in group 2). CONCLUSION: LM implants had less crestal bone loss and shallower histologic pocket depth compared with their RBT counterparts. Also, LM implants had higher bone fill when a rescue therapy (GBR) was performed. PMID- 28817741 TI - Reconstruction of a Severely Atrophied Alveolar Ridge by Computer-Aided Gingival Simulation and 3D-Printed Surgical Guide: A Case Report. AB - Dental implants positioned in severely atrophied anterior maxillae require esthetic or functional compromises. This case report describes the rehabilitation of a severely atrophied alveolar ridge with a three-dimensional (3D) computer aided design/computer-aided manufacture (CAD/CAM) surgical guide. A 50-year-old woman had a severely atrophied anterior maxilla with unfavorably positioned dental implants. Functional and esthetic prosthodontic restoration was difficult to achieve. An anterior segmental osteotomy was planned to reposition the dental implants. A 3D surgical guide was designed for precise relocation of the segment. The surgical guide firmly grasped the impression copings of the dental implants, minimizing surgical errors. Three-dimensional gingival simulation was used preoperatively to estimate the appropriate position of the gingiva. Rigid fixation to the surrounding bone allowed immobilization of the implant-bone segment. Satisfactory esthetic and functional outcomes were attained 6 months after surgery. Finally, a severely atrophied alveolar ridge with unfavorably positioned dental implants was recovered with minimal esthetic and functional deterioration using gingival simulation and a 3D CAD/CAM surgical guide. PMID- 28817742 TI - Minimum Abutment Height to Eliminate Bone Loss: Influence of Implant Neck Design and Platform Switching. AB - PURPOSE: This retrospective study quantitatively analyzed the minimum prosthetic abutment height to eliminate bone loss after 4.7-mm-diameter implant placement in maxillary bone and how grafting techniques can affect the marginal bone loss in implants placed in maxillary areas. MATERIALS AND METHODS: Two different implant types with a similar neck design were singularly placed in two groups of patients: the test group, with platform-switched implants, and the control group, with conventional (non-platform-switched) implants. Patients requiring bone augmentation underwent unilateral sinus augmentation using a transcrestal technique with mineralized xenograft. Radiographs were taken immediately after implant placement, after delivery of the prosthetic restoration, and after 12 months of loading. RESULTS: The average mesial and distal marginal bone loss of the control group (25 patients) was significantly more than twice that of the test group (26 patients), while their average abutment height was similar. Linear regression analysis highlighted a statistically significant inverse relationship between marginal bone loss and abutment height in both groups; however, the intercept of the regression line, both mesially and distally, was 50% lower for the test group than for the control group. The marginal bone loss was annulled with an abutment height of 2.5 mm for the test group and 3.0 mm for the control group. No statistically significant differences were found regarding marginal bone loss of implants placed in native maxillary bone compared with those placed in the grafted areas. CONCLUSION: The results suggest that the shorter the abutment height, the greater the marginal bone loss in cement-retained prostheses. Abutment height showed a greater influence in platform-switched than in non-platform-switched implants on the limitation of marginal bone loss. PMID- 28817743 TI - The Nuremberg Code 70 Years Later. PMID- 28817744 TI - Predictors of Corneal Perforation or Need for Therapeutic Keratoplasty in Severe Fungal Keratitis: A Secondary Analysis of the Mycotic Ulcer Treatment Trial II. AB - Importance: Identifying patients with infectious keratitis who are at risk of experiencing a poor outcome may be useful to allocate resources toward high-risk patients, particularly in resource-poor settings. Objective: To determine baseline patient and ulcer characteristics that predict a high risk of developing corneal perforation and/or the need to undergo therapeutic penetrating keratoplasty (TPK). Design, Setting, and Participants: This is a secondary analysis of Mycotic Ulcer Treatment Trial II, a multicenter, double-masked, placebo-controlled randomized clinical trial that enrolled 240 patients with smear-positive filamentous fungal corneal ulcers who enrolled between May 2010 and August 2015. Participants had a baseline visual acuity of 20/400 or worse and were randomized to receive oral voriconazole or a placebo (all participants received topical voriconazole, 1%). After 39 participants (16.3%) were enrolled, topical natamycin, 5%, was also added. Main Outcomes and Measures: The primary outcome of this secondary analysis was the rate of corneal perforation or the need to undergo TPK. Results: The mean (SD) age at enrollment was 49 (13) years, 104 participants (43.3%) were women, and all were of Southeast Asian descent. The presence of hypopyon at baseline indicated 2.28 times the odds of the patient developing corneal perforation and/or needing TPK (95% CI, 1.18-4.40; P = .01). Study participants whose infiltrate involved the posterior one-third had a 71.4% risk of developing corneal perforation and/or needing TPK. For each 1-mm increase in the geometric mean of the infiltrate, there was 1.37 (95% CI, 1.12-1.67; P = .002) increased odds of developing perforation and/or needing TPK. Other clinical features such as visual acuity, baseline culture positivity, type of filamentous fungal organism and duration of symptoms, and demographic characteristics, such as sex and occupation, were not significant predictors in the multivariable regression analysis. Conclusions and Relevance: These results suggest that risk stratification from baseline ulcer characteristics can identify those at highest risk for developing corneal perforation and/or needing TPK. Trial Registration: clinicaltrials.gov Identifier: NCT00996736. PMID- 28817746 TI - Is "Do Everything!" Always Appropriate? PMID- 28817745 TI - Association of Vision Loss With Cognition in Older Adults. AB - Importance: Visual dysfunction and poor cognition are highly prevalent among older adults; however, the relationship is not well defined. Objective: To evaluate the association of measured and self-reported visual impairment (VI) with cognition in older US adults. Design, Setting, and Participants: Cross sectional analysis of 2 national data sets: the National Health and Nutrition Examination Survey (NHANES), 1999-2002, and the National Health and Aging Trends Study (NHATS), 2011-2015. The NHANES was composed of a civilian, noninstitutionalized community, and the NHATS comprised Medicare beneficiaries in the contiguous United States. Vision was measured at distance, near, and by self report in the NHANES and by self-report alone in the NHATS. Sample weights were used to ensure result generalizability. Main Outcomes and Measures: The NHANES measured Digit Symbol Substitution Test (DSST) score and relative DSST impairment (DSST score <=28, lowest quartile in study cohort), and the NHATS measured probable or possible dementia, classified per NHATS protocol. Results: The NHANES comprised 2975 respondents aged 60 years and older who completed the DSST measuring cognitive performance. Mean (SD) age was 72 (8) years, 52% of participants were women (n = 1527), and 61% were non-Hispanic white (n = 1818). The NHATS included 30 202 respondents aged 65 years and older with dementia status assessment. The largest proportion (40%; n = 12 212) were between 75 and 84 years of age. Fifty-eight percent were women (n = 17 659), and 69% were non Hispanic white (n = 20 842). In the NHANES, distance VI (beta = -5.1; 95% CI, 8.6 to -1.6; odds ratio [OR], 2.8; 95% CI, 1.1-6.7) and subjective VI (beta = 5.3; 95% CI, -8.0 to -2.6; OR, 2.7; 95% CI, 1.6-4.8) were both associated with lower DSST scores and higher odds of DSST impairment after full adjustment with covariates. Near VI was associated with lower DSST scores but not higher odds of DSST impairment. The NHATS data corroborated these results, with all vision variables associated with higher odds of dementia after full adjustment (distance VI: OR, 1.9; 95% CI, 1.6-2.2; near VI: OR, 2.6; 95% CI, 2.2-3.1; either distance or near VI: OR, 2.1; 95% CI, 1.8-2.4). Conclusions and Relevance: In a nationally representative sample of older US adults, vision dysfunction at distance and based on self-reports was associated with poor cognitive function. This was substantiated by a representative sample of US Medicare beneficiaries using self reported visual function, reinforcing the value of identifying patients with visual compromise. Further study of longitudinal interactions between vision and cognition is warranted. PMID- 28817747 TI - An Erysipeloid Cutaneous Eruption in a Woman With Advanced Breast Cancer. PMID- 28817748 TI - The Bitter, Expensive Pill at the End of Life. PMID- 28817749 TI - Patients With Lung Cancer Need Love Too. PMID- 28817750 TI - The "Surgeon on Service" Model for Timely, Economically Viable Inpatient Care of Tracheostomy Patients in Academic Pediatric Otolaryngology. AB - Importance: The traditional practice model for pediatric otolaryngologists at high-volume academic centers is to simultaneously balance outpatient care responsibilities with those of the inpatient service, emergency department, and ambulatory care clinics. This model leads to challenges with care coordination, timeliness of nonemergency operative care, and consistent participation in care and consultation at the attending surgeon level. The "surgeon on service" (SOS) model-where faculty members rotate to manage the inpatient service in lieu of outpatient responsibilities-has been described as one method to address this conundrum. The operational and economic feasibility of the SOS model has been demonstrated; however, its impact on care coordination, time from consultation to surgical care, and length of stay (LOS) have not been evaluated. Objective: To determine the impact of the SOS model on the quality principles of timeliness and efficiency of tracheostomy tube placement and to determine if the SOS model is fiscally feasible in an academic pediatric otolaryngology practice. Design, Setting, and Participants: Medical record review of patients undergoing tracheostomy in a pediatric academic medical center and survey of their treating physician trainees, comparing the 6-month SOS pilot phase (postimplementation, January-June 2016) with the 6-month preimplementation period (January-June 2015). Intervention: Implementation of the SOS model. Main Outcomes and Measures: Time to tracheostomy, frequency of successful coordination of tracheostomy with gastrostomy tube placement, total LOS, productivity measured in work relative value units, and responses to trainee surveys. Results: Of the 41 patients included in the study (24 boys and 17 girls; mean age, 3 years; range, 3 months to 17 years), 15 were treated before SOS implementation, and 26 after. Also included were 21 trainees. Before SOS implementation, median time to tracheostomy was 7 days (range, 2-20 days); after SOS implementation, it was 4 days (range, 1 10 days) (difference between the medians, before to after, -3 days; 95% CI, -5 to 0 days). There was no significant difference in overall LOS or ability to coordinate tracheostomy with gastrostomy tube placement. Preimplementation trainee surveys cited dissatisfaction with the communication channels to the primary team when the consulting surgeon was not immediately available to perform tracheostomy. No challenges were reported after implementation. Productivity was comparable to that in the outpatient setting. Conclusions and Relevance: In this study, the presence of a rotating inpatient pediatric otolaryngologist was a productive approach to patient care associated with more timely performance of tracheostomy. Other benefits were an improved balance of service with education to trainees and a better perception of communication with consulting services. PMID- 28817751 TI - A Peaked Pupil. PMID- 28817752 TI - Technical Refinements and Outcomes of the Modified Anterior Septal Transplant. AB - Importance: Severe anterior septal deviation and resultant nasal obstruction represent a difficult surgical task to correct. The goal of surgery is to straighten the anterior dorsal and caudal struts, while maintaining nasal tip and midvault support. This study presents a novel extracorporeal septoplasty technique to straighten the crooked anterior septum. Objective: To describe the novel anterior septal transplant technique, which consists of complete resection of the caudal septum and reconstruction with extended spreader grafts and a columellar strut, without a separate caudal septal replacement graft. Design, Setting, and Participants: This study was a retrospective case series at a tertiary academic referral center. Participants were sequential adult patients undergoing anterior septal transplant from January 1, 2008, to December 31, 2015. Main Outcomes and Measures: Patient-reported nasal obstruction using Nasal Obstruction Symptom Evaluation (NOSE) scores and objective photographic analysis. Nasal tip deviation, projection, and rotation were measured. Preoperative and postoperative outcomes were compared. Complications are reported. Results: Seventy-one patients (mean age, 46 years [age range, 16-72 years]; 48 [67.6%] female and 23 [32.4%] male) were included in the case series. Postoperative NOSE scores (mean [SD], 24.00 [24.58]) were significantly better than preoperative NOSE scores (mean [SD], 72.25 [14.55]) (P < .001). A separate cohort of 32 patients (mean age, 42 years [age range, 13-72 years]; 23 [71.9%] female and 9 [28.1%] male) had photographs available for analysis. In the frontal view, nasal deviation improved from a mean (SD) of 2.9 (2.0) degrees before surgery to a mean (SD) of 1.4 (1.7) degrees after surgery (P = .004). In the base view, the deviation was corrected from a mean (SD) of 4.9 (2.8) degrees to a mean (SD) of 1.7 (1.2) degrees (P < .001). Tip rotation and projection were unchanged after surgery. Four patients had mild dorsal irregularities after surgery. Conclusions and Relevance: Anterior septal transplant by the described technique is a safe and effective treatment option for severe anterior septal deviation. Level of Evidence: 4. PMID- 28817754 TI - Complex Relationships Between Vision and Cognition in Older People. PMID- 28817755 TI - Measuring Toxic Effects and Time to Treatment Failure for Nivolumab Plus Ipilimumab in Melanoma. AB - Importance: Nivolumab plus ipilimumab (nivo + ipi) is a standard treatment of advanced melanoma. Two randomized trials describe high objective response rates by Response Evaluation Criteria in Solid Tumors. The trials assessed toxic effects using the Common Terminology Criteria for Adverse Events (CTCAE), which may underestimate incidence of clinically significant immune-related adverse events (AEs). Objective: To describe detailed toxic effects and time to treatment failure of patients with melanoma treated with nivo + ipi in a prospective cohort. Design, Setting, and Participants: A cohort of 64 adults with advanced or unresectable melanoma were examined at a single tertiary cancer and enrolled in an expanded access program of nivo + ipi conducted from December 2014 to January 2016. Interventions: Intravenous nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) administered every 3 weeks for up to 4 doses, followed by nivolumab (3 mg/kg) every 2 weeks or pembrolizumab (2 mg/kg) every 3 weeks until unacceptable toxic effects, disease progression, or complete response. Main Outcomes and Measures: Clinically significant immune-related AEs were defined as CTCAE grade 2 or higher or any immune-related AEs requiring systemic steroids. Time to treatment failure was defined as the interval between initiating therapy and the earliest of clinical progression, new locally directed or systemic treatment other than anti programmed cell death 1 protein (anti-PD-1) monotherapy, or death. Results: Overall 64 adults with advanced or unresectable melanoma were enrolled (male to female ratio, 1:1; median [range] age, 56 [22-82] years); 25 patients (39%) received all 4 doses of nivo + ipi, and 31 patients (48%) received no maintenance anti-PD-1 therapy. Most who discontinued treatment (n = 31 [80%]) stopped because of toxic effects. Among those patients who were progression free at 12 weeks, time to treatment failure was similar between those who did or did not modify therapy for toxic effects. Fifty-eight patients (91%) had a clinically significant immune-related AE (median, 2/patient), and 46 patients (72%) required systemic steroids. Infliximab or mycophenolate was required in 16 patients (25%) for steroid-refractory immune-related AEs. Seven patients (11%) developed hyperglycemia, 32 patients (50%) had an emergency department visit, and 23 patients (36%) required a hospital admission related to an immune-related AE. Four of 31 patients (13%) who stopped combination therapy early for toxic effects developed a new, clinically significant immune-related AE more than 16 weeks after the last treatment. Conclusions and Relevance: We observed a 91% incidence of clinically significant immune-related AEs leading to frequent emergency department visits, hospitalizations, and systemic immunosuppression. Immuno oncology trials should routinely report these metrics. Most patients do not tolerate 4 doses of nivo + ipi; however, 4 doses may not be required for clinical benefit. PMID- 28817753 TI - Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma: Updated Results From a Phase 1/2 Open-label Study. AB - Importance: The data reported herein were accepted for assessment by the US Food and Drug Administration for Biologics License Application under priority review to establish the clinical benefit of durvalumab as second-line therapy for locally advanced or metastatic urothelial carcinoma (UC), resulting in its recent US approval. Objective: To report a planned update of the safety and efficacy of durvalumab in patients with locally advanced/metastatic UC. Design, Setting, and Participants: This is an ongoing phase 1/2 open-label study of 191 adult patients with histologically or cytologically confirmed locally advanced/metastatic UC whose disease had progressed on, were ineligible for, or refused prior chemotherapy from 60 sites in 9 countries as reported herein. Intervention: Patients were administered durvalumab intravenous infusion, 10 mg/kg every 2 weeks, for up to 12 months or until progression, starting another anticancer therapy, or unacceptable toxic effects. Main Outcomes and Measures: Primary end points were safety and confirmed objective response rate (ORR) per blinded independent central review (Response Evaluation Criteria In Solid Tumors [RECIST], version 1.1). Results: A total of 191 patients with UC had received treatment. As of October 24, 2016 (90-day update), the median follow-up was 5.78 months (range, 0.4-25.9 months). The median age of patients was 67.0 years and most were male (136 [71.2%]) and white (123 [71.1%]). All patients had stage 4 disease, and 190 (99.5%) had prior anticancer therapy (182 [95.3%] postplatinum). The ORR was 17.8% (34 of 191; 95% CI, 12.7%-24.0%), including 7 complete responses. Responses were early (median time to response, 1.41 months), durable (median duration of response not reached), and observed regardless of programmed cell death ligand-1 (PD-L1) expression (ORR, 27.6% [n = 27; 95% CI, 19.0%-37.5%] and 5.1% [n = 4; 95% CI, 1.4%-12.5%] in patients with high and low or negative expression of PD-L1, respectively). Median progression-free survival and overall survival were 1.5 months (95% CI, 1.4-1.9 months) and 18.2 months (95% CI, 8.1 months to not estimable), respectively; the 1-year overall survival rate was 55% (95% CI, 44%-65%), as estimated by Kaplan-Meier method. Grade 3/4 treatment related adverse events (AEs) occurred in 13 patients (6.8%); grade 3/4 immune mediated AEs occurred in 4 patients (2.1%); and treatment-related AEs led to discontinuation of 3 patients (1.6%), 2 of whom had immune-mediated AEs that led to death (autoimmune hepatitis and pneumonitis). Conclusions and Relevance: Durvalumab, 10 mg/kg every 2 weeks, demonstrates favorable clinical activity and an encouraging and manageable safety profile in patients with locally advanced/metastatic UC. Trial Registration: clinicaltrials.gov Identifier: NCT01693562. PMID- 28817756 TI - Incorrect Middle Initial in Byline. PMID- 28817761 TI - Is "Do Everything!" Always Appropriate?-Reply. PMID- 28817760 TI - Association Between Hypercoagulability and Severe Obstructive Sleep Apnea. AB - Importance: Obstructive sleep apnea (OSA) is related to the increased risk of cardiovascular disease. Although the pathogenesis of this association remains unclear, an alteration in coagulability is suspected as a link. Objective: To investigate the association between the severity of OSA and blood coagulability. Design, Setting, and Participants: A retrospective cohort study conducted at a tertiary care university hospital evaluated 146 patients with OSA from January 1, 2009, to July 31, 2015. The participants were divided into 4 groups according to the severity of OSA: control, mild, moderate, and severe. Main Outcomes and Measures: Association between the severity of OSA and coagulation test results, including platelet count, bleeding time, prothrombin time (PT) in seconds and as international normalized ratio (INR), and activated partial thromboplastin time. Results: Of the 146 patients, 135 (92.5%) were men; mean (SD) age was 34.8 (11.1) years. The control group included 41 (28.1%) patients; mild OSA, 32 (21.9%); moderate OSA, 30 (20.5%); and severe OSA, 43 (29.5%). Significant correlations were found between the apnea-hypopnea index and the PT seconds (Spearman r coefficient, -0.30; 95% CI, -0.44 to -0.14) and PT INR (Spearman r coefficient, 0.30; 95% CI, -0.44 to -0.14). There were significant differences between the OSA severity groups for PT seconds for the control group (mean, 11.26 [0.78] seconds) vs the moderate OSA group (10.74 [0.62] seconds; mean difference [MD], 0.52; 95% CI, 0.27 to 1.01) and the severe OSA group (10.67 [0.77] seconds; MD, 0.59; 95% CI, 0.14 to 1.03). Significant differences were also noted in PT INR between the control group (1.00 [0.07]) vs the moderate OSA group (0.95 [0.05]; MD, 0.04; 95% CI, 0.01 to 0.07) and the severe OSA group (0.94 [0.07]; MD, 0.05; 95% CI, 0.02 to 0.08). However, there was no significant difference between the control and mild OSA groups in PT seconds. Conclusions and Relevance: These results suggest that patients with moderate to severe OSA have elevated blood coagulability markers compared with healthy individuals, which may contribute to the occurrence of cardiovascular complications. PMID- 28817762 TI - Issues in Palliative Care: Part Two. PMID- 28817763 TI - Successful Readministration of Clozapine in a Patient With a History of Clozapine Induced Elevation of Creatine Phosphokinase. PMID- 28817764 TI - Limited Functioning After Remission of an Anxiety Disorder as a Trait Effect Versus a Scar Effect: Results of a Longitudinal General Population Study. AB - OBJECTIVE: After remission of an anxiety disorder, subjects often experience persistent functional impairments. We examined whether impairments in mental and physical functioning following remission are a continuation of premorbid lower functioning (trait effect), due to impairments that develop during the anxiety disorder and persist beyond recovery (scar effect), or both. METHODS: Data were derived from the Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS 2), a prospective psychiatric epidemiologic study among the general population with a 3-wave design (6-year follow-up, with the study starting in 2007 and ending in 2015). DSM-IV anxiety disorders were measured with the Composite International Diagnostic Interview. Functioning was assessed with the Medical Outcomes Study 36-Item Short Form Health Survey. We evaluated trait effects using between-subjects comparison and scar effects using within-subjects comparisons. RESULTS: Compared to healthy controls, individuals with anxiety disorders had showed significant impairment in mental functioning (beta = -11.6 [SE = 0.78]; P < .001) and physical functioning (beta = -12.1 [SE = 1.14]; P < .001) prior to the onset of the anxiety disorder (n = 199), indicating a trait effect. In those who developed an anxiety disorder that remitted within the 6-year follow-up (n = 92), functioning after remission (at second follow-up) was similar to functioning before onset (at baseline), indicating that a scar effect was absent. A trend toward mental scarring was visible in the subgroup with recurrent anxiety disorders (P = .03). CONCLUSIONS: Persistent functional limitations following remission largely reflect a preexisting trait effect. Since lower levels of functioning are associated with relapse, investments in functional improvement seem worthwhile. Relapse prevention might help to prevent mental scarring. PMID- 28817765 TI - Preventive Effects of Lamotrigine in Bipolar II Versus Bipolar I Disorder. AB - OBJECTIVE: The preventive effects of mood stabilizers on recurrence/relapse in bipolar disorders have been investigated mostly in bipolar I disorder (BPI) patients, with limited reports on bipolar II disorder (BPII) patients. Here, we conducted an explorative data analysis to investigate whether the preventive effect of lamotrigine on recurrence /relapse in BPII is better than in BPI. METHODS: Data from Japanese patients with a diagnosis of BPI or BPII according to DSM-IV-TR were analyzed in an open-label, noninterventional, naturalistic, prospective postmarketing surveillance study of lamotrigine. This study was carried out from October 2011 to November 2014, and each patient was observed for 1 year. The time to recurrence/relapse of mood episodes after commencement of lamotrigine treatment was evaluated as a primary endpoint. Kaplan-Meier curves were generated to compare the time to recurrence/relapse of mood episodes in BPI with in BPII using a log-rank test. RESULTS: Lamotrigine was associated with a significantly longer time to recurrence/relapse of mood episodes in BPII than in BPI (log-rank test, P = .0103). Lamotrigine also prolonged time to recurrence/relapse of mania-related episodes, including hypomanic episodes, more in BPII than in BPI (P = .0110). CONCLUSIONS: Although the preventive effect of lamotrigine on recurrence/relapse of mood episodes in BPI has been established in a variety of clinical studies, the present study suggests that lamotrigine may be more suitable for maintenance treatment in BPII than in BPI. PMID- 28817766 TI - Characteristics and Risk Factors for Negative Academic Events: A 27-Year Serial Prevalence Study of 9.7 Million Japanese College Students. AB - Objective: To examine the prevalence of and the factors contributing to leaves of absence and school discontinuation in Japanese college students over a 27-year period. Trends in these academic events over time were assessed, and students at elevated risk and psychosocial difficulties in need of supportive intervention were identified. Methods: Surveys were collected from the majority of Japanese national universities between 1985 and 2012, yielding data on a total of 9.7 million Japanese university students. Each year, data collected included the number of students enrolled at a university and the number of students who discontinued school and took leaves of absence. The reasons for these academic events were also collected in the surveys. Results: We found that instances of these academic events have become prevalent over the past decades among Japanese university students. The rates of leaves of absence and school discontinuation for men were consistently higher than that for women throughout the study. Negative reasons such as apathetic state were the dominant reason for these academic events. Males, especially in 4-year programs (liberal arts and sciences), were more likely to have negative events due to negative reasons such as apathetic state. These students were not diagnosed psychiatrically. Conclusion: The population of students at elevated risk should receive psychosocial interventions and be provided mental health support. PMID- 28817767 TI - Understanding How Acoustic Vibrations Modulate the Optical Response of Plasmonic Metal Nanoparticles. AB - Measurements of acoustic vibrations in nanoparticles provide an opportunity to study mechanical phenomena at nanometer length scales and picosecond time scales. Vibrations in noble-metal nanoparticles have attracted particular attention because they couple to plasmon resonances in the nanoparticles, leading to strong modulation of optical absorption and scattering. There are three mechanisms that transduce the mechanical oscillations into changes in the plasmon resonance: (1) changes in the nanoparticle geometry, (2) changes in electron density due to changes in the nanoparticle volume, and (3) changes in the interband transition energies due to compression/expansion of the nanoparticle (deformation potential). These mechanisms have been studied in the past to explain the origin of the experimental signals; however, a thorough quantitative connection between the coupling of phonon and plasmon modes has not yet been made, and the separate contribution of each coupling mechanism has not yet been quantified. Here, we present a numerical method to quantitatively determine the coupling between vibrational and plasmon modes in noble-metal nanoparticles of arbitrary geometries and apply it to silver and gold spheres, shells, rods, and cubes in the context of time-resolved measurements. We separately determine the parts of the optical response that are due to shape changes, changes in electron density, and changes in deformation potential. We further show that coupling is, in general, strongest when the regions of largest electric field (plasmon mode) and largest displacement (phonon mode) overlap. These results clarify reported experimental results and should help guide future experiments and potential applications. PMID- 28817768 TI - Metal-Free Synthesis of Homopropargylic Alcohols from Aldehydes. AB - The synthesis of homopropargylic alcohols under metal-free and mild condition is described. This transformation is based on a one-pot procedure involving sequential alpha-alkynylation of acyclic aldehydes using hypervalent iodine reagents and borohydride reduction. The chemistry exhibits broad substrate scope and good scalability, providing a convenient route for the alpha-alkynylation of aldehydes along with the formation of a quaternary carbon center. The applicability of the method is demonstrated by the gram-scale synthesis of the key synthetic precursor of botulinum toxin inhibitors. PMID- 28817769 TI - Paper-Based Surface-Enhanced Raman Scattering Lateral Flow Strip for Detection of Neuron-Specific Enolase in Blood Plasma. AB - An inexpensive and disposable paper-based lateral flow strip (PLFS) has been developed as an immunoassay, in which surface-enhanced Raman scattering (SERS) is utilized for sensing signal transduction. The Au nanostar@Raman Reporter@silica sandwich nanoparticles are developed as the SERS probes, which is the key to the high sensitivity of the device. Compared with a colorimetric PLFS, the SERS-PLFS exhibits superior performance in terms of sensitivity and limit of detection (LOD) in a blood plasma-containing sample matrix. In addition, the SERS-PLFS has been successfully used for detection of neuron-specific enolase (NSE), a traumatic brain injury (TBI) protein biomarker, in diluted blood plasma samples, achieving a LOD of 0.86 ng/mL. Moreover, the SERS-PLFS was successfully employed to measure the NSE level in clinical blood plasma samples taken from deidentified TBI patients. This work demonstrates that the SERS-PLFS has great potential in assisting screening of TBI patients in the point-of-care setting. PMID- 28817770 TI - Photoinduced, Copper-Catalyzed Alkylation of Amines: A Mechanistic Study of the Cross-Coupling of Carbazole with Alkyl Bromides. AB - We have recently reported that a variety of couplings of nitrogen, sulfur, oxygen, and carbon nucleophiles with organic halides can be achieved under mild conditions (-40 to 30 degrees C) through the use of light and a copper catalyst. Insight into the various mechanisms by which these reactions proceed may enhance our understanding of chemical reactivity and facilitate the development of new methods. In this report, we apply an array of tools (EPR, NMR, transient absorption, and UV-vis spectroscopy; ESI-MS; X-ray crystallography; DFT calculations; reactivity, stereochemical, and product studies) to investigate the photoinduced, copper-catalyzed coupling of carbazole with alkyl bromides. Our observations are consistent with pathways wherein both an excited state of the copper(I) carbazolide complex ([CuI(carb)2]-) and an excited state of the nucleophile (Li(carb)) can serve as photoreductants of the alkyl bromide. The catalytically dominant pathway proceeds from the excited state of Li(carb), generating a carbazyl radical and an alkyl radical. The cross-coupling of these radicals is catalyzed by copper via an out-of-cage mechanism in which [CuI(carb)2]- and [CuII(carb)3]- (carb = carbazolide), both of which have been identified under coupling conditions, are key intermediates, and [CuII(carb)3]- serves as the persistent radical that is responsible for predominant cross coupling. This study underscores the versatility of copper(II) complexes in engaging with radical intermediates that are generated by disparate pathways, en route to targeted bond constructions. PMID- 28817771 TI - Ice-Templated and Cross-Linked Amyloid Fibril Aerogel Scaffolds for Cell Growth. AB - Amyloid fibrils prepared from beta-lactoglobulin were used to form freeze-dried and cross-linked aerogels. By varying the fibril concentration and freezing gradient, it was possible to control the pore structure and elastic modulus of the aerogels within one order of magnitude from ~20 to ~200 kPa. Using butane tetracarboxylic acid as cross-linker, these aerogels maintained their monolithic shape under aqueous conditions, displaying elastic behavior and a modulus in the range of ~4-40 kPa. When explored as scaffolds for cell growth, the amyloid fibril aerogels demonstrated biocompatibility and led to the successful penetration and permeation of two epithelial cell lines (Caco-2 and HT29) throughout the scaffold. These soft, elastic, and water-stable biomaterials expand the scope of amyloid fibril aerogels, making them suitable for wet-state applications such as heterogeneous catalysis, purification membranes, and 3D matrices for cell growth. PMID- 28817772 TI - Quantifying and Elucidating Thermally Enhanced Minority Carrier Diffusion Length Using Radius-Controlled Rutile Nanowires. AB - The minority carrier diffusion length (LD) is a crucial property that determines the performance of light absorbers in photoelectrochemical (PEC) cells. Many transition-metal oxides are stable photoanodes for solar water splitting but exhibit a small to moderate LD, ranging from a few nanometers (such as alpha Fe2O3 and TiO2) to a few tens of nanometers (such as BiVO4). Under operating conditions, the temperature of PEC cells can deviate substantially from ambient, yet the temperature dependence of LD has not been quantified. In this work, we show that measuring the photocurrent as a function of both temperature and absorber dimensions provides a quantitative method for evaluating the temperature dependent minority carrier transport. By measuring photocurrents of nonstoichiometric rutile TiO2-x nanowires as a function of wire radius (19-75 nm) and temperature (10-70 degrees C), we extract the minority carrier diffusion length along with its activation energy. The minority carrier diffusion length in TiO2-x increases from 5 nm at 25 degrees C to 10 nm at 70 degrees C, implying that enhanced carrier mobility outweighs the increase in the recombination rate with temperature. Additionally, by comparing the temperature-dependent photocurrent in BiVO4, TiO2, and alpha-Fe2O3, we conclude that the ratio of the minority carrier diffusion length to the depletion layer width determines the extent of temperature enhancement, and reconcile the widespread temperature coefficients, which ranged from 0.6 to 1.7% K-1. This insight provides a general design rule to select light absorbers for large thermally activated photocurrents and to predict PEC cell characteristics at a range of temperatures encountered during realistic device operation. PMID- 28817773 TI - Surface Reaction Barriometry: Methane Dissociation on Flat and Stepped Transition Metal Surfaces. AB - Accurately simulating heterogeneously catalyzed reactions requires reliable barriers for molecules reacting at defects on metal surfaces, such as steps. However, first-principles methods capable of computing these barriers to chemical accuracy have yet to be demonstrated. We show that state-resolved molecular beam experiments combined with ab initio molecular dynamics using specific reaction parameter density functional theory (SRP-DFT) can determine the molecule-metal surface interaction with the required reliability. Crucially, SRP-DFT exhibits transferability: the functional devised for methane reacting on a flat (111) face of Pt (and Ni) also describes its reaction on stepped Pt(211) with chemical accuracy. Our approach can help bridge the materials gap between fundamental surface science studies on regular surfaces and heterogeneous catalysis in which defected surfaces are important. PMID- 28817774 TI - Efficient Concentration of Indium(III) from Aqueous Solution Using Layered Silicates. AB - A synthetic layered alkali silicate, magadiite, and a natural montmorillite were found to concentrate indium(III) ion from aqueous solution by ion exchange reactions. The adsorption was examined by the reaction between silicates and aqueous solution of indium(III) chloride of different concentration at room temperature for 10 min. The adsorption isotherms were H type, indicating strong interactions between the silicates and indium(III) ion. The maximum adsorbed indium(III) amount for magadiite was quite high, ca. 0.70 mmol/g silicate, which corresponded to 96% of the ideal cation exchange capacity of magadiite derived from the chemical formula of Na2Si14O29. In addition, the selectivity of the indium was very high, and efficient adsorption of indium was observed from the sodium chloride solutions and the solutions containing zinc, nickel, and copper. The large adsorption capacity, high selectivity of indium, and short reaction time (10 min at room temperature) make the adsorption on magadiite useful for the concentration of indium(III) ion from aqueous environments. PMID- 28817775 TI - Electronic Structure and Properties of Berkelium Iodates. AB - The reaction of 249Bk(OH)4 with iodate under hydrothermal conditions results in the formation of Bk(IO3)3 as the major product with trace amounts of Bk(IO3)4 also crystallizing from the reaction mixture. The structure of Bk(IO3)3 consists of nine-coordinate BkIII cations that are bridged by iodate anions to yield layers that are isomorphous with those found for AmIII, CfIII, and with lanthanides that possess similar ionic radii. Bk(IO3)4 was expected to adopt the same structure as M(IO3)4 (M = Ce, Np, Pu), but instead parallels the structural chemistry of the smaller ZrIV cation. BkIII-O and BkIV-O bond lengths are shorter than anticipated and provide further support for a postcurium break in the actinide series. Photoluminescence and absorption spectra collected from single crystals of Bk(IO3)4 show evidence for doping with BkIII in these crystals. In addition to luminescence from BkIII in the Bk(IO3)4 crystals, a broad-band absorption feature is initially present that is similar to features observed in systems with intervalence charge transfer. However, the high-specific activity of 249Bk (t1/2 = 320 d) causes oxidation of BkIII and only BkIV is present after a few days with concomitant loss of both the BkIII luminescence and the broadband feature. The electronic structure of Bk(IO3)3 and Bk(IO3)4 were examined using a range of computational methods that include density functional theory both on clusters and on periodic structures, relativistic ab initio wave function calculations that incorporate spin-orbit coupling (CASSCF), and by a full-model Hamiltonian with spin-orbit coupling and Slater-Condon parameters (CONDON). Some of these methods provide evidence for an asymmetric ground state present in BkIV that does not strictly adhere to Russel-Saunders coupling and Hund's Rule even though it possesses a half-filled 5f 7 shell. Multiple factors contribute to the asymmetry that include 5f electrons being present in microstates that are not solely spin up, spin-orbit coupling induced mixing of low-lying excited states with the ground state, and covalency in the BkIV-O bonds that distributes the 5f electrons onto the ligands. These factors are absent or diminished in other f7 ions such as GdIII or CmIII. PMID- 28817776 TI - Electrophilic Cyclization of Phenylalkynediols to Naphthyl(aryl)iodonium Triflates with Chelating Hydroxyls: Preparation and X-ray Analyses. AB - Alkynediols containing one propargylic alcohol as well as a second alcohol, which is propargylic or homopropargylic, react with PhI+CN-OTf (Stang's reagent) or 3,5 (CF3)2C6H3I+CN-OTf to afford naphthyl(aryl)iodonium triflates. The reaction occurs at room temperature over the course of 6-12 h and provides 36-82% yields of microcrystalline solids. Slow diffusion of Et2O into CH3CN solutions of the salts afforded X-ray quality crystals of five compounds with hydroxyl groups forming five- and six-membered chelation complexes with the iodine atom. Crystallizations from larger scale reactions (>=~0.25 mmol) were generally facile from CH2Cl2. PMID- 28817777 TI - Predicting NOx Catalysis by Quantifying Ce3+ from Surface and Lattice Oxygen. AB - Our work introduces a novel technique based on the magnetic response of Ce3+ and molecular oxygen adsorbed on the surface of nanoceria and ceria-based catalysts that quantifies the number and type of defects and demonstrates that this information is the missing link that finally enables predictive design of NOx catalysis in ceria-based systems. The new insights into ceria catalysis are enabled by quantifying the above for different ceria nanoparticle shapes (i.e., surface terminations) and O2 partial pressure. We used ceria nanorods, cubes, and spheres and evaluated them for catalytic reduction of NO by CO. We then demonstrated the quantitative prediction of the reactivity of nanomaterials via their magnetism in different atmospheric environments. We find that the observed enhancement of reactivity for ceria nanocubes and nanorods is not directly due to improved reactivity on those surface terminations but rather due to the increased ease of generating lattice defects in these materials. Finally, we demonstrate that the method is equally applicable to highly topical and industrially relevant ceria mixed oxides, using nanoscale alumina-supported ceria as a representative case-a most ill-defined catalyst. Because the total oxide surface is a mixture of active ceria and inactive support and ceria is not likely present as crystallographically well-defined phases, reactivity does not easily scale with surface area or a surface termination. The key parameter to design efficient NO reduction in ceria-based catalysts is knowing and controlling the surface localized excess Ce3+ ion areal density. PMID- 28817779 TI - The price may not be right: the value of comparison shopping for prescription drugs. AB - OBJECTIVES: To measure variations in drug prices across and within zip codes that may reveal simple strategies to improve patients' access to prescribed medications. STUDY DESIGN: We compared drug prices at different types of pharmacies across and within local markets. In-store prices were compared with a Web-based service providing discount coupons for prescription medications. Prices were collected for 2 generic antibiotics because most patients have limited experience with them and are less likely to know the price ranges for them. METHODS: Drug prices were obtained via telephone from 528 pharmacies in Los Angeles (LA) County, California, from July to August 2014. Online prices were collected from GoodRx, a popular Web-based service that aggregates available discounts and directly negotiates with retail outlets. RESULTS: Drug prices found at independent pharmacies and by using discount coupons available online were lower on average than at grocery, big-box, or chain drug stores for 2 widely prescribed antibiotics. The lowest-price prescription was offered at a grocery, big-box, or chain drug store in 6% of zip codes within the LA County area. Drug prices varied dramatically within a zip code, however, and were less expensive in lower-income areas. The average price difference within a zip code was $52 for levofloxacin and $17 for azithromycin. CONCLUSIONS: Price shopping for medications within a small geographic area can yield considerable cost savings for the uninsured and consumers in high-deductible health plans with high negotiated prices. Clinicians and patient advocates have an incentive to convey this information to patients to improve adherence to prescribed medicines and lower the financial burden of purchasing prescription drugs. PMID- 28817778 TI - The Oxidation State of [4Fe4S] Clusters Modulates the DNA-Binding Affinity of DNA Repair Proteins. AB - A central question important to understanding DNA repair is how certain proteins are able to search for, detect, and fix DNA damage on a biologically relevant time scale. A feature of many base excision repair proteins is that they contain [4Fe4S] clusters that may aid their search for lesions. In this paper, we establish the importance of the oxidation state of the redox-active [4Fe4S] cluster in the DNA damage detection process. We utilize DNA-modified electrodes to generate repair proteins with [4Fe4S] clusters in the 2+ and 3+ states by bulk electrolysis under an O2-free atmosphere. Anaerobic microscale thermophoresis results indicate that proteins carrying [4Fe4S]3+ clusters bind to DNA 550 times more tightly than those with [4Fe4S]2+ clusters. The measured increase in DNA binding affinity matches the calculated affinity change associated with the redox potential shift observed for [4Fe4S] cluster proteins upon binding to DNA. We further devise an electrostatic model that shows this change in DNA-binding affinity of these proteins can be fully explained by the differences in electrostatic interactions between DNA and the [4Fe4S] cluster in the reduced versus oxidized state. We then utilize atomic force microscopy (AFM) to demonstrate that the redox state of the [4Fe4S] clusters regulates the ability of two DNA repair proteins, Endonuclease III and DinG, to bind preferentially to DNA duplexes containing a single site of DNA damage (here a base mismatch) which inhibits DNA charge transport. Together, these results show that the reduction and oxidation of [4Fe4S] clusters through DNA-mediated charge transport facilitates long-range signaling between [4Fe4S] repair proteins. The redox modulated change in DNA-binding affinity regulates the ability of [4Fe4S] repair proteins to collaborate in the lesion detection process. PMID- 28817781 TI - Availability and variation of publicly reported prescription drug prices. AB - OBJECTIVES: To examine how often retail prices for prescription drugs are available on state public reporting websites, the variability of these reported prices, and zip code characteristics associated with greater price variation. STUDY DESIGN: Searches of state government-operated websites in Michigan, Missouri, New York, and Pennsylvania for retail prices for Advair Diskus (250/50 fluticasone propionate/salmeterol), Lyrica (pregabalin 50 mg), Nasonex (mometasone 50 mcg nasal spray), Spiriva (tiotropium 18 mcg cp-handihaler), Zetia (ezetimibe 10 mg), atorvastatin 20 mg, and metoprolol 50 mg. METHODS: Data were collected for a 25% random sample of 1330 zip codes. For zip codes with at least 1 pharmacy, we used chi2 tests to compare how often prices were reported. For zip codes with at least 2 reported prices, we used Kruskal-Wallis tests to compare the median difference between the highest and lowest prices and a generalized linear model to identify zip code characteristics associated with greater price variation. RESULTS: Price availability varied significantly (P <.001) across states and drugs, ranging from 52% for metoprolol in Michigan to 1% for atorvastatin in Michigan. Price variation also varied significantly (P <.001) across states and drugs, ranging from a median of $159 for atorvastatin in Pennsylvania to a median of $24 for Nasonex in Missouri. The mean price variation was $52 greater (P <.001) for densely populated zip codes and $60 greater (P <.001) for zip codes with mostly nonwhite residents. CONCLUSIONS: Publicly reported information on state prescription drug price websites is often deficient. When prices are reported, there can be significant variation in the prices of prescriptions, which could translate into substantial savings for consumers who pay out-of-pocket for prescription drugs. PMID- 28817780 TI - US internists' awareness and use of overtreatment guidelines: a national survey. AB - OBJECTIVES: To assess physician views and perceived adoption of overtreatment guidelines and measure whether adoption of these guidelines influenced the recommendation of a targeted service. STUDY DESIGN: A cross-sectional survey mailed from July 2014 to January 2015 to 902 internists who completed residency between 2003 and 2013, randomly selected from the American Medical Association Masterfile. METHODS: Poisson regression was used to model the rate of recommending a targeted service included in the guidelines, based on the level of guideline adoption. RESULTS: A total of 456 physicians responded (51% response rate). Most expressed familiarity with overtreatment guidelines (88.5%), a comfort level with discussing these guidelines with patients (79.9%), and described overtreatment guidelines as a useful tool in their practice (81.6%). Physicians in the highest tertile of guideline adoption reported double-digit rates of recommending antibiotics for sinusitis (29.7%), mammogram at end of life (16.5%), and electrocardiogram testing for asymptomatic patients (11.0%). Physicians in the bottom tertile of guideline adoption reported lower rates of recommending x rays (-12.0%; 95% confidence interval [CI], -19.4% to -4.5%; P = .002), magnetic resonance imaging for lower back pain (-4.8%; 95% CI, -8.1% to 1.5%; P = .004), and cardiac testing for asymptomatic patients (-10.2%; 95% CI, 18.9% to -1.5%; P = .02). CONCLUSIONS: US internal medicine physicians who completed residency between 2003 and 2013 reported high levels of adoption of overtreatment guidelines. Physicians who reported the highest levels of guideline adoption reported recommending services targeted by these guidelines in their practice. PMID- 28817782 TI - Cost-effectiveness of a patient navigation program to improve cervical cancer screening. AB - OBJECTIVES: To assess the cost-effectiveness of a community-based patient navigation program to improve cervical cancer screening among Hispanic women 18 or older in San Antonio, Texas. STUDY DESIGN: We used a microsimulation model of cervical cancer to project the long-term cost-effectiveness of a community-based patient navigation program compared with current practice. METHODS: We used program data from 2012 to 2015 and published data from the existing literature as model input. Taking a societal perspective, we estimated the lifetime costs, life expectancy, and quality-adjusted life-years and conducted 2-way sensitivity analyses to account for parameter uncertainty. RESULTS: The patient navigation program resulted in a per-capita gain of 0.2 years of life expectancy. The program was highly cost-effective relative to no intervention (incremental cost effectiveness ratio of $748). The program costs would have to increase up to 10 times from $311 for it not to be cost-effective. CONCLUSIONS: The 3-year community-based patient navigation program effectively increased cervical cancer screening uptake and adherence and improved the cost-effectiveness of the screening program for Hispanic women 18 years or older in San Antonio, Texas. Future research is needed to translate and disseminate the patient navigation program to other socioeconomic and demographic groups to test its robustness and design. PMID- 28817783 TI - The association between insurance type and cost-related delay in care: a survey. AB - OBJECTIVES: Massachusetts has insurance rates similar to those projected under the Affordable Care Act, but many of the state's patients are insured through private insurance plans with high out-of-pocket costs. We aimed to explore the relationship between insurance type (private vs public) and delays in care due to cost, stratified by income. STUDY DESIGN: Cross-sectional study. METHODS: We conducted a study of English-speaking adults recruited from the waiting rooms of the emergency department or outpatient clinics of a large healthcare system in western Massachusetts. Our primary outcome was the association between insurance type and cost-related delay in care, stratified by income. RESULTS: Of 800 individuals approached, 619 (77%) completed the survey. Participants were 60.6% male and 40.2% white, 37.2% Hispanic, and 12.6% black. The majority (61.4%) of those surveyed had public insurance, 34.1% had private insurance, and 4.5% were uninsured. Overall, 13.3% reported delays in seeking care that were related to cost. The impact of insurance on delay of care differed significantly by income tertile (P = .02): in the middle-income group ($12,500 to <$25,000 per person annually), privately insured respondents were more likely to delay care due to cost compared with publicly insured subjects (15.6% vs 8.1%; odds ratio [OR], 4.4; 95% confidence interval [CI], 1.9-10.2, unadjusted; OR, 2.2; 95% CI, 0.9 5.8, adjusted). CONCLUSIONS: Cost-related delays in care are prevalent despite the presence of an insurance mandate. Middle-income, privately insured patients report more cost-related delays in care compared with publicly insured patients with similar incomes. PMID- 28817784 TI - Hydrogen peroxide regulates angiogenesis-related factors in tumor cells. AB - Tumor angiogenesis is required for tumor development and growth, and is regulated by several factors including ROS. H2O2 is a ROS with an important role in cell signaling, but how H2O2 regulates tumor angiogenesis is still poorly understood. We have xenografted tumor cells with altered levels of H2O2 by catalase overexpression into zebrafish embryos to study redox-induced tumor neovascularization. We found that vascular recruitment and invasion were impaired if catalase was overexpressed. In addition, the overexpression of catalase altered the transcriptional levels of several angiogenesis-related factors in tumor cells, including TIMP-3 and THBS1. These two anti-angiogenic factors were found to be H2O2-regulated by two different mechanisms: TIMP-3 expression in a cell-autonomous manner; and, THBS1 expression that was non-cell-autonomous. Our work shows that intracellular H2O2 regulates the expression of angiogenic factors and the formation of a vessel network. Understanding the molecular mechanisms that govern this multifunctional effect of H2O2 on tumor angiogenesis could be important for the development of more efficient anti-angiogenic therapies. PMID- 28817785 TI - Diving into the world of alcohol teratogenesis: a review of zebrafish models of fetal alcohol spectrum disorder. AB - The term fetal alcohol spectrum disorder (FASD) refers to the entire suite of deleterious outcomes resulting from embryonic exposure to alcohol. Along with other reviews in this special issue, we provide insight into how animal models, specifically the zebrafish, have informed our understanding of FASD. We first provide a brief introduction to FASD. We discuss the zebrafish as a model organism and its strengths for alcohol research. We detail how zebrafish has been used to model some of the major defects present in FASD. These include behavioral defects, such as social behavior as well as learning and memory, and structural defects, disrupting organs such as the brain, sensory organs, heart, and craniofacial skeleton. We provide insights into how zebrafish research has aided in our understanding of the mechanisms of ethanol teratogenesis. We end by providing some relatively recent advances that zebrafish has provided in characterizing gene-ethanol interactions that may underlie FASD. PMID- 28817786 TI - Propofol attenuates BV2 microglia inflammation via NMDA receptor inhibition. AB - Activated microglia, involved in the occurrence and improvement of sepsis associated encephalopathy, can induce the expression of pro-inflammatory cytokines and pro-inflammatory enzymes, resulting in inflammation-mediated neuronal cell death. It was reported that propofol could inhibit lipopolysaccharide (LPS) induced pro-inflammatory cytokine and pro-inflammatory enzyme expression in BV2 and primary microglial cells. However, the underlying mechanism is not well known. In the present study, we investigated whether and how propofol inhibited LPS-induced the expression of pro-inflammatory cytokines and pro-inflammatory enzymes in BV2 cells. LPS induced pro-inflammatory cytokine and pro-inflammatory enzyme expression, NF-kappaB, extracellular regulated kinase 1/2 (ERK), calcium (Ca2+)/calmodulin-dependent protein kinase II (CaMK II) phosphorylation, and BV2 cell Ca2+ accumulation. Propofol could reverse these effects induced by LPS. MK801, an inhibitor of the NMDA receptor, could attenuate LPS-induced Ca2+ accumulation, the expression of pro-inflammatory cytokines and pro-inflammatory enzymes, and phosphorylation of NF-kappaB, ERK, and CaMK II, which was similar to propofol. Moreover, these effects of propofol could be counteracted by rapastinel, an activator of the NMDA receptor. The present study suggested that propofol, via inhibiting the NMDA receptor, attenuating Ca2+ accumulation, and inhibiting CaMK II, ERK1/2, and NF-kappaB phosphorylation, down regulated LPS-induced pro-inflammatory cytokine and pro-inflammatory enzyme expression. PMID- 28817787 TI - Evaluation of the electron transfer flavoprotein as an antibacterial target in Burkholderia cenocepacia. AB - There are hundreds of essential genes in multidrug-resistant bacterial genomes, but only a few of their products are exploited as antibacterial targets. An example is the electron transfer flavoprotein (ETF), which is required for growth and viability in Burkholderia cenocepacia. Here, we evaluated ETF as an antibiotic target for Burkholderia cepacia complex (Bcc). Depletion of the bacterial ETF during infection of Caenorhabditis elegans significantly extended survival of the nematodes, proving that ETF is essential for survival of B. cenocepacia in this host model. In spite of the arrest in respiration in ETF mutants, the inhibition of etf expression did not increase the formation of persister cells, when treated with high doses of ciprofloxacin or meropenem. To test if etf translation could be inhibited by RNA interference, antisense oligonucleotides that target the etfBA operon were synthesized. One antisense oligonucleotide was effective in inhibiting etfB translation in vitro but not in vivo, highlighting the challenge of reduced membrane permeability for the design of drugs against B. cenocepacia. This work contributes to the validation of ETF of B. cenocepacia as a target for antibacterial therapy and demonstrates the utility of a C. elegans liquid killing assay to validate gene essentiality in an in vivo infection model. PMID- 28817788 TI - The joint effect of the endothelin receptor B gene (EDNRB) polymorphism rs10507875 and nitric oxide synthase 3 gene (NOS3) polymorphism rs869109213 in Slovenian patients with type 2 diabetes mellitus and diabetic retinopathy. AB - Increasing evidence suggests that endothelin and nitric oxide synthase genes and their products exert biological effects on the vasculature via the nitric oxide or endothelin pathway. The aim of the study was to evaluate the association of rs10507875 and rs869109213 (alone or in interaction) with diabetic retinopathy (DR) in subjects with type 2 diabetes mellitus (T2DM). We genotyped the single nucleotide polymorphism rs10507875 of the endothelin receptor B gene (EDNRB) and variable number tandem repeats rs869109213 of the nitric oxide synthase 3 gene (NOS3) in 270 Slovenian patients with DR and T2DM and 256 controls with T2DM without clinical signs of DR. The genotyping was performed using either real-time polymerase chain reaction (PCR) or standard PCR. We found a significant association between the genotypes of NOS3 rs869109213 polymorphism and the risk of DR in the co-dominant model (4a4b genotype; 1.99-fold increased risk [1.09 3.65]; 95% confidence interval [CI]; p = 0.02), co-dominant model (4a4a genotype; 4.16-fold increased risk [1.03-16.74]; 95% CI; p = 0.04), and dominant model (4a4a and 4a4b genotypes; 2.22-fold increased risk [1.26-3.92]; 95% CI; p = 0.01) compared to the 4b4b genotype. Moreover, the joint effect of the two polymorphisms on DR risk was greater than the individual effect of each polymorphism in the analyzed genetic models. Additionally, adjusted odds ratio showed an increased risk in dominant * dominant (4.15-fold [1.40-12.26]; 95% CI; p = 0.01) and recessive * dominant (2.24-fold [1.25-4.01]; 95% CI; p = 0.02) genotype combinations of the two polymorphisms. In conclusion, our results indicate that NOS3 rs869109213 polymorphism alone or in a combination with EDNRB rs10507875 polymorphism may be associated with DR in Slovenian patients with T2DM. PMID- 28817789 TI - Teach Our Children: Stroke Education for Indigenous Children, First Nations, Ontario, Canada, 2009-2012. AB - BACKGROUND: Because of the heightened risk for stroke among indigenous people, we conducted this multiyear community case study from 2009 through 2012 to address stroke education needs among children aged 11 to 13 years residing in northern urban, rural, and remote First Nations in Ontario, Canada. The goal was to determine what young people understand about stroke and to develop an age appropriate and culturally appropriate educational product. COMMUNITY CONTEXT: This project responded to First Nations requests that we educate their young people about the signs and symptoms of stroke and the need for early response. Ten First Nations and 4 indigenous health organizations took part; 7 contributed to the educational product. METHODS: This study was developed under the guidance of the Northwestern Ontario Regional Stroke Network Aboriginal Advisory Committee. It employed indigenous researchers and facilitators to ensure that methods used (questions assessing children's knowledge of stroke and their ideas on how best to deliver messages) reflected the cultural values of participating study sites. OUTCOME: Indigenous children had limited knowledge about stroke and its signs, symptoms, and consequences; children in remote communities were better informed than those in other locations. Educators agreed that a DVD was the most effective way to deliver stroke information to children in this age group. The principal outcome from this 3-year community engagement was an 11.5-minute DVD titled Act F-A-S-T 1-2-3!. Follow-up indicated that the educational tool continued to be used to educate indigenous children and adults about stroke signs and symptoms, the need for early response, and risk reduction. INTERPRETATION: Although indigenous communities are each unique in their culture and traditions, all have a strong commitment to improving health and are generous in their support for research that addresses their needs. Our study provides examples of the engagement and participatory research strategies that were effective, the practical supports required, limitations to the study, and how barriers to stroke education can be overcome. PMID- 28817790 TI - Maximum Lifetime Body Mass Index and Mortality in Mexican American Adults: the National Health and Nutrition Examination Survey III (1988-1994) and NHANES 1999 2010. AB - INTRODUCTION: Studies in US Hispanic adults indicate no deleterious association between obesity and death. We tested the hypothesis that accounting for weight history would provide more insight into this nonassociation. METHODS: We used the National Health and Nutrition Examination Survey (NHANES) to examine associations between maximum lifetime body mass index (BMI) and all-cause and cause-specific mortality among US-residing Mexican American adults. BMI was classified as underweight (<18.5 kg/m2), normal weight (18.5-24.9), overweight (25.0-29.9), obese class I (30.0-34.9), and obese class II (>=35.0). We used Cox proportional hazards to examine the association between maximum lifetime BMI and BMI at survey and all-cause and specific causes of death (ie, cardiovascular disease, cancer, diabetes, and other) controlling for age, sex, and smoking in 6,242 Mexican American adults enrolled in NHANES III (1988-1994) and NHANES 1999-2010. RESULTS: Mexican Americans categorized as obese class II at maximum lifetime and time of survey had increased risk of all-cause mortality (hazard ratio [HR], 2.12; 95% confidence interval [CI], 1.54 - 2.93 and HR, 1.52; 95% CI, 1.10-2.10). Those reporting a maximum lifetime BMI of class I or class II obesity but who were classified as normal weight at survey had increased risk of all-cause mortality (HR = 2.49; 95% CI, 1.72-3.61 and HR = 3.56; 95% CI, 1.15-11.06, respectively). CONCLUSION: Increased all-cause mortality risk in Mexican Americans with a lifetime BMI of 35 or greater refutes prior studies, suggesting that maximum lifetime BMI should be included when evaluating obesity-mortality associations in this population. PMID- 28817791 TI - Using Practice Facilitation to Increase Rates of Colorectal Cancer Screening in Community Health Centers, North Carolina, 2012-2013: Feasibility, Facilitators, and Barriers. AB - INTRODUCTION: Practice facilitation involves trained individuals working with practice staff to conduct quality improvement activities and support delivery of evidence-based clinical services. We examined the feasibility of using practice facilitation to assist federally qualified health centers (FQHCs) to increase colorectal cancer screening rates in North Carolina. METHODS: The intervention consisted of 12 months of facilitation in 3 FQHCs. We conducted chart audits to obtain data on changes in documented recommendation for colorectal cancer screening and completed screening. Key informant interviews provided qualitative data on barriers to and facilitators of implementing office systems. RESULTS: Overall, the percentage of eligible patients with a documented colorectal cancer screening recommendation increased from 15% to 29% (P < .001). The percentage of patients up to date with colorectal cancer screening rose from 23% to 34% (P = .03). Key informants in all 3 clinics said the implementation support from the practice facilitator was critical for initiating or improving office systems and that modifying the electronic medical record was the biggest challenge and most time-consuming aspect of implementing office systems changes. Other barriers were staff turnover and reluctance on the part of local gastroenterology practices to perform free or low-cost diagnostic colonoscopies for uninsured or underinsured patients. CONCLUSION: Practice facilitation is a feasible, acceptable, and promising approach for supporting universal colorectal cancer screening in FQHCs. A larger-scale study is warranted. PMID- 28817792 TI - Making Human Stars: A New Method to Generate Human Astrocytes. AB - Human astrocytes are increasingly appreciated as important contributors to brain function in health and disease, but techniques to study them are limited. In this issue of Neuron, Sloan and colleagues (2017) describe a new 3D culture model that generates mature human astrocytes, opening the door to future studies of their function. PMID- 28817793 TI - Precision Neuroscience: Dense Sampling of Individual Brains. AB - In this issue, Gordon et al. (2017) use dense sampling of resting and task fMRI within individuals to demonstrate that patterns of correlation in resting fMRI are closely aligned with functional architecture as identified using task fMRI. PMID- 28817794 TI - A Triad of Crystals Sheds Light on MDGA Interference with Neuroligation. AB - Neurexins and neuroligins form trans-synaptic complexes that promote synapse development. In this issue of Neuron, Aricescu and colleagues (Elegheert et al., 2017) complement and strengthen two recent reports by the Kim and Rudenko teams (Kim et al., 2017; Gangwar et al., 2017) to dissect the molecular determinants by which MDGAs challenge the neurexin-neuroligin partnership. PMID- 28817795 TI - Hippocampal Dentate Mossy Cells Improve Their CV and Trk into the Limelight. AB - The impact of dentate mossy cells on hippocampal activity remained uncertain despite a long history of investigation. In this issue of Neuron, Hashimotodani et al. (2017) discover a presynaptically expressed form of long-term potentiation at mossy cell outputs, shedding light on their mysterious function. PMID- 28817796 TI - The Strange Case of Aggression and the Brain. AB - Territorial male mice are aggressive toward intruding males, but socially bonded males are not. Through manipulation of activity in a subset of neurons in the ventromedial hypothalamus, Yang et al. (2017) report that social and physiological factors non-linearly interact to control male aggression. PMID- 28817797 TI - Wrapped to Adapt: Experience-Dependent Myelination. AB - Activity of the nervous system has long been recognized as a critical modulator of brain structure and function. Influences of experience on the cytoarchitecture and functional connectivity of neurons have been appreciated since the classic work of Hubel and Wiesel (1963; Wiesel and Hubel, 1963a, 1963b). In recent years, a similar structural plasticity has come to light for the myelinated infrastructure of the nervous system. While an innate program of myelin development proceeds independently of nervous system activity, increasing evidence supports a role for activity-dependent, plastic changes in myelin forming cells that influence myelin structure and neurological function. Accumulating evidence of complementary and likely temporally overlapping activity independent and activity-dependent modes of myelination are beginning to crystallize in a model of myelin plasticity, with broad implications for neurological function in health and disease. PMID- 28817799 TI - Human Astrocyte Maturation Captured in 3D Cerebral Cortical Spheroids Derived from Pluripotent Stem Cells. AB - There is significant need to develop physiologically relevant models for investigating human astrocytes in health and disease. Here, we present an approach for generating astrocyte lineage cells in a three-dimensional (3D) cytoarchitecture using human cerebral cortical spheroids (hCSs) derived from pluripotent stem cells. We acutely purified astrocyte-lineage cells from hCSs at varying stages up to 20 months in vitro using immunopanning and cell sorting and performed high-depth bulk and single-cell RNA sequencing to directly compare them to purified primary human brain cells. We found that hCS-derived glia closely resemble primary human fetal astrocytes and that, over time in vitro, they transition from a predominantly fetal to an increasingly mature astrocyte state. Transcriptional changes in astrocytes are accompanied by alterations in phagocytic capacity and effects on neuronal calcium signaling. These findings suggest that hCS-derived astrocytes closely resemble primary human astrocytes and can be used for studying development and modeling disease. PMID- 28817798 TI - Toward a Wiring Diagram Understanding of Appetite Control. AB - Prior mouse genetic research has set the stage for a deep understanding of appetite regulation. This goal is now being realized through the use of recent technological advances, such as the ability to map connectivity between neurons, manipulate neural activity in real time, and measure neural activity during behavior. Indeed, major progress has been made with regard to meal-related gut control of appetite, arcuate nucleus-based hypothalamic circuits linking energy state to the motivational drive, hunger, and, finally, limbic and cognitive processes that bring about hunger-mediated increases in reward value and perception of food. Unexpected findings are also being made; for example, the rapid regulation of homeostatic neurons by cues that predict future food consumption. The aim of this review is to cover the major underpinnings of appetite regulation, describe recent advances resulting from new technologies, and synthesize these findings into an updated view of appetite regulation. PMID- 28817801 TI - A Sensitized IGF1 Treatment Restores Corticospinal Axon-Dependent Functions. AB - A major hurdle for functional recovery after both spinal cord injury and cortical stroke is the limited regrowth of the axons in the corticospinal tract (CST) that originate in the motor cortex and innervate the spinal cord. Despite recent advances in engaging the intrinsic mechanisms that control CST regrowth, it remains to be tested whether such methods can promote functional recovery in translatable settings. Here we show that post-lesional AAV-assisted co-expression of two soluble proteins, namely insulin-like growth factor 1 (IGF1) and osteopontin (OPN), in cortical neurons leads to robust CST regrowth and the recovery of CST-dependent behavioral performance after both T10 lateral spinal hemisection and a unilateral cortical stroke. In these mice, a compound able to increase axon conduction, 4-aminopyridine-3-methanol, promotes further improvement in CST-dependent behavioral tasks. Thus, our results demonstrate a potentially translatable strategy for restoring cortical dependent function after injury in the adult. PMID- 28817802 TI - Molecular Memory of Morphologies by Septins during Neuron Generation Allows Early Polarity Inheritance. AB - Transmission of polarity established early during cell lineage history is emerging as a key process guiding cell differentiation. Highly polarized neurons provide a fascinating model to study inheritance of polarity over cell generations and across morphological transitions. Neural crest cells (NCCs) migrate to the dorsal root ganglia to generate neurons directly or after cell divisions in situ. Using live imaging of vertebrate embryo slices, we found that bipolar NCC progenitors lose their polarity, retracting their processes to round for division, but generate neurons with bipolar morphology by emitting processes from the same locations as the progenitor. Monitoring the dynamics of Septins, which play key roles in yeast polarity, indicates that Septin 7 tags process sites for re-initiation of process growth following mitosis. Interfering with Septins blocks this mechanism. Thus, Septins store polarity features during mitotic rounding so that daughters can reconstitute the initial progenitor polarity. PMID- 28817800 TI - TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics. AB - Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 * 10-6). Postmortem neuropathology of five TIA1 mutations carriers showed a consistent pathological signature with numerous round, hyaline, TAR DNA-binding protein 43 (TDP-43)-positive inclusions. TIA1 mutations significantly increased the propensity of TIA1 protein to undergo phase transition. In live cells, TIA1 mutations delayed stress granule (SG) disassembly and promoted the accumulation of non-dynamic SGs that harbored TDP-43. Moreover, TDP-43 in SGs became less mobile and insoluble. The identification of TIA1 mutations in ALS/FTD reinforces the importance of RNA metabolism and SG dynamics in ALS/FTD pathogenesis. PMID- 28817803 TI - Developmental Dysfunction of VIP Interneurons Impairs Cortical Circuits. AB - GABAergic interneurons play important roles in cortical circuit development. However, there are multiple populations of interneurons and their respective developmental contributions remain poorly explored. Neuregulin 1 (NRG1) and its interneuron-specific receptor ERBB4 are critical genes for interneuron maturation. Using a conditional ErbB4 deletion, we tested the role of vasoactive intestinal peptide (VIP)-expressing interneurons in the postnatal maturation of cortical circuits in vivo. ErbB4 removal from VIP interneurons during development leads to changes in their activity, along with severe dysregulation of cortical temporal organization and state dependence. These alterations emerge during adolescence, and mature animals in which VIP interneurons lack ErbB4 exhibit reduced cortical responses to sensory stimuli and impaired sensory learning. Our data support a key role for VIP interneurons in cortical circuit development and suggest a possible contribution to pathophysiology in neurodevelopmental disorders. These findings provide a new perspective on the role of GABAergic interneuron diversity in cortical development. VIDEO ABSTRACT. PMID- 28817804 TI - Structural Mechanism for Modulation of Synaptic Neuroligin-Neurexin Signaling by MDGA Proteins. AB - Neuroligin-neurexin (NL-NRX) complexes are fundamental synaptic organizers in the central nervous system. An accurate spatial and temporal control of NL-NRX signaling is crucial to balance excitatory and inhibitory neurotransmission, and perturbations are linked with neurodevelopmental and psychiatric disorders. MDGA proteins bind NLs and control their function and interaction with NRXs via unknown mechanisms. Here, we report crystal structures of MDGA1, the NL1-MDGA1 complex, and a spliced NL1 isoform. Two large, multi-domain MDGA molecules fold into rigid triangular structures, cradling a dimeric NL to prevent NRX binding. Structural analyses guided the discovery of a broad, splicing-modulated interaction network between MDGA and NL family members and helped rationalize the impact of autism-linked mutations. We demonstrate that expression levels largely determine whether MDGAs act selectively or suppress the synapse organizing function of multiple NLs. These results illustrate a potentially brain-wide regulatory mechanism for NL-NRX signaling modulation. PMID- 28817805 TI - LTP at Hilar Mossy Cell-Dentate Granule Cell Synapses Modulates Dentate Gyrus Output by Increasing Excitation/Inhibition Balance. AB - Excitatory hilar mossy cells (MCs) in the dentate gyrus receive inputs from dentate granule cells (GCs) and project back to GCs locally, contralaterally, and along the longitudinal axis of the hippocampus, thereby establishing an associative positive-feedback loop and connecting functionally diverse hippocampal areas. MCs also synapse with GABAergic interneurons that mediate feed forward inhibition onto GCs. Surprisingly, although these circuits have been implicated in both memory formation (e.g., pattern separation) and temporal lobe epilepsy, little is known about activity-dependent plasticity of their synaptic connections. Here, we report that MC-GC synapses undergo a presynaptic, NMDA receptor-independent form of long-term potentiation (LTP) that requires postsynaptic brain-derived neurotrophic factor (BDNF)/TrkB and presynaptic cyclic AMP (cAMP)/PKA signaling. This LTP is input specific and selectively expressed at MC-GC synapses, but not at the disynaptic inhibitory loop. By increasing the excitation/inhibition balance, MC-GC LTP enhances GC output at the associative MC GC recurrent circuit and may contribute to dentate-dependent forms of learning and epilepsy. PMID- 28817806 TI - Specialized Mechanosensory Nociceptors Mediating Rapid Responses to Hair Pull. AB - The somatosensory system provides animals with the ability to detect, distinguish, and respond to diverse thermal, mechanical, and irritating stimuli. While there has been progress in defining classes of neurons underlying temperature sensation and gentle touch, less is known about the neurons specific for mechanical pain. Here, we use in vivo functional imaging to identify a class of cutaneous sensory neurons that are selectively activated by high-threshold mechanical stimulation (HTMRs). We show that their optogenetic excitation evokes rapid protective and avoidance behaviors. Unlike other nociceptors, these HTMRs are fast-conducting Adelta-fibers with highly specialized circumferential endings wrapping the base of individual hair follicles. Notably, we find that Adelta HTMRs innervate unique but overlapping fields and can be activated by stimuli as precise as the pulling of a single hair. Together, the distinctive features of this class of Adelta-HTMRs appear optimized for accurate and rapid localization of mechanical pain. VIDEO ABSTRACT. PMID- 28817807 TI - Mir-21 Promotes Cardiac Fibrosis After Myocardial Infarction Via Targeting Smad7. AB - BACKGROUND/AIMS: Cardiac fibrosis after myocardial infarction (MI) has been identified as an important factor in the deterioration of heart function. Previous studies have demonstrated that miR-21 plays an important role in various pathophysiological processes in the heart. However, the role of miR-21 in fibrosis regulation after MI remains unclear. METHODS: To induce cardiac infarction, the left anterior descending coronary artery was permanently ligated of mice. First, we explored the expression of miR-21 in the infarcted zone in mice model of MI via RT-qPCR. Next, we examined the effects of TGF-beta1 on miR 21 expression in cardiac fibroblasts (CFs). Then, CFs were infected with miR-21 mimics or miR-21 inhibitors to investigate the effects of miR-21 on the process of CFs activation in vitro. Further, bioinformatics analysis and luciferase reporter assay were performed to identify and validate the target gene of miR-21. At last, in-vivo study was done to confirm MiR-21 regulated myocardial fibrosis after MI in mice. RESULTS: MiR-21 was up-regulated in the infarcted zone after MI in vivo. TGF-beta1 treatment increased miR-21 expression in CFs. Overexpression of miR-21 promoted the effects of TGF-beta1-induced activation of CFs, evidenced by increased expression of Col-1, alpha-SMA and F-actin, whereas inhibition of miR-21 attenuated the process of fibrosis. Bioinformatics, Western blot analysis and luciferase reporter assay demonstrated that Smad7 is a direct target of miR 21. In addition, in-vivo study revealed that MiR-21 regulated myocardial fibrosis after MI in mice. CONCLUSION: These findings suggested that miR-21 has a critical role in CF activation and cardiac fibrosis after MI through via TGF-beta/Smad7 signaling pathway. Thus, miR-21 promises to be a potential therapy in treatment of cardiac fibrosis after MI. PMID- 28817808 TI - PPARalpha Agonist Stimulated Angiogenesis by Improving Endothelial Precursor Cell Function Via a NLRP3 Inflammasome Pathway. AB - BACKGROUND: Impaired wound healing is a common complication of diabetes and is the leading cause of lower extremity amputation. Treatment with fenofibrate, a peroxisome proliferators-activated receptor alpha (PPARalpha) agonist, was associated with a lower risk of amputations, particularly minor amputations without known large-vessel diseases, probably through non-lipid mechanisms. The current study aimed to test our hypothesis that fenofibrate stimulates angiogenesis and restores endothelial precursor cell (EPC) function via inhibiting Nod-like receptor protein 3 (NLRP3) inflammasome in streptozotocin (STZ)-induced diabetic mice. METHODS: Male C57BL/6 mice were randomly divided into three groups: control, STZ-induced diabetic mice and fenofibrate treated diabetic group. Wound closure was assessed by wound area and CD31 positive capillaries. Both the migration and tube formation capacities of EPCs were measured. Intracellular nitric oxide (NO) and superoxide (O2-) levels were determined. Activity of NLRP3 inflammasome in EPCs was assessed by measuring thioredoxin-interacting protein (TXNIP), NLRP3, and caspase-1 expression. RESULTS: Compared with the untreated diabetic mice, wound closure and capillary densities were significantly increased in fenofibrate treated group. Fenofibrate treatment restored EPC function, increased NO production, and decreased O2- level in EPCs of diabetic mice. Furthermore, fenofibrate deregulated the activity of NLRP3 inflammasome by reducing TXNIP, NLRP3 and caspase-1 expression in EPCs of diabetic mice. In vitro, fenofibrate prevented high glucose induced EPC dysfunction, deregulated NLRP3 inflammasome activity. In addition, fenofibrate inhibited IL-1beta expression caused by combination use of high glucose and lipopolysaccharide. CONCLUSION: Fenofibrate can accelerate wound healing in diabetic mice, which at least in part was mediated by improving the impaired EPC function via a NLRP3 inflammasome pathway, suggesting the significance of PPARalpha agonists in the treatment of diabetes. PMID- 28817809 TI - Evaluation of Infliximab Therapy in Children with Crohn's Disease Using Trough Levels Predictors. AB - BACKGROUND: In adults, infliximab (IFX) levels correlate with disease activity, and antibodies to IFX (ATIs) predict treatment failure. We aimed to determine the association of IFX levels and ATIs with disease activity in a paediatric population. We prospectively collected blood, stool, and clinical data from 65 patients (age 10.5-15.1 years) with Crohn's disease (CD) before IFX administration, and measured IFX trough levels, ATIs, and faecal calprotectin levels (CPT). Samples were collected during maintenance therapy. We used multivariate analysis to identify the predictors of IFX levels. SUMMARY: Lower levels of IFX were associated with ATIs positivity (OR 0.027, 95% CI 0.009 0.077). Higher C-reactive protein (CRP) level, erythrocyte sedimentation rate, and CPT levels were found in patients with lower IFX levels. The optimal combination of sensitivity (0.5) and specificity (0.74) for disease activity was calculated for IFX levels >=1.1 ug/mL using CRP level <5 mg/L as a marker of laboratory remission. In a model that used CPT <=100 ug/g as the definition of remission, the optimal IFX trough level was 3.5 ug/mL. No independent association between remission and ATIs was found in our study population. However, we found an independentz association between IFX levels and serum albumin levels (OR 1.364, 95% CI 1.169-1.593), p < 0.001. Key Messages: The paediatric population was similar to adult populations in terms of the association between IFX and ATIs as well as between IFX and disease activity. PMID- 28817810 TI - TGF-beta1 is Involved in Vitamin D-Induced Chondrogenic Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells by Regulating the ERK/JNK Pathway. AB - BACKGROUND/AIMS: Osteoarthritis (OA) is characterized by degradation of cartilage, sole cell type of which is chondrocytes. Bone marrow-derived mesenchymal stem cells (BMSCs) possess multipotency and can be directionally differentiated into chondrocytes under stimulation. This study was aimed to explore the possible roles of vitamin D and transforming growth factor-beta1 (TGF beta1) in the chondrogenic differentiation of BMSCs. METHODS: BMSCs were isolated from femurs and tibias of rats and characterized by flow cytometry. After stimulation with vitamin D, BMSC proliferation and migration were measured by Cell Counting Kit-8 (CCK-8) and Transwell assays, respectively. Chondrogenic differentiation was estimated through expression levels of specific markers by qRT-PCR and Western blot analysis. After stable transfection, the effects of aberrantly expressed TGF-beta1 on vitamin D-induced alterations, including BMSC viability, migration and chondrogenic differentiation, were all evaluated utilizing CCK-8 assay, Transwell assay, qRT-PCR and Western blot analysis. Finally, the phosphorylation levels of key kinases in the extracellular signal regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways were determined by Western blot analysis. RESULTS: Vitamin D remarkably promoted BMSC viability, migration and chondrogenic differentiation. These alterations of BMSCs induced by vitamin D were reinforced by TGF-beta1 overexpression while were reversed by TGF beta1 silencing. Additionally, the phosphorylation levels of ERK, JNK and c-Jun were enhanced by TGF-beta1 overexpression but were reduced by TGF-beta1 knockdown. CONCLUSION: Vitamin D promoted BMSC proliferation, migration and chondrogenic differentiation. TGF-beta1 might be implicated in the vitamin D induced alterations of BMSCs through regulating ERK/JNK pathway. PMID- 28817811 TI - Downregulation of MicroRNA-330 Correlates with the Radiation Sensitivity and Prognosis of Patients with Brain Metastasis from Lung Cancer. AB - BACKGROUND: The present study sought to explore the role of microRNA-330 (miR 330) in predicting the radiation response and prognosis of patients with brain metastasis (BM) from lung cancer (LC). METHODS: Patients with BM from LC were identified and classified into radiation-sensitive and radiation-resistant groups according to the overall survival rate, local and distant recurrence rate after conventional whole-brain radiation therapy. Quantitative realtime polymerase chain reaction (qRT-PCR) was used to detect miR-330 expression in serum. Receiver operating characteristic (ROC) curves were used to evaluate the prognostic value of miR-330 for the radiation sensitivity of brain metastasis from LC. Related clinical factors for radiation sensitivity were assessed by logistic regression analysis, and a survival analysis was conducted using COX regression and the Kaplan-Meier method. RESULTS: MiR-330 exhibited lower expression in the radiation sensitive group than in the radiation-resistant group. The area under the ROC curve of miR-330 for predicting radiation sensitivity was 0.898 (optimal cut-off value, 0.815), with a sensitivity of 71.7% and a specificity of 90.1%. After radiation therapy, patients with low miR-330 expression, compared to patients with high miR-330 expression, displayed a lower survival rate and a median survival time. MiR-330 expression was correlated with extracranial metastasis, maximum BM diameter, tumor-node-metastasis (TNM) stage and node (N) stage. Logistic regression and COX regression analyses revealed that extracranial metastasis, TNM stage, N stage and miR-330 expression were factors that influenced both radiation sensitivity and individual prognostic factors in patients with BM from LC. CONCLUSIONS: These findings indicate that the downregulation of miR-330 correlates with radiation sensitivity and poor prognosis in patients with BM from LC. PMID- 28817812 TI - The miR-34a/Bcl-2 Pathway Contributes to Auditory Cortex Neuron Apoptosis in Age Related Hearing Loss. AB - HYPOTHESIS: The miR-34a/Bcl-2 signaling pathway may play a role in the mechanisms related to age-related hearing loss (AHL) in the auditory cortex. BACKGROUND: The auditory cortex plays a key role in the recognition and processing of complex sound. It is difficult to explain why patients with AHL have poor speech recognition, so increasing numbers of studies have focused on its central change. Although micro (mi)RNAs in the central nervous system have recently been increasingly reported to be associated with age-related diseases, the molecular mechanisms of AHL in the auditory cortex are not fully understood. METHODS: The auditory brainstem response was used to assess the hearing ability of C57BL/6 mice, and q-PCR, immunohistochemistry, and Western blotting were used to detect the expression levels of miR-34a and Bcl-2 in the mouse auditory cortex. TUNEL and DNA fragmentation were adopted to detect the apoptosis of neurons in the auditory cortex. To verify the relationship of miR-34a and Bcl-2, we transfected an miR-34a mimic or miR-34a inhibitor into primary auditory cortex neurons. RESULTS: In this study, miR-34a/Bcl-2 signaling was examined in auditory cortex neurons during aging. miR-34a and apoptosis increased in the auditory cortex neurons of C57BL/6 mice with aging, whereas an age-related decrease in Bcl-2 was determined. In the primary neurons of the auditory cortex, miR-34a overexpression inhibited Bcl-2, leading to an increase in apoptosis. Moreover, miR-34a knockdown increased Bcl-2 expression and diminished apoptosis. CONCLUSION: Our results support a link between age-related apoptosis in auditory cortex neurons and miR 34a/Bcl-2 signaling, which may serve as a potential mechanism of the expression of AHL in the auditory cortex. PMID- 28817813 TI - The Effect of Tegafur-Uracil on Survival in T Categories as Defined in the Eighth Edition of the TNM Classification: An Exploratory Analysis of Postoperative Adjuvant Tegafur-Uracil on Survival in Patients with Adenocarcinoma of the Lung. AB - BACKGROUND: Tegafur-uracil (UFT) improves survival in patients with stage I adenocarcinoma of the lung. We evaluated the effect of UFT on survival in maximum primary tumor diameter (T) categories as defined in the eighth edition of the TNM Classification (TNM8). METHODS: Tumors were subgrouped on the basis of T category (TNM8) as follows: T1a, T <=1 cm; T1b, 1 < T <=2 cm; T1c, 2 < T <=3 cm; T2a, 3 < T <=4 cm; T2b , 4 < T <=5 cm; T3, 5 < T <=7 cm. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox proportional hazard models. RESULTS: UFT was associated with improved survival. The adjusted HRs were as follows: for T1a, 0.79 (95% CI 0.14-4.50); for T1b, 1.16 (95% CI 0.63-2.12); for T1c, 0.74 (95% CI 0.43-1.27); for T2a, 0.45 (95% CI 0.21-0.96); for T2b, 0.55 (95% CI 0.10-3.07), and for T3, 0.70 (95% CI 0.20-2.50). CONCLUSIONS: The adjuvant chemotherapy with UFT tended to improve survival in patients with adenocarcinoma of the lung of each T category based on TNM8, except T1b. PMID- 28817814 TI - Cardiac Computed Tomography Angiographic Findings as Predictors of Late Heart Failure in an Asymptomatic Diabetic Cohort: An 8-Year Prospective Follow-Up Study. AB - OBJECTIVES: Predictive models for heart failure (HF) in heterogeneous populations have had limited success. We examined cardiac computed tomography angiography (CTA) predictors of HF or cardiovascular death (HF-CVD) in a prospective study of asymptomatic diabetics undergoing baseline assessment by CTA. METHODS: The subjects (n = 735, aged 55-74 years, 51.2% women) had no clinical history of cardiovascular disease at study entry. Coronary artery calcium (CAC) score, CTA defined coronary atherosclerosis, cardiac chamber volumes, and clinical data were collected and late outcome events recorded over 8.4 +/- 0.6 years (range 7.3 9.3). RESULTS: HF-CVD occurred in 41 (5.6%) subjects, with HF occurring mostly (19/23, 82.6%) in subjects without preceding myocardial infarction. Baseline univariate clinical outcome predictors of HF-CVD included older age (p = 0.027), the duration of diabetes (p = 0.004), HbA1c (p < 0.0001), microvascular disease (retinopathy, microalbuminuria) (p < 0.0001), and systolic blood pressure (p = 0.035). Baseline univariate CTA predictors included CAC score (p = 0.004), coronary stenosis (p = 0.047), and a CTA-defined left/right atrial (LA/RA) volume ratio >1 (p < 0.0001). Independent predictors were an LA/RA volume ratio >1, microvascular disease, and systolic blood pressure (model C-statistic 0.792, 95% CI 0.758-0.824). Measures of the extent of coronary artery disease (CAD) were not independent predictors of HF-CVD. CONCLUSIONS: In a low- to moderate-risk asymptomatic diabetic population, CTA LA enlargement (LA/RA volume ratio) but not the extent of CAD had independent prognostic value for HF-CVD in addition to the clinical variables. PMID- 28817815 TI - Arterial and Venous Thrombosis in Haemophilia Patients: Experiences from a Danish Haemophilia Centre. PMID- 28817817 TI - Assessment of Direct-to-Consumer Genetic Testing Policy in Korea Based on Consumer Preference. AB - AIMS: In June 2016, Korea permitted direct-to-consumer genetic testing (DTC-GT) on 42 genes. However, both the market and industry have not yet been fully activated. Considering the aforementioned context, this study provides important insights. METHODS: The Korean DTC-GT policy assessment is based on consumer preference analysis using a discrete choice experiment. In August 2016, a web based survey was conducted to collect data from 1,200 respondents. RESULTS: The estimation results show that consumers prefer a DTC-GT product that is cheap, tests various items or genes, offers accurate test results, and guarantees the confidentiality of all information. However, consumers are not entirely satisfied by current DTC-GT products due to the existence of insufficient and/or inadequate policies. First, the permitted testing of 42 genes is insufficient to satisfy consumers' curiosity regarding their genes. Second, the accuracy of the DTC-GT products has not been fully verified, assessed, and communicated to consumers. Finally, regulatory loopholes that allow information leaks in the DTC-GT process can occur. CONCLUSIONS: These findings imply that DTC-GT requires an improvement in government policy-making criteria and the implementation of practical measures to guarantee test accuracy and genetic information. PMID- 28817818 TI - Computed Tomography: The Better Pulmonologist? PMID- 28817816 TI - Exosomes Derived from Human Bone Marrow Mesenchymal Stem Cells Promote Tumor Growth Through Hedgehog Signaling Pathway. AB - BACKGROUND/AIMS: Mesenchymal stem/stromal cells (MSCs) are known to home to sites of tumor microenvironments where they participate in the formation of the tumor microenvironment and to interplay with tumor cells. However, the potential functional effects of MSCs on tumor cell growth are controversial. Here, we, from the view of bone marrow MSC-derived exosomes, study the molecular mechanism of MSCs on the growth of human osteosarcoma and human gastric cancer cells. METHODS: MSCs derived from human bone marrow (hBMSCs) were isolated and cultured in complete DMEM/F12 supplemented with 10% exosome-depleted fetal bovine serum and 1% penicillin-streptomycin, cell culture supernatants containing exosomes were harvested and exosome purification was performed by ultracentrifugation. Osteosarcoma (MG63) and gastric cancer (SGC7901) cells, respectively, were treated with hBMSC-derived exosomes in the presence or absence of a small molecule inhibitor of Hedgehog pathway. Cell viability was measured by transwell invasion assay, scratch migration assay and CCK-8 test. The expression of the signaling molecules Smoothened, Patched-1, Gli1 and the ligand Shh were tested by western blot and RT-PCR. RESULTS: In this study, we found that hBMSC-derived exosomes promoted MG63 and SGC7901 cell growth through the activation of Hedgehog signaling pathway. Inhibition of Hedgehog signaling pathway significantly suppressed the process of hBMSC-derived exosomes on tumor growth. CONCLUSION: Our findings demonstrated the new roles of hedgehog signaling pathway in the hBMSCs derived exosomes induced tumor progression. PMID- 28817819 TI - Progressive Kyphosis Associated with Tethered Cord Syndrome Treated by Posterior Vertebral Column Resection in a Pediatric Patient. AB - Posterior vertebral column resection is a novel surgical approach for the treatment of progressive kyphosis associated with tethered cord syndrome that was first treated with untethering surgery. A patient with tethered cord syndrome associated with kyphosis first underwent untethering surgery, resulting in progressive kyphosis. Posterior vertebral column resection was performed to correct the kyphosis while shortening the spinal column to prevent the spinal cord from stretch injury. Good correction of kyphosis and reduction of tension on the neural elements were achieved without any neurological deficits. In progressive kyphosis associated with tethered cord syndrome, posterior vertebral column resection after untethering surgery represents a safe and efficacious but technically challenging option. PMID- 28817820 TI - Endo-Urological Techniques for Benign Uretero-Ileal Strictures Have Poor Efficacy and Affect Renal Function. AB - INTRODUCTION: Uretero-ileal strictures (UES) following urinary diversion are therapeutically challenging. We compared the efficacy, safety and renal outcome following therapeutic endo-urological techniques (EUTs) and open surgical revision of the anastomosis (SRA) for UES. MATERIAL AND METHODS: We retrospectively analysed all EUTs and SRAs performed for UES in 2 hospitals between 1987 and 2015. Restenosis was defined as recurrent radiographically diagnosed hydronephrosis and re-intervention. Renal function (estimated glomerular filtration rate [eGFR]) decrease was correlated with the number of EUTs per patient. RESULTS: Eighty-five UES were treated with 105 EUTs and 31 open revisions. Due to total obstruction, 28 (27%) EUTs were aborted. During a median follow-up of 33 months, restenosis occurred following 53 out of 77 (69%) completed EUTs and 4 out of 31 (13%) SRAs (p < 0.001 on univariable and multivariable analyses). No serious (Clavien >=3b) EUT-related complications occurred vs. 5 (19%) related to SRA (p < 0.001). The number of finalised EUTs was independently associated with eGFR loss (beta = 12.3 mL/min/1.73 m2 loss per EUT, p = 0.008), with a significant cutoff value of >1 EUTs. SRA did not affect renal function (beta = 6.8 mL/min/1.73 m2 loss, p = 0.276). CONCLUSIONS: Although EUTs are less invasive, they have an inferior efficacy to SRA. Our results suggest that a maximum of one EUT may be attempted without significantly compromising renal function. PMID- 28817821 TI - Endoscopic Lung Volume Reduction: An Expert Panel Recommendation - Update 2017. AB - Interest in endoscopic lung volume reduction (ELVR) technologies for emphysema is consistently growing. In the last couple of months, several endoscopic options (e.g., endo- or intrabronchial valves, coil implants, and thermal vapor ablation) that have been evaluated in randomized controlled trials have been reported with the ultimate goal of improving respiratory mechanics and alleviating chronic dyspnea. Patients presenting with severe air trapping and thoracic hyperinflation have the greatest potential to derive benefit from ELVR procedures. Baseline assessment should ideally include cardiological evaluation, high-resolution computed tomography scan and perfusion scintigraphy, full pulmonary function tests, and cardiopulmonary exercise testing. This expert statement updates best practice recommendations regarding patient selection and utilization of these various techniques for the treatment of patients with advanced emphysema. PMID- 28817822 TI - Predictors of Postoperative Non-Chylous Massive Discharge after Pancreaticoduodenectomy for Pancreatic Ductal Adenocarcinoma. AB - BACKGROUND: Pancreaticoduodenectomy (PD) is performed for pancreatic ductal adenocarcinoma (PDA) located at the pancreas head/body. Non-chylous massive discharge after PD is frequently encountered and can cause a vicious cycle of complications associated with severe dehydration and protein loss. METHODS: From August 2008 to June 2015, 102 patients who underwent PD for PDA were retrospectively reviewed. High non-chylous discharge was defined as postoperative daily serous discharge exceeding 10 mL/kg. Predictive factors for high non chylous discharge were assessed using multivariable analysis. RESULTS: Fifty-one patients (50%) developed high non-chylous discharge. Body mass index (BMI) and hemoglobin, total protein, and cholinesterase levels were significantly lower in the high-discharge group compared to the corresponding levels in the low discharge group. The incidence of postoperative pancreatic fistula and delayed gastric emptying was significantly lower and higher in the high-discharge group than in the low-discharge group, respectively. Multivariable analysis revealed that BMI <22.0 kg/m2, hemoglobin <12.0 g/dL and intraoperative blood loss >=800 mL were independent predictive factors for high non-chylous discharge. CONCLUSIONS: Preoperative low levels of BMI and hemoglobin and intraoperative high blood loss were independent predictive factors for high non-chylous discharge. Improvement of preoperative general and nutritional condition may reduce the incidence of high non-chylous discharge. PMID- 28817823 TI - Comparison of Renal Outcome among Japanese Patients with or without Microangiopathic Hemolysis in Malignant Phase Hypertension: A Single-Center Retrospective Study. AB - BACKGROUND/AIMS: Although microangiopathic hemolysis (MAH) is a well-known complication of malignant phase hypertension (MPH), only less data on whether MAH in MPH predicts renal outcome exist. Therefore, we evaluated whether MAH was associated with the renal outcome in patients with MPH. METHODS: We conducted a single-center, retrospective, cohort study. Data from 35 patients diagnosed with MPH between October 1998 and January 2015 were analyzed. MPH was defined as the presence of a diastolic blood pressure of >=120 mm Hg and grades III/IV hypertensive retinopathy according to the Keith-Wagener-Barker classification. MAH was defined as the presence of a low platelet count (<150 * 109/L) together with either an elevated level of lactate dehydrogenase (LDH; >220 U/L), or the presence of schistocytes, or both and the normalization of platelet and LDH level or schistocyte levels after adequate blood pressure control was achieved. The primary outcome was dialysis induction. RESULTS: Fifteen patients had MAH. Those with MAH had significantly severe renal dysfunction at the onset of MPH. The length of follow-up (median, interquartile range) of patients with MAH and those without MAH were 30 (16-94) and 48 (25-115) months, respectively. Dialysis was induced in 9 of 15 patients with MAH and in 6 of 20 patients without MAH. Renal survival in patients with MAH was worse than that in those without, but this was not statistically significant (p = 0.08). By multivariate Cox regression analysis, MAH was not shown to contribute to dialysis induction. CONCLUSION: MAH did not predict renal outcome in MPH. PMID- 28817824 TI - Parametric Linkage Analysis Identifies Five Novel Genome-Wide Significant Loci for Familial Lung Cancer. AB - OBJECTIVE: One of four American cancer patients dies of lung cancer. Environmental factors such as tobacco smoking are known to affect lung cancer risk. However, there is a genetic factor to lung cancer risk as well. Here, we perform parametric linkage analysis on family-based genotype data in an effort to find genetic loci linked to the disease. METHODS: 197 individuals from families with a high-risk history of lung cancer were recruited and genotyped using an Illumina array. Parametric linkage analyses were performed using an affected-only phenotype model with an autosomal dominant inheritance using a disease allele frequency of 0.01. Three types of analyses were performed: single variant two point, collapsed haplotype pattern variant two-point, and multipoint analysis. RESULTS: Five novel genome-wide significant loci were identified at 18p11.23, 2p22.2, 14q13.1, 16p13, and 20q13.11. The families most informative for linkage were also determined. CONCLUSIONS: The 5 novel signals are good candidate regions, containing genes that have been implicated as having somatic changes in lung cancer or other cancers (though not in germ line cells). Targeted sequencing on the significant loci is planned to determine the causal variants at these loci. PMID- 28817826 TI - Safety and Efficacy of the S-1/Temozolomide Regimen in Patients with Metastatic Neuroendocrine Tumors. AB - PURPOSE: Both capecitabine alone and capecitabine in combination with temozolomide have activities against neuroendocrine tumors (NETs). However, the role of S-1 in NETs is still unknown. We performed a study to evaluate the safety and efficacy of the S-1/temozolomide (STEM) regimen in patients with locally advanced or metastatic NETs. METHODS: A retrospective review was conducted in 20 patients with locally advanced or metastatic NETs treated with the STEM regimen. Of the patients, 15 (75.00%) had failed 1 or more lines of treatment with somatostatin analogues, sunitinib, everolimus, anlotinib, or other chemotherapy regimens. The patients received S-1 at 40 mg/m2 orally twice daily on days 1-14 and temozolomide 200 mg orally once daily on days 10-14 of a 21-day cycle. The patients were followed up for evidence of object response, toxicity, and progression-free survival. RESULTS: Response to treatment was assessed using RECIST 1.1. Eight patients (40.00%) achieved a partial response (PR), and another 8 (40.00%) had stable disease (SD). The clinical benefit rate (PR and SD) was 80.00%. The median progression-free survival was not achieved. Only 1 patient (5.00%) had grade 3 adverse events. Among the patients with NETs of different origins, 4 (40.00%) and 5 (50.00%) with pancreatic NETs attained PR and SD, respectively. Four (40.00%) and 3 patients (30.00%) with nonpancreatic NETs attained PR and SD, respectively. CONCLUSIONS: The STEM regimen is exceptionally highly active and well tolerated in patients with locally advanced or metastatic NETs. Even in patients who showed disease progression with previous therapies, it is still highly active. In this 20-patient study, the regimen appeared to be similarly active in pancreatic endocrine tumors and nonpancreatic NETs. PMID- 28817825 TI - Muscle Strength and Muscle Mass in Older Patients during Hospitalization: The EMPOWER Study. AB - BACKGROUND: Low muscle strength and muscle mass are associated with an increased length of hospital stay and higher mortality rate in inpatients. To what extent hospitalization affects muscle strength and muscle mass is unclear. OBJECTIVE: We aimed to assess muscle strength and muscle mass at admission and during hospitalization in older patients and its relation with being at risk of geriatric conditions. METHODS: The EMPOWER study included patients aged 70 years and older, admitted to 4 wards of the VU University Medical Center in the Netherlands between April and December 2015. At admission, patients were screened for being at risk of 4 geriatric conditions: delirium, falls, malnutrition, and functional disability. At admission and at discharge, muscle strength and muscle mass were assessed. RESULTS: A total of 373 patients (mean age, standard deviation [SD]: 79.6, 6.38 years) were included at admission, and 224 patients (mean age, SD: 80.1, 6.32 years) at discharge. At admission, lower muscle strength in both female and male patients and low muscle mass in male patients were associated with being at risk of a higher cumulative number of geriatric conditions. Muscle strength increased during hospitalization, but no change in muscle mass was observed. Changes in muscle measures were not associated with being at risk of geriatric conditions. DISCUSSION: Older patients with lower muscle strength and muscle mass at admission were at risk of a higher cumulative number of geriatric conditions. However, being at risk of geriatric conditions did not forecast further decrease in muscle strength and muscle mass during hospitalization. PMID- 28817827 TI - Role of Next-Generation Sequencing as a Diagnostic Tool for the Evaluation of Bone and Soft-Tissue Tumors. AB - Bone and soft-tissue tumors are in general rare. Diagnosing these tumors is challenging based on the significant number of different tumor entities, the rareness of these tumors, and the considerable morphological heterogeneity which can be found within a single tumor entity. Considering that more than half of the described soft-tissue tumors and approximately 25% of the bone tumors harbor recurrent genetic alterations, the use of auxiliary molecular examinations should be strongly considered. Molecular analyses are important to confirm the diagnosis, to guide treatment, to provide information about prognosis, and to allow patient recruitment for basket trials based on the molecular signature of a tumor. In addition, novel molecular alterations detected by next-generation sequencing (NGS) obtain further insights into the pathogenesis of these rare tumors and allow a more detailed genetic classification. Based on our single center results of NGS using the Ion AmpliSeq Cancer Hotspot Panel v2 and the Ion AmpliSeq Comprehensive Cancer Panel (Thermo Fisher Scientific) for mutational analyses as well as the Archer FusionPlex Sarcoma Kit (ArcherDX, Inc) to detect gene fusions in 26 genes since early 2016, we have experienced NGS as a very sensitive method to detect genetic alterations. In our experience, the use of the Archer FusionPlex Sarcoma Kit is superior to fluorescent in situ hybridization as an auxiliary tool in the routine workup of soft-tissue and bone tumors. PMID- 28817829 TI - Altered Expression Profile of Circular RNAs in the Serum of Patients with Diabetic Retinopathy Revealed by Microarray. AB - PURPOSE: Diabetic retinopathy (DR) is the leading cause of blindness among working age adults. Circular RNAs (circRNAs) are a kind of noncoding RNAs that are involved in the development of some diseases. Here, we aimed to determine the possible role of circRNAs in the pathogenesis of DR by determining the expression profile of circRNAs in the serum of DR patients. METHODS: Nineteen subjects with type 2 diabetes mellitus with proliferative DR (T2DR), 15 subjects with type 2 diabetes mellitus without DR (T2DM), and 21 age-matched nondiabetic control subjects were included in the study. Expression profiles in the serum samples from 5 subjects of each group were studied by circular microarray and validated by quantitative real-time polymerase chain re- action (qRT-PCR) in another 40 subjects. Bioinformatic software was used to predict the microRNA response elements. RESULTS: Thirty circRNAs were significantly upregulated in the serum of T2DR patients compared with the serum from both T2DM and control patients. Further, the altered expression of 7 circRNAs (hsa_circRNA_063981, hsa_circRNA_ 404457, hsa_circRNA_100750, hsa_circRNA_406918, hsa_ circRNA_104387, hsa_circRNA_103410, and hsa_circRNA_ 100192) were verified by qRT-PCR. CONCLUSION: This study suggested a potential role of circRNAs in the pathogenesis of DR and provides novel molecular targets for clinical therapy. PMID- 28817828 TI - Fall-Prone Older People's Attitudes towards the Use of Virtual Reality Technology for Fall Prevention. AB - BACKGROUND: Virtual reality (VR) technology is a relatively new rehabilitation tool that can deliver a combination of cognitive and motor training for fall prevention. The attitudes of older people to such training are currently unclear. OBJECTIVE: This study aimed to investigate: (1) the attitudes of fall-prone older people towards fall prevention exercise with and without VR; (2) attitudinal changes after intervention with and without VR; and (3) user satisfaction following fall prevention exercise with and without VR. METHODS: A total of 281 fall-prone older people were randomly assigned to an experimental group receiving treadmill training augmented by VR (TT+VR, n = 144) or a control group receiving treadmill training alone (TT, n = 137). Two questionnaires were used to measure (1) attitudes towards fall prevention exercise with and without VR (AQ); and (2) user satisfaction (USQ). AQ was evaluated at baseline and after intervention. USQ was measured after intervention only. RESULTS: The AQ revealed that most participants had positive attitudes towards fall prevention exercise at baseline (82.2%) and after intervention (80.6%; p = 0.144). In contrast, only 53.6% were enthusiastic about fall prevention exercise with VR at baseline. These attitudes positively changed after intervention (83.1%; p < 0.001), and 99.2% indicated that they enjoyed TT+VR. Correlation analyses showed that postintervention attitudes were strongly related to user satisfaction (USQ: r = 0.503; p < 0.001). CONCLUSIONS: Older people's attitudes towards fall prevention exercise with VR were positively influenced by their experience. From the perspective of the user, VR is an attractive training mode, and thus improving service provision for older people is important. PMID- 28817830 TI - MicroRNA-200a Inhibits Transforming Growth Factor beta1-Induced Proximal Tubular Epithelial-Mesenchymal Transition by Targeting beta-Catenin. AB - BACKGROUND: The epithelial-mesenchymal transition (EMT) is a crucial event in the development of renal interstitial fibrosis (RIF). A growing body of evidence indicates that beta-catenin plays an important role in various types of fibrosis. Although members of the microRNA (miRNA)-200 family have been suggested to suppress EMT in cancer and fibrosis, the function of miRNA-200a in regulating the progression of RIF is unknown. We speculate that miRNA-200a may hinder this progression through the suppression of beta-catenin. METHODS: Transforming growth factor beta1 (TGF beta1) was used to induce EMT of proximal tubule epithelial (HK 2) cells in vitro, quantitative real time polymerase chain reaction (qPCR) and Western Blot analysis measured the miRNA-200a and beta-catenin expression. qPCR, Western Blot analysis, Migration Assay and cell immunofluorescence were applied to detect the influence of up- and downregulated miRNA-200a expression and beta catenin siRNA on beta-catenin and EMT. Dual luciferase report plasmid (CTNNB1 UTR WT/MT) verifies the target relationship between miRNA-200a and CTNNB1 (beta catenin gene). RESULTS: miRNA-200a is downregulated and beta-catenin is upregulated during TGF beta1-induced EMT. Upregulation of miRNA-200a inhibits beta-catenin and attenuates TGF beta1-induced EMT and cell migration, while its downregulation increases beta-catenin and induces EMT and HK-2 cell migration. Further, knocking down beta-catenin suppressed the EMT induced by miRNA-200a downregulation. miRNA-200a directly targets for CTNNB1. CONCLUSIONS: miRNA-200a inhibits TGF beta1-induced EMT by directly targeting beta-catenin in proximal tubule epithelial cells. PMID- 28817832 TI - Successful Use of Grenz Rays for Disseminated Superficial Actinic Porokeratosis: Report of 8 Cases. AB - BACKGROUND: Disseminated superficial actinic porokeratosis (DSAP) is a rare keratinization disorder with potential malignant transformation, for which present treatment strategies show limited success. AIM: To evaluate the response of DSAP lesions to grenz ray radiotherapy (RTx). METHODS: Data of patients treated with RTx at University Hospital Zurich, Switzerland, between 2004 and 2015, were reviewed. Patients with DSAP, who received at least 1 RTx treatment session and who had been followed up for at least 4 weeks were included in the further data analysis. RESULTS: The study cohort consisted of 8 patients with a median age of 73 years (range 54-84). All were treated with grenz rays for DSAP. Most (7/8) patients showed complete clinical clearing of the lesions. All patients experienced temporary side effects of RTx, which resolved within 4 weeks after the last irradiation. CONCLUSION: We suggest radiotherapy with grenz rays as a treatment option for DSAP. PMID- 28817831 TI - Practical Value of Anti-Xa Activity in the Evaluation of Extracorporeal Circuit Anticoagulation during Haemodialysis: Results of a Cross-Sectional Single-Centre Study. AB - BACKGROUND/AIMS: Anticoagulation of the extracorporeal circuit is essential for adequate haemodialysis (HD). Low molecular weight heparins (LMWHs) are safe and sufficient towards achieving this goal. In the Netherlands, dosage is based on bodyweight and adjusted based on clinical events. LMWH levels during dialysis can be quantified through measurement of the anti-Xa activity and a target range of 0.5-1.0 IU/mL has been proposed. We aimed to evaluate the practical value of the anti-Xa activity to guide LMWH dosage in HD patients. Additionally, the value of the activated partial thromboplastin time (APTT) was investigated. METHODS: All prevalent adult HD patients of our dialysis clinic were included. APTT and anti Xa activity were measured before, during and after 2 dialysis sessions. Clinical and dialysis characteristics, including LMWH dosage, were derived from digital patient charts. RESULTS: Our final study cohort consisted of 83 patients. LMWH dosage during dialysis was appropriate for bodyweight in 61% of cases, of which 50% reached an anti-Xa activity within the putative target range of 0.5-1.0 IU/mL. Forty-six percent of patients had an anti-Xa activity >1.0 IU/mL. Anti-Xa levels during and after dialysis were significantly correlated (r = 0.803, p < 0.01). No thrombotic or haemorrhagic complications were observed in this study. Correlation of APTT with anti-Xa activity was poor. CONCLUSION: Anti-Xa activity measurements during dialysis can identify patients in whom LMWH dosage should be lowered in a subsequent dialysis session. Whether such an intervention leads to a decrease in haemorrhagic complications needs to be evaluated in prospective studies. PMID- 28817833 TI - FMNL2 destabilises COMMD10 to activate NF-kappaB pathway in invasion and metastasis of colorectal cancer. AB - BACKGROUND: Diaphanous-related formins (DRFs), actin necleator, have been known to participate in the progression of cancer cells. We previously reported that FMNL2 (Formin-like2), a member of DRFs, was a positive regulator in colorectal cancer (CRC) metastasis, yet proteins and pathways required for the function of this pro-invasive DRFs remain to be identified. METHODS: The relationship between FMNL2 and COMMD10 was examined using Co-IP, GST pull-down, immunofluorescence and in vitro ubiquitination assay. The in vitro and in vivo function of COMMD10 in CRC was evaluated using CCK-8 proliferation assay, plate colony formation, cell cycle, apoptosis and animal models. The inhibition of NF-kappaB signalling by COMMD10 was detected using dual-luciferase reporter assay and western blotting. Co-IP, GST pull-down and nuclear protein extraction assay were performed to evaluate the effect on p65 by COMMD10. Real-time PCR and western blotting were performed to detect expressions of FMNL2, COMMD10 and p65 in paired tissues. RESULTS: FMNL2 targets COMMD10 for ubiquitin-mediated proteasome degradation in CRC cells. COMMD10 targets p65 NF-kappaB (nuclear factor-kappaB) subunit and reduces its nuclear translocation, thereby leading to the inactivation of NF kappaB pathway and suppression of CRC invasion and metastasis. Inhibition of NF kappaB signalling by COMMD10 is necessary for FMNL2-mediated CRC cell behaviours. Downregulation of COMMD10 predicts poor prognosis of CRC patients. The expressions of FMNL2, COMMD10 and p65 are highly linked in CRC tissues. CONCLUSIONS: These data demonstrate that the FMNL2/COMMD10/p65 axis acts as a critical regulator in the maintenance of metastatic phenotypes and is strongly associated with negative clinical outcomes. PMID- 28817834 TI - MDM2 promotes epithelial-mesenchymal transition and metastasis of ovarian cancer SKOV3 cells. AB - BACKGROUND: Metastasis accounts for the most lethal reason for the death of ovarian cancer patients, but remains largely untreated. Epithelial-mesenchymal transition (EMT) is critical for the conversion of early-stage ovarian tumours into metastatic malignancies. Thus the exploration of the signalling pathways promoting EMT would open potential opportunities for the treatment of metastatic ovarian cancer. Herein, the putative role of MDM2 in regulating EMT and metastasis of ovarian cancer SKOV3 cells was investigated. METHODS: The regulatory effects by MDM2 on cell motility was emulated by wound-healing and transwell assays. The effects on EMT transition and Smad pathway were studied by depicting the expression levels of epithelial marker E-cadherin as well as key components of Smad pathway. To evaluate the clinical relevance of our findings, the correlation of MDM2 expression levels with the stages of 104 ovarian cancer patients was investigated by immunohistochemistry assay. RESULTS: We demonstrate that MDM2 functions as a key factor to drive EMT and motility of ovarian SKOV3 cells, by facilitating the activation of TGF-beta-Smad pathway, which results in the increased transcription of snail/slug and the subsequent loss of E-cadherin levels. Such induction of EMT is sustained in either E3 ligase-depleted MDM2 or E3 ligase inhibitor HLI-373-treated cells, while being impaired by the N-terminal deletion of MDM2, which is also reflected by the inhibitory effects against EMT by Nutlin-3a, the N-terminal targeting agent. The expression levels of MDM2 is highly correlated with the stages of the ovarian cancer patients, and the higher expression of MDM2 together with TGFB are closely correlated with poor prognosis and predict a high risk of ovarian cancer patients. CONCLUSIONS: This study suggests that MDM2 activates Smad pathway to promote EMT in ovarian cancer metastasis, and targeting the N-terminal of MDM2 can reprogram EMT and impede the mobility of cancer cells. PMID- 28817835 TI - History of thyroid disease and survival of ovarian cancer patients: results from the Ovarian Cancer Association Consortium, a brief report. AB - BACKGROUND: Findings from in vitro studies suggest that increased exposure to thyroid hormones can influence progression of ovarian tumours. However, epidemiologic evidence on this topic is limited. METHODS: We pooled data from 11 studies from the Ovarian Cancer Association Consortium. Using multivariate Cox proportional hazards models, we estimated associations between hyper- and hypothyroidism and medications prescribed for these conditions with 5-year all cause survival among women diagnosed with invasive ovarian cancer. RESULTS: Overall, there was a nonsignificant association with history of hyperthyroidism (n=160 cases) and mortality (HR=1.22; 95% CI=0.97-1.53). Furthermore, diagnosis of hyperthyroidism within the 5 years before ovarian cancer diagnosis was associated with an increased risk of death (HR=1.94; 95% CI=1.19-3.18). A more modest association was observed with history of hypothyroidism (n=624 cases) and mortality (HR=1.16; 95% CI=1.03-1.31). Neither duration of hypothyroidism nor use of thyroid medications was associated with survival. CONCLUSIONS: In this large study of women with ovarian cancer, we found that recent history of hyperthyroidism and overall history of hypothyroidism were associated with worse 5-year survival. PMID- 28817836 TI - Sitting, physical activity, and serum oestrogen metabolism in postmenopausal women: the Women's Health Initiative Observational Study. AB - BACKGROUND: Prolonged sitting and lower levels of physical activity have been associated with increased levels of parent oestrogens (oestrone and oestradiol), the key hormones in female cancers, in postmenopausal women. However, it is unknown whether sitting and physical activity are associated with circulating oestrogen metabolite levels. METHODS: Among 1804 postmenopausal women enrolled in the Women's Health Initiative Observational Study, 15 serum oestrogens/oestrogen metabolites were quantified using liquid chromatography-tandem mass spectrometry. Physical activity and sitting were self-reported via questionnaire. Using baseline, cross-sectional data, geometric means (GM) of oestrogens/oestrogen metabolites (pmol l-1) were estimated using inverse probability weighted linear regression, adjusting for potential confounders and stratified on menopausal hormone therapy (MHT) use. RESULTS: Longer time spent sitting (?10 vs ?5h per day) was associated with higher levels of unconjugated oestrone, independent of moderate- to vigorous-intensity physical activity and body mass index, among both never/former (GM=70.6 vs 57.7) and current MHT users (GM=242 vs 179) (P-trend ?0.03). Among never/former MHT users, sitting (?10 vs ?5h per day) was positively associated with 2-methoxyestradiol (GM=16.4 vs 14.4) and 4-methoxyestradiol (GM=2.36 vs 1.98) (P-trend ?0.04), independent of parent oestrogens. Inverse associations between moderate- to vigorous-intensity physical activity (?15 vs 0 metabolic equivalent task-hours per week) and parent oestrogens were found as expected. After adjustment for parent oestrogens, physical activity was not associated with oestrogen metabolites. CONCLUSIONS: Our data suggest that prolonged sitting and lower moderate- to vigorous-intensity physical activity are associated with higher levels of postmenopausal oestrogens/oestrogen metabolites, the oestrogen metabolism patterns that have previously been associated with higher endometrial and breast cancer risk. PMID- 28817837 TI - Influence of dietary insulin scores on survival in colorectal cancer patients. AB - BACKGROUND: Although hyperinsulinemia is hypothesised to be involved in colorectal carcinogenesis, it remains unclear whether a diet inducing an elevated insulin response influences colorectal cancer (CRC) survival. METHODS: We examined the association of post-diagnosis dietary insulin scores with survival among 2006 patients from two large prospective cohorts who were diagnosed with CRC from 1976 to 2010. Dietary insulin load was calculated as a function of the food insulin index. Dietary insulin index was calculated by dividing insulin load by total energy intake. Cox proportional hazards models were used to calculate hazard ratios (HRs) for CRC-specific mortality and overall mortality, adjusted for other risk factors for cancer survival. RESULTS: The adjusted HRs for CRC specific mortality comparing the highest to the lowest quintiles were 1.82 (95% CI: 1.20-2.75, Ptrend=0.006) for dietary insulin load and 1.66 (95% CI: 1.10 2.50, Ptrend=0.004) for dietary insulin index. We also observed an increased risk for overall mortality, with adjusted HRs of 1.33 (95% CI: 1.03-1.72, Ptrend=0.03) for dietary insulin load and 1.32 (95% CI: 1.02-1.71, Ptrend=0.02) for dietary insulin index, comparing extreme quintiles. The increase in CRC-specific mortality associated with higher dietary insulin scores was more apparent among patients with body mass index (BMI)?25 kg m-2 than BMI<25 kg m-2 (Pinteraction=0.01). CONCLUSIONS: Higher dietary insulin scores after CRC diagnosis were associated with a statistically significant increase in CRC specific and overall mortality. PMID- 28817838 TI - Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228). AB - BACKGROUND: The hepatic artery infusion (HAI) of irinotecan, oxaliplatin and 5 fluorouracil with intravenous cetuximab achieved outstanding efficacy in previously treated patients with initially unresectable liver metastases from colorectal cancer. This planned study aimed at the identification of pharmacogenetic predictors of outcomes. METHODS: Circulating mononuclear cells were analysed for 207 single-nucleotide polymorphisms (SNPs) from 34 pharmacology genes. Single-nucleotide polymorphisms passing stringent Hardy-Weinberg equilibrium test were tested for their association with outcomes in 52 patients (male/female, 36/16; WHO PS, 0-1). RESULTS: VKORC1 SNPs (rs9923231 and rs9934438) were associated with early and objective responses, and survival. For rs9923231, T/T achieved more early responses than C/T (50% vs 5%, P=0.029) and greatest 4 year survival (46% vs 0%, P=0.006). N-acetyltransferase-2 (rs1041983 and rs1801280) were associated with up to seven-fold more macroscopically complete hepatectomies. Progression-free survival was largest in ABCB1 rs1045642 T/T (P=0.026) and rs2032582 T/T (P=0.035). Associations were found between toxicities and gene variants (P<0.05), including neutropenia with ABCB1 (rs1045642) and SLC0B3 (rs4149117 and rs7311358); and diarrhoea with CYP2C9 (rs1057910), CYP2C19 (rs3758581), UGT1A6 (rs4124874) and SLC22A1 (rs72552763). CONCLUSION: VKORC1, NAT2 and ABCB1 variants predicted for HAI efficacy. Pharmacogenetics could guide the personalisation of liver-targeted medico-surgical therapies. PMID- 28817840 TI - Nuciferine Relaxes Tracheal Rings via the Blockade of VDLCC and NSCC Channels. AB - This study aimed to elucidate the mechanisms of nuciferine (a main aporphine alkaloid of lotus leaf extract), which can induce relaxation in contracted tracheal rings. Under Ca2+-free and 2 mM Ca2+ conditions, we found that nuciferine had no effect on the resting muscle tone of tracheal rings. In contrast, nuciferine relaxed high K+-contracted mouse tracheal rings in a dose dependent manner and inhibited both Ca2+ influx and voltage-dependent L-type Ca2+ channel currents induced by high K+. Similarly, nuciferine also inhibited acetylcholine-induced contractions in mouse tracheal rings in a dose-dependent manner. Meanwhile, both acetylcholine-induced intracellular Ca2+ influx and whole cell currents of nonselective cation channels were blocked by nuciferine. Together, the results indicate that nuciferine-induced relaxation in tracheal rings mainly occurred due to the inhibition of extracellular Ca2+ influx through the blockade of voltage-dependent L-type Ca2+ channels and/or nonselective cation channels. These results suggest that nuciferine has a therapeutic effect on respiratory diseases associated with the aberrant contraction of airway smooth muscles and/or bronchospasm. PMID- 28817839 TI - Evaluating the effect of immune cells on the outcome of patients with mesothelioma. AB - BACKGROUND: We systematically assessed the prognostic and predictive value of infiltrating adaptive and innate immune cells in a large cohort of patients with advanced mesothelioma. METHODS: A tissue microarray from 302 samples was constructed. Markers of adaptive immune response in T-cells (CD8+, FOXP3+, CD4+, CD45RO+, CD3+) and B-cells (CD20+), and of innate immune response; neutrophils (NP57+), natural killer cells (CD56+) and macrophages (CD68+) were evaluated. RESULTS: We found that in the epithelioid tumours, high CD4+ and CD20+ counts, and low FOXP3+, CD68+ and NP57+ counts linked to better outcome. In the non epithelioid group low CD8+ and low FOXP3+ counts were beneficial.On multivariate analysis low FOXP3+ remained independently associated with survival in both groups. In the epithelioid group additionally high CD4+, high CD20+, and low NP57+ counts were prognostic. CONCLUSIONS: Our data demonstrate for the first time, in predominately advanced disease, the association of key markers of adaptive and innate immunity with survival and the differential effect of histology. A better understanding of the immunological drivers of the different subtypes of mesothelioma will assist prognostication and disease-specific clinical decision-making. PMID- 28817842 TI - Opioid Overview. AB - Opioids are an important component of pain management strategies for many patients, but their use is associated with serious life-threatening adverse drug responses, such as respiratory depression, as well as a potential for abuse and dependence. This paper presents an overview of opioid pharmacology, pharmacokinetics and toxicology, as well as approaches to maintain or treat opioid dependence. PMID- 28817841 TI - [Practical use of continuous apomorphine infusion via pump]. AB - Parkinson's disease is the second most common neurodegenerative illness after Alzheimer's disease. In its advanced stages, it is characterized by various special symptoms. In addition to non-motor signs, motor complications are most prominent and most often can only be inadequately improved with pulsatile oral therapies. However, with the aid of continuous dopaminergic stimulation, improvements can be achieved even in advanced stages of the disease. This will not only alleviate motor and non-motor symptoms, but will also lead to a better quality of life. In this context, continuous subcutaneous apomorphine administration by means of a pump has been well established. Its benefits, indications, limitations and practical implementation will be thoroughly described in the expert recommendation. Particularly noteworthy is the rather broad therapeutic window of apomorphine pump treatment, which can be optimally utilized by simple drug titration in a rapidly reversible process. This article presents the results of an expert meeting on apomorphine therapy which took place on July 6, 2016, in Frankfurt (M), Germany. PMID- 28817843 TI - Basics of Opioid Pharmacology. AB - The use of opioids in the treatment of chronic nonmalignant pain is neither endorsed nor proscribed by evidence-based medicine, except for the finding that opioids have certain risks. Also challenging for clinicians are consensus definitions for opioid pharmacology which are poorly chosen, changing, or euphemistic. This paper collects opioid consensus definitions for addiction, physical dependence, tolerance, and withdrawal, and offers practical discussion of the concepts they address. Addiction is a short-circuiting or overdrive of the mesocorticolimbic system of the brain. Physical dependence on opioids means that after chronic opioid dosing an abrupt cessation or marked dose decrease causes an opioid withdrawal syndrome. Physical dependence and addiction are unrelated neuroplastic phenomena which occur in different parts of the brain. Tolerance means a decreasing drug effect for a given dose over time. This applies to desired drug effects and to drug side-effects. PMID- 28817844 TI - Trends in Substance Use Across the Nation and South Dakota. AB - With the discovery of morphine in the early 1800s, substance abuse quickly followed. Next came the production of heroin and other synthetic opioids, along with increases in nonmedical use of prescription medications. In the 21st century, drug abuse and addiction continues to rise nationwide with the three most common drugs abused in adolescents being marijuana, synthetic marijuana, and hallucinogens. Among adolescents and adults nationwide, rates of alcohol, opioids, and amphetamine use have increased over the last decade. In South Dakota, the most prevalent drugs consist of alcohol, methamphetamine, heroin, and prescription opioids. Through the implementation and use of the Prescription Drug Monitoring Program (PDMP) by the South Dakota Board of Pharmacy (SDBOP), hydrocodone/acetaminophen has been identified as the most dispensed controlled substance in the state with roughly 21,000 prescriptions dispensed last November alone. While the PDMP does not necessarily encompass all controlled substances used by the patient (e.g., those purchased from illicit sources), the generation of PDMP reports by physicians and pharmacists is still beneficial. With increased use of the PDMP along with urine drug screens and patient interviews, health care professionals can continue to work collaboratively to help curb the growing epidemic of substance use. PMID- 28817845 TI - Opioid Analgesics for Chronic Non-Cancer Pain: A Guideline on Opioid Prescribing. AB - INTRODUCTION: Over the past decade, the use of opioid analgesics has risen dramatically both in the U.S. and South Dakota. Opioids have been increasingly used to treat chronic non-cancer pain; however, the utilization of opioids for this role has limited and questionable utility. The U.S. has also seen a rise of opioid abuse, addiction, misuse, and overdose. The various pharmacological and non-pharmacological strategies to help physicians manage chronic non-cancer pain and a guideline on appropriate opioid prescribing are presented. DISCUSSION: Before the decision is made to begin opioid therapy for chronic non-cancer pain, other pharmacological and non-pharmacological therapeutic strategies should be explored. The schema for responsible opioid prescribing can be dived into the following: the initial assessment, initiating opioid therapy, maintenance therapy, and the discontinuation of opioid treatment. These categories are explored, and a general approach to prescribing opioids for chronic non-cancer pain is presented. CONCLUSION: The Centers for Disease Control and Prevention (CDC) has declared opioid prescription abuse an "epidemic." There are a variety of methods clinicians can utilize to relieve chronic non-cancer pain. If opioid therapy is sought, clinicians should be mindful of the current state of opioid abuse and misuse. This guideline may aid clinicians in appropriate opioid prescribing. PMID- 28817846 TI - Prescription Drug Abuse - A Law Enforcement Perspective. PMID- 28817848 TI - Cannabis and Medicinal Properties. PMID- 28817847 TI - No Pain, No Thebaine: Opioids in the Emergency Department. AB - BACKGROUND: Opioid misuse has reached epidemic levels. Forty-six people die every day in the U.S. from prescription opioids. Opioid-taking patients cost emergency departments (EDs) and society more than non-opioid-taking patients. Many patients prescribed opioids will go on to become addicted, yet we find it much easier to prescribe these medications than explain to the patient why they are not indicated. The ED takes care of many of these people, whether by prescribing opioids, or treating opioid misuse. We examine the ED's role in this epidemic. METHODS: Data were obtained through literature search and the authors' personal experiences treating patients in the ED. The search was limited to specific harm to patients, hospitals, and society caused by opioid misuse, physiology of pain, and possible methods to manage the problem. CONCLUSIONS: The ED clearly deserves some of the blame for the opioid epidemic. A consistent reinforcement of appropriate expectations for management of chronic pain across the medical spectrum will do much to manage the problem. We offer some ways to improve the problem, including pain contracts, pain guidelines, alternative therapies, pain management referrals, high-risk patient profiles, legislation, and drug take-back programs. PMID- 28817849 TI - Psychotropic Medication Prescription Trends in South Dakota Youth. AB - Following the 1999 U.S. Surgeon General's Report on Mental Health, support for the collection of national statistics on mental health disorders and treatment in children was indicated.1 The National Institute of Mental Health followed by funding research to conduct national surveys.2 The National Health and Nutrition Examination Survey, National Comorbidity Survey Adolescent Supplement, and National Ambulatory Medical Care surveys were reviewed and compared to trends in children and adolescents enrolled in South Dakota Medicaid. The South Dakota Medicaid data was consistent with the national trend of increased psychotropic medication prescriptions in youth. PMID- 28817850 TI - Child and Adolescent Drug Abuse Prevention: A Rural Community-Based Approach. AB - Substance abuse is a significant problem among South Dakota youth. Other than marijuana, prescription drugs and over the counter medications account for the most commonly abused drugs by high school seniors. Physicians play a significant role in future substance prevention efforts. Adolescents and research related to rural communities are areas of discussion. Community prevention coalitions are a commonly utilized mechanism for supporting community-based substance prevention efforts. Access to community coalitions, relevant student data, evidence-based practices, school based interventions and the use of technology are essential areas of prevention efforts in South Dakota and other rural communities in the U.S. The authors discuss child and adolescent substance abuse prevention, especially as it relates to physicians and families in rural populations. Effective prevention efforts in rural communities must integrate alliances with physicians, community coalitions and evidence-based school prevention programs with existing social media. It is crucial to have culturally specific programming within the context of prevention, especially for the Native American youth in South Dakota. This paper recommends the use of community coalitions and computer technologies to reduce the costs associated with other outpatient and inpatient substance abuse programs. PMID- 28817851 TI - Substance Abuse Treatment for Adolescents in South Dakota. AB - In the state of South Dakota, there are 39 accredited substance abuse providers who service over 11,000 individuals each year. Knowledge of which substance abuse providers are accredited is important for families looking to find financially affordable substance abuse treatment/care for their loved ones. In order to begin the process of entry into a substance abuse treatment program, an adolescent must first complete a needs assessment with one of the accredited providers. The needs assessment will help to identify the severity of the substance use disorder as well as identify the appropriate level of treatment/care for the individual. PMID- 28817852 TI - Case Report of Intractable Vomiting and Abdominal Pain Related to Heavy Daily Cannabis Use. AB - CASE: A highly anxious and dehydrated adolescent came to a local emergency department with complaints of intractable emesis, weight loss, and abdominal pain. He stated that bathing and "guzzling water" ameliorated symptoms. He admitted to using marijuana socially. Efforts at palliation with benzodiazepines, atypical antipsychotics, and antiemetic medications were unable to soothe the patient. After thorough initial diagnostics and physical exam failed to elucidate etiology, the patient was referred to an inpatient psychiatric facility for further evaluation of potential psychosomatic or affective causes. During psychiatric evaluation and upon obtaining additional information from family and reviewing the work done by primary care providers, the patient was questioned stringently about his marijuana use patterns. Questioning revealed that the patient had previous chemical dependency treatment, legal charges related to drug use, and heavy daily marijuana use including "dabbing," ingestion of THC candy, and smoking up to several grams a day. DISCUSSION: Cannabinoid hyperemesis syndrome (CHS) consists of intractable emesis, abdominal pain, and weight loss. There is often a history of symptom amelioration with bathing and showering. These patients may or may not admit to heavy marijuana use. Cannabis effects vary and are dose dependent. Historically, CHS would require over a year of heavy daily use. In this day and age of higher THC potency marijuana and even higher THC potency "dabs," it is anticipated that more cases of cannabis related syndromes in general, and CHS in particular will be presenting more frequently to ambulatory and emergency room settings. The patients will potentially be younger and have a shorter duration of heavy cannabis use before symptoms start. A high index of suspicion will be required to prevent expensive and potentially invasive workups and thus delaying diagnosis and treatment. PMID- 28817853 TI - Treating Addiction to Prescription Opioids. AB - For over 30 years, medication-assisted treatment for preventing relapse in opiate use disorder has been limited to methadone maintenance and withdrawal treatments followed by naltrexone; however, buprenorphine has emerged as an exciting and successful pharmacotherapy alternative. Buprenorphine is a partial MU-opioid receptor agonist with less abuse potential and a favorable safety profile compared to methadone and offers a great opportunity of office-based opioid addiction treatment (OBOT) to improve patient access. However, we have limited number of providers certified to prescribe buprenorphine in South Dakota. We need to address potential barriers for its expansion, including concerns of diversion and abuse, insufficient knowledge on buprenorphine and addiction treatment, and lack of access to addiction specialists and treatment resources. Since buprenorphine does retain some abuse potential, good office practice needs to be implemented as we expand its access. We need to choose appropriate candidates for OBOT with clear expectations at the intake. We need to enforce urine drug screens, pill counts, and use of prescription monitoring programs. It is also important to provide or refer patients to addiction counseling services and more intensive levels of care including methadone maintenance and residential care when needed. PMID- 28817854 TI - Quality Focus: Appropriate Prescription Drug Pain Management. PMID- 28817855 TI - The Patient as Population - Progress vs. Improvement. PMID- 28817856 TI - Back to Basics: The Effect of Healthy Diet and Exercise on Chronic Disease Management. AB - INTRODUCTION: The increase in obesity rates in the U.S. and other less developed industrial countries have led to a worldwide epidemic of chronic disease states. Increased obesity rates are implicated in the treatment failures for illnesses such as coronary artery disease, diabetes, heart failure, hypertension and cancer. Effective prevention of obesity through diet and exercise contributes to the successful medical management of multiple chronic disease states. OBJECTIVE: Review the last 10 years of literature (2006-2016) on the effects of diet and exercise as they relate to the prevention of chronic disease. METHOD/DATA REVIEWED: Cochran Database of Systematic Reviews and other original articles using the National Center for Biotechnical Information database. CONCLUSION: The success in management of chronic disease lies in a physician's ability to educate patients and effective utilization of the resources available to that provider. Patient accountability for their individual chronic disease states is a problem related to patient education, patient participation, access to care, and payment resources. Financial, racial, and socioeconomic barriers must be addressed in the creation of an effective plan. Teaching on the importance of diet and exercise needs to occur early in life and be continually reinforced for successful outcomes. In the last 10 years, there has not been a significant study suggesting a single successful model of diet and exercise that can control chronic diseases. Cardiac, diabetic, and cancer patients have reduced hospital admissions, improved diabetic control, and improved quality of life scores related to coordinated diet and exercise programs, however. Patients may be unwilling or unable to be accountable for health care coordination. The development of exercise and obesity prevention policies and the adjustment in financial rewards to health care organizations will have a major impact in implementing these programs over the next 10 years. PMID- 28817857 TI - Patient-Centered Home Model of Care and the Role of Patient Care Teams in the Treatment and Management of Chronic Disease. AB - Patient-centered medical home (PCMH) is a concept of a team of providers caring for a panel of patients with the goals to improve the quality of care while simultaneously decreasing the cost of that care. The clinical evidence that the PCMH approach achieves either goal is mixed. More studies are in progress that will provide more data. PMID- 28817858 TI - Foundations, Core Principles, Values, and Necessary Competencies of Interprofessional Team-Based Health Care. AB - Health care reform has focused on improving health care delivery, quality, and patient safety. An interprofessional, team-based approach to health care is considered by many experts to be essential to meeting these goals. The evidence for this is growing. Core principles for team-based care and the interprofessional competencies necessary for a team to function effectively have been identified and can be taught. Resources for interprofessional education, which must begin at the health professions student level, are available to academic institutions, healthcare systems, and professional organizations to prepare students and current health care professionals for this cultural change. Models of successful collaborative practices exist in many forms and will continue to evolve as our expertise in best practices for interprofessional education and practice advance. PMID- 28817859 TI - Collaboration in Primary Care Through the Integration of Behavioral Health Professionals. AB - Rising costs, poorer outcomes, and dissatisfied patients have challenged medical systems to rethink their approach to health care delivery. Although up to 70 percent of primary care visits stem from psychosocial issues, behavioral health services have traditionally occurred in separate buildings and systems. In order to decrease barriers and meet patients' and providers' needs, primary care practices have begun integrating behavioral health professionals into their clinics. Various levels of integration exist, but the best models fully integrate behavioral health clinicians into primary care teams, allowing for seamless collaboration. Behavioral health professionals are able to support the treatment of a number of mental and physical health conditions, and can provide such services as part of regular primary care visits. Although a number of obstacles exist to developing and optimizing integrated behavioral health services, efforts are underway nationally to decrease barriers and support further training and implementation. PMID- 28817860 TI - Where Personalized Medicine, Patient Engagement, and Primary Care Collide. AB - Personalized medicine and patient engagement have become common buzzwords in the context of health care reform. Independently both concepts have showed some promise in impacting health outcomes, but when synergistically applied, they have more power, as both are critical pieces of personalized health care (PHC). PHC is a health care model that embraces the need for patient engagement along with personalized medicine technologies to make the health care process more personalized, patient-driven, and proactive. Primary care presents an ideal setting for the application of PHC through the use of patient engagement techniques such as patient portals, patient-generated health data, and self management programs, with the goal of supporting a preventative proactive health care approach. PMID- 28817861 TI - Population Health Management and Cancer Screening. AB - Population health management (PHM) is a new health care model being implemented. It has been defined as "the health outcomes of a group of individuals, including the distribution of such outcomes within the group." This includes health outcomes and patterns of health determinants, and policies and interventions that link these two. Moving from a fee-for-service payment system to a quality- or value-based system, this model places on the clinician more responsibility for the costs of health care and its reimbursements. Screening for disease is an area that could benefit from PHM. Electronic health records (EHRs) employ algorithms to capture PHMrelated data such as diagnostic codes, clinical quality indicators, and other parameters useful in identifying those for whom screening is appropriate and in monitoring the efficacy at implementing the screening in the clinic's population. Registries of patients at risk for a variety of diseases are created in the EHR, and these patients can be notified to visit with their clinician for a shared decision-making conversation about the screening. PHM requires a team approach to input, analyze, and implement this data. The physicians must be the driving force behind population health, but advanced practice clinicians, nurses, case managers, quality coordinators, information technology support, and many others collaborate to make this successful. PMID- 28817862 TI - Practice Guidelines for Hypertension. AB - Hypertension is very prevalent in South Dakota affecting approximately one-third of the adult population. Management and treatment of the disease has recently been the subject of considerable debate centered on what should be the blood pressure goal depending on the patient's age and co-morbid conditions. Recently, a randomized trial of intensive versus standard blood pressure control indicated that a systolic blood pressure of less than 120 mmHg in patients at high risk for cardiovascular events but without diabetes, resulted in significantly lower rates of non-fatal major cardiovascular events and death from any cause. Several studies have also looked at goals for hypertensive patients with diabetes. This article will review some of these recent studies and controversies associated with them. Medication and non-medication recommendations for control of blood pressure will also be discussed. PMID- 28817863 TI - Prevention, Detection, and Management of Diabetes in South Dakota. AB - Diabetes mellitus (DM) is increasing in prevalence nationwide and in South Dakota, with an especially high prevalence in its American Indian population. Screening is not recommended for type 1 DM, but is for type 2 DM and pre-diabetes in certain populations. Fasting glucose, two-hour glucose tolerance test, or hemoglobin A1c are appropriate screening options. Treatment can include diabetic self-management education programs and medications. In addition to glycemic control, other cardiovascular risk factors must be reduced in these patients and specific testing and consultations should be performed to detect complications such as nephropathy or retinopathy. Along with routine age-appropriate immunizations, most diabetic patients should receive the pneumococcal polysaccharide vaccine (PPSV-23), influenza, and the hepatitis B series. Progression from pre-diabetes to type 2 DM can be prevented or delayed in some patients through lifestyle interventions and/or metformin. The South Dakota Diabetes Coalition (www.sddiabetescoalition.org) is an excellent resource for clinicians and patients. PMID- 28817865 TI - Utilization of Community Resources. AB - This article will highlight and provide selected examples of existing community services. It will attempt to serve as a reminder and reference for providers to help them improve efforts at utilizing available resources and perhaps institute new services. Coordinating care across all aspects of delivery can help achieve improved control of population health and chronic disease. Community resources can assist the efforts of providers in delivering more complete and continuous care. Those in health care are aided when a collaborative effort is used to help improve care. It is generally accepted that addressing chronic disease at a population level will help diminish cost and improve patient well-being. Social, economic and environmental factors account for a significant influence on health care outcomes. PMID- 28817864 TI - Tobacco Cessation Strategies: It Takes a Village. AB - Smoking is the leading cause of preventable death and chronic diseases in the U.S. Identifying smokers and providing appropriate intervention is therefore an integral part of each clinic visit. A combination of pharmacotherapy as well as behavioral counseling provides the best results. Pharmacotherapy includes nicotine replacement (patch, gum, lozenges), bupropion and varenicline. More recently, electronic nicotinic delivery systems (such as e-cigarettes, vaporizers/vape pens, and hookah pens) have become popular. Behavioral counseling includes identifying barriers to quitting or risk factors for relapse, and developing effective strategies to deal with these issues. A successful program requires a team-based approach, enlisting the help of adjuvant staff to reinforce cessation counseling and provide support services. The South Dakota Quitline is one of many good resources that the clinician can utilize to help with cessation and has one of the best quit rates in the nation. PMID- 28817866 TI - Genomic Medicine in Primary Care. AB - Genomic medicine is a powerful tool with great potential to improve outcomes in the primary care setting. From a broad perspective, genomic medicine can be applied to rare disease, common disease and pharmacogenetics. There are applications in which it can be used to better identify rare disease, improve screening for common disease, reduce adverse drug effects and help to identify the right medication more quickly. This article provides specific examples of clinical applications for genomic medicine in the realm of cardiovascular disease to provide a better understanding of its potential use in primary care. PMID- 28817867 TI - False Reassurance Based on Non-Significant Results. PMID- 28817868 TI - Re: Body Mass Index and age are Predictors for Symptom Improvement after High Power Laser Vaporization for Benign Prostatic Hyperplasia. PMID- 28817869 TI - Re: Impact of Combination Therapy 5-Alpha Reductase Inhibitors (5-ARI) plus Alpha Blockers (AB) on Erectile Dysfunction and Decrease of Libido in Patients with LUTS/BPH: A Systematic Review with Meta-Analysis. PMID- 28817870 TI - Re: Quality of Life in Patients with Lower Urinary Tract Symptoms Associated with BPH: Change over Time in Real-Life Practice According to Treatment-The QUALIPROST Study. PMID- 28817871 TI - Re: A Prospective Longitudinal Survey of Erectile Function Status in Symptomatic Benign Prostatic Hyperplasia Patients Treated with Dutasteride. PMID- 28817872 TI - Re: Office-Based Ultrasound-Guided Renal Core Biopsy is Safe and Efficacious in the Management of Small Renal Masses. PMID- 28817873 TI - Re: Outcomes of Artificial Urinary Sphincter Placement in Octogenarians. PMID- 28817874 TI - Re: Absorbent Products Use and Symptom Distress in Women Who Have Urinary Incontinence and Heart Failure. PMID- 28817875 TI - Re: Geriatric Conditions in a Population-Based Sample of Older Homeless Adults. PMID- 28817876 TI - Re: Geriatric Syndromes in Hospitalized Older Adults Discharged to Skilled Nursing Facilities. PMID- 28817877 TI - Re: Functional Outcomes after Transurethral Resection of the Prostate in Nursing Home Residents. PMID- 28817878 TI - Re: Diagnostic Performance of Diffusion-Weighted Magnetic Resonance Imaging in Differentiating Human Renal Lesions (Benignity or Malignancy): A Meta-Analysis. PMID- 28817879 TI - Re: Domestically Produced Chinese Minimally Invasive Surgical Robot System "Micro Hand S" is Applied to Clinical Surgery Preliminarily in China. PMID- 28817880 TI - Re: Formalin Disinfection of Prostate Biopsy Needles May Reduce Post-Biopsy Infectious Complications. PMID- 28817881 TI - Re: Improvement in Renal Function and Symptoms of Patients Treated with Laparoscopic Pyeloplasty for Ureteropelvic Junction Obstruction with Less than 20% Split Renal Function. PMID- 28817882 TI - Re: Warmed and Humidified Carbon Dioxide for Abdominal Laparoscopic Surgery: Meta Analysis of the Current Literature. PMID- 28817883 TI - Re: Association between Radiation Therapy, Surgery, or Observation for Localized Prostate Cancer and Patient-Reported Outcomes after 3 Years. PMID- 28817884 TI - Re: Clinical Experience with Penile Traction Therapy among Men Undergoing Collagenase Clostridium histolyticum for Peyronie Disease. PMID- 28817885 TI - Re: Sexual Function and Quality of Life before and after Penile Prosthesis Implantation following Radial Forearm Flap Phalloplasty. PMID- 28817886 TI - Re: Effects of Testosterone Replacement Therapy on Hypogonadal Men with Osteopenia or Osteoporosis: A Subanalysis of a Prospective Randomized Controlled Study in Japan (EARTH Study). PMID- 28817887 TI - Re: Clinical, Genetic, Biochemical, and Testicular Biopsy Findings among 1,213 Men Evaluated for Infertility. PMID- 28817888 TI - Re: Testicular Shear Wave Elastography in Normal and Infertile Men: A Prospective Study on 601 Patients. PMID- 28817889 TI - Re: Semen Quality Impairment is Associated with Sexual Dysfunction According to its Severity. PMID- 28817890 TI - Re: Causes of Male Infertility: A 9-Year Prospective Monocentre Study on 1737 Patients with Reduced Total Sperm Counts. PMID- 28817891 TI - Re: Characterising the Safety of Clomiphene Citrate in Male Patients through Prostate-Specific Antigen, Haematocrit, and Testosterone Levels. PMID- 28817892 TI - Re: Outcome in Adults with Anorectal Malformations in Relation to Modern Classification-Which Patients do we Need to Follow Beyond Childhood? PMID- 28817893 TI - Re: Peristeen(r) Transanal Irrigation in Paediatric Patients with Anorectal Malformations and Spinal Cord Lesions: A Multicentre Italian Study. PMID- 28817894 TI - Re: Calcification Score Evaluation in Patients Listed for Renal Transplantation. PMID- 28817895 TI - Re: Sperm Concentration and Forward Motility are Not Correlated with Age in Adolescents with an Idiopathic Varicocele and Symmetrical Testicular Volumes. PMID- 28817896 TI - Re: Chronic Orchalgia after Surgical Exploration for Acute Scrotal Pain in Children. PMID- 28817897 TI - Re: Effect of Home Monitoring via Mobile App on the Number of In-Person Visits following Ambulatory Surgery: A Randomized Clinical Trial. PMID- 28817898 TI - Re: Short-Form Charlson Comorbidity Index for Assessment of Perioperative Mortality after Radical Cystectomy. PMID- 28817899 TI - Re: Preoperative Frailty Predicts Postoperative Complications and Mortality in Urology Patients. PMID- 28817900 TI - Re: Preoperative Urine Culture Results Correlate Poorly with Bacteriology of Urologic Prosthetic Device Infections. PMID- 28817901 TI - Re: Multicenter Investigation of the Micro-Organisms Involved in Penile Prosthesis Infection: An Analysis of the Efficacy of the AUA and EAU Guidelines for Penile Prosthesis Prophylaxis. PMID- 28817902 TI - Re: Multicenter Investigation of the Micro-Organisms Involved in Penile Prosthesis Infection: An Analysis of the Efficacy of the AUA and EAU Guidelines for Penile Prosthesis Prophylaxis. PMID- 28817903 TI - Re: Successful Placement of Penile Prostheses in Men with Severe Corporal Fibrosis following Vacuum Therapy Protocol. PMID- 28817904 TI - Re: Uric Acid versus Non-Uric Acid Renal Stones: In Vivo Differentiation with Spectral CT. PMID- 28817905 TI - Re: CYP3A4 Induction by Rifampin: An Alternative Pathway for Vitamin D Inactivation in Patients with CYP24A1 Mutations. PMID- 28817906 TI - Re: Urolithiasis in Inflammatory Bowel Disease and Bariatric Surgery. PMID- 28817907 TI - Re: Characterization of Urolithiasis in Patients following Lower Urinary Tract Reconstruction with Intestinal Segments. PMID- 28817908 TI - Re: Management of Small Renal Masses: American Society of Clinical Oncology Clinical Practice Guideline. PMID- 28817909 TI - Re: Irreversible Electroporation of Small Renal Masses: Suboptimal Oncologic Efficacy in an Early Series. PMID- 28817910 TI - Re: New Strategies in Bladder Cancer: A Second Coming for Immunotherapy. PMID- 28817911 TI - Re: Prediction Model for Recurrence Probabilities after Intravesical Chemotherapy in Patients with Intermediate-Risk Non-Muscle-Invasive Bladder Cancer, Including External Validation. PMID- 28817913 TI - Re: Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients with Bone Metastases: A Randomized Clinical Trial. PMID- 28817912 TI - Re: Videotaping of Surgical Procedures and Outcomes following Extraperitoneal Laparoscopic Radical Prostatectomy for Clinically Localized Prostate Cancer. PMID- 28817914 TI - Re: Testicular Seminoma Clinical Stage 1: Treatment Outcome on a Routine Care Level. PMID- 28817915 TI - Re: Outcome of Men with Relapse after Adjuvant Carboplatin for Clinical Stage I Seminoma. PMID- 28817916 TI - Re: AKT-Mediated Stabilization of Histone Methyltransferase WHSC1 Promotes Prostate Cancer Metastasis. PMID- 28817917 TI - Re: Phosphorylation-Induced Conformational Dynamics in an Intrinsically Disordered Protein and Potential Role in Phenotypic Heterogeneity. PMID- 28817918 TI - Re: MicroRNA-141 Suppresses Prostate Cancer Stem Cells and Metastasis by Targeting a Cohort of Pro-Metastasis Genes. PMID- 28817919 TI - Re: Cost-Effectiveness Analysis of Anticholinergics versus Botox for Urgency Urinary Incontinence: Results from the Anticholinergic versus Botox Comparison Randomized Trial. PMID- 28817920 TI - Re: An International Urogynecological Association (IUGA)/International Continence Society (ICS) Joint Report on the Terminology for the Conservative and Nonpharmacological Management of Female Pelvic Floor Dysfunction. PMID- 28817921 TI - Re: The Management of Neurogenic Lower Urinary Tract Dysfunction after Spinal Cord Injury. PMID- 28817922 TI - Re: Risk Factors and Functional Abnormalities Associated with Adult Onset Secondary Nocturnal Enuresis in Women. PMID- 28817923 TI - Re: The Potential Role of Unregulated Autonomous Bladder Micromotions in Urinary Storage and Voiding Dysfunction; Overactive Bladder and Detrusor Underactivity. PMID- 28817924 TI - Re: The Role of Acupuncture in Managing Overactive Bladder; A Review of the Literature. PMID- 28817925 TI - Re: Incontinence Rates after Midurethral Sling Revision for Vaginal Exposure or Pain. PMID- 28817926 TI - Yeast multistress resistance and lag-phase characterisation during wine fermentation. AB - Saccharomyces cerevisiae has been used to perform wine fermentation for several millennia due to its endurance and unmatched qualities. Nevertheless, at the moment of inoculation, wine yeasts must cope with specific stress factors that still challenge wine makers by slowing down or compromising the fermentation process. To better assess the role of genetic and environmental factors that govern multistress resistance during the wine fermentation lag phase, we used a factorial plan to characterise the individual and combined impact of relevant stress factors on eight S. cerevisiae and two non-S. cerevisiae wine yeast strains that are currently commercialised. The S. cerevisiae strains are very genetically diverse, belonging to the wine and flor groups, and frequently contain a previously described XVIVIII translocation that confers increased resistance to sulphites. We found that low temperature and osmotic stress substantially affected all strains, promoting considerably extended lag phases. SO2 addition had a partially temperature-dependent effect, whereas low phytosterol and thiamine concentrations impacted the lag phase in a strain dependent manner. No major synergic effects of multistress were detected. The diversity of lag-phase durations and stress responses observed among wine strains offer new insights to better control this critical step of fermentation. PMID- 28817928 TI - Examining the Roles of Technology in Aging and Quality of Life. PMID- 28817927 TI - Identification of biosynthetic gene clusters from metagenomic libraries using PPTase complementation in a Streptomyces host. AB - The majority of environmental bacteria are not readily cultured in the lab, leaving the natural products they make inaccessible using culture-dependent discovery methods. Cloning and heterologous expression of DNA extracted from environmental samples (environmental DNA, eDNA) provides a means of circumventing this discovery bottleneck. To facilitate the identification of clones containing biosynthetic gene clusters, we developed a model heterologous expression reporter strain Streptomyces albus::bpsA DeltaPPTase. This strain carries a 4? phosphopantetheinyl transferase (PPTase)-dependent blue pigment synthase A gene, bpsA, in a PPTase deletion background. eDNA clones that express a functional PPTase restore production of the blue pigment, indigoidine. As PPTase genes often occur in biosynthetic gene clusters (BGCs), indigoidine production can be used to identify eDNA clones containing BGCs. We screened a soil eDNA library hosted in S. albus::bpsA DeltaPPTase and identified clones containing non-ribosomal peptide synthetase (NRPS), polyketide synthase (PKS) and mixed NRPS/PKS biosynthetic gene clusters. One NRPS gene cluster was shown to confer the production of myxochelin A to S. albus::bpsA DeltaPPTase. PMID- 28817929 TI - Oxidized Polymeric Phenolics: Could They Be Considered Photoprotectors? AB - Photooxidative sunburn is the consequence of photosystem overexcitations. It results in tissue color changes as a result of chlorophyll degradation and accumulation of oxidized polymeric phenolics (OPPs), resulting from scavenging of reactive oxygen species (ROS). From a productive point of view, OPPs should be considered as damages, decreasing the economical and esthetical values of plants and crops. However, from a physiological perspective, OPPs could be also play a screening role against excessive photosynthetically active radiation (PAR), because they follow the criteria proposed for the identification of photoprotectors, as follows: (i) As a result of the complex conjugated double bond systems, OPPs absorb and, thus, screen the visible PAR. (ii) The accumulation of brown OPPs is well-known to be stimulated by light exposure, resulting in sunburn symptoms. (iii) OPPs induce PAR resistance; for example, the sunburned brown skin allows the fruit ripening to proceed without further interferences. (iv) The screen provided by the accumulated OPPs in death cells protect underlying tissues, demonstrating an increased resistance to radiation when other physiological processes are not functioning. PMID- 28817930 TI - Identification of a New Zinc Binding Chemotype by Fragment Screening. AB - The discovery of a new zinc binding chemotype from screening a nonbiased fragment library is reported. Using the orthogonal fragment screening methods of native state mass spectrometry and surface plasmon resonance a 3-unsubstituted 2,4 oxazolidinedione fragment was found to have low micromolar binding affinity to the zinc metalloenzyme carbonic anhydrase II (CA II). This affinity approached that of fragment sized primary benzenesulfonamides, the classical zinc binding group found in most CA II inhibitors. Protein X-ray crystallography established that 3-unsubstituted 2,4-oxazolidinediones bound to CA II via an interaction of the acidic ring nitrogen with the CA II active site zinc, as well as two hydrogen bonds between the oxazolidinedione ring oxygen and the CA II protein backbone. Furthermore, 3-unsubstituted 2,4-oxazolidinediones appear to be a viable starting point for the development of an alternative class of CA inhibitor, wherein the medicinal chemistry pedigree of primary sulfonamides has dominated for several decades. PMID- 28817931 TI - Palladium-Catalyzed Carbonylative Transformation of Organic Halides with Formic Acid as the Coupling Partner and CO Source: Synthesis of Carboxylic Acids. AB - A palladium-catalyzed carbonylative transformation of organic halides with formic acid as the coupling partner to produce carboxylic acids has been developed. With a catalytic amount of DCC as the activator of formic acid, the process can be realized successfully through benzoic formic anhydride as the intermediate. Both vinyl and aryl (pseudo)halides were conveniently transformed into the corresponding acids in good yields. PMID- 28817932 TI - Concentrations, Stability, and Isolation of the Furan Fatty Acid 9-(3-Methyl-5 pentylfuran-2-yl)-nonanoic Acid from Disposable Latex Gloves. AB - Because of their antioxidant properties, furan fatty acids (furan-FAs) are valuable minor compounds with a widespread occurrence in all living matter. Unfortunately, pure standards are not readily available, because they usually contribute only 1% to the lipid fraction. A known exception of this is the milky fluid of Hevea brasiliensis, commonly known as latex, in which the furan-FA 9-(3 methyl-5-pentylfuran-2-yl)-nonanoic acid (9M5) contributes about 90% to the triacylglycerides. In this study, we investigated the content of 9M5 in 30 different disposable latex gloves, which ranged from 0.7 to 8.2 mg/g of glove. The light degradability of 9M5 in latex gloves was investigated, and different amounts of 9M5 in disposable latex gloves were attributed to varying exposure time to light. Additionally, over 100 mg of the methyl or ethyl ester of 9M5 (purity of >98%) could be extracted from disposable latex gloves, employing cold extraction and silver ion chromatography. With this method, standards for the quantitation of furan-FAs are obtained easily and rapidly in all laboratories. PMID- 28817933 TI - Biochemical Characterization and Substrate Degradation Mode of a Novel Exotype beta-Agarase from Agarivorans gilvus WH0801. AB - Agarases are important hydrolytic enzymes for the biodegradation of agar. Understanding the degradation mode and hydrolysis products of agarases is essential for their utilization in oligosaccharide preparations. Herein, we cloned and expressed AgWH50B, a novel neoagarotetraose-forming beta-agarase from Agarivorans gilvus WH0801 that has high specific activity and a fast reaction rate. AgWH50B consists of a C-terminal glycoside hydrolase family 50 catalytic domain with two tandem noncatalytic carbohydrate-binding modules (CBMs) in the N terminus (residues 45-214 and 236-442). AgWH50B exhibited good enzymatic properties with high specific activity and catalytic efficiency (1523.2 U/mg and a Vmax of 1700 MUmol/min/mg) under optimal hydrolysis conditions of pH 7.0 and 40 degrees C. Analysis of the hydrolysis products revealed that this enzyme is an exotype beta-agarase and that the dominant product of agarose or oligosaccharide degradation was neoagarotetraose. These findings suggest that AgWH50B could be utilized to yield abundant neoagarotetraose. PMID- 28817934 TI - Mannose Surfaces Exhibit Self-Latching, Water Structuring, and Resilience to Chaotropes: Implications for Pathogen Virulence. AB - Several viral and fungal pathogens, including HIV, SARS, Dengue, Ebola, and Cryptococcus neoformans, display a preponderance of mannose residues on their surface, particularly during the infection cycle or in harsh environments. The innate immune system, on the other hand, abounds in mannose receptors which recognize mannose residues on pathogens and trigger their phagocytosis. We pose the question if there is an advantage for pathogens to display mannose on their surface, despite these residues being recognized by the immune system. The surface properties and interactions of opposing monolayers of mannobiose (disaccharide of mannose) were probed using atomic force spectroscopy. Unlike its diastereoisomer lactose, mannobiose molecules exhibited lateral packing interactions that manifest on the surface scale as a self-recognizing latch. A break-in force is required for opposing surfaces to penetrate and a breakout (or self-adhesion force) of similar magnitude is required for penetrated surfaces to separate. A hierarchy of self-adhesion forces was distinguished as occurring at the single residue (~25 pN), cluster (~250 pN), monolayer (~1.1 nN), and supramonolayer level. The break-in force and break-out force appear resilient to the presence of simple chaotropes that attenuate a layer of structured water around the mannose surface. The layer of structured water otherwise extends to distances several times longer than a mannobiose residue, indicating a long-range propagation of the hydrogen bonding imposed by the residues. The span of the structured water increases with the velocity of an approaching surface, similar to shear thickening, but fissures at higher approach velocities. Our studies suggest that mannose residues could guide interpathogen interactions, such as in biofilms, and serve as a moated fortress for pathogens to hide behind to resist detection and harsh environments. PMID- 28817940 TI - [Confirming the Utility of RAISUS Antifungal Susceptibility Testing by New Software]. AB - Clinical and Laboratory Standards Institute (CLSI) methods for susceptibility tests of yeast are used in Japan. On the other hand, the methods have some disadvantage; 1) reading at 24 and 48 h, 2) using unclear scale, approximately 50% inhibition, to determine MICs, 3) calculating trailing growth and paradoxical effects. These makes it difficult to test the susuceptibility for yeasts. Old software of RAISUS, Ver. 6.0 series, resolved problem 1) and 2) but did not resolve problem 3). Recently, new software of RAISUS, Ver. 7.0 series, resolved problem 3). We confirmed that using the new software made it clear whether all these issue were settled or not. Eighty-four Candida isolated from Aichi Medical University was used in this study. We compared the MICs obtained by using RAISUS antifungal susceptibility testing of yeasts RSMY1, RSMY1, with those obtained by using ASTY. The concordance rates (+/-four-fold of MICs) between the MICs obtained by using ASTY and RSMY1 with the new software were more than 90%, except for miconazole (MCZ). The rate of MCZ was low, but MICs obtained by using CLSI methods and Yeast-like Fungus DP 'EIKEN' methods, E-DP, showed equivalent MICs of RSMY1 using the new software. The frequency of skip effects on RSMY1 using the new software markedly decreased relative to RSMY1 using the old software. In case of showing trailing growth, the new software of RAISUS made it possible to choice the correct MICs and to put up the sign of trailing growth on the result screen. New software of RAISUS enhances its usability and the accuracy of MICs. Using automatic instrument to determine MICs is useful to obtain objective results easily. PMID- 28817941 TI - [A Case of Severe Legionella longbeachae Pneumonia and Usefulness of LAMP Assay]. AB - Urinary antigen test is frequently used as a routine laboratory test for early diagnosis of Legionella infection, which is especially suitable for ordinary Legionella pneumophila serogroup 1, but not for other types of Legionella. We report a case of severe pneumonia caused by Legionella longbeachae, where a method of loop-mediated isothermal amplification (LAMP) assay contributed an important role for the early detection. This case involved an 83-year-old man who developed fever, dyspnea, and productive cough. Since the medication of prescribed ceftriaxone had not been effective, he visited the emergency room of our hospital, where an X-ray revealed a severe pneumonia harboring a consolidation with air bronchogram in his right lower lung. His sputum and urine were subjected to the routine bacterial culture or the urinary antigen test for Legionella, which initially brought negative results. However, a positive result of LAMP assay enabled early diagnosis of Legionella pneumonia. Later, the bacterial cultures of sputum made some progress and 16S rRNA sequencing provided a proof of L. longbeachae. This LAMP assay may bring a benefit for the patients with Legionella pneumonia by enabling early detection of not only specific L. pneumophila serogroup 1, but also of the other Legionella species. PMID- 28817942 TI - [The Current Status of Diagnostic Tools for Leptospirosis]. AB - Leptospirosis is a worldwide zoonosis caused by pathogenic Leptospira spp. The severity of leptospirosis vary from mild, flu-like disease to a more severe form, Weil's disease causing jaundice, hemorrhage, renal failure, and even death. Every year, 300,000-500,000 cases of severe leptospirosis are reported around the world, with the case fatality rate being 10-30%. The usual diagnostic tools for leptospirosis are 1) direct observation of leptospires in blood and urine under dark-field microscope, 2) isolation of leptospires from blood, cerebrospinal fluid (CSF), or urine samples by culture, 3) microscopic agglutination test (MAT) to detect anti-Leptospira antibodies in serum, and 4) PCR to detect Leptospira DNA. At presents, the gold standards for diagnosis are culture isolation and MAT. However, it is actually not easy to isolate leptospires from clinical samples. On the other hand, it takes several days before the results of MAT become positive after the onset of illness. Moreover, MAT requires skilled handling, and also needs the maintenance of live Leptospira cells representing all serogroups. Hence other simple or rapid diagnostic tests are needed at the bedside. The micro capsule agglutination test (MCAT) to detect antibody and immunochromatographic assay to detect urinary antigen are currently in the research and development phases. In this paper, the characteristics of each diagnostic test for leptospirosis are described. PMID- 28817943 TI - [MALDI-TOF MS Comparison of Blood Culture Positive Bottle Pretreatment Kit]. AB - Identification of bacteria of sepsis or bacteremia is a useful result for treatment policy. In recent years, bacterial identification has become possible from blood culture bottles by MALDI-TOF, but it is not as accurate as bacterial identification from agar colonies. Blood culture pretreatment kit (MALDI Sepcityper Kit) is currently on sale from Bruker. However, the current situation has not reached good accuracy. This time, a new blood culture pretreatment kit appeared, so I studied. Up to now, the blood culture pretreatment kit was only MALDI Sepcityper Kit using enzyme digestion method. Rapid BAC pro (Nittobo) is a pretreatment kit using nanomaterials. This time, comparison examination (total number 40 samples) was done. Among them, 33 specimens were identified by MALDI Sepcityper Kit. There were 21 specimens that could be identified by rapid BAC pro. In this study, rapid BAC pro did not show superior results over MALDI Sepcityper Kit. PMID- 28817944 TI - Tracking Brain Development and Dimensional Psychiatric Symptoms in Children: A Longitudinal Population-Based Neuroimaging Study. AB - OBJECTIVE: Psychiatric symptomatology during childhood predicts persistent mental illness later in life. While neuroimaging methodologies are routinely applied cross-sectionally to the study of child and adolescent psychopathology, the nature of the relationship between childhood symptoms and the underlying neurodevelopmental processes remains unclear. The authors used a prospective population-based cohort to delineate the longitudinal relationship between childhood psychiatric problems and brain development. METHOD: A total of 845 children participated in the study. Psychiatric symptoms were measured with the parent-rated Child Behavior Checklist at ages 6 and 10. MRI data were collected at ages 8 and 10. Cross-lagged panel models and linear mixed-effects models were used to determine the associations between psychiatric symptom ratings and quantitative anatomic and white matter microstructural measures over time. RESULTS: Higher ratings for externalizing and internalizing symptoms at baseline predicted smaller increases in both subcortical gray matter volume and global fractional anisotropy over time. The reverse relationship did not hold; thus, baseline measures of gray matter and white matter were not significantly related to changes in symptom ratings over time. CONCLUSIONS: Children presenting with behavioral problems at an early age show differential subcortical and white matter development. Most neuroimaging models tend to explain brain differences observed in psychopathology as an underlying (causal) neurobiological substrate. However, the present work suggests that future neuroimaging studies showing effects that are pathogenic in nature should additionally explore the possibility of the downstream effects of psychopathology on the brain. PMID- 28817946 TI - Subjective Meanings and Identification With Middle Age. AB - The "middle-age" life period has not been researched extensively and lacks a theoretical conceptualization. The present study explores subjective experiences of members of this age-group. This is a qualitative research, based on in-depth interviews and thematic analysis, which looks into the life stories of 25 Israeli residents aged 48-64 years. The results indicate that the definition of middle age is not clear-cut, and some participants regard their age negatively. Yet, participants report that this period is characterized by a relief of tasks, broader choice opportunity, a sense of liberation, peace of mind, experience, self-awareness, and self-acceptance. Description of middle age as a peak in life, with concerns about future old age, came up repeatedly. Middle-aged individuals' difficulties to identify with their age-group and the social concept that dichotomizes age into young versus old are discussed. The article calls for further research of and engagement with middle age. PMID- 28817945 TI - Management of Breast Milk Oversupply in Traditional Persian Medicine. AB - Comprehensive explanation about milk oversupply is not available in the current literature because few studies have been done on this topic. In traditional Persian medicine, milk oversupply and its management have been described. The aim of this study was to investigate milk oversupply from the perspective of medieval Persian practitioners. In this study, some main medical resources of traditional Persian medicine such as Al-Havi and the Canon of Medicine were studied to extract valuable information about milk oversupply. Etiology of milk overproduction according to traditional Persian medicine is based on humors theory and cannot be easily compared with current medical concepts. Diet modifications and natural remedies have been applied for managing this condition but the majority of traditional Persian medicine interventions for reducing milk oversupply have not been scientifically investigated in modern medicine. The knowledge of milk oversupply in traditional Persian medicine may be helpful to conduct further related studies. PMID- 28817947 TI - Mortality and Health Service Use Following Acute Myocardial Infarction Among Persons with HIV: A Population-Based Study. AB - People with HIV have higher rates of acute myocardial infarction (AMI) than HIV negative individuals. We compared mortality risk and health service use following AMI among people with and without HIV between January 1, 2002, and March 31, 2015. We conducted a population-based study using Ontario's administrative databases. Our primary outcomes were risk of inpatient death and death at 30 days following hospital discharge. In secondary analyses, we compared use of revascularization procedures within 90 days of AMI, as well as readmission or emergency department visits for heart disease and cardiology follow-up within 90 days of discharge. We studied 259,475 AMI patients, of whom 345 (0.13%) were people with HIV. AMI patients with HIV were younger than HIV-negative patients (mean age +/- standard deviation: 54.4 +/- 10.5 years vs. 69.3 +/- 14.3 years). Following multivariable adjustment, the odds ratios for inpatient death and death at 30 days following discharge were 1.04 [95% confidence intervals (CI) 0.64 1.56] and 2.42 (95% CI 1.00-4.92), respectively. In secondary analyses, no differences were observed in receipt of revascularization procedures (hazard ratio (HR) 0.98; 95% CI 0.85-1.12), readmission or emergency department visit for heart disease (HR 1.18; 95% CI 0.85-1.62), or cardiology follow-up (HR 0.88; 95% CI 0.76-1.01). People with HIV experience AMI at younger ages and may be at higher risk of death in the 30 days following hospital discharge, underscoring the importance of targeting modifiable cardiovascular disease risk factors in these patients. PMID- 28817948 TI - Effects of dietary supplementation of resveratrol on performance, egg quality, yolk cholesterol and antioxidant enzyme activity of laying hens. AB - 1. This experiment was conducted to evaluate the effects of dietary supplementation of resveratrol on laying performance, egg quality, egg yolk cholesterol and antioxidant enzyme activities of laying hens. 2. A total of 360 Beijing PINK-1 laying hens (60 weeks old) were randomly distributed among five dietary treatments, each of which included 6 replicates of 12 hens. Dietary treatments were basal diet supplemented with 0 (control), 0.5, 1.0, 2.0 and 4.0 g/kg diet resveratrol. The study lasted for 9 weeks including 1 week of adaptation and 8 weeks of the main experimental period. 3. The results indicated that dietary resveratrol significantly improved feed conversion ratios during 5-8 weeks and 1-8 weeks of the trial. Increasing dietary concentrations of the resveratrol linearly improved Haugh unit and albumen height of eggs. 4. The content of total cholesterol (TC), total triglyceride (TG), low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL C) in serum and cholesterol in yolk was significantly decreased by dietary resveratrol, and there were significant linear correlations between these indexes and resveratrol supplemental levels. 5. Dietary resveratrol supplementation significantly improved serum Glutathione peroxidase (GSH-Px) enzyme activity and decreased serum malondialdehyde (MDA) content in groups with 2.0 and 4.0 g/kg resveratrol as compared to the control, respectively. However, supplementation of resveratrol did not affect the activity of serum superoxide dismutase (SOD). 6. It is concluded that resveratrol supplementation has a positive effect on performance, lipid-related traits and antioxidant activity of laying hens. PMID- 28817949 TI - Linear Trend in Single-Case Visual and Quantitative Analyses. AB - The frequently used visual analysis of single-case data focuses on data aspects such as level, trend, variability, overlap, immediacy of effect, and consistency of data patterns; most of these aspects are also commonly quantified besides inspecting them visually. The present text focuses on trend, because even linear trend can be operatively defined in several different ways, while there are also different approaches for controlling for baseline trend. We recommend using a quantitative criterion for choosing a trend line fitting technique and comparing baseline and intervention slopes, instead of detrending. We implement our proposal in a free web-based application created specifically for following the What Works Clearinghouse Standards recommendations for visual analysis. This application is especially destined to applied researchers and provides graphical representation of the data, visual aids, and quantifications of the difference between phases in terms of level, trend, and overlap, as well as two quantifications of the immediate effect. An evaluation of the consistency of effects across replications of the AB sequence is also provided. For methodologists and statisticians, we include formulas and examples of the different straight line fitting and detrending techniques to improve the reproducibility of results and simulations. PMID- 28817950 TI - Editorial Comment on: Vascular Disease and Kidney Stones: Abdominal Aortic Calcifications Are Associated with Low Urine pH and Hypocitraturia by Patel et al. PMID- 28817952 TI - Professional Socialization: A Grounded Theory of the Clinical Reasoning Processes That RNs and LPNs Use to Recognize Delirium. AB - Delirium is an acute disorder of attention and cognition. It affects half of older adults in acute care settings and is a cause of increasing mortality and costs. Registered nurses (RNs) and licensed practical nurses (LPNs) frequently fail to recognize delirium. The goals of this research were to identify the reasoning processes that RNs and LPNs use to recognize delirium, to compare their reasoning processes, and to generate a theory that explains their clinical reasoning processes. Theoretical sampling was employed to elicit data from 28 participants using grounded theory methodology. Theoretical coding culminated in the emergence of Professional Socialization as the substantive theory. Professional Socialization emerged from participants' responses and was based on two social processes, specifically reasoning to uncover and reasoning to report. Professional Socialization makes explicit the similarities and variations in the clinical reasoning processes between RNs and LPNs and highlights their main concerns when interacting with delirious patients. PMID- 28817951 TI - Cessation-related information, motivation, and behavioral skills in smokers living with HIV. AB - There is a need for new, targeted smoking cessation interventions for smokers living with HIV. The Information-Motivation-Behavioral Skills (IMB) model has been applied effectively to HIV-related health behaviors and was used in this qualitative study to elicit factors that could lead to the development of innovative and successful cessation interventions for this population. Twenty individuals who smoked from two clinics providing care to people living with HIV participated in open-ended interviews, responding to questions covering the domains of the IMB model, as applied to smokers living with HIV. Participants were enrolled from a larger survey cohort to recruit into groups based on the impact of HIV diagnosis on smoking as well as attempting to enroll a mix of demographics characteristics. Interviews were recorded, transcribed, coded and thematically analyzed using a grounded theory qualitative approach. Interviews continued until thematic saturation was reached. Major themes included: Presence of knowledge deficits regarding HIV-specific health risks of smoking; use of smoking for emotional regulation, where many reported close contacts who smoke and concern with the effect of cessation on their social networks; Use of smoking cessation aids or a telephone-based wellness intervention were acceptable to most. Providing HIV-specific information in cessation advice is of the utmost importance for clinicians caring for smokers living with HIV, as this theme was noted consistently as a potential motivator to quit. Innovative and effective interventions must account for the social aspect of smoking and address other methods of emotional regulation in this population. PMID- 28817953 TI - The Evidence Base for Interventions Targeting Individuals With Work-Related PTSD: A Systematic Review and Recommendations. AB - The purpose of this study was to summarize the evidence base for interventions targeting individuals with work-related posttraumatic stress disorder (PTSD), to make recommendations for clinicians and administrative decision makers involved in their rehabilitation, and to guide future research in this area. Particular attention was given to studies that were conducted in naturalistic clinical settings or in a workers' compensation claim context. Electronic searches of Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, PsycINFO, CINAHL, PILOTS, and EMBASE identified 11 articles. Study populations included railroad personnel, police officers, disaster workers, and individuals with industrial injuries. Interventions included trauma-focused cognitive-behavioral therapy and eye movement desensitization and reprocessing. Several studies specifically targeted workers who had failed to return to work (RTW) after standard PTSD treatment. The results suggest that psychotherapy interventions are beneficial for helping clients recover from PTSD symptoms and RTW. In studies that reported on work status, RTW rates increased over time and generally lay between 58% and 80% across follow-up time points. Narrative impressions were supplemented by calculation of Risk Differences for individuals working at pretreatment versus posttreatment. Clinical consideration, methodological issues limiting the current body of work, and recommendations for future research are discussed. PMID- 28817955 TI - Redox Signaling Mechanisms in Nervous System Development. AB - SIGNIFICANCE: Numerous studies have demonstrated the actions of reactive oxygen species (ROS) as regulators of several physiological processes. In this study, we discuss how redox signaling mechanisms operate to control different processes such as neuronal differentiation, oligodendrocyte differentiation, dendritic growth, and axonal growth. Recent Advances: Redox homeostasis regulates the physiology of neural stem cells (NSCs). Notably, the neuronal differentiation process of NSCs is determined by a change toward oxidative metabolism, increased levels of mitochondrial ROS, increased activity of NADPH oxidase (NOX) enzymes, decreased levels of Nrf2, and differential regulation of different redoxins. Furthermore, during the neuronal maturation processes, NOX and MICAL produce ROS to regulate cytoskeletal dynamics, which control the dendritic and axonal growth, as well as the axonal guidance. CRITICAL ISSUES: The redox homeostasis changes are, in part, attributed to cell metabolism and compartmentalized production of ROS, which is regulated, sensed, and transduced by different molecules such as thioredoxins, glutaredoxins, peroxiredoxins, and nucleoredoxin to control different signaling pathways in different subcellular regions. The study of how these elements cooperatively act is essential for the understanding of nervous system development, as well as the application of regenerative therapies that recapitulate these processes. FUTURE DIRECTIONS: The information about these topics in the last two decades leads us to the conclusion that the role of ROS signaling in development of the nervous system is more important than it was previously believed and makes clear the importance of exploring in more detail the mechanisms of redox signaling. Antioxid. Redox Signal. 28, 1603-1625. PMID- 28817956 TI - The Role of Intrinsic Brain Functional Connectivity in Vulnerability and Resilience to Bipolar Disorder. AB - OBJECTIVE: Bipolar disorder is a heritable disorder characterized by mood dysregulation associated with brain functional dysconnectivity. Previous research has focused on the detection of risk- and disease-associated dysconnectivity in individuals with bipolar disorder and their first-degree relatives. The present study seeks to identify adaptive brain connectivity features associated with resilience, defined here as avoidance of illness or delayed illness onset in unaffected siblings of patients with bipolar disorder. METHOD: Graph theoretical methods were used to examine global and regional brain network topology in head motion-corrected resting-state functional MRI data acquired from 78 patients with bipolar disorder, 64 unaffected siblings, and 41 healthy volunteers. RESULTS: Global network properties were preserved in patients and their siblings while both groups showed reductions in the cohesiveness of the sensorimotor network. In the patient group, these sensorimotor network abnormalities were coupled with reduced integration of core default mode network regions in the ventromedial cortex and hippocampus. Conversely, integration of the default mode network was increased in the sibling group compared with both the patient group and the healthy volunteer group. CONCLUSIONS: The authors found that trait-related vulnerability to bipolar disorder was associated with reduced resting-state cohesiveness of the sensorimotor network in patients with bipolar disorder. However, integration of the default mode network emerged as a key feature differentiating disease expression and resilience between the patients and their siblings. This is indicative of the presence of neural mechanisms that may promote resilience, or at least delay illness onset. PMID- 28817957 TI - Case Report of Onychomycosis and Tinea Corporis Due to Microsporum gypseum. AB - BACKGROUND: Microsporum gypseum is a geophilic dermatophyte that colonises keratinous substances in the soil. Fur-bearing animals carry this dermatophyte but are rarely infected. Human infection can be acquired from the soil, carrier or infected animals, and rarely other humans. M gypseum is an uncommon cause of cutaneous infection in humans and typically manifests as tinea corporis, tinea barbae, and tinea capitis. Onychomycosis is rarely caused by M gypseum. CASE SUMMARY: We present a case of a 32-year-old white man who presented with a red scaly rash and nail dystrophy after adopting a pet rat 10 years prior to presentation. A fungal culture of a nail clipping grew out M gypseum, and the patient was treated with terbinafine daily for 6 weeks for dystrophic onychomycosis and tinea corporis. After the 6 weeks of treatment, the erythema at the proximal nail fold and distal finger had improved but still persisted. An additional 6 weeks of terbinafine daily completely resolved the clinical manifestations of onychomycosis. CONCLUSION: The increase in incidence of M gypseum onychomycosis over the past 2 decades is thought to be due to phylogenetic evolution of the dermatophyte from soil saprophyte to a human parasite. Increasing domestication of mammals is also thought to contribute to increasing incidence. Treatment consists of an extended course of terbinafine or itraconazole. PMID- 28817954 TI - Dissecting Amyloid Beta Deposition Using Distinct Strains of the Neurotropic Parasite Toxoplasma gondii as a Novel Tool. AB - Genetic and pathologic data suggest that amyloid beta (Abeta), produced by processing of the amyloid precursor protein, is a major initiator of Alzheimer's disease (AD). To gain new insights into Abeta modulation, we sought to harness the power of the coevolution between the neurotropic parasite Toxoplasma gondii and the mammalian brain. Two prior studies attributed Toxoplasma-associated protection against Abeta to increases in anti-inflammatory cytokines (TGF-beta and IL-10) and infiltrating phagocytic monocytes. These studies only used one Toxoplasma strain making it difficult to determine if the noted changes were associated with Abeta protection or simply infection. To address this limitation, we infected a third human amyloid precursor protein AD mouse model (J20) with each of the genetically distinct, canonical strains of Toxoplasma (Type I, Type II, or Type III). We then evaluated the central nervous system (CNS) for Abeta deposition, immune cell responses, global cytokine environment, and parasite burden. We found that only Type II infection was protective against Abeta deposition despite both Type II and Type III strains establishing a chronic CNS infection and inflammatory response. Compared with uninfected and Type I-infected mice, both Type II- and Type III-infected mice showed increased numbers of CNS T cells and microglia and elevated pro-inflammatory cytokines, but neither group showed a >2-fold elevation of TGF-beta or IL-10. These data suggest that we can now use our identification of protective (Type II) and nonprotective (Type III) Toxoplasma strains to determine what parasite and host factors are linked to decreased Abeta burden rather than simply with infection. PMID- 28817958 TI - Inspiring the Future of Medicine: The Healthcare Improvement & iNnovation in Quality (THINQ) Collaborative at UCLA Health. PMID- 28817959 TI - A Health Behavior Prediction Model for Patients With Coronary Artery Disease. AB - The aim of this study was to determine the relationships among functional status, hostility, social support, illness perceptions, and health behaviors in patients with coronary artery disease using structural equation modeling. Participants comprised 215 patients with coronary artery disease who had received percutaneous coronary artery intervention or a coronary artery bypass graft in two general hospitals in Seoul, Korea. Using structured interviews with questionnaires, data accrued from July to August, 2015. Fitness of the model was verified with AMOS 21.0. As social support increased, it negatively aligned with cognitive-illness perceptions. Higher levels of hostility and greater negative cognitive-illness perceptions aligned with negative emotional-illness perceptions. Social support indirectly affected emotional-illness perceptions. Lower levels of functional status, greater social support, and more positive cognitive-illness perceptions aligned with health behaviors. Social support indirectly affected health behaviors. In conclusion, nurses should focus on coronary artery disease patients' physical functions and cognitive-illness perceptions to provide support. PMID- 28817960 TI - Effectiveness of pedicle screw inclusion at the fracture level in short-segment fixation constructs for the treatment of thoracolumbar burst fractures: a computational biomechanics analysis. AB - When treating thoracolumbar burst fractures (BF), short-segment posterior fixation (SSPF) represents a less invasive alternative to the traditional long segment posterior fixation (LSPF) approach. However, hardware failure and loss of sagittal alignment have been reported in patients treated with SSPF. Including pedicle screws at the fracture level in SSPF constructs has been proposed to improve stiffness and reliability of the construct. Accordingly, the biomechanical performance of the proposed construct was compared to LSPF via a computational analysis. Pedicle screws at fracture level improved the performance of the short-segment construct. However, LSPF still represent a biomechanically superior option for treating thoracolumbar BF. PMID- 28817961 TI - Evaluating the Ergonomics of Flexible Ureteroscopy. AB - INTRODUCTION: To date, the ergonomics of flexible ureteroscopy (URS) have not been well described. We performed a study to assess the biomechanical stresses on urologists performing URS and to investigate the effect of ureteroscope type on these parameters. METHODS: Electromyography (EMG) was used to quantify the activation level of muscle groups involved in URS. Surface EMG electrodes (Delsys, Boston, MA) were placed on the right and left thenar, flexor carpi ulnaris (FCU), extensor carpi ulnaris (ECU), biceps, triceps, and deltoid. Three endoscopes were studied: single-use digital (Boston Scientific LithoVue), reusable digital (Karl Storz Flex-Xc), and reusable fiber-optic (Karl Storz Flex X2). Each ureteroscope was used to perform a set sequence of navigation and procedural tasks in a training model. EMG data were processed and normalized to compare the maximum voluntary contractions between muscle groups. Cumulative muscular workload (CMW) and average muscular work per second (AWS) were used for comparative analysis. RESULTS: For navigational tasks, CMW and AWS were greatest for the ECU, followed in descending order by right and left thenar, FCU, biceps, deltoid, and triceps. For procedural tasks, CMW and AWS were greatest for the right thenar, followed in descending order by the left thenar, ECU, FCU, triceps, biceps, and deltoid. During navigational tasks, both LithoVue and Flex-Xc had lower CMWs for every muscle group than Flex-X2 (p < 0.05). LithoVue and Flex-Xc had similar AWS and both were lower than Flex-X2 for the right thenar, ECU, biceps, and deltoid activation (p < 0.05). During procedural tasks, both LithoVue and Flex-Xc had lower CMWs and AWS for right and left thenar, ECU, and biceps than Flex-X2 (p < 0.05). CONCLUSIONS: This study provides the first description of EMG-measured ergonomics of URS. Both the single-use and reusable digital ureteroscopes have similar profiles, and both have significantly better ergonomic metrics than the reusable fiber-optic ureteroscope. PMID- 28817962 TI - Patients With Diabetic Foot Disease Fear Major Lower-Extremity Amputation More Than Death. AB - BACKGROUND: The aim of this study was to identify the most-feared complications of diabetes mellitus (DM), comparing those with diabetic foot pathology with those without diabetic foot pathology. METHODS: We determined the frequency of patients ranking major lower-extremity amputation (LEA) as their greatest fear in comparison to blindness, death, diabetic foot infection (DFI), or end-stage renal disease (ESRD) requiring dialysis. We further categorized the study group patients (N = 207) by their pathology such as diabetic foot ulcer (DFU), Charcot neuroarthropathy, foot infection, or acute neuropathic fractures and dislocations. The control group (N = 254) was comprised of patients with diabetes who presented with common non-diabetes-related foot pathology. RESULTS: A total of 461 patients were enrolled in this study and included 254 patients without diabetic foot complications and 207 patients with diabetic foot problems. When comparing patients with and without diabetic disease, no significant differences were observed with regard to their fear of blindness, DFI, or ESRD requiring dialysis. Patients with diabetic foot disease (61 of 207, 31.9%) were 136% more likely (odds ratio [OR] = 2.36; 95% CI = 1.51-3.70; P = .002] to rank major LEA as their greatest fear when compared with diabetic patients without foot disease (42 of 254, 16.5%) and were 49% less likely (OR = 0.51; 95% CI = 0.34-0.79; P = .002) to rank death as their greatest fear compared with patients without diabetic foot disease. CONCLUSION: Patients with diabetic foot pathology fear major LEA more than death, foot infection, or ESRD. Variables that were associated with ranking LEA as the greatest fear were the presence of a diabetic related foot complication, duration of DM >=10 years, insulin use, and the presence of peripheral neuropathy. LEVELS OF EVIDENCE: Level II: Prospective, Case controlled study. PMID- 28817963 TI - Lipoproteins and Cardiovascular Redox Signaling: Role in Atherosclerosis and Coronary Disease. AB - SIGNIFICANCE: Lipoproteins, such as low-density lipoprotein, play a causal role in the development of atherosclerosis and coronary disease. Recent Advances: Lipoproteins can stimulate vascular production of reactive oxygen species, which act as important signaling molecules in the cardiovascular system contributing to the pathophysiology of endothelial dysfunction, hypertension, and atherosclerosis. CRITICAL ISSUES: Modified lipoproteins have emerged as important regulators of redox signaling, such as oxidized or carbamylated low-density lipoprotein or modified high-density lipoproteins, that contain oxidized lipids, an altered protein cargo, and associated small molecules, such as symmetric dimethylarginine. FUTURE DIRECTIONS: In this review, we provide an overview on signaling pathways stimulated by modified lipoproteins in the cardiovascular system and their potential role in cardiovascular disease development. Moreover, we highlight novel aspects of how gut microbiome-related mechanisms-a growing research field-may contribute to lipoprotein modification with subsequent impact on cardiovascular redox signaling. Antioxid. Redox Signal. 29, 337-352. PMID- 28817964 TI - Understanding coping strategies among people living with scleroderma: a focus group study. AB - PURPOSE: Systemic sclerosis or scleroderma is a chronic, rare connective tissue disease with negative physical and psychological implications. Coping strategies used by scleroderma patients have not been studied in-depth. The objective of the present study was to gain a greater understanding of the coping strategies employed by people living with scleroderma. METHOD: Three semi-structured focus group discussions were conducted with a total of 22 people with scleroderma. Interviews were recorded, transcribed, and analyzed using content analysis. Coping strategies discussed were analyzed through Lazarus and Folkman's theoretical model of coping, including: (1) problem-focused, (2) emotion-focused, and (3) meaning-focused coping. RESULTS: Participants reported using a combination of problem-focused (e.g., professional help; seeking disease-related information), emotion-focused (e.g., social support; adaptive distraction techniques), and meaning-focused coping strategies (e.g., benefit finding; goal reappraisal) to help them to cope with and manage their disease. However, many patients reported having difficulty in accessing support services. CONCLUSIONS: Scleroderma patients use similar coping strategies as patients with more common diseases, but they may not have access to the same level of support services. Accessible interventions, including self-management programs, aimed at improving problem- and emotion-focused coping are needed. Further, increased access to support groups may provide patients with opportunities to obtain social support and enhance coping. PMID- 28817965 TI - Trametes versicolor ethanol extract, a promising candidate for health-promoting food supplement. AB - This study aimed to estimate antiradical, antioxidant (AO) and cytotoxic activities of the fungus Trametes versicolor ethanol fruiting body extract. The extract was found to effectively scavenge both O2*- and NO* (29.62 and 52.48 MUg/mL, respectively). It also showed a good AO activity in the polarographic HPMC assay (950%/mL). p-Hydroxybenzoic acid may be one of the responsible compounds for the afore-mentioned activities. The same extract also exhibited a concentration-dependent cytotoxicity against MCF-7 and HepG2 tumour cell lines reaching IC50 values of 123.51 and 134.29 MUg/mL, respectively with no cytotoxic activity against normal MRC-5 cells. Gentisic, syringic and protocatechuic acids may be among the bioactive principles for the observed cytotoxicity. Taken all together, T. versicolor ethanol extract can be considered as a promising candidate for development of health promoting food supplement. PMID- 28817966 TI - Attitudes and Barriers to Healthy Diet and Physical Activity: A Latent Profile Analysis. AB - Healthy diet and physical activity (PA) prevent and reduce chronic disease. Social cognitive theory delineates multiple attitudes and barriers that influence these behaviors. Understanding covariation in these attitudes and barriers is complex. We examined whether individuals could be grouped into a small number of categories that are easier to study. Interviews were conducted with 982 adults from two low-income, predominantly African American neighborhoods in the same city. Social cognitive constructs, including self-efficacy, social norms, and internal and external barriers to diet and exercise, and walking were self reported. We measured moderate to vigorous physical activity with accelerometers and diet with 24-hour recalls. We conducted a latent profile analysis of attitudes and barriers to diet and PA and identified four classes: (a) moderate diet and negative exercise attitudes, where participants were roughly average on dietary attitudes but reported exercise-related challenges, including lower social support, outcome expectancies, physical functioning, and self-efficacy; (b) few barriers and benefits of healthy diet and exercise, where participants reported fewer barriers and lower outcome expectancies for diet and PA; (c) moderate overall attitudes, where participants had average scores on most indicators but below-average exercise self-efficacy and slightly more exercise barriers; and (d) positive overall attitudes, characterized by more positive attitudes toward both diet and PA across most domains, particularly regarding self-efficacy to overcome exercise barriers. These profiles could inform efforts to tailor individual-level interventions for diet and PA of persons at high risk of chronic diseases. PMID- 28817967 TI - Pimavanserin, a novel antipsychotic for management of Parkinson's disease psychosis. AB - INTRODUCTION: Parkinson's disease psychosis (PDP) may develop in up to 60% of Parkinson's patients and is associated with increased morbidity and mortality. It also correlates with depression and dementia, and can contribute to caregiver stress and burnout. Pimavanserin is the first FDA approved drug for the treatment of hallucinations and delusions associated with PDP. Areas covered: For this review, a MEDLINE literature search (via PubMed) and information provided by ACADIA Pharmaceuticals were used. This review will discuss the pathophysiology and current management of PDP. In addition, this review will focus on the rationales behind the development of pimavanserin, mechanism of action, pharmacokinetics, pharmacodynamics, and the clinical trials evaluating the efficacy and safety of pimavanserin. Last, the review will address the drug's package insert warning. Expert commentary: Pimavanserin, a 5HT2A receptor inverse agonist, is the first FDA approved drug for the treatment of PDP which has been shown to reduce psychosis in PD through its unique mechanism of action. Pimavanserin, does not worsen PD motor symptoms and has an acceptable safety profile. The development of pimavanserin as an antipsychotic opened a new therapeutic avenue in the treatment of PDP as well as targeting psychosis in other disorders such as Alzheimer's disease. PMID- 28817969 TI - HIV-related stigma and subjective well-being: The mediating role of the Belief in a Just World. AB - The primary aim of this study was to explore the relationship between the domains of HIV-related stigma and subjective well-being in people living with HIV ( N = 90), giving a special emphasis to the role of Belief in a Just World. A significant relationship emerged between the domains of stigma and the components of subjective well-being, which is not direct, but is rather mediated by Belief in a Just World. The findings indicate that exposure to stigma can lead to a decrease in Belief in a Just World, which potentially leads to a sense of lack of control over one's life, with a final, negative outcome for subjective well being. PMID- 28817968 TI - Destabilizing the interplay between miR-1275 and IGF2BPs by Tamarix articulata and quercetin in hepatocellular carcinoma. AB - Insulin-like growth factor-2 binding proteins (IGF2BPs) are oncogenic RNA-binding proteins, highly up-regulated in HCC, and were recently validated as direct targets of the tumour suppressor miR-1275. It is worth noting that around 47% of FDA approved anticancer drugs are derived from plants. Modulation by miRNAs and their cellular signalling cascades could constitute new pathways by which these phytochemicals exert their effects. This study aimed to investigate the potential use of Tamarix articulata, quercetin and epigallocatechin gallate (EGCG) in HCC and how these phytochemicals could epigenetically modulate the IGF axis using their impact on miR-1275. T. articulata ethyl acetate fraction significantly reduced the viability of Huh-7 cells compared to control cells. Treatment with T. articulata ethyl acetate fraction, quercetin and EGCG significantly enhanced miR 1275, while suppressed IGF2BP1 and IGF2BP3 mRNA expression levels. In summary, T. articulata, quercetin and EGCG have important implications for HCC molecular targeted therapy through destabilizing the interplay between miR-1275 and the IGF axis. PMID- 28817970 TI - Three new cassane diterpenes from the seeds of Caesalpinia minax Hance. AB - Four fractions were prepared from the crude extract of Caesalpinia minax Hance and the inhibitory activity of nitric oxide (NO) production release of RAW 264.7 cells stimulated by lipopolysaccharide (LPS) was evaluated. The ethyl acetate (EtOAc) fraction showed obvious inhibitory effect. Bioassay-guided fractionation led to the isolation of three new cassane diterpenes, caesalmin X (1), caesalmin Y (2) and caesalmin Z (3), together with 19 known cassane diterpenoids (4-22). Their structures were mainly characterised on the basis of extensive spectroscopic analyses and comparison with reported data. Moreover, three compounds (20-22) which possessed furanditerpenoid 7,17-lactone structures, displayed moderate activities, with IC50 value of 29.85, 27.38 and 25.40 MUM, respectively. PMID- 28817971 TI - Effects of solid acellular type-I/III collagen biomaterials on in vitro and in vivo chondrogenesis of mesenchymal stem cells. AB - INTRODUCTION: Type-I/III collagen membranes are advocated for clinical use in articular cartilage repair as being able of inducing chondrogenesis, a technique termed autologous matrix-induced chondrogenesis (AMIC). Area covered: The current in vitro and translational in vivo evidence for chondrogenic effects of solid acellular type-I/III collagen biomaterials. Expert commentary: In vitro, mesenchymal stem cells (MSCs) adhere to the fibers of the type-I/III collagen membrane. No in vitro study provides evidence that a type-I/III collagen matrix alone may induce chondrogenesis. Few in vitro studies compare the effects of type I and type-II collagen scaffolds on chondrogenesis. Recent investigations suggest better chondrogenesis with type-II collagen scaffolds. A systematic review of the translational in vivo data identified one long-term study showing that covering of cartilage defects treated by microfracture with a type-I/III collagen membrane significantly enhanced the repair tissue volume compared with microfracture alone. Other in vivo evidence is lacking to suggest either improved histological structure or biomechanical function of the repair tissue. Taken together, there is a paucity of in vitro and preclinical in vivo evidence supporting the concept that solid acellular type-I/III collagen scaffolds may be superior to classical approaches to induce in vitro or in vivo chondrogenesis of MSCs. PMID- 28817972 TI - Real-world research and the role of observational data in the field of gynaecology - a practical review. AB - OBJECTIVES: In the context of women's health, we examine (1) the role that observational ('real-world') studies have in overcoming limitations of randomised clinical trials, (2) the relative advantages and disadvantages of different study designs, (3) the importance of outcome data from observational studies when making health-economic or clinical decisions, and (4) provide insights into changing perceptions of observational clinical data. METHODS: PubMed and internet searches were used to identify (i) guidance and expert commentary on designing, conducting, analysing, and reporting clinical trials or observational studies, (ii) supporting evidence of the rapid growth of observational ('real world') studies and publications since the turn of millennium in the fields of contraception, reproductive health, obstetrics or gynaecology. RESULTS: The rapidly growing use and validation of large, computerised medical records and related databases (e.g., health insurance or national registries) have played a major part in changing perceptions of observational data among researchers and clinicians. In the past 10 years, a distinct increase in the number of observational studies published tends to confirm their growing acceptance, appreciation and use. CONCLUSIONS: Observational studies can provide information that is impossible or infeasible to obtain otherwise (e.g., impractical, very expensive, or ethically unacceptable). Greater understanding, dissemination, uptake and use of observational data might be expected to drive ongoing evolution of research, data collection, analysis, and validation, in turn improving quality and therefore credibility, utility, and further application by clinicians. PMID- 28817973 TI - The AGMA1 polyamidoamine mediates the efficient delivery of siRNA. AB - AGMA1, a prevailingly cationic, guanidine-bearing, linear, amphoteric polyamidoamine is an effective siRNA condensing agent. Here two AGMA1 samples of different molecular weight, i.e. AGMA1-5 and AGMA1-10 were evaluated as siRNA condensing agents and transfection promoters. AGMA1-10 formed stable polyplexes with a size lower than 50 nm and positive zeta potential. AGMA1-5 polyplexes were larger, about 100 nm in size. AGMA1-10 polyplexes, but not AGMA1-5 proved to be an effective intracellular siRNA carrier, able to trigger gene silencing in Hela and PC3 cell lines without eliciting cytotoxic effects. AGMA1-10 knocked down AKT 1 expression upon transfection with an AKT-1 specific siRNA. The polyplex entry mechanism was investigated and was mediated by macropinocytosis. In conclusion, AGMA1 has potential as an efficient, non-toxic tool for the intracellular delivery of siRNA and warrants further investigation. PMID- 28817974 TI - Applications of the real-time quaking-induced conversion assay in diagnosis, prion strain-typing, drug pre-screening and other amyloidopathies. AB - INTRODUCTION: The development of in vitro protein misfolding amplification assays for the detection and analysis of abnormally folded proteins, such as proteinase K resistant prion protein (PrPres) was a major innovation in the prion field. In prion diseases, these types of assays imitate the pathological conversion of the cellular PrP (PrPC) into a proteinase resistant associated conformer or amyloid, called PrPres. Areas covered: The most prominent protein misfolding amplification assays are the protein misfolding cyclic amplification (PMCA), which is based on sonication and the real-time quaking-induced conversion (RT-QuIC) technique based on shaking. The more recently established RT-QuIC is fully automatic and enables the monitoring of misfolded protein aggregates in real-time by using a fluorescent dye. Expert commentary: RT-QuIC is a very robust and highly reproducible test system which is applicable in diagnosis, prion strain-typing, drug pre-screening and other amyloidopathies. PMID- 28817975 TI - Triarylmethyl-based biradical as a superoxide probe. AB - Superoxide radical represents one of the most biologically relevant reactive oxygen species involved in numerous physiological and pathophysiological processes. Superoxide measurement through the decay of an electron paramagnetic resonance (EPR) signal of a triarylmethyl (TAM) radical possesses the advantage of a high selectivity and relatively high rate constant of TAM reaction with the superoxide. Hereby we report a straightforward synthesis and characterization of a TAM-TAM biradical showing a high reactivity with superoxide (second-order rate constant, (6.7 +/- 0.2) * 103 M-1 s-1) enabling the measurement of superoxide radical by following the increase of a sharp EPR signal associated with the formation of a TAM-quinone-methide monoradical product. PMID- 28817976 TI - An open-source model and solution method to predict co-contraction in the finger. AB - A novel open-source biomechanical model of the index finger with an electromyography (EMG)-constrained static optimization solution method are developed with the goal of improving co-contraction estimates and providing means to assess tendon tension distribution through the finger. The Intrinsic model has four degrees of freedom and seven muscles (with a 14 component extensor mechanism). A novel plugin developed for the OpenSim modelling software applied the EMG-constrained static optimization solution method. Ten participants performed static pressing in three finger postures and five dynamic free motion tasks. Index finger 3D kinematics, force (5, 15, 30 N), and EMG (4 extrinsic muscles and first dorsal interosseous) were used in the analysis. The Intrinsic model predicted co-contraction increased by 29% during static pressing over the existing model. Further, tendon tension distribution patterns and forces, known to be essential to produce finger action, were determined by the model across all postures. The Intrinsic model and custom solution method improved co-contraction estimates to facilitate force propagation through the finger. These tools improve our interpretation of loads in the finger to develop better rehabilitation and workplace injury risk reduction strategies. PMID- 28817978 TI - Transcutaneous electrical nerve stimulation (TENS) as an adjunct for pain management in perioperative settings: a critical review. AB - INTRODUCTION: Surgical procedures are ever more complex. Day-case surgical loads are increasing and the length of hospital stays are reducing. Management of pain in perioperative settings remains a challenge. Expert panels recommend a multimodal approach which is often interpreted by medical practitioners as polypharmacy. There is variability in non-pharmacological interventions offered to patients, although transcutaneous electrical nerve stimulation (TENS) has been used since the 1970s. Recommendations from expert panels are inconsistent about the use of TENS in perioperative pain settings. Areas covered: This critical review outlines the challenges of managing pain in perioperative settings and uses a narrative synthesis to evaluate the findings of systematic reviews on the clinical efficacy of TENS for pain in perioperative settings. Expert commentary: Moderate evidence from systematic reviews suggests that TENS is superior to placebo (no current) TENS for reducing analgesic consumption and improving pain, pulmonary function, and nausea and vomiting. Therefore, it seems reasonable to offer TENS as an adjunct to core treatment for surgical pain, especially because it is inexpensive and has a favorable safety profile compared with long-term medication. Practical considerations for the integration of TENS into service delivery are discussed. PMID- 28817977 TI - A Short and Efficient Transduction Protocol for Mouse Hematopoietic Stem Cells with Lentiviral Vectors. AB - Transduction of hematopoietic stem and progenitor cells (HSPCs) with lentiviral vectors (LVs) constitutes a new therapeutic option for the treatment of various monogenic diseases affecting the lymphohematopoietic system. The development of detailed preclinical studies of gene therapy in animal disease models constitutes an essential step in expanding the application of gene therapy in a wide variety of inherited and acquired diseases. Here we describe an efficient protocol to transduce HSPCs from wild-type and Fanconi anemia mice with either gene-marking or therapeutic LVs. In this protocol, purified lineage-, Sca-1+, c-Kit+ bone marrow cells were transduced in vitro for a short period of time under conditions that facilitated efficient transduction of HSPCs capable of engrafting in transplanted recipients. PMID- 28817979 TI - Labor market position after a rejection of a disability pension application: a register-based cohort study. AB - PURPOSE: To study labor market positions of rejected disability pension applicants and to examine which characteristics predict ending up in these positions after the rejection. METHODS: Nationwide Finnish register data was used to describe employment, unemployment and disability pension trajectories of rejected applicants (n = 5740) from four years before to four years after the rejection. Demographic, occupational and health-related determinants of labor market position after the rejection were examined among those employed and not employed at the time of the rejection. RESULTS: The proportion of the employed steeply decreased and that of unemployed increased before the rejection of a disability pension application. Four years after the rejection, 30% of the rejected applicants were employed, 24% were unemployed and 30% received disability pension. Employment at the time of the rejection, younger age, shorter unemployment history, public sector employment and milder work disability increased future employment. Manual work, public sector employment and previous long-term unemployment predicted future unemployment. Apart from higher age, associations with receiving disability pension were relatively weak. CONCLUSIONS: For many rejected disability pension applicants return to work is challenging. Special efforts should be targeted to support the remaining work ability and to promote employment opportunities of the rejected applicants. Implications for Rehabilitation Employment, unemployment and receiving disability pension were equally common labor market positions four years after the rejection. Rejected DP applicants with unemployment history need special efforts to increase their employability. As a disability pension application, even if rejected, clearly indicates some degree of work ability problems, rehabilitation should be targeted at this time point to support employment. PMID- 28817980 TI - Pathways to pulmonary hypertension in sickle cell disease: the search for prevention and early intervention. AB - INTRODUCTION: Pulmonary hypertension (PH) develops in a significant number of patients with sickle cell disease (SCD), resulting in increased morbidity and mortality. This review focuses on PH pathophysiology, risk stratification, and new recommendations for screening and treatment for patients with SCD. Areas covered: An extensive PubMed literature search was performed. While the pathophysiology of PH in SCD is yet to be fully deciphered, it is known that the etiology is multifactorial; hemolysis, hypercoagulability, hypoxemia, ischemic reperfusion injury, oxidative stress, and genetic susceptibility all contribute in varying degrees to endothelial dysfunction. Hemolysis, in particular, seems to play a key role by inciting an imbalance in the regulatory axis of nitric oxide and arginine metabolism. Systematic risk stratification starting in childhood based on clinical features and biomarkers that enable early detection is necessary. Multi-faceted, targeted interventions, before irreversible vasculopathy develops, will allow for improved patient outcomes and life expectancy. Expert commentary: Despite progress in our understanding of PH in SCD, clinically proven therapies remain elusive and additional controlled clinical trials are needed. Prevention of disease starts in childhood, a critical window for intervention. Given the complex and multifactorial nature of SCD, patients will ultimately benefit from combination therapies that simultaneously targets multiple mechanisms. PMID- 28817981 TI - The use of flexible intramedullary nails in limb lengthening. AB - INTRODUCTION: Lower and upper limb length discrepancy and deformity, congenital or acquired, are amongst the most common conditions in children for orthopaedic referral. Over the last twenty years, surgical techniques have evolved in an attempt to decrease Healing Index and minimise these complications. Areas covered: The flexible intramedullary nailing (FIN) is a minimally invasive intramedullary osteosynthesis. In combination with an external fixator, it is appropriated for pediatric bone lengthenings and lengthening of bones of small diameter in adults. In the study the Scopus and/or PubMed indexed publications about this combined technique were analyzed. Expert commentary: The use of titanium or stainless steel or hydroxyapatite-coated bent elastic nails is appropriate in limb lengthening for congenital and acquired limb length discrepancy. Hydroxyapatite-coated FIN should be applied for long-term reinforcement of lengthened bone in patients with metabolic bone disorders, skeletal dysplasias with compromised bone formation. Osteoinductive surface of nails is favorable for bone formation and as well as for stable position of nails without risks of migration in long-term follow-up. The FIN is an unique intramedullary fixation which respects the bone biology which is mandatory for a good bone consolidation. PMID- 28817983 TI - The use of soft robotics in cardiovascular therapy. AB - INTRODUCTION: Robots have been employed in cardiovascular therapy as surgical tools and for automation of hospital systems. Soft robots are a new kind of robot made of soft deformable materials, that are uniquely suited for biomedical applications because they are inherently less likely to injure body tissues and more likely to adapt to biological environments. Awareness of the soft robotic systems under development will help promote clinician involvement in their successful clinical translation. Areas covered: The most advanced soft robotic systems, across the size scale from nano to macro, that have shown the most promise for clinical application in cardiovascular therapy because they offer solutions where a clear therapeutic need still exists. We discuss nano and micro scale technology that could help improve targeted therapy for cardiac regeneration in ischemic heart disease, and soft robots for mechanical circulatory support. Additionally, we suggest where the gaps in the technology currently lie. Expert commentary: Soft robotic technology has now matured from the proof-of-concept phase to successful animal testing. With further refinement in materials and clinician guided application, they will be a useful complement for cardiovascular therapy. PMID- 28817982 TI - Current challenges in optimizing systemic therapy for patients with pancreatic cancer: expert perspectives from the Australasian Gastrointestinal Trials Group (AGITG) with invited international faculty. AB - INTRODUCTION: Despite recent progress, the outlook for most patients with pancreatic cancer remains poor. There is variation in how patients are managed globally due to differing interpretations of the evidence, partly because studies in this disease are challenging to undertake. This article collates the evidence upon which current best practice is based and offers an expert opinion from an international faculty on how latest developments should influence current treatment paradigms. Areas covered: Optimal chemotherapy for first and subsequent lines of therapy; optimal management of locally advanced, non-metastatic cancer including the role of neoadjuvant chemo(radio)therapy, current evidence for adjuvant chemotherapy, major advances in pancreatic cancer genomics and challenges in supportive care particularly relevant to patients with pancreatic cancer. For each section, literature was reviewed by comprehensive search techniques, including clinical trial websites and abstracts from international cancer meetings. Expert commentary: For each section, a commentary is provided. Overall the challenges identified were: difficulties in diagnosing pancreatic cancer early, challenges for performing randomised clinical trials in all stages of the disease, some progress in systemic therapy with new agents and in identifying molecular subtypes that may be clinically relevant and move towards personalized therapy, but still, pancreatic cancer remains a very poor prognosis cancer with significant palliative care needs. PMID- 28817984 TI - Study on optimizing dyeing of cotton using date pits extract as a combined source of coloring matter and bio-mordant. AB - In this research, extraction of colouring matter from date pits powder was conferred by conventional and ultrasonic methods. Phenolic compounds present in the resulted extract were identified by HPLC analysis. Total phenolic, total flavonoid and total metallic contents were quantified; and the highest levels were obtained in case of ultrasonic extraction process at a frequency of 25 kHz. The different resultant extracts were diluted with distilled water and unified to a polyphenolic content of 48 mg per 100 mL. Dyeing results have been discussed as a function of the bio-metallic contents present in the extract. It was found that the highest colour strengths and the better fastness properties were registered in case of dyeing experiments developed using the ultrasonic extracts. Those above results could be due to the highest metallic content present in the ultrasonic extracts, which has functioned as a bio-mordant properly extracted from date pits powder. PMID- 28817987 TI - Targeting cannabinoid receptors in gastrointestinal cancers for therapeutic uses: current status and future perspectives. PMID- 28817985 TI - Rapid characterisation and identification of compounds in Saposhnikoviae Radix by high-performance liquid chromatography coupled with electrospray ionisation quadrupole time-of-flight mass spectrometry. AB - Saposhnikoviae Radix (SR), the dried root of Saposhnikovia divaricata (Turcz.) Schischk. (Umbelliferae), is commonly used as a traditional Chinese medicine. In this study, a rapid and accurate method was firstly, developed for the qualitative analysis of SR by high-performance liquid chromatography coupled with electrospray ionisation quadrupole time-of-flight mass spectrometry (HPLC-ESI-Q TOF-MS/MS). A total of 45 compounds were identified or tentatively characterised, including 13 chromones, 28 coumarins and four others. Among them, 16 compounds were identified from SR for the first time. In addition, six chromones reference standards, including two isolated compounds of 3'-O-angeloylhamaudol and norcimifugin from the extraction of SR, were used to study the fragmentation pathways of chromones. The developed method was effective for characterising the compounds of SR, and the results of the study enriched the understanding of the chemical connotation. PMID- 28817988 TI - Interferon dimers: IFN-PEG-IFN. AB - Increasingly complex proteins can be made by a recombinant chemical approach where proteins that can be made easily can be combined by site-specific chemical conjugation to form multifunctional or more active protein therapeutics. Protein dimers may display increased avidity for cell surface receptors. The increased size of protein dimers may also increase circulation times. Cytokines bind to cell surface receptors that dimerise, so much of the solvent accessible surface of a cytokine is involved in binding to its target. Interferon (IFN) homo-dimers (IFN-PEG-IFN) were prepared by two methods: site-specific bis-alkylation conjugation of PEG to the two thiols of a native disulphide or to two imidazoles on a histidine tag of two His8-tagged IFN (His8IFN). Several control conjugates were also prepared to assess the relative activity of these IFN homo-dimers. The His8IFN-PEG20-His8IFN obtained by histidine-specific conjugation displayed marginally greater in vitro antiviral activity compared to the IFN-PEG20-IFN homo dimer obtained by disulphide re-bridging conjugation. This result is consistent with previous observations in which enhanced retention of activity was made possible by conjugation to an N-terminal His-tag on the IFN. Comparison of the antiviral and antiproliferative activities of the two IFN homo-dimers prepared by disulphide re-bridging conjugation indicated that IFN-PEG10-IFN was more biologically active than IFN-PEG20-IFN. This result suggests that the size of PEG may influence the antiviral activity of IFN-PEG-IFN homo-dimers. PMID- 28817989 TI - Optimal skin antiseptic agents for prevention of surgical site infection in cesarean section: a meta-analysis with trial sequential analysis. AB - PURPOSE: The best choice of antiseptic agent for skin preparation at cesarean section remains controversial. We performed this meta-analysis to assess whether chlorhexidine (CH)-based skin antisepsis was more effective than povidone iodine (PI)-based antisepsis for the prevention of surgical site infection (SSI) after cesarean section. METHODS: PubMed, EMBASE, and the Cochrane Library were systematically searched to identify English publications that compared chlorhexidine gluconate (CH) as a skin preparation agent with PI in cesarean section. The primary outcome was SSI rate. Review Manager 5.3 was used to analyze the collected data and trial sequential analysis (TSA) Software 0.9 (Cochrane Collaboration, Oxford, UK) beta was applied to estimate whether the overall pooled outcome was conclusive. RESULTS: Six articles involving 4385 participants were included in this study. The outcomes showed that CH-based skin antisepsis, compared with PI-based antisepsis, was not associated with a decreased overall rate of SSI (risk ratio [RR], 0.74; 95% confidence interval [CI], 0.54-1.02; p = .07). TSA indicated that the current available evidence was inconclusive. There were no differences in adverse skin reactions in the two groups. CONCLUSIONS: This study provides evidence that CH-based antisepsis for skin preparation does not show an additional advantage in reducing risk of SSI after cesarean section. However, additional high-quality, randomized clinical trials are needed to confirm these findings. PMID- 28817986 TI - Formation of artifactual DMPO-OH spin adduct in acid solutions containing nitrite ions. AB - We investigated aqueous solutions containing nitrite ions and DMPO (5,5-dimethyl 1-pyrroline-N-oxide) by electron spin resonance (ESR) in the pH range from 1 to 6. A DMPO-OH signal was observed below pH 3.0 in the presence of nitrite ions, whereas in the absence of nitrite ion, an extremely weak signal was observed below pH 1.5. Addition of methanol, a hydroxyl radical scavenger, to this system did not lead to the appearance of a detectable DMPO-CH2OH signal. The possibility of this DMPO-OH signal being due to a genuine spin trapping process with hydroxyl radical was, therefore, ruled out. The reactivities of reactive nitrogen species (RNS) in this system with DMPO have also been investigated by density functional theory (DFT) at the IEFPCM (water)/B3LYP/6-311 + G ** level of theory. On the basis of the pH dependence of the signal intensity and the redox potential E degrees (versus SHE) calculated by DFT theory, we propose that the origin of this signal is "inverted spin trapping" via one-electron oxidation of DMPO by H2ONO+, followed by the nucleophilic addition of water. Prevention of these false positive results when detecting hydroxyl radical using ESR spin trapping requires an awareness of both the presence of nitrite ions in the solution and the solution pH. PMID- 28817990 TI - Using qualitative methods to understand factors contributing to patient satisfaction among dermatology patients: a systematic review. AB - PURPOSE: In this systematic review, we aimed to synthesize data that identify factors contributing to patient satisfaction in dermatology care using qualitative methods. MATERIALS AND METHODS: We performed a comprehensive search of the literature using the PubMed database for articles published between January 1, 2000 and February 9, 2015. The initial search yielded 186 articles, of which 13 were included after applying inclusion and exclusion criteria. RESULTS: The systematic review of 13 articles included a total of 330 patients. Using in field observations and semistructured interviews, studies found that qualitative methods and analysis increased the provider's sensitivity to patient needs and enhanced patient care. Analyses using qualitative methods found increased patient satisfaction in their healthcare provider is associated with (1) confidence in the provider's diagnosis, (2) perception of patient-centered, individualized recommendations and (3) quality of patient education and provider explanation during a visit. CONCLUSIONS: Patient satisfaction is measured using either quantitative or qualitative methods. Quantitative methods result in standardized data that often does not capture the nuances of patient experience. In contrast, qualitative methodology is integral to gathering patient perspectives on patient care and satisfaction and should be included in future research models. PMID- 28817992 TI - Acknowledging mental illness in psychiatrists. PMID- 28817991 TI - Trajectories of Change in Body Weight During Inpatient Treatment for Anorexia Nervosa. AB - BACKGROUND: Identifying distinct trajectories of change in body weight during inpatient treatment for anorexia nervosa (AN) may provide knowledge about the process of weight restoration and may help detect optimal body weight response patterns among individuals who are at risk for not achieving weight restoration or leaving treatment prematurely. OBJECTIVE: This study explored the extent to which distinct trajectories of change in body weight existed among individuals during inpatient treatment for AN. DESIGN: Group-based trajectory modeling was used to identify distinct trajectories of change in body weight among 500 individuals receiving inpatient treatment for AN. RESULTS: Four distinct trajectories were identified: weight gain ( n = 197), treatment resistant ( n = 177), weight plateau ( n = 82), and weight fluctuate ( n = 44). CONCLUSION: Clinically, it is important to consider the heterogeneity of changes in body weight during inpatient treatment to help guide interventions and outcomes. PMID- 28817993 TI - Early psychosis in central Vietnam: A longitudinal study of short-term functional outcomes and their predictors. AB - BACKGROUND: Few longitudinal studies have investigated the functional outcomes of individuals with recent-onset psychotic illness in low- and middle-income countries. AIMS: To investigate short-term functional remission and its predictors in a central Vietnamese sample. METHODS: A naturalistic 6-month prospective cohort study recruited 79 patients of public health facilities who had experienced a first episode of schizophrenia or related illness in the past 18 months. Individuals and their family members were interviewed using standardised assessments of community functioning, symptoms, treatment, demographics and various psychosocial variables. Rates of functional remission (i.e. no or minimal impairment) were calculated based on rigorous, culturally appropriate criteria. Generalised estimating equations were used to explore predictors of remission. RESULTS: Rates of global functional remission were 28% at baseline and 53% at follow-up. In individual functional domains, remission was least common for occupational activities, intermediate for relationships and relatively common for daily living activities. Global functional remission was significantly associated with absence of negative and cognitive symptoms, average or better household economic status and unimpaired premorbid functioning. CONCLUSION: Remission rates appeared similar to those seen in many international intervention studies. However, individuals from poor households had markedly unfavourable outcomes, suggesting the need for community-based interventions targeting low-socioeconomic status (SES) groups. PMID- 28817994 TI - Maternal serum and fetal cord-blood ischemia-modified albumin concentrations in normal pregnancy and preeclampsia: a systematic review and meta-analysis. AB - BACKGROUND/AIMS: A meta-analysis of maternal serum ischemia-modified albumin (IMA) and fetal cord-blood IMA concentrations in normal pregnancy (NP) compared to non-pregnant healthy controls (HC) and in preeclampsia (PE) compared with normal pregnant controls were studied. METHODS: All major databases were searched for eligible studies. We included eight studies comparing serum IMA between NP and HC, 14 studies comparing serum IMA between PE and NP and five studies comparing cord-blood IMA between PE and NP groups. Meta-analyses on these included studies were performed using Review Manager 5.3. Pooled-overall effect size as standardized mean difference (SMD), publication bias, subgroup, and sensitivity analysis data were generated. RESULTS: Random-effects meta-analysis indicated a significant increase in serum IMA in the NP group (SMD = 0.98, p = .01) and the PE group (SMD = 0.94, p < .0001) as compared with HC and NP groups, respectively. And, the cord-blood IMA has been found to be significantly increased in PE (SMD = 6.51, p < .0001) compared with the NP group. CONCLUSIONS: This meta-analysis, the first of its kind showed that the increased serum IMA concentrations were indicative of increased oxidative stress in NP and PE. Measurement of maternal serum IMA and fetal cord-blood IMA concentrations were useful as simple, novel, and inexpensive markers of oxidative stress (OS) status in PE patients. Future large-scale studies are needed to explore IMA in relationship to the disease severity in PE. PMID- 28817995 TI - Intrapartum test for detection of Group B Streptococcus colonization during labor. AB - PURPOSE: The purpose of this study was to evaluate the potential improvement of introducing an intrapartum test for the detection of Group B Streptococcus (GBS) during labor and to estimate its cost-effectiveness versus antepartum GBS screening culture. MATERIALS AND METHODS: Three hundred and thirteen women at beginning of labor, with unknown GBS status or with antepartum GBS screening culture were enrolled. A vaginal-rectal specimen was collected from each woman for GBS detection by real-time PCR. Results of intrapartum test and antepartum GBS screening culture were compared. RESULTS: Antepartum culture results did not always reflect the intrapartum maternal GBS colonization status since in 15.1% of the cases it was not concordant with intrapartum test. However, selecting only women, who underwent antepartum culture and intrapartum test at the same time, the percentage of concordance was 96.6%. Based on intrapartum test results, 74.9% of the total number of intrapartum antibiotic prophylaxis (IAP) was administered uselessly, while 1.9% of women did not receive IAP although they were positive to intrapartum test. Intrapartum test resulted less cost-effective than antepartum culture but it became more cost-effective at a cost threshold of about 16.00 ?. CONCLUSIONS: The clinical introduction of intrapartum test could be a valuable mean for identification of GBS colonization during labor, allowing an appropriate management of mothers and neonates with consequent benefit for their health and with limited costs for Healthcare System. PMID- 28817996 TI - Meningioma With Tyrosine-Rich Crystalloids: A Case Report and Review of the Literature. AB - We report a case of fibrous meningioma with tyrosine-rich crystalloid in the frontal lobe of a middle-aged woman. The patient presented with a history of several years of worsening headaches and blurry vision, which progressed to include syncopal episodes and right-sided weakness. Imaging demonstrated a dural based extra-axial mass arising from the right orbital roof and extending superiorly along the right frontal convexity causing right-to-left midline shift. The patient underwent a craniotomy and operative resection. Tumor architecture and cytology was similar to that of a Schwannian neoplasm, with spindled cells arranged in a fascicular architecture and displaying focal nuclear palisading. Immunohistochemical stains confirmed a diagnosis of fibrous meningioma. Light microscopy demonstrated extracellular deposits of eosinophilic crystalline material parallel to the spindled tumor cells, reminiscent of "tyrosine-rich" crystals described in salivary gland neoplasms. This is the third meningioma featuring tyrosine-rich crystalloid reported in the literature; we also summarize the previous 2 reports. PMID- 28817997 TI - Positive impact of cladribine on quality of life in people with relapsing multiple sclerosis. AB - BACKGROUND: A number of elements of the pivotal 'cladribine tablets treating multiple sclerosis orally' (CLARITY) trial have remained unpublished. OBJECTIVE: To report the impact of cladribine on health-related quality of life (QoL) in people with relapsing multiple sclerosis (pwRMS). METHODS: QoL data from the phase III trial of two different doses (3.5 and 5.25 mg/kg) of oral cladribine in pwRMS were acquired from the European Medicines Agency through Freedom of Information. Spearman's rank correlation was used to analyse the relationship between baseline QoL scores and baseline Expanded Disability Status Scale (EDSS) scores. Responses of the Euro Quality of Life 5 Dimensions (EQ-5D) and Multiple Sclerosis Quality of Life-54 (MSQOL-54) questionnaires were compared between treatment and control groups using univariate analyses of covariance. RESULTS: In total, n = 5148 EQ-5D responses and n = 894 MSQOL-54 physical, mental health and dimension scores were extracted. Baseline EQ-5D indices correlated with EDSS scores. After 2 years, pwRMS taking 3.5 ( p = .001) and 5.25 mg/kg ( p = .022) reported significantly improved EQ-5D index scores compared with placebo. Positive, yet non-significant, differences were detected in MSQOL-54 scores between cladribine and placebo. CONCLUSION: Analysis of the CLARITY dataset suggests that, over and above its established clinical efficacy, cladribine leads to improved QoL over 96 weeks. ClinicalTrials.gov identifier: NCT00213135. PMID- 28817999 TI - Correction to: Fuke, Aizawa, Suganuma, Takagi, and Naito, Effect of combined consumption of Lactobacillus brevis KB290 and beta-carotene on minor diarrhoea predominant irritable bowel syndrome-like symptoms in healthy subjects: a randomised, double-blind, placebo-controlled, parallel-group trial. PMID- 28817998 TI - Defining fetal growth restriction: abdominal circumference as an alternative criterion. AB - PURPOSE: The purpose of this study is to determine if using abdominal circumference percentile (AC) to define fetal growth restriction (FGR) improves ultrasound at >=36 weeks as a screening test for small for gestational age (SGA). MATERIALS AND METHODS: All non-anomalous singletons undergoing ultrasound at a single center at >=36 weeks during 12/2008-5/2014 were included. FGR was defined as (estimated fetal weight) estimated fetal weight (EFW) and/or abdominal circumference (AC) < 10 for gestational age (GA). The primary outcome was SGA (birthweight <=10th percentile for GA). Data were stratified by maternal race/ethnicity and BMI. Sensitivity, specificity, false-positive rate (FPR), positive- and negative-predictive values (positive-predictive value (PPV), negative-predictive value (NPV)), and areas under the receiver-operating characteristic (ROC) curve (AUC were calculated. RESULTS: There were 1594 ultrasounds. Median (IQR) ultrasound GA was 37.3 (36.6-38.0), days to delivery 10.6 (5.0-18.4), and delivery GA 39.29 (38.6-39.9). EFW <10 had the following characteristics: sensitivity 50.6%, FPR 2.0%, PPV 83.8%, and AUC 0.743. Using AC <10, these were 64.0, 2.9, 81.3, and 0.806, respectively. Using AC or EFW <10, these were 67.5, 3.3, 80.3, and 0.821, respectively; this criterion has the largest AUC (p < .008). This finding persisted when stratified by maternal race/ethnicity and BMI. CONCLUSIONS: AC <10 is more sensitive and has a similar PPV compared with EFW <10 for SGA. Using AC <10 or EFW <10 has the best balance of sensitivity and specificity as a screening test and has a low FPR. AC may be a reasonable alternative criterion to EFW for FGR diagnosis. PMID- 28818000 TI - Exploring the relation between visual mental imagery and affect in the daily life of previously depressed and never depressed individuals. AB - Previously depressed individuals experience disturbances in affect. Affective disturbances may be related to visual mental imagery, given that imagery-based processing of emotional stimuli causes stronger affective responses than verbal processing in experimental laboratory studies. However, the role of imagery-based processing in everyday life is unknown. This study assessed mental imagery in the daily life of previously and never depressed individuals. Higher levels of visual mental imagery was hypothesised to be associated with more affective reactivity to both negatively and positively valenced mental representations. This study was the first to explore mental imagery in daily life using experience sampling methodology. Previously depressed (n = 10) and matched never depressed (n = 11) individuals participated in this study. Momentary affect and imagery-based processing were assessed using the "Imagine your mood" smartphone application. Participants recorded on average 136 momentary reports over a period of 8 weeks. The expected association between visual mental imagery and affective reactivity was not found. Unexpectedly, in both previously and never depressed individuals, higher levels of imagery-based processing of mental representations in daily life were significantly associated with better momentary mood and more positive affect, regardless of valence. The causality of effects remains to be examined in future studies. PMID- 28818001 TI - Pulmonary drug delivery system: newer patents. AB - Inhalational route for drug delivery and desired effects has been known since centuries. This lung-targeted therapy has benefited asthmatics and those with chronic respiratory problems. The technique has evolved greatly from crude pots and pipes to modern sophisticated drug-dispensing devices. This mode is effective, rapid and safe. Its outcome, however, is majorly determined by drug formulation, device structure and patient's coordinating skill. In spite of great advances in this field, more efforts are required to meet the unmet needs. This noninvasive mode is being increasingly studied for transfer of drugs for systemic action with promising results. The present article is an attempt to capture the recent development and progress in this field and review relevant newer patents. PMID- 28818002 TI - Green Care as Psychosocial Intervention for Depressive Symptoms: What Might Be the Key Ingredients? AB - BACKGROUND: Green care is an umbrella term for psychosocial interventions that integrate biotic and abiotic elements of nature to promote an individual's health and well-being. Green care decreases depressive symptoms but the parts of the interventions that lead to this effect are unknown. OBJECTIVES: Review of literature to evaluate perceived social support, behavioral activation, and self efficacy as key ingredients to decrease depressive symptoms in psychosocial interventions and extrapolate those mediators, or key ingredients, to green care. DESIGN: A literature search of three databases was conducted to find relevant studies examining a psychosocial intervention for adults, the mediator of interest, and depressive symptoms. RESULTS: Evidence supports behavioral activation, social support, and self-efficacy as mediators of psychosocial interventions to improve depressive symptoms. CONCLUSIONS: Green care offers a portal for individuals with different depressive symptoms and severities to be treated alongside each other while receiving targeted interventions to meet the needs of each individual participant. Additionally, it offers the opportunity for psychiatric nurses to concurrently target all three active key ingredients. PMID- 28818003 TI - Hybrid a-CNH+TiO2+TiN-type surface layers produced on NiTi shape memory alloy for cardiovascular applications. AB - AIM: The goal was to improve the properties of NiTi shape memory alloy to make it suitable for cardiac applications. For this purpose, a hybrid a-CNH+TiO2+TiN-type surface layer was produced on NiTi alloy and characterized. MATERIALS & METHODS: The NiTi alloy subjected to hybrid process combining low-temperature oxynitriding under glow discharge conditions and radio frequency chemical vapor deposition process was examined for microstructure, surface topography, corrosion resistance, wettability and surface-free energy, Ni ion release and platelets adhesion, aggregation and activation. RESULTS: The hybrid surface layers showed slightly increased surface roughness, better corrosion resistance, a more hydrophobic nature, decreased surface free energy, smaller release of nickel ions and reduced platelets activation. CONCLUSION: The produced layers could expand the range of NiTi medical applications. PMID- 28818004 TI - Identification and treatment of augmentation in patients with restless legs syndrome: practical recommendations. AB - Restless legs syndrome (RLS) is a chronic disorder causing clinically significant discomfort to approximately 3% of adults. Although RLS was first identified centuries ago, our understanding of this disorder, its causes, and its treatments is still evolving. In particular, our knowledge of the potential negative effects of RLS treatments, including dopaminergic augmentation, continues to expand. Augmentation, which refers to a paradoxical treatment-related increase in RLS symptoms, has been associated with all three dopamine agonists approved for the treatment of RLS - rotigotine, pramipexole, and ropinirole. This review presents key information on prevention and treatment of dopaminergic augmentation from the recently published consensus-based guidelines issued by the International RLS Study Group task force in conjunction with the European RLS Study Group and the RLS Foundation for first-line treatment of RLS/Willis-Ekbom disease. If dopamine agonists are used to treat RLS, it is recommended that the dosage should be kept as low as possible without exceeding the maximum dose recommended for RLS treatment. As the frequency of augmentation with the rotigotine patch may only be slightly lower than that associated with pramipexole or ropinirole, medications that are effective and have little risk of augmentation, such as alpha-2-delta ligands, may be considered for initial RLS treatment. In addition, we present our clinical experience with treating patients with dopaminergic augmentation by highlighting 2 case studies and practical considerations when treating different patient populations. Applying current RLS augmentation diagnosis and treatment guidelines, as well as collecting detailed histories of worsening RLS symptoms, is critical for patient safety and effective management of RLS augmentation. PMID- 28818005 TI - Computational biology: future challenges for the patenting of repurposed drugs. PMID- 28818006 TI - The Role of the BDNF Val66Met Polymorphism in Recovery of Aphasia After Stroke. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) is assumed to play a role in mediating neuroplasticity after stroke. Carriers of the function-limiting Val66Met (rs6265) single nucleotide polymorphism (SNP) may have a downregulation in BDNF secretion, which may lead to a poorer prognosis after stroke compared to noncarriers in motor learning and motor function recovery. The present study investigates whether this polymorphism may also affect the recovery of poststroke aphasia (ie, language impairment). OBJECTIVE: To study the influence of the BDNF Val66Met polymorphism on the recovery of poststroke aphasia. METHODS: We included 53 patients with poststroke aphasia, all participating in an inpatient rehabilitation program with speech and language therapy. All patients were genotyped for the Val66Met SNP and subdivided into carriers (at least one Met allele) and noncarriers (no Met allele). Primary outcome measures included the improvement over rehabilitation time on the Amsterdam-Nijmegen Everyday Language Test (ANELT) and the Boston Naming Test (BNT). RESULTS: The outcome measures showed a large variability in the improvement scores on both the ANELT and BNT. There was no significant difference between noncarriers and carriers in the primary outcome measures. CONCLUSION: This study investigated the effect of the BDNF Val66Met polymorphism on clinical recovery of poststroke aphasia. In contrast to earlier studies describing a reducing effect of this polymorphism on motor function recovery after stroke, the present study does not support a reduction in language recovery for carriers compared to noncarriers with poststroke aphasia. PMID- 28818007 TI - Kiwi OmniCup Handheld vs. Mityvac M-Style Conventional Vacuum System: A Retrospective Observational Study. AB - INTRODUCTION: To improve choice of vacuum-assisted delivery (VAD) system, we compared outcomes of Kiwi handheld system and Mityvac M-style conventional system (both use disposable plastic cups). MATERIALS AND METHODS: Retrospective observational study with data collection from electronic medical records. The study was conducted at a tertiary medical center, with approximately 7000 deliveries annually. Categorical and continuous variables were analyzed using chi square test and t-test, respectively. p value < 0.05 considered significant. The main outcomes assessed were the overall failure rate of each system, failure rates for occipito-anterior (OA) vs. occipito-transverse/occipito-anterior (OT/OP) positions, +1 vs. +2 fetal stations, and early maternal/neonatal outcomes. RESULTS: During a 10-month period, there were 507 (8.4%) attempted VADs, 36 failed (7.1%) and 8 (1.5%) converted to cesarean section. Of these, 364 were Kiwi-assisted and 143 Mityvac-assisted. Background characteristics were similar. The handheld system had more failures overall (9.6 vs. 0.7%), at OA (7.6 vs. 0.9%) and non-OA positions (17.3% vs. none), at + 1 (13.25 vs. 0.96%) and at + 2/3 stations (6.1% vs. none), than the conventional system did, respectively. There was a higher rate of early post-partum hemorrhage (15.3 vs. 7.4%) in the conventional group. Both systems had similar rates of third/fourth degree perineal tears, shoulder dystocia and adverse neonatal outcomes. CONCLUSIONS: Our results suggest more failures with Kiwi compared to Mityvac, overall and at any fetal position/station, without a significant difference in adverse outcome profile. PMID- 28818008 TI - Occupational therapy student experiences of a university mental health course based on an integrated application of problem-based and team-based learning. AB - BACKGROUND: The goal of problem-based and team-based learning (PBL/TBL) is to maximize student engagement and encourage interactive learning. Combining these methods in course design is described as a win-win situation that optimizes student learning, professional development, and uses varied teaching approaches that fit well within health science. More research is needed in the effectiveness of such a hybrid approach. OBJECTIVES: The aim of this study was to explore student experiences of a newly developed mental health course based on an integrated application of PBL and TBL in a university occupational therapy program in Sweden. METHODS: In this grounded theory study data were collected through logbooks (n = 13) and supplemental open-ended interviews (n = 7) at the end of the course. RESULTS: The analysis resulted in two core categories: 1) learning is facilitated by a course design based on the integrated application of PBL and TBL, a current topic, and teachers who are perceived as engaging, and 2) a perceived safe setting facilitates learning and creates a good study environment. There were six related sub-categories. CONCLUSIONS: Combining elements of PBL and TBL may have a range of benefits in promoting student learning and professional development. Other aspects may also have a role to play. PMID- 28818009 TI - Transparency of Biobank Access in Canada: An Assessment of Industry Access and the Availability of Information on Access Policies and Resulting Research. AB - A key issue impacting public trust in biobanks is how these resources are utilized, including who is given access to biobank data and samples. To assess the conditions under which researchers are given access to Canadian biobanks, we reviewed websites and contacted Canadian biobanks to determine the availability of information on access policies and procedures; research resulting from access biobank data and samples; and conditions on private industry access to biobanks. We also conducted expert interviews with key Canadian stakeholders ( n = 11) to obtain their perspectives on biobank transparency and access policies. Among 21 Canadian biobanks, there was wide variation in the access information made publicly available, and the majority of these allowed access by industry applicants. Biobanks should be governed by the principles of transparency, accountability, and accessibility, and attention must be given to the conditions around the commercialization of biobank-based research. PMID- 28818010 TI - Translation and Adaptation of a Nursing Swearing Impact Questionnaire Into Chinese. AB - BACKGROUND: Verbal aggression and swearing are the most frequently encountered violence in the health care industry. Nurses are the most frequent victims. Not known is the incidence and impact of swearing against nurses in China. OBJECTIVES: (a) Develop a Chinese version of the Nursing Swearing Impact Questionnaire; (b) report the preliminary findings from the use of the tool. METHOD: Using a translation-back translation procedure, focus groups and expert review, followed by a survey of 32 participants. RESULTS: The Chinese version of the Nursing Swearing Impact Questionnaire has been developed, and cultural differences and different attitudes toward verbal aggression and swearing in disparate groups and workplaces have been highlighted. CONCLUSIONS: This is the first Chinese tool to research nurses' perspectives and experiences of swearing in the workplace. Nurses in China face serious challenges, and the impact of swearing on nurses requires more attention. PMID- 28818011 TI - In silico prediction of new inhibitors for the nucleotide pool sanitizing enzyme, MTH1, using drug repurposing. PMID- 28818012 TI - Clinical application of prophylactic internal iliac artery balloon occlusion combined with uterine artery embolization in patients with abnormally invasive placenta. AB - BACKGROUND: The purpose of this study is to investigate the role of prophylactic internal iliac artery balloon occlusion combined with uterine artery embolization (UAE) in patients with abnormally invasive placenta. METHODS: Forty cases with abnormally invasive placenta who visited our hospital were analyzed retrospectively from May 2014 to September 2015. Twenty cases who had prophylactic balloon occlusion of internal iliac artery with/without UAE were in the study group, while the other 20 cases in the control group. Volume of estimated blood loss and blood transfusion, rate of hysterectomy, surgery duration, postoperative complication and length of hospitalization were compared between two groups. RESULTS: The mean estimated blood loss in the study group (800 ml,500-1800 ml) was less than that in the control group (1875 ml, 500-7600 ml) (p = .01). Only two cases had blood transfusion in the study group, while 12 cases in the control group. No case was performed hysterectomy in the study group, while one case had the operation in the control group. There was no significant difference in surgery duration, postoperative complications and length of hospitalization between two groups. CONCLUSION: Prophylactic balloon occlusion of internal iliac artery combined with UAE is effective and safe for patients with abnormally invasive placenta. PMID- 28818013 TI - Relationship between Doppler findings and fetal brain apparent diffusion coefficient in early-onset intra-uterine growth restriction. AB - OBJECTIVE: The aim of the study is to assess the relationship between uteroplacental Doppler sonography findings and cerebral diffusion measured by diffusion-weighted magnetic resonance imaging (DWI) in fetuses with early-onset intrauterine growth restriction (IUGR). MATERIALS AND METHODS: The study included 54 pregnant women with fetal IUGR and 15 healthy controls (n: 15). Fetuses with IUGR were classified into four groups based on Doppler findings: group 1 (n = 12), umbilical artery (UA) pulsatility index (PI) > 95pc; group 2 (n = 11), UA PI >95 pc and middle cerebral artery PI < 5pc; group 3 (n = 21), absent end diastolic (A-EDF) in UA; group 4 (n = 10), reversed EDF in UA. After Doppler evaluation, DWI was performed in all patients within hours. The groups were compared with respect to apparent diffusion coefficient (ADC) levels. FINDINGS: In cases with fetal IUGR, significant decreases were detected in ADC values of periatrial white matter (PAWM) (p = .01), frontal white matter (FWM) (p = .038), thalamus (p = .004), and basal ganglia (p = .013) compared to controls. In Doppler subgroup analysis adjusted for gestational age, ADC values of FWM, thalami, and pons were significantly lower in group 4 than control group (p = .02, p = .02, and p = .037, respectively). In PAWM, ADC values were significantly lower in group 4 than control and Group 1 (p = .004). No significant differences with regard to ADC values in basal ganglia, cerebellum was found between Doppler groups and control. CONCLUSIONS: In fetuses with IUGR, ADC values as measured by DWI decreases. The critical Doppler finding that is associated with reduced diffusion in some brain areas (FWM, PAWM, thalami, pons) is reverse end-diastolic flow in umbilical artery. Further prospective studies with larger sample size are needed to introduce cerebral ADC values in the management of IUGR. PMID- 28818014 TI - Cytoreductive prostatectomy in metastatic prostate cancer: a systematic review. AB - The impact of cytoreductive radical prostatectomy on oncological outcome in patients with prostate cancer and limited number of bone metastases is unclear. Data from cancer registries, multi-institutional databases and a single institutional case-control study indicate a possible benefit of combined cytoreduction and hormonal therapy compared to hormonal therapy alone. However, the results may be biased by a number of factors. The evidence from studies on cytoreductive prostatectomy is reviewed. PMID- 28818015 TI - BioGlue-Associated Loss of Aortic Valve Leaflet Motility Sonographically Masked by Both Newly Replaced Mechanical Aortic and Mitral Valves. AB - BioGlue is a surgical adhesive widely used to help reinforce complex cardiac and vascular repairs. Since its introduction, several case reports have emerged revealing complications that all providers should be mindful of whenever the product is used. This report considers a unique situation where BioGlue was used after double cardiac valve repair that resulted in adhesion of the new mechanical aortic valve leaflets and was difficult to visualize with transesophageal echocardiography. PMID- 28818016 TI - Association between proportion of US medical graduates and program characteristics in gastroenterology fellowships. AB - BACKGROUND: Gastroenterology is one of the most competitive internal medicine fellowship. However, factors that associated with program competitiveness have not been documented. OBJECTIVE: The objective of this study was to evaluate associations between characteristics of gastroenterology fellowship programs and their competitiveness through the proportion of US medical graduates for the academic year 2016/17. DESIGN: This study used a retrospective, cross-sectional design with data obtained from the American Medical Association. The proportion of US medical graduates in gastroenterology fellowships was used as an indicator of program competitiveness. Using both univariate and multivariate linear regression analyses, we analyzed the association between the proportion of medical graduates in each program and 27 program characteristics based on a significance level of 0.05. RESULTS: In total, 153 out of 171 gastroenterology fellowship programs satisfied the inclusion criteria. A multivariate analysis revealed that a higher proportion of US medical graduates was significantly associated with five program characteristics: that it was a university-based program (p < 0.001), the ratio of full-time paid faculty to fellow positions (p < 0.001), the proportion of females in the program (p = 0.002), location in the Pacific region (p = 0.039), and a non-smoker hiring policy (p = 0.042). CONCLUSIONS: Among the five significant factors, being university based, located in the Pacific, and having a non-smoker hiring policy were likely to remain unchanged over a long period. However, program directors and candidates should pay attention to equivalence between full-time paid faculty and fellowship positions, and the proportion of women in the program. The former indicates the level of supervision while the latter has become increasingly important owing to the higher proportion of women in medicine. PMID- 28818017 TI - Support for new mothers and fertility in the United Kingdom: Not all support is equal in the decision to have a second child. AB - Low fertility across Europe highlights the need to understand reproductive decisions in high-income countries better. Availability of support may be one factor influencing reproductive decisions, though within high-income countries availability varies between environments, including socio-economic environments. We test whether receiving higher levels of support, from different sources (informal and formal) and of different types (practical and emotional), is positively correlated with second births in the United Kingdom (UK) Millennium Cohort Study, and whether these relationships differ by socio-economic position (SEP). Our hypothesis is only partially supported: receiving emotional support correlates with higher likelihood of second birth, but the opposite is true for practical support. Availability of different types of support varies across SEP, but relationships between support and fertility are similar, with one exception: kin-provided childcare increases the likelihood of birth only among lower-SEP women. Our results highlight that not all support is equal in the decision to have a second child. PMID- 28818018 TI - Effect of operational parameters and Pd/In catalyst in the reduction of nitrate using copper electrode. AB - Water with high concentration of nitrate may cause damage to health and to the environment. This study investigated how concentration, current density, flow, pH, the use of Pd/In catalyst and operating mode (constant current density and constant cell potential) have an influence in the electrochemical reduction of nitrate and in the formation of gaseous compounds using copper electrode. Experiments were performed in two-compartment electrolytic cells separated by a cationic membrane with nitrate model solutions prepared as a surrogate of concentrated brines from membrane desalination plants. The results show that the electroreduction process has potential for reduction of nitrate and that it is influenced by the operational conditions. The best conditions found for the treatment - with satisfactory reduction of nitrate, formation of gaseous compounds and reproducibility - were at nitrate concentrations of 600 and 1000 mg L-1, current density of 1.1 mA cm-2 and without pH control, since in these conditions the production of gaseous compounds is higher than the production of nitrite. When Pd/In catalyst was used, the nitrate reduction was 50% after 6 h of experiment and the predominant product were gaseous compounds. When compared to the experiment without the catalyst, the arrangement with Pd/In was the most efficient one. PMID- 28818020 TI - Preserving Self: Theorizing the Social and Psychological Processes of Living With Parkinson Disease. AB - The purpose of this constructivist grounded theory article is to identify, explore, and theorize the social and psychological processes used by people with Parkinson disease. Analytic procedures generated the five-stage theory of Preserving self of people with Parkinson disease: (a) making sense of symptoms, (b) defining turning points, (c) experiencing identity dilemmas, (d) reconnecting the self, and (e) envisioning a future. Reminders of former selves and capabilities were painful; participants desperately sought normalcy. Participants developed creative methods for maintaining independence but frequently overestimated their abilities and took risks. Participants were 15 men and 10 women (ages 40-95), most of whom lived with their families. Disease status was ascertained through medication logs and two scales: Hoehn and Yahr staging and Activities of Daily Living. Data included 62 in-depth interviews, nonparticipant observation, and participant photos, videos, and related documents. Recommendations were derived from the theory to support processes of Preserving Self as interventions designed to reduce the loss of self and to enhance Preserving self. These recommendations included developing relationships, teaching expected and unexpected feelings and behaviors, and involvement with sensory integrating activities. PMID- 28818019 TI - Pembrolizumab in the treatment of metastatic non-small cell lung cancer: a review of current evidence. AB - Immune checkpoint inhibitors (ICPIs) are considered one of the most important breakthroughs in cancer treatment of the past decade; notably, different studies of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have reported impressive clinical activity and durable responses in patients with advanced non-small cell lung cancer (NSCLC). These findings have led to the changing of the current therapeutic algorithm of advanced NSCLC, adding a new standard first-line treatment option for patients with PD-L1 positive tumors. Pembrolizumab, a highly selective anti-PD-1 humanized monoclonal antibody, was approved by the United States Food and Drug Administration (US FDA) in October 2016 for previously untreated metastatic NSCLC patients whose tumors have high PD-L1 expression, tumor proportion score (TPS) ? 50%, as well as for metastatic NSCLC patients whose tumors express PD-L1 with TPS ? 1% progressing on or after platinum-based chemotherapy. However, many issues remain outstanding, mainly regarding the identification of an optimal biomarker which can help selecting patients more likely to respond to ICPIs. In this review, we discuss the clinical results obtained so far with the anti-PD-1 pembrolizumab in advanced NSCLC, commenting on the role of PD-L1 as a predictive factor and providing an update of the future perspectives. PMID- 28818021 TI - Applying Behavior Change Theories and Qualitative Methods in Substance Misuse Implementation Research: Conceptualizing the Adoption of Breaking Free Online in Real-World Clinical Practice. AB - There is insufficient research examining the implementation of complex novel interventions within health care. This may be due to a lack of qualitative research providing subjective insights into these implementation processes. The authors investigate the advantages of applying behavior change theories to conceptualize qualitative data describing the processes of implementation of complex interventions. Breaking Free Online (BFO), a digital treatment intervention for substance misuse, is described as an example of a complex intervention. The authors review previous qualitative research which explored initial diffusion, or spread, of the BFO program, and its subsequent normalization as part of standard treatment for substance misuse within the health and social care charity, "Change, Grow, Live" (CGL). The use of behavior change models to structure qualitative interview findings enabled identification of facilitators and barriers to the use of BFO within CGL. These findings have implications for the development of implementation research in novel health care interventions. PMID- 28818022 TI - Early career intentions of medical students: are we selecting the graduates we need for the 21st century? PMID- 28818023 TI - Pre-emptive product patentability declarations. PMID- 28818024 TI - Enforceability of second medical use claims in the UK. PMID- 28818025 TI - Improvement of (transition metal-modified) activated carbon regeneration by H2O2 promoted catalytic wet air oxidation. AB - Oxidative regeneration of activated carbon (AC) exhausted with phenolic compounds is still a challenging issue due to the frequent porosity loss. Addition of low H2O2 amount is investigated as a way to promote catalytic wet air oxidation (CWAO) of adsorbed pollutants and thereby to recover absorbent properties. Commercial AC and transition metal (iron or copper)-modified counterparts are tested in repeated adsorption/batch peroxide-promoted CWAO of phenol. Cycles are operated in both fixed bed and slurry reactors to vary the initial pollutant distribution in between the two phases. Influence of metal location is also studied by adding iron salt to the pollutant solution prior to perform peroxide promoted oxidation on bare carbon. Regeneration results are analyzed through a detailed analysis of both the solid and the liquid phases during the oxidative treatment. It is proved that a convenient H2O2 dosage can increase the lifetime of adsorbent in adsorption-oxidation cycles, but coupling with (un)supported metal oxide does not provide significant gain. PMID- 28818027 TI - Need for strategies to maximise student attainment at the clinical stage of training. PMID- 28818026 TI - Herpesviral infection in a Guiana dolphin ( Sotalia guianensis) from the northern coast of Brazil. AB - We describe herein herpesvirus-associated genital lesions in a Guiana dolphin ( Sotalia guianensis) from the northern Brazilian coast. Papillary lesions on the vulva, with epithelial hyperplasia, swollen keratinocytes, and intranuclear inclusions, were positive for a herpesvirus ( Gammaherpesvirinae subfamily). PMID- 28818028 TI - Investigating the performance of an anaerobic baffled bioreactor for the biodegradation of alkaline-surfactant-polymer in oilfield water. AB - The anaerobic baffled reactor (ABR) was used to treat alkaline-surfactant-polymer (ASP) flooding wastewater in the Daqing oilfield. With the ABR, hydraulic retention time (HRT)was reduced from 72 to 24 h, the bioreactor purification capability gradually improved. After the ABR running for 100 days, the removal rate of raw oil, suspended solid and surfactant reached 99.8%, 94.4% and 50%, respectively; alkali, polymer and viscosity were removed at a rate of about 16%, 7% and 20%, respectively. There were 39 kinds of organic materials detected by GCMS in the original water sample, while only 12 kinds of organics were left in the ABR outfall. The above results showed that the anaerobic, facultative anaerobic and aerobic compartment of ABR have strong capability of biodegrading petroleum pollution matter. Pyrosequencing analysis of the 16S rRNA indicated that Acinetobacter, Arcobacter, Pseudomonas and Paracoccus were the dominant bacteria genera present in the ABR reactor, among them Acinetobacter was the dominant species in the bacterial community. PMID- 28818029 TI - Magnetic sorbents biomineralization on the basis of iron sulphides. AB - Biomineralization means mineral formation under the influence of organisms. Sulphate-reducing bacteria (SRB) constitute an essential role of iron sulphide minerals precipitation. Their composition involves amorphous, non-stoichiometric or crystalline iron sulphides, weakly or strongly magnetic. Variation in environmental conditions can alter the reactive iron species within the mineral, potentially modifying their magnetic properties. Biogenic iron sulphide minerals can be used as heavy metals and toxic ions adsorbents in soil or water remediation. For these reasons, a series of laboratory-scale iron sulphide synthesis experiments with the aim to study the chemical composition, mineralogy and magnetic properties of iron sulphide precipitates were carried out using SRB under various cultivation mode and nutrient medium composition. Energy-dispersive X-ray analysis (EDX) showed formation of iron sulphides in all biogenic samples and iron phosphates in abiotic controls. Results of X-ray diffraction analysis (XRD) in biomineralized samples confirmed nanocrystalline greigite, mackinawite and sulphur alpha. Magnetic measurements showed that sample prepared by static cultivation without addition of fresh nutrient medium was the most magnetic, magnetic hysteresis of sample formed under semicontinuous mode without any nutrient supply was the lowest. Abiotic samples contained only vivianite and they did not prove any significant response to magnetic field. PMID- 28818030 TI - Vitamin E (alpha-Tocopherol) Exhibits Antitumour Activity on Oral Squamous Carcinoma Cells ORL-48. AB - Cancers involving the oral cavity, head, and neck regions are often treated with cisplatin. In cancer therapy, the main target is to eliminate unwanted cancerous cells. However, reports on the nonselective nature of this drug have raised few concerns. Incorrect nutritional habits and lifestyle practices have been directly linked to cancer incidence. Nutrients with antioxidant activity inhibit cancer cells development, destroying them through oxidative stress and apoptosis. alpha tocopherol, the potent antioxidant form of vitamin E is a known scavenger of free radicals. In vitro study exhibited effective antitumor activity of alpha tocopherol on ORL-48 at 2.5 +/- 0.42 ug/mL. Cisplatin exhibited stronger activity at 1.0 +/- 0.15 ug/mL, but unlike alpha-tocopherol it exhibited cytotoxicity on normal human epidermal keratinocytes at very low concentration (<0.1 ug/mL). Despite the lower potency of alpha-tocopherol, signs of apoptosis such as the shrinkage of cells and appearance of apoptotic bodies were observed much earlier than cisplatin in time lapse microscopy. No apoptotic vesicles were formed with cisplatin, instead an increased population of cells in the holoclone form which may suggest different induction mechanisms between both agents. High accumulation of cells in the G0/G1 phase were observed through TUNEL and annexin V-biotin assays, while the exhibition of ultrastructural changes of the cellular structures verified the apoptotic mode of cell death by both agents. Both cisplatin and alpha-tocopherol displayed cell cycle arrest at the Sub G0 phase. alpha-tocopherol thus, showed potential as an antitumour agent for the treatment of oral cancer and merits further research. PMID- 28818031 TI - Danggui Buxue Decoction, a Classical Formula of Traditional Chinese Medicine, Fails to Prevent Myelosuppression in Breast Cancer Patients Treated With Adjuvant Chemotherapy: A Prospective Study. AB - Danggui Buxue Decoction (DBD), a classical formula of traditional Chinese medicine (TCM), has an impact on promoting hematopoiesis. The aim of our study was to determine whether DBD can prevent myelosuppression in breast cancer patients treated with adjuvant chemotherapy. We conducted a phase II randomized prospective controlled clinical study. From December 2013 to February 2015, 106 patients were enrolled and randomly assigned (1:1) to the TCM group and control group. The primary end point was incidence of grade 3-4 neutropenia. The secondary end points included incidence of grade 3-4 neutropenia in each cycle, incidence of anemia, and incidence of thrombopenia during 4 cycles. Seventeen patients withdrew from this study, and 89 patients were included in the final analysis. Incidences of grade 3-4 neutropenia during 4 cycles were 57.1% in the TCM group and 59.6% in the control group, and there was no significant difference ( P = .816). Similarly, no significant differences were observed between the 2 groups for incidence of grade 3-4 neutropenia in each cycle. While incidences of anemia were 54.8% and 66.6% for the TCM group and control group, respectively ( P = .280), incidences of thrombopenia were 11.9% for the TCM group and 4.3% for the control group ( P = .248). No significant differences were observed for the incidence of other nonhematological toxicities between the 2 groups. DBD failed to prevent myelosuppression in breast cancer patients treated with adjuvant chemotherapy. Further studies are warranted to validate the efficacy of DBD in selected patients. PMID- 28818033 TI - Erratum - Assessing calibration of prognostic risk scores. PMID- 28818032 TI - Prevention strategy for father-to-child transmission of hepatitis B virus: a systematic review and meta-analysis. AB - OBJECTIVE: Father-to-child transmission (FTCT) occurs in infants born to hepatitis B virus (HBV) infected father. In this study, we aim to summarize the prevention strategy for FTCT of HBV by systematic review and meta-analysis. METHODS: PubMed and China Knowledge Resource Integrated Database were systematically searched. We systematically reviewed the prevention strategy for father, mother, and infant before, during pregnancy and after birth. We also examined trial sequential analysis (TSA) for the required information size (RIS). RESULTS: Fourteen studies with 2825 father-mother-child pairs included in the studies. Two publications assessed father antiretroviral therapy before pregnancy, with the mean FTCT incidence 3.5% in the antiretroviral therapy group and 12.0% in the control group. The summary OR compared between two groups was 0.280 (95% CI 157-0.500; Z = 4.30, p < .00001) by random-effects model. TSA showed further studies were needed. Twelve publications assessed maternal immunoprophylaxis before and during pregnancy, with the mean FTCT incidence 14.9% in the maternal immunoprophylaxis group and 32.8% in the control group. The summary OR compared between two groups was 0.343 (95% CI 252-0.468; Z = 6.77, p < .00001) by random-effects model. TSA showed no further studies were needed. No randomized controlled trials (RCT) and non-RCTs were found assessing neonate and infant immunoprophylaxis for FTCT prevention. CONCLUSION: Father antiretroviral therapy before pregnancy, maternal immunoprophylaxis before and during pregnancy, and neonate and infant immunoprophylaxis are important prevention strategy for FTCT of HBV. However, this conclusion should be confirmed by high quality randomized controlled trials. PMID- 28818034 TI - Utility of hepatobiliary scintigraphy in diagnosing or excluding biliary atresia in premature neonates and full-term infants with conjugated hyperbilirubinemia who received parenteral nutrition. AB - PURPOSE: Hepatobiliary scintigraphy (HBS) is used to aid in the diagnosis of Biliary Atresia in full-term infants with conjugated hyperbilirubinemia. There is little information on the utility of the HBS in premature infants with conjugated hyperbilirubinemia and infants with parenteral nutrition associated cholestasis (PNAC). The purpose of this study is to assess the utility of HBS in differentiating Biliary Atresia and PNAC in premature neonates and full-term infants who received parenteral nutrition (PN). MATERIALS AND METHODS: Retrospective data collection and analysis on infants who developed conjugated hyperbilirubinemia and had HBS performed during their stay at level IV neonatal intensive care unit between 2005 and 2015. RESULTS: A total of 20 patients with exposure to PN had HBS; two patients were confirmed to have Biliary Atresia. There were no statistically significant differences between patients with Biliary Atresia versus PNAC in demographics, days on PN, or gamma glutamyl-transferase levels. Stool color was statistically significantly different between the two groups; patients with Biliary Atresia had acholic stools more consistently than patients without Biliary Atresia. HBS had 100% sensitivity, 17% specificity, positive-predictive value of 12%, and a negative-predictive value (NPV) of 100%. CONCLUSIONS: These data indicate that the ability of HBS to aid in diagnosing Biliary Atresia is poor in a population of preterm neonates and full-term infants with PNAC. Although there is 100% sensitivity, the poor specificity (17%) should be acknowledged when utilizing HBS to diagnose Biliary Atresia in this vulnerable patient population. NPV of 100% is helpful in ruling out Biliary Atresia in this population. PMID- 28818035 TI - Comparative analysis of inosine-substituted duplex DNA by circular dichroism and X-ray crystallography. AB - Leveraging structural biology tools, we report the results of experiments seeking to determine if the different mechanical properties of DNA polymers with base analog substitutions can be attributed, at least in part, to induced changes from classical B-form DNA. The underlying hypothesis is that different inherent bending and twisting flexibilities may characterize non-canonical B-DNA, so that it is inappropriate to interpret mechanical changes caused by base analog substitution as resulting simply from 'electrostatic' or 'base stacking' influences without considering the larger context of altered helical geometry. Circular dichroism spectra of inosine-substituted oligonucleotides and longer base-substituted DNAs in solution indicated non-canonical helical conformations, with the degree of deviation from a standard B-form geometry depending on the number of I?C pairs. X-ray diffraction of a highly inosine-substituted DNA decamer crystal (eight I?C and two A?T pairs) revealed an A-tract-like conformation with a uniformly narrow minor groove, reduced helical rise, and the majority of sugars adopting a C1'-exo (southeastern) conformation. This contrasts with the standard B-DNA geometry with C2'-endo sugar puckers (south conformation). In contrast, the crystal structure of a decamer with only four I?C pairs has a geometry similar to that of the reference duplex with eight G?C and two A?T pairs. The unique crystal geometry of the inosine-rich duplex is noteworthy given its unusual CD signature in solution and the altered mechanical properties of some inosine-containing DNAs. PMID- 28818036 TI - eccCL: parallelized GPU implementation of Ensemble Classifier Chains. AB - BACKGROUND: Multi-label classification has recently gained great attention in diverse fields of research, e.g., in biomedical application such as protein function prediction or drug resistance testing in HIV. In this context, the concept of Classifier Chains has been shown to improve prediction accuracy, especially when applied as Ensemble Classifier Chains. However, these techniques lack computational efficiency when applied on large amounts of data, e.g., derived from next-generation sequencing experiments. By adapting algorithms for the use of graphics processing units, computational efficiency can be greatly improved due to parallelization of computations. RESULTS: Here, we provide a parallelized and optimized graphics processing unit implementation (eccCL) of Classifier Chains and Ensemble Classifier Chains. Additionally to the OpenCL implementation, we provide an R-Package with an easy to use R-interface for parallelized graphics processing unit usage. CONCLUSION: eccCL is a handy implementation of Classifier Chains on GPUs, which is able to process up to over 25,000 instances per second, and thus can be used efficiently in high-throughput experiments. The software is available at http://www.heiderlab.de . PMID- 28818037 TI - Association of coral algal symbionts with a diverse viral community responsive to heat shock. AB - BACKGROUND: Stony corals provide the structural foundation of coral reef ecosystems and are termed holobionts given they engage in symbioses, in particular with photosynthetic dinoflagellates of the genus Symbiodinium. Besides Symbiodinium, corals also engage with bacteria affecting metabolism, immunity, and resilience of the coral holobiont, but the role of associated viruses is largely unknown. In this regard, the increase of studies using RNA sequencing (RNA-Seq) to assess gene expression provides an opportunity to elucidate viral signatures encompassed within the data via careful delineation of sequence reads and their source of origin. RESULTS: Here, we re-analyzed an RNA-Seq dataset from a cultured coral symbiont (Symbiodinium microadriaticum, Clade A1) across four experimental treatments (control, cold shock, heat shock, dark shock) to characterize associated viral diversity, abundance, and gene expression. Our approach comprised the filtering and removal of host sequence reads, subsequent phylogenetic assignment of sequence reads of putative viral origin, and the assembly and analysis of differentially expressed viral genes. About 15.46% (123 million) of all sequence reads were non-host-related, of which <1% could be classified as archaea, bacteria, or virus. Of these, 18.78% were annotated as virus and comprised a diverse community consistent across experimental treatments. Further, non-host related sequence reads assembled into 56,064 contigs, including 4856 contigs of putative viral origin that featured 43 differentially expressed genes during heat shock. The differentially expressed genes included viral kinases, ubiquitin, and ankyrin repeat proteins (amongst others), which are suggested to help the virus proliferate and inhibit the algal host's antiviral response. CONCLUSION: Our results suggest that a diverse viral community is associated with coral algal endosymbionts of the genus Symbiodinium, which prompts further research on their ecological role in coral health and resilience. PMID- 28818038 TI - Role of the type VI secretion systems during disease interactions of Erwinia amylovora with its plant host. AB - BACKGROUND: Type VI secretion systems (T6SS) are widespread among Gram-negative bacteria and have a potential role as essential virulence factors or to maintain symbiotic interactions. Three T6SS gene clusters were identified in the genome of E. amylovora CFBP 1430, of which T6SS-1 and T6SS-3 represent complete T6SS machineries, while T6SS-2 is reduced in its gene content. RESULTS: To assess the contribution of T6SSs to virulence and potential transcriptomic changes of E. amylovora CFBP 1430, single and double mutants in two structural genes were generated for T6SS-1 and T6SS-3. Plant assays showed that mutants in T6SS-3 were slightly more virulent in apple shoots while inducing less disease symptoms on apple flowers, indicating that T6SSs have only a minor effect on virulence of E. amylovora CFBP 1430. The mutations led under in vitro conditions to the differential expression of type III secretion systems, iron acquisition, chemotaxis, flagellar, and fimbrial genes. Comparison of the in planta and in vitro transcriptome data sets revealed a common differential expression of three processes and a set of chemotaxis and motility genes. Additional experiments proved that T6SS mutants are impaired in their motility. CONCLUSION: These results suggest that the deletion of T6SSs alters metabolic and motility processes. Nevertheless, the difference in lesion development in apple shoots and flower necrosis of T6SS mutants was indicative that T6SSs influences the disease progression and the establishment of the pathogen on host plants. PMID- 28818039 TI - The impact of RNA sequence library construction protocols on transcriptomic profiling of leukemia. AB - BACKGROUND: RNA sequencing (RNA-seq) has become an indispensable tool to identify disease associated transcriptional profiles and determine the molecular underpinnings of diseases. However, the broad adaptation of the methodology into the clinic is still hampered by inconsistent results from different RNA-seq protocols and involves further evaluation of its analytical reliability using patient samples. Here, we applied two commonly used RNA-seq library preparation protocols to samples from acute leukemia patients to understand how poly-A-tailed mRNA selection (PA) and ribo-depletion (RD) based RNA-seq library preparation protocols affect gene fusion detection, variant calling, and gene expression profiling. RESULTS: Overall, the protocols produced similar results with consistent outcomes. Nevertheless, the PA protocol was more efficient in quantifying expression of leukemia marker genes and showed better performance in the expression-based classification of leukemia. Independent qRT-PCR experiments verified that the PA protocol better represented total RNA compared to the RD protocol. In contrast, the RD protocol detected a higher number of non-coding RNA features and had better alignment efficiency. The RD protocol also recovered more known fusion-gene events, although variability was seen in fusion gene predictions. CONCLUSION: The overall findings provide a framework for the use of RNA-seq in a precision medicine setting with limited number of samples and suggest that selection of the library preparation protocol should be based on the objectives of the analysis. PMID- 28818041 TI - Erratum to: Nephron development and extrarenal features in a child with congenital nephrotic syndrome caused by null LAMB2 mutations. PMID- 28818040 TI - In silico prediction and characterization of secondary metabolite biosynthetic gene clusters in the wheat pathogen Zymoseptoria tritici. AB - BACKGROUND: Fungal pathogens of plants produce diverse repertoires of secondary metabolites, which have functions ranging from iron acquisition, defense against immune perturbation, to toxic assaults on the host. The wheat pathogen Zymoseptoria tritici causes Septoria tritici blotch, a foliar disease which is a significant threat to global food security. Currently, there is limited knowledge of the secondary metabolite arsenal produced by Z. tritici, which significantly restricts mechanistic understanding of infection. In this study, we analyzed the genome of Z. tritici isolate IP0323 to identify putative secondary metabolite biosynthetic gene clusters, and used comparative genomics to predict their encoded products. RESULTS: We identified 32 putative secondary metabolite clusters. These were physically enriched at subtelomeric regions, which may facilitate diversification of cognate products by rapid gene rearrangement or mutations. Comparative genomics revealed a four gene cluster with significant similarity to the ferrichrome-A biosynthetic locus of the maize pathogen Ustilago maydis, suggesting this siderophore is deployed by Z. tritici to acquire iron. The Z. tritici genome also contains several isoprenoid biosynthetic gene clusters, including one with high similarity to a carotenoid/opsin producing locus in several fungi. Furthermore, we identify putative phytotoxin biosynthetic clusters, suggesting Z. tritici can produce an epipolythiodioxopiperazine, and a polyketide and non-ribosomal peptide with predicted structural similarities to fumonisin and the Alternaria alternata AM-toxin, respectively. Interrogation of an existing transcriptional dataset suggests stage specific deployment of numerous predicted loci during infection, indicating an important role of these secondary metabolites in Z. tritici disease. CONCLUSIONS: We were able to assign putative biosynthetic products to numerous clusters based on conservation amongst other fungi. However, analysis of the majority of secondary metabolite loci did not enable prediction of a cluster product, and consequently the capacity of these loci to play as yet undetermined roles in disease or other stages of the Z. tritici lifecycle is significant. These data will drive future experimentation for determining the role of these clusters and cognate secondary metabolite products in Z. tritici virulence, and may lead to discovery of novel bioactive molecules. PMID- 28818042 TI - Coreference annotation and resolution in the Colorado Richly Annotated Full Text (CRAFT) corpus of biomedical journal articles. AB - BACKGROUND: Coreference resolution is the task of finding strings in text that have the same referent as other strings. Failures of coreference resolution are a common cause of false negatives in information extraction from the scientific literature. In order to better understand the nature of the phenomenon of coreference in biomedical publications and to increase performance on the task, we annotated the Colorado Richly Annotated Full Text (CRAFT) corpus with coreference relations. RESULTS: The corpus was manually annotated with coreference relations, including identity and appositives for all coreferring base noun phrases. The OntoNotes annotation guidelines, with minor adaptations, were used. Interannotator agreement ranges from 0.480 (entity-based CEAF) to 0.858 (Class-B3), depending on the metric that is used to assess it. The resulting corpus adds nearly 30,000 annotations to the previous release of the CRAFT corpus. Differences from related projects include a much broader definition of markables, connection to extensive annotation of several domain-relevant semantic classes, and connection to complete syntactic annotation. Tool performance was benchmarked on the data. A publicly available out-of-the-box, general-domain coreference resolution system achieved an F-measure of 0.14 (B3), while a simple domain-adapted rule-based system achieved an F-measure of 0.42. An ensemble of the two reached F of 0.46. Following the IDENTITY chains in the data would add 106,263 additional named entities in the full 97-paper corpus, for an increase of 76% percent in the semantic classes of the eight ontologies that have been annotated in earlier versions of the CRAFT corpus. CONCLUSIONS: The project produced a large data set for further investigation of coreference and coreference resolution in the scientific literature. The work raised issues in the phenomenon of reference in this domain and genre, and the paper proposes that many mentions that would be considered generic in the general domain are not generic in the biomedical domain due to their referents to specific classes in domain-specific ontologies. The comparison of the performance of a publicly available and well-understood coreference resolution system with a domain-adapted system produced results that are consistent with the notion that the requirements for successful coreference resolution in this genre are quite different from those of the general domain, and also suggest that the baseline performance difference is quite large. PMID- 28818043 TI - Erratum to: Re-classification within the serogroups O3 and O8 of Citrobacter strains. PMID- 28818044 TI - Effects of the vertically transmitted microsporidian Facilispora margolisi and the parasiticide emamectin benzoate on salmon lice (Lepeophtheirus salmonis). AB - BACKGROUND: Microsporidia are highly specialized, parasitic fungi that infect a wide range of eukaryotic hosts from all major taxa. Infections cause a variety of damaging effects on host physiology from increased stress to death. The microsporidian Facilispora margolisi infects the Pacific salmon louse (Lepeophtheirus salmonis oncorhynchi), an economically and ecologically important ectoparasitic copepod that can impact wild and cultured salmonids. RESULTS: Vertical transmission of F. margolisi was demonstrated by using PCR and in situ hybridization to identify and localize microsporidia in female L. salmonis and their offspring. Spores and developmental structures of F. margolisi were identified in 77% of F1 generation copepods derived from infected females while offspring from uninfected females all tested negative for the microsporidia. The transcriptomic response of the salmon louse to F. margolisi was profiled at both the copepodid larval stage and the pre-adult stage using microarray technology. Infected copepodids differentially expressed 577 transcripts related to stress, ATP generation and structural components of muscle and cuticle. The infection also impacted the response of the copepodid to the parasiticide emamectin benzoate (EMB) at a low dose of 1.0 ppb for 24 h. A set of 48 transcripts putatively involved in feeding and host immunomodulation were up to 8-fold underexpressed in the F. margolisi infected copepodids treated with EMB compared with controls or either stressor alone. Additionally, these infected lice treated with EMB also overexpressed 101 transcripts involved in stress resistance and signalling compared to the other groups. In contrast, infected pre-adult lice did not display a stress response, suggesting a decrease in microsporidian virulence associated with lice maturity. Furthermore, copepodid infectivity and moulting was not affected by the microsporidian infection. CONCLUSIONS: This study demonstrated that F. margolisi is transmitted vertically between salmon louse generations and that biological impacts of infection differ depending on the stage of the copepod host. The infection caused significant perturbations of larval transcriptomes and therefore must be considered in future studies in which impacts to host development and environmental factors are assessed. Fitness impacts are probably minor, although the interaction between pesticide exposure and microsporidian infection merits further study. PMID- 28818045 TI - BMC ecology image competition 2017: the winning images. AB - For the fifth year, BMC Ecology is proud to present the winning images from our annual image competition. The 2017 edition received entries by talented shutterbug-ecologists from across the world, showcasing research that is increasing our understanding of ecosystems worldwide and the beauty and diversity of life on our planet. In this editorial we showcase the winning images, as chosen by our Editorial Board and guest judge Chris Darimont, as well as our selection of highly commended images. Enjoy! PMID- 28818046 TI - Can resources moderate the impact of levels of frailty on adverse outcomes among (pre-) frail older people? A longitudinal study. AB - BACKGROUND: Higher levels of frailty result in higher risks of adverse frailty outcomes such as hospitalisation and mortality. There are, however, indications that more factors than solely frailty play a role in the development of these outcomes. The presence of resources, e.g. sufficient income and good self management abilities, might slow down the pathway from level of frailty to adverse outcomes (e.g. mortality). In the present paper we studied whether resources (i.e. educational level, income, availability of informal care, living situation, sense of mastery and self-management abilities) moderate the impact of the level of frailty on the adverse outcomes mortality, hospitalisation and the development of disability over a two-year period. METHODS: Longitudinal data on a sample of 2420 community-dwelling pre-frail and frail older people were collected. Participants filled out a questionnaire every six months, including measures of frailty, resources and outcomes. To study the moderating effects of the selected resources their interaction effects with levels of frailty on outcomes were studied by means of multiple logistics and linear regression models. RESULTS: Frail older participants had increased odds of mortality and hospitalisation, and had more deteriorating disability scores compared to their pre-frail counterparts. No moderating effects of the studied resources were found for the outcomes mortality and hospitalisation. Only for the outcome disability statistically significant moderating effects were present for the resources income and living situation, yet these effects were in the opposite direction to what we expected. Overall, the studied resources showed hardly any statistically significant moderating effects and the directions of the trends were inconsistent. CONCLUSIONS: Frail participants were more at risk of mortality, hospitalisation, and an increase in disability. However, we were unable to demonstrate a clear moderating effect of the studied resources on the adverse outcomes associated with frailty (among pre-frail and frail participants). More research is needed to increase insight into the role of moderating factors. Other resources or outcome measures should be considered. PMID- 28818047 TI - Second opinion for degenerative spinal conditions: an option or a necessity? A prospective observational study. AB - BACKGROUND: Second opinions may improve quality of patient care. The primary objective of this study was to determine the concordance between first and second diagnoses and opinions regarding need for spinal surgery among patients with back or neck pain that have been recommended spinal surgery. METHODS: We performed a prospective observational study of patients who had been recommended for spinal surgery and received a second opinion between May 2011 and May 2012 at the Hospital Israelita Albert Einstein on the advice of their health insurance company. A physiatrist and orthopaedic surgeon independently performed the second assessment. If both agreed surgery was indicated, or consensus could not be reached, participants attended a spine review panel for a final recommendation. Descriptive analyses compared diagnoses and management plans of the first and second opinions. RESULTS: Of 544 referred patients, 16 (2.9%) did not meet inclusion criteria, 43 (7.9%) refused participation and 485 were included. Diagnoses differed from the first opinion for 290 (59.8%). Diagnoses of cervical and lumbar radiculopathy were concordant in 36/99 (36.4%) and 116/234 (49.6%) respectively. The second opinion was for conservative treatment for 168 (34.6%) participants, 27 (5.6%) were not considered to have a spine condition, and 290 (59.8%) were referred to the review board. 60 participants did not attend the board review and therefore did not receive a final recommendation. Board review was conservative treatment for an additional 67 participants, 20 were not considered to have a spine condition and 143 participants were recommended surgery. Overall, 33.6% received a final opinion of surgery (143/425) although only 66 (15.5%) received the same surgical recommendation, 235 (55.3%) were advised to have conservative treatment, and 47 (11.1%) were not considered to have a spinal diagnosis. CONCLUSIONS: We found a large discordance between first and second opinions regarding diagnosis and need for spinal surgery. This suggests that obtaining a second opinion could reduce potentially unnecessary surgery. TRIAL REGISTRATION: Current Controlled Trials ISRCTN07143259 . Registered 21 November 2011. PMID- 28818048 TI - Identification of cancer risk and associated behaviour: implications for social marketing campaigns for cancer prevention. AB - BACKGROUND: Community misconception of what causes cancer is an important consideration when devising communication strategies around cancer prevention, while those initiating social marketing campaigns must decide whether to target the general population or to tailor messages for different audiences. This paper investigates the relationships between demographic characteristics, identification of selected cancer risk factors, and associated protective behaviours, to inform audience segmentation for cancer prevention social marketing. METHODS: Data for this cross-sectional study (n = 3301) are derived from Cancer Council New South Wales' 2013 Cancer Prevention Survey. Descriptive statistics and logistic regression models were used to investigate the relationship between respondent demographic characteristics and identification of each of seven cancer risk factors; demographic characteristics and practice of the seven 'protective' behaviours associated with the seven cancer risk factors; and identification of cancer risk factors and practising the associated protective behaviours, controlling for demographic characteristics. RESULTS: More than 90% of respondents across demographic groups identified sun exposure and smoking cigarettes as moderate or large cancer risk factors. Around 80% identified passive smoking as a moderate/large risk factor, and 40-60% identified being overweight or obese, drinking alcohol, not eating enough vegetables and not eating enough fruit. Women and older respondents were more likely to identify most cancer risk factors as moderate/large, and to practise associated protective behaviours. Education was correlated with identification of smoking as a moderate/large cancer risk factor, and with four of the seven protective behaviours. Location (metropolitan/regional) and country of birth (Australia/other) were weak predictors of identification and of protective behaviours. Identification of a cancer risk factor as moderate/large was a significant predictor for five out of seven associated cancer-protective behaviours, controlling for demographic characteristics. CONCLUSIONS: These findings suggest a role for both audience segmentation and whole-of-population approaches in cancer-prevention social marketing campaigns. Targeted campaigns can address beliefs of younger people and men about cancer risk factors. Traditional population campaigns can enhance awareness of being overweight, alcohol consumption, and poor vegetable and fruit intake as cancer risk factors. PMID- 28818049 TI - Post-treatment haemolysis in African children with hyperparasitaemic falciparum malaria; a randomized comparison of artesunate and quinine. AB - BACKGROUND: Parenteral artesunate is the treatment of choice for severe malaria. Recently, haemolytic anaemia occurring 1 to 3 weeks after artesunate treatment of falciparum malaria has been reported in returning travellers in temperate countries. METHODS: To assess these potential safety concerns in African children, in whom most deaths from malaria occur, an open-labelled, randomized controlled trial was conducted in Kinshasa, Democratic Republic of Congo. 217 children aged between 6 months and 14 years with acute uncomplicated falciparum malaria and parasite densities over 100,000/MUL were randomly allocated to intravenous artesunate or quinine, hospitalized for 3 days and then followed for 42 days. RESULTS: The immediate reduction in haemoglobin was less with artesunate than with quinine: median (IQR) fall at 72 h 1.4 g/dL (0.90-1.95) vs. 1.7 g/dL (1.10-2.40) (p = 0.009). This was explained by greater pitting then recirculation of once infected erythrocytes. Only 5% of patients (in both groups) had a >= 10% reduction in haemoglobin after day 7 (p = 0.1). One artesunate treated patient with suspected concomitant sepsis had a protracted clinical course and required a blood transfusion on day 14. CONCLUSIONS: Clinically significant delayed haemolysis following parenteral artesunate is uncommon in African children hospitalised with acute falciparum malaria and high parasitaemias. TRIAL REGISTRATION: ClinicalTrials.gov ; Identifier: NCT02092766 (18/03/2014). PMID- 28818050 TI - Administration of two probiotic strains during early childhood does not affect the endogenous gut microbiota composition despite probiotic proliferation. AB - BACKGROUND: Probiotics are increasingly applied to prevent and treat a range of infectious, immune related and gastrointestinal diseases. Despite this, the mechanisms behind the putative effects of probiotics are poorly understood. One of the suggested modes of probiotic action is modulation of the endogenous gut microbiota, however probiotic intervention studies in adults have failed to show significant effects on gut microbiota composition. The gut microbiota of young children is known to be unstable and more responsive to external factors than that of adults. Therefore, potential effects of probiotic intervention on gut microbiota may be easier detectable in early life. We thus investigated the effects of a 6 month placebo-controlled probiotic intervention with Bifidobacterium animalis subsp. lactis (BB-12(r)) and Lactobacillus rhamnosus (LGG(r)) on gut microbiota composition and diversity in more than 200 Danish infants (N = 290 enrolled; N = 201 all samples analyzed), as assessed by 16S rRNA amplicon sequencing. Further, we evaluated probiotic presence and proliferation by use of specific quantitative polymerase chain reaction (qPCR). RESULTS: Probiotic administration did not significantly alter gut microbiota community structure or diversity as compared to placebo. The probiotic strains were detected in 91.3% of the fecal samples from children receiving probiotics and in 1% of the placebo treated children. Baseline gut microbiota was not found to predict the ability of probiotics to establish in the gut after the 6 month intervention. Within the probiotics group, proliferation of the strains LGG(r) and BB-12(r) in the gut was detected in 44.7% and 83.5% of the participants, respectively. A sub-analysis of the gut microbiota including only individuals with detected growth of the probiotics LGG(r) or BB-12(r) and comparing these to placebo revealed no differences in community structure or diversity. CONCLUSION: Six months of probiotic administration during early life did not change gut microbiota community structure or diversity, despite active proliferation of the administered probiotic strains. Therefore, alteration of the healthy infant gut microbiota is not likely to be a prominent mechanism by which these specific probiotics works to exert beneficial effects on host health. TRIAL REGISTRATION: NCT02180581 . Registered 30 June 2014. PMID- 28818051 TI - Erratum to: systematic review and meta-analysis of the effect of increased vegetable and fruit consumption on body weight and energy intake. PMID- 28818052 TI - Proteomic analysis during of spore germination of Moniliophthora perniciosa, the causal agent of witches' broom disease in cacao. AB - BACKGROUND: Moniliophthora perniciosa is a phytopathogenic fungus responsible for witches' broom disease of cacao trees (Theobroma cacao L.). Understanding the molecular events during germination of the pathogen may enable the development of strategies for disease control in these economically important plants. In this study, we determined a comparative proteomic profile of M. perniciosa basidiospores during germination by two-dimensional SDS-PAGE and mass spectrometry. RESULTS: A total of 316 proteins were identified. Molecular changes during the development of the germinative tube were identified by a hierarchical clustering analysis based on the differential accumulation of proteins. Proteins associated with fungal filamentation, such as septin and kinesin, were detected only 4 h after germination (hag). A transcription factor related to biosynthesis of the secondary metabolite fumagillin, which can form hybrids with polyketides, was induced 2 hag, and polyketide synthase was observed 4 hag. The accumulation of ATP synthase, binding immunoglobulin protein (BiP), and catalase was validated by western blotting. CONCLUSIONS: In this study, we showed variations in protein expression during the early germination stages of fungus M. perniciosa. Proteins associated with fungal filamentation, and consequently with virulence, were detected in basidiospores 4 hag., for example, septin and kinesin. We discuss these results and propose a model of the germination of fungus M. perniciosa. This research can help elucidate the mechanisms underlying basic processes of host invasion and to develop strategies for control of the disease. PMID- 28818053 TI - The impact of self-interviews on response patterns for sensitive topics: a randomized trial of electronic delivery methods for a sexual behaviour questionnaire in rural South Africa. AB - BACKGROUND: Self-interviews, where the respondent rather than the interviewer enters answers to questions, have been proposed as a way to reduce social desirability bias associated with interviewer-led interviews. Computer-assisted self-interviews (CASI) are commonly proposed since the computer programme can guide respondents; however they require both language and computer literacy. We evaluated the feasibility and acceptability of using electronic methods to administer quantitative sexual behaviour questionnaires in the Somkhele demographic surveillance area (DSA) in rural KwaZulu-Natal, South Africa. METHODS: We conducted a four-arm randomized trial of paper-and-pen-interview, computer-assisted personal-interview (CAPI), CASI and audio-CASI with an age-sex urbanicity stratified sample of 504 adults resident in the DSA in 2015. We compared respondents' answers to their responses to the same questions in previous surveillance rounds. We also conducted 48 cognitive interviews, dual coding responses using the Framework approach. RESULTS: Three hundred forty (67%) individuals were interviewed and covariates and participation rates were balanced across arms. CASI and audio-CASI were significantly slower than interviewer-led interviews. Item non-response rates were higher in self-interview arms. In single paper meta-analysis, self-interviewed individuals reported more socially undesirable sexual behaviours. Cognitive interviews found high acceptance of both self-interviews and the use of electronic methods, with some concerns that self interview methods required more participant effort and literacy. CONCLUSIONS: Electronic data collection methods, including self-interview methods, proved feasible and acceptable for completing quantitative sexual behaviour questionnaires in a poor, rural South African setting. However, each method had both benefits and costs, and the choice of method should be based on context specific criteria. PMID- 28818054 TI - Comparison of the trapezius and the adductor pollicis muscle as predictor of good intubating conditions: a randomized controlled trial. AB - BACKGROUND: Adequate muscle relaxation is important for ensuring optimal conditions for intubation. Although acceleromyography of the adductor pollicis muscle is commonly used to assess conditions for intubation, we hypothesized that acceleromyography of the trapezius is more indicative of optimal intubating conditions. The primary outcome was the difference between both measurement sites with regard to prediction of good or acceptable intubating conditions. METHODS: Neuromuscular blockade after injection of rocuronium 0.3 mg/kg IV was measured simultaneously with acceleromyography of the adductor pollicis muscle and the trapezius muscle in sixty female patients, American Society of Anesthesiologists physical status I to III, undergoing general anesthesia for gynecologic surgery. Exclusion criteria were: expected difficult tracheal intubation (e.g. history of difficult intubation, reduced mouth opening (< 2 cm) and/or Mallampati Score 4), increased risk of pulmonary aspiration (e.g. gastroesophageal reflux or delayed gastric emptying) allergies to drugs used during the study, pregnancy, neuromuscular diseases, medication with potential to influence neuromuscular function (e.g. furosemide, magnesium, cephalosporins) and hepatic or renal insufficiency (serum bilirubin >26 MUmol/L, serum creatinine >90 MUmol/l). Patients were randomized to 2 groups: group A (n = 30): endotracheal intubation after onset of the neuromuscular block at the adductor pollicis muscle. Group B (n = 30): endotracheal intubation after onset at the trapezius muscle. Intubating conditions were compared between both groups by means of a standardised score (the Copenhagen score) with Fisher's exact test. RESULTS: Onset of the block after rocuronium injection was observed at the adductor pollicis muscle compared to the trapezius with 2.8 (1.1) versus 2.5 (1.1) min (mean +/- SD; P = 0.006). Intubating conditions were poor in 2 patients (7%) of group A, and in 1 patient (3%) of group T. They were acceptable (either excellent or good) in 28 patients (93%) in group A, and in 1 patient (97%) in group T (P = 0.82). CONCLUSIONS: Performing acceleromyography at the trapezius muscle reduced the time between injection of neuromuscular blocking agents and intubation by 18 s (11%). Thus, trapezius muscle acceleromyography is an acceptable alternative to adductor pollicis muscle acceleromyography in predicting acceptable intubating conditions, which allows for earlier indication of adequate intubating conditions. TRIAL REGISTRATION: ClinicalTrial.gov Identifier: NCT01849198 . Registered April 29, 2013. PMID- 28818055 TI - Patterns of HIV testing practices among young gay and bisexual men living in Scotland: a qualitative study. AB - BACKGROUND: Increasing overall rates, and frequency, of HIV testing in populations at risk is a key public health objective and a critical dimension of HIV prevention efforts. In the UK, men who have sex with men (MSM) remain one of the communities most at risk of HIV and, within this, young gay men are a key risk group. Understanding HIV testing practices is important in the development of interventions to promote testing among young gay and bisexual men. METHODS: Qualitative interviews were conducted with thirty young gay and bisexual men (aged 18-29) in Scotland. Thematic analysis of men's accounts of their approach to HIV testing identified three overarching patterns of testing: 'habitual', 'reactive' and ' ad hoc'. RESULTS: This qualitative study, the first to explore patterns of HIV testing practices among young gay and bisexual men in the UK, contributes novel findings around the role of social support and 'community' in shaping young men's approaches to HIV testing. The findings suggest that social support can play an important role in encouraging and facilitating HIV testing among young gay men, however, social norms of non-testing also have the potential to act as a barrier to development of a regular routine. Men with habitual testing practices framed HIV testing as both a personal and 'community' responsibility, and more effective than testing in response to risk events or emergent symptoms. Men who reported reactive testing practices described testing for HIV primarily in response to perceived exposure to sexual risk, along with 'transitional moments' such as starting, ending or changes to a relationship. Among young men who reported testing on an ad hoc basis, inconvenience and disruptions to HIV testing practices, particularly where men lacked social support, acted as a barrier to developing a routine of regular testing. CONCLUSIONS: Our findings suggest that interventions which seek to increase rates of HIV testing and testing frequency among young gay and bisexual men should include a specific focus on promoting and supporting positive testing practices within young men's friendship groups and wider gay communities. PMID- 28818056 TI - Adaptation of Chinese and English versions of the Ankylosing Spondylitis quality of life (ASQoL) scale for use in Singapore. AB - BACKGROUND: To cross-culturally adapt and validate the Singapore Chinese and Singapore English versions of the Ankylosing Spondylitis Quality of Life (ASQoL) scales. METHODS: Translation of the ASQoL into Singapore Chinese and English was performed by professional and lay translation panels. Field-testing for face and content validity was performed by interviewing ten Chinese speaking and ten English speaking axial spondyloarthritis (AxSpA) patients. AxSpA patients (either Chinese or English speaking) were invited to take part in validation surveys. The Health Assessment Questionnaire (HAQ), Short Form Health Survey (SF-36), Bath Indices, and other measures of disease activity were used as comparator scales for convergent validity. A separate sample of AxSpA patients were invited to participate in a test-retest postal study, with 2 weeks between administrations. RESULTS: The cross-sectional study included 183 patients (77% males, 82% English speaking), with a mean (SD) age of 39.4 (13.7) years. The ASQoL had excellent internal consistency (Cronbach's alpha = 0.88), and correlated moderately with all the comparator scales. The ASQoL was able to distinguish between patients grouped by disease activity and perceived general health. The ASQoL fulfilled the Rasch model analysis for fit, reliability and unidimensionality requirements. No significant differential item functioning was noted for gender, age below or above 50 years, and language of administration. Test-retest reliability was good (r = 0.81). CONCLUSIONS: The ASQoL was adapted into Singapore Chinese and English language versions, and shown to be culturally relevant, valid and reliable when used with combined samples of AxSpA patients who speak either Chinese or English. PMID- 28818058 TI - Evaluation of therapy management and outcome in Takotsubo syndrome. AB - BACKGROUND: To date there is no validated evidence for standardized treatment of patients with Takotsubo syndrome (TTS). Medication therapy after final TTS diagnosis remains unclear. Previous data on patient outcome is ambivalent. Aim of this study was to evaluate medication therapy in TTS and to analyze patient outcome. METHODS: Within an observational retrospective cohort study we analyzed our medical records and included 72 patients with TTS that underwent cardiovascular magnetic resonance imaging (CMR) after a median of 2 days interquartile range (IQR 1-3.5). We investigated medication therapy at discharge. Medication implementation and major adverse clinical events (MACE) were prospectively evaluated after a median follow-up of 24 months (IQR 6-43). Left ventricular function, myocardial oedema and late gadolinium enhancement were analyzed in a CMR follow-up if available. RESULTS: Antithrombotic therapy was recommended in 69 (96%) patients including different combinations. Antiplatelet monotherapy was prescribed in 28 (39%) patients. Dual antiplatelet therapy was recommended in 29 (40%) patients. Length of therapy duration varied from one to twelve months. Only in one case oral anticoagulation was prescribed due to apical ballooning with a left ventricular ejection fraction <30%. In all other cases oral anticoagulation was recommended due to other indications. beta-adrenoceptor antagonists and ACE inhibitors were recommended in 63 (88%), mineralocorticoid receptor antagonists were prescribed in 31 (43%) patients. After a median of 2 months (IQR 1.3-2.9) left ventricular function significantly recovered (49.1% +/- 10.1 vs. 64.1% +/- 5.7, P < 0.001) and myocardial oedema significantly decreased (13.5 +/- 11.3 vs. 0.6% +/- 2.4, P = <0.001) in the CMR follow-up. The 30-day mortality was 1%. MACE rate after 24 months was 12%. CONCLUSION: Although therapy guidelines for TTS currently do not exist, we found that the majority of patients were treated with antithrombotic and heart failure therapy for up to twelve months. Left ventricular function and myocardial oedema recovered rapidly within the first two months. Outcome analysis showed a low bleeding rate and a high short-term survival. Therefore, TTS patients might benefit from antithrombotic and heart failure therapy at least for the first two months. PMID- 28818057 TI - Effect of counselling during pulmonary rehabilitation on self-determined motivation towards physical activity in people with chronic obstructive pulmonary disease - protocol of a mixed methods study. AB - BACKGROUND: Physical activity promotion in people with Chronic Obstructive Pulmonary Disease (COPD) is focus of research and public health. Patient-centred interventions like counselling are promising approaches to help patients reducing sedentary behaviour. Aim of the present study is to investigate if a physical activity counselling program during pulmonary rehabilitation increases physical activity level in daily life in people with COPD. METHODS: A two-armed, single blind randomised controlled trial including 56 people with COPD will be conducted in an outpatient pulmonary rehabilitation. Patients will participate in a 12-week rehabilitation program; individuals randomized to the interventional group will additionally participate in five counselling sessions with a physiotherapist, based on the principles of motivational interviewing. The participants' physical activity level will be measured using an accelerometer (SenseWear Pro(r)) before, directly and 3 months after pulmonary rehabilitation. Semi-structured interviews will be conducted to learn more about barriers and facilitators regarding daily physical activity. DISCUSSION: If the strategy successfully improves the physical activity level in people with COPD, counselling might be implemented in pulmonary rehabilitation. TRIAL REGISTRATION: Clinical Trials.gov NCT02455206 (05/21/2015), Swiss National Trails Portal SNCTP000001426 (05/21/2015). PMID- 28818059 TI - Influence of sense of coherence on adolescents' self-perceived dental aesthetics; a cross-sectional study. AB - BACKGROUND: Sense of coherence (SOC) is a psychosocial factor capable of influencing perception of health, improving one's ability to manage life. It is the central construct of salutogenesis. SOC allows for identification and mobilization of resources to effectively manage or solve problems, promoting health and quality of life. Using Wilson-Cleary's conceptual model we hypothesized that SOC might contribute to self-perception of dental aesthetics. The aim of this study was to investigate whether SOC levels were related to self perception of dental aesthetics against assessed normative orthodontic treatment need among adolescents. METHODS: A cross-sectional study was conducted with 615 male and female adolescents aged 12 to 15 years. Data collection comprised socio demographic and socio-economic characteristics, SOC (SOC 13), self-perceived dental aesthetics (Oral Aesthetic Subjective Impact Scale), and assessment of orthodontic treatment need (Dental Aesthetic Index). Statistical analysis involved Pearson's chi-square test, Kruskal-Wallis test, Mann-Whitney test and multiple linear regression. Spearman's correlation coefficient was calculated for the determination of the strength of correlations among the numerical variables. The level of significance was set at 5% (p < 0.05). RESULTS: 50.1% of the participants were classified as having a high SOC (>= median). Overall, SOC was associated with self-perceived dental aesthetics (p = 0.048). In the adolescents with no orthodontic treatment need, those with a low SOC perceived their dental aesthetics more negatively than those with high levels of SOC. The multiple regression analysis demonstrated an inverse relationship between SOC and: 1) age (p = 0.007), SOC being higher in the younger age group; 2) self-perceived dental aesthetics (p = 0.001), a higher SOC being associated with those who had a positive dental self-perception. CONCLUSIONS: SOC was associated with self perceived dental aesthetics and adolescents with a high SOC were more likely to perceive their dental aesthetics more positively. SOC did not seem to influence self-perception of dental aesthetics in adolescents who were clinically assessed as having an orthodontic treatment need, however, in those where there was no orthodontic treatment need, a low SOC was associated with a negative self perception of dental appearance. PMID- 28818061 TI - Estimating correlation between multivariate longitudinal data in the presence of heterogeneity. AB - BACKGROUND: Estimating correlation coefficients among outcomes is one of the most important analytical tasks in epidemiological and clinical research. Availability of multivariate longitudinal data presents a unique opportunity to assess joint evolution of outcomes over time. Bivariate linear mixed model (BLMM) provides a versatile tool with regard to assessing correlation. However, BLMMs often assume that all individuals are drawn from a single homogenous population where the individual trajectories are distributed smoothly around population average. METHODS: Using longitudinal mean deviation (MD) and visual acuity (VA) from the Ocular Hypertension Treatment Study (OHTS), we demonstrated strategies to better understand the correlation between multivariate longitudinal data in the presence of potential heterogeneity. Conditional correlation (i.e., marginal correlation given random effects) was calculated to describe how the association between longitudinal outcomes evolved over time within specific subpopulation. The impact of heterogeneity on correlation was also assessed by simulated data. RESULTS: There was a significant positive correlation in both random intercepts (rho = 0.278, 95% CI: 0.121-0.420) and random slopes (rho = 0.579, 95% CI: 0.349-0.810) between longitudinal MD and VA, and the strength of correlation constantly increased over time. However, conditional correlation and simulation studies revealed that the correlation was induced primarily by participants with rapid deteriorating MD who only accounted for a small fraction of total samples. CONCLUSION: Conditional correlation given random effects provides a robust estimate to describe the correlation between multivariate longitudinal data in the presence of unobserved heterogeneity (NCT00000125). PMID- 28818062 TI - Ocular toxicity due to Trametinib and Dabrafenib. AB - BACKGROUND: To report a case of uveitis and neuroretinal detachment in a patient treated with Trametinib and Dabrafenib due to metastatic cutaneous melanoma stage IV. CASE PRESENTATION: We evaluated slit lamp examination, fundoscopy, optical coherence tomography, fluorescein and indocyanine green angiography in a 66 years old man suffering visual loss. Fundoscopy showed serous neuroretinal detachment of the fovea accompanied with white spots surrounding the fovea in both eyes. Although therapy with Trametinib and Dabrafenib was stopped uveitis anterior was seen 2 weeks later. After a year, the therapy was started again and the serous neuroretinal detachment appeared once more, however without inflammatory reaction of the anterior chamber. CONCLUSION: Patients treated with Trametinib and Dabrafenib should undergo consecutive eye examinations from the beginning of the therapy. PMID- 28818060 TI - RNA-transfection of gamma/delta T cells with a chimeric antigen receptor or an alpha/beta T-cell receptor: a safer alternative to genetically engineered alpha/beta T cells for the immunotherapy of melanoma. AB - BACKGROUND: Adoptive T-cell therapy relying on conventional T cells transduced with T-cell receptors (TCRs) or chimeric antigen receptors (CARs) has caused substantial tumor regression in several clinical trials. However, genetically engineered T cells have been associated with serious side-effects due to off target toxicities and massive cytokine release. To obviate these concerns, we established a protocol adaptable to GMP to expand and transiently transfect gamma/delta T cells with mRNA. METHODS: PBMC from healthy donors were stimulated using zoledronic-acid or OKT3 to expand gamma/delta T cells and bulk T cells, respectively. Additionally, CD8+ T cells and gamma/delta T cells were MACS isolated from PBMC and expanded with OKT3. Next, these four populations were electroporated with RNA encoding a gp100/HLA-A2-specific TCR or a CAR specific for MCSP. Thereafter, receptor expression, antigen-specific cytokine secretion, specific cytotoxicity, and killing of the endogenous gamma/delta T cell-target Daudi were analyzed. RESULTS: Using zoledronic-acid in average 6 million of gamma/delta T cells with a purity of 85% were generated from one million PBMC. MACS-isolation and OKT3-mediated expansion of gamma/delta T cells yielded approximately ten times less cells. OKT3-expanded and CD8+ MACS-isolated conventional T cells behaved correspondingly similar. All employed T cells were efficiently transfected with the TCR or the CAR. Upon respective stimulation, gamma/delta T cells produced IFNgamma and TNF, but little IL-2 and the zoledronic acid expanded T cells exceeded MACS-gamma/delta T cells in antigen-specific cytokine secretion. While the cytokine production of gamma/delta T cells was in general lower than that of conventional T cells, specific cytotoxicity against melanoma cell lines was similar. In contrast to OKT3-expanded and MACS-CD8+ T cells, mock-electroporated gamma/delta T cells also lysed tumor cells reflecting the gamma/delta T cell-intrinsic anti-tumor activity. After transfection, gamma/delta T cells were still able to kill MHC-deficient Daudi cells. CONCLUSION: We present a protocol adaptable to GMP for the expansion of gamma/delta T cells and their subsequent RNA-transfection with tumor-specific TCRs or CARs. Given the transient receptor expression, the reduced cytokine release, and the equivalent cytotoxicity, these gamma/delta T cells may represent a safer complementation to genetically engineered conventional T cells in the immunotherapy of melanoma (Exper Dermatol 26: 157, 2017, J Investig Dermatol 136: A173, 2016). PMID- 28818063 TI - Variations in adolescents' motivational characteristics across gender and physical activity patterns: A latent class analysis approach. AB - BACKGROUND: Neglecting to take account of the underlying context or type of physical activity (PA) that underpins overall involvement has resulted in a limited understanding of adolescents' PA participation. The purpose of the present research was to identify male and female adolescents' leisure time PA patterns and examine whether psychological processes derived from self determination theory differ as a function of the pattern of PA undertaken. METHODS: Nine hundred ninety-five students (61.2% females, 38.8% males; M age = 13.72 years, SD = 1.25) from eight secondary schools in Dublin, Ireland completed a physical activity recall 7 day diary and measures of intrinsic motivation, competence, relatedness, autonomy and autonomy support. Based on the diary five binary indicators of physical activity were derived reflecting recommended levels of MVPA on a minimum of 3 days, at least three sessions of non-organized physical activity (e.g. jog), team sport, individual sport, and organized non-sport physical activity (e.g. dance). Latent class analysis was used to identify subgroups of adolescents that engaged in similar patterns of physical activity. Profiles of physical activity participation were subsequently compared on motivational characteristics using Kruskal-Wallis tests. RESULTS: Latent class analysis revealed six distinct classes for girls (Organized Run/Swim & Dance/Gym; Organized Dance; Leisure Active Team Sport; Active Individual Sport; Walk/Run/Outdoor games; Non-Participation) and five for boys (Leisure Active Gym; Leisure Active Individual Sport; Active Team Sport; Active Mixed Type; Non Participation). Significant differences were found between the classes. Girls characterized by participation in team or individual sport, and boys represented by team sport participation demonstrated significantly higher self-determined motivational characteristics relative to other profiles of physical activity. CONCLUSION: This research offers a nuanced insight into the underlying type of activities that constitute overall patterns of PA among adolescent boys and girls and further reveals that psychological processes vary dependent on the profile of physical activity undertaken. The findings may be useful for informing interventions aimed at promoting physical activity among young people. PMID- 28818064 TI - Association between migration and cognitive status among middle-aged and older adults: a systematic review. AB - BACKGROUND: This study aimed to synthesize the current literature examining the association between migration and cognitive function among middle-aged and older adults. METHODS: We used the PRISMA as a guideline for this systematic review and searched the following databases: PubMed, CINAHL, EMBASE, and Global Health. RESULTS: Twenty-five published studies were included. Twenty-two studies were focused on international migrants, while only 3 studied internal migrants. Fourteen studies were conducted in the United States, followed by UK (n = 2), Israel (n = 2), India (n = 2) and other countries like Canada and Australia. Some studies showed that middle-aged and older migrants demonstrated poorer cognitive function comparing to non-migrants in hosting places; while other studies indicated no association between migration and cognitive function. A higher level of acculturation was associated with better performance on cognitive function tests among migrants. CONCLUSION: It is unclear how or whether migration and cognitive function are related. The quality of current literature suffered from methodological deficiencies. Additional research is needed to examine the linkages using more comprehensive measures of migration and cognitive function. PMID- 28818065 TI - Case reports of two pedigrees with recessive arrhythmogenic right ventricular cardiomyopathy associated with homozygous Thr335Ala variant in DSG2. AB - BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease, involving changes in ventricular myocardial tissue and leading to fatal arrhythmias. Mutations in desmosomal genes are thought to be the main cause of ARVC. However, the exact molecular genetic etiology of the disease still remains largely inconclusive, and this along with large variabilities in clinical manifestations complicate clinical diagnostics. CASE PRESENTATION: We report two families (n = 20) in which a desmoglein-2 (DSG2) missense variant c.1003A > G, p.(Thr335Ala) was discovered in the index patients using next generation sequencing panels. The presence of this variant in probands' siblings and children was studied by Sanger sequencing. Five homozygotes and nine heterozygotes were found with the mutation. Participants were evaluated clinically where possible, and available medical records were obtained. All patients homozygous for the variant fulfilled the current diagnostic criteria for ARVC, whereas none of the heterozygous subjects had symptoms suggestive of ARVC or other cardiomyopathies. CONCLUSIONS: The homozygous DSG2 variant c.1003A > G co-segregated with ARVC, indicating autosomal recessive inheritance and complete penetrance. More research is needed to establish a detailed understanding of the relevance of rare variants in ARVC associated genes, which is essential for informative genetic counseling and rational family member testing. PMID- 28818066 TI - Hepatoprotective and antioxidant effects of single clove garlic against CCl4 induced hepatic damage in rabbits. AB - BACKGROUND: The increase in demand and consumption of single clove garlic or 'Solo garlic' (Allium sativum) has resulted in an increase in research on its therapeutic properties. The present study aims to evaluate the antioxidant activities, oxidant-scavenging efficiency and preventive effects of SCG (single clove garlic) and MCG (multi clove garlic) on CCl4-induced acute hepatotoxicity in male rabbits. METHODS: For this purpose, rabbits were orally administered with 3 ml of CCl4 /kg of body weight, followed by 0.8 g of MCG or SCG/kg twice a week for three successive weeks. Oxidative hepatotoxicity was then assessed. RESULTS: SCG extracts exhibited higher antioxidant capacity than the MCG extract. Scavenging ability of SCG showed significant (p < 0.05) elevation against 2,2 diphenyl-1-picrylhydrazyl (DPPH) and superoxide radicals in comparison to MCG. In addition, total phenolic content of SCG was significantly elevated (p < 0.001), thereby suggesting that the composition of garlic storage constituents varies with the number of cloves present. CCl4-induced hepatotoxicity demonstrated histological changes including severe damage in the structure of liver tissues which correlated well to oxidative stress levels. Simultaneously, administration of SCG resulted in a significant reduction of serum alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TB) levels in addition to improvement in some histological parameters. Low levels of lipid peroxidation (malondialdehyde, MDA) (p < 0.001), along with a huge reduction in peroxidase (POx) (p < 0.001) revealed protection against oxidative toxicity in the liver homogenate. Higher levels of catalase (CAT) (p < 0.001) and superoxide dismutase (SOD) (p < 0.05) when compared to the MCG test (TM) group indicates that removal of H2O2 is based on CAT activity in SCG test (TS) group rather than the POx activity demonstrated in the former group. CONCLUSION: The present study indicates that SCG possesses more protective ability than MCG against CCl4-induced liver injury and might be an effective alternative medicine against acute oxidative liver toxicity. PMID- 28818067 TI - A longitudinal study of the implementation experiences of the Australian National Disability Insurance Scheme: investigating transformative policy change. AB - BACKGROUND: Internationally there has been a growth in the use of publicly funded service markets as a mechanism to deliver health and social services. This has accompanied the emergence of 'self-directed care' in a number of different policy areas including disability and aged care - often referred to as 'personalisation' (Giaimo and Manow, Comp. Pol Stud 32:967-1000, 1999; Needham, Public Money Manage 30:136-8, 2010; [Hood], [The Idea of Joined-up Government: A Historical Perspective], [2005]; Klijn and Koppenjan, Public Manage 2:437-54, 2000, Greener, Policy Polit 36:93-108, 2008). These reforms are underpinned by an idea that individuals should be placed in control of their own service needs, given funding directly by government and encouraged to exercise choice and control through purchasing their own services. A major challenge for governments in charge of these reforms is determining the best way to structure and govern emerging service markets markets. Given the growing international embrace of market-based reform mechanisms to provide essential services to citizens, finding ways to ensure they promote, and not diminish, people's health and wellbeing is vital. METHODS: The Australian National Disability Insurance Scheme (NDIS) is Australia's first national approach to the use of personalised budgets. The program of research outlined in this paper brings together streams from a range of different studies in order to investigate the implementation of the NDIS longitudinally across different administrative levels of government, service providers and scheme participants. CONCLUSION: This programme of research will make a contribution to our understanding of the Australian scheme and how individualised funding operates within this context, but will also generate much needed evidence that will have relevance to other jurisdictions and help fill a gap in the evidence base. PMID- 28818068 TI - Erratum to: A governance model for integrated primary/secondary care for the health-reforming first world - results of a systematic review. PMID- 28818069 TI - Path modeling of knowledge, attitude and practice toward palliative care consultation service among Taiwanese nursing staff: a cross-sectional study. AB - BACKGROUND: The Taiwanese government has promoted palliative care consultation services (PCCS) to support terminally ill patients in acute ward settings to receive palliative care since 2005. Such an intervention can enhance the quality of life and dignity of terminally ill patients. However, research focusing on the relationship between the knowledge, attitude and practice of a PCCS using path modelling in nursing staff is limited. Therefore, the aim of this study was to elucidate the effect of path modeling on the knowledge, attitude and practice toward PCCS in Taiwanese nursing staff. METHODS: This was a cross-sectional, descriptive study design using convenience sampling. Data collected included demographics, knowledge, attitude and practice as measured by the PCCS inventory (KAP-PCCSI). Two hundred and eighty-four nursing staff from a medical center in northern Taiwan participated in the study in 2013. We performed descriptive statistics, regression analysis, and path modeling using SPSS 19.0 and set p < 0.05 as the statistical significance threshold. RESULTS: The results showed that the identical factor significantly associated with knowledge, attitude, and practice toward PCCS among nurses was the frequency of contact with PCCS. In addition, higher level of knowledge toward PCCS was associated with working in haematology and oncology wards, and participation in education related to palliative care. A more positive attitude toward PCCS was associated with working in a haematology and oncology ward, and experience of friends or relatives dying. Higher level of practice toward PCCS was associated with nurses who participated in education related to palliative care. In the path modeling, we found that holders of a master's degree indirectly positive affected practice toward PCCS. Possession of a bachelor degree or above, being single, working within a haematology and oncology ward, and frequency of contact with PCCS positively affected practice toward PCCS. CONCLUSIONS: Based on this study, it is proposed that consultation with PCCS has a positive impact on the care of terminally ill patients. Encouragement of staff to undertake further education can improve the practice of ward staff providing palliative care. PMID- 28818070 TI - rs1859168 A > C polymorphism regulates HOTTIP expression and reduces risk of pancreatic cancer in a Chinese population. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) are aberrantly expressed in many types of human cancer including pancreatic cancer (PC) and correlated with tumorigenesis and cancer prognosis, whereas knowledge about regulatory mechanism of lncRNA expression is few known. This study aimed to explore whether polymorphisms in lncRNAs genes are associated with PC susceptibility by affecting its expression. METHODS: We first genotyped three common single-nucleotide polymorphisms (SNPs) of lncRNA genes (HOTTIP rs1859168, HOTAIR rs4759314, and H19 rs217727) in 416 paired PC patients and controls, and then validated the results in another 505 paired PC patients and controls. The genotype-phenotype correlation was examined in 50 PC tissue samples with different genotypes as well as by luciferase reporter assay. RESULTS: In the discovery set, only the HOTTIP rs1859168 A > C showed to be significantly associated with a reduced PC risk (CC vs AA: odds ratio (OR) = 0.71, 95% confidence interval (95%CI) = 0.57-0.88, P = 0.002; recessive model: adjusted OR = 0.51, 95%CI = 0.38-0.68, P < 0.001; additive model: adjusted OR = 0.67, 95%CI = 0.51-0.82, P < 0.001). The results in validation set and pooled population also indicated that the C allele of HOTTIP rs1859168 could significantly decrease the risk of PC. In addition, the genotype phenotype association analysis suggested that HOTTIP expression level was significantly lower in PC samples with CC genotype than that in samples with AA and AC genotype. Furthermore, the C allele of HOTTIP rs1859168 could significantly decrease the relative luciferase activity compared to the A allele in three PC cell lines. CONCLUSIONS: The current findings provided evidence that the functional rs1859168 A > C polymorphism may decrease the PC risk by down regulating the HOTTIP expression. PMID- 28818071 TI - Completeness of malaria indicator data reporting via the District Health Information Software 2 in Kenya, 2011-2015. AB - BACKGROUND: Health facility-based data reported through routine health information systems form the primary data source for programmatic monitoring and evaluation in most developing countries. The adoption of District Health Information Software (DHIS2) has contributed to improved availability of routine health facility-based data in many low-income countries. An assessment of malaria indicators data reported by health facilities in Kenya during the first 5 years of implementation of DHIS2, from January 2011 to December 2015, was conducted. METHODS: Data on 19 malaria indicators reported monthly by health facilities were extracted from the online Kenya DHIS2 database. Completeness of reporting was analysed for each of the 19 malaria indicators and expressed as the percentage of data values actually reported over the expected number; all health facilities were expected to report data for each indicator for all 12 months in a year. RESULTS: Malaria indicators data were analysed for 6235 public and 3143 private health facilities. Between 2011 and 2015, completeness of reporting in the public sector increased significantly for confirmed malaria cases across all age categories (26.5-41.9%, p < 0.0001, in children aged <5 years; 30.6-51.4%, p < 0.0001, in persons aged >=5 years). Completeness of reporting of new antenatal care (ANC) clients increased from 53.7 to 70.5%, p < 0.0001). Completeness of reporting of intermittent preventive treatment in pregnancy (IPTp) decreased from 64.8 to 53.7%, p < 0.0001 for dose 1 and from 64.6 to 53.4%, p < 0.0001 for dose 2. Data on malaria tests performed and test results were not available in DHIS2 from 2011 to 2014. In 2015, sparse data on microscopy (11.5% for children aged <5 years; 11.8% for persons aged >=5 years) and malaria rapid diagnostic tests (RDTs) (8.1% for all ages) were reported. In the private sector, completeness of reporting increased significantly for confirmed malaria cases across all age categories (16.7-23.1%, p < 0.0001, in children aged <5 years; 19.4-28.6%, p < 0.0001, in persons aged >=5 years). Completeness of reporting also improved for new ANC clients (16.2-23.6%, p < 0.0001), and for IPTp doses 1 and 2 (16.6-20.2%, p < 0.0001 and 15.5-20.5%, p < 0.0001, respectively). In 2015, less than 3% of data values for malaria tests performed were reported in DHIS2 from the private sector. CONCLUSIONS: There have been sustained improvements in the completeness of data reported for most key malaria indicators since the adoption of DHIS2 in Kenya in 2011. However, major data gaps were identified for the malaria-test indicator and overall low reporting across all indicators from private health facilities. A package of proven DHIS2 implementation interventions and performance-based incentives should be considered to improve private-sector data reporting. PMID- 28818072 TI - Use of hospital-based health care services among children aged 1 through 9 years who were born very preterm - a population-based study. AB - BACKGROUND: Very preterm (VPT) children, with a birth weight below 1500 g or delivered before 32 weeks of gestational age, are at increased risk of poorer long-term health outcomes and higher rates of hospitalization in childhood. However, considerable variation exists in the need for in-hospital care within this population. We assessed the utilization and distribution of hospital-based care from ages 1 through 9 years for a nationwide population. METHODS: This was a population-based cohort of VPT children born in the period 2001-2009. We evaluated their utilization of hospital care in 2008-2010, when aged 1-9 years old. Outcomes were the incidence of hospital admissions and outpatient visits. We used Poisson regression models with multiple imputation of missing data. RESULTS: Children born VPT had more hospital admissions compared with the general population of children aged 1-9 years. The rates of hospital admissions and outpatient visits were strongly related to clinical characteristics of the child at birth and age at admission/outpatient visit but to only a variable and minor degree to characteristics pertaining to maternal health, the sociodemographic factors, and geographical proximity to hospital services. CONCLUSIONS: Prior to this study, hospital utilization during the period 5-9 years old has been poorly documented. We found that excess utilization of hospital resources on average declines with increasing age. We also noted substantial differences in the use of hospital care across age groups and clinical factors for VPT children. The added information from the health status of mothers, social background, and geographic measures of access was limited. PMID- 28818074 TI - Erratum to: on the plausibility of socioeconomic mortality estimates derived from linked data: a demographic approach. PMID- 28818073 TI - Role of the lncRNA ABHD11-AS1 in the tumorigenesis and progression of epithelial ovarian cancer through targeted regulation of RhoC. AB - BACKGROUND: There is increasing evidence in support of the role of lncRNAs in tumor cell proliferation, differentiation and apoptosis. METHODS: We examined the expression of the lncRNA ABHD11-AS1 in epithelial ovarian cancer (EOC) tissues and normal ovarian tissues by real-time quantitative PCR (qRT-PCR). After inducing ABHD11-AS1 downregulation by small interfering RNA (siRNA) or ABHD11-AS1 overexpression by plasmid transfection, we examined the EOC cell phenotypes and expression of related molecules. RESULTS: Expression of the lncRNA ABHD11-AS1 in EOC tissues was higher than that in normal ovarian tissue. It was positively associated with the tumor stage (stage I/II vs. stage III/IV), and it was lower in the well-differentiated group than in the poorly/moderately differentiated group. Overexpression of ABHD11-AS1 in the ovarian cancer cell lines A2780 and OVCAR3 promoted ovarian cancer cell proliferation, invasion and migration, and inhibited apoptosis. Silencing of ABHD11-AS1 had the opposite effect. Subcutaneous injection of tumor cells in nude mice showed that ABHD11-AS1 could significantly promote tumor growth. In addition, intraperitoneal injection of tumor cells in the nude mice resulted in an increase in the metastatic ability of the tumor. Further, overexpression of ABHD11-AS1 upregulated the expression of RhoC and its downstream molecules P70s6k, MMP2 and BCL-xL. Silencing of ABHD11 AS1 had the opposite effect. The RNA pull-down assay showed that ABHD11-AS1 can combine directly with RhoC. Silencing of RhoC was found to inhibit the cancer promoting effects of lncRNA ABHD11-AS1. Thus, it seems that RhoC is a major target of the lncRNA ABHD11-AS1. CONCLUSIONS: This is the first study to demonstrate the role of RhoC in the tumor-promoting effects of the lncRNA ABHD11 AS1. The present findings shed light on new therapeutic targets for ovarian cancer treatment. PMID- 28818075 TI - Perspectives of basic wheelchair users on improving their access to wheelchair services in Kenya and Philippines: a qualitative study. AB - BACKGROUND: The United Nations has called for countries to improve access to mobility devices when needed. The World Health Organization has published guidelines on the provision of manual wheelchairs in less-resourced settings. Yet little is known about the extent to which appropriate wheelchairs are available and provided according to international guidelines. This study's purpose was to describe wheelchair users' experiences receiving services and acquiring wheelchair skills in urban and peri-urban areas of Kenya and the Philippines. METHODS: Local researchers in Nairobi and Manila interviewed 48 adult basic wheelchair users, with even distribution of those who had and had not received wheelchair services along with their wheelchair. Recordings were transcribed in the local language and translated into English. The study team coded transcripts for predetermined and emergent themes, using Atlas-ti software. A qualitative content analysis approach was taken with the WHO service delivery process as an organizing framework. RESULTS: Wheelchair users frequently described past experiences with ill-fitting wheelchairs and little formal training to use wheelchairs effectively. Through exposure to multiple wheelchairs and self advocacy, they learned to select wheelchairs suitable for their needs. Maintenance and repair services were often in short supply. Participants attributed shorter duration of wheelchair use to lack of repair. Peer support networks emerged as an important source of knowledge, resources and emotional support. Most participants acknowledged that they received wheelchairs that would have been difficult or impossible for them to pay for, and despite challenges, they were grateful to have some means of mobility. Four themes emerged as critical for understanding the implementation of wheelchair services: barriers in the physical environment, the need for having multiple chairs to improve access, perceived social stigma, and the importance of peer support. CONCLUSIONS: Interventions are needed to provide wheelchairs services efficiently, at scale, in an environment facilitating physical access and peer support, and reduced social stigma. TRIAL REGISTRATION: Not applicable since this was a descriptive study. PMID- 28818076 TI - Extensive protein hydrolyzation is indispensable to prevent IgE-mediated poultry allergen recognition in dogs and cats. AB - BACKGROUND: The central premise for the commercialization of diets with hydrolyzed ingredients is that the small-sized digested peptides would be unable to crosslink allergen-specific IgE at the surface of tissue mast cells and induce their degranulation. Evidence for the validity of this concept to diagnose food allergies in dogs and cats is limited, however. Our objectives were to study the recognition of standard and variably hydrolyzed poultry extracts by sera from dogs and cats with elevated chicken-specific serum IgE. RESULTS: Forty sera from dogs and 40 from cats with undetectable, low, medium or high serum levels of chicken-specific IgE were tested by ELISA on plates coated with the positive controls chicken, duck and turkey meat extracts and the negative controls beef meat (dogs) or wheat (cats). Plates were also coated with a non-hydrolyzed chicken meal, and mildly- or extensively-hydrolyzed poultry feather extracts. The frequencies of dogs with positive IgE against the various extracts were: chicken meat: 100%, duck and turkey meats: 97%, beef meat: 3%, non-hydrolyzed chicken meal: 73%, mildly-hydrolyzed poultry feathers: 37% and extensively-hydrolyzed poultry feathers: 0%. For cats, these respective percentages were (with wheat replacing beef as a negative control): 100, 84, 97, 7, 7, 0 and 0%. To detect any allergenic cross-reactivity between poultry meat-based and feather hydrolysate derived extracts, an IgE ELISA inhibition was also done. Ten canine sera with the highest level of anti-poultry IgE in the previous experiment were incubated overnight with a previously optimized 50 MUg amount of each of the extracts used above. We performed ELISA on plates coated with chicken, duck or turkey meats with or without inhibitors. The median inhibition percentages after incubation with the non-hydrolyzed chicken meal were ~22%, with the mildly-hydrolyzed poultry feathers: 14-22%, and those with the extensively-hydrolyzed poultry feathers: 5 to 10%; the last inhibition level was similar to that of the beef meat negative control. CONCLUSIONS: Altogether, these results suggest that an extensive-but not partial-hydrolyzation of the poultry feather extract is necessary to prevent the recognition of allergenic epitopes by poultry-specific IgE. PMID- 28818077 TI - Evaluation of piperonyl butoxide in enhancing the efficacy of pyrethroid insecticides against resistant Anopheles gambiae s.l. in Ghana. AB - BACKGROUND: Malaria vector control methods involving the use of pyrethroids remain the strategies being used against malaria vectors in Ghana. These methods include the use of long-lasting insecticidal nets and indoor residual spraying in many areas in Ghana. However, there is evidence that pyrethroid resistance is widespread in many areas in Ghana. Synergists have been shown to be useful in inhibiting the enzymes that are responsible for the development of resistance and hence enhance the insecticide susceptibility of Anopheles gambiae sensu lato (s.l.) in many areas. The present study investigated the effect of piperonyl butoxide (PBO) on the susceptibility status of An. gambiae s.l. across some sentinel sites in Ghana. METHODS: Three to five day old An. gambiae s.l. reared from larvae were used in WHO susceptibility tube assays. Batches of 20-25 female adult An. gambiae s.l. were exposed simultaneously to the insecticide alone and to the PBO + insecticide. The knock down rate after 60 min and mortality at 24 h were recorded. RESULTS: Deltamethrin and permethrin resistance of An. gambiae s.l. was observed in all the sites in 2015 and 2016. The mortality after 24 h post exposure for deltamethrin ranged from 16.3% in Weija to 82.3% in Kade, whereas that for permethrin ranged from 3.8% in Gomoa Obuasi to 91.3% in Prestea. A significant increase in susceptibility to deltamethrin and less to permethrin was observed during both 2015 and 2016 years in most of the sites when An. gambiae s.l. mosquitoes were pre-exposed to PBO. CONCLUSION: Findings from this study showed that the use of PBO significantly enhanced the susceptibility of An. gambiae s.l. mosquitoes in most of the sentinel sites. It is recommended that vector control strategies incorporating PBO as a synergist can be effective in killing mosquitoes in the presence of deltamethrin and permethrin resistance. PMID- 28818078 TI - Development of a silicon limitation inducible expression system for recombinant protein production in the centric diatoms Thalassiosira pseudonana and Cyclotella cryptica. AB - BACKGROUND: An inducible promoter for recombinant protein expression provides substantial benefits because under induction conditions cellular energy and metabolic capability can be directed into protein synthesis. The most widely used inducible promoter for diatoms is for nitrate reductase, however, nitrogen metabolism is tied into diverse aspects of cellular function, and the induction response is not necessarily robust. Silicon limitation offers a means to eliminate energy and metabolic flux into cell division processes, with little other detrimental effect on cellular function, and a protein expression system that works under those conditions could be advantageous. RESULTS: In this study, we evaluate a number of promoters for recombinant protein expression induced by silicon limitation and repressed by the presence of silicon in the diatoms Thalassiosira pseudonana and Cyclotella cryptica. In addition to silicon limitation, we describe additional strategies to elevate recombinant protein expression level, including inclusion of the 5' fragment of the coding region of the native gene and reducing carbon flow into ancillary processes of pigment synthesis and formation of photosynthetic storage products. We achieved yields of eGFP to 1.8% of total soluble protein in C. cryptica, which is about 3.6-fold higher than that obtained with chloroplast expression and ninefold higher than nuclear expression in another well-established algal system. CONCLUSIONS: Our studies demonstrate that the combination of inducible promoter and other strategies can result in robust expression of recombinant protein in a nuclear based expression system in diatoms under silicon limited conditions, separating the protein expression regime from growth processes and improving overall recombinant protein yields. PMID- 28818079 TI - Which physical and social environmental factors are most important for adolescents' cycling for transport? An experimental study using manipulated photographs. AB - BACKGROUND: Ecological models emphasize that cycling for transport is determined by an interplay between individual, physical and social environmental factors. The current study investigated (a) which physical and social environmental factors determine adolescents' preferences towards cycling for transport and (b) which individual, physical and social environmental factors are associated with their intention to actually cycle for transport. METHODS: An online questionnaire consisting of questions on individual and social environmental variables, and 15 choice-based conjoint tasks with manipulated photographs was completed by 882 adolescents (55.3% male; 13.9 +/- 1.6 years). Within the choice tasks, participants were asked to indicate which of two situations they would prefer to cycle to a friend's house. The manipulated photographs were all modified versions of one semi-urban street which differed in the following physical micro environmental attributes (separation of cycle path, evenness of cycle path, speed limit, speed bump, traffic density, amount of vegetation and maintenance). In addition, each photograph was accompanied by two sentences which described varying cycling distances and co-participation in cycling (i.e. cycling alone or with a friend). After each choice task participants were also asked if they would actually cycle in that situation in real life (i.e. intention). Hierarchical Bayes analyses were performed to calculate relative importances and part-worth utilities of environmental attributes. Logistic regression analyses were performed to investigate which individual, physical and social environmental factors were associated with adolescents' intention to actually cycle for transport. RESULTS: Adolescents' preference to cycle for transport was predominantly determined by separation of cycle path, followed by shorter cycling distance and co-participation in cycling. Higher preferences were observed for a separation between the cycle path and motorized traffic by means of a hedge versus a curb, versus a marked line. Similar findings were observed for intention to cycle. Furthermore, evenness of the cycle path and general maintenance of the street were also of considerable importance among adolescents, but to a lesser extent. CONCLUSIONS: Results of this experimental study justify investment by local governments in well-separated cycling infrastructure, which seemed to be more important than cycling distance and the social environment. PMID- 28818080 TI - Standardized, systemic phenotypic analysis reveals kidney dysfunction as main alteration of Kctd1 I27N mutant mice. AB - BACKGROUND: Increased levels of blood plasma urea were used as phenotypic parameter for establishing novel mouse models for kidney diseases on the genetic background of C3H inbred mice in the phenotype-driven Munich ENU mouse mutagenesis project. The phenotypically dominant mutant line HST014 was established and further analyzed. METHODS: Analysis of the causative mutation as well as the standardized, systemic phenotypic analysis of the mutant line was carried out. RESULTS: The causative mutation was detected in the potassium channel tetramerization domain containing 1 (Kctd1) gene which leads to the amino acid exchange Kctd1 I27N thereby affecting the functional BTB domain of the protein. This line is the first mouse model harboring a Kctd1 mutation. Kctd1 I27N homozygous mutant mice die perinatally. Standardized, systemic phenotypic analysis of Kctd1 I27N heterozygous mutants was carried out in the German Mouse Clinic (GMC). Systematic morphological investigation of the external physical appearance did not detect the specific alterations that are described in KCTD1 mutant human patients affected by the scalp-ear-nipple (SEN) syndrome. The main pathological phenotype of the Kctd1 I27N heterozygous mutant mice consists of kidney dysfunction and secondary effects thereof, without gross additional primary alterations in the other phenotypic parameters analyzed. Genome-wide transcriptome profiling analysis at the age of 4 months revealed about 100 differentially expressed genes (DEGs) in kidneys of Kctd1 I27N heterozygous mutants as compared to wild-type controls. CONCLUSIONS: In summary, the main alteration of the Kctd1 I27N heterozygous mutants consists in kidney dysfunction. Additional analyses in 9-21 week-old heterozygous mutants revealed only few minor effects. PMID- 28818081 TI - What makes gouty inflammation so variable? AB - Acute gout arthritis flares contribute dominantly to gout-specific impaired health-related quality of life, representing a progressively increasing public health problem. Flares can be complex and expensive to treat, partly due to the frequent comorbidities. Unmet needs in gout management are more pressing given the markedly increasing gout flare hospital admission rates. In addition, chronic gouty arthritis can cause joint damage and functional impairment. This review addresses new knowledge on the basis for the marked, inherent variability of responses to deposited urate crystals, including the unpredictable and self limited aspects of many gout flares. Specific topics reviewed include how innate immunity and two-signal inflammasome activation intersect with diet, metabolism, nutritional biosensing, the microbiome, and the phagocyte cytoskeleton and cell fate. The paper discusses the roles of endogenous constitutive regulators of inflammation, including certain nutritional biosensors, and emerging genetic and epigenetic factors. Recent advances in the basis of variability in responses to urate crystals in gout provide information about inflammatory arthritis, and have identified potential new targets and strategies for anti-inflammatory prevention and treatment of gouty arthritis. PMID- 28818082 TI - Comparing chronic condition rates using ICD-9 and ICD-10 in VA patients FY2014 2016. AB - BACKGROUND: Management of patients with chronic conditions relies on accurate measurement. It is unknown how transition to the ICD-10 coding system affected reporting of chronic condition rates over time. We measured chronic condition rates 2 years before and 1 year after the transition to ICD-10 to examine changes in prevalence rates and potential measurement issues in the Veterans Affairs (VA) health care system. METHODS: We developed definitions for 34 chronic conditions using ICD-9 and ICD-10 codes and compared the prevalence rates of these conditions from FY2014 to 2016 in a 20% random sample (1.0 million) of all VA patients. In each year we estimated the total number of patients diagnosed with the conditions. We regressed each condition on an indicator of ICD-10 (versus ICD 9) measurement to obtain the odds ratio associated with ICD-10. RESULTS: Condition prevalence estimates were similar for most conditions before and after ICD-10 transition. We found significant changes in a few exceptions. Alzheimer's disease and spinal cord injury had more than twice the odds of being measured with ICD-10 compared to ICD-9. HIV/AIDS had one-third the odds, and arthritis had half the odds of being measured with ICD-10. Alcohol dependence and tobacco/nicotine dependence had half the odds of being measured in ICD-10. CONCLUSION: Many chronic condition rates were consistent from FY14-16, and there did not appear to be widespread undercoding of conditions after ICD-10 transition. It is unknown whether increased sensitivity or undercoding led to decreases in mental health conditions. PMID- 28818083 TI - Optimization of the biotechnological production of a novel class of anti-MRSA antibiotics from Chitinophaga sancti. AB - BACKGROUND: Recently, the discovery of the elansolids, a group of macrolides, was reported. The molecules show activity against methicillin-resistant Staphylococcus aureus as well as other gram-positive organisms. This fact renders those substances a promising starting point for future chemical development. The active atropisomers A1/A2 are formed by macrolactonization of the biosynthesis product A3 but are prone to ring opening and subsequent formation of several unwanted side products. Recently it could be shown that addition of different nucleophiles to culture extracts of Chitinophaga sancti enable the formation of new stable elansolid derivatives. Furthermore, addition of such a nucleophile directly into the culture led exclusively to formation of a single active elansolid derivative. Due to low product yields, methods for production of gram amounts of these molecules have to be established to enable further development of this promising compound class. RESULTS: Production of elansolid A2 by C. sancti was enabled using a synthetic medium with sucrose as carbon source to a final concentration of 18.9 mg L-1. A fed-batch fermentation was ensued that resulted in an elansolid A2 concentration of 55.3 mg L-1. When using glucose as carbon source in a fed-batch fermentation only 34.4 mg L-1 elansolid A2 but 223.1 mg L-1 elansolid C1 were produced. This finding was not unexpected since elansolids A1/A2 and A3 have been reported to easily react with nucleophiles like anthranilic acid, a precursor of tryptophan biosynthesis. Due to the fact that nucleophiles can be incorporated in vivo, a fed-batch cultivation under identical conditions, with addition of anthranilic acid was carried out and lead to almost exclusive formation of elansolid C1 (257.5 mg L-1). CONCLUSION: Reproducible elansolid A2 and C1 production is feasible in different synthetic media at relatively high concentrations that will allow further investigation and semi synthetic optimization. The feeding of anthranilic acid enables the exclusive production of the stable elansolid derivative C1, which reduces product loss by unspecific reactions and eases downstream processing. This derivative shows activity in the same range as the elansolids A1/A2. Hence, the method can possibly serve as a model-process for incorporation of other nucleophiles and biotechnological production of specifically designed molecules. PMID- 28818084 TI - Do the venous blood samples replicate malaria parasite densities found in capillary blood? A field study performed in naturally-infected asymptomatic children in Cameroon. AB - BACKGROUND: The measure of new drug- or vaccine-based approaches for malaria control is based on direct membrane feeding assays (DMFAs) where gametocyte infected blood samples are offered to mosquitoes through an artificial feeder system. Gametocyte donors are identified by the microscopic detection and quantification of malaria blood stages on blood films prepared using either capillary or venous blood. However, parasites are known to sequester in the microvasculature and this phenomenon may alter accurate detection of parasites in blood films. The blood source may then impact the success of mosquito feeding experiments and investigations are needed for the implementation of DMFAs under natural conditions. METHODS: Thick blood smears were prepared from blood obtained from asymptomatic children attending primary schools in the vicinity of Mfou (Cameroon) over four transmission seasons. Parasite densities were determined microscopically from capillary and venous blood for 137 naturally-infected gametocyte carriers. The effect of the blood source on gametocyte and asexual stage densities was then assessed by fitting cumulative link mixed models (CLMM). DMFAs were performed to compare the infectiousness of gametocytes from the different blood sources to mosquitoes. RESULTS: Prevalence of Plasmodium falciparum asexual stages among asymptomatic children aged from 4 to 15 years was 51.8% (2116/4087). The overall prevalence of P. falciparum gametocyte carriage was 8.9% and varied from one school to another. No difference in the density of gametocyte and asexual stages was found between capillary and venous blood. Attempts to perform DMFAs with capillary blood failed. CONCLUSIONS: Plasmodium falciparum malaria parasite densities do not differ between capillary and venous blood in asymptomatic subjects for both gametocyte and trophozoite stages. This finding suggests that the blood source should not interfere with transmission efficiency in DMFAs. PMID- 28818085 TI - A rare case of acute toxoplasmosis in a stray dog due to infection of T. gondii clonal type I: public health concern in urban settings with stray animals? AB - BACKGROUND: Typing of Toxoplasma gondii strains is important in epidemiological surveys, to understand the distribution and virulence of different clones of the parasite among human and animal populations. Stray dogs can be consider sentinel animals for contaminated environments playing an important but probably under- evaluated role in the epidemiology of T. gondii. We reported a rare case of acute toxoplasmosis in a stray dog due to clonal type I infection. The clonal type I, sporadic in Europe, is frequently associated with severe toxoplasmosis in humans and the control of its circulation is particularly relevant for public health. The symptomatology suggested a potential infection with the high similar parasite Neospora caninum but differential diagnosis showed that only T. gondii was involved highlighting the importance of multiple diagnostic methods beyond the clinical signs. CASE PRESENTATION: A female stray dog approximately six-month of age presented muscular atrophy of the femoral region and hyperextension of hind limbs. Body condition score (BCS) was 20% below ideal weight, ribs had almost no fat and the sensor state was depressed. Haematological values were normal and the dog did not show any neurological abnormalities. Serological analysis showed a positive response for T. gondii immunoglobulin G (IgG) antibodies and exclude N. caninum infection. To confirm T. gondii infection, a muscle biopsy was performed and genomic DNA was extracted. PCR analysis resulted positive to T. gondii and strain genotyping reveals clonal type I infection. The dog recovered after 4 weeks of treatment with clindamycin hydrochloride and aquatic physiotherapy. CONCLUSIONS: Our study reports a rare and severe case of T. gondii clonal type I infection in a stray dog feeding in garbage containers. The data confirm the importance of an in vivo early diagnosis for toxoplasmosis in dog. Clinical signs are often related to specific T. gondii genotype and parasite genotyping is important in the epidemiological survey of toxoplasmosis in public health. The detection of parasitic DNA in the tissue could be an useful diagnostic method in facilitating early treatment of the disease, which is important for a timely clinical recovery. PMID- 28818086 TI - Mediterranean diet, folic acid, and neural tube defects. AB - The Mediterranean diet has been for a very long time the basis of food habits all over the countries of the Mediterranean basin, originally founded on rural models and low consumption of meat products and high-fat/high-processed foods. However, in the modern era, the traditional Mediterranean diet pattern is now progressively eroding due to the widespread dissemination of the Western-type economy, life-style, technology-driven culture, as well as the globalisation of food production, availability and consumption, with consequent homogenisation of food culture and behaviours. This transition process may affect many situations, including pregnancy and offspring's health. The problem of the diet during pregnancy and the proper intake of nutrients are nowadays a very current topic, arousing much debate. The Mediterranean dietary pattern, in particular, has been associated with the highest risk reduction of major congenital anomalies, like the heterogeneous class of neural tube defects (NTDs). NTDs constitute a major health burden (0.5-2/1000 pregnancies worldwide) and still remain a preventable cause of still birth, neonatal and infant death, or significant lifelong disabilities. Many studies support the finding that appropriate folate levels during pregnancy may confer protection against these diseases. In 1991 one randomised controlled trial (RCT) demonstrated for the first time that periconceptional supplementation of folic acid is able to prevent the recurrence of NTDs, finding confirmed by many other subsequent studies. Anyway, the high rate of unplanned/unintended pregnancies and births and other issues hindering the achievement of adequate folate levels in women in childbearing age, induced the US government and many other countries to institute mandatory food fortification with folic acid. The actual strategy adopted by European Countries (including Italy) suggests that women take 0,4 mg folic acid/die before conception. The main question is which intervention, between folic acid supplementation, foods fortification or both, linked to a healthy life-style and diet pattern may represent the best method in preventing NTDs. The aim of this review is to describe the actual situation in NTDs prevention, with a special attention to the Italiancontext concerning this delicate and controversial subject. PMID- 28818087 TI - Bugs, drugs, and HIV: the role of the vaginal microbiome in HIV risk and antiretroviral efficacy for HIV prevention. PMID- 28818088 TI - Assessment of the effect of left atrial cryoablation enhanced by ganglionated plexi ablation in the treatment of atrial fibrillation in patients undergoing open heart surgery. AB - BACKGROUND: The aim of our study was to investigate, whether enhancement of left atrial cryoablation by ablation of the autonomic nervous system of left atrium leads to influencing the outcomes of surgical treatment of atrial fibrillation in patients with structural heart disease undergoing open-heart surgery. METHODS: The observed patient file consisted of 100 patients, who have undergone a combined open-heart surgery at our department between July 2012 and December 2014. The patients were indicated for the surgical procedure due to structural heart disease, and suffered from paroxysmal, persistent, or long-standing persistent atrial fibrillation. In all cases, left atrial cryoablation was performed in the extent of isolation of pulmonary veins, box lesion, connecting lesion with mitral annulus, amputation of the left atrial appendage and connecting lesion of the appendage base with left pulmonary veins. Furthermore, 35 of the patients underwent mapping and radiofrequency ablation of ganglionated plexi, together with discision and ablation of the ligament of Marshall (Group GP). A control group was consisted of 65 patients without ganglionated plexi intervention (Group LA). The main primary outcome was establishment and duration of sinus rhythm in the course of one-year follow-up. RESULTS: Evaluation of the number of patients with a normal sinus rhythm in per cent has shown comparable values in both groups (Group GP - 93.75%, Group LA - 86.67%, p = 0.485); comparable results were also observed in patients with normal sinus rhythm without anti-arrhythmic treatment in the 12th month (Group GP - 50%, Group LA - 47%, p = 0.306). We have not observed any relation between the recurrence of atrial fibrillation and the presence of a mitral valve surgery, or between the presence of a mitral and tricuspid valves surgery and between the left atrial diameter > 50 mm. CONCLUSIONS: Enhancement of left atrial cryoablation by gangionated plexi ablation did not influence the outcomes of surgical ablation due to atrial fibrillation in our population in the course of 12-month follow-up. TRIAL REGISTRATION: The study was approved retrospectively by the Ethics Committee of the University Hospital Ostrava ( reference number 867/2016). PMID- 28818089 TI - Frequency of eating home cooked meals and potential benefits for diet and health: cross-sectional analysis of a population-based cohort study. AB - BACKGROUND: Reported associations between preparing and eating home cooked food, and both diet and health, are inconsistent. Most previous research has focused on preparing, rather than eating, home cooked food; used small, non-population based samples; and studied markers of nutrient intake, rather than overall diet quality or health. We aimed to assess whether frequency of consuming home cooked meals was cross-sectionally associated with diet quality and cardio-metabolic health. METHODS: We used baseline data from a United Kingdom population-based cohort study of adults aged 29 to 64 years (n = 11,396). Participants self-reported frequency of consuming home cooked main meals. Diet quality was assessed using the Mediterranean Diet Score, Dietary Approaches to Stop Hypertension (DASH) score, fruit and vegetable intake calculated from a 130-item food frequency questionnaire, and plasma vitamin C. Markers of cardio-metabolic health were researcher-measured body mass index (BMI), percentage body fat, haemoglobin A1c (HbA1c), cholesterol and hypertension. Differences across the three exposure categories were assessed using linear regression (diet variables) and logistic regression (health variables). RESULTS: Eating home cooked meals more frequently was associated with greater adherence to DASH and Mediterranean diets, greater fruit and vegetable intakes and higher plasma vitamin C, in adjusted models. Those eating home cooked meals more than five times, compared with less than three times per week, consumed 62.3 g more fruit (99% CI 43.2 to 81.5) and 97.8 g more vegetables (99% CI 84.4 to 111.2) daily. More frequent consumption of home cooked meals was associated with greater likelihood of having normal range BMI and normal percentage body fat. Associations with HbA1c, cholesterol and hypertension were not significant in adjusted models. Those consuming home cooked meals more than five times, compared with less than three times per week, were 28% less likely to have overweight BMI (99% CI 8 to 43%), and 24% less likely to have excess percentage body fat (99% CI 5 to 40%). CONCLUSIONS: In a large population-based cohort study, eating home cooked meals more frequently was associated with better dietary quality and lower adiposity. Further prospective research is required to identify whether consumption of home cooked meals has causal effects on diet and health. PMID- 28818090 TI - Trends in maternal and neonatal mortality in South Africa: a systematic review protocol. AB - BACKGROUND: Measuring and monitoring progress towards Millennium Development Goals (MDG) 4 and 5 requires valid and reliable estimates of maternal and neonatal mortality. In South Africa, there are conflicting reports on the estimates of maternal and neonatal mortality, derived from both direct and indirect estimation techniques. This study aims to systematically review the estimates made of maternal and neonatal mortality in the period from 1990 to 2015 in South Africa and determine trends over this period. METHODS: For the purpose of this review, searches for eligible studies will be conducted in MEDLINE, Africa-Wide Information, African Index Medicus, African Journals Online, Scopus, Web of Science and CINAHL databases. Searches will be restricted to articles written in English and presenting data covering the period between 1990 and 2015. Reference lists of retrieved articles will also be screened for additional publications. Three independent reviewers will be involved in the study selection, data extractions and achieving consensus. Study quality and risk of bias will thereafter be assessed by two authors. The results will be presented as rates/ratio with their corresponding 95% confidence/uncertainty intervals. DISCUSSION: Identifying trends in maternal and neonatal mortality will help to track progress in MDGs 4 and 5 and will serve in evaluating interventions focusing on reducing maternal and child mortality in the country. This study will, in particular, provide the context for understanding inconsistencies in reported estimates of maternal and neonatal mortality by considering estimation methods, data sources and definitions used. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016042769. PMID- 28818091 TI - Non-canonical soluble amyloid-beta aggregates and plaque buffering: controversies and future directions for target discovery in Alzheimer's disease. AB - The specific amyloid-beta (Abeta) species or other amyloid-precursor protein cleavage products that are most directly related to human neurodegeneration and clinical dementia of the Alzheimer's type have not yet been directly identified. Without a clear understanding of the most relevant species, it is difficult to determine whether therapeutic candidates successfully engaged the correct target(s). Here, we review some of the controversies regarding soluble Abeta aggregates (also termed oligomers, dimers, trimers, Abeta*56, amylospheroids, etc.) and propose experiments designed to move forward towards new therapeutic approaches. Specifically, we review the increasing evidence for the relevance of non-canonical forms of Abeta, the much more potent toxicity attributable to native species than to synthetic Abeta, and the evidence implicating the ratio of soluble Abeta aggregates to plaques in differentiating demented patients from non demented high Abeta plaque pathology controls. To move forward, we propose four related directions. 1) Narrowing the focus to species derived from human Alzheimer's disease (AD) brain tissue, as opposed to synthetic Abeta, cell culture-derived species, or species primarily present in animal models. 2) Careful study of differences between patients with dementia of the Alzheimer's type vs. non-demented controls with high Abeta plaque pathology. This will involve testing the hypothesis that, under some circumstances, plaques may buffer soluble toxic species, but later release them into the surrounding milieu. 3) Investigations of other protein constituents of soluble Abeta aggregates in addition to Abeta itself. Our initial data based on chemical cleavage experiments indicate that other proteins do appear to be part of the human brain soluble Abeta aggregates. 4) Multimodal experimental assessments of toxicity, including longer term effects on synapse loss, related deleterious cellular responses, and degeneration in human-derived neuron-like cells. Overall, the goal is to identify specific Abeta species, other amyloid precursor protein cleavage products, or other key proteins in aggregates present in human AD brains, less abundant in non demented high pathology control brains, and robustly toxic in a wide variety of relevant assays. These species themselves, the enzymatic or cellular processes involved in their production, and their routes of clearance would be highly relevant therapeutic targets for dementia of the Alzheimer's type. PMID- 28818092 TI - Associations of thyroid hormone serum levels with in-vivo Alzheimer's disease pathologies. AB - BACKGROUND: The present study investigated the relationships between thyroid hormone serum levels or thyroid-stimulating hormone (TSH) and two Alzheimer's disease (AD)-specific biomarkers, cerebral amyloid beta (Abeta) burden and glucose metabolism, in AD-signature brain regions in cognitively normal (CN) middle-aged and older individuals. METHODS: This study assessed 148 CN individuals who received comprehensive clinical and neuropsychological assessments that included 11C-Pittsburgh Compound B (PiB)-positron emission tomography (PET) scans, 18F-deoxyglucose (FDG)-PET scans, and the quantification of serum triiodothyronine (T3), free T3, free thyroxine (fT4), and TSH levels. RESULTS: All participants were clinically euthyroid. Independent negative associations were found between serum fT4 levels and global cerebral Abeta deposition after controlling for the effects of age, gender, and the apolipoprotein E epsilon4 (APOEepsilon4) genotype. Although serum TSH levels were not associated with global cerebral Abeta deposition, they had a significant negative association with glucose metabolism in the precuneus/posterior cingulate cortex after controlling for age, gender, and the APOEepsilon4 genotype. No other thyroid hormones exhibited relationships with either brain Abeta burden or glucose metabolism. CONCLUSIONS: Even in a clinical euthyroid state, low serum fT4 and high serum TSH levels appear to be differentially associated with AD specific brain changes. PMID- 28818093 TI - Case report: value of gene expression profiling in the diagnosis of atypical neuroblastoma. AB - BACKGROUND: Nephroblastoma and neuroblastoma belong to the most common abdominal malignancies in childhood. Similarities in the initial presentation may provide difficulties in distinguishing between these two entities, especially if unusual variations to prevalent patterns of disease manifestation occur. Because of the risk of tumor rupture, European protocols do not require biopsy for diagnosis, which leads to misdiagnosis in some cases. CASE PRESENTATION: We report on a 41/2 year-old girl with a renal tumor displaying radiological and laboratory characteristics supporting the diagnosis of nephroblastoma. Imaging studies showed tumor extension into the inferior vena cava and bilateral lung metastases while urine catecholamines and MIBG-scintigraphy were negative. Preoperative chemotherapy with vincristine, actinomycine D and adriamycin according to the SIOP2001/GPOH protocol for the treatment of nephroblastoma was initiated and followed by surgical tumor resection. Histopathology revealed an undifferentiated tumor with expression of neuronal markers, suggestive of neuroblastoma. MYCN amplification could not be detected. DNA-microarray analysis was performed using Affymetrix genechip human genome U133 plus 2.0 and artificial neural network analysis. Results were confirmed by multiplex RT-PCR. RESULTS: Principal component analysis using 84 genes showed that the patient sample was clearly clustering with neuroblastoma tumors. This was confirmed by hierarchical clustering of the multiplex RT-PCR data. The patient underwent treatment for high risk neuroblastoma comprising chemotherapy including cisplatin, etoposide, vindesine, dacarbacine, ifosfamide, vincristine, adriamycine and autologous stem cell transplantation followed by maintenance therapy with 13-cis retinoic acid (GPOH NB2004 High Risk Trial Protocol) and is in complete long-term remission. CONCLUSION: The use of gene expression profiling in an individual patient strongly contributed to clarification in a diagnostic dilemma which finally led to a change of diagnosis from nephroblastoma to neuroblastoma. This case underlines the importance of gene-expression profiling in the correct diagnosis of childhood neoplasms with atypical presentation to ensure that adequate treatment regimens can be applied. PMID- 28818094 TI - Radiotoxicity in robotic radiosurgery: proposing a new quality index for optimizing the treatment planning of brain metastases. AB - BACKGROUND: As irradiated brain volume at 12 Gy (V12) is a predictor for radionecrosis, the purpose of the study was to develop a model for Cyberknife (CK) plans that is able to predict the lowest achievable V12 at a given tumor size and prescription dose (PD), and to suggest a new quality index regarding V12 for optimizing the treatment planning of brain metastases. METHOD: In our model V12 was approximated as a spherical shell around the tumor volume. The radial distance between tumor surface and the 12 Gy isodose line was calculated using an approximation of the mean dose gradient in that area. Assuming a radially symmetrical irradiation from the upper half space, the dose distribution is given by the superposition of single fields. The dose profiles of a single field were derived by the measured off-center ratios (OCR) of the CK system. Using the calculated gradients of the sum dose profiles, minimal-V12 was estimated for different tumor sizes. The model calculation was tested using a phantom dataset and retrospectively applied on clinical cases. RESULTS: Our model allows the prediction of a best-case scenario for V12 at a given tumor size and PD which was confirmed by the results of the isocentric phantom plans. The results of the non isocentric phantom plans showed that an optimization of coverage caused an increase in V12. This was in accordance with the results of the retrospective analysis. V12 s of the clinical cases were on average twice that of the predicted model calculation. A good agreement was achieved for plans with an optimal conformity index (nCI). Re-planning of cases with high V12 showed that lower values could be reached by selecting smaller collimators and by allowing a larger number of total MU and more MU per beam. CONCLUSIONS: V12 is a main parameter for assessing plan quality in terms of radiotoxicity. The index f12 defined as the ratio of V12 from the actual plan with the evaluated V12 from our model describes the conformity of an optimally possible V12 and thus can be used as a new quality index for optimizing treatment plans. PMID- 28818095 TI - Frequency, distribution and immunologic nature of infusion reactions in subjects receiving pegloticase for chronic refractory gout. AB - BACKGROUND: To assess frequency and distribution of infusion reactions (IRs) in responders and nonresponders in randomized clinical trials (RCTs) of intravenous pegloticase and the utility of the National Institute of Allergy and Infectious Disease/Food and Allergy and Anaphylaxis Network (NIAID/FAAN) criteria for identifying anaphylaxis in subjects experiencing IRs. METHODS: IRs from two RCTs of pegloticase were evaluated and categorized as anaphylaxis, hypersensitivity, or other. Serum levels of tryptase and total hemolytic complement (CH50) were evaluated at the time of all IRs. Frequency of IRs by each category was evaluated in all subjects, responders or nonresponders to pegloticase. RESULTS: There were 113 IRs in 1695 infusions. Of the 113 IRs, 6 met criteria for anaphylaxis, 53 had one feature of anaphylaxis and were designated as "hypersensitivity", and 54 had no features and were designated "other". In subjects receiving pegloticase every 2 weeks (Q2w), a total of 852 infusions were administered and the IR frequency was 0.5% in responders and 9.7% in nonresponders. In subjects receiving pegloticase every 4 weeks (Q4w), a total of 846 infusions were given and the IR frequency was 2.6% in responders and 12.2% in nonresponders. There were no differences among the three categories of IRs with regard to clinical course or biochemical evidence of immune activation determined by CH50 or tryptase levels. CONCLUSION: IRs mostly occurred in nonresponders. NIAID/FAAN criteria for anaphylaxis did not identify pegloticase-related IRs as having a higher frequency of immune activation or a more severe course. The results are consistent with the conclusion that discontinuance of pegloticase if uric acid rises to >6 mg/dL will decrease the frequency of IRs. PMID- 28818097 TI - Two Drosophila model neurons can regenerate axons from the stump or from a converted dendrite, with feedback between the two sites. AB - BACKGROUND: After axon severing, neurons recover function by reinitiating axon outgrowth. New outgrowth often originates from the remaining axon stump. However, in many mammalian neurons, new axons initiate from a dendritic site when the axon is injured close to the cell body. METHODS: Drosophila sensory neurons are ideal for studying neuronal injury responses because they can be injured reproducibly in a variety of genetic backgrounds. In Drosophila, it has been shown that a complex sensory neuron, ddaC, can regenerate an axon from a stump, and a simple sensory neuron, ddaE, can regenerate an axon from a dendrite. To provide a more complete picture of axon regeneration in these cell types, we performed additional injury types. RESULTS: We found that ddaE neurons can initiate regeneration from an axon stump when a stump remains. We also showed that ddaC neurons regenerate from the dendrite when the axon is severed close to the cell body. We next demonstrated if a stump remains, new axons can originate from this site and a dendrite at the same time. Because cutting the axon close to the cell body results in growth of the new axon from a dendrite, and cutting further out may not, we asked whether the initial response in the cell body was similar after both types of injury. A transcriptional reporter for axon injury signaling, puc GFP, increased with similar timing and levels after proximal and distal axotomy. However, changes in dendritic microtubule polarity differed in response to the two types of injury, and were influenced by the presence of a scar at the distal axotomy site. CONCLUSIONS: We conclude that both ddaE and ddaC can regenerate axons either from the stump or a dendrite, and that there is some feedback between the two sites that modulates dendritic microtubule polarity. PMID- 28818096 TI - Immunohistochemical prognostic markers of esophageal squamous cell carcinoma: a systematic review. AB - BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy, with a high incidence and poor prognosis. In the past several decades, hundreds of proteins have been reported to be associated with the prognosis of ESCC, but none has been widely accepted to guide clinical care. This study aimed to identify proteins with great potential for predicting prognosis of ESCC. METHODS: We conducted a systematic review on immunohistochemical (IHC) prognostic markers of ESCC according to the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. Literature related to IHC prognostic markers of ESCC were searched from PubMed, Embase, Web of Science, and Cochrane Library until January 30th, 2017. The risk of bias of these original studies was evaluated using the Quality in Prognosis Studies (QUIPS) tool. RESULTS: We identified 11 emerging IHC markers with reproducible results, including eight markers [epidermal growth factor receptor (EGFR), Cyclin D1, vascular endothelial growth factor (VEGF), Survivin, Podoplanin, Fascin, phosphorylated mammalian target of rapamycin (p-mTOR), and pyruvate kinase M2 (PKM2)] indicating unfavorable prognosis and 3 markers (P27, P16, and E-cadherin) indicating favorable prognosis of ESCC. CONCLUSION: Strong evidence supports that these 11 emerging IHC markers or their combinations may be useful in predicting prognosis and aiding personalized therapy decision-making for ESCC patients. PMID- 28818098 TI - Sex chromosomes drive gene expression and regulatory dimorphisms in mouse embryonic stem cells. AB - BACKGROUND: Pre-implantation embryos exhibit sexual dimorphisms in both primates and rodents. To determine whether these differences reflected sex-biased expression patterns, we generated transcriptome profiles for six 40,XX, six 40,XY, and two 39,X mouse embryonic stem (ES) cells by RNA sequencing. RESULTS: We found hundreds of coding and non-coding RNAs that were differentially expressed between male and female cells. Surprisingly, the majority of these were autosomal and included RNA encoding transcription and epigenetic and chromatin remodeling factors. We showed differential Prdm14-responsive enhancer activity in male and female cells, correlating with the sex-specific levels of Prdm14 expression. This is the first time sex-specific enhancer activity in ES cells has been reported. Evaluation of X-linked gene expression patterns between our XX and XY lines revealed four distinct categories: (1) genes showing 2-fold greater expression in the female cells; (2) a set of genes with expression levels well above 2-fold in female cells; (3) genes with equivalent RNA levels in male and female cells; and strikingly, (4) a small number of genes with higher expression in the XY lines. Further evaluation of autosomal gene expression revealed differential expression of imprinted loci, despite appropriate parent-of-origin patterns. The 39,X lines aligned closely with the XY cells and provided insights into potential regulation of genes associated with Turner syndrome in humans. Moreover, inclusion of the 39,X lines permitted three-way comparisons, delineating X and Y chromosome-dependent patterns. CONCLUSIONS: Overall, our results support the role of the sex chromosomes in establishing sex-specific networks early in embryonic development and provide insights into effects of sex chromosome aneuploidies originating at those stages. PMID- 28818099 TI - Biosemantics guided gene expression profiling of Sjogren's syndrome: a comparative analysis with systemic lupus erythematosus and rheumatoid arthritis. AB - BACKGROUND: Sjogren's syndrome (SS) shares many clinical and pathological similarities with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). These autoimmune diseases mostly affect women. In this study, concept profile analysis (CPA) and gene expression meta-analysis were used to identify genes potentially involved in SS pathogenesis. METHODS: Human genes associated with SS, SLE, and RA were identified using the CPA tool, Anni 2.1. The differential mRNA expression of genes common to SS and SLE (SS-SLE) was determined in female peripheral blood mononuclear cells (PBMCs) using NCBI-GEO2R. Differentially expressed (DE) SS-SLE PBMC genes in common with the SS-SLE CPA identified genes were analyzed for differential expression in salivary glands or synovial biopsies, and for genes common to SS and RA and SLE and RA, analyzing differential expression in salivary glands in SS, synovial fibroblasts in RA, and synovial fluid in SLE. Among common genes, DE genes found in salivary gland mRNA expression in patients with SS were used for gene enrichment and SS molecular network construction. Secondary analysis was performed to identify DE genes unique to the disease site tissues, by excluding PBMC and CPA common DE genes to complement the SS network. RESULTS: We identified 22 DE genes in salivary gland datasets in SS that have not previously been clearly associated with SS pathogenesis. Among these, higher levels of checkpoint kinase 1 (CHEK1), V-Ets avian erythroblastosis virus E26 oncogene homolog 1 (ETS1), and lymphoid enhancer binding factor 1 (LEF1) were significantly correlated with higher matrix metalloproteinase 9 (MMP9) levels. Higher MMP9 levels have been implicated in degradation of salivary gland structural integrity, leading to hypo-salivation in patients with SS. Salivary gland mRNA expression of MMP9 and the expression of cytokine CXCL10 were higher in patients with SS. CXCL10 has been shown to increase MMP9 expression and therefore may also play an important role in SS pathogenesis. CONCLUSION: Using CPA and gene expression analysis, we identified factors targeting MMP9 expression and/or function, namely CHEK1, CXCL10, ETS1, LEF1, and tissue inhibitor of metalloproteinase 1; altered mRNA expression of these could increase expression/activity of MMP9 in a concerted manner, thereby potentially impacting SS pathogenesis. PMID- 28818100 TI - miR-140-5p suppresses the proliferation, migration and invasion of gastric cancer by regulating YES1. AB - BACKGROUND: The aberrant expression of microRNA-140-5p (miR-140-5p) has been described in gastric cancer (GC). However, the role of miR-140-5p in GC remains unclear. In this study, the prognostic relevance of miR-140-5p in GC was investigated and YES1 was identified as a novel target of miR-140-5p in regulating tumor progression. METHODS: miR-140-5p level was determined in 20 paired frozen specimens through quantitative real-time PCR, and analyzed in tissue microarrays through in situ hybridization. The target of miR-140-5p was verified through a dual luciferase reporter assay, and the effects of miR-140-5p on phenotypic changes in GC cells were investigated in vitro and in vivo. RESULTS: Compared with that in adjacent normal tissues, miR-140-5p expression decreased in cancerous tissues. The downregulated miR-140-5p in 144 patients with GC was significantly correlated with the reduced overall survival of these patients. miR-140-5p could inhibit GC cell proliferation, migration and invasion by directly targeting 3'-untranlated region of YES1. miR-140-5p could also remarkably reduce the tumor size in GC xenograft mice. CONCLUSIONS: miR-140-5p serves as a potential prognostic factor in patients with GC, and miR-140-5p mediated YES1 inhibition is a novel mechanism behind the suppressive effects of miR-140-5p in GC. PMID- 28818101 TI - A new method for sequencing the hypervariable Plasmodium falciparum gene var2csa from clinical samples. AB - BACKGROUND: VAR2CSA, a member of the Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family, mediates the binding of P. falciparum-infected erythrocytes to chondroitin sulfate A, a surface-associated molecule expressed in placental cells, and plays a central role in the pathogenesis of placental malaria. VAR2CSA is a target of naturally acquired immunity and, as such, is a leading vaccine candidate against placental malaria. This protein is very polymorphic and technically challenging to sequence. Published var2csa sequences, mostly limited to specific domains, have been generated through the sequencing of cloned PCR amplicons using capillary electrophoresis, a method that is both time consuming and costly, and that performs poorly when applied to clinical samples that are commonly polyclonal. A next-generation sequencing platform, Pacific Biosciences (PacBio), offers an alternative approach to overcome these issues. METHODS: PCR primers were designed that target a 5 kb segment in the 5' end of var2csa and the resulting amplicons were sequenced using PacBio sequencing. The primers were optimized using two laboratory strains and were validated on DNA from 43 clinical samples, extracted from dried blood spots on filter paper or from cryopreserved P. falciparum-infected erythrocytes. Sequence reads were assembled using the SMRT-analysis ConsensusTools module. RESULTS: Here, a PacBio sequencing-based approach for recovering a segment encoding the majority of VAR2CSA's extracellular region is described; this segment includes the totality of the first four domains in the 5' end of var2csa (~5 kb), from clinical malaria samples. The feasibility of the method is demonstrated, showing a high success rate from cryopreserved samples and more limited success from dried blood spots stored at room temperature, and characterized the genetic variation of the var2csa locus. CONCLUSIONS: This method will facilitate a detailed analysis of var2csa genetic variation and can be adapted to sequence other hypervariable P. falciparum genes. PMID- 28818102 TI - Field evaluation of the efficacy of Mycobacterium bovis BCG vaccine against tuberculosis in goats. AB - BACKGROUND: Control of animal tuberculosis (TB) through vaccination has emerged as a long-term strategy to complement test and slaughter control strategy. A pilot trial under field conditions was conducted in a goat herd with high TB prevalence to assess the efficacy of the Mycobacterium bovis BCG vaccine. RESULTS: Twenty-three goat kids vaccinated with BCG and other 22 unvaccinated control kids were euthanized at 18 months post-vaccination. Gross pathological and histopathological examination of target tissues was performed for detection of tuberculous lesions and assessment of vaccine efficacy. Mycobacterial culture and DNA detection were used to confirm Mycobacterium caprae infection. Vaccination significantly reduced the number of animals with TB lesions compared to unvaccinated controls (35% and 77%, respectively; P < 0.01). This reduction was even higher if only extra-pulmonary infection was considered (17% and 68%, respectively; P < 0.001). CONCLUSIONS: This trial demonstrates that BCG vaccination of goats can significantly reduce the TB lesion rates in high disease exposure conditions, indicating that vaccination could contribute to the control of TB in domestic goats. PMID- 28818103 TI - Enhancement of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) accumulation in Arxula adeninivorans by stabilization of production. AB - BACKGROUND: In recent years the production of biobased biodegradable plastics has been of interest of researchers partly due to the accumulation of non biodegradable plastics in the environment and to the opportunity for new applications. Commonly investigated are the polyhydroxyalkanoates (PHAs) poly(hydroxybutyrate) and poly(hydroxybutyrate-co-hydroxyvalerate) (PHB-V). The latter has the advantage of being tougher and less brittle. The production of these polymers in bacteria is well established but production in yeast may have some advantages, e.g. the ability to use a broad spectrum of industrial by products as a carbon sources. RESULTS: In this study we increased the synthesis of PHB-V in the non-conventional yeast Arxula adeninivorans by stabilization of polymer accumulation via genetic modification and optimization of culture conditions. An A. adeninivorans strain with overexpressed PHA pathway genes for beta-ketothiolase, acetoacetyl-CoA reductase, PHAs synthase and the phasin gene was able to accumulate an unexpectedly high level of polymer. It was found that an optimized strain cultivated in a shaking incubator is able to produce up to 52.1% of the DCW of PHB-V (10.8 g L-1) with 12.3%mol of PHV fraction. Although further optimization of cultivation conditions in a fed-batch bioreactor led to lower polymer content (15.3% of the DCW of PHB-V), the PHV fraction and total polymer level increased to 23.1%mol and 11.6 g L-1 respectively. Additionally, analysis of the product revealed that the polymer has a very low average molecular mass and unexpected melting and glass transition temperatures. CONCLUSIONS: This study indicates a potential of use for the non-conventional yeast, A. adeninivorans, as an efficient producer of polyhydroxyalkanoates. PMID- 28818104 TI - Neuroprotective properties of curcumin in toxin-base animal models of Parkinson's disease: a systematic experiment literatures review. AB - BACKGROUND: Curcumin (diferuloylmethane), a polyphenol extracted from the plant Curcuma longa, is widely used in Southeast Asia, China and India in food preparation and for medicinal purposes. Meanwhile, the neuroprotective actions of curcumin have been documented for experimental therapy in Parkinson's disease (PD). METHODS: In this study, we used a systematic review to comprehensively assess the efficacy of curcumin in experimental PD. Using electronic and manual search for the literatures, we identified studies describing the efficacy of curcumin in animal models of PD. RESULTS: We identified 13 studies with a total of 298 animals describing the efficacy of curcumin in animal models of PD. The methodological quality of all preclinical trials is ranged from 2 to 5. The majority of the experiment studies demonstrated that curcumin was more significantly neuroprotection effective than control groups for treating PD. Among them, five studies indicated that curcumin had an anti-inflammatory effect in the PD animal models (p < 0.05). Meanwhile, four studies showed the antioxidant capability of curcumin, by which it protected substantia nigra neurons and improved striatal dopamine levels. Furthermore, two studies in this review displayed that curcumin treatment was also effective in reducing neuronal apoptosis and improving functional outcome in animal models of PD. Most of the preclinical studies demonstrated the positive findings while one study reported that curcumin had no beneficial effects against Mn-induced disruption of hippocampal metal and neurotransmitter homeostasis. CONCLUSIONS: The results demonstrated a marked efficacy of curcumin in experimental model of PD, suggesting curcumin probably a candidate neuroprotective drug for human PD patients. PMID- 28818105 TI - Severe neutropenia revealing a rare presentation of dengue fever: a case report. AB - BACKGROUND: Arboviruses are a common cause of fever in the returned traveler often associated with leucopenia, especially lymphopenia and thrombocytopenia. Transient neutropenia has been described in a few cases of arboviruses. However, prolonged and severe neutropenia (<500/mm3) has rarely been reported in dengue fever, especially in the returned traveler in Europe. CASE PRESENTATION: A 26 year-old healthy female without any medical past history, flying back from Thailand, presented a transient fever with severe neutropenia (<500/mm3). Laboratory tests showed a mild hepatic cytolysis and thrombocytopenia, mimicking malaria or viral hepatitis. While she underwent protective isolation, NS1 antigen returned positive in favor of a dengue fever. Outcome was favorable without any antimicrobial therapy. CONCLUSION: Physicians should be wary of possible unusual presentation of dengue fever with prolonged neutropenia. Although such biological sign is more often associated with malaria or severe bacterial infection, it may be a sign of arbovirus. PMID- 28818106 TI - Morphoproteomics, E6/E7 in-situ hybridization, and biomedical analytics define the etiopathogenesis of HPV-associated oropharyngeal carcinoma and provide targeted therapeutic options. AB - BACKGROUND: Human papillomavirus (HPV) has been identified as an etiopathogenetic factor in oropharyngeal squamous cell carcinoma. The HPV E6 and E7 oncogenes are instrumental in promoting proliferation and blocking differentiation leading to tumorigenesis. Although surgical intervention can remove such tumors, the potential for an etiologic field effect with recurrent disease is real. A downstream effector of E7 oncoprotein, enhancer of zeste homolog 2 (EZH2), is known to promote proliferation and to pose a block in differentiation and in turn, could lead to HPV-induced malignant transformation. However, the EZH2 pathway is amenable to low toxicity therapies designed to promote differentiation to a more benign state and prevent recurrent disease by inhibiting the incorporation of HPV into the genome. This is the first study using clinical specimens to demonstrate EZH2 protein expression in oropharyngeal carcinoma (OPC). METHODS: The study included eight patients with oropharyngeal carcinoma, confirmed p16INK4a- positive by immunohistochemistry (IHC). The tissue expression of E6/E7 messenger RNA (mRNA) was measured by RNAscope(r) in-situ hybridization technology. Expression of EZH2, Ki-67, and mitotic indices were assessed by morphoproteomic analysis. Biomedical analytics expanded the results with data from Ingenuity Pathway Analysis (IPA) and KEGG databases to construct a molecular network pathway for further insights. RESULTS: Expression of E6 and E7 oncogenes in p16INK4a- positive oropharyngeal carcinoma was confirmed. EZH2 and its correlates, including elevated proliferation index (Ki-67) and mitotic progression were also present. Biomedical analytics validated the relationship between HPV- E6 and E7 and the expression of the EZH2 pathway. CONCLUSION: There is morphoproteomic and mRNA evidence of the association of p16INK4a-HPV infection with the E6 and E7 oncogenes and the expression of EZH2, Ki-67 and mitotic progression in oropharyngeal carcinoma. The molecular network biology was confirmed by biomedical analytics as consistent with published literature. This is significant because the biology lends itself to targeted therapeutic options using metformin, curcumin, celecoxib and sulforaphane as therapeutic strategies to prevent progression or recurrence of disease. PMID- 28818107 TI - Patellofemoral kinematics in dogs with cranial cruciate ligament insufficiency: an in-vivo fluoroscopic analysis during walking. AB - BACKGROUND: Complete rupture of the cranial cruciate ligament (CrCL) in dogs causes profound disturbance to stifle joint biomechanics. The objective of this study was to characterize the effects of cranial cruciate ligament (CrCL) insufficiency on patellofemoral (PF) kinematics in dogs during walking. Ten client-owned dogs (20-40 kg) with natural unilateral complete CrCL rupture were included. Dogs underwent computed tomographic scans to create digital bone-models of the patella and femur. Lateral projection fluoroscopy of the stifles was performed during treadmill walking. Sagittal plane PF kinematics were calculated throughout the gait cycle by overlaying digital bone models on fluoroscopic images using a previously described 2D-3D registration technique. For acquisition of kinematics in the contralateral (control) stifle, fluoroscopy was repeated 6 months after stabilizing surgery of the affected side. Results were compared between the pre-operative CrCL-deficient and 6-month post-operative control stifles. RESULTS: Craniocaudal PF translation was similar between CrCL-deficient and control stifles throughout the gait cycle. The patella was more distal and positioned in greater flexion throughout the gait cycle in CrCL-deficient stifles when compared to the control stifle at equivalent time points. There was no significant difference in PF poses between CrCL-deficient and control stifles at equivalent femorotibial flexion angles; however, common femorotibial flexion angles were only found over a small range during the swing phase of gait. CONCLUSIONS: CrCL insufficiency altered PF kinematics during walking, where the changes were predominately attributable to the femorotibial joint being held in more flexion. Abnormal PF kinematics may play a role in the development of osteoarthritis that is commonly observed in the PF joint CrCL-deficient stifles. PMID- 28818108 TI - Association of parents' and children's physical activity and sedentary time in Year 4 (8-9) and change between Year 1 (5-6) and Year 4: a longitudinal study. AB - BACKGROUND: Parents could be important influences on child physical activity and parents are often encouraged to be more active with their child. This paper examined the association between parent and child physical activity and sedentary time in a UK cohort of children assessed when the children were in Year 1 (5-6 years old) and in Year 4 (8-9 years old). METHODS: One thousand two hundred twenty three children and parents provided data in Year 4 and of these 685 participated in Year 1. Children and parents wore an accelerometer for five days including a weekend. Mean minutes of sedentary time and moderate-to-vigorous intensity physical activity (MVPA) were derived. Multiple imputation was used to impute all missing data and create complete datasets. Linear regression models examined whether parent MVPA and sedentary time at Year 4 and at Year 1 predicted child MVPA and sedentary time at Year 4. Change in parent MVPA and sedentary time was used to predict change in child MVPA and sedentary time between Year 1 and Year 4. RESULTS: Imputed data showed that at Year 4, female parent sedentary time was associated with child sedentary time (0.13, 95% CI = 0.00 to 0.27 mins/day), with a similar association for male parents (0.15, 95% CI = -0.02 to 0.32 mins/day). Female parent and child MVPA at Year 4 were associated (0.16, 95% CI = 0.08 to 0.23 mins/day) with a smaller association for male parents (0.08, 95% CI = -0.01 to 0.17 mins/day). There was little evidence that either male or female parent MVPA at Year 1 predicted child MVPA at Year 4 with similar associations for sedentary time. There was little evidence that change in parent MVPA or sedentary time predicted change in child MVPA or sedentary time respectively. CONCLUSIONS: Parents who were more physically active when their child was 8-9 years old had a child who was more active, but the magnitude of association was generally small. There was little evidence that parental activity from three years earlier predicted child activity at age 8-9, or that change in parent activity predicted change in child activity. PMID- 28818109 TI - Metastatic colorectal cancer responsive to regorafenib for 2 years: a case report. AB - BACKGROUND: Regorafenib is an oral multikinase inhibitor that has been demonstrated as clinically effective in patients with metastatic colorectal cancer in phase III studies. Although disease control was achieved in 40% of the pretreated patients with metastatic colorectal cancer in the pivotal studies, radiological response has rarely been reported. Severe adverse events associated with regorafenib are known to occur during the first and second courses of treatment. We present a case of a 62-year-old Japanese patient whose metastatic colorectal cancer has been responding to treatment with regorafenib for 2 years. CASE PRESENTATION: A 54-year-old Japanese man visited our institute exhibiting general malaise, and he was diagnosed with ascending colon cancer in April 2006. He underwent right hemicolectomy, and the final staging was T3N0M0, stage II. After 19 months, pulmonary metastasis and anastomotic recurrences were detected, and a series of operations were performed to resect both metastatic lesions. After that, liver metastasis, a duodenal metastasis with right renal invasion, right adrenal metastasis, and para-aortic lymph node metastases were observed during follow-up, and chemotherapy and resection were performed. The patient had metastatic para-aortic lymph nodes after the fifth tumor resection and underwent multiple lines of chemotherapy in April 2014. Regorafenib monotherapy was started at 80 mg/day. Then, regorafenib was increased to 120 mg/day in the second cycle. Regorafenib monotherapy led to 60% tumor shrinkage within the initial 2 months, and the tumor further decreased in size over 4 months until it became unrecognizable on imaging studies. The clinical effects of regorafenib monotherapy have shown a partial response according to Response Evaluation Criteria in Solid Tumors criteria. No severe adverse events were observed, except for mild fatigue and hand-foot syndrome. The patient has received 24 courses of regorafenib over 2 years without exhibiting tumor progression. CONCLUSIONS: To the best of our knowledge, this is the longest treatment with regorafenib without tumor progression ever reported. A reduced dosage of regorafenib at induction may ameliorate the cutaneous and hepatic toxicity associated with its use. PMID- 28818111 TI - Estimates of cancer incidence and mortality in China, 2013. AB - INTRODUCTION: Population-based cancer registration data are collected by the National Central Cancer Registry in China every year. Cancer incident cases and cancer deaths in 2013 were analyzed. METHODS: Through the procedure of quality control, reported data from 255 registries were accepted to establish the national database for cancer estimates. Incidences and mortalities were calculated with stratification by area (urban/rural), sex (male/female), age group (0, 1-4, 5-9, 10-14 ... 80-84, and 85-year-old and above), and cancer site. The structure of Segi's population was used for the calculation of age standardized rates (ASR). Top 10 most common cancers and leading causes of cancer deaths were listed. RESULTS: In 2013, 3,682,200 new cancer cases and 2,229,300 cancer deaths were estimated in China based on the pooled data from 255 cancer registries, covering 16.65% of the national population. The incidence was 270.59/100,000, with an ASR of 186.15/100,000; the mortality was 166.83/100,000, with an ASR of 108.94/100,000. The top 10 most common cancer sites were the lung, stomach, liver, colorectum, female breast, esophagus, thyroid, cervix, brain, and pancreas. The ten leading causes of cancer deaths were lung cancer, liver cancer, gastric cancer, esophageal cancer, colorectal cancer, pancreatic cancer, female breast cancer, brain tumor, leukemia, and lymphoma. CONCLUSIONS: Cancer leaves serious disease burden in China with high incidence and mortality. Lung cancer was the most common cancer and the leading cause of cancer death in China. Efficient control strategy is needed, especially for major cancers. PMID- 28818110 TI - Microbial community composition along the digestive tract in forage- and grain fed bison. AB - BACKGROUND: Diversity and composition of microbial communities was compared across the 13 major sections of the digestive tract (esophagus, reticulum, rumen, omasum, abomasum, duodenum, jejunum, ileum, cecum, ascending colon, transverse colon, descending colon, and rectum) in two captive populations of American bison (Bison bison), one of which was finished on forage, the other on grain. RESULTS: Microbial diversity fell to its lowest levels in the small intestine, with Bacteroidetes reaching their lowest relative abundance in that region, while Firmicutes and Euryarchaeota attained their highest relative abundances there. Gammaproteobacteria were most abundant in the esophagus, small intestine, and colon. The forage-finished bison population exhibited higher overall levels of diversity, as well as a higher relative abundance of Bacteroidetes in most gut sections. The grain-finished bison population exhibited elevated levels of Firmicutes and Gammaproteobacteria. Within each population, different sections of the digestive tract exhibited divergent microbial community composition, although it was essentially the same among sections within a given region of the digestive tract. Shannon diversity was lowest in the midgut. For each section of the digestive tract, the two bison populations differed significantly in microbial community composition. CONCLUSIONS: Similarities among sections indicate that the esophagus, reticulum, rumen, omasum, and abomasum may all be considered to house the foregut microbiota; the duodenum, jejunum, and ileum may all be considered to house the small intestine or midgut microbiota; and the cecum, ascending colon, transverse colon, descending colon, and rectum may all be considered to house the hindgut microbiota. Acid from the stomach, bile from the gall bladder, digestive enzymes from the pancreas, and the relatively low retention time of the small intestine may have caused the midgut's low microbial diversity. Differences in microbial community composition between populations may have been most strongly influenced by differences in diet (forage or grain). The clinical condition of the animals used in the present study was not evaluated, so further research is needed to establish whether the microbial profiles of some bison in this study are indeed indicative of dysbiosis, a predisposing factor to ruminal acidosis and its sequelae. PMID- 28818112 TI - Prevalence and its associated psychological variables of symptoms of depression and anxiety among ovarian cancer patients in China: a cross-sectional study. AB - BACKGROUND: It is well known that cancer patients tend to have high levels of perceived stress and symptoms of depression and anxiety. However, there is less study on the association between perceived stress and symptoms of depression and anxiety among ovarian cancer patients in China. And the mediating effect of hope and resilience needs to be further studied. In this study, we aim to examine the prevalence of depression and anxiety symptoms, to analyze the association between perceived stress and symptoms of depression and anxiety, and to test whether hope and resilience mediate the association of perceived stress with symptoms of depression and anxiety among Chinese patients with ovarian cancer. METHOD: A total of 220 questionnaires were distributed and collected from the First Affiliated Hospital of China Medical University and Shengjing Hospital of China Medical University. All participants in this study were ovarian cancer inpatients. After excluding the incomplete questionnaires, 198 questionnaires were valid for the analysis. Qualified patients were asked to response to the questionnaires including Hospital anxiety and depression scale (HADS), perceived stress scale (PSS-10), and the Herth hope scale and the resilience scale. Hierarchical regression analyses were used to test the associations among perceived stress, symptoms of depression and anxiety, and hope and resilience. Bootstrapping method was conducted to examine whether the indirect effect of hope and resilience was significant respectively. RESULTS: The prevalence of symptoms of depression and anxiety in ovarian cancer patients was 47.0% and 51.5% respectively. Perceived stress correlated significantly with symptoms of depression (r = 0.709, P < 0.01) and anxiety (r = 0.660, P < 0.01). Hope (a*b = 0.155, BCa 95% CI: 0.094, 0.223) partly mediated the association between perceived stress and symptoms of depression; similarly, hope (a*b = 0.129, BCa 95% CI: 0.048, 0.205) partly mediated the effect of perceived stress on symptoms of anxiety. However, resilience (a*b = 0.004, BCa 95% CI: -0.030, 0.040) did not mediate the association between perceived stress and symptoms of depression. And resilience (a*b = 0.041,BCa 95% CI: -0.013, 0.098) did not mediate the association between perceived stress and symptoms of anxiety. CONCLUSIONS: The present study suggests that perceived stress might be one of the impact factors of symptoms of depression and anxiety, while hope might ease symptoms of depression and anxiety. In view of the role of hope, medical workers and patient caregivers should pay more attention to hope, and then to intervene perceived stress among patients with ovarian cancer. PMID- 28818113 TI - Respiratory syncytial virus (RSV) entry is inhibited by serine protease inhibitor AEBSF when present during an early stage of infection. AB - BACKGROUND: Host proteases have been shown to play important roles in many viral activities such as entry, uncoating, viral protein production and disease induction. Therefore, these cellular proteases are putative targets for the development of antivirals that inhibit their activity. Host proteases have been described to play essential roles in Ebola, HCV, HIV and influenza, such that specific protease inhibitors are able to reduce infection. RSV utilizes a host protease in its replication cycle but its potential as antiviral target is unknown. Therefore, we evaluated the effect of protease inhibitors on RSV infection. METHODS: To measure the sensitivity of RSV infection to protease inhibitors, cells were infected with RSV and incubated for 18 h in the presence or absence of the inhibitors. Cells were fixed, stained and studied using fluorescence microscopy. RESULTS: Several protease inhibitors, representing different classes of proteases (AEBSF, Pepstatin A, E-64, TPCK, PMSF and aprotinin), were tested for inhibitory effects on an RSV A2 infection of HEp-2 cells. Different treatment durations, ranging from 1 h prior to inoculation and continuing for 18 h during the assay, were evaluated. Of all the inhibitors tested, AEBSF and TPCK significantly decreased RSV infection. To ascertain that the observed effect of AEBSF was not a specific feature related to HEp-2 cells, A549 and BEAS-2B cells were also used. Similar to HEp-2, an almost complete block in the number of RSV infected cells after 18 h of incubation was observed and the effect was dose-dependent. To gain insight into the mechanism of this inhibition, AEBSF treatment was applied during different phases of an infection cycle (pre-, peri- and post-inoculation treatment). The results from these experiments indicate that AEBSF is mainly active during the early entry phase of RSV. The inhibitory effect was also observed with other RSV isolates A1998/3-2 and A2000/3 4, suggesting that this is a general feature of RSV. CONCLUSION: RSV infection can be inhibited by broad serine protease inhibitors, AEBSF and TPCK. We confirmed that AEBSF inhibition is independent of the cell line used or RSV strain. The time point at which treatment with the inhibitor was most potent, was found to coincide with the expected moment of entry of the virion with the host cell. PMID- 28818114 TI - The impact of subsidized low aromatic fuel (LAF) on petrol (gasoline) sniffing in remote Australian indigenous communities. AB - BACKGROUND: Since 2005, the Australian Government has subsidized the production and distribution of Low Aromatic Fuel (LAF) as a deterrent against petrol (gasoline) sniffing in remote Indigenous communities. LAF is used in place of unleaded petrol as a fuel for vehicles and other engines. This paper reports findings from an independent evaluation of the LAF rollout. METHODS: Forty one Indigenous communities were surveyed between 2010 and 2014, with each community being visited twice at a two yearly interval. Quantitative data on prevalence of petrol sniffing were collected, as well as qualitative data on the acceptability of LAF, evidence of substitution for inhaled petrol with other drugs, and programs such as recreational, training and employment opportunities. Prevalence rates of sniffing per 1000 population for each survey year and community were calculated by dividing the total number of sniffers by the population aged 5-39 years and multiplying by 1000. RESULTS: Between 2011-12 and 2013-14, the total estimated number of people sniffing petrol declined from 289 to 204, a fall of 29.4%. At both times, the median petrol sniffing prevalence rate was lower in communities with LAF than in communities without LAF. In 17 of the 41 communities, comparable data were available over a longer period, commencing in 2005-06. Fifteen of these communities stocked LAF over the entire period. In these communities, the median rate of petrol sniffing declined by 96%, from 141.6 per 1000 population in 2005-06 to 5.5 in 2013-14 (p < 0.05). LAF was widely accepted, although acceptance was often qualified by a belief that LAF harmed engines. Anecdotal reports suggest that the fall in petrol sniffing may have been offset by increased use of cannabis and other drugs, but the relationship is not one of simple cause-and-effect, with evidence that an increase in cannabis use in communities commenced before the LAF rollout began. Provision of services in communities has improved in recent years, but many programs continue to be inadequately resourced. CONCLUSIONS: The rollout of LAF appears to have contributed to reducing petrol sniffing and associated harms in Australian Indigenous communities. PMID- 28818115 TI - The use of genetic markers to estimate relationships between dogs in the course of criminal investigations. AB - OBJECTIVE: Attacks on humans by dogs in a pack, though uncommon, do happen, and result in severe, sometimes fatal, injuries. We describe the role that canine genetic markers played during the investigation of a fatal dog-pack attack involving a 50-year-old male truck driver in a parking lot in Tuscany (Italy). Using canine specific STR genetic markers, the local authorities, in the course of their investigations, reconstructed the genetic relationships between the dogs that caused the deadly aggression and other dogs belonging to the owner of the parking who, at the moment of the aggression, was located in another region of Italy. RESULTS: From a Bayesian clustering algorithm, the most likely number of clusters was two. The average relatedness among the dogs responsible for the aggression was higher than the average relatedness among the other dogs or between the two groups. Taken together, all these results indicate that the two groups of dogs are clearly distinct. Genetic relationships showed that the two groups of dogs were not related. It was therefore unlikely that the murderous dogs belonged to the owner of the parking lot who, on grounds of this and additional evidence, was eventually acquitted. PMID- 28818117 TI - Spatial and temporal distribution of Ligula intestinalis (Cestoda: Diphyllobothriidea) in usipa (Engraulicypris sardella) (Pisces: Cyprinidae) in Lake Nyasa. AB - Engraulicypris sardella is an endemic and economically important cyprinid species in Lake Nyasa/Malawi which has recently been infected by the tapeworm Ligula intestinalis. This parasite is known to induce severe pathological and behavioural effects on other cyprinids, including castration, followed by a collapse of infected populations. As a first step to understanding the dynamics between this parasite and E. sardella, we studied the spatial and temporal variation in prevalence over a period of 1 year. Overall prevalence was about 15%, but we observed a consistently higher prevalence in the littoral compared to the pelagic zone. Fish in the upper water levels showed the highest prevalence, with a marked decline with increasing water depth down to 150 m. The proportion of infected fish varied over time, with a significantly higher prevalence in the rainy season. In a huge lake like the Nyasa, with a surface area of 29,000 km2 and a maximum depth of 785 m, the transmission success of the parasite appears to show large variations in time and space. We suggest that these conditions could lead the parasite to become persistent within the lake, rather than the typical epidemic situation as observed in smaller bodies of water. PMID- 28818118 TI - Effects of age and stimulus material on character introductions of Swedish speaking four- to six-year-olds. AB - This study investigates effects of age on character introductions in the oral narratives of seventy-two monolingual Swedish-speaking four- to six-year-olds, comparing results from the Multilingual Assessment Instrument for Narratives (MAIN; Gagarina et al., 2012, 2015), and the Edmonton Narrative Norms Instrument (ENNI; Schneider et al., 2005). The proportion of appropriate referring expressions for introducing story characters clearly increases from age four to six. However, the children's performance is strongly stimulus-dependent. All age groups perform better on MAIN than on ENNI. One should thus be careful when drawing conclusions about the age at which children are able to use referring expressions appropriately. PMID- 28818116 TI - Distinct white matter microstructural abnormalities and extracellular water increases relate to cognitive impairment in Alzheimer's disease with and without cerebrovascular disease. AB - BACKGROUND: Mixed vascular and neurodegenerative dementia, such as Alzheimer's disease (AD) with concomitant cerebrovascular disease, has emerged as the leading cause of age-related cognitive impairment. The brain white matter (WM) microstructural changes in neurodegeneration well-documented by diffusion tensor imaging (DTI) can originate from brain tissue or extracellular free water changes. The differential microstructural and free water changes in AD with and without cerebrovascular disease, especially in normal-appearing WM, remain largely unknown. To cover these gaps, we aimed to characterize the WM free water and tissue microstructural changes in AD and mixed dementia as well as their associations with cognition using a novel free water imaging method. METHODS: We compared WM free water and free water-corrected DTI measures as well as white matter hyperintensity (WMH) in patients with AD with and without cerebrovascular disease, patients with vascular dementia, and age-matched healthy control subjects. RESULTS: The cerebrovascular disease groups had higher free water than the non-cerebrovascular disease groups. Importantly, besides the cerebrovascular disease groups, patients with AD without cerebrovascular disease also had increased free water in normal-appearing WM compared with healthy control subjects, reflecting mild vascular damage. Such free water increases in WM or normal-appearing WM (but not WMH) contributed to dementia severity. Whole-brain voxel-wise analysis revealed a close association between widespread free water increases and poorer attention, executive functioning, visual construction, and motor performance, whereas only left hemispheric free water increases were related to language deficits. Moreover, compared with the original DTI metrics, the free water-corrected DTI metric revealed tissue damage-specific (frontal and occipital) microstructural differences between the cerebrovascular disease and non-cerebrovascular disease groups. In contrast to both lobar and subcortical/brainstem free water increases, only focal lobar microstructural damage was associated with poorer cognitive performance. CONCLUSIONS: Our findings suggest that free water analysis isolates probable mild vascular damage from WM microstructural alterations and underscore the importance of normal appearing WM changes underlying cognitive and functional impairment in AD with and without cerebrovascular disease. Further developed, the combined free water and tissue neuroimaging assays could help in differential diagnosis, treatment planning, and disease monitoring of patients with mixed dementia. PMID- 28818120 TI - Editor's Note. PMID- 28818119 TI - Characterization of the interaction between the small RNA-encoded peptide SR1P and GapA from Bacillus subtilis. AB - Small regulatory RNAs (sRNAs) are the most prominent post-transcriptional regulators in all kingdoms of life. A few of them, e.g. SR1 from Bacillus subtilis, are dual-function sRNAs. SR1 acts as a base-pairing sRNA in arginine catabolism and as an mRNA encoding the small peptide SR1P in RNA degradation. Both functions of SR1 are highly conserved among 23 species of Bacillales. Here, we investigate the interaction between SR1P and GapA by a combination of in vivo and in vitro methods. De novo prediction of the structure of SR1P yielded five models, one of which was consistent with experimental circular dichroism spectroscopy data of a purified, synthetic peptide. Based on this model structure and a comparison between the 23 SR1P homologues, a series of SR1P mutants was constructed and analysed by Northern blotting and co-elution experiments. The known crystal structure of Geobacillus stearothermophilus GapA was used to model SR1P onto this structure. The hypothetical SR1P binding pocket, composed of two alpha-helices at both termini of GapA, was investigated by constructing and assaying a number of GapA mutants in the presence and absence of wild-type or mutated SR1P. Almost all residues of SR1P located in the two highly conserved motifs are implicated in the interaction with GapA. A critical lysine residue (K332) in the C-terminal alpha-helix 14 of GapA corroborated the predicted binding pocket. PMID- 28818121 TI - Different Places, Different Ideas: Reimagining Practice in American Psychiatric Nursing After World War II. AB - In 1952, Hildegard Peplau published her textbook Interpersonal Relations in Nursing: A Conceptual Frame of Reference for Psychodynamic Nursing. This was the same year the American Psychiatric Association (APA) published the first edition of the Diagnostic and Statistical Manual of Mental Disorders (1st ed.; DSM-I; APA). These events occurred in the context of a rapidly changing policy and practice environment in the United States after World War II, where the passing of the National Mental Health Act in 1946 released vast amounts of funding for the establishment of the National Institute of Mental Health and the development of advanced educational programs for the mental health professions including nursing. This article explores the work of two nurse leaders, Hildegard Peplau and Dorothy Mereness, as they developed their respective graduate psychiatric nursing programs and sought to create new knowledge for psychiatric nursing that would facilitate the development of advanced nursing practice. Both nurses had strong ideas about what they felt this practice should look like and developed distinct and particular approaches to their respective programs. This reflected a common belief that it was only through nurse-led education that psychiatric nursing could shape its own practice and control its own future. At the same time, there are similarities in the thinking of Peplau and Mereness that demonstrate the link between the specific social context of mental health immediately after World War II and the development of modern psychiatric nursing. Psychiatric nurses were able to gain significant control of their own education and practice after the war, but this was not without a struggle and some limitations, which continue to impact on the profession today. PMID- 28818122 TI - Evolving as Necessity Dictates: Home and Public Health in the 19th and 20th Centuries. PMID- 28818123 TI - "Women's Mission Among Women": Unacknowledged Origins of Public Health Nursing. PMID- 28818125 TI - More than Educators: New Zealand's Plunket Nurses, 1907-1950. PMID- 28818124 TI - The Triumph of Proximity: The Impact of District Nursing Schemes in 1890s' Rural Ireland. PMID- 28818126 TI - To Care and Educate: The Continuity Within Queen's Nursing in Scotland, c. 1948 2000. PMID- 28818127 TI - Nursing and the "New Style of Life": Trained Nursing in the Spanish-Speaking Caribbean, 1898-1961. PMID- 28818128 TI - Dazzling Visions: American Women, Race, and the Imperialist Origins of Modern Nursing in Cuba, 1898-1916. PMID- 28818129 TI - "Called to Nurse": Nursing, Race, and Americanization in Early 20th-Century Puerto Rico. PMID- 28818130 TI - "Fighting for Its Rightful Place": Nursing, Dictatorship, and Modernization in the Dominican Republic, 1930-1961. PMID- 28818131 TI - Lillian Sholtis Brunner, 1918-2016. PMID- 28818132 TI - Jean Whelan, 1949-2017. PMID- 28818133 TI - No Mas Bebes; No More Babies. PMID- 28818134 TI - Care and Caregiving Reconsidered. PMID- 28818136 TI - New Dissertations. PMID- 28818138 TI - Continuing Education and Board Certification Promote Higher Standards in Practice. PMID- 28818139 TI - Bed Rest and Intermittent Centrifugation Effects on Human Balance and Neuromotor Reflexes. AB - INTRODUCTION: The effects of repeated centrifugation in association with head down tilt (HDT) bed rest (BR) on the mediation of basic reflexes associated with the major postural muscles was investigated as a potential countermeasure for maintaining balance control and neuromotor reflex function. METHODS: There were 15 male volunteers who were exposed to 21 d of 6 degrees HDT-BR. Eight were treated with daily 1-h artificial gravity (AG) exposures aboard a short radius centrifuge that provided 1-g footward loading at heart level. The other seven served as HDT-BR control subjects. Balance control was assessed using a standard computerized dynamic posturography (CDP) protocol that was modified by adding low frequency pitch-plane head movements. Neuromotor reflex function was assessed using tendon stretch reflexes (MSR) and functional stretch reflex (FSR) data collected from the triceps surae muscle group. RESULTS: CDP performance was degraded by HDT-BR in both groups (ranging from 24 to 26%), but was unaffected by AG. BR also degraded MSR and FSR functions in both groups, with increased peak reflex latencies between 1.5 and 1.95 ms, but AG maintained pre-BR latencies for the MSR subjects. DISCUSSION: AG exposure did not modify balance control from pre BR responses, but did help prevent decrements in FSR latencies post-BR.Paloski WH, Reschke MF, Feiveson AH. Bed rest and intermittent centrifugation effects on human balance and neuromotor reflexes. Aerosp Med Hum Perform. 2017; 88(9):812 818. PMID- 28818140 TI - Dynamic Cerebral Autoregulation During the Combination of Mild Hypercapnia and Cephalad Fluid Shift. AB - BACKGROUND: Mild hypercapnia combined with a cephalad fluid shift [e.g., that occurring during spaceflight or laparoscopic surgery with head-down tilt (HDT)] might affect cerebral autoregulation. However, no reports have described the effects of the combination on dynamic cerebral autoregulation. Therefore, we tested the hypothesis that the combination of mild hypercapnia and a cephalad fluid shift would attenuate dynamic cerebral autoregulation. METHODS: There were 15 healthy male volunteers who were exposed to 4 10-min protocols in which they received air in the supine position (Placebo/Supine), 3% carbon dioxide (CO2) in the supine position (CO2/Supine), air with -10 degrees HDT (Placebo/HDT) and 3% CO2 with -10 degrees HDT (CO2/HDT). Dynamic cerebral autoregulation was evaluated using a transfer function analysis of the beat-to-beat variability in mean arterial blood pressure (ABP) and mean cerebral blood flow (CBF) velocity. RESULTS: The phase in the low-frequency range was significantly lower during CO2/HDT than all other protocols, where CO2/HDT was -25% lower than Placebo/Supine (CO2/HDT, 0.49 +/- 0.21; Placebo/Supine, 0.65 +/- 0.16 radians). The transfer function gain in the low-frequency range was significantly higher during CO2/HDT than all other protocols, where CO2/HDT was 26% higher than Placebo/Supine (CO2/HDT, 1.08 +/- 0.34; Placebo/Supine, 0.86 +/- 0.28 cm . s-1 . mmHg-1). However, neither the CO2/Supine nor Placebo/HDT showed significant differences compared with the Placebo/Supine. DISCUSSION: Even short-term exposure to 3% CO2 plus HDT increased synchrony and the magnitude of transmission between ABP and CBF in the low-frequency range. Thus, the combination of mild hypercapnia and a cephalad fluid shift attenuated dynamic cerebral autoregulation.Kurazumi T, Ogawa Y, Yanagida R, Morisaki H, Iwasaki K. Dynamic cerebral autoregulation during the combination of mild hypercapnia and cephalad fluid shift. Aerosp Med Hum Perform. 2017; 88(9):819-826. PMID- 28818141 TI - Autonomic Cardiovascular Responses to Orthostatic Stress After a Short Artificial Gravity Exposure. AB - BACKGROUND: Intermittent artificial gravity (AG) training over days and weeks has been shown to improve the human orthostatic tolerance limit (OTL) and improve cardiovascular regulation in response to orthostatic stress. Effects of a single AG exposure are currently unknown. METHODS: We tested cardiovascular responses to orthostatic stress in 16 hypovolemic subjects (9 men and 7 women), once following a single, short (~90 min) bout of AG and once following a similar period of head down bed rest (HDBR). Hypovolemia was produced by intravenous furosemide infusion (20 mg) and orthostatic stress was produced by combined 70 degrees head-up tilt (HUT) and progressively increasing lower body negative pressure until symptoms of presyncope developed. To assess reflex-induced changes in cardiovascular regulation, heart rate and blood pressure variability were analyzed by spectral analysis and baroreflex activity was evaluated by transfer function analysis. RESULTS: Compared to HDBR, a short AG exposure increased men's low frequency (0.04-0.15 Hz) power of systolic blood pressure (SBPLF), but did not change women's SBPLF responses to orthostatic stress. In response to 70 degrees HUT, compared to supine, low frequency phase delay (PhaseLF) between systolic blood pressure and RR intervals increased by ~20% following HDBR, but did not change following AG, reflecting improved baroreflex activity at a milder level of orthostatic stress after AG. CONCLUSIONS: These results indicate that a short bout of AG increased both sympathetic and baroreflex responsiveness to orthostatic stress in hypovolemia-induced, cardiovascular-deconditioned men and women, which may contribute to the AG-induced improvement of OTL shown in our previous reports.Zhang Q, Evans JM, Stenger MB, Moore FB, Knapp CF. Autonomic cardiovascular responses to orthostatic stress after a short artificial gravity exposure. Aerosp Med Hum Perform. 2017; 88(9):827-833. PMID- 28818142 TI - Psychophysiological Assessment in Pilots Performing Challenging Simulated and Real Flight Maneuvers. AB - BACKGROUND: The objective assessment of psychophysiological arousal during challenging flight maneuvers is of great interest to aerospace medicine, but remains a challenging task. In the study presented here, a vector-methodological approach was used which integrates different psychophysiological variables, yielding an integral arousal index called the Psychophysiological Arousal Value (PAV). METHODS: The arousal levels of 15 male pilots were assessed during predetermined, well-defined flight maneuvers performed under simulated and real flight conditions. RESULTS: The physiological data, as expected, revealed inter- and intra-individual differences for the various measurement conditions. As indicated by the PAV, air-to-air refueling (AAR) turned out to be the most challenging task. In general, arousal levels were comparable between simulator and real flight conditions. However, a distinct difference was observed when the pilots were divided by instructors into two groups based on their proficiency in AAR with AWACS (AAR-Novices vs. AAR-Professionals). AAR-Novices had on average more than 2000 flight hours on other aircrafts. They showed higher arousal reactions to AAR in real flight (contact: PAV score 8.4 +/- 0.37) than under simulator conditions (7.1 +/- 0.30), whereas AAR-Professionals did not (8.5 +/- 0.46 vs. 8.8 +/- 0.80). DISCUSSION: The psychophysiological arousal value assessment was tested in field measurements, yielding quantifiable arousal differences between proficiency groups of pilots during simulated and real flight conditions. The method used in this study allows an evaluation of the psychophysiological cost during a certain flying performance and thus is possibly a valuable tool for objectively evaluating the actual skill status of pilots.Johannes B, Rothe S, Gens A, Westphal S, Birkenfeld K, Mulder E, Rittweger J, Ledderhos C. Psychophysiological assessment in pilots performing challenging simulated and real flight maneuvers. Aerosp Med Hum Perform. 2017; 88(9):834-840. PMID- 28818143 TI - Locomotion Strategy and Magnitude of Ground Reaction Forces During Treadmill Training on ISS. AB - INTRODUCTION: Creation of the cosmonaut in-flight physical training process is currently based on the leading role of support afferents in the development of hypogravity changes in the motor system. We assume that the strength of support afferents is related to the magnitude of the ground reaction forces (GRF). For this purpose it was necessary to compare the GRF magnitude on the Russian BD-2 treadmill for different locomotion types (walking and running), modes (active and passive), and subjects. METHODS: Relative GRF values were analyzed while subjects performed walking and running during active and passive modes of treadmill belt movement under 1 G (N = 6) and 0 G (N = 4) conditions. RESULTS: For different BD 2 modes and both types of locomotion, maximum GRF values varied in both 0 G and 1 G. Considerable individual variations were also found in the locomotion strategies, as well as in maximum GRF values. In 0 G, the smallest GRF values were observed for walking in active mode, and the largest during running in passive mode. In 1 G, GRF values were higher during running than while walking, but the difference between active and passive modes was not observed; we assume this was due to the uniqueness of the GRF profile. DISCUSSION: The maximum GRF recorded during walking and running in active and passive modes depended on the individual pattern of locomotion. The maximum GRF values that we recorded on BD-2 were close to values found by other researchers. The observations from this study could guide individualized countermeasures prescriptions for microgravity.Fomina E, Savinkina A. Locomotion strategy and magnitude of ground reaction forces during treadmill training on ISS. Aerosp Med Hum Perform. 2017; 88(9):841-849. PMID- 28818144 TI - Refining Selection for Elite Troops by Predicting Military Training Outcome. AB - INTRODUCTION: Paratrooper training courses are very demanding, leading to a high number of drop-outs, despite existing selection criteria. This study investigated physiological, neuropsychological, and subjective data of completers and drop outs during paratrooper training to identify potential predictive indices. METHODS: Tested were 24 paratrooper soldiers before (t0), after 8 wk (t1), and at the end of a 12-wk training camp (t2). There were 11 soldiers who completed the course and 13 dropped out. The Training OPtimalisation test (TOPtest) uses two maximum exercise events to assess changes in measured parameters. The TOPtest was administered at t0, t1, and t2; physiological [i.e., adrenocorticotrophic hormone (ACTH), cortisol, heart rate (HR)], neuropsychological (Stroop, Flanker, Go NoGo, Task Switch), and subjective data [Profile of Mood States (POMS)] were collected. Physiological and subjective raw data was gathered pre- and post-test from each of the two maximum exercise tests. The pre/post-test change of each parameter's raw values was calculated as the parameter's reactivity (or delta score). RESULTS: At t0, drop-outs showed a significantly smaller HR reactivity (117.9 +/- 14.0 vs.107.7 +/- 10.6). Delta scores of tension and fatigue values differed significantly between completers and drop-outs at t0. Completers' physiological reactivity during the TOPtest at t2 (HR: 105.91 +/- 13.68 vs. 95.55 +/- 10.28) was significantly reduced and became comparable to the drop-outs' reactivity at t0. Delta scores of fatigue and tension values showed a similar pattern. DISCUSSION: Reactivity of HR, tension, and fatigue parameter values were found to have predictive value in identifying completers vs. drop-outs of an elite paratrooper training course.Vrijkotte S, Meeusen R, Roelands B, Kubesch S, Mairesse O, de Schutter G, Pattyn N. Refining selection for elite troops by predicting military training outcome. Aerosp Med Hum Perform. 2017; 88(9):850 857. PMID- 28818145 TI - Protective Effects of Emotional Intelligence and Proactive Coping on Civil Pilots' Mental Health. AB - INTRODUCTION: Pilots' mental health is an issue of crucial importance that may endanger flight safety. As such, it is of profound significance to address the question of what characteristics are protective of mental health among pilots. The present study aimed to explore the indirect effects of emotional intelligence (EI) on depression and anxiety via proactive coping, and examine the moderating role of previous flight experience (PFE) in the conditional indirect effect of EI on depression through proactive coping. METHODS: A cross-sectional regression design was used to measure EI (Trait Meta Mood Scale), proactive coping (Proactive Coping Scale), depression (The PHQ-9), and anxiety (The GAD-7) among 319 Chinese civil pilots from China Southern Airlines. Mediation and moderated mediation effects were explored using regression analyses and were confirmed by the bootstrapping approach. RESULTS: Pilots reported relatively low levels of depression (M = 0.39, SD = 0.24) and anxiety (M = 0.22, SD = 0.23). Married pilots had higher levels of depression (t = 2.46) and anxiety (t = 3.07) than single pilots. Proactive coping mediated the association between EI and depression (B = -0.25), as well as the relationship between EI and anxiety (B = 0.23). Moreover, conditional process analysis showed that PFE moderated the indirect effect of EI on depression through proactive coping (b3 = 0.005), in which simple slope analysis showed a stronger mediating effect for pilots with more PFE (simple slope = -0.14). DISCUSSION: The results showed that EI and proactive coping had protective potential in the prevention of depression and anxiety. Implications for the promotion of mental health and diminishing depression and anxiety among pilots are discussed.Guo Y, Ji M, You X, Huang J. Protective effects of emotional intelligence and proactive coping on civil pilots' mental health. Aerosp Med Hum Perform. 2017; 88(9):858-865. PMID- 28818146 TI - Metabolic Syndrome and Cardio-Cerebrovascular Risk Disparities Between Pilots and Aircraft Mechanics. AB - INTRODUCTION: In the Republic of Korea Air Force, the health of pilots is strictly supervised, but there is comparatively not enough interest in aircraft mechanics' health. Among mechanics, who are heavily involved in military aircraft maintenance, the occurrence of sudden cardio-cerebrovascular diseases (CCVDs) is a possible risk factor during the maintenance process, which should be performed perfectly. METHODS: We performed health examinations on 2123 male aircraft pilots and 1271 aircraft mechanics over 30 yr of age and determined the prevalence of metabolic syndrome (MetS), an important risk factor for CCVDs. RESULTS: The prevalence of MetS in the aircraft mechanics (21.3%) was significantly higher than in the pilots (12.6%), and the gap in prevalence tended to grow as age increased. Among aircraft mechanics in their 30s and 40s, the prevalence of MetS was lower than in the general population. However, the prevalence of MetS among aircraft mechanics in their 50s (36.0%) was similar to that in the general population (35.7%). CONCLUSIONS: Systematic health management is needed for aircraft mechanics for aviation safety and for the maintenance of military strength via the prevention of CCVDs.Kim M-B, Kim H-J, Kim S-H, Lee S-H, Lee S-H, Park W-J. Metabolic syndrome and cardio-cerebrovascular risk disparities between pilots and aircraft mechanics. Aerosp Med Hum Perform. 2017; 88(9):866-870. PMID- 28818147 TI - Attention-Deficit/Hyperactivity Disorder and Fatal Accidents in Aviation Medicine. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with symptoms of inattention and/or hyperactivity impulsivity that interfere with functioning and/or development. ADHD occurs in about 2.5% of adults. ADHD can be an excluding medical condition among pilots due to the risk of attentional degradation and therefore impact on flight safety. Diagnosis of ADHD is complex, which complicates aeromedical assessment. This study highlights fatal accident cases among pilots with ADHD and discusses protocols to detect its presence to help to assess its importance to flight safety. METHODS: To identify fatal accidents in aviation (including airplanes, helicopters, balloons, and gliders) in the United States between the years 2000 to 2015, the National Transportation Safety Board (NTSB) database was searched with the terms ADHD, attention deficit hyperactivity disorder, and attention deficit disorder (ADD). RESULTS: The NTSB database search for fatal aviation accidents possibly associated with ADHD yielded four accident cases of interest in the United States [4/4894 (0.08%)]. Two of the pilots had ADHD diagnosed by a doctor, one was reported by a family member, and one by a flight instructor. An additional five cases were identified searching for ADD [5/4894 (0.1%)]. Altogether, combined ADHD and ADD cases yielded nine accident cases of interest (0.18%). DISCUSSION: It is generally accepted by aviation regulatory authorities that ADHD is a disqualifying neurological condition. Yet FAA and CASA provide specific protocols for tailor-made pilot assessment. Accurate evaluation of ADHD is essential because of its potential negative impact on aviation safety.Laukkala T, Bor R, Budowle B, Sajantila A, Navathe P, Sainio M, Vuorio A. Attention deficit/hyperactivity disorder and fatal accidents in aviation medicine. Aerosp Med Hum Perform. 2017; 88(9):871-875. PMID- 28818148 TI - Cross-Sectional Survey of Physicians on Providing Volunteer Care for In-Flight Medical Events. AB - BACKGROUND: Airline carriers have equipment, procedures, and protocols in place to handle in-flight medical events (IFMEs). Community physicians may be asked for aid during IFMEs. Cross-Sectional Survey of Physicians on Providing Volunteer Care for In-Flight Medical Events surveyed self-assessed awareness and knowledge, perceived barriers, and suggestions for improving responses to IFMEs. METHODS: We composed a survey regarding clinicians' self-assessed understanding of in-flight resources, procedures, flight environmental issues, and Good Samaritan protections. The survey was distributed primarily via electronic mail to medical staff list serves to a total of approximately 1300 physicians representing 2 health networks that serve urban, suburban, and rural areas in both inpatient and outpatient settings. RESULTS: Total number of responses was 418. Physician response rate was 29.2% (379/1300). In 3% (39/1300), the responder either failed to indicate their background or was another type of health care professional (e.g., dentist, medical student, physician assistant). Of the physicians, 37.5% (142/379) were primary care and 42% (177/418) of responders reported at least one experience of being asked to volunteer. When asked how well they understand the protocols with which medical events are handled, 64% (262/412) responded "not at all" and 23% (94/412) reported "a little" knowledge. Only 56% (223/397) answered that 75% or more of U.S. flights have ground medical support available. There were 73% (298/411) who believed airlines were required to have medical supplies, but 54% (222/410) reported no knowledge of supplies available. A total of 69% (279/403) believed or were sure that the U.S. has a Good Samaritan law that applies to IFMEs. DISCUSSION: Many physicians lack basic knowledge about IFMEs. Responders may assist more effectively if better informed about protocols and the availability of ground medical support. Education and timely information support are recommended.Chatfield E, Bond WF, McCay B, Thibeault C, Alves PM, Squillante M, Timpe J, Cook CJ, Bertino RE. Cross-Sectional Survey of Physicians on Providing Volunteer Care for In-Flight Medical Events. Aerosp Med Hum Perform. 2017; 88(9):876-879. PMID- 28818149 TI - Cerebellar Infarction Presenting with Acute Vestibular Syndrome in Two U.S. Air Force Pilots. AB - BACKGROUND: Cerebellar infarction is an uncommon but serious cause of isolated acute vestibular symptoms, particularly in young, healthy individuals, and can easily be overlooked. We present two cases of cerebellar infarction in U.S. Air Force pilots, one of which occurred during flight. CASE REPORTS: A 41-yr-old man developed acute vertigo, disequilibrium, nausea, and headache, with progressive slow symptomatic improvement, and presented to medical attention 4 d after symptom onset. Brain magnetic resonance imaging showed right inferomedial cerebellar infarction. Echocardiography discovered patent foramen ovale and atrial septal aneurysm. A 40-yr-old man developed severe vertigo, nausea, and vomiting during initial aircraft descent. Head computed tomography scan was performed acutely and was normal. Initial assessment was benign paroxysmal positional vertigo. Brain magnetic resonance imaging 1 mo after symptom onset showed a small right inferior cerebellar infarction. Patent foramen ovale and bilateral atrial enlargement were seen on echocardiography. Both pilots made full neurological recoveries and were eventually returned to flight status. DISCUSSION: Central causes of isolated acute vestibular symptoms are uncommon and are often not considered in otherwise healthy individuals. Cerebellar infarction is one of these uncommon but increasingly recognized causes of acute vestibular symptoms. As evaluation and management of central causes are much different from peripheral conditions, prompt localization confirmation is paramount. Accurate evidence-based bedside screening methods are available for rapid localization. Awareness of the possibility of central etiologies and careful clinical evaluation with application of bedside screening methods in patients with acute vestibular symptoms will reduce the number of inaccurate diagnoses.Hesselbrock RR. Cerebellar infarction presenting with acute vestibular syndrome in two U.S. Air Force pilots. Aerosp Med Hum Perform. 2017; 88(9):880-883. PMID- 28818150 TI - You're the Flight Surgeon. AB - Casstevens EA. You're the flight surgeon: an unexpected twist. Aerosp Med Hum Perform. 2017; 88(9):884-887. PMID- 28818151 TI - You're the Flight Surgeon. AB - Hatcher DR. You're the flight surgeon: migraine aura without headaches. Aerosp Med Hum Perform. 2017; 88(9):887-891. PMID- 28818152 TI - Dr. William Carpentier-Apollo 11 Flight Surgeon. PMID- 28818153 TI - This Month in Aerospace Medicine History. PMID- 28818155 TI - PAP Therapy's Effect on Cardiometabolic Risk Markers in Pediatric Patients. PMID- 28818154 TI - Physiology-Based Modeling May Predict Surgical Treatment Outcome for Obstructive Sleep Apnea. AB - STUDY OBJECTIVES: To test whether the integration of both anatomical and nonanatomical parameters (ventilatory control, arousal threshold, muscle responsiveness) in a physiology-based model will improve the ability to predict outcomes after upper airway surgery for obstructive sleep apnea (OSA). METHODS: In 31 patients who underwent upper airway surgery for OSA, loop gain and arousal threshold were calculated from preoperative polysomnography (PSG). Three models were compared: (1) a multiple regression based on an extensive list of PSG parameters alone; (2) a multivariate regression using PSG parameters plus PSG derived estimates of loop gain, arousal threshold, and other trait surrogates; (3) a physiological model incorporating selected variables as surrogates of anatomical and nonanatomical traits important for OSA pathogenesis. RESULTS: Although preoperative loop gain was positively correlated with postoperative apnea-hypopnea index (AHI) (P = .008) and arousal threshold was negatively correlated (P = .011), in both model 1 and 2, the only significant variable was preoperative AHI, which explained 42% of the variance in postoperative AHI. In contrast, the physiological model (model 3), which included AHIREM (anatomy term), fraction of events that were hypopnea (arousal term), the ratio of AHIREM and AHINREM (muscle responsiveness term), loop gain, and central/mixed apnea index (control of breathing terms), was able to explain 61% of the variance in postoperative AHI. CONCLUSIONS: Although loop gain and arousal threshold are associated with residual AHI after surgery, only preoperative AHI was predictive using multivariate regression modeling. Instead, incorporating selected surrogates of physiological traits on the basis of OSA pathophysiology created a model that has more association with actual residual AHI. COMMENTARY: A commentary on this article appears in this issue on page 1023. CLINICAL TRIAL REGISTRATION: ClinicalTrials.Gov; Title: The Impact of Sleep Apnea Treatment on Physiology Traits in Chinese Patients With Obstructive Sleep Apnea; Identifier: NCT02696629; URL: https://clinicaltrials.gov/show/NCT02696629. PMID- 28818156 TI - Time for Surgeons to Think Outside the Anatomical Box. PMID- 28818157 TI - Tumor Response Evaluation Criteria: Standardization Ensures Success. PMID- 28818158 TI - Adverse Effects of Caffeine on Development of Femur of BALB/c Mice and Protective Role of Vitamin D3. AB - OBJECTIVE: To determine the effects of caffeine ingestion on the development of femur and role of vitamin D3 in preventing these effects in BALB/c mice. STUDY DESIGN: Experimental study. PLACE AND DURATION OF STUDY: Department of Anatomy, Army Medical College, Rawalpindi, in cooperation with NIH (National Institute of Health), Islamabad, from October 2014 to October 2015. METHODOLOGY: Thirty (100%) BALB/c mice, 50% male and female each, three weeks old, weighing 12-14 grams were taken and divided equally and randomly into three groups, each having 10 (33.3%) mice; 5 (16.6%) male and female. G1 (control group) was given normal diet with water ad libitum. G2and G3(experimental groups) were given 10 mg of caffeine per 100g body weight, three days a week, through oral gavage for 60 days on alternate days. However, experimental group G3was additionally provided 0.1ug vitamin D3daily, through oral gavage for 60 days. Experimental groups were compared with control group and data was analyzed statistically. RESULTS: The mean weight of mice femur of G1(control group) was 0.387 +/-0.019 g; while mean weights of right femur of G2and G3(experimental groups) were 0.316 +/-0.020 g and 0.345 +/-0.020 g, respectively. Similarly, mean right femur length of group G1 was 20.70 +/ 0.609 mm; while for groups G2 and G3, it was 24.382 +/-1.087 mm and 22.966 +/ 0.822 mm, respectively. In comparison with group G1for groups G2and G3, femur weight decreased, however femur length increased. CONCLUSION: Caffeine intake caused femur length to increase and weight to decrease, but treatment with vitamin D3. PMID- 28818159 TI - Effects of Iron Administration on the Diameter of Cells of Growth Cartilage of Rat Pups During Pregnancy. AB - OBJECTIVE: To determine the effect of oral iron administration on pregnant rats on the diameter of cells of growth plate of rat pups. STUDY DESIGN: Experimental study. PLACE AND DURATION OF STUDY: Anatomy Department, Army Medical College, Rawalpindi in collaboration with National Institute of Health (NIH), Islamabad from March to November 2016. METHODOLOGY: Group Acontaining 8 pregnant rats was control group, and group B containing same number of pregnant rats was the study group. Control group Awas on standard diet throughout pregnancy. Iron was given to the experimental group B for 21 days (throughout pregnancy) in the form of syrup 0.5ml daily (2.75 mg of elemental iron) given in water. Rat infants were born via spontaneous vaginal delivery. Inclusion criteria for infants was pups born at term which were active and taking feed. Femur from each rat infant of right side was removed for the growth plate investigation. Processing, embedding and staining with Hematoxylin and Eosin, Perl's stain for histological study was done. The cell diameter in hypertrophy and proliferative zone was evaluated. Mean values of the diameter of chondrocytes in both the zones of growth cartilage of femur were measured. RESULTS: Diameter of the cells in hypertrophy and proliferative zones was considerably decreased in group B as compared to group A. CONCLUSION: Administration of iron during pregnancy with normal iron status can disturb growth of the rat infant through its accumulation in the epiphyseal plate of femur. The cell diameter of the hypertrophy and proliferative zones was markedly reduced in iron administered group as compared to the control group. PMID- 28818160 TI - Determination of Mean Glycated Haemoglobin in Healthy Adults of a Local Population. AB - OBJECTIVE: To determine the mean hemoglobin HbA1C levels of disease-free adults in a local population and its optimum cutoff for the diagnosis of diabetes. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Department of Chemical Pathology and Endocrinology, Armed Forces Institute of Pathology, Rawalpindi, from January to September 2015. METHODOLOGY: Healthy subjects aged 18 years and above of either gender were recruited from local population. Pregnant ladies and individuals with known diabetes, chronic kidney disease, chronic liver disease, congestive cardiac failure, anemia, hemoglobinopathies, mental illness and individuals on glucocorticoid therapy were excluded. Fasting plasma glucose (FPG) or 2-hour plasma glucose (2-h PG) was analyzed using hexokinase methodology and glycated hemoglobin (Hb A1C) was also analyzed using turbidimetric inhibition immunoassay technique. Receiver operating characteristic (ROC) curves were plotted. Differences among the groups were tested by one-way ANOVA, and p <0.05 was considered statistically significant. RESULTS: Among 558 subjects, 88.8% (496) were normoglycaemic (NG), 5.7% (32) were with impaired glucose fasting (IFG), and 5.4% (30) were diagnosed with diabetes mellitus (DM). A1C was 5.00 +/ 0.44% in NG and 6.28 +/-1.16% in diabetics. FPG in NG was 4.55 +/-0.95 mmol/Land in diabetics was 8.28 +/-1.78 mmol/L. The optimal HbA1C cutoff value for diagnosis of DM was at 6.05% (AUC 0.827 95% CI 0.732 to 0.923, p <=0.05 with its sensitivity of 53.3% and specificity of 98.5%. However, HbA1C showed suboptimal sensitivity and specificity for prediabetes. CONCLUSION: The mean HbAIC and cutoff point for diabetes in the study population is 5.07 +/-0.58% and 6.05%, respectively (AUC 0.827, 95% CI: 0.732 to 0.923, p<0.001) with 53.3% sensitivity and 98.5% specificity. PMID- 28818161 TI - Using Mind Maps to Improve Medical Student Performance in a Pharmacology Course at Kunming Medical University. AB - OBJECTIVE: To determine whether students using mind maps would improve their performance in a final examination at the end of lecture-based pharmacology course. STUDY DESIGN: Aquasi-experimental study. PLACE AND DURATION OF STUDY: Kunming Medical University, from September 2014 to January 2015. METHODOLOGY: One hundred and twenty-two (122) third year undergraduate medical students, starting a 48-hour lecturebased pharmacology course, volunteered to use mind maps as one of their study strategies (intervention group), while the remaining 100 students in the class continued to use their usual study strategies (control group) over the duration of the course. The performance of both groups in the final course examination was compared. Students in the intervention group also completed a questionnaire on the usefulness of mind maps during the course and in preparation for the final examination. RESULTS: The students' performance of intervention group was superior to performance of the control group in all parts of a multi modal final examination. For the multiple choice questions and comprehensive scores, average marks of 45.97 +/-7.22 and 68.07 +/-12.77, respectively were acquired by the control group, and 51.77 +/-4.95 (p<0.01) and 80.05 +/-7.54 (p<0.01), respectively by the intervention group. The median IQR scores for "filling in the blanks" questions, short answers questions and case analyses, were 6.00 (6.00), 8.00 (3.50), 8.75 (5.88), respectively for the control group, and were all significantly higher at 8.00 (4.00) (p=0.024), 10.00 (2.00) (p<0.001), and 11.00 (3.25) (p=0.002), respectively for the interventiongroup. Questionnaire responses showed that 95.45% thought that mind maps helped them to prepare more efficiently for the final exam; 90.91% believed that mind maps helped them to better understand all of pharmacology. Ninety-one percent also thought that mind maps would help them to better understand other disciplines, and 86.36% students would like the lecturers to utilize mind mapping as an alternative to conventional teaching formats, such as the use of Power Point. CONCLUSION: The addition of mind maps to students' study of pharmacology at Kunming Medical University improved their performance in all aspects of a multi modal final examination. PMID- 28818162 TI - Impact of a Social Media Group Page on Undergraduate Medical Physiology Learning. AB - OBJECTIVE: To investigate the impact of associating classroom learning of medical physiology with a Facebook group page in an all-women medical college of a conservative small city in Pakistan. STUDY DESIGN: Qualitative interpretivist study using semi-structured interviews. PLACE AND DURATION OF STUDY: Women Medical College Abbottabad, Pakistan, from March to December 2014. METHODOLOGY: Aclosed Facebook study group was established at a local medical college in Pakistan. It was used to upload learning resources and initiate discussions, coordinated with classroom lectures of physiology. Thirteen semistructured interviews were conducted with volunteer students according to a standard protocol. RESULTS: Five major themes were identified. Facebook group is something new and exciting; it motivated self-study, research, collaborative learning and improved class attendance. Convenience of easily accessible resources allowed the students to concentrate on the lecture rather than note taking. It was easier to communicate with the instructor through Facebook than face to face. Lurkers were also learning. High achievers who had adapted to the current didactic system of teaching were less receptive of the collaborative learning and favored teaching geared towards exam preparation. CONCLUSION: Using social media for e-learning in undergraduate medical education can enhance the student learning experience, especially in resource-limited regions where Information and communication technology is not an integrated part of the teaching process. PMID- 28818163 TI - Evaluation of 'CKD-EPI Pakistan' Equation for estimated Glomerular Filtration Rate (eGFR): AComparison of eGFR Prediction Equations in Pakistani Population. AB - OBJECTIVE: To evaluate the results of 24-hour urinary creatinine clearance (CrCl) with estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), CKD-EPI Pakistan (CKD-EPI Pak), Cockcroft Gault (CG) and 4-variable Modification of Diet in Renal Disease (MDRD) equations. STUDY DESIGN: Descriptive, cross-sectional study. PLACE AND DURATION OF STUDY: Section of Clinical Chemistry, Department of Pathology and Laboratory Medicine, The Aga Khan University, Karachi, from June to October 2013. METHODOLOGY: Laboratory data of subjects >=18 years ordering 24-hour urinary CrCl from June to October 2013 was retrieved. Statistical comparison of eGFR using CKD-EPI, CKD-EPI Pak, CG and MDRD with the timed urine collection CrCl was done using regression analysis. RESULTS: The mean age of the group (n=670) was 51.3 +/-15.4 years with a median of 53 (IQR:22.3) years, 55.7% being males. Median BMI of males and females was 26.98 kg/m2(IQR: 7.09) and 26.16 kg/m2(IQR: 6.97), respectively. Mean GFR using 24-hour creatinine clearance was 57.1 +/-35.9 ml/min/1.73m2 with a median of 51 ml/min/1.73m2. Urinary creatinine clearance showed strong correlation with CG, MDRD, CKD-EPI and CKD-EPI Pak, showing r=0.78, r=0.79, r=0.82, and r=0.82, respectively. Sensitivity was highest for the CKD-EPI Pakistan (84.7%). Similarly, CKD-EPI Pakistan equation showed the highest agreement (88.7%) with CrCl compared to the other formulae. CONCLUSION: The CKD EPI Pak equation is more accurate and precise than the CG, CKD-EPI and MDRD in estimating GFR in Pakistani population. PMID- 28818164 TI - Outcome in Chronic Subdural Hematoma After Subdural vs. Subgaleal Drain. AB - OBJECTIVE: To compare the outcome after surgery for chronic subdural hematoma when the drain is placed in subdural space or subgaleal space. STUDY DESIGN: Quasi experimental study. PLACE AND DURATION OF STUDY: Combined Military Hospital, Lahore, from July 2015 to June 2016. METHODOLOGY: Patients with chronic subdural hematoma of both genders and age, ranging between 55 to 85 years, were included. Patients on antiplatelet/anticoagulant therapy and acute on chronic subdural hematoma were excluded. Patients were divided in two equal groups each depending on whether drain was placed in subgaleal space (Group 1), and subdual space (Group 2), (n=31 patients each). Patients were positioned flat in bed after surgery. Clinical and radiological parameters and clinical outcome were compared between the two groups. Statistical test with significance of p <0.05 was utilized using Statistical Package of Social Sciences (SPSS version 17). RESULTS: Median age of the 62 patients was 72 +/-12.5 years. Headache was the most common symptom reported in both groups, (n=47,75.8%) patients. Median thickness of hematoma was 15 +/-6.5 mm. Patients with subdural drain placement had more complications such as pneumocephalus 11 (35.4%) vs. 6 (19.3%), and intracerebral hemorrhage 4 (12.9%) vs. 2 (6.4%). Clinical outcome was good in both groups 27 (87%) in Group 1 and 28 (90%) in Group 2. CONCLUSION: Patients of both groups had good outcome after surgery. Complications like pneumocephalus and intracerebral hemorrhage were more common in subdural location of drain, though not reaching statistically significance level to favor one technique over another. PMID- 28818165 TI - Effectiveness and Safety of Sofosbuvir in Treatment-NaiveChildren with Hepatitis C Infection. AB - OBJECTIVE: To determine the effectiveness and safety of Sofosbuvir and Ribavirin combination in treatment-naivechildren with HCV infection. STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: Gastroentrology, Hepatology Department, The Children's Hospital and The Institute of Child Health, Lahore, from January to December 2016. METHODOLOGY: HCV PCR positive treatment naivepatients, 5 to 18 years of age, were enrolled by consecutive nonprobability sampling. Clinical features and investigations including complete blood count, bilirubin, ALT, PTand HCV genotyping were done. All patients were started on Sofosbuvir 400 mg once daily and Ribavirin 10-15 mg/kg/day. Patients were followed on 4-weekly basis. PCR was done after 4 weeks; if positive then again at 12 weeks. End of treatment and 12 weeks post treatment PCR was done in all patients. Total duration of therapy was 24 weeks. Computer program SPSS version 20 was used for data analysis. RESULTS: Atotal of 35 patients with mean age of 10.24 +/-2.80 years, including 22 boys (62.86%), and 13 girls (37.14%) were included. The most common HCV genotype was genotype 3 encountered in 27 (77.15%), followed by genotype 1 in 6 (17.14%), while 2 (5.71%) patients were untypable. Thirty (85.71%) patients achieved rapid virological response while the rest 5 (14.28%) had early virological response. End-of-treatment PCR was negative in all patients. SVR was achieved by 34 (97.14%) patients. The treatment was well tolerated. Headache was observed in 8 (22.86%) patients, which improved spontaneously. CONCLUSION: Sofosbuvir and Ribavirin combination is highly effective in HCV genotypes 1 and 3 with no major undesirable short-term side effects. PMID- 28818166 TI - Assessment of Quality of Sleep and its Relationship with Psychiatric Morbidity and Socio-Demographic Factors in the Patients of Chronic Renal Disease Undergoing Hemodialysis. AB - OBJECTIVE: To assess the subjective sleep quality and its relationship with the presence of psychiatric morbidity in the patients suffering from chronic kidney disease (CKD) and undergoing the procedure of hemodialysis (HD); and analyze the associated socio-demographic factors. STUDY DESIGN: Cross-sectional descriptive study. PLACE AND DURATION OF STUDY: Nephrology Department, Military Hospital, Rawalpindi, from July to December 2016. METHODOLOGY: Patients of CKD undergoing the HD were included in the final analysis. Quality of sleep was determined by using the Pittsburgh Sleep Quality Index (PSQI). Psychiatric morbidity was determined by the General Health Questionnaire 12 (GHQ-12). Relationship of education, BMI, gender, age, duration of dialysis, dialysis count per week, marital status, level of family income, psychiatric morbidity, occupation, biochemical markers (urea, creatinine, BUN, albumin, calcium, phosphorous and hemoglobin), tobacco smoking, and use of naswar was determined with the sleep quality. RESULTS: One hundred and forty patients were screened through the PSQI; 44 (31.4%) had good quality of sleep while 96 (68.6%) had poor sleep quality. Statistical analysis revealed that presence of psychiatric morbidity, increasing age, female gender, being unmarried, low family income, and low frequency of dialysis had significant association with the poor sleep quality. CONCLUSION: Poor sleep quality was highly prevalent among the patients of CKD receiving the hemodialysis. The patients with low family income, more age, and with two or less dialysis sessions per week should be screened thoroughly for the sleep problems. Presence of psychiatric morbidity emerged as an independent factor responsible for the poor sleep quality in our target population. PMID- 28818167 TI - Long-term Outcomes of Paclitaxel-Eluting Versus Sirolimus-Eluting Stent for Percutaneous Coronary Intervention: AMeta-Analysis. AB - The relative long-term efficacy and safety of sirolimus-eluting stents (SES) compared with paclitaxel-eluting stents (PES) in multiple comparative studies remains controversial. This report evaluates 29 randomized trials with 18,379 patients in whom long-term (more than 1 year) outcomes were evaluated. The primary outcomes were target lesion revascularization (TLR) and the secondary end points were death, cardiac death, myocardial infarction (MI), major adverse cardiac events (MACEs), target vessel revascularization (TVR) and stent thrombosis (ST). In comparison with PES, SES significantly reduced the long-term risk of TLR (RR=0.68; 95% CI=0.57 to 0.80, p<0.001), TVR (RR=0.69; 95% CI= 0.60 to 0.79, p<0.001) and MACE (RR=0.82; 95% CI= 0.77 to 0.88, p<0.001), while there were no significant difference with respect to death, cardiac death, MI and STbetween the two groups. SES performance was significantly better for reducing the former three outcomes and comparable for the majority of the secondary end points when compared against PES. PMID- 28818168 TI - Penile Shaft Strangulation with Wrought Iron Metallic Pipe. AB - Penile strangulation due to any solid encircling ornament or metal is rarely reported. Venous outflow obstruction due to any constricting item around the shaft leads to venous congestion, urinary obstruction, and rarely gangrene of the penile shaft skin. We report a case presenting with penile near-strangulation due to iron-lead metallic junction pipe which was cut using a heavy electric metal cutter. PMID- 28818169 TI - Tuberculosis of Open Cholecystectomy Wound. AB - Tuberculosis of the wound is a rare entity. A50-year lady presented with an "on and off discharging wound" from the postoperative wound site of open cholecystectomy, which was done 7 years ago. Patient did not respond to standard antibiotic treatment regimens; and also the culture remained equivocal during this period. We explored the wound and found a mass in subcutaneous tissue. Resection of mass was done and wound left open for closure by secondary intention. Histopathology of the resected mass revealed tuberculosis. Patient was started on anti-tuberculous therapy (ATT). Patient responded to the ATTtherapy, with satisfactory healed wound at one month follow-up visit. Thus, surgeons should keep in mind the increased possibility for the tuberculous etiology of wound infection in chronic, non-healing wounds. PMID- 28818170 TI - Post-Chemotherapy Neuroblastoma-like Differentiation in Ewing Sarcoma of Humerus: Report of a Rare Case with Review of Literature. AB - A21-year patient initially presented with a fracture of the humerus following minor trauma. Abone scan and biopsy were done due to the suspicion of pathological fracture and the biopsy confirmed the diagnosis of Ewing Sarcoma (EWS). Two months after initial presentation, chemotherapy was started and 5 cycles were given over a span of 6 months. Surgical resection of the tumor was then performed. The post-chemotherapy resection specimen, on histological examination, showed the presence of areas of neuroblastoma-like differentiation in otherwise morphologically classic EWS. Cytogenetic analysis by FISH revealed EWSR1 gene rearrangement. Four similar cases have been reported earlier in literature, all in females below 20 years of age. Our case is unique as it is the first case of post-chemotherapy neuroblastoma-like differentiation of EWS in a 21 year male. PMID- 28818171 TI - Rapid and Promising Technique to Treat Gummy Smile - Lip Repositioning. AB - Beautiful smile is a booster to person's confidence. Gummy smile is a term used for excessive gingival display (EGD). Its etiology is multifactorial. Bone vertical maxillary excess (VME) is one of the cause of EGD. In this case series, lip repositioning was performed to treat mild to moderate degree of gingival display ( 2 to 8 mm) due to VME. Lip repositioning is simple, promising, meticulous and comparatively cheap alternative technique for treating gummy smile. PMID- 28818172 TI - Clinical Profile and Short-Term Outcome of Pediatric Hyperleukocytic Acute Leukemia from a Developing Country. AB - This study was conducted to determine the frequency, clinical profile, and short term outcome of children with hyperleukocytosis at two pediatric oncology centers in Karachi. Of a total 1,045 patients, 13.97% (n=146) patients had hyperleukocytosis. Majority (61.7%, n=90) were under 10 years of age and 76% (n=146) were male. The symptom duration before diagnosis was more than 30 days in 49.3% (n=72). The median WBC count was 181 x109/L(IQR=130.45298.3) and extreme hyperleukocytosis (>200 x109/L) was observed in 44.5% (n=65) patients. Majority (94.5%, n=138) of patients were diagnosed with acute lymphoblastic leukemia. One or more complications developed in 78% (n=114) of cases. Clinical and laboratory tumor lysis syndrome (TLS) was observed in 17.1% (n=25) and 39% (n=57) patients, respectively. Pulmonary and neurological complications related to leukostasis were noted in 9.5% (n=14) and 27.3% (n=40) of cases, respectively. Infectious complications occurred in 23.2% (n=34) patients. The case-specific mortality was 20.5% (n=30). No mortality was related to early complications of hyperleukocytosis. PMID- 28818173 TI - Mirror Mirror on The Wall - Who is Right of Us All. PMID- 28818174 TI - Reviewers' Role in Research. PMID- 28818175 TI - Solitary Fibrous Tumor / Hemangiopericytoma of Palate - Report of a Case with Immunohistochemical Interpretation Using CD 34. PMID- 28818176 TI - Leiomyoma of Bladder in a Male Patient with Unusual Presentation. PMID- 28818178 TI - Second-Degree Burns after the Application of a Mustard-and-Honey Body Wrap. PMID- 28818177 TI - Angioedema. AB - BACKGROUND: Acute angioedema of the upper airways can be life-threatening. An important distinction is drawn between mast-cell-mediated angioedema and bradykinin-mediated angioedema; the treatment of these two entities is fundamentally different. METHODS: This review is based on pertinent articles retrieved by a selective search in PubMed and on guidelines concerning the treatment of angioedema. The authors draw on their own clinical experience in their assessment of the literature. RESULTS: In the emergency clinical situation, the most important information comes from accompanying manifestations such as itching and urticaria and from the patient's drug history and family history. When angioedema affects the head and neck, securing the upper airways is the highest priority. Angioedema is most commonly caused by mast-cell mediators, such as histamine. This type of angioedema is sometimes accompanied by urticaria and can be effectively treated with antihistamines or glucocorticoids. In case of a severe allergic reaction or anaphylaxis, epinephrine is given intramuscularly in a dose that is adapted to the patient's weight (150 MUg for body weight >10 kg, 300 MUg for body weight >30 kg). Bradykinin-mediated angioedema may arise as either a hereditary or an acquired tendency. Acquired angioedema can be caused by angiotensin converting enzyme (ACE) inhibitors and by angiotensin II receptor blockers. Bradykinin-mediated angioedema should be treated specifically with C1 esterase inhibitor concentrates or bradykinin-2 receptor antagonists. CONCLUSION: Angioedema of the upper airways requires a well-coordinated diagnostic and therapeutic approach. Steroids and antihistamines are very effective against mast cell-mediated angioedema, but nearly useless against bradykinin-mediated angioedema. For angioedema induced by ACE inhibitors, no causally directed treatment has yet been approved. PMID- 28818179 TI - Multiple Trauma and Emergency Room Management. AB - BACKGROUND: The care of severely injured patients remains a challenge. Their initial treatment in the emergency room is the essential link between first aid in the field and definitive in-hospital treatment. METHODS: We present important elements of the initial in-hospital care of severely injured patients on the basis of pertinent publications retrieved by a selective search in PubMed and the current German S3 guideline on the care of severely and multiply traumatized patients, which was last updated in 2016. RESULTS: The goal of initial emergency room care is the rapid recognition and prompt treatment of acutely life threatening injuries in the order of their priority. The initial assessment includes physical examination and ultrasonography according to the FAST concept (Focused Assessment with Sonography in Trauma) for the recognition of intraperitoneal hemorrhage. Patients with penetrating chest injuries, massive hematothorax, and/or severe injuries of the heart and lungs undergo emergency thoracotomy; those with signs of hollow viscus perforation undergo emergency laparotomy. If the patient is hemo - dynamically stable, the most important diagnostic procedure that must be performed is computerized tomography with contrast medium. Therapeutic decision-making takes the patient's physiological parameters into account, along with the overall severity of trauma and the complexity of the individual injuries. Depending on the severity of trauma, the immediate goal can be either the prompt restoration of organ structure and function or so-called damage control surgery. The latter focuses, in the acute phase, on hemostasis and on the avoidance of secondary damage such as intra abdominal contamination or compartment syndrome. It also involves the temporary treatment of fractures with external fixation and the planning of definitive care once the patient's organ functions have been securely stabilized. CONCLUSION: The care of the severely injured patient should be performed in structured fashion according to the A-B-C-D-E scheme, which involves the securing of the airway, breathing, and circulation, the recognition of neurologic deficits, and whole body examination by the interdisciplinary team. PMID- 28818180 TI - Protecting the Health of Pregnant Women. PMID- 28818181 TI - Primary Prevention Ahead of Pregnancy. PMID- 28818182 TI - In Reply. PMID- 28818183 TI - Regulation by Means of Diet/Nutrition. PMID- 28818184 TI - Importance in Neuroprotection. PMID- 28818186 TI - Problem with the Separating Gel in a Blood Sample Tube in a Patient with Multiple Myeloma. PMID- 28818185 TI - In Reply. PMID- 28818187 TI - Ileus in Adults. AB - BACKGROUND: Ileus is one of the more common suspected diagnoses in everyday clinical practice. The term can refer either to mechanical or to functional ileus. Any physician who takes care of patients can be confronted with these entities; thus, all should be familiar with them and competent in their management. METHODS: Recommendations are summarized for the diagnostic evaluation and treatment of ileus of various causes on the basis of a selective literature review. RESULTS: The manifestations of ileus and its degree of severity generally depend on the site of blockage. The rule until recently was that a patient with suspected mechanical ileus should be taken to surgery within 12 hours; today, however, ileus-particularly of the small bowel-can often be successfully treated conservatively. Likewise, functional ileus only rarely requires surgery: supportive measures, depending on the etiology, usually suffice. CONCLUSION: Proper treatment depends on the timely determination of the pathogenesis (mechanical versus functional) and on close interdisciplinary collaboration. A special challenge is posed by patients with peritoneal involvement with cancer who present with symptoms of ileus, in whom a clear distinction between mechanical and functional causation cannot always be drawn. PMID- 28818189 TI - Hemodialysis treatment engenders anxiety and emotional distress?. AB - AIMS: Anxiety is common in maintenance hemodialysis (MHD) patients. The extent to which anxiety is engendered by the dialysis treatment itself is not known. We investigated whether anxiety occurs with individual hemodialysis treatments and examined factors associated with these symptoms. MATERIALS AND METHODS: This was a cross-sectional study examining 246 MHD patients. Anxiety and other emotional distresses associated with hemodialysis treatments were examined with a questionnaire. Patients were also assessed with the Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI). RESULTS: Patients were 57 +/- 15 (SD) years; 58% male, 46% diabetic, and undergoing MHD for a median of 40 months (range: 6 - 210 months). 32 - 51% of patients reported anxiety when coming to dialysis, hearing an alarm sound, being connected to the dialysis machine by a new person or seeing paramedics in the dialysis unit. 12 - 18% of patients experienced severe anxiety with one or more of these events. Dialysis-related anxiety correlated with severity of anxiety and depression as determined by BAI and BDI (p < 0.0001 for each comparison) but generally not with dialysis vintage. Even among patients with no or minimal anxiety according to BAI, 9 - 23% reported a little bit to moderate anxiety and 9 - 15% described quite a bit to extreme anxiety with hemodialysis treatments. The frequency that patients described distressing thoughts and feelings correlated directly with their degree of anxiety or depression as determined by BAI and BDI. CONCLUSION: Patients commonly experience anxiety, which is often severe, with MHD treatments. Hemodialysis induced anxiety is directed related to the presence and severity of underlying anxiety and depression. Hemodialysis-associated anxiety is prevalent and may be severe even in patients with minimal or no anxiety and/or depression, as determined by BAI and BDI. The frequency and severity of hemodialysis anxiety does not decrease with greater dialysis vintage except for a reduction in anxiety when hearing the dialysis machine alarm.?. PMID- 28818188 TI - Healthcare outcomes in undocumented immigrants undergoing two emergency dialysis approaches?. AB - BACKGROUND: Current estimates suggest 6,500 undocumented end-stage renal disease (ESRD) patients in the United States are ineligible for scheduled hemodialysis and require emergent dialysis. In order to remain in compliance with Emergency Medicaid, an academic health center altered its emergency dialysis criteria from those emphasizing interdialytic interval to a set emphasizing numerical thresholds. We report the impact of this administrative change on the biochemical parameters, utilization, and adverse outcomes in an undocumented patient cohort. METHODS: This retrospective case series examines 19 undocumented ESRD patients during a 6-month transition divided into three 2-month periods (P1, P2, P3). In P1, patients received emergent dialysis based on interdialytic interval and clinical judgment. In P2 (early transition) and P3 (equilibrium), patients were dialyzed according to strict numerical criteria coupled with clinical judgment. RESULTS: Emergent criteria-based dialysis (P2 and P3) was associated with increased potassium, blood urea nitrogen (BUN), and acidosis as compared to P1 (p < 0.05). Overnight hospitalizations were more common in P2 and P3 (p < 0.05). More frequent adverse events were noted in P2 as compared to P1 and P3, with an odds ratio (OR) for the composite endpoint (intubation, bacteremia, myocardial infarction, intensive care unit admission) of 48 (5.9 - 391.2) and 16.5 (2.5 - 108.6), respectively. Per-patient reimbursement-to-cost ratios increased during criteria-based dialysis periods (P1: 1.49, P2: 2.3, P3: 2.49). DISCUSSION: Strict adherence to criteria-based dialysis models increases biochemical abnormalities while improving Medicaid reimbursement for undocumented immigrants. Alternatives to emergent dialysis are required which minimize cost, while maintaining dignity, safety, and quality of life.?. PMID- 28818191 TI - MACRA Is a Law: Practice Transformation Is the Goal. PMID- 28818190 TI - Aortic Bioprosthetic Valve Durability: Incidence, Mechanisms, Predictors, and Management of Surgical and Transcatheter Valve Degeneration. AB - In recent times, there has been a considerable increase in the use of aortic bioprostheses (vs. mechanical prostheses) for treating aortic valve disease, and this tendency is likely to continue in the near future. However, the occurrence of structural valve degeneration, limiting valve durability, remains an important drawback of surgical and transcatheter bioprostheses. In this paper, we provide an overview of bioprosthetic valve durability, focusing on the definition, incidence, mechanisms, predictive factors, and management of structural degeneration of aortic bioprostheses. PMID- 28818192 TI - Vascular Burden Impact on Echocardiographic Valvular Graft Degeneration Following a Ross Procedure in Young Adults. PMID- 28818193 TI - The Time-Varying Risk of Cardiovascular and Noncardiovascular Readmissions Early After Acute Myocardial Infarction. PMID- 28818194 TI - Coronary Artery Disease Affects Symptomatology of Aortic Valve Stenosis. PMID- 28818195 TI - Reply: Coronary Artery Disease Affects Symptomatology of Aortic Valve Stenosis. PMID- 28818196 TI - Aspirin for the Prevention of Infective Endocarditis? PMID- 28818197 TI - Reply: Aspirin for the Prevention of Infective Endocarditis? PMID- 28818198 TI - Correction. PMID- 28818199 TI - Correction. PMID- 28818200 TI - Relationship of Alcohol Consumption to All-Cause, Cardiovascular, and Cancer Related Mortality in U.S. Adults. AB - BACKGROUND: Previous studies have revealed inconsistent findings regarding the association of light to moderate alcohol consumption with cardiovascular disease (CVD) and cancer mortality. OBJECTIVES: The aim of this study was to examine the association between alcohol consumption and risk of mortality from all causes, cancer, and CVD in U.S. adults. METHODS: Data were obtained by linking 13 waves of the National Health Interview Surveys (1997 to 2009) to the National Death Index records through December 31, 2011. A total of 333,247 participants >=18 years of age were included. Self-reported alcohol consumption patterns were categorized into 6 groups: lifetime abstainers; lifetime infrequent drinkers; former drinkers; and current light, moderate, or heavy drinkers. Secondary exposure included participants' binge-drinking status. The main outcome was all cause, cancer, or CVD mortality. RESULTS: After a median follow-up of 8.2 years (2.7 million person-years), 34,754 participants died of all causes (including 8,947 CVD deaths and 8,427 cancer deaths). Compared with lifetime abstainers, those who were light or moderate alcohol consumers were at a reduced risk of mortality for all causes (light-hazard ratio [HR]: 0.79; 95% confidence interval [CI]: 0.76 to 0.82; moderate-HR: 0.78; 95% CI: 0.74 to 0.82) and CVD (light-HR: 0.74; 95% CI: 0.69 to 0.80; moderate-HR: 0.71; 95% CI: 0.64 to 0.78), respectively. In contrast, there was a significantly increased risk of mortality for all causes (HR: 1.11; 95% CI: 1.04 to 1.19) and cancer (HR: 1.27; 95% CI: 1.13 to 1.42) in adults with heavy alcohol consumption. Binge drinking >=1 d/week was also associated with an increased risk of mortality for all causes (HR: 1.13; 95% CI: 1.04 to 1.23) and cancer (HR: 1.22; 95% CI: 1.05 to 1.41). CONCLUSIONS: Light and moderate alcohol intake might have a protective effect on all-cause and CVD-specific mortality in U.S. adults. Heavy or binge drinking was associated with increased risk of all-cause and cancer-specific mortality. PMID- 28818201 TI - Alcohol and Health: Praise of the J Curves. PMID- 28818203 TI - Cancer and Clot: Between a Rock and a Hard Place. PMID- 28818202 TI - Risk of Arterial Thromboembolism in Patients With Cancer. AB - BACKGROUND: The risk of arterial thromboembolism in patients with cancer is incompletely understood. OBJECTIVES: The authors aimed to better define this epidemiological relationship, including the effects of cancer stage. METHODS: Using the Surveillance Epidemiology and End Results-Medicare linked database, the authors identified patients with a new primary diagnosis of breast, lung, prostate, colorectal, bladder, pancreatic, or gastric cancer or non-Hodgkin lymphoma from 2002 to 2011. They were individually matched by demographics and comorbidities to a Medicare enrollee without cancer, and each pair was followed through 2012. Validated diagnosis codes were used to identify arterial thromboembolism, defined as myocardial infarction or ischemic stroke. Cumulative incidence rates were calculated using competing risk survival statistics. Cox hazards analysis was used to compare rates between groups at discrete time points. RESULTS: The authors identified 279,719 pairs of patients with cancer and matched control patients. The 6-month cumulative incidence of arterial thromboembolism was 4.7% (95% confidence interval [CI]: 4.6% to 4.8%) in patients with cancer compared with 2.2% (95% CI: 2.1% to 2.2%) in control patients (hazard ratio [HR]: 2.2; 95% CI: 2.1 to 2.3). The 6-month cumulative incidence of myocardial infarction was 2.0% (95% CI: 1.9% to 2.0%) in patients with cancer compared with 0.7% (95% CI: 0.6% to 0.7%) in control patients (HR: 2.9; 95% CI: 2.8 to 3.1). The 6-month cumulative incidence of ischemic stroke was 3.0% (95% CI: 2.9% to 3.1%) in patients with cancer compared with 1.6% (95% CI: 1.6% to 1.7%) in control patients (HR: 1.9; 95% CI: 1.8 to 2.0). Excess risk varied by cancer type (greatest for lung), correlated with cancer stage, and generally had resolved by 1 year. CONCLUSIONS: Patients with incident cancer face a substantially increased short-term risk of arterial thromboembolism. PMID- 28818205 TI - Strain Echocardiography: The New Gold Standard for Imaging Ventricular Function? PMID- 28818204 TI - Geometry as a Confounder When Assessing Ventricular Systolic Function: Comparison Between Ejection Fraction and Strain. AB - BACKGROUND: Preserved left ventricular (LV) ejection fraction (EF) and reduced myocardial strain are reported in patients with hypertrophic cardiomyopathy, ischemic heart disease, diabetes mellitus, and more. OBJECTIVES: The authors performed a combined mathematical and echocardiographic study to understand the inconsistencies between EF and strains. METHODS: An analytical equation showing the relationship between EF and the 4 parameters, global longitudinal strain (GLS), global circumferential strain (GCS), wall thickness, and short-axis diameter, was derived from an elliptical LV model. The equation was validated by measuring the 4 parameters by echocardiography in 100 subjects with EF ranging from 16% to 72% and comparing model-predicted EF with measured EF. The effect of the different parameters on EF was explored in the model and compared with findings in the patients. RESULTS: Calculated EF had very good agreement with measured EF (r = 0.95). The model showed that GCS contributes more than twice as much to EF than GLS. A significant reduction of GLS could be compensated by a small increase of GCS or wall thickness or reduced diameter. The model further demonstrated how EF can be maintained in ventricles with increased wall thickness or reduced diameter, despite reductions in both longitudinal and circumferential shortening. This was consistent with similar EF in 20 control subjects and 20 hypertrophic cardiomyopathy patients with increased wall thickness and reductions in both circumferential and longitudinal shortening (all p < 0.01). CONCLUSIONS: Reduced deformation despite preserved EF can be explained through geometric factors. Due to geometric confounders, strain better reflects systolic function in patients with preserved EF. PMID- 28818207 TI - beta-Adrenergic Blockade in Ischemia-Reperfusion Injury: betaARKing Up a New Tree. PMID- 28818206 TI - Pharmacological and Activated Fibroblast Targeting of Gbetagamma-GRK2 After Myocardial Ischemia Attenuates Heart Failure Progression. AB - BACKGROUND: Cardiac fibroblasts are a critical cell population responsible for myocardial extracellular matrix homeostasis. Upon injury or pathological stimulation, these cells transform to an activated myofibroblast state and play a fundamental role in myocardial fibrosis and remodeling. Chronic sympathetic overstimulation, a hallmark of heart failure (HF), induces pathological signaling through G protein betagamma (Gbetagamma) subunits and their interaction with G protein-coupled receptor kinase 2 (GRK2). OBJECTIVES: This study investigated the hypothesis that Gbetagamma-GRK2 inhibition and/or ablation after myocardial injury would attenuate pathological myofibroblast activation and cardiac remodeling. METHODS: The therapeutic potential of small molecule Gbetagamma-GRK2 inhibition, alone or in combination with activated fibroblast- or myocyte specific GRK2 ablation-each initiated after myocardial ischemia-reperfusion (I/R) injury-was investigated to evaluate the possible salutary effects on post-I/R fibroblast activation, pathological remodeling, and cardiac dysfunction. RESULTS: Small molecule Gbetagamma-GRK2 inhibition initiated 1 week post-injury was cardioprotective in the I/R model of chronic HF, including preservation of cardiac contractility and a reduction in cardiac fibrotic remodeling. Systemic small molecule Gbetagamma-GRK2 inhibition initiated 1 week post-I/R in cardiomyocyte-restricted GRK2 ablated mice (also post-I/R) still demonstrated significant cardioprotection, which suggested a potential protective role beyond the cardiomyocyte. Inducible ablation of GRK2 in activated fibroblasts (i.e., myofibroblasts) post-I/R injury demonstrated significant functional cardioprotection with reduced myofibroblast transformation and fibrosis. Systemic small molecule Gbetagamma-GRK2 inhibition initiated 1 week post-I/R provided little to no further protection in mice with ablation of GRK2 in activated fibroblasts alone. Finally, Gbetagamma-GRK2 inhibition significantly attenuated activation characteristics of failing human cardiac fibroblasts isolated from end stage HF patients. CONCLUSIONS: These findings suggested consideration of a paradigm shift in the understanding of the therapeutic role of Gbetagamma-GRK2 inhibition in treating HF and the potential therapeutic role for Gbetagamma-GRK2 inhibition in limiting pathological myofibroblast activation, interstitial fibrosis, and HF progression. PMID- 28818209 TI - Stress in a Dish: Exploring the Mechanisms of Takotsubo Syndrome. PMID- 28818208 TI - Catecholamine-Dependent beta-Adrenergic Signaling in a Pluripotent Stem Cell Model of Takotsubo Cardiomyopathy. AB - BACKGROUND: Takotsubo syndrome (TTS) is characterized by an acute left ventricular dysfunction and is associated with life-threating complications in the acute phase. The underlying disease mechanism in TTS is still unknown. A genetic basis has been suggested to be involved in the pathogenesis. OBJECTIVES: The aims of the study were to establish an in vitro induced pluripotent stem cell (iPSC) model of TTS, to test the hypothesis of altered beta-adrenergic signaling in TTS iPSC-cardiomyocytes (CMs), and to explore whether genetic susceptibility underlies the pathophysiology of TTS. METHODS: Somatic cells of patients with TTS and control subjects were reprogrammed to iPSCs and differentiated into CMs. Three-month-old CMs were subjected to catecholamine stimulation to simulate neurohumoral overstimulation. We investigated beta-adrenergic signaling and TTS cardiomyocyte function. RESULTS: Enhanced beta-adrenergic signaling in TTS-iPSC CMs under catecholamine-induced stress increased expression of the cardiac stress marker NR4A1; cyclic adenosine monophosphate levels; and cyclic adenosine monophosphate-dependent protein kinase A-mediated hyperphosphorylation of RYR2 S2808, PLN-S16, TNI-S23/24, and Cav1.2-S1928, and leads to a reduced calcium time to transient 50% decay. These cellular catecholamine-dependent responses were mainly mediated by beta1-adrenoceptor signaling in TTS. Engineered heart muscles from TTS-iPSC-CMs showed an impaired force of contraction and a higher sensitivity to isoprenaline-stimulated inotropy compared with control subjects. In addition, altered electrical activity and increased lipid accumulation were detected in catecholamine-treated TTS-iPSC-CMs, and were confirmed by differentially expressed lipid transporters CD36 and CPT1C. Furthermore, we uncovered genetic variants in different key regulators of cardiac function. CONCLUSIONS: Enhanced beta-adrenergic signaling and higher sensitivity to catecholamine-induced toxicity were identified as mechanisms associated with the TTS phenotype. (International Takotsubo Registry [InterTAK Registry] [InterTAK]; NCT01947621). PMID- 28818210 TI - Clinical Use of High-Sensitivity Cardiac Troponin in Patients With Suspected Myocardial Infarction. AB - High-sensitivity cardiac troponin (hs-cTn) assays have been used clinically by thousands of physicians in many countries throughout the world since their clinical introduction 7 years ago. In the early diagnosis of myocardial infarction (MI), beyond doubt, the most important indication of hs-cTn assays, these simple, inexpensive, and highly reproducible tools complement detailed clinical assessment including chest pain characteristics and the electrocardiogram. Hs-cTn assays for the first time allowed the precise quantification of cardiomyocyte injury around the 99th percentile and thereby substantially increased the accuracy of MI detection from blood obtained at presentation to the emergency department (ED). Higher accuracy at ED presentation enabled the development and extensive validation of early hs-cTn-based diagnostic algorithms, which substantially reduced the time required for the safe rule-out or rule-in of MI. This review summarizes key principles underlying the safe and effective use of hs-cTn in the ED in patients with suspected MI. PMID- 28818211 TI - Evaluation of thrombolysis using tissue plasminogen activator in lower extremity deep venous thrombosis with concomitant femoral-popliteal venous segment involvement. AB - OBJECTIVE: Current guidelines recommend thrombolytic therapy for iliofemoral deep venous thrombosis (DVT). Anticoagulation is the standard treatment for femoral popliteal and tibial-level DVT. The objective of this study was to evaluate the efficacy of catheter-directed thrombolysis (CDT) using tissue plasminogen activator vs standard anticoagulation alone in patients with lower extremity DVT involving the femoral-popliteal segment. METHODS: A retrospective review was performed of patients referred to the vascular surgery service with lower extremity DVT from 2006 to 2015. Patients who had DVT involving the femoral popliteal segment were identified, including some patients who had concomitant involvement of iliofemoral and tibial veins. Patients with pure iliofemoral and tibial vein DVT were excluded from this analysis. Review of medical records, follow-up ultrasound studies, hypercoagulable panel, and venography were performed. Comparison of outcomes between patients who received thrombolytic therapy using tissue plasminogen activator and patients who received standard anticoagulation alone was performed. The primary outcomes measured were restoration of patency of the femoral-popliteal segment at 3 months, incidence of post-thrombotic syndrome (PTS), and valvular dysfunction. Secondary outcomes were incidence of bleeding, in-hospital mortality, and pulmonary embolism. RESULTS: The study cohort was composed of 191 patients (CDT, n = 89; anticoagulation alone, n = 102) who met inclusion criteria. Most patients with thrombus involving the femoral-popliteal segment also had proximal venous segment involvement, with 93% of the patient cohort having proximal iliofemoral DVT. Patients who did not receive CDT were older (mean age of 64 years vs 51 years; P < .001) and had more associated comorbidities, such as diabetes, immobility, and cancer. A significant number of patients who received CDT had a positive family history for DVT (21.3% vs 8.8%; P = .023), and it was more likely to be their first episode of DVT (73.0% vs 55.9%; P = .016). Patients who received CDT were more likely to have restoration of patency (74.7% vs 11.1%; P < .001) and lower incidence of PTS (21.3% vs 73.4%; P < .001) and valvular dysfunction (23.0% vs 66.7%; P < .001) compared with patients who were treated with anticoagulation alone. Incidence of bleeding was significantly more for patients treated with anticoagulation alone (14.7% vs 5.6%; P = .018) compared with patients who received CDT. On multivariate analysis, age was the predominant risk factor for bleeding. There was no significant difference in mortality and pulmonary embolism. CONCLUSIONS: In patients with acute proximal DVT and concomitant femoral-popliteal venous segment involvement, CDT resulted in superior patency at 3 months and less PTS and valvular reflux. This was achieved without increase in bleeding complications compared with anticoagulation alone. Age was the major factor predictive of bleeding in either group. The results of this study may not be applicable to patients with pure femoral-popliteal venous segment DVT because only 3% of patients had this finding. PMID- 28818212 TI - National trends in hospitalizations for venous thromboembolism. AB - OBJECTIVE: The management of venous thromboembolism (VTE) has evolved during the last decade. This study sheds light on the national trends in hospital admissions, outcomes, and economic burden for VTE. METHODS: The National Inpatient Sample (NIS) was reviewed between 2003 and 2013 for hospitalizations for VTE, defined as admissions with a principal diagnosis of deep venous thrombosis (DVT) or pulmonary embolism (PE). Outcomes measured were incidence, inpatient mortality, rates of interventions, hospital length of stay (LOS), and charges. A multivariate analysis was used to identify independent predictors of mortality in patients with VTE. RESULTS: There were 3,368,409 admissions for VTE (54% female; mean age, 62.9 years), at an average of 818 per 100,000 admissions per year. Hospitalizations for PE and VTE significantly increased (P < .01), with no change for DVT (P = .13). Use of catheter-directed thrombolysis increased (0.8% to 2.7%; P < .01), with no significant change in use during the study period (P = .10). The mortality associated with hospitalizations for VTE, PE, and DVT decreased (P < .01). Mean LOS decreased from 5.79 to 4.77 days (P < .01), whereas mean hospital charges increased from $29,755 to $39,171 (P < .01). At the national level, the economic burden of VTE hospitalizations increased from $7.8 billion in 2003 to $12.1 billion in 2013 (P < .01). Older age (odds ratio [OR], 1.03), female gender (OR, 1.05), race (OR, 1.43 for Asian, 1.18 for African American, and 1.18 for Hispanic compared with white), PE (OR, 4.12), and Charlson Comorbidity Index (CCI) >=3 (OR, 2.75) were all predictors of inpatient mortality (P < .01 for all ORs). CONCLUSIONS: Hospitalizations for VTE increased during the past decade, whereas mortality decreased. Despite a decrease in LOS, there is a rise in economic burden of VTE on the health care system. PMID- 28818213 TI - The natural history and outcomes of line-associated upper extremity deep venous thromboses in critically ill patients. AB - OBJECTIVE: Anticoagulation remains the standard of care for line-associated upper extremity deep venous thrombosis (UEDVT). This treatment carries the risk of hemorrhagic complications, possibly more so in surgical patients. Considering the low-risk profile of UEDVT-which is associated with fewer, less severe pulmonary emboli than lower extremity deep venous thrombosis-current UEDVT treatment guidelines may be overly aggressive. The goal of this study was to review outcomes of line-associated UEDVT in critically ill patients and to define the efficacy of current treatment protocols in pulmonary embolism (PE) prevention while avoiding hemorrhagic complications. METHODS: A retrospective review was performed of 193 consecutive patients admitted to the medical and surgical intensive care unit (ICU) at a tertiary care hospital between 2009 and 2014 diagnosed with acute line-associated UEDVT by duplex ultrasound. The examined treatment arms included anticoagulation with intent to reach therapeutic levels, prophylactic or subtherapeutic anticoagulation, and no anticoagulation. Primary outcomes included major hemorrhage (defined as any intracranial hemorrhage or any hemorrhage resulting in transfusion, ICU readmission, or death), PE, in-hospital mortality, total hospital length of stay (LOS), and ICU LOS. RESULTS: Of the 10,907 patients, 161 (1.48%) were diagnosed with acute line-associated UEDVT, 81 of 6027 in the medical ICU (1.34%) and 80 of 4880 in the surgical ICU (1.64%), after exclusion of 32 patients with concurrent lower extremity deep venous thrombosis. In total, 122 patients (75.8%) received anticoagulation with intent to reach therapeutic levels, 23 (14.3%) received prophylactic anticoagulation, and 16 (9.94%) received no anticoagulation. Major hemorrhage was significantly more common than symptomatic PE in all patients (15.5% vs 4.97%; P < .001). A single fatal PE and two fatal hemorrhages were recorded across the series. There was no significant difference in in-hospital mortality (34.8% vs 16.7%; P = .726) or ICU LOS (33.1 vs 18.3 days; P = .739) for patients who developed major hemorrhage or symptomatic PE. On multivariate analysis, incidence of symptomatic PE was not significantly related to Acute Physiology and Chronic Health Evaluation III score (P = .963), anticoagulation regimen (P = .940), catheter type (P = .313), or bacteremia (P = .833). CONCLUSIONS: Major hemorrhagic complications are more common than symptomatic PE after anticoagulation for line associated UEDVT in ICU patients, raising concern that current treatment guidelines are too aggressive. These data necessitate further prospective investigation to determine the optimal treatment protocol for line-associated UEDVT in this critically ill cohort. PMID- 28818214 TI - Treatment outcomes and risk factors for bowel infarction in patients with acute superior mesenteric venous thrombosis. AB - OBJECTIVE: The prognosis of acute superior mesenteric venous thrombosis (SMVT) remains obscure. We aimed to investigate the treatment outcomes and possible risk factors for bowel infarction in these patients. METHODS: We retrospectively included 66 patients with acute SMVT between January 2002 and June 2016. Each patient underwent contrast-enhanced computed tomography as part of the initial diagnosis. The standard protocol for management included a nonsurgical approach with early anticoagulation and selective exploration. For the analysis of the risk factors for bowel infarction, patients were divided into bowel resection (BR) and non-BR groups. Outcomes of interest were causes of SMVT, percentage of BR after nonsurgical treatment, and risk factors for BR. RESULTS: Of 66 patients, 15 (23%) underwent BR; of these, 9 underwent urgent BR because of peritoneal signs and definite findings of bowel infarction on computed tomography scan, 4 underwent BR after failed anticoagulation, and 2 underwent BR because of delayed stricture. Clinically, vomiting (P = .003), abdominal distention (P = .003), rebound tenderness (P = .005), and leukocytosis (P = .001) were associated with BR. On radiologic examination, bowel wall thickening (P < .001), enhancement defects of the bowel wall (P < .001), and ascites (P = .007) were associated with BR. Twenty-seven (41%) patients presented with isolated SMVT, and the remaining patients demonstrated a coexisting portal vein (PV) thrombosis in addition to SMVT. All 15 BRs occurred in patients with combined PV thrombosis and SMVT (P < .001). Complete thrombosis of the superior mesenteric vein and PV was also associated with BR (P = .028 for superior mesenteric vein; P = .025 for PV). BR was performed in 1 (4%) of 24 patients with transient risk factors compared with 14 (33%) of 42 patients without transient risk factors (P = .006). Three patients (4.5%) died in the hospital. CONCLUSIONS: In patients with acute SMVT, the extent of thrombus and etiology were associated with the severity of acute SMVT. Patients with transient risk factors and isolated SMVT tended to have a benign disease course. With early anticoagulation, acute SMVT does not seem to have the grave prognosis that is associated with arterial thrombosis. PMID- 28818215 TI - Age is not a barrier to good outcomes after varicose vein procedures. AB - BACKGROUND: The Vascular Quality Initiative (VQI) Varicose Vein Registry (VVR) represents a patient-centered database launched in January 2015. Previous work describing overall trends and outcomes of varicose vein procedures across the United States demonstrates a benefit from these procedures. The existing gaps in evidence to support current and future Medicare coverage of varicose vein procedures necessitate further description of clinical outcomes in patients >=65 years old compared with the population <65 years old. METHODS: This study analyzed prospectively captured anatomic, procedural, and outcome data for all patients in a national cohort of all VQI VVR-participating centers. The VQI VVR database was queried for all patients undergoing varicose vein procedures between January 2015 and July 2016. Preprocedural and postprocedural Clinical, Etiology, Anatomy, and Pathophysiology (CEAP) classification, Venous Clinical Severity Score (VCSS), and patient-reported outcomes (PROs) were compared between patients <65 years and >=65 years old. Univariate descriptive statistics of demographic and procedural data were performed. Student t-tests were then performed on change in CEAP classification, VCSS score, and PROs (heaviness, achiness, throbbing, swelling, itching, appearance, and impact on work) for each group. RESULTS: There were 4841 varicose vein procedures performed from January 2015 to May 2016. There were 3441 procedures performed in 2691 patients (3631 limbs) in the group <65 years old and 1400 procedures performed in 1068 patients (1467 limbs) in the group >=65 years old. Truncal veins alone were the most common veins treated in both groups. The majority of patients were white and female in both groups. Most of the demographic characteristics were clinically similar (although statistically different) in both groups with the exception of a higher body mass index in the group <65 years old and a history of bilateral varicose vein treatment, and anticoagulation was more common among patients >=65 years old. Patients in both groups experienced statistically significant improvement in VCSS, PROs, and CEAP class. There was no difference in overall complications between age groups. CONCLUSIONS: All patients demonstrated an associated improvement in both clinical outcomes (CEAP class, VCSS) and PROs. There was no significant difference in the improvement in CEAP class and VCSS between patients younger and older than 65 years, although the younger population reported greater improvement in PROs. Given these findings, patients older than 65 years appear to benefit from varicose vein procedures and should not be denied interventions on their varicose veins and venous insufficiency on the basis of their age only. PMID- 28818216 TI - Invited Commentary. PMID- 28818217 TI - Thirty-sixth-month follow-up of first-in-human use of cyanoacrylate adhesive for treatment of saphenous vein incompetence. AB - OBJECTIVE: The objective of this study was to evaluate the long-term safety and effectiveness of endovenous cyanoacrylate (CA)-based closure of incompetent great saphenous veins. METHODS: This was a prospective, single-arm, single-center feasibility study conducted at the Canela Clinic (La Romana, Dominican Republic) to assess the effectiveness and safety of a CA-based adhesive for great saphenous vein closure at 36 months after treatment. Thirty-eight subjects were treated by injection of small boluses of CA under ultrasound guidance and without the use of perivenous tumescent anesthesia or postprocedure graduated compression stockings. Periodic scheduled follow-up was performed during 36 months. RESULTS: At month 36, there were 29 subjects who were available for follow-up. Complete occlusion of the treated veins was confirmed by duplex ultrasound in all subjects with the exception of two subjects showing recanalization at month 1 and month 3. Kaplan Meier analysis revealed an occlusion rate at month 36 of 94.7% (95% confidence interval, 87.9%-100%). The mean Venous Clinical Severity Score (VCSS) improved from 6.1 +/- 2.7 at baseline to 2.2 +/- 0.4 at month 36 (P < .0001). Pain, edema, and varicosities (VCSS subdomains) improved in 75.9%, 62.1%, and 41.4% of subjects, respectively, at month 36. Overall adverse events were mild or moderate and self-limited. CONCLUSIONS: CA adhesive appears to be an effective and safe treatment for saphenous vein closure, with long-term occlusion rates comparable to those of other thermal and nonthermal methods and with no reported serious adverse events. PMID- 28818218 TI - Invited Commentary. PMID- 28818219 TI - Contemporary outcomes after venography-guided treatment of patients with May Thurner syndrome. AB - OBJECTIVE: Patients with May-Thurner syndrome (MTS) present with a spectrum of findings ranging from mild left leg edema to extensive iliofemoral deep venous thrombosis (DVT). Whereas asymptomatic left common iliac vein (LCIV) compression can be seen in a high proportion of normal individuals on axial imaging, the percentage of these persons with symptomatic compression is small, and debate exists about the optimal clinical and diagnostic criteria to treat these lesions in patients with symptomatic venous disease. We evaluated our approach to venography-guided therapy for individuals with symptomatic LCIV compression and report the outcomes. METHODS: All patients with suspected May-Thurner compression of the LCIV between 2008 and 2015 were analyzed retrospectively. Patients with chronic iliocaval lesions not associated with compression of the LCIV were excluded from analysis. Criteria for intervention included LCIV compression in the setting of (1) leg edema/venous claudication with associated venographic findings (collateralization, iliac contrast stagnation, and contralateral cross cross-filling), or (2) left leg deep venous thrombosis. Outcome measures included presenting Clinical, Etiology, Anatomy, Pathophysiology (CEAP) score, postintervention CEAP score, primary patency, and secondary patency. Technical success was defined as successful stent implantation without intraoperative device complications, establishment of in-line central venous flow, and less than 30% residual LCIV stenosis. RESULTS: Of the 63 patients evaluated, 32 (51%) had nonthrombotic MTS and presented with leg edema (100%) or venous claudication (47%). Thirty-one patients (49%) had thrombotic MTS and presented with acute (26%) or chronic (71%) DVT, leg edema (100%), or venous claudication (74%). The mean presenting CEAP score was 3.06 and 3.23 for nonthrombotic and thrombotic MTS, respectively. Forty-four patients (70%) underwent successful intervention with primary stenting (70%) or thrombolysis and stenting (30%); 14 nonthrombotic MTS patients were treated conservatively with compression therapy alone, and 5 thrombotic MTS patients were treated with lysis or angioplasty alone. Clinical improvement and decrease in CEAP score occurred in 95% and 77% of stented patients compared with 58% and 32% of nonstented patients. Complete symptom resolution was achieved in 48% of patients overall, or 64% of stented patients and only 21% of nonstented patients. Complications included two early reocclusions. Primary and secondary 2-year patency rates were 93% and 97% (mean follow-up, 20.3 months) for stented patients. CONCLUSIONS: Venography-guided treatment of MTS is associated with excellent 1-year patency rates and a significant reduction in symptoms and CEAP score. Treating symptomatic MTS patients on the basis of physiologically relevant venographic findings rather than by intravascular ultrasound imaging alone results in excellent long-term patency and clinical outcomes but may result in undertreatment of some patients who could benefit from stent implantation. PMID- 28818220 TI - Invited Commentary. PMID- 28818222 TI - Invited Commentary. PMID- 28818221 TI - Venography versus intravascular ultrasound for diagnosing and treating iliofemoral vein obstruction. AB - OBJECTIVE: The Venogram vs IVUS for Diagnosing Iliac vein Obstruction (VIDIO) trial was designed to compare the diagnostic efficacy of intravascular ultrasound (IVUS) with multiplanar venography for iliofemoral vein obstruction. METHODS: During a 14-month period beginning July 2014, 100 patients with chronic Clinical, Etiologic, Anatomic, and Pathophysiologic clinical class C4 to C6 venous disease and suspected iliofemoral vein obstruction were enrolled at 11 U.S. and 3 European sites. The inferior vena cava and common iliac, external iliac, and common femoral veins were imaged. Venograms were measured for vein diameter; IVUS provided diameter and area measurements. Multiplanar venograms included three views: anteroposterior and 30-degree right and left anterior oblique views. A core laboratory evaluated the deidentified images, determining stenosis severity as the ratio between minimum luminal diameter and reference vessel diameter, minimal luminal area, and reference vessel area. A 50% diameter stenosis by venography and a 50% cross-sectional area reduction by IVUS were considered significant. Analyses assessed change in procedures performed on the basis of imaging method and concordance of measurements between each imaging method. RESULTS: Venography identified stenotic lesions in 51 of 100 subjects, whereas IVUS identified lesions in 81 of 100 subjects. Compared with IVUS, the diameter reduction was on average 11% less for venography (P < .001). The intraclass correlation coefficient was 0.505 for vein diameter stenosis calculated with the two methods. IVUS identified significant lesions not detected with three-view venography in 26.3% of patients. Investigators revised the treatment plan in 57 of 100 cases after IVUS, most often because of failure of venography to detect a significant lesion (41/57 [72%]). IVUS led to an increased number of stents in 13 of 57 subjects (23%) and the avoidance of an endovascular procedure in 3 of 57 subjects (5%). Overall, IVUS imaging changed the treatment plan in 57 patients; 54 patients had stents placed on the basis of IVUS detection of significant iliofemoral vein obstructive lesions not appreciated with venography, whereas 3 patients with significant lesions on venography had no stent placed on the basis of IVUS. CONCLUSIONS: IVUS is more sensitive for assessing treatable iliofemoral vein stenosis compared with multiplanar venography and frequently leads to revised treatment plans and the potential for improved clinical outcome. PMID- 28818223 TI - Impact of an inferior vena cava filter retrieval algorithm on filter retrieval rates in a cancer population. AB - OBJECTIVE: Our primary purpose was to assess the impact of an inferior vena cava filter retrieval algorithm in a cancer population. Because cancer patients are at persistently elevated risk for development of venous thromboembolism (VTE), our secondary purpose was to assess the incidence of recurrent VTE in patients who underwent filter retrieval. METHODS: Patients with malignant disease who had retrievable filters placed at a tertiary care cancer hospital from August 2010 to July 2014 were retrospectively studied. A filter retrieval algorithm was established in August 2012. Patients and referring physicians were contacted in the postintervention period when review of the medical record indicated that filter retrieval was clinically appropriate. Patients were classified into preintervention (August 2010-July 2012) and postintervention (August 2012-July 2014) study cohorts. Retrieval rates and clinical pathologic records were reviewed. RESULTS: Filter retrieval was attempted in 34 (17.4%) of 195 patients in the preintervention cohort and 66 (32.8%) of 201 patients in the postintervention cohort (P < .01). The median time to filter retrieval in the preintervention and postintervention cohorts was 60 days (range, 20-428 days) and 107 days (range, 9-600 days), respectively (P = .16). In the preintervention cohort, 49 of 195 (25.1%) patients were lost to follow-up compared with 24 of 201 (11.9%) patients in the postintervention cohort (P < .01). Survival was calculated from the date of filter placement to death, when available. The overall survival for patients whose filters were retrieved was longer compared with the overall survival for patients whose filters were not retrieved (P < .0001). Of the 80 patients who underwent successful filter retrieval, two patients (2.5%) suffered from recurrent VTE (n = 1 nonfatal pulmonary embolism; n = 1 deep venous thrombosis). Both patients were treated with anticoagulation without filter replacement. CONCLUSIONS: Inferior vena cava filter retrieval rates can be significantly increased in patients with malignant disease with a low rate (2.5%) of recurrent VTE after filter retrieval. PMID- 28818224 TI - Invited Commentary. PMID- 28818225 TI - Patient-centered outcomes of a dual action pneumatic compression device in comparison to compression stockings for patients with chronic venous disease. AB - OBJECTIVE: The ACTitouch (AT) device (Tactile Medical, Minneapolis, Minn) represents a new generation of pneumatic compression devices by combining sustained compression with intermittent pneumatic compression. The sustained compression mode provides automatic pressure adjustment every 30 minutes, ensuring pressure consistency regardless of leg volume changes and environmental influences. Designed for mobile patients, this device has not been studied in comparison to standard compression stockings (CS). METHODS: A two-arm, randomized, multicenter pilot study was conducted. Patients with primary chronic venous disease (C3-C6) and a documented history of low adherence to compression therapy were randomized at 10 centers to use the AT device or 30 to 40 mm Hg graduated CS. Primary end points were patient-reported comfort and ease of use. Secondary end points included compliance (measured by a device meter and patient diaries), limb volume change (by water displacement and circumferences), and change in disease severity (using Venous Clinical Severity Score, Venous Insufficiency Epidemiological and Economic Study on Quality of Life/Symptoms, and EuroQol-5 Dimension 3-Level). Patients were assessed at 15 and 30 days after randomization. Eighty-nine patients (136 limbs) received either AT (66 limbs) or CS (70 limbs). RESULTS: Patients in the AT group found the device easy to apply (71% compared with 37.5% in the CS group; P = .0001), easy to remove (89% compared with 59% in the CS group; P = .0001), and comfortable to wear (71% compared with 58% in the CS group; P = .125). Compliance with compression was not significantly different between the groups (100% vs 88%, AT and CS groups, respectively, at 15 days; 87% vs 85% at the end of the study; P = .97). Daily use was not different either (10.7 hours in the AT group, 11.7 +/- 2.7 hours in the CS group). In the AT group, in addition to self-reporting, the patient's compliance was objectively measured by a usage meter built into the device. The average time of compression use reported by patients was 2.5 hours higher than measured by the device, and the limits of agreement were -6 hours to +11 hours. These findings indicate that self-reported time of use is highly unreliable and tends to overestimate the actual use. CONCLUSIONS: This is the first trial comparing an adaptive pneumatic compression device with CS in previously noncompliant patients with C3 to C6 chronic venous disease. The study demonstrated that even within limitations of a pilot project, use of the AT device is comparable to CS in the patient's acceptance and compliance and likely to have equal or better clinical outcomes. PMID- 28818226 TI - Percutaneous ultrasound-guided sclerotherapy with polidocanol microfoam for lymphatic malformations. AB - BACKGROUND: Lymphatic malformations (LMs) are low-flow congenital lesions that consist of cysts of varying size. Sclerotherapy with intralesional bleomycin and OK-432 has been reported to yield dramatically beneficial results for this disorder. However, inflammation-related symptoms are often seen after treatment with these sclerosing agents. On the other hand, polidocanol (POL) is reportedly associated with fewer allergic and inflammatory reactions. Up to now, however, very few reports have documented the use of POL microfoam for treatment of LMs. This study was performed to assess the efficacy and safety of POL microfoam sclerotherapy for LMs. METHODS: Between 2003 and 2016, cases were identified from a prospectively compiled database on low-flow congenital vascular malformations before undertaking a retrospective electronic chart review. Patients were included if they had LMs that had been treated by POL microfoam sclerotherapy. The location, size, and type of LMs were assessed using ultrasound and magnetic resonance imaging. Twenty-gauge venous catheters were inserted into the lymphatic space under ultrasound visualization. The LMs were then fully aspirated if they were macrocystic in form. Microfoam composed of 3% POL was then injected under ultrasound guidance. Microcystic LMs were treated by direct injection with POL microfoam under ultrasound guidance. The outcome was assessed by clinical examination combined with findings of postsclerotherapy imaging using ultrasound and magnetic resonance imaging. RESULTS: During a 13-year period, 32 patients met the inclusion criteria. These were 11 (34%) male patients and 21 (66%) female patients with a mean age of 18 years. The LMs were localized to the head and neck (47%), the trunk (38%), and the extremities (15%). The lesions were subdivided into macrocystic (56%), mixed macrocystic and microcystic (31%), and microcystic (13%) LMs. The average lesion size was 6.6 * 4.6 * 3.0 cm. The mean number of treatment sessions was 2.8 (range, 1-15), with a mean foam volume of 4.6 (range, 1-10) mL. Excellent (47%) and moderate (41%) responses were seen in 88% of the patients. Notably, half of the patients achieved excellent or moderate resolution with a single treatment session. Intralesional hemorrhage occurred in four patients (13%) but resolved spontaneously. Only one patient with mixed macrocystic and microcystic LMs developed post-therapy infection. However, the other patients did not develop any post-therapy inflammation-related symptoms, including fever, pain, and marked swelling. CONCLUSIONS: Percutaneous sclerotherapy using POL microfoam appears to be safe and effective for treatment of LMs. Ultrasound-guided POL microfoam sclerotherapy should be considered for such lesions, particularly those that are exclusively macrocystic. PMID- 28818227 TI - Impact of an educational program on the quality of life of patients with lymphedema: A preliminary evaluation. AB - OBJECTIVE: We report on the preliminary evaluation of a well-designed program, Living with Lymphedema. This longitudinal cohort study assessed patients' quality of life using questionnaires. Our main objective was to evaluate the satisfaction of the patients and their adherence to the program. This was done using a specific questionnaire of satisfaction as well as by noting patients' adherence to the program (number of patients attending all three consultations). The secondary objective was to assess the effect of the program on the patient's quality of life. The assessment criteria were the evolution of the Medical Outcomes Study 36-Item Short Form Health Survey and EuroQol questionnaire scores between the first (C1) and third (C3) consultations. METHODS: The Living with Lymphedema program targeted all patients with lymphedema in the Grenoble (France) conurbation and within the GRANTED health care network that includes vascular medicine specialists, primary care physicians, physical therapists, and dietitians in the Alpine region of France. All studied patients were ambulatory patients. The GRANTED network took care only of the educational aspect of the disease. All patients with primary or secondary lymphedema were offered the Living with Lymphedema program, whatever their age and the location of the lymphedema (upper or lower limbs). The collection of patient data conformed to the ethical and administrative regulations of the regional health authority. Grenoble Institutional Review Board (CPP Sud-Est V; No. 5891) approval for the study was specifically obtained for this evaluation on December 24, 2012. The program was built around one-to-one consultations, group workshops, and more specialized appointments. It was complementary to the routine medical care received by the patient (not evaluated in this study). It proposed three individual "educational" consultations, seven group workshops, and two specialized consultations with a dietitian. All the consultations or workshops were led by certified professionals trained in therapeutic education. RESULTS: The cohort was the 34 patients included in the program. We found a significant improvement in the physical dimension of the Medical Outcomes Study 36-Item Short Form Health Survey score (P = .01) between C1 and C3 but not for the psychic dimension. Visual analog scale scores of the ability to cope with the lymphedema showed a statistically significant improvement between C1 and C3 (P = .05). No difference was observed in adherence to compression therapy. CONCLUSIONS: This therapeutic educational program showed a significant improvement in several criteria of quality of life and in the autonomy of patients with lymphedema. PMID- 28818229 TI - Invited commentary. PMID- 28818228 TI - Phenotypic and functional transformation in smooth muscle cells derived from varicose veins. AB - OBJECTIVE: Varicose veins (VVs) are a common disorder of venous dilation and tortuosity, but the underlying mechanism is unclear. The functional integrity and phenotypic differences of VVs are also unclear. This study tested the hypothesis that phenotypic and functional differences exist between smooth muscle cells (SMCs) derived from VVs and normal veins. METHODS: SMCs were isolated from 28 samples of varicose great saphenous veins (VGSVs) and normal great saphenous (NGSVs) and cultured. Proliferation, migration, adhesion, and aging capacity in SMCs were compared in the two veins. Bas, Bcl-2, caspase-3, matrix metalloproteinase (MMP)-2 MMP-9, tissue inhibitor of metalloproteinases (TIMP)-1, and TIMP-2 messenger (m)RNA expression and protein content were detected by fluorescence quantitative polymerase chain reaction and immunoblotting. RESULTS: The microfilament structure of the framework was increased in SMCs in the VGSV group. Proliferation, migration, adhesion, and the aging cell count in SMCs in the VGSV group were significantly higher than the corresponding regions in the NGSV group (P < .05). Bas and caspase-3 mRNA expression and protein content were decreased, whereas Bcl-2 mRNA expression and protein content were increased in the VGSV group compared with the NGSV group (P < .05). MMP-2, MMP-9, TIMP-1, and TIMP-2 mRNA expression and protein content in the VGSV group were increased compared with the NGSV group (P < .05). CONCLUSIONS: SMCs derived from VGSVs are more dedifferentiated and demonstrate increased proliferative and synthetic capacity. These results suggest the presence of phenotypic and functional differences between SMCs derived from VGSVs and NGSVs. The phenotypic and functional abnormalities in SMCs may be associated with the pathogenesis in VGSVs. PMID- 28818230 TI - Symptomatic compression of right iliac vein after right iliac artery stent placement. AB - Right lower extremity edema can be a presenting symptom of iliocaval compression syndrome, even in the absence of deep vein thrombosis. It has been reported in idiopathic and rarely, iatrogenic, cases secondary to variant anatomy, arterial stents, and bony hardware. Classically seen in the more confined left common iliac vein as May-Thurner syndrome, it is rare on the right side. We report an unusual case of acute right common iliac vein compression after right iliac stent placement leading to symptomatic right leg edema. Venous stenting resulted in resolution of symptoms at the 6-month follow-up. PMID- 28818231 TI - Duplicate superior vena cava on arteriovenous fistulography. PMID- 28818232 TI - Review of the endothelial pathogenic mechanism of TIE2-related venous malformation. AB - BACKGROUND: Venous malformation (VM) is a type of disease involving vascular morphogenesis in humans. Clinically, VM can be sporadic or inherited. TIE2, also known as TEK or HYK, is a member of the receptor tyrosine kinase subfamily and is highly conserved among species. In 1996, an arginine-to-tryptophan substitution at position 849 (R849W) in TIE2 was found to induce hereditary VM. Additional alterations in TIE2 involved in the pathogenesis of inherited or sporadic VM have since been reported. METHODS: The relevant key literature was selectively reviewed, including case reports, reviews, research studies, and meta-analyses. RESULTS: TIE2 can be thought of as the basis for VM, with a potential role in determining locations, through intracorporal endothelium-specific distribution and expression from the embryonic phase. It has a sophisticated protein structure, and various point mutations destroy its function and physiologic processes by obviously different activation mechanisms, of which some inhibit dephosphorylation and others maintain phosphorylation. Extracellularly, whereas angiopoietins (ANGs) are ligands of TIE2, the chaotic balance between ANG1 and ANG2 in VM is related to their effects on switching between the cell-cell/cell extracellular matrix contact conditions and vascular quiescence/angiogenesis state, resulting in corrupted contacts. Intracellularly, among diverse cellular pathways, phosphatidylinositol 4,5-bisphosphate 3-kinase/AKT serine-threonine kinase, mitogen-activated protein kinase, and Dok-related protein are irreplaceable keys underlying changes in endothelial morphology and behavioral biology in VM. For example, R849W and L914F (a leucine-to-phenylalanine substitution at position 914), the most important and frequent TIE2 mutations associated with VM, share similar phenotypes but differ with respect to signaling pathways, heredity, and triggering factors. CONCLUSIONS: Based on this comprehensive analysis, we propose an avalanche theory, in which mutant TIE2 is a trigger and pathogenic core, the intercellular network is a tool, altered extracellular matrix and contacts are the final foothold, and fragile contacts are the result. Precise classification according to TIE2 mutation type in VM, especially the mutation site, is important for future targeted therapies. PMID- 28818233 TI - Transcatheter embolization of persistent embryonic veins in venous malformation syndromes. AB - Persistent embryonic veins represent a major source of venous hypertension and morbidity in venous malformation syndromes, such as Klippel-Trenaunay syndrome and congenital lipomatous overgrowth, vascular malformations, epidermal nevus, and skeletal deformities syndrome. Surgical stripping and phlebectomy are the most commonly reported alternatives to compression therapy for refractory cases. These techniques, although effective in those patients who meet the necessary anatomic criteria, can be associated with bleeding, wound-related complications, and recurrence. Herein, we present a less invasive endovascular technique for elimination of these incompetent persistent embryonic veins. This technique has fewer anatomic restrictions and can be a suitable first-line option for management of refractory venous insufficiency in this particular population of patients. PMID- 28818234 TI - The Dutch lymphedema guidelines based on the International Classification of Functioning, Disability, and Health and the chronic care model. AB - Lymphedema is a chronic and progressive condition due to an imbalance between lymphatic filtration and transport capacity. A relative overload of fluid is caused by lymphatic impairment (afterload impairment); an absolute overload is caused by increased filtration (preload raised). Lymphedema can result in considerable disability and loss of quality of life. The Dutch Society of Dermatology organized a task force to create guidelines using the International Classification of Functioning, Disability, and Health. As lymphedema is a chronic condition, a new approach was chosen according to the chronic care model. In the development of the guidelines, the following topics of lymphedema care were proposed: (1) lymphedema detection; (2) clinimetric instruments; and (3) rational treatment modalities. A systematic review of the literature published up to June 2013 was conducted. Statements were based on scientific evidence and experience. The guidelines propose recommendations based on an interdisciplinary approach to lymphedema using a continuum of care from prevention to initial treatment phase, maintenance phase, and follow-up. An integrated treatment program can be conservative or surgical. A therapeutic program depends on stage and origin of lymphedema; International Classification of Functioning, Disability, and Health based limitations; needs of the patient; ability to perform self-management; and ability to reduce patient-related risk factors, such as overweight and lack of exercise. PMID- 28818235 TI - How to submit a MIPS quality measure if you are not participating in an approved registry. PMID- 28818236 TI - Regarding "Saphenous vein wall thickness in age and venous reflux-associated remodeling in adults". PMID- 28818237 TI - Regarding the commentary for "Chronic refractory venous ulcer exacerbated by a congenital pelvic arteriovenous malformation successfully treated via transarterial Onyx embolization". PMID- 28818238 TI - Reply. PMID- 28818239 TI - Setting the Stage: Advancing a Cancer Prevention Agenda for Young Adults. PMID- 28818240 TI - Reducing Cancer and Cancer Disparities: Lessons From a Youth-Generated Diabetes Prevention Campaign. AB - Adolescence and young adulthood, a period essential for determining exposures over the life-course, is an ideal time to intervene to lower cancer risk. This demographic group can be viewed as both the target audience and generator of messages for cancer prevention, such as skin cancer, obesity-, tobacco-, and human papillomavirus-related cancers. The purpose of this paper is to encourage innovative health communications that target youth; youth behavior; and the structural, environmental, and social determinants of youth behavior as critical areas of focus for cancer prevention and disparities reduction. The authors describe the rationale, processes, products, and early impacts of an award winning youth diabetes prevention communication campaign model (The Bigger Picture) that harnesses spoken-word messages in school-based and social media presentations. The campaign supports minority adolescent and young adult artists to create content that aligns with values held closely by youth-values likely to resonate and affect change, such as defiance against authority, inclusion, and social justice. This campaign can be leveraged to prevent obesity, which is a cancer risk factor. Then, the authors propose concrete ways that The Bigger Picture's pedagogical model could be adapted for broader cancer prevention messaging for youth of color and youth stakeholders regarding tobacco-related cancers, skin cancers, and human papillomavirus-related cancers. The goal is to demonstrate how a youth-generated and youth-targeted prevention campaign can: (1) reframe conversations about cancer prevention, (2) increase awareness that cancer prevention is about social justice and health equity, and (3) catalyze action to change social norms and confront the social and environmental drivers of cancer disparities. PMID- 28818241 TI - Prevalence of Modifiable Cancer Risk Factors Among U.S. Adults Aged 18-44 Years. AB - INTRODUCTION: Carcinogen exposure and unhealthy habits acquired in young adulthood can set the stage for the development of cancer at older ages. This study measured the current prevalence of several cancer risk factors among young adults to assess opportunities to intervene to change the prevalence of these risk factors and potentially reduce cancer incidence. METHODS: Using 2015 National Health Interview Survey data (analyzed in 2016), the prevalence of potential cancer risk factors was estimated among U.S. adults aged 18-44 years, based on responses to questions about diet, physical activity, tobacco product use, alcohol, indoor tanning, sleep, human papillomavirus vaccine receipt, and obesity, stratified by sex, age, and race/ethnicity. RESULTS: The prevalence of some risk factors varied by age and race/ethnicity. Obesity (one in four people) and insufficient sleep (one in three people) were common among men and women. Physical inactivity (one in five men, one in four women); binge drinking (one in four men, one in eight women); cigarette smoking (one in five men, one in seven women); and frequent consumption of red meat (one in four men, one in six women) also were common. More than half of the population of adults aged 18-44 years consumed sugar-sweetened beverages daily and processed meat at least once a week. Most young adults had never had the human papillomavirus vaccine. CONCLUSIONS: Findings can be used to target evidence-based environmental and policy interventions to reduce the prevalence of cancer risk factors among young adults and prevent the development of future cancers. PMID- 28818242 TI - Young Adult Risk Factors for Cancer: Obesity, Inflammation, and Sociobehavioral Mechanisms. AB - INTRODUCTION: The paper assesses social disparities in the burdens of metabolic and inflammatory risks for cancer in the U.S. young adult population and examines psychosocial and behavioral mechanisms in such disparities. METHODS: Using data of 7,889 individuals aged 12-32 years from the National Longitudinal Study of Adolescent to Adult Health from 1994 to 2009, generalized linear models were used to assess the sex, race/ethnicity, and SES differences in the risks of obesity and inflammation, measured by C-reactive protein. Further tests examined the extent to which social isolation, smoking, physical inactivity, alcohol abuse, and illicit drug use explain social differentials in each biomarker outcome. RESULTS: Women, blacks, Hispanics, and socioeconomically disadvantaged groups had higher risks of obesity and elevated C-reactive protein, with the SES gradients being more pronounced in female participants. Health-related behaviors showed large variation across sex, race, and SES strata. After adjusting for these behavioral variables, sex, and race disparities in obesity and excess inflammation in blacks diminished, whereas the adolescent SES disparity in obesity remained. The associations of adolescent and young adult SES disadvantage and inflammation were also explained by behavioral mechanisms. Behavioral factors associated with higher risks of obesity and inflammation differed, with the exception of fast food consumption, a risk factor for both. CONCLUSIONS: This study provides new knowledge of social distribution of early life exposures to physiologic precedents to cancer development later in life with implications for prevention and early intervention of modifiable risky behaviors in adolescents and young adults. PMID- 28818243 TI - Mental Health Problems and Cancer Risk Factors Among Young Adults. AB - INTRODUCTION: Chronic mental health problems often emerge in young adulthood, when adults begin to develop lifelong health behaviors and access preventive health services. The associations between mental health problems and modifiable cancer risk factors in young adulthood are not well understood. METHODS: In 2016, the authors analyzed 2014 Behavioral Risk Factor Surveillance System data on demographic characteristics, health service access and use, health status, and cancer risk factors (tobacco use, alcohol use, overweight or obesity, physical activity, and sleep) for 90,821 young adults aged 18-39 years with mental health problems (depressive disorder or frequent mental distress) compared to other young adults. RESULTS: Mental health problems were associated with white race; less than a high school education; lower income; being out of work or unable to work; being uninsured (for men only); poor health; previous diagnosis of asthma, skin cancer, or diabetes; and not having a recent checkup. After controlling for demographic characteristics, health service use, and health status, mental health problems among young adults were associated with smoking, binge drinking, inadequate sleep, having no leisure time physical activity, and being overweight or obese (among women only). Cervical cancer screening was not associated with mental health problems after controlling for demographic characteristics, health service use, and health status. CONCLUSIONS: Mental health problems in young adulthood were associated with potentially modifiable factors and behaviors that increase risk for cancer. Efforts to prevent cancer and promote health must attend to mental health disparities to meet the needs of young adults. PMID- 28818244 TI - Breastfeeding and Breast Cancer Risk Reduction: Implications for Black Mothers. AB - Breast cancer is the most commonly diagnosed cancer and a leading cause of death from cancer among U.S. women. Studies have suggested that breastfeeding reduces breast cancer risk among parous women, and there is mounting evidence that this association may differ by subtype such that breastfeeding may be more protective of some invasive breast cancer types. The purpose of this review is to discuss breast cancer disparities in the context of breastfeeding and the implications for black mothers. Black women in the U.S. have lower rates of breastfeeding and nearly twice the rates of triple-negative breast cancer (an aggressive subtype) compared with white women. In addition to individual challenges to breastfeeding, black women may also differentially face contextual barriers such as a lack of social and cultural acceptance in their communities, inadequate support from the healthcare community, and unsupportive work environments. More work is needed to improve the social factors and policies that influence breastfeeding rates at a population level. Such efforts should give special consideration to the needs of black mothers to adequately address disparities in breastfeeding among this group and possibly help reduce breast cancer risk. Interventions such as peer counseling, hospital policy changes, breastfeeding-specific clinic appointments, group prenatal education, and enhanced breastfeeding programs have been shown to be effective in communities of color. A comprehensive approach that integrates interventions across multiple levels and settings may be most successful in helping mothers reach their breastfeeding goals and reducing disparities in breastfeeding and potentially breast cancer incidence. PMID- 28818245 TI - Estimation of Breast Cancer Incident Cases and Medical Care Costs Attributable to Alcohol Consumption Among Insured Women Aged <45 Years in the U.S. AB - INTRODUCTION: This study estimated the percentage of breast cancer cases, total number of incident cases, and total annual medical care costs attributable to alcohol consumption among insured younger women (aged 18-44 years) by type of insurance and stage at diagnosis. METHODS: The study used the 2012-2013 National Survey on Drug Use and Health, cancer incidence data from two national registry programs, and published relative risk measures to estimate the: (1) alcohol attributable fraction of breast cancer cases among younger women by insurance type; (2) total number of breast cancer incident cases attributable to alcohol consumption by stage at diagnosis and insurance type among younger women; and (3) total annual medical care costs of treating breast cancer incident cases attributable to alcohol consumption among younger women. Analyses were conducted in 2016; costs were expressed in 2014 U.S. dollars. RESULTS: Among younger women enrolled in Medicaid, private insurance, and both groups, 8.7% (95% CI=7.4%, 10.0%), 13.8% (95% CI=13.3%, 14.4%), and 12.3% (95% CI=11.4%, 13.1%) of all breast cancer cases, respectively, were attributable to alcohol consumption. Localized stage was the largest proportion of estimated attributable incident cases. The estimated total number of breast cancer incident alcohol-attributable cases was 1,636 (95% CI=1,570, 1,703) and accounted for estimated total annual medical care costs of $148.4 million (95% CI=$140.6 million, $156.1 million). CONCLUSIONS: Alcohol-attributable breast cancer has estimated medical care costs of nearly $150 million per year. The current findings could be used to support evidence-based interventions to reduce alcohol consumption in younger women. PMID- 28818246 TI - Cancer Prevention During Early Adulthood: Highlights From a Meeting of Experts. AB - Using a life course approach, the Centers for Disease Control and Prevention's Division of Cancer Prevention and Control and the National Association of Chronic Disease Directors co-hosted a 2-day meeting with 15 multidisciplinary experts to consider evidence linking factors in early adulthood to subsequent cancer risk and strategies for putting that evidence into practice to reduce cancer incidence. This paper provides an overview of key themes from those meeting discussions, drawing attention to the influence that early adulthood can have on lifetime cancer risk and potential strategies for intervention during this phase of life. A number of social, behavioral, and environmental factors during early adulthood influence cancer risk, including dietary patterns, physical inactivity, medical conditions (e.g., obesity, diabetes, viral infections), circadian rhythm disruption, chronic stress, and targeted marketing of cancer-causing products (e.g., tobacco, alcohol). Suggestions for translating research into practice are framed in the context of the four strategic directions of the National Prevention Strategy: building healthy and safe community environments; expanding quality preventive services in clinical and community settings; empowering people to make healthy choices; and eliminating health disparities. Promising strategies for prevention among young adults include collaborating with a variety of community sectors as well as mobilizing young adults to serve as advocates for change. Young adults are a heterogeneous demographic group, and targeted efforts are needed to address the unique needs of population subgroups that are often underserved and under-represented in research studies. PMID- 28818248 TI - Cancer Risk-Promoting Information: The Communication Environment of Young Adults. AB - Young adulthood represents a time of myriad transitions, which leave young adults (YAs) more susceptible to the influences of cancer risk-promoting information. The tobacco, alcohol, indoor tanning, and food and beverage industries engage in aggressive marketing strategies through both traditional and social media to target this age group to consume their products, which have known links to cancer. Despite this barrage of messaging, detailed data are lacking on the communication behaviors of subgroups of this diverse age group, particularly those from low SES. This paper explores the available data on media usage among YAs and describes the cancer risk-promoting information environment, with a focus on communication inequalities and their implications for cancer research and control. Nationally representative data on media consumption patterns indicate that the majority of YAs access a diverse range of traditional and social media platforms, but these data do not fully describe differences at the intersection of age and important factors such as SES, gender, race/ethnicity, or urban/rural residence. Meanwhile, risk-promoting information is heavily marketed to YAs across media, with an increasing focus on using social media sites to normalize products and evade marketing restrictions. Gaps in the available data on YAs' media consumption behaviors, coupled with aggressive risk-promoting marketing strategies toward YAs, may impede cancer control efforts. Relationships between exposure to various cancer risk-promoting information, concurrent risk behaviors, SES disparities, and communication inequalities should be investigated to develop innovative and effective control programs and policies to promote cancer control in this important group. PMID- 28818247 TI - Alcohol Screening and Brief Intervention: A Potential Role in Cancer Prevention for Young Adults. AB - Excessive or risky alcohol use is a preventable cause of significant morbidity and mortality in the U.S. and worldwide. Alcohol use is a common preventable cancer risk factor among young adults; it is associated with increased risk of developing at least six types of cancer. Alcohol consumed during early adulthood may pose a higher risk of female breast cancer than alcohol consumed later in life. Reducing alcohol use may help prevent cancer. Alcohol misuse screening and brief counseling or intervention (also called alcohol screening and brief intervention among other designations) is known to reduce excessive alcohol use, and the U.S. Preventive Services Task Force recommends that it be implemented for all adults aged >=18 years in primary healthcare settings. Because the prevalence of excessive alcohol use, particularly binge drinking, peaks among young adults, this time of life may present a unique window of opportunity to talk about the cancer risk associated with alcohol use and how to reduce that risk by reducing excessive drinking or misuse. This article briefly describes alcohol screening and brief intervention, including the Centers for Disease Control and Prevention's recommended approach, and suggests a role for it in the context of cancer prevention. The article also briefly discusses how the Centers for Disease Control and Prevention is working to make alcohol screening and brief intervention a routine element of health care in all primary care settings to identify and help young adults who drink too much. PMID- 28818249 TI - Health Literacy: Cancer Prevention Strategies for Early Adults. AB - Health literacy, the degree to which individuals have the capacity to obtain, process, and understand health information and services needed to make health decisions, is an essential element for early adults (aged 18-44 years) to make informed decisions about cancer. Low health literacy is one of the social determinants of health associated with cancer-related disparities. Over the past several years, a nonprofit organization, a university, and a cancer center in a major urban environment have developed and implemented health literacy programs within healthcare systems and in the community. Health system personnel received extensive health literacy training to reduce medical jargon and improve their patient education using plain language easy-to-understand written materials and teach-back, and also designed plain language written materials including visuals to provide more culturally and linguistically appropriate health education and enhance web-based information. Several sustainable health system policy changes occurred over time. At the community level, organizational assessments and peer leader training on health literacy have occurred to reduce communication barriers between consumers and providers. Some of these programs have been cancer specific, including consumer education in such areas as cervical cancer, skin cancer, and breast cancer that are targeted to early adults across the cancer spectrum from prevention to treatment to survivorship. An example of consumer driven health education that was tested for health literacy using a comic book style photonovel on breast cancer with an intergenerational family approach for Chinese Americans is provided. Key lessons learned from the health literacy initiatives and overall conclusions of the health literacy initiatives are also summarized. PMID- 28818250 TI - Bars, Nightclubs, and Cancer Prevention: New Approaches to Reduce Young Adult Cigarette Smoking. AB - INTRODUCTION: Tobacco contributes to multiple cancers, and it is largely preventable. As overall smoking prevalence in California declines, smoking has become concentrated among high-risk groups. Targeting social/cultural groups (i.e., "peer crowds") that share common values, aspirations, and activities in social venues like bars and nightclubs may reach high-risk young adult smokers. Lack of population data on young adult peer crowds limits the ability to assess the potential reach of such interventions. METHODS: This multimodal population based household survey included young adults residing in San Francisco and Alameda counties. Data were collected in 2014 and analyzed in 2016. Multivariable logistic regressions assessed smoking by sociodemographic factors, attitudes, self-rated health, peer crowd affiliation, and bar/nightclub attendance. RESULTS: Smoking prevalence was 15.1% overall; 35.3% of respondents sometimes or frequently attended bars. In controlled analyses, bar attendance (AOR=2.13, 95% CI=1.00, 4.53) and binge drinking (AOR=3.17, 95% CI=1.59, 6.32) were associated with greater odds of smoking, as was affiliation with "Hip Hop" (AOR=4.32, 95% CI=1.48, 12.67) and "Country" (AOR=3.13, 95% CI=1.21, 8.09) peer crowds. Multivariable models controlling for demographics estimated a high probability of smoking among bar patrons affiliating with Hip Hop (47%) and Country (52%) peer crowds. CONCLUSIONS: Bar attendance and affiliation with certain peer crowds confers significantly higher smoking risk. Interventions targeting Hip Hop and Country peer crowds could efficiently reach smokers, and peer crowd-tailored interventions have been associated with decreased smoking and binge drinking. Targeted interventions in bars and nightclubs may be an efficient way to address these cancer risks. PMID- 28818252 TI - Origins of Cancer Disparities in Young Adults: Logic Models to Guide Research. AB - Cancer disparities research is motivated by persistent inequities in cancer outcomes by race, ethnicity, social status, neighborhood location, and other subpopulation characteristics. These inequities have proven to be persistent and difficult to alter. Part of the reason for the frustration with slow progress is a lack of appreciation of the long-term nature of the undertaking. It is highly likely that the disparities observed in adulthood find their origins in young adulthood, if not earlier. A long-term perspective is needed, recognizing that successes may take many years to realize. This commentary presents the experience of the Center for Health And Risk in Minority youth and young adults project, which is a comprehensive center of excellence funded by the National Institute of Minority Health and Health Disparities for addressing disparities and chronic disease prevention in minority youth and young adults. The use of logic models is advanced for this kind of research because they can provide a theory of change and illustrate the course of knowledge translation over time. Logic models for cancer disparities research can place individual project activities in a realistic context that at one time indicates what is possible and reasonable to expect during the duration of a typical research project as well as the future steps that need to be taken on the way to an expected ultimate impact on cancer inequities. PMID- 28818253 TI - Introduction: Evolution of carotid atherosclerotic disease therapies. PMID- 28818251 TI - Teens, Tweets, and Tanning Beds: Rethinking the Use of Social Media for Skin Cancer Prevention. AB - The incidence of skin cancer is rising in the U.S., and melanoma, the deadliest form, is increasing disproportionately among young white women. Indoor tanning is a modifiable risk factor for all skin cancers and continues to be used at the highest rates in young white women. Adolescents and young adults report personal appearance-based reasons for using indoor tanning. Previous research has explored the influences on tanning bed use, including individual factors as well as relationships with peers, family, schools, media influences, legislation, and societal beauty norms. Adolescents and young adults also have high rates of social media usage, and research is emerging on how best to utilize these platforms for prevention. Social media has the potential to be a cost-effective way to reach large numbers of young people and target messages at characteristics of specific audiences. Recent prevention efforts have shown that comprehensive prevention campaigns that include technology and social media are promising in reducing rates of indoor tanning among young adults. This review examines the literature on psychosocial influences on indoor tanning among adolescents and young adults, and highlights ways in which technology and social media can be used for prevention efforts. PMID- 28818254 TI - Medical treatment strategies to reduce perioperative morbidity and mortality after carotid surgery. AB - There is a paucity of high-quality evidence regarding what constitutes "optimal medical therapy" for the purposes of reducing morbidity/mortality after carotid endarterectomy (CEA). All patients should be prescribed antiplatelet therapy. Low dose aspirin (75 to 325 mg) should be continued throughout the perioperative period and there is no evidence that higher doses confer additional benefit. There is emerging evidence that early implementation of dual antiplatelet therapy in recently symptomatic patients (aspirin 75 mg plus clopidogrel 75 mg) can reduce recurrent cerebral events before CEA and that dual antiplatelet therapy will significantly reduce stroke due to early postoperative carotid thrombosis. Evidence suggests that dual antiplatelet therapy is not associated with a significant increase in bleeding complications, although it is essential to aggressively treat post-CEA hypertension. Antiplatelet therapy should be withheld for 24 hours after completion of thrombolysis. Statins should be started preoperatively; the rationale being that they will reduce perioperative myocardial infarction and stroke (especially in symptomatic patients), as well as reduce recurrent cerebral events before CEA. Heparin reversal using protamine is becoming increasingly common and there is no evidence that this significantly increases perioperative thromboembolic stroke, but it does seem to reduce the prevalence of neck hematomas, which can be associated with an increased risk of stroke/death after re-exploration. Post-CEA hypertension is especially common in recently symptomatic patients undergoing surgery within the first 7 to 14 days after onset of symptoms. Untreated, it is associated with high rates of intracerebral hemorrhage, stroke due to the hyperperfusion syndrome, and major cardiac events. Each unit should have written guidance for treating this condition promptly. This is especially important when CEA is performed in the first few days after onset of symptoms and, especially, when CEA is performed soon after thrombolysis. PMID- 28818255 TI - Clinical need, design, and goals for the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis trial. AB - Prior clinical trials produced evidence-based treatment recommendations for patients with asymptomatic carotid stenosis that may not be appropriate for clinical decision-making today. High-quality patient outcomes data to allow informed decision making regarding the optimal management of high-grade asymptomatic internal carotid artery stenosis is lacking. The results of the Asymptomatic Carotid Atherosclerosis Study were published in 1995 based on a randomized patient enrollment in the 1990s. Outcomes after endarterectomy, stenting, and medical treatment for these patients have all improved in the subsequent 2 decades. Therefore, the time has come to test whether contemporary intensive medical therapy is an acceptable alternative to contemporary endarterectomy or stenting and is the rationale for the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis (CREST-2) trial. This National Institute of Neurological Disorders and Stroke-sponsored prospective, multicenter clinical trial has the investigators, study teams, asymptomatic patients, and robust study design needed to provide these answers. Two randomized clinical trials are planned: carotid revascularization and intensive medical management versus medical management alone in patients with asymptomatic high grade carotid stenosis randomize in a 1:1 ratio; the other trial will randomize patients in a 1:1 ratio to carotid stenting with embolic protection versus no stenting. ClinicalTrials.gov Identifier: NCT02089217. PMID- 28818256 TI - Will mesh-covered stents help reduce stroke associated with carotid stent angioplasty? AB - Carotid stent angioplasty (CAS) has been shown to protect patient from future stroke long-term efficacy similar to carotid endarterectomy (CEA). The risk of minor stroke in the perioperative period is higher than with CEA and not related to cerebral protection during the CAS procedure since a significant portion of the neurologic events occur between 1 and 30 days following stent deployment. This observation suggests mechanisms integral to the stent itself may be pertinent such as plaque embolization thru the stent struts may occur. It appears that this embolic risk can be reduced by use of specific carotid stent designs that include a mesh covering to minimize the open struts areas and thus embolization through the carotid stent. Improvements in stent design that eliminate post-procedural debris embolization will expand the application of CAS for severe internal carotid artery atherosclerotic stenosis. PMID- 28818257 TI - High-risk carotid plaque: lessons learned from histopathology. AB - The pathophysiology and natural history of atherosclerotic carotid disease is predicated on a more extensive knowledge of lesion progression gained in the studies conducted in the coronary arteries, and these will be reviewed. While the precise sequence of lesion progression leading to carotid plaque vulnerability and cerebrovascular events remain less well understood, specific early and more advanced progressive lesion morphologies associated with stroke risk have been characterized. Of late, there has been a conscious effort for stroke prevention in symptomatic and asymptomatic patients to move beyond luminal stenosis as the only guidance to predict future cerebrovascular events. Driving this strategy are recent advances in medical imaging modalities to assess carotid atherosclerosis vulnerability particularly involving molecular imaging, which is now positioned at the forefront to provide a more detailed and mechanistic assessment of stroke risk. As such, we will spotlight the pathology of high-risk carotid plaques in patients with symptomatic and asymptomatic carotid disease with further reference into more recent mechanistic insights involving a recognized macrophage-mediated inflammatory change, intraplaque neoangiogenesis/hemorrhage, hypoxia, and microcalcification, as potential morphologic indicators of stroke risk. PMID- 28818258 TI - Imaging of high-risk carotid plaques: ultrasound. AB - Duplex ultrasonography has a well-established role in the assessment of the degree of stenosis caused by carotid atherosclerosis. This assessment is derived from Doppler velocity changes induced by the narrowing lumen of the artery. New research into the mechanisms for plaque rupture and atheroembolic stroke indicates that the degree of narrowing is an imperfect predictor of stroke risk, and that other factors, such as plaque composition and remodeling and biomechanical forces acting on the plaque, can play a role. New advances in ultrasound imaging technology have made it possible to investigate these measures of plaque vulnerability to identify pre-embolic unstable carotid plaques. Efforts have been made to quantify the morphologic appearance of the plaque in B-mode images and to correlate them with histology. Additional research has resulted in the first generation of clinically available 3-dimensional ultrasound transducers that reduce operator-dependence and variability. Finally, ultrasonography provides real-time imaging and physiologic information that can be utilized to measure disruptive forces acting on carotid plaques. We review some of these exciting developments in ultrasonography and discuss how these may impact clinical practice. PMID- 28818259 TI - Imaging of the high-risk carotid plaque: magnetic resonance imaging. AB - The emergence of the concept of high-risk atherosclerotic plaque has led to considerable interest in noninvasive imaging techniques to identify high-risk features before clinical sequelae. For plaques in the carotid arteries, magnetic resonance imaging has undergone considerable histologic validation to link imaging features to indicators of plaque instability, including plaque burden, intraplaque hemorrhage, fibrous cap disruption, lipid rich necrotic core, and calcification. Recently introduced imaging technologies, especially those focused on three-dimensional imaging sequences, are now poised for integration into the clinical workup of patients with suspected carotid atherosclerosis. The purpose of this article is to review the carotid plaque magnetic resonance imaging techniques that are most ready for integration into the clinic. PMID- 28818260 TI - Transcranial Doppler monitoring for microemboli: a marker of a high-risk carotid plaque. AB - In the United States, 90% of carotid intervention is being performed for asymptomatic carotid stenosis, even though 90% of patients would be better treated with intensive medical therapy. This is being justified by comparing risks of stroke or death with medical therapy during clinical trials completed decades ago (approximately 2% per year) with risks of intervention with carotid artery stenting (CAS) versus carotid endarterectomy in recent trials that did not have a medical arm. Such extrapolations are, simply put, invalid. Even though the two most recent papers comparing carotid endarterectomy with CAS reported that the long-term risk (after first deducting periprocedural risks) is similar to that with medical therapy (approximately 0.5% per year), when the periprocedural risks are considered (approximately 3% with stenting v 1.5% with CAS), most patients would be better treated with intensive medical therapy. Furthermore, it must be recognized that the low risks observed in clinical trials with highly selected surgeons and interventionalists are much lower than in real-world practice. It is therefore necessary to have ways to identify, among patients with asymptomatic carotid stenosis, the few (approximately 10% to 15%) who could benefit from intervention. Indicators of vulnerable plaque, such as ulceration, juxtaluminal lucent plaque, intraplaque hemorrhage on magnetic resonance imaging, and plaque inflammation on positron emission tomography/computed tomography are in development for that purpose. The best-validated approach is detection of microemboli on transcranial Doppler. A prospective single-center study of 468 patients showed that microemboli identified high-risk asymptomatic stenosis; this was validated by a prospective multicenter international study in 467 patients. Increased risk with microemboli persisted in the era of lower risks with intensive medical therapy. Patients with asymptomatic carotid stenosis should not be offered CAS or carotid endarterectomy without first being identified as high risk; percent stenosis does not do so. Currently, the best way to improve the risk to benefit ratio for intervention is transcranial Doppler embolus detection. PMID- 28818261 TI - Contemporary medical therapies of atherosclerotic carotid artery disease. AB - Contemporary medical therapy consists of identification and treatment of all patient-modifiable vascular risk factors. Specific atherosclerotic disease therapies are designed to reduce the risk of thrombosis, and the disease progression in order to reduce the risk of future cardiovascular events. Contemporary medical management emphasizes the need to support the patient in achieving lifestyle modifications and to adjust medication to achieve individualized target values for specific quantifiable risk factors. Antiplatelet therapy in the form of aspirin or clopidogrel is routinely used for the prevention of ischemic stroke in patients who have had a transient ischemic attack or stroke. There is evidence from a recent trial that the use of combination antiplatelet therapy with aspirin and clopidogrel started within 24 hours of minor stroke or transient ischemic attack reduces the risk of recurrent stroke compared to the use of aspirin alone, and therefore we use aspirin plus clopidogrel in recently symptomatic patients with carotid stenosis pending carotid revascularization. Anticoagulation with heparins or vitamin K antagonist is not recommended except in patients at risk for cardio-embolic events. Lowering blood pressure to target levels has been shown to slow down the progression of carotid artery stenosis and reduces the intima-media thickness of the carotid plaque, while lowering lipid levels with statins has become an essential element in the medical therapy of carotid artery stenosis. Diabetes management should be optimized. Lifestyle choices, including tobacco smoking, physical inactivity, unhealthy diet, obesity, and excessive alcohol intake, are all important modifiable vascular risk factors. The combination of dietary modification, physical exercise, and use of aspirin, a statin, and an antihypertensive agent can be expected to give a cumulative relative stroke risk reduction of 80%. The evidence suggests that intensive medical therapy is so effective that carotid revascularization may no longer be necessary in many of the patients in whom carotid surgery or stenting is currently performed. Two large ongoing trials are therefore comparing the risks and benefits of carotid revascularization versus intensive medical therapy alone. PMID- 28818262 TI - Brain-derived neurotrophic factor mediates cognitive improvements following acute exercise. AB - The mechanisms causing improved cognition following acute exercise are poorly understood. This article proposes that brain-derived neurotrophic factor (BDNF) is the main factor contributing to improved cognition following exercise. Additionally, it argues that cerebral blood flow (CBF) and oxidative stress explain the release of BDNF from cerebral endothelial cells. One way to test these hypotheses is to block endothelial function and measure the effect on BDNF levels and cognitive performance. The CBF and oxidative stress can also be examined in relationship to BDNF using a multiple linear regression. If these hypotheses are true, there would be a linear relationship between CBF+oxidative stress and BDNF levels as well as between BDNF levels and cognitive performance. The novelty of these hypotheses comes from the emphasis on the cerebral endothelium and the interplay between BDNF, CBF, and oxidative stress. If found to be valid, these hypotheses would draw attention to the cerebral endothelium and provide direction for future research regarding methods to optimize BDNF release and enhance cognition. Elucidating these mechanisms would provide direction for expediting recovery in clinical populations, such as stroke, and maintaining quality of life in the elderly. PMID- 28818263 TI - Link between mast cells and bacteria: Antimicrobial defense, function and regulation by cytokines. AB - Bacteria and their products, such as LPS, act on mast cells (MCs) to induce the secretion of multiple cytokines, including IL-1, TNF, IL-18 and IL-33, which can be dosed in the site of infected tissues. Antigen-binding IgE cross-links FcepsilonRI on mast cells involves the generation and activation of PKCdelta, ERK, tyrosine kinases (Syk and Lyn) and mitogen-activated protein kinases (MAPKs), inducing the release of chemical mediators which provoke inflammation and hypersensitive reaction. Other stimuli, including, cytokines, neuropeptides, chemical and physical activators, can also act on MCs to release a plethora of inflammatory compounds. Activated MCs produce a broad spectrum of inflammatory cytokines, chemokines, lipid compounds and vasoactive amines, all involved in immune response. By producing TNF, MCs have an antibacterial defense and a protective function; while pathogenic bacteria and their products, such as LPS, have an inflammatory response through MC activation. LPS binding TLR4 produce MC generation IL-1 family members, and chemokines, which may recruit inflammatory cells at the infection site; whereas in KitW/W-v mice, where MCs are genetically absent, the inflammatory effect is not present. We report for the first time a link between MCs and bacteria emphasizing the mediation of inflammatory cytokines/chemokines. We can conclude that mast cells fight bacteria, and their immune response is perfectly integrated in the immune network. We hope that the understanding of microbial and mast cell interaction leads to more efficient therapeutic development in relation to microbial resistance. PMID- 28818264 TI - The potential management of oral candidiasis using anti-biofilm therapies. AB - Candida albicans is a minor component of the oral microbiota and an opportunistic pathogen that takes advantage of the immunocompromised host and causes oral mucositis and oral candidiasis. This organism is able to undergo phenotypic modification from a yeast to hyphae growth phase, one of the key arsenals for immune cell evasion, tissue invasion and biofilm formation. The latter property coupled with overgrowth and immune compromising factors such as HIV/AIDS, cancer treatments, organ transplantation, diabetes, corticosteroid use, dentures, and broad-spectrum antibiotic use have modified the fungus from a normal component of the microflora to a foe of an oral cavity and resulting in reduced sensitivity towards commonly utilised antifungal agents. Hence, the need for alternative therapy to curb this plight is of importance. Making use of biomolecules produced by Streptococcus mutans, application of lactoferrin which is a nonspecific host defense factor found in saliva with metal chelating and broader antimicrobial properties, use of probiotics which have the capacity to boost the host immunity through eliciting Immunoglobulin A synthesis, and perturbing the pathogen's environment via competition of space and food, and application of photodynamic therapy can help to manage the burden of oral candidiasis. PMID- 28818265 TI - Is periodontitis a risk factor for infections in cirrhotic patients? PMID- 28818266 TI - MicroRNA-93 elevation after myocardial infarction is cardiac protective. AB - Coronary Artery Disease (CAD) is one of the most serious diseases that endangers human health worldwide, myocardial infarction (MI) is an acute form of CAD. Recent developments in MI therapies have resulted in significant reductions in mortality. However, subsequent chronic congestive heart failure and ventricle remodeling plagues an increasing number of MI patients. MicroRNAs (miR) have been reported to be involved in the process of cardiac remodeling, a recent study shows that miR-93 is elevated in the blood of CAD patients. Similar to human CAD, we found miR-93 is elevated both in ventricle tissue and blood in mice MI model, and miR-93 is secreted from cardiomyocytes cultured under hypoxia. Interestingly, miR-93 inhibits apoptosis and protects cardiomyocytes from ischemia/reperfusion injury. In other type of ischemic disease like stoke and peripheral arterial disease, miR-93 shows long term protective effects via enhancing angiogenesis, inducing macrophage M2 polarization and antioxidant effects. These effects are favorable for ventricle remodeling inhibition after MI. In a pilot experiment, we indicated that miR-93 knockdown deteriorate cardiac remodeling in 30days after MI in mice models. Therefore, we hypothesize that miR-93 upregulation and secretion from cardiomyocytes after MI is adaptive, which could inhibit cardiac remodeling and heart failure. PMID- 28818267 TI - Is small intestinal bacterial overgrowth involved in the pathogenesis of functional dyspepsia? AB - Functional dyspepsia is a highly prevalent disease, with significant impacts on patients' quality of life and economic robustness of health care systems worldwide. It constitutes a constellation of symptoms located in the gastro duodenal region while its pathogenesis remains poorly understood. Accumulating evidence suggest that small intestinal bacterial overgrowth is associated with the etiology of functional gastrointestinal disorders. We herein present the hypothesis that a causal link between small intestinal bacterial overgrowth and functional dyspepsia might exist. Development of functional dyspepsia symptoms may derive from abnormal fermentation of carbohydrates due to increased proliferation of coliform bacteria, resulting in luminal distension, increased intestinal permeability and immune response perpetuation in predisposed hosts, secondary to an episode of infectious gastroenteritis. Moreover, the treatment of functional dyspepsia remains challenging and we explore the feasibility of innovative therapeutic modalities based on our hypothesis. PMID- 28818268 TI - "Metformin-resistant" folic acid producing probiotics or folic acid against metformin's adverse effects like diarrhea. AB - Metformin, first line medication in the treatment of type2 diabetes by millions of patients worldwide, causes gastrointestinal adverse effects (i.e. diarrhea) in approximately 30% of patients, frequently leading to discontinuation. Interestingly, metformin was reported to increase life span in a microscopic worm, Caenorhabditis elegans, by decreasing folate and methionine production of bacteria that this worm uses as a food source. Metformin can be expected to have a similar effect on some microorganisms of human gut microbiota. This can disturb the balance of gut microbiota and cause gastrointestinal adverse effects by altering folate production of some types of bacteria and suppress their growth. Metformin resistant probiotics can be discovered or generated by artificial evolution/selection, and used to prevent these adverse effects. These patients can also be managed with folate supplementation. PMID- 28818269 TI - When a model becomes the real thing: A neuro-cognitive account of 'demonic' possession. PMID- 28818270 TI - The glass ceiling: A biological phenomenon. AB - Many brilliant and ambitious young women lose their drive for top careers after childbirth. New maternal impulses are at odds with their original ambitions and for many mothers stress and frustration will be the result as they have to combine child care with workweeks of 60-80h to reach or remain at the top. Pregnancy hormones modify the female's brain as has been demonstrated already for decades in animals. This brain plasticity due to adult neurogenesis in the so called maternal circuitry of the limbic system is long-lasting and perhaps lifelong. In humans hormonal and neuro-imaging studies show ample evidence for fundamental and long lasting pregnancy induced brain changes, not only in the limbic system, but also in the cortical networks like theory of mind and mirror neuron system. Recent research shows pronounced and long lasting brain changes in several of these areas. It can be concluded that there exists a maternal brain that drives mother's behaviour and priorities. Research in men shows that the more fathers are involved in raising their children, the more caring behaviour they develop. Structural anatomical changes are found in neural regions involved in parental motivation. These studies show that brain plasticity in fathers is experience dependent. In Nordic countries, a policy of paid paternal leave followed by a flexible shared parental leave, stimulates fatherly behaviour. This might reduce men's eagerness for top careers, thus creating better opportunities for women. Demolition of women's glass ceiling starts with the father. PMID- 28818271 TI - The vestibulocochlear bases for wartime posttraumatic stress disorder manifestations. AB - Preliminary findings based on earlier retrospective studies of 229 wartime head injuries managed by the Walter Reed Army Medical Center (WRAMC)/National Naval Medical Center (NNMC) Neurosurgery Service during the period 2003-08 detected a threefold rise in Posttraumatic Stress Disorder (PTSD) manifestations (10.45%) among Traumatic Brain Injuries (TBI) having concomitant vestibulocochlear injuries compared to 3% for the TBI group without vestibulo-cochlear damage (VCD), prompting the authors to undertake a more focused study of the vestibulo auditory pathway in explaining the development of posttraumatic stress disorder manifestations among the mostly Blast-exposed head-injured. The subsequent historical review of PTSD pathophysiology studies, the evidence for an expanded vestibular system and of a dominant vestibular system, the vascular vulnerability of the vestibular nerves in stress states as well as the period of cortical imprinting has led to the formation of a coherent hypotheses utilizing the vestibulocochlear pathway in understanding the development of PTSD manifestations. Neuroimaging and neurophysiologic tests to further validate the vestibulocochlear concept on the development of PTSD manifestations are proposed. PMID- 28818272 TI - On human parthenogenesis. AB - Spontaneous parthenogenetic and androgenetic events occur in humans, but they result in tumours: the ovarian teratoma and the hydatidiform mole, respectively. However, the observation of fetiform (ovarian) teratomas, the serependious identification of several chimeric human parthenotes and androgenotes in the last two decades, along with the creation of viable bi-maternal mice in the laboratory based on minor genetic interferences, raises the question of whether natural cases of clinically healthy human parthenotes have gone unnoticed to science. Here we present a hypothesis based on three elements to support the existence of such elusive individuals: mutations affecting (i) genomic imprinting, (ii) meiosis and (iii) oocyte activation. Additionally, we suggest that the routine practice of whole genome sequencing on every single newborn worldwide will be the ultimate test to this controversial, yet astonishing hypothesis. Finally, several medical implications of such intriguing event are presented. PMID- 28818273 TI - A novel genetic model to explore the Brenner hypothesis: Linking nephron endowment and number with hypertension. AB - Nephron endowment, the total number of nephrons an individual is born with, is determined by both genetic and environmental factors during embryonic development. In 1988, Brenner hypothesized that there was an inverse relationship between nephron number and hypertension. Over the course of one's lifetime it is predicted that even healthy individuals will lose a significant percentage of nephrons as part of normal aging. Thus, a low nephron endowment at birth or in combination with age- or disease-related nephron loss could pre-dispose individuals to the development of hypertension. Currently, it is not clear what minimal number (ie, threshold) of nephrons is associated with susceptibility to glomeruli injury or hypertension, due in part to the lack of relevant animal models. The BPH2 mouse is a unique genetic model of hypertension that has a normotensive line (BPN3 mice) as well as a hypotensive line (BPL1 mice) derived from the original breeding of eight common inbred strains of mice. Thus, we hypothesize that the differences in blood pressure observed in BPH2, BPN3, and BPL1 mice will correlate inversely with nephron number as predicted by the Brenner hypothesis. If our hypothesis is true, then the BPH2 mouse model will provide a unique experimental model to study the impact of nephron endowment and nephron number on susceptibility to renal injury and hypertension. PMID- 28818275 TI - Electromagnetic fields may act via calcineurin inhibition to suppress immunity, thereby increasing risk for opportunistic infection: Conceivable mechanisms of action. AB - While a good number of studies have demonstrated that modern, man-made ambient electromagnetic fields can have both stimulatory and inhibitory effect on immune system function, the precise mechanisms have yet to be completely elucidated. It is hypothesized here that, depending on the parameters, one of the means by which long-term electromagnetic field exposure has the potential to eventually lead to immunosuppression is via downstream inhibition of the enzyme calcineurin - a protein phosphatase, which activates the T-cells of the immune system and can be blocked by pharmaceutical agents. Calcineurin is the target of a class of pharmaceuticals called calcineurin inhibitors (e.g., cyclosporine, pimecrolimus and tacrolimus). When organ transplant recipients take such pharmaceuticals to prevent or suppress organ transplant rejection, one of the major side effects is immunosuppression leading to increased risk of opportunistic infection: e.g., fungal, viral (Epstein-Barr virus, cytomegalovirus), atypical bacterial (Nocardia, Listeria, mycobacterial, mycoplasma), and parasitic (e.g., toxoplasmosis) infections. Frequent anecdotal reports, as well as a number of scientific studies, have shown that electromagnetic field exposures may indeed produce the same effect: a weakened immune system leading to an increase in the same or similar opportunistic infections: i.e., fungal, viral, atypical bacterial, and parasitic infections. Furthermore, numerous research studies have shown that man-made electromagnetic fields have the potential to open voltage gated calcium channels, which can in turn produce a pathological increase of intracellular calcium, leading downstream to the pathological production of a series of reactive oxygen species. Finally, there are a number of research studies demonstrating the inhibition of calcineurin by a pathological production of reactive oxygen species. Hence, it is hypothesized here that exposures to electromagnetic fields have the potential to inhibit immune system response by means of an eventual pathological increase in the influx of calcium into the cytoplasm of the cell, which induces a pathological production of reactive oxygen species, which in turn can have an inhibitory effect on calcineurin. Calcineurin inhibition leads to immunosuppression, which in turn leads to a weakened immune system and an increase in opportunistic infection. PMID- 28818274 TI - The affection of the disturbance of the hydrodynamics of blood in case of stress on pathological increase of level of low density lipoproteins in blood. The formation of cylindrical plaques, and their participation in the development of acute ischemic disorders of heart and brain. AB - In this article is given the new insight about the affection of stress on the increase of level of low density lipoproteins (LDL) in the blood, which is connected with the disturbance of hydrodynamics in the bloodstream, the attention was paid to the cylindrical cholesterol plaque, and it's classification. The disturbance of hydrodynamics of blood under the stress leads to the formation of a cylindrical cholesterol plaque, which repeats the contour of the vessel, and leads to the ischemic disorders of the heart and brain. The cylindrical cholesterol plaque goes through several stages of development: friable, yielding, dense, old. In the case of destruction of friable, fresh cholesterol plaque, releases a big quantity of low-density lipoproteins. This leads to the pathological increase of level of LDL in the blood. In the case of long disturbance of hydrodynamics, occurs the formation of strong links between low density lipoproteins. Yielding cholesterol plaque is formed. Further maturation of cylindrical cholesterol plaque, leads to it's densifying and damage. We may emphasize, that short periods of strong contraction and expansion of vessels lead to the increase of level of LDL in the blood. Self-dependent restoration of normal level of LDL in blood occurs in the case of restoration of pressure in the limits of numbers, which are specific for particular person, and which don't exceed the physiological standard. Among patients with long duration of stress, the duration of vasospasm increases. LDL, without having a possibility to crumble, begin to stick together and form the yielding cylindrical plaque. It is characterized by having of not so strong connection with the vascular wall, and maintains only at the expanse of iteration of the vascular wall, it has cylindrical shape, is elastic and yellow. The thickness and length of walls depends on the degree of cross-clamping during the time of formation of yielding cylindrical plaque. In the case of stopping of spasm, yielding cylindrical plaque can resolve slowly. Among hypotensive and individuals, which have normal pressure, the increase of level of LDL isn't noted. There aren't such investigations, where such link was noted. The increasing of level of LDL among these people (especially under the stress) can say about cases of short-term increase of pressure, which could be unnoticed. These patients require pressure monitoring and, accordingly, the adjustment of the state of stress and anger. PMID- 28818276 TI - The role of incremental parsing in syntactically conditioned word learning. AB - In a series of three experiments, we use children's noun learning as a probe into their syntactic knowledge as well as their ability to deploy this knowledge, investigating how the predictions children make about upcoming syntactic structure change as their knowledge changes. In the first two experiments, we show that children display a developmental change in their ability to use a noun's syntactic environment as a cue to its meaning. We argue that this pattern arises from children's reliance on their knowledge of verbs' subcategorization frame frequencies to guide parsing, coupled with an inability to revise incremental parsing decisions. We show that this analysis is consistent with the syntactic distributions in child-directed speech. In the third experiment, we show that the change arises from predictions based on verbs' subcategorization frame frequencies. PMID- 28818278 TI - Self-Measured Blood Pressure Monitoring Improves Outcomes: Recommendation of the Community Preventive Services Task Force. PMID- 28818277 TI - Economics of Self-Measured Blood Pressure Monitoring: A Community Guide Systematic Review. AB - CONTEXT: The health and economic burden of hypertension, a major risk factor for cardiovascular disease, is substantial. This systematic review evaluated the economic evidence of self-measured blood pressure (SMBP) monitoring interventions to control hypertension. EVIDENCE ACQUISITION: The literature search from database inception to March 2015 identified 22 studies for inclusion with three types of interventions: SMBP used alone, SMBP with additional support, and SMBP within team-based care (TBC). Two formulae were used to convert reductions in systolic BP (SBP) to quality-adjusted life years (QALYs) to produce cost per QALY saved. All analyses were conducted in 2015, with estimates adjusted to 2014 U.S. dollars. EVIDENCE SYNTHESIS: Median costs of intervention were $60 and $174 per person for SMBP alone and SMBP with additional support, respectively, and $732 per person per year for SMBP within TBC. SMBP alone and SMBP with additional support reduced healthcare cost per person per year from outpatient visits and medication (medians $148 and $3, respectively; median follow-up, 12-13 months). SMBP within TBC exhibited an increase in healthcare cost (median, $369 per person per year; median follow-up, 18 months). SMBP alone varied from cost saving to a maximum cost of $144,000 per QALY saved, with two studies reporting an increase in SBP. The two translated median costs per QALY saved were $2,800 and $4,000 for SMBP with additional support and $7,500 and $10,800 for SMBP within TBC. CONCLUSIONS: SMBP monitoring interventions with additional support or within TBC are cost effective. Cost effectiveness of SMBP used alone could not be determined. PMID- 28818279 TI - Letter Regarding "Improving the Nutritional Impact of the Supplemental Nutrition Assistance Program". PMID- 28818280 TI - Response to Letter Regarding "Improving the Nutritional Impact of the Supplemental Nutrition Assistance Program". PMID- 28818281 TI - American Journal of Preventive Medicine 2016 Article of the Year. PMID- 28818282 TI - The obesity paradox in patients with severe soft tissue infections. AB - BACKGROUND: The "obesity paradox" has been demonstrated in chronic diseases but not in acute surgery. We sought to determine whether obesity is associated with improved outcomes in patients with severe soft tissue infections (SSTIs). METHODS: The 2006 to 2010 Nationwide Inpatient Sample was used to identify adult patients with SSTIs. Patients were categorized into nonobese and obese (nonmorbid [body mass index 30 to 39.9] and morbid [body mass index >= 40]). Logistic regression provided risk-adjusted association between obesity categories and inhospital mortality. RESULTS: There were 2,868 records with SSTI weighted to represent 14,080 patients. Obese patients were less likely to die in hospital than nonobese patients (odds ratio [OR] = .42; 95% confidence interval [CI], .25 to .70; P = .001). Subanalysis revealed a similar trend, with lower odds of mortality in nonmorbid obesity (OR = .46; 95% CI, .23 to .91; P = .025) and morbid obesity (OR = .39; 95% CI, .19 to .80; P = .011) groups. CONCLUSIONS: Obesity is independently associated with reduced inhospital mortality in patients with SSTI regardless of the obesity classification. This suggests that the obesity paradox exists in this acute surgical population. PMID- 28818283 TI - Understanding readmissions following operations of the thyroid and parathyroid glands. AB - BACKGROUND: In anticipation of bundled-payment models for thyroid and parathyroid disease, a better understanding of resource utilization following surgery is required. We sought to characterize the use of hospital services following such operations using an analysis of readmissions. METHODS: Patients age 18+years who underwent a thyroid or parathyroid operation in CA or NY (2008-2011) were classified by procedure type. Primary outcome was readmission within 90 days. Univariate and multivariable logistic regression were used to determine factors associated with readmission. Subset analysis was performed for thyroid cancer patients. RESULTS: Among 59,427 patients, 34.2% had thyroid cancer. Eleven percent (n = 6462) were readmitted within 90 days, with 27% readmitted to a different hospital than the index. 66.2% of thyroid cancer patients were readmitted for a related condition. CONCLUSION: Eleven percent of patients are admitted to the hospital within 90 days of an operation in the thyroid or parathyroid glands. Patient factors and diseases necessitate the use of hospital services. Bundled payments must consider the patients' needs for hospital-based services in calculating costs for surgically treated endocrine disorders. PMID- 28818284 TI - Sustainability of future bioenergy production. PMID- 28818286 TI - Adding sound to theory of mind: Comparing children's development of mental-state understanding in the auditory and visual realms. AB - Theory of mind (ToM) gradually develops during the preschool years. Measures of ToM usually target visual experience, but auditory experiences also provide valuable social information. Given differences between the visual and auditory modalities (e.g., sights persist, sounds fade) and the important role environmental input plays in social-cognitive development, we asked whether modality might influence the progression of ToM development. The current study expands Wellman and Liu's ToM scale (2004) by testing 66 preschoolers using five standard visual ToM tasks and five newly crafted auditory ToM tasks. Age and gender effects were found, with 4- and 5-year-olds demonstrating greater ToM abilities than 3-year-olds and girls passing more tasks than boys; there was no significant effect of modality. Both visual and auditory tasks formed a scalable set. These results indicate that there is considerable consistency in when children are able to use visual and auditory inputs to reason about various aspects of others' mental states. PMID- 28818288 TI - Melanoma Arising in a Melanocytic Nevus. AB - The association of melanoma with a preexisting melanocytic nevus varies considerably between series, depending on whether the association is based on histological signs (4%-72%) or a clinically evident lesion (42%-85%). Histological association with a nevus correlates with favorable prognostic factors, whereas a clinical association correlates with unfavorable factors. In this review, we discuss the characteristics of nevus-associated melanoma from different perspectives: Whiteman's divergent pathway hypothesis for the development of cutaneous melanoma; and the factors involved in nevogenicity, including both the genetic and molecular factors involved in the development of the melanoma and its precursor lesions. Finally, a cumulative analysis of the 16 162 cases reported in the literature revealed that 29.8% of melanomas are histologically associated with a melanocytic nevus. PMID- 28818287 TI - Application of flexible endoscopy-based biopsy in the diagnosis of tumour pathologies in otorhinolaryngology. AB - INTRODUCTION AND OBJECTIVES: Interventional endoscopy allows us to act on the pathology of the patient with minimal discomfort, low costs and high efficiency. We assessed the validity of flexible endoscopic biopsies in our hospital, in lesions suspected of malignancy in the rhino-pharyngo-laryngeal space. SUBJECTS AND METHODS: Retrospective study of patients with a pathology suspected of malignancy assessed between 2006-2016 in our centre. We evaluated the effectiveness, the tolerance and the number of complications. We calculated the cost reduction in comparison with direct laryngoscopy in the operating room. We compared our sample with others of similar characteristics described in the literature. RESULTS: Thirty patients were studied with a flexible endoscopic biopsy during that period. Nineteen patients obtained positive results which allowed them to start treatment for their pathology. Seven cases had no evidence of malignancy and required another biopsy under general anaesthesia, which confirmed the carcinoma diagnosis. Two samples ruled out malignancy which was confirmed by laryngeal microsurgery. One case showed inflammation and the lesion was cured after antibiotherapy. It was impossible to collect the sample in one case. Thus, we obtained sensitivity levels of 73% with a specificity of 100%. There were no complications. The cost reduction in our sample was above 80%. CONCLUSIONS: Flexible endoscopic biopsy has advantages over direct laryngoscopy that are relevant in the diagnosis of oncological pathology in otorhinolaryngology. PMID- 28818289 TI - Dermatopathic Lymphadenopathy: Is Our Diagnostic Approach Correct? PMID- 28818290 TI - Hepatic resection: a safe and effective surgery. AB - INTRODUCTION: We analyze major liver resections performed in 10 years, with the objective of evaluating perioperative results. As secondary objectives, factors related to major complications and comparative analyses of 25-year periods are evaluated. METHODS: Retrospective analysis of patients undergoing major hepatic resection (3 or more segments) from January 2005 to December 2014, from pre, intra and postoperative data. The Clavien classification is used for postoperative morbidity. RESULTS: A total of 416 major hepatectomies were performed. Transfusions were performed in 38 patients (9.1%). A Pringle maneuver was used in 47.7% of the cases. Half of the patients had no complications, and only 96 patients (23%) had a major complication. Bile leakage was the most frequent complication (n=72, 17.3% of patients), especially due to malignant disease and biliary reconstruction, high risk ASA (III-IV) and prolonged surgical time. Thirteen patients met criteria for liver failure, of which 7died (5 associated a bacterial infection). The mean hospital stay was 12.5 days, with an 11,8% readmission rate. When comparing 25-year periods, at present more complex patients are operated on, with a lower incidence of transfusions and complications (ns). CONCLUSIONS: Liver surgery has increased significantly in recent years. Surgical management of the liver now allows safe and effective surgery, with a very low complication rate. The limit of resectability depends on the residual hepatic volume. PMID- 28818292 TI - Pre-existing psychological depression confers increased risk of adverse cardiovascular outcomes following cardiac surgery: A systematic review and meta analysis. PMID- 28818291 TI - What should we do when a peritoneal pseudomixoma is discovered during the repair of an abdominal wall hernia? PMID- 28818293 TI - Transaortic mitral valve surgery: Going down the rabbit hole again. PMID- 28818294 TI - Examining the future in retrospect. PMID- 28818295 TI - Total endovascular treatment for extent type 1 and 5 thoracoabdominal aortic aneurysms. AB - OBJECTIVE: The study objective was to describe the results of thoracic endovascular aortic repair with the intentional coverage of the celiac artery and distal supramesenteric landing zone for extent type 1 and type 5 thoracoabdominal aortic aneurysms. METHODS: Inclusion criteria were thoracic endovascular aortic repair with celiac artery coverage to treat elective or urgent extent type 1 and 5 thoracoabdominal aortic aneurysms. Primary end points were in-hospital and follow-up survival, freedom from aortic-related mortality, and freedom from reintervention. RESULTS: Thoracoabdominal disease extent was type 1 in 12 patients (71%) and type 5 in 5 patients (29%). Urgent repair was performed in 4 patients (23.5%). Primary technical success was 100%. Early mortality and visceral ischemia did not occur. Permanent spinal cord ischemia rate was 6% (n = 1). Follow-up ranged from 3 to 120 months (interquartile range, 12-36.5). Survival estimate was 85% +/- 9% (95% confidence interval, 67-94) at 1 year and 49% +/- 17% (95% confidence interval, 21-78) at 5 years. Cumulative freedom from aortic-related mortality was 94%, and estimated freedom from reintervention at 1 and 5 years was 93% +/- 7% (95% confidence interval, 68-99). Neither type 1 endoleaks nor distal stent-graft migration causing superior mesenteric artery occlusion was detected. CONCLUSIONS: Thoracic endovascular aortic repair with intentional coverage of celiac artery for extent 1 and 5 thoracoabdominal aortic aneurysms had satisfactory results in selected patients at high risk for open repair. Visceral ischemia did not occur, but spinal cord ischemia is still high at 6%. At midterm follow-up, neither endoleak development nor aortic reintervention was related to the inadequate distal landing zone. Follow-up survival is satisfactory and comparable to open repair. PMID- 28818296 TI - Foot disorders in the elderly: A mini-review. PMID- 28818297 TI - Rothman Index variability predicts clinical deterioration and rapid response activation. AB - BACKGROUND: The overall utility of the Rothman Index (RI), a global measure of inpatient acuity, for surgical patients is unclear. We evaluate whether RI variability can predict rapid response team (RRT) activation in surgical patients. METHODS: Surgical patients who underwent RRT activation from 2013 to 2015 were matched to four control cases. RI variability was gauged by maximum minus minimum RI (MMRI) and RI standard deviation (RISD) within a 24-h period before RRT. The primary outcome measured was RRT activation, and our secondary outcome was in-hospital mortality. RESULTS: Two hundred seventeen (217) patients underwent RRT. RISD (odds ratio, OR, 1.31, 95% confidence interval, CI, 1.23 1.38, P < 0.001; area under receiver operating characteristic, AUROC, curve 0.74, 95% CI 0.70-0.77) and MMRI (OR 1.10, 95% CI 1.08-1.12, P < 0.001; AUROC 0.76, 95% CI 0.72-0.79) predicted increased likelihood of RRT. CONCLUSIONS: RISD is predictive of RRT. PMID- 28818298 TI - Enhancing the Pediatric Drug Development Framework to Deliver Better Pediatric Therapies Tomorrow. AB - Health care professionals involved in the clinical management of children have long appreciated the limited number of therapies suitably evaluated for their optimal use in the pediatric population. In the past century, advances in regulatory policy significantly evolved adult drug evaluation. The scarcity of available patient populations, practical complexities of drug development research, and minimal financial returns have hampered pharmaceutical investment in the study of therapies for children. More recently, pediatric policy and legislation in the United States and Europe have instituted a system of obligations and incentives to stimulate investment in pediatric drug development. These initiatives, in conjunction with a more sophisticated process of drug discovery and development, have led to significant advancements in the labeling of drugs for pediatric use. Facilitated by the emergence of new targets, precision medicine, and innovations in regulatory science, there is now a subtle shift in focus toward drug development research for children rather than simply in children. Although there has been an increase in pediatric studies of investigational agents and labeling of pediatric information for use, there have been unintended consequences of existing policies. As a result, limited progress has been made in certain therapeutic areas and for off-patent therapies. Future policy reform to enhance the availability and accessibility of pediatric medicines should not only reflect an understanding not only of the successes of existing policy and legislative initiatives but also constructively address failures and unintended consequences. Taken together, policy reform, global cooperation, and innovation in regulatory science will more ably deliver better pediatric therapies tomorrow. PMID- 28818299 TI - Current preterm birth prevention strategies. PMID- 28818302 TI - Mitochondrial Ca2+-activated K+ channels and their role in cell life and death pathways. AB - Ca2+-activated K+ channels (KCa) are expressed at the plasma membrane and in cellular organelles. Expression of all KCa channel subtypes (BK, IK and SK) has been detected at the inner mitochondrial membrane of several cell types. Primary functions of these mitochondrial KCa channels include the regulation of mitochondrial ROS production, maintenance of the mitochondrial membrane potential and preservation of mitochondrial calcium homeostasis. These channels are therefore thought to contribute to cellular protection against oxidative stress through mitochondrial mechanisms of preconditioning. In this review, we summarize the current knowledge on mitochondrial KCa channels, and their role in mitochondrial function in relation to cell death and survival pathways. More specifically, we systematically discuss studies on the role of these mitochondrial KCa channels in pharmacological preconditioning, and according protective effects on ischemic insults to the brain and the heart. PMID- 28818300 TI - Birth outcome racial disparities: A result of intersecting social and environmental factors. AB - Adverse birth outcomes such as preterm birth, low-birth weight, and infant mortality continue to disproportionately affect black and poor infants in the United States. Improvements in healthcare quality and access have not eliminated these disparities. The objective of this review was to consider societal factors, including suboptimal education, income inequality, and residential segregation, that together lead to toxic environmental exposures and psychosocial stress. Many toxic chemicals, as well as psychosocial stress, contribute to the risk of adverse birth outcomes and black women often are more highly exposed than white women. The extent to which environmental exposures combine with stress and culminate in racial disparities in birth outcomes has not been quantified but is likely substantial. Primary prevention of adverse birth outcomes and elimination of disparities will require a societal approach to improve education quality, income equity, and neighborhoods. PMID- 28818303 TI - NKCC1 Chloride Importer Antagonists Attenuate Many Neurological and Psychiatric Disorders. AB - In physiological conditions, adult neurons have low intracellular Cl- [(Cl-)I] levels underlying the gamma-aminobutyric acid (GABA)ergic inhibitory drive. In contrast, neurons have high (Cl-)I levels and excitatory GABA actions in a wide range of pathological conditions including spinal cord lesions, chronic pain, brain trauma, cerebrovascular infarcts, autism, Rett and Down syndrome, various types of epilepsies, and other genetic or environmental insults. The diuretic highly specific NKCC1 chloride importer antagonist bumetanide (PubChem CID: 2461) efficiently restores low (Cl-)I levels and attenuates many disorders in experimental conditions and in some clinical trials. Here, I review the mechanisms of action, therapeutic effects, promises, and pitfalls of bumetanide. PMID- 28818301 TI - In Vitro fertilization and adverse obstetric and perinatal outcomes. AB - Most IVF-conceived children are healthy, but IVF has also been associated with adverse obstetric and perinatal outcomes as well as congenital anomalies. There is also literature suggesting an association between IVF and neurodevelopmental disorders as well as potentially long-term metabolic outcomes. The main driver for adverse outcomes is the higher risk of multiple gestations in IVF, but as the field moves toward single embryo transfer, the rate of multiple gestations is decreasing. Studies have shown that singleton IVF pregnancies still have a higher incidence of adverse outcomes compared to unassisted singleton pregnancies. Infertility itself may be an independent risk factor. Animal models suggest that epigenetic changes in genes involved in growth and development are altered in IVF during the hormonal stimulation and embryo culture. Further animal research and prospective human data are needed to elucidate the mechanisms by which IVF may contribute to adverse outcomes and to decrease risks. PMID- 28818304 TI - Organic Nanoparticle-Based Combinatory Approaches for Gene Therapy. AB - Engineered organic nanoparticle (ONP)-mediated co-delivery of genes and therapeutic agents is emerging as a powerful tool in the treatment of several genetic and non-genetic disorders. The ONP-based combinatory approach provides a technological platform that delivers genes with chemo/radio/photo/immunotherapies for the prevention or treatment of disease progression. PMID- 28818305 TI - Treatment of the ventral intermediate nucleus for medically refractory tremor: A cost-analysis of stereotactic radiosurgery versus deep brain stimulation. AB - INTRODUCTION: Medically refractory tremor treatment has evolved over the past half-century from intraoperative thalamotomy to deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus (VIM). Within the past 15years, unilateral radiosurgical VIM thalamotomy has emerged as a comparably efficacious treatment modality. METHODS: An extensive literature search of VIM DBS series was performed; the total cost of VIM DBS was calculated from hospitals geographically representative of the entire United States using current procedural terminology and work relative value unit (RVU) codes. The 2016 Medicare Ambulatory Payment Classification for stereotactic radiosurgery (SRS) was added to the work RVU to determine the total cost of VIM SRS for both Gamma Knife and linear accelerator SRS. Cost estimates assumed that VIM DBS was performed without intraoperative microelectrode recording. RESULT: The mean unilateral VIM DBS cost was $17,932.41 per patient. For SRS VIM, the total costs for Gamma Knife ($10,811.77) and linear accelerator ($10,726.40) were 40% less expensive than for unilateral VIM DBS. CONCLUSION: Radiosurgery of the VIM is 40% less expensive than unilateral VIM DBS in treatment of medically refractory tremor, regardless of radiosurgical modality. This finding argues for increased radiation oncology involvement in the management of medically refractory tremor patients. PMID- 28818306 TI - Time-Harmonic Ultrasound elastography of the Descending Abdominal Aorta: Initial Results. AB - Stiffening of central large vessels is considered a key pathophysiologic factor within the cardiovascular system. Current diagnostic parameters such as pulse wave velocity (PWV) indirectly measure aortic stiffness, a hallmark of coronary diseases. The aim of the present study was to perform elastography of the proximal abdominal aorta based on externally induced time-harmonic shear waves. Experiments were performed in 30 healthy volunteers (25 young, 5 old, >50 y) and 5 patients with longstanding hypertension (PWV >10 m/s). B-Mode-guided sonographic time-harmonic elastography was used for measurement of externally induced shear waves at 30-Hz vibration frequency. Thirty-hertz shear wave amplitudes (SWAs) within the abdominal aorta were measured and displayed in real time and processed offline for differences in SWA between systole and diastole (DeltaSWA). Data were analyzed using the Kruskal-Wallis test and receiver operating characteristic curve analysis. The change in SWA over the cardiac cycle was reduced significantly in all patients as assessed with DeltaSWA (volunteers: mean = 10 +/- 5 MUm, patients: mean = 4 +/- 1 MUm; p < 0.001). The best separation of healthy volunteers from patients was obtained with a DeltaSWA threshold of 4.7 MUm, resulting in a sensitivity of 0.9 and a specificity of 1.0, with an overall area under the curve of 0.96. Time harmonic elastography of the abdominal aorta is feasible and shows promise for the exploitation of time varying shear wave amplitudes as a diagnostic marker for aortic wall stiffening. Patients with elevated PWVs suggesting increased aortic wall stiffness were best identified by DeltaSWA-a parameter that could be related to the ability of the vessel walls to distend on passages of the pulse wave. PMID- 28818307 TI - The impracticality of surgically removing intramuscular long-acting injectable antipsychotic medication. PMID- 28818308 TI - A honey bee can threat ear: Sudden sensorineural hearing loss. AB - Sudden sensorineural hearing loss is an otologic emergency. Many etiological factors can lead to this pathology. Honey bee (Apis mellifera) sting may lead to local and systemic reactions due to sensitization of the patient. In this paper we described a sudden sensorineural hearing loss occurred after honey bee sting. PMID- 28818309 TI - Can the addition of low dose lidocaine improve the effectiveness of narcotics in reducing renal colic pain? PMID- 28818310 TI - Fracture analysis of tube boiler for physical explosion accident. AB - Material and failure analysis techniques are key tools for determining causation in case of explosive and bursting accident result from material and process defect of product in the field of forensic science. The boiler rupture generated by defect of the welding division, corrosion, overheating and degradation of the material have devastating power. If weak division of boiler burner is fractured by internal pressure, saturated vapor and water is vaporized suddenly. At that time, volume of the saturated vapor and water increases up to thousands of volume. This failure of boiler burner can lead to a fatal disaster. In order to prevent an explosion and of the boiler, it is critical to introduce a systematic investigation and prevention measures in advance. In this research, the cause of boiler failure is investigated through forensic engineering method. Specifically, the failure mechanism will be identified by fractography using scanning electron microscopes (SEM) and Optical Microscopes (OM) and mechanical characterizations. This paper presents a failure analysis of household welding joints for the water tank of a household boiler burner. Visual inspection was performed to find out the characteristics of the fracture of the as-received material. Also, the micro structural changes such as grain growth and carbide coarsening were examined by optical microscope. Detailed studies of fracture surfaces were made to find out the crack propagation on the weld joint of a boiler burner. It was concluded that the rupture may be caused by overheating induced by insufficient water on the boiler, and it could be accelerated by the metal temperature increase. PMID- 28818311 TI - Characterization of the flow cytometric assay for ex vivo monitoring of cytotoxicity mediated by antigen-specific cytotoxic T lymphocytes. AB - Several non-radioactive methods have widely been utilized to detect antigen specific cytotoxic T lymphocyte (CTL) responses instead of the classical 51Cr release assay. These methods include intracellular cytokine staining, major histocompatibility complex-class I tetramers, and the CD107a mobilization assay. However, they do not directly measure target-cell death. In contrast, several attempts have been made to develop the flow cytometric CTL (FC-CTL) assay for evaluation of cytotoxicity. However, further improvement is necessary for it to become standardized. Here, we evaluated the characteristics of the FC-CTL assay based on the uptake of propidium iodide (PI) using target cell lines expressing the green fluorescent protein (GFP). The FC-CTL assay was found to be sensitive enough to detect primary CTL responses. The usage of a pre-established GFP expressing target cell line facilitated the procedure of the assay, and enabled a clear discrimination between target and effector cells. Time-course analyses demonstrated that PI-stained target cells were detected as early as surface CD107a expression after antigenic stimulation. Thus, the PI/GFP-based FC-CTL assay is sufficiently sensitive to practically detect the early stages of target cell death, and may have a great potential for becoming a standard tool to measure CTL activity. PMID- 28818312 TI - Thermodynamic and spectroscopic study of Al3+ interaction with glycine, l cysteine and tranexamic acid in aqueous solution. AB - In this paper a thermodynamic and spectroscopic study on the interaction between Al3+ and glycine (Gly), l-cysteine (Cys), tranexamic acid (Tranex) is reported. Speciation models have been obtained by processing potentiometric titration data to determine stability constants of the species formed in aqueous solution at T=298.15K, 0.15<=I/molL-1<=1 in NaCl. Thermodynamic formation parameters have been obtained from calorimetric titration data, at T=298.15K, I=0.15molL-1 using NaCl as ionic medium. Al3+-Cys system was also investigated by spectrophotometric and 1H NMR measurements. 1H NMR experiments were performed on Al3+-Tranex system as well. Different speciation models have been observed for the three systems. The results showed the formation of MLH, ML and M2L2(OH)2 species for Gly, ML, M2L and MLOH for Cys, MLH and MLOH for Tranex. The formed species are quite stable, i.e. for ML, logbeta=7.18, 11.91 for Gly and Cys, respectively, at I=0.15molL-1 and T=298.15K. For all the systems the dependence of formation constants on ionic strength over the range 0.1-1molL-1 is reported. The sequestering ability of the ligands under study was also evaluated by pL0.5 empiric parameter. For Gly, Cys and Tranex, pL0.5=2.51, 3.74, 3.91 respectively, at pH=5, I=0.15molL-1 and T=298.15K. PMID- 28818313 TI - Controlled single-cell cyclic compression and transcription analysis: A pilot study. AB - An innovative platform for the study of the molecular mechanisms at the basis of mechanotransduction has been implemented, developing an experimental approach capable of providing controlled dynamic compression stimuli and retrieving the biomolecular response with single-cell sensitivity. The system provides the ability to perform compression-release cycles on single cells with controlled forces in the nN range and a user-defined repetition rate. Experimental procedures to perform qPCR from a small set of single cells were finely tuned. The experimental platform was tested in the context of bone (cell line hFOB 1.19), a physiological environment highly subjected to mechanical stimuli. Target genes were identified in the literature, based on their involvement in the osteogenesis process or in the bone response to mechanical stimuli. qPCR analysis shows an increase in expression of the chosen targets, and confirms the effectiveness of the presented approach for studying living single cells response to dynamic compression. PMID- 28818314 TI - Comparison of disaggregative effect of A-type EGCG dimer and EGCG monomer on the preformed bovine insulin amyloid fibrils. AB - In the present study, the disruptive effects of epigallocatechin-3-gallate (EGCG) and A-type dimeric epigallocatechin-3-gallate (A-type EGCG dimer) on the preformed bovine insulin amyloid fibrils were studied by several biophysical methods including thioflavin-T (ThT) fluorescence assay, 1-anilinonaphthalene-8 sulfonic (ANS) fluorescence assay, Congo red (CR) binding assay, dynamic light scattering (DLS), transmission electron microscopy (TEM), Gel electrophoresis (SDS-PAGE) and Bradford assay. Our results demonstrated that A-type EGCG dimer showed significantly more potential disaggregative effects on the bovine insulin amyloid fibrils than EGCG. A-type EGCG dimer could not only dramatically promote the disaggregation of the preformed bovine insulin amyloid fibrils, but also restructure the amyloid fibrils into amorphous aggregates. While, EGCG could only shorten and thin the fibrils, but induce no small amorphous aggregates. Our present results provided additional evidence for the more potent disaggregation effects of dimeric polyphenols than monomeric polyphenols and suggested that A type EGCG dimer seems to have potential application as an excellent anti amyloidogenic agent. PMID- 28818315 TI - Screening for familial cancer risk: Focus on breast cancer. AB - A breast or an ovarian cancer occurring at a young age and/or in a family where other cases preexist suggests that those patients should be candidates for screening for mutations. Despite decades of medical research, less than 30% of cases with a suggestive personal and/or family history of hereditary breast cancer have an identified causative gene mutation. The vast majority of these cases are due to a mutation in one of the highly penetrant breast cancer genes (BRCA1, BRCA2, PTEN, TP53, CDH1, and STK11) and various guidelines direct the management of these patients. A minority of cases are due to mutations in moderate-penetrance genes (PALB2, ATM, BRIP1, and CHEK2). A small number of low penetrance alleles have been identified using advanced genetic testing methods. While these may contribute to risk in a polygenic fashion, this is likely to be relevant to a minority of cases and their identification should not be considered routine practice. Mutation testing currently requires a high index of suspicion for a specific contributing etiology, but next-generation sequencing may improve the identification of such genes and the clinical management of these cases. Where no genetic susceptibility is identified, lifetime breast cancer risk can be calculated with standard tools. Breast cancer risk management then depends on the calculated lifetime risk. The psychological consequences of such screening for mutation carriers and non-carriers are discussed. PMID- 28818316 TI - Predicting In-Hospital Mortality in Patients With Acute Coronary Syndrome in China. AB - Currently available risk scores (RSs) were derived from populations with very few participants from China. We aimed to develop an RS based on data from patients with acute coronary syndrome in China and to compare its performance with the commonly promoted Global Registry of Acute Coronary Events (GRACE) RS. Clinical Pathways for Acute Coronary Syndromes-Phase 2 was a trial of a quality improvement intervention in China. Patients recruited from 75 hospitals from October 2007 to August 2010 were divided into training and validation sets based on immediate or delayed implementation. A Clinical Pathways for Acute Coronary Syndromes (CPACS) RS for in-hospital mortality was developed separately by gender, using the training set (6,790 patients). Discrimination and calibration of the CPACS RS and GRACE RS were compared on the validation set (3,801 patients). Although discrimination of the GRACE RS was acceptable, this was improved with the CPACS RS (c-statistic 0.82 vs 0.87, p = 0.012 for men; c statistic 0.78 vs 0.85, p = 0.006 for women). The absolute bias was significantly lower with CPACS RS for both genders (7.6% vs 97.5% in men and 21.5% vs 77.2% in women), compared with the GRACE RS, which systematically overestimated risk. The CPACS RS underestimated risk in women, but only in those already above threshold levels currently used to define a clinical high-risk population. In conclusion, the GRACE RS substantially overestimates the risk of in-hospital death in patients presenting to the hospital with a suspected acute coronary syndrome in China. We have developed and independently validated a new RS utilizing data from Chinese patients. PMID- 28818317 TI - Reconsidering the Gatekeeper Paradigm for Percutaneous Coronary Intervention in Stable Coronary Disease Management. AB - Major randomized clinical trials over the last decade support the role of optimal medical therapy for the initial management approach for patients with stable coronary artery disease (CAD), whereas percutaneous coronary intervention (PCI) ought to be reserved for patients with persistent symptoms despite optimal medical therapy. Likewise, several studies have continued to demonstrate the superiority of coronary artery bypass grafting surgery over PCI in many patients with extensive multivessel CAD, especially those with diabetes. Nevertheless, the decision-making paradigm for patients with stable CAD often continues to propagate the upfront use of "ad hoc PCI" and disadvantages alternative therapeutic approaches. In our editorial, we discuss how multiple systemic and interpersonal factors continue to favor early revascularization with PCI in stable patients. We discuss whether the interventional cardiologist can be an unbiased "gatekeeper" for the use of PCI or whether other physicians should also be involved with the patient in decision-making. Finally, we offer suggestions that can redefine the gatekeeper role to facilitate an evidence-based approach that embraces shared decision-making. PMID- 28818318 TI - Sex and Gender Differences in Thromboprophylactic Treatment of Patients With Atrial Fibrillation After the Introduction of Non-Vitamin K Oral Anticoagulants. AB - To examine sex differences in thromboprophylaxis in patients with atrial fibrillation before and after the introduction of non-vitamin K oral anticoagulants, we performed a cross-sectional registry study based on anonymized individual-level patient data of all individuals with a diagnosis of nonvalvular atrial fibrillation (International Classification of Diseases, Tenth Revision code I48) in the region of Stockholm, Sweden (2.2 million inhabitants), in 2011 and 2015, respectively. Thromboprophylaxis improved considerably during the period. During 2007 to 2011, 23,198 men and 18,504 women had an atrial fibrillation diagnosis. In 2011, more men than women (53% men vs 48% women) received oral anticoagulants (almost exclusively warfarin) and more women received aspirin only (35% women vs 30% men), whereas there was no sex difference for no thromboprophylaxis (17%). During 2011 to 2015, 27,237 men and 20,461 women had a diagnosis of atrial fibrillation. Compared with the earlier time period, a higher proportion used oral anticoagulants (71% women vs 70% men), but fewer women >=80 years received anticoagulants (67% women vs 72% men), more women received aspirin (15% women vs 13% men), and fewer women had no thromboprophylaxis (15% women vs 17% men). Patients with co-morbidities potentially complicating oral anticoagulant use used more oral anticoagulant in 2015 compared with 2011. The sex differences observed in 2011 with fewer women using oral anticoagulants had disappeared in 2015 except in women 80 years and older and in patients with complicated co-morbidity. PMID- 28818319 TI - [A comparative cost analysis of single-use versus reusable fiberoptic bronchoscopes: Is single-use fiberscope worth it?] AB - OBJECTIVE: To present a minimization-cost analysis to compare reusable and single use fiberscopes in a French health institution. MATERIALS AND METHODS: The amortization cost assessment has been achieved over a period of five years, and took into account the acquisition and maintenance costs, as well as the costs related to disinfection of reusable fiberscopes. The cost of single-use fiberscopes was calculated according to its acquisition and elimination costs. Finally, we compared the costs of single-use vs. reusable use during nights, weekends and days off to estimate the additional cost of the referencing of single-use fiberscopes for theses specific periods. RESULTS: The total cost of reusable fiberscopes was 62,511 ? including VAT over 5 years whereas the cost of single-use fiberscope was 79,200 ? including VAT over 5 years. The total cost of single-use fiberscopes if utilized during nights, weekends and days off was estimated to 19,800 ? including VAT over 5 years, with an estimated activity at 15 intubations per year. Conversely, the cost of the utilization of reusable fiberscopes during nights, weekends and days off was estimate to 13,075 ? including VAT over 5 years. CONCLUSION: This study shows that the utilization costs of single use and reusable fiberscopes are very close. But because of the benefits of single-use fiberscopes and according to current recommendations, we consider to acquire single-use fiberscope especially for emergencies such as difficult tracheal intubation and for restrictive periods (nights, weekends and day off). PMID- 28818320 TI - [Use of a Delphi survey to assess the hospital economic impact of innovative products: The example of idarucizumab a dabigatran-specific reversal agent]. AB - OBJECTIVES: The economic impact of therapeutic innovations on the hospital patient management cannot be easily estimated. The objective of this study is to illustrate the use of a Delphi survey as a support tool to identify the changes following the use of idarucizumab in dabigatran-treated patients with uncontrolled/life-threatening bleeding or who required emergency surgery/urgent procedures. METHODS: The Delphi questionnaires have been administrated to 8 emergency physicians or anesthetists from 6 different hospital centers. Following the answers, an economic valorization has been carried out on every parameter on which a consensus was reached (at least 4 answers showing an identical trend). A mean management cost for each etiology with and without the use of idarucizumab has thus been identified. RESULTS: For gastro-intestinal and other life threatening bleedings (excepted intracranial bleedings), the total management cost of the hospital stay was respectively 6058 ? (-35%) and 6219 ? (-34%) following the use of the reversal agent. The hospital management cost for intracranial bleeding is slightly increasing to 9790 ? (+3%). The cost of a stay for emergency surgery decreases to 6962? (-2%). CONCLUSIONS: This study shows a positive economic impact following the use of the dabigatran-specific reversal agent for patients with uncontrolled/life-threatening bleeding excepted in the case of intracranial bleeding. Moreover, it points out that a Delphi survey is an easy way to predict the hospital economic impact of a therapeutic innovation when no other evaluation is possible. PMID- 28818321 TI - Influence of computed tomography contrast agent on radiotherapy dose calculation for pancreatic carcinoma: A dosimetric study based on tomotherapy and volumetric modulated arc therapy techniques. AB - The main purpose of our investigation was to quantify the dosimetric influence of intravenous contrast agent for pancreatic cancer radiotherapy treatment. This study focused on complex modulated irradiation techniques of tomotherapy (TOMO) and volumetric-modulated arc therapy (VMAT) to investigate if novel conformal treatment methods could reduce the influence of contrast agent. In our study, patients with pancreatic cancer were enrolled to have 2 computed tomography (CT) scans in the same position without and with intravenous contrast agent for treatment planning. Then tumors and organ at risks were countered on contrast enhanced CT (CECT) images. Each patient's CECT was assigned a TOMO plan and a VMAT plan. Then these plans were copied onto the non-CECT image and dose distribution was calculated with the same algorithm and structure sets. Finally, the dose distribution and the dose difference were analyzed for the target volume and organs at risk between the 2 sets of images. The statistic dosimetric result showed that for both TOMO and VMAT, no significant dose difference between CECT and non-CECT-based plan was observed. Dose difference was clinically negligible because the average relative percentage dose difference was 1% +/- 1% for target volume, except a blurring effect at the higher dose region of the target volume. It implied that intravenous contrast agent will not affect dose calculation for pancreatic cancer radiotherapy significantly. Also the dose deviation based on TOMO showed no statistical difference compared with that on VMAT. For both superposition/conversation algorithm used by TOMO and Monte Carlo algorithm used by VMAT, the dosimetric difference was nonsignificant. A full analysis demonstrated a negligible dose difference of less than 1% between CECT-based plan and non-CECT-based plan. Therefore, contrast-enhanced CT image can be used directly for dose calculation of TOMO and VMAT plans for pancreatic cancer. It is unnecessary to scan twice then make a fusion of CECT and non-CECT, which would result to additional unnecessary radiation dose to patient and decrease work efficiency. PMID- 28818322 TI - Stability of biodegradable metal (Mg-Ca-Zn alloy) screws compared with absorbable polymer and titanium screws for sagittal split ramus osteotomy of the mandible using the finite element analysis model. AB - Mg-Ca-Zn alloy has been suggested for the application of fixation materials during maxillofacial surgery. We investigated the stability of Mg-Ca-Zn alloy for clinical application during orthognathic surgery. The finite element model for the fixation of sagittal split ramus osteotomy was constructed. In the bicortical screw fixation of the mandible setback condition, the stress distributions of Mg Ca-Za alloy, polylactic acid polymer, and titanium were evaluated using the virtual model with occlusal loading of 132 N. The deformations of the three different materials of fixation screw were observed according to masticatory force ranging from 132 to 1,000 N. When comparing the stress distribution placed on cortical bone between the polymer and magnesium alloy groups, the magnesium alloy screws could bear more stress, thereby decreasing the stress, which might be distributed to other biologic components, such as the condyle and cortical ramus of the mandible. Deformations of the screws according to functional load were minimal, and the deformation remained <0.21 mm at the initial functional load of the mandible after surgery, regardless of materials used. The biodegradable magnesium alloy screw can bear more stress and decrease the detrimental effect on the stability of sagittal split ramus osteotomy setback surgery. PMID- 28818323 TI - Medial buttress plate augmentation of cannulated screw fixation in vertically unstable femoral neck fractures: Surgical technique and preliminary results. AB - OBJECTIVE: To evaluate the outcome and complications of unstable Pauwels type 3 femoral neck fractures treated with a combination fixation of three cannulated screws and a medial buttress plate. PATIENTS AND METHODS: From October 2015 to June 2016, 28 patients under 60 years of age with Pauwels type 3 femoral neck fracture were treated with open reduction and internal fixation using a direct anterior approach. Fracture consisted of three cannulated screws augmented with a medial buttress plate. All reductions achieved Garden's alignment index grade one. Touch down weight bearing was permitted post-operatively for 6 weeks, and subsequently advanced to full weight bearing. One patient was lost to follow-up, which the remaining 27 patients were followed at 1 week, 6 weeks, 3 months, 6 months and 12 months post-operatively. RESULT: Union without femoral neck shortening was achieved in 89% of cases. Implant failure was seen in 3 cases and was associated femoral neck shortening. Reduction loss with backing out of the cannulated screws occurred in these cases, and in one case there was also plate and screw breakage. There were no cases of avascular necrosis identified at a mean follow-up was 13.6 months CONCLUSION: At short time follow-up, treatment of Pauwels type 3 femoral neck fractures using cannulated screws combined with medial buttress plate improves the fracture union rate compared to historical series using cannulated screws alone. The method of medial buttress plate augmentation does not appear to increase any implant related complications, including avascular necrosis. PMID- 28818325 TI - Foreword. PMID- 28818324 TI - The treatment of segmental tibial fractures: does patient preference differ from surgeon choice? AB - INTRODUCTION: Segmental tibial fractures are complex injuries with a prolonged recovery time. Current definitive treatment options include intramedullary fixation or a circular external fixator. However, there is uncertainty as to which surgical option is preferable and there are no sufficiently rigorous multi centre trials that have answered this question. The objective of this study was to determine whether patient and surgeon opinion was permissive for a randomised controlled trial (RCT) comparing intramedullary nailing to the application of a circular external fixator. MATERIALS AND METHODS: A convenience questionnaire survey of attending surgeons was conducted during the United Kingdom's Orthopaedic Trauma Society annual meeting 2017 to determine the treatment modalities used for a segmental tibial fracture (n=63). Patient opinion was obtained from clinical patients who had been treated for a segmental tibial fracture as part of a patient and public involvement focus group with questions covering the domains of surgical preference, treatment expectations, outcome, the consent process and follow-up regime (n=5). RESULTS: Based on the surgeon survey, 39% routinely use circular frame fixation following segmental tibial fracture compared to 61% who use nail fixation. Nail fixation was reported as the treatment of choice for a closed injury in a healthy patient in 81% of surgeons, and by 86% for a patient with a closed fracture who was obese. Twenty-one percent reported that they would use a nail for an open segmental tibia fracture in diabetics who smoked, whilst 57% would opt for a nail for a closed injury with compartment syndrome, and only 27% would use a nail for an open segmental injury in a young fit sports person. The patient and public preference exercise identified that sleep, early functional outcomes and psychosocial measures of outcomes are important. CONCLUSION: We concluded that a RCT comparing definitive fixation with an intramedullary nail and a circular external fixator is justified as there remains uncertainty on the optimal surgical management for segmental tibial fractures. Furthermore, psychosocial factors and early post-operative outcomes should be reported as core outcome measures as part of such a trial. PMID- 28818326 TI - Dual-wavelength light-emitting diode-based ultraviolet absorption detector for nano-flow capillary liquid chromatography. AB - The design of a miniaturized LED-based UV-absorption detector was significantly improved for on-column nanoflow LC. The detector measures approximately 27mm*24mm*10mm and weighs only 30g. Detection limits down to the nanomolar range and linearity across 3 orders of magnitude were obtained using sodium anthraquinone-2-sulfonate as a test analyte. Using two miniaturized detectors, a dual-detector system was assembled containing 255nm and 275nm LEDs with only 216nL volume between the detectors A 100MUm slit was used for on-column detection with a 150MUm i.d. packed capillary column. Chromatographic separation of a phenol mixture was demonstrated using the dual-detector system, with each detector producing a unique chromatogram. Less than 6% variation in the ratios of absorbances measured at the two wavelengths for specific analytes was obtained across 3 orders of magnitude concentration, which demonstrates the potential of using absorption ratio measurements for target analyte detection. The dual detector system was used for simple, but accurate, mobile phase flow rate measurement at the exit of the column. With a flow rate range from 200 to 2000nL/min, less than 3% variation was observed. PMID- 28818327 TI - Preparation of molecularly imprinted polymers for warfarin and coumachlor by multi-step swelling and polymerization method and their imprinting effects. AB - Monodisperse molecularly imprinted polymers (MIPs) for warfarin (WF) and coumachlor (CC), MIPWF and MIPCC, respectively, were prepared using 4 vinylpyridine (4-VPY) as a functional monomer and ethylene glycole dimethacrylate (EDMA) as a crosslinker by multi-step swelling and polymerization. Six kinds of MIPWF, MIPWF1 - MIPWF6, were prepared varying the concentrations of WF and 4-VPY, while maintaining the EDMA concentration constant, and their retention and molecular recognition properties were evaluated using a mixture of sodium phosphate buffer and acetonitrile as a mobile phase in LC. In addition to shape recognition, hydrogen bonding, ionic and hydrophobic interactions could affect the retention and molecular recognition of WF on MIPWF, and ionic interactions seem to govern the retention and molecular recognition of WF above mobile phase pH 6 associated with higher molar ratio of 4-VPY to EDMA. Furthermore, MIPCC was prepared under the same conditions with MIPWF6, which gave the highest imprinting factor for WF. WF could be recognized more strongly on MIPCC than MIPWF6, and the imprinting factors of WF on MIPWF6 and MIPCC, respectively, are 2.68 and 5.03 using 20mM sodium phosphate buffer - acetonitrile (30/70, v/v)(final pH 6.1) as the mobile phase. This result indicates that the use of CC as a template molecule instead of WF could be useful for getting a higher imprinting factor for WF and for avoiding the leakage problem in the assay of WF in LC. PMID- 28818328 TI - Deep eutectic solvent-based ultrasound-assisted dispersive liquid-liquid microextraction coupled with high-performance liquid chromatography for the determination of ultraviolet filters in water samples. AB - In the present study, a simple and rapid sample preparation method designated ultrasound-assisted dispersive liquid-liquid microextraction based on a deep eutectic solvent (DES) followed by high-performance liquid chromatography with ultraviolet (UV) detection (HPLC-UVD) was developed for the extraction and determination of UV filters from water samples. The model analytes were 2,4 dihydroxybenzophenone (BP-1), benzophenone (BP) and 2-hydroxy-4 methoxybenzophenone (BP-3). The hydrophobic DES was prepared by mixing trioctylmethylammonium chloride (TAC) and decanoic acid (DecA). Various influencing factors (selection of the extractant, amount of DES, ultrasound duration, salt addition, sample volume, sample pH, centrifuge rate and duration) on UV filter recovery were systematically investigated. Under optimal conditions, the proposed method provided good recoveries in the range of 90.2-103.5% and relative standard deviations (inter-day and intra-day precision, n=5) below 5.9%. The enrichment factors for the analytes ranged from 67 to 76. The limits of detection varied from 0.15 to 0.30ngmL-1, depending on the analytes. The linearities were between 0.5 and 500ngmL-1 for BP-1 and BP and between 1 and 500ngmL-1 for BP-3, with coefficients of determination greater than 0.99. Finally, the proposed method was applied to the determination of UV filters in swimming pool and river water samples, and acceptable relative recoveries ranging from 82.1 to 106.5% were obtained. PMID- 28818329 TI - Influence of different packing methods on the hydrodynamic stability of chromatography columns. AB - It is well known that packing non-uniformity may cause peak asymmetry and limit the performance of packed-bed chromatographic columns. However, understanding of the reasons leading to packing non-uniformity is still limited. Therefore, the effect of different column packing methods, i.e. dynamic axial compression (DAC), flow packing, and combinations of both on the hydrodynamic packing heterogeneity and stability of packings composed of polymer-based compressible porous resins with a mean diameter of 90MUm was investigated experimentally as well as in silico. Deterministic Euler-Lagrange modeling of a small chromatographic column with a diameter of 9.6mm and a bed height of 30mm was applied by coupling Computational Fluid Dynamics (CFD) and the Discrete Element Method (DEM). Interparticle micromechanics as well as the fluid-particle and particle-wall interactions were taken into account. Experiments and simulations revealed substantial non-uniformity of compression force transmission and axial packing density distribution during both dynamic axial compression and flow packing which was related to wall support and interparticle friction. By combining both packing methods sequentially (dynamic axial compression followed by flow packing or vice versa), the compression forces were more homogeneous resulting in improved packing procedures. Repeated alternating application of flow packing and DAC (the so-called hybrid packing method) resulted in the most homogeneous packing density distribution and the highest packing stability which was kept nearly constant during long-term operation with cyclic hydrodynamic load. The hydrodynamic stability of the chromatographic column was evaluated by calculating the integral porosity deviation and packing induced flow velocity dispersion. The hybrid packing method gave the best results for both parameters. PMID- 28818330 TI - Manufacturing in the Eye of the Storm:Shen Hong and the Nine Great Installations Project During China's Cultural Revolution. AB - The construction of nine high-end technical installations (hereafter Project NGI, for Nine Great Installations or ) in the 1960s and 1970s was an indispensable part of the development of China's defense and heavy industries. The project put more than 1400 machines into operation or trial operation during the Culture Revolution (1966-1976), and they served essential technical functions in sectors such as aviation, aerospace, machinery, metallurgy, and electronics, and directly advancing the development of these fields. It took more than a decade for Project NGI to go from planning to completion-a surprisingly uninterrupted and steady development while China fell into unprecedented turmoil. One important reason for Project NGI's success was the vital leadership of Shen Hong (, 1906-1998), the technical director of the project and a high-ranking official. Supported by state leaders such as Zhou Enlai and Nie Rongzhen, Shen and his colleagues adopted a suitable roadmap for technological development, coordinated the best-performing manufacturing forces in the country, and successfully manufactured the NGI machines. Project NGI is significant for the history of Chinese science, technology, and medicine during the Cultural Revolution not because it was technologically original, but because it represents an extraordinary case, in which the project's technological development seemed to be largely exempted from the interference of the turbulent Cultural Revolution. The project's national defense orientation, its pragmatism, and the contemporary dogma of self-reliance (), in addition to Shen Hong's political maneuvering, all contributed to the creation of a relatively calm and favorable environment around Project NGI. Despite the widespread turmoil in the country, Shen managed to assemble a stable and continuously productive team, which executed experiments, absorbed previously introduced Soviet technologies, stayed informed about advanced European and American technologies, and ultimately accomplished the construction of the NGI machines. PMID- 28818331 TI - Molecular epidemiology of Epizootic haematopoietic necrosis virus (EHNV). AB - Low genetic diversity of Epizootic haematopoietic necrosis virus (EHNV) was determined for the complete genome of 16 isolates spanning the natural range of hosts, geography and time since the first outbreaks of disease. Genomes ranged from 125,591-127,487 nucleotides with 97.47% pairwise identity and 106-109 genes. All isolates shared 101 core genes with 121 potential genes predicted within the pan-genome of this collection. There was high conservation within 90,181 nucleotides of the core genes with isolates separated by average genetic distance of 3.43 * 10-4 substitutions per site. Evolutionary analysis of the core genome strongly supported historical epidemiological evidence of iatrogenic spread of EHNV to naive hosts and establishment of endemic status in discrete ecological niches. There was no evidence of structural genome reorganization, however, the complement of non-core genes and variation in repeat elements enabled fine scale molecular epidemiological investigation of this unpredictable pathogen of fish. PMID- 28818332 TI - Antimicrobial activity and acetylcholinesterase inhibition by extracts from chromatin modulated fungi. AB - Major health challenges as the increasing number of cases of infections by antibiotic multiresistant microorganisms and cases of Alzheimer's disease have led to searching new control drugs. The present study aims to verify a new way of obtaining bioactive extracts from filamentous fungi with potential antimicrobial and acetylcholinesterase inhibitory activities, using epigenetic modulation to promote the expression of genes commonly silenced. For such finality, five filamentous fungal species (Talaromyces funiculosus, Talaromyces islandicus, Talaromyces minioluteus, Talaromyces pinophilus, Penicillium janthinellum) were grown or not with DNA methyltransferases inhibitors (procainamide or hydralazine) and/or a histone deacetylase inhibitor (suberohydroxamic acid). Extracts from T. islandicus cultured or not with hydralazine inhibited Listeria monocytogenes growth in 57.66+/-5.98% and 15.38+/-1.99%, respectively. Increment in inhibition of acetylcholinesterase activity was observed for the extract from P. janthinellum grown with procainamide (100%), when compared to the control extract (39.62+/-3.76%). Similarly, inhibition of acetylcholinesterase activity increased from 20.91+/-3.90% (control) to 92.20+/-3.72% when the tested extract was obtained from T. pinophilus under a combination of suberohydroxamic acid and procainamide. Concluding, increases in antimicrobial activity and acetylcholinesterase inhibition were observed when fungal extracts in the presence of DNA methyltransferases and/or histone deacetylase modulators were tested. PMID- 28818334 TI - The use of acupuncture in first aid of burns-Clinical report. AB - Burns are a very painful skin injury, or injury of soft tissues. The development of post-traumatic stress disorder can develop, even in those with minor injuries (Ia-IIb degree). Development of problems is very rapid and intense since, according to developmental embryology, the skin and central nervous system (CNS) descend from the same germ layer-ectoderm. This clinical report presents the results acquired from the data of 1008 patients suffering from burns treated by the acupuncture (ACU)-from 1983-2015 in the surgery ward of the hospital in Vysoke Myto in the Czech Republic. The data of 1008 patients were processed and evaluated. 1. The report demonstrates a positive effect of ACU treatment signs on the skin were monitored, i.e. reddening, pigmentation, scars. During the treatment the elimination of many of these signs was observed. Improvement of healing process and improvement in the final wound healing were evaluated and shown by the statistical method-the chi2 test. For demonstrating the effect of ACU treatment of BT the Pearson's and the Cramer's contingency coefficient were examined. 2. The time of the first application of the ACU treatment after burn was followed and evaluated with a random set. The best results were achieved when the first ACU treatment was applied as soon as possible after BT injury (ideally immediately, optimally within 48h). The positive effect of ACU on burns is medical, economical and biopsychosocial. PMID- 28818335 TI - [Usefulness of venous-arterial extracorporeal membrane oxygenation in post surgical management of refractory cardiogenic shock in complex aortic disease]. PMID- 28818336 TI - Association between premature ventricular complexes during exercise, long-term occurrence of life-threatening arrhythmia and mortality. AB - OBJECTIVE: Exercise-induced premature ventricular complexes (EiPVCs) are often considered as benign arrhythmias, although they are associated with a high risk of all-cause death in the general healthy population. However, an intermediate pathophysiological process remains unclear, particularly in patients with known cardiovascular disease. The aim of this study was to find an association between EiPVCs, the occurrence of life-threatening ventricular arrhythmias (LACO), and all-cause mortality in patients with cardiovascular disease. METHODS: This was an observational study of a cohort of patients with coronary artery disease (CAD) or idiopathic cardiomyopathy (ICM). Stress testing was performed as a part of the routine cardiovascular evaluation. The occurrence of EiPVCs was evaluated during exercise testing (ET). At follow-up, long-term occurrence of LACO was evaluated. A bivariate and multivariate analysis was performed. RESULTS: Out of the total of 1442 patients analysed, 700 (49%) had EiPVCs. During 14 years of following-up after ET, 106 LACO outcomes were observed. Long-term all-cause mortality was 4% (n=61). A bivariate analysis showed that patients with EiPVCs had an increased risk for LACO (RR=2.81, 95% CI; 1.9-4.3, P<.001), and for mortality (RR=2.1, CI95% 1.2-3.4, P<.01). Occurrence of LACO was also associated with a higher mortality risk (RR=5.7, 95% CI; 3.4-9.4, P<.001). After a post hoc analysis, LACO remained as a highly predictive variable for mortality. CONCLUSION: Patients with EiPVCs have a high risk of LACO and all-cause mortality. The presence of LACO could be an intermediate stage between EiPVCs and mortality in subjects with cardiovascular disease. PMID- 28818337 TI - The mobile technology era: Potential benefits in pediatric urology. AB - Mobile technology has been increasingly used in the world of medicine. We describe an application of mobile phones in the evaluation of urinary symptoms in infants, neonates, and toddlers. We believe this is a cheap, accessible and easy to-use solution in pediatric urology for physicians and nurses around the world. In this video, we demonstrate some unique features of various anatomic and functional pediatric urology conditions, which are detectable in voiding clips taken by a cellphone camera. PMID- 28818338 TI - Spinal anesthesia for pediatric urological surgery: Reducing the theoretic neurotoxic effects of general anesthesia. AB - BACKGROUND: Spinal anesthesia (SA) is an effective technique that has been used in children for years. With growing concern with regard to the risks of general anesthesia (GA), we developed a SA program to provide an alternative option. We present our initial experience with this program. OBJECTIVE: To implement a SA program at a large tertiary care pediatric center and assess the safety and efficacy of the technique as an alternative to GA for urologic surgery. STUDY DESIGN/METHODS: We prospectively collected data on all children undergoing SA at our institution. We recorded demographics, procedure, time required for placement of the SA, length of surgery, success of lumbar puncture, success of attaining adequate surgical anesthesia, need for supplemental systemic sedation, conversion to GA, and perioperative complications. RESULTS: SA was attempted in 105 consecutive children (104 boys, 1 girl) with a mean age of 7.4 +/- 4.3 months (range 19 days-24 months) and mean weight of 8.3 +/- 1.7 kg (range 3.5-13.7). Placement of the SA was successful in 93/105 children (89%). Inability to achieve lumbar puncture (cerebrospinal fluid was not obtained) meant that SA was abandoned in seven (7%) patients and GA was administered. In five patients in whom SA was successful and surgery was begun, 5/93 (5%) required conversion to GA: two because of evisceration of intestine through large hernia defects related to coughing and abdominal irritation, two because of lack of motor blockade despite an adequate sensory block, and one because of an inability to place an intravenous catheter in the lower extremities (required per SA protocol). If necessary, an intravenous catheter can be placed in the upper extremity, but this must be weighed against the fact that the block has already been placed and is of limited duration. Overall, SA was successful (SA was placed and surgery was completed without conversion to GA) in 88/105 children (84%). No additional sedation and no systemic anesthetic agents were required in 75/88 children (85%). The average time required to place the SA was 3.8 +/- 2.7 min (range 1-12). The average time for the surgical procedure was 38.3 +/- 23.1 min (range 10-122). No patient required conversion to GA because of recession of block. There were no surgical complications. DISCUSSION/CONCLUSIONS: SA is a safe and efficacious technique for routine pediatric urological procedures. SA should be considered for cases such as neonatal torsion or patients with significant cardiac or pulmonary comorbidities when the risks of GA are often weighed against the risks of non-intervention. PMID- 28818333 TI - Li-Fraumeni Syndrome Disease Model: A Platform to Develop Precision Cancer Therapy Targeting Oncogenic p53. AB - Li-Fraumeni syndrome (LFS) is a rare hereditary autosomal dominant cancer disorder. Germline mutations in TP53, the gene encoding p53, are responsible for most cases of LFS. TP53 is also the most commonly mutated gene in human cancers. Because inhibition of mutant p53 is considered to be a promising therapeutic strategy to treat these diseases, LFS provides a perfect genetic model to study p53 mutation-associated malignancies as well as to screen potential compounds targeting oncogenic p53. In this review we briefly summarize the biology of LFS and current understanding of the oncogenic functions of mutant p53 in cancer development. We discuss the strengths and limitations of current LFS disease models, and touch on existing compounds targeting oncogenic p53 and in vitro clinical trials to develop new ones. Finally, we discuss how recently developed methodologies can be integrated into the LFS induced pluripotent stem cell (iPSC) platform to develop precision cancer therapy. PMID- 28818339 TI - Impact of machining on the flexural fatigue strength of glass and polycrystalline CAD/CAM ceramics. AB - OBJECTIVES: To assess the effect of machining on the flexural fatigue strength and on the surface roughness of different computer-aided design, computer-aided manufacturing (CAD/CAM) ceramics by comparing machined and polished after machining specimens. METHODS: Disc-shaped specimens of yttria-stabilized polycrystalline tetragonal zirconia (Y-TZP), leucite-, and lithium disilicate based glass ceramics were prepared by CAD/CAM machining, and divided into two groups: machining (M) and machining followed by polishing (MP). The surface roughness was measured and the flexural fatigue strength was evaluated by the step-test method (n=20). The initial load and the load increment for each ceramic material were based on a monotonic test (n=5). A maximum of 10,000 cycles was applied in each load step, at 1.4Hz. Weibull probability statistics was used for the analysis of the flexural fatigue strength, and Mann-Whitney test (alpha=5%) to compare roughness between the M and MP conditions. RESULTS: Machining resulted in lower values of characteristic flexural fatigue strength than machining followed by polishing. The greatest reduction in flexural fatigue strength from MP to M was observed for Y-TZP (40%; M=536.48MPa; MP=894.50MPa), followed by lithium disilicate (33%; M=187.71MPa; MP=278.93MPa) and leucite (29%; M=72.61MPa; MP=102.55MPa). Significantly higher values of roughness (Ra) were observed for M compared to MP (leucite: M=1.59MUm and MP=0.08MUm; lithium disilicate: M=1.84MUm and MP=0.13MUm; Y-TZP: M=1.79MUm and MP=0.18MUm). SIGNIFICANCE: Machining negatively affected the flexural fatigue strength of CAD/CAM ceramics, indicating that machining of partially or fully sintered ceramics is deleterious to fatigue strength. PMID- 28818340 TI - LPS binding to HMGB1 promotes angiogenic behavior of endothelial cells through inhibition of p120 and CD31 via ERK/P38/Src signaling. AB - Lipopolysaccharide (LPS) is known to mediate angiogenic effects in endothelial cells. The underlying mechanisms, however, remain largely unknown. In this study, we showed that LPS induced high motility group box protein 1 (HMGB1) secretion in human pulmonary microvascular endothelial cells (HPMECs). Knockdown and overexpression of HMGB1 by adenoviral vectors effectively inhibited and promoted LPS-induced HPMEC migration and capillary-like tube formation, respectively. On the other hand, HMGB1 exerted an inhibitory effect on LPS-suppressed expression of platelet-endothelial cell adhesion molecule (CD31) and p120 catenin (p120); HMGB1 knockdown reversed this effect. These results suggest a functional synergy between LPS and HMGB1 in angiogenesis. Mechanistically, physical interaction of LPS with HMGB1 mediated dissociation of p120, beta-catenin, and gamma-catenin from vascular endothelial cadherin (VE-cadherin), but without affecting VE cadherin expression. The synergistic effect of LPS and HMGB1 was closely associated with ERK/P38/Src signaling pathway, as evidenced by the reduced degree of migration and capillary-like tube formation in HPMECs treated with signaling pathway inhibitor. Collectively, our study shows a novel mechanism whereby LPS and HMGB1 synergistically regulate the angiogenic behavior of endothelial cells. PMID- 28818341 TI - Harnessing the Power of Genomics to Secure the Future of Seafood. AB - Best use of scientific knowledge is required to maintain the fundamental role of seafood in human nutrition. While it is acknowledged that genomic-based methods allow the collection of powerful data, their value to inform fisheries management, aquaculture, and biosecurity applications remains underestimated. We review genomic applications of relevance to the sustainable management of seafood resources, illustrate the benefits of, and identify barriers to their integration. We conclude that the value of genomic information towards securing the future of seafood does not need to be further demonstrated. Instead, we need immediate efforts to remove structural roadblocks and focus on ways that support integration of genomic-informed methods into management and production practices. We propose solutions to pave the way forward. PMID- 28818342 TI - Novel treatment technologies for PFAS compounds: A critical review. AB - Perfluorinated compounds such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) have recently drawn great attention due to their wide distribution in aquatic environments. The understanding of the physicochemical properties and fate and transport of PFAs in groundwater is still limited. Preliminary studies indicate that these compounds can readily bioaccumulate and pose human and animal health concerns. Due to their physicochemical properties, PFOS and PFOA are water soluble, nonvolatile and persistent in the environment, which is a cause of concern related to their treatment with conventional remediation technologies. Extraction with inefficient carbon adsorption is one of the most common treatment technologies for remediation of PFOS- or PFOA-impacted groundwater. Several other innovative and promising technologies, including sonochemistry, bioremediation and photolysis, have been tested for their effectiveness in removal of perfluorinated compounds. This paper provides a baseline for understanding research needs to better develop treatment technologies for PFOA and PFOS in groundwater. Frontiers for improving the state of practice for PFOA and PFOS treatment include the development of more cost-effective ex situ treatment methods and the development and demonstration of promising in situ treatment technologies at the pilot and full scale. PMID- 28818343 TI - High dietary phosphorus intake is associated with an increased risk of type 2 diabetes in the large prospective E3N cohort study. AB - Phosphorus is an essential nutrient; the adult recommended daily intake ranges from 550 to 700 mg/day, with a tolerated upper limit of 4000 mg/day. Phosphorus intake has increased in the general population in recent years, and simultaneously an alarming rise of type 2 diabetes incidences has been observed. No study has investigated the relationship between phosphorus intake and the risk of type 2 diabetes. To evaluate the association between phosphorus intake and incidence of type 2 diabetes. Among 71,270 women from the French E3N-EPIC cohort, 1845 cases of incident type 2 diabetes were validated during follow-up (1993 2011). Adjusted Cox proportional hazards regression models were used to calculate hazard ratios and 95% confidence intervals (95% CI) for the associations between phosphorus intake and type 2 diabetes risk, adjusted on potential confounders. The overall mean (+/-SD) phosphorus intake was 1477 mg/day (+/-391 mg/day). High phosphorus intake was associated with risk of type 2 diabetes. In multivariate models, compared with women in the 1st quartile of phosphorus intake (<1203 mg/day), those included in the 2nd (1203-1434.0 mg/day), 3rd (1434-1700 mg/day), and 4th (>1700 mg/day) were at a higher risk of type 2 diabetes, with a hazards ratios (95% CI) of 1.18 (1.00-1.38), 1.41 (1.20-1.66) and 1.54 (1.25-1.90), respectively. Our results may have important public health implications for dietary recommendations in the prevention of type 2 diabetes. More studies are warranted to better understand the biological mechanisms underlying this positive association. PMID- 28818344 TI - The 2016 ESPEN Arvid Wretlind lecture: The gut in stress. AB - The gut has a major influence on the course of the human stress response in critical illness for several reasons; the quantity of its immune tissue, the extent of interface with the external environment, the expanse of the microbiome, and its access to the systemic circulation. In critical illness, it is not uncommon to lose mucosal barrier function, which exposes the host to the downside effects of luminal contents and epithelial cell regulation. In that setting, the microbiome is converted to a pathobiome, upregulation of metabolic and immune responses occurs, and homeostatic defense systems are compromised. Awareness of this process mandates that greater attention be given to the interplay between the gut and systemic responses, and that modulation of the gastrointestinal tract be considered in every therapeutic intervention in the critical care setting. PMID- 28818346 TI - Planning and guidance: New tools to enhance the human skills in interventional oncology. AB - Navigation systems have the potential to achieve a high accuracy for percutaneous ablation of tumors even for those in difficult locations. In the last years, successful research has been conducted to make navigation devices applicable to percutaneous tumor ablation with special planning software that now allows high accuracy even for deep-located small lesions close to critical structures. Because of the high number of available navigation systems, this review focuses on those with preexisting clinical studies. PMID- 28818348 TI - A case of otitis media with effusion due to leiomyoma of the Eustachian tube. PMID- 28818345 TI - Mobile Group II Introns as Ancestral Eukaryotic Elements. AB - The duality of group II introns, capable of carrying out both self-splicing and retromobility reactions, is hypothesized to have played a profound role in the evolution of eukaryotes. These introns likely provided the framework for the emergence of eukaryotic retroelements, spliceosomal introns and other key components of the spliceosome. Group II introns are found in all three domains of life and are therefore considered to be exceptionally successful mobile genetic elements. Initially identified in organellar genomes, group II introns are found in bacteria, chloroplasts, and mitochondria of plants and fungi, but not in nuclear genomes. Although there is no doubt that prokaryotic and organellar group II introns are evolutionary related, there are remarkable differences in survival strategies between them. Furthermore, an evolutionary relationship of group II introns to eukaryotic retroelements, including telomeres, and spliceosomes is unmistakable. PMID- 28818347 TI - Use of supplemental long-chain omega-3 fatty acids and risk for cardiac death: An updated meta-analysis and review of research gaps. AB - BACKGROUND: Randomized controlled trials (RCTs) assessing use of long-chain omega 3 polyunsaturated fatty acids (LC-OM3), primarily eicosapentaenoic acid, and/or docosahexaenoic acid have shown mixed results. OBJECTIVE: The objectives of the study were to update and further explore the available RCT data regarding LC-OM3 supplementation and risk for cardiac death and to propose testable hypotheses for the mixed results obtained in RCTs regarding supplemental LC-OM3 use and cardiac risk. METHODS: A literature search was conducted using PubMed and Ovid/MEDLINE for RCTs assessing LC-OM3 supplements or pharmaceuticals with intervention periods of at least 6 months and reporting on the outcome of cardiac death. Meta analysis was used to compare cumulative frequencies of cardiac death events between the LC-OM3 and control groups, including sensitivity and subset analyses. RESULTS: Fourteen RCTs were identified for the primary analysis (71,899 subjects). In the LC-OM3 arms, 1613 cardiac deaths were recorded (4.48% of subjects), compared with 1746 cardiac deaths in the control groups (4.87% of subjects). The pooled relative risk estimate showed an 8.0% (95% confidence interval 1.6%, 13.9%, P = .015) lower risk in the LC-OM3 arms vs controls. Subset analyses showed numerically larger effects (12.9%-29.1% lower risks, all P < .05) in subsets of RCTs with eicosapentaenoic acid + docosahexaenoic acid dosages >1 g/d and higher risk samples (secondary prevention, baseline mean or median triglycerides >=150 mg/dL, low-density lipoprotein cholesterol >=130 mg/dL, statin use <40% of subjects). Heterogeneity was low (I2 <= 15.5%, P > .05) for the primary and subset analyses. CONCLUSION: LC-OM3 supplementation is associated with a modest reduction in cardiac death. PMID- 28818349 TI - Fifteen-Year Decrease in General Surgery Resident Breast Operative Experience: Are We Training Proficient Breast Surgeons? AB - OBJECTIVE: The goal of the study was to evaluate trends in general surgery resident breast cases over the past 15 years. STUDY DESIGN: The Accreditation Council for Graduate Medical Education (ACGME) Case Logs Statistics Reports from 2000 to 2015 were reviewed for average breast-specific case numbers and trends over time. ACGME data were available for all cases and breast-specific cases including the following: excisional biopsy/lumpectomy, simple mastectomy, modified radical mastectomy, and sentinel lymph node excision. SETTING: The study evaluation was conducted at Cleveland Clinic, Cleveland, Ohio. PARTICIPANTS: No individuals directly participated in this project. However, all general surgery residents at ACGME-accredited programs are represented in this analysis by virtue of the ACGME Case Logs Statistics Reports. RESULTS: Total residency case volume increased by 2% (2000-2015, p = 0.0159), with 2015 graduates logging 985.5 cases. In contrast, breast cases decreased by 17.1%. The largest drops were in modified radical mastectomy (61.5% decrease, p = 0.0001) and excisional biopsy/lumpectomy (25.8% decrease). Simple mastectomy increased from 6.0 to 10.8 cases (p = 0.0001). Sentinel lymph node excision fluctuated, but has been down-trending recently (67.3% decrease from 2010 to 2015, p = 0.0001). Decreased experience is occurring at both junior and senior resident levels. CONCLUSIONS: Breast case operative experience for general surgery residents decreased by 17% between 2000 and 2015, despite increase in overall operative volume. Residents have less experience in more advanced cases including axillary management, raising concern about the proficiency of graduating surgeons with respect to these procedures. It is reasonable to set national minimums for resident breast operative experience to ensure that individuals are appropriately trained to perform these cases in practice. PMID- 28818350 TI - Candidate Quality Measures for Hand Surgery. AB - PURPOSE: Quality measures are tools used by physicians, health care systems, and payers to evaluate performance, monitor the outcomes of interventions, and inform quality improvement efforts. A paucity of quality measures exist that address hand surgery care. We completed a RAND/UCLA (University of California Los Angeles) Delphi Appropriateness process with the goal of developing and evaluating candidate hand surgery quality measures to be used for national quality measure development efforts. METHODS: A consortium of 9 academic upper limb surgeons completed a RAND/UCLA Delphi Appropriateness process to evaluate the importance, scientific acceptability, usability, and feasibility of 44 candidate quality measures. These addressed hand problems the panelists felt were most appropriate for quality measure development. Panelists rated the measures on an ordinal scale between 1 (definitely not valid) and 9 (definitely valid) in 2 rounds (preliminary round and final round) with an intervening face-to-face discussion. Ratings from 1 to 3 were considered not valid, 4 to 6 as equivocal or uncertain, and 7 to 9 as valid. If no more than 2 of the 9 ratings were outside the 3-point range that included the median (1-3, 4-6, or 7-9), the panelists were considered to be in agreement. If 3 or more of the panelists' ratings of a measure were within the 1 to 3 range and 3 or more ratings were in the 7 to 9 range, the panelists were considered to be in disagreement. RESULTS: There was agreement on 43% (19) of the measures as important, 27% (12) as scientifically sound, 48% (21) as usable, and 59% (26) as feasible to complete. Ten measures met all 4 of these criteria and were, therefore, considered valid measurements of quality. Quality measures that were developed address outcomes (patient-reported outcomes for assessment and improvement of function) and processes of care (utilization rates of imaging, antibiotics, occupational therapy, ultrasound, and operative treatment). CONCLUSIONS: The consortium developed 10 measures of hand surgery quality using a validated methodology. These measures merit further development. CLINICAL RELEVANCE: Quality measures can be used to evaluate the quality of care provided by physicians and health systems and can inform quality and value-based reimbursement models. PMID- 28818351 TI - Recent trends in management and outcome of patients with acute coronary syndromes and atrial fibrillation. AB - AIMS: To describe the clinical characteristics, contemporary trends of in hospital management and outcome of patients admitted for an acute coronary syndrome (ACS) with associated atrial fibrillation (AF). METHODS: We analyzed data from four Italian nationwide prospective registries, conducted between 2001 and 2014, including consecutive ACS patients. RESULTS: Out of 16,803 ACS patients, 1019 (6.1%) presented with concomitant AF: 668 with non-ST elevation (NSTE)-ACS and 351 with ST-elevation myocardial infarction (STEMI). As compared to no-AF patients, those with AF were older and had significantly more prior cardiac events and comorbidities (all p<0.005). A progressive increase occurred over time in the rates of coronary angiography and percutaneous coronary intervention, both in NSTE-ACS (p for trend=0.0002 and 0.0008, respectively) and STEMI patients with AF at admission (both p for trend <0.0001), with trends similar to those observed in non-AF patients. Among STEMI patients, in-hospital mortality decreased by 50% in those without AF (7.5% in 2001 to 3.3% in 2014, p<0.0001), with a similar decrease in those with AF (20% vs 10.7%, p=0.20), even though not statistically significant. At multivariable analysis, AF on admission was not an independent predictor of in-hospital mortality [odds ratio (OR): 0.82; 95% confidence intervals (CI): 0.52-1.30; p=0.41 for NSTE-ACS, and OR: 1.07; 95% CI: 0.73-1.57; p=0.74 for STEMI]. CONCLUSIONS: Over the last 14years, the in hospital management of ACS patients with AF has significantly improved as for patients without AF, with comparable effect in terms of outcome. PMID- 28818352 TI - Longitudinal sequential biventricular assessment in adults with transposition of the great arteries and relationship with adverse outcomes. AB - BACKGROUND: In a cohort of congenitally corrected transposition of the great arteries (cc-TGA) and transposition of the great arteries after atrial switch procedure (d-TGA) the study objectives were: 1) to assess the change of quantitative systemic right ventricle (sRV) parameters over time and; 2) to examine the relationship of quantitative sRV parameters with adverse clinical outcomes. METHODS AND RESULTS: Single-center cohort study that included 49 (39%) cc-TGA and 76 (61%) d-TGA patients >18years who had at least one MUGA sRV assessment, 18/39 had more than one respectively. The primary clinical endpoint was all-cause mortality, heart transplantation and/or heart failure hospitalization. At a median clinical follow-up of 7years following the first MUGA, the primary endpoint occurred more often in cc-TGA versus d-TGA patients (18 (36.7%) vs. 9 (11.8%), p=0.03). Median time between the MUGA assessments was 5.8 (cc-TGA) and 4.9years (d-TGA). At last MUGA follow-up: 6 (33%) cc-TGA/14 (36%) d-TGA patients showed a significant decline in sRVEF (>5%); 6 (33%) cc TGA/17 (44%) d-TGA patients had a significant increase in sRVEDVi; and 7 (39%) cc TGA/19 (49%) PA-TGA patients had a significant increase in sRVESVi. Baseline sRV parameters were not associated with the primary end point or sRV changes over time. CONCLUSIONS: An important proportion of both patient cohorts demonstrated a significant change in sRV parameters over time and these are likely related to multiple factors that vary between individuals given population heterogeneity. The TGA patients have distinct clinical trajectories with increased adverse heart failure outcomes in the cc-TGA population and sRV parameters were not related to adverse heart failure events in either group. PMID- 28818353 TI - Does calcium burden impact culprit lesion morphology and clinical results? An ADAPT-DES IVUS substudy. AB - BACKGROUND: Increasing coronary lesion calcification is thought to be associated with adverse percutaneous coronary intervention (PCI) and clinical outcomes. We investigated the effects of calcium burden on culprit lesion morphology and clinical events after intravascular ultrasound (IVUS)-guided PCI in the ADAPT-DES study. METHODS: ADAPT-DES was a prospective, multicenter registry of 8582 consecutive patients undergoing successful PCI using DES. A pre-specified virtual histology (VH)-IVUS substudy of 638 culprit lesions (638 patients) had both pre- and post-PCI VH-IVUS. We divided lesions into tertiles according to pre-PCI percent dense calcium volume (DCV%=dense calcium/plaque volume*100). RESULTS: Compared with low and intermediate DCV% tertiles, patients in the high DCV% tertile had the largest arc of superficial calcium, highest percentage of necrotic core volume, and smallest remodeling index; they were also more likely to have advanced lesion morphology such as attenuated plaque and VH thin-cap fibroatheromas. In the high DCV% tertile IVUS guidance was associated with a minimum stent area that was smaller than tertiles with less calcium (p=0.01), but acceptable range, and similar stent expansion (73.8+/-16.8% vs. 74.0+/-19.2% vs. 72.4+/-17.3%, p=0.62) after more frequent use of rotational atherectomy and higher maximum inflation pressure. There was no significant association between pre-PCI DCV% and 2-year target lesion revascularization or major adverse cardiac events (cardiac death, myocardial infarction, or stent thrombosis). CONCLUSIONS: Increasing coronary artery calcification burden was associated with more advanced, complex VH-IVUS lesion morphology, but not with adverse clinical outcomes, perhaps due to more aggressive PCI techniques that optimized stent expansion. PMID- 28818354 TI - Retrospective study of the impact of unrecognised Kawasaki disease, coronary aneurysm and ectasia. AB - BACKGROUND: Coronary artery aneurysms resulting from unrecognised or untreated Kawasaki Disease (KD) have thrombotic and stenotic potential leading to myocardial infarction. We aimed to characterise the prevalence and outcomes of patients presenting to a UK-based adult tertiary cardiology service with angiographic evidence of aneurysm or ectasia. METHODS: Retrospective review was undertaken of reports and original coronary angiograms in all patients under 50years old undergoing coronary angiography between 2011 and 2015. Aneurysm/ectasia were defined by calibre discrepancy >1.5* and the number of segments involved. Aneurysms were categorised as being probable, or unlikely to represent unrecognised KD. RESULTS: Aneurysm or ectasia was observed in 49 of 1578 patients (3.7%). Eleven patients had angiographic findings consistent with probable antecedent KD (0.8%), a further 18 patients had evidence of coronary artery aneurysm (1.4%) and ectasia was observed in 20 patients (1.5%). The commonest mode of presentation was ST elevation myocardial infarction, observed in 71.4% of patients. Review of angiogram written reports demonstrated a spurious application of the terms aneurysm and ectasia, with a sensitivity of 10.3% & 55.0%, and a positive predictive value of reporting of 50.0% & 52.4%, respectively. CONCLUSIONS: As the first UK study to characterise the angiographic prevalence of Kawasaki Disease, both aneurysm and ectasia were observed with a relatively low frequency. However, their presence is associated with high-risk acute ischaemic presentations. Furthermore, we demonstrated a poor level of reporting of coronary abnormalities and advocate an increased awareness of Kawasaki disease and coronary aneurysm/ectasia amongst adult cardiologists. PMID- 28818356 TI - Comparing flexible bronchoscope and laryngoscope for tracheal intubation in critically ill patients. PMID- 28818355 TI - AR-V7 in Peripheral Whole Blood of Patients with Castration-resistant Prostate Cancer: Association with Treatment-specific Outcome Under Abiraterone and Enzalutamide. AB - BACKGROUND: It has been demonstrated that androgen receptor splice variant 7 (AR V7) expression in circulating tumor cells (CTCs) predicts poor treatment response in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone or enzalutamide. OBJECTIVE: To develop a practical and robust liquid profiling approach for direct quantification of AR-V7 in peripheral whole blood without the need for CTC capture and to determine its potential for predicting treatment response in mCRPC patients. DESIGN, SETTING, AND PARTICIPANTS: Whole blood samples from a prospective biorepository of 85 mCRPC patients before treatment initiation with abiraterone (n=56) or enzalutamide (n=29) were analyzed via droplet digital polymerase chain reaction. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The association of AR-V7 status with prostate-specific antigen (PSA) response defined by PSA decline >=50% and with PSA-progression-free survival (PSA-PFS), clinical PFS, and overall survival (OS) was assessed. RESULTS AND LIMITATIONS: High AR-V7 expression levels in whole blood were detectable in 18% (15/85) of patients. No patient with high AR-V7 expression achieved a PSA response, and AR-V7 status was an independent predictor of PSA response in multivariable logistic regression analysis (p=0.03). High AR-V7 expression was associated with shorter PSA-PFS (median 2.4 vs 3.7 mo; p<0.001), shorter clinical PFS (median 2.7 vs 5.5 mo; p<0.001), and shorter OS (median 4.0 vs. 13.9 mo; p<0.001). On multivariable Cox regression analysis, high AR-V7 expression remained an independent predictor of shorter PSA-PFS (hazard ratio [HR] 7.0, 95% confidence interval [CI] 2.3-20.7; p<0.001), shorter clinical PFS (HR 2.3, 95% CI 1.1-4.9; p=0.02), and shorter OS (HR 3.0, 95% CI 1.4-6.3; p=0.005). CONCLUSIONS: Testing of AR-V7 mRNA levels in whole blood is a simple and promising approach to predict poor treatment outcome in mCRPC patients receiving abiraterone or enzalutamide. PATIENT SUMMARY: We established a method for determining AR-V7 status in whole blood. This test predicted treatment resistance in patients with metastatic castration-resistant prostate cancer undergoing treatment with abiraterone or enzalutamide. Prospective validation is needed before application to clinical practice. PMID- 28818357 TI - Development of a risk score to predict extubation failure in patients with traumatic brain injury: Methodological issues. PMID- 28818358 TI - Black Toenail Sign in MELAS Syndrome. AB - BACKGROUND: Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is a mitochondrial disorder often causing progressive brain injury that is not confined to large arterial territories. Severe insults ultimately lead to gyral necrosis affecting the cortex and juxtacortical white matter; the neuroimaging correlate is partial gyral signal suppression on T2/FLAIR sequences that resemble black toenails. We aimed to characterize the imaging features and the natural history of MELAS-related gyral necrosis. MATERIALS AND METHODS: Databases at two children's hospitals were searched for brain magnetic resonance imaging studies of individuals with MELAS. Examinations with motion artifact and those lacking T2/FLAIR sequences were excluded. The location, the cumulative number, and the maximum transverse diameter of necrotic gyral lesions were assessed using T2-weighted images and T2/FLAIR sequences. Wilcoxon signed-rank test was employed to evaluate the relationship between disease duration and the number of necrotic lesions. RESULTS: One hundred twenty four examinations from patients with 14 unique MELAS patients (16 +/- 3 years) were evaluated. Six of the eight patients who developed brain lesions also developed gyral necroses (mean 13, range 0 to 44). Necrotic lesions varied in maximal diameter from 4 to 25 mm. Cumulative necrotic lesions correlated with disease duration (P < 0.001). CONCLUSIONS: The black toenail sign signifying gyral necrosis is a common imaging feature in individuals with MELAS syndrome. The extent of gyral necrosis correlates with disease duration. PMID- 28818359 TI - Environment of care: Is it time to reassess microbial contamination of the operating room air as a risk factor for surgical site infection in total joint arthroplasty? AB - In the modern operating room (OR), traditional surgical mask, frequent air exchanges, and architectural barriers are viewed as effective in reducing airborne microbial populations. Intraoperative sampling of airborne particulates is rarely performed in the OR because of technical difficulties associated with sampling methodologies and a common belief that airborne contamination is infrequently associated with surgical site infections (SSIs). Recent studies suggest that viable airborne particulates are readily disseminated throughout the OR, placing patients at risk for postoperative SSI. In 2017, virtually all surgical disciplines are engaged in the implantation of selective biomedical devices, and these implants have been documented to be at high risk for intraoperative contamination. Approximately 1.2 million arthroplasties are performed annually in the United States, and that number is expected to increase to 3.8 million by the year 2030. The incidence of periprosthetic joint infection is perceived to be low (<2.5%); however, the personal and fiscal morbidity is significant. Although the pharmaceutic and computer industries enforce stringent air quality standards on their manufacturing processes, there is currently no U.S. standard for acceptable air quality within the OR environment. This review documents the contribution of air contamination to the etiology of periprosthetic joint infection, and evidence for selective innovative strategies to reduce the risk of intraoperative microbial aerosols. PMID- 28818360 TI - Clinical and arthroscopic outcome of single bundle anterior cruciate ligament reconstruction: Comparison of remnant preservation versus conventional technique. AB - BACKGROUND: The purpose of this study was to compare the clinical outcomes and second-look arthroscopic findings of remnant preservation technique with those of conventional anterior cruciate ligament (ACL) reconstruction in single bundle ACL reconstructions. METHODS: One hundred sixty two consecutive patients underwent ACL reconstruction by one surgeon, with 93 patients receiving remnant preservation technique (Group A) and 69 patients receiving conventional ACL reconstruction (Group B). The mean follow-up was 15months. Clinical outcomes were assessed using Lysholm scores and the International Knee Documentation Committee form (IKDC form) evaluation. Post-operative knee stability was evaluated through manual knee laxity evaluation, pivot-shift test, and a Telos device. RESULTS: Differences in post-operative stability (manual knee laxity, pivot shift test and Telos device) were not significant between the groups (p=0.681, p=0.610, p=0.696). And also no significant differences were noted with respect to the IKDC form and the latest Lysholm scores. But in the second-look arthroscopic findings, synovial coverage was confirmed to be excellent in 36% (22/61) of Group A patients and 23% (7/30) of Group B patients. CONCLUSIONS: ACL reconstruction with both techniques was found to result in acceptable stability, clinical outcomes and second-look arthroscopic findings. With regard to synovial coverage, the remnant reservation techniques were found to be superior to conventional ACL reconstruction. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 28818361 TI - Strategy for patients with co-existence of meningioma and intracerebral aneurysm, especially unruptured aneurysm (-seven cases and review of the literature-). AB - BACKGROUND: Intracerebral aneurysms co-existing with meningiomas are rare. Treatment strategies for intracerebral aneurysms co-existing with meningiomas have not yet been established. METHODS: We studied 62 patients with intracerebral aneurysms co-existing with meningiomas in the literature including our seven cases, evaluated the various managements and outcomes, and discussed the strategy for intracerebral aneurysms, especially unruptured cases, co-existing with meningiomas. The aim of this study was to develop a guide for the management of non-subarachnoid hemorrhage (SAH) intracerebral aneurysms co-existing with meningiomas. RESULTS: Most intracerebral aneurysms co-existing with meningiomas are unruptured. Of course, aneurysms presenting with SAH should be treated first followed by the resection of meningiomas. In addition, intracerebral aneurysms inside or adjacent to meningiomas have a high risk of intraoperative rupture during the surgery for meningiomas, and it may be necessary to treat them first followed by the resection of meningiomas with one or two-step surgery. In nine out of 62 patients, ten intracerebral unruptured aneurysms were not treated; however, no intracerebral aneurysms ruptured during the follow-up period, and outcomes of these patients were good in eight and poor in only one. CONCLUSIONS: Intracerebral unruptured aneurysms remote from meningiomas may be treated according to the guidelines for unruptured aneurysms. In advance of microsurgery and endovascular techniques, both lesions should be treated, if possible. PMID- 28818362 TI - Two year follow-up of Crohn's patients substituted to certolizumab anti-TNFa therapy: SAVANT 2. AB - The effectiveness of ant-TNF 'biologic' therapy in is well supported in the management of moderate to severe Crohn's Disease (CD). Our first 'SAVANT' study was to our knowledge the first study report one- year outcomes in patients (n=60) who switched from previous anti-TNFa treatment to Cimzia/Certolizumab. This current study (SAVANT 2) follows up on longer term outcomes and provides additional clinical and biochemical data that may contribute to therapeutic responses. This IRB approved study was a retrospective analysis of the initial patients included in SAVANT 1. Patients who were switched to TNF antagonist Certolizumab as an alternative biologic were followed an additional year. Retrospective consideration of immunomodulator use, smoking status and clinical data were also evaluated. Of 60 patients with moderate-severe CD who participated in the SAVANT 1 study, 15 patients were excluded due to inadequate follow up. 45 patients were studied for a total of two years following substitution with Certolizumab from prior anti TNF agent therapy. Clinical remission at 1 year was 75% (45/60) and 55% (25/45) at the second year. At the second year, 5 more patients had discontinued Certolizumab due to worse disease or adverse events, indicating a cumulative two-year failure rate of 33% (20/60). Smoking and concomitant use of immunomodulators were similar between 'success' and 'failure' groups. SAVANT 2, the first study to report long term outcomes of switching from Infliximab or Adalimumab to Certolizumab showed that at 2 years, 25 patient's maintained clinical remission. The discontinuation rates were 25 and 11% at years 1 & 2 respectively. The 5 patients who lost responsiveness after the first year were women, the majority of smoked. Additional prospective studies to assess the appropriateness and feasibility of biologic substitution are still needed. PMID- 28818363 TI - Peer Review in Radiology: How Can We Learn From Our Mistakes? PMID- 28818364 TI - Involvement of SchRabGDI1 from Solanum chilense in endocytic trafficking and tolerance to salt stress. AB - Physiological responses of plants to salinity stress requires the coordinated activation of many genes. A salt-induced gene was isolated from roots of the wild tomato species Solanum chilense and named SchRabGDI1 because it encodes a protein with high identity to GDP dissociation inhibitors of plants. These proteins are regulators of the RabGTPase cycle that play key roles in intracellular vesicular trafficking. The expression pattern of SchRabGDI1 showed an early up-regulation in roots and leaves under salt stress. Functional activity of SchRabGDI1 was shown by restoring the defective phenotype of the yeast sec19-1 mutant and the capacity of SchRabGDI1 to interact with RabGTPase was demonstrated through BiFC assays. Expression of SchRabGDI1 in Arabidopsis thaliana plants resulted in increased salt tolerance. Also, the root cells of transgenic plants showed higher rate of endocytosis under normal growth conditions and higher accumulation of sodium in vacuoles and small vesicular structures under salt stress than wild type. Our results suggest that in salt tolerant species such as S. chilense, bulk endocytosis is one of the early mechanisms to avoid salt stress, which requires the concerted expression of regulatory genes involved in vesicular trafficking of the endocytic pathway. PMID- 28818365 TI - The endophytic fungus Piriformospora indica enhances Arabidopsis thaliana growth and modulates Na+/K+ homeostasis under salt stress conditions. AB - The mutualistic, endophytic fungus Piriformospora indica has been shown to confer biotic and abiotic stress tolerance to host plants. In this study, we investigated the impact of P. indica on the growth of Arabidopsis plants under normal and salt stress conditions. Our results demonstrate that P. indica colonization increases plant biomass, lateral roots density, and chlorophyll content under both conditions. Colonization with P. indica under salt stress was accompanied by a lower Na+/K+ ratio and less pronounced accumulation of anthocyanin, compared to control plants. Moreover, P. indica colonized roots under salt stress showed enhanced transcript levels of the genes encoding the high Affinity Potassium Transporter 1 (HKT1) and the inward-rectifying K+ channels KAT1 and KAT2, which play key roles in regulating Na+ and K+ homeostasis. The effect of P. indica colonization on AtHKT1;1 expression was also confirmed in the Arabidopsis line gl1-HKT:AtHKT1;1 that expresses an additional AtHKT1;1 copy driven by the native promoter. Colonization of the gl1-HKT:AtHKT1;1 by P. indica also increased lateral roots density and led to a better Na+/K+ ratio, which may be attributed to the observed increase in KAT1 and KAT2 transcript levels. Our findings demonstrate that P. indica colonization promotes Arabidopsis growth under salt stress conditions and that this effect is likely caused by modulation of the expression levels of the major Na+ and K+ ion channels, which allows establishing a balanced ion homeostasis of Na+/K+ under salt stress conditions. PMID- 28818366 TI - Expression of recombinant SnRK1 in E. coli. Characterization of adenine nucleotide binding to the SnRK1.1/AKINbetagamma-beta3 complex. AB - The SnRK1 complexes in plants belong to the family of AMPK/SNF1 kinases, which have been associated with the control of energy balance, in addition to being involved in the regulation of other aspects of plant growth and development. Analysis of complex formation indicates that increased activity is achieved when the catalytic subunit is phosphorylated and bound to regulatory subunits. SnRK1.1 subunit activity is higher than that of SnRK1.2, which also exhibits reduced activation due to the regulatory subunits. The catalytic phosphomimetic subunits (T175/176D) do not exhibit high activity levels, which indicate that the amino acid change does not produce the same effect as phosphorylation. Based on the mammalian AMPK X-ray structure, the plant SnRK1.1/AKINbetagamma-beta3 was modeled by homology modeling and Molecular Dynamics simulations (MD). The model predicted an intimate and extensive contact between a hydrophobic region of AKINbetagamma and the beta3 subunit. While the AKINbetagamma prediction retains the 4 CBS domain organization of the mammalian enzyme, significant differences are found in the putative nucleotide binding pockets. Docking and MD studies identified two sites between CBS 3 and 4 which may bind adenine nucleotides, but only one appears to be functional, as judging from the predicted binding energies. The recombinant AKINbetagamma-betas complexes were found to bind adenine nucleotides with dissociation constant (Kd) in the range of the AMP low affinity site in AMPK. The saturation binding data was consistent with a one-site model, in agreement with the in silico calculations. As has been suggested previously, the effect of AMP was found to slow down dephosphorylation but did not influence activity. PMID- 28818367 TI - Metabolic features involved in drought stress tolerance mechanisms in peanut nodules and their contribution to biological nitrogen fixation. AB - Legumes belong to the most important crops worldwide. They increase soil fertility due their ability to establish symbiotic associations with soil microorganisms, known as rhizobia, capable of fixing nitrogen from the atmosphere. However, they are frequently exposed to abiotic stress conditions in particular drought. Such adverse conditions impair the biological nitrogen fixation (BNF) and depend largely on the legume. Therefore, two peanut cultivars with contrasting tolerance to drought, namely the more tolerant EC-98 and the sensitive Granoleico, were investigated to elucidate the relative contribution of BNF to the tolerance to drought. The tolerant cultivar EC-98 sustained growth and BNF similar to the control condition despite the reduced water potential and photosynthesis, suggesting the functioning of distinct metabolic pathways that contributed to enhance the tolerance. The biochemical and metabolomics approaches revealed that nodules from the tolerant cultivar accumulated trehalose, proline and gamma-aminobutyric acid (GABA), metabolites with known function in protecting against drought stress. The amide metabolism was severely affected in nodules from the sensitive cultivar Granoleico as revealed by the low content of asparagine and glutamine in the drought stressed plants. The sensitive cultivar upon rehydration was unable to re-establish a metabolism similar to well-watered plants. This was evidenced by the low level of metabolites and, transcripts and specific activities of enzymes from the carbon (sucrose synthase) and nitrogen (glutamine synthetase) metabolism which decreased below the values of control plants. Therefore, the increased content of metabolites with protective functions under drought stress likely is crucial for the full restoration upon rehydration. Smaller changes of drought stress-related metabolites in nodule are another trait that contributes to the effective control of BNF in the tolerant peanut cultivar (EC-98). PMID- 28818368 TI - Review: Metabolic engineering of unusual lipids in the synthetic biology era. AB - The plant kingdom produces a variety of fatty acid structures, many of which possess functional groups useful for industrial applications. The species that produce these unusual fatty acids are often not suitable for large scale commercial production. The ability to create genetically modified plants, together with emerging synthetic biology approaches, offers the potential to develop alternative oil seed crops capable of producing high levels of modified lipids. In some cases, by combining genes from different species, non-natural lipids with a targeted structure can be conceived. However, the expression of the biosynthetic enzymes responsible for the synthesis of unusual fatty acids typically results in poor accumulation of the desired product. An improved understanding of fatty acid flux from synthesis to storage revealed that specialized enzymes are needed to traffic unusual fatty acids. Co-expression of some of these additional enzymes has incrementally increased the levels of unusual fatty acids in transgenic seeds. Understanding how the introduced pathways interact with the endogenous pathways will be important for further enhancing the levels of unusual fatty acids in transgenic plants. Eliminating endogenous activities, as well as segregating the different pathways, represent strategies to further increase accumulation of unusual lipids. PMID- 28818369 TI - Brassinosteroid and gibberellin control of seedling traits in maize (Zea mays L.). AB - In this study, we established two doubled haploid (DH) libraries with a total of 207 DH lines. We applied BR and GA inhibitors to all DH lines at seedling stage and measured seedling BR and GA inhibitor responses. Moreover, we evaluated field traits for each DH line (untreated). We conducted genome-wide association studies (GWAS) with 62,049 genome wide SNPs to explore the genetic control of seedling traits by BR and GA. In addition, we correlate seedling stage hormone inhibitor response with field traits. Large variation for BR and GA inhibitor response and field traits was observed across these DH lines. Seedling stage BR and GA inhibitor response was significantly correlate with yield and flowering time. Using three different GWAS approaches to balance false positive/negatives, multiple SNPs were discovered to be significantly associated with BR/GA inhibitor responses with some localized within gene models. SNPs from gene model GRMZM2G013391 were associated with GA inhibitor response across all three GWAS models. This gene is expressed in roots and shoots and was shown to regulate GA signaling. These results show that BRs and GAs have a great impact for controlling seedling growth. Gene models from GWAS results could be targets for seeding traits improvement. PMID- 28818370 TI - Overexpression of VpEIFP1, a novel F-box/Kelch-repeat protein from wild Chinese Vitis pseudoreticulata, confers higher tolerance to powdery mildew by inducing thioredoxin z proteolysis. AB - An F-box protein (VpEIFP1) induced by Erysiphe necator was isolated from Vitis pseudoreticulata, a wild Chinese grapevine species naturally resistant to powdery mildew (PM). It contains an F-box domain and two Kelch-repeat motifs. Expression profiles indicate the VpEIFP1 is strongly induced at both transcriptional and translational levels by PM infection. A subcellular localisation assay showed that VpEIFP1 is predominantly located in the nucleus and cytoplasm. Overexpression of VpEIFP1 accelerated the accumulation of hydrogen peroxide (H2O2) and up-regulated the expressions of ICS2, NPR1 and PR1 involved in defence responses, resulting in suppression of PM germination and growth. As an F-box protein, VpEIFP1 interacts with thioredoxin z (VpTrxz) in the yeast-two-hybrid (Y2H) assay and in the bimolecular fluorescence complementation (BiFC) assay. Decreased amounts of VpTrxz protein in transgenic grapevine leaves overexpressing VpEIFP1 were restored by proteasome inhibitor MG132, implying that VpEIFP1 mediated VpTrxz for degradation through the SCFVpEIFP1 (Skp1-Cullin-F-box) E3 ubiquitin ligase complex. The RNA interference line of VpTrxz showed increased H2O2 accumulation following PM inoculation. We propose VpEIFP1 positively modulates the grapevine defence response to PM by inducing the degradation of VpTrxz via the ubiquitin/26S proteasome system. PMID- 28818371 TI - Assessment of molecular and epigenetic changes in the albinism of Agave angustifolia Haw. AB - Albinism in plants is a rare phenomenon that occurs in nature and is characterized by the total or partial loss of photosynthetic pigments. Although progress has been made in understanding the nature of this phenomenon, the precise causes and biological basis are still unexplored. Here, we study the genetic and epigenetic differences between green (G), variegated (V) and albino (A) A. angustifolia Haw. plantlets obtained by in vitro propagation in order to present new insights into albinism from a plant system that offers a unique set of biological phenotypic characteristics. Low transcript levels of genes involved in carotenoids and photosynthesis such as PSY, PDS, LCYE, rubS, PEPCase and LHCP suggest a disruption in these processes in albino plants. Due to a high level of genetic similarity being found between the three phenotypes, we analyzed global DNA methylation and different histone marks (H3K4me2, H3K36me2, H3K9ac, H3K9me2 and H3K27me3). Although no significant differences in global 5-methyl deoxicytidine were found, almost a 2-4.5-fold increase in H3K9ac was observed in albino plants in comparison with variegated or green plants, suggesting a change in chromatin compaction related to A. angustifolia albinism. PMID- 28818372 TI - Functional characterization of rice CW-domain containing zinc finger proteins involved in histone recognition. AB - Histone recognition is important for understanding the mechanisms of histone modification, which play a pivotal role in transcriptional regulation during plant development. Here, we identified three cysteine-tryptophan (CW)-domain containing zinc finger (ZF) proteins involved in histone recognition, namely OsCW ZF3, OsCW-ZF5 and OsCW-ZF7. Protein sequence analysis showed that they have two unknown motifs in addition to the CW domain. All three OsCW-ZFs were expressed in aerial tissues, with relatively high levels in developing panicles. Subcellular localization revealed that the OsCW-ZFs target the cell nucleus and CW domains are not necessary for their nuclear localization. In contrast to OsCW-ZF3 and OsCW-ZF5 where the CW domains bind histone H3 lysine 4 with different methylated forms (H3K4me), the CW domain from OsCW-ZF7 recognizes only trimethylated histone H3 lysine 4 (H3K4me3). Analysis of mutant suggested that three conserved tryptophan residues in the CW domain are essential for binding to H3K4me. Further study found that OsCW-ZF7 interacts with TAFII20, a transcription initiation factor TFIID 20kDa subunit. Knockout of OsCW-ZF7 caused defective development of awns. This study provides new insights into our understanding of the CW domain and lays a foundation for further investigation of its roles in rice. PMID- 28818373 TI - Depressed expression of FAE1 and FAD2 genes modifies fatty acid profiles and storage compounds accumulation in Brassica napus seeds. AB - In plants, the enzymes fatty acid dehydrogenase 2 (FAD2) and fatty acid elongase 1 (FAE1) have been shown in previous studies to play important roles in the de novo biosynthesis of fatty acids. However, the effects of depressed expression of FAD2 and FAE1 on seed storage compounds accumulation remains to be elucidated. In this study, we produced RNA interfering transgenic rapeseeds lines, BnFAD2-Ri, BnFAE1-Ri and BnFAD2/BnFAE1-Ri, which exhibited depressed expression of the BnFAD2 and BnFAE1 genes under the control of seed-specific napin A promoter. These transgenic rapeseeds showed normal growth and development as compared with the wild type (CY2). Depressed expression of BnFAD2 and BnFAE1 genes modified fatty acid profiles, leading to increased oleic acid and decreased erucic acid contents in transgenic seeds. Consistent with these results, the ratios of C18:1/C18:2 and C18:1/C18:3 in C18 unsaturated fatty acids were greatly increased due to increased oleic acid content in transgenic seeds. Moreover, depressed expression of BnFAD2 and BnFAE1 genes resulted in slightly decreased oil contents and increased protein contents in transgenic seeds. Our results demonstrated that depressed expression of BnFAD2 and BnFAE1 greatly improves seed nutritional quality by modulating the fatty acid metabolism and storage products accumulation and that BnFAD2 and BnFAE1 are reliable targets for genetic improvement of rapeseed in seed nutritional quality. PMID- 28818374 TI - Cell wall modifications of two Arabidopsis thaliana ecotypes, Col and Sha, in response to sub-optimal growth conditions: An integrative study. AB - With the global temperature change, plant adaptations are predicted, but little is known about the molecular mechanisms underlying them. Arabidopsis thaliana is a model plant adapted to various environmental conditions, in particular able to develop along an altitudinal gradient. Two ecotypes, Columbia (Col) growing at low altitude, and Shahdara (Sha) growing at 3400m, have been studied at optimal and sub-optimal growth temperature (22 degrees C vs 15 degrees C). Macro- and micro-phenotyping, cell wall monosaccharides analyses, cell wall proteomics, and transcriptomics have been performed in order to accomplish an integrative analysis. The analysis has been focused on cell walls (CWs) which are assumed to play roles in response to environmental changes. At 15 degrees C, both ecotypes presented characteristic morphological traits of low temperature growth acclimation such as reduced rosette diameter, increased number of leaves, modifications of their CW composition and cuticle reinforcement. Altogether, the integrative analysis has allowed identifying several candidate genes/proteins possibly involved in the cell wall modifications observed during the temperature acclimation response. PMID- 28818376 TI - An overview on the strategies to exploit rice endosperm as production platform for biopharmaceuticals. AB - Cereal seed has been utilized as production platform for high-value biopharmaceutical proteins. Especially, protein bodies (PBs) in seeds are not only natural specialized storage organs of seed storage proteins (SSPs), but also suitable intracellular deposition compartment for recombinant proteins. When various recombinant proteins were produced as secretory proteins by attaching N terminal ER signal peptide and C terminal KDEL endoplasmic reticulum (ER) retention signal or as fusion proteins with SSPs, high amounts of recombinant proteins can be predominantly accumulated in the PBs. Recombinant proteins bioencapsulated in PBs exhibit high resistance to digestive enzymes in gastrointestinal tract than other intracellular compartments and are highly stable at ambient temperature, thus allowing oral administration of PBs containing recombinant proteins as oral drugs or functional nutrients in cost effective minimum processed formulation. In this review, we would like to address key factors determining accumulation levels of recombinant proteins in PBs. Understanding of bottle neck parts and improvement of specific deposition to PBs result in much higher levels of production of high quality recombinant proteins. PMID- 28818375 TI - Lipid remodelling: Unravelling the response to cold stress in Arabidopsis and its extremophile relative Eutrema salsugineum. AB - Environmental constraints limit the geographic distribution of many economically important crops. Cold stress is an important abiotic stress that affects plant growth and development, resulting in loss of vigour and surface lesions. These symptoms are caused by, among other metabolic processes, the altered physical and chemical composition of cell membranes. As a major component of cell membranes lipids have been recognized as having a significant role in cold stress, both as a mechanical defence through leaf surface protection and plasma membrane remodelling, and as signal transduction molecules. We present an overview integrating gene expression and lipidomic data published so far in Arabidopsis and its relative the extremophile Eutrema salsugineum. This data enables a better understanding of the contribution of the lipidome in determining the ability to tolerate suboptimal temperature conditions. Collectively this information will allow us to identify the key lipids and pathways responsible for resilience, enabling the development of new approaches for crop tolerance to stress. PMID- 28818377 TI - Heterologous expression of GmSIP1;3 from soybean in tobacco showed and growth retardation and tolerance to hydrogen peroxide. AB - Aquaporins (AQPs) are transmembrane protein channels that are members of Major Intrinsic Proteins (MIP) superfamily. AQPs play important roles in plant reproduction, cell elongation, osmoregulation, influence leaf physiology and are responsive to drought and salt tolerance. Small intrinsic proteins (SIPs)belongs to one of the groups of AQPs, which are mainly localized to endoplasmic reticulum(ER). While this group of aquaporin is being well studied in Arabidopsis, grape and other plant species, not much is known about the molecular regulatory mechanisms driven by ER-type AQPs in Glycine Max. In this study, the function of GmSIP1;3 is studied in detail by using both yeast and plant systems. GmSIP1;3 showed a ubiquitous expression pattern in all different tissues in Glycine Max. Heterologous expression of GmSIP1;3 in Nicotiana tabacum conferred a short root phenotype,growth retardation at seedling stage and significant tolerance to oxidative stress (H2O2) both in yeast and plant systems. Auxin (IAA) content significantly increased in transgenic plants compared with that of wild type, however, the abscisic acid (ABA) content was significantly reduced. Subcellular localization and colocalization analyses showed GmSIP1;3 localized to ER plasma membrane. On the basis of these observations, we postulate that GmSIP1;3 is involved in oxidative stress pathways. PMID- 28818378 TI - NSR1/MYR2 is a negative regulator of ASN1 expression and its possible involvement in regulation of nitrogen reutilization in Arabidopsis. AB - Nitrogen (N) is a major macronutrient that is essential for plant growth. It is important for us to understand the key genes that are involved in the regulation of N utilization. In this study, we focused on a GARP-type transcription factor known as NSR1/MYR2, which has been reported to be induced under N-deficient conditions. Our results demonstrated that NSR1/MYR2 has a transcriptional repression activity and is specifically expressed in vascular tissues, especially in phloem throughout the plant under daily light-dark cycle regulation. The overexpression of NSR1/MYR2 delays nutrient starvation- and dark-triggered senescence in the mature leaves of excised whole aerial parts of Arabidopsis plants. Furthermore, the expression of asparagine synthetase 1 (ASN1), which plays an important role in N remobilization and reallocation, i.e. N reutilization, in Arabidopsis, is negatively regulated by NSR1/MYR2, since the expressions of NSR1/MYR2 and ASN1 were reciprocally regulated during the light dark cycle and ASN1 expression was down-regulated in overexpressors of NSR1/MYR2 and up-regulated in T-DNA insertion mutants of NSR1/MYR2. Therefore, the present results suggest that NSR1/MYR2 plays a role in N reutilization as a negative regulator through controlling ASN1 expression. PMID- 28818379 TI - Influence of TaGW2-6A on seed development in wheat by negatively regulating gibberellin synthesis. AB - Gibberellins (GA) are involved in seed development and E3 ubiquitin-ligases actively participate in GA perception and signal transduction. TaGW2-6A encodes a RING E3 ubiquitin-ligase that negatively regulates grain size. Therefore, Chinese Spring (CS) and its TaGW2-6A allelic variants (NIL31) were investigated to elucidate the relative contribution of GA to the regulation of seed development in wheat. The expression levels of GA biosynthesis and response genes were higher in NIL31 than CS, especially those of GA 3-oxidase and GASA4. The expression of TaGW2-6A exhibited the opposite pattern compared with those of the GA biosynthesis and response genes in CS and NIL31. The results showed that the GA content of NIL31 was significantly higher than that of CS. Thus, TaGW2-6A had a negative relationship on GA synthesis and response genes. Moreover, after GA treatment, CS and NIL31 exhibited the opposite phenotypes and GA contents. These results demonstrate that allelic variation in TaGW2-6A increases the seed size via the GA hormone pathway. Transcriptional analysis and cytological analysis showed that TaGW2-6A allelic variants regulated GA synthesis via GA 3-oxidases, thereby leading to the higher expression of GASA4 to control endosperm cell elongation and division during grain filling. Finally, germination experiments were performed to elucidate the relationships between TaGW2-6A and GA synthesis and response genes in wheat with full fertility. These results provide new insights into the effects of the ubiquitination system mediated by TaGW2-6A on the GA hormone signaling pathway, thereby improving our understanding of the role of TaGW2-6A in seed development in wheat. PMID- 28818380 TI - Molecular cloning and expression analysis of duplicated polyphenol oxidase genes reveal their functional differentiations in sorghum. AB - Polyphenol oxidase (PPO) is believed to play a role in plant growth, reproduction, and resistance to pathogens and pests. PPO causes browning of grains in cereals. In this study, genetic mapping of sorghum grain for phenol color reaction (PHR) was performed using a recombinant inbred line population. Only one locus was detected between SSR markers SM06072 and Xtxp176 on chromosome 6. Two linked orthologous genes (Sb06PPO1 and Sb06PPO2) within the mapped region were discovered and cloned. Transformation experiments using Nipponbare (a PHR negative rice cultivar) showed that Sb06PPO1 from LTR108 and two Sb06PPO2 alleles from both varieties could complement Nipponbare, whereas Sb06PPO1 from 654 could not. Subsequent quantitative real-time PCR (qPCR) experiments showed that Sb06PPO1 and Sb06PPO2 functioned diversely, Sb06PPO1 was mainly expressed in young panicles before flowering. Sb06PPO2 was strongly expressed in flowering panicles, especially in hulls and branches at filling stage. Moreover, the expression of Sb06PPO1 was found to be significantly up-regulated by exogenous ABA and salt, whereas Sb06PPO2 was not changed significantly, further demonstrating functional differentiation between the two genes. PMID- 28818381 TI - AgFNS overexpression increase apigenin and decrease anthocyanins in petioles of transgenic celery. AB - Apigenin and anthocyanin biosyntheses share common precursors in plants. Flavone synthase (FNS) converts naringenin into apigenin in higher plants. Celery is an important edible and medical vegetable crop that contains apigenin in its tissues. However, the effect of high AgFNS gene expression on the apigenin and anthocyanins contents of purple celery remains to be elucidated. In this study, the AgFNS gene was cloned from purple celery ('Nanxuan liuhe purple celery') and overexpressed in this purple celery to determine its influence on anthocyanins and apigenin contents. Results showed that the AgFNS gene was 1068bp, which encodes 355 amino acid residues. Evolution analysis showed that the AgFNS protein belongs to the FSN I type. In AgFNS transgenic celery, the anthocyanins content in petioles was lower than that wild-type celery plants. Apigenin content increased in the petioles of AgFNS transgenic celery. The transcript levels of the AgPAL, AgC4H, AgCHS, and AgCHI genes were up-regulated, whereas those of the AgF3H, AgF3'H, AgDFR, AgANS, and Ag3GT genes were down-regulated in the petioles of AgFNS transgenic plants compared with wild-type celery plants. This work provides basic knowledge about the function of the AgFNS gene in the anthocyanin and apigenin biosyntheses of celery. PMID- 28818382 TI - Cell-specific expression of plant nutrient transporter genes in orchid mycorrhizae. AB - Orchid mycorrhizal protocorms and roots are heterogeneous structures composed of different plant cell-types, where cells colonized by intracellular fungal coils (the pelotons) are close to non-colonized plant cells. Moreover, the fungal coils undergo rapid turnover inside the colonized cells, so that plant cells containing coils at different developmental stages can be observed in the same tissue section. Here, we have investigated by laser microdissection (LMD) the localization of specific plant gene transcripts in different cell-type populations collected from mycorrhizal protocorms and roots of the Mediterranean orchid Serapias vomeracea colonized by Tulasnella calospora. RNAs extracted from the different cell-type populations have been used to study plant gene expression, focusing on genes potentially involved in N uptake and transport and previously identified as up-regulated in symbiotic protocorms. Results clearly showed that some plant N transporters are differentially expressed in cells containing fungal coils at different developmental stages, as well as in non colonized cells, and allowed the identification of new functional markers associated to coil-containing cells. PMID- 28818383 TI - Methyl jasmonate and salicylic acid are able to modify cell wall but only salicylic acid alters biomass digestibility in the model grass Brachypodium distachyon. AB - In addition to playing a key role in the response to environmental changes, cell walls are also considered as a valuable feedstock for cellulosic ethanol. Here we explored the effects of the stress-response hormones, salicylic acid and methyl jasmonate, on cell wall biosynthesis and biomass digestibility in Brachypodium distachyon, a species recently considered as a suitable model for biomass conversion. We found that in response to salicylic acid or methyl jasmonate treatment, plant growth was reduced coupled with significant changes in cell wall composition. Cellulose content increased in response to methyl jasmonate whereas a reduction in lignin content was found after salicylic acid application. Moreover, hemicellulose composition was altered and increases in caffeic acid, ferulic acid and p-coumaric acid content were detected in response to both treatments. The hormonal profile and the expression pattern of genes involved in cell wall biosynthesis were also modified. Biomass digestibility was reduced in leaf tissue after salicylic acid treatment and was negatively correlated with ferulic acid and p-coumaric acid content. The results obtained here aid in our understanding of cell wall dynamics in response to stress and will enable the development of new strategies to improve cell wall digestibility in bioenergy feedstock. PMID- 28818384 TI - Rice peroxisomal ascorbate peroxidase knockdown affects ROS signaling and triggers early leaf senescence. AB - H2O2, which is continually produced by aerobic metabolism, is a cytotoxic molecule when in high levels. However, low levels can act as a signaling molecule able to regulate the expression of stress responses, senescence, programmed cell death, plant growth, and development. Ascorbate peroxidase (APX) enzyme plays an essential role in the control of intracellular H2O2 levels. Here, the function of a gene encoding a peroxisomal APX (OsAPX4) from rice (Oryza sativa L.) was studied. OsAPX4 gene expression can be detected in roots and panicles, but the highest expression level occurs in leaves. Silencing of OsAPX4 and OsAPX3 expression in RNAiOsAPX4 did not affect the growth of plants under growth chamber conditions, but aging transgenic plants interestingly displayed an early senescence phenotype. Leaf fragments from silenced plants were also more sensitive to induced senescence conditions. RNAiOsAPX4 plants did not present detectable changes in intracellular H2O2 levels, but biochemical analyses showed that transgenic plants displayed some decreased APX activity in the chloroplastic fraction. Also, the peroxisomal enzyme glycolate oxidase exhibited lower activity, whereas catalase activity was similar to non-transformed rice. The results imply that OsAPX4 gene has an important role in leaf senescence pathway mediated by ROS signaling. PMID- 28818385 TI - Molecular cloning and characterization of PtrZPT2-1, a ZPT2 family gene encoding a Cys2/His2-type zinc finger protein from trifoliate orange (Poncirus trifoliata (L.) Raf.) that enhances plant tolerance to multiple abiotic stresses. AB - In plants, most Cys2/His2 (C2H2) zinc finger proteins with two zinc finger domains (ZPT2) are involved in abiotic stress responses. In this study, a ZPT2 family gene PtrZPT2-1 was cloned from trifoliate orange (Poncirus trifoliata (L.) Raf.). PtrZPT2-1 is composed of 245 amino acids, has a putative molecular weight of 25.99kDa and an isoelectric point of 8.41. PtrZPT2-1 contained two C2H2 zinc finger domains, one nuclear localization signal (B-box), one transcription repression domain (DLN-box), and one protein-protein interaction domain (L-box). PtrZPT2-1 was localized to the nucleus. The PtrZPT2-1 expression was strongly induced by cold, drought, salt and ABA stresses. Overexpression of PtrZPT2-1 increased the survival rates, and the ABA, soluble sugar and proline levels but decreased the ion leakage, the malondialdehyde (MDA) content and reduced the H2O2 accumulation in the transgenic tobacco after cold, drought or salt treatments. Furthermore, the expression levels of 15 abiotic stress-related genes were significantly increased in the transgenic tobacco overexpressing PtrZPT2-1 after cold, drought or salt stress treatments. Our results indicated that overexpression of PtrZPT2-1 in the transgenic tobacco could improve the cold, drought and salt resistance of the plants by increasing the levels of osmotic regulatory solutes and decreasing the accumulation of H2O2. PMID- 28818386 TI - Heterologous expression of two GPATs from Jatropha curcas alters seed oil levels in transgenic Arabidopsis thaliana. AB - Oils and fats are stored in endosperm during seed development in the form of triacylglycerols. Three acyltransferases: glycerol-3-phosphate acyltransferase (GPAT), lysophosphatidyl acyltransferase (LPAT) and diacylglycerol acyltransferase (DGAT) are involved in the storage lipid biosynthesis and catalyze the stepwise acylation of glycerol backbone. In this study two members of GPAT gene family (JcGPAT1 and JcGPAT2) from Jatropha seeds were identified and characterized. Sequence analysis suggested that JcGPAT1 and JcGPAT2 are homologous to Arabidopsis acyltransferase-1 (ATS1) and AtGPAT9 respectively. The sub-cellular localization studies of these two GPATs showed that JcGPAT1 localizes into plastid whereas JcGPAT2 localizes in to endoplasmic reticulum. JcGPAT1 and JcGPAT2 expressed throughout the seed development with higher expression in fully matured seed compared to immature seed. The transcript levels of JcGPAT2 were higher in comparison to JcGPAT1 in different developmental stages of seed. Over-expression of JcGPAT1 and JcGPAT2 under constitutive and seed specific promoters in Arabidopsis thaliana increased total oil content. Transgenic seeds of JcGPAT2-OE lines accumulated 43-60% more oil than control seeds whereas seeds of Arabidopsis lines over-expressing plastidial GPAT lead to only 13-20% increase in oil content. Functional characterization of GPAT homologues of Jatropha in Arabidopsis suggested that these are involved in oil biosynthesis but might have specific roles in Jatropha. PMID- 28818387 TI - Plant response to biotic stress: Is there a common epigenetic response during plant-pathogenic and symbiotic interactions? AB - Plants constantly interact with pathogenic and symbiotic microorganisms. Recent studies have revealed several regulatory mechanisms controlling these interactions. Among them, the plant defense system is activated not only in response to pathogenic, but also in response to symbiotic microbes. Interestingly, shortly after symbiotic microbial recognition, the plant defense system is suppressed to promote plant infection by symbionts. Research studies have demonstrated the influence of the plant epigenome in modulating both pathogenic and symbiotic plant-microbe interactions, thereby influencing plant survival, adaptation and evolution of the plant response to microbial infections. It is however unclear if plant pathogenic and symbiotic responses share similar epigenomic profiles or if epigenomic changes differentially regulate plant microbe symbiosis and pathogenesis. In this mini-review, we provide an update of the current knowledge of epigenomic control on plant immune responses and symbiosis, with a special attention being paid to knowledge gap and potential strategies to fill-in the missing links. PMID- 28818388 TI - Genetic analysis of rootstock-mediated nitrogen (N) uptake and root-to-shoot signalling at contrasting N availabilities in tomato. AB - Selecting rootstocks for high nitrogen acquisition ability may allow decreased N fertilizer application without reducing tomato yields, minimizing environmental nitrate pollution. A commercial hybrid tomato variety was grafted on a genotyped population of 130 recombinant inbred lines (RILs) derived from Solanum pimpinellifolium, and compared with self- and non-grafted controls under contrasting nitrate availabilities (13.8 vs 1.0mM) in the nutrient solution. Grafting itself altered xylem sap composition under N-sufficient conditions, particularly Na+ (8.75-fold increase) concentration. N deprivation decreased shoot dry weight by 72.7% across the grafted RIL population, and one RIL rootstock allowed higher total leaf N content than the best of controls, suggesting more effective N uptake. Sixty-two significant QTLs were detected by multiple QTL mapping procedure for leaf N concentration (LNC), vegetative growth, and the xylem sap concentrations of Mn and four phytohormone groups (cytokinins, gibberellins, salicylic acid and jasmonic acid). Only three LNC QTLs could be common between nitrogen treatments. Clustering of rootstock QTLs controlling LNC, leaf dry weight and xylem sap salicylic acid concentration in chromosome 9 suggests a genetic relationship between this rootstock phytohormone and N uptake efficiency. Some functional candidate genes found within 2 Mbp intervals of LNC and hormone QTLs are discussed. PMID- 28818389 TI - Common and variable clinical, histological, and imaging findings of recessive RYR1-related centronuclear myopathy patients. AB - Mutations in RYR1 give rise to diverse skeletal muscle phenotypes, ranging from classical central core disease to susceptibility to malignant hyperthermia. Next generation sequencing has recently shown that RYR1 is implicated in a wide variety of additional myopathies, including centronuclear myopathy. In this work, we established an international cohort of 21 patients from 18 families with autosomal recessive RYR1-related centronuclear myopathy, to better define the clinical, imaging, and histological spectrum of this disorder. Early onset of symptoms with hypotonia, motor developmental delay, proximal muscle weakness, and a stable course were common clinical features in the cohort. Ptosis and/or ophthalmoparesis, facial weakness, thoracic deformities, and spinal involvement were also frequent but variable. A common imaging pattern consisted of selective involvement of the vastus lateralis, adductor magnus, and biceps brachii in comparison to adjacent muscles. In addition to a variable prominence of central nuclei, muscle biopsy from 20 patients showed type 1 fiber predominance and a wide range of intermyofibrillary architecture abnormalities. All families harbored compound heterozygous mutations, most commonly a truncating mutation combined with a missense mutation. This work expands the phenotypic characterization of patients with recessive RYR1-related centronuclear myopathy by highlighting common and variable clinical, histological, and imaging findings in these patients. PMID- 28818390 TI - Three novel recessive mutations in LAMA2, SYNE1, and TTN are identified in a single case with congenital muscular dystrophy. AB - Congenital muscular dystrophies (CMD) are a group of heterogeneous disorders. Here, targeted next generation sequencing of 168 CMD-associated genes was performed on collected clinic samples to identify potential mutations. A loss-of function mutation (c.4676-4682delGCTGCAA; p.Cys1560Thrfs*33) of the LAMA2 gene in a consanguineous family was identified and confirmed by Sanger sequencing. The second recessive mutation in SYNE1 (c.2881C>T; p.Arg961Trp) was found in the SAP motif, which was predicted to be involved in chromosomal organization. The third homozygous mutation (c.32462C>T; p.Pro10821Leu) in TTN was mapped to the third PPAK motif of the encoded protein. Muscle biopsies of the proband showed large variations in muscle fiber size, necrotic and regenerating fibers and an increase in endomysial collagen tissue. To the best of our knowledge, this is the first case with CMD and mildly enlarged heart, carrying three novel recessive mutations in LAMA2, SYNE1, and TTN. PMID- 28818391 TI - Role of capillary pericytes and precapillary arterioles in the vascular mechanism of betahistine in a guinea pig inner ear model. AB - AIMS: Betahistine is a histamine analogue that is used for the treatment of Meniere's disease. Animal studies showed that it increases local blood flow in the stria vascularis. In terms of its mode of action, recent studies have prompted discussion of whether betahistine actively affects cochlear microcirculation by dilations of pericytes or of precapillary arterioles or by mere downstream effects. Hence, we investigated the effects of betahistine on cochlear capillary pericytes and precapillary arterioles. MAIN METHODS: The stria vascularis was visualized in 12 guinea pigs by in vivo fluorescence microscopy. In these, 152 pericytes were stained and local diameter at sites of pericyte somas and downstream controls as well as intravascular blood flow were measured before and after betahistine application. Moreover, in two guinea pigs the precapillary arterioles were visualized by 2-photon-microscopy before and after betahistine application. KEY FINDINGS: There was no significant change in capillary diameter at sites of pericyte somas after betahistine application compared to controls, baseline or downstream controls, even though cochlear blood flow increased significantly. The two-photon measurements indicated an active dilation of precapillary arterioles. SIGNIFICANCE: Since we found no evidence that betahistine affects cochlear microcirculation by cochlear pericytes, its main mode of action is evidently active dilation of pre-capillary arterioles. These findings are in line with similar effects reported in the central nervous system and indicate an active effect on cochlear microcirculation. PMID- 28818392 TI - How Predictable Are Human Stratum Corneum Lipid/Water Partition Coefficients? Assessment and Useful Correlations for Dermal Absorption. AB - Partition coefficients between human stratum corneum lipids and water (Ksclip/w) are collected or deduced from a variety of sources in a manner that approximately doubles the available data compared to the current state-of-the-art model (Hansen et al., Adv Drug Deliv Rev. 2013;65(2):251-264). An additional datum for water itself in porcine SC that considerably extends the molecular size and lipophilicity range of the data set is considered. The data are analyzed in terms of an extended linear free energy relationship involving octanol/water partition coefficients, Abraham solvation parameters, and a secondary, power law molecular weight dependence. The optimum fit to log Ksclip/w for the full data set reduces the standard error of prediction from 0.50 for a Hansen-like model to 0.39; corresponding multiplicative errors in Ksclip/w are reduced from a factor of 3.1 to one of 2.5. The difference in performance is driven by the water datum, which requires a more complex dependence on molecular size than that afforded by Abraham parameters. In the absence of the water value, the Hansen-like model, which does not include a dependence on molecular size, is essentially optimum. A comparison is presented to fluid-phase phospholipid-water systems, which have a demonstrably different structure-property relationship. PMID- 28818393 TI - The modulation of the phosphorylation status of NKCC1 in organ cultured bovine lenses: Implications for the regulation of fiber cell and overall lens volume. AB - In previous work, we have shown the Sodium/Potassium/2 Chloride Cotransporter (NKCC1) to be a key effector of lens fiber cell volume regulation. Since others have shown that the activity of NKCC1 is regulated via its phosphorylation status, the purpose of this study was to investigate whether NKCC1 phosphorylation can be modulated in organ cultured bovine lenses, and to see how this relates to changes in lens wet weight. Western blotting was first used to confirm the expression of NKCC1, phosphorylated NKCC1 (NKCC1-P) and the regulatory kinases WNK/SPAK and phosphatases PP1/PP2A in bovine lenses at the protein level. Changes to NKCC1-P status were then assessed by organ culturing bovine lenses in either isotonic, hypertonic or hypotonic solutions in the presence or absence of the NKCC inhibitor, bumetanide, or phosphatase inhibitors okadaic acid and calyculin A. After 1-22 h of culturing, lenses were weighed, assessed for transparency and the cortical protein fractions analyzed by western blot using antibodies to detect total NKCC1 and NKCC1-P. NKCC1, NKCC1-P, SPAK, PP1 and PP2A were all detected in the membrane fraction of bovine lenses. Under hypertonic conditions, NKCC1 is phosphorylated and activated to mediate a regulatory volume increase. Finally, NKCC1-P signal increased in the presence of phosphatase inhibitors indicating that PP1/PP2A can dephosphorylate NKCC1. These results show that the phosphorylation status and hence activity of NKCC1 is dynamically regulated and that in response to hypertonic stress, NKCC1 activity is increased to effect a regulatory volume increase that limits cell shrinkage. These findings support the view that the lens dynamically regulates ion fluxes to maintain steady state lens volume, and suggest that dysfunction of this regulation maybe an initiating factor in the localized fiber cell swelling that is a characteristic of diabetic lens cataract. PMID- 28818394 TI - Focal adhesion kinase family is involved in matrix contraction by transdifferentiated Muller cells. AB - Transdifferentiated Muller cells that adopt a fibroblastic/myofibroblastic phenotype have been identified in epiretinal membranes (ERMs) in several ocular disorders, and have been implicated to play a role in the formation and/or the contraction of ERMs. We have previously demonstrated that dasatinib, a dual inhibitor of Src-family kinases and Abl kinase, can prevent matrix contraction by transdifferentiated Muller cells. In this study, we examined molecules involved in matrix contraction downstream of primary dasatinib targets. Tyrosine phosphorylation of focal adhesion kinase (FAK) family members FAK and PYK2 was significantly reduced by dasatinib, and select inhibitors for these kinases PF431396, which inhibits both FAK and PYK2, and PF573228, which only inhibits FAK and not PYK2, significantly reduced matrix contraction by transdifferentiated Muller cells. Dasatinib and PF431396 significantly reduced phosphorylation of Hic 5, a protein implicated to play a role in focal adhesions and cell signaling. Our data shows that FAK family members are involved in matrix contraction by transdifferentiated Muller cells, and also implicates that Hic-5 is situated downstream of the FAK family within the signaling pathway. PMID- 28818396 TI - Identification and susceptibility testing of Candida spp. directly from yeast positive blood cultures with Vitek 2. AB - Culture-based identification and antifungal susceptibility take 48-72hours after positivity. We analyzed the performance of Vitek2 directly from 40 yeast-positive blood-cultures; agreement of 100% was observed for the tested antifungals; identification showed the same species in 31/40. The method reduces time (13 to 18h) for preliminary results. PMID- 28818395 TI - Lymphocyte Fate and Metabolism: A Clonal Balancing Act. AB - Activated lymphocytes perform a clonal balancing act, yielding a daughter cell that differentiates owing to intense PI3K signaling, alongside a self-renewing sibling cell with blunted anabolic signaling. Divergent cellular anabolism versus catabolism is emerging as a feature of several developmental and regenerative paradigms. Metabolism can dictate cell fate, in part, because lineage-specific regulators are embedded in the circuitry of conserved metabolic switches. Unequal transmission of PI3K signaling during regenerative divisions is reminiscent of compartmentalized PI3K activity during directed motility or polarized information flow in non-dividing cells. The diverse roles of PI3K pathways in membrane traffic, cell polarity, metabolism, and gene expression may have converged to instruct sibling cell feast and famine, thereby enabling clonal differentiation alongside self-renewal. PMID- 28818397 TI - Life cycle inventory and mass-balance of municipal food waste management systems: Decision support methods beyond the waste hierarchy. AB - When assessing the environmental and human health impact of a municipal food waste (FW) management system waste managers typically rely on the principles of the waste hierarchy; using metrics such as the mass or rate of waste that is 'prepared for recycling,' 'recovered for energy,' or 'sent to landfill.' These metrics measure the collection and sorting efficiency of a waste system but are incapable of determining the efficiency of a system to turn waste into a valuable resource. In this study a life cycle approach was employed using a system boundary that includes the entire waste service provision from collection to safe end-use or disposal. A life cycle inventory of seven waste management systems was calculated, including the first service wide inventory of FW management through kitchen in-sink disposal (food waste disposer). Results describe the mass, energy and water balance of each system along with key emissions profile. It was demonstrated that the energy balance can differ significantly from its' energy generation, exemplified by mechanical biological treatment, which was the best system for generating energy from waste but only 5th best for net-energy generation. Furthermore, the energy balance of kitchen in-sink disposal was shown to be reduced because 31% of volatile solids were lost in pre-treatment. The study also confirmed that higher FW landfill diversion rates were critical for reducing many harmful emissions to air and water. Although, mass-balance analysis showed that the alternative end-use of the FW material may still contain high impact pollutants. PMID- 28818398 TI - The recovery of waste and off-gas in Large Combustion Plants subject to IPPC National Permit in Italy. AB - The recovery of off-gas, waste, and biomass in Large Combustion Plants for energy production gives the opportunity to recycle waste and by-products and to recover materials produced in agricultural and industrial activities. The paper illustrates the Italian situation regarding the production of energy from off gas, biomass, and waste in Large Combustion Plants subject to Integrated Pollution Prevention and Control (IPPC) National Permit. Moreover, it focuses on the 4 Italian Large Combustion Plants producing energy from biomass and waste. For these ones it illustrates the specific issues related to and provides a description of the solutions adopted in the 4 Italian plants. Given that air emission performance is the most relevant aspect of this kind of plants, the paper specifically focuses and reports results about this subject. In particular, in Italy among 113 LCPs subject to IPPC National Permit we have found that 4 plants use as fuel waste (i.e. solid or liquid biomasses and Solid Recovered Fuels), or a mixture of waste and traditional fuels (co-combustion of Solid Recovered Fuels and coal), and that 11 plants use as fuel off-gases listed in Annex X (i.e. Refinery Fuel Gas, Syngas, and gases produced in iron and steel industries). Moreover, there are 2 IPPC chemical plants that recovery energy from different off-gases not listed in Annex X. Regarding the 4 LCPs that produce energy from waste combustion or co-combustion, we find that they take into account all the specific issues related to this kind of plants (i.e. detailed waste characterization, waste acceptance procedures, waste handling and storage, waste pretreatment and emissions to air), and adopt solutions that are best available techniques to prevent pollution. Moreover for one of these plants, the only one for which we have a significant set of monitoring data because it obtained the IPPC National Permit in 2008, we find that energy efficiency and air emissions of the principal pollutants are in good compliance with European coal- and lignite-fired combustion plants co-incinerating waste and with BAT-AELs reported in the BREF document. PMID- 28818399 TI - Nano-carbons from waste tyre rubber: An insight into structure and morphology. AB - This study reports on the novel and sustainable synthesis of high value carbon nanoparticles (CNPs) from waste tyre rubber (WTR), using an innovative high temperature approach. As waste tyres are composed, primarily, of carbon - accounting for some 81.2wt% - they represent a promising source of carbon for many potential applications. However, cost-effective options for their processing are limited and, consequently, billions of waste tyres have accumulated in landfills and stockpiles, posing a serious global environmental threat. The rapid, high temperature transformation of low value WTR to produce valuable CNPs, reported here, addresses this challenge. In this study, the transformation of WTRs was carried out at 1550 degrees C over different reaction times (5s to 20min). The structure and morphology of the resulting CNPs were investigated using X-ray diffraction (XRD), Raman spectroscopy, X-ray photon spectroscopy (XPS), N2 isothermal adsorption method and scanning electron microscopy (SEM). The formation of CNPs with diameters of 30 and 40nm was confirmed by Field Emission Electron Microscopy (FE-SEM). Longer heating times also resulted in CNPs with regular and uniform spherical shapes and a specific surface area of up to 117.7m2/g, after 20min. A mechanism that describes the formation of CNPs through mesophase nuclei intermediate is suggested. PMID- 28818400 TI - Characterization of the constitutive behavior of municipal solid waste considering particle compressibility. AB - This paper presents a characterization of the mechanical behavior of municipal solid waste (MSW) under consolidated drained and undrained triaxial conditions. The constitutive model was established based on a deviatoric hardening plasticity model. A power form function and incremental hyperbolic form function were proposed to describe the shear strength and the hardening role of MSW. The stress ratio that corresponds to the zero dilatancy was not fixed but depended on mean stress, making the Rowe's rule be able to describe the stress-dilatancy of MSW. A pore water pressure reduction coefficient, which attributed to the compressibility of a particle and the solid matrix, was introduced to the effective stress formulation to modify the Terzaghi's principle. The effects of particle compressibility and solid matrix compressibility on the undrained behavior of MSW were analyzed by parametric analysis, and the changing characteristic of stress-path, stress-strain, and pore-water pressure were obtained. The applicability of the proposed model on MSW under drained and undrained conditions was verified by model predictions of three triaxial tests. The comparison between model simulations and experiments indicated that the proposed model can capture the observed different characteristics of MSW response from normal soil, such as nonlinear shear strength, pressure dependent stress dilatancy, and the reduced value of pore water pressure. PMID- 28818401 TI - Impact of co-landfill proportion of bottom ash and municipal solid waste composition on the leachate characteristics during the acidogenesis phase. AB - Incineration has become an important municipal solid waste (MSW) treatment strategy, and generates a large amount of bottom ash (BA). Although some BA is reused, much BA and pretreatment residues from BA recycling are disposed in landfill. When BA and MSW are co-landfilled together, acid neutralization capacity and alkaline earth metal dissolution of BA, as well as different components of MSW may change environmental conditions within the landfill, so the degradation of organic matter and the physical and chemical properties of leachate would be affected. In this study, the effect of co-landfilled BA and MSW on the leachate characteristics during the hydrolysis and acidogenesis phase was studied using different BA/MSW ratios and MSW compositions. The results showed that the co-landfill system increased leachate pH, electric conductivity and alkalinity. For MSW with a high content of degradable components, the release and degradation of total organic carbon (TOC) and volatile fatty acids (VFA) from MSW were promoted when the BA ratio by wet weight was less than 50%, and the biodegradability of leachate was improved. When the BA ratio exceeded 50%, the degradation of organic matters was inhibited. For MSW with low content of degradable components, when the proportion of BA was less than 20%, the release and degradation of TOC and VFA from MSW were promoted and alkalinity increased. When the BA ratio exceeded 20%, the degradation of organic matters was inhibited. The 50% BA ratio could improve the bio-treatability of leachate indicated by the leachate pH and C/N ratio. However, BA inhibited the release of nitrogen (TN and NH4+-N) at all BA ratios and MSW compositions. At the same time, the addition of BA increased the risk of leachate collection system clogging due to the dissolution and re-precipitation of alkaline earth metals contained in BA. PMID- 28818402 TI - Association of hemolysis with high dose intravenous immunoglobulin therapy in pediatric patients: An open-label prospective trial. AB - : Immunoglobulin therapy can be used to treat a wide variety of diseases. However, intravenous immunoglobin products can cause several adverse reactions, including hemolysis. The objective of this study was to determine the extent of anemia and hemolysis after high dose intravenous immunoglobin (2g/kg) and its relationship to the ABO blood type system and hemolytic anemia blood parameters in pediatric patients. Incidence of 'Intravenous immunoglobulin related hemolysis' was %19 (6/31) after high dose intravenous immunoglobulin therapy. The blood parameters were measured before IVIG infusion (1-24h before infusion) and 3 10 days after the first day of infusion. In terms of decrease in Hb levels; decline of <1g/dL was detected in 25 patients (80.6%), >=1g/dL in 2 patients (6.5%) and >2g/dL (severe hemolysis) in 4 patients (12.9%) after infusion. The decrease in hemoglobin, haptoglobin levels, the increase of reticulocyte count or direct bilirubin were statistically significant after infusion. Five of 6 hemolysis patients had non-O blood group, however statistically significant difference was not noted between these two groups. Also, intravenous immunoglobulin-related hemolysis was determined significantly higher in female than male patients. CONCLUSION: Mild to moderate hemolysis may be undetected after infusion and the true incidence of such reactions is difficult to document without careful clinical and laboratory follow-up. A careful risk assessment analysis should be performed before intravenous immunoglobulin infusion. PMID- 28818403 TI - Heavy metal levels in patients with ineffective erythropoiesis. AB - OBJECTIVES: Iron is taken into enterocytes at the duodenum via apical divalent metal-ion transporter 1 protein. Besides iron, divalent metal-ion transporter 1 also transports other divalent metals. We aimed to investigate blood heavy metal levels in patients with ineffective erythropoiesis. METHODS: Blood levels of heavy metals including Pb, Al, Cd, Cr, Co, Cu, and Zn were measured in patients with thalassemia major (TM), thalassemia intermedia (TI), congenital dyserythropoietic anemia (CDA), and age- and sex-matched healthy controls. RESULTS: Blood samples were obtained from 68 patients (51 patients with TM, 8 with TI, 9 with CDA), and a control group that included 65 volunteers. Patients with TM were found to have lower Al, Pb, and Zn, and higher Cd levels compared with the control group. The patients treated with deferasirox were further analyzed and Pb and Zn levels were found lower compared with the control group. DISCUSSION: Patients with TM had tendency to have elevated levels of plasma cadmium; however, the median level was not at a toxic level. Increased metal-ion transporter 1 activity may cause heavy metal accumulation, but deferasirox chelation may be protective against heavy metals besides iron. PMID- 28818405 TI - Dolores Gonzalez-Pacanowska: The Sweet Side of Drug Discovery. PMID- 28818404 TI - Report of the ISHLT Working Group on Primary Lung Graft Dysfunction Part III: Mechanisms: A 2016 Consensus Group Statement of the International Society for Heart and Lung Transplantation. PMID- 28818406 TI - Rethinking Schistosomiasis Vaccine Development: Synthetic Vesicles. AB - There is currently no vaccine against schistosomiasis. With few Schistosoma vaccine candidates in clinical trials, unexplored antigens from the vulnerable schistosomulum should be considered as possible vaccine candidates. In addition, we suggest developing synthetic vesicles as a new delivery vehicle and adjuvant for immunoprophylactic schistosomula vaccine candidates. PMID- 28818407 TI - Effects of copper oxide nanoparticles and copper ions to zebrafish (Danio rerio) cells, embryos and fry. AB - The use of engineered metal nanoparticles (NPs) is continuously increasing and so is the need for information regarding their toxicity. This study compares the toxicity of CuO NPs with ionic Cu in three zebrafish model systems; zebrafish hepatoma cell line (ZFL), fish embryo toxicity test (FET) and fry locomotion. In the ZFL tests, no significant cytotoxicity (cell death, decreased metabolic or cell membrane integrity) was detected for either treatment, though both significantly affected reactive oxygen species (ROS) production. Embryo mortality was affected by both Cu ions and CuO NPs with similar concentration-response relationships, whereas only Cu ions affected fry mortality (24h LC50~30MUM, ~2mgCuL-1 for Cu ions and no significant mortality observed at up to 200MUM, 12.7mgCuL-1 for CuO NP). Both Cu forms increased fry swimming activity during light cycles and decreased activity during dark cycles: Cu ions had significant impact at lower concentrations than CuO NPs. The implications are that Cu ions generally are more toxic than CuO NPs to embryos and fry but there is a marked difference in toxicity among the different zebrafish model systems. Metal NPs release into the environment may have adverse effects on fish and other aquatic organisms. PMID- 28818408 TI - Serial Assessment of Natriuretic Peptides in Patients Undergoing Interventional Closure of the Left Atrial Appendage. AB - BACKGROUND: Closure of the left atrial appendage (LAA) to prevent cardioembolic events is an alternative therapy to oral anticoagulation in patients with non valvular atrial fibrillation. The LAA is an important source of natriuretic peptides and its exclusion from the circulation may alter the blood level of these hormones, thereby influencing their diagnostic value and clinical effects. METHODS: We aimed to prospectively assess potential changes in mid-regional pro A type natriuretic peptide (MR-proANP) and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels 6 weeks and 6 months after interventional LAA closure using the WATCHMAN device. RESULTS: In 29 consecutive patients with successful LAA closure baseline MR-proANP level was 274+/-208pmol/l and decreased by -24.5+/ 68 (p=0.07) and -15.0+/-44pmol/l (p=0.10) after 6 weeks and 6 months, respectively. The drop in the MR-proANP level after 6 weeks and 6 months was significant in patients with elevated (>=214pmol/l) baseline MR-proANP level (n=15: -54.3+/-78.0, p<0.01 and -31.8+/-45.4pmol/l, p=0.03, respectively) and those with reduced left ventricular ejection fraction (LVEF<45%, n=7: -87.4+/ 97.3, p=0.02 and -60.3+/-42.6pmol/l, p=0.01, respectively). Baseline NT-proBNP level (median 1054pg/ml; IQR 621-1977pg/ml), sodium, potassium, mean systolic or diastolic blood pressure did not change significantly in the mentioned patient groups. CONCLUSIONS: After LAA closure, MR-proANP level decreased significantly in patients with elevated baseline MR-proANP level or reduced LVEF, whereas NT proBNP level remained unchanged, thereby altering the correlation coefficient between the two biomarkers. Our findings should be considered when using these biomarkers for diagnostic or prognostic evaluation in patients with interventional LAA closure. PMID- 28818409 TI - Endomyocardial Fibrosis: A Rare Case of Diastolic Heart Failure in a European Caucasian Elderly Woman. PMID- 28818410 TI - Optical Coherence Tomography Guided Percutaneous Coronary Intervention. AB - Optical coherence tomography (OCT) is an increasingly available intracoronary imaging modality that provides high-resolution imaging of coronary arteries. Its fundamental reliance on the emission and reflection of light enables rapid data acquisition without compromise of image resolution. As such, OCT can inform operators planning percutaneous coronary intervention (PCI) by accurately defining luminal geometry and detailing plaque composition. Following PCI, OCT imaging delivers a thorough assessment of the treated arterial segment and can identify specific features not always visible on alternate imaging modalities, including stent edge-related dissection, plaque tissue prolapse, incomplete stent apposition and the presence of intra-coronary thrombus. Clinical trials highlight that procedural strategy is frequently altered based on OCT findings, while concerns over final stent dimensions have been mitigated through use of a sizing protocol based on external elastic lamina dimensions in the reference arterial segment. Randomised trials are now warranted to definitively ascertain whether OCT-guidance improves clinical outcomes when utilised during PCI. PMID- 28818411 TI - Long-term supplementation with EGCG and beta-alanine decreases mortality but does not affect cognitive or muscle function in aged mice. AB - We have previously shown that 6weeks of a diet containing epigallocatechin gallate (EGCG) and beta-alanine (B-ALA) was not effective in improving either cognitive or muscle function in aged (18month) mice (Gibbons et al. Behav Brain Res 2014). However, diet reduced oxidative stress in the brain, and previous studies using longer-term interventions have documented beneficial effects in cognitive, but not muscle, function. Therefore, we investigated the effect of 6months of feeding on measures of cognitive and muscle function in mice. Mice (12months, N=15/group) were fed AIN-93M containing 0.15% EGCG and 0.34% B-ALA or standard AIN-93M for 6months, then underwent a battery of tests for cognitive and muscle function at 18months. Interestingly, a higher percentage of mice receiving EGCG and B-ALA (E+B, 80%) survived to study end compared to control (Ctrl, 40%) mice (p=0.02). E+B did not affect arm preference in the Y-maze test (p=0.74, novel arm) and did not alter performance in an active avoidance test (p=0.16, avoidances per 50 trials). E+B increased rotarod performance (p=0.03), did not affect grip strength (p=0.91), and decreased time to exhaustion in a treadmill fatigue test (p=0.02) compared to Ctrl. In conclusion, E+B reduced mortality, had no effect on cognitive function and variable effects on muscle function. PMID- 28818412 TI - Are extramedian symptoms associated with peripheral causes in patient with carpal tunnel syndrome? Electrodiagnostic and ultrasonographic study. AB - OBJECTIVE: To evaluate the relationship between extramedian spreading of sensorial symptoms and median and ulnar nerve cross-sectional area (CSA) and to compare the ultrasonographic and electrophysiological findings in patients with carpal tunnel syndrome (CTS) with or without extramedian sensory symptoms. DESIGN: Cross-sectional study. MATERIALS AND METHODS: Patients with CTS were divided into two groups as with or without extramedian symptoms and were assessed clinically, electrophysiologically and ultrasonographically by three blind investigators. In electrophysiological tests, median and ulnar nerve conduction studies were performed. Nerve cross-sectional areas were measured at hook of hamate, psiform bone, radio-ulnar joint, one-third distal part of forearm, and medial epicondyle by ultrasonography. FINDINGS: The study was completed with 61 patients (108 hands). Extramedian symptoms were present in 31 patients (54 hands). Finger grip strength was lower, pain values evaluated with visual analogue scale were higher in patients with extramedian symptoms (p<0.05). There was no statistically significant difference in electrophysiological and ultrasonographic parameters. CONCLUSION: According to our results, extramedian symptoms are not related to nerve conduction studies or nerve ultrasonography, these symptoms may be explained with central sensitization in patient with CTS. PMID- 28818413 TI - Transactions at a Northeastern Supermarket Chain: Differences by Supplemental Nutrition Assistance Program Use. AB - INTRODUCTION: Although one in seven Americans receives Supplemental Nutrition Assistance Program (SNAP) benefits, little is known about how these benefits for food are spent because individual-level sales data are not publicly available. The purpose of this study is to compare transactions made with and without SNAP benefits at a large regional supermarket chain. METHODS: Sales data were obtained from a large supermarket chain in the Northeastern U.S. for a period of 2 years (April 2012-April 2014). Multivariate multiple regression models were used to quantify relative differences in dollars spent on 31 predefined SNAP-eligible food categories. Analyses were completed in 2016. RESULTS: Transactions with SNAP benefit use included higher spending on less healthful food categories, including sugar-sweetened beverages ($1.08), red meat ($1.55), and convenience foods ($1.34), and lower spending on more healthful food categories, such as fruits ( $1.51), vegetables (-$1.35), and poultry (-$1.25) compared to transactions without SNAP benefit use. CONCLUSIONS: These findings provide objective data to compare purchases made with and without SNAP benefits. Next steps should be to test proposed SNAP modifications to determine whether they would have the intended effect of promoting healthier purchasing patterns among SNAP beneficiaries. PMID- 28818414 TI - Utilization of Away-From-Home Food Establishments, Dietary Approaches to Stop Hypertension Dietary Pattern, and Obesity. AB - INTRODUCTION: Eating meals away from home has been associated with the consumption of unhealthy foods and increased body weight. However, more rigorous assessment of the contribution of different types of away-from-home food establishments to overall diet quality and obesity is minimal. This study examined usage of these food establishments, accordance to the Dietary Approaches to Stop Hypertension (DASH) dietary pattern and obesity status in a nationally representative sample of adults in the United Kingdom. METHODS: A cross-sectional analysis of data from a national survey (N=2,083 aged >=19 years, from 2008 to 2012) with dietary intake measured using a 4-day food diary, and height and weight measured objectively. Exposures included usage of (i.e., by proportion of energy) all away-from-home food establishments combined, and fast-food outlets, restaurants, and cafes separately. Outcomes included accordance with the DASH diet, and obesity status. Multivariable logistic regressions were conducted in 2016 to estimate associations between food establishments, diet quality, and obesity. RESULTS: People consuming a higher proportion of energy from any away from-home food establishment had lower odds of DASH accordance (OR=0.45, 95% CI=0.31, 0.67) and increased odds of obesity (OR=1.48, 95% CI=1.10, 1.99). After adjustment, only use of fast-food outlets was significantly associated with lower odds of DASH accordance (OR=0.48, 95% CI=0.33, 0.69) and higher odds of obesity (OR=1.30, 95% CI=1.01, 1.69). CONCLUSIONS: Although a greater reliance on eating away-from-home is associated with less-healthy diets and obesity, dietary public health interventions that target these food establishments may be most effective if they focus on modifying the use of fast-food outlets. PMID- 28818415 TI - Modifiable Lifestyle Risk Factors and Incident Diabetes in African Americans. AB - INTRODUCTION: The associations of modifiable lifestyle risk factors with incident diabetes are not well investigated in African Americans (AAs). This study investigated the association of modifiable lifestyle risk factors (exercise, diet, smoking, TV watching, and sleep-disordered breathing burden) with incident diabetes among AAs. METHODS: Modifiable lifestyle risk factors were characterized among 3,252 AAs in the Jackson Heart Study who were free of diabetes at baseline (2000-2004) using baseline questionnaires and combined into risk factor categories: poor (0-3 points), average (4-7 points), and optimal (8-11 points). Incidence rate ratios (IRR) for diabetes (fasting glucose >=126 mg/dL, physician diagnosis, use of diabetes drugs, or glycosylated hemoglobin A1c >=6.5%) were estimated using Poisson regression modeling adjusting for age, sex, education, occupation, systolic blood pressure, and BMI. Outcomes were collected 2005-2012 and data analyzed in 2016. RESULTS: Over 7.6 years, there were 560 incident diabetes cases (mean age=53.3 years, 64% female). An average or optimal compared to poor risk factor categorization was associated with a 21% (IRR=0.79, 95% CI=0.62, 0.99) and 31% (IRR=0.69, 95% CI=0.48, 1.01) lower risk of diabetes. Among participants with BMI <30, IRRs for average or optimal compared to poor categorization were 0.60 (95% CI=0.40, 0.91) and 0.53 (95% CI=0.29, 0.97) versus 0.90 (95% CI=0.67, 1.21) and 0.83 (95% CI=0.51, 1.34) among participants with BMI >=30. CONCLUSIONS: A combination of modifiable lifestyle factors are associated with a lower risk of diabetes among AAs, particularly among those without obesity. PMID- 28818416 TI - Adolescent Sports Participation, E-cigarette Use, and Cigarette Smoking. AB - INTRODUCTION: Although sport participation among adolescents has been found to lower the risk of traditional cigarette smoking, no studies to date have assessed if this type of physical activity lowers the risk of e-cigarette use among adolescents. METHODS: National data from the 2014 and 2015 Monitoring the Future study of 12th-grade students were used and analyses were conducted in 2016. Measures for past 30-day e-cigarette use and traditional cigarette smoking were used to assess differences between adolescents who participated in at least one competitive sport during the past year and adolescents who did not. Differences in e-cigarette use and traditional cigarette smoking were assessed between 13 different sports to determine which sports were associated with a greater or lower risk of these behaviors. RESULTS: Adolescents who participated in at least one competitive sport were less likely to engage in past 30-day traditional cigarette smoking (AOR=0.73, 95% CI=0.538, 0.973) and past 30-day dual use of traditional cigarettes and e-cigarettes (AOR=0.66, 95% CI=0.438, 0.982) when compared with their nonparticipating peers. Adolescents who participated in baseball/softball and wrestling were at greatest risk of e-cigarette use. Of the 13 assessed sports, none were found to lower the odds of e-cigarette use. CONCLUSIONS: No significant evidence was found that participation in a sport was a protective factor against e-cigarette use. Certain types of athletes are at an elevated risk of e-cigarette use, and prevention efforts targeted at these specific sports should be considered by school administrators. PMID- 28818417 TI - Referral for Expert Physical Activity Counseling: A Pragmatic RCT. AB - INTRODUCTION: Primary care physicians are well placed to offer physical activity counseling, but insufficient time is a barrier. Referral to an exercise specialist is an alternative. In Australia, exercise specialists are publicly funded to provide face-to-face counseling to patients who have an existing chronic illness. This trial aimed to (1) determine the efficacy of primary care physicians' referral of insufficiently active patients for counseling to increase physical activity, compared with usual care, and (2) compare the efficacy of face to-face counseling with counseling predominantly via telephone. STUDY DESIGN: Three-arm pragmatic RCT. SETTING/PARTICIPANTS: Two hundred three insufficiently active (<7,000 steps/day) primary care practice patients (mean age 57 years; 70% female) recruited in New South Wales, Australia, in 2011-2014. INTERVENTION: (1) Five face-to-face counseling sessions by an exercise specialist, (2) one face-to face counseling session followed by four telephone calls by an exercise specialist, or (3) a generic mailed physical activity brochure (usual care). The counseling sessions operationalized social cognitive theory via a behavior change counseling framework. MAIN OUTCOME MEASURES: Change in average daily step counts between baseline and 12 months. Data were analyzed in 2016. RESULTS: Forty (20%) participants formally withdrew; completion rates at 3 and 6 months were 64% and 58%, respectively. Intervention attendance was high (75% received five sessions). The estimated mean difference between usual care and the combined intervention groups at 12 months was 1,002 steps/day (95% CI=244, 1,759, p=0.01). When comparing face-to-face with predominantly telephone counseling, the telephone group had a non-significant higher mean daily step count (by 619 steps) at 12 months. CONCLUSIONS: Provision of expert physical activity counseling to insufficiently active primary care patients resulted in a significant increase in physical activity (approximately 70 minutes of walking per week) at 12 months. Face-to-face only and counseling conducted predominantly via telephone were both effective. This trial provides evidence to expand public funding for expert physical activity counseling and for delivery via telephone in addition to face to-face consultations. TRIAL REGISTRATION: This trial is registered at www.anzctr.org.au/ ACTRN12611000884909. PMID- 28818418 TI - Case-Finding for Persistent Airway Obstruction in Farmers: A Questionnaire With Optimal Diagnosis Criteria. AB - INTRODUCTION: Appropriate identification of subjects who are candidates for spirometry through case-finding questionnaires may help solve the problem of chronic obstructive pulmonary disease misdiagnosis. The performance of case finding questionnaires depends at least partially on the characteristics of the population used for their development. The use of an accurate threshold for the forced expiratory volume in 1 second / forced vital capacity ratio to define persistent airway obstruction is also vital in ascertaining chronic obstructive pulmonary disease. METHODS: Using a population examined between October 2012 and May 2013 that included a large subset of agricultural workers both exposed and unexposed to tobacco smoking, the authors aimed to select a combination of items that would identify persons most likely to have persistent airway obstruction defined as forced expiratory volume in 1 second / forced vital capacity less than the lower limit of normal according to the Global Lung Initiative-2012 equations. Two thirds of the population (n=3,397) were randomly selected to develop a questionnaire, and one third (n=1,698) was reserved for questionnaire validation. Statistical analysis was performed in 2016. RESULTS: The selected items were sex, dyspnea, BMI, tobacco smoking habits, age, history of respiratory diseases, and history of occupation at risk. The C-index of the model was 0.84 (95% CI=0.80, 0.88) for the development population and 0.76 (95% CI=0.66, 0.86) for the validation population. Using the selected items in combination, the sensitivity and specificity in identifying persistent airway obstruction were 76% and 77%, respectively, in the development population (and 68% and 73%, respectively, in the validation population) for a threshold value of 2.50%. CONCLUSIONS: This seven-item questionnaire is the first developed from a population comprising a large subset of agricultural workers and using the Global Lung Initiative-2012 equations. PMID- 28818419 TI - A School-Based Brand Marketing Program's Adherence to Federal Nutrition Criteria. AB - INTRODUCTION: The Healthy, Hunger-Free Kids Act of 2010 gave the U.S. Department of Agriculture authority to regulate school wellness policies, which include nutritional standards for foods advertised in schools. Brand marketing programs, which encourage students to purchase a company's products in exchange for money or rewards, were not explicitly prohibited. This study assesses the nutritional quality of products participating in "Box Tops for Education" ("Box Tops"), one of the largest national brand marketing programs in schools. METHODS: Participating foods and beverages were obtained from the Box Tops product list and matched to nutrient information and ingredients from manufacturer websites in 2016 (N=949). Products were categorized as beverages (n=13); entrees (n=171); snacks (n=677); or fruits and vegetables exempt from the Smart Snacks in School Standards ("Smart Snacks" standards) (n=88) to assess the percentage that met the Smart Snacks standards. RESULTS: Of the foods participating in the Box Tops program, 69% of beverages, 26% of entrees, and 23% of snacks met the Smart Snacks standards. Most foods met the standards for trans fats (98%); calories (90%); and sugar (89%); but fewer met the requirements for sodium (60%). Noncompliant snacks contained more than twice the recommended sodium (mean=420 mg, SD=191 mg) and percent calories from saturated fat (mean=22%, SD=13%). CONCLUSIONS: Fewer than one third of Box Tops foods met the Smart Snacks standards. Schools should consider whether the benefit of participation outweighs the harm of exposing kids to unhealthful marketing. Alternatively, schools could opt not to participate unless companies limit redeemable products to household items or healthful options meeting the Smart Snacks standards. PMID- 28818421 TI - ErbB signaling antagonist ameliorates behavioral deficit induced by phencyclidine (PCP) in mice, without affecting metabolic syndrome markers. AB - Schizophrenia is a severe syndrome that affects about 1% of the world population. Since the mid-1950s, antipsychotics have been used to treat schizophrenia with preference for treating positive symptoms; however, their tolerance level is low, there are numerous side effects, and only some patients respond to the treatment. Antipsychotic medications that are more effective, better tolerated, and with fewer adverse effects are urgently needed. Given the accumulating evidence of the role filled by the ErbB signaling network in the biology of the dopamine, GABA, and glutamate systems, and in the etiology of schizophrenia, we hypothesized that the ErbB network is a candidate for development of a novel agent through which various symptoms of schizophrenia and other psychiatric disorders might be treated. Herein, we studied, in mice, the capability of blocking the ErbB signaling, in comparison with the atypical antipsychotic drug clozapine, to counter schizophrenia-like behavior induced by acute and sub-chronic phencyclidine (PCP), and determined whether inhibition of the ErbB networks induced weight gain and affected social and exploratory behavior, and metabolic syndrome markers. We demonstrated that administration of the pan-ErbB inhibitor JNJ28871063 (JNJ) reduced the level of activity in the open field induced by an acute injection of PCP. Moreover, the ability of JNJ to attenuate the effect of PCP is as effective as clozapine. In addition and like clozapine, JNJ normalized social behavior impairment induced by sub-chronic PCP and stress. Adult JNJ treated mice displayed normal sociability and exploratory behavior, and their serum cholesterol, LDL, and HDL levels were lower than in the saline-treated mice. Sub-chronic treatment did not affect weight gain, glucose levels, and the activity of hepatic enzymes catalase and SOD. These data suggest that treatment with JNJ attenuates abnormal behaviors induced by PCP, and has similar effects as the antipsychotic drug clozapine, with no adverse effects. Thus, the ErbB signaling can serve as a new starting point for non-dopaminergic-based drug development of schizophrenia. PMID- 28818420 TI - Predicting Sexual Assault Perpetration in the U.S. Army Using Administrative Data. AB - INTRODUCTION: The Department of Defense uses a universal prevention framework for sexual assault prevention, with each branch implementing its own branch-wide programs. Intensive interventions exist, but would be cost effective only if targeted at high-risk personnel. This study developed actuarial models to identify male U.S. Army soldiers at high risk of administratively recorded sexual assault perpetration. METHODS: This study investigated administratively recorded sexual assault perpetration among the 821,807 male Army soldiers serving 2004 2009. Administrative data were also used to operationalize the predictors. Penalized discrete-time (person-month) survival analysis (conducted in 2016) was used to select the smallest possible number of stable predictors to maximize number of sexual assaults among the 5% of soldiers with highest predicted risk of perpetration (top-ventile concentration of risk). Separate models were developed for assaults against non-family and intra-family adults and minors. RESULTS: There were 4,640 male soldiers found to be perpetrators against non-family adults, 1,384 against non-family minors, 380 against intra-family adults, and 335 against intra-family minors. Top-ventile concentration of risk was 16.2%-20.2% predicting perpetration against non-family adults and minors and 34.2%-65.1% against intra-family adults and minors. Final predictors consisted largely of measures of prior crime involvement and the presence and treatment of mental disorders. CONCLUSIONS: Administrative data can be used to develop actuarial models that identify a high proportion of sexual assault perpetrators. If a system is developed to consolidate administrative predictors routinely, then predictions could be generated periodically to identify those in need of preventive intervention. Whether this would be cost effective, though, would depend on intervention costs, effectiveness, and competing risks. PMID- 28818422 TI - Feasibility and Effects of a Physical Activity Program Using Gerontechnology in Assisted Living Communities for Older Adults. AB - BACKGROUND: The number of older adults residing in assisted living communities is increasing. Despite the benefits of physical activity (PA) on physical and cognitive capacities, and the opportunities for being active offered in these living environments, this population is highly sedentary and more at risk of physical decline. This study aimed to assess the feasibility, the acceptability, and the effects of PA intervention using gerontechnology in assisted living communities. METHODS: Forty-two older adults in 4 assisted living communities were recruited and randomly assigned to an exercise intervention group (EX) or a control group (CON) using a 2:1 ratio. The EX group followed a 12-week PA program (2 sessions per week) using gerontechnology. Body composition, health status, quality of life, and functional capacities were evaluated at baseline, 12 weeks, and 24 weeks after baseline. RESULTS: Differences between groups were observed in the number of reported comorbidities (EX: 3.1 +/- 1.6 vs CON: 5.0 +/- 1.8; P = .007), SF-36 total score (EX: 80% +/- 10% vs CON: 66% +/- 15%; P = .004), and Short Physical Performance Battery (SPPB) total score (EX: 9.1 +/- 1.8 vs CON: 7.5 +/- 1.4; P = .006) at baseline. The EX group completed 89% +/- 17% of the 24 prescribed sessions and realized 67% +/- 13% of them in autonomy, reaching a quality level of 87% +/- 6%. Of the EX participants, 93.8% enjoyed the exercises a lot or well, and 92.8% of them rated the exercises as being either easy or a little difficult. Changes between baseline and follow-up were statistically different between groups for walking speed (EX: +0.10 +/- 0.20 vs CON: -0.04 +/- 0.16 m/s; P = .04) and the SPPB score (EX: +1.1 +/- 2.0 vs CON: -0.4 +/- 1.6; P = .03). CONCLUSION: We found that PA intervention using gerontechnology in assisted living communities for older adults was feasible and acceptable, but more importantly induced improvement in functional capacities and walking speed, which is the main predictor of mortality in the elderly population. PMID- 28818423 TI - Design and synthesis of multiple antigenic peptides and their application for dengue diagnosis. AB - Major difficulty in development of dengue diagnostics is availability of suitable antigens. To overcome this, we made an attempt to develop a peptide based diagnosis which offers significant advantage over other methods. With the help of in silico methods, two epitopes were selected from envelope protein and three from NS1 protein of dengue virus. These were synthesized in combination as three multiple antigenic peptides (MAPs). We have tested 157 dengue positive sera confirmed for NS1 antigen. MAP1 showed 96.81% sera positive for IgM and 68.15% positive for IgG. MAP2 detected 94.90% IgM and 59.23% IgG positive sera. MAP3 also detected 96.17% IgM and 59.87% IgG positive sera. To the best of our knowledge this is the first study describing the use of synthetic multiple antigenic peptides for the diagnosis of dengue infection. This study describes MAPs as a promising tool for the use in serodiagnosis of dengue. PMID- 28818425 TI - The Hartford Consensus: Survey of the Public and Healthcare Professionals on Active Shooter Events in Hospitals. PMID- 28818424 TI - Interlaboratory study for the establishment of Brazilian Bothrops Reference Venom and Antivenom for potency evaluation of Bothrops antivenom. AB - A collaborative study was performed for the establishment of the 5th lot of Brazilian Bothrops Reference Venom and the 1st lot of Brazilian Bothrops Reference Antivenom. All Brazilian manufacturers of Antibothrops Immunoglobulins and the National Control Laboratory participated of the study. The declared potency of the 5th lot of the Bothrops Reference Venom is 40.29 MUg/0.5 ml, and the potency of the 1st lot of Bothrops Reference Antivenom is 6.51 mg/ml. For the potency evaluation of Bothrops Reference Venom the inter assay precision (gCV) was 3.25% in lab 01; 3.51% in INCQS; 4.71% in lab 03 and 25.11% in lab 02, and the inter laboratory precision was 13.76%. The intra assay precision of Bothrops Reference Antivenom determinations was 4.38% in INCQS; 8.47% in lab 02; 10.51% in lab 03 and 20.05% in lab 01. The inter assay precision was 3.51% in INCQS; 9.65% in lab 02; 18.03% in lab 01 and 20.23% in lab 03. The inter laboratory precision was 15.85%. Despite the high number of invalid results (55.6% for the pharmacopoeial method and 69.4% for the proposed method) the parallel line assay, have better inter laboratorial precision (gCV = 16.62%) than the pharmacopoeial potency assay (gCV = 38.28%). PMID- 28818426 TI - Investigation of the Escherichia coli membrane transporters involved in the secretion of d-lactate-based oligomers by loss-of-function screening. AB - d-Lactate (LA)-based oligomers (D-LAOs) are unusual oligoesters consisting of d LA and d-3-hydroxybutyrate that are produced and secreted by engineered Escherichia coli grown on glucose. The cells heterologously express LA polymerizing polyhydroxyalkanoate synthase and monomer-supplying enzymes. In this study, we attempted to identify the D-LAO secretion route in E. coli, which is thought to be mediated by intrinsic membrane proteins. To this end, a loss-of function screening of D-LAO secretion was carried out using 209 single-gene membrane protein deletants, which are involved in the transport of organic compounds. Among the deletants of the outer membrane-associated proteins, DeltaompF and DeltaompG exhibited diminished D-LAOs secretion and elevated intracellular D-LAO accumulation. When the ompF and ompG expression levels were down- and up-regulated with plasmids harboring these genes, the secreted amounts of the D-LAOs were changed in correspondence with their expression levels. These results suggest that porins mediate D-LAOs transport through the outer membrane. In particular, OmpF is likely to be the major porin involved in the spontaneous secretion of D-LAOs due to the high basal expression of ompF in the parental strain. Among the deletants of the inner membrane-associated proteins, the DeltamngA, DeltaargT, DeltamacA, DeltacitA and DeltacpxA strains were selected by the screening. These genes are also candidate transporters related to D-LAO secretion, suggesting the presence of multiple secretion routes across the inner membrane. To the best of our knowledge, this is the first report on the mechanism of the microbial secretion of oligoesters. PMID- 28818428 TI - Thromboembolism in Anaplastic Lymphoma Kinase-Rearranged Non-Small Cell Lung Cancer. PMID- 28818427 TI - Molecular cloning and functional characterization of NADPH-dependent cytochrome P450 reductase from the green microalga Botryococcus braunii, B race. AB - The green microalga Botryococcus braunii of the B race accumulates various lipophilic compounds containing a 10,11-oxidosqualene epoxide moiety in addition to large amounts of triterpene hydrocarbons. While 2,3-squalene epoxidases have already been isolated and characterized from the alga, the enzyme that catalyzes the 10,11-epoxidation of squalene has remained elusive. In order to obtain a molecular tool to explore a 10,11-squalene epoxidase, cDNA cloning of an NADPH dependent cytochrome P450 reductase (CPR) that is required by both squalene epoxidases and cytochrome P450 enzymes was carried out. The isolated cDNA contained an open reading frame (1998 bp) that encoded for a protein with 665 amino acid residues with a predicted molecular weight of 71.46 kDa and a theoretical pI of 5.49. Analysis of the deduced amino acid sequence revealed the presence of conserved motifs, including FMN, FAD, and NADPH binding domains, which are typical of other CPRs and necessary for enzyme activity. By truncation of the N-terminal transmembrane anchor and addition of a 6* His-tag, BbCPR was heterologously produced in Escherichia coli and purified by Ni-NTA affinity chromatography. The purified recombinant enzyme showed optimal reducing activity of cytochrome c at around a neutral pH at a temperature range of 30-37 degrees C. For steady state kinetic parameters, the recombinant enzyme had a km for cytochrome c and NADPH of 11.7+/-1.6 and 9.4+/-1.4 MUM, and a kcat for cytochrome c and NADPH of 2.78+/-0.09 and 3.66+/-0.11 MUmol/min/mg protein, respectively. This is the first study to perform the functional characterization of a CPR from eukaryotic microalgae. PMID- 28818429 TI - Exposure shapes the perception of affective touch. AB - Touch is a common occurrence in our lives, where affective and inter-personal aspects of touch are important for our well-being. We investigated whether touch exposure affects hedonic and discriminative aspects of tactile perception. The perceived pleasantness and intensity of gentle forearm stroking, over different velocities, was assessed in individuals reporting to seldom receive inter personal touch, and in controls who received touch often. The groups did not differ in their stroking intensity judgements, nor in tactile discrimination sensitivity; however, individuals with low touch exposure evaluated the pleasantness of touch differently. These individuals did not differentiate pleasantness over the stroking velocities in the same way as the control group. The pleasantness curve for the low touch exposure group was significantly flatter and they rated 3cm/s stroking as significantly less pleasant. Other physiological and questionnaire measures were obtained and the appreciation of touch from familiar persons was positively related to the pleasantness of touch in controls, but this was not found in low touch exposure individuals. This suggests that the association of human caresses from well-known individuals, with the pleasure derived, may depend on continued exposure to it. PMID- 28818430 TI - Analysis of genetic polymorphisms and mutations at 19 STR loci in Hebei Han population. PMID- 28818432 TI - Single-Color Digital PCR Provides High-Performance Detection of Cancer Mutations from Circulating DNA. AB - We describe a single-color digital PCR assay that detects and quantifies cancer mutations directly from circulating DNA collected from the plasma of cancer patients. This approach relies on a double-stranded DNA intercalator dye and paired allele-specific DNA primer sets to determine an absolute count of both the mutation and wild-type-bearing DNA molecules present in the sample. The cell-free DNA assay uses an input of 1 ng of nonamplified DNA, approximately 300 genome equivalents, and has a molecular limit of detection of three mutation DNA genome equivalent molecules per assay reaction. When using more genome equivalents as input, we demonstrated a sensitivity of 0.10% for detecting the BRAF V600E and KRAS G12D mutations. We developed several mutation assays specific to the cancer driver mutations of patients' tumors and detected these same mutations directly from the nonamplified, circulating cell-free DNA. This rapid and high-performance digital PCR assay can be configured to detect specific cancer mutations unique to an individual cancer, making it a potentially valuable method for patient specific longitudinal monitoring. PMID- 28818433 TI - Dose-ranging design and analysis methods to identify the minimum effective dose (MED). AB - In dose ranging clinical trials, it is critical to investigate the dose-response profile and to identify a minimum effective dose (MED) to guide the dose selection for phase 3 confirmatory trials. Traditional dose ranging trials focus on pairwise comparisons between placebo and each investigational dose, while in recent years MCP-Mod (Multiple Comparison Procedures & Modeling) arose and gained popularity in the design and analysis of dose ranging trials. Comprehensive comparison between MCP-Mod and other methods have been made on continuous variables assuming a normal distribution. In this article, we extend the comparison to binary/binomial response variables. Via simulation, the rate of correct and incorrect MED identification are compared for Dunnett's test, trend test and MCP-Mod for a variety of underlying dose response profiles including both monotone and non-monotone dose responses and are compared under a large number of trial design settings. The precision of MED estimation using MCP-Mod is also evaluated comparing the design options of more dose levels and smaller sample size per dose versus fewer dose levels and larger sample size per dose. PMID- 28818431 TI - Wearable technology for cardiology: An update and framework for the future. AB - The field of cardiology has long used wearable medical devices to monitor heart rate and rhythm. The past decade has seen the emergence of many new wearable devices, including several that have been widely adopted by both physicians and consumers. In this review, we discuss existing and forthcoming devices designed to measure activity, heart rate, heart rhythm, and thoracic fluid. We also offer several frameworks to classify and better understand wearable devices, such that we may weigh their potential benefit in improving healthcare with the many challenges that must be addressed to reap these benefits. PMID- 28818435 TI - A Parent Reveals the Biases That she Faced to get Care for her Daughter. AB - A poor, African-American mother describes the difficulties that she has in getting a comprehensive medical evaluation for her child in an Emergency Room. Eventually, she finds the care and the caring that she needs at a medical clinic in a community health center. PMID- 28818434 TI - Adjusting for covariates in evaluating markers for selecting treatment, with application to guiding chemotherapy for treating estrogen-receptor-positive, node positive breast cancer. AB - In many clinical contexts, biomarkers that predict treatment efficacy are highly sought after. Such treatment selection or predictive biomarkers have the potential to identify subgroups most likely to benefit from the treatment, and may therefore be used to improve clinical outcomes and reduce medical costs. A methodological challenge in evaluating these biomarkers is determining how to take into account other variables that predict clinical outcomes, or that influence the biomarker distribution, generically termed covariates. We distinguish between two questions that arise when evaluating markers in the context of covariates. First, what is the biomarker's added value for selecting treatment, over and above the covariates? Second, what is the marker's performance within covariate strata-does performance vary? We lay out statistical methodology for addressing each of these questions. We argue that the common approach of testing for the marker's statistical interaction with treatment, in the context of a multivariate model that includes the covariates as predictors, does not directly address either question. We illustrate the methodology in new analyses of the Oncotype DX Recurrence Score, a marker used to select adjuvant chemotherapy for the treatment of estrogen-receptor-positive breast cancer. PMID- 28818437 TI - Correction. PMID- 28818436 TI - Use of the Hemangioma Severity Scale to facilitate treatment decisions for infantile hemangiomas. AB - BACKGROUND: The Hemangioma Severity Scale (HSS) assesses the severity of an infantile hemangioma (IH). OBJECTIVE: First, to compare HSS scores between patients with IH for whom propranolol treatment was indicated at their first visit and those who were not treated. Second, to assess suitable cutoff values for the need for propranolol treatment. METHOD: All patients with IH who attended our tertiary referral center since 2008 and were 0 to 6 months of age at their first visit were included. They were divided into propranolol and no-propranolol groups on the basis of choice of treatment at their first visit. HSS scores were assessed, and median scores were compared. RESULTS: A total of 657 children (342 in the propranolol group) were included. The median HSS score (25th-75th percentile) in the propranolol group was 10 (range, 8-14) compared with 7 (range, 4-9) in the no-propranolol group (P < .001). Cutoff values of 6 or lower (no indication for treatment) and 11 or higher (indication for treatment) resulted in 94% sensitivity and 89% specificity, respectively. LIMITATIONS: HSS scoring was not completely blinded. CONCLUSION: The HSS with cutoff values of 6 or lower and 11 or higher could be used as a triage tool for propranolol treatment. Patient age, IH type, and parental preference may also contribute to treatment decisions. PMID- 28818438 TI - Cancer risks and survival in patients with multiple primary melanomas: Association with family history of melanoma and germline CDKN2A mutation status. AB - BACKGROUND: Worse outcomes have been noted in patients with multiple primary melanomas (MPMs) than in patients with single primary melanomas. OBJECTIVE: We investigated how family history of melanoma and germline CDKN2A mutation status of MPM patients affects risks of developing subsequent melanomas and other cancers and survival outcomes. METHODS: Comprehensive data on cancer diagnoses and deaths of MPM patients, their first-degree relatives, and matched controls were obtained through Swedish national health care and population registries. RESULTS: Familial MPM cases with germline CDKN2A mutations were youngest at the diagnosis of their second melanoma (median age 42 years) and had among the MPM cohorts the highest relative risks (RR) compared to controls of developing >2 melanomas (RR 238.4, 95% CI 74.8-759.9). CDKN2A mutated MPM cases and their first degree relatives were the only cohorts with increased risks of nonskin cancers compared to controls (RR 3.6, 95% CI 1.9-147.1 and RR 3.2, 95% CI 1.9-5.6, respectively). In addition, CDKN2A mutated MPM cases had worse survival compared with both cases with familial (HR 3.0, 95% CI 1.3-8.1) and sporadic wild-type MPM (HR 2.63, 95% CI 1.3-5.4). LIMITATIONS: Our study examined outcomes in subgroups of MPM patients, which affected the sample size of the study groups. CONCLUSION: This study demonstrates that CDKN2A mutation status and family history of melanoma significantly affects outcomes of MPM patients. PMID- 28818439 TI - Variations in risk of asthma and seasonal allergies between early- and late-onset pediatric atopic dermatitis: A cohort study. AB - BACKGROUND: Atopic dermatitis is associated with other allergic conditions, but variations in this "atopic march" are poorly understood. OBJECTIVE: To determine the impact of the age of atopic dermatitis onset on the risk for asthma and seasonal allergies. METHODS: A cohort study was performed using the Pediatric Eczema Elective Registry, which is an observational cohort of subjects with pediatric onset atopic dermatitis. RESULTS: In total, 3966 children were included, and 73% reported atopic dermatitis onset before age 2 years. At baseline, subjects with atopic dermatitis onset at ages 3 to 7 or 8 to 17 years had significantly lower rates of seasonal allergies and asthma than those with onset before age 2. During follow-up, the adjusted relative risks for incident seasonal allergies were 0.82 (95% confidence interval, 0.72-0.91) and 0.64 (95% CI confidence interval, 0.47-0.83) in the 3- to 7- and 8- to 17-years-old at onset groups compared with the age 2 years or younger at onset group. The adjusted risk for incident asthma was not significantly different between the older onset groups and the earliest onset group. LIMITATIONS: Misclassification bias may arise from using self-reported onset age data. CONCLUSIONS: The timing of atopic dermatitis onset may explain part of the variation in the atopic march. These findings may improve future risk stratification of patients for treatment. PMID- 28818440 TI - Re: Birth outcomes for Australian mother-infant pairs who received an influenza vaccine during pregnancy 2012-2014: The FluMum study. PMID- 28818441 TI - Birth outcomes for Australian mother-infant pairs who received an influenza vaccine during pregnancy 2012-2014: The FluMum study. PMID- 28818442 TI - MRI-based treatment planning and dose delivery verification for intraocular melanoma brachytherapy. AB - PURPOSE: Episcleral plaque brachytherapy (EPB) planning is conventionally based on approximations of the implant geometry with no volumetric imaging following plaque implantation. We have developed an MRI-based technique for EPB treatment planning and dose delivery verification based on the actual patient-specific geometry. METHODS AND MATERIALS: MR images of 6 patients, prescribed 85 Gy over 96 hours from Collaborative Ocular Melanoma Study-based EPB, were acquired before and after implantation. Preimplant and postimplant scans were used to generate "preplans" and "postplans", respectively. In the preplans, a digital plaque model was positioned relative to the tumor, sclera, and nerve. In the postplans, the same plaque model was positioned based on the imaged plaque. Plaque position, point doses, percentage of tumor volume receiving 85 Gy (V100), and dose to 100% of tumor volume (Dmin) were compared between preplans and postplans. All isodose plans were computed using TG-43 formalism with no heterogeneity corrections. RESULTS: Shifts and tilts of the plaque ranged from 1.4 to 8.6 mm and 1.0 to 3.8 mm, respectively. V100 was >=97% for 4 patients. Dmin for preplans and postplans ranged from 83 to 118 Gy and 45 to 110 Gy, respectively. Point doses for tumor apex and base were all found to decrease from the preimplant to the postimplant plan, with mean differences of 16.7 +/- 8.6% and 30.5 +/- 11.3%, respectively. CONCLUSIONS: By implementing MRI for EPB, we eliminate reliance on approximations of the eye and tumor shape and the assumption of idealized plaque placement. With MRI, one can perform preimplant as well as postimplant imaging, facilitating EPB treatment planning based on the actual patient-specific geometry and dose delivery verification based on the imaged plaque position. PMID- 28818444 TI - Influence of Tube Current Settings on Diagnostic Detection of Root Fractures Using Cone-beam Computed Tomography: An In Vitro Study. AB - INTRODUCTION: This study assessed the influence of tube current settings (milliamperes [mA]) on the diagnostic detection of root fractures (RFs) using cone-beam computed tomographic (CBCT) imaging. METHOD: Sixty-eight human anterior and posterior teeth were submitted to root canal preparation, and 34 root canals were filled. The teeth were divided into 2 groups: the control group and the fractured group. RFs were induced using a universal mechanical testing machine; afterward, the teeth were placed in a phantom. Images were acquired using a Scanora 3DX unit (Soredex, Tuusula, Finland) with 5 different mA settings: 4.0, 5.0, 6.3, 8.0, and 10.0. Two examiners (E1 and E2) classified the images according to a 5-point confidence scale. Intra- and interexaminer reproducibility was assessed using the kappa statistic; diagnostic performance was assessed using the area under the receiver operating characteristic curve (AUROC). RESULTS: Intra- and interexaminer reproducibility showed substantial (kappaE1 = 0.791 and kappaE2 = 0.695) and moderate (kappaE1 * E2 = 0.545) agreement, respectively. AUROC was significantly higher (P <= .0389) at 8.0 and 10.0 mA and showed no statistical difference between the 2 tube current settings. CONCLUSIONS: Tube current has a significant influence on the diagnostic detection of RFs in CBCT images. Despite the acceptable diagnosis of RFs using 4.0 and 5.0 mA, those settings had lower discrimination abilities when compared with settings of 8.0 and 10.0 mA. PMID- 28818443 TI - Types of External Root Resorption of Replanted Teeth: Analysis of the Clinical Aspects and of Interleukin-4 Gene Polymorphisms Involvement. AB - INTRODUCTION: The absence or presence of root resorption on the surface of a replanted tooth indicates an immune-inflammatory reaction. Recent research even suggests the participation of host predominant immunologic profile on types of resorptions detected on the root surface. Because interleukin 4 (IL-4) is an important anti-inflammatory cytokine, this study aimed to investigate the association of clinical variables and polymorphisms in IL4 with types of resorption of replanted teeth after 1 year of follow-up. METHODS: One hundred twenty-seven avulsed teeth that were replanted were selected. Periapical radiographs were taken after replantation and for 1 year to detect the types of root resorption. Real-time polymerase chain reaction was used to genotype IL4 polymorphisms. The chi2 and Z tests were performed to verify the association of clinical and genetic variables with the outcomes of replanted teeth (P < .05). RESULTS: An association was observed of extra-alveolar time, storage medium, and development of the root (P < .05), but not of IL4 polymorphisms, with the outcomes of replanted teeth (P > .05). CONCLUSIONS: Extraoral time, storage medium, and development of the root, but not IL4 polymorphisms, may influence the types of resorption of avulsed and replanted teeth in the first year after trauma. PMID- 28818445 TI - Editorial Special Issue on the Occasion of Prof. Dr. Alf Puhler's 75th birthday. PMID- 28818446 TI - Characterization of a highly selective inhibitor of the Aurora kinases. AB - Aurora kinases play an essential role in mitosis and cell cycle regulation. In recent years Aurora kinases have proved popular cancer targets and many inhibitors have been developed. The majority of these clinical candidates are multi-targeted, rendering them inappropriate as tools for studying Aurora kinase mediated signaling. Here we report discovery of a highly selective inhibitor of Aurora kinases A, B and C, with potent cellular activity and minimal off-target activity (PLK4). The X-ray co-crystal structure of Aurora A in complex with compound 2 is reported, and provides insights into the structural determinants of ligand binding and selectivity. PMID- 28818447 TI - On the synthesis of quinone-based BODIPY hybrids: New insights on antitumor activity and mechanism of action in cancer cells. AB - Fluorescent quinone-based BODIPY hybrids were synthesised and characterised by NMR analysis and mass spectrometry. We measured their cytotoxic activity against cancer and normal cell lines, performed mechanistic studies by lipid peroxidation and determination of reduced (GSH) and oxidized (GSSG) glutathione, and imaged their subcellular localisation by confocal microscopy. Cell imaging experiments indicated that nor-beta-lapachone-based BODIPY derivatives might preferentially localise in the lysosomes of cancer cells. These results assert the potential of hybrid quinone-BODIPY derivatives as promising prototypes in the search of new potent lapachone antitumor drugs. PMID- 28818448 TI - Elucidation of a carboxylate O-methyltransferase NcmP in nocamycin biosynthetic pathway. AB - Nocamycins belong to the tetramic acid family natural products and show potent antimicrobial activity. Recently, the biosynthetic gene cluster of nocamycin was identified from the rare actinomycete Saccharothrix syringae and an S adenosylmethionine (SAM) dependent methyltransferase gene NcmP was found to be located within the gene cluster. In this report, the methyltransferase gene NcmP was disrupted and a new nocamycin intermediate nocamycin E was isolated from the mutant strain. Meanwhile, NcmP was heterologously expressed in Escherichia coli BL21 (DE3) and biochemically characterized as a carboxylate O-methyltransferase in nocamycin biosynthetic pathway. Compared to nocamycin I, nocamycin E showed inferior antibacterial activity, indicating the methyl group is essential to antibacterial activity. PMID- 28818449 TI - Rational design, synthesis and preliminary antitumor activity evaluation of a chlorambucil derivative with potent DNA/HDAC dual-targeting inhibitory activity. AB - Histone deacetylases (HDACs) play a pivotal role not only in gene expression but also in DNA repair. Herein, we report the successful design, synthesis and evaluation of a chlorambucil derivative named vorambucil with a hydroxamic acid tail as a DNA/HDAC dual-targeting inhibitor. Vorambucil obtained both potent DNA and HDACs inhibitory activities. Molecular docking results supported the initial pharmacophoric hypothesis and rationalized the potent inhibitory activity of vorambucil against HDAC1, HDAC2 and HDAC6. Vorambucil showed potent antiproliferative activity against all the test four cancer cell lines with IC50 values of as low as 3.2-6.2MUM and exhibited 5.0-18.3-fold enhanced antiproliferative activity than chlorambucil. Vorambucil also significantly inhibits colony formation of A375 cancer cells. Further investigation showed that vorambucil remarkably induced apoptosis and arrested the cell cycle of A375 cells at G2/M phase. Vorambucil could be a promising candidate and a useful tool to elucidate the role of those DNA/HDAC dual-targeting inhibitors for cancer therapy. PMID- 28818450 TI - Development and delivery of a physiotherapist-led exercise intervention in a randomised controlled trial for subacromial impingement syndrome (the SUPPORT trial). AB - PURPOSE: This paper describes the development, content and delivery of a physiotherapist- led individualised, supervised and progressed exercise programme for use in a factorial randomised controlled trial testing treatments for subacromial impingement syndrome. METHODS: To develop the intervention, a survey of community physiotherapists and national guidelines provided the basis for a consensus workshop through which a protocol was developed for the SUPPORT trial physiotherapist-led exercise programme (SUPPORT: SUbacromial impingement syndrome and Pain: a randomised controlled trial Of exeRcise and injection). The protocol included three stages of exercise progression: (1) scapular stability and active exercise with no resistance (2) range of motion exercise with scapular control, isometrics and stretches, and (3) through range resistance exercise. A two day training programme was developed for physiotherapists which included the trial background, current evidence and strategies to improve exercise adherence. RESULTS: Twenty physiotherapists were trained to deliver the exercise intervention. In the SUPPORT trial, 128 participants were randomised to physiotherapist-led exercise. Ninety nine (81%) participants had their first physiotherapy session within 2 to 3 weeks and 71 (56%) received six to eight treatment sessions. Frequently-used exercises were: stage 1 scapular setting with glenohumeral joint (GHJ) flexion to 90 degrees , stage 2 GHJ medial rotation stretch, stage 3 scapular setting through lateral rotation, with resistance bands. CONCLUSION: We combined clinical and research expertise with national guidance in order to develop a physiotherapist-led, individualised, progressed and supervised exercise intervention for use within a randomised trial. The effectiveness of the intervention is being evaluated within the SUPPORT trial. Trial registration number ISRCTN 42399123. PMID- 28818451 TI - The association between displacement of sedentary time and chronic musculoskeletal pain: an isotemporal substitution analysis. AB - OBJECTIVES: Physical activity is an effective intervention for the prevention and management of chronic musculoskeletal pain (CMP). However, there is a lack of research to inform the intensity of physical activity that should be recommended. The aim of this study was to investigate the association between substituting 10minutes of sedentary time with either 10minutes of light physical activity (LPA) or moderate-to-vigorous physical activity (MVPA) and the CMP prevalence ratio. DESIGN: Secondary Analysis (November 2015) of data from the Health Survey for England (2008). PARTICIPANTS: 2313 adults (>=16years). MAIN OUTCOME MEASURES: Sedentary time, LPA and MVPA were measured using accelerometry. We used isotemporal models to quantify the prevalence ratio for CMP of replacing 10minutes of sedentary time with 10minutes of LPA or MVPA. RESULTS: The prevalence of CMP in this sample was 17%. The unadjusted prevalence ratio was 0.99 (95% CI: 0.97 to 1.01) for LPA and 0.76 (0.70 to 0.84) for MVPA. The fully adjusted prevalence ratio was 1.01 (95% CI: 0.99 to 1.02) for LPA and 0.89 (0.82 to 0.96) for MVPA. CONCLUSIONS: Substituting 10minutes of sedentary time with an equivalent period of LPA was not associated with a reduction in the prevalence ratio for CMP, whereas the equivalent replacement with MVPA showed a small protective relationship. Regarding CMP prevalence, physical activity intensity appears to be important, with MVPA rather than LPA showing a protective relationship. Prospective studies are needed to investigate causality. PMID- 28818452 TI - Letter to the Editor re 'Encouraging healthy spine habits to prevent low back pain in children: An observational study of adherence to exercise'. PMID- 28818453 TI - Two-locus clines on the real line with a step environment. AB - The shape of allele-frequency clines maintained by migration-selection balance depends not only on the properties of migration and selection, but also on the dominance relations among alleles and on linkage to other loci under selection. We investigate a two-locus model in which two diallelic, recombining loci are subject to selection caused by an abrupt environmental change. The habitat is one dimensional and unbounded, selection at each locus is modeled by step functions such that in one region one allele at each locus is advantageous and in the other deleterious. We admit an environmentally independent, intermediate degree of dominance at both loci, including complete dominance. First, we derive an explicit expression for the single-locus cline with dominance, thus generalizing classical results by Haldane (1948). We show that the slope of the cline in the center (at the step) or, equivalently, the width of the cline, is independent of the degree of dominance. Second, under the assumption of strong recombination relative to selection and migration, the first-order approximations of the allele frequency clines at each of the loci and of the linkage disequilibrium are derived. This may be interpreted as the quasi-linkage-equilibrium approximation of the two-locus cline. Explicit asymptotic expressions for the clines are deduced as x->+/-infinity. For equivalent loci, explicit expressions for the whole clines are derived. The influence of dominance and of linkage on the slope of the cline in the center and on a global measure of steepness are investigated. This global measure reflects the influence of dominance. Finally, the accuracy of the approximations and the dependence of the shape of the two-locus cline on the full range of recombination rates is explored by numerical integration of the underlying system of partial differential equations. PMID- 28818454 TI - The anti-tumor effect of intravesical administration of normal urothelial cells on bladder cancer. AB - BACKGROUND AIMS: Urothelial bladder cancer (UBC) is the second most common cancer of the genitourinary tract and for advanced forms of the disease it has a high mortality rate. There are no approved new molecularly targeted agents or chemotherapeutics for advanced UBC beyond cisplatin-based chemotherapy except the recently approved anti-programmed death ligand 1 (anti-PD-1/PD-L1) antibody. With complex genetic and epigenetic alterations in tumors, despite several druggable targets identified, to cure UBC is still a challenging unmet medical need. Like other cancers, UBC to the host body is considered as a wound, aging stem cell disease and immunosuppressive disorder. Therefore, we proposed a novel cellular approach to target the host body by intravesical instilling of normal urothelial cells that could repair the injury and reduce inflammation by activating body reparative capacity and because non-self cells are transplanted, host body immune responses could be induced in the tumor microenvironment of UBC to restrain and even eliminate tumor cells. METHODS: In this study, we isolated and expanded normal male murine urothelial cells and intravesically administered them into the bladders of female mice of two orthotopic bladder tumor models and one urothelial injury model. RESULTS: We showed that the instillation of normal urothelial cells containing stem/progenitor cell population into bladders could have anti-tumor effect in orthotopic tumor models, possibly by activating immune responses and helping injured urothelium tissue recovery in a chemically induced urothelial injury model. CONCLUSIONS: Our findings could lead to an innovative and revolutionary cell therapy modality with normal urothelial cells as an effective and safe therapeutic option for UBC. PMID- 28818455 TI - Adipose-derived stromal cells enhance auditory neuron survival in an animal model of sensory hearing loss. AB - BACKGROUND: A cochlear implant (CI) is an electronic prosthesis that can partially restore speech perception capabilities. Optimum information transfer from the cochlea to the central auditory system requires a proper functioning auditory nerve (AN) that is electrically stimulated by the device. In deafness, the lack of neurotrophic support, normally provided by the sensory cells of the inner ear, however, leads to gradual degeneration of auditory neurons with undesirable consequences for CI performance. METHODS: We evaluated the potential of adipose-derived stromal cells (ASCs) that are known to produce neurotrophic factors to prevent neural degeneration in sensory hearing loss. For this, co cultures of ASCs with auditory neurons have been studied, and autologous ASC transplantation has been performed in a guinea pig model of gentamicin-induced sensory hearing loss. RESULTS: In vitro ASCs were neuroprotective and considerably increased the neuritogenesis of auditory neurons. In vivo transplantation of ASCs into the scala tympani resulted in an enhanced survival of auditory neurons. Specifically, peripheral AN processes that are assumed to be the optimal activation site for CI stimulation and that are particularly vulnerable to hair cell loss showed a significantly higher survival rate in ASC treated ears. DISCUSSION/CONCLUSION: ASC transplantation into the inner ear may restore neurotrophic support in sensory hearing loss and may help to improve CI performance by enhanced AN survival. PMID- 28818456 TI - Response to the Letter to the Editor-Fresnel Prism Intraocular Lens and Scharioth Macula Lens. PMID- 28818457 TI - Relationship between sleep duration and childhood obesity: Systematic review including the potential underlying mechanisms. AB - AIM: The prevalence of obesity is continually increasing worldwide. Determining risk factors for obesity may facilitate effective preventive programs. The present review focuses on sleep duration as a potential risk factor for childhood obesity. The aim is to summarize the evidence on the association of sleep duration and obesity and to discuss the underlying potential physiological and/or pathophysiological mechanisms. DATA SYNTHESIS: The Ovid MEDLINE, Scopus and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for papers using text words with appropriate truncation and relevant indexing terms. All studies objectively measuring sleep duration and investigating the association between sleep duration and obesity or factors (lifestyle and hormonal) possibly associated with obesity were included, without making restrictions based on study design or language. Data from eligible studies were extracted in tabular form and summarized narratively. After removing duplicates, 3540 articles were obtained. Finally, 33 studies (including 3 randomized controlled trials and 30 observational studies) were included in the review. CONCLUSION: Sleep duration seems to influence weight gain in children, however, the underlying explanatory mechanisms are still uncertain. In our review only the link between short sleep duration and the development of insulin resistance, sedentarism and unhealthy dietary patterns could be verified, while the role of other mediators, such as physical activity, screen time, change in ghrelin and leptin levels, remained uncertain. There are numerous evidence gaps. To answer the remaining questions, there is a need for studies meeting high methodological standards and including a large number of children. PMID- 28818458 TI - Colonic delivery of indometacin loaded PGA-co-PDL microparticles coated with Eudragit L100-55 from fast disintegrating tablets. AB - The aim of this work was to investigate the efficient targeting and delivery of indometacin (IND), as a model anti-inflammatory drug to the colon for treatment of inflammatory bowel disease. We prepared fast disintegrating tablets (FDT) containing IND encapsulated within poly(glycerol-adipate-co-omega pentadecalactone), PGA-co-PDL, microparticles and coated with Eudragit L100-55 at different ratios (1:1.5, 1:1, 1:0.5). Microparticles encapsulated with IND were prepared using an o/w single emulsion solvent evaporation technique and coated with Eudragit L-100-55 via spray drying. The produced coated microparticles (PGA co-PDL-IND/Eudragit) were formulated into optimised FTD using a single station press. The loading, in vitro release, permeability and transport of IND from PGA co-PDL-IND/Eudragit microparticles was studied in Caco-2 cell lines. IND was efficiently encapsulated (570.15+/-4.2MUg/mg) within the PGA-co-PDL microparticles. In vitro release of PGA-co-PDL-IND/Eudragit microparticles (1:1.5) showed significantly (p<0.05, ANOVA/Tukey) lower release of IND 13.70+/ 1.6 and 56.46+/-3.8% compared with 1:1 (89.61+/-2.5, 80.13+/-2.6%) and 1:0.5 (39.46+/-0.9 & 43.38+/-3.12) after 3 and 43h at pH 5.5 and 6.8, respectively. The permeability and transport studies indicated IND released from PGA-co-PDL IND/Eudragit microparticles had a lower permeability coefficient of 13.95+/ 0.68*10-6cm/s compared to free IND 23.06+/-3.56*10-6cm/s. These results indicate the possibility of targeting anti-inflammatory drugs to the colon using FDTs containing microparticles coated with Eudragit. PMID- 28818459 TI - A novel delocalized lipophilic cation-chlorambucil conjugate inhibits P glycoprotein in HepG2/ADM cells. AB - Multidrug resistance (MDR) limits the application of a large number of cancer fighting agents in clinical therapy. One reason is that P-glycoprotein (Pgp) efflux pumps are usually overexpressed and lead to drug efflux in the cancer cells, which limits the viability of many chemotherapeutics. Current available inhibitors which block the Pgp pump efflux are usually not widely used in clinical practice, because they change other drug pharmacokinetic profiles or increase side effects. Here, through covalent linkage of cancer-targeting delocalized lipophilic cation FF and DNA-damaging drug nitrogen mustard chlorambucil (CLB), we rationally designed and synthesized a tumor-targeting anticancer agent FFCLB. And we found and proved that the FFCLB was capable of reducing the outflow of Pgp substrates efficiently. This conjugate selectively improves adriamycin uptake and toxicity through reducing MDR1 mRNA and Pgp protein expression. Based on molecular targeted strategy, this study can facilitate the discovery of superior MDR reducing agents to provide a more effective and safer way of resensitizing MDR. PMID- 28818460 TI - The design and synthesis of a novel compound of berberine and baicalein that inhibits the efficacy of lipid accumulation in 3T3-L1 adipocytes. AB - The combination of berberine and baicalein may have a better therapeutic effect against disease. To explore the combined effect of baicalein and berberine in the treatment of obesity, we designed and synthesized a hybrid compound, and its biological activities were evaluated in 3T3-L1 adipocytes. The structures of the berberine-baicalein (BBS) compounds were confirmed by 1H NMR, 13C NMR, ultraviolet spectroscopy and high resolution mass spectrometry (HRMS). The present study showed that the IC50 values of the inhibitory effects of baicalein, berberine and BBS against 3T3-L1 cells were 29.81+/-0.90, 21.84+/-1.67 and 9.42+/ 0.60uM, respectively. The expression of mRNAs related to lipolysis and lipogenesis were examined by quantitative real-time PCR. The results showed that BBS could up-regulate the expression of the Atgl gene and down-regulate the mRNA expression of Srebp-1c, Fasn, Scd1, and Acc in 3T3-L1 adipocytes. These results indicate that BBS may have a stronger effect than baicalein and berberine on the viability of 3T3-L1 preadipocytes. In addition, BBS may have therapeutic effects and pharmacological activities against obesity. This "medicine couple" may be beneficial for studies of traditional Chinese medicine. PMID- 28818461 TI - Discovery and process development of a novel TACE inhibitor for the topical treatment of psoriasis. AB - Targeting the TNFalpha pathway is a validated approach to the treatment of psoriasis. In this pathway, TACE stands out as a druggable target and has been the focus of in-house research programs. In this article, we present the discovery of clinical candidate 26a. Starting from hits plagued with poor solubility or genotoxicity, 26a was identified through thorough multiparameter optimisation. Showing robust in vivo activity in an oxazolone-mediated inflammation model, the compound was selected for development. Following a polymorph screen, the hydrochloride salt was selected and the synthesis was efficiently developed to yield the API in 47% overall yield. PMID- 28818462 TI - Discovery of non-zwitterionic aryl sulfonamides as Nav1.7 inhibitors with efficacy in preclinical behavioral models and translational measures of nociceptive neuron activation. AB - Since zwitterionic benzenesulfonamide Nav1.7 inhibitors suffer from poor membrane permeability, we sought to eliminate this characteristic by replacing the basic moiety with non-basic bicyclic acetals and monocyclic ethers. These efforts led to the discovery of the non-zwitterionic aryl sulfonamide 49 as a selective Nav1.7 inhibitor with improved membrane permeability. Despite its moderate cellular activity, 49 exhibited robust efficacy in mouse models of neuropathic and inflammatory pain and modulated translational electromyogram measures associated with activation of nociceptive neurons. PMID- 28818463 TI - Ribosomally-synthesised cyclic peptides from plants as drug leads and pharmaceutical scaffolds. AB - Owing to their exceptional stability and favourable pharmacokinetic properties, plant-derived cyclic peptides have recently attracted significant attention in the field of peptide-based drug design. This article describes the three major classes of ribosomally-synthesised plant peptides - the cyclotides, the PawS derived peptides and the orbitides - and reviews their applications as leads or scaffolds in drug design. These ribosomally-produced peptides have a range of biological activities, including anti-HIV, cytotoxic and immunomodulatory activity. In addition, recent interest has focused on their use as scaffolds to stabilise bioactive peptide sequences, thereby enhancing their biopharmaceutical properties. There are now more than 30 published papers on such 'grafting' applications, most of which have been reported only in the last few years, and several such studies have reported in vivo activity of orally delivered cyclic peptides. In this article, we describe approaches to the synthesis of cyclic peptides and their pharmaceutically-grafted derivatives as well as outlining their biosynthetic routes. Finally, we describe possible bioproduction routes for pharmaceutically active cyclic peptides, involving plants and plant suspension cultures. PMID- 28818464 TI - One-pot synthesis of bioactive cyclopentenones from alpha-linolenic acid and docosahexaenoic acid. AB - Oxidation products of the poly-unsaturated fatty acids (PUFAs) arachidonic acid, alpha-linolenic acid and docosahexaenoic acid are bioactive in plants and animals as shown for the cyclopentenones prostaglandin 15d-PGJ2 and PGA2, cis-(+)-12 oxophytodienoic acid (12-OPDA), and 14-A-4 neuroprostane. In this study an inexpensive and simple enzymatic multi-step one-pot synthesis is presented for 12 OPDA, which is derived from alpha-linolenic acid, and the analogous docosahexaenoic acid (DHA)-derived cyclopentenone [(4Z,7Z,10Z)-12-[[-(1S,5S)-4 oxo-5-(2Z)-pent-2-en-1yl]-cyclopent-2-en-1yl] dodeca-4,7,10-trienoic acid, OCPD]. The three enzymes utilized in this multi-step cascade were crude soybean lipoxygenase or a recombinant lipoxygenase, allene oxide synthase and allene oxide cyclase from Arabidopsis thaliana. The DHA-derived 12-OPDA analog OCPD is predicted to have medicinal potential and signaling properties in planta. With OCPD in hand, it is shown that this compound interacts with chloroplast cyclophilin 20-3 and can be metabolized by 12-oxophytodienoic acid reductase (OPR3) which is an enzyme relevant for substrate bioactivity modulation in planta. PMID- 28818465 TI - Girdin protein expression is associated with poor prognosis in patients with invasive breast cancer. AB - Girdin is an actin-binding Akt substrate that is an integral component of the PI3K/Akt signalling pathway. However, the clinicopathological significance of Girdin expression in breast cancer has not been clarified. The purpose of this study was to characterise the clinicopathological implication of Girdin expression in breast cancer. Immunohistochemistry-based protein expression analyses of 892 human breast cancer tissues showed that Girdin was expressed in 289 (32.4%) cases. Girdin expression was significantly associated with larger tumour size, frequent lymph node invasion, advanced cancer stage, and expression of oestrogen and progesterone receptors. Patients who had breast cancer with Girdin expression experienced significantly poorer overall survival (OS) (p=0.021) and disease-free survival (DFS) (p=0.002) than those without Girdin expression. In subtype analyses, Girdin expression was significantly correlated with poorer OS and DFS in HER2 subtype (p=0.004 and p=0.034, respectively). In triple negative breast cancer (TNBC) subtype, Girdin expression was significantly correlated with poorer DFS (p=0.035), and there was a trend toward poorer OS (p=0.060) in TNBC patients with Girdin expression. Multivariate analysis revealed that Girdin expression was an independent prognostic factor for OS (p=0.022) and DFS (p=0.030) in patients with breast cancer. In HER2 subtype under multivariate analysis, Girdin expression retained its role as an independent prognostic predictor for worse OS (p=0.023), and there was a trend toward poorer DFS (p=0.086) in patients with HER2 subtype expressing Girdin. Girdin expression may serve as a useful prognostic factor for invasive breast cancer, especially for the HER2 subtype. PMID- 28818466 TI - Sink or swim? Vertical movement and nutrient storage in phytoplankton. AB - A simulation model of vertically migrating phytoplankton is presented, using a Lagrangian, individual-based computational approach. Algal cells acquire and store nutrient at the bottom of the habitat, using stored nutrient to grow while in shallower waters. Stored nutrient also governs movement: cells sink when their nutrient quota falls below a threshold; otherwise they rise (or at least sink more slowly). Although the bottom of the habitat provides the growth-limiting nutrient, it also entails a risk of mortality. For a parameter set representing phosphorus-limited algae with a fixed nutrient storage capacity, neither continual sinking nor continual rising are optimal strategies. Instead, an adaptive dynamics approach suggests there is an optimal movement strategy in which cells rise when their storage capacity is partially filled, and otherwise sink. When the movement strategy is fixed in such a way and storage capacity is free to evolve, storage capacity approaches an optimal value several times higher than the minimal quota permitting population growth. Vertical movement and nutrient storage affect the vertical distribution of total nutrient. When cells always sink, total nutrient declines exponentially from the nutrient source at the bottom to a surface minimum. When cells always rise, there is a peak of total nutrient at the bottom, and another at the surface, with a minimum between. When cells move optimally, the vertical distribution of total nutrient can be close to uniform, or have a peak at mid-depth. PMID- 28818467 TI - Mathematical modelling and analysis of the brassinosteroid and gibberellin signalling pathways and their interactions. AB - The plant hormones brassinosteroid (BR) and gibberellin (GA) have important roles in a wide range of processes involved in plant growth and development. In this paper we derive and analyse new mathematical models for the BR signalling pathway and for the crosstalk between the BR and GA signalling pathways. To analyse the effects of spatial heterogeneity of the signalling processes, along with spatially-homogeneous ODE models we derive coupled PDE-ODE systems modelling the temporal and spatial dynamics of molecules involved in the signalling pathways. The values of the parameters in the model for the BR signalling pathway are determined using experimental data on the gene expression of BR biosynthetic enzymes. The stability of steady state solutions of our mathematical model, shown for a wide range of parameters, can be related to the BR homeostasis which is essential for proper function of plant cells. Solutions of the mathematical model for the BR signalling pathway can exhibit oscillatory behaviour only for relatively large values of parameters associated with transcription factor brassinazole-resistant1's (BZR) phosphorylation state, suggesting that this process may be important in governing the stability of signalling processes. Comparison between ODE and PDE-ODE models demonstrates distinct spatial distribution in the level of BR in the cell cytoplasm, however the spatial heterogeneity has significant effect on the dynamics of the averaged solutions only in the case when we have oscillations in solutions for at least one of the models, i.e. for possibly biologically not relevant parameter values. Our results for the crosstalk model suggest that the interaction between transcription factors BZR and DELLA exerts more influence on the dynamics of the signalling pathways than BZR-mediated biosynthesis of GA, suggesting that the interaction between transcription factors may constitute the principal mechanism of the crosstalk between the BR and GA signalling pathways. In general, perturbations in the GA signalling pathway have larger effects on the dynamics of components of the BR signalling pathway than perturbations in the BR signalling pathway on the dynamics of the GA pathway. The perturbation in the crosstalk mechanism also has a larger effect on the dynamics of the BR pathway than of the GA pathway. Large changes in the dynamics of the GA signalling processes can be observed only in the case where there are disturbances in both the BR signalling pathway and the crosstalk mechanism. Those results highlight the robustness of the GA signalling pathway. PMID- 28818468 TI - Prediction of interface residue based on the features of residue interaction network. AB - Protein-protein interaction plays a crucial role in the cellular biological processes. Interface prediction can improve our understanding of the molecular mechanisms of the related processes and functions. In this work, we propose a classification method to recognize the interface residue based on the features of a weighted residue interaction network. The random forest algorithm is used for the prediction and 16 network parameters and the B-factor are acting as the element of the input feature vector. Compared with other similar work, the method is feasible and effective. The relative importance of these features also be analyzed to identify the key feature for the prediction. Some biological meaning of the important feature is explained. The results of this work can be used for the related work about the structure-function relationship analysis via a residue interaction network model. PMID- 28818469 TI - Vaccine epidemiology: Its role in promoting sound immunization programs in Japan. AB - In Japan, the Vaccine Epidemiology Research Group created by the Ministry of Health, Labour and Welfare has played an important role in demonstrating the solid scientific basis for vaccine efficacy and safety since 2002. Members of the group, including epidemiologists, clinicians and microbiologists, have been conducting collaborative studies on vaccines for influenza, pertussis, rotavirus gastroenteritis, polio and pneumonia. So far, the group has achieved several works and contributed to the national vaccination program, including research on the immunogenicity of low doses of influenza vaccine among young children, the immunogenicity and effectiveness of the 2009 influenza pandemic vaccine among various risk groups, the interchangeability of live/inactivated polio vaccines, the health impact of influenza on pregnant women, and the monitoring of influenza vaccine effectiveness using case-control studies with a test-negative design. As part of the 18th Annual Meeting of the Japanese Society of Vaccinology, these accomplishments were featured in the Vaccine Epidemiology Symposium. This report summarizes the recent epidemiological studies on vaccine in Japan as a prologue to the next six papers collected from the symposium. PMID- 28818470 TI - Basic principle of population-based cohort study to evaluate influenza vaccine effectiveness among elderly Japanese. AB - Influenza vaccines minimize the risk of influenza-related morbidity, complication, and death in elderly people. Although evaluating vaccine effectiveness (VE) is important for promoting immunization programs and coping with influenza epidemics, it is difficult to evaluate its effectiveness in Japan, where no frameworks to use large databases, such as a vaccination registry and health maintenance organization datasets, are available. Therefore, another analytic epidemiological investigations to evaluate VE in Japan are required. Herein, we describe the basic principles of a cohort study, which might be the most comprehensive, but expensive, study design. It is particularly important to be aware of the potential bias and confounding factors that should be minimized in the study design and analysis. We focus on "laboratory-confirmed influenza" and "influenza-like illness", and discuss why it is important to follow up with equal intensity, and how to control for bias; problems that often arise in population-based observational cohort studies. PMID- 28818471 TI - Basic principles of test-negative design in evaluating influenza vaccine effectiveness. AB - Based on the unique characteristics of influenza, the concept of "monitoring" influenza vaccine effectiveness (VE) across the seasons using the same observational study design has been developed. In recent years, there has been a growing number of influenza VE reports using the test-negative design, which can minimize both misclassification of diseases and confounding by health care seeking behavior. Although the test-negative designs offer considerable advantages, there are some concerns that widespread use of the test-negative design without knowledge of the basic principles of epidemiology could produce invalid findings. In this article, we briefly review the basic concepts of the test-negative design with respect to classic study design such as cohort studies or case-control studies. We also mention selection bias, which may be of concern in some countries where rapid diagnostic testing is frequently used in routine clinical practices, as in Japan. PMID- 28818472 TI - Control selection and confounding factors: A lesson from a Japanese case-control study to examine acellular pertussis vaccine effectiveness. AB - When using a case-control study design to examine vaccine effectiveness, both the selection of control subjects and the consideration of potential confounders must be the important issues to ensure accurate results. In this report, we described our experience from a case-control study conducted to evaluate the effectiveness of acellular pertussis vaccine combined with diphtheria-tetanus toxoids (DTaP vaccine). Newly diagnosed pertussis cases and age- and sex-matched friend controls were enrolled, and the history of DTaP vaccination was compared between groups. Logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) of vaccination for development of pertussis. After adjustment for potential confounders, four doses of DTaP vaccination showed a lower OR for pediatrician-diagnosed pertussis (OR=0.11, 95% CI, 0.01-0.99). In addition, the decreasing OR of four doses vaccination was more pronounced for laboratory-confirmed pertussis (OR=0.07, 95%CI, 0.01-0.82). Besides, positive association with pertussis was observed in subjects with a history of steroid treatment (OR=5.67) and those with a recent contact with a lasting cough (OR=4.12). When using a case-control study to evaluate the effectiveness of vaccines, particularly those for uncommon infectious diseases such as pertussis, the use of friend-controls may be optimal due to the fact that they shared a similar experience for exposure to the pathogen as the cases. In addition, to assess vaccine effectiveness as accurately as possible, the effects of confounding should be adequately controlled with a matching or analysis technique. PMID- 28818473 TI - Effectiveness of 23-valent pneumococcal polysaccharide vaccine and seasonal influenza vaccine for pneumonia among the elderly - Selection of controls in a case-control study. AB - We conducted a case-control study to elucidate associations between pneumonia in elderly individuals and 23-valent pneumococcal polysaccharide vaccine (PPSV23) and seasonal influenza vaccine (influenza vaccine). Here, we examined selection of controls in our study using an analytic epidemiology approach. The study period was from October 1, 2009 through September 30, 2014. Cases comprised >=65 year-old patients newly diagnosed with pneumonia. For every case with pneumonia, two patients with other diseases (one respiratory medicine, one non-respiratory medicine) who were sex-, age-, visit date- and visit hospital-matched were selected as controls. Odds ratios (ORs) and 95% confidence intervals (CIs) of vaccination for pneumonia were calculated using conditional logistic regression model. Similar analyses were also conducted based on the clinical department of controls. Analysis was conducted in 234 cases and 438 controls. Effectiveness of pneumococcal vaccination or influenza vaccination against pneumonia was not detected. Proportions of either vaccination in controls were greater among respiratory medicine (pneumococcal vaccine, 38%; influenza vaccine, 55%) than among non-respiratory medicine (23%; 48%). Analysis using controls restricted to respiratory medicine showed marginally significant effectiveness of pneumococcal vaccination (OR, 0.59; 95%CI, 0.34-1.03; P=0.064) and influenza vaccination (0.64; 0.40-1.04; 0.072). However, this effectiveness might have been overestimated by selection bias of controls, as pneumonia cases are not necessarily respiratory medicine patients. In the analysis using controls restricted to non-respiratory medicine, OR of pneumococcal vaccination for pneumonia was close to 1, presumably because the proportion of pneumococcal vaccination was higher in cases than in controls. Because pneumococcal vaccine was not routinely administered during the study period, differences in recommendations of vaccination by physician in different clinical departments might have greatly affected vaccination proportions. When we select controls, we should consider the background factors (underlying diseases, clinical department, etc.) which affect physicians' recommendation of vaccination. PMID- 28818474 TI - Estimating influenza disease burden among pregnant women: Application of self control method. AB - To evaluate influenza disease burden among pregnant women, an epidemiological study using the self-control method was conducted. Study subjects were 12,838 pregnant women who visited collaborating maternity hospitals and clinics in Osaka Prefecture, Japan, before the 2013/14 influenza season. As a study outcome, hospitalization due to respiratory illnesses between the 2010/11 and 2013/14 seasons was collected from each study subject through a baseline survey at the time of recruitment and a second survey after the 2013/14 season. The hospitalization rates during pregnancy and non-pregnancy periods was calculated separately. To compare the hospitalization rate during pregnancy with that during non-pregnancy within the same single study subject, Mantel-Haenzel rate ratios (RRMH) were calculated. During the four seasons examined in this study, nine and 17 subjects were hospitalized due to respiratory illnesses during pregnancy and non-pregnancy periods, respectively. The hospitalization rate was 2.54 per 10,000 woman-months during pregnancy and 1.08 per 10,000 woman-months during non pregnancy. The RRMH for the hospitalization rate during pregnancy compared with that during non-pregnancy was 4.30 (95% confidence interval, 1.96-9.41). Our results suggest that during the influenza season, pregnant women have a higher risk than non-pregnant women for hospitalization due to respiratory illnesses. The self-control method appears to be an appropriate epidemiological method for evaluating the disease burden of influenza among pregnant women. PMID- 28818475 TI - Oseltamivir use and severe abnormal behavior in Japanese children and adolescents with influenza: Is a self-controlled case series study applicable? AB - OBJECTIVE: Since the 1990s, self-controlled designs including self-controlled case series (SCCS) studies have been occasionally used in post-marketing evaluation of drug or vaccine safety. An SCCS study was tentatively applied to evaluate the relationship between oseltamivir use and abnormal behavior Type A (serious abnormal behavior potentially leading to an accident or harm to another person) in influenza patients. METHODS: From the original prospective cohort study with approximately 10,000 Japanese children and adolescents with influenza (aged <18years), 28 subjects (mean age: 7.3years) who developed abnormal behavior Type A after the first visit to the collaborating hospitals/clinics were analyzed. We hypothesized four combination patterns of the effect period (i.e., the period that effect of oseltamivir on occurrence of abnormal behavior Type A is likely) and the control period. Mantel-Haenszel rate ratio (M-H RR) and its 95% confidence interval (CI) were calculated as the relative risk estimate. RESULTS: Among 28 subjects in the SCCS study, 24 subjects (86%) were administered oseltamivir and 4 subjects (14%) were not. Abnormal behavior Type A was more likely to occur in the effect period than the control period in every pattern (M H RR: 1.90-29.1). We observed the highest estimate when the effect period was set between the initial intake of oseltamivir and Tmax (M-H RR: 29.1, 95% CI: 4.21 201). CONCLUSION: Abnormal behavior Type A was more likely to develop up to approximately 30 times during the period between the initial intake of oseltamivir and Tmax. However, this period overlapped with the early period of influenza where high fever was observed. Since useful approaches to control the influence of the natural disease course of influenza were not available in this study, we could not deny the possibility that abnormal behavior was induced by influenza itself. The SCCS study was not an optimal method to evaluate the relationship between oseltamivir use and abnormal behavior. PMID- 28818476 TI - Complex Anatomic Abnormalities of the Lower Leg Muscles and Tendons Associated With Phocomelia: A Case Report. AB - Musculoskeletal anatomy is widely known to have components that stray from the norm in the form of variant muscle and tendon presence, absence, origin, insertion, and bifurcation. Although these variant muscles and tendons might be deemed incidental and insignificant findings by most, they can be important contributors to pathologic physiology or, more importantly, an option for effective treatment. In the present case report, we describe a patient with phocomelia and Mullerian abnormalities secondary to in utero thalidomide exposure. The patient had experienced recurrent bilateral foot pain accompanied by numbness, stiffness, swelling, and longstanding pes planus. These symptoms persisted despite conservative treatment with orthotics, steroids, and nonsteroidal anti-inflammatory drugs. Radiographic imaging showed dysmorphic and degenerative changes of the ankle and foot joints. Further investigation with magnetic resonance imaging revealed complex anatomic abnormalities, including the absence of the posterior tibialis and peroneus brevis, lateralization of the peroneus longus, and the presence of a variant anterior compartment muscle. The variant structure was likely a previously described anterior compartment variant, anterior fibulocalcaneus, and might have been a source of the recurrent pain. Also, the absence of the posterior tibialis might have caused the pes planus in the present patient, considering that posterior tibialis tendon dysfunction is the most common cause of acquired pes planus. Although thalidomide infrequently affects the lower extremities, its effects on growth and development were likely the cause of this rare array of anatomic abnormalities and resulting ankle and foot pathologic features. PMID- 28818477 TI - Human imprinting disorders: Principles, practice, problems and progress. AB - Epigenetic regulation orchestrates gene expression with exquisite precision, over a huge dynamic range and across developmental space and time, permitting genomically-homogeneous humans to develop and adapt to their surroundings. Every generation, these epigenetic marks are re-set twice: in the germline, to enable differentiation of sperm and eggs, and at fertilisation, to create the totipotent zygote that then begins growth and differentiation into a new human. A small group of genes evades the second, zygotic wave of epigenetic reprogramming, and these genes retain an epigenetic 'imprint' of the parent from whom they were inherited. Imprinted genes are (as a general rule) expressed from one parental allele only. Some imprinted genes are critical regulators of growth and development, and thus disruption of their normal monoallelic expression causes congenital imprinting disorders, with clinical features impacting growth, development, behaviour and metabolism. Imprinting disorders as a group have characteristics that challenge diagnosis and management, including clinical and molecular heterogeneity, overlapping clinical features, somatic mosaicism, and multi-locus involvement. New insights into the biology and epigenomics of the early embryo offers new clues about the origin and importance of imprinting disorders. PMID- 28818478 TI - Mutations in DDHD1, encoding a phospholipase A1, is a novel cause of retinopathy and neurodegeneration with brain iron accumulation. AB - Defects of phospholipids remodelling and synthesis are inborn errors of metabolism responsible for various clinical presentations including spastic paraplegia, retinopathy, optic atrophy, myo- and cardiomyopathies, and osteo cutaneous manifestations. DDHD1 encodes a phospholipase A1, which is involved in the remodelling of phospholipids. We previously described a relatively pure hereditary spastic paraplegia (HSP) phenotype associated with mutations in DDHD1. Here we report a complex form of HSP associated with retinal dystrophy and a pattern of neurodegeneration with brain iron accumulation (NBIA) on brain MRI, due to a novel homozygous mutation in DDHD1. This observation enlarges the clinical spectrum of DDHD1-associated disorders and sheds light on a new aetiology for syndromes associating retinopathy and NBIA. It also emphasizes the role of complex lipids in the retina. PMID- 28818479 TI - A structured assessment of motor function, behavior, and communication in patients with Wolf-Hirschhorn syndrome. AB - The present study aimed to increase the knowledge about Wolf-Hirschhorn syndrome (WHS), especially concerning motor function, autism spectrum disorders (ASD), and adapted behavior, but also regarding clinical symptoms in general. Motor function was evaluated via systematic observation. Standardized assessments such as the Vineland Adapted Behavior Scales II (VABS II), the Social Communication Questionnaire (SCQ), and the Child Behavior Checklist (CBCL) or Adult Behavior Checklist (ABCL) were used for the behavioral assessment. In total, two males and eight females between one and 48 years of age with a genetically confirmed diagnosis of WHS and their parents participated in this study. Deletion sizes were known for seven of the ten patients and varied between 55 Kb and 20 Mb. The chromosome coordinates were known for six of them, and none of those had the same break points in their deletion. The main finding in this study was that patients with WHS may have a better outcome regarding motor skills and expressive communication than previously described. We could confirm the main medical findings described earlier, but found also a population with a less severe dysmorphology, fewer congenital malformations, and fewer medical challenges than expected. Sleep problems may persist into adulthood and need a more thorough investigation. Research on possible indications of ASD is strongly needed for targeted interventions. In conclusion, a more thorough assessment of communication, possible ASD, and sleep in larger groups of patients with WHS are needed to confirm and further investigate the findings from this study and to provide more targeted interventions for WHS patients. PMID- 28818480 TI - [Infection control practices while performing prostate biopsies in France: A CIAFU survey]. AB - : In 2008, the French Public Health Committee admitted that associating ultrasound probe protection, and related precautions, and low-level disinfection would be equivalent to the intermediate level disinfection. In 2010, the French Urology Association (AFU) updated guidelines regarding trans-rectal prostate biopsies, namely preventive measures related to cross-transmission of infections. We report an evaluation of compliance to them, driven in 2016 by AFU's infection committee. Although not recommended, almost one third of the urologists still perform biopsies under general anesthesia, and two thirds of them ask for a urine culture before biopsies. Several improvements are still needed: sterilization of needle guide should always be done when not of single use, the ultrasonography gel should be sterile, probes protection should be EC labeled, and compliance to probe processing between two patients should increase. Most of urologists happened to experience blood or feces contamination of probes. Less than half of probes are entirely floodable, and when intermediate level disinfection is done, glutaraldehyde is still referred as disinfectant by one third of the urologists. LEVEL OF EVIDENCE: 4. PMID- 28818481 TI - Identification of Streptococcus pneumoniae lytA, plyA and psaA genes in pleural fluid by multiplex real-time PCR. AB - INTRODUCTION: The aim was to evaluate the utility of a multiplex real-time PCR to detect Streptococcus pneumoniae lytA, plyA and psaA genes in pleural fluid (PF). METHODS: A collection of 81 PF samples was used. Sixty were considered positive for S. pneumoniae according to previous results (54 by an in-house lytA gene PCR and eight by universal rRNA PCR). RESULTS: The sensitivity for detection of the lytA, plyA and psaA genes by multiplex PCR was 100% (60/60), 98.3% (59/60) and 91.7% (55/60), respectively. The detection of all three genes was negative in 21 samples formerly confirmed as negative for S. pneumoniae (100% specificity) by the other procedures (9 by in-house lytA PCR and 12 by rRNA PCR). CONCLUSIONS: The use of this multiplex PCR may be a useful option to identify S. pneumoniae directly in PF samples. PMID- 28818482 TI - Drawbacks of the use of cotrimoxazole in foreign-body infections. AB - INTRODUCTION: The anti-staphylococcal efficacy of cotrimoxazole in the setting of difficult-to-treat infections seems to be compromised by large amounts of pus and devitalized tissue, and, therefore, high levels of thymidine. Our objective was to evaluate the activity of cotrimoxazole against a staphylococcal foreign-body infection experimental model, which also yields significant quantities of thymidine. MATERIAL AND METHODS: We used a rat tissue-cage model of infection (with high inherent thymidine levels) caused by a strain of methicillin susceptible Staphylococcus aureus (MSSA; ATCC 29213). MIC values were determined (microdilution method) and compared in the presence or absence of tissue-cage fluid samples. RESULTS: The inefficacy of cotrimoxazole was found to be similar to that of the control group. The MIC of cotrimoxazole was 4-8 fold higher in the presence of rat tissue-cage fluid. CONCLUSIONS: The inefficacy of cotrimoxazole in our foreign-body infection model by MSSA, and the probable negative impact of the presence of thymidine on its efficacy, challenge the use of this drug in acute phases of foreign-body infections. It should be reserved as an alternative treatment when the infection is more controlled. PMID- 28818483 TI - Intermittent hypoxia and cancer: Undesirable bed partners? AB - The deleterious effects of intermittent hypoxia (IH) on cancer biology have been primarily evaluated in the context of the aberrant circulation observed in solid tumors which results in recurrent intra-tumoral episodic hypoxia. From those studies, IH has been linked to an accelerated tumor progression, metastasis and resistance to therapies. More recently, the role of IH in cancer has also been studied in the context of obstructive sleep apnea (OSA), since IH is a hallmark characteristic of this condition. Such recent studies are undoubtedly adding more information regarding the role of IH on tumor malignancy. In terms of the IH patterns associated with OSA, this altered oxygenation paradigm has been recently proposed as a determinant factor in fostering cancer incidence and progression from both in vitro and in vivo experimental models. Here, we summarize all the available evidence to date linking IH effects on several types of cancer. PMID- 28818484 TI - The physiology of submaximal exercise: The steady state concept. AB - The steady state concept implies that the oxygen flow is invariant and equal at each level along the respiratory system. The same is the case with the carbon dioxide flow. This condition has several physiological consequences, which are analysed. First, we briefly discuss the mechanical efficiency of exercise and the energy cost of human locomotion, as well as the roles played by aerodynamic work and frictional work. Then we analyse the equations describing the oxygen flow in lungs and in blood, the effects of ventilation and of the ventilation - perfusion inequality, and the interaction between diffusion and perfusion in the lungs. The cardiovascular responses sustaining gas flow increase in blood are finally presented. An equation linking ventilation, circulation and metabolism is developed, on the hypothesis of constant oxygen flow in mixed venous blood. This equation tells that, if the pulmonary respiratory quotient stays invariant, any increase in metabolic rate is matched by a proportional increase in ventilation, but by a less than proportional increase in cardiac output. PMID- 28818485 TI - Role of stromal derived factor-1a (SDF-1a) for spermatogenesis of busulfan injured rats. AB - SDF-1a is a member of CXC chemokine family that plays a crucial role in stem cell migration, cell apoptosis and development. The role of intra-scrotal administration of SDF-1a in spermatogenesis of busulfan-treated rats was investigated in this study. Two injections of busulfan (15mg/kg) with a 14days interval between were given intraperitoneally to male Wistar rats. Rats were then treated for seven days with 500ng/mL SDF-1a. Real-time PCR and immunohistochemistry were performed for evaluation of various cell markers for proliferation and spermatogenesis, and sperm parameters were assessed. In the SDF 1a group, there was a significant increase in testis weight, sperm count and viability. DAZL, DDX4, and TP2 showed increased expression levels in the SDF-1a group. PCNA and BrdU revealed highest expression rates in the SDF-1a group (p<=0.0001). These findings showed the protective role of SDF-1a in busulfan induced testis injury most likely through stimulation of SSCs proliferation. PMID- 28818486 TI - Implementation of Media Production Activities in an Intervention Designed to Reduce Sugar-Sweetened Beverage Intake Among Adults. AB - OBJECTIVE: To inform the implementation of media production activities with adult populations by describing the construction of counter-advertisements (counter ads) within a behavioral intervention. METHODS: SIPsmartER participants could create 2 types of counter ads during the intervention's media literacy lesson. Participants (n = 40) were from rural southwestern Virginia. Most were female (85%) and white (93%), and 28% were low health literate. Descriptive statistics and Fisher exact tests were used to compare completion rates, content, techniques used, and persuasive intent with counter ad type and health literacy status. RESULTS: Each participant produced 2.1 (SD, 0.8) counter-ads. Ads included health risks (64%) and nutrition facts (16%). The majority used persuasive techniques (72%) and were persuasive for drinking fewer sugar-sweetened beverages (72%). There were differences by type but not health literacy status. CONCLUSIONS AND IMPLICATIONS: Findings suggested that counter-ads can be used in behavioral interventions for adults. Guidance is provided to support their implementation. PMID- 28818487 TI - SNAP-Based Incentive Programs at Farmers' Markets: Adaptation Considerations for Temporary Assistance for Needy Families (TANF) Recipients. AB - OBJECTIVE: To describe the design, implementation, and consumer response to a coupon-style intervention aimed to increase Supplemental Nutrition Assistance Program (SNAP) use at a farmers' market (FM) among Temporary Assistance for Needy Families (TANF) participants. DESIGN: A quasi-experimental trial to evaluate redemption response to 2 coupon interventions; baseline surveys characterized coupon redeemers and non-redeemers. SETTING: Urban. PARTICIPANTS: The TANF recipients were assigned to either a plain (n = 124) or targeted marketing coupon intervention (n = 130). INTERVENTION(S): Both groups received 10 $2 coupons to double fruit and vegetable SNAP purchases at the FM. The targeted marketing group also received an oral presentation designed to reduce perceived barriers to FM use. MAIN OUTCOME MEASURE: Coupon redemption. ANALYSIS: The researchers used t tests and chi-square/Fisher exact tests to examine associations between redeemers and non-redeemers; logistic regression was used to adjust for the intervention. RESULTS: No male and few female participants redeemed coupons (6.3%). Among women, those with knowledge of vegetable preparation were 3 times more likely to redeem coupons than were those with little or no knowledge (odds ratio = 3.77; 95% confidence interval, 1.03-13.77). CONCLUSIONS AND IMPLICATIONS: Stand-alone coupon incentive programs may not be a high-reach strategy for encouraging FM use among the population using TANF. Complementary strategies to build vegetable preparation knowledge and skills are needed. PMID- 28818488 TI - Education for WIC Peer Counselors About Breastfeeding the Late Preterm Infant. AB - Mothers of late preterm infants need ongoing support because they often find establishing breastfeeding (BF) to be complex and difficult. Special Supplemental Nutrition Program for Women, Infants and Children peer counselors provide BF information and emotional support to new mothers in many communities. However, their current training does not include education about BF for the late preterm infant. The purpose of this report is to present important information about BF and the late preterm infant that can enhance peer counselors' ability to offer appropriate support. The effect of this education on outcomes such as BF rates, maternal self-efficacy, infant hospital readmissions, and peer counselors' self efficacy needs to be investigated. PMID- 28818489 TI - Tu Salud !Si Cuenta! Your Health Matters! A Community-wide Campaign in a Hispanic Border Community in Texas. AB - OBJECTIVE: To evaluate a community-wide campaign, Tu Salud !Si Cuenta! (TSSC), in improving eating behaviors and anthropometric outcomes in Hispanic border communities. DESIGN: A quasi-experimental study with matched intervention and comparison communities. Cross-sectional assessments with randomly sampled adults, examined by actual exposure and site (unexposed intervention, exposed intervention, and unexposed comparison). SETTING AND PARTICIPANTS: Predominately Mexican Americans located in Brownsville, TX (intervention) and Laredo, TX (control). INTERVENTION: The TSSC campaign included television and radio segments, community health worker discussions, and newsletters delivered in Brownsville from 2005 to 2010. MAIN OUTCOME MEASURES: Healthy and unhealthy eating indices and average hip and waist circumferences. ANALYSIS: Univariable and multivariable regression models. RESULTS: The sample (n = 799; 400 comparison and 399 intervention) was 98% of Mexican origin; 54% had completed grade 9 or higher. Exposure to any TSSC component was associated with a lower rate of unhealthy food consumption. Compared with the unexposed intervention group, the exposed intervention for the newsletter had a higher rate of healthy eating (adjusted rate ratio = 1.18; P < .01). Compared with the unexposed intervention, the exposed intervention for the community health worker discussion had a smaller hip circumference (adjusted mean difference = -5.77 cm; P < .05) and a smaller waist circumference (adjusted mean difference = -5.25 cm; P < .05). CONCLUSIONS AND IMPLICATIONS: This study provides evidence for the use of community-wide campaigns for nutrition and obesity-related outcomes in Hispanic communities. PMID- 28818490 TI - Inhibition of quorum sensing-controlled biofilm formation in Pseudomonas aeruginosa by quorum-sensing inhibitors. AB - Antimicrobial therapy against extensively drug-resistant (XDR) P. aeruginosa biofilms is less efficient compared to the treatment of equal bacterial counts of free-floating planktonic cells, which has become a serious threat in hospital environment. P. aeruginosa regulate their cooperative activities and physiological processes through a cell to cell chemical communication process called Quorum sensing (QS). This attracted our interest to synthesize, and to chemically characterize two anti-QS compounds, N-(4-{4-fluoroanilno} butanoyl) -l homoserine lactone (FABHL) and N-(4-{4-chlororoanilno} butanoyl) -l-homoserine lactone (CABHL) to inhibit biofilm formation via disabling the QS circuits. Structural and morphological properties of these compounds were characterized by 1H Nuclear Magnetic Resonance (NMR), 13C NMR and High-resolution mass spectrometry (HRMS). Two biofilm forming XDR P. aeruginosa isolates were included in this study. Anti-biofilm property of FABHL or CABHL was confirmed by biofilm formation assay and it was shown to occur without affecting the bacterial growth. Anti-QS property of FABHL or CABHL was determined by evaluating the expression levels of QS genes (lasR and rhlR) by quantitative real time PCR (qRT-PCR). Although, FABHL and CABHL downregulates the expression levels of QS genes, lasR expression was significantly reduced. Molecular modeling studies revealed that the binding energy of FABHL and CABHL with LasR protein was -4.27 and -4.51, respectively. Hence, the synthesized compounds have the potential to serve as a potent anti-biofilm agent via disabling the QS systems. Lethality of FABHL and CABHL against PBMCs was assessed by 3-(4, 5- dimethylthiazol-2-yl)-2, 5-diphynyl tetrazolium bromide (MTT) assay. Cell viability was observed for both the compounds. PMID- 28818491 TI - Cryotherapy versus high-intensity focused ultrasound for treating prostate cancer: Oncological and functional results. AB - CONTEXT AND OBJECTIVE: The increasingly early diagnosis of prostate cancer requires a search for therapeutic alternatives with good oncological results that in turn facilitate a good long-term quality of life. This review analyses 2 minimally invasive therapies for treating localised prostate cancer in terms of oncological and functional results, as well as the complications resulting from the therapies. ACQUISITION OF EVIDENCE: A systematic literature review was conducted of the treatment of localised prostate cancer with 2 ablative techniques as the primary therapy: cryosurgery or cryotherapy and high intensity focused ultrasound (HIFU). We included patients who underwent procedures that included the entire gland, with hemiablation or focal therapy, which were indicated for low to intermediate-risk prostate cancer according to the D'Amico criteria. We excluded patients with high-risk prostate cancer and those who underwent any prior treatment for prostate cancer. SYNTHESIS OF THE EVIDENCE: After conducting the literature search and excluding the studies that did not meet the protocol criteria, we reviewed a total of 14 studies, with a total of 350 patients treated using cryotherapy and 1107 treated with HIFU. All studies were either prospective or retrospective and were not randomised. The patients' mean age was younger than 75 years. Overall, the rate of disease recurrence in the patients treated with cryotherapy varied between 13.2% and 26%, while the rate for those treated with HIFU varied between 7.3% and 67.9%. The overall demonstrated continence at 12 months was 97.6-100% for cryotherapy and 96-100% for HIFU. In terms of sexual potency rates, cryotherapy showed complete potency at 12 months for 86-100% of the patients treated with focal cryotherapy and slightly lower rates for hemiablation (76.9-100%) and total therapy (39%). HIFU showed potency rates of 89%, 52-80% and 33-78% for focal therapy, hemiablation and total therapy, respectively. CONCLUSIONS: Both techniques have comparable functional results, although the somewhat poorer oncological results for HIFU reflect a steeper learning curve, which could lead to its use in centres with high volumes of patients. PMID- 28818492 TI - [Dexmedetomidine preconditioning protects against lipopolysaccharides-induced injury in the human alveolar epithelial cells]. AB - BACKGROUND AND OBJECTIVES: Dexmedetomidine (DEX) has demonstrated the preconditioning effect and shown protective effects against organize injury. In this study, using A549 (human alveolar epithelial cell) cell lines, we investigated whether DEX preconditioning protected against acute lung injury (ALI) in vitro. METHODS: A549 were randomly divided into four groups (n=5): control group, DEX group, lipopolysaccharides (LPS) group, and D-LPS (DEX+LPS) group. Phosphate buffer saline (PBS) or DEX were administered. After 2h preconditioning, the medium was refreshed and the cells were challenged with LPS for 24h on the LPS and D-LPS group. Then the malondialdehyde (MDA), superoxide dismutase (SOD), Bcl-2, Bax, caspase-3 and the cytochrome c in the A549 were tested. The apoptosis was also evaluated in the cells. RESULTS: Compare with LPS group, DEX preconditioning reduced the apoptosis (26.43%+/-1.05% vs. 33.58%+/ 1.16%, p<0.05) in the A549, which is correlated with decreased MDA (12.84+/-1.05 vs. 19.16+/-1.89nmol.mg-1 protein, p<0.05) and increased SOD activity (30.28+/ 2.38 vs. 20.86+/-2.19U.mg-1 protein, p<0.05). DEX preconditioning also increased the Bcl-2 level (0.53+/-0.03 vs. 0.32+/-0.04, p<0.05) and decreased the level of Bax (0.49+/-0.04 vs. 0.65+/-0.04, p<0.05), caspase-3 (0.54+/-0.04 vs. 0.76+/ 0.04, p<0.05) and cytochrome c. CONCLUSION: DEX preconditioning has a protective effect against ALI in vitro. The potential mechanisms involved are the inhibition of cell death and improvement of antioxidation. PMID- 28818493 TI - Progression-Free Survival and Time to Progression as Real Surrogate End Points for Overall Survival in Advanced Breast Cancer: A Meta-Analysis of 37 Trials. AB - BACKGROUND: Progression-free survival (PFS) and time to progression (TTP) have been reported to correlate with overall survival (OS) in several cancer types. To our knowledge, however, the correlation between them is unclear. METHODS: A literature-based meta-analysis was performed to assess whether PFS and TTP can be considered reliable surrogate end points for OS in a phase 3 clinical trial of advanced breast cancer (ABC). The median hazard ratios of PFS/TTP and OS were analyzed by determining their nonparametric Spearman rank correlation coefficients (Rs). RESULTS: A total of 37 trials with 38 treatment arms and 14,966 patients were selected for analysis. The Rs between the median PFS/TTP and OS was 0.405 (95% confidence interval [CI], 0.191-0.582; P = .003), and the correlation coefficient between the hazard ratios of PFS/TTP and OS was 0.555 (95% CI, 0.277-0.748; P = .003). PFS/TTP was closely correlated with OS in the trials of targeted therapy-based treatment (Rs = 0.872; 95% CI, 0.619-0.962; P = .0001) and of PFS/TTP or OS benefit (Rs = 0.753 and Rs = 0.821, respectively) for ABC. CONCLUSIONS: Both PFS and TTP can be considered valid surrogate end points for OS in the trials of targeted therapy-based treatments and clinical benefits for ABC. Further research is necessary to clarify the surrogacy of PFS/TTP for OS in other trials of targeted therapy-based treatments for ABC. PMID- 28818494 TI - GTS-21 reduces microvascular permeability during experimental endotoxemia. AB - INTRODUCTION: No effective pharmacological therapy is currently available to attenuate tissue edema formation due to increased microvascular permeability in sepsis. Cholinergic mediators have been demonstrated to exert anti-inflammatory effects via the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) during inflammation. GTS-21, a partial alpha7nAChR agonist, is an appealing therapeutic substance for sepsis-induced microvascular inflammation due to its demonstrated cholinergic anti-inflammatory properties and its favorable safety profile in clinical trials. This study evaluated the effect of GTS-21 on microvascular permeability and leukocyte adhesion during experimental endotoxemia. METHODS: Male Wistar rats (n=60) were anesthetized and prepared for intravital microscopy (IVM). Sevoflurane inhalation combined with propofol (10mg/kg) and fentanyl (5MUg/kg) was used for anesthesia induction, followed by continuous intravenous anesthesia with propofol (10-40mg/kg/h) and fentanyl (10MUg/kg/h). The rat mesentery was prepared for evaluation of macromolecular leakage, leukocyte adhesion and venular wall shear rate in postcapillary venules using IVM. Following baseline IVM recording, GTS-21 (1mg/kg) was applied simultaneously with, 1h prior to and 1h after administration of lipopolysaccharide (LPS, 5mg/kg). Test substances (crystalloid solution, LPS, GTS-21) were administered as volume equivalent intravenous infusions over 5min in the respective treatment groups. The consecutive IVMs were performed at 60, 120 and 180min after the baseline IVM. The systemic inflammatory response was evaluated by measuring TNF alpha levels after the 180min IVM. RESULTS: Microvascular permeability was significantly reduced in animals treated with GTS-21 simultaneously and 1h after induction of endotoxemia. Leukocyte adhesion, venular wall shear rate and TNF alpha levels were not affected by GTS-21 treatment compared to the untreated endotoxemic animals. CONCLUSION: GTS-21 has a protective effect on microvascular barrier function during endotoxemia. Considering its anti-inflammatory efficacy and safety profile, its clinical use might prove beneficial for the treatment of capillary leakage in sepsis therapy. PMID- 28818495 TI - Direct in silico visualization of ligands channelling through proteins: The next generation frontier of computational biology: Comment on 'Ligand diffusion via enhanced sampling molecular dynamics' by Jakub Rydzewski and Wieslaw Nowak. PMID- 28818496 TI - Nonlinear dynamical systems: Comment on "Modeling human behavior in economics and social science" by Marina Dolfin, Leone Leonida and Nisrine Outada. PMID- 28818498 TI - Antifungal activity of the essential oil obtained from Cryptocarya alba against infection in honey bees by Nosema ceranae. AB - The honeybee disease nosemosis type C is a serious problem since its causative agent, microsporidium Nosema ceranae, is widespread among adult honey bees. Some of the feasible alternative treatments that are used to control this disease are plant extracts. The aim of the present work was to evaluate the effects of essential oils of Chilean plant species, such as Cryptocarya alba, which is used against N. ceranae, and to identify and quantify the majority active compounds in the EO as well as their potential use for the control of nosemosis. Essential oils were obtained using the stripping steam technique with Clevenger equipment and were subsequently analyzed by Gas chromatography-mass spectrometry. Mortality was recorded daily over at least 8days as worker honeybees were exposed to a range of doses of EO dispersed in a sucrose solution. C. alba oil appears to be nontoxic to A. mellifera adults at the tested concentration (the same concentration inhibits the growth of N. ceranae), showing that this oil can be used for the treatment of nosemosis. EO effectiveness was demonstrated against N. ceranae by calculating the percentage of decrease in infected bees from untreated infected groups vs infected groups treated with EO or the reference drug fumagillin. It was determined that a dose of 4ug EO/bee was most effective in controlling N. ceranae development. We determined innocuous doses of C. alba essential oil for honeybees. We demonstrated the antifungal activity of C. alba EO at 4MUg/bee against N. ceranae and compared it to its major monoterpenes, such as beta-phellandrene (20MUg/bee), eucalyptol (20MUg/bee) and alpha-terpineol (20MUg/bee). The major compounds of C. alba EO, alpha-terpineol, eucalyptol and beta-phellandrene, had significant effects against Apis mellifera infection by N. ceranae, but the antifungal effect of the complete essential oil on N. ceranae was larger than the effect of alpha-terpineol, eucalyptol or beta- phellandrene separately, showing that C. alba oil may be a candidate for the treatment or prevention of nosemosis. PMID- 28818497 TI - Drp1 regulates mitochondrial morphology and cell proliferation in cutaneous squamous cell carcinoma. AB - BACKGROUND: Dynamin-related protein 1 (Drp1) mediates mitochondrial fission. Recently, several studies have shown that Drp1 plays an important role in some cancers. However, little is known about Drp1 in cutaneous squamous cell carcinoma (SCC). OBJECTIVE: To investigate the role of Drp1 in the tumorigenesis of cutaneous SCCs. METHODS AND RESULTS: We investigated cell proliferation, cell cycle, mitochondrial morphology, and MAPK signaling pathway using cutaneous SCC A431 and DJM1 cells that were transfected with shRNA vectors targeting Drp1. The Drp1 gene-knockdown SCC cells showed lower cell proliferation than scramble control cells, as assessed by direct cell counting and clonogenic assays. DNA content analysis showed Drp1 knockdown to cause G2/M arrest. Morphologically, the depletion of Drp1 resulted in an elongated, hyper-fused mitochondrial network. The MEK inhibitor PD325901 suppressed cell proliferation, as well as inhibiting the phosphorylation of ERK1/2 and Drp1Ser616. Also, PD325901 caused the dysregulation of the mitochondrial network. In tumor xenografts of DJM1 cells, the knockdown of Drp1 suppressed tumor growth in vivo, and clinically, the expression levels of Drp1 were higher in cutaneous SCCs than in normal epidermis, and correlated positively with the advanced clinical stages. CONCLUSION: Our results reveal a crucial function for Drp1 in regulating tumor growth, mitochondrial morphology, and cell cycle in cutaneous SCC, suggesting that Drp1 could be a novel target for skin tumor therapies. PMID- 28818499 TI - Editor's perspectives - August 2017. PMID- 28818501 TI - Is human brain masculinization estrogen receptor-mediated? Reply to Luoto and Rantala. AB - Human genetic males are unlike rodent males in that neither the ability to convert testosterone to estrogen nor a functional estrogen receptor (ER) appears necessary for male-typical behavior, but a functional androgen receptor (AR) is required. Brain masculinization is probably mainly AR-mediated in human genetic males. ER binding may nevertheless have important masculinizing or defeminizing effects in human genetic females. Probably the strongest available evidence on this issue is derived from females exposed to synthetic estrogens in utero due to their mother's treatment with DES. As we review, the totality of evidence from this population indicates little or no effect of estrogens on sexuality in genetic females. In addition, if brain masculinization were ER-mediated in humans, it seems unlikely that sex hormone-binding globulin would bind estrogens so effectively as to prevent them from masculinizing the brain. In sum, current evidence suggests that estrogen plays a limited role in masculinizing the human brain and behavior. PMID- 28818500 TI - Cryptic sexual dimorphism in spatial memory and hippocampal oxytocin receptors in prairie voles (Microtus ochrogaster). AB - Sex differences are well documented and are conventionally associated with intense sex-specific selection. For example, spatial memory is frequently better in males, presumably due to males' tendency to navigate large spaces to find mates. Alternatively, monogamy (in which sex-specific selection is relatively relaxed) should diminish or eliminate differences in spatial ability and the mechanisms associated with this behavior. Nevertheless, phenotypic differences between monogamous males and females persist, sometimes cryptically. We hypothesize that sex-specific cognitive demands are present in monogamous species that will influence neural and behavioral phenotypes. The effects of these demands should be observable in spatial learning performance and neural structures associated with spatial learning and memory. We analyzed spatial memory performance, hippocampal volume and cell density, and hippocampal oxytocin receptor (OTR) expression in the socially monogamous prairie vole. Compared to females, males performed better in a spatial memory and spatial learning test. Although we found no sex difference in hippocampal volume or cell density, male OTR density was significantly lower than females, suggesting that performance may be regulated by sub-cellular mechanisms within the hippocampus that are less obvious than classic neuroanatomical features. Our results suggest an expanded role for oxytocin beyond facilitating social interactions, which may function in part to integrate social and spatial information. PMID- 28818502 TI - Trapezoidal mandibular osteotomy for augmentation of the airway in sleep apnoea. PMID- 28818503 TI - Use of buccal cortex as interpositional graft in mandibular setbacks. PMID- 28818504 TI - Diagnostic yield of transbronchial lung cryobiopsy in interstitial lung diseases. PMID- 28818505 TI - Schizophrenia with prominent catatonic features: A selective review. AB - A widely accepted consensus holds that a variety of motor symptoms subsumed under the term 'catatonia' have been an integral part of the symptomatology of schizophrenia since 1896, when Kraepelin proposed the concept of dementia praecox (schizophrenia). Until recently, psychiatric classifications included catatonic schizophrenia mainly through tradition, without compelling evidence of its validity as a schizophrenia subtype. This selective review briefly summarizes the history, psychopathology, demographic and epidemiological data, and treatment options for schizophrenia with prominent catatonic features. Although most catatonic signs and symptoms are easy to observe and measure, the lack of conceptual clarity of catatonia and consensus about the threshold and criteria for its diagnosis have hampered our understanding of how catatonia contributes to the pathophysiology of schizophrenic psychoses. Diverse study samples and methodologies have further hindered research on schizophrenia with prominent catatonic features. A focus on the motor aspects of broadly defined schizophrenia using modern methods of detecting and quantifying catatonic signs and symptoms coupled with sophisticated neuroimaging techniques offers a new approach to research in this long-overlooked field. PMID- 28818506 TI - Development and evaluation of beta-galactosidase-sensitive antibody-drug conjugates. AB - The selective destruction of tumour cells while sparing healthy tissues is one of the main challenges in cancer therapy. Antibody-drug conjugates (ADCs) are arguably the most rapidly expanding class of targeted cancer therapies. Efficient drug conjugation and release technologies are essential for the development of these new therapeutic agents. In response to the ever-increasing demand for efficient drug release systems, we have developed a new class of beta galactosidase-cleavable linkers for ADCs. Within this framework, novel payloads comprising a galactoside linker, the monomethyl auristatin E (MMAE) and cysteine reactive groups were synthesized, conjugated with trastuzumab and evaluated both in vitro and in vivo. The ADCs with galactoside linkers demonstrated superior therapeutic efficacy in mice compared to the marketed trastuzumab emtansine used for the treatment of breast cancer. PMID- 28818507 TI - Optimizing the quality of endoscopy in inflammatory bowel disease: focus on surveillance and management of colorectal dysplasia using interactive image- and video-based teaching. AB - BACKGROUND AND AIMS: Varying recommendations regarding the detection and management of dysplasia can lead to uncertainty and may impede the uptake of strategies that could improve surveillance in patients with inflammatory bowel disease (IBD). An educational event was held to assist in disseminating the recently published Surveillance for Colorectal Endoscopic Neoplasia Detection and Management in Inflammatory Bowel Disease Patients: International Consensus Recommendations (SCENIC). METHODS: Specialists in IBD and endoscopy led the Optimizing Quality of Endoscopy in IBD course. The American Society for Gastrointestinal Endoscopy (ASGE) organized the course, and the Crohn's and Colitis Foundation of America (CCFA) provided endorsement. One was held in March 2015 at the ASGE Institute for Training and Technology in Chicago, Illinois, and the second in September 2016 preceding the ASGE Endofest in Chandler, Arizona. The program included interactive case-based discussions and didactic presentations on topics including the rationale and current approach of surveillance in IBD; endoscopic characterization and nomenclature of active and quiescent disease; detection of dysplasia during IBD surveillance; role of image enhanced endoscopy in IBD surveillance, with a focus on chromoendoscopy technique; and management of dysplasia in IBD. Participants were surveyed before and after the course to assess their perspectives and practice. RESULTS: Eighteen presenters or panel members and approximately 92 IBD and endoscopist physician leaders attended the meeting. Most attendees were aged 30 to 49 years (88.1%), had been in practice less than 10 years (89.7%), were from academic medical centers (90.7%), and spent >50% of their time caring for patients with IBD (59.7%). Recommended quality improvements for endoscopy in IBD included the use of endoscopic scoring systems to describe disease activity, the use of a modified Paris classification to characterize visible dysplastic lesions (polypoid, nonpolypoid with description of presence of ulcer and distinct or indistinct borders), the use of chromoendoscopy for dysplasia detection, and the endoscopic removal of visible dysplastic lesions. In the follow-up survey, participants were asked to indicate whether they had changed their practice as a result of attending the course. Ninety-three percent (93%) indicated they had changed their practice. For dysplasia detection, the use of chromoendoscopy increased: 51.7% of respondents reported using chromoendoscopy in most surveillance colonoscopies compared with 34.3% before the course. For dysplasia management, the use of EMR increased for polypoid and nonpolypoid lesions 10 to 20 mm in size; and the referral of dysplastic lesions 20 mm or larger that appeared endoscopically resectable shifted toward removal by an experienced endoscopist. CONCLUSIONS: Evidence-based advances in endoscopy have occurred in the characterization and nomenclature of active and quiescent disease, polypoid and nonpolypoid dysplasia in IBD, and in the detection and management of dysplasia in colonic IBD. Implementation of updated guidelines and recommendations into clinical practice may be facilitated by interactive image- and video-based courses on the topic. PMID- 28818508 TI - The role of the IL-8 signaling pathway in the infiltration of granulocytes into the livers of patients with alcoholic hepatitis. AB - BACKGROUND AND AIM: IL-8 (C-X-L motif chemokine ligase 8) and CXCR2 (C-X-C-motif chemokine receptor 2) are up regulated in alcoholic hepatitis (AH) liver biopsies. One of the consequences is the attraction and chemotactic neutrophilic infiltrate seen at the AH stage of alcoholic liver disease. MATERIALS AND METHODS: Human formalin-fixed, paraffin-embedded (FFPE) liver biopsies from patients who have AH were studied by (2.1) RNA sequencing, (2.2) PCR and (2.3) semi quantitation of specific proteins in biopsy sections using immunohistochemical measurements of antibody fluorescent intensity with morphometric technology. RESULTS: Immunohistochemistry of IL-8 showed that the expression was increased in the cytoplasm of the hepatocytes in AH liver biopsies compared to the controls. IL-8 and ubiquitin were co-localized in the MDBs. Numerous neutrophils were found throughout and satellitosis of neutrophils around MDBs was present. This suggested that IL-8 may be involved in MDB pathogenesis. RNA seq analysis revealed activation by IL-8 which included neutrophil chemotaxis by LIM domain kinase 2 (LIMK2) (17.5 fold increase) and G protein subunit alpha 15 (GNA15) (27.8 fold increase). CONCLUSIONS: The formation of MDBs by liver cells showed colocalization of ubiquitin and IL-8 in the MDBs. This suggested that IL-8 in these hepatocytes attracted the neutrophils to form satellitosis. This correlated with up regulation of the proteins downstream from the IL-8 pathways including LIMK2, GNG2 (guanine nucleotide binding proteins) and PIK3CB (phosphatidyl isitol-4, 5-biophosphate-3-kinase, catalytic subunit beta). PMID- 28818509 TI - The use of high-flow nasal cannula in the pediatric emergency department. AB - OBJECTIVES: To summarize the current literature describing high-flow nasal cannula use in children, the components and mechanisms of action of a high-flow nasal cannula system, the appropriate clinical applications, and its role in the pediatric emergency department. SOURCES: A computer-based search of PubMed/MEDLINE and Google Scholar for literature on high-flow nasal cannula use in children was performed. DATA SUMMARY: High-flow nasal cannula, a non-invasive respiratory support modality, provides heated and fully humidified gas mixtures to patients via a nasal cannula interface. High-flow nasal cannula likely supports respiration though reduced inspiratory resistance, washout of the nasopharyngeal dead space, reduced metabolic work related to gas conditioning, improved airway conductance and mucociliary clearance, and provision of low levels of positive airway pressure. Most data describing high-flow nasal cannula use in children focuses on those with bronchiolitis, although high-flow nasal cannula has been used in children with other respiratory diseases. Introduction of high-flow nasal cannula into clinical practice, including in the emergency department, has been associated with decreased rates of endotracheal intubation. Limited prospective interventional data suggest that high-flow nasal cannula may be similarly efficacious as continuous positive airway pressure and more efficacious than standard oxygen therapy for some patients. Patient characteristics, such as improved tachycardia and tachypnea, have been associated with a lack of progression to endotracheal intubation. Reported adverse effects are rare. CONCLUSIONS: High-flow nasal cannula should be considered for pediatric emergency department patients with respiratory distress not requiring immediate endotracheal intubation; prospective, pediatric emergency department-specific trials are needed to better determine responsive patient populations, ideal high flow nasal cannula settings, and comparative efficacy vs. other respiratory support modalities. PMID- 28818510 TI - Breathing mode influence on craniofacial development and head posture. AB - OBJECTIVE: The incidence of abnormal breathing and its consequences on craniofacial development is increasing, and is not limited to children with adenoid faces. The objective of this study was to evaluate the cephalometric differences in craniofacial structures and head posture between nasal breathing and oral breathing children and teenagers with a normal facial growth pattern. METHOD: Ninety-eight 7-16 year-old patients with a normal facial growth pattern were clinically and radiographically evaluated. They were classified as either nasal breathing or oral breathing patients according to the predominant mode of breathing through clinical and historical evaluation, and breathing respiratory rate predomination as quantified by an airflow sensor. They were divided in two age groups (G1: 7-9) (G2: 10-16) to account for normal age-related facial growth. RESULTS: Oral breathing children (8.0+/-0.7 years) showed less nasopharyngeal cross-sectional dimension (MPP) (p=0.030), whereas other structures were similar to their nasal breathing counterparts (7.6+/-0.9 years). However, oral breathing teenagers (12.3+/-2.0 years) exhibited a greater palate length (ANS-PNS) (p=0.049), a higher vertical dimension in the lower anterior face (Xi-ANS-Pm) (p=0.015), and a lower position of the hyoid bone with respect to the mandibular plane (H-MP) (p=0.017) than their nasal breathing counterparts (12.5+/-1.9 years). No statistically significant differences were found in head posture. CONCLUSION: Even in individuals with a normal facial growth pattern, when compared with nasal breathing individuals, oral breathing children present differences in airway dimensions. Among adolescents, these dissimilarities include structures in the facial development and hyoid bone position. PMID- 28818511 TI - Vitamin D enhances antiepileptic and cognitive effects of lamotrigine in pentylenetetrazole-kindled rats. AB - Despite long use of antiepileptic drugs, it remains a challenge to achieve seizure control while reducing adverse effects and preventing cognitive impairment. Several lines of evidence suggest a role of vitamin D in epilepsy. So this study aimed to investigate the effect of vitamin D on epileptogenesis, cognitive dysfunction and antiepileptic activity of lamotrigine, in a rat model of chemical kindling. Rats were kindled by pentylenetetrazole injections every other day over four weeks, together with daily oral treatment by either vehicle, vitamin D, lamotrigine or combination of vitamin D and lamotrigine. The non treated kindled rats developed generalized seizures and had poor cognitive performance in water maze, associated with prooxidative status; elevated malondialdehyde and nitric oxide with lowered glutathione levels; in brain tissues. Treatment with either vitamin D, lamotrigine or both leads to significant reduction of seizure activity score, improvement of cognitive performance, and amelioration of the disturbed oxidative stress biomarkers. These findings indicate that, vitamin D has anti-epileptic, cognitive improving and antioxidant effects, on its own and enhance the effects of lamotrigine, in a chronic model of epileptic seizures. Thus, vitamin D supplementation may be a useful addition to antiepileptic drugs improving seizure control and cognitive function in patients with epilepsy. PMID- 28818512 TI - pLoc-mEuk: Predict subcellular localization of multi-label eukaryotic proteins by extracting the key GO information into general PseAAC. AB - Many efforts have been made in predicting the subcellular localization of eukaryotic proteins, but most of the existing methods have the following two limitations: (1) their coverage scope is less than ten locations and hence many organelles in an eukaryotic cell cannot be covered, and (2) they can only be used to deal with single-label systems in which each of the constituent proteins has one and only one location. Actually, proteins with multiple locations are particularly interesting since they may have some exceptional functions very important for in-depth understanding the biological process in a cell and for selecting drug target as well. Although several predictors (such as "Euk-mPLoc", "Euk-PLoc 2.0" and "iLoc-Euk") can cover up to 22 different location sites, and they also have the function to treat multi-labeled proteins, further efforts are needed to improve their prediction quality, particularly in enhancing the absolute true rate and in reducing the absolute false rate. Here we propose a new predictor called "pLoc-mEuk" by extracting the key GO (Gene Ontology) information into the general PseAAC (Pseudo Amino Acid Composition). Rigorous cross validations on a high-quality and stringent benchmark dataset have indicated that the proposed pLoc-mEuk predictor is remarkably superior to iLoc-Euk, the best of the aforementioned three predictors. To maximize the convenience of most experimental scientists, a user-friendly web-server for the new predictor has been established at http://www.jci-bioinfo.cn/pLoc-mEuk/, by which users can easily get their desired results without the need to go through the complicated mathematics involved. PMID- 28818513 TI - Corrigendum to "Cognitive impairment and BDNF serum levels" [Polish J. Neurol. Neurosurg. 51 (2017) 24-32]. PMID- 28818514 TI - Effects of low-dose irradiation on mice with Escherichia coli-induced sepsis. AB - Although favorable immune responses to low-dose irradiation (LDI) have been observed in normal mice, i.e., a hormesis effect, little is known about the effects of LDI in infectious diseases. In this study, we examined the effects of LDI on mice with sepsis, a severe and often lethal hyperinflammatory response to bacteria. Female C57BL/6 mice were whole-body irradiated with 10cGy 48h before Escherichia coli infection, and survival, bacterial clearance, cytokines, and antioxidants were quantified. LDI pretreatment significantly increased survival from 46.7% in control mice to 75% in mice with sepsis. The bacterial burden was significantly lower in the blood, spleen, and kidney of LDI-treated mice than in those of control septic mice. The levels of pro-inflammatory cytokines, e.g., IL 1beta and IL-6, as well as anti-inflammatory IL-10 were markedly reduced in pre LDI septic mice. Nitric oxide production by peritoneal macrophages was also reduced in pre-LDI septic mice. Immune cells in the spleen increased and Nrf2 and HO-1 were induced in pre-LDI septic mice. LDI stimulates the immune response and minimizes lethality in septic mice via enhanced bacterial clearance and reduced initial proinflammatory responses. PMID- 28818515 TI - Integrative analysis of hepatic microRNA and mRNA to identify potential biological pathways associated with monocrotaline-induced liver injury in mice. AB - Pyrrolizidine alkaloids (PAs) are a type of natural hepatotoxic compounds. Monocrotaline (MCT), belongs to PAs, is a main compound distributed in medicinal herb Crotalaria ferruginea Grah. ex Benth. This study aims to identify the potential biological signaling pathway associated with MCT-induced liver injury by analyzing the integrative altered hepatic microRNA (miRNA) and mRNA expression profile. C57BL/6 mice were orally given with MCT (270, 330mg/kg). Serum alanine/aspartate aminotransferase (ALT/AST) activity, total bilirubin (TBil) amount and liver histological evaluation showed the liver injury induced by MCT. Results of miRNA chip analysis showed that the hepatic expression of 15 miRNAs (whose signal intensity>200) was significantly altered in MCT-treated mice, and among them total 11 miRNAs passed further validation by using Real-time PCR assay. Results of mRNA chip analysis demonstrated that the hepatic expression of 569 genes was up-regulated and of other 417 genes was down-regulated in MCT treated mice. There are total 426 predicted target genes of those above altered 11 miRNAs, and among them total 10 genes were also altered in mice treated with both MCT (270mg/kg) and MCT (330mg/kg) from the results of mRNA chip. Among these above 10 genes, total 8 genes passed further validation by using Real-time PCR assay. Only 1 biological signaling pathway was annotated by using those above 8 genes, which is phagosome. In conclusion, this study demonstrated the integrative altered expression profile of liver miRNA and mRNA, and identified that innate immunity may be critically involved in MCT-induced liver injury in mice. PMID- 28818517 TI - PPAR agonists for primary biliary cholangitis. PMID- 28818516 TI - Autoimmune potential of perchloroethylene: Role of lipid-derived aldehydes. AB - Tetrachloroethene (perchloroethylene, PCE), an ubiquitous environmental contaminant, has been implicated in inducing autoimmunity/autoimmune diseases (ADs), including systemic lupus erythematosus (SLE) and scleroderma in humans. However, experimental evidence suggesting the potential of PCE in mediating autoimmunity is lacking. This study was, therefore, undertaken to explore PCE's potential in inducing/exacerbating an autoimmune response. Six-week old female MRL+/+ mice, in groups of 6 each, were treated with PCE (0.5mg/ml) via drinking water for 12, 18 and 24weeks and markers of autoimmunity and oxidative stress were evaluated. PCE exposure led to significant increases in serum anti-nuclear antibodies (ANA), anti-dsDNA and anti-scleroderma-70 (anti-Scl-70) antibodies at 18weeks and, to a greater extent at 24weeks, suggesting that PCE exposure exacerbated autoimmunity in our animal model. The increases in autoantibodies were associated with time-dependent increases in malondialdehyde (MDA)-protein adducts and their antibodies, as well as significantly decreased levels of antioxidants GSH and SOD. The splenocytes isolated from mice treated with PCE for 18 and 24weeks showed greater Th17 cell proliferation and increased release of IL 17 in culture supernatants following stimulation with MDA-mouse serum albumin adducts, suggesting that MDA-modified proteins may act as an immunologic trigger by activating Th17 cells and contribute to PCE-mediated autoimmunity. Our studies thus provide an experimental evidence that PCE induces/exacerbates an autoimmune response and lipid-derived aldehydes (such as MDA) contribute to this response. PMID- 28818519 TI - Decomposition characteristics of three different kinds of aquatic macrophytes and their potential application as carbon resource in constructed wetland. AB - Decomposition of aquatic macrophytes usually generates significant influence on aquatic environment. Study on the aquatic macrophytes decomposition may help reusing the aquatic macrophytes litters, as well as controlling the water pollution caused by the decomposition process. This study verified that the decomposition processes of three different kinds of aquatic macrophytes (water hyacinth, hydrilla and cattail) could exert significant influences on water quality of the receiving water, including the change extent of pH, dissolved oxygen (DO), the contents of carbon, nitrogen and phosphorus, etc. The influence of decomposition on water quality and the concentrations of the released chemical materials both followed the order of water hyacinth > hydrilla > cattail. Greater influence was obtained with higher dosage of plant litter addition. The influence also varied with sediment addition. Moreover, nitrogen released from the decomposition of water hyacinth and hydrilla were mainly NH3-N and organic nitrogen while those from cattail litter included organic nitrogen and NO3--N. After the decomposition, the average carbon to nitrogen ratio (C/N) in the receiving water was about 2.6 (water hyacinth), 5.3 (hydrilla) and 20.3 (cattail). Therefore, cattail litter might be a potential plant carbon source for denitrification in ecological system of a constructed wetland. PMID- 28818520 TI - Owlready: Ontology-oriented programming in Python with automatic classification and high level constructs for biomedical ontologies. AB - OBJECTIVE: Ontologies are widely used in the biomedical domain. While many tools exist for the edition, alignment or evaluation of ontologies, few solutions have been proposed for ontology programming interface, i.e. for accessing and modifying an ontology within a programming language. Existing query languages (such as SPARQL) and APIs (such as OWLAPI) are not as easy-to-use as object programming languages are. Moreover, they provide few solutions to difficulties encountered with biomedical ontologies. Our objective was to design a tool for accessing easily the entities of an OWL ontology, with high-level constructs helping with biomedical ontologies. METHODS: From our experience on medical ontologies, we identified two difficulties: (1) many entities are represented by classes (rather than individuals), but the existing tools do not permit manipulating classes as easily as individuals, (2) ontologies rely on the open world assumption, whereas the medical reasoning must consider only evidence-based medical knowledge as true. We designed a Python module for ontology-oriented programming. It allows access to the entities of an OWL ontology as if they were objects in the programming language. We propose a simple high-level syntax for managing classes and the associated "role-filler" constraints. We also propose an algorithm for performing local closed world reasoning in simple situations. RESULTS: We developed Owlready, a Python module for a high-level access to OWL ontologies. The paper describes the architecture and the syntax of the module version 2. It details how we integrated the OWL ontology model with the Python object model. The paper provides examples based on Gene Ontology (GO). We also demonstrate the interest of Owlready in a use case focused on the automatic comparison of the contraindications of several drugs. This use case illustrates the use of the specific syntax proposed for manipulating classes and for performing local closed world reasoning. CONCLUSION: Owlready has been successfully used in a medical research project. It has been published as Open Source software and then used by many other researchers. Future developments will focus on the support of vagueness and additional non-monotonic reasoning feature, and automatic dialog box generation. PMID- 28818518 TI - Seladelpar (MBX-8025), a selective PPAR-delta agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double blind, randomised, placebo-controlled, phase 2, proof-of-concept study. AB - BACKGROUND: Many patients with primary biliary cholangitis have an inadequate response to first-line therapy with ursodeoxycholic acid. Seladelpar is a potent, selective agonist for the peroxisome proliferator-activated receptor-delta (PPAR delta), which is implicated in bile acid homoeostasis. This first-in-class study evaluated the anti-cholestatic effects and safety of seladelpar in patients with an inadequate response to ursodeoxycholic acid. METHODS: The study was a 12-week, double-blind, placebo-controlled, phase 2 trial of patients with alkaline phosphatase of at least 1.67 times the upper limit of normal (ULN) despite treatment with ursodeoxycholic acid. Patients, recruited at 29 sites in North America and Europe, were randomly assigned to placebo, seladelpar 50 mg/day, or seladelpar 200 mg/day while ursodeoxycholic acid was continued. Randomisation was done centrally (1:1:1) by a computerised system using an interactive voice-web response system with a block size of three. Randomisation was stratified by region (North America and Europe). The primary outcome was the percentage change from baseline in alkaline phosphatase over 12 weeks, analysed in the modified intention-to-treat (ITT) population (any randomised patient who received at least one dose of medication and had at least one post-baseline alkaline phosphatase evaluation). This study is registered with ClinicalTrials.gov (NCT02609048) and the EU Clinical Trials Registry (EudraCT2015-002698-39). FINDINGS: Between Nov 4, 2015, and May 26, 2016, 70 patients were screened at 29 sites in North America and Europe. During recruitment, three patients treated with seladelpar developed fully reversible, asymptomatic grade 3 alanine aminotransferase increases (one on 50 mg, two on 200 mg), ranging from just over five to 20 times the ULN; as a result, the study was terminated after 41 patients were randomly assigned. The modified ITT population consisted of 12 patients in the placebo group, 13 in the seladelpar 50 mg group, and 10 in the seladelpar 200 mg group. Mean changes from baseline in alkaline phosphatase were -2% (SD 16) in the placebo group, -53% (14) in the seladelpar 50 mg group, and -63% (8) in the seladelpar 200 mg group. Changes in both seladelpar groups versus placebo were significant (p<0.0001 for both groups vs placebo), with no significant difference between the two seladelpar groups (p=0.1729). All five patients who received seladelpar for 12 weeks had normal alkaline phosphatase values at the end of treatment, based on a central laboratory ULN for alkaline phosphatase of 116 U/L. The most frequently reported adverse events were pruritus (16%; one patient on placebo, four on seladelpar 50 mg, and one on seladelpar 200 mg), nausea (13%; one patient on placebo, three on seladelpar 50 mg, and one on seladelpar 200 mg), diarrhoea (10%; two patients on placebo, one on seladelpar 50 mg, and one on seladelpar 200 mg), dyspepsia (8%; two patients on seladelpar 50 mg and one on seladelpar 200 mg), muscle spasms (8%; three patients on seladelpar 200 mg), myalgia (8%; one patient on placebo and two on seladelpar 200 mg), and dizziness (8%; one patient on placebo and two on seladelpar 50 mg). INTERPRETATION: Seladelpar normalised alkaline phosphatase levels in patients who completed 12 weeks of treatment. However, treatment was associated with grade 3 increases in aminotransferases and the study was stopped early. The effects of seladelpar should be explored at lower doses. FUNDING: CymaBay Therapeutics. PMID- 28818521 TI - Current approach of the axilla in patients with early-stage breast cancer. AB - The surgical approach of the axilla in patients with early-stage breast cancer has witnessed considerable evolution during the past 25 years. The previously undisputed gold standard of axillary-lymph-node dissection for staging has now been replaced by sentinel-lymph-node biopsy for patients with clinically negative axilla. For selected patients with limited sentinel-lymph-node involvement, completion axillary-lymph-node dissection can be omitted or replaced by axillary radiotherapy, reducing morbidity. The clinical interest of axillary staging after neoadjuvant chemotherapy is increasing and this approach might contribute to morbidity reduction, and to the further tailoring of future systemic and locoregional treatment decisions by response assessment. Refinement of the sentinel-lymph-node biopsy technique might overcome the slightly impaired success rates in this setting. New techniques for lymphatic mapping attempt to further simplify the procedure. In view of the declining influence of axillary nodal status on adjuvant therapy decision-making, ongoing clinical trials will evaluate whether sentinel-lymph-node biopsy can be avoided altogether in selected patients. PMID- 28818522 TI - Reduced critical care utilization: Another victory for effective bystander interventions in cardiac arrest. PMID- 28818523 TI - Cognitive impairments and subjective cognitive complaints after survival of cardiac arrest: A prospective longitudinal cohort study. AB - BACKGROUND: Cardiac arrest can lead to hypoxic brain injury, which can affect cognitive functioning. OBJECTIVE: To investigate the course of objective and subjective cognitive functioning and their association during the first year after cardiac arrest. METHODS: A multi-centre prospective longitudinal cohort study with one year follow-up (measurements at two weeks, three months and one year). Cognitive functioning was measured with a neuropsychological test battery and subjective cognitive functioning with the Cognitive Failures Questionnaire. RESULTS: 141 cardiac arrest survivors participated. Two weeks post cardiac arrest 16% to 29% of survivors were cognitively impaired varying on the different tests, at three months between 9% and 23% and at one year 10%-22% remained impaired with executive functioning being affected most. Significant reduction of cognitive impairments was seen for all tests, with most recovery during the first three months after cardiac arrest. Subjective cognitive complaints were present at two weeks after cardiac arrest in 11%, 12% at three months and 14% at one year. There were no significant associations between cognitive impairments and cognitive complaints at any time point. CONCLUSIONS: Cognitive impairments are common in cardiac arrest survivors with executive functioning being mostly affected. Most recovery is seen in the first three months after cardiac arrest. After one year, a substantial number of patients remain impaired, especially in executive functioning. Because of absence of associations between impairments and complaints, cognitive testing using a sensitive test battery is important and should be part of routine follow-up after a cardiac arrest. PMID- 28818524 TI - Loss of sestrin 2 potentiates the early onset of age-related sensory cell degeneration in the cochlea. AB - Sestrin 2 (SESN2) is a stress-inducible protein that protects tissues from oxidative stress and delays the aging process. However, its role in maintaining the functional and structural integrity of the cochlea is largely unknown. Here, we report the expression of SESN2 protein in the sensory epithelium, particularly in hair cells. Using C57BL/6J mice, a mouse model of age-related cochlear degeneration, we observed a significant age-related reduction in SESN2 expression in cochlear tissues that was associated with early onset hearing loss and accelerated age-related sensory cell degeneration that progressed from the base toward the apex of the cochlea. Hair cell death occurred by caspase-8 mediated apoptosis. Compared to C57BL/6J control mice, Sesn2 KO mice displayed enhanced expression of proinflammatory genes and activation of basilar membrane macrophages, suggesting that loss of SESN2 function provokes the immune response. Together, these results suggest that Sesn2 plays an important role in cochlear homeostasis and immune responses to stress. PMID- 28818525 TI - Whole-transcriptome microarray analysis reveals regulation of Rab4 by RBM5 in neurons. AB - : RNA binding motif 5 (RBM5) is a nuclear protein that modulates gene transcription and mRNA splicing in cancer cells. The brain is among the highest RBM5-expressing organ in the body but its mRNA target(s) or functions in the CNS have not been elucidated. Here we knocked down (KO) RBM5 in primary rat cortical neurons and analyzed total RNA extracts by gene microarray vs. neurons transduced with lentivirus to deliver control (non-targeting) shRNA. The mRNA levels of Sec23A (involved in ER-Golgi transport) and the small GTPase Rab4a (involved in endocytosis/protein trafficking) were increased in RBM5 KO neurons relative to controls. At the protein level, only Rab4a was significantly increased in RBM5 KO extracts. Also, elevated Rab4a levels in KO neurons were associated with decreased membrane levels of oligomeric serotonin transporters (SERT). Finally, RBM5 KO was associated with increased uptake of membrane-derived monomeric SERT. SIGNIFICANCE: Rab4a is involved in the regulation of endocytosis and protein trafficking in cells. In the CNS it regulates diverse neurobiological functions including (but not limited to) trafficking of transmembrane proteins involved in neurotransmission (e.g. SERT), maintaining dendritic spine size, promoting axonal growth, and modulating cognition. Our findings suggest that RBM5 regulates Rab4a in rat neurons. PMID- 28818527 TI - Prostate Specific Antigen Testing after Radical Prostatectomy-Can We Stop at 20 Years? AB - PURPOSE: We examined the clinical features and outcomes associated with delayed biochemical recurrence after radical prostatectomy, specifically among men with more than 20 years of followup. MATERIALS AND METHODS: A total of 16,720 men underwent radical prostatectomy and 2,699 experienced biochemical recurrence. We determined predictors of delayed biochemical recurrence as well as metastasis free and cancer specific survival rates for recurrence at various time points after radical prostatectomy. We performed subset analysis of the 732 men with 20 or more years of recurrence-free followup. Cumulative incidence curves for metastasis and prostate cancer death were calculated and stratified by biochemical recurrence time points. RESULTS: Predictors of delayed biochemical recurrence included elevated prostate specific antigen at radical prostatectomy, higher clinical and pathological stage, and positive surgical margins. Delayed biochemical recurrence was associated with favorable cumulative incidence curves for metastasis and prostate cancer death compared to early biochemical recurrence. Among the 732 men with undetectable prostate specific antigen at 20 years biochemical recurrence developed in 17 (2.3%), metastatic disease developed in a single patient and none died of prostate cancer. The actuarial probability of biochemical recurrence among men with undetectable prostate specific antigen at 20 years increased with adverse pathological features. CONCLUSIONS: Men with delayed biochemical recurrence have favorable clinical features and improved survival. Men with undetectable prostate specific antigen 20 years after radical prostatectomy had a low rate of recurrence and no deaths from prostate cancer. This suggests that 20 years is a reasonable time to discontinue prostate specific antigen testing. PMID- 28818526 TI - Which Patients with Upper Tract Urothelial Carcinoma Can be Safely Treated with Flexible Ureteroscopy with Holmium:YAG Laser Photoablation? Long-Term Results from a High Volume Institution. AB - PURPOSE: We tested the effects of tumor size, distribution and grade on progression-free survival in patients with upper tract urothelial carcinoma treated with flexible ureteroscopy with Ho:YAG laser photoablation. MATERIALS AND METHODS: Included in analysis were data on 92 consecutive patients with upper tract urothelial carcinoma treated with Ho:YAG laser photoablation from 2003 to 2015 at a single tertiary care referral center. Stringent followup was offered according to EAU (European Association of Urology) guidelines. Progression during followup was defined by tumor upgrading, distant metastases and/or a relapsing tumor that could not be completely removed with a conservative approach. Kaplan Meier curves were used to assess the rate of disease progression according to tumor size (1 or less cm vs greater than 1 cm), tumor distribution (unifocal vs multifocal) and tumor grade (low vs high). Cox regression analysis was done to test the impact of clinical and pathological characteristics on the rate of progression-free survival. RESULTS: At a median followup of 52 months (IQR 27.8 76.4) the progression-free survival rate was 68% vs 72% in patients with a tumor size of 1 or less vs greater than 1 cm (p = 0.9), 72% vs 69% in patients with unifocal vs multifocal lesions (p = 0.6) and 75% vs 52% in patients with a low vs a high grade tumor (p = 0.03). On multivariable Cox regression analysis tumor grade at first treatment was the only independent predictor of disease progression (HR 5.16, 95% CI 1.19-22.26, p = 0.03). CONCLUSIONS: High tumor grade independently decreased progression-free survival in patients with upper tract urothelial carcinoma treated with Ho:YAG laser photoablation. Tumor size greater than 1 cm and multifocality did not increase the risk of disease progression in patients treated conservatively with Ho:YAG laser photoablation. PMID- 28818528 TI - Imaging in Autonomic Neuroscience: Seeing is believing. PMID- 28818529 TI - Statistical response to issues with the determination of the troponin 99th percentile. PMID- 28818530 TI - Recent developments in clinical trials of botulinum neurotoxins. AB - Botulinum neurotoxins (BoNTs) are increasingly used in clinical practice for several indications. Following the pioneering years of discoveries, the recent years have witnessed an increase of new indications and new toxin brands. We review here the clinical trials on BoNTs performed since 2014 and put them into perspective. We also review the ongoing trials listed by the National Institutes of Health registry (Clinicaltrials.gov). The following indications are reviewed here: blepharospasm, cervical dystonia, spasticity, cerebral palsy, urinary incontinence, headache, topical formulations, postoperative cardiac arrhythmia, keloids and scars. For each of these indications the latest trials are reviewed and commented. PMID- 28818531 TI - The position of fluorine in CP-118,954 affects AChE inhibition potency and PET imaging quantification for AChE expression in the rat brain. AB - The in vitro inhibition potency against acetylcholinesterase (AChE) of fluorinated derivatives of CP-118,954 (1) has been shown to depend upon the position of aromatic fluorine (F) substitution on the N-benzyl moiety. Indeed, the meta-F-substituted compound 3 (IC50=1.4nM) shows similar potency with the parent compound 1 (IC50=1.2nM), whereas the ortho-F derivative 2 (IC50=3.2nM) and para-F derivative 4 (IC50=10.8nM) were found to be less potent AChE inhibitors. A comparative in vivo microdialysis study in rats showed that 3 has the strongest effect on the neuropharmacological properties as AChE inhibitor. For PET imaging studies, a radiolabeled ligand ([18F]3) was synthesized through nucleophilic aromatic substitution reaction of diaryliodonium salt-based aldehyde precursor followed by reductive alkylation in a two-step radiolabeling procedure with 11.5 +/- 1.2% (n=24, non-decay corrected) radiochemical yield and over 99% radiochemical purity. In a comparative PET imaging study of the three 18F containing derivatives of CP-118,954 ([18F]2-4), [18F]3 showed the highest radioactivity in the AChE-rich region of normal rat brain which visually reflected the in vitro AChE-binding affinity of 3. These findings support [18F]3 as a promising AChE-targeted PET imaging ligand for the assessment of cholinergic activity into the brain, providing also insights into the AChE ligand disposition, which depends upon the position of the aromatic fluorine in the benzyl moiety. PMID- 28818532 TI - Myricetin solid lipid nanoparticles: Stability assurance from system preparation to site of action. AB - Myricetin - a natural flavonoid - has attracted a great interest due to its antioxidant and free-radical scavenging potential. However, its physicochemical instability critically impairs its dosage form design, evaluation and administration. In an attempt to protect from degradation, MYR was encapsulated into Gelucire-based solid lipid nanoparticles (SLNs). The impact of medium pH, processing temperature and different additives on the drug degradation either in free or nanoencapsulated form was assessed. MYR stability was further monitored in essential biorelevant fluids. Investigations have led to the recommendation that the presence of fat-soluble antioxidant is necessary during SLN preparation to protect the drug at high temperature. Meanwhile, physiological buffers as well as simulated fluids should be supplemented with stabilizers as tween 80 and Poloxamer 407, in addition to water-soluble antioxidant such as sodium sulfite. Interestingly, mucin-containing fluids are suggested to provide better protection to MYR, in contrast, cell culture media do not guarantee MYR stability. The degradation kinetics changed from 1st to 2nd order mechanism after MYR nanoencapsulation. In presence of the aforementioned additives, MYR-SLNs significantly reduced the drug degradation rate constant up to 300-folds and prolonged the half-life time up to 4500-folds compared to free MYR in physiological buffers (One-way ANOVA, p<0.05). As a proof of concept, in vitro release experiment in presence of phosphate buffer (pH7.4) supplemented with these additives ensured sustained release of MYR over >8h with no signs of degradation. The study emphasizes virtuous guidance regarding appropriate nanoencapsulation conditions and evaluation attributes ensuing MYR physicochemical stability. PMID- 28818533 TI - The association between bouted and non-bouted physical activity on retinopathy prevalence. AB - OBJECTIVE: We evaluated the specific differential association between non-bouted, lifestyle physical activities (vs. structured exercise; i.e., bouted physical activity) on retinopathy prevalence among a national sample of the broader U.S. adult population. METHODS: Data from the 2005-2006 National Health and Nutrition Examination Survey (NHANES) was used to identify 1501 adults, between 40 and 85years. Bouted and non-bouted physical activities were assessed using objective accelerometer monitoring. A 10-minute bout was defined as 10+ consecutive minutes above the moderate-to-vigorous physical activity (MVPA) cut-point, with the allowance of 1-2-minute interruption intervals. Non-bout MVPA was determined by the number of MVPA minutes not accrued in a bout. Participants were screened for non-proliferative retinopathy using Early Treatment Diabetic Retinopathy Study grading criteria, as well as objective retinal imaging assessments using the Canon Non-Mydriatic Retinal Camera CR6-45NM. Individuals were excluded if they had been diagnosed with coronary artery disease, congestive heart failure, heart attack or stroke. RESULTS: Participants with worse retinopathy engaged in less bouted and non-bouted physical activity, had a higher BMI and were more likely to have diabetes and hypertension. For every 1min/day increase in non-bouted MVPA, participants had a 7% reduced odds of moderate-to-severe retinopathy compared to no retinopathy (OR=0.93; 95% CI: 0.87-0.99; P=0.04); results were similar in an unadjusted model (OR=0.93; 95% CI: 0.89-0.97; P=0.007). Bouted MVPA was not associated with retinopathy prevalence in the multivariate model. CONCLUSION: In this nationally representative sample of adults, those who engaged in non-bouted physical activity had reduced odds of a diagnosis of moderate-to-severe retinopathy. PMID- 28818534 TI - Endoscopic Treatment of Vesicoureteral Reflux in Infants. Can We Do It and Should We Do It? AB - OBJECTIVE: To evaluate the outcomes of endoscopic treatment of vesicoureteral reflux (VUR) performed on infants, and to discuss the possible role of this approach in selected cases. MATERIAL AND METHODS: A retrospective analysis was conducted on the patients who underwent endoscopic injection of a bulking substance for VUR in our institution, and a comparison was made with patients treated during infancy and those treated later in life. RESULTS: A total of 463 ureteral units were included (296 children), of whom 47 were patients less than 1 year of age (infants, INF group); the remaining 416 were included in a second group (children, CHL). In this study, the percentage of high-grade VUR and presence of reflux nephropathy were significantly higher in younger patients. Both early failure and recurrence rate were significantly higher in the INF group when compared with the CHL group. No complications were observed in the INF group. CONCLUSION: Endoscopic treatment of VUR is feasible in patients less than 1 year of age. The effectiveness is lower than when patients are treated at a later age but was still over 80% in our series. There were no complications reported related to the procedure itself or to the general anesthesia. Once it is known that endoscopic treatment of VUR can be performed, controversy arises about the indication of treating patients with VUR. Careful selection of VUR cases that are less likely to spontaneously resolve, presence of breakthrough infections, and parental preference, all play a role in the decision-making process. PMID- 28818535 TI - Use of the Ileum for Ureteral Stricture and Obstruction in Bilateral, Unilateral, and Single-kidney Cases. AB - OBJECTIVE: To investigate the functional outcomes of ileal ureter replacement for complex ureteral loss, including bilateral and single ureter stricture, as a result of various etiologies. METHODS: In 2013-2016, 31 patients underwent ileal ureter replacement surgery. The data for their assessments included etiology, combined surgical procedures, ureteral replacement type, postoperative complications, and changes in renal function. RESULTS: The 31 study patients had a median age of 56.0 (range 18-65) years and were followed for a median of 23.6 (range 6.5-43.2) months. There were 14 bilateral, 12 unilateral, and 5 single kidney cases. The main indication for surgery was ureteral defects after gynecological surgery and radiation in 24 patients (77.4%). The mean operation time was 370.6 minutes and the median hospital stay was 25.2 (range 6-79) days. Various types of ileal arrangement were performed to cover bilateral ureter loss. After 30 days past surgery, 24 patients (77.4%) were in a stable state and 5 (16.1%) had decreased serum levels of creatinine. Short-term complications greater than grade 3 on the Clavien scale occurred in 10 patients (33.3%), and long-term complications occurred in 27 (87.1%). However, all cases were well relieved by conservative care, and surgical intervention was needed in only 1 case. Apart from 2 patients who died because of the progression of cervical cancer, all patients had stent-free status at 22.4 months. CONCLUSION: Ileal ureter replacement is a useful reconstructive surgery for complex ureteral loss, such as bilateral and single-kidney cases resulting from various etiologies. PMID- 28818536 TI - Glansectomy as Primary Management of Penile Squamous Cell Carcinoma: An International Study Collaboration. AB - OBJECTIVE: To analyze the recurrence and survival outcomes of glansectomy in patients with penile squamous cell carcinoma. MATERIALS AND METHODS: We performed a retrospective review of 410 patients across 5 international tertiary referral centers between 1999 and 2016. All patients had tumors involving the glans penis and underwent glansectomy as primary treatment. The Kaplan-Meier method and log rank test were used to calculate survival and recurrence. Median follow-up was 42 months (interquartile range [IQR] 29-56). RESULTS: The median age was 64 years (IQR 53-72). Median tumor size was 2.2 cm (IQR 1.5-3.0). A total of 240 patients (58.5%) had pT2 disease, whereas only 43 patients (10.5%) had pT3 or pT4 disease. The majority of the cohort had poorly differentiated tumors (43.7%). Most recurrences were local at 7.6% (31 patients). Only 14 patients (3.4%) had regional recurrence and 9 patients (2.2%) had distant recurrence. When stratified by pathologic stage, tumors that were pT2 or higher were (P < .001) and were more likely to be poorly differentiated (P < .001). There were no differences in recurrence location among pathologic stages (P = .15). The 1-, 2-, and 5-year recurrence-free survival were 98%, 94%, and 78%, respectively. There were no differences in overall survival when stratified by stage (P = .67). CONCLUSION: Glansectomy is an oncologically safe treatment modality for squamous cell carcinoma of the glans in appropriately selected invasive tumors. PMID- 28818537 TI - Predicting Grade and Stage at Cystoscopy in Newly Presenting Bladder Cancers-a Prospective Double-Blind Clinical Study. AB - OBJECTIVE: To assess urologists' ability to predict the grade and stage of new bladder cancers from the cystoscopic features alone. PATIENTS AND METHODS: We conducted a prospective clinical study on consecutive patients who underwent transurethral resection of bladder tumor (TURBT) for new bladder cancers. Using only cystoscopic tumor morphology at the time of initial TURBT, 3 urology consultants predicted the grade and stage, recording these on a proforma along with tumor features. Predictions were compared with assessments by uropathologists, blinded to the clinical prediction. We analyzed the accuracy in (1) predicting the exact grade and stage of the cancer; (2) differentiating between low- and high-grade cancers; and (3) discerning between Ta, T1, and T2 cancers. RESULTS: Of 248 patients, 224 were suitable for analysis. The positive predictive values for low- and high-grade cancers were 85.8% and 71.3%, respectively. The overall likelihood of a consultant predicting high-grade cancers as being low grade was 16/83 (19.3%). When tumors were large (>30 mm), this likelihood dropped significantly to 7.3% (4/55) (odds ratio = 3.1, 95% confidence interval = 1.0-9.7, P = .04). Non-muscle-invasive and muscle-invasive cancers were predicted accurately in 93.4% and 85.2% patients, respectively. Six of 161 (3.7%) tumors predicted to be non-muscle-invasive bladder cancer were actually muscle invasive on histology. CONCLUSION: For clinical purposes, in newly presenting patients with bladder cancer, urologists appear to reliably predict lower grade and muscle-invasive disease, confirming widely held belief. This allows for appropriate and efficient use of surgical expertise, available technology, and selection of participants for clinical trials on the basis of prehistology risk categories. PMID- 28818538 TI - Impact of Positron Emission Tomography and Endoscopic Ultrasound Length of Disease Difference on Treatment Planning in Patients with Oesophageal Cancer. AB - AIMS: Treatment decision making and planning in patients with oesophageal cancer are guided by radiological measurement of length of disease (LoD). This study aimed to investigate differences in positron emission tomography (PET) and endoscopic ultrasound (EUS) LoD. Their prognostic significance was also assessed. MATERIALS AND METHODS: LoD was measured from PET and EUS staging investigations by one observer for each modality. Bland-Altman analysis and Wilcoxon signed rank tests assessed agreement and differences in measurements. In terms of radiotherapy planning, the proportion of cases with a clinically significant difference of more than 2 cm between PET and EUS was also calculated. Univariable and multivariable analysis assessed association with overall survival. A P-value < 0.05 was considered statistically significant. RESULTS: Consecutive patients (n = 160, median age 66.0 years [range 24-83], males = 124, adenocarcinomas = 115) staged with PET/CT and EUS between 2011 and 2014 were included. PET tended to under-measure LoD compared with EUS. The median PET and EUS LoD was 6.4 and 8.0 cm, respectively. PET and EUS LoD was significantly different (Z = -7.021, P < 0.001). EUS LoD was more than 2 cm longer than PET LoD in 61 cases (38.1%). In eight cases (5.0%), PET LoD was more than 2 cm longer than EUS LoD. Both variables had prognostic significance in univariable analysis, but were not independent predictors of overall survival. CONCLUSION: There are significant differences in PET and EUS measurement of LoD. This could affect clinical decision making and radiotherapy treatment planning. Clinically significant differences between EUS and PET LoD could lead to a risk of geographical miss in up to 38.1% of cases if the PET/CT measurement alone had been used for radiotherapy planning. These results highlight the continued benefit of EUS in the oesophageal cancer staging and treatment pathway. PMID- 28818539 TI - Playing a rigged game: Inequality's effect on physiological stress responses. AB - High income and wealth inequality corresponds with high rates of various health and social problems. One possible factor that could be contributing to this correlation is stress experienced by those being treated unfairly in an unequal society. The present experiment attempted to simulate aspects of income inequality in a lab setting while recording several measures of stress. Participants (n=96) were assigned to one of four groups and played a memory game against a confederate opponent to earn "money" to spend in a lab market. The four groups depended on the difficulty of the problems and the fairness of the game that they and their opponents experienced. Stress attitudes were assessed with the Short Stress State Questionnaire (SSSQ) and four physiological measures: salivary cortisol, medial frontalis and corrugator facial muscle EMG, heart rate, heart rate variability (HRV), and skin conductance levels (SCL). Cortisol levels and HRV scores were the highest in groups that competed in an unfair game regardless of the difficulty of the problem compared to the groups playing a fair game. The group playing an unfair game with hard problems (disadvantaged) also had elevated facial muscle activity indicating negative affect and reported higher distress on the stress questionnaire. The results of this experiment showed that experiencing inequality even for a short time elicited several stress responses even if the participant benefited from the inequality. PMID- 28818540 TI - Comparative assessment of HPHC yields in the Tobacco Heating System THS2.2 and commercial cigarettes. AB - There has been a sustained effort in recent years to develop products with the potential to present less risk compared with continued smoking as an alternative for adult smokers who would otherwise continue to smoke cigarettes. During the non-clinical assessment phase of such products, the chemical composition and toxicity of their aerosols are frequently compared to the chemical composition and toxicity of the smoke from a standard research cigarette - the 3R4F reference cigarette. In the present study, it is demonstrated that results of these analytical comparisons are similar when considering commercially available cigarette products worldwide. A market mean reduction of about 90% is observed on average across a broad range of harmful and potentially harmful constituents (HPHC) measured in the aerosol of a candidate modified risk tobacco product, the Tobacco Heating System 2.2 (THS2.2), compared against the levels of HPHC of cigarettes representative of selected markets; this mean reduction is well in line with the reduction observed against 3R4F smoke constituents in previous studies. PMID- 28818541 TI - Understanding threats to polio vaccine commitment among caregivers in high priority areas of Afghanistan: a polling study. AB - BACKGROUND: Eradication of poliovirus from endemic countries relies on vaccination of children with oral polio vaccine (OPV) many times a year until the age of 5 years. We aimed to determine caregivers' commitment to OPV in districts of Afghanistan at high risk for polio transmission and to examine what knowledge, attitudes, or experiences could threaten commitment. METHODS: We designed and analysed a poll using face-to-face interviews among caregivers of children under 5 years of age. The sample was drawn via a stratified multistage cluster design with random route household selection. We calculated the percentage of committed and uncommitted caregivers. All percentages were weighted. We then compared percentages of uncommitted caregivers among those with varying knowledge, attitudes, and experiences, using logistic regression to control for possible demographic confounders. FINDINGS: Between Dec 19, 2014, and Jan 5, 2015, we interviewed 1980 caregivers, 21% of whom were "uncommitted" to accepting OPV. Multiple measures of knowledge, attitudes, and experiences are associated with lack of commitment. For example, compared with their relevant counterparts, caregivers are more likely to be uncommitted if they did not trust vaccinators "a great deal" (54% vs 9%), if they do not know that polio spreads through contaminated water (41% vs 14%), or if they believe rumours that OPV is not halal (50% vs 21%). INTERPRETATION: To enhance OPV commitment, it might be useful to consider a multifactorial approach that highlights building trust in vaccinators, providing facts about transmission, sharing positive messages to overcome key rumours, and strengthening community support for vaccination. FUNDING: Harvard T H Chan School of Public Health and UNICEF. PMID- 28818542 TI - Patterns of bacteraemia aetiology. PMID- 28818543 TI - Understanding commitment to polio vaccination. PMID- 28818545 TI - New anti-HCV drug combinations: who will benefit? PMID- 28818544 TI - Trends in antimicrobial resistance in bloodstream infection isolates at a large urban hospital in Malawi (1998-2016): a surveillance study. AB - BACKGROUND: Bacterial bloodstream infection is a common cause of morbidity and mortality in sub-Saharan Africa, yet few facilities are able to maintain long term surveillance. The Malawi-Liverpool-Wellcome Trust Clinical Research Programme has done sentinel surveillance of bacteraemia since 1998. We report long-term trends in bloodstream infection and antimicrobial resistance from this surveillance. METHODS: In this surveillance study, we analysed blood cultures that were routinely taken from adult and paediatric patients with fever or suspicion of sepsis admitted to Queen Elizabeth Central Hospital, Blantyre, Malawi from 1998 to 2016. The hospital served an urban population of 920 000 in 2016, with 1000 beds, although occupancy often exceeds capacity. The hospital admits about 10 000 adults and 30 000 children each year. Antimicrobial susceptibility tests were done by the disc diffusion method according to British Society of Antimicrobial Chemotherapy guidelines. We used the Cochran-Armitage test for trend to examine trends in rates of antimicrobial resistance, and negative binomial regression to examine trends in icidence of bloodstream infection over time. FINDINGS: Between Jan 1, 1998, and Dec 31, 2016, we isolated 29 183 pathogens from 194 539 blood cultures. Pathogen detection decreased significantly from 327.1/100 000 in 1998 to 120.2/100 000 in 2016 (p<0.0001). 13 366 (51.1%) of 26 174 bacterial isolates were resistant to the Malawian first line antibiotics amoxicillin or penicillin, chloramphenicol, and co-trimoxazole; 68.3% of Gram-negative and 6.6% of Gram-positive pathogens. The proportions of non-Salmonella Enterobacteriaceae with extended spectrum beta-lactamase (ESBL) or fluoroquinolone resistance rose significantly after 2003 to 61.9% in 2016 (p<0.0001). Between 2003 and 2016, ESBL resistance rose from 0.7% to 30.3% in Escherichia coli, from 11.8% to 90.5% in Klebsiella spp and from 30.4% to 71.9% in other Enterobacteriaceae. Similarly, resistance to ciprofloxacin rose from 2.5% to 31.1% in E coli, from 1.7% to 70.2% in Klebsiella spp and from 5.9% to 68.8% in other Enterobacteriaceae. By contrast, more than 92.0% of common Gram positive pathogens remain susceptible to either penicillin or chloramphenicol. Meticillin-resistant Staphylococcus aureus (MRSA) was first reported in 1998 at 7.7% and represented 18.4% of S aureus isolates in 2016. INTERPRETATION: The rapid expansion of ESBL and fluoroquinolone resistance among common Gram-negative pathogens, and the emergence of MRSA, highlight the growing challenge of bloodstream infections that are effectively impossible to treat in this resource limited setting. FUNDING: Wellcome Trust, H3ABionet, Southern Africa Consortium for Research Excellence (SACORE). PMID- 28818546 TI - Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial. AB - BACKGROUND: The once-daily, ribavirin-free, pangenotypic, direct-acting antiviral regimen, glecaprevir coformulated with pibrentasvir, has shown high rates of sustained virological response in phase 2 and 3 studies. We aimed to assess the efficacy and safety of 12 weeks of coformulated glecaprevir and pibrentasvir in patients with hepatitis C virus (HCV) infection and compensated cirrhosis. METHODS: We did this single-arm, open-label, multicentre phase 3 study at 40 sites in Belgium, Canada, Germany, South Africa, Spain, and the USA. We enrolled patients aged 18 years or older with HCV genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. Patients were either HCV treatment-naive or had not responded to treatment with interferon or pegylated interferon with or without ribavirin, or sofosbuvir plus ribavirin with or without pegylated interferon. Oral glecaprevir (300 mg) coformulated with pibrentasvir (120 mg) was administered once daily for 12 weeks. The primary efficacy endpoint was sustained virological response at post-treatment week 12 (HCV RNA <15 IU/mL). We assessed efficacy and safety in all patients who received at least one dose of study drug (intention-to-treat population). This study is registered with ClinicalTrials.gov, number NCT02642432. FINDINGS: Between Dec 7, 2015, and May 4, 2016, we enrolled 146 patients with compensated cirrhosis, of whom 48 (33%) had genotype 1a HCV infection, 39 (27%) had genotype 1b infection, 34 (23%) had genotype 2 infection, 16 (11%) had genotype 4 infection, two (1%) had genotype 5 infection, and seven (5%) had genotype 6 infection. 12 weeks after treatment, 145 patients (99%, 95% CI 98-100) achieved sustained virological response, with one (1%) relapse at post-treatment week 8. We recorded 101 (69%) adverse events, of which 65 (64%) were mild. The most common adverse events were fatigue (n=28 [19%]) and headache (n=20 [14%]). 11 (8%) patients had serious adverse events, none of which were deemed related to study drugs. No patients had elevations in alanine aminotransferase and no patients prematurely discontinued treatment because of adverse events. INTERPRETATION: Our results show that 99% of patients treated with once-daily glecaprevir plus pibrentasvir achieved a sustained virological response at 12 weeks. Furthermore, this drug regimen had a favourable safety profile in previously treated or untreated patients with chronic HCV genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. These findings could help simplify treatment algorithms and reduce treatment burden. FUNDING: AbbVie. PMID- 28818547 TI - Contracting infectious diseases in Sub-Saharan African wetlands: A question of use? A review. AB - Worldwide the pressure on water is increasing. In parts of Sub-Saharan Africa (SSA), natural wetlands constitute the only accessible water resources, providing water free of charge, agricultural potential and livelihoods in otherwise uninhabitable landscapes, which is why they are being used extensively. The degradation and contamination of water which result from the use of wetlands has the potential to spread disease-causing microorganisms and provide increased breeding habitats for disease vectors, Despite this importance, case studies are lacking and knowledge gaps remain about whether and how different kinds of wetland use influence the exposure to health risks and transmission of infectious diseases. This descriptive literature review aimed at identifying publications from peer-reviewed journals and book chapters that (i) address water-related infectious diseases in SSA wetlands and (ii) link those diseases to use-related exposures. The resulting overview includes 27 publications and shows that depending on the type of use, people in wetlands are exposed to different risk factors and water-related infectious diseases. Exposure to infectious agents depends on occupational characteristics, and time spent in wetlands. Disease transmission is driven by users' contact to water, characteristics of pathogens and vectors of disease. The amount of available literature varies significantly. Whereas several publications have linked crop production and the domestic use of wetland water to contraction of diseases, fewer are available on health risks identified with pastoralism in wetlands and other uses. Some risk factors are well researched, such as irrigation schemes favouring schistosomiasis prevalence. For others, including proximity of pastoralists to their livestock and the associated trachoma risk, knowledge remains limited. This review establishes connections of selected diseases with different transmission pathways that are linked to specific risk factors, transmission pathways and resulting diseases. All of these have been integrated into a detailed conceptual framework which simplifies the complexity of the relationships, while at the same time identifying missing links which might provide stimulus for future research tackling the potential research gaps. It concludes that socio-cultural and behavioural considerations regarding the wetland users are not sufficiently evaluated and should receive increased attention in future investigations. PMID- 28818548 TI - Severe acute interstitial lung disease after nivolumab in three non-small cell lung cancer patients with imaging findings of airway obstruction adjacent to lung tumors. AB - Nivolumab has been associated with unique adverse events known as immune-related adverse events. Although interstitial lung disease (ILD) is a life-threatening immune-related adverse event, the risk of ILD during nivolumab treatment is unclear. In this report, we encountered three patients with stage IV non-small cell lung cancer with signs of lung obstruction caused by tumor-mediated compression on imaging who developed acute ILD within 10 days of commencing nivolumab treatment. The first case involved a 74-year-old Japanese female never smoker, the second a 67-year-old Japanese female never-smoker, and the third a 75 year-old Japanese female current-smoker. The first patient was administered nivolumab as third-line chemotherapy, the second was administered nivolumab as fifth-line chemotherapy, and the third was administered nivolumab as second-line chemotherapy. Regardless of aggressive treatments for ILD, 2 of 3 patients died. The findings of these cases suggest that obstructive findings in the lungs, which easily cause infections, may be an important risk factor for nivolumab-induced ILD. PMID- 28818550 TI - Perinephric and Sinus Fat Invasion in Stage pT3a Tumors Managed by Partial Nephrectomy. AB - INTRODUCTION: We evaluated the influence of perinephric fat invasion (PFI) compared with sinus fat invasion (SFI) on disease-free survival (DFS) and cancer specific survival (CSS) after partial nephrectomy (PN) for stage pT3a renal cell carcinoma (RCC). MATERIALS AND METHODS: Data were recorded from the consecutive records of patients who had undergone underwent PN for cT1-T2 RCC from 2007 to 2016. Of these patients, 143 had stage pT3a with SFI or PFI found on final pathologic examination. The demographic, perioperative, and pathologic variables were reviewed. DFS and CSS analyses were performed. The factors predicting disease progression in this population were assessed. RESULTS: After a median follow-up period of 28 months (range 15-41 months), 19 patients (13.3%) had developed recurrence, including 5 local and 14 distant metastases, with 11 cancer specific deaths (7.7%). No differences were found in DFS (5 years, 60.9% vs. 55.3%; log-rank P = .7) or CSS (5 years, 81% vs. 74.2%; log-rank P = .8) between the SFI and PFI groups. For the pT3a fat invasion population, the 2- and 5-year DFS and CSS rates were 83.6% and 58.6% and 93.6% and 78%, respectively. SFI (P = .5) and positive surgical margins (P = .1) did not predict for progression. On multivariate Cox regression, increased tumor size (hazard ratio, 1.5; 95% confidence interval, 1.1-1.9; P < .01) and higher tumor grade (hazard ratio, 3.6; 95% confidence interval, 1.1-4.6; P = .04) were independent predictors of disease progression in the pT3a fat invasion population. CONCLUSION: In our series of patients with pT3a RCC after PN, SFI compared with PFI was not associated with an increased risk of progression or cancer-specific death. PMID- 28818551 TI - Adverse Pathology After Neoadjuvant Chemotherapy and Radical Cystectomy: The Role of Adjuvant Chemotherapy. AB - BACKGROUND: The current guidelines do not recommend adjuvant chemotherapy (AC) for patients with adverse pathologic findings after neoadjuvant chemotherapy (NAC) and radical cystectomy (RC) for bladder cancer. We sought to evaluate the association of AC with overall survival (OS) in these patients. MATERIALS AND METHODS: The National Cancer Database was used to identify patients with adverse pathologic findings (ypT3N0, ypT4N0, or ypTanyN1-N3) after NAC and RC for bladder cancer from 2006 to 2012. The clinicopathologic variables were abstracted, and the patients were stratified according to the receipt of AC. OS was estimated using the Kaplan-Meier method and log-rank test. Associations between AC and OS were evaluated in multivariable Cox proportional hazards regression models among all patients and stratified by pathologic classification. RESULTS: A total of 1361 patients were identified: 444 (32.6%) with ypT3N0, 162 (11.9%) with ypT4N0, and 755 (55.5%) with ypTanyN1-N3. The median OS for the entire cohort was 22.9 months, which differed by pathologic classification: 34.6 months with ypT3N0, 21.4 months with ypT4N0, and 19.3 months with ypTanyN1-N3 (P < .01). AC was used in 328 patients (24.1%), and no difference in OS was observed by receipt of AC (24.6 months with AC vs. 22.0 months without; P = .18). On multivariable analysis, AC was not independently associated with OS (hazard ratio, 0.86; 95% confidence interval, 0.74-1.01; P = .06). CONCLUSION: Patients with adverse pathologic findings at RC after previous NAC have a median OS of approximately 2 years, which was not significantly improved with AC. Clinical trials with newer systemic agents are warranted for patients in this setting to guide future therapy. PMID- 28818549 TI - Integration of DPC and clinical microbiological data in Japan reveals importance of confirming a negative follow-up blood culture in patients with MRSA bacteremia. AB - Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is one of the commonest and most life-threatening of all infectious diseases. The morbidity and mortality rates associated with MRSA bacteremia are higher than those associated with bacteremia caused by other pathogens. A common guideline in MRSA bacteremia treatment is to confirm bacteremia clearance through additional blood cultures 2 4 days after initial positive cultures and as needed thereafter. However, no study has presented statistical evidence of how and to what extent confirming a negative follow-up blood culture impacts clinical outcome. We present this evidence for the first time, by combining clinical microbiological data of blood cultures and the DPC administrative claims database; both had been systematically accumulated through routine medical care in hospitals. We used electronic medical records to investigate the clinical background and infection source in detail. By analyzing data from a university hospital, we revealed how survival curves change when a negative follow-up blood culture is confirmed. We also demonstrated confirmation of a negative culture is significantly associated with clinical outcomes: there was a more than three-fold increase in mortality risk (after adjusting for clinical background) if a negative blood culture was not confirmed within 14 days of the initial positive blood culture. Although we used data from only one university hospital, our novel approach and results will be a basis for future studies in several hospitals in Japan to provide statistical evidence of the clinical importance of confirming a negative follow-up blood culture in bacteremia patients, including those with MRSA infections. PMID- 28818552 TI - Spatial, temporal, and health associations of eating alone: A cross-cultural analysis of young adults in urban Australia and Japan. AB - Eating alone is driven by social and cultural factors, not solely by individual preferences. In academic research, eating alone is often simply treated as an alternative to social, commensal eating, and little is known about the practice of eating alone itself. This study employs a cross-cultural analysis to explore social and cultural associations of eating alone. The analysis is based on 1) cultural domain data, derived from principal component analysis of freelist responses, a set of words or phrases related to the topic of eating alone; and 2) in-depth interviews with 72 young adults aged 20-40 in urban Australia and Japan. Many Australian and Japanese young adult participants associated eating alone with both pleasure and stress of being isolated from others. However, the comparison of principal components between Australian and Japanese groups and gender subgroups showed cross-cultural variations and complexity in the context of eating alone including: locations and timings of eating alone, and associations with healthy/unhealthy eating. Analyses of interviews are included to deepen understandings of cultural domains. These key associations are influenced by a range of social and cultural environments such as fast food cultures, work and life environments, and the scope of public health nutrition programs. The association between eating alone and healthy eating among young adults indicates that individualistic understandings of food intake in current public health nutrition programs are more favorable to eating alone and foster a gap between ideas of healthy eating and commensal eating as a cultural ideal. PMID- 28818553 TI - The training and creativity of professional chefs: Stoking the imagination in global gastronomic discourse. AB - The sameness of eating out has been criticised in some quarters of food media in recent years. In this paper I demonstrate through the case of three chefs in Hong Kong how this sameness is the product of global gastronomic discourse. I suggest that chefs play a crucial role in providing the content that fuels gastronomic discourses and also in delivering the experiences of the discourse on the plate to diners. The experience of chefs in cuisines such as Thai, Vietnamese and Spanish allows them to prepare dishes that attract plaudits from food media and fuel the imagination of potential diners. This experience includes professional training in a cuisine under a well-known exponent of the cuisine, which allows them to be associated with the image of their mentor. The other route is vocational culinary training, which gives the chefs the ability to create dishes that stoke the imagination of diners. PMID- 28818554 TI - Reply to "prolongation of terminal latency of the phrenic nerve in amyotrophic lateral sclerosis - Is it clinically useful, and what are the mechanisms?" PMID- 28818555 TI - Pyridoxine-5'-phosphate oxidase (Pnpo) deficiency: Clinical and biochemical alterations associated with the C.347g>A (P..Arg116gln) mutation. AB - BACKGROUND: Pyridoxal-5'-phosphate oxidase (PNPO) deficiency presents as a severe neonatal encephalopathy responsive to pyridoxal-5'-phosphate (PLP) or pyridoxine. Recent studies widened the phenotype of this condition and detected genetic variants on PNPO gene whose pathogenic role and clinical expression remain to be established. OBJECTIVE: This paper aims to characterize the functional effects of the c.347G>A (p.Arg116Gln) mutation in the PNPO gene in order to define its pathogenicity and describe the clinical features of new patients with epilepsy carrying this mutation. METHODS: Arg116Gln protein variant was expressed as recombinant protein. The mutant protein was characterized with respect to structural and kinetic properties, thermal stability, binding constants of cofactor (FMN) and product (PLP). We also reviewed clinical data of 3 new patients carrying the mutation. RESULTS: The Arg116Gln mutation does not alter the overall enzyme structure and only slightly affects its catalytic efficiency; nevertheless, this mutation affects thermal stability of PNPO, reduces its affinity for FMN and impairs transfer of PLP to PLP-dependent enzymes. Three boys with seizure onset between 8months and 3years of age, carrying the Arg116Gln mutation, are described. These three patients exhibited different seizure types associated with interictal EEG abnormalities and slow background activity. Mild/moderate intellectual disability was observed in 2/3 patients. A dramatic therapeutic response to pyridoxine was observed in the only patient who still had active seizures when starting treatment, while in all three patients interictal EEG discharges and background activity improved after pyridoxine treatment was initiated. CONCLUSIONS: The reported data support a pathogenic role of the c.347G>A (p.Arg116Gln) mutation in PNPO deficiency. The later onset of symptoms and the milder epilepsy phenotype of these expand the disease phenotype. PMID- 28818556 TI - Receptor binding kinetics equations: Derivation using the Laplace transform method. AB - INTRODUCTION: Measuring unlabeled ligand receptor binding kinetics is valuable in optimizing and understanding drug action. Unfortunately, deriving equations for estimating kinetic parameters is challenging because it involves calculus; integration can be a frustrating barrier to the pharmacologist seeking to measure simple rate parameters. Here, a well-known tool for simplifying the derivation, the Laplace transform, is applied to models of receptor-ligand interaction. The method transforms differential equations to a form in which simple algebra can be applied to solve for the variable of interest, for example the concentration of ligand-bound receptor. METHODS: The goal is to provide instruction using familiar examples, to enable investigators familiar with handling equilibrium binding equations to derive kinetic equations for receptor-ligand interaction. First, the Laplace transform is used to derive the equations for association and dissociation of labeled ligand binding. Next, its use for unlabeled ligand kinetic equations is exemplified by a full derivation of the kinetics of competitive binding equation. Finally, new unlabeled ligand equations are derived using the Laplace transform. These equations incorporate a pre-incubation step with unlabeled or labeled ligand. RESULTS: Four equations for measuring unlabeled ligand kinetics were compared and the two new equations verified by comparison with numerical solution. Importantly, the equations have not been verified with experimental data because no such experiments are evident in the literature. Equations were formatted for use in the curve-fitting program GraphPad Prism 6.0 and fitted to simulated data. DISCUSSION: This description of the Laplace transform method will enable pharmacologists to derive kinetic equations for their model or experimental paradigm under study. Application of the transform will expand the set of equations available for the pharmacologist to measure unlabeled ligand binding kinetics, and for other time-dependent pharmacological activities. PMID- 28818557 TI - DNA aptamer identification and characterization for E. coli O157 detection using cell based SELEX method. AB - Escherichia coli (E. coli) O157:H7 is a foodborne pathogen that causes symptoms in humans. Its rapid identification should be considered to avoid toxic effects of the pathogen. In this study, systematic evolution of ligands by exponential enrichment using whole cells (Cell-SELEX) method was used for recognizing E. coli strain, O157 by single-stranded DNA library of aptamer. Nine rounds of cell-selex procedure were applied using O157, as a whole-cell target, with O42, K12, Top10, DH5alpha E. coli cells, Shigella flexneri and Salmonella typhi as counterparts. The specific interaction between selected DNA aptamers and targeted cell was assessed. After applying six rounds of SELEX for selection of DNA aptamers, the candidate sequences were obtained. Finally, specific aptamer was selected as an ideal aptamer for detection and capturing of E. coli O157. Dissociation constant of the selected aptamer were calculated (107.6 +/- 67.8 pM). In addition, the secondary structure prediction and cross reactivity assays were performed. The isolated aptamer efficiency was confirmed and it was shown that the new DNA aptamer sequence has the ability to use for detection. This specific O157:H7 aptamer have the potential for application as a diagnostic ligand and could be used for detection of the related food borne diseases. PMID- 28818558 TI - Current and emerging pharmacotherapies for obesity in Australia. AB - BACKGROUND: Obesity is a major issue in Australia and globally. Many individuals struggle to maintain weight loss with lifestyle modification, and adjunctive pharmacotherapy may help. Historically, there have been limited pharmacotherapies for managing obesity. In addition, previous treatments such as phentermine fenfluramine, rimonabant and sibutramine were withdrawn due to safety issues, resulting in lingering safety concerns. METHODS: This is a narrative review of published data examining four new pharmacotherapy options for weight management in Australia. Of four new therapeutic options, three may be approved in Australia shortly and one - liraglutide 3.0mg - was approved in December 2015. Liraglutide is a glucagon-like peptide-1 receptor agonist that appears to act by increasing satiety and reducing food intake. Lorcaserin is a selective agonist of the serotonin2C receptor, which mediates anorectic activity. The naltrexone/bupropion extended release (ER) combination utilises synergistic effects of the two component drugs, mediated via neurons in the hypothalamus, to reduce energy intake. Phentermine/topiramate ER combines the appetite suppressant phentermine with topiramate, an anti-epileptic with appetite-suppressant effects. All can result in meaningful improvements in obesity-related diseases, including diabetes and cardiovascular disorders) in large phase 3 trials, with efficacy demonstrated over 3 years for liraglutide 3.0 mg and 1-2 years for the rest. CONCLUSIONS: The landscape of obesity treatment is changing rapidly. Of the new therapeutic options presented, all options have associated adverse events requiring long-term safety data, but the availability of new options is a welcome development. PMID- 28818559 TI - To Boldly Go Where One Has Gone Before. AB - Americans are suffering from a culture of taking pills. Six out of ten Americans utilize at least one prescription drug, and more than one in ten use five or more prescription medicines. Although this torrent of taking pills is already high, drug use in the USA has not yet crested. Prescription drugs have specific targets, but often they adversely affect other tissues and organs. In keeping with the mission of the National Institutes of Health, Brain, Behavior, and Immunity searches for the underlying cause and potential efficacy of both drug and non-drug interventions. When the journal was first published in 1987, it challenged the scientific tidal wave that emphasized specialization in a single, specific discipline such as molecular biology, neuroscience or immunology. The focus of the journal was to support and extend biomedical research by publishing cutting edge findings in psychoneuroimmunology. Brain, Behavior, and Immunity began serving as the official journal of the Psychoneuroimmunology Research Society (PNIRS) in 2000. During its first 16years of existence, Brain, Behavior, and Immunity published 600 papers. During the subsequent 15years, there has been a steep, linear rise in publications that continues to this day, amounting to the publication of nearly 2500 articles in psychoneuroimmunology. Some of the current and hottest topics in the field are investigating ancient health practices such as mindfulness-based meditation, Tai Chi, exercise, perinatal health and the gut microbiome. As such, Brain, Behavior, and Immunity continues to advance biomedical research by boldly going forward. Just as it originally challenged the specialization philosophy that is so prevalent in medicine, it is now exploring the integrative physiological events that underlie century-old health practices. This approach has revealed that some age-old interventions are just as efficacious as prescription drugs. A world in which century-old therapies meet modern technologies could well be the best medicine for all of us. PMID- 28818560 TI - Rotigotine for nocturnal hypokinesia in Parkinson's disease: Quantitative analysis of efficacy from a randomized, placebo-controlled trial using an axial inertial sensor. AB - BACKGROUND: Nocturnal hypokinesia is a common symptom in Parkinson's disease (PD), negatively affecting quality of life of both patients and caregivers. However, evidence-based treatment strategies are limited. OBJECTIVE: To evaluate the efficacy of rotigotine transdermal patch, using a wearable sensor, in the management of nocturnal immobility. METHODS: 34 PD subjects with nocturnal immobility were randomized to receive rotigotine transdermal patch (mean +/- SD of 10.46 +/- 4.63 mg/24 h, n = 17) or placebo patch (n = 17). Treatment was titrated to an optimal dose over 1-8 weeks, then maintained for 4 weeks. Primary endpoints were objective parameters assessing axial rotation measured using an axial inertial sensor (the NIGHT-Recorder) over two nights at the patients' home. Scale-based assessments were also performed. RESULTS: There was a significant difference, in favor of rotigotine, in change from baseline score in the number of turns in bed (ANCOVA, p = 0.001), and degree of axial turn (p = 0.042). These objective improvements were mirrored by significantly greater improvements in clinical scale-based assessments, including the Unified Parkinson's Disease Rating Scale (UPDRS) total scores (p = 0.009), UPDRS-motor scores (p < 0.001), UPDRS-axial scores (p = 0.01), the Modified Parkinson's Disease Sleep Scale (p < 0.001), the Nocturnal Akinesia Dystonia and Cramp Scale (p = 0.003) and the eight item PD Questionnaire (PDQ-8) scores (p = 0.01) from baseline to end of treatment in patients given rotigotine compared to placebo. CONCLUSION: We show that the rotigotine patch provides a significant improvement in nocturnal symptoms as assessed using both objective measures and clinical rating scales. The study demonstrates the feasibility of using wearable sensors to record objective outcomes in PD-related clinical trials. PMID- 28818561 TI - The rise and fall of impulse control behavior disorders. AB - INTRODUCTION: Impulse control disorders (ICDs) are psychiatric disorders characterized by the failure to resist an impulse or by the temptation to perform an act that is harmful to oneself or to others. METHODS: ICDs, including pathological gambling, hypersexuality, compulsive eating and shopping, can occur as a complication of Parkinson's disease (PD) together with other behavioral disorders, including dopamine dysregulation syndrome. This review is based on a literature search updated to May 2017, focusing on the epidemiology, clinical features, and therapeutic options of ICDs associated with PD. RESULTS: Studies on the prevalence of ICDs confirm that they represent common phenomena associated with PD, with some centers reporting up to 40% of the PD population affected; the relative prevalence of the main ICDs shows significant variability, with a majority of the studies reporting that hypersexuality is the commonest one. Risk factors associated with the development of ICDs in PD were systematically evaluated, confirming the correlation between these disorders and male gender, younger age at PD onset and family history for addiction. CONCLUSIONS: We will discuss the recent advances on the functional neuroanatomy, the role of dopamine serotonin interactions and the cognitive profile associated with ICDs. Management of PD-related ICDs is still based on poor evidence, and this topic should be the object for future research. PMID- 28818562 TI - Conduction recovery and avoidance of permanent pacing after transcatheter aortic valve implantation. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) is an established treatment option for patients with severe aortic stenosis and high surgical risk. Currently, various prosthesis types are available. Atrioventricular block (AVB) requiring pacemaker (PM) implantation is a typical complication after TAVI. This study investigated the recovery of AV node conduction and mid-term outcome of patients with or without PM implantation after TAVI according to prosthesis type. METHODS: From July 2008 to May 2015, 856 transcatheter heart valves were implanted at our center (age: 80.5+/-6.1 years; logistic EuroSCORE: 15.4%). These patients were followed up regularly in our outpatient clinic. RESULTS: PM implantation was performed in 16.9% of patients due to severe conduction disturbances, mainly third-degree AVB. The need for PM implantation differed between the various prosthesis types: Medtronic CoreValve (Medtronic Inc., Minneapolis, MN, USA): 22.8% (n=272), Edwards Sapien XT (Edwards Lifesciences, Irvine, CA, USA): 13.0% (n=262), Edwards Sapien 3 (Edwards Lifesciences, Irvine, CA, USA): 16.2% (n=234), Direct Flow Medical (Direct Flow Medical, Santa Rosa, CA, USA): 7.3% (n=41), St. Jude Medical Portico (St. Jude Medical, St. Paul, MN, USA): 15.4% (n=26), Boston Scientific Lotus (Boston Scientific, Marlborough, MA, USA): 21.4% (n=14) and Medtronic Evolut R (Medtronic Inc., Minneapolis, MN, USA): 14.3% (n=7). Kaplan-Meier analysis for all-cause mortality did not reveal any differences between the various prosthesis types. PM implantation rates declined over the years of experience in a stable intervention team; 45% of PM patients showed sufficient AV node conduction after PM reprogramming at our follow-up examination. CONCLUSIONS: Mid-term all-cause survival after TAVI seems to be independent of prosthesis type and PM implantation after TAVI. Intrinsic AV node conduction recovers in a significant proportion of patients. Therefore, regular PM interrogations including reprogramming are required to avoid unnecessary permanent right ventricular stimulation. PMID- 28818563 TI - [Lower lymphocyte response in severe cases of acute bronchiolitis due to respiratory syncytial virus]. AB - INTRODUCTION: Acute bronchiolitis (AB) of the infant has a serious outcome in 6 16% of the hospital admitted cases. Its pathogenesis and evolution is related to the response of the T lymphocytes. The objective of the present study is to determine if the lower systemic lymphocytic response is related to a worse outcome of AB in hospitalised infants. PATIENTS AND METHOD: Retrospective observational-analytical study of cases-controls nested in a cohort of patients admitted due to RSV-AB between the period from October 2010 to March 2015. Those with a full blood count in the first 48hours of respiratory distress were included. Infants with underlying disease, bacterial superinfection, and premature infants <32 weeks of gestation were excluded. The main dichotomous variable was PICU admission. Other variables were: gender, age, post-menstrual age, gestational and post-natal tobacco exposure, admission month, type of lactation, and days of onset of respiratory distress. Lymphocyte counts were categorised by quartiles. Bivariate analysis was performed with the main variable and then by logistic regression to analyse confounding factors. RESULTS: The study included 252 infants, of whom 6.6% (17) required PICU admission. The difference in mean+/-SD of lymphocytes for patients admitted to and not admitted to PICU was 4,044+/-1755 and 5,035+/-1786, respectively (Student-t test, P<.05). An association was found between PICU admission and lymphocyte count <3700/ml (Chi-squared, P=.019; OR: 3.2) and it was found to be maintained in the logistic regression, regardless of age and all other studied factors (Wald 4.191 P=.041, OR: 3.8). CONCLUSIONS: A relationship was found between lymphocytosis <3700/ml in the first days of respiratory distress and a worse outcome in previously healthy infants <12 months and gestational age greater than 32 weeks with RSV-AB. PMID- 28818564 TI - Validity of a smartphone protractor to measure sagittal parameters in adult spinal deformity. AB - BACKGROUND CONTEXT: Smartphones have become an integral tool in the daily life of health-care professionals (Franko 2011). Their ease of use and wide availability often make smartphones the first tool surgeons use to perform measurements. This technique has been validated for certain orthopedic pathologies (Shaw 2012; Quek 2014; Milanese 2014; Milani 2014), but never to assess sagittal parameters in adult spinal deformity (ASD). This study was designed to assess the validity, reproducibility, precision, and efficiency of using a smartphone protractor application to measure sagittal parameters commonly measured in ASD assessment and surgical planning. PURPOSE: This study aimed to (1) determine the validity of smartphone protractor applications, (2) determine the intra- and interobserver reliability of smartphone protractor applications when used to measure sagittal parameters in ASD, (3) determine the efficiency of using a smartphone protractor application to measure sagittal parameters, and (4) elucidate whether a physician's level of experience impacts the reliability or validity of using a smartphone protractor application to measure sagittal parameters in ASD. STUDY DESIGN/SETTING: An experimental validation study was carried out. METHODS: Thirty standard 36" standing lateral radiographs were examined. Three separate measurements were performed using a marker and protractor; then at a separate time point, three separate measurements were performed using a smartphone protractor application for all 30 radiographs. The first 10 radiographs were then re-measured two more times, for a total of three measurements from both the smartphone protractor and marker and protractor. The parameters included lumbar lordosis, pelvic incidence, and pelvic tilt. Three raters performed all measurements-a junior level orthopedic resident, a senior level orthopedic resident, and a fellowship-trained spinal deformity surgeon. All data, including the time to perform the measurements, were recorded, and statistical analysis was performed to determine intra- and interobserver reliability, as well as accuracy, efficiency, and precision. Statistical analysis using the intra- and interclass correlation coefficient was calculated using R (version 3.3.2, 2016) to determine the degree of intra- and interobserver reliability. RESULTS: High rates of intra- and interobserver reliability were observed between the junior resident, senior resident, and attending surgeon when using the smartphone protractor application as demonstrated by high inter- and intra-class correlation coefficients greater than 0.909 and 0.874 respectively. High rates of inter- and intraobserver reliability were also seen between the junior resident, senior resident, and attending surgeon when a marker and protractor were used as demonstrated by high inter- and intra-class correlation coefficients greater than 0.909 and 0.807 respectively. The lumbar lordosis, pelvic incidence, and pelvic tilt values were accurately measured by all three raters, with excellent inter- and intra-class correlation coefficient values. When the first 10 radiographs were re-measured at different time points, a high degree of precision was noted. Measurements performed using the smartphone application were consistently faster than using a marker and protractor-this difference reached statistical significance of p<.05. CONCLUSIONS: Adult spinal deformity radiographic parameters can be measured accurately, precisely, reliably, and more efficiently using a smartphone protractor application than with a standard protractor and wax pencil. A high degree of intra- and interobserver reliability was seen between the residents and attending surgeon, indicating measurements made with a smartphone protractor are unaffected by an observer's level of experience. As a result, smartphone protractors may be used when planning ASD surgery. PMID- 28818565 TI - Raw starch microparticles have immunostimulant activity in mice vaccinated with BCG and challenged with Mycobacterium tuberculosis. AB - The main challenge for vaccine development or improvement is the lack of safe adjuvants or immunostimulants that induce protective immune responses and can be used for mucosal immunization, which is a highly desirable strategy for vaccination against infectious diseases acquired by oral or intranasal routes. One promising alternative is the use of biodegradable and biocompatible polymeric microparticles. Recently, we developed an immobilization and delivery system with starch microparticles (SMPs) and a starch-binding domain (SBDtag) suitable for the mucosal administration of antigens and the induction of antigen-specific immune responses. Here, we explore the immunostimulant and reinforcing potential of the system using BALB/c mice with progressive pulmonary tuberculosis (PPT). The heat shock protein alpha-crystallin from Mycobacterium tuberculosis immobilized on SMPs (uAcr-SBDtag) or SMPs alone were administered nasally as boosters to BCG-vaccinated mice without any extra adjuvant. The mice were challenged intratracheally with either moderately virulent or highly virulent M. tuberculosis strains. Our results showed that the administration of either the immobilized antigen or SMPs asa booster for the BCG vaccination induced a significant reduction of bacterial loads in the lungs of mice, even more than in mice that received the BCG vaccination alone. Since no difference was observed in pulmonary bacillary burdens between the two reinforced groups, the obtained effect was most likely primarily caused by the starch. As determined by histological study, the administration of boosters did not contribute to the progress of pneumonia, which diminishes the safety concerns related to the administration of SMPs intranasally. Taken together, our findings suggest that this system may be considered asa new carbohydrate-based adjuvant suitable for mucosal vaccines against tuberculosis and other infectious diseases, and more generally, they highlight the potential of particulate alpha-glucans as immune response modifiers. PMID- 28818566 TI - A synthetic human cytomegalovirus pp65-IE1 fusion antigen efficiently induces and expands virus specific T cells. AB - Infection with human cytomegalovirus (HCMV) can cause severe complications in newborns and immunocompromised patients, and a prophylactic or therapeutic vaccine against HCMV is not available. Here, we generated a HCMV vaccine candidate fulfilling the regulatory requirements for GMP-compliant production and clinical testing. A novel synthetic fusion gene consisting of the coding sequences of HCMV pp65 and IE1 having a deleted nuclear localization sequence and STAT2 binding domain was introduced into the genome of the attenuated vaccinia virus strain MVA. This recombinant MVA, MVA-syn65_IE1, allowed for the production of a stable ~120kDa syn65_IE1 fusion protein upon tissue culture infection. MVA syn65_IE1 infected CD40-activated B cells activated and expanded pp65- and IE1 specific T cells derived from HCMV-seropositive donors to at least equal levels as control recombinant MVA expressing single genes for pp65 or IE1. Additionally, we show that MVA-syn65_IE1 induced HCMV pp65- and IE1-epitope specific T cells in HLA-A2.1-/HLA-DR1-transgenic H-2 class I-/class II-knockout mice. Thus, MVA syn65_IE1 represents a promising vaccine candidate against HCMV and constitutes a basis for the generation of a multivalent vaccine targeting relevant pathogens in immunocompromised patients. PMID- 28818567 TI - A protein chimera including PspA in fusion with PotD is protective against invasive pneumococcal infection and reduces nasopharyngeal colonization in mice. AB - Despite the success of the available polysaccharide-based vaccines against Streptococcus pneumoniae in preventing invasive diseases, this bacterium remains a major cause of death in many parts of the world. New vaccine strategies are needed in order to increase protection. Thus, the utilization of fusion proteins is being investigated as an alternative to the current formulations. In the present work, we demonstrate that a chimeric protein, composed of PspA and PotD in fusion is able to maintain the protective characteristics of both parental proteins, providing protection against systemic infection while reducing nasal colonization. The hybrid was not able to improve the response against invasive disease elicited by PspA alone, but the inclusion of PotD was able to reduce colonization, an effect never observed using subcutaneous immunization with PspA. The mechanisms underlying the protective efficacy of the rPspA-PotD hybrid protein were investigated, revealing the production of antibodies with an increased binding capacity to pneumococcal strains of diverse serotypes and genetic backgrounds, enhanced opsonophagocytosis, and secretion of IL-17 by splenocytes. These findings reinforce the use of chimeric proteins based on surface antigens as an effective strategy against pneumococcal infections. PMID- 28818568 TI - Reasons for non-vaccination: Parental vaccine hesitancy and the childhood influenza vaccination school pilot programme in England. AB - INTRODUCTION: In 2013, the annual influenza immunisation programme in England was extended to children to reduce the burden of influenza, but uptake was sub optimal at 53.2%. AIM: To explore the reasons some parents decided not to vaccinate their child against influenza as part of the pilot programme offered in schools. METHODS: Cross-sectional qualitative study conducted between February and July 2015. 913 parents whose children were not vaccinated against influenza in the school pilots in West Yorkshire and Greater Manchester, England, were asked to comment on their reasons for non-vaccination and invited to take part in a semi-structured interview. 138 parents returned response forms, of which 38 were eligible and interested in participating and 25 were interviewed. Interview transcripts were coded by theme in NVivo. RESULTS: A third of parents who returned response forms had either vaccinated their child elsewhere, intended to have them vaccinated, or had not vaccinated them due to medical reasons (valid or perceived). Most interviewees were not convinced of the need to vaccinate their child against influenza. Parents expressed concerns about influenza vaccine effectiveness and vaccine side effects. Several parents interviewed declined the vaccine for faith reasons due to the presence of porcine gelatine in the vaccine. CONCLUSIONS: To significantly decrease the burden of influenza in England, influenza vaccination coverage in children needs to be >60%. Hence, it is important to understand the reasons why parents are not vaccinating their children, and to tailor the communication and immunisation programme accordingly. Our finding that a third of parents, who did not consent to their child being vaccinated as part of the school programme, had actually vaccinated their child elsewhere, intended to have their child vaccinated, or had not vaccinated them due to medical reasons, illustrates the importance of including additional questions or data sources when investigating under-vaccination. PMID- 28818569 TI - Two cases of pelvic sarcoma in the acetabulum with >10-year follow-ups after carbon ion radiotherapy. PMID- 28818570 TI - Prevalence and risk factors of deep vein thrombosis in patients undergoing lumbar spine surgery. AB - BACKGROUND: Spinal surgery is classified as a moderate risk for DVT. The occurrence of DVT after various spinal surgical procedures was reviewed retrospectively, and the perioperative risk factors in the high-risk group were identified. In addition, the administration of the factor Xa inhibitor to DVT subjects with unstable thrombosis was evaluated to reveal its effectiveness in the prevention of PTE and postoperative complications. METHODS: This study included 588 subjects who underwent lumbar spine surgery. The patient population consisted of the following four groups: the fracture group (F group), the laminectomy group (La group), the TLIF group (T group), and the long fusion group (Lo group). Bilateral lower limb venous ultrasonography was performed on the day before surgery, the day after surgery, and one week after surgery. The incidence of DVT was determined for each group and potential risk factors were evaluated in the group with the highest incidence of DVT. Subjects with DVT who had unstable thrombosis received anticoagulant therapy (factor Xa inhibitor) and their treatment results were assessed. RESULTS: The overall incidence of DVT was 32.3% (190/588). A significantly high incidence of DVT was observed in the Lo group (54.3%; 75/138). Logistic regression and ROC analysis of potential risk factors in the Lo group identified a D-dimer value of 19.5 ug/ml at one week postoperatively as a risk factor of DVT (p = 0.02; odds ratio, 4.09; 95% CI, 2.82 7.88). Overall, 15.8% of subjects (30/190) received anticoagulant therapy. These subjects experienced neither PTE nor epidural hematoma. A follow-up ultrasonography performed at three weeks postoperatively detected the disappearance/resolution of DVT in 86.7% of these subjects (26/30). CONCLUSION: The incidence of DVT varied according to the invasiveness of the procedure. Successful management of DVT hinges on preoperative risk management involving prophylactic treatment and early diagnosis, in order to avoid PTE and other complications. PMID- 28818571 TI - Timing of palliative care team referrals for inpatients receiving rapid response services: A retrospective pilot study in a US hospital. AB - BACKGROUND/OBJECTIVES: Research indicates up to one-third of rapid response team calls relate to end-of-life symptoms. The CriSTAL criteria were developed as a screening tool to identify high risk of death within three months. The primary purpose of this pilot study was to investigate the timing of palliative care referrals in patients receiving rapid response team services, and patients' CriSTAL criteria score on admission. The potential feasibility of using the CriSTAL tool to stimulate earlier Palliative Care Team (PCT) referral served as an underlying goal, and investigation of a relationship between specific CriSTAL criteria and the prediction of in-hospital death was a secondary objective. DESIGN: A retrospective chart review of rapid response calls made in 2015 was used to identify patient risk of death on admission based on the CriSTAL criteria. The presence and timing of PCT referral as well as patient survival status to hospital discharge were documented for comparison. SETTING/PARTICIPANTS: A sample of 183 charts from 584 inpatients involved in over 600 RRT events recorded in 2015. The study was undertaken in a 676-bed teaching hospital in the Midwestern U.S. METHODS/RESULTS: Ninety-one patients died during the hospital stay while 92 patients from the 493 individuals who survived were randomly selected for full analysis. Applying CriSTAL criteria to the 141 individuals aged 50 years or older indicated that frailty (OR=1.43, 95%CI 1.08 1.89, p=0.012), being a male (OR=3.14; 95%CI 1.40-7.05, p=0.006), and the presence of two or more comorbidities (OR=3.71, 95%CI 1.67-8.24, p=0.001) were the most significant predictors of in-hospital death after adjusting for age. A CriSTAL score of 6 was the optimal cut-off for high-risk of in-hospital death. Palliative care consultations within the high-risk population occurred for 45.2% of the deceased and 40.4% of the survivors. Consultation often occurred within two days of the RRT event and many patients (46.8%) died within one day of the consultation. CONCLUSION: A positive relationship was found between the CriSTAL score, palliative care referral, and in-hospital mortality in patients who received RRT services. The study indicates a need for earlier PCT referral, showcases the potential to identify high risk of in-hospital death upon admission and supports the feasibility of using the CriSTAL criteria tool to encourage earlier PCT referrals. PMID- 28818573 TI - Complete sequences of qnrD-carrying plasmids in Proteus spp. collected from French animals. PMID- 28818572 TI - Ribavirin inhibits Zika virus (ZIKV) replication in vitro and suppresses viremia in ZIKV-infected STAT1-deficient mice. AB - Zika fever, a mosquito-borne infectious disease caused by Zika virus (ZIKV), is an epidemic disease for which no effective therapy has been established. The recent outbreaks of ZIKV in Brazil and French Polynesia have been linked to a considerable increase in the incidence of fetal microcephaly and other diseases such as Guillain-Barre syndrome. Because there is currently no specific therapy or vaccine, the early exploitation of a method to prevent expansion of ZIKV is a high priority. To validate commonly used antiviral drugs, we evaluated the effect of ribavirin, a drug used to treat hepatitis C with interferon-beta (IFN-beta), on ZIKV replication. In mammalian cells, we observed an inhibitory effect of ribavirin on ZIKV replication and ZIKV-induced cell death without cytotoxic effect. Furthermore, we found that STAT1-deficient mice, which lack type I IFN signaling, were highly sensitive to ZIKV infection and exhibited lethal outcome. Ribavirin abrogated viremia in ZIKV-infected STAT-1-deficient mice. These data suggest that the inhibition of viral RNA-dependent RNA polymerases may be effective for treatment of ZIKV infection. Our data provide a new insight into the mechanisms for inhibition of ZIKV replication and prevention of Zika fever. PMID- 28818574 TI - Antimicrobial resistance determinants and susceptibility profiles of pneumococcal isolates recovered in Trinidad and Tobago. AB - OBJECTIVES: In Latin America and the Caribbean, pneumococcal infections are estimated to account for 12000-18000 deaths, 327000 pneumonia cases, 4000 meningitis cases and 1229 sepsis cases each year in children under five years old. Pneumococcal antimicrobial resistance has evolved into a worldwide health problem in the last few decades. This study aimed to determine the antimicrobial susceptibility profiles of pneumococcal isolates collected in Trinidad and Tobago and their associated genetic determinants. METHODS: Whole-genome sequences were obtained from 98 pneumococcal isolates recovered at several regional hospitals, including 83 invasive and 15 non-invasive strains, recovered before (n=25) and after (n=73) introduction of pneumococcal conjugate vaccines (PCVs). A bioinformatics pipeline was used to identify core genomic and accessory elements conferring antimicrobial resistance phenotypes, including beta-lactam non susceptibility. RESULTS AND DISCUSSION: Forty-one isolates (41.8%) were predicted as resistant to at least one antimicrobial class, including 13 (13.3%) resistant to at least three classes. The most common serotypes associated with antimicrobial resistance were 23F (n=10), 19F (n=8), 6B (n=6) and 14 (n=5). The most common serotypes associated with penicillin non-susceptibility were 19F (n=7) and 14 (n=5). Thirty-nine isolates (39.8%) were positive for PI-1 or PI-2 type pili: 30 (76.9%) were PI-1+, 4 (10.3%) were PI-2+ and 5 (12.8%) were positive for both PI-1 and PI-2. Of the 13 multidrug-resistant isolates, 10 belonged to globally distributed clones PMEN3 and PMEN14 and were isolated in the post-PCV period, suggesting clonal expansion. PMID- 28818575 TI - beta-Lactam resistance among Haemophilus influenzae isolates in Poland. AB - OBJECTIVES: Haemophilus influenzae is a human-specific Gram-negative coccobacillus responsible for a significant number of respiratory tract infections and severe invasive infections such as meningitis and sepsis. The purpose of this study was to characterise the mechanisms of beta-lactam resistance among Polish H. influenzae isolates and to evaluate the resistance detection methods applied. METHODS: This study was conducted on 117 Polish H. influenzae isolates collected in 2012. Minimum inhibitory concentrations were assessed by broth microdilution. All strains were evaluated using the disk diffusion method and the algorithm proposed by the Nordic Committee on Antimicrobial Susceptibility Testing (NordicAST). To detect changes in penicillin binding protein 3 (PBP3), PCR screening was performed, followed by ftsI gene sequencing. RESULTS: Neither beta-lactamase production nor PBP3 alterations were demonstrated in 76 isolates (65.0%). Susceptibility to ampicillin, amoxicillin, amoxicillin/clavulanic acid, cefuroxime (intravenous) and ceftriaxone was observed in 70.9%, 78.6%, 98.3%, 82.9% and 100% of the isolates, respectively. beta-Lactamase production characterised 21 isolates (17.9%). Screening PCR identified 20 isolates (17.1%) with PBP3 alterations, and according to subsequent ftsI sequencing all these strains were finally recognised as gBLNAR (genetically beta-lactamase-negative, ampicillin-resistant), among which 65.0% were ampicillin resistant. According to molecular classification of PBP3 alterations, 95.0% of gBLNAR belonged to group II, representing four subgroups IIa-IId. CONCLUSIONS: Haemophilus influenzae resistance to antibiotics requires continuous attention, effective detection methods and a rational policy of antibiotic usage. The algorithm proposed by NordicAST can be applied in routine laboratory work, whereas sequencing of the ftsI gene may be useful in molecular epidemiology studies. PMID- 28818576 TI - The effect of mutations in the lid region of Thermomyces lanuginosus lipase on interactions with triglyceride surfaces: A multi-scale simulation study. AB - Lipases naturally function at the interface formed between amphiphilic molecules and the aqueous environment. Thermomyces lanuginosus lipase (TLL) is a well characterised lipase, known to exhibit interfacial activation during which a lid region covering the active site becomes displaced upon interaction with an interface. In this study, we investigate the effect the amino acid sequence of the lid region on interfacial binding and lid dynamics of TLL. Three TLL variants were investigated, a wild-type variant, a variant containing an esterase lid region (Esterase), and a Hybrid variant, containing both wild-type lid residues and esterase lid residues. Multiple coarse-grained molecular dynamics simulations revealed that the interfacial binding orientation of TLL was significantly affected by the nature of amino acids in the lid region, and atomistic simulations indicated effects on the structural dynamics of the lid itself. The atomistic simulations, as well as steered molecular dynamics simulations, also indicated that the Esterase lid region was less flexible than the wild-type lid region, whereas the Hybrid variant displayed superior lid flexibility and stability in the open conformation both at the interface, and in aqueous solution. Additional experiments performed to investigate the activity and binding behaviour of the lipase variants indicated a slightly higher specific activity for the Hybrid variant compared to the wild-type variant, correlating the observations of increased lid flexibility. Together, these results are in line with previous experimental studies, highlighting the importance of the nature of the amino acid residues within the functional lid region of lipases, particularly regarding interfacial binding orientation, activation, and structural stability. PMID- 28818577 TI - Applications of cardiac magnetic resonance imaging in sickle cell disease. AB - Cardiac magnetic resonance imaging (CMR) has evolved from an effective research tool to a non-invasive clinical modality with versatile applications. The accuracy of volume measurements and functional assessment and the ability to identify unique myocardial tissue characteristics non-invasively are the primary advantages of CMR. The use of CMR in sickle cell disease (SCD) has been limited clinically to myocardial iron assessment. The use of other CMR applications to characterize the cardiac pathology in SCD is slowly emerging but remains limited to research level. In this review, we discuss some of the applications of CMR in studying cardiovascular diseases and its potential uses in SCD for research and clinical purposes. PMID- 28818578 TI - Can exercise training counteract doxorubicin-induced oxidative damage of testis proteome? AB - The use of the chemotherapeutic drug doxorubicin (DOX) is limited by its toxicity in several organs such as testes. So, we analyzed the effect of endurance treadmill exercise training (EX) performed before sub-chronic DOX treatment on sperm count and motility, testes markers of oxidative damage and apoptosis. Tissue profiling of proteins more susceptible to oxidation was made to identify the molecular pathways regulated by oxidative modifications, as nitration and carbonylation. Twenty-four adult male rats were divided into four groups (n=6/group): sedentary saline (SED+SAL), sedentary sub-chronically injected with DOX (2mg-kg-1 per week, during 7 weeks; SED+DOX), 12 weeks trained saline (EX+SAL) and trained treated with DOX (EX+DOX). DOX treatment started 5 weeks after the beginning of the exercise program. Testes caspase-3, -8 and -9, as well as aconitase activities, the content of malondialdehyde (MDA), sulfhydryl groups (-SH), carbonyl and nitrotyrosine derivatives were determined. Modified proteins were identified by 2D-Western blot followed by MALDI-TOF/TOF mass spectrometry, and bioinformatic analysis was performed to assess the biological processes regulated by these chemical modifications. The decreased sperm motility induced by DOX was not modified by exercise. Significant increases in MDA content in SED+DOX and in caspase-3 and -9 activities in EX+DOX were found. Despite no significant differences in the levels of carbonylated and nitrated proteins, exercise modulated testis proteome susceptibility to oxidation in DOX-treated group, with less modified proteins identified. Zinc finger Ran-binding domain containing protein 2 (ZRAB2) and AN1-type zinc finger protein 3 (ZFAN3) were among the proteins found oxidativelly modified. Although no marked alterations in testes oxidative damage were noticed, proteomic analysis of oxidativelly modified proteins highlighted the protective role of exercise against oxidative damage of some proteins involved in metabolism and stress response against DOX. PMID- 28818579 TI - Developing integrated PBPK/PD coupled mechanistic pathway model (miRNA-BDNF): An approach towards system toxicology. AB - Integration of a dynamic signal transduction pathway into the tissue dosimetry model is a major advancement in the area of computational toxicology. This paper illustrates the ways to incorporate the use of existing system biological model in the field of toxicology via its coupling to the Physiological based Pharmacokinetics and Pharmacodynamics (PBPK/PD) model. This expansion framework of integrated PBPK/PD coupled mechanistic system pathway model can be called as system toxicology that describes the kinetics of both - the chemicals and - biomolecules, help us to understand the dynamic and steady-state behaviors of molecular pathways under perturbed condition. The objective of this article is to illustrate a system toxicology based approach by developing an integrated PBPK/PD coupled miRNA-BDNF pathway model and to demonstrate its application by taking a case study of the PFOS mediated neurotoxicity. System dynamic involves miRNA mediated BDNF regulation, which plays an important role in the control of neuronal cell proliferation, differentiation, and survivability. PMID- 28818581 TI - Renal transplantation in systemic lupus erythematosus: Comparison of graft survival with other causes of end-stage renal disease. AB - INTRODUCTION: End-stage renal disease (ESRD) due to lupus nephritis (LN) occurs in 10%-30% of patients. Initially systemic lupus erythematosus (SLE) was a contraindication for kidney transplantation (KT). Today, long-term graft survival remains controversial. Our objective was to compare the survival after KT in patients with SLE or other causes of ESRD. METHODS: All SLE patients who had undergone KT in a retrospective cohort were included. Renal graft survival was compared with that of 50 controls, matched for age, sex, and year of transplantation. Survival was evaluated by the Kaplan-Meier test and the Cox proportional hazards model. RESULTS: Twenty-five subjects with SLE were included. The estimated 1-year, 2- and 5-year survival rates for patients with SLE were 92%, 66% and 66%. Renal graft survival did not differ between patients with SLE and other causes of ESRD (P=.39). The multivariate analysis showed no significant difference in graft survival between the two groups (hazard ratio, HR=1.95, 95% confidence interval [CI] 0.57-6.61, P=.28). The recurrence rate of LN was 8% and was not associated with graft loss. Acute rejection was the only variable associated with graft loss in patients with SLE (HR=16.5, 95% CI 1.94-140.1, P=.01). CONCLUSIONS: Renal graft survival in SLE patients did not differ from that reported for other causes of ESRD. PMID- 28818580 TI - Effects of sulfur mustard on mesenchymal stem cells. AB - : Chronic wound healing disorders that occur as a result of a sulfur mustard (SM) exposure present a particular challenge. These chronic wounds are similar to other chronic wounds. In the past, it has been shown that mesenchymal stem cells (MSC) play an important role in the healing of chronic wounds. An important property to support wound healing is their ability to migrate. However, we were able to show that SM leads to a reduction in MSC migration even at low concentrations. Currently, exposed MSCs are still able to differentiate. Further alterations are not known. The current investigation therefore focused onto the question how SM affects MSC. MATERIAL & METHODS: The effect of SM on MSC was investigated. Here, the alkylation of DNA was considered, and DNA adducts were quantified over a period of 48h. The modification of the nuclei under the influence of SM was analyzed as well as proliferation of the cells by immunohistochemical staining with Ki-67 and quantification. For the quantification of the apoptosis rate, antibodies against cleaved Caspase-3, 8, and apoptosis inducing factor (AIF) were used. The senescence analysis was performed after histological staining against beta-galactosidase. Quantifications were carried out by using the TissueQuest System and the software TissueFAX. RESULTS: SM exposure of MSC results in a dose dependent formation of nuclear DNA adducts. 4h after exposure the cells display a decreasing concentration of DNA adducts. This process is accompanied by a change of nuclei shape but without an increase of apoptosis induction. In parallel the number of cells undergoing senescence increases as a function of the SM concentration. DISCUSSION: SM exposure of MSC leads to adduct formation on chromosomal DNA. These DNA adducts can be reduced without MSC are undergoing apoptosis. This indicates an active DNA damage response (DDR) pathway in combination with the formation of persistent nuclear DNA damage foci. This process is accompanied by a reduced capability of proliferation and a transition into the senescent state. PMID- 28818582 TI - Associations between meeting combinations of 24-h movement guidelines and health related quality of life in children from 12 countries. AB - OBJECTIVES: To examine whether meeting vs not meeting movement/non-movement guidelines (moderate-to-vigorous physical activity [MVPA], screen time, sleep duration), and combinations of these recommendations, are associated with health related quality of life (HRQoL) in children from 12 countries in five major geographic regions of the world and explore whether the associations vary by study site. STUDY DESIGN: Observational, multinational cross-sectional study. METHODS: This study included 6106 children aged 9-11 years from sites in Australia, Brazil, Canada, China, Colombia, Finland, India, Kenya, Portugal, South Africa, the United Kingdom, and the United States. Participants completed the KIDSCREEN-10 to provide a global measure of their HRQoL. Sleep duration and MVPA were assessed using 24-h accelerometry. Screen time was assessed through self-report. Meeting the recommendations was defined as >=60 min/day for MVPA, <=2 h/day for screen time, and between 9 and 11 h/night for sleep duration. Age, sex, highest parental education, unhealthy diet pattern score, and body mass index z-score were included as covariates in statistical models. RESULTS: In the full sample, children meeting the screen time recommendation, the screen time + sleep recommendation, and all three recommendations had significantly better HRQoL than children not meeting any of these guidelines. Differences in HRQoL scores between sites were also found within combinations of movement/non-movement behaviors. For example, while children in Australia, Canada, and USA self reported better HRQoL when meeting all three recommendations, children in Kenya and Portugal reported significantly lower HRQoL when meeting all three recommendations (relative to not meeting any). CONCLUSIONS: Self-reported HRQoL is generally higher when children meet established movement/non-movement recommendations. However, differences between study sites also suggest that interventions aimed at improving lifestyle behaviors and HRQoL should be locally and culturally adapted. PMID- 28818583 TI - Timing of fertile period for successful pregnancy in American Bully dogs. AB - Determination of the timing of the estrus cycle is essential for fertile mating. There are physiological variations among breeds, between bitches, and between cycles of the same bitch. If serial monitoring and many tools are applied, the exact moment of ovulation could be pin-pointed. However, it leads to time and costly difficulties. Progesterone concentrations during estrus cycles follow a specific pattern, and it is largely used in timing of fertile period. Although it has similar pattern in general, it is likely that breed-specific differences exist. The aim of this study was to investigate the way of timing the fertile period for successful pregnancy in American Bully dogs based on vaginal cytology and progesterone assay with minimized cost. To identify the empirical relations among reproductive characteristics, we performed statistical analyses on data from proestrus-to-estrus 27 American Bully dogs referred for 7 months. We found the significant correlations between the cyclic changes of vaginal cytology and progesterone assay. The relationship of serum progesterone concentrations with the days from vaginal discharge onset was analyzed through linear regression assay. In conclusion, we addressed two standards in the timing of fertile period with a minimal number of progesterone assays in the breeding management of American Bully dogs. PMID- 28818584 TI - [Neonatal intoxication to vitamin D in premature babies: A series of 16 cases]. AB - INTRODUCTION: Preterm neonates are particularly at risk of vitamin D (25-D) deficiency. To prevent rickets and osteopenia in this population, international guidelines vary between 800 and 1000IU per day of vitamin D in Europe and recommend 400IU per day in the USA. Target levels of circulating 25-D are not well identified, with the lower target level 50-75nmol/L and the upper target level probably 120nmol/L. METHODS: Between 2013 and 2015, 16 premature infants (born<35WG) were referred to pediatric nephrology clinics because of symptoms secondary to 25-D overdose during the neonatal period. Clinical and biological data were retrospectively reviewed to better define this population. The results are presented as the median (range). RESULTS: Gestational age was 27 (24-35)WG with a birth weight of 810 (560-2120)g. Nephrocalcinosis was the initial symptom in 37% of cases, hypercalcemia in 44%, and hypercalciuria in 19%. Daily vitamin D doses were 333 (35-676)IU. Age and body weight at initial symptom were 36.6 (27.6 47.6)WG and 2300 (640-3760)g, respectively. The 25-D level at the time of the first dosage was 210 (119-350)nmol/L and the 1-25 vitamin D level was 370 (245 718)pmol/L (local normal values for age<240). During follow-up, 12 patients displayed nephrocalcinosis, ten hypercalciuria, and three hypercalcemia. The 25-D level normalized in ten patients within 10 (3-32)months after vitamin D withdrawal. Nephrocalcinosis improved in ten of 12 patients, within 12 (3 30)months. Vitamin D could be readministered in ten patients. When searched (n=3), no CYP24A1 mutation was identified in two patients, but was identified in the heterozygous state in one. CONCLUSION: A 25-D overdose should be systematically ruled out in the presence of nephrocalcinosis, hypercalcemia, and/or hypercalciuria during infancy in children born preterm. Studies are required to assess the exact frequency of 25-D deficiency and overdose in this population, as well as to evaluate the potential deleterious effects of this imbalance on bone, kidney, and brain development. PMID- 28818585 TI - [Vitamin K in the neonate: Recommendations update]. AB - Hemorrhagic disease of the newborn is not common but may be very serious, with cerebral, hepatic, or adrenal gland bleeding. Its prevention is based upon vitamin K1 administration from birth. Scientific studies to validate appropriate treatment policies are scarce, with recommendations coming from expert opinions, retrospective studies, or controversies on possible side effects. After analysis of recent literature data, we propose an oral administration of three doses of 2mg of vitamin K1 at birth, at discharge from the maternity ward, and at 1 month postnatal age for term infants. For premature infants born with a birth weight above 1500g, a weekly dose of 2mg up to term equivalent age may be recommended. For premature infants below 1500g, a weekly dose of 1mg up to 1500g body weight, then a weekly dose of 2mg up to term equivalent age seems appropriate. If oral administration is not possible, the intravenous or intramuscular route may be used with a 50% reduction in dosing. PMID- 28818586 TI - A Rare Presentation of the Syndrome of Inappropriate Antidiuretic Hormone in a 12 Year-Old Girl as the Initial Presentation of an Immature Ovarian Teratoma. AB - BACKGROUND: Immature ovarian teratoma is very rare in childhood. We report on a 12-year-old girl with immature ovarian teratoma who presented initially with syndrome of inappropriate antidiuretic hormone. CASE: A 12-year-old girl presented with acute abdomen and distention. Initial laboratory tests showed hyponatremia (sodium, 123 mmol/L), that did not respond to fluid management. Computed tomography imaging showed a 15 cm * 9 cm * 20 cm mass in the right ovary with multifocal internal fat, and dystrophic calcifications. She underwent exploratory laparotomy with a right salpingo-oophorectomy, omentectomy, and peritoneal stripping. The pathology revealed metastatic immature teratoma. Hyponatremia resolved soon after the surgery. SUMMARY AND CONCLUSION: Although a rare diagnosis, immature ovarian teratoma must be considered in a girl who presents with abdominal mass and hyponatremia. PMID- 28818587 TI - Phenanthrene-responsive microRNAs and their targets in wheat roots. AB - MicroRNAs (miRNAs) play key roles in plant growth, development and responses to abiotic stress. Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants. However, it is yet unknown how miRNAs work during PAH uptake by plant roots. Thus, in this study we ascertain phenanthrene (a model PAH)-responsive miRNAs using small RNA high-throughput deep sequencing and their target genes in wheat roots. We identified 108 conserved and non-conserved miRNA members belonging to 82 miRNA families and found 11 differentially expressed miRNAs, among which four miRNAs (miR156, miR164, miR171a and miR9678-3p) were up regulated and the other seven miRNAs (miR398, miR531, miR1121, miR5048-5p, miR9653b, miR9773 and miR9778) were down-regulated. ABC-transporter-related Gene CA704421 and CA697226 did not respond to phenanthrene exposure. miR156 and miR164 might regulate directly the growth and development of wheat roots by targeting SPL and NAC, respectively. miR398 and miR1121 could regulate oxidative reactions to respond to phenanthrene stress. Additionally, miR9773 might involve phenanthrene metabolism through acting on CYP450. Therefore, it is concluded that phenanthrene triggers variation in miRNA expression, which is associated with uptake of and response to phenanthrene. These findings are of significance for further understanding miRNA regulation mechanisms on PAH uptake, and providing guidance for screening of resistant cultivars in crop production and phytoremediation of PAH-contaminated soils or water at genetic level. PMID- 28818588 TI - Comprehensive analysis of fly ash induced changes in physiological/growth parameters, DNA damage and oxidative stress over the life cycle of Brassica juncea and Brassica alba. AB - Fly ash (FA) being a heterogeneous mixture of heavy metal affects plant system in various ways. Previous studies have shown bioaccumulation of toxic metals in the plants and disturbance in cellular activities. Here, we have studied the impacts of FA treatment through the life cycle of economically important, annual crop plant mustard (Brassica juncea and Brassica alba). Result revealed that FA did not alter germination rate and photosynthetic pigment levels. Tolerance index of B. juncea was higher compared to B. alba. Seed setting was significantly affected by FA in B. alba. Significant increase in DNA damage was observed in both B. alba and B. juncea. Proline accumulation was significantly higher in B. alba. In B. juncea catalase activity and reduced glutathione content declined in initial days which were restored at the end of experimental period. Significant decrease in non-enzymatic antioxidants was noted in B. alba. Higher accumulation of Pb and As was noted in shoot of B. juncea and in B. alba Cu, Pb, Cr and As accumulated in shoots. As observed from these results, both plants could translocate certain toxic heavy metals from roots to the shoot which affected the physiological and biochemical balance and induced genotoxic response. PMID- 28818589 TI - Elimination of fungicides in biopurification systems: Effect of fungal bioaugmentation on removal performance and microbial community structure. AB - Bioaugmentation with ligninolytic fungi represents a potential way to improve the performance of biomixtures used in biopurification systems for the treatment of pesticide-containing agricultural wastewater. The fungus Trametes versicolor was employed in the bioaugmentation of a biomixture to be used in the simultaneous removal of seven fungicides. Liquid cultures of the fungus were able to remove tebuconazole, while no evidence of carbendazim, metalaxyl and triadimenol depletion was found. When applied in the biomixture, the bioaugmented matrix failed to remove all the triazole fungicides (including tebuconazole) under the assayed conditions, but was efficient to eliminate carbendazim, edifenphos and metalaxyl (the latter only after a second pesticide application). The re-addition of pesticides markedly increased the elimination of carbendazim and metalaxyl; nonetheless, no clear enhancement of the biomixture performance could be ascribed to fungal bioaugmentation, not even after the re-inoculation of fungal biomass. Detoxification efficiently took place in the biomixture (9 d after pesticide applications) according to acute tests on Daphnia magna. DGGE-analysis revealed only moderate time-divergence in bacterial and fungal communities, and a weak establishment of T. versicolor in the matrix. Data suggest that the non bioaugmented biomixture is useful for the treatment of fungicides other than triazoles. PMID- 28818590 TI - Emerging and legacy flame retardants in indoor dust from East China. AB - To understand human exposure to dust-associated flame retardants in the biggest metropolitan area (city of Shanghai) of East China, our study determined a suite of legacy and emerging flame retardants in dust from dwellings, cars, and university computer labs. The results exhibited a consistent dominance of organophosphate flame retardants (OPFRs) over polybrominated diphenyl ethers (PBDEs) and other alternative flame retardants (AFRs) regardless of microenvironments. In addition to OPFRs, some alternative flame retardants, such as decabromodiphenyl ethane (DBDPE), 2-ethylhexyltetrabromobenzoate (EH-TBB), bis(2-ethylhexyl)-3,4,5,6-tetrabromobenzoate (BEH-TEBP), and 1,2-bis(2,4,6 tribromophenoxy)ethane (BTBPE), were also frequently detected. Among them, DBDPE exhibited concentrations comparable to those of PBDEs. Comparison with international studies indicated that concentrations of ?PBDEs (0.2-12.3 MUg/g dry weight or dw) and ?OPFRs (3.8-165.5 MUg/g dw) from Shanghai dwellings (bedroom and living room) were generally in the middle of concentration ranges reported worldwide, whereas elevated DBDPE concentrations (0.1-9.5 MUg/g dw) was observed compared with most other countries or regions. OPFR compositions in house dust from this study also differed from those from many other countries. This suggested inter-regional differences in market demands on the quantities and types of flame retardants. Human intake estimation suggested elevated exposure for toddlers when compared with adults, although the daily intake estimations of individual flame retardants were generally 2-4 orders of magnitude lower than the reference doses. The findings from this preliminary study developed a baseline for future evaluation of the sources and fate of emerging flame retardants and related human exposure risks in East China. PMID- 28818591 TI - Mobile phosphorus stratification in sediments by aluminum immobilization. AB - There is a great heterogeneity in the distribution of mobile phosphorus (P) in natural sediments, while the assessment of P immobilization by amendment agents has mostly neglected this feature. In this study, the effects of aluminum sulfate (ALS) on P immobilization were investigated via a 60-day microcosm experiment using sampled sediment cores. The high-resolution dialysis (HR-Peeper) and diffusive gradients in thin films (DGT) techniques were first employed to establish the profiles of soluble reactive P (SRP) and DGT-labile P in aluminum amended sediments at 2 and 1 mm resolutions, respectively. Both concentrations of two mobile P forms decreased with increasing ALS dosages. The static layers with extremely low P concentrations (<=0.060 mg L-1 for SRP and <=0.024 mg L-1 for DGT labile P) were observed in the upper 6-16 mm sediment layers at 6-15 ALS/Pmobile treatments (mobile P is the sum of NH4Cl-P, BD-P, and NaOH-nrP; mol mol-1). The static layer was followed by an active layer in which the upward release potential (RAL) decreased from 33.4 to 21.9 for SRP and from 92.2 to 51.0 for DGT labile P, respectively. As the formation of the static layer is a key to sustaining P immobilization in sediments, the minimal dosage of 9 ALS/Pmobile is required for ALS capping. Modeling with DGT Induced Fluxes in Sediments (DIFS) showed a greater increase in adsorption rate constant (k1, maximum 7.2-fold) compared to adsorption rate constant (k1, maximum 2.2-fold), demonstrating that the release of P from sediment solids became increasingly difficult after ALS amendment. PMID- 28818592 TI - The impact of chemosensitisation on bioaccumulation and sediment toxicity. AB - Cellular multixenobiotic resistance (MXR) transport proteins enhance the efflux of numerous organic pollutants. However, MXR proteins may be blocked or saturated by xenobiotic compounds, acting as inhibitors - also called chemosensitisers. Although effective on a cellular level, the environmental relevance of chemosensitisers has not been conclusively demonstrated. Since sediments are an important source of bioaccumulating compounds in aquatic ecosystems, sediments and sediment-associated hydrophobic pollutants were investigated for their potential to increase exposure and toxicity in the presence of chemosensitisation. In this study, we address this issue by (1) comparing the net uptake of 17 hydrophobic environmental pollutants by zebrafish (Danio rerio) embryos in the presence and absence of the model chemosensitiser verapamil and (2) investigating the impact of verapamil on the dose-dependent effect on zebrafish embryos exposed to polluted sediment extracts. None of the 17 pollutants showed a reproducible increase in bioaccumulation upon chemosensitisation with verapamil. Instead, internal concentrations were subject to intra-species variation by a factor of approximately two. However, a significant increase in toxicity was observed upon embryo co-exposure to verapamil for one of three sediment extracts. In contrast, another sediment extract exhibited less toxicity when combined with verapamil. In general, the results indicate only a minor impact of verapamil on the uptake of moderately hydrophobic chemicals in zebrafish embryos. PMID- 28818593 TI - Nitrofurantoin hydrolytic degradation in the environment. AB - Occurrence of pharmaceuticals, especially antibiotics in the environment increased attention to their environmental fate. Hydrolysis is one of two abiotic processes by which compounds are degraded in the environment. According to authors knowledge this is the first study investigating hydrolytic degradation of nitrofurantoin at pH-values normally found in the environment. Nitrofurantoin hydrolytic degradation appeared to be much slower at acidic (pH 4) solution compared to neutral (pH 7) and alkaline (pH 9) solutions at all three investigated temperatures (20 degrees C, 40 degrees C and 60 degrees C). In all cases nitrofurantoin hydrolysis followed the first-order kinetics with half lives ranged from 0.5 days at pH 9 and 60 degrees C to 3.9 years at pH 4 and 20 degrees C. Temperature dependence of the hydrolysis rate constant was quantified by Arrhenius equation; obtained Ea values were as follows: 100.7 kJ mol-1 at pH 4, 111.2 kJ mol-1 at pH 7 and 102.3 kJ mol-1 at pH 9. Increase in hydrolysis rate constants for each 10 degrees C increase in temperature were 3.4, 3.9 and 3.5 at pH 4, pH 7 and pH 9, respectively. The structures of hydrolytic degradation products were determined and degradation pathways were suggested. Three main processes occurred depending on pH-values: protonation of the nitrofurantoin followed by cleavage of the NN single bond, heterocyclic non-aromatic ring cleavage, and reduction of the non-aromatic heterocyclic ring. PMID- 28818594 TI - Ultraviolet and solar photocatalytic ozonation of municipal wastewater: Catalyst reuse, energy requirements and toxicity assessment. AB - The present study evaluated the treatment of municipal wastewater containing phenol using solar and ultraviolet (UV) light photocatalytic ozonation processes to explore comparative performance. Important aspects such as catalyst reuse, mineralization of pollutants, energy requirements, and toxicity of treated wastewater which are crucial for practical implementation of the processes were explored. The activity of the photocatalysts did not change significantly even after three consecutive uses despite approximately 2% of the initial quantity of catalyst being lost in each run. Analysis of the change in average oxidation state (AOS) demonstrated the formation of more oxidized degradation products (DeltaAOS values of 1.0-1.7) due to mineralization. The energy requirements were determined in terms of electrical energy per order (EEO) and the collector area per order (ACO). The EEO (kWh m-3 Order-1) values were 26.2 for ozonation, 38-47 for UV photocatalysis and 7-22 for UV photocatalytic ozonation processes. On the other hand, ACO (m2 m-3 order-1) values were 31-69 for solar photocatalysis and 8 13 for solar photocatalytic ozonation. Thus photocatalytic ozonation processes required less energy input compared to the individual processes. The cytotoxicity of the wastewater was analysed using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide (MTT) assay with Vero cells. The cell viability increased from 28.7% in untreated wastewater to 80% in treated wastewater; thus showing that the treated wastewater was less toxic. The effectiveness of photocatalytic ozonation, recovery and reusability of the photocatalysts, as well as detoxification of the wastewater make this low energy consumption process attractive for wastewater remediation. PMID- 28818595 TI - Fish embryo toxicity test, threshold approach, and moribund as approaches to implement 3R principles to the acute fish toxicity test. AB - The acute fish toxicity test (AFT) is requested by EU legal frameworks for hazard classification and risk assessment. AFT is one of the few regulatory required tests using death as an endpoint. This paper reviews efforts made to reduce, refine and replace (3Rs) AFT. We make an inventory of information requirements for AFT, summarize studies on 3Rs of AFT and give recommendations. The fish embryo toxicity test (FET) is proposed as a replacement of AFT and analyses have focused on two aspects: assessing the capacity of FET in predicting AFT and defining the applicability domain of FET. Six comparison studies have consistently shown a strong correlation of FET and AFT. In contrast, the applicability domain of FET has not yet been fully defined. FET has not yet been accepted as a replacement of AFT by any EU legal frameworks to fulfill information requirements because FET is insensitive to some chemicals. It is recommended that the outlier chemicals that do not correlate between FET and AFT should be further investigated. When necessary, additional FET data should be generated. Another effort to reduce and refine AFT is incorporation of FET into the threshold approach. Furthermore, moribund as an endpoint of fish death has been introduced in revising AFT guideline to reduce the duration of suffering for refinement. This endpoint, however, needs further work on the link of moribund and death. Global regulatory acceptance of the moribund endpoint would be critical for this development. PMID- 28818597 TI - Is there a J-shaped relationship between the fatty liver index and risk of microalbuminuria in the general population? AB - BACKGROUND: We investigated whether the fatty liver index (FLI), as a clinical indicator of hepatic fat accumulation based on body mass index, gamma-glutamyl transferase, triglycerides, and waist circumference, has an association with microalbuminuria. METHODS: We analyzed anthropometric and biochemical data from a nation-wide, population-based, cross-sectional study. A total of 1605 participants included were healthy native Korean 40years or older and divided into quintiles according to their log-FLI and sex. Microalbuminuria was defined as urine albumin/creatinine ratio (UACR) between 30 and 300mg/g. RESULTS: Participants in higher quintiles of log-FLI were more obese and hypertensive and had greater glycemic exposure, poorer lipid profiles, and greater increases in log-UACR compared with lower quintiles. Linear regression analysis demonstrated that log-FLI was associated with systolic and diastolic blood pressure, body mass index, waist circumference, fasting plasma glucose, glycated hemoglobin, and log UACR. In logistic regression adjusted for age, sex, body mass index, waist circumference, and fasting plasma glucose, the OR of microalbuminuria was elevated in quintile 1 (adjusted OR=2.161, 95% CI=0.453-10.31) and quintile 5 (adjusted OR=6.387, 95% CI=1.317-51.58), when compared to quintile 2. CONCLUSIONS: There appears to be a J-shaped association between FLI and UACR in healthy general population. PMID- 28818596 TI - Cardiometabolic phenotypes and mitochondrial DNA copy number in two cohorts of UK women. AB - The mitochondrial genome is present at variable copy number between individuals. Mitochondria are vulnerable to oxidative stress, and their dysfunction may be associated with cardiovascular disease. The association of mitochondrial DNA copy number with cardiometabolic risk factors (lipids, glycaemic traits, inflammatory markers, anthropometry and blood pressure) was assessed in two independent cohorts of European origin women, one in whom outcomes were measured at mean (SD) age 30 (4.3) years (N=2278) and the second at 69.4 (5.5) years (N=2872). Mitochondrial DNA copy number was assayed by quantitative polymerase chain reaction. Associations were adjusted for smoking, sociodemographic status, laboratory factors and white cell traits. Out of a total of 12 outcomes assessed in both cohorts, mitochondrial DNA copy number showed little or no association with the majority (point estimates were close to zero and nearly all p-values were >0.01). The strongest evidence was for an inverse association in the older cohort with insulin (standardised beta [95%CI]: -0.06, [-0.098, -0.022], p=0.002), but this association did not replicate in the younger cohort. Our findings do not provide support for variation in mitochondrial DNA copy number having an important impact on cardio-metabolic risk factors in European origin women. PMID- 28818598 TI - Serotype determination of Salmonella by xTAG assay. AB - Currently, no protocols or commercial kits are available to determine the serotypes of Salmonella by using Luminex MAGPIX(r). In this study, an xTAG assay for serotype determination of Salmonella suitable for Luminex MAGPIX(r) is described and 228 Salmonella isolates were serotype determined by this xTAG assay. The xTAG assay consists of two steps: 1) Multiplex PCR to amplify simultaneously O, H and Vi antigen genes of Salmonella, and 2) Magplex-TAGTM microsphere hybridization to identify accurately the specific PCR products of different antigens. Compared with the serotyping results of traditional serum agglutination test, the sensitivity and specificity of the xTAG assay were 95.1% and 100%, respectively. The agreement rate of these two assays was 95.2%. Compared with Luminex xMAP(r) Salmonella Serotyping Assay (SSA) kit, the advantages of this xTAG assay are: First, the magnetic beads make it applicable to both the Luminex(r)100/200TM and MAGPIX(r) systems. Second, only primers rather than both primers and probes are needed in the xTAG assay, and the process of coupling antigen-specific oligonucleotide probes to beads is circumvented, which make the xTAG assay convenient to be utilized by other laboratories. The xTAG assay may serve as a rapid alternative or complementary method for traditional Salmonella serotyping tests, especially for laboratories that utilize the MAGPIX(r) systems. PMID- 28818599 TI - A new cost and time effective method for multilocus microsatellite typing (MLMT) studies: Application of Leishmania tropica isolates and clinical samples from Turkey. AB - Molecular techniques are widely used in the field of parasitology to identify the genetic profile of the microbiological agents. Microsatellite typing studies are comprised of the amplification of polymorphic markers to analyze the fragment sizes using bioinformatics tools. Current methods need fluorescently labeled primers and size markers to obtain fragment peaks in ABI PRISM(r) systems and due to low discrimination power of gel-electrophoresis, it is not possible to differentiate primer-dimers from small fragments In the present study, we designed a new method for fragment analysis studies, which reduce the time by eliminating the classical PCR, the gel-electrophoresis and the preparation steps of fragment analysis. Ten previously studied Leishmania tropica strains and one Giemsa-stained slide were tested by new method and obtained fragment peaks were compared to the previous data obtained from ABI PRISM(r) system. Overall twelve makers were tested and the signal peak from each fragment was compared to classical ABI PRISM(r)-based fragment analysis and noted as identical. The new protocol is time saving, cost effective, and eliminates the human error comparing to classical MLMT analysis protocol. We believe that this method enables the easy detection of the fragment lengths without having bioinformatics experience and the obtained data can be easily shared with other laboratories. PMID- 28818600 TI - A reverse-hybridization test for the identification of 76 pneumococcal serotypes, 42 individually and 34 in pairs. AB - The S. PneumoStrip test is a recently developed reverse hybridization strip-based commercial assay that allows for the identification of 76 pneumococcal serotypes, 42 individually and 34 in pairs, according to their specific gene sequences. The test was validated with reference strains of 92 different pneumococcal serotypes and with a selection of 75 clinical isolates representing 55 serotypes, showing 100% sensitivity and specificity. The test was also applied to 64 pneumococcal invasive isolates (23 different serotypes) consecutively collected between June 2016 and March 2017, with 60 (93.8%) being serotyped. Four isolates belonging to serotypes 13, 29, and 35B (2 isolates), which are not included in the test, did not produce a hybridization signal with serotype specific probes. The identification of most serotypes causing invasive pneumococcal disease together with the simplicity of performance and results interpretation, and the use of routine laboratory equipment make this test very suitable for most clinical and research laboratories. PMID- 28818601 TI - Complete genome sequence of Pseudomonas antarctica PAMC 27494, a bacteriocin producing psychrophile isolated from Antarctica. AB - Antimicrobial-producing, cold-adapted microorganisms have great potential for biotechnological applications in food, pharmaceutical, and cosmetic industries. Pseudomonas antarctica PAMC 27494, a psychrophile exhibiting antimicrobial activity, was isolated from an Antarctic freshwater sample. Here we report the complete genome of P. antarctica PAMC 27494. The strain contains a gene cluster encoding microcin B which inhibits DNA regulations by targeting the DNA gyrase. PAMC 27494 may produce R-type pyocins and also contains a complete set of proteins for the biosynthesis of adenosylcobalamin and possibly induces plant growth by supplying pyrroloquinoline quionone molecules. PMID- 28818602 TI - Operational modelling of bigeye tuna (Thunnus obesus) spatial dynamics in the Indonesian region. AB - With INDESO, Indonesia has implemented a system for the monitoring and management of its tuna resources. Despite increasing catch, very few is known about the dynamics and real abundance of tuna species in the Indonesian waters and adjacent oceanic regions. The SEAPODYM model was implemented in an operational chain of production for the Indonesian region to simulate tuna spatial dynamics in realtime. This challenging objective imposed developing a global scale model at coarse resolution to provide initial and boundaries conditions of the regional model. A parameter optimization approach was used to provide the best solution fitting several hundreds of thousand catch observations, over a long historical simulation at coarse resolution. Then downscaling method and regional modelling at high resolution (1/12 degrees x day) were validated to produce realtime and forecast on a weekly basis. The architecture of this application, the approach for its parameterization and some key results are presented and discussed. PMID- 28818603 TI - Effects of suspended sediments and nutrient enrichment on juvenile corals. AB - Three to six-month-old juveniles of Acropora tenuis, A. millepora and Pocillopora acuta were experimentally co-exposed to nutrient enrichment and suspended sediments (without light attenuation or sediment deposition) for 40days. Suspended sediments reduced survivorship of A. millepora strongly, proportional to the sediment concentration, but not in A. tenuis or P. acuta juveniles. However, juvenile growth of the latter two species was reduced to less than half or to zero, respectively. Additionally, suspended sediments increased effective quantum yields of symbionts associated with A. millepora and A. tenuis, but not those associated with P. acuta. Nutrient enrichment did not significantly affect juvenile survivorship, growth or photophysiology for any of the three species, either as a sole stressor or in combination with suspended sediments. Our results indicate that exposure to suspended sediments can be energetically costly for juveniles of some coral species, implying detrimental longer-term but species specific repercussions for populations and coral cover. PMID- 28818604 TI - Newly discovered seagrass beds and their potential for blue carbon in the coastal seas of Hainan Island, South China Sea. AB - Eight new seagrass beds were discovered along the coastline of Hainan Island in South China Sea with an area of 203.64ha. The leaf N content of all seagrasses was above the median value, indicative of N limitation, with their C:N ratio recorded significantly lower than the limiting criteria. This suggested that N is not limiting but in replete status. Further, the lower C content observed in the seagrass leaves was accompanied by higher nutrient concentration. The mean seagrass biomass C was 0.23+/-0.16MgCha-1, while the average sediment organic carbon (SOC) stock was 7.02+/-3.57MgCha-1. The entire SOC stock of the newly discovered seagrass beds was 1306.45 Mg C, and the overall SOC stock of seagrass bed at Hainan Island was 40858.5 Mg C. These seagrass beds are under constant threats from sea reclamation, nutrient input, aquaculture activities for oyster and snail farming, and fishing activities. PMID- 28818605 TI - Anthropogenic (PBDE) and naturally-produced (MeO-PBDE) brominated compound levels in Bizerte Lagoon clams (Ruditapes decussatus): Levels and human health risk assessment. AB - Information on the occurrence of organobrominated compounds in bivalves from Tunisia is scarce. To the best of our knowledge, this is the first report of these compounds in clams from Tunisia. The aim of this study is to measure natural and synthetic organobrominated compound concentrations and evaluate congener distribution and pollution sources in a clam species (Ruditapes decussatus) from three sites of the Bizerte Lagoon. Total synthetic organobrominated pollutant levels in clam ranged from 34.8 to 188ngg-1lw. For natural organobrominated compounds, concentrations varied from 18.2 to 49.5ngg 1lw. Total PBDE and MeO-PBDE concentrations in clams from the Bizerte Lagoon were similar or slightly lower than those reported for other species from other locations around the world. The health risks associated with the consumption of this species were assessed and posed no threat to public health concerning PBDE intakes. PMID- 28818606 TI - Recent Advances in Targeting ROS1 in Lung Cancer. AB - ROS1 is a validated therapeutic target in NSCLC. In a phase I study, the multitargeted MET proto-oncogene, receptor tyrosine kinase/anaplastic lymphoma kinase/ROS1 inhibitor crizotinib demonstrated remarkable efficacy in ROS1 rearranged NSCLCs and consequently gained approval by the United States Food and Drug Administration and by the European Medicines Agency in 2016. However, similar to other oncogene-driven lung cancers, ROS1-rearranged lung cancers treated with crizotinib eventually acquire resistance, leading to disease relapse. Novel ROS1 inhibitors and therapeutic strategies are therefore needed. Insights into the mechanisms of resistance to ROS1-directed tyrosine kinase inhibitors are now beginning to emerge and are helping to guide the development of new ROS1 inhibitors. This review discusses the biology and diagnosis of ROS1 rearranged NSCLC, and current and emerging treatment options for this disease. Future challenges in the field are highlighted. PMID- 28818607 TI - Potential Impact of Including Time to First Cigarette in Risk Models for Selecting Ever-Smokers for Lung Cancer Screening. AB - INTRODUCTION: Selecting individuals on the basis of model-predicted risks has been reported to improve lung cancer screening efficiency. On the basis of case control studies, time to first cigarette (TTFC), a nicotine dependency measurement, has been a strong independent predictor of lung cancer risk. Our objective was to verify the TTFC-lung cancer association in the prospective National Lung Screening Trial and evaluate whether adding TTFC can improve lung cancer risk-prediction models. METHODS: Using Cox models, we examined associations between TTFC (<=5, 6-14, 15-29, 30-59, and >=60 minutes) and lung cancer incidence and death in 18,729 National Lung Screening Trial participants, adjusting for smoking and other lung cancer risk factors comprehensively. We estimated 5-year individual lung cancer incidence by using models without and with TTFC and dichotomized into screening or no-screening groups based on risk thresholds of 1% and 2%. Area under the receiver operating curve values were calculated for models without and with TTFC. RESULTS: Smokers with a TTFC of 60 minutes or more had a much lower standardized 5-year lung cancer incidence risk 1.54% (1.52%-1.56%) for TTFC 60 minutes or more versus 4.07% (4.04%-4.09%) for TTFC 5 minutes or less-and lung cancer death risk-0.59% (0.57%-0.61%) for TTFC 60 minutes or more versus 2.26% (2.23%-2.28%) for TTFC 5 minutes or less (p trend < 0.001). Adding TTFC to the lung cancer incidence model improved the area under the receiver operating curve by 0.0079 (95% confidence interval = 0.0019-0.0138 [p = 0.0085]). Among 8994 smokers without a lung cancer diagnosis, 180 (2.00%) and 155 (1.67%) more people would be assigned to the no-screening group by adding TTFC to the model (p values for percent changes <0.001) at the 1% and 2% risk thresholds, respectively. CONCLUSION: Including TTFC, which can be elicited by a single question at very low cost and noninvasively question, into risk models might better identify smokers with lower risk and could therefore be a safe, convenient tool to improve identification of those who benefit less from lung cancer screening. PMID- 28818608 TI - Potential Resistance Mechanisms Revealed by Targeted Sequencing from Lung Adenocarcinoma Patients with Primary Resistance to Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs). AB - INTRODUCTION: EGFR tyrosine kinase inhibitors (TKIs) have greatly improved the prognosis of lung adenocarcinoma. However, approximately 5% to 10% of patients with lung adenocarcinoma with EGFR sensitive mutations have primary resistance to EGFR TKI treatment. The underlying mechanism is unknown. METHODS: This study used next-generation sequencing to explore the mechanisms of primary resistance by analyzing 11 patients with primary resistance and 11 patients sensitive to EGFR TKIs. Next-generation targeted sequencing was performed on the Illumina X platform for 483 cancer-related genes. EGFR mutation was initially detected using the amplification refractory mutation system. RESULTS: Potential primary resistance mechanisms were revealed by mutations unique to the EGFR TKI resistance group. Among the 11 resistant patients, 45% (five of 11) harbored a known resistance mechanism, such as MNNG HOS Transforming gene (MET) amplification de novo T790M mutation or overlapping T790M and phosphatase and tensin homolog gene (PTEN) loss and erb-b2 receptor tyrosine kinase 2 gene (ERBB2) amplification. In six of 11 resistant cases (54%), potential novel mutations that might lead to drug resistance were identified (including transforming growth factor beta receptor 1 gene [TGFBR1] mutation and/or EGFR structural rearrangement mechanistic target of rapamycin kinase gene [MTOR] mutation, transmembrane protease, serine 2 gene [TMPRSS2] fusion gene, and v-myc avian myelocytomatosis viral oncogene homolog gene [MYC] amplification). By analyzing somatic mutation patterns, the frequency of C:G->T:A transitions in the patients with primary resistance was significantly higher than that in sensitive group and occurred more frequently in the non-CpG region (Cp(A/C/T)->T). CONCLUSION: The mechanisms of primary resistance to EGFR TKIs may be highly heterogeneous. Mutations in EGFR and its downstream pathway, as well as mutations that affect tumor cell function, are related to primary resistance. Somatic single-nucleotide mutation patterns might be associated with primary resistance to EGFR TKIs. PMID- 28818609 TI - Multicenter Comparison of 22C3 PharmDx (Agilent) and SP263 (Ventana) Assays to Test PD-L1 Expression for NSCLC Patients to Be Treated with Immune Checkpoint Inhibitors. AB - INTRODUCTION: Among the several agents targeting the programmed cell death 1 (PD 1) pathway, pembrolizumab is currently the only one approved for the treatment of patients with NSCLC in association with a companion diagnostic assay, the anti-PD L1 immunohistochemical (IHC) 22C3 PharmDx (Agilent Technologies, Santa Clara, CA) using the Dako Autostainer (Dako, Carpinteria, CA). However, the Dako platform is not present in each pathology department, and this technical limitation is a major problem for the diffusion of the PD-L1 IHC predictive test for pembrolizumab. METHODS: The Italian Society of Anatomic Pathology and Cytopathology and the Italian Association of Medical Oncology in an independent, multicenter study compared the in vitro diagnostics PD-L1 IHC 22C3 pharmDx test (Agilent) on the Dako Autostainer and the in vitro diagnostics Ventana PD-L1 (SP263) test on the Ventana BenchMark platform (Ventana Medical Systems, Tucson, AZ). Using serial sections from tissue microarrays, 100 lung adenocarcinomas were locally stained and scored in four centers with the same antibody batches. RESULTS: A high analytical correlation (more than 90% at the lower 95% confidence interval [CI] value) between PD-L1 expression levels obtained with the 22C3 and SP263 assays was observed. At the proposed clinically relevant cutoffs (>=50% and >=1%), the overall concordances between 22C3 and SP263 data were 0.99 (95% CI: 0.96-1) and 0.80 (95% CI: 0.68-0.91), respectively. The lower agreement between data obtained with the 22C3 and SP263 clones at the cutoff of 1% or higher was mainly related to the lower (about 80%) interrater agreement at this cutoff with each clone. CONCLUSIONS: These results indicate a high correlation between PD-L1 IHC expression data obtained with the Agilent PD-L1 IHC 22C3 pharmDx and the Ventana PD-L1 (SP263) tests in NSCLC and suggest that the two assays could be utilized interchangeably as an aid to select patients for first-line and second line treatment with pembrolizumab and potentially with other anti-PD-1/PD-L1 checkpoint inhibitors. PMID- 28818610 TI - Surfactant and continuous positive airway pressure for the prevention of chronic lung disease: History, reality, and new challenges. AB - The discovery of surfactant was one of the most significant research events to occur in the history of neonatology. Certainly, surfactant saved lives for premature infants who were otherwise considered non-viable. However, the prevention of chronic lung disease did not progress and it became clear that a significant portion of the help surfactant provides to the premature lung is counteracted by mechanical ventilation. A dilemma exists over the priorities in premature management to intubate and administer surfactant or not to intubate and support these infants non-invasively with the use of continuous positive airway pressure. A new hydrophilic surfactant preparation has been developed with the hope to enable the introduction of surfactant therapy without the need for tracheal intubation. Clinical trials on this product are currently in progress. This article provides the history and prospect of respiratory distress management in premature infants and evaluates the current evidence for non-invasive practices. PMID- 28818611 TI - Teasing as a risk factor for abnormal eating behaviours: A prospective study in an adolescent population. AB - INTRODUCTION: There are discrepancies in the literature about the role of teasing in the onset of eating pathology. This article aims to establish the influence of teasing in abnormal eating behaviors and attitudes in the adolescent population. MATERIAL AND METHODS: This is a two-year prospective study conducted in 7,167 adolescents between 13 and 15 years of age. In a first assessment, teasing about weight and teasing about abilities were measured by means of the POTS.questionnaire. Its association with eating psychopathology after two years was analyzed controlling nutritional status (BMI), body dissatisfaction, drive to thinness, perfectionism (EDI), emotional symptoms and hyperactivity (SDQ) which had also been measured in the first assessment. The analysis was carried out independently for both genders. RESULTS: The multivariant analysis found no significant or independent effect of teasing about weight or teasing about abilities in the onset of later eating psychopathology. The obtained models were similar for both genders although in girls, but not in boys, controlling BMI was enough to make any effect of teasing disappear. CONCLUSIONS: Teasing about weight or abilities has no direct effect, neither in boys nor in girls of 13 to 15 years old, in the development of eating psychopathology. PMID- 28818612 TI - Epidemiological and clinical variables related with the predominant polarity on bipolar disorder: A systematic review. AB - INTRODUCTION: Current classification of bipolar disorder (BD) in type i or type ii, however useful, may be insufficient to provide relevant clinical information in some patients. As a result, complementary classifications are being proposed, like the predominant polarity (PP) based, which is defined as a clear tendency in the patient to present relapses in the manic or depressive poles. METHODS: We carried out a search in PubMed and Web of Science databases, following the Preferred Items for Reporting of Systematic Reviews and Meta-Analyses -PRISMA- guidelines, to identify studies about BD reporting PP. The search is updated to June 2016. RESULTS: Initial search revealed 907 articles, of which 16 met inclusion criteria. Manic PP was found to be associated with manic onset, drug consumption prior to onset and a better response to atypical antipsychotics and mood stabilisers. Depressive PP showed an association with depressive onset, more relapses, prolonged acute episodes, a greater suicide risk and a later diagnosis of BD. Depressive PP was also associated with anxiety disorders, mixed symptoms, melancholic symptoms and a wider use of quetiapine and lamotrigine. LIMITATIONS: Few prospective studies. Variability in some results. CONCLUSION: PP may be useful as a supplement to current BD classifications. We have found consistent data on a great number of studies, but there is also contradictory information regarding PP. Further studies are needed, ideally of a prospective design and with a unified methodology. PMID- 28818613 TI - Network analysis: A new way of understanding psychopathology? AB - Current taxonomic systems are based on a descriptive and categorical approach where psychopathological symptoms and signs are caused by a hypothetical underlying mental disorder. In order to circumvent the limitations of classification systems, it is necessary to incorporate new conceptual and psychometric models that allow to understand, analyze and intervene in psychopathological phenomena from another perspective. The main goal was to present a new approach called network analysis for its application in the field of psychopathology. First of all, a brief introduction where psychopathological disorders are conceived as complex dynamic systems was carried out. Key concepts, as well as the different types of networks and the procedures for their estimation, are discussed. Following this, centrality measures, important for the understanding of the network as well as to examine the relevance of the variables within the network were addressed. These factors were then exemplified by estimating a network of self-reported psychopathological symptoms in a representative sample of adolescents. Finally, a brief recapitulation is made and future lines of research are discussed. PMID- 28818614 TI - The transcription of atypical protein kinase C in hemocytes of the giant freshwater prawn, Macrobrachium rosenbergii, during the molt stage and injection of pathogen-associated compounds. AB - Protein kinase C (PKC), which is involved in cell signaling pathways, comprises a family of serine/threonine kinases ubiquitously present in animals and its members are grouped on the basis of structural and activation characteristics into novel, classical, and atypical PKC forms. In this study, an atypical PKC of Macrobrachium rosenbergii, designated MraPKC, was successfully cloned, and its protein comprised structural domains similar to those of atypical PKC homologues, including the Phox and Bem1 (PB1) domain, a zinc finger phorbol-ester/DAG-type signature, protein kinase signatures, and a cAMP-dependent, cGMP-dependent, and PKC (AGC) kinase C-terminal domain. Phylogenetic analyses revealed a close evolutionary relationship between MraPKC and aPKCs of insects. MraPKC transcripts were detected in all tissues examined through an RT-PCR, with the highest level detected in muscles. A quantitative real-time PCR was used to evaluate MraPKC expression in hemocytes of M. rosenbergii in various molt stages, and in prawn challenged with Vibrio alginolyticus, Lactococcus garvieae, and white spot syndrome virus (WSSV) as well as in prawns injected with pathogen-associated molecular patterns (PAMPs), including lipopolysaccharide (LPS), peptidoglycan (PG), and polyinosinic:polycytidylic acid (Poly:IC). Results revealed that the expression pattern of MraPKC was distinctly modulated during molting, with significant enhancement in the C stage. MraPKC transcripts significantly increased in hemocytes of prawns infected with L. garvieae at 6-24 h and those injected with PG at 12-24 h. In contrast, significantly decreased expression of MraPKC was observed in hemocytes of prawns injected with V. alginolyticus and LPS for 3 and 12 h, respectively, and a similar phenomenon was observed in hemocytes of those injected with WSSV and Poly:IC for 12 h each. Therefore, MraPKC might play crucial roles in biological processes, and it may mediate the signaling pathway induced by varied pathogens for the potential regulation of host innate defense. PMID- 28818615 TI - Deep transcriptome profiling sheds light on key players in nucleus implantation induced immune response in the pearl oyster Pinctada martensii. AB - Immunological rejection of the pearl oysters following nucleus implantation is a major issue limiting the successful rate of cultured pearls. To date, the molecular mechanism of immune tolerance during pearl formation in the pearl oysters is still largely unknown. Through the RNA sequencing platform and comparative transcriptomic analysis, we investigated the chronic gene expression changes at seven time points (0, 5, 10, 15, 20, 30, 60 days post implantation or dpi) over a period of 60 days following nucleus implantation in the pearl oyster Pinctada martensii. A total of 81,390 unique transcripts (or unigenes) with a combined length of 96.8 million bp and a N50 value of 2227 bp were obtained. When compared with sequences in the nr, nt, Swiss-Prot, KEGG, COG and GO databases, 36,380 unigenes can find homologous genes. Pairwise comparison of gene expression among all the samples showed that the largest number (or 6846) of differentially expressed genes was observed at 10 dpi. The number then decreased to below 5000 at 15, 20 and 30 dpi and increased again to 6679 at 60 dpi. PCA analysis further showed that the seven time points can be roughly divided into four groups. Comparative transcriptomic analysis between the four groups identified a variety of genes showing differential expression at different time points, including many immune-related genes such as those encoding for toll-like receptor, lectin, scavenger receptor, and peroxidase. In addition, GO and KEGG enrichment analysis revealed that these differentially expressed genes were mainly associated with metabolism, ribosome function, immune response, signaling transduction, and cytoskeleton organization. Notably, two KEGG pathways, namely "cell adhesion molecules" and "primary immunodeficiency" were significantly enriched during the whole process. This finding indicates that genes in these pathways are likely to play critical roles in the immune tolerance of the pearl oysters. To conclude, the data obtained contribute to a better understanding of the molecular mechanisms of nucleus implantation induced immune response in the pearl oysters, and will facilitate the development of effective measures to improve the performance of pearl culture. PMID- 28818616 TI - Molecular insights of two STAT1 variants from rock bream (Oplegnathus fasciatus) and their transcriptional regulation in response to pathogenic stress, interleukin-10, and tissue injury. AB - Signal transducers and activators of transcription 1 (STAT1) is critically involved in mediating cytokine-driven signaling, and triggers the transcription of target genes to activate cellular functions. Although the structural and functional aspects of STAT members have been well described in mammals, only limited information is available for the STAT genes in teleost fishes. In the present study, two variants of STAT1 genes (RbSTAT1 and RbSTAT1L) were identified from rock bream and characterized at the cDNA and genomic sequence levels. RbSTAT1 and RbSTAT1L were found to share a common domain architecture with mammalian STAT1. Phylogenetic analysis revealed that RbSTAT1 shows a common evolutionary trajectory with other STAT1 counterparts, whereas RbSTAT1L showed a separate path, implying that it could be a novel member of the STAT family. The genomic organizations of RbSTAT1 and RbSTAT1L illustrated a similar exon-intron pattern with 23 exons in the coding sequence. Transcription factor-binding sites, which are mostly involved in the regulation of immune responses, were predicted at the putative promoter regions of the RbSTAT1 and RbSTAT1L genes. SYBR Green qPCR analysis revealed the ubiquitous expression of RbSTAT1 and RbSTAT1L transcripts in different fish tissues with the highest level observed in peripheral blood cells. Significantly modulated transcripts were noted upon viral (rock bream iridovirus [RBIV]), bacterial (Edwardsiella tarda and Streptococcus iniae), and pathogen-associated molecular pattern (lipopolysaccharide and poly I:C) stimulations. The WST-1 cell viability assay affirmed the potential antiviral capacity of RbSTAT1 and RbSTAT1L against RBIV. A possible role of RbSTAT1 and RbSTAT1L in the wound healing process was revealed according to their modulated expression in injured fish. In addition, the transcriptional regulation of RbSTAT1 and RbSTAT1L was analyzed by qPCR following stimulation with rock bream interleukin-10. Taken together, these findings suggest that the STAT1 mediated Janus kinase/STAT pathway might at least in part be involved in the regulatory mechanisms underlying the immune defensive roles against microbial pathogens and the wound healing process. PMID- 28818617 TI - l-amino acid oxidase expression profile and biochemical responses of rabbitfish (Siganus oramin) after exposure to a high dose of Cryptocaryon irritans. AB - Cryptocaryon irritans is an important protozoan parasite which infects almost all kinds of marine teleosts, causing heavy economic losses. In our previous studies, we found that rabbitfish (Siganus oramin) displayed high resistance to C. irritans infection, and a novel protein, l-amino acid oxidase (LAAO), was identified from the serum that was lethal to C. irritans. In this study, the rabbitfish were firstly infected with a high dose of C. irritans, then the LAAO mRNA expression pattern and the activity of three enzymes [superoxide dismutase (SOD), Na+/K+-ATPase and Ca2+/Mg2+-ATPase] were measured in various tissues. The results indicated that, after infection, the feeding and swimming of rabbitfish was normal, and the infection intensity in the host was low. Tissue distribution analysis showed that LAAO mRNA was most pronounced in the head kidney and gill, with lower expression observed in the muscle. After infection with C. irritans, the LAAO mRNA was up-regulated early post infection (from 6 to 24 h) in both gill and spleen, but then returned to normal levels, implying that LAAO may play an important role in the host's early immune response. The SOD activity in the liver was significantly higher in the infection group than in the control group by 48 h post infection, while Na+/K+-ATPase and Ca2+/Mg2+-ATPase activities in the gill were decreased by 12 and 24 h after infection; no significant difference was detected at the other time points throughout the experiment. Together, these results suggest that biochemical responses of rabbitfish are relatively mild after infection with a high dose of parasite, and the LAAO may play an important role in the host's defense against C. irritans. PMID- 28818618 TI - Ctenopharyngodon idella p53 mediates between NF-kappaB and PKR at the transcriptional level. AB - p53, NF-kappaB and PKR are well-known to be involved in antiviral response. Although p53 has been reported in fish, its role in the regulation of NF-kappaB and PKR is not well understood. Here, we cloned and characterized the full length of cDNA sequence of grass carp (Ctenopharyngodon idella) p53 (Cip53) and its promoter sequence. The full length cDNA of Cip53 was 1879 bp with an ORF of 1116 bp encoding a polypeptide of 371 amino acids. Phylogenetic tree analysis revealed that Cip53 shares high homology with Dario rerio p53 (Drp53). Similar to those of Cip65 and CiPKR, the expression of Cip53 in CIK cells was significantly up regulated after stimulation with poly I:C. To further understand the roles of fish p53 in the transcriptional control of NF-kappaB and PKR, Cip53 and Cip65 were expressed in E. coli BL21 and purified by affinity chromatography with the Ni-NTA His-Bind resin. In vitro, gel mobility shift assays demonstrated that the high affinity interaction between Cip65 and Cip53 promoter. Similarly, Cip53 bound to CiPKR promoter with high affinity. Dual-luciferase reporter assays showed that Cip65 activated Cip53 promoter and Cip53 activated CiPKR promoter, respectively. In addition, the role of p53 in p65-p53-PKR transcription pathway was explored. When Cip53 was knockdown in CIK cells, the mRNA levels of Cip65 and CiPKR were decreased. Taken together, p53 may play pivotal roles in transcription pathway of NF-kappaB and PKR in fish. PMID- 28818619 TI - Lymph node targeting strategies to improve vaccination efficacy. AB - With the rapid development of nanotechnology as well as growing interest in immunotherapy, a great number of vaccine delivery vehicles have been explored in order to elicit potent adaptive immune responses against various infections or tumors. Recent studies have shown that targeting vaccine to antigen-presenting cells (APCs) within lymph nodes is an effective strategy for improving antigen specific adaptive immune response. However, the characteristics of vaccine vehicles, such as size, surface charge and the degree of PEGylation, affect lymph node transfer and subsequent APC uptake, leading to different levels of immune responses. Thus, a comprehensive review of barriers, difficulties and corresponding strategies in lymph node targeting is important. In this review, we summarize the critical factors that affect lymph node delivery and survey recently reported successful vaccine carriers, which may be helpful for the rational design of vaccine vehicles. PMID- 28818620 TI - Secrets from immortal worms: What can we learn about biological ageing from the planarian model system? AB - Understanding how some animals are immortal and avoid the ageing process is important. We currently know very little about how they achieve this. Research with genetic model systems has revealed the existence of conserved genetic pathways and molecular processes that affect longevity. Most of these established model organisms have relatively short lifespans. Here we consider the use of planarians, with an immortal life-history that is able to entirely avoid the ageing process. These animals are capable of profound feats of regeneration fueled by a population of adult stem cells called neoblasts. These cells are capable of indefinite self-renewal that has underpinned the evolution of animals that reproduce only by fission, having disposed of the germline, and must therefore be somatically immortal and avoid the ageing process. How they do this is only now starting to be understood. Here we suggest that the evidence so far supports the hypothesis that the lack of ageing is an emergent property of both being highly regenerative and the evolution of highly effective mechanisms for ensuring genome stability in the neoblast stem cell population. The details of these mechanisms could prove to be very informative in understanding how the causes of ageing can be avoided, slowed or even reversed. PMID- 28818621 TI - Codon usage bias in the N gene of rabies virus. AB - Since its emergence, rabies virus (RABV) has been a major worldwide concern especially in developing countries. The nucleoprotein (N) of RABV is highly conserved and key for genetic typing, thus a better understanding of the N gene evolutionary trajectory can assist the development of control measures. We found that the N gene of RABV has a low codon usage bias with a mean effective number of codons (ENC) value of 56.33 influenced by both mutation pressure and natural selection. However, neutrality analysis indicated that natural selection dominates over mutation pressure. Additionally, we found that dinucleotide bias partly contributed to RABV codon usage bias. On the other hand, based on the clades of phylogenetic tree, we found that the evolutionary rate of the Africa 2 clade was the highest with a mean value of 3.75*10-3 substitutions per site per year. Above all, our results regarding N gene of RABV codon usage will serve future RABV evolution research. PMID- 28818622 TI - Benefits of immune protection versus immunopathology costs: A synthesis from cytokine KO models. AB - The inflammatory response can produce damage to host tissues and in several infectious diseases the most severe symptoms are due to immunopathology rather than a direct effect of pathogen multiplication. One hypothesis for the persistence of inflammatory damage posits that the benefits of protection towards infection outweigh the costs. We used data on knocked-out (KO) cytokine models [and the corresponding wild-type (WT) controls] to test this hypothesis. We computed differences in pathogen load and host survival between WT and KO and divided them by the WT values. Using this ratio provides an internal control for variation in pathogen species, host strain, pathogen dose, and inoculation route. We predicted that i) if mortality is essentially due to immunopathology, there should be a loose association between pathogen load and host survival; ii) if mortality is essentially due to pathogen proliferation, we expect a tight association between pathogen load and host survival. The results provide strong support to this latter hypothesis. In 85% of WT - KO comparisons (n=126), an increase in pathogen load was associated with an increase in host mortality, and a decrease in pathogen load was associated with a decrease in host mortality. Overall, these findings are in agreement with the idea that immunopathology persists because immune protection confers immediate benefits in terms of infection clearance. PMID- 28818623 TI - Leptospira species molecular epidemiology in the genomic era. AB - Leptospirosis is a zoonotic disease which global burden is increasing often related to climatic change. Hundreds of whole genome sequences from worldwide isolates of Leptospira spp. are available nowadays, together with online tools that permit to assign MLST sequence types (STs) directly from raw sequence data. In this work we have applied R7L-MLST to near 500 genomes and strains collection globally distributed. All 10 pathogenic species as well as intermediate were typed using this MLST scheme. The correlation observed between STs and serogroups in our previous work, is still satisfied with this higher dataset sustaining the implementation of MLST to assist serological classification as a complementary approach. Bayesian phylogenetic analysis of concatenated sequences from R7-MLST loci allowed us to resolve taxonomic inconsistencies but also showed that events such as recombination, gene conversion or lateral gene transfer played an important role in the evolution of Leptospira genus. Whole genome sequencing allows us to contribute with suitable epidemiologic information useful to apply in the design of control strategies and also in diagnostic methods for this illness. PMID- 28818624 TI - White matter microstructure integrity in relation to reading proficiency?. AB - Components of reading proficiency such asaccuracy, fluency, and comprehension require the successful coordination of numerous, yet distinct, cortical regions. Underlying white matter tracts allow for communication among these regions. This study utilized unique residualized tract - based spatial statistics methodology to identify the relations of white matter microstructure integrity to three components of reading proficiency in 49 school - aged children with typically developing phonological decoding skills and 27 readers with poor decoders. Results indicated that measures of white matter integrity were differentially associated with components of reading proficiency. In both typical and poor decoders, reading comprehension correlated with measures of integrity of the right uncinate fasciculus; reading comprehension was also related to the left inferior longitudinal fasciculus in poor decoders. Also in poor decoders, word reading fluency was related to the right uncinate and left inferior fronto - occipital fasciculi. Word reading was unrelated to white matter integrity in either group. These findings expand our knowledge of the association between white matter integrity and different elements of reading proficiency. PMID- 28818625 TI - The therapeutic potential of CRTH2/DP2 beyond allergy and asthma. AB - Prostaglandin (PG) D2 has been in the focus of research for quite a long time, but its biological effects and its roles in human disease are still not fully characterized. When in 2001 a second major PGD2 receptor termed chemoattractant receptor homologue expressed on Th2 cells (CRTH2; alternative name DP2) was discovered, diverse investigations started to shed more light on the complex and often controversial actions of the prostaglandin. With various immunomodulating effects, such as induction of migration, activation, and cytokine release of leukocytes observed both in vivo and in vitro, CRTH2 has emerged as a promising target for the treatment of allergic diseases. However, with more and more research being performed on CRTH2, it has also become clear that its biological actions are far more diverse than expected at the beginning. In this review, we aim to summarize the roles that PGD2 - and CRTH2 in particular - might play in diseases of the central nervous system, kidney, intestine, lung, hair and skin, bone and cartilage, and in cancer. Based on current data we propose that blocking CRTH2 might be a potential therapeutic approach to numerous conditions beyond classical allergic diseases and asthma. PMID- 28818626 TI - Wild populations of Triatoma infestans: Compilation of positive sites and comparison of their ecological niche with domestic population niche. AB - BACKGROUND: For several years, the wild populations of Triatoma infestans, main vector of Trypanosoma cruzi causing Chagas disease, have been considered or suspected of being a source of reinfestation of villages. The number of sites reported for the presence of wild T. infestans, often close to human habitats, has greatly increased, but these data are scattered in several publications, and others obtained by our team in Bolivia have not been published yet. METHODOLOGY/PRINCIPAL FINDINGS: Herein is compiled the largest number of wild sites explored for the presence of T. infestans collected with two methods The standardized methods aimed to determine the relationship between wild T. infestans and the ecoregion, and the directed method help to confirm the presence/absence of triatomines in the ecoregions. Entomological indices were compared between ecoregions and an environmental niche modelling approach, based on bioclimatic variables, was applied. The active search for wild T. infestans in Bolivia suggests a discontinuous distribution from the Andean valleys to the lowlands (Chaco), while the models used suggest a continuous distribution between the two regions and very large areas where wild populations remain to be discovered. The results compile the description of different habitats where these populations were found, and we demonstrate that the environmental niches of wild and domestic populations, defined by climatic variables, are similar but not equivalent, showing that during domestication, T. infestans has conquered new spaces with wider ranges of temperature and precipitation. CONCLUSIONS/SIGNIFICANCE: The great diversity of wild T. infestans habitats and the comparison of their ecological niches with that of domestic populations confirm the behavioural plasticity of the species that increase the possibility of contact with humans. The result of the geographical distribution model of the wild populations calls for more entomological vigilance in the corresponding areas in the Southern Cone countries and in Bolivia. The current presentation is the most comprehensive inventory of wild T. infestans-positive sites that can be used as a reference for further entomological vigilance in inhabited areas. PMID- 28818627 TI - Cross-sectional analysis of the association between bedtime and malaria exposure in the Ouest and Sud-Est Departments of Haiti. AB - INTRODUCTION: The governments of Haiti and the Dominican Republic have a binational agreement to work towards malaria elimination for the island of Hispaniola by the year 2020. Understanding malaria-related knowledge and behaviors can help inform elimination efforts. This study examined the association between social-behavioral factors, like bedtime and bed net ownership, with malaria seroconversion status among people in the Ouest and Sud Est departments of Haiti. METHODS: In 2013, cross-sectional survey data (n=377) and blood samples were collected from a convenience sample of individuals within community, clinic and school settings. Logistic regression models were constructed to examine associations between social-behavioral factors and malaria exposure, adjusting for potential confounders. RESULTS: Compared to people going to bed between 6 and 8 pm, those going to bed between 8 and 10 pm were 2.67 (OR, 95% CI: 1.16-6.14) times as likely to have been exposed to malaria. Participants who reported going to bed after 10 pm were 5.96 times as likely to have had previous malaria exposure (OR, 95% CI: 2.26-15.7), compared to 6-8 pm. No significant associations were found between malaria exposure and either insecticide use nor bed net ownership. DISCUSSION: These findings are consistent with suspected feeding behaviors of Anopheles albimanus, which prefers feeding at night and outdoors. Study findings may improve overall understanding of malaria transmission in Haiti and potentially guide future studies conducted in this region. PMID- 28818629 TI - Hospice, She Yelped: Examining the Quantity and Quality of Decision Support Available to Patient and Families Considering Hospice. AB - CONTEXT: Whether to engage hospice is one of the most difficult medical decisions patients and families make. Meanwhile, misperceptions about hospice persist. Within this context, the breadth and depth of patient decision support materials for hospice are unknown. OBJECTIVES: The objective of this study was to identify available patient decision aids (PtDAs) relating information about hospice care and compare that information with the informational needs expressed by real-world health care consumers. METHODS: First, the research team conducted an environmental scan of available PtDAs that included hospice as a treatment option and met six basic criteria defined by the International Patient Decision Aid Standards. Second, laypersons conducted an organic Web search for information regarding hospice, followed by a semi-structured interview eliciting perceptions of the available information. The setting was the University of Colorado Health Care System. Participants included 20 laypersons aged 18 years or older. RESULTS: The environmental scan identified 7PtDAs that included hospice. No PtDAs were designed primarily around hospice; rather, hospice was referenced under the umbrella of another treatment option. The layperson search identified information distinct from the scan; no participant accessed any of the above 7PtDAs. Many participants found the available online material confusing and biased, while failing to provide clear information on cost and lacking desired patient and caregiver testimonials. CONCLUSION: We found no formal PtDA designed primarily to help patients/families contemplating hospice. Furthermore, accessible online information about hospice does not appear to meet patient and caregiver decisional needs. These findings support the development and dissemination of high-quality decision support materials for hospice. PMID- 28818630 TI - Palliative Care in Moldova. AB - The article describes the important steps of palliative care development in Moldova, the current status, main achievements and challenges to be addressed in the future. It covers background information, policy development, medicines access and availability, education, and training, as well as services' provision. Palliative care development in Moldova registered real progress in spite of frequent political changes at governmental levels and difficulties to ensure the continuity of the development process during the last 10 years. However, the unmet need for palliative care for patients with life-limiting illnesses from different disease and age groups remains high. Further effort is needed to increase the availability and access to opioid analgesics and other essential palliative care medications. Government commitment and support, together with adequate funding, trained and educated health care professionals, and easy access to and availability of medicines, are essential to ensure the successful implementation of palliative care services nationwide, and to deliver the most appropriate qualitative palliative care for patients. To speed up palliative care development, a national strategy on palliative care development should be considered. The authors took part and continue to be involved in different ways in palliative care development in the country. PMID- 28818628 TI - A prospective multicentre study of the epidemiology and outcomes of bloodstream infection in cirrhotic patients. AB - OBJECTIVES: To describe the current epidemiology of bloodstream infection (BSI) in patients with cirrhosis; and to analyse predictors of 30-day mortality and risk factors for antibiotic resistance. METHODS: Cirrhotic patients developing a BSI episode were prospectively included at 19 centres in five countries from September 2014 to December 2015. The discrimination of mortality risk scores for 30-day mortality were compared by area under the receiver operator risk and Cox regression models. Risk factors for multidrug-resistant organisms (MDRO) were assessed with a logistic regression model. RESULTS: We enrolled 312 patients. Gram-negative bacteria, Gram-positive bacteria and Candida spp. were the cause of BSI episodes in 53%, 47% and 7% of cases, respectively. The 30-day mortality rate was 25% and was best predicted by the Sequential Organ Failure Assessment (SOFA) and Chronic Liver Failure-SOFA (CLIF-SOFA) score. In a Cox regression model, delayed (>24 hours) antibiotic treatment (hazard ratio (HR) 7.58; 95% confidence interval (CI) 3.29-18.67; p < 0.001), inadequate empirical therapy (HR 3.14; 95% CI 1.93-5.12; p < 0.001) and CLIF-SOFA score (HR 1.35; 95% CI 1.28-1.43; p < 0.001) were independently associated with 30-day mortality. Independent risk factors for MDRO (31% of BSIs) were previous antimicrobial exposure (odds ratio (OR) 2.91; 95% CI 1.73-4.88; p < 0.001) and previous invasive procedures (OR 2.51; 95% CI 1.48-4.24; p 0.001), whereas spontaneous bacterial peritonitis as BSI source was associated with a lower odds of MDRO (OR 0.30; 95% CI 0.12-0.73; p 0.008). CONCLUSIONS: MDRO account for nearly one-third of BSI in cirrhotic patients, often resulting in delayed or inadequate empirical antimicrobial therapy and increased mortality rates. Our data suggest that improved prevention and treatment strategies for MDRO are urgently needed in the liver cirrhosis patients. PMID- 28818631 TI - Topical Medical Cannabis: A New Treatment for Wound Pain-Three Cases of Pyoderma Gangrenosum. AB - Pain associated with integumentary wounds is highly prevalent, yet it remains an area of significant unmet need within health care. Currently, systemically administered opioids are the mainstay of treatment. However, recent publications are casting opioids in a negative light given their high side effect profile, inhibition of wound healing, and association with accidental overdose, incidents that are frequently fatal. Thus, novel analgesic strategies for wound-related pain need to be investigated. The ideal methods of pain relief for wound patients are modalities that are topical, lack systemic side effects, noninvasive, self administered, and display rapid onset of analgesia. Extracts derived from the cannabis plant have been applied to wounds for thousands of years. The discovery of the human endocannabinoid system and its dominant presence throughout the integumentary system provides a valid and logical scientific platform to consider the use of topical cannabinoids for wounds. We are reporting a prospective case series of three patients with pyoderma gangrenosum that were treated with topical medical cannabis compounded in nongenetically modified organic sunflower oil. Clinically significant analgesia that was associated with reduced opioid utilization was noted in all three cases. Topical medical cannabis has the potential to improve pain management in patients suffering from wounds of all classes. PMID- 28818632 TI - The Views of Clergy Regarding Ethical Controversies in Care at the End of Life. AB - CONTEXT: Although religion often informs ethical judgments, little is known about the views of American clergy regarding controversial end-of-life ethical issues including allowing to die and physician aid in dying or physician-assisted suicide (PAD/PAS). OBJECTIVE: To describe the views of U.S. clergy concerning allowing to die and PAD/PAS. METHODS: A survey was mailed to 1665 nationally representative clergy between 8/2014 to 3/2015 (60% response rate). Outcome variables included beliefs about whether the terminally ill should ever be "allowed to die" and moral/legal opinions concerning PAD/PAS. RESULTS: Most U.S. clergy are Christian (98%). Clergy agreed that there are circumstances in which the terminally ill should be "allowed to die" (80%). A minority agreed that PAD/PAS was morally (28%) or legally (22%) acceptable. Mainline/Liberal Christian clergy were more likely to approve of the morality (56%) and legality (47%) of PAD/PAS, in contrast to all other clergy groups (6%-17%). Greater end-of-life medical knowledge was associated with moral disapproval of PAD/PAS (adjusted odds ratio [AOR], 1.51; 95% CI, 1.04-2.19, P = 0.03). Those reporting distrust in health care were less likely to oppose legalization of PAD/PAS (AOR 0.93; 95% CI, 0.87-0.99, P < 0.02). Religious beliefs associated with disapproval of PAD/PAS included "life's value is not tied to the patient's quality of life" (AOR 2.12; 95% CI, 0.1.49-3.03, P < 0.001) and "only God numbers our days" (AOR 2.60; 95% CI, 1.77-3.82, P < 0.001). CONCLUSION: Most U.S. clergy approve of "allowing to die" but reject the morality or legalization of PAD/PAS. Respectful discussion in public discourse should consider rather than ignore underlying religious reasons informing end-of-life controversies. PMID- 28818633 TI - Patient- and Caregiver-Reported Assessment Tools for Palliative Care: Summary of the 2017 Agency for Healthcare Research and Quality Technical Brief. AB - CONTEXT: Assessment tools are data collection instruments that are completed by or with patients or caregivers and which collect data at the individual patient or caregiver level. OBJECTIVES: The objectives of this study are to 1) summarize palliative care assessment tools completed by or with patients or caregivers and 2) identify needs for future tool development and evaluation. METHODS: We completed 1) a systematic review of systematic reviews; 2) a supplemental search of previous reviews and Web sites, and/or 3) a targeted search for primary articles when no tools existed in a domain. Paired investigators screened search results, assessed risk of bias, and abstracted data. We organized tools by domains from the National Consensus Project Clinical Practice Guidelines for Palliative Care and selected the most relevant, recent, and highest quality systematic review for each domain. RESULTS: We included 10 systematic reviews and identified 152 tools (97 from systematic reviews and 55 from supplemental sources). Key gaps included no systematic review for pain and few tools assessing structural, cultural, spiritual, or ethical/legal domains, or patient-reported experience with end-of-life care. Psychometric information was available for many tools, but few studies evaluated responsiveness (sensitivity to change) and no studies compared tools. CONCLUSION: Few to no tools address the spiritual, ethical, or cultural domains or patient-reported experience with end-of-life care. While some data exist on psychometric properties of tools, the responsiveness of different tools to change and/or comparisons between tools have not been evaluated. Future research should focus on developing or testing tools that address domains for which few tools exist, evaluating responsiveness, and comparing tools. PMID- 28818635 TI - Linking the Tao, biomathics and information through the logic of energy. AB - The knowledge accumulated in West and East is incomplete in different ways. The mainstream Western approach has contributed the basis for modern science, but indications have appeared in the Western literature that something has been missing in it that Eastern thought could offer. This paper explores the similarities and differences between Eastern and Western approaches to knowledge and whether a trend exists toward their conjunction or convergence. I suggest that a process of conjunction of these different modes of exploration of what the concepts of 'Life and Mind' really entail, at the interface of philosophy and science, is taking place in the areas of information and biomathics. These conjunctions in China and in the West are characterized by scientific and philosophical systems which are holistic rather than reductionist. I argue that a non-standard, non-truth-functional logic of energy, based on the work of Stephane Lupasco (1900-1988), provides a thread linking these approaches. Grounded in modern physics, it can describe the qualitative changes which are the focus of Chinese thought. In biology, Lupasco showed how the principles of this logic of dynamic relations operate in intra- and inter-cellular processes and at higher levels of organization. This paper supports key, primarily Chinese concepts and critiques the logical and categorial distinctions underlying and restricting the Western world-view. The paper also supports the implicit openness of Integral Biomathics to qualitative Eastern perspectives. Its finality is to find, from the conjunction, "better ideas for better exploration" of the nature of mind and life. This is not an academic exercise but a moral imperative for both Eastern and Western society. PMID- 28818634 TI - Mining Naive Rabbit Antibody Repertoires by Phage Display for Monoclonal Antibodies of Therapeutic Utility. AB - Owing to their high affinities and specificities, rabbit monoclonal antibodies (mAbs) have demonstrated value and potential primarily as basic research and diagnostic reagents, but, in some cases, also as therapeutics. To accelerate access to rabbit mAbs bypassing immunization, we generated a large naive rabbit antibody repertoire represented by a phage display library encompassing >10 billion independent antibodies in chimeric rabbit/human Fab format and validated it by next-generation sequencing. Panels of rabbit mAbs selected from this library against two emerging cancer targets, ROR1 and ROR2, revealed high diversity, affinity, and specificity. Moreover, ROR1- and ROR2-targeting rabbit mAbs demonstrated therapeutic utility as components of chimeric antigen receptor engineered T cells, further corroborating the value of the naive rabbit antibody library as a rich and virtually unlimited source of rabbit mAbs. PMID- 28818636 TI - East-West paths to unconventional computing. AB - Unconventional computing is about breaking boundaries in thinking, acting and computing. Typical topics of this non-typical field include, but are not limited to physics of computation, non-classical logics, new complexity measures, novel hardware, mechanical, chemical and quantum computing. Unconventional computing encourages a new style of thinking while practical applications are obtained from uncovering and exploiting principles and mechanisms of information processing in and functional properties of, physical, chemical and living systems; in particular, efficient algorithms are developed, (almost) optimal architectures are designed and working prototypes of future computing devices are manufactured. This article includes idiosyncratic accounts of 'unconventional computing' scientists reflecting on their personal experiences, what attracted them to the field, their inspirations and discoveries. PMID- 28818637 TI - Percutaneous retrieval of a dislodged Amplatzer septal occluder device from the pulmonary artery with sole use of a snare and device lassoing. PMID- 28818638 TI - Association of hemoglobin A1c variability and the incidence of heart failure with preserved ejection fraction in patients with type 2 diabetes mellitus and arterial hypertension. AB - BACKGROUND: This study aimed to investigate the association between variability in hemoglobin A1c (HbA1c) and left ventricular (LV) diastolic function and incidence of symptomatic heart failure with preserved ejection fraction (HFpEF) in patients with type 2 diabetes mellitus (T2DM) and arterial hypertension. METHODS: A retrospective cohort study was conducted on eligible patients with T2DM and hypertension and without clinical signs or symptoms of heart failure in our hospital medical record database. Variability in HbA1c was measured by standard deviation (SD) and coefficient of variation (CV). Risk of new onset of symptomatic HFpEF was evaluated by multivariable cox regression analysis. RESULTS: A total of 201 subjects were categorized according to the median value of HbA1c variability indicators. Over a median follow-up of 7.3 years, the percentage of subjects who had new incidence of symptomatic HFpEF was higher in those with higher HbA1c-SD level (5/105 vs. 13/96, P=0.029) and higher HbA1c-CV level (5/101 vs. 13/100, P=0.046). Multivariable cox regression analysis also showed that higher HbA1c variability [HbA1c-SD (HR 1.754, 95% CI: 1.003-3.104, P=0.049) or HbA1c-CV (HR 1.604 95% CI: 1.064-2.419, P=0.024)] was associated with the presence of new-onset symptomatic HFpEF, independent of HbA1c-mean level, in T2DM and hypertensive patients. Moreover, lower HbA1c variability generated more prominent improvement in LV diastolic function (E/E') during the follow-up. CONCLUSIONS: HbA1c variability may provide additional valuable information as a potential predictor of the progression of HFpEF in T2DM and hypertensive patients. PMID- 28818639 TI - Addictive behaviors and healthcare renunciation for economic reasons in a French population-based sample. AB - BACKGROUND: Healthcare renunciation for economic reasons is a major health concern, but it has been scarcely investigated among drug users, even if drug users constitute a vulnerable population in need of medical care. This study investigated associations of healthcare renunciation for economic reasons and addictive behaviors (alcohol, tobacco, cannabis, illicit drug use, and gambling) in a population-based sample of adults living in France, a country with universal health coverage. METHODS: Data were collected using the 2014 Health Barometer, a French cross-sectional survey conducted among a random representative sample of the general population aged 18-64 (n=12,852). Measures included healthcare renunciation, substance use (alcohol, tobacco, cannabis, and other illicit drugs) and gambling. Experimental/recreational and heavy/chronic use were assessed. Logistic regressions were used to test the relationship between healthcare renunciation and addictive behaviors, controlling for relevant covariates. RESULTS: A total of 25% of the participants had renounced care at least once in the previous twelve months. Most variables of drug use were significantly associated with increased healthcare renunciation. This was the case for heavy/hazardous use and experimental/recreational use. Regular gambling was not associated with healthcare renunciation, but disordered gambling was. CONCLUSION: This study showed that addictive behaviors, including substance use and gambling, were part of the burden of vulnerability of people who forgo care. Therefore, drug use and gambling patterns should be a focus in the development of policies to reduce health inequalities, not only for heavy and chronic drug users. PMID- 28818640 TI - The influence of physical activity in the anti-tumor immune response in experimental breast tumor. AB - This study aimed to investigate the influence of physical activity in innate immunity to conduce to an effective antitumoral immune response analyzing the phenotype and activation status of infiltrating cells. We analysed the intracellular cytokines and the transcription factors of tumor infiltrating lymphocytes (TILS) and spleen leukocytes. The Nos2 gene expression was evaluated in spleen cells and futhermore the ROS production was measured and spleen cells; another cell evaluated was dendritic cells (TIDCs), their cytokines expression and membrane molecules; finally to understood the results obtained, we analysed the dendritic cells obtained from bone marrow. Were used female Balb/c mice divided into 4 groups: two controls without tumor, sedentary (GI) and trained (GII) and two groups with tumor, sedentary (GIII) or trained (GIV). The physical activity (PA) was realized acoording swimming protocol. Tumor was induced by injection of 4T1 cells. All experiments were performed in biological triplicate. After the experimental period, the tumor was removed and the cells were identified by flow cytometry with labeling to CD4, CD8, CD11c, CD11b, CD80, CD86 and Ia, and intracelular staining IL-10, IL-12, TNF-alpha, IFN-gamma, IL-17, Tbet, GATA3, RORgammat and FoxP3. The bone marrow of the animals was obtained to analyse the derivated DCs by flow cytometry and culture cells to obtain the supernatant to measure the cytokines. Our results demonstrated that the PA inhibit the tumoral growth although not to change the number of TILS, but reduced expression of GATA-3, ROR-gammaT, related with poor prognosis, and TNF-alpha intracellular; however occur one significantly reduction in TIDCS, but these cells expressed more co-stimulatory and presentation molecules. Furthermore, we observed that the induced PA stimulated the gene expression of Tbet and the production of inflammatory cytokines suggesting an increase of Th1 systemic response. The results evaluating the systemic influence in DCs showed that the PA improve significantly the number of those cells in bone marrow as well the number of co-stimulatory molecules. Therefore, we could conclude that PA influence the innate immunity by interfering to promote in process of maturation of DCs both in tumor and systemically, that by its turn promote a modification in acquired immune cells, representing by T helper to induce an important alteration transcription factors that are responsible to maintain a suppressive microenviroment, and thereby, allowing the latter cells can thus activate antitumor immune response. The PA was able improve the Th1 systemic response by enhance to Tbet gene expression, promote a slightly increased of Th1-type cytokines and decrease Gata3 and Foxp3 gene expression in which can inhibit the Th1 immune response. PMID- 28818641 TI - Pernambuco index: predictability of the complexity of surgery for impacted lower third molars. AB - This study aimed to develop and validate an index of surgical difficulty for the removal of impacted lower third molars. The study was performed in two steps. The first was a cross-sectional analysis of clinical, demographic, and radiographic variables collected from patients undergoing the removal of an impacted lower third molar between 2008 and 2012. The second step was a prospective cohort study involving the same surgical procedures to validate the index; this was performed between 2013 and 2016. Univariate regression analysis was applied, followed by multiple linear regression analysis. A total of 753 surgical procedures were analyzed in the first stage, which led to the identification of the most important variables and their levels of significance. The index was then applied to 280 surgical procedures. The preoperative difficulty was in concordance with the index results in all cases. Among cases with a low level of difficulty, 93.1% had been indexed as low difficulty; likewise, among cases with a high level of difficulty, there was 87.9% concordance with the index. With the use of reference statistics in the development and quality assurance processes, this validated index has proven to be a reliable and easily applicable instrument, with high sensitivity, specificity, and accuracy. PMID- 28818642 TI - The expression of endogenous hydrogen sulfide signal during distraction osteogenesis in a rabbit model. AB - The hydrogen sulfide (H2S) signal system plays an important role in bone metabolism. However, the role of endogenous H2S during distraction osteogenesis (DO) remains unclear. Sixty-two male New Zealand White rabbits were subjected to right mandibular DO. Before distraction, the animals were divided randomly into two groups: group A, 0.5mm twice/day for 10 days; group B, 1.25mm twice/day for 4 days. Plasma and distraction gap tissue were harvested to determine the H2S signal. The osteogenesis effect was also evaluated. The newly regenerated bone in group A presented a higher level of mineralization and biomechanical strength than that in group B. The bone mineralization density in group A was 1.95-fold that in group B (P=0.028), while the biomechanical strength in group A was 1.26 fold that in group B (P=0.042) at the end of the experiment. The H2S signal was detected during the whole process of DO. The relative plasma H2S concentrations in group A were noticeably higher than those in group B at the middle of distraction (P<0.001), at the end of the distraction (P=0.034), and 2 weeks after the end of distraction (P=0.002). The results suggest that the endogenous H2S signal system plays a major role during DO. PMID- 28818643 TI - Combined effects of oil exposure, temperature and ultraviolet radiation on buoyancy and oxygen consumption of embryonic mahi-mahi, Coryphaena hippurus. AB - The Deepwater Horizon oil spill occurred in the summer of 2010 and coincided with the spawning window of the ecologically and economically important pelagic fish mahi-mahi (Coryphaena hippurus). During summer months, early life stage mahi-mahi were likely also exposed to other naturally occurring stressors such as increased temperature and ultraviolet radiation (UV). Previous research has shown that co exposure to oil and additional natural stressors can affect the timing and duration of negative buoyancy in mahi-mahi embryos. The current study aimed to elucidate the factors affecting the onset of negative buoyancy and to also explore possible mechanisms behind buoyancy change. Embryos co-exposed to oil and/or increased temperature and UV radiation displayed early onset of negative buoyancy with concurrent increases in oxygen consumption and sinking rates, which are normally only seen during the period directly preceding hatch. Results also suggest a behavioral response in which embryos avoid UV radiation by sinking down the water column but reestablish positive buoyancy once the UV radiation is removed. These findings imply that embryos can dynamically change their position in the water column in response to external cues and thus may have much greater control over buoyancy than previously thought. PMID- 28818644 TI - Radioecological assessment and radiometric dating of sediment cores from dynamic sedimentary systems of Pra and Volta estuaries (Ghana) along the Equatorial Atlantic. AB - The Volta and Pra estuaries (Ghana, West Africa) are dynamical sedimentary systems whose natural equilibrium is being affected by anthropogenic activities. This paper reports depth-distributions of 210Pb, 226Ra, 234Th, 40K, 228Ra and 137Cs for two sediment cores from these estuaries. Bulk densities were not steady state and well correlated with 40K (p < 0.00005). Unsupported 210Pb profiles were incomplete, non-monotonic and showed large fluctuations. The assumptions involved in the common 210Pb-based dating models were not meet in these dynamical scenarios, and the use of 137Cs as a time-marker is difficult in Equatorial and South-Hemisphere countries due to its low fallout rates. Chronologies have been solved with the new 210Pb-based TERESA model, which operates with varying but statistically correlated fluxes and sediment accumulation rates (SAR). The core from the Volta reflects the conditions prevailing after the construction of the Akosombo Dam, with a mean SAR of 1.05 +/- 0.03 g cm-2.y-1, while a higher value of 2.73 +/- 0.06 g cm-2.y-1 was found in the Pra, affected by intense gold mining activities along its course. Radiological and radioecological assessments have been conducted by applying the UNSCEAR protocols and the ERICA model, respectively. The measured radionuclide concentrations do not pose any significant risk for the environment and human health. PMID- 28818645 TI - Improved performance comparisons of radioxenon systems for low level releases in nuclear explosion monitoring. AB - The Comprehensive Nuclear-Test-Ban Treaty bans all nuclear tests and mandates development of verification measures to detect treaty violations. One verification measure is detection of radioactive xenon isotopes produced in the fission of actinides. The International Monitoring System (IMS) currently deploys automated radioxenon systems that can detect four radioxenon isotopes. Radioxenon systems with lower detection limits are currently in development. Historically, the sensitivity of radioxenon systems was measured by the minimum detectable concentration for each isotope. In this paper we analyze the response of radioxenon systems using rigorous metrics in conjunction with hypothetical representative releases indicative of an underground nuclear explosion instead of using only minimum detectable concentrations. Our analyses incorporate the impact of potential spectral interferences on detection limits and the importance of measuring isotopic ratios of the relevant radioxenon isotopes in order to improve discrimination from background sources particularly for low-level releases. To provide a sufficient data set for analysis, hypothetical representative releases are simulated every day from the same location for an entire year. The performance of three types of samplers are evaluated assuming they are located at 15 IMS radionuclide stations in the region of the release point. The performance of two IMS-deployed samplers and a next-generation system is compared with proposed metrics for detection and discrimination using representative releases from the nuclear test site used by the Democratic People's Republic of Korea. PMID- 28818646 TI - Best practice in research: Consensus Statement on Ethnopharmacological Field Studies - ConSEFS. AB - BACKGROUND: Ethnopharmacological research aims at gathering information on local and traditional uses of plants and other natural substances. However, the approaches used and the methods employed vary, and while such a variability is desirable in terms of scientific diversity, research must adhere to well defined quality standards and reproducible methods OBJECTIVES: With ConSEFS (the Consensus Statement on Ethnopharmacological Field Studies) we want to define best practice in developing, conducting and reporting field studies focusing on local and traditional uses of medicinal and food plants, including studies using a historical approach. METHODS: After first developing an initial draft the core group invited community-wide feedback from researchers both through a web-based consultation and a series of workshops at conferences during 2017. OUTCOMES: The consultation resulted in a large number of responses. Feedback was received via a weblink on the Journal of Ethnopharmacology's website (ca. 100 responses), other oral and written responses (ca. 50) and discussions with stakeholders at four conferences. The main outcome is a checklist, covering best practice for designing, implementing and recording ethnopharmacological field studies and historical studies. CONCLUSIONS: Prior to starting ethnopharmacological field research, it is essential that the authors are fully aware of the best practice in the field. For the first time in the field of ethnopharmacology a community wide document defines guidelines for best practice on how to conduct and report such studies. It will need to be updated and further developed. While the feedback has been based on responses by many experienced researchers, there is a need to test it in practice by using it both in implementing and reporting field studies (or historical studies), and peer-review. PMID- 28818647 TI - Malocclusion Class II division 1 skeletal and dental relationships measured by cone-beam computed tomography. AB - OBJECTIVES: The purpose of this study was to locate traditionally-used landmarks in two-dimensional (2D) images and newly-suggested ones in three-dimensional (3D) images (cone-beam computer tomographies [CBCTs]) and determine possible relationships between them to categorize patients with Class II-1 malocclusion. METHODS: CBCTs from 30 patients diagnosed with Class II-1 malocclusion were obtained from the University of Alberta Graduate Orthodontic Program database. The reconstructed images were downloaded and visualized using the software platform AVIZO(r). Forty-two landmarks were chosen and the coordinates were then obtained and analyzed using linear and angular measurements. Ten images were analyzed three times to determine the reliability and measurement error of each landmark using Intra-Class Correlation coefficient (ICC). Descriptive statistics were done using the SPSS statistical package to determine any relationships. RESULTS: ICC values were excellent for all landmarks in all axes, with the highest measurement error of 2mm in the y-axis for the Gonion Left landmark. Linear and angular measurements were calculated using the coordinates of each landmark. Descriptive statistics showed that the linear and angular measurements used in the 2D images did not correlate well with the 3D images. The lowest standard deviation obtained was 0.6709 for S-GoR/N-Me, with a mean of 0.8016. The highest standard deviation was 20.20704 for ANS-InfraL, with a mean of 41.006. CONCLUSION: The traditional landmarks used for 2D malocclusion analysis show good reliability when transferred to 3D images. However, they did not reveal specific skeletal or dental patterns when trying to analyze 3D images for malocclusion. Thus, another technique should be considered when classifying 3D CBCT images for Class II-1malocclusion. PMID- 28818648 TI - ? PMID- 28818649 TI - Sequence analysis of mtDNA COI barcode region revealed three haplotypes within Culex pipiens assemblage. AB - Members of the Culex (Culex) pipiens assemblage are known vectors of deadly encephalitides, periodic filariasis, and West Nile virus throughout the world. However, members of this assemblage are morphologically indistinguishable or hard to distinguish and play distinct roles in transmission of the diseases. The current study aimed to provide further evidence on utility of the two most popular nuclear (ITS2-rDNA) and mitochondrial (COI barcode region) genetic markers to identify members of the assemblage. Culex pipiens assemblage specimens from different climate zones of Iran were collected and identified to species level based on morphological characteristics. Nucleotide sequences of the loci for the specimens plus available data in the GenBank were analyzed to find species specific genetic structures useful for diagnosis purposes. ITS2 region was highly divergent within species or populations suggesting lack of consistency as a reliable molecular marker. In contrast, sequence analysis of 710 bp of COI gene revealed three fixed haplotypes named here "C, T, H" within the assemblage which can be distinguished by HaeIII and AluI enzymes. There were a correlation between the haplotypes and the world climate regions, where the haplotypes H/T and C are present mainly in temperate and tropical regions of the world, respectively. In the New world, Australia, and Japan only haplotype H is found. In conjunction between tropical and temperate regions such Iran, China, and Turkey, a mix of C/H or C/H/T are present. Although, the haplotypes are not strictly species-specific, however, Cx. quinquefasciatus was mainly of haplotype C. Due to the lack of mating barrier and questionable taxonomic situation of the complex members, the mentioned haplotypes in combination with other morphological and molecular characters might be used to address the genetic structure of the studied populations. PMID- 28818650 TI - Recombinant vs native Anisakis haemoglobin (Ani s 13): Its appraisal as a new gold standard for the diagnosis of allergy. AB - Recombinant allergens are currently the best option for serodiagnosis of human anisakiasis in terms of sensitivity and specificity. However, previous reports showed high rates of anisakiasis patients who were negative to Ani s 7 and especially to Ani s 1. Recently, Anisakis haemoglobin was described as a major allergen (Ani s 13). Although Ani s 13 belongs to a conserved protein family, it seems not to be a cross-reacting antigen because of the absence of IgE recognition against Ascaris haemoglobin in Anisakis patients. The aim of this study is to develop a more sensitive and specific diagnosis tool for Anisakis based on the recently discovered allergen Ani s 13. We obtained and purified recombinant Anisakis haemoglobin (rAni s 13) and the native form (nAni s 13). The recognition of both recombinant and native haemoglobins by anti-haemoglobin IgE from patients' sera was assessed by indirect ELISA and immunoblotting using 43 Anisakis sensitised patients and 44 non-Anisakis sensitised patients. Native Ani s 13 was also treated with periodate to study if oxidation of glycans destroys antibody binding. Furthermore, it was structurally characterised by negative staining electron microscopy and analytical ultracentrifugation. Recombinant Ani s 13 was only recognised by four patients with gastro-allergic anisakiasis (GAA) and immunoblotting analyses showed no bands. However, nAni s 13 was detected by 72.1% of Anisakis sensitised patients measured by indirect ELISA. Particularly, 18 (90%) out of 20 GAA patients were positive. Tetramers and octamers were the most abundant homomers of nAni s 13 but octamers had higher content of bound heme. None of the non-Anisakis sensitised patients were positive. Combined use of purified native form of Ani s 13 with current gold standards would improve the sensitivity and specificity for diagnosing anisakiasis. PMID- 28818651 TI - Genomic characterization of a paediatric MRSA outbreak by next-generation sequencing. AB - INTRODUCTION: Twelve strains of meticillin-resistant Staphylococcus aureus (MRSA) isolated during a suspected outbreak in a paediatric intensive care unit were analysed by whole-genome sequencing (WGS). AIM: To define the clonality of MRSA strains to a high discriminative power, and to evaluate the presence of genetic determinants responsible for antibiotic resistance and virulence. RESULTS: Ten out of 12 strains belonged to multi-locus sequence type ST2625, while the other two strains were ST8. Among the ST2625 strains, analysis based on 1126 genes showed that they were clonal, sharing more than 98.3% of allelic identities, and one strain was isolated from a healthcare worker. All ST2625 strains were characterized by the SCC-Mec cassette IVa, and resistoma analysis indicated correspondence between phenotypic and genotypic characteristics. The study of 63 genes associated with virulence was correlated with the pattern of clonality shown. CONCLUSION: This analysis confirmed the occurrence of an outbreak. As such, standard infection control measures were strictly enforced, and this led to prompt termination of the outbreak. PMID- 28818652 TI - Adsorption-desorption mediated separation of low concentrated D2O from water with hydrophobic activated carbon fiber. AB - The adsorption and desorption of D2O on hydrophobic activated carbon fiber (ACF) occurs at a smaller pressure than the adsorption and desorption of H2O. The behavior of the critical desorption pressure difference between D2O and H2O in the pressure range of 1.25-1.80kPa is applied to separate low concentrated D2O from water using the hydrophobic ACF, because the desorption branches of D2O and H2O drop almost vertically. The deuterium concentration of all desorbed water in the above pressure range is lower than that of water without adsorption-treatment on ACF. The single adsorption-desorption procedure on ACF at 1.66kPa corresponding to the maximum difference of adsorption amount between D2O and H2O reduced the deuterium concentration of desorbed water to 130.6ppm from 143.0ppm. Thus, the adsorption-desorption procedure of water on ACF is a promising separation and concentration method of low concentrated D2O from water. PMID- 28818653 TI - Robust and thermal-healing superhydrophobic surfaces by spin-coating of polydimethylsiloxane. AB - HYPOTHESIS: Superhydrophobic surfaces easily lose their excellent water repellency after damages, which limit their broad applications in practice. Thus, the fabrication of superhydrophobic surfaces with excellent durability and thermal healing should be taken into consideration. EXPERIMENTS: In this work, robust superhydrophobic surfaces with thermal healing were successfully fabricated by spin-coating method. To achieve superhydrophobicity, cost-less and fluoride-free polydimethylsiloxane (PDMS) was spin-coated on rough aluminum substrates. FINDINGS: After being spin-coated for one cycle, the superhydrophobic PDMS coated hierarchical aluminum (PDMS-H-Al) surfaces showed excellent tolerance to various chemical and mechanical damages in lab, and outdoor damages for 90days. When the PDMS-H-Al surfaces underwent severe damages such as oil contamination (peanut oil with high boiling point) or sandpaper abrasion (500g of force for 60cm), their superhydrophobicity would lose. Interestingly, through a heating process, cyclic oligomers generating from the partially decomposed PDMS acted as low-surface-energy substance on the damaged rough surfaces, leading to the recovery of superhydrophobicity. The relationship between the spin-coating cycles and surface wettability was also investigated. This paper provides a facile, fluoride-free and efficient method to fabricate superhydrophobic surfaces with thermal healing. PMID- 28818654 TI - Water-based fractionation of a commercial humic acid. Solid-state and colloidal characterization of the solubility fractions. AB - BACKGROUND AND HYPOTHESIS: Humic acid (HA) is of considerable environmental significance, being a major component of soil, as well as being considered for application in other technological areas. However, its structure and colloidal properties continue to be the subject of debate, largely owing to its molecular complexity and association with other humic substances and mineral matter. As a class, HA is considered to comprise supramolecular assemblies of heterogeneous species, and herein we consider a simple route for the separation of some HA sub fractions. EXPERIMENTS: A commercial HA sample from Sigma-Aldrich has been fractionated into two soluble (S1, S2) and two insoluble (I1, I2) fractions by successive dissolution in deionized water at near-neutral pH. These sub-fractions have been characterized by solution and solid-state approaches. FINDINGS: Using this simple approach, the HA has been shown to contain non-covalently bonded species with different polarity and water solubility. The soluble and insoluble fractions have very different chemical structures, as revealed particularly by their solid-state properties (13C NMR and IR spectroscopy, and TGA); in particular, S1 and S2 are characterized by higher carbonyl and aromatic contents, compared with I1 and I2. As shown by solution SAXS measurements and AFM, the soluble fractions behave as hydrophilic colloidal aggregates of at least 50nm diameter. PMID- 28818655 TI - High efficiency removal of methylene blue using SDS surface-modified ZnFe2O4 nanoparticles. AB - Recent studies have shown that hazardous organic dye substances can be removed from aqueous solutions by spinel ferrite nanomaterials. We found that Sodium Dodecyl Sulfonate (SDS) surface-modified mesoporous ZnFe2O4 nanoparticles (10 50nm) have a remarkably high maximum adsorptive capacity (~699.30mg/g) for aqueous Methylene Blue (MB) removal at T of 288K and pH of 12. Unmodified ZnFe2O4 nanoparticles suffer from particle agglomeration, which reduces surface area, thus reducing their adsorptive capacity. Here it is shown that when modified with SDS, the specific surface area increased by ~34%. It is also shown that the anionic SDS surfactant significantly increased the electrostatic attraction to the cationic MB compound. Moreover, it was found that adsorption of MB positively correlated with the aqueous solution's pH, which is attributed to a stronger negative charge on the SDS modified ZnFe2O4 surface at high pHs. The SDS-modified ZnFe2O4 adsorption of MB fitted well with the Langmuir adsorption isotherm model, and kinetic data fitted into a pseudo-second-order model. Thermodynamic parameters indicated that the adsorption was spontaneous and exothermic in nature, and physisorption dominated the adsorption of MB. The findings of this study demonstrate the potential for enhanced removal of MB contamination from aqueous solutions by SDS-modified ZnFe2O4 nanoparticles and, therefore, the potential for them to remove cationic organic dye from wastewater. PMID- 28818656 TI - Synthesis and liquid-liquid extraction of non-agglomerated Al(OH)3 particles for deposition of cellulose matrix composite films. AB - A cathodic electrophoretic deposition (EPD) method has been developed for the deposition of quaternized hydroxyethyl cellulose ethoxylate (QHECE) films. A quartz crystal microbalance was used for in-situ investigation of the deposition yield in dilute QHECE solutions. The deposition rate increased with increasing QHECE concentration in the range of 1-10gL-1. Aluminium hydroxide (AH) was prepared by a chemical precipitation method and used as a flame retardant additive for QHECE. AH particle agglomeration was avoided by a new strategy, based on combined synthesis and liquid-liquid extraction method. In the biomimetic surface modification approach, 3,4-dihydroxybenzaldehyde (R'-CHO) and 2,3,4-trihydroxybenzaldehyde (R''-CHO) were used for particle modification during synthesis. The Schiff base reaction at the water-n-butanol interface between R' CHO or R''-CHO adsorbed on the particle surface in water, and hexadecylamine in the n-butanol phase, allowed for efficient particle modification and phase transfer from water to the n-butanol phase. The extraction mechanism was confirmed by FTIR investigation. The modified particles showed good suspension stability and were utilized for the EPD of smooth and uniform QHECE-AH films. The formation a composite material, which contained flame retardant AH in the QHECE matrix was confirmed by the thermogravimetric and differential thermal analyses. Further development of the particle synthesis and liquid-liquid extraction method can be used for the fabrication of advanced QHECE composites, containing various functional materials. PMID- 28818657 TI - Activity-guided isolation and structural identification of immunomodulating substances from Pleurotus eryngii byproducts. AB - A two-step extraction process was used to investigate the bioactive substances from the byproducts of the fungus Pleurotus eryngii. Methanol extraction followed by extraction using different polar solvents coupled with silica column chromatography was carried out to separate the bioactive components. The immunomodulating activity of the extracts was investigated using Ana-1 mouse macrophage cells. At 25MUg/mL, the butyl alcohol extract showed the highest enhancement of Ana-1 cell proliferative activity and secretion of cytokines. Using silica-gel column chromatography, the butyl alcohol extract was purified to seven elution fractions. Fr. 2 showed the highest promotion of Ana-1 macrophage cell proliferation and TNF-alpha, IL-6 secretion. HPLC-QTOF-MS/MS was used to determine the structure of the active substance in Fr. 2. Adenosine was identified as the primary active component in Fr. 2 with a chemical formula of C10H13N5O4. Adenosine may be useful as a natural immunostimulatory agent and anti tumor agent. PMID- 28818658 TI - Cue-dependent inhibition in posttraumatic stress disorder and attention deficit/hyperactivity disorder. AB - OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are common among military veterans, but the comorbidity of these two psychiatric disorders remains largely unstudied. Evaluating response inhibition and cue-dependent learning as behavioral and neurocognitive mechanisms underlying ADHD/PTSD can inform etiological models and development of tailored interventions. METHOD: A cued go/no-go task evaluated response inhibition in 160 adult males. Participants were recruited from the community and a Veterans Administration medical center. Four diagnostic groups were identified: ADHD-only, PTSD-only, ADHD+PTSD, controls. RESULTS: Group differences were observed across most indices of inhibitory functioning, reaction time, and reaction time variability, whereby PTSD-only and ADHD+PTSD participants demonstrated deficits relative to controls. No cue dependency effects were observed. CONCLUSION: Finding complement prior work on neurocognitive mechanisms underlying ADHD, PTSD, and ADHD+PTSD. Lack of expected group differences for the ADHD-only group may be due to limited power. Additional work is needed to better characterize distinctions among clinical groups, as well as to test effects among women and youth. PMID- 28818659 TI - A new methodology to identify surface water bodies at risk by using pesticide monitoring data: The glyphosate case study in Lombardy Region (Italy). AB - In the last decades, several monitoring programs were established as an effect of EU Directives addressing the quality of water resources (drinking water, groundwater and surface water). Plant Protection Products (PPPs) are an obvious target of monitoring activities, since they are directly released into the environment. One of the challenges in managing the risk of pesticides at the territorial scale is identifying the locations in water bodies needing implementation of risk mitigation measures. In this, the national pesticides monitoring plans could be very helpful. However, monitoring of pesticides is a challenging task because of the high number of registered pesticides, cost of analyses, and the periodicity of sampling related to pesticide application and use. Extensive high-quality data-sets are consequently often missing. More in general, the information that can be obtained from monitoring studies are frequently undervalued by risk managers. In this study, we propose a new methodology providing indications about the need to implement mitigation measures in stretches of surface water bodies on a territory by combining historical series of monitoring data and GIS. The methodology is articulated in two distinct phases: a) acquisition of monitoring data and setting-up of informative layers of georeferenced data (phase 1) and b) statistical and expert analysis for the identification of areas where implementation of limitation or mitigation measures are suggested (phase 2). Our methodology identifies potentially vulnerable water bodies, considering temporal contamination trends and relative risk levels at selected monitoring stations. A case study is presented considering glyphosate monitoring data in Lombardy Region (Northern of Italy) for the 2008-2014 period. PMID- 28818660 TI - Environmental effects are stronger than human effects on mammalian predator-prey relationships in arid Australian ecosystems. AB - Climate (drought, rainfall), geology (habitat availability), land use change (provision of artificial waterpoints, introduction of livestock), invasive species (competition, predation), and direct human intervention (lethal control of top-predators) have each been identified as processes driving the sustainability of threatened fauna populations. We used a systematic combination of empirical observational studies and experimental manipulations to comprehensively evaluate the effects of these process on a model endangered rodent, dusky hopping-mice (Notomys fuscus). We established a large manipulative experiment in arid Australia, and collected information from relative abundance indices, camera traps, GPS-collared dingoes (Canis familiaris) and dingo scats, along with a range of related environmental data (e.g. rainfall, habitat type, distance to artificial water etc.). We show that hopping-mice populations were most strongly influenced by geological and climatic effects of resource availability and rainfall, and not land use, invasive species, or human effects of livestock grazing, waterpoint provision, or the lethal control of dingoes. Hopping-mice distribution declined along a geological gradient of more to less available hopping-mice habitat (sand dunes), and their abundance was driven by rainfall. Hopping-mice populations fluctuated independent of livestock presence, artificial waterpoint availability or repeated lethal dingo control. Hopping-mice populations appear to be limited first by habitat availability, then by food availability, then by predation. Contemporary top-predator control practices (for protection of livestock) have little influence on hopping-mice behaviour or population dynamics. Given our inability to constrain the effects of predation across broad scales, management actions focusing on increasing available food and habitat (e.g. alteration of fire and herbivory) may have a greater chance of improving the conservation status of hopping-mice and other small mammals in arid areas. Our study also reaffirms the importance of using systematic and experimental approaches to detect true drivers of population distribution and dynamics where multiple potential drivers operate simultaneously. PMID- 28818661 TI - Variation in organochlorine and mercury levels in first and replacement eggs of a single-egg clutch breeder, the thick-billed murre, at a breeding colony in the Canadian Arctic. AB - Contaminant concentrations may vary among sequentially-laid eggs in multi-egg clutches, and this variation has implications for the interpretation of contaminant concentrations in monitoring programs. The thick-billed murre (Uria lomvia) is a key species for monitoring contaminants in the Canadian Arctic and lays only a single egg per year. Therefore, the potential issue of intra-clutch variation in contaminant concentrations is avoided. However, if the egg is removed or lost early in the incubation stage, the adult female murre will relay. In this study, we examined contaminant concentrations and patterns in first-laid and replacement eggs of thick-billed murres breeding in northern Hudson Bay in order to determine whether or not these eggs could be sampled interchangeably. Concentrations of the major legacy organochlorines (e.g. PCBs, DDT, chlordanes) were generally higher, and total mercury concentrations lower, in the replacement eggs compared with the first-laid eggs. The organochlorine profile was comprised primarily of SigmaDDT and Sigma70PCB, and Sigma70PCB was comprised primarily of hexa-hepta PCBs in both first-laid and replacement eggs. As both concentrations and organochlorine patterns showed differences between first-laid and replacement eggs, we recommend that randomly selected first-laid eggs of thick-billed murres be consistently sampled for contaminant monitoring in the Canadian Arctic. PMID- 28818662 TI - Organic matter quality structures benthic fatty acid patterns and the abundance of fungi and bacteria in temperate lakes. AB - Benthic microbial communities (BMCs) play important roles in the carbon cycle of lakes, and benthic littoral zones in particular have been previously highlighted as biogeochemical hotspots. Dissolved organic matter (DOM) presents the major carbon pool in lakes, and although the effect of DOM composition on the pelagic microbial community composition is widely accepted, little is known about its effect on BMCs, particularly aquatic fungi. Therefore, we investigated the composition of benthic littoral microbial communities in twenty highly diverse lakes in northeast Germany. DOM quality was analyzed via size exclusion chromatography (SEC), fluorescence parallel factor analyses (PRAFACs) and UV-Vis spectroscopy. We determined the BMC composition and biomass using phospholipid derived fatty acids (PLFA) and extended the interpretation to the analysis of fungi by applying a Bayesian mixed model. We present evidence that the quality of DOM structures the BMCs, which are dominated by heterotrophic bacteria and show low fungal biomass. The fungal biomass increases when the DOM pool is processed by microorganisms of allochthonous origin, whereas the opposite is true for bacteria. PMID- 28818663 TI - A lightweight, inexpensive robotic system for insect vision. AB - Designing hardware for miniaturized robotics which mimics the capabilities of flying insects is of interest, because they share similar constraints (i.e. small size, low weight, and low energy consumption). Research in this area aims to enable robots with similarly efficient flight and cognitive abilities. Visual processing is important to flying insects' impressive flight capabilities, but currently, embodiment of insect-like visual systems is limited by the hardware systems available. Suitable hardware is either prohibitively expensive, difficult to reproduce, cannot accurately simulate insect vision characteristics, and/or is too heavy for small robotic platforms. These limitations hamper the development of platforms for embodiment which in turn hampers the progress on understanding of how biological systems fundamentally work. To address this gap, this paper proposes an inexpensive, lightweight robotic system for modelling insect vision. The system is mounted and tested on a robotic platform for mobile applications, and then the camera and insect vision models are evaluated. We analyse the potential of the system for use in embodiment of higher-level visual processes (i.e. motion detection) and also for development of navigation based on vision for robotics in general. Optic flow from sample camera data is calculated and compared to a perfect, simulated bee world showing an excellent resemblance. PMID- 28818664 TI - Lactate dehydrogenase-A is indispensable for vascular smooth muscle cell proliferation and migration. AB - The proliferation and migration of vascular smooth muscle cells (VSMCs) have been implicated in the pathogenesis of atherosclerosis. Increased aerobic glycolysis is a key feature of cellular phenotypes including cancer and immune cells. However, the role of aerobic glycolysis in the atherogenic phenotype of VSMCs remains largely unknown. Here, we investigated the role of lactate dehydrogenase A (LDHA), which is a key enzyme for glycolysis, in the proliferation and migration of VSMCs. Activation of primary rat VSMCs with fetal bovine serum (FBS) or platelet-derived growth factor (PDGF) increased their proliferation and migration, glycolytic activity, and expression of LDHA. Wound healing and transwell migration assays demonstrated that small interfering RNA-mediated knockdown of LDHA and pharmacological inhibition of LDHA by oxamate both effectively inhibited VSMC proliferation and migration. Inhibition of LDHA activity by oxamate reduced PDGF-stimulated glucose uptake, lactate production, and ATP production. Taken together, this study shows that enhanced glycolysis in PDGF- or FBS-stimulated VSMCs plays an important role in their proliferation and migration and suggests that LDHA is a potential therapeutic target to prevent vessel lumen constriction during the course of atherosclerosis and restenosis. PMID- 28818665 TI - IRF-5 accelerates leukocyte adhesion to endothelial cells in ischemia-reperfusion injury through regulating the transcription of VCAM-1. AB - Ischemia-reperfusion injury (IRI) has been implicated in many pathological conditions, including cardiovascular diseases. Adhesion of leukocytes to the surface of endothelial cells has been considered as one of the principle steps in the pathological cascade of inflammatory tissue damage during IRI. The role of the transcriptional factor interferon regulatory factor-5 (IRF-5) in endothelial physiology remains unknown. Here, we report that IRF-5 is expressed in human umbilical vein endothelial cells (HUVECs) and is rapidly upregulated in response to IRI, mediated by the JAK2/STAT3 pathway. Importantly, IRF-5 is involved in IRI induced attachment of THP-1 leukocytes to HUVECs. Mechanistically, it was found that IRF-5 targeted the expression of vascular cell adhesion molecule 1 (VCAM-1) at the transcriptional level by binding to its promoter. In conclusion, we identify IRF-5 as a new regulator and thus a therapeutic target in IRI-driven cardiovascular pathologies. PMID- 28818666 TI - Clinical significance of SPARC in esophageal squamous cell carcinoma. AB - BACKGROUND: Secreted protein acidic and rich in cysteine (SPARC) is matricellular protein that modulates interactions between cells and the extracellular matrix. The role of SPARC in carcinogenesis is controversialin that SPARC can be a tumor suppressor, but overexpression of SPARC is associated with poorer prognosis. METHODS: We collected 145 esophageal squamous cell carcinoma and adjacent normal tissues in Shantou, a high incidence region for esophageal cancer. The mRNA and protein expression levels of SPARC in cancer tissue and in adjacent normal mucosa were measured by qRT-PCR, western blot and immunohistochemistry (IHC). RESULTS: The mRNA and protein levels of SPARCwere5.78-fold higher in cancer tissues compared with the case-matched normal epithelium. High expression levels of SPARC in ESCC parenchyma, as detected by IHC, were related to lymph node metastasis and poor prognosis (p = 0.049 and p = 0.04). CONCLUSION: High expression of SPARC in the parenchyma may be a potential predictor of prognosis, suggesting SPARC could serve as a therapeutic target in ESCC. PMID- 28818667 TI - Endoconduits with "Pave and Crack" Technique Avoid Open Ilio-femoral Conduits with Sustainable Mid-term Results. AB - OBJECTIVE/BACKGROUND: The objective was to evaluate the feasibility and mid-term outcomes of endoconduits (EC) with the "pave and crack" technique during endovascular aneurysm repair (EVAR) of varying complexity. METHODS: This was a retrospective study. All patients undergoing EC between July 2009 and October 2015 were included. The primary endpoint was technical success of the EC defined as the ability to successfully deliver the aortic stent graft through the EC without rupture, dissection, or thrombosis of the iliac or femoral arteries, and with the absence of haemodynamically significant blood loss related to the EC. Secondary outcomes included EC patency and mortality. RESULTS: Nineteen patients underwent EVAR with EC (16 juxtarenal or thoraco-abdominal, two infrarenal and one thoracic; four were ruptured). Fourteen patients (73.7%) had TASC D lesions. In 10 cases (52.6%) adjunctive open/endovascular procedures to improve the femoral outflow were required. EC was technically successful in all cases and all EC were patent at EVAR completion. Thirty day mortality occurred in two cases (10.5%) One of these patients had been treated for rupture. One patient required two endovascular re-interventions at 1 and 5 years post-operatively to restore patency of the EC. No open re-interventions related to the EC were necessary. After a median follow-up period of 17 (interquartile range 5-37) months, the primary assisted patency of the EC was 88.9% (SE 10.5). No new onset of claudication or lower limb amputations occurred during the follow-up. CONCLUSION: EC allows EVAR of varying complexity without the need for open surgical ilio femoral conduits in patients with concomitant advanced iliac occlusive disease. Intra-operative haemodynamic instability was always avoided and mid-term patency was high. PMID- 28818670 TI - Depictive and metric body size estimation in anorexia nervosa and bulimia nervosa: A systematic review and meta-analysis. AB - A distorted representation of one's own body is a diagnostic criterion and core psychopathology of both anorexia nervosa (AN) and bulimia nervosa (BN). Despite recent technical advances in research, it is still unknown whether this body image disturbance is characterized by body dissatisfaction and a low ideal weight and/or includes a distorted perception or processing of body size. In this article, we provide an update and meta-analysis of 42 articles summarizing measures and results for body size estimation (BSE) from 926 individuals with AN, 536 individuals with BN and 1920 controls. We replicate findings that individuals with AN and BN overestimate their body size as compared to controls (ES=0.63). Our meta-regression shows that metric methods (BSE by direct or indirect spatial measures) yield larger effect sizes than depictive methods (BSE by evaluating distorted pictures), and that effect sizes are larger for patients with BN than for patients with AN. To interpret these results, we suggest a revised theoretical framework for BSE that accounts for differences between depictive and metric BSE methods regarding the underlying body representations (conceptual vs. perceptual, implicit vs. explicit). We also discuss clinical implications and argue for the importance of multimethod approaches to investigate body image disturbance. PMID- 28818672 TI - Glutathione monoethyl ester prevents TDP-43 pathology in motor neuronal NSC-34 cells. AB - Oxidative stress is recognised as central in a range of neurological diseases including Amyotrophic lateral sclerosis (ALS), a disease characterised by fast progressing death of motor neurons in the brain and spinal cord. Cellular pathology includes cytosolic protein aggregates in motor neurons and glia of which potentially cytotoxic hyper-phosphorylated fragments of the Transactive response DNA Binding Protein 43 kDa (TDP-43) constitute a major component. This is closely associated with an additional loss of nuclear TDP-43 expression indicating a "loss of function" mechanism, accelerating motor neuron (MN) loss. Furthermore, mutations in TDP-43 cause familial ALS and ALS-like disease in animal models. In this study, we investigated the role of glutathione (GSH) in modulating oxidative stress responses in TDP-43 pathology in motor neuron NSC-34 cells. Results demonstrate that depletion of GSH produces pathology similar to that of mutant TDP-43, including occurrence of cytosolic aggregates, TDP-43 phosphorylation and nuclear clearing of endogenous TDP-43. We also demonstrate that introduction of mutant TDP-43A315T and silencing of endogenous TDP-43, but not overexpression of wild-type TDP-43, result in similar pathology, including depletion of intracellular GSH, possibly resulting from a decreased expression of a regulatory subunit of gamma-glutamylcysteine ligase (GCLM), a rate limiting enzyme in GSH synthesis. Importantly, treatment of mutant cells with GSH monoethyl ester (GSHe) that directly increases intracellular GSH and bypasses the need for GSH synthesis, protected against mutant-induced TDP-43 pathology, including reducing aggregate formation, nuclear clearance, reactive oxygen species (ROS) production and cell death. Our data strongly suggest that oxidative stress is central to TDP-43 pathology and may result from a loss of function affecting GSH synthesis and that treatments directly aimed at restoring cellular GSH content may be beneficial in preventing cell death in TDP-43-mediated ALS. PMID- 28818668 TI - A bipolar role of the transcription factor ERG for cnidarian germ layer formation and apical domain patterning. AB - Germ layer formation and axial patterning are biological processes that are tightly linked during embryonic development of most metazoans. In addition to canonical WNT, it has been proposed that ERK-MAPK signaling is involved in specifying oral as well as aboral territories in cnidarians. However, the effector and the molecular mechanism underlying latter phenomenon is unknown. By screening for potential effectors of ERK-MAPK signaling in both domains, we identified a member of the ETS family of transcription factors, Nverg that is bi polarily expressed prior to gastrulation. We further describe the crucial role of NvERG for gastrulation, endomesoderm as well as apical domain formation. The molecular characterization of the obtained NvERG knock-down phenotype using previously described as well as novel potential downstream targets, provides evidence that a single transcription factor, NvERG, simultaneously controls expression of two different sets of downstream targets, leading to two different embryonic gene regulatory networks (GRNs) in opposite poles of the developing embryo. We also highlight the molecular interaction of cWNT and MEK/ERK/ERG signaling that provides novel insight into the embryonic axial organization of Nematostella, and show a cWNT repressive role of MEK/ERK/ERG signaling in segregating the endomesoderm in two sub-domains, while a common input of both pathways is required for proper apical domain formation. Taking together, we build the first blueprint for a global cnidarian embryonic GRN that is the foundation for additional gene specific studies addressing the evolution of embryonic and larval development. PMID- 28818669 TI - Notch and Fgf signaling during electrosensory versus mechanosensory lateral line organ development in a non-teleost ray-finned fish. AB - The lateral line system is a useful model for studying the embryonic and evolutionary diversification of different organs and cell types. In jawed vertebrates, this ancestrally comprises lines of mechanosensory neuromasts over the head and trunk, flanked on the head by fields of electrosensory ampullary organs, all innervated by lateral line neurons in cranial lateral line ganglia. Both types of sense organs, and their afferent neurons, develop from cranial lateral line placodes. Current research primarily focuses on the posterior lateral line primordium in zebrafish, which migrates as a cell collective along the trunk; epithelial rosettes form in the trailing zone and are deposited as a line of neuromasts, within which hair cells and supporting cells differentiate. However, in at least some other teleosts (e.g. catfishes) and all non-teleosts, lines of cranial neuromasts are formed by placodes that elongate to form a sensory ridge, which subsequently fragments, with neuromasts differentiating in a line along the crest of the ridge. Furthermore, in many non-teleost species, electrosensory ampullary organs develop from the flanks of the sensory ridge. It is unknown to what extent the molecular mechanisms underlying neuromast formation from the zebrafish migrating posterior lateral line primordium are conserved with the as-yet unexplored molecular mechanisms underlying neuromast and ampullary organ formation from elongating lateral line placodes. Here, we report experiments in an electroreceptive non-teleost ray-finned fish, the Mississippi paddlefish Polyodon spathula, that suggest a conserved role for Notch signaling in regulating lateral line organ receptor cell number, but potentially divergent roles for the fibroblast growth factor signaling pathway, both between neuromasts and ampullary organs, and between paddlefish and zebrafish. PMID- 28818671 TI - Incidence and risk of cardiotoxicity in cancer patients treated with targeted therapies. AB - BACKGROUND: Cardiotoxicityis a serious side effect of molecularly targeted agents. The purpose of this study was to evaluate the incidence and Relative Risk (RR) of developing all-grade and high-grade cardiotoxicity in patients with solid tumors receiving targeted agents through a revised meta-analysis of available clinical trials. METHODS: The scientific literature regarding cardiotoxicity was extensively analyzed using MEDLINE, PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL). Eligible studies were selected according to PRISMA statement. Summary incidence, RR, and 95% CIs were calculated using random effects or fixed-effects models based on the heterogeneity of selected studies. RESULTS: Our search yielded a total of 4998 clinical studies; of them, 31 trials were finally considered for this meta-analysis. A total of 28,538 patients were included; 7995 of these patients had breast cancer (28%), 6151 (22%) prostate cancer and 14,392 (50%) were treated for other malignancies. The highest RR of high-grade events was observed with Vandetanib (RR=7.71, 95% CI 1.04-56.99), followed by Ramucirumab (RR=5.0) and Aflibercept (RR=4.1). Grouping by drug category, the highest incidence of high-grade cardiotoxicity was shown by anti VEGFR-TKIs (RR 5.62, 95% CI 1.49-21.24) and anti-VEGF mAbs/VEGF-trap (RR 1.82, 95% CI 1.24-2.69). Grouping by tumor type, the highest incidence of cardiotoxicity was observed in thyroid cancer (8%), followed by gastric cancer (4%). CONCLUSIONS: Treatment with targeted agents in cancer patients is correlated with a significant increase in the risk of cardiotoxicity. Frequent clinical monitoring should be emphasized when using these and newer biological agents. PMID- 28818673 TI - 1,25-Dihydroxyvitamin-D3 induces brain proteomic changes in cuprizone mice during remyelination involving calcium proteins. AB - Dietary supplementation of vitamin D is commonly recommended to patients with multiple sclerosis. We recently found that high-dose of the hormonally active 1,25-dihydroxyvitamin-D3 (1,25D) promotes myelin repair in the cuprizone model for de- and remyelination. In the present study, we quantified 5062 proteins, of which 125 were differentially regulated in brain tissue from 1,25D treated mice during remyelination, compared to placebo. Proteins upregulated in the early remyelination phase were involved in calcium binding, e.g. calretinin (>1.3 fold, p < 0.005), S10A5 and secretagogin, and involved in mitochondrial function, e.g. NADH-ubiquinone oxidoreductase chain 3, and acyl-coenzyme A synthetase. Calretinin, S10A5 and secretagogin expression levels were characterized using immunohistochemistry. Calretinin immunoreactivity was significantly increased (>3 fold, p = 0.016) in the medial septal nuclei of 1,25D treated mice in the early remyelination phase. Our results indicate that vitamin D may influence remyelination by mechanisms involving an increase in calretinin expression and potentially other calcium binding proteins. PMID- 28818674 TI - Effects of Electroacupuncture Administered 24hours Prior to Surgery on Postoperative Nausea and Vomiting and Pain in Patients Undergoing Gynecologic Laparoscopic Surgery: A Feasibility Study. AB - OBJECTIVE: Our study aimed to investigate the feasibility and effectiveness of preoperative electroacupuncture (EA), delivered 24hours before surgery, on postoperative nausea and vomiting (PONV) and postoperative pain in patients undergoing gynecologic laparoscopic surgery. METHODS: In this randomized controlled trial, 40 patients scheduled for elective gynecologic laparoscopic surgery were randomly assigned to the usual care (UC) group and the EA group (n = 20 each). Both groups received the routine treatment consisting of intravenous dexamethasone (5mg) after induction of anesthesia and intravenous tropisetron (5mg) before the end of the operation. The patients in the EA group received EA at bilateral neiguan (PC6) and zusanli (ST36) within 24hours prior to the surgery. The incidence and severity of PONV and pain were recorded at 6hours, 12hours, and 24hours after the operation. Time to first flatus passage was also recorded. Bonferroni-corrected independent sample t-tests were used to analyze the data. RESULTS: In the first six hours after surgery, 15% and 20% of the patients experienced postoperative nausea in the EA and the UC groups, respectively. The incidences of postoperative vomiting were 5% for the EA group and 20% for the UC group. PONV reduced to zero over 12hours in both groups and there was no statistically significant difference in PONV between the two groups at any time point. The EA group rated their postoperative pain statistically significantly lower than the UC group did at six hours postoperative (EA: 1.9 +/- .8; UC: 2.9 +/- .9, P = .001). The two groups did not differ in pain at 12 and 24hours. The EA group had a shorter time to pass first flatus than the UC group did (EA: 20.3hours +/- 6.1; UC: 26.4 +/- 5.2, P = .002). The common EA-related adverse effects were minor, and did not require medical attention. The patients tolerated the EA treatment well. CONCLUSION: It is feasible and safe to deliver one-session EA treatment within 24hours preoperatively to preempt postoperative pain. One-session preoperative EA may also accelerate motility of the gastrointestinal track. Properly powered studies are needed to further test the effectiveness of preoperative EA on PONV. PMID- 28818675 TI - Presence of quintuple dhfr N51, C59, S108 - dhps A437, K540 mutations in Plasmodium falciparum isolates from pregnant women and the general population in Nanoro, Burkina Faso. AB - Sulphadoxine-pyrimethamine (SP) is only used for intermittent preventive treatment during pregnancy (IPTp) in most Sub-Saharan African countries. However, there are concerns about the efficacy of IPTp-SP because of increasing resistance. Combinations of point mutations in the dhps and dhfr genes of Plasmodium falciparum are associated with SP resistance, in particular the quintuple dhfr (N51, C59, S108) - dhps (codons A437, K540) mutant. In Nanoro, Burkina Faso, filter paper samples from pregnant women at first antenatal care visit and at delivery plus samples from the general population (GP) were studied for dhfr and dhps mutations by sequencing. Quintuple mutants were present in 2 delivery and 4 GP samples. This is the first time the quintuple mutation is found in Burkina Faso and although the prevalence is still very low, emergence of the quintuple mutation could highly diminish the efficacy of IPTp-SP. Close surveillance of SP resistance mutations is therefore warranted. PMID- 28818676 TI - The importance of parental verbal and embodied mentalizing in shaping parental experiences of stress and coparenting. AB - Parental mentalizing-recognizing that children are separate psychological entities, who have their own thoughts, wishes, and intentions that motivate their behaviors-is traditionally considered a verbal, linguistic capacity. This paper aimed to examine the relation between parental verbal mentalizing (parental reflective function; PRF) and its nonverbal form-parental embodied mentalizing (PEM)-and how both constructs contribute to parents' subjective experience of parenting, namely parental stress and coparental alliance. 68 mothers and their three-months-old babies were observed to assess PEM, interviewed to code PRF, and completed self-reports of coparental alliance and parental stress. PEM was found to be positively correlated with PRF. Mediation analyses revealed that higher PEM, but not PRF, was associated with lower parental stress, mediated by positive reports of coparental alliance. The findings support adopting a multifaceted approach when studying parental mentalizing, both in terms of assessing parental mentalizing beyond its verbal expressions to include also embodied aspects, as well as investigating its impact beyond infant development to include the familial context within it operates. Conceptual, empirical and clinical implications are discussed. PMID- 28818677 TI - Low prevalence of hepatitis B and hepatitis C virus serum markers in a cohort of pregnant women from Southern Italy. AB - BACKGROUND: Mother-to-child transmission is still considered a major factor in the spread of hepatitis viruses. Nevertheless, epidemiological data on hepatitis B virus (HBV) and hepatitis C virus (HCV) in reproductive-age women are limited even in areas like the South of Italy where both viruses had been widespread. AIM: The aim of this study was to investigate the prevalence of HBV and HCV serum markers in a large cohort of pregnant women from Southern Italy. METHODS: Data concerning 7558 pregnant women consecutively admitted to an Obstetric Division of a Sicilian University Hospital over a six-year period (January 2010-December 2015) were retrospectively collected from clinical notes. RESULTS: Positivity for both HBV s-antigen (HBsAg) and antibodies to HCV (anti- HCV) was very low (0.5% and 0.2%, respectively). HBsAg prevalence was significantly higher in non-Italian than in Italian women (p<0.001). On the contrary, all the anti-HCV positive cases were of Italian origin. Age was not significantly different between positive and negative women. CONCLUSION: These results confirm the dramatic decline of HBV and HCV prevalence that recently occurred in Southern Italy, and highlight the importance and cost-effectiveness of systematic HBV and HCV screening in childbearing age women in order to properly apply the available preventive measures and definitively eliminate the risk of vertical transmission for both viruses. PMID- 28818678 TI - Renal function changes in HCV-infected patients with chronic kidney disease during and after treatment with direct antiviral agents. PMID- 28818679 TI - Improved Assays for AGG Interruptions in Fragile X Premutation Carriers. AB - The learning disability fragile X syndrome results from the presence of >200 CGG/CCG repeats in exon 1 of the X-linked gene FMR1. Such alleles arise by expansion from maternally transmitted FMR1 premutation alleles, alleles having 55 to 200 repeats. Expansion risk is directly related to maternal repeat number. However, AGG interruptions to the repeat tract are important modifiers of expansion risk. Thus, the ability to identify such interruptions is crucial for the appropriate genetic counseling of females who are premutation carriers. First generation triplet-primed PCR assays allow these interruptions to be detected. However, because the triplet primer used has multiple binding sites in the repeat tract, interpreting the results is not straightforward and it is not always possible to unambiguously determine the AGG-interruption status in females because of the difficulties associated with the presence of a second X chromosome. Interpretation is further complicated by any repeat size mosaicism that may be present. We have developed second-generation PCR assays that prime specifically at the interruptions. These assays are simpler to interpret and better able to evaluate this important determinant of expansion risk in females even in those with a mixture of premutation allele sizes. PMID- 28818680 TI - Clinical Validation of Copy Number Variant Detection from Targeted Next Generation Sequencing Panels. AB - Next-generation sequencing (NGS) technology has rapidly replaced Sanger sequencing in the assessment of sequence variations in clinical genetics laboratories. One major limitation of current NGS approaches is the ability to detect copy number variations (CNVs) approximately >50 bp. Because these represent a major mutational burden in many genetic disorders, parallel CNV assessment using alternate supplemental methods, along with the NGS analysis, is normally required, resulting in increased labor, costs, and turnaround times. The objective of this study was to clinically validate a novel CNV detection algorithm using targeted clinical NGS gene panel data. We have applied this approach in a retrospective cohort of 391 samples and a prospective cohort of 2375 samples and found a 100% sensitivity (95% CI, 89%-100%) for 37 unique events and a high degree of specificity to detect CNVs across nine distinct targeted NGS gene panels. This NGS CNV pipeline enables stand-alone first-tier assessment for CNV and sequence variants in a clinical laboratory setting, dispensing with the need for parallel CNV analysis using classic techniques, such as microarray, long range PCR, or multiplex ligation-dependent probe amplification. This NGS CNV pipeline can also be applied to the assessment of complex genomic regions, including pseudogenic DNA sequences, such as the PMS2CL gene, and to mitochondrial genome heteroplasmy detection. PMID- 28818681 TI - Sanction changes and drunk-driving injuries/deaths in Taiwan. AB - Driving under the influence (DUI) is one of the major causes of traffic accidents in Taiwan. About 5% of injuries involve DUI, and nearly 20% of deaths are due to alcohol-related crashes. During early 2006 to the end of 2014, the authorities in Taiwan increased the severity of fine and jail penalties for DUI offenders three times. At the same time, the monthly drunk-driving injures decreased nearly 40% and the monthly alcohol-related traffic death dropped more than 80%. In this paper, we examine the effects of sanction changes on the reduction of drunk driving casualties during this period. We find that drunk-driving injuries and deaths significantly dropped after the statutory changes. The reduction was immediate following all sanction changes that raised the maximum fines or jail terms of DUI offenders. Policies that increased the maximum jail terms of DUI offenders seem to have a better gradual effect on the reduction of alcohol related traffic casualties. Although increased sanctions are found to be effective in reducing drunk-driving casualties, we need more future research to examine the policy-to-perception and the policy-to-behavior links. PMID- 28818682 TI - The epidemiology of driving in later life: Sociodemographic, health and functional characteristics, predictors of incident cessation, and driving expectations. AB - AIM: To describe population-level characteristics of drivers and non-drivers in a cohort of older Australians and identify predictors of driving cessation and expectations. METHODS: The sample comprised the oldest cohort of the PATH Through Life project who were assessed 4 times between 2001 and 2013. At waves 3 and 4 questions on driving were included in the study interview. Data were also collected on health, physical and cognitive function and psychosocial wellbeing. Descriptive analyses compared drivers and non-drivers on sociodemographic, health and functional variables and regression models identified predictors of cessation and driving expectations. RESULTS: 92.5% of the sample were current drivers. They reported better physical, mental and cognitive health than non-drivers. Drivers expected to drive for another 12.6 years, the majority drove 6+ days per week. Four percent of the sample ceased driving over the four year follow-up. Predictors of cessation were financial problems, driving expectations and driving fewer kilometres per week. Predictors of expectations were poorer self-rated health, mastery, difficulties reading maps, self-rated visual function, years of driving experience, and fewer kilometres driven per week. CONCLUSION: Driving is normative for many older Australians in their 70s. Similar factors are associated with actual cessation and expectation of driving suggesting that older adults do have a sense of their expected driving life. PMID- 28818683 TI - Modeling the impact of latent driving patterns on traffic safety using mobile sensor data. AB - Smartphones are now equipped with sensors capable of recording vehicle performance data at a very fine temporal resolution in a cost-effective way. In this paper, mobile sensor data from smartphones was used to identify and quantify unsafe driving patterns and their relationship with traffic crash incidences. Statistical models that account for measurement error associated with microscopic traffic measures computed using mobile sensor data were developed. The models with microscopic traffic measures were shown to be statistically better than traditional models that only control for roadway geometry and traffic exposure variables. Also, generalized count models that account for measurement error, spatial dependency effects, and random parameter heterogeneity were found to perform better than standard count models. PMID- 28818684 TI - T Cell-Mediated Rejection of Human CD34+ Cells Is Prevented by Costimulatory Blockade in a Xenograft Model. AB - A xenograft model of stem cell rejection was developed by co-transplantating human CD34+ and allogeneic CD3+ T cells into NOD-scid gamma-chainnull mice. T cells caused graft failure when transplanted at any CD34/CD3 ratio between 1:50 and 1:.1. Kinetics experiments showed that 2 weeks after transplantation CD34+ cells engrafted the marrow and T cells expanded in the spleen. Then, at 4 weeks only memory T cells populated both sites and rejected CD34+ cells. Blockade of T cell costimulation was tested by injecting the mice with abatacept (CTLA4-IgG1) from day -1 to +27 (group A), from day -1 to +13 (group B), or from day +14 to +28 (group C). On day +56 groups B and C had rejected the graft, whereas in group A graft failure was completely prevented, although with lower stem cell engraftment than in controls (P = .03). Retransplantation of group A mice with same CD34+ cells obtained a complete reconstitution of human myeloid and B cell lineages and excluded latent alloreactivity. In this first xenograft model of stem cell rejection we showed that transplantation of HLA mismatched CD34+ cells may be facilitated by treatment with abatacept and late stem cell boost. PMID- 28818685 TI - Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. AB - Ethyl carbamate (EC), a multisite carcinogenic chemical causing tumors in various animal species, is probably carcinogenic to humans. However, information about the possible carcinogenic and toxicological effects of EC in humans is quite limited. Because EC is found in many dietary foods (such as fermented foods) and tobacco and its products, and exposure of humans to EC often occurs inevitably, its toxicological effects in humans need to be studied. This study was conducted to understand the metabolomic and transcriptomic changes in human hepatocellular carcinoma cells (HepG2) exposed to 100 mM EC for short term (4 h) and long term (12 h) period, respectively. The results revealed multiple influences of EC on the metabolome and transcriptome of HepG2 cells, which was exposure time dependent and well correlated with the kinetic changes of cell viability and mortality. EC treatment affected multiple metabolic pathways, inducing oxidative stress, reducing detoxification capacity, depleting energy, decreasing reducing power, disrupting membrane integrity, and damaging DNA and protein. These metabolomic and transcriptomic biomarkers of EC on human cell metabolism identified in this study would facilitate further studies on the risk assessment and the mitigation of dietary EC. PMID- 28818686 TI - Methyleugenol and selected oxidative metabolites affect DNA-Damage signalling pathways and induce apoptosis in human colon tumour HT29 cells. AB - Previously the food carcinogen methyleugenol was found to be cytotoxic and genotoxic in multiple cell lines and in primary hepatocytes. In this study, the question addressed was whether methyleugenol and the selected oxidative metabolites, 1'-hydroxymethyleugenol, methyleugenol-2',3'-epoxide and 3' oxomethylisoeugenol trigger a DNA damage response in the human colon carcinoma HT29 cell line. Most notably investigations by flow cytometry revealed that the metabolites induce an accumulation of HT29 cells in the G2 phase of the cell cycle. DNA damage response is characterised by a time-delayed phosphorylation of ATM (ataxia-telangiectasia, mutated)/ATR (ATM- and Rad3-related) kinases and checkpoint kinase 1 after 2 h of incubation, and the tumour suppressor protein p53 only after 24 h of incubation. The test compounds induced apoptotic cell death indicated by cleavage of caspase 3 and poly-(ADP-ribose)-polymerase after a prolonged incubation time up to 72 h. In addition, activation of ATM/ATR signalling cascade might contribute to apoptosis induction to a certain extent. However, clarification of this relationship awaits experimental confirmation. PMID- 28818687 TI - Consumer exposure to certain ingredients of cosmetic products: The case for tea tree oil. AB - Reliable exposure data are essential to evaluate the safety of ingredients in cosmetics. The study reported here was carried out on behalf of the Australian Tea Tree Industry Association in order to support safety assessment of TTO in consumer cosmetic products. Data regarding the use of TTO-containing cosmetic products were collected through a web-survey among 2535 qualified users of validated TTO-containing cosmetics in 5 European countries. Data regarding the percentage of TTO present in the individual products (TTO-inclusion) were collected from the suppliers of those products. Beyond TTO exposure-measures there were several significant findings: One is a special "TTO-effect" for several categories of TTO-containing cosmetic products showing a positive correlation between consumers' strength of TTO-orientation and frequency of product use, combined with a negative correlation between frequency of product use and amount of product used per application. Another is significant differences regarding the intensity of product use between TTO-containing cosmetics and respective types of products in general. Thus it seems not to be appropriate to evaluate the toxicological safety of certain ingredients of cosmetic products from exposure data on "generic" types of cosmetic products. PMID- 28818688 TI - Anodization of magnesium for biomedical applications - Processing, characterization, degradation and cytocompatibility. AB - : This article reports anodization of Mg in KOH electrolyte and the associated surface, degradation, and biological properties for bioresorbable implant applications. The preparation procedures for electrodes and anodization setup significantly enhanced reproducibility of samples. The results of anodization performed at the applied potentials of 1.8, 1.9, or 2.0V showed that the sample anodized at 1.9V and annealed, referred to as the 1.9 AA sample, had homogenous surface microstructure and elemental composition, and a reduction in corrosion current density in the electrochemical testing. In comparison with Mg control, the 1.9 AA sample showed a distinct mode of degradation, e.g., continuous growth of a passivation layer enriched with Ca and P instead of typical localized pitting and undermining, and a greater release rate of Mg2+ ions when immersed in physiologically relevant media. In the direct culture with bone marrow derived mesenchymal stem cells (BMSCs) in vitro, the 1.9 AA sample did not affect BMSC adhesion and morphology under indirect contact; however, the 1.9 AA sample showed a reduction in cell spreading under direct contact. The change in surface topography/composition at the dynamic interface of the anodized-annealed Mg sample might have contributed to the change in BMSC morphology. In summary, this study demonstrated the potential of anodic oxidation to modulate the degradation behaviors of Mg-based biomaterials and BMSC responses in vitro, and confirmed the value of direct culture method for studying cytocompatibility of Mg-based biomaterials for medical implant applications. STATEMENT OF SIGNIFICANCE: Magnesium (Mg)-based biomaterials have been specifically designed and actively explored for biodegradable implant applications since the early 2000s. To realize the benefits of Mg-based materials for medical implant applications, it is critical to control the rate of Mg degradation (i.e. corrosion) in the body. We investigated an environmentally friendly anodization process using KOH electrolyte for modifying the surface of Mg-based materials, and the resulted surface, degradation, and biological properties for biomedical applications. This study reported critical considerations that are important for repeatability of anodization process, homogeneity of surface microstructure and composition, and in vitro evaluations of the degradation and biological properties of surface treated Mg samples. The details in preparation of electrodes, anodization setup, annealing, and sample handling before and after surface treatment (e.g. re embedding) reported in this article are valuable for studying a variety of electrochemical processes for surface treatment of Mg-based metals, because of enhanced reproducibility. PMID- 28818689 TI - Sol gel-derived hydroxyapatite films over porous calcium polyphosphate substrates for improved tissue engineering of osteochondral-like constructs. AB - : Integration of in vitro-formed cartilage on a suitable substrate to form tissue engineered implants for osteochondral defect repair is a considerable challenge. In healthy cartilage, a zone of calcified cartilage (ZCC) acts as an intermediary for mechanical force transfer from soft to hard tissue, as well as an effective interlocking structure to better resist interfacial shear forces. We have developed biphasic constructs that consist of scaffold-free cartilage tissue grown in vitro on, and interdigitated with, porous calcium polyphosphate (CPP) substrates. However, as CPP degrades, it releases inorganic polyphosphates (polyP) that can inhibit local mineralization, thereby preventing the formation of a ZCC at the interface. Thus, we hypothesize that coating CPP substrate with a layer of hydroxyapatite (HA) might prevent or limit this polyP release. To investigate this we tested both inorganic or organic sol-gel processing methods, asa barrier coating on CPP substrate to inhibit polyP release. Both types of coating supported the formation of ZCC in direct contact with the substrate, however the ZCC appeared more continuous in the tissue formed on the organic HA sol gel coated CPP. Tissues formed on coated substrates accumulated comparable quantities of extracellular matrix and mineral, but tissues formed on organic sol gel (OSG)-coated substrates accumulated less polyP than tissues formed on inorganic sol-gel (ISG)-coated substrates. Constructs formed with OSG-coated CPP substrates had greater interfacial shear strength than those formed with ISG coated and non-coated substrates. These results suggest that the OSG coating method can modify the location and distribution of ZCC and can be used to improve the mechanical integrity of tissue-engineered constructs formed on porous CPP substrates. STATEMENT OF SIGNIFICANCE: Articular cartilage interfaces with bone through a zone of calcified cartilage. This study describes a method to generate an "osteochondral-like" implant that mimics this organization using isolated deep zone cartilage cells and a sol-gel hydroxyapatite coated bone substitute material composed of calcium polyphosphate (CPP). Developing a layer of calcified cartilage at the interface should contribute to enhancing the success of this "osteochondral-like" construct following implantation to repair cartilage defects. PMID- 28818690 TI - Early estimates of 2016/17 seasonal influenza vaccine effectiveness in primary care in France. AB - BACKGROUND: The ongoing 2016/17 influenza epidemic in France is characterized by the circulation of A(H3N2) viruses, known to cause more severe illness among at risk populations. OBJECTIVES: The purpose of our study was to provide early influenza vaccine effectiveness (IVE) estimates for the ongoing influenza epidemic in France and compare these estimates over the six post-pandemic IVE. STUDY DESIGN: We used clinical and virological data collected in primary care by the French Sentinelles network. IVE in preventing influenza infection was estimated by the test-negative design method. The screening method was used to estimate IVE in preventing medically-attended influenza-like illness among target groups (<65year with chronic diseases and >=65 years) since 2010/11 influenza epidemic. RESULTS: Early IVE estimates in primary care against influenza A(H3N2) were 48% (95% confidence interval (CI): 22-66) overall and 39% (95% CI: -17 to 69) among elderly (aged 65 and older). In comparison to the last six epidemics, 2016/17 early IVE in preventing influenza-like illness among target groups showed VE estimates higher to those reported during the 2011/12 and 2014/15 epidemics. CONCLUSIONS: The moderate 2016/17 IVE estimates were higher than those estimated during influenza A(H3N2) epidemics with vaccine mismatch. PMID- 28818691 TI - Multi-center evaluation of the cobas(r) Liat(r) Influenza A/B & RSV assay for rapid point of care diagnosis. AB - Point of Care Testing (POCT) provides the capability for rapid laboratory test results in patient care environments where a traditional clinical laboratory is not available. POCTs have shorter turn-around times (TATs), they may be performed by non-laboratory personnel, and the need for transport time is eliminated. The Food and Drug Administration (FDA) recently granted Clinical Laboratory Improvements Amendment (CLIA) waiver status to the cobas(r) Influenza A/B & RSV assay, a rapid, accurate point-of-care test for Influenza and respiratory syncytial virus (RSV) performed on the Liat(r) System. The performance characteristics of this test were determined though a multi-site study consisting of different point of care testing environments. Prospectively collected Nasopharyngeal (NP) swabs from 1361 patients seen at 8 primary care clinics and 4 emergency departments (EDs) and 295 retrospectively identified specimens were tested for Influenza A/B and RSV on the cobas(r) Liat(r) platform. Performance characteristics were determined through comparison to ProFlu+, a laboratory-based PCR test for Influenza A/B and RSV (reference test). Discordant specimens were adjudicated following bi-directional sequencing. The cobas(r) Influenza A/B and RSV assay showed sensitivities of 99.6%, 99.3%, and 96.8% for Influenza A, Influenza B, and RSV, respectively as determined from percent positive agreement (PPA) following comparison to the reference test. Sequencing confirmed cobas(r) Influenza A/B and RSV results in 49.2% of reference test discordant specimens, while crossing threshold data suggest increased sensitivity compared to the reference test. The cobas(r) Influenza A/B and RSV assay was found to be a rapid, sensitive POCT for the detection of these viruses, and provides laboratory quality PCR-based diagnostic results in point of care settings. PMID- 28818692 TI - Suppression of irrelevant sounds during auditory working memory. AB - Auditory working memory (WM) processing in everyday acoustic environments depends on our ability to maintain relevant information online in our minds, and to suppress interference caused by competing incoming stimuli. A challenge in communication settings is that the relevant content and irrelevant inputs may emanate from a common source, such as a talkative conversationalist. An open question is how the WM system deals with such interference. Will the distracters become inadvertently filtered before processing for meaning because the primary WM operations deplete all available processing resources? Or are they suppressed post perceptually, through an active control process? We tested these alternative hypotheses by measuring magnetoencephalography (MEG), EEG, and functional MRI (fMRI) during a phonetic auditory continuous performance task. Contextual WM maintenance load was manipulated by adjusting the number of "filler" letter sounds in-between cue and target letter sounds. Trial-to-trial variability of pre and post-stimulus activations in fMRI-informed cortical MEG/EEG estimates was analyzed within and across 14 subjects using generalized linear mixed effect (GLME) models. High contextual WM maintenance load suppressed left auditory cortex (AC) activations around 250-300 ms after the onset of irrelevant phonetic sounds. This effect coincided with increased 10-14 Hz alpha-range oscillatory functional connectivity between the left dorsolateral prefrontal cortex (DLPFC) and left AC. Suppression of AC responses to irrelevant sounds during active maintenance of the task context also correlated with increased pre-stimulus 7-15 Hz alpha power. Our results suggest that under high auditory WM load, irrelevant sounds are suppressed through a "late" active suppression mechanism, which prevents short-term consolidation of irrelevant information without affecting the initial screening of potentially meaningful stimuli. The results also suggest that AC alpha oscillations play an inhibitory role during auditory WM processing. PMID- 28818693 TI - Hybrid photoacoustic and electrophysiological recording of neurovascular communications in freely-moving rats. AB - Uncovering the relationships between neural activities and capillary-level hemodynamics such as blood flow and concentration of hemoglobin in the brain plays an important role in the study of animal behaviors and brain disorders. Here, we developed a miniature probe integrating a photoacoustic sensor and micro electrodes to simultaneously record the dynamics of blood flow and total hemoglobin inside a single capillary and the activities of surrounding neurons with high spatiotemporal resolution in freely-moving rats. In the somatosensory cortex of rats, we observed: 1) early hemodynamic response prior to the changes in local field potential during pentylenetetrazol-induced localized and generalized seizure onsets in both freely-moving and anesthetized rats; and 2) different hemodynamic and neural responses to generalized seizure onsets between freely-moving and anaesthetized rats. These findings suggest that this high resolution hybrid technique will enable a wide range of new studies of behaviors and brain disorders in small animals. PMID- 28818694 TI - Diffusion time dependence of microstructural parameters in fixed spinal cord. AB - Biophysical modelling of diffusion MRI is necessary to provide specific microstructural tissue properties. However, estimating model parameters from data with limited diffusion gradient strength, such as clinical scanners, has proven unreliable due to a shallow optimization landscape. On the other hand, estimation of diffusion kurtosis (DKI) parameters is more robust, and its parameters may be connected to microstructural parameters, given an appropriate biophysical model. However, it was previously shown that this procedure still does not provide sufficient information to uniquely determine all model parameters. In particular, a parameter degeneracy related to the relative magnitude of intra-axonal and extra-axonal diffusivities remains. Here we develop a model of diffusion in white matter including axonal dispersion and demonstrate stable estimation of all model parameters from DKI in fixed pig spinal cord. By employing the recently developed fast axisymmetric DKI, we use stimulated echo acquisition mode to collect data over a two orders of magnitude diffusion time range with very narrow diffusion gradient pulses, enabling finely resolved measurements of diffusion time dependence of both net diffusion and kurtosis metrics, as well as model intra- and extra-axonal diffusivities, and axonal dispersion. Our results demonstrate substantial time dependence of all parameters except volume fractions, and the additional time dimension provides support for intra-axonal diffusivity to be larger than extra-axonal diffusivity in spinal cord white matter, although not unambiguously. We compare our findings for the time-dependent compartmental diffusivities to predictions from effective medium theory with reasonable agreement. PMID- 28818695 TI - Direct detection of neural activity in vitro using magnetic resonance electrical impedance tomography (MREIT). AB - We describe a sequence of experiments performed in vitro to verify the existence of a new magnetic resonance imaging contrast - Magnetic Resonance Electrical Impedance Tomography (MREIT) -sensitive to changes in active membrane conductivity. We compared standard deviations in MREIT phase data from spontaneously active Aplysia abdominal ganglia in an artificial seawater background solution (ASW) with those found after treatment with an excitotoxic solution (KCl). We found significant increases in MREIT treatment cases, compared to control ganglia subject to extra ASW. This distinction was not found in phase images from the same ganglia using no imaging current. Further, significance and effect size depended on the amplitude of MREIT imaging current used. We conclude that our observations were linked to changes in cell conductivity caused by activity. Functional MREIT may have promise as a more direct method of functional neuroimaging than existing methods that image correlates of blood flow such as BOLD fMRI. PMID- 28818696 TI - Cortical networks for reference-frame processing are shared by language and spatial navigation systems. AB - To help us live in the three-dimensional world, our brain integrates incoming spatial information into reference frames, which are based either on our own body (egocentric) or independent from it (allocentric). Such frames, however, may be crucial not only when interacting with the visual world, but also in language comprehension, since even the simplest utterance can be understood from different perspectives. While significant progress has been made in elucidating how linguistic factors, such as pronouns, influence reference frame adoption, the neural underpinnings of this ability are largely unknown. Building on the neural reuse framework, this study tested the hypothesis that reference frame processing in language comprehension involves mechanisms used in navigation and spatial cognition. We recorded EEG activity in 28 healthy volunteers to identify spatiotemporal dynamics in (1) spatial navigation, and (2) a language comprehension task (sentence-picture matching). By decomposing the EEG signal into a set of maximally independent activity patterns, we localised and identified a subset of components which best characterised perspective-taking in both domains. Remarkably, we find individual co-variability across these tasks: people's strategies in spatial navigation are also reflected in their construction of sentential perspective. Furthermore, a distributed network of cortical generators of such strategy-dependent activity responded not only in navigation, but in sentence comprehension. Thus we report, for the first time, evidence for shared brain mechanisms across these two domains - advancing our understanding of language's interaction with other cognitive systems, and the individual differences shaping comprehension. PMID- 28818697 TI - Kinematic differences during a jump cut maneuver between individuals with and without a concussion history. AB - Recent evidence suggests that athletes are at a higher risk of lower-body injuries in the months and years following a concussion. However, little is known about how people modify their movements post-concussion. This study examined kinematics during a jump cut motion in young adults with a concussion history (n=9; 4 males, 5 females; 3.1years' post-injury) and 10 controls (6 males, 4 females). Peak center of mass and peak knee angles during the landing phase of a jump-cut maneuver were evaluated. Participants with a concussion history demonstrated decreased knee varus (left: Mconc=-0.5+/-1.0 degrees , Mctrl=3.6+/ 1.0 degrees ; right: Mconc=5.1+/-1.2 degrees , Mctrl=7.8+/-1.12 degrees ) and external rotation (left: Mconc=2.5+/-1.6 degrees , Mctrl=13.0+/-1.5 degrees ; right: Mconc=7.7+/-1.6 degrees , Mctrl=12.8+/-1.5 degrees ) regardless of whether the cut was oriented towards to the left or right. The kinematic patterns demonstrated in individuals with a concussion history may be suggestive of increased knee injury risk. This study adds to the growing body of literature linking orthopedic injury in those no longer displaying the acute signs and symptoms of concussion. PMID- 28818698 TI - A novel EPM2A mutation in a patient with Lafora disease presenting with early parkinsonism symptoms in childhood. PMID- 28818699 TI - Apathy in people with epilepsy and its clinical significance: A case-control study. AB - PURPOSE: Apathy as a state of decreased motivation has not been highlighted in people with epilepsy (PWE). We investigated its clinical significance in PWE. METHODS: We invited adult PWE who had been administered antiepileptic drugs (AEDs) for at least 1year and compared them with age- and gender-matched healthy controls. Eligible participants completed several questionnaires including the Apathy Evaluation Scale-Self (AES-S), the Korean version of the Neurological Disorders Depression Inventory for Epilepsy (K-NDDI-E), the Generalized Anxiety Disorder-7 (GAD-7), the Epworth Sleepiness Scale (ESS), and the Insomnia Severity Index (ISI), and the Quality of Life in Epilepsy-10 (QOLIE-10). We investigated the degree of interictal apathy in PWE compared with controls and identified its predictors. We also measured the impact of apathy on patients' QOL. RESULTS: The mean overall AES-S score in PWE was similar to that of controls. However, the score was significantly higher in patients with uncontrolled epilepsy than controls (p<0.01). Among subscale scores of the AES-S, the mean behavioral score was significantly higher in PWE than controls (p<0.01). Education level, employment, household income, disease duration, AED-related factors, seizure control, and scores of the K-NDDI-E, GAD-7, ESS, and ISI were associated with the overall AES-S score by univariate analyses. However, major predictors were the K NDDI-E (beta=0.476, p<0.001) and duration of AED intake (beta=0.151, p<0.01). The degree of apathy was significantly higher in patients receiving AEDs for 20 years or more than those receiving AEDs for 1-9 years (p<0.01). The overall AES-S score was inversely correlated with the overall QOLIE-10 score (p<0.001). CONCLUSION: Duration of AED intake in PWE seems to be a critical factor for apathy regardless of comorbid depression. PMID- 28818700 TI - Vascularized Jejunal Mesenteric Lymph Node Transfer: A Novel Surgical Treatment for Extremity Lymphedema. AB - BACKGROUND: Vascularized lymph node transfer (VLNT) is a surgical treatment for lymphedema. Multiple donor sites have been described and each has significant disadvantages. We propose the jejunal mesentery as a novel donor site for VLNT. STUDY DESIGN: We performed a cadaveric anatomic study analyzing jejunal lymph nodes (LNs) and describe outcomes from the first patients who received jejunal mesenteric VLNT for treatment of lymphedema. RESULTS: In 5 cadavers, the average numbers of total LNs and peripheral LNs were identified in the proximal, middle, and distal segments of jejunum. Totals counted were 19.2/13.8/9.6, (SD 7.0/4.4/1.1), respectively; of those, 10.4/6.8/3.4 (SD 3.6/2.3/2.6), respectively, were in the periphery. There were significantly more total and peripheral lymph nodes in the proximal segment compared with the middle and distal segments (p = 0.027 and p = 0.008, respectively). The jejunal VLNT was used in 15 patients for treatment of upper (n = 8) or lower (n = 7) extremity lymphedema. Average follow-up was 9.1 (+/-6.4) months (range 1 to 19 months). Of 14 patients with viable flaps (93.3%), 12 had subjective improvement (87.5%). Ten patients had preoperative measurements, and of those, 7 had objective improvement in lymphedema (70%). CONCLUSIONS: The jejunal mesenteric VLNT is an excellent option for lymphedema treatment because there is no risk of donor site lymphedema or nerve damage, and the scar is easily concealed. Harvest from the periphery of the proximal jejunum is optimal. Improvement from lymphedema can be expected in a majority of patients. PMID- 28818701 TI - LapCap: A Novel Device to Reduce Entry Complications. PMID- 28818702 TI - The effects of cannabinoid receptors activation and glucocorticoid receptors deactivation in the amygdala and hippocampus on the consolidation of a traumatic event. AB - Ample evidence demonstrates that fear learning contributes significantly to many anxiety pathologies including post-traumatic stress disorder (PTSD). The endocannabinoid (eCB) system may offer therapeutic benefits for PTSD and it is a modulator of the hypothalamic pituitary adrenal (HPA) axis. Here we compared the separated and combined effects of blocking glucocorticoid receptors (GRs) using the GR antagonist RU486 and enhancing CB1r signaling using the CB1/2 receptor agonist WIN55,212-2 in the CA1 and basolateral amygdala (BLA) on the consolidation of traumatic memory. Traumatic memory was formed by exposure to a severe footshock in an inhibitory avoidance apparatus followed by exposure to trauma reminders. Intra-BLA RU486 (10ng/side) and WIN55,212-2 (5MUg/side) administered immediately after shock exposure dampened the consolidation of the memory about the traumatic event and attenuated the increase in acoustic startle response in rats exposed to shock and reminders. In the CA1, WIN55,212-2 impaired consolidation and attenuated the increase in acoustic startle response whereas RU486 had no effect. The effects of WIN55,212-2 were found to be mediated by CB1 receptors, but not by GRs. Moreover, post-shock systemic WIN55,212-2 (0.5mg/kg) administration prevented the increase in GRs and CB1 receptor levels in the CA1 and BLA in rats exposed to shock and reminders. The findings suggest that the BLA is a locus of action of cannabinoids and glucocorticoids in modulating consolidation of traumatic memory in a rat model of PTSD. Also, the findings highlight novel targets for the treatment of emotional disorders and PTSD in particular. PMID- 28818703 TI - Traceable PEO-poly(ester) micelles for breast cancer targeting: The effect of core structure and targeting peptide on micellar tumor accumulation. AB - Traceable poly(ethylene oxide)-poly(ester) micelles were developed through chemical conjugation of a near-infrared (NIR) dye to the poly(ester) end by click chemistry. This strategy was tried for micelles with poly(epsilon-caprolactone) (PCL) or poly(alpha-benzyl carboxylate-epsilon-caprolactone) (PBCL) cores. The surface of both micelles was also modified with the breast cancer targeting peptide, P18-4. The results showed the positive contribution of PBCL over PCL core on micellar thermodynamic and kinetic stability as well as accumulation in primary orthotopic MDA-MB-231 tumors within 4-96 h following intravenous administration in mice. This was in contrast to in vitro studies where better uptake of PEO-PCL versus PEO-PBCL micelles by MDA-MB-231 cells was observed. The presence of P18-4 enhanced the in vitro cell uptake and homing of both polymeric micelles in breast tumors, but only at early time points. In conclusion, the use of developed NIR labeling technique provided means for following the fate of PEO poly(ester) based nano-carriers in live animals. Our results showed micellar stabilization through the use of PBCL over PCL cores, to have a more significant effect in enhancing the level and duration of nano-carrier accumulation in primary breast tumors than the modification of polymeric micellar surface with breast tumor targeting peptide, P18-4. PMID- 28818704 TI - Orphan Drug Regulation: A missed opportunity for children and adolescents with cancer. AB - BACKGROUND: Oncology represents a major sector in the field of orphan drug development in Europe. The objective was to evaluate whether children and adolescents with cancer benefited from the Orphan Drug Regulation. METHODS: Data on orphan drug designations (ODDs) and registered orphan drugs from 8th August 2000 to 10th September 2016 were collected from the Community Register of medicinal products for human use. Assessment history, product information and existence of paediatric investigation plans were searched and retrieved from the European Medicine Agency website. RESULTS: Over 16 years, 272 of 657 oncology ODDs (41%) concerned a malignant condition occurring both in adults and children. The five most common were acute myeloid leukaemia, high-grade glioma, acute lymphoblastic leukaemia, graft-versus-host disease and soft-tissue sarcomas. 74% of 31 marketing authorisations (MAs) for an indication both in adults and children (26 medicines) had no information for paediatric use in their Summary of Product Characteristics (SmPC) at the time of the first MA. Furthermore, 68% still have no paediatric information in their most recently updated SmPC, at a median of 7 years after. Only 15 ODDs (2%) pertained to a malignancy occurring specifically in children and only two drugs received an MA: Unituxin for high risk neuroblastoma and Votubia for sub-ependymal giant-cell astrocytoma. CONCLUSION: The Orphan Drug Regulation failed to promote the development of innovative therapies for malignancies occurring in children. Major delays and waivers occurred through the application of the Paediatric Medicines Regulation. The European regulatory environment needs to be improved to accelerate innovation for children and adolescents dying of cancer. PMID- 28818705 TI - Hormone replacement therapy after risk-reducing salpingo-oophorectomy minimises endocrine and sexual problems: A prospective study. AB - BACKGROUND: There has been some doubts raised in earlier studies about the efficacy of hormone replacement therapy (HRT) in reducing endocrine and sexual problems in women who have undergone a risk-reducing salpingo-oophorectomy (RRSO). METHODS: In this prospective, observational study, we recruited 178 premenopausal women with a high risk for ovarian cancer. Fifty-seven women opted for RRSO and 121 for gynaecological screening (GS). Women completed questionnaires before surgery (T1) and 3 (T2) and 9 (T3) months post surgery, or at equivalent time points for the GS-group. Menopausal symptoms were assessed with the Functional Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES) and sexual functioning with the Sexual Activity Questionnaire (SAQ). Groups were compared using repeated measures mixed effect models for continuous variables, and generalised estimating equations for longitudinal ordered categorical data. RESULTS: Twenty-seven women who underwent RRSO used HRT after surgery (HRT-users) and 30 did not (HRT-non-users). There were no significant group differences at baseline on the outcome variables. Compared to the HRT-users, the HRT-non-users exhibited a significant increase in overall endocrine symptoms (p = 0.001, effect size (ES) = -0.40 and p < 0.001, ES = -0.59 at T1 and T2, respectively), and in sexual discomfort (p < 0.001, ES = 0.74 and p < 0.001, ES = 1.17). The effect size provides an indication of the magnitude of the observed group differences. An effect size of 0.50 or greater is generally considered to be clinically relevant. No significant differences over time were observed between the HRT users and the GS-group on any of the outcomes. CONCLUSION: Our results suggest that HRT use in the first year after RRSO has beneficial effects in terms of minimising endocrine symptoms and sexual symptoms in premenopausal women who have undergone RRSO. PMID- 28818706 TI - Diabetes increases interleukin-17 levels in periapical, hepatic, and renal tissues in rats. AB - OBJECTIVES: This study aimed to evaluate the association between endodontic infection and diabetes on interleukin-17 levels in periapical, hepatic, and renal tissues of rats. DESIGN: Forty male rats were divided into groups: normoglycemic rats (N), normoglycemic rats with apical periodontitis (N-AP), rats with experimental diabetes (ED), and rats with experimental diabetes and apical periodontitis (ED-AP). Diabetes was induced by intravenous streptozotocin injection, and blood sugar levels were monitored to confirm disease development. Apical periodontitis (AP) was induced by pulp exposure to the oral environment during 30days. After 30days, hepatic and renal tissues were obtained, and IL-17 levels were quantified by ELISA. The right hemi-jaw was used to quantify IL-17 levels by immunohistochemistry. The values obtained in parametric tests were tabulated and analyzed statistically by analysis of variance (ANOVA) and Tukey tests, and the values obtained for scores were statistically analyzed by using the Kruskal-Wallis and Dun tests. The level of significance was set at 5%. RESULTS: ED and ED-AP groups expressed significantly higher IL-17 levels in both hepatic and renal tissues (p<0.05), compared to N and N-AP groups. Apical periodontitis (AP) in ED-AP group was significantly more severe than that in N-AP group (p<0.05). Furthermore, there was a significantly larger increase in the IL 17 levels in ED-AP group compared to N group (p<0.05). CONCLUSION: Our results indicate that diabetes increases IL-17 levels in hepatic and renal tissues and also enhances IL-17 production in apical periodontitis area of rats. PMID- 28818707 TI - A biomarker of anxiety in children and adolescents: A review focusing on the error-related negativity (ERN) and anxiety across development. AB - BACKGROUND: Anxiety disorders are the most common form of psychopathology and often begin early in development. Therefore, there is interest in identifying neural biomarkers that characterize pathways leading to anxiety disorders early in the course of development. A substantial amount of work focuses on the error related negativity (ERN) as a biomarker of anxiety. While two previous reviews have focused on the relationship of the ERN and anxiety in adults, no previous review has focused on this issue in children and adolescents. RESULTS AND CONCLUSIONS: Overall, 22 studies were included in the current review. A number of patterns emerged, including: 1.) The ERN is enhanced in clinically anxious children at all ages (6-18 years old), regardless of the task used to measure the ERN. 2.) Studies focusing on anxiety symptoms and temperamental fear suggest that the relationship between the ERN and normative anxiety may change across development. 3.) The ERN can predict the onset of anxiety disorders across different developmental periods. 4.) The ERN relates to other markers of risk for anxiety (e.g., aversive startle potentiation) in children and adolescents. PMID- 28818708 TI - Non-technical skills assessment for prelicensure nursing students: An integrative review. AB - BACKGROUND: In nursing, non-technical skills are recognized as playing an important role to increase patient safety and successful clinical outcomes (Pearson and McLafferty, 2011). Non-technical skills are cognitive and social resource skills that complement technical skills and contribute to safe and efficient task performance (Flin et al., 2008). In order to effectively provide non-technical skills training, it is essential to have an instrument to measure these skills. METHODOLOGY: An online search was conducted. Articles were selected if they referred to and/or described instruments assessing non-technical skills for nurses and/or prelicensure nursing students in educational, clinical and/or simulated settings with validation evidence (inclusion criteria). RESULTS: Of the 53 articles located, 26 met the inclusion criteria. Those referred to and/or described 16 instruments with validation evidence developed to assess non technical skills in multidisciplinary teams including nurses. CONCLUSION: Although articles have shown 16 valid and reliable instruments, to our knowledge, no instrument has been published or developed and validated for the assessment of non-technical skills of only nurses in general, relevant for use in high-fidelity simulation-based training for prelicensure nursing students. Therefore, there is a need for the development of such an instrument. PMID- 28818709 TI - Blood global DNA methylation is decreased in non-severe chronic obstructive pulmonary disease (COPD) patients. AB - BACKGROUND: Alterations in global DNA methylation have been associated with oxidative stress (OS). Since chronic obstructive pulmonary disease (COPD) is characterized by increased oxidative stress we aimed to evaluate the levels of global DNA methylation in this patient group. METHODS: We assessed methylcytosine (mCyt) levels in DNA from blood collected in 43 COPD patients (29 with mild and 14 with moderate disease) and 43 age- and sex-matched healthy controls. RESULTS: DNA methylation was significantly lower in COPD patients vs. controls (4.20 +/- 0.18% mCyt vs. 4.29 +/- 0.18% mCyt, p = 0.02). Furthermore, DNA methylation in COPD patients with moderate disease was significantly lower than that in patients with mild disease (4.14 +/- 0.15% mCyt vs. 4.23 +/- 0.19% mCyt, p < 0.05). Univariate logistic regression analysis showed that lower DNA methylation levels were associated with presence of COPD (crude OR = 0.06, 95% CI 0.00 to 0.67, p = 0.023). This relationship remained significant after adjusting for several confounders (OR 0.03, 95% CI 0.00 to 0.67; p = 0.028). Receiver operating characteristics (ROC) curve analysis demonstrated the area under the curve of mCyt was 0.646, with 46.6% sensitivity and 79.1% specificity for presence of COPD. CONCLUSIONS: There were no significant correlations between methylation and OS indices. The presence and severity of COPD is associated with progressively lower DNA methylation in blood. However, this epigenetic alteration seems independent of oxidative stress. PMID- 28818710 TI - Multivariate soil fertility relationships for predicting the environmental persistence of 2,4,6-trinitrotoluene (TNT) and 1,3,5-trinitro-1,3,5 tricyclohexane (RDX) among taxonomically distinct soils. AB - After nearly a century of use in numerous munition platforms, TNT and RDX contamination has turned up largely in the environment due to ammunition manufacturing or as part of releases from low-order detonations during training activities. Although the basic knowledge governing the environmental fate of TNT and RDX are known, accurate predictions of TNT and RDX persistence in soil remain elusive, particularly given the universal heterogeneity of pedomorphic soil types. In this work, we proposed overcoming this problem by considering the environmental persistence of these munition constituents (MC) as multivariate mathematical functions over a variety of taxonomically distinct soil types, instead of a single constant or parameter of a specific absolute value. To test this idea, we conducted experiments where the disappearance kinetics of TNT and RDX were measured over a >300 h period in taxonomically distinct soils. Classical fertility-based soil measurements were log-transformed, statistically decomposed, and correlated to TNT and RDX disappearance rates (k-TNTand k-RDX) using multivariate dimension-reduction and correlation techniques. From these efforts, we generated multivariate linear functions for k parameters across different soil types based on a statistically reduced set of their chemical and physical properties: Calculations showed that the soil properties exhibited strong covariance, with a prominent latent structure emerging as the basis for relative comparisons of the samples in reduced space. Loadings describing TNT degradation were largely driven by properties associated with alkaline/calcareous soil characteristics, while the degradation of RDX was attributed to the soil organic matter content - reflective of an important soil fertility characteristic. In spite of the differing responses to the munitions, batch data suggested that the overall nutrient dynamics were consistent for each soil type, as well as readily distinguishable from the other soil types used in this study. Thus, we hypothesized that the latent structure arising from the strong covariance of full multivariate geochemical matrix describing taxonomically distinguished "soil types" may provide the means for potentially predicting complex phenomena in soils. PMID- 28818711 TI - The influence of solid retention time on IFAS-MBR systems: Assessment of nitrous oxide emission. AB - The aim of the present study was to investigate the nitrous oxide (N2O) emissions from a moving bed based Integrated Fixed Film Activated Sludge (IFAS) - membrane bioreactor (MBR) pilot plant, designed according to the University of Cape Town (UCT) layout. The experimental campaign had a duration of 110 days and was characterized by three different sludge retention time (SRT) values (infinity, 30 d and 15 d). Results highlighted that N2O concentrations decreased when the biofilm concentrations increased within the aerobic reactor. Results have shown an increase of N2O with the decrease of SRT. Specifically, an increase of N2O-N emission factor occurred with the decrease of the SRT (0.13%, 0.21% and 0.76% of influent nitrogen for SRT = infinity, SRT = 30 d and SRT = 15 d, respectively). Moreover, the MBR tank resulted the key emission source (up to 70% of the total N2O emission during SRT = infinity period) whereas the highest N2O production occurred in the anoxic reactor. Moreover, N2O concentrations measured in the permeate flow were not negligible, thus highlighting its potential detrimental contribution for the receiving water body. The role of each plant reactor as N2O N producer/consumer varies with the SRT variation, indeed the aerobic reactor was a N2O consumer at SRT = infinity and a producer at SRT = 30 d. PMID- 28818712 TI - (Non-) robustness of vulnerability assessments to climate change: An application to New Zealand. AB - Assessments of vulnerability to climate change are a key element to inform climate policy and research. Assessments based on the aggregation of indicators have a strong appeal for their simplicity but are at risk of over-simplification and uncertainty. This paper explores the non-robustness of indicators-based assessments to changes in assumptions on the degree of substitution or compensation between indicators. Our case study is a nationwide assessment for New Zealand. We found that the ranking of geographic areas is sensitive to different parameterisations of the aggregation function, that is, areas that are categorised as highly vulnerable may switch to the least vulnerable category even with respect to the same climate hazards and population groups. Policy implications from the assessments are then compromised. Though indicators-based approaches may help on identifying drivers of vulnerability, there are weak grounds to use them to recommend mitigation or adaptation decisions given the high level of uncertainty because of non-robustness. PMID- 28818713 TI - Historical human exposure to perfluoroalkyl acids in the United States and Australia reconstructed from biomonitoring data using population-based pharmacokinetic modelling. AB - Perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS) and perfluorohexanesulfonic acid (PFHxS) are found in the blood of humans and wildlife worldwide. Since the beginning of the 21st century, a downward trend in the human body burden, especially for PFOS and PFOA, has been observed while there is no clear temporal trend in wildlife. The inconsistency between the concentration decline in human serum and in wildlife could be indicative of a historical exposure pathway for humans linked to consumer products that has been reduced or eliminated. In this study, we reconstruct the past human exposure trends in two different regions, USA and Australia, by inferring the historical intake from cross-sectional biomonitoring data of PFOS, PFOA and PFHxS using a population-based pharmacokinetic model. For PFOS in the USA, the reconstructed daily intake peaked at 4.5ng/kg-bw/day between 1988 and 1999 while in Australia it peaked at 4.0ng/kg-bw/day between 1984 and 1996. For PFOA in the USA and Australia, the peak reconstructed daily intake was 1.1ng/kg-bw/day in 1995 and 3.6ng/kg-bw/day in 1992, respectively, and started to decline in 2000 and 1995, respectively. The model could not be satisfactorily fitted to the biomonitoring data for PFHxS within reasonable boundaries for its intrinsic elimination half life, and thus reconstructing intakes of PFHxS was not possible. Our results indicate that humans experienced similar exposure levels and trends to PFOS and PFOA in the USA and Australia. Our findings support the hypothesis that near field consumer product exposure pathways were likely dominant prior to the phase out in industrialized countries. The intrinsic elimination half-life, which represents elimination processes that are common for all humans, and elimination processes unique to women (i.e., menstruation, cord-blood transfer and breastfeeding) were also investigated. The intrinsic elimination half-lives for PFOS and PFOA derived from model fitting for men were 3.8 and 2.4years, respectively, for the USA, and 4.9 and 2years respectively for Australia. Our results show that menstruation is a depuration pathway for PFOA for women, similarly but to a lesser extent compared to previous reports for PFOS. However menstruation, cord-blood transfer and breastfeeding together do not fully explain the apparently more rapid elimination of PFOA and PFOS by women compared to men; the intrinsic elimination half-lives in women were up to 13% lower for PFOS and up to 12% lower for PFOA compared to the corresponding half-lives in men. PMID- 28818714 TI - The role of physical activity in improving physical fitness in children with intellectual and developmental disabilities. AB - BACKGROUND: One in three children in North America are considered overweight or obese. Children with intellectual and developmental disabilities (IDD) are at an increased risk for obesity than their typically developing peers. Decreased physical activity (PA) and low physical fitness may be contributing factors to this rise in obesity. AIM: Because children with IDD are at an increased risk of diseases related to inactivity, it is important to improve health-related physical fitness to complete activities of daily living and improve health. METHODS AND PROCEDURES: The focus of this research is on improving the performance of physical fitness components through physical activity programming among a group of children with IDD, ages 7-12 years. The Brockport Physical Fitness Test was used assess levels of physical fitness of 35 children with IDD (25 boys, 10 girls) before and after participation in a 10-week program. OUTCOMES AND RESULTS: The results of paired sampled t-tests showed participation in 15-h PA program can significantly increase aerobic capacity and muscular strength and endurance in children with IDD. CONCLUSIONS AND IMPLICATIONS: This study is aimed at understanding the role of PA in helping children with IDD to develop the fitness capacities essential to participation in a wide variety of activities. PMID- 28818715 TI - Screening for single nucleotide polymorphisms in highly degraded DNA by using the amplified fragment length polymorphism technique. AB - Short tandem repeat (STR) analysis is generally used for human identification of forensic samples; however, standard STR analysis sometimes fails to generate full profiles since DNA is frequently degraded by various environmental factors. Recently, single nucleotide polymorphism (SNP) analysis has attracted attention for human identification since the shorter amplicons are better suited for degraded samples. Though various SNP loci are used for analysis of degraded samples, it is unclear which ones are more appropriate. To identify SNPs that were resistant to degradation, we artificially degraded DNA obtained from the buccal swabs of six volunteers and the K562 cell line by heat treatment. Subsequently, the amplified fragment length polymorphism (AFLP) technique was used for SNP screening. We focused on the AFLP bands detected in both the heat treated and untreated samples, and DNA extracted from these bands was directly sequenced. DNA degradation increased as the duration of heat treatment increased, and no STR profiles could be generated after 6h of heat treatment. When the AFLP band patterns were compared between 6h heat-treated and untreated samples, eight common bands were detected. The sequences of the DNA fragments of these common bands had higher adenine-thymine (A-T) content and included 17 SNPs. The SNPs detected in the heat-treated and untreated samples were considered to be resistant to degradation. Although there was a little information available in databases regarding the nine SNPs identified in this study, this study shows that some of these SNPs might be useful for human identification of extremely degraded DNA. PMID- 28818716 TI - Positron emission tomography (PET) imaging of nicotine-induced dopamine release in squirrel monkeys using [18F]Fallypride. AB - BACKGROUND: Nicotine, the principal psychoactive tobacco constituent, is thought to produce its reinforcing effects via actions within the mesolimbic dopamine (DA) system. The objective of the current study was to examine the effect of nicotine on DA D2/D3 receptor availability in the nonhuman primate brain with the use of the radioligand [18F]fallypride and positron emission tomography (PET). METHODS: Ten adult male squirrel monkeys were used in the current study. Each subject underwent two PET scans, one with an injection (IV) of saline and subsequently one with an injection of nicotine (0.032mg/kg). The DA D2/D3 antagonist, [18F]fallypride, was delivered IV at the beginning of each scan, and nicotine or saline was delivered at 45min into the scan. Regions of interest (ROI) were drawn on specific brain regions and these were used to quantify standard uptake values (SUVs). The SUV is defined as the average concentration of radioactivity in the ROI x body weight/injected dose. Using the cerebellum as a reference region, SUV ratios (SUVROI/SUVcerebellum) were calculated to compare saline and nicotine effects in each ROI. RESULTS: Two-way repeated ANOVA revealed a significant decrease of SUV ratios in both striatal and extrastriatal regions following an injection of nicotine during the PET scans. CONCLUSIONS: Like other drugs of abuse, these results indicate that nicotine administration may produce DA release, as suggested by the decrease in [18F]fallypride signal in striatal regions. These findings from a nonhuman primate model provide further evidence that the mesolimbic DA system is affected by the use of products that contain nicotine. PMID- 28818717 TI - The effect of post-traumatic stress disorder on the risk of developing prescription opioid use disorder: Results from the National Epidemiologic Survey on Alcohol and Related Conditions III. AB - OBJECTIVE: To evaluate the effect of baseline post-traumatic stress disorder (PTSD) and each symptoms cluster on the risk of developing opioid use disorder (OUD) in those exposed to opioid painkillers and to assess the effect of comorbid PTSD and OUD on functioning, OUD severity, and treatment seeking compared with individuals with OUD only. METHODS: We obtained data from 4025 individuals exposed to opioid painkillers from the National Epidemiologic Survey on Alcohol and Related Conditions III. We matched individuals with baseline PTSD with individuals without PTSD on demographics, developmental background, family history, personalities, and exposure to stressful life events with propensity score methodology. We controlled for clinical diagnoses and other risk factors that may have occurred after PTSD onset. Quality of life was assessed with the SF 12; the number of diagnostic criteria met indicated OUD severity. RESULTS: Baseline PTSD predicted OUD after controlling for matching variables and other risk factors, including baseline mood/anxiety disorders and other substance use disorders (odds ratio[OR]: 1.58; 95% confidence interval[CI]: 1.14-2.17; p=0.02). Among individuals with PTSD, arousal/reactivity cluster predicted OUD. Individuals with comorbid PTSD and OUD had lower mean scores on the SF-12 scale and greater severity of OUD than individuals with OUD. There were no differences in help-seeking. CONCLUSION: Baseline PTSD increases the risk of developing OUD after exposure to opioid painkillers. Clinicians should screen for PTSD diagnosis and arousal/reactivity symptoms prior to prescribing painkillers. Integrated treatments are strongly recommended for patients with this dual diagnosis. PMID- 28818718 TI - Template selection and refinement considerations for modelling aminergic GPCR ligand complexes. AB - G protein-coupled receptors (GPCRs) are important targets for development of drugs for the treatment of many diseases. However, crystal structures are available for only a small fraction of these membrane bound proteins. Accurate homology models will provide opportunities for effective drug design targeting GPCRs. Recently, several serotonin receptor crystal structures were solved and needed to be evaluated as potential templates. In the first part of this work different measures of similarity in template selection were explored and methods for homology modelling, docking and refinement of aminergic GPCR-ligand complexes were developed and evaluated by comparing models of the D3-R/eticlopride complex with the crystal structure. Homology models of the three alpha1 adrenergic receptor subtypes and of a serotonin receptor subtype were then constructed using these methods These models were evaluated by docking a range of antagonists into them. PMID- 28818719 TI - Green approach for one-pot synthesis of silver nanorod using cellulose nanocrystal and their cytotoxicity and antibacterial assessment. AB - Herein, this research addresses an innovative approach for one-pot synthesis of highly stabilized silver nanorods in powder form at concentration as high as feasible to be proposed in large-scale production via cellulose nanocrystals (CNC). For the first time, CNC without any surface modification in the presence of alkali is acting as both reducing and stabilizing agent for assembling of Ag nanorods. Extraction of CNC from cotton is carried out as per to acid hydrolysis technique. Thorough assessments of Ag nanorods formation, structural and morphological characteristics of Ag nanorods were investigated by making use of UV-vis spectroscopy, TEM, DLS, AFM and X-ray diffraction (XRD) analysis. Also, the antibacterial activity and cytotoxicity of Ag nanorod were investigated. Research outputs signify that, Ag nanorods has been successfully prepared through an effectively approach by virtue of the textural feature of CNC as a mediator. Results revealed the great tendency of CNC toward reducing and stabilizing the as formed Ag nanorods even at high concentration. Results also demonstrated that Ag nanorods have not merely remarkably antibacterial activity towards Gram-positive and Gram-negative bacteria, but safe for using in human life, which exhibited no effect on eukaryotic cells. PMID- 28818720 TI - Fabrication of pure chitosan nanofibrous membranes as effective absorbent for dye removal. AB - The pure chitosan nanofibrous membranes with average fiber diameter of 86+/-18, 114+/-17,164+/-28nm were successfully prepared by electrospinning. Batch adsorption experiments of using chitosan nanofibrous membranes as adsorbent to remove acid blue-113 were conducted. The adsorption capacity of 1377mg/g was achieved by the chitosan nanofibrous membrane with average fiber diameter of 86nm, which was superior to the chitosan microscale sample with the adsorption capacity of 412mg/g. The average fiber diameter and the corresponding equilibrium adsorption capacity of pure chitosan nanofibrous membranes fitted well with linear relationship in our test range. The results also showed that the adsorption followed with pseudo second-order kinetics model, and the adsorption behavior was accordance with the Langmuir isotherm model. The pure chitosan nanofibrous membrane showed promise and feasibility as an effective adsorbent for dye removal. PMID- 28818721 TI - Immunomodulatory effects of herbal formula of astragalus polysaccharide (APS) and polysaccharopeptide (PSP) in mice with lung cancer. AB - OBJECTIVE: This study is to investigate the immunomodulatory effects of the herbal formula of astragalus polysaccharide (APS) and polysaccharopeptide (PSP) in mouse models of immunosuppression and lung cancer. METHODS: Immune parameters were recorded for these model mice. Peripheral white blood cells (WBC) were detected with the automatic blood cell analyzer. Spleen and thymus indices, and tumor inhibition ratio were obtained. Percentage of peripheral blood CD4+ and CD8+ T lymphocytes were detected by flow cytometry. Serum levels of Th1 (IL-2, TNF, and IFN-gamma), Th2 (IL-4, IL-6, and IL-10), and Th17 (IL-17A) were detected with the BD cytometric bead array (CBA) mouseTh1/Th2/Th17 cytokine kit. RESULTS: Compared with the NS group, the PSP and APS herbal formula significantly improved the WBC, thymus index, spleen index, CD4+/CD8+ ratio, TNF, IFN-gamma, IL-2, andIL 17Ainimmunosuppressivemice and lung cancer mice (P<0. 05). On the contrary, IL-10 was relatively low in the PSP+APS herbal formula group (P<0. 05). Besides, the PSP+APS herbal formula group induced comparable tumor inhibiting effect with the AMD group (23.3% and 24.1%, respectively). CONCLUSION: The PSP+APS herbal formula have immunomodulatory effects and anti-tumor activity in mice with of lung cancer. PMID- 28818722 TI - Interaction of manganese nanoparticle with cytochrome c: A multi-spectroscopic study. AB - In this paper, the conformational changes of cytochrome c (cyt c) upon interaction with manganese nanoparticle (Mn-NP) were examined using dynamic light scattering (DLS), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), zeta potential, fluorescence spectroscopy, and circular dichroism (CD) spectroscopy methods. DLS and TEM analysis exhibited the structure of Mn-NP was less than 50nm. FTIR bands were similar to those reported for Mn-NP. Zeta potential measurements showed positive charge distribution for Mn NP (4.71+/-0.71mV) at pH 7.8. It was revealed that the mechanism of fluorescence quenching incorporated both dynamic and static quenching. Also, binding site and binding constant increased as the temperature is raised. The positive sign of DeltaH degrees and DeltaS degrees suggested that hydrophobic forces are indicative forces in the interaction between cyt c and Mn-NP. Synchronous fluorescence spectra revealed that the conformation of protein was not perturbed around tryptophan (Trp) and tyrosine (Tyr) residues. CD analysis suggested that there was a conformational change at tertiary structure levels of cyt c in the vicinity of phenylalanine (Phe) residues, while the secondary structure of protein was not altered. This study facilitates a deeper insight on the interaction mechanisms between NPs and biological macromolecules. PMID- 28818723 TI - Chitosan: A macromolecule as green corrosion inhibitor for mild steel in sulfamic acid useful for sugar industry. AB - The present investigation aims at investigation of low cost nontoxic carbohydrate biopolymer chitosan as corrosion inhibitor alone and in combination with KI for mild steel in 1M sulfamic acid medium using gravimetric, electrochemical and surface analysis techniques. It is found that chitosan alone exhibits inhibition efficiency of 73.8% at 200ppm concentration. However, in combination with KI (5ppm), it gave more than 90% inhibition efficiency. The significant increase in the inhibition performance of chitosan has been explained by the synergistic mechanism. The results of Potentiodynamic polarization study shows that chitosan and its blend with KI decreases both anodic and cathodic reactions occurring at mild steel surface in 1M sulfamic acid medium by blocking active sites of the metal and acts as mixed type inhibitor. EIS study reveals that the polarization resistance increases with increase in the concentration of inhibitors which increases charge transfer resistance across the metal/solution interface. The adsorption of chitosan followed the Langmuir adsorption isotherm. The formation of inhibitor film on metal surface was supported by scanning electron microscopy (SEM) and atomic force microscopy (AFM) surface studies. PMID- 28818724 TI - Enzyme sensitive smart inulin-dehydropeptide conjugate self-assembles into nanostructures useful for targeted delivery of ornidazole. AB - Molecular self-assembly of biodegradable amphiphilic polymers allows rational design of biocompatible nanomaterials for drug delivery. Use of substituted polysaccharides for such applications offers the ease of design and synthesis, and provides higher biofunctionality and biocompatibility to nanomaterials. The present work focuses on the synthesis, characterization and potential biomedical applications of self-assembled polysaccharide-based materials. We demonstrated that the synthesized amphiphilic inulin self-assembled in aqueous medium into nanostructures with average size in the range of 146-486nm and encapsulated hydrophobic therapeutic molecule, ornidazole. Hydrophophic dehydropeptide was conjugated with inulin via a biocompatible ester linkage. Dehydrophenylalanine, an unusual amino acid, was incorporated in the peptide to make it stable at a broader range of pH as well as against proteases. The resulting core-shell type of nanostructures could encapsulate ornidazole in the hydrophobic core and released it in a controlled fashion. By taking the advantage of inulin, which gets degraded in the colon by colonic bacteria, the effect of enzyme, inulinase, present in the microflora of the large intestine, on inulin-peptide degradation followed by drug release has been studied. Altogether, small peptide conjugated to inulin offers novel scaffold for the future design of nanostructures with potential applications in the field of targeted drug delivery. PMID- 28818725 TI - Optimized extraction and characterization of pectin from jackfruit (Artocarpus integer) wastes using response surface methodology. AB - The present study was initiated to experimentally optimize the conditions for extraction using Central Composite Design. The optimum temperature and time for the extraction of pectin from Jackfruit wastes using oxalic acid were found to be 90 degrees C and 60min respectively. The yield of pectin under these optimum conditions was 38.42%. Extraction time and temperature showed a significant (p<0.05) effect on the pectin yield. This agreed well with the experimental result of 39.05+/-0.59g/g of pectin, under similar conditions. Experimental studies on a large scale using 10kg of jackfruit wastes, gave a yield of 38% pectin. Pectin isolated from Jackfruit wastes can be classified as low methoxyl pectin with promising applications in low sugar products. PMID- 28818726 TI - Identification of functional interactome of a key cell division regulatory protein CedA of E.coli. AB - Cell division is compromised in DnaAcos mutant Escherichia coli cells that results in filamentous cell morphology. This is countered by over-expression of CedA protein that induces cytokinesis and thus, regular cell morphology is regained; however via an unknown mechanism. To understand the process systematically, exact role of CedA should be deciphered. Protein interactions are crucial for functional organization of a cell and their identification helps in revealing exact function(s) of a protein and its binding partners. Thus, this study was intended to identify CedA binding proteins (CBPs) to gain more clues of CedA function. We isolated CBPs by pull down assay using purified recombinant CedA and identified nine CBPs by mass spectrometric analysis (MALDI-TOF MS and LC MS/MS), viz. PDHA1, RL2, DNAK, LPP, RPOB, G6PD, GLMS, RL3 and YBCJ. Based on CBPs identified, we hypothesize that CedA plays a crucial and multifaceted role in cell cycle regulation and specific pathways in which CedA participates may include transcription and energy metabolism. However, further validation through in-vitro and in-vivo experiments is necessary. In conclusion, identification of CBPs may help us in deciphering mechanism of CedA mediated cell division during chromosomal DNA over-replication. PMID- 28818727 TI - Neuroprotective effects of plant polysaccharides: A review of the mechanisms. AB - Polysaccharides are an important class of phytochemicals, and many studies have demonstrated their beneficial effects in the context of a number of pathologies including neurological disorders. Numerous studies have indicated that polysaccharides exhibit neuroprotection through a variety of mechanisms. We performed a comprehensive review of the literature to consolidate studies for the period 2010-2016, and assessed the protection mechanisms on brain function of polysaccharide-rich extracts from natural sources. Studies were identified by conducting electronic searches on PubMed, Web of Science and Google Scholar. Reference lists of articles were also reviewed for additional relevant studies. Only articles published in English were included in this review. In total, 21 types of polysaccharides from 16 kinds of plants sources have shown neuroprotective properties. In vivo and in vitro experiments have demonstrated the ability of polysaccharide-rich extracts to provide neuroprotective effects through promotion of neurite outgrowth, and NF-kappaB, PI3K/Akt, MAPK, Nrf2/HO-1 signaling pathways. This review will give a better understanding of the neurotrophic effects of polysaccharides and the concomitant modulations of signaling pathways. It is useful for designing more effective agents for management of neurological diseases. PMID- 28818728 TI - Fractionation of lignin macromolecules by sequential organic solvents systems and their characterization for further valuable applications. AB - Lignin solvent fractionation is one of the promising methods for homogenizing and utilizing lignin commercially. In this work, fractionation characteristics of two lignin fractions were compared to investigate the potential of utilization of fractionated lignin. Two lignins [milled wood lignin(MWL) and organosolv lignin(OL) from yellow poplar] were sequentially fractionated with ethyl acetate(F1), 2-butanone(F2), methanol(F3), acetone(F4), and dioxane/water(F5). Yields of five MWL fractions F1 to F5 were 11.7%, 11.7%, 15.3%, 11.8%, and 49.6%, respectively, and yields of OL fractions were 26.2%, 26.1%, 18.7%, 3.7% and 25.4%. Average molecular weight of F1 (lowest molecular weight fraction) ranged from 1000 to 2400Da, whereas that of F5 (highest molecular weight fraction) was above 10000Da. According to functional group analysis, contents of phenolic hydroxyl groups and methoxyl groups decreased gradually with increasing molecular weight. DFRC analysis was performed to investigate the frequency of beta-O-4 linkages and it revealed that the higher molecular weight fractions yielded larger amounts of DFRC monomers, indicating that those fractions more frequently contain aryl ether linkages. TG/DTG showed that the low molecular weight fractions generally have lower initial thermal stability. Tg of the fractions ranged from 126 degrees C to 156 degrees C, increasing as the molecular weight of the lignin fraction increased. PMID- 28818729 TI - Characterization of citrus pectin films integrated with clove bud essential oil: Physical, thermal, barrier, antioxidant and antibacterial properties. AB - The increasing demand for bio-based materials to be used in food packaging has stimulated the development of novel, environmentally-friendly edible films. Antimicrobial films were developed by incorporating different levels of clove bud essential oil (0.5%, 1.0%, and 1.5%) into the citrus pectin in order to modify the functional properties of the films. Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry analysis (DSC) and X-ray diffraction (XRD) were performed, together with the determination of physical, optical, mechanical, antioxidant and antimicrobial properties of pectin emulsified films. The inclusion of oil significantly enhanced the water barrier properties of the films. Addition of oil leads to more opaque films with relatively heterogeneous microstructure, resulting in an increase in film opacity. The composite films were more resistant to breakage and more flexible than the control films. Differential scanning calorimetry (DSC) demonstrated that films incorporating CEO exhibited improved heat stability with slightly higher degradation temperature, compared with control films. The inhibitory effect of pectin films with CEO was also evaluated on three common foodborne bacteria. These results revealed that clove oil has a good potential to be incorporated into citrus pectin to make antimicrobial edible films or coatings for various food applications. PMID- 28818730 TI - Enterohepatic fistula in a Crohn's disease patient: A case report. AB - INTRODUCTION: Fistulous tracts are a hallmark of Crohn's Disease. However, solid organ to intestinal fistulas are rare with previously few case reports of colosplenic fistulas and one case report of an enterohepatic fistula. PRESENTATION OF CASE: We review the available literature and present the first case report of an enterohepatic fistula in a female with Crohn's Disease to be treated operatively. The patient did well postoperatively with complete resolution of her fistula. DISCUSSION: Crohn's Disease is an inflammatory bowel disease that can present with fistulas. However, a fistula between the liver and bowel is exceedingly rare with only one previous case report. This is the first report of an enteroheptic fistula that has been managed successfully with an operation. CONCLUSION: Not all enteroenteric fistulas are apparent preoperatively. When discovered, laparoscopic enterohepatic fistula takedown is feasible for this rare disease process manifestation. PMID- 28818731 TI - Association between severities of striae gravidarum and Obstetric Anal Sphincter Injuries (OASIS). AB - OBJECTIVES: to examine the association between the severities of Striae Gravidarum (SG) and Obstetric Anal Sphincter Injuries (OASIS) and to measure the symptoms regarding urinary incontinence, fecal/flatus incontinence, and dyspareunia, at 6 and 12 months postpartum. DESIGN: this is a cohort study. SETTING: four university teaching medical centers in Israel, two in the north and two in the center of the country. PARTICIPANTS: women with OASIS were interviewed and assessed for SG. OASIS was divided into 4 groups: 3A, 3B, 3C and 4. Inclusion criteria were:OASIS diagnosis, non-instrumental vaginal childbirth, birth between 37 and 42 gestational weeks, singleton newborn, neonatal birth weight of Severity scoring of SG severity scoring, using Atwal's Numerical Scoring System,observed 4 body sites; Abdomen, Breasts, Hips, and Buttocks., Total severity score (TSS) for all sites range between 0 and 24 and categorized: 0-3: no SG (NSG) and 4 and over: SG. The Pelvic Floor Symptom Bother Questionnaire (PFBQ),a validated, structured questionnaire, was used for the 6 and 12 month follow-up assessments, with nine items regarding pelvic floor dysfunction (urinary and bowel impairment uterine prolapse and sexual function). MEASUREMENTS AND FINDINGS: eighty women who had OASIS were enlisted, interviewed and assessed for SG. The average score for women with some SG was 6.10 (SD = 4.12). There were 58 (72.5%) women with OASIS level 3A; 12 (15%) had 3B; 4 (5.0%) had 3C and 6 (7.5%) had 4th degree anal injuries, respectively. Forty two (52.5%) of the women had SG and 38 (47.5%) had no SG. There was no association between SG severity and OASIS (3A, 3B, 3C+4th) chi2 (6) = 8.4014; p = 0.2. As there were only 10 women with OASIS of 3C and 4, we re-analyzed the association between SG severity and OASIS severity of 3A and 3B. There was a significant association between SG severity and OASIS severity (3A, 3B) chi2 (3) = 9.306; p = 0.025. ADDITIONAL FINDINGS: women with SG were younger (mean = 26.74, SD = 3.57) than women without SG (mean = 29.29, SD = 4.40) (t(78) = 2.86, p = .005). Three symptoms had a significant reduction in the bother degree between 6 and 12 months: urinary incontinence (p = 0.017), flatus incontinence (p = 0.031) and sexuality (p = 0.016). KEY CONCLUSIONS: the innovation of this research is the association between SG severity and OASIS severity (3A, 3B), added information regarding OASIS risk factors. PMID- 28818732 TI - Family factors and parenting in Ukraine. AB - The present study aimed to estimate the use of positive and negative parenting practices in Ukraine and explore relationships between parenting practices, intimate partner violence (IPV), alcohol use, and sociodemographics. Parents of children (N=320) ages 9-16 from three Ukrainian regions answered questions from the Alabama Parenting Questionnaire (APQ), the Revised Conflict Tactics Scales (CTS-R), Family Adaptability and Cohesion Evaluation Scale (FACES), and the Alcohol Use Section of the Drinking and Drug History and Current Use Patterns questionnaire. Ukrainian parents who reported lower use of alcohol, balanced family functioning and lower intimate partner violence were more likely to use positive parenting and less likely to use negative parenting practices. Parents with lower education were more likely to use negative parenting practices. Furthermore, alcohol use, IPV, parent education and higher family income were significantly and indirectly related with positive and negative parenting scores. The model explained 61% of variance in the positive parenting, 67% in the negative parenting. PMID- 28818734 TI - The predictors of perceived social support among former foster youth. AB - Based on a 5-wave panel survey of 732 foster youth, the current study examined the respective relationships between foster youths' individual characteristics, youths' social connections with individuals and formal institutions, and the development of perceived social support across the transition to adulthood. Several youth characteristics - including self-reported delinquency and attachment insecurity - were found to be statistically significantly associated with perceived social support. Attachment insecurity also appeared to mediate the relationships between social support and several other youth-level characteristics, including prior placement disruptions and placement with relatives. Social connections with different types of individuals - including caregivers, relatives, natural mentors, and romantic partners - were found to be associated with additive increases in perceived social support. However, some types of connections (e.g., romantic partners, natural mentors) appeared to be associated with much larger increases in social support than other connections (e.g., school or employment). Collectively, the findings help inform agencies' efforts to bolster foster youths' social connections as they transition to adulthood. PMID- 28818733 TI - Effects of childhood trauma exposure and cortisol levels on cognitive functioning among breast cancer survivors. AB - Cognitive functioning difficultiesin breast cancer patients receiving chemotherapy are common, but not all women experience these impairments. Exposure to childhood trauma may impair cognitive functioning following chemotherapy, and these impairments may be mediated by dysregulation of hypothalamic-pituitary adrenal (HPA) axis function and cortisol slope. This study evaluated the association between childhood trauma exposure, cortisol, and cognition in a sample of breast cancer survivors. 56 women completed measures of trauma exposure (the Traumatic Events Survey), salivary cortisol, and self-reported cognitive functioning (the Functional Assessment of Cancer Therapy - Cognitive). We examined correlations between childhood trauma exposure and cognitive functioning, then used linear regression to control for factors associated with cognition (age, education, time since chemotherapy, depression, anxiety, and insomnia), and the MacArthur approach to test whether cortisol levels mediated the relationship between trauma and cognitive functioning. 57.1% of the sample had experienced at least one traumatic event in childhood, with 19.6% of the sample witnessing a serious injury, 17.9% experiencing physical abuse, and 14.3% experiencing sexual abuse. Childhood trauma exposure and cognitive functioning were moderately associated (r=-0.29). This association remained even when controlling for other factors associated with cognition; the final model explained 47% of the variance in cognitive functioning. The association between childhood trauma and cognitive functioning was mediated by steeper cortisol slope (partial r=0.35, p=0.02). Childhood trauma exposure is associated with self reported cognitive functioning among breast cancer survivors and is mediated by cortisol dysregulation. Trauma should be considered, among other factors, in programs aiming to address cognition in this population. PMID- 28818735 TI - Prospective assessment of social network quality among depressed mothers treated with brief psychotherapy: The Social Network Quality (SNQ) scales. AB - OBJECTIVE: Social relationships play important roles in emotional health, and are common targets of psychotherapeutic interventions. To better evaluate social relationship structure and function in the context of psychotherapy trials, this study introduces and psychometrically evaluates the Social Network Quality (SNQ) scales, which supplement the Social Network Index (SNI). The original SNI evaluates social network structure (i.e., extent of participation in diverse social roles and number of social relationships). The SNQ adds two social network quality scales evaluating levels of: (a) positivity/support, and (b) negativity/stress, within and across specific social roles. METHOD: Participants included 168 depressed mothers of psychiatrically-ill children participating in a psychotherapy treatment trial utilizing interpersonal therapy (IPT) and brief supportive therapy (BSP). The SNI, SNQ, and measures of social functioning and psychopathology were collected at baseline and at 3-month intervals over a one year period. RESULTS: SNQ scores showed meaningful concurrent relationships with measures of social support and interpersonal distress, as well as incremental utility in explaining variance in relationship and mood outcomes above and beyond the SNI. SNQ scores also detected global and relationship-specific changes in social relationship quality following psychotherapy treatment. CONCLUSION: This report demonstrates that SNQ scales reliably assess psychotherapy-induced changes in relationship quality. PMID- 28818737 TI - Genome-wide DNA methylation profiling of articular cartilage reveals significant epigenetic alterations in Kashin-Beck disease and osteoarthritis. AB - OBJECTIVE: To determine genome-wide DNA methylation profiles of knee cartilage from patients with Kashin-Beck disease (KBD) and osteoarthritis (OA). METHOD: Knee cartilage was collected from 14 grade III KBD patients, 5 primary OA patients and 13 healthy subjects. The genome-wide methylation profiles of 5 KBD cartilage, 5 OA cartilage and 5 normal cartilage were determined by Illumina HumanMethylation450 array. Illumina Methylation Analyzer package was employed for identifying differentially methylated CpG sites. Functional annotation and enrichment analysis of differentially methylated genes (DMG) were conducted using GeneRIF database, Ingenuity Pathway Analysis (IPA) and The Database for Annotation, Visualization and Integrated Discovery (DAVID). Mass spectrometry (MS) and immunohistochemistry (IHC) were conducted to validate the functional relevance of identified KBD associated gene. RESULTS: We identified a total of 1212 differentially methylated CpG sites in KBD vs Normal, annotated to 264 hypermethylated and 368 hypomethylated genes. Comparing the DNA methylation profiles of KBD vs Normal and OA vs Normal detected overlap of 367 differentially methylated CpG sites (annotated to 182 genes) as well as 845 KBD-specific differentially methylated CpG sites (annotated to 471 unique genes). MS and IHC confirmed the hypermethylation status and decreased protein expression of HAPLN1 gene in KBD cartilage. CONCLUSION: Our data implicate epigenetic dysregulation of a host of genes in KBD and OA. Furthermore, we observed common causal epigenetic changes shared by KBD and OA. PMID- 28818736 TI - Co-option of endogenous viral sequences for host cell function. AB - Eukaryotic genomes are littered with sequences of diverse viral origins, termed endogenous viral elements (EVEs). Here we used examples primarily drawn from mammalian endogenous retroviruses to document how the influx of EVEs has provided a source of prefabricated coding and regulatory sequences that were formerly utilized for viral infection and replication, but have been occasionally repurposed for cellular function. While EVE co-option has benefited a variety of host biological functions, there appears to be a disproportionate contribution to immunity and antiviral defense. The mammalian embryo and placenta offer opportunistic routes of viral transmission to the next host generation and as such they represent hotbeds for EVE cooption. Based on these observations, we propose that EVE cooption is initially driven as a mean to mitigate conflicts between host and viruses, which in turn acts as a stepping-stone toward the evolution of cellular innovations serving host physiology and development. PMID- 28818738 TI - Walking during the encoding of described environments enhances a heading independent spatial representation. AB - Previous studies demonstrated that physical movement enhanced spatial updating in described environments. However, those movements were executed only after the encoding of the environment, minimally affecting the development of the spatial representation. Thus, we investigated whether and how participants could benefit from the execution of physical movement during the encoding of described environments, in terms of enhanced spatial updating. Using the judgement of relative directions task, we compared the effects of walking both during and after the description of the environment, and walking only after the description on spatial updating. Spatial updating was evaluated in terms of accuracy and response times in different headings. We found that the distribution of response times across Headings seemed not to be related to the physical movement executed, whereas the distribution of accuracy scores seemed to significantly change with the action executed. Indeed, when no movement occurred during the encoding of the environment, a preference for the learning heading was found, which did not emerge when walking during encoding occurred. Therefore, the results seem to suggest that physical movement during encoding supports the development of a heading-independent representation of described environments, reducing the anchoring for a preferred heading in favor of a global representation. PMID- 28818739 TI - Dynamic lexical decisions in French: Evidence for a feedback inconsistency effect. PMID- 28818740 TI - Assessment of genotoxicity of four volatile pollutants from cigarette smoke based on the in vitro gammaH2AX assay using high content screening. AB - To evaluate the genotoxic effects of formaldehyde, acetaldehyde, acrolein and benzene on A549 cells, the in vitro gammaH2AX assay was used in combination with high content screening (HCS) technology. All aldehydes showed a significant genotoxicity in a dose/time-dependent effect on the induction of gammaH2AX. Benzene failed to show a significant genotoxicity based on the gammaH2AX assay. However, hydroquinone (one of metabolites of benzene) showed a significant genotoxicity in vitro. Based on the dose-response of gammaH2AX and Hill model, the ability to induce DNA double-strand break can be evaluated as acrolein>formaldehyde>acetaldehyde>benzene. The slow DNA damage/repair mechanism may be more important than the fast one for aldehydes based on time-course of gammaH2AX and two-component model. Overall, all toxicants were genotoxic in a dose- or time-dependent manner based on the in vitro gammaH2AX HCS assay, and acrolein had a strong potential to induce DNA damage followed by formaldehyde, acetaldehyde and benzene in sequence. PMID- 28818741 TI - Identification of sterols from the soft coral Dendronephthya gigantea and their anti-inflammatory potential. AB - Exploration of anti-inflammatory phytochemicals has received tremendous attention worldwide owing to the rapid increase in inflammatory diseases. Current study reveals the identification of eight 3beta-hydroxy-Delta5-steroidal congeners from a nonpolar column fraction of the ethanol solubles from the soft coral Dendronephthya gigantea collected from Jeju Island South Korea, using GC-MS/MS analysis. The sterol-rich fraction (DGEH21) showed a significant anti inflammatory activity as exhibited by the inhibition of NO production (IC50 4.33+/-0.50MUg/mL) and PGE2 production in LPS-stimulated RAW 264.7 macrophages. It also suppressed the expression levels of proinflammatory cytokines, TNF-alpha, IL-1beta, and IL-6 in a dose-dependent manner. Furthermore, DGEH21 effectively downregulated the expression levels of iNOS, and COX-2 and reduced NO and ROS production as well as cell death in LPS-stimulated in-vivo zebrafish embryo model. However, DGEH21 at relatively high concentrations indicated cytotoxicity in both RAW cells and zebrafish embryos with RAW cell viability being nearly 80% after treatment with 25MUg/mL DGEH21. This study highlights the synergistic anti inflammatory activity of several steroids found in D. gigantea. Their actions may be useful in the development of anti-inflammatory cosmeceuticals, pharmaceutical agents, and other consumer products. PMID- 28818742 TI - CITRUS, cervical cancer screening trial by randomization of HPV testing intervention for upcoming screening: Design, methods and baseline data of 18,471 women. AB - BACKGROUND: To assess the efficacy of screening with concurrent liquid-based cytology and human papillomavirus (HPV) testing for primary cervical cancer screening, we initiated a randomized trial entitled CervIcal cancer screening Trial by Randomization of HPV testing intervention for Upcoming Screening (CITRUS). METHODS: Between June 2013 and March 2015, women aged 30-64 years of age who participated in a regular cervical cancer screening program (every 2 years) were invited to enrollment of our study. After giving their informed consent, 18,402 women were randomly assigned to liquid-based cytology as the control group (n=9145) or to HPV DNA testing with liquid-based cytology as the intervention group (n=9257). We subsequently compared the incidence rate of cervical intraepithelial neoplasia (CIN), the rate of false positive tests and the rate of overdiagnosis, as well as assessing the risks and benefits of receiving screening for women in both groups. The primary outcome of our study was the incidence of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) during the study period of around 6 years. RESULTS: In the control group, 97.9% of women were NILM, and 2.06% ASC-US or worse (ASC-US+). In the intervention group, 87.13% of women were NILM/HPV negative, 0.72% ASC-US/HPV negative, 10.34% NILM/HPV positive, 0.69% ASC-US/HPV positive, 0.90% worse than ASC-US/either HPV. Positive HPV testing was not linearly related to age in our study. CONCLUSIONS: Insights from CITRUS will provide future prospects for cervical cancer screening focused on the use of HPV testing in Japan. CLINICAL TRIAL REGISTRATION NUMBER: NCT01895517, UMIN000010843, TRIUC1312. PMID- 28818743 TI - Learning and combining image neighborhoods using random forests for neonatal brain disease classification. AB - It is challenging to characterize and classify normal and abnormal brain development during early childhood. To reduce the complexity of heterogeneous data population, manifold learning techniques are increasingly applied, which find a low-dimensional representation of the data, while preserving all relevant information. The neighborhood definition used for constructing manifold representations of the population is crucial for preserving the similarity structure and it is highly application dependent. The recently proposed neighborhood approximation forests learn a neighborhood structure in a dataset based on a user-defined distance. We propose a framework to learn multiple pairwise distances in a population of brain images and to combine them in an unsupervised manner optimally in a manifold learning step. Unlike other methods that only use a univariate distance measure, our method allows for a natural combination of multiple distances from heterogeneous sources. As a result, it yields a representation of the population that preserves the multiple distances. Furthermore, our method also selects the most predictive features associated with the distances. We evaluate our method in neonatal magnetic resonance images of three groups (term controls, patients affected by intrauterine growth restriction and mild isolated ventriculomegaly). We show that combining multiple distances related to the condition improves the overall characterization and classification of the three clinical groups compared to the use of single distances and classical unsupervised manifold learning. PMID- 28818744 TI - Cytotoxic, genotoxic and antimicrobial activity of caffeic and rosmarinic acids and their lithium, sodium and potassium salts as potential anticancer compounds. AB - PURPOSE: The aim of this study was to examine the cytotoxic, genotoxic, antioxidant and antimicrobial activity of caffeic and rosmarinic acids and their salts with Li, Na and K with use of Escherichia coli K-12 recA:gfp strain as a model organism. METHODS: Cytotoxic potency of tested chemicals were calculated on the basis on the dose that confers inhibition percentage such as 20% for each concentrations of analysed chemicals. Genotoxic properties were calculated on the basis of the fold increase (FI) of SFI values normalized with control. Antioxidant potencies were established on the base of DPPH assay. Antimicrobial activity of chemicals were established on the value of minimal inhibitory concentration (MIC). RESULTS: Obtained results indicated that lower concentrations of tested compounds exhibited stronger GFP fluorescence response after rosmarinic acids and their salts treatment. Genotoxic effects seemed to be independent of the salt ions. The caffeic acid salts with Li, Na and K showed reduced genotoxic effect in comparison to the caffeic acid while increased cytotoxic effect than that of caffeic acid. Moreover, caffeinate salts exhibited better antimicrobial activity against E. coli (MIC=250MUg/mL) than K caffeinate salt (MIC>500MUg/mL). The MIC values of Li, Na and K rosmarinate salts were above 500MUg/mL against all tested microorganisms. CONCLUSION: The results of the experiment show that there is no clear positive correlation between the antioxidant potency of caffeic and rosmarinic acids and their Li, Na and K salts and their cytotoxic effect. Used salts ions Li, Na and K do not significantly affect the antioxidant effect of natural phenolic compounds and they do not have a significant impact on the biological parameters such as cyto- and genotoxicity. Perhaps it is connected with the reaction environment including polarity of the solvent (water). PMID- 28818745 TI - A systematic review on the role of eicosanoid pathways in rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis is characterized by the production of eicosanoids, cytokines, adhesion molecules, infiltration of T and B lymphocytes in the synovium and oxygen reduction accompanied by the cartilage degradation. Eicosanoids are responsible for the progressive destruction of cartilage and bone, however neither steroids, nor the non steroidal anti-inflammatory drugs (NSAIDs), cannot slow down cartilage and bone destruction providing only symptomatic improvement. The current rheumatoid arthritis treatment options include mainly the use of disease-modifying anti-rheumatic drugs, the corticosteroids, the NSAIDs and biological agents. METHODS: PubMed, Cochrane, and Embase electronic database were used as the main sources for extracting several articles, reviews, original papers in English for further review and analysis on the implication of arachidonic acid metabolites with rheumatoid arthritis and different strategies of targeting arachidonic acid metabolites, different enzymes or receptors for improving the treatment of rheumatoid arthritis patients. RESULTS: We first focused on the role of individual prostaglandins and leukotrienes, in the inflammatory process of arthritis, concluding with an outline of the current clinical situation of rheumatoid arthritis and novel treatment strategies targeting the arachidonic acid pathway. CONCLUSIONS: Extended research is necessary for the development of these novel compounds targeting the eicosanoid pathway, by increasing the levels of anti-inflammatory eicosanoids (PGD2,15dPGJ2), by inhibiting the production of pro-inflammatory eicosanoids (PGE2, LTB4, PGI2) involved in rheumatoid arthritis or also by developing dual compounds displaying both the COX-2 inhibitor/TP antagonist activity within a single compound. PMID- 28818746 TI - Patients with atrial fibrillation and coronary artery disease - Double trouble. AB - Coronary artery disease (CAD) is the most common cardiovascular disease while atrial fibrillation (AF) is the most common cardiac arrhythmia. Both diseases share associated risk factors - hypertension, diabetes mellitus, sleep apnea, obesity and smoking. Moreover, inflammation plays a causative role in both diseases. The prevalence of CAD in patients with AF is from 17% to 46.5% while the prevalence of AF among patients with CAD is low and it is estimated from 0.2% to 5%. AF is a well-established factor of poor short- and long-term prognosis in patients with acute myocardial infarction (AMI) and is associated with a marked increase in overall mortality. The arrhythmia is common after cardiac surgeries and occurs in about 20 to 40% of patients after coronary artery bypass graft (CABG) surgery. It is predicted that between 5 and 15% of AF patients will require stenting at some point in their lives and will receive triple therapy with aspirin, clopidogrel or ticagrelor and oral anticoagulation (OAC). This requires careful consideration of antithrombotic therapy, balancing bleeding risk, stroke risk, and in-stent thrombosis with subsequent acute coronary syndromes. Co-prescription of OAC with antiplatelet therapy, in particular triple therapy, increases the absolute risk of major bleeding. In addition, major bleeding is associated with an up to 5-fold increased risk of death following an acute coronary syndrome. Coexistence of AF and CAD worsens the prognosis even in carefully treated patients. PMID- 28818747 TI - Antidepressant-like activity of methyl jasmonate involves modulation of monoaminergic pathways in mice. AB - PURPOSE: The efficacy of current antidepressant drugs has been compromised by adverse effects, low remission and delay onset of action necessitating the search for alternative agents. Methyl jasmonate (MJ), a bioactive compound isolated from Jasminum grandiflorum has been shown to demonstrate antidepressant activity but its mechanism of action remains unknown. Thus, the role of monoaminergic systems in the antidepression-like activity of MJ was investigated in this study. MATERIALS AND METHODS: Mice were given i.p. injection of MJ (5, 10 and 20mg/kg), imipramine (10mg/kg) and vehicle (10mL/kg) 30min before the forced swim test (FST) and tail suspension test (TST) were carried out. The involvement of monoaminergic systems in the anti-depressant-like effect of MJ (20mg/kg) was evaluated using p-chlorophenylalanine (pCPA), metergoline, yohimbine, prazosin, sulpiride and haloperidol in the TST. RESULTS: MJ significantly decrease the duration of immobility in the FST and TST relative to control suggesting antidepressant-like property. However, pretreatment with yohimbine (1mg/kg, i.p., an alpha2-adrenergic receptor antagonist) or prazosin (62.5MUg/kg, i.p., an alpha1-adrenoceptor antagonist) attenuated the antidepressant-like activity of MJ. Also, pCPA; an inhibitor of serotonin biosynthesis (100mg/kg, i.p) or metergoline (4mg/kg, i.p., 5-HT2 receptor antagonist) reversed the anti immobility effect of MJ. Sulpiride (50mg/kg, i.p., a D2 receptor antagonist) or haloperidol (0.2mg/kg, i.p., a dopamine receptor antagonist) reversed the anti immobility effect of MJ. CONCLUSION: The results of this study suggest that serotonergic, noradrenergic and dopaminergic systems may play a role in the antidepressant-like activity of MJ. PMID- 28818748 TI - Association of Brain-derived neurotrophic factor gene polymorphisms with body mass index: A systematic review and meta-analysis. AB - BACKGROUND: Many studies with inconsistent results have assessed the association of Brain-derived neurotrophic factor (BDNF) gene polymorphisms with prevalence of obesity and overweight. This review aims to provide a summary of the literature evaluating the relation between BDNF genotype and body mass index (BMI). METHODS: A systematic search through PubMed, Scopus, Science direct, Ovid and Cochrane was performed. We included observational studies with cross-sectional and case control design, which investigated relationship between all kinds of BDNF polymorphisms with BMI, as a representative index of obesity and overweight. Newcastle-Ottawa Scale was used to assess the quality of included articles. RESULTS: Thirty five studies were included in quantitative synthesis. Analyses were performed separately using OR, beta coefficient and mean. Significant association were documented between rs925946 and BMI (OR=1.12, 95% CI=1.08-1.17, P heterogeneity=0.317), rs10501087 and BMI (OR=1.14, 95% CI=1.04-1.24, P heterogeneity=0.861), rs6265 and BMI (OR=1.13, 95% CI=1.07-1.19, P heterogeneity=0.406), rs988712 and BMI (OR=1.29, 95% CI=1.18-1.40, P heterogeneity=0.602). According to pooled beta coefficient analysis, significant result was only observed in the rs925946 polymorphism subgroup. Pooled mean analysis showed that overall effects for the association between BDNF polymorphisms and BMI were not statistically significant. CONCLUSION: This meta analysis suggests that some polymorphisms in BDNF gene including rs925946, rs10501087, rs6265 and rs988712 can be considered as genetic determinants of obesity. PMID- 28818750 TI - Whole genome sequence phylogenetic analysis of four Mexican rabies viruses isolated from cattle. AB - Phylogenetic analysis of the rabies virus in molecular epidemiology has been traditionally performed on partial sequences of the genome, such as the N, G, and P genes; however, that approach raises concerns about the discriminatory power compared to whole genome sequencing. In this study we characterized four strains of the rabies virus isolated from cattle in Queretaro, Mexico by comparing the whole genome sequence to that of strains from the American, European and Asian continents. Four cattle brain samples positive to rabies and characterized as AgV11, genotype 1, were used in the study. A cDNA sequence was generated by reverse transcription PCR (RT-PCR) using oligo dT. cDNA samples were sequenced in an Illumina NextSeq 500 platform. The phylogenetic analysis was performed with MEGA 6.0. Minimum evolution phylogenetic trees were constructed with the Neighbor Joining method and bootstrapped with 1000 replicates. Three large and seven small clusters were formed with the 26 sequences used. The largest cluster grouped strains from different species in South America: Brazil, and the French Guyana. The second cluster grouped five strains from Mexico. A Mexican strain reported in a different study was highly related to our four strains, suggesting common source of infection. The phylogenetic analysis shows that the type of host is different for the different regions in the American Continent; rabies is more related to bats. It was concluded that the rabies virus in central Mexico is genetically stable and that it is transmitted by the vampire bat Desmodus rotundus. PMID- 28818749 TI - A conjugate protein containing HIV TAT, ISG20, and a PRRSV polymerase binding inhibits PRRSV replication and may be a novel therapeutic platform. AB - Porcine Reproductive and Respiratory Syndrome (PRRS), which is caused by Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) infection, has caused substantial economic losses for the global swine industry. To date, there are limited commercially available measures to control the spread of PRRSV. The available vaccines are unstable and there is no anti-PRRSV therapeutic available. Therefore, this study designed a novel recombinant antiviral protein that included a novel polypeptide that binds to the PRRSV polymerase (p9), the transduction ability of the HIV TAT, and the nucleotide degradation activity of interferon stimulated gene 20 (ISG20). The recombinant proteins TAT-p9-ISG20 and p9-ISG20 were expressed in MARC-145 cells by transient transfection and then tested for antiviral activity and entry efficiency. The p9-ISG20 construct had greater antiviral activity than either p9 alone (1.37-fold) or ISG20 alone (1.9 fold). Addition of the HIV TAT protein increased the entry efficiency of p9-ISG20 by 1.57-fold, which was associated with increased anti-viral activity (1.52-fold) compared to P9-ISG20. In summary, TAT-p9-ISG20 achieved a synergistic effect by combining three different antiviral proteins and may be a novel PRRSV therapeutic platform. PMID- 28818751 TI - Nutritional modulation of intestinal drug-metabolizing cytochrome P450 by butyrate of different origin in chicken. AB - Intestinal cytochrome P450 (CYP) enzymes play key role in the first pass metabolism of orally ingested xenobiotics, providing a primary metabolic barrier, being of special importance in maintaining animal health and production. This study was aimed to investigate how intestinal drug-metabolizing CYPs can be modulated by nutritional factors in broiler chicken. We investigated the effects of the natural growth promoter (n-)butyrate of different origin (feed supplementation of protected or non-protected forms and/or inducing caecal microbial production by supporting higher level of dietary non-starch polysaccharides [NSP]) on the activity of duodenal CYPs. To observe the connection between intestinal CYP activity and butyrate concentration, the distribution of differently originated butyrate was also assessed by measuring its concentration in various intestinal segments and different vessels of portal and systemic circulation. Butyrate of different origin showed varying distribution properties as being absorbed from different parts of the gastrointestinal tract. Intestinal CYP1A and CYP2H2 activities were increased by dietary butyrate supplementation and by the increased caecal microbial butyrate production, while CYP3A37 activity was minimally influenced by microbial butyrate only. The present study proved that both dietary and microbial butyrate could alter the activity of CYPs in the duodenal epithelium. Our findings suggest that intestinal CYPs could be induced not only by the intestinal luminal butyrate, but also from basolateral side, by the already absorbed butyrate. Such action of butyrate can be of special importance from food safety and pharmacotherapeutic point of view as it may modify the metabolism and intestinal kinetics of simultaneously applied xenobiotics. PMID- 28818752 TI - Risk factors for on-farm mortality in beef suckler cows under extensive keeping management. AB - The on-farm mortality of cows in cow-calf herds has a significant influence on the economic efficiency of the farm. It is also an indicator of suboptimal animal health and welfare. The present study analysed the registry data of beef cows in Estonia from the years 2013 to 2015. The datasets incorporated 8084 parturitions of primiparous cows and 21,283 parturitions of 9234 multiparous cows. A Weibull proportional hazard random effect model was used for risk factor analysis, in which the on-farm mortality, including death and euthanasia, was the event of interest. The first 30days post-calving were associated with the highest mortality hazard for primiparous and multiparous cows (including 28.9% and 21.1% of deaths, respectively). In multiparous cows, the lowest mortality hazard was confirmed for animals with parity of three to five, increasing significantly after that. Primiparous cows that did not have a stillborn calf had a significantly higher mortality hazard when calving over 44months of age compared to cows calving younger than 36months. Stillbirth and abortion were significant risk factors for mortality. Cows with dystocia experienced a higher mortality hazard, especially during the first week post-calving. In multiparous cows, a higher herd mean age at first calving was associated with a higher mortality hazard. This study highlights the fact that the early post-partum period and factors associated with calving, such as age at first calving, dystocia, stillbirth and abortion, are critical for beef cow survival. PMID- 28818753 TI - Benzoylsalicylic acid derivatives as defense activators in tobacco and Arabidopsis. AB - Systemic acquired resistance (SAR) is a long lasting inducible whole plant immunity often induced by either pathogens or chemical elicitors. Salicylic acid (SA) is a known SAR signal against a broad spectrum of pathogens in plants. In a recent study, we have reported that benzoylsalicylic acid (BzSA) is a SAR inducer in tobacco and Arabidopsis plants. Here, we have synthesized BzSA derivatives using SA and benzoyl chlorides of various moieties as substrates. The chemical structures of BzSA derivatives were elucidated using Infrared spectroscopy (IR), Nuclear magnetic spectroscopy (NMR) and High-resolution mass spectrometer (HRMS) analysis. The bioefficacy of BzSA derivatives in inducing defense response against tobacco mosaic virus (TMV) was investigated in tobacco and SA abolished transgenic NahG Arabidopsis plants. Interestingly, pre-treatment of local leaves of tobacco with BzSA derivatives enhanced the expression of SAR genes such as NPR1 [Non-expressor of pathogenesis-related (PR) genes 1], PR and other defense marker genes (HSR203, SIPK, WIPK) in systemic leaves. Pre-treatment of BzSA derivatives reduced the spread of TMV infection to uninfected areas by restricting lesion number and diameter both in local and systemic leaves of tobacco in a dose-dependent manner. Furthermore, pre-treatment of BzSA derivatives in local leaves of SA deficient Arabidopsis NahG plants induced SAR through AtPR1 and AtPR5 gene expression and reduced leaf necrosis and curling symptoms in systemic leaves as compared to BzSA. These results suggest that BzSA derivatives are potent SAR inducers against TMV in tobacco and Arabidopsis. PMID- 28818754 TI - Daily thanatomicrobiome changes in soil as an approach of postmortem interval estimation: An ecological perspective. AB - Understanding human decomposition is critical for its use in postmortem interval (PMI) estimation, having a significant impact on forensic investigations. In recognition of the need to establish the scientific basis for PMI estimation, several studies on decomposition have been carried out in the last years. The aims of the present study were: (i) to identify soil microbiota communities involved in human decomposition through high-throughput sequencing (HTS) of DNA sequences from the different bacteria, (ii) to monitor quantitatively and qualitatively the decay of such signature species, and (iii) to describe succesional changes in bacterial populations from the early putrefaction state until skeletonization. Three donated individuals to the University of Tennessee FAC were studied. Soil samples around the body were taken from the placement of the donor until advanced decay/dry remains stage. Bacterial DNA extracts were obtained from the samples, HTS techniques were applied and bioinformatic data analysis was performed. The three cadavers showed similar overall successional changes. At the beginning of the decomposition process the soil microbiome consisted of diverse indigenous soil bacterial communities. As decomposition advanced, Firmicutes community abundance increased in the soil during the bloat stage. The growth curve of Firmicutes from human remains can be used to estimate time since death during Tennessee summer conditions. PMID- 28818755 TI - Biochemical abnormalities in basal ganglia and executive dysfunction in acute- and euthymic-episode patients with bipolar disorder: A proton magnetic resonance spectroscopy study. AB - BACKGROUND: Recent studies found abnormal biochemical metabolism and executive cognitive deficits in acute bipolar disorder (BD). However, the evidence concerning in euthymic BD is limited. Thus, a comparison between acute and euthymic BD is conductive to better understanding the association between cognition and the outcome of neuroimaging. This study sought to investigate the relationship between the executive function and the biochemical metabolism in acute- and euthymic-episode BD patients and delineate the prominent endophenotype of BD. METHODS: Three groups of participants were recruited in this study: 30 BD patients with an acute depressive episode, 22 euthymic BD patients, and 31 healthy controls. All participants were interviewed using the Structured Clinical Interview for DSM-IV, and underwent two-dimensional multivoxel proton magnetic resonance spectroscopy (1H-MRS) to obtain the bilateral metabolite levels in the lenticular nucleus of basal ganglia(BG). The ratios of N-acetylaspartate (NAA)/creatine (Cr) and Choline-containing compounds (Cho) /Cr ratios were calculated. Executive function was assessed by using the Wisconsin Card Sorting Test (WCST) and Trail Making Test, Part-B(TMT-B). RESULTS: The comparison of biochemical changes showed that the NAA/Cr ratios in bilateral lenticular nucleus in both acute and euthymic BD patients was significantly lower than that in healthy controls at a confidence level of p<0.05. In the comparison of executive function, both acute and euthymic BD patients showed significantly decreased numbers of categories completed, and increased numbers of total errors, perseverative and noperseverative errors, and TMT-B uptake compared to the healthy controls at a confidence level of p<0.05. There were no significant differences between the acute BD and euthymic BD groups in the biochemical metabolite ratios and executive function. We found that the NAA/Cr ratio in the left in BG in the acute -episode BD patients was positively correlated with the number of categories completed, whereas it was negatively correlated with the total errors and TMT-B uptake. There was no correlation between the NAA/Cr and Cho/Cr ratios in the bilateral BG and the scores of SWCT and TMT-B in euthymic episode BD patients. LIMITATION: The sample size was relatively small and not all the euthymic-episode patients are the ones with an acute episode. CONCLUSIONS: Our findings suggest that biochemical abnormalities in the lenticular nucleus and the executive dysfunction may occur early in the course of BD, and persist during remission, and are the most likely markers of endophenotypes of BD. The dysfunction of the neuronal function in the lenticular nucleus may be correlated with the cold dysfunction in patients with acute BD. PMID- 28818756 TI - Interactions between aluminium, iron and silicon in Cucumber sativus L. grown under acidic conditions. AB - Aluminium (Al) is one of the major stressors for plants in acidic soils, negatively affecting plant growth and nutrient balances. Significant efforts have been undertaken to understand mechanisms of Al tolerance in plants. However, little is known of the relevance of iron (Fe) and silicon (Si) nutrition under Al stress conditions. The objectives of this study were to determine whether effects induced by Fe and Si are of importance for limitation of Al moving via xylem in plants (Cucumis sativus L.). Cucumber plants (cv. Phoenix and Solovei) were grown (i) hydroponically in a complete nutrient solution at pH 4.0, either with (+Fe) or in Fe-free (-Fe) nutrient solution, without (-Si) or with (+Si) supply of Si, without (-Al) or with (+Al) exposure of Al and (ii) in soil. Xylem sap concentrations of Al, Fe and Si were measured. To characterise the pattern of xylem sap transport of Al and Fe, metabolomic changes of root tissues were investigated. Although the growth of cucumber plants was not significantly affected by Al3+ (Al-tolerant), Al exposure decreased xylem sap Fe (+Fe plants) and increased ferric chelate reductase (FC-R) activity of roots (-Fe plants). On the other hand, Fe supply greatly mitigated the Al-induced increase in xylem sap Al. The ameliorative effect of Fe depended on plant genotypes and was more pronounced in the more Fe-efficient cultivar Phoenix, which presented the highest level of xylem sap Fe. Xylem sap Fe was positively correlated with root serine, succinic and fumaric acids, suggesting that a probable underlying mechanism of Al tolerance might involve the chelation of Fe by biosynthesis of these chelating compounds. The Si-modulated root succinate increase appears to be of great importance for facilitating long-distance transport of Fe, thereby hindering Al transport from roots to shoots. The results highlight for the first time the importance of both Fe and Si supply in plant exclusion of Al under acidic conditions. PMID- 28818757 TI - Expression of a Na+/H+ antiporter RtNHX1 from a recretohalophyte Reaumuria trigyna improved salt tolerance of transgenic Arabidopsis thaliana. AB - Reaumuria trigyna is an endangered recretohalophyte and a small xeric shrub that is endemic to the eastern Alxa and western Ordos areas of Inner Mongolia, China. Using transcriptome data, we identified a 1662-bp open reading frame encoding a 553-amino-acid protein corresponding to a Na+/H+ antiporter (RtNHX1) from R. trigyna. RtNHX1 was rapidly up-regulated by NaCl and exogenous abscisic acid treatment and had different tissue-specific expression patterns before and after salt-stress treatment. Overexpression of RtNHX1 enhanced seed germination, biomass accumulation, chlorophyll content, and root elongation in transgenic Arabidopsis plants under salt stress and rescued the salt-sensitive deficiencies of the nhx1 mutant. POD and CAT enzyme activities, proline content, and RWC all increased significantly in salt-stressed transgenic Arabidopsis plants, whereas MDA content did not. Additionally, there was a corresponding upregulation of some antioxidant-enzyme, proline biosynthesis and other stress responsive genes (AtPOD1, AtCAT1, AtP5CS1, AtP5CS2, AtRD29A, AtRD29B, AtKIN1, and AtABI2). The transgenic Arabidopsis plants accumulated more K+ and less Na+ in their leaves and had lower Na+/K+ ratios than WT plants. This was reflected in the upregulation of some ion transport-related genes (AtAVP1, AtSOS1, AtKUP6, and AtKUP8). When RtNHX1 was expressed in the AXT3 yeast strain, the accumulation of Na+ and K+ in the vacuole increased and the Na+/K+ ratio decreased. These results reveal that R. trigyna RtNHX1 is a functional antiporter that sequesters Na+ and K+ in the vacuole and could confer salt tolerance on transgenic Arabidopsis plants by maintaining Na+/K+ homeostasis and enhancing osmotic and antioxidant regulatory capacity. These results suggest that RtNHX1 may be a good target for improving salt tolerance in plants. PMID- 28818758 TI - Phytoremediation of arsenic from the contaminated soil using transgenic tobacco plants expressing ACR2 gene of Arabidopsis thaliana. AB - We have cloned, characterized and transformed the AtACR2 gene (arsenic reductase 2) of Arabidopsis thaliana into the genome of tobacco (Nicotiana tabacum, var Sumsun). Our results revealed that the transgenic tobacco plants are more tolerant to arsenic than the wild type ones. These plants can grow on culture medium containing 200MUM arsenate, whereas the wild type can barely survive under this condition. Furthermore, when exposed to 100MUM arsenate for 35days the amount of arsenic accumulated in the shoots of transgenic plants was significantly lower (28MUg/g d wt.) than that found in the shoots of non transgenic controls (40MUg/g d wt.). However, the arsenic content in the roots of transgenic plants was significantly higher (2400MUg/g d. wt.) than that (2100MUg/g d. wt.) observed in roots of wild type plants. We have demonstrated that Arabidopsis thaliana AtACR2 gene is a potential candidate for genetic engineering of plants to develop new crop cultivars that can be grown on arsenic contaminated fields to reduce arsenic content of the soil and can become a source of food containing no arsenic or exhibiting substantially reduced amount of this metalloid. PMID- 28818759 TI - Increased cell wall thickness of endodermis and protoxylem in Aeluropus littoralis roots under salinity: The role of LAC4 and PER64 genes. AB - Enhanced cell wall lignification is one of the major salinity tolerance strategies in the roots of halophytes. A deep insight into the exact root developmental system in halophytes may be of great importance for understanding plant salt tolerance mechanisms. In this work the developmental and anatomical changes in the roots of halophyte Aeluropus littoralis along with expression patterns of two genes encoding for cell wall laccase (LAC4) and peroxidase (PER64) were investigated. The plants were treated with 0, 300 and 600mM NaCl and root samples were collected 3, 6 and 9days after treatment (DAT). Upon salinity treatment, root diameter and parenchyma thickness were increased significantly in the tip and middle segments compared to upper zones, but the change trend was reversed with the time. It was interestingly revealed that protoxylem was the tissue of target for lignification at root tips, while the highest lignification rates were observed in metaxylem and endodermis in upper segments. Compared to endodermis, protoxylem is restrictively involved in early stages of salt stress in root tips as an efficient barrier against Na+ flow. Gene expression analysis revealed that LAC4 expression was higher in root tips resulting in enhanced protoxylem lignification while PER64 expression was higher in more differentiated zones leading to endodermis thickening. The overall results of this study reveal the crucial role of LAC4 as an important gene in specialized protoxylem lignification in undifferentiated root tips leading to enhanced tolerance in early stages of salt stress. PMID- 28818760 TI - Slow gait speed is associated with executive function decline in older people with mild to moderate dementia: A one year longitudinal study. AB - OBJECTIVES: This study aimed to document change in neuropsychological, physical and functional performance over one year and to investigate the relationship between baseline gait speed and cognitive decline in this period in older people with dementia. METHODS: One hundred and seventy-seven older people with dementia (Mini-Mental State Examination 11-23; Addenbrooke's Cognitive Examination-Revised <83) residing in the community or low level care facility completed baseline neuropsychological, physical and functional assessments. Of these, 134 participants agreed to reassessment of the above measures one year later. RESULTS: Overall, many neuropsychological, physical and functional performance measures declined significantly over the one year study period. Baseline gait speed was significantly associated with decline in verbal fluency (B(109)=2.893, p=0.046), specifically phonemic/letter fluency (B(109)=2.812, p=0.004) while controlling for age, education, dementia drug use and baseline cognitive performance. There was also a trend for an association between baseline gait speed and decline in clock drawing performance (B(107)=0.601, p=0.071). CONCLUSIONS: Older people with mild to moderate dementia demonstrate significant decline in neuropsychological, physical and functional performance over one year. Baseline gait speed is associated with decline in executive function over one year, suggesting shared pathways/pathology between gait and cognition. PMID- 28818761 TI - The effect of disability and depression on cognitive function and screening factors. AB - INTRODUCTION: There is increasing evidence that subtle losses in cognitive function may be symptomatic of a transition to early dementia. The objectives of this study were to: 1) test the effect of depressive symptoms and/or disability on cognitive impairment, 2) explore the interaction between depression and disability and the association with cognitive impairment, and 3) evaluate risk factors of health assessment to discriminate between elderly people with or without cognitive impairment. MATERIAL AND METHODS: The subjects were the community-dwellings aged 65 years and over who live in the sample city of southern Taiwan. 2734 persons were recruited by random sampling in the community, and the data was collected with face to face interviews by the training interviewers. RESULTS: The effect of disability on cognitive impairment is stronger than the effect in depression. It also implies the possibility that disability may mediate the association between depression and cognitive impairment. Screening for risk factors of cognitive impairment was defined in this study and may be feasible for general population. CONCLUSIONS: This study suggests that disability and depression assessments may serve as useful predictors of cognitive impairment. It is hoped that for elderly people, early assessment through screening factors could be arranged to this high-risk subgroup to reduce the risk of developing future dementia. Screening for functional disability and depressive symptoms would help to put management strategies in place that may reduce the associated cognition impairment burden. PMID- 28818762 TI - Reflector-guided breast tumor localization versus wire localization for lumpectomies: A comparison of surgical outcomes. AB - PURPOSE: To compare surgical outcomes of SAVI SCOUT reflector localization (SSL) versus wire localization (WL) for breast tumors. METHODS: Retrospective review of 42 SSL cases and 42 WL cases. WL patients were consecutively matched for clinical pathologic features. Final surgical outcome measures were tumor specimen volume, margin status, and re-excision rates. RESULTS: No significant differences were present in median specimen volumes (SSL-15.2cm3 vs. WL-16.3cm3), positive margin rate (SSL-9.5% vs. WL-7.1%), close margin rate (SSL-7.1% vs. WL-11.9%) or re excision rate (SSL-7.1% vs. WL-9.5%). CONCLUSION: SSL is an acceptable alternative to WL with no significant differences in surgical outcomes. PMID- 28818763 TI - The qualitative and quantitative image analysis of MR imaging in patients with acute-on-chronic liver failure. AB - PURPOSE: To evaluate the distinctive features of ACLF and chronic liver disease (CLD) on MR images using quantitative and qualitative analyses. METHODS: Twelve patients with ACLF and 36 patients with CLD who had undergone MR images were included. MR imaging findings from both groups were assessed. RESULTS: Gallbladder edema, esophageal varix, and ascites were significantly more prevalent in the ACLF group (all P-values <0.05). The liver to muscle SI ratio on T2-WI was significantly higher in the ACLF group (P=0.002). CONCLUSION: MR imaging findings could be helpful in differentiating between patients with ACLF and those with CLD. PMID- 28818764 TI - Screening of biologically important Zn2+ by a chemosensor with fluorescent turn on-off mechanism. AB - Reported herein the synthesis, characterization and biologically important zinc ion binding propensity of a weakly fluorescent chemosensor, 4-methyl-2,6-bis((E) (2-(4-phenylthiazol-2-yl)hydrazono)methyl)phenol (1). 1H NMR spectroscopic titration experiment reveals the binding knack of 1 to the essential Zn2+. The photo-physical studies of 1 exhibit an enhancement in the fluorescence by several folds upon binding with the zinc ions attributed to PET-off process, with a binding constant value of 5.22*103M-1. 1 exhibits an excellent detection range for Zn2+ with lower detection limit value of 2.31*10-8M. The selectivity of 1 was studied with various mono and divalent metal cations and it was observed that most cations either quenches the fluorescence or remains unchanged except for Cd2+, which shows a slight enhancement in fluorescence intensity of 1. The ratiometric displacement of Cd2+ ions by Zn2+ ions shows an excellent selectivity towards in-situ detection of Zn2+ ions. Photo-physical studies also support the reversible binding of 1 to Zn2+ ions having on and off mechanism in presence of EDTA. Such recognition of the biologically important zinc ions finds potential application in live cell imaging. PMID- 28818765 TI - Cu2+ modulated nitrogen-doped grapheme quantum dots as a turn-off/on fluorescence sensor for the selective detection of histidine in biological fluid. AB - A highly sensitive sensor for detection of histidine (His) based on the nitrogen doped graphene quantum dots (N-GQDs)-Cu2+ system has been designed. The N-GQDs were synthesized by one-step hydrothermal approach according to previous report. The fluorescence of N-GQDs can be effectively quenched by Cu2+ due to the binding between Cu2+ and functional groups on the surface of N-GQDs. The high affinity of His to Cu2+ enables Cu2+ to be dissociated from the surface of N-GQDs and recovering the fluorescence. The sensor displayed a sensitive response to His in the concentration range of 0-35MUmolL-1, with a detection limit of 72.2nmolL-1. The proposed method is successfully applied to detect His in samples with a recovery range of 96-102%. PMID- 28818766 TI - Design, synthesis and in vivo study of novel pyrrolidine-based 11beta-HSD1 inhibitors for age-related cognitive dysfunction. AB - Recent findings suggest that treatment with 11beta-HSD1 inhibitors provides a novel approach to deal with age-related cognitive dysfunctions, including Alzheimer's disease. In this work we report potent 11beta-HSD1 inhibitors featuring unexplored pyrrolidine-based polycyclic substituents. A selected candidate administered to 12-month-old SAMP8 mice for four weeks prevented memory deficits and displayed a neuroprotective action. This is the first time that 11beta-HSD1 inhibitors have been studied in this broadly-used mouse model of accelerated senescence and late-onset Alzheimer's disease. PMID- 28818767 TI - Recent advances of pyrazole-containing derivatives as anti-tubercular agents. AB - One-third of the world's population infected tuberculosis (TB), and more than 1 million deaths annually. The co-infection between the mainly pathogen Mycobacterium tuberculosis (MTB) and HIV, and the incidence of drug-resistant TB, multi-drug resistant TB, extensively drug-resistant TB as well as totally drug resistant TB have further aggravated the mortality and spread of this disease. Thus, there is an urgent need to develop novel anti-TB agents against both drug susceptible and drug-resistant TB. The wide spectrum of biological activities and successful utilization of pyrazole-containing drugs in clinic have inspired more and more attention towards this kind of heterocycles. Numerous of pyrazole containing derivatives have been synthesized for searching new anti-TB agents, and some of them showed promising potency and may have novel mechanism of action. This review aims to outline the recent achievements in pyrazole-containing derivatives as anti-TB agents and their structure-activity relationship. PMID- 28818769 TI - Substituted methoxybenzyl-sulfonyl-1H-benzo[d]imidazoles evaluated as effective H+/K+-ATPase inhibitors and anti-ulcer therapeutics. AB - Efforts were made to synthesize a series of substituted methoxybenzyl-sulfonyl-1H benzo[d]imidazole derivatives (8a-l) and investigate their anti-ulcer therapeutics. Prior to evaluating antiulcer potentials of 8a-l, a preliminary binding assay against H+/K+-ATPase from goat gastric mucosa was carried out, since it plays an important role in the ulcer development. In order to get more insight into the binding mode of the compounds to H+/K+-ATPase, a molecular docking study was carried out and the best binding affinities were unveiled. Many of the substituted methoxybenzyl-sulfonyl-1H-benzo[d]imidazole derivatives (8a-l) were active for the proposed activity. The key finding was that, least inhibitory constant (ki) values of 8a-l were found between 0.02 and 1.8 MUM in the molecular docking study. Almost the same range was reflected/correlated in the H+/K+-ATPase inhibition assay (IC50 0.14-1.29 MUM). Remarkably, compounds 8a-l showed a relative activity percentage range of 72-92%. Efficient HRBC membrane stabilization activity of 8a-l ensured the non-harm/safety and the suitability/alternative towards anti-ulcer therapy. PMID- 28818768 TI - Novel Gomisin B analogues as potential cytotoxic agents: Design, synthesis, biological evaluation and docking studies. AB - As part of pharmacological-phytochemical integrated studies on medicinal flora, Gomisin B (1) was isolated as major phytochemical lead from schisandra grandiflora, a plant traditionally used in different Asian systems of medicine. A series of 1,2,3-triazoles derivatives were synthesized at the C-7' position of the gomisin B core through diastereoselective Michael addition followed by regioselective Huisgen 1,3-dipolar cycloaddition reactions. All these triazolyl derivatives (5a-5q) were well characterized using modern spectroscopic techniques and evaluated for their anti-cancer activity against a panel of five human cancerous cell-lines. Among them, compound 5b exhibited the best cytotoxicity against SIHA cell (IC50 0.24 MUM) which was more than the standard drug doxorubicin, while the other derivatives were exhibited moderate to low activities in tested cell lines. The cell cycle analysis indicated that compound 5b stalled HeLa cells at G2/M phase. 5b promoted tubulin polymerization and this was supported by the docking studies, wherein 5b showed significant binding affinity at the colchicine binding pocket of tubulin. Overall, we identified a novel small molecule that demonstrated anticancer activity by promoting in vitro tubulin assembly. PMID- 28818770 TI - Hereditary multiple exostoses as a novel cause of bilateral popliteal artery aneurysms in the elderly. AB - Hereditary multiple exostoses (HME) is a genetic condition characterized by the development of multiple osteochondromas during childhood and adolescence. On rare occasions, these bony tumors can be associated with vascular injury, most commonly involving the popliteal artery. Such patients typically present with vascular complications in adolescence and young adulthood. We report an autopsy study of an elderly man who presented with bilateral popliteal artery pseudoaneurysms in the setting of HME at age 81. This is the oldest patient presenting with a vascular complication due to HME reported to date, as well as the only known case of bilateral popliteal pseudoaneurysms caused by HME. This is also the only autopsy study of this vascular complication so far reported. Our case illustrates that vascular complications from HME can occur even in the elderly, and may show bilateral involvement. PMID- 28818771 TI - One-pot synthesis of oxazolidine-2-thione and thiozolidine-2-thione from sugar azido-alcohols. AB - A controlled and facile synthesis of various glycosyl 1,3-oxazolidine-2-thiones and 1,3- thiozolidine-2-thiones has been accomplished from corresponding sugar azido alcohols utilizing Staudinger reaction (PPh3 and CS2) via isothiocynate route. A series of reactions were performed to investigate the effects of CS2 and PPh3 on the selectivity of product formed. The excessive addition of CS2 with PPh3(1.2 equiv) afforded oxazolidine-2-thione alone, while the solitary addition of PPh3 for 30 min followed by addition of CS2 to the reaction mixture resulted both the products in different ratios, which were successfully isolated using column chromatography (SiO2). Furthermore, synthesis of 1,3-oxathiolan-2-imine from glycosyl epoxide has also been attempted. Structures of all the developed compounds have been elucidated using extensive spectroscopic techniques including IR, NMR and MS analysis. PMID- 28818772 TI - Multipath ultrasonic gas flow-meter based on multiple reference waves. AB - Several technologies can be used in ultrasonic gas flow-meters, such as transit time, Doppler, cross-correlation and etc. In applications, the approach based on measuring transit-time has demonstrated its advantages and become more popular. Among those techniques which can be applied to determine time-of-flight (TOF) of ultrasonic waves, including threshold detection, cross correlation algorithm and other digital signal processing algorithms, cross correlation algorithm has more advantages when the received ultrasonic signal is severely disturbed by the noise. However, the reference wave for cross correlation computation has great influence on the precise measurement of TOF. In the applications of the multipath flow-meters, selection of the reference wave becomes even more complicated. Based on the analysis of the impact factors that will introduce noise and waveform distortion of ultrasonic waves, an averaging method is proposed to determine the reference wave in this paper. In the multipath ultrasonic gas flow-meter, the analysis of each path of ultrasound needs its own reference wave. In case study, a six-path ultrasonic gas flow-meter has been designed and tested with air flow through the pipeline. The results demonstrate that the flow rate accuracy and the repeatability of the TOF are significantly improved by using averaging reference wave, compared with that using random reference wave. PMID- 28818773 TI - Adversity-driven changes in hypothalamic-pituitary-adrenal axis functioning during adolescence. The trails study. AB - The hypothalamic-pituitary-adrenal (HPA) axis has been proposed to be a key mechanism underlying the link between adversity and mental health, but longitudinal studies on adversity and HPA-axis functioning are scarce. Here, we studied adversity-driven changes in HPA-axis functioning during adolescence (N=141). HPA-axis functioning (basal cortisol, cortisol awakening response, anticipation of, reaction to and recovery after a stress task) was measured twice, at age 16 and 19. Adversity (i.e., social defeat and loss/illness) since age 16 was measured extensively with the Life Stress Interview at age 19. Adolescents who reported being exposed to social defeat showed increases in basal cortisol (n2=0.029) and decreases in reaction to the stress task (n2=0.030) from age 16-19, compared to their peers in the loss/illness and no stress group. The current study provides unique longitudinal data on the role of adversity in HPA axis functioning. Evidence is provided that adversity can affect the body's neuroendocrine response to stress, dependent on the nature of both the HPA measures and adverse events under study. PMID- 28818774 TI - A quantum-dot-based fluoroassay for detection of food-borne pathogens. AB - Evaluation of the distribution capability of food-borne pathogens existing in food products by taking the advantage of quantum dots (QDs) for their photoluminescence properties was carried out. Bacteria namely Escherichia coli (E. coli) labelled with CdSe-QDs were examined both on an Agar nutrient and ground fish substrates in order to observe their growth rate in different environments in the Lab. A sample with an appropriate concentration ratio 107CFU/mL of bacteria/CdSe-QDs was empirically selected from the samples which were grown on the Agar containing plates. The selected sample was also tested on a ground fish substrate as a real food sample. The bacterial growth was observed under the irradiation of UV light and the growth patterns were investigated for 3 successive days. The growth patterns indicated that E. coli can stay alive and can be distributed on food products so that the growth can be easily monitored. This approach makes bacterial growth on food products detectable so that it can be used as a bacteria-QD assay for an easy detection of food borne pathogens grown on a food sample. PMID- 28818775 TI - alpha-Bisabolol improves 5-aminolevulinic acid retention in buccal tissues: Potential application in the photodynamic therapy of oral cancer. AB - CONTEXT: 5-Aminolevulinic acid (5-ALA) is a prodrug used in photodynamic therapy (PDT) of tumors, including cancer of the oral mucosa. 5-ALA poorly penetrates oral tissues due to its high hydrophilicity, which impairs its local effects in PDT. OBJECTIVES: To examine whether alpha-bisabolol (alpha-Bis) influences the 5 ALA permeability in the porcine buccal mucosa, to an extent that improves its application in PDT (which requires low permeation and high retention in the buccal mucosa). METHODS: In vitro permeability studies with 5-ALA (1% and 10% w/w) associated with alpha-Bis (1% to 20% w/w) in propylene glycol were carried out at 4h and 24h using porcine buccal mucosa in a modified Franz cell system. The in vitro release profiles (0.5 to 48h) of the selected formulation and its respective control were determined using artificial membranes. Samples of buccal mucosa treated with the formulation were submitted to histopathological analysis, using a routine optical microscopy technique. RESULTS: The association of 1% 5 ALA and 5% alpha-Bis provided the best results; after 4h of treatment with this formulation, the 5-ALA permeation was low and its retention in the mucosa was six fold higher than that promoted by the control formulation (5-ALA alone). Histological analysis of the porcine buccal mucosa evidenced that 5% alpha-Bis altered the tissue morphology, which probably promoted 5-ALA retention. We concluded that 5% alpha-Bis is a potential adjuvant in formulations containing 5 ALA that could improve its retention after topical oral administration for the PDT treatment of cancer. PMID- 28818776 TI - Bacillus thuringiensis coated zinc oxide nanoparticle and its biopesticidal effects on the pulse beetle, Callosobruchus maculatus. AB - Insect pests belonging to the genus Callosobruchus are the major cause of damage to stored pulse crops. Recently, nanotechnology has emerged as a promising tool for pest control. In the present study, we report for the first time the synthesis and biological evaluation of Bacillus thuringiensis coated zinc oxide nanoparticles (Bt-ZnO NPs) on the pulse beetle, Callosobruchus maculatus. The biologically synthesized Bt-ZnO NPs were extensively characterized using UV-Vis spectroscopy, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), Transmission electron microscopy (TEM) and Zeta potential. The bio physical characterization revealed that the Bt-ZnO NPs has a hexagonal wurtzite structures with an average particle size of 20nm. In addition, zeta potential measurement demonstrated that the Bt-ZnO NPs are negatively charged (-12.7mV) and are moderately stable. The biopesticidal effect of Bt-ZnO NPs was tested against the pulse beetle, C. maculatus. Treatment with Bt-ZnO NPs reduced the fecundity (eggs laid) and hatchability of C. maculatus in a dose-dependent manner. A significant delay in the larval, pupal and total development period of C. maculatus was observed after treatment with Bt-ZnO NPs at 25MUg/mL. Furthermore, Bt-ZnO NPs are highly effective in the control of C. maculatus and caused 100% mortality at 25MUg/mL. The LC50 value was estimated to be 10.71MUg/mL. In addition, treatment with Bt-ZnO NPs decreased the mid-gut alpha-amylase, cysteine protease, alpha-glucosidase and glutathione S-transferase (GST) activity in C. maculatus. Our results suggest that Bt-ZnO NPs are effective against C. maculatus and could be used as nanobiopesticides in the control of stored grain insect pests in the future. PMID- 28818777 TI - Algae biomass as a precursor for synthesis of nitrogen-and sulfur-co-doped carbon dots: A better probe in Arabidopsis guard cells and root tissues. AB - The challenge of controlling algal blooms and reusing algal biomass remain unsolved worldwide. We introduce a facile method to reuse Nannochloropsis biocrude oil (NBO) for the synthesis of nitrogen and sulfur co-doped carbon dots (N-S-C-dots). N-S-C-dots can pass through the heavily thickened wall of mature Arabidopsis thaliana (A. thaliana) guard cells because of high solubility and excellent biocompatibility. N-S-C-dots exhibit multicolor luminescence and could effectively reduce the interference of autofluorescence in plant cells by changing filters. Bioimaging of root tissues reveals that 2 major factors affect the transmission of N-S-C-dots: high osmotic pressure and intensity of cellular metabolism. This study highlights the potential application of CDs for bioimaging in plant cells and demonstrates the significance of investigating the reuse of algal biomass. PMID- 28818778 TI - Potential effect of compounds isolated from Coffea arabica against UV-B induced skin damage by protecting fibroblast cells. AB - Ultraviolet (UV) radiation has adverse effects on extracellular matrix (ECM) proteins, leading to formation of wrinkles a hallmark of premature skin aging. The adverse effects of UV radiation are associated with induction of matrix metalloproteinases (MMPs) expression and degradation of collagen and elastin. The present study investigated anti-wrinkle effects of chlorogenic acid (CGA), pyrocatechol (PC) and 3,4,5-tricaffeoyl quinic acid (TCQ), isolated from beans of Coffea arabica, against UV-B stimulated mouse fibroblast cells (CCRF) by measuring expression levels of MMP-1, 3, 9, and type-I procollagen. The three compounds were isolated and purified from coffee grounds using column chromatography and structural examination was evaluated by nuclear magnetic resonance (NMR) analysis. Among the three isolated compounds, CGA effectively suppressed the expression of the MMP-1, 3, and 9 and increased synthesis of type I procollagen as compared UV-B-stimulated CCRF cells. In addition, CGA dose dependently inhibited intracellular reactive oxygen species (ROS) production in CCRF cells stimulated by UV radiation. Moreover, CGA displayed a good sun protection factor (SPF) and in vitro DNA damage protection together with inhibition of enzyme xanthine oxidase. The enzyme inhibitory kinetic behavior of CGA was determined by Lineweaver-Burk plot, displayed a mixed type enzyme inhibition with 260.3+/-4.5MUM, Ki value. The results indicate that CGA has potential to be used as a preventive agent against premature skin aging induced by UV radiation. PMID- 28818779 TI - In vitro culture responses, callus growth and organogenetic potential of brinjal (Solanum melongena L.) to He-Ne laser irradiation. AB - The present investigation was designed to analyze the influence of Helium-Neon (He-Ne 632.8nm) laser irradiation on defense enzymes, proline content and in vitro responses of callus induction, shoot initiation and on plantlet regeneration potential of brinjal. The seeds of Mattu Gulla (Solanum melongena L.) were irradiated with 20, 25 and 30J/cm2 of He-Ne laser followed by surface sterilization and sprouted on Murashige and Skoog medium without plant growth regulators. The activity of defense enzymes, proline content and the organogenetic potential of hypocotyl, leaf and shoot tip explants were determined from thirty day old seedlings. During seed germination, most of the seedlings showed normal two cotyledons whereas small number of seedlings showed tricotyledonous at 20J/cm2 treatment and no other morphological abnormalities were observed during further growth and development. There was no substantial variation was noted in both beta-1,3-glucanase and chitinase activity as well as proline content which proves the He-Ne laser irradiation does not causes any stresses for the plant. The in vitro culture of hypocotyl, leaf and shoot tip explants from laser irradiated seedlings showed differential responses as compared to un-irradiated control. The laser induced enhancement of callus induction, growth rate of callus tissues and shoot tip, percentage of responses of shoot and root initiation, days to shoot and root initiation, shoots formed per callus, number of roots per shoots, length of roots and nuclear DNA content of in vitro raised plants were evaluated. Among the tested laser doses (20, 25 and 30J/cm2), 25J/cm2 showed significant biostimulatory effect over un-irradiated control seedlings. The present observations reveal and endorsed our earlier reports with substantial enhancement of in vitro and ex vitro by He-Ne laser irradiation. PMID- 28818780 TI - Prognostic value of left ventricular-arterial coupling in elderly patients with septic shock. AB - PURPOSE: To investigate the predictive value of left ventricular-arterial coupling (VAC) for clinical prognosis of elderly patients with septic shock. MATERIALS AND METHODS: This was a single-center prospective cohort study of 63 elderly patients with septic shock treated between August 2014 and January 2016 at the 30-bed intensive care unit (ICU) of Zhejiang Hospital (China). Left VAC was evaluated by transthoracic echocardiography (TTE). End-systolic elastance (Ees) and left ventricular ejection fraction (LVEF) were measured; arterial elastance (Ea) was calculated. The 28-day survival was evaluated. RESULTS: Compared with non-survivors, survivors had a significantly lower Ea/Ees ratio (P<0.01), mainly because survivors had higher Ees values (P<0.01), but without difference in Ea (P=0.720). LVEF was greater (47.5+/-7.3 vs. 43.6+/-6.4, P=0.03); LVESV was smaller in survivors compared to non-survivors (P<0.05). The multivariate Cox proportional regression analysis showed that APACHEII scores (hazard ratio (HR)=1.12, 95% confidence interval (95%CI):1.01-1.25, P=0.04), blood lactate levels (HR=1.21, 95%CI:1.07-1.36, P=0.002), and VAC (HR=2.57, 95%CI:1.29-5.13, P=0.007) were independently associated with 28-day mortality of elderly patients with septic shock. The optimal cutoff point of VAC for predicting 28-day mortality was 2.14 with 56.7% sensibility and 87.9% specificity; the area under the curve was 0.74. CONCLUSIONS: Left VAC has prognostic value in elderly patients with septic shock. PMID- 28818781 TI - Dopamine-modified highly porous hydroxyapatite microtube networks with efficient near-infrared photothermal effect, enhanced protein adsorption and mineralization performance. AB - In the last decade, the porous hydroxyapatite (HAP) scaffold has been investigated for the application in tissue engineering owing to its good bioactivity and high biocompatibility. In this work, the dopamine-modified highly porous hydroxyapatite microtube three-dimensional (3-D) networks with efficient near-infrared photothermal effect, enhanced protein adsorption and mineralization performance have been prepared through a facile method. The dopamine-modified highly porous HAP networks exhibit ultrahigh porosity (90.6%), uniform pore distribution, interconnected pore structure and outstanding mechanical properties. After being modified with dopamine, the protein adsorption amount, cell attachment performance, and mineralization ability of the dopamine-modified highly porous HAP network can be greatly improved. In addition, the as-prepared dopamine-modified highly porous HAP networks exhibit good biocompatibility, excellent near-infrared photothermal effect, and good mechanical properties. The experimental results indicate that the dopamine-modified highly porous HAP networks are promising for various applications. PMID- 28818782 TI - Mesoporous silica nanoparticles (MSNs)-based organic/inorganic hybrid nanocarriers loading 5-Fluorouracil for the treatment of colon cancer with improved anticancer efficacy. AB - Novel methods to improve the anticancer performance of 5-fluorouracil (5-FU) is quite necessary for clinical medicines. In the present work, we fabricated a novel type of mesoporous silica nanoparticles (MSNs)-based inorganic/organic hybrid nanoparticles covalently attached with poly(oligo(ethylene glycol) monomethyl ether methacrylate) (POEGMA) for improved stabilization and targeting peptide (RGD) for targeted delivery with the aim of improving the anticancer performance of 5-FU. Atom transfer radical polymerization (ATRP) initiator functionalized MSN (MSN-Br) was synthesized at first, which was followed by surface-initiated ATRP of water soluble OEGMA and carboxyl-containing monomer (2 succinyloxyethyl methacrylate, SEMA). Functionalization of RGD onto the hydrophilic P(OEGMA-co-SEMA) chains afforded the final hybrid nanoparticle, MSN P(OEGMA-co-RGD). 5-FU can be effectively loaded into the meso-pores of MSN P(OEGMA-co-RGD) (5-FU@MSN-RGD) with drug content ~7.5wt%. And the dynamic diameter (Dh) and zeta potential (zeta) of 5-FU@MSN-RGD were determined to be 199.3+/-5.4nm and -8.7+/-0.5mV, respectively. It was demonstrated that MSN P(OEGMA-co-RGD) exhibited improved internalization into colon cancer cells and enhanced accumulation in tumor tissues. In addition, compared with free 5-FU, 5 FU@MSN-RGD showed enhanced anticancer efficacy both in vitro and in vivo, implying promising clinical applications. PMID- 28818783 TI - Development of a porous 3D graphene-PDMS scaffold for improved osseointegration. AB - Osseointegration in orthopedic surgery plays an important role for bone implantation success. Traditional treatment of implant surface aimed at improved osseointegration has limited capability for its poor performance in supporting cell growth and proliferation. Polydimethylsiloxane (PDMS) is a widely used silicon-based organic polymer material with properties that are useful in cosmetics, domestic applications and mechanical engineering. In addition, the biocompatibility of PDMS, in part due to the high solubility of oxygen, makes it an ideal material for cell-based implants. Notwithstanding its potential, a property that can inhibit PDMS bioactivity is the high hydrophobicity, limiting its use to date in tissue engineering. Here, we describe an efficient approach to produce porous, durable and cytocompatible PDMS-based 3D structures, coated with reduced graphene oxide (RGO). The RGO/PDMS scaffold has good mechanical strength and with pore sizes ranging from 10 to 600MUm. Importantly, the scaffold is able to support growth and differentiation of human adipose stem cells (ADSCs) to an osteogenic cell lineage, indicative of its potential as a transition structure of an osseointegrated implant. PMID- 28818785 TI - A single-tube approach for in vitro diagnostics using diatomaceous earth and optical sensor. AB - Versatile, simple and efficient sample preparation is desirable for point-of-care testing of emerging diseases such as zoonoses, but current sample preparation assays are insensitive, labour-intensive and time-consuming and require multiple instruments. We developed a single-tube sample preparation approach involving direct pathogen enrichment and extraction from human specimens using diatomaceous earth (DE). Amine-modified DE was used to directly enrich a zoonotic pathogen, Brucella, in a large sample volume. Next, a complex of amine-modified DE and dimethyl suberimidate was used for nucleic acid extraction from the enriched pathogen. Using our single-tube approach, the pathogen can be enriched and extracted within 60min at a level of 1 colony formation unit (CFU) from a 1ml sample volume in the same tube. The performance of this approach is 10-100 times better than that of a commercial kit (102 to 103CFU/ml) but does not require a large centrifuge. Finally, we combined the single-tube approach with a bio optical sensor for rapid and accurate zoonotic pathogen detection in human urine samples. Using the combination system, Brucella in human urine can be efficiently enriched (~ 8-fold) and the detection limit is enhanced by up to 100 times (1CFU/ml bacteria in urine) compared with the commercial kit. This combined system is fast and highly sensitive and thus represents a promising approach for disease diagnosis in the clinical setting. PMID- 28818784 TI - Does polysaccharide is an idea template selection for glycosyl imprinting? AB - A novel glycoprotein imprinting strategy was proposed and was applied to the detection of the carbohydrate antigen 19-9. The glycosylated complex of glycoprotein was used as template to construct a glycosyl imprinted sensor. The eluted imprinted cavities showed good affinity for template glycosyls and glycoproteins carrying template glycosyl. The effect of template saccharide structure on glycosyl imprinted sensors is further discussed. More complex template structures can lead to better sensor performance including selectivity and sensitivity. As a result, the polysaccharide imprinted sensor showed preeminent linear response to CA19-9 in the range of 0.1-5U/mL, with a detection limit of 0.028U/mL (3delta/K), while the linear of the monosaccharide imprinted sensor was 1-60U/mL and the detection limit was 0.17U/mL. The complex structure on the template surface provides more possibilities for the recognition of the template molecules, consequently, led to the significant anti-interference capability of the polysaccharide imprinted sensor. Furthermore, recoveries ranging from 93.0% to 103.5% were achieved when human serum samples were assayed using the polysaccharide imprinted sensor. PMID- 28818786 TI - A pilot yoga physical education curriculum to promote positive body image. AB - We examined the effects of a pilot yoga-based physical education (PE) curriculum by testing for change in trait body surveillance, physical self-worth, and body appreciation. Further, we examined the relationships among change in body image variables and the role of state mindfulness in predicting state body surveillance during classes. Adolescents participated in 12 weeks of yoga-based (n=20; Mage=16.45, 90% female) or traditional (n=23;Mage=14.52, 57% female) PE. Results showed significant (p=.004), moderate decreases in trait body surveillance and minimal nonsignificant (p=.11) increases in physical self-worth. Change in trait body surveillance was inversely related to change in physical self-worth and body appreciation in yoga participants. Multi-level modeling analyses revealed that more mindful students also surveyed their body less during class. Intentionally structured yoga participation may support positive body image among adolescents. PMID- 28818787 TI - Socializing girls whose bodies may not align with contemporary ideals of thinness: An interpretive study of US mothers' accounts. AB - We sought to understand how mothers of young adolescent girls who are perceived as overweight or at risk for becoming so and whose body mass indices are at the 70th percentile or higher socialize their daughters about body, weight, eating, and health. In-depth interviews were conducted with 13 US mothers, and data were analyzed using constant comparison processes. Findings revealed that mothers adopted a variety of strategies - including teaching, modeling, managing, avoiding, and comforting - to achieve varied socialization goals for their daughters. Specifically, mothers sought to help their daughters to accept the self, reject the hegemonic ideal, maintain "healthful" eating, avoid overeating/monitor the self for over-eating, engage in regular physical activity, and/or navigate stigmatizing social situations. Mothers' sometimes experienced ambivalence or uncertainty as they socialized their daughters about the body, suggesting that they may benefit from professional counseling designed to resolve this tension/hesitancy. PMID- 28818788 TI - Does the work environment matter? Sexual objectification and waitresses' body dissatisfaction. AB - We investigated the relations between working in sexually objectifying restaurant environments and body dissatisfaction in a sample of 252 United States waitresses. Supporting our hypotheses, results indicated that working in sexually objectifying restaurant environments was positively correlated with waitresses' body dissatisfaction. Our findings also supported a theorized serial three-chain mediation model in which working in sexually objectifying restaurant environments was related to body dissatisfaction through more thin ideal internalization and greater self-objectification/body surveillance. Furthermore, thin ideal internalization had a direct, unique link to body dissatisfaction. Our findings highlight the importance of working conditions and internalization processes in understanding waitresses' body image concerns. PMID- 28818789 TI - Immune mechanisms of respiratory viral infections in asthma. AB - The more severe pathology respiratory viral infections produce in asthma sufferers is a result of a dysregulated immune response. Excess type 2 inflammation is a well-described feature of virally induced asthma exacerbations, with growing evidence that production of antiviral interferons may also be impaired. However, the mechanisms underlying these are little understood. This review summarizes the current understanding and recent discoveries of the cellular and molecular events that follow viral infections in asthma. In particular, we discuss differences in viral sensing and intracellular signalling pathways upstream of interferon induction in asthma, and the role of epithelial derived cytokines in orchestrating type 2 immunopathology, including type 2 innate lymhpoid cells (ILC2s). PMID- 28818790 TI - Effects of semantic neighborhood density in abstract and concrete words. AB - Concrete and abstract words are thought to differ along several psycholinguistic variables, such as frequency and emotional content. Here, we consider another variable, semantic neighborhood density, which has received much less attention, likely because semantic neighborhoods of abstract words are difficult to measure. Using a corpus-based method that creates representations of words that emphasize featural information, the current investigation explores the relationship between neighborhood density and concreteness in a large set of English nouns. Two important observations emerge. First, semantic neighborhood density is higher for concrete than for abstract words, even when other variables are accounted for, especially for smaller neighborhood sizes. Second, the effects of semantic neighborhood density on behavior are different for concrete and abstract words. Lexical decision reaction times are fastest for words with sparse neighborhoods; however, this effect is stronger for concrete words than for abstract words. These results suggest that semantic neighborhood density plays a role in the cognitive and psycholinguistic differences between concrete and abstract words, and should be taken into account in studies involving lexical semantics. Furthermore, the pattern of results with the current feature-based neighborhood measure is very different from that with associatively defined neighborhoods, suggesting that these two methods should be treated as separate measures rather than two interchangeable measures of semantic neighborhoods. PMID- 28818791 TI - Low-density lipoprotein modified by myeloperoxidase oxidants induces endothelial dysfunction. AB - Low-density lipoprotein (LDL) modified by hypochlorous acid (HOCl) produced by myeloperoxidase (MPO) is present in atherosclerotic lesions, where it is implicated in the propagation of inflammation and acceleration of lesion development by multiple pathways, including the induction of endothelial dysfunction. Thiocyanate (SCN-) ions are utilised by MPO to produce the oxidant hypothiocyanous acid (HOSCN), which reacts with LDL in a different manner to HOCl. Whilst the reactivity of HOCl-modified LDL has been previously studied, the role of HOSCN in the modification of LDL in vivo is poorly defined, although emerging evidence suggests that these particles have distinct biological properties. This is important because elevated plasma SCN- is linked with both the propagation and prevention of atherosclerosis. In this study, we demonstrate that both HOSCN- and HOCl-modified LDL inhibit endothelium-mediated vasorelaxation ex vivo in rat aortic ring segments. In vitro experiments with human coronary artery endothelial cells show that HOSCN-modified LDL decreases in the production of nitric oxide (NO*) and induces the loss of endothelial nitric oxide synthase (eNOS) activity. This occurs to a similar extent to that seen with HOCl-modified LDL. In each case, these effects are related to eNOS uncoupling, rather than altered expression, phosphorylation or cellular localisation. Together, these data provide new insights into role of MPO and LDL modification in the induction of endothelial dysfunction, which has implications for both the therapeutic use of SCN- within the setting of atherosclerosis and for smokers, who have elevated plasma levels of SCN-, and are more at risk of developing cardiovascular disease. PMID- 28818794 TI - Comprehensive and comparative ecotoxicological and human risk assessment of polycyclic aromatic hydrocarbons (PAHs) in reef surface sediments and coastal seawaters of Iranian Coral Islands, Persian Gulf. AB - The concentration and spatial distribution along with ecotoxicological risk of 30 polycyclic aromatic hydrocarbons were investigated in the reef surface sediments (RSSs) and coastal seawater (CSW) of ten coral Islands from the Persian Gulf, Iran, in January 2015. For all sampling sites, assessment of ecological risk was undertaken using several approaches. Mean concentration of ?30PAHs varied between 70 and 884ngL-l with an overall mean value of 464ngL-l in the CSW, while the RSS ranged from 274 to 1098ngg-1dw with a total average of 619ngg-1dw. The results showed a gradient in PAH concentration and toxicity estimates from the northern Hormoz site increasing to the eastern Kharg site. Most of the toxicity estimates were in the moderate range or less than risk values for damage to the marine environment. The calculated Dermal Hazard Quotient (HQs), the sum of HQs (HI) and other cancer risk values of most compounds were less than safety values at most sites. It means that the possibility of negative effects of PAHs via dermal absorption from sediments for children and adults is low. Some sampling sites studied have already been impacted with hazardous pollutants for an extended period of time and evidence from this investigation demonstrates that mixtures of PAHs may be carcinogenic to humans, especially in the western part of the Gulf. PMID- 28818793 TI - Cellular adaptation to xenobiotics: Interplay between xenosensors, reactive oxygen species and FOXO transcription factors. AB - Cells adapt to an exposure to xenobiotics by upregulating the biosynthesis of proteins involved in xenobiotic metabolism. This is achieved largely via activation of cellular xenosensors that modulate gene expression. Biotransformation of xenobiotics frequently comes with the generation of reactive oxygen species (ROS). ROS, in turn, are known modulators of signal transduction processes. FOXO (forkhead box, class O) transcription factors are among the proteins deeply involved in the cellular response to stress, including oxidative stress elicited by the formation of ROS. On the one hand, FOXO activity is modulated by ROS, while on the other, FOXO target genes include many that encode antioxidant proteins - thereby establishing a regulatory circuit. Here, the role of ROS and of FOXOs in the regulation of xenosensor transcriptional activities will be discussed. Constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptors (PPARs), arylhydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) all interact with FOXOs and/or ROS. The two latter not only fine-tune the activities of xenosensors but also mediate interactions between them. As a consequence, the emerging picture of an interplay between xenosensors, ROS and FOXO transcription factors suggests a modulatory role of ROS and FOXOs in the cellular adaptive response to xenobiotics. PMID- 28818792 TI - Regulation of type I interferon responses by mitochondria-derived reactive oxygen species in plasmacytoid dendritic cells. AB - Mitochondrial reactive oxygen species (mtROS) generated continuously under physiological conditions have recently emerged as critical players in the regulation of immune signaling pathways. In this study we have investigated the regulation of antiviral signaling by increased mtROS production in plasmacytoid dendritic cells (pDCs), which, as major producers of type I interferons (IFN), are the key coordinators of antiviral immunity. The early phase of type I IFN production in pDCs is mediated by endosomal Toll-like receptors (TLRs), whereas the late phase of IFN response can also be triggered by cytosolic retinoic acid inducible gene-I (RIG-I), expression of which is induced upon TLR stimulation. Therefore, pDCs provide an ideal model to study the impact of elevated mtROS on the antiviral signaling pathways initiated by receptors with distinct subcellular localization. We found that elevated level of mtROS alone did not change the phenotype and the baseline cytokine profile of resting pDCs. Nevertheless increased mtROS levels in pDCs lowered the TLR9-induced secretion of pro inflammatory mediators slightly, whereas reduced type I IFN production markedly via blocking phosphorylation of interferon regulatory factor 7 (IRF7), the key transcription factor of the TLR9 signaling pathway. The TLR9-induced expression of RIG-I in pDCs was also negatively regulated by enhanced mtROS production. On the contrary, elevated mtROS significantly augmented the RIG-I-stimulated expression of type I IFNs, as well as the expression of mitochondrial antiviral signaling (MAVS) protein and the phosphorylation of Akt and IRF3 that are essential components of RIG-I signaling. Collectively, our data suggest that increased mtROS exert diverse immunoregulatory functions in pDCs both in the early and late phase of type I IFN responses depending on which type of viral sensing pathway is stimulated. PMID- 28818795 TI - Mitigating inhibition of undissociated volatile fatty acids (VFAs) for enhanced sludge-rice bran composting with ferric nitrate amendment. AB - This study investigated the effect of ferric nitrate on mitigating the inhibition of volatile fatty acids (VFAs) during the initial phase of sewage sludge composting amended with rice bran. During the 34-day lab-scale composting, the supplementation of ferric nitrate enhanced the degradation of VFAs by up to 3 times as compared to the control. The organic matters loss (OML) rate in the treatment reactor was almost doubled with supplementation of ferric nitrate as compared to the control reactor during the initial phase. Eventually the treatment reactor achieved a 39.0% OML by the end of composting, which was 22% higher than the control. Ferric nitration addition mitigated the inhibition of VFAs by stimulating denitrification which consumed protons and VFAs. Ferric nitrate addition also decreased the electrical conductivity by 23% in the final compost product, reducing the possibility of phytotoxicity issue upon soil application. In summary, the results demonstrated that ferric nitrate addition could be an effective strategy for enhanced sludge composting. PMID- 28818796 TI - Dispersion induced ozone pretreatment of waste activated biosolids: Arriving biomethanation modelling parameters, energetic and cost assessment. AB - In this study, the phase separated effect of dispersion induced ozone pretreatment (DOP) was investigated. Solid reduction, biomass lysis and biomethane production were used as essential parameters to assess the potential of DOP over ozone pretreatment (OP). A higher suspended solid reduction of about 25.2% was achieved in DOP than OP 18%. The ozone dosage of 0.014gO3/g SS supported a maximal biomass lysis of about 32.8% when the biosolids were subjected to prior dispersion at 30s and 3000rpm. However, the same ozone dosage without phase separation achieved 9.6% biomass lysis. The second exponential model results of the biomethane assay showed that DOP enhanced the accessibility of disintegrated biosolids for methane production and induced about 1150mL/g VS of methane production. The energy analysis reveals that DOP provides significant amount of positive net energy (152.65kWh/ton) when compared to OP ( 12.42kWh/ton). PMID- 28818797 TI - H2O2 induced cost effective microwave disintegration of dairy waste activated sludge in acidic environment for efficient biomethane generation. AB - This study aimed to improve the biomethane potential of dairy waste activated sludge (WAS) by H2O2-acidic pH induced microwave disintegration (HAMW-D) pretreatment approach. The results of HAMW-D compared with the microwave disintegration (MW-D) alone for energy and economic factors. In the two phase disintegration process, the H2O2 concentration of about 0.5mg/g SS under acid pH of 5 was found to be optimum for effective dissociation of Extracellular Polymeric Substances (EPS) matrix. A higher liquefaction of about 46.6% was achieved in HAMW-D when compared to that of MW-D (30%). It subsequently improved the methane yield of about 250mL/g VS in HAMW-D, which was 9.6% higher than MW-D. A net profit of about 49?/ton was achieved for HAMW-D, therefore it is highly recommended for WAS pretreatment. PMID- 28818798 TI - Advances towards understanding and engineering direct interspecies electron transfer in anaerobic digestion. AB - Direct interspecies electron transfer (DIET) is a recently discovered microbial syntrophy where cell-to-cell electron transfer occurs between syntrophic microbial species. DIET between bacteria and methanogenic archaea in anaerobic digestion can accelerate the syntrophic conversion of various reduced organic compounds to methane. DIET-based syntrophy can naturally occur in some anaerobic digester via conductive pili, however, can be engineered via the addition of various non-biological conductive materials. In recent years, research into understanding and engineering DIET-based syntrophy has emerged with the aim of improving methanogenesis kinetics in anaerobic digestion. This article presents a state-of-art review focusing on the fundamental mechanisms, key microbial players, the role of electrical conductivity, the effectiveness of various conductive additives, the significance of substrate characteristics and organic loading rates in promoting DIET in anaerobic digestion. PMID- 28818799 TI - An ultrafiltration and high performance liquid chromatography coupled with diode array detector and mass spectrometry approach for screening and characterizing thrombin inhibitors from Rhizoma Chuanxiong. AB - Thrombin (THR) plays a significant role in thromboembolic diseases, direct THR inhibitors are a class of important clinical anticoagulant drugs. This study established a THR in-solution based biospecific extraction combined with ultrafiltration and high performance liquid chromatography coupled with diode array detector and mass spectrometry analysis (TUA) method to screen and identify ligands for THR in Rhizoma Chuanxiong. After evaluating the reliability of the present TUA method using positive (argatroban) and negative (adenosine, tirofiban, ticagrelor) control drugs, this method was successfully applied to detect eight potential active compounds in Rhizoma Chuanxiong. Two new THR targeted compounds isochlorogenic acid C and senkyunolide I with high THR inhibitory activity (IC50 206.48 and 197.23MUM, respectively) were identified by liquid chromatography/mass spectrometry and enzyme inhibitory activity test finally. They were reported with direct THR inhibition activity for the first time and their ligand-THR interactions were explored by in silico molecular docking research. In addition, based on the TUA screening result, four compounds gained similar structure with the two hit compounds were also investigated as promising candidates targeting THR with high binding energy (>5.0kcal/mol). These results may prove that the proposed method could effectively screen THR inhibitors in complex mixtures. PMID- 28818800 TI - The step-wise framework to design a chromatography-based hydrophobicity assay for viral particles. AB - A high-salt, hydrophobic interaction chromatography (HIC) method was developed to measure the relative hydrophobicity of a diverse set of solutes. Through the careful control of buffer pH and salt concentration, this assay was then used to ascertain for the first time the relative hydrophobicity values of three different bacteriophage, four mammalian viruses, and a range of biotech medicinal proteins as benchmarked to protein standards previously characterized for hydrophobicity. PMID- 28818801 TI - Development and validation of a reliable method for thiopurine methyltransferase (TPMT) enzyme activity in human whole blood by LC-MS/MS: An application for phenotypic and genotypic correlations. AB - A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the determination of thiopurine methyltransferase (TPMT) activity in human whole blood lysate, based on conversion of 6-mercaptopurine (6-MP) by TPMT to 6 methylmercaptopurine (6-MMP) using S-adenosyl-l-methionine (SAM) as the methyl donor. This method was improved from the previous laborious method for washing of red cell lysate preparation to develop whole blood EDTA lysate. In addition, the TPMT incubation was optimized and the chromatography was performed in a short runtime of 7min on a C18-column by detection via triple quadrupole mass spectrometry. The MS/MS was optimally tuned to monitor mass to charge a ratio (m/z) for 6-MMP 167.2->151.9 and the isotope 6-MMP-d3 with m/z of 170.5->152.2 were applied as an internal standard. The calibration curve covered the range of 2.5-360ng/ml and the correlation coefficient was greater than 0.999. The accuracy of this method was determined in four concentrations of control of quality that ranged between 99.33 and 106.33%. The intra-assay coefficient of variation (CV) was less than 4.41% and the inter-assay was less than 5.43%. This method developed for measuring TPMT by LC-MS/MS is a reliable, safe, and simple with a small volume requirement (100MUl of whole blood EDTA). The assay was used to study TPMT activity in 132 Thai children with a range from 29.0 to 89.1nmol 6 MMP/g Hb/h with means and median values of TPMT activity 55.9+/-12.47nmol 6-MMP/g Hb/h and 54.2nmol 6-MMP/g Hb/h. The genotype-phenotype association of TPMT was evaluated for common ethnic Thai single nucleotide polymorphisms (SNP) in 30 samples and demonstrated good concordance. PMID- 28818802 TI - Development and validation of a GC-MS method for the determination of hydroxyzine and its active metabolite, cetirizine, in whole blood. AB - A simple, rapid, sensitive and accurate gas chromatography-mass spectrometric method was developed and validated for the simultaneous determination of hydroxyzine and cetirizine in whole blood. Solid-phase extraction procedure using Bond Elut LRC Certify II columns was used for the isolation of hydroxyzine and cetirizine from 1mL whole blood followed by derivatization with a mixture of acetic anhydride:n-propanol (1:1, v/v). Limits of detection and quantification were 1.50 and 5.00ng/mL, respectively. The assay was linear within the concentration range of 5.00-1000.0ng/mL and the correlation coefficient was R2>=0.993 for both analytes. Absolute recovery was determined at three quality control concentration levels and was found to be at least 87.2% for both substances. Intra-day and inter-day accuracy values for both hydroxyzine and cetirizine were ranged from -1.2 to 3.8% and -2.7 to 2.0%, respectively, at the three concentration levels studied, whereas their respective intra-day and inter day precision values were less than 9.9 and 6.5%, respectively, in terms of relative standard deviation (%RSD). The developed method was successfully applied for the quantification of hydroxyzine and cetirizine concentrations in whole blood, during the investigation of clinical cases where these two antihistamines were detected. PMID- 28818803 TI - Polymorphic characterization and bioavailability of 20(R)-25-methoxyl-dammarane 3beta,12beta,20-triol, a novel dammarane triterpenoid saponin, as anticancer agents. AB - This research, for the first time, obtained and reported three novel Form I, Form II, and Form III of 20(R)-25-methoxyl-dammarane-3beta,12beta,20-triol polymorphs, which were distinguished by PXRD, IR, DSC, and SEM. This study firstly exploited a rapid and feasible UHPLC-ESI-MS/MS method to determine plasma levels of 20(R) 25-OCH3-PPD within 4.5min. The composition of mobile phase was acetonitrile and 5mM ammonium acetate water (85:15, v/v) at a flow rate of 0.2mL/min on the BEH C18 Column (2.1mm*50mm, 1.7MUm). The approach enhanced the efficiency of analysis compared to reported methods, making a 3-fold reduction in runtimes. The research exhibited that optimal crystal Form I displays higher bioavailability (P<0.05) compared to the other crystal forms. These findings hold great significance in the early research stages of 20(R)-25-OCH3-PPD polymorphs. PMID- 28818804 TI - An on-spot internal standard addition approach for accurately determining colistin A and colistin B in dried blood spots using ultra high-performance liquid chromatography-tandem mass spectrometry. AB - Outbreaks of multidrug-resistant Gram-negative bacterial infections have been reported worldwide. Colistin, an antibiotic with known nephrotoxicity and neurotoxicity, is now being used to treat multidrug-resistant Gram-negative strains. In this study, we applied an on-spot internal standard addition approach coupled with an ultra high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify colistin A and B from dried blood spots (DBSs). Only 15MUL of whole blood was required for each sample. An internal standard with the same yield of extraction recoveries as colistin was added to the spot before sample extraction for accurate quantification. Formic acid in water (0.15%) with an equal volume of acetonitrile (50:50v/v) was used as the extraction solution. With the optimized extraction process and LC-MS/MS conditions, colistin A and B could be quantified from a DBS with respective limits of quantification of 0.13 and 0.27MUgmL-1, and the retention times were < 2min. The relative standard deviations of within-run and between-run precisions for peak area ratios were all < 17.3%. Accuracies were 91.5-111.2% for lower limit of quantification, low, medium, and high QC samples. The stability of the easily hydrolyzed prodrug, colistin methanesulfonate, was investigated in DBSs. Less than 4% of the prodrug was found to be hydrolyzed in DBSs at room temperature after 48h. The developed method applied an on-spot internal standard addition approach which benefited the precision and accuracy. Results showed that DBS sampling coupled with the sensitive LC-MS/MS method has the potential to be an alternative approach for colistin quantification, where the bias of prodrug hydrolysis in liquid samples is decreased. PMID- 28818805 TI - Association between consumption of private well water contaminated by low levels of arsenic and dysglycemia in a rural region of Quebec, Canada. AB - The association between arsenic (As) exposure and diabetes is not clearly defined for populations exposed to low or moderate levels of inorganic As (iAs) in drinking water (< 150ug/L). In the present study, the relationship between iAs concentration in drinking water (contaminated at a median level of 10.5ug/L) or As biomarkers (ie, urine and nails) and diabetes or prediabetes (defined as level of glycosylated hemoglobin - HbA1c - higher than 6%, self-reported diagnosis of diabetes by a physician, or the use of insulin or oral hypoglycemic drugs) was evaluated in 257 adults from Canada. For that we used logistic regression models and reported the odds ratio (OR) comparing participants in the 80th vs 20th percentile of iAs exposure indicators. The association between iAs exposure indicators and HbA1c was also explored for 234 adults and 35 children not taking insulin or oral hypoglycemic drugs using a linear regression analysis. All models were controlled for confounding variables (age, gender, first-degree family history of diabetes, obesity or overweight in adults' model). We attempted to exclude adults with organic arsenic of marine origin in their urine by removing participants with detectable arsenobetaine or arsenocholine in urinary models. iAs biomarkers (toenail and urine) were not associated with diabetes or prediabetes in adults. iAs in well water was associated with a borderline significantly increased odds of diabetes or prediabetes (OR = 2.39; 95% CI: 0.99 5.72). Higher well water iAs concentrations were significantly associated with increased HbA1c in both adults and children (beta: 0.002; p = 0.041 and beta: 0.003; p < 0.0001 respectively). In children, HbA1c was also associated with toenail As concentration (beta: 0.18; p = 0.016). These results suggest low-level iAs exposure is associated with a continuum of dysglycemia. PMID- 28818806 TI - Differences in the relationship between traumatic experiences, self-esteem, negative cognition, and Internet addiction symptoms among North Korean adolescent defectors and South Korean adolescents: A preliminary study. AB - North Korean adolescent defectors experience adaptation difficulties along with a wide range of psychosocial problems, but no study has yet examined their Internet addiction symptoms. We compared early traumatic experiences, self-esteem, negative cognition, and Internet addiction symptoms, as well as the relationships between these variables, between North Korean adolescent defectors and South Korean adolescents. Fifty-six North Korean adolescent defectors and 112 age- and sex- matched South Korean adolescents participated. The analyses examined the relationship between traumatic experiences and Internet addiction symptoms, with negative automatic thoughts or low self-esteem as mediators of these relations. North Korean adolescent defectors tended to have higher levels of negative automatic thoughts and more severe Internet addiction symptoms, as well as better self-esteem, than did South Korean adolescents. Furthermore, only among North Korean adolescent defectors, traumatic experiences were positively associated with Internet addition symptoms via increasing negative automatic thoughts. North Korean adolescent defectors are more susceptible to Internet addiction, negative cognitions, and early traumatic experiences compared to South Korean adolescents. However, the cross-sectional design of this study precludes consideration of the causality of these relationships. Interventions aiming to correct negative cognitions and increase self-esteem may be helpful for North Korean adolescent defectors with problematic Internet use. PMID- 28818807 TI - Early treatment initiation in lower-risk myelodysplastic syndromes produces an earlier and higher rate of transfusion independence. AB - Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis resulting in refractory cytopenias. Red blood cell (RBC) transfusions can improve anemia; however, prolonged transfusion dependence (TD) is associated with increased morbidity and mortality. Disease-modifying therapy (DMT) for MDS can reduce transfusion requirements, although the optimum timing of DMT initiation is unclear. This retrospective study analyzed linked SEER registry and Medicare claims (2006-2012) to estimate the impact of DMT-initiation (azacitidine, decitabine, or lenalidomide) timing (<= 3 vs.>3months from start of TD) on the likelihood of achieving transfusion independence (TI) among 508 TD patients with MDS. Mean time to DMT was 28days for early initiators (n=351) and 187days for late initiators (n=157). Fewer early initiators used erythropoiesis-stimulating agents before achieving TI versus late initiators (61.5% vs. 73.9%; P=0.007). In multivariate analyses, early DMT initiation predicted TI achievement (HR, 1.69; P<0.001); patients who met minimum active therapy-exposure requirements were more likely to achieve TI (HR, 2.12; P<0.001). Higher rates of TI were associated with reduced time between onset of TD and DMT initiation. Similarly, patients meeting the minimum treatment-exposure threshold had higher TI rates. PMID- 28818808 TI - Potent induction of apoptosis by givinostat in BCR-ABL1-positive and BCR-ABL1 negative precursor B-cell acute lymphoblastic leukemia cell lines. AB - We have previously shown that givinostat can induce potent apoptosis in the BCR ABL1-positive, TP53-wild type B-cell acute lymphoblastic leukemia (B-ALL) cell line SUP-B15. We extend our studies here to two additional B-ALL cell lines, BCR ABL1-negative CCRF-SB and p210 BCR-ABL1-positive NAML1. Givinostat induced significant cell growth inhibition in both cell lines, with an IC50 of 0.65+/ 0.052MUM and 0.25+/-0.028MUM in CCRF-SB and NAML1, respectively. The key signal protein of the BCR-ABL1, Crk-L1, was significantly reduced by givinostat treatment in NAML1. As in SUP-B15, givinostat induced apoptosis in both cell lines but showed different levels of cleavage of the procaspase proteins Casp-3, Casp-7 and PARP. Levels of cell cycle-DNA repair regulator p21, CHK1 and FANCD2 levels were markedly affected by givinostat treatment. These data further enrich our understanding of the mechanisms of the antineoplastic effects of givinostat in B-ALL and provide a preclinical rationale for the inclusion of givinostat or similar agent in leukemia therapy. PMID- 28818809 TI - Differential oxidative and antioxidative response of duckweed Lemna minor toward plant growth promoting/inhibiting bacteria. AB - Bacteria colonizing the plant rhizosphere are believed to positively or negatively affect the host plant productivity. This feature has inspired researchers to engineer such interactions to enhance crop production. However, it remains to be elucidated whether rhizobacteria influences plant oxidative stress vis-a-vis other environmental stressors, and whether such influence is associated with their growth promoting/inhibiting ability. In this study, two plant growth promoting bacteria (PGPB) and two plant growth-inhibiting bacteria (PGIB) were separately inoculated into axenic duckweed (Lemna minor) culture under laboratory conditions for 4 and 8 days in order to investigate their effects on plant oxidative stress and antioxidant activities. As previously characterized, the inoculation of PGPB and PGIB strains accelerated and reduced the growth of L. minor, respectively. After 4 and 8 days of cultivation, compared to the PGPB strains, the PGIB strains induced larger amounts of O2*-, H2O2, and malondialdehyde (MDA) in duckweed, although all bacterial strains consistently increased O2*- content by two times more than that in the aseptic control plants. Activities of five antioxidant enzymes were also elevated by the inoculation of PGIB, confirming the severe oxidative stress condition in plants. These results suggest that the surface attached bacteria affect differently on host oxidative stress and its response, which degree correlates negatively to their effects on plant growth. PMID- 28818810 TI - Evaluating quality of life in epilepsy: The role of screening for adverse drug effects, depression, and anxiety. AB - OBJECTIVE: The objective of this study was to evaluate the contribution of validated screening tools for antiepileptic drug (AED) adverse effects, depression, and anxiety to measure the quality of life (QoL) in people with epilepsy (PWE). METHODS: Patients in a tertiary epilepsy service were screened for quality of life (using QOLIE-31), major depressive disorder (MDD) (NDDI-E), generalized anxiety disorder (GAD) (GAD-7), and AED effects (AEP). Mini International Neuropsychiatric Interview (MINI) generalized anxiety disorder module was also performed. For AEP validation in French, the internal structural validity was analyzed. Dimensional (NDDI-E and GAD-7 scores) and categorical (MDD and GAD) analyses were performed to investigate interactions between QoL and AEP. RESULTS: A total of 132 (87 females) subjects were included. The French version of the AEP demonstrated satisfactory psychometric properties (Cronbach's alpha 0.87). Correlations between NDDI-E, GAD-7, AEP, and QOLIE-31 scores were high, and significant for all subscales of QOLIE-31; no effect of seizure-related variables was seen. Some sex differences in QOLIE-31 subscales were found, and mean AEP score was higher in females. Age, sex, NDDI-E, GAD-7, and AEP scores accounted for 61% of variance of QOLIE-31 scores. Differential effects were seen on QOLIE-31 subscales: AEP strongly correlated with all subscales; GAD-7 scores more strongly correlated with "Seizure Worry"; NDDI-E with "Energy-Fatigue"; and both NDDI-E and GAD-7 scores strongly correlated with "Emotional Well-Being". Categorical analysis of groups with MDD alone, GAD alone, MDD+GAD, and neither MDD nor GAD showed significant differences in AEP and QOLIE-31 scores, with MDD+GAD showing the most AED effects and the poorest QoL. SIGNIFICANCE: The combination of screening tools for depression (NDDI-E), anxiety (GAD-7), and AED effects (AEP) has a strong power for evaluating QoL in PWE. Coexisting MMD and GAD were associated with the poorest quality of life and the highest AEP scores. PMID- 28818811 TI - Brain tumors and epileptic spasms: Natural history and outcomes. AB - While brain tumors are a frequent cause of seizures, they rarely cause epileptic spasms (ES). The objective of this study was to investigate features of tumor associated ES. We conducted a retrospective review of patients with ES and a brain tumor. Demographics; pathologic, radiologic, and EEG data; treatment response; and long-term outcome were collected. Twenty four patients were identified; 11 met inclusion criteria. Epileptic spasm (ES) onset occurred prior to tumor diagnosis in seven patients (63%), and after tumor resection in 4 patients (36%). Spasms and ictal EEG often had focal features (45%). Gross total tumor resection resulted in ES freedom in 3/7 patients. There was poor response to first-line therapy (ACTH/vigabatrin; 1/5 with ES freedom). Low grade tumors predominated (8/11) with dual pathology (associated cortical malformation) in 2 patients. All tumors involved cortex; half involved subcortical regions and/or brainstem. Ten patients developed other seizure types; eight experienced refractory epilepsy, and nine had a Modified Rankin Scale of >3. In summary, EEG in tumor-associated ES often has focal features of either the semiology or EEG. Complete tumor resection yielded ES freedom in only a subset of patients. Most patients developed refractory epilepsy and adverse developmental outcomes. PMID- 28818812 TI - Airborne ultrafine particles in a Pacific Island country: Characteristics, sources and implications for human exposure. AB - The Pacific Islands carry a perception of having clean air, yet emissions from transport and burning activities are of concern in regard to air quality and health. Ultrafine particle number concentrations (PNCs), one of the best metrics to demonstrate combustion emissions, have not been measured either in Suva or elsewhere in the Islands. This work provides insight into PNC variation across Suva and its relationship with particle mass (PM) concentration and composition. Measurements over a short monitoring campaign provide a vignette of conditions in Suva. Ambient PNCs were monitored for 8 day at a fixed location, and mobile PNC sampling for two days. These were compared with PM concentration (TSP, PM10, PM2.5, PM1) and are discussed in relation to black carbon (BC) content and PM2.5 sources, determined from elemental concentrations; for the October 2015 period and longer-term data. Whilst Suva City PM levels remained fairly low, PM2.5 = 10 12 MUg m-3, mean PNC (1.64 +/- 0.02 * 104 cm-3) was high compared to global data. PNCs were greater during mobile sampling, with means of 10.3 +/- 1.4 * 104 cm-3 and 3.51 +/- 0.07 * 104 cm-3 when travelling by bus and taxi, respectively. Emissions from road vehicles, shipping, diesel and open burning were identified as PM sources for the October 2015 period. Transport related ultrafine particle emissions had a significant impact on microscale ambient concentrations, with PNCs near roads being 1.5 to 2 times higher than nearby outdoor locations and peak PNCs occurring during peak traffic times. Further data, particularly on transport and wet-season exposures, are required to confirm results. Understanding PNC in Suva will assist in formulating effective air emissions control strategies, potentially reducing population exposure across the Islands and in developing countries with similar emission characteristics. Suva's PNC was high in comparison to global data; high exposures were related to transport and combustion emissions, which were also identified as significant PM2.5 sources. PMID- 28818813 TI - Nitrogen loss from anaerobic ammonium oxidation coupled to Iron(III) reduction in a riparian zone. AB - Anaerobic ammonium oxidation coupled to iron(III) reduction (termed Feammox) is a recently discovered pathway of nitrogen cycling. However, little is known about the pathways of N transformation via Feammox process in riparian zones. In this study, evidence for Feammox in riparian zones with or without vegetation cover was demonstrated using isotope tracing technique and high-throughput sequencing technology. The results showed that Feammox could occur in riparian zones, and demonstrated that N2 directly from Feammox was dominant Feammox pathway. The Feammox rates in vegetated soil samples was 0.32-0.37 mg N kg-1 d-1, which is higher than that in un-vegetated soil samples (0.20 mg N kg-1 d-1). Moreover, the growth of vegetation led to a 4.99-6.41% increase in the abundance of iron reducing bacteria (Anaeromyxobacter, Pseudomonas and Geobacter) and iron reducing bacteria play an essential role in Feammox process. An estimated loss of 23.7 43.9 kg N ha-1 year-1 was associated with Feammox in the examined riparian zone. Overall, the co-occurrence of ammonium oxidation and iron reduction suggest that Feammox can play an essential role in the pathway of nitrogen removal in riparian zones. PMID- 28818814 TI - Exposure to polybrominated diphenyl ethers and perfluoroalkyl substances in a remote population of Alaska Natives. AB - BACKGROUND: Many Alaska Native communities rely on a traditional marine diet that contains persistent organic pollutants (POPs). The indoor environment is also a source of POPs. Polybrominated diphenyl ethers (PBDEs) and perfluoroalkyl substances (PFASs) are present both in the traditional diet and the home indoor environment. OBJECTIVES: We assessed exposure to PBDEs and PFASs among residents of two remote Alaska Native villages on St. Lawrence Island. Ninespine stickleback (Pungitious pungitious) and Alaska blackfish (Dallia pectoralis) were used to detect accumulation of these compounds in the local environment. METHODS: Concentrations of PBDEs and PFASs were measured in dust collected from 49 households on St. Lawrence Island, as well as in blood serum from 85 island residents. Resident ninespine stickleback and Alaska blackfish were used as sentinels to detect accumulation of PBDEs and PFASs in the food web. RESULTS: Serum concentrations of perfluorononanoic acid (PFNA) and perfluoroundecanoic acid (PFUnDA) were elevated, despite low concentrations of PFASs in dust samples. Concentrations of PBDEs in dust and serum were similar to those from the contiguous United States. Statistical associations between dust and serum concentrations are apparent for a small number of PBDEs, suggesting a possible route of exposure. Predominant compounds were similar between human sera and stickleback; however, blackfish accumulated PFASs not found in either stickleback or human sera. CONCLUSION: Household dust contributes to PBDE exposure, but not PFAS exposure. Elevated concentrations of long chain PFASs in serum are likely due to exposure from traditional foods. The presence of both PFASs and PBDEs in sentinel fish species suggests atmospheric deposition and bioaccumulation, as well as local environmental contamination. PMID- 28818815 TI - Mercury concentrations in China's coastal waters and implications for fish consumption by vulnerable populations. AB - We assessed mercury (Hg) pollution in China's coastal waters, including the Bohai Sea, the Yellow Sea, the East China Sea and the South China Sea, based on a nationwide dataset from 301 sampling sites. A methylmercury (MeHg) intake model for humans based on the marine food chain and human fish consumption was established to determine the linkage between water pollutants and the pollutant intake by humans. The predicted MeHg concentration in fish from the Bohai Sea was the highest among the four seas included in the study. The MeHg intake through dietary ingestion was dominant for the fish and was considerably higher than the MeHg intake through water respiration. The predicted MeHg concentrations in human blood in the coastal regions of China ranged from 1.37 to 2.77 MUg/L for pregnant woman and from 0.43 to 1.00 MUg/L for infants, respectively, based on different diet sources. The carnivorous fish consumption advisory for pregnant women was estimated to be 288-654 g per week to maintain MeHg concentrations in human blood at levels below the threshold level (4.4 MUg/L established by the US Environmental Protection Agency). With a 50% increase in Hg concentrations in water in the Bohai Sea, the bioaccumulated MeHg concentration (4.5 MUg/L) in the fish consumers will be higher than the threshold level. This study demonstrates the importance in controlling Hg pollution in China's coastal waters. An official recommendation guideline for the fish consumption rate and its sources will be necessary for vulnerable populations in China. PMID- 28818816 TI - Oil sorbents from plastic wastes and polymers: A review. AB - A large volume of the waste produced across the world is composed of polymers from plastic wastes such as polyethylene (HDPE or LDPE), polypropylene (PP), and polyethylene terephthalate (PET) amongst others. For years, environmentalists have been looking for various ways to overcome the problems of such large quantities of plastic wastes being disposed of into landfill sites. On the other hand, the usage of synthetic polymers as oil sorbents in particular, polyolefins, including polypropylene (PP) and polyethylene (PE) have been reported. In recent years, the idea of using plastic wastes as the feed for the production of oil sorbents has gained momentum. However, the studies undertaking such feasibility are rather scattered. This review paper is the first of its kind reporting, compiling and reviewing these various processes. The production of an oil sorbent from plastic wastes is being seen to be satisfactorily achievable through a variety of methods Nevertheless, much work needs to be done regarding further investigation of the numerous parameters influencing production yields and sorbent qualities. For example, differences in results are seen due to varying operating conditions, experimental setups, and virgin or waste plastics being used as feeds. The field of producing oil sorbents from plastic wastes is still very open for further research, and seems to be a promising route for both waste reduction, and the synthesis of value-added products such as oil sorbents. In this review, the research related to the production of various oil sorbents based on plastics (plastic waste and virgin polymer) has been discussed. Further oil sorbent efficiency in terms of oil sorption capacity has been described. PMID- 28818817 TI - Insights From Flutracking: Thirteen Tips to Growing a Web-Based Participatory Surveillance System. AB - Flutracking is a weekly Web-based survey of influenza-like illness (ILI) in Australia that has grown from 400 participants in 2006 to over 26,000 participants every week in 2016. Flutracking monitors both the transmission and severity of ILI across Australia by documenting symptoms (cough, fever, and sore throat), time off work or normal duties, influenza vaccination status, laboratory testing for influenza, and health seeking behavior. Recruitment of Flutrackers commenced via health department and other organizational email systems, and then gradually incorporated social media promotion and invitations from existing Flutrackers to friends to enhance participation. Invitations from existing participants typically contribute to over 1000 new participants each year. The Flutracking survey link was emailed every Monday morning in winter and took less than 10 seconds to complete. To reduce the burden on respondents, we collected only a minimal amount of demographic and weekly data. Additionally, to optimize users' experiences, we maintained a strong focus on "obvious design" and repeated usability testing of naive and current participants of the survey. In this paper, we share these and other insights on recruitment methods and user experience principles that have enabled Flutracking to become one of the largest online participatory surveillance systems in the world. There is still much that could be enhanced in Flutracking; however, we believe these principles could benefit others developing similar online surveillance systems. PMID- 28818818 TI - Validation of a Smartphone-Based Approach to In Situ Cognitive Fatigue Assessment. AB - BACKGROUND: Acquired Brain Injuries (ABIs) can result in multiple detrimental cognitive effects, such as reduced memory capability, concentration, and planning. These effects can lead to cognitive fatigue, which can exacerbate the symptoms of ABIs and hinder management and recovery. Assessing cognitive fatigue is difficult due to the largely subjective nature of the condition and existing assessment approaches. Traditional methods of assessment use self-assessment questionnaires delivered in a medical setting, but recent work has attempted to employ more objective cognitive tests as a way of evaluating cognitive fatigue. However, these tests are still predominantly delivered within a medical environment, limiting their utility and efficacy. OBJECTIVE: The aim of this research was to investigate how cognitive fatigue can be accurately assessed in situ, during the quotidian activities of life. It was hypothesized that this assessment could be achieved through the use of mobile assistive technology to assess working memory, sustained attention, information processing speed, reaction time, and cognitive throughput. METHODS: The study used a bespoke smartphone app to track daily cognitive performance, in order to assess potential levels of cognitive fatigue. Twenty-one participants with no prior reported brain injuries took place in a two-week study, resulting in 81 individual testing instances being collected. The smartphone app delivered three cognitive tests on a daily basis: (1) Spatial Span to measure visuospatial working memory; (2) Psychomotor Vigilance Task (PVT) to measure sustained attention, information processing speed, and reaction time; and (3) a Mental Arithmetic Test to measure cognitive throughput. A smartphone-optimized version of the Mental Fatigue Scale (MFS) self-assessment questionnaire was used as a baseline to assess the validity of the three cognitive tests, as the questionnaire has already been validated in multiple peer-reviewed studies. RESULTS: The most highly correlated results were from the PVT, which showed a positive correlation with those from the prevalidated MFS, measuring 0.342 (P<.008). Scores from the cognitive tests were entered into a regression model and showed that only reaction time in the PVT was a significant predictor of fatigue (P=.016, F=2.682, 95% CI 9.0-84.2). Higher scores on the MFS were related to increases in reaction time during our mobile variant of the PVT. CONCLUSIONS: The results show that the PVT mobile cognitive test developed for this study could be used as a valid and reliable method for measuring cognitive fatigue in situ. This test would remove the subjectivity associated with established self-assessment approaches and the need for assessments to be performed in a medical setting. Based on our findings, future work could explore delivering a small set of tests with increased duration to further improve measurement reliability. Moreover, as the smartphone assessment tool can be used as part of everyday life, additional sources of data relating to physiological, psychological, and environmental context could be included within the analysis to improve the nature and precision of the assessment process. PMID- 28818819 TI - Quantifying Human Movement Using the Movn Smartphone App: Validation and Field Study. AB - BACKGROUND: The use of embedded smartphone sensors offers opportunities to measure physical activity (PA) and human movement. Big data-which includes billions of digital traces-offers scientists a new lens to examine PA in fine grained detail and allows us to track people's geocoded movement patterns to determine their interaction with the environment. OBJECTIVE: The objective of this study was to examine the validity of the Movn smartphone app (Moving Analytics) for collecting PA and human movement data. METHODS: The criterion and convergent validity of the Movn smartphone app for estimating energy expenditure (EE) were assessed in both laboratory and free-living settings, compared with indirect calorimetry (criterion reference) and a stand-alone accelerometer that is commonly used in PA research (GT1m, ActiGraph Corp, convergent reference). A supporting cross-validation study assessed the consistency of activity data when collected across different smartphone devices. Global positioning system (GPS) and accelerometer data were integrated with geographical information software to demonstrate the feasibility of geospatial analysis of human movement. RESULTS: A total of 21 participants contributed to linear regression analysis to estimate EE from Movn activity counts (standard error of estimation [SEE]=1.94 kcal/min). The equation was cross-validated in an independent sample (N=42, SEE=1.10 kcal/min). During laboratory-based treadmill exercise, EE from Movn was comparable to calorimetry (bias=0.36 [-0.07 to 0.78] kcal/min, t82=1.66, P=.10) but overestimated as compared with the ActiGraph accelerometer (bias=0.93 [0.58-1.29] kcal/min, t89=5.27, P<.001). The absolute magnitude of criterion biases increased as a function of locomotive speed (F1,4=7.54, P<.001) but was relatively consistent for the convergent comparison (F1,4=1.26, P<.29). Furthermore, 95% limits of agreement were consistent for criterion and convergent biases, and EE from Movn was strongly correlated with both reference measures (criterion r=.91, convergent r=.92, both P<.001). Movn overestimated EE during free-living activities (bias=1.00 [0.98-1.02] kcal/min, t6123=101.49, P<.001), and biases were larger during high-intensity activities (F3,6120=1550.51, P<.001). In addition, 95% limits of agreement for convergent biases were heterogeneous across free-living activity intensity levels, but Movn and ActiGraph measures were strongly correlated (r=.87, P<.001). Integration of GPS and accelerometer data within a geographic information system (GIS) enabled creation of individual temporospatial maps. CONCLUSIONS: The Movn smartphone app can provide valid passive measurement of EE and can enrich these data with contextualizing temporospatial information. Although enhanced understanding of geographic and temporal variation in human movement patterns could inform intervention development, it also presents challenges for data processing and analytics. PMID- 28818822 TI - Reply. PMID- 28818820 TI - Opportunities of mHealth in Preconception Care: Preferences and Experiences of Patients and Health Care Providers and Other Involved Professionals. AB - BACKGROUND: The importance of the preconception period and preconception care (PCC) are broadly acknowledged and the potential benefits regarding health promotion have been studied extensively. PCC provides the opportunity to identify, prevent, and treat modifiable and nonmodifiable risk factors to optimize the health of couples trying to become pregnant. The prevalence of modifiable and nonmodifiable risk factors in these couples is high, but the uptake of PCC remains low. OBJECTIVE: The aim of this study is to identify the preferences and experiences of women and men (patients) trying to become pregnant and of health care providers and other involved professionals regarding mobile health (mHealth), in particular the coaching platform Smarter Pregnancy, and its potential role in PCC. METHODS: Patients who participated in the Smarter Pregnancy randomized controlled trial (RCT) and health care providers and professionals also involved in PCC were invited to participate in a qualitative study. The barriers, benefits, and opportunities of big data collection by mHealth were discussed in focus group sessions, prompted with statements regarding PCC. RESULTS: We composed five focus groups, consisting of 27 patients in total (23 women and 4 men), who participated in the RCT, and nine health care providers and other professionals. Of the patients, 67% (18/27) were familiar with the concept of PCC, but only 15% (4/27) received any form of PCC. A majority of 56% (combined percentages of statements 1 [n=18], 2 [n=11], and 3 [n=16]) of the patients believed in the benefit of receiving PCC, and all agreed that men should be involved in PCC as well. Patients did not have a problem using anonymized data obtained from mHealth tools for scientific purposes. Patients and health care providers and other professionals both acknowledged the lack of awareness regarding the importance of PCC and stated that mHealth provides several opportunities to support clinical PCC. CONCLUSIONS: Our findings substantiate previous studies addressing the low uptake of PCC due to unawareness or lack of perception of its relevance by couples who are trying to become pregnant. The positive judgment and experiences with mHealth, in particular Smarter Pregnancy, will stimulate future research and further development of effective and cost-effective personalized mHealth apps for patients, health care providers, and other professionals as an add-on to clinical PCC. PMID- 28818821 TI - Patient Participation at Health Care Conferences: Engaged Patients Increase Information Flow, Expand Propagation, and Deepen Engagement in the Conversation of Tweets Compared to Physicians or Researchers. AB - BACKGROUND: Health care conferences present a unique opportunity to network, spark innovation, and disseminate novel information to a large audience, but the dissemination of information typically stays within very specific networks. Social network analysis can be adopted to understand the flow of information between virtual social communities and the role of patients within the network. OBJECTIVE: The purpose of this study is to examine the impact engaged patients bring to health care conference social media information flow and how they expand dissemination and distribution of tweets compared to other health care conference stakeholders such as physicians and researchers. METHODS: From January 2014 through December 2016, 7,644,549 tweets were analyzed from 1672 health care conferences with at least 1000 tweets who had registered in Symplur's Health Care Hashtag Project from 2014 to 2016. The tweet content was analyzed to create a list of the top 100 influencers by mention from each conference, who were then subsequently categorized by stakeholder group. Multivariate linear regression models were created using stepwise function building to identify factors explaining variability as predictor variables for the model in which conference tweets were taken as the dependent variable. RESULTS: Inclusion of engaged patients in health care conference social media was low compared to that of physicians and has not significantly changed over the last 3 years. When engaged patient voices are included in health care conferences, they greatly increase information flow as measured by total tweet volume (beta=301.6) compared to physicians (beta=137.3, P<.001), expand propagation of information tweeted during a conference as measured by social media impressions created (beta=1,700,000) compared to physicians (beta=270,000, P<.001), and deepen engagement in the tweet conversation as measured by replies to their tweets (beta=24.4) compared to physicians (beta=5.5, P<.001). Social network analysis of hubs and authorities revealed that patients had statistically significant higher hub scores (mean 8.26*10-4, SD 2.96*10-4) compared to other stakeholder groups' Twitter accounts (mean 7.19*10-4, SD 3.81*10-4; t273.84=4.302, P<.001). CONCLUSIONS: Although engaged patients are powerful accelerators of information flow, expanders of tweet propagation, and greatly deepen engagement in conversation of tweets on social media of health care conferences compared to physicians, they represent only 1.4% of the stakeholder mix of the top 100 influencers in the conversation. Health care conferences that fail to engage patients in their proceedings may risk limiting their engagement with the public, disseminating scientific information to a narrow community and slowing flow of information across social media channels. PMID- 28818823 TI - Regarding "Perfusion MR Imaging Using a 3D Pulsed Continuous Arterial Spin Labeling Method for Acute Cerebral Infarction Classified as Branch Atheromatous Disease Involving the Lenticulostriate Artery Territory". PMID- 28818824 TI - Clinical Impact of Flat Panel Volume CT Angiography in Evaluating the Accurate Intraoperative Deployment of Flow-Diverter Stents. AB - BACKGROUND AND PURPOSE: The deployment of flow-diverter stents may be difficult to analyse on regular DSA. The purpose of our study was to investigate the clinical impact of stent-dedicated flat panel volume CT angiography to evaluate intraoperatively the satisfactory deployment of flow-diverter stents. MATERIALS AND METHODS: From January 2009 to April 2015, 83 consecutive patients (mean age, 51 years; 62 women) were treated in our institution with flow-diverter stents. Eighty-seven aneurysms (82 unruptured, 5 ruptured; 77 anterior, 10 posterior circulation) were treated in these 83 patients (4 patients had 2 aneurysms, both treated by means of flow-diverter stents). One patient was treated for a traumatic carotid cavernous fistula. In 80% of the cases (68/85) a flat panel volume CT angiography was performed in the angiographic suite just after the flow diverter stent deployment. Stent visualization was assessed by 2 independent reviewers. The clinical impact of stent malapposition was evaluated. RESULTS: Flow-diverter stent visualization was satisfactory in 73.5% of the cases. In 2 cases (2.9%) the flat panel volume CT angiography prompted the operator to perform an additional intrastent angioplasty for a condition that was previously underestimated. Four patients (4.7%) experienced acute thromboembolic complications; 3 others had delayed thromboembolic complications. Only 1 of these patients had thromboembolic complications (acute or delayed) related to stent misdeployment, which was easily managed intraoperatively with no clinical consequence. CONCLUSIONS: Flat panel volume CT angiography is an interesting tool to depict flow-diverter stent misdeployment and may encourage the operator to perform intrastent angioplasty (2.9% of the cases in our experience) to reduce the risks of thromboembolic complications. PMID- 28818825 TI - MR Imaging Features of the Cerebellum in Adult-Onset Neuronal Intranuclear Inclusion Disease: 8 Cases. AB - Neuronal intranuclear inclusion disease is a neurodegenerative disorder pathologically characterized by eosinophilic hyaline intranuclear inclusions. A high-intensity signal along the corticomedullary junction on DWI has been described as a specific MR imaging finding of the cerebrum in neuronal intranuclear inclusion disease. However, MR imaging findings of the cerebellum in neuronal intranuclear inclusion disease have not been fully evaluated. Here, we review MR imaging findings of the cerebellum in a series of 8 patients with pathologically confirmed neuronal intranuclear inclusion disease. The MR imaging results showed cerebellar atrophy (8/8 patients) and high-intensity signal on FLAIR images in the medial part of the cerebellar hemisphere right beside the vermis (the "paravermal area") (6/8) and in the middle cerebellar peduncle (4/8). The paravermal abnormal signals had a characteristic distribution, and they could be an indicator of the diagnosis of neuronal intranuclear inclusion disease even when using the results of past MR imaging examinations in which DWI findings were not examined. PMID- 28818826 TI - Test-Retest and Interreader Reproducibility of Semiautomated Atlas-Based Analysis of Diffusion Tensor Imaging Data in Acute Cervical Spine Trauma in Adult Patients. AB - BACKGROUND AND PURPOSE: DTI is a tool for microstructural spinal cord injury evaluation. This study evaluated the reproducibility of a semiautomated segmentation algorithm of spinal cord DTI. MATERIALS AND METHODS: Forty-two consecutive patients undergoing acute trauma cervical spine MR imaging underwent 2 axial DTI scans in addition to their clinical scan. The datasets were put through a semiautomated probabilistic segmentation algorithm that selected white matter, gray matter, and 24 individual white matter tracts. Regional and white matter tract volume, fractional anisotropy, and mean diffusivity values were calculated. Two readers performed the nonautomated steps to evaluate interreader reproducibility. The coefficient of variation and intraclass correlation coefficient were used to assess test-retest and interreader reproducibility. RESULTS: Of 42 patients, 30 had useable data. Test-retest reproducibility of fractional anisotropy was high for white matter as a whole (coefficient of variation, 3.8%; intraclass correlation coefficient, 0.93). Test-retest coefficient-of-variation ranged from 8.0%-18.2% and intraclass correlation coefficients from 0.47-0.80 across individual white matter tracts. Mean diffusivity metrics also had high test-retest reproducibility (white matter: coefficient-of-variation, 5.6%; intraclass correlation coefficient, 0.86) with coefficients of variation from 11.6%-18.3% and intraclass correlation coefficients from 0.57-0.74 across individual tracts, with better agreement for larger tracts. The coefficients of variation of fractional anisotropy and mean diffusivity both had significant negative relationships with white matter volume (26%-27% decrease for each doubling of white matter volume, P < .01). CONCLUSIONS: DTI spinal cord segmentation is reproducible in the setting of acute spine trauma, specifically for larger white matter tracts and total white or gray matter. PMID- 28818828 TI - REPLY. PMID- 28818827 TI - Endovascular Treatment of Dural Arteriovenous Fistulas of the Transverse and Sigmoid Sinuses Using Transarterial Balloon-Assisted Embolization Combined with Transvenous Balloon Protection of the Venous Sinus. AB - BACKGROUND AND PURPOSE: Combined transarterial balloon-assisted endovascular embolization with double-lumen balloon microcatheters and concomitant transvenous balloon protection was described as a promising treatment technique for dural arteriovenous fistulae of the transverse and sigmoid sinus. The purpose of this study was to evaluate the technical efficacy and safety of this combined treatment technique. MATERIALS AND METHODS: Nine consecutive patients presenting with dural arteriovenous fistulas of the transverse and sigmoid sinuses underwent combined transarterial and transvenous balloon-assisted endovascular embolization. Prospectively collected data were reviewed to assess the technical success rate, complication rate, and clinical outcome. RESULTS: Six patients presented with clinically symptomatic Borden type I, and 3 patients, with Borden type II dural arteriovenous fistulas of the transverse and sigmoid sinuses (3 men, 6 women; mean age, 50.4 years). Transarterial embolization was performed with a double-lumen balloon with Onyx and concomitant transvenous sinus protection with a dedicated venous remodeling balloon. Complete angiographic occlusion at the latest follow-up (mean, 4.8 months) was achieved in 6 patients, and near-complete occlusion, in 2 patients. Clinical cure or remission of symptoms was obtained in 6 and 2 patients, respectively. One patient with a residual fistula underwent further treatment in which the dural arteriovenous fistula was cured by sinus occlusion. Complete occlusion of the dural arteriovenous fistula was visible on the follow-up angiography after final treatment in 8 patients. One patient refused follow-up angiography but was free of symptoms. There were no immediate or delayed postinterventional complications. CONCLUSIONS: Transarterial balloon-assisted embolization of dural arteriovenous fistulas of the transverse and sigmoid sinuses with combined transvenous balloon protection is safe and offers a high rate of complete dural arteriovenous fistula occlusion and remission of clinical symptoms. PMID- 28818829 TI - Open Globe Injury: Ultrasound First! PMID- 28818830 TI - High-Speed Melting Analysis: The Effect of Melting Rate on Small Amplicon Microfluidic Genotyping. AB - BACKGROUND: High-resolution DNA melting analysis of small amplicons is a simple and inexpensive technique for genotyping. Microfluidics allows precise and rapid control of temperature during melting. METHODS: Using a microfluidic platform for serial PCR and melting analysis, 4 targets containing single nucleotide variants were amplified and then melted at different rates over a 250-fold range from 0.13 to 32 degrees C/s. Genotypes (n = 1728) were determined manually by visual inspection after background removal, normalization, and conversion to negative derivative plots. Differences between genotypes were quantified by a genotype discrimination ratio on the basis of inter- and intragenotype differences using the absolute value of the maximum vertical difference between curves as a metric. RESULTS: Different homozygous curves were genotyped by melting temperature and heterozygous curves were identified by shape. Technical artifacts preventing analysis (0.3%), incorrect (0.06%), and indeterminate (0.4%) results were minimal, occurring mostly at slow melting rates (0.13-0.5 degrees C/s). Genotype discrimination was maximal at around 8 degrees C/s (2-8 degrees C/s for homozygotes and 8-16 degrees C/s for heterozygotes), and no genotyping errors were made at rates >0.5 degrees C/s. PCR was completed in 10-12.2 min, followed by melting curve acquisition in 4 min down to <1 s. CONCLUSIONS: Microfluidics enables genotyping by melting analysis at rates up to 32 degrees C/s, requiring <1 s to acquire an entire melting curve. High-speed melting reduces the time for melting analysis, decreases errors, and improves genotype discrimination of small amplicons. Combined with extreme PCR, high-speed melting promises nucleic acid amplification and genotyping in < 1 min. PMID- 28818831 TI - Oral contraceptives, breastfeeding and the risk of developing rheumatoid arthritis: results from the Swedish EIRA study. AB - OBJECTIVES: To study whether oral contraceptive (OC) use or breastfeeding (BF) influence the risk of rheumatoid arthritis (RA), stratifying the cases by presence/absence of anticitrullinated protein antibodies (ACPA), and whether these factors interact with known risk factors in the development of ACPA positive RA. METHODS: Women aged >=18 years, participants in the population-based case-control Swedish Epidemiological Investigation of RA study (2641 cases/4251 controls), completed an extensive questionnaire regarding OC, BF and potential confounders. We calculated ORs, with 95% CIs, adjusted for age, residential area, smoking and alcohol consumption. Attributable proportion due to interaction (AP) was estimated to evaluate presence of interaction. RESULTS: Compared with never users, ever and past OC users had a decreased risk of ACPA-positive RA (OR=0.84 (95% CI 0.74 to 0.96); OR=0.83 (95% CI 0.73 to 0.95), respectively). No significant associations were found for ACPA-negative RA. Long duration of OC use (>7 years vs never use) decreased the risk of both ACPA-positive (p=0.0037) and ACPA-negative RA (p=0.0356).A history of long BF decreased the risk only of ACPA positive RA in a dose-dependent manner (p=0.0086), but this trend did not remain after adjustments. A significant interaction was observed between the lack of OC use and smoking (AP=0.28 (95% CI 0.14-0.42)) on the risk of ACPA-positive RA. No interactions were found for BF. CONCLUSIONS: OC decreased the risk of RA, especially ACPA-positive RA, where an interaction with smoking was observed. A long duration of OC use decreased the risk of both disease subsets. We could not confirm an association between BF and a decreased risk of either ACPA-positive or ACPA-negative RA. PMID- 28818832 TI - B cell OX40L supports T follicular helper cell development and contributes to SLE pathogenesis. AB - OBJECTIVES: TNFSF4 (encodes OX40L) is a susceptibility locus for systemic lupus erythematosus (SLE). Risk alleles increase TNFSF4 expression in cell lines, but the mechanism linking this effect to disease is unclear, and the OX40L-expressing cell types mediating the risk are not clearly established. Blockade of OX40L has been demonstrated to reduce disease severity in several models of autoimmunity, but not in SLE. We sought to investigate its potential therapeutic role in lupus. METHODS: We used a conditional knockout mouse system to investigate the function of OX40L on B and T lymphocytes in systemic autoimmunity. RESULTS: Physiologically, OX40L on both B and T cells contributed to the humoral immune response, but B cell OX40L supported the secondary humoral response and antibody affinity maturation. Our data also indicated that loss of B cell OX40L impeded the generation of splenic T follicular helper cells. We further show that in two models of SLE-a spontaneous congenic model and the H2-IAbm12 graft-versus-host induced model-loss of B cell OX40L ameliorates the autoimmune phenotype. This improvement was, in each case, accompanied by a decline in T follicular helper cell numbers. Importantly, the germline knockout did not exhibit a markedly different phenotype from the B cell knockout in these models. CONCLUSIONS: These findings contribute to a model in which genetically determined increased OX40L expression promotes human SLE by several mechanisms, contingent on its cellular expression. The improvement in pathology in two models of systemic autoimmunity indicates that OX40L is an excellent therapeutic target in SLE. PMID- 28818833 TI - Using whiteboards to support college students' learning of complex physiological concepts. AB - Research underscores the importance of retrieval-based practice and application of knowledge for meaningful learning. However, the didactic lecture format continues to persist in traditional university physiology courses. A strategy called whiteboarding, where students use handheld dry erase boards and work in small groups to actively retrieve, discuss, and apply concepts presented in the lecture, has the potential to address challenges associated with actively engaging students in science courses for greater learning. The purpose of this study was to empirically examine the potential benefits of whiteboarding for increasing students' understanding of animal physiology concepts. Student performance on physiology questions assessing concepts taught using lecture only vs. concepts taught using lecture and whiteboarding were compared within the term that whiteboarding was used, as well as across whiteboard and lecture-only terms taught by the same instructor. Results showed that when whiteboarding was incorporated in the course, student performance on items that assessed concepts corresponding to the whiteboarding activities were significantly higher compared with performance on items that assessed concepts taught through lecture only. These patterns in student performance were found within and across terms. Taken together, findings point to whiteboarding as an effective tool that can be integrated in traditional lecture courses to promote students' understanding of physiology. PMID- 28818834 TI - Designing and implementing a physiology course for a new doctoral occupational therapy program with student feedback. AB - Recently, the Occupational Therapy Department requested a custom-designed medical physiology course for the students in the new occupational therapy doctoral program. The first author, a physiologist with extensive experience in teaching both undergraduate preprofessional and medical students in human physiology, was recruited to design and implement the course. The course was designed to be consistent with the constructivist philosophy that guides the occupational therapy curriculum. The course was offered for the first time during fall/spring 2015/2016 and included both first- and second-year occupational therapy doctoral students. A number of anonymous assessment tools were used to evaluate students' perceptions regarding the effectiveness of various pedagogies used in the course in enhancing their learning. A summative course assessment survey with comments was used at the end of the course. This paper describes the model of course design and the student feedback, which generated some suggestions for improvement of the course. This approach in designing a new course for a new disciplinary group of students should be helpful to other faculty involved in developing courses for health career programs populated by students with variable physiology backgrounds and different educational needs. The final relevant feedback from the course would be to have the students evaluate the usefulness of the course to their future careers immediately following their certification examinations in a year or two and during their subsequent clinical experiences; however, that information will likely be more difficult to obtain. PMID- 28818836 TI - The Care Continuum: An Evolving Model for Care and Research in Rare Diseases. PMID- 28818835 TI - Src-dependent phosphorylation of MU-opioid receptor at Tyr336 modulates opiate withdrawal. AB - Opiate withdrawal/negative reinforcement has been implicated as one of the mechanisms for the progression from impulsive to compulsive drug use. Increase in the intracellular cAMP level and protein kinase A (PKA) activities within the neurocircuitry of addiction has been a leading hypothesis for opiate addiction. This increase requires the phosphorylation of MU-opioid receptor (MOR) at Tyr336 by Src after prolonged opiate treatment in vitro Here, we report that the Src mediated MOR phosphorylation at Tyr336 is a prerequisite for opiate withdrawal in mice. We observed the recruitment of Src in the vicinity of MOR and an increase in phosphorylated Tyr336 (pY336) levels during naloxone-precipitated withdrawal. The intracerebroventricular or stereotaxic injection of a Src inhibitor (AZD0530), or Src shRNA viruses attenuated pY336 levels, and several somatic withdrawal signs. This was also observed in Fyn-/- mice. The stereotaxic injection of wild-type MOR, but not mutant (Y336F) MOR, lentiviruses into the locus coeruleus of MOR-/- mice restored somatic withdrawal jumping. Regulating pY336 levels during withdrawal might be a future target for drug development to prevent opiate addictive behaviors. PMID- 28818837 TI - Parent Coping Support Interventions During Acute Pediatric Hospitalizations: A Meta-Analysis. AB - CONTEXT: Parents may experience psychological distress when a child is acutely hospitalized, which can negatively affect child outcomes. Interventions designed to support parents' coping have the potential to mitigate this distress. OBJECTIVE: To describe interventions designed to provide coping support to parents of hospitalized children and conduct a meta-analysis of coping support intervention outcomes (parent anxiety, depression, and stress). DATA SOURCES: We searched Pubmed, Embase, PsycINFO, Psychiatry Online, and Cumulative Index to Nursing and Allied Health Literature from 1985 to 2016 for English-language articles including the concepts "pediatric," "hospitalization," "parents," and "coping support intervention." STUDY SELECTION: Two authors reviewed titles and abstracts to identify studies meeting inclusion criteria and reviewed full text if a determination was not possible using the title and abstract. References of studies meeting inclusion criteria were reviewed to identify additional articles for inclusion. DATA EXTRACTION: Two authors abstracted data and assessed risk of bias by using a structured instrument. RESULTS: Initial searches yielded 3450 abstracts for possible inclusion. Thirty-two studies met criteria for inclusion in the systematic review and 12 studies met criteria for inclusion in the meta analysis. The most commonly measured outcomes were parent depression, anxiety, and stress symptoms. In meta-analysis, combined intervention effects significantly reduced parent anxiety and stress but not depression. Heterogeneity among included studies was high. LIMITATIONS: Most included studies were conducted at single centers with small sample sizes. CONCLUSIONS: Coping support interventions can alleviate parents' psychological distress during children's hospitalization. More evidence is needed to determine if such interventions benefit children. PMID- 28818838 TI - Pre-initiation complex assembly functions as a molecular switch that splits the Mcm2-7 double hexamer. AB - Initiation of chromosomal DNA replication in eukaryotes involves two steps: licensing and firing. In licensing, a core component of the replicative helicase, the Mcm2-7 complex, is loaded onto replication origins as an inactive double hexamer, which is activated in the firing step by firing factors. A reaction intermediate called the pre-initiation complex (pre-IC) has been proposed to assemble transiently during firing, but the existence of the pre-IC has not yet been confirmed. Here, we show, by systematic chromatin immunoprecipitation, that a distinct intermediate that fits the definition of the pre-IC assembles during firing in the budding yeast Saccharomyces cerevisiae Pre-IC assembly is observed in the absence of Mcm10, one of the firing factors, and is mutually dependent on all the firing factors whose association to replication origins is triggered by cyclin-dependent kinase. In the pre-IC, the Mcm2-7 double hexamer is separated into single hexamers, as in the active helicase. Our data indicate that pre-IC assembly functions as an all-or-nothing molecular switch that splits the Mcm2-7 double hexamer. PMID- 28818839 TI - Do electronic cigarettes increase cigarette smoking in UK adolescents? Evidence from a 12-month prospective study. AB - BACKGROUND: In cross-sectional surveys, increasing numbers of adolescents report using both electronic cigarettes (e-cigarettes) and cigarettes. This study assessed whether adolescent e-cigarette use was associated prospectively with initiation or escalation of cigarette use. METHODS: Data were from 2836 adolescents (aged 13-14 years at baseline) in 20 schools in England. At baseline, breath carbon monoxide levels, self-reported e-cigarette and cigarette use, sex, age, friends and family smoking, beliefs about cigarette use and percentage receiving free school meals (measure of socioeconomic status) were assessed. At 12-month follow-up, self-reported cigarette use was assessed and validated by breath carbon monoxide levels. RESULTS: At baseline, 34.2% of adolescents reported ever using e-cigarettes (16.0% used only e-cigarettes). Baseline ever use of e-cigarettes was strongly associated with subsequent initiation (n=1726; OR 5.38, 95% CI 4.02 to 7.22; controlling for covariates, OR 4.06, 95% CI 2.94 to 5.60) and escalation (n=318; OR 1.91, 95% CI 1.14 to 3.21; controlling for covariates, this effect became non-significant, OR 1.39, 95% CI 0.97 to 1.82) of cigarette use. CONCLUSIONS: This is the first study to report prospective relationships between ever use of e-cigarettes and initiation and escalation of cigarette use among UK adolescents. Ever use of e-cigarettes was robustly associated with initiation but more modestly related to escalation of cigarette use. Further research with longer follow-up in a broader age range of adolescents is required. PMID- 28818841 TI - Distinct intestinal adaptation for vitamin B12 and bile acid absorption revealed in a new mouse model of massive ileocecal resection. AB - Ileocecal resection (ICR), one of several types of intestinal resection that results in short bowel syndrome (SBS), causes severe clinical disease in humans. We here describe a mouse model of massive ICR in which 75% of the distal small intestine is removed. We demonstrate that mice underwent 75% ICR show severe clinical signs and high mortality, which may recapitulate severe forms of human SBS, despite an adaptive response throughout the remnant intestine. By using this model, we also investigated whether the epithelium of the remnant intestine shows enhanced expression of factors involved in region-specific functions of the ileum. Cubn mRNA and its protein product, which play an essential role in vitamin B12 absorption in the ileum, are not compensatory up-regulated in any part of the remnant intestine, demonstrating a clear contrast with post-operative up regulation of genes involved in bile acid absorption. Our study suggests that functional adaptation by phenotypical changes in the intestinal epithelium is not a general feature for nutrient absorption systems that are confined to the ileum. We also propose that the mouse model developed in this study will become a unique system to facilitate studies on SBS with ICR in humans. PMID- 28818840 TI - HCN4 ion channel function is required for early events that regulate anatomical left-right patterning in a nodal and lefty asymmetric gene expression-independent manner. AB - Laterality is a basic characteristic of all life forms, from single cell organisms to complex plants and animals. For many metazoans, consistent left right asymmetric patterning is essential for the correct anatomy of internal organs, such as the heart, gut, and brain; disruption of left-right asymmetry patterning leads to an important class of birth defects in human patients. Laterality functions across multiple scales, where early embryonic, subcellular and chiral cytoskeletal events are coupled with asymmetric amplification mechanisms and gene regulatory networks leading to asymmetric physical forces that ultimately result in distinct left and right anatomical organ patterning. Recent studies have suggested the existence of multiple parallel pathways regulating organ asymmetry. Here, we show that an isoform of the hyperpolarization-activated cyclic nucleotide-gated (HCN) family of ion channels (hyperpolarization-activated cyclic nucleotide-gated channel 4, HCN4) is important for correct left-right patterning. HCN4 channels are present very early in Xenopus embryos. Blocking HCN channels (Ih currents) with pharmacological inhibitors leads to errors in organ situs. This effect is only seen when HCN4 channels are blocked early (pre-stage 10) and not by a later block (post-stage 10). Injections of HCN4-DN (dominant-negative) mRNA induce left-right defects only when injected in both blastomeres no later than the 2-cell stage. Analysis of key asymmetric genes' expression showed that the sidedness of Nodal, Lefty, and Pitx2 expression is largely unchanged by HCN4 blockade, despite the randomization of subsequent organ situs, although the area of Pitx2 expression was significantly reduced. Together these data identify a novel, developmental role for HCN4 channels and reveal a new Nodal-Lefty-Pitx2 asymmetric gene expression-independent mechanism upstream of organ positioning during embryonic left-right patterning. PMID- 28818842 TI - What's new in paediatric hypertension? AB - Paediatric hypertension predisposes to hypertension and cardiovascular disease in adult life. Despite clear guidelines, there remains a lack of screening. Diagnosis remains challenging given the high rate of false-positive high blood pressure (BP) readings at a single visit; thus, multiple visits are required to confirm the diagnosis. Depending on the normative data sets used, hypertension in overweight and obese children can be underestimated by up to 20%. Specific BP targets are required for subgroups such as adolescents, children with chronic kidney disease (CKD) and type 1 diabetes. High dietary salt intake is a risk factor for cardiovascular disease. Given the rise in processed food consumption, children in developed nations are likely to benefit from salt restriction at a population-based level. PMID- 28818843 TI - Seizures, safety and submersion: sense and sensibility. PMID- 28818844 TI - Conservative treatment versus surgery for uncomplicated appendicitis in children: a systematic review and meta-analysis. AB - OBJECTIVES: To compare conservative treatment with index admission appendicectomy in children with acute uncomplicated appendicitis. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase and the Cochrane Library (CENTRAL) from 1950 to 18 February 2017. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies that assessed both appendicectomy and non-operative management of acute uncomplicated appendicitis in children of less than 18 years of age. Endpoints were postintervention complications, readmission and efficacy (successful outcome of the initial therapy). RESULTS: Five studies met the inclusion criteria (conservative treatment n=189; surgical intervention n=253). Compared with patients undergoing index admission appendicectomy, conservative treatment showed a reduced treatment efficacy (relative risk 0.77, 95% CI 0.71 to 0.84; p<0.001) and an increased readmission rate (relative risk 6.98, 95% CI 2.07 to 23.6; p<0.001), with a comparable rate of complications (relative risk 1.07, 95% CI 0.26 to 4.46). Exclusion of patients with faecoliths improved treatment efficacy in conservatively treated patients. One study was randomised, with the remaining four comprising cohorts assembled by patient or physician choice. Different antibiotic regimens were used between investigations. Follow-up varied from 1 to 4 years. CONCLUSIONS: Conservative treatment was less efficacious and was associated with a higher readmission rate. Index admission appendicectomy should in the present still be considered to be the treatment of choice for the management of uncomplicated appendicitis in children. PMID- 28818845 TI - A Scoping Review for Strategies to Increase Living Kidney Donation. AB - BACKGROUND AND OBJECTIVES: The literature on strategies to increase the number of potential living kidney donors is extensive and has yet to be characterized. Scoping reviews are a novel methodology for systematically assessing a wide breadth of a given body of literature and may be done before conducting a more targeted systematic review. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a scoping review and summarized the evidence for existing strategies to increase living kidney donation. RESULTS: Our review identified seven studies that tested interventions using rigorous methods (i.e., randomized, controlled trials) and outcome measures, all of which focused on using education targeted at potential recipients to increase living donation. Of these, two studies that targeted the potential recipients' close social network reported statistically significant results. Other interventions were identified, but their effect was assessed through quasiexperimental or observational study designs. CONCLUSIONS: We identified an important gap in the literature for evidence-based strategies to increase living kidney donation. From the limited data available, strategies directed at potential recipients and their social networks are the most promising. These results can inform transplant programs that are considering strategies to increase living kidney donation and highlight the need for conduct of high-quality study to increase living donation. PMID- 28818846 TI - Statistical Methods for Modeling Time-Updated Exposures in Cohort Studies of Chronic Kidney Disease. AB - When estimating the effect of an exposure on a time-to-event type of outcome, one can focus on the baseline exposure or the time-updated exposures. Cox regression models can be used in both situations. When time-dependent confounding exists, the Cox model with time-updated covariates may produce biased effect estimates. Marginal structural models, estimated through inverse-probability weighting, were developed to appropriately adjust for time-dependent confounding. We review the concept of time-dependent confounding and illustrate the process of inverse probability weighting. We fit a marginal structural model to estimate the effect of time-updated systolic BP on the time to renal events such as ESRD in the Chronic Renal Insufficiency Cohort. We compare the Cox regression model and the marginal structural model on several attributes (effects estimated, result interpretation, and assumptions) and give recommendations for when to use each method. PMID- 28818847 TI - A French Cohort Study of Kidney Retransplantation after Post-Transplant Lymphoproliferative Disorders. AB - BACKGROUND AND OBJECTIVES: Post-transplant lymphoproliferative disorders arising after kidney transplantation portend an increased risk of morbidity and mortality. Retransplantation of patients who had developed post-transplant lymphoproliferative disorder remains questionable owing to the potential risks of recurrence when immunosuppression is reintroduced. Here, we investigated the feasibility of kidney retransplantation after the development of post-transplant lymphoproliferative disorder. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We reviewed the data from all patients who underwent kidney retransplantation after post-transplant lymphoproliferative disorder in all adult kidney transplantation centers in France between 1998 and 2015. RESULTS: We identified a total of 52 patients with kidney transplants who underwent 55 retransplantations after post transplant lymphoproliferative disorder. The delay from post-transplant lymphoproliferative disorder to retransplantation was 100+/-44 months (28-224); 98% of patients were Epstein-Barr virus seropositive at the time of retransplantation. Induction therapy for retransplantation was used in 48 patients (i.e., 17 [31%] patients received thymoglobulin, and 31 [57%] patients received IL-2 receptor antagonists). Six patients were also treated with rituximab, and 53% of the patients received an antiviral drug. The association of calcineurin inhibitors, mycophenolate mofetil, and steroids was the most common maintenance immunosuppression regimen. Nine patients were switched from a calcineurin inhibitor to a mammalian target of rapamycin inhibitor. One patient developed post-transplant lymphoproliferative disorder recurrence at 24 months after retransplantation, whereas post-transplant lymphoproliferative disorder did not recur in 51 patients. CONCLUSIONS: The recurrence of post-transplant lymphoproliferative disorder among patients who underwent retransplantation in France is a rare event. PMID- 28818848 TI - Moving from Intuition to Data: Building the Evidence to Support and Increase Living Donor Kidney Transplantation. PMID- 28818850 TI - Improved pregnant women's understanding of research information by an enhanced informed consent form: a randomised controlled study nested in neonatal research. AB - OBJECTIVE: This study aimed to test the applicability and effectiveness of the enhanced informed consent form (ICF) methodology, proposed by the Strategic Initiative for Developing Capacity in Ethical Review (SIDCER), in neonatal research requiring maternal consent. DESIGN: A single-centre open-label randomised controlled study. SETTING: Antenatal care clinics at Phramongkutklao Hospital, Thailand. PATIENTS: 234 pregnant women who were at risk of preterm labour were enrolled; 232 individuals completed the study. INTERVENTIONS: The participants were randomly assigned to read either the SIDCER ICF or the conventional ICF. MAIN OUTCOME MEASURES: The participants' understanding of essential trial-related information was assessed using 25 closed-ended questions. The primary endpoint was the proportion of the participants who obtained the satisfactory level of understanding at 80% (score of >=20/25). RESULTS: 72.5% (87/120) of the participants in the SIDCER ICF group and 59.8% (67/112) of the conventional ICF group achieved the primary endpoint (relative risk (RR)=1.212, 95% CI 1.005 to 1.462, p=0.041). The superiority of the SIDCER ICF over the conventional ICF was significant, particularly among the participants whose education was at the high school level or below (63.5% vs 44.1%, RR=1.441, 95% CI 1.022 to 2.030, p=0.031). CONCLUSIONS: The SIDCER ICF methodology is applicable to neonatal research requiring maternal consent. The SIDCER ICF significantly improved the understanding of pregnant women, particularly among those with lower levels of education. The present study confirms the value of the SIDCER ICF methodology in research involving individuals with a limited academic background. PMID- 28818849 TI - eGFR and the Risk of Community-Acquired Infections. AB - BACKGROUND AND OBJECTIVES: Community-acquired infections are common, contributing to adverse outcomes and increased health care costs. We hypothesized that, with lower eGFR, the incidence of community-acquired infections increases, whereas the pattern of site-specific infections varies. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 1,139,470 health care users (mean age =52+/-18 years old, 53% women) from the Stockholm CREAtinine Measurements Project, we quantified the associations of eGFR with the risk of infections, overall and major types, over 12 months. RESULTS: A total of 106,807 counts of infections were recorded throughout 1,128,313 person-years. The incidence rate of all infections increased with lower eGFR from 74/1000 person-years for individuals with eGFR=90-104 ml/min per 1.73 m2 to 419/1000 person-years for individuals with eGFR<30 ml/min per 1.73 m2. Compared with eGFR of 90-104 ml/min per 1.73 m2, the adjusted incidence rate ratios of community-acquired infections were 1.08 (95% confidence interval, 1.01 to 1.14) for eGFR of 30-59 ml/min per 1.73 m2 and 1.53 (95% confidence interval, 1.39 to 1.69) for eGFR<30 ml/min per 1.73 m2. The relative proportions of lower respiratory tract infection, urinary tract infection, and sepsis became increasingly higher along with lower eGFR strata (e.g., low respiratory tract infection accounting for 25% versus 15% of community-acquired infections in eGFR<30 versus 90-104 ml/min per 1.73 m2, respectively). Differences in incidence associated with eGFR were in general consistent for most infection types, except for nervous system and upper respiratory tract infections, for which no association was observed. CONCLUSIONS: This region-representative health care study finds an excess community-acquired infections incidence in individuals with mild to severe CKD. Lower respiratory tract infection, urinary tract infection, and sepsis are major infections in CKD. PMID- 28818851 TI - Inotropes for preterm babies during the transition period after birth: friend or foe? AB - During the transition to extrauterine life, preterm infants are at high risk of developing circulatory failure. Currently, hypotension is used as major diagnostic criteria for starting treatments such as fluid boluses, inotropes or steroids. Most of these treatment options have not been studied in large randomised controlled trials for efficacy and safety and are under discussions. A wide variety in their use is reported in the literature and clear evidence about which inotrope or other treatment should be preferred is lacking. In addition, there is ongoing debate about the appropriate threshold values for blood pressure. Other diagnostic measures for poor circulation are functional echocardiography, near-infrared spectroscopy, capillary refill time, base excess and serum lactate. Large randomised controlled trials for the use of dopamine and dobutamine in preterm infants <32 weeks gestation are under way to fill the knowledge gaps on the assessment of circulatory compromise and on efficacy and safety of the studied age-appropriate drug formulations. PMID- 28818852 TI - Accuracy of 11 formulae to guide umbilical arterial catheter tip placement in newborn infants. AB - BACKGROUND: Umbilical arterial catheter (UAC) insertion is a common procedure in the neonatal intensive care unit (NICU). Correct placement of the tip of the UAC at first attempt minimises handling of the infant and reduces the risk of infection and complications. We aimed to determine the accuracy of 11 published formulae to guide UAC placement. METHODS: This was a one-year prospective observational study in a tertiary NICU. Clinicians used their preferred formula for UAC insertion, with X-rays performed immediately post-procedure to check the tip position. Birth weight and measurements included in the 11 formulae were recorded within 48 hours. The gold standard insertion distance was defined as the distance from the abdominal wall to the mid-descending aorta, at T8 level on X ray (range T6-T10). Insertion length using the 11 formulae was calculated and compared with this gold standard distance. RESULTS: One hundred and three infants were included, with median (IQR) gestational age and weight of 28 (26-33.5) weeks and 980 (780-2045) g, respectively. The predicted value of the 11 formulae to place the UAC in correct position ranged from 51.0% to 73.8%. Formulae that involved direct body part measurements showed the highest predicted success rates, smallest mean difference from T8 and narrowest limits of agreement using the Bland-Altman method. CONCLUSION: Success rates for accurate UAC placement are highest when formulae that involve body measurements are used. However, even the most accurate method would result in more than 25% of UACs needing manipulation to achieve an optimal position. PMID- 28818853 TI - Interobserver agreement and image quality of functional cardiac ultrasound measures used in a randomised trial of delayed cord clamping in preterm infants. AB - OBJECTIVE: Functional cardiac ultrasound measures are used clinically and in trials for assessing the haemodynamic status of newborn infants. Superior vena cava (SVC) flow and right ventricular output (RVO) are established measures of systemic blood flow on the first postnatal day. The objective was to assess image quality and interobserver agreement of these measures in preterm infants enrolled in a randomised trial of immediate versus delayed cord clamping. DESIGN AND SETTING: Image quality and interobserver agreement for SVC flow, RVO and ductus arteriosus (DA) size were assessed on measurements taken at 3-6, 6-12 and 20-28 hours for the first 10 infants enrolled at each of four sites (total 40). Bland Altman plots were constructed; mean difference (bias) and limits of agreement (LOA) were calculated. Potential sources of variation were explored. RESULTS: Quality was judged satisfactory for >97% of images. The mean difference and LOA between the observers were 5.4 mL/kg/min and -49.0 to 59.8 mL/kg/min for SVC flow, -26.6 mL/kg/min and -131.4 to 78.2 mL/kg/min for RVO, and 0 mm and -0.8 to 0.8 mm for DA diameter, respectively. The principal source of measurement error for SVC flow was diameter, and for RVO, diameter and velocity time integral. The difference between observers for both SVC and RVO was significantly associated with site. CONCLUSION: Interobserver variability for SVC flow is consistent with that previously reported, but higher for RVO. The findings should be incorporated into clinical practice, training, accreditation and trial design. PMID- 28818854 TI - Nasal midazolam vs ketamine for neonatal intubation in the delivery room: a randomised trial. AB - OBJECTIVE: To compare the effectiveness of sedation by intranasal administration of midazolam (nMDZ) or ketamine (nKTM) for neonatal intubation. DESIGN: A multicentre, prospective, randomised, double-blind study. SETTING: Delivery rooms at four tertiary perinatal centres in France. PATIENTS: Preterm neonates with respiratory distress requiring non-emergent endotracheal intubation for surfactant instillation. INTERVENTIONS: Treatment was randomly allocated, with each neonate receiving a bolus of 0.1 mL/kg in each nostril, corresponding to 0.2 mg/kg for nMDZ and 2 mg/kg for nKTM. The drug was repeated once 7 min later at the same dose if adequate sedation was not obtained. MAIN OUTCOME MEASURES: Success was defined by adequate sedation before intubation and adequate comfort during the procedure. Intubation features, respiratory and cardiovascular events were recorded. RESULTS: Sixty newborns, with mean (SD) gestational age and birth weight of 28 (3) weeks and 1100 (350) g, were included within the first 20 min of life. nMDZ was associated with a higher success rate (89% vs 58%; RR: 1.54, 95% CI 1.12 to 2.12, p<0.01) and shorter delays between the first dose and intubation (10 (6) vs 16 (8) min, p<0.01).Number of attempts, time to intubation, mean arterial blood pressure measures over the first 12 hours after birth and length of invasive ventilation were not different. CONCLUSIONS: nMDZ was more efficient than nKTM to adequately sedate neonates requiring intubation in the delivery room. The haemodynamic and respiratory effects of both drugs were comparable. CLINICAL TRIAL: This clinical trial was recorded on the National Library of Medicine registry (NCT01517828). PMID- 28818855 TI - Paradigm of Biased PAR1 (Protease-Activated Receptor-1) Activation and Inhibition in Endothelial Cells Dissected by Phosphoproteomics. AB - OBJECTIVE: Thrombin is the key serine protease of the coagulation cascade and mediates cellular responses by activation of PARs (protease-activated receptors). The predominant thrombin receptor is PAR1, and in endothelial cells (ECs), thrombin dynamically regulates a plethora of phosphorylation events. However, it has remained unclear whether thrombin signaling is exclusively mediated through PAR1. Furthermore, mechanistic insight into activation and inhibition of PAR1 mediated EC signaling is lacking. In addition, signaling networks of biased PAR1 activation after differential cleavage of the PAR1 N terminus have remained an unresolved issue. APPROACH AND RESULTS: Here, we used a quantitative phosphoproteomics approach to show that classical and peptide activation of PAR1 induce highly similar signaling, that low thrombin concentrations initiate only limited phosphoregulation, and that the PAR1 inhibitors vorapaxar and parmodulin 2 demonstrate distinct antagonistic properties. Subsequent analysis of the thrombin-regulated phosphosites in the presence of PAR1 inhibitors revealed that biased activation of PAR1 is not solely linked to a specific G-protein downstream of PAR1. In addition, we showed that only the canonical thrombin PAR1 tethered ligand induces extensive early phosphoregulation in ECs. CONCLUSIONS: Our study provides detailed insight in the signaling mechanisms downstream of PAR1. Our data demonstrate that thrombin-induced EC phosphoregulation is mediated exclusively through PAR1, that thrombin and thrombin-tethered ligand peptide induce similar phosphoregulation, and that only canonical PAR1 cleavage by thrombin generates a tethered ligand that potently induces early signaling. Furthermore, platelet PAR1 inhibitors directly affect EC signaling, indicating that it will be a challenge to design a PAR1 antagonist that will target only those pathways responsible for tissue pathology. PMID- 28818856 TI - Deletion of NF-kappaB/RelA in Angiotensin II-Sensitive Mesenchymal Cells Blocks Aortic Vascular Inflammation and Abdominal Aortic Aneurysm Formation. AB - OBJECTIVE: Infusion of angiotensin II (Ang II) induces extracellular matrix remodeling and inflammation resulting in abdominal aortic aneurysms (AAAs) in normolipidemic mice. Although Ang II activates mesenchymal cells in the media and adventitia to become fibrogenic, the sentinel role of this mesenchymal population in modulating the inflammatory response and aneurysms is not known. We test the hypothesis that these fibrogenic mesenchymal cells play a critical role in Ang II induced aortic wall vascular inflammation and AAA formation. APPROACH AND RESULTS: Ang II infusion increased phospho-Ser536-RelA and interleukin (IL)-6 immunostaining in the abdominal aorta. In addition, aortic mRNA transcripts of RelA-dependent cytokines IL-6 and IL-1beta were significantly elevated suggesting that Ang II functionally activates RelA signaling. To test the role of mesenchymal RelA in AAA formation, we generated RelA-CKO mice by administering tamoxifen to double transgenic mice harboring RelA-flox alleles and tamoxifen inducible Col1a2 promoter-driven Cre recombinase (Col1a2-CreERT). Tamoxifen administration to Col1a2-CreERT*mT/mG mice induced Cre expression and RelA depletion in aortic smooth muscle cells and fibroblasts but not in endothelial cells. Infusion of Ang II significantly increased abdominal aortic diameter and the incidence of AAA in RelA wild-type but not in RelA-CKO mice, independent of changes in systolic blood pressure. Furthermore, mesenchymal cell-specific RelA CKO mice exhibited decreased expression of IL-6 and IL-1beta cytokines and decreased recruitment of C68+ and F4/80lo*Ly6Chi monocytes during Ang II infusion. CONCLUSIONS: Fibrogenic mesenchymal RelA plays a causal role in Ang II induced vascular inflammation and AAA in normolipidemic mice. PMID- 28818857 TI - Modeling Inborn Errors of Hepatic Metabolism Using Induced Pluripotent Stem Cells. AB - Inborn errors of hepatic metabolism are because of deficiencies commonly within a single enzyme as a consequence of heritable mutations in the genome. Individually such diseases are rare, but collectively they are common. Advances in genome-wide association studies and DNA sequencing have helped researchers identify the underlying genetic basis of such diseases. Unfortunately, cellular and animal models that accurately recapitulate these inborn errors of hepatic metabolism in the laboratory have been lacking. Recently, investigators have exploited molecular techniques to generate induced pluripotent stem cells from patients' somatic cells. Induced pluripotent stem cells can differentiate into a wide variety of cell types, including hepatocytes, thereby offering an innovative approach to unravel the mechanisms underlying inborn errors of hepatic metabolism. Moreover, such cell models could potentially provide a platform for the discovery of therapeutics. In this mini-review, we present a brief overview of the state-of-the-art in using pluripotent stem cells for such studies. PMID- 28818859 TI - Renal Denervation Suppresses Coronary Hyperconstricting Responses After Drug Eluting Stent Implantation in Pigs In Vivo Through the Kidney-Brain-Heart Axis. AB - OBJECTIVE: Drug-eluting stent-induced coronary hyperconstricting responses remain an important issue. The adventitia harbors a variety of components that potently modulate vascular tone, including sympathetic nerve fibers (SNF) and vasa vasorum. Catheter-based renal denervation (RDN) inhibits sympathetic nerve activity. We, thus, examined whether RDN suppresses drug-eluting stent-induced coronary hyperconstricting responses, and if so, what mechanisms are involved. APPROACH AND RESULTS: Protocol 1: pigs implanted with everolimus-eluting stents into the left coronary arteries underwent coronary angiography at 1 month after implantation for assessment of coronary vasomotion and adventitial SNF formation. Drug-eluting stent-induced coronary hyperconstricting responses were significantly enhanced associated with enhanced coronary adventitial SNF and vasa vasorum formation. Protocol 2: pigs implanted with everolimus-eluting stents were randomly assigned to the RDN or sham group. The RDN group underwent renal ablation. At 1 month, RDN significantly caused marked damage of the SNF at the renal arteries without any stenosis, thrombus, or dissections. Notably, RDN significantly upregulated the expression of alpha2-adrenergic receptor-binding sites in the nucleus tractus solitarius, attenuated muscle sympathetic nerve activity, and decreased systolic blood pressure and plasma renin activity. In addition, RDN attenuated coronary hyperconstricting responses to intracoronary serotonin at the proximal and distal stent edges associated with decreases in SNF and vasa vasorum formation, inflammatory cell infiltration, and Rho-kinase expression/activation. Furthermore, there were significant positive correlations between SNF and vasa vasorum and between SNF and coronary vasoconstricting responses. CONCLUSIONS: These results provide the first evidence that RDN ameliorates drug-eluting stent-induced coronary hyperconstricting responses in pigs in vivo through the kidney-brain-heart axis. PMID- 28818858 TI - PAI-1 (Plasminogen Activator Inhibitor-1) Expression Renders Alternatively Activated Human Macrophages Proteolytically Quiescent. AB - OBJECTIVE: Macrophages are versatile immune cells capable of polarizing into functional subsets depending on environmental stimulation. In atherosclerotic lesions, proinflammatory polarized macrophages are associated with symptomatic plaques, whereas Th2 (T-helper cell type 2) cytokine-polarized macrophages are inversely related with disease progression. To establish a functional cause for these observations, we analyzed extracellular matrix degradation phenotypes in polarized macrophages. APPROACH AND RESULTS: We provide evidence that proinflammatory polarized macrophages rely on membrane-bound proteases including MMP-14 (matrix metalloproteinase-14) and the serine protease uPA (urokinase plasminogen activator) together with its receptor uPAR for extracellular matrix degradation. In contrast, Th2 cytokine alternatively primed macrophages do not show different proteolytic activity in comparison to unpolarized macrophages and lack increased localization of MMP-14 and uPA receptor to the cell membrane. Nonetheless, they express the highest amount of the serine protease uPA. However, uPA activity is blocked by similarly increased expression of its inhibitor PAI-1 (plasminogen activator inhibitor 1). When inhibiting PAI-1 or when analyzing macrophages deficient in PAI-1, Th2 cytokine-polarized macrophages display the same matrix degradation capability as proinflammatory-primed macrophages. Within atherosclerotic lesions, macrophages positive for the alternative activation marker CD206 express high levels of PAI-1. In addition, to test changed tissue remodeling capacities of alternatively activated macrophages, we used a bleomycin lung injury model in mice reconstituted with PAI-1-/- bone marrow. These results supported an enhanced remodeling phenotype displayed by increased fibrosis and elevated MMP activity in the lung after PAI-1 loss. CONCLUSIONS: We were able to demonstrate matrix degradation dependent on membrane-bound proteases in proinflammatory stimulated macrophages and a forced proteolytical quiescence in alternatively polarized macrophages by the expression of PAI-1. PMID- 28818860 TI - The Chickpea Early Flowering 1 (Efl1) Locus Is an Ortholog of Arabidopsis ELF3. AB - In climates that experience short growing seasons due to drought, heat, or end-of season frost, early flowering is a highly desirable trait for chickpea (Cicer arietinum). In this study, we mapped, sequenced, and characterized Early flowering3 (Efl3), an ortholog of Arabidopsis (Arabidopsis thaliana) EARLY FLOWERING3 (ELF3) that confers early flowering in chickpea. In a recombinant inbred line population derived from a cross between CDC Frontier and ICCV 96029, this gene was mapped to the site of a quantitative trait locus on Ca5 that explained 59% of flowering time variation under short days. Sequencing of ELF3 in ICCV 96029 revealed an 11-bp deletion in the first exon that was predicted to result in a premature stop codon. The effect of this mutation was tested by transgenic complementation in the Arabidopsis elf3-1 mutant, with the CDC Frontier form of CaELF3a partially complementing elf3-1 while the ICCV 96029 form had no effect on flowering time. While induction of FLOWERING LOCUS T homologs was very early in ICCV 96029, an analysis of circadian clock function failed to show any clear loss of rhythm in the expression of clock genes in ICCV 96029 grown under continuous light, suggesting redundancy with other ELF3 homologs or possibly an alternative mode of action for this gene in chickpea. The 11-bp deletion was associated with early flowering in global chickpea germplasm but was not widely distributed, indicating that this mutation arose relatively recently. PMID- 28818862 TI - Dietary Approaches for Stroke Prevention. PMID- 28818861 TI - Auxin Signaling. PMID- 28818863 TI - Detection of Left Ventricular Thrombus by Cardiac Magnetic Resonance in Embolic Stroke of Undetermined Source. AB - BACKGROUND AND PURPOSE: We aimed to use contrast-enhanced cardiac magnetic resonance (CE-CMR) imaging to elucidate the prevalence of left ventricular (LV) thrombus in patients suspected of embolic stroke of undetermined source (ESUS) with previous myocardial infarction or LV dysfunction (LV ejection fraction [LVEF] <50%). METHODS: We prospectively investigated 797 consecutive patients who presented to our hospital with acute ischemic stroke between 2014 and 2015. Patients with myocardial infarction or LVEF<50% underwent CE-CMR imaging. ESUS was diagnosed according to proposal criteria based on transthoracic echocardiography findings. RESULTS: The prevalence of ESUS was 22% (178 of 797) on initial diagnosis. Among 60 patients with myocardial infarction or LVEF<50%, the stroke subtypes were as follows: small artery disease, 17% (10 of 60); large artery atherosclerosis, 5% (3 of 60); cardioembolic stroke, 49% (29 of 60); ESUS, 23% (14 of 60); and undetermined causes other than ESUS, 6% (4 of 60). Of 60 patients examined via CE-CMR, LV thrombus was confirmed in 12 patients, whereas only 1 had been detected on transthoracic echocardiography (P=0.04). Importantly, 29% (4 of 14) of patients with ESUS had LV thrombus. A prediction model based on CE-CMR findings showed higher performance in LV thrombus detection, permitting a net improvement of 0.46 (95% confidence interval, 0.08-0.82; P=0.016) in cardioembolic stroke reclassification. Compared with patients without LV thrombus, those with LV thrombus had lower LVEF (median: 26% versus 40%; P=0.003). Notably, 42% (5 of 12) of patients with LV thrombus had LVEF>=30%. CONCLUSIONS: When ESUS-suspected patients have myocardial infarction or LV dysfunction, CE-CMR may help improve detection of cardioembolic stroke and provide relevant information for anticoagulation therapy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02251665. PMID- 28818864 TI - Palliative Care for Hospitalized Patients With Stroke: Results From the 2010 to 2012 National Inpatient Sample. AB - BACKGROUND AND PURPOSE: Substantial variability exists in the use of life prolonging treatments for patients with stroke, especially near the end of life. This study explores patterns of palliative care utilization and death in hospitalized patients with stroke across the United States. METHODS: Using the 2010 to 2012 nationwide inpatient sample databases, we included all patients discharged with stroke identified by International Classification of Diseases Ninth Revision codes. Strokes were subclassified as ischemic, intracerebral, and subarachnoid hemorrhage. We compared demographics, comorbidities, procedures, and outcomes between patients with and without a palliative care encounter (PCE) as defined by the International Classification of Diseases-Ninth Revision code V66.7. Pearson chi2 test was used for categorical variables. Multivariate logistic regression was used to account for hospital, regional, payer, and medical severity factors to predict PCE use and death. RESULTS: Among 395 411 patients with stroke, PCE was used in 6.2% with an increasing trend over time (P<0.05). We found a wide range in PCE use with higher rates in patients with older age, hemorrhagic stroke types, women, and white race (all P<0.001). Smaller and for-profit hospitals saw lower rates. Overall, 9.2% of hospitalized patients with stroke died, and PCE was significantly associated with death. Length of stay in decedents was shorter for patients who received PCE. CONCLUSIONS: Palliative care use is increasing nationally for patients with stroke, especially in larger hospitals. Persistent disparities in PCE use and mortality exist in regards to age, sex, race, region, and hospital characteristics. Given the variations in PCE use, especially at the end of life, the use of mortality rates as a hospital quality measure is questioned. PMID- 28818865 TI - Letter by Kunz et al Regarding Article, "Systematic Review of the Cost and Cost Effectiveness of Rapid Endovascular Therapy for Acute Ischemic Stroke". PMID- 28818867 TI - Exploring Potential Germline-Associated Roles of the TRIM-NHL Protein NHL-2 Through RNAi Screening. AB - TRIM-NHL proteins are highly conserved regulators of developmental pathways in vertebrates and invertebrates. The TRIM-NHL family member NHL-2 in Caenorhabditis elegans functions as a miRNA cofactor to regulate developmental timing. Similar regulatory roles have been reported in other model systems, with the mammalian ortholog in mice, TRIM32, contributing to muscle and neuronal cell proliferation via miRNA activity. Given the interest associated with TRIM-NHL family proteins, we aimed to further investigate the role of NHL-2 in C. elegans development by using a synthetic RNAi screening approach. Using the ORFeome library, we knocked down 11,942 genes in wild-type animals and nhl-2 null mutants. In total, we identified 42 genes that produced strong reproductive synthetic phenotypes when knocked down in nhl-2 null mutants, with little or no change when knocked down in wild-type animals. These included genes associated with transcriptional processes, chromosomal integrity, and key cofactors of the germline small 22G RNA pathway. PMID- 28818866 TI - Systematic Identification of Determinants for Single-Strand Annealing-Mediated Deletion Formation in Saccharomyces cerevisiae. AB - To ensure genomic integrity, living organisms have evolved diverse molecular processes for sensing and repairing damaged DNA. If improperly repaired, DNA damage can give rise to different types of mutations, an important class of which are genomic structural variants (SVs). In spite of their importance for phenotypic variation and genome evolution, potential contributors to SV formation in Saccharomyces cerevisiae (budding yeast), a highly tractable model organism, are not fully recognized. Here, we developed and applied a genome-wide assay to identify yeast gene knockout mutants associated with de novo deletion formation, in particular single-strand annealing (SSA)-mediated deletion formation, in a systematic manner. In addition to genes previously linked to genome instability, our approach implicates novel genes involved in chromatin remodeling and meiosis in affecting the rate of SSA-mediated deletion formation in the presence or absence of stress conditions induced by DNA-damaging agents. We closely examined two candidate genes, the chromatin remodeling gene IOC4 and the meiosis-related gene MSH4, which when knocked-out resulted in gene expression alterations affecting genes involved in cell division and chromosome organization, as well as DNA repair and recombination, respectively. Our high-throughput approach facilitates the systematic identification of processes linked to the formation of a major class of genetic variation. PMID- 28818868 TI - Erythropoietin stimulates murine and human fibroblast growth factor-23, revealing novel roles for bone and bone marrow. PMID- 28818870 TI - Fra-2 negatively regulates postnatal alveolar septation by modulating myofibroblast function. AB - Mice that globally overexpress the transcription factor Fos-related antigen-2 (Fra-2) develop extensive pulmonary fibrosis and pulmonary vascular remodeling. To determine if these phenotypes are a consequence of ectopic Fra-2 expression in vascular smooth muscle cells and myofibroblasts, we generated mice that overexpress Fra-2 specifically in these cell types (alpha-SMA-rtTA;tetO-Fra-2). Surprisingly, these mice did not develop vascular remodeling or pulmonary fibrosis but did develop a spontaneous emphysema-like phenotype characterized by alveolar enlargement. Secondary septa formation is an important step in the normal development of lung alveoli, and alpha-smooth muscle actin (SMA) expressing fibroblasts (myofibroblasts) play a crucial role in this process. The mutant mice showed reduced numbers of secondary septa at postnatal day 7 and enlarged alveolae starting at postnatal day 12, suggesting impairment of secondary septa formation. Lineage tracing using alpha-SMA-rtTA mice crossed to a floxed TdTomato reporter revealed that embryonic expression of alpha-SMA Cre marked a population of cells that gave rise to nearly all alveolar myofibroblasts. Comprehensive transcriptome analyses (RNA sequencing) demonstrated that the overwhelming majority of genes whose expression was significantly altered by overexpression of Fra-2 in myofibroblasts encoded secreted proteins, components of the extracellular matrix (ECM), and cell adhesion-associated genes, including coordinate upregulation of pairs of integrins and their principal ECM ligands. In addition, primary myofibroblasts isolated from the mutant mice showed reduced migration capacity. These findings suggest that Fra-2 overexpression might impair myofibroblast functions crucial for secondary septation, such as myofibroblast migration across alveoli, by perturbing interactions between integrins and locally produced components of the ECM. PMID- 28818869 TI - Clinical risks and healthcare utilization of hematopoietic cell transplantation for sickle cell disease in the USA using merged databases. AB - Advances in allogeneic hematopoietic cell transplantation for sickle cell disease have improved outcomes, but there is limited analysis of healthcare utilization in this setting. We hypothesized that, compared to late transplantation, early transplantation (at age <10 years) improves outcomes and decreases healthcare utilization. We performed a retrospective study of children transplanted for sickle cell disease in the USA during 2000-2013 using two large databases. Univariate and Cox models were used to estimate associations of demographics, sickle cell disease severity, and transplant-related variables with mortality and chronic graft-versus-host disease, while Wilcoxon, Kruskal-Wallis, or linear trend tests were applied for the estimates of healthcare utilization. Among 161 patients with a 2-year overall survival rate of 90% (95% confidence interval [CI] 85-95%) mortality was significantly higher in those who underwent late transplantation versus early (hazard ratio (HR) 21, 95% CI 2.8-160.8, P=0.003) and unrelated compared to matched sibling donor transplantation (HR 5.9, 95% CI 1.7-20.2, P=0.005). Chronic graftversus host disease was significantly more frequent among those translanted late (HR 1.9, 95% CI 1.0-3.5, P=0.034) and those who received an unrelated graft (HR 2.5, 95% CI 1.2-5.4; P=0.017). Merged data for 176 patients showed that the median total adjusted transplant cost per patient was $467,747 (range: $344,029-$799,219). Healthcare utilization was lower among recipients of matched sibling donor grafts and those with low severity disease compared to those with other types of donor and disease severity types (P<0.001 and P=0.022, respectively); no association was demonstrated with late transplantation (P=0.775). Among patients with 2-year pre- and post-transplant data (n=41), early transplantation was associated with significant reductions in admissions (P<0.001), length of stay (P<0.001), and cost (P=0.008). Early transplant outcomes need to be studied prospectively in young children without severe disease and an available matched sibling to provide conclusive evidence for the superiority of this approach. Reduced post-transplant healthcare utilization inpatient care indicates that transplantation may provide a sustained decrease in healthcare costs over time. PMID- 28818871 TI - Sexual dimorphism of the pulmonary transcriptome in neonatal hyperoxic lung injury: identification of angiogenesis as a key pathway. AB - Bronchopulmonary dysplasia (BPD) is characterized by impaired alveolar secondary septation and vascular growth. Exposure to high concentrations of oxygen (hyperoxia) contributes to the development of BPD. The male sex is considered an independent risk factor for the development of BPD. The reasons underlying sexually dimorphic outcomes in premature neonates are not known. We hypothesized that sex-specific modulation of biological processes in the lung under hyperoxic conditions contributes to sex-based differences. Neonatal male and female mice (C57BL/6) were exposed to hyperoxia [95% [Formula: see text], postnatal day (PND) 1-5: saccular stage of lung development] and euthanized on PND 7 or 21. Pulmonary gene expression was studied using RNA-Seq on the Illumina HiSeq 2500 platform. Analysis of the pulmonary transcriptome revealed differential sex-specific modulation of crucial pathways such as angiogenesis, response to hypoxia, inflammatory response, and p53 pathway. Candidate genes from these pathways were validated at the mRNA level by qPCR. Analysis also revealed sex-specific differences in the modulation of crucial transcription factors. Focusing on the differential modulation of the angiogenesis pathway, we also showed sex-specific differential activation of Hif-1alpha-regulated genes using ChIP-qPCR and differences in expression of crucial genes (Vegf, VegfR2, and Phd2) modulating angiogenesis. We demonstrate the translational relevance of our findings by showing that our murine sex-specific differences in gene expression correlate with those from a preexisting human BPD data set. In conclusion, we provide novel molecular insights into differential sex-specific modulation of the pulmonary transcriptome in neonatal hyperoxic lung injury and highlight angiogenesis as one of the crucial differentially modulated pathways. PMID- 28818875 TI - Heredity of supraglottic exercise-induced laryngeal obstruction. PMID- 28818873 TI - Assessing anesthetic activity through modulation of the membrane dipole potential. AB - There is great individual variation in response to general anesthetics (GAs) leading to difficulties in optimal dosing and sometimes even accidental awareness during general anesthesia (AAGA). AAGA is a rare, but potentially devastating, complication affecting between 0.1% and 2% of patients undergoing surgery. The development of novel personalized screening techniques to accurately predict a patient's response to GAs and the risk of AAGA remains an unmet clinical need. In the present study, we demonstrate the principle of using a fluorescent reporter of the membrane dipole potential, di-8-ANEPPs, as a novel method to monitor anesthetic activity using a well-described inducer/noninducer pair. The membrane dipole potential has previously been suggested to contribute a novel mechanism of anesthetic action. We show that the fluorescence ratio of di-8-ANEPPs changed in response to physiological concentrations of the anesthetic, 1-chloro-1,2,2 trifluorocyclobutane (F3), but not the structurally similar noninducer, 1,2 dichlorohexafluorocyclobutane (F6), to artificial membranes and in vitro retinal cell systems. Modulation of the membrane dipole provides an explanation to overcome the limitations associated with the alternative membrane-mediated mechanisms of GA action. Furthermore, by combining this technique with noninvasive retinal imaging technologies, we propose that this technique could provide a novel and noninvasive technique to monitor GA susceptibility and identify patients at risk of AAGA. PMID- 28818876 TI - Prenatal stress exposure is associated with increased dyspnoea perception in adulthood. PMID- 28818874 TI - Airway calibre variation is a major determinant of exhaled nitric oxide's ability to capture asthma control. AB - Changes in airway calibre have the potential to modify exhaled nitric oxide fraction (FENO) values and could hamper how FENO captures changes in asthma control. Here, our objective was to assess whether forced expiratory volume in 1 s (FEV1) variations alter the ability of FENO to reflect asthma control.FENO, asthma control (Asthma Control Questionnaire (ACQ)) and FEV1 were measured at least two times in 527 patients during 1819 pairs of visits. Determinants of FENO ACQ discordance probability were evaluated through a logistic regression analysis. The effectiveness of FENO at capturing either asthma control worsening or improvement between two visits was then assessed by undertaking a stratified receiver operating characteristic curves analysis.When FEV1 and FENO change in the same direction, the odds of FENO-ACQ being discordant are multiplied by 3 (p<0.001). The area under the curve values were 0.765 (95% CI 0.713-0.805) (improvement; p<0.001) and 0.769 (95% 0.706-0.810) (worsening; p<0.001) or 0.590 (95% 0.531-0.653) (improvement; p=0.001) and 0.498 (95% 0.416-0.567) (worsening; p=0.482) when FEV1 and FENO changed in the opposite or same direction, respectively.The manner in which FENO and FEV1 vary concomitantly when asthma control changes determines the ability of FENO to capture this change: parallel or opposite changes in FEV1 and FENO either decrease or increase this ability to capture asthma control changes. PMID- 28818877 TI - Neuropsychiatric adverse effects of montelukast in children. PMID- 28818878 TI - Serum sCD163 as a biomarker of adipose tissue inflammation in obstructive sleep apnoea patients: limits and perspectives. PMID- 28818879 TI - Serum sCD163 as a biomarker of adipose tissue inflammation in obstructive sleep apnoea patients: limits and perspectives. PMID- 28818880 TI - Fooling the brain to alleviate dyspnoea. PMID- 28818881 TI - Selexipag for the treatment of connective tissue disease-associated pulmonary arterial hypertension. AB - Patients with connective tissue disease-associated pulmonary arterial hypertension (PAH-CTD) have a poor prognosis compared with other aetiologies. The underlying CTD can influence treatment response and outcomes. We characterised the GRIPHON study PAH-CTD subgroup and evaluated response to selexipag.Of 334 patients with PAH-CTD, PAH was associated with systemic sclerosis (PAH-SSc) in 170, systemic lupus erythematosus (PAH-SLE) in 82 and mixed CTD/CTD-other in 82. For the primary composite endpoint of morbidity/mortality, hazard ratios (HR) and 95% CI were calculated using Cox proportional hazard models.Compared with the overall GRIPHON population, the CTD subgroup was slightly older with a greater proportion of females and shorter time since diagnosis. Patients with PAH-SSc appeared to be more impaired at baseline, with a more progressive disease course. The converse was observed for PAH-SLE. Selexipag reduced the risk of composite morbidity/mortality events in patients with PAH-CTD by 41% (HR 0.59; 95% CI 0.41 0.85). Treatment effect was consistent irrespective of baseline PAH therapy or CTD subtype (interaction p=0.87 and 0.89, respectively). Adverse events were predominately prostacyclin-related and known for selexipag treatment.GRIPHON has allowed the comprehensive characterisation of patients with PAH-CTD. Selexipag delayed progression of PAH and was well-tolerated among PAH-CTD patients, including those with PAH-SSc and PAH-SLE. PMID- 28818882 TI - Neuropsychiatric adverse drug reactions in children initiated on montelukast in real-life practice. AB - Although montelukast is generally well tolerated, postmarketing studies have reported serious neuropsychiatric adverse drug reactions (ADRs) leading to a United States Food and Drug Administration black box warning. The objective of this study was to determine the incidence of neuropsychiatric ADRs leading to discontinuation of montelukast in asthmatic children.We conducted a retrospective cohort study in children aged 1-17 years initiated on montelukast. In a nested cohort study, children initiated on montelukast as monotherapy or adjunct therapy to inhaled corticosteroids (ICS) were matched to those initiated on ICS monotherapy. A non-leading parental interview served to ascertain the occurrence of any ADRs with any asthma medication, and circumstances related to, and evolution of, the event.Out of the 106 participants who initiated montelukast, most were male (58%), Caucasian (62%) with a median (interquartile range) age of 5 (3-8) years. The incidence (95% CI) of drug cessation due to neuropsychiatric ADRs was 16 (10-26)%, mostly occurring within 2 weeks. Most frequent ADRs were irritability, aggressiveness and sleep disturbances. The relative risk of neuropsychiatric ADRs associated with montelukast versus ICS was 12 (2-90).In the real-life setting, asthmatic children initiated on montelukast experienced a notable risk of neuropsychiatric ADRs leading to drug cessation, that is significantly higher than that associated with ICS. PMID- 28818883 TI - Determinants and outcomes of prolonged anxiety and depression in idiopathic pulmonary fibrosis. PMID- 28818884 TI - Contributions of a hand-held fan to self-management of chronic breathlessness. AB - This study explored the benefits of a hand-held fan as perceived by patients with chronic breathlessness and their carers.A secondary multimethod analysis was conducted of interview data collected in three clinical trials. Two researchers independently coded level of benefit qualitatively reported by each patient. Univariate and multivariate statistics were used to explore perceived benefit as a factor of sex, age and diagnosis. Qualitative analysis used an integrative method.133 patients commented on the fan, of whom 72 had a carer. Diagnoses included nonmalignant (n=91, 68.4%) and malignant (n=21, 15.8%) conditions. Of 111 patients who provided codable data, four (3.6%) perceived no benefit, 16 (14.4%) were uncertain, 80 (72.0%) perceived some benefit and 11 (10.0%) perceived very substantial benefit. Multivariate analysis was inconclusive. Benefit was described in terms of shorter recovery time, especially after activity. 10 (7.5%) patients said the fan reduced their need for home oxygen or inhaled beta-agonist medications. Negative perceptions of a few included dislike of the cooling sensation and embarrassment in public.Findings suggest that a hand held fan is a portable intervention with few disadvantages from which most patients with chronic breathlessness will derive benefit alongside other nonpharmacological and pharmacological strategies. Research is needed to optimise guidance on fan administration. PMID- 28818885 TI - Draft Genome Sequences of Two Gammaproteobacterial Methanotrophs Isolated from Rice Ecosystems. AB - The genomes of the aerobic methanotrophs "Methyloterricola oryzae" strain 73aT and Methylomagnum ishizawai strain 175 were sequenced. Both strains were isolated from rice plants. Methyloterricola oryzae strain 73aT represents the first isolate of rice paddy cluster I, and strain 175 is the second representative of the recently described genus Methylomagnum. PMID- 28818886 TI - Draft Genome Sequences of Two Pseudomonas aeruginosa Bloodstream Infection Isolates Associated with Rapid Patient Death. AB - The morbidity and mortality associated with Pseudomonas aeruginosa bloodstream infections are significant. New strategies are required to treat such infections. We report here the draft genome sequences of two antibiotic-sensitive P. aeruginosa bloodstream infection isolates that were associated with rapid death in nonneutropenic patients. PMID- 28818888 TI - Genome Sequence of Lactobacillus sakei LK-145 Isolated from a Japanese Sake Cellar as a High Producer of d-Amino Acids. AB - This announcement reports the complete genome sequence of strain LK-145 of Lactobacillus sakei isolated from a Japanese sake cellar as a potent strain for the production of large amounts of d-amino acids. Three putative genes encoding an amino acid racemase were identified. PMID- 28818887 TI - Draft Genome Sequences of Escherichia coli O104 Strains of Bovine and Human Origin. AB - Cattle harbor and shed in their feces several Escherichia coli O104 serotypes. All O104 strains examined were intimin negative and belonged to the B1 phylogroup, and some were Shiga toxigenic. We report here the genome sequences of bovine O104:H7 (n = 5), O104:H23 (n = 2), O104:H8 (n = 1), and O104:H12 (n = 1) isolates and human clinical isolates of O104:H7 (n = 5). PMID- 28818889 TI - Genome Sequences of Five Multidrug-Resistant Escherichia coli Sequence Type 117 Isolates Recovered from Dairy Calves. AB - Escherichia coli sequence type 117 (ST117) strains have been recovered from poultry with colibacillosis, as well as from urinary tract infections and fatal septic infections in humans. To further investigate ST117 isolates recovered from nonpoultry food animals, we sequenced the genomes of five ST117 isolates from dairy calves in Pennsylvania. PMID- 28818890 TI - Complete Genome Sequences of Mumps and Measles Virus Isolates from Three States in the United States. AB - We report here the full coding sequence of nine paramyxovirus genomes, including two full-length mumps virus genomes (genotypes G and H) and seven measles virus genomes (genotypes B3 and D4, D8, and D9), from respiratory samples of patients from California, Virginia, and Alabama obtained between 2010 and 2014. PMID- 28818891 TI - Complete Genome Sequence of Pseudoalteromonas piscicida Strain DE2-B, a Bacterium with Broad Inhibitory Activity toward Human and Fish Pathogens. AB - Pseudoalteromonas piscicida strain DE2-B is a halophilic bacterium which has broad inhibitory activity toward vibrios and other human and fish pathogens. We report the first closed genome sequence for this species, which consists of two chromosomes (4,128,210 and 1,188,838 bp). Annotation revealed multiple genes encoding proteases with potential antibacterial properties. PMID- 28818892 TI - Draft Genome Sequences of Two Enterobacter cloacae subsp. cloacae Strains Isolated from Australian Hematology Patients with Bacteremia. AB - Enterobacter cloacae is a common member of the gut microbiota in healthy individuals. However, it is also an opportunistic pathogen, capable of causing bacteremia. We report the draft genomes of two Enterobacter cloacae subspecies cloacae strains isolated from hematology patients with bacteremia. Both isolates carry genes encoding extended-spectrum beta-lactamases. PMID- 28818893 TI - Complete Genome Sequence of a Hobi-Like Virus Isolated from a Nelore Cow with Gastroenteric Disease in the State of Sao Paulo, Brazil. AB - The Hobi-like virus presents antigenic and molecular differences in relation to bovine virus diarrhea virus 1 and 2. The description of the complete genome of the Hobi-like virus SV757/15, isolated from a Nelore cow with gastroenteric disease in Brazil, will help in understanding the evolution and diversity of pestiviruses. PMID- 28818894 TI - Draft Genome Sequence of Chilean Antarctic Pseudomonas sp. Strain K2I15. AB - We announce the draft genome sequence of Pseudomonas sp. strain K2I15, isolated from the rhizosphere of Deschampsia antarctica Desv. The genome sequence had 6,645,031 bp with a G+C content of 60.4%. This genome provides insights into the niche adaptation, prophage carriage, and evolution of this specific Antarctic bacteria. PMID- 28818895 TI - Genome Sequence of the Thermophilic Biomass-Degrading Fungus Malbranchea cinnamomea FCH 10.5. AB - We report here the annotated draft genome sequence of the thermophilic biomass degrading fungus Malbranchea cinnamomea strain FCH 10.5, isolated from compost at a waste treatment plant in Vietnam. The genome sequence contains 24.96 Mb with an overall GC content of 49.79% and comprises 9,437 protein-coding genes. PMID- 28818896 TI - Genome Sequences of Three Novel Isolates of Human Parainfluenza Virus 2 Associated with Acute Respiratory Infection. AB - Using target capture of viral nucleic acid and next-generation sequencing, we generated the genome sequences of three novel human parainfluenza virus 2 isolates. Isolates ACRI_0185 (GenBank accession number MF077311), ACRI_0230 (MF077312), and ACRI_0248 (MF077313) were collected in October 2016, February 2017, and March 2017, respectively, from pediatric patients with acute respiratory infection in Arkansas. PMID- 28818897 TI - Draft Genome Sequence of Bacillus sp. Strain K2I17, Isolated from the Rhizosphere of Deschampsia antarctica Desv. AB - We present here the draft genome sequence of Bacillus sp. strain K2I17, which was isolated from the rhizosphere of Deschampsia antarctica Desv. The genomic sequence contained 6,113,341 bp. This genome provides insights into the possible new biomedical and biotechnical applications of this specific Antarctic bacterium. PMID- 28818898 TI - Draft Genome Sequences of Two Unclassified Chitinophagaceae Bacteria, IBVUCB1 and IBVUCB2, Isolated from Environmental Samples. AB - We report here the draft genome sequences of two Chitinophagaceae bacteria, IBVUCB1 and IBVUCB2, assembled from metagenomes of surface samples from freshwater lakes. The genomes are >99% complete and may represent new genera within the Chitinophagaceae family, indicating a larger diversity than currently identified. PMID- 28818899 TI - Draft Genome Sequence of Sphingobacterium sp. CZ-UAM, Isolated from a Methanotrophic Consortium. AB - Sphingobacterium sp. CZ-UAM was isolated from a methanotrophic consortium in mineral medium using methane as the only carbon source. A draft genome of 5.84 Mb with a 40.77% G+C content is reported here. This genome sequence will allow the investigation of potential methanotrophy in this isolated strain. PMID- 28818900 TI - Genome Sequence of an Australian Monophasic Salmonella enterica subsp. enterica Typhimurium Isolate (TW-Stm6) Carrying a Large Plasmid with Multiple Antimicrobial Resistance Genes. AB - We report the genome sequence of a monophasic Salmonella enterica subsp. enterica Typhimurium strain (TW-Stm6) isolated in Australia that is similar to epidemic multidrug-resistant strains from Europe and elsewhere. This strain carries additional antibiotic and heavy-metal resistance genes on a large (275-kb) IncHI2 plasmid. PMID- 28818901 TI - Draft Genome Sequence of Lactobacillus fermentum BFE 6620, a Potential Starter Culture for African Vegetable Foods, Isolated from Fermented Cassava. AB - We report the draft genome sequence of Lactobacillus fermentum BFE 6620 from fermented cassava used as a potential starter culture for African vegetable fermentation. Sequence analysis showed the assembled genome size to be 1,982,893 bp, encoding a predicted total of 2,003 protein-coding genes, 14 rRNAs, 54 tRNAs, and 3 noncoding RNAs (ncRNAs). PMID- 28818902 TI - Draft Genome Sequence of Ideonella sp. Strain A 288, Isolated from an Iron Precipitating Biofilm. AB - Here, we report the draft genome sequence of the betaproteobacterium Ideonella sp. strain A_228. This isolate, obtained from a bog iron ore-containing floodplain area in Germany, provides valuable information about the genetic diversity of neutrophilic iron-depositing bacteria. The Illumina NextSeq technique was used to sequence the draft genome sequence of the strain. PMID- 28818903 TI - Draft Genome Sequence of Staphylococcus aureus S681, a Tetracycline-Sensitive Livestock-Associated Methicillin-Resistant Clonal Complex 398 Strain. AB - We present the draft genome sequence of an atypical tetracycline-susceptible livestock-associated methicillin-resistant Staphylococcus aureus (MRSA) strain. It contains 2,817,340 bp and 2,858 coding sequences, including 6 rRNA operons, 56 tRNAs, and 4 noncoding RNA (ncRNA) genes. The strain harbors a tet(M) gene, but 15 point mutations in amino acids are present that likely impair the functionality of TetM. PMID- 28818904 TI - First Genome Sequence of Shallot Latent Carlavirus from Allium macrostemon Bunge. AB - A wild Japanese garlic plant (Allium macrostemon Bunge, wild onion) with leaves showing chlorotic stripes was collected in Saitama Prefecture, Japan. Genome sequencing showed that it was infected with shallot latent carlavirus. The genomic sequence of this virus is reported for the first time from wild onion. PMID- 28818905 TI - Complete Genome Sequence of Mycobacterium stephanolepidis. AB - Mycobacterium stephanolepidis is a rapid-growing nonpigmented species isolated from marine teleost fish (Stephanolepis cirrhifer) and is closely related to Mycobacterium chelonae Here, we report the complete sequence of its genome, comprising a 4.9-Mb chromosome. The sequence represents essential data for future phylogenetic and comparative genome studies of this fish pathogen. PMID- 28818906 TI - Draft Genome Sequence of Aquitalea magnusonii Strain H3, a Plant Growth-Promoting Bacterium of Duckweed (Lemna minor). AB - Aquitalea magnusonii strain H3 is a promising plant growth-promoting bacterium for duckweed. Here, we report the draft genome sequence of strain H3 comprising 4,750,601 bp in 73 contigs. Several genes associated with plant root colonization were identified. PMID- 28818907 TI - Draft Genome Sequence of the d-Xylose-Fermenting Yeast Spathaspora xylofermentans UFMG-HMD23.3. AB - Here, we report the draft genome sequence of the yeast Spathaspora xylofermentans UFMG-HMD23.3 (=CBS 12681), a d-xylose-fermenting yeast isolated from the Amazonian forest. The genome consists of 298 contigs, with a total size of 15.1 Mb, including the mitochondrial genome, and 5,948 predicted genes. PMID- 28818909 TI - Draft Genome Sequence of Grammothele lineata SDL-CO-2015-1, a Jute Endophyte with a Potential for Paclitaxel Biosynthesis. AB - Grammothele lineata strain SDL-CO-2015-1, a basidiomycete fungus, was identified as an endophyte from a jute species, Corchorus olitorius var. 2015, and found to produce paclitaxel, a diterpenic polyoxygenated pseudoalkaloid with antitumor activity. Here, we report the draft genome sequence (42.8 Mb with 9,395 genes) of this strain. PMID- 28818908 TI - Deep Sequencing Reveals a Divergent Ugandan cassava brown streak virus Isolate from Malawi. AB - Illumina sequencing of RNA from a cassava cutting from northern Malawi produced a genome of Ugandan cassava brown streak virus (UCBSV-MW-NB7_2013). Sequence comparisons revealed stronger similarity to an isolate from nearby Tanzania (93.4% pairwise nucleotide identity) than to those previously reported from Malawi (86.9 to 87.0%). PMID- 28818910 TI - Draft Genome Sequence of a Clinical Isolate of Streptococcus mutans Strain HM. AB - We report the draft genome sequence of Streptococcus mutans strain HM isolated from a 4-year-old girl with infective endocarditis. The genomics information will provide information on the genetic diversity and virulence potential of S. mutans strain HM. PMID- 28818911 TI - Complete Genome Sequence of a Naturally Occurring Simian Foamy Virus Isolate from Rhesus Macaque (SFVmmu_K3T). AB - The full-length genome sequence of a simian foamy virus (SFVmmu_K3T), isolated from a rhesus macaque (Macaca mulatta), was obtained using high-throughput sequencing. SFVmmu_K3T consisted of 12,983 bp and had a genomic organization similar to that of other SFVs, with long terminal repeats (LTRs) and open reading frames for Gag, Pol, Env, Tas, and Bet. PMID- 28818912 TI - Complete Genome Sequence of Enterobacter cloacae 704SK10, an OXA-48-Encoding Wastewater Isolate. AB - Here we present the complete genome sequence of Enterobacter cloacae 704SK10, a Swiss wastewater isolate encoding an OXA-48 carbapenemase. Assembly resulted in closed sequences of the 4,876,946-bp chromosome, a 111,184-bp IncF plasmid, and an OXA-48-encoding IncL plasmid (63,458 bp) nearly identical to the previously described plasmid pOXA-48. PMID- 28818913 TI - Draft Genome Sequence of Klebsiella pneumoniae 704SK6, an OXA-48- and CTX-M-15 Encoding Wastewater Isolate. AB - The Swiss wastewater isolate Klebsiella pneumoniae 704SK6, encoding OXA-48 and CTX-M-15 beta-lactamases, was fully sequenced. The assembly resulted in an open chromosome of 5,208,104 bp in size (G+C content, 57.6%) and four closed plasmid sequences of 209,651, 197,670, 65,998, and 63,605 bp in size. PMID- 28818914 TI - Complete Genome Sequence of Citrobacter freundii 705SK3, an OXA-48-Encoding Wastewater Isolate. AB - We present the genome sequence of Citrobacter freundii 705SK3, a wastewater isolate harboring an IncL OXA-48-encoding plasmid. Assembly of the genome resulted in a 5,242,839-bp circular chromosome (GC content, 52%) and two closed plasmids of 296,175 bp and 63, 458 bp in size. PMID- 28818915 TI - Collaborative environmental governance: Achieving collective action in social ecological systems. AB - Managing ecosystems is challenging because of the high number of stakeholders, the permeability of man-made political and jurisdictional demarcations in relation to the temporal and spatial extent of biophysical processes, and a limited understanding of complex ecosystem and societal dynamics. Given these conditions, collaborative governance is commonly put forward as the preferred means of addressing environmental problems. Under this paradigm, a deeper understanding of if, when, and how collaboration is effective, and when other means of addressing environmental problems are better suited, is needed. Interdisciplinary research on collaborative networks demonstrates that which actors get involved, with whom they collaborate, and in what ways they are tied to the structures of the ecosystems have profound implications on actors' abilities to address different types of environmental problems. PMID- 28818917 TI - Erratum for the Research Article "Observation of the Wigner-Huntington transition to metallic hydrogen" by R. P. Dias and I. F. Silvera. PMID- 28818920 TI - 2.7-million-year-old ice opens window on past. PMID- 28818916 TI - A pathology atlas of the human cancer transcriptome. AB - Cancer is one of the leading causes of death, and there is great interest in understanding the underlying molecular mechanisms involved in the pathogenesis and progression of individual tumors. We used systems-level approaches to analyze the genome-wide transcriptome of the protein-coding genes of 17 major cancer types with respect to clinical outcome. A general pattern emerged: Shorter patient survival was associated with up-regulation of genes involved in cell growth and with down-regulation of genes involved in cellular differentiation. Using genome-scale metabolic models, we show that cancer patients have widespread metabolic heterogeneity, highlighting the need for precise and personalized medicine for cancer treatment. All data are presented in an interactive open access database (www.proteinatlas.org/pathology) to allow genome-wide exploration of the impact of individual proteins on clinical outcomes. PMID- 28818918 TI - Revisit NIH biosafety guidelines. PMID- 28818921 TI - Where has all the Zika gone? PMID- 28818922 TI - Australia to ax support for long-term ecology sites. PMID- 28818923 TI - Astrophysics missions vie for NASA money. PMID- 28818924 TI - U.S.-Mexico water pact aims for a greener Colorado delta. PMID- 28818925 TI - 'Safe spaces' may save the European mink. PMID- 28818926 TI - On the trail of yellow fever. PMID- 28818928 TI - Circulating peptide prevents preeclampsia. PMID- 28818927 TI - Playing marble run to make methane. PMID- 28818929 TI - Vortex generation reaches a new plateau. PMID- 28818930 TI - How microbes survive in the open ocean. PMID- 28818931 TI - Ductal sex determination. PMID- 28818932 TI - Addressing spin states with infrared light. PMID- 28818933 TI - What do revised U.S. rules mean for human research? PMID- 28818935 TI - Editor's note. PMID- 28818934 TI - Evaluating Science's open-data policy. PMID- 28818936 TI - Helping less-prepared students excel. PMID- 28818937 TI - Best cost estimate of greenhouse gases. PMID- 28818939 TI - Preventing mussel adhesion using lubricant-infused materials. AB - Mussels are opportunistic macrofouling organisms that can attach to most immersed solid surfaces, leading to serious economic and ecological consequences for the maritime and aquaculture industries. We demonstrate that lubricant-infused coatings exhibit very low preferential mussel attachment and ultralow adhesive strengths under both controlled laboratory conditions and in marine field studies. Detailed investigations across multiple length scales-from the molecular scale characterization of deposited adhesive proteins to nanoscale contact mechanics to macroscale live observations-suggest that lubricant infusion considerably reduces fouling by deceiving the mechanosensing ability of mussels, deterring secretion of adhesive threads, and decreasing the molecular work of adhesion. Our study demonstrates that lubricant infusion represents an effective strategy to mitigate marine biofouling and provides insights into the physical mechanisms underlying adhesion prevention. PMID- 28818940 TI - Two-dimensional sp2 carbon-conjugated covalent organic frameworks. AB - We synthesized a two-dimensional (2D) crystalline covalent organic framework (sp2c-COF) that was designed to be fully pi-conjugated and constructed from all sp2 carbons by C=C condensation reactions of tetrakis(4-formylphenyl)pyrene and 1,4-phenylenediacetonitrile. The C=C linkages topologically connect pyrene knots at regular intervals into a 2D lattice with pi conjugations extended along both x and y directions and develop an eclipsed layer framework rather than the more conventionally obtained disordered structures. The sp2c-COF is a semiconductor with a discrete band gap of 1.9 electron volts and can be chemically oxidized to enhance conductivity by 12 orders of magnitude. The generated radicals are confined on the pyrene knots, enabling the formation of a paramagnetic carbon structure with high spin density. The sp2 carbon framework induces ferromagnetic phase transition to develop spin-spin coherence and align spins unidirectionally across the material. PMID- 28818941 TI - A molecular spin-photovoltaic device. AB - We fabricated a C60 fullerene-based molecular spin-photovoltaic device that integrates a photovoltaic response with the spin transport across the molecular layer. The photovoltaic response can be modified under the application of a small magnetic field, with a magnetophotovoltage of up to 5% at room temperature. Device functionalities include a magnetic current inverter and the presence of diverging magnetocurrent at certain illumination levels that could be useful for sensing. Completely spin-polarized currents can be created by balancing the external partially spin-polarized injection with the photogenerated carriers. PMID- 28818938 TI - Comprehensive single-cell transcriptional profiling of a multicellular organism. AB - To resolve cellular heterogeneity, we developed a combinatorial indexing strategy to profile the transcriptomes of single cells or nuclei, termed sci-RNA-seq (single-cell combinatorial indexing RNA sequencing). We applied sci-RNA-seq to profile nearly 50,000 cells from the nematode Caenorhabditis elegans at the L2 larval stage, which provided >50-fold "shotgun" cellular coverage of its somatic cell composition. From these data, we defined consensus expression profiles for 27 cell types and recovered rare neuronal cell types corresponding to as few as one or two cells in the L2 worm. We integrated these profiles with whole-animal chromatin immunoprecipitation sequencing data to deconvolve the cell type specific effects of transcription factors. The data generated by sci-RNA-seq constitute a powerful resource for nematode biology and foreshadow similar atlases for other organisms. PMID- 28818942 TI - An unusual white dwarf star may be a surviving remnant of a subluminous Type Ia supernova. AB - Subluminous Type Ia supernovae, such as the Type Iax-class prototype SN 2002cx, are described by a variety of models such as the failed detonation and partial deflagration of an accreting carbon-oxygen white dwarf star or the explosion of an accreting, hybrid carbon-oxygen-neon core. These models predict that bound remnants survive such events with, according to some simulations, a high kick velocity. We report the discovery of a high proper motion, low-mass white dwarf (LP 40-365) that travels at a velocity greater than the Galactic escape velocity and whose peculiar atmosphere is dominated by intermediate-mass elements. Strong evidence indicates that this partially burnt remnant was ejected following a subluminous Type Ia supernova event. This supports the viability of single degenerate supernova progenitors. PMID- 28818943 TI - Zones, spots, and planetary-scale waves beating in brown dwarf atmospheres. AB - Brown dwarfs are massive analogs of extrasolar giant planets and may host types of atmospheric circulation not seen in the solar system. We analyzed a long-term Spitzer Space Telescope infrared monitoring campaign of brown dwarfs to constrain cloud cover variations over a total of 192 rotations. The infrared brightness evolution is dominated by beat patterns caused by planetary-scale wave pairs and by a small number of bright spots. The beating waves have similar amplitudes but slightly different apparent periods because of differing velocities or directions. The power spectrum of intermediate-temperature brown dwarfs resembles that of Neptune, indicating the presence of zonal temperature and wind speed variations. Our findings explain three previously puzzling behaviors seen in brown dwarf brightness variations. PMID- 28818944 TI - Conversion of object identity to object-general semantic value in the primate temporal cortex. AB - At the final stage of the ventral visual stream, perirhinal neurons encode the identity of memorized objects through learning. However, it remains elusive whether and how object percepts alone, or concomitantly a nonphysical attribute of the objects ("learned"), are decoded from perirhinal activities. By combining monkey psychophysics with optogenetic and electrical stimulations, we found a focal spot of memory neurons where both stimulations led monkeys to preferentially judge presented objects as "already seen." In an adjacent fringe area, where neurons did not exhibit selective responses to the learned objects, electrical stimulation induced the opposite behavioral bias toward "never seen before," whereas optogenetic stimulation still induced bias toward "already seen." These results suggest that mnemonic judgment of objects emerges via the decoding of their nonphysical attributes encoded by perirhinal neurons. PMID- 28818945 TI - Deriving genomic diagnoses without revealing patient genomes. AB - Patient genomes are interpretable only in the context of other genomes; however, genome sharing enables discrimination. Thousands of monogenic diseases have yielded definitive genomic diagnoses and potential gene therapy targets. Here we show how to provide such diagnoses while preserving participant privacy through the use of secure multiparty computation. In multiple real scenarios (small patient cohorts, trio analysis, two-hospital collaboration), we used our methods to identify the causal variant and discover previously unrecognized disease genes and variants while keeping up to 99.7% of all participants' most sensitive genomic information private. PMID- 28818946 TI - A central neural circuit for itch sensation. AB - Although itch sensation is an important protective mechanism for animals, chronic itch remains a challenging clinical problem. Itch processing has been studied extensively at the spinal level. However, how itch information is transmitted to the brain and what central circuits underlie the itch-induced scratching behavior remain largely unknown. We found that the spinoparabrachial pathway was activated during itch processing and that optogenetic suppression of this pathway impaired itch-induced scratching behaviors. Itch-mediating spinal neurons, which express the gastrin-releasing peptide receptor, are disynaptically connected to the parabrachial nucleus via glutamatergic spinal projection neurons. Blockade of synaptic output of glutamatergic neurons in the parabrachial nucleus suppressed pruritogen-induced scratching behavior. Thus, our studies reveal a central neural circuit that is critical for itch signal processing. PMID- 28818947 TI - Methanogenic heterodisulfide reductase (HdrABC-MvhAGD) uses two noncubane [4Fe 4S] clusters for reduction. AB - In methanogenic archaea, the carbon dioxide (CO2) fixation and methane-forming steps are linked through the heterodisulfide reductase (HdrABC)-[NiFe] hydrogenase (MvhAGD) complex that uses flavin-based electron bifurcation to reduce ferredoxin and the heterodisulfide of coenzymes M and B. Here, we present the structure of the native heterododecameric HdrABC-MvhAGD complex at 2.15 angstrom resolution. HdrB contains two noncubane [4Fe-4S] clusters composed of fused [3Fe-4S]-[2Fe-2S] units sharing 1 iron (Fe) and 1 sulfur (S), which were coordinated at the CCG motifs. Soaking experiments showed that the heterodisulfide is clamped between the two noncubane [4Fe-4S] clusters and homolytically cleaved, forming coenzyme M and B bound to each iron. Coenzymes are consecutively released upon one-by-one electron transfer. The HdrABC-MvhAGD atomic model serves as a structural template for numerous HdrABC homologs involved in diverse microbial metabolic pathways. PMID- 28818948 TI - Vinculin forms a directionally asymmetric catch bond with F-actin. AB - Vinculin is an actin-binding protein thought to reinforce cell-cell and cell matrix adhesions. However, how mechanical load affects the vinculin-F-actin bond is unclear. Using a single-molecule optical trap assay, we found that vinculin forms a force-dependent catch bond with F-actin through its tail domain, but with lifetimes that depend strongly on the direction of the applied force. Force toward the pointed (-) end of the actin filament resulted in a bond that was maximally stable at 8 piconewtons, with a mean lifetime (12 seconds) 10 times as long as the mean lifetime when force was applied toward the barbed (+) end. A computational model of lamellipodial actin dynamics suggests that the directionality of the vinculin-F-actin bond could establish long-range order in the actin cytoskeleton. The directional and force-stabilized binding of vinculin to F-actin may be a mechanism by which adhesion complexes maintain front-rear asymmetry in migrating cells. PMID- 28818949 TI - In situ architecture, function, and evolution of a contractile injection system. AB - Contractile injection systems mediate bacterial cell-cell interactions by a bacteriophage tail-like structure. In contrast to extracellular systems, the type 6 secretion system (T6SS) is defined by intracellular localization and attachment to the cytoplasmic membrane. Here we used cryo-focused ion beam milling, electron cryotomography, and functional assays to study a T6SS in Amoebophilus asiaticus The in situ architecture revealed three modules, including a contractile sheath tube, a baseplate, and an anchor. All modules showed conformational changes upon firing. Lateral baseplate interactions coordinated T6SSs in hexagonal arrays. The system mediated interactions with host membranes and may participate in phagosome escape. Evolutionary sequence analyses predicted that T6SSs are more widespread than previously thought. Our insights form the basis for understanding T6SS key concepts and exploring T6SS diversity. PMID- 28818951 TI - When personal becomes professional. PMID- 28818950 TI - Elimination of the male reproductive tract in the female embryo is promoted by COUP-TFII in mice. AB - The sexual differentiation paradigm contends that the female pattern of the reproductive system is established by default because the male reproductive tracts (Wolffian ducts) in the female degenerate owing to a lack of androgen. Here, we discovered that female mouse embryos lacking Coup-tfII (chicken ovalbumin upstream promoter transcription factor II) in the Wolffian duct mesenchyme became intersex-possessing both female and male reproductive tracts. Retention of Wolffian ducts was not caused by ectopic androgen production or action. Instead, enhanced phosphorylated extracellular signal-regulated kinase signaling in Wolffian duct epithelium was responsible for the retention of male structures in an androgen-independent manner. We thus suggest that elimination of Wolffian ducts in female embryos is actively promoted by COUP-TFII, which suppresses a mesenchyme-epithelium cross-talk responsible for Wolffian duct maintenance. PMID- 28818952 TI - Enasidenib Approved for AML, but Best Uses Unclear. AB - The FDA approved the targeted therapy enasidenib for patients with refractory or relapsed acute myeloid leukemia with mutant IDH2 The drug produces remissions in some patients and may reduce the need for blood transfusions, although researchers acknowledge that the FDA's approval came with less supporting evidence than usual. PMID- 28818954 TI - On the way to the Tokyo Summer Olympic Games (2020). Prevention of severe head and neck injuries in judo: it's time for action. PMID- 28818955 TI - BJSM educational editorials: methods matter. PMID- 28818956 TI - Infographic: treating runners with patellofemoral pain: appropriate education is key. PMID- 28818957 TI - Unravelling confusion in sports medicine and sports science practice: a systematic approach to using the best of research and practice-based evidence to make a quality decision. PMID- 28818958 TI - Author response-sham surgery versus labral repair or biceps tenodesis for type II SLAP lesions of the shoulder: a three-armed randomised clinical trial. PMID- 28818959 TI - Accessing off-field brains in sport; an applied research model to develop practice. PMID- 28818953 TI - New Horizons for Precision Medicine in Biliary Tract Cancers. AB - Biliary tract cancers (BTC), including cholangiocarcinoma and gallbladder cancer, are poor-prognosis and low-incidence cancers, although the incidence of intrahepatic cholangiocarcinoma is rising. A minority of patients present with resectable disease but relapse rates are high; benefit from adjuvant capecitabine chemotherapy has been demonstrated. Cisplatin/gemcitabine combination chemotherapy has emerged as the reference first-line treatment regimen; there is no standard second-line therapy. Selected patients may be suitable for liver directed therapy (e.g., radioembolization or external beam radiation), pending confirmation of benefit in randomized studies. Initial trials targeting the epithelial growth factor receptor and angiogenesis pathways have failed to deliver new treatments. Emerging data from next-generation sequencing analyses have identified actionable mutations (e.g., FGFR fusion rearrangements and IDH1 and IDH2 mutations), with several targeted drugs entering clinical development with encouraging results. The role of systemic therapies, including targeted therapies and immunotherapy for BTC, is rapidly evolving and is the subject of this review.Significance: The authors address genetic drivers and molecular biology from a translational perspective, in an intent to offer a clear view of the recent past, present, and future of BTC. The review describes a state-of-the art update of the current status and future directions of research and therapy in advanced BTC. Cancer Discov; 7(9); 943-62. (c)2017 AACR. PMID- 28818960 TI - Infographic: Recommendations for running injuries. PMID- 28818961 TI - An analogy between socioeconomic deprivation level and loss of health from adverse effects of medical treatment in England. AB - BACKGROUND: The purpose of this study was to show whether and how levels, trends and patterns obtained from estimates of premature deaths from adverse effects (AEs) of medical treatment depended on the deprivation level in England over the 24-year period, 1990-2013. We provide a report to inform decision-making strategies to reduce the burden of disease arising from AEs of medical treatment in the most deprived areas of the country. METHODS: Comparative analysis was driven by a single cause-of-injury category-AEs of medical treatment-from the Global Burden of Disease 2013 study. We report the mean values with 95% uncertainty intervals (UIs) for five socioeconomic deprivation areas of England. RESULTS: In the most deprived areas of England, the death rate declined from 2.27 (95% UI 1.65 to 2.57) to 1.54 (1.28 to 2.08) deaths (32.16% change). The death rate in the least deprived areas was 1.22 (0.88 to 1.38) in 1990; it was 1.17 (0.97 to 1.59) in 2013 (4.1% change). Regarding disability-adjusted life year (DALY) rates, the same trend is observed. Although the gap between the most deprived and least deprived populations of England narrowed with regards to number of deaths, and rates of deaths and DALYs from AEs of medical treatment, inequalities between marginal levels of deprivation remain. CONCLUSIONS: The study suggests that a relationship between deprivation level and health loss from the AEs of medical treatment across England is possible. This could then be used when devising and prioritising health policies and strategies. PMID- 28818962 TI - Comparing levels of evidence between Choosing Wisely and Essential Evidence Plus. PMID- 28818963 TI - USPSTF is unable to recommend for or against lipid screening to identify multifactorial dyslipidaemia in childhood: no recommendation is not without consequences. AB - Paediatric lipid screening has been recommended for decades to identify youth at increased risk for early atherosclerotic disease but is controversial and not universally adopted. A 2016 review by the US Preventive Services Task Force (USPSTF) found inadequate evidence to recommend for or against lipid screening in childhood. In this Perspective article, we examine this controversial and important topic more broadly. We consider whether the USPSTF framework is asking the right questions, and whether the answers to these questions should be valued equally, whether the USPSTF questions are answerable and by what types of evidence and whether the burden of proof is appropriate. We argue that using a broader framework that includes the magnitude of potential benefits and harms, considering more types of evidence beyond randomised controlled trials, and more fully incorporating patient and parent perspectives could lead to more practical and more widely applicable guidance for practitioners, guide future research priorities and be more inclusive of patient priorities. PMID- 28818964 TI - Caffeine does not increase the arrhythmic burden in patients with heart failure and left ventricular systolic dysfunction. PMID- 28818965 TI - Parent-delivered CBT may reduce intervention cost, but questions arise about effectiveness. PMID- 28818966 TI - Meta-analysis using individual participant data from randomised trials: opportunities and limitations created by access to raw data. AB - Meta-analysis based on individual participant data (IPD), often described as the 'gold standard' for effectiveness evidence synthesis, is increasingly being deployed despite being more resource intensive than collating study-level results. Its professed virtues include the ability to incorporate unreported data and to standardise variables and their definitions across trials. In reality, the unreported data, although present in shared datasets, might still not be usable in the analysis. The characteristics of trial participants and their outcomes may be too diversely captured for harmonisation and too time and resource consuming to standardise. Embarking on an IPD meta-analysis can lead to unanticipated challenges which ought to be handled with pragmatism. The aim of this article is to discuss the opportunities created by access to IPD and the practical limitations placed on such meta-analyses, using an international IPD meta analysis of trials on the effect of lifestyle interventions in pregnancy as an example. Despite the increasing uptake of IPD meta-analysis, they encounter old problems shared by other research methods. When embarking on IPD meta-analysis, it is essential to evaluate the trade-offs between the ambitions, and what is achievable due to constraints imposed by the condition of collected IPD. Furthermore, incorporation of aggregate data from trials where IPD was not available should be a mandatory sensitivity analysis that makes the evidence synthesis up-to-date. PMID- 28818967 TI - An unusual cause of chest pain. PMID- 28818968 TI - The turbulent cascade in five dimensions. AB - To the naked eye, turbulent flows exhibit whirls of many different sizes. To each size, or scale, corresponds a fraction of the total energy resulting from a cascade in five dimensions: scale, time, and three-dimensional space. Understanding this process is critical to strategies for modeling geophysical and industrial flows. By tracking the flow regions containing energy in different scales, we have detected the statistical predominance of a cross-scale link whereby fluid lumps of energy at scale Delta appear within lumps of scale 2Delta and die within those of scale Delta/2. Our approach uncovers the energy cascade in a simple water-like fluid, offering insights for turbulence models while paving the way for similar analyses in conducting fluids, quantum fluids, and plasmas. PMID- 28818969 TI - Distinct phases of Polycomb silencing to hold epigenetic memory of cold in Arabidopsis. AB - Gene silencing by Polycomb complexes is central to eukaryotic development. Cold induced epigenetic repression of FLOWERING LOCUS C (FLC) in the plant Arabidopsis provides an opportunity to study initiation and maintenance of Polycomb silencing. Here, we show that a subset of Polycomb repressive complex 2 factors nucleate silencing in a small region within FLC, locally increasing H3K27me3 levels. This nucleation confers a silenced state that is metastably inherited, with memory held in the local chromatin. Metastable memory is then converted to stable epigenetic silencing through separate Polycomb factors, which spread across the locus after cold to enlarge the domain that contains H3K27me3. Polycomb silencing at FLC thus has mechanistically distinct phases, which involve specialization of distinct Polycomb components to deliver first metastable then long-term epigenetic silencing. PMID- 28818970 TI - DNA replication-coupled histone modification maintains Polycomb gene silencing in plants. AB - Propagation of patterns of gene expression through the cell cycle requires prompt restoration of epigenetic marks after the twofold dilution caused by DNA replication. Here we show that the transcriptional repressive mark H3K27me3 (histone H3 lysine 27 trimethylation) is restored in replicating plant cells through DNA replication-coupled modification of histone variant H3.1. Plants evolved a mechanism for efficient K27 trimethylation on H3.1, which is essential for inheritance of the silencing memory from mother to daughter cells. We illustrate how this mechanism establishes H3K27me3-mediated silencing during the developmental transition to flowering. Our study reveals a mechanism responsible for transmission of H3K27me3 in plant cells through cell divisions, enabling H3K27me3 to function as an epigenetic mark. PMID- 28818971 TI - Dynamic multinuclear sites formed by mobilized copper ions in NO x selective catalytic reduction. AB - Copper ions exchanged into zeolites are active for the selective catalytic reduction (SCR) of nitrogen oxides (NO x ) with ammonia (NH3), but the low temperature rate dependence on copper (Cu) volumetric density is inconsistent with reaction at single sites. We combine steady-state and transient kinetic measurements, x-ray absorption spectroscopy, and first-principles calculations to demonstrate that under reaction conditions, mobilized Cu ions can travel through zeolite windows and form transient ion pairs that participate in an oxygen (O2) mediated CuI->CuII redox step integral to SCR. Electrostatic tethering to framework aluminum centers limits the volume that each ion can explore and thus its capacity to form an ion pair. The dynamic, reversible formation of multinuclear sites from mobilized single atoms represents a distinct phenomenon that falls outside the conventional boundaries of a heterogeneous or homogeneous catalyst. PMID- 28818972 TI - Fertile offspring from sterile sex chromosome trisomic mice. AB - Having the correct number of chromosomes is vital for normal development and health. Sex chromosome trisomy affects 0.1% of the human population and is associated with infertility. We show that during reprogramming to induced pluripotent stem cells (iPSCs), fibroblasts from sterile trisomic XXY and XYY mice lose the extra sex chromosome through a phenomenon we term trisomy-biased chromosome loss (TCL). Resulting euploid XY iPSCs can be differentiated into the male germ cell lineage and functional sperm that can be used in intracytoplasmic sperm injection to produce chromosomally normal, fertile offspring. Sex chromosome loss is comparatively infrequent during mouse XX and XY iPSC generation. TCL also applies to other chromosomes, generating euploid iPSCs from cells of a Down syndrome mouse model. It can also create euploid iPSCs from human trisomic patient fibroblasts. The findings have relevance to overcoming infertility and other trisomic phenotypes. PMID- 28818974 TI - Pregnant and nil by mouth. PMID- 28818973 TI - Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism. AB - TERT promoter mutations (TPMs) are the most common noncoding mutations in cancer. The timing and consequences of TPMs have not been fully established. Here, we show that TPMs acquired at the transition from benign nevus to malignant melanoma do not support telomere maintenance. In vitro experiments revealed that TPMs do not prevent telomere attrition, resulting in cells with critically short and unprotected telomeres. Immortalization by TPMs requires a gradual up-regulation of telomerase, coinciding with telomere fusions. These data suggest that TPMs contribute to tumorigenesis by promoting immortalization and genomic instability in two phases. In an initial phase, TPMs do not prevent bulk telomere shortening but extend cellular life span by healing the shortest telomeres. In the second phase, the critically short telomeres lead to genome instability and telomerase is further up-regulated to sustain cell proliferation. PMID- 28818975 TI - Inherited thrombocytopenia and Occam's razor. PMID- 28818976 TI - Splicing together the origins of MDS-RS. PMID- 28818978 TI - Innately interesting interactions. PMID- 28818977 TI - Accept the complement (blockade). PMID- 28818979 TI - Incidental brown adipose tissue in bone marrow biopsy. PMID- 28818980 TI - Relapse of an acute leukemia of mixed lineage as an isolated orbital mass. PMID- 28818981 TI - Putti MC, Pizzi M, Bertozzi I, et al. Bone marrow histology for the diagnosis of essential thrombocythemia in children: a multicenter Italian study. Blood. 2017;129(22):3040-3042. PMID- 28818982 TI - SF3B1 mutation arises at the multipotent HSC level. PMID- 28818983 TI - Current Concepts in 68Ga-DOTATATE Imaging of Neuroendocrine Neoplasms: Interpretation, Biodistribution, Dosimetry, and Molecular Strategies. AB - 68Ga-DOTATATE PET/CT provides information on the location of somatostatin receptor-expressing tumors. Integrating this imaging data effectively in patient care requires the clinical history; the histopathology and biomarker information; and the grade, stage, and prior imaging results. Previous therapies and technical aspects of the study should be considered, given their ability to alter the interpretation of the images. This includes physiologic biodistribution of the radiotracer, as well as conditions that engender false-positive results. This article provides a guide to the performance and interpretation of 68Ga-DOTATATE PET/CT and describes its role in the diagnostic algorithm of neuroendocrine neoplasms and its overall utility in their management. PMID- 28818985 TI - Somatostatin Antagonists for Radioligand Therapy of Nonendocrine Tumors. PMID- 28818986 TI - David Versus the Goliaths for the Detection of Bone Metastases. PMID- 28818984 TI - Pseudoreference Regions for Glial Imaging with 11C-PBR28: Investigation in 2 Clinical Cohorts. AB - The translocator protein (TSPO) is a commonly used imaging target to investigate neuroinflammation. Although TSPO imaging demonstrates great promise, its signal exhibits substantial interindividual variability, which needs to be accounted for to uncover group effects that are truly reflective of neuroimmune activation. Recent evidence suggests that relative metrics computed using pseudoreference approaches can minimize within-group variability and increase sensitivity to detect physiologically meaningful group differences. Here, we evaluated various ratio approaches for TSPO imaging and compared them with standard kinetic modeling techniques, analyzing 2 different disease cohorts. Patients with chronic low back pain (cLBP) or amyotrophic lateral sclerosis (ALS) and matching healthy controls received 11C-PBR28 PET scans. The occipital cortex, cerebellum and whole brain were first evaluated as candidate pseudoreference regions by testing for the absence of group differences in SUV and distribution volume (VT) estimated with an arterial input function. The SUV from target regions (cLBP study, thalamus; ALS study, precentral gyrus) was normalized with the SUV from candidate pseudoreference regions (i.e., occipital cortex, cerebellum, and whole brain) to obtain SUVRoccip, SUVRcereb, and SUVRWB The sensitivity to detect group differences in target regions was compared using various SUVR approaches, as well as distribution volume ratio (DVR) estimated with (blDVR) or without arterial input function (refDVR), and VT Additional voxelwise SUVR group analyses were performed. We observed no significant group differences in pseudoreference VT or SUV, excepting whole-brain VT, which was higher in cLBP patients than controls. Target VT elevations in patients (P = 0.028 and 0.051 in cLBP and ALS, respectively) were similarly detected by SUVRoccip and SUVRWB, and by refDVR and blDVR (less reliably by SUVRcereb). In voxelwise analyses, SUVRoccip, but not SUVRcereb, identified regional group differences initially observed with SUVRWB, and in additional areas suspected to be affected in the pathology examined. All ratio metrics were highly cross-correlated, but generally were not associated with VT. Although important caveats need to be considered when using relative metrics, ratio analyses appear to be similarly sensitive to detect pathology related group differences in 11C-PBR28 signal as classic kinetic modeling techniques. The occipital cortex may be a suitable pseudoreference region, at least for the populations evaluated, pending further validation in larger cohorts. PMID- 28818987 TI - Response Assessment of 68Ga-DOTA-E-[c(RGDfK)]2 PET/CT in Lung Adenocarcinoma Patients Treated with Nintedanib Plus Docetaxel. AB - Nintedanib is an oral angiokinase inhibitor used as second-line treatment for non small cell lung cancer. New radiotracers, such as 68Ga-DOTA-E-[c(RGDfK)]2, that target alphavbeta3 integrin might have an impact as a noninvasive method for assessing angiogenesis inhibitors. Methods: From July 2011 through October 2015, 38 patients received second-line nintedanib plus docetaxel. All patients underwent PET/CT with 68Ga-DOTA-E-[c(RGDfK)]2 radiotracer and blood-sample tests to quantify angiogenesis factors (fibroblast growth factor, vascular endothelial growth factor, and platelet-derived growth factor AB) before and after completing 2 therapy cycles. Results: Of the 38 patients, 31 had available baseline and follow-up PET/CT. Baseline lung tumor volume addressed with 68Ga-DOTA-E [c(RGDfK)]2 PET/CT correlated with serum vascular endothelial growth factor levels, whereas baseline lung/liver SUVmax index correlated with platelet-derived growth factor AB. After treatment, the overall response rate and disease control rate were 7.9% and 47.3%, respectively. A greater decrease in lung tumor volume ( 37.2% vs. -27.6%) was associated with a better disease control rate in patients (P = 0.005). Median progression-free survival was 3.7 mo. Nonsmokers and patients with a higher baseline lung tumor volume were more likely to have a higher progression-free survival (6.4 vs. 3.74 [P = 0.023] and 6.4 vs. 2.1 [P = 0.003], respectively). Overall survival was not reached. Patients with a greater decrease in lung SUVmax (not reached vs. 7.1 mo; P = 0.016) and a greater decrease in the lung/spleen SUVmax index (not reached vs. 7.1; P = 0.043) were more likely to have a longer overall survival. Conclusion:68Ga-DOTA-E-[c(RGDfK)]2 PET/CT is a potentially useful tool for assessing responses to angiogenesis inhibitors. Further analysis and novel studies are warranted to identify patients who might benefit from this therapy. PMID- 28818988 TI - Multiregional Tumor Drug-Uptake Imaging by PET and Microvascular Morphology in End-Stage Diffuse Intrinsic Pontine Glioma. AB - Inadequate tumor uptake of the vascular endothelial growth factor antibody bevacizumab could explain lack of effect in diffuse intrinsic pontine glioma. Methods: By combining data from a PET imaging study using 89Zr-labeled bevacizumab and an autopsy study, a 1-on-1 analysis of multiregional in vivo and ex vivo 89Zr-bevacizumab uptake, tumor histology, and vascular morphology in a diffuse intrinsic pontine glioma patient was performed. Results: In vivo 89Zr bevacizumab measurements showed heterogeneity between lesions. Additional ex vivo measurements and immunohistochemistry of cervicomedullary metastasis samples showed uptake to be highest in the area with marked microvascular proliferation. In the primary pontine tumor, all samples showed similar vascular morphology. Other histologic features were similar between the samples studied. Conclusion: In vivo 89Zr-bevacizumab PET serves to identify heterogeneous uptake between tumor lesions, whereas subcentimeter intralesional heterogeneity could be identified only by ex vivo measurements. 89Zr-bevacizumab uptake is enhanced by vascular proliferation, although our results suggest it is not the only determinant of intralesional uptake heterogeneity. PMID- 28818989 TI - Metabolic Imaging of Infection. AB - Metabolic imaging has come to occupy a prominent place in the diagnosis and management of microbial infection. Molecular probes available for infection imaging have undergone a rapid evolution starting with nonspecific agents that accumulate similarly in infection, sterile inflammation, and neoplastic tissue and then extending to more targeted probes that seek to identify specific microbial species. This focus review describes the metabolic and molecular imaging techniques currently available for clinical use in infection imaging and those that have demonstrated promising results in preclinical studies with the potential for clinical applications. PMID- 28818990 TI - Clinical Use and Utility of Amyloid Imaging. AB - Currently, 3 amyloid PET tracers are approved and commercially available for clinical use. They allow for the accurate in vivo detection of amyloid plaques, one hallmark of Alzheimer disease. Here, we review the current knowledge on the clinical use and utility of amyloid imaging. Appropriate use criteria for the clinical application of amyloid imaging are established, and most currently available data point to their validity. Visual amyloid image analysis is highly standardized. Disclosure of amyloid imaging results is desired by many cognitively impaired subjects and seems to be safe once appropriate education is delivered to the disclosing clinicians. Regarding clinical utility, increasing evidence points to a change in diagnosis via amyloid imaging in about 30% of cases, to an increase in diagnostic confidence in about 60% of cases, to a change in patient management in about 60% of cases, and specifically to a change in medication in about 40% of cases. Also, amyloid imaging results seem to have a relevant impact on caregivers. Further, initial simulation studies point to a potential positive effect on patient outcome and to cost effectiveness of amyloid imaging. These features, however, will require confirmation in prospective clinical trials. More work is also required to determine the clinical utility of amyloid imaging specifically in subjects with mild cognitive impairment and in comparison with or in conjunction with other Alzheimer disease biomarkers. In summary, the clinical use of amyloid imaging is being studied, and the currently available data point to a relevant clinical utility of this imaging technique. Ongoing research will determine whether this accurate and noninvasive approach to amyloid plaque load detection will translate into a benefit to cognitively impaired subjects. PMID- 28818991 TI - Immune Modulation Therapy and Imaging: Workshop Report. AB - A workshop at the National Cancer Institute on May 2, 2016, considered the current state of imaging in assessment of immunotherapy. Immunotherapy has shown some remarkable and prolonged responses in the treatment of tumors. However, responses are variable and frequently delayed, complicating the evaluation of new immunotherapy agents and customizing treatment for individual patients. Early anatomic imaging may show that a tumor has increased in size, but this could represent pseudoprogression. On the basis of imaging, clinicians must decide if they should stop, pause, or continue treatment. Other imaging technologies and approaches are being developed to improve the measurement of response in patients receiving immunotherapy. Imaging methods that are being evaluated include radiomic methods using CT, MRI, and 18F-FDG PET, as well as new radiolabeled small molecules, antibodies, and antibody fragments to image the tumor microenvironment, immune status, and changes over the course of therapy. Current studies of immunotherapy can take advantage of these available imaging options to explore and validate their use. Collection of CT, PET, and MR images along with outcomes from trials is critical to develop improved methods of assessment. PMID- 28818993 TI - Nuclear Medicine Training: What Now? AB - Although the multidisciplinary nature of nuclear medicine (NM) and clinical molecular imaging is a key strength of the specialty, the breadth of disciplines involved in the practice of NM creates challenges for education and training. The evolution of NM science and technology-and the practice of clinical molecular imaging and theranostics-has created a need for changes in the approach to specialty training. The broader U.S. community of imaging physicians has been slow to accept this change, in good part due to historical divides between the NM and nuclear radiology (NR) communities. In this Journal of Nuclear Medicine Hot Topics discussion, we review the historical pathways to training; discuss the training needs for the modern practice of NM, clinical molecular imaging, and radionuclide therapy; and suggest a path forward for an approach to training that matches the needs of the evolving clinical specialty. PMID- 28818992 TI - Long-Half-Life 89Zr-Labeled Radiotracers Can Guide Percutaneous Biopsy Within the PET/CT Suite Without Reinjection of Radiotracer. AB - The rationale for this study was to evaluate the feasibility of within-suite 89Zr labeled radiotracer PET/CT-guided biopsy performed without reinjection. Methods: From 2013 to 2016, 12 patients (7 men, 5 women; mean age, 61 y; range, 40-75 y) with metastatic prostate or breast carcinoma suspected either on imaging or because of biochemical progression underwent 14 percutaneous biopsies after diagnostic PET/CT using 89Zr-labeled radiotracers (mean dose, 180 MBq; range, 126 189 MBq) targeting prostate-specific membrane antigen (n = 7) or human epidermal growth factor receptor 2 (n = 5). Biopsy was performed within a PET/CT suite without radiotracer reinjection. Results: There were no complications in any biopsies, which were performed a mean of 6.2 d (range, 0-13 d) after injection of the radiotracer. The biopsy sites were bone (n = 7), pleura (n = 3), lymph nodes (n = 2), and liver (n = 2). On pathologic examination of the biopsy samples, all were positive for malignancy. The initial diagnostic imaging findings were concordant with the biopsy results. The additional radiation (mean dose-length product) due to the CT procedures was 1,581 mGy/cm (range, 379-2,686 mGy/cm). Conclusion: PET/CT-guided biopsy using 89Zr-labeled radiotracers is safe and effective without tracer reinjection. PMID- 28818994 TI - Efficacy and Safety of Diacerein in Patients With Inadequately Controlled Type 2 Diabetes: A Randomized Controlled Trial. AB - OBJECTIVE: To assess, in a randomized, double-blind, and placebo-controlled trial, the efficacy and safety of diacerein, an immune modulator anti inflammatory drug, in improving glycemic control of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Eighty-four patients with HbA1c between 7.5 and 9.5% (58-80 mmol/mol) were randomized to 48-week treatment with placebo (n = 41) or diacerein 100 mg/day (n = 43). The primary outcome was the difference in mean HbA1c changes during treatment. Secondary outcomes were other efficacy and safety measurements. A general linear regression with repeated measures, adjusted for age, sex, diabetes duration, and each baseline value, was used to estimate differences in mean changes. Both intention-to-treat (ITT) analysis and per-protocol analysis (excluding 10 patients who interrupted treatment) were performed. RESULTS: Diacerein reduced HbA1c compared with placebo by 0.35% (3.8 mmol/mol; P = 0.038) in the ITT analysis and by 0.41% (4.5 mmol/mol; P = 0.023) in the per-protocol analysis. The peak of effect occurred at the 24th week of treatment (-0.61% [6.7 mmol/mol; P = 0.014] and -0.78% [8.5 mmol/mol; P = 0.005], respectively), but it attenuated toward nonsignificant differences at the 48th week. No significant effect of diacerein was observed in other efficacy and safety measures. Diarrhea occurred in 65% of patients receiving diacerein and caused treatment interruption in 16%. Seven patients in the diacerein group reduced insulin dosage, whereas 10 in the placebo group increased it; however, mild hypoglycemic events were equally observed. CONCLUSIONS: Diacerein reduced mean HbA1c levels, with peak of effect at the 24th week of treatment. The drug was well tolerated and may be indicated as adjunct treatment in patients with type 2 diabetes, particularly in those with osteoarthritis. PMID- 28818995 TI - Maternal DCAF2 is crucial for maintenance of genome stability during the first cell cycle in mice. AB - Precise regulation of DNA replication and genome integrity is crucial for gametogenesis and early embryogenesis. Cullin ring-finger ubiquitin ligase 4 (CRL4) has multiple functions in the maintenance of germ cell survival, oocyte meiotic maturation, and maternal-zygotic transition in mammals. DDB1-cullin-4 associated factor-2 (DCAF2, also known as DTL or CDT2) is an evolutionarily conserved substrate receptor of CRL4. To determine whether DCAF2 is a key CRL4 substrate adaptor in mammalian oocytes, we generated a novel mouse strain that carries a Dcaf2 allele flanked by loxP sequences, and specifically deleted Dcaf2 in oocytes. Dcaf2 knockout in mouse oocytes leads to female infertility. Although Dcaf2-null oocytes were able to develop and mature normally, the embryos derived from them were arrested at one- to two-cell stage, owing to prolonged DNA replication and accumulation of massive DNA damage. These results indicate that DCAF2 is a previously unrecognized maternal factor that safeguards zygotic genome stability. Maternal DCAF2 protein is crucial for prevention of DNA re-replication in the first and unique mitotic cell cycle of the zygote.This article has an associated First Person interview with the first author of the paper. PMID- 28818996 TI - Regulation of Cx37 channel and growth-suppressive properties by phosphorylation. AB - Growth suppression mediated by connexin 37 (Cx37; also known as GJA4) requires interaction between its C-terminus and functional pore-forming domain. Using rat insulinoma cells, we show that Cx37 induces cell death and cell cycle arrest, and slowed cell cycling. Whether differential phosphorylation might regulate intramolecular interactions, and consequently the growth-suppressive phenotype, is unknown. Protein kinase C inhibition increased the open state probability of low-conductance gap junction channels (GJChs) and reduced GJCh closed state probability. Substituting alanine at serine residues 275, 302 and 328 eliminated Cx37-induced cell death, supported proliferation and reduced the GJCh closed state probability. With additional alanine for serine substitutions at residues 285, 319, 321 and 325, Cx37-induced cell death was eliminated and the growth arrest period prolonged, and GJCh closed state probability was restored. With aspartate substitution at these seven sites, apoptosis was induced and the open state probability of large conductance GJChs (and hemichannels) was increased. These data suggest that differential phosphorylation of the C-terminus regulates channel conformation and, thereby, cell cycle progression and cell survival. PMID- 28818998 TI - Lower body negative pressure reduces optic nerve sheath diameter during head-down tilt. AB - The microgravity ocular syndrome (MOS) results in significant structural and functional ophthalmic changes during 6-mo spaceflight missions consistent with an increase in cerebrospinal fluid (CSF) pressure compared with the preflight upright position. A ground-based study was performed to assess two of the major hypothesized contributors to MOS, headward fluid shifting and increased ambient CO2, on intracranial and periorbital CSF. In addition, lower body negative pressure (LBNP) was assessed as a countermeasure to headward fluid shifting. Nine healthy male subjects participated in a crossover design study with five head down tilt (HDT) conditions: -6, -12, and -18 degrees HDT, -12 degrees HDT with 20 mmHg LBNP, and -12 degrees HDT with a 1% CO2 environment, each for 5 h total. A three-dimensional volumetric scan of the cranium and transverse slices of the orbita were collected with MRI, and intracranial CSF volume and optic nerve sheath diameter (ONSD) were measured after 4.5 h HDT. ONSD increased during -6 degrees (P < 0.001), -12 degrees (P < 0.001), and -18 degrees HDT (P < 0.001) and intracranial CSF increased during -12 degrees HDT (P = 0.01) compared with supine baseline. Notably, LBNP was able to reduce the increases in ONSD and intracranial CSF during HDT. The addition of 1% CO2 during HDT, however, had no further effect on ONSD, but rather ONSD increased from baseline in a similar magnitude to -12 degrees HDT with ambient air (P = 0.001). These findings demonstrate the ability of LBNP, a technique that targets fluid distribution in the lower limbs, to directly influence CSF and may be a promising countermeasure to help reduce increases in CSF.NEW & NOTEWORTHY This is the first study to demonstrate the ability of lower body negative pressure to directly influence cerebrospinal fluid surrounding the optic nerve, indicating potential use as a countermeasure for increased cerebrospinal fluid on Earth or in space. PMID- 28818997 TI - The CCR2 3'UTR functions as a competing endogenous RNA to inhibit breast cancer metastasis. AB - Diverse RNA transcripts acting as competing endogenous RNAs (ceRNAs) can co regulate each other's expression by competing for shared microRNAs. CCR2 protein, the receptor for CCL2, is implicated in cancer progression. However, we found that a higher CCR2 mRNA level is remarkably associated with prolonged survival of breast cancer patients. These conflicting results prompted us to study the non coding function of CCR2 mRNA. We found that the CCR2 3' untranslated region (UTR) inhibited MDA-MB-231 and MCF-7 cell metastasis by repressing epithelial mesenchymal transition (EMT) in vitro, and suppressed breast cancer metastasis in vivo Mechanistically, the CCR2 3'UTR modulated the expression of the RhoGAP protein STARD13 via acting as a STARD13 ceRNA in a microRNA-dependent and protein coding-independent manner. The CCR2 3'UTR blocked the activation of RhoA-ROCK1 pathway, which is the downstream effector of STARD13, and thus decreased the phosphorylation level of myosin light chain 2 (MLC2) and formation of F-actin. Additionally, the function of the CCR2 3'UTR was dependent on STARD13 expression. In conclusion, our results confirmed that the CCR2 3'UTR acts as a metastasis suppressor by acting as a ceRNA for STARD13 and thus inhibiting RhoA-ROCK1-MLC-F actin pathway in breast cancer cells.This article has an associated First Person interview with the first author of the paper. PMID- 28818999 TI - Short-term arrival strategies for endurance exercise performance at moderate altitude. AB - For sea level-based endurance athletes who compete at moderate and high altitudes, many are not logistically able to arrive at altitude weeks before the event to fully acclimatize. For those who can only arrive at altitude the night before competition, we asked if there is a physiological and performance advantage in reducing altitude exposure time to 2 h before competition. On three separate visits, 10 cyclists completed overnight laboratory exposures of: 1) a 14 h exposure to normobaric hypoxia (16.2% O2, simulating 2,500 m; 14H), 2) a 12-h exposure to normoxia, then a 2-h hypoxic exposure (2H), and 3) a 14-h exposure to normoxia (CON). Immediately following each exposure, subjects completed a 20-km cycle ergometry time trial in normoxia (CON) or 16.2% O2 (14H and 2H). Measures of plasma volume changes, sleep quality, ventilatory acclimatization, perceived exertion, oxygen uptake, and 20-km time were collected. No significant differences were observed in performance measures or perceived exertion between hypoxic trials. Plasma volume loss was significantly greater during 14H than 2H and CON. No differences in ventilatory acclimatization or sleep quality were observed between trials. Although some divergent 20-km performance responses were observed between 14H and 2H, they were not explained by the physiological measures completed. The data suggest that endurance athletes who are logistically restricted from arriving at altitude more than the evening before competition would not gain an advantage by delaying their arrival until a few hours before the competition, although unique individual responses may ultimately influence optimal arrival strategy.NEW & NOTEWORTHY For athletes who cannot arrive at altitude multiple days before an endurance competition to properly acclimatize, this study asked if shortening hypoxic exposure time to 2 h before a competition was more advantageous than arrival at altitude the evening before competition. Our data suggest that athletes who cannot arrive at altitude with adequate time for complete acclimatization can choose the short-term arrival strategy that best fits with the logistics of their travel. PMID- 28819000 TI - Hypoxia-induced myocardial regeneration. AB - The underlying cause of systolic heart failure is the inability of the adult mammalian heart to regenerate damaged myocardium. In contrast, some vertebrate species and immature mammals are capable of full cardiac regeneration following multiple types of injury through cardiomyocyte proliferation. Little is known about what distinguishes proliferative cardiomyocytes from terminally differentiated, nonproliferative cardiomyocytes. Recently, several reports have suggested that oxygen metabolism and oxidative stress play a pivotal role in regulating the proliferative capacity of mammalian cardiomyocytes. Moreover, reducing oxygen metabolism in the adult mammalian heart can induce cardiomyocyte cell cycle reentry through blunting oxidative damage, which is sufficient for functional improvement following myocardial infarction. Here we concisely summarize recent findings that highlight the role of oxygen metabolism and oxidative stress in cardiomyocyte cell cycle regulation, and discuss future therapeutic approaches targeting oxidative metabolism to induce cardiac regeneration. PMID- 28819002 TI - Feedback modulation of surrounding pressure determines the onset of negative effort dependence in a collapsible tube bench model of the pharyngeal airway. AB - Negative effort dependence (NED), decreased airflow despite increased driving pressure, has been proposed as a specific obstructive sleep apnea (OSA) phenotypic characteristic. We examined conditions under which NED occurs in a collapsible tube, pharyngeal airway bench model with the chamber enclosed, focusing on relationships with surrounding pressure levels and longitudinal strain. Using a vacuum source, graded airflows (V; 0-5 l/s) were generated through a thin-walled latex tube enclosed within a rigid, cylindrical chamber, sealed with initial chamber pressures (Pci) of 0-5 cmH2O (separate runs), or opened to the atmosphere. Upstream minus downstream pressure (Pu - Pd), maximum airflow (Vmax), and chamber pressure (Pc) were measured at 0-50% longitudinal strain. NED occurred across the range of Pci and strains studied but was most pronounced for the chamber open condition. With a sealed chamber, V increased and Pc decreased with increasing Pu - Pd until the onset of NED at Vmax and a Pc value that was designated as critical (Pcc). Pcc was lowest (-17 cmH20) and Vmax was highest (~5 l/s) with chamber sealed: Pci = 0 cmH2O and 12.5 to 25% strain. We conclude that for our collapsible tube model, the achievable Vmax before the onset of NED depends on both the initial conditions (Pci and strain) and the dynamics of feedback between driving pressure and chamber pressure (chamber sealed vs. open). NED-based phenotypic analyses for OSA may need to focus on potential feedback control mechanisms (eg lung volume change, muscle activity) that may link peripharyngeal tissue pressure levels to driving pressures for airflow.NEW & NOTEWORTHY A collapsible tube, pharyngeal airway bench model was used to study the role of surrounding pressure and longitudinal wall strain at the onset of negative effort dependence (NED). NED occurred to varying degrees across all conditions tested, but maximum airflow was achieved with 1) low initial surrounding pressure, 2) a feedback mechanism between surrounding pressure and driving pressure; and 3) a moderate amount of strain applied. Potential impacts on OSA phenotypic analyses are discussed. PMID- 28819003 TI - Skeletal muscle signaling, metabolism, and performance during sprint exercise in severe acute hypoxia after the ingestion of antioxidants. AB - The aim of this study was to determine if reactive oxygen species (ROS) could play a role in blunting Thr172-AMP-activated protein kinase (AMPK)-alpha phosphorylation in human skeletal muscle after sprint exercise in hypoxia and to elucidate the potential signaling mechanisms responsible for this response. Nine volunteers performed a single 30-s sprint (Wingate test) in two occasions while breathing hypoxic gas ([Formula: see text] = 75 mmHg): one after the ingestion of placebo and another following the intake of antioxidants (alpha-lipoic acid, vitamin C, and vitamin E), with a randomized double-blind design. Vastus lateralis muscle biopsies were obtained before, immediately after, and 30- and 120-min postsprint. Compared with the control condition, the ingestion of antioxidants resulted in lower plasma carbonylated proteins, attenuated elevation of the AMP-to-ATP molar ratio, and reduced glycolytic rate (P < 0.05) without significant effects on performance or Vo2 The ingestion of antioxidants did not alter the basal muscle signaling. Thr172-AMPKalpha and Thr184/187-transforming growth factor-beta-activated kinase 1 (TAK1) phosphorylation were not increased after the sprint regardless of the ingestion of antioxidants. Thr286-CaMKII phosphorylation was increased after the sprint, but this response was blunted by the antioxidants. Ser485-AMPKalpha1/Ser491-AMPKalpha2 phosphorylation increased immediately after the sprints coincident with increased Akt phosphorylation. In summary, antioxidants attenuate the glycolytic response to sprint exercise in severe acute hypoxia and modify the muscle signaling response to exercise. Ser485 AMPKalpha1/Ser491-AMPKalpha2 phosphorylation, a known mechanism of Thr172 AMPKalpha phosphorylation inhibition, is increased immediately after sprint exercise in hypoxia, probably by a mechanism independent of ROS.NEW & NOTEWORTHY The glycolytic rate is increased during sprint exercise in severe acute hypoxia. This study showed that the ingestion of antioxidants before sprint exercise in severe acute hypoxia reduced the glycolytic rate and attenuated the increases of the AMP-to-ATP and the reduction of the NAD+-to-NADH.H+ ratios. This resulted in a modified muscle signaling response with a blunted Thr286-CaMKII but similar AMP activated protein kinase phosphorylation responses in the sprints preceded by the ingestion of antioxidants. PMID- 28819001 TI - Epigenomics and human adaptation to high altitude. AB - Over the past decade, major technological and analytical advancements have propelled efforts toward identifying the molecular mechanisms that govern human adaptation to high altitude. Despite remarkable progress with respect to the identification of adaptive genomic signals that are strongly associated with the "hypoxia-tolerant" physiological characteristics of high-altitude populations, many questions regarding the fundamental biological processes underlying human adaptation remain unanswered. Vital to address these enduring questions will be determining the role of epigenetic processes, or non-sequence-based features of the genome, that are not only critical for the regulation of transcriptional responses to hypoxia but heritable across generations. This review proposes that epigenomic processes are involved in shaping patterns of adaptation to high altitude by influencing adaptive potential and phenotypic variability under conditions of limited oxygen supply. Improved understanding of the interaction between genetic, epigenetic, and environmental factors holds great promise to provide deeper insight into the mechanisms underlying human adaptive potential, and clarify its implications for biomedical research. PMID- 28819004 TI - Acute oxygen sensing by the carotid body: from mitochondria to plasma membrane. AB - Maintaining oxygen homeostasis is crucial to the survival of animals. Mammals respond acutely to changes in blood oxygen levels by modulating cardiopulmonary function. The major sensor of blood oxygen that regulates breathing is the carotid body (CB), a small chemosensory organ located at the carotid bifurcation. When arterial blood oxygen levels drop in hypoxia, neuroendocrine cells in the CB called glomus cells are activated to signal to afferent nerves that project to the brain stem. The mechanism by which hypoxia stimulates CB sensory activity has been the subject of many studies over the past 90 years. Two discrete models emerged that argue for the seat of oxygen sensing to lie either in the plasma membrane or mitochondria of CB cells. Recent studies are bridging the gap between these models by identifying hypoxic signals generated by changes in mitochondrial function in the CB that can be sensed by plasma membrane proteins on glomus cells. The CB is important for physiological adaptation to hypoxia, and its dysfunction contributes to sympathetic hyperactivity in common conditions such as sleep-disordered breathing, chronic heart failure, and insulin resistance. Understanding the basic mechanism of oxygen sensing in the CB could allow us to develop strategies to target this organ for therapy. In this short review, I will describe two historical models of CB oxygen sensing and new findings that are integrating these models. PMID- 28819005 TI - Blood pressure and leg deoxygenation are exaggerated during treadmill walking in patients with peripheral artery disease. AB - The purpose of this study was to investigate blood pressure (BP) and leg skeletal muscle oxygen saturation (Smo2) during treadmill walking in patients with peripheral artery disease (PAD) and healthy subjects. Eight PAD patients (66 +/- 8 yr, 1 woman) and eight healthy subjects (65 +/- 7 yr, 1 woman) walked on a treadmill at 2 mph (0.89 m/s). The incline increased by 2% every 2 min, from 0 to 15% or until maximal discomfort. BP was measured every 2 min with an auscultatory cuff. Heart rate (HR) was recorded continuously with an ECG. Smo2 in the gastrocnemius muscle was measured on each leg using near-infrared spectroscopy. The change in systolic BP from seated to peak walking time (PWT) was greater in PAD (healthy: 23 +/- 9 vs. PAD: 44 +/- 19 mmHg, P = 0.007). HR was greater in PAD patients compared with controls at PWT (P = 0.011). The reduction in Smo2 (PWT - seated) was greater in PAD (healthy: 15 +/- 12 vs. PAD: 49 +/- 5%, P < 0.001) in the most affected leg and in the least affected leg (healthy: 12 +/- 11 vs. PAD: 32 +/- 18%, P = 0.003). PAD patients have an exaggerated decline in leg Smo2 during walking compared with healthy subjects, which may elicit the exaggerated rise in BP and HR during walking in PAD.NEW & NOTEWORTHY This is the first study to simultaneously measure skeletal muscle oxygen saturation and blood pressure (BP) during treadmill exercise in patients with peripheral arterial disease. We found that BP and leg deoxygenation responses to slow-paced, graded treadmill walking are greater in patients with peripheral arterial disease compared with healthy subjects. These data may help explain the high cardiovascular risk in patients with peripheral arterial disease. PMID- 28819006 TI - Increased tissue oxygenation explains the attenuation of hyperemia upon repetitive pneumatic compression of the lower leg. AB - The rapid hyperemia evoked by muscle compression is short lived and was recently shown to undergo a rapid decrease even in spite of continuing mechanical stimulation. The present study aims at investigating the mechanisms underlying this attenuation, which include local metabolic mechanisms, desensitization of mechanosensitive pathways, and reduced efficacy of the muscle pump. In 10 healthy subjects, short sequences of mechanical compressions (n = 3-6; 150 mmHg) of the lower leg were delivered at different interstimulus intervals (ranging from 20 to 160 s) through a customized pneumatic device. Hemodynamic monitoring included near-infrared spectroscopy, detecting tissue oxygenation and blood volume in calf muscles, and simultaneous echo-Doppler measurement of arterial (superficial femoral artery) and venous (femoral vein) blood flow. The results indicate that 1) a long-lasting (>100 s) increase in local tissue oxygenation follows compression-induced hyperemia, 2) compression-induced hyperemia exhibits different patterns of attenuation depending on the interstimulus interval, 3) the amplitude of the hyperemia is not correlated with the amount of blood volume displaced by the compression, and 4) the extent of attenuation negatively correlates with tissue oxygenation (r = -0,78, P < 0.05). Increased tissue oxygenation appears to be the key factor for the attenuation of hyperemia upon repetitive compressive stimulation. Tissue oxygenation monitoring is suggested as a useful integration in medical treatments aimed at improving local circulation by repetitive tissue compression.NEW & NOTEWORTHY This study shows that 1) the hyperemia induced by muscle compression produces a long-lasting increase in tissue oxygenation, 2) the hyperemia produced by subsequent muscle compressions exhibits different patterns of attenuation at different interstimulus intervals, and 3) the extent of attenuation of the compression-induced hyperemia is proportional to the level of oxygenation achieved in the tissue. The results support the concept that tissue oxygenation is a key variable in blood flow regulation. PMID- 28819007 TI - Effects of antenatal melatonin therapy on lung structure in growth-restricted newborn lambs. AB - Oxidative stress arising from suboptimal placental function contributes to a multitude of pathologies in infants compromised by fetal growth restriction (FGR). FGR infants are at high risk for respiratory dysfunction after birth and poor long-term lung function. Our objective was to investigate the contribution of oxidative stress to adverse lung development and the effects of melatonin administration, a powerful antioxidant, on lung structure in FGR lambs. Placental insufficiency and FGR was surgically induced in 13 fetal sheep at ~105 days of gestation by ligation of a single umbilical artery. Maternal intravenous melatonin infusion was commenced in seven of the ewes 4 h after surgery and continued until birth. Lambs delivered normally at term and lungs were collected 24 h after birth for histological assessment of lung structure and injury and compared with appropriately grown control lambs (n = 8). FGR fetuses were hypoxic and had lower glucose during gestation compared with controls. Melatonin administration prevented chronic hypoxia. Within the lung, FGR caused reduced secondary septal crest density and altered elastin deposition compared with controls. Melatonin administration had no effect on the changes to lung structure induced by FGR. We conclude that chronic FGR disrupts septation of the developing alveoli, which is not altered by melatonin administration. These findings suggest that oxidative stress is not the mechanism driving altered lung structure in FGR neonates. Melatonin administration did not prevent disrupted airway development but also had no apparent adverse effects on fetal lung development.NEW & NOTEWORTHY Fetal growth restriction (FGR) results in poor respiratory outcomes, which may be caused by oxidation in utero. We investigated the contribution of oxidative stress to adverse lung development and the effects of melatonin administration, a powerful antioxidant, on lung structure in FGR lambs. FGR disrupted septation of the developing alveoli, which is not altered by melatonin administration. Oxidative stress may not be the mechanism driving altered lung structure in FGR neonates. PMID- 28819008 TI - Effect of a patent foramen ovale in humans on thermal responses to passive cooling and heating. AB - Humans with a patent foramen ovale (PFO) have a higher esophageal temperature (Tesoph) than humans without a PFO (PFO-). Thus the presence of a PFO might also be associated with differences in thermal responsiveness to passive cooling and heating such as shivering and hyperpnea, respectively. The purpose of this study was to determine whether thermal responses to passive cooling and heating are different between PFO- subjects and subjects with a PFO (PFO+). We hypothesized that compared with PFO- subjects PFO+ subjects would cool down more rapidly and heat up slower and that PFO+ subjects who experienced thermal hyperpnea would have a blunted increase in ventilation. Twenty-seven men (13 PFO+) completed two trials separated by >48 h: 1) 60 min of cold water immersion (19.5 +/- 0.9 degrees C) and 2) 30 min of hot water immersion (40.5 +/- 0.2 degrees C). PFO+ subjects had a higher Tesoph before and during cold water and hot water immersion (P < 0.05). However, the rate of temperature change was similar between groups for each condition. Within a subset of 18 subjects (8 PFO+) who experienced thermal hyperpnea, PFO+ subjects experienced thermal hyperpnea at a higher absolute Tesoph but with a blunted magnitude compared with PFO- subjects. These data suggest that PFO+ subjects have a higher Tesoph at rest and have blunted thermal hyperpnea during passive heating.NEW & NOTEWORTHY Patent foramen ovale (PFO) is found in ~25-40% of the population. The presence of a PFO appears to be associated with a greater core body temperature and blunted ventilatory responses during passive heating. The reason for this blunted ventilatory response to passive heating is unknown but may suggest differences in thermal sensitivity in PFO+ subjects compared with PFO- subjects. PMID- 28819010 TI - New insight on the S100A1-STIP1 complex highlights the important relationship between allostery and entropy in protein function. AB - Calcium signaling serves as a nexus of many vital cellular processes. Of particular importance is the role the calcium signaling plays in the prevention of protein misfolding, and the S100 family of calcium-binding proteins is a key player in this pathway. While the S100 proteins carry out a range of roles, the interaction of S100A1 and the stress-inducible phosphoprotein 1 (STIP1) has been shown to be particularly important. A recent study by Maciejewski et al. in Biochemical Journal (Biochemical Journal (2017) 474, 1853-1866) revealed new insights into the nature of the S100A1-STIP1 interaction. Not only did the present paper indicate the stoichiometry of binding for this interaction (three S100A1 dimers : one STIP1), it also demonstrated that the binding interaction is highly co-operative and that each S100A1-STIP1-binding interaction is entropically driven. The findings presented raise important new questions regarding the relationship between entropy and allostery in protein function. Recently, the dynamical underpinnings of allostery in protein function have become a topic of increased interest. A broad range of investigations have demonstrated that allostery can be mediated by entropic processes such as changes in the flexibility of the protein backbone and in the range of motions explored by side chains. The S100A1-STIP1 complex as described by Maciejewski et al. suggests a new system in which an allosteric-binding interaction driven by entropic processes may be systematically dissected in the future. PMID- 28819011 TI - TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. AB - Despite recent advances in lymphoma treatment, mantle cell lymphoma (MCL) remains incurable, and we are still unable to identify patients who will not benefit from the current standard of care. Here, we explore the prognostic value of recurrent genetic aberrations in diagnostic bone marrow (BM) specimens from 183 younger patients with MCL from the Nordic MCL2 and MCL3 trials, which represent current standard-of-care regimens. In the univariate model, mutations of TP53 (11%) and NOTCH1 (4%), and deletions of TP53 (16%) and CDKN2A (20%), were significantly associated with inferior outcomes (together with MIPI, MIPI-c, blastoid morphology, and Ki67 > 30%); however, in multivariate analyses, only TP53 mutations (HR, 6.2; P < .0001) retained prognostic impact for overall survival (OS), whereas TP53 mutations (HR, 6.9; P < .0001) and MIPI-c high-risk (HR, 2.6; P = .003) had independent prognostic impact on time to relapse. TP53-mutated cases had a dismal outcome, with a median OS of 1.8 years, and 50% relapsed at 1.0 years, compared to a median OS of 12.7 years for TP53-unmutated cases (P < .0001). TP53 mutations were significantly associated with Ki67 > 30%, blastoid morphology, MIPI high-risk, and inferior responses to both induction- and high dose chemotherapy. In conclusion, we show that TP53 mutations identify a phenotypically distinct and highly aggressive form of MCL with poor or no response to regimens including cytarabine, rituximab, and autologous stem-cell transplant (ASCT). We suggest patients with MCL should be stratified according to TP53 status, and that patients with TP53 mutations should be considered for experimental frontline trials exploring novel agents. PMID- 28819012 TI - How herpesviruses pass on their genomes. AB - Herpesvirus genomes exist and replicate as episomes inside the host cell nucleus during latent infection. Chiu et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201702013) find that unlike Epstein-Barr virus, which partitions viral genomes faithfully during cell division, Kaposi's Sarcoma associated herpesvirus clusters viral genomes into loci that are distributed unequally to daughter cells. PMID- 28819009 TI - The AAA+ ATPase p97, a cellular multitool. AB - The AAA+ (ATPases associated with diverse cellular activities) ATPase p97 is essential to a wide range of cellular functions, including endoplasmic reticulum associated degradation, membrane fusion, NF-kappaB (nuclear factor kappa-light chain-enhancer of activated B cells) activation and chromatin-associated processes, which are regulated by ubiquitination. p97 acts downstream from ubiquitin signaling events and utilizes the energy from ATP hydrolysis to extract its substrate proteins from cellular structures or multiprotein complexes. A multitude of p97 cofactors have evolved which are essential to p97 function. Ubiquitin-interacting domains and p97-binding domains combine to form bi functional cofactors, whose complexes with p97 enable the enzyme to interact with a wide range of ubiquitinated substrates. A set of mutations in p97 have been shown to cause the multisystem proteinopathy inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia. In addition, p97 inhibition has been identified as a promising approach to provoke proteotoxic stress in tumors. In this review, we will describe the cellular processes governed by p97, how the cofactors interact with both p97 and its ubiquitinated substrates, p97 enzymology and the current status in developing p97 inhibitors for cancer therapy. PMID- 28819013 TI - Yaron Fuchs: Exploring the mysterious mixture of life and death. AB - Fuchs studies how cell death controls stem cell-driven processes. PMID- 28819015 TI - Adrenal Cushing's syndrome during pregnancy. AB - Cushing syndrome (CS) during pregnancy is a rare condition with only a few cases reported in the literature. Misdiagnosis of CS is common because of overlapping features like fatigue, weight gain, striae and emotional changes that can occur during normal pregnancy. Changes in maternal hormones and their binding proteins complicate assessment of glucocorticoid hormone levels during gestation. CS during pregnancy is most frequently due to an adrenal adenoma and to a lesser degree to adrenocorticotropic hormone (ACTH) hypersecretion by a pituitary adenoma. Furthermore, aberrant expression of luteinizing hormone (LH) receptors in the adrenal cortex has been suggested to be involved in the pathogenesis of adrenal CS during pregnancy. We report three pregnant women with ACTH-independent Cushing's syndrome and an adrenal tumor. After uncomplicated delivery, patient 1 underwent in vivo testing for aberrant hormone receptor expression by the adenoma. Cortisol responses were found after administration of luteinizing hormone-releasing hormone (LHRH), human chorionic gonadotropin (hCG), glucagon, vasopressin and a standard mixed meal. All patients were treated with laparoscopic adrenalectomy. Adrenal tumor tissue of two patients showed positive immunohistochemical staining of LH receptors. Considering the cortisol responses to LHRH and hCG, and the development of CS during pregnancy in these patients, it is likely that ACTH-independent hypercortisolism was induced by the pregnancy associated rise in hCG levels that activated aberrantly expressed LH receptors in the adrenal adenoma. Remarkably, adrenal adenomas may simultaneously express multiple aberrant receptors and individual ligands may play a role in the regulation of cortisol production in CS during pregnancy. PMID- 28819016 TI - A syndromic extreme insulin resistance caused by biallelic POC1A mutations in exon 10. AB - POC1A encodes a protein with a role in centriole assembly and stability, and in ciliogenesis. Biallelic loss-of-function mutations affecting POC1A cause SOFT syndrome, an ultra-rare condition characterized by short stature, onychodysplasia, facial dysmorphism and hypotrichosis. Using exome sequencing, we identified a homozygous frameshift mutation (c.1047_1048dupC; p.G337Rfs*25) in a patient presenting with short stature, facial hirsutism, alopecia, dyslipidemia and extreme insulin resistance. The truncating variant affected exon 10, which is retained in only two of the three POC1A-mature RNAs, due to alternative processing of the transcript. Clinical discrepancies with SOFT syndrome support the hypothesis that POC1A mutations affecting exon 10 are associated with a distinct condition, corroborating a previous hypothesis based on a similar case. Furthermore, this report provides an additional example of a genetic condition presenting with clinical heterogeneity due to alternative transcript processing. In conclusion, POC1A mutations in exon 10 should be taken into account in patients with extreme insulin resistance and short stature. PMID- 28819014 TI - Cyclin A2 modulates kinetochore-microtubule attachment in meiosis II. AB - Cyclin A2 is a crucial mitotic Cdk regulatory partner that coordinates entry into mitosis and is then destroyed in prometaphase within minutes of nuclear envelope breakdown. The role of cyclin A2 in female meiosis and its dynamics during the transition from meiosis I (MI) to meiosis II (MII) remain unclear. We found that cyclin A2 decreases in prometaphase I but recovers after the first meiotic division and persists, uniquely for metaphase, in MII-arrested oocytes. Conditional deletion of cyclin A2 from mouse oocytes has no discernible effect on MI but leads to disrupted MII spindles and increased merotelic attachments. On stimulation of exit from MII, there is a dramatic increase in lagging chromosomes and an inhibition of cytokinesis. These defects are associated with an increase in microtubule stability in MII spindles, suggesting that cyclin A2 mediates the fidelity of MII by maintaining microtubule dynamics during the rapid formation of the MII spindle. PMID- 28819017 TI - Adrenocortical carcinoma and succinate dehydrogenase gene mutations: an observational case series. AB - OBJECTIVE: Germline loss-of-function mutations in succinate dehydrogenase (SDHx) genes results in rare tumor syndromes that include pheochromocytoma, paraganglioma, and others. Here we report a case series of patients with adrenocortical carcinoma (ACC) that harbor SDHx mutations. PATIENTS AND RESULTS: We report four unrelated patients with ACC and SDHx mutations. All cases presented with Cushing syndrome and large adrenal masses that were confirmed to be ACC on pathology. All four ACC specimens were found to have truncating mutations in either SDHC or SDHA, while cases 1, 2 and 3 also had the mutations confirmed in the germline: Case 1: SDHC c.397C > T, pR133X; Case 2: SDHC c.43C > T, p.R15X; Case 3: SDHA c.91C > T, p.R31X; Case 4: SDHA c.1258C > T, p.Q420X. Notably, Case 1 had a father and daughter who both harbored the same SDHC germline mutation, and the father had a paraganglioma and renal cell carcinoma. A combination of next generation sequencing, and/or immunohistochemistry, and/or mass spectroscopy was used to determine whether there was loss of heterozygosity and/or loss of SDH protein expression or function within the ACC. Potential evidence of loss of heterozygosity was observed only in Case 2. CONCLUSIONS: We observed truncating mutations in SDHA or SDHC in the ACC and/or germline of four unrelated patients. Given how statistically improbable the concurrence of ACC and pathogenic germline SDHx mutations is expected to be, these observations raise the question whether ACC may be a rare manifestation of SDHx mutation syndromes. Further studies are needed to investigate the possible role of SDH deficiency in ACC pathogenesis. PMID- 28819018 TI - Adjuvant treatment of anogenital warts with systemic interferon: a systematic review and meta-analysis. AB - BACKGROUND: Interferons are natural messenger proteins that are used to treat various disease entities. Due to their immunomodulating, antiviral and antiproliferative effects, the systemic administration of interferons after ablative treatment for anogenital warts (AGWs) has been advocated to increase clearance and decrease recurrence rates. However, studies investigating the efficacy of adjuvant systemic interferon have yielded inconsistent results. The objective of this systematic review and meta-analysis was to comprehensively assess and evaluate the available evidence from randomised controlled trials. METHODS: A literature search was conducted in Cochrane Central Register of Controlled Trials, Embase and MEDLINE. Available data were classified according to the interferon type and dosage. Pooled effect estimates were calculated for predefined outcomes. The Cochrane Collaboration's risk of bias tool was used to assess the included trials and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to evaluate our confidence in the effect estimates. RESULTS: Twelve trials were identified that met the inclusion criteria and assessed immunocompetent patients with external AGW. Compared with placebo, adjuvant alpha-, beta- and gamma-interferon were generally not significantly superior in terms of complete clearance over the short, intermediate or long term, nor with regard to intermediate- or long-term recurrence. However, the low-dose subgroup of adjuvant alpha-interferon was significantly superior compared with placebo regarding intermediate-term complete clearance and recurrence. Further data were available for the comparison of different dosages of alpha- and beta-interferon and for comparisons of the three interferon types. No significant differences were seen in these comparisons regarding efficacy. Data on quality of life were not available. CONCLUSIONS: The GRADE quality of the evidence ranged from 'very low' to 'high'. The significantly higher efficacy of low-dose alpha-interferon compared with placebo was based on a single trial, and our confidence in the effect estimates rated as 'low'. Overall, we found no reliable evidence favouring the systemic use of interferon after ablative treatment of AGW. PMID- 28819019 TI - Retrospectively assessed physical work environment during working life and risk of sickness absence and labour market exit among older workers. AB - OBJECTIVE: To determine the prospective association between retrospectively assessed physical work environment during working life and prospectively assessed sickness absence and labour market exit among older workers. METHODS: Using Cox regression analyses we estimated the 4-year to 6-year prospective risk of register-based long-term sickness absence (LTSA), disability pension, early retirement and unemployment from exposure to different physical work environmental factors during working life among 5076 older workers (age 49-63 at baseline) from the Copenhagen Aging and Midlife Biobank cohort. RESULTS: Very hard physical work throughout working life was a risk factor for LTSA (HR 1.66,95% CI 1.32 to 2.07), disability pension (HR 2.21,95% CI 1.04 to 4.72) and early retirement (HR 1.57,95% CI 1.13 to 2.17). Both short-term (<10 years) and long-term (>=20 years) exposures to lifting or carrying of heavy burdens predicted the risk of LTSA (HRs 1.49-1.56) and disability pension (HRs 2.26 3.29). In contrast, exposure to dust was associated with LTSA and disability pension only following 20 or more exposure years. CONCLUSIONS: Retrospectively assessed hard physical work during working life and exposure to several factors in the physical work environment, especially heavy lifting, were important for labour market exit and sickness absence. This study underscores the importance of reducing physical work exposures throughout the working life course for preventing sickness absence and premature exit from the labour market. PMID- 28819020 TI - Inquiry is ordered into child deaths at Indian hospital. PMID- 28819021 TI - Phenotypic Heterogeneity of Circulating Tumor Cells Informs Clinical Decisions between AR Signaling Inhibitors and Taxanes in Metastatic Prostate Cancer. AB - The heterogeneity of an individual patient's tumor has been linked to treatment resistance, but quantitative biomarkers to rapidly and reproducibly evaluate heterogeneity in a clinical setting are currently lacking. Using established tools available in a College of American Pathologists-accredited and Clinical Laboratory Improvement Amendments-certified clinical laboratory, we quantified digital pathology features on 9,225 individual circulating tumor cells (CTC) from 179 unique metastatic castration-resistant prostate cancer (mCRPC) patients to define phenotypically distinct cell types. Heterogeneity was quantified on the basis of the diversity of cell types in individual patient samples using the Shannon index and associated with overall survival (OS) in the 145 specimens collected prior to initiation of the second or later lines of therapy. Low CTC phenotypic heterogeneity was associated with better OS in patients treated with androgen receptor signaling inhibitors (ARSI), whereas high heterogeneity was associated with better OS in patients treated with taxane chemotherapy. Overall, the results show that quantifying CTC phenotypic heterogeneity can help inform the choice between ARSI and taxanes in mCRPC patients. Cancer Res; 77(20); 5687 98. (c)2017 AACR. PMID- 28819022 TI - beta-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8+ T Cells and Undermines Checkpoint Inhibitor Therapy. AB - The immune context of tumors has significant prognostic value and is predictive of responsiveness to several forms of therapy, including immunotherapy. We report here that CD8+ T-cell frequency and functional orientation within the tumor microenvironment is regulated by beta2-adrenergic receptor (beta-AR) signaling in host immune cells. We used three strategies-physiologic (manipulation of ambient thermal environment), pharmacologic (beta-blockers), and genetic (beta2-AR knockout mice) to reduce adrenergic stress signaling in two widely studied preclinical mouse tumor models. Reducing beta-AR signaling facilitated conversion of tumors to an immunologically active tumor microenvironment with increased intratumoral frequency of CD8+ T cells with an effector phenotype and decreased expression of programmed death receptor-1 (PD-1), in addition to an elevated effector CD8+ T-cell to CD4+ regulatory T-cell ratio (IFNgamma+CD8+:Treg). Moreover, this conversion significantly increased the efficacy of anti-PD-1 checkpoint blockade. These data highlight the potential of adrenergic stress and norepinephrine-driven beta-AR signaling to regulate the immune status of the tumor microenvironment and support the strategic use of clinically available beta blockers in patients to improve responses to immunotherapy. Cancer Res; 77(20); 5639-51. (c)2017 AACR. PMID- 28819023 TI - Therapeutic Effects of XPO1 Inhibition in Thymic Epithelial Tumors. AB - Exportin 1 (XPO1) mediates nuclear export of many cellular factors known to play critical roles in malignant processes, and selinexor (KPT-330) is the first XPO1 selective inhibitor of nuclear export compound in advanced clinical development phase for cancer treatment. We demonstrated here that inhibition of XPO1 drives nuclear accumulation of important cargo tumor suppressor proteins, including transcription factor FOXO3a and p53 in thymic epithelial tumor (TET) cells, and induces p53-dependent and -independent antitumor activity in vitro Selinexor suppressed the growth of TET xenograft tumors in athymic nude mice via inhibition of cell proliferation and induction of apoptosis. Loss of p53 activity or amplification of XPO1 may contribute to resistance to XPO1 inhibitor in TET. Using mass spectrometry-based proteomics analysis, we identified a number of proteins whose abundances in the nucleus and cytoplasm shifted significantly following selinexor treatment in the TET cells. Furthermore, we found that XPO1 was highly expressed in aggressive histotypes and advanced stages of human TET, and high XPO1 expression was associated with poorer patient survival. These results underscore an important role of XPO1 in the pathogenesis of TET and support clinical development of the XPO1 inhibitor for the treatment of patients with this type of tumors. Cancer Res; 77(20); 5614-27. (c)2017 AACR. PMID- 28819024 TI - Trastuzumab Increases HER2 Uptake and Cross-Presentation by Dendritic Cells. AB - Early-phase clinical trials evaluating CD8+ T cell-eliciting, HER2-derived peptide vaccines administered to HER2+ breast cancer patients in the adjuvant setting suggest synergy between the vaccines and trastuzumab, the mAb targeting the HER2 protein. Among 60 patients enrolled in clinical trials evaluating the E75 + GM-CSF and GP2 + GM-CSF vaccines, there have been no recurrences in patients vaccinated after receiving trastuzumab as part of standard therapy in the per treatment analyses conducted after a median follow-up of greater than 34 months. Here, we describe a mechanism by which this synergy may occur. Flow cytometry showed that trastuzumab facilitated uptake of HER2 by dendritic cells (DC), which was mediated by the Fc receptor and was specific to trastuzumab. In vitro, increased HER2 uptake by DC increased cross-presentation of E75, the immunodominant epitope derived from the HER2 protein, an observation confirmed in two in vivo mouse models. This increased E75 cross-presentation, mediated by trastuzumab treatment, enabled more efficient expansion of E75-specific cytotoxic T cells (E75-CTL). These results demonstrate a mechanism by which trastuzumab links innate and adaptive immunity by facilitating activation of antigen-specific T cells. On the basis of these data, we conclude that HER2-positive breast cancer patients that have been treated with trastuzumab may experience a more robust antitumor immune response by restimulation of T cells with the E75 peptide vaccine, thereby accounting for the improved disease-free survival observed with combination therapy. Cancer Res; 77(19); 5374-83. (c)2017 AACR. PMID- 28819026 TI - Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration Resistant Prostate Cancer. AB - Resistance invariably develops to antiandrogen therapies used to treat newly diagnosed prostate cancers, but effective treatments for castration-resistant disease remain elusive. Here, we report that the transcriptional coactivator CBP/p300 is required to maintain the growth of castration-resistant prostate cancer. To exploit this vulnerability, we developed a novel small-molecule inhibitor of the CBP/p300 bromodomain that blocks prostate cancer growth in vitro and in vivo Molecular dissection of the consequences of drug treatment revealed a critical role for CBP/p300 in histone acetylation required for the transcriptional activity of the androgen receptor and its target gene expression. Our findings offer a preclinical proof of concept for small-molecule therapies to target the CBP/p300 bromodomain as a strategy to treat castration-resistant prostate cancer. Cancer Res; 77(20); 5564-75. (c)2017 AACR. PMID- 28819025 TI - MRE11 Promotes Tumorigenesis by Facilitating Resistance to Oncogene-Induced Replication Stress. AB - Hypomorphic mutations in the genes encoding the MRE11/RAD50/NBS1 (MRN) DNA repair complex lead to cancer-prone syndromes. MRN binds DNA double-strand breaks, where it functions in repair and triggers cell-cycle checkpoints via activation of the ataxia-telangiectasia mutated kinase. To gain understanding of MRN in cancer, we engineered mice with B lymphocytes lacking MRN, or harboring MRN in which MRE11 lacks nuclease activities. Both forms of MRN deficiency led to hallmarks of cancer, including oncogenic translocations involving c-Myc and the immunoglobulin locus. These preneoplastic B lymphocytes did not progress to detectable B lineage lymphoma, even in the absence of p53. Moreover, Mre11 deficiencies prevented tumorigenesis in a mouse model strongly predisposed to spontaneous B-cell lymphomas. Our findings indicate that MRN cannot be considered a standard tumor suppressor and instead imply that nuclease activities of MRE11 are required for oncogenesis. Inhibition of MRE11 nuclease activity increased DNA damage and selectively induced apoptosis in cells overexpressing oncogenes, suggesting MRE11 serves an important role in countering oncogene-induced replication stress. Thus, MRE11 may offer a target for cancer therapeutic development. More broadly, our work supports the idea that subtle enhancements of endogenous genome instability can exceed the tolerance of cancer cells and be exploited for therapeutic ends. Cancer Res; 77(19); 5327-38. (c)2017 AACR. PMID- 28819027 TI - Combination Therapy with Bispecific Antibodies and PD-1 Blockade Enhances the Antitumor Potency of T Cells. AB - The DOCK-AND-LOCK (DNL) method is a platform technology that combines recombinant engineering and site-specific conjugation to create multispecific, multivalent antibodies of defined composition with retained bioactivity. We have applied DNL to generate a novel class of trivalent bispecific antibodies (bsAb), each comprising an anti-CD3 scFv covalently conjugated to a stabilized dimer of different antitumor Fabs. Here, we report the further characterization of two such constructs, (E1)-3s and (14)-3s, which activate T cells and target Trop-2- and CEACAM5-expressing cancer cells, respectively. (E1)-3s and (14)-3s, in the presence of human T cells, killed target cells grown as monolayers at subnanomolar concentrations, with a similar potency observed for drug-resistant cells. Antitumor efficacy was demonstrated for (E1)-3s coadministered with human peripheral blood mononuclear cells (PBMC) in NOD/SCID mice harboring xenografts of MDA-MB-231, a triple-negative breast cancer line constitutively expressing Trop-2 and PD-L1. Growth inhibition was observed following treatment with (E1)-3s or (14)-3s combined with human PBMC in 3D spheroids generated from target cell lines to mimic the in vivo behavior and microenvironment of these tumors. Moreover, addition of an antagonistic anti-PD-1 antibody increased cell death in 3D spheroids and extended survival of MDA-MB-231-bearing mice. These preclinical results emphasize the potential of combining T-cell-redirecting bsAbs with antagonists or agonists that mitigate T-cell inhibition within the tumor microenvironment to improve immunotherapy of solid cancers in patients. They also support the use of 3D spheroids as a predictive alternative to in vivo models for evaluating T-cell functions. Cancer Res; 77(19); 5384-94. (c)2017 AACR. PMID- 28819028 TI - PADI2-Mediated Citrullination Promotes Prostate Cancer Progression. AB - Onset of castration-resistance prostate cancer (CRPC) after long-term androgen deprivation therapy remains a major obstacle in the treatment of prostate cancer. The peptidylarginine deiminase PADI2 has been implicated in chronic inflammatory diseases and cancer. Here we show that PADI2 is an androgen-repressed gene and is upregulated in CRPC. PADI2 expression was required for survival and cell-cycle progression of prostate cancer cells, and PADI2 promoted proliferation of prostate cancer cells under androgen-deprived or castration conditions in vitro and in vivo Cytoplasmic PADI2 protected the androgen receptor (AR) against proteasome-mediated degradation and facilitated AR binding to its target genes after nuclear translocation and citrullination of histone H3 amino acid residue R26. In contrast, mutant PADI2 D180A failed to affect AR stability, nuclear translocation, or transcriptional activity. PADI2 mediated AR control in a manner dependent on its enzymatic activity and nuclear localization, as correlated with increased histone H3 citrullination. Notably, coadministration of the PADI inhibitor Cl-Amidine and the AR signaling inhibitor enzalutamide synergized in inhibiting CRPC cell proliferation in vitro and tumor growth in vivo Overall, our results establish PADI2 as a key mediator for AR in prostate cancer progression, especially CRPC, and they suggest PADI as novel therapeutic targets in this disease setting. Cancer Res; 77(21); 5755-68. (c)2017 AACR. PMID- 28819029 TI - Loss of Tumor Suppressor STAG2 Promotes Telomere Recombination and Extends the Replicative Lifespan of Normal Human Cells. AB - Sister chromatids are held together by cohesin, a tripartite ring with a peripheral SA1/2 subunit, where SA1 is required for telomere cohesion and SA2 for centromere cohesion. The STAG2 gene encoding SA2 is often inactivated in human cancer, but not in in a manner associated with aneuploidy. Thus, how these tumors maintain chromosomal cohesion and how STAG2 loss contributes to tumorigenesis remain open questions. Here we show that, despite a loss in centromere cohesion, sister chromatids in STAG2 mutant tumor cells maintain cohesion in mitosis at chromosome arms and telomeres. Telomere maintenance in STAG2 mutant tumor cells occurred by either telomere recombination or telomerase activation mechanisms. Notably, these cells were refractory to telomerase inhibitors, indicating recombination can provide an alternative means of telomere maintenance. STAG2 silencing in normal human cells that lack telomerase led to increased recombination at telomeres, delayed telomere shortening, and postponed senescence onset. Insofar as telomere shortening and replicative senescence prevent genomic instability and cancer by limiting the number of cell divisions, our findings suggest that extending the lifespan of normal human cells due to inactivation of STAG2 could promote tumorigenesis by extending the period during which tumor driving mutations occur. Cancer Res; 77(20); 5530-42. (c)2017 AACR. PMID- 28819031 TI - Meet the First Authors. PMID- 28819032 TI - New Initiatives to Improve the Rigor and Reproducibility of Articles Published in Circulation Research. PMID- 28819033 TI - Allele-Specific Gene Silencing: Another Step in the Inexorable Advance of Gene Therapy for Cardiac Arrhythmia Management. PMID- 28819034 TI - When High Throughput Meets Mechanistic Studies: A State-of-the-Art Approach in Brugada Syndrome. PMID- 28819035 TI - Besides Imprinting: Meg3 Regulates Cardiac Remodeling in Cardiac Hypertrophy. PMID- 28819030 TI - Estimates of burden and consequences of infants born small for gestational age in low and middle income countries with INTERGROWTH-21st standard: analysis of CHERG datasets. AB - Objectives To estimate small for gestational age birth prevalence and attributable neonatal mortality in low and middle income countries with the INTERGROWTH-21st birth weight standard.Design Secondary analysis of data from the Child Health Epidemiology Reference Group (CHERG), including 14 birth cohorts with gestational age, birth weight, and neonatal follow-up. Small for gestational age was defined as infants weighing less than the 10th centile birth weight for gestational age and sex with the multiethnic, INTERGROWTH-21st birth weight standard. Prevalence of small for gestational age and neonatal mortality risk ratios were calculated and pooled among these datasets at the regional level. With available national level data, prevalence of small for gestational age and population attributable fractions of neonatal mortality attributable to small for gestational age were estimated.Setting CHERG birth cohorts from 14 population based sites in low and middle income countries.Main outcome measures In low and middle income countries in the year 2012, the number and proportion of infants born small for gestational age; number and proportion of neonatal deaths attributable to small for gestational age; the number and proportion of neonatal deaths that could be prevented by reducing the prevalence of small for gestational age to 10%.Results In 2012, an estimated 23.3 million infants (uncertainty range 17.6 to 31.9; 19.3% of live births) were born small for gestational age in low and middle income countries. Among these, 11.2 million (0.8 to 15.8) were term and not low birth weight (>=2500 g), 10.7 million (7.6 to 15.0) were term and low birth weight (<2500 g) and 1.5 million (0.9 to 2.6) were preterm. In low and middle income countries, an estimated 606 500 (495 000 to 773 000) neonatal deaths were attributable to infants born small for gestational age, 21.9% of all neonatal deaths. The largest burden was in South Asia, where the prevalence was the highest (34%); about 26% of neonatal deaths were attributable to infants born small for gestational age. Reduction of the prevalence of small for gestational age from 19.3% to 10.0% in these countries could reduce neonatal deaths by 9.2% (254 600 neonatal deaths; 164 800 to 449 700).Conclusions In low and middle income countries, about one in five infants are born small for gestational age, and one in four neonatal deaths are among such infants. Increased efforts are required to improve the quality of care for and survival of these high risk infants in low and middle income countries. PMID- 28819036 TI - Training for Success. PMID- 28819037 TI - Michael Potente: No Time to Waste. PMID- 28819038 TI - Cardiovascular Research in Germany. PMID- 28819039 TI - Large Animal Model Efficacy Testing Is Needed Prior to Launch of a Stem Cell Clinical Trial: An Evidence-Lacking Conclusion Based on Conjecture. PMID- 28819040 TI - Application of PCSK9 Inhibitors in Practice: Challenges and Opportunities. PMID- 28819041 TI - Letter by El-Battrawy et al Regarding Article, "The Brugada Syndrome Susceptibility Gene HEY2 Modulates Cardiac Transmural Ion Channel Patterning and Electrical Heterogeneity". PMID- 28819042 TI - Response by Veerman et al to Letter Regarding Article, "The Brugada Syndrome Susceptibility Gene HEY2 Modulates Cardiac Transmural Ion Channel Patterning and Electrical Heterogeneity". PMID- 28819045 TI - Fundus fluorescein angiography in Susac's syndrome. PMID- 28819043 TI - Increased acetylation of microtubules rescues human tau-induced microtubule defects and neuromuscular junction abnormalities in Drosophila. AB - Tau normally associates with and stabilizes microtubules (MTs), but is hyperphosphorylated and aggregated into neurofibrillary tangles in Alzheimer's disease and related neurodegenerative diseases, which are collectively known as tauopathies. MTs are regulated by different forms of post-translational modification, including acetylation; acetylated MTs represent a more stable microtubule population. In our previous study, we showed that inhibition of histone deacetylase 6 (HDAC6), which deacetylates tubulin at lysine 40, rescues defects in MTs and in neuromuscular junction growth caused by tau overexpression. However, HDAC6 also acts on other proteins that are involved in distinct biological processes unrelated to tubulins. In order to examine directly the role of increased tubulin acetylation against tau toxicity, we generated a site directed alpha-tubulinK40Q mutation by CRISPR/Cas9 technology to mimic the acetylated MTs and found that acetylation-mimicking alpha-tubulin rescued tau induced MT defects and neuromuscular junction developmental abnormalities. We also showed that late administration of ACY-1215 and tubastatin A, two potent and selective inhibitors of HDAC6, rescued the tau-induced MT defects after the abnormalities had already become apparent. Overall, our results indicate that increasing MT acetylation by either genetic manipulations or drugs might be used as potential strategies for intervention in tauopathies. PMID- 28819044 TI - The Parkinson's disease-associated protein DJ-1 plays a positive nonmitochondrial role in endocytosis in Dictyostelium cells. AB - The loss of function of DJ-1 caused by mutations in DJ1 causes a form of familial Parkinson's disease (PD). However, the role of DJ-1 in healthy and in PD cells is poorly understood. Even its subcellular localization in mammalian cells is uncertain, with both cytosolic and mitochondrial locations having been reported. We show here that DJ-1 is normally located in the cytoplasm in healthy Dictyostelium discoideum cells. With its unique life cycle, straightforward genotype-phenotype relationships, experimental accessibility and genetic tractability, D.discoideum offers an attractive model to investigate the roles of PD-associated genes. Furthermore, the study of mitochondrial biology, mitochondrial genome transcription and AMP-activated protein kinase-mediated cytopathologies in mitochondrial dysfunction have been well developed in this organism. Unlike mammalian systems, Dictyostelium mitochondrial dysfunction causes a reproducible and readily assayed array of aberrant phenotypes: defective phototaxis, impaired growth, normal rates of endocytosis and characteristic defects in multicellular morphogenesis. This makes it possible to study whether the underlying cytopathological mechanisms of familial PD involve mitochondrial dysfunction. DJ-1 has a single homologue in the Dictyostelium genome. By regulating the expression level of DJ-1 in D. discoideum, we show here that in unstressed cells, DJ-1 is required for normal rates of endocytic nutrient uptake (phagocytosis and, to a lesser extent, pinocytosis) and thus growth. Reduced expression of DJ-1 had no effect on phototaxis in the multicellular migratory 'slug' stage of the life cycle, but resulted in thickened stalks in the final fruiting bodies. This pattern of phenotypes is distinct from that observed in Dictyostelium to result from mitochondrial dyfunction. Direct measurement of mitochondrial respiratory function in intact cells revealed that DJ-1 knockdown stimulates whereas DJ-1 overexpression inhibits mitochondrial activity. Together, our results suggest positive roles for DJ-1 in endocytic pathways and loss-of function cytopathologies that are not associated with impaired mitochondrial function. PMID- 28819046 TI - Tuberculous tales: an East London experience. AB - Tuberculous meningitis presents a diagnostic and therapeutic challenge, and considering its long history and increasing global incidence, the evidence base for its treatment is relatively scanty. Many UK neurologists will have little first-hand experience of this deadly condition, and if faced with a patient with possible tuberculous meningitis will find decision making less than straightforward. In parts of East London (UK) the rates of tuberculosis and tuberculous meningitis are among the highest in Western Europe, and so the neurologists and respiratory physicians at the Royal London Hospital have encountered many such patients over the years. We have found experience to be a valuable teacher and so would like to share five cases that illustrate the complexities of diagnosis and management of the disease, and complications of its treatment. PMID- 28819047 TI - Unusual case of bilateral hand weakness. AB - A 35-year-old man presented with myalgia and bilateral hand weakness, 3 days after the onset of lethargy, fevers and rigours. The hand weakness caused functional impairment including difficulty pressing keys on his mobile phone. On examination, there was mild bilateral hand weakness with normal reflexes. His serum creatine kinase was mildly raised at 503 U/L (24-195), viral PCR throat swab was negative and electromyogram showed subtle myopathic changes in the distal forearm muscles. Nerve conduction studies found no evidence of neuropathy. Forced vital capacity was reduced on admission (1.5 L) but improved within 24 hours (2.3 L). We gave supportive intravenous fluids and his weakness improved within 48 hours. He was discharged and reported that the weakness had fully resolved within weeks. The diagnosis was viral myositis. Distal forearm myositis rarely follows H1N1 influenza in adults but is an important differential for postinfective neurological symptoms. PMID- 28819048 TI - Development of Methods for Recovering Endotoxins from Surfaces and from Air in Production Environment of Injectable Drugs. AB - The aim of this work is to develop and validate methods for quantifying endotoxins on surfaces and in the air of the manufacturing environment of injectable drugs, in order to use them to evaluate the quality of the process and the risk for the products processed therein. The method for recovering endotoxins from surfaces is a direct method that provides sampling surfaces by swabbing and extraction of endotoxins from the swabs with an appropriate diluent, while the method for airborne endotoxins provides an air-active sampling on a glass fiber filter and endotoxins extraction with an appropriate diluent.LAY ABSTRACT: Bacterial endotoxins are present in the environments devoted to the manufacturing of injectable drugs and could be a real risk for the quality and the safety of such drugs. So the quality control laboratories should have analytical methods to recover bacterial endotoxins from environmental samples. The aim of this publication is to show how we succeeded in developing and validating methods to quantify bacterial endotoxins on surfaces and in the air. PMID- 28819049 TI - A Comparison of Protein Stability in Prefillable Syringes Made of Glass and Plastic. AB - The development of protein therapeutics requires stabilization of these labile molecules during shipment and storage. Biologics, particularly monoclonal antibodies, are frequently packaged at high concentration in prefillable syringes traditionally made of glass. However, some biologics are unstable in glass due to sensitivity to silicone oil, tungsten, glue, or metal ions. Syringes made from the plastic cyclic olefin polymer, Daikyo Crystal Zenith(r) (CZ), with a Flurotec laminated piston, have none of these issues. This study compared the stability of several proteins including biotherapeutics when stored up to 14 months at 5 degrees C and 25 degrees C in prefillable siliconized syringes made of glass or silicone oil-free CZ syringes, and when subjected to mild agitation by end-over end rotation at room temperature. At each time point, proteins were analyzed by several techniques including turbidity, size exclusion high-performance liquid chromatography, reversed phase high-performance liquid chromatography, ion exchange chromatography, electrophoresis, and light scattering to monitor changes in aggregation and degradation. The results show that proteins have comparable stability when stored in glass syringes or in syringes made of CZ sterilized by E beam or autoclave. In addition, proteins stressed by agitation were generally more stable and aggregated less in syringes made of CZ than in ones made of glass.LAY ABSTRACT: Biotherapeutic protein drugs such as monoclonal antibodies are frequently packaged at high concentration in prefillable syringes, which allows the drug to be directly administered by the patient or caregiver. Protein drugs, or biologics, can be unstable, and may aggregate, particularly when shaken. These aggregates can be immunogenic, stimulating the body's immune system to produce antibodies that can reduce the drug's efficacy. Although prefillable syringes are traditionally made of glass, some biologics are unstable in glass syringes due to the presence of substances used in their manufacture, including silicone oil, which is necessary for lubricity. Syringes made from the plastic cyclic olefin polymer, Daikyo Crystal Zenith(r) (CZ), have none of these issues. This study compared the stability of several biotherapeutic proteins when stored up to 14 months at 5 degrees C and 25 degrees C in prefillable siliconized syringes made of glass or silicone oil-free CZ syringes, and when mildly agitated at room temperature. Proteins were analyzed by several techniques to detect changes in aggregation and degradation. The results show that biotherapeutic proteins have similar stability whether stored in syringes made of glass or CZ. In addition, proteins subjected to agitation were generally more stable and aggregated less in CZ syringes than in glass syringes. PMID- 28819050 TI - PDA PAC iAM 2017 Survey on Post Approval Change: Is the Regulatory Environment Hindering Much-Needed Innovation in the Pharma Industry? PMID- 28819051 TI - The effects of 8 weeks voluntary wheel running on the contractile performance of isolated locomotory (soleus) and respiratory (diaphragm) skeletal muscle during early ageing. AB - Decreased skeletal muscle performance with increasing age is strongly associated with reduced mobility and quality of life. Increased physical activity is a widely prescribed method of reducing the detrimental effects of ageing on skeletal muscle contractility. The present study used isometric and work loop testing protocols to uniquely investigate the effects of 8 weeks of voluntary wheel running on the contractile performance of isolated dynapenic soleus and diaphragm muscles of 38-week-old CD1 mice. When compared with untrained controls, voluntary wheel running induced significant improvements in maximal isometric stress and work loop power, a reduced resistance to fatigue, but greater cumulative work during fatiguing work loop contractions in isolated muscle. These differences occurred without appreciable changes in lactate dehydrogenase, citrate synthase, sarco-endoplasmic reticulum ATPase or myosin heavy chain expression synonymous with this form of training in younger rodent models. Despite the given improvement in contractile performance, the average running distance significantly declined over the course of the training period, indicating that this form of training may not be sufficient to fully counteract the longer-term ageing-induced decline in skeletal muscle contractile performance. Although these results indicate that regular low-intensity physical activity may be beneficial in offsetting the age-related decline in skeletal muscle contractility, future work focusing on the maintenance of a healthy body mass with increasing age and its effects on myosin-actin cross-bridge kinetics and Ca2+ handling is needed to clarify the mechanisms causing the improved contractile performance in trained dynapenic skeletal muscle. PMID- 28819052 TI - Dolphin blubber/axial muscle shear: implications for rigid transdermal intramuscular tracking tag trauma in whales. AB - Whale tracking tags often penetrate semi-rigid blubber, with intramuscular sharp tips and toggling barbs under the subdermal sheath to reduce premature shedding. Tag sites can show persistent regional swellings or depressions. Fibroelastic blubber grips a tag, so if muscle shears relative to blubber during locomotion, the tag tip could cavitate the muscle within overall shearing distance. We modeled shearing of blubber relative to muscle, within the dorsal-ventral peduncular movement range of four common dolphin (Delphinus delphis) cadavers (mean length 186 cm). The net change in angle and hence tip distance moved was calculated with dorsal and ventral flexion, and compared between 1.5 mm diameter needles inserted into blubber only and through blubber into muscle. The greatest shearing value was 3.6 cm, and shearing was most pronounced in the areas ventral and caudal to the dorsal fin. Scaled dummy tags were also inserted and the animal cyclically flexed dorsally and ventrally for 18 h. Tag sites were dissected and cavities around the tag tips documented. If this shearing is comparable in large whales, depressions and regional swellings observed with intramuscular tracking tags are likely the result of tissue loss and repair, respectively. Placing tags para-sagittally anterior to the dorsal fin would cause the least trauma, but pain from such tags remains a concern. PMID- 28819053 TI - Novel neurobiological properties of elements in the escape circuitry of the shrimp. AB - Escape behaviors in penaeid shrimp are mediated by large myelinated medial giant fibers which course from the brain to the last abdominal ganglion in the ventral nerve cord. In each abdominal segment, the medial giant axons make synaptic connections with paired myelinated motor giant axons that excite the abdominal deep flexor muscles and drive the tailflips that constitute the escape behavior. I examined (1) anatomical features of the abdominal motor giant fibers and (2) electrical properties of both the medial and motor giant axons in the pink shrimp, Farfantepenaeus duorarum The motor giant axons in the paired third roots of shrimp abdominal ganglia emerge from a single fused neurite that originates from two clusters of cell bodies within the ganglion. Injection of large positive currents into the abdominal medial giant fibers generates action potentials that are transmitted to the opposite medial giant axon through putative collateral synapses within the ganglia. Transmission across the medial-to-motor giant synapse is fast and resistant to fatigue, with synaptic delays equal to or less than those previously documented at the lateral-to-motor giant electrical synapse in crayfish. Transmission was found to be extremely reliable even with presynaptic spike frequencies as high as 250 Hz. While action potentials within the medial giant fibers are transmitted across the medial-to-motor giant synapse with a large safety factor, neither prolonged positive nor prolonged negative currents pass through the synaptic nexus, irrespective of the site of injection. The lack of DC current passage along with the inability of neurobiotin or biocytin to spread through the synaptic nexus raises the possibility that the synaptic mechanism may be capacitative. PMID- 28819054 TI - Role of GnIH in photoperiodic regulation of seasonal reproduction in the Eurasian tree sparrow. AB - Seasonal reproductive cycles of most birds are regulated by photoperiod via neuroendocrine control. Gonadotropin-inhibitory hormone (GnIH) in the hypothalamus has been reported to act as neuroendocrine integrator of photoperiodic cues. In this study, both captive and field investigations were carried out to understand the effects of photoperiod and seasonality on GnIH expression in subtropical tree sparrows. Monthly observations of GnIH mRNA and peptide expression in wild birds over a year revealed a significant increase in GnIH mRNA level and number of GnIH-ir neurons during the non-breeding season when compared with their expression in the breeding season. GnIH-ir neurons were found primarily in the paraventricular nucleus (PVN) with their fibers projecting into the median eminence and some other areas of the brain. In an 8 month-long experiment, birds exposed to short days had higher GnIH expression compared with birds exposed to long days regardless of sampling month. Long-day birds with regressed testes had similar GnIH levels to short-day birds. Though the number of GnIH peptide-expressing neurons ran almost parallel to the levels of GnIH mRNA, they were inversely related to gonadal size in both sexes under natural and artificial photoperiodic conditions. These results clearly indicate an inhibitory role of GnIH in photoperiodic regulation of seasonal reproduction in the tree sparrow. PMID- 28819055 TI - Temperature effects on the cardiorespiratory control of American bullfrog tadpoles based on a non-invasive methodology. AB - Temperature effects on cardiac autonomic tonus in amphibian larval stages have never been investigated. Therefore, we evaluated the effect of different temperatures (15, 25 and 30 degrees C) on the cardiorespiratory rates and cardiac autonomic tonus of premetamorphic tadpoles of the bullfrog, Lithobates catesbeianus To this end, a non-invasive method was developed to permit measurements of electrocardiogram (ECG) and buccal movements (fB; surface electromyography of the buccal floor). For evaluation of autonomic regulation, intraperitoneal injections of Ringer solution (control), atropine (cholinergic muscarinic antagonist) and sotalol (beta-adrenergic antagonist) were performed. Ringer solution injections did not affect heart rate (fH) or fB across temperatures. Cardiorespiratory parameters were significantly augmented by temperature (fH: 24.5+/-1.0, 54.5+/-2.0 and 75.8+/-2.8 beats min-1 at 15, 25 and 30 degrees C, respectively; fB: 30.3+/-1.1, 73.1+/-4.0 and 100.6+/-3.7 movements min-1 at 15, 25 and 30 degrees C, respectively). A predominant vagal tone was observed at 15 degrees C (32.0+/-3.2%) and 25 degrees C (27.2+/-6.7%) relative to the adrenergic tone. At 30 degrees C, the adrenergic tone increased relative to the lower temperature. In conclusion, the cholinergic and adrenergic tones seem to be independent of temperature for colder thermal intervals (15-25 degrees C), while exposure to a hotter ambient temperature (30 degrees C) seems to be followed by a significant increase in adrenergic tone and may reflect cardiovascular adjustments made to match oxygen delivery to demand. Furthermore, while excluding the use of implantable electrodes or cannulae, this study provides a suitable non-invasive method for investigating cardiorespiratory function (cardiac and respiratory rates) in water-breathing animals such as the tadpole. PMID- 28819057 TI - Neurointervention: a call to science. PMID- 28819056 TI - Effects of sublethal doses of thiacloprid and its formulation Calypso(r) on the learning and memory performance of honey bees. AB - Learning and memory play a central role in the behavior and communication of foraging bees. We have previously shown that chronic uptake of the neonicotinoid thiacloprid affects the behavior of honey bees in the field. Foraging behavior, homing success, navigation performance and social communication were impaired. Thiacloprid collected at a feeding site at low doses accumulates in foragers over time. Here, we applied a laboratory standard procedure (the proboscis-extension response conditioning) in order to assess which processes, acquisition, memory consolidation and/or memory retrieval were compromised after bees were fed either with thiacloprid or the formulation of thiacloprid named Calypso(r) at different sublethal doses. Extinction and generalization tests allowed us to investigate whether bees respond to a learned stimulus, and how selectively. We showed that thiacloprid, as active substance and as formulation, poses a substantial risk to honey bees by disrupting learning and memory functions. These data support and specify the data collected in the field. PMID- 28819058 TI - Concerns about NHS treatment of older people are often unreported, survey finds. PMID- 28819059 TI - Pancreas transplantation: the donor's side of the story. PMID- 28819060 TI - Intrathecal rituximab for IgG4-related hypertrophic pachymeningitis. PMID- 28819061 TI - Abnormal BAEP and internal auditory canal MRI in intracranial hypotension. PMID- 28819062 TI - Nodes, paranodes and neuropathies. AB - This review summarises recent evidence supporting the involvement of the specialised nodal and perinodal domains (the paranode and juxtaparanode) of myelinated axons in the pathology of acquired, inflammatory, peripheral neuropathies.The identification of new target antigens in the inflammatory neuropathies heralds a revolution in diagnosis, and has already begun to inform increasingly targeted and individualised therapies. Rapid progress in our basic understanding of the highly specialised nodal regions of peripheral nerves serves to strengthen the links between their unique microstructural identities, functions and pathologies. In this context, the detection of autoantibodies directed against nodal and perinodal targets is likely to be of increasing clinical importance. Antiganglioside antibodies have long been used in clinical practice as diagnostic serum biomarkers, and associate with specific clinical variants but not to the common forms of either acute or chronic demyelinating autoimmune neuropathy. It is now apparent that antibodies directed against several region-specific cell adhesion molecules, including neurofascin, contactin and contactin-associated protein, can be linked to phenotypically distinct peripheral neuropathies. Importantly, the immunological characteristics of these antibodies facilitate the prediction of treatment responsiveness. PMID- 28819063 TI - STARD for Abstracts: essential items for reporting diagnostic accuracy studies in journal or conference abstracts. PMID- 28819065 TI - Effects of the Fort McMurray wildfires on the health of evacuated workers: follow up of 2 cohorts. AB - BACKGROUND: Wildfire engulfed Fort McMurray, Alberta on May 3, 2016, leading to a total evacuation. Access to 2 active cohorts allowed us to rapidly assess health effects in those evacuated. METHODS: People working in Fort McMurray who had been recruited before the fire for 2 occupational health cohort studies completed a questionnaire (online or via telephone) 3-26 weeks after evacuation. The questionnaire asked about respiratory and mental health and experiences since the fire. RESULTS: Of the 129 participants, 109 were in the Fort McMurray area on May 3. Thirty-seven (33.9%) of the participants who were in Fort McMurray on May 3 reported a health condition, including respiratory symptoms (n = 17) and mental ill health (n = 17), immediately after the fire. At follow-up, a mean of 102 days after the fire, 11 participants (10.1%) reported a fire-related health condition, including mental ill health (n = 8) and respiratory symptoms (n = 2). There was no difference before and after the fire in use of alcohol, cigarettes, recreational drugs or medication. One in 4 participants (32 [24.6%]) had not worked since the fire, and fewer than half (58 [44.6%]) had returned to Fort McMurray. Of the 90 participants evacuated, 15 (16.7%) had scores indicative of moderate or severe anxiety or depression on the Hospital Anxiety and Depression Scale. Those evacuated had significantly higher mean anxiety (p = 0.01) and depression (p = 0.04) scores than those not evacuated. Regression modelling showed that anxiety scores were higher for women, with longer time since the fire and with evacuation to a motel. Depression scores were higher for women and with financial loss because of lack of work. INTERPRETATION: Although evacuation was associated with higher anxiety and depression scores, persisting ill health was not widespread at early follow-up after the fire. Although these results are encouraging, these "healthy worker" results cannot be generalized to all evacuees. PMID- 28819064 TI - The Tumor Microenvironment Regulates Sensitivity of Murine Lung Tumors to PD-1/PD L1 Antibody Blockade. AB - Immune checkpoint inhibitors targeting the interaction between programmed cell death-1 (PD-1) and its ligand PD-L1 induce tumor regression in a subset of non small cell lung cancer patients. However, clinical response rates are less than 25%. Evaluation of combinations of immunotherapy with existing therapies requires appropriate preclinical animal models. In this study, murine lung cancer cells (CMT167 and LLC) were implanted either orthotopically in the lung or subcutaneously in syngeneic mice, and response to anti-PD-1/PD-L1 therapy was determined. Anti-PD-1/PD-L1 therapy inhibited CMT167 orthotopic lung tumors by 95%. The same treatments inhibited CMT167 subcutaneous tumors by only 30% and LLC orthotopic lung tumors by 35%. CMT167 subcutaneous tumors had more Foxp3+ CD4+ T cells and fewer PD-1+ CD4+ T cells compared with CMT167 orthotopic tumors. Flow cytometric analysis also demonstrated increased abundance of PD-L1high cells in the tumor microenvironment in CMT167 tumor-bearing lungs compared with CMT167 subcutaneous tumors or LLC tumor-bearing lungs. Silencing PD-L1 expression in CMT167 cells resulted in smaller orthotopic tumors that remained sensitive to anti-PD-L1 therapy, whereas implantation of CMT167 cells into PD-L1- mice blocked orthotopic tumor growth, indicating a role for PD-L1 in both the cancer cell and the microenvironment. These findings indicate that the response of cancer cells to immunotherapy will be determined by both intrinsic properties of the cancer cells and specific interactions with the microenvironment. Experimental models that accurately recapitulate the lung tumor microenvironment are useful for evaluation of immunotherapeutic agents. Cancer Immunol Res; 5(9); 767-77. (c)2017 AACR. PMID- 28819066 TI - Neuroplasticity of selective attention: Research foundations and preliminary evidence for a gene by intervention interaction. AB - This article reviews the trajectory of our research program on selective attention, which has moved from basic research on the neural processes underlying selective attention to translational studies using selective attention as a neurobiological target for evidence-based interventions. We use this background to present a promising preliminary investigation of how genetic and experiential factors interact during development (i.e., gene * intervention interactions). Our findings provide evidence on how exposure to a family-based training can modify the associations between genotype (5-HTTLPR) and the neural mechanisms of selective attention in preschool children from lower socioeconomic status backgrounds. PMID- 28819067 TI - Health economics of targeted intraoperative radiotherapy (TARGIT-IORT) for early breast cancer: a cost-effectiveness analysis in the United Kingdom. AB - OBJECTIVE: The clinical effectiveness of targeted intraoperative radiotherapy (TARGIT-IORT) has been confirmed in the randomised TARGIT-A (targeted intraoperative radiotherapy-alone) trial to be similar to a several weeks' course of whole-breast external-beam radiation therapy (EBRT) in patients with early breast cancer. This study aims to determine the cost-effectiveness of TARGIT-IORT to inform policy decisions about its wider implementation. SETTING: TARGIT-A randomised clinical trial (ISRCTN34086741) which compared TARGIT with traditional EBRT and found similar breast cancer control, particularly when TARGIT was given simultaneously with lumpectomy. METHODS: Cost-utility analysis using decision analytic modelling by a Markov model. A cost-effectiveness Markov model was developed using TreeAge Pro V.2015. The decision analytic model compared two strategies of radiotherapy for breast cancer in a hypothetical cohort of patients with early breast cancer based on the published health state transition probability data from the TARGIT-A trial. Analysis was performed for UK setting and National Health Service (NHS) healthcare payer's perspective using NHS cost data and treatment outcomes were simulated for both strategies for a time horizon of 10 years. Model health state utilities were drawn from the published literature. Future costs and effects were discounted at the rate of 3.5%. To address uncertainty, one-way and probabilistic sensitivity analyses were performed. MAIN OUTCOME MEASURES: Quality-adjusted life-years (QALYs). RESULTS: In the base case analysis, TARGIT-IORT was a highly cost-effective strategy yielding health gain at a lower cost than its comparator EBRT. Discounted TARGIT IORT and EBRT costs for the time horizon of 10 years were L12 455 and L13 280, respectively. TARGIT-IORT gained 0.18 incremental QALY as the discounted QALYs gained by TARGIT-IORT were 8.15 and by EBRT were 7.97 showing TARGIT-IORT as a dominant strategy over EBRT. Model outputs were robust to one-way and probabilistic sensitivity analyses. CONCLUSIONS: TARGIT-IORT is a dominant strategy over EBRT, being less costly and producing higher QALY gain. TRIAL REGISTRATION NUMBER: ISRCTN34086741; post results. PMID- 28819068 TI - Rural emergency care 360 degrees : mobilising healthcare professionals, decision makers, patients and citizens to improve rural emergency care in the province of Quebec, Canada: a qualitative study protocol. AB - INTRODUCTION: Emergency departments (EDs) are an important safety net for rural populations. Results of our earlier studies suggest that rural Canadian hospitals have limited access to advanced imaging services and intensive care units and that patients are transferred over large distances. They also revealed significant geographical variations in rural services. In the absence of national standards, our studies raise questions about inequities in rural access to emergency services and the risks for citizens. Our goal is to build recommendations for improving services by mobilising stakeholders interested in rural emergency care. With help and full engagement of stakeholders, we will (1) identify solutions for improving quality and performance in rural EDs; (2) formulate and prioritise recommendations; (3) transfer knowledge of the recommendations to rural EDs and support operationalisation and (4) assess knowledge transfer and explore further impacts of this participatory action research project. METHODOLOGY: We will use a participatory action research approach. We will plan for a governance structure that includes all stakeholdersa?TM representatives, so throughout this project, stakeholders are fully engaged at every step. Our sample will be 26 EDs in rural Quebec. We will conduct semistructured individual and focus group interviews with relevant and representative participants, including patients and citizens (estimated n=200). Interviews will be thematically analysed to extract potential solutions and other qualitative information.An expert panel (A+/-15) will use an analysis grid to develop consensus recommendations from solutions suggested and will evaluate feasibility, impacts, costs, conditions for implementation and establish monitoring indicators. Recommendations will be transferred to stakeholders using tailored knowledge translation strategies (web platform, meetings and so on). DISCUSSION AND EXPECTED RESULTS: This study will result in a comprehensive consensus list of feasible and high-priority recommendations enabling decision makers in emergency care to implement improvements in rural emergency care in Quebec. ETHICS AND DISSEMINATION: This protocol has been approved by the CSSS Alphonse-Desjardins research ethics committee (Project number: MP 2017-009). The qualitative material will be kept confidential and the data will be presented in a way that respects confidentiality. The dissemination plan for the study includes publications in scientific and professional journals. We will also use social media to disseminate our findings and activities such as communications in public conferences. PMID- 28819069 TI - Factors influencing career intentions on completion of general practice vocational training in England: a cross-sectional study. AB - OBJECTIVES: General practice is experiencing a growing crisis with the numbers of doctors who are training and then entering the profession in the UK failing to keep pace with workforce needs. This study investigated the immediate to medium term career intentions of those who are about to become general practitioners (GPs) and the factors that are influencing career plans. DESIGN: Online questionnaire survey, with quantitative answers analysed using descriptive statistics and free text data analysed using a thematic framework approach. SETTING AND PARTICIPANTS: Doctors approaching the end of 3-year GP vocational training in the West Midlands, England. RESULTS: 178 (57.2%) doctors completed the survey. Most participants planned to work as salaried GPs or locums rather than entering a general practice partnership for at least the first 5 years post completion of training; others failed to express a career plan or planned to leave general practice completely or work overseas. Many were interested in developing portfolio careers.The quality of general practice experience across undergraduate, foundation and vocational training were reported as influencing personal career plans, and in particular perceptions about workload pressure and morale within the training practices in which they had been placed. Experience of a poor work-life balance as a trainee had a negative effect on career intentions, as did negative perceptions about how general practice is portrayed by politicians and the media. CONCLUSION: This study describes a number of potentially modifiable factors related to training programmes that are detrimentally influencing the career plans of newly trained GPs. In addition, there are sociodemographic factors, such as age, gender and having children, which are also influencing career plans and so need to be accommodated. With ever increasing workload in general practice, there is an urgent need to understand and where possible address these issues at national and local level. PMID- 28819070 TI - Claudin-5-Binders Enhance Permeation of Solutes across the Blood-Brain Barrier in a Mammalian Model. AB - A current bottleneck in the development of central nervous system (CNS) drugs is the lack of drug delivery systems targeting the CNS. The intercellular space between endothelial cells of the blood-brain barrier (BBB) is sealed by complex protein-based structures called tight junctions (TJs). Claudin-5 (CLDN-5), a tetra-transmembrane protein is a key component of the TJ seal that prevents the paracellular diffusion of drugs into the CNS. In the present study, to investigate whether CLDN-5 binders can be used for delivery of drugs to the CNS, we generated monoclonal antibodies (mAbs) specific to the extracellular domains of CLDN-5. In an in vitro model of the BBB, the anti-CLDN-5 mAbs attenuated trans epithelial/endothelial electrical resistance and enhanced solute permeation. These anti-CLDN-5 mAbs are potential leads for the development of novel drug delivery systems targeting the CNS. PMID- 28819072 TI - [Overview of Hereditary Spinocerebellar Ataxias in Japan]. AB - Hereditary spinocerebellar degenerations (SCD) are a group of neurodegenerative disorders characterized by slowly progressive ataxia associated with non cerebellar neurological signs and symptoms. In the Japanese population, dominantly inherited SCDs are much more common than recessively inherited or X linked SCDs. The most common dominantly inherited SCD in Japan, as well as in many other countries, is Machado-Joseph disease, also known as spinocerebellar ataxia type 3 (MJD/SCA3). MJD/SCA3 is frequently accompanied by non-cerebellar symptoms, including progressive external ophthalmoplegia, pyramidal signs, dystonia, rigidity, dysarthria, and distal muscle atrophies. SCA6 and SCA31 represent a pure cerebellar subtype of SCD, occasionally accompanied by non cerebellar signs. Detailed medical history and neurological examination are important for clinicians to diagnose hereditary SCDs, although genetic testing can help confirm the diagnosis. Despite increasing understanding of the molecular mechanisms underlying these fatal diseases, preventive therapies are currently lacking. PMID- 28819073 TI - [Recent Topics in Autosomal Dominantly Inherited Spinocerebellar Ataxias]. AB - Among various dominantly inherited spinocerebellar ataxias (SCAs), it is revealed that the molecular mechanism of so called "non-coding microsatellite repeat expansion disorders" was involved in RNA gain-of-function as well as "RAN translation". Recently, the "polyglutamine disorders" caused by the coding CAG repeat expansions were also clarified that they were involved in RNA mechanism or RAN translation. The common molecular mechanism might exist between SCAs of which the repeat expansions were located in both coding and non-coding regions. PMID- 28819071 TI - Genetic and Nongenetic Factors Associated with Protein Abundance of Flavin Containing Monooxygenase 3 in Human Liver. AB - Hepatic flavin-containing mono-oxygenase 3 (FMO3) metabolizes a broad array of nucleophilic heteroatom (e.g., N or S)-containing xenobiotics (e.g., amphetamine, sulindac, benzydamine, ranitidine, tamoxifen, nicotine, and ethionamide), as well as endogenous compounds (e.g., catecholamine and trimethylamine). To predict the effect of genetic and nongenetic factors on the hepatic metabolism of FMO3 substrates, we quantified FMO3 protein abundance in human liver microsomes (HLMs; n = 445) by liquid chromatography-tandem mass chromatography proteomics. Genotyping/gene resequencing, mRNA expression, and functional activity (with benzydamine as probe substrate) of FMO3 were also evaluated. FMO3 abundance increased 2.2-fold (13.0 +/- 11.4 pmol/mg protein vs. 28.0 +/- 11.8 pmol/mg protein) from neonates to adults. After 6 years of age, no significant difference in FMO3 abundance was found between children and adults. Female donors exhibited modestly higher mRNA fragments per kilobase per million reads values (139.9 +/- 76.9 vs. 105.1 +/- 73.1; P < 0.001) and protein FMO3 abundance (26.7 +/- 12.0 pmol/mg protein vs. 24.1 +/- 12.1 pmol/mg protein; P < 0.05) compared with males. Six single nucleotide polymorphisms (SNPs), including rs2064074, rs28363536, rs2266782 (E158K), rs909530 (N285N), rs2266780 (E308G), and rs909531, were associated with significantly decreased protein abundance. FMO3 abundance in individuals homozygous and heterozygous for haplotype 3 (H3), representing variant alleles for all these SNPs (except rs2066534), were 50.8% (P < 0.001) and 79.5% (P < 0.01), respectively, of those with the reference homozygous haplotype (H1, representing wild-type). In summary, FMO3 protein abundance is significantly associated with age, gender, and genotype. These data are important in predicting FMO3-mediated heteroatom-oxidation of xenobiotics and endogenous biomolecules in the human liver. PMID- 28819074 TI - [Molecular Pathogenesis of Polyglutamine Diseases]. AB - Polyglutamine diseases result from gain-of-function mutations. The expanded polyglutamine tracts lead to conformational changes in proteins, resulting in their aggregation. The intermediates including monomers or oligomers, are more toxic than the aggregates to neurons. At the molecular level, protein misfolding, transcriptional dysregulation, deranged calcium homeostasis, impaired cytoskeleton/axonal transport, mitochondrial dysfunction, and RNA toxicity contribute to disease progression. Understanding the underlying pathogenesis facilitates development of therapy for polyglutamine diseases. PMID- 28819075 TI - [Advances in Neurological Therapeutics for Friedreich Ataxia and Machado-Joseph Disease]. AB - We reviewed advances in therapeutics for both Friedreich ataxia and Machado Joseph disease. Various clinical trials have been carried out, mainly for Friedreich ataxia; however, the therapeutic reports from these trials have not provided much evidence for success. Some interesting clinical trials have been reported, and further developments are expected. Regenerative therapy using umbilical cord mesenchymal stem cells and a therapeutic study investigating a new pathomechanism in animal and/or cell culture studies were reported. We expect that these results will translate to therapeutic strategies for patients with these disorders. In addition, biomarkers play an important role when novel treatments are discovered and clinical trials are performed: hence at present, a number of biomarkers such as gait analysis by triaxial accelerometers and prism adaptation of hand-reaching movements, are being examined. PMID- 28819076 TI - [Molecularly-Targeted Therapy of Spinocerebellar Ataxia Type 1 by HMGB1]. AB - Spinocerebellar ataxia type 1 (SCA1) is an untreatable neurodegenerative disease. We reported a decrease in HMGB1 levels in the nucleus of cerebellar neurons in mouse SCA 1. The decrease in this DNA architectural protein leads to the impairment of DNA repair and transcription, the two essential nuclear functions, and eventually causes neurodegeneration. We have designed a gene therapy using AAV-HMGB1 and tested it using the mouse model. Based on the results of these proof of concept (POC) studies, we are now preparing GMP-level AAV vector and designing human clinical trials. PMID- 28819077 TI - [Gluten Ataxia: Anti-Transglutaminase-6 Antibody as a New Biomarker]. AB - Gluten-related disorders (GRDs) are conditions that develop in response to the common trigger of gluten ingestion and manifest as a variety of clinical symptoms. GRDs have been considered rare in Asian countries, including Japan, because of lower consumption of wheat products than in Europe and the U.S.A. and differences in genetic background. Recently, however, GRDs, such as celiac disease and gluten ataxia, have been reported in Japan, albeit sporadically and their presence is now recognized in this country. Gluten ataxia is defined as an anti-gliadin antibody positive sporadic ataxia. Recently, it was reported that the presence of anti-transglutaminase-6 (TG6) antibody can be used to diagnose gluten ataxia. Herein, we will review evidence relating to gluten ataxia and report two cases of anti-TG6 antibody positive gluten ataxia. In patients with gluten ataxia, sensory disturbance is generally considered to be so mild that it contributes minimally to ataxia. However, our patients showed a positive Romberg sign. Deep sensory disturbance, in addition to cerebellar disturbance, may have been involved in the clinical symptoms of our cases. PMID- 28819078 TI - [Associative Learning between Orientation and Color in Early Visual Areas]. AB - Associative learning is an essential neural phenomenon where the contingency of different items increases after training. Although associative learning has been found to occur in many brain regions, there is no clear evidence that associative learning of visual features occurs in early visual areas. Here, we developed an associative decoded functional magnetic resonance imaging (fMRI) neurofeedback (A DecNef) to determine whether associative learning of color and orientation can be induced in early visual areas. During the three days' training, A-DecNef induced fMRI signal patterns that corresponded to a specific target color (red) mostly in early visual areas while a vertical achromatic grating was simultaneously, physically presented to participants. Consequently, participants' perception of "red" was significantly more frequently than that of "green" in an achromatic vertical grating. This effect was also observed 3 to 5 months after training. These results suggest that long-term associative learning of two different visual features such as color and orientation, was induced most likely in early visual areas. This newly extended technique that induces associative learning may be used as an important tool for understanding and modifying brain function, since associations are fundamental and ubiquitous with respect to brain function. PMID- 28819079 TI - [An Adult Case of Enterovirus D68 Encephalomyelitis Presenting as Bilateral Facial Nerve Palsy and Dysphagia]. AB - A 33-year-old man was admitted to our hospital with bilateral facial nerve paralysis, dysphagia, and muscle weakness in the neck and trunk following fever, headache and throat pain. T2-weighted brain magnetic resonance imaging (MRI) showed hyperintense lesions in the tegmentum of the brain stem and the ventral region of the superior cervical cord. Based on the characteristic findings on the brain MRI, we diagnosed the patient with enteroviral encephalomyelitis. Steroid therapy was administered; however, his bilateral facial nerve paralysis and dysphagia were refractory to this therapy. Subsequently, enterovirus D68 was detected in the serum using polymerase chain reaction (PCR) analysis. At that time, an outbreak of enteroviral D68 infection was reported in Japan. Finally, we diagnosed encephalomyelitis caused by enteroviral D68 infection. Characteristic MRI findings were very useful in narrowing down the differential diagnosis in this patient. (Received March 3, 2017; Accepted April 20, 2017; Published August 1, 2017). PMID- 28819080 TI - A survey on selection, use, maintenance, and management of chemical protective gloves at workplaces in Japan. AB - OBJECTIVES: The aim of this study was to survey the selection, use, and maintenance of chemical protective gloves (CPGs) at real workplaces. METHODS: Subjects comprised 817 workers using CPGs at seven domestic manufacturing plants in Japan. We administered an anonymous questionnaire survey comprising the following aspect related to CPGs: environment of use, conditions of use, method of selection, knowledge/awareness pertaining to their use, method of use, precautionary measures associated with their use, maximum time of use, and maintenance. We compared responses provided by management staff and field workers. Chi square test was used for the analysis. RESULTS: Respondents included 661 (80.9%) manufacturing workers, 121 (14.8%) managers or supervisors, and 35 (4.3%) others. In total, 70.5% organic solvents, 28.9% acid or/and alkali, 18.1% dust, and 10.3% carcinogenic substances were the chemical substances handled using CPGs. The reason for deciding to wear CPGs was "the use of chemical substances" for 46.5%, "notice in safety data sheet (SDS) " for 29.8%, and "management staffs' guidance" for 21.4% respondents. "The grasp of chemical substances" was 70.1% (91.1% excluding "not applicable" ). "Warning of caution on skin and eyes" was indicated by 69.5% (91.0%) and "educational reasons for use of CPGs" was accepted by 68.1% (90.7%) respondents. On the other hand, the rate of responses such as "obtaining permeability test results of target substances" and "mixed substances are selected considering substances with short permeation time" was 25.2% (38.4%) and 29.2% (48.4%), respectively. The rate of "yes" as a response in the item concerning "permeation test" was low. On comparing the response provided by the management staff and field workers, the rate of "the permeation test result of the target substance was obtained" was 27.7% for management staff and 41.2% for field workers (p = 0.022). Regarding the cuffs of CPGs, the rate of "to fold back and to prevent sagging" and "mounted with tape" were 30.5% and 21.8% for management staff and 50.2% and 42.2% for field workers (p = 0.001 and p = 0.001), respectively. DISCUSSION: This survey results suggested that the knowledge of "permeation test" of CPGs was not yet popular at industrial workplaces. It is necessary to disseminate knowledge related to "permeation test" to the users from manufacturers of CPGs. Additionally, the employer should appoint an administrator to ensure that CPGs are worn and increase the understanding of correct knowledge and usage of CPGs among workers. PMID- 28819081 TI - Sterilization of Gastrointestinal Endoscope in Medical Institutions in Fukuoka Prefecture. PMID- 28819083 TI - The forgotten realm of the new and emerging psychosocial risk factors. AB - In Europe, employers of all private and public enterprises have a legal obligation to protect their employers by all the different types of workplace hazards to the safety and health of workers. The most important methods developed for the work-related stress risk assessment are based on the Cox's research commissioned by European Agency for Safety and Health at Work (EU-OSHA) and are the Management Standard HSE for work-related stress in United Kingdom, the START method in Germany, the Screening, Observation, Analysis, Expertise (SOBANE) in Belgium, and the National Institute for Prevention and Safety at Work (INAIL ISPESL) model in Italy, the latter based on the British Management Standard. Unfortunately, the definition of "work-related stress" elaborated by EU-OSHA was criticized, because it is not completely equal to the broader "psychosocial risk," which includes new and emerging psychosocial risk factors, such as the combined exposure to physical and psychosocial risks, job insecurity, work intensification and high demands at work, high emotional load related to burnout, work-life balance problems, and violence and harassment at work. All these new emerging psychosocial hazards could require different and additional methodologies to save workers' health and safety. For this reason, the concept that stakeholders and policy makers should keep in mind in order to develop better national regulations and strategies is that work-related stress risk and psychosocial risk factors are not the same. PMID- 28819082 TI - Dysregulation of Calpain Proteolytic Systems Underlies Degenerative Vascular Disorders. AB - Chronic vascular diseases such as atherosclerosis, aneurysms, diabetic angiopathy/retinopathy as well as fibrotic and proliferative vascular diseases are generally complicated by the progression of degenerative insults, which are characterized by endothelial dysfunction, apoptotic/necrotic cell death in vascular/immune cells, remodeling of extracellular matrix or breakdown of elastic lamella. Increasing evidence suggests that dysfunctional calpain proteolytic systems and defective calpain protein metabolism in blood vessels contribute to degenerative disorders. In vascular endothelial cells, the overactivation of conventional calpains consisting of calpain-1 and -2 isozymes can lead to the disorganization of cell-cell junctions, dysfunction of nitric oxide synthase, sensitization of Janus kinase/signal transducer and activator of transcription cascades and depletion of prostaglandin I2, which contributes to degenerative disorders. In addition to endothelial cell dysfunctions, calpain overactivation results in inflammatory insults in macrophages and excessive fibrogenic/proliferative signaling in vascular smooth muscle cells. Moreover, calpain-6, a non-proteolytic unconventional calpain, is involved in the conversion of macrophages to a pro-atherogenic phenotype, leading to the pinocytotic deposition of low-density lipoprotein cholesterol in the cells. Here, we discuss the recent progress that has been made in our understanding of how calpain contributes to degenerative vascular disorders. PMID- 28819084 TI - The Significance of Lactate and Lipid Peaks for Predicting Primary Neuroepithelial Tumor Grade with Proton MR Spectroscopy. AB - PURPOSE: 1H-MRS is a non-invasive technique used to assess the metabolic activity of brain tumors. The technique is useful for the preoperative prediction of tumor grade, which is important for treatment planning and accurate prognosis. We used 1H-MRS to study the lactate peak, which appears in various conditions, including hyperglycemia, ischemia, and hypoxia and lipid peak, which is associated with necrotic cells. The purpose of this study was to retrospectively examine the frequency and significance of lactate and lipid peaks in relation to brain tumor grade. MATERIALS AND METHODS: Fifty-five patients diagnosed with neuroepithelial tumors of Grades I (3 cases), II (11 cases), III (15 cases), and IV (26 cases) were enrolled. Biopsies were excluded. Single voxel (TE = 144 ms) point resolved 1H-MRS spectroscopy sequences were retrospectively analyzed. An inverted doublet peak at 1.3 ppm was defined as lactate, a negative and positive peak was defined as combined lactate and lipid, and a clear upward peak was defined as lipid. RESULTS: Lactate peaks were detected in all grades of brain tumors and were least common in Grade II tumors (9.1%). The frequency of combined lactate-lipid peaks was 0% (Grades I and II), 8.3% (Grade III), and 44% (Grade IV). Grade IV tumors were significantly different to the other grades. There were three cases with a lipid peak. All were glioblastoma. CONCLUSIONS: The presence of a lac peak may be useful to largely rule out the Grade II tumors, and allow the subsequent differentiation of Grade I tumors from Grade III or IV tumors by conventional imaging. The presence of a lipid peak may be associated with Grade IV tumors. PMID- 28819085 TI - Histological Grading of Hepatocellular Carcinomas with Intravoxel Incoherent Motion Diffusion-weighted Imaging: Inconsistent Results Depending on the Fitting Method. AB - PURPOSE: To compare the abilities of three intravoxel incoherent motion (IVIM) imaging approximation methods to discriminate the histological grade of hepatocellular carcinomas (HCCs). METHODS: Fifty-eight patients (60 HCCs) underwent IVIM imaging with 11 b-values (0-1000 s/mm2). Slow (D) and fast diffusion coefficients (D*) and the perfusion fraction (f) were calculated for the HCCs using the mean signal intensities in regions of interest drawn by two radiologists. Three approximation methods were used. First, all three parameters were obtained simultaneously using non-linear fitting (method A). Second, D was obtained using linear fitting (b = 500 and 1000), followed by non-linear fitting for D* and f (method B). Third, D was obtained by linear fitting, f was obtained using the regression line intersection and signals at b = 0, and non-linear fitting was used for D* (method C). A receiver operating characteristic analysis was performed to reveal the abilities of these methods to distinguish poorly differentiated from well-to-moderately-differentiated HCCs. Inter-reader agreements were assessed using intraclass correlation coefficients (ICCs). RESULTS: The measurements of D, D*, and f in methods B and C (Az-value, 0.658 0.881) had better discrimination abilities than did those in method A (Az-value, 0.527-0.607). The ICCs of D and f were good to excellent (0.639-0.835) with all methods. The ICCs of D* were moderate with methods B (0.580) and C (0.463) and good with method A (0.705). CONCLUSION: The IVIM parameters may vary depending on the fitting methods, and therefore, further technical refinement may be needed. PMID- 28819086 TI - Measurement of Cerebrospinal Fluid Flow Dynamics Using Phase Contrast MR Imaging with Bilateral Jugular Vein Compression: A Feasibility Study in Healthy Volunteers. AB - We measured the changes in the cerebrospinal fluid (CSF) flow dynamics after compression of the bilateral jugular veins using phase contrast-magnetic resonance imaging (PC-MRI). PC-MRI was performed in 10 healthy male volunteers using a 3T clinical scanner with a two-dimensional gradient echo sequence. We successfully measured the changes in CSF flow velocity using PC-MRI with and without compression of the bilateral jugular veins. The relative velocity range decreased by about 30% when the bilateral jugular veins were compressed. PMID- 28819087 TI - Investigation and characterization of beta-lactam resistance in Escherichia coli strains isolated from bamboo rats (Rhizomys sinensis) in Zhejiang province, China. AB - This study was undertaken to investigate drug resistance in Escherichia coli (E. coli) strains isolated from bamboo rats in Zhejiang province of China. One hundred and fifty-four E. coli strains were isolated from dead bamboo rats. Polymerase chain reaction (PCR) was used to detect the representative genes encoding resistance to commonly used beta-lactam antibiotics. Highest resistance was observed for cefradine (24.03%), followed by penicillin (20.78%) and ceftazidime (20.13%). The isolation rates of beta-lactam resistance genes were 53.25, 48.70, 15.58 and 14.29% for bla TEM, bla CTX-M, bla OXA and bla SHV, respectively, while 62 (40.26%) E. coli isolates harbored multiple beta-lactam resistance genes. These results also suggested that long term use of these antibiotics leads to antibimicrobial resistance. We believe that this study will provide a guideline for veterinarians and a research basis for examining resistance-encoding genes in other food animals like bamboo rats. PMID- 28819088 TI - Lissencephaly in a Pekingese. AB - A 1-year-old neutered male Pekingese was presented for evaluation and further treatment of cluster seizures. The dog had behavioral abnormalities, and a prosencephalic lesion was suspected following neurological examination. The dog showed signs of learning difficulty. Magnetic resonance imaging of the brain revealed a remarkably smooth cerebral cortex with a reduced number of gyri, as well as a cystic lesion associated with the quadrigeminal cistern. A diagnosis of lissencephaly, concurrent with a quadrigeminal cisternal cyst, was made. High dose and multiple anticonvulsants were necessary to control the seizures. This is the first report of lissencephaly in a Pekingese. PMID- 28819089 TI - Follow-Up Practices of Surgeons and Medical Oncologists in Australia and New Zealand Following Resection of Esophagogastric Cancers. AB - PURPOSE: Follow-up practices for patients who have undergone surgical resection of esophagogastric malignancies are variable and poorly documented. To better understand practice, a questionnaire was used to survey surgeons and medical oncologists to determine whether any consensus exists. METHODS: An opt-in online questionnaire was sent to esophagogastric surgeons and medical oncologists via the membership lists for the Australian and New Zealand Gastric and Oesophageal Surgery Association (ANZGOSA), the Australian Gastro-Intestinal Trials Groups (AGITG), and the Medical Oncology Group of Australia (MOGA). The questionnaire proposed five clinical scenarios and provided a range of follow-up options for each scenario. Clinicians were asked to indicate which best matched their clinical practice. RESULTS: Most clinicians follow patients for at least 3-5 years following resection of gastric or esophageal cancer. In total, 52% perform routine surveillance imaging, with individual scenarios not altering this. Tumor markers are infrequently used. Endoscopy and routine blood tests are used by around half the respondents. CONCLUSION: There was little consensus about the use of investigations to monitor patients following esophagogastric cancer surgery. Choices do not follow guidelines or evidence. The identified patterns of postoperative surveillance practice appear not to be evidence based, and generally do not match recently published Australian guidelines. PMID- 28819090 TI - Management of Spontaneous Intracerebral Hematoma. AB - The incidence of spontaneous intracerebral hematoma (SICH) is even now high worldwide, especially higher in Japan than in Western countries, despite the development of advances in blood pressure (BP) management and food/alcohol intake education. Although mortality and morbidity for SICH are high, some controversies remain regarding the appropriate acute phase of treatment. Recent studies have revealed that BP lowering treatment than 140 mmHg resulted in better outcomes. However the efficacy of surgical treatment for SICH has not been well established, with the exception of that for cerebellar SICH over 3 cm in diameter and life-saving procedures, although many randomized control studies and systematic reviews focused on surgical treatment have been reported. In this review, we summarize some issues and discuss strategies in development for the treatment of SICH. PMID- 28819092 TI - A New Score to Predict Recipient Mortality from Preoperative Donor and Recipient Characteristics in Living Donor Liver Transplantation (DORMAT Score). AB - BACKGROUND Recipient outcomes in adult living donor liver transplantation depend on various characteristics in both recipient and donor. We aimed to derive a score based upon preoperative characteristics in donor and recipient that could predict the recipient mortality in adult living donor liver transplantation. MATERIAL AND METHODS Retrospective data of 100 living donor liver transplantation recipients and their respective donors were analyzed for preoperative factors that correlated with recipient mortality. Statistically significant factors were weighted appropriately to derive a regression equation to obtain a donor-to recipient match (DORMAT) score. This score was applied to 71 patients prospectively and their outcome was analyzed. RESULTS Donor-recipient match (DORMAT) score, derived using regression analysis of the significant variables was [0.002 (Recipient age) + 0.013 (Recipient BMI) + 0.055 (SBP) + 0.344 (HRS) + 0.022 (Pre-op culture positivity) + 0.01 (Donor age) - 0.639]*100. DORMAT score, when validated to a prospective cohort of 71 adult-to-adult LDLT patients, had a C-statistic (area under ROC curve) of 0.712. The mortality rate was seen to increase with increasing DORMAT score. CONCLUSIONS DORMAT score is a useful clinical decision-making tool to predict recipient mortality in adult living donor liver transplantation. PMID- 28819091 TI - Review of Current Evidence Regarding Surgery in Elderly Patients with Meningioma. AB - The Japanese population features the highest rate of elderly individuals worldwide. Moreover, Japan has the highest number of computed tomography/magnetic resonance imaging devices in the world, which has led to an increase in the incidental detection of meningioma in healthy elderly patients. Many previous papers have discussed the risks and indications for surgery in this patient population, but available information remains insufficient, and the definition of "elderly" has not been standardized. This review tried to clarify the published evidence and challenges associated with elderly meningioma based on a search of the PubMed database using the terms "meningioma," "elderly," and "surgery" for English-language clinical studies and collected related papers published from 2000 to 2016. Twenty-four papers were reviewed and classified by definition of elderly age: over 60, 65, 70, and 80 years old. Six of seven papers that defined the elderly cutoff as over 65 years old were published after 2010, which suggested the consensus definition. Four preoperative grading scoring systems were described and associated with mortality. The 1-year and 5-year mortality rates ranged from 0% to 16.7% and from 7% to 27%, which were comparable with unselected cohorts. Review of risk factor analysis emphasized the importance of considering the preoperative status, presence of comorbidities, and optimum surgical timing during patient selection. Careful choice of patients can also lead to better quality of life. A prospective randomized study considering patient frailty should address the causes and prevention of complications. PMID- 28819093 TI - Non-Seminomatous Germ Cell Tumor Presenting with Superior Vena Cava Syndrome. AB - BACKGROUND Primary mediastinal non-seminomatous germ cell tumors (NSGCTs) are aggressive and carry a poor five-year disease free survival rate even with aggressive treatment. We describe a young adult male with primary mediastinal NSGCT presenting with airway obstruction and superior vena cava syndrome (SVCS). CASE REPORT The patient presented with four weeks of nonproductive cough, weight loss, and right-sided pleuritic chest pain. Chest computed topography (CT) imaging demonstrated a right-sided mediastinal mass determined as a yolk sac tumor on biopsy. The patient underwent induction chemotherapy with etoposide and cisplatin for stage III NSGCT. In the interim, he developed SVCS warranting a second cycle of chemotherapy along with intravenous steroids, with notable improvement in symptoms. However, serial alpha-fetoprotein (AFP) measurements showed progressively increasing levels up to a maximum of 18,781 ng/mL indicating treatment failure. He is currently on salvage chemotherapy. CONCLUSIONS Obstruction of the SVC by external compression is often a manifestation of a malignant process in the thorax. SVCS is a medical emergency and occurs in 6% of patients with mediastinal GCTs. Historically, irradiation was initiated without a histologic diagnosis to relieve the life-threatening obstruction. However, newer data suggest that it is acceptable to defer therapy until a full diagnostic workup is completed. This case highlights the malignant nature of primary mediastinal NSGCTs. In addition, inasmuch as SVCS is dramatic in presentation, it is important to recognize that symptomatic obstruction often develops over weeks or longer. In a hemodynamically stable patient, an accurate histologic diagnosis prior to starting treatment is essential in guiding therapy. PMID- 28819094 TI - Atrioventricular Conduction Delay Predicts Impaired Exercise Capacity in Patients with Heart Failure with Reduced Ejection Fraction. AB - BACKGROUND Atrioventricular conduction delay (AVCD) impairs left ventricular (LV) filling and consequently leads to a reduction of cardiac output. We hypothesized that in patients with severely depressed LV function and coexisting intraventricular conduction disturbances (IVCD), AVCD can affect exercise performance. Therefore, we evaluated the association of AVCD and exercise capacity in patients with heart failure (HFREF) and coexisting IVCD. MATERIAL AND METHODS We included patients with stable, chronic HFREF, LVEF <35%, sinus rhythm, and QRS >=120 ms. PR interval and peak oxygen consumption (VO2 peak) were specifically investigated. Multiple regression analysis was used to adjust the association between PR interval and VO2 peak for possible confounders. RESULTS Most (57.5%) of the 40 included patients [20% female, aged 63+/-12, 47.5% of ischemic etiology (IHD)] were in NYHA class III. Mean PR interval was 196+/-38.1 ms. There were 26 (65%) patients with PR interval <=200 ms and 14 (35%) with >200 ms. Groups were similar in clinical, laboratory, echocardiographic parameters, QRS morphology, and treatment regimens. VO2 peak was lower in patients with longer PR interval group as compared to shorter PR interval group (12.3+/-4.1 vs. 17.06+/-4.4, p=0.002). In the regression model, PR interval, female sex, and IHD remained important predictors of VO2 peak (partial=-0.50, p=0.003; rpartial= 0.48, p=0.005; rpartial=-0.44, p=0.01; R2=0.61). CONCLUSIONS Delayed AV conduction contributes to decreased exercise capacity in patients with HFREF and coexisting IVCD. PMID- 28819095 TI - Non-coding RNAs participate in the regulatory network of CLDN4 via ceRNA mediated miRNA evasion. AB - Thousands of genes have been well demonstrated to play important roles in cancer progression. As genes do not function in isolation, they can be grouped into "networks" based on their interactions. In this study, we discover a network regulating Claudin-4 in gastric cancer. We observe that Claudin-4 is up-regulated in gastric cancer and is associated with poor prognosis. Claudin-4 reinforce proliferation, invasion, and EMT in AGS, HGC-27, and SGC-7901 cells, which could be reversed by miR-596 and miR-3620-3p. In addition, lncRNA-KRTAP5-AS1 and lncRNA TUBB2A could act as competing endogenous RNAs to affect the function of Claudin 4. Our results suggest that non-coding RNAs play important roles in the regulatory network of Claudin-4. As such, non-coding RNAs should be considered as potential biomarkers and therapeutic targets against gastric cancer.Non-coding RNAs can modify the expression of proteins in cancer networks. Here the authors reveal a regulatory network in gastric cancer whereby claudin-4 expression is reduced by specific miRNAs, which are in turn bound by specific lncRNAs acting as competing endogenous RNAs (ceRNAs), resulting in increased claudin-4 expression. PMID- 28819096 TI - Controlled radical fluorination of poly(meth)acrylic acids in aqueous solution. AB - Fluorinated alkenes exhibit very poor reactivity in copolymerization with non fluorinated polar monomers such as acrylates. Herein we describe a convenient method for the synthesis of poly(vinyl fluoride-co-acrylic acid) and poly(2 fluoropropene-co-methacrylic acid) copolymers. Thus, the silver-catalyzed decarboxylative radical fluorination of poly(acrylic acid) with Selectfluor in water at room temperature affords poly(vinyl fluoride-co-acrylic acid) copolymers in high yields with well-defined molecular weights and polydispersities. A linear correlation is observed between the extent of fluorination and the amount of Selectfluor, indicating that the copolymer of virtually any monomer ratio can be readily accessed by controlling the amount of Selectfluor. This controlled decarboxylative fluorination is extended to poly(methacrylic acid), leading to well-defined poly(2-fluoropropene-co-methacrylic acid) copolymers.Fluorinated alkenes have very poor reactivity in copolymerizations with non-fluorinated polar monomers. Here the authors show silver-catalyzed decarboxylative radical fluorination of poly(acrylic acid) with Selectfluor in water at room temperature to form poly(vinyl fluoride-co-acrylic acid) copolymers. PMID- 28819098 TI - Protection and consolidation of stone heritage by self-inoculation with indigenous carbonatogenic bacterial communities. AB - Enhanced salt weathering resulting from global warming and increasing environmental pollution is endangering the survival of stone monuments and artworks. To mitigate the effects of these deleterious processes, numerous conservation treatments have been applied that, however, show limited efficacy. Here we present a novel, environmentally friendly, bacterial self-inoculation approach for the conservation of stone, based on the isolation of an indigenous community of carbonatogenic bacteria from salt damaged stone, followed by their culture and re-application back onto the same stone. This method results in an effective consolidation and protection due to the formation of an abundant and exceptionally strong hybrid cement consisting of nanostructured bacterial CaCO3 and bacterially derived organics, and the passivating effect of bacterial exopolymeric substances (EPS) covering the substrate. The fact that the isolated and identified bacterial community is common to many stone artworks may enable worldwide application of this novel conservation methodology.Salt weathering enhanced by global warming and environmental pollution is increasingly threatening stone monuments and artworks. Here, the authors present a bacterial self-inoculation approach with indigenous carbonatogenic bacteria and find that this technique consolidates and protects salt damaged stone. PMID- 28819100 TI - Blockage of the lysosome-dependent autophagic pathway contributes to complement membrane attack complex-induced podocyte injury in idiopathic membranous nephropathy. AB - Dysregulation of autophagy-mediated podocyte homeostasis is proposed to play a role in idiopathic membranous nephropathy (IMN). In the present study, autophagic activity and lysosomal alterations were investigated in podocytes of IMN patients and in cultured podocytes exposed to sublytic terminal complement complex, C5b-9. C5b-9 upregulated the number of LC3 positive puncta and the expression of p62 in patient podocytes and in C5b-9 injuried podocyte model. The lysosomal turnover of LC3-II was not influenced, although the BECN1 expression level was upregulated after exposure of podocytes to C5b-9. C5b-9 also caused a significant increase in the number of autophagosomes but not autolysosomes, suggesting that C5b-9 impairs the lysosomal degration of autophagosomes. Moreover, C5b-9 exacerbated the apoptosis of podocytes, which could be mimicked by chloroquine treatment, indicating that C5b-9 triggered podocyte injury, at least partially through inhibiting autophagy. Subsequent studies revealed that C5b-9 triggered lysosomal membrane permeabilization, which likely caused the decrease in enzymatic activity, defective acidification of lysosomes, and suppression of DQ-ovalbumin degradation. Taken together, our results suggest that the lysosomal-dependent autophagic pathway is blocked by C5b-9, which may play a key role in podocyte injury during the development of IMN. PMID- 28819097 TI - The non-coding RNA BC1 regulates experience-dependent structural plasticity and learning. AB - The brain cytoplasmic (BC1) RNA is a non-coding RNA (ncRNA) involved in neuronal translational control. Absence of BC1 is associated with altered glutamatergic transmission and maladaptive behavior. Here, we show that pyramidal neurons in the barrel cortex of BC1 knock out (KO) mice display larger excitatory postsynaptic currents and increased spontaneous activity in vivo. Furthermore, BC1 KO mice have enlarged spine heads and postsynaptic densities and increased synaptic levels of glutamate receptors and PSD-95. Of note, BC1 KO mice show aberrant structural plasticity in response to whisker deprivation, impaired texture novel object recognition and altered social behavior. Thus, our study highlights a role for BC1 RNA in experience-dependent plasticity and learning in the mammalian adult neocortex, and provides insight into the function of brain ncRNAs regulating synaptic transmission, plasticity and behavior, with potential relevance in the context of intellectual disabilities and psychiatric disorders.Brain cytoplasmic (BC1) RNA is a non-coding RNA that has been implicated in translational regulation, seizure, and anxiety. Here, the authors show that in the cortex, BC1 RNA is required for sensory deprivation-induced structural plasticity of dendritic spines, as well as for correct sensory learning and social behaviors. PMID- 28819099 TI - The genetic basis of natural variation in a phoretic behavior. AB - Phoresy is a widespread form of commensalism that facilitates dispersal of one species through an association with a more mobile second species. Dauer larvae of the nematode Caenorhabditis elegans exhibit a phoretic behavior called nictation, which could enable interactions with animals such as isopods or snails. Here, we show that natural C. elegans isolates differ in nictation. We use quantitative behavioral assays and linkage mapping to identify a genetic locus (nict-1) that mediates the phoretic interaction with terrestrial isopods. The nict-1 locus contains a Piwi-interacting small RNA (piRNA) cluster; we observe that the Piwi Argonaute PRG-1 is involved in the regulation of nictation. Additionally, this locus underlies a trade-off between offspring production and dispersal. Variation in the nict-1 locus contributes directly to differences in association between nematodes and terrestrial isopods in a laboratory assay. In summary, the piRNA rich nict-1 locus could define a novel mechanism underlying phoretic interactions.Nematodes use a characteristic set of movements, called nictation, to hitchhike on more mobile animals. Here, Lee et al. identify a genetic locus in the nematode Caenorhabditis elegans that underlies nictation and contributes to successful hitchhiking, but at expense of reduced offspring production. PMID- 28819101 TI - Hypotension in ICU Patients Receiving Vasopressor Therapy. AB - Vasopressor infusion (VPI) is used to treat hypotension in an ICU. We studied compliance with blood pressure (BP) goals during VPI and whether a statistical model might be efficacious for advance warning of impending hypotension, compared with a basic hypotension threshold alert. Retrospective data were obtained from a public database. Studying adult ICU patients receiving VPI at submaximal dosages, we analyzed characteristics of sustained hypotension episodes (>15 min) and then developed a logistic regression model to predict hypotension episodes using input features related to BP trends. The model was then validated with prospective data. In the retrospective dataset, 102-of-215 ICU stays experienced >1 hypotension episode (median of 2.5 episodes per day in this subgroup). When trained with 75% of retrospective dataset, testing with the remaining 25% of the dataset showed that the model and the threshold alert detected 99.6% and 100% of the episodes, respectively, with median advance forecast times (AFT) of 12 and 0 min. In a second, prospective dataset, the model detected 100% of 26 episodes with a median AFT of 22 min. In conclusion, episodes of hypotension were common during VPI in the ICU. A logistic regression model using BP temporal trend features predicted the episodes before their onset. PMID- 28819102 TI - Group association and vocal behaviour during foraging trips in Gentoo penguins. AB - In contrast to their terrestrial call, the offshore call of penguins during their foraging trips has been poorly studied due to the inaccessibility of the foraging site-the open ocean-to researchers. Here, we present the first description of the vocal behaviour of penguins in the open ocean and discuss the function of their vocal communication. We deployed an animal-borne camera on gentoo penguins (Pygoscelis papua) and recorded their foraging behaviour during chick guarding. From the video recordings, we collected 598 offshore calls from 10 individuals in two breeding seasons (2014-2015 and 2015-2016), and we analysed the acoustic characteristics and behavioural contexts of these calls, including diving patterns, group association events, and foraging behaviour. The offshore calls varied in their dominant frequency and length, and penguins produced calls of different lengths in succession. Group associations were observed within one minute following an offshore call in almost half of the instances (43.18%). Penguins undertook dives of shallower depths and shorter durations after producing an offshore call than those before producing an offshore call. Our findings show that penguins may use vocal communication in the ocean related with group association during foraging trips. PMID- 28819103 TI - Mass production of polymer nano-wires filled with metal nano-particles. AB - Despite the ongoing progress in nanotechnology and its applications, the development of strategies for connecting nano-scale systems to micro- or macroscale elements is hampered by the lack of structural components that have both, nano- and macroscale dimensions. The production of nano-scale wires with macroscale length is one of the most interesting challenges here. There are a lot of strategies to fabricate long nanoscopic stripes made of metals, polymers or ceramics but none is suitable for mass production of ordered and dense arrangements of wires at large numbers. In this paper, we report on a technique for producing arrays of ordered, flexible and free-standing polymer nano-wires filled with different types of nano-particles. The process utilizes the strong response of photosensitive polymer brushes to irradiation with UV-interference patterns, resulting in a substantial mass redistribution of the polymer material along with local rupturing of polymer chains. The chains can wind up in wires of nano-scale thickness and a length of up to several centimeters. When dispersing nano-particles within the film, the final arrangement is similar to a core-shell geometry with mainly nano-particles found in the core region and the polymer forming a dielectric jacket. PMID- 28819104 TI - Der f 31, a novel allergen from Dermatophagoides farinae, activates epithelial cells and enhances lung-resident group 2 innate lymphoid cells. AB - Airway epithelial cell-derived thymic stromal lymphopoietin (TSLP) and IL-33 can enhance lung-resident group 2 innate lymphoid cells (ILC2s), and they play an important role in the development of allergic diseases. This study tests the hypothesis that Der f 31 (Dermatophagoides farinae-31), an allergen, modulates airway epithelial cell functions and increases the frequency of lung ILC2s. Our previous research identified cofilin (Der f 31) as a novel allergen. In this study, we found that recombinant Der f 31 (r-Der f 31) upregulated the expression of co-stimulatory molecules in DCs and promoted Th2-skewed polarization. The levels of TSLP and IL-33 in epithelial cells were upregulated by r-Der f 31 via the activation of Toll-like receptor 2. Furthermore, in in vivo studies, r-Der f 31 induced eosinophil-like airway allergy and increased the number of lung resident ILC2s. In summary, Der f 31 can modulate the functions of airway epithelial cells and increase levels of lung-resident ILC2s. PMID- 28819105 TI - A novel method for genome-wide profiling of dynamic host-pathogen interactions using 3' end enriched RNA-seq. AB - Marek's disease is a contagious lymphoproliferative disease of chickens and typical model of viral oncogenesis. Mapping changes or different states over the course of infection for both host and pathogen would provide important insights into dynamic host-pathogen interactions. Here we introduced 3' end enriched RNA seq as a novel method to study host-pathogen interactions in chicken embryo fibroblasts cells challenged with Marek's disease virus. The method allowed accurate profiling of gene expression and alternative polyadenylation sites for host and pathogen simultaneously. We totally identified 476 differentially expressed genes and 437 APA switching genes in host, including switching in tandem 3' UTRs and switching between coding region and 3' UTR. Most of these genes were related to innate immunity, apoptosis and metabolism, but two sets of genes overlapped a little, suggesting two complementary mechanisms in gene regulation during MDV infection. In summary, our results provided a relatively comprehensive insight into dynamic host-pathogen interactions in regulation of gene transcription during infection of Marek's disease virus and suggested that 3' end enriched RNA-seq was a promising method to investigate global host pathogen interactions. PMID- 28819107 TI - Medial prefrontal cortical thinning mediates shifts in other-regarding preferences during adolescence. AB - Adolescence is a time of significant cortical changes in the 'social brain', a set of brain regions involved in sophisticated social inference. However, there is limited evidence linking the structural changes in social brain to development of social behavior. The present study investigated how cortical development of the social brain relates to other-regarding behavior, in the context of fairness concerns. Participants aged between 9 to 23 years old responded to multiple rounds of ultimatum game proposals. The degree to which each participant considers fairness of intention (i.e., intention-based reciprocity) vs. outcome (i.e., egalitarianism) was quantified using economic utility models. We observed a gradual shift in other-regarding preferences from simple rule-based egalitarianism to complex intention-based reciprocity from early childhood to young adulthood. The preference shift was associated with cortical thinning of the dorsomedial prefrontal cortex and posterior temporal cortex. Meta-analytic reverse-inference analysis showed that these regions were involved in social inference. Importantly, the other-regarding preference shift was statistically mediated by cortical thinning in the dorsomedial prefrontal cortex. Together these findings suggest that development of the ability to perform sophisticated other-regarding social inference is associated with the structural changes of specific social brain regions in late adolescence. PMID- 28819106 TI - Identification and Characterization of a Bacterial Homolog of Chloride Intracellular Channel (CLIC) Protein. AB - Chloride intracellular channels (CLIC) are non-classical ion channels lacking a signal sequence for membrane targeting. In eukaryotes, they are implicated in cell volume regulation, acidification, and cell cycle. CLICs resemble the omega class of Glutathione S-transferases (GST), yet differ from them in their ability to form ion channels. They are ubiquitously found in eukaryotes but no prokaryotic homolog has been characterized. We found that indanyloxyacetic acid 94 (IAA-94), a blocker of CLICs, delays the growth of Escherichia coli. In silico analysis showed that the E. coli stringent starvation protein A (SspA) shares sequence and structural homology with CLICs. Similar to CLICs, SspA lacks a signal sequence but contains an omega GST fold. Electrophysiological analysis revealed that SspA auto-inserts into lipid bilayers and forms IAA-94-sensitive ion channels. Substituting the ubiquitously conserved residue leucine 29 to alanine in the pore-forming region increased its single-channel conductance. SspA is essential for cell survival during acid-induced stress, and we found that acidic pH increases the open probability of SspA. Further, IAA-94 delayed the growth of wild-type but not sspA null mutant E. coli. Our results for the first time show that CLIC-like proteins exist in bacteria in the form of SspA, forming functional ion channels. PMID- 28819108 TI - Spag6 Mutant Mice Have Defects in Development and Function of Spiral Ganglion Neurons, Apoptosis, and Higher Sensitivity to Paclitaxel. AB - Mammalian Sperm Associated Antigen 6 (SPAG6) is the orthologue of Chlamydomonas PF16, a protein localized in the axoneme central apparatus. Recent studies showed that Spag6 has a role in brain neuronal proliferation and differentiation. The mammalian spiral ganglion neurons (SGNs) are specialzed bipolar neurons in the inner ear. However, the role of SPAG6 in SGN has not been elucidated. Therefore, We hypothesized that a Spag6 knockout would affect the development and function of SGNs. We utilized Spag6-deficient mice and SGN explants to define the role of SPAG6. On postnatal day 30 (P30) mutant mice had lower SGN density compared to their wild-type littermates, and more apoptosis was evident in the mutants. Increased Bax expression, a disturbed distribution of cytochrome c, and cleaved caspase-3 positive staining indicated that increased apoptosis involved a mitochondrial pathway. Transmission electron microscopy revealed abnormalities in the ultrastructure of mutant SGNs as early as P7. In vitro, lack of SPAG6 affected the growth of neurites and growth cones. Additionally, SPAG6 deficiency decreased synapse density in SGN explants. Finally, Spag6 mutant SGNs were more sensitive to the microtubule stabilizing agent, paclitaxel. These findings suggest that Spag6 plays a crucial role in SGN development and function. PMID- 28819110 TI - Development and assessment of a lysophospholipid-based deep learning model to discriminate geographical origins of white rice. AB - Geographical origin determination of white rice has become the major issue of food industry. However, there is still lack of a high-throughput method for rapidly and reproducibly differentiating the geographical origins of commercial white rice. In this study, we developed a method that employed lipidomics and deep learning to discriminate white rice from Korea to China. A total of 126 white rice of 30 cultivars from different regions were utilized for the method development and validation. By using direct infusion-mass spectrometry-based targeted lipidomics, 17 lysoglycerophospholipids were simultaneously characterized within minutes per sample. Unsupervised data exploration showed a noticeable overlap of white rice between two countries. In addition, lysophosphatidylcholines (lysoPCs) were prominent in white rice from Korea while lysophosphatidylethanolamines (lysoPEs) were enriched in white rice from China. A deep learning prediction model was built using 2014 white rice and validated using two different batches of 2015 white rice. The model accurately discriminated white rice from two countries. Among 10 selected predictors, lysoPC(18:2), lysoPC(14:0), and lysoPE(16:0) were the three most important features. Random forest and gradient boosting machine models also worked well in this circumstance. In conclusion, this study provides an architecture for high throughput classification of white rice from different geographical origins. PMID- 28819109 TI - TLR4-Mediated Placental Pathology and Pregnancy Outcome in Experimental Malaria. AB - Malaria-associate pregnancy has a significant impact on infant morbidity and mortality. The detrimental effects of malaria infection during pregnancy have been shown to correlate with immune activation in the placental tissue. Herein we sought to evaluate the effect of Toll-like receptors (TLRs) activation on placental malaria (PM) development by using the Plasmodium berghei NK65GFP infection model. We observed that activation of the innate immune system by parasites leads to PM due to local inflammation. We identified TLR4 activation as the main pathway involved in the inflammatory process in the placental tissue since the absence of functional TLR4 in mice leads to a decrease in the pro inflammatory responses, which resulted in an improved pregnancy outcome. Additionally, a similar result was obtained when infected pregnant mice were treated with IAXO-101, a TLR4/CD14 blocker. Together, this study illustrates the importance of TLR4 signalling for the generation of the severe inflammatory response involved in PM pathogenesis. Therefore, our results implicate that TLR4 blockage could be a potential candidate for therapeutic interventions to reduce malaria-induced pathology both in the mother and the fetus. PMID- 28819111 TI - Community outbreaks of group A Streptococcus revealed by genome sequencing. AB - The frequent occurrence of disease outbreaks in humans caused by group A Streptococcus (GAS) is an on-going public health threat. Conventional bacterial typing methods lack the discriminatory power to confidently confirm or refute outbreaks in hospital and community settings. Microbial whole genome sequencing (WGS) provides a potential solution to this, but, there has been limited population-based surveillance with accompanying sequence data. We performed retrospective genomic surveillance of 93 clinical GAS isolates from individuals in a defined geographic region. Detailed clinical information was obtained for closely related clusters of isolates. Genomic sequence data was contextualised through comparison with international data. We identified 18 different emm genotypes within our bacterial population, and revealed both highly diverse and closely related isolates. This high level of diversity was maintained even in the context of international sequence data. We also identified two emm1 clusters, and one emm3 cluster, of closely-related isolates that differed only by 1 to 4 single nucleotide polymorphisms. Analysis of clinical information identified no healthcare associated contact between patients, indicating cryptic community transmission. Our findings suggest that genomic surveillance of GAS would increase detection of transmission and highlight opportunities for intervention. PMID- 28819112 TI - Tracing nitrate sources with dual isotopes and long term monitoring of nitrogen species in the Yellow River, China. AB - A heavy load of nitrogenous compounds reflects nutrient loss and influences water quality in large rivers. Nitrogenous concentrations and dual isotopes of nitrate were measured to ascertain the spatial and temporal distributions of nitrate transformation in the Yellow River, the second-longest river in China. Assessment of the long-term record indicates that [NO3--N] has increased by two-fold over the past three decades. Weekly observation of ammonium over a twelve-year period revealed high concentrations and suggests impairment of water quality, particularly since 2011. The estimated total dissolved nitrogen flux was 7.2 times higher in middle reaches than that at head waters. Anthropogenic nitrogen sources become more important in lower section of the upper reaches and middle reaches because of intensive agricultural activities and urban input. Nitrate in the lower reaches was mainly derived from transportation of upstream nitrate and point sources from cities. The spatial variation of ammonium and nitrate isotopes show that nitrification is a key process governing nitrogen transformation. Riverine biological processes could potentially be responsible for the shift of nitrate isotope signature. The first step to reducing nitrogen load and improving water quality will be containment and careful management of sources from urban input, sewage waste and irrigation runoff. PMID- 28819113 TI - Insights into the role of endonuclease V in RNA metabolism in Trypanosoma brucei. AB - Inosine may arise in DNA as a result of oxidative deamination of adenine or misincorporation of deoxyinosine triphosphate during replication. On the other hand, the occurrence of inosine in RNA is considered a normal and essential modification induced by specific adenosine deaminases acting on mRNA and tRNA. In prokaryotes, endonuclease V (EndoV) can recognize and cleave inosine-containing DNA. In contrast, mammalian EndoVs preferentially cleave inosine-containing RNA, suggesting a role in RNA metabolism for the eukaryotic members of this protein family. We have performed a biochemical characterization of EndoV from the protozoan parasite Trypanosoma brucei. In vitro, TbEndoV efficiently processes single-stranded RNA oligonucleotides with inosine, including A to I-edited tRNA like substrates but exhibits weak activity over DNA, except when a ribonucleotide is placed 3' to the inosine. Immunolocalization studies performed in procyclic forms indicate that TbEndoV is mainly cytosolic yet upon nutritional stress it redistributes and accumulates in stress granules colocalizing with the DEAD-box helicase TbDhh1. RNAi-mediated depletion of TbEndoV results in moderate growth defects in procyclic cells while the two EndoV alleles could be readily knocked out in bloodstream forms. Taken together, these observations suggest an important role of TbEndoV in RNA metabolism in procyclic forms of the parasite. PMID- 28819114 TI - Isothermal Amplification of Long, Discrete DNA Fragments Facilitated by Single Stranded Binding Protein. AB - Isothermal amplification methods for detection of DNA and RNA targets have expanded significantly in recent years, promising a new wave of simple and rapid molecular diagnostics. Current isothermal methods result in the generation of short fragments (<150 base pairs) or highly branched long DNA products. Here we report the amplification of discrete target fragments of several kilobases at 37 degrees C from both double- and single-stranded circular template DNA using specific primer pairs. In contrast to existing methods, this amplification requires only the single-stranded DNA-binding protein gp32 from bacteriophage T4 and a strand-displacing DNA polymerase. In addition to the discrete amplicon products, this method also produces higher molecular weight products consisting of multiple repeated copies of the amplicon and template DNA. We demonstrate that two features of gp32 enable this amplification: a facilitation of primer strand invasion into double-stranded DNA, and a suppression of non-homologous primer annealing and nonspecific amplification. The ability presented here to produce long, discrete DNA products in an isothermal reaction extends the scope of isothermal amplification to enable more useful applications of these promising methods. PMID- 28819115 TI - Genome-wide identification and expression profiling of long non-coding RNAs in auditory and vestibular systems. AB - Mammalian genomes encode multiple layers of regulation, including a class of RNA molecules known as long non-coding RNAs (lncRNAs). These are >200 nucleotides in length and similar to mRNAs, they are capped, polyadenylated, and spliced. In contrast to mRNAs, lncRNAs are less abundant and have higher tissue specificity, and have been linked to development, epigenetic processes, and disease. However, little is known about lncRNA function in the auditory and vestibular systems, or how they play a role in deafness and vestibular dysfunction. To help address this need, we performed a whole-genome identification of lncRNAs using RNA-seq at two developmental stages of the mouse inner ear sensory epithelium of the cochlea and vestibule. We identified 3,239 lncRNA genes, most of which were intergenic (lincRNAs) and 721 are novel. We examined temporal and tissue specificity by analyzing the developmental profiles on embryonic day 16.5 and at birth. The spatial and temporal patterns of three lncRNAs, two of which are in proximity to genes associated with hearing and deafness, were explored further. Our findings indicate that lncRNAs are prevalent in the sensory epithelium of the mouse inner ear and are likely to play key roles in regulating critical pathways for hearing and balance. PMID- 28819116 TI - Silencing of TGF-beta1 in tumor cells impacts MMP-9 in tumor microenvironment. AB - Transforming growth factor (TGF)-beta1 contributes to autocrine and paracrine functions in the tumor microenvironment (TME). The present study examined the effects of TGF-beta1 crosstalk in TME and its role in mediating tumor formation and progression by targeted abrogation of TGF-beta1 expression in metastatic cells in situ. Using species-specific primers, we found a significant increase in MMP-9 gene expression in the tumor-reactive stroma during late-stage metastasis in the lung. This effect was also confirmed in cancer-associated fibroblasts (CAFs) when co-cultured with the tumor cells. Knockdown of TGF-beta1 expression in the tumor cells negatively affected matrix metalloproteinase (MMP)-9 gene expression. Fibroblasts, cultured in the presence of tumor cells with intact TGF beta1, showed a significant increase in proliferation rate, as well as expression of VEGF, bFGF, and SDF-1, which was not seen when TGF-beta1 expression was abrogated in tumor cells. Absence of TGF-beta1 in tumor cells also failed to result in myofibroblast differentiation. Co-implantation of CAFs and tumor cells with either intact TGF-beta1 expression or devoid of TGF-beta1 in vivo showed a significant increase in tumor growth kinetics in both cell types, suggesting a possible activation TGF-beta receptor signaling in tumor cells in response to TGF beta from the TME. PMID- 28819117 TI - Neuronal Encoding of Self and Others' Head Rotation in the Macaque Dorsal Prefrontal Cortex. AB - Following gaze is a crucial skill, in primates, for understanding where and at what others are looking, and often requires head rotation. The neural basis underlying head rotation are deemed to overlap with the parieto-frontal attention/gaze-shift network. Here, we show that a set of neurons in monkey's Brodmann area 9/46dr (BA 9/46dr), which is involved in orienting processes and joint attention, becomes active during self head rotation and that the activity of these neurons cannot be accounted for by saccade-related activity (head rotation neurons). Another set of BA 9/46dr neurons encodes head rotation performed by an observed agent facing the monkey (visually triggered neurons). Among these latter neurons, almost half exhibit the intriguing property of encoding both execution and observation of head rotation (mirror-like neurons). Finally, by means of neuronal tracing techniques, we showed that BA 9/46dr takes part into two distinct networks: a dorso/mesial network, playing a role in spatial head/gaze orientation, and a ventrolateral network, likely involved in processing social stimuli and mirroring others' head. The overall results of this study provide a new, comprehensive picture of the role of BA 9/46dr in encoding self and others' head rotation, likely playing a role in head-following behaviors. PMID- 28819118 TI - Exploring the Sorption Mechanism of Ni(II) on Illite: Batch Sorption, Modelling, EXAFS and Extraction Investigations. AB - The sorption mechanism of nickel (Ni) at the illite/water interface was investigated using batch, sorption modelling, extended X-ray absorption fine structure (EXAFS), and extraction approaches. The results showed that Ni(II) sorption on illite was strongly dependent on pH, contact time, temperature, and initial Ni(II) concentration. At a low initial Ni(II) concentration, the ion exchange species of =X2Ni degrees and the inner-sphere complexes including =SsONi+, =SwONi+ and =SwONiOH degrees species are observed on the sorption edges of Ni(II) on illite. As the initial Ni(II) concentration increased to 1.7 * 10-3 mol/L, precipitates including surface-induced precipitation of s-Ni(OH)2 and amorphous Ni(OH)2 became more significant, especially under neutral to alkaline conditions. EXAFS analysis confirmed that Ni-Al layered double hydroxide (LDH) can gradually form with an increase in the contact time. At pH 7.0, alpha-Ni(OH)2 was produced in the initial stage and then transformed to the more stable form of Ni-Al LDH with increasing contact time because of the increased Al3+ dissolution. With an increase in temperatures, alpha-Ni(OH)2 phase on illite transformed to Ni Al LDH phase, indicating a lower thermodynamic stability compared to Ni-Al LDH phase. These results are important to understand the geochemical behaviors to effectively remediate soil contaminated with Ni(II). PMID- 28819119 TI - The Synergistic Effects of the Micro and Nano Particles in Micro-nano Composites on Enhancing the Resistance to Electrical Tree Degradation. AB - A new method of increasing the durability and reliability of polymer dielectrics has been proposed by designing a composite structure of the micro and nano particles. The synergistic effects of the micro particles and nano particles are found to enhance the resistance to electrical tree and extend the lifetime of polymer dielectrics for insulations. Epoxy loaded with the micro and nano SiO2 particles at different concentrations are prepared as micro-nano composites. The micro particles show the blocking effects on the electrical tree channel and the interfaces of the nano particles lead to the inhibiting effects on the tree inception and propagation. The lifetime of the micro-nano composite samples in the experiments extends to 4 times of the neat epoxy. The new type of micro-nano composites can be widely applied in future electronic and electrical energy areas. PMID- 28819120 TI - Dual-delivery of FGF-2/CTGF from Silk Fibroin/PLCL-PEO Coaxial Fibers Enhances MSC Proliferation and Fibrogenesis. AB - The success of mesenchymal stem cell transplantation is highly dependent on their survival and controlled fate regulation. This study demonstrates that dual delivery of connective tissue growth factor (CTGF) and fibroblast growth factor 2 (FGF-2) from a core-shell fiber of Silk Fibroin/poly(L-lactic acid-co-epsilon caprolactone)-polyethylene oxide (SF/PLCL-PEO) enhanced fibrogenic lineage differentiation of MSCs. The core-shell structure was confirmed by transmission electron microscopy (TEM), fluorescence microscopy and attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopy. A sequential release of FGF-2 and CTGF was successfully achieved in this manner. FGF-2 plays an important role in stem cell proliferation and, meanwhile when accompanied with CTGF, has a slightly additive effect on fibrogenic differentiation of MSCs, whereas CTGF promotes fibrogenesis and alleviates osteogenesis, chondrogenesis and adipogenesis. PMID- 28819121 TI - Mucus organisation is shaped by colonic content; a new view. AB - The colonic mucus barrier is commonly described as a continuous double layer covering the epithelium, separating the microbiota from the intestinal tissue. This model is currently considered valid throughout the colon. The colon is characterised by regional anatomo-functional specificities such as presence and consistency of contents and location. In this study, we characterised the organisation of the colonic mucus barrier in proximal and distal colon of rodents by histological and FISH staining, taking into account aforementioned specificities. By using longitudinal sections and imaging extensive areas of tissue with and without colonic contents, we have obtained a spatiotemporal overview of mucus organisation in the colon. We describe for the first time that the colonic mucus layer covers the faeces instead of the epithelium in the distal colon. This faecal mucus layer confines the microbiota to the faeces and prevents it from remaining in empty distal colon. In the proximal colon, the mucus did not form a separating layer between bacteria and epithelium. We conclude that the organisation of colonic mucus is reliant on the presence of the colonic content, and the location within the colon. Our findings reopen the discussion on the nature of the colonic mucus barrier. PMID- 28819122 TI - Anti-inflammatory drugs suppress ultrasound-mediated mesenchymal stromal cell tropism to kidneys. AB - Mesenchymal stromal cells (MSC) are potential renal therapeutics. Clinically, results are mixed partly because MSC tropism to kidneys is minimal following infusion. Ultrasound augmentation of the renal microenvironment is becoming increasingly-important in renal MSC therapies. We demonstrated pulsed-focused ultrasound (pFUS) increases enhanced homing permeability and retention of MSC in mouse kidneys. Here, we characterized the temporal proteomic response to pFUS in mouse kidneys and its association with MSC tropism. pFUS induced molecular cascades of initial increases in tumor necrosis factor-alpha (TNFalpha) and interleukin (IL)-1alpha, that activated nuclear factor kappa-light-chain-enhancer of activated B cells (NFkappaB) and cyclooxygenase-2 (COX2) pathways without cell death. This was followed by a 24-48 hour-long response of increased cell adhesion molecules (CAM), trophic and anti-inflammatory factors. Pretreating animals with anti-inflammatory drugs etanercept (TNFalpha inhibitor), anakinra (IL-1 receptor antagonist), prednisone (NFkappaB translocation inhibitor), or ibuprofen (COX inhibitor) suppressed molecular changes and inhibited renal MSC tropism. We further examined the role of COX2 using a COX2-knock-out mouse where pFUS was unable to increase MSC tropism. These results demonstrate that renal micro environmental changes induce MSC tropism and could influence the therapeutic efficacy of MSC. Optimizing the microenvironment and understanding drug effects will enable improvements in MSC therapies for renal disease. PMID- 28819123 TI - Active prosthesis dependent functional cortical reorganization following stroke. AB - The present study investigated the neural correlates associated with gait improvements triggered by an active prosthesis in patients with drop-foot following stroke during the chronic stage. Eleven patients took part in the study. MEG recordings in conjunction with somatosensory stimulation of the left and right hand as well as gait analyses were performed shortly before or after prosthesis implantation surgery and 3-4 months later. Plastic changes of the sensorimotor cortex of the ipsi- and contralesional hemisphere were revealed. Gait analysis indicated that all patients improved their gait with the active prosthesis. Patients with larger plastic changes within the lesioned hemisphere maintained their improved gait performance even when the prosthesis was turned off. Patients with larger contralesional changes also improved their gait with the active prosthesis. However, their gait measures decreased when the prosthesis was turned off. The current data provide the neural basis of gait improvement triggered by an active prosthesis and has important implications with respect to the choice of the type of active prosthesis (implantable vs removable) and to the selection procedure of the patients (length of testing period). PMID- 28819124 TI - Long-term (2001-2013) observations of water-soluble dicarboxylic acids and related compounds over the western North Pacific: trends, seasonality and source apportionment. AB - To better understand the impact of East Asian pollutants on the molecular composition of marine organic aerosols, we conducted long-term (2001-2013) observations of water-soluble dicarboxylic acids and related compounds in total suspended particulate samples collected at Chichijima Island in the western North Pacific (WNP). Seasonal variations of all the diacids and related compounds showed maxima in winter and spring and minima in summer, except for azelaic acid (C9), which maximized in summer to autumn. The overall annual concentrations of the total diacids, omega-oxoacids and alpha-dicarbonyls showed an increase during 2001-2013. We found a significant (p < 0.05) decadal increase in the inter-annual trends of pyruvic and glyoxylic (p > 0.05) acids, and methylglyoxal (MeGly). In contrast, phthalic acid (p < 0.05) and glyoxal (Gly) showed a decrease in their trends. We also found a significant decrease in the trend of the Gly/MeGly mass ratios. These results demonstrate that the enhanced concentrations of diacids over the WNP are majorly attributed to the aqueous-phase photooxidation of biogenic volatile organic compounds from East Asia followed by long-range atmospheric transport. Further, positive matrix factorization analysis showed a biogenic photochemical contribution (42%) was the dominant source of oxalic acid in the WNP. PMID- 28819125 TI - Inflammation and bone mineral density: A Mendelian randomization study. AB - Osteoporosis is a common age-related disorder leading to an increase in osteoporotic fractures and resulting in significant suffering and disability. Inflammation may contribute to osteoporosis, as it does to many other chronic diseases. We examined whether inflammation is etiologically relevant to osteoporosis, assessed from bone mineral density (BMD), as a new potential target of intervention, or whether it is a symptom/biomarker of osteoporosis. We obtained genetic predictors of inflammatory markers from genome-wide association studies and applied them to a large genome wide association study of BMD. Using two-sample Mendelian randomization, we obtained unconfounded estimates of the effect of high-sensitivity C-reactive protein (hsCRP) on BMD at the forearm, femoral neck, an d lumbar spine. After removing potentially pleiotropic single nucleotide polymorphisms (SNPs) possibly acting via obesity-related traits, hsCRP, based on 16 SNPs from genes including CRP, was not associated with BMD. A causal relation of hsCRP with lower BMD was not evident in this study. PMID- 28819126 TI - Targeted blockade of TGF-beta and IL-6/JAK2/STAT3 pathways inhibits lung cancer growth promoted by bone marrow-derived myofibroblasts. AB - To investigate the role of TGF-beta and IL-6 in myofibroblasts (MFs) - lung cancer cell interactions, lung cancer cells (Lewis and CTM-167 cell lines) were stimulated by IL-6, MF-conditioned medium (MF-CM) or MFs, with or without TGF beta signaling inhibitor - SB431542 and/or JAK2/STAT3 inhibitor - JSI-124. MFs were stimulated by TGF-beta, cancer cell-CM or cancer cells, with or without SB431542 and JSI-124. Cell proliferation, the levels of cytokines, expression of mRNA and protein were determined. Mice bearing xenograft tumors were intraperitoneally treated with SB431542 or JSI-124 and monitored for up to 45 days. In co-culture systems, MFs secreted high levels of IL-6, while cancer cells produced high levels of TGF-beta. Recombinant IL-6 and MF-CM activated STAT3 and upregulated TGF-beta in cancer cells. In contrast, cancer cell-CM or TGF-beta stimulated MFs to produce IL-6. Blockade of JAK2/STAT3 and TGF-beta signaling by specific inhibitors significantly inhibited cell proliferation in vitro and tumor growth in vivo of lung cancer cells. Our study demontrated that the TGF-beta and IL-6/JAK2/STAT3 signaling pathways form a positive feedback signaling loop that mediated the interactions between MFs and lung cancer cells. Targeted inhibiton of this signaling loop could be a new approach for lung cancer prevention and therapy. PMID- 28819127 TI - Multiple E3s promote the degradation of histone H3 variant Cse4. AB - The histone H3-like protein Cse4/CENP-A acts as a key molecular marker that differentiates the special centromeric chromatin structures from bulk nucleosomes. As altered Cse4/CENP-A activity leads to genome instability, it is pivotal to understand the mechanism underlying Cse4 regulation. Here, we demonstrate that four ubiquitin ligases (i.e., Ubr1, Slx5, Psh1, and Rcy1) work in parallel to promote Cse4 turnover in yeast. Interestingly, Cse4 overexpression leads to cellular toxicity and cell cycle delay in yeast cells lacking PSH1, but not in cells lacking UBR1, suggesting different roles of these two degradation pathways. Our findings suggest that various ubiquitin ligases collaborate to keep the Cse4 level in check, providing a basis for further delineating the intricate network involved in Cse4 regulation. PMID- 28819128 TI - Porous Polystyrene Monoliths and Microparticles Prepared from Core Cross-linked Star (CCS) Polymers-Stabilized Emulsions. AB - A hydrophobic CCS polymer of poly(benzyl methacrylate) (PBzMA) was prepared in toluene by reversible addition-fragmentation chain transfer (RAFT)-mediated dispersion polymerization. The CCS polymer, with poly(benzyl methacrylate) as the arm and crosslinked N, N'-bis(acryloyl)cystamine (BAC) as the core, was confirmed by characterization with gel permeation chromatography (GPC) and nuclear magnetic resonance (NMR) spectroscopy. Three kinds of oils (toluene, anisole and styrene) were chosen to study the emulsification properties of PBzMA CCS polymer. The oils can be emulsified by CCS polymer to form water-in-oil (w/o) emulsions. Moreover, w/o high internal phase emulsions (HIPEs) can be obtained with the increase of toluene and styrene volume fractions from 75% to 80%. Porous polystyrene monolith and microparticles were prepared from the emulsion templates and characterized by the scanning electronic microscopy (SEM). With the internal phase volume fraction increased, open-pore porous monolith was obtained. PMID- 28819129 TI - Dielectric properties of Y and Nb co-doped TiO2 ceramics. AB - In this work, the (Y0.5Nb0.5)xTi1-xO2 (x = 0.001, 0.01, 0.02, 0.04, 0.06 and 0.1) ceramics (as called YNTO) were fabricated by synthesized through a standard solid state reaction. As revealed by the X-ray diffraction (XRD) spectra, the YNTOs exhibit tetragonal rutile structure. Meanwhile, the grain size of YNTO ceramics increased and then decreased with the increase of x value, and the largest value reached when x = 0.02. All the YNTO samples display colossal permittivity (~102 105) over a wide temperature and frequency range. Moreover, the optimal ceramic, (Y0.5Nb0.5)0.02Ti0.98O2, exhibits high performance over a broad temperature range from 20 degrees C to 180 degrees C; specifically, at 1 kHz, the dielectric constant and dielectric loss are 6.55 * 104 and 0.22 at room temperature, and they are 1.03 * 105 and 0.11 at 180 degrees C, respectively. PMID- 28819130 TI - A multielectrode array microchannel platform reveals both transient and slow changes in axonal conduction velocity. AB - Due to their small dimensions, electrophysiology on thin and intricate axonal branches in support of understanding their role in normal and diseased brain function poses experimental challenges. To reduce experimental complexity, we coupled microelectrode arrays (MEAs) to bi-level microchannel devices for the long-term in vitro tracking of axonal morphology and activity with high spatiotemporal resolution. Our model allowed the long-term multisite recording from pure axonal branches in a microscopy-compatible environment. Compartmentalizing the network structure into interconnected subpopulations simplified access to the locations of interest. Electrophysiological data over 95 days in vitro (DIV) showed an age-dependent increase of axonal conduction velocity, which was positively correlated with, but independent of evolving burst activity over time. Conduction velocity remained constant at chemically increased network activity levels. In contrast, low frequency (1 Hz, 180 repetitions) electrical stimulation of axons or network subpopulations evoked amplitude dependent direct (5-35 ms peri-stimulus) and polysynaptic (35-1,000 ms peri stimulus) activity with temporarily (<35 ms) elevated propagation velocities along the perisomatic branches. Furthermore, effective stimulation amplitudes were found to be significantly lower (>250 mV) in microchannels when compared with those reported for unconfined cultures (>800 mV). The experimental paradigm may lead to new insights into stimulation-induced axonal plasticity. PMID- 28819131 TI - Impulsiveness does not prevent cooperation from emerging but reduces its occurrence: an experiment with zebra finches. AB - Reciprocal altruism, the most probable mechanism for cooperation among unrelated individuals, can be modelled as a Prisoner's Dilemma. This game predicts that cooperation should evolve whenever the players, who expect to interact repeatedly, make choices contingent to their partner's behaviour. Experimental evidence, however, indicates that reciprocity is rare among animals. One reason for this would be that animals are very impulsive compared to humans. Several studies have reported that temporal discounting (that is, strong preferences for immediate benefits) has indeed a negative impact on the occurrence of cooperation. Yet, the role of impulsive action, another facet of impulsiveness, remains unexplored. Here, we conducted a laboratory experiment in which male and female zebra finches (Taenyopigia guttata) were paired assortatively with respect to their level of impulsive action and then played an alternating Prisoner's Dilemma. As anticipated, we found that self-controlled pairs achieved high levels of cooperation by using a Generous Tit-for-Tat strategy, while impulsive birds that cooperated at a lower level, chose to cooperate with a fixed probability. If the inability of impulsive individuals to use reactive strategies are due to their reduced working memory capacity, thus our findings might contribute to explaining interspecific differences in cooperative behaviour. PMID- 28819132 TI - Treatment Associated Changes of Functional Connectivity of Midbrain/Brainstem Nuclei in Major Depressive Disorder. AB - Previous functional magnetic resonance imaging (fMRI) studies demonstrated an abnormally coordinated network functioning in Major Depression Disorder (MDD) during rest. The main monoamine-producing nuclei within midbrain/brainstem are functionally integrated within these specific networks. Therefore, we aimed to investigate the resting-state functional connectivity (RSFC) of these nuclei in 45 MDD patients and differences between patients receiving two different classes of antidepressant drugs. Patients showed reduced RSFC from the ventral tegmental area (VTA) to dorsal anterior cingulate cortex (dACC) and stronger RSFC to the left amygdala and dorsolateral prefrontal cortex (DLPFC). Patients treated with antidepressants influencing noradrenergic and serotonergic neurotransmission showed different RSFC from locus coeruleus to DLPFC compared to patients treated with antidepressants influencing serotonergic neurotransmission only. In the opposite contrast patients showed stronger RSFC from dorsal raphe to posterior brain regions. Enhanced VTA-RSFC to amygdala as a central region of the salience network may indicate an over-attribution of the affective salience to internally oriented processes. Significant correlation between decreased VTA-dACC functional connectivity and the BDI-II somatic symptoms indicates an association with diminished volition and behavioral activation in MDD. The observed differences in the FC of the midbrain/brainstem nuclei between two classes of antidepressants suggest differential neural effects of SSRIs and SNRIs. PMID- 28819133 TI - Combined transcriptome and metabolome analyses of metformin effects reveal novel links between metabolic networks in steroidogenic systems. AB - Metformin is an antidiabetic drug, which inhibits mitochondrial respiratory-chain complex I and thereby seems to affect the cellular metabolism in many ways. It is also used for the treatment of the polycystic ovary syndrome (PCOS), the most common endocrine disorder in women. In addition, metformin possesses antineoplastic properties. Although metformin promotes insulin-sensitivity and ameliorates reproductive abnormalities in PCOS, its exact mechanisms of action remain elusive. Therefore, we studied the transcriptome and the metabolome of metformin in human adrenal H295R cells. Microarray analysis revealed changes in 693 genes after metformin treatment. Using high resolution magic angle spinning nuclear magnetic resonance spectroscopy (HR-MAS-NMR), we determined 38 intracellular metabolites. With bioinformatic tools we created an integrated pathway analysis to understand different intracellular processes targeted by metformin. Combined metabolomics and transcriptomics data analysis showed that metformin affects a broad range of cellular processes centered on the mitochondrium. Data confirmed several known effects of metformin on glucose and androgen metabolism, which had been identified in clinical and basic studies previously. But more importantly, novel links between the energy metabolism, sex steroid biosynthesis, the cell cycle and the immune system were identified. These omics studies shed light on a complex interplay between metabolic pathways in steroidogenic systems. PMID- 28819134 TI - Long Term Glaucoma Drug Delivery Using a Topically Retained Gel/Microsphere Eye Drop. AB - The purpose of this study was to characterize and determine the efficacy of a long-term, non-invasive gel/microsphere (GMS) eye drop for glaucoma. This novel drug delivery system is comprised of a thermoresponsive hydrogel carrier and drug loaded polymer microspheres. In vitro release of brimonidine from the GMS drops and gel properties were quantified. A single brimonidine-loaded GMS drop was administered to 5 normotensive rabbits and intraocular pressure (IOP) was monitored for 28 days. Here we report that IOP reduction in rabbits receiving a single brimonidine GMS drop was comparable to that of rabbits receiving twice daily, standard brimonidine drops. GMS drops were retained in the inferior fornix in all animals for the length of the study. Our results suggest in vivo efficacy over 28 days from a single GMS drop and a potential decrease in systemic absorption, based on a lack of substantial IOP effects on the fellow untreated eye, compared to brimonidine twice-daily eye drops. To our knowledge, this represents the first long-term, drug-releasing depot that can be administered as a traditional eye drop. PMID- 28819136 TI - The possible molecular mechanisms of bisphenol A action on porcine early embryonic development. AB - Bisphenol A (BPA) is an environmental contaminant widely used in the plastic industry. BPA has been demonstrated to be an endocrine disruptor and has an adverse effect on the embryonic development of mammals. However, the mechanism of action of BPA is limited. In this study, we investigated the role and mechanism of BPA in porcine embryonic development. First, the parthenotes were treated with different concentrations of BPA. We found that blastocyst formation was impaired and the parthenotes were arrested at the 4-cell stage after treatment with 100 MUm BPA. Second, ROS increased following the addition of BPA, which further caused mitochondrial damage, and cytochrome c was released from the mitochondria to induce apoptosis. The adaptive response was demonstrated through LC3 immunofluorescence staining and by assessing autophagy-related gene expression. In addition, BPA caused DNA damage through the p53-p21 signaling pathway. Thus, our results indicate that BPA displays an adverse effect on porcine early embryonic development through mitochondrial and DNA damage. PMID- 28819135 TI - Ribosomal transcription is regulated by PGC-1alpha and disturbed in Huntington's disease. AB - PGC-1alpha is a versatile inducer of mitochondrial biogenesis and responsive to the changing energy demands of the cell. As mitochondrial ATP production requires proteins that derive from translation products of cytosolic ribosomes, we asked whether PGC-1alpha directly takes part in ribosomal biogenesis. Here, we show that a fraction of cellular PGC-1alpha localizes to the nucleolus, the site of ribosomal transcription by RNA polymerase I. Upon activation PGC-1alpha associates with the ribosomal DNA and boosts recruitment of RNA polymerase I and UBF to the rDNA promoter. This induces RNA polymerase I transcription under different stress conditions in cell culture and mouse models as well as in healthy humans and is impaired already in early stages of human Huntington's disease. This novel molecular link between ribosomal and mitochondrial biogenesis helps to explain sarcopenia and cachexia in diseases of neurodegenerative origin. PMID- 28819137 TI - Precise stacking of decellularized extracellular matrix based 3D cell-laden constructs by a 3D cell printing system equipped with heating modules. AB - Three-dimensional (3D) cell printing systems allow the controlled and precise deposition of multiple cells in 3D constructs. Hydrogel materials have been used extensively as printable bioinks owing to their ability to safely encapsulate living cells. However, hydrogel-based bioinks have drawbacks for cell printing, e.g. inappropriate crosslinking and liquid-like rheological properties, which hinder precise 3D shaping. Therefore, in this study, we investigated the influence of various factors (e.g. bioink concentration, viscosity, and extent of crosslinking) on cell printing and established a new 3D cell printing system equipped with heating modules for the precise stacking of decellularized extracellular matrix (dECM)-based 3D cell-laden constructs. Because the pH adjusted bioink isolated from native tissue is safely gelled at 37 degrees C, our heating system facilitated the precise stacking of dECM bioinks by enabling simultaneous gelation during printing. We observed greater printability compared with that of a non-heating system. These results were confirmed by mechanical testing and 3D construct stacking analyses. We also confirmed that our heating system did not elicit negative effects, such as cell death, in the printed cells. Conclusively, these results hold promise for the application of 3D bioprinting to tissue engineering and drug development. PMID- 28819138 TI - Cooperative interaction of BMP signalling and Foxn1 gene dosage determines the size of the functionally active thymic epithelial compartment. AB - Thymopoiesis strictly depends on the function of the Foxn1 transcription factor that is expressed in the thymic epithelium. During embryonic development, initial expression of the Foxn1 gene is induced in the pharyngeal endoderm by mesenchyme derived BMP4 signals. Here, by engineering a time-delayed feedback system of BMP inhibition in mouse embryos, we demonstrate that thymopoiesis irreversibly fails if Foxn1 gene expression does not occur during a defining time span in mid gestation. We also reveal an epistatic interaction between the extent of BMP signalling and the gene dosage of Foxn1. Our findings illustrate the complexities of the early steps of thymopoiesis and indicate that sporadic forms of thymic hypoplasia in humans may result from the interaction of genes affecting the magnitude of BMP signalling and Foxn1 expression. PMID- 28819140 TI - Enhancement of Perivascular Spaces in 7 T MR Image using Haar Transform of Non local Cubes and Block-matching Filtering. AB - Perivascular spaces (PVSs) in brain have a close relationship with typical neurological diseases. The quantitative studies of PVSs are meaningful but usually difficult, due to their thin and weak signals and also background noise in the 7 T brain magnetic resonance images (MRI). To clearly distinguish the PVSs in the 7 T MRI, we propose a novel PVS enhancement method based on the Haar transform of non-local cubes. Specifically, we extract a certain number of cubes from a small neighbor to form a cube group, and then perform Haar transform on each cube group. The Haar transform coefficients are processed using a nonlinear function to amplify the weak signals relevant to the PVSs and to suppress the noise. The enhanced image is reconstructed using the inverse Haar transform of the processed coefficients. Finally, we perform a block-matching 4D filtering on the enhanced image to further remove any remaining noise, and thus obtain an enhanced and denoised 7 T MRI for PVS segmentation. We apply two existing methods to complete PVS segmentation, i.e., (1) vesselness-thresholding and (2) random forest classification. The experimental results show that the PVS segmentation performances can be significantly improved by using the enhanced and denoised 7 T MRI. PMID- 28819139 TI - Landscape of submitochondrial protein distribution. AB - The mitochondrial proteome comprises ~1000 (yeast)-1500 (human) different proteins, which are distributed into four different subcompartments. The sublocalization of these proteins within the organelle in most cases remains poorly defined. Here we describe an integrated approach combining stable isotope labeling, various protein enrichment and extraction strategies and quantitative mass spectrometry to produce a quantitative map of submitochondrial protein distribution in S. cerevisiae. This quantitative landscape enables a proteome wide classification of 986 proteins into soluble, peripheral, and integral mitochondrial membrane proteins, and the assignment of 818 proteins into the four subcompartments: outer membrane, inner membrane, intermembrane space, or matrix. We also identified 206 proteins that were not previously annotated as localized to mitochondria. Furthermore, the protease Prd1, misannotated as intermembrane space protein, could be re-assigned and characterized as a presequence peptide degrading enzyme in the matrix.Protein localization plays an important role in the regulation of cellular physiology. Here the authors use an integrated proteomics approach to localize proteins to the mitochondria and provide a detailed map of their specific localization within the organelle. PMID- 28819141 TI - Constructing the novel ultrafine amorphous iron oxyhydroxide/g-C3N4 nanosheets heterojunctions for highly improved photocatalytic performance. AB - Ultrafine particles, more heterojunction interfaces and amorphous materials can effectively enhance the photocatalytic activity of photocatalysts. In this work, a facile in-situ precipitation method was developed to prepare ultrafine amorphous iron oxyhydroxide/ultrathin g-C3N4 nanosheets heterojunction composites. The amorphous iron oxyhydroxide possessed an ultrafine particle size and a wide range of visible light absorption. In this process, the ultrafine particles not only shortened the diffusion distance of photogenerated carriers, but also facilitated the formation of more heterojunctions with ultrathin g-C3N4 nanosheets. The photocatalytic activities were evaluated using rhodamine B, methylene blue, and methyl orange as pollution models under visible light irradiation. Notably, the optimal photocatalytic activity of a-FeOOH/CNNS-800 composite is ~17.8 times higher than that of CNNS towards the degradation of rhodamine B under visible light. The outstanding photocatalytic activities were ascribed to the narrower band gap, the enhanced visible light absorbance, abundant heterojunction interfaces, and the effective separation of the photogenerated charges driven by the matched band edge in the heterostructures. We trusted that the facile and easy-to-extend synthesis method can be further expanded to synthesize other ultrafine semiconductors coupled with g-C3N4 for enhancing the photocatalytic activities. PMID- 28819142 TI - Development and inter-laboratory assessment of droplet digital PCR assays for multiplex quantification of 15 genetically modified soybean lines. AB - Quantification of genetically modified organisms (GMOs) in food and feed products is often required for their labelling or for tolerance thresholds. Standard-curve based simplex quantitative polymerase chain reaction (qPCR) is the prevailing technology, which is often combined with screening analysis. With the rapidly growing number of GMOs on the world market, qPCR analysis becomes laborious and expensive. Innovative cost-effective approaches are therefore urgently needed. Here, we report the development and inter-laboratory assessment of multiplex assays to quantify GMO soybean using droplet digital PCR (ddPCR). The assays were developed to facilitate testing of foods and feed for compliance with current GMO regulations in the European Union (EU). Within the EU, the threshold for labelling is 0.9% for authorised GMOs per ingredient. Furthermore, the EU has set a technical zero tolerance limit of 0.1% for certain unauthorised GMOs. The novel multiplex ddPCR assays developed target 11 GMO soybean lines that are currently authorised, and four that are tolerated, pending authorisation in the EU. Potential significant improvements in cost efficiency are demonstrated. Performance was assessed for the critical parameters, including limits of detection and quantification, and trueness, repeatability, and robustness. Inter laboratory performance was also determined on a number of proficiency programme and real-life samples. PMID- 28819143 TI - Immunomodulatory and antioxidant effects of total flavonoids of Spatholobus suberectus Dunn on PCV2 infected mice. AB - Oxidative stress plays an important role in the pathogenesis of virus infection and antioxidants are becoming promising candidates as therapeutic agents. This study is designed to investigate the effect of total flavonoids of Spatholobus suberectus Dunn (TFSD) on oxidative stress in mice induced by porcine circovirus type 2 (PCV2) infection. The PCV2 infection leads to significant decrease in thymus and spleen indices, elevation of xanthine oxidase (XOD) and myeloperoxidase (MPO) activities, reduction in GSH level and GSH to GSSG ratio and decline of superoxide dismutase (SOD) activity, indicating the formation of immunosuppression and oxidative stress. TFSD treatment recovered the alteration of viscera index, antioxidant content and activities of oxidative-associated enzymes to a level similar to control. Our findings suggested that PCV2 induced immunosuppression and oxidative stress in mice and TFSD might be able to protect animals from virus infection via regulation of immune function and inhibition of oxidative stress. PMID- 28819144 TI - Predicting hair cortisol levels with hair pigmentation genes: a possible hair pigmentation bias. AB - Cortisol concentrations in hair are used to create hormone profiles spanning months. This method allows assessment of chronic cortisol exposure, but might be biased by hair pigmentation: dark hair was previously related to higher concentrations. It is unclear whether this association arises from local effects, such as increased hormone extractability, or whether the association represents systemic differences arising from population stratification. We tested the hypothesis that hair pigmentation gene variants are associated with varying cortisol levels independent of genetic ancestry. Hormone concentrations and genotype were measured in 1674 children from the Generation R cohort at age 6. We computed a polygenic score of hair color based on 9 single nucleotide polymorphisms. This score was used to predict hair cortisol concentrations, adjusted for genetic ancestry, sex, age and corticosteroid use. A 1-standard deviation (SD) higher polygenic score (darker hair) was associated with 0.08 SD higher cortisol levels (SE = 0.03, p = 0.002). This suggests that variation in hair cortisol concentrations is partly explained by local hair effects. In multi ancestry studies this hair pigmentation bias can reduce power and confound results. Researchers should therefore consider adjusting analyses by reported hair color, by polygenic scores, or by both. PMID- 28819145 TI - Remote sensing of seasonal light use efficiency in temperate bog ecosystems. AB - Despite storing approximately half of the atmosphere's carbon, estimates of fluxes between wetlands and atmosphere under current and future climates are associated with large uncertainties, and it remains a challenge to determine human impacts on the net greenhouse gas balance of wetlands at the global scale. In this study we demonstrate that the relationship between photochemical reflectance index, derived from high spectral and temporal multi-angular observations, and vegetation light use efficiency was strong (r2 = 0.64 and 0.58 at the hotspot and darkspot, respectively), and can be utilized to estimate carbon fluxes from remote at temperate bog ecosystems. These results improve our understanding of the interactions between vegetation physiology and spectral characteristics to understand seasonal magnitudes and variations in light use efficiency, opening new perspectives on the potential of this technique over extensive areas with different landcover. PMID- 28819147 TI - Nitrogen Starvation Impacts the Photosynthetic Performance of Porphyridium cruentum as Revealed by Chlorophyll a Fluorescence. AB - Nitrogen is one of the most important nutrients needed for plants and algae to survive, and the photosynthetic ability of algae is related to nitrogen abundance. Red algae are unique photosynthetic eukaryotic organisms in the evolution of algae, as they contain phycobilisomes (PBSs) on their thylakoid membranes. In this report, the in vivo chlorophyll (Chl) a fluorescence kinetics of nitrogen-starved Porphyridium cruentum were analyzed to determine the effects of nitrogen deficiency on photosynthetic performance using a multi-color pulse amplitude modulation (PAM) chlorophyll fluorometer. Due to nitrogen starvation, the photochemical efficiency of PSII and the activity of PSII reaction centers (RCs) decreased, and photoinhibition of PSII occurred. The water-splitting system on the donor side of PSII was seriously impacted by nitrogen deficiency, leading to the inactivation of the oxygen-evolving complex (OEC) and decreased light energy conversion efficiency. In nitrogen-starved cells, a higher proportion of energy was used for photochemical reactions, and thermal dissipation was reduced, as shown by qP and qN. The ability of nitrogen-starved cells to tolerate and resist high photon flux densities was weakened. Our results showed that the photosynthetic performance of P. cruentum was severely impacted by nitrogen deficiency. PMID- 28819148 TI - Analysis and comparative genomics of R997, the first SXT/R391 integrative and conjugative element (ICE) of the Indian Sub-Continent. AB - The aim of this study was to analyse R997, the first integrative and conjugative element (ICE) isolated from the Indian Sub-Continent, and to determine its relationship to the SXT/R391 family of ICEs. WGS of Escherichia coli isolate AB1157 (which contains R997) was performed using Illumina sequencing technology. R997 context was assessed by de novo assembly, gene prediction and annotation tools, and compared to other SXT/R391 ICEs. R997 has a size of 85 Kb and harbours 85 ORFs. Within one of the variable regions a HMS-1 beta-lactamase resistance gene is located. The Hotspot regions of the element contains restriction digestion systems and insertion sequences. R997 is very closely related to the SXT-like elements from widely dispersed geographic areas. The sequencing of R997 increases the knowledge of the earliest isolated SXT/R391 elements and may provide insight on the emergence of these elements on the Indian sub-continent. PMID- 28819146 TI - Liquid-liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein Tau. AB - The protein Tau aggregates into tangles in the brain of patients with Alzheimer's disease. In solution, however, Tau is intrinsically disordered, highly soluble, and binds to microtubules. It is still unclear what initiates the conversion from an innocuous phase of high solubility and functionality to solid-like neurotoxic deposits. Here, we show that the microtubule-binding repeats of Tau, which are lysine-rich, undergo liquid-liquid phase separation in solution. Liquid-liquid demixing causes molecular crowding of amyloid-promoting elements of Tau and drives electrostatic coacervation. Furthermore, we demonstrate that three-repeat and four-repeat isoforms of Tau differ in their ability for demixing. Alternative splicing of Tau can thus regulate the formation of Tau-containing membrane-less compartments. In addition, phosphorylation of Tau repeats promotes liquid-liquid phase separation at cellular protein conditions. The combined data propose a mechanism in which liquid droplets formed by the positively charged microtubule binding domain of Tau undergo coacervation with negatively charged molecules to promote amyloid formation.Tau forms aggregates in the brains of Alzheimer patients. Here, the authors identify conditions, where the microtubule-binding repeats of Tau undergo a phosphorylation-dependent liquid-liquid phase separation, leading to molecular crowding in the formed Tau liquid droplets and characterize them by NMR and other biophysical methods. PMID- 28819149 TI - Single-step generation of metal-plasma polymer multicore@shell nanoparticles from the gas phase. AB - Nanoparticles composed of multiple silver cores and a plasma polymer shell (multicore@shell) were prepared in a single step with a gas aggregation cluster source operating with Ar/hexamethyldisiloxane mixtures and optionally oxygen. The size distribution of the metal inclusions as well as the chemical composition and the thickness of the shells were found to be controlled by the composition of the working gas mixture. Shell matrices ranging from organosilicon plasma polymer to nearly stoichiometric SiO2 were obtained. The method allows facile fabrication of multicore@shell nanoparticles with tailored functional properties, as demonstrated here with the optical response. PMID- 28819151 TI - The investigation of stress in freestanding GaN crystals grown from Si substrates by HVPE. AB - We investigate the stress evolution of 400 um-thick freestanding GaN crystals grown from Si substrates by hydride vapour phase epitaxy (HVPE) and the in situ removal of Si substrates. The stress generated in growing GaN can be tuned by varying the thickness of the MOCVD AlGaN/AlN buffer layers. Micro Raman analysis shows the presence of slight tensile stress in the freestanding GaN crystals and no stress accumulation in HVPE GaN layers during the growth. Additionally, it is demonstrated that the residual tensile stress in HVPE GaN is caused only by elastic stress arising from the crystal quality difference between Ga- and N-face GaN. TEM analysis revealed that the dislocations in freestanding GaN crystals have high inclination angles that are attributed to the stress relaxation of the crystals. We believe that the understanding and characterization on the structural properties of the freestanding GaN crystals will help us to use these crystals for high-performance opto-electronic devices. PMID- 28819150 TI - The Galphai-GIV binding interface is a druggable protein-protein interaction. AB - Heterotrimeric G proteins are usually activated by the guanine-nucleotide exchange factor (GEF) activity of GPCRs. However, some non-receptor proteins are also GEFs. GIV (a.k.a Girdin) was the first non-receptor protein for which the GEF activity was ascribed to a well-defined protein sequence that directly binds Galphai. GIV expression promotes metastasis and disruption of its binding to Galphai blunts the pro-metastatic behavior of cancer cells. Although this suggests that inhibition of the Galphai-GIV interaction is a promising therapeutic strategy, protein-protein interactions (PPIs) are considered poorly "druggable" targets requiring case-by-case validation. Here, we set out to investigate whether Galphai-GIV is a druggable PPI. We tested a collection of >1,000 compounds on the Galphai-GIV PPI by in silico ligand screening and separately by a chemical high-throughput screening (HTS) assay. Two hits, ATA and NF023, obtained in both screens were confirmed in secondary HTS and low throughput assays. The binding site of NF023, identified by NMR spectroscopy and biochemical assays, overlaps with the Galphai-GIV interface. Importantly, NF023 did not disrupt Galphai-Gbetagamma binding, indicating its specificity toward Galphai-GIV. This work establishes the Galphai-GIV PPI as a druggable target and sets the conceptual and technical framework for the discovery of novel inhibitors of this PPI. PMID- 28819152 TI - Dissecting the genomic activity of a transcriptional regulator by the integrative analysis of omics data. AB - In the study of genomic regulation, strategies to integrate the data produced by Next Generation Sequencing (NGS)-based technologies in a meaningful ensemble are eagerly awaited and must continuously evolve. Here, we describe an integrative strategy for the analysis of data generated by chromatin immunoprecipitation followed by NGS which combines algorithms for data overlap, normalization and epigenetic state analysis. The performance of our strategy is illustrated by presenting the analysis of data relative to the transcriptional regulator Estrogen Receptor alpha (ERalpha) in MCF-7 breast cancer cells and of Glucocorticoid Receptor (GR) in A549 lung cancer cells. We went through the definition of reference cistromes for different experimental contexts, the integration of data relative to co-regulators and the overlay of chromatin states as defined by epigenetic marks in MCF-7 cells. With our strategy, we identified novel features of estrogen-independent ERalpha activity, including FoxM1 interaction, eRNAs transcription and a peculiar ontology of connected genes. PMID- 28819153 TI - Giant onsite electronic entropy enhances the performance of ceria for water splitting. AB - Previous studies have shown that a large solid-state entropy of reduction increases the thermodynamic efficiency of metal oxides, such as ceria, for two step thermochemical water splitting cycles. In this context, the configurational entropy arising from oxygen off-stoichiometry in the oxide, has been the focus of most previous work. Here we report a different source of entropy, the onsite electronic configurational entropy, arising from coupling between orbital and spin angular momenta in lanthanide f orbitals. We find that onsite electronic configurational entropy is sizable in all lanthanides, and reaches a maximum value of ~4.7 k B per oxygen vacancy for Ce4+/Ce3+ reduction. This unique and large positive entropy source in ceria explains its excellent performance for high-temperature catalytic redox reactions such as water splitting. Our calculations also show that terbium dioxide has a high electronic entropy and thus could also be a potential candidate for solar thermochemical reactions.Solid state entropy of reduction increases the thermodynamic efficiency of ceria for two-step thermochemical water splitting. Here, the authors report a large and different source of entropy, the onsite electronic configurational entropy arising from coupling between orbital and spin angular momenta in f orbitals. PMID- 28819154 TI - RpoS-independent evolution reveals the importance of attenuated cAMP/CRP regulation in high hydrostatic pressure resistance acquisition in E. coli. AB - High hydrostatic pressure (HHP) processing is an attractive non-thermal alternative to food pasteurization. Nevertheless, the large inter- and intra species variations in HHP resistance among foodborne pathogens and the ease by which they can acquire extreme resistance are an issue of increasing concern. Since RpoS activity has been considered as a central determinant in the HHP resistance of E. coli and its pathovars, this study probed for the potential of an E. coli MG1655 DeltarpoS mutant to acquire HHP resistance by directed evolution. Despite the higher initial HHP sensitivity of the DeltarpoS mutant compared to the wild-type strain, evolved lineages of the former readily managed to restore or even succeed wild-type levels of resistance. A number of these DeltarpoS derivatives were affected in cAMP/CRP regulation, and this could be causally related to their HHP resistance. Subsequent inspection revealed that some of previously isolated HHP-resistant mutants derived from the wild-type strain also incurred a causal decrease in cAMP/CRP regulation. cAMP/CRP attenuated HHP-resistant mutants also exhibited higher resistance to fosfomycin, a preferred treatment for STEC infections. As such, this study reveals attenuation of cAMP/CRP regulation as a relevant and RpoS-independent evolutionary route towards HHP resistance in E. coli that coincides with fosfomycin resistance. PMID- 28819155 TI - Context conditioning in humans using commercially available immersive Virtual Reality. AB - Despite a wealth of knowledge on how humans and nonhuman animals learn to associate meaningful events with cues in the environment, far less is known about how humans learn to associate these events with the environment itself. Progress on understanding spatiotemporal contextual processes in humans has been slow in large measure by the methodological constraint of generating and manipulating immersive spatial environments in well-controlled laboratory settings. Fortunately, immersive Virtual Reality (iVR) technology has improved appreciably and affords a relatively straightforward methodology to investigate the role of context on learning, memory, and emotion while maintaining experimental control. Here, we review context conditioning literature in humans and describe challenges to study contextual learning in humans. We then provide details for a novel context threat (fear) conditioning paradigm in humans using a commercially available VR headset and a cross-platform game engine. This paradigm resulted in the acquisition of subjective threat, threat-conditioned defensive responses, and explicit threat memory. We make the paradigm publicly available and describe obstacles and solutions to optimize future studies of context conditioning using iVR. As computer technology advances to replicate the sensation of realistic environments, there are increasing opportunities to bridge the translational gap between rodent and human research on how context modulates cognition, which may ultimately lead to more optimal treatment strategies for anxiety- and stress related disorders. PMID- 28819156 TI - Cell damage produced by magnetic fluid hyperthermia on microglial BV2 cells. AB - We present evidence on the effects of exogenous heating by water bath (WB) and magnetic hyperthermia (MHT) on a glial micro-tumor phantom. To this, magnetic nanoparticles (MNPs) of 30-40 nm were designed to obtain particle sizes for maximum heating efficiency. The specific power absorption (SPA) values (f = 560 kHz, H = 23.9 kA/m) for as prepared colloids (533-605 W/g) dropped to 98-279 W/g in culture medium. The analysis of the intracellular MNPs distribution showed vesicle-trapped MNPs agglomerates spread along the cytoplasm, as well as large (~0.5-0.9 MUm) clusters attached to the cell membrane. Immediately after WB and MHT (T = 46 degrees C for 30 min) the cell viability was ~70% and, after 4.5 h, decreased to 20-25%, demonstrating that metabolic processes are involved in cell killing. The analysis of the cell structures after MHT revealed a significant damage of the cell membrane that is correlated to the location of MNPs clusters, while local cell damage were less noticeable after WB without MNPs. In spite of the similar thermal effects of WB and MHT on the cell viability, our results suggest that there is an additional mechanism of cell damage related to the presence of MNPs at the intracellular space. PMID- 28819157 TI - A Preliminary Investigation of the Association of Sleep With Inflammation and Oxidative Stress Biomarkers and Functional Outcomes After Stroke Rehabilitation. AB - This study examined the association of sleep with inflammation and oxidative stress biomarkers, and with functional outcomes, after stroke rehabilitation. The rehabilitation effects on biomarkers and functional outcomes were also evaluated. Twenty subacute stroke survivors received 4 weeks of upper limb rehabilitation. Baseline inflammatory (i.e., soluble intercellular adhesion molecule-1, sICAM-1) and oxidative stress biomarkers (i.e., glutathione peroxidase, GPx and malondialdehyde, MDA) were assessed, as were sleep outcomes. Positive correlations were observed between baseline level of sICAM-1 and number of awakenings at post-treatment (rho = 0.51, p < 0.05) as well as between baseline level of MDA and post-performance time of the Wolf Motor Function Test (WMFT time) (rho = 0.46, p < 0.05). In addition, MDA levels were significantly decreased, and functional outcomes of the modified Rankin Scale (mRS), functional ability scale of the WMFT, and Stroke Impact Scale (SIS-total, and SIS-physical function) were improved after the rehabilitation. This pilot study emphasizes the relationship among biomarkers, sleep, and functional outcomes after stroke rehabilitation. Oxidative stress markers may be useful predictors of functional outcomes in subacute stroke survivors. PMID- 28819159 TI - Identification of boric acid as a novel chemoattractant and elucidation of its chemoreceptor in Ralstonia pseudosolanacearum Ps29. AB - Chemotaxis enables bacteria to move toward more favorable environmental conditions. We observed chemotaxis toward boric acid by Ralstonia pseudosolanacearum Ps29. At higher concentrations, the chemotactic response of R. pseudosolanacearum toward boric acid was comparable to or higher than that toward L-malate, indicating that boric acid is a strong attractant for R. pseudosolanacearum. Chemotaxis assays under different pH conditions suggested that R. pseudosolanacearum recognizes B(OH)3 (or B(OH3) + B(OH)4-) but not B(OH)4 alone. Our previous study revealed that R. pseudosolanacearum Ps29 harbors homologs of all 22R. pseudosolanacearum GMI1000 mcp genes. Screening of 22 mcp single-deletion mutants identified the RS_RS17100 homolog as the boric acid chemoreceptor, which was designated McpB. The McpB ligand-binding domain (LBD) was purified in order to characterize its binding to boric acid. Using isothermal titration calorimetry, we demonstrated that boric acid binds directly to the McpB LBD with a K D (dissociation constant) of 5.4 uM. Analytical ultracentrifugation studies revealed that the McpB LBD is present as a dimer that recognizes one boric acid molecule. PMID- 28819158 TI - Discovering Condition-Specific Gene Co-Expression Patterns Using Gaussian Mixture Models: A Cancer Case Study. AB - A gene co-expression network (GCN) describes associations between genes and points to genetic coordination of biochemical pathways. However, genetic correlations in a GCN are only detectable if they are present in the sampled conditions. With the increasing quantity of gene expression samples available in public repositories, there is greater potential for discovery of genetic correlations from a variety of biologically interesting conditions. However, even if gene correlations are present, their discovery can be masked by noise. Noise is introduced from natural variation (intrinsic and extrinsic), systematic variation (caused by sample measurement protocols and instruments), and algorithmic and statistical variation created by selection of data processing tools. A variety of published studies, approaches and methods attempt to address each of these contributions of variation to reduce noise. Here we describe an approach using Gaussian Mixture Models (GMMs) to address natural extrinsic (condition-specific) variation during network construction from mixed input conditions. To demonstrate utility, we build and analyze a condition-annotated GCN from a compendium of 2,016 mixed gene expression data sets from five tumor subtypes obtained from The Cancer Genome Atlas. Our results show that GMMs help discover tumor subtype specific gene co-expression patterns (modules) that are significantly enriched for clinical attributes. PMID- 28819160 TI - Effects of catalase on chloroplast arrangement in Opuntia streptacantha chlorenchyma cells under salt stress. AB - In arid and semiarid regions, low precipitation rates lead to soil salinity problems, which may limit plant establishment, growth, and survival. Herein, we investigated the NaCl stress effect on chlorophyll fluorescence, photosynthetic pigments, movement and chloroplasts ultrastructure in chlorenchyma cells of Opuntia streptacantha cladodes. Cladodes segments were exposed to salt stress at 0, 100, 200, and 300 mM NaCl for 8, 16, and 24 h. The results showed that salt stress reduced chlorophyll content, F v /F m , PhiPSII, and qP values. Under the highest salt stress treatments, the chloroplasts were densely clumped toward the cell center and thylakoid membranes were notably affected. We analyzed the effect of exogenous catalase in salt-stressed cladode segments during 8, 16, and 24 h. The catalase application to salt-stressed cladodes counteracted the NaCl adverse effects, increasing the chlorophyll fluorescence parameters, photosynthetic pigments, and avoided chloroplast clustering. Our results indicate that salt stress triggered the chloroplast clumping and affected the photosynthesis in O. streptacantha chlorenchyma cells. The exogenous catalase reverted the H2O2 accumulation and clustering of chloroplast, which led to an improvement of the photosynthetic efficiency. These data suggest that H2O2 detoxification by catalase is important to protect the chloroplast, thus conserving the photosynthetic activity in O. streptacantha under stress. PMID- 28819161 TI - Correlations of age and growth rate with microbiota composition in Atlantic cod (Gadus morhua) larvae. AB - Little information is available on the link between host development (growth rate and ontogeny) and the composition of the microbiota in fish larvae. This study was carried out to examine potential correlations of microbiota composition with age and growth rate of Atlantic cod larvae. Small and large cod larvae of the same age, representing slow and fast growing individuals, were sampled 10 times during a period of 42 days post hatching (dph), and the composition of the larval microbiota was investigated using a PCR/DGGE (Denaturing Gradient Gel Electrophoresis) strategy. We found significant differences in the intestinal microbiota of small and large larvae of the same age for 4 of the 10 age stages studied. We further found that the variation in the composition of the larval microbiota was more strongly correlated to age than to growth rate for larvae up to 28 dph, whereas for the older larvae growth rate and age was equally correlated to the composition of the microbiota. These results indicate that larval development may structure the microbiota through a change in selection pressure due to host-microbe and microbe-microbe interactions, and that the composition of the microbiota may influence larval development through improved energy gain. PMID- 28819162 TI - Inter-brain network underlying turn-based cooperation and competition: A hyperscanning study using near-infrared spectroscopy. AB - The present study examined neural substrates underlying turn-based cooperation and competition in a real two-person situation. We simultaneously measured pairs of participants' activations in their bilateral frontal, temporal, and parietal regions using a 96-channel near-infrared spectroscopy (NIRS) system, when participants played a turn-taking disk-game on a computer. NIRS data demonstrated significant inter-brain neural synchronization (INS) across participant pairs' right posterior superior temporal sulcus (pSTS) in both the cooperation and competition conditions, and the competition condition also involved significant INS in the right inferior parietal lobule (IPL). In addition, competitive dyads' INS in the bilateral inferior frontal gyrus (IFG) may play as a role of mediation in relationship between their empathy score and disk-manipulation latency, but cooperative dyads' INS did not. These results suggest that first the right pSTS may be commonly involved in both cooperation and competition due to task demands of joint attention and intention understanding, while the right IPL may be more important for competition due to additional requirements of mentalizing resources in competing contexts. Second, participants' empathy may promote INS in the bilateral IFG across competitors, and in turn affect their competitive performance. PMID- 28819163 TI - Fusion protein analysis reveals the precise regulation between Hsp70 and Hsp100 during protein disaggregation. AB - ClpB, a bacterial Hsp100, is a ring-shaped AAA+ chaperone that can reactivate aggregated proteins in cooperation with DnaK, a bacterial Hsp70, and its co factors. ClpB subunits comprise two AAA+ modules with an interstitial rod-shaped M-domain. The M-domain regulates ClpB ATPase activity and interacts directly with the DnaK nucleotide-binding domain (NBD). Here, to clarify how these functions contribute to the disaggregation process, we constructed ClpB, DnaK, and aggregated YFP fusion proteins in various combinations. Notably, i) DnaK activates ClpB only when the DnaK substrate-binding domain (SBD) is in the closed conformation, affording high DnaK-peptide affinity; ii) although NBD alone can activate ClpB, SBD is required for disaggregation; and iii) tethering aggregated proteins to the activated ClpB obviates SBD requirements. These results indicate that DnaK activates ClpB only when the SBD tightly holds aggregated proteins adjacent to ClpB for effective disaggregation. PMID- 28819164 TI - Hypoxia triggers IFN-I production in muscle: Implications in dermatomyositis. AB - Dermatomyositis is an inflammatory myopathy characterized by symmetrical proximal muscle weakness and skin changes. Muscle biopsy hallmarks include perifascicular atrophy, loss of intramuscular capillaries, perivascular and perimysial inflammation and the overexpression of IFN-inducible genes. Among them, the retinoic-acid inducible gene 1 (RIG-I) is specifically overexpressed in perifascicular areas of dermatomyositis muscle. The aim of this work was to study if RIG-I expression may be modulated by hypoxia using an in vitro approach. We identified putative hypoxia response elements (HRE) in RIG-I regulatory regions and luciferase assays confirmed that RIG-I is a new HIF-inducible gene. We observed an increase expression of RIG-I both by Real time PCR and Western blot in hypoxic conditions in human muscle cells. Cell transfection with a constitutive RIG-I expression vector increased levels of phospho-IRF-3, indicating that RIG-I promotes binding of transcription factors to the enhancer sequence of IFN. Moreover, release of IFN-beta was observed in hypoxic conditions. Finally, HIF-1alpha overexpression was confirmed in the muscle biopsies and in some RIG-I positive perifascicular muscle fibres but not in controls. Our results indicate that hypoxia triggers the production of IFN-I in vitro, and may contribute to the pathogenesis of DM together with other inflammatory factors. PMID- 28819165 TI - ATP-sensitive inwardly rectifying potassium channel regulation of viral infections in honey bees. AB - Honey bees are economically important pollinators of a wide variety of crops that have attracted the attention of both researchers and the public alike due to unusual declines in the numbers of managed colonies in some parts of the world. Viral infections are thought to be a significant factor contributing to these declines, but viruses have proven a challenging pathogen to study in a bee model and interactions between viruses and the bee antiviral immune response remain poorly understood. In the work described here, we have demonstrated the use of flock house virus (FHV) as a model system for virus infection in bees and revealed an important role for the regulation of the bee antiviral immune response by ATP-sensitive inwardly rectifying potassium (KATP) channels. We have shown that treatment with the KATP channel agonist pinacidil increases survival of bees while decreasing viral replication following infection with FHV, whereas treatment with the KATP channel antagonist tolbutamide decreases survival and increases viral replication. Our results suggest that KATP channels provide a significant link between cellular metabolism and the antiviral immune response in bees. PMID- 28819166 TI - Histone/protein deacetylase 11 targeting promotes Foxp3+ Treg function. AB - Current interest in Foxp3+ T-regulatory (Treg) cells as therapeutic targets in transplantation is largely focused on their harvesting pre-transplant, expansion and infusion post-transplantation. An alternate strategy of pharmacologic modulation of Treg function using histone/protein deacetylase inhibitors (HDACi) may allow more titratable and longer-term dosing. However, the effects of broadly acting HDACi vary, such that HDAC isoform-selective targeting is likely required. We report data from mice with constitutive or conditional deletion of HDAC11 within Foxp3+ Treg cells, and their use, along with small molecule HDAC11 inhibitors, in allograft models. Global HDAC11 deletion had no effect on health or development, and compared to WT controls, Foxp3+ Tregs lacking HDAC11 showed increased suppressive function, and increased expression of Foxp3 and TGF-beta. Likewise, compared to WT recipients, conditional deletion of HDAC11 within Tregs led to long-term survival of fully MHC-mismatched cardiac allografts, and prevented development of transplant arteriosclerosis in an MHC class II mismatched allograft model. The translational significance of HDAC11 targeting was shown by the ability of an HDAC11i to promote long-term allograft allografts in fully MHC-disparate strains. These data are powerful stimuli for the further development and testing of HDAC11-selective pharmacologic inhibitors, and may ultimately provide new therapies for transplantation and autoimmune diseases. PMID- 28819167 TI - Artificial DnaJ Protein for protein production and conformational diseases. AB - For secreted proteins, proper protein folding is essential not only for biological function but also for secretion itself. Proteins with folding problems are trapped in the endoplasmic reticulum (ER) and are eventually degraded in the cytoplasm. In this study, we exploited co-expression of an artificial fusion protein, based on the sequence of a DnaJ protein, which could interact as co chaperones in the Hsp70-based protein-folding system, with target recombinant secreted proteins to enhance their production and secretion. The J-domain sequence or a fragment thereof was conjugated to a target protein-binding domain that was capable of binding to a portion of the target-protein sequence. Production of many of the target proteins was significantly upregulated when co expressed with the J-domain fusion protein. Surprisingly, the enhancement of secretion was observed even when the J-domain had a mutation in the HPD motif, which is necessary for J-protein-Hsp70 interactions, suggesting the phenomenon observed is independent on functional J-protein-Hsp70 interactions. This technology has great potential for not only enhancing the production of recombinant proteins, but also to treat conformational diseases such as cystic fibrosis, and Alpha-1 antitrypsin deficiency. PMID- 28819168 TI - Resistance training regulates gene expression of molecules associated with intramyocellular lipids, glucose signaling and fiber size in old rats. AB - Sarcopenia is a complex multifactorial process, some of which involves fat infiltration. Intramyocellular lipid (IMCL) accumulation is postulated to play a role on sarcopenia during aging, which is believed to be due alterations in glucose homeostasis in the skeletal muscle. Sarcopenia, along with intramuscular lipids, is associated with physical inactivity. Resistance training (RT) has been indicated to minimize the age-induced muscle skeletal adaptations. Thus, we aimed to investigate the effects of RT on mRNA levels of regulatory components related to intramyocellular lipid, glucose metabolism and fiber size in soleus and gastrocnemius muscles of aged rats. Old male rats were submitted to RT (ladder climbing, progressive load, 3 times a week for 12 weeks). Age-induced accumulation of IMCL was attenuated by RT, which was linked to a PPARy-mediated mechanism, concomitant to enhanced regulatory components of glucose homeostasis (GLUT-4, G6PDH, Hk-2 and Gly-Syn-1). These responses were also linked to decreased catabolic (TNF-alpha, TWEAK/Fn14 axis; FOXO-1, Atrogin-1 and MuRF1; Myostatin) and increased anabolic intracellular pathways (IGF-1-mTOR-p70S6sk-1 axis; MyoD) in muscles of trained aged rats. Our results point out the importance of RT on modulation of gene expression of intracellular regulators related to age induced morphological and metabolic adaptations in skeletal muscle. PMID- 28819170 TI - Self-shedding and sweeping of condensate on composite nano-surface under external force field: enhancement mechanism for dropwise and filmwise condensation modes. AB - In this work, we propose the concept to use the hydrophilic or neutral surface for condensation heat transfer and to use the superhydrophobic surface for enhancement by self-shedding and sweeping of condensate. Molecular dynamics simulation results show that no matter the vapor condenses on the solid surface in dropwise or filmwise mode, the grown-up condensate self-sheds and falls off the superhydrophobic surface, sweeping the growing condensate on the condensing surface downstream. We characterize the dynamics of condensate that the continuous self-shedding and sweeping effectively remove the droplets from the solid surface in dropwise mode or thin the condensate film on the solid surface in filmwise mode, which significantly enhances the condensation heat transfer. We reveal that the mechanism for self-shedding is two-fold: (1) that the external force on condensate bulk defeats the adhesive force between the condensate and the solid surface triggers the self-shedding; (2) the release of the surface free energy of condensate promotes the self-shedding. We also reveal that the mechanism of heat transfer enhancement is essentially due to the timely suppression over the growing condensate bulk on the condensing surface through the self-shedding and sweeping. Finally, we discuss the possible applications. PMID- 28819169 TI - CD206+ M2-like macrophages regulate systemic glucose metabolism by inhibiting proliferation of adipocyte progenitors. AB - Adipose tissue resident macrophages have important roles in the maintenance of tissue homeostasis and regulate insulin sensitivity for example by secreting pro inflammatory or anti-inflammatory cytokines. Here, we show that M2-like macrophages in adipose tissue regulate systemic glucose homeostasis by inhibiting adipocyte progenitor proliferation via the CD206/TGFbeta signaling pathway. We show that adipose tissue CD206+ cells are primarily M2-like macrophages, and ablation of CD206+ M2-like macrophages improves systemic insulin sensitivity, which was associated with an increased number of smaller adipocytes. Mice genetically engineered to have reduced numbers of CD206+ M2-like macrophages show a down-regulation of TGFbeta signaling in adipose tissue, together with up regulated proliferation and differentiation of adipocyte progenitors. Our findings indicate that CD206+ M2-like macrophages in adipose tissues create a microenvironment that inhibits growth and differentiation of adipocyte progenitors and, thereby, control adiposity and systemic insulin sensitivity.Adipose tissue contains macrophages that can influence both local and systemic metabolism via the secretion of cytokines. Here, Nawaz et al. report that M2-like macrophages, present in adipose tissue, create a microenvironment that inhibits proliferation of adipocyte progenitors due to the secretion of TGF beta1. PMID- 28819172 TI - Suppression for an intermediate phase in ZnSb films by NiO-doping. AB - The structural evolution and phase-change kinetics of NiO-doped ZnSb films are investigated. NiO-doped ZnSb films exhibit a single-step crystallization process, which is different from that of undoped ZnSb. NiO-doped ZnSb can directly crystallize into a stable ZnSb phase at temperatures greater than 320 degrees C with suppression of a metastable ZnSb phase. These characteristics enlarge the amorphous/crystalline resistance ratio by approximately five orders of magnitude. Moreover, NiO doping of ZnSb films increases crystallization temperature from 260 to 275 degrees C, improves data retention temperature from 201.7 to 217.3 degrees C and increases crystalline activation energy from 5.64 to 6.34 eV. The improvement of the thermal parameters in the nanocomposite can be attributed to stable ZnSb grain growth refinement owing to the dispersion of NiO particles in the sample matrix. This provides additional nucleation sites and produces more ZnSb/NiO interfaces, which can initiate the nucleation and accelerate crystallization. The kinetic exponent n decreases from 1.12 to 0.44, which confirms the ultrafast one-dimensional growth and heterogeneous phase transition of the NiO-doped ZnSb films. The improved thermal stability, larger resistance ratio and direct transition to a stable phase with ultrafast one-dimensional crystal growth indicate the good potential of these materials in phase-change memory applications. PMID- 28819171 TI - Thyroid function and ischemic heart disease: a Mendelian randomization study. AB - To clarify the role of thyroid function in ischemic heart disease (IHD) we assessed IHD risk and risk factors according to genetically predicted thyroid stimulating hormone (TSH), free thyroxine (FT4) and thyroid peroxidase antibody (TPOAb) positivity. Separate-sample instrumental variable analysis with genetic instruments (Mendelian randomization) was used in an extensively genotyped case (n = 64,374)-control (n = 130,681) study, CARDIoGRAMplusC4D. Associations with lipids, diabetes and adiposity were assessed using the Global Lipids Genetics Consortium Results (n = 196,475), the DIAbetes Genetics Replication And Meta analysis case (n = 34,380)-control (n = 114,981) study, and the Genetic Investigation of ANthropometric Traits (body mass index in 152,893 men and 171,977 women, waist-hip ratio in 93,480 men and 116,741 women). Genetically predicted thyroid function was not associated with IHD (odds ratio (OR) per standard deviation for TSH 1.05, 95% confidence interval (CI) 0.97 to 1.12; for FT4 1.01, 95% CI 0.91 to 1.12; for TPOAb positivity 1.10, 95% CI 0.83 to 1.46) or after Bonferroni correction with risk factors, except for an inverse association of FT4 with low-density lipoprotein-cholesterol. The associations were generally robust to sensitivity analyses using a weighted median method and MR Egger. This novel study provides little indication that TSH, FT4 or TPOAb positivity affects IHD, despite potential effects on its risk factors. PMID- 28819173 TI - Disentangling the coupling between sea ice and tundra productivity in Svalbard. AB - The rapid decline in Arctic sea ice poses urgent questions concerning its ecological effects, such as on tundra terrestrial productivity. However, reported sea ice/terrestrial productivity linkages have seldom been constrained, and the mechanism governing them remains elusive, with a diversity of spatial scales and metrics proposed, at times in contradiction to each other. In this study, we use spatially explicit remotely sensed sea ice concentration and high-resolution terrestrial productivity estimates (Normalised Difference Vegetation Index, NDVI) across the Svalbard Archipelago to describe local/sub-regional and large-scale components of sea ice/terrestrial productivity coupling. Whereas the local/sub regional component is attributed to sea breeze (cold air advection from ice covered ocean onto adjacent land during the growing season), the large-scale component might reflect co-variability of sea ice and tundra productivity due to a common forcing, such as large-scale atmospheric circulation (North Atlantic Oscillation, NAO). Our study clarifies the range of mechanisms in sea ice/terrestrial productivity coupling, allowing the generation of testable hypotheses about its past, present, and future dynamics across the Arctic. PMID- 28819174 TI - Interleukin-17 receptor A (IL-17RA) as a central regulator of the protective immune response against Giardia. AB - The protozoan parasite Giardia is a highly prevalent intestinal pathogen with a wide host range. Data obtained in mice, cattle and humans revealed the importance of IL-17A in the development of a protective immune response against Giardia. The aim of this study was to further unravel the protective effector mechanisms triggered by IL-17A following G. muris infection in mice, by an RNA-sequencing approach. C57BL/6 WT and C57BL/6 IL-17RA KO mice were orally infected with G. muris cysts. Three weeks post infection, intestinal tissue samples were collected for RNA-sequencing, with samples from uninfected C57BL/6 WT and C57BL/6 IL-17RA KO animals serving as negative controls. Differential expression analysis showed that G. muris infection evoked the transcriptional upregulation of a wide array of genes, mainly in animals with competent IL-17RA signaling. IL-17RA signaling induced the production of various antimicrobial peptides, such as angiogenin 4 and alpha- and beta-defensins and regulated complement activation through mannose binding lectin 2. The expression of the receptor that regulates the secretion of IgA into the intestinal lumen, the polymeric immunoglobulin receptor, was also dependent on IL-17RA signaling. Interestingly, the transcriptome data showed for the first time the involvement of the circadian clock in the host response following Giardia infection. PMID- 28819175 TI - In vivo therapeutic efficacy of frog skin-derived peptides against Pseudomonas aeruginosa-induced pulmonary infection. AB - Pseudomonas aeruginosa is an opportunistic and frequently drug-resistant pulmonary pathogen especially in cystic fibrosis sufferers. Recently, the frog skin-derived antimicrobial peptide (AMP) Esc(1-21) and its diastereomer Esc(1-21) 1c were found to possess potent in vitro antipseudomonal activity. Here, they were first shown to preserve the barrier integrity of airway epithelial cells better than the human AMP LL-37. Furthermore, Esc(1-21)-1c was more efficacious than Esc(1-21) and LL-37 in protecting host from pulmonary bacterial infection after a single intra-tracheal instillation at a very low dosage of 0.1 mg/kg. The protection was evidenced by 2-log reduction of lung bacterial burden and was accompanied by less leukocytes recruitment and attenuated inflammatory response. In addition, the diastereomer was more efficient in reducing the systemic dissemination of bacterial cells. Importantly, in contrast to what reported for other AMPs, the peptide was administered at 2 hours after bacterial challenge to better reflect the real life infectious conditions. To the best of our knowledge, this is also the first study investigating the effect of AMPs on airway-epithelia associated genes upon administration to infected lungs. Overall, our data highly support advanced preclinical studies for the development of Esc(1-21)-1c as an efficacious therapeutic alternative against pulmonary P. aeruginosa infections. PMID- 28819176 TI - Use of Biocompatible Sorafenib-gold Nanoconjugates for Reversal of Drug Resistance in Human Hepatoblatoma Cells. AB - The present study identifies the potential of highly biocompatible SF-GNP nano conjugate to enhance the chemotherapeutic response to combat drug resistance in cancer cells. We developed a stable colloidal suspension of sorafenib-gold nanoconjugate (SF-GNP) of <10 nm size in aqueous medium for reverting the cancer drug resistance in SF-resistant HepG2 cells in a 3D ex-vivo model system. In-vivo biocompatibility assay of SF-GNPs showed absence of systemic toxicological effects including hematological, biochemical and histological parameters. More importantly, the histopathological analysis of vital organs such as liver, brain, lung, kidney and heart showed very least or no sign of inflammation, cell infiltration, necrosis, tissue disorganization or fibrotic reactions after intra peritoneal administration of SF-GNP nanoconjugates in animals. However, SF-GNP nanoconjugates significantly reduced (>80%) the percentage cell survival and the size and number of SF resistant solid tumor colonies of HepG2 cells in 3D model system. The exposure of SF-GNP nanoconjugate to SF resistant HepG2 cell colonies also provided evidence for anti-proliferative effect and reversal of drug resistance by elucidating the molecular regulatory mechanisms of extracellular matrix factor (CD147), tumor growth factor (TGF-beta), hepatoma upregulated protein (hURP) and drug transporter (ABCG-2). PMID- 28819177 TI - Comparative Transcriptome Analysis of SE initial dedifferentiation in cotton of different SE capability. AB - Somatic embryogenesis (SE) is a critical transition from vegetative to embryogenic growth in higher plants; however, few studies have investigated the mechanism that regulates SE initial differentiation. Most cotton varieties have not undergone regeneration by SE, so only a few varieties can be used in genetic engineering. Here, two varieties of cotton with different SE capabilities (HD, higher differentiation and LD, lower differentiation) were analyzed by high throughout RNA-Seq at the pre-induction stage (0h) and two induction stages (3h and 3d) under callus-induction medium (CIM). About 1150 million clean reads were obtained from 98.21% raw data. Transcriptomic analysis revealed that "protein kinase activity" and "oxidoreductase activity" were highly represented GO terms during the same and different treatment stages among HD and LD. Moreover, several stress-related transcription factors might play important roles in SE initiation. The SE-related regulation genes (SERKs) showed different expression patterns between HD and LD. Furthermore, the complex auxin and ethylene signaling pathway contributes to initiation of differentiation in SE. Thus, our RNA-sequencing of comparative transcriptome analysis will lay a foundation for future studies to better define early somatic formation in cotton with different SE capabilities. PMID- 28819178 TI - Curcumin liposomes interfere with quorum sensing system of Aeromonas sobria and in silico analysis. AB - Aeromonas sobria is opportunistic pathogen frequently found in environment and food. Interfering with its quorum sensing (QS) system could be a promising way to alleviate its virulence. In this study, curcumin liposomes were prepared and their characteristics like particle size, zeta potential, PDI (Polymey Disperse Index), encapsulation efficiency and loading capacity were measured. The quorum sensing inhibitory effect of curcumin liposomes under sub-MIC (Minimum Inhibitory Concentration) on siderophore production, swimming and swarming motility, extracellular proteases, biofilm formation and AHLs (N-acylhomoserine lactones) production of A. sobria were also determined. The results showed that, the curcumin liposomes with high encapsulation capacity (84.51 +/- 0.58%) were stable and homogeneous. QS-regulated phenotypes of the pathogen were significantly inhibited by curcumin liposomes. The in silico analysis revealed that the QS system of A. sobria may be inhibited by released curcumin from curcumin liposomes through interacting with the built LuxI type protein and blocking the production of AHLs. PMID- 28819179 TI - Identification of Polo-like kinases as potential novel drug targets for influenza A virus. AB - In recent years genome-wide RNAi screens have revealed hundreds of cellular factors required for influenza virus infections in human cells. The long-term goal is to establish some of them as drug targets for the development of the next generation of antivirals against influenza. We found that several members of the polo-like kinases (PLK), a family of serine/threonine kinases with well-known roles in cell cycle regulation, were identified as hits in four different RNAi screens and we therefore studied their potential as drug target for influenza. We show that knockdown of PLK1, PLK3, and PLK4, as well as inhibition of PLK kinase activity by four different compounds, leads to reduced influenza virus replication, and we map the requirement of PLK activity to early stages of the viral replication cycle. We also tested the impact of the PLK inhibitor BI2536 on influenza virus replication in a human lung tissue culture model and observed strong inhibition of virus replication with no measurable toxicity. This study establishes the PLKs as potential drug targets for influenza and contributes to a more detailed understanding of the intricate interactions between influenza viruses and their host cells. PMID- 28819180 TI - EGFR is a pivotal regulator of thrombin-mediated inflammation in primary human nucleus pulposus culture. AB - We found that the coagulation and cytokine pathways were important mechanisms involve in the degeneration of intervertebral discs (IVD) using a microarray approach to analyze gene expression in different grades of specimens. Furthermore, using a cytokine/chemokine array, a significant increase in CXCL8 expression was observed in human nucleus pulposus (NP) cells after thrombin treatment. The enhancement of CXCL8 expression by thrombin was activated by the PAR1 receptor. Importantly, analysis of degenerated human NP tissue samples showed that EGFR expression positively correlated with the grade of tissue degeneration. In NP cells, thrombin caused an increase in phosphorylation of the EGFR at the Tyr1068, and treatment with the pharmacological EGFR inhibitor, AG1473 effectively blocked thrombin-enhanced CXCL8 production. Surprisingly, inhibition of STAT3 for 24 h decreased expression of EGFR. Treatment with thrombin also increased Akt and GSK3alpha/beta activation; this activation was also blocked by EGFR inhibitor. Although c-Src, ERK, and FAK were activated by thrombin, only c-Src and ERK were involved in the STAT3/CXCL8 induction. Our findings indicate that stimulation of an inflammatory response in NP cells by thrombin is part of a specific pathophysiology that modulates the EGFR activation through activation of Src/ERK/STAT3 signaling. PMID- 28819181 TI - Capnography monitoring the hypoventilation during the induction of bronchoscopic sedation: A randomized controlled trial. AB - We hypothesize that capnography could detect hypoventilation during induction of bronchoscopic sedation and starting bronchoscopy following hypoventilation, may decrease hypoxemia. Patients were randomized to: starting bronchoscopy when hypoventilation (hypopnea, two successive breaths of at least 50% reduction of the peak wave compared to baseline or apnea, no wave for 10 seconds) (Study group, n = 55), or when the Observer Assessment of Alertness and Sedation scale (OAAS) was less than 4 (Control group, n = 59). Propofol infusion was titrated to maintain stable vital signs and sedative levels. The hypoventilation during induction in the control group and the sedative outcome were recorded. The patient characteristics and procedures performed were similar. Hypoventilation was observed in 74.6% of the patients before achieving OAAS < 4 in the control group. Apnea occurred more than hypopnea (p < 0.0001). Hypoventilation preceded OAAS < 4 by 96.5 +/- 88.1 seconds. In the study group, the induction time was shorter (p = 0.03) and subjects with any two events of hypoxemia during sedation, maintenance or recovery were less than the control group (1.8 vs. 18.6%, p < 0.01). Patient tolerance, wakefulness during sedation, and cooperation were similar in both groups. Significant hypoventilation occurred during the induction and start bronchoscopy following hypoventilation may decrease hypoxemia without compromising patient tolerance. PMID- 28819182 TI - Impact of extracellular matrix on engraftment and maturation of pluripotent stem cell-derived cardiomyocytes in a rat myocardial infarct model. AB - Pluripotent stem cell-derived cardiomyocytes show great promise in regenerating the heart after myocardial infarction; however, several uncertainties exist that must be addressed before clinical trials. One practical issue is graft survival following transplantation. Although a pro-survival cocktail with Matrigel has been shown to enhance graft survival, the use of Matrigel may not be clinically feasible. The purpose of this study was to test whether a hyaluronan-based hydrogel, HyStem, could be a substitute for Matrigel. Human induced pluripotent stem cell-derived cardiomyocytes diluted with HyStem alone, HyStem plus pro survival factors, or a pro-survival cocktail with Matrigel (PSC/MG), were transplanted into a rat model of acute myocardial infarction. Histological analysis at 4 weeks post transplantation revealed that, among the three groups, recipients of PSC/MG showed the largest graft size. Additionally, the grafted cardiomyocytes in the recipients of PSC/MG had a more matured phenotype compared to those in the other two groups. These findings suggest that further studies will be required to enhance not only graft size, but also the maturation of grafted cardiomyocytes. PMID- 28819183 TI - Distribution bias and biochemical characterization of TOP1MT single nucleotide variants. AB - Mitochondrial topoisomerase I (TOP1MT) is a type IB topoisomerase encoded in the nucleus of vertebrate cells. In contrast to the other five human topoisomerases, TOP1MT possesses two high frequency single nucleotide variants (SNVs), rs11544484 (V256I, Minor Allele Frequency = 0.27) and rs2293925 (R525W, MAF = 0.45), which tend to be mutually exclusive across different human ethnic groups and even more clearly in a cohort of 129 US patients with breast cancer and in the NCI-60 cancer cell lines. We expressed these two TOP1MT variants and the double-variant (V256I-R525W) as recombinant proteins, as well as a less common variant E168G (rs200673353, MAF = 0.001), and studied their biochemical properties by magnetic tweezers-based supercoil relaxation and classical DNA relaxation assays. Variants showed reduced DNA relaxation activities, especially the V256I variant towards positively supercoiled DNA. We also found that the V256I variant was enriched to MAF = 0.64 in NCI-60 lung carcinoma cell lines, whereas the TOP1MT R525W was enriched to MAF = 0.65 in the NCI-60 melanoma cell lines. Moreover, TOP1MT expression correlated with the 256 variants in the NCI-60 lung carcinoma cell lines, valine with high expression and isoleucine with low expression. Our results are discussed in the context of evolution between the nuclear and mitochondrial topoisomerases and potential cancer predisposition. PMID- 28819184 TI - Black phosphorus ink formulation for inkjet printing of optoelectronics and photonics. AB - Black phosphorus is a two-dimensional material of great interest, in part because of its high carrier mobility and thickness dependent direct bandgap. However, its instability under ambient conditions limits material deposition options for device fabrication. Here we show a black phosphorus ink that can be reliably inkjet printed, enabling scalable development of optoelectronic and photonic devices. Our binder-free ink suppresses coffee ring formation through induced recirculating Marangoni flow, and supports excellent consistency (< 2% variation) and spatial uniformity (< 3.4% variation), without substrate pre-treatment. Due to rapid ink drying (< 10 s at < 60 degrees C), printing causes minimal oxidation. Following encapsulation, the printed black phosphorus is stable against long-term (> 30 days) oxidation. We demonstrate printed black phosphorus as a passive switch for ultrafast lasers, stable against intense irradiation, and as a visible to near-infrared photodetector with high responsivities. Our work highlights the promise of this material as a functional ink platform for printed devices.Atomically thin black phosphorus shows promise for optoelectronics and photonics, yet its instability under environmental conditions and the lack of well-established large-area synthesis protocols hinder its applications. Here, the authors demonstrate a stable black phosphorus ink suitable for printed ultrafast lasers and photodetectors. PMID- 28819185 TI - Deletion of EP4 in S100a4-lineage cells reduces scar tissue formation during early but not later stages of tendon healing. AB - Tendon injuries heal via scar tissue rather than regeneration. This healing response forms adhesions between the flexor tendons in the hand and surrounding tissues, resulting in impaired range of motion and hand function. Mechanistically, inflammation has been strongly linked to adhesion formation, and Prostaglandin E2 (PGE2) is associated with both adhesion formation and tendinopathy. In the present study we tested the hypothesis that deletion of the PGE2 receptor EP4 in S100a4-lineage cells would decrease adhesion formation. S100a4-Cre; EP4 flox/flox (EP4cKOS100a4) repairs healed with improved gliding function at day 14, followed by impaired gliding at day 28, relative to wild type. Interestingly, EP4cKOS100a4 resulted in only transient deletion of EP4, suggesting up-regulation of EP4 in an alternative cell population in these mice. Loss of EP4 in Scleraxis-lineage cells did not alter gliding function, suggesting that Scx-lineage cells are not the predominant EP4 expressing population. In contrast, a dramatic increase in alpha-SMA+, EP4+ double-positive cells were observed in EP4cKOS100a4 suggesting that EP4cKOS100a4 repairs heal with increased infiltration of EP4 expressing alpha-SMA myofibroblasts, identifying a potential mechanism of late up-regulation of EP4 and impaired gliding function in EP4cKOS100a4 tendon repairs. PMID- 28819186 TI - CD24 induces changes to the surface receptors of B cell microvesicles with variable effects on their RNA and protein cargo. AB - The CD24 cell surface receptor promotes apoptosis in developing B cells, and we recently found that it induces B cells to release plasma membrane-derived, CD24 bearing microvesicles (MVs). Here we have performed a systematic characterization of B cell MVs released from WEHI-231 B lymphoma cells in response to CD24 stimulation. We found that B cells constitutively release MVs of approximately 120 nm, and that CD24 induces an increase in phosphatidylserine-positive MV release. RNA cargo is predominantly comprised of 5S rRNA, regardless of stimulation; however, CD24 causes a decrease in the incorporation of protein coding transcripts. The MV proteome is enriched with mitochondrial and metabolism related proteins after CD24 stimulation; however, these changes were variable and could not be fully validated by Western blotting. CD24-bearing MVs carry Siglec 2, CD63, IgM, and, unexpectedly, Ter119, but not Siglec-G or MHC-II despite their presence on the cell surface. CD24 stimulation also induces changes in CD63 and IgM expression on MVs that is not mirrored by the changes in cell surface expression. Overall, the composition of these MVs suggests that they may be involved in releasing mitochondrial components in response to pro-apoptotic stress with changes to the surface receptors potentially altering the cell type(s) that interact with the MVs. PMID- 28819187 TI - Administration of mesenchymal stromal cells before renal ischemia/reperfusion attenuates kidney injury and may modulate renal lipid metabolism in rats. AB - Mesenchymal stromal cells (MSC) have been demonstrated to attenuate renal ischemia/reperfusion (I/R) damage in rodent models. The mechanisms of such nephro protection remain largely unknown. Furthermore, the optimal timing of MSC administration has been poorly investigated. Here, we compare the impact of MSC injection 7 days before (MSCD - 7) versus 1 day after (MSCD + 1) renal I/R in rats. Control groups received equivalent volumes of saline at similar time-points (SD - 7 and SD + 1). Right nephrectomy was performed, and left renal ischemia lasted 45 min. After 48-hour reperfusion, we observed significantly improved renal function parameters, reduced apoptotic index and neutrophil/macrophage infiltration in kidney parenchyma, and lower expression of tubular damage markers and pro-inflammatory cytokines in MSCD - 7 in comparison to MSCD + 1 and saline control groups. Next, comparative high-throughput RNA sequencing of MSCD - 7 vs. SD - 7 non-ischemic right kidneys highlighted significant down-regulation of fatty acid biosynthesis and up-regulation of PPAR-alpha pathway. Such a preferential regulation towards lipid catabolism was associated with decreased levels of lipid peroxidation products, i.e. malondialdehyde and 4-hydroxy-2 nonenal, in MSCD - 7 versus SD - 7 ischemic kidneys. Our findings suggest that MSC pretreatment may exert protective effects against renal I/R by modulating lipid metabolism in rats. PMID- 28819188 TI - Highly Stabilized Core-Satellite Gold Nanoassemblies in Vivo: DNA-Directed Self Assembly, PEG Modification and Cell Imaging. AB - Au nanoparticles (NPs) have important applications in bioimaging, clinical diagnosis and even therapy due to its water-solubility, easy modification and drug-loaded capability, however, easy aggregation of Au NPs in normal saline and serum greatly limits its applications. In this work, highly stabilized core satellite Au nanoassemblies (CSAuNAs) were constructed by a hierarchical DNA directed self-assembly strategy, in which satellite Au NPs number could be effectively tuned through varying the ratios of core-AuNPs-ssDNA and satellite AuNPs-ssDNAc. It was especially interesting that PEG-functionalized CSAuNAs (PEG CSAuNAs) could not only bear saline solution but also resist the enzymatic degradation in fetal calf serum. Moreover, cell targeting and imaging indicated that the PEG-CSAuNAs had promising biotargeting and bioimaging capability. Finally, fluorescence imaging in vivo revealed that PEG-CSAuNAs modified with N acetylation chitosan (CSNA) could be selectively accumulate in the kidneys with satisfactory renal retention capability. Therefore, the highly stabilized PEG CSAuNAs open a new avenue for its applications in vivo. PMID- 28819190 TI - Renal injury: Early apoptotic extracellular vesicles in injury and repair. PMID- 28819189 TI - Vascular Hysteresis Loops and Vascular Architecture Mapping in Patients with Glioblastoma treated with Antiangiogenic Therapy. AB - In this study, we investigated the variability of vascular hysteresis loop (VHL) shapes and the spatial heterogeneity of neovascularization and microvascular alterations using vascular architecture mapping (VAM) in patients with recurrent glioblastoma during bevacizumab mono-therapy. VAM data were acquired in 13 patients suffering from recurrent glioblastoma prior to and 3 months after bevacizumab treatment onset using a dual contrast agent injections approach as part of routine MRI. Two patients were additionally examined after the first cycle of bevacizumab to check for early treatment response. VHLs were evaluated as biomarker maps of neovascularization activity: microvessel type indicator (MTI) and curvature (Curv) of the VHL-long-axis. Early response to bevacizumab was dominated by reduction of smaller microvasculature (around 10 um). In the 3 month follow-up, responding tumors additionally showed a reduction in larger microvasculature (>20 um). VAM biomarker images revealed spatially heterogeneous microvascular alterations during bevacizumab treatment. Responding, non responding, progressive, and remote-progressive tumor areas were observed. MTI may be useful to predict responding and non-responding tumor regions, and Curv to assess severity of vasogenic edema. Analysis of VHLs in combination with VAM biomarkers may lead to a new perspective on investigating the spatial heterogeneity of neovascularization and microvascular alterations in glioblastoma during antiangiogenic therapy. PMID- 28819191 TI - Increasing spring temperatures favor oak seed production in temperate areas. AB - The changes in reproductive phenology (i.e. timing of flowering and fruiting) observed in recent decades demonstrate that tree reproduction has already been altered by climate change. However, understanding the impact of these changes in reproductive success and fitness remains a major challenge for ecologists. We describe here a previously unreported phenomenon: a significant increase in the reproductive effort (seed production) of temperate oaks with increasing spring temperature, observed over the last decade. In contrast, no relationship was found between seed production and precipitation. This sensitivity of seed production to temperature was confirmed by a "space-for-time" substitution based on elevation gradients. Our findings suggest that global warming may enhance oak reproductive effort in temperate ecosystems. Nevertheless, while fitness can be enhanced by higher levels of seed production, it also depends on the frequency and synchronization of mast seeding production, which may also be influenced by climate change. PMID- 28819192 TI - Scalable fabrication of the graphitic substrates for graphene-enhanced Raman spectroscopy. AB - We propose direct synthesis of ultra-thin graphitic films on a dielectric substrate using sacrificial Ni catalyst layer, which significantly increases the crystallinity of the photoresist pyrolyzed at the temperature of 800 degrees C and above. A considerable amount of multilayer graphene in the photoresist film pyrolyzed in the presence of the Ni catalyst gives rise to an enhancement of the Raman signal of dye Sudan III molecules deposited on the substrate. We demonstrate comparable enhancement of the Raman signal from Sudan III molecules deposited on the fabricated graphitic substrate and those deposited on graphene, which was conventionally transferred to the silica substrate. PMID- 28819193 TI - Experiments suggesting extra-digestive effects of enteral pancreatic amylase and its peptides on glucose homeostasis in a pig model. AB - The studies presented were designed to highlight the impact of pancreatic enzymes on glycemic control and insulin response. Blood glucose and plasma insulin levels were monitored after intravenous, oral or direct gut glucose tolerance tests (GTT) in 6 pigs with an intact gastrointestinal tract and in 12 pigs following duodenal-jejunal bypass (DJB) surgery. In the intact pigs, pancreatic enzymes (Creon(r)) given orally 1 h prior to the GTT, lowered the blood glucose levels during the oral and meal GTT and reduced the plasma insulin response during the intravenous and meal GTT. In DJB pigs, blood glucose and plasma insulin levels were higher following glucose loading into the by-passed biliopancreatic limb as compared to that following glucose loading orally or into the common intestinal limb. Infusion of amylase or amylase peptides together with glucose into the biliopancreatic limb lowered blood glucose levels in DJB pigs. These preliminary data suggest new, extra-digestive, actions of enteral pancreatic enzymes - probably amylase or its peptides - on glucose homeostasis, with an reduction in net glucose absorption into the blood and in insulin response. This ability of digestive enzymes (amylase) to reduce post-prandial hyperglycaemia in an insulin independent manner could aid in preventing the development of obesity and diabetes. PMID- 28819195 TI - Human cytomegalovirus escapes immune recognition by NK cells through the downregulation of B7-H6 by the viral genes US18 and US20. AB - Human cytomegalovirus (HCMV) is a major human pathogen, causing serious diseases in immunocompromised populations and congenially infected neonates. One of the main immune cells acting against the virus are Natural Killer (NK) cells. Killing by NK cells is mediated by a small family of activating receptors such as NKp30 that interact with the cellular ligand B7-H6. The outcome of B7-H6-NKp30 interaction was, so far, mainly studied with regard to NK recognition and killing of tumors. Here, we demonstrated that the expression of B7-H6 is upregulated following HCMV infection and that HCMV uses two of its genes: US18 and US20, to interfere with B7-H6 surface expression, in a mechanism involving endosomal degradation, in order to evade NK cell recognition. PMID- 28819194 TI - HDAC3 inhibition ameliorates spinal cord injury by immunomodulation. AB - Following spinal cord injury (SCI), the innate immune response of microglia and infiltrating macrophages clears up cellular debris and promotes tissue repair, but it also inflicts secondary injury from inflammatory responses. Immunomodulation aimed at maximizing the beneficial effects while minimizing the detrimental roles of the innate immunity may aid functional recovery after SCI. However, intracellular drivers of global reprogramming of the inflammatory gene networks in the innate immune cells are poorly understood. Here we show that SCI resulted in an upregulation of histone deacetylase 3 (HDAC3) in the innate immune cells at the injury site. Remarkably, blocking HDAC3 with a selective small molecule inhibitor shifted microglia/macrophage responses towards inflammatory suppression, resulting in neuroprotective phenotypes and improved functional recovery in SCI model. Mechanistically, HDAC3 activity is largely responsible for histone deacetylation and inflammatory responses of primary microglia to classic inflammatory stimuli. Our results reveal a novel function of HDAC3 inhibitor in promoting functional recovery after SCI by dampening inflammatory cytokines, thus pointing towards a new direction of immunomodulation for SCI repair. PMID- 28819196 TI - Specialized odorant receptors in social insects that detect cuticular hydrocarbon cues and candidate pheromones. AB - Eusocial insects use cuticular hydrocarbons as components of pheromones that mediate social behaviours, such as caste and nestmate recognition, and regulation of reproduction. In ants such as Harpegnathos saltator, the queen produces a pheromone which suppresses the development of workers' ovaries and if she is removed, workers can transition to a reproductive state known as gamergate. Here we functionally characterize a subfamily of odorant receptors (Ors) with a nine exon gene structure that have undergone a massive expansion in ants and other eusocial insects. We deorphanize 22 representative members and find they can detect cuticular hydrocarbons from different ant castes, with one (HsOr263) that responds strongly to gamergate extract and a candidate queen pheromone component. After systematic testing with a diverse panel of hydrocarbons, we find that most Harpegnathos saltator Ors are narrowly tuned, suggesting that several receptors must contribute to detection and discrimination of different cuticular hydrocarbons important in mediating eusocial behaviour.Cuticular hydrocarbons (CHC) mediate the interactions between individuals in eusocial insects, but the sensory receptors for CHCs are unclear. Here the authors show that in ants such as H. saltator, the 9-exon subfamily of odorant receptors (HsOrs) responds to CHCs, and ectopic expression of HsOrs in Drosophila neurons imparts responsiveness to CHCs. PMID- 28819197 TI - Mortierella alpina CS10E4, an oleaginous fungal endophyte of Crocus sativus L. enhances apocarotenoid biosynthesis and stress tolerance in the host plant. AB - Crocus sativus is the only plant species which produces apocarotenoids like crocin, picrocrocin and safranal in significant amounts. These compounds impart organoleptic properties to saffron (dried stigmas of Crocus flower) making it world's costliest spice. Crocus apocarotenoids have tremendous medicinal properties as well. Effect of endophytes on Crocus apocarotenoid production and the molecular mechanism involved has not been reported so far. Here we studied the effect of an oleaginous fungal endophyte, Mortierella alpina CS10E4 on Crocus growth, apocarotenoid metabolism and tolerance to corm rot disease. The results demonstrated that there was a significant improvement in many morphological and physiological traits in endophyte treated Crocus plants including total biomass and size of corms, stigma biomass, number of apical sprouting buds, and number of adventitious roots. The endophyte also shifted metabolic flux towards enhanced production of apocarotenoids by modulating the expression of key pathway genes. Further, M. alpina CS10E4 enhanced tolerance to corm rot disease by releasing arachidonic acid which acts as conserved defense signal and induces jasmonic acid production in endophyte treated Crocus corms. This is first report on effect of a fungal endophyte on Crocus apocarotenoid metabolism and stress tolerance. PMID- 28819198 TI - Regulation of CCR7-dependent cell migration through CCR7 homodimer formation. AB - The chemokine receptor CCR7 contributes to various physiological and pathological processes including T cell maturation, T cell migration from the blood into secondary lymphoid tissues, and tumor cell metastasis to lymph nodes. Although a previous study suggested that the efficacy of CCR7 ligand-dependent T cell migration correlates with CCR7 homo- and heterodimer formation, the exact extent of contribution of the CCR7 dimerization remains unclear. Here, by inducing or disrupting CCR7 dimers, we demonstrated a direct contribution of CCR7 homodimerization to CCR7-dependent cell migration and signaling. Induction of stable CCR7 homodimerization resulted in enhanced CCR7-dependent cell migration and CCL19 binding, whereas induction of CXCR4/CCR7 heterodimerization did not. In contrast, dissociation of CCR7 homodimerization by a novel CCR7-derived synthetic peptide attenuated CCR7-dependent cell migration, ligand-dependent CCR7 internalization, ligand-induced actin rearrangement, and Akt and Erk signaling in CCR7-expressing cells. Our study indicates that CCR7 homodimerization critically regulates CCR7 ligand-dependent cell migration and intracellular signaling in multiple cell types. PMID- 28819199 TI - Transcriptome Analysis of the Effects of Shell Removal and Exogenous Gibberellin on Germination of Zanthoxylum Seeds. AB - The zanthoxylum seeds are oil-rich and have a very thick, dense and oily shell. In the natural conditions the seeds have a very low germination rate. Prior to treatment with GAs to promote germination, the seeds were usually soaked in sulfuric acid to remove shells easily. A high-throughput sequencing of mRNAs was performed to investigate the effects of the above treatments on the germination of zanthoxylum seeds. Seven libraries were assembled into 100,982 unigenes and 59,509 unigenes were annotated. We focused on the expression profiles of the key genes related to the oil metabolisms and hormone regulations during seed germination. Our data indicated the endogenous ABA of seeds was rich. The effects that the exogenous GAs promoted germination were apparent in the secong day of germination. Especially, for the first time our results indicated the exogenous GAs lowered the aerobic metabolism including the oil metabolisms during imbibition. We inferred that the exogenous GAs had inhibitory effects on the oil metabolisms to avoide oxidative damages to the imbibed seeds, and the seed shell played the role similiar to the exogenous GAs in the initial stage of germination in the natural conditions. PMID- 28819200 TI - Periostin-binding DNA aptamer treatment attenuates renal fibrosis under diabetic conditions. AB - Diabetic nephropathy, the major cause of chronic kidney disease, is associated with progressive renal fibrosis. Recently, accumulation of periostin, an extracellular matrix protein, was shown to augment renal fibrosis. Aptamers have higher binding affinities without developing the common side effects of antibodies. Thus, we evaluated the effect of periostin inhibition by an aptamer based inhibitor on renal fibrosis under diabetic conditions. In vitro, transforming growth factor-beta1 (TGF-beta1) treatment significantly upregulated periostin, fibronectin, and type I collagen mRNA and protein expressions in inner medullary collecting duct (IMCD) cells. These increases were attenuated significantly in periostin-binding DNA aptamer (PA)-treated IMCD cells exposed to TGF-beta1. In vivo, PA treatment attenuated the increased blood urea nitrogen levels in the diabetic mice significantly. Fibronectin and type I collagen mRNA and protein expressions increased significantly in the kidneys of diabetic mice: PA administration abrogated these increases significantly. Immunohistochemistry and Sirius Red staining also revealed that fibronectin expression was significantly higher and tubulointersititial fibrosis was significantly worse in diabetic mice kidneys compared with control mice. These changes were ameliorated by PA treatment. These findings suggested that inhibition of periostin using a DNA aptamer could be a potential therapeutic strategy against renal fibrosis in diabetic nephropathy. PMID- 28819202 TI - Mechanism of transformation in Mycobacteria using a novel shockwave assisted technique driven by in-situ generated oxyhydrogen. AB - We present a novel method for shockwave-assisted bacterial transformation using a miniature oxyhydrogen detonation-driven shock tube. We have obtained transformation efficiencies of about 1.28 * 106, 1.7 * 106, 5 * 106, 1 * 105, 1 * 105 and 2 * 105 transformants/ug of DNA for Escherichia coli, Salmonella Typhimurum, Pseudomonas aeruginosa, Mycobacterium smegmatis, Mycobacterium tuberculosis (Mtb) and Helicobacter pylori respectively using this method which are significantly higher than those obtained using conventional methods. Mtb is the most difficult bacteria to be transformed and hence their genetic modification is hampered due to their poor transformation efficiency. Experimental results show that longer steady time duration of the shockwave results in higher transformation efficiencies. Measurements of Young's modulus and rigidity of cell wall give a good understanding of the transformation mechanism and these results have been validated computationally. We describe the development of a novel shockwave device for efficient bacterial transformation in complex bacteria along with experimental evidence for understanding the transformation mechanism. PMID- 28819201 TI - Linker histone H1 prevents R-loop accumulation and genome instability in heterochromatin. AB - Linker histone H1 is an important structural component of chromatin that stabilizes the nucleosome and compacts the nucleofilament into higher-order structures. The biology of histone H1 remains, however, poorly understood. Here we show that Drosophila histone H1 (dH1) prevents genome instability as indicated by the increased gammaH2Av (H2AvS137P) content and the high incidence of DNA breaks and sister-chromatid exchanges observed in dH1-depleted cells. Increased gammaH2Av occurs preferentially at heterochromatic elements, which are upregulated upon dH1 depletion, and is due to the abnormal accumulation of DNA:RNA hybrids (R-loops). R-loops accumulation is readily detectable in G1 phase, whereas gammaH2Av increases mainly during DNA replication. These defects induce JNK-mediated apoptosis and are specific of dH1 depletion since they are not observed when heterochromatin silencing is relieved by HP1a depletion. Altogether, our results suggest that histone H1 prevents R-loops-induced DNA damage in heterochromatin and unveil its essential contribution to maintenance of genome stability.While structural importance of linker histone H1 in packaging eukaryotic genome into chromatin is well known, its biological function remains poorly understood. Here the authors reveal that Drosophila linker histone H1 prevents DNA:RNA hybrids accumulation and genome instability in heterochromatin. PMID- 28819203 TI - Differential diagnostic performance of acoustic radiation force impulse imaging in small (<=20 mm) breast cancers: Is it valuable? AB - To evaluate acoustic radiation force impulse (ARFI) inthe differential diagnosis of small (<=20 mm) solid breast lesions and identify the most efficient ARFI parameters. Conventional ultrasonography and ARFIwere performed in 120 patients with 121 small solid breast lesions. The area ratios (ARs) of the lesion on virtual touch tissue compared to B-mode were calculated. The shear wave velocity of the inner (SWVi) and boundary (SWVb) of the lesions and surrounding fatty tissue (SWVf) was measured. The ratio of SWVi to SWVf (SWVrat) was calculated. AR, SWVi, SWVb, and SWVrat were significantly larger in malignant lesions (all P < 0.001). A cutoff AR of 1.17 yielded the highest area under the receiver operating characteristic curveamong the various parameters (91.2% sensitivity, 85.9% specificity, 88.4% accuracy) for the differential diagnosis of small breast lesions, but this value did not significantly differ from SWVi (P = 0.1144). This AR cutoff indowngradingcategory 4a to category 3 would avoid 83.3% unnecessary biopsies, and improved diagnostic specificity up to 73.4% without decreasing sensitivity. AR and SWVi are efficient parameters for the differential diagnosis of small breast lesions, whichwill improve diagnostic specificity and reduce unnecessary biopsies. PMID- 28819204 TI - Prognostic factors and outcomes of unplanned extubation. AB - This study investigated the prognostic factors and outcomes of unplanned extubation (UE) in patients in a medical center's 6 intensive care units (ICUs) and calculated their mortality risk. We retrospectively reviewed the medical records of all adult patients in Chi Mei Medical Center who underwent UE between 2009 and 2015. During the study period, there were 305 episodes of UE in 295 ICU patients (men: 199 [67.5%]; mean age: 65.7 years; age range: 18-94 years). The mean Acute Physiology and Chronic Health Evaluation (APACHE) II score was 16.4, mean therapeutic intervention scoring system (TISS) score was 26.5, and mean Glasgow coma scale score was 10.4. One hundred thirty-six patients (46.1%) were re-intubated within 48 h. Forty-five died (mortality rate: 15.3%). Multivariate analyses showed 5 risk factors-respiratory rate, APACHE II score, uremia, liver cirrhosis, and weaning status-were independently associated with mortality. In conclusion, five risk factors including a high respiratory rate before UE, high APACHE II score, uremia, liver cirrhosis, and not in the process of being weaned were associated with high mortality in patients who underwent UE. PMID- 28819206 TI - Network robustness assessed within a dual connectivity framework: joint dynamics of the Active and Idle Networks. AB - Network robustness against attacks has been widely studied in fields as diverse as the Internet, power grids and human societies. But current definition of robustness is only accounting for half of the story: the connectivity of the nodes unaffected by the attack. Here we propose a new framework to assess network robustness, wherein the connectivity of the affected nodes is also taken into consideration, acknowledging that it plays a crucial role in properly evaluating the overall network robustness in terms of its future recovery from the attack. Specifically, we propose a dual perspective approach wherein at any instant in the network evolution under attack, two distinct networks are defined: (i) the Active Network (AN) composed of the unaffected nodes and (ii) the Idle Network (IN) composed of the affected nodes. The proposed robustness metric considers both the efficiency of destroying the AN and that of building-up the IN. We show, via analysis of well-known prototype networks and real world data, that trade offs between the efficiency of Active and Idle Network dynamics give rise to surprising robustness crossovers and re-rankings, which can have significant implications for decision making. PMID- 28819205 TI - Fast wide-volume functional imaging of engineered in vitro brain tissues. AB - The need for in vitro models that mimic the human brain to replace animal testing and allow high-throughput screening has driven scientists to develop new tools that reproduce tissue-like features on a chip. Three-dimensional (3D) in vitro cultures are emerging as an unmatched platform that preserves the complexity of cell-to-cell connections within a tissue, improves cell survival, and boosts neuronal differentiation. In this context, new and flexible imaging approaches are required to monitor the functional states of 3D networks. Herein, we propose an experimental model based on 3D neuronal networks in an alginate hydrogel, a tunable wide-volume imaging approach, and an efficient denoising algorithm to resolve, down to single cell resolution, the 3D activity of hundreds of neurons expressing the calcium sensor GCaMP6s. Furthermore, we implemented a 3D co culture system mimicking the contiguous interfaces of distinct brain tissues such as the cortical-hippocampal interface. The analysis of the network activity of single and layered neuronal co-cultures revealed cell-type-specific activities and an organization of neuronal subpopulations that changed in the two culture configurations. Overall, our experimental platform represents a simple, powerful and cost-effective platform for developing and monitoring living 3D layered brain tissue on chip structures with high resolution and high throughput. PMID- 28819207 TI - Long-term consistency in chimpanzee consolation behaviour reflects empathetic personalities. AB - In contrast to a wealth of human studies, little is known about the ontogeny and consistency of empathy-related capacities in other species. Consolation-post conflict affiliation from uninvolved bystanders to distressed others-is a suggested marker of empathetic concern in non-human animals. Using longitudinal data comprising nearly a decade of observations on over 3000 conflict interactions in 44 chimpanzees (Pan troglodytes), we provide evidence for relatively stable individual differences in consolation behaviour. Across development, individuals consistently differ from one another in this trait, with higher consolatory tendencies predicting better social integration, a sign of social competence. Further, similar to recent results in other ape species, but in contrast to many human self-reported findings, older chimpanzees are less likely to console than are younger individuals. Overall, given the link between consolation and empathy, these findings help elucidate the development of individual socio-cognitive and -emotional abilities in one of our closest relatives.Non-human animals are known to exhibit behaviours suggestive of empathy, but the development and maintenance of these traits is unexplored. Here, Webb and colleagues quantify individual consolation tendencies over 10 years across two chimpanzee groups and show evidence of consistent 'empathetic personalities'. PMID- 28819208 TI - Extrinsic mechanical forces mediate retrograde axon extension in a developing neuronal circuit. AB - To form functional neural circuits, neurons migrate to their final destination and extend axons towards their targets. Whether and how these two processes are coordinated in vivo remains elusive. We use the zebrafish olfactory placode as a system to address the underlying mechanisms. Quantitative live imaging uncovers a choreography of directed cell movements that shapes the placode neuronal cluster: convergence of cells towards the centre of the placodal domain and lateral cell movements away from the brain. Axon formation is concomitant with lateral movements and occurs through an unexpected, retrograde mode of extension, where cell bodies move away from axon tips attached to the brain surface. Convergence movements are active, whereas cell body lateral displacements are of mainly passive nature, likely triggered by compression forces from converging neighbouring cells. These findings unravel a previously unknown mechanism of neuronal circuit formation, whereby extrinsic mechanical forces drive the retrograde extension of axons.How neuronal migration and axon growth coordinate during development is only partially understood. Here the authors use quantitative imaging to characterise the morphogenesis of the zebrafish olfactory placode and report an unexpected phenomenon, whereby axons extend through the passive movement of neuron cell bodies away from tethered axon tips. PMID- 28819209 TI - Synergistic Immuno Photothermal Nanotherapy (SYMPHONY) for the Treatment of Unresectable and Metastatic Cancers. AB - Metastatic spread is the mechanism in more than 90 percent of cancer deaths and current therapeutic options, such as systemic chemotherapy, are often ineffective. Here we provide a proof of principle for a novel two-pronged modality referred to as Synergistic Immuno Photothermal Nanotherapy (SYMPHONY) having the potential to safely eradicate both primary tumors and distant metastatic foci. Using a combination of immune-checkpoint inhibition and plasmonic gold nanostar (GNS)-mediated photothermal therapy, we were able to achieve complete eradication of primary treated tumors and distant untreated tumors in some mice implanted with the MB49 bladder cancer cells. Delayed rechallenge with MB49 cancer cells injection in mice that appeared cured by SYMPHONY did not lead to new tumor formation after 60 days observation, indicating that SYMPHONY treatment induced effective long-lasting immunity against MB49 cancer cells. PMID- 28819210 TI - Zeb2 is a negative regulator of midbrain dopaminergic axon growth and target innervation. AB - Neural connectivity requires neuronal differentiation, axon growth, and precise target innervation. Midbrain dopaminergic neurons project via the nigrostriatal pathway to the striatum to regulate voluntary movement. While the specification and differentiation of these neurons have been extensively studied, the molecular mechanisms that regulate midbrain dopaminergic axon growth and target innervation are less clear. Here we show that the transcription factor Zeb2 cell-autonomously represses Smad signalling to limit midbrain dopaminergic axon growth and target innervation. Zeb2 levels are downregulated in the embryonic rodent midbrain during the period of dopaminergic axon growth, when BMP pathway components are upregulated. Experimental knockdown of Zeb2 leads to an increase in BMP-Smad dependent axon growth. Consequently there is dopaminergic hyperinnervation of the striatum, without an increase in the numbers of midbrain dopaminergic neurons, in conditional Zeb2 (Nestin-Cre based) knockout mice. Therefore, these findings reveal a new mechanism for the regulation of midbrain dopaminergic axon growth during central nervous system development. PMID- 28819211 TI - Dynamic local connectivity uncovers altered brain synchrony during propofol sedation. AB - Human consciousness is considered a result of the synchronous "humming" of multiple dynamic networks. We performed a dynamic functional connectivity analysis using resting state functional magnetic resonance imaging (rsfMRI) in 14 patients before and during a propofol infusion to characterize the sedation induced alterations in consciousness. A sliding 36-second window was used to derive 59 time points of whole brain integrated local connectivity measurements. Significant changes in the connectivity strength (Z Corr) at various time points were used to measure the connectivity fluctuations during awake and sedated states. Compared with the awake state, sedation was associated with reduced cortical connectivity fluctuations in several areas connected to the default mode network and around the perirolandic cortex with a significantly decreased correlation of connectivity between their anatomical homologues. In addition, sedation was associated with increased connectivity fluctuations in the frequency range of 0.027 to 0.063 Hz in several deep nuclear regions, including the cerebellum, thalamus, basal ganglia and insula. These findings advance our understanding of sedation-induced altered consciousness by visualizing the altered dynamics in several cortical and subcortical regions and support the concept of defining consciousness as a dynamic and integrated network. PMID- 28819212 TI - Quantifying the free energy landscape between polymers and minerals. AB - Higher organisms as well as medical and technological materials exploit mineral polymer interactions, however, mechanistic understanding of these interactions is poorly constrained. Dynamic force spectroscopy can probe the free energy landscape of interacting bonds, but interpretations are challenged by the complex mechanical behavior of polymers. Here we restate the difficulties inherent to applying DFS to polymer-linked adhesion and present an approach to gain quantitative insight into polymer-mineral binding. PMID- 28819213 TI - In vivo regulation of glycogen synthase kinase 3beta activity in neurons and brains. AB - Glycogen synthase kinase 3beta (GSK3beta) is a multifunctional protein kinase involved in many cellular activities including development, differentiation and diseases. GSK3beta is thought to be constitutively activated by autophosphorylation at Tyr216 and inactivated by phosphorylation at Ser9. The GSK3beta activity has previously been evaluated by inhibitory Ser9 phosphorylation, but it does not necessarily indicate the kinase activity itself. Here, we applied the Phos-tag SDS-PAGE technique to the analysis of GSK3beta phosphoisotypes in cells and brains. There were three phosphoisotypes of GSK3beta; double phosphorylation at Ser9 and Tyr216, single phosphorylation at Tyr216 and the nonphosphorylated isotype. Active GSK3beta with phosphorylation at Tyr216 represented half or more of the total GSK3beta in cultured cells. Although levels of phospho-Ser9 were increased by insulin treatment, Ser9 phosphorylation occurred only in a minor fraction of GSK3beta. In mouse brains, GSK3beta was principally in the active form with little Ser9 phosphorylation, and the phosphoisotypes of GSK3beta changed depending on the regions of the brain, age, sex and disease conditions. These results indicate that the Phos-tag SDS-PAGE method provides a simple and appropriate measurement of active GSK3beta in vivo, and the activity is regulated by the mechanism other than phosphorylation on Ser9. PMID- 28819214 TI - HIV-1 Nef-induced cardiotoxicity through dysregulation of autophagy. AB - Cardiovascular disease is a leading cause of co-morbidity in HIV-1 positive patients, even those in whom plasma virus levels are well-controlled. The pathogenic mechanism of HIV-1-associated cardiomyopathy is unknown, but has been presumed to be mediated indirectly, owing to the absence of productive HIV-1 replication in cardiomyocytes. We sought to investigate the effect of the HIV-1 auxiliary protein, Nef, which is suspected of extracellular release by infected CD4+ T cells on protein quality control and autophagy in cardiomyocytes. After detection of Nef in the serum of HIV-1 positive patients and the accumulation of this protein in human and primate heart tissue from HIV-1/SIV-infected cells we employed cell and molecular biology approaches to investigate the effect of Nef on cardiomyocyte-homeostasis by concentrating on protein quality control (PQC) pathway and autophagy. We found that HIV-1 Nef-mediated inhibition of autophagy flux leads to cytotoxicity and death of cardiomyocytes. Nef compromises autophagy at the maturation stage of autophagosomes by interacting with Beclin 1/Rab7 and dysregulating TFEB localization and cellular lysosome content. These effects were reversed by rapamycin treatment. Our results indicate that HIV-1 Nef-mediated inhibition of cellular PQC is one possible mechanism involved in the development of HIV-associated cardiomyopathy. PMID- 28819215 TI - Dilution of whisky - the molecular perspective. AB - Whisky is distilled to around 70% alcohol by volume (vol-%) then diluted to about 40 vol-%, and often drunk after further slight dilution to enhance its taste. The taste of whisky is primarily associated with amphipathic molecules, such as guaiacol, but why and how dilution enhances the taste is not well understood. We carried out computer simulations of water-ethanol mixtures in the presence of guaiacol, providing atomistic details on the structure of the liquid mixture. We found that guaiacol is preferentially associated with ethanol, and, therefore, primarily found at the liquid-air interface in mixtures that contain up to 45 vol % of ethanol. At ethanol concentrations of 59 vol-% or higher, guaiacol is increasingly surrounded by ethanol molecules and is driven to the bulk. This indicates that the taste of guaiacol in the whisky would be enhanced upon dilution prior to bottling. Our findings may apply to other flavour-giving amphipathic molecules and could contribute to optimising the production of spirits for desired tastes. Furthermore, it sheds light on the molecular structure of water-alcohol mixtures that contain small solutes, and reveals that interactions with the water may be negligible already at 89 vol-% of ethanol. PMID- 28819216 TI - Identification of Endogenous Reference Genes for RT-qPCR Expression Analysis in Urochloa brizantha Under Abiotic Stresses. AB - Urochloa brizantha is one of the most important warm season forage grasses in tropical countries. Despite its importance, there are few studies on gene expression in this species under stressful conditions. Real-time (RT-qPCR) is an accurate technique for gene quantification analysis, but reference genes must be validated under the same conditions used to assess the expression of the target genes. Here, we evaluated the stability of nine reference genes: Actin 12, Eukaryotic initiation factor 4 A, Elongation factor-1 alpha, FTSH protease 4, U2 auxiliary fator, Succinol Co-enzyme A, Tubulin alfa-5, Tubulin beta-6, Ubiquitin conjugating enzyme. Total RNA was extract from leaf tissues of U. brizantha subjected to 6, 12 and 24 h of cold and heat stresses (10 and 45 degrees C, respectively), and drought, including moderate (-0.5 to -0.7 MPa), severe (-1.1 to -1.8 MPa) and recovery after re-watering. The RefFinder web-based tool was used to rank the most stable reference genes for each stress. Elongation factor-1 alpha, Elongation factor-1 alpha or Ubiquitin conjugating enzyme, and Eukaryotic initiation factor 4 A were the most stable genes for heat, cold and drought stress, respectively. The expression of Rubisco large subunit gene was normalized against the most stable gene selected by ReFfinder for each stress. PMID- 28819217 TI - Anti-biofilm effects of anthranilate on a broad range of bacteria. AB - Anthranilate, one of tryptophan degradation products has been reported to interfere with biofilm formation by Pseudomonas aeruginosa. Here, we investigated the effects of anthranilate on biofilm formation by various bacteria and the mechanisms responsible. Anthranilate commonly inhibited biofilm formation by P. aeruginosa, Vibrio vulnificus, Bacillus subtilis, Salmonella enterica serovar Typhimurium, and Staphylococcus aureus, and disrupted biofilms preformed by these bacteria. Because anthranilate reduced intracellular c-di-GMP and enhanced swimming and swarming motilities in P. aeruginosa, V. vulnificus, B. subtilis, and S. enterica, it is likely that anthranilate disrupts biofilms by inducing the dispersion of these bacteria. On the other hand, in S. aureus, a non-flagellate bacterium that has no c-di-GMP signaling, anthranilate probably inhibits biofilm formation by reducing slime production. These results suggest that anthranilate has multiple ways for biofilm inhibition. Furthermore, because of its good biofilm inhibitory effects and lack of cytotoxicity to human cells even at high concentration, anthranilate appears to be a promising agent for inhibiting biofilm formation by a broad range of bacteria. PMID- 28819218 TI - Low threshold Rhodamine-doped whispering gallery mode microlasers fabricated by direct laser writing. AB - The combination of the outstanding properties of whispering gallery modes with both the flexibility and ease of processing of polymers is particularly attractive for photonics applications. However, the versatile fabrication of polymeric nano/microdevices with the desired photonic performance has proven challenging. Here, we report on lasing in Rhodamine B doped whispering gallery mode microcavities fabricated by direct laser writing via two-photon polymerization. Threshold pump energies as low as 12 nJ were achieved for free space pulsed excitation at 532 nm. To the best of our knowledge, this is the lowest laser threshold attained for microcavities fabricated in a single step of femtosecond laser writing, a remarkable feat that stands out from other fabrication methods. PMID- 28819219 TI - The fabrication of an ICA-SF/PLCL nanofibrous membrane by coaxial electrospinning and its effect on bone regeneration in vitro and in vivo. AB - GBR is currently accepted as one of the most effective approaches for bone defect regeneration relating to dental implant. Icariin is the main active ingredient in the extraction of total flavonoids from the Chinese traditional herb Epimediumbrevicornum Maxim. In this study, ICA was successfully incorporated into the nanofibers barrier membrane (ICA-SF/PLCL) as osteoinduction factor by coaxial electrospinning and was released in a sustained and controlled manner. The entire release period included two stages: an initial burst stage (47.54 +/- 0.06% on 5 d) and a decreasing and constant stage (82.09 +/- 1.86% on 30 d). The membrane has good biocompatibility with BMMSCs anchored and significantly promoted its osteogenic activity. Moreover, in vivo experiment, bone defect covered by ICA SF/PLCL membrane in rat cranium were statistically repaired compare to other groups. 12 weeks after implantation, in the test group, the new bone formation spread to cover most of the defect region with volume and density of approximately 15.95 +/- 3.58 mm3 and 14.02 +/- 0.93%. These results demonstrated that ICA-SF/PLCL nanofibrous membrane could be a promising barrier applicated for GBR. PMID- 28819220 TI - Nosema ceranae, Fipronil and their combination compromise honey bee reproduction via changes in male physiology. AB - The honey bee is threatened by biological agents and pesticides that can act in combination to induce synergistic effects on its physiology and lifespan. The synergistic effects of a parasite/pesticide combination have been demonstrated on workers and queens, but no studies have been performed on drones despite their essential contribution to colony sustainability by providing semen diversity and quality. The effects of the Nosema ceranae/fipronil combination on the life traits and physiology of mature drones were examined following exposure under semi-field conditions. The results showed that the microsporidia alone induced moderate and localized effects in the midgut, whereas fipronil alone induced moderate and generalized effects. The parasite/insecticide combination drastically affected both physiology and survival, exhibiting an important and significant generalized action that could jeopardize mating success. In terms of fertility, semen was strongly impacted regardless of stressor, suggesting that drone reproductive functions are very sensitive to stress factors. These findings suggest that drone health and fertility impairment might contribute to poorly mated queens, leading to the storage of poor quality semen and poor spermathecae diversity. Thus, the queens failures observed in recent years might result from the continuous exposure of drones to multiple environmental stressors. PMID- 28819221 TI - Functional validation of GPIHBP1 and identification of a functional mutation in GPIHBP1 for milk fat traits in dairy cattle. AB - In a previous genome-wide association study (GWAS) on milk production traits in a Chinese Holstein population, we revealed that GPIHBP1 is a novel promising candidate gene for milk fat content traits. In this study, we performed over expression and RNAi experiments on GPIHBP1 in bovine primary mammary epithelial cells. The results showed that the expression of several important milk fat related genes (LPL, CD36, VLDLR, ACACA and FASN) increased or decreased when the expression of GPIHBP1 was up- or down-regulated. To identify the potential functional SNP involved, we explored the genetic variants of GPIHBP1 and found that a G/A mutation (chr14:2553998) in the promoter region of GPIHBP1 significantly reduced promoter activity and had an effect on transcription factor binding sites. This finding was consistent with the lower expression of GPIHBP1 observed in the mammary gland tissue of cows harboring the homozygous AA mutation compared with wild-type homozygous GG or heterozygous AG. Furthermore, association analysis showed that cows with the AA genotype outperformed those with the GG and AG genotypes in terms of the milk fat percentage. Our study demonstrates that GPIHBP1 could be a strong candidate gene for milk fat content traits and, in particular, the G to A mutation at chr14:2553998 within GPIHBP1 could be a functional mutation related to its effects. PMID- 28819222 TI - Identification and Functional Characterization of Tomato CircRNAs Derived from Genes Involved in Fruit Pigment Accumulation. AB - CircRNAs, a class of widespread circular RNAs produced from precursor mRNA back splicing, have been implicated in regulation of gene expression in eukaryotes, but their biological functions in plants have not yet been elucidated. By deep sequencing of rRNA-removed and RNase R-digested RNA samples we have identified several thousands of putative back-splicing sites in tomato fruit (Solanum lycopersicum) and show that the abundance of some of these circRNAs derived from fruit pigment biosynthesis genes are regulated by fruit ripening. Herein, we overexpressed a circRNA derived from Phytoene Synthase 1 (PSY1) in tomato 'Ailsa Craig' and microTom. The PSY1 mRNA abundance, the lycopene and beta-carotene accumulation were decreased significantly in the transgenic tomato fruits, likely due to the continuous highly expressed circRNAs and/or the low abundant linear RNAs generated from the overexpression vector. Besides, overexpression of a circRNA derived from Phytoene Desaturase (PDS) showed similar results. Our results provide biological insights into plant circRNAs. PMID- 28819223 TI - Levobuipivacaine-Induced Dissemination of A549 Lung Cancer Cells. AB - While anaesthetics are frequently used on cancer patients during surgical procedures, their consequence on cancer progression remains to be elucidated. In this study, we sought to investigate the influence of local anesthetics on lung cancer cell dissemination in vitro and in vivo. A549 human non-small lung cancer cells were treated with various local anaesthetics including ropivacaine, lidocaine, levobupivacaine and bupivacaine. Cell barrier property was assessed using an electric cell-substrate impedance sensing (ECIS) system. The epithelial to-mesenchymal transition (EMT) of treated cells was studied by immunofluorescence staining. In vitro and in vivo cancer cell dissemination were investigated.Gene expression microarray and quantitative real-time PCR (qrt-PCR) assays were used to identify the genes responsible for levobupivacaine-mediated cancer cell dissemination.The results illustrated that only levobupivacaine induced EMT in the treated cells and also caused the dissemination of cancer cells in vitro. In addition, after intravenous injection, levobupivacaine encouraged cancer cell dissemination in vivo. Gene expression microarray, qrt-PCR and immunoblotting revealed that after levobupivacaine treatment, the hypoxia inducible factor (HIF)- 2alpha gene was upregulated in cancer cells. Our findings suggest that levobupivacaine may induce A549 lung cancer cell dissemination both in vitro and in vivo. More specifically, HIF-2alpha signaling possibly contributes to levobupivacaine-mediated A549 lung cancer cell dissemination. PMID- 28819224 TI - The Role of Rho-GTPases and actin polymerization during Macrophage Tunneling Nanotube Biogenesis. AB - Macrophage interactions with other cells, either locally or at distances, are imperative in both normal and pathological conditions. While soluble means of communication can transmit signals between different cells, it does not account for all long distance macrophage interactions. Recently described tunneling nanotubes (TNTs) are membranous channels that connect cells together and allow for transfer of signals, vesicles, and organelles. However, very little is known about the mechanism by which these structures are formed. Here we investigated the signaling pathways involved in TNT formation by macrophages using multiple imaging techniques including super-resolution microscopy (3D-SIM) and live-cell imaging including the use of FRET-based Rho GTPase biosensors. We found that formation of TNTs required the activity and differential localization of Cdc42 and Rac1. The downstream Rho GTPase effectors mediating actin polymerization through Arp2/3 nucleation, Wiskott-Aldrich syndrome protein (WASP) and WASP family verprolin-homologous 2 (WAVE2) proteins are also important, and both pathways act together during TNT biogenesis. Finally, TNT function as measured by transfer of cellular material between cells was reduced following depletion of a single factor demonstrating the importance of these factors in TNTs. Given that the characterization of TNT formation is still unclear in the field; this study provides new insights and would enhance the understanding of TNT formation towards investigating new markers. PMID- 28819226 TI - A theory for spiral wave drift induced by ac and polarized electric fields in chemical excitable media. AB - Spiral waves are shown to undergo directional drifts in the presence of ac and polarized electric fields when their frequencies are twice of the spiral frequencies. Here, we propose a quantitative description for the spiral wave drift induced by weak electric fields, and provide the explicit equations for the spiral wave drift speed and direction. Numerical simulations are performed to demonstrate the quantitative agreement with analytical results in both weakly and highly excitable media. PMID- 28819225 TI - Cytochrome P450/ABC transporter inhibition simultaneously enhances ivermectin pharmacokinetics in the mammal host and pharmacodynamics in Anopheles gambiae. AB - Mass administration of endectocides, drugs that kill blood-feeding arthropods, has been proposed as a complementary strategy to reduce malaria transmission. Ivermectin is one of the leading candidates given its excellent safety profile. Here we provide proof that the effect of ivermectin can be boosted at two different levels by drugs inhibiting the cytochrome or ABC transporter in the mammal host and the target mosquitoes. Using a mini-pig model, we show that drug mediated cytochrome P450/ABC transporter inhibition results in a 3-fold increase in the time ivermectin remains above mosquito-killing concentrations. In contrast, P450/ABC transporter induction with rifampicin markedly impaired ivermectin absorption. The same ketoconazole-mediated cytochrome/ABC transporter inhibition also occurs outside the mammal host and enhances the mortality of Anopheles gambiae. This was proven by using the samples from the mini-pig experiments to conduct an ex-vivo synergistic bioassay by membrane-feeding Anopheles mosquitoes. Inhibiting the same cytochrome/xenobiotic pump complex in two different organisms to simultaneously boost the pharmacokinetic and pharmacodynamic activity of a drug is a novel concept that could be applied to other systems. Although the lack of a dose-response effect in the synergistic bioassay warrants further exploration, our study may have broad implications for the control of parasitic and vector-borne diseases. PMID- 28819227 TI - Suspected limited mobility of a Middle Pleistocene woman from Southern Italy: strontium isotopes of a human deciduous tooth. AB - We present the Sr isotopic composition of enamel of the most ancient deciduous tooth ever discovered in Italy to assess human mobility in Middle Pleistocene. Reconstructing ancient mobility is crucial for understanding human strategy at exploiting temporally and spatially patchy resources, with most studies focusing on indirect evidences, ultimately affecting our interpretation on hominin territoriality and energetic costs invested by hominin groups. Here, we use the high spatial resolution and micro-destructivity options offered by the Laser Ablation Multi-Collector Inductively Coupled Plasma Mass Spectrometry technique, to determine the 87Sr/ 86Sr intra-tooth variability of a human deciduous incisor from the Middle Pleistocene layers of the Isernia La Pineta site (Italy). We compared these data with the Sr isotopic signature of local micro-mammals, the broadest home-range of the macro-mammals and with modern plant samples. Our study reveals that while macro-mammals have possibly migrated through the landscape for up to 50 km, the pregnant woman from Isernia was probably local, given that the isotopic ratio of the enamel falls within the local range and is comparable with the signature of the local plants in a radius of 10 km. This is the first case study of Sr isotopic composition determination in such ancient deciduous tooth. PMID- 28819228 TI - Convergent and divergent genetic changes in the genome of Chinese and European pigs. AB - Since 10,000 BC, continuous human selection has led to intense genetic and phenotypic changes in pig (Sus scrofa) domestication. Through whole genome analysis of 257 individuals, we demonstrated artificial unidirectional and bidirectional selection as the primary force to shape the convergent and divergent changes between Chinese domestic pigs (CHD) and European domestic pigs (EUD). We identified 31 genes in unidirectional selection regions that might be related to fundamental domestication requirements in pigs. And these genes belong predominantly to categories related to the nervous system, muscle development, and especially to metabolic diseases. In addition, 35 genes, representing different breeding preference, were found under bidirectional selection for the distinct leanness and reproduction traits between CHD and EUD. The convergent genetic changes, contributing physical and morphological adaption, represent the common concerns on pig domestication. And the divergent genetic changes reflect distinct breeding goals between Chinese and European pigs. Using ITPR3, AHR and NMU as examples, we explored and validated how the genetic variations contribute to the phenotype changes. PMID- 28819229 TI - Cryo-EM analysis of homodimeric full-length LRRK2 and LRRK1 protein complexes. AB - Leucine-rich repeat kinase 2 (LRRK2) is a large multidomain protein implicated in the pathogenesis of both familial and sporadic Parkinson's disease (PD), and currently one of the most promising therapeutic targets for drug design in Parkinson's disease. In contrast, LRRK1, the closest homologue to LRRK2, does not play any role in PD. Here, we use cryo-electron microscopy (cryo-EM) and single particle analysis to gain structural insight into the full-length dimeric structures of LRRK2 and LRRK1. Differential scanning fluorimetry-based screening of purification buffers showed that elution of the purified LRRK2 protein in a high pH buffer is beneficial in obtaining high quality cryo-EM images. Next, analysis of the 3D maps generated from the cryo-EM data show 16 and 25 A resolution structures of full length LRRK2 and LRRK1, respectively, revealing the overall shape of the dimers with two-fold symmetric orientations of the protomers that is closely similar between the two proteins. These results suggest that dimerization mechanisms of both LRRKs are closely related and hence that specificities in functions of each LRRK are likely derived from LRRK2 and LRRK1's other biochemical functions. To our knowledge, this study is the first to provide 3D structural insights in LRRK2 and LRRK1 dimers in parallel. PMID- 28819230 TI - Genomic signatures of local adaptation reveal source-sink dynamics in a high gene flow fish species. AB - Understanding source-sink dynamics is important for conservation management, particularly when climatic events alter species' distributions. Following a 2011 'marine heatwave' in Western Australia, we observed high recruitment of the endemic fisheries target species Choerodon rubescens, towards the cooler (southern) end of its distribution. Here, we use a genome wide set of 14 559 single-nucleotide polymorphisms (SNPs) to identify the likely source population for this recruitment event. Most loci (76%) showed low genetic divergence across the species' range, indicating high levels of gene flow and confirming previous findings using neutral microsatellite markers. However, a small proportion of loci showed strong patterns of differentiation and exhibited patterns of population structure consistent with local adaptation. Clustering analyses based on these outlier loci indicated that recruits at the southern end of C. rubescens' range originated 400 km to the north, at the centre of the species' range, where average temperatures are up to 3 degrees C warmer. Survival of these recruits may be low because they carry alleles adapted to an environment different to the one they now reside in, but their survival is key to establishing locally adapted populations at and beyond the range edge as water temperatures increase with climate change. PMID- 28819231 TI - In Vitro Micropatterned Human Pluripotent Stem Cell Test (uP-hPST) for Morphometric-Based Teratogen Screening. AB - Exposure to teratogenic chemicals during pregnancy may cause severe birth defects. Due to high inter-species variation of drug responses as well as financial and ethical burdens, despite the widely use of in vivo animal tests, it's crucial to develop highly predictive human pluripotent stem cell (hPSC) based in vitro assays to identify potential teratogens. Previously we have shown that the morphological disruption of mesoendoderm patterns formed by geometrically-confined cell differentiation and migration using hPSCs could potentially serve as a sensitive morphological marker in teratogen detection. Here, a micropatterned human pluripotent stem cell test (uP-hPST) assay was developed using 30 pharmaceutical compounds. A simplified morphometric readout was developed to quantify the mesoendoderm pattern changes and a two-step classification rule was generated to identify teratogens. The optimized uP-hPST could classify the 30 compounds with 97% accuracy, 100% specificity and 93% sensitivity. Compared with metabolic biomarker-based hPSC assay by Stemina, the uP-hPST could successfully identify misclassified drugs Bosentan, Diphenylhydantoin and Lovastatin, and show a higher accuracy and sensitivity. This scalable uP-hPST may serve as either an independent assay or a complement assay for existing assays to reduce animal use, accelerate early discovery-phase drug screening and help general chemical screening of human teratogens. PMID- 28819232 TI - Ensemble of Thermostatically Controlled Loads: Statistical Physics Approach. AB - Thermostatically controlled loads, e.g., air conditioners and heaters, are by far the most widespread consumers of electricity. Normally the devices are calibrated to provide the so-called bang-bang control - changing from on to off, and vice versa, depending on temperature. We considered aggregation of a large group of similar devices into a statistical ensemble, where the devices operate following the same dynamics, subject to stochastic perturbations and randomized, Poisson on/off switching policy. Using theoretical and computational tools of statistical physics, we analyzed how the ensemble relaxes to a stationary distribution and established a relationship between the relaxation and the statistics of the probability flux associated with devices' cycling in the mixed (discrete, switch on/off, and continuous temperature) phase space. This allowed us to derive the spectrum of the non-equilibrium (detailed balance broken) statistical system and uncover how switching policy affects oscillatory trends and the speed of the relaxation. Relaxation of the ensemble is of practical interest because it describes how the ensemble recovers from significant perturbations, e.g., forced temporary switching off aimed at utilizing the flexibility of the ensemble to provide "demand response" services to change consumption temporarily to balance a larger power grid. We discuss how the statistical analysis can guide further development of the emerging demand response technology. PMID- 28819233 TI - Biology, physiology and gene expression of grasshopper Oedaleus asiaticus exposed to diet stress from plant secondary compounds. AB - We studied the role of plant primary and secondary metabolites in mediating plant insect interactions by conducting a no-choice single-plant species field experiment to compare the suitability, enzyme activities, and gene expression of Oedaleus asiaticus grasshoppers feeding on four host and non-host plants with different chemical traits. O. asiaticus growth showed a positive relationship to food nutrition content and a negative relationship to secondary compounds content. Grasshopper amylase, chymotrypsin, and lipase activities were positively related to food starch, crude protein, and lipid content, respectively. Activity of cytochrome P450s, glutathione-S-transferase, and carboxylesterase were positively related to levels of secondary plant compounds. Gene expression of UDP glucuronosyltransferase 2C1, cytochrome P450 6K1 were also positively related to secondary compounds content in the diet. Grasshoppers feeding on Artemisia frigida, a species with low nutrient content and a high level of secondary compounds, had reduced growth and digestive enzyme activity. They also had higher detoxification enzyme activity and gene expression compared to grasshoppers feeding on the grasses Cleistogenes squarrosa, Leymus chinensis, or Stipa krylovii. These results illustrated Oedaleus asiaticus adaptive responses to diet stress resulting from toxic chemicals, and support the hypothesis that nutritious food benefits insect growth, but plant secondary compounds are detrimental for insect growth. PMID- 28819234 TI - Transcriptome of neonatal preBotzinger complex neurones in Dbx1 reporter mice. AB - We sequenced the transcriptome of brainstem interneurons in the specialized respiratory rhythmogenic site dubbed preBotzinger Complex (preBotC) from newborn mice. To distinguish molecular characteristics of the core oscillator we compared preBotC neurons derived from Dbx1-expressing progenitors that are respiratory rhythmogenic to neighbouring non-Dbx1-derived neurons, which support other respiratory and non-respiratory functions. Results in three categories are particularly salient. First, Dbx1 preBotC neurons express kappa-opioid receptors in addition to MU-opioid receptors that heretofore have been associated with opiate respiratory depression, which may have clinical applications. Second, Dbx1 preBotC neurons express the hypoxia-inducible transcription factor Hif1a at levels three-times higher than non-Dbx1 neurons, which links core rhythmogenic microcircuits to O2-related chemosensation for the first time. Third, we detected a suite of transcription factors including Hoxa4 whose expression pattern may define the rostral preBotC border, Pbx3 that may influence ipsilateral connectivity, and Pax8 that may pertain to a ventrally-derived subset of Dbx1 preBotC neurons. These data establish the transcriptomic signature of the core respiratory oscillator at a perinatal stage of development. PMID- 28819235 TI - Expression of long non-coding RNA MFI2-AS1 is a strong predictor of recurrence in sporadic localized clear-cell renal cell carcinoma. AB - Prediction of recurrence is a challenge for the development of adjuvant treatments in clear-cell renal cell carcinoma (ccRCC). In these tumors, expression of long non-coding RNAs (lncRNAs) are deregulated and closely associated with prognosis. Thus, we aimed to predict ccRCC recurrence risk using lncRNA expression. We identified prognostic lncRNAs in a training set of 351 localized ccRCCs from The Cancer Genome Atlas and validated lncRNA-based recurrence classification in an independent cohort of 167 localized ccRCCs. We identified lncRNA MFI2-AS1 as best candidate in the training set. In the validation cohort, MFI2-AS1 expression was independently associated with shorter disease-free survival (Hazard Ratio (HR) for relapse 3.5, p = 0.0001). Combined with Leibovich classification, MFI2-AS1 status improved prediction of recurrence (C-index 0.70) compared to MFI2-AS1 alone (0.67) and Leibovich classification alone (0.66). In patients with aggressive tumors (Leibovich >=5), MFI2-AS1 expression was associated with dramatically increased risk of relapse (HR 12.16, p < 0.0001) compared to patients with undetectable MFI2-AS1 who had favorable outcomes. Compared to normal samples, MFI2-AS1 was upregulated in tumor tissue, and higher expression was associated with metastatic dissemination. Overall, MFI2 AS1 status improves patient stratification in localized ccRCC, which supports further integration of lncRNAs in molecular cancer classifications. PMID- 28819236 TI - Impact of sex, fat distribution and initial body weight on oxytocin's body weight regulation. AB - Obesity is considered as a worldwide problem in both males and females. Although many studies have demonstrated the efficiency of oxytocin (Oxt) as an anti obesity peptide, there is no comparative study of its effect in males and females. This study aims to determine factors (sex, initial body weight, and fat distribution) that may affect the ability of Oxt to regulate body weight (BW). With regard to sex, Oxt reduced BW similarly in males and females under both high fat diet (HFD) and standard chow-fed condition. The BW reduction induced by Oxt correlated with initial BW in male and female mice under HFD conditions. Oxt showed an equal efficacy in fat degradation in both the visceral and subcutaneous fat mass in both males and females fed with HFD. The effect of Oxt on BW reduction was attenuated in standard chow-fed male and female mice. Therefore, our results suggest that administration of Oxt is more effective in reducing BW in subjects with a high initial BW with increased fat accumulation. The present data contains important information for the possible clinical application of Oxt for the treatment of obesity. PMID- 28819237 TI - Disruption of the plant-specific CFS1 gene impairs autophagosome turnover and triggers EDS1-dependent cell death. AB - Cell death, autophagy and endosomal sorting contribute to many physiological, developmental and immunological processes in plants. They are mechanistically interconnected and interdependent, but the molecular basis of their mutual regulation has only begun to emerge in plants. Here, we describe the identification and molecular characterization of CELL DEATH RELATED ENDOSOMAL FYVE/SYLF PROTEIN 1 (CFS1). The CFS1 protein interacts with the ENDOSOMAL SORTING COMPLEX REQUIRED FOR TRANSPORT I (ESCRT-I) component ELCH (ELC) and is localized at ESCRT-I-positive late endosomes likely through its PI3P and actin binding SH3YL1 Ysc84/Lsb4p Lsb3p plant FYVE (SYLF) domain. Mutant alleles of cfs1 exhibit auto-immune phenotypes including spontaneous lesions that show characteristics of hypersensitive response (HR). Autoimmunity in cfs1 is dependent on ENHANCED DISEASE SUSCEPTIBILITY 1 (EDS1)-mediated effector-triggered immunity (ETI) but independent from salicylic acid. Additionally, cfs1 mutants accumulate the autophagy markers ATG8 and NBR1 independently from EDS1. We hypothesize that CFS1 acts at the intersection of autophagosomes and endosomes and contributes to cellular homeostasis by mediating autophagosome turnover. PMID- 28819240 TI - Nature and characteristics of temperature background effect for interactive respiration process. AB - Indoor air quality (IAQ) is much more crucial to human health than its atmospheric air quality counterpart. Improving indoor air environment requires investigating how different indoor air stability affects airflow trajectory. By presenting both manikin experiment and Computational Fluid Dynamics (CFD) simulation, we find that temperature background effect, i.e., indoor air stability, which is a measure of the nature or attribute of the capacity to keep the original or initial inertia force or inertia transmission state instead of turbulence diffusion or transmission restraining state, i.e., a kind of inertia stability, rather than a turbulence diffusion characteristic stability, is markedly affecting the interactive respiration process. So we define and derive a new parameter called G c number as a criterion to judge air stability. Furthermore, we find the phenomenon of inertia conjugation. Air stability and inertia conjugation, which named together as temperature background effect, work together on interactive respiration process. This work gives us a re-orientation of temperature difference agents and thus improves human being's living environment. PMID- 28819238 TI - Effects of environmental enrichment upon ethanol-induced conditioned place preference and pre-frontal BDNF levels in adolescent and adult mice. AB - Environmental enrichment (EE) provides a non-pharmacological tool to alter drug induced reward, yet its effects on ethanol-induced reward remain controversial. We analyzed adolescent vs. adult (mice) differences in the influence of EE on ethanol-induced conditioned place preference (CPP). The effects of these treatments on brain-derived neurotrophic factor (BDNF) levels in the prefrontal cortex were examined in a separate group of animals. Ethanol-induced CPP was found in adults, and it was similar in EE and in animals reared under standard housing conditions (SC). Adolescents kept under EE, but not those in SC, exhibited CPP. Among SC, but not among EE, adolescents, BDNF levels were significantly lower in those treated with ethanol than in those given vehicle. These results indicate that, compared to adults, adolescent exhibited reduced sensitivity to ethanol's rewarding effects, yet the youth but not the adults exhibited sensitivity to the promoting effect of EE upon CPP by ethanol. Ethanol significantly reduced BDNF levels in adolescents reared under standard housing conditions, but not in adult mice nor in adolescents given EE housing conditions. The present results add to the plethora of adolescent-specific responses to ethanol or to environmental stimuli that may put the youth at risk for escalation of ethanol intake. PMID- 28819239 TI - Sequential conformational transitions and alpha-helical supercoiling regulate a sensor histidine kinase. AB - Sensor histidine kinases are central to sensing in bacteria and in plants. They usually contain sensor, linker, and kinase modules and the structure of many of these components is known. However, it is unclear how the kinase module is structurally regulated. Here, we use nano- to millisecond time-resolved X-ray scattering to visualize the solution structural changes that occur when the light sensitive model histidine kinase YF1 is activated by blue light. We find that the coiled coil linker and the attached histidine kinase domains undergo a left handed rotation within microseconds. In a much slower second step, the kinase domains rearrange internally. This structural mechanism presents a template for signal transduction in sensor histidine kinases.Sensor histidine kinases (SHK) consist of sensor, linker and kinase modules and different models for SHK signal transduction have been proposed. Here the authors present nano- to millisecond time-resolved X-ray scattering measurements, which reveal a structural mechanism for kinase domain activation in SHK. PMID- 28819241 TI - Platinum Nanoparticle-embedded Porous Diamond Spherical Particles as an Active and Stable Heterogeneous Catalyst. AB - Platinum nanoparticle-embedded porous diamond spherical particles (PtNP@PDSPs), as an active and stable catalyst, were fabricated by spray-drying of an aqueous slurry containing nanodiamond (ND) particles, platinum nanoparticles (PtNP), and polyethylene glycol (PEG) to form ND/PtNP/PEG composite spherical particles, followed by removal of PEG and a short-time diamond growth on the surface. The average diameter of the PtNP@PDSPs can be controlled in the range of 1-5 MUm according to the spray-drying conditions. The Brunauer-Emmett-Teller (BET) surface area and average pore diameter of the PtNP@PDSPs were estimated to be ca. 170-300 m2 g-1 and ca. 4-13 nm, respectively. When ND with the size of 20-30 nm was used, the size of PtNP in the PtNP@PDSP was almost unchanged at 5-6 nm even after high temperature processes and reuse test for catalytic reaction, showing stable supporting. The catalytic activity of the PtNP@PDSPs for the dehydrogenation of cyclohexane was higher than that for a Pt/C catalyst, which is attributed to the stable PtNP support by the three-dimensional packing of ND and efficient mass transfer via the interconnected through-hole pores in the PDSPs. PMID- 28819242 TI - The saliva microbiome profiles are minimally affected by collection method or DNA extraction protocols. AB - Saliva has attracted attention as a diagnostic fluid due to the association of oral microbiota with systemic diseases. However, the lack of standardised methods for saliva collection has led to the slow uptake of saliva in microbiome research. The aim of this study was to systematically evaluate the potential effects on salivary microbiome profiles using different methods of saliva collection, storage and gDNA extraction. Three types of saliva fractions were collected from healthy individuals with or without the gDNA stabilising buffer. Subsequently, three types of gDNA extraction methods were evaluated to determine the gDNA extraction efficiencies from saliva samples. The purity of total bacterial gDNA was evaluated using the ratio of human beta-globin to bacterial 16S rRNA PCR while 16S rRNA gene amplicon sequencing was carried out to identify the bacterial profiles present in these samples. The quantity and quality of extracted gDNA were similar among all three gDNA extraction methods and there were no statistically significant differences in the bacterial profiles among different saliva fractions at the genus-level of taxonomic classification. In conclusion, saliva sampling, processing and gDNA preparation do not have major influence on microbiome profiles. PMID- 28819243 TI - Temporal profiling of depression vulnerability in a preclinical model of sustained depression. AB - Major Depression is a prevalent mental disorder that is characterized by negative mood and reduced motivation, and frequently results in social withdrawal and memory-related deficits. Repeated stressors, such as adverse life events, increase the risk for development of the disorder. Consequently, individual variability in stress response greatly weighs on depression-vulnerability and resilience. Here, we employed the social defeat-induced persistent stress (SDPS) paradigm to identify depression-prone individuals and to examine the temporal development of depression in the months following exposure to brief defeat stress. Male Wistar rats were socially defeated (5 defeat episodes) and single housed for a prolonged period of time (~24 weeks). We assessed the emergence of a sustained depressive-like state by repeatedly evaluating social motivation (social approach avoidance) and spatial memory (object place recognition) in SDPS rats during the isolation period. Individual variability in the effects of SDPS yielded two extreme subpopulations: an SDPS-prone group that showed gradual affective and cognitive deterioration in terms of social approach and memory retention, and a SDPS-resilient group that did not develop this phenotype. Notably, in SDPS-prone individuals, the affective deficits preceded later cognitive impairments, providing a novel temporal profile of the development of pathology in this preclinical model of sustained depression. PMID- 28819244 TI - Light Scattering By Optically-Trapped Vesicles Affords Unprecedented Temporal Resolution Of Lipid-Raft Dynamics. AB - A spectroscopic technique is presented that is able to identify rapid changes in the bending modulus and fluidity of vesicle lipid bilayers on the micrometer scale, and distinguish between the presence and absence of heterogeneities in lipid-packing order. Individual unilamellar vesicles have been isolated using laser tweezers and, by measuring the intensity modulation of elastic back scattered light, changes in the biophysical properties of lipid bilayers were revealed. Our approach offers unprecedented temporal resolution and, uniquely, physical transformations of lipid bilayers can be monitored on a length scale of micrometers. As an example, the deformation of a membrane bilayer following the gel-to-fluid phase transition in a pure phospholipid vesicle was observed to take place across an interval of 54 +/- 5 ms corresponding to an estimated full-width of only ~1 m degrees C. Dynamic heterogeneities in packing order were detected in mixed-lipid bilayers. Using a ternary mixture of lipids, the modulated-intensity profile of elastic back-scattered light from an optically-trapped vesicle revealed an abrupt change in the bending modulus of the bilayer which could be associated with the dissolution of ordered microdomains (i.e., lipid rafts). This occurred across an interval of 30 +/- 5 ms (equivalent to ~1 m degrees C). PMID- 28819245 TI - Fourier ptychographic microscopy with sparse representation. AB - Fourier ptychographic microscopy (FPM) is a novel computational microscopy technique that provides intensity images with both wide field-of-view and high resolution. By combining ideas from synthetic aperture and phase retrieval, FPM iteratively stitches together a number of variably illuminated, low-resolution intensity images in Fourier space to reconstruct a high-resolution complex sample image. Although FPM is able to bypass the space-bandwidth product (SBP) limit of the optical system, it is vulnerable to the various capturing noises and the reconstruction is easy to trap into the local optimum. To efficiently depress the noise and improve the performance of reconstructed high-resolution image, a FPM with sparse representation is proposed in this paper. The cost function of the reconstruction is formulated as a regularized optimization problem, where the data fidelity is constructed based on a maximum likelihood theory, and the regulation term is expressed as a small number of nonzero elements over an appropriate basis for both amplitude and phase of the reconstructed image. The Nash equilibrium is employed to obtain the approximated solution. We validate the proposed method with both simulated and real experimental data. The results show that the proposed method achieves state-of-the-art performance in comparison with other approaches. PMID- 28819246 TI - Transcriptome analysis reveals plant response to colchicine treatment during on chromosome doubling. AB - Colchicine was commonly used to artificially double chromosomes while the transcriptome changes in colchicine treated plants has rarely been characterized. To understand the molecular mechanism of colchicine on chromosome doubling, we characterized transcriptome data of diploid orchardgrass root after colchicine treatment. Our results showed that 3381 of differentially expressed genes (DEGs) were mainly affected by water stress, 1258 DEGs that were expressed significantly in sample DacR5tr but not in DacR5ck were considered to be mainly affected by colchicine and combination of water and colchicine. These DEGs mainly regulated by colchicine were enriched to gene ontology (GO) accessions of cation binding, catalytic activity, membrane and transporter activity, and enriched to Kyoto Encyclopedia of Genes and Genome (KEGG) pathways of phenylpropanoid biosynthesis, phenylalanine metabolism, plant hormone signal transduction and starch and sucrose metabolism. Genes related to microtubule, spindle, chromosomal kinetochore, vesicle, cellulose and processes of cytoplasm movement, chromatid segregation, membrane and cell wall development were inhibited by colchicine. Our results revealed that colchicine restrained the microtubules and inhibited gene expression of cytokinesis, which might slow down the cell activity, delay the cell into anaerobic respiration, resulting in apoptosis at late stage, and relieving of waterlogging. PMID- 28819247 TI - Delta inulin-based adjuvants promote the generation of polyfunctional CD4+ T cell responses and protection against Mycobacterium tuberculosis infection. AB - There is an urgent need for the rational design of safe and effective vaccines to protect against chronic bacterial pathogens such as Mycobacterium tuberculosis. AdvaxTM is a novel adjuvant based on delta inulin microparticles that enhances immunity with a minimal inflammatory profile and has entered human trials to protect against viral pathogens. In this report we determined if Advax displays broad applicability against important human pathogens by assessing protective immunity against infection with M. tuberculosis. The fusion protein CysVac2, comprising the M. tuberculosis antigens Ag85B (Rv1886c) and CysD (Rv1285) formulated with Advax provided significant protection in the lungs of M. tuberculosis-infected mice. Protection was associated with the generation of CysVac2-specific multifunctional CD4+ T cells (IFN-gamma+TNF+IL-2+). Addition to Advax of the TLR9 agonist, CpG oligonucleotide (AdvaxCpG), improved both the immunogenicity and protective efficacy of CysVac2. Immunisation with CysVac2/AdvaxCpG resulted in heightened release of the chemoattractants, CXCL1, CCL3, and TNF, and rapid influx of monocytes and neutrophils to the site of vaccination, with pronounced early priming of CysVac2-specific CD4+ T cells. As delta inulin adjuvants have shown an excellent safety and tolerability profile in humans, CysVac2/AdvaxCpG is a strong candidate for further preclinical evaluation for progression to human trials. PMID- 28819249 TI - Carbon nanotube/Co3O4 nanocomposites selectively coated by polyaniline for high performance air electrodes. AB - We herein report the preparation of carbon nanotube (CNT)/Co3O4 nanocomposites selectively coated with polyaniline (PANI) via an electropolymerization method, for use as an effective electrode material for Li-air (Li-O2) batteries. The Co3O4 catalyst attached to the CNTs facilitated the dissociation of reaction products and reduced the overpotential of the cells. As the carbon surface activates the side reactions, the PANI coating on the carbon surface of the electrode suppressed the side reaction at the electrode/Li2O2 and electrode/electrolyte interfaces, thus enhancing the cycle performance of the electrode. In addition, the catalytic activity of Co3O4 on the CNT/Co3O4 nanocomposites remained unaffected, as the Co3O4 surface was not covered with a PANI layer due to the nature of the electropolymerization method. Overall, the synergic effect of the PANI layer and the Co3O4 catalyst leads to a superior cyclic performance and a low overpotential for the electrode based on selectively PANI-coated CNT/Co3O4 nanocomposites. PMID- 28819248 TI - A portable microfluidic platform for rapid molecular diagnostic testing of patients with myeloproliferative neoplasms. AB - The ability to simultaneously detect JAK2 V617F and MPL W515K/L mutations would substantially improve the early diagnosis of myeloproliferative neoplasms (MPNs) and decrease the risk of arterial thrombosis. The goal of this study is to achieve a point of care testing platform for simultaneous analysis of major genetic alterations in MPN. Here, we report a microfluidic platform including a glass capillary containing polypropylene matrix that extracts genomic DNA from a drop of whole blood, a microchip for simultaneous multi-gene mutation screening, and a handheld battery-powered heating device. The umLchip system was successfully used for point-of-care identification of the JAK2 V617F and MPL W515K/L mutations. The umLchip assays were then validated by mutation analysis with samples from 100 MPN patients who had previously been analyzed via unlabeled probe melting curve analysis or real-time PCR. The results from the umLchip were in perfect agreement with those from the other methods, except for one discrepant result that was negative in the unlabeled probe melting curve analysis but positive in the umLchip. After T-A cloning, sequences of cloned PCR products revealed JAK2 V617F mutation in the sample. The portable microfluidic platform may be very attractive in developing point-of-care diagnostics for MPL W515K/L and JAK2 V617F mutations. PMID- 28819250 TI - Oblique scanning laser microscopy for simultaneously volumetric structural and molecular imaging using only one raster scan. AB - Multi-modal three dimensional (3D) optical imaging combining both structural sensitivity and molecular specificity is highly desirable in biomedical research. In this paper, we present a method termed oblique scanning laser microscopy (OSLM) to combine optical coherence tomography (OCT), for simultaneously volumetric structural and molecular imaging with cellular resolution in all three dimensions. Conventional 3D laser scanning fluorescence microscopy requires repeated optical sectioning to create z-stacks in depth. Here, the use of an obliquely scanning laser eliminates the z-stacking process, then allows highly efficient 3D OCT and fluorescence imaging by using only one raster scan. The current setup provides ~3.6 * 4.2 * 6.5 MUm resolution in fluorescence imaging, ~7 * 7 * 3.5 MUm in OCT in three dimensions, and the current speed of imaging is up to 100 frames per second (fps) over a volume about 0.8 * 1 * 0.5 mm3. We demonstrate several mechanisms for molecular imaging, including intrinsically expressed GFP fluorescence, autofluorescence from Flavin proteins, and exogenous antibody-conjugated dyes. We also demonstrate potential applications in imaging human intestinal organoids (HIOs), colon mucosa, and retina. PMID- 28819252 TI - Soft electroporation for delivering molecules into tightly adherent mammalian cells through 3D hollow nanoelectrodes. AB - Electroporation of in-vitro cultured cells is widely used in biological and medical areas to deliver molecules of interest inside cells. Since very high electric fields are required to electroporate the plasma membrane, depending on the geometry of the electrodes the required voltages can be very high and often critical to cell viability. Furthermore, in traditional electroporation configuration based on planar electrodes there is no a priori certain feedback about which cell has been targeted and delivered and the addition of fluorophores may be needed to gain this information. In this study we present a nanofabricated platform able to perform intracellular delivery of membrane-impermeable molecules by opening transient nanopores into the lipid membrane of adherent cells with high spatial precision and with the application of low voltages (1.5-2 V). This result is obtained by exploiting the tight seal that the cells present with 3D fluidic hollow gold-coated nanostructures that act as nanochannels and nanoelectrodes at the same time. The final soft-electroporation platform provides an accessible approach for controlled and selective drug delivery on ordered arrangements of cells. PMID- 28819251 TI - G9a regulates breast cancer growth by modulating iron homeostasis through the repression of ferroxidase hephaestin. AB - G9a, a H3K9 methyltransferase, shows elevated expression in many types of human cancers, particularly breast cancer. However, the tumorigenic mechanism of G9a is still far from clear. Here we report that G9a exerts its oncogenic function in breast cancer by repressing hephaestin and destruction cellular iron homeostasis. In the case of pharmacological inhibition or short hairpin RNA interference mediated suppression of G9a, the expression and activity of hephaestin increases, leading to the observed decrease of intracellular labile iron content and the disturbance of breast cancer cell growth in vitro and in vivo. We also provide evidence that G9a interacts with HDAC1 and YY1 to form a multi-molecular complex that contributes to hephaestin silencing. Furthermore, high G9a expression and low hephaestin expression correlate with poor survival of breast cancer are investigated. All these suggest a G9a-dependent epigenetic program in the control of iron homeostasis and tumor growth in breast cancer.G9a is a histone methyltransferase highly expressed in several cancers including breast cancer. Here the authors propose a mechanism through which G9a promotes breast cancer by regulating iron metabolism through the repression of ferroxidase hephaestin. PMID- 28819253 TI - Majority of human traits do not show evidence for sex-specific genetic and environmental effects. AB - Sex differences in the etiology of human trait variation are a major topic of interest in the social and medical sciences given its far-reaching implications. For example, in genetic research, the presence of sex-specific effects would require sex-stratified analysis, and in clinical practice sex-specific treatments would be warranted. Here, we present a study of 2,335,920 twin pairs, in which we tested sex differences in genetic and environmental contributions to variation in 2,608 reported human traits, clustered in 50 trait categories. Monozygotic and dizygotic male and female twin correlations were used to test whether the amount of genetic and environmental influences was equal between the sexes. By comparing dizygotic opposite sex twin correlations with dizygotic same sex twin correlations we could also test whether sex-specific genetic or environmental factors were involved. We observed for only 3% of all trait categories sex differences in the amount of etiological influences. Sex-specific genetic factors were observed for 25% of trait categories, often involving obviously sex dependent trait categories such as puberty-related disorders. Our findings show that for most traits the number of sex-specific genetic variants will be small. For those traits where we do report sexual dimorphism, sex-specific approaches may aid in future gene-finding efforts. PMID- 28819254 TI - Investigations of Phase Transformation in Monocrystalline Silicon at Low Temperatures via Nanoindentation. AB - Nanoindentations of monocrystalline silicon are conducted to investigate the phase transformation process at a temperature range from 292 K to 210 K. The load displacement curves are obtained and the residual indents are detected by Raman spectra. MD simulations are also conducted to identify the phase state during nanoindentation. The results show that the low temperature has no influence on the generation of Si-II during loading process of indentation, but the phenomenon of pop-out is inhibited with the temperature decreasing. The probability of pop out occurrence has a dramatic drop from 260 K to 230 K. Both the generation and propagation of Si-III/XII transformed from Si-II are inhibited by the low temperature, and only a-Si was generated as a final phase state. PMID- 28819256 TI - FBN30 in wild Anopheles gambiae functions as a pathogen recognition molecule against clinically circulating Plasmodium falciparum in malaria endemic areas in Kenya. AB - Malaria is a worldwide health problem that affects two-thirds of the world population. Plasmodium invasion of anopheline mosquitoes is an obligatory step for malaria transmission. However, mosquito-malaria molecular interactions in nature are not clear. A genetic variation within mosquito fibrinogen related protein 30 (FBN30) was previously identified to be associated with Plasmodium falciparum infection in natural Anopheles gambiae populations at malaria endemic areas in Kenya, and reducing FBN30 expression by RNAi makes mosquitoes more susceptible to P. berghei. New results show that FBN30 is a secreted octamer that binds to both P. berghei and clinically circulating P. falciparum from malaria endemic areas in Kenya, but not laboratory P. falciparum strain NF54. Moreover, the natural genetic mutation (T to C) within FBN30 signal peptide, which changes the position 10 amino acid from phenylalanine to leucine, reduces protein expression by approximately half. This change is consistent to more susceptible An. gambiae to P. falciparum infection in the field. FBN30 in natural An. gambiae is proposed to work as a pathogen recognition molecule in inhibiting P. falciparum transmission in malaria endemic areas. PMID- 28819255 TI - Mouse strain differences in SSRI sensitivity correlate with serotonin transporter binding and function. AB - Selective serotonin reuptake inhibitors (SSRIs) bind 5-HT transporters, leading to the accumulation of 5-HT and amelioration of depression. Although different mouse strains show varying sensitivity to SSRIs in mouse models of depression, the underlying mechanism of these strain differences remains unclear. Here, the SSRI citalopram dose-dependently reduced immobility time in both the FST and TST in DBA/2J mice but not C57BL/6J mice, whereas fluoxetine showed the opposite results. Paroxetine similarly reduced immobility time in both strains. The affinity of citalopram for the 5-HT transporter was 700-fold higher in DBA/2J mice than in C57BL/6J mice, whereas the affinity of fluoxetine was 100-fold higher in C57BL/6J mice than in DBA/2J mice. Furthermore, high citalopram concentrations were required for [3H]5-HT uptake in C57BL/6J but not in DBA/2J mouse cortical synaptosomes, whereas fluoxetine showed the opposite results. The effects of paroxetine on 5-HT transporter binding and synaptosomal 5-HT uptake were similar in the two strains. These results suggest that immobility duration depends on 5-HT transporter binding levels, which lead to apparent strain differences in immobility time in the FST and TST. Furthermore, differences in 5 HT transporter binding may cause variations in SSRI effects on behaviors. PMID- 28819257 TI - Cytolytic DNA vaccine encoding lytic perforin augments the maturation of- and antigen presentation by- dendritic cells in a time-dependent manner. AB - The use of cost-effective vaccines capable of inducing robust CD8+ T cell immunity will contribute significantly towards the elimination of persistent viral infections and cancers worldwide. We have previously reported that a cytolytic DNA vaccine encoding an immunogen and a truncated mouse perforin (PRF) protein significantly augments anti-viral T cell (including CD8+ T cell) immunity. Thus, the current study investigated whether this vaccine enhances activation of dendritic cells (DCs) resulting in greater priming of CD8+ T cell immunity. In vitro data showed that transfection of HEK293T cells with the cytolytic DNA resulted in the release of lactate dehydrogenase, indicative of necrotic/lytic cell death. In vitro exposure of this lytic cell debris to purified DCs from naive C57BL/6 mice resulted in maturation of DCs as determined by up-regulation of CD80/CD86. Using activation/proliferation of adoptively transferred OT-I CD8+ T cells to measure antigen presentation by DCs in vivo, it was determined that cytolytic DNA immunisation resulted in a time-dependent increase in the proliferation of OT-I CD8+ T cells compared to canonical DNA immunisation. Overall, the data suggest that the cytolytic DNA vaccine increases the activity of DCs which has important implications for the design of DNA vaccines to improve their translational prospects. PMID- 28819258 TI - Groundwater nitrate response to sustainable nitrogen management. AB - Throughout the world, nitrogen (N) losses from intensive agricultural production may end up as undesirably high concentrations of nitrate in groundwater with a long-term impact on groundwater quality. This has human and environmental health consequences, due to the use of groundwater as a drinking water resource, and causes eutrophication of groundwater-dependent ecosystems such as wetlands, rivers and near-coastal areas. At national scale, the measured nitrate concentrations and trends in Danish oxic groundwater in the last 70 years correlate well with the annual agricultural N surpluses. We also show that the N use efficiency of agriculture is related to the groundwater nitrate concentrations. We demonstrate an inverted U-shape of annual nitrate concentrations as a function of economic growth from 1948 to 2014. Our analyses evidence a clear trend of a reversal at the beginning of the 1980s towards a more sustainable agricultural N management. This appears to be primarily driven by societal demand for groundwater protection linked to economic prosperity and an increased environmental awareness. However, the environmental and human health thresholds are still exceeded in many locations. Groundwater protection is of fundamental global importance, and this calls for further development of environmentally and economically sustainable N management in agriculture worldwide. PMID- 28819259 TI - Dendritic calcium spikes are clearly detectable at the cortical surface. AB - Cortical surface recording techniques such as EEG and ECoG are widely used for measuring brain activity. The prevailing assumption is that surface potentials primarily reflect synaptic activity, although non-synaptic events may also contribute. Here we show that dendritic calcium spikes occurring in pyramidal neurons (that we showed previously are cognitively relevant) are clearly detectable in cortical surface potentials. To show this we developed an optogenetic, non-synaptic approach to evoke dendritic calcium spikes in vivo. We found that optogenetically evoked calcium spikes were easily detectable and had an unexpected waveform near the cortical surface. Sensory-evoked dendritic calcium spikes were also clearly detectable with amplitudes that matched the contribution of synaptic input. These results reveal how dendritic calcium spikes appear at the cortical surface and their significant impact on surface potentials, suggesting that long-standing surface recording data may contain information about dendritic activity that is relevant to behavior and cognitive function.Surface EEG recordings are thought to primarily detect synaptic activity. Here the authors devise an optogenetic method to evoke dendritic calcium spikes in layer 5 pyramidal cells of the rat somatosensory cortex, and report that optogenetically evoked, as well as sensory-evoked dendritic calcium spikes make a significant contribution to surface EEG recordings. PMID- 28819260 TI - Thermodynamic and Kinetic Analyses of Iron Response Element (IRE)-mRNA Binding to Iron Regulatory Protein, IRP1. AB - Comparison of kinetic and thermodynamic properties of IRP1 (iron regulatory protein1) binding to FRT (ferritin) and ACO2 (aconitase2) IRE-RNAs, with or without Mn2+, revealed differences specific to each IRE-RNA. Conserved among animal mRNAs, IRE-RNA structures are noncoding and bind Fe2+ to regulate biosynthesis rates of the encoded, iron homeostatic proteins. IRP1 protein binds IRE-RNA, inhibiting mRNA activity; Fe2+ decreases IRE-mRNA/IRP1 binding, increasing encoded protein synthesis. Here, we observed heat, 5 degrees C to 30 degrees C, increased IRP1 binding to IRE-RNA 4-fold (FRT IRE-RNA) or 3-fold (ACO2 IRE-RNA), which was enthalpy driven and entropy favorable. Mn2+ (50 uM, 25 degrees C) increased IRE-RNA/IRP1 binding (K d) 12-fold (FRT IRE-RNA) or 6-fold (ACO2 IRE-RNA); enthalpic contributions decreased ~61% (FRT) or ~32% (ACO2), and entropic contributions increased ~39% (FRT) or ~68% (ACO2). IRE-RNA/IRP1 binding changed activation energies: FRT IRE-RNA 47.0 +/- 2.5 kJ/mol, ACO2 IRE-RNA 35.0 +/- 2.0 kJ/mol. Mn2+ (50 uM) decreased the activation energy of RNA-IRP1 binding for both IRE-RNAs. The observations suggest decreased RNA hydrogen bonding and changed RNA conformation upon IRP1 binding and illustrate how small, conserved, sequence differences among IRE-mRNAs selectively influence thermodynamic and kinetic selectivity of the protein/RNA interactions. PMID- 28819261 TI - Modified Vaccinia Virus Ankara Preferentially Targets Antigen Presenting Cells In Vitro, Ex Vivo and In Vivo. AB - Modified Vaccinia virus Ankara (MVA) is a promising vaccine vector with an excellent safety profile. However, despite extensive pre-clinical and clinical testing, surprisingly little is known about the cellular tropism of MVA, especially in relevant animal species. Here, we performed in vitro, ex vivo and in vivo experiments with recombinant MVA expressing green fluorescent protein (rMVA-GFP). In both human peripheral blood mononuclear cells and mouse lung explants, rMVA-GFP predominantly infected antigen presenting cells. Subsequent in vivo experiments performed in mice, ferrets and non-human primates indicated that preferential targeting of dendritic cells and alveolar macrophages was observed after respiratory administration, although subtle differences were observed between the respective animal species. Following intramuscular injection, rMVA GFP was detected in interdigitating cells between myocytes, but also in myocytes themselves. These data are important in advancing our understanding of the basis for the immunogenicity of MVA-based vaccines and aid rational vaccine design and delivery strategies. PMID- 28819263 TI - Children, chimpanzees, and bonobos adjust the visibility of their actions for cooperators and competitors. AB - Chimpanzees and bonobos are highly capable of tracking other's mental states. It has been proposed, however, that in contrast to humans, chimpanzees are only able to do this in competitive interactions but this has rarely been directly tested. Here, pairs of chimpanzees or bonobos (Study 1) and 4-year-old children (Study 2) were presented with two almost identical tasks differing only regarding the social context. In the cooperation condition, players' interests were matched: they had to make corresponding choices to be mutually rewarded. To facilitate coordination, subjects should thus make their actions visible to their partner whose view was partially occluded. In the competition condition, players' interests were directly opposed: the partner tried to match the subject's choice but subjects were only rewarded if they chose differently, so that they benefited from hiding their actions. The apes successfully adapted their decisions to the social context and their performance was markedly better in the cooperation condition. Children also distinguished between the two contexts, but somewhat surprisingly, performed better in the competitive condition. These findings demonstrate experimentally that chimpanzees and bonobos can take into account what others can see in cooperative interactions. Their social-cognitive skills are thus more flexible than previously assumed. PMID- 28819262 TI - Three-dimensional imaging of vortex structure in a ferroelectric nanoparticle driven by an electric field. AB - Topological defects of spontaneous polarization are extensively studied as templates for unique physical phenomena and in the design of reconfigurable electronic devices. Experimental investigations of the complex topologies of polarization have been limited to surface phenomena, which has restricted the probing of the dynamic volumetric domain morphology in operando. Here, we utilize Bragg coherent diffractive imaging of a single BaTiO3 nanoparticle in a composite polymer/ferroelectric capacitor to study the behavior of a three-dimensional vortex formed due to competing interactions involving ferroelectric domains. Our investigation of the structural phase transitions under the influence of an external electric field shows a mobile vortex core exhibiting a reversible hysteretic transformation path. We also study the toroidal moment of the vortex under the action of the field. Our results open avenues for the study of the structure and evolution of polar vortices and other topological structures in operando in functional materials under cross field configurations.Imaging of topological states of matter such as vortex configurations has generally been limited to 2D surface effects. Here Karpov et al. study the volumetric structure and dynamics of a vortex core mediated by electric-field induced structural phase transition in a ferroelectric BaTiO3 nanoparticle. PMID- 28819264 TI - Microplastics in Spanish Table Salt. AB - Marine debris is widely recognized as a global environmental problem. One of its main components, microplastics, has been found in several sea salt samples from different countries, indicating that sea products are irremediably contaminated by microplastics. Previous studies show very confusing results, reporting amounts of microparticles (MPs) in salt ranging from zero to 680 MPs/kg, with no mention of the possible causes of such differences. Several errors in the experimental procedures used were found and are reported in the present work. Likewise, 21 different samples of commercial table salt from Spain have been analyzed for MPs content and nature. The samples comprise sea salts and well salts, before and after packing. The microplastic content found was of 50-280 MPs/kg salt, being polyethylene-terephthalate (PET) the most frequently found polymer, followed by polypropylene (PP) and polyethylene (PE), with no significant differences among all the samples. The results indicate that even though the micro-particles might originate from multiple sources, there is a background presence of microplastics in the environment. PMID- 28819265 TI - The chemical signatures underlying host plant discrimination by aphids. AB - The diversity of phytophagous insects is largely attributable to speciation involving shifts between host plants. These shifts are mediated by the close interaction between insects and plant metabolites. However, there has been limited progress in understanding the chemical signatures that underlie host preferences. We use the pea aphid (Acyrthosiphon pisum) to address this problem. Host-associated races of pea aphid discriminate between plant species in race specific ways. We combined metabolomic profiling of multiple plant species with behavioural tests on two A. pisum races, to identify metabolites that explain variation in either acceptance or discrimination. Candidate compounds were identified using tandem mass spectrometry. Our results reveal a small number of compounds that explain a large proportion of variation in the differential acceptability of plants to A. pisum races. Two of these were identified as L phenylalanine and L-tyrosine but it may be that metabolically-related compounds directly influence insect behaviour. The compounds implicated in differential acceptability were not related to the set correlated with general acceptability of plants to aphids, regardless of host race. Small changes in response to common metabolites may underlie host shifts. This study opens new opportunities for understanding the mechanistic basis of host discrimination and host shifts in insects. PMID- 28819266 TI - Amalaki rasayana, a traditional Indian drug enhances cardiac mitochondrial and contractile functions and improves cardiac function in rats with hypertrophy. AB - We evaluated the cardioprotective effect of Amalaki Rasayana (AR), a rejuvenating Ayurvedic drug prepared from Phyllanthus emblica fruits in the reversal of remodeling changes in pressure overload left ventricular cardiac hypertrophy (LVH) and age-associated cardiac dysfunction in male Wistar rats. Six groups (aging groups) of 3 months old animals were given either AR or ghee and honey (GH) orally; seventh group was untreated. Ascending aorta was constricted using titanium clips in 3 months old rats (N = 24; AC groups) and after 6 months, AR or GH was given for further 12 months to two groups; one group was untreated. Histology, gene and protein expression analysis were done in heart tissues. Chemical composition of AR was analyzed by HPLC, HPTLC and LC-MS. AR intake improved (P < 0.05) cardiac function in aging rats and decreased LVH (P < 0.05) in AC rats as well as increased (P < 0.05) fatigue time in treadmill exercise in both groups. In heart tissues of AR administered rats of both the groups, SERCA2, CaM, Myh11, antioxidant, autophagy, oxidative phosphorylation and TCA cycle proteins were up regulated. ADRB1/2 and pCREB expression were increased; pAMPK, NF-kB were decreased. AR has thus a beneficial effect on myocardial energetics, muscle contractile function and exercise tolerance capacity. PMID- 28819267 TI - Decoding disease-causing mechanisms of missense mutations from supramolecular structures. AB - The inheritance modes of pathogenic missense mutations are known to be highly associated with protein structures; recessive mutations are mainly observed in the buried region of protein structures, whereas dominant mutations are significantly enriched in the interfaces of molecular interactions. However, the differences in phenotypic impacts among various dominant mutations observed in individuals are not fully understood. In the present study, the functional effects of pathogenic missense mutations on three-dimensional macromolecular complex structures were explored in terms of dominant mutation types, namely, haploinsufficiency, dominant-negative, or toxic gain-of-function. The major types of dominant mutation were significantly associated with the different types of molecular interactions, such as protein-DNA, homo-oligomerization, or intramolecular domain-domain interactions, affected by mutations. The dominant negative mutations were biased toward molecular interfaces for cognate protein or DNA. The haploinsufficiency mutations were enriched on the DNA interfaces. The gain-of-function mutations were localized to domain-domain interfaces. Our results demonstrate a novel use of macromolecular complex structures for predicting the disease-causing mechanisms through inheritance modes. PMID- 28819268 TI - Heterogenous oceanic redox conditions through the Ediacaran-Cambrian boundary limited the metazoan zonation. AB - Recent studies have enhanced our understanding of the linkage of oxygenation and metazoan evolution in Early Cambrian time. However, little of this work has addressed the apparent lag of animal diversification and atmospheric oxygenation during this critical period of Earth history. This study utilizes the geochemical proxy and N isotope record of the Ediacaran-Cambrian boundary preserved in intra shelf basin, slope, and slope basin deposits of the Yangtze Sea to assess the ocean redox state during the Early Cambrian metazoan radiation. Though ferruginous conditions appear to have prevailed through the water column during this time, episodes of local bottom-water anoxia extending into the photic-zone impacted the slope belt of the basin. Heterogenous oceanic redox conditions are expressed by trace element concentrations and Fe speciation, and spatial variation of N isotopes. We propose that the coupling of ocean chemistry and Early Cambrian animal diversification was not a simple cause-and-effect relationship, but rather a complex interaction. Specifically, it is likely that animal diversification expanded not only temporally but also spatially from the shallow shelf to deep-water environments in tandem with progressive oxygenation of the extensive continental margin. PMID- 28819269 TI - Characteristic Assessment of Diesel-degrading Bacteria Immobilized on Natural Organic Carriers in Marine Environment: the Degradation Activity and Nutrient. AB - Oil spill has led to severe environmental and ecological problems. Due to the harsh environmental conditions, the bioremediation technology is not successfully used to remedy the oil spill in marine environment. In this study, immobilization technology was used to immobilize bacteria on natural organic carriers (i.e., wood chips and maize straw). The higher surface area of in wood chips leads to larger biomass density (0.0242 gVSS/g) than that of maize straw of 0.0097 gVSS/g carrier. Compared with biodegradation efficiency of free bacteria (44.79%), the immobilized bacteria on wood chips and maize straw reached to 73.39% and 52.28%, respectively. The high biological activity of the immobilized bacteria can be also explained by nutrients, such as TN (total nitrogen) and TP (total phosphorus), released from wood chips and maize straw, which was 8.83 mg/g and 5.53 mg/g, 0.0624 mg/g and 0.0099 mg/g, respectively. PMID- 28819270 TI - Fungal community assemblage of different soil compartments in mangrove ecosystem. AB - The fungal communities of different soil compartments in mangrove ecosystem are poorly studied. We sequenced the internal transcribed spacer (ITS) regions to characterize the fungal communities in Avicennia marina root-associated soils (rhizosphere and pneumatophore) and bulk soil compartments. The rhizosphere but not pneumatophore soil compartment had significantly lower fungal species richness than bulk soil. However, bulk soil fungal diversity (Shannon diversity index) was significantly higher than both pneumatophore and rhizosphere soil compartments. The different soil compartments significantly affected the fungal community composition. Pairwise sample analyses showed that bulk soil microbial community composition significantly different from rhizosphere and pneumatophore soil compartments. There was, however no significant difference observed between rhizosphere and pneumatophore soil fungal community composition and they shared relatively more OTUs between them. Further, there was a significant correlation observed between fungal community compositional changes and carbon or nitrogen availability of different soil compartments. These results suggest that few characteristics such as fungal richness and taxa abundance of rhizosphere and pneumatophore soil compartments were significantly different in mangrove ecosystem. PMID- 28819271 TI - A magnetoelectric flux gate: new approach for weak DC magnetic field detection. AB - The magnetic flux gate sensors based on Faraday's Law of Induction are widely used for DC or extremely low frequency magnetic field detection. Recently, as the fast development of multiferroics and magnetoelectric (ME) composite materials, a new technology based on ME coupling effect is emerging for potential devices application. Here, we report a magnetoelectric flux gate sensor (MEFGS) for weak DC magnetic field detection for the first time, which works on a similar magnetic flux gate principle, but based on ME coupling effect. The proposed MEFGS has a shuttle-shaped configuration made of amorphous FeBSi alloy (Metglas) serving as both magnetic and magnetostrictive cores for producing a closed-loop high frequency magnetic flux and also a longitudinal vibration, and one pair of embedded piezoelectric PMN-PT fibers ([011]-oriented Pb(Mg,Nb)O3-PbTiO3 single crystal) serving as ME flux gate in a differential mode for detecting magnetic anomaly. In this way, the relative change in output signal of the MEFGS under an applied DC magnetic anomaly of 1 nT was greatly enhanced by a factor of 4 to 5 in comparison with the previous reports. The proposed ME flux gate shows a great potential for magnetic anomaly detections, such as magnetic navigation, magnetic based medical diagnosis, etc. PMID- 28819272 TI - Rapid peat accumulation favours the occurrence of both fen and bog microbial communities within a Mediterranean, free-floating peat island. AB - The unique environment of a 4m-thick, free-floating peat island within the Posta Fibreno lake (Central Italy) was analyzed using DNA-based techniques to assess bacterial and fungal community members identity and abundance. Two depths were sampled at 41 and 279 cm from the surface, the former corresponding to an emerged portion of Sphagnum residues accumulated less than 30 yrs ago, and the latter mainly consisting of silty peat belonging to the deeply submerged part of the island, dating back to 1520-1660 AD. The corresponding communities were very diverse, each of them dominated by a different member of the Delta-proteobacteria class for prokaryotes. Among Eukaryotes, Ascomycota prevailed in the shallow layer while Basidiomycota were abundant in the deep sample. The identity of taxa partitioning between acidic surface layer and neutral core is very reminiscent of the differences reported between bogs and fens respectively, supporting the view of Posta Fibreno as a relic transitional floating mire. Moreover, some microbial taxa show an unusual concurrent species convergence between this sub Mediterranean site and far Nordic or circumpolar environments. This study represents the first report describing the biotic assemblages of such a peculiar environment, and provides some insights into the possible mechanisms of its evolution. PMID- 28819273 TI - Enhanced anaerobically digested swine wastewater treatment by the composite of polyaluminum chloride (PAC) and Bacillus megatherium G106 derived EPS. AB - A strain was isolated from biological sludge to produce EPS by using anaerobically digested swine wastewater (ADSW). Potential of the EPS in ADSW treatment were discussed. Results showed that the optimal fermentation medium for EPS production was determined as 4 g K2HPO4, 2 g KH2PO4, and 2 g sucrose dissolved in 1 L ADSW. After fermentation for 60 h, 2.98 g EPS with main backbone of polysaccharides can be extracted from 1 L of fermentation broth. The EPS showed good performances in ADSW treatment, after conditioned by this EPS, removal efficiencies of COD, ammonia, and TP reached 70.2%, 76.5% and 82.8%, respectively, which were higher than that obtained when chemicals were selected as conditioning agents. Removal efficiencies were further improved when the EPS and polyaluminum chloride (PAC) were used simultaneously, and finally reached 91.6%, 90.8%, and 92.5%, respectively, under the optimized conditioning process by the composite of EPS of 16 mg/L, PAC of 12 g/L, pH of 7.5, and agitation speed of 200 r/min. PMID- 28819274 TI - Distinct carbon sources affect structural and functional maturation of cardiomyocytes derived from human pluripotent stem cells. AB - The immature phenotype of human pluripotent stem cell derived cardiomyocytes (hPSC-CMs) constrains their potential in cell therapy and drug testing. In this study, we report that shifting hPSC-CMs from glucose-containing to galactose- and fatty acid-containing medium promotes their fast maturation into adult-like CMs with higher oxidative metabolism, transcriptional signatures closer to those of adult ventricular tissue, higher myofibril density and alignment, improved calcium handling, enhanced contractility, and more physiological action potential kinetics. Integrated "-Omics" analyses showed that addition of galactose to culture medium improves total oxidative capacity of the cells and ameliorates fatty acid oxidation avoiding the lipotoxicity that results from cell exposure to high fatty acid levels. This study provides an important link between substrate utilization and functional maturation of hPSC-CMs facilitating the application of this promising cell type in clinical and preclinical applications. PMID- 28819275 TI - A novel in vitro potency assay of antisera against Thai Naja kaouthia based on nicotinic acetylcholine receptor binding. AB - Snake envenomation is an important medical problem. One of the hurdles in antivenom development is the in vivo assay of antivenom potency which is expensive, gives variable results and kills many animals. We report a novel in vitro assay involving the specific binding of the postsynaptic neurotoxins (PSNTs) of elapid snakes with purified Torpedo californica nicotinic acetylcholine receptor (nAChR). The potency of an antivenom is determined by its antibody ability to bind and neutralize the PSNT, thus preventing it from binding to nAChR. The PSNT of Naja kaouthia (NK3) was immobilized on microtiter wells and nAChR was added to bind with it. The in vitro IC50 of N. kaouthia venom that inhibited 50% of nAChR binding to the immobilized NK3 was determined. Varying concentrations of antisera against N. kaouthia were separately pre-incubated with 5xIC50 of N. kaouthia venom. The remaining free NK3 were incubated with nAChR before adding to the NK3 coated plates. The in vitro and in vivo median effective ratio, ER50s of 12 batches of antisera showed correlation (R 2) of 0.9809 (p < 0.0001). This in vitro assay should be applicable to antisera against other elapid venoms and should reduce the use of live animals and accelerate development of life-saving antivenoms. PMID- 28819276 TI - A new mathematical model and experimental validation on foamy-oil flow in developing heavy oil reservoirs. AB - To model foamy-oil flow in the development of heavy oil reservoirs, three depletion experiments were conducted with foamy oil treated as a pseudo-single phase flow. In this pseudo single phase, dispersed bubbles are viewed as a part of the oil, and the redefined effective permeability varies with the changes of pressure depletion rate, oil viscosity, and gas saturation. A mathematical expression for the effective permeability was developed based on experiments, where the viscosity of foamy oil is assumed to be approximately equal to the saturated oil under equivalent conditions. The compressibility coefficient of foamy oil is treated as a volume-weighted compressibility coefficient of that of oil and gas phases. A new mathematical model for foamy-oil flow was proposed with consideration of foamy-oil supersaturation. To validate the mathematical model, the oil recovery and the production gas-oil ratio (GOR) calculated by the new model, conventional black oil model, supersaturation model and pseudo-bubble point (PBP) model were all compared with those of the experimental data. The new model provided a substantially improved fit to the experimental data compared with the rest three models, which verifies the suitability of the mathematical model presented for simulating foamy-oil flow in the development of heavy oil reservoirs. PMID- 28819277 TI - Tree height strongly affects estimates of water-use efficiency responses to climate and CO2 using isotopes. AB - Various studies report substantial increases in intrinsic water-use efficiency (W i ), estimated using carbon isotopes in tree rings, suggesting trees are gaining increasingly more carbon per unit water lost due to increases in atmospheric CO2. Usually, reconstructions do not, however, correct for the effect of intrinsic developmental changes in W i as trees grow larger. Here we show, by comparing W i across varying tree sizes at one CO2 level, that ignoring such developmental effects can severely affect inferences of trees' W i . W i doubled or even tripled over a trees' lifespan in three broadleaf species due to changes in tree height and light availability alone, and there are also weak trends for Pine trees. Developmental trends in broadleaf species are as large as the trends previously assigned to CO2 and climate. Credible future tree ring isotope studies require explicit accounting for species-specific developmental effects before CO2 and climate effects are inferred.Intrinsic water-use efficiency (W i ) reconstructions using tree rings often disregard developmental changes in W i as trees age. Here, the authors compare W i across varying tree sizes at a fixed CO2 level and show that ignoring developmental changes impacts conclusions on trees' W i responses to CO2 or climate. PMID- 28819278 TI - Interleukin 4 induces apoptosis of acute myeloid leukemia cells in a Stat6 dependent manner. AB - Cytokines provide signals that regulate immature normal and acute myeloid leukemia (AML) cells in the bone marrow microenvironment. We here identify interleukin 4 (IL4) as a selective inhibitor of AML cell growth and survival in a cytokine screen using fluorescently labeled AML cells. RNA-sequencing of the AML cells revealed an IL4-induced upregulation of Stat6 target genes and enrichment of apoptosis-related gene expression signatures. Consistent with these findings, we found that IL4 stimulation of AML cells induced Stat6 phosphorylation and that disruption of Stat6 using CRISPR/Cas9-genetic engineering rendered cells partially resistant to IL4-induced apoptosis. To evaluate whether IL4 inhibits AML cells in vivo, we expressed IL4 ectopically in AML cells transplanted into mice and also injected IL4 into leukemic mice; both strategies resulted in the suppression of the leukemia cell burden and increased survival. Notably, IL4 exposure caused reduced growth and survival of primary AML CD34+CD38- patient cells from several genetic subtypes of AML, whereas normal stem and progenitor cells were less affected. The IL4-induced apoptosis of AML cells was linked to Caspase-3 activation. Our results demonstrate that IL4 selectively induces apoptosis of AML cells in a Stat6-dependent manner-findings that may translate into new therapeutic opportunities in AML. PMID- 28819279 TI - Application of current prognostic models for primary myelofibrosis in the setting of post-polycythemia vera or post-essential thrombocythemia myelofibrosis. PMID- 28819280 TI - Results of NOPHO ALL2008 treatment for patients aged 1-45 years with acute lymphoblastic leukemia. AB - Adults with acute lymphoblastic leukemia (ALL) do worse than children. From 7/2008 to 12/2014, Nordic and Baltic centers treated 1509 consecutive patients aged 1-45 years with Philadelphia chromosome-negative ALL according to the NOPHO ALL2008 without cranial irradiation. Overall, 1022 patients were of age 1-9 years (A), 266 were 10-17 years (B) and 221 were 18-45 years (C). Sixteen patients (three adults) died during induction. All others achieved remission after induction or 1-3 intensive blocks. Subsequently, 45 patients (12 adults) died, 122 patients relapsed (32 adults) with a median time to relapse of 1.6 years and 13 (no adult) developed a second malignancy. Median follow-up time was 4.6 years. Among the three age groups, older patients more often had higher risk ALL due to T-ALL (32%/25%/9%, P<0.001), KMT2A rearrangements (6%/5%/3%, P<0.001) and higher day 29 residual leukemia for B-lineage (P<0.001), but not T-ALL (P=0.53). Event free survival rates (pEFS5y) were 89+/-1% (A), 80+/-3% (B) and 74+/-4% (C) with significant differences only for non-high risk groups. Except for thrombosis, pancreatitis and osteonecrosis, the risk of 19 specified toxicities was not enhanced by age above 10 years. In conclusion, a pediatric-based protocol is tolerable and effective for young adults, despite their increased frequency of higher risk features. PMID- 28819281 TI - Mechanisms of resistance to the BCR-ABL1 allosteric inhibitor asciminib. PMID- 28819282 TI - Adding molecular data to prognostic models can improve predictive power in treated patients with myelodysplastic syndromes. PMID- 28819283 TI - The C-terminal multimerization domain is essential for leukemia development by CBFbeta-SMMHC in a mouse knockin model. PMID- 28819284 TI - Is there a need for morphologic exam to detect relapse in AML if multi-parameter flow cytometry is employed? PMID- 28819285 TI - Phosphorylation of SOS1 on tyrosine 1196 promotes its RAC GEF activity and contributes to BCR-ABL leukemogenesis. AB - Son of Sevenless 1 (SOS1) is a dual guanine nucleotide exchange factor (GEF) that activates the small GTPases RAC and RAS. Although the molecular mechanisms of RAS GEF catalysis have been unveiled, how SOS1 acquires RAC GEF activity and what is the physio-pathological relevance of this activity is much less understood. Here we show that SOS1 is tyrosine phosphorylated on Y1196 by ABL. Phosphorylation of Y1196 controls SOS1 inter-molecular interaction, is required to promote the exchange of nucleotides on RAC in vitro and for platelet-derived growth factor (PDGF) activation of RAC- and RAC-dependent actin remodeling and cell migration. SOS1 is also phosphorylated on Y1196 by BCR-ABL in chronic myelogenous leukemic cells. Importantly, in these cells, SOS1 is required for BCR-ABL-mediated activation of RAC, cell proliferation and transformation in vitro and in a xenograft mouse model. Finally, genetic removal of Sos1 in the bone marrow derived cells (BMDCs) from Sos1fl/fl mice and infected with BCR-ABL causes a significant delay in the onset of leukemogenesis once BMDCs are injected into recipient, lethally irradiated mice. Thus, SOS1 is required for full transformation and critically contribute to the leukemogenic potential of BCR ABL. PMID- 28819286 TI - Shift current photovoltaic effect in a ferroelectric charge-transfer complex. AB - Shift current is a steady-state photocurrent generated in non-centrosymmetric single crystals and has been considered to be one of the major origins of the bulk photovoltaic effect. The mechanism of this effect is the transfer of photogenerated charges by the shift of the wave functions, and its amplitude is closely related to the polarization of the electronic origin. Here, we report the photovoltaic effect in an organic molecular crystal tetrathiafulvalene-p chloranil with a large ferroelectric polarization mostly induced by the intermolecular charge transfer. We observe a fairly large zero-bias photocurrent with visible-light irradiation and switching of the current direction by the reversal of the polarization. Furthermore, we reveal that the travel distance of photocarriers exceeds 200 MUm. These results unveil distinct features of the shift current and the potential application of ferroelectric organic molecular compounds for novel optoelectric devices.The bulk photovoltaics refers to an effect whereby electrons move directionally in non-centrosymmetric crystals upon light radiation. Here, Nakamura et al. observe this effect in a ferroelectric organic charge-transfer complex, which shows large diffusion distance of photogenerated electrons over 200 um. PMID- 28819287 TI - Characterization of polycrystalline lead oxide for application in direct conversion X-ray detectors. AB - While polycrystalline lead oxide (poly-PbO) is known to be one of the most promising photoconductors for utilization in X-ray detectors, its major performance parameters such as charge yield and mobility-lifetime product (MUtau) are still not well established and require further investigation. Combining the conventional X-ray induced photocurrent and pulse height spectroscopy techniques we examine the X-ray photogeneration and recombination processes in poly-PbO. The measurements indicate that the amount of energy required to release a single electron hole pair W +/- (inverse of charge yield) strongly depends on applied electric field and at 10 V/MUm reaches ~20 eV/ehp. Fitting the measured pulse height spectra with the Hecht formula provided MUtau for holes and electrons to be 4.1 * 10-8 cm2/V and 10-9 cm2/V, respectively. Obtained MUtau values combined with recently reported mobility values of charge carriers in PbO suggest a new direction towards improvement of PbO technology by incorporation of Frisch grid or X-ray transistor architectures. PMID- 28819288 TI - Quantum correlation of qubit-reservoir system in dissipative environments. AB - In this work, the dynamics of quantum correlation (QC) in terms of geometric discord and its transfer coupled with dissipative reservoirs are investigated. Taken two canonical cases where the qubits of interest are initially prepared in extended Werner-like state and W-like states into account, we specifically reveal the dynamical behaviors of the geometric discord as each qubit locally interacts with its surrounding infinite degree-of-freedom reservoir. In the scenarios, the short-term and long-term dynamics of the geometric discord for the qubit- and reservoir-subsystem as well as its transfers between them are observed detailedly. It turns out that the geometric discord of qubit-subsystem decays asymptotically to zero while the counterpart of reservoir-subsystem can revive from time t = 0 to steady value, which sheds light on a transfer of the discord from the qubit-subsystem to the corresponding reservoir-subsystem. PMID- 28819289 TI - ESCRT-III Membrane Trafficking Misregulation Contributes To Fragile X Syndrome Synaptic Defects. AB - The leading cause of heritable intellectual disability (ID) and autism spectrum disorders (ASD), Fragile X syndrome (FXS), is caused by loss of the mRNA-binding translational suppressor Fragile X Mental Retardation Protein (FMRP). In the Drosophila FXS disease model, we found FMRP binds shrub mRNA (human Chmp4) to repress Shrub expression, causing overexpression during the disease state early use critical period. The FXS hallmark is synaptic overelaboration causing circuit hyperconnectivity. Testing innervation of a central brain learning/memory center, we found FMRP loss and Shrub overexpression similarly increase connectivity. The ESCRT-III core protein Shrub has a central role in endosome-to-multivesicular body membrane trafficking, with synaptic requirements resembling FMRP. Consistently, we found FMRP loss and Shrub overexpression similarly elevate endosomes and result in the arrested accumulation of enlarged intraluminal vesicles within synaptic boutons. Importantly, genetic correction of Shrub levels in the FXS model prevents synaptic membrane trafficking defects and strongly restores innervation. These results reveal a new molecular mechanism underpinning the FXS disease state. PMID- 28819290 TI - Progress towards non-invasive diagnosis and follow-up of celiac disease in children; a prospective multicentre study to the usefulness of plasma I-FABP. AB - This prospective study investigates whether measurement of plasma intestinal fatty acid binding protein (I-FABP), a sensitive marker for small intestinal epithelial damage, improves non-invasive diagnosing of celiac disease (CD), and whether I-FABP levels are useful to evaluate mucosal healing in patients on a gluten-free diet (GFD). Ninety children with elevated tTG-IgA titres and HLA DQ2/DQ8 positivity were included (study group). Duodenal biopsies were taken, except in those fulfilling the ESPGHAN criteria. Plasma I-FABP levels and tTG-IgA titres were assessed sequentially during six months of follow-up. Eighty children with normal tTG-IgA titres served as control group. In 61/90 (67.8%) of the children in the study group an increased I-FABP level was found; in all these children CD diagnosis was confirmed. Interestingly, in 14/30 (46.7%) children with slightly elevated tTG-IgA titres (<10x upper limit of normal), an increased I-FABP level was found. In all these children the diagnosis of CD was confirmed histologically. After gluten elimination for six weeks I-FABP levels had decreased towards levels in the control group. Measurement of plasma I-FABP, in addition to tTG-IgA, EMA-IgA and HLAtyping, enables non-invasive diagnosing of CD in a substantial number of children, and might therefore be of value in the diagnostic approach of CD. PMID- 28819291 TI - A single-molecule assessment of the protective effect of DMSO against DNA double strand breaks induced by photo-and gamma-ray-irradiation, and freezing. AB - Dimethyl sulfoxide (DMSO) is widely used as a cryoprotectant for organs, tissues, and cell suspension in storage. In addition, DMSO is known to be a useful free radical scavenger and a radio-protectant. To date, many in vitro assays using cultured cells have been performed for analysing the protective effect of DMSO against genomic DNA damage; however, currently it has been rather difficult to detect DNA double strand breaks (DSBs) in a quantitative manner. In the present study, we aimed to observe the extent of DNA damage by use of single molecular observation with a fluorescence microscope to evaluate DSBs induced by photo- and gamma-ray-irradiation, or freeze/thawing in variable concentrations of DMSO. As a result, we found that 2% DMSO conferred the maximum protective effect against all of the injury sources tested, and these effects were maintained at higher concentrations. Further, DMSO showed a significantly higher protective effect against freezing-induced damage than against photo- and gamma-ray-irradiation induced damage. Our study provides significant data for the optimization of DNA cryopreservation with DMSO, as well as for the usage of DNA as the protective agent against the injuries caused by active oxygen and radiations. PMID- 28819292 TI - Vitrification versus slow freezing for human ovarian tissue cryopreservation: a systematic review and meta-anlaysis. AB - Vitrification is a well-accepted procedure for cryopreservation of gametes and embryos. Less is known, however, about its performance in preserving ovarian tissue, for which slow freezing is the current convention. Increasing interest is being focused on vitrification, but there are as yet no standard protocols for its use with ovarian tissue. In part, this is because of the variety of cell types and complex nature of ovarian tissue. We performed a meta-analysis of 14 studies that compared vitrification with slow freezing for cryopreservation of ovarian tissue. In the pooled analysis, there was no significant difference between the two methods in terms of the proportion of intact primordial follicles, but vitrification was associated with significantly less DNA damage. Secondary endpoints included the number of stromal cells, significantly higher with vitrification, and primordial follicle density, which did not differ between the two methods. The present meta-analysis suggests that vitrification may be more effective than slow freezing, with less primordial follicular DNA strand breaks and better preservation of stromal cells. These advantages should lead to improved ovarian function after transplantation. PMID- 28819293 TI - Effects of temporal correlations in social multiplex networks. AB - Multi-layered networks represent a major advance in the description of natural complex systems, and their study has shed light on new physical phenomena. Despite its importance, however, the role of the temporal dimension in their structure and function has not been investigated in much detail so far. Here we study the temporal correlations between layers exhibited by real social multiplex networks. At a basic level, the presence of such correlations implies a certain degree of predictability in the contact pattern, as we quantify by an extension of the entropy and mutual information analyses proposed for the single-layer case. At a different level, we demonstrate that temporal correlations are a signature of a 'multitasking' behavior of network agents, characterized by a higher level of switching between different social activities than expected in a uncorrelated pattern. Moreover, temporal correlations significantly affect the dynamics of coupled epidemic processes unfolding on the network. Our work opens the way for the systematic study of temporal multiplex networks and we anticipate it will be of interest to researchers in a broad array of fields. PMID- 28819294 TI - Seismic waveform tomography with shot-encoding using a restarted L-BFGS algorithm. AB - In seismic waveform tomography, or full-waveform inversion (FWI), one effective strategy used to reduce the computational cost is shot-encoding, which encodes all shots randomly and sums them into one super shot to significantly reduce the number of wavefield simulations in the inversion. However, this process will induce instability in the iterative inversion regardless of whether it uses a robust limited-memory BFGS (L-BFGS) algorithm. The restarted L-BFGS algorithm proposed here is both stable and efficient. This breakthrough ensures, for the first time, the applicability of advanced FWI methods to three-dimensional seismic field data. In a standard L-BFGS algorithm, if the shot-encoding remains unchanged, it will generate a crosstalk effect between different shots. This crosstalk effect can only be suppressed by employing sufficient randomness in the shot-encoding. Therefore, the implementation of the L-BFGS algorithm is restarted at every segment. Each segment consists of a number of iterations; the first few iterations use an invariant encoding, while the remainder use random re-coding. This restarted L-BFGS algorithm balances the computational efficiency of shot encoding, the convergence stability of the L-BFGS algorithm, and the inversion quality characteristic of random encoding in FWI. PMID- 28819295 TI - Tailoring Heterovalent Interface Formation with Light. AB - Integrating different semiconductor materials into an epitaxial device structure offers additional degrees of freedom to select for optimal material properties in each layer. However, interfaces between materials with different valences (i.e. III-V, II-VI and IV semiconductors) can be difficult to form with high quality. Using ZnSe/GaAs as a model system, we explore the use of ultraviolet (UV) illumination during heterovalent interface growth by molecular beam epitaxy as a way to modify the interface properties. We find that UV illumination alters the mixture of chemical bonds at the interface, permitting the formation of Ga-Se bonds that help to passivate the underlying GaAs layer. Illumination also helps to reduce defects in the ZnSe epilayer. These results suggest that moderate UV illumination during growth may be used as a way to improve the optical properties of both the GaAs and ZnSe layers on either side of the interface. PMID- 28819296 TI - Intravoxel incoherent motion diffusion-weighted imaging for discriminating the pathological response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. AB - To investigate the usefulness of intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) in discriminating the pathological complete response (pCR) to neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC), 42 patients underwent preoperative IVIM-DWI before (pre-nCRT) and after nCRT (post nCRT). The values of pre-nCRT and post-nCRT IVIM-DWI parameters (ADC, D, D* and f), together with the percentage changes (?% parametric value) induced by nCRT, were compared between the pCR (tumour regression grade [TRG] 4) and non-pCR (TRG 0, 1, 2 or 3) groups and between the GR (TRG 3 or 4) and PR (TRG 0, 1 or 2) groups based on the Dworak TRG system. After nCRT, the ADC and D values for LARC increased significantly (all P < 0.05). The TRG score revealed a positive correlation with pref (r = 0.357, P = 0.020), postD (r = 0.551, P < 0.001) and Delta%D (r = 0.605, P < 0.001). The pCR group (n = 10) had higher preD*, pref, postD, ?%ADC and ?%D values than the non-pCR group (n = 32) (all P < 0.05). The GR group (n = 15) exhibited higher postD, ?%ADC and ?%D values than the PR group (n = 27) (all P < 0.05). Based on ROC analysis, ?%D had a higher area under the curve value than ?%ADC (P = 0.009) in discriminating the pCR from non-pCR groups. In conclusion, IVIM-DWI may be helpful in identifying the pCR to nCRT for LARC and is more accurate than traditional DWI. PMID- 28819297 TI - Energy-free machine learning force field for aluminum. AB - We used the machine learning technique of Li et al. (PRL 114, 2015) for molecular dynamics simulations. Atomic configurations were described by feature matrix based on internal vectors, and linear regression was used as a learning technique. We implemented this approach in the LAMMPS code. The method was applied to crystalline and liquid aluminum and uranium at different temperatures and densities, and showed the highest accuracy among different published potentials. Phonon density of states, entropy and melting temperature of aluminum were calculated using this machine learning potential. The results are in excellent agreement with experimental data and results of full ab initio calculations. PMID- 28819298 TI - Transcriptome-based network analysis reveals renal cell type-specific dysregulation of hypoxia-associated transcripts. AB - Accumulating evidence suggests that dysregulation of hypoxia-regulated transcriptional mechanisms is involved in development of chronic kidney diseases (CKD). However, it remains unclear how hypoxia-induced transcription factors (HIFs) and subsequent biological processes contribute to CKD development and progression. In our study, genome-wide expression profiles of more than 200 renal biopsies from patients with different CKD stages revealed significant correlation of HIF-target genes with eGFR in glomeruli and tubulointerstitium. These correlations were positive and negative and in part compartment-specific. Microarrays of proximal tubular cells and podocytes with stable HIF1alpha and/or HIF2alpha suppression displayed cell type-specific HIF1/HIF2-dependencies as well as dysregulation of several pathways. WGCNA analysis identified gene sets that were highly coregulated within modules. Characterization of the modules revealed common as well as cell group- and condition-specific pathways, GO-Terms and transcription factors. Gene expression analysis of the hypoxia-interconnected pathways in patients with different CKD stages revealed an increased dysregulation with loss of renal function. In conclusion, our data clearly point to a compartment- and cell type-specific dysregulation of hypoxia-associated gene transcripts and might help to improve the understanding of hypoxia, HIF dysregulation, and transcriptional program response in CKD. PMID- 28819299 TI - The correlation between CRB1 variants and the clinical severity of Brazilian patients with different inherited retinal dystrophy phenotypes. AB - Inherited retinal dystrophies are characterized by progressive retina degeneration and mutations in at least 250 genes have been associated as disease causing. CRB1 is one of many genes analyzed in molecular diagnosis for inherited retinal dystrophy. Crumbs homolog-1 protein encoded by CRB1 is important for cell to-cell contact, polarization of epithelial cells and the morphogenesis of photoreceptors. Pathogenic variants in CRB1 lead to a huge variety of phenotypes ranging from milder forms of inherited retinal dystrophy, such as retinitis pigmentosa to more severe phenotypes such as Leber congenital amaurosis. In this study, seven novel likely-pathogenic variants were identified: four missense variants (p.Leu479Pro, p.Ala921Pro, p.Cys948Arg and p.Asp1031Asn), two frameshift deletions (c.2536_2542del7 and c.3460_3461delTG) and one frameshift indel variant (c.276_294delinsTGAACACTGTAC). Furthermore, two patients with cone-rod dystrophy due to mutations in CRB1 were reported, supporting previous data, in which mutations in CRB1 can also cause cone-rod dystrophy. Finally, our data suggested there was a direct relation between phenotype severity and the mutation effect on protein functionality in 15 Brazilian CRB1 patients. PMID- 28819300 TI - YebC, a putative transcriptional factor involved in the regulation of the proteolytic system of Lactobacillus. AB - The proteolytic system of Lactobacillus plays an essential role in bacterial growth, contributes to the flavor development of fermented products, and can release bioactive health-beneficial peptides during milk fermentation. In this work, a genomic analysis of all genes involved in the proteolytic system of L. delbrueckii subsp. lactis CRL 581 was performed. Genes encoding the cell envelope associated proteinase, two peptide transport systems, and sixteen peptidases were identified. The influence of the peptide supply on the transcription of 23 genes involved in the proteolytic system of L. delbrueckii subsp. lactis was examined after cell growth in a chemically defined medium (CDM) and CDM supplemented with Casitone. prtL, oppA 1, optS, optA genes as well as oppDFBC and optBCDF operons were the most highly expressed genes in CDM; their expression being repressed 6- to 115-fold by the addition of peptides. The transcriptional analysis was confirmed by proteomics; the up-regulation of the PrtL, PepG, OppD and OptF proteins in the absence of peptides was observed while the DNA-binding protein YebC was up-regulated by peptides. Binding of YebC to the promoter region of prtL, oppA 1, and optS, demonstrated by electrophoretic mobility shift assays, showed that YebC acts as a transcriptional repressor of key proteolytic genes. PMID- 28819301 TI - Asymmetry of the temporal code for space by hippocampal place cells. AB - Hippocampal place cells convey spatial information through spike frequency ("rate coding") and spike timing relative to the theta phase ("temporal coding"). Whether rate and temporal coding are due to independent or related mechanisms has been the subject of wide debate. Here we show that the spike timing of place cells couples to theta phase before major increases in firing rate, anticipating the animal's entrance into the classical, rate-based place field. In contrast, spikes rapidly decouple from theta as the animal leaves the place field and firing rate decreases. Therefore, temporal coding has strong asymmetry around the place field center. We further show that the dynamics of temporal coding along space evolves in three stages as the animal traverses the place field: phase coupling, sharp precession and phase decoupling. These results suggest that independent mechanisms may govern rate and temporal coding. PMID- 28819302 TI - Generation and intracellular trafficking of a polysialic acid-carrying fragment of the neural cell adhesion molecule NCAM to the cell nucleus. AB - Polysialic acid (PSA) and its major protein carrier, the neural cell adhesion molecule NCAM, play important roles in many nervous system functions during development and in adulthood. Here, we show that a PSA-carrying NCAM fragment is generated at the plasma membrane by matrix metalloproteases and transferred to the cell nucleus via endosomes and the cytoplasm. Generation and nuclear import of this fragment in cultured cerebellar neurons is induced by a function triggering NCAM antibody and a peptide comprising the effector domain (ED) of myristoylated alanine-rich C kinase substrate (MARCKS) which interacts with PSA within the plane of the plasma membrane. These treatments lead to activation of the fibroblast growth factor (FGF) receptor, phospholipase C (PLC), protein kinase C (PKC) and phosphoinositide-3-kinase (PI3K), and subsequently to phosphorylation of MARCKS. Moreover, the NCAM antibody triggers calmodulin dependent activation of nitric oxide synthase, nitric oxide (NO) production, NO dependent S-nitrosylation of matrix metalloprotease 9 (MMP9) as well as activation of matrix metalloprotease 2 (MMP2) and MMP9, whereas the ED peptide activates phospholipase D (PLD) and MMP2, but not MMP9. These results indicate that the nuclear PSA-carrying NCAM fragment is generated by distinct and functionally defined signal transducing mechanisms. PMID- 28819303 TI - Automated Segmentation of Light-Sheet Fluorescent Imaging to Characterize Experimental Doxorubicin-Induced Cardiac Injury and Repair. AB - This study sought to develop an automated segmentation approach based on histogram analysis of raw axial images acquired by light-sheet fluorescent imaging (LSFI) to establish rapid reconstruction of the 3-D zebrafish cardiac architecture in response to doxorubicin-induced injury and repair. Input images underwent a 4-step automated image segmentation process consisting of stationary noise removal, histogram equalization, adaptive thresholding, and image fusion followed by 3-D reconstruction. We applied this method to 3-month old zebrafish injected intraperitoneally with doxorubicin followed by LSFI at 3, 30, and 60 days post-injection. We observed an initial decrease in myocardial and endocardial cavity volumes at day 3, followed by ventricular remodeling at day 30, and recovery at day 60 (P < 0.05, n = 7-19). Doxorubicin-injected fish developed ventricular diastolic dysfunction and worsening global cardiac function evidenced by elevated E/A ratios and myocardial performance indexes quantified by pulsed-wave Doppler ultrasound at day 30, followed by normalization at day 60 (P < 0.05, n = 9-20). Treatment with the gamma-secretase inhibitor, DAPT, to inhibit cleavage and release of Notch Intracellular Domain (NICD) blocked cardiac architectural regeneration and restoration of ventricular function at day 60 (P < 0.05, n = 6-14). Our approach provides a high-throughput model with translational implications for drug discovery and genetic modifiers of chemotherapy-induced cardiomyopathy. PMID- 28819304 TI - Novel STAT binding elements mediate IL-6 regulation of MMP-1 and MMP-3. AB - Dynamic remodelling of the extracellular matrix (ECM) is a key feature of cancer progression. Enzymes that modify the ECM, such as matrix metalloproteinases (MMPs), have long been recognised as important targets of anticancer therapy. Inflammatory cytokines are known to play a key role in regulating protease expression in cancer. Here we describe the identification of gamma-activated site (GA S)-like, signal transducer and activator of transcription (STAT) binding elements (SBEs) within the proximal promoters of the MMP-1 and MMP-3 genes, which in association with AP-1 components (c-Fos or Jun), bind STAT-1 in a homodimer like complex (HDLC). We further demonstrate that MMP expression and binding of this complex to SBEs can either be enhanced by interleukin (IL)-6, or reduced by interferon gamma (IFN-gamma), and that IL-6 regulation of MMPs is not STAT-3 dependent. Collectively, this data adds to existing understanding of the mechanism underlying cytokine regulation of MMP expression via STAT-1, and increases our understanding of the links between inflammation and malignancy in colon cancer. PMID- 28819305 TI - Cardiorespiratory pathogenesis of sickle cell disease in a mouse model. AB - The nature and development of cardiorespiratory impairments associated with sickle cell disease are poorly understood. Given that the mechanisms of these impairments cannot be addressed adequately in clinical studies, we characterized cardiorespiratory pathophysiology from birth to maturity in the sickle cell disease SAD mouse model. We identified two critical phases of respiratory dysfunction in SAD mice; the first prior to weaning and the second in adulthood. At postnatal day 3, 43% of SAD mice showed marked apneas, anemia, and pulmonary vascular congestion typical of acute chest syndrome; none of these mice survived to maturity. The remaining SAD mice had mild lung histological changes in room air with an altered respiratory pattern, seizures, and a high rate of death in response to hypoxia. Approximately half the SAD mice that survived to adulthood had an identifiable respiratory phenotype including baseline tachypnea at 7-8 months of age, restrictive lung disease, pulmonary hypertension, cardiac enlargement, lower total lung capacity, and pulmonary vascular congestion. All adult SAD mice demonstrated impairments in exercise capacity and response to hypoxia, with a more severe phenotype in the tachypneic mice. The model revealed distinguishable subgroups of SAD mice with cardiorespiratory pathophysiology mimicking the complications of human sickle cell disease. PMID- 28819306 TI - Prognostic Significance of EDIL3 Expression and Correlation with Mesenchymal Phenotype and Microvessel Density in Lung Adenocarcinoma. AB - We examined the prognostic significance of Epidermal Growth Factor-like repeats and Discoidin I-Like Domains 3 (EDIL3) expression and its correlations with mesenchymal phenotype and microvessel density in non-small cell lung carcinoma (NSCLC). A total of 268 NSCLC specimens were evaluated retrospectively by immunohistochemical staining for EDIL3, EMT markers (e-cadherin, beta-catenin, and vimentin), and CD31 to measure microvessel density. EDIL3, e-cadherin, beta catenin, and vimentin were expressed in 16%, 22.8%, 3.7%, and 10.1% of the specimens, respectively. The mRNA level of EDIL3 in tumor was correlated with the level of EDIL3 protein expression using immunohistochemistry. In lung adenocarcinoma patients, EDIL3 expression was significantly correlated with low e cadherin expression, high vimentin expression, and increased microvessel density (P < 0.001, P = 0.001, and P = 0.023, respectively). In lung squamous cell carcinoma patients, EDIL3 expression was significantly correlated with low e cadherin expression and high vimentin expression (P = 0.021 and P = 0.002, respectively). In lung adenocarcinoma patients, EDIL3 was an independent prognostic factor for overall survival in a multivariate analysis (hazard ratio: 2.552, P = 0.004). EDIL3 is significantly correlated with mesenchymal phenotype, angiogenesis, and tumor progression in lung adenocarcinoma. PMID- 28819307 TI - CRISPR/Cas9 editing reveals novel mechanisms of clustered microRNA regulation and function. AB - MicroRNAs (miRNAs) are important regulators of diverse physiological and pathophysiological processes. MiRNA families and clusters are two key features in miRNA biology. Here we explore the use of CRISPR/Cas9 as a powerful tool to delineate the function and regulation of miRNA families and clusters. We focused on four miRNA clusters composed of miRNA members of the same family, homo clusters or different families, hetero-clusters. Our results highlight different regulatory mechanisms in miRNA cluster expression. In the case of the miR-497~195 cluster, editing of miR-195 led to a significant decrease in the expression of the other miRNA in the cluster, miR-497a. Although no gene editing was detected in the miR-497a genomic locus, computational simulation revealed alteration in the three dimensional structure of the pri-miR-497~195 that may affect its processing. In cluster miR-143~145 our results imply a feed-forward regulation, although structural changes cannot be ruled out. Furthermore, in the miR-17~92 and miR-106~25 clusters no interdependency in miRNA expression was observed. Our findings suggest that CRISPR/Cas9 is a powerful gene editing tool that can uncover novel mechanisms of clustered miRNA regulation and function. PMID- 28819308 TI - An Optimal Mean Based Block Robust Feature Extraction Method to Identify Colorectal Cancer Genes with Integrated Data. AB - It is urgent to diagnose colorectal cancer in the early stage. Some feature genes which are important to colorectal cancer development have been identified. However, for the early stage of colorectal cancer, less is known about the identity of specific cancer genes that are associated with advanced clinical stage. In this paper, we conducted a feature extraction method named Optimal Mean based Block Robust Feature Extraction method (OMBRFE) to identify feature genes associated with advanced colorectal cancer in clinical stage by using the integrated colorectal cancer data. Firstly, based on the optimal mean and L 2,1 norm, a novel feature extraction method called Optimal Mean based Robust Feature Extraction method (OMRFE) is proposed to identify feature genes. Then the OMBRFE method which introduces the block ideology into OMRFE method is put forward to process the colorectal cancer integrated data which includes multiple genomic data: copy number alterations, somatic mutations, methylation expression alteration, as well as gene expression changes. Experimental results demonstrate that the OMBRFE is more effective than previous methods in identifying the feature genes. Moreover, genes identified by OMBRFE are verified to be closely associated with advanced colorectal cancer in clinical stage. PMID- 28819309 TI - Visualization and Detection of Ciliary Beating Pattern and Frequency in the Upper Airway using Phase Resolved Doppler Optical Coherence Tomography. AB - Ciliary motion plays a critical role in the overall respiratory health of the upper airway. These cilia beat at a native frequency and in a synchronized pattern to continuously transport foreign particulate trapped in a layer of mucous out of the upper airway. Disruption of ciliary motion can lead to severe respiratory diseases and compromised respiratory function. Currently, the study of cilia requires expensive high speed cameras and high powered microscopes which is unsuitable for in vivo imaging and diagnosis. Doppler based optical coherence tomography has the potential to visualize the microscopic motion of cilia during their beating cycle. We demonstrate the development of a high-speed Doppler optical coherence tomography system that not only can rapidly determine the cilia beat frequency, but also simultaneously visualize the temporal cilia beating pattern which plays critical roles in cilia function. PMID- 28819311 TI - The mechanism for the different effects of texture on yield strength and hardness of Mg alloys. AB - A study regarding the effect of texture on tensile yield strength and hardness of an extruded Mg-15Gd-0.5Zr rod was performed, with a great emphasis laid on the relevant mechanisms. A 7% pre-tension along the extrusion direction (ED) in the solid solution condition was used to transform the texture from a broad distribution of basal poles with a peak approximately 45 degrees with respect to the ED into a texture with basal poles largely perpendicular to the ED. This texture variation enhances the yield strength of peak aged sample by approximately 103 MPa, while hardly increases the peak hardness. The analysis about the ratio of the critical resolved shear stress (CRSS) to Schmid factor shows that this texture variation results in a larger fraction of grains favoring prismatic slip with a higher activation stress under tension along the ED. In contrast, the complex stress state during hardness test initiates multiple deformation modes, which renders the value of hardness insensitive to the texture variation. This different dependence of deformation modes on texture mainly accounts for the different increments in hardness and tensile yield strength. PMID- 28819310 TI - Genome-wide Target Enrichment-aided Chip Design: a 66 K SNP Chip for Cashmere Goat. AB - Compared with the commercially available single nucleotide polymorphism (SNP) chip based on the Bead Chip technology, the solution hybrid selection (SHS)-based target enrichment SNP chip is not only design-flexible, but also cost-effective for genotype sequencing. In this study, we propose to design an animal SNP chip using the SHS-based target enrichment strategy for the first time. As an update to the international collaboration on goat research, a 66 K SNP chip for cashmere goat was created from the whole-genome sequencing data of 73 individuals. Verification of this 66 K SNP chip with the whole-genome sequencing data of 436 cashmere goats showed that the SNP call rates was between 95.3% and 99.8%. The average sequencing depth for target SNPs were 40X. The capture regions were shown to be 200 bp that flank target SNPs. This chip was further tested in a genome wide association analysis of cashmere fineness (fiber diameter). Several top hit loci were found marginally associated with signaling pathways involved in hair growth. These results demonstrate that the 66 K SNP chip is a useful tool in the genomic analyses of cashmere goats. The successful chip design shows that the SHS based target enrichment strategy could be applied to SNP chip design in other species. PMID- 28819313 TI - The protein and mRNA expression levels of glial cell line-derived neurotrophic factor in post stroke depression and major depressive disorder. AB - Previous studies have indicated that the level of glial cell line-derived neurotrophic factor (GDNF) may be correlated with stroke and depression. Here, we investigated whether GDNF can be a discriminant indicator for post stroke depression (PSD). 159 participants were divided into four groups: PSD, stroke without depression (Non-PSD), major depressive disorder (MDD) and normal control (NC) group, and the protein and mRNA expression levels of GDNF in serum were measured. The results showed that only MDD group had statistical difference in protein and mRNA levels compared with the other three groups (Bonferroni test, P < 0.05). The results of receiver operating curve (ROC) analysis supported GDNF as general distinguishing models in PSD and MDD groups with the area under the curve (AUC) at 0.797 (P < 0.001) and 0.831 (P < 0.001) respectively. In addition, the Spearman analysis demonstrated that the GDNF protein level negatively correlated with the value of Hamilton depression rating scale (HAMD) in PSD patients (correlation coefficient = -0.328, P = 0.047). Together, these findings suggest the protein and mRNA expression levels of GDNF decreased in patients with depression. GDNF may serve as a potential biomarker for differential diagnosis of PSD from MDD patients. PMID- 28819312 TI - Shared peptide binding of HLA Class I and II alleles associate with cutaneous nevirapine hypersensitivity and identify novel risk alleles. AB - Genes of the human leukocyte antigen (HLA) system encode cell-surface proteins involved in regulation of immune responses, and the way drugs interact with the HLA peptide binding groove is important in the immunopathogenesis of T-cell mediated drug hypersensitivity syndromes. Nevirapine (NVP), is an HIV-1 antiretroviral with treatment-limiting hypersensitivity reactions (HSRs) associated with multiple class I and II HLA alleles. Here we utilize a novel analytical approach to explore these multi-allelic associations by systematically examining HLA molecules for similarities in peptide binding specificities and binding pocket structure. We demonstrate that primary predisposition to cutaneous NVP HSR, seen across ancestral groups, can be attributed to a cluster of HLA-C alleles sharing a common binding groove F pocket with HLA-C*04:01. An independent association with a group of class II alleles which share the HLA-DRB1-P4 pocket is also observed. In contrast, NVP HSR protection is afforded by a cluster of HLA B alleles defined by a characteristic peptide binding groove B pocket. The results suggest drug-specific interactions within the antigen binding cleft can be shared across HLA molecules with similar binding pockets. We thereby provide an explanation for multiple HLA associations with cutaneous NVP HSR and advance insight into its pathogenic mechanisms. PMID- 28819314 TI - A symbiotic-like biologically-driven regenerating fabric. AB - Living organisms constantly maintain their structural and biochemical integrity by the critical means of response, healing, and regeneration. Inanimate objects, on the other hand, are axiomatically considered incapable of responding to damage and healing it, leading to the profound negative environmental impact of their continuous manufacturing and trashing. Objects with such biological properties would be a significant step towards sustainable technology. In this work we present a feasible strategy for driving regeneration in fabric by means of integration with a bacterial biofilm to obtain a symbiotic-like hybrid - the fabric provides structural framework to the biofilm and supports its growth, whereas the biofilm responds to mechanical tear by synthesizing a silk protein engineered to self-assemble upon secretion from the cells. We propose the term crossbiosis to describe this and other hybrid systems combining organism and object. Our strategy could be implemented in other systems and drive sensing of integrity and response by regeneration in other materials as well. PMID- 28819315 TI - MCE domain proteins: conserved inner membrane lipid-binding proteins required for outer membrane homeostasis. AB - Bacterial proteins with MCE domains were first described as being important for Mammalian Cell Entry. More recent evidence suggests they are components of lipid ABC transporters. In Escherichia coli, the single-domain protein MlaD is known to be part of an inner membrane transporter that is important for maintenance of outer membrane lipid asymmetry. Here we describe two multi MCE domain-containing proteins in Escherichia coli, PqiB and YebT, the latter of which is an orthologue of MAM-7 that was previously reported to be an outer membrane protein. We show that all three MCE domain-containing proteins localise to the inner membrane. Bioinformatic analyses revealed that MCE domains are widely distributed across bacterial phyla but multi MCE domain-containing proteins evolved in Proteobacteria from single-domain proteins. Mutants defective in mlaD, pqiAB and yebST were shown to have distinct but partially overlapping phenotypes, but the primary functions of PqiB and YebT differ from MlaD. Complementing our previous findings that all three proteins bind phospholipids, results presented here indicate that multi-domain proteins evolved in Proteobacteria for specific functions in maintaining cell envelope homeostasis. PMID- 28819316 TI - Association of ambient Particulate matter 2.5 with intensive care unit admission due to pneumonia: a distributed lag non-linear model. AB - Air pollution in China has become a major environmental problem. There is a lack of evidence on the impact of haze (especially PM2.5) on intensive care unit admission due to pneumonia (ICUp). We hypothesized that PM2.5 was independently associated with ICUp and there was a non-linear time lag effect. All ICU admissions occurred from January 1, 2014 to December 31, 2016 in Sir Run-Run Shaw hospital were included in the study. The primary reasons for admission were categorized into pneumonia and non-pneumonia. Distributed lag non-linear model (DLNM) was built to account for the effect of air quality parameters in both value and temporal lag dimensions. There was a total of 7487 ICU admissions during the study period, including 391 admissions due to pneumonia. The DLNM showed that the relative risk (RR) of ICUp increased with PM2.5 concentrations. At a PM2.5 concentration of 200 mcg/m3, the RR increased from 1.06 (95% CI: 0.57 1.95) at day 0 to 1.40 (95% CI: 1.05-1.86) at day 3, and returned normal at day 6 (RR: 1.13; 95% CI: 0.83-1.55). The study showed that PM2.5 was independently associated with the risk of ICUp, and the maximum effect occurred at 3 to 4 days after exposure. PMID- 28819317 TI - Intradialytic Central Venous Oxygen Saturation is Associated with Clinical Outcomes in Hemodialysis Patients. AB - Central venous oxygen saturation (ScvO2) in the superior vena cava is predominantly determined by cardiac output, arterial oxygen content, and oxygen consumption by the upper body. While abnormal ScvO2 levels are associated with morbidity and mortality in non-uremic populations, ScvO2 has received little attention in hemodialysis patients. From 1/2012 to 8/2015, 232 chronic hemodialysis patients with central venous catheters as vascular access had their ScvO2 monitored during a 6-month baseline period and followed for up to 36 months. Patients were stratified into upper and lower two tertiles by a ScvO2 of 61.1%. Survival analysis employed Kaplan-Meier curves and adjusted Cox proportional hazards models. Patients in the lower tertiles of ScvO2 were older, had longer hemodialysis vintage, lower systolic blood pressure, lower ultrafiltration rates, higher leukocyte counts and neutrophil-to-lymphocyte ratios. Kaplan-Meier analysis indicated a shorter survival time in the lower tertiles of ScvO2 (P = 0.005, log-rank test). In adjusted Cox analysis, a 1 percent point decrease in mean ScvO2 was associated with a 4% increase in mortality (HR 1.04 [95% CI 1.01-1.08], P = 0.044), indicating that low ScvO2 is associated with poor outcomes. Research on the relative contributions of cardiac output and other factors is warranted to further elucidate the pathophysiology underlying this novel finding. PMID- 28819318 TI - Ultrafast Response in AC-Driven Electrochemiluminescent Cell Using Electrochemically Active DNA/Ru(bpy)32+ Hybrid Film with Mesoscopic Structures. AB - Electrochemiluminescence (ECL) refers to light emission induced by an electrochemical redox reaction. The stability, emission response, and light intensity of the ECL device are known to be improved by using an alternating current (AC) voltage. In this paper, an AC-driven ECL device is fabricated with DNA/Ru(bpy)32+ hybrid film-modified electrode. The Ru(bpy)32+ complex exhibits significant electrochemical reactivity in the DNA/Ru(bpy)32+ hybrid film prepared by electrochemical adsorption. The hybrid film contains unique micrometre-scale aggregates of Ru(bpy)32+ in DNA matrix. The physicochemical properties of the hybrid film and its AC-driven ECL characteristics in the electrochemical device are studied. Orange-coloured ECL is observed to be emitted from only the aggregated structures in the hybrid film at the high AC frequency of 10 kHz, which corresponds to a response time shorter than 100 MUs. PMID- 28819319 TI - Gamma-glutamyl-transpeptidase to platelet ratio is not superior to APRI,FIB-4 and RPR for diagnosing liver fibrosis in CHB patients in China. AB - The gamma-glutamyl transpeptidase to platelet ratio (GPR) is a novel index to estimate liver fibrosis in chronic hepatitis B (CHB). Few studies compared diagnostic accuracy of GPR with other non-invasive fibrosis tests based on blood parameters. We analyzed diagnostic values of GPR for detecting liver fibrosis and compared diagnostic performances of GPR with APRI (aspartate aminotransferase-to platelet ratio index), FIB-4 (fibrosis index based on the four factors), NLR (neutrophil-to-lymphocyte ratio), AAR (aspartate aminotransferase/alanine aminotransferase ratio) and RPR (red cell distribution width-to-platelet ratio) in HBeAg positive CHB and HBeAg negative CHB. We found AUROCs of GPR in predicting significant liver fibrosis, advanced liver fibrosis and liver cirrhosis were 0.732 (95% CI 0.663 to 0.801), 0.788 (95% CI 0.729 to 0.847) and 0.753 (95% CI 0.692 to 0.814), respectively. Further comparisons showed the diagnostic performance of GPR was not significantly different with APRI, FIB-4 and RPR in identifying significant fibrosis, advanced fibrosis and cirrhosis, but it was significantly superior to AAR and NLR in both HBeAg positive CHB and HBeAg negative CHB. In conclusion, GPR does not show advantages than APRI, FIB-4 and RPR in identifying significant liver fibrosis, advanced liver fibrosis and liver cirrhosis in both HBeAg positive CHB and HBeAg negative CHB in China. PMID- 28819320 TI - Genome-wide identification and expression analysis of E2 ubiquitin-conjugating enzymes in tomato. AB - The ubiquitin-proteasomal degradation mechanism has gained the attention over the past decade. The E2 ubiquitin conjugating enzymes are the crucial part of ubiquitination mechanism and they are believed to hold imperative association for plant development. It accepts ubiquitin from the E1 enzyme and interacts with the E3 ligase to transfer ubiquitin or directly transfers ubiquitin to the substrate. The functional aspects of E2 ubiquitin enzymes in plant systems are unclear. Tomato is being used as a model plant and rarely explored to study E2 ubiquitin enzyme. We have utilized in-silico methods to analyze E2 enzymes in Solanum lycopersicum and 59 genes were identified with UBC family domains. The physio chemical properties, chromosomal localization, structural organization, gene duplication, promoter analysis, gene ontology and conserved motifs were investigated along with phylogenetic analysis of tomato E2 genes exploring evolutionary relations. The gene expression analysis of RNA sequencing data revealed expression profile of tomato E2 genes in seedling, root, leaf, seed, fruit, and flower tissues. Our study aid in the understanding of distribution, expansion, evolutionary relation and probable participation in plant biological processes of tomato E2 enzymes that will facilitate strong base for future research on ubiquitin-mediated regulations in tomato and other plant systems. PMID- 28819321 TI - SH3BP4, a novel pigmentation gene, is inversely regulated by miR-125b and MITF. AB - Our previous work has identified miR-125b as a negative regulator of melanogenesis. However, the specific melanogenesis-related genes targeted by this miRNA had not been identified. In this study, we established a screening strategy involving three consecutive analytical approaches-analysis of target genes of miR 125b, expression correlation analysis between each target gene and representative pigmentary genes, and functional analysis of candidate genes related to melanogenesis-to discover melanogenesis-related genes targeted by miR-125b. Through these analyses, we identified SRC homology 3 domain-binding protein 4 (SH3BP4) as a novel pigmentation gene. In addition, by combining bioinformatics analysis and experimental validation, we demonstrated that SH3BP4 is a direct target of miR-125b. Finally, we found that SH3BP4 is transcriptionally regulated by microphthalmia-associated transcription factor as its direct target. These findings provide important insights into the roles of miRNAs and their targets in melanogenesis. PMID- 28819322 TI - NAMPT enzyme activity regulates catabolic gene expression in gingival fibroblasts during periodontitis. AB - Periodontal disease is one of the most prevalent chronic disorders worldwide. It is accompanied by inflammation of the gingiva and destruction of periodontal tissues, leading to alveolar bone loss. Here, we focused on the role of adipokines, which are locally expressed by periodontal tissues, in the regulation of catabolic gene expression leading to periodontal inflammation. The expression of the nicotinamide phosphoribosyltransferase (NAMPT) adipokine was dramatically increased in inflamed human and mouse gingival tissues. NAMPT expression was also increased in lipopolysaccharide- and proinflammatory cytokine-stimulated primary cultured human gingival fibroblasts (GF). Adenovirus-mediated NAMPT (Ad-Nampt) overexpression upregulated the expression and activity of COX-2, MMP1 and MMP3 in human GF. The upregulation of IL-1beta- or Ad-Nampt-induced catabolic factors was significantly abrogated by the intracellular NAMPT (iNAMPT) inhibitor, FK866 or by the sirtuin (SIRT) inhibitor, nicotinamide (NIC). Recombinant NAMPT protein or extracellular NAMPT (eNAMPT) inhibition using a blocking antibody did not alter NAMPT target gene expression levels. Moreover, intragingival Ad-Nampt injection mediated periodontitis-like phenotypes including alveolar bone loss in mice. SIRT2, a part of the SIRT family, was positively associated with NAMPT actions in human GF. Furthermore, in vivo inhibition of the NAMPT-NAD+-SIRT axis by NIC injection in mice ameliorated the periodontal inflammation and alveolar bone erosion caused by intragingival injection of Ad-Nampt. Our findings indicate that NAMPT is highly upregulated in human GF, while its enzymatic activity acts as a crucial mediator of periodontal inflammation and alveolar bone destruction via regulation of COX-2, MMP1, and MMP3 levels. PMID- 28819323 TI - Excessive body fat linked to blunted somatosensory cortex response to general reward in adolescents. AB - BACKGROUND AND AIMS: The brain reward system is key to understanding adolescent obesity in the current obesogenic environment, rich in highly appetising stimuli, to which adolescents are particularly sensitive. We aimed to examine the association between body fat levels and brain reward system responsivity to general (monetary) rewards in male and female adolescents. METHODS: Sixty-eight adolescents (34 females; mean age (s.d.)= 16.56 (1.35)) were measured for body fat levels with bioelectric impedance, and underwent a functional magnetic resonance imaging (fMRI) scan during the Monetary Incentive Delay (MID) task. The MID task reliably elicits brain activations associated with two fundamental aspects of reward processing: anticipation and feedback. We conducted regression analyses to examine the association between body fat and brain reward system responsivity during reward anticipation and feedback, while controlling for sex, age and socioeconomic status. We also analysed the moderating impact of sex on the relationship between fat levels and brain responsivity measures. Brain imaging analyses were corrected for multiple comparisons, with a cluster-defining threshold of P<0.001, and minimum cluster size of 38 contiguous voxels. RESULTS: Higher body fat levels were associated with lower activation of the primary somatosensory cortex (S1) and the supramarginal gyrus during reward feedback after controlling for key sociodemographic variables. Although we did not find significant associations between body fat and brain activations during reward anticipation, S1/supramarginal gyrus activation during feedback was linked to increased negative prediction error, that is, less reward than expected, in illustrative post hoc analyses. Sex did not significantly moderate the association between body fat and brain activation in the MID task. CONCLUSIONS: In adolescents, higher adiposity is linked to hypo-responsivity of somatosensory regions during general (monetary) reward feedback. Findings suggest that adolescents with excess weight have blunted activation in somatosensory regions involved in reward feedback learning. PMID- 28819324 TI - Nano-hybrid plasmonic photocatalyst for hydrogen production at 20% efficiency. AB - The efficient conversion of light energy into chemical energy is key for sustainable human development. Several photocatalytic systems based on photovoltaic electrolysis have been used to produce hydrogen via water reduction. However, in such devices, light harvesting and proton reduction are carried separately, showing quantum efficiency of about 10-12%. Here, we report a nano hybrid photocatalytic assembly that enables concomitant reductive hydrogen production and pollutant oxidation with solar-to-fuel efficiencies up to 20%. The modular architecture of this plasmonic material allows the fine-tuning of its photocatalytic properties by simple manipulation of a reduced number of basic components. PMID- 28819325 TI - Nitenpyram seed treatment effectively controls against the mirid bug Apolygus lucorum in cotton seedlings. AB - The mirid bug Apolygus lucorum (Meyer-Dur) has become a major pest in cotton fields and has led to significant yield losses due to the widespread use of transgenic Bt cotton in China. Eight neonicotinoid seed treatments were investigated to determine their effects on the management of A. lucorum in cotton fields. All neonicotinoid seed treatments reduced the cotton damage caused by A. lucorum, and nitenpyram at the rate of 4 g/kg seed showed the most favorable efficacy in suppressing A. lucorum populations throughout the cotton seedling stage. The neonicotinoid seed treatments had no effect on the emergence rate of cotton seeds. Although the neonicotinoid seed treatments were not significantly different from the spray treatments in the cotton yield, the seed treatments reduced the need for three pesticide applications and showed a tremendous advantage in labor costs throughout the cotton seedling stage. Overall, the neonicotinoid seed treatments, particularly the nitenpyram seed treatment, can provide effective protection and should play an important role in the management of early season A. lucorum in Bt cotton fields. PMID- 28819326 TI - Pulling away from the pack in drug launches. PMID- 28819327 TI - Inflammatory diseases: An IL-9 solution to inflammation resolution. PMID- 28819328 TI - Synthetic Models for Nickel-Iron Hydrogenase Featuring Redox-Active Ligands. AB - The nickel-iron hydrogenase enzymes efficiently and reversibly interconvert protons, electrons, and dihydrogen. These redox proteins feature iron-sulfur clusters that relay electrons to and from their active sites. Reported here are synthetic models for nickel-iron hydrogenase featuring redox-active auxiliaries that mimic the iron-sulfur cofactors. The complexes prepared are NiII(MU H)FeIIFeII species of formula [(diphosphine)Ni(dithiolate)(MU H)Fe(CO)2(ferrocenylphosphine)]+ or NiIIFeIFeII complexes [(diphosphine)Ni(dithiolate)Fe(CO)2(ferrocenylphosphine)]+ (diphosphine = Ph2P(CH2)2PPh2 or Cy2P(CH2)2PCy2; dithiolate = -S(CH2)3S-; ferrocenylphosphine = diphenylphosphinoferrocene, diphenylphosphinomethyl(nonamethylferrocene) or 1,1' bis(diphenylphosphino)ferrocene). The hydride species is a catalyst for hydrogen evolution, while the latter hydride-free complexes can exist in four redox states - a feature made possible by the incorporation of the ferrocenyl groups. Mixed valent complexes of 1,1'-bis(diphenylphosphino)ferrocene have one of the phosphine groups unbound, with these species representing advanced structural models with both a redox-active moiety (the ferrocene group) and a potential proton relay (the free phosphine) proximal to a nickel-iron dithiolate. PMID- 28819329 TI - Efficient computation of electrograms and ECGs in human whole heart simulations using a reaction-eikonal model. AB - Anatomically accurate and biophysically detailed bidomain models of the human heart have proven a powerful tool for gaining quantitative insight into the links between electrical sources in the myocardium and the concomitant current flow in the surrounding medium as they represent their relationship mechanistically based on first principles. Such models are increasingly considered as a clinical research tool with the perspective of being used, ultimately, as a complementary diagnostic modality. An important prerequisite in many clinical modeling applications is the ability of models to faithfully replicate potential maps and electrograms recorded from a given patient. However, while the personalization of electrophysiology models based on the gold standard bidomain formulation is in principle feasible, the associated computational expenses are significant, rendering their use incompatible with clinical time frames. In this study we report on the development of a novel computationally efficient reaction-eikonal (R-E) model for modeling extracellular potential maps and electrograms. Using a biventricular human electrophysiology model, which incorporates a topologically realistic His-Purkinje system (HPS), we demonstrate by comparing against a high resolution reaction-diffusion (R-D) bidomain model that the R-E model predicts extracellular potential fields, electrograms as well as ECGs at the body surface with high fidelity and offers vast computational savings greater than three orders of magnitude. Due to their efficiency R-E models are ideally suitable for forward simulations in clinical modeling studies which attempt to personalize electrophysiological model features. PMID- 28819331 TI - About the Cover. PMID- 28819330 TI - Synthesis and Investigation of Mixed MU-Opioid and delta-Opioid Agonists as Possible Bivalent Ligands for Treatment of Pain. AB - Several studies have suggested functional association between MU-opioid and delta opioid receptors and showed that MU-activity could be modulated by delta-ligands. The general conclusion is that agonists for the delta-receptor can enhance the analgesic potency and efficacy of MU-agonists. Our preliminary investigations demonstrate that new bivalent ligands constructed from the MU-agonist fentanyl and the delta-agonist enkephalin-like peptides are promising entities for creation of new analgesics with reduced side effects for treatment of neuropathic pain. A new superposition of the mentioned pharmacophores led to novel MU bivalent/delta-bivalent compounds that demonstrate both MU-opioid and delta opioid receptor agonist activity and high efficacy in anti-inflammatory and neuropathic pain models with the potential of reduced unwanted side effects. PMID- 28819332 TI - Assessing Smart Phones for Generating Life-space Indicators. AB - Life-space is a promising method for estimating older adults' functional status. However, traditional life-space measures are costly and time consuming because they often rely on active subject participation. This study assesses the feasibility of using the global positioning system (GPS) function of smart phones to generate life-space indicators. We first evaluated the location accuracy of smart phone collected GPS points versus those acquired by a commercial GPS unit. We then assessed the specificity of the smart phone processed life-space information against the traditional diary method. Our results suggested comparable location accuracy between the smart phone and the standard GPS unit in most outdoor situations. In addition, the smart phone method revealed more comprehensive life-space information than the diary method, which leads to higher and more consistent life-space scores. We conclude that the smart phone method is more reliable than traditional methods for measuring life-space. Further improvements will be required to develop a robust application of this method that is suitable for health-related practices. PMID- 28819333 TI - Expression of Autophagy-Related Proteins in Hurthle Cell Neoplasm Is Different from That in Follicular Neoplasm. AB - PURPOSE: We aimed to evaluate expression of autophagy-related proteins in Hurthle cell neoplasm (HCN) and follicular neoplasm (FN) and assess the clinical implications. METHODS: 265 FNs (112 follicular carcinomas and 153 follicular adenomas) and 108 HCNs (27 Hurthle cell carcinomas and 81 Hurthle cell adenomas) were made into a tissue microarray. Immunohistochemical staining and Western blot for autophagy-related proteins (beclin-1, light chain (LC) 3A, LC3B, p62, and BNIP3) were performed, and the results were statistically analyzed. RESULTS: A higher expression rate of beclin-1, LC3B, p62, and BNIP3 was found in HCN than in FN (P < 0.001). The expression rate of beclin-1, LC3B, p62, and BNIP3 was the highest in HCCs followed by HCAs, FCs, and FAs in that order (P < 0.001). HCCs were positive for the largest number of autophagy-related proteins followed by HCAs, FCs, and FAs (P < 0.001), and most of the positive markers identified in HCCs were the high autophagy type (P < 0.001), defined by positive staining for three or more of the five autophagy-related proteins. CONCLUSION: The autophagy related proteins, beclin-1, LC3A, LC3B, p62, and BNIP3, were more frequently expressed in HCNs than in FNs, and HCCs showed the highest expression rate. PMID- 28819334 TI - Cytokine Signature in End-Stage Renal Disease Patients on Hemodialysis. AB - Hemodialysis is a modality of blood filtration in which accumulated toxins and water are removed from the body. This treatment is indicated for patients at the end stage of renal disease. Vascular access complications are responsible for 20 25% of all hospitalizations in dialyzed patients. The occurrence of thrombosis in the vascular access is a serious problem that may severely compromise or even make the hemodialysis impossible, which is vital for the patient. The aim of this study was to investigate inflammatory profile in patients undergoing hemodialysis as well as the association between these alterations and vascular access thrombosis. A total of 195 patients undergoing hemodialysis have been evaluated; of which, 149 patients had not experienced vascular access thrombosis (group I) and 46 patients had previously presented this complication (group II). Plasma levels of cytokines including interleukin (IL-) 2, IL-4, IL-5, IL-10, TNF-alpha, and IFN-gamma were measured by cytometric bead array. Our results showed that patients with previous thrombotic events (group II) had higher levels of the IL 2, IL-4, IL-5, and IFN-gamma when compared to those in group I. Furthermore, a different cytokine signature was detected in dialyzed patients according to previous occurrences or not of thrombotic events, suggesting that elevated levels of T-helper 1 and T-helper 2 cytokines might, at least in part, contribute to this complication. PMID- 28819335 TI - Quantitative, Comparable Coherent Anti-Stokes Raman Scattering (CARS) Spectroscopy: Correcting Errors in Phase Retrieval. AB - Coherent anti-Stokes Raman scattering (CARS) microspectroscopy has demonstrated significant potential for biological and materials imaging. To date, however, the primary mechanism of disseminating CARS spectroscopic information is through pseudocolor imagery, which explicitly neglects a vast majority of the hyperspectral data. Furthermore, current paradigms in CARS spectral processing do not lend themselves to quantitative sample-to-sample comparability. The primary limitation stems from the need to accurately measure the so-called nonresonant background (NRB) that is used to extract the chemically-sensitive Raman information from the raw spectra. Measurement of the NRB on a pixel-by-pixel basis is a nontrivial task; thus, reference NRB from glass or water are typically utilized, resulting in error between the actual and estimated amplitude and phase. In this manuscript, we present a new methodology for extracting the Raman spectral features that significantly suppresses these errors through phase detrending and scaling. Classic methods of error-correction, such as baseline detrending, are demonstrated to be inaccurate and to simply mask the underlying errors. The theoretical justification is presented by re-developing the theory of phase retrieval via the Kramers-Kronig relation, and we demonstrate that these results are also applicable to maximum entropy method-based phase retrieval. This new error-correction approach is experimentally applied to glycerol spectra and tissue images, demonstrating marked consistency between spectra obtained using different NRB estimates, and between spectra obtained on different instruments. Additionally, in order to facilitate implementation of these approaches, we have made many of the tools described herein available free for download. PMID- 28819336 TI - Further Examining Berry's Model: The Applicability of Latent Profile Analysis to Acculturation. AB - This study used latent profile analysis (LPA) to identify acculturation profiles. A 3-profile solution fit the data best, and comparisons on demographic and psychosocial outcomes as a function of profile yielded expected results. The findings support using LPA as a parsimonious way to model acculturation without anticipating profiles in advance. PMID- 28819337 TI - Predation Cues in Solitary bee Nests. AB - Predation at the nesting site can significantly affect solitary bees' reproductive success. We tested female red mason bees' (Osmia bicornis L.) acceptance of potential nesting sites, some of which were marked with cues coming from predated conspecifics (crushed bees) or from a predator itself (rodent excreta). In our experiment, females did not avoid nests marked with either of the two predator cues. We suggest that bee females do not recognize these two cues as risky. Alternatively, costs of abandoning natal aggregation might be too high compared with any perceived predation risk of staying. Moreover, the presence of crushed bees can provide positive information about the presence of conspecifics and, possibly, information about a nesting aggregation that may be preferred by bees when choosing a nesting site. PMID- 28819338 TI - Urbanism, Neighborhood Context, and Social Networks. AB - Theories of urbanism suggest that the urban context erodes individuals' strong social ties with friends and family. Recent research has narrowed focus to the neighborhood context, emphasizing how localized structural disadvantage affects community-level cohesion and social capital. In this paper, we argue that neighborhood context also shapes social ties with friends and family- particularly for community-dwelling seniors. We hypothesize that neighborhood disadvantage, residential instability, and disorder restrict residents' abilities to cultivate close relationships with neighbors and non-neighbor friends and family. Using data from the National Social Life, Health, and Aging Project (NSHAP), we find that older adults who live in disadvantaged neighborhoods have smaller social networks. Neighborhood disadvantage is also associated with less close network ties and less frequent interaction - but only among men. Furthermore, residents of disordered neighborhoods have smaller networks and weaker ties. We urge scholars to pay greater attention to how neighborhood context contributes to disparities in network-based access to resources. PMID- 28819340 TI - Corrigendum to "Epstein-Barr Virus-Induced Gene 3 (EBI3) Blocking Leads to Induce Antitumor Cytotoxic T Lymphocyte Response and Suppress Tumor Growth in Colorectal Cancer by Bidirectional Reciprocal-Regulation STAT3 Signaling Pathway". AB - [This corrects the article DOI: 10.1155/2016/3214105.]. PMID- 28819339 TI - Depression after Stroke in Sub-Saharan Africa: A Systematic Review and Meta Analysis. AB - OBJECTIVE: We aimed to conduct a systematic review and meta-analysis of prevalence and characteristics of poststroke depression (PSD) in sub-Saharan Africa (SSA). METHODS: We searched Medline, PsycINFO, and African Journals OnLine using keywords for stroke and depression and the .mp. operator for all 54 SSA countries/regions. Further information was retrieved through a manual search of references from relevant published and unpublished articles. We included only peer-reviewed original studies with epidemiological or experimental designs, conducted random-effect meta-analysis, and identified the most commonly associated factors by weight (inverse of variance method). RESULTS: Seventeen studies, comprising 1483 stroke survivors, met the criteria for syntheses. The pooled frequency of clinically diagnosed PSD was 31% (95% CI = 26%-36%), versus 13.9% in healthy control pairs. Prevalence did not vary much across healthcare settings but was affected by methods of depression ascertainment. PSD was significantly associated with low education, cognitive impairment, physical disability, poor quality of life, and divorced marital status. CONCLUSION: Almost 1 in 3 individuals with stroke in SSA has clinical depression. Despite limitations around quality of identified studies, results of the present systematic review overlap with findings in the global literature and highlight useful targets for the design and trial of tailored intervention for PSD in SSA. PMID- 28819341 TI - Reliability of the acetabular reconstruction technique using autogenous bone graft from resected femoral head in hip dysplasia: Influence of the change of hip joint center on clinical outcome. AB - INTRODUCTION: The previous studies have not reached on consensus as to the outcome of acetabular reconstruction with autogenous bone graft for dysplastic hips, especially in severe cases such as Crowe type IV. The current study aimed to determine the survivorship of the arthroplasty and the grafts as well as the change of hip joint center averagely 9.8 years (range, 5-19) after cementless total hip arthroplasty. MATERIALS AND METHODS: We reviewed 52 cases including 19 cases of complete hip dislocation of which acetabular defects were augmented with autogenous bone grafts taken from the resected femoral heads. For radiographic evaluation, in addition to checking failures of THA, acetabular coverages of the grafts as well as lateral center-edge angles were measured and compared between two time points, immediately postoperative and the final evaluations. Those outcomes were also analyzed according to the degree of hip dysplasia, grouping the subjects by Crowe classification. Translations of the reconstructed hip joint center after THA were measured and checked if they affected clinical outcomes or caused any complications. To assess clinically, Harris hip score and visualized analogue pain scale were reviewed. RESULTS: Mean coverage ratio of the sockets with the grafts was 28.4% immediately after the surgery (range, 11.1%-65.0%) and 27.2% at the final follow-up (range, 11.1%-63.6%). When comparing high grade dysplasia (Crowe type III, IV) to low grade dysplasia (Crowe type I, II), there was no significant difference of the above outcomes (p = 0.476). As to the location of hip joint center, 14 outliers were located distally within the normal horizontal range especially in cases with Crowe type IV. Those outliers showed no difference on clinical outcome. The mean HHS was 52.2 (range, 19-87) and VAS was 7.2 (range, 5-9) preoperatively, each of which was improved to 92.9 (range, 63 100) and 1.4 (range, 0-4) postoperatively. No failures were experienced during the study period. CONCLUSIONS: Acetabular augmentation using autogenous bone graft from the resected femoral head is found to be a successful method for dysplastic hip, even in severe cases such as Crowe type IV, showing favorable results in more than 8 years. When inevitable, a degree of compromise on hip joint center can be needed in dealing with severe hip dysplasia. PMID- 28819342 TI - Bilateral ruptures of the extensor mechanism of the knee: A systematic review. AB - INTRODUCTION: We conduct a systematic and qualitative review of the current literature to evaluate studies that described bilateral ruptures of the extensor mechanism of the knee. METHODS: A comprehensive literature search was performed to evaluate all studies included in the literature until September 2016. RESULTS: Fourteen studies with a total of 44 patients met the inclusion criteria. There were 14 patients with CRF (61%), 6 patients were affected by diabetes mellitus (14%) while other 6 patients were obese patients (14%). CONCLUSION: CRF represents the most frequent comorbidity in patients with bilateral quadriceps/patellar tendon ruptures. PMID- 28819343 TI - Mid-term migration of a cementless, porous acetabular cup: A 5 year Radiostereometric analysis. AB - PURPOSE: The aim of the study was to determine the 5 year migratory and wear patterns, adverse events and clinical outcomes of a cementless, porous acetabular cup. METHODS: RSA imaging of a cohort of 11 patients was retrospective analysed at 5 years post Total Hip Arthroplasty (THA). Changes in pain, function and symptoms of the hip at 5 years post-THA were compared to preoperative and 2 year postoperative assessments on the Harris Hip Score (HHS) and Hip dysfunction and Osteoarthritis Outcome Score (HOOS). RESULTS: The majority of cup migration occurred up to 6 months and stabilised thereafter (6 months to 5 years, p = 0.091 0.866, Wilcoxon Signed Rank test). The direction of rotation around the 3 axes was evenly distributed among the cups between anterior-posterior rotation, internal-external rotation and increased-decreased inclination. The majority of the cups translated proximally, at an average migration of 0.36 mm (+/-95%CI 0.17) at 5-years post-THA. Following initial bedding in, up to 6 months, there was no detectable polyethylene wear between 6 months and 5 years. At 5 years postoperatively, a statistically significant difference was observed across all HOOS subscales in comparison to preoperative values, with higher means reported at 5 years (p < 0.001). The total mean HHS displayed a statistically significant improvement, increasing from 'poor' preoperatively to 'good' at 5 years post-THA. CONCLUSION: Following initial migration between discharge and 6 months, the cementless porous acetabular cup demonstrated a tendency for stabilisation from 6 months up to 5 years post-THA, suggesting good mid-term fixation. Additionally, improvements in clinical outcome measures of pain, function and quality-of-life remained high following THA at 5 years post-surgery. PMID- 28819344 TI - Positioning Performance of Power and Manual Drivers in Posterior Spinal Fusion Procedures. AB - This work presents an analysis and comparison of the efficacy of two methods for pedicle screw placement during posterior spinal fusion surgery. A total of 100 screws (64 manual and 36 power driven), all placed utilizing a surgical navigation system, were analyzed and compared. Final screw placement was compared to initial surgical plans using the navigation system, and the final screw locations were analyzed on the basis of angular deviation from these planned trajectories as well as screw translation within a critical reference plane. The power driver was found to insignificantly decrease the resulting angular deviation of these pedicle screws with a mean deviation of 3.35 degrees compared to 3.44 degrees with the manual driver (p = 0.853). Conversely, the power driver was found to increase the translational distance in the critical region, with mean deviations of 2.45 mm for the power driver compared to 1.54 mm with the manual driver. The increase in translational deviation was significant (p = 0.002) indicating that there may be some loss in performance from the adoption of the power driver. PMID- 28819345 TI - Point-of-Care Molecular Test for Zika Infection. AB - The recent outbreak of Zika virus (ZIKV) infection has led to a serious threat to public health. Rapid and sensitive diagnostics for ZIKV infection are crucial because Zika infection is usually mild and often asymptomatic, but may have serious consequences to infants born to infected mothers. We report on a simple, sensitive, inexpensive, point-of-care (POC) diagnostic technology for rapid detection of ZIKV in saliva. We use a chemically heated cup for isothermal amplification without a need for electrical power. The detection results can be directly read out by eye. PMID- 28819346 TI - Smart Grid (Wireless Communications): IEEE Wireless Communications. PMID- 28819348 TI - The Solidification of Multicomponent Alloys. AB - Various topics taken from the author's research portfolio that involve multicomponent alloy solidification are reviewed. Topics include: ternary eutectic solidification and Scheil-Gulliver paths in ternary systems. A case study of the solidification of commercial 2219 aluminum alloy is described. Also described are modifications of the Scheil-Gulliver analysis to treat dendrite tip kinetics and solid diffusion for multicomponent alloys. PMID- 28819347 TI - Acceptability of aggression among children who reside with substance-abusing parents: The influence of behavioral dysregulation, exposure to neighborhood violence, and interparental violence. AB - The present study examined how interparental violence, neighborhood violence, behavioral regulation during parental conflict, and age predicted beliefs about the acceptability of aggression and the acceptance of retaliation against an aggressive peer among youths. Participants were 110 families (mothers, fathers, and children) in which one or both parents met criteria for substance use disorder. Results of a bootstrapped path model revealed higher exposure to neighborhood violence predicted greater acceptability of general aggression, whereas higher father-to-mother violence perpetration predicted lower acceptability of general aggression. Higher exposure to neighborhood violence, behavioral dysregulation during parental conflict, and older child age predicted greater approval of retaliation toward an aggressive peer. Findings are interpreted as related to the cognitive-contextual framework. PMID- 28819349 TI - The Anexo in Northern California: An Alcoholics Anonymous-Based Recovery Residence in Latino Communities. AB - Our ethnographic study on help-seeking pathways of Latino immigrants in northern California reveals that they turn to anexos in their treatment and recovery quest. Anexos are linguistically- and culturally-specific recovery houses with origins in Mexico and Alcoholics Anonymous and a long history in Latino communities across the United States. Drawing on the findings of our study, we characterize the anexos and compare them to other recovery residences using National Alliance for Recovery Residences (NARR) criteria. The description and comparison reveal that anexos cannot be placed into a single NARR residence category. We discuss why this is the case. PMID- 28819350 TI - Understanding Sarcopenia Development: A Role for Healthy Behaviors. AB - For decades the biomedical community has documented the accelerated loss of muscle mass that occurs with advancing aging, termed sarcopenia. The timely review article ("Attenuation of Adverse Effects of Aging on Skeletal Muscle by Regular Exercise and Nutritional Support") by Arthur Leon presents our current state of knowledge on the biological processes responsible for age-induced loss of muscle mass and function. This loss of skeletal muscle has critical health implications as it can negatively affect morbidity and mortality. A significant theme throughout the review is that a lifelong commitment to regular physical activity and good dietary habits is extremely important to combat age related reductions in muscle mass and function. However, multi-targeted therapeutic approaches, in conjunction with nutrition and exercise, may be beneficial to prevent or treat sarcopenia. Additionally, while significant progress has been made in our understanding of the molecular and biochemical contributors to sarcopenia, further research using well-controlled clinical trials are needed to determine the long-term benefit of exercise and nutrition on aging skeletal muscle. PMID- 28819351 TI - A Systematic Analysis of Term Reuse and Term Overlap across Biomedical Ontologies. AB - Reusing ontologies and their terms is a principle and best practice that most ontology development methodologies strongly encourage. Reuse comes with the promise to support the semantic interoperability and to reduce engineering costs. In this paper, we present a descriptive study of the current extent of term reuse and overlap among biomedical ontologies. We use the corpus of biomedical ontologies stored in the BioPortal repository, and analyze different types of reuse and overlap constructs. While we find an approximate term overlap between 25-31%, the term reuse is only <9%, with most ontologies reusing fewer than 5% of their terms from a small set of popular ontologies. Clustering analysis shows that the terms reused by a common set of ontologies have >90% semantic similarity, hinting that ontology developers tend to reuse terms that are sibling or parent-child nodes. We validate this finding by analysing the logs generated from a Protege plugin that enables developers to reuse terms from BioPortal. We find most reuse constructs were 2-level subtrees on the higher levels of the class hierarchy. We developed a Web application that visualizes reuse dependencies and overlap among ontologies, and that proposes similar terms from BioPortal for a term of interest. We also identified a set of error patterns that indicate that ontology developers did intend to reuse terms from other ontologies, but that they were using different and sometimes incorrect representations. Our results stipulate the need for semi-automated tools that augment term reuse in the ontology engineering process through personalized recommendations. PMID- 28819352 TI - Metabolomics of biomarker discovery in ovarian cancer: a systematic review of the current literature. AB - INTRODUCTION: Metabolomics is the emerging member of "omics" sciences advancing the understanding, diagnosis and treatment of many cancers, including ovarian cancer (OC). OBJECTIVES: To systematically identify the metabolomic abnormalities in OC detection, and the dominant metabolic pathways associated with the observed alterations. METHODS: An electronic literature search was performed, up to and including January 15th 2016, for studies evaluating the metabolomic profile of patients with OC compared to controls. QUADOMICS tool was used to assess the quality of the twenty-three studies included in this systematic review. RESULTS: Biological samples utilized for metabolomic analysis include: serum/plasma (n = 13), urine (n = 4), cyst fluid (n = 3), tissue (n = 2) and ascitic fluid (n = 1). Metabolites related to cellular respiration, carbohydrate, lipid, protein and nucleotide metabolism were significantly altered in OC. Increased levels of tricarboxylic acid cycle intermediates and altered metabolites of the glycolytic pathway pointed to perturbations in cellular respiration. Alterations in lipid metabolism included enhanced fatty acid oxidation, abnormal levels of glycerolipids, sphingolipids and free fatty acids with common elevations of palmitate, oleate, and myristate. Increased levels of glutamine, glycine, cysteine and threonine were commonly reported while enhanced degradations of tryptophan, histidine and phenylalanine were found. N-acetylaspartate, a brain amino acid, was found elevated in primary and metastatic OC tissue and ovarian cyst fluid. Further, elevated levels of ketone bodies including 3-hydroxybutyrate were commonly reported. Increased levels of nucleotide metabolites and tocopherols were consistent through out the studies. CONCLUSION: Metabolomics presents significant new opportunities for diagnostic biomarker development, elucidating previously unknown mechanisms of OC pathogenesis. PMID- 28819353 TI - A metabolomics guided exploration of marine natural product chemical space. AB - INTRODUCTION: Natural products from culture collections have enormous impact in advancing discovery programs for metabolites of biotechnological importance. These discovery efforts rely on the metabolomic characterization of strain collections. OBJECTIVE: Many emerging approaches compare metabolomic profiles of such collections, but few enable the analysis and prioritization of thousands of samples from diverse organisms while delivering chemistry specific read outs. METHOD: In this work we utilize untargeted LC-MS/MS based metabolomics together with molecular networking to. RESULT: This approach annotated 76 molecular families (a spectral match rate of 28 %), including clinically and biotechnologically important molecules such as valinomycin, actinomycin D, and desferrioxamine E. Targeting a molecular family produced primarily by one microorganism led to the isolation and structure elucidation of two new molecules designated maridric acids A and B. CONCLUSION: Molecular networking guided exploration of large culture collections allows for rapid dereplication of know molecules and can highlight producers of uniques metabolites. These methods, together with large culture collections and growing databases, allow for data driven strain prioritization with a focus on novel chemistries. PMID- 28819355 TI - Box Office Forecasting considering Competitive Environment and Word-of-Mouth in Social Networks: A Case Study of Korean Film Market. AB - Accurate box office forecasting models are developed by considering competition and word-of-mouth (WOM) effects in addition to screening-related information. Nationality, genre, ratings, and distributors of motion pictures running concurrently with the target motion picture are used to describe the competition, whereas the numbers of informative, positive, and negative mentions posted on social network services (SNS) are used to gauge the atmosphere spread by WOM. Among these candidate variables, only significant variables are selected by genetic algorithm (GA), based on which machine learning algorithms are trained to build forecasting models. The forecasts are combined to improve forecasting performance. Experimental results on the Korean film market show that the forecasting accuracy in early screening periods can be significantly improved by considering competition. In addition, WOM has a stronger influence on total box office forecasting. Considering both competition and WOM improves forecasting performance to a larger extent than when only one of them is considered. PMID- 28819354 TI - Mediating Roles of PPARs in the Effects of Environmental Chemicals on Sex Steroids. AB - Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors that are widely involved in various physiological functions. They are widely expressed through the reproductive system. Their roles in the metabolism and function of sex steroids and thus the etiology of reproductive disorders receive great concern. Various kinds of exogenous chemicals, especially environmental pollutants, exert their adverse impact on the reproductive system through disturbing the PPAR signaling pathway. Chemicals could bind to PPARs and modulate the transcription of downstream genes containing PPRE (peroxisome proliferator response element). This will lead to altered expression of genes related to metabolism of sex steroids and thus the abnormal physiological function of sex steroids. In this review, various kinds of environmental ligands are summarized and discussed. Their interactions with three types of PPARs are classified by various data from transcript profiles, PPRE reporter in cell line, in silico docking, and gene silencing. The review will contribute to the understanding of the roles of PPARs in the reproductive toxicology of environmental chemicals. PMID- 28819356 TI - Comparison of Efficacy of Self-Expandable Metallic Stent Placement in the Unresectable Esophageal Cancer Patients. AB - This is a retrospective study to evaluate the prevention of complications of metallic stent placement in patients with unresectable advanced esophageal cancer. A total of 87 patients were treated with 4 types of metal stents in the esophagus over a period of 18 years. Stent placement was technically successful. The most common prior treatment was chemoradiotherapy. There were no significant differences in the rate of patients with no complications among the prior treatments. Approximately, 30% of patients had the most common chest pain in complications. Stent placement within one month after the completion of chemoradiotherapy should be avoided for the prevention of the chest pain. There was no significant difference in the rate of patients with no complications by lesion location. The rate of no complications was higher for the Niti-S stent than the Gianturco Z-stent or Ultraflex stent. Of note, no complications were noted for the Niti-S ultrathin stent at all. Among cases of stent-related death, the most common type of complication was respiratory disorder caused by the stent that seems to be thick and hard. Therefore, the stent with thin and flexible characteristics like the Niti-S ultrathin stent will solve the various problems of esophageal stent placement. PMID- 28819357 TI - The Diagnostic Yield of Colonoscopy Stratified by Indications. AB - INTRODUCTION: Danish centers reserve longer time for screening colonoscopies and allocate the most experienced endoscopists to these cases. The objective of this study is to determine the diagnostic yield in colonoscopies for different indications to improve planning of colonoscopy activity and allocation of the highly skilled endoscopists. METHODS: Nine hundred and ninety-nine randomly collected patients from a prospectively maintained database were grouped in defined referral indication groups. Five groups were compared in respect of the detection rate of adenomas and cancers. RESULTS: Two hundred and eighty-nine of 1098 colonoscopies in 999 patients showed significant neoplastic findings, resulting in 591 adenoma resections. Eighty-five percent were treated with a snare resection, and 15% with endoscopic mucosa resection (EMR). Positive findings in the indication groups were (1) symptoms, 25%; (2) positive screening, 17%; (3) previous resection of adenomas, 45%; (4) previous resection of colorectal cancer, 15%; and (5) surveillance of patients with high-risk family history of cancer, 35%. CONCLUSION: The majority of adenomas found during colonoscopy can be treated with simple techniques. If individualized time slots are considered, the adenoma follow-up colonoscopies are likely to be the most time-consuming group with more than twice the number of adenomas detected as compared to other indications. PMID- 28819358 TI - Surgical Treatment for Chronic Pancreatitis: Past, Present, and Future. AB - The pancreas was one of the last explored organs in the human body. The first surgical experiences were made before fully understanding the function of the gland. Surgical procedures remained less successful until the discovery of insulin, blood groups, and finally the possibility of blood donation. Throughout the centuries, the surgical approach went from radical resections to minimal resections or only drainage of the gland in comparison to an adequate resection combined with drainage procedures. Today, the well-known and standardized procedures are considered as safe due to the high experience of operating surgeons, the centering of pancreatic surgery in specialized centers, and optimized perioperative treatment. Although surgical procedures have become safer and more efficient than ever, the overall perioperative morbidity after pancreatic surgery remains high and management of postoperative complications stagnates. Current research focuses on the prevention of complications, optimizing the patient's general condition preoperatively and finding the appropriate timing for surgical treatment. PMID- 28819359 TI - Screening for Cushing Syndrome at the Primary Care Level: What Every General Practitioner Must Know. AB - Cushing's syndrome is a rare entity, and a high index of suspicion is needed for screening in a primary care setting. The clinical awareness of the primary care physician (PCP) to the highly indicative signs and symptoms such as facial plethora, proximal myopathy, reddish purple striae, and easy bruisability should alert him to look for biochemical evidence of Cushing's syndrome through any of the first-line screening tests, namely, 24-hour urinary free cortisol, overnight dexamethasone suppression test, or late-night salivary cortisol. Commonly used random cortisol measurements are unreliable; hence, general practitioners are encouraged to understand the use of these more reliable tests with increased sensitivity and specificity for screening Cushing's syndrome. In this write-up, we set out to increase awareness about the presentation of Cushing's syndrome and current recommended screening methods as well as their strengths and weaknesses. We relied mainly on the recommendations by the Endocrine Society Guidelines. PMID- 28819360 TI - Hexavalent Chromium Removal from Model Water and Car Shock Absorber Factory Effluent by Nanofiltration and Reverse Osmosis Membrane. AB - Nanofiltration and reverse osmosis are investigated as a possible alternative to the conventional methods of Cr(VI) removal from model water and industrial effluent. The influences of feed concentration, water recovery, pH, and the coexisting anions were studied. The results have shown that retention rates of hexavalent chromium can reach 99.7% using nanofiltration membrane (NF-HL) and vary from 85 to 99.9% using reverse osmosis membrane (RO-SG) depending upon the composition of the solution and operating conditions. This work was also extended to investigate the separation of Cr(VI) from car shock absorber factory effluent. The use of these membranes is very promising for Cr(VI) water treatment and desalting industry effluent. Spiegler-Kedem model was applied to experimental results in the aim to determine phenomenological parameters, the reflection coefficient of the membrane (sigma), and the solute permeability coefficient (Ps ). The convective and diffusive parts of the mass transfer were quantified with predominance of the diffusive contribution. PMID- 28819361 TI - Unilateral Headache Status after Intra-Aortic Balloon Pump Placement. AB - INTRODUCTION: Intra-aortic balloon pump (IABP) counterpulsation is a catheter based treatment for coronary artery disease and decompensated heart failure to increase coronary blood flow and improve cardiac output. IABP is generally well tolerated, and complications are usually related to peripheral vasculature or red blood cell and platelet consumption. The usual insertion site via femoral artery renders the patient bedbound. Recently, axillary artery has been used in patients with atherosclerotic peripheral vascular disease and documented small arteries or in those awaiting transplant to ensure ambulation and prevent deconditioning. CASE REPORT: We present a patient with ischemic cardiomyopathy and severe left ventricular dysfunction, awaiting Orthotropic Heart Transplant. His worsening intractable angina and dyspnea necessitated IABP placement via left axillary artery, significantly improving his condition. He subsequently experienced migraine-type persistent unilateral headache refractory to standard pain management. Multiple strategies were utilized to treat his pain, but the patient insisted that his pain commenced after IABP placement. Ultimately, the removal of the pump led to complete resolution with no recurrence. CONCLUSION: The authors hypothesize that the unilaterally directed blood flow and direct increase in cerebral perfusion from the intra-aortic balloon pump may have caused vasodilation of the extracranial arteries, leading to a persistent and debilitating headache in this susceptible patient. PMID- 28819362 TI - Recurrent CSF Rhinorrhea Misdiagnosed as Chronic Allergic Rhinitis with Subsequent Development of Bacterial Meningitis. AB - INTRODUCTION: Cerebrospinal fluid (CSF) rhinorrhea results from an abnormal communication of the dura mater to the nasal mucosa. The majority of cases of CSF rhinorrhea are the result of trauma or surgery involving the skull base. Spontaneous CSF rhinorrhea is a rare clinical entity with increased risk of ascending infection. Delay in diagnosis places the patient at risk of developing meningitis. CASE PRESENTATION: A 36-year-old African American female with significant medical history of obesity and hypertension presented to the emergency department with headache, altered level of consciousness, fever, and neck stiffness. Previously, the patient was diagnosed with chronic allergic sinusitis by multiple providers. Physical exam findings and laboratory tests were consistent with bacterial meningitis. The patient was admitted and started on appropriate antibiotic therapy. The patient continued to complain of persistent unilateral clear nasal drainage. The initial report from the computerized tomography scan of the sinuses indicated findings consistent with chronic sinusitis. Magnetic resonance imaging of the orbits revealed findings consistent with CSF rhinorrhea. Otolaryngology was consulted for surgical intervention. CONCLUSION: Suspected CSF rhinorrhea should prompt immediate biochemical and radiologic evaluation and surgical consultation. CSF rhinorrhea places patients at risk of developing bacterial meningitis. PMID- 28819363 TI - Combined Analysis of Endothelial, Hematopoietic, and Mesenchymal Stem Cell Compartments Shows Simultaneous but Independent Effects of Age and Heart Disease. AB - Clinical trials using stem cell therapy for heart diseases have not reproduced the initial positive results obtained with animal models. This might be explained by a decreased regenerative capacity of stem cells collected from the patients. This work aimed at the simultaneous investigation of endothelial stem/progenitor cells (EPCs), mesenchymal stem/progenitor cells (MSCs), and hematopoietic stem/progenitor cells (HSCs) in sternal bone marrow samples of patients with ischemic or valvular heart disease, using flow cytometry and colony assays. The study included 36 patients referred for coronary artery bypass grafting or valve replacement surgery. A decreased frequency of stem cells was observed in both groups of patients. Left ventricular dysfunction, diabetes, and intermediate risk in EuroSCORE and SYNTAX score were associated with lower EPCs frequency, and the use of aspirin and beta-blockers correlated with a higher frequency of HSCs and EPCs, respectively. Most importantly, the distribution of frequencies in the three stem cell compartments showed independent patterns. The combined investigation of the three stem cell compartments in patients with cardiovascular diseases showed that they are independently affected by the disease, suggesting the investigation of prognostic factors that may be used to determine when autologous stem cells may be used in cell therapy. PMID- 28819365 TI - Regulation of Stemness in Carcinoma Cells. PMID- 28819364 TI - The Crosstalk between Ovarian Cancer Stem Cell Niche and the Tumor Microenvironment. AB - Ovarian cancer is one of the most important causes of cancer-related death among women in the world. Despite advances in ovarian cancer treatment, 70-80% of women who initially respond to therapy eventually relapse and die. There is evidence that a small population of cells within the tumors called cancer stem cells (CSCs) could be responsible for treatment failure due to their enhanced chemoresistance and tumorigenicity. These cells reside in a niche that maintains the principal properties of CSCs. These properties are associated with the capacity of CSCs to interact with different cells of the tumor microenvironment including mesenchymal stem cells, endothelial cells, immune cells, and fibroblasts, promoting cancer progression. This interaction can be mediated by cytokines, growth factors, lipids, and/or extracellular vesicles released in the CSC niche. In this review, we will discuss how the interaction between ovarian CSCs and the tumor microenvironment can contribute to the maintenance of the CSC niche and consequently to tumor progression in ovarian cancer. PMID- 28819366 TI - Paracrine Potential of the Human Adipose Tissue-Derived Stem Cells to Modulate Balance between Matrix Metalloproteinases and Their Inhibitors in the Osteoarthritic Cartilage In Vitro. AB - Adipose tissue represents an abundant source of stem cells. Along with anti inflammatory effects, ASC secrete various factors that may modulate metabolism of extracellular matrix in osteoarthritic (OA) cartilage, suggesting that the presence of ASC could be advantageous for OA cartilage due to the recovery of homeostasis between matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs). To evaluate these effects, cartilage explants (CE) were cocultured with ASC for 3 and 7 days under stimulation with or without IL 1beta. The pattern of gene expression in CE was modified by ASC, including the upregulation of COL1A1 and COL3A1 and the downregulation of MMP13 and COL10A1. The production of MMP-1, MMP-3, and MMP-13 by ASC was not significant; moreover, cocultures with ASC reduced MMP-13 production in CE. In conclusion, active production of TIMP-1, TIMP-2, TIMP-3, IL-6, IL-8, and gelatinases MMP-2 and MMP-9 by ASC may be involved in the extracellular matrix remodelling, as indicated by the altered expression of collagens, the downregulated production of MMP-13, and the reduced chondrocyte apoptosis in the cocultured CE. These data suggest that ASC modulated homeostasis of MMPs/TIMPs in degenerated OA cartilage in vitro and might be favourable in case of the intra-articular application of ASC therapy for the treatment of OA. PMID- 28819367 TI - Short-term effectiveness of inpatient cancer rehabilitation: A longitudinal controlled cohort study. AB - Background: Inpatient rehabilitation for cancer patients has been demonstrated to improve patients' health related quality of life (HRQoL) effectively. The purpose of this study was to compare changes in general health and HRQoL of cancer patients who were referred to inpatient rehabilitation (IR) with those in two control groups who underwent outpatient management either with advice for inpatient rehabilitation (A+) or without (A-). Methods: In this naturalistic, longitudinal, controlled cohort study, changes in general health and HRQoL were assessed at either discharge of acute hospital or start of rehabilitation (baseline) and at the follow-up 3 weeks later or end of rehabilitation. Outcome variables included general health and HRQoL assessed by the Short Form 36 (SF-36) and the Functional Assessment of Cancer Therapy (FACT), and fatigue (FACT-F), depression and anxiety by the Hospital Anxiety and Depression Scale (HADS). Changes on the scores were compared with bivariate and multivariate analyses using standardized mean differences (SMD). Results: IR patients (n=133) were on average older, reported lower HRQoL and health, and suffered more frequently from carcinoma than patients of the A+ (n=30) and the A- (n=82) groups. In the IR patients, pain, physical functioning, mental health, vitality, and fatigue improved significantly compared to the A+ controls. Compared to the A- group, the bivariate effects were lower but still statistically significant on many scales. Conclusions: IR showed moderate, statistically significant superior effects over outpatient management of cancer patients after acute treatment. Findings indicate that inpatient cancer rehabilitation can be recommended as an effective management after acute treatment. As today, referrals to inpatient rehabilitation for cancer patients are still not based on structured standardized procedures, the implementation of such screening is needed to address patients' needs and to render the potential for rehabilitation more reliable. PMID- 28819368 TI - Lack of Breastfeeding History in Parous Women with Inflammatory Breast Cancer Predicts Poor Disease-Free Survival. AB - Purpose: Breastfeeding alters the breast microenvironment, and several lines of evidence suggest the breast microenvironment contributes to the clinical phenotype of inflammatory breast cancer. We investigated breastfeeding history as a modifier of locoregional recurrence (LRR), distant metastasis (DM), disease free survival (DFS), and overall survival (OS) in parous women with inflammatory breast cancer. Methods: Parous women with inflammatory breast cancer were identified from a prospective registry at The University of Texas MD Anderson Cancer Center. We compared patient and tumor characteristics, LRR, DM, DFS, and OS patients with (BF+) and without (BF-) a history of breastfeeding. Results: Eighty-two patients were included. At a median follow-up of 50 months, BF+ patients had significantly lower risk of LRR (9.0% vs. 23.6%; p=0.01), a lower risk of DM (26.8% vs. 53.8%; p=0.008), and better DFS (73.1% vs. 48.1%; p=0.006) than BF- patients. On multivariate analysis, BF+ history was associated with significantly lower risk of DM (hazard ratio 0.38, 95% confidence interval 0.15 0.97; p=0.04) and better DFS (hazard ratio 0.37, 95% confidence interval 0.15 0.93; p=0.04) after adjusting for established predictive and prognostic variables. The prognostic significance of breastfeeding may be most pronounced in women with triple-negative IBC. Conclusion: A lack of breastfeeding history in parous women with inflammatory breast cancer may predict worse prognosis. We speculate that breastfeeding-induced alterations in the breast microenvironment may alter the aggressiveness of inflammatory breast cancer. PMID- 28819369 TI - In vitro Cytotoxic Activities of the Oral Platinum(IV) Prodrug Oxoplatin and HSP90 Inhibitor Ganetespib against a Panel of Gastric Cancer Cell Lines. AB - Gastric cancer exhibits a poor prognosis and is the third most common cause of cancer death worldwide. Chemotherapy of metastatic gastric cancer is based on combinations of platinum drugs and fluoropyrimidines, with added agents. Oxoplatin is a stable oral platinum(IV) prodrug which is converted to a highly active tetrachlorido(IV) complex under acidic conditions. In the present work, we studied the cytotoxic effects of oxoplatin against a panel of four gastric cancer cell lines in vitro. Furthermore, the role of HSP90 in chemoresistance of these lines was investigated using the specific inhibitor ganetespib. The KATO-III, MKN 1, MKN-28, MKN-45 lines were used in MTT chemosensitivity, cell cycle and apoptosis assays. KATO-III is a signet ring diffuse cell type, MKN-1 an adenosquamous primary, MKN-28 a well-differentiated intestinal type and the MKN 45 a poorly differentiated, diffuse type gastric carcinoma line. Cytotoxicity was tested in MTT assays and intracellular signal transduction with proteome profiler Western blot arrays. Interactions of platinum drugs and ganetespib were calculated with help of the Chou-Talalay method. The prodrug oxoplatin revealed low activity against the four gastric cancer cell lines, whereas the platinum tetrachlorido(IV) complex and cisplatin gave IC50 values of 1-3 ug/ml with increasing chemoresistance observed in the order of MKN-1, KATO-III, MKN-28 to MKN-45. With exception of KATO-III and MKN-28/oxoplatin, all other cell lines featured marked synergistic toxicity with clinically achievable concentrations of ganetespib. Oral administration of a platinum agent such as oxoplatin would be of great value for patients and care providers alike. These results suggest that the oncogene-stabilizing HSP90 chaperone represents an important mediator of chemoresistance in gastric cancer. Ganetespib reduced the phosphorylation of p53, Akt1/2/3 and PRAS40, as well as of WNK1, a kinase which regulates intracellular chloride concentrations. Intracellular chloride was reported to control proliferation of gastric cancer cell lines. Expression of MUC1 was not downregulated in contrast to the expression of CAIX, a prognostic marker in gastric cancer. In conclusion, the HSP90 inhibitor ganetespib synergizes with platinum anticancer drugs and modulates intracellular signal transduction in direction of a less proliferative and aggressive phenotype. PMID- 28819370 TI - Metformin Inhibits Gemcitabine Induced Apoptosis in Pancreatic Cancer Cell Lines. AB - Many preclinical and clinical studies are currently evaluating metformin in combination with classical therapeutic agents as anti-cancer therapy. In this study we used three distinct pancreatic cancer cell lines and evaluated cell death by trypan blue assay and Western Blots using antibodies directed against cleaved caspase 3 and PARP. Surprisingly, we observed that 20mM metformin did not enhance, but rather inhibited gemcitabine induced cell death in murine 7265PDA, 6606PDA and 6606l cells. Microenvironmental aspects such as oxygen supply or the pH value did not influence the inhibition of cancer cell apoptosis by metformin. Glucose concentration in the medium, however, had a major effect on the impact of metformin. Medium with 0.5g/L glucose strongly increased metformin induced apoptosis and also prevented the inhibitory effect of metformin on gemcitabine induced cell apoptosis, when compared with medium containing 4.5g/L glucose. We conclude that the combination of metformin with gemcitabine has inappropriate effects for a successful treatment of pancreatic cancer. Thus, it might be more promising to use metformin in combination with other drugs that reduce the uptake or the metabolism of glucose. PMID- 28819371 TI - Knockdown of Tubulin Polymerization Promoting Protein Family Member 3 inhibits cell proliferation and invasion in human colorectal cancer. AB - Tubulin Polymerization Promoting Protein Family Member 3 (TPPP3), a member of the TPPP protein family, has been reported to play important roles in initiation and progression of human cancers. However, the expression and underlying function of TPPP3 in colorectal cancer (CRC) have not yet been fully clarified. In this study, the mRNA and protein levels of TPPP3 in 96 clinical CRC specimens were determined by RT-PCR and immunohistochemistry. The relation between TPPP3 expression and clinicopathologic characteristics and overall survival (OS) were evaluated. Further experiments showed that knockdown of TPPP3 inhibited cell proliferation, migration and invasion and induced cell apoptosis in vitro. In addition, TPPP3 silencing resulted in a decrease of angiogenesis and S phase fraction. Thus, our results suggested that TPPP3 played an important role in CRC progress and might serve as novel therapeutic target for CRC treatment. PMID- 28819372 TI - Survival changes in Patients with Synovial Sarcoma, 1983-2012. AB - Background: Synovial sarcoma (SyS) is a rare malignancy that typically invades the extremities and occurs predominantly in adolescents. Studies on incidence and survival in SyS that were based on a large population had not been reported yet. Methods: To evaluate changes in incidence and survival in SyS over three decades, we accessed data on SyS cases in each decade between 1983 and 2012 (1983-1992, 1993-2002, and 2003-2012) from the Surveillance, Epidemiology, and End Results (SEER) database. The survival difference between decades, age groups, sexes, race, pathologic types, sites, stages and socioeconomic status (SES) over three decades were accessed by comparing Kaplan-Meier curves. Results: We located 2,070 SyS cases in 18 SEER registry regions between 1983 and 2012. Our study demonstrated that the incidence of SyS per 1,000,000 continued to increase from 0.906 to 1.348 to 1.548 in the total population and in most age groups and that the age of incidence peak was 15-29 years in three decades. But, the survival of patients with SyS did not significantly improve throughout the three decades, with 5-year survival rates of 69.4%, 61.1% and 60.5% respectively (p > 0.05). Interestingly, the widening survival gaps among races, sexes, pathological types and various SES over time were observed, with narrowing p values. Conclusions: This study demonstrated the increasing incidence and unimproved survival rates across three decades in a large sample, indicating the urgency for further development of diagnosis, improving health care providers' awareness of SyS and lead to the development of novel treatments. PMID- 28819373 TI - Increased Transgenerational Intestinal Tumorigenesis in Offspring of Ionizing Radiation Exposed Parent APC1638N/+ Mice. AB - The purpose of the study was to assess transgenerational intestinal tumorigenic effects of low dose ionizing radiation employing a well-characterized mouse model of human colorectal cancer. Mice (6 to 8 weeks old APC1638N/+ mice; n=20 per study group) were exposed to whole-body 25 cGy x-rays and mated 2 days post irradiation. Intestinal tumorigenesis in male and female F1 mice from No Parents Irradiated (NPI), Both Parents Irradiated (BPI), and Male Parent Irradiated (MPI) groups were compared 210 days after birth. Male and female Direct Parent Irradiated (DPI) groups were additional controls for male and female F1 groups respectively. Data showed higher intestinal tumor frequency (+/- standard error of the mean) in male and female F1 from BPI (male: 7.81 +/- 0.91; female: 5.45 +/ 0.36) as well as from MPI (male: 6.30 +/- 0.33; female: 4.45 +/- 0.33) mice relative to F1 from NPI mice (male: 4.2 +/- 0.48; female: 3.35 +/- 0.37). Compared to male and female DPI (male: 5.55 +/- 0.40; female: 3.60 +/- 0.22), tumor frequency in F1 mice of BPI and MPI, though higher, was not statistically significant except for DPI vs. BPI in male mice. Additionally, both BPI and MPI showed increased frequency of larger tumors relative to NPI. In summary, our observations demonstrated that the APC1638N/+ mice due to its low spontaneous tumor frequency could serve as an effective model to study risk of transgenerational carcinogenesis in gastrointestinal tissues after exposure to clinically relevant low doses of ionizing radiation. PMID- 28819374 TI - Variant CD44 expression is enriching for a cell population with cancer stem cell like characteristics in human lung adenocarcinoma. AB - Background: Preliminary studies have identified cancer stem cells (CSCs) in various cancers and there are several ongoing clinical studies targeting these cells. CD44 (standard or variant isoforms) and/or aldehyde dehydrogenase (ALDH) expression is the most commonly used markers for the identification of CSCs. The goal of the current study was to examine the ability of CD44v, either alone or in combination with ALDH, to identify CSCs within human lung cancer cells lines. Methods: We examined several lung adenocarcinoma cell lines for the ability of CD44v and/or ALDH expression to enrich for cells with CSC characteristics such as in vitro differential proliferation rate, chemotherapeutic-resistance, tumorsphere formation, and in vivo tumorigenicity. We also compared their in vivo secondary tumor formation, and histological characteristics of their xenograft tumors, and examined their expression of PD-L1, EGFR, xCT, and reactive oxygen species (ROS). Results: Both CD44vhigh/ALDHhigh and CD44vhigh/ALDHlow cells were enriched in cells with CSC characteristics, with the CD44vhigh/ALDHlow cells being more proliferative and more resistant to chemotherapeutics, whereas CD44vhigh/ALDHhigh cells were more efficient in forming tumorspheres in vitro, in making primary xenograft tumors, and in propagating secondary tumors in vivo. Applying stricter sorting gates to select for cells with the highest CD44v/ALDH expression caused the CD44vhigh/ALDHlow cells to lose their high proliferation rates and chemotherapeutic resistance ability, but enriched for the tumorsphere forming cells among the CD44vhigh/ALDHhigh and CD44vhigh/ALDHlow cells. CD44vhigh expression was associated with PD-L1 and xCT expression in both H1650 and HCC827 cells. This association was not modified by ALDH expression in the H1650 cell line. However, in the HCC827 cell line, ALDH expression was negatively associated with PD-L1 and positively associated with xCT expression. Conclusion: Lung adenocarcinoma cells with high CD44v expression are enriched for CSCs. Addition of ALDH as an enrichment marker bestowed some CSCs characteristics to CD44vhigh/ALDHlow cells and others to CD44vhigh/ALDHhigh cells. We propose that lung adenocarcinoma contains different CSCs, each of them endowed with different CSC characteristics. PMID- 28819375 TI - Bone Marrow Derived Mesenchymal Stem Cells Involve in the Lymphangiogenesis of Lung Cancer and Jinfukang Inhibits the Involvement In Vivo. AB - Lymphangiogenesis plays an important role in cancer metastasis. Bone marrow derived mesenchymal stem cells (BMMSCs) migrate to the site of tumorigenesis and in turn promote the metastasis. However, whether BMMSCs involve in the lymphangiogenesis of lung cancer is unclear. Jinfukang has clinically been used for the treatment of non small cell lung cancer (NSCLC) in China. In this study, to investigate the involvement of BMMSCs in lymphangiogenesis in lung cancer, and evaluate the inhibitory effect of Jinfukang on the lymphangiogenesis, chimeric mice were prepared by transplanting bone marrow from green fluorescent protein (GFP) transgenic mice (C57BL/6-EGFP) into irradiated C57BL/6 mice. Then, the chimeric mice were injected subcutaneously with freshly prepared Lewis lung carcinoma cell suspension to make lung tumor model, and the model mice were further orally administrated with Jinfukang once per day for 3 weeks. Four weeks after the bone marrow transplantation, GFP-positive cells primarily existed in bone marrow of acceptor mice, and three more weeks after, Lewis lung carcinoma cells formed a tumor mass in chimeric mice. Observation of GFP-positive cells revealed that BMMSCs transferred into the lung tumor. Immunofluorescent analyses of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), a lymphatic endothelium marker, demonstrated a part of lymphatic endothelial cells in lung cancer were derived from BMMSCs, and those lymphatic endothelial cells contributed to the lung tumor lymphangiogenesis. Furthermore, Jinfukang treatment resulted in a significant reduction of the average weight of the tumor mass in chimeric mice, and displayed a significant lower number of LYVE-1 positive cells. The present results suggest that BMMSCs transfer to tumor, differentiate into lymphatic endothelial cells, and involve in the lymphangiogenesis in lung cancer of mice. Jinfukang inhibits the lung tumor mass via suppression of the BMMSCs transformation and lung tumor lymphangiogenesis. Our findings might provide the potential for the cancer therapies. PMID- 28819376 TI - PART1 expression is associated with poor prognosis and tumor recurrence in stage I-III non-small cell lung cancer. AB - Purpose: Long noncoding RNAs (lncRNAs) have been demonstrated as effective markers for cancer detection and prognosis prediction. The aim of this study was to determine whether tissue PART1 could be used as a biomarker for prognosis prediction of non-small cell lung cancer (NSCLC). Methods: PART1 expression was detected in 208 cases of stage I-III NSCLC specimens and adjacent normal tissues. The Cox proportional-hazards regression model was used to analyze the association between PART1 expression and overall survival (OS) and disease-free survival (DFS) of the patients. Results: It was found that the expression of PART1 was significantly up-regulated in 73.1% (152/208) stage I-III NSCLC specimens compared with adjacent normal tissues. High tissue PART1 expression was associated with shorter OS and could serve as an independent prognostic biomarker in stage I-III NSCLC patients (hazard ratio [HR] = 2.11, 95% CI = 1.18-3.78, P = 0.012). In addition, high tissue PART1 expression indicated poor DFS in stage I III NSCLC patients (HR = 1.94, 95% CI: 1.37-2.76, P < 0.001). Conclusions: PART1 may prove to be a promising biomarker for prediction of survival and tumor recurrence in stage I-III NSCLC. PMID- 28819377 TI - Effect of pomalidomide on relapsed/refractory multiple myeloma: a systematic review and meta-analysis. AB - In this work, we aim to further analyze the effect of pomalidomide for relapsed and/or refractory multiple myeloma (RRMM). A systematic literature search of PubMed, MEDLINE and EMBASE was conducted on September 20, 2016. Pooled effect size (ES) with corresponding 95% confidence intervals (CIs) were calculated using random-effects model. STATA software (version 12.0; Stata Corporation; College Station, TX, USA) was employed to do all statistical analyses. A total of 8 studies were included for analysis. The combined results demonstrated that the pooled proportion of overall response rate (ORR) was 0.35 (95% CI 0.27 to 0.43, P=0.000), and the pooled proportion of complete response rate (CRR) was 0.02 (95% CI 0.01 to 0.03, P=0.541). Pomalidomide was generally well tolerated by patients reported in the studies. Further studies would be required to conduct more prospective randomized controlled trials (RCTs) with larger samples to assess the proper place of pomalidomide as single agent or combined with other agents for RRMM. PMID- 28819378 TI - HIF is not essential for suppression of experimental tumor growth by mTOR inhibition. AB - The Hypoxia Inducible Transcription Factor (HIF) is the master regulator of cellular response to hypoxic adaptation. Solid tumors inevitably harbour hypoxic regions with subsequent stabilization and activation of HIF and HIF target genes due to poor vascularization and rapid growth. The mammalian target of rapamycin (mTOR) is a global regulator of cellular growth and proliferation, which can also regulate HIF expression independantly of hypoxia via specific activation of cellular translation and transcription. An effective blockade of mTOR results in attenuation of HIF under hypoxic conditions in vitro. This mechanism could enable a simultaneous inhibition of both the mTOR- and the HIF-pathway, resulting in an effective tool for cancer targeting. We set out to analyze the effect of mTOR inhibition and the involvement of mTOR regulation on HIF in vivo in a subcutaneous xenograft model in nude mice. Our results demonstrate that mTOR inhibition in our model leads to a clear reduction in tumor growth of various cellular origins, most likely due to inhibition of cellular proliferation. Moreover, these effects can also be achieved independently of the HIF status of the tumor cells. The HIF levels per se seem to remain unaffected by mTOR inhibition, probably due to the profound hypoxic environment in these threedimensional structures, consequently leading to a strong HIF stabillization. Therefore, treatment of these experimental tumors with mTOR inhibitors is an effective tool to achieve size regression. The involvement of and the effect on HIF in this in vivo setting is nevertheless negligible. PMID- 28819379 TI - Hypoxia-inducible factor-1 alpha Correlates with Tumor-Associated Macrophages Infiltration, Influences Survival of Gastric Cancer Patients. AB - Background: Hypoxia was a common feature for accelerating tumor metastasis by both inducting epithelial-mesenchymal transition (EMT) of tumor cells and polarization of tumor-associated macrophages (TAMs). The association and roles between hypoxia, EMT and TAMs in the biological behavior of gastric cancer (GC) for the time being recurrence is unclear. Material and methods: hypoixa by expression of hypoxia-inducible factor-1 alpha (HIF-1alpha), polarized functional status of infiltrated TAMs by immunohistochemical staining of CD68 and CD163, and the expression of E-cadherin as EMT property had been evaluated in 236 patients consecutive with histologically confirmed GC. Clinical significance was assessed for all these patients. Results: High expression of HIF-1alpha was found in patients with aggressive features, especially for recurrent patients. High infiltration of TAMs and abnormal expression of EMT-marker were also related to aggressive characteristics and predicted poor prognosis in GC. Meanwwhile, there existed a significant correlation among expression of HIF-1alpha, infiltration of TAMs and EMT marker in GC tissues. Multivariate Cox analysis revealed that high expression of HIF-1alpha combined TAMs infiltration were independent prognostic factors for disease-specific survival rate. Conclusion: HIF-1alpha is an unfavorable indicator for prognosis, may promote tumor progression through the induction of EMT and establishment of a pro-tumor immunosuppressive microenvironment. Further investigation into the therapeutic effects of blocking hypoxia is possible a potential strategy for GC treatment. PMID- 28819380 TI - Phase II Trial of Adjuvant Immunotherapy with Autologous Tumor-derived Gp96 Vaccination in Patients with Gastric Cancer. AB - Background/Aims: Autologous, tumor-derived, heat shock protein gp96 peptide complexes have antitumor potential. We conducted the first Phase II trial to evaluate the safety and efficacy of gp96 vaccination in adjuvant settings for patients with gastric cancer. Methods: We enrolled 73 consecutive patients from October 2012 to December 2015. Thirty-eight patients received gp96 vaccination plus chemotherapy and 35 received chemotherapy alone. The primary endpoints were disease-free survival (DFS) and toxicity. The secondary endpoints were overall survival (OS) and tumor-specific immune responses. Results: There were comparable baseline characteristics between the two groups. Tumor-specific immune responses increased significantly after gp96 vaccination. gp96 vaccination plus chemotherapy was well tolerated and there were no gp96-related serious adverse events. Patients who received gp96 vaccination had improved DFS compared with those who did not [p = 0.045; hazard ratio (HR): 0.47; 95% confidence interval (CI): 0.23-0.96]. The 2-year OS rates were 81.9% and 67.9% for the gp96 vaccination and chemotherapy alone group, respectively (p = 0.123; HR: 0.42; 95% CI: 0.15-1.24). Conclusion: gp96 vaccination elicits tumor-specific immune responses and can be safely used in adjuvant settings combined with chemotherapy. Patients with less-aggressive diseases might benefit from gp96 therapy. PMID- 28819381 TI - Low Preoperative albumin-to-globulin ratio Predict Poor Survival and Negatively Correlated with Fibrinogen in Resectable Esophageal Squamous Cell Carcinoma. AB - Background: Although various inflammation-based indexes in esophageal carcinoma have been documented, but the prognostic value of the albumin-to-globulin ratio(AGR) and its correlation with fibrinogen in resectable ESCC remain unknown. Methods: The levels of pre-treatment serum common acute phase proteins (including CRP, albumin and fribrinogen) were retrospectively analyzed in 447 patients with ESCC who underwent surgical resection at our department. The prognostic value was explored by univariate and multivariate cox hazard analysis. The correlation between AGR and acute phase proteins were also analyzed. Results: Patients with decreased levels of AGR and increased CRP had significantly lower 5-year survival rates than those with higher AGR, not only in the whole ESCC cohort but also in the subgroups stratified according to the disease T, N classifications, and metastasis, whereas the other acute phase proteins were not independent prognostic factors for ESCC. In addition, a lower AGR level was observed more often in patients with a high fibrinogen level than in those with a low fibrinogen level. Spearman's rank correlation analysis revealed that the AGR level presented a negative correlation with the fibrinogen level (r =-0.317, p<0.001). Conclusions: The 5-year survival was shorter in resectable ESCC patients exhibiting decreased pre-treatment AGR and increased CRP. Thus, the serum AGR and CRP may be a clinical prognostic factor for resectable ESCC patients. In addition, a negative correlation was present between the levels of AGR and fibrinogen, the common indexes of acute phase reactants. PMID- 28819382 TI - Effectiveness of the Benign and Malignant Diagnosis of Mediastinal and Hilar Lymph Nodes by Endobronchial Ultrasound Elastography. AB - Background and Objectives: Endobronchial ultrasound elastography is a new technique for describing the stiffness of tissue during endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA). The aims of this study were to investigate the diagnostic value of Endobronchial ultrasound (EBUS) elastography for distinguishing the difference between benign and malignant lymph nodes among mediastinal and hilar lymph node. Materials and Methods: From June 2015 to August 2015, 47 patients confirmed of mediastinal and hilar lymph node enlargement through examination of Computed tomography (CT) were enrolled, and a total of 78 lymph nodes were evaluated by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). EBUS-guided elastography of lymph nodes was performed prior to EBUS-TBNA. A convex probe EBUS was used with a new EBUS processor to assess elastographic patterns that were classified based on color distribution as follows: Type 1, predominantly non-blue (green, yellow and red); Type 2, part blue, part non-blue (green, yellow and red); Type 3, predominantly blue. Pathological determination of malignant or benign lymph nodes was used as the gold standard for this study. The elastographic patterns were compared with the final pathologic results from EBUS-TBNA. Results: On pathological evaluation of the lymph nodes, 45 were benign and 33 were malignant. The lymph nodes that were classified as Type 1 on endobronchial ultrasound elastography were benign in 26/27 (96.3%) and malignant in 1/27 (3.7%); for Type 2 lymph nodes, 15/20 (75.0%) were benign and 5/20 (25.0%) were malignant; Type 3 lymph nodes were benign in 4/31 (12.9%) and malignant in 27/31 (87.1%). In classifying Type 1 as 'benign' and Type 3 as 'malignant,' the sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy rates were 96.43%, 86.67%, 87.10%, 96.30%, 91.38%, respectively. Conclusion: EBUS elastography of mediastinal and hilar lymph nodes is a noninvasive technique that can be performed reliably and may be helpful in the prediction of benign and malignant lymph nodes among mediastinal and hilar lymph node during EBUS-TBNA. PMID- 28819383 TI - Metformin Inhibits Tumorigenesis and Tumor Growth of Breast Cancer Cells by Upregulating miR-200c but Downregulating AKT2 Expression. AB - Background: Metformin has been reported to inhibit the growth of various types of cancers, including breast cancer. Yet the mechanisms underlying the anticancer effects of metformin are not fully understood. Growing evidence suggests that metformin's anticancer effects are mediated at least in part by modulating microRNAs, including miR-200c, which has a tumor suppressive role in breast cancer. We hypothesized that miR-200c has a role in the antitumorigenic effects of metformin on breast cancer cells. Methods: To delineate the role of miR-200c in the effects of metformin on breast cancer, plasmids containing pre-miR-200c or miR-200c inhibitor were transfected into breast cancer cell lines. The MDA-MB 231, BT549, MCF-7, and T-47-D cells' proliferation, apoptosis, migration, and invasion were assessed. The antitumor role of metformin in vivo was investigated in a MDA-MB-231 xenograft tumor model in SCID mice. Results: Metformin significantly inhibited the growth, migration, and invasion of breast cancer cells, and induced their apoptosis; these effects were dependent on both dose and time. Metformin also suppressed MDA-MB-231 tumor growth in SCID mice in vivo. Metformin treatment was associated with increased miR-200c expression and decreased c-Myc and AKT2 protein expression in both breast cancer cells and tumor tissues. Overexpression of miR-200c exhibited effects on breast cancer cells similar to those of metformin treatment. In contrast, inhibiting the expression of miR-200c increased the growth, migration, and invasion of MCF-7 and MDA-MB-231 cells. Conclusion: Metformin inhibits the growth and invasiveness of breast cancer cells by upregulation of miR-200c expression by targeting AKT2. These findings provide novel insight into the molecular functions of metformin that suggest its potential as an anticancer agent. PMID- 28819384 TI - The comparison of EGFR-TKI failure modes and subsequent management between exon 19 deletion and exon 21 L858R mutation in advanced non-small-cell lung cancer. AB - Background: Advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion (19 Del) and exon 21 L858R mutation (L858R) might be distinct diseases. Therefore, it is necessary to take EGFR mutation subgroups into consideration for making choices of subsequent treatment after tyrosine kinase inhibitors (TKIs) failure. Patients and methods: 174 patients who developed to EGFR-TKI failure were categorized into three cohorts of dramatic progression, gradual progression and local progression. Chi-square was used to compare the distribution of failure modes between 19 Del and L858R. Kaplan-Meier method and Cox Regression were performed for analyses of survival in different subsequent treatments. Results: The distribution of EGFR-TKI failure modes showed no significant difference between 19 Del and L858R. Patients in gradual progression had a longer progression-free survival (PFS) and overall survival (OS) compared with other failure modes in whole population, 19 Del cohort and L858R cohort. 19 Del patients with dramatic progression would obtain survival benefit from chemotherapy, while those with gradual progression got no survival benefit neither from chemotherapy nor previous TKI continuation. However, patients with dramatic or gradual progression would benefit from previous TKI continuation in L858R cohort. Conclusion: For advanced EGFR-positive NSCLC patients with acquired resistance to EGFR-TKI, subsequent treatment should be personalized according to EGFR-TKI failure modes & EGFR mutation subtypes. PMID- 28819385 TI - A Randomized, Open-Label, Safety and Exploratory Efficacy Study of Kanglaite Injection (KLTi) plus Gemcitabine versus Gemcitabine in Patients with Advanced Pancreatic Cancer. AB - Background: This study was designed to assess the safety and preliminary efficacy of KLTi plus gemcitabine in patients with locally advanced or metastatic pancreatic cancer. Methods: In a randomized, open-label study, patients with locally advanced or metastatic pancreatic cancer were randomized 2:1 to receive KLTi plus gemcitabine or gemcitabine monotherapy. Three sequential cohorts were tested at 30 g/day, 50 g/day, and 30 g/day. Gemcitabine was administered at 1000 mg/m2 on days 1, 8 and 15 of each 28 day cycle. KLTi was administered on days 1 5, 8-12, and 15-19 of each 28 day cycle. Patients received study treatment until disease progression. The primary endpoint was progression-free survival in the ITT population. Safety evaluation was based on patients who received any study treatment. ClinicalTrials.gov identifier NCT00733850. Results: Eighty-five patients were randomized including 41 (28:13) in Cohort 1, 18 (12:6) in Cohort 2, and 26 (17:9) in Cohort 3. Due to a different dose and/or shift in patient populations in Cohort 2 and 3, efficacy data for the 30 gm dose are presented in this manuscript for Cohort 1 alone, and for the combination of Cohort 1+3. The 30 gm KLTi + gemcitabine group had a statistically significant improvement in progression-free survival (PFS) as assessed by blinded independent radiology review in the ITT population, with a median of 112 days, versus 58 days in the gemcitabine group (HR 0.50; 95% CI: 0.27, 0.92), p = 0.0240. The incidence rates of TEAEs, CTCAE Grade 3 or higher TEAEs, and SAEs were similar between the two arms. There were no deaths related to KLTi + gemcitabine treatment. Conclusion: Kanglaite Injection (30 g/day) plus a standard regimen of gemcitabine demonstrated encouraging clinical evidence of anti-neoplastic activity and a well tolerated safety profile. PMID- 28819386 TI - The tumor microenvironment and inflammatory breast cancer. AB - Inflammatory breast cancer (IBC) is a rare and very aggressive subtype of breast cancer with clinical manifestations similar to acute inflammation. The prognosis of IBC is still poor even though combination therapy with surgery, chemotherapy, and target therapy, mainly due to a lack of fully understanding of the cellular and molecular mechanisms of IBC pathogenesis and progression. In the present article, we have comprehensively reviewed the connection of the pathogenesis of IBC and inflammation, immune reaction and cancer, particularly focused on the role and mechanism of tumor microenvironment related to IBC formation, tumor cell proliferation, migration, invasion and metastasis as well as the clinical manifestations of IBC. As the diverse cells including inflammatory cells, immune cells, and tumor cells and the soluble molecules produced by these cells in the microenvironment play an essential role in IBC development and progression. Therefore, anti-inflammatory therapy and immunotherapy with available agents warrant further investigation in the treatment of IBC. PMID- 28819387 TI - TBK1 Promote Bladder Cancer Cell Proliferation and Migration via Akt Signaling. AB - Bladder cancer is a challenging and fatal malignancy and the improvement in prognosis is limited over years. Deep understanding the mechanism of bladder cancer tumorigenesis and progression will help to discover novel and effective treatment strategies. In this study, we identify non-canonical IkB kinase TBK1 is up-regulated in bladder cancer tissue and cell lines. Knockdown of TBK1 markedly inhibits cell proliferation and migration. Inhibition of TBK1 kinase activity by BX795 significantly attenuates bladder cancer cell proliferation and migration. Mechanistic study shows that overexpression of TBK1 promoted the phosphorylation of Akt, whereas knockdown of TBK1 reverses this action. Taken together, our data suggest that TBK1 modulates the malignant behaviors of bladder cancer cell via Akt signaling, revealing new insights in discovering new therapy target for bladder cancer. PMID- 28819389 TI - Discovery of Non-invasive Glycan Biomarkers for Detection and Surveillance of Gastric Cancer. AB - Purpose: Gastric cancer (GC), one of the world's top five most common cancers, is the third leading cause of cancer related death. It is urgent to identify non invasive biomarkers for GC. The objective of our study was to find out non invasive biomarkers for early detection and surveillance of GC based on glycomic analysis. Method: Ethyl esterification derivatization combined with MALDI-TOF MS analysis was employed for the comprehensive serum glycomic analysis in order to investigate glycan markers that would indicate the onset and progression of gastric cancer. Upon the discovery of the candidate biomarkers, those with great potential were further validated in an independent test set. Peaks were acquired by the software of MALDI-MS sample acquisition and processing and analyzed by the software of Progenesis MALDI. ? Results: The differences in glycosylation were found between non-cancer controls and gastric cancer samples: hybrid and multi branched type (tri-, tetra-antennnary glycans) N-glycans were increased in GC, yet monoantennary, galactose, bisecting type and core fucose N-glycans were decreased. In training set, core fucose (AUC=0.923, 95%CI: 0.8485 to 0.9967) played an excellent diagnostic performance for the early detection of gastric cancer. The diagnostic potential of core fucose was further validated in an independent cohort (AUC=0.854, 95%CI: 0.7592 to 0.9483). Besides, several individual glycan structures reached both statistical criteria (p-values less than 0.05 and AUC scores that were at least moderately accurate) when comparing different stages of GC samples. Conclusion: We comprehensively evaluate the serum glycan changes in different stages of GC patients including peritoneal metastasis for the first time. We determined several N-glycan biomarkers, some of these have potential in distinguishing the early stage GC from healthy controls, and the others can help to monitor the progression of GC. The findings also enhance understanding of gastric cancer. PMID- 28819388 TI - Role of Y Box Protein-1 in cancer: As potential biomarker and novel therapeutic target. AB - The Y-box binding protein (YB-1) is known to be a multifunctional transcription and translation factor during expression of several proteins. It is a vital oncoprotein that regulates cancer cell progression and proliferation. YB-1 is over-expressed in various human cancers such as breast cancer, colon cancer, lung cancer, gastric cancer, oesophageal cancer and glioblastoma. Nuclear expression of YB-1 is found to be associated with multidrug resistance and cancer cell progression. YB-1 is reported to regulate many cellular signalling pathways in different types of cancer proliferation. Knowledge about nuclear localization and nuclear level expression of YB-1 in different cancers has been correlated with prospective prognosis of cancer. This review discusses the prospects of YB-1 as a potential biomarker as well as therapeutic target in lieu of their role during cancer progression and multidrug resistance. PMID- 28819390 TI - Fluorofenidone Inhibits the Proliferation of Lung Adenocarcinoma Cells. AB - Background: Lung carcinoma is the leading cause of malignant tumor related mortality in China in recent decades, and the development of new and effective therapies for patients with advanced lung carcinoma is needed. We recently found that fluorofenidone (FD), a newly developed pyridine compound, reduced the activation of Stat3 (Signal transducer and activator of transcription 3) in fibroblasts. Stat3 plays a crucial role in the development of lung cancer and may represent a new therapeutic target. In this study, we examined the effect of FD on human lung adenocarcinoma cells in vivo and in vitro. Methods: The effect of FD on the growth of lung cancer cells was measured with a CCK-8 assay, colony formation assay and xenograft tumor model. A flow cytometry analysis was performed to study cell cycle arrest and apoptosis. Western blotting and immunohistochemistry were used to observe the expression of Stat3. Changes in the expression of RNA induced by FD were assessed using gene chip and real-time RT PCR assays. Results: In vitro, FD inhibited the growth of lung adenocarcinoma A549 and SPC-A1 cells in a dose-dependent manner. After treatment with FD, the A549 and SPC-A1 cells were arrested in the G1 phase, and apoptosis was induced. In vivo, this compound significantly inhibited the growth of tumors that were subcutaneously implanted in mice. Moreover, FD decreased Stat3 activity in lung cancer cells and xenograft tumor tissue, and microarray chip results showed that FD altered the gene expression profile of lung cancer cells. Specifically, NUPR1, which plays a significant role in cancer development, was down-regulated by FD in lung cancer cells. Conclusion: Our study supports the clinical evaluation of FD as a potential lung adenocarcinoma therapy. PMID- 28819391 TI - A critical reappraisal for the value of tumor size as a prognostic variable in rectal adenocarcinoma. AB - Background and Objectives: To investigate critical prognostic factors for local recurrence in patients with rectal adenocarcinoma. Methods: We enrolled 221 consecutive patients who had histologically confirmed adenocarcinoma of the rectum and underwent surgery in our hospital between January 2000 and December 2014. Total mesorectal excision was performed in all patients undergoing a sphincter-sparing procedure or abdominal perineal resection of rectal cancer. To evaluate prognostic factors for local recurrence, we performed univariate and multivariate Cox regression analyses of the local recurrence rate in all patients. Overall survival rates were calculated using the Kaplan-Meier method, and Kaplan-Meier survival curves were compared using the log-rank test. Results: After the inclusion of only model variables of local recurrence with the highest or lowest univariate risk, a tumor size of <5 cm, a negative circumferential margin, well-to-moderately differentiated adenocarcinoma, low anterior resection, not receiving adjuvant RT, pathological T1-T3 stages, and upper- and middle-third rectal cancers were identified as strong prognostic factors with hazard ratios of 0.18, 0.20, 0.03, 0.01, 0.25, 0.18 and 0.18, respectively (95% confidence intervals [CIs], 0.06-0.58, 0.05-0.82, 0.03-0.38, 0.04-0.23, 0.05-0.64,0.09-0.70 and 0.06-0.54, respectively). After the multivariate Cox regression analysis of the local recurrence rate, a pathological tumor size of >=5 cm was identified as the only prognostic risk factor (95% CI, 0.03-0.66; P = 0.013). The 5-year local recurrence rates among the patients having tumors measuring <5 cm and >=5 cm in size were 1.40% and 23.00%, respectively (log-rank, P = 0.0001). The 5-year overall survival rates in the patients having tumors measuring <5 cm and >=5 cm in size were 82.60% and 71.20%, respectively (log-rank, P = 0.001). Conclusion: A pathological tumor size of >=5 cm is an independent prognostic factor for local recurrence in rectal adenocarcinoma. PMID- 28819392 TI - Long-term Trends in Primary Sites of Gastric Adenocarcinoma in Japan and the United States. AB - Background: The incidence and characteristics of gastric cancer have been shown to vary widely across Western and Eastern countries. Our study had two aims: to evaluate long-term trends in gastric adenocarcinoma in Japan over a period of 70 years, and to anticipate the future of gastric cancer in Japan, through comparison with data from the United States. Methods: Japanese patient data for 19,306 incident cases of gastric adenocarcinoma from 1946 - 2014 were collected from the Gastric Cancer Database at the Cancer Institute Hospital, Tokyo, Japan (CIH-GCDB). U.S. patient data for 78,625 incident cases of gastric cancer from 1973 - 2012 were obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. Changes over time in patient and tumor characteristics were investigated in these two cohorts. Results: There was a marked reduction of cancer incidence in the lower third of the stomach in the CIH-GCDB; over 70% to around 30%. The incidence in the upper third has been increasing steadily over time; 3% to 19%, although the number of cardia tumors has not changed. An increase in elderly and obese patients was also noted. In the U.S. population, there was a significant difference in the primary site across races. A notable overall increase in cardia cancer was evident in the Western population during the study period, with no similar change evident in the Japanese population over the last 15 years. In the East Asian population, the proportional frequency of tumors in the cardia was lower and that of tumors in the pyloric antrum was higher. Conclusion: In Japan, cancer in the antrum or pylorus of the stomach has been declining, whereas cancer in the body has been increasing. Unlike the Western population in the United States, adenocarcinoma of esophago-gastric junction is not increasing in Japan. PMID- 28819393 TI - Phosphoglycerate Mutase 1 Predicts the Poor Prognosis of Oral Squamous Cell Carcinoma and is Associated with Cell Migration. AB - Oral squamous cell carcinoma (OSCC) is a common malignant tumor with high metastatic potential. However, no good biomarker has been identified to refine which subtype is of high metastatic potential to make decisions regarding the elective and therapeutic management of lymphatic metastases. In this study, we investigated the role of the metabolic enzyme phosphoglycerate mutase 1 (PGAM1) in OSCC. PGAM1 expression was examined in tissue samples of 122 OSCC patients using immunohistochemistry, and the correlation between clinicopathological expression and PGAM1 expression was determined. Survival curves were generated using the Kaplan-Meier method, and multivariate analysis was performed by the Cox proportional hazards model. Moreover, PGAM1 was knocked down in the OSCC cell lines Cal27 and HN12, followed by determination of the change in cell migration and signaling pathways. PGAM1 expression is correlated with age, lymphatic metastasis and tumor recurrence and is closely associated with poor overall survival (OS) and disease-free survival (DFS). Intriguingly, PGAM1 is an independent risk factor for OS and DFS. After knocking down PGAM1 in Cal27 and HN12 cells, cell migration was remarkably decreased along with signaling pathway molecules, such as proto-oncogene c-SRC (SRC), Focal adhesion kinase (FAK) and Paxillin. The effect on cell migration was abolished following pretreatment with an SRC inhibitor. This study suggested that PGAM1 is a poor prognostic biomarker of OSCC and may be used to select patients of high metastatic potential in the clinic, and PGAM1 promotes the migration of OSCC cells is associated with the SRC pathway. PMID- 28819394 TI - A Role for The ATP7A Copper Transporter in Tumorigenesis and Cisplatin Resistance. AB - The ATP7A protein is a ubiquitously expressed copper-translocating P-type ATPase that controls cytoplasmic copper concentrations by mediating cellular copper egress. In vitro studies have previously demonstrated that ATP7A abundance in various tumor cell lines is correlated with increased resistance to cisplatin, a widely-used chemotherapy agent. However, to date no studies have examined a role for ATP7A in tumor growth or cisplatin sensitivity in vivo. In this study, we deleted ATP7A in H-RAS transformed tumorigenic mouse embryonic fibroblasts (MEFRAS7A-). Interestingly, loss of ATP7A was found to markedly suppress tumorigenesis in MEFRAS7A- cells relative to wild type parental cells. This was associated with hyperaccumulation of copper and sensitivity to reactive oxygen species and hypoxia. Tumor grafts lacking ATP7A were markedly more sensitive to cisplatin chemotherapy compared to ATP7A-expressing control tumors. These findings identify ATP7A at the nexus between tumorigenesis and cisplatin resistance pathways, underscoring its potential as a therapeutic target for regulating both tumor growth and the efficacy of cisplatin treatment. PMID- 28819395 TI - Downregulation of ABC Transporters in Non-neoplastic Tissues Confers Better Prognosis for Pancreatic and Colorectal Cancer Patients. AB - Transport of a wide variety of substrates, including xenobiotics, is one of the main functions attributed to human ATP-binding cassette (ABC) proteins. Overexpression of ABC genes is considered to be an important mechanism facilitating the development of chemoresistance. Relationships between the expression levels of ABC genes in tumor tissues and established clinicopathological features were extensively studied previously. The current study tested our hypothesis that the expression levels of ABC genes in non neoplastic (control) tissues also provide important information in relation to the relevant tumor progression. Expression levels of all human ABC genes (48 protein coding and one pseudogene), measured by qRT-PCR, were bioinformatically analyzed. The data originated from four independently collected cohorts covering three types of tumors - breast, colorectal and pancreatic carcinomas. ABC gene expression profiles (signatures) in non-neoplastic tissues (matched to tumor samples from three different tumor types) were characteristically clustered into three main types - those with the vast majority of the genes downregulated, upregulated or heterogeneously regulated. The clusters with mostly downregulated and upregulated genes were shown to possess significant relations to good and poor prognostic markers, respectively, in pancreatic and colorectal cancers. The present findings support the theory that the expression of ABC genes in non neoplastic tissues can significantly contribute to tumor pathogenesis. Suggested multi-gene panels, consisting of the reduced number of ABC genes, have the potential to be implemented as new prognostic markers, which are especially urgent in pancreatic cancer. The results can also stimulate further primary research in carcinogenesis. PMID- 28819396 TI - Expression and Significances of G-Protein-Coupled Receptor Kinase 3 in Hepatocellular Carcinoma. AB - Objective: To investigate expression, clinical, pathologic and prognostic significances of G-protein-coupled receptor kinase 3 (GRK3) in hepatocellular carcinoma (HCC). Materials and Methods: Expression of GRK3 was detected using Western blotting and tissue microarray-based immunohistochemical staining in 8 and 395 patients (training set: n=164; validation set: n=231) with HCC underwent hepatectomy, respectively. GRK3 expression and its associations with cliniopathologic variables and tumor-specific survival were evaluated. Results: Expression of GRK3 was lower in tumor than in non-tumor tissues from 4 out of 8 patients. In the training set, the H-score of tumoral GRK3 staining was much lower than that in adjacent non-tumor liver tissues. In addition, GRK3 was associated with tumor-node-metastasis (TNM) stage and serum alpha-fetoprotein (AFP) level. Patients with high GRK3 tumors were found to carry significantly better tumor-specific survival, compared with those with low GRK3 ones. Furthermore, GRK3 was identified as one of independent predictors of favorable prognosis, adjusted for clinicopathologic parameters. Importantly, these results were further validated in the independent validation set. In all patients and 7 out of 10 subgroups, GRK3 was also revealed to be prognostic. Conclusions: GRK3 is down-regulated and predicts good prognosis in HCC. Therefore, GRK3 might function as a tumor suppressor gene in HCC. PMID- 28819397 TI - Iron Chelators and Exogenic Photosensitizers. Synergy through Oxidative Stress Gene Expression. AB - In non-invasive anticancer photodynamic therapy (PDT), a nontoxic photosensitizer (PS), which is activated by visible light, is used as a magic bullet that selectively destroys cancer cells. Recently, we described the combined therapy of 5-aminolevulinic acid (ALA-PDT) with thiosemicarbazone (TSC), i.e. an iron chelating agent. This resulted in a strong synergistic effect. Herein, we investigated a novel strategy using a combination of PDT consist of the xenobiotic-porphyrin type PS with TSC. We observed a synergistic effect for all of the pairs of TSC-PS. This approach can be rationalized by the fact that both chlorin and TSC can affect the generation of reactive oxygen species (ROS). In order to elucidate the plausible mechanism of action, we also combined the investigated PSs with DFO, which forms complexes that are redox inactive. We detected a slight antagonism or additivity for this combination. This may suggest that the ability of an iron chelator (IC) to participate in the production of ROS and the generation of oxidative stress is important. PMID- 28819398 TI - Clinical Impact of Vitamin K Dosing on Sorafenib Treatment for Hepatocellular Carcinoma. AB - Background: Some researchers have suggested that vitamin K enhances the antitumor effect of sorafenib for hepatocellular carcinoma (HCC) in vitro and in vivo. In this study, we examined the clinical impact of vitamin K dosing for sorafenib treatment. Methods: Twenty-nine out of 65 patients treated with sorafenib for HCC were simultaneously dosed with vitamin K. We retrospectively investigated progression-free survival (PFS) and overall survival (OS) in the vitamin K-dosed group and sorafenib alone group. We also examined the changes in serum des-gamma carboxy prothrombin (DCP) levels, which vitamin K is involved with. Results: The median PFS was prolonged in the sorafenib + vitamin K group compared with the sorafenib alone group (6.0 months and 2.0 months, respectively; P<0.001, hazard ratio?HR?: 0.25). The median OS was also significantly extended (12.5 months vs. 10.0 months; P=0.009, HR: 0.47). Despite suppressed tumor growth, serum DCP levels had increased in cases of disease-controlled patients in the sorafenib alone group 8 weeks after the beginning of treatment, (2.28+/-0.91 to 2.64+/ 1.03, P= 0.048). In contrast, the serum DCP levels of the sorafenib + vitamin K group had declined both in patients with controlled disease and in patients with progressive disease (1.97+/-0.57 to 1.29+/-0.28, P=0.002 and 2.90+/-1.32 to 1.78+/-0.53, P=0.034, respectively). Conclusions: To the best of our knowledge, this is the first clinical report showing enhanced antitumor action of sorafenib by vitamin K. Our clinical findings suggest that vitamin K may have the synergistic effect by suppressing production of DCP, a tumor growth and angiogenesis factor. PMID- 28819399 TI - Outcomes of cancer therapy administered to treatment-naive lung cancer patients in the intensive care unit. AB - Objectives: Therapy outcomes for newly diagnosed, critically ill lung cancer patients have seldom been evaluated. This study evaluated therapy outcomes for treatment-naive lung cancer patients in the intensive care unit (ICU). Materials and Methods: Patients were excluded if they had previously received lung cancer treatment, such as systemic chemotherapy, targeted therapy, radiotherapy, or surgical lung resection before ICU admission. The therapeutic strategies for the treatment-naive patients were determined while they were in the ICU. The patients' demographic data, clinical outcomes, and treatment-related toxicities were analyzed. Results: Newly diagnosed lung cancer patients (n = 72) who did not receive any anticancer treatment before ICU admission were included. Most patients had locally advanced disease, and 61 (84.7%) required intensive care due to cancer-related events. In the ICU, 24 (33.3%) patients received chemotherapy, 24 (33.3%) received epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy and 24 (33.3%) received best supportive care (BSC). Patients receiving chemotherapy or EGFR-TKIs in the ICU demonstrated better ICU (p = 0.011) and in-hospital (p = 0.034) survival than those receiving BSC only. Among patients requiring mechanical ventilation, those receiving chemotherapy had higher weaning rates than those receiving EGFR-TKIs or BSC (p = 0.002). In multivariate analysis, receipt of chemotherapy (hazard ratio [HR], 0.443; p = 0.083) and mechanical ventilation (HR, 0.270; p = 0.022) were significantly associated with longer ICU survival after adjusting for clinical factors. Conclusions: Anticancer therapy in the ICU might provide better short-term ICU survival for treatment-naive, critically ill lung cancer patients. PMID- 28819400 TI - Rapid Breast Cancer Disease Progression Following Cyclin Dependent Kinase 4 and 6 Inhibitor Discontinuation. AB - Background: CDK 4 and 6 inhibitors (CDK4/6i), which arrest unregulated cancer cell proliferation, show clinical efficacy in breast cancer. Unexpectedly, a patient treated on a CDK4/6i-based trial, as first-line therapy in metastatic breast cancer, developed rapid disease progression following discontinuation of study drug while receiving standard second-line therapy off trial. We thus sought to expand this observation within a population of patients treated similarly at The University of Texas MD Anderson Cancer Center. Methods: Using an IRB-approved protocol, 4 patients previously enrolled on CDK4/6i trials were analyzed for outcomes after discontinuing study drug. These patients were treated on a randomized trial of first-line endocrine therapy +/- a CDK4/6i. Rapid disease progression was defined as progression occurring within 4 months of CDK4/6i discontinuation. Results: In total, 4 patients developed rapid disease progression and died; 2 of whom died within 6 months of CDK4/6i discontinuation. Conclusion: This case series suggests a potential for rapid disease progression following CDK4/6i discontinuation. However, the clinical course following progression must be validated in large CDK4/6i clinical trials and standard-of care cohorts. If confirmed, such observations may alter the algorithm for subsequent therapy in patients with disease progression on CDK4/6i. Nevertheless, the need remains to define a mechanistic basis for this rapid progression and formulate alternative therapeutic strategies. PMID- 28819401 TI - Identification and validation of soluble carrier family expression signature for predicting poor outcome of renal cell carcinoma. AB - The soluble carrier (SLC) family plays an important role in cell metabolism. The purpose of the current study was to screen SLCs as potential prognostic factors in clear cell renal cell carcinoma (ccRCC). A total of 509 patients with ccRCC from The Cancer Genome Atlas (TCGA) cohort were enrolled in this study. The expression profile of SLCs was obtained from the TCGA RNAseq database. Metadata of the TCGA cohort, including age, sex, TNM stage, tumor grade, American Joint Committee on Cancer stage, laterality, and overall survival, were collected. Univariate and multivariate Cox proportional hazards regression models were used to analyze the relative factors. Prognosis-associated genes were further validated in a Fudan University Shanghai Cancer Center (FUSCC) cohort consisting of 178 patients. Among a total of 364 SLC transporters, 61 were independent predictors of ccRCC patient overall survival. Among the 61 SLC transporters, 26 were significantly downregulated and 23 were significantly upregulated in tumor tissues compared with non-malignant kidney tissues. Analyses of two open source, RNA expression data sets on sunitinib response revealed that SLC10A2 was downregulated in tyrosine kinase inhibitor-resistant samples. We validated SLC10A2 expression in the FUSCC cohort and showed that SLC10A2 expression was an independent prognostic predictor of overall survival of ccRCC (hazard ratio=0.432, 95% CI: 0.204-0.915). Our results identified a number of associations of SLC gene expression with prognosis of ccRCC patients, indicating that these genes may represent possible oncogenes that could serve as therapeutic targets of ccRCC. PMID- 28819402 TI - PD-L1 Expression Is Associated with FOXP3+ Regulatory T-Cell Infiltration of Soft Tissue Sarcoma and Poor Patient Prognosis. AB - Background: Programmed death ligand-1(PD-L1) functions as a negative mediator of immune response through different pathways in anti-tumor immunity. Recent studies have reported that PD-L1 plays a pivotal role in the function of regulatory T cells (Tregs). Although increases in FOXP3+ Tregs infiltration and PD-L1 expression have been revealed in several cancers, their correlation with soft tissue sarcoma remains unknown. Methods: We included 163 cases of soft tissue sarcoma who were diagnosed and underwent extensive and radical resection at the Sun Yat-sen University Cancer Center, Guangzhou, China, from 2000-2010. PD-L1 and FOXP3 expression was evaluated by immunohistochemistry. Correlation between their expressions and associations with clinicopathological features were studied. Results: Among 163 STS samples, 19 (11.7%) exhibited PD-L1 positivity, and 41 (25.2%) cases expressed high FOXP3+ Treg infiltration. Significant correlation between PD-L1 expression and FOXP3+Treg infiltration in STS was identified (r=0.450, p<0.001). In univariate analysis, PD-L1 expression was significantly associated with high tumor grade and the age of patients, while the presence of FOXP3+ in tumor infiltrating Tregs was significantly associated with the age of patients, high tumor stage, higher tumor grade and tumor depth. Multivariate analysis revealed PD-L1 and FOXP3 as independent prognostic indicators significantly associated with OS and DFS. Conclusions: Our study revealed that PD L1 and FOXP3+Tregs may work synergistically in promoting immune evasion of the tumors in soft tissue sarcoma. A combined strategy to block PD-L1/PD-1 with simultaneous depletion of Tregs may show promise in enhancing the therapeutic efficacy of these patients. PMID- 28819403 TI - Impact of Statin Use on Outcomes in Triple Negative Breast Cancer. AB - Purpose: We sought to investigate if the use of HMG Co-A reductase inhibitors (statins) has an impact on outcomes among patients with triple negative breast cancer (TNBC). Methods: We reviewed the cases of women with invasive, non metastatic TNBC, diagnosed 1997-2012. Clinical outcomes were compared based on statin use (defined as ever use during treatment vs. never use). We identified a subset of women for whom a 5-value lipid panel (5VLP) was available, including total cholesterol, low density lipoprotein, high density lipoprotein, very low density lipoprotein, and triglycerides. The Kaplan-Meier method was used to estimate median overall survival (OS), distant metastases-free survival (DMFS), and local-regional recurrence-free survival (LRRFS). A Cox proportional hazards regression model was used to test the statistical significance of prognostic factors. Results: 869 women were identified who met inclusion criteria, with a median follow-up time of 75.1 months (range 2.4-228.9 months). 293 (33.7%) patients used statins and 368 (42.3%) had a 5VLP. OS, DMFS, and LRRFS were not significant based on statin use or type. Controlling for the 5VLP values, on multivariable analysis, statin use was significantly associated with OS (HR 0.10, 95% CI 0.01-0.76), but not with DMFS (HR 0.14, 95% CI 0.01-1.40) nor LRRFS (HR 0.10 95% CI 0.00-3.51). Conclusions: Statin use among patients with TNBC is not associated with improved OS, although it may have a benefit for a subset of patients. Prospective assessment would be valuable to better assess the potential complex correlation between clinical outcome, lipid levels, and statin use. PMID- 28819404 TI - Activin B Regulates Adhesion, Invasiveness, and Migratory Activities in Oral Cancer: a Potential Biomarker for Metastasis. AB - Activin B, a homodimer of inhibin beta b (INHBB), is a multifunctional cytokine belonging to the transforming growth factor-beta (TGF-beta) family. However, the molecular functions and clinical relevance of activin B have not been determined in oral cancer. We investigated the critical roles of activin B in oral squamous cell carcinoma (OSCC). We performed quantitative reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemistry to study INHBB expression in OSCC-derived cell lines and OSCC clinical samples. The INHBB expression levels were significantly (P < 0.05) overexpressed in OSCCs compared to normal counterparts in vitro and in vivo. Activin B-positivity in OSCC cases was significantly (P < 0.05) correlated with regional lymph node metastasis. The INHBB knockdown (shINHBB) cells promoted cellular adhesion and suppression of cellular invasiveness and migration. After treatment of shINHBB cells with activin B, those activities were restored similar to the shMock cells. In the processes of invasiveness and metastasis, the cells cause epithelial-mesenchymal transition (EMT). TGF-beta and its family members are promoters of the EMT process. To investigate whether activin B is related to EMT, we examined the expressions of EMT-related genes and found that INHBB was related closely to EMT. Our results suggested for the first time that activin B indicates tumoral metastasis in OSCCs and might be a useful biomarker for OSCC metastasis. PMID- 28819405 TI - Linc00152 promotes Cancer Cell Proliferation and Invasion and Predicts Poor Prognosis in Lung adenocarcinoma. AB - Background: The long non-coding RNA Linc00152 stimulates tumor progression in cancer. However, its clinical significance and biological functions in lung adenocarcinoma remains unknown. We evaluate the expression of Linc00152 in lung adenocarcinoma and its possible correlation with clinicopathologic features and patient survival to reveal its biological effects in cancer progression and prognosis. Methods: Total RNA extraction was performed on 110 pairs of lung adenocarcinoma and adjacent normal tissue samples, and then RT-qPCR was conducted. Chi-square test analysis was used to calculate the correlation between pathological parameters and the Linc00152 mRNA levels. Kaplan-Meier and Cox proportional hazards analyses were used to analyze the overall survival (OS) and disease-free survival (DFS) rates. We also detected the potential functional effects of overexpression and knockdown of Linc00152 in vitro cell proliferation, tumor cell invasion and migration, as well as in vivo nude mouse xenograft and metastasis models. Results: The Linc00152 expression levels were higher in lung adenocarcinoma samples than in the adjacent normal tissues. Linc00152 expression levels tightly correlated with lymph node metastasis station, remote metastasis and TNM staging. The Kaplan-Meier analysis suggested that high Linc00152 expression caused significantly poorer OS and DFS rates, and a multivariate analysis revealed that Linc00152 was an independent risk factor for both DFS and OS. Overexpression of Linc00152 in lung cancer cells stimulated proliferation, tumor cell invasion and migration. Knockdown of Linc00152 inhibited cell growth and cell invasion and migration. Finally, Linc00152 knockdown inhibited lung tumor growth and tumor metastasis in nude mice models. Conclusions: Our study suggests that Linc00152 independently predicts poor prognosis and promotes tumor progression in lung adenocarcinoma. Linc00152 needs to be considered as a potential molecular target in future cancer pharmacology. PMID- 28819406 TI - Adjuvant Therapeutic Modalities Following Three-field Lymph Node Dissection for Stage II/III Esophageal Squamous Cell Carcinoma. AB - Background: The rates of locoregional and distant recurrence for esophageal squamous cell carcinoma (ESCC) patients underwent radical esophagectomy remain high. The purpose of this study is to explore an optimal postoperative therapeutic modality by investigating the efficacy of various adjuvant therapies in the treatment of ESCC. Methods: We retrospectively reviewed 408 ESCC patients underwent thoracic esophagectomy and 3-field lymph node dissection from 2010 to 2015. Patients were classified into surgery alone (Group S), adjuvant chemotherapy (Group CT) and postoperative chemotherapy plus radiotherapy (Group CRT), respectively. Univariate and multivariate Cox regression analyses were used to analyze prognostic factors and survival. Results: The overall survival (OS) and disease-free survival (DFS) were similar among groups. Postoperative CT and CRT both were beneficial for patients with positive lymph nodes, particularly for those with 3 or more lymph nodes involvement and metastasis in the middle thoracic segment compared with surgery alone. The 3-year OS and DFS for patients with 3 or more lymph nodes involvement were 30.8%, 53.7%, 50.5% and 19.9%, 41.6%, 34.0% for Group S, CT, and CRT, respectively (p=0.04; p=0.004, respectively). There was no notable difference in OS and DFS between the adjuvant Group CT and CRT (p=0.42; p=0.49, respectively). Postoperative CRT significantly reduced the rates of distant metastasis and overall recurrence for patients with positive lymph nodes (p=0.042; p=0.01, respectively). Number of metastatic lymph nodes, extent of resection, and AJCC stage were independent predictors of survival. Grade 1-2 myelosuppression was experienced significantly more frequently by patients in Group CRT than those in Group CT (P=0.03). Late toxicities were rare and manageable overall. Conclusions: Postoperative CT and CRT both were associated with better survival for patients with positive lymph nodes, particularly for those with 3 or more lymph nodes involvement and metastasis in the middle thoracic segment. Postoperative CRT was significantly more effective at reducing the rates of distant metastasis and overall recurrence for patients with positive lymph nodes. PMID- 28819407 TI - CCR7 promote lymph node metastasis via regulating VEGF-C/D-R3 pathway in lung adenocarcinoma. AB - Lymph node metastasis is still an important issue in metastatic process of lung adenocarcinoma. C-C chemokine receptor 7 (CCR7) has been proved to be closely associated with the metastasis of lung adenocarcinoma, and the mechanism is poorly understood. In order to investigate the relationship between CCR7 and lymph node metastasis in lung adenocarcinoma, and to explore the role of CCR7 in treating lung adenocarcinoma, 40 clinical specimens were collected to define the relationship between CCR7 and lymph node metastasis in lung adenocarcinoma by immunohistochemistry. The siRNA was used to suppress CCR7 expression in A549 cells. The scratch test, transwell test, qRT-PCR, western blot, flow cytometry and immunofluorescence were used to investigate the lymph node metastasis-related function of CCR7 in vitro. The athymic mice subcutaneous injection was used to research lung adenocarcinoma formation in vivo. Clinical case studies show that higher expression of CCR7 in lung adenocarcinoma tissues was associated with a higher lymph node metastasis. Inhibition of expression of CCR7 can reduce the migration and invasion and suppress the expression of VEGF-C, VEGF-D and VEGF-R3 in vitro and in vivo. Moreover, CCR7 silence also suppressed WNT and p-ERK pathways in vitro. All the results indicate that CCR7 can promote lymph node metastasis in lung adenocarcinoma by regulating VEGF-C/D-R3 pathway. Thus CCR7 is proposed to be a potential prediction for poor prognosis of lung adenocarcinoma, and a therapeutic target for lymph node metastasis. PMID- 28819408 TI - Opposite Effects of SET7/9 on Apoptosis of Human Acute Myeloid Leukemia Cells and Lung Cancer Cells. AB - SET7/9 is a protein lysine methyltransferases (PLMTs or PKMTs) which methylates both histone H3K4 and non-histone proteins including transcriptional factors, tumor suppressors, and membrane-associated receptors. Methylation of these proteins alters protein activity and leads to changes in cellular behavior and a series of biological processes. This study aims to investigate the role of SET7/9 in human acute myeloid leukemia (AML) and non-small-cell lung cancer (NSCLC). We examined the expression of SET7/9 in AML cells and NSCLC cells and detected the methylation status of the SET7/9 promoter region. To evaluate the effect of SET7/9 expression changes on cell apoptosis, cell apoptosis rates were determined after SET7/9 overexpression or down-regulation. Our results showed that SET7/9 induces apoptosis of AML cells and inhibits apoptosis of NSCLC cells, suggesting differential effects of SET7/9 on cellular apoptosis and carcinogenesis depending on different cancer types and genetic contexts. Furthermore, we also demonstrated that SET7/9 suppresses cell apoptosis via modulation of E2F1 under circumstance of p53 deficiency in NSCLC cells. PMID- 28819409 TI - A retrospective discussion of the prognostic value of combining prothrombin time(PT) and fibrinogen(Fbg) in patients with Hepatocellular carcinoma. AB - Aims: The levels of coagulation system tests have been studied in various cancers. In this study, our aim is to evaluate the prognostic value of pretreatment plasma coagulation tests in hepatocellular carcinoma (HCC) patients. Patient and methods: A retrospective study was performed in 539 patients with HCC, and follow-up period was at least 60 months until recurrence or death. The prognostic significance of coagulation system tests (prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen) were determined by univariate and multivariate Cox hazard models. Then, according to the results of the multivariate analyses, we proposed the coagulation-Based Stage, which combined the independent risk factors (prothrombin time and fibrinogen). Results: Coagulation system tests including prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (Fbg) were analyzed. Patients with prolonged PT (>=12.1 sec) levels had significantly poor overall survival (OS) and disease-free survival (DFS), not only in the entire cohort (HR: 1.661, 95%CI: 1.125-2.451, p=0.011 vs. HR: 1.660, 95%CI: 1.125-2.451, p=0.011), but also in the subgroups stratified by pathological stage (stage I-II and stage III-IV). Additionally, high Fbg (>=2.83 g/L) levels experienced significantly decreased OS and DFS (HR: 2.158, 95%CI: 1.427-3.263, p<0.001 vs. HR: 2.161, 95%CI: 1.429-3.267, p<0.001), not only in the entire cohort but also in the subgroups stratified by pathological stage (stage I-II and stage III-IV). All the patients were then stratified (based on combined PT and Fbg) into three groups, The OS for HCC patients were (41.37+/-17.76), (31.83+/-19.84) and (18.68+/-18.41) months, and the DFS for HCC patients were (41.15+/-17.88), (31.65+/-19.81) and (18.66+/-18.39) months. Conclusions: Our findings suggest that the combination of plasma PT and Fbg levels should be evaluated as the valuable predictor of survival in patients with HCC. PMID- 28819410 TI - Characterization of the Role of the Malate Dehydrogenases to Lung Tumor Cell Survival. AB - Cellular compartmentalization of biochemical processes in eukaryotic cells is critical for many functions including shuttling of reducing equivalents across membranes. Although coordination of metabolic flux between different organelles is vital for cell physiology, its impact on tumor cell survival is not well understood. By using an integrative approach, we have dissected the role of the key metabolic enzymes Malate dehydrogenases (MDH1 and MDH2) to the survival of Non-small Cell Lung Carcinomas. Here, we report that while both the MDH1 (cytosolic) and the MDH2 (mitochondrial) enzymes display elevated levels in patients compared to normal counterparts, only high expression of MDH1 is associated with poor prognosis. We further show that the MDH1 enzymatic activity is significantly higher in NSCLC cells than that of MDH2. Accordingly, genetic depletion of MDH1 leads to significantly higher toxicity than depletion of MDH2. These findings provide molecular insights into the metabolic characteristics of the malate isoenzymes and mark MDH1 as a potential therapeutic target in these tumors. PMID- 28819411 TI - Comprehensive study of prognostic risk factors of patients underwent pneumonectomy. AB - Introduction: To investigate postoperative complications and the prognostic risk factors of patients underwent pneumonectomy. Methods: Four hundred and six patients underwent pneumonectomy were subjected to the study. All the clinicopathologic data including age, gender, smoking history, surgical treatment, postoperative complications, tumor staging and the follow-up information were investigated. Results: The 30-day and 90-day mortality rates were 3.2% and 6.2%, respectively. Postoperative complications developed in 149 patients (36.7%), mainly included arrhythmia, transfusion, pulmonary infection, bronchopleural fistula and acute respiratory distress syndrome. During the follow up, 189 patients experienced a relapse, consisting of 51 patients with local recurrence and 138 with distant recurrence. The median survival time was 24.4 months and the overall 1-year, 3-year and 5-year survival rates were 82.7%, 50.9% and 32.5%, respectively. Moreover, the overall 1-year, 3-year, 5-year survival rates for patients with non-small cell lung cancer (NSCLC) were 84.1%, 52.1% and 32.5%, respectively and patients with small cell lung cancer (SCLC) were 56.1%, 38.5% and 28.8%, respectively. Among NSCLCs, adenocarcinomas had a worse prognosis than squamous carcinomas. Compared to right pneumonectomy, patients with left pneumonectomy had a better prognosis. Multivariable analysis revealed ICU stay, disease stage, nodal stage and adjuvant chemotherapy were all significant predictors of overall survival (OS). Conclusions: Pneumonectomy is still a valuable and effective treatment option for patients with advanced lung cancer. Surgeons should be more cautious when patients had higher disease stage, adenocarcinoma and right-side lung cancer. Neoadjuvant chemotherapy did not affect the prognosis. Pneumonectomy could also achieve acceptable survival outcomes in well-selected SCLC patients. PMID- 28819412 TI - CT-guided 125I brachytherapy for locally recurrent nasopharyngeal carcinoma. AB - Purpose: The study evaluated the feasibility, clinical effectiveness, and quality of life of computed tomography (CT)-guided 125I brachytherapy for locally recurrent nasopharyngeal carcinoma (NPC). Methods: We recruited 81 patients diagnosed with locally recurrent NPC after previous radiotherapy with or without chemotherapy. Thirty-nine patients received 125I brachytherapy (group A) and 42 received re-irradiation (IMRT, group B). The evaluated outcomes were local control, complications, and quality of life. Cox proportional hazards regression analysis was used to compare local tumor progression-free survival (LTPFS) and overall survival (OS) in the two treatment groups. Results: The median follow-up was 30 months (range, 5-68 months), median LTPFS was 21 in group A and 17 months in group B. The 1-, 2-, and 3-year OS in group A were 84.6%, 51.3%, 30.7%, and 85.7%, 50.0%, and 32.6% in group B. In group A, 10/39 patients (25.6%) experienced at least one >=grade III complication; no grade V complications occurred. In group B, 28/42 (66.7%) experienced at least one >=grade III complication and 6/42 (14.3%) died of severe grade V complications. No significant between-group difference existed in the Quality of Life score on the EORTC QLQ-H&N35 questionnaire before treatment. In group A, quality of life was significantly improved after treatment; but did not improve, or even deteriorated in group B. Conclusions: 125I brachytherapy was a feasible, safe, and effective treatment for locally recurrent NPC. 125I brachytherapy significantly reduced complications caused by re-irradiation and improved patients' quality of life. PMID- 28819413 TI - The role of beta-catenin in the initiation and metastasis of TA2 mice spontaneous breast cancer. AB - Purpose: Tientsin Albino 2 (TA2) mice have a high incidence of spontaneous breast cancer. Tumor initiation is related to mouse mammary tumor virus (MMTV) infection. MMTV is hormonally regulated and may promote tumor formation via Wnt/beta-catenin signaling pathway. This study attempts to clarify the relationship between beta-catenin expression and the initiation and metastasis of spontaneous breast cancer in TA2 mice. Materials and Methods: Pathological samples illustrating the development of spontaneous breast cancer in TA2 mice were collected and the presence of virus particles was verified in the cancer tissue by electron microscope. Expression of Wnt/beta-catenin signaling-pathway related proteins including beta-catenin, Wnt 5a, GSK-3beta, and cyclin D1 were detected. MA-891 cell line derived from TA2 spontaneous breast cancer was cultured and siRNA was used to inhibit the expression of beta-catenin in the primary culture cell line. Cell cycle analyses and comparisons of the invasiveness and migration capability of tumor cells were performed before and after beta-catenin inhibition. Downstream protein expression of beta-catenin was studied by western blot, co-immunoprecipitation assay. Tumorigenesis and metastasis were compared with that of negative control, siRNA control, and siRNA beta-catenin-1512. Furthermore, proteins related to the proliferation and invasion of tumor were detected by western blot. Results: beta-catenin expression was found to be located in the membrane and cytoplasm in normal mammary tissue and precancerous lesions, respectively. However, in the breast cancer tissue, beta-catenin expression was located in the nuclei. After transfection with siRNA 1512, the cells showed decreased proliferation, invasiveness and migration capability, tumorigenicity, and metastasis, and the expression of the proteins related to tumor proliferation and metastasis such as c-myc, Cyclin D1, MMP-9, and VEGF were down-regulated. Conclusion: These results confirmed that the expression and location of beta-catenin were associated with the initiation and metastasis of spontaneous breast cancer in TA2 mice. PMID- 28819414 TI - Depletion of CTCF in Breast Cancer Cells Selectively Induces Cancer Cell Death via p53. AB - CCCTC-binding factor (CTCF), a ubiquitous 11-zinc finger multifunctional protein, has distinct molecular functions, such as transcriptional activation, repression, and chromatin barrier activity, in a locus-specific manner. Elevated CTCF levels in breast cancer cells are known to contribute to tumorigenesis; however, the underlying mechanism remains elusive. We investigated the effect of CTCF expression on breast cancer cell survival and elucidated its mechanism. CTCF depletion in MCF-7 cells led to a decreased cell growth and proliferation, surpassing the growth of normal cells under co-culture system of MCF-7-GFP and MCF10A. Here we propose that the phenotypes observed in CTCF-depleted MCF-7 cancer cells, such as reduced cell proliferation, increased apoptosis, and cell cycle arrest, are closely linked with the activation of p53. The consensus CTCF binding site, located approximately 800 bp upstream of the first exon of TP53, was marked by H3K27me3, but not by the active mark H3K4me3, although CTCF is expressed. Knockdown of CTCF conversely led to the recruitment of H3K4me3 instead of H3K27me3, accompanying with the higher enrichment of PolII in the proximal promoter region of TP53. With the activation of p53, increased p21 and Bax expressions were observed in CTCF knockdown MCF-7 cells. Elucidating functional roles of CTCF and regulation mechanisms may help to guide CTCF and/or its related molecules as a therapeutic target to prevent cancer cell growth. PMID- 28819415 TI - SZRD1 is a Novel Protein that Functions as a Potential Tumor Suppressor in Cervical Cancer. AB - SZRD1 is a novel gene screened out by high-throughput platform, and so far there exists no systematic function reports. The purpose of our study is to discover the function and mechanism of this novel human gene. Bioinformatics analysis indicates that SZRD1 is a highly conserved intracellular protein. After overexpression of SZRD1, we found that SZRD1 could arrest the cell cycle in G2 phase and play a role in inhibiting cell proliferation and inducing apoptosis. In contrast, after knockdown of endogenous SZRD1, we concluded that it could promote cell proliferation. The mechanism investigations showed that overexpression of SZRD1 could downregulate the phosphorylation of ERK1/2, AKT, STAT3 and downstream signaling molecules, and then arrest the cells in G2 phase by upregulating P21. Tissue microarray analysis showed that the expression of SZRD1 was downregulated in cervical squamous cell carcinomas compared with normal squamous epithelium, and the ratio of downregulation correlated with the stage of the cancer. Overall, we clarified the function of this novel protein SZRD1, which indicated it may be a potential novel tumor suppressor in cervical cancer. PMID- 28819416 TI - Expression of CD133 in endometrial cancer cells and its implications. AB - Cancer stem cells are an attractive therapeutic target for cancer. The present study examined stem cell characteristics of CD133+ cells isolated from endometrial cancer. Phenotypic characteristics, proliferation, migration, anchorage-independent growth, chemoresistance, gene expression profile and tumorigenicity of CD133+ tumor cells were assessed. Primary tumor exhibited immunoreactivity for CD133. Endometrial CD133+ tumor cells enhanced proliferation rate, colony formation, chemotaxis migration ability, and chemoresistance to cisplatin, paclitaxel, and doxorubicin than CD133- cells. CD133+ cells expressed more cancer stem cells markers such as EpCAM, aldehyde dehydrogenase 1 and insulin-like growth factor-1 receptor than CD133- cells. Moreover, CD133+ cells also increased expression of embryonic stem cell markers including oct4, nanog, sox2, and cmyc than CD133- cells. Finally, CD133+ tumor cells could generate xenograft but not CD133- tumor cells. CD133 and Ki67 were extensively expressed in the xenograft. In conclusion, endometrial CD133+ tumor cells displayed cancer stem cell characteristics and might represent a valuable tool for identifying endometrial cancer stem cells and hence a potential therapeutic target. PMID- 28819417 TI - MDM2 SNP309 and SNP285 Act as Negative Prognostic Markers for Non-small Cell Lung Cancer Adenocarcinoma Patients. AB - Objectives: Two functional polymorphisms in the MDM2 promoter region, SNP309T>G and SNP285G>C, have been shown to impact MDM2 expression and cancer risk. Currently available data on the prognostic value of MDM2 SNP309 in non-small cell lung cancer (NSCLC) is contradictory and unavailable for SNP285. The goal of this study was to clarify the role of these MDM2 SNPs in the outcome of NSCLC patients. Materials and Methods: In this study we genotyped SNP309 and SNP285 in 98 NSCLC adenocarcinoma patients and determined MDM2 mRNA and protein levels. In addition, we assessed the prognostic value of these common SNPs on overall and progression free survival, taking into account the TP53 status of the tumor. Results and Conclusion: We found that the SNP285C allele, but not the SNP309G allele, was significantly associated with increased MDM2 mRNA expression levels (p = 0.025). However, we did not observe an association with MDM2 protein levels for SNP285. The SNP309G allele was significantly associated with the presence of wild type TP53 (p = 0.047) and showed a strong trend towards increased MDM2 protein levels (p = 0.068). In addition, patients harboring the SNP309G allele showed a worse overall survival, but only in the presence of wild type TP53. The SNP285C allele was significantly associated with an early age of diagnosis and metastasis. Additionally, the SNP285C allele acted as an independent predictor for worse progression free survival (HR = 3.97; 95% CI = 1.51 - 10.42; p = 0.005). Our data showed that both SNP309 (in the presence of wild type TP53) and SNP285 act as negative prognostic markers for NSCLC patients, implicating a prominent role for these variants in the outcome of these patients. PMID- 28819418 TI - CENPH Inhibits Rapamycin Sensitivity by Regulating GOLPH3-dependent mTOR Signaling Pathway in Colorectal Cancer. AB - Background: Centromere protein H (CENPH) is known as a fundamental component of the active centromere complex, and its overexpression is correlated with poor prognosis in various solid tumors. mTOR inhibitor rapamycin has been shown to possess antitumor activity, as well as prevent intestinal tumorigenesis. However, the prognostic value of CENPH in colorectal cancer (CRC) and the role of CENPH in rapamycin sensitivity remain unknown. Materials and methods: The effect of CENPH on the cell proliferation, clonogenicity, and cell response to rapamycin in CRC were evaluated by MTT and/or colony formation assays. For the underlying mechanisms, the interaction between CENPH and GOLPH3 were detected by co immunoprecipitation, GST pull-down, and His-tag pull-down assays, as well as the laser scanning confocal microscopy. The status of kinases in mTOR signaling was determined by Western blot. Finally, the clinical significance of CENPH was analyzed using public CRC datasets with CENPH transcripts and clinical information. Results: CENPH inhibited CRC malignant phenotypes, conferred reduced sensitivity to rapamycin, and attenuated both mTORC1 and mTORC2 in mTOR signaling pathway through the interaction with golgi phosphoprotein 3 (GOLPH3), which has been identified as a potential oncogene and modulates the response to rapamycin. Moreover, elevated levels of CENPH were detected in CRC tissues, compared with normal colorectal tissues. High levels of CENPH expression gradually decreased according to CRC tumor stages. Patients with high CENPH expression had favorable survival. Conclusions: Our results suggest that CENPH inhibits rapamycin sensitivity by regulating GOLPH3 dependent mTOR pathway. High CENPH expression is associated with better prognosis in CRC patients. Taken together, CENPH may serve as a potential predictor for rapamycin sensitivity and therapeutic target for CRC patients. PMID- 28819419 TI - Osteopontin -- a promising biomarker for cancer therapy. AB - Osteopontin (OPN), a multifunctional protein, has emerged as a potentially valuable biomarker for diagnosing and treating cancers. Recent research focuses on its involvement in tumor biology including the cell proliferation, survival, angiogenesis, invasion, and metastasis. Understanding the molecular mechanisms and pharmacological effects of OPN in cancer development could lead to new targets for improving cancer diagnosis and treatment. This review explains how the structurally conserved domains of OPN are associated with OPN signaling mediators and CD44, and how the conserved OPN domains determine biological functions. The authors have reviewed representative works of OPN expression in breast cancer and colorectal cancer to elucidate the relationship between OPN and cancer/tumor biology. It has also been shown that the prognostic sensitivity in non-small cell lung cancer, hepatocellular carcinoma, gastric cancer, and ovarian cancer improved compared to the individual marker when OPN was analyzed in conjunction with other markers. The therapeutic approaches based on OPN inhibitors are discussed to illustrate recent research progress. Previous clinical data has indicated that OPN has played a unique role in cancer development, but further investigation is required to understand the underlying mechanism. More clinical trials are also required to examine the applicability and efficacy of OPN inhibitors in cancer therapy. PMID- 28819420 TI - Loss of Complement Factor H in Plasma Increases Endothelial Cell Migration. AB - Tumor growth depends on angiogenesis, the growth of new blood vessels. Complement factor H (CFH) is a plasma glycoprotein that functions as a regulator of the complement system. The aim of this study is to delineate the role of CFH in angiogenesis. A conditional null allele of the Cfh gene was generated in C57BL/6J mice by flanking the exon 3 with loxP sites. The Cfhflox/flox mice were crossed with Rosa26-Cre mice to obtain the mice homozygotes of Cfh deletion (Cfh-/-). The Cfh-/- mice were examined by in vivo angiogenesis assays. Mouse endothelial cells were treated with media containing 5% of mouse plasma from the wildtype or Cfh-/- mice and assayed for proliferation, viability and migration. The Cfh-/- mice did not display any obvious abnormalities. They demonstrated a pro-angiogenic phenotype in matrigel plug assay, but not in aorta ring assay. In vitro, loss of Cfh in plasma does not affect proliferation or viability, but significantly increases migration of mouse endothelial cells. Our findings suggest that plasma CFH inhibits angiogenesis by reduction of endothelial cell migration. Thus the mutation of CFH might lead to excessive tumor angiogenesis. PMID- 28819421 TI - Simultaneous Quantification of Serum Multi-Phospholipids as Potential Biomarkers for Differentiating Different Pathophysiological states of lung, stomach, intestine, and pancreas. AB - Background: Aberrant lipid metabolism is closely associated with cancer. Materials & Methods: Serum levels of sphingomyelins (SM) (34:1), phosphatidylcholine (PC) (34:2), PC(34:1), PC(36:4), PC(36:3), and PC(36:2) in 1449 serum samples (including 599 normal controls, 69 patients with benign lung diseases (BLDs), 61 with benign colorectal diseases, 54 with benign gastric diseases, 67 with benign pancreatic diseases, and 246 with lung cancer (LC), 144 with colorectal cancer, 94 with gastric cancer, 115 with pancreatic cancer) were quantified simultaneously based on their respective calibration equations with correlation coefficient of >0.98. Results: Receiver operating characteristic (ROC) analysis indicated that 18 panels obtained from these six phospholipids have high diagnostic ability to differentiate between different pathophysiological states. For example, a combination of SM(34:1), PC(34:2), PC(34:1), PC(36:3), and PC(36:2) to differentiating male patients with early stage LC from male normal controls plus male BLDs with a value under ROC curve (AUC) of 0.957, a sensitivity of 88.9%, and a specificity of 90.8%. SM(34:1) and PC(34:1) to differentiating female patients with early stage LC from female normal controls plus female BLDs with an AUC of 0.903, a sensitivity of 90.0%, and a specificity of 77.5%. Conclusion: Change trends of these six phospholipids were significantly correlated with gender, physiological states, and cancer stages. PMID- 28819422 TI - The Neutrophil-Lymphocyte Ratio Predicts Recurrence of Cervical Intraepithelial Neoplasia. AB - OBJECTIVE: The purpose of the present study was to determine the prognostic significance of the neutrophil-lymphocyte ratio (NLR) in recurrence of cervical intraepithelial neoplasia (CIN). METHODS: We evaluated the NLR as a prognostic marker in the entire cohort of 230 patients who had undergone surgical resection and were diagnosed with CIN. Subjects were categorized into two different groups based on the NLR (NLR-high and NLR-low) using cutoff values determined by receiver operating characteristic (ROC) analysis. The primary research objective for this study was to validate the impact of the NLR on recurrence-free survival (RFS) in patients with CIN. The secondary objective was to evaluate the impact of other hematologic parameters on RFS in CIN patients. RESULTS: Using the entire cohort, the most appropriate NLR cut-off value for CIN recurrence selected on the ROC curve was 2.1. The NLR-low and NLR-high groups included 167 (72.6%) and 63 patients (27.4%), respectively. According to Kaplan-Meier analysis, RFS rates during the entire follow-up period were considerably lower in the NLR-high group than in the NLR-low group (P = 0.0125). In multivariate survival analysis using Cox proportional hazard model, we identified the NLR, absolute eosinophil count (AEC), hemoglobin concentration, and mean corpuscular volume (MCV) as valuable prognostic factors that impact RFS. CONCLUSIONS: The NLR is an independent prognosticator for RFS following surgical resection in CIN patients. We also found that the AEC, hemoglobin level, and MCV were strongly associated with RFS, as determined by multivariate analysis using a Cox model. These hematological parameters might provide additional prognostic value beyond that offered by standard clinicopathologic parameters. PMID- 28819423 TI - Reelin promotes adhesion of multiple myeloma cells to bone marrow stromal cells via integrin beta1 signaling. AB - The close interaction between tumor cells and bone marrow stromal cells plays a crucial role in the tumorigenesis of multiple myeloma (MM). Reelin, an extracellular matrix protein, is found expressed in myeloma cells and is negatively associated with prognosis. We examined the role of Reelin in myeloma cell adhesion to bone marrow stromal cells and the signaling pathways involved. The results revealed that Reelin promoted the adhesion of myeloma cells to HS-5, a bone marrow stromal cell line, via the activation of beta1 integrin. The resulting phosphorylation of focal adhesion kinase (FAK) led to the activation of Syk/STAT3 and Akt. Reelin's high affinity receptor ApoER2 indirectly modulated the adhesion of myeloma cells by promoting Reelin expression via Sp1. These findings indicate an important role for Reelin/integrin-beta1-induced myeloma cell adhesion to bone marrow stromal cells and highlight the therapeutic potential of targeting Reelin/integrin/FAK axis. PMID- 28819424 TI - Circulating tumor cells and microemboli can differentiate malignant and benign pulmonary lesions. AB - The presence of circulating tumor cells (CTC) or microemboli (CTM) in the peripheral blood can theoretically anticipate malignancy of solid lesions in a variety of organs. We aimed to preliminarily assess this capability in patients with pulmonary lesions of suspected malignant nature. We used a cell-size filtration method (ScreenCell) and cytomorphometric criteria to detect CTC/CTM in a 3 mL sample of peripheral blood that was taken just before diagnostic percutaneous CT-guided fine needle aspiration (FNA) or core biopsy of the suspicious lung lesion. At least one CTC/CTM was found in 47 of 67 (70%) patients with final diagnoses of lung malignancy and in none of 8 patients with benign pulmonary nodules. In particular they were detected in 38 (69%) of 55 primary lung cancers and in 9 (75%) of 12 lung metastases from extra-pulmonary cancers. Sensitivity of CTC/CTM presence for malignancy was 70.1% (95%CI: 56.9-83.1%), specificity 100%, positive predictive value 100% and negative predictive value 28.6% (95%CI: 11.9-45.3%). Remarkably, the presence of CTC/CTM anticipated the diagnosis of primary lung cancer in 3 of 5 patients with non-diagnostic or inconclusive results of FNA or core biopsy, whereas CTC/CTM were not observed in 1 patient with sarcoidosis and 1 with amarthocondroma. These results suggest that presently, due to the low sensitivity, the search of CTC/CTM cannot replace CT guided percutaneous FNA or core biopsy in the diagnostic work-up of patients with suspicious malignant lung lesions. However, the high specificity may as yet indicate a role in cases with non-diagnostic or inconclusive FNA or core biopsy results that warrants to be further investigated. PMID- 28819425 TI - Selective Gastric Cancer Patients with Peritoneal Seeding Benefit from Gastrectomy after Palliative Chemotherapy: A Propensity Score Matching Analysis. AB - Background: The present study aimed to explore whether gastric cancer patients with peritoneal seeding after receiving palliative chemotherapy could benefit from gastrectomy and to identify patients with peritoneal seeding who should be selected to receive gastrectomy. Methods: A total of 201 gastric cancer patients were diagnosed with peritoneal seeding and received palliative chemotherapy. Propensity score matching (PSM) was performed to balance the selection bias. Results: After PSM, compared with non-gastrectomy group, gastrectomy group had a longer median overall survival (OS) (23.60 vs. 13.80 moths; P=0.034). Patients with R0 resection had a median OS of 43.60 months compared with 11.27 months in patients who underwent R1/2 resection (P<0.001). The median OS times between the R1/2 resection and non-gastrectomy groups were not different (P=0.139). Subgroup analysis revealed that only patients receiving more than 4 periods of first-line chemotherapy benefited from gastrectomy (P=0.018), whereas patients receiving 1-4 periods of first-line chemotherapy did not (P=0.275). Multivariate analysis showed that gastrectomy (P=0.012) and the period of first-line chemotherapy (P<0.001) were independent prognostic factors. The overall postoperative morbidity was 3.03% (1/33) in the gastrectomy group, and no treatment-related death was observed. Conclusions: The present study indicated that gastrectomy after palliative chemotherapy is a safe procedure and showed a survival benefit for gastric cancer patients with peritoneal seeding. Moreover, clinically curative R0 gastrectomy and more than 4 periods of palliative chemotherapy resulted in better clinical outcomes. PMID- 28819426 TI - Central Role of CEMIP in Tumorigenesis and Its Potential as Therapeutic Target. AB - CEMIP (KIAA1199) was identified as migratory indicator protein which had been crudely studied in the last decade. Firstly its mutation site was reported to cause hearing loss due to the folding change of protein structure, meanwhile the over-expression of CEMIP referred to dreadful invasion and uncontrolled proliferation of tumor with distant metastasis, dedifferentiation, and limited survival opportunity of patients. Especially, over-expressed CEMIP also protected malignant tumor from strict microenvironment in hypoxia, low glucose and cracked barrier, leading to enhanced adaptability of tumor by stimulating the Wnt, EGFR, FGFR pathway. Here, we intend to elaborate the clinical function and dysregulation of CEMIP under the tumorous circumstance since CEMIP plays an important role in cytokine pathway and its over-expression in tumors provide a novel target for individual therapy. Targeting CEMIP would thereby dysregulate the cytokine pathway which would in turn, decide the growth and death of the vicious tumour cells. PMID- 28819427 TI - Develop and validation a nomogram to predict the recurrent probability in patients with major salivary gland cancer. AB - Objectives: Prediction of recurrent risk in patients with major salivary gland carcinoma (MSGC) after surgical treatment is an important but difficult task because of a broad spectrum of tumor histological subtypes and diverse clinical behaviors. This study aimed to develop and validate a nomogram to predict the recurrent probability in patients with MSGC. Methods: A total of 231 consecutive patients with MSGC received curative-intend surgery between 2002 and 2014 from one medical center were selected as the training set. Clinicopathologic variables with the most significant values in the multivariate Cox regression were selected to build into a nomogram to estimate the recurrence probability. An independent validation set of 139 patients treated at the same period from 3 other hospitals were selected for external validation and calibration. Results: The nomogram was developed on six significant predictive factors, including the smoking history, tumor grade, perineural invasion, lymphatic invasion, pathologic T- and N classification, of tumor recurrence retained in the multivariate Cox model. The nomogram had a highly predictive performance, with a bootstrapped corrected concordance index of 0.82 for the training set and 0.78 for the validation set. The nomogram showed good calibration in predict 2-year and 5-year recurrence probability both in the training and validation set. Conclusions: We developed and externally validated an accurate nomogram for prediction the tumor recurrence probability of patients with MSGC after surgical treatment. This nomogram may be used to assist clinician and patient in elaborating the recurrent risk and making decision for appropriate adjuvant treatment. PMID- 28819428 TI - Development of a new analog of SGK1 inhibitor and its evaluation as a therapeutic molecule of colorectal cancer. AB - Colorectal cancer (CRC) is one of the most leading causes of cancer-related death worldwide. The serum and glucocorticoid inducible kinase SGK1 is highly expressed and involved in several tumors. GSK650394, a SGK1 inhibitor, has been proved to be effective in impeding tumor growth in vitro. In this study, we developed a novel analog of GSK650394, and evaluated its effects on CRC cells and tumor growth both in vitro and in vivo. HCT116 cells were treated with a concentration gradient of new developed compounds and cholecystokinin octapeptide (CCK-8) assay was used to calculate the IC50 value of every analog. Cell proliferation analysis was estimated from EdU staining and flow cytometry in vitro, and immunohistochemistry of Ki67 and PCNA in vivo. Cell migration analysis was examined using the transwell assay. In vivo tumor growth was determined in athymic nude mice by injecting the HCT116 cells in the subcutaneous tissue, followed by the injection of QGY-5-114-A. We found that new developed GSK650394 analog QGY-5-114-A has lower IC50 value, and treatment with QGY-5-114-A significantly inhibited CRC cell proliferation and migration in vitro. Besides that, colonic tumor growth was also dramatically restricted by QGY-5-114-A in vivo. In conclusion, pharmacological treatment with QGY-5-114-A impedes CRC tumor cell proliferation, migration and tumor growth. PMID- 28819429 TI - MAP2K1 Mutation in Colorectal Cancer Patients: Therapeutic Challenge Using Patient-Derived Tumor Cell Lines. AB - BACKGROUND: The MAP2K1 K57T mutation is known to be a potential mechanism of primary and secondary resistance to EGFR inhibitors in metastatic colorectal cancer (CRC) and has also been reported to promote resistance to BRAF and MEK inhibitors. It is important to overcome therapeutic resistance to EGFR inhibitors to improve the treatment outcomes of metastatic CRC. METHODS: We established patient-derived tumor cells (PDCs) from metastatic lesions that newly appeared during treatment with a BRAF inhibitor (LGX-818) plus an EGFR inhibitor (cetuximab) in a patient with BRAF-mutant CRC. To investigate therapeutic options to overcome acquired resistance due to MAP2K1 mutation in BRAF-mutant CRC, we performed cell viability assays using the PDCs. RESULTS: We tested whether the PDCs were resistant to an EGFR inhibitor (cetuximab) and a BRAF inhibitor (sorafenib) as these cells were established at the time of resistance to the EGFR plus BRAF inhibitors. Moreover, the anti-tumor effect of AZD6244 (MEK inhibitor) was evaluated because PDCs harbored a MAP2K1 mutation at the time of resistance to the EGFR plus BRAF inhibitors. MTT proliferation assays showed that monotherapy with cetuximab, sorafenib, or AZD6244 did not suppress cell viability. We next tested viability of the PDCs to combination treatment with cetuximab plus AZD6244 and sorafenib plus AZD6244. Proliferation of PDCs was significantly inhibited by sorafenib and AZD6244, but not by cetuximab plus AZD6244. Investigation of the combined effect of sorafenib and AZD6244 using the calculated combination index (CI) showed synergistic effects of sorafenib and AZD6244 in combination therapy applied to PDCs with the MAP2K1 K57T mutation. CONCLUSION: Our results suggest that combination treatment with BRAF and MEK inhibitors might be a novel treatment strategy for MAP2K1 K57T-mutant CRC. This finding will be helpful to guide treatment of patients with CRC that is resistant to EGFR inhibitors. PMID- 28819430 TI - Importance of maintaining body weight for prevention of distant metastasis of nasopharyngeal carcinoma: An alternative workflow for cancer-risk assessment. AB - Purpose: To design an alternative workflow for cancer-risk assessment to predict distant metastasis (DM) of nasopharyngeal carcinoma (NPC). Methods: We enrolled 234 patients with non-disseminated NPC and a family history of cancer who underwent intensity-modulated radiotherapy and concurrent chemo-radiotherapy with/without induction chemotherapy in our primary cohort. We conducted univariate and multivariate analyses of the associated prognostic factors, built a nomogram model for distant-metastasis-free survival (DMFS), and confirmed the prognostic value of weight-loss ratio (WTratio). The secondary cohort included 97 patients with available pre-DNA levels who were treated at our cancer center. We performed internal validation with the primary cohort and external validation with the secondary cohort, and compared the new DMFS model with the current 7th TNM staging system. Results: In the primary cohort, 95.9% patients experienced weight loss. The N group (N2-3 vs. N0-1, P = 0.037) and pre-DNA level (P = 0.02) were independent prognostic factors for DMFS in NPC patients. Smoking (P = 0.051) and WTratio (P = 0.052) showed a significant trend for DMFS. WTratio was an independent prognostic factor for DMFS (P = 0.03). Smoking, WTratio, N group, and pre-DNA level were merged to build a risk-score model for DMFS using a nomogram, which could predict survival after internal and external validation. Conclusions: Maintaining body weight during treatment is essential to prevent DM of NPC. Compared with the current 7th TNM staging system, the new DMFS model might better predict DM of NPC. The alternative workflow designed could be applied for prognostic analysis of other cancers. PMID- 28819431 TI - Tat-interactive Protein-60KDA (TIP60) Regulates the Tumorigenesis of Lung Cancer In Vitro. AB - Histone acetyltransferases (HATs) play vital functions in the tumorigenesis of many solid organ malignancies. We previously screened a human HATs cDNA library and identified Tat-interactive protein-60KDa (TIP60) as a candidate critical HATs in the origination of lung cancer. In this study, our data suggested that overexpression of TIP60 inhibited the cell viability of A549 and H1299 cells since day 2. Compared to the control group, the viability of these two lung cancer cells was inhibited by 25% and 19% at day 6 with the overexpression of TIP60. It increased by 36% and 26% when TIP60 was knockdown for 6 days. The invasion ability of these two cells was also restrained when TIP60 was overexpressed. While knockdown of TIP60 had the opposite effect. Inhibition of TIP60 significantly promoted the expression of molecules in AKT signaling pathway especially c-Myc. Furthermore, compared to paired tumor-adjacent tissue, lung cancer tumors had low expression of TIP60. Therefore, we concluded that TIP60 might inhibit the viability and invasion ability of lung cancer cells through down-regulation of AKT signaling pathway. PMID- 28819432 TI - Silencing of HJURP induces dysregulation of cell cycle and ROS metabolism in bladder cancer cells via PPARgamma-SIRT1 feedback loop. AB - Holliday Junction Recognition Protein (HJURP) is a centromeric histone chaperone involving in de novo histone H3 variant CenH3 (CENP-A) recruitment. Our transcriptome and in vivo study revealed that HJURP is significantly upregulated in bladder cancer (BCa) tissues at both mRNA and protein levels. Knockdown of HJURP inhibited proliferation and viability of BCa cell lines revealed by CCK-8, colony formation and Ki-67-staining assays, and induced apoptosis and reactive oxygen species (ROS) production, as well as triggered cell cycle arrest at G0/G1 phase possibly via loss of CENP-A. Interestingly, in the HJURP-reduced BCa cells the levels of PPARgamma and acetylated-p53 were increased, while the ratio of phosphorylated/total SIRT1 protein was decreased. Moreover, after treatment of the BCa cells using PPARgamma antagonist (GW9662) and SIRT1 agonist (resveratrol, RSV) respectively, thee phenotypes of cell cycle arrest, increased ROS production and inhibited proliferation rate were all rescued. Taken together, our results suggested that HJURP might regulate proliferation and apoptosis via the PPARgamma SIRT1 negative feedback loop in BCa cells. PMID- 28819433 TI - Alcohol Consumption and Lung Cancer According to Ile349Val Polymorphism in ADH3 Gene: Beyond the Tobacco Smoking Effect. AB - Objectives: Smoking is the leading cause of lung cancer. However, several studies have suggested other factors such as alcohol consumption could also play a role through polymorphisms associated with alcohol metabolism. We investigated the association between alcohol consumption and lung cancer according to the Ile349Val polymorphism in the alcohol dehydrogenase 3 ADH3 gene. Methods: We carried out a hospital-based case-control study, a total of 402 incident cases of lung cancer and 383 controls were genotyped for the Ile349Val polymorphism by polymerase chain reaction combined with restriction fragment length polymorphism. Alcohol consumption and other variables were measured using questionnaires in personal interviews. We used multiple logistic regressions to estimate adjusted odd ratios using and 95% confidence intervals. Results: In multivariate analysis, an increased risk of lung cancer was observed for the highest category of alcohol consumption (>=30 g/day), although it does not reach statistical significance (OR=1.60, 95% CI: 0.91-2.83). Besides, an increased risk of lung cancer was observed in the highest category of alcohol consumption for the Ile/Val genotype compared with the Ile/Ile genotype (OR=2.35, 95% CI: 1.04-5.33). Conclusions: This study suggests that beyond smoking consumption, a high consumption of alcohol might increase the risk of lung cancer. No clear association was found between alcohol consumption and lung cancer according to the Ile349Val polymorphism in ADH3 gene. PMID- 28819434 TI - Identification of Transcription Factor YY1 as a Regulator of a Prostate Cancer Specific Pathway Using Proteomic Analysis. AB - Prostate-specific antigen, a biomarker used to diagnose prostate cancer, exhibits poor sensitivity. Although previous studies have focused on identifying a new diagnostic biomarker, the molecules or networks identified in these studies are also present in other cancers, making it difficult to detect prostate cancer specifically. A unique characteristic of the prostate gland is the increased mitochondrial energy metabolism when normal prostate cells progress to cancer cells. Thus, we attempted to find a prostate cancer-specific signature present in this unique environment. Proteins that were differentially expressed between a prostate cell line and three prostate cancer cell lines were identified using proteomic analysis. Not surprisingly, the most prevalent proteins detected by network analysis of proteins that were up-regulated at least 1.2-fold in cancer cells, compared to that in normal prostate cells, were those involved in mitochondrial energy metabolism. In addition, we showed that Yin Yang 1 (YY1) was a major transcription factor involved in regulating energy metabolism. To determine whether YY1 regulates genes associated with mitochondrial energy metabolism in prostate cells, cells were subjected to quantitative polymerase chain reaction analysis in the presence or absence of the YY1 inhibitor NP-001. Notably, inhibition of YY1 resulted in reduced expression of genes related to the Krebs cycle and electron transport chain in prostate cancer cell lines. Based on this finding, we suggest that there is a tumor-specific signature that regulates mitochondrial energy metabolism in prostate cancer cells. This work provides a foundation for further work on identifying a means for the specific diagnosis of prostate cancer. PMID- 28819435 TI - Pattern of distant extrahepatic metastases in primary liver cancer: a SEER based study. AB - Background and Aims: Primary liver cancer remains still the common cause of cancer-related deaths globally and the prognosis for patients with extrahepatic metastasis is poor. The aim of our study was to assess extrahepatic metastatic pattern of different histological subtypes and evaluate prognostic effects of extrahepatic metastasis in patients with advanced disease. Methods: Based on the Surveillance, Epidemiology and End Results (SEER) database, eligible patients diagnosed with primary liver cancer was identified between 2010 to 2012. We adopted Chi-square test to compared metastasis distribution among different histological types. We compared survival difference of patients with different extrahepatic metastasises by Kaplan-Meier analysis. Cox proportional hazard models were performed to identify other prognostic factors of overall survival. Results: We finally identified 8677 patients who were diagnosed with primary liver cancer from 2010 to 2012 and 1775 patients were in distant metastasis stages. Intrahepatic cholangiocarcinoma was more invasive and had a higher percentage of metastasis compared with hepatocellular carcinoma. Lung was the most common metastasis and brain was the least common site for both hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Extrahepatic metastasis could consider as an independent prognostic factor for patients with liver cancer. Patients with brain metastasis had the worst prognosis, compared with other metastasis in overall survival (OS) and cancer-specific survival (CSS) analysis. Conclusions: Different histological subtypes of liver cancer had different metastasis patterns. There were profound differences in risk of mortality among distant extrahepatic metastatic sites. Results from our studies would provide some information for follow-up strategies and future studies. PMID- 28819436 TI - Epithelial-mesenchymal transition: potential regulator of ABC transporters in tumor progression. AB - Epithelial-mesenchymal transition (EMT) can directly contribute to some malignant phenotypes of tumor cells including invasion, metastasis and resistance to chemotherapy. Although EMT is widely demonstrated to play a critical role in chemoresistance and metastasis, the potential signaling network between EMT and drug resistance is still unclear. The distribution of drugs in the internal and external environment of the tumor cells is tightly linked with ATP-binding cassette (ABC) transporters. Recent studies have shown that ABC transporters expression changed continuously during EMT. We believe that EMT is an important regulator of ABC transporters. In this review, we discuss how EMT regulates ABC transporters and their potential linkages. And we hope the knowledge of EMT and ABC transporters will offer more effective targets to experimental research. PMID- 28819438 TI - Elevated expression of Derlin-1 associates with unfavorable survival time of squamous cell carcinoma of the head and neck and promotes its malignance. AB - Derlin-1 is over-expressed to function as an oncoprotein in breast, lung and colon cancers. However, the implications of Derlin-1 involved in squamous cell carcinoma of the head and neck (SCCHN) remain unknown. This study aims to investigate the effects of Derlin-1 expression on SCCHN tissues and cells. The potential mechanism of Derlin-1 regulating SCCHN cell proliferation, apoptosis and metastasis was also indicated in this work. Western blot and immunohistochemistry (IHC) assays showed that Derlin-1 was over-expressed in 114 SCCHN samples and five SCCHN cell lines. We found that the expression of Derlin-1 was positively associated with lymph node metastasis, clinical stage and recurrence in our SCCHN patients' samples. Survival analysis indicated that high expression of Derlin-1 was significantly associated with shorter overall survival (OS) and disease-free survival (DFS). Knock down expression of Derlin-1 in SCCHN cell lines was found to inhibit cell proliferation, metastasis and promote cell apoptosis. Further experiments showed that signals of PI3K/Akt, p53 and Smad2/3 may involve in these processes. In all, Derlin-1 might be a novel prognostic marker of SCCHN patients and plays an oncogenic role in SCCHN cell progression. PMID- 28819437 TI - Impact of Detection Method and Accompanying Ductal Carcinoma in Situ on Prognosis of T1a,bN0 Breast Cancer. AB - Background: T1a,bN0 breast cancer is not easily detected. Before mammography became widespread, most cases were discovered only after the development of symptoms. The presence of ductal carcinoma in situ (DCIS) affects the detectability of associated invasive cancer; however, the prognostic value of concomitant DCIS is controversial. This study compared the characteristics of screening-detected and symptom-detected T1a,bN0 breast cancer, and investigated the impact of accompanying DCIS on detection and prognosis. Patients and Methods: Data were collected from a single hospital between 2000 and 2009. Of 5,690 primary breast cancers patients, 438 met the criteria for T1a,bN0M0. Logistic regression models were used to identify prognostic indicators and their association with the detection method. Survival analyses were performed to estimate distant relapse-free survival (DRFS) and breast cancer-specific survival (BCSS). Results: Tumors in 79 and 359 patients were detected by screening and development of symptoms, respectively. Symptomatic cancer patients were younger, more likely to receive a mastectomy, and had larger accompanying DCIS lesions; their 10-year DRFS rates were worse than those of patients with screening detected tumors (91.1% vs. 100% respectively, p=0.049). Patients with large accompanying DCIS (>=2 cm) had markedly worse 10-year DRFS (77.1% vs. 97.4%, p<0.001) and BCSS (94.3% vs. 98.9%, p<0.001). Conclusion: T1a,bN0 breast cancers detected owing to symptoms are more likely to have larger accompanying DCIS. T1a,bN0 patients with large accompanying DCIS have worse DRFS and BCSS. It is important to consider associated DCIS size when evaluating prognosis in T1a,bN0 breast cancer patients. PMID- 28819439 TI - Development and Validation of a Serum Biomarker Panel for the Detection of Esophageal Squamous Cell Carcinoma through RNA Transcriptome Sequencing. AB - Serum tumor markers for the diagnosis of esophageal squamous cell carcinoma (ESCC) have low sensitivity. This study aims to identify new serum markers for ESCC diagnosis from RNA sequencing (RNA-seq) data. RNA-seq was performed using six pairs of ESCC and matched normal tissues. The candidates for ESCC were screened from the differentially expressed genes. The candidates were analyzed by ELISA from the serum of a test group and a validation group. Real-time PCR, Western blotting and immunohistochemistry were used to detect the expression of the candidates in tumor cell lines and tumor tissues. Ten genes were selected from the RNA-seq data. Serum levels of ADAM12, CHI3L1, MMP13 and SPP1 were significantly higher in the ESCC patients than in the healthy controls. A diagnostic model combining CHI3L1, MMP13, and SPP1 was established. The area under the curve (AUC) values for serum CHI3L1, MMP13, and SPP1 and the diagnostic model for discriminating ESCC patients from controls were 0.732, 0.881, 0.661 and 0.928, respectively. In the validation cohort, the AUC values were 0.753, 0.789, 0.696 and 0.843, respectively. Moreover, the AUC of the model for classifying patients with early ESCC was 0.918 in the test group and 0.857 in the validation group. Overexpression of CHI3L1, MMP13 and SPP1 was observed in the tumor cell lines and tissues. The diagnostic model composed of CHI3L1, MMP13 and SPP1 discriminates ESCC patients with high sensitivity. Our data highlight the potential of this diagnostic model for the noninvasive diagnosis of ESCC. PMID- 28819440 TI - MicroRNA-204-5p inhibits invasion and metastasis of laryngeal squamous cell carcinoma by suppressing forkhead box C1. AB - Background and aim: Understanding the molecular biological mechanisms underlying laryngeal squamous cell carcinoma (LSCC) invasion and metastasis is crucial for diagnosis, treatment, and prognosis. We aimed to examine the expression of the tumor suppressor microRNA-204-5p (miR-204-5p) and its target gene, forkhead box C1 (FOXC1), in human LSCC and explore their roles in the malignant behaviors of LSCC Hep-2 and TU-177 cells. Methods: The regulatory effects of miR-204-5p on the 3' untranslated region of FOXC1 predicted by bioinformatics were tested by dual luciferase reporter assay. Quantitative RT-PCR was used to detect mRNA expression in 43 fresh samples of LSCC and corresponding adjacent normal mucosa (ANM). FOXC1 protein expression was examined by immunohistochemistry. miR-204-5p mimics and FOXC1 siRNA were transfected into LSCC cell lines Hep-2 and TU-177 to observe malignant behavior. miR-204-5p mimics were injected into Hep-2 or TU-177 xenograft tumors in nude mice to examine tumor growth.Results: The miR-204-5p mRNA level was lower in all 43 LSCC samples than in the ANM samples, but the FOXC1 level was higher in the LSCC samples than in the ANM samples. The miR-204 5p level was lower for stage III and IV cancer and lymph node N+ status samples than for stage I and II cancer and N0 status samples. FOXC1 mRNA and protein levels were higher for N+ than for N0 LSCC. The miR-204-5p mRNA levels were lower in Hep-2 and TU-177 cells than in ANM tissues, but FOXC1 mRNA levels were higher in Hep-2 and TU-177 cells than in ANM tissues. Dual-luciferase reporter assays demonstrated the targeted regulatory effects of miR-204-5p on the FOXC1 3' UTR. Cell proliferation and colony formation was facilitated with miR-204-5p mimics and FOXC1 siRNA, with weaker cell migration and invasion than the controls. Moreover, miR-204-5p overexpression or FOXC1 knockdown inhibited the EMT process in LSCC cells. In vivo experiments demonstrated that injection of miR-204-5p into Hep-2 and TU-177 xenograft tumors in nude mice significantly inhibited tumor growth. Conclusions: miR-204-5p is involved in the invasion and metastasis of LSCC. It has a targeted regulatory effect on FOXC1 expression; malignant LSCC behaviors, including cell proliferation, invasion, and metastasis, are suppressed, and tumor growth in vivo is inhibited. This suggests that miR-204-5p may be a target for molecular therapy of LSCC in the future. PMID- 28819442 TI - Interferon-alpha Promotes the Expression of Cancer Stem Cell Markers in Oral Squamous Cell Carcinoma. AB - Objectives: IFNalpha can stimulate an antitumor immune response and has a direct inhibition on cancer cells. This study is to test whether IFNalpha can activate dormant cancer stem cell (CSC) in oral squamous cell carcinoma (OSCC) to facilitate their elimination by chemotherapy. Materials and methods: Nude mouse transplantation tumor model was established and administrated with IFNalpha and saline. The influence on CD44 and ALDH1A1 expression under IFNalpha treatment was detected by in vivo experiments. Flow cytometry, western blot, and immunofluorescence were used to detect the expression of CD44 and ALDH1A1 after INFa treatment in OSCC cell lines. Tumorsphere formation assay was conducted under incubation with IFNalpha for 2 weeks. Chromatin immunoprecipitation (ChIP) assays was used to examine the IFNalpha-induced transcriptional regulation of CD44 and ALDH1A1 expression. That IFNalpha-primed enhanced killing effect of chemotherapy was evaluated by MTT and western blot. Results: IFNalpha transcriptionally activated the expression of CD44 and ALDH1A1 expression both in vivo and in vitro. IFNalpha-primed enhanced the cytotoxic inhibition effect of CDDP, erlotinib and nimotuzumab on OSCC cells. Conclusion: These results suggest that IFNalpha could be administrated to patients prior to chemotherapeutic drugs, which will facilitate the killing of cancer stem cells in OSCC. PMID- 28819441 TI - VSV based virotherapy in ovarian cancer: the past, the present and ...future? AB - The standard approach to treating patients with advanced epithelial ovarian cancer (EOC) after primary debulking surgery remains taxane and platinum-based chemotherapy. Despite treatment with this strategy, the vast majority of patients relapse and develop drug-resistant metastatic disease that may be driven by cancer stem cells (CSCs) or cancer initiating cells (CICs). Oncolytic viruses circumvent typical drug-resistance mechanisms, therefore they may provide a safe and effective alternative treatment for chemotherapy-resistant CSCs/CICs. Among oncolytic viruses vesicular stomatitis virus (VSV) has demonstrated oncolysis and preferential replication in cancer cells. In this review, we summarize the recent findings regarding existing knowledge on biology of the ovarian cancer and the role of ovarian CSCs (OCSCs) in tumor dissemination and chemoresistance. In addition we also present an overview of recent advances in ovarian cancer therapies with oncolytic viruses (OV). We focus particularly on key genetic or immune response pathways involved in tumorigenesis in ovarian cancer which facilitate oncolytic activity of vesicular stomatitis virus (VSV). We highlight the prospects of targeting OCSCs with VSV. The importance of testing an emerging ovarian cancer animal models and ovarian cancer cell culture conditions influencing oncolytic efficacy of VSV is also addressed. PMID- 28819443 TI - Predictive Value of Primary Tumor Site for Loco-regional Recurrence in Early Breast Cancer Patients with One to Three Positive Axillary Lymphadenophy. AB - Introduction: It remains controversial on high risks for early breast cancer patients with one to three axillary nodes after mastectomy who is predisposition to locoregional recurrence. The present study is to investigate the relationship between primary tumor site and loco-regional recurrence (LRR) and explore the predictive value of clinicopathological characteristics in LRR for early breast cancer patients with one to three positive axillary lymph nodes after mastectomy. Methods: We reviewed the clinical data of 656 consecutively diagnosed patients with pT1-2N1M0 breast cancer who were treated in Sun Yat-sen University Cancer Center with radical operation without postoperative radiotherapy between March 1998 and December 2010. The primary tumor sites included outer quadrant in 455 patients (69.36%), inner quadrant in 156 patients (23.78%)and central quadrant in 45 patients (6.86%). LRR and LRR-free survival (LRFS) in combination with clinical and pathological features were analyzed to screen out patients with higher risk of LRR. Results: The median follow-up time was 64.9 months. The 5-, 10-year LRR for the cohort was 8.6% and 12.9%, respectively; the 5-, 10-year LRFS was 86.2% and 76.4%, respectively. Multivariate analyses showed that age of <=35 years, inner quadrant tumor and non-luminal subtype were independent risk factors for LRR and LRFS. Patients with primary tumor in inner quadrant showed higher LRR and poorer LRFS when risk factors are >=2 than those with tumors in other sites. Conclusions: Inner quadrant tumor was an independent predictor for LRR and LRFS in patients with early breast cancer and one to three positive axillary lymph nodes, which would be more accurate in combination with other prognostic indexes including patients' age, pathological T stage, Ki67 status, molecular subtypes. PMID- 28819444 TI - Association of HLA-DRB1, HLA-DQB1 Polymorphisms with HPV 16 E6 Variants among Young Cervical Cancer Patients in China. AB - Potential correlation of human papillomavirus (HPV) 16 E6 variants and human leukocyte antigen (HLA) class II polymorphisms has been suggested in patients with cervical cancer, so far little information is available about the possible interaction between E6 variants and HLA class II variability during the obviously accelerated progression to cervical cancer in young women. In this study, we aimed to explore the association between the HPV16 E6 variants and HLA-DRB1, DQB1 alleles in a Chinese young cervical cancer population. The HLA-DRB1, HLA-DQB1 polymophisms were genotyped by low-resolution polymerase chain reaction (PCR) with sequence-specific primer. HPV16 E6 DNA was tested by Sanger fluorescent dye dideoxy-termination technique. The difference of DRB1, DQB1 polymorphisms between young cervical cancer patients (<=35ys, n=61) and older ones (>35ys, n=85) and the association with E6 variants were analyzed. Results showed that the distribution pattern of HLA-DRB1, DQB1 alleles was different between young cervical cancer patients and older ones. The allele frequency of DQB1*0501 in young patients was significantly lower than older ones (6.6% vs. 23.5%, p<0.05). The HPV16 E6 A4 lineage was the exclusive type observed in young patients, and its prevalence was significantly higher than that of older cases (82.86% vs.41.94%, p<0.05). DRB1*03 was not found in young patients positive for the HPV16 E6 A4 lineage, whereas it was observed in 19.2 % older patients with A4 positive(Pc<0.05). In conclusion, specific association between certain HPV16 E6 variant and genetic polymorphisms of HLA may play a role during the progression of early onset cervical cancer in young patients. Certain HLA-DRB1 and HLA-DQB1 alleles may be related to the A4 lineage among young cervical cancer patients, which was the unique HPV16 E6 variant found in Chinese young patients. Our finding may provide an insight into the pathogenic factors that associated with cervical cancer in young women. PMID- 28819445 TI - DNA-dependent protein kinase catalytic subunit functions in metastasis and influences survival in advanced-stage laryngeal squamous cell carcinoma. AB - Background: DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is known to function in several types of cancer. In this study, we investigated the expression and clinicopathologic significance of DNA-PKcs in laryngeal squamous cell carcinoma (LSCC). Methods: We conducted a retrospective study of 208 patients with advanced-stage LSCC treated at Sun Yat-sen University Cancer Center, Guangzhou, China. We assessed DNA-PKcs and p16INK4a (p16) status using immunohistochemistry. We examined the association between DNA-PKcs expression and clinicopathologic features and survival outcomes. To evaluate the independent prognostic relevance of DNA-PKcs, we used univariate and multivariate Cox regression models. We estimated overall survival (OS) and distant metastasis-free survival (DMFS) using the Kaplan-Meier method. Results: Immunohistochemical analyses revealed that 163/208 (78.4%) of the LSCC tissue samples exhibited high DNA-PKcs expression. High DNA-PKcs expression was significantly associated with survival outcomes (P = 0.016) and distant metastasis (P = 0.02; chi-squared test). High DNA-PKcs expression was associated with a significantly shorter OS and DMFS than low DNA-PKcs expression (P = 0.029 and 0.033, respectively; log rank test), and was associated with poor OS in the p16-positive subgroup (P = 0.047). Multivariate analysis identified DNA-PKcs as an independent prognostic indicator of OS and DMFS in all patients (P = 0.039 and 0.037, respectively). Conclusions: Our results suggest that patients with LSCC in whom DNA-PKcs expression is elevated have a higher incidence of distant metastasis and a poorer prognosis. DNA-PKcs may represent a marker of tumor progression in patients with p16-positive LSCC. PMID- 28819446 TI - Incremental Value of Circulating MiR-122-5p to Predict Outcome after Out of Hospital Cardiac Arrest. AB - Rationale. The value of microRNAs (miRNAs) as biomarkers has been addressed in various clinical contexts. Initial studies suggested that miRNAs, such as the brain-enriched miR-124-3p, might improve outcome prediction after out-of-hospital cardiac arrest. The aim of this study is to determine the prognostic value of miR 122-5p in a large cohort of comatose survivors of out-of-hospital cardiac arrest. Methods. We analyzed 590 patients from the Targeted Temperature Management trial (TTM-trial). Circulating levels of miR-122-5p were measured in serum samples obtained 48 hours after return of spontaneous circulation. The primary end-point was poor neurological outcome at 6 months evaluated by the cerebral performance category score. The secondary end-point was survival at the end of the trial. Results. Forty-eight percent of patients had a poor neurological outcome at 6 months and 43% were dead at the end of the trial. Levels of miR-122-5p were lower in patients with poor neurological outcome compared to patients with good neurological outcome (p<0.001), independently of targeted temperature management regimen. Levels of miR-122-5p were significant univariate predictors of neurological outcome (odds ratios (OR), 95% confidence intervals (CI): 0.71 [0.57 0.88]). In multivariable analyses, miR-122-5p was an independent predictor of neurological outcome and improved the predictive value of a clinical model including miR-124-3p (integrated discrimination improvement of 0.03 [0.02-0.04]). In Cox proportional hazards models, miR-122-5p was a significant predictor of survival at the end of the trial. Conclusion. Circulating levels of miR-122-5p improve the prediction of outcome after out-of-hospital cardiac arrest. PMID- 28819447 TI - Targeting Activated Platelets: A Unique and Potentially Universal Approach for Cancer Imaging. AB - Rationale The early detection of primary tumours and metastatic disease is vital for successful therapy and is contingent upon highly specific molecular markers and sensitive, non-invasive imaging techniques. We hypothesized that the accumulation of activated platelets within tumours is a general phenomenon and thus represents a novel means for the molecular imaging of cancer. Here we investigate a unique single chain antibody (scFv), which specifically targets activated platelets, as a novel biotechnological tool for molecular imaging of cancer. Methods The scFvGPIIb/IIIa, which binds specifically to the activated form of the platelet integrin receptor GPIIb/IIIa present on activated platelets, was conjugated to either Cy7, 64Cu or ultrasound-enhancing microbubbles. Using the Cy7 labelled scFvGPIIb/IIIa, fluorescence imaging was performed in mice bearing four different human tumour xenograft models; SKBr3, MDA-MB-231, Ramos and HT-1080 cells. Molecular imaging via PET and ultrasound was performed using the scFvGPIIb/IIIa-64Cu and scFvGPIIb/IIIa-microbubbles, respectively, to further confirm specific targeting of scFvGPIIb/IIIa to activated platelets in the tumour stroma. Results Using scFvGPIIb/IIIa we successfully showed specific targeting of activated platelets within the microenvironment of human tumour xenografts models via three different molecular imaging modalities. The presence of platelets within the tumour microenvironment, and as such their relevance as a molecular target epitope in cancer was further confirmed via immunofluorescence of human tumour sections of various cancer types, thus validating the translational importance of our novel approach to human disease. Conclusion Our study provides proof of concept for imaging and localization of tumours by molecular targeting activated platelets. We illustrate the utility of a unique scFv as a versatile biotechnological tool which can be conjugated to various contrast agents for molecular imaging of cancer using three different imaging modalities. These findings warrant further development of this activated platelet specific scFvGPIIb/IIIa, potentially as a universal marker for cancer diagnosis and ultimately for drug delivery in an innovative theranostic approach. PMID- 28819448 TI - Preparation and Application of Cell Membrane-Camouflaged Nanoparticles for Cancer Therapy. AB - Cancer is one of the leading causes of death worldwide. Many treatments have been developed so far, although effective, suffer from severe side effects due to low selectivity. Nanoparticles can improve the therapeutic index of their delivered drugs by specifically transporting them to tumors. However, their exogenous nature usually leads to fast clearance by mononuclear phagocytic system. Recently, cell membrane-camouflaged nanoparticles have been investigated for cancer therapy, taking advantages of excellent biocompatibility and versatile functionality of cell membranes. In this review, we summarized source materials and procedures that have been used for constructing and characterizing biomimetic nanoparticles with a focus on their application in cancer therapy. PMID- 28819449 TI - Self-Assembly DNA Polyplex Vaccine inside Dissolving Microneedles for High Potency Intradermal Vaccination. AB - The strong immunogenicity induction is the powerful weapon to prevent the virus infections. This study demonstrated that one-step synthesis of DNA polyplex vaccine in microneedle (MN) patches can induce high immunogenicity through intradermal vaccination and increase the vaccine stability for storage outside the cold chain. More negative charged DNA vaccine was entrapped into the needle region of MNs followed by DNA polyplex formation with branched polyethylenimine (bPEI) pre-coated in the cavities of polydimethylsiloxane (PDMS) molds that can deliver more DNA vaccine to immune-cell rich epidermis with high transfection efficiency. Our data in this study support the safety and immunogenicity of the MN-based vaccine; the MN patch delivery system induced an immune response 3.5 fold as strong as seen with conventional intramuscular administration; the DNA polyplex formulation provided excellent vaccine stability at high temperature (could be stored at 45oC for at least 4 months); the DNA vaccine is expected to be manufactured at low cost and not generate sharps waste. We think this study is significant to public health because there is a pressing need for an effective vaccination in developing countries. PMID- 28819450 TI - Circulating Tumor Cells: Moving Biological Insights into Detection. AB - Circulating tumor cells (CTCs) have shown promising potential as liquid biopsies that facilitate early detection, prognosis, therapeutic target selection and monitoring treatment response. CTCs in most cancer patients are low in abundance and heterogeneous in morphological and phenotypic profiles, which complicate their enrichment and subsequent characterization. Several methodologies for CTC enrichment and characterization have been developed over the past few years. However, integrating recent advances in CTC biology into these methodologies and the selection of appropriate enrichment and characterization methods for specific applications are needed to improve the reliability of CTC biopsies. In this review, we summarize recent advances in the studies of CTC biology, including the mechanisms of their generation and their potential forms of existence in blood, as well as the current CTC enrichment technologies. We then critically examine the selection of methods for appropriately enriching CTCs for further investigation of their clinical applications. PMID- 28819451 TI - A High-Affinity Repebody for Molecular Imaging of EGFR-Expressing Malignant Tumors. AB - The accurate detection of disease-related biomarkers is crucial for the early diagnosis and management of disease in personalized medicine. Here, we present a molecular imaging of human epidermal growth factor receptor (EGFR)-expressing malignant tumors using an EGFR-specific repebody composed of leucine-rich repeat (LRR) modules. The repebody was labeled with either a fluorescent dye or radioisotope, and used for imaging of EGFR-expressing malignant tumors using an optical method and positron emission tomography. Our approach enabled visualization of the status of EGFR expression, allowing quantitative evaluation in whole tumors, which correlated well with the EGFR expression levels in mouse or patients-derived colon cancers. The present approach can be effectively used for the accurate detection of EGFR-expressing cancers, assisting in the development of a tool for detecting other disease biomarkers. PMID- 28819453 TI - S100-SPECT uncovers cellular and molecular events of pre-metastatic niche formation and following organ-specific cancer metastasis. AB - Great progress has been made in in vivo imaging for cancer metastasis. Eisenblaetter et al. developed an innovative S100A8/A9-specific single photon emission computed tomography (SPECT) probe for imaging and succeeded in detecting the metastatic organ favored by the cancer before the cancer arrival. By utilizing this advanced method, researchers have also found that cancer-derived monocytes are the main source of the abundant production of S100A8/A9 in the pre metastatic area. The CCL2-CCR2 axis is associated with S100A8/A9 production. Clinical establishment of this technique is expected to enable accurate prediction and monitoring of cancer metastasis during therapy. PMID- 28819452 TI - Co-Activation of PKC-delta by CRIF1 Modulates Oxidative Stress in Bone Marrow Multipotent Mesenchymal Stromal Cells after Irradiation by Phosphorylating NRF2 Ser40. AB - The high mortality associated with pancytopenia and multi-organ failure resulting from hematopoietic disorders of acute radiation syndrome (h-ARS) creates an urgent need for developing more effective treatment strategies. Here, we showed that bone marrow multipotent mesenchymal stromal cells (BMMSCs) effectively regulate oxidative stress following radiative injury, which might be on account of irradiation-induced elevation of protein levels of CR6-interacting factor 1(CRIF1) and nuclear factor E2-related factor 2(NRF2). Crif1-knockdown BMMSCs presented increased oxidative stress and apoptosis after irradiation, which were partially due to a suppressed antioxidant response mediated by decreased NRF2 nuclear translocation. Co-immunoprecipitation (Co-IP) experiments indicated that CRIF1 interacted with protein kinase C-delta (PKC-delta). NRF2 Ser40 phosphorylation was inhibited in Crif1-deficient BMMSCs even in the presence of three kinds of PKC agonists, suggesting that CRIF1 might co-activate PKC-delta to phosphorylate NRF2 Ser40. After radiative injury, the supporting effect of BMMSCs for the colony forming ability of HSCs in vitro was reduced, and the deficiency of CRIF1 aggravated such damage. Thus, CRIF1 plays an essential role in PKC delta/NRF2 pathway modulation to alleviate oxidative stress in BMMSCs after irradiative injury, and at some level it may maintain the HSCs-supporting effect of BMMSCs after radiative injuries. PMID- 28819454 TI - A Novel MPEG-PDLLA-PLL Copolymer for Docetaxel Delivery in Breast Cancer Therapy. AB - Satisfactory drug loading capacity and stability are the two main factors that determine the anti-cancer performance. In general, the stability of the micelles is reduced when the drug loading (DL) is increased. Therefore, it was a challenge to have high drug loading capacity and good stability. In this study, we introduced a hydrophilic poly (L-Lysine) (PLL) segment with different molecular weights into the monomethoxy poly (ethylene glycol)-poly (D, L-lactide) (MPEG PDLLA) block copolymer to obtain a series of novel triblock MPEG-PDLLA-PLL copolymers. We found that the micelles formed by a specific MPEG2k-PDLLA4k-PLL1k copolymer could encapsulate docetaxel (DTX) with a satisfactory loading capacity of up to 20% (w/w) via the thin film hydration method, while the stability of drug loaded micellar formulation was still as good as that of micelles formed by MPEG2k-PDLLA1.7k with drug loading of 5% (w/w). The results from computer simulation study showed that compared with MPEG2k-PDLLA1.7k, the molecular chain of MPEG2k-PDLLA4k-PLL1k could form a more compact funnel-shaped structure when interacted with DTX. This structure favored keeping DTX encapsulated in the copolymer molecules, which improved the DL and stability of the nano formulations. The in vitro and in vivo evaluation showed that the DTX loaded MPEG2k-PDLLA4k-PLL1k (DTX/MPEG2k-PDLLA4k-PLL1k) micelles exhibited more efficiency in tumor cell growth inhibition. In conclusion, the MPEG2k-PDLLA4k PLL1k micelles were much more suitable than MPEG2k-PDLLA1.7k for DTX delivery, and then the novel nano-formulations showed better anti-tumor efficacy in breast cancer therapy. PMID- 28819455 TI - Microvesicles as Potential Biomarkers for the Identification of Senescence in Human Mesenchymal Stem Cells. AB - Senescence in human mesenchymal stem cells (MSCs) not only contributes to organism aging and the development of a variety of diseases but also severely impairs their therapeutic properties as a promising cell therapy. Studies searching for efficient biomarkers that represent cellular senescence have attracted much attention; however, no single marker currently provides an accurate cell-free representation of cellular senescence. Here, we studied characteristics of MSC-derived microvesicles (MSC-MVs) that may reflect the senescence in their parental MSCs. We found that senescent late passage (LP) MSCs secreted higher levels of MSC-MVs with smaller size than did early passage (EP) MSCs, and the level of CD105+ MSC-MVs decreased with senescence in the parental MSCs. Also, a substantially weaker ability to promote osteogenesis in MSCs was observed in LP than EP MSC-MVs. Comparative analysis of RNA sequencing showed the same trend of decreasing number of highly-expressed miRNAs with increasing number of passages in both MSCs and MSC-MVs. Most of the highly-expressed genes in LP MSCs and the corresponding MSC-MVs were involved in the regulation of senescence related diseases, such as Alzheimer's disease. Furthermore, based on the miRNA profiling, transcription factors (TF) and genes regulatory networks of MSC senescence, and the datasets from GEO database, we confirmed that expression of miR-146a-5p in MSC-MVs resembled the senescent state of their parental MSCs. Our findings provide evidence that MSC-MVs are a key factor in the senescence associated secretory phenotype of MSCs and demonstrate that their integrated characteristics can dynamically reflect the senescence state of MSCs representing a potential biomarker for monitoring MSC senescence. PMID- 28819456 TI - Therapeutic Effect of Astroglia-like Mesenchymal Stem Cells Expressing Glutamate Transporter in a Genetic Rat Model of Depression. AB - Recent studies have proposed that abnormal glutamatergic neurotransmission and glial pathology play an important role in the etiology and manifestation of depression. It was postulated that restoration of normal glutamatergic transmission, by enhancing glutamate uptake, may have a beneficial effect on depression. We examined this hypothesis using unique human glial-like mesenchymal stem cells (MSCs), which in addition to inherent properties of migration to regions of injury and secretion of neurotrophic factors, were differentiated to express high levels of functional glutamate transporters (excitatory amino acid transporters; EAAT). Additionally, gold nanoparticles (GNPs), which serve as contrast agents for CT imaging, were loaded into the cells for non-invasive, real time imaging and tracking of MSC migration and final location within the brain. MSC-EAAT (2*105; 10 MUl) were administered (i.c.v.) to Flinder Sensitive Line rats (FSLs), a genetic model for depression, and longitudinal behavioral and molecular changes were monitored. FSL rats treated with MSC-EAAT showed attenuated depressive-like behaviors (measured by the forced swim test, novelty exploration test and sucrose self-administration paradigm), as compared to controls. CT imaging, Flame Atomic Absorption Spectroscopy analysis and immunohistochemistry showed that the majority of MSCs homed specifically to the dentate gyrus of the hippocampus, a region showing structural brain changes in depression, including loss of glial cells. mRNA and protein levels of EAAT1 and BDNF were significantly elevated in the hippocampus of MSC-EAAT-treated FSLs. Our findings indicate that MSC-EAATs effectively improve depressive-like manifestations, possibly in part by increasing both glutamate uptake and neurotropic factor secretion in the hippocampus. PMID- 28819457 TI - Type 1 Diabetes: Urinary Proteomics and Protein Network Analysis Support Perturbation of Lysosomal Function. AB - While insulin replacement therapy restores the health and prevents the onset of diabetic complications (DC) for many decades, some T1D patients have elevated hemoglobin A1c values suggesting poor glycemic control, a risk factor of DC. We surveyed the stool microbiome and urinary proteome of a cohort of 220 adolescents and children, half of which had lived with T1D for an average of 7 years and half of which were healthy siblings. Phylogenetic analysis of the 16S rRNA gene did not reveal significant differences in gut microbial alpha-diversity comparing the two cohorts. The urinary proteome of T1D patients revealed increased abundances of several lysosomal proteins that correlated with elevated HbA1c values. In silico protein network analysis linked such proteins to extracellular matrix components and the glycoprotein LRG1. LRG1 is a prominent inflammation and neovascularization biomarker. We hypothesize that these changes implicate aberrant glycation of macromolecules that alter lysosomal function and metabolism in renal tubular epithelial cells, cells that line part of the upper urinary tract. PMID- 28819458 TI - Focused Ultrasound Hyperthermia Mediated Drug Delivery Using Thermosensitive Liposomes and Visualized With in vivo Two-Photon Microscopy. AB - The future of nanomedicines in oncology requires leveraging more than just the passive drug accumulation in tumors through the enhanced permeability and retention effect. Promising results combining mild hyperthermia (HT) with lyso thermosensitive liposomal doxorubicin (LTSL-DOX) has led to improved drug delivery and potent antitumor effects in pre-clinical studies. The ultimate patient benefit from these treatments can only be realized when robust methods of HT can be achieved clinically. One of the most promising methods of non-invasive HT is the use of focused ultrasound (FUS) with MRI thermometry for anatomical targeting and feedback. MRI-guided focused ultrasound (MRgFUS) is limited by respiratory motion and large blood vessel cooling. In order to translate exciting pre-clinical results to the clinic, novel heating approaches capable of overcoming the limitations on clinical MRgFUS+HT must be tested and evaluated on their ability to locally release drug from LTSL-DOX. Methods: In this work, a new system is described to integrate focused ultrasound (FUS) into a two-photon microscopy (2PM) setting to image the release of drug from LTSL-DOX in real-time during FUS+HT in vivo. A candidate scheme for overcoming the limitations of respiratory motion and large blood vessel cooling during MRgFUS+HT involves applying FUS+HT to 42 degrees C in short ~30s bursts. The spatiotemporal drug release pattern from LTSL-DOX as a result is quantified using 2PM and compared against continuous (3.5min and 20min at 42 degrees C) FUS+HT schemes and unheated controls. Results: It was observed for the first time in vivo that these short duration temperature elevations could produce substantial drug release from LTSL DOX. Ten 30s bursts of FUS+HT was able to achieve almost half of the interstitial drug concentration as 20min of continuous FUS+HT. There was no significant difference between the intravascular area under the concentration-time curve for ten 30s bursts of FUS+HT and 3.5min of continuous FUS+HT. Conclusion: We have successfully combined 2PM with FUS+HT for imaging the release of DOX from LTSL DOX in vivo in real-time, which will permit the investigation of FUS+HT heating schemes to improve drug delivery from LTSL-DOX. We have evaluated the ability to release DOX in short 30s FUS+HT bursts to 42 degrees C as a method to overcome limitations on clinical MRgFUS+HT and have found that such exposures are capable of releasing measurable amounts of drug. Such an exposure has the potential to overcome limitations that hamper conventional MRgFUS+HT treatments in targets that are associated with substantial tissue motion. PMID- 28819459 TI - Exosomes Derived From Natural Killer Cells Exert Therapeutic Effect in Melanoma. AB - Objective: Exosomes are nanovesicles that are released from normal and tumor cells and are detectable in cell culture supernatant and human biological fluids. Although previous studies have explored exosomes released from cancer cells, little is understood regarding the functions of exosomes released by normal cells. Natural killer (NK) cells display rapid immunity to metastatic or hematological malignancies, and efforts have been undertaken to clinically exploit the antitumor properties of NK cells. However, the characteristics and functions of exosomes derived from NK cells remain unknown. In this study, we explored NK cell-derived exosome-mediated antitumor effects against aggressive melanoma in vitro and in vivo. Methods: B16F10 cells were transfected with enhanced firefly luciferase (effluc) and thy1.1 genes, and thy1.1-positive cells were immunoselected using microbeads. The resulting B16F10/effluc cells were characterized using reverse transcriptase polymerase chain reaction (RT-PCR), western blotting, and luciferase activity assays. Exosomes derived from NK-92MI cells (NK-92 Exo) were isolated by ultracentrifugation and density gradient ultracentrifugation. NK-92 Exo were characterized by transmission electron microscopy and western blotting. We also performed an enzyme-linked immunosorbent assay to measure cytokines retained in NK-92 Exo cells. The in vitro cytotoxicity of NK-92 Exo against the cancer cells was determined using a bioluminescence imaging system (BLI) and CCK-8 assays. To investigate the possible side effects of NK-92 Exo on healthy cells, we also performed the BLI and CCK-8 assays using the human kidney PhoenixTM-Ampho cell line. Flow cytometry and western blotting confirmed that NK-92 Exo induced apoptosis in the B16F10/effluc cells. In vivo, we used a B16F10/effluc cell xenograft model to detect the immunotherapeutic effect of NK-92 Exo. We injected NK-92 Exo into tumors, and tumor growth progression was monitored using the IVIS Lumina imaging system and ultrasound imaging. Tumor mass was monitored after in vivo experiments. Results: RT-PCR and western blotting confirmed effluc gene expression and protein levels in B16F10/effluc cells. B16F10/effluc activity was found to increase with increasing cell numbers, using BLI assay. For NK-92 Exo characterization, western blotting was performed on both ultracentrifuged and density gradient-isolated exosomes. The results confirmed that NK cell-derived exosomes express two typical exosome proteins, namely CD63 and ALIX. We demonstrated by western blot analysis that NK 92 Exo presented two functional NK proteins, namely perforin and FasL. Moreover, we confirmed the membrane expression of FasL. The enzyme-linked immunosorbent assay results indicated that NK-92 Exo can secrete tumor necrosis factor (TNF) alpha, which affected the cell proliferation signaling pathway. The antitumor effect of NK-92 Exo against B16F10/effluc cells in vitro was confirmed by BLI (p < 0.001) and CCK-8 assays (p < 0.001). Furthermore, in normal healthy cells, even after 24 h of co-culture, NK-92 Exo did not exhibit significant side effects. In the in vivo experiments, tumors in the vehicle control group were significantly increased, compared with those in the NK-92 Exo-treated group (p < 0.05). Conclusion: The results of the current study suggest that exosomes derived from NK cells exert cytotoxic effects on melanoma cells and thus warrant further development as a potential immunotherapeutic strategy for cancer. PMID- 28819461 TI - New developments in the pathology of malignant lymphoma: a review of the literature published from January to April 2017. PMID- 28819460 TI - A Tumor-pH-Responsive Supramolecular Photosensitizer for Activatable Photodynamic Therapy with Minimal In Vivo Skin Phototoxicity. AB - A major challenge in photodynamic therapy (PDT) is the development of new tumor targeting photosensitizers. The tumor-specific activation is considered to be an effective strategy for designing these photosensitizers. Herein, we describe a novel tumor-pH-responsive supramolecular photosensitizer, LDH-ZnPcS8, which is not photoactive under neutral conditions but is precisely and efficiently activated in a slightly acidic environment (pH 6.5). LDH-ZnPcS8 is prepared by using a simple coprecipitation method based on the electrostatic interaction between negatively charged octasulfonate-modified zinc(II) phthalocyanine (ZnPcS8) and cationic hydroxide layers of layered double hydroxide (LDH). The in vitro photodynamic activities of LDH-ZnPcS8 in cancer cells are dramatically enhanced relative to those of ZnPcS8 alone. The results of in vivo fluorescence imaging demonstrate that the nanohybrid is activated in tumor tissues, where it displays an excellent PDT effect resulting in 95.3% tumor growth inhibition. Furthermore, the minimal skin phototoxicity of LDH-ZnPcS8 highlights its high potential as a novel photosensitizer for activatable PDT. PMID- 28819462 TI - Virtual Factory Framework for Supporting Production Planning and Control. AB - Developing optimal production plans for smart manufacturing systems is challenging because shop floor events change dynamically. A virtual factory incorporating engineering tools, simulation, and optimization generates and communicates performance data to guide wise decision making for different control levels. This paper describes such a platform specifically for production planning. We also discuss verification and validation of the constituent models. A case study of a machine shop is used to demonstrate data generation for production planning in a virtual factory. PMID- 28819463 TI - Role and Correlation of High Resolution Ultrasound and Magnetic Resonance Imaging in Evaluation of Patients with Shoulder Pain. AB - BACKGROUND: The study aimed to evaluate of the role of high-resolution ultrasound and magnetic resonance imaging in patients with shoulder pain. MATERIAL/METHODS: This prospective study included 50 patients referred for ultrasound and MRI because of shoulder pain. All patients were examined clinically, followed by radiography of the affected shoulder. High-resolution ultrasound examination of the involved shoulder was performed together with an examination of the contralateral normal shoulder, followed by MRI of the symptomatic shoulder in all 50 patients. RESULTS: In the present study, the majority of patients were in age group 56-65 years, 56% were males and 44% were females (of a total of 50 patients). A total of 40 patients were diagnosed as having rotator cuff tears on ultrasound (USG) and MRI. USG showed complete-thickness tears in 25 patients and partial-thickness tears in 15 patients. MRI detected 28 complete- and 12 partial thickness tears of the rotator cuff. In the diagnosis of rotator cuff tears, the strength of agreement between ultrasound and magnetic resonance imaging was good (kappa coefficient=0.79). CONCLUSIONS: Ultrasonography of the shoulder shows promising results in the diagnosis of rotator cuff tears and in differentiating partial from complete tears. A wide availability, cost effectiveness and better tolerability of ultrasonography make it a modality of first choice for evaluating rotator cuff tears. PMID- 28819464 TI - A Pictorial Review of the Many Faces of Gossypiboma - Observations in 6 Cases. AB - Gossypiboma or textiloma is the result of a foreign-body reaction to extraneous material, usually a surgical sponge that was accidentally retained within the body. The diagnosis of a retained surgical sponge is often delayed due to its infrequent occurrence and protean appearances. The purpose of this pictorial review is to define the common sonographic and CT features of gossypiboma. A retrospective review of sonographic and CT images of 6 surgically proven cases of retained surgical sponges was undertaken. PMID- 28819465 TI - Chemical Control and Spectral Fingerprints of Electronic Coupling in Carbon Nanostructures. AB - The optical and electronic properties of atomically thin materials such as single walled carbon nanotubes and graphene are sensitively influenced by substrates, the degree of aggregation, and the chemical environment. However, it has been experimentally challenging to determine the origin and quantify these effects. Here we use time-dependent density-functional-theory calculations to simulate these properties for well-defined molecular systems. We investigate a series of core-shell structures containing C60 enclosed in progressively larger carbon shells and their perhydrogenated or perfluorinated derivatives. Our calculations reveal strong electronic coupling effects that depend sensitively on the interparticle distance and on the surface chemistry. In many of these systems we predict considerable orbital mixing and charge transfer between the C60 core and the enclosing shell. We predict that chemical functionalization of the shell can modulate the electronic coupling to the point where the core and shell are completely decoupled into two electronically independent chemical systems. Additionally, we predict that the C60 core will oscillate within the confining shell, at a frequency directly related to the strength of the electronic coupling. This low-frequency motion should be experimentally detectable in the IR region. PMID- 28819466 TI - [Marjolin's ulcer: rare and late complication of decubitus ulcers in a paraplegic patient]. PMID- 28819467 TI - [Mirizzi's syndrome: a rare cause of biliary tract obstruction: about a case and review of the literature]. AB - Mirizzi's syndrome is a rare complication of chronic vesicular lithiasis with prevalence ranging from 0.7% to 1.4% among patients who have undergone cholecystectomy. It is characterized by cholestatic icterus associated with compression of the common bile duct due to lodged calculus in the vesicular neck or in the cystic duct. The disease can evolve toward the erosion through the common hepatic duct wall and, therefore, it can cause the formation of a gallbladder-biliary fistula. We here report a case of Mirizzi's syndrome type I in order to highlight the role of preoperative diagnosis which is made easier by endoscopic retrograde cholangiography or by cholangio-MRI, allowing to avoid iatrogenic bile duct injuries. We conducted a review of the available literature on various aspects of this syndrome, including its pathogenesis, diagnosis and management. PMID- 28819468 TI - Paediatric fractures in a sub-saharan tertiary care center: a cohort analysis of demographic characteristics, clinical presentation, therapeutic patterns and outcomes. AB - INTRODUCTION: Paediatric fractures are often of good prognosis due to auto correction of insufficient fracture reduction by bone remodeling. In sub-Saharan Africa, traditional healers are renowned for managing fractures and there is a neglect for specialized pediatric fracture care. We aimed to determine the demographic characteristics, clinical presentation, treatment patterns and outcomes of paediatric fractures in a tertiary health care centre in Yaounde. METHODS: We conducted a prospective cohort study of all consenting consecutive cases of fractures in patients younger than 16 years managed between January 2011 and June 2015 at the University Teaching Hospital, Cameroon. We analysed demographic data, injury characteristics, fracture patterns, treatment details, therapeutic challenges and outcome of treatment at 12 months of follow-up. RESULTS: We enrolled 147 fractures from 145 children with a mean age of 7 years and male-to-female sex ratio of 2.5:1. The main mechanisms of injury were games (53%) and accidental falls (20.7%). Forearm fractures were the most common fractures (38%). The mainstay of management was non-operative in 130 (88.5%) fractures, with 29.3% manipulations under anesthesia and 17 (11.5%) open reductions with internal fixation. The most surgically reduced fractures were supracondylar humeral fractures. Major difficulties were long therapeutic delay, lack of diligent anaesthesia and the lack of fluoroscopy. The outcome of treatment was favorable in 146 (99.3%) paediatric fractures. CONCLUSION: With the growing population of sub-Saharan Africa and the objective of becoming an emergent region, public policies should match the technical realities. PMID- 28819469 TI - Aggressive fibromatosis of the oral cavity in a 5 year old boy: a rare case report. AB - Fibrous tissue proliferations express a wide spectrum of histologic and morphologic variation in both infants and adults. This ranges from hypertrophic scar formation at one end to malignant fibrosarcoma at the other end of the spectrum. Aggressive fibromatosis is an intermediate tumor which is in proximity to fibrosarcomas. These are locally invasive and often recur after excision, but do not metastasize. Histologically, they are characterized by proliferating fibroblasts with little mitotic activity. Aggressive fibromatosis in the head and neck region is not common, and very sporadically occurs in the oral cavity or jaw bones. Here we report a rare case of aggressive fibromatosis occurring in a 5 year old boy. PMID- 28819471 TI - [Giant right palpebral lipoma]. PMID- 28819470 TI - Causes of death and factors associated with early mortality of HIV-infected adults admitted to Korle-Bu Teaching Hospital. AB - INTRODUCTION: This study sought to identify common causes of death as well as the factors associated with the high inpatient mortality rate of HIV-infected patients at the Korle-Bu Teaching Hospital (KBTH). METHODS: The retrospective study reviewed the medical records of 547 HIV-infected adults aged 18 years or older admitted to the KBTH between the months of January 2012 and October 2013. Using standardized abstraction forms, clinical and demographic data of eligible patients was collected. Data was summarized using descriptive statistics. Demographic and clinical characteristics of patients who died within 7 days (early) and after (late) admission were compared using Rank Sum tests or Chi square tests. RESULTS: Of 547 eligible patients during the period, 222 (40.6%) died during hospitalization, with 124 (55.9%) of them dying within a week of admission. Of the 222 patients who died, 190 (85.6%) were previously known HIV positive. Yet, 141 (63.5%) of the 222 patients who died had no prior highly active antiretroviral therapy (HAART). The most common admitting diagnoses were anemia (34.2%), cerebral toxoplasmosis (29.3%), and pneumonia (25.7%); the most common causes of death were tuberculosis (34.7%), anemia (30.2%) and cerebral toxoplasmosis (27.5%). Tuberculosis was the only factor significantly associated with early death (P<0.05). CONCLUSION: The inpatient mortality rate among HIV infected adults admitted to the KBTH is high. A majority of the patients were not receiving HAART despite known HIV diagnosis. Earlier initiation of HAART may lower the risk of opportunistic infections and HIV mortality rates. Additionally, a high index of suspicion and initiation of empiric treatment for TB may reduce early deaths. PMID- 28819472 TI - [Career concerns among occupational physicians serving on the Institutes for Occupational Safety and Health in Tunisia]. AB - INTRODUCTION: Career dissatisfaction among occupational physicians (OP) may affect their performance and the quality of healthcare services provided. Our study aims to assess the job satisfaction of OP serving on the Institutes for Occupational Safety and Health(IOSH) in Tunisia and to identify the determinant factors. METHODOLOGY: We conducted a national cross-sectional validated SAPHORA JOB survey among all the OP serving on 22 IOSH. RESULTS: 58% of OP serving on the IOSH were dissatisfied with their career. Career satisfaction was statistically influenced by the number of healthcare facilities for which they were responsible (p=0.016), the work organisation (p=0.010), the work impact (p=0.011), the salary (p<10-3) and knowledge on current regulation (p=0.047). CONCLUSION: The standardisation of pay scale and career ladders for OP serving on the IOSH based on a revision of legislative texts is recommended. Improving organization and working conditions may allow success in the workplace and benefit enhancement. PMID- 28819473 TI - Giant mixed Sertoli-Leydig-Granulosa sex cord tumor of the testis; clinical, histopathological, and radiological features: a case report. AB - Sex cord tumors of the testis in post pubertal men are rare. Mixed leydig-Sertoli Granulosa sex cord tumors are exceptionally rare. To the best of our knowledge there are only three reported similar cases in the literature. We reported a case of a 27-year-old male who presented with huge left scrotal mass of 6-years duration. The gross tumor specimen after resection measured 11 cm in diameter. Histological examination revealed mixed sex cord stromal tumor. This case demonstrates the limited ability of accurate diagnostic determination preoperatively, with pathologic examination and immune-histochemical staining post-orchiectomy representing the only definitive means of diagnosis. It also highlights the unique radiological appearances of this tumor, which were not previously reported in literature. PMID- 28819474 TI - Expanding health insurance scheme in the informal sector in Nigeria: awareness as a potential demand-side tool. AB - INTRODUCTION: The implementation and expansion of a health insurance scheme in the informal sector, particularly in developing countries, is a challenge. With the aid of an innovative Information-Education and Communication model, titled 'Understanding the concept of health insurance: An innovative social marketing tool', an assessment of the awareness and perception of the scheme among market women was carried out. METHODS: This is a cross-sectional descriptive survey, carried out among market women in Ibadan, Nigeria. In a multi-stage sampling technique, a total of 351 women were interviewed using an interviewer administered, semi-structured questionnaire. The data was analysed using SPSS version 16. Chi-square test was used to test associations between selected variables of interest. Logistic regression model was used to determine predictors of awareness of the National Health Insurance Scheme (NHIS). A model controlling for participants' enrolment status was built and Adjusted Odds Ratio (AOR) reported. Level of statistical significance was set at p < 0.05. RESULTS: A total of 344 market women aged 18 years and above participated in the study, a response rate of 98.0%. Respondents' educational status was the only predictor significantly associated with awareness of the NHIS. Respondents with post primary education had 10 times the odds of being aware of the NHIS than respondents with no education or only primary education (Adjusted Odds Ratio = 10.3; 95% CI = 4.1-26.0). CONCLUSION: Innovative models to enable potential beneficiaries, especially among the informal sector, to better comprehend and accept the concept of prepayment methods of financing healthcare costs is important in efforts to implement and expand a social health insurance scheme. PMID- 28819475 TI - [Seborrheic keratoses: an unusual location]. PMID- 28819476 TI - [Giant idiopathic hydronephrosis: toward a two-step therapeutic approach]. AB - Giant hydronephrosis is rare. It is usually caused by ureteropelvic junction syndrome. We here report the unusual case of a patient hospitalized with giant hydronephrosis associated with impaired general condition. Diagnosis was based on CT scan. The patient underwent deferred nephrectomy after percutaneous drainage. PMID- 28819477 TI - Evaluation of the adverse drug reaction surveillance system Kadoma City, Zimbabwe 2015. AB - INTRODUCTION: Medicines have the potential to cause adverse drug reactions and because of this Zimbabwe monitor reactions to medicines through the Adverse Drug Reaction Surveillance System. The Medicines Control Authority of Zimbabwe monitors reactions to medicines through the Adverse Drugs Reactions Surveillance System. The system relies on health professionals to report adverse drug reactions to maximize patient safety. We report results of an evaluation of the Adverse Drugs Reactions Surveillance System in Kadoma District. METHODS: A descriptive cross-sectional study was conducted using the updated CDC guidelines in six health facilities in Kadoma City. Data were collected using a pretested interviewer administered questionnaire, checklists and records review. Data was analyzed using Epi InfoTM to calculate frequencies and means. Qualitative data were analyzed manually. Written informed consent was obtained from all study participants. RESULTS: The surveillance system did not meet up to its objectives as it failed to detect the adverse drug reactions and there was no monitoring of increases in known events. Fewer than half (43%) of the participants were aware of at least 2 objectives of the surveillance system but 83% of health workers willing to participate. However the system was not acceptable, 79% did not perceive the system to be necessary with the majority saying ''why should we fill in the forms when the reactions were already known or minor''. Though the system was supposed to identify potential patient risk factors for particular types of events health workers were reluctant to participate as evidenced by only one form filled out of 20 reactions experienced in the district. The system was simple as the notification form has 16 fields which require easily obtainable information from the patient records. CONCLUSION: The surveillance system was not useful and was not acceptable to health workers but was simple and stable. Health workers lacked knowledge. Sharing of results with the Medicines Control Authority of Zimbabwe through the Matrons facilitated training of health workers in Kadoma City. Health workers were encouraged to notify any drug reaction and to completely fill in the notification forms. Patients were also encouraged to report any drug reaction to health care workers. PMID- 28819478 TI - [Granulocytic sarcoma of the dorsal spine: an unusual cause of spinal cord compression]. PMID- 28819479 TI - An assessment of policymakers' engagement initiatives to promote evidence informed health policy making in Nigeria. AB - In most developing countries including Nigeria, one of the most challenging issues associated with evidence-to-policy link is the capacity constraints of policymakers to access, synthesize, adapt and utilize available research evidence. The purpose of this review is to assess the efforts and various initiatives that have been undertaken to deliberately engage policymakers and other stakeholders in the health sector in Nigeria for the promotion of evidence informed policymaking. A MEDLINE Entrez Pubmed search was performed and studies that investigated policy making process, evidence to policy link, research to policy mechanism, and researchers/policymakers interaction in Nigeria in relation to health policy were sought. Of the 132 publications found, 14(10.6%) fulfilled the study inclusion criteria and were selected and included in the review. Of the fourteen scientific publications identified, 11 of the studies targeted both researchers and policymakers and the principal tool of intervention was training workshops which focused on various aspects of evidence informed policymaking. All the studies indicated positive outcomes and impacts in relation to quantifiable improvement in policymakers' knowledge and competence in evidence to policy process. Capacity strengthening engagement mechanism is needed for both researchers to generate better evidence and for policymakers and health-care professionals to better use available evidence. PMID- 28819480 TI - [An unusual intraurethral foreign body: a case report]. AB - In medical literature there are several case reports of foreign bodies introduced into the urethra. Foreign bodies are usually inserted as result of erotic activities, psychiatric disorders and, rarely, in an attempt to evacuate the urine. Diagnosis is based on clinical examination and imaging tests. Endoscopic management is the treatment of choice but, in some cases, open surgery may be necessary. The therapeutic approach should be systematically complemented by a psychiatric assessment of the patient. We report the case a 64-year old man with a personal history of behavioral disorders who introduced an electric wire in his urethra. The patient underwent endoscopic extraction under regional anesthesia. The patient at the time of discharge was referred to a psychiatrist. PMID- 28819481 TI - Misplaced subclavian central venous catheter. AB - Percutaneous Central Venous Catheter (CVC) insertion using internal jugular and Subclavian veins routes is common procedure for all intensive care admitted patients and some patients in the ward as demand arises in central and referral hospitals of Botswana. This is a case report of a patient on whom a third attempt of re-inserting a CVC for fluid and total parenteral nutrition (TPN) was made. X ray showed that left Subclavian inserted catheter was mis-directed to internal jugular vein of the same side creating discomfort to the patient. Ultra sound is recommended for routine investigation to confirm proper Central venous catheter placement as it can reduce failure, minimize complication and reduce cost of treatment. PMID- 28819482 TI - [Non-consummation of marriage and vaginismus: about three clinical cases]. AB - Vaginismus is a relationship issue. It is a cause of non-consummation of marriage, infertility and alteration in sexual relationship quality. We present three case reports from our daily clinical practice in order to highlight the possible causes of vaginismus, its clinical and relational characteristics and its cultural particularities. Patients were treated in the Department of Psychiatry at the Military Hospital Moulay Ismail, Meknes, over an observation period of two years. PMID- 28819483 TI - [Malignant teratoma: about a case and a review of the literature]. AB - Dermoid cysts account for 10-20% of ovarian germ cell tumors. Malignant transformation within ovarian dermoid cyst has been reported in 1-2 per cent of the cases. The treatment remains controversial. In women of childbearing age and in the first stages of the disease unilateral annexectomy without adjuvant therapy is recommended. In menopausal women extensive surgery is sometimes performed, no matter what stage of the disease the person is experiencing. We report the case of a menopausal patient with malignant transformation within ovarian dermoid cyst who underwent surgery. She had a favorable outcome. PMID- 28819484 TI - [Spontaneous splenic rupture: about a case and review of the literature]. AB - This study reports a case of spontaneous subcapsular splenic ruptured hematoma (with hemoperitoneum) and provides update on this rare disease. Non-traumatic ruptures can be fatal. Diagnosis is sometimes difficult. They often reveal an underlying pathology including infections, tumors or hematologic disorders. Symptomatology commonly has an abrupt onset but progressive forms are also possible. The majority of patients undergo splenectomy. PMID- 28819485 TI - [A pustular rash]. PMID- 28819486 TI - [Erosive lesion of the nipple]. PMID- 28819487 TI - An evaluation of Wb123 antibody elisa in individuals treated with ivermectin and albendazole, and implementation challenges in Africa. AB - The development of antibody testing for the diagnosis of lymphatic filariasis (LF) is intended to enhance the monitoring and evaluation activities of the Global Program for the Elimination of LF. This is due to the fact that antibody tests are expected to be the most sensitive at detecting exposure to LF compared to antigen that takes longer to develop. To this end a new antibody-based enzyme linked immunosorbent assay (ELISA) to Wuchereria bancrofti antigen Wb123 has been developed and further designed into a point of care rapid diagnostic test, under evaluation. In pre-treatment surveys, individuals were tested for antigen using the immuno-chromatographic test (ICT) card, and night blood microfilariae, after which all positives were treated using Ivermectin and Albendazole. The Wb123 ELISA was tested in antigen positive individuals, three months after they were treated. Samples were also tested for ICT and night blood microfilariae. The results revealed a reduction in microfilariae and ICT prevalence after treatment. Antigen and antibody prevalence increased with age. However, there was no correlation with the antibody responses observed. The mean WB123 antibody titers were higher among ICT positives, but not significantly different from ICT negative persons. While the Wb123 is targeted for use in untreated populations, further evaluations and guidelines will be required to define its use in populations that have undergone treatment for the control of LF. PMID- 28819488 TI - [Elbow abscess revealing cat-scratch disease: about a case]. AB - Cat-scratch disease (CSD) is a common cause of chronic benign lymphadenopathy in the child and the young adult. Bartonella henselae is the agent responsible for this disease. Common symptoms include regional lymphadenopathy associated with fever. We report a clinically atypical and potentially misleading case of a 18 year old girl with CSD revealed by elbow abscess. PMID- 28819489 TI - [Elastic stable intramedullary nailing (ESIN) in the treatment of both-bone forearm fractures in the child: about 87 cases]. AB - This study aims to describe the complications of elastic stable intramedullary nailing (ESIN) in the treatment of both-bone forearm diaphyseal fractures in the child. Between January 2009 and December 2013, 87 children with both-bone forearm diaphyseal fractures were treated by elastic stable intramedullary nailing with Metaizeau nails. 76 boys and 11 girls, with an average age of 12 years, were enrolled in the study. Nailing was promptly performed in 50 cases and after secondary displacement during plaster-cast treatment in the other cases. Both bones were nailed in all cases. All patients underwent systematic plaster immobilization for a period of about one month. On average, nails were removed after about 6 months. Functional outcomes were studied over a mean follow-up period of 10 months. Complications were marked by 14 superficial infections (14 cases), osteitis associated with material (2 cases), refracture (3 cases), pseudarthrosis (3 cases), delayed fracture consolidation (2 cases) and proximal radioulnar synostosis (1 case). Although intramedullary nailing ideally is an osteosynthesis technique suitable for the treatment of fractures in children, it is more invasive than orthopaedic treatment.Indications for treatment should remain within well-established limits. PMID- 28819490 TI - Maternofetal outcome of asymptomatic bacteriuria among pregnant women in a Nigerian Teaching Hospital. AB - INTRODUCTION: Asymptomatic bacteriuria has been reported to be associated with adverse pregnancy outcome. This study sought to determine the prevalence and complications of asymptomatic bacteriuria amongst parturient in the University of Port Harcourt Teaching Hospital (UPTH). METHODS: The study was a prospective cohort study involving 220 eligible antenatal attendees. Urine culture and sensitivity was conducted for each participant and the fetomaternal outcome between affected and unaffected women were compared and p value <0.05 was considered significant. RESULTS: Sixty-five of the participants had asymptomatic bacteriuria giving a prevalence of 29.5%. Twenty-three (35.4%) cultures yielded Klebsiella spp while Fifty-eight (89%) of the cultured organisms were sensitive to Nitrofurantoin. There was no statistical difference in the rate of prelabour rupture of membranes, preeclampsia, preterm delivery, birth asphyxia and low birth weight between affected and unaffected women. CONCLUSION: Contrary to widely held view, there was no significant increase in adverse pregnancy outcome amongst affected women. PMID- 28819491 TI - [Psychiatric and psychological evaluation of Tako-Tsubo syndrome: about a case]. AB - Stress cardiomyopathy or Tako Tsubo cardiomyopathy is a cardiac pathology evoking acute coronary syndrome characterized by electrocardiographic signs, cardiac enzyme elevation and no obstructive coronary lesions. It generally affects postmenopausal women and it usually occurs after periods of intense stress. Disease onset is widely variable, ranging from anginal pain (most common) to cardiogenic shock. Exact pathophysiological mechanism continues to be debated. Various hypotheses have been posited. Abrupt elevation of adrenaline levels appears to be the most credible. In particular, there is no consensus on treatment and prevention. Questions may then be asked about the existence of an underlying psychiatric pathology or a personality predisposition and, therefore, about the role of the psychiatrist in the management of this condition. PMID- 28819492 TI - [Labour in women with scarred uterus in the Democratic Republic of the Congo: trial of scar and factors influencing the outcome]. AB - OBJECTIVE: Our study aims to identify risks factors associated with failed trial of scar and to set a predictive score of labour in women with scarred uterus in the Democratic Republic of the Congo. METHODS: We conducted a multicenter cross sectional analytic study of patients with scarred uterus in four maternity units in the Democratic Republic of the Congo (DRC) from 1 January to 31 December 2013. Logistic regression model was used to identify factors associated with failed trial of scar. We set a predictive score based on this model in order to predict trial of scar failure in maternity units in the DRC. ROC curve was used to assess the ability of the set score to identify patients at risk for trial of scar failure. The cut off point for the predictive score was determined on the basis of the Youden-index-based optimal sensitivity and specificity. All the tests in our study were carried out by using a significance threshold of alpha=0.05. RESULTS: Two explanatory factors in trial of scar failure were retained. They were the socio-demographic factor (maternal age) and three obstetric factors (fundal height, fetal presentation and premature rupture of membranes). Predictive score was set to predict trial of scar failure. This score was determined based on four elements: maternal age, evaluation of the gestational sac on admission, fundal height and fetal presentation. The minimum score was set at 4 and the maximum score was set at 16. The threshold value was set at 7. A total score greater than or equal to 7 reflects a risk of trial of scar failure. CONCLUSION: We set a predictive score to predict trial of scar failure. This score was determined based on four elements: maternal age, evaluation of the gestational sac on admission, fundal height and fetal presentation. A total score greater than or equal to 7 reflects a risk of trial of scar failure. PMID- 28819493 TI - [Cesarean section in Lubumbashi, Democratic Republic of the Congo I: frequency, indications and maternal and perinatal mortality]. PMID- 28819494 TI - Functioning and disability in recent research from Cameroon: a narrative synthesis. AB - INTRODUCTION: People living with disabilities in Cameroon face many barriers to daily functioning and social participation. However, there is limited research on disabilities and their impact. We sought to examine the research related to disability from Cameroon. METHODS: We conducted a systematic review, bibliometric analysis, and narrative synthesis of research related to disability, functioning, and social participation from Cameroon published during 2005-2014. The articles were screened in duplicate to identify articles addressing impacts of disability on functioning. Disability was contextualized using the International Classification of Functioning, Disability and Health (ICF) framework. Data were analyzed narratively per identified themes using an inductive data-driven approach. RESULTS: A total of 46 studies were included following full-text review of which 36 addressed non-communicable diseases and conditions, 7 addressed infectious diseases and 3 addressed neglected tropical diseases. Among ICF Activity and Participation Restrictions, work and employment was the highest reported category (19 studies), followed by intimate relationships (14 studies), and looking after one's health (8 studies). Among ICF Environmental Factors, societal attitudes were the highest reported category (21 studies), followed by health services, systems and policies (14 studies) and support and relationships (11 studies). Among other common themes, knowledge and awareness was the highest reported category (22 studies), closely followed by traditional beliefs (20 studies) and financial barriers (9 studies). CONCLUSION: There is a small body of primary research from Cameroon on disability. The main themes related to disability are stigma, limited knowledge and awareness, poor quality of care and hindered employment opportunities. Further efforts are required to investigate the complexities of living with a disability in Cameroon and strategies to enhance adequate participation in activities of daily life. PMID- 28819496 TI - [Doctor, please look at my tongue!] PMID- 28819495 TI - Birth preparedness and complication readiness among pregnant women in Osogbo Metropolis, Southwest Nigeria. AB - INTRODUCTION: High maternal mortality is a major problem in Nigeria. Birth Preparedness and Complication Readiness will ensure that women can have professional delivery thus reducing obstetric complications. This study assessed the birth preparedness and complication readiness among pregnant women in Osogbo metropolis, a south western community in Nigeria. METHODS: A community based descriptive cross sectional survey was used. A total of 180 women were selected using multistage sampling technique. Pretested semi-structured interviewer administered questionnaires were used to elicit information about previous obstetric history, knowledge of the danger signs of pregnancy and level of birth preparedness. Composite score and mean were computed. Data analysis was done using Statistical Package for Social Sciences (SPSS) version 17. P-value was set at < 0.05. RESULTS: The mean age was 26.11 +/- 3.63 years. A total of 51.1% were carrying their 2nd or 3rdpregnancies. A total of 70.8% were aware of danger signs in pregnancy and the commonest danger sign mentioned was bleeding per vagina. In all, 82.1% were well prepared for birth. Being in the younger age group (p = 0.026), being more educated (p < 0.0001) and being aware of danger signs in pregnancy (p < 0.0001) was more significantly associated with being well prepared. CONCLUSION: The respondents were well prepared for birth with the younger women, educated ones and those knowledgeable of danger signs being better prepared. Continuous education about the Birth Preparedness and Complication Readiness should be sustained in order to maintain and improve women's preparedness. PMID- 28819497 TI - [Volvulus of the small intestine caused by mesenteric lipoma]. AB - We report the case of a 7-year old girl presenting with sub-occlusive syndrome associated with acute paroxysmal abdominal pain at the level of the upper abdomen, vomiting and no evacuation of faeces. Physical examination showed discomfort with palpation of the upper abdomen. Abdominal ultrasound showed poorly limited intraperitoneal tissue formation without vascular features on doppler, exercising a mass effect on the neighborhood structures; mesenteric vessels were in their normal position. This mass on CT scan scorresponded to a well limited lipomatous formation exercising a mass effect on the caecum associated with volvulus of the small intestine. The diagnosis of volvulus of the small intestine caused by mesenteric lipoma was retained. Surgical exploration confirmed this diagnosis. The patient underwent unrolling of the small intestine and lipoma enucleation. The postoperative course was uneventful after a follow-up of 6 months. Anatomo-pathological examination confirmed the lipomateuse nature of the mass. PMID- 28819498 TI - Why regulatory indifference towards pharmaceutical pollution of the environment could be a missed opportunity in public health protection. a holistic view. AB - The last generation has witnessed bludgeoning of the world's population, a spike in disease burden, and unprecedented levels of pharmaceutical consumption and production. Unfortunately, pharmaceuticals have left their industrial and household confines and leaked into the environment. Pharmaceuticals are now major environmental pollutants, and are ubiquitous in waters and soils. Unlike other environmental contaminants, pharmaceutical pollutants are not yet regulated globally, simply because acute risk assessments show insignificant human health hazard. But the pitfalls of pharmaceutical pollutants extend beyond acute effects to delayed effects from bioaccumulation, amplified effects from drug-drug interactions, exacerbation of drug resistance, and reduction in aquatic and terrestrial food production. Therefore, ignoring pharmaceutical pollutants deprives society of holistic public health protection. PMID- 28819499 TI - Multiple jejunal perforation secondary to intestinal tuberculosis infection: a case report. AB - Abdominal tuberculosis (TB) may affect any part of the gastrointestinal tract resulting in significant morbidity and mortality. There is an increase in the incidence of abdominal TB favored by the emergence of multi-drug resistant Mycobacterium tuberculosis and immunosuppression especially from HIV co infection. Our case is that of a 31 year old HIV-positive woman, adherent to antiretroviral therapy, who presented with a 2 month history of progressive abdominal distention, drenching night sweat and fatigue, but without fever. She was admitted on a presumptive diagnosis of peritoneal TB, and suddenly developed signs and symptoms of an acute abdomen. Laboratory investigations showed a CD4+ count of 155 cells/uL, white blood cell count of 15,700 cells/mm3 and haemoglobin of 8.0g/dl. An emergency laparotomy revealed small bowel caseous necrosis with multiple jejunal perforations. Ziehl-Nelsen staining of operative specimen was positive for acid fast bacilli. Given her immunodeficiency status, clinical signs and symptoms, CD4 cell count > 50 cells/uL, and intestinal sample showing caseous necrosis and perforations, a final diagnosis of intestinal TB was made. In conclusion, abdominal tuberculosis may mimic a number of intra-abdominal pathologies; thus should always be considered as a differential diagnosis in patients presenting with acute abdomen in TB-endemic areas especially in an HIV positive individual. PMID- 28819500 TI - [Parotid metastasis from carcinoma of the breast: report of a case and review of the literature]. AB - Parotid metastasis from carcinoma of the breast is very rare, only a few cases have been reported in the literature. We here report the case of a 43-year old patient treated for right breast cancer in whom left parotid metastasis (confirmed histologically) occurred two years after the end of the treatment. PMID- 28819501 TI - HIV-infected adolescents have low adherence to antiretroviral therapy: a cross sectional study in Addis Ababa, Ethiopia. AB - INTRODUCTION: For antiretroviral therapy (ART) to work effectively, adherence is very crucial. However, most studies done on ART adherence are either on children or on adults. There is limited information on the level of adherence among adolescents. METHODS: Using a cross-sectional study design, we interviewed 273 HIV-infected adolescents receiving ART from three hospitals in Addis Ababa. We used a structured questionnaire to measure adherence levels using patient self reports. Bivariate and multivariate methods were used for analysis. RESULTS: We interviewed 273 adolescents aged 13 to 19 years, and 144 (52.7%) of the participants were girls. Their mean age was 15.4 years (SD+/- 1.75). The self reported adherence rate of the respondents was 79.1% (216/273). On bivariate analysis, variables like WHO clinical stage, being on Cotrimoxazole Prophylactic Therapy (CPT), marital and living status of the parent, whether parent was on ART or not and having special instructions for ART medications were associated with optimum adherence. However of those, only WHO stage IV (adjusted OR, 12.874 95% CI, 2.079-79.706), being on CPT (adjusted OR, 0.339 95% CI, 0.124-0.97) and adolescents with widowed parent (adjusted OR, 0.087 with 95% CI, 0.021-0.359) were found to be significantly associated with optimum ART adherence. CONCLUSION: The level of self-reported ART adherence among HIV-infected adolescents at the three hospitals was below the recommended threshold. Though earlier presentation of adolescents to care should be encouraged, more targeted adherence support should be planned for those who present at an early stage of their illness. PMID- 28819502 TI - Pattern and outcome of dog bite injuries among children in Ado-Ekiti, Southwest Nigeria. AB - INTRODUCTION: Dog bites in humans are a major public health problem. Globally, millions of people are bitten by dogs but most of the fatal cases occur in children. There is paucity of data on dog bite related diseases among Nigerian children. Objectives: to determine the pattern of dog bite injuries and associated health problems among children seen at Ekiti State University Teaching Hospital. METHODS: This is a retrospective study on the clinical data of patients managed for dog bite related injuries between January 2010 and June 2014. RESULTS: In all, 84 cases of dog bite injuries were managed constituting 0.89% of the total consultations; six (7.1%) had rabies. Most of the victims were aged 6 12 years (60.7%) and majority (71.4%) was boys. Eighty two percent of the victims presented within 24hrs of the injury. Thirty-six (43%) had WHO grade 3 dog bite injury at presentation and the lower limb was the commonest (57.1%) bite site. Use of herbal preparation was the most common pre-hospital treatment 60%. Although 92.9% received anti-rabies vaccine, only 64.3% of them completed the vaccination schedule. The case fatality rate for dog bite was 7.14%. The six that died all presented late, had no post exposure prophylaxis and died within 24 hours of admission. CONCLUSION: There is need for public enlightenment on dangers associated with dog bites and also for the government to defray the high cost of post exposure prophylaxis treatment for children. PMID- 28819503 TI - [Neuroendocrine carcinoma of the cervix: a case report and review of the literature]. AB - Small cell neuroendocrine carcinomas of the gynecologic tract are unusual, accounting for only 2% of the cervical cancers. Given the rarity of these tumors and the absence of randomized trials, their diagnosis and treatment programmes are difficult and are essentially based on those of neuroendocrine tumors of the lung. As in the case of the neuroendocrine tumors of the lung and despite multimodal treatment they are associated with a poor prognosis. We here report a new case of small cell neuroendocrine carcinoma of the cervix and, throught a literature review, we highlight the various aspects of this rare entity. PMID- 28819504 TI - [Pink papule on the temple]. PMID- 28819505 TI - Use of validated community-based trachoma trichiasis (TT) case finders to measure the total backlog and detect when elimination threshold is achieved: a TT methodology paper. AB - INTRODUCTION: The World Health Organization recommends TT surveys to be conducted in adults aged 15+ years (TT 15 survey) and certifies elimination of TT as a public health problem when there is less than 1 unknown case per 1,000 people of all ages. There is no standard survey method to accurately confirm this elimination prevalence threshold of 0.1% because rare conditions require large and expensive prevalence survey samples. The aim of this study was to develop an accurate operational research method to measure the total backlog of TT in people of all ages and detect when the elimination threshold is achieved. METHODS: Between July to October 2016, an innovative Community-based, Mapping, Mop-up and Follow-up (CMMF) approach to elimination of TT as a public health problem was developed and tested in Esoit, Siana, Megwara and Naikara sub-locations in Narok County in Kenya. The County had ongoing community-based TT surgical camps and case finders. TT case finders were recruited from existing pool of Community health volunteers (CHV) in the Community Health Strategy Initiative Programme of the Ministry of Health. They were trained, validated and supervised by experienced TT surgeons. A case finder was allocated a population unit with 2 to 3 villages to conduct a de jure pre-survey census, examine all people in the unit and register those with TT (TT all survey). Identified cases were confirmed by TT surgeons prior to surgery. Operated patients were reviewed at 1 day, 2 weeks and 3-6 months. The case finders will also be used to identify and refer new and recurrent cases. People with other eye and medical conditions were treated and referred accordingly. Standardised data collection and computer based data capture tools were used. Case finders kept registers with details of all persons with TT, those operated and those who refused to be operated (refusals). These details informed decision and actions on follow-up and counselling. Progress towards achievement of elimination threshold was assessed by dividing the number of TT cases diagnosed by total population in the population unit multiplied by 1,000. RESULTS: Narok County Government adopted both the CMMF approach and TT all survey method. All persons in 4,784 households in the four sub-locations were enumerated and examined. The total population projection was 29,548 and pre survey census 22,912 people. Fifty-three cases of TT were diagnosed. The prevalence was 0.23% and this is equivalent to 2.3 cases per thousand population of all ages. Prior to this study, the project required to operate on at least 30 cases (excess cases) to achieve the elimination threshold of 1 case per 1000 population. CONCLUSION: The total backlog of TT was confirmed and the project is now justified to lay claim of having eliminated TT as a public health problem in the study area. TT all method may not be appropriate in settings with high burden of TT. Nomadic migrations affect estimation of population size. Non-trachomatous TT could not be ruled-out. PMID- 28819506 TI - [Parathyroid carcinoma: about a case and review of the literature]. AB - Parathyroid carcinoma is a very rare malignant tumor of the parathyroid gland. Clinically, this cancer is characterized by the presence of severe primary hyperparathyroidism. Diagnosis is based on histological examination but is not always easy. Surgery is the treatment of choice. We report the case of a 59-year old woman with a personal history of arterial hypertension and of recurrent renal lithiasis, presenting with diffuse bone pain associated with asthenia. Neck examination showed hard basi-cervical swelling with nonpalpable lower edge. Laboratory tests showed hypercalcaemia 4.1 mmol/l, hyperparathyroidism with very high parathyroid hormone (PTH) value (1088 pg/ml or 13 times normal). Technetium 99m-sestamibi scintigraphy showed fixed MIBI abnormality in the projection of the left inferior parathyroid. The patient underwent left inferior parathyroidectomy, with ipsilateral mediastinal-recurrent nerve dissection. The postoperative course was marked by normalization of plasma calcium and THP. Anatomopathological examination showed parathyroid carcinoma. The diagnosis of parathyroid carcinoma is generally based on the combination of biological, radiological and histological signs. The severity of this pathology is due to severe hypercalcaemia and to the risk of recurrence and distant metastases, justifying prolonged monitoring. PMID- 28819507 TI - Parry-romberg syndrome: about a case. PMID- 28819508 TI - Perceived risk of reinfection among individuals treated for sexually transmitted infections in Northern Ethiopia: implication for use in clinical practice. AB - INTRODUCTION: The prevention of reinfection of sexually transmitted infections (STIs) is highly dependent on the level of risk perception and the subsequent adoption of preventive behaviors. While perceived risk is assumed to be key to adoption of preventive measures, the evidence regarding the predictors of perceived risk to STI reinfection are limited. METHODS: This paper is based on a cross sectional facility based survey conducted in North Ethiopia from January to June; 2015. Patients attending public health facilities for STI care responded to a structured questionnaire at clinic exist. Ordinal logistic regression was employed to identify factors associated with risk perception. RESULTS: Of the 1082 STI patients who participated in the study, 843(77.91%) indicated a high perceived risk of STI reinfection. The major factor associated with low perceived risk of reinfection was willingness to notify partner; the odds of being willing to notify partner was greater among those who perceived low risk (AOR=3.01, 95% CI: 2.13-4.25). In addition, low perceived risk was associated with female index cases (AOR=1.49, 95% CI: 1.07-2.08), those who had high school education and above (AOR=1.68, 95% CI: 1.07-2.65), those aged 25 years and above (AOR=1.52, 95% CI: 1.09-2.12), those who had a single partner (AOR=1.82, 95% CI: 1.20-2.74), and those who had low perceived stigma (AOR=1.42, 95% CI: 1.04-1.95). CONCLUSION: The perceived risk of STI reinfection is high and strongly associated with willing to notify partner. Efforts to prevent STI reinfection need to consider interventions that enhance partner notification. PMID- 28819509 TI - Prevalence and intensity of soil transmitted helminths among school children of Mendera Elementary School, Jimma, Southwest Ethiopia. AB - INTRODUCTION: Soil transmitted helminths are wide spread in developing countries and in Ethiopia the prevalence of STHs varies in different parts of the country. The aim of this study was to determine the prevalence and intensity of soil transmitted helminths among school children of Mendera Elementary School Jimma town, Southwestern Ethiopia. METHODS: A cross-sectional study was conducted between March 29 and April 9, 2010 to determine the prevalence and intensity of soil transmitted helminths among elementary school children. The study participants were randomly selected from class enrollment list after proportional allocation of the total sample size to each grade. Data about the background characteristics were collected using structured questionnaire. The stool samples were examined by McMaster method for the egg count which was used to determine intensity of infection. Data were analyzed using SPSS for windows version 16 and p-value less than 5% was considered as statistically significant. RESULTS: Of the total 715 stool specimens examined, 346 were positive for at least one intestinal parasite making the prevalence 48.4%. The most prevalent parasites were Ascaris lumbricoides 169 (23.6%) and Trichuris trichiura 165 (23.1%). The prevalence of soil transmitted helminth in this study was 45.6% (326/715). There was statistically significant difference in the prevalence of Trichuriasis between those who use latrine always and who use sometimes (p = 0.010). Females are two times more likely to be positive for Ascaris than males (p = 0.039). Majority of the students had light infection of soil transmitted helminths and none of them had heavy intensity of infection of Trichuriasis and hookworms. CONCLUSION: Nearly half of the school children were infected with at least one STHs and majority of the students had light infection of soil transmitted helminths. Students who did not wash their hands after defecation were three times more likely to be positive for Ascaris infection than those who washed their hands after defecation. Therefore, measures like health information dissemination on the advantage of washing hands after defecation and on proper use of latrine should be taken into account to alleviate the problem. PMID- 28819510 TI - Leucocytoclastic vasculitis due to Oxicam. PMID- 28819511 TI - Male partner involvement in the prevention of mother to child transmission of HIV infection in Mwanza Region, Tanzania. AB - INTRODUCTION: Globally, there are 3.3 million children < 15 years of age living with HIV infection. About 95% of HIV infected children have acquired infection from their mothers. Although new pediatric HIV infection in Tanzania has declined by 48% and Prevention of Mother to Child Transmission (PMTCT) coverage of highly active anti-retroviral therapy (HAART) has increased to 77%, the MTCT rate remains high (15%). Poor male partner involvement in PMTCT services is one of the factors contributing to reduced effectiveness of the PMTCT and hence failure to achieve the elimination of maternal to child transmission of HIV. This study examined the predictors of male involvement in PMTCT services in Mwanza Region, Tanzania from perspectives of the mother. METHODS: A cross sectional study involving selected health facilities was conducted in Mwanza urban from October 2013 through January 2014. HIV positive pregnant women attending ante-natal clinic (ANC) were interviewed using a semi structured questionnaire. Univariate analysis was used to describe the study respondents where bivariate and logistic regression was used to determine predictors of male involvement. RESULTS: A total of 300 HIV positive mothers attending ANC with the mean age of 27.5 + 5.6 were interviewed. Few mothers (24.7%) had their male partners involved in PMTCT. Predictors of male partner involvement in PMTCT were mothers being proactive (Adjusted Odds Ratio (AOR) 28.6; Confidence Interval (CI) 7-116), perceived partners knowledge on PMTCT (AOR 24.6, CI 5.9-102.8), exposure to TV/Radio announcements on PMTCT (AOR 4.6, CI 1.5-14) and married status of the mother (AOR 3.7, CI 1.5-9). Mothers who never wanted to be escorted by their male partners and busy partners were associated with reduced odds of male involvement into PMTCT (AOR 0.07, CI 0.007-0.68) and (AOR 0.46 CI 0.21-0.99) respectively. Male partner involvement was associated with 98% reduced odds of violence (Crude Odds Ratio 0.018 CI 0.002-0.14). CONCLUSION: Male partner involvement in PMTCT is still low in Mwanza Region. Proactive mothers, partner's knowledge on PMTCT and announcements from television/radio were the major facilitating factors for male involvement in PMTCT as perceived by mothers. Busy male partners and mothers who did not want to be escorted by their partners were a hindrance to male involvement in PMTCT services. These factors highlight the importance of women role in promotion of PMTCT male involvement. PMID- 28819512 TI - [Spontaneous bilateral carotid-cavernous fistulas: about a case and review of the literature]. AB - We report a clinical case of spontaneous bilateral carotid-cavernous fistulas. Bilateral pulsatile exophthalmos and symmetric cavernous sinuses detected by CT scan helped to suspect the diagnosis. Arteriography confirmed the diagnosis. The patient underwent embolization with favorable neurologic and ophthalmic evolution. Carotid-cavernous fistula is a rare but severe complication associated with a poor functional (blindness) and vital (meningeal and intracerebral hemorrhage) prognosis. The concomitant use of arteriography and embolization has considerably improved the prognosis. PMID- 28819513 TI - Strengthening and expanding the capacity of health worker education in Zambia. AB - INTRODUCTION: Zambia is facing a chronic shortage of health care workers. The paper aimed at understanding how the Medical Education Partnership Initiative (MEPI) program facilitated strengthening and expanding of the national capacity and quality of medical education as well as processes for retaining faculty in Zambia. METHODS: Data generated through documentary review, key informant interviews and observations were analyzed using a thematic approach. RESULTS: The MEPI program triggered the development of new postgraduate programs thereby increasing student enrollment. This was achieved by leveraging of existing and new partnerships with other universities and differentiating the old Master in Public Health into specialized curriculum. Furthermore, the MEPI program improved the capacity and quality of training by facilitating installation and integration of new technology such as the eGranary digital library, E-learning methods and clinical skills laboratory into the Schools. This technology enabled easy access to relevant data or information, quicker turn around of experiments and enhanced data recording, display and analysis features for experiments. The program also facilitated transforming of the academic environment into a more conducive work place through strengthening the Staff Development program and support towards research activities. These activities stimulated work motivation and interest in research by faculty. Meanwhile, these processes were inhibited by the inability to upload all courses on to Moodle as well as inadequate operating procedures and feedback mechanisms for the Moodle. CONCLUSION: Expansion and improvement in training processes for health care workers requires targeted investment within medical institutions and strengthening local and international partnerships. PMID- 28819514 TI - [Fortuitous detection of composite heterozygous S/C sickle cell disease]. AB - Composite S/C sickle cell disease accounts for 20%-30% of major sickle cell syndromes. We report a case of fortuitous detection of composite heterozygous S/C sickle cell disease in the context of retinal detachment. The patient had been hospitalized in the Department of Ophthalmology for treatment-resistant decreased visual acuity detected 06 months before. The patient's clinical history was marked by total hip replacement (THR) twelve years before. Our study highlights the wide clinical variability of sickle cell disease underlying the importance of early screening and adapted clinical monitoring of patients at-risk, in order to avoid its evolution toward irreversible organic sequelae such as sickle cell retinopathy. PMID- 28819515 TI - ? PMID- 28819516 TI - A severed IP ligament as a cause for trans-vaginal uterine bleeding post termination of pregnancy: a case report. AB - Uterine perforation is an uncommon yet serious complication of surgical management of first and second trimester termination of pregnancies. The rate of uterine perforation is under reported, as patients are usually asymptomatic. Although uncommon, uterine perforation can cause life-threatening complications for some patients. This case report discusses a second trimester surgical termination resulting in uterine perforation and haemorrhage secondary to an avulsion of the infundibulopelvic ligament and prolapse of the left fallopian tube and ovary into the uterine cavity. A literature search was undertaken to compare this case report to those previously published. To the best of our knowledge, this is the first case report in Australia that discusses a unique case of a severed infundibulo-pelvic ligament as a cause for trans-vaginal uterine bleeding post second trimester termination of pregnancy. PMID- 28819517 TI - Dental, dermatological and radiographic findings in a case of Gorlin-Goltz Syndrome: report and review. AB - Gorlin-Goltz syndrome (GGS) is a rare autosomal dominant disorder. The disease shows multiple organ involvement with variable clinical presentation. Thus a multidisciplinary approach is required for its prompt clinical diagnosis and management of this condition. This paper highlights a case of GGS presenting in a young male patient with cranial, facial, dermatological, dental and skeletal involvement. The diagnosis of the syndrome was based on its clinical presentation, radiological features and histopathological findings. A review of the diagnostic criteria is also presented. PMID- 28819518 TI - [A rare case of giant galactocele associated with prolactinoma]. AB - Galactocele is a rare cystic formation, a benign breast lesion, occurring when breast duct is blocked and engorged. It generally affects postpartum women, either breastfeeding or not. Only a few cases have been reported in the literature and they were not related to lactation, as in the case of postmenopausal women or of men; moreover, their relationship to the overproduction of prolactin, a growth factor stimulating mammary epithelial cells, is not very well defined at this time. We here report the unusual case of a 30-year old patient with no personal history of childbirth or abortion. She was treated in the Division of Endocrinology for pituitary microadenoma with Cabergoline, that she stopped for 1 year. Even taking into account this rare association, it is important to emphasize the role of hormones in the progression of breast anatomy. PMID- 28819519 TI - Simultaneous ipsilateral fractures of distal and proximal ends of the radius. AB - We treated a patient with a rare combination of ipsilateral fractures of the distal and proximal ends of the radius. A man aged 42 years had simultaneous fractures of the distal and proximal ends of the radius (radial neck) following a roadside accident. The distal end fracture of the radius was treated with surgical reduction and T-plate volar fixation, and the undisplaced radial neck fracture was treated by an above elbow splintage for 2 weeks. The elbow mobilization was started at 2 weeks. The distal radius was protected for another 4 weeks in a below elbow functional brace. Ipsilateral proximal and distal radial fracture is an uncommon injury pattern. The series illustrates a number of problems associated with this combination. Firstly, one should be aware of this rare injury pattern and there should be greater emphasis on clinical examination of elbow in cases of wrist injuries and vice versa. Once diagnosed, one faces the dilemma of appropriate management in these cases. The appropriate management will depend on the injury characteristics including the age of the patient and the fracture pattern. One should try to preserve the radial head to prevent a possible proximal radial migration especially in younger patients. PMID- 28819520 TI - The ban on blood donation on men who have sex with men: time to rethink and reassess an outdated policy. AB - During the 1980s the HIV/AIDS epidemic outbreak occurred. Due to the high prevalence of the disease on men who had sex with men (MSM) a lifetime ban on blood donations on men who had sex with men (MSM) was implemented. In the recent years, organizations like the European Union (EU) and the World Health Organization (WHO) have established new guidelines introducing the term of "risky sexual behavior" without any reference to the sex orientation of the potential donor, however many countries are hesitant to review the ban on men who had sex with men (MSM). Given the lack of screening methods for HIV back in the '80s the ban on men who had sex with men seemed like the only choice in order to limit the disease. However, nowadays the screening methods have advanced and the possibility of a transfusion related HIV infection is extremely low. Many countries, considering the new data available, have reformed their policies and moved from the lifetime ban to 5-year and 1-year deferrals but only a fraction of countries have adopted the guidelines for the "risky sexual behavior" assessment. The ban that forbid men who have sex with men from donating blood was implemented more than 30 years ago. During the '80s, the epidemiology was different and it seems not only hypocritical but also naive to rely on guidelines that are far outdated and old-fashioned. The medical community has a duty to secure safe blood for every person who might need it, let us not waste safe potential donors and stigmatize them by focusing on outdated policies. PMID- 28819521 TI - Boerhaave's syndrome: food particles in chest tube. PMID- 28819522 TI - [Metastatic paratesticular liposarcoma]. AB - We report the dramatic case of a 18-year old patient with immediately metastatic round cells paratesticular liposarcoma. It is a rare tumor that develops in the fatty tissue surrounding the testicle and the spermatic cord. Clinical and radiological signs are nonspecific and diagnosis is usually based on surgical specimen examination. The treatment involves radical inguinal orchiectomy, sometimes extended to adjacent structures. Adjuvant radiation therapy could be used in the case of locally advanced mass or incomplete resection. Despite its slow progression, prolonged monitoring is required due to the high risk of late recurrence. PMID- 28819523 TI - [Cutaneous tuberculosis in Bamako, Mali]. AB - INTRODUCTION: Tuberculosis is the most common mycobacteriosis in sub-Saharan Africa. Cutaneous tuberculosis is rare and underdiagnosed due to its clinical polymorphism and to the smallness of technical equipment. This study aims to describe the epidemiological, clinical, histopathological aspects of cutaneous tuberculosis in Bamako (Mali). METHODS: We conducted a cross-sectional descriptive study from January 1991 to December 2008. The study was performed in the Department of Dermatology at the National Center for Disease Control and in the Department of Pneumophtisiology at the Hospital of Point G. The patients with tuberculosis confirmed by histological and/or biological examination were included in the study. RESULTS: Out of 4269 patients? medical records, 61 cases of cutaneous tuberculosis were identified (1.43%). Men accounted for 59% of the cases (36 patients) and women 41% (25 cases); sex-ratio was 1.44. The age of the patients ranged from 3 months to 61 years, with an average age of 27.56 +/- 36 years. The average length of follow-up was 10.9 +/- 10 months. The identified clinical forms were scrofuloderma (41 cases), ulcerative form (13 cases), verrucous form (4 cases), and tuberculous Lupus (3 cases). Tuberculosis was associated with HIV in 7 cases, with leprosy in 3 cases. CONCLUSION: Cutaneous tuberculosis is underdiagnosed in Mali. Efforts are needed to improve the accessibility and the technical equipment available in the Departments, in order to conduct an extensive interdisciplinary study on this pathology. PMID- 28819524 TI - Impact of vaccine mandate on Tdap vaccination coverage among Illinois students 2014-15. AB - In response to recent pertussis resurgence, a multi-agency recommendation that students receive a one-time Tdap vaccine was introduced. Post mandate there was sequential increase in the Tdap vaccine uptake in the targeted population. PMID- 28819525 TI - Digital ischemia and tobacco. PMID- 28819526 TI - [Bilateral three-level lumbar spondylolysis]. PMID- 28819527 TI - [Evaluation of the compliance rate of partograph use in a Tunisian Maternity ward: a targeted clinical audit]. AB - Partograph is an essential tool in routine delivery room practices. It is a written reflection of the quality of mother and child health management during delivery and in the immediate post-partum period. Our study aims to assess compliance rate of partograph use within our maternity ward and to propose areas for improvement of its quality. We conducted a retrospective clinical audit of 400 patients? medical records who gave birth on the labour ward at University of Kairouan from 1 January to 31 December 2014. The reference guidelines used were those from the French Health High Authority (2006) containing 29 criteria divided into 3 categories (PARTOten, PARTOobs, PARTOeve). The overall compliance rate (OCR) of partograph use in our audit was 55.9%. With regard to the first area, such as " La tenue du partogramme " (partograph use, PARTOten) the overall compliance rate was 88, 9%. With regard to the second area, such as " la tracabilite du deroulement du travail " (track labor progression, PARTOobs) the overall compliance rate was 51, 4%. With regard to the third area, such as " la tracabilite des actes, des evenements et des traitements au cours du travail " (the tracing of actions, events and treatments during labor, PARTOeve) the overall compliance rate was 27.4%. Our study has helped identify several areas for improvement. The ultimate goal of this clinical audit was the improvement of professional practices. Therefore, we implemented an action plan (training, awareness raising?) followed by a review aimed to verify the continuity of the corrective actions. PMID- 28819528 TI - [Parietal tuberculosis complicated by pulmonary embolism]. AB - Tuberculosis is a frequent infectious disease in developing countries. It can affect the lung or spread to other parts of the body. Extra-pulmonary tuberculosis poses a major diagnostic problem. We report the case of a patient with pulmonary embolism revealing parietal tuberculosis. This study emphasizes the importance of etiologic assessment in patients with pulmonary embolism. PMID- 28819529 TI - [Epidemiological profile of maternal complications related to cesarean section at the Al Farabi Hospital in Oujda]. AB - In Morocco cesarean section rate has increased from 2% in 1992 to 16% in 2011. This was associated with increased per- and postoperative mortality and morbidity, which was 19% in our case series. This study is the first of its kind to be conducted in the eastern region of Morocco and aims to analyze the comprehensive epidemiologic profile of maternal complications related to cesarean section on the basis of 2417 cases observed in the Maternity Department at the El Farabi Hospital, Oujda. We conducted an observational, descriptive, retrospective study of a series of 2416 patients undergoing cesarean section in the Maternity Department at the El Farabi Hospital, Oujda, over the period 1 January 2011-31 December 2013. Out of 24464 deliveries, 2416 were cesarean sections, reflecting a rate of 9.87%. The frequency of complications related to cesarean section was 19.45%. Postoperative complications accounted for 63.6% of the complications dominated by infection. Haemorrhagic complications accounted for 25.53% of all complications. 4 cases of maternal deaths were recorded. If the increased rate of cesarean sections has contributed to improve maternal-fetal prognosis, the surgical act itself is not complication-free, which leads us to review its indications for improved patient management. PMID- 28819530 TI - Assessment of sphenoid sinus related anatomic variations with computed tomography. AB - INTRODUCTION: Frequent and broad application of endoscopic sinus surgery (ESS) in parallel with experience makes it imperative to know the anatomy and the existing pathology very well before surgery. This study examines the association between anomalies in the sphenoid sinus area in paranasal sinuses computed tomography (PNS-CT) and pathological findings and determines variations of sphenoid sinus. METHODS: A total of 200 cases (100 women, 100 men) who had PNS-CT in the emergency and radiology polyclinics within the period of one year were included in this study. Bone tissue anomalies and soft tissue pathologies were assessed in the CT. RESULTS: Pterygoid process was found in 36.75% of our cases, anterior clinoid pneumatization was found in 21.25%; vidian canal in 34.25%, foramen rotundum in 17.5% and ICA in 12.75% had protrusion into the sphenoid sinus; 8.25% were found to have onodi cell, 11.25% were found to have multiple septation, 16.75% were found to have mucosal thickening and 2.5% were found to have retention cyst. CONCLUSION: The importance of PNS-CT in terms of determining anatomic variations before ESC and predicting possible complications during surgery has been emphasized once more. In our study, as sphenoid sinus pneumatization increased, the projection of neighbouring vein and nerve structures into the sinus was found to increase as well. PMID- 28819531 TI - Dermoscopy of pyogenic granuloma. PMID- 28819532 TI - A case of enterobiasis presenting as post-traumatic-stress-disorder (PTSD): a curious case of the infection with predominant mental health symptoms, presenting for the first time in the settings of a refugee camp. AB - Enterobiasis (oxyuriasis) is a common infection in human caused by Enterobius vermicularis (E. vermicularis), a human intestinal helminth. Because of the easy way of its transmission among people, it has an extremely high prevalence in overcrowded conditions, such as nurseries and primary schools. Oxyuriasis's symptoms are extremely diverse in children, ranging from nausea, diarrhea, insomnia, irritability, recurrent cellulitis, loss of appetite, nightmares and endometritis. Here we report a curious case of oxyuriasis in the settings of a refugee camp in Greece. The patient was a 10-year old Syrian female, who presented with unusual and vague symptoms like insomnia and irritability. Given the violent background of the Syrian warzone that the patient had escaped, she was firstly diagnosed with post traumatic stress disorder (PTSD) before eventually getting correctly diagnosed with enterobiasis. This infection is the first documented case of enterobiasis in the settings of a refugee camp and can highlight the unsanitary living conditions that refugees have to endure in those camps. PMID- 28819533 TI - Catamenial pneumothorax revealing diaphragmatic endometriosis: a case report and revue of literature. AB - Catamenial pneumothorax (CP) is a rare entity of spontaneous, recurring pneumothorax in women. We aim to discuss the etiology, clinical course, and surgical treatment of a 42-year-old woman with CP. This patient had a right-sided spontaneous pneumothoraces occurred one week after menses. She had under-gone video-assisted thoracoscopic surgery (VATS) because of a persistent air leak under chest tube. VATS revealed multiple diaphragmatic fenestrations with an upper right nodule. Defects were removed and a large part of the diaphragm was resected. Pleural abrasion was then performed over the diaphragm. Diaphragmatic endometriosis was confirmed by microscopic examination. Medical treatment with GnRH agonists was prescribed, and after recovery, the patient has been symptoms free for 20 months. PMID- 28819534 TI - [Essential bone cyst involving the calcaneus detected during ankle sprain imaging examination: risk of progression and management]. PMID- 28819535 TI - Clinical features and antinuclear antibodies profile among adults with systemic lupus erythematosus and lupus nephritis: a cross-sectional study. AB - INTRODUCTION: Limited data is available regarding the clinical manifestations and pattern of Systemic Lupus Erythematosus (SLE) in Sudan. This study aimed to determine the clinical manifestations and Antinuclear Antibodies (ANA) profile among Sudanese adults with SLE and lupus nephritis (LN). METHODS: A descriptive study was conducted in Omdurman Military Hospital, Sudan. It included all adults with SLE and on regular follow-up during the study period (December 2012 to May 2013). These were investigated regarding their demographic details, clinical features, and immunological profile (ANA, anti-double stranded DNA, and ANA profile 3 levels). Patients with LN had their pattern of renal involvement described; furthermore, associations between the various SLE reactive antibodies and the histological diagnosis of lupus were studied. RESULTS: Sixty-two Sudanese adults with SLE were included, their mean age was 31 +/- 10.9 year. Females made 93.5% of patients. A clear predominance of those of Arab ancestry was seen, with most patients being from the Ja'alin and Shaigiya ethnic groups accounting for 29% and 12.9%, respectively. Arthritis was the dominant clinical manifestation seen in 85.5%, whereas renal involvement was seen in 66.1% of patients. Lupus nephritis class III was the dominant histological lesion, seen in 39% of patients. On correlating the ANA profile to the histopathological diagnosis of LN, anti-Nucleosomes and anti-AMA-M2 autoantibodies were found to be significantly associated with LN class IV and class VI, respectively (P values < 0.05). CONCLUSION: Further epidemiological studies regarding SLE and its ANA profile remain essential as they might help predicting the clinical patterns of the disease and its prognosis. PMID- 28819536 TI - [Aneurysmal bone cyst of the clavicle: about a case]. AB - Anevrysmal bone cyst is an aggressive, destructive but benign lesion in the long bones, spine or basin, affecting mainly children and young adults. However, it is a very rare tumor. We here report the case of a 8-year old boy with a very rare localization of anevrysmal cyst in the clavicle, initially presenting with pathologic bone fracture, that is a benign cystic lesion. The child underwent complete radical resection of the cyst located at the level of the right clavicle, followed by anatomopathological examination of surgical specimen which confirmed the diagnosis. Patient's evolution was marked by the absence of recurrences and by good radiologic bone remodeling. Radical cyst resection seems to avoid recidivism. This study aims to update the current understanding of this rare orthopaedic condition by comparing our results with those reported in the world literature. PMID- 28819538 TI - [Secondary hypertrophic osteoarthropathy (HOA) or Pierre-Marie Bamberger syndrome revealing bronchial adenocarcinoma]. PMID- 28819537 TI - [NOD2 gene mutation in Moroccan patients with Crohn's disease: prevalence, genotypic study and correlation of NOD2 gene mutation with the phenotype of Crohn's disease]. AB - The aim of this study was to determine the prevalence of NOD2/CARD15 gene mutations in a group of Moroccan patients with Crohn's disease and to study its correlation with genotype-phenotypic expression. We conducted a cross-sectional case-control study over a period of 16 months. 101 patients with Crohn's disease were enrolled between January 2012 and April 2013 as well as a control group of 107 patients. We performed a genetic analysis to identify 3 NOD2 gene variants: p.Arg702Trp, p.Gly908Arg and p.Leu1007fsins. Then we conducted a study of the correlation between genotype and phenotypic expression. The genetic analysis of patients with Crohn's disease highlighted the presence of NOD2 mutation in 14 patients (13.77%) versus 7 patients (6.53%) in the control group. The study of the frequency of different alleles showed p.Gly908Arg mutation in 6.43%, p.Leu1007fsins in 0.99% and p.Arg702Trp in 0.49% versus 2.80%, 0% and 0.46% in the control group respectively. The study of the correlation between genotype and phenotypic expression showed that CARD15 mutation is associated with ileocecal Crohn's disease, with fistulizing and stenosing behavior in Crohn's disease as well as with severe evolution and frequent recourse to surgery and immunosuppressants. The prevalence of NOD2/ CARD15 mutation in our case series is low. This mutation is correlated with severe Crohn's disease. PMID- 28819539 TI - [Plastic repair of tricuspid valve: Carpentier's ring annuloplasty versus De VEGA technique]. AB - Tricuspid valve disease has been neglected for a long time by cardiologists and surgeons, but for some years now leakage of tricuspid valve has been demonstrated as a prognostic factor in the evolution of patients with left heart valve disease undergoing surgery. Several techniques for plastic repair of tricuspid valve have been developed and the published studies differ on the results of these techniques; we conducted this study to assess the results of plastic repair of tricuspid valve in a population of patients with a high prevalence of rheumatic disease and to compare Carpentier's ring annuloplasty techniques with DEVEGA plasty. We conducted a retrospective study of patients undergoing plastic repair of tricuspid valve in the Department of Cardiology at the Medicine University of Sfax over a period of 25 years. We compared the results from the Group 1 (Carpentier's ring annuloplasty) with Group 2 (DeVEGA plasty). 91 patients were included in our study, 45 patients in the Group 1 and 46 patients in the Group 2. Most patients had mean or severe TI (83%) before surgery, ring dilation was observed in 90% of patients with no significant difference between the two groups. Immediate results were comparable between the two techniques but during monitoring recurrent, at least mean, insufficiency was significantly more frequent in the DeVEGA plasty Group. The predictive factors for significant recurring long term TI were DeVEGA technique (OR=3.26[1.12-9.28]) in multivariate study and preoperative pulmonary artery systolic pressure (OR=1.06 (1.01-1.12)). Plastic repair of tricuspid valve using Carpentier's ring seems to guarantee better results than DeVEGA plasty. On the other hand, preoperative high PASP is predictive of recurrent leakage of tricuspid valve even after plasty; hence the importance of surgery in the treatment of patients at an early stage of the disease. PMID- 28819540 TI - Use of Global initiative for asthma (GINA) guidelines in asthma management among paediatric residents in a Sub Saharan African country: a cross-sectional descriptive study. AB - INTRODUCTION: Clinical practice guidelines are systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances. Despite abundance of asthma guidelines, prevalence has continued to increase globally. There is need to assess how the contents of asthma guidelines are put to clinical use by doctors in the management of children with asthma. This study aims at evaluating the clinical practice of paediatric residents in applying GINA guidelines. METHODS: Cross sectional descriptive study of paediatric residents from 23 university teaching hospitals in Nigeria using structured questionnaire. Data analyses were with Statistical Package for Social Sciences (SPSS) version 19 (Chicago IL). Chi square was used to assess for any significant associations between categorical variables. A p < 0.05 was regarded to be statistically significant. RESULTS: Sixty-six paediatric residents aged 27- 40 years were enrolled into the study (37 females and 29 males). One-third had spent more than three years in residency training. Fifty-eight residents (87.9%) were aware of the GINA guidelines while 46 (69.7%) were familiar with its contents. Only 39 (59.1%) residents adhered to the GINA guidelines. Twenty of the 35 junior residents (57.1%) compared to 26 of 31 (83.9%) senior residents were familiar with the GINA guidelines (p=0.031) while 15 of 35 junior residents (42.9%) compared to 24 of 31 senior residents (77.4%) consistently follow the GINA guidelines (p=0.006). Adherence to GINA guidelines was not influenced significantly by years of graduation or training (p>0.05). CONCLUSION: The use of the GINA guidelines was poor among paediatric residents. Application of contents rather than just availability of asthma guidelines may partly account for increasing asthma prevalence globally. PMID- 28819541 TI - Mortality among 5-17 year old children in Kenya. AB - INTRODUCTION: Global mortality trends have changed over time and are expected to continue changing with a reduction in communicable diseases and an increase of non-communicable disease. Increased survival of children beyond five years may change mortality patterns for these children. There are few studies in Africa that explore the causes of mortality in children over five years. The objective of this study was to determine the mortality rate and clinical profiles of children aged 5-17 years who died in six Kenyan hospitals in 2013. METHODS: Retrospective review of patients' medical records to abstract data on diagnosis for those who died in year 2013. Data was analysed to provide descriptive statistics and explored differences in mortality rates between age groups and gender. RESULTS: We retrieved 4,520 patient records. The in-hospital mortality rate was 3.5% (95%CI 3.0-4.1) with variations in deaths between the ages and gender. Among the deaths, 60% suffered from communicable diseases, maternal and nutritional causes; 41.3% suffered from non-communicable diseases. A further 11.9% succumbed to traumatic injuries. The predominant clinical diagnoses among patients who died were HIV/AIDS, respiratory tract infections and malaria. CONCLUSION: Infectious causes had the highest proportion of diagnoses among children aged 5-17 years who died. PMID- 28819542 TI - Mulberry Fruit Extract Affords Protection against Ethyl Carbamate-Induced Cytotoxicity and Oxidative Stress. AB - Ethyl carbamate (EC) is a food and environmental toxicant and is a cause of concern for human exposure. Several studies indicated that EC-induced toxicity was associated with oxidative stress. Mulberry fruits are reported to have a wide range of bioactive compounds and pharmacological activities. The present study was therefore aimed to investigate the protective property of mulberry fruit extract (MFE) on EC-induced cytotoxicity and oxidative stress. Chemical composition analysis showed that total phenolic content and total flavonoid content in MFE were 502.43 +/- 5.10 and 219.12 +/- 4.45 mg QE/100 g FW. Cyanidin 3-O-glucoside and cyanidin-3-O-rutinoside were the major anthocyanins in MFE. In vitro antioxidant studies (DPPH, ABTS, and FRAP assays) jointly exhibited the potent antioxidant capacity of MFE. Further study indicated that MFE protected human liver HepG2 cells from EC-induced cytotoxicity by scavenging overproduced cellular ROS. EC treatment promoted intracellular glutathione (GSH) depletion and caused mitochondrial membrane potential (MMP) collapse, as well as mitochondrial membrane lipid peroxidation, whereas MFE pretreatment significantly inhibited GSH depletion and restored the mitochondrial membrane function. Overall, our study suggested that polyphenolic-rich MFE could afford a potent protection against EC induced cytotoxicity and oxidative stress. PMID- 28819543 TI - Diosmin Attenuates Methotrexate-Induced Hepatic, Renal, and Cardiac Injury: A Biochemical and Histopathological Study in Mice. AB - The current study was designed to investigate the beneficial role of diosmin, a biologically active flavonoid, against methotrexate- (MTX-) induced hepatic, renal, and cardiac injuries in mice. Male Swiss albino mice received a single intraperitoneal injection of MTX (at 20 mg/kg, body weight) either alone or in combination with oral diosmin (at 50 or 100 mg/kg body weight, for 10 days). Serum was used to evaluate tissue injury markers, while hepatic, renal, and cardiac tissue samples were obtained for determination of antioxidant activity as well as histopathological examination. Diosmin treatment ameliorated the MTX induced elevation of serum alkaline phosphatase, aminotransferases, urea, creatinine, lactate dehydrogenase, and creatine kinases as well as plasma proinflammatory cytokines (interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha). Additionally, both diosmin doses significantly reduced tissue levels of malondialdehyde and nitric oxide and increased those of glutathione, glutathione peroxidase, glutathione reductase, glutathione S-transferase, superoxide dismutase, and catalase, compared to the MTX-intoxicated group. Histopathological examination showed that diosmin significantly minimized the MTX induced histological alterations and nearly restored the normal architecture of hepatic, renal, and cardiac tissues. Based on these findings, diosmin may be a promising agent for protection against MTX-induced cytotoxicity in patients with cancer and autoimmune diseases. PMID- 28819544 TI - Hypoxia Downregulates MAPK/ERK but Not STAT3 Signaling in ROS-Dependent and HIF-1 Independent Manners in Mouse Embryonic Stem Cells. AB - Hypoxia is involved in the regulation of stem cell fate, and hypoxia-inducible factor 1 (HIF-1) is the master regulator of hypoxic response. Here, we focus on the effect of hypoxia on intracellular signaling pathways responsible for mouse embryonic stem (ES) cell maintenance. We employed wild-type and HIF-1alpha deficient ES cells to investigate hypoxic response in the ERK, Akt, and STAT3 pathways. Cultivation in 1% O2 for 24 h resulted in the strong dephosphorylation of ERK and its upstream kinases and to a lesser extent of Akt in an HIF-1 independent manner, while STAT3 phosphorylation remained unaffected. Downregulation of ERK could not be mimicked either by pharmacologically induced hypoxia or by the overexpression. Dual-specificity phosphatases (DUSP) 1, 5, and 6 are hypoxia-sensitive MAPK-specific phosphatases involved in ERK downregulation, and protein phosphatase 2A (PP2A) regulates both ERK and Akt. However, combining multiple approaches, we revealed the limited significance of DUSPs and PP2A in the hypoxia-mediated attenuation of ERK signaling. Interestingly, we observed a decreased reactive oxygen species (ROS) level in hypoxia and a similar phosphorylation pattern for ERK when the cells were supplemented with glutathione. Therefore, we suggest a potential role for the ROS dependent attenuation of ERK signaling in hypoxia, without the involvement of HIF 1. PMID- 28819545 TI - Circulating miRNAs in Pediatric Pulmonary Hypertension Show Promise as Biomarkers of Vascular Function. AB - BACKGROUND/OBJECTIVES: The objective of this study was to evaluate the utility of circulating miRNAs as biomarkers of vascular function in pediatric pulmonary hypertension. METHOD: Fourteen pediatric pulmonary arterial hypertension patients underwent simultaneous right heart catheterization (RHC) and blood biochemical analysis. Univariate and stepwise multivariate linear regression was used to identify and correlate measures of reactive and resistive afterload with circulating miRNA levels. Furthermore, circulating miRNA candidates that classified patients according to a 20% decrease in resistive afterload in response to oxygen (O2) or inhaled nitric oxide (iNO) were identified using receiver-operating curves. RESULTS: Thirty-two circulating miRNAs correlated with the pulmonary vascular resistance index (PVRi), pulmonary arterial distensibility, and PVRi decrease in response to O2 and/or iNO. Multivariate models, combining the predictive capability of multiple promising miRNA candidates, revealed a good correlation with resistive (r = 0.97, P2-tailed < 0.0001) and reactive (r = 0.86, P2-tailed < 0.005) afterloads. Bland-Altman plots showed that 95% of the differences between multivariate models and RHC would fall within 0.13 (mmHg-min/L)m2 and 0.0085/mmHg for resistive and reactive afterloads, respectively. Circulating miR-663 proved to be a good classifier for vascular responsiveness to acute O2 and iNO challenges. CONCLUSION: This study suggests that circulating miRNAs may be biomarkers to phenotype vascular function in pediatric PAH. PMID- 28819547 TI - Continuous Force Decoding from Deep Brain Local Field Potentials for Brain Computer Interfacing. AB - Current Brain Computer Interface (BCI) systems are limited by relying on neuronal spikes and decoding limited to kinematics only. For a BCI system to be practically useful, it should be able to decode brain information on a continuous basis with low latency. This study investigates if force can be decoded from local field potentials (LFP) recorded with deep brain electrodes located at the Subthalamic nucleus (STN) using data from 5 patients with Parkinson's disease, on a continuous basis with low latency. A Wiener-Cascade (WC) model based decoder was proposed using both time-domain and frequency-domain features. The results suggest that high gamma band (300-500Hz) activity, in addition to the beta (13 30Hz) and gamma band (55-90Hz) activity is the most informative for force prediction but combining all features led to better decoding performance. Furthermore, LFP signals preceding the force output by up to 1256 milliseconds were found to be predictive of the force output. PMID- 28819548 TI - A random forest classifier for detecting rare variants in NGS data from viral populations. AB - We propose a random forest classifier for detecting rare variants from sequencing errors in Next Generation Sequencing (NGS) data from viral populations. The method utilizes counts of varying length of k-mers from the reads of a viral population to train a Random forest classifier, called MultiRes, that classifies k-mers as erroneous or rare variants. Our algorithm is rooted in concepts from signal processing and uses a frame-based representation of k-mers. Frames are sets of non-orthogonal basis functions that were traditionally used in signal processing for noise removal. We define discrete spatial signals for genomes and sequenced reads, and show that k-mers of a given size constitute a frame. We evaluate MultiRes on simulated and real viral population datasets, which consist of many low frequency variants, and compare it to the error detection methods used in correction tools known in the literature. MultiRes has 4 to 500 times less false positives k-mer predictions compared to other methods, essential for accurate estimation of viral population diversity and their de-novo assembly. It has high recall of the true k-mers, comparable to other error correction methods. MultiRes also has greater than 95% recall for detecting single nucleotide polymorphisms (SNPs) and fewer false positive SNPs, while detecting higher number of rare variants compared to other variant calling methods for viral populations. The software is available freely from the GitHub link https://github.com/raunaq m/MultiRes. PMID- 28819550 TI - Effects of storage temperature on airway exosome integrity for diagnostic and functional analyses. AB - Background: Extracellular vesicles contain biological molecules specified by cell type of origin and modified by microenvironmental changes. To conduct reproducible studies on exosome content and function, storage conditions need to have minimal impact on airway exosome integrity. Aim: We compared surface properties and protein content of airway exosomes that had been freshly isolated vs. those that had been treated with cold storage or freezing. Methods: Mouse bronchoalveolar lavage fluid (BALF) exosomes purified by differential ultracentrifugation were analysed immediately or stored at +4 degrees C or -80 degrees C. Exosomal structure was assessed by dynamic light scattering (DLS), transmission electron microscopy (TEM) and charge density (zeta potential, zeta). Exosomal protein content, including leaking/dissociating proteins, were identified by label-free LC-MS/MS. Results: Freshly isolated BALF exosomes exhibited a mean diameter of 95 nm and characteristic morphology. Storage had significant impact on BALF exosome size and content. Compared to fresh, exosomes stored at +4 degrees C had a 10% increase in diameter, redistribution to polydisperse aggregates and reduced zeta. Storage at -80 degrees C produced an even greater effect, resulting in a 25% increase in diameter, significantly reducing the zeta, resulting in multilamellar structure formation. In fresh exosomes, we identified 1140 high-confidence proteins enriched in 19 genome ontology biological processes. After storage at room temperature, 848 proteins were identified. In preparations stored at +4 degrees C, 224 proteins appeared in the supernatant fraction compared to the wash fractions from freshly prepared exosomes; these proteins represent exosome leakage or dissociation of loosely bound "peri-exosomal" proteins. In preparations stored at -80 degrees C, 194 proteins appeared in the supernatant fraction, suggesting that distinct protein groups leak from exosomes at different storage temperatures. Conclusions: Storage destabilizes the surface characteristics, morphological features and protein content of BALF exosomes. For preservation of the exosome protein content and representative functional analysis, airway exosomes should be analysed immediately after isolation. PMID- 28819551 TI - Investigating Changes in Serum Biochemical Parameters in Opium Addicts Before and During Addiction Treatment. AB - BACKGROUND: Iran is one of the major consumers of opium and opiate substances in the world. Addiction has become a very important issue in the 21st century and an urgent one in Iran. The consumption of this substance leaves a variety of impacts on the human body. The goal of this study is to investigate the changes of the biochemical parameters derived from opiate substances in addicts during their treatment. METHODS: This is a cross-sectional research that focused on 40 individuals dependent on the consumption of opium. Their blood samples were taken before and during treatment, and their fasting blood sugar (FBS), sodium, calcium, phosphorus, creatinine, urea, uric acid, total protein, triglycerides, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and total cholesterol were measured. Data were analyzed by SPSS using paired t-test. FINDINGS: The results showed that serum uric acid, LDL, cholesterol, and the total protein levels significantly decreased during the treatment in comparison with the time before the treatment (P < 0.050). Yet, the serum fasting glucose, urea, creatinine, HDL, triglycerides, calcium, phosphorous, sodium, and potassium showed no significant change the time prior and during the treatment. CONCLUSION: Given the findings of the analysis, opium addiction has a number of destructive impacts on the lipid profile and uric acid. In addition, the level of total protein decreased during the treatment. PMID- 28819549 TI - Metastatic state of parent cells influences the uptake and functionality of prostate cancer cell-derived extracellular vesicles. AB - Extracellular vesicles (EVs), including microvesicles and exosomes, mediate intercellular signalling which has a profound role in cancer progression and in the development of metastasis. Internalisation of EVs can prompt functional changes in the recipient cells, the nature of which depends on the molecular composition and the cargo of the EVs. We hypothesised that the metastatic stage of cancerous parent cells would determine the uptake efficacy and the subsequent functional effects of the respective cancer cell-derived EVs. To address this question, we compared the internalisation of EVs derived from two metastatic site derived prostate cancer cell lines (PC-3 and LNCaP), human telomerase reverse transcriptase immortalised primary malignant prostate epithelial cells (RC92a/hTERT), and a benign epithelial prostate cell line (PNT2). EVs isolated from the metastatic site-derived PC-3 and LNCaP cells were more efficiently internalised by the PC-3 and PNT2 cells compared to the EVs from the primary malignant RC92a/hTERT cells or the benign PNT2 cells, as determined by high content microscopy, confocal microscopy, and flow cytometry. EV uptake was also influenced by the phase of the cell cycle, so that an increased EV-derived fluorescence signal was observed in the cells at the G2/M phase compared to the G0/G1 or S phases. Finally, differences were also observed in the functions of the recipient cells based on the EV source. Proliferation of PNT2 cells and to a lesser extent also PC-3 cells was enhanced particularly by the EVs from the metastatic-site-derived prostate cancer cells in comparison to the EVs from the benign cells or primary cancer cells, whereas migration of PC-3 cells was enhanced by all cancerous EVs. RESPONSIBLE EDITOR Takahiro Ochiya, National Cancer Center, Japan. PMID- 28819546 TI - Oxidative Stress: Harms and Benefits for Human Health. AB - Oxidative stress is a phenomenon caused by an imbalance between production and accumulation of oxygen reactive species (ROS) in cells and tissues and the ability of a biological system to detoxify these reactive products. ROS can play, and in fact they do it, several physiological roles (i.e., cell signaling), and they are normally generated as by-products of oxygen metabolism; despite this, environmental stressors (i.e., UV, ionizing radiations, pollutants, and heavy metals) and xenobiotics (i.e., antiblastic drugs) contribute to greatly increase ROS production, therefore causing the imbalance that leads to cell and tissue damage (oxidative stress). Several antioxidants have been exploited in recent years for their actual or supposed beneficial effect against oxidative stress, such as vitamin E, flavonoids, and polyphenols. While we tend to describe oxidative stress just as harmful for human body, it is true as well that it is exploited as a therapeutic approach to treat clinical conditions such as cancer, with a certain degree of clinical success. In this review, we will describe the most recent findings in the oxidative stress field, highlighting both its bad and good sides for human health. PMID- 28819552 TI - The Effects of Opium Addiction on the Immune System Function in Patients with Fungal Infection. AB - BACKGROUND: The use of narcotics such as opium exposes addicts as susceptible targets of different diseases so that they might easily be exposed to different diseases such as fungal infections. The present study aimed to investigate the effects of addiction to opium and fungal infection on plasma levels of certain cytokines including interleukin-4 (IL-4), IL-6, IL-17, Interferon gamma (IFN gamma) and transforming growth factor-beta (TGF-beta). METHODS: Present study included 72 individuals who were divided into 4 groups: 1) opium-addicted with fungal infection; 2) opium-addicted without fungal infection; 3) non-opium addicted with fungal infection; and 4) normal individuals (non-opium-addicted and non-fungal infection). The fungal samples, after being detected and confirmed by a physician, were prepared based on clinical symptoms and then analyzed by direct smear and culture method. The measurement of the plasma level of cytokines was done by enzyme-linked immunosorbent assay (ELISA) method. FINDINGS: The comparison of the mean of the plasma level of cytokines showed that addiction to opium and fungal infection had significant effect on the plasma levels of IL-17, IFN-gamma, TGF-beta cytokines in all studied groups. The interaction of addiction to opium and fungal infection was only significant in the case of plasma level of IL-6. CONCLUSION: Addiction to opium and fungal infection, either separately or simultaneously, poses significant effect on the immune system and causes disorders in the cytokine network and the immune system and also provides a suitable environment for fungal infection. PMID- 28819553 TI - Pattern of Substance Use and Related Factors in Male Prisoners. AB - BACKGROUND: Prisoner's addiction is one of the major problems in many countries which imposes very high medical costs and social harm to communities. This study investigated the pattern of substance use and related factors in male prisoners in one of the prisons in southeastern Iran. METHODS: This cross-sectional study was carried out in 2016. The study population was inmates of a prison in southeast Iran. Sampling was carried out randomly according to the list of prisoners. Data were collected using a form and were analyzed with statistics software SPSS. FINDINGS: More than four-fifths (75.3%) of the subjects consumed at least one substance (alcohol, tobacco and other drugs), 74.4% were smoking, 73.2% used a narcotic substance, and about one-fifth (19.3%) reported drinking alcohol. With a frequency of 62.0%, opium was the most frequently utilized narcotic substance. Poppy juice (31.6%), cannabis (29.8%), crystal (16.9%) and tramadol (16.9%) were the next frequent substances used. A percentage of 41.5% subjects reported using two or more drugs. A percentage of 80.7% subjects reported substance use among their friends, 39.2% by siblings and 37.2% by father. Regression analysis showed predictor variables of substance use were education, substance use by prisoner before being imprisoned, substance use by father, friends and siblings. CONCLUSION: This study showed a remarkable prevalence of substance use in prisons, which was more than general population. Therefore, it is necessary to consider alternative penalties of imprisonment due to the factors associated with substance use. Screening of people at high risk for substance use should be considered on admission to prison, and primary prevention measures should be focused on them. PMID- 28819554 TI - Comparing Blood Lead Level among Oral/inhaled Opium Addicts with a Non-addict Control Group in the Southeast of Iran. AB - BACKGROUND: Opium is widely used among addicts in the Middle East countries such as Iran. Recent reports suggest that opium sellers cheat their customers by adding lead to the opium. Contaminated opium can threaten the health of consumers. This study was designed to evaluate the lead concentration in blood sample of oral and inhaled opium user's referring to Amir Al-Momenin Hospital in Zabol, Iran, during spring 2015 in comparison with those of control group. METHODS: Blood lead level (BLL) of 188 subjects with a mean age of 52.06 years in three categories - including oral opium addicted (55 patients), inhaled opium addicted (55 patients), and healthy control group (n = 78) - was assessed. The BLL of all the subjects was assessed using an atomic absorption spectrophotometer. FINDINGS: Almost all participants consumed "Tariak" (99.09%). Mean +/- standard deviation (SD) duration of opium addiction was 13.21 +/- 10.26 years. The average blood lead concentration among oral users, inhaled users, and control group were 34.31 +/- 21.54, 41.13 +/- 26.40, and 9.86 +/- 4.40 ug/dl, respectively (P = 0.001). CONCLUSION: Our study showed significant differences of BLLs between opium users and control group. We also did not find any association between blood lead concentration and method of opium consumption. PMID- 28819555 TI - The Role of Sexual Behaviors in the Relapse Process in Iranian Methamphetamine Users: A Qualitative Study. AB - BACKGROUND: The awareness of sexual experiences could be an effective factor in preventing high-risk sexual behavior pertaining to relapse during the recovery period of substances. This research explored the role of sexual behaviors among Iranian methamphetamine (MA) users in relapse process. METHODS: The study was conducted with a qualitative approach using content analysis method. 28 participants were selected through purposeful and theoretical sampling. Data were collected based on face-to-face, in-depth, semi-structured interviews based on open-ended questions. Interviews continued until the data saturation had occurred. All interviews were examined in four stages of codes, sub-categories, categories and themes according to the content analysis of explanations and descriptions of sexual behaviors. FINDINGS: Two main themes were emerged from the analysis of interviews, including extreme pleasure seeking (including the main categories of sexual tunnel vision and sexual totalitarianism) and comprehended threat (including the main categories of internal conflict and external disorganization) as well as 10 subcategories. CONCLUSION: The results indicated that sexual behaviors played an important role in relapse process among Iranian MA users and needed to be considered and managed properly in the planning of prevention, treatment, and rehabilitation. PMID- 28819556 TI - An Ecological Study of the Association between Opiate Use and Incidence of Cancers. AB - BACKGROUND: Cancer is the second leading cause of death after cardiovascular disease. In recent years it has been hypothesized that opiate use could be a risk factor for cancer. This study aimed to evaluate a possible association between opiate use and common cancers using ecological statistics from around the world. METHODS: To investigate the association we used ordinary linear regression models. The log10-transformed age-standardized incidence rate (ASR) of cancers was used as dependent variables in the models. We adjusted for smoking, alcohol use per capita, human development index (HDI), and body mass index (BMI) as confounding variables. We extracted these variables from different data sources including the GLOBOCAN 2012, the United Nations Office on Drugs and Crime (UNODC) annual reports, World Health Organization database, the United Nations Development Program (UNDP) report 2012, and published literature. We estimated two separate models for each cancer, one for males and the other for both sexes. FINDINGS: Opiate prevalence ranged from 0.01% to 2.65% and its median was 0.20%. In the multiple regression models for both sexes, opiate use was significantly associated with bladder (beta = 0.59), kidney (beta = 0.16), oral cavity (beta = 0.27), esophagus (beta = 0.33), larynx (beta = 0.17) and other pharynx (beta = 0.36) cancers. In the models based on the male data, the coefficient and the significances were approximately the same for the above cancers but larynx cancer was no longer significantly associated with opiate use. CONCLUSION: There was a significant association between opiate use and risk of cancers. We suggest that more studies should be conducted, especially in high-risk areas of the world. PMID- 28819558 TI - The Role of Parenting Skills Training in the Prevention of Addiction of Children. PMID- 28819557 TI - Effects of Maternal Separation on Nicotine-Induced Conditioned Place Preference and Later Spatial Learning and Memory Function in Adolescent Male Rats. AB - BACKGROUND: Disturbances in maternal care have been associated with increased risk for drug abuse later in life. However, there has been little investigation of the effects of maternal separation (MS), a model of early life stress, on nicotine dependence, specifically during adolescence. In the present study, we aimed to investigate the effect of MS on nicotine-conditioned place preference (CPP) in adolescent male rats. We also examined the impact of nicotine on spatial learning and memory impairments induced by MS. METHODS: Rat pups were exposed to daily MS for 15 (MS15) or 180 (MS180) minutes during the first 2 weeks of life or reared under normal animal facility rearing (AFR) conditions. In postnatal day (PND) 28-34, they were conditioned with nicotine [0.6 mg/kg, subcutaneously (SC)] or saline and tested for preference over a period of 6 conditioning trials. Morris water maze (MWM) testing was performed to assess spatial cognitive function. FINDINGS: The MS procedure used in our study failed to affect nicotine reward as measured by CPP in the adolescent male rats. Notably, significant spatial learning deficit was seen in the MS180 rats compared to those in the AFR and MS15 groups and nicotine administration modified the MS-induced learning defect in adolescent male rats. CONCLUSION: In conclusion, although MS revealed no influence on the sensitivity to the nicotine's reinforcing effects in adolescent male rats, the simultaneous effect of MS on learning performance may be altered by nicotine intake. PMID- 28819559 TI - Growth inhibitory efficacy of natural products in a model for triple negative molecular subtype of clinical breast cancer. AB - Global gene expression profiling identifies predictive and prognostic biomarkers and rationalizes breast cancer subtype-targeted treatment. The Anthracyclin/Taxol and survival pathway specific small molecular inhibitors, constitute current treatment options. These options are associated with acquired tumor resistance and emergence of drug-resistant cancer stem cells. Dietary supplements and constitutive bioactive phytochemicals with relatively low systemic toxicity may provide testable alternatives for current therapy. Human breast epithelial cell lines 184-B5 (non-tumorigenic triple negative cell type) and MDA-MB-231 (breast carcinoma derived triple negative cell type) were used as the experimental models. Putative cancer chemo-preventive natural products and their constitutive bioactive agents represented the test agents. Anchorage independent growth, cell cycle progression and cell apoptosis quantified the treatment efficacy. Compared to the 184-B5 cells, the MDA-MB-231 cells exhibited anchorage-independent growth indicative of persistent cancer risk. Additionally, the MDA-MB-231 cells exhibited hyper-proliferation, accelerated cell cycle progression and inhibited apoptosis indicative of loss of homeostatic growth control. The test agents inhibited anchorage-independent growth via cytostatic and pro-apoptotic effects. The triple negative carcinoma-derived Doxorubicin-resistant phenotype exhibited cancer stem cell markers, including tumor spheroid formation and expression of CD44, NANOG and c-Myc. These data identify clinically relevant mechanistic leads for the efficacy of natural products in the aggressive therapy-resistant breast cancer subtype and suggests a testable approach for cancer stem cell-targeted therapy. PMID- 28819560 TI - A novel peptide blocking cancer cell invasion by structure-based drug design. AB - The receptor for the urokinase-type plasminogen activator (uPA), uPAR, facilitates tumor cell invasion and metastasis by focusing on several ligands, including uPA, integrins and vitronectin. With computational prediction algorithms and structure-based drug design, we identified peptides containing the Gly-Lys-Gly-Glu-Gly-Glu-Gly-Lys-Gly sequence (peptide H1), which strongly interacts with uPAR. The aim of the present study was to investigate the effect of allosteric inhibition at the uPAR interface using a novel synthetic peptide and its function on ovarian cancer cell invasion. The molecular and functional mechanisms of H1 were determined by complementary biochemical and biological methods in the promyeloid U937 cell line as well as ovarian cancer cell lines, including serous carcinoma SKOV3 and clear cell carcinoma TOV21G. The effects of H1 treatment on cancer cell invasion were evaluated in vitro. H1 inhibited cancer cell invasion, without affecting cell viability, accompanied by the suppression of extracellular signal-regulated kinase (ERK)-1 phosphorylation and then matrix metalloproteinase (MMP)-9 expression. H1 failed to block the interaction of uPA uPAR protein-protein interaction in cells, but antagonized the uPA function. H1 failed to disrupt the uPA-uPAR complex, but abolished the invasion of ovarian cancer cells at least through suppression of the ERK-MMP-9 signaling pathway. Further studies are needed to confirm our observations and to describe the underlying molecular mechanism. PMID- 28819562 TI - Re-evaluation of glycated hemoglobin and glycated albumin with continuous glucose monitoring system as markers of glycemia in patients with liver cirrhosis. AB - [This retracts the article DOI: 10.3892/br.2016.808.]. PMID- 28819561 TI - Factors associated with the decrease in hepatitis B surface antigen titers following interferon therapy in patients with chronic hepatitis B: Is interferon and adefovir combination therapy effective? AB - The purpose of antiviral therapy in chronic hepatitis B (CHB) is generally to achieve a decrease and ultimately disappearance of HBs antigen (HBsAg). Interferon (IFN) therapy of CHB appears to be less effective in Asian countries than in European countries, and the advantage of IFN and nucleotide(s) analog (NA) combination therapy has yet to be fully investigated. The present study focused on the factors associated with a decrease in HBs antigen following IFN monotherapy or IFN + NA combination therapy. A total of 35 patients with CHB who received IFN-based therapy (mean +/- standard deviation age 36.7+/-8.5 years; 27 males and 8 females) were enrolled in this study. Of the 35 patients, 21 patients received pegylated IFN monotherapy and 14 patients received IFN and adefovir (ADV) combination therapy. We examined the factors associated with reductions in the HBsAg titer of >1.0 log IU/ml from the initial HBsAg titer to the end of treatment and to 24 weeks after treatment. Although 13 patients (37%) had a reduction in HBsAg of >1.0 IU/ml at the end of treatment, it was only maintained to 24 weeks after treatment in 7 patients (20%). The HBV core-related antigen (HBcrAg) titer before treatment was significantly higher in patients with a decrease in HBsAg at the end of treatment than in patients without a decrease in HBsAg (6.56+/-0.78 vs. 5.30+/-1.66 log IU/ml, P<0.05). Moreover, an increase in alanine aminotransferase (ALT) of >2 times from baseline occurred significantly more frequently in patients with a decrease in HBsAg (62 vs. 14%, P<0.05). The proportion of patients with a decrease in HBsAg was significantly greater in patients who received IFN monotherapy than in patients who received IFN and ADV combination therapy (43 vs. 29%, P<0.05). The present results revealed that the HBcr antigen titer before therapy and an on-treatment elevation of ALT (indicative of host instruction flare) are important factors associated with a decrease in HBsAg titers after IFN-based therapy. The efficacy of IFN and ADV combination therapy was not apparent in terms of a reduction in the HBsAg titer. PMID- 28819563 TI - Novel CLCN7 compound heterozygous mutations in intermediate autosomal recessive osteopetrosis. AB - Osteopetrosis is a heritable disorder of the skeleton that is characterized by increased bone density on radiographs caused by defects in osteoclast formation and function. Mutations in >10 genes are identified as causative for this clinically and genetically heterogeneous disease in humans. We report two novel missense variations in a compound heterozygous state in the CLCN7 gene, detected through targeted exome sequencing, in a 15-year-old Japanese female with intermediate autosomal recessive osteopetrosis. PMID- 28819564 TI - A review of the impact of obesity on common gastrointestinal malignancies. AB - Obesity is a global pandemic and is a well-recognized risk factor for various gastrointestinal diseases. The prevalence of obesity is increasing across all age groups. There is an emergent need for focused guidelines aimed at reducing the incidence, prevalence, and associated risks of obesity. The impact of obesity on gastrointestinal cancers being multifactorial adversely influences the associated risk, disease course, prognosis, and overall survival. We have summarized the current literature highlighting the association between obesity and common gastrointestinal cancers, with specific focus on esophageal adenocarcinoma, colon cancer, hepatocellular cancer, cholangiocarcinoma, and pancreatic malignancies. PMID- 28819566 TI - Development of Poly Lactic/Glycolic Acid (PLGA) Microspheres for Controlled Release of Rho-Associated Kinase Inhibitor. AB - PURPOSE: The purpose of this study was to investigate the feasibility of poly lactic/glycolic acid (PLGA) as a drug delivery carrier of Rho kinase (ROCK) inhibitor for the treatment of corneal endothelial disease. METHOD: ROCK inhibitor Y-27632 and PLGA were dissolved in water with or without gelatin (W1), and a double emulsion [(W1/O)/W2] was formed with dichloromethane (O) and polyvinyl alcohol (W2). Drug release curve was obtained by evaluating the released Y-27632 by using high performance liquid chromatography. PLGA was injected into the anterior chamber or subconjunctiva in rabbit eyes, and ocular complication was evaluated by slitlamp microscope and histological analysis. RESULTS: Y-27632 incorporated PLGA microspheres with different molecular weights, and different composition ratios of lactic acid and glycolic acid were fabricated. A high molecular weight and low content of glycolic acid produced a slower and longer release. The Y-27632 released from PLGA microspheres significantly promoted the cell proliferation of cultured corneal endothelial cells. The injection of PLGA did not induce any evident eye complication. CONCLUSIONS: ROCK inhibitor-incorporated PLGA microspheres were fabricated, and the microspheres achieved the sustained release of ROCK inhibitor over 7-10 days in vitro. Our data should encourage researchers to use PLGA microspheres for treating corneal endothelial diseases. PMID- 28819565 TI - Genomic and immune heterogeneity are associated with differential responses to therapy in melanoma. AB - Appreciation for genomic and immune heterogeneity in cancer has grown though the relationship of these factors to treatment response has not been thoroughly elucidated. To better understand this, we studied a large cohort of melanoma patients treated with targeted therapy or immune checkpoint blockade (n = 60). Heterogeneity in therapeutic responses via radiologic assessment was observed in the majority of patients. Synchronous melanoma metastases were analyzed via deep genomic and immune profiling, and revealed substantial genomic and immune heterogeneity in all patients studied, with considerable diversity in T cell frequency, and few shared T cell clones (<8% on average) across the cohort. Variables related to treatment response were identified via these approaches and through novel radiomic assessment. These data yield insight into differential therapeutic responses to targeted therapy and immune checkpoint blockade in melanoma, and have key translational implications in the age of precision medicine. PMID- 28819567 TI - Systemic Associations with Residual Subretinal Fluid after Ranibizumab in Diabetic Macular Edema. AB - PURPOSE: To investigate the impact of systemic diseases on the occurrence of subretinal fluid (SRF) in diabetic macular edema (DME) and prognostic factors for residual SRF following three consecutive monthly intravitreal ranibizumab. METHODS: Ninety-seven eyes from 68 patients with DME who completed 3 consecutive monthly injections of ranibizumab were enrolled. Systemic parameters mainly included chronic kidney disease (CKD), hypertension, HbA1c, and insulin dependence. Renal parameters for CKD were serum creatinine, estimated glomerular filtration rate (eGFR), and serum albumin. Ocular factors were baseline central macular thickness (CMT), severity of diabetic retinopathy (DR), and status of panretinal photocoagulation (PRP). RESULTS: Chronic kidney disease had significant correlation with baseline SRF (R = 0.397, p < 0.001 after partial correlation with adjustment for age and DR severity). As for CKD, lower serum albumin, but not eGFR or serum creatinine, was associated with baseline presence of SRF (p = 0.026, p = 0.08 and p = 0.53, resp., after adjustment for age and DR severity). Overall, lower eGFR and lower HbA1c values, contrary to popular belief, predicted the presence of residual SRF following intravitreal injections (p = 0.016 and p < 0.001, resp.). CONCLUSIONS: Tight sugar control and poorer baseline kidney function may slow the resorption of SRF after anti-VEGF injections in patients with DME in the short term. PMID- 28819568 TI - Nebivolol Attenuates Neutrophil Lymphocyte Ratio: A Marker of Subclinical Inflammation in Hypertensive Patients. AB - BACKGROUND: High value of neutrophil lymphocyte ratio (NLR) is a strong independent predictor and biomarker of ongoing vascular inflammation in various cardiovascular disorders. OBJECTIVE: The main focus of the study is to investigate the effect of nebivolol on NLR in mild to moderate hypertensive patients in comparison with metoprolol. In addition, BMI, blood pressure, TLC count, blood sugar, and lipid profile were also assayed before and after treatment. MATERIALS AND METHODS: In this 12-week prospective double-blinded randomized study, 120 patients with mild to moderate hypertension were randomly divided into two groups to prescribed daily dose of tab nebivolol 5-10 mg and metoprolol 50-100 mg, respectively, for 12 weeks. The data were analyzed using SPSS 16 software. RESULTS: A total of 100 patients completed the study. Both drugs lowered blood pressure significantly, nebivolol 20.5/10.5 and metoprolol 22.5/11.2 (p < 0.001) from baseline. Regarding inflammation, nebivolol reduced total leukocyte count (p = 0.005) and neutrophil count (p = 0.003) and increased lymphocyte count (p = 0.004) as compared to metoprolol. Similarly, nebivolol but not metoprolol significantly reduced NLR ratio (p = 0.07). Nebivolol improved lipid profile and blood sugar compared to metoprolol, but values were nonsignificant. CONCLUSION: Nebivolol has a strong impact on reducing NLR, a marker of subclinical inflammation in hypertensive patients. Moreover NLR can be used as a disease and drug monitoring tool in these patients. PMID- 28819569 TI - A study on IL8RB gene polymorphism as a potential immuno-compromised adherent in exaggeration of parenteral and mammo-crine oxidative stress during mastitis in buffalo. AB - The genetic markers in inflammatory responses during mastitis afford a reasonable way for improving milk production in the Egyptian buffalo breed. Among them is the interleukin 8 Receptor Gene (IL8RB) (CXCR2); a chemokine receptor gene augments the neutrophil migration during infection. To understand its role better during mastitis in Egyptian buffalos, twenty-five dairy animals representing the normal, sub-clinically, clinically and chronically affected buffalos were randomly selected from different districts. Screening criteria for mastitis were based on somatic cell count and California mastitis test assays on their milk samples. Biochemically, mastitis induced an increase in milk lactate dehydrogenase, alkaline phosphatase and catalase activities and serum malanoaldehyde concentration. The total antioxidant concentrations, however, decreased in serum and milk during mammary inflammation. The protein profiling of milk whey proved an accelerated mammary inflammatory influx of blood-borne proteins during mastitis. The genomic DNAs were extracted from blood samples and the CXCR2 sequence of 1246 bp covering a part of intron 1, exon 2 and a part of 3'UTR were submitted to Genbank (accession # KY399457.1). The study clearly defined the presence of four SNPs. Three were detected as synonymous substitutions in coding region and one in the 3'UTR region. Only SNP C/A at c.127 was found to be highly associated with mastitis. In conclusion, the results warrant the potential correlation between the genetic SNP variance for certain genes and the incidence of mastitis in buffalo breed. PMID- 28819571 TI - Incidental Finding of an Undiagnosed Coarctation of the Aorta Causing Dilated Cardiomyopathy in an Adult. AB - 31-year-old male with no past medical history apart from high blood pressure noted by GP one week prior to admission presented with a three-week history of a flu-like illness and symptoms of heart failure with severe global left ventricular dilation and dysfunction on Transthoracic Echocardiography (TTE). Two weeks following admission he complained of left arm pain and CT upper limb confirmed embolic occlusion of the left brachial artery and incidental severe coarctation of the proximal descending aorta after the origin of the left subclavian artery. Follow-up TTE suggested the presence of coarctation of the aorta on a suprasternal view which was not performed at the time of his first TTE. His heart failure and blood pressure responded very well to medical therapy and he has been referred for surgical correction of his aortic coarctation. PMID- 28819570 TI - HCV Integrated Care: A Randomized Trial to Increase Treatment Initiation and SVR with Direct Acting Antivirals. AB - BACKGROUND AND AIMS: Psychiatric or substance use disorders are barriers to successful HCV antiviral treatment. In a randomized, controlled trial (RCT), the effects of HCV Integrated Care (IC) for increasing treatment rates and sustained viral response (SVR) were studied with direct acting antivirals (DAA). METHODS: In 2012-13, VA patients, whose screening was positive for depression, PTSD, or substance use (N = 79), were randomized to IC or Usual Care (UC). IC consisted of brief psychological interventions and case management. The primary endpoint was SVR among patients followed for an average of 16.6 months. RESULTS: 42% of the study participants were previously homeless and 79% had HCV genotype 1. Twice as many IC participants (45%) initiated treatment compared with UC participants (23%) (chi2 = 4.59, p = 0.032). Among those treated, SVR rates did not significantly differ (IC: 12/18 = 67%; UC: 5/9 = 55%; p = 0.23). Among all randomized participants, IC participants trended toward better SVR rates (30.0% versus 12.8% in UC; p = 0.07). CONCLUSIONS: Although first-generation DAAs are no longer used, this smaller RCT helps confirm the results of a larger multisite RCT showing that Integrated Care results in higher treatment initiation and SVR rates among HCV-infected persons with comorbid psychological disorders. Integrated mental health services can facilitate treatment among the most challenging HCV patients, many of whom have not been successfully treated. This trial is registered with ClinicalTrials.gov number NCT00722423. PMID- 28819572 TI - A CAD/CAM Zirconium Bar as a Bonded Mandibular Fixed Retainer: A Novel Approach with Two-Year Follow-Up. AB - Stainless steel alloys containing 8% to 12% nickel and 17% to 22% chromium are generally used in orthodontic appliances. A major concern has been the performance of alloys in the environment in which they are intended to function in the oral cavity. Biodegradation and metal release increase the risk of hypersensitivity and cytotoxicity. This case report describes for the first time a CAD/CAM zirconium bar as a bonded mandibular fixed retainer with 2-year follow up in a patient who is subjected to long-term treatment with fixed orthodontic appliance and suspected to have metal hypersensitivity as shown by the considerable increase of nickel and chromium concentrations in a sample of patient's unstimulated saliva. The CAD/CAM design included a 1.8 mm thickness bar on the lingual surface of lower teeth from canine to canine with occlusal rests on mesial side of first premolars. For better retention, a thin layer of feldspathic ceramic was added to the inner surface of the bar and cemented with two dual-cured cement types. The patient's complaint subsided 6 weeks after cementation. Clinical evaluation appeared to give good functional value where the marginal fit of digitized CAD/CAM design and glazed surface offered an enhanced approach of fixed retention. PMID- 28819573 TI - An Interstitial 4q Deletion with a Mosaic Complementary Ring Chromosome in a Child with Dysmorphism, Linear Skin Pigmentation, and Hepatomegaly. AB - Interstitial deletions of 4q are rarely reported, vary in size, and have limited genotype-phenotype correlations. Here, genome-wide array CGH analysis identified a 21.6 Mb region of copy number loss at 4q12-q21.1 in a patient diagnosed with dysmorphism, linear skin pigmentation, and hepatomegaly. An additional small ring chromosome was detected in 5/30 cells examined via G-banding. Confirmation of the origin of the ring chromosome was obtained by FISH analysis which identified that the ring chromosome contained material from the deleted region of chromosome 4 and was therefore complementary to the 21.6 Mb deletion. Further microarray studies in the proband using a different microarray platform showed no evidence of mosaicism. This case highlights the importance of an integrated approach to cytogenetic analysis and demonstrates the value of G-banding for detecting mosaicism, as current microarray platforms are unable to detect low level mosaics. PMID- 28819574 TI - Sequential Kinase Inhibition (Idelalisib/Ibrutinib) Induces Clinical Remission in B-Cell Prolymphocytic Leukemia Harboring a 17p Deletion. AB - B-cell prolymphocytic leukemia (B-PLL) is a rare lymphoid neoplasm with an aggressive clinical course. Treatment strategies for B-PLL remain to be established, and, until recently, alemtuzumab was the only effective therapeutic option in patients harboring 17p deletions. Herein, we describe, for the first time, a case of B-cell prolymphocytic leukemia harboring a 17p deletion in a 48 year-old man that was successfully treated sequentially with idelalisib rituximab/ibrutinib followed by allogeneic hematopoietic stem cell transplant (allo-HSCT). After 5 months of therapy with idelalisib-rituximab, clinical remission was achieved, but the development of severe diarrhea led to its discontinuation. Subsequently, the patient was treated for 2 months with ibrutinib and the quality of the response was maintained with no severe adverse effects reported. A reduced-intensity conditioning allo-HSCT from a HLA-matched unrelated donor was performed, and, thereafter, the patient has been in complete remission for 10 months now. In conclusion, given the poor prognosis of B-PLL and the lack of effective treatment modalities, the findings here suggest that both ibrutinib and idelalisib should be considered as upfront therapy of B-PLL and as a bridge to allo-HSCT. PMID- 28819576 TI - Pitfall in the Diagnosis of Diabetes Insipidus and Pregnancy. AB - Diabetes insipidus (DI) during pregnancy and the perinatal period is an uncommon medical problem characterized by polyuria and excessive thirst. Diagnosis of DI may be overlooked in the setting of pregnancy, a time when increased water intake and urine output are commonly reported. We report two cases: one of transient DI in a young woman during her third trimester of twin pregnancy in association with acute fatty liver and hypertension and one of postpartum DI secondary to Sheehan syndrome from rupture of a splenic artery aneurysm. These cases illustrate the spectrum with which DI related to pregnancy and delivery can present and highlight the difficulty in making the diagnosis since the symptoms are often initially overlooked. PMID- 28819575 TI - Therapeutic Approach to the Management of Severe Asymptomatic Hyponatremia. AB - Hyponatremia is an electrolyte imbalance encountered commonly in the hospital and ambulatory settings. It can be seen in isolation or present as a complication of other medical conditions. It is therefore a challenge to determine the appropriate therapeutic intervention. An understanding of the etiology is key in instituting the right treatment. Clinicians must not be too hasty to correct a random laboratory value without first understanding the physiologic principle. We present such a case of a patient who presented with sodium of 98 mmol/L, the lowest recorded in the current literature, and yet was asymptomatic. Following appropriate management driven by an understanding of the underlying pathophysiologic mechanism, the patient was managed to full recovery without any clinically significant neurological sequelae. PMID- 28819577 TI - The Role of Laparoscopy in the Management of a Diagnostic Dilemma: Jejunal Ectopic Pancreas Developing into Jejunojejunal Intussusception. AB - Ectopic pancreas (EP) is a rare congenital anomaly defined as the presence of pancreatic tissue in topographic anomaly. It is usually silent but it may become clinically evident when complicated by acute conditions. The development of laparoscopic surgery has changed the way to manage such conditions, especially in the setting of emergency surgery, thanks to its diagnostic and therapeutic role with excellent results. We decided to perform an emergency diagnostic exploratory laparoscopy in a 29-year-old man with an acute abdomen and nonspecific radiological images for intestinal occlusion. A jejunojejunal intussusception was found, caused by a mass. We decided to carry out minilaparotomy to perform a resection of the affected jejunum. Histological examination confirmed the presence of a jejunal ectopic pancreas. Adult intussusception caused by EP represents 5% of all cases of intussusception. As CT scan, especially when performed in emergency setting for small bowel obstruction diagnosis, can usually demonstrate nondiagnostic findings suggestive of intussusception of unknown origin, laparoscopic exploration could help surgeons in order to perform a resolute diagnosis and treat the pathology. PMID- 28819578 TI - Corrigendum to "A Survey of Eyespot Sexual Dimorphism across Nymphalid Butterflies". AB - [This corrects the article DOI: 10.1155/2013/926702.]. PMID- 28819580 TI - Analytical Method for the Validation of Three Polyphenols as a Marker Compound for the Standardization of Solidago virgaurea subsp. gigantea Extracts and Antiadipogenesis of Harvesting Time and Location. AB - Protocatechuic acid (PC), chlorogenic acid (CA), and kaempferol-3-O-rutinoside (K O-R), isolated from the Solidago virgaurea subsp. gigantea (SV) extract, were quickly and efficiently separated using HPLC. Our chromatographic method was found to effectively separate PC, CA, and K-O-R at retention times of 5.36, 8.22, and 17.04 min, respectively. Linearity of PC, CA, and K-O-R was found to be in the range of 4.85-485.00, 47.5-1900.00, and 8.50-850.00 MUg/ml. Recoveries ranged between 101.32 and 103.30%, 95.82 and 100.25%, and 96.18 and 99.37%, for PC, CA, and K-O-R, respectively. The antiadipogenesis activity of SV extracts collected from five different months and from seven different regions was evaluated using an Oil Red O staining assay in 3T3-L1 cells. Extract from SV collected in April from the Ulleung Island produced over 106.89% inhibition of adipogenesis without cytotoxicity at 50 MUg/ml. This extract had a high amount of PC and K-O-R. The developed HPLC method was found to be fast, accurate, precise, and reproducible and could be applied to qualitative and quantitative analysis of three bioactive compounds in SV extracts. The SV extract collected in April from Ulleung Island can be used as a functional food ingredient preventing obesity. PMID- 28819579 TI - Dual-Task Performance in GBA Parkinson's Disease. AB - INTRODUCTION: Parkinson's disease patients carrying a heterozygous mutation in the gene glucocerebrosidase (GBA-PD) show faster motor and cognitive decline than idiopathic Parkinson's disease (iPD) patients, but the mechanisms behind this observation are not well understood. Successful dual tasking (DT) requires a smooth integration of motor and nonmotor operations. This study compared the DT performances between GBA-PD and iPD patients. METHODS: Eleven GBA-PD patients (p.N370S, p.L444P) and eleven matched iPD patients were included. Clinical characterization included a motor score (Unified PD Rating Scale-III, UPDRS-III) and nonmotor scores (Montreal Cognitive Assessment, MoCA, and Beck's Depression Inventory). Quantitative gait analysis during the single-task (ST) and DT assessments was performed using a wearable sensor unit. These parameters corrected for UPDRS and MoCA were then compared between the groups. RESULTS: Under the DT condition "walking while checking boxes," GBA-PD patients showed slower gait and box-checking speeds than iPD patients. GBA-PD and iPD patients did not show significant differences regarding dual-task costs. CONCLUSION: This pilot study suggests that DT performance with a secondary motor task is worse in GBA-PD than in iPD patients. This finding may be associated with the known enhanced motor and cognitive deficits in GBA-PD compared to iPD and should motivate further studies. PMID- 28819581 TI - Electrochemical Evaluation of trans-Resveratrol Levels in Red Wine Based on the Interaction between Resveratrol and Graphene. AB - trans-Resveratrol is often considered as one of the quality standards of red wine, and the development of a sensitive and reliable method for monitoring the trans-resveratrol levels in red wine is an urgent requirement for the quality control. Here, a novel voltammetric approach was described for probing trans resveratrol using a graphene-modified glassy carbon (GC) electrode. The proposed electrode was prepared by one-step electrodeposition of reduced graphene oxide (ERGO) at a GC electrode. Compared with the bare GC electrode, the introduced graphene film on the electrode surface dramatically improved the sensitivity of the sensor response due to the pi-pi interaction between the graphene and trans resveratrol. The developed sensor exhibited low detection limit of 0.2 MUM with wide linear range of 0.8-32 MUM and high stability. For the analysis of trans resveratrol in red wine, the high anti-interference ability and the good recoveries indicated the great potential for practical applications. PMID- 28819583 TI - Theoretical study of Ni+ assisted C-C and C-H bond activations of propionaldehyde in the gas phase. AB - The reactions of Ni+ with propionaldehyde in the gas phase have been systematically investigated using density functional theory at the B3LYP/def2 TZVP level. The decomposition reaction mechanism has been identified. Our calculations indicated that Ni+ can assist decomposition of propionaldehyde to form Ni+CO and C2H6 through two types of reaction channel: C-C bond activation and C-H bond activation. In addition, charge decomposition analysis (CDA) was carried out to obtain a deeper understanding for orbital interaction of the initial complex. The bonding properties of the species involved were discussed by means of diverse analysis methods including electron localization function (ELF) and atoms in molecules (AIM). PMID- 28819582 TI - Relationship of Metabolic Alterations and PD-L1 Expression in Cisplatin Resistant Lung Cancer. AB - Despite numerous reports on immune checkpoint inhibitor for the treatment of non small cell lung cancer (NSCLC), the response rate remains low but durable. Thus cisplatin still plays a major role in the treatment of NSCLC. While there are many mechanisms involved in cisplatin resistance, alteration in metabolic phenotypes with elevated levels of reactive oxygen species (ROS) are found in several cisplatin resistant tumors. These resistant cells become more reliant on mitochondria oxidative metabolism instead of glucose. Consequently, high ROS and metabolic alteration contributed to epithelial-mesenchymal transition (EMT). Importantly, recent findings indicated that EMT has a crucial role in upregulating PD-L1 expression in cancer cells. Thus, it is very likely that cisplatin resistance will lead to high expression of PD-L1/PD-1 which makes them vulnerable to anti PD-1 or anti PD-L1 antibody treatment. An understanding of the interactions between cancer cells metabolic reprogramming and immune checkpoints is critical for combining metabolism targeted therapies with immunotherapies. PMID- 28819585 TI - Costs for mitochondrial medicine will remain high as long as mitochondrial disorders are misdiagnosed. PMID- 28819584 TI - The Recent Advances on Liver Cancer Stem Cells: Biomarkers, Separation, and Therapy. AB - As the third major reason of mortality related to cancer in the world, liver cancer is also the fifth most frequent cancer. Unluckily, a majority of patients succumb and relapse though many progresses have been made in detection and therapy of liver cancer. It has been put forward that in liver cancer, cancer stem cells (CSCs) hold main responsibility for the formation, invasion, metastasis, and recurrence of tumor. Strategies that are intended to target liver CSCs are playing a more and more significant role in supervising the development of liver cancer treatment and assessing new therapeutic methods. Herein, a brief review about molecule markers, signal pathways, separation, and treatment on liver cancer stem cells (LCSCs) is provided in this paper. PMID- 28819586 TI - The cardiac glycoside convallatoxin inhibits the growth of colorectal cancer cells in a p53-independent manner. AB - Cardiac glycosides are plant-derived molecules that have shown antiproliferative properties against cancer cells, though the mechanism of action is not completely understood. We show that one cardiac glycoside, convallatoxin, presents antiproliferative effects against colorectal cancer cells in culture and that the resulting cell death is independent of the p53 tumor suppressor. Our data suggest that convallatoxin may be useful in the treatment of cancers that harbor inactivating mutations in the p53 signaling pathway. PMID- 28819587 TI - Empiric H. pylori therapy-10-day concomitant, bismuth quadruple or 14-day triple therapy: none is best. PMID- 28819588 TI - Corrigendum: Heterogeneous Family of Cyclomodulins: Smart Weapons That Allow Bacteria to Hijack the Eukaryotic Cell Cycle and Promote Infections. AB - [This corrects the article on p. 208 in vol. 7, PMID: 28589102.]. PMID- 28819589 TI - New Orthopaedic Residents and Research: How do we Approach. PMID- 28819590 TI - Minimally Invasive Total Hip Replacement in an Ipsilateral Post-traumatic above knee Amputation: A Case Report. AB - INTRODUCTION: Total hip replacement (THR) is a highly successful operation in alleviating pain and improving the overall function of the hip, in end-stage arthritis of the hip, in otherwise fit patients. However, THR as a surgical option in post-traumatic hip arthritis with ipsilateral above-knee amputation is rarely reported. CASE REPORT: We are presenting a case report of a 30-year-old male, who had previously underwent an above-knee amputation due to road-traffic accident, presenting 24 h after the injury with segmental fracture femur and popliteal artery laceration, for which the limb could not be salvaged. He had an impacted anteroinferior dislocation of the ipsilateral hip with significant cartilage damage of the femoral head which required open reduction. Subsequently, he developed traumatic arthritis of the involved hip which required conversion to an uncemented THR, using a minimally invasive (MIS) anterolateral approach. The preoperative management, surgical technique, and postoperative rehabilitation are described to highlight the technical challenges, these lower limb amputees may present along with review of literature of such rare cases. CONCLUSION: THR in an above-knee amputee with posttraumatic hip arthritis using MIS technique is an encouraging surgical option for early functional recovery and minimizing surgical complications. PMID- 28819591 TI - Aggressive Vertebral Body Hemangioma Causing Compressive Myelopathy - Two Case Reports. AB - INTRODUCTION: Hemangiomas are benign tumors characterized by proliferation of blood vessels. A few hemangiomas are aggressive, characterized by bone expansion and extraosseous extension. These benign tumors may be mistaken for metatasis resulting in unnecessary biopsies, which have a high risk of hemorrhage. These hemangiomas can spread not just into the paraspinal soft tissues but also into the epidural region of the spinal canal causing cord compression and paraparesis. These clinical symptoms can be relieved by surgical decompression of the posterior elements, embolization or radiotherapy. CASE REPORT: In this case report the authors describe the imaging features of two aggressive vertebral body hemangiomas in two patients with back pain. One patient had isolated motor deficit while the other patient had both sensory and motor deficit. On imaging this benign tumor was seen involving both the vertebral body and its posterior elements with paraspinal and epidural extension causing compressive myelopathy. CONCLUSION: Thus, these case reports help identify the characteristic imaging features of an aggressive vertebral body hemangioma, preventing unnecessary and often risky biopsy. The clinical symptoms of the patient can be relieved by surgical decompression of the posterior elements or by radiotherapy. Use of onyx for intraarterial embolization is now believed to be the safest and most efficacious method for treatment of aggressive vertebral body hemangiomas. However, in the absence of definite guidelines, a multicentric study is warranted to prove that embolization with onyx is better than surgery with post-operative radiotherapy. PMID- 28819592 TI - Insufficiency Fractures of the Distal Tibia and Fibula Following Total Hip Arthroplasty: A Case Report. AB - INTRODUCTION: Although periprosthetic fractures of the femur have been well documented, insufficiency fractures following total hip arthroplasty (THA) have been rarely described. We report a case of an insufficiency fracture in the distal tibia and fibula that occurred after THA. CASE REPORT: A 54-year-old woman presented with severe pain in the bilateral hip joints and was diagnosed with end stage osteoarthritis. She underwent THA on the right side. Although the postoperative course was uneventful, she suddenly experienced severe pain and swelling in the right leg without any history of trauma 22 weeks after the surgery. She was first diagnosed with cellulitis by her local doctor and was treated with oral antibiotics. Her symptoms persisted, and she returned to our hospital 1 month later. Her right distal leg and ankle were diffusely swollen and tender. Plain radiographs revealed a sclerotic linear zone in the distal tibia and fibula. She was diagnosed with insufficiency fractures in the distal tibia and fibula following THA. Local disuse osteoporosis and increased mechanical stress after THA as a result of pain relief could be the causes for her fracture. Her right leg and ankle were immobilized with a splint for another 4 weeks. Her symptoms subsided gradually, and fracture union was confirmed on the follow-up X ray. CONCLUSION: Insufficiency fractures should be suspected in patients complaining of unexplainable pain, even in the distant area of the affected limb, for at least 6 months following THA. PMID- 28819593 TI - An Isolated Pure Dislocation of Fifth Carpometacarpal Joint: Case Report and Review of Literature. AB - INTRODUCTION: Isolated pure dislocation of the fifth carpometacarpal (CMC) joint is a very rare injury and classified depending on displacement of the metacarpal base. This rare injury is often difficult to recognize and is liable to be overlooked. The purpose of this case report is to present a patient with an isolated dislocation of the fifth CMC joint that was satisfactorily treated with closed reduction and ulnar gutter pop slab. CASE REPORT: A 21-year-old male presented with severe pain on the right carpus following a fall with injury to right hand. There was a mild swelling at fifth CMC joint region and a bony prominence was felt dorsally, little finger presented an abduction deformity, and there was apparent shortening of the fifth ray. A diagnosis of isolated dislocation of fifth CMC dislocation was made based on radiographs. Immediate closed reduction was done in emergency room by applying longitudinal traction and direct pressure on metacarpal base dorsally, reduction was stable and confirmed by postreduction radiographs. CONCLUSION: Isolated pure dislocation of the fifth CMC joint is very rare injury and is prone to be missed in emergency room and particular attention should be made to diagnose it in polytrauma patients. PMID- 28819594 TI - Modified Nicoll's Graft for Treatment of Gap Non-union of Ulna: A Rare Case Report. AB - INTRODUCTION: Despite the multitude of studies for the treatment of non-unions, no clear criterion has been established for treating a fracture of non-union. Non union of radius and ulna produces a discrepancy in length which must be restored for adequate rotation and function. Nicoll described a technique of bridging gaps in long bones with solid blocks of cancellous bone and fixing the fragments with metal plates. We utilized modified Nicoll's graft using corticocancellous graft taken from iliac crest. CASE REPORT: In the present case, a 17-year-old male patient of eastern India presented with gap non-union of 3 cm in ulna of non dominant hand, left side after 3 years and 6 months of trauma. There was linear surgical scar mark of 8 cm overlying ulna, but there was no sign of infection. He was functionally crippled with severe restriction of range of motion. CONCLUSION: The tricortical cancellous bone graft under optimal compression provides a good solution for the management of gap non-union of both bone forearm for deficit up to 3 cm with no evidence of infection. PMID- 28819596 TI - Complex Regional Pain Syndrome following an Episode of Herpes Zoster: A Case Report. AB - INTRODUCTION: Complex regional pain syndrome (CRPS) is characterized by searing pain, hyperalgesia, edema, allodynia, and skin changes. CRPS may be difficult to diagnose and to treat given poorly understood mechanisms as well as its presentation of symptoms that may mimic common conditions such as joint stiffness in this condition as well as rheumatoid arthritis. CASE REPORT: A 71-year-old female presented to our clinic post shingles of the right upper extremity. We diagnosed her with CRPS based on the Budapest diagnostic criteria and the clinical findings of pain and decreased the range of motion along with edema, hypersensitivity, discoloration and allodynia of the right thumb and index finger. She was treated with vitamin C as well as gabapentin and physical therapy. The patient was unable to go consistently to physical therapy due to insurance limitations, and we found no clinical benefit of vitamin C in reducing her symptoms. She was lost to follow-up during her treatment but re-emerged at 21 months. At that time she reported, she was largely unchanged in regards to her right-hand symptoms but did believe the gabapentin was helpful and still continued to take 300 mg daily. CONCLUSION: This case report highlights the usefulness of the Budapest diagnostic criteria to make the diagnosis of CRPS when associated with shingles, which can cause long-term pain and mimic some findings. Prompt diagnosis is important, as recovery typically extends beyond 6 months; our patient still reported continued symptoms at 21 months post initial presentation. Our primary treatment plan was physical therapy, which she discontinued due to insurance limitations. We recommend that patients, physicians, and third-party payers work together to extend access to physical therapy. More investigation is warranted regarding symptomatic treatment, as we found limited clinical benefit of gabapentin and vitamin C. PMID- 28819595 TI - Early Intraprosthetic Dislocation of a Dual Mobility Acetabular Construct after Total Hip Arthroplasty. AB - INTRODUCTION: The concept of a dual mobility (DM) cup has been in existence for more than 40 years and was initially popularized in Europe. Only recently has it started to garner attention in the United States. Its design, consisting of a small femoral head articulating within a larger polyethylene (PE) insert, which articulates with an outer shell, has found increasing use in patients that are at risk for post-operative dislocations. This case report describes a case of recurrent total hip arthroplasty (THA) dislocation managed with the implantation of a DM cup with an acute intraprosthetic dislocation of the DM construct. CASE REPORT: A 52-year-old woman underwent an uneventful left THA through a posterior approach. Within 6 weeks of her surgery, she had four dislocations, managed with closed reductions. She then underwent an open revision of her acetabular component with conversion to a DM construct. 5 weeks after her revision, she had another dislocation treated with closed reduction in the operating room, with the resultant eccentric location of the femoral head in the acetabular component. Computed tomography (CT) confirmed intraprosthetic dislocation with the PE liner lodged in the gluteal tissue. She was taken to the operating room with a plan to revise her acetabular component to another DM construct, but with an increase in the anteversion despite initial anteversion being "appropriate" on CT imaging. Intraoperatively, the PE liner was embedded in gluteal tissue as depicted on the CT. The abductors were intact. There was no impingement in extension and maximal external rotation when trialed with a conventional head/liner construct. A new DM construct was then implanted. CONCLUSION: Intraprosthetic dislocation is a rare occurrence and unique complication to DM constructs. It is not common in the short-term setting postoperatively to our knowledge, and this case report represents an early report of intraprosthetic dislocation in the literature. Care should be taken during reduction of dislocated DM constructs to avoid intraprosthetic dislocations. Open revisions can be managed with revisions to another DM construct or to a constrained liner construct to maximize stability. PMID- 28819597 TI - Case Report: Oblique Fracture of the Ulnar Sesamoid Bone of the Metacarpophalangeal Joint, a Rare Pathology. AB - INTRODUCTION: Fractures of the sesamoid bones of the metacarpophalangeal joint (MCPJ) are a rare pathology in hand trauma. Only a few case reports and case series were found in literature. The diagnosis of an ulnar sesamoid bone fracture of the MCPJ is difficult and can pose a differential diagnostic problem with Stener lesions or ulnar collateral ligament (UCL) instability. This pathology is frequently missed with subsequent poor functional outcomes. Correct and early diagnosis is important as this will allow for correct treatment with full recovery of function without sequelae. CASE PRESENTATION: We report a case of a 35-year-old male Caucasian patient after a thumb injury due to a fall with his mountain bike. X-ray showed a fracture of the ulnar sesamoid of the MCPJ of the pollex, which is rarely reported in this literature. Anamnesis, clinical examination, and X-ray evaluation contributed to our diagnosis. The ulnar sesamoid bone fracture of the MCPJ of the right pollex was initially treated conservatively with immobilization, rest and ice application. After 3-4 weeks, physiotherapy with thenar muscles exercises was started. 10 weeks after the injury, our patient reported a total recovery of function and pain-free thumb movement during daily activities. CONCLUSION: Ulnar sesamoid fractures are rarely reported in current literature. This type of injury should be recognized as early as possible since it can be easily missed. Then a benign course can be expected after short immobilization of the MCPJ of the thumb during circa 2 weeks. UCL instability or a Stener lesion should be excluded at the emergency department by performing an ultrasound. With this case report, we underline the importance of early diagnosis and exclusion of an unstable Stener lesion. PMID- 28819598 TI - Two-staged Bilateral, Femoral Alignment Osteotomy with Concomitant Total Knee Arthroplasty in an Achondroplasia Patient - A Case Report. AB - INTRODUCTION: Achondroplasia is the most common form of dwarfism in humans and is orthopedically characterized by shortened extremities and an exaggerated lumbar lordosis. The surgical challenges are maintenance of axial alignment during limb lengthening as well as joint preservation and alignment restoration. CASE REPORT: We present a 46-year-old female suffering from achondroplasia with severe pain in both knees. Severe varus deformities of both femurs and degeneration of both knee joints became apparent on clinical and radiological examination. On each femur, we performed one-staged, lateral closed-wedge osteotomy, and total knee arthroplasty (TKA). Subsequently, the patient was relieved of knee joint pain and gained a greater range of motion. CONCLUSION: One-staged valgization osteotomy and concomitant TKA represents a challenging, yet reasonable, surgical solution in axially severe malaligned and joint degenerated patients. PMID- 28819599 TI - Synovial Chondromatosis: A Rare Differential Diagnosis of Hip Pain in a Child. AB - INTRODUCTION: Primary synovial chondromatosis (SC) is a disease of the synovium occurring in the third to fifth decade of life with the peak incidence in the fifth decade and commonly involves the knee in 50% cases. The diagnosis of SC is primarily radiological and intraoperative. Primary SC of the hip is rare, and their prevalence is not known. CASE REPORT: A 7-year-old female child presented with pain and limp left hip for 6 weeks. She had a stiff hip gait. Clinical examination revealed a fixed abduction, flexion deformity, and restricted internal rotation with apparent lengthening of 2 cm. The ultrasonography revealed synovial effusion with synovial deposits. Magnetic resonance imaging revealed features of tuberculous synovitis, inflammatory synovitis, or a rare possibility of SC. Arthrotomy was performed following failed hip aspiration. Multiple chondral loose bodies were noted on incision of capsule. Partial synovectomy was also performed. The synovium histopathology revealed multiple synovial chondral inclusions. A final diagnosis of SC was made. CONCLUSION: We report this case of primary SC, 7-year-old female patient with symptoms of hip pain, limp, and fixed deformities restricting hip function as a first of its kind in the mentioned age group. Hence, although rare SC may be considered as one of the differential diagnosis in hip symptoms in children <10 years of age. PMID- 28819600 TI - Extensively Drug-resistant Tuberculosis of the Lumbar Spine in a Six-year-old Child: A Case Report. AB - INTRODUCTION: The emergence of extensively drug-resistant tuberculosis (XDR-TB) is a challenging paradigm shift faced by the TB control programs worldwide today. The treatment is further compounded with unique management difficulties faced in pediatric patients. Treatment of XDR-TB requires prolonged chemotherapy with second-line drugs which offer lesser potency and increased risk of drug-related side effects. We present a case of spinal XDR-TB in a child, managed with extended second-line antitubercular chemotherapy (ATT). CASE REPORT: A 6-year old, Caucasian male child complained of persistent back pain for 3 weeks, with lumbar tenderness without neurodeficit. Radiographs showed fourth lumbar (L4) vertebral body collapse. Magnetic resonance imaging showed features suggestive of TB spondylodiscitis. The erythrocyte sedimentation rate (ESR) was raised. In view of the high prevalence rate of TB, on clinical suspicion, empirical first-line ATT (isoniazid + rifampicin + ethambutol + pyrazinamide) was given for 6 months, under the Revised National Tuberculosis Control Program (RNTCP). In the course of ATT, child developed iliopsoas abscess which was drained surgically. Repeat radiological evaluation showed almost complete L4 body destruction and 10 cm * 8 cm pre-vertebral abscess. ESR was further raised. Vertebral biopsy culture showed growth of Mycobacterium tuberculosis complex susceptible only to capreomycin (Cm). Second-line ATT (moxifloxacin + clofazimine + linezolid + isoniazid + amoxicillin-clavulanate + para-aminosalicylic [PAS] acid) with daily intramuscular Cm was initiated, under the RNTCP Programmatic Management of Drug Resistant TB initiative. At 3 months, tenderness was absent, ESR decreased, and radiology showed consolidation of L3 and L5 vertebral bodies and their interspace. At 6 months, injectable Cm was stopped, oral ATT continued for 18 months. No major drug-related side effects were noted. At final follow-up, imaging showed complete L4 body absence, intact posterior elements, surrounding bony consolidation, resolution of abscess without neurodeficit, or deformity. CONCLUSION: XDR-TB should be suspected if there is clinical and/or radiological progression of TB in spite of chemotherapy or a prior history of treatment for TB. Effective treatment of XDR-TB requires a high index of suspicion and prompt, aggressive drug sensitivity-based ATT. PMID- 28819601 TI - Carcinoma of Unknown Primary Mimicking Multiple Myeloma. AB - INTRODUCTION: Pathological fractures due to secondaries in the bone are common with carcinoma of lung, breast, prostate, and in multiple myeloma. Multiple pathological fractures after a trivial fall, indicating metastases warrants detailed investigations for the search of primary. Skeletal secondaries should be strongly suspected in addition to obvious diagnosis of multiple myeloma in such cases. CASE REPORT: We report a case of pathological fractures at multiple sites: The vertebral column, proximal shaft of femur, and contralateral fracture neck of femur. This patient presented with typical features of multiple myeloma, but on complete evaluation was found to be due to extensive metastases in the bones secondary to adenocarcinoma, the primary site of which remained unknown, despite extensive search and evaluation, making it a case of carcinoma of unknown primary. CONCLUSION: While dealing with patients with extensive skeletal lesions and pathological fractures, secondaries due to adenocarcinoma elsewhere should be kept in mind along with other probabilities such as multiple myeloma. PMID- 28819602 TI - Fracture Dislocation of Shoulder with Brachial Plexus Palsy: A Case Report and Review of Management Options. AB - INTRODUCTION: Injuries causing fracture dislocation of shoulder and brachial plexus palsy are extremely rare. As per authors' knowledge, three part fracture of proximal humerus with shoulder dislocation and brachial plexus palsy has not been reported in the literature. CASE PRESENTATION: A 53 year old female sustained a three part fracture of right proximal humerus along with dislocation of shoulder joint and brachial plexus palsy following a fall from a flight of stairs. Fracture was managed by plating of proximal humerus and brachial palsy was followed up with electrodiagnostic studies and regular physiotherapy. Fracture united by three months and patient had near complete recovery of brachial palsy. Authors have discussed diagnostic modalities and management options in the article. CONCLUSION: Clinician should always look for clinical evidence of brachial plexus injury in patients with anterior shoulder dislocation. Signs of nerve injury with shoulder fracture dislocation are easily overlooked or incorrectly attributed to pain due to bony injury. Subsequent loss of shoulder function in elderly is often thought to be due to immobilization and stiffness. Clinical suspicion can help in diagnosing the often missed neurological injuries and can help in improving outcomes. PMID- 28819603 TI - Bilateral Ankle Fusion in Leak Syndrome Induced Deformity: A Case Report. AB - INTRODUCTION: Systemic capillary leak syndrome (SCLS) is a rare condition of unknown etiology defined by sudden episode of hypotension, high hematocrit, and low serum protein concentration due to capillary hyperpermeability. Several treatments have been published for this pathology and eventual compartment syndrome but not for the disabling consequences. This clinical case highlights the negative orthopedic consequences of a severe systemic attack and reports a subsequent deformity treatment option that resulted in the patient quality of life improvement. To our knowledge, orthopedic surgery for SCLS induced foot and ankle deformity is presented for the first time. CASE REPORT: A 40-year-old Caucasian female patient was referred to our institution for bilateral foot and ankle deformity after compartment syndrome during SCLS attack. She presented a bilateral rigid equino-cavo-varus-adductus deformity causing walk impairment. Bilateral ankle fusion by retrograde nailing was performed in a two-staged procedure. Rigid claw toes were also surgically addressed in an additional procedure. Radiologically, apparent ankle fusion occurred at 3 months post operative in both sides. Deformity correction allowed the patient to regain walking capacity. A right ankle tibiotalar failed arthrodesis was noticed at 24 months post-operative. Prophylactic human immunoglobulin therapy was initiated after the last surgery with no recurrent attack registered during the 38 months follow-up period. CONCLUSION: Bilateral ankle fusion improved this patient quality of life by restituting walking capacity and lowering the probability of lower limb deformity related ulcers and infections. Major and minor complications are also discussed. This report contributes to the global knowledge about this syndrome and elicits the importance of the induced deformities surgical correction. PMID- 28819604 TI - Posterior Knee Loose Bodies: Treated by Posterior Knee Arthroscopy. AB - INTRODUCTION: The posterior portion of the knee joint, which includes the tibial attachment of the posterior cruciate ligament and the posterior horn of the menisci, has been called a "blind spot" because it is difficult to observe this area under arthroscopy through standard anterior portals. Posteromedial, posterolateral, and posterior transseptal portals have been developed for visualization and instrumentation of the posteromedial and posterolateral compartments of the knee joint. CASE REPORT: A 57-year-old man presented of persistent left posterior knee pain for 1 year. Radiographs and magnetic resonance imaging showed posterior knee encapsulated loose bodies. The symptoms did not respond to physiotherapy and analgesics. The loose bodies were removed via posterior knee arthroscopy. The symptoms subsided afterward. CONCLUSION: Lateral portal of the knee allows establishment of the posterolateral portal under endoscopic visualization, and the loose bodies of the posterior compartment of the knee can be effectively removed via the posterior knee arthroscopy. PMID- 28819605 TI - Recurrent Extra- and Intra-articular Synovial Chondromatosis of the Ankle with Tarsal Tunnel Syndrome: A Rare Case Report. AB - INTRODUCTION: Synovial chondromatosis is a rare, benign monoarticular condition characterized by the metaplastic formation of cartilaginous nodules from the synovium of joints (intra-articular), tendons and bursae (extra-articular). These nodules have the potential to detach and form loose bodies within the joint space. The most common locations are the large joints such as the knees, hips, elbows, and shoulders, with less common locations being the foot and ankle joints. Synovial chondromatosis primarily occurs in men between the third and fifth decades of life, and it typically presents as chronic joint pain with swelling, decreased joint range of motion, and osteoarthritis. Treatment is usually centered on excision and retrieval of nodules and loose bodies. Prognosis is usually good with a low-moderate likelihood of recurrence. CASE REPORT: We report the very rare case of a 27-year-old male with recurrent intra- and extra articular ankle synovial chondromatosis, who also reported symptoms consistent with tarsal tunnel syndrome. His initial presentation was left ankle pain which was managed by open surgical debridement. Two years after, he re-presented with continued pain and tingling along the plantar aspect of his foot. On his second presentation, a dual approach was taken with arthroscopic as well as open debridement. He reported resolution of his symptoms postoperatively as well as at 3 years of follow-up. CONCLUSION: Simultaneous extra- and intra-articular chondromatosis of the ankle is very rare and can be difficult to treat. It is important to recognize this disease as a rare but plausible cause of tarsal tunnel syndrome. Treatment may be complicated with early or late recurrence despite complete excision, highlighting the need for intentional follow-up of all cases. PMID- 28819606 TI - Intra-articular Loose Body with Concomitant Bankart Lesion after a Traumatic Shoulder Dislocation: A Case Report. AB - INTRODUCTION: The spectrum of pathoanatomic lesions encountered in anterior shoulder dislocation is broad. There could be a presence of loose bodies, chondral and osteochondral, in the shoulder joint and also concomitant rotator cuff partial tears resulting from acute and chronic shoulder instability. CASE REPORT: We present one case report of a 46-year-old male Chinese with an uncommon case of Bankart lesion, with a full thickness chondral defect over the superior glenoid articular surface manifesting as a large intra-articular loose cartilaginous body. The patient presented with persistent shoulder pain with signs of shoulder instability. He underwent arthroscopic repair of his Bankart lesion with the removal of intra-articular loose body. We aim to discuss the diagnosis, radiological imaging, as well as, arthroscopic treatment of loose body in the glenohumeral joint due to anterior shoulder dislocation in our report. CONCLUSION: In our case report, we highlight the importance to identify other associated injuries from the history and examination after an episode of traumatic anterior shoulder dislocation. Arthroscopic treatment is a useful minimally invasive option to remove the large fragment of intra-articular loose body and also repair the Bankart lesion in the same setting. Both of these lesions must be treated as they are crucial for pain relief, as well as stabilizing the shoulder, to prevent further episodes of dislocation. PMID- 28819607 TI - A Gustilo Type 3B Open Tibial Fracture Treated with a Proximal Flexor Hallucis Longus Flap: A Case Report. AB - INTRODUCTION: In the treatment of Gustilo Type 3B open tibial fractures, it is important to perform soft tissue reconstruction and bone reconstruction simultaneously. Gastrocnemius muscle and soleus muscle flaps are generally used as rotational flaps for the tibia. The distal third of the tibia can often not be covered with the gastrocnemius muscle and soleus muscle flaps. Treatment distal to the distal third of the tibia is difficult because fewer flap options are available. In the present report, we describe our experience with a Gustilo Type 3B open tibial fracture treated by gastrocnemius muscle and soleus muscle flaps, along with an additional proximally based flexor hallucis longus flap, which is a rare procedure. CASE REPORT: The participant was a 17-year-old male who injured his left tibia in a motorcycle traffic accident. Physical examination revealed a wound of 13 cm * 7 cm extending from the medial lower leg to the posterior aspect, with extensive skin loss. There was no nerve or vascular injury. The tibia was exposed, with detachment of the periosteum. The radiograph revealed a tibial shaft fracture. The AO/OTA classification was 42-A3.3, and it was classified as a Gustilo-Anderson Type 3B fracture. Gastrocnemius muscle and soleus muscle flaps were lifted in the area of the soft-tissue defect and then, placed over the tibia. Despite this, the distal portion of the tibia remained uncovered. Therefore, a flexor hallucis longus flap was lifted and placed over the distal portion of the tibia. On day 7 after the injury, the external fixation device was removed and the tibial shaft was fixated with two Ender nails (4.5 mm in diameter). The clinical course was satisfactory, and the skin graft and flap were successful. Bone union was achieved without infection, and the resulting range of motion was normal. CONCLUSION: For the treatment of Gustilo-Anderson Type 3B open tibial fractures, early treatment of the soft-tissue defect is vital. We surgically treated a Gustilo-Anderson Type 3B open tibial fracture with gastrocnemius muscle and soleus muscle flaps, along with an additional proximally based flexor hallucis longus flap, which is a rare procedure. In the event of a soft-tissue defect in the distal third of the tibia, the use of a proximally based flexor hallucis longus flap is an effective surgical approach. PMID- 28819608 TI - Profunda Femoris Artery Pseudoaneurysm after Intramedullary Fixation for a Pertrochanteric Hip Fracture. AB - INTRODUCTION: Vascular complications after femoral fixation are rare and not only easy to recognize but also potentially life-threatening. The aim of this case report is to describe how a pseudoaneurysm of the deep femoral artery can complicate an intramedullary nailing after a pertrochanteric fracture and how it can be treated. CASE REPORT: We report the case of a 90-year-old female who developed a pseudoaneurysm of the profunda femoris artery 16 days after intramedullary femoral nailing for a pertrochanteric hip fracture. Stenting of the artery was urgently performed with a consequent resolution of the symptoms. CONCLUSION: Diagnosis of vascular complications after hip surgery may be very challenging because symptoms are often nonspecific. Despite their rarity, it is important to know this type of complications to address the diagnostic pathway in the right direction and to treat them promptly. PMID- 28819609 TI - Combined Fluoroscopic and Arthroscopic Detection and Removal of a Foreign Body Lost During Elective Shoulder Arthroscopy: A Case Report. AB - INTRODUCTION: We report a case of a lost metal platelet from a radiofrequency ablation probe (VAPR VUE Radiofrequency System, Cool Pulse 90, DePuy, Synthes, Switzerland) in the shoulder joint during elective arthroscopic cuff repair. To the best of our knowledge, this kind of an incident during elective arthroscopy has not been described in the literature so far. In addition, we present an algorithm on how to deal with such an incident. CASE REPORT: A 69-year-old woman underwent an arthroscopic subacromial decompression and rotator cuff repair for a torn supraspinatus tendon. While performing the subacromial decompression and after swapping the portals from lateral to posterior, the metal platelet of the electrocautery device got detached from the instrument and lost in the operation field. Several attempts to visualize the lost platelet with the camera failed. Finally, intraoperative fluoroscopic imaging was used to detect the platelet. To confirm the definitive whereabouts of the platelet, two spinal needles were positioned perpendicular to another under x-ray control, both pointing at the missing platelet. After determining the exact location, the platelet could finally be visualized with the camera and removed. Due to this incident, the operation time was extended extensively, and the patient as well as the theatre team was exposed to an unnecessary amount of radiation. CONCLUSION: This report indicates that an extraordinary incident such as the detachment of a component of the arthroscopic equipment during surgery is possible and should be kept in mind by the surgeon. Therefore, we believe that it is essential to perform a test of integrity at least at the end of every operation. In addition, we are presenting an algorithm on how to deal with the situation of a lost foreign body during arthroscopy, which can be applied to any joint. PMID- 28819610 TI - A Rare Case of Massive Rotator Cuff Tear and Biceps Tendon Rupture with Posterior Shoulder Dislocation in a Young Adult - Surgical Decision-making and Outcome. AB - INTRODUCTION: Massive rotator cuff tears (RCTs) in the context of shoulder dislocations are relatively uncommon in the young adult (<40 years) and if reported are more commonly described in association with acute traumatic anterior glenohumeral dislocations. They have rarely been described with posterior dislocations, regardless of patient age. This is the 1st case reported in the context of posterior dislocations, where a triad of biceps tendon rupture, posterior dislocation, and RCTs was observed during surgery. It provides an important reminder to readers about certain injuries commonly overlooked during the assessment of an acute traumatic shoulder. CASE REPORT: We report an atypical case of a massive RCT involving a 34-year-old Asian male who landed on his outstretched hand after falling off a bicycle. A tear involving the supraspinatus and subscapularis was visualized during surgery, along with long head of biceps (LHB) tendon rupture. This was after an initial failure to achieve closed reduction of the posteriorly dislocated left shoulder. CONCLUSION: It is easy to miss the posterior instability, the associated RCTs or the biceps tendon injuries. Biceps tendon rupture should be a consideration when one is unable to reduce a posteriorly dislocated shoulder. The interposed torn LHB tendon trapped within the glenohumeral joint was the likely physical block in the initial failure to achieve closed reduction. With timely diagnosis, prudent physical examination, early imaging and surgery, and excellent results can potentially be achieved to return a young patient to full functionality. PMID- 28819611 TI - Acute Stress Fracture of the Pelvis after Total Hip Arthroplasty: A Case Report. AB - INTRODUCTION: Acute hip pain following total hip arthroplasty (THA) could have numerous causes to include stress fracture of the pelvis. Stress fractures of the pelvis are rare and have been reported to involve the medial wall and the pubic ramus. A unique case is presented demonstrating the clinical presentation and management of an acute stress fracture of ilium and anterior column following a THA. CASE REPORT: A 72-year-old man underwent an uncomplicated right THA. He was noted to have femoral head resorption and thin osteoporotic bone intraoperatively. He initially did well postoperatively and ambulating without pain or assistive devices. Within 1 month of surgery, he returned with acute right hip pain without any traumatic event. Radiographs showed migration of the acetabular component and computed tomography scan confirmed a fracture through the ilium. The patient underwent revision surgery, where the fracture was reduced and internal fixation was achieved with a reconstruction plate and acetabular cage construct. At 9 months postoperatively, the patient remained pain-free with full weight bearing and with stable radiographs. CONCLUSION: Elderly patients who undergo THA may have low bone mineral density. These patients can develop stress fractures in their pelvis after surgery. These fractures may involve the medial wall, posterior column, or posterior wall. In patients who develop atraumatic pain postoperatively, it is important to consider for potential stress fractures of the ilium and evaluate appropriately with imaging. In these cases, revision surgery can be necessary to provide fixation of the stress fracture. PMID- 28819612 TI - Uncommon Floating Knee in a Teenager: A Case Report of Ipsilateral Physeal Fractures in Distal Femur and Proximal Tibia. AB - INTRODUCTION: The concomitance of ipsilateral physeal fractures of the distal femur and the proximal tibia is an extremely scarce entity. It is conceptually similar to floating knee in the pediatric population. CASE REPORT: One case with this injury is reported in a 16-year-old teenager. He was treated surgically by close reduction and internal fixation. The diagnosis of the tibial fracture was initially missed, and the fracture was seen on the post-operative radiographs. Orthopedic treatment was made for this injury. 2 years after, no angular deformity neither shortening of the limb were found. CONCLUSION: These rare injuries could have serious immediate and remote complication with a considerable functional impact. The diagnosis of proximal tibia physeal fracture could be missed in the context of a concomitant more impressive distal femur fracture. The possibility of a combination of these two injuries should then be kept in mind. Anatomic reduction should be made as soon as possible using a gentle technique, and attention should be given to the diagnosis of the neurovascular complications. PMID- 28819613 TI - Aseptic Loosening after Total Hip Arthroplasty in an Acromegalic Patient: A Case Report. AB - INTRODUCTION: Acromegaly is a rare disorder characterized by excess secretion of growth hormone and its principle mediator, insulin-like growth factor-1. Although acromegaly is frequently associated with osteoarthritis, the outcome of arthroplasty in this population is not documented. CASE REPORT: We report here a case of aseptic loosening of an uncemented total hip arthroplasty acetabulum in an acromegalic patient that was revised with a cemented cup. It has been suggested that the incidence of this complication is increased in other pathology with a similarly high bone-turnover (e.g., Paget's disease), but this complication has however not yet been reported in the setting of acromegaly. CONCLUSION: Although coincidence cannot be ruled out, multiple metabolic hypotheses could account for an altered osseointegration process in the presence of acromegaly, which could lead to a higher risk of loosening. PMID- 28819614 TI - Acute Compartment Syndrome after an Olecranon Fracture in a Patient with Mild Hemophilia B. AB - INTRODUCTION: Compartment syndrome is a serious condition characterized by compartmental pressures within 20 mmHg of diastolic blood pressure, or clinical signs of pain, paresthesia, pallor, and lack of pulses. Often a surgical intervention is necessary. Increased surveillance for compartment syndrome is important when a patient with a bleeding disorder sustains a traumatic injury. CASE REPORT: We present a case of forearm compartment syndrome in a patient with mild hemophilia B who sustained an olecranon fracture. The patient received factor replacement and he underwent emergent forearm fasciotomies to avoid muscle necrosis. Over the subsequent week, the patient returned to the operating room 3 times for repeat irrigation and debridements, partial wound closure, open reduction internal fixation of his olecranon fracture and eventual skin grafting of the volar forearm wound. CONCLUSION: Failure to recognize compartment syndrome in even mild forms of hemophilia may result in loss of function, neurologic deficits, and limb amputations. The management of acute compartment syndrome in patients with hemophilia requires timely recognition, replacement of clotting factors, and emergent fasciotomies. PMID- 28819615 TI - Effects of Vestibular Rehabilitation Interventions in the Elderly with Chronic Unilateral Vestibular Hypofunction. AB - INTRODUCTION: Although vestibular rehabilitation therapy (VRT) methods are relatively popular in treating patients with body balance deficits of vestibular origin, only limited studies have been conducted into customized exercises for unilateral vestibular hypofunction (UVH). Furthermore, very little evidence is available on the outcomes of VRT in the elderly population with chronic UVH. MATERIALS AND METHODS: A total of 21 patients, aged 61 to 74 years, with UVH participated in this study. The dizziness handicap inventory (DHI) was performed immediately before, and 2 and 8 weeks after treatment. RESULTS: All patients showed a reduction in DHI scores during the study. The average decrease in DHI score was 25.98 points after 2 weeks' intervention (P<0.001) and 32.54 points at the end of the study. This improvement was observed in all DHI subscores, and was most profound in the functional aspect. The correlation between the degree of final recovery and canal paresis was not significant (P>0.05). There were no relationships between the scores and gender. CONCLUSION: Our study demonstrates that VRT is an effective method for the management of elderly patients with UVH, and shows maximal effect on functional aspects. PMID- 28819616 TI - Maternal Risk Factors Associated with the Development of Cleft Lip and Cleft Palate in Mexico: A Case-Control Study. AB - INTRODUCTION: Cleft lip and palate, the most common developmental deformity, is seen worldwide and the etiology involves a combination of genetic and environmental factors. The purpose of this study was to determine the maternal risk factors associated with the development of cleft lip and cleft palate. MATERIALS AND METHODS: We conducted a case control study at the Women's Hospital in Culiacan, Mexico. Medical records were analyzed, including patients who delivered babies with and without cleft lip and cleft palate from January 2010 to December 2015. Multiple variables were analyzed, including gestational age, weight at birth, the use of folic acid and multivitamins during pregnancy, smoking, alcohol abuse, the use of recreational drugs, history of sexually transmitted infections, marital status, socioeconomic status, education, and nutritional status. RESULTS: We found that the maternal risk factors with the strongest association for the development of cleft lip and cleft palate were the following: patients who were not taking folic acid during pregnancy [OR 3.27, 95% CI 1.32-8.09], P=0.00; patients who were not taking vitamin supplementation during pregnancy [OR 2.6, 95% CI 1.19-7.27], P=0.02; smoking during pregnancy [OR 2.05, 95% CI 1.23-3.41], P=0.01; and alcohol abuse during pregnancy [OR 1.90, 95% CI 1.17-3.08], P=0.03. CONCLUSIONS: The main risk factors associated with the development of cleft lip and cleft palate in a Mexican population at the Women's hospital in Culiacan, Sinaloa, Mexico were smoking, alcohol abuse, and patients not taking folic acid and multivitamins during pregnancy. PMID- 28819617 TI - The Antioxidant Effect of Curcumin on Cochlear Fibroblasts in Rat Models of Diabetes Mellitus. AB - INTRODUCTION: The aim of this study was to investigate the potential of curcumin as an antioxidant to increase the expression of superoxide dismutase (SOD) in fibroblasts of the cochlear lateral wall in rat models of diabetes mellitus. MATERIALS AND METHODS: Twenty-four male Wistar rats Rattus norvegicus were randomly divided into six groups: group 1 as the control group; group 2 as the diabetic group; group 3 and 4 as the diabetic groups that received curcumin therapy of 200 and 400 mg/kg b.w. for 3 days, respectively; and group 5 and 6 as the diabetic groups that received curcumin therapy of 200 and 400 mg/kg b.w. for 8 days, respectively. All rats underwent termination and necropsy procedure on their temporal bones for immunohistochemical assay to determine the expression of SOD. RESULTS: The decreased expression of SOD was detected in the diabetic group (without curcumin treatment). The treatment of curcumin at doses of 200 and 400 mg/kg b.w. for 3 and 8 days led to significant differences (P<0.05) in the expression of the SOD compared to diabetic group (without curcumin treatment). No significant differences were found in terms of dose and duration of curcumin administration on the expression of SOD. CONCLUSION: Curcumin may act as an antioxidant against oxidative stress due to diabetes mellitus via increased expression of SOD on cochlear fibroblasts in rat models of diabetes mellitus. PMID- 28819618 TI - Serum Levels of Cyfra 21 in Patients with Benign and Malignant Salivary Gland Tumors. AB - INTRODUCTION: Cyfra 21 is a serum-soluble fragment of cytokeratin19. Increased Cyfra 21 serum levels and their benefit as a tumor marker have been shown in some malignancies. This study aimed to evaluate the serum levels of Cyfra 21 in patients with benign and malignant salivary gland tumors. MATERIALS AND METHODS: In this cross-sectional study, the serum level of Cyfra 21 in 44 patients with malignant salivary gland tumors and 16 cases of pleomorphic adenoma were compared with 28 healthy controls using enzyme-linked immunosorbent assay (ELISA). Data were analyzed statistically using the Kruskal Wallis test, analysis of variance (ANOVA) and Spearman's correlation tests. RESULTS: Mean serum levels of Cyfra 21 were 0.135 +/- 0.285 ng/ ml in the control group, 0.167 +/- 0.142 ng/ ml in patients with pleomorphic adenoma and 1.059 +/- 3.251 ng/ml in patients with malignant salivary gland tumors. There was no significant difference among groups. Cyfra 21 levels did not correlate with location of tumor, clinical stage or cigarette smoking. CONCLUSION: Results of the present study showed no significant difference in Cyfra 21 serum level in salivary gland tumors compared with normal individuals. In addition, Cyfra 21 serum level was not sufficiently sensitive to function as a tumor marker in salivary gland tumors. PMID- 28819619 TI - Is the Persian Version of the "Olfactory Disorder Questionnaire" Reliable and Valid? AB - INTRODUCTION: The Questionnaire for Olfactory Dysfunction (QOD) is a self reporting olfactory-related quality of life questionnaire. The aim of this study was to determine the reliability and validity of the Persian version of this questionnaire. MATERIALS AND METHODS: One hundred and thirteen patients with olfactory problems were enrolled in this study. The English version of the QOD was first translated into Persian. The reliability was then tested by determining the Cronbach alpha coefficient to assess internal consistency. The QOD was reviewed by a panel of experts, followed by calculating the content validity index to determine the content validity. RESULTS: Based on the reliability analysis, the total Cronbach alpha was 0.88. The items in the "life quality" and "parosmia" domains had a good internal consistency in total, as well as in both genders and in different age subgroups. For the "sincerity" domain, however, low internal consistency was revealed (Cronbach alpha = 0.25). When questions related to the sincerity domain were omitted, the Cronbach alpha reached 0.89. The overall scale validity index for clarity and relevance were 0.88 and 0.87, respectively. CONCLUSION: The Persian version of the QOD seems to be a reliable and valid tool for the assessment of quality of life in patients with olfactory dysfunction. The "sincerity" domain cannot be used separately or should be substantially modified in order to be applicable to the Iranian population. However, there is no need to change the whole format of the questionnaire. PMID- 28819620 TI - Fishbones in the Upper Aerodigestive Tract: A Review of 24 Cases of Adult Patients. AB - INTRODUCTION: We present a retrospective study series and discussion of the current literature to discuss the management of fishbones in the upper aerodigestive tract. MATERIALS AND METHODS: From January 2013 to July 2016, all patients referred to our referral center because of a fishbone in the upper aerodigestive tract were analysed. RESULTS: Of the 24 patients, 95% of them reported discomfort in the throat. It was noted that 58% of physical examinations and nasofibroscopy results were normal. Ten fishbones were found in the upper aerodigestive tract. They were removed by foreign body forceps or by endoscopy depending on the location. Foreign body-related complications were not observed. Ten patients with no identifiable fishbone had no symptoms after 48 hours. Other patients, including the 10 patients with the fishbone removed, were asymptomatic after 10 days. CONCLUSION: From our experience, we recommend a systematic nasofibroscopy. If it is normal, the patient is assessed at 48h. The complementary investigation by CT scan and/or oesophagoscopy must be reserved in cases of suspicion of oesophageal localization or complication. Otherwise, rigid or flexible endoscopy may be performed when laryngoscopy is unsuccessful or for the treatment of foreign bodies lodged below this area. PMID- 28819621 TI - An Unusual Cause of Postaural Swelling: Kimura's Disease. AB - INTRODUCTION: Kimura's disease (KD) is an allergic inflammatory disorder of unknown etiology endemic in Orientals. Kimura's disease was first mentioned by Kimm and Szeto in China in 1937. Kimura's disease is commonly encountered in Asia and is mostly reported in Japan, China, Singapore and Honkong. However, only a few cases have been reported in the Indian subcontinent. CASE REPORT: A case of Kimura's disease in a young male managed by surgery is reported in addition to a literature review. CONCLUSION: Diagnosis is made on the basis of histopathological analysis, clinical presentation, and laboratory investigations. Long term follow-up is required as Kimura's disease is prone for recurrence. PMID- 28819622 TI - Mixed Pyolaryngocele: A Rare Case of Deep Neck Infection. AB - INTRODUCTION: Pyolaryngocele is a very rare and serious complication of laryngocele. It can present as deep neck space infection and mislead the diagnosis. Our aim is to bring this unusual entity to the attention of surgeons and describe its clinical features. CASE REPORT: We report a case of a 45-year old male patient with a five-week history of neck swelling, dysphonia, dyspnea and odynophagia. An urgent CT scan showed a mixed pyolaryngocele. The management consisted of a high dose antibiotic and an excision of the residual laryngocele via an external approach. CONCLUSION: A pyolaryngocele is an unusual complication of laryngocele, which becomes secondarily infected, causing many symptoms. Removing the laryngocele is still the best treatment option to prevent this complication and recurrence. PMID- 28819623 TI - Pharyngocutaneous Fistula as a Rare Late Postoperative Complication Following Submandibulectomy: A Case Report. AB - INTRODUCTION: Submandibular gland excision is the gold standard treatment for submandibular gland disease. Although submandibulectomy is a relatively standardized surgical procedure, complications are frequently reported. These complications include nerve paralysis or paresis, aesthetic sequelae, hematoma, salivary fistulas or sialoceles, wound infections, hypertrophic scars and inflammations caused by residual lithiasis in the salivary duct. CASE REPORT: We report a case of a rare complication of submandibular gland excision, pharyngocutaneous fistula, which appeared 6 years after previous surgery. The patient underwent surgery, during which a fistula tract from the skin to the pharynx was found and excised. CONCLUSION: The authors believe that inappropriate execution of the surgical procedure could result in postoperative complications. PMID- 28819624 TI - Diffuse Idiopathic Skeletal Hyperostosis Involving Cervical and Lumbar Spine Presenting with Dysphagia: A Case Report. AB - INTRODUCTION: Diffuse Idiopathic Skeletal Hyperostosis (DISH) is a very rare cause of dysphagia when it occurs in the cervical spine. It can also affect the lumbar region where it causes deformity. CASE REPORT: In this article, a rare case of Diffuse Idiopathic Skeletal Hyperostosis involving both the cervical and lumbar spine, presenting with dysphagia and spinal stiffness leading to a stooping posture, is reported. CONCLUSION: Cases of simultaneous involvement of cervical and lumbar vertebrae by Diffuse Idiopathic Skeletal Hyperostosis, presenting with symptoms of both area involvement, are rarely reported in the English literature. When investigating a case of dysphagia, a high level of suspicion is required to diagnose such a condition. PMID- 28819625 TI - Antagonistic Properties of Some Halophilic Thermoactinomycetes Isolated from Superficial Sediment of a Solar Saltern and Production of Cyclic Antimicrobial Peptides by the Novel Isolate Paludifilum halophilum. AB - This study has focused on the isolation of twenty-three halophilic actinomycetes from two ponds of different salinity and the evaluation of their ability to exert an antimicrobial activity against both their competitors and several other pathogens. From the 23 isolates, 18 strains showed antagonistic activity, while 19 showed activities against one or more of the seven pathogen strains tested. Six strains exhibited consistent antibacterial activity against Gram-negative and Gram-positive pathogens characterized at the physiological and molecular levels. These strains shared only 94-95% 16S rRNA sequence identity with the closely related species of the Thermoactinomycetaceae family. Among them, the potent strain SMBg3 was further characterized and assigned to a new genus in the family for which the name Paludifilum halophilum (DSM 102817T) is proposed. Sequential extraction of the antimicrobial compounds with ethyl acetate revealed that the crude extract from SMBg3 strain had inhibitory effect on the growth of the plant pathogen Agrobacterium tumefaciens and the human pathogens Staphylococcus aureus, Salmonella enterica, Escherichia coli, and Pseudomonas aeruginosa. Based on the HRESI-MS spectral data, the cyclic lipopeptide Gramicidin S and four cyclic dipeptides (CDPs) named cyclo(L-4-OH-Pro-L-Leu), cyclo(L-Tyr-L-Pro), cyclo(L-Phe L-Pro), and cyclo(L-Leu-L-Pro) were detected in the fermentation broth of Paludifilum halophilum. To our knowledge, this is the first report on the isolation of these compounds from members of the Thermoactinomycetaceae family. PMID- 28819626 TI - Robust Significance Analysis of Microarrays by Minimum beta-Divergence Method. AB - Identification of differentially expressed (DE) genes with two or more conditions is an important task for discovery of few biomarker genes. Significance Analysis of Microarrays (SAM) is a popular statistical approach for identification of DE genes for both small- and large-sample cases. However, it is sensitive to outlying gene expressions and produces low power in presence of outliers. Therefore, in this paper, an attempt is made to robustify the SAM approach using the minimum beta-divergence estimators instead of the maximum likelihood estimators of the parameters. We demonstrated the performance of the proposed method in a comparison of some other popular statistical methods such as ANOVA, SAM, LIMMA, KW, EBarrays, GaGa, and BRIDGE using both simulated and real gene expression datasets. We observe that all methods show good and almost equal performance in absence of outliers for the large-sample cases, while in the small sample cases only three methods (SAM, LIMMA, and proposed) show almost equal and better performance than others with two or more conditions. However, in the presence of outliers, on an average, only the proposed method performs better than others for both small- and large-sample cases with each condition. PMID- 28819627 TI - Pharmacokinetics and Pharmacodynamics Evaluation of Tramadol in Thermoreversible Gels. AB - We evaluated pharmacokinetics (PK) and pharmacodynamics (PD) induced by new formulations of tramadol (TR) in thermoreversible gels. The poloxamer- (PL-) tramadol systems were prepared by direct dispersion of the drug in solutions with PL 407 and PL 188. The evaluated formulations were as follows: F1: TR 2% in aqueous solution and F2: PL 407 (20%) + PL 188 (10%) + TR 2%; F3: PL 407 (25%) + PL 188 (5%) + TR 2%; F4: PL 407 (20%) + TR 2%. New Zealand White rabbits were divided into four groups (n = 6) and treated by subcutaneous route with F1, F2, F3, or F4 (10 MUg.kg-1). PK evaluation used TR and M1 plasma levels. PD evaluation was performed with the measurement of both pupils' diameters. F2 showed higher TR plasma concentration after 180 minutes and presented lower M1 concentrations at almost all evaluated periods. Areas under the curve (ASC0-480 and ASC0-infinity ) and clearance of F2 presented differences compared to F1. F2 presented significant correlation (Pearson correlation) between the enhancement of TR and M1 concentrations and the decrease of pupil size (miosis). Thus, F2 was effective in altering pharmacokinetics and pharmacodynamics effects of TR. PMID- 28819628 TI - Abnormal Biomarkers of Homocysteine Metabolism in Neonates with Conotruncal Heart Defects. AB - OBJECTIVES: The etiology of conotruncal heart defects (CHD) remains unknown; however relation between homocysteine, folate levels, and congenital heart disease was found. With this perspective in mind, the aim of the study was to investigate biomarkers of homosyteine metabolism pathway in mothers and their neonates with CHD. MATERIAL AND METHODS: Forty-three pairs of mothers and their neonates with CHD and forty pairs of mothers and neonates with nonconotruncal heart defects (non-CHD) were enrolled. The control group (CG) consisted of fifty nine pairs of mothers and their healthy neonates. For estimating the plasma total homocysteine (tHcy), serum folates, and cobalamin levels, mothers' venous blood samples and umbilical cord blood were taken in all groups. RESULTS: We observed higher tHcy levels in newborns with CHD in comparison to their mothers and to neonates with non-CHD. Cobalamin levels were significantly lower in neonates with CHD compared to other children. Folates and cobalamin levels were lower in CHD mothers compared to their children. CONCLUSIONS: Elevated homocysteine levels in neonates with CHD and folate metabolism disturbances in their mothers were noticed. The observed differences in homocysteine and cobalamin levels between neonates with CHD suggest the influence of various agents disturbing homocysteine metabolic pathways. PMID- 28819629 TI - Mixed Lactobacillus plantarum Strains Inhibit Staphylococcus aureus Induced Inflammation and Ameliorate Intestinal Microflora in Mice. AB - Objective. Staphylococcus aureus is an important pathogen that causes intestinal infection. We examined the immunomodulatory function of single and mixed Lactobacillus plantarum strains, as well as their impacts on the structure of the microbiome in mice infected with Staphylococcus aureus. The experiment was divided into three groups: protection, treatment, and control. Serum IFN-gamma and IL-4 levels, as well as intestinal sIgA levels, were measured during and 1 week after infection with Staphylococcus aureus with and without Lactobacillus plantarum treatment. We used 16s rRNA tagged sequencing to analyze microbiome composition. IFN-gamma/IL-4 ratio decreased significantly from infection to convalescence, especially in the mixed Lactobacillus plantarum group. In the mixed Lactobacillus plantarum group the secretion of sIgA in the intestine of mice (9.4-9.7 ug/mL) was significantly higher than in the single lactic acid bacteria group. The dominant phyla in mice are Firmicutes, Bacteroidetes, and Proteobacteria. Treatment with mixed lactic acid bacteria increased the anti inflammatory factor and the secretion of sIgA in the intestine of mice infected with Staphylococcus aureus and inhibited inflammation. PMID- 28819630 TI - Examining Health Inequalities in Latvia: A Decade of Association between Socioeconomic Position and Perceived Health Status. AB - The relationship between socioeconomic position (SEP) and population health is contextual. This study identifies the determinants of SEP producing health inequalities in the Latvian population. We also estimate the proportional contribution of different socioeconomic strata- (SES-) related determinants in Latvian health inequalities and measure the changes in the relative contributions of such determinants over the period 2005-2015. Using the household survey data (2005-2015), we construct a principal component analysis based SES index. A regression-based concentration index (CI) is our measure of health inequality to examine the distribution of perceived health status. Finally, we identify and estimate the contribution of predictors of health inequalities by decomposing CI with Oaxaca-Blinder decomposition. SES-related health inequalities have declined from 2005 (CI: 0.201) to 2015 (CI: 0.137) in Latvia-better-off Latvians enjoyed better perceived health during that period. The proportional contributions of education and working status have increased in 2015 compared to 2005. Although we have generated the first evidence to suggest policy relevant measures in addressing Latvian health inequalities, our decomposition method explains the extent of variation in perceived health instead of covariance between health and SEP. PMID- 28819631 TI - Effect of Tranexamic Acid on Hematologic Values and Blood Loss in Reverse Total Shoulder Arthroplasty. AB - PURPOSE: Use of tranexamic acid (TXA) in the setting of arthroplasty of the lower extremity has been previously described. The aim of this study was to evaluate the benefit of a single dose of TXA (500 mg vial) administered intravenously just prior to RTSA in an Asian population. METHODS: The records of 48 patients (no TXA, n = 24, versus TXA, n = 24) that underwent RTSA for cuff tear arthropathy were retrospectively reviewed. All patients had a Hemovac drain positioned for 2 days after surgery. Hemoglobin (Hb) and hematocrit (Hct) were checked on postoperative day 2 and compared with preoperative levels. RESULTS: Hematologic change on postoperative day 2 as determined by Hb level after surgery was statistically lower in the TXA group (2.8 +/- 0.8 versus 2.1 +/- 0.8 (mg/dL), P = 0.006). Mean fall in Hct level was also significantly less in the TXA group (8.0 +/- 2.5 versus 6.1 +/- 2.6 (L/L), P = 0.012). Total Hemovac drainage tended to be lower in the TXA group (263.4 +/- 129.3 versus 203.5 +/- 84.2 (ml), P = 0.064). TXA was found to have no noticeable side effects. CONCLUSION: The use of a single intravenous dose of TXA immediately prior to RTSA reduces hematologic deterioration postoperatively and the amount of Hemovac drainage. TXA could avoid unnecessary transfusion and its associated medical side effects and cost. PMID- 28819632 TI - Detection of Islet Cell Immune Reactivity with Low Glycemic Index Foods: Is This a Concern for Type 1 Diabetes? AB - Dietary management of autoimmune diabetes includes low glycemic foods classified from the glycemic index, but it does not consider the role that immunoreactive foods may play with the immunological etiology of the disease. We measured the reactivity of either monoclonal or polyclonal affinity-purified antibodies to insulin, insulin receptor alpha, insulin receptor beta, zinc transporter 8 (ZnT8), tyrosine phosphatase-based islet antigen 2 (IA2), and glutamic acid decarboxylase (GAD) 65 and 67 against 204 dietary proteins that are commonly consumed. Dietary protein determinants included unmodified (raw) and modified (cooked and roasted) foods, herbs, spices, food gums, brewed beverages, and additives. There was no immune reactivity between insulin or insulin receptor beta and dietary proteins. However, we identified strong to moderate immunological reactivity with antibodies against insulin receptor alpha, ZnT8, IA2, GAD-65, and GAD-67 with several dietary proteins. We also identified 49 dietary proteins found in foods classified as low glycemic foods with immune reactivity to autoimmune target sites. Laboratory analysis of immunological cross reactivity between pancreas target sites and dietary proteins is the initial step necessary in determining whether dietary proteins may play a potential immunoreactive role in autoimmune diabetes. PMID- 28819633 TI - Clinical Laboratory Evaluation of Electronic Cigarettes/Electronic Nicotine Delivery Systems: Methodological Challenges. AB - OBJECTIVE: Evaluating electronic cigarettes (ECIGs) in the clinical laboratory is critical to understanding their effects. However, laboratory evaluation of ECIGs can be challenging, as they are a novel, varied, and evolving class of products. The objective of this paper is to describe some methodological challenges to the clinical laboratory evaluation of ECIGs. METHODS: The authors gathered information about challenges involved in the laboratory evaluation of ECIGs. Challenges were categorized and solutions provided when possible. RESULTS: Methods used to study combustible cigarettes may need to be adapted to account for ECIG novelty and differences within the class. Challenges to ECIG evaluation can include issues related to 1) identification of ECIG devices and liquids, 2) determination of short -term ECIG abstinence, 3) measurement of use behavior, and 4) assessment of dependence. These challenges are discussed, and some suggestions to inform ECIG evaluation using clinical laboratory methods are provided. CONCLUSIONS: Awareness of challenges and developing, validating, and reporting methods used to address them aids interpretation of results and replication efforts, thus enhancing the rigor of science used to protect public health through appropriate, empirically-based, ECIG regulation. PMID- 28819634 TI - Cervical cancer control in HIV-infected women: Past, present and future. AB - Since the initial recognition of acquired immunodeficiency syndrome (AIDS) in 1981, an increased burden of cervical cancer was identified among human immunodeficiency virus (HIV)-positive women. Introduction of antiretroviral therapy (ART) decreased risks of opportunistic infections and improved overall survival. HIV-infected women are living longer. Introduction of the human papillomavirus (HPV) vaccine, cervical cancer screening and early diagnosis provide opportunities to reduce cervical cancer associated mortality. In line with 2030 Sustainable Development Goals to reduce mortality from non-communicable diseases, increased efforts need to focus on high burden countries within sub Saharan Africa (SSA). Despite limitations of resources in SSA, opportunities exist to improve cancer control. This article reviews advancements in cervical cancer control in HIV-positive women. PMID- 28819635 TI - Strengthening care and research for women's cancers in Sub-Saharan Africa. AB - *The burden of gynecologic cancers in low resource settings is overwhelming.*Areas with the highest needs have few human resources and limited infrastructure.*Cancer specialists can best help by leveraging ongoing work to assist local leaders. PMID- 28819636 TI - Short-Term Moderate Sleep Restriction Decreases Insulin Sensitivity in Young Healthy Adults. AB - CONTEXT AND PURPOSE: The literature suggests that severe sleep loss of more than a few hours a night decreases glucose tolerance and insulin sensitivity. The aim of this study was to determine whether moderate sleep restriction had similar effects. METHODS: Fifteen healthy non-obese (BMI=24.5+/-3.4 kg/m2) young adults (20.6+/-1.3 years) completed two 2-hour oral glucose tolerance tests (OGTT): one was after 3 days of time-in-bed restriction by 1-3 hours each night, and the other was after 3 days of ad libitum sleep. Glucose and insulin concentrations during OGTT, and fasting glucagon and cortisol concentrations were determined. The homeostasis model of insulin resistance (HOMA-IR), Matsuda index, and the quantitative insulin sensitivity check index (QUICKI) were calculated. RESULTS: The total time-in-bed during the sleep restriction and the ad libitum phase was 5.98+/-0.76 and 7.98+/-0.54 hours/day, and total sleep time was 5.16+/-0.49 and 6.65+/-0.64 hours/day, respectively. Glucose concentrations before and 30, 60, 90, and 120 minutes following consumption of glucose and area under the curve were not different for the two OGTT (p > 0.10 for all). Insulin concentration at fasting and area under the curve during the OGTT were significantly higher (p = 0.034 and 0.038, respectively) following restricted sleep than following ad libitum sleep. Fasting glucagon concentration was also higher (p = 0.003). The HOMA-IR, Matsuda index, and QUICKI all suggested decreased insulin sensitivity following restricted sleep. CONCLUSION: Short-term moderate sleep restriction reduced insulin sensitivity compared to ad libitum sleep in this group of healthy young adults. PMID- 28819638 TI - Connecting androgen receptor signaling and the DNA damage response: Development of new therapies for advanced prostate cancer. AB - Androgen receptor-mediated cell signaling involves complex molecular pathways that are interconnected with DNA damage response, including replication stress driven DNA repair. Understanding the relationships between androgen receptor signaling and DNA damage response at the molecular level will likely lead to novel and effective combination therapy for advanced prostate cancer. PMID- 28819637 TI - Cigarette Smoking and Its Hazards in Kidney Transplantation. AB - Cigarette smoking affects many organs. It causes vasoconstriction through activation of sympathetic nervous system which leads to elevation of blood pressure and reduction in glomerular filtration rate and filtration pressure. It also causes thickening of renal arterioles. Cigarette smoking increases the risk of microalbuminuria and accelerates progression of microalbuminuria to macroalbuminuria. Furthermore, it causes rapid loss of glomerular filtration rate in chronic kidney disease patients. After kidney donation, these factors may be injurious to the solitary kidney. Kidney donors with history of cigarette smoking are prone to develop perioperative complications, pneumonia, and wound infection. Postkidney transplantation various stressors including warm and cold ischemia time, delayed graft function, and exposure to calcineurin inhibitors may result in poor graft function. Continuation of cigarette smoking in kidney transplant recipients will add further risk. In this review, we will specifically discuss the effects of cigarette smoking on normal kidneys, live kidney donors, and kidney transplant recipients. This will include adverse effects of cigarette smoking on graft and patient survival, cardiovascular events, rejection, infections, and cancers in kidney transplant recipients. Lastly, the impact of kidney transplantation on behavior and smoking cessation will also be discussed. PMID- 28819640 TI - Slow dynamics of electrons at a metal-Mott insulator boundary in an organic system with disorder. AB - The Mott transition-a metal-insulator transition caused by repulsive Coulomb interactions between electrons-is a central issue in condensed matter physics because it is the mother earth of various attractive phenomena. Outstanding examples are high-Tc (critical temperature) cuprates and manganites exhibiting colossal magnetoresistance. Furthermore, spin liquid states, which are quantum fluctuation-driven disordered ground states in antiferromagnets, have recently been found in magnetic systems very near the Mott transition. To date, intensive studies on the Mott transition have been conducted and appear to have established a nearly complete framework for understanding the Mott transition. We found an unknown type of Mott transition in an organic spin liquid material with a slightly disordered lattice. Around the Mott transition region of this material under pressure, nuclear magnetic resonance experiments capture the emergence of slow electronic fluctuations of the order of kilohertz or lower, which is not expected in the conventional Mott transition that appears as a clear first-order transition at low temperatures. We suggest that they are due to the unconventional metal-insulator fluctuations emerging around the disordered Mott transition in analogy to the slowly fluctuating spin phase, or Griffiths phase, realized in Ising spin systems with disordered lattices. PMID- 28819639 TI - Antioxidant Treatment in Male Mice Prevents Mitochondrial and Synaptic Changes in an NMDA Receptor Dysfunction Model of Schizophrenia. AB - Glutamate theories of schizophrenia suggest that the disease is associated with a loss of NMDA receptors, specifically on GABAergic parvalbumin-expressing interneurons (PVIs), leading to changes in the excitation-inhibition balance in the prefrontal cortex (PFC). Oxidative stress contributes to the loss of PVI and the development of schizophrenia. Here, we investigated whether the glutathione precursor N-acetyl cysteine (NAC) can prevent changes in synaptic transmission at pyramidal cells and PVIs that result from developmental NMDAR blockade and how these changes are related to mitochondrial dysfunction in the PFCs of mice. Perinatal treatment with ketamine induced persistent changes in the reduced glutathione/oxidized glutathione (glutathione disulfide) ratio in the medial PFC, indicating long-lasting increases in oxidative stress. Perinatal ketamine treatment also reduced parvalbumin expression, and it induced a decline in mitochondrial membrane potential, as well as elevations in mitochondrial superoxide levels. At the level of synaptic function ketamine reduced inhibition onto layer 2/3 pyramidal cells and increased excitatory drive onto PVI, indicating long-lasting disruptions in the excitation-inhibition balance. These changes were accompanied by layer-specific alterations in NMDAR function in PVIs. All of these changes were mitigated by coadministration of NAC. In addition, NAC given only during late adolescence was also able to restore normal mitochondria function and inhibition at pyramidal cells. These results show that ketamine induced alterations in PFC physiology correlate with cell type-specific changes in mitochondria function. The ability of NAC to prevent or restore these changes supports the usefulness of antioxidant supplementation in the treatment of schizophrenia. PMID- 28819641 TI - In search of multipath interference using large molecules. AB - The superposition principle is fundamental to the quantum description of both light and matter. Recently, a number of experiments have sought to directly test this principle using coherent light, single photons, and nuclear spin states. We extend these experiments to massive particles for the first time. We compare the interference patterns arising from a beam of large dye molecules diffracting at single, double, and triple slit material masks to place limits on any high-order, or multipath, contributions. We observe an upper bound of less than one particle in a hundred deviating from the expectations of quantum mechanics over a broad range of transverse momenta and de Broglie wavelength. PMID- 28819642 TI - From the generalized reflection law to the realization of perfect anomalous reflectors. AB - The use of the generalized Snell's law opens wide possibilities for the manipulation of transmitted and reflected wavefronts. However, known structures designed to shape reflection wavefronts suffer from significant parasitic reflections in undesired directions. We explore the limitations of the existing solutions for the design of passive planar reflectors and demonstrate that strongly nonlocal response is required for perfect performance. A new paradigm for the design of perfect reflectors based on energy surface channeling is introduced. We realize and experimentally verify a perfect design of an anomalously reflective surface using an array of rectangular metal patches backed by a metallic plate. This conceptually new mechanism for wavefront manipulation allows the design of thin perfect reflectors, offering a versatile design method applicable to other scenarios, such as focusing reflectors, surface wave manipulations, or metasurface holograms, extendable to other frequencies. PMID- 28819643 TI - Membrane localization of acetylated CNK1 mediates a positive feedback on RAF/ERK signaling. AB - Spatiotemporal control is a common mechanism that modulates activity and function of signal transducers in the signaling network. We identified acetylation of CNK1 (connector enhancer of kinase suppressor of Ras-1) as a late step in the activation of CNK1 signaling, accompanied with prolonged stimulation of extracellular signal-regulated kinase (ERK). We identified the acetyltransferase CREB (cyclic adenosine 3',5'-monophosphate response element-binding protein) binding protein and the deacetylase SIRT2 (sirtuin type 2) as novel binding partners of CNK1, modulating the acetylation state of CNK1. Acetylation of CNK1 at position Lys414 located in the pleckstrin homology domain drives membrane localization of CNK1 in growth factor-stimulated cells. Inhibition of ERK signaling abolishes CNK1 acetylation. Cosmic database search identified CNK1 mutants at position Arg426 near the acetylation site in several human tumor types. These mutants show constitutive acetylation and membrane localization. CNK1 mutants substituting Arg426, the acetylation mimetic mutant CNK1-K414Q, and membrane-anchored CNK1 mutants all interact with the protein kinase CRAF and stimulate ERK-dependent cell proliferation and cell migration. In RAS-transformed cells, CNK1 is acetylated and membrane-bound and drives cell proliferation. Thus, growth factor-stimulated ERK signaling induces CNK1 acetylation, and acetylated CNK1 promotes ERK signaling, demonstrating a novel function of CNK1 as positive feedback regulator of the RAF/MEK (mitogen-activated protein kinase kinase)/ERK pathway. In addition, acetylation of CNK1 is an important step in oncogenic signaling, promoting cell proliferation and migration. PMID- 28819644 TI - HfSe2 and ZrSe2: Two-dimensional semiconductors with native high-kappa oxides. AB - The success of silicon as a dominant semiconductor technology has been enabled by its moderate band gap (1.1 eV), permitting low-voltage operation at reduced leakage current, and the existence of SiO2 as a high-quality "native" insulator. In contrast, other mainstream semiconductors lack stable oxides and must rely on deposited insulators, presenting numerous compatibility challenges. We demonstrate that layered two-dimensional (2D) semiconductors HfSe2 and ZrSe2 have band gaps of 0.9 to 1.2 eV (bulk to monolayer) and technologically desirable "high-kappa" native dielectrics HfO2 and ZrO2, respectively. We use spectroscopic and computational studies to elucidate their electronic band structure and then fabricate air-stable transistors down to three-layer thickness with careful processing and dielectric encapsulation. Electronic measurements reveal promising performance (on/off ratio > 106; on current, ~30 MUA/MUm), with native oxides reducing the effects of interfacial traps. These are the first 2D materials to demonstrate technologically relevant properties of silicon, in addition to unique compatibility with high-kappa dielectrics, and scaling benefits from their atomically thin nature. PMID- 28819645 TI - 3D imaging of optically cleared tissue using a simplified CLARITY method and on chip microscopy. AB - High-throughput sectioning and optical imaging of tissue samples using traditional immunohistochemical techniques can be costly and inaccessible in resource-limited areas. We demonstrate three-dimensional (3D) imaging and phenotyping in optically transparent tissue using lens-free holographic on-chip microscopy as a low-cost, simple, and high-throughput alternative to conventional approaches. The tissue sample is passively cleared using a simplified CLARITY method and stained using 3,3'-diaminobenzidine to target cells of interest, enabling bright-field optical imaging and 3D sectioning of thick samples. The lens-free computational microscope uses pixel super-resolution and multi-height phase recovery algorithms to digitally refocus throughout the cleared tissue and obtain a 3D stack of complex-valued images of the sample, containing both phase and amplitude information. We optimized the tissue-clearing and imaging system by finding the optimal illumination wavelength, tissue thickness, sample preparation parameters, and the number of heights of the lens-free image acquisition and implemented a sparsity-based denoising algorithm to maximize the imaging volume and minimize the amount of the acquired data while also preserving the contrast to-noise ratio of the reconstructed images. As a proof of concept, we achieved 3D imaging of neurons in a 200-MUm-thick cleared mouse brain tissue over a wide field of view of 20.5 mm2. The lens-free microscope also achieved more than an order-of-magnitude reduction in raw data compared to a conventional scanning optical microscope imaging the same sample volume. Being low cost, simple, high throughput, and data-efficient, we believe that this CLARITY-enabled computational tissue imaging technique could find numerous applications in biomedical diagnosis and research in low-resource settings. PMID- 28819646 TI - A molecular quantum spin network controlled by a single qubit. AB - Scalable quantum technologies require an unprecedented combination of precision and complexity for designing stable structures of well-controllable quantum systems on the nanoscale. It is a challenging task to find a suitable elementary building block, of which a quantum network can be comprised in a scalable way. We present the working principle of such a basic unit, engineered using molecular chemistry, whose collective control and readout are executed using a nitrogen vacancy (NV) center in diamond. The basic unit we investigate is a synthetic polyproline with electron spins localized on attached molecular side groups separated by a few nanometers. We demonstrate the collective readout and coherent manipulation of very few (<= 6) of these S = 1/2 electronic spin systems and access their direct dipolar coupling tensor. Our results show that it is feasible to use spin-labeled peptides as a resource for a molecular qubit-based network, while at the same time providing simple optical readout of single quantum states through NV magnetometry. This work lays the foundation for building arbitrary quantum networks using well-established chemistry methods, which has many applications ranging from mapping distances in single molecules to quantum information processing. PMID- 28819647 TI - Large polarons in lead halide perovskites. AB - Lead halide perovskites show marked defect tolerance responsible for their excellent optoelectronic properties. These properties might be explained by the formation of large polarons, but how they are formed and whether organic cations are essential remain open questions. We provide a direct time domain view of large polaron formation in single-crystal lead bromide perovskites CH3NH3PbBr3 and CsPbBr3. We found that large polaron forms predominantly from the deformation of the PbBr3- frameworks, irrespective of the cation type. The difference lies in the polaron formation time, which, in CH3NH3PbBr3 (0.3 ps), is less than half of that in CsPbBr3 (0.7 ps). First-principles calculations confirm large polaron formation, identify the Pb-Br-Pb deformation modes as responsible, and explain quantitatively the rate difference between CH3NH3PbBr3 and CsPbBr3. The findings reveal the general advantage of the soft [PbX3]- sublattice in charge carrier protection and suggest that there is likely no mechanistic limitations in using all-inorganic or mixed-cation lead halide perovskites to overcome instability problems and to tune the balance between charge carrier protection and mobility. PMID- 28819648 TI - Response to Comment on "How will induced seismicity in Oklahoma respond to decreased saltwater injection rates?" AB - Goebel et al. question our forecasted response of induced seismicity to reduction of saltwater injection rates in north-central Oklahoma and raise the concern that "the probability of future damaging earthquakes may be underestimated." We compare our prediction to earthquake data recorded in the 8 months after publication. Observed seismicity rates and magnitudes agree with the forecast of our model. Our use of a probabilistic model accounts for uncertainties and observed M >= 4.5 to date confirm the conservative nature of our prediction. The "realistic parameter range" suggested by Goebel et al. is based on a misunderstanding of our statistical model and disagrees with the long-term decay of seismicity in the region. PMID- 28819650 TI - Wear behavior of Al-7%Si-0.3%Mg/melon shell ash particulate composites. AB - The present study examined wear characteristics of A356/melon shell ash particulate composites. Dry-sliding the stainless steel ball against specimen disc revealed the abrasive wear behavior of the composites under loads of 2 and 5N. The composite showed lower wear rate of 2.182 * 10-4 mm3/Nm at 20 wt% reinforced material under load of 5N. Results showed that wear rate decreased significantly with increasing weight percentage of melon shell ash particles. Microstructural analyses of worn surfaces of the composites reveal evidence of plastic deformation of matrix phase. The wear resistance of A356 increased considerably with percentage reinforcement. In other words, the abrasive mass loss decreased with increasing percentage of reinforcement addition at the both applied loads. The control sample suffered a highest mass loss at 5 N applied load. PMID- 28819649 TI - Prosocial apathy for helping others when effort is required. AB - Prosocial acts - those that are costly to ourselves but benefit others - are a central component of human co-existence1-3. While the financial and moral costs of prosocial behaviours are well understood4-6, everyday prosocial acts do not typically come at such costs. Instead, they require effort. Here, using computational modelling of an effort-based task we show that people are prosocially apathetic. They are less willing to choose to initiate highly effortful acts that benefit others compared to benefitting themselves. Moreover, even when choosing to initiate effortful prosocial acts, people show superficiality, exerting less force into actions that benefit others than themselves. These findings replicated, were present when the other was anonymous or not, and when choices were made to earn rewards or avoid losses. Importantly, the least prosocially motivated people had higher subclinical levels of psychopathy and social apathy. Thus, although people sometimes 'help out', they are less motivated to benefit others and sometimes 'superficially prosocial', which may characterise everyday prosociality and its disruption in social disorders. PMID- 28819651 TI - Never Let a Crisis Go to Waste: Recruiting the Next Generation of Infectious Diseases Physicians. PMID- 28819652 TI - Quantitative first-principles calculations of valence and core excitation spectra of solid C60. AB - We present calculated valence and C 1s near-edge excitation spectra of solid C60 and experimental results measured with high-resolution electron energy-loss spectroscopy. The near-edge calculations are carried out using three different methods: solution of the Bethe-Salpeter equation (BSE) as implemented in the OCEAN suite (Obtaining Core Excitations with ab initio methods and the NIST BSE solver), the excited-electron core-hole approach (XCH), and the constrained occupancy method using the Stockholm-Berlin core-excitation code, StoBe. The three methods give similar results and are in good agreement with experiment, though the BSE results are the most accurate. The BSE formalism is also used to carry out valence level calculations using the NIST Bethe-Salpeter Equation solver (NBSE). Theoretical results include self-energy corrections to the band gap and band widths, lifetime-damping effects, and Debye-Waller effects in the core-excitation case. A comparison of spectral features to those observed experimentally illustrates the sensitivity of certain features to computational details, such as self-energy corrections to the band structure and core-hole screening. PMID- 28819653 TI - Targeting Cytokines in GVHD Therapy. AB - Transplantation of donor-derived allogeneic hematopoietic cells causes increased survival in patients suffering from various blood cancers and other hematologic and immunologic diseases. However, this health benefit is limited to certain patients. One major complication is graft-versus-host disease (GVHD) that occurs when donor-derived immune cells recognize host cells/tissues as foreign and perpetrate subsequent destruction. Cytokines are a major class of effector molecules that are involved in GVHD pathogenesis. Proinflammatory cytokines released by activated immune cells including T cells lead to the onset of GVHD. T cell depletion (TCD) is an effective approach for GVHD prevention. Several immune suppressive drugs are also used to treat GVHD. However, these prophylactic and treatment strategies often lead to an immune compromised state that increases the risk for infection and cancer relapse. Considering the adverse effects of TCD and overall immune suppression, more selective managements such as approaches targeting proinflammatory cytokines have emerged as a promising strategy to control GVHD. Therefore, this work is dedicated to review recent development in the studies of cytokines and their future implication in GVHD therapy. PMID- 28819654 TI - Use of the Quick Dementia Rating System (QDRS) as an Initial Screening Measure in a Longitudinal Cohort at Risk for Alzheimer's Disease. AB - The Quick Dementia Rating System (QDRS) and Clinical Dementia Rating Scale (CDR) assess global cognitive and functional decline. We evaluated whether the shorter QDRS was a valid screen for problems identified by the CDR in individuals with minimal clinical abnormalities. Agreement between QDRS-Global and CDR-Global was assessed for 54 participants from the Wisconsin Registry for Alzheimer's Prevention. Resource-savings achieved by adopting an "administer CDR-only-if-QDRS Global>0" approach were estimated based on 238 subsequent participants. Agreement statistics (concordance = 88.9%) supported use of the QDRS as an initial informant report and modifying center protocol to administer CDRs only when QDRS>0 reduced CDR assessments by 79.8%. PMID- 28819655 TI - High-throughput Bayesian Network Learning using Heterogeneous Multicore Computers. AB - Aberrant intracellular signaling plays an important role in many diseases. The causal structure of signal transduction networks can be modeled as Bayesian Networks (BNs), and computationally learned from experimental data. However, learning the structure of Bayesian Networks (BNs) is an NP-hard problem that, even with fast heuristics, is too time consuming for large, clinically important networks (20-50 nodes). In this paper, we present a novel graphics processing unit (GPU)-accelerated implementation of a Monte Carlo Markov Chain-based algorithm for learning BNs that is up to 7.5-fold faster than current general purpose processor (GPP)-based implementations. The GPU-based implementation is just one of several implementations within the larger application, each optimized for a different input or machine configuration. We describe the methodology we use to build an extensible application, assembled from these variants, that can target a broad range of heterogeneous systems, e.g., GPUs, multicore GPPs. Specifically we show how we use the Merge programming model to efficiently integrate, test and intelligently select among the different potential implementations. PMID- 28819656 TI - Simulating the reactions of substituted pyridinio-N-phosphonates with pyridine as a model for biological phosphoryl transfer. AB - Phosphoryl transfer reactions can proceed through several plausible mechanisms, and the potential for both solvent and substrate-assisted pathways (involving proton transfer to the phosphoryl oxygens) complicates both experimental and computational interpretations. To avoid this problem, we have used electronic structure calculations to probe the mechanisms of the reactions of pyridinio-N phosphonates with pyridine. These compounds avoid the additional complexity introduced by proton transfer between the nucleophile and the leaving group, while also serving as a valuable model for biological P-N cleavage. Through a comparative study of a range of substrates of varying basicity, we demonstrate a unified concerted mechanism for the phosphoryl transfer reactions of these model compounds, proceeding through a dissociative transition state. Finally, a comparison of these transition states with previously characterized transition states for related compounds provides a more complete model for non-enzymatic phosphoryl transfer, which is a critical stepping stone to being able to fully understand phosphoryl transfer in biology. PMID- 28819657 TI - Dendrimers meet zwitterions: development of a unique antifouling nanoplatform for enhanced blood pool, lymph node and tumor CT imaging. AB - We report the synthesis and characterization of antifouling zwitterion carboxybetaine acrylamide (CBAA)-modified dendrimer-entrapped gold nanoparticles (Au DENPs) for enhanced CT imaging applications. The CBAA-modified nanodevice displays a better protein resistance property, less macrophage cellular uptake and liver accumulation, and longer blood half-delay time than the PEGylated counterpart material, thereby enabling enhanced blood pool, lymph node, and tumor CT imaging. PMID- 28819658 TI - Weld formation during material extrusion additive manufacturing. AB - Material extrusion (ME) is a layer-by-layer additive manufacturing process that is now used in personal and commercial production where prototyping and customization are required. However, parts produced from ME frequently exhibit poor mechanical performance relative to those from traditional means; moreover, fundamental knowledge of the factors leading to development of inter-layer strength in this highly non-isothermal process is limited. In this work, we seek to understand the development of inter-layer weld strength from the perspective of polymer interdiffusion under conditions of rapidly changing mobility. Our framework centers around three interrelated components: in situ thermal measurements (via infrared imaging), temperature dependent molecular processes (via rheology), and mechanical testing (via mode III fracture). We develop the concept of an equivalent isothermal weld time and test its relationship to fracture energy. For the printing conditions studied the equivalent isothermal weld time for Tref = 230 degrees C ranged from 0.1 ms to 100 ms. The results of these analysis provide a basis for optimizing inter-layer strength, the limitations of the ME process, and guide development of new materials. PMID- 28819659 TI - Solvent hydrophobicity induced complex coacervation of dsDNA and in situ formed zein nanoparticles. AB - Zein, a predominantly hydrophobic protein, was sustained as a stable dispersion in ethanol-water (80 : 20, % (v/v)) binary solvent at room temperature (25 degrees C). Addition of aqueous dsDNA solution (1% (w/v)) to the above dispersion prepared with the protein concentration of Czein = 0.01-0.5% (w/v) caused a concomitant change in ethanol content from 14-35% (v/v), which in turn generated zein nanoparticles in situ of size 80-120 nm increasing with water content. The subsequent associative interaction between DNA (polyanion; 2000 bps) and the positively charged zein nanoparticles, (at pH = 4) was driven by Coulombic forces, and by the solvent hydrophobicity due to the ethanol content of the binary solvent. Experimentally, two interesting regions of interaction were observed from turbidity, zeta potential, particle sizing, and viscosity data: (i) for Czein < 0.2% (w/v), zein nanoparticles of size 80 nm bind to dsDNA (primary complex) causing its condensation (apparent hydrodynamic size decreased from ~2100 to 560 nm), and (ii) for 0.2% < Czein < 0.5% (w/v) larger nanoparticles (>80 nm) were selectively bound to primary complexes to form partially charge neutralized interpolymer soluble complexes (secondary complexes), followed by complex coacervation. During this process, there was depletion of water in the vicinity of the nucleic acid, which was replaced by hydration provided by the ethanol-water binary solvent. Equilibrium coacervate samples were probed for their microstructure by small angle neutron scattering, and for their viscoelastic properties by rheology. The interplay of solvent hydrophobicity, electrostatic interaction, and zein nanoparticle size dependent charge neutralization had a commensurate effect on this hitherto unexplored coacervation phenomenon. PMID- 28819660 TI - Nanostructured materials on 3D nickel foam as electrocatalysts for water splitting. AB - Highly efficient and low-cost electrocatalysts are essential for water spitting via electrolysis in an economically viable fashion. However, the best catalytic performance is found with noble metal-based electrocatalysts, which presents a formidable obstacle for the commercial success of electrolytic water splitting based H2 production due to their relatively high cost and scarcity. Therefore, the development of alternative inexpensive earth-abundant electrode materials with excellent electrocatalytic properties is of great urgency. In general, efficient electrocatalysts must possess several key characteristics such as low overpotential, good electrocatalytic activity, high stability, and low production costs. Direct synthesis of nanostructured catalysts on a conducting substrate may potentially improve the performance of the resultant electrocatalysts because of their high catalytic surface areas and the synergistic effect between the electrocatalyst and the conductive substrate. In this regard, three dimensional (3D) nickel foams have been advantageously utilized as electrode substrates as they offer a large active surface area and a highly conductive continuous porous 3D network. In this review, we discuss the most recent developments in nanostructured materials directly synthesized on 3D nickel foam as potential electrode candidates for electrochemical water electrolysis, namely, the oxygen evolution reaction (OER) and the hydrogen evolution reaction (HER). We also provide perspectives and outlooks for catalysts grown directly on 3D conducting substrates for future sustainable energy technologies. PMID- 28819661 TI - A computational study of the influence of methyl substituents on competitive ring closure to alpha- and beta-lactones. AB - Ring-closure of substituted 2-chlorosuccinates to alpha- or beta-lactones has been studied by means of MP2/6-311+G(d,p)//MP2/6-31+G(d) calculations in water treated as a polarised continuum (PCM) and in vacuum. Optimised geometries have been obtained for 2-chlorosuccinate and its 2-methyl, 3,3-dimethyl, and 2,3,3 trimethyl derivatives, along with the transition structures and products for intramolecular nucleophilic displacement leading to the 3- or 4-membered rings. Relative enthalpies and Gibbs free energies of activation and reaction are presented, along with key geometrical parameters, and changes in electrostatic potential-derived atomic charges. The difference in free-energy barriers for alpha- and beta-lactone formation from the 2-methyl substrate at 298 K is less than 1 kJ mol-1. Primary 14C kinetic isotope effects calculated for substitution at C2 are significantly smaller for alpha-lactone formation than for beta, suggesting a possible way to distinguish between the competing pathways of reaction. The B3LYP method without dispersion corrections predicts the wrong relative stability order for methyl-substituted succinate dianions in PCM water. PMID- 28819662 TI - Chiral amplification of disodium cromoglycate chromonics induced by a codeine derivative. AB - Chromonic liquid crystals (CLC) are lyotropic phases formed by discotic mesogens in water. Simple chiral dopants such as amino acids have been reported to turn chromonic liquid crystals into their cholesteric counterparts. Here we report a chirality amplification effect in the nematic phase of a 9 wt% disodium cromoglycate (DSCG) lyotropic liquid crystal (LLC) upon doping with a water soluble codeine derivative. The transition on cooling the isotropic to the nematic phase showed the presence of homochiral spindle-shaped droplets (tactoids). NMR DOSY experiments on a triple gradient probe revealed a small degree of diffusion anisotropy for the alkaloid embedded in the liquid crystal structure. These results in combination with XRD, CD and POM experiments agree with a supramolecular aggregation model based on simple columnar stacks. PMID- 28819663 TI - Rheological characterization of yield stress gels formed via electrostatic heteroaggregation of metal oxide nanoparticles. AB - Mixtures of fumed fractal metal oxide nanoparticles (np's) dispersed in water, at a solution pH where one species is positively charged and the other is negatively charged, form yield stress gels at volume fractions as low as 1.5%, due to electrostatic heteroaggregation into networks as confirmed by small-angle neutron scattering. These gels exhibit a measurable yield stress and an apparent viscosity that follows a power law relationship with shear rate. Rotational and oscillatory shear rheology is presented for binary mixtures of fumed silica, fumed alumina, and fumed titania in aqueous dispersions. Gels were characterized at various particle concentrations, solution pHs, mixture ratios, and salt concentrations. The strength of the gel network, as evaluated by the storage modulus and yield stress, is maximized when the mixture contains a mixture of particles with an approximately equal, but opposite, number of charged groups. PMID- 28819664 TI - Antimicrobial carbon nanospheres. AB - Carbon nanomaterials have found numerous applications in various fields. However, their synthesis and functionalization usually require complicated procedures or tough experimental conditions. Herein, we report for the first time the synthesis of a new type of functional nanomaterial, quaternized carbon nanospheres (QCNSs), with superior antibacterial activity via a one-pot hydrothermal treatment of chitosan and hexadecylbetaine (abbreviated as BS-16). During the hydrothermal process, the direct reaction and carbonization between the amine-containing chitosan and the carboxyl-containing BS-16 were realized within only one step. The as-prepared QCNSs feature a well-defined spherical morphology and a homogeneous size distribution with an average diameter of ~110 nm. In particular, the QCNSs could effectively kill Gram-positive bacteria with a minimum inhibitory concentration (MIC) of 2.0-5.0 MUg mL-1. Meanwhile, the QCNSs showed excellent cytocompatibility towards normal human liver and lung cells and good hemocompatibility towards red blood cells. Moreover, in bacteria-infected macrophage cells, the QCNSs could selectively kill bacteria while the macrophage cells remained unaffected, which further confirmed their biocompatibility. Besides, we have also elucidated the antibacterial mechanism of the QCNSs by disrupting the bacterial cell walls/membranes via the bacterial adsorption and insertion of the long alkyl chain-containing quaternary ammonium groups on the particle surface. The present work provides a novel method for the preparation of functional carbon nanomaterials, which may promote the development of metal-free antibacterial agents. PMID- 28819665 TI - Efficient photoelectrochemical water splitting on ultrasmall defect-rich TaOx nanoclusters enhanced by size-selected Pt nanocluster promoters. AB - Formation of nanoclusters has attracted a lot of attention in recent years because of their distinct properties from isolated atoms and bulk solids. Here, we focus on the catalytic properties of supported transition metal oxide nanoclusters, such as TaO2, with a well-defined size distribution below 10 nm. We show that their catalytic performance can be greatly enhanced by introducing a reaction promoter such as Pt. Different combinations of precisely size-selected, defect-rich TaOx and Pt nanoclusters are produced by a gas-phase aggregation technique in a special DC magnetron sputtering system. Argon flow rate and aggregation length are carefully optimized to control the sizes of these ultrasmall TaOx and Pt nanoclusters by using a quadrupole mass filter, and TEM studies reveal the different crystalline nature of TaOx (amorphous) and Pt (crystalline) nanoclusters. We have further demonstrated the size-dependent photoanode activity of (TaOx, Pt) nanocluster systems in a photoelectrochemical water splitting reaction, where the Pt nanocluster promoters are found to provide a significant enhancement in the photocurrent density, approximately tripled that was observed from just TaOx nanocluster catalysts alone. The photocurrent density and photoconversion efficiency tend to reduce when Pt nanoclusters become overpopulated due to blocking of the photosensitive TaOx surface. Reducing the Pt nanocluster size resolves this problem by incorporating a greater number of smaller nanocluster promoters without blocking TaOx, which leads to further enhancement in the photocurrent density. The enhanced photocatalytic activity is attributed to synergetic effects introduced by the Pt nanoclusters that act as temporary charge storage sites to facilitate effective separation of a large number of electron-hole pairs, generated from a large number of active sites on the defect-rich amorphous TaOx nanoclusters upon illumination. PMID- 28819666 TI - pH-Responsive prodrug nanoparticles based on a sodium alginate derivative for selective co-release of doxorubicin and curcumin into tumor cells. AB - In order to realize a combination of chemotherapy and selective drug release into tumor cells, novel pH-sensitive prodrugnanoparticles were designed and prepared via the self-assembly of a synthetic amphiphilic macromolecular prodrug for the selective co-delivery of doxorubicin (Dox) and curcumin (Cur). Dox was covalently conjugated to the oxidized sodium alginate through a Schiff base reaction to produce an amphiphilic macromolecular prodrug, and the prodrug was subsequently self-assembled into nanoparticles (Dox-NPs) in an aqueous solution, which were responsive to the acidic environment in tumor cells. Additionally, a second chemotherapeutic agent, Cur, was encapsulated in the core of nanoparticles (Cur Dox-NPs) via hydrophobic effects, with a significant drug loading capacity. Cur Dox-NPs exhibited an efficient release of both Dox and Cur in acidic media and further studies of their intracellular uptake and drug release confirmed that Dox NPs were easily taken up by cells and selectively released the drug into the human breast cancer cell line MCF-7. In vitro cytotoxicity studies of the NPs showed a remarkable efficacy against MCF-7 cell lines, whereas an improved safety profile was observed in the human breast epithelial cell line MCF-10A. Furthermore, in vivo studies in zebrafish further confirmed an efficient absorption of Dox-NPs. In vivo cardiotoxicity experiments on a zebrafish model showed that Dox-NPs exhibited an improved cardiotoxicity profile in comparison with free Dox. This study demonstrated that this novel pH-sensitive prodrug nanoparticle system may provide a simple and efficient platform for the selective co-delivery of multiple drugs to tumor cells. PMID- 28819667 TI - Synthesis and optical and electrochemical properties of a phenanthrodithiophene (fused-bibenzo[c]thiophene) derivative. AB - We designed and developed a fused-bibenzo[c]thiophene, namely, 2,9-bis(tert butyldimethylsilyl)phenanthro[9,8-bc:10,1-b'c']dithiophene (PHDT-Si), as a new pi building block in the emitters, photosensitizers and semiconductors for organic optoelectronic devices. Based on photophysical (photoabsorption, fluorescence and time-resolved fluorescence spectroscopy) and electrochemical measurements (cyclic voltammetry), and density functional theory (DFT) calculations, this work reveals that the fused-bibenzo[c]thiophene PHDT-Si, which is prepared by an efficient synthesis method, has a rigid, high planar and expanded pi-conjugation structure, and possesses intense photoabsorption and fluorescence properties (lambda = 598 nm (epsilonmax = 41 000 M-1 cm-1) and lambda = 613 nm (Phif = 0.74) in toluene) in the long-wavelength region and undergoes an electrochemically reversible oxidation process, compared to non-fused 1,1'-bis(tert-butyldimethylsilyl)-4,4' bibenzo[c]thiophene (BBT-Si). PMID- 28819668 TI - Ultralow flexural properties of copper microhelices fabricated via electrodeposition-based three-dimensional direct-writing technology. AB - Helical metallic micro/nanostructures as functional components have considerable potential for future miniaturized devices, based on their unique mechanical and electrical properties. Thus, understanding and controlling the mechanical properties of metallic helices is desirable for their practical application. Herein, we implemented a direct-writing technique based on the electrodeposition method to grow copper microhelices with well-defined and programmable three dimensional (3D) features. The mechanical properties of the 3D helical structures were studied by the electrically induced quasistatic and dynamic electromechanical resonance technique. These methods mainly explored the static pull-in process and the dynamic electromechanical response, respectively. It was found that the center-symmetric and vertical double copper microhelix structure with 1.2 MUm wire diameter has a flexural rigidity of 0.9 * 10-14 N m2 and the single vertical copper microhelix structure with 1.1 MUm wire diameter has a flexural rigidity of 0.5989 * 10-14 N m2. By comparing with microwires and other reported micro/nanohelices, we found that the copper microhelices reported here had an ultralow stiffness (about 0.13 +/- 0.01 N m-1). It is found that the experimental results agree well with the finite element calculations. The proposed method can be used to fabricate and measure the flexural properties of three-dimensional complex micro/nanowire structures, and may have a profound effect on the application of microhelices in various useful microdevices such as helix-based microelectromechanical switches, sensors and actuators based on their unique mechanical properties. PMID- 28819670 TI - Mimicking wettability alterations using temperature gradients for water nanodroplets. AB - A sessile droplet or a film usually moves from hotter regions to colder regions, due to variations in interfacial tension. This, known as the so-called Marangoni effect, is true for most pure liquids like water for which the surface tension decreases with an increase in temperature. In stark contrast to this existing understanding, we bring forth the coupled effect of wettability and temperature gradients on the dynamics of the three-phase contact line. By simultaneously tracking the dynamic evolution of the three-phase contact line due to the evaporation and diffusion of molecules through molecular dynamics simulations, we explore the coterminous effects of the change of surface tension coefficients and wetting parameters with temperature on sessile droplets residing on surfaces with different wettabilities. We demonstrate, for the very first time, that the inverse Marangoni effect, which is believed to be exclusively observed in mixtures and self-rewetting fluids, is feasible in pure water at scales where inertial effects are negligible. The results of the study find application in electronic chip cooling where by the combined tuning of surface characteristics and Marangoni forces, droplets can be passively transported to warmer regions for efficient thermal management. PMID- 28819669 TI - Drastic difference between hole and electron injection through the gradient shell of CdxSeyZn1-xS1-y quantum dots. AB - Ultrafast fluorescence spectroscopy was used to investigate the hole injection in CdxSeyZn1-xS1-y gradient core-shell quantum dot (CSQD) sensitized p-type NiO photocathodes. A series of CSQDs with a wide range of shell thicknesses was studied. Complementary photoelectrochemical cell measurements were carried out to confirm that the hole injection from the active core through the gradient shell to NiO takes place. The hole injection from the valence band of the QDs to NiO depends much less on the shell thickness when compared to the corresponding electron injection to n-type semiconductor (ZnO). We simulate the charge carrier tunneling through the potential barrier due to the gradient shell by numerically solving the Schrodinger equation. The details of the band alignment determining the potential barrier are obtained from X-ray spectroscopy measurements. The observed drastic differences between the hole and electron injection are consistent with a model where the hole effective mass decreases, while the gradient shell thickness increases. PMID- 28819671 TI - Fullerenol nanoparticles suppress RANKL-induced osteoclastogenesis by inhibiting differentiation and maturation. AB - Bone health requires regulation of homeostatic equilibrium between osteoblasts and osteoclasts. The over-activation of osteoclasts can disrupt bone metabolism, resulting in osteoporosis and other bone-loss diseases. Fullerenol, a polyhydroxy derivative of fullerene, exhibits excellent biocompatibility. Here we show that fullerenol nanoparticles exert two functions: inhibition of osteoclastic differentiation and blockage of pre-osteoclast fusion to restructure osteoclast maturation and function. Experimentally, the nanoparticles reduced pre-osteoclast migration and inhibited ruffled border formation to block their maturation. In addition, fullerenol dose-dependently restricted the differentiation of bone marrow macrophage cells (BMMs) to form osteoclasts following treatment with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor (NF)-kappaB (RANKL) to activate NF-kappaB and mitogen activating protein kinase (MAPK) signaling pathways. It is possible that the very small size of fullerenol allows it to directly cross the cellular membrane to access the cytoplasm and regulate osteoclastogenesis from BMMs. Our results suggest that fullerenol could be used to treat bone-loss diseases such as osteoporosis. PMID- 28819672 TI - Folding sticky elastica: dynamics and reversibility of folds in Langmuir monolayers. AB - Lipid monolayers at the air/water interface are often subject to large mechanical stresses when compressed laterally. For large enough compression they fold in the out-of-plane direction to relax stress. The repetitive folding and unfolding of lung surfactant monolayers during breathing plays a critical role in conserving monolayer material at the air/water interface lining the lung. Although the mechanisms behind the folding have been explored recently, relatively little information exists regarding the implications of folding dynamics on the long term stability of the monolayer. We address this question by investigating the dynamical effect of folding rate in a lipid monolayer containing nano-particles, using a combination of analytic theory, simulation and experiment. We find that the presence of adsorbed particles are essential for monolayer rupture during unfolding. These particles act as linkers pinning the folds shut. The rate of folding affects reversibility as well. We construct a reversibility phase diagram spanned by the compression period and the size of the adsorbed particles showing the complex interaction of fold morphology, particle diffusion, and linker unbinding that results in reversible or irreversible folding. PMID- 28819673 TI - Erratum to: The Extent of Heavy Metal Pollution and Their Potential Health Risk in Topsoils of the Massively Urbanized District of Shanghai. PMID- 28819674 TI - [Imaging techniques in modern trauma diagnostics]. AB - Modern trauma room management requires interdisciplinary teamwork and synchronous communication between a team of anaesthesists, surgeons and radiologists. As the length of stay in the trauma room influences morbidity and mortality of a severely injured person, optimizing time is one of the main targets. With the direct involvement of modern imaging techniques the injuries caused by trauma should be detected within a very short period of time in order to enable a priority-orientated treatment. Radiology influences structure and process quality, management and development of trauma room algorithms regarding the use of imaging techniques. For the individual case interventional therapy methods can be added. Based on current data and on the Frankfurt experience the current diagnostic concepts of trauma diagnostics are presented. PMID- 28819675 TI - Pharmacoepidemiology resources in Ireland-an introduction to pharmacy claims data. AB - INTRODUCTION: Administrative health data, such as pharmacy claims data, present a valuable resource for conducting pharmacoepidemiological and health services research. Often, data are available for whole populations allowing population level analyses. Moreover, their routine collection ensures that the data reflect health care utilisation in the real-world setting compared to data collected in clinical trials. SETTING AND METHODS: The Irish Health Service Executive-Primary Care Reimbursement Service (HSE-PCRS) community pharmacy claims database is described. The availability of demographic variables and drug-related information is discussed. The strengths and limitations associated using this database for conducting research are presented, in particular, internal and external validity. Examples of recently conducted research using the HSE-PCRS pharmacy claims database are used to illustrate the breadth of its use. RESULTS AND CONCLUSIONS: The HSE-PCRS national pharmacy claims database is a large, high-quality, valid and accurate data source for measuring drug exposure in specific populations in Ireland. The main limitation is the lack of generalisability for those aged <70 years and the lack of information on indication or outcome. PMID- 28819677 TI - Direct analysis of terpenes from biological buffer systems using SESI and IR MALDESI. AB - Terpenes are the largest class of natural products with a wide range of applications including use as pharmaceuticals, fragrances, flavorings, and agricultural products. Terpenes are biosynthesized by the condensation of a variable number of isoprene units resulting in linear polyisoprene diphosphate units, which can then be cyclized by terpene synthases into a range of complex structures. While these cyclic structures have immense diversity and potential in different applications, their direct analysis in biological buffer systems requires intensive sample preparation steps such as salt cleanup, extraction with organic solvents, and chromatographic separations. Electrospray post-ionization can be used to circumvent many sample cleanup and desalting steps. SESI and IR MALDESI are two examples of ionization methods that employ electrospray post ionization at atmospheric pressure and temperature. By coupling the two techniques and doping the electrospray solvent with silver ions, olefinic terpenes of different classes and varying degrees of volatility were directly analyzed from a biological buffer system with no sample workup steps. PMID- 28819676 TI - Granger causality supports abnormal functional connectivity of beta oscillations in the dorsolateral striatum and substantia nigra pars reticulata in hemiparkinsonian rats. AB - Synchronized oscillatory neuronal activity in the beta frequency range has been reported in the basal ganglia (BG) of patients with Parkinson disease (PD) and PD animal models. The coherent abnormal oscillatory activities in the dorsolateral striatum (dStr) and substantia nigra pars reticulata (SNr) that accompany parkinsonian states have not been resolved. In this study, we recorded local field potentials (LFPs) in the dStr and SNr of 6-hydroxydopamine (6-OHDA)-induced dopamine (DA)-lesioned rats in an awake, resting state. Analyses of power spectral density and coherence data demonstrated augmented LFP power in the 24-36 Hz (high beta) range in both the dStr and SNr together with increased dStr-SNr coherence in the 24-36-Hz range, relative to sham controls; both effects were reversed by levodopa (L-dopa) treatment. Partial Granger causality analysis revealed a dStr->SNr propagation directionality of these beta oscillations. These findings support the involvement of increased synchronization of high beta activity in the dStr and the SNr, and suggest that dorsolateral striatal activity plays a determinant role in leading the coherent activity with the SNr in the development of parkinsonian pathophysiology. PMID- 28819678 TI - [Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy]. PMID- 28819679 TI - Neuromuscular electrical stimulation is effective in strengthening the quadriceps muscle after anterior cruciate ligament surgery. AB - PURPOSE: Reduced ability to contract the quadriceps muscles is often found immediately following anterior cruciate ligament (ACL) surgery. This can lead to muscle atrophy and decreased function. Application of neuromuscular electrical stimulation (NMES) may be a useful adjunct intervention to ameliorate these deficits following ACL surgery. The purpose of this review was to determine whether NMES in addition to standard physical therapy is superior to standard physical therapy alone in improving quadriceps strength or physical function following ACL surgery. METHODS: A computer-assisted literature search was conducted utilizing PubMed, CINAHL, PEDro and Cochrane Library databases for randomized clinical trials where patients after ACL surgery received NMES with the outcome of muscle strength and/or physical function. Random effect models were used to pool summary estimates using standardized mean differences (SMD) for strength outcomes. Physical function outcomes were assessed qualitatively. Methodological quality was assessed from the Physiotherapy Evidence Database (PEDro)-score. RESULTS: Eleven studies met our inclusion criteria; results from six of these were pooled in the meta-analysis showing a statistically significant short-term effect of NMES (4-12 weeks) after surgery compared to standard physical therapy [SMD = 0.73 (95% CI 0.29, 1.16)]. Physical function also improved significantly more in the NMES groups. PEDro scores ranged from 3/10 to 7/10 points. CONCLUSION: NMES in addition to standard physical therapy appears to significantly improve quadriceps strength and physical function in the early post operative period compared to standard physical therapy alone. LEVEL OF EVIDENCE: I. PMID- 28819680 TI - Quantitative approach to the posterior cranial fossa and craniocervical junction in asymptomatic children with achondroplasia. AB - PURPOSE: We propose an magnetic resonance imaging (MRI)-based quantitative morphovolumetric approach to the posterior cranial fossa (PCF) and craniocervical junction (CCJ) changes in achondroplastic patients investigating possible associations with ventriculomegaly and medullary compression. METHODS: We analyzed MRI of 13 achondroplastic children not treated by surgery. 3D FSPGR T1 weighted images were used to analyze (1) PCF synchondroses; (2) PCF volume (PCFV), PCF brain volume (PCFBV), PCFV/PCFBV ratio, cerebellar volume, cerebrospinal fluid (CSF) spaces volume, and IV ventricle volume; (3) PCF (clivus, supraocciput, exocciput lengths, tentorial angle) and CCJ (AP and LL diameters of foramen magnum (FM)) morphometry; (4) measurements of FM and jugular foramina (JF) areas; and (5) supratentorial ventricular volume. RESULTS: All patients showed synostosis of spheno-occipital synchondroses, eight showed synostosis of intra-occipital synchondroses, nine showed CCJ impingement on the cervical cord but only three had cervical myelopathy. Compared to controls, clivus and exocciput lengths, LL and AP diameters of FM, FM area and JF area were significantly reduced, supraocciput length, tentorial angle, PCFV, PCFBV, cerebellar volume, supratentorial ventricular system volume were significantly increased. A correlation was found between clivus length and supratentorial ventricular volume, premature closure of intra-occipital synchondroses and FM area while a trend was found between FM area and supraocciput length. CONCLUSION: Our analysis demonstrates a relationship between the shortening of the clivus and the ventriculomegaly. On the other hand the premature closure of PCF synchondroses, the shape, and the growth direction of supraocciput bone contribute to reduce the FM area, causing in some patients medullary compression. PMID- 28819681 TI - Low-Level Environmental Cadmium Exposure Induces Kidney Tubule Damage in the General Population of Korean Adults. AB - Cadmium (Cd) is the most potent nephrotoxic heavy metal and may affect bone; it also has a long biological half-life in the human body. This study was designed to assess the effect of environmental low-level Cd exposure on kidney function and bone in the general population. The subjects of this cross-sectional study were 1907 healthy Korean adults who had not been exposed to Cd occupationally. We analyzed the concentrations of Cd in the urine, markers of renal tubule damage, such as beta2-microglobulin (beta2-MG) and N-acetyl-beta-D-glucosaminidase (NAG) activity in the urine, calculated the estimated glomerular filtration rate (eGFR) using serum creatinine, and measured bone mineral density (BMD). Also, we analyzed malondialdehyde (MDA) levels in the urine. The geometric mean concentration of Cd in urine was higher in women (1.36 MUg/g creatinine) than in men (0.82 MUg/g creatinine). Urinary Cd was significantly positively correlated with urinary beta2-MG and NAG activity, whereas it was negatively correlated with eGFR and BMD. The risk of renal tubule damage was significantly associated with urine Cd level, and the association remained significant after controlling for various confounding variables. However, no association was observed between urinary Cd level and glomerular dysfunction or bone damage. The concentration of MDA was increased with urinary Cd level in a dose-dependent manner. These findings suggest that low-level environmental Cd exposure may cause microscopic damage to renal tubules through oxidative stress but might not impair kidney glomeruli or bones. PMID- 28819682 TI - Laparoscopy or laparotomy as the way of entrance in myoma enucleation. AB - PURPOSE: Uterine myomas are the main cause of benign uterine diseases in premenopausal women. Objective of the present paper is to investigate the current best treatment modalities of myomas, depending on age of the patient and her desire to preserve fertility, as well as on clinical presentation of this pathology, such as size, number, and location of fibroids and, furthermore, on surgical experience of the gynecologist. METHODS: The design of our work is a systematic literature review of existing studies, reviews, and meta-analysis conducted in PubMed and Cochrane Library to identify relevant literature. Commonly, the myomectomy is to be recommended in women desiring to preserve fertility when myomas are associated with symptoms such as excessive bleeding, pelvic discomfort, or palpable abdominally fibroids. The decision of surgical approach for myomectomy should be individualized, depending on size and location, as well as on surgeon's experience. The different modalities of myomectomy, laparoscopic, hysteroscopic, robotic-assisted, or laparotomic are in detail presented in the paper, according to Society of Obstetricians and Gynecologists of Canada (SOGC) clinical practice guidelines and taking into consideration possible concerns of myomectomy such as uterine rupture, development of adhesions, and myomas' recurrence. PMID- 28819683 TI - An iPhone application using a novel stool color detection algorithm for biliary atresia screening. AB - BACKGROUND: The stool color card has been the primary tool for identifying acholic stools in infants with biliary atresia (BA), in several countries. However, BA stools are not always acholic, as obliteration of the bile duct occurs gradually. This study aims to introduce Baby Poop (Baby unchi in Japanese), a free iPhone application, employing a detection algorithm to capture subtle differences in colors, even with non-acholic BA stools. METHODS: The application is designed for use by caregivers of infants aged approximately 2 weeks-1 month. Baseline analysis to determine optimal color parameters predicting BA stools was performed using logistic regression (n = 50). Pattern recognition and machine learning processes were performed using 30 BA and 34 non-BA images. Additional 5 BA and 35 non-BA pictures were used to test accuracy. RESULTS: Hue, saturation, and value (HSV) were the preferred parameter for BA stool identification. A sensitivity and specificity were 100% (95% confidence interval 0.48-1.00 and 0.90-1.00, respectively) even among a collection of visually non acholic, i.e., pigmented BA stools and relatively pale-colored non-BA stools. CONCLUSIONS: Results suggest that an iPhone mobile application integrated with a detection algorithm is an effective and convenient modality for early detection of BA, and potentially for other related diseases. PMID- 28819684 TI - Comparison of transcriptome profiles by Fusarium oxysporum inoculation between Fusarium yellows resistant and susceptible lines in Brassica rapa L. AB - KEY MESSAGE: Resistant and susceptible lines in Brassica rapa have different immune responses against Fusarium oxysporum inoculation. Fusarium yellows caused by Fusarium oxysporum f. sp. conglutinans (Foc) is an important disease of Brassicaceae; however, the mechanism of how host plants respond to Foc is still unknown. By comparing with and without Foc inoculation in both resistant and susceptible lines of Chinese cabbage (Brassica rapa var. pekinensis), we identified differentially expressed genes (DEGs) between the bulked inoculated (6, 12, 24, and 72 h after inoculation (HAI)) and non-inoculated samples. Most of the DEGs were up-regulated by Foc inoculation. Quantitative real-time RT-PCR showed that most up-regulated genes increased their expression levels from 24 HAI. An independent transcriptome analysis at 24 and 72 HAI was performed in resistant and susceptible lines. GO analysis using up-regulated genes at 24 HAI indicated that Foc inoculation activated systemic acquired resistance (SAR) in resistant lines and tryptophan biosynthetic process and responses to chitin and ethylene in susceptible lines. By contrast, GO analysis using up-regulated genes at 72 HAI showed the overrepresentation of some categories for the defense response in susceptible lines but not in the resistant lines. We also compared DEGs between B. rapa and Arabidopsis thaliana after F. oxysporum inoculation at the same time point, and identified genes related to defense response that were up-regulated in the resistant lines of Chinese cabbage and A. thaliana. Particular genes that changed expression levels overlapped between the two species, suggesting that they are candidates for genes involved in the resistance mechanisms against F. oxysporum. PMID- 28819685 TI - Cardiomyocyte dimethylarginine dimethylaminohydrolase-1 (DDAH1) plays an important role in attenuating ventricular hypertrophy and dysfunction. AB - Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases that limits nitric oxide bioavailability. Dimethylarginine dimethylaminohydrolase-1 (DDAH1) exerts a critical role for ADMA degradation and plays an important role in NO signaling. In the heart, DDAH1 is observed in endothelial cells and in the sarcolemma of cardiomyocytes. While NO signaling is important for cardiac adaptation to stress, DDAH1 impact on cardiomyocyte homeostasis is not clear. Here we used the MerCreMer-LoxP model to specifically disrupt cardiomyocyte DDAH1 expression in adult mice to determine the physiological impact of cardiomyocyte DDAH1 under basal conditions and during hypertrophic stress imposed by transverse aortic constriction (TAC). Under control conditions, cardiomyocyte-specific DDAH1 knockout (cDDAH KO) had no detectable effect on plasma ADMA and left ventricular (LV) hypertrophy or function in adult or aging mice. In response to TAC, DDAH1 levels were elevated 2.5-fold in WT mice, which exhibited no change in LV or plasma ADMA content and moderate LV hypertrophy and LV dysfunction. In contrast, cDDAH1 KO mice exposed to TAC showed no increase in LV DDAH1 expression, slightly increased LV tissue ADMA levels, no increase in plasma ADMA, but significantly exacerbated LV hypertrophy, fibrosis, nitrotyrosine production, and LV dysfunction. These findings indicate cardiomyocyte DDAH1 activity is dispensable for cardiac function under basal conditions, but plays an important role in attenuating cardiac hypertrophy and ventricular remodeling under stress conditions, possibly through locally confined regulation of subcellular ADMA and NO signaling. PMID- 28819686 TI - The sensory substrate of multimodal communication in brown-headed cowbirds: are females sensory 'specialists' or 'generalists'? AB - Many animals communicate with multimodal signals. While we have an understanding of multimodal signal production, we know relatively less about receiver filtering of multimodal signals and whether filtering capacity in one modality influences filtering in a second modality. Most multimodal signals contain a temporal element, such as change in frequency over time or a dynamic visual display. We examined the relationship in temporal resolution across two modalities to test whether females are (1) sensory 'specialists', where a trade-off exists between the sensory modalities, (2) sensory 'generalists', where a positive relationship exists between the modalities, or (3) whether no relationship exists between modalities. We used female brown-headed cowbirds (Molothrus ater) to investigate this question as males court females with an audiovisual display. We found a significant positive relationship between female visual and auditory temporal resolution, suggesting that females are sensory 'generalists'. Females appear to resolve information well across multiple modalities, which may select for males that signal their quality similarly across modalities. PMID- 28819687 TI - Central not peripheral vestibular processing impairs gait coordination. AB - Gait coordination is generated by neuronal inter-connections between central pattern generators in the spinal cord governed by cortical areas. Malfunction of central vestibular processing areas generates vestibular symptoms in the absence of an identifiable peripheral vestibular system lesion. Walking in the dark enforces a coordinated afference primarily from the vestibular and somatosensory systems. We hypothesized that patients with aberrant central vestibular processing would demonstrate unique gait characteristics, and have impaired gait coordination compared with those patients with abnormal peripheral vestibular function and healthy controls. One-hundred and eighteen subjects were recruited. Peripheral vestibular function was determined based on laboratory and clinical examinations. Patients with abnormal central vestibular processing had normal peripheral vestibular function. Subjects were instructed to walk at a comfortable pace during three visual conditions; eyes open, eyes open and closed intermittently, and eyes closed. Both patient groups showed a similar spatiotemporal gait pattern, significantly different from the pattern of the healthy controls. However, only the central vestibular patient group had an abnormal coordination of gait as measured by the phase coordination index (PCI). There were no significant interactions between the groups and walking conditions. Peripheral vestibular deficits impair gait though our data suggest that it is the central processing of such peripheral vestibular information that has a greater influence. This impairment may be related to a neural un-coupling between the brain and central pattern generator of the spinal cord based on the abnormal PCI, which seems to be a good indicator of the integrity of this linkage. PMID- 28819688 TI - Airway reconstruction using decellularized tracheal allografts in a porcine model. AB - PURPOSE: Tracheal cartilage reconstruction is an essential approach for the treatment of tracheal congenital abnormalities or injury. Here, we evaluated the use of allogeneic decellularized tracheas as novel support scaffolds. METHODS: Six weaned pigs (4-week-old domestic males) were transplanted with allogeneic tracheal graft patches (three decellularized and three fresh tracheal scaffolds) onto artificial defects (approximately 15 * 15 mm). After 11 weeks, the tracheas were evaluated by bronchoscopy and histological studies. RESULTS: No pigs displayed airway symptoms during the observation period. Tracheal lumen restored by fresh graft patches showed more advanced narrowing than that treated with decellularized grafts by bronchoscopy. Histologically, fresh grafts induced typical cellular rejection; this was decreased with decellularized grafts. In addition, immunohistochemistry demonstrated regenerating foci of recipient cartilage along the adjacent surface of decellularized tracheal grafts. CONCLUSION: Decellularized allogeneic tracheal scaffolds could be effective materials for restoring impaired trachea. PMID- 28819689 TI - Beware of the coronary arteries with implantable cardiac electronic devices. AB - The transvenous implantation of cardiac devices may sometimes cause serious complications involving the coronary arteries. The left anterior descending artery may be injured during nonapical right ventricular implantation while a right atrial lead may injure the right or circumflex coronary artery. Injury of a left internal mammary graft to a coronary artery may cause myocardial infarction. PMID- 28819690 TI - Conductance-based refractory density approach: comparison with experimental data and generalization to lognormal distribution of input current. AB - The conductance-based refractory density (CBRD) approach is an efficient tool for modeling interacting neuronal populations. The model describes the firing activity of a statistical ensemble of uncoupled Hodgkin-Huxley-like neurons, each receiving individual Gaussian noise and a common time-varying deterministic input. However, the approach requires experimental validation and extension to cases of distributed input signals (or input weights) among different neurons of such an ensemble. Here the CBRD model is verified by comparing with experimental data and then generalized for a lognormal (LN) distribution of the input weights. The model with equal weights is shown to reproduce efficiently the post-spike time histograms and the membrane voltage of experimental multiple trial response of single neurons to a step-wise current injection. The responses reveal a more rapid reaction of the firing-rate than voltage. Slow adaptive potassium channels strongly affected the shape of the responses. Next, a computationally efficient CBRD model is derived for a population with the LN input weight distribution and is compared with the original model with equal input weights. The analysis shows that the LN distribution: (1) provides a faster response, (2) eliminates oscillations, (3) leads to higher sensitivity to weak stimuli, and (4) increases the coefficient of variation of interspike intervals. In addition, a simplified firing-rate type model is tested, showing improved precision in the case of a LN distribution of weights. The CBRD approach is recommended for complex, biophysically detailed simulations of interacting neuronal populations, while the modified firing-rate type model is recommended for computationally reduced simulations. PMID- 28819691 TI - Hypoxia affects tissue oxygenation differently in the thigh and calf muscles during incremental running. AB - PURPOSE: The present study was performed to determine the impact of hypoxia on working muscle oxygenation during incremental running, and to compare tissue oxygenation between the thigh and calf muscles. METHODS: Nine distance runners and triathletes performed incremental running tests to exhaustion under normoxic and hypoxic conditions (fraction of inspired oxygen = 0.15). Peak pulmonary oxygen uptake ([Formula: see text]) and tissue oxygen saturation (StO2) were measured simultaneously in both the vastus lateralis and medial gastrocnemius. RESULTS: Hypoxia significantly decreased peak running speed and [Formula: see text] (p < 0.01). During incremental running, StO2 in the vastus lateralis decreased almost linearly, and the rate of decrease from warm-up (180 m min-1) to [Formula: see text] was significantly greater than in the medial gastrocnemius under both normoxic and hypoxic conditions (p < 0.01). StO2 in both muscles was significantly decreased under hypoxic compared with normoxic conditions at all running speeds (p < 0.01). The rate at which StO2 was decreased by hypoxia was greater in the vastus lateralis as the running speed increased, whereas it changed little in the medial gastrocnemius. CONCLUSIONS: These results suggest that the thigh is more deoxygenated than the calf under hypoxic conditions, and that the effects of hypoxia on tissue oxygenation differ between these two muscles during incremental running. PMID- 28819693 TI - The MINDMAP project: mental well-being in urban environments : Design and first results of a survey on healthcare planning policies, strategies and programmes that address mental health promotion and mental disorder prevention for older people in Europe. AB - BACKGROUND: The MINDMAP consortium (2016-2019) aims to identify opportunities provided by the urban environment for the promotion of mental well-being and functioning of older people in Europe by bringing together European cities with urban longitudinal ageing studies: GLOBE, HAPIEE, HUNT, LASA, LUCAS, RECORD, Rotterdam Study, Turin Study. A survey on mental healthcare planning policies and programmes dedicated to older persons covering the range from health promotion to need of nursing care was performed for profound data interpretation in Amsterdam, Eindhoven, Hamburg, Helsinki, Kaunas, Krakow, London, Nord-Trondelag, Paris, Prague, Rotterdam and Turin. OBJECTIVES: To collect detailed information on healthcare planning policies and programmes across these European cities to evaluate variations and to delineate recommendations for sciences, policies and planners using experience from evidence-based practice feedback from the MINDMAP cities. MATERIALS AND METHODS: The MINDMAP partners identified experts in the 12 cities with the best background knowledge of the mental health sector. After pretesting, semi-structured telephone interviews (1-2 h) were performed always by the same person. A structured evaluation matrix based on the geriatric functioning continuum and the World Health Organization (WHO) Public Health Framework for Healthy Ageing was applied. RESULTS: A complete survey (12 out of 12) was performed reporting on 41 policies and 280 programmes on the city level. It appeared from extensive analyses that the focus on older citizens, specific target groups, and multidimensional programmes could be intensified. CONCLUSION: There is a broad variety to cope with the challenges of ageing in health, and to address both physical and mental capacities in older individuals and their dynamic interactions in urban environments. PMID- 28819692 TI - Molecular characterization of atypical antigenic variants of canine rabies virus reveals its reintroduction by wildlife vectors in southeastern Mexico. AB - Rabies is an infectious viral disease that is practically always fatal following the onset of clinical signs. In Mexico, the last case of human rabies transmitted by dogs was reported in 2006 and canine rabies has declined significantly due to vaccination campaigns implemented in the country. Here we report on the molecular characterization of six rabies virus strains found in Yucatan and Chiapas, remarkably, four of them showed an atypical reaction pattern when antigenic characterization with a reduced panel of eight monoclonal antibodies was performed. Phylogenetic analyses on the RNA sequences unveiled that the three atypical strains from Yucatan are associated with skunks. Analysis using the virus entire genome showed that they belong to a different lineage distinct from the variants described for this animal species in Mexico. The Chiapas atypical strain was grouped in a lineage that was considered extinct, while the others are clustered within classic dog variants. PMID- 28819694 TI - Thoracic corpectomy for neoplastic vertebral bodies using a navigated lateral extracavitary approach-a single-center consecutive case series: technique and analysis. AB - Thoracic myelopathy is often caused by vertebral body fractures resulting from neoplastic conditions, traumatic events, or infectious diseases. One of the preferred procedures for treating it is the lateral extracavitary approach (LECA) with single-level or multilevel decompressive corpectomy and reconstruction. The aim of this retrospective study was to analyze the thoracic lateral extracavitary approach with corpectomy using vertebral body replacement systems (VBR-S) and dorsal reconstruction. Twenty-four patients with metastatic or primary lesions of thoracic vertebrae T2-T12 underwent spinal decompression and ventral column reconstruction with correction of spinal deformity via a LECA. One-level to four level corpectomies were performed with additional navigated dorsal pedicle screw fixation at an average of two levels above and below the corpectomy lesion. None of the patients received preoperative spinal embolization, and the majority of the patients were admitted to radiotherapy postoperatively. Their mean age was 56 years (+/- 15), with a female-to-male sex ratio of 8 to 16. Patients with a minimum follow-up period of 16 months were included. The Karnofsky index, preoperative and postoperative numeric rating scale (NRS), and Frankel scale were measured. In addition, intraoperative loss of blood (LOB), units of packed red blood cell (PRBC) transfusions, the duration of the operation, and the hospitalization period were evaluated and correlated with preoperative and postoperative values. The majority of the patients were suffering from metastatic lesions and were treated with a 1 level corpectomy (median 1 level, range 1 to 4). The mean duration of surgery was 288 min (+/- 121) and the mean LOB was 1626 mL (+/- 1486 mL), with approximately two PRBC units per patient used. All patients were transferred to the intensive care unit (ICU) postoperatively, with a mean ICU stay of 2.0 days (+/- 1 day). The mean hospitalization period was 13 days (+/- 7 days). No implant-related failures or procedure-related deaths were observed. Significant differences were noted between the preoperative and postoperative Karnofsky index (74 vs. 84%) and NRS (4 vs. 2). One patient required revision surgery due to a superficial wound infection, and another needed revision surgery due to a dural tear. In another patient, an iatrogenic dural tear was repaired during the same surgical procedure and did not lead to postoperative complications. Four pleural effusions and one pneumothorax were observed, so that the overall complication rate was approximately 33%. Four of the patients died within 2 years of the operation due to progression of the primary disease. Lateral corpectomy and sagittal reconstruction of the thoracic spine using VBR-S conducted via a navigated LECA approach yields favorable results, despite the burden of neoplastic disease. These challenging procedures are accompanied by increased LOB and hospitalization periods, with moderate transfusion requirements. Surgery-related complications are low and local tumor control is satisfactory, despite the progression of the underlying neoplastic disease. However, optimal surgical therapy does not ensure long-term survival.Study design Retrospective analysis of thoracic corpectomiesLevel of evidence 4. PMID- 28819695 TI - Theoretical modeling of mechanical homeostasis of a mammalian cell under gravity directed vector. AB - Translocation of dense nucleus along gravity vector initiates mechanical remodeling of a eukaryotic cell. In our previous experiments, we quantified the impact of gravity vector on cell remodeling by placing an MC3T3-E1 cell onto upward (U)-, downward (D)-, or edge-on (E)- orientated substrate. Our experimental data demonstrate that orientation dependence of nucleus longitudinal translocation is positively correlated with cytoskeletal (CSK) remodeling of their expressions and structures and also is associated with rearrangement of focal adhesion complex (FAC). However, the underlying mechanism how CSK network and FACs are reorganized in a mammalian cell remains unclear. In this paper, we developed a theoretical biomechanical model to integrate the mechanosensing of nucleus translocation with CSK remodeling and FAC reorganization induced by a gravity vector. The cell was simplified as a nucleated tensegrity structure in the model. The cell and CSK filaments were considered to be symmetrical. All elements of CSK filaments and cytomembrane that support the nucleus were simplified as springs. FACs were simplified as an adhesion cluster of parallel bonds with shared force. Our model proposed that gravity vector-directed translocation of the cell nucleus is mechanically balanced by CSK remodeling and FAC reorganization induced by a gravitational force. Under gravity, dense nucleus tends to translocate and exert additional compressive or stretching force on the cytoskeleton. Finally, changes of the tension force acting on talin by microfilament alter the size of FACs. Results from our model are in qualitative agreement with those from experiments. PMID- 28819696 TI - What are the treatment options for blister-like aneurysms? AB - Treatment of blood blister-like aneurysms (BBAs) of the supraclinoidal internal carotid artery (ICA) is challenging and the optimal treatment is yet to be defined. The treatment options for ICA BBAS are microsurgery, endovascular therapy, or a combination of the two. The microsurgical armamentarium consists mainly of direct aneurysm clipping with or without protective EC-IC bypass, clip wrapping, or trap ligation with ICA sacrifice with or without EC-IC bypass. The endovascular treatment options are mainly endovascular ICA ligation, multiple overlapping stents (>= 3) with or without coiling, covered stents, or flow diverters. In four recent meta-analyses of BBAs, neither microsurgical nor endovascular therapy had an impact on clinical outcome in multivariate analysis. Microsurgery offered aneurysm obliteration rates superior to endovascular techniques, but came at a higher risk of intraoperative bleeding. Endovascular therapy increased the likelihood of a second treatment, conversion to another treatment modality, and incomplete aneurysm obliteration. In this review, we discuss pros and cons of the above approaches while adding our own viewpoints to the discussion. PMID- 28819697 TI - Mechanistic understanding of crystal violet dye sorption by woody biochar: implications for wastewater treatment. AB - Dye-based industries, particularly small and medium scale, discharge their effluents into waterways without treatment due to cost considerations. We investigated the use of biochars produced from the woody tree Gliricidia sepium at 300 degrees C (GBC300) and 500 degrees C (GBC500) in the laboratory and at 700 degrees C from a dendro bioenergy industry (GBC700), to evaluate their potential for sorption of crystal violet (CV) dye. Experiments were conducted to assess the effect of pH reaction time and CV loading on the adsorption process. The equilibrium adsorption capacity was higher with GBC700 (7.9 mg g-1) than GBC500 (4.9 mg g-1) and GBC300 (4.4 mg g-1), at pH 8. The CV sorption process was dependent on the pH, surface area and pore volume of biochar (GBC). Both Freundlich and Hill isotherm models fitted best to the equilibrium isotherm data suggesting cooperative interactions via physisorption and chemisorption mechanisms for CV sorption. The highest Hill sorption capacity of 125.5 mg g-1 was given by GBC700 at pH 8. Kinetic data followed the pseudo-second-order model, suggesting that the sorption process is more inclined toward the chemisorption mechanism. Pore diffusion, pi-pi electron donor-acceptor interaction and H bonding were postulated to be involved in physisorption, whereas electrostatic interactions of protonated amine group of CV and negatively charged GBC surface led to a chemisorption type of adsorption. Overall, GBC produced as a by-product of the dendro industry could be a promising remedy for CV removal from an aqueous environment. PMID- 28819698 TI - Sublethal effects of pyrethroid and neonicotinoid insecticides on Iphiseiodes zuluagai Denmark and Muma (Mesostigmata: Phytoseiidae). AB - The predator mite Iphiseiodes zuluagai Denmark & Muma is an important biological control agent of mite pests, and it is one of the most common species found in citrus orchards. This study assessed, under laboratory conditions, the toxicity and duration of the harmful effects of five insecticides, the three pyrethroids deltamethrin, esfenvalerate and lambda-cyhalothrin, and the two neonicotinoids imidacloprid and thiamethoxam on I. zuluagai. Furthermore, we estimated the life table parameters of the predator. Our results showed that deltamethrin and lambda cyhalothrin caused higher mortality of larvae and adults than imidacloprid and thiamethoxam. In contrast, esfenvalerate provided larval mortality similar to imidacloprid and thiamethoxam, but it did not cause significant adult mortality of the predator. Mites that developed on pyrethroid residues showed lower survival of the immature stages, fecundity, and longevity compared to neonicotinoid residues and the control treatment. The estimated life-table parameters indicated that deltamethrin, lambda-cyhalothrin and esfenvalerate caused greater reduction in R o and r of I. zuluagai compared with imidacloprid and thiamethoxam, which were similar to the control treatment. Besides the impacts on biological and population parameters, the duration of the harmful activity of pyrethroid insecticides was longer than the neonicotinoids. Therefore, the use of pyrethroid insecticides to control pest insects may involve serious implications for integrated pest-management programs that aim to exploit the biological control by I. zuluagai in citrus orchards. PMID- 28819700 TI - Sporadic endometrial adenocarcinoma with MMR deficiency due to biallelic MSH2 somatic mutations. AB - The invalidation of the Mismatch Repair (MMR) system is responsible for a so called "deficient MMR" phenotype (dMMR) characterized by microsatellite instability and abnormal pattern of expression of MMR proteins in tumor tissue. This phenotype occurs in at least 20% of sporadic endometrial adenocarcinomas by epigenetic silencing of MLH1 gene. It is also observed in virtually all tumors occurring in patients with Lynch syndrome by monoallelic germline mutation in one of the MMR genes. The determination of this phenotype (dMMR vs. proficient MMR pMMR) has therefore a pivotal place in the diagnosis algorithm for Lynch syndrome by monoallelic germline mutation in one of the MMR genes. The determination of this phenotype (dMMR vs. proficient MMR-pMMR) has therefore a pivotal place in the diagnosis algorithm for Lynch syndrome. We report the case of a woman with an early-onset endometrial adenocarcinoma who was suspected to be affected with Lynch syndrome based on tumor dMMR phenotype (MSI associated with loss of expression of MSH2 and MSH6 proteins). After complete germline and somatic evaluations, this phenotype was eventually explained by two MSH2 somatic mutations and the diagnosis of Lynch-like syndrome due to an unidentified MSH2 germline mutation was ruled out. Somatic mosaicism at low mutation rate was unlikely as no mutation was detected by DNA analysis from various tissue samples. Nevertheless, the three patient's children were tested for the two mutations and these tests were negative. Biallelic somatic mutations of one MMR gene is a mechanism of invalidation of the MMR system in sporadic cases. Clinicians have to be aware of this mechanism because of the great clinical implication for the patients and their relatives. PMID- 28819699 TI - CUDC-907, a dual HDAC and PI3K inhibitor, reverses platinum drug resistance. AB - Platinum (Pt)-based anticancer drugs are the mainstay of treatment for solid cancers. However, resistance to Pt drugs develops rapidly, which can be caused by overexpression of multidrug resistance transporters and activation of DNA repair. CUDC-907 is a potent molecular targeted anticancer agent, rationally designed to simultaneously inhibit histone deacetylase (HDAC) and phosphatidylinositol 3 kinase (PI3K). We investigated the potentiation effect of CUDC-907 on Pt drugs in resistant cancer cells. ABCC2 stably-transfected HEK293 cells and two pairs of parental and Pt-resistant cancer cell lines were used to test for the circumvention of resistance by CUDC-907. Chemosensitivity was assessed by the sulphorhodamine B assay. Drug combinations were evaluated by the median effect analysis. ABCC2 transport activity was examined by flow cytometric assay. Cellular Pt drug accumulation and DNA platination were detected by inductively coupled plasma optical emission spectroscopy. ABCC2, ERCC1 and p21 expression were evaluated by quantitative real-time PCR. Cell cycle analysis and apoptosis assay were performed by standard flow cytometric method. The combination of CUDC 907 with cisplatin were found to exhibit synergistic cytotoxic effect in cisplatin-resistant cancer cells. In Pt-resistant cancer cells, CUDC-907 apparently circumvented the resistance through inhibition of ABCC2 and DNA repair but induction of cell cycle arrest. In the presence of CUDC-907, cellular accumulation of Pt drugs and formation of DNA-Pt adducts were found to be increased whereas expression levels of ABCC2 and ERCC1 was inhibited in Pt resistant cells. The data advocates further development of CUDC-907 as a resistance reversal agent for use in combination cancer chemotherapy. PMID- 28819701 TI - Suppressive Effects of TSAHC in an Experimental Mouse Model and Fibroblast-Like Synoviocytes of Rheumatoid Arthritis. AB - The purpose of this study is to investigate the effect of TSAHC [4'-(p toluenesulfonylamido)-4-hydroxychalcone] in K/BxN serum transfer arthritis model and fibroblast-like synoviocytes of rheumatoid arthritis (RA-FLS). In in vivo experiments, TSAHC attenuated the incidence and severity of arthritis in comparison with the vehicle group. Histological findings showed that TSAHC decreased the inflammation, bone erosion, cartilage damage, and osteoclasts activity in the ankle. Furthermore, we confirmed by biochemical analysis that the observations were associated with the decreased expression of proinflammatory cytokines, matrix metalloproteinases (MMPs), and RANKL in serum and ankle. In in vitro experiments, TSAHC induced apoptosis, while it significantly suppressed tumor necrosis factor-alpha (TNF-alpha)-induced cell proliferation in RA-FLS. Moreover, TSAHC inhibited mRNA expression of TNF-alpha-induced interleukin (IL) 6, MMP-1, MMP-3, and MMP-13. Evaluation of signaling events showed that TSAHC inhibited the translocation and transcriptional activity of nuclear factor-kappa B (NF-kappaB) by regulating phosphorylated-IkappaB-alpha (p-IkappaB-alpha) and IkappaB-alpha in TNF-alpha-induced RA-FLS. Our results suggest that TSAHC inhibits experimental arthritis in mice and suppresses TNF-alpha-induced RA-FLS activities via NF-kappaB pathway. Therefore, TSAHC may have therapeutic potential for the treatment of RA. PMID- 28819702 TI - DNAzyme Based Amplified Biosensor on Ultrasensitive Fluorescence Detection of Pb (II) Ions from Aqueous System. AB - A label -free DNAzyme amplified biosensor is found to be highly selective and sensitive towards fluorescent detection of Pb2+ ions in aqueous media. The DNAzyme complex has designed by the hybridization of the enzyme and substrate strand. In the presence of Pb2+, the DNAzyme activated and cleaved the substrate strand of RNA site (rA) into two oligonucleotide fragments. Further, the free fragment was hybridized with a complementary strand on the surface of MBs. After magnetic separation, SYBER Green I was added and readily intercalate with the dsDNA to gives a bright fluorescence signal with intensity directly proportional to the concentration of Pb2+ions. A detection limit of 5 nM in Pb2+ the detection range 0 to 500 nM was obtained. This label- free fluorescent biosensor has been successfully applied to the determination of environmental water samples. Then results open up the possibility for real-time quantitative detection of Pb2+ with convenient potential applications in the biological and environmental field. Graphical Abstract. PMID- 28819704 TI - Shining light on membrane proteins. PMID- 28819703 TI - Novel prostate cancer immunotherapy with a DNA-encoded anti-prostate-specific membrane antigen monoclonal antibody. AB - Prostate-specific membrane antigen (PSMA) is expressed at high levels on malignant prostate cells and is likely an important therapeutic target for the treatment of prostate carcinoma. Current immunotherapy approaches to target PSMA include peptide, cell, vector or DNA-based vaccines as well as passive administration of PSMA-specific monoclonal antibodies (mAb). Conventional mAb immunotherapy has numerous logistical and practical limitations, including high production costs and a requirement for frequent dosing due to short mAb serum half-life. In this report, we describe a novel strategy of antibody-based immunotherapy against prostate carcinoma that utilizes synthetic DNA plasmids that encode a therapeutic human mAb that target PSMA. Electroporation-enhanced intramuscular injection of the DNA-encoded mAb (DMAb) plasmid into mice led to the production of functional and durable levels of the anti-PSMA antibody. The anti-PSMA produced in vivo controlled tumor growth and prolonged survival in a mouse model. This is likely mediated by antibody-dependent cellular cytotoxicity (ADCC) effect with the aid of NK cells. Further study of this novel approach for treatment of human prostate disease and other malignant conditions is warranted. PMID- 28819705 TI - Clinical features and long-term outcomes of primary spinal malignant melanoma: a single center experience. AB - Primary malignant melanomas are very rare tumors in the spinal canal. In this study, the authors review their experience in a series of seven patients with histologically proven primary spinal malignant melanoma (PSMM) and discuss the clinical features, treatment strategy, and long-term outcomes. Clinical data of seven patients with PSMM treated at a single institution were retrospectively analyzed. There were three male and four female patients, with a mean age of 44 years. The mean duration of illness was 5.4 months. The tumors showed hyperintensity in six cases on T1-weighted image (WI) and isointensity or hypointensity in five cases on T2WI. Gross total resection (GTR) of the tumor was achieved in two cases, and subtotal resection (STR) was achieved in five cases. Four STR patients underwent postoperative local radiation therapy. Postoperative MRI results showed no tumor recurrence in all four female patients after an average follow-up period of 64.5 months. Three male patients had tumor recurrence and dissemination after postoperative 14.7 months (8-24 months), and all died 16.3 months (10-25 months) after initial diagnosis. PSMM should be considered in the differential diagnosis of a middle-aged patient with spinal lesion if the tumor shows hyperintensity on T1WI and hypointensity or isointensity on T2WI on MRI. STR followed by radiotherapy is not excessively associated with deterioration of the final outcome compared to GTR. Our study suggests that PSMM might have female predominance in favorable outcome. Surgical resection followed by adjuvant radiotherapy and regular follow-up are recommended. PMID- 28819707 TI - Metastatic melanoma: prognostic factors and survival in patients with brain metastases. AB - Brain metastases from malignant melanoma carry a poor prognosis. Novel systemic agents have improved overall survival (OS), but the value of whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) remains uncertain. The melanoma-specific graded prognostic assessment (msGPA) provides useful prognostic information, but the relevance to the modern-day population has not been validated. Since 2011, 53 patients received treatment for brain metastases from malignant melanoma at the Rosemere Cancer Centre medical oncology clinic. Data were collated on demographic factors and survival. Survival analyses were performed using Kaplan-Meier methods. Cox regression was used to identify prognostic factors on univariate and multivariate analysis. OS from the date of diagnosis of brain metastases was 4.83 months (range 0.27-30.4 months). On univariate analysis, BRAF, performance status and msGPA were significant prognostic indicators for OS (p = 0.0056, p = 0.0039 and p = 0.0001 respectively). msGPA remained significant on multivariate analysis (p = 0.0006). OS for BRAF-positive patients receiving targeted treatment (n = 22) was significantly better than for BRAF-negative patients (n = 26), with median survival times of 8.2 and 3.7 months respectively (p = 0.0039, HR 2.36). SRS combined with systemic agents (n = 16) produced an OS of 13.5 months. Patients receiving WBRT alone (n = 21) had a poor prognosis (2.2 months). The msGPA remains a valid prognostic indicator in the era of novel systemic treatments for melanoma. BRAF-positive patients receiving targeted agents during their treatment had favorable survival outcomes. WBRT alone should be use with caution in the active management of melanoma brain metastases. PMID- 28819706 TI - Generation of a functional humanized Delta-like ligand 4 transgenic mouse model. AB - Humanized mouse models are important tools in many areas of biological drug development including, within oncology research, the development of antagonistic antibodies that have the potential to block tumor growth by controlling vascularization and are key to the generation of in vivo proof-of-concept efficacy data. However, due to cross reactivity between human antibodies and mouse target such studies regularly require mouse models expressing only the human version of the target molecule. Such humanized knock-in/knock-out, KIKO, models are dependent upon the generation of homozygous mice expressing only the human molecule, compensating for loss of the mouse form. However, KIKO strategies can fail to generate homozygous mice, even though the human form is expressed and the endogenous mouse locus is correctly targeted. A typical strategy for generating KIKO mice is by ATG fusion where the human cDNA is inserted downstream of the endogenous mouse promoter elements. However, when adopting this strategy it is possible that the mouse promoter fails to express the human form in a manner compensating for loss of the mouse form or alternatively the human protein is incompatible in the context of the mouse pathway being investigated. So to understand more around the biology of KIKO models, and to overcome our failure with a number of ATG fusion strategies, we developed a range of humanized models focused on Delta-like 4 (Dll4), a target where we initially failed to generate a humanized model. By adopting a broader biologic strategy, we successfully generated a humanized DLL4 KIKO which led to a greater understanding of critical biological aspects for consideration when developing humanized models. PMID- 28819708 TI - In situ remediation of chlorinated solvent-contaminated groundwater using ZVI/organic carbon amendment in China: field pilot test and full-scale application. AB - Chlorinated solvents in groundwater pose threats to human health and the environment due to their carcinogenesis and bioaccumulation. These problems are often more severe in developing countries such as China. Thus, methods for chlorinated solvent-contaminated groundwater remediation are urgently needed. This study presents a technique of in situ remediation via the direct-push amendment injection that enhances the reductive dechlorination of chlorinated solvents in groundwater in the low-permeability aquifer. A field-based pilot test and a following real-world, full-scale application were conducted at an active manufacturing facility in Shanghai, China. The chlorinated solvents found at the clay till site included 1,1,1-trichloroethane (1,1,1-TCA), 1,1-dichloroethane (1,1-DCA), 1,1-dichloroethylene (1,1-DCE), vinyl chloride (VC), and chloroethane (CA). A commercially available amendment (EHC(r), Peroxychem, Philadelphia, PA) combining zero-valent iron and organic carbon was used to treat the above pollutants. Pilot test results showed that direct-push EHC injection efficiently facilitated the in situ reductive remediation of groundwater contaminated with chlorinated solvents. The mean removal rates of 1,1,1-TCA, 1,1-DCA, and 1,1-DCE at 270 days post-injection were 99.6, 99.3, and 73.3%, respectively, which were obviously higher than those of VC and CA (42.3 and 37.1%, respectively). Clear decreases in oxidation-reduction potential and dissolved oxygen concentration, and increases in Fe2+ and total organic carbon concentration, were also observed during the monitoring period. These indicate that EHC promotes the anaerobic degradation of chlorinated hydrocarbons primarily via long-term biological reductive dechlorination, with instant chemical reductive dechlorination acting as a secondary pathway. The optimal effective time of EHC injection was 0-90 days, and its radius of influence was 1.5 m. In full-scale application, the maximum concentrations of 1,1,1-TCA and 1,1-DCA in the contaminate plume fell below the relevant Dutch Intervention Values at 180 days post-injection. Moreover, the dynamics of the target pollutant concentrations mirrored those of the pilot test. Thus, we have demonstrated that the direct-push injection of EHC successfully leads to the remediation of chlorinated solvent-contaminated groundwater in a real-world scenario. The parameters determined by this study (e.g., effectiveness, injection amount, injection depth, injection pressures, and radius of influence) are applicable to other low-permeability contaminated sites where in situ remediation by enhanced reductive dechlorination is required. PMID- 28819709 TI - Use of direct oral anticoagulants in patients on immunomodulatory agents. AB - Immunomodulatory agents (IMiDs) are used to treat multiple hematologic malignancies. Their use is also associated with increased risk of venous thromboembolism (VTE). Direct oral anticoagulants (DOACs) have been increasingly utilized but due to their relative novelty, their role in malignancy has only been recently investigated. The objective of this study was to assess the safety and efficacy of DOACs in patients receiving IMiDs. This was a retrospective study of patients at our institution treated with an IMiD and concomitant warfarin or DOAC between January 1, 2010 and December 31, 2015. Information on demographic and clinical characteristics was collected. Separate encounters were collected for each specific combination of IMiD and anticoagulant. Bleeding and thrombotic events were recorded. There were four bleeding events in the DOAC group; all were non-major. There were six bleeding events in the warfarin group, two of which were major (gastrointestinal bleeding (GIB) and subarachnoid hemorrhage (SAH)) and four of which were non-major. Of the two major bleeds in this group, neither event occurred with concomitant antiplatelet therapy. There was one thrombotic event in the DOAC group, which was a myocardial infarction, suspected to be related to carfilzomib. There were no thrombotic events in the warfarin group. This was a retrospective, single-institution study assessing the safety and efficacy of DOACs as compared to warfarin in patients on IMiDs. DOACs may represent an attractive alternative to warfarin for VTE prophylaxis in patients on IMiDs but prospective studies in this population are warranted. PMID- 28819710 TI - Epidemiology and 'big data'. PMID- 28819711 TI - Measurement invariance, the lack thereof, and modeling change. AB - PURPOSE: Measurement invariance issues should be considered during test construction. In this paper, we provide a conceptual overview of measurement invariance and describe how the concept is implemented in several different statistical approaches. Typical applications look for invariance over things such as mode of administration (paper and pencil vs. computer based), language/translation, age, time, and gender, to cite just a few examples. To the extent that the relationships between items and constructs are stable/invariant, we can be more confident in score interpretations. METHODS: A series of simulated examples are reported which highlight different kinds of non-invariance, the impact it can have, and the effect of appropriately modeling a lack of invariance. One example focuses on the longitudinal context, where measurement invariance is critical to understanding trends over time. Software syntax is provided to help researchers apply these models with their own data. RESULTS: The simulation studies demonstrate the negative impact an erroneous assumption of invariance may have on scores and substantive conclusions drawn from naively analyzing those scores. CONCLUSIONS: Measurement invariance implies that the links between the items and the construct of interest are invariant over some domain, grouping, or classification. Examining a new or existing test for measurement invariance should be part of any test construction/implementation plan. In addition to reviewing implications of the simulation study results, we also provide a discussion of the limitations of current approaches and areas in need of additional research. PMID- 28819712 TI - Optical Coherence Tomography to Differentiate Papilledema from Pseudopapilledema. AB - PURPOSE OF REVIEW: Mild papilledema may be difficult to distinguish by clinical observation from pseudopapilledema. An accurate diagnosis is critical to avoid invasive workup and unwarranted treatment. In this review, we focus on the development and subsequent role of optical coherence tomography (OCT) in detecting and differentiating optic nerve head drusen (ONHD) from papilledema and other causes of acquired swelling of the optic disc. RECENT FINDINGS: Newer OCT technologies which permit deeper penetration to improve detection of ONHD were also reviewed. Enhanced depth imaging (EDI) spectral-domain OCT and swept-source (SS) OCT are currently recognized as the most reliable and sensitive tools to diagnose ONHD. OCT devices currently available provide a means to quantify drusen dimensions, to evaluate the integrity of neighboring structures and to monitor axonal and neuronal damage, yielding additional information to better understand the relationship between the morphological features of drusen, and their effects on the structure and function of the optic nerve. PMID- 28819713 TI - Plasma Growth Differentiation Factor-15 is a Potential Biomarker for Pediatric Pulmonary Arterial Hypertension Associated with Congenital Heart Disease. AB - We aimed to investigate plasma growth differentiation factor-15 (GDF-15) levels in pediatric pulmonary arterial hypertension secondary to congenital heart disease (PAH-CHD), and assess the association with hemodynamic parameters. Plasma GDF-15 levels were measured in children with PAH-CHD (n = 46) and compared to children with CHD without PAH (n = 39). Normal individuals (n = 30) served as health control group. Plasma GDF-15 levels were significantly elevated in patients with PAH-CHD compared with those with CHD without PAH (median 1415 ng/L, interquartile range [IQR] 926.7-2111.7 ng/L vs. 890.6 ng/L, IQR 394.7-1094.3 ng/L, p < 0.01). Elevated plasma GDF-15 levels were positively related to Functional Class, uric acid, N-terminal pro-B-type natriuretic peptide (NT proBNP), pulmonary artery systolic pressure, mean pulmonary artery pressure, pulmonary blood flow/systemic blood flow and pulmonary vascular resistance, and a lower mixed venous oxygen saturation (Svo2). The area under the curve (AUC) for adding GDF-15 to NT-proBNP was not superior to the AUC of NT-pro BNP alone (AUC difference 0.0295, p = 0.324) (NT-proBNP, AUC 0.823, 95% CI 0.725-0.897; GDF-15 plus NT-proBNP, AUC 0.852, 95% CI 0.759-0.92), whereas it revealed a slightly greater specificity and positive predictive value. The diagnostic power of NT-pro BNP was not inferior to GDF-15 (AUC difference 0.0443, p = 0.43). Plasma GDF-15 levels might be a surrogate marker for pediatric PAH-CHD. PMID- 28819714 TI - Utilization of waste bittern from saltern as a source for magnesium and an absorbent for carbon dioxide capture. AB - During solar salt production, large quantities of bittern, a liquid by-product containing high inorganic substance concentrations, are produced. The purpose of this research was to examine the utilization of waste bittern generated from salterns as a source for Mg production and as an absorbent for carbon dioxide (CO2) capture. The study was conducted in a sequential two-step process. At NaOH/Mg molar ratios of 2.70-2.75 and pH 9.5-10.0, > 99% Mg precipitation from the bittern was achieved. After washing with water, 100-120 g/L of precipitate containing 94% Mg(OH)2 was recovered from the bittern. At the optimum NH4OH concentration of 5%, 120 g of sodium bicarbonate precipitate per liter of bittern were recovered, which was equivalent to 63 g CO2 captured per liter of bittern. These results can be used to support the use of bittern as a resource and reduce economic losses during solar salt production. PMID- 28819715 TI - Automatic detection of hemorrhagic pericardial effusion on PMCT using deep learning - a feasibility study. AB - Post mortem computed tomography (PMCT) can be used as a triage tool to better identify cases with a possibly non-natural cause of death, especially when high caseloads make it impossible to perform autopsies on all cases. Substantial data can be generated by modern medical scanners, especially in a forensic setting where the entire body is documented at high resolution. A solution for the resulting issues could be the use of deep learning techniques for automatic analysis of radiological images. In this article, we wanted to test the feasibility of such methods for forensic imaging by hypothesizing that deep learning methods can detect and segment a hemopericardium in PMCT. For deep learning image analysis software, we used the ViDi Suite 2.0. We retrospectively selected 28 cases with, and 24 cases without, hemopericardium. Based on these data, we trained two separate deep learning networks. The first one classified images into hemopericardium/not hemopericardium, and the second one segmented the blood content. We randomly selected 50% of the data for training and 50% for validation. This process was repeated 20 times. The best performing classification network classified all cases of hemopericardium from the validation images correctly with only a few false positives. The best performing segmentation network would tend to underestimate the amount of blood in the pericardium, which is the case for most networks. This is the first study that shows that deep learning has potential for automated image analysis of radiological images in forensic medicine. PMID- 28819717 TI - Mitigation of Acute Aluminum Toxicity by Sodium Selenite and N-Acetylcysteine in Adult Male Rats. AB - The objective of this study is to investigate the toxic effects of aluminum and the potential alleviation of selenite and N-acetylcysteine (NAC) on this toxicity. Acute aluminum toxicity was induced by intraperitoneal (i.p.) injection of AlCl3 (30 mg Al3+/kg) for four consecutive days. Al3+ damaged the synthetic capability and regeneration power of liver cells and induced inflammation. It also damaged the kidney and disturbed the lipid profile enhancing the total cholesterol level and LDL-cholesterol level increasing the risks of atherosclerosis. Al3+ reduced the cellular antioxidant milieu typified by the decrease in reduced glutathione, vitamin E, and four antioxidant enzymes and induced lipid peroxidation (LPO). Selenite at 1 mg Se/kg and NAC at 150 mg/kg injected either simultaneously with or after Al3+ mitigated most of these damaging effects probably by the virtue of scavenging the free radicals, binding aluminum and stimulating its excretion and reducing its bioavailability, bolstering the endogenous antioxidant defense systems, stabilizing the cell membrane, and preventing LPO. The beneficial effects of selenite and NAC against aluminum toxicity were also confirmed by the light and electron histopathology study. There were no significant differences between the two regimens used (protection and therapeutic) in the current study probably due to the short time of exposure, and the abrogation of Al3+ toxicity offered by selenite was better than that provided by NAC on the histopathology level. PMID- 28819718 TI - A tree branch instead of a ligature: an unusual accidental hanging. AB - A unique case of accidental hanging due to compression of the neck of an adult by the branches of a coffee tree is reported. The decedent was a 42-year-old male who was found dead in a semi prone position on a slope. His neck was lodged in a wedge formed by two branches of a coffee tree, with his legs angled downwards on the slope. Autopsy revealed two friction abrasions located horizontally on either side of the front of the neck, just above the larynx. The findings were compatible with compression of the neck by the branches of the tree, with the body weight of the decedent contributing to compression. Subsequent complete autopsy examination confirmed the cause of death as hanging. Following an inquest the death was ruled to be accidental. PMID- 28819716 TI - Neurological Complications of Therapeutic Monoclonal Antibodies: Trends from Oncology to Rheumatology. AB - PURPOSE OF REVIEW: This review is to describe the scope of neurological complications associated with monoclonal antibody-based therapies, applied across medical specialties, to demonstrate the common and rare neurological syndromes that may be encountered in clinical practice according to the therapeutic agent being receive, and to explain appropriate work-up, diagnosis, and management of drug complications, as supported by the literature. RECENT FINDINGS: The number of commercially available, evidence-based therapeutic monoclonal antibodies continues to expand. In oncology, immune checkpoint inhibitors are particularly important, as a wide range of central and peripheral nervous system complications are described. In rheumatology, anti-TNF alpha drugs remain associated with demyelinating syndromes. The number of therapeutic monoclonal antibodies encountered in practice continues to grow, as does the number of described neurological complications. Recognition of a possible drug complication is key, as these are typically complex patients at risk of other causes of neurological injury. Identification of a complication of therapy often leads to intervention and a change in management. PMID- 28819719 TI - Activity of cabazitaxel in patients with metastatic castration-resistant prostate cancer after treatment with single or dual regimens of novel androgen receptor targeting agents. AB - The purpose of this study was to evaluate the efficacy of cabazitaxel for patients with metastatic castration-resistant prostate cancer (mCRPC) after sequential therapy with docetaxel (DTX) and single or dual regimens of novel androgen receptor-axis-targeted (ARAT) agents. We retrospectively reviewed 84 consecutive patients treated with cabazitaxel at Kobe University Hospital and related hospitals from September 2014 to September 2016. The association of each prognostic parameter with progression-free survival (PFS) was evaluated, including the sequence of therapy. Patients were divided according to their treatment after receiving cabazitaxel as follows: group 1 (after DTX and single regimen of novel ARAT agent) and group 2 (after DTX and dual novel ARAT agents). Median PFS for cabazitaxel treatment was 10.3 months (range 4.5-14.2 months). Prostate-specific antigen (PSA) response rates (>=30%) were 46.8 and 46.1% in group 1 and group 2, respectively [p = 0.96, hazard ratio (HR) 1.02, 95% confidence interval (CI) 0.57-1.80]. PSA response rates (>=50%) were 43.8 and 26.9% in patients of group 1 and group 2, respectively (p = 0.18, HR 1.54, 95% CI 0.78-3.04). Univariate analysis revealed that PFS for cabazitaxel treatment was significantly associated with baseline alkaline phosphatase, bone metastasis, and prior sequential therapy. Multivariate analysis revealed that bone metastasis and prior sequential therapy were independently associated with PFS. Prior sequential therapy with single regimen or dual regimens of novel ARAT agents was independently associated with PFS of patients with mCRPC treated with cabazitaxel. The effect of cabazitaxel after the administration of DTX and single novel ARAT agent was more sustained. PMID- 28819720 TI - Immunohistochemical null-phenotype for mismatch repair proteins in colonic carcinoma associated with concurrent MLH1 hypermethylation and MSH2 somatic mutations. AB - Microsatellite instability, a well-established driver pathway in colorectal carcinogenesis, can develop in both sporadic and hereditary conditions via different molecular alterations in the DNA mismatch repair (MMR) genes. MMR protein immunohistochemistry (IHC) is currently widely used for the detection of MMR deficiency in solid tumors. The IHC test, however, can show varied staining patterns, posing challenges in the interpretation of the staining results in some cases. Here we report a case of an 80-year-old female with a colonic adenocarcinoma that exhibited an unusual "null" IHC staining pattern with complete loss of all four MMR proteins (MLH1, MSH2, MSH6, and PMS2). This led to subsequent MLH1 methylation testing and next generation sequencing which demonstrated that the loss of all MMR proteins was associated with concurrent promoter hypermethylation of MLH1 and double somatic truncating mutations in MSH2. These molecular findings, in conjunction with the patient's age being 80 years and the fact that the patient had no personal or family cancer history, indicated that the MMR deficiency was highly likely sporadic in nature. Thus, the stringent Lynch syndrome type surveillance programs were not recommended to the patient and her family members. This case illustrates a rare but important scenario where a null IHC phenotype signifies complex underlying molecular alternations that bear clinical management implications, highlighting the need for recognition and awareness of such unusual IHC staining patterns. PMID- 28819721 TI - Inherited, not acquired, Gitelman syndrome in a patient with Sjogren's syndrome: importance of genetic testing to distinguish the two forms. AB - Gitelman syndrome (GS) is an autosomal recessive, salt-losing renal tubulopathy caused by mutations in the SLC12A3 gene; however, it can also be acquired in patients with autoimmune disease, especially in those with Sjogren's syndrome. Differentiating between the inherited and acquired forms of GS is clinically difficult. We report a case of inherited, not acquired, GS in a patient with Sjogren's syndrome. A 41-year-old woman, who had been diagnosed with Sjogren's syndrome at 27-years-old, had shown chronic hypokalemia (2.5-3.5 mmol/L). Laboratory tests showed hypokalemic alkalosis, hypomagnesemia, and hypocalciuria, corresponding to GS. Although acquired GS associated with Sjogren's syndrome was initially suspected, a genetic test identified a novel homozygous mutation of c.1336-2A > T in the SLC12A3 gene, which resulted in aberrant splicing in the SLC12A3 transcript with the exclusion of exons 11 and 12. Thus, the GS was diagnosed as not the acquired but the inherited form. In the diagnosis of GS in patients with autoimmune disease, genetic testing of SLC12A3 is essential for differentiating the two forms. PMID- 28819723 TI - Guselkumab: First Global Approval. AB - Guselkumab (TremfyaTM) is a human monoclonal IgG1lambda antibody being developed by Janssen Biotech, Inc. that has been approved in the USA as a treatment for moderate-to-severe plaque psoriasis. Guselkumab inhibits the binding of interleukin 23 (IL-23) to its cell surface receptor, disrupting the type 17 helper T cell/IL-17 pathway. This article summarizes the milestones in the development of guselkumab leading to this first approval for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. PMID- 28819722 TI - Carbon and amide detect backbone assignment methods of a novel repeat protein from the staphylocoagulase in S. aureus. AB - The C-terminal repeat domain of staphylocoagulase that is secreted by the S. aureus is believed to play an important role interacting with fibrinogen and promotes blood clotting. To study this interaction by NMR, full assignment of each amide residue in the HSQC spectrum was required. Despite of the short sequence of the repeat construct, the HSQC spectrum contained a substantial amount of overlapped and exchange broadened resonances, indicating little secondary or tertiary structure. This caused severe problems while using the conventional, amide based NMR method for the backbone assignment. With the growing interest in small apparently disordered proteins, these issues are being faced more frequently. An alternative strategy to improve the backbone assignment capability involved carbon direct detection methods. Circumventing the amide proton detection offers a larger signal dispersion and more uniform signal intensity. For peptides with higher concentrations and in combination with the cold carbon channels of new cryoprobes, higher fields, and sufficiently long relaxation times, the disadvantage of the lower sensitivity of the 13C nucleus can be overcome. Another advantage of this method is the assignment of the proline backbone residues. Complete assignment with the carbon-detected strategy was achieved with a set of only two 3D, one 2D, and a HNCO measurement, which was necessary to translate the information to the HSQC spectrum. PMID- 28819724 TI - Hydrogeochemistry and water quality of the Kordkandi-Duzduzan plain, NW Iran: application of multivariate statistical analysis and PoS index. AB - Kordkandi-Duzduzan plain is one of the fertile plains of East Azarbaijan Province, NW of Iran. Groundwater is an important resource for drinking and agricultural purposes due to the lack of surface water resources in the region. The main objectives of the present study are to identify the hydrogeochemical processes and the potential sources of major, minor, and trace metals and metalloids such as Cr, Mn, Cd, Fe, Al, and As by using joint hydrogeochemical techniques and multivariate statistical analysis and to evaluate groundwater quality deterioration with the use of PoS environmental index. To achieve these objectives, 23 groundwater samples were collected in September 2015. Piper diagram shows that the mixed Ca-Mg-Cl is the dominant groundwater type, and some of the samples have Ca-HCO3, Ca-Cl, and Na-Cl types. Multivariate statistical analyses indicate that weathering and dissolution of different rocks and minerals, e.g., silicates, gypsum, and halite, ion exchange, and agricultural activities influence the hydrogeochemistry of the study area. The cluster analysis divides the samples into two distinct clusters which are completely different in EC (and its dependent variables such as Na+, K+, Ca2+, Mg2+, SO42-, and Cl-), Cd, and Cr variables according to the ANOVA statistical test. Based on the median values, the concentrations of pH, NO3-, SiO2, and As in cluster 1 are elevated compared with those of cluster 2, while their maximum values occur in cluster 2. According to the PoS index, the dominant parameter that controls quality deterioration is As, with 60% of contribution. Samples of lowest PoS values are located in the southern and northern parts (recharge area) while samples of the highest values are located in the discharge area and the eastern part. PMID- 28819725 TI - Simultaneous Improvement of Resolving Power and Signal-to-Noise Ratio Using a Modified Hadamard Transform-Inverse Ion Mobility Spectrometry Technique. AB - In order to improve the resolving power (RP) and signal-to-noise ratio (SNR) of ion mobility spectrometry (IMS) simultaneously, a modified Hadamard transform inverse ion mobility spectrometry (MHT-IIMS) technique was developed. In this novel technique, a series of isolating codes were appended to each element of the pseudo random binary sequence (PRBS), and then the modified modulation sequence was formed and used to control the ion gate of the inverse IMS (IIMS). Experimental results demonstrate that the MHT-IIMS technique can significantly enhance the resolving power and SNR simultaneously by measuring the spectra of reaction ions. Furthermore, the gas sample CCl4 and CHCl3 were measured for evaluating the capability of detecting those samples which have single and multiple product ions. The results show that this novel technique is able to simultaneously improve the resolving power and SNR notablely for the real sample detection without any significant instrumental changes. Graphical Abstract ?. PMID- 28819726 TI - Population Pharmacokinetics of Stiripentol in Paediatric Patients with Dravet Syndrome Treated with Stiripentol, Valproate and Clobazam Combination Therapy. AB - AIM: The aim of this study was to describe the pharmacokinetics of stiripentol in children with Dravet syndrome and to determine the concentrations of stiripentol achieved in this population for the usual 25 mg/kg twice-daily dose. METHODS: Thirty-five children with epilepsy were included in a prospective population pharmacokinetic study (using MONOLIX software). Four blood samples were drawn per patient. Stiripentol area under the plasma concentration-time curve (AUC) values and trough concentrations were simulated for 7000 theoretical children weighing between 10 and 70 kg for the 25 mg/kg twice-daily dose. RESULTS: The pharmacokinetics of stiripentol was described using a one-compartment model with zero-order absorption and first-order elimination. The apparent clearance (CL/F) and apparent volume of distribution (V d/F) of stiripentol were related to body weight by allometric equations. A dose-dependent non-linearity was also observed with an allometric model relating CL/F to the weight-normalised dose. Mean population estimates (% inter-individual variability) were 4.2 L/h (21%) for CL/F and 82 L (25%) for V d/F. The AUC of stiripentol increased by 300% when body weight increased from 10 to 70 kg. CONCLUSION: This population pharmacokinetic model of stiripentol in children with Dravet syndrome confirmed the dose dependent non-linearity that has been evidenced in adults. It also supported that a 25 mg/kg twice-daily dose might lead to excessive exposure in children >30 kg, suggesting an eventual dose adjustment during adolescence. CLINICAL TRIAL IDENTIFIER: This study is part of the STIPOP study (EUDRACT number: 2007-001784 30). PMID- 28819727 TI - Abiraterone Acetate: A Review in Metastatic Castration-Resistant Prostrate Cancer. AB - Oral abiraterone acetate (Zytiga(r)) is a selective inhibitor of CYP17 and thereby inhibits androgen biosynthesis, with androgen signalling crucial in the progression from primary to metastatic prostate cancer (PC) and subsequently, in the development of metastatic castration-resistant PC (mCRPC). In large phase 3 trials and in the clinical practice setting, oral abiraterone acetate in combination with prednisone was an effective treatment and had an acceptable, manageable tolerability and safety profile in chemotherapy-naive and docetaxel experienced men with mCRPC. In the pivotal global phase 3 trials, relative to placebo (+prednisone), abiraterone acetate (+prednisone) prolonged overall survival (OS) at data maturity (final analysis) and radiographic progression-free survival (rPFS) at all assessed timepoints. Given its efficacy in prolonging OS and its convenient once-daily oral regimen, in combination with prednisone, abiraterone acetate is an important first-line option for the treatment of mCRPC. PMID- 28819728 TI - Comment on: "Anthropometric and Physical Qualities of Elite Male Youth Rugby League Players". PMID- 28819729 TI - Prognostic significance of CDX2 immunoexpression in poorly differentiated clusters of colorectal carcinoma. AB - CDX2 is a transcription factor that acts as a tumor suppressor in colorectal cancer (CRC). Its loss triggers metastatic process and tumor progression; however, its prognostic role in patients with CRC is still controversial. Poorly differentiated clusters (PDCs) are aggregates of neoplastic cells which likely have high metastatic potential in CRC. In this study, we analyzed and compared CDX2 expression in PDC (CDX2-PDC) and corresponding main tumor (CDX2 main tumor) in 42 CRCs showing at least 10 PDC (PDC G3). Five of 42 CRCs (12%) were classified as CDX2 main tumor negative (4/5 were also PDC-CDX2 negative); all had tumor recurrence and died of CRC. Twenty nine of 42 cases were CDX2-PDC negative. Among CRC CDX2 main tumor positive, 15 had recurrences and 13 died from CRC; 13 and 11 of them, respectively, were CDX2-PDC negative. By assigning one point to CDX2 main tumor or CDX2-PDC positivity, we assessed CDX2-staining score for each case. Twelve cases had CDX2-staining score 2 (CDX2 positive in main tumor and PDC); 26 had score 1 (CDX2 positive in main tumor or PDC), and 4 had CDX2 score 0 (CDX2 negative in main tumor and PDC). In our patients, CDX2-staining score had higher prognostic value compared to CDX2 main tumor or CDX2-PDC alone. In addition, it represented a significant and independent prognostic variable for disease-free survival (DFS) and cancer-specific survival (CSS). Our findings suggest that, although loss of CDX2 in the main tumor identifies high-risk patients with high specificity, CDX2-PDC should also be considered in CDX2 main tumor positive cases to predict prognosis. PMID- 28819731 TI - Erratum to: A novel tubulin polymerization inhibitor, MPT0B206, downregulates Bcr Abl expression and induces apoptosis in imatinib-sensitive and imatinib-resistant CML cells. PMID- 28819730 TI - Creep feeding effects on male Nellore calves influencing behavior and performance of their dams. AB - The objective of the present study was to evaluate the effect of different schemes of calves' supplementation in a creep feeding system, on the behavior of Bos indicus calves and dams, and also the influence of the calves' supplementation on dams' performance. Forty-eight Nellore male calves (147 +/- 7 kg body weight and 3 months of age) in the suckling phase and their dams (476 +/- 9 kg and 6 years of age) were studied in a completely randomized design. The experiment was divided into two periods of 71 days. The treatments were 5- and 10 g supplement dry matter (DM)/kg BW day offered in periods 1 and 2, respectively (5S/10S); 10- and 5-g supplement DM/kg BW day offered in periods 1 and 2, respectively (10S/5S); 7.5-g supplement DM/kg BW day in both periods 1 and 2 (7.5S); and mineral mix ad libitum in both periods 1 and 2 (MM). No differences (P < 0.05) in body condition score (BCS), final body weight (FBW), and average daily gain (ADG) were found in dams' performance. Calves from MM treatment spent more time (P < 0.05) grazing than the supplemented calves from 5S/10S and 10S/5S treatments, in the first period. No difference in suckling time was found between the treatments (P > 0.05) in the first evaluated period. Calves from 10S/5S treatment spent more time suckling and less time eating supplements (P < 0.05) than 5S/10S treatment animals, in the second evaluated period. Dams of MM treatment's calves had more idle time and lower grazing time when compared with the mothers of calves from 5S/10S and 10S/5S treatments. It was concluded that different schedules of Nellore calves' supplementation on pasture do not affect their mothers' performance, and supplementation decreases the grazing time of calves in the suckling phase. PMID- 28819732 TI - Erratum to: Fructose-1,6-bisphosphate reverts iron-induced phenotype of hepatic stellate cells by chelating ferrous ions. PMID- 28819733 TI - [The association between allergic rhinitis control and sleep quality]. AB - BACKGROUND: Allergic rhinitis (AR) is the most common form of atopic disease, comprising 50% of atopic diseases. Recently, this disease has increasingly been the focus of intensive research. Previous work has shown that AR has a significant impact on sleep quality. To date there are no published studies demonstrating a quantitative association between the extent of control of AR and the severity of compromised sleep quality. METHODS: Patients with AR were prospectively recruited into our cross-sectional study. Sleep quality was assessed using five of the sleep subdomain questions from the 22-item Sinonasal Outcome Test (SNOT-22). Control of AR was assessed using the Rhinitis Control Assessment Test (RCAT). Association was sought between the degree of allergic rhinitis control (RCAT) as independent variable and sleep quality as dependent variable using linear regression. RESULTS: A total of 104 patients (54.8% female and 45.2% male) with an average age of 41.4 years (SD: 15.9 years) were included in the study. There were statistically significant associations between the RCAT score and the score of each of the five SNOT-22 questions used to assess decreased sleep quality (p < 0.001). These associations remained significant (p < 0.001) even after controlling participants' clinical and demographic characteristics. CONCLUSION: This is the first study showing that level of control of AR correlates with the severity of subjectively perceived sleep quality detriment. These results indicate that an improvement in AR control could lead to improved subjective sleep quality but a prospective interventional study is needed to confirm these results. PMID- 28819734 TI - Commentary on: comparison of endoscopic and microscopic tympanoplasty. PMID- 28819735 TI - Evaluation of the OnSite malaria rapid test performance in Miandrivazo, Madagascar. AB - The performance of the malaria rapid diagnostic test OnSite-for detecting pan specific pLDH and Plasmodium falciparum specific HRP2 - was assessed during the malaria transmission peak period in Miandrivazo, in the southwestern part of Madagascar from April 20 to May 6, 2010. At the laboratory, the quality control OnSite Malaria Rapid Test according to the WHO/TDR/FIND method demonstrated that the test had good sensitivity. Of the 218 OnSite tests performed at the Miandrivazo Primary Health Center on patients with fever or a recent history of fever, four (1.8%, 95% CI: 0.6-4.9%) were invalid. Ninety four (43,1%) cases of malaria were confirmed by microscopy, of which 90 were P. falciparum malaria and 4 Plasmodium vivax malaria. With a Cohen's kappa coefficient of 0.94, the agreement between microscopy and OnSite is excellent. Compared with the rapid test CareStartTM commonly used within the public health structures in Madagascar, the sensitivity and specificity of the OnSite test were 97.9% and 96.8%. PMID- 28819736 TI - Pain and compression neuropathy in primary inguinal hernia. AB - PURPOSE: Enlargement of the ilioinguinal nerve at the external inguinal ring is observed in 34% of patients undergoing primary open inguinal herniorrhaphy; in 88% of patients it occurs at the fascial edge where the hernia mushrooms with abdominal pressure. Compression neuropathy occurs near many anatomical nerve constriction sites and is associated with enlargement of the peripheral nerve accompanied by sensory changes. METHODS: In this prospective study, Carolina Comfort Scale (CCS) questionnaire data was collected for 35 primary hernia repairs. Each patient underwent primary inguinal herniorrhaphy that included ilioinguinal neurectomy. All nerves were sampled proximal to the external inguinal ring. Any nerves with grossly increased overall diameter to any degree distal to the external ring were additionally sampled in the thickened portions. A neuropathologist performed histologic evaluation of the H&E-stained cross sections. RESULTS: Paired comparison of proximal and distal nerves revealed a greater overall diameter and greater measured nerve-specific diameter in distal nerve segments. Nerves with increased overall diameter were also found to have a statistically significant positive correlation with four of eight pain measures. Additionally, increased nerve-specific diameter correlates with increased pain on four of eight pain values, but age effect on nerve diameter blunts this finding. CONCLUSIONS: Increased preoperative CCS pain values in primary open inguinal hernia are significantly correlated with gross enlargement of the overall diameter and nerve-specific diameter of the ilioinguinal nerve beyond the external inguinal ring. This is consistent with a compression neuropathy. PMID- 28819737 TI - Further Controversies About Brain Tissue Oxygenation Pressure-Reactivity After Traumatic Brain Injury. AB - BACKGROUND: Continuous monitoring of cerebral autoregulation is considered clinically useful due to its ability to warn against brain ischemic insults, which may translate to a relationship with adverse outcome. It is typically performed using the pressure reactivity index (PRx) based on mean arterial pressure and intracranial pressure. A new ORx index based on brain tissue oxygenation and cerebral perfusion pressure (CPP) has been proposed that similarly allows for evaluation of cerebrovascular reactivity. Conflicting results exist concerning its clinical utility. METHODS: Retrospective analysis was performed in 85 patients with traumatic brain injury (TBI). ORx was calculated using three time windows of 5, 20, and 60 min. Correlation coefficients and individual "optimal CPP" (CPPopt) were calculated using both PRx and ORx, and relation to patient outcome investigated. RESULTS: Correlation coefficients for all comparisons between PRx and ORx indicated poor association between these indices (range from -0.04 to 0.07). PRx was significantly lower in patients with good outcome (p = 0.01), while none of the ORx indices proved to be significantly different in the two outcome groups. Higher mortality related to average CPP < CPPopt was found regardless of which index was used to calculate CPPopt. CONCLUSION: In the TBI setting, ORx does not appear to correlate with vascular pressure reactivity as assessed with PRx. Its potential use for individualizing CPP thresholds remains unclear. PMID- 28819738 TI - High-dose 8% capsaicin patch in treatment of chemotherapy-induced peripheral neuropathy: single-center experience. AB - High-dose capsaicin patch is effective in treatment of neuropathic pain in HIV associated neuropathy and diabetic neuropathy. There are no studies assessing effectiveness of high-dose capsaicin patch in treatment of chemotherapy-induced peripheral neuropathy. We sought to determine the effectiveness of treatment of pain associated with chemotherapy-induced peripheral neuropathy with high-dose capsaicin patch. Our study group consisted of 18 patients with clinically confirmed oxaliplatin-induced neuropathy. Baseline characteristic including underling disease, received cumulative dose of neurotoxic agent, neuropathic symptoms, prior treatment and initial pain level were recorded. Pain was evaluated with Numeric Rating Scale prior to treatment with high-dose capsaicin and after 1.8 day and after 8 and 12 weeks after introducing treatment. Patients were divided into two groups accordingly to the amount of neurotoxic agent that caused neuropathy (high sensitivity and low sensitivity group). Most frequent symptoms of chemotherapy-induced neuropathy were: pain (88.89%), paresthesis (100%), sock and gloves sensation (100%) and hypoesthesis (100%). Initial pain level was 7.45 +/- 1.14. Mean cumulative dose of oxaliplatin after which patients developed symptoms was 648.07 mg/m2. Mean pain level after 12 weeks of treatment was 0.20 +/- 0.41. When examined according to high and low sensitivity to neurotoxic agent patients with low sensitivity had higher pain reduction, especially after 8 days after introducing treatment (69.55 +/- 12.09 vs. 49.40 +/ 20.34%; p = 0.02) and after 12 weeks (96.96 +/- 5.56 vs. 83.93 +/- 18.59%; p = 0.04). High-dose capsaicin patch is an effective treatment for pain associated with chemotherapy-induced neuropathy in patients treated with oxaliplatin. Patients with lower sensitivity to neurotoxic agents have better response to treatment and pain reduction. PMID- 28819740 TI - Inotuzumab Ozogamicin: First Global Approval. AB - Intravenous inotuzumab ozogamicin (Besponsa(r); Pfizer) is an anti-CD22 monoclonal antibody-calicheamicin conjugate that binds to CD22-expressing tumour cells. Upon binding, the complex is internalised and the cytotoxic calicheamicin derivative is released inside the cell, inducing double-strand DNA breakage and subsequent cell death. In June 2017, the EMA granted inotuzumab ozogamicin approval as monotherapy for the treatment of adults with relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukaemia (ALL). The use of inotuzumab ozogamicin in adult patients with Philadelphia chromosome-positive, relapsed or refractory CD22-positive B-cell precursor ALL is restricted to those who have failed treatment with at least one tyrosine kinase inhibitor. Inotuzumab ozogamicin was granted priority review for the treatment of relapsed or refractory B-cell precursor ALL by the US FDA in February 2017. In the USA, a phase III trial evaluating inotuzumab ozogamicin in combination with frontline chemotherapy in adults with newly diagnosed B-cell ALL has recently been initiated and inotuzumab ozogamicin is under phase II evaluation in childhood CD22-positive B-cell ALL. Inotuzumab ozogamicin combination therapies are also being evaluated in the phase I/II or II setting in ALL and chronic myeloid leukaemia and in the phase I setting in Burkitt's lymphoma. This article summarises the milestones in the development of inotuzumab ozogamicin leading to this first approval for ALL. PMID- 28819739 TI - Oligosaccharide elicitor prepared from Salecan triggers the defense responses of Arabidopsis thaliana Col0 against Botrytis cinerea infection. AB - Oligosaccharides from the water-soluble beta-glucan, Salecan, were investigated to evaluate the activation effect on the defense responses of Arabidopsis thaliana Col0. Salecan oligosaccharides (ScOs, DP 5-10) were prepared at first by acid hydrolysis and gel filtration chromatography and then employed for foliar spray on Arabidopsis seedlings and plants. After ScOs treatment, increase of hydrogen peroxide was histologically and analytically detected in leaves. Transcription levels of several indicator genes which correspond to the signaling pathways and pathogenesis-related proteins were up-regulated at different time by means of quantitative RT-PCR analysis. Importantly, the sequential activation of salicylic acid-mediated and jasmonate-mediated signaling pathway was observed in leaves. Furthermore, pot test and antimicrobial test gave the fact that pretreatment with ScOs restrained the leaf lesions caused by infection of Botrytis cinerea Bc0510 via the enhancement of defense responses of A. thaliana. In conclusion, Salecan oligosaccharides serve as an elicitor which can be used for biological control of plant pathogen. PMID- 28819742 TI - Authors' Reply to McMahon et al. Comment on: "Anthropometric and Physical Qualities of Elite Male Youth Rugby League Players". PMID- 28819741 TI - Signaling Pathways as Potential Therapeutic Targets in Hepatocarcinogenesis. PMID- 28819744 TI - Correlations Do Not Show Cause and Effect: Not Even for Changes in Muscle Size and Strength. AB - It is well known that resistance exercise results in increased muscle strength, but the cause of the improvement is not well understood. It is generally thought that initial increases in strength are caused by neurological factors, before being predominantly driven by increases in muscle size. Despite this hypothesis, there is currently no direct evidence that training-induced increases in muscle size contribute to training-induced increases in muscle strength. The evidence used to support this hypothesis is exclusively correlational analyses and these are often an afterthought using data collected to answer a different question of interest. Not only do these studies not infer causality, but they have inherent limitations associated with measurement error and limited inter-individual variability. To answer the question as to whether training-induced increases in muscle size lead to training-induced increases in strength requires a study designed to produce differential effects on muscle size based on group membership (i.e., one group increases muscle size and one does not) and observe how this impacts muscle strength. We have performed studies in our laboratory in which muscle strength increases similarly independent of whether muscle growth is or is not present, illustrating that the increases in muscle strength are not likely driven by increases in muscle size. The hypothesis that training-induced increases in muscle size contribute to training-induced increases in muscle strength requires more appropriately designed studies, and until such studies are completed, this statement should not be made as there are no data to support this hypothesis. PMID- 28819743 TI - Halorubrum salsamenti sp. nov., a Novel Halophilic Archaeon Isolated from a Brine of Salt Mine. AB - A non-motile, spherical or oval extremely halophilic archaeon, strain Y69T, was isolated from a brine of the Yunnan salt mine, China. Colonies on JCM 168 agar plate were round (1-2 mm in diameter), moist, and orange-pigmented. Phylogenetic analysis of the almost-complete 16S rRNA gene sequence showed that the isolate belonged to the species of the genus Halorubrum, with a close relationship to Halorubrum aidingense 31-hongT (98.5%), Halorubrum lacusprofundi ATCC 49239T (98.2%), and Halorubrum kocurii BG-1T (98.0%). The major polar lipids of strain Y69T were phosphatidylglycerol phosphate methyl ester, phosphatidylglycerol sulfate and a sulfated diglycosyl diether. Strain Y69T grew in 15-30% (w/v) NaCl. The temperature and pH ranges for growth were 25-50 degrees C and 6.5-9.0, respectively. Optimal growth occurred at 20% (w/v) NaCl, 42 degrees C, and pH 8.0. Mg2+ was required for growth. The DNA G+C content was determined to be 65.1 mol% by the thermal denaturation method. DNA-DNA hybridization values between strain Y69T and the closely related species were lower than 70%. Based on the data presented in this study, strain Y69T represents a novel species for which the name Halorubrum salsamenti sp. nov. is proposed. The type of the strain is Y69T (=CGMCC 1.15455T = JCM 31270T). PMID- 28819745 TI - Bioassessment of the Effluents Discharged from Two Export Oriented Industrial Zones Located in Kelani River Basin, Sri Lanka Using Erythrocytic Responses of the Fish, Nile Tilapia (Oreochromis niloticus). AB - Complex effluents originating from diverse industrial processes in industrial zones could pose cytotoxic/genotoxic hazards to biota in the receiving ecosystems which cannot be revealed by conventional monitoring methods. This study assessed potential cytotoxicity/genotoxicity of treated effluents of two industrial zones which are discharged into Kelani river, Sri Lanka combining erythrocytic abnormality tests and comet assay of the tropical model fish, Nile tilapia. Exposure of fish to the effluents induced erythrocytic DNA damage and deformed erythrocytes with serrated membranes, vacuolations, nuclear buds and micronuclei showing cytotoxic/genotoxic hazards in all cases. Occasional exceedance of industrial effluent discharge regulatory limits was noted for color and lead which may have contributed to the observed cytotoxicity/genotoxicity of effluents. The results demonstrate that fish erythrocytic responses could be used as effective bioanalytical tools for cytotoxic/genotoxic hazard assessments of complex effluents of industrial zones for optimization of the waste treatment process in order to reduce biological impacts. PMID- 28819746 TI - The Effects of Resistance Exercise Training on Anxiety: A Meta-Analysis and Meta Regression Analysis of Randomized Controlled Trials. AB - BACKGROUND: The salutary effects of resistance exercise training (RET) are well established, including increased strength and function; however, less is known regarding the effects of RET on mental health outcomes. Aerobic exercise has well documented positive effects on anxiety, but a quantitative synthesis of RET effects on anxiety is needed. OBJECTIVES: To estimate the population effect size for resistance exercise training (RET) effects on anxiety and to determine whether variables of logical, theoretical, and/or prior empirical relation to anxiety moderate the overall effect. METHODS: Thirty-one effects were derived from 16 articles published before February 2017, located using Google Scholar, MEDLINE, PsycINFO, PubMed, and Web of Science. Trials involved 922 participants (mean age = 43 +/- 21 years, 68% female/32% male) and included both randomization to RET (n = 486) or a non-active control condition (n = 436), and a validated anxiety outcome measured at baseline, mid-, and/or post-intervention. Hedges' d effect sizes were computed and random effects models were used for all analyses. Meta-regression quantified the extent to which participant and trial characteristics moderated the mean effect. RESULTS: RET significantly reduced anxiety symptoms (Delta = 0.31, 95% CI 0.17-0.44; z = 4.43; p < 0.001). Significant heterogeneity was not indicated (Q T(30) = 40.5, p > 0.09; I 2 = 28.3%, 95% CI 10.17-42.81); sampling error accounted for 77.7% of observed variance. Larger effects were found among healthy participants (Delta = 0.50, 95% CI 0.22-0.78) compared to participants with a physical or mental illness (Delta = 0.19, 95% CI 0.06-0.31, z = 2.16, p < 0.04). Effect sizes did not significantly vary according to sex (beta = -0.31), age (beta = -0.10), control condition (beta = 0.08), program length (beta = 0.07), session duration (beta = 0.08), frequency (beta = -0.10), intensity (beta = -0.18), anxiety recall time frame (beta = 0.21), or whether strength significantly improved (beta = 0.19) (all p >= 0.06). CONCLUSIONS: RET significantly improves anxiety symptoms among both healthy participants and participants with a physical or mental illness. Improvements were not moderated by sex, or based on features of RET. Future trials should compare RET to other empirically-supported therapies for anxiety. PMID- 28819747 TI - Word-wide meta-analysis of Quercus forests ectomycorrhizal fungal diversity reveals southwestern Mexico as a hotspot. AB - Quercus is the most diverse genus of ectomycorrhizal (ECM) host plants; it is distributed in the Northern and Southern Hemispheres, from temperate to tropical regions. However, their ECM communities have been scarcely studied in comparison to those of conifers. The objectives of this study were to determine the richness of ECM fungi associated with oak forests in the Cuitzeo basin in southwestern Mexico; and to determine the level of richness, potential endemism and species similarity among ECM fungal communities associated with natural oak forests worldwide through a meta-analysis. The ITS DNA sequences of ECM root tips from 14 studies were included in the meta-analysis. In total, 1065 species of ECM fungi have been documented worldwide; however, 812 species have been only found at one site. Oak forests in Europe contain 416 species, Mexico 307, USA 285, and China 151. Species with wider distributions are Sebacinaceae sp. SH197130, Amanita subjunquillea, Cenococcum geophilum, Cortinarius decipiens, Russula hortensis, R. risigallina, R. subrubescens, Sebacinaceae sp. SH214607, Tomentella ferruginea, and T. lapida. The meta-analysis revealed (1) that Mexico is not only a hotspot for oak species but also for their ECM mycobionts. (2) There is a particularly high diversity of ECM Pezizales in oak seasonal forests from western USA to southwestern Mexico. (3) The oak forests in southwestern Mexico have the largest number of potential endemic species. (4) Globally, there is a high turnover of ECM fungal species associated with oaks, which indicates high levels of alpha and beta diversity in these communities. PMID- 28819748 TI - Lipoxin A4 Attenuates Bronchopulmonary Dysplasia via Upregulation of Let-7c and Downregulation of TGF-beta1 Signaling Pathway. AB - Transforming growth factor-beta (TGF-beta) superfamily members are key regulators for lung development and progress of bronchopulmonary dysplasia (BPD). The mechanisms by which lipoxin A4 (LXA4) attenuates development of BPD have not been clarified. Neonatal murine BPD models were inducted by hyperoxia treatment. Neonatal mice were exposed to room air or 85% O2 hyperoxia with or without treatment with 5S,6R-methyl-LXA4 or anti-TGF-beta antibodies. Mouse lung epithelial cells (MLE-12 cells) and mouse embryonic fibroblasts (NIH/3T3 cells) were cultured in room air or 85% O2 followed by treatment of LXA4, anti-TGF-beta antibodies, and let-7c mimic/anti-microRNA transfections. Treatment with 5S,6R methyl-LXA4 and anti-TGF-beta antibodies both attenuated the mice alveolar simplification induced by hyperoxia. Hyperoxia treatment significantly altered pulmonary basal mRNA and protein expressions of several important extracellular matrix (ECM) and ECM remodeling proteins including fibronectin, alpha-smooth muscle actin (alpha-SMA), tissue inhibitor of metalloproteinase-1 (TIMP-1), elastin, tenascin C, collagen I, and matrix metalloproteinase-1 (MMP-1). 5S,6R methyl-LXA4 and anti-TGF-beta antibodies suppressed the mRNA and protein expressions of TGF-beta1 and TGF-betaR1 but not TGF-betaR2 in the lungs exposed to hyperoxia. Treatment with LXA4 and anti-TGF-beta antibodies alleviated hyperoxia-induced injury of the NIH/3T3 cells identified by morphologic observation and flow cytometry, and expressions of ECM, ECM remodeling proteins, and TGF-beta1 signaling pathway, but reversed by transfection with let-7c anti miRNA. LXA4 upregulated the let-7c expression in MLE-12 cells, transfection with let-7c anti-miRNA, inhibited the LXA4-induced let-7c expression in MLE-12 cells exposed to hyperoxia and reduced the relative luciferase activity of let-7c binding with let-7c binding sites of the TGF-betaR1 3' UTR. Treatment with 5S,6R methyl-LXA4 and anti-TGF-beta antibodies significantly improved histology, ECM, and ECM remodeling proteins in the lungs isolated from the murine BPD model induced by hyperoxia. The LXA4-imparted protective effects on hyperoxia-induced lung injury are mediated by upregulation of let-7c and inhibition of TGF-beta1 and subsequent downregulation of TGF-beta1 signaling pathway. PMID- 28819749 TI - Time-Dependent-Asymmetric-Linear-Parsimonious Ancestral State Reconstruction. AB - The time-dependent-asymmetric-linear parsimony is an ancestral state reconstruction method which extends the standard linear parsimony (a.k.a. Wagner parsimony) approach by taking into account both branch lengths and asymmetric evolutionary costs for reconstructing quantitative characters (asymmetric costs amount to assuming an evolutionary trend toward the direction with the lowest cost). A formal study of the influence of the asymmetry parameter shows that the time-dependent-asymmetric-linear parsimony infers states which are all taken among the known states, except for some degenerate cases corresponding to special values of the asymmetry parameter. This remarkable property holds in particular for the Wagner parsimony. This study leads to a polynomial algorithm which determines, and provides a compact representation of, the parametric reconstruction of a phylogenetic tree, that is for all the unknown nodes, the set of all the possible reconstructed states associated with the asymmetry parameters leading to them. The time-dependent-asymmetric-linear parsimony is finally illustrated with the parametric reconstruction of the body size of cetaceans. PMID- 28819750 TI - Saving my mailwoman's back: Scientific publishing in the age of millennials. PMID- 28819751 TI - The suspension sutures during minimally invasive radical prostatectomy. PMID- 28819753 TI - Growth hormone treatment improves final height and nutritional status of children with chronic kidney disease and growth deceleration. AB - PURPOSE: Growth retardation is a common complication of chronic kidney disease (CKD) in children. Treatment with recombinant human growth hormone (rhGH) has been used to help short children with CKD to attain a height more in keeping with their age group, but the scientific evidence regarding the effect of rhGH on final height is scarce. METHODS: Final heights of children with CKD receiving rhGH treatment (cases) were compared with final heights of a matched cohort of children with CKD that did not receive rhGH therapy (controls). RESULTS: Sixty eight rhGH-treated cases (44 boys) were compared with 92 untreated controls (60 boys). Mean duration of rhGH therapy was 4.2 +/- 0.9 years; rhGH dose was 0.3 +/- 0.07 mg/kg/week. Height SDS at baseline was lower in rhGH-treated patients than in controls (-2.00 +/- 1.02 versus -0.96 +/- 1.11, p < 0.001). Baseline height SDS was significantly lower than target height SDS in both groups. Height SDS significantly improved from baseline to final height attainment in rhGH-treated patients, while it slightly decreased in controls (mean SDS variation 0.69 +/- 1.05 in rhGH-treated cases versus -0.15 +/- 1.2 in controls). Final height SDS was -1.25 +/- 1.06 in rhGH-treated cases and -1.06 +/- 1.17 in controls (p = 0.29). Target adjusted final height SDS was -0.91 +/- 1.03 in rhGH-treated cases and -0.61 +/- 1.17 in controls (p = 0.1). CONCLUSIONS: Long-term rhGH therapy is able to reduce the linear growth deceleration of children with CKD, and ultimately to improve their final height, reducing the difference with target height. PMID- 28819752 TI - Progression of understanding for the role of Epstein-Barr virus and management of nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is very common in southern China and Southeast Asia. In regions where NPC is endemic, undifferentiated subtypes constitute most cases and are invariably associated with Epstein-Barr virus (EBV) infection, whereas the differentiated subtype is more common in other parts of the world. Undifferentiated NPC is a unique malignancy with regard to its epidemiology, etiology, and clinical presentation. Clinically, NPC is highly invasive and metastatic, but sensitive to both chemotherapy and radiotherapy (RT). Overall prognosis has dramatically improved over the past three decades because of advances in management, including the improvement of RT technology, the broader application of chemotherapy, and more accurate disease staging. Despite the excellent local control with modern RT, distant failure remains a challenging problem. Advances in molecular technology have helped to elucidate the molecular pathogenesis of NPC. This article reviews the contribution of EBV gene products to NPC pathogenesis and the current management of NPC. PMID- 28819754 TI - Development of the hybrid cells in series model to simulate ammonia nutrient pollutant transport along the Umgeni River. AB - Discharge of organic waste results in high nutrient pollution of the water bodies which is a major menace to the environment. A high quantity of nutrients such as ammonia causes a reduction in the dissolved oxygen level and induces algal growth in the water bodies. Water quality models have been the tools to evaluate the rate at which streams can disperse the pollutants they receive. Many water quality models are flawed either because of their inadequacy to completely simulate the advection component of the pollutant transport, or because of the limited application of the models, due to inaccurate estimation of model parameters. The hybrid cell in series (HCIS) developed by Ghosh et al. (2004) has been able to overcome such difficulties associated with the mixing cell-based models. Thus, the current study focuses on developing an analytical solution for the pollutant transport of the ammonia concentration through the plug flow, the first and second well-mixed cells of the HCIS model. The HCIS model coupled with the first order kinetic equation for ammonia nutrient was developed to simulate the ammonia pollutant concentration in the water column. The ammonia concentration at various points along the river system was assessed by considering the effects of the transformation of ammonia to nitrite, the uptake of ammonia by the algae, the respiration rate of the algae and the input of benthic source to the ammonia concentration in the water column. The proposed model was tested using synthetic data, and the HCIS-NH3 model simulations for spatial and temporal variation of ammonia pollutant transport were analysed. The simulated results of the HCIS-NH3 model agreed with the Fickian-based advection dispersion equation (ADE) for simulating ammonia concentration solved using an explicit finite difference scheme. The HCIS-NH3 model also showed a good agreement with the observed data from the Umgeni River, except during rainy periods. PMID- 28819755 TI - Importance of FNA Technique for Decreasing Non-diagnostic Rates in Thyroid Nodules. AB - To identify potential interventions that may lower the high non-diagnostic rates associated with ultrasound guided (US) fine needle aspiration (FNA) biopsy of the thyroid nodule. A case series of 164 thyroid nodule US-guided FNA was identified retrospectively. The following variables were analyzed in regards to diagnostic and non-diagnostic sampling: patient age, gender, size of nodule, biopsy technique (capillary vs. aspiration), needle gauge (23 vs. 25), and physician experience. The FNA diagnosis, and final pathology, when applicable, was recorded for each sample using the Bethesda criteria. Data was analyzed using the Fisher's exact test or the chi square test. After multivariate logistic regression, capillary action was independently associated with lower non-diagnostic rates (p = 0.01), while increasing patient age was associated with higher non-diagnostic rates (p = 0.018). Physician experience (p = 0.014) was not independently associated with lower non-diagnostic rates. Nodules that were "cystic >50%" were significantly more likely to yield a non-diagnostic result (p < 0.0001). After taking into account confounding variables, including physician experience, our data reveals a statistically significant decrease in non-diagnostic rates with the use of capillary action vs. aspiration technique in US-guided FNA. A major focus in healthcare today is providing cost-effective and minimally invasive care to the patient. In the setting of a rising incidence of thyroid disease, we believe our study demonstrates the need for a prospective analysis of the relationship between technique and non-diagnostic rates. PMID- 28819756 TI - Nanofibers grafted on titanium alloy: the effects of fiber alignment and density on osteoblast mineralization. AB - The surface of medical implant alloy Ti-6Al-4V was chemically modified to allow it to covalently bond with collagen/PVA nanofibers. These nanofibers were successfully attached to the Ti-6Al-4V surface in three different morphologies: randomly oriented high-density fiber, COL(H); randomly oriented low-density fiber, COL(L); and aligned high-density fiber, COL(A). The effects of the morphology of these covalently-bound collagen nanofibers on the growth and differentiation of osteoblasts were studied for 21 days. The low-density nanofibers covered approximately 80% of the Ti64 surface, while the high-density nanofibers covered nearly 100%. These covalently attached fibrous coatings remained attached to the metal surface after 3 weeks of cell culture. In the first week the aligned fibers of COL(A) allowed the osteoblasts to stretch and elongate in the direction of the fibers. This directional elongation was not seen in the cells on the randomly-oriented samples. Cells proliferated and differentiated on all three surfaces over time. By the end of the test, the amount of type I collagen secreted by the cells on COL(H) was the highest, while the degree of mineralization was highest on COL(A) among the three samples (p < 0.05). Different nanofiber morphologies changed the cell morphology and the secretion of cellular products. The mechanisms remained to be investigated. The surface of medical implant alloy Ti-6Al-4V was chemically modified to allow it to covalently bond with collagen/PVA nanofibers. The SEM micrographs in the top row show the random and aligned morphology of the collagen-PVA nanofibers. The nanofibers on COL(A) were aligned in the general direction indicated by the arrow. The second row are images from EDX titanium element mapping. The location of the titanium elements are shown as bright dots. The low-density nanofibers, COL(L), covered approximately 80% of the Ti64 surface, while the high-density nanofibers, COL(H) and COL(A), covered nearly 100%. All three surfaces demonstrated good biocompatibility for the cultured osteoblasts. The fiber alignment seemed to have an effect on early cellular morphology (day 7), collagen secretion and calcium deposition, while the density of the fibers seemed to have no significant effect on cell behavior. SEM micrographs of osteoblasts after 7 and 14 days of cell culture are shown in the third and fourth rows. The surface of COL(L) has more cell-free spots indicated by (*) on day 7 as other two surfaces were covered by cells. The nanofibers could no longer be observed and were covered with mineralized granules (circles) after 14 days of cell culture. The cells appear stretched out on the mineralized granules. PMID- 28819758 TI - An in silico biomechanical analysis of the stent-esophagus interaction. AB - Despite all technological innovations in esophageal stent design over the past 20 years, the association between the stent design's mechanical behavior and its effect on the clinical outcome has not yet been thoroughly explored. A parametric numerical model of a commercially available esophageal bioresorbable polymeric braided wire stent is set up, accounting for stent design aspects such as braiding angle, strut material, wire thickness, degradation and friction between the wires comprising a predictive tool on the device's mechanical behavior. Combining this tool with complex multilayered numerical models of the pathological in vivo stressed, actively contracting and buckling esophagus could provide clinicians and engineers with a patient-specific window into the mechanical aspects of stent-based esophageal intervention. This study integrates device and soft tissue mechanics in one computational framework to potentially aid in the understanding of the occurrence of specific symptoms and complications after stent placement. PMID- 28819757 TI - Development of CYP21A2 Genotyping Assay for the Diagnosis of Congenital Adrenal Hyperplasia. AB - BACKGROUND: Steroid 21-hydroxylase deficiency due to CYP21A2 gene mutations represents more than 90% of all congenital adrenal hyperplasia cases. This deficiency is screened by measuring levels of 17-hydroxyprogesterone, which may vary, causing false positive or false negative results. In order to assist the diagnosis, molecular methodologies have been employed. This work aimed to perform genotyping assays to detect mutations in the CYP21A2 gene and compare the findings with other population studies. METHODS: The SNaPshot assay was developed to simultaneously detect 12 frequent point mutations in the CYP21A2 gene (p.Arg409Cys, p.Gln319Ter, p.Arg357Trp, p.Leu308PhefsTer6, p.Val237Glu, IVS2 13A/C > G, p.Ile173Asn, p.Pro31Leu, p.Pro454Ser, p.Val282Leu, p.Gly111ValfsTer21 and p.His63Leu). The direct sequencing and multiplex ligation-dependent probe amplification assays were used to confirm point mutations present in the developed method. The latter was also used to search large deletions and gene conversion, complementing the investigation. A total of 166 cases were studied. RESULTS: The SNaPshot assay was successfully developed to detect the 12 mutations. The results of mutation analysis indicated 84 pathogenic alleles in 48 cases, with p.Val282Leu (27.1%) and IVS2-13A/C > G (20.8%) being the most frequently found mutations. Between the findings of this study and those of other South American studies, there were significant differences in frequency for p.Pro31Leu and p.Val282Leu (p < 0.001). A new variant T in IVS2-13A/C > G was identified in two patients via the SNaPshot assay. CONCLUSION: The molecular strategy developed for CYP21A2 gene mutation screening allowed us to detect the principle mutations described around the world. Furthermore, the first Southern Brazilian mutation frequencies concerning the CYP21A2 gene were obtained. PMID- 28819759 TI - Melatonin increases the effect of 5-fluorouracil-based chemotherapy in human colorectal adenocarcinoma cells in vitro. AB - Melatonin has antitumor activity via several mechanisms including its anti proliferative and pro-apoptotic effects. Moreover, it has been proven that melatonin in combination with chemotherapeutic agents enhances chemotherapy triggered apoptosis in several types of cancer. Therefore, this study was intended to evaluate whether melatonin is able to strengthen the anti-cancer potential of different chemotherapeutic drugs in human colorectal adenocarcinoma HT-29 cells. We found that treatment with 20 uM cisplatin (CIS) or 1 mM 5 fluorouracil (5-FU) for 72 h induced a decrease in HT-29 cell viability. Furthermore, 1 mM melatonin significantly (P < 0.05) increased the cytotoxic effects of 5-FU. Likewise, simultaneous stimulation with 1 mM melatonin and 1 mM 5-FU significantly (P < 0.05) enhanced the ratio of cells with an overproduction of intracellular reactive oxygen species and substantially augmented the population of apoptotic cells compared to the treatment with 5-FU alone. Nonetheless, melatonin only displayed moderate chemosensitizing effects in CIS treated HT-29 cells, as suggested by a slight increment in the fraction of early apoptotic cells that was observed only after 48 h. Consistently, co-stimulation of HT-29 cells with 20 uM CIS or 1 mM 5-FU in the presence of 1 mM melatonin further increased caspase-3 activation. Apart from this, the cytostatic activity displayed by CIS due to S phase arrest was not affected by concomitant stimulation with melatonin. Overall, our results indicate that melatonin increases the sensitivity of HT-29 cells to 5-FU treatment and, consequently, the indolamine could be potentially applied to colorectal adenocarcinoma treatment as a potent chemosensitizing agent. PMID- 28819760 TI - Effect of alisertib, an investigational aurora a kinase inhibitor on the QTc interval in patients with advanced malignancies. AB - Aims A primary objective of this study was to investigate the effect of single and multiple doses of alisertib, an investigational Aurora A kinase inhibitor, on the QTc interval in patients with advanced malignancies. The dose regimen used was the maximum tolerated dose which was also the recommended phase 3 dose (50 mg twice daily [BID] for 7 days in 21-day cycles). Methods Patients received a single dose of alisertib (50 mg) on Day 1, and multiple doses of alisertib (50 mg BID) on Days 4 through to the morning of Day 10 of the first cycle of treatment. Triplicate ECGs were collected at intervals over 10 to 24 h via Holter recorders on Days -1 (baseline), 1 and 10. Changes from time-matched baseline values were calculated for various ECG parameters including QTc, heart rate, PR and QRS intervals. Alisertib pharmacokinetics were also assessed during the study, and an exposure-QTc analysis was conducted. Results Fifty patients were included in the QTc analysis. The upper bounds of the 95% confidence intervals for changes from time-matched baseline QTcF and QTcI values were <5 ms across all study days, time points and correction methods. Alisertib did not produce clinically relevant effects on heart rate, PR or QRS intervals. There was no evidence of a concentration-QTc effect relationship. Conclusions Alisertib does not cause QTc prolongation and can be concluded to not have any clinically relevant effects on cardiac repolarization or ECG parameters at the single agent maximum tolerated dose of 50 mg BID. PMID- 28819762 TI - Separating the "Limbs" of Yoga: Limited Effects on Stress and Mood. AB - Though millions of people practice yoga to reduce stress and improve their mood, it is unclear which aspect of yoga is responsible for these effects. To investigate relevant aspects, or "limbs" of yoga, participants who were novices in the practice of yoga engaged in a single yoga manipulation (i.e., poses, breath work, meditation, or listening to a lecture about yoga) for 20 min before experiencing a mild stressor. Participants' heart rate, blood pressure, mood, and anxiety level were assessed, both immediately after the yoga manipulation and after the mild stressor. The 20-min yoga manipulation did not differentially affect any of the measures, including participants' stress response after the mild stressor. Results are discussed regarding the individual components of a yoga practice. PMID- 28819761 TI - Effect of Health Literacy on Help-seeking Behavior in Morbidly Obese Patients Agreeing to Bariatric Surgery. AB - BACKGROUND: We aimed to evaluate the effect of health literacy on agreement for bariatric surgery among morbidly obese patients. METHODS: The data of 242 morbidly obese patients (body mass index-BMI >= 40 kg/m2) were evaluated in a cross-sectional case-control pattern. The patients were classified into two groups as those who were attending the clinic for the purpose of receiving bariatric surgery (n = 138) and those who did not (n = 104). The Turkish version of the European Health Literacy Survey Questionnaire (HLS-EU-Q47), consisting of 47 questions, was used for the health literacy evaluation. RESULTS: It was seen that patients who accepted bariatric surgery were younger and had higher weight and BMI values (p < 0.001). HLS-EU-Q47 index results were 33.33 (15.63-50) in the group who agreed to bariatric surgery and 26.04 (8.33:46.88) in the group who did not agree to bariatric surgery, and a statistically significant difference was determined between the two groups (p < 0.001). From the HLS-EU-Q47 questionnaire, an insufficient level (0-25) was found for 2.9% of the group who agreed to bariatric surgery and 45.2% of the group who did not (p < 0.001). The problematic limited level was similar in the two groups (> 25-33) (respectively, 36.2%, 37.5%, p = 0.840). A sufficient level (> 33-42) and a perfect level were higher in the group who agreed to bariatric surgery (respectively, 42.8%, 18.1%, p < 0.001). CONCLUSION: There is a relationship between health literacy and acceptance of bariatric surgery in morbidly obese patients. The higher the health literacy level, the more the agreement to bariatric surgery increased. PMID- 28819763 TI - Factors Associated with Teacher Delivery of a Classroom-Based Tier 2 Prevention Program. AB - Teachers sometimes struggle to deliver evidence-based programs designed to prevent and ameliorate chronic problem behaviors of young children with integrity. Identifying factors associated with variations in the quantity and quality of delivery is thus an important goal for the field. This study investigated factors associated with teacher treatment integrity of BEST in CLASS, a tier-2 prevention program designed for young children at risk for developing emotional/behavioral disorders. Ninety-two early childhood teachers and 231 young children at-risk for emotional/behavioral disorders participated in the study. Latent growth curve analyses indicated that both adherence and competence of delivery increased across six observed time points. Results suggest that teacher education and initial levels of classroom quality may be important factors to consider when teachers deliver tier-2 (i.e., targeted to children who are not responsive to universal or tier-1 programming) prevention programs in early childhood settings. Teachers with higher levels of education delivered the program with more adherence and competence initially. Teachers with higher initial scores on the Emotional Support subscale of the Classroom Assessment Scoring System (CLASS) delivered the program with more competence initially and exhibited higher growth in both adherence and competence of delivery across time. Teachers with higher initial scores on the Classroom Organization subscale of the CLASS exhibited lower growth in adherence across time. Contrary to hypotheses, teacher self-efficacy did not predict adherence, and teachers who reported higher initial levels of Student Engagement self-efficacy exhibited lower growth in competence of delivery. Results are discussed in relation to teacher delivery of evidence-based programs in early childhood classrooms. PMID- 28819764 TI - sEcad and EGF Levels Increased in Urine of Non-ferrous Metal Workers and Medium of Uroepithelial Cell Line Treated by Arsenic. AB - Inorganic arsenic (iAs) is a carcinogen and could increase the risks of bladder, lung, and skin cancer. Mining and smelting of non-ferrous metals are common occupational arsenic exposures. In this study, 125 individuals working in non ferrous metal smelting plants were separated into two groups according to urinary total arsenic (TAs) levels: group 1, TAs < 100 MUg/g Cr; group 2, TAs >= 100 MUg/g Cr. Demographic characteristics of participants were obtained by questionnaire interview. Levels of E-cadherin soluble ectodomain fragment (sEcad) and epidermal growth factor (EGF) in workers urine were determined by ELISA test. We found that concentrations of sEcad and EGF present in urine were significantly elevated in the high urinary arsenic group 2 compared with the low urinary arsenic group 1. Urinary levels of the shedding of E-cadherin soluble ectodomain fragment (sEcad) and epidermal growth factor (EGF) were positively related to the concentrations of iAs in urine after adjusting for the confounding effects. A positive correlation between sEcad and EGF concentrations in urine was also observed. In order to verify the effects of iAs on sEcad and EGF, the human uroepithelial cell line (SV-HUC-1) was treated with NaAsO2 for 24 h in vitro. sEcad and EGF levels in the 4 MUM NaAsO2-treated SV-HUC-1 cell medium significantly increased compared to the control group. In conclusion, urinary levels of sEcad and EGF increased in higher urinary arsenic workers of non ferrous metal plants and are closely associated with urinary iAs concentration. The results suggested that sEcad and EGF may potentially be preclinical prognostic factors of bladder injury and early detection in arsenic exposure individuals. PMID- 28819765 TI - Reducing health disparities among indigenous populations: the role of collaborative approaches to improve public health systems. PMID- 28819767 TI - Comparative Efficacy of Drugs for Preventing Acute Kidney Injury after Cardiac Surgery: A Network Meta-Analysis. AB - BACKGROUND: Acute kidney injury (AKI) occurs frequently after cardiac surgery and has been associated with increased hospital length of stay, mortality, and costs. OBJECTIVE: We aimed to evaluate the efficacy of pharmacologic strategies for preventing AKI after cardiac surgery. METHODS: We searched PubMed, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL) up to 6 May 2017 and the reference lists of relevant articles about trials. The outcome was the occurrence of AKI. This is the first network meta-analysis of the different prevention strategies using Bayesian methodology. RESULTS: The study included 63 articles with 19,520 participants and evaluated the effect of ten pharmacologic strategies to prevent AKI in patients undergoing cardiac surgery. Compared with placebo, the odds ratio (OR) for the occurrence of AKI was 0.24 [95% confidence interval (CI) 0.16-0.34] with natriuretic peptide, 0.33 (95% CI 0.14-0.70) with fenoldopam, 0.54 (95% CI 0.31-0.84) with dexmedetomidine, 0.56 (95% CI 0.29-0.95) with low dose erythropoietin, 0.63 (95% CI 0.43-0.88) with levosimendan, 0.76 (95% CI 0.52 1.10) with steroids, 0.83 (95% CI 0.48-1.40) with high-dose erythropoietin, 0.85 (95% CI 0.64-1.14) with N-acetylcysteine, 0.96 (95% CI 0.69-1.29) with sodium bicarbonate, and 1.05 (95% CI 0.70-1.41) with statins. The surface under the cumulative ranking curve probabilities indicated that natriuretic peptide was the best treatment therapy and that fenoldopam ranked second. CONCLUSIONS: Natriuretic peptide is probably the preferred pharmacologic strategy to prevent AKI in adult patients undergoing cardiac surgery, especially in those at high risk of AKI. PMID- 28819766 TI - [German S3 guideline for renal cell carcinoma : Presentation and discussion of essential aspects for the radiation oncologist]. AB - PURPOSE: We aim to introduce and discuss the statements and recommendations of the German S3 guideline on renal cell cancer for daily practice of radiation oncologists. METHODS: This report comprises indication, treatment decision, dose prescription and current literature including treatment of oligometastatic disease. RESULTS: According to different stages of the disease and the structure of the guideline we focus on five treatment situations and recommendations for decision making: (1) Neo-/adjuvant treatment before or after nephrectomy: No indication for radiotherapy. (2) Small renal mass: Stereotactic ablative radiotherapy is currently seen as experimental option due to small patient numbers reported in the literature. However, local tumor control achieved by SBRT appears favourable with >90% at 2 years. (3) Oligometastasis: Radiation treatment with higher local doses or stereotactic treatment is possible after interdisciplinary discussion. Indications for palliative (4) and symptomatic treatment (5) are not different compared to other tumor entities. CONCLUSION: Currently, there is no evidence-based indication for radiation treatment in the primary setting (adjuvant/neoadjuvant or definitive) of renal cell cancer. In the future stereotactic radiotherapy should have a stronger role in the treatment of medically inoperable patients with primary renal cell cancer and especially in the setting of oligometastasis. PMID- 28819769 TI - Disparities in Breast Cancer: Private Patients Have Better Outcomes Than Public Patients. AB - INTRODUCTION: Different outcomes in breast cancer have been reported for low and high socio-economic groups. We present data quantifying disparities between South African public and private patients. METHODS: Records of 240 consecutive patients treated in 2008 in a public versus 97 patients in a private health facility were reviewed for demographic and oncologic data. RESULTS: The average of patients was 56.2 versus 51.9 years (p = 0.032). Stage at presentation was 0 in 0.83 versus 25.8%, I in 4.5 versus 15.5%, II in 41.3 versus 37.1%, III in 37.1 versus 18.6% and IV in 16.3 versus 3.1% public versus private patients. Seventy-three percent of patients were symptomatic versus 57.7%. Of patients with stage 0-III disease, 17.9 versus 20% had simple tumour excision and 7.5 versus 14%, oncoplastic tumour excision. The mastectomy rate was similar (52 vs. 60%), but immediate reconstruction was performed in 10 versus 63%. Public patients were less likely to have radiotherapy. The pathology was similar, 27.2 versus 20, 54 versus 52, 87 versus 61% of patients with stage I, II and III disease, respectively, had chemotherapy. Hormonal therapy for premenopausal patients in private was a LHRH agonist in 9.3%, ovarian ablation/BSO in 11.7% of public patients; biologicals were given in 7.2 versus 0% of patients. Overall survival for public versus private was 66 versus 80% (p < 0.001) months. Better per stage survival of private patients 100 versus 100, 72.7 versus 93.3, 84.8 versus 88.9, 57.3 versus 77.8 and 33 versus 33% for stages 0, I, II, III and IV, did not reach statistical significance. CONCLUSION: The greatest impact on outcome was stage at presentation, but more aggressive therapy for each stage resulted in a trend to better outcome for private patients. PMID- 28819770 TI - Total Suspended Solids Effects on Freshwater Lake Biota Other than Fish. AB - Protective benchmarks for the effects of total suspended solids (TSS) on freshwater aquatic biota primarily focus on fish; whether these benchmarks will also protect their prey or co-existing lower trophic level aquatic biota was uncertain. We conducted an extensive literature review of TSS effects on those organisms comprising the food webs upon which fish living in lakes depend: phytoplankton, zooplankton, periphyton, and benthic invertebrates. The available literature indicates that TSS benchmarks that protect sensitive life stages of lake fish will also protect their supporting food webs; in other words, the function of lake aquatic communities will be protected and maintained. PMID- 28819768 TI - Maternal obesity is associated with gut microbial metabolic potential in offspring during infancy. AB - Children born to obese mothers are at increased risk for obesity, but the mechanisms behind this association are not fully understood. Our study aimed to investigate differences in the functions encoded by the microbiome of infants at 18 months of age when the transition from early infant-feeding to solid family foods is established. To investigate the impact of maternal prepregnancy body mass index on infants' gut microbiome, faecal samples from infants born to normoweight (n = 21) and obese mothers (n = 18) were analysed by 16S rRNA gene sequencing and a functional-inference-based microbiome analysis. Our results indicated that Firmicutes was significantly enriched in infants born to normoweight mothers whereas Bacteroidetes was significantly enriched in infants born to obese women. In both microbiomes, the greatest number of genes (>50%) that were assigned a function encoded for proteins involved in "metabolism" among tier 1 KEGG Orthology (KO) categories. At lower KO functional categories, the microbiome of infants born to normoweight mothers was characterized by a significant enrichment in the abundances of "pentose phosphate pathway" (p = 0.037), "lysine biosynthesis" (p = 0.043), "glycerolipid metabolism" (p = 0.042), and "C5-branched dibasic acid metabolism" (p = 0.045). Notably, the microbiome of infants born to obese mothers was significantly enriched in "streptomycin biosynthesis" (p = 0.047), "sulphur metabolism" (p = 0.041), "taurine and hypotaurine metabolism" (p = 0.036), and "lipopolysaccharide biosynthesis" (p = 0.043). In summary, our study showed that maternal prepregnancy obesity may imprint a selective gut microbial composition during late infancy with distinct functional performances. PMID- 28819771 TI - The Impact of Bridging LRT on Survival in Patients Listed for Liver Transplantation. AB - PURPOSE: Locoregional therapy (LRT) is recommended for certain groups of patients with hepatocellular carcinoma (HCC) listed for orthotopic liver transplantation (OLT) with expected wait times greater than 6 months. A retrospective single center study was performed to evaluate the effect of LRT on the outcomes of patients with HCC listed for OLT. METHODS: Institutional database was reviewed to identify the patients listed for OLT with HCC (March 1998-December 2010). Patient and tumor characteristics were recorded with a follow-up period of 6.5 years from diagnosis. RESULTS: Out of 359 listed patients, 72 patients were delisted (delisted group) and 287 underwent orthotopic liver transplantation (OLT group). One hundred fifty-five and 45 patients from the OLT and delisted groups underwent locoregional therapy (LRT), respectively. Median wait time and sum of largest tumor diameter were significantly higher for patients receiving LRT. LRT was associated with significantly better survival among delisted patients at the end of follow-up (1249.6 +/- 137.4 vs. 742.1 +/- 155.4 days, p = 0.028). In the OLT group, survival was similar between LRT and no LRT group, but survival was significantly better in patients with largest tumor diameter >=30 mm (1949.4 +/- 95.1 vs. 1694.8 +/- 135.5, p = 0.02). CONCLUSION: Patients with HCC and the largest tumor greater than 30 mm treated with LRT prior to OLT have improved survival compared to patients not receiving LRT. Additionally, for patients who did not undergo transplant survival is significantly longer for those receiving LRT. PMID- 28819772 TI - Convergence and determinants of health expenditures in OECD countries. AB - This study examines the trend and determinants of health expenditures in OECD countries over the 1975-2004 period. Based on recent developments in the economic growth literature we propose and test the hypothesis that health care expenditures in countries of similar economic development level may converge. We hypothesise that the main drivers for growth in health care costs include: aging population, technological progress and health insurance. The results reveal no evidence that health expenditures among OECD countries converge. Nevertheless, there is evidence of convergence among three sub-groups of countries. We found that the main driver of health expenditure is technological progress. Our results also suggest that health care is a (national) necessity, not a luxury good as some other studies in this field have found. PMID- 28819773 TI - TLR9 gene polymorphism -1486T/C (rs187084) is associated with uterine cervical neoplasm in Mexican female population. AB - PURPOSE: The aim of this work was to evaluate the association of single nucleotide polymorphisms in TLR9 (-1486 T/C [rs187084], -1237T/C [rs5743836] and G2848A [rs352140]) with HPV infection, squamous intraepithelial lesions, and uterine cervical neoplasm in a Mexican population. Additionally, the peripheral expression of TLR9 was evaluated to evaluate the differences in the TLR9 expression associated with every genotype in the locus -1486 of the TLR9 gene. The serum concentration of TLR9 was evaluated in a randomly selected subsample. METHODS: Genotyping was performed using predesigned 5' endonuc lease assays and the association of the polymorphisms with the diagnosis groups were assessed by performing multinomial regression models. The relative expression of TLR9 in peripheral blood mononuclear cells was evaluated by real-time polymerase chain reaction and the association of the level of TLR9 expression with the diagnosis was evaluated by performing multinomial regression models. The serum concentration of TLR9 was evaluated in a subsample of patients diagnosed with uterine cervical neoplasm by ELISA. RESULTS: The results showed that genotype TT in the -1486 locus of TLR9 was significantly associated with HPV infection (OR = 3.25, 95% CI 1.12-9.46), squamous intraepithelial cervical lesion (OR = 3.76, 95% CI 1.36-10.41), and uterine cervical neoplasm (OR = 5.30, 95% CI 1.81-15.55). Moreover, the highest level of TLR9 expression was significantly associated with a greater risk for developing squamous intraepithelial cervical lesion and uterine cervical neoplasm. The serum TLR9 concentration was higher in patients with uterine cervical cancer than in controls. CONCLUSION: Our findings indicate that genotype TT in the -1486 locus of the TLR9 gene could comprise a risk genotype for HPV infection, squamous intraepithelial cervical lesion, and uterine cervical neoplasm in Mexican female population. Further studies with larger samples are needed to evaluate if the peripheral expression of TLR9 could be used as a biomarker of uterine cervical neoplasm progression. PMID- 28819774 TI - Whole exome sequencing of wild-derived inbred strains of mice improves power to link phenotype and genotype. AB - The house mouse is a powerful model to dissect the genetic basis of phenotypic variation, and serves as a model to study human diseases. Despite a wealth of discoveries, most classical laboratory strains have captured only a small fraction of genetic variation known to segregate in their wild progenitors, and existing strains are often related to each other in complex ways. Inbred strains of mice independently derived from natural populations have the potential to increase power in genetic studies with the addition of novel genetic variation. Here, we perform exome-enrichment and high-throughput sequencing (~8* coverage) of 26 wild-derived strains known in the mouse research community as the "Montpellier strains." We identified 1.46 million SNPs in our dataset, approximately 19% of which have not been detected from other inbred strains. This novel genetic variation is expected to contribute to phenotypic variation, as they include 18,496 nonsynonymous variants and 262 early stop codons. Simulations demonstrate that the higher density of genetic variation in the Montpellier strains provides increased power for quantitative genetic studies. Inasmuch as the power to connect genotype to phenotype depends on genetic variation, it is important to incorporate these additional genetic strains into future research programs. PMID- 28819775 TI - Sublobar resection versus lobectomy in patients aged <=35 years with stage IA non small cell lung cancer: a SEER database analysis. AB - PURPOSE: Sublobar resection has been increasingly adopted in elderly patients with stage IA non-small cell lung cancer (NSCLC), but the equivalency of sublobar resection versus lobectomy among young patients with stage IA NSCLC is unknown. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) registry, we identified patients aged <=35 years who were diagnosed between 2004 and 2013 with pathological stage IA NSCLC and treated with sublobar resection or lobectomy. We used propensity-score matching to minimize the effect of potential confounders that existed in the baseline characteristics of patients in different treatment groups. The overall survival (OS) and lung cancer-specific survival (LCSS) rates of patients who underwent sublobar resection or lobectomy were compared in stratification analysis. RESULTS: Overall, we identified 188 patients who had stage IA disease, 32 (17%) of whom underwent sublobar resection. We did not identify any difference in OS/LCSS between patients who received sublobar resection versus lobectomy before (log-rank p = 0.6354) or after (log-rank p = 0.5305) adjusting for propensity scores. Similarly, we still could not recognize different OS/LCSS rates among stratified T stage groups or stratified lymph node removed groups before or after adjusting for propensity scores. CONCLUSIONS: Sublobar resection is not inferior to lobectomy for young patients with stage IA NSCLC. Considering sublobar resection better preserves lung function and has reduced overall morbidity, sublobar resection may be preferable for the treatment of young patients with stage IA NSCLC. PMID- 28819776 TI - Tongxinluo Capsule () for Cardiac Syndrome X: A Systematic Review and Meta Analysis. AB - OBJECTIVE: To evaluate the efficacy and safety of Tongxinluo Capsule (, TXL) for patients with cardiac syndrome X (CSX). METHODS: Randomized controlled trials (RCTs) regarding TXL in the treatment of CSX were searched in Chinese Biomedicine Literature Database, China National Knowledge Infrastructure, Chinese Scientific Journal Database, Wanfang Database, PubMed, EMBASE, Cochrane Central Register of Controlled Trial, websites of the Chinese and International Clinical Trial Registry platform up to June 30, 2015. The intervention was either TXL alone or TXL combined with conventional treatment, while the control intervention was conventional treatment with or without placebo. Data extraction, methodological quality assessment and data analyses were performed according to the Cochrane criteria. The primary outcome was a composite event of death, acute myocardial infarction (AMI), angina requiring hospitalization, revascularization, and heart failure. The secondary outcome measures were angina symptom improvement, electrocardiograph (ECG) improvement, and serum endothelin-1 (ET-1) level. The adverse events were also recorded. RevMan 5.3 software was applied for data analyses. RESULTS: Twelve RCTs (696 patients) were included. Compared with conventional treatment, the addition of TXL to conventional treatment showed some benefits on relieving angina symptoms [risk ratio (RR): 1.46, 95% confidence interval (CI) (1.25, 1.71), P<0.01], and improving ECG [RR: 1.45, 95% CI (1.21, 1.74), P<0.01]. The pooled result did not support a benefit of TXL on reducing the incidence of primary outcome [RR: 0.20, 95% CI (0.02, 1.61), P=0.13]. In addition, TXL decreased serum ET-1 concentration of CSX patients [standardized mean number:-1.63, 95% CI (-2.29,-0.96), P<0.01]. No serious adverse events were reported. CONCLUSIONS: TXL documents potential benefits on attenuating angina symptoms, improving ECG and decreasing serum ET-1 level for CSX patients. However, more rigorous RCTs with high quality are needed to confirm its efficacy and safety. PMID- 28819777 TI - Qingkailing Injection () for Treatment of Children Pneumonia Induced by Respiratory Syncytial Virus: A Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVE: To evaluate the efficacy and safety of Qingkailing Injection (, QKL) for treatment of children pneumonia caused by respiratory syncytial virus (RSV). METHODS: Randomized clinical trials (RCTs) comparing QKL with ribavirin injection in the treatment of children pneumonia induced by RSV were searched in PubMed, Science Direct, Cochrane Library, Chinese VIP database, CNKI and Wanfang databases from their inception to March 2014. Meta-analyses were performed using RevMan 5.2 software. The methodological quality of the selected RCTs was evaluated by the Modified Jadad Score. The primary outcome measures were effective rate and the secondary outcomes were relief time of fever and cough. RESULTS: Seven RCTs with 992 cases published from 2008 to 2013 were identified. The meta-analysis results indicated that QKL was more effective in cure rate [risk ratios (RR)=1.32, 95% CI (1.17, 1.50), P<0.01], total effective rate [RR=1.07, 95% CI (1.02, 1.13), P=0.009] and less fever clearance time [mean difference=-0.73, 95% CI (-1.22,-0.23), P=0.004], compared with ribavirin injection in the treatment of RSV-induced children pneumonia. No dead case was reported in all trials. There were 3 trials mentioned adverse events, 2 reported no obvious adverse event occurred while 1 reported adverse events described as skin hypersensitivity, elevation of ALT, a mild abnormal of hepatic and renal function in both QKL and ribavirin group. CONCLUSIONS: QKL was an effective and relatively safe option for the treatment of RSV-induced children pneumonia. These therapeutic effects were promising but need to be interpreted with caution due to variations in the treatment and methodological weakness in the studies. PMID- 28819778 TI - Impact of Jumihaidokuto (Shi-Wei-Bai-Du-Tang) on treatment of chronic spontaneous urticaria: A randomized controlled study. AB - OBJECTIVE: To study the effect of Jumihaidokuto (Shi-Wei-Bai-Du-Tang, ) in the management of chronic spontaneous urticaria. METHODS: A randomized two-arm, parallel group study was conducted to compare the effect of Jumihaidokuto (6 g daily) with a control for 8 weeks. Concomitant therapy (e.g., antihistamines) was continued. Twenty-one subjects with severe chronic urticaria were enrolled in this study. The primary treatment outcome was the severity score proposed by the Japanese Dermatological Association. Secondary outcomes were quality of life (Skindex-16), itch intensity (Visual Analogue Scale), and patients' subjective disability due to wheal or itch. After the subjects were randomly assigned to groups by block randomization, 10 received Jumihaidokuto, and 11 did not. All subjects had already taken antihistamines. RESULTS: Improvement was significant when comparing the severity score of the Jumihaidokuto group with that of the control group (P<0.01). Skindex-16 values for both groups gradually decreased in the same fashion. CONCLUSION: Concomitant use of Jumihaidokuto with antihistamine was more effective than antihistamine alone in the management of chronic idiopathic urticaria. (Trial Registration No. UMIN000007251). PMID- 28819779 TI - Curcuma wenyujin Y. H. Chen et C. Ling n-Butyl alcohol extract inhibits AGS cell Helicobacter pylori CagA+VacA+ promoted invasiveness by down-regulating caudal type homeobox transcription factor and claudin-2 expression. AB - OBJECTIVE: To investigate the effects and possible mechanisms of action of Curcuma wenyujin Y. H. Chen et C. Ling n-Butyl alcohol extract (CWNAE) on repression of human gastric cancer (GC) AGS cell invasion induced by co-culturing with Helicobacter pylori (HP). METHODS: AGS cells were cultured with HP of positive or negative cytotoxin-associated gene A (CagA) and vacuolating cytotoxin gene A (VacA) expression (CagA+/- or VacA+/-) and divided into 5 group. Group A was cultured without HP as a control, Group B with HPCagA+VacA+, Group C with HPCagA-VacA-, Group D with HPCagA+VacA+ and CWNAE, and Group E with HPCagA-VacA- and CWNAE. Methylthiazolyldiphenyl-tetrazolium bromide (MTT) and tumor invasion assays, examinations of morphology and ultramicroscopic structures, quantitative real-time polymerase chain reaction and Western blots were performed to measure the effects and uncover the mechanisms behind these effects of HPCagA+VacA+ and CWNAE on the epithelial-mesenchymal transition (EMT) of AGS cells. RESULTS: The 10% inhibitory concentration of CWNAE against AGS cells after a 48 h incubation was 19.73+/-1.30 MUg/mL. More AGS cells were elongated after co-culturing with HPCagA+VacA+ than after culturing with HPCagA-VacA-. In tumor invasion assays, HPCagA+VacA+ significantly enhanced the invasiveness of AGS cells compared to the other experimental groups (all P value <0.05), and this effect was inhibited by CWNAE. Treatment with CWNAE normalized tight junctions and reduced the number of pseudopodia of AGS cells co-cultured with HPCagA+VacA+. HPCagA+VacA+ up-regulated zincfinger ebox binding homeobox 1 (ZEB1) in AGS cells after co-culturing for 24 h. Expression of caudal type homeobox transcription factor (CDX-2) and claudin-2 was significantly increased by HPCagA+VacA+ (P<0.05), but not by HPCagA-VacA-. CONCLUSION: HPCagA+VacA+ promoted the invasiveness of AGS cells through up regulation of ZEB1 transcription and claudin-2 and CDX-2 expression. CWNAE inhibited these effects of HPCagA+VacA+ on AGS cells by down-regulating ZEB1 transcription, and CDX-2 and claudin-2 expression. PMID- 28819780 TI - Preliminary Research on Syndrome Types of Chinese Medicine in Children with Primary Nephrotic Syndrome. AB - OBJECTIVE: To provide an objective reference for the syndrome types of Chinese medicine (CM) associated with pediatric primary nephrotic syndrome (PNS). METHODS: A cross-sectional study was performed. Data on clinical symptoms, CM syndrome types, biochemical indices, and medications used were collected from 98 children with PNS. Then, the correlation between CM syndromes and biochemical indices, as well as medications used, was analyzed. RESULTS: The four most common symptoms in children with PNS were brown urine, red tongue, excessive sweating, and swelling of the face and limbs. The syndromes of qi deficiency of Fei (Lung) and Shen (Kidney) (FSQD) and yin deficiency of Gan (Liver) and Shen (GSYD) were the most common main CM syndrome types. FSQD syndrome score correlated significantly with the total cholesterol level, urine protein/creatinine ratio, and urine IgG and albumin levels (P<0.01 or P<0.05). The use of maintenance glucocorticoids combined with immunosuppressive agents correlated with FSQD syndrome, and the use of maintenance glucocorticoids alone correlated with GSYD syndrome (P<0.05). CONCLUSION: Two of the most common CM syndrome types were FSQD and GSYD syndromes. FSQD syndrome may be caused by some factors related to lipid levels, protein loss, and the use of immunosuppressive agents. The use of maintenance glucocorticoids may cause GSYD syndrome. PMID- 28819781 TI - Comparison of synthetic mammography, reconstructed from digital breast tomosynthesis, and digital mammography: evaluation of lesion conspicuity and BI RADS assessment categories. AB - PURPOSE: To compare the interpretive performance of synthetic mammography (SM), reconstructed from digital breast tomosynthesis (DBT), and full-field digital mammography (FFDM) in a diagnostic setting, covering different conditions of breast density and mammographic signs. METHODS: A retrospective analysis was conducted on 231 patients, who underwent FFDM and DBT (from which SM images were reconstructed) between September 2014-September 2015. The study included 250 suspicious breast lesions, all biopsy proven: 148 (59.2%) malignant and 13 (5.2%) high-risk lesions were confirmed by surgery, 89 (35.6%) benign lesions had radiological follow-up. Two breast radiologists, blinded to histology, independently reviewed all cases. Readings were performed with SM alone, then with FFDM, collecting data on: probability of malignancy for each finding, lesion conspicuity, mammographic features and dimensions of detected lesions. RESULTS: Agreement between readers was good for BI-RADS classification (Cohen's k coefficient = 0.93 +/- 0.02) and for lesion dimension (Wilcoxon's p = 0.76). Visibility scores assigned to SM and FFDM for each lesion were similar for non dense and dense breasts, however, there were significant differences (p = 0.0009) in distribution of mammographic features subgroups. SM and FFDM had similar sensitivities in non-dense (respectively 94 vs. 91%) and dense breasts (88 vs. 80%) and for all mammographic signs (93 vs. 87% for asymmetric densities, 96 vs. 75% for distortion, 92 vs. 85% for microcalcifications, and both 94% for masses). Based on all data, there was a significant difference in sensitivity for SM (92%) vs. FFDM (87%), p = 0.02, whereas the two modalities yielded similar results for specificity (SM: 60%, FFDM: 62%, p = 0.21). CONCLUSIONS: SM alone showed similar interpretive performance to FFDM, confirming its potential role as an alternative to FFDM in women having tomosynthesis, with the added advantage of halving the patient's dose exposure. PMID- 28819782 TI - The effects of beta-D-mannuronic acid (M2000), as a novel NSAID, on COX1 and COX2 activities and gene expression in ankylosing spondylitis patients and the murine monocyte/macrophage, J774 cell line. AB - Ankylosing spondylitis (AS) is a debilitating chronic inflammatory disease with genetic predisposition, which is characterized by the involvement of spine and sacroiliac joints. Due to the relatively unsuccessful treatments, we designed beta-D-mannuronic (M2000) with the beneficial effects in various experimental models as a novel non-steroidal anti-inflammatory drug (NSAID). The aims of our present study were: first, to compare the therapeutic effects of M2000, as a novel designed NSAID, with naproxen and placebo in Iranian patients with AS during 12 weeks; second, to evaluate the effect of M2000 on gene expression of cyclooxygenase enzyme (COX-1/COX-2), a key enzyme in the initiation of inflammatory pathways in AS patients; and third, to assess the activity of COX-1 and COX-2 enzymes in the presence/absence of M2000 at the different doses in the murine macrophage, J774 cell line. This was a sub-study of phase II, randomized, placebo-controlled trial with three treatment arms: M2000, naproxen, and placebo. The outcome measures were the mean changes from baseline to week 12. The gene expression was assessed by real-time PCR. The COX-1 and COX-2 activities were evaluated by ELISA in J774 cell line induced by LPS and arachidonic acid (AA). Our findings demonstrated that M2000 had beneficial therapeutic effects on pain, stiffness, and inflammation, whereas no adverse effects were observed following the use of M2000 after 12 weeks. The analysis of gene expression showed that M2000 could effectively reduce the expression levels of COX-1 and COX-2 in comparison with untreated patients. In addition, the enzymatic activities in the presence of M2000 were significantly less than LPS- and AA-treated groups. Our results indicate that M2000, as a novel designed NSAID with immunosuppressive properties, can be considered as one of the therapeutic options for the treatment of inflammatory diseases without adverse events. Clinical trial identifier IRCT2013062213739N1/ http://www.IRCT.ir . PMID- 28819783 TI - Factors associated with hospital readmission following diverting ileostomy creation. AB - BACKGROUND: The creation of a diverting loop ileostomy is associated with the risk of readmission due to stoma-related complications. We hypothesized that the assessment of our institution-specific readmissions following ileostomy creation would help identifying at-risk groups which should be the focus of future preventative strategies. METHODS: Patients who underwent loop ileostomy formation from 2009 to 2013 were reviewed. We evaluated readmissions within 30 days after discharge following loop ileostomy construction. Possible associations between readmission and demographic, disease-related and treatment-related factors were assessed using univariate and multivariate analyses. RESULTS: Out of 1267 patients undergoing loop ileostomy construction, 163 patients (12.9%) were readmitted. The main causes of readmissions were organ/space infections (43, 3.4%), small bowel obstruction/ileus (42, 3.3%) and dehydration (38, 3%). Independent factors associated with overall readmission were cardiovascular (OR = 2.0) and renal comorbidity (OR = 2.9), preoperative chemo/radiotherapy (OR = 4.0), laparoscopic approach (OR = 1.7) and longer operative time (OR = 1.2). Cancer diagnosis was associated with reduced readmission rates (OR = 0.2). Independent factors associated with readmission due to dehydration were chemo/radiotherapy (OR = 4.7) and laparoscopic approach (OR = 2.6). CONCLUSIONS: Dehydration associated with diverting ileostomy creation was relevant as an individual cause of readmission, but its overall incidence was relatively rare. Dedicated strategies to prevent dehydration should be directed to patients who received chemoradiotherapy and/or laparoscopic surgery. PMID- 28819784 TI - [Injuries of the peroneal tendons : Often overlooked]. AB - CLINICAL ISSUE: Injuries of the peroneal tendons are rare and often overlooked. Typical pathologies are tendinitis, tears and dislocation. Accompanying injuries are fractures. They are often associated with instability in the ankle and rearfoot deformities; therefore, these pathologies should be excluded or taken into consideration in the treatment. The clinical examination is crucial for the diagnosis. DIAGNOSTIC WORK-UP: Ultrasound and magnetic resonance imaging (MRI) examinations are very helpful; however, the true extent of the tendon pathology is often first seen during surgery. Bony injuries and deformities are assessed radiographically and by computed tomography (CT). PERFORMANCE: Although conservative treatment is generally used at the beginning of therapy, progression is more likely to occur in the case of tears; therefore, the correct timing for an operative therapy should not be missed. Dislocations are the domain of operative therapy. Acute tendinitis, on the other hand, is usually accessible to conservative therapy if it is not the result of a gross deformity. ACHIEVEMENTS: Rehabilitation after operative treatment is demanding and prolonged especially after operative therapy of peroneal tendon tears. The results to be expected appear promising. PMID- 28819785 TI - Assessment of the safety and efficacy of primary retropupillary fixation of iris claw intraocular lenses in children with large lens subluxations. AB - PURPOSE: To evaluate whether retropupillary fixation of the iris-claw intraocular lens (IOL) is a safe and effective treatment option in children with large lens subluxations. METHODS: Fourteen eyes of children between the ages of 8-17 years with lens subluxations more than 7 clock hours underwent pars plana lensectomy vitrectomy with implantation of the iris-claw IOL in the retropupillary position as a primary procedure. The best corrected visual acuity (BCVA), intraocular pressure (IOP), corneal endothelial count (EC) and the lens position using ultrasound biomicroscopy (UBM) were assessed pre- and postoperatively. RESULTS: Postoperatively, all patients had an increase in the BCVA with a mean of 0.351 +/ 0.154 log MAR units which was statistically significant as compared to the preoperative value of 0.771 +/- 0.132 log MAR units (p = 0.003). The difference between the mean preoperative IOP (13.642 +/- 2.437 mmHg) and the mean postoperative intraocular pressure at the end of 6 months (13.5 +/- 2.244 mmHg) was not statistically significant (p = 0.671). The mean EC decreased by 0.99% from 2838.42 +/- 474.76 cells/mm2 preoperatively to 2810 +/- 461.24 cells/mm2 at the end of 6 months postoperatively (p = 0.117). The lens position was analyzed using UBM and was found to be parallel to the iris plane in all cases at the end of 6 months. CONCLUSIONS: Our study shows that primary retropupillary iris-claw IOL implantation can be a safe and efficacious option for children with large (>7 clock hours) lens subluxations that is at least comparable to scleral-fixated PCIOLs. PMID- 28819786 TI - Yeast caspase-dependent apoptosis in Saccharomyces cerevisiae BY4742 induced by antifungal and potential antitumor agent clotrimazole. AB - Clotrimazole is an antifungal medication commonly used in the treatment of fungal infections. There is also promising research on using clotrimazole against other diseases such as malaria, beriberi, tineapedis and cancer. It was aimed to investigate the apoptotic phenotype in Saccharomyces cerevisiae induced by clotrimazole. The exposure of S. cerevisiae to 10 uM clotrimazole for 3, 6 and 9 h caused to decrease in cell viability by 24.82 +/- 0.81, 56.00 +/- 1.54 and 77.59 +/- 0.53%, respectively. It was shown by Annexin V-PI assay that 110 uM clotrimazole treatment caused to death by 35.5 +/- 2.48% apoptotic and only 13.1 +/- 0.08% necrotic pathway within 30 min. The occurrence of DNA strand breaks and condensation could be visualised by the TUNEL and DAPI stainings, respectively. Yeast caspase activity was induced 12.34 +/- 0.71-fold after 110 uM clotrimazole treatment for 30 min compared to the control. The dependency of clotrimazole induced apoptosis to caspase was also shown using Deltayca1 mutant. PMID- 28819787 TI - Flexible semi-parametric regression of state occupational probabilities in a multistate model with right-censored data. AB - Inference for the state occupation probabilities, given a set of baseline covariates, is an important problem in survival analysis and time to event multistate data. We introduce an inverse censoring probability re-weighted semi parametric single index model based approach to estimate conditional state occupation probabilities of a given individual in a multistate model under right censoring. Besides obtaining a temporal regression function, we also test the potential time varying effect of a baseline covariate on future state occupation. We show that the proposed technique has desirable finite sample performances and its performance is competitive when compared with three other existing approaches. We illustrate the proposed methodology using two different data sets. First, we re-examine a well-known data set dealing with leukemia patients undergoing bone marrow transplant with various state transitions. Our second illustration is based on data from a study involving functional status of a set of spinal cord injured patients undergoing a rehabilitation program. PMID- 28819788 TI - Insulin-like growth factor-1 activates different catalytic subunits p110 of PI3K in a cell-type-dependent manner to induce lipogenesis-dependent epithelial mesenchymal transition through the regulation of ADAM10 and ADAM17. AB - The activation of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) is critical for the induction of epithelial-mesenchymal transition (EMT) by growth factors, including insulin-like growth factor 1 (IGF-1). The activation of intracellular lipogenesis provides proliferative and survival signals for cancer cells. In this study, we investigated the connection between lipogenesis-related EMT processes and IGF-1-mediated PI3K p110 isoform activation in primary (SW480 cells) and metastatic (SW620) colon carcinoma cells. We also examined the underlying signaling pathway that promotes fatty acid synthesis in IGF-1 activated colon cancer cells. IGF-1 stimulation upregulated the expression of lipogenic enzymes as well as the activation of Nardilysin (N-arginine dibasic convertase, NRD1) and its downstream targets, a disintegrin and metalloproteases 10 (ADAM10) and ADAM17. The upregulation of the Lyn/Syk-mediated PI3K p110delta isoform in SW480 cells and the Lyn-dependent PI3K p110alpha isoform in SW620 cells triggered fatty acid production and cell motility in IGF-1-activated colon cancer cells. Pharmacological inhibition with A66 (PI3K p110alpha specific inhibitor) and CAL-101 (PI3K p110delta specific inhibitor) efficiently inhibited EMT in colon cancer cells by blocking the NRD1/ADAM family protein signaling pathway. Gene silencing of NRD1 and ADAM family proteins attenuated the generation of intracellular fatty acid and the migratory activity of colon cancer cells. Our results suggest that the different isoforms of the PI3K p110 subunit could be therapeutic targets for primary and metastatic colon cancer and that regulation of the NRD1/ADAM signaling pathway controls lipogenesis-mediated EMT in IGF-1-stimulated colon cancer cells. PMID- 28819789 TI - Left Gastric Artery Lymph Nodes Should Be Included in D1 Lymph Node Dissection in Gastric Cancer. AB - BACKGROUND: The Japanese Classification of Gastric Carcinoma includes the left gastric artery (#7) lymph nodes (LNs) in the recommended extent of D1 LN dissection, but this recommendation has not been validated in western institutions. METHODS: We reviewed data from a prospectively maintained database of gastric cancer patients who underwent resection at our academic cancer center and had a separate pathologic assessment of #7 LN in 2005-2016. Risk factors for #7 LN metastases and overall survival were examined by uni- and multivariable analyses. RESULTS: We identified 173 patients; 114 (66%) were treated with preoperative therapy, most commonly with chemoradiation therapy (47%, 81/173). We identified 22 patients (13%) who had #7 LN metastases, which accounted for 35% (22/63) of node-positive patients. No preoperative factors were associated with #7 LN metastases by univariable analyses. Patients with #7 metastases were not associated with shorter overall survival after adjustment by nodal stage (hazard ratio 1.49, 95% confidence interval 0.67-3.32; p = 0.33). CONCLUSION: Metastasis to #7 LN station was common in gastric cancer, but the survival impact was not significant after adjustment by nodal stage. We conclude that #7 LNs should be routinely dissected in gastric cancer patients, and this station should be included within the extent of D1 LN dissection. PMID- 28819790 TI - Contemplative Meditation and Neuroscience: Prospects for Mental Health. AB - Numerous studies show that personal spirituality developed through prayer positively influences mental health. Phenomenological and neuroscientific studies of mindfulness, an Eastern meditative prayer form, reveal significant health benefits now yielding important insights useful for guiding treatment of psychological disorders. By contrast, and despite its practice for millennia, Christian meditation is largely unrepresented in studies of clinical efficacy. Resemblances between mindfulness and disciplinary acts in Christian meditation taken from the ancient Greek practice of askesis suggest that Christian meditation will prove similarly beneficial; furthermore, psychological and neuroscientific studies suggest that its retention of a dialogical and transcendent praxis will additionally benefit social and existential psychotherapy. This paper thus argues that study of contemplative meditation for its therapeutic potential is warranted. PMID- 28819791 TI - Delayed Gastric Emptying in Side-to-Side Gastrojejunostomy in Pancreaticoduodenectomy: Result of a Propensity Score Matching. AB - BACKGROUND: Delayed gastric emptying (DGE) is one of the most common morbidities of pancreaticoduodenectomy (PD). The aim of this study was to clarify whether the incidence of DGE can be reduced by side-to-side gastric greater curvature-to jejunal anastomosis in subtotal stomach-preserving pancreaticoduodenectomy (SSPPD). METHODS: The clinical data of 253 patients who had undergone PD were examined. Of a total of 188 patients who had undergone SSPPD, a gastrojejunostomy (GJ) was performed with end-to-side anastomosis in 87 patients (SSPPD-ETS group), and a GJ was performed with a greater curvature side-to-jejunal side anastomosis in 101 patients (SSPPD-STS group). After propensity score matching, the matched cohort consisted of 74 patients in each group. The postoperative data were evaluated according to the International Study Group of Pancreatic Surgery grade of DGE. RESULTS: The total incidence of DGE was 9.4% in the SSPPD-ETS group and 4% in the SSPPD-STS group, with no significant difference (p = 0.1902). A significant difference was observed between the two groups in the incidence of DGE grade C (p = 0.0426). CONCLUSIONS: The incidence of total DGE was not reduced statistically in the STS group compared with the ETS group, but reduced DGE grade C. Side-to-side anastomosis might be associated with a reduced incidence of DGE grade C. PMID- 28819792 TI - Validation of the ACR/EULAR classification criteria for systemic sclerosis in patients with early scleroderma. AB - The aim of this study was to validate the 2013 ACR/EULAR classification criteria for systemic sclerosis (SSc) in patients with SSc, including patients with early SSc. Fifty-six consecutive patients with early SSc (2001 LeRoy and Medsger criteria), 122 patients with established SSc (1980 ACR classification criteria), and 141 patients with SSc-like disorders were included in this cross-sectional study. The diagnostic performance of the 2013 ACR/EULAR criteria was compared with the 1980 ACR criteria in several subsets of patients. The performance of individual variables was also obtained. Receiver operating characteristic (ROC) curves and optimal cut-off values were computed. The sensitivity and specificity in the whole cohort of 178 SSc patients were 77.6 and 98.5%, respectively, using the 2013 ACR/EULAR criteria and 68.5 and 100%, respectively, using the 1980 ACR criteria. Twenty-eight percent of the patients with early SSc met the 2013 ACR/EULAR criteria. Among the patients with early SSc, 53% of those who had Raynaud's phenomenon, abnormal capillaroscopy and positive SSc-related antibodies met the 2013 ACR/EULAR criteria. The area under the ROC curve was 0.975 (95% confidence interval 0.962-0.987). The best cut-off value for the total score was >=8 (sensitivity 82%; specificity 97.9%). The individual variables with the highest specificity values were proximal skin thickening, sclerodactyly (specificity 100%), telangiectasia and SSc-related antibodies (specificity 98.6%). Raynaud's phenomenon had the best sensitivity (99.4%) but had low specificity (4.2%). In conclusion, the 2013 ACR/EULAR classification criteria showed high accuracy and increased sensitivity in the classification of patients with early SSc. PMID- 28819793 TI - The mechanisms underlying the production of discontinuous gas exchange cycles in insects. AB - This review examines the control of gas exchange in insects, specifically examining what mechanisms could explain the emergence of discontinuous gas exchange cycles (DGCs). DGCs are gas exchange patterns consisting of alternating breath-hold periods and bouts of gas exchange. While all insects are capable of displaying a continuous pattern of gas exchange, this episodic pattern is known to occur within only some groups of insects and then only sporadically or during certain phases of their life cycle. Investigations into DGCs have tended to emphasise the role of chemosensory thresholds in triggering spiracle opening as critical for producing these gas exchange patterns. However, a chemosensory basis for episodic breathing also requires an as-of-yet unidentified hysteresis between internal respiratory stimuli, chemoreceptors, and the spiracles. What has been less appreciated is the role that the insect's central nervous system (CNS) might play in generating episodic patterns of ventilation. The active ventilation displayed by many insects during DGCs suggests that this pattern could be the product of directed control by the CNS rather than arising passively as a result of self-sustaining oscillations in internal oxygen and carbon dioxide levels. This paper attempts to summarise what is currently known about insect gas exchange regulation, examining the location and control of ventilatory pattern generators in the CNS, the influence of chemoreceptor feedback in the form of O2 and CO2/pH fluctuations in the haemolymph, and the role of state-dependent changes in CNS activity on ventilatory control. This information is placed in the context of what is currently known regarding the production of discontinuous gas exchange patterns. PMID- 28819794 TI - In Vitro Selection and Identification of Potential Probiotics Isolated from the Gastrointestinal Tract of Nile Tilapia, Oreochromis niloticus. AB - Fish gut bacteria can be used as probiotics for aquaculture. The aim of this study is to screen and identify beneficial probiotic bacteria from the gut of Nile tilapia, Oreochromis niloticus. Nine out of one hundred thirty-five isolates were non-pathogenic through intraperitoneal injection and had antibacterial activities with at least a strain from the five isolated fish pathogens, Aeromonas sobria, Aeromonas hydrophila, Pseudomonas aeruginosa, Pseudomonas putida, and Staphylococcus aureus. Further tests showed that such isolates can survive in the presence of high bile concentration (10%) and at different acidic pH values. A strains (14HT) was sensitive to all selected antibiotics, two strains were (9HT and 11HT) resistant to streptomycin and three strains (9HT, 11HT and 38HT) had resistance to two antibiotics. Four isolates (11HT, 33HT, 38HT and 41HT) had an amylase and a protease activities and one strain (47HT) showed only amylase activity. Based on 16S rRNA gene analysis, the isolated strains were identified as follows: Lactococcus lactis (8HT, 9HT, 11HT and 33HT); Enterococcus faecalis (14HT), Lysinibacillus sp. (38HT) and Citrobacter freundii (39HT, 41HT and 47HT). PMID- 28819795 TI - Leptin Regulation of Synaptic Function at Hippocampal TA-CA1 and SC-CA1 Synapses: Implications for Health and Disease. AB - Growing evidence indicates that the endocrine hormone leptin regulates hippocampal synaptic function in addition to its established role as a hypothalamic satiety signal. Indeed, numerous studies show that leptin facilitates the cellular events that underlie hippocampal learning and memory including activity-dependent synaptic plasticity and glutamate receptor trafficking, indicating that leptin may be a potential cognitive enhancer. Although there has been extensive investigation into the modulatory role of leptin at hippocampal Schaffer collateral (SC)-CA1 synapses, recent evidence indicates that leptin also potently regulates excitatory synaptic transmission at the anatomically distinct temporoammonic (TA) input to hippocampal CA1 neurons. The cellular mechanisms underlying activity-dependent synaptic plasticity at TA CA1 synapses differ from those at SC-CA1 synapses and the TA input is implicated in spatial and episodic memory formation. Furthermore, the TA input is an early target for neurodegeneration in Alzheimer's disease (AD) and aberrant leptin function is linked to AD. Here, we review the evidence that leptin regulates hippocampal synaptic function at both SC- and TA-CA1 synapses and discuss the consequences for neurodegenerative disorders like AD. PMID- 28819797 TI - Anesthesia in Yemen: Working with Medecins Sans Frontieres. PMID- 28819796 TI - Simultaneous EEG-PET-fMRI measurements in disorders of consciousness: an exploratory study on diagnosis and prognosis. AB - Previous studies could demonstrate that functional magnetic resonance imaging (fMRI), fludeoxyglucose positron emission tomography (FDG-PET), and electroencephalography (EEG) measures contain information about patients suffering from disorders of consciousness (DOC) and thus improve the clinical diagnosis. Additionally, the technical modalities were able to predict the outcome of patients. However, most studies lack proven reproducibility in a clinical setting. We here applied a standardized combined EEG/fMRI/FDG-PET measurement to a cohort of 20 patients suffering from DOC and focused on parameters that have been demonstrated to contain information about diagnosis and prognosis of these patients. We evaluated EEG band power, fMRI connectivity in networks associated with consciousness and sensory networks, as well as absolute glucose uptake in the brain as potential markers of preserved consciousness or favorable outcome. Acquired data were analyzed by a principal component analysis to identify the most important markers in a hypothesis-free manner. These were then analyzed with statistical group comparisons. Absolute FDG-PET could prove that glucose metabolism in the occipital lobe is significantly higher in minimally conscious than in vegetative state patients. Delta band power showed to be prognostic marker for a favorable outcome. We conclude that absolute FDG-PET is a suitable tool to evaluate the level consciousness in DOC patients. Additionally, we propose delta band power as marker of a favorable outcome in DOC patients. We suggest that these findings promote a standardized technical evaluation of DOC patients to improve diagnosis and prognosis. PMID- 28819798 TI - Functional Organometallic Poly(arylene ethynylene)s: From Synthesis to Applications. AB - This review focuses on the recent development in the rigid-rod metallopolymers of late transition metals based on triple-bond building blocks. The synthesis, structure-property relationships and potential applications of organometallic poly(arylene ethynylene)s will be discussed in detail. These functional metal based polymers can exhibit intriguing optical, electronic and magnetic properties. Considerable focus is placed on the design strategies towards tuning the optical bandgap and emission color (spanning almost the whole visible spectrum) of this class of metallopolymers, and the investigation of their use as active materials for light/electrical energy conversion and energy and information storage. The ongoing scientific challenges and future prospects of this research field are also highlighted. PMID- 28819799 TI - Accuracy of cannulated pedicle screw versus conventional pedicle screw for extra pedicular screw placement in dysplastic pedicles without cancellous channel in adolescent idiopathic scoliosis: a computerized tomography (CT) analysis. AB - PURPOSE: This study aimed at studying the accuracy and safety of extra-pedicular screw insertion for dysplastic pedicles in AIS comparing cannulated screw system versus conventional screw system. METHODS: 104 AIS patients with 1524 pedicle screws were evaluated using CT scan. 302 screws were inserted in dysplastic pedicles using fluoroscopic guidance technique. 155 screws were inserted using a cannulated system (Group 1), whereas 147 screws were inserted using standard screws (Group 2). The pedicle perforations were assessed using a classification by Rao et al.; G0: no violation; G1: <2 mm perforation; G2: 2-4 mm perforation; and G3: >4 mm perforation). For anterior perforations, the pedicle perforations were assessed using a modified grading system (Grade 0: no violation, Grade 1: less than 4 mm perforation; Grade 2: 4 mm to 6 mm perforation; and Grade 3: more than 6 mm perforation). RESULTS: The perforation rate in Group 1 was 4.5% and in Group 2 was 15.6% (p = 0.001). Most of the perforations were anterior perforations (53.3%). The anterior perforation rate in Group 1 was 1.9% compared to 8.8% in Group 2 (p = 0.009). Group 1 has a medial perforation rate of 1.3% compared to Group 2, 6.1% (p = 0.031). The rate of critical pedicle perforation in Group 1 was 2.6% and in Group 2 was 6.8% (p = 0.102). In Group 1, there were no critical medial perforation but there was one G2 lateral perforation, one G2 superior perforation and two G3 anterior perforations. In Group 2, there were three G2 medial perforations, one G2 lateral perforation, one G2 anterior perforation and five G3 anterior perforations. CONCLUSION: Usage of cannulated screw system significantly increases the accuracy of pedicle screw insertion in dysplastic pedicles in AIS. PMID- 28819800 TI - Nanotechnology: from In Vivo Imaging System to Controlled Drug Delivery. AB - Science and technology have always been the vitals of human's struggle, utilized exclusively for the development of novel tools and products, ranging from micro- to nanosize. Nanotechnology has gained significant attention due to its extensive applications in biomedicine, particularly related to bio imaging and drug delivery. Various nanodevices and nanomaterials have been developed for the diagnosis and treatment of different diseases. Herein, we have described two primary aspects of the nanomedicine, i.e., in vivo imaging and drug delivery, highlighting the recent advancements and future explorations. Tremendous advancements in the nanotechnology tools for the imaging, particularly of the cancer cells, have recently been observed. Nanoparticles offer a suitable medium to carryout molecular level modifications including the site-specific imaging and targeting. Invention of radionuclides, quantum dots, magnetic nanoparticles, and carbon nanotubes and use of gold nanoparticles in biosensors have revolutionized the field of imaging, resulting in easy understanding of the pathophysiology of disease, improved ability to diagnose and enhanced therapeutic delivery. This high specificity and selectivity of the nanomedicine is important, and thus, the recent advancements in this field need to be understood for a better today and a more prosperous future. PMID- 28819801 TI - Botulinum Toxin Treatment in Multiple Sclerosis-a Review. AB - Purpose of review The purpose of this review is to provide updated information on the role of botulinum neurotoxin (BoNT) therapy in multiple sclerosis (MS). This review aims to answer which symptoms of multiple sclerosis may be amenable to BoNT therapy. Recent findings We searched the literature on the efficacy of BoNTs for treatment of MS symptoms up to April 1st 2017 via the Yale University Library's search engine including but not limited to Pub Med and Ovis SP. The level of efficacy was defined according to the assessment's criteria set forth by the Subcommittee on Guideline Development of the American Academy of Neurology. Significant efficacy was found for two indications based on the available blinded studies (class I and II) and has been suggested for several others through open label clinical trials. Summary There is level A evidence (effective- two or more class I) that injection of BoNT-A into the bladder's detrusor muscle improves MS related neurogenic detrusor overactivity (NDO) and MS-related overactive (OA) bladder. There is level B evidence (probably effective- two class II studies) for utility of intramuscular BoNT-A injections for spasticity of multiple sclerosis. Emerging data based on retrospective class IV studies demonstrates that intramuscular injection of BoNTs may help other symptoms of MS such as focal tonic spasms, focal myokymia, spastic dysphagia, and double vision in internuclear ophthalmoplegia. There is no data on MS-related trigeminal neuralgia and sialorrhea, two conditions which have been shown to respond to BoNT therapy in non-MS population. PMID- 28819803 TI - If at first you don't succeed ... adoption of iPad marking for high-stakes assessments. AB - Large-scale interview and simulation-based assessments such as objective structured clinical examinations (OSCEs) and multiple mini interviews (MMIs) are logistically complex to administer, generate large volumes of assessment data, and are strong candidates for the adoption of computer-based marking systems. Adoption of new technologies can be challenging, and technical failures, which are relatively commonplace, can delay and/or create resistance to ongoing implementation.This paper reports on the adoption process of an electronic marking system for OSCEs and MMIs following an unsuccessful initial trial. It describes how, after the initial setback, a staged implementation, progressing from small to larger-scale assessments, single to multiple assessment types, and lower to higher stakes assessments, was used to successfully adopt and embed iPad based marking within our medical school.Critical factors in the success of this approach included thorough appraisal and selection of technologies, rigorous assurance of system reliability and security, constant review and refinement, and careful attention to implementation and end-user training. Engagement of stakeholders is also crucial, especially in the case of previous failures or setbacks. The early identification and recruitment of staff to provide specific expertise and support for adoption of an innovation helps to facilitate this process with four key roles proposed; those of innovation advocate, champion, expert and sponsor. PMID- 28819802 TI - Significance of human chorionic gonadotropin as a predictor of resistance to standard chemo-radiotherapy for pure germinoma. AB - Intracranial pure germinomas in children generally respond well to standard chemo radiotherapy. However, some patients are refractory to standard therapy and require additional treatment. To investigate the characteristics of this subgroup, we retrospectively analyzed the clinical features and treatment outcomes of a cohort of 21 patients with intracranial pure germinomas who were diagnosed between April 2002 and December 2016 at Ehime University Hospital in Japan. Pure germinoma diagnosis was verified by histological examination of the tumor after surgery, and all patients received standard chemo-radiotherapy. A suite of clinical features, including neuroimaging, human chorionic gonadotropin beta subunit (HCG-beta), and alpha-fetoprotein (AFP) in the cerebrospinal fluid (CSF), as well as immunohistochemical expression of HCG-beta, AFP, and Ki-67 in the tumor tissue were analyzed. Nineteen of the 21 patients had a complete response to standard chemo-radiotherapy without early recurrence of the tumors. Of these 19 patients, 17 did not have elevated CSF HCG-beta levels or express HCG beta in the tumor tissue. However, the two patients who were refractory to standard therapy had elevated CSF HCG-beta levels and expressed HCG-beta in the tumor cells. These data suggest that patients with pure germinoma presenting with both an elevation of HCG-beta in the CSF and HCG-beta expression in the tumor tissue may be refractory to frontline treatment. These markers may predict aggressive germinoma and may ultimately facilitate the development of more effective treatment options. PMID- 28819805 TI - Diversity and evolution of leaf anatomical characters in Taxaceae s.l. fluorescence microscopy reveals new delimitating characters. AB - Taxaceae s.l. comprise six genera (including Cephalotaxus) and about 35 species; The present study aims to give new insights into the evolution of this family, especially into the phylogenetic position of Cephalotaxus. Moreover, only little is known about comparative leaf anatomy of this family and this study aims to expose and interpret the diversity and evolution of leaf anatomical characters and to assess their applicability to identify taxa at the generic and species level. A detailed phylogeny was reconstructed, using both maximum likelihood and Bayesian inference, with a combined dataset of four molecular markers from the plastid and nuclear genomes. Leaf sections from 132 specimens, representing 32 species and four varieties (fresh and herbarium material) were inspected, using fluorescence microscopy. Ancestral characters were reconstructed using Mesquite. The phylogenetic analyses provided full support for Cephalotaxus as sister group to Taxaceae s.str. Within the latter, two monophyletic tribes Taxeae (comprising Austrotaxus, Pseudotaxus, and Taxus) and Torreyeae (comprising Amentotaxus and Torreya) were fully supported. Fluorescence microscopy was shown to be very useful for identifying leaf tissues and their constitution. We were able to show that particularly sclerified tissues have highest potential for the discrimination of both freshly collected samples and rehydrated herbarium specimens at the generic and species level. A correlation between the presence of different sclereid types could be shown and sclereids were hypothesized to pose a primitive trait in the evolution of Taxaceae s.l. New identification keys were generated on the basis of leaf anatomical characters. The microscopic method presented here is applicable for further studies within gymnosperms and probably in angiosperms, as well. PMID- 28819808 TI - miR398 and miR395 are involved in response to SO2 stress in Arabidopsis thaliana. AB - Sulfur dioxide (SO2) is a common air pollutant that has adverse effects on plants. MicroRNAs (miRNAs) are small noncoding RNA that play critical roles in plant development and stress response. In this study, we found that two miRNAs, miR398 and miR395, were differentially expressed in Arabidopsis shoots under SO2 stress. The expression of miR398 was down-regulated, and the transcript levels of its target genes, Cu/Zn superoxide dismutases (CSD1 and CSD2), were increased during SO2 exposure. The activity of superoxide dismutase (SOD), one of the major antioxidant enzymes, was enhanced with the increase in the CSD transcript level, suggesting an important role of miR398 in response to SO2-induced oxidative stress. Meanwhile, the expression of miR395 was increased, and the transcript levels of its target genes, ATP sulfurylases (APS3 and APS4) and a low-affinity sulfate transporter (SULTR2;1), were decreased in Arabidopsis shoots, showing that miR395 played important roles in the regulation of sulfate assimilation and translocation during SO2 exposure. The content of glutathione (GSH), an important sulfur-containing antioxidant, was enhanced with the changes in sulfur metabolism in Arabidopsis shoots under SO2 stress. These results showed that both miR398 and miR395 were involved in protecting plants from oxidative damage during SO2 exposure. Many stress-responsive cis-elements were found in the promoter regions of MIR398 and MIR395, suggesting that these miRNAs might respond to various environmental conditions, including SO2 stress. Overall, our study provides an insight into the regulatory roles of miRNAs in response to SO2 stress in plants, and highlights the molecular mechanisms of plant adaptation to environmental stress. PMID- 28819809 TI - Effect of synthetic and natural-derived novel endodontic irrigant solutions on mechanical properties of human dentin. AB - This study aimed to evaluate the effects of different synthetic and natural derived root canal irrigants (6% sodium hypochlorite [NaOCl], 6% calcium hypochlorite [Ca(OCl)2] and 6.5% grape seed extract [GSE]) on dentin mechanical properties (flexural strength, ultimate tensile strength [UTS] and fracture resistance). Rectangular-shaped beams and hourglass-shaped sections obtained from mid-coronal and root dentin were treated with 6% NaOCl, 6% Ca(OCl)2 or 6.5% GSE for 30 min. The irrigant solutions were replaced every 5 min. Then, the dentin specimens were rinsed with distilled water (DW) followed by incubation with 17% EDTA for 1 min, and thoroughly rinsed with DW again. Specimens from the control group were tested without prior irrigation. After treatment with the irrigants, dentin beams were used to assess the flexural strength (n = 10) while UTS was evaluated using the root dentin hourglass-shaped sections (n = 10). Similarly, roots with 1 mm of dentinal wall thickness were obtained from human teeth and treated with the same irrigant solutions (n = 10). A compressive loading was applied to the coronal surfaces of roots until fracture. The values of each mechanical test were statistically analyzed individually by one-way ANOVA followed by Tukey HSD test (P < 0.05). NaOCl significantly reduced the mechanical properties of dentin in all mechanical tests (P < 0.05) and no statistical difference was found among Ca(OCl)2, GSE and control group (P > 0.05). It can be concluded that Ca(OCl)2 and GSE may be alternative irrigant solutions, since they do not negatively affect the dentin mechanical properties. PMID- 28819810 TI - Laser-assisted surgery of the upper aero-digestive tract: a clarification of nomenclature. A consensus statement of the European Laryngological Society. AB - Acronyms and abbreviations are frequently used in otorhinolaryngology and other medical specialties. CO2 laser-assisted transoral surgery of the pharynx, the larynx and the upper airway is a family of commonly performed surgical procedures termed transoral laser microsurgery (TLM). The abbreviation TLM can be confusing because of alternative modes of delivery. Classification and definition of the different types of procedures, performed transorally or transnasally, are proposed by the Working Committee for Nomenclature of the European Laryngological Society, emphasizing the type of laser used and the way this laser is transmitted. What is usually called TLM, would more clearly be defined as CO2 laser transoral microsurgery or CO2 TOLMS or CO2 laser transoral surgery only (with a handpiece) would be defined as CO2 TOLS. KTP transnasal flexible laser surgery would be KTP TNFLS. Transoral use of the flexible CO2 wave-guide with a handpiece would be a CO2 TOFLS. One can argue that these clarifications are not necessary and that the abbreviation TLM for transoral laser microsurgery is more than sufficient. But this is not the case. Laser surgery, office-based laser surgery and microsurgery are frequently and erroneously interchanged for one another. These classifications allow for a clear understanding of what was performed and what the results meant. PMID- 28819811 TI - Circulating extracellular vesicles in the aging process: impact of aerobic exercise. AB - Our aim was to investigate transitory and delayed exercise effects on serum extracellular vesicles (EVs) in aging process. Male Wistar rats of 3-, 21-, and 26-month old were allocated into exercised and sedentary groups. The exercise protocol consisted in a daily moderate treadmill exercise (20 min daily during 2 weeks). Trunk blood was collected 1 and 18 h after the last exercise session, and circulating EVs were obtained. CD63 levels and acetylcholinesterase (AChE) activity were used as markers of exosome, a subtype of EVs. In addition, the quantification of amyloid-beta (Abeta) levels and the oxidative status parameters, specifically reactive species content, superoxide dismutase (SOD) activity, and SOD1 content were evaluated. Aged rats showed reduced CD63 levels and increased AChE activity in circulating exosomes compared to young ones. Moreover, higher reactive species levels were found in circulating EVs of aged rats. Delayed exercise effects were observed on peripheral EVs, since CD63, reactive species content, and AChE activity were altered 18 h after the last exercise session. Our results suggest that the healthy aging process can modify circulating EVs profile, and exercise-induced beneficial effects may be related to its modulation on EVs. PMID- 28819813 TI - [Teriparatide as a therapy approach in sacral insufficiency fractures]. AB - As a result of immense heterogeneity with regard to morphology and stability, the recent literature lacks consensus concerning the treatment of sacral insufficiency fractures. We report the case of a 79-year-old woman with bilateral sacral insufficiency fractures following anterior pelvic ring fractures who was treated with teriparatide. During a two-week hospital stay, the patient was successfully mobilised and the regularly conducted pelvic X-ray controls showed full consolidation of the fractures. PMID- 28819812 TI - Involvement of superoxide generated by NADPH oxidase in the shedding of procoagulant vesicles from human monocytic cells exposed to bupivacaine. AB - It is known that a variety of sized procoagulant vesicles that express tissue factor are released from several types of cells including monocytes by mechanisms related to the induction of apoptosis, while it has not yet been evaluated whether superoxide is involved in the production of such vesicles. Here, we report that a local anesthetic bupivacaine induces apoptosis in human monocytic cells THP-1 within a short observation period, where the shedding of procoagulant vesicles is associated. The property as procoagulant vesicles was evaluated using flow cytometry by the binding of FITC-conjugated fibrinogen to vesicles in the presence of fresh frozen plasma and the suppression of this binding by heparin. Bupivacaine (1 mg/ml) increased the apoptotic cells and procoagulant vesicles. LY294002 (100 uM), that inhibits the recruiting of intracellular component of NADPH oxidase to construct the activated form of this enzyme complex, or superoxide dismutase (1500 unit/ml) suppressed bupivacaine-provoked induction of apoptosis and the increase of procoagulant vesicles. We suggest that this simple experimental system is useful to explore the molecular mechanisms of action of superoxide in the shedding of procoagulant vesicles from human monocytic cells. PMID- 28819814 TI - Cognitive Behavioral Therapy for IBS: How Useful, How Often, and How Does It Work? AB - PURPOSE OF REVIEW: While dietary and medical treatments are beneficial for specific GI symptoms for some IBS patients, they have an unsatisfactory track record for the full range of GI symptoms for more severe patients. A number of psychological interventions have been developed over the past two decades to help patients' self-manage symptoms. This review discusses the last 5 years of research on psychological treatments, with a focus on cognitive behavioral therapy (CBT) and hypnosis. RECENT FINDINGS: Recent systematic reviews indicate that psychological interventions are efficacious and their gains are maintained long-term. Treatment gains are not a function of the number of sessions. Psychological interventions are at least moderately efficacious treatments for IBS symptoms. Of different psychotherapies, CBT and hypnosis appear efficacious in minimal-contact formats (e.g., fewer sessions, phone contact). Research is still needed to identify theoretically relevant active ingredients that underlie treatment effects. PMID- 28819815 TI - [Pediatric finger and hand injuries : An epidemiological study]. AB - BACKGROUND: The hand is the second most frequently injured region of the body in children. The aim of this study was to evaluate age-related injury patterns, trauma mechanisms, as well as the need for surgery in pediatric patients with injuries to the hand. PATIENTS AND METHODS: This was a retrospective study analyzing the data between January 2008 and December 2014 at Frankfurt University Hospital. All patients were younger than 18 years old. All patients suffering trauma to the hand or the fingers were included. The injury mechanism, injury pattern as well as need for surgery were analyzed according to different age groups (0-3 years, 4-7 years, 8-12 years and 13-17 years). Major injuries were defined as fractures, dislocations, amputations and injuries of the tendons or nerves. Minor injuries included contusions and superficial wounds. RESULTS: Overall, 2823 emergency pediatric patients with an injury to the hand or fingers were included (61.5% male, median age 10.3 years). Of the injuries 60.4% were located on the fingers and 39.6% on the hand. Major injuries were found in 703 patients (24.9%) and minor injuries in 2120 patients (75.1%). Of those patients with a major injury, 74.8% suffered a fracture, 9.4% an injury of nerves and tendons and 7.0% an amputation. The most common trauma mechanism for major injuries was sports (24.2%), followed by crushing (17.9%) and falls (14.7%). Overall, 436 patients (15.5%) were surgically treated of which 9.4% were operated on in the operation room and 6.1% in the emergency room. CONCLUSION: Almost 75% of all children who presented to the emergency department following trauma to the fingers or the hand revealed minor injuries; however, 25% suffered a relevant, major injury. Overall, 15.5% had to be surgically treated. The most frequently found major injuries were fractures of the hand and the fingers. PMID- 28819817 TI - Estimation of entrance surface air kerma due to diagnostic X-ray examinations of adult patients in Uttarakhand, India and establishment of local diagnostic reference levels. AB - It is well established that diagnostic X-ray practices must be optimised to keep patient radiation dose as low as compatible with providing the diagnostic information required. For effective optimisation of diagnostic exposures, the International Commission on Radiological Protection (ICRP) introduced the concept of diagnostic reference levels (DRLs) in 1996. The present study aimed to carry out an extensive dose survey of diagnostic radiography installations in the Uttarakhand region of India to establish local DRL Values for the different diagnostic practices. During the survey, air kerma values were measured for 297 diagnostic X-ray machines installed at 270 medical centres in the region and the entrance surface air kerma (K a,e) was estimated for ten commonly performed radiographic projections. These included chest posterior-anterior (PA), cervical spine anterior-posterior (AP), skull PA, abdomen AP, KUB (kidney, ureter and bladder), lumbar spine AP, lumbar spine lateral (LAT), pelvis AP, thoracic spine AP, and thoracic spine LAT. Wide variations were observed in the estimated values of K a,e for individual projections. The third quartile of the distribution of the median values of the estimated K a,e for a given projection was calculated to establish local DRL Values. The majority of the acquired dose data were found to be comparable to or less than the proposed national and international DRLs. The local DRL Values reported in this study may be used to improve radiological practice by reducing patient doses during radiography examinations. The obtained data may also contribute to a national patient dose database for establishing future national DRLs. PMID- 28819816 TI - A new non-radioactive deoxyhypusine synthase assay adaptable to high throughput screening. AB - Deoxyhypusine synthase (DHS) catalyzes the post-translational modification of eukaryotic translation factor 5A (eIF5A) by the polyamine, spermidine, that converts one specific lysine residue to deoxyhypusine [N epsilon -4 aminobutyl(lysine)], which is subsequently hydroxylated to hypusine [N epsilon -4 amino-2-hydroxybutyl(lysine)]. Hypusine synthesis represents the most critical function of polyamine. As eIF5A has been implicated in various human diseases, identification of specific inhibitors of hypusine modification is of vital importance. DHS catalyzes a complex reaction that occurs in two stages, first, the NAD-dependent cleavage of spermidine to form an enzyme-butylimine intermediate and enzyme-bound NADH, and second, the transfer of the butylimine moiety from the enzyme intermediate to the eIF5A precursor and subsequent reduction of the eIF5A-butylimine intermediate by enzyme-bound NADH to form deoxyhypusine [N epsilon -4-aminobutyl(lysine)]. Our data demonstrate that there is a measurable release of enzyme-bound NADH in the absence of eIF5A precursor and that the DHS activity can be determined by coupling the first phase reaction with the NADH-Glo assay in which the generation of luminescence is dependent on NADH derived from the DHS partial reaction. The conventional DHS assay that measures the incorporation of radioactivity from [1,8-3H]spermidine into the eIF5A precursor in the complete reaction cannot be readily adapted for high throughput screening (HTS). In contrast, the non-radioactive DHS/NADH-Glo coupled assay is highly specific, sensitive and reproducible and could be configured for HTS of small molecule libraries for the identification of new inhibitors of DHS. Furthermore, the coupled assay provides new insights into the dynamics of the DHS reaction especially regarding the fate of NADH. PMID- 28819818 TI - Diosmin Prevents Isoproterenol-Induced Heart Mitochondrial Oxidative Stress in Rats. AB - Cardiac mitochondrial oxidative stress causes mitochondrial damage that plays an important role in the pathology of myocardial infarction. The preventive effects of diosmin on cardiac mitochondrial oxidative stress in isoproterenol-induced myocardial infarcted rats were evaluated. Rats were pretreated with diosmin (10 mg/kg body weight) daily for 10 days. Myocardial infarction was induced in rats by isoproterenol (100 mg/kg body weight) injection twice at an interval of 24 h (on 11th and 12th day). Isoproterenol-induced myocardial infarcted rats showed a significant increase in the levels of cardiac diagnostic markers, heart mitochondrial lipid peroxidation, calcium ion, and a significant decrease in the levels of heart mitochondrial glutathione peroxidase, reduced glutathione, glutathione-S-transferase, isocitrate, malate, alpha-ketoglutarate, and succinate dehydrogenases. Transmission electron microscopic findings revealed damaged mitochondria with loss of cristae, swelling, and vacuolation in isoproterenol induced rats' heart. Diosmin pretreatment showed significant preventive effects on all the biochemical parameters, and the structure of mitochondria was evaluated. Furthermore, the transmission electron microscopic study confirms the biochemical findings. The antioxidant and negative inotropic effects of diosmin inhibited cardiac mitochondrial oxidative stress and prevented mitochondrial damage in myocardial infarcted rats. PMID- 28819819 TI - Evaluation of the Leaching Potential of Anthranilamide Insecticides Through the Soil. AB - The mobility of two relatively new antranilic diamide insecticides, cyanantraniliprole (CY) and cholantraniliprole (CH) in soil was examined, by means of disturbed columns loaded with a typical semiarid Mediterranean soil (Calcaric fluvisol) under laboratory conditions. Both insecticides appeared in leachates, with 52% of CY and 41% of CH of the initial mass added (1 ug g-1) present. For CY, 21% and 19% were recovered from the upper and bottom layers of the soil, respectively, while for CH, 33% and 22% were recovered from the upper and bottom layers respectively. Based on the calculated half-lives (29 and 27 days for CY and CH, respectively) and their log K OC (about 2.5 for both), the calculated Groundwater Ubiquity Score (GUS) index was higher than 5 for both, indicating they have the potential to leach. Two transformation products, C13H9Cl2N2O (IN-ECD73) and C19H12BrClN6O (IN-J9Z38) corresponding to the degradation of CH and CY, respectively were also identified and detected in leachates and soil. PMID- 28819820 TI - Genome-wide characterization of the WRKY gene family in radish (Raphanus sativus L.) reveals its critical functions under different abiotic stresses. AB - KEY MESSAGE: The radish WRKY gene family was genome-widely identified and played critical roles in response to multiple abiotic stresses. The WRKY is among the largest transcription factors (TFs) associated with multiple biological activities for plant survival, including control response mechanisms against abiotic stresses such as heat, salinity, and heavy metals. Radish is an important root vegetable crop and therefore characterization and expression pattern investigation of WRKY transcription factors in radish is imperative. In the present study, 126 putative WRKY genes were retrieved from radish genome database. Protein sequence and annotation scrutiny confirmed that RsWRKY proteins possessed highly conserved domains and zinc finger motif. Based on phylogenetic analysis results, RsWRKYs candidate genes were divided into three groups (Group I, II and III) with the number 31, 74, and 20, respectively. Additionally, gene structure analysis revealed that intron-exon patterns of the WRKY genes are highly conserved in radish. Linkage map analysis indicated that RsWRKY genes were distributed with varying densities over nine linkage groups. Further, RT-qPCR analysis illustrated the significant variation of 36 RsWRKY genes under one or more abiotic stress treatments, implicating that they might be stress-responsive genes. In total, 126 WRKY TFs were identified from the R. sativus genome wherein, 35 of them showed abiotic stress-induced expression patterns. These results provide a genome-wide characterization of RsWRKY TFs and baseline for further functional dissection and molecular evolution investigation, specifically for improving abiotic stress resistances with an ultimate goal of increasing yield and quality of radish. PMID- 28819821 TI - Anti-PD-1 Antibodies as a Therapeutic Strategy in Classical Hodgkin Lymphoma. AB - Classical Hodgkin lymphoma (cHL) is defined by malignant Reed-Sternberg (RS) cells that recruit non-malignant immune cells into a supportive tumour microenvironment. In cHL, this is driven, in part, by genomic alterations of the 9p24.1 locus encoding the immune checkpoint ligands PD-L1 and PD-L2. Therapeutic anti-PD-1 antibodies have been developed that competitively inhibit the interaction between PD-1 and its ligands. Clinical trials of anti-PD-1 antibodies in cHL demonstrate high overall response rates but relapses still occur and new clinical challenges exist for toxicity management and response assessment. This review discusses the biological and clinical features of anti-PD-1 antibody therapy in cHL. PMID- 28819822 TI - Endovascular Aneurysm Repair with Balloon Thrombectomy for Acute Thrombosis of Abdominal Aortic Aneurysm. AB - Acute occlusion of abdominal aortic aneurysm (AAA) is a rare complication and is usually treated with surgical reconstruction. We present a case of acute AAA occlusion that was successfully treated by endovascular aneurysm repair (EVAR) with Fogarty balloon thrombectomy. A 77-year-old man with a history of acute myocardial ischemia presented with limb weakness and coldness. Contrast-enhanced computed tomography showed a 42-mm-diameter infrarenal AAA that was completely thrombosed in the distal portion. The proximal neck of the aneurysm was patent, and its shape was suitable for EVAR. Therefore, we performed balloon thrombectomy of the aortoiliac thrombus that was followed by EVAR. EVAR can be a less invasive alternative than traditional treatment for acute occlusion of AAA. PMID- 28819823 TI - Inner nuclear layer cystoid spaces are a poor prognostic factor in typical age related macular degeneration and polypoidal choroidal vasculopathy. AB - PURPOSE: To investigate predictive factors for changes in best-corrected visual acuity (BCVA) at 24 months after intravitreal ranibizumab (IVR) for neovascular age-related macular degeneration (nAMD). METHODS: This retrospective study included 55 eyes of 55 consecutive patients (32 men and 23 women) with nAMD who received three consecutive monthly IVR injections and were re-treated as needed over a 24-month period. We used the mean changes in logarithm of the minimal angle of resolution (logMAR) BCVA at 24 months as the dependent variable in regression analysis. RESULTS: The presence of intraretinal cystoid spaces in the inner nuclear layer (INLc, P = 0.004) and baseline subfoveal choroidal thickness (SFCT, P = 0.013) predicted BCVA changes from baseline to 24 months. The presence of INLc and thinning of SFCT were associated with decreased BCVA at 24 months. Thirty-five eyes without INLc showed improved logMAR BCVA, from 0.550 +/- 0.273 to 0.368 +/- 0.274 (P = 0.045); however, 20 eyes with INLc showed decreased logMAR BCVA, from 0.708 +/- 0.347 to 0.971 +/- 0.523 (P < 0.001) through the 24 month follow-up. The mean number of IVR injections during the follow-up period was 8.74 +/- 4.76 in eyes without INLc and 10.63 +/- 4.72 in eyes with INLc, without a statistically significant difference (P = 0.144). CONCLUSION: Eyes with INLc or thinned SFCT showed worse visual outcomes compared with eyes without the INLc or with thick SFCT. Furthermore, eyes without INLc showed improved BCVA; however, eyes with INLc showed decreased BCVA with an as-needed regimen. PMID- 28819824 TI - [Update pulmonary arterial hypertension : Definitions, diagnosis, therapy]. AB - The term pulmonary arterial hypertension comprises a group of pulmonary vascular diseases of different etiologies that are characterized by similar precapillary vascular remodeling processes and result in exertional dyspnea and right heart insufficiency. The specific pharmacological treatment approach considers the risk of mortality and phenotypical properties and includes treatment with phosphodiesterase type 5 inhibitors, endothelin receptor antagonists and prostanoids, as well as with more novel substances, such as a soluble guanylyl cyclase stimulator and an oral prostacyclin receptor agonist. The prognosis of the disease is mainly determined by the right heart insufficiency for which there is currently no specific pharmacological treatment. Lung transplantation may be offered as a last option. This review provides an overview of the current European guidelines from 2015 and the recommendations of the Cologne Consensus Conference for pulmonary hypertension from 2016. PMID- 28819825 TI - CEUS LI-RADS: algorithm, implementation, and key differences from CT/MRI. AB - Contrast-enhanced ultrasound (CEUS) is a specialized form of ultrasound (US) performed with an intravenous injection of microbubble contrast agents. It has been successfully used for a variety of applications including characterization of liver tumors. In April 2014, the American College of Radiology (ACR) convened a working group of international experts to develop ACR CEUS Liver Imaging Reporting and Data System (CEUS LI-RADS). An initial version of CEUS LI-RADS was published in August 2016. Although the CEUS LI-RADS concept and principles for liver lesion characterization, using dynamic contrast enhancement features, are similar to those for CT or MRI, there are significant differences between CT/MRI and CEUS LI-RADS. Therefore, CEUS LI-RADS has different diagnostic features and a unique characterization algorithm. The size of a lesion, the type and degree of arterial phase enhancement, the presence of washout, and the timing and degree of washout are the major features used for categorization. This paper describes key differences between CT/MRI and CEUS, and provides a diagnostic algorithm of CEUS LI-RADS with detailed, step-by-step instructions and imaging examples of CEUS LI RADS categories. PMID- 28819826 TI - The outcome of the partial resurfacing arthroplasty of the hip shows high numbers of failures and conversion to total arthroplasty. AB - PURPOSE: Local cartilage and bony defects, which are too large for joint preserving cartilage treatment are difficult to treat. The implantation of a mini resurfacing implant (Hemicap(r), 2med, Hamburg, Germany) may be a possible alternative treatment for these patients. This partial replacement fills the defect and restores a smooth and continuous articular surface. The aim of this study was to determine short- to midterm results of the treatment of local cartilage defects of the femoral head using the Hemicap(r). METHODS: Since 04/2011 16 patients with osteonecrosis of the femoral head greater ARCO stage II or local femoral cartilage lesions (< 35 mm) were treated with the implantation of the Hemicap(r) implant. A clinical and radiological follow-up was conducted. RESULTS: The clinical results showed a significant improvement of the function and pain of the hip according to the Harris Hip Score from 56 (+/-14) preoperative to 77 (+/-15) post-operative 25 months after implantation of the Hemicap(r). In the meantime, in four patients the Hemicap(r) had to be converted to a total hip arthroplasty due to loosening, progredience of the osteonecrosis or degeneration of the acetabulum. CONCLUSIONS: The implantation of the mini resurfacing implant Hemicap(r) seemed to be an alternative treatment for local cartilage defects of the femoral head to postpone the implantation of a total hip arthroplasty. However, the clinical outcome seems to be inferior to total hip arthroplasty. Furthermore, due to a high rate of conversion to total hip arthroplasty (25%) the application of this implant is questionable. If the implant is considered as a treatment option at least patient selection and enlightenment for this treatment with the high risk of failure and progression of osteoarthritis is very important. PMID- 28819828 TI - [Patio repair for urethrocutaneous fistulae : Results of a multicentre retrospective study]. AB - BACKGROUND: Urethrocutaneous (UC) fistulae are common complications after hypospadias surgery and they have been a serious problem for surgeons since the repair was first attempted. We present the results of our multicentre retrospective study for repairing UC fistulae using the Patio ("preserve the tract and turn it inside out") repair described by Malone. MATERIALS AND METHODS: A total of 16 boys (Eschweiler 2, Lingen 4, Reading 10) at the ages of 1-10 years were treated for UC fistulae. Instead of excising the fistula tract, it is preserved and turned inside out, this creates a flap valve inside the urethral lumen. After a circumferential incision around the skin and meticulous dissection of the fistula tract, a 2/0 nylon suture is passed down the tract and brought out through the external urinary meatus. As a result, the fistula tract is inserted into the urethral lumen. In order to keep the fistula tract inverted, it is sutured to the tip of the external urinary meatus, or fixed by an angler lead (modification from Lingen). Due to the narrow base, the excess tissue atrophies postoperatively and leads to an appealing cosmetic result. RESULTS: A total of 9 fistula repairs were performed on an outpatient basis without using a transurethral catheter; 7 boys were treated on an inpatient basis with an average length of stay in the hospital for 1-2 days with/without catheterization. During a mean follow-up of up to 4.5 years, only one fistula recurrence occurred; no other complications were observed. CONCLUSION: The Patio repair for urethrocutaneous fistula is an outpatient, simply reproducible surgical technique without the necessity of transurethral catheterization. The short-term results are impressive; long-term results of a larger patient cohort will follow. PMID- 28819827 TI - Interaction between SELP genetic polymorphisms with inflammatory cytokine interleukin-6 (IL-6) gene variants on cardiovascular disease in Chinese Han population. AB - The aim of the study is to investigate the impact of SELP and IL-6 genetic single nucleotide polymorphisms (SNPs) and its gene-gene interaction on cardiovascular disease (CVD) risk based on Chinese population. A total of 1082 subjects (519 males, 563 females), with a mean age of 53.9 +/- 13.1 years, were selected, including 540 CVD patients and 542 normal control participants. Logistic regression model was used to examine the association between six SNPs and CVD risk. Odds ratio (OR) and 95% confident interval (95% CI) were calculated. Generalized multifactor dimensionality reduction (GMDR) was employed to analyze the gene-gene interaction. CVD risk was significantly higher in carriers with rs1800805-A allele than those with GG genotype (GA + AA vs. GG), adjusted OR (95% CI) = 1.69 (1.31-2.16), and CVD risk was also higher in carriers with rs6136-AC or CC genotype than those with AA genotype (AC + CC vs. AA), adjusted OR (95% CI) = 1.78 (1.28-2.26), and higher in carriers with rs1800796-GC or CC genotype than those with GG genotype (CC + GC vs. GG), adjusted OR (95% CI) = 1.67 (1.25-2.14). GMDR analysis suggested a significant two-locus model (p = 0.0010) involving rs1800805 and rs1800796. Overall, the cross-validation consistency of this model was 10/10, and the testing accuracy was 62.17%, and participants with rs1800805 GA or AA and rs1800796-GC or CC genotype have the highest CVD risk, compared to participants with rs1800805-GG and rs1800796-GG genotypes, and OR (95% CI) was 2.52 (1.81-2.66). Our results support an important association of rs1800805, rs6136 minor allele of SELP gene, rs1800796 within IL-6 gene, and additional interaction between rs1800805 and rs1800796 with increased risk of CVD. PMID- 28819829 TI - Surgical treatment for symptomatic non-ossifying fibromas of the lower extremity with calcium sulfate grafts in skeletally immature patients. AB - BACKGROUND: Non-ossifying fibromas (NOFs) are common benign bone lesions found in children and adolescents. They usually involve metaphysis of long bones, tend to gradually disappear with age and usually do not require surgery, while they are not associated with pathological fractures. The aim of this study was to evaluate the outcome and efficacy of a single-stage procedure, comprising curettage of the lesion and calcium sulfate pellet (CaSP) grafting, in skeletally immature patients with large, symptomatic NOF of the lower extremity, and the possible limitations of the procedure. METHODS: Nine skeletally immature patients with symptomatic NOF of the lower extremity were treated between 2013 and 2016. Details of age, history of presentation, location and size (in mm) of the lesion, histology and follow-up details were recorded. Lesions were classified in Ritschl radio-morphological stages. CaSP integration was assessed by Irwing's classification. The average size of lesions was 54.6 mm in length (range 31-95). All lesions were symptomatic. The average bone expansion in relation to the bone diameter was 67.4% in the transversal plane (range 31-100) and 77.8% in the sagittal plane (range 55-100). Mean patient age at time of treatment was 9.8 years (range 7-14); mean follow-up was 2 years (range 2-4). All the patients were symptomatic, and 8 out of 9 (89%) NOFs were Ritschl type B. All the patients were treated surgically with a single-step approach, as described. RESULTS: On average, 86 mL of CaSPs was used per case (range 10-250). None of the patients required internal fixation. At last follow-up visit, CaSPs were fully incorporated in all the patients according to Irwing's classification (Stage 3). No serous drainage from wounds was recorded in any of the patients. No cases of pathological fracture, bone deformity, growth arrest or growth disturbance or infection were observed. At last follow-up visit, all the patients had resumed full sport and daily life activities. CONCLUSIONS: CaSPs offer a safe, cheap, convenient alternative to the autograft as an implant substitute that helps regeneration of bone in the defects produced by curettage of large, symptomatic NOFs. Chemical cauterization of bone walls does not interfere with CaSP integration into bone tissue. PMID- 28819830 TI - Identification and characterization of tyrosine kinases in anole lizard indicate the conserved tyrosine kinase repertoire in vertebrates. AB - The tyrosine kinases (TKs) play principal roles in regulation of multicellular aspects of the organism and are implicated in many cancer types and congenital disorders. The anole lizard has recently been introduced as a model organism for laboratory-based studies of organismal function and field studies of ecology and evolution. However, the TK family of anole lizard has not been systematically identified and characterized yet. In this study, we identified 82 TK-encoding genes in the anole lizard genome and classified them into 28 subfamilies through phylogenetic analysis, with no member from ROS and STYK1 subfamilies identified. Although TK domain sequences and domain organization in each subfamily were conserved, the total number of TKs in different species was much variable. In addition, extensive evolutionary analysis in metazoans indicated that TK repertoire in vertebrates tends to be remarkably stable. Phylogenetic analysis of Eph subfamily indicated that the divergence of EphA and EphB occurred prior to the whole genome duplication (WGD) but after the split of Urochordates and vertebrates. Moreover, the expression pattern analysis of lizard TK genes among 9 different tissues showed that 14 TK genes exhibited tissue-specific expression and 6 TK genes were widely expressed. Comparative analysis of TK expression suggested that the tissue specifically expressed genes showed different expression pattern but the widely expressed genes showed similar pattern between anole lizard and human. These results may provide insights into the evolutionary diversification of animal TK genes and would aid future studies on TK protein regulation of key growth and developmental processes. PMID- 28819831 TI - Biodiversity variability and metal accumulation strategies in plants spontaneously inhibiting fly ash lagoon, India. AB - Out of 29 plant species taken into consideration for biodiversity investigations, the present study screened out Cyperus rotundus L., Calotropis procera (Aiton) W.T. Aiton, Croton bonplandianus Baill., Eclipta prostrata (L.) L., and Vernonia cinerea (L.) Less. as the most suitable metal-tolerant plant species (high relative density and frequency) which can grow on metal-laden fly ash (FA) lagoon. Total (aqua-regia), residual (HNO3) and plant available (CaCl2) metal concentrations were assessed for the clean-up of metal-contaminated FA disposal site using naturally colonized plants. The total metal concentration (in mg kg-1) in FA followed an order of Mn (229.8) > Ni (228.4) > Zn (89.4) > Cr (61.2) > Pb (56.6) > Cu (51.5) > Co (41.9) > Cd (9.7). The HNO3- and CaCl2-extracted metals were 0.57-15.68% and 0.03-7.82% of the total metal concentration, respectively. The concentration of Ni and Cr in FA in the present study was highest among the previously studied Indian and average world power plants and Cd, Ni, and Cr were above soil toxicity limit. The variation in total, residual, and plant-available metal (single extraction) concentration indicated the presence of different proportions of metals in FA lagoon which affects the metal uptake potential of the vegetation growing on it. It has been reported that plant-available metal extractant (CaCl2) is the most suitable extractant for assessment of metal transfer from soil to plant. However in the present study, Spearman's correlation showed best significant correlation between total metal concentration in FA and shoot metal concentration (r = 0.840; p < 0.01) which suggest aqua-regia as the best extractant for understanding the bioavailability and transfer of metal, and in calculation of BCF for moderately contaminated site. It can be stated that plant-available extractant is not always suitable for understanding the availability of metal, but total metal concentration can provide a better insight especially for moderate or low metal-contaminated sites. Principle component analysis revealed that all the plants showed positive correlation with Co and Cd which suggest its subsequent uptake in root and shoot. The biological indices (BCF, BAF, and TF) revealed that E. prostrata (10 mg Cd kg-1) and C. procera (3.5 mg Cd kg-1) can be utilized efficiently for the phytoextraction of Cd and phytostabilization of other potentially toxic metals (Pb, Cr, and Co) from FA lagoon. All the plants were tolerant to Pb pollution (TF > 1, BAF > 1, and BCF > 1); hence, there was a negligible translocation of Pb to the aerial tissues of these plants which shows their suitability in phytostabilization. In addition, V. cinerea accumulated elevated concentration of potentially toxic Cr (50 mg Cr kg 1) and Ni (67 mg Ni kg-1) which could also help in the phytoremediation of FA lagoon. PMID- 28819832 TI - Protective role of humic acids against picloram-induced genomic instability and DNA methylation in Phaseolus vulgaris. AB - Picloram (4-amino-3,5,6-trichloropicolinic acid) is a liquid auxinic herbicide used to control broad-leaved weeds. Picloram is representing a possible hazard to ecosystems and human health. Therefore, in this study, DNA methylation changes and DNA damage levels in Phaseolus vulgaris exposed to picloram, as well as whether humic acid (HA) has preventive effects on these changes were investigated. Random amplified polymorphic DNA (RAPD) techniques were used for identification of DNA damage and coupled restriction enzyme digestion-random amplification (CRED-RA) techniques were used to detect the changed pattern of DNA methylation. According to the obtained results, picloram (5, 10, 20, and 40 mg/l) caused DNA damage profile changes (RAPDs) increasing, DNA hypomethylation and genomic template stability (GTS) decreasing. On the other hand, different concentrations of applied HA (2, 4, 6, 8, and 10%) reduced hazardous effects of picloram. The results of the experiment have explicitly indicated that HAs could be an alternative for reducing genetic damage in plants. In addition to the alleviate effects of humic acid on genetic damage, its epigenetic effect is hypomethylation. PMID- 28819833 TI - [Lymphocytic myocarditis in a patient with metastatic clear cell renal cell carcinoma treated with Nivolumab]. AB - Immune checkpoint inhibitors against the PD-1 protein offer a new therapy option for many solid cancers. We report a patient with metastatic renal cell cancer treated with Nivolumab. As a rare immune-mediated adverse event, we describe a fatal lymphocytic myocarditis two weeks after starting immune therapy. The cause of death was first diagnosed at autopsy. This case report underlines the importance and need of clinical autopsies as an instrument of quality assurance and detection of rare therapy-induced adverse effects. PMID- 28819834 TI - Recurrence of endovascularly and microsurgically treated intracranial aneurysms review of the putative role of aneurysm wall biology. AB - Although endovascular therapy has been proven safe and has become in many centers the primary method of treatment for intracranial aneurysms, the long-term durability of endovascular embolization remains a concern; at least for some aneurysms despite initial good result. While healing after clipping relies on mechanical occlusion, restoration after endovascular occlusion mainly requires the induction of a biological response. Healing after embolization depends on the growth of new tissue over the thrombus formed by the embolization material, or alternatively, on the organization of thrombus into fibrous tissue. This review highlights the fundamental importance of aneurysm wall biology on the healing process and long-term occlusion after intracranial aneurysm (IA) treatment. It seems likely that the effect of luminal thrombus on the IA wall, as well as the IA wall condition at the time of thrombosis, determine if thrombus organizes into scar tissue (neointima formation by infiltration of cells originating from the IA wall) or if the wall undergoes continuous remodeling, which is primarily destructive (loss of mural cells). In the latter, intraluminal thrombus organization fails and the impaired healing increases the chance of recurrence. Mechanisms underlying IA reopening, the influence of intraluminal thrombosis on the IA wall, and clinical implications of the IA wall condition are discussed in detail, along with how knowledge of IA wall biology can offer new solutions for IA treatment and affect the patient selection for and follow-up after endovascular treatment. PMID- 28819836 TI - Management of contralateral breast following mastectomy and breast reconstruction using a mirror adjustment with crescent mastopexy technique. AB - INTRODUCTION: Heterologous breast reconstruction after mastectomy sometimes requires the management of the contralateral breast to achieve symmetric long lasting aesthetic results. Some techniques could be used for the symmetrization of contralateral breast with or without implants as breast augmentation, reduction mammoplasty, mastopexy, with T inverted, J, vertical, periareolar, semi circular, or axillary scars. The aim of this study is to present the use of crescent mastopexy technique with implants in contralateral adjustment following monolateral breast reconstruction compared with a control group in which patients underwent other contralateral procedures. We used BREAST-Q to evaluate breast perception and patient's satisfaction and surgeon-rated aesthetic outcomes were measured using the Kroll evaluation (a global and itemized aesthetic tool). MATERIALS AND METHODS: A retrospective study was designed. We enrolled in the study 55 patients who had undergone breast reconstruction with implants and contralateral breast symmetrization procedure at our hospital between 2010 and 2016, and they answered to BREAST-Q postoperative module after almost 1 year from breast reconstruction. The study population consisted of 2 groups of women: patient underwent contralateral adjustment with crescent mastopexy and augmentation and patients underwent other contralateral procedures. Statistical analysis was performed using descriptive and summary statistics to identify a central tendency between the two groups, we applied Fisher's exact test to the results to obtain answers 1 year after the last procedure for the two groups. RESULTS: This cross-sectional study compared two cohorts in which 55 women underwent monolateral mastectomy and breast reconstruction with contralateral adjustment, 15 of these underwent contralateral crescent mastopexy with augmentation, and 40 (control group) underwent contralateral breast adjustment with other mastopexy and augmentation technique (27 patients underwent T inverted mastopexy, 2 J mastopexy, 6 vertical scar mastopexy, 5 periareolar mastopexy). Nineteen patients suffered of co-morbidities (smoking, autoimmune disease, cardiological, neurological, and dismetabolic). All patients answered the postoperative BREAST-Q reconstruction module almost 1 year from last surgical procedure. CONCLUSIONS: In patients with a pseudoptosis or mild ptosis of the contralateral breast, crescent mastopexy could be a valid procedure with minimal scars, better symmetry, and global cosmetic results than other procedures. This is the first study which compares crescent mastopexy with augmentation with other mastopexy procedures. Level III: evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group. LEVEL (III): Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group. PMID- 28819835 TI - Efficacy and Safety of Linagliptin in 2681 Asian Patients Stratified by Age, Obesity, and Renal Function: A Pooled Analysis of Randomized Clinical Trials. AB - INTRODUCTION: Asian patients with type 2 diabetes (T2D) are younger, leaner, and more likely to develop renal dysfunction than White populations. In this multiethnic analysis of data from phase 3 trials, we investigated the efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin in Asians stratified by these subphenotypes. METHODS: Data from randomized, double-blind, placebo-controlled trials evaluating linagliptin (as monotherapy, add-on therapy to metformin +/- sulfonylurea, combined with pioglitazone or added to insulin) were pooled with efficacy data from 11 randomized trials of at least 24 weeks and safety data from 15 trials of various durations. RESULTS: In the efficacy set, 1404 Asian patients received linagliptin [mean (standard deviation) age 54.5 (10.1) years; body mass index (BMI) 26.0 (3.9) kg/m2] and 661 received placebo [age 55.0 (9.7) years; BMI 26.1 (3.9) kg/m2] with the same glycated hemoglobin (HbA1c): 8.2 (0.9)% in both groups. At 24 weeks, the placebo-corrected adjusted mean +/- standard error change from baseline in HbA1c with linagliptin was -0.73 +/- 0.04% (95% confidence interval -0.81, -0.65; P < 0.0001). Reductions in HbA1c were similar upon stratification by age [<65 years, -0.71 +/- 0.05% (-0.80, 0.62; P < 0.0001); >=65 years, -0.81 +/- 0.10% (-1.01, -0.60; P < 0.0001)], BMI (<25 kg/m2, -0.82 +/- 0.06% [-0.94, -0.70; P < 0.0001]; >=25 kg/m2, -0.65 +/- 0.06% [-0.76, -0.54; P < 0.0001]) and estimated glomerular filtration rate [<90 mL/min/1.73 m2, -0.71 +/- 0.06% (-0.82, -0.60; P < 0.0001); >=90 mL/min/1.73 m2, 0.75 +/- 0.06% (-0.87, -0.64; P < 0.0001)]. In the safety set (linagliptin, n = 1842; placebo, n = 839), 52.2% and 54.6% of patients, respectively, experienced adverse events. The rates of drug-related adverse events were 10.9% in the linagliptin group and 10.4% in the placebo group. The respective rates of hypoglycemia were 8.3% and 9.5%, mainly among patients treated with sulfonylurea or insulin. Severe hypoglycemia was rare (<1.0% in either group). CONCLUSION: Linagliptin effectively reduced hyperglycemia in Asian patients with uncontrolled T2D, irrespective of age, BMI, renal function, or ethnic subgroups, and was well tolerated. FUNDING: Boehringer Ingelheim, Eli Lilly and Company, and the Diabetes Alliance. PMID- 28819837 TI - Microfluidic Capture and Multiplex Immunofluorescence of Circulating Tumor Cells to Identify Cancer of Origin. AB - Circulating tumor cells (CTCs) are an important biomarker and their analysis can be considered a form of "liquid biopsy." The purpose of this book chapter is to describe the use of the 4-channel CMx (cells captured in maximum) microfluidic chip, containing special micropatterns coated with an antibody-conjugated supported lipid bilayer (SLB) on its surface, to capture and isolate CTCs from the blood of cancer patients. Captured CTCs are subsequently released by an air foam to an immunofluorescence (IF) staining panel that enables further analysis, including the identification of the primary cancer source of the CTCs. PMID- 28819838 TI - Microfluidic Separation of Circulating Tumor Cells Based on Size and Deformability. AB - Circulating tumor cells (CTCs) have been implicated as the seeds of cancer metastasis and therefore have the potential to provide significant prognostic and diagnostic values. Here, we describe a procedure for separating CTCs from whole blood based on size and deformability using the microfluidic ratchet device. This device leverages the ratcheting motion of single cells created as they are deformed through funnel-shaped constrictions using oscillatory flow in order to divert cells based on differences in size and deformability. Subsequent methods for CTC identification and enumeration using immunofluorescence after separation are also described. PMID- 28819839 TI - A Novel Microfluidic Device for Isolation of Circulating Tumor Cells from Pancreatic Cancer Blood Samples. AB - Enumeration of circulating tumor cells (CTCs) can provide valuable prognostic information to guide cancer treatment as well as help monitor disease progression. Analysis of these rare malignant cells has the potential to further our understanding of cancer metastasis by gaining insights into CTC characteristics and properties. Microfluidics presents a unique platform to isolate and study CTCs. In this chapter, we describe the detailed procedures for the fabrication and use of a microfluidic device to detect CTCs from the blood of pancreatic cancer patients. PMID- 28819840 TI - Microfluidic-Based Enrichment and Retrieval of Circulating Tumor Cells for RT-PCR Analysis. AB - Molecular analysis of circulating tumor cells (CTCs) is hindered by low sensitivity and high level of background leukocytes of currently available CTC enrichment technologies. We have developed a novel device to enrich and retrieve CTCs from blood samples by using a microfluidic chip. The Celsee PREP100 device captures CTCs with high sensitivity and allows the captured CTCs to be retrieved for molecular analysis. It uses the microfluidic chip which has approximately 56,320 capture chambers. Based on differences in cell size and deformability, each chamber ensures that small blood escape while larger CTCs of varying sizes are trapped and isolated in the chambers. In this report, we used the Celsee PREP100 to capture cancer cells spiked into normal donor blood samples. We were able to show that the device can capture as low as 10 cells with high reproducibility. The captured CTCs were retrieved from the microfluidic chip. The cell recovery rate of this back-flow procedure is 100% and the level of remaining background leukocytes is very low (about 300-400 cells). RNA from the retrieved cells are extracted and converted to cDNA, and gene expression analysis of selected cancer markers can be carried out by using RT-PCR assays. The sensitive and easy-to-use Celsee PREP100 system represents a promising technology for capturing and molecular characterization of CTCs. PMID- 28819841 TI - Microscale Laminar Vortices for High-Purity Extraction and Release of Circulating Tumor Cells. AB - Circulating tumor cells (CTCs) are disseminated tumor cells that reflect the tumors of origin and can provide a liquid biopsy that would potentially enable noninvasive tumor profiling, treatment monitoring, and identification of targeted treatments. Accurate and rapid purification of CTCs holds great potential to improve cancer care but the task remains technically challenging. Microfluidic isolation of CTCs within microscale vortices enables high-throughput and size based purification of rare CTCs from bodily fluids. Collected cells are highly pure, viable, and easily accessible, allowing seamless integration with various downstream applications. Here, we describe how to fabricate the High-Throughput Vortex Chip (Vortex-HT) and to process diluted whole blood for CTC collection. Lastly, immunostaining and imaging protocols for CTC classification and corresponding CTC image galleries are reported. PMID- 28819842 TI - Separable Bilayer Microfiltration Device for Label-Free Enrichment of Viable Circulating Tumor Cells. AB - Analysis of rare circulating tumor cells enriched from metastatic cancer patients yields critical information on disease progression, therapy response, and the mechanism of cancer metastasis. Here we describe in detail a label-free enrichment process of circulating tumor cells based on its unique physical properties (size and deformability). Viable circulating tumor cells can be successfully enriched and analyzed, or easily released for further characterization due to the novel separable two-layer design. PMID- 28819843 TI - Microfilter-Based Capture and Release of Viable Circulating Tumor Cells. AB - Microfilters with slot-pore geometry can be used for size-based capture of circulating tumor cells (CTC) from the blood of cancer patients. The slot pore geometry reduces the shear stress that the cells would typically experience during filtration process and allows the cells to remain viable. The microfilter provides a platform capable of high CTC capture efficiency; however, the release of these cells from the filter following capture is nontrivial, possibly due to the strong nonspecific electrostatic adhesion of CTC to the microfilter surface. Techniques such as reverse flow or cell scraping result in recovery of only a small percentage of captured cells. We describe, in detail, a protocol for novel application of thermo-responsive polymer poly(N-iso-propylacrylamide) (PIPAAm) to release viable CTCs from microfilters with slot pores. Following fabrication of the microfilter, a coating of PIPAAm is applied to the surface to exploit its thermoresponsive interfacial properties to release the cells. Typically, cancer patient's blood is filtered at room temperature (below 32 degrees C) when PIPAAm is hydrophilic. Thereafter, the filter is placed in either culture medium or a buffer maintained at 37 degrees C, which renders PIPAAm hydrophobic, allowing subsequent release of the electrostatically bound cells with high efficiency. Using this method, viable CTC captured directly from cancer patients' blood can be subjected to downstream off-chip culture, analyses, and characterization. PMID- 28819844 TI - Fourier Ptychographic Microscopy for Rapid, High-Resolution Imaging of Circulating Tumor Cells Enriched by Microfiltration. AB - Examining the hematogenous compartment for evidence of metastasis has increased significantly within the oncology research community in recent years, due to the development of technologies aimed at the enrichment of circulating tumor cells (CTCs), the subpopulation of primary tumor cells that gain access to the circulatory system and are responsible for colonization at distant sites. In contrast to other technologies, filtration-based CTC enrichment, which exploits differences in size between larger tumor cells and surrounding smaller, non-tumor blood cells, has the potential to improve CTC characterization through isolation of tumor cell populations with greater molecular heterogeneity. However, microscopic analysis of uneven filtration surfaces containing CTCs is laborious, time-consuming, and inconsistent, preventing widespread use of filtration-based enrichment technologies. Here, integrated with a microfiltration-based CTC and rare cell enrichment device we have previously described, we present a protocol for Fourier Ptychographic Microscopy (FPM), a method that, unlike many automated imaging platforms, produces high-speed, high-resolution images that can be digitally refocused, allowing users to observe objects of interest present on multiple focal planes within the same image frame. The development of a cost effective and high-throughput CTC analysis system for filtration-based enrichment technologies could have profound clinical implications for improved CTC detection and analysis. PMID- 28819845 TI - Automated Microfluidic Filtration and Immunocytochemistry Detection System for Capture and Enumeration of Circulating Tumor Cells and Other Rare Cell Populations in Blood. AB - Isolation by size using a filter membrane offers an antigen-independent method for capturing rare cells present in blood of cancer patients. Multiple cell types, including circulating tumor cells (CTCs), captured on the filter membrane can be simultaneously identified via immunocytochemistry (ICC) analysis of specific cellular biomarkers. Here, we describe an automated microfluidic filtration method combined with a liquid handling system for sequential ICC assays to detect and enumerate non-hematologic rare cells in blood. PMID- 28819846 TI - Filter-Adapted Fluorescent In Situ Hybridization (FA-FISH) for Filtration Enriched Circulating Tumor Cells. AB - Circulating tumor cells (CTCs) may represent an easily accessible source of tumor material to assess genetic aberrations such as gene-rearrangements or gene amplifications and screen cancer patients eligible for targeted therapies. As the number of CTCs is a critical parameter to identify such biomarkers, we developed fluorescent in situ hybridization (FISH) for CTCs enriched on filters (filter adapted-FISH, FA-FISH). Here, we describe the FA-FISH protocol, the combination of immunofluorescent staining (DAPI/CD45) and FA-FISH techniques, as well as the semi-automated microscopy method that we developed to improve the feasibility and reliability of FISH analyses in filtration-enriched CTC. PMID- 28819847 TI - Negative Enrichment and Isolation of Circulating Tumor Cells for Whole Genome Amplification. AB - Circulating tumor cells (CTCs) are a rare population of cells found in the peripheral blood of patients with many types of cancer such as breast, prostate, colon, and lung cancers. Higher numbers of these cells in blood are associated with a poorer prognosis of patients. Genomic profiling of CTCs would help characterize markers specific for the identification of these cells in blood, and also define genomic alterations that give these cells a metastatic advantage over other cells in the primary tumor. Here, we describe an immunomagnetic method to enrich CTCs from the blood of patients with breast cancer, followed by single cell laser capture microdissection to isolate single CTCs. Whole genome amplification of isolated CTCs allows for many downstream applications to be performed to aide in their characterization, such as whole genome or exome sequencing, Single Nucleotide Polymorphism (SNP) and copy number analysis, and targeted sequencing or quantitative Polymerase Chain Reaction (qPCR) for genomic analyses. PMID- 28819848 TI - Capture and Genetic Analysis of Circulating Tumor Cells Using a Magnetic Separation Device (Magnetic Sifter). AB - Circulating tumor cells (CTCs) are currently widely studied for their potential application as part of a liquid biopsy. These cells are shed from the primary tumor into the circulation, and are postulated to provide insight into the molecular makeup of the actual tumor in a minimally invasive manner. However, they are extremely rare in blood, with typical concentrations of 1-100 in a milliliter of blood; hence, a need exists for a rapid and high-purity method for isolating CTCs from whole blood. Here, we describe the application of a microfabricated magnetic sifter toward isolation of CTCs from whole blood at volumetric flow rates of 10 mL/h, along with the use of a PDMS-based nanowell system for single-cell gene expression profiling. This method allows rapid isolation of CTCs and subsequent integration with downstream genetic profiling methods for clinical applications such as targeted therapy, therapy monitoring, or further biological studies. PMID- 28819849 TI - RareCyte(r) CTC Analysis Step 1: AccuCyte(r) Sample Preparation for the Comprehensive Recovery of Nucleated Cells from Whole Blood. AB - The RareCyte platform addresses important technology limitations of current circulating tumor cell (CTC) collection methods, and expands CTC interrogation to include advanced phenotypic characterization and single-cell molecular analysis. In this respect, it represents the "next generation" of cell-based liquid biopsy technologies. In order to identify and analyze CTCs, RareCyte has developed an integrated sample preparation, imaging and individual cell retrieval process. The first step in the process, AccuCyte(r), allows the separation, collection, and transfer to a slide the nucleated cell fraction of the blood that contains CTCs. Separation and collection are based on cell density-rather than size or surface molecular expression-and are performed within a closed system, without wash or lysis steps, enabling high CTC recovery. Here, we describe our technique for nucleated cell collection from a blood sample, and the spreading of these nucleated cells onto glass slides permitting immunofluorescent staining, cell identification, and individual cell picking described in subsequent chapters. In addition to collection of rare cells such as CTCs, AccuCyte also collects cells of the circulating immune system onto archivable slides as well as plasma from the same sample. PMID- 28819850 TI - RareCyte(r) CTC Analysis Step 2: Detection of Circulating Tumor Cells by CyteFinder(r) Automated Scanning and Semiautomated Image Analysis. AB - The RareCyte CyteFinder instrument is an automated scanner that allows rapid identification of circulating tumor cells (CTCs) on microscope slides prepared by the AccuCyte process (see Chapter 13 ) and stained by immunofluorescence. Here, we present the workflow for CyteFinder scanning, analysis, and CyteMapper scan review which includes CTC confirmation and report generation. PMID- 28819851 TI - RareCyte(r) CTC Analysis Step 3: Using the CytePicker(r) Module for Individual Cell Retrieval and Subsequent Whole Genome Amplification of Circulating Tumor Cells for Genomic Analysis. AB - The CytePicker module built into the RareCyte CyteFinder instrument allows researchers to easily retrieve individual cells from microscope slides for genomic analyses, including array CGH, targeted sequencing, and next-generation sequencing. Here, we describe the semiautomated retrieval of CTCs from the blood processed by AccuCyte (see Chapter 13) and amplification of genomic DNA so that molecular analysis can be performed. PMID- 28819852 TI - Enumeration, Dielectrophoretic Capture, and Molecular Analysis of Circulating Tumor Cells. AB - The identification of therapeutically targetable mutations in circulating tumor cells (CTCs) from cancer patient blood is increasingly used to personalize patient care. Here, we describe a novel approach for the enumeration, capture, and molecular analysis of CTCs from blood using an FDA-approved CTC enrichment and enumeration platform followed by dielectrophoretic capture and next generation sequencing. PMID- 28819853 TI - Enumeration of Circulating Tumor Cells and Disseminated Tumor Cells in Blood and Bone Marrow by Immunomagnetic Enrichment and Flow Cytometry (IE/FC). AB - Enumerating circulating tumor cells (CTCs) in blood and disseminated tumor cells (DTCs) in bone marrow has shown to be clinically useful, as elevated numbers of these cells predict poor clinical outcomes. Accurate detection and quantification is, however, difficult and technically challenging because CTCs and DTCs are extremely rare. We have developed a novel quantitative detection method for enumeration of CTCs and DTCs. Our approach consists of two steps: (1) EPCAM-based immunomagnetic enrichment followed by (2) flow cytometry (IE/FC). The assay takes approximately 2 h to complete. In addition to tumor cell enumeration, IE/FC offers opportunities for direct isolation of highly pure tumor cells for downstream molecular characterization. PMID- 28819854 TI - Flow Cytometric Detection of Circulating Tumor Cells Using a Candidate Stem Cell Marker, p75 Neurotrophin Receptor (p75NTR). AB - The most widely studied detection for circulating tumor cells (CTCs) in peripheral blood of cancer patients has been based on immunomagnetic enrichment using antibodies against epithelial cell adhesion molecule (EpCAM), which is overexpressed in epithelial cells. A neurotrophin receptor p75 (p75NTR) is expressed in a candidate stem cell fraction in esophageal squamous cell carcinoma (ESCC), which shows significantly higher colony formation, enhanced tumor formation in mice, along with strong expression of epithelial mesenchymal transition-related genes. Here, we describe a method to detect CTCs in ESCC based on the combined expression of EpCAM and p75NTR using flow cytometry, demonstrating the feasibility of expression analysis of multiple cell surface markers in viable cells. PMID- 28819855 TI - Multispectral Imaging Analysis of Circulating Tumor Cells in Negatively Enriched Peripheral Blood Samples. AB - A variety of biomarkers are present on cells in peripheral blood of patients with a variety of disorders, including solid tumor malignancies. While rare, characterization of these cells for specific protein levels with the advanced technology proposed, will lead to future validation studies of blood samples as "liquid biopsies" for the evaluation of disease status and therapeutic response. While circulating tumor cells (CTCs) have been isolated in the blood samples of patients with solid tumors, the exact role of CTCs as clinically useful predictive markers is still debated. Current commercial technology has significant bias in that a positive selection technology is used that preassumes specific cell surface markers (such as EpCAM) are present on CTCs. However, CTCs with low EpCAM expression have been experimentally demonstrated to be more likely to be missed by this method. In contrast, this application uses a previously developed, technology that performs a purely negative enrichment methodology on peripheral blood, yielding highly enriched blood samples that contain CTCs as well as other, undefined cell types. The focus of this contribution is the use of multispectral imaging of epifluorescent, microscopic images of these enriched cells in order to help develop clinically relevant liquid biopsies from peripheral blood samples. PMID- 28819856 TI - Fiber-Optic Array Scanning Technology (FAST) for Detection and Molecular Characterization of Circulating Tumor Cells. AB - Circulating tumor cell (CTC) as an important component in "liquid biopsy" holds crucial clinical relevance in cancer prognosis, treatment efficiency evaluation, prediction and potentially early detection. Here, we present a Fiber-optic Array Scanning Technology (FAST) that enables antigen-agnostic, size-agnostic detection of CTC. By immunofluorescence staining detection of a combination of a panel of markers, FAST technology can be applied to detect rare CTC in non-small cell lung cancer (NSCLC) setting with high sensitivity and specificity. In combination with Automated Digital Microscopy (ADM) platform, companion markers on CTC such as Vimentin and Programmed death-ligand 1 (PD-L1) can also be analyzed to further characterize these CTCs. FAST data output is also compatible with downstream single cell picking platforms. Single cell can be isolated post ADM confirmation and used for "actionable" genetic mutations analysis. PMID- 28819857 TI - A Noninvasive and Real-Time Method for Circulating Tumor Cell Detection by In Vivo Flow Cytometry. AB - The quantification of circulating tumor cells (CTCs) has been considered a potentially powerful tool in cancer diagnosis and prognosis, as CTCs have been shown to appear very early in cancer development. Great efforts have been made to develop methods that were less invasive and more sensitive to detect CTCs earlier. There is growing evidence that CTC clusters have greater metastatic potential than single CTCs. Therefore, the detection of CTC clusters is also important. This chapter is aimed to introduce a noninvasive technique for CTCs detection named in vivo flow cytometry (IVFC), which has been demonstrated to be capable of monitoring CTCs dynamics continuously. Furthermore, IVFC could be helpful for CTC cluster enumeration. PMID- 28819858 TI - EpCAM-Independent Enrichment and Detection of Viable Circulating Tumor Cells Using the EPISPOT Assay. AB - Identification and characterization of circulating tumor cells (CTCs) in peripheral blood can provide information on the direction and the efficacy of treatments. Current techniques such as CellSearch(r) are lim i ted in differentiating between apoptotic and viable CTCs. In contrast, the fluorescent EPISPOT assay allows for the identification of viable cell s by detecting proteins secreted/released/shed by functional single epithelial cancer cells. In addition, as CTCs are rare events, it is required to combine the EPISPOT assay with an enrichment step. In this article, the EPISPOT assay, as well as two technologies for enrichment of viable CTCs, RosetteSepTM and ParsortixTM techniques, will be presen ted and di scussed in detail. PMID- 28819859 TI - Utilizing Matrigel Transwell Invasion Assay to Detect and Enumerate Circulating Tumor Cells. AB - Metastasis is the cause of 90% of human cancer deaths. Circulating tumor cells (CTCs) in the peripheral blood and/or lymphatic vessels are cells shed from primary tumors and considered to be precursors of metastasis. Study of CTCs allows the serial monitoring of tumor progression and may provide predictive and prognostic biomarkers in clinic. Current CTC isolation and detection technologies encounter several challenges, including: heterogeneity of CTCs, low cell viability and/or high rate of contamination post-isolation, and the inability to distinguish viable/invasive from nonviable/nonfunctional CTCs, all of which can limit in vitro and in vivo characterization of CTCs. Here, we describe a new method to detect and enumerate of CTCs based on their invasive property. PMID- 28819861 TI - How Useful are Clinical Criteria for Diagnosing Malignant, Paramalignant and Benign Pleural Effusions? PMID- 28819860 TI - Circulating Tumor Cells: Markers and Methodologies for Enrichment and Detection. AB - Cancer is a leading cause of disease worldwide; however, nowadays many points of its initiation processes are unknown. In this chapter, we are focusing on the role of liquid biopsies in cancer detection and progression. CTCs are one of the main components of liquid biopsies, they represent a subset of tumor cells that have acquired the ability to disseminate from the primary tumor and intravasate to the circulatory system. The greatest challenge in the detection of CTCs is their rarity in the blood. Human blood consists of white blood cells (5-10 * 106/mL), red blood cells (5-9 * 109/mL), and platelets (2.5-4 * 108/mL); very few CTCs will be present even in patients with known metastatic disease, with often less than one CTC per mL of blood. CTCs are found in frequencies on the order of 1-10 CTCs per mL of whole blood in patients with metastatic disease, and it is reduced in half for non-metastatic stages. Therefore, accurate methodologies for their capture and analysis are really important. The main aim of the present chapter is to describe different methodologies for CTCs capturing and analysis. PMID- 28819862 TI - Radiation dose with digital breast tomosynthesis compared to digital mammography: per-view analysis. AB - OBJECTIVES: To compare radiation dose delivered by digital mammography (FFDM) and breast tomosynthesis (DBT) for a single view. METHODS: 4,780 FFDM and 4,798 DBT images from 1,208 women enrolled in a screening trial were used to ground dose comparison. Raw images were processed by an automatic software to determine volumetric breast density (VBD) and were used together with exposure data to compute the mean glandular dose (MGD) according to Dance's model. DBT and FFDM were compared in terms of operation of the automatic exposure control (AEC) and MGD level. RESULTS: Statistically significant differences were found between FFDM and DBT MGDs for all views (CC: MGDFFDM=1.366 mGy, MGDDBT=1.858 mGy; p<0.0001; MLO: MGDFFDM=1.374 mGy, MGDDBT=1.877 mGy; p<0.0001). Considering the 4,768 paired views, Bland-Altman analysis showed that the average increase of DBT dose compared to FFDM is 38 %, and a range between 0 % and 75 %. CONCLUSIONS: Our findings show a modest increase of radiation dose to the breast by tomosynthesis compared to FFDM. Given the emerging role of DBT, its use in conjunction with synthetic 2D images should not be deterred by concerns regarding radiation burden, and should draw on evidence of potential clinical benefit. KEY POINTS: * Most studies compared tomosynthesis in combination with mammography vs. mammography alone. * There is some concern about the dose increase with tomosynthesis. * Clinical data show a small increase in radiation dose with tomosynthesis. * Synthetic 2D images from tomosynthesis at zero dose reduce potential harm. * The small dose increase should not be a barrier to use of tomosynthesis. PMID- 28819863 TI - Effects of testosterone treatment on hypothalamic neuroplasticity in female-to male transgender individuals. AB - Diffusion-weighted imaging (DWI) is used to measure gray matter tissue density and white matter fiber organization/directionality. Recent studies show that DWI also allows for assessing neuroplastic adaptations in the human hypothalamus. To this end, we investigated a potential influence of testosterone replacement therapy on hypothalamic microstructure in female-to-male (FtM) transgender individuals. 25 FtMs were measured at baseline, 4 weeks, and 4 months past treatment start and compared to 25 female and male controls. Our results show androgenization-related reductions in mean diffusivity in the lateral hypothalamus. Significant reductions were observed unilaterally after 1 month and bilaterally after 4 months of testosterone treatment. Moreover, treatment induced increases in free androgen index and bioavailable testosterone were significantly associated with the magnitude of reductions in mean diffusivity. These findings imply microstructural plasticity and potentially related changes in neural activity by testosterone in the adult human hypothalamus and suggest that testosterone replacement therapy in FtMs changes hypothalamic microstructure towards male proportions. PMID- 28819866 TI - Game on: Addressing Resident Wellness and Burnout Within Training Programs. PMID- 28819867 TI - Resident Burnout: Urgent Need for Peer-Appointed "Wellbeing Officers" to Strengthen Resilience. PMID- 28819865 TI - Melatonin, mitochondria, and the metabolic syndrome. AB - A number of risk factors for cardiovascular disease including hyperinsulinemia, glucose intolerance, dyslipidemia, obesity, and elevated blood pressure are collectively known as metabolic syndrome (MS). Since mitochondrial activity is modulated by the availability of energy in cells, the disruption of key regulators of metabolism in MS not only affects the activity of mitochondria but also their dynamics and turnover. Therefore, a link of MS with mitochondrial dysfunction has been suspected since long. As a chronobiotic/cytoprotective agent, melatonin has a special place in prevention and treatment of MS. Melatonin levels are reduced in diseases associated with insulin resistance like MS. Melatonin improves sleep efficiency and has antioxidant and anti-inflammatory properties, partly for its role as a metabolic regulator and mitochondrial protector. We discuss in the present review the several cytoprotective melatonin actions that attenuate inflammatory responses in MS. The clinical data that support the potential therapeutical value of melatonin in human MS are reviewed. PMID- 28819868 TI - One-level step section histological analysis is insufficient to confirm complete pathological response after neoadjuvant chemoradiation for rectal cancer. AB - BACKGROUND: Neoadjuvant chemoradiation therapy (nCRT) for rectal cancer may lead to cure. As we currently lack reliable methods to clinically confirm the absence of disease, some patients undergo radical resection and have pathological complete response (pCR) still undergo surgery. Furthermore, it is uncertain if conventional one-level histopathological analysis is accurate enough to determine complete response. Confirming pCR is essential to determine the prognosis and to consider the patient's inclusion in trials of adjuvant therapy. The aim of this study was to determine whether the current 1-level approach is sufficient to confirm pCR. METHODS: Four hundred and thirty-five patients with rectal cancer who received nCRT followed by radical resection were analyzed. All cases identified as pCR by 1-level step section histological evaluation were reassessed with 3-level step sections and immunohistochemical analysis to verify the presence of residual disease. RESULTS: Out of 435 patients, 75 (17.2%) were staged as ypT0. Of these, 6 had lymph node involvement and 1 had distant metastasis, leaving 68 (15.6%) who had pCR. After the additional step sections, residual tumor was detected in 12 (17.6%) of these 68. The final pCR rate was 12.9%. Distant recurrence was detected in 7.1% of real-pCR patients compared to 16.7% in the false-pCR group (p = 0.291). Sensitivity of clinical assessment for detecting pCR was 35.7%, and the accuracy of 1-section histological evaluation to identify pCR was 82.4%. CONCLUSIONS: Histopathological analysis with 1-level step section is insufficient to determine complete tumor eradication. The 3-level sections methodology revealed residual tumor cells in patients initially classified as ypT0. Further studies with larger sample size are required to verify the clinical relevance of these residual tumor cells. Caution should continue to be applied to watch and wait strategies following nCRT. PMID- 28819864 TI - Molecular processes involved in B cell acute lymphoblastic leukaemia. AB - B cell leukaemia is one of the most frequent malignancies in the paediatric population, but also affects a significant proportion of adults in developed countries. The majority of infant and paediatric cases initiate the process of leukaemogenesis during foetal development (in utero) through the formation of a chromosomal translocation or the acquisition/deletion of genetic material (hyperdiploidy or hypodiploidy, respectively). This first genetic insult is the major determinant for the prognosis and therapeutic outcome of patients. B cell leukaemia in adults displays similar molecular features as its paediatric counterpart. However, since this disease is highly represented in the infant and paediatric population, this review will focus on this demographic group and summarise the biological, clinical and epidemiological knowledge on B cell acute lymphoblastic leukaemia of four well characterised subtypes: t(4;11) MLL-AF4, t(12;21) ETV6-RUNX1, t(1;19) E2A-PBX1 and t(9;22) BCR-ABL1. PMID- 28819869 TI - New echocardiographic parameters in the diagnosis of heart failure with preserved ejection fraction. AB - Heart failure with preserved ejection fraction (HFpEF) is a serious clinical disease. The pathophysiology of HFpEF is complex, and specific diagnostic criteria have evolved over time. Limited data are available on the quantification of diastolic function using two-dimensional real-time echocardiography, and a simple parameter has not yet been established. The aim of this work is to evaluate new echocardiographic parameters-the diastolic wall strain of the posterior wall (DWS PW) and the vortex formation time (VFT). Echocardiographic data from 111 subjects with exertional dyspnea and normal left ejection fraction (Group A) and 20 healthy volunteers (Group B) were retrospectively evaluated. In addition to the standard parameters used in the diagnosis of HFpEF, DWS PW and VFT were assessed in all patients. HFpEF was diagnosed in 38 patients with dyspnea (Group A1). The remaining 73 patients did not meet the established criteria for a positive diagnosis of HFpEF (Group A2). We discovered that both observed parameters were significantly lower in patients with HFpEF than in other groups. Multivariate analysis revealed that both DWS PW and VFT independently predicted the presence of HFpEF. DWS PW and VFT are simple parameters in the evaluation of diastolic function and may play a potential role as a part of an integrated approach to the assessment of HFpEF. PMID- 28819870 TI - Surgical complications of extraspinal tumors in the cervical spine: a report of 110 cases and literature review. AB - PURPOSE: To assess the safety of surgical intervention for extraspinal tumors in the cervical spine. METHODS: 110 consecutive patients were enrolled and followed up at least 12 months or until death. The complication rates and risk factors were documented and analyzed. RESULTS: The quality of life in the surviving patients was significantly improved. The overall local recurrence rate was 17.3%. Twenty percent of patients developed distant metastasis. The perioperative mortality rate (30 days after surgery) was 0.9%. The complication related mortality was 1.8%. The rates of overall complication and major complication were 41.8% and 20.9%, respectively. The independent predictors for overall complications were Karnofsky score <60, multisegmental resection, and operation time >3 h. The independent predictors of major complications were comorbidity, tumor location at C1-C2, and combined approach. CONCLUSIONS: Surgery for cervical spine tumor could improve the quality of life, though it might be accompanied with high morbidity and mortality. It is a highly demanding procedure; however, it can be performed to an acceptable degree of safety. PMID- 28819871 TI - Health-Related Quality of Life and Patients' Empowerment in the Health Care of Primary Immune Deficiencies. PMID- 28819872 TI - [Hearing restoration with cochlear implants after translabyrinthine vestibular schwannoma resection]. AB - BACKGROUND: Hearing restoration after translabyrinthine vestibular schwannoma resection is a challenge. Because the cochlea can begin to ossify a few months after cochlear or labyrinthine injury, the time interval for cochlear implant surgery is limited. To avoid complete ossification and to prolong the time interval until cochlear implantation, it is possible to insert a placeholder (depth gauge) into the cochlea and perform the cochlear implant surgery at a later time point (two-stage approach). OBJECTIVE: The aim of this retrospective case series was to present the outcomes after restoration of hearing with cochlea implants in six patients and to evaluate the use of the depth gauge in practice. METHODS: The hearing outcome of all patients with (n = 3) and without (n = 3) insertion of a depth gauge was measured with the Freiburg monosyllabic test without background noise at 65 dB. The first measurement was performed prior to the translabyrinthine vestibular schwannoma resection, the last measurement was performed up to 48 months after cochlear implantation. RESULTS: All 6 patients reached 22.5 +/- 36.57% prior to vestibular schwannoma resection and 41.3 +/- 26% 12 months after cochlear implantation. The understanding values of the patients with a depth gauge were 25.8 +/- 16% after 12 months which is below the values of the other patients with 56.6 +/- 25.0%. No severe intraoperative or postoperative complications occurred in any patient. CONCLUSION: The two-stage approach for cochlear implantation with depth gauge insertion following labrynthine incision and intact nerve appears to represent a very promising and safe variation for hearing restoration. Intensified research on this approach seems to be justified and necessary. PMID- 28819873 TI - Similarities and differences between doxycycline and minocycline: clinical and antimicrobial stewardship considerations. AB - Doxycycline and, to a lesser extent, minocycline, have been used for decades to treat various serious systemic infections, but many physicians remain unfamiliar with their spectrum, interpretation of susceptibility results, pharmacokinetic/pharmacodynamic (PK/PD) properties, optimal dosing regimens, and their activity against MRSA, VRE, and multidrug-resistant (MDR) Gram-negative bacilli, e.g., Acinetobacter sp. This article reviews the optimal use of doxycycline and minocycline to treat a variety of infections and when minocycline is preferred instead of doxycycline. PMID- 28819874 TI - Effect of elicitors on the production of pyrroloquinazoline alkaloids by stimulating anthranilate synthase activity in Adhatoda vasica Nees cell cultures. AB - MAIN CONCLUSION: Pyrroloquinazoline alkaloids are medicinally important compounds, determined by HPLC from cell cultures of Adhatoda vasica . The maximum production of vasicinone (12-fold) and vasicine (8.3-fold) was enhanced by stimulating the anthranilate synthase activity via feeding of tryptophan and sorbitol. The decoction of Adhatoda vasica leaves is used for the treatment of throat irritations, inflammations and recommended as expectorant. The plant species contains pyrroloquinazoline alkaloids and has been reported to demonstrate various biological activities. To investigate the effect of elicitors to increase the production of alkaloids, five groups (auxins and cytokinins, biotic elicitors, polysaccharides, amino acids and salts) of elicitors were evaluated. Maximum production of vasicinone (72.74 +/- 0.74 mg/g DW; 12-fold) and vasicine (99.44 +/- 0.28 mg/g DW; 8.3-fold) was enhanced by feeding of tryptophan and sorbitol at 50 mM concentration in cell cultures. Fourteen free amino acids were estimated from the elicited cells. Sorbitol stimulated up to a maximum accumulation of serine (8.2-fold). The maximal anthranilate synthase (AS) activity (7.5 +/- 0.47 pkat/mg protein; 2.9-fold) was induced by salicylic acid and sorbitol. Anthranilate synthase functions as rate-limiting factor for the biosynthesis of pyrroloquinazoline alkaloids. Our results support the widespread use of tryptophan and sorbitol as elicitors to raise the production of vasicinone, vasicine, 2-acetyl benzyl amine and other pyrroloquinazoline alkaloids in cell cultures of A. vasica. PMID- 28819875 TI - Pathways from Birth Weight to ADHD Symptoms through Fluid Reasoning in Youth with or without Intellectual Disability. AB - Although individual differences in fluid reasoning reliably mediate predictions of attention-deficit/hyperactivity disorder (ADHD) symptoms from birth weight in youth with typical cognitive development (TD), it is unknown if this indirect effect operates similarly in the development of ADHD symptoms secondary to intellectual disability (ID). Thus, we evaluated mediation by fluid reasoning in a longitudinal sample of 163 youth (45% female) with (n = 52) or without (n = 111) ID who were followed prospectively from age 5 to age 13. At age 9, youth completed the Arithmetic subtest of the Wechsler Intelligence Scale for Children, a measure of fluid reasoning. At ages 9 and 13, mothers and teachers separately rated youth ADHD symptoms and mothers completed a diagnostic interview. Mediation was tested via path analysis with bootstrapped confidence intervals, and moderated mediation estimated whether indirect effects differed between ID and TD youth or based on youth IQ. Controlling for demographic factors and age 9 ADHD symptoms, age 9 Arithmetic mediated birth weight and multi-method/informant age 13 ADHD symptoms, such that birth weight positively predicted Arithmetic, which negatively predicted ADHD symptoms. Neither ID status nor IQ moderated the observed indirect effect through Arithmetic, suggesting that it was similar for ID and TD youth as well as across the range of youth IQs. These findings support previous evidence that fluid reasoning, as measured by Arithmetic, may causally mediate birth weight and ADHD symptoms, and suggest that this pathway operates similarly with respect to the development of ADHD symptoms in youth with ID. PMID- 28819876 TI - Measuring Recurring Stigma in the Lives of Individuals with Mental Illness. AB - We present an exploratory factor analysis of the 8-item Daily Indignities of Mental Illness (DIMI) scale, created to measure the detection and perceptions of recurring stigma among individuals with recent psychiatric hospitalizations. Structured in-person interviews were conducted with individuals with recent psychiatric hospitalizations in metropolitan New York. The 8-item DIMI scale's internal consistency for the sample (n = 65), measured by Cronbach's alpha, was 0.869. Statistically significantly higher DIMI scale scores were observed among individuals with more than 2 psychotic episodes and those reporting seeing relatives less often after hospitalization. The DIMI scale possesses good internal consistency for research contextualizing perceptions around the occurrence or recurrence of mental illness-related stigma among individuals with recent psychiatric hospitalizations. PMID- 28819877 TI - Engineering of Escherichia coli for the synthesis of N-hydroxycinnamoyl tryptamine and serotonin. AB - Plants synthesize various phenol amides. Among them, hydroxycinnamoyl (HC) tryptamines and serotonins exhibit antioxidant, anti-inflammatory, and anti atherogenic activities. We synthesized HC-tryptamines and HC-serotonin from several HCs and either tryptamine or serotonin using Escherichia coli harboring the 4CL (4-coumaroyl CoA ligase) and CaHCTT [hydroxycinnamoyl-coenzyme A:serotonin N-(hydroxycinnamoyl)transferase] genes. E. coli was engineered to synthesize N-cinnamoyl tryptamine from glucose. TDC (tryptophan decarboxylase) and PAL (phenylalanine ammonia lyase) along with 4CL and CaHCTT were introduced into E. coli and the phenylalanine biosynthetic pathway of E. coli was engineered. Using this strategy, approximately 110.6 mg/L of N-cinnamoyl tryptamine was synthesized. By feeding 100 MUM serotonin into the E. coli culture, which could induce the synthesis of cinnamic acid or p-coumaric acid, more than 99 MUM of N-cinnamoyl serotonin and N-(p-coumaroyl) serotonin were synthesized. PMID- 28819878 TI - Aspergillus Bronchitis in Patients with Cystic Fibrosis. AB - Aspergillus fumigatus frequently colonizes the airways of patients with cystic fibrosis (CF) and may cause various severe infections, such as bronchitis. Serological data, sputum dependent markers and longitudinal data of treated cases of Aspergillus bronchitis were evaluated for further description of this infection. This study, which comprises three substudies, aimed to analyze epidemiological data of Aspergillus in CF and the entity of Aspergillus bronchitis. In a first step, data of the German Cystic Fibrosis Registry were used to evaluate the frequency of Aspergillus colonization in patients with CF (n = 2599). Then a retrospective analysis of 10 cases of Aspergillus bronchitis was performed to evaluate longitudinal data for lung function and clinical presentation parameters: sputum production, cough and physical capacity. Finally, a prospective cohort study (n = 22) was conducted to investigate serological markers for Aspergillus bronchitis: total serum IgE, specific serum IgE, specific serum IgG, as well as sputum galactomannan, real-time PCR detection of Aspergillus DNA in sputum and fungal cultures. Analysis of the German CF registry revealed an Aspergillus colonization rate of 32.5% among the 2599 patients. A retrospective data analysis of 10 treated cases revealed the clinical course of Aspergillus bronchitis, including repeated positive sputum culture findings for A. fumigatus, no antibiotic treatment response, total serum IgE levels <200 kU/l, no observation of new pulmonary infiltrates and appropriate antifungal treatment response. Antifungal treatment durations of 4 +/- 1.6 (2-6) weeks significantly reduced cough (P = 0.0067), sputum production (P < 0.0001) and lung function measures (P = 0.0358) but not physical capacity (P = 0.0794). From this retrospective study, a prevalence of 1.6% was calculated. In addition, two cases of Aspergillus bronchitis were identified in the prospective cohort study according to immunological, molecular and microbiological parameters. A prevalence of 9% was assessed. Aspergillus bronchitis appears to occur in a minority of colonized CF patients. Antifungal treatment may reduce respiratory symptoms and restore lung function. PMID- 28819879 TI - Lower Extremity Bypass Using Bovine Carotid Artery Graft (Artegraft): An Analysis of 124 Cases with Long-Term Results. AB - INTRODUCTION: Although biological grafts have been utilized as a vascular conduit in leg bypass for many years, reports of a bovine carotid artery graft (BCAG) in lower extremity revascularization have been scarce. This study analyzed the outcome of lower leg bypass using BCAG. METHODS: A retrospective review of a prospectively collected database of all patients undergoing lower extremity bypass using BCAG from 2002 to 2017 was performed. Clinical outcomes including graft patency and limb salvage were evaluated. RESULTS: A total of 124 BCAG (Artegraft, North Brunswick, NJ) were implanted in 120 patients for lower extremity revascularization. Surgical indications included disabling claudication in 12%, rest pain in 36%, tissue loss in 48%, and infected prosthetic graft replacement in 3%. Autologous saphenous vein was either inadequate or absent in 72% of patients. BCAG was used in 46 patients (37%) who had a prior failed ipsilateral leg bypass. Distal anastomosis was performed in the above-knee popliteal artery, below-knee popliteal artery, and tibial artery in 30 cases (25%), 32 cases (26%), and 48 cases (39%), respectively. Distal anastomotic patch was created in all tibial artery to allow BCAG-tibial reconstruction. The yearly primary patency rates in 5 years were 86.5, 76.4, 72.2, 68.3, and 67.5%, respectively. The corresponding yearly secondary patency rates were 88.5, 84.7, 82.4, 78.5, and 75.6%, respectively. The limb salvage rate at one year was 83.6% and at five years was 86.2% for patients with critical limb ischemia. Multivariate analysis showed poor runoff score (P = 0.03, 95% CI, 1.3-5.3; OR, 1.6) was independently associated with graft occlusion. CONCLUSION: BCAG is an excellent vascular conduit and provides good long-term results in lower extremity bypass. PMID- 28819880 TI - Theoretical analysis of C-F bond cleavage mediated by cob[I]alamin-based structures. AB - In the present work, C-F bond cleavage mediated by the super-reduced form of cobalamin (i.e., CoICbl) was theoretically studied at the ONIOM(BP86/6 311++G(d,p):PM6) + SMD level of theory. Dispersion effects were introduced by employing Grimme's empirical dispersion at the ONIOM(BP86-D/6-311++G(d,p):PM6) + SMD level. In the first stage of the study, cobalamin was characterized in terms of the coordination number of the central cobalt atom. The ONIOM(BP86/6 311++G(d,p):PM6) results showed that the base-off form of the system is slightly more stable than its base-on counterpart (DeltaE = E base-off - E base-on ~ -2 kcal/mol). The inclusion of dispersive forces in the description of the system stabilizes the base-on form, which becomes as stable as its base-off counterpart. Moreover, in the latter case, the energy barrier separating both structures was found to be negligible, with a computed value of 1.02 kcal/mol. In the second stage of the work, the reaction CoICbl + CH3F -> MeCbl + F- was studied considering the base-off and the base-on forms of CoICbl. The reaction that occurs in the presence of the base-on form of CoICbl was found to be kinetically more favorable (DeltaE ? = 13.7 kcal/mol) than that occurring in the presence of the base-off form (DeltaE ? = 41.2 kcal/mol). Further reaction-force analyses of the processes showed that the energy barrier to C-F bond cleavage arises largely due to structural rearrangements when the reaction occurs on the base-on form of the CoICbl complex, but is mainly due to electronic rearrangements when the reaction takes place on the base-off form of the complex. The latter behavior emerges from differences in the synchronicity of the bond strengthening/weakening processes along the reaction path; the base-on mode of CoICbl is able to decrease the synchronicity of the chemical events. This work gives new molecular-level insights into the role of Cbl-based systems in the cleavage of C-F bonds. These insights have potential implications for research into processes for degrading fluorine-containing pollutants. PMID- 28819881 TI - Resveratrol induces apoptosis and inhibits adipogenesis by stimulating the SIRT1 AMPKalpha-FOXO1 signalling pathway in bovine intramuscular adipocytes. AB - Sirtuin type 1 (SIRTl) and AMP-activated protein kinase (AMPK) play important roles in regulating energy metabolism, cell proliferation and differentiation, ageing, apoptosis, and metabolism. The effect of 100, 200, and 400 MUm Resveratrol (RES), an activator of SIRT1, on apoptosis of bovine intramuscular adipocytes was investigated by nuclear staining, flow cytometry, quantitative real-time polymerase chain reaction, and western blotting. Results show that RES inhibited adipogenesis, decreased cell viability, and increased apoptotic rates in a dose-dependent way. RES up-regulated SIRT1, AMPKalpha, forkhead box O1 (FOXO1), hormone-sensitive lipase (HSL), lipoprotein lipase (LPL), caspase-3, and Bax; and down-regulated peroxisome proliferator-activated receptor-gamma (PPARgamma), fatty acid synthase (FAS), and Bcl-2, at both mRNA and protein level. The effect of RES was abolished by addition of sirtinol (an inhibitor of SIRT1). This is the first study demonstrating a role for AMPK-SIRT1-FOXO1 signalling pathway in regulating apoptosis in bovine intramuscular adipocytes. Our findings provide important information on the mechanism by which RES controls deposition of cattle intramuscular fat via adipocyte apoptosis. PMID- 28819883 TI - How the Political Becomes Private: In Vitro Fertilization and the Catholic Church in Poland. AB - The Polish debate on in vitro fertilization (IVF) is extremely heated and highly politicized. The hierarchs of the Catholic vehemently oppose the use of IVF. In this text, I present the Church's approach to IVF. Basing on the documentary film, Three Conversations about Life, and ethnographic research, as well as an analysis of Vatican documents and official statements of Polish bishops, I show how the positions of clergy might influence private lives. I indicate series of tensions associated with the "politics of morality" of the Catholic Church and the daily lives of people, who have children thanks to IVF. PMID- 28819882 TI - Novel Immunotherapies for Multiple Myeloma. AB - PURPOSE OF REVIEW: The treatment landscape of multiple myeloma is rapidly changing; however, despite improvement in patients' survival, it still remains a largely incurable disease. One hallmark of myeloma is substantial immune dysfunction leading to an increased infection rate and the inability of immune surveillance to detect neoplastic cells. Here, we critically analyze clinical approaches to harness the immune system to overcome this defect with a focus on antibody based and adoptive cellular therapies. RECENT FINDINGS: Clinical trials exploring these immunotherapies to treat myeloma are now well underway and show promising results. In relapsed myeloma, monoclonal antibodies directed against plasma cell antigens and immune checkpoints have already shown substantial efficacy. In parallel, trials of adoptive cellular therapy have exciting promise in myeloma, having induced dramatic responses in a handful of early study participants. Taken together, immunotherapeutic approaches hold enormous potential in the field of multiple myeloma and in the near future can be combined with or even replace the current standard of care. PMID- 28819884 TI - Different Look in to the Role of Flagella in Pathogenesis of Helicobacter pylori. PMID- 28819885 TI - Adenosine-assisted clipping of intracranial aneurysms. AB - Temporary parent vessel clip occlusion in aneurysm surgery is not always practical or feasible. Adenosine-induced transient cardiac arrest may serve as an alternative. We retrospectively reviewed our clinical database between September 2011 and July 2014. All patients who underwent microsurgical clipping of intracranial aneurysms under adenosine-induced asystole were included. A total of 18 craniotomies were performed, and 18 aneurysms were clipped under adenosine induced asystole (7 basilar arteries, 8 internal carotid arteries, 1 middle cerebral artery, and 1 anterior communicating artery) in 16 patients (10 females, 6 males). Nine cases were elective and seven after subarachnoid hemorrhage. Mean age was 54 years (range 39-70). The indications for adenosine use were proximal control in narrow surgical corridors in 13 cases and "aneurysm softening" in 4 cases. A single dose was used in 14 patients; 3 patients had multiple boluses. The median (range) total dose was 30 (18-135) mg. Adenosine induced a bradycardia with concomitant arterial hypotension in all patients, and the majority also had asystole for 5-15 sec. Transient cardiac arrhythmias were noted in one patient (AFib in need of electroconversion after two boluses). Nine clinical scenarios where adenosine-induced temporary cardiac arrest and deep hypotension was an effective adjunct to temporary clipping during microsurgical clipping of intracranial aneurysms were identified. PMID- 28819886 TI - Robotic Versus Laparoscopic Pancreaticoduodenectomy: a NSQIP Analysis. AB - BACKGROUND: An increasing body of literature is supporting the safety of minimally invasive pancreaticoduodenectomy compared to open pancreaticoduodenectomy, but there are limited comparative studies between laparoscopic and robotic pancreaticoduodenectomy. The aim of this study was to compare the rate of postoperative 30-day overall complications between laparoscopic and robotic pancreaticoduodenectomy. METHODS: Patients who underwent laparoscopic and robotic pancreaticoduodenectomy were abstracted from the 2014 2015 pancreas-targeted American College of Surgeons National Surgical Quality Improvement Program. A multivariable logistic regression model was developed to determine if the type of minimally invasive approach was associated with 30-day overall complications. RESULTS: We identified 428 minimally invasive pancreaticoduodenectomy cases, of which 235 (55%) were performed laparoscopically and 193 (45%) robotically. Patients who underwent the robotic approach were more likely to be white compared to those who underwent the laparoscopic approach and were less likely to have pulmonary disease, undergo preoperative radiotherapy, and have vascular and multivisceral resection. On multivariable analysis, we found that the type of minimally invasive approach, whether laparoscopic or robotic, was not associated with overall complications. The predictors of 30-day overall complications were higher body mass index (odds ratio [OR], 1.05; 95% confidence interval [CI], 1.02-1.09), vascular resection (OR, 2.10; 95% CI, 1.23 3.58), and longer operative time (OR, 1.002; 95% CI, 1.001-1.004). CONCLUSIONS: Robotic pancreaticoduodenectomy was associated with a similar 30-day overall complication rate to laparoscopic pancreaticoduodenectomy. Further studies are needed to corroborate these findings and to establish the best approach to perform this complex operation. PMID- 28819887 TI - Can germ cell neoplasia in situ be diagnosed by measuring serum levels of microRNA371a-3p? AB - PURPOSE: Diagnosing germ cell neoplasia in situ (GCNis) can detect germ cell tumours (GCTs) at the pre-invasive stage. To date, testicular biopsy with the potential of surgical complications is the only way of safely diagnosing GCNis. Recently, microRNAs (miRs) 371-3, and miR 367 were shown to be valuable serum biomarkers of GCTs. We explored the usefulness of these candidate miRs as a marker for GCNis. METHODS: 27 patients with GCNis and no concomitant GCT were enrolled. All patients underwent measuring serum levels of miR-371a-3p and miR 367-3p before treatment, 11 had repeat measurement after treatment, 2 also had testicular vein blood examinations. Serum levels were measured by quantitative PCR. In addition, four orchiectomy specimens of patients with GCT were examined immunohistochemically and by in situ hybridization (ISH) with a probe specific for miR-371a-3p to look for the presence of this miR in GCNis cells. RESULTS: The median serum level of miR-371a-3p was significantly higher in patients with GCNis than in controls, miR-367 levels were not elevated. Overall, 14 patients (51.9%) had elevated serum levels of miR-371a-3p. The highest levels were found in patients with bilateral GCNis. Levels in testicular vein serum were elevated in both of the cases. After treatment, all elevated levels dropped to normal. In two orchiectomy specimens, miR-371a-3p was detected by ISH in GCNis cells. CONCLUSIONS: Measuring miR-371a-3p serum levels can replace control biopsies after treatment of GCNis. In addition, the test can guide clinical decision making regarding the need of testicular biopsy in cases suspicious of GCNis. PMID- 28819889 TI - Visualization of 57Fe-Labeled Heme Isotopic Fine Structure and Localization of Regions of Erythroblast Maturation in Mouse Spleen by MALDI FTICR-MS Imaging. AB - Epoetin beta pegol (continuous erythropoiesis receptor activator; C.E.R.A.), or methoxy-polyethylene glycol-modified epoetin beta, is a long-acting erythropoiesis stimulating agent (ESA) that effectively maintains hemoglobin levels. It promotes proliferation of erythroid progenitor cells in hematopoietic organs and leads to increased reticulocyte and hemoglobin levels. However, the detailed erythropoietic effects of various ESAs on their target organs have yet to be clarified, and new approaches are needed to analyze tissue iron localization with structural information. Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) techniques are widely used in basic pharmaceutical research. High-resolution Fourier transform ion cyclotron resonance (FTICR) mass spectrometry (MS) imaging enables the spatial mapping and identification of biomolecules. In this study, mice administered with C.E.R.A. were fed a diet containing the stable iron isotope 57Fe. The 57Fe-heme+ isotopic fine structure peak (m/z 617.1772) was separated from the non-labeled heme+ isotopic peak (Delta0.0029) by FTICR-MS with a resolving power of more than 500,000. We optimized the platform to analyze the distribution of 57Fe-heme in the spleen using MALDI FTICR-MS imaging. The combination of the ultrahigh resolution power of FTICR-MS and a stable isotope labeling technique has the potential to be very effective in basic pharmaceutical research. Graphical Abstract ?. PMID- 28819890 TI - Assessing risk factors of acute kidney injury after liver transplantation. PMID- 28819888 TI - Paraquat-Induced Movement Disorder in Relation to Oxidative Stress-Mediated Neurodegeneration in the Brain of Drosophila melanogaster. AB - Exposure to pesticides like paraquat (PQ) is considered as a risk factor for Parkinson's disease (PD). PQ has been shown to induce PD-like phenotype in experimental animals. Drosophila, a valuable laboratory model organism, is widely used to study neurodegenerative disorders including PD. The acute (single dose) PQ model of PD in Drosophila is associated with high mortality as well as reversibility of locomotor deficits and, therefore, does not replicate the disease phenotype. We have investigated the relevance of the acute and multiple (sublethal) dose of PQ to induce PD-like symptoms in Drosophila and shown that multiple-dose of PQ induces irreversible locomotor impairment without significant mortality. Our study has provided ultrastructural evidence for neurodegeneration involving mitochondrial damage in the brain caused by free radical-induced oxidative stress, which leads to locomotor impairment in Drosophila. The multiple (sublethal) dose of PQ could be an appropriate Drosophila model to induce PD-like symptoms of movement disorder associated with neurodegeneration, which could be useful to evaluate neuroprotective compounds. PMID- 28819891 TI - Optimizing through computational modeling to reduce dogboning of functionally graded coronary stent material. AB - Coronary artery disease is the leading cause of death among the men and women. One of the most suitable treatments for this problem is balloon angioplasty with stenting. Functionally graded material (FGM) stents have shown suitable mechanical behavior in simulations. While their deformation was superior to uniform materials, the study was aimed at finding the most suitable configuration to reach the optimum performance. A combination of finite element method (FEM) and optimization algorithm have been used to fulfil this objective. To do that, three different conditions have been investigated in a Palmaz-Schatz geometry, where in the first and second ones the stent was a combination of steel and CoCr alloy (L605), and the third condition was a combination of CoCr alloy (L605) and CoCr alloy (F562). In the first and third conditions, dogboning was the objective function, but in the second condition a non-uniform deformation indicator was chosen as the objective function. In all three conditions the heterogeneous index was the control variable. The stent in the third condition showed a poor performance. While in the steel/CoCr alloy (L605) stents the heterogeneous index of 0.374 showed the lowest maximum dogboning, the heterogeneous index of 5 had more uniform deformation. Overall due to the lower dogboning of the steel/CoCr alloy (L605) stent with heterogeneous index of 0.374, this stent is recommended as the optimum stent in this geometrical configuration. PMID- 28819892 TI - Post-ictal missing dentures. PMID- 28819893 TI - [Cochlear implantation in a girl with 7q-microdeletion syndrome]. AB - One of the rare genetic diseases with sensory hearing loss is the microdeletion 7q syndrome. First described in the 1990s, only 7 cases of patients with this disease are described in the literature. Although this mutation is not well known, otological treatment is necessary if the DFNA5 gene is affected. A mutation in this gene leads to progressive hearing loss. Affected children therefore need regular evaluation of their hearing to ensure adequate treatment with hearing aids at early stages. We now present a case of an affected child with sensory hearing loss, mental retardation and anogenital malformations. In the following we describe the course of disease and possible treatment options. We especially describe the possibility of cochlear implantation. We can show with this case report that, even though massive mental retardation is shown, cochlear implantation is useful in this patient. Associated disabilities as cardiac and pulmonary problems may occur and should be treated before cochlear implantation. This is the first report of cochlear implantation in a child affected with microdeletion 7q syndrome. PMID- 28819894 TI - Cross-cultural adaptation and validation of the Dutch version of the core outcome measures index for low back pain. AB - PURPOSE: The core outcome measures index (COMI) is a validated multidimensional instrument for assessing patient-reported outcome in patients with back problems. The aim of the present study is to translate the COMI into Dutch and validate it for use in native Dutch speakers with low back pain. METHODS: The COMI was translated into Dutch following established guidelines and avoiding region specific terminology. A total of 89 Dutch-speaking patients with low back pain were recruited from 8 centers, located in the Dutch-speaking part of Belgium. Patients completed a questionnaire booklet including the validated Dutch version of the Roland Morris disability questionnaire, EQ-5D, the WHOQoL-Bref, the Numeric Rating Scale (NRS) for pain, and the Dutch translation of the COMI. Two weeks later, patients completed the Dutch COMI translation again, with a transition scale assessing changes in their condition. RESULTS: The patterns of correlations between the individual COMI items and the validated reference questionnaires were comparable to those reported for other validated language versions of the COMI. The intraclass correlation for the COMI summary score was 0.90 (95% CI 0.84-0.94). It was 0.75 and 0.70 for the back and leg pain score, respectively. The minimum detectable change for the COMI summary score was 1.74. No significant differences were observed between repeated scores of individual COMI items or for the summary score. CONCLUSION: The reproducibility of the Dutch translation of the COMI is comparable to that of other validated spine outcome measures. The COMI items correlate well with the established item-specific scores. The Dutch translation of the COMI, validated by this work, is a reliable and valuable tool for spine centers treating Dutch-speaking patients and can be used in registries and outcome studies. PMID- 28819895 TI - Optimal Lymphadenectomy in Small Bowel Neuroendocrine Tumors: Analysis of the NCDB. AB - BACKGROUND: Current National Comprehensive Cancer Network guidelines for resectable small bowel neuroendocrine tumors (NETs) recommend regional lymphadenectomy. However, no consensus exists on the optimal nodal harvest. METHODS: The National Cancer Database was queried for patients with resectable small bowel NETs (1998-2013). Patients with metastatic disease and missing lymph node harvest data were excluded. We performed logistic regression of factors determining nodal positivity and multivariable survival analyses. RESULTS: Of 11,852 patients, 81.8% underwent lymphadenectomy. 79.3% were node positive (N+) and 46.9% of patients had tumors < 1 cm. Independent predictors of N+ were large tumor size, ileal location, and neuroendocrine carcinoma histology. Logistic regression found no difference between observed and expected proportions of N+ patients with lymphadenectomy greater than or equal to eight nodes. Lower metastatic node ratio predicted improved survival on multivariable analysis and is associated with high-volume institutions. CONCLUSION: Small bowel NETs have high rates of nodal metastasis, even in patients with small tumors, and many patients do not undergo lymphadenectomy despite the clear benefit. Lymphadenectomy of eight nodes is optimal to identify N+ patients. Additionally, minimizing metastatic node ratio with complete regional lymphadenectomy is associated with improved survival in these patients. PMID- 28819897 TI - Teachers' and Parents' Perspectives on a Curricular Subject of "Religion and Spirituality" for Indian Schools: A Pilot Study Toward School Mental Health Program. AB - Religious-spiritual (R/S) education helps medical students cope with caregiving stress and gain skills in interpersonal empathy needed for clinical care. Such R/S education has been introduced into K-12 and college curricula in some developed nations and has been found to positively impact student's mental health. Such a move has not yet been seen in the Indian education system. This paper aimed to examine perspectives of teachers and parents in India on appropriateness, benefits, and challenges of including R/S education into the school curriculum and also to gather their impressions on how a R/S curriculum might promote students' health. A cross-sectional study of religiously stratified sample of teachers and parents was initiated in three preselected schools in India and the required sample size (N = 300) was reached through snowballing technique. A semi-structured questionnaire, with questions crafted from "Religion and Spirituality in Medicine, Physicians Perspective" (RSMPP) and "American Academy of Religion's (AAR) Guidelines for Religious Literacy," was used to determine participants' perspectives. Findings revealed that teachers' and parents' "comfort in integrating R/S into school curriculum" was associated with their gender (OR 1.68), education status (OR 1.05), and intrinsic religiosity (OR 1.05). Intrinsic religiosity was significantly (p = 0.025) high among parents while "intrinsic spirituality" was high (p = 0.020) among teachers. How participants' R/S characteristics influence their support of R/S education in school is discussed. In conclusion, participants believe R/S education will fosters students' emotional health and interpersonal skills needed for social leadership. A curriculum that incorporates R/S education, which is based on AAR guidelines and clinically validated interpersonal spiritual care tools would be acceptable to both teachers and parents. PMID- 28819899 TI - Significance of intravascular ultrasound and exercise stress echocardiography in diagnosis of exercise-induced vasospastic angina at the site of moderate stenosis. AB - Recently, exercise-induced spastic coronary artery occlusion at the site of moderate stenosis, which Prinzmetal's angina or cardiac syndrome X does not cover, was reported. Multi-modality imaging is important for the diagnosis of coronary artery disease with a complex ischemic mechanism. However, the previous report did not include findings from intracoronary imaging at the site of moderate coronary stenosis. We report a case of exercise-induced vasospastic angina at the site of moderate stenosis, where multi-modality imaging, including exercise stress echocardiography and intravascular ultrasound, was utilized to make a definitive diagnosis and investigate underlying causes. PMID- 28819900 TI - Effect of Polyethylene Glycol on the NiO Photocathode. AB - In this study, a uniform nanoporous NiO film, with a thickness of up to 2.6 MUm, was prepared using polyethylene glycol (PEG). The addition of PEG significantly decreased the cracks in the NiO film and prevented the peeling of the NiO film from a fluorine-doped tin oxide substrate. The NiO cathode was prepared using CdSeS quantum dots (QDs) as the sensitizer, with an optimized photoelectric conversion of 0.80%. The optimized QD-sensitized NiO films were first assembled with the TiO2 anode to prepared QD-sensitized p-n-type tandem solar cells. The open circuit voltage was greater than that obtained using the separated NiO cathode or TiO2 anode. PMID- 28819901 TI - The logic and challenges of imaging sarcoidosis with whole body FDG PET. PMID- 28819898 TI - Regulation of hepatic Na+/K+-ATPase in obese female and male rats: involvement of ERK1/2, AMPK, and Rho/ROCK. AB - In this study, we assessed whether the disturbed regulation of sodium/potassium adenosine-triphosphatase (Na+/K+-ATPase) occurs as a consequence of obesity induced IR in sex-specific manner. We also assessed whether alterations of IRS/PI3K/Akt, ERK1/2, AMPKalpha, and RhoA/ROCK signaling cascades have an important role in this pathology. Female and male Wistar rats (150-200 g, 8 weeks old) were fed a standard laboratory diet or a high-fat (HF) diet (42% fat) for 10 weeks. The activity of hepatic Na+/K+-ATPase and Rho, and the association of IRS 1/p85 were assessed in liver. Furthermore, the protein level of alpha1 Na+/K+ ATPase in plasma membrane fractions, and protein levels of IRS-1, PI3K-p85, p110, RhoA, ROCK1, ROCK2, ERK1/2, AMPKalpha, ERalpha, and ERbeta in liver lysates were assessed. The expression of hepatic alpha1 Na+/K+-ATPase mRNA was also analyzed by qRT-PCR. The results show that HF-fed female rats exhibited an increase in hepatic ERK1/2 (p < 0.05) and AMPKalpha (p < 0.05) phosphorylation levels, unchanged level of Na+/K+-ATPase alpha1 mRNA, decreased level of Na+/K+ ATPase activity (p < 0.05), and decreased alpha1 Na+/K+-ATPase protein expression (p < 0.01). In liver of HF-fed male rats, results show decreased levels of Na+/K+ ATPase activity (p < 0.01), both protein and mRNA of alpha1 subunit (p < 0.05), but significant increase in Rho activity (p < 0.05). Our results indicate significant sex differences in alpha1 Na+/K+-ATPase mRNA expression and activation of ERK1/2, AMPKalpha, and Rho in the liver. Exploring the sex-specific factors and pathways that promote obesity-related diseases may lead to a better understanding of pathogenesis and discovering new therapeutic targets. PMID- 28819902 TI - Ablation Therapy for Barrett's Esophagus: New Rules for Changing Times. AB - PURPOSE OF REVIEW: In this review, we discuss different endoscopic techniques in the eradication of Barrett's esophagus (BE) as well as some controversies in the field of treatment. RECENT FINDINGS: Patients with T1a esophageal adenocarcinoma and BE of high-grade dysplasia should undergo endoscopic ablative therapy. The most studied technique to date is radiofrequency ablation. It can be combined with endoscopic mucosal resection in cases containing nodular and flat lesions. Cryotherapy and APC have shown promise with good efficacy and safety profiles so far, but are not mainstream as more studies are needed. Surveillance is still required post-ablation since recurrence is common. Low-grade dysplasia can be treated with either endo-ablative therapy or surveillance. Non-dysplastic BE treatment is controversial and so far, only surveillance is recommended. Research is ongoing to better risk stratify these patients. Our ability to diagnose and treat BE has come a long way in the past few years with the goal of preventing its progression into malignancy. The advent of endoscopic techniques in the eradication of BE has provided a less invasive and safer modality of treatment as compared to surgical esophagectomy. Data in the form of randomized trials and high-volume registries has provided good evidence to support the efficacy of these techniques and their long-term durability. PMID- 28819903 TI - Inhibition of PTEN Attenuates Endoplasmic Reticulum Stress and Apoptosis via Activation of PI3K/AKT Pathway in Alzheimer's Disease. AB - Amyloid plaques and neurofibrillary tangles are pathologic hallmarks of Alzheimer's disease (AD). Endoplasmic reticulum (ER) stress has been implicated in the loss of neurons in AD. The phosphatase and tensin homolog deleted on chromosome ten (PTEN) plays an important role in regulating neuronal survival processes. However, the direct effects of the PTEN on ER stress and apoptosis in AD have not been elucidated. In this study, we demonstrate that the expression of PTEN and ER stress related proteins, GRP78 and CHOP, increased in APP/PS1 transgenic AD mice compared with WT mice. A PTEN inhibitor, dipotassium bisperoxo (5-hydroxypyridine-2-carboxyl)-oxovanadate (bpv) could decrease apoptosis, induce AKT phosphorylation and inhibit the ER stress response proteins in hippocampus in APP/PS1 transgenic AD model mice. Furthermore, treatment with the specific PI3K inhibitor, LY294002, significantly blocked the anti-apoptotic effects of bpv in AD mice. The expression in GRP78, CHOP and apoptosis levels by bpv was reversed after PI3K inhibitor treatment. Taken together, our results indicate that the neuroprotective role of bpv involves the suppression of ER stress via the activation of the PI3K/AKT signalling pathways in APP/PS1 transgenic AD model mice. PMID- 28819904 TI - Somatic mutations of calreticulin in patients with myelodysplastic/myeloproliferative neoplasms-unclassifiable. PMID- 28819905 TI - Adsorption properties of kaolinite-based nanocomposites for Fe and Mn pollutants from aqueous solutions and raw ground water: kinetics and equilibrium studies. AB - Raw kaolinite was used in the synthesis of metakaolinite/carbon nanotubes (K/CNTs) and kaolinite/starch (K/starch) nanocomposites. Raw kaolinite and the synthetic composites were characterized using XRD, SEM, and TEM techniques. The synthetic composites were used as adsorbents for Fe and Mn ions from aqueous solutions and natural underground water. The adsorption by the both composites is highly pH dependent and achieves high efficiency within the neutral pH range. The experimental adsorption data for the uptake of Fe and Mn ions by K/CNTs were found to be well represented by the pseudo-second-order kinetic model rather than the intra-particle diffusion model or Elovich model. For the adsorption using K/starch, the uptake results of Fe ions was well fitted by the second-order model, whereas the uptake of Mn ions fitted well to the Elovich model rather than pseudo-second-order and intra-particle diffusion models The equilibrium studies revealed the excellent fitting of the removal of Fe and Mn ions by K/CNTs and Fe using K/starch with the Langmuir isotherm model rather than with Freundlich and Temkin models. But the adsorption of Mn ions by K/starch is well fitted with Freundlich rather than Temkin and Langmuir isotherm models. The thermodynamic studies reflected the endothermic nature and the exothermic nature for the adsorption by K/CNTs and K/starch nanocomposites, respectively. Natural ground water contaminated by 0.4 mg/L Fe and 0.5 mg/L Mn was treated at the optimum conditions of pH 6 and 120 min contact time. Under these conditions, 92.5 and 72.5% Fe removal efficiencies were achieved using 20 mg of K/CNTs and K/starch nanocomposites, respectively. Also, K/CNTs nanocomposite shows higher efficiency in the removal of Mn ions as compared to K/starch nanocomposite. PMID- 28819906 TI - Correlation between adrenal function, growth hormone secretion, and insulin sensitivity in children with idiopathic growth hormone deficiency. AB - PURPOSE: Patients with growth hormone deficiency (GHD) demonstrate an increased cortisol/cortisone ratio which could potentially explain the metabolic features of GHD, while GH treatment (GHT) could increase the cortisol metabolism. METHODS: In 35 children (27 M, mean age 10.1 years) with idiopathic GHD at baseline and after 12 months of GHT and in 25 controls, in addition to metabolic parameters, we assessed adrenal function by morning serum cortisol, its peak, and its area under the curve (AUCCOR) during insulin tolerance test (ITT). RESULTS: A cortisol peak <18 ug/dl was shown in 22 and 31% of GHD children at baseline and after GHT, respectively. At baseline, GHD children had lower fasting glucose (p < 0.001) and ISI-Matsuda (p = 0.042), with concomitant higher Homa-IR (p = 0.006) and morning cortisol (p = 0.012) than controls. Morning cortisol was negatively correlated with GH (p < 0.001), fasting glucose (p < 0.001) and ISI-Matsuda (p < 0.001) and positively with Homa-IR (p = 0.010). Both cortisol peak and AUCCOR were negatively correlated with GH (all p < 0.001) and ISI-Matsuda (p = 0.016 and p = 0.001, respectively). After 12 months of GHT, a significant increase in fasting glucose (p < 0.001), and Homa-IR (p = 0.011) was documented, with a concomitant decrease in morning cortisol (p = 0.002), AUCCOR (p = 0.038), total (p = 0.003) and LDL-cholesterol (p = 0.016). No significant correlations were found among cortisol levels and all parameters were investigated. CONCLUSIONS: Cortisol levels correlate with GH secretion and with many metabolic parameters in GHD children, while the metabolic effects during GHT are mainly due to GHT per se and less to cortisol reduction. PMID- 28819907 TI - Weight and Eating Concerns in Women's Reproductive Health. AB - PURPOSE OF REVIEW: Women's weight status affects their reproductive functioning, and, likewise, women's lifetime weight trajectories are influenced by reproductive events. We examine the relationship between polycystic ovary syndrome (PCOS), pregnancy, the postpartum period, and gynecological cancers with weight, body image, and other psychiatric issues. RECENT FINDINGS: Women with overweight or obesity are at higher risk for PCOS, and the mood and anxiety symptoms often comorbid with PCOS are linked to weight as well as the core symptoms of the disorder. Excessive gestational weight gain can influence one's body image and mood, and it predicts lasting effects on postpartum weight retention. Finally, overweight and obesity are related to several gynecological cancers. These diseases also impact mood, anxiety, and poor body image. Weight management interventions may be of some benefit in improving the disease states and pregnancy outcomes discussed here, but feasibility, logistics, and costs are issues that remain in delivering such interventions. PMID- 28819908 TI - The effect of cationically-modified phosphorylcholine polymers on human osteoblasts in vitro and their effect on bone formation in vivo. AB - The effect of introducing cationic charge into phosphorylcholine (PC)-based polymers has been investigated in this study with a view to using these materials as coatings to improve bone formation and osseointegration at the bone-implant interface. PC-based polymers, which have been used in a variety of medical devices to improve biocompatibility, are associated with low protein adsorption resulting in reduced complement activation, inflammatory response and cell adhesion. However, in some applications, such as orthopaedics, good integration between the implant and bone is needed to allow the distribution of loading stresses and a bioactive response is required. It has previously been shown that the incorporation of cationic charge into PC-based polymers may increase protein adsorption that stimulates subsequent cell adhesion. In this paper, the effect of cationic charge in PC-based polymers on human osteoblasts (HObs) in vitro and the effect of these polymers on bone formation in the rat tibia was assessed. Increasing PC positive surface charge increased HOb cell adhesion and stimulated increased cell differentiation and the production of calcium phosphate deposits. However, when implanted in bone these materials were at best biotolerant, stimulating the production of fibrous tissue and areas of loosely associated matrix (LAM) around the implant. Their development, as formulated in this study, as bone interfacing implant coatings is therefore not warranted. PMID- 28819909 TI - Adjunctive Breast-Specific Gamma Imaging for Detecting Cancer in Women with Calcifications at Mammography. AB - BACKGROUND: Mammography detects calcium deposits sensitively, but the specificity for differentiating malignancy from benign calcifications is low. Thus, we investigated whether adjunctive breast-specific gamma imaging (BSGI) has incremental value for detecting cancer in women with suspicious calcifications detected by mammography, and compared BSGI with adjunctive ultrasonography (US). METHODS: The medical records of women without a personal history of breast cancer who underwent mammography for breast evaluation from 2009 to 2014 were reviewed retrospectively. Patients who had calcifications detected by mammography, with a result of Breast Imaging Reporting and Data System (BI-RADS) categories 3-5, underwent adjunctive US and BSGI and were included in this study. A total of 302 breast lesions in 266 women (mean age +/- standard deviation 49 +/- 9 years) were selected for this study. RESULTS: For detecting breast cancer using mammography plus BSGI, the sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating curve with 95% confidence intervals were 94% (91-96), 90% (86-93), 91% (87-94), 94% (90-96), and 0.92 (0.89 0.95), respectively. For mammography plus US, the respective values were 97% (94 98), 51% (46-57), 68% (63-73), 94% (90-96), and 0.74 (0.70-0.78). CONCLUSIONS: Adjunctive BSGI had higher specificity than adjunctive US without loss of sensitivity. This finding suggests that adjunctive BSGI may be a useful complementary initial imaging method to improve the detection of breast cancer in women who have calcifications with suspicious morphology at mammography. PMID- 28819910 TI - The Challenge of Assessing Adherence to Subcutaneous Biological Drugs in Immune Mediated Inflammatory Diseases. Letter to the Editor Regarding Michetti P, Weinman J, Mrowietz U, et al. Adv Ther (2017);34:91-108. doi:10.1007/s12325-016 0441-3. PMID- 28819911 TI - Neighborhood, Family, and Peer Factors Associated with Early Adolescent Smoking and Alcohol Use. AB - There is broad agreement that neighborhood contexts are important for adolescent development, but there is less consensus about their association with adolescent smoking and alcohol use. Few studies have examined associations between neighborhood socioeconomic contexts and smoking and alcohol use while also accounting for differences in family and peer risk factors for substance use. Data drawn from the Seattle Social Development Project (N = 808), a gender balanced (female = 49%), multiethnic, theory-driven longitudinal study originating in Seattle, WA, were used to estimate trajectories of smoking and alcohol use from 5th to 9th grade. Time-varying measures of neighborhood socioeconomic, family, and peer factors were associated with smoking and alcohol use at each wave after accounting for average growth in smoking and alcohol use over time and demographic differences. Results indicated that living in more socioeconomically disadvantaged neighborhoods, lower family income, lower family general functioning, more permissive family smoking environments, and affiliation with deviant peers were independently associated with increased smoking. Lower family functioning, more permissive family alcohol use environments, and deviant peers were independently associated with increased alcohol use. The effect of neighborhood disadvantage on smoking was mediated by family income and deviant peers while the effect of neighborhood disadvantage on alcohol use was mediated by deviant peers alone. Family functioning and family substance use did not mediate associations between neighborhood disadvantage and smoking or alcohol use. The results highlight the importance of neighborhood, family, and peer factors in early adolescent smoking and alcohol use. Future studies should examine the unique association of neighborhood disadvantage with adolescent smoking net of family socioeconomics, functioning, and substance use, as well as peer affiliations. Better understanding of the role of contextual factors in early adolescent smoking and alcohol use can help bolster efforts to prevent both short and long harms from substance use. PMID- 28819912 TI - A case of Q fever with erythema nodosum. AB - BACKGROUND: Acute Q fever is asymptomatic in 60% of the patients, while the reminder may present with fever, pneumoniae, and hepatitis. Skin manifestations are uncommon including transient punctiform rashes, purpuric, or maculopapular eruptions. Erythema nodosum have seldom been reported. CASE PRESENTATION: A 37 year-old female presented with fever for 1 month and skin lesions consists of erythematous painful nodule of the legs. Serological testing for Coxiella burnetii was positive. Treatment consisted with doxycycline for 2 weeks. Evolution was favorable. The patient completely recovered and had no evidence of skin lesion 1 month later. CONCLUSION: Because of its nonspecific clinical presentation, Q fever with erythema nodosum is probably underestimated. Q fever should be evocated when facing unexplained erythema nodosum even if there is not other typical clinical manifestation of Q fever. PMID- 28819913 TI - Chemoradiation and Local Excision for T2N0 Rectal Cancer Offers Equivalent Overall Survival Compared to Standard Resection: a National Cancer Database Analysis. AB - BACKGROUND: Local excision (LE) alone is associated with worse survival compared to radical surgery (RS) for T2 rectal cancer, but LE with additional chemoradiation (CRT) may improve outcomes. The objective of this study was to compare combined CRT and LE versus RS for T2 rectal cancer. METHODS: The 2004 2014 National Cancer Database was queried for patients with T2N0M0 rectal cancer undergoing LE with neoadjuvant(NA-CRT + LE) or adjuvant(LE + Adj-CRT) CRT, or RS. The main outcome was 5-year overall survival (OS). Cox proportional hazards was used to determine the independent effect of treatment on OS. RESULTS: A total of 4822 patients were included (4367 RS, 242 CRT + LE, 213 LE + Adj-CRT). Mean follow-up was 48.6 (SD28.5) months. There were no differences in patient characteristics, but more high-risk features in the LE + Adj-CRT group. There were no differences in 90-day mortality. Five-year OS was similar (RS 77.4% vs. CRT + LE 76.1% vs. LE + Adj-CRT 79.7%, p = 0.786). Older age, male gender, and higher Charlson score were independently associated with worse OS, whereas treatment type was not. If 90-day mortality was excluded, LE + Adj-CRT was independently associated with worse OS compared to RS. CONCLUSIONS: CRT with LE for T2N0M0 rectal cancer was not associated with worse OS compared to RS, and may be a viable treatment modality. PMID- 28819914 TI - Psychometric Characteristics of Non-instrumental Swallowing and Feeding Assessments in Pediatrics: A Systematic Review Using COSMIN. AB - As early diagnosis of swallowing and feeding difficulties in infants and children is of utmost importance, there is a need to evaluate the quality of the psychometric properties of pediatric assessments of swallowing and feeding. A systematic review was performed summarizing the psychometric properties of non instrumental assessments for swallowing and feeding difficulties in pediatrics; no data were identified for the remaining twelve assessments. The COSMIN taxonomy and checklist were used to evaluate the methodological quality of 23 publications on psychometric properties. For each assessment, an overall quality score for each measurement property was determined. As psychometric data proved incomplete, conflicting or indeterminate for all assessments, only preliminary conclusions could be drawn; the most robust assessment based on current data is the dysphagia disorder survey (DDS). However, further research is needed to provide additional information on all psychometric properties for all assessments. PMID- 28819915 TI - Suppression of methionine-induced colon injury of young rats by cysteine and N acetyl-L-cysteine. AB - Changes in the methionine metabolism can cause a state called hyperhomocysteinemia, inducing oxidative stress in the gut. The production of free radicals is important in the colon damage caused by methionine. This study aimed at evaluating the effect of the use of L-cysteine and N-acetyl-L-cysteine on the colon morphometry of young rats treated with methionine. A total number of 32 male rats were distributed in a randomized experimental design in 4 groups: control group treated with saline; methionine group; cysteine + methionine group, and N-acetyl-L-cysteine + methionine group. After 21 days of treatment, rats were sacrificed and the colon samples were taken for histological and biochemical analysis. Methionine load increased depth of crypts, the lamina muscularis mucosae thickness, the mucosal height, and the number of cells in lamina propria (p < 0.01). Combination of methionine with L-cysteine (C group) and with N-acetyl L-cysteine (N group) reversed methionine effects. Methionine treatment increased the GPx activity and MDA concentration, while L-cysteine and N-acetyl-L-cysteine increased the catalase activity compared to methionine group. It was concluded that the use of L-cysteine and N-acetyl-L-cysteine was beneficial to decrease intestinal mucosal height and oxidative damage when methionine was used in combination with them. PMID- 28819916 TI - Early Surgical Intervention for Acute Ulcerative Colitis Is Associated with Improved Postoperative Outcomes. AB - BACKGROUND: Timing of surgical intervention for acute ulcerative colitis has not been fully examined during the modern immunotherapy era. Although early surgical intervention is recommended, historical consensus for "early" ranges widely. The purpose of this study was to evaluate outcomes according to timing of urgent surgery for acute ulcerative colitis. METHODS: All non-elective total colectomies in ulcerative colitis patients were identified in the National Inpatient Sample from 2002 to 2014. Procedures, comorbidities, diagnoses, and in-hospital outcomes were collected using International Classification of Disease, 9th Revision codes. An operation was defined as early if within 24 hours of admission. Results were compared between the early versus delayed surgery groups. RESULTS: We found 69,936 patients that were admitted with ulcerative colitis, and 2650 patients that underwent non-elective total colectomy (3.8%). Early intervention was performed in 20.4% of patients who went to surgery. More early operations were performed laparoscopically (28.1% versus 23.3%, p = 0.021) and on more comorbid patients (Charlson Index, p = 0.008). Median total hospitalization costs were $20,948 with an early operation versus $33,666 with a delayed operation (p < 0.001). Delayed operation was an independent risk for a complication (OR = 1.46, p = 0.001). Increased hospitalization costs in the delayed surgery group were statistically significantly higher with a reported complication (OR = 3.00, p < 0.001) and lengths of stay (OR = 1.26, p < 0.001). CONCLUSION: Delayed operations for acute ulcerative colitis are associated with increased postoperative complications, increased lengths of stay, and increased hospital costs. Further prospective studies could demonstrate that this association leads to improved outcomes with immediate surgical intervention for medically refractory ulcerative colitis. PMID- 28819917 TI - Polyglandular autoimmune syndromes. AB - BACKGROUND: In recent years, scientific knowledge pertaining to the rare ORPHAN polyglandular autoimmune syndrome (registered code ORPHA 282196) has accumulated. OBJECTIVE: To offer current demographic, clinical, serological and immunogenic data on PAS. METHODS: Review of the pertinent and current literature. RESULTS: Polyglandular autoimmune syndromes (PAS) are multifactorial diseases with at least two coexisting autoimmune-mediated endocrinopathies. PAS show a great heterogeneity of syndromes and manifest sequentially with a large time interval between the occurrence of the first and second glandular autoimmune disease. PAS cluster with several non-endocrine autoimmune diseases. In most endocrinopathies of PAS, the autoimmune process causes an irreversible loss of function, while chronic autoimmune aggressions can simultaneously modify physiological processes in the affected tissue and lead to altered organ function. The rare juvenile PAS type I is inherited in a monogenetic manner, whereas several susceptibility gene polymorphisms have been reported for the more prevalent adult types. Relevant for a timely diagnosis at an early stage is the screening for polyglandular autoimmunity in patients with monoglandular autoimmune disease and/or first degree relatives of patients with PAS. The most prevalent adult PAS type is the combination of type 1 diabetes with autoimmune thyroid disease. CONCLUSIONS: Early detection of specific autoantibodies and latent organ-specific dysfunction is advocated to alert physicians to take appropriate action in order to prevent full-blown PAS disease. PMID- 28819918 TI - Network Analysis of Se-and Zn-related Proteins in the Serum Proteomics Expression Profile of the Endemic Dilated Cardiomyopathy Keshan Disease. AB - Keshan disease (KD) is an endemic cardiomyopathy with high mortality. Selenium (Se) and zinc (Zn) deficiencies are closely related to KD. The molecular mechanism of KD pathogenesis is still unclear. There are only few studies on the interaction of trace elements and proteins associated with the pathogenesis of KD. In this study, isobaric tags for relative and absolute quantitation (iTRAQ) coupled two-dimensional liquid chromatography tandem mass spectrometry (2DLC MS/MS) technique analysis was used to analyze the differential expression of proteins from serum samples. Comparative Toxicogenomics Database (CTD) was used to screen Se- and Zn-associated proteins. Then, pathway and network analyses of Se- and Zn-associated proteins were constituted by Cytoscape ClueGO and GeneMANIA plugins. One hundred and five differentially expressed proteins were obtained by 2DLC-MS/MS, among them 19 Se- and 3 Zn-associated proteins. Fifty-two pathways were identified from ClueGO and 1 network from GeneMANIA analyses. The results showed that Se-associated proteins STAT3 and MAPK1 and Zn-associated proteins HIF1A and PARP1, the proteins involved in HIF-1 signaling pathway and apoptosis pathway, may play significant roles in the pathogenesis of KD. The approach of this study would be also beneficial for further dissecting molecular mechanism of other trace element-associated disease. PMID- 28819919 TI - The Microbial Mother Meets the Independent Organ: Cultural Discourses of Reproductive Microbiomes. AB - The human microbiome is changing the way experts and non-experts think about germs and microorganisms. This essay is a gender analysis of contemporary discourses surrounding the human reproductive microbiome, specifically the vaginal microbiota and the penile microbiota. I first historically situate the human reproductive microbiome within the germ theory of disease. Then, I draw on Heather Paxson's Foucauldian and Latourian concept of microbiopolitics to argue that microbiopolitics is not only about how humans should live with microorganisms; but it also impacts how humans and microbes live together as gendered beings. I illustrate this gendering through two figures: the microbial mother and the independent organ. PMID- 28819920 TI - "No Country for Old Men": Huxley's Brave New World and the Value of Old Age. AB - This article inserts Aldous Huxley's Brave New World (1932) into a bioethical conversation about the value of old age and old people. Exploring literary treatments of bioethical questions can supplement conversations within bioethics proper, helping to reveal our existing assumptions and clear the way for more considered views; indeed, as Peter Swirski has argued, literary texts can serve as thought experiments that illuminate the ramifications of philosophical ideas. This essay examines the novel's representation of a society without old people in conjunction with ideas about aging and life narratives put forward by philosophers and bioethicists such as Ezekiel Emanuel, Gilbert Meilaender, and Alasdair MacIntyre. While critics, and Huxley himself, view the Brave New World as dystopian primarily because of its depiction of a totalitarian society where art, truth, and meaning are sacrificed to pleasure and distraction and where the ruled are programmed not to question the values of their rulers, the novel also makes clear that the excision of old age has significant political, moral, and emotional costs. PMID- 28819921 TI - Perspective. PMID- 28819922 TI - Therapeutic Alliance, Client Need for Approval, and Perfectionism as Differential Moderators of Response to eHealth and Traditionally Delivered Treatments for Comorbid Depression and Substance Use Problems. AB - PURPOSE: This study sought to undertake an exploratory analysis of the impact of therapeutic alliance and dysfunctional attitudes (perfectionism and need for approval) on outcomes for participants receiving therapist-delivered and eHealth interventions for comorbid depression and alcohol/cannabis use problems. These factors have been shown in previous research to moderate response to psychological treatment for depression and related disorders. METHOD: Participants (N = 274) with concurrent depression and alcohol/cannabis misuse were randomized to 10 sessions of therapist-delivered cognitive behavior therapy/motivational interviewing (CBT/MI), computer-delivered CBT/MI with brief therapist assistance (SHADE CBT/MI), or supportive counseling (PCT). Follow-up occurred at 3, 6, and 12 months post-baseline. Exploratory moderator analyses examined changes in depression, alcohol use, and cannabis use over the 3-12-month follow-up timepoints, adjusting for baseline, as a function of treatment allocation, and the hypothesized moderators of therapeutic alliance, perfectionism, and need for approval. RESULTS: The sample size and number of comparisons in the analysis mean that the results are considered preliminary and need replication in larger trials. The analysis revealed that "client initiative," a subscale of therapeutic alliance, moderated change in depression scores between 3- and 12-month follow-up for the PCT group, with higher scores associated with decreases in depression over time. Higher therapeutic "bond" early in treatment for SHADE CBT/MI participants was associated with reduced cannabis use over time. Participants with higher "perfectionism" scores at baseline who received therapist CBT/MI reported increases in depression over the follow-up period, but reductions in depression if they received SHADE CBT/MI. Therapist CBT/MI participants high on "need for approval" at baseline reported better alcohol use outcomes over time. CONCLUSION: The preliminary nature of these results do not justify firm conclusions. However, the specific variables of perfectionism, need for approval, and client initiative show promise as moderators of treatment efficacy for comorbid depression and alcohol/cannabis use problems. Further research is justified to determine whether these factors can assist in tailoring the modality and strategies offered in the delivery of psychotherapy to this population. PMID- 28819923 TI - Severe dysphagia rapidly reverted after iron supplementation. PMID- 28819924 TI - Dynamic imaging of mitochondrial membrane proteins in specific sub-organelle membrane locations. AB - Mitochondria are cellular organelles with multifaceted tasks and thus composed of different sub-compartments. The inner mitochondrial membrane especially has a complex nano-architecture with cristae protruding into the matrix. Related to their function, the localization of mitochondrial membrane proteins is more or less restricted to specific sub-compartments. In contrast, it can be assumed that membrane proteins per se diffuse unimpeded through continuous membranes. Fluorescence recovery after photobleaching is a versatile technology used in mobility analyses to determine the mobile fraction of proteins, but it cannot provide data on subpopulations or on confined diffusion behavior. Fluorescence correlation spectroscopy is used to analyze single molecule diffusion, but no trajectory maps are obtained. Single particle tracking (SPT) technologies in live cells, such as tracking and localization microscopy (TALM), do provide nanotopic localization and mobility maps of mitochondrial proteins in situ. Molecules can be localized with a precision of between 10 and 20 nm, and single trajectories can be recorded and analyzed; this is sufficient to reveal significant differences in the spatio-temporal behavior of diverse mitochondrial proteins. Here, we compare diffusion coefficients obtained by these different technologies and discuss trajectory maps of diverse mitochondrial membrane proteins obtained by SPT/TALM. We show that membrane proteins in the outer membrane generally display unhindered diffusion, while the mobility of inner membrane proteins is restricted by the inner membrane architecture, resulting in significantly lower diffusion coefficients. Moreover, tracking analysis could discern proteins in the inner boundary membrane from proteins preferentially diffusing in cristae membranes, two sub-compartments of the inner mitochondrial membrane. Thus, by evaluating trajectory maps it is possible to assign proteins to different sub compartments of the same membrane. PMID- 28819925 TI - The behavioural ecology of irrational behaviours. AB - Natural selection is often envisaged as the ultimate cause of the apparent rationality exhibited by organisms in their specific habitat. Given the equivalence between selection and rationality as maximizing processes, one would indeed expect organisms to implement rational decision-makers. Yet, many violations of the clauses of rationality have been witnessed in various species such as starlings, hummingbirds, amoebas and honeybees. This paper attempts to interpret such discrepancies between economic rationality (defined by the main axioms of rational choice theory) and biological rationality (defined by natural selection). After having distinguished two kinds of rationality we introduce irrationality as a negation of economic rationality by biologically rational decision-makers. Focusing mainly on those instances of irrationalities that can be understood as exhibiting inconsistency in making choices, i.e. as non conformity of a given behaviour to axioms such as transitivity or independence of irrelevant alternatives, we propose two possible families of Darwinian explanations that may account for these apparent irrationalities. First, we consider cases where natural selection may have been an indirect cause of irrationality. Second, we consider putative cases where violations of rationality axioms may have been directly favored by natural selection. Though the latter cases (prima facie) seem to clearly contradict our intuitive representation of natural selection as a process that maximizes fitness, we argue that they are actually unproblematic; for often, they can be redescribed as cases where no rationality axiom is violated, or as situations where no adaptive solution exists in the first place. PMID- 28819926 TI - Targeting metabolic pathways for head and neck cancers therapeutics. AB - Cancer cells have distinctive energy metabolism pathways that support their rapid cell division. The preference for anaerobic glycolysis under the normal oxygen condition is known as the Warburg effect and has been observed in head and neck cancers. These metabolic changes are controlled by cancer-related transcription factors, such as tumor suppressor gene and hypoxia inducible factor 1alpha. In addition, various metabolic enzymes also actively regulate cancer-specific metabolism including the switch between aerobic and anaerobic glycolysis. For a long time, these metabolic changes in cancer cells have been considered a consequence of transformation required to maintain the high rate of tumor cell replication. However, recent studies indicate that alteration of metabolism is sufficient to initiate tumor transformation. Indeed, oncogenic mutations in the metabolic enzymes, isocitrate dehydrogenase and succinate dehydrogenase, have been increasingly found in various cancers, including head and neck cancers. In the present review, we introduce recent findings regarding the cancer metabolism, including the molecular mechanisms of how they affect cancer pathogenesis and maintenance. We also discuss the current and future perspectives on therapeutics that target metabolic pathways, with an emphasis on head and neck cancer. PMID- 28819927 TI - Switching From Immediate-Release to Delayed-Release Prednisone in Moderate to Severe Rheumatoid Arthritis: A Practice-Based Clinical Study. AB - INTRODUCTION: Rheumatoid arthritis (RA) produces debilitating morning stiffness. Exogenous glucocorticoids can help with these symptoms when timed appropriately. Bedtime dosing of delayed-release prednisone (DR-prednisone) matches the rise of inflammatory cytokines before awakening and can improve stiffness and other RA symptoms. A prospective open-label study was conducted in patients currently on stable doses of immediate-release prednisone (IR-prednisone) who were switched to DR-prednisone to analyze the incremental benefit of better timed and lower dose glucocorticoid therapy. METHODS: Twelve US sites enrolled patients with moderate severe RA into a 12-week prospective study. Patients were switched from IR- to DR prednisone while maintaining other existing background therapies. Change from baseline in morning stiffness severity, morning stiffness duration, swollen and tender joint counts (S-TJC), 28 joint disease activity score (DAS28), and patient/physician global assessment (PGA/PhGA), among others, were measured. Post hoc analyses were performed on those completing 10 weeks of treatment and those with >60 min of morning stiffness at baseline. RESULTS: Fifty-six patients had at least one follow-up visit and were similar in demographics to previous controlled trials with DR-prednisone with regard to baseline age and DAS28-CRP but had lower morning stiffness and RA duration. DR-prednisone produced a trend toward lower morning stiffness severity and duration with a reduction in daily prednisone dose of almost 1 mg. Patients treated with DR-prednisone for >=10 weeks demonstrated significant reductions in morning stiffness duration, SJC, TJC, DAS28-CRP, and PhGA (all p <= 0.04). Patients treated for >=10 weeks with >60 min of baseline morning stiffness produced similar results in these measures as well as a 21% reduction in morning stiffness severity (p = 0.02). CONCLUSION: Patients switched to DR-prednisone from IR-prednisone in this practice-based study maintained or improved their outcomes across a variety of domains, and results were comparable to previous controlled trials in which patients completed at least 10 weeks of treatment. FUNDING: Horizon Pharma USA, Inc. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02287610. PMID- 28819928 TI - Development of a Rating Tool for Mobile Cancer Apps: Information Analysis and Formal and Content-Related Evaluation of Selected Cancer Apps. AB - Mobile apps are offered in large numbers and have different qualities. The aim of this article was to develop a rating tool based on formal and content-related criteria for the assessment of cancer apps and to test its applicability on apps. After a thorough analysis of the literature, we developed a specific rating tool for cancer apps based on the MARS (mobile app rating system) and a rating tool for cancer websites. This instrument was applied to apps freely available in stores and focusing on some cancer topic. Ten apps were rated on the basis of 22 criteria. Sixty percent of the apps (6/10) were rated poor and insufficient. The rating by different scientists was homogenous. The good apps had reliable sources were regularly updated and had a concrete intent/purpose in their app description. In contrast, the apps that were rated poor had no distinction of scientific content and advertisement. In some cases, there was no imprint to identify the provider. As apps of poor quality can give misinformation and lead to wrong treatment decisions, efforts have to be made to increase usage of high quality apps. Certification would help cancer patients to identify reliable apps, yet acceptance of a certification system must be backed up. PMID- 28819929 TI - A comparative study of the adhesion of biosynthesized gold and conjugated gold/prodigiosin nanoparticles to triple negative breast cancer cells. AB - This paper explores the adhesion of biosynthesized gold nanoparticles (AuNPs) and gold (Au) nanoparticle/prodigiosin (PG) drug nanoparticles to breast cancer cells (MDA-MB-231 cells). The AuNPs were synthesized in a record time (less than 30 s) from Nauclea latifolia leaf extracts, while the PG was produced via bacterial synthesis with Serratia marcescens sp. The size distributions and shapes of the resulting AuNPs were characterized using transmission electron microscopy (TEM), while the resulting hydrodynamic diameters and polydispersity indices were studied using dynamic light scattering (DLS). Atomic Force Microscopy (AFM) was used to study the adhesion between the synthesized gold nanoparticles (AuNPs)/LHRH-conjugated AuNPs and triple negative breast cancer cells (MDA-MB-231 cells), as well as the adhesion between LHRH-conjugated AuNP/PG drug and MDA-MB 231 breast cancer cells. The adhesion forces between LHRH-conjugated AuNPs and breast cancer cells are shown to be five times greater than those between AuNPs and normal breast cells. The increase in adhesion is shown to be due to the over expression of LHRH receptors on the surfaces of MDA-MB-231 breast cancer cells, which was revealed by confocal immuno-fluorescence microscopy. The implications of the results are then discussed for the selective and specific targeting and treatment of triple negative breast cancer. PMID- 28819930 TI - Association Between Patient Satisfaction and Short-Term Outcomes After Major Cancer Surgery. AB - OBJECTIVE: The aim of this study was to investigate whether patient satisfaction, as measured by the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey, is associated with short-term outcomes after major cancer surgery. MATERIALS AND METHODS: We first used national Medicare claims to identify patients who underwent a major extirpative cancer surgery from 2011 to 2013. Next, we used Hospital Compare data to assign the HCAHPS score to the hospital where the patient underwent surgery. We then performed univariate statistical analyses and fit multilevel logistic regression models to evaluate the relationship between excellent patient satisfaction and short-term cancer surgery outcomes for all surgery types combined and then by each individual surgery type. RESULTS: We identified 373,692 patients who underwent major cancer surgery for one of nine cancers at 2617 hospitals. In both unadjusted and adjusted analyses, hospitals with higher proportions of patients reporting excellent satisfaction had lower complication rates (p < 0.001), readmissions (p < 0.001), mortality (p < 0.001), and prolonged length of stay (p < 0.001) than hospitals with lower proportions of satisfied patients, but with modest differences. This finding held true broadly across individual cancer types for complications, mortality, and prolonged length of stay, but less so for readmissions. CONCLUSIONS: Hospital-wide excellent patient satisfaction scores are associated with short-term outcomes after major cancer surgery overall, but are modest in magnitude. PMID- 28819931 TI - Phenotypic and genotypic characterization of antioxidant enzyme system in human population exposed to radiation from mobile towers. AB - In the present era, cellular phones have changed the life style of human beings completely and have become an essential part of their lives. The number of cell phones and cell towers are increasing in spite of their disadvantages. These cell towers transmit radiation continuously without any interruption, so people living within 100s of meters from the tower receive 10,000 to 10,000,000 times stronger signal than required for mobile communication. In the present study, we have examined superoxide dismutase (SOD) enzyme activity, catalase (CAT) enzyme activity, lipid peroxidation assay, and effect of functional polymorphism of SOD and CAT antioxidant genes against mobile tower-induced oxidative stress in human population. From our results, we have found a significantly lower mean value of manganese superoxide dismutase (MnSOD) enzyme activity, catalase (CAT) enzyme activity, and a high value of lipid peroxidation assay in exposed as compared to control subjects. Polymorphisms in antioxidant MnSOD and CAT genes significantly contributed to its phenotype. In the current study, a significant association of genetic polymorphism of antioxidant genes with genetic damage has been observed in human population exposed to radiations emitted from mobile towers. PMID- 28819933 TI - Nutcracker Syndrome and Sickle Cell Trait. PMID- 28819932 TI - Twice-Daily vs. Once-Daily Dosing with 0.075% Bromfenac in DuraSite: Outcomes from a 14-Day Phase 2 Study. AB - INTRODUCTION: Bromfenac is a well-known topical ophthalmic nonsteroidal anti inflammatory drug (NSAID) that is commercialized in the USA and other regions of the world. A new formulation, 0.075% bromfenac in DuraSite(r), was developed to treat postoperative inflammation and reduce pain in patients who have undergone cataract surgery. We hypothesized that efficacy and safety would be enhanced with twice-daily (BID) dosing compared to once-daily (QD) dosing. METHODS: This was a multicenter, double-masked, comparative study in which 40 and 45 subjects were randomized to groups receiving BID dosing and QD dosing, respectively. Subjects self-instilled the study drug for 14 days postoperative and were followed for an additional 2-week evaluation phase. The primary efficacy endpoint was the proportion of subjects with an anterior chamber cell (ACC) grade of 0 at day 15. RESULTS: A total of 45 subjects had cleared ACC (grade "0") at day 15, of whom 21 were in the BID group (52.5%) and 24 were in the QD group (53.5%). A secondary analysis found 7/40 (17.5%) subjects in the BID group and 10/45 (22.2%) subjects in the QD group achieved an ACC grade of 0 at day 8. There were more adverse events in the QD group (n = 16) than in the BID group (n = 12). CONCLUSION: Similar outcomes were observed for subjects using Bromfenac 0.075% in DuraSite(r) in the BID and QD dosing regimens for the treatment of post-cataract surgery inflammation. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01190878. FUNDING: InSite Vision (now a division of Sun Pharma). PMID- 28819934 TI - Erratum to: Selenium nanoparticles with low-level ionizing radiation exposure ameliorate nicotine-induced inflammatory impairment in rat kidney. PMID- 28819936 TI - Introducing navigation during melanoma-related sentinel lymph node procedures in the head-and-neck region. AB - BACKGROUND: Intraoperative sentinel node (SN) identification in patients with head-and-neck malignancies can be challenging due to unexpected drainage patterns and anatomical complexity. Here, intraoperative navigation-based guidance technologies may provide outcome. In this study, gamma camera-based freehandSPECT was evaluated in combination with the hybrid tracer ICG-99mTc-nanocolloid. MATERIALS AND METHODS: Eight patients with melanoma located in the head-and-neck area were included. Indocyanine green (ICG)-99mTc-nanocolloid was injected preoperatively, whereafter lymphoscintigraphy and SPECT/CT imaging were performed in order to define the location of the SN(s). FreehandSPECT scans were generated in the operation room using a portable gamma camera. For lesion localization during surgery, freehandSPECT scans were projected in an augmented reality video view that was used to spatially position a gamma-ray detection probe. Intraoperative fluorescence imaging was used to confirm the accuracy of the navigation-based approach and identify the exact location of the SNs. RESULTS: Preoperatively, 15 SNs were identified, of which 14 were identified using freehandSPECT. Navigation towards these nodes using the freehandSPECT approach was successful in 13 nodes. Fluorescence imaging provided optical confirmation of the navigation accuracy in all patients. In addition, fluorescence imaging allowed for the identification of (clustered) SNs that could not be identified based on navigation alone. CONCLUSIONS: The use of gamma camera-based freehandSPECT aids intraoperative lesion identification and, with that, supports the transition from pre- to intraoperative imaging via augmented reality display and directional guidance. PMID- 28819935 TI - Plasma Biomarkers of Inflammation Reflect Seizures and Hemorrhagic Activity of Cerebral Cavernous Malformations. AB - The clinical course of cerebral cavernous malformations (CCMs) is highly variable. Based on recent discoveries implicating angiogenic and inflammatory mechanisms, we hypothesized that serum biomarkers might reflect chronic or acute disease activity. This single-site prospective observational cohort study included 85 CCM patients, in whom 24 a priori chosen plasma biomarkers were quantified and analyzed in relation to established clinical and imaging parameters of disease categorization and severity. We subsequently validated the positive correlations in longitudinal follow-up of 49 subjects. Plasma levels of matrix metalloproteinase-2 and intercellular adhesion molecule 1 were significantly higher (P = 0.02 and P = 0.04, respectively, FDR corrected), and matrix metalloproteinase-9 was lower (P = 0.04, FDR corrected) in patients with seizure activity at any time in the past. Vascular endothelial growth factor and endoglin (both P = 0.04, FDR corrected) plasma levels were lower in patients who had suffered a symptomatic bleed in the prior 3 months. The hierarchical clustering analysis revealed a cluster of four plasma inflammatory cytokines (interleukin 2, interferon gamma, tumor necrosis factor alpha, and interleukin 1 beta) separating patients into what we designated "high" and "low" inflammatory states. The "high" inflammatory state was associated with seizure activity (P = 0.02) and more than one hemorrhagic event during a patient's lifetime (P = 0.04) and with a higher rate of new hemorrhage, lesion growth, or new lesion formation (P < 0.05) during prospective follow-up. Peripheral plasma biomarkers reflect seizure and recent hemorrhagic activity in CCM patients. In addition, four clustered inflammatory biomarkers correlate with cumulative disease aggressiveness and predict future clinical activity. PMID- 28819937 TI - The presence of A5935G, G5949A, G6081A, G6267A, T9540C mutations in MT-CO1 and MT CO3 genes and other variants of MT-CO1 and MT-CO3 gene fragments in the study population diagnosed with endometrial cancer. AB - OBJECTIVES: The specific purpose of this study was the assessment of A5935G, G5949A, G6081A, G6267A mutations in MT-CO1 and T9540C in MT-CO3, and alterations detected during the analysis of MT-CO gene fragments in subject and control groups. A secondary aim was to assess the relationship between MT-CO1 and MT-CO3 gene alterations and endometrial cancer incidence and evaluation of the prognostic value of MT-CO1 and MT-CO3 gene alterations. MATERIAL AND METHODS: In this study, we investigated A5935G, G5949A, G6081A, G6267A mutations in MT-CO1 and T9540C in MT-CO3, and alterations detected during the analysis of MT-CO gene fragments in formalin-fixed, paraffin-embedded endometrial and benign endometrial hyperplasia of a cohort of 125 subjects. RESULTS: The T9540C mutation in MT-CO3 was detected in one patient from the subject group. None of the remaining muta tions were detected. The research showed that the presence of alterations in MT CO1 and MT-CO3 typical of other types of cancer is not a risk factor for endometrial cancer. Analysis of MT-CO1 and MT-CO3 gene fragments revealed 10 alterations (6 and 4 respectively). The alterations detected were identified in 10% of the tested group and 8% of the control group. CONCLUSIONS: The research showed that the presence of alterations in MT-CO1 (A5935G, G5949A, G6081A, G6267A) typical of other types of cancer is not a risk factor for endometrial cancer. Three new alterations detected in this study (A6052G, A9545G, G9575A) were described for the first time. PMID- 28819938 TI - See and treat strategy by LEEP conization in patients with abnormal cervical cytology. AB - OBJECTIVES: To determine the overtreatment and re-LEEP rates of see and treat strategy (S & T) in women who underwent S & T by LEEP and to identify the risk factors for overtreatment and surgical margin and/or endocervical curettage positivity. MATERIAL AND METHODS: A total of 800 patients who underwent S & T in Istanbul University Cerrahpasa Medical Faculty between June 2010 and June 2016 were retrospectively analyzed. RESULTS: Overtreatment rate was found to be 46.6%, decreasing with higher grade of cervical smear abnormalities. Age more than 45, low grade of cervical cytologic abnormality and absence of glandular involvement were associated with higher overtreatment rates. The more advanced the histopathology, the more increased risk of surgical margin on LEEP and ECC positivity (p < 0.0001, for both). Glandular involvement was associated with both surgical margin and ECC positivity. CONCLUSIONS: S & T can be used in patients with high grade cytologic anomaly with an acceptable overtreatment rate. In addition, bigger pieces of specimens may need to be removed during LEEP in patients who have suspicious images of higher grade of abnormalities on colposcopy to reduce surgical margin or ECC positivity. When high rate of ECC positivity in patients with HSIL cytology is considered, we suggest performing ECC to every patients with HSIL. PMID- 28819939 TI - Serum levels of soluble interleukin-2 receptor in association with oxidative stress index in patients with different types of HPV. AB - OBJECTIVES: The aim of this paper is to determine the oxidative-antioxidative status and levels of soluble interleukin-2 recep-tor (sIL-2R) in serum of patients with different types of HPV infections and to compare it with patients who are negative for HPV. MATERIAL AND METHODS: A total of 80 women were divided into three groups as follows: Group 1 consisted of 25 women who were positive for HPV types 16 or 18; Group 2 consisted of 25 women who were positive for other types of HPV includ-ing type 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 or 68; Group 3 consisted of 30 patients who were negative for HPV as a control group. Serum sIL-2R and plasma oxidative stress index (OSI) were analyzed. RESULTS: Serum sIL 2R levels were significantly higher in group 1 compared to group 2 and 3. OSI was found significantly increased in groups 1 and 2 compared to group 3. Also, we found a weak positive correlation between IL-2R and OSI. CONCLUSION: sIL-2R and oxidative stress may have a role in HPV infection, especially in case of high risk types. PMID- 28819940 TI - The analysis of repeatability and reproducibility of bladder neck mobility measurements obtained during pelvic floor sonography performed introitally with 2D transvaginal probe. AB - OBJECTIVES: The aim of the study was the evaluation of repeatability and reproducibility of chosen urethral neck mobility measurements obtained during introital pelvic floor sonography performed with a 2D transvaginal probe. MATERIAL AND METHODS: In order to assess the repeatability and reproducibility, independent measurements on the ultra-sound image were taken by two specialists on 92 female patients at rest and at strain (Valsalva maneuver). 2D ultrasound examination was performed introitally with a transvaginal probe (PFS-TV). The location of the urethral internal orifice was defined with coordinates of two points. Point CI marks the urethral anterior edge visualized on ultrasound as closer to the pubic symphysis. Point CII marks the posterior edge visualized more peripherally from pubic symphysis. RESULTS: Repeatability and reproducibility measurements of point CI location and mobility were good and very good (0.6710 0.9961), while of point CII - were medium, good and very good (0.5738-0.9944). Point CI was clearly visible in all cases. It was not possible to accurately mark point CII in 4.3-17.4% of cases. CONCLUSIONS: The possibility to visualize point CI in every single case with very good and good repeatability and reproduc ibility of measurements of this point's location and mobility allows the usage of CI point as a universal reference point for evaluation of bladder neck mobility and position during PFS-TV in the clinical practice and for research purposes. PMID- 28819941 TI - Maternal and neonatal outcomes of pregnancy at 39 weeks and beyond with mild gestational diabetes mellitus. AB - OBJECTIVES: The purpose of this study was to retrospectively analyze maternal and neonatal outcomes in pregnant women with mild gestational diabetes mellitus at 39 weeks compared to 40 weeks. MATERIAL AND METHODS: Clinical data of 372 cases of mild gestational diabetes mellitus form First Affiliated Hospital of Sun Yat-sen University were analyzed retrospectively. There were 108 mild GDM patients that delivered at 40-40+6 weeks in our research group, and 264 patients that delivered in 39-39+6 weeks in the control group. Neonatal and maternal outcomes were compared between the two groups. RESULTS: There was no difference between the two groups in the rate of cesarean section (42.6% vs. 45.5%, p = 0.614). The incidence of large for gestational age between the two groups was also not different (11.1% vs. 10.6%, p = 0.887). The rate of postpartum hemorrhage and shoulder dystocia of the two groups was not different either (p > 0.05). There was no significant difference in the incidence of fetal distress, neonatal asphyxia, neonatal pathological jaundice, neonatal hypoglycemia, and neonatal respiratory distress syndrome in the two groups (p > 0.05). CONCLUSIONS: There were no significant differences in adverse pregnancy outcomes and neonatal outcomes in women with mild gestational diabetes between deliveries at 39 and 40 weeks. PMID- 28819942 TI - Study of the relationship between AGEs and oxidative stress damage to trophoblast cell mitochondria. AB - OBJECTIVES: To study the influence of AGEs on placental trophoblast mitochondria oxidative stress, and to explore the possible pathogenesis which may participate in pre-eclampsia. MATERIAL AND METHODS: Human trophoblast cells from early pregnancy were cultured by an enzyme-digestion method. When trophoblast cells reached approximately 70-80% after passages, they were incubated with pre eclampsia serum for 24 hours. A fluorescent dye assay was applied to measure the mitochondrial membrane potential; ELISA was used to measure the activity of the mitochondrial permeability transition pore. mtDNA was detected by Real-time fluorescence quantitative Reverse Transcription-Polymerase Chain Reaction (RT PCR). We continued to culture one group of cells with pre-eclampsia maternal serum, and other cells were pulsed with 600 mg/L AGEs. Cells were incubated for 16 hours before assaying the levels of mitochondrial oxidative stress damage. RESULTS: The levels of mitochondria oxidative stress damage in the AGEs group were higher than in the pre-eclampsia group 1 and pre-eclampsia group 2. There was no statistically significant difference in mitochondrial oxidative stress damage between the pre-eclampsia group 1 and group 2. CONCLUSIONS: The AGEs are involved in the pathogenesis of pre-eclampsia, possibly through the enhancement of mito-chondrial oxidative stress damage. PMID- 28819943 TI - The MMP-9/TIMP-1 imbalance and the reduced level of TGF-beta in the cervical area of amniotic membrane is a possible risk factor of PROM and premature labor - proof-of-concept study. AB - OBJECTIVES: To assess the level MMP-9, TIMP-1 and TGF-beta in placental and cervical region of amniotic membranes derived from at-term, pre-term and PROM deliveries. MATERIAL AND METHODS: 14 amniotic membranes have been assessed; the quantitative analysis of MMP-9, TGF-beta and TIMP-1 was assayed using respective Quantikine Immunoassay Kit. RESULTS: The MMP-9 level in PROM samples was similar to the level of MMP-9 in at-term membranes and comparable between the cervical and placental region of these membranes. The concentration of TGF-beta and TIMP-1 was decreased in the cervical area of AM derived from deliveries complicated with PROM. CONCLUSION: The MMP9/TIMP-1 imbalance, as well as the reduced level of TGF beta may be possible risk factors of pre-term labor and PROM. PMID- 28819944 TI - Contribution of inherited thrombophilia to recurrent miscarriage in the Polish population. AB - INTRODUCTION: The aim of the study was to evaluate the contribution of genetic variants determining inherited thrombophilia to recurrent miscarriage (RM) in the Polish population. The following polymorphisms were analyzed: 1691G>A, 1328T>C of coagulation factor V, 20210G>A of coagulation factor II, R353Q (11496G>A) of coagulation factor VII, 667C>T, 1298A>C, 1793G>A of MTHFR. MATERIAL AND METHODS: A total of 359 women with >= 2 subsequent recurrent miscarriages (303 < 13 weeks of gestation (w.g.) and 56 between 13-22 w.g.) and 400 healthy controls were included in the study. Frequency of the genetic polymor-phisms was determined with the PCR/RFLP method. RESULTS: Higher frequency of the 20210GA genotype was found in the RM < 13 w.g. (2.97 vs. 1.50% in controls, OR = 2.01, ns) and the RM 13-22 w.g. (5.36 vs. 1.50% in controls, OR = 3.72, p = 0.09) subgroups. Statistically significantly higher frequency of the 11496GA genotype was noted in controls as compared to the RM 13-22 w.g. subgroup (10.71 vs. 23.00% in controls, OR = 0.40, p = 0.02). Statistically significantly higher frequency of the 1793GA genotype was observed in the RM < 13 w.g. subgroup as compared to controls (12.21 vs. 7.75% in controls, OR = 1.66, p = 0.03). No significant correlations were found as far as the rest of the analyzed polymorphisms are concerned. CONCLUSIONS: The obtained results suggest that the 1793G>A MTHFR, R353Q (11496G>A) factor VII gene and the 20210G>A factor II gene polymorphisms play a role in the etiology of RM in the Polish population. PMID- 28819945 TI - Adolescent pregnancies: complications, birth outcomes and the possible solutions. AB - OBJECTIVES: In this study we aim to evaluate antenatal, perinatal and postnatal outcomes and complications of adolescent pregnancies, as well as to discuss the social and psychological consequences of these pregnancies. MATERIAL AND METHODS: We compare a total of 243 pregnant women at age 14-18 years to a vast control group at age 19-36 who all delivered at Bursa Yuksek Ihtisas Training and Research Hospital between years 2005-2014. RESULTS: Antenatal care (folic acid supplementation, pre-conception counseling) was significantly higher in adolescent pregnancy group. Unplanned pregnancy rate was significantly higher in in study group (p < 0.001). Preterm delivery (before 37th week) ratio was statistically higher in pregnancy complications. CONCLUSIONS: Adolescent pregnancy is a social entity which should be regulated and prevented by legal measures. Planned pregnancies should be promoted and the public should be educated and informed about the Hazards of adolescent pregnancies. Press institutions, public broadcasting services support the efforts to decrease adolescent pregnancies. PMID- 28819946 TI - Inflammatory bowel disease and pregnancy. AB - Inflammatory bowel disease (IBD) comprising Crohn's disease (CD), ulcerative colitis (UC), and IBD-unclassified (IBD-U) may appear at any age. As such, IBD commonly affects young patients in their reproductive age. Rate of voluntary childlessness among women with IBD far exceed that of the general population, as patients with IBD fear not only the effect of pregnancy on the course of inflammatory bowel disease, but also the increased risk of the offspring developing the disease, adverse pregnancy outcomes, the effect IBD treatment may have on the health and development of the infant or the risk of relapse during pregnancy and the influence of lactation on child development and disease course. This article aims at improving pre-conception counseling of patients with inflammatory bowel disease. PMID- 28819947 TI - Secondary dysmenorrhea due to a rudimentary, non-communicating functional uterine horn. AB - Unicornuate uterus with a rudimentary horn is a rare congenital Mullerian anomaly, which may lead to many obstetrical and gynaecological complications. This pathology occurs in approximately 1/100 000 women. A rudimentary horn forms due to insufficient development of the Mullerian duct. The diagnosis of this anomaly is usually delayed, as it remains asymptomatic until adolescence and its main symptom is dysmenorrhea. PMID- 28819948 TI - The role of selenium in thyroid gland pathophysiology. AB - It is now assumed that proper functioning of the thyroid gland (TG), beside iodine, requires also a number of elements, including selenium, iron, zinc, copper, and calcium. In many cases, only an adequate supply of one of these microelements (e.g. iodine) may reveal symptoms resulting from deficits of other microelements (e.g. iron or selenium). Selenium is accounted to the trace elements of key importance for homeostasis of the human system, in particular, for the proper functioning of the immune system and the TG. Results of epidemiological studies have demonstrated that selenium deficit may affect as many as one billion people in many countries all over the world. A proper sequence of particular supplementations is also worth emphasising for the significant correlations among the supplemented microelements. For example, it has been demonstrated that an excessive supplementation of selenium may enhance the effects of iodine deficit in endemic regions, while proper supplementation of selenium in studied animals may alleviate the consequences of iodine excess, preventing destructive-inflammatory lesions in the TG. This paper is a summary of the current knowledge on the role of selenium in the functionality of the TG. PMID- 28819949 TI - Addison's disease concomitant with corticotropin deficiency and pituitary CRH resistance - a case report. AB - : A 36-year-old woman was found to have a low morning ACTH concentration despite a history of Addison's disease. Past medical history: At the age of 23 years the subject developed Graves's disease, which was treated with radioiodine. At about the same time, she claimed to have two episodes of pancreatitis treated with cholecystectomy. About seven months later she was euthyroid on L-thyroxine (TSH 1.51 mIU/mL) but was admitted with hypotension, hyponatraemia (sodium 109 mmol/L), and low morning cortisol (119 nmol/L). Further investigations confirmed primary adrenal failure with ACTH concentration of 779 pg/mL (ref. range 0-60) prior to the dose of hydrocortisone. About nine years later she complained about tiredness. Clinically she was normotensive and not pigmented. BMI 22.3 kg/m2. Periods were regular. ACTH concentration was surprisingly low (ACTH 8.53 pg/mL, ref. range 0-46), despite very low cortisol (3.37 nmol/L). She was admitted for further assessment. INVESTIGATIONS: Pituitary MRI scan was unremarkable. An insulin tolerance test was performed and showed a clear increase of ACTH (from 15.2 to 165 pg/mL). There was, however, hardly any increase of ACTH after CRH stimulation (from 6.05 pg/mL to 10.2 pg/mL), thus demonstrating central CRH resistance. In summary, this patient developed secondary adrenal failure in the setting of previous Addison's disease. Interestingly, hypoglycaemia (but not CRH) provided a stimulus for ACTH release, thus demonstrating CRH resistance. The case confirms that besides CRH, other factors are responsible for stimulation of the ACTH-cortisol axis during insulin tolerance test. PMID- 28819950 TI - Successful EUS-guided ethanol ablation of insulinoma, four-year follow-up. Case report and literature review. AB - INTRODUCTION: EUS-guided ethanol ablation of insulinoma is a new method of treatment of this neuroendocrine tumour. Ablation is recommended in patients who are poor surgical candidates or refuse surgery. We present a case of an 81-year old female with symptomatic insulinoma, treated successfully with EUS-guided alcoholic ablation, along with a literature review including 28 other previously described cases. The effectiveness, safety of the therapy, and technical procedure-related issues are summarised. To the best of our knowledge, this is the first described case of successful insulinoma EUS-guided ablation in Poland. MATERIAL AND METHODS: We searched the PubMed/Medline database to identify cases of EUS-guided alcoholic ablation. Our analysis included 14 articles (case reports or case series), with a total of 27 patients and 31 tumours described, published before February 2017. RESULTS: The described tumours were relatively small (mean 13 mm), and the most common location was pancreatic head. The mean ethanol volume injected to the tumour was 1.8 ml and the concentration of infused alcohol varied from 95% to 98%.Side effects were observed in six cases; apart from one, they were mild and self-limiting. There was only one severe adverse event, treated conservatively with success. The median follow-up was 14.4 months (2-55 months). In all described cases ablation led to improvement of the symptoms and normalisation of glycaemia. CONCLUSIONS: The EUS-guided alcoholic ablation of insulinoma is a safe and effective method of treatment in patients who are poor surgical candidates and/or refuse surgery. The adverse effects are rare and mild and were observed when the volume of injected ethanol was equal to or above 3.0 ml. However, the data is limited, the follow-up is relatively short, and prospective studies are needed to confirm the long-term effects of treatment. The study shows also that there are important procedural differences (concentration and volume of alcohol, needle gauge, number of sessions) between the endoscopists, which should be specified. PMID- 28819952 TI - Cardioorthopedics - is it necessary in clinical practice? A study of patients with hip replacement surgery. PMID- 28819951 TI - Metformin - a new old drug. AB - For many years metformin has been the gold standard in the treatment of type 2 diabetes. According to recommendations of the most important diabetes associations, this is the first-choice drug for use as monotherapy in patients with newly diagnosed type 2 diabetes. Metformin is also recommended in combined treatment when monotherapy is no longer effective. It is then combined with a sulfony-lurea, an incretin, flozin, or insulin, irrespective of the number of insulin injections per day. Besides its properties used in the treatment of diabetes, metformin has been treated for some time as a drug of a so-called pleiotropic activity, as each year brings new reports about its favourable effect in different conditions. At present, the scope of reimbursed indications of this drug has been expanded to include prediabetes, insulin resistance syndromes, and polycystic ovary syndrome. Metformin does not stimulate insulin secretion by the beta cells of the pancreas, and thus it is a drug that does not cause hypoglycaemia. The blood glucose-lowering effect of the drug is a consequence of hepatic glucose production inhibition, and of peripheral tissue (muscle tissue, fatty tissue) sensitisation to the effect of insulin of both endogenous and exogenous origin. The exact mechanism of metformin action at the cellular level remained unknown for a long time. Studies performed in recent years have provided a great deal of information that enables better understanding of the mechanism of action of the drug as well as the clinical effects resulting from its use. Metformin, besides improvement of glycaemia, is neutral to body weight, is cardioprotective, improves lipid profile, and has a probable anti-cancer effect. Metformin accumulation in the intestinal mucosa may interfere with FDG (18F deoxyglucose) PET-CT image assessment. The aim of this article is a detailed discussion of metformin properties, its mechanisms of action, and clinical effects. PMID- 28819953 TI - Impact of post-dilatation on the reduction of paravalvular leak and mortality after transcatheter aortic valve implantation. AB - BACKGROUND: Post-implantation paravalvular leak (PVL) remains a significant complication of transcatheter aortic valve implantation (TAVI). More importantly, its occurrence may impact long-term mortality. AIM: We sought to evaluate the effects of balloon post-dilatation (PD) on the reduction of PVL and mortality in patients undergoing TAVI. METHODS: A total of 101 consecutive patients undergoing TAVI were enrolled. Angiography, echocardiography, and the aortic regurgitation index (ARI) were used to assess the severity of PVL before and after balloon PD. Patients were divided into two groups based whether or not PD after TAVI was performed. Reduction of PVL, change of ARI, and clinical outcomes were assessed. RESULTS: Balloon post-dilatation was performed in 23 (22.8%) patients. In 95.6%, PVL reduction was successful (no or mild PVL). PD increased the ARI from 23.4% (22.4-24.0) to 27.1% (26.1-28.3); p < 0.001. Thirty-day mortality rate was 14.1% in the PD (-) group vs. 0.0% in the PD (+) group; p = 0.07. One-year mortality (21.8% vs. 4.3%, p = 0.97) and procedural stroke rate (7.7% vs. 8.7%, p = 0.99) were not different between the groups. CONCLUSIONS: Balloon post-dilatation may be a safe and effective technique to reduce moderate to severe PVL after TAVI. PMID- 28819954 TI - Contemporary outcomes of catheter ablation of accessory pathways: complications and learning curve. AB - BACKGROUND AND AIM: The aim of this study was to examine contemporary results of accessory pathway (AP) ablation in a sizeable number of patients, focusing on periprocedural complications and the learning curve. METHODS: We performed a retrospective cohort study of consecutive AP ablation procedures at three centresby the same operator. In total 629 electrophysiological studies and 610 AP ablation procedures were performed in 570 patients (age: 33 +/- 18.9 years). RESULTS: There was one (0.16%) serious and there were 14 (2.3%) minor periprocedural complications. Five hundred and ninety APs were successfully ablated: single/multiple procedure success was 93.4%/96.7%, while the average fluoroscopy time was 13.5 min. There was significantly higher success and less fluoroscopy use with increased experience, while periprocedural complications seemed evenly distributed over the years. The learning was most pronounced for the first 120 cases. However, the learning curve fully flattened only after approximately 400 ablations. CONCLUSIONS: This study suggests that in the modern era AP ablation is safer than it was in the first two decades after the introduction of catheter ablation of APs. Perhaps, in experienced centres there should be a lower threshold for referring asymptomatic/mildly symptomatic patients with pre-excitation for electrophysiological study. PMID- 28819955 TI - Giant left main coronary artery aneurysm revealed by a myocardial infarction. PMID- 28819956 TI - Successful use of Impella CP(r) in cardiogenic shock after cardiac arrest: a first in Poland. PMID- 28819957 TI - Four-dimensional flow magnetic resonance imaging in hypertrophic obstructive cardiomyopathy. PMID- 28819958 TI - Abdominal ascitic fluid: tricky concealing of the electrocardiogram. PMID- 28819959 TI - Long-term results of endovascular treatment for May-Thurner syndrome. PMID- 28819960 TI - Unusual diagnosis hidden by poorly controlled asthma. PMID- 28819961 TI - [Bioresorbable scaffolds in the treatment of coronary artery disease. Expert consensus statement of the Association of Cardiovascular Interventions of the Polish Cardiac Society (ACVI PCS)]. AB - Bioresorbable scaffold coated with antimitotic drug is the latest development in the coronary stents technology. The concept of temporary scaffolding and natural vessel healing after angioplasty is a very attractive alternative to conventional metal stents. The results of the first observational studies have confirmed their ultimate biodegradation. Newest results of randomised trials and registries in broader clinical and anatomical indications also revealed the limitations of the first generation of scaffolds. The relatively thick polymeric struts and compliance with specific implantation protocol may influence the results. In this document, the group of experts presents the current state of knowledge, with a particular focus on the advantages and limitations of the new technology; it presents practical guidelines for optimal implantation techniques and clarifies documented indications for patients and lesions selection. PMID- 28819963 TI - Progress towards poliomyelitis eradication: Afghanistan, January 2016-June 2017. PMID- 28819962 TI - Monte Carlo simulations support non-Cerenkov radioluminescence production in tissue. AB - There is experimental evidence for the production of non-Cerenkov radioluminescence in a variety of materials, including tissue. We constructed a Geant4 Monte Carlo simulation of the radiation from P32 and Tc99m interacting in chicken breast and used experimental imaging data to model a scintillation-like emission. The same radioluminescence spectrum is visible from both isotopes and cannot otherwise be explained through fluorescence or filter miscalibration. We conclude that chicken breast has a near-infrared scintillation-like response with a light yield three orders of magnitude smaller than BGO. PMID- 28819964 TI - Human cases of influenza at the human-animal interface, January 2015-April 2017. PMID- 28819966 TI - Characterization of Nanopipet-Supported ITIES Tips for Scanning Electrochemical Microscopy of Single Solid-State Nanopores. AB - Nanoscale scanning electrochemical microscopy (SECM) is a powerful scanning probe technique that enables high-resolution imaging of chemical processes at single nanometer-sized objects. However, it has been a challenging task to quantitatively understand nanoscale SECM images, which requires accurate characterization of the size and geometry of nanoelectrode tips. Herein, we address this challenge through transmission electron microscopy (TEM) of quartz nanopipets for SECM imaging of single solid-state nanopores by using nanopipet supported interfaces between two immiscible electrolyte solutions (ITIES) as tips. We take advantage of the high resolution of TEM to demonstrate that laser pulled quartz nanopipets reproducibly yield not only an extremely small tip diameter of ~30 nm, but also a substantial tip roughness of ~5 nm. The size and roughness of a nanopipet can be reliably determined by optimizing the intensity of the electron beam not to melt or deform the quartz nanotip without a metal coating. Electrochemically, the nanoscale ITIES supported by a rough nanotip gives higher amperometric responses to tetrabutylammonium than expected for a 30 nm diameter disc tip. The finite element simulation of sphere-cap ITIES tips accounts for the high current responses and also reveals that the SECM images of 100 nm diameter Si3N4 nanopores are enlarged along the direction of the tip scan. Nevertheless, spatial resolution is not significantly compromised by a sphere-cap tip, which can be scanned in closer proximity to the substrate. This finding augments the utility of a protruded tip, which can be fabricated and miniaturized more readily to facilitate nanoscale SECM imaging. PMID- 28819967 TI - Enzymatic PEG-Poly(amine-co-disulfide ester) Nanoparticles as pH- and Redox Responsive Drug Nanocarriers for Efficient Antitumor Treatment. AB - We have designed and constructed novel multifunctional nanoparticle drug-delivery systems that are stable under physiological conditions and responsive to tumor relevant pH and intracellular reduction potential. The nanoparticles were fabricated from enzymatically synthesized poly(ethylene glycol) (PEG)-poly(omega pentadecalactone-co-N-methyldiethyleneamine-co-3,3'-dithiodipropionate) (PEG PPMD) and PEG-poly(epsilon-caprolactone-co-N-methyldiethyleneamine-co-3,3' dithiodipropionate) (PEG-PCMD) block copolymers via self-assembly processes in aqueous solution. At acidic pH and in the presence of a reductant (e.g., d,l dithiothreitol or glutathione), the nanosized micelle particles rapidly swell and disintegrate due to the protonation of amino groups and reductive cleavage of disulfide bonds in the micelle cores. Consistently, docetaxel (DTX)-loaded PEG PPMD and PEG-PCMD micelles can be triggered synergistically by acidic endosomal pH and a high intracellular reduction potential to rapidly release the drug for efficient killing of cancer cells. The drug formulations based on PEG-PPMD and PEG-PCMD copolymers exhibited a substantially higher potency than free DTX in inhibiting tumor growth in mice, whereas their therapeutic effects on important organ tissues were minimal. These results demonstrate that PEG-PPMD and PEG-PCMD nanoparticles have a great potential to serve as site-specific, controlled drug delivery vehicles for safe and efficient antitumor treatment. PMID- 28819965 TI - Enzymes Involved in AMPylation and deAMPylation. AB - Posttranslational modifications are covalent changes made to proteins that typically alter the function or location of the protein. AMPylation is an emerging posttranslational modification that involves the addition of adenosine monophosphate (AMP) to a protein. Like other, more well-studied posttranslational modifications, AMPylation is predicted to regulate the activity of the modified target proteins. However, the scope of this modification both in bacteria and in eukaryotes remains to be fully determined. In this review, we provide an up to date overview of the known AMPylating enzymes, the regulation of these enzymes, and the effect of this modification on target proteins. PMID- 28819968 TI - Popcorn-Derived Porous Carbon Flakes with an Ultrahigh Specific Surface Area for Superior Performance Supercapacitors. AB - Popcorn-derived porous carbon flakes have been successfully fabricated from the biomass of maize. Utilizing the "puffing effect", the nubby maize grain turned into materials with an interconnected honeycomb-like porous structure composed of carbon flakes. The following chemical activation method enabled the as-prepared products to possess optimized porous structures for electrochemical energy storage devices, such as multilayer flake-like structures, ultrahigh specific surface area (SBET: 3301 m2 g-1), and a high content of micropores (microporous surface area of 95%, especially the optimized sub-nanopores with the size of 0.69 nm) that can increase the specific capacitance. The as-obtained sample displayed excellent specific capacitance of 286 F g-1 at 90 A g-1 for supercapacitors. Moreover, the unique porous structure demonstrated an ideal way to improve the volumetric energy density performance. A high energy density of 103 Wh kg-1 or 53 Wh L-1 has been obtained in the case of ionic liquid electrolyte, which is the highest among reported biomass-derived carbon materials and will satisfy the urgent requirements of a primary power source for electric vehicles. This work may prove to be a fast, green, and large-scale synthesis route by using the large nubby granular materials to synthesize applicable porous carbons in energy storage devices. PMID- 28819969 TI - Fast and Universal Approach to Encapsulating Transition Bimetal Oxide Nanoparticles in Amorphous Carbon Nanotubes under an Atmospheric Environment Based on the Marangoni Effect. AB - Transition metal oxide nanoparticles capsuled in amorphous carbon nanotubes (ACNTs) are attractive anode materials of lithium-ion batteries (LIBs). Here, we first designed a fast and universal method with a hydromechanics conception which is called Marangoni flow to fabricate transition bimetal oxides (TBOs) in the ACNT composite with a better electrochemistry performance. Marangoni flows can produce a liquid column with several centimeters of height in a tube with one side immersed in the liquid. The key point to induce a Marangoni flow is to make a gradient of the surface tension between the surface and the inside of the solution. With our research, we control the gradient of the surface tension by controlling the viscosity of a solution. To show how our method could be generally used, we synthesize two anode materials such as (a) CoFe2O4@ACNTs, and (b) NiFe2O4@ACNTs. All of these have a similar morphology which is ~20 MUm length with a diameter of 80-100 nm for the ACNTs, and the particles (inside the ACNTs) are smaller than 5 nm. In particular, there are amorphous carbons between the nanoparticles. All of the composite materials showed an outstanding electrochemistry performance which includes a high capacity and cycling stability so that after 600 cycles the capacity changed by less than 3%. PMID- 28819970 TI - Chemical Selectivity at Grain Boundary Dislocations in Monolayer Mo1-xWxS2 Transition Metal Dichalcogenides. AB - Grain boundaries (GBs) are unavoidable crystal defects in polycrystalline materials and significantly influence their properties. However, the structure and chemistry of GBs in 2D transition metal dichalcogenide alloys have not been well established. Here we report significant chemical selectivity of transition metal atoms at GB dislocation cores in Mo1-xWxS2 monolayers. Different from classical elastic field-driven dislocation segregation in bulk crystals, the chemical selectivity in the 2D crystals originates prominently from variation of atomic coordination numbers at dislocation cores. This observation provides atomic insights into the topological effect on the chemistry of crystal defects in 2D materials. PMID- 28819971 TI - A Radical-Based Synthesis of Lingzhiol. AB - The polycyclic natural product lingzhiol [(+/-)-1] was synthesized from dimethoxytetralone 8 via cyclization of an intermediate benzylic radical, generated from spiroepoxide 14, onto an alkynyl substituent generating tetracyclic compound 13 with an exocyclic double bond. After oxidative cleavage of the double bond of 13 and reduction of the keto function of 23, the correct diastereomer, 12-syn, was converted to lingzhiol (1) via known steps. In a similar manner, lingzhiol analogue 39 was synthesized from 5-methoxy-1-tetralone (27). PMID- 28819972 TI - Solvent Toolkit for Electrochemical Characterization of Hybrid Perovskite Films. AB - Organohalide lead (hybrid) perovskites have emerged as competitive semiconducting materials for photovoltaic devices due to their high performance and low cost. To further the understanding and optimization of these materials, solution-based methods for interrogating and modifying perovskite thin films are needed. In this work, we report a hydrofluoroether (HFE) solvent-based electrolyte for electrochemical processing and characterization of organic-inorganic trihalide lead perovskite thin films. Organic perovskite films are soluble in most of the polar organic solvents, and thus until now, they were not considered suitable for electrochemical processing. We have enabled electrochemical characterization and demonstrated a processing toolset for these materials utilizing highly fluorinated electrolytes based on a HFE solvent. Our results show that chemically orthogonal electrolytes based on HFE solvents do not dissolve organic perovskite films and thus allow electrochemical characterization of the electronic structure, investigation of charge transport properties, and potential electrochemical doping of the films with in situ diagnostic capabilities. PMID- 28819973 TI - Mobile Platform for Multiplexed Detection and Differentiation of Disease-Specific Nucleic Acid Sequences, Using Microfluidic Loop-Mediated Isothermal Amplification and Smartphone Detection. AB - New tools are needed to enable rapid detection, identification, and reporting of infectious viral and microbial pathogens in a wide variety of point-of-care applications that impact human and animal health. We report the design, construction, and characterization of a platform for multiplexed analysis of disease-specific DNA sequences that utilizes a smartphone camera as the sensor in conjunction with a hand-held "cradle" that interfaces the phone with a silicon based microfluidic chip embedded within a credit-card-sized cartridge. Utilizing specific nucleic acid sequences for four equine respiratory pathogens as representative examples, we demonstrated the ability of the system to utilize a single 15 MUL droplet of test sample to perform selective positive/negative determination of target sequences, including integrated experimental controls, in approximately 30 min. Our approach utilizes loop-mediated isothermal amplification (LAMP) reagents predeposited into distinct lanes of the microfluidic chip, which when exposed to target nucleic acid sequences from the test sample, generates fluorescent products that when excited by appropriately selected light emitting diodes (LEDs), are visualized and automatically analyzed by a software application running on the smartphone microprocessor. The system achieves detection limits comparable to those obtained by laboratory-based methods and instruments. Assay information is combined with the information from the cartridge and the patient to populate a cloud-based database for epidemiological reporting of test results. PMID- 28819974 TI - Room-Temperature Synthesis of Mn-Doped Cesium Lead Halide Quantum Dots with High Mn Substitution Ratio. AB - Here we report the room-temperature, atmospheric synthesis of Mn-doped cesium lead halide (CsPbX3) perovskite quantum dots (QDs). The synthesis is performed without any sort of protection, and the dual-color emission mechanism is revealed by density functional theory. The Mn concentration reaches a maximum atomic percentage of 37.73 at%, which is significantly higher in comparison to those achieved in earlier reports via high temperature hot injection method. The optical properties of as-prepared nanocrystals (NCs) remain consistent even after several months. Therefore, red-orange LEDs were fabricated by coating the composite of PS and as-prepared QDs onto ultraviolet LED chips. Additionally, the present approach may open up new methods for doping other ions in CsPbX3 QDs under room temperature, the capability of which is essential for applications such as memristors and other devices. PMID- 28819975 TI - Compatibility of Nitric Oxide Release with Implantable Enzymatic Glucose Sensors Based on Osmium (III/II) Mediated Electrochemistry. AB - The compatibility of nitric oxide (NO) release coatings with implantable enzymatic glucose sensors based on osmium (III/II) mediated electrochemical detection is examined for the first time. NO-releasing osmium-mediated glucose sensors are prepared using a S-nitrosothiol impregnated outer tubing and are tested in vitro in both phosphate buffer (pH 7.4) and whole porcine blood. It is demonstrated that after 3 days of continuous NO release at or above physiological levels, there are no negative effects on the osmium mediated electrochemical currents. Indeed, such sensors maintain their functionality, sensitivity, and accuracy for detecting glucose levels in blood. The results suggest that improved performance of both intravascular and, potentially, subcutaneous Os(III/II) mediated glucose sensors may be realized by taking advantage of NO's well-known anticlotting, anti-inflammatory, and antimicrobial properties. PMID- 28819976 TI - Interrupting Base-Mediated Benzofuran Ring Transformation with Michael Acceptors. AB - A simple two-stage approach for the synthesis of 3-(2-arylbenzofuran-3 yl)propanoates and propanamides has been developed employing simple acrylates and acrylamides and readily available 3-aroylbenzofurans. The key step of this process involves a base-mediated ring opening of the 3-aroylbenzofurans and subsequent Michael addition of the resulting 1,3-dicarbonyl intermediate with acrylate/acrylamide, followed by the deformylation in one-pot. The resulting products undergo an acid-mediated dehydrative cyclization to arrive at these targets. PMID- 28819977 TI - Nazarov Cyclization and Tandem [4 + 2]-Cycloaddition Reactions of Donor-Acceptor Cyclopropanes. AB - The development of aryl vinyl/divinyl donor-acceptor cyclopropanes (DACs) as novel Nazarov cyclization (NC) precursors is described. The 1,3-zwitterion, generated from DACs embedded in the divinyl framework, acts as a pentadienyl cation, a requisite for Nazarov cyclization. A cyclic allyl cation in the course of NC was trapped with external nucleophiles to provide an interrupted NC product. Indeed, an allyl cation in this reaction is analogous to a 1,4 zwitterion that on reaction with dipolarophiles provided an easy access to substituted pyrans with excellent yield and diastereoselectivity via NC followed by a formal [4 + 2] cycloaddition. PMID- 28819979 TI - Influence of a Novel Dimeric Ceramide Molecule on the Nanostructure and Thermotropic Phase Behavior of a Stratum Corneum Model Mixture. AB - The stratum corneum (SC) is the outermost layer of the skin and is composed of a multilayered assembly of mostly ceramids (Cer), free fatty acids, cholesterol (Chol), and cholesterol sulfate (Chol-S). Because of the tight packing of these lipids, the SC features unique barrier properties defending the skin from environmental influences. Under pathological conditions, where the skin barrier function is compromised, topical application of molecules that rigidify the SC may lead to a restored barrier function. To this end, molecules are required that incorporate into the SC and bring back the original rigidity of the skin barrier. Here, we investigated the influence of a novel dimeric ceramide (dim-Cer) molecule designed to feature a long, rigid hydrocarbon chain ideally suited to forming an orthorhombic lipid phase. The influence of this molecules on the thermotropic phase behavior of a SC mixture consisting of Cer[AP18] (55 wt %), cholesterol (Chol, 25 wt %), steric acid (SA, 15 wt %), and cholesterol sulfate (Chol-S, 5 wt %) was studied using a combination of neutron diffraction and 2H NMR spectroscopy. These methods provide detailed insights into the packing properties of the lipids in the SC model mixture. Dim-Cer remains in an all-trans state of the membrane-spanning lipid chain at all investigated temperatures, but the influence on the phase behavior of the other lipids in the mixture is marginal. Biophysical experiments are complemented by permeability measurements in model membranes and human skin. The latter, however, indicates that dim-Cer only partially provides the desired effect on membrane permeability, necessitating further optimization of its structure for medical applications. PMID- 28819978 TI - Nanostructured Fibrous Membranes with Rose Spike-Like Architecture. AB - Nanoparticles have been used for engineering composite materials to improve the intrinsic properties and/or add functionalities to pristine polymers. The majority of the studies have focused on the incorporation of spherical nanoparticles within the composite fibers. Herein, we incorporate anisotropic branched-shaped zinc oxide (ZnO) nanoparticles into fibrous scaffolds fabricated by electrospinning. The addition of the branched particles resulted in their protrusion from fibers, mimicking the architecture of a rose stem. We demonstrated that the encapsulation of different-shape particles significantly influences the physicochemical and biological activities of the resultant composite scaffolds. In particular, the branched nanoparticles induced heterogeneous crystallization of the polymeric matrix and enhance the ultimate mechanical strain and strength. Moreover, the three-dimensional (3D) nature of the branched ZnO nanoparticles enhanced adhesion properties of the composite scaffolds to the tissues. In addition, the rose stem-like constructs offered excellent antibacterial activity, while supporting the growth of eukaryote cells. PMID- 28819980 TI - Superior Fluorogen-Activating Protein Probes Based on 3-Indole-Malachite Green. AB - A series of novel fluorogenic dyes based on 3-indole-Malachite Green, MGs 5-7, have been developed that are dark in solution but highly fluorescent when bound to the cognate reporter, fluorogen-activating protein (FAP). Significantly, the new MGs 5-7 probes are superior to the traditional MG 1 with high fluorescent efficiency and low toxicity to cells while maintaining the large "pseudo-Stokes" shifts (Deltalambda = lambdaex - lambdaem) and the malachite green (MG)-like fluorescence OFF-ON switching mechanism in both live mammalian cells and bacterial cells when bound to FAP. PMID- 28819981 TI - Highly-Efficient Guiding of Motile Microtubules on Non-Topographical Motor Patterns. AB - Molecular motors, highly efficient biological nanomachines, hold the potential to be employed for a wide range of nanotechnological applications. Toward this end, kinesin, dynein, or myosin motor proteins are commonly surface-immobilized within engineered environments in order to transport cargo attached to cytoskeletal filaments. Being able to flexibly control the direction of filament motion, and in particular on planar, non-topographical surfaces, has, however, remained challenging. Here, we demonstrate the applicability of a UV-laser-based ablation technique to programmably generate highly localized patterns of functional kinesin-1 motors with different shapes and sizes on PLL-g-PEG-coated polystyrene surfaces. Straight and curved motor tracks with widths of less than 500 nm could be generated in a highly reproducible manner and proved to reliably guide gliding microtubules. Though dependent on track curvature, the characteristic travel lengths of the microtubules on the tracks significantly exceeded earlier predictions. Moreover, we experimentally verified the performance of complex kinesin-1 patterns, recently designed by evolutionary algorithms for controlling the global directionality of microtubule motion on large-area substrates. PMID- 28819982 TI - HIV testing in the dental setting: perspectives and practices of experienced dental professionals. AB - The dental setting is a largely untapped venue to identify patients with undiagnosed HIV infection. Yet, uptake of rapid HIV testing within the dental community remains low. This study sought to better understand the experiences of dental professionals who have administered the test and how these experiences might inform efforts to promote greater uptake of rapid HIV testing in dental settings. Qualitative interviews were conducted with United States dentists (N = 37) and hygienists (N = 5) who offered rapid HIV testing in their practices. The data revealed both the impeding and facilitating factors they experienced in implementing testing in their setting, as well as the reactions of their staff, colleagues, and patients. Overall, participants viewed rapid HIV testing favorably, regarding it as a valuable public health service that is simple to administer, generally well accepted by patients and staff, and easily integrated into clinical practice. Many had experience with a reactive test result. Participants described facilitating factors, such as supportive follow-up resources. However, they also cited persistent barriers that limit acceptance by their dental colleagues, including insufficient reimbursement and perceived incompatibility with scope of practice. The widespread adoption of routine HIV testing amongst dental professionals will likely require an expanded notion of the proper scope of their professional role in overall patient health, along with greater support from national dental organizations, dental education, and dental insurance companies, especially in the form of sufficient reimbursement. PMID- 28819983 TI - An evaluation of the effectiveness of a risk-based monitoring approach implemented with clinical trials involving implantable cardiac medical devices. AB - Background Risk-based monitoring is a concept endorsed by the Food and Drug Administration to improve clinical trial data quality by focusing monitoring efforts on critical data elements and higher risk investigator sites. BIOTRONIK approached this by implementing a comprehensive strategy that assesses risk and data quality through a combination of operational controls and data surveillance. This publication demonstrates the effectiveness of a data-driven risk assessment methodology when used in conjunction with a tailored monitoring plan. Methods We developed a data-driven risk assessment system to rank 133 investigator sites comprising 3442 subjects and identify those sites that pose a potential risk to the integrity of data collected in implantable cardiac device clinical trials. This included identification of specific risk factors and a weighted scoring mechanism. We conducted trend analyses for risk assessment data collected over 1 year to assess the overall impact of our data surveillance process combined with other operational monitoring efforts. Results Trending analyses of key risk factors revealed an improvement in the quality of data collected during the observation period. The three risk factors follow-up compliance rate, unavailability of critical data, and noncompliance rate correspond closely with Food and Drug Administration's risk-based monitoring guidance document. Among these three risk factors, 100% (12/12) of quantiles analyzed showed an increase in data quality. Of these, 67% (8/12) of the improving trends in worst performing quantiles had p-values less than 0.05, and 17% (2/12) had p-values between 0.05 and 0.06. Among the poorest performing site quantiles, there was a statistically significant decrease in subject follow-up noncompliance rates, protocol noncompliance rates, and incidence of missing critical data. Conclusion One year after implementation of a comprehensive strategy for risk-based monitoring, including a data-driven risk assessment methodology to target on-site monitoring visits, statistically significant improvement was seen in a majority of measurable risk factors at the worst performing site quantiles. For the three risk factors which are most critical to the overall compliance of cardiac rhythm management medical device studies: follow-up compliance rate, unavailability of critical data, and noncompliance rate, we measured significant improvement in data quality. Although the worst performing site quantiles improved but not significantly in some risk factors such as subject attrition, the data-driven risk assessment highlighted key areas on which to continue focusing both on-site and centralized monitoring efforts. Data-driven surveillance of clinical trial performance provides actionable observations that can improve site performance. Clinical trials utilizing risk-based monitoring by leveraging a data-driven quality assessment combined with specific operational procedures may lead to an improvement in data quality and resource efficiencies. PMID- 28819984 TI - Adherence to Diurnal Cortisol Sampling Among Mother-Child Dyads From Maltreating and Nonmaltreating Families. AB - There has been increasing interest in evaluating whether interventions for child maltreatment can improve and/or prevent child physiological dysregulation via measurement of diurnal cortisol. The assessment of diurnal cortisol typically involves the home-based collection of saliva multiple times per day, bringing forth important methodological considerations regarding adherence to collection instructions. To date, there has been no data regarding adherence to home collection of diurnal cortisol among maltreating families. The current study provides data on adherence to in-home sampling of salivary cortisol among 166 maltreating and demographically similar nonmaltreating mother-child dyads using electronic monitoring devices (Medication Event Monitoring System caps). Mothers collected saliva samples on themselves and their children 3 times per day (waking, midday, and evening) for 2 consecutive days. Analyses reveal that although maltreating families were more likely to be nonadherent to the collection protocol on their initial attempt, with additional support and resampling, maltreating and nonmaltreating families were comparable on most measures of adherence. Suggestions for best practices, including the use of electronic monitoring devices, for diurnal cortisol collection with maltreating families are provided. PMID- 28819985 TI - Prediction of labor outcome using serial transperineal ultrasound in the first stage of labor. AB - OBJECTIVE: The objective of this study is to evaluate the feasibility of predicting labor outcome using serial transperineal ultrasound (TPU) in the early active phase of labor. METHODS: This is a single center prospective observational study in a tertiary obstetrics unit in Hong Kong. Nulliparous women carrying singleton pregnancy at the onset of active phase of labor were recruited. Serial 3D volumes by TPU were acquired and then repeated after 1 and 2 h, which were subsequently analyzed for fetal head symphyseal distance (HSD), angle of progression (AoP), and fetal head progression distance (PD). The women were classified into two groups, according to whether they had vaginal delivery or cesarean section (CS) for reasons other than non-progressive labor (Group A) or CS for non-progressive labor (Group B). The TPU parameters were then compared between the groups. RESULTS: Group A consisted of 74 (60.0%) women with vaginal delivery, 27 (21.8%) with instrumental delivery and 3 (2.4%) CS for reasons other than non-progressive labor, while Group B consisted of 20 (16.1%) women who had a CS for non-progressive labor. Group B had a significant slower hourly progression rate of AoP, HSD, and PD at 1-h and 2-h from the initial assessment, compared with Group A. Multivariate logistic regression analysis demonstrated that PD progression at 2-h and the use of oxytocin were significant independent predictors for CS for non-progressive labor. CONCLUSION: It is feasible to predict CS for non-progressive labor in the early active phase of labor by a slower rate of fetal head descent determined by TPU. PMID- 28819986 TI - Knowledge of Palliative Care Among Community-Dwelling Adults. AB - OBJECTIVE: To identify what laypersons know about palliative care using the Palliative Care Knowledge Scale (PaCKS). A secondary aim was to establish preliminary normative data for the PaCKS. METHODS: A sample of 301 adults were recruited via Amazon's Mechanical Turk database. Participants were administered the PaCKS along with a demographic questionnaire. RESULTS: The mean score on the 13-item PaCKS was 5.25 (standard deviation = 4.77, range: 0-13), the median was 5, and the mode was 0, with a significant proportion of participants selecting "I don't know" for every item. Women scored significantly higher than men, and 45- to 54- and 55- to 64-year-olds scoring highest. The PaCKS was also significantly positively correlated with education. CONCLUSION: Broadly, laypersons lack knowledge about some key aspects of palliative care, though palliative care knowledge is highly variable across individuals and some groups. Targeted educational interventions are essential to improve knowledge of palliative care in order to increase access to this type of life-enhancing, supportive service. PMID- 28819988 TI - Behavior change following HIV diagnosis: findings from a Cohort of Los Angeles MSM. AB - The effect of an HIV diagnosis on subsequent behavior of men who have sex with men (MSM) remains unclear. From 2009 to 2012 the NIDA funded Metromates Study enrolled and followed for one year MSM seeking testing for HIV in Los Angeles, assessing those with new HIV diagnoses for acute/recent HIV infection. Behavioral data were collected via Computer-Assisted Self-Interview from 321 men of whom 125 were classified as recently HIV infected, 91 as not recently HIV infected, and 105 as HIV-negative. Differences over time between those with recent HIV infection, not recent HIV infection, and no HIV were evaluated using bivariate and multivariable analyses for repeat measures to assess associations between HIV group, behaviors and condomless receptive (CRAI), intersertive (CIAI), or any condomless anal intercourse (CAI). Participants were mostly young (59% < 30 years of age) and minority. Median number of partners reported in past year dropped significantly over time among recently infected MSM (10 to 5) and HIV negative men (5 to 3) but not for not recently HIV infected. No changes comparing baseline to follow-up were noted in reports of CAI within each HIV-group. Based on GEE multivariable analyses adjusting for age, and race/ethnicity after HIV testing recently HIV infected and not recently HIV infected men practiced more CAI within serodiscordant partnerships than HIV negative MSM: more CRAI than the HIV negatives (AOR = 4.90; 95% CI 1.80-13.29 and AOR = 5.01; 95% CI 1.77-14.16 among recently infected and not recently infected, respectively) but only more CIAI among not recently infected (AOR 3.48; 95% CI 1.31-9.24) when compared to HIV negatives. For MSM seeking HIV testing in Los Angeles at that time, there was little indication of behavior change following HIV diagnosis and continued CAI, suggesting that without rapid linkage to care and viral suppression significant transmissions may have been ongoing. PMID- 28819987 TI - Maximum home blood pressure is a useful indicator of diabetic nephropathy in patients with type 2 diabetes mellitus: KAMOGAWA-HBP study. AB - OBJECTIVE: Maximum home systolic blood pressure has been shown to predict target organ damage. We aimed to clarify the association between maximum home systolic blood pressure and urine albumin to creatinine ratio, an indicator of early-phase diabetic nephropathy in patients with type 2 diabetes. METHODS: In 1040 patients, we assessed the relationship of mean or maximum home systolic blood pressure and urine albumin to creatinine ratio, and compared the area under the receiver operating characteristic curve of mean or maximum home systolic blood pressure for diabetic nephropathy (urine albumin to creatinine ratio ?30 mg/g Cr). RESULTS: Multivariate linear regression analyses indicated that mean morning systolic blood pressure ( beta = 0.010, p < 0.001) and maximum morning systolic blood pressure ( beta = 0.008, p < 0.001) were significantly associated with urine albumin to creatinine ratio. Area under the receiver operating characteristic curve (95% confidence interval) for diabetic nephropathy in mean and maximum morning systolic blood pressure was 0.667 (0.634-0.700; p < 0.001) and 0.671 (0.638-0.703; p < 0.001), respectively. CONCLUSION: Maximum home systolic blood pressure, as well as mean home systolic blood pressure, was significantly associated with diabetic nephropathy in patients with type 2 diabetes. PMID- 28819989 TI - Evaluating the addition of oxaliplatin to single agent fluoropyrimidine in the treatment of locally advanced rectal cancer: a systematic review and meta analysis. AB - INTRODUCTION: Multimodality treatment of patients with locally advanced rectal cancer (LARC) has significantly improved local disease control, however the unaltered overall survival (OS) implicates an inability to further control micrometastases, providing rationale for intensified systemic treatment. A systematic review was conducted to evaluate the efficacy and toxicity of adding oxaliplatin to a fluoropyrimidine (intervention) compared with fluoropyrimidine alone (control) in the treatment of LARC. METHODS: We searched CENTRAL, Medline Ovid, PubMed and EMBASE databases. Randomised trials comparing the intervention and control delivered either pre- or post-operatively were included. RESULTS: Seven trials involving 4444 patients were identified; five studies evaluated the intervention vs control preoperatively; one study peri-operatively; and one, post operatively. There was no significant difference in OS with oxaliplatin addition, HR 0.89, 95% CI, 0.75 to 1.06. There was however an improvement in disease free survival, 3-year local and distant recurrence rates (RR) favouring oxaliplatin. Preoperative oxaliplatin improved pathological complete response (pCR), but with a greater toxicity and reduced compliance with radiation. CONCLUSION: There is no OS benefit with oxaliplatin, despite improved pCR, local and distant RR. Before drawing definitive conclusions, longer follow-up in included trials and availability of published data from other eligible studies, including the induction setting, are needed. PMID- 28819990 TI - Effects of maternal high-fat diet and sedentary lifestyle on susceptibility of adult offspring to ozone exposure in rats. AB - Epidemiological and experimental data suggest that obesity exacerbates the health effects of air pollutants such as ozone (O3). Maternal inactivity and calorically rich diets lead to offspring that show signs of obesity. Exacerbated O3 susceptibility of offspring could thus be manifested by maternal obesity. Thirty day-old female Long-Evans rats were fed a control (CD) or high-fat (HF) (60% calories) diet for 6 wks and then bred. GD1 rats were then housed with a running wheel (RW) or without a wheel (SED) until parturition, creating four groups of offspring: CD-SED, CD-RW, HF-SED and HF-RW. HF diet was terminated at PND 35 and all offspring were placed on CD. Body weight and %fat of dams were greatest in order; HF-SED > HF-RW > CD-SED > CD-RW. Adult offspring were exposed to O3 for two consecutive days (0.8 ppm, 4 h/day). Glucose tolerance tests (GTT), ventilatory parameters (plethysmography), and bronchoalveolar fluid (BALF) cell counts and protein biomarkers were performed to assess response to O3. Exercise and diet altered body weight and %fat of young offspring. GTT, ventilation and BALF cell counts were exacerbated by O3 with responses markedly exacerbated in males. HF diet and O3 led to significant exacerbation of several BALF parameters: total cell count, neutrophils and lymphocytes were increased in male HF-SED versus CD-SED. Males were hyperglycemic after O3 exposure and exhibited exacerbated GTT responses. Ventilatory dysfunction was also exacerbated in males. Maternal exercise had minimal effects on O3 response. The results of this exploratory study suggest a link between maternal obesity and susceptibility to O3 in their adult offspring in a sex-specific manner. PMID- 28819991 TI - Infliximab biosimilar CT-P13 therapy is effective and safe in maintaining remission in Crohn's disease and ulcerative colitis - experiences from a single center. AB - BACKGROUND: CT-P13, the first biosimilar monoclonal antibody to infliximab (IFX), has been confirmed to be efficacious in inducing remission in inflammatory bowel diseases (IBD). The aim of this study was to evaluate the long-term efficacy and safety of CT-P13 therapy in Crohn's disease (CD) and ulcerative colitis (UC), and to identify predictors of sustained clinical response during a 54-week CT-P13 treatment period. PATIENTS AND METHODS: Patients with CD and UC, who were administered CT-P13, were prospectively enrolled. Clinical response was assessed at week 14 and week 54. Predictive factors for disease outcome at week 54 were evaluated. RESULTS: 57 CD and 57 UC patients were included; 55 CD and 49 UC patients completed the induction therapy and 50 CD and 46 UC patients completed the 54-week treatment period. Clinical remission was achieved in 65.5% of CD and 75.5% of UC patients at week 14. Rate of continuous clinical response was 51% in both CD and UC at week 54. None of the examined parameters were predictive to the clinical outcome neither in CD, nor in UC. CONCLUSION: This study confirmed the long-term efficacy and safety of CT-P13 therapy in IBD. Response rates at week 54 were similar in CD and UC. PMID- 28819993 TI - Lactobacillus helveticus-fermented milk containing lactononadecapeptide (NIPPLTQTPVVVPPFLQPE) improves cognitive function in healthy middle-aged adults: a randomised, double-blind, placebo-controlled trial. AB - This study aimed to determine the effects of a Lactobacillus helveticus-fermented milk drink containing lactononadecapeptide (NIPPLTQTPVVVPPFLQPE) on the cognitive function of healthy middle-aged adults. A randomised, double-blind controlled study was conducted in healthy participants who were randomly assigned to receive a L. helveticus-fermented milk drink (190 g/day) or the equivalent amount of a placebo drink once a day for eight weeks. Cognitive function was evaluated using the Japanese version of the repeatable battery for the assessment of neuropsychological status (RBANS) test. There was a statistically significant improvement in the total score, attention score, and delayed memory score of participants who received the L. helveticus-fermented milk drink. There was also a significant difference in the attention score between the placebo and test groups after eight weeks (p = .028). Therefore, supplementation of healthy middle aged adults with a L. helveticus-fermented milk drink for eight weeks improved both attention and delayed memory. PMID- 28819994 TI - The mechanistic antitumor study of myricanol 5-fluorobenzyloxy ether in human leukemic cell HL-60. AB - AIM: The aim of the study was to explore the growth inhibitory effect of myricanol 5-fluorobenzyloxy ether (5FEM) and the underlying mechanism in human leukemic cells HL-60. MATERIALS & METHODS: 5FEM was obtained by chemical modification of myricanol with fluorobenzyloxy ether at the OH(5) position. The cytotoxicity, cell apoptosis, cell cycle and the expression of key apoptosis related genes in HL-60 were evaluated. RESULTS & CONCLUSION: 5FEM can significantly inhibited growth of HL-60 cells, increased the G2/M population and upregulated the expression of Bax, Fas, FasL, caspase-9 and p21 and downregulated that of Bcl-2 and survivin. The results enhance our understanding of 5FEM and aid the discovery of novel myricanol derivatives as potential antitumor agents. PMID- 28819995 TI - The effect of different fish feed compositions on delta13C and delta15N signatures of sea bass and its potential value for tracking mariculture-derived nutrients. AB - Increasing demand for fish and seafood calls for an expansion of aquaculture production. At the same time, the status of the marine environment must not be jeopardised. Stable isotopes are potential markers for tracking feed-based nutrient flows from aquaculture into marine biota. Here, we demonstrate how four experimental diets (main protein components: fishmeal, soya protein concentrate, wheat gluten, and Jatropha kernel meal) and a commercial diet induce characteristic delta13C and delta15N signals in sea bass (Dicentrarchus labrax) during nine weeks of laboratory feeding under replicate conditions. The plant protein-based diets containing wheat gluten and soya, and the commercial feed consistently induced the largest isotopic differentiation of the fish, both from the feed source and from the pre-experimental condition. The large difference of the fish on plant-protein-based diets compared to the range of natural isotopic variation in the macrozoobenthos of the North Sea lends support to the idea that plant-based feeds are suitable for tracing mariculture-derived organic matter under practical conditions. The commercial feed had a similar effect as the experimental feeds and would be a cost-effective option for an offshore aquaculture experiment. PMID- 28819992 TI - Insulin delivery and nocturnal glucose control in children and adolescents with type 1 diabetes. AB - INTRODUCTION: Nocturnal glucose control remains challenging in children and adolescents with type 1 diabetes due to highly variable overnight insulin requirements. The issue may be addressed by glucose responsive insulin delivery based on real-time continuous glucose measurements. Areas covered: This review outlines recent developments of glucose responsive insulin delivery systems from a paediatric perspective. We cover threshold-based suspend application, predictive low glucose suspend, and more advanced single hormone and dual-hormone closed-loop systems. Approaches are evaluated in relation to nocturnal glucose control particularly during outpatient randomised controlled trials. Expert opinion: Significant progress translating research from controlled clinical centre settings to free-living unsupervised home studies have been achieved over the past decade. Nocturnal glycaemic control can be improved whilst reducing the risk of hypoglycaemia with closed-loop systems. Following the US regulatory approval of the first hybrid closed-loop system in non-paediatric population, large multinational closed-loop clinical trials and pivotal studies including paediatric populations are underway or in preparation to facilitate the use of closed-loop systems in clinical practice. PMID- 28819996 TI - Commercial golf glove effects on golf performance and forearm muscle activity. AB - The study aimed to determine whether or not commercial golf gloves influence performance variables and forearm muscle activity during golf play. Fifteen golfers participated in the laboratory based study, each performing 8 golf swings with a Driver and 7-iron whilst wearing a glove and 8 without wearing the glove. Club head speed, ball speed and absolute carry distance performance variables were calculated. Surface electromyography was recorded from the flexor digitorum superficialis and extensor carpi radialis brevis on both forearm muscles. Club head speed, ball speed and absolute carry distance was significantly higher when using the Driver with the glove in comparison to the Driver without the glove (p < 0.05). No significant differences were evident when using the 7-iron and no significant differences were displayed in muscle activity in either of the conditions. Findings from this study suggest that driving performance is improved when wearing a glove. PMID- 28819997 TI - Comparisons of cancer staging systems should be based on overall performance in the population. PMID- 28819998 TI - Reliability and validity of the script concordance test for postgraduate students of general practice. AB - BACKGROUND: The script concordance test (SCT) is a validated method of examining students' clinical reasoning. Medical students' professional skills are assessed during their postgraduate years as they study for a specialist qualification in general practice. However, no specific provision is made for assessing their clinical reasoning during their postgraduate study. OBJECTIVE: The aim was to demonstrate the reliability and validity of the SCT in general practice and to determine if this tool could be used to assess medical students' progress in acquiring clinical reasoning. METHODS: A 135-question SCT was administered to postgraduate medical students at the beginning of their first year of specialized training in general practice, and then every six months throughout their three year training, as well as to a reference panel of 20 expert general practitioners. For score calculation, we used the combined scoring method as the calculator made available by the University of Montreal's School of Medicine in Canada. For the validity, student' scores were compared with experts, p <.05 was considered statistically significant. RESULTS: Ninety students completed all six assessments. The experts' mean score (76.7/100) was significantly higher than the students' score across all assessments (p <.001), with a Cronbach's alpha value of over 0.65 for all assessments. CONCLUSION: The SCT was found to be reliable and capable of discriminating between students and experts, demonstrating that this test is a valid tool for assessing clinical reasoning skills in general practice. PMID- 28820000 TI - Novel combination strategies for enhancing efficacy of immune checkpoint inhibitors in the treatment of metastatic solid malignancies. AB - INTRODUCTION: Immune-checkpoint inhibitor (ICPI) drugs, which include antibodies against CTLA-4, PD-1 and PD-L1, have been shown to induce durable complete responses in a proportion of patients with particular efficacy demonstrated in both the first line and refractory setting in advanced NSCLC and melanoma. However, these drugs remain effective only in a minority of unselected patients. Areas covered: This review will focus on mechanisms of resistance to ICPI and underline the importance of identification of novel predictive markers of responsiveness. The rationale for the combination of ICPI with specific chemotherapies, targeted therapies and other immuno-oncology drugs in order to improve efficacy will be provided. Expert opinion: There are near-endless permutations of combination strategies of these agents with ICPI that have become feasible treatment strategies. Development of an understanding of resistance mechanisms to ICPI by a shift towards translational approaches to comprehensive genomic profiling and interrogation of the tumor microenvironment will encourage recruitment of patients into biomarker-driven combination trials. More than ever, industry professionals, clinicians and scientists will need to collaborate to increase the investment in clinical trials of those therapeutic agents and combination strategies which are most likely to be transformative for patients. PMID- 28819999 TI - High glucose induces HGF-independent activation of Met receptor in human renal tubular epithelium. AB - CONTEXT: The role of hepatocyte growth factor (HGF) in diabetic kidney damage remains controversial. OBJECTIVE: To test the hypothesis that high glucose levels activate pathways related to HGF and its receptor Met and that this could participate in glucose-induced renal cell damage. MATERIALS AND METHODS: HK2 cells, a human proximal tubule epithelial cell line, were stimulated with high glucose for 48 hours. Levels of pMet/Met, pEGFR/EGFR, pSTAT3/STAT3, pAkt/Akt and pERK1/2/ERK1/2 were studied by immunoblotting. Absence of HGF was verified by qRT PCR and ELISA. RESULTS: High glucose level activated Met and its downstream pathways STAT3, Akt and ERK independently of HGF. High glucose induced an integrin ligand fibronectin. HGF-independent Met phosphorylation was prevented by inhibition of integrin alpha5beta1, Met inhibitor crizotinib, Src inhibitors PP2 and SU5565, but not by EGFR inhibitor AG1478. High glucose increased the expression of TGFbeta-1, CTGF and the tubular damage marker KIM-1 and increased apoptosis of HK2 cells, effects inhibited by crizotinib. CONCLUSION: High glucose activated Met receptor in HK2 cells independently of HGF, via induction of integrin alpha5beta1 and downstream signaling. This mode of Met activation was associated with tubular cell damage and apoptosis and it may represent a novel pathogenic mechanism and a treatment target in diabetic nephropathy. PMID- 28820001 TI - Introduction. PMID- 28820002 TI - Applicability of the Arabic version of Vocal Tract Discomfort Scale (VTDS) with student singers as professional voice users. AB - AIM: This pilot study aimed to evaluate the internal consistency, convergent construct validity and criterion validity of Arabic version of the Vocal Tract Discomfort Scale (VTDS), and to investigate the correlation between the scores of the VTDS, the VHI and the acoustic measures of fundamental frequency (F0), shimmer, jitter and signal-to-noise ratio (SNR). METHODOLOGY: A cross-sectional study where 97 participants participated (47 males and 50 females) (mean age 20.5 +/- 2.1 years) (31 student singers and 66 other non-professional voice user students). Participants were without self-perceived voice disorders who completed the VTDS-Arab scale and the Voice Handicap Index (VHI-Arab), and recorded a vocal sample of/a:/at a comfortable level. RESULTS: A positive internal consistency that signifies reliability was confirmed by Cronbach's alpha = .884 and 0.874 for the VTDS-Arab frequency and severity subscales, respectively. A moderate positive correlation was found between the VTDS-Arab (frequency, severity, total) and the VHI-Arab total where values of Pearson's correlation coefficient were r= 0.459, 0.430 and 0.451, respectively. Weak correlations were found between all of the acoustic measures and the scores of the VTDS-Arab and VHI-Arab (total and subscales). The area under curve for the VTDS was AUC= 0.824, 0.804 and 0.817 for the VTDS frequency, VTDS severity and VTDS total, respectively. CONCLUSIONS: The VTDS-Arab is a valid and reliable tool in measuring vocal tract sensations and predicting the perception of vocal handicap in student singers and can be used to predict the vocal load among professional voice users. PMID- 28820003 TI - The need for systematic diagnosis of exercise-induced respiratory syndromes: the example of swimming-induced pulmonary edema. PMID- 28820004 TI - Drug-Induced Liver Injury in Children: Clinical Observations, Animal Models, and Regulatory Status. AB - Drug-induced liver injury in children (cDILI) accounts for about 1% of all reported adverse drug reactions throughout all age groups, less than 10% of all clinical DILI cases, and around 20% of all acute liver failure cases in children. The overall DILI susceptibility in children has been assumed to be lower than in adults. Nevertheless, controversial evidence is emerging about children's sensitivity to DILI, with children's relative susceptibility to DILI appearing to be highly drug-specific. The culprit drugs in cDILI are similar but not identical to DILI in adults (aDILI). This is demonstrated by recent findings that a drug frequently associated with aDILI (amoxicillin/clavulanate) was rarely associated with cDILI and that the drug basiliximab caused only cDILI but not aDILI. The fatality in reported cDILI studies ranged from 4% to 31%. According to the US Food and Drug Administration-approved drugs labels, valproic acid, dactinomycin, and ampicillin appear more likely to cause cDILI. In contrast, deferasirox, isoniazid, dantrolene, and levofloxacin appear more likely to cause aDILI. Animal models have been explored to mimic children's increased susceptibility to valproic acid hepatotoxicity or decreased susceptibility to acetaminophen or halothane hepatotoxicity. However, for most drugs, animal models are not readily available, and the underlying mechanisms for the differential reactions to DILI between children and adults remain highly hypothetical. Diagnosis tools for cDILI are not yet available. A critical need exists to fill the knowledge gaps in cDILI. This review article provides an overview of cDILI and specific drugs associated with cDILI. PMID- 28820007 TI - A 12-week pilot study of acceptance of a computer-based chronic disease self monitoring system among patients with type 2 diabetes mellitus and/or hypertension. AB - This study tested a structural model examining the effects of perceived usefulness, perceived ease of use, attitude, subjective norm, perceived behavioral control, health consciousness, and application-specific self-efficacy on the acceptance (i.e. behavioral intention and actual usage) of a computer based chronic disease self-monitoring system among patients with type 2 diabetes mellitus and/or hypertension. The model was tested using partial least squares structural equation modeling, with 119 observations that were obtained by pooling data across three time points over a 12-week period. The results indicate that all of the seven constructs examined had a significant total effect on behavioral intention and explained 74 percent of the variance. Also, application-specific self-efficacy and behavioral intention had a significant total effect on actual usage and explained 17 percent of the variance. This study demonstrates that technology acceptance is determined by patient characteristics, technology attributes, and social influences. Applying the findings may increase the likelihood of acceptance. PMID- 28820006 TI - An Immunohistochemical Investigation of Renal Phospholipidosis and Toxicity in Rats. AB - Immunohistochemical staining for the lysosome-associated membrane protein 2 (LAMP 2) has been proposed previously as an alternative to electron microscopy to identify hepatic phospholipidosis. This study used LAMP-2 immunohistochemistry (IHC) to diagnose phospholipidosis in rats exhibiting renal tubular injury. Rats were administered toreforant, a histamine H4 receptor antagonist by oral gavage at a dose of 3, 10, or 100 mg/kg/d for 6 months. Hematoxylin and eosin staining revealed renal tubular epithelial cell vacuolation, hypertrophy, degeneration, and luminal dilation in the 100 mg/kg/d group animals. Renal tubular injury was confirmed using kidney injury marker 1 (KIM-1) IHC. The involvement of phosopholipidosis in the renal injury was investigated by LAMP-2. Adipophilin IHC was included to differentiate phospholipidosis from lipidosis. Increased LAMP-2 staining was observed in the 100 mg/kg/d group animals when compared to vehicle group animals. Lysosome-associated membrane protein-2 staining was most prominent in the outer stripe of the outer medulla where KIM-1 staining was also most prominent. By contrast, adipophilin staining was not increased. Phospholipidosis was also confirmed by electron microscopy. These data support the use of LAMP-2 IHC as a diagnostic tool and suggest an association between phospholipidosis and the renal tubular injury caused by toreforant. PMID- 28820005 TI - Inhibition of Endocannabinoid-Metabolizing Enzymes in Peripheral Tissues Following Developmental Chlorpyrifos Exposure in Rats. AB - Repeated developmental exposure to the organophosphate (OP) insecticide chlorpyrifos (CPF) inhibits brain fatty acid amide hydrolase (FAAH) activity at low levels, whereas at higher levels, it inhibits brain monoacylglycerol lipase (MAGL) activity. FAAH and MAGL hydrolyze the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG), respectively. Peripherally, AEA and 2-AG have physiological roles in the regulation of lipid metabolism and immune function, and altering the normal levels of these lipid mediators can negatively affect these processes. Exposure to CPF alters brain endocannabinoid hydrolysis activity, but it is unclear whether low-level exposure alters this activity in peripheral tissues important in metabolic and immune function. Therefore, rat pups were exposed orally from day 10 to 16 to 0.5, 0.75, or 1.0 mg/kg CPF or 0.02 mg/kg PF-04457845 (a specific FAAH inhibitor). At 12 hours postexposure, FAAH, MAGL, and cholinesterase (ChE) activities were determined. All treatments inhibited FAAH activity in brain, spleen, and liver. CPF inhibited ChE activity in spleen and liver (all dosages) and in brain (highest dosage only). CPF inhibited total 2-AG hydrolysis and MAGL-specific activity in brain and spleen (high dosage only). In liver, total 2-AG hydrolysis was inhibited by all treatments and could be attributed to inhibition of non-MAGL-mediated 2-AG hydrolysis, indicating involvement of other enzymes. MAGL-specific activity in liver was inhibited only by the high CPF dosage, whereas PF-04457845 slightly increased this activity. Overall, exposure to low levels of CPF and to PF 04457845 can alter endocannabinoid metabolism in peripheral tissues, thus potentially affecting physiological processes. PMID- 28820008 TI - Radioscapholunate fusion with triquetrum and distal pole of scaphoid excision: long-term follow-up. AB - : The purpose of this study was to assess the long-term outcomes of radioscapholunate fusion, with and without distal pole of scaphoid excision and excision of the triquetrum. These compromised three operative groups. Seventeen patients were identified with a minimum of 10 years follow-up, with a mean of 15 years (range 10-19). Fifteen of the 17 patients were satisfied with their outcome. Two were converted to total wrist fusion. The mean outcomes scores were; pain visual analogue scale score 2.1/10, Quick Disabilities of the Arm, Shoulder, and Hand 29 and Modified Mayo Wrist score 60. Patients with excision of the triquetrum had a mean radial-ulnar arc increase of 10 degrees compared with the other two groups, but this was not statistically significant. The mean space for the scaphocapitate joint was 1.7 mm and lunocapitate joint was 1.3 mm at latest follow-up. Close adherence to the indications and surgical technique provided a sustainable good clinical outcome. Patients who obtained a good result at 2 years were likely to achieve a good long-term outcome. LEVEL OF EVIDENCE: IV. PMID- 28820009 TI - Expression of a Vibrio parahaemolyticus toxin in Escherichia coli results in chromosomal DNA degradation. AB - A toxin-antitoxin system, vp1842/vp1843, locates within a superintegron on the Vibrio parahaemolyticus genome chromosome I whose toxin gene vp1843 encodes a DNA nicking endonuclease. We found that the vp1843 expression in Escherichia coli cells strongly induced chromosomal DNA degradation. On the basis of these observations, we discuss a possible physiological role of vp1842/vp1843 in V. parahaemolyticus. PMID- 28820010 TI - Diagnosing asthma and chronic obstructive pulmonary disease with machine learning. AB - This study examines the clinical decision support systems in healthcare, in particular about the prevention, diagnosis and treatment of respiratory diseases, such as Asthma and chronic obstructive pulmonary disease. The empirical pulmonology study of a representative sample (n = 132) attempts to identify the major factors that contribute to the diagnosis of these diseases. Machine learning results show that in chronic obstructive pulmonary disease's case, Random Forest classifier outperforms other techniques with 97.7 per cent precision, while the most prominent attributes for diagnosis are smoking, forced expiratory volume 1, age and forced vital capacity. In asthma's case, the best precision, 80.3 per cent, is achieved again with the Random Forest classifier, while the most prominent attribute is MEF2575. PMID- 28820011 TI - Unusual Complication of the Nuss Procedure: Fistulization of the Internal Thoracic Artery to the Pulmonary Artery. AB - Although minimally invasive repair of pectus excavatum has been shown to have a low complication rate in large series, several case reports have documented life threatening complications, including bleeding and cardiac perforation. We present a rare case of an arteriovenous malformation from the internal thoracic artery to the pulmonary artery caused by occlusion of the internal thoracic artery by the Nuss bar followed by an unidentified angiogenic process. The patient became symptomatic and required transcatheter coil embolization. PMID- 28820012 TI - Effect of rotational prosthetic alignment variation on tibiofemoral contact pressure distribution and joint kinematics in total knee replacement. AB - In total knee replacement surgery, implant alignment is one of the most important criteria for successful long-term clinical outcome. During total knee replacement implantation, femoral and tibial alignment are determined through appropriate bone resections, which could vary based on patient anatomy, implant design and surgical technique and further influence loading conditions and clinical outcomes. The current research focused on three critical alignment parameters for total knee replacement insertion: femoral component internal/external (I/E) rotation, varus-valgus tibiofemoral angulation and posterior tibial slope. A computational finite element model of total knee replacement implant was developed and validated comparing with kinematic outputs generated from experimentally simulated knee joint motion. The FE model was then used to assess 12 different alignment scenarios based on previous case reports. Postoperative knee kinematics and joint contact pressure during simulated gait motion were assessed. According to the parametric study, FE model cases with femoral rotation revealed extra tibial I/E rotation in the predefined direction but negligible change in tibial anterior-posterior translation; cases with increased tibial slope showed notably increased tibial external rotation and anterior translation; cases with varus tibiofemoral angle presented slightly more tibial external rotation, whereas cases with valgus angle presented an observable increase in tibial internal rotation at the middle phase of the gait cycle. Finally, the response surface obtained from the postprocessing study demonstrated good statistical correlation with existing case study results, providing reliable estimation of peak tibiofemoral contact pressure affected by combinations of alignment parameters. The observations indicate that femoral external alignment should be favored clinically for enhanced patellar tracking and reduced contact pressure concentration for better long-term performance. Posterior tibial slope enables deep knee flexion. Extra femoral internal rotation as well as tibiofemoral varus-valgus alignment could be avoided in surgery due to deficiency in patellar tracking and high pressure concentration. PMID- 28820013 TI - Diagnostic performance of central vein sign for multiple sclerosis with a simplified three-lesion algorithm. AB - BACKGROUND: Detection of a "central vein sign" (CVS) on FLAIR* magnetic resonance imaging (MRI) is highly specific and sensitive for multiple sclerosis (MS). We evaluated the specificity and sensitivity of simplified CVS algorithms for MS diagnosis. METHODS: MRIs from 10 participants with MS without additional comorbidities for MRI white matter abnormalities; 10 with MS and additional comorbidities for white matter abnormalities; 10 with migraine, white matter abnormalities, and no additional comorbidities; and 10 who had previously been erroneously diagnosed with MS were evaluated. 3T MRI T2-FLAIR and T2*-weighted sequences were acquired to create FLAIR* images. Three MS physician reviewers, blinded to diagnosis, evaluated two different algorithms: (1) three lesions pre selected on FLAIR were subsequently evaluated for CVS on FLAIR*( select3). (2) FLAIR* was evaluated for up to three lesions with CVS ( select3*). RESULTS: For select3, average specificity across reviewers for MS was 0.98 and sensitivity 0.52 and a correct prediction of diagnosis demonstrated kappa = 0.29. For select3*, specificity was 0.81, sensitivity was 0.83, and kappa was 0.31. CONCLUSION: A simplified determination of CVS in three white matter lesions on 3T FLAIR* MRI demonstrated good specificity and sensitivity and fair inter-rater reliability for a diagnosis of MS and with further study, may be a candidate for clinical application. PMID- 28820014 TI - Postinfectious Anti-Myelin Oligodendrocyte Glycoprotein Antibody Positive Optic Neuritis and Myelitis. AB - We report the case of a 9-year-old girl admitted with fever, headache, and a cerebrospinal fluid lymphocytic pleocytosis. Polymerase chain reaction was positive for human herpes virus 6. She subsequently developed ataxia and bilateral loss of vision. Magnetic resonance imaging (MRI) showed bilateral optic nerve lesions with extension to optic chiasm and a short-segment myelitis. Serologic studies were positive for Borrelia burgdorferi IgM. Anti-aquaporin 4 antibody was negative and anti-myelin oligodendrocyte glycoprotein antibody (MOG) positive. After intravenous methylprednisolone, ceftriaxone, and intravenous immunoglobulin, her vision slowly recovered. The patient was discharged with only mild visual acuity loss, 1 month after admission. Brain MRI was repeated later and was normal and MOG assay became negative. In our view, this patient suffered from a postinfectious, anti-MOG-mediated, spinal cord and optic nerve demyelination. PMID- 28820015 TI - Erratum. PMID- 28820016 TI - Why we stay with our social partners: Neural mechanisms of stay/leave decision making. AB - How do we decide to keep interacting (e.g., stay) with a social partner or to switch (e.g., leave) to another? This paper investigated the neural mechanisms of stay/leave decision-making. We hypothesized that these decisions fit within a framework of value-based decision-making, and explored four potential mechanisms underlying a hypothesized bias to stay. Twenty-six participants underwent functional Magnetic Resonance Imaging (fMRI) while completing social and nonsocial versions of a stay/leave decision-making task. On each trial, participants chose between four alternative options, after which they received a monetary reward. Crucially, in the social condition, reward magnitude was ostensibly determined by the generosity of social partners, whereas in the nonsocial condition, reward amounts were ostensibly determined in a pre programmed manner. Results demonstrated that participants were more likely to stay with options of relatively high expected value, with these values updated through Reinforcement Learning mechanisms and represented neurally within ventromedial prefrontal cortex. Moreover, we demonstrated that greater brain activity in ventromedial prefrontal cortex, caudate nucleus, and septo hypothalamic regions for social versus nonsocial decisions to stay may underlie a bias towards staying with social partners in particular. These findings complement existing social psychological theories by investigating the neural mechanisms of actual stay/leave decisions. PMID- 28820018 TI - Evidence-based creativity: Working between art and science in the field of fine dining. AB - This article examines how scientific knowledge drives creativity in the small but influential culinary movement of 'modernist cuisine'. Originating in the mid 1990s, modernist cuisine began with a small group of avant-garde chefs using science to produce wildly innovative culinary creations. Since then, many of the movement's innovations, as well as its more general 'science-based' approach to cooking, have gained adoption among a diverse range of culinary professionals. But while science has enabled modernist chefs to produce a wide array of innovations and refinements, the group's embrace of scientific values poses a potential threat to the subjective, intuition-driven logic of culinary creativity. Using data gathered through interviews and participant observation, I describe how modernist chefs navigate the potential challenges of using science in a creative field. I find that advocates of modernist cuisine address these challenges by adopting two separate rhetorical repertoires - one emphasizing science-based cooking's advantages over traditional methods, and another that minimizes the differences between these approaches. Observing the strategic deployment of these repertoires illustrates the challenges to incorporating science into creative fields and reveals a complex and nuanced relationship between objectivity, evidence, and aesthetic judgement. PMID- 28820017 TI - Directive and nondirective social support in the workplace - is this social support distinction important for subjective health complaints, job satisfaction, and perception of job demands and job control? AB - AIMS: Social support is associated with well-being and positive health outcomes. However, positive outcomes of social support might be more dependent on the way support is provided than the amount of support received. A distinction can be made between directive social support, where the provider resumes responsibility, and nondirective social support, where the receiver has the control. This study examined the relationship between directive and nondirective social support, and subjective health complaints, job satisfaction and perception of job demands and job control. METHODS: A survey was conducted among 957 Norwegian employees, working in 114 private kindergartens (mean age 40.7 years, SD = 10.5, 92.8% female), as part of a randomized controlled trial. This study used only baseline data. A factor analysis of the Norwegian version of the Social Support Inventory was conducted, identifying two factors: nondirective and directive social support. Hierarchical regression analyses were then performed. RESULTS: Nondirective social support was related to fewer musculoskeletal and pseudoneurological complaints, higher job satisfaction, and the perception of lower job demands and higher job control. Directive social support had the opposite relationship, but was not statistically significant for pseudoneurological complaints. CONCLUSIONS: It appears that for social support to be positively related with job characteristics and subjective health complaints, it has to be nondirective. Directive social support was not only without any association, but had a significant negative relationship with several of the variables. Nondirective social support may be an important factor to consider when aiming to improve the psychosocial work environment. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02396797. Registered 23 March 2015. PMID- 28820019 TI - The Supplemental Nutrition Assistance Program and frequency of sugar-sweetened soft drink consumption among low-income adults in the US. AB - BACKGROUND: The Supplemental Nutrition Assistance Program (SNAP) was designed to help low-income people purchase nutritious foods in the US. In recent years, there has been a consistent call for banning purchases of sugar drinks in SNAP. AIM: The aim of this study was to examine the association between SNAP participation and the frequency of sugar-sweetened soft drink (SSD) consumption among low-income adults in the US. METHOD: Data came from the 2009-2010 National Health and Nutrition Examination Survey. Low-income adults aged >=20 years with a household income <=250% of the Federal Poverty Level ( N = 1200) were categorized into two groups based on the household's SNAP receipt: SNAP recipients ( n = 393) and non-recipients ( n = 807). Propensity-score matching was used to minimize observable differences between these two groups that may explain the difference in SSD consumption, generating the final sample of 393 matched pairs (SNAP recipients, n = 393; non-recipients, n = 393). An ordinal logistic regression was conducted on the matched sample. RESULTS: SNAP recipients were more likely to report higher levels of SSD consumption, compared with non-recipients (adjusted odds ratio (AOR) = 1.55, 95% confidence interval (CI) = 1.17-2.07). Male gender (AOR = 1.69, 95% CI = 1.17-2.46), younger age (AOR = 0.97, 95% CI = 0.96-0.99), lower education level (AOR = 2.28, 95% CI = 1.33-3.89), and soda availability in homes (AOR = 2.24, 95% CI = 1.77-2.83) were also associated with higher levels of SSD consumption among low-income adults. CONCLUSIONS: SNAP participation was associated with frequent SSD consumption. To reduce SSD consumption, strategic efforts need to focus on educating people about the harms of SSD and promoting nutritious food choices with SNAP benefits. PMID- 28820021 TI - e-Roster policy: Insights and implications of codifying nurse scheduling. AB - Following a decade of dissemination, particularly within the British National Health Service, electronic rostering systems were recently endorsed within the Carter Review. However, electronic rostering necessitates the formal codification of the roster process. This research investigates that codification through the lens of the 'Roster Policy', a formal document specifying the rules and procedures used to prepare staff rosters. This study is based upon analysis of 27 publicly available policies, each approved within a 4-year period from January 2010 to July 2014. This research finds that, at an executive level, codified knowledge is used as a proxy for the common language and experience otherwise acquired on a ward through everyday interaction, while at ward level, the nurse rostering problem continues to resist all efforts at simplification. Ultimately, it is imperative that executives recognise that electronic rostering is not a silver bullet and that information from such systems requires careful interpretation and circumspection. PMID- 28820020 TI - Multiple emulsions as effective platforms for controlled anti-cancer drug delivery. AB - AIM: Developing pH-responsive multiple emulsion platforms for effective glioblastoma multiforme therapy with reduced toxicity, a drug release study and modeling. MATERIALS & METHODS: Cancer cell line: U87 MG, multiple emulsions with pH-responsive biopolymer and encapsulated doxorubicin (DOX); preparation of multiple emulsions in a Couette-Taylor flow biocontactor, in vitro release study of DOX (fluorescence intensity analysis), in vitro cytotoxicity study (alamarBlue cell viability assay) and numerical simulation of DOX release rates. RESULTS: The multiple emulsions offered a high DOX encapsulation efficiency (97.4 +/- 1%) and pH modulated release rates of a drug. Multiple emulsions with a low concentration of DOX (0.02 MUM) exhibited broadly advanced cell (U87 MG) cytotoxicity than free DOX solution used at the same concentration. CONCLUSION: Emulsion platforms could be explored for potential delivery of chemotherapeutics in glioblastoma multiforme therapy. PMID- 28820022 TI - Self-reported school demands and psychosomatic problems among adolescents - changes in the association between 1988 and 2011? AB - AIMS: The aim of the present study was to examine changes over time in the relationship between self-reported school demands and psychosomatic problems, also considering the impact of student influence and teacher support. METHODS: Data from a cross-sectional study (Young in Varmland) including eight data collections (1988-2011) among Swedish students aged 15-16 were used ( n = 20,115). Analyses with multinomial logistic regression and descriptive statistics were applied. RESULTS: Between 1988 and 2011, the proportions of students with a higher degree of psychosomatic problems increased, as did the proportion of students experiencing school demands that were too high. Finer-level analyses based on stratification of student groups did not show any associations at the aggregated level between increases of school demands and psychosomatic problems. Similarly, individual level analyses showed that the strength of the association between school demands and psychosomatic problems was not affected by year of investigation. CONCLUSIONS: Changes in school demands over time could not explain the increasing trend in psychosomatic problems among adolescents. Since the relationship between school demands and psychosomatic problems is strong across time, there is, however, a continued need for school-based interventions. More studies are required to gain further understanding of adolescent mental health from a trend perspective. PMID- 28820023 TI - Use of oxalic acid as inducer in photocatalytic oxidation of cresol red in aqueous solution under natural and artificial light. AB - This work was carried out in the field of water treatment using advanced oxidation processes (AOPs), especially photolysis of carboxylic acid that leads to the formation in situ of hydroxyl radical (.OH). Cresol red (CR) degradation induced by organic acids/UV system was investigated in aqueous solution. The preliminary study of CR-organic acid mixture in the dark and at room temperature allowed confirming the absence of interaction under our experimental conditions. However, upon irradiation at 365 nm, the proportion of elimination of CR was 89% after 5 h of irradiation. Indeed, the CR degradation efficiency depends on the acid concentration and the pH of the medium. The concentration of acid is optimized to the 5 * 10-3 M. pH 2.39 was the optimal one when C2HO- 4 was the most important species at this pH. The use of i-PrOH as .OH confirmed the involvement of .OH in photodegradation of CR induced by Ox. The addition of metal ions including Zn2+ and Cu2+ to the CR-organic acid mixture slowed the CR degradation unlike Fe2+, hence an improvement of its disappearance was observed. The results showed a faster degradation of the pollutant under excitation by sunlight. This environmentally friendly method appears to be very effective in the treatment of wastewater. PMID- 28820024 TI - Correlation Between Placental Matrix Metalloproteinase 9 and Tumor Necrosis Factor-alpha Protein Expression Throughout Gestation in Normal Human Pregnancy. AB - Matrix metalloproteinases (MMPs), specifically MMP-9 plays a role in human placentation. The enzyme confers an invasive ability to cytotrophoblasts and degrades the endometrial matrix as the cells infiltrate the decidua to keep up with placental growth. Since tumor necrosis factor-alpha (TNF-alpha) can induce the synthesis of MMP-9, we investigated the patterns of changes in and correlation between placental villous MMP-9 and TNF-alpha expressions throughout normal human gestation. Placentas were obtained from 179 normal pregnant women who underwent elective abortion or term delivery. Chorionic villi isolated from placental samples were grouped as first, second, and third trimester (70/7-130/7, 131/7-236/7, and 370/7-424/7 weeks, respectively). Chorionic villous TNF-alpha and MMP-9 proteins were assayed using enzyme immunoassay kits. There were significant differences in MMP-9 and TNF-alpha protein expressions among the trimester groups ( P = .001). The MMP-9 protein increased progressively with an increase in gestational age (GA), but TNF-alpha peaked in the second trimester. Within each trimester group, we searched for the effects of variation of GA in days on the 2 variables. A significant positive correlation between MMP-9 and GA was noted in the first trimester ( r = 0.364, P = .005). No other comparisons were significant. When GA was controlled for, partial correlation revealed a significant positive correlation between TNF-alpha and MMP-9 only in the second trimester ( r = 0.300, P = .018). We hypothesize that the TNF-alpha peak and the positive correlation between TNF-alpha and MMP-9 in the second trimester of normal human gestation could contribute toward a successful pregnancy outcome. PMID- 28820025 TI - Interaction Between Progesterone and Interleukin-1beta in Modulating Progesterone Receptor Expression and the Inflammatory Phenotype in Human Cervical Fibroblasts. AB - Progesterone helps maintain cervical structure during pregnancy via the progesterone receptor (PR). Two PR isoforms exist, PR-A and PR-B, which have overlapping as well as isoform-specific target genes. During late gestation, leukocytes infiltrate the cervical stroma accompanied by increased cervical cytokine levels, resembling an inflammatory process. We examined interleukin (IL) 1beta regulation of the expression of PR-A, PR-B, and genes governing prostaglandin synthesis in human cervical fibroblasts (HCFs). Since progesterone has been shown to exert anti-inflammatory actions, we also examined the capacity of progesterone (R5020) to ameliorate the actions of IL-1beta in HCFs. Interleukin-1beta induced both PR-A and PR-B mRNA in HCFs. Interleukin-1beta induced a rapid and transient loss of both PR-A and PR-B protein, followed by a latent (24 hours) increase in both PR isoforms. R5020 negated the IL-1beta induced increase in PR-A and PR-B mRNA and protein as well as the rapid IL-1beta induced downregulation of nuclear PR. Interleukin-1beta induced prostaglandin G/H synthase-2 (PGHS-2), but not prostaglandin G/H synthase-1 (PGHS-1), as well as prostaglandin E synthase-1 (PGES-1), but not prostaglandin F synthase (PGFS). R5020 did not ameliorate IL-1beta induction of PGHS-2 or PGES-1. Blockade of prostaglandin synthesis (indomethacin) prevented both the IL-1beta-induced increase in PR mRNA and the acute decrease in PR-A and PR-B protein, implicating a role for prostaglandins in regulating PR expression in HCFs. Although progesterone may function to maintain PR expression in a milieu of increasing cytokines in the late gestation human cervix, it does not exert an anti inflammatory role with regard to prostaglandin E2 (PGE2) production. PMID- 28820026 TI - Pilot validation of an individualised pharmacokinetic algorithm for protamine dosing after systemic heparinisation for cardiopulmonary bypass. AB - INTRODUCTION: This manuscript represents a pilot study assessing the feasibility of a single-compartment, individualised, pharmacokinetic algorithm for protamine dosing after cardiopulmonary bypass. METHODS: A pilot cohort study in a specialist NHS cardiothoracic hospital targeting patients undergoing elective cardiac surgery using cardiopulmonary bypass. Patients received protamine doses according to a pharmacokinetic algorithm (n = 30) or using an empirical, fixed dose model (n = 30). Categorical differences between the groups were evaluated using the Chi-squared test or Fisher's exact test. Continuous data was analysed using a paired Student's t-test for parametric data and the paired samples Wilcoxon test for non-parametric data. RESULTS: Patients who had protamine dosing according to the algorithm demonstrated a lower protamine requirement post-bypass relative to empirical management as measured by absolute dose (243 +/- 49mg vs. 305 +/- 34.7mg; p<0.001) and the heparin to protamine ratio (0.79 +/- 0.12 vs. 1.1 +/- 0.15; p<0.001). There was no difference in the pre- to post-bypass activated clotting time (ACT) ratio (1.05 +/- 0.12 vs. 1.02 +/- 0.15; p=0.9). Patients who received protamine according to the algorithm had no significant difference in transfusion requirement (13.3% vs. 30.0%; p=0.21). CONCLUSIONS: This study showed that an individualized pharmacokinetic algorithm for the reversal of heparin after cardiopulmonary bypass is feasible in comparison with a fixed dosing strategy and may reduce the protamine requirement following on-pump cardiac surgery. PMID- 28820027 TI - Atelectasis after airway extubation during veno-arterial extracorporeal membrane oxygenation support. AB - Veno-arterial extracorporeal membrane oxygenation (VA ECMO) is used in cardiopulmonary failure patients to provide temporary assisted circulation. Usually, prolonged intubation and invasive mechanical ventilation are required in patients with ECMO support. We report on two cases of patients who had no pre existing injuries of the affected lung, underwent VA ECMO support after open heart surgery and received airway extubation (AE) or awake ECMO with the recovery of left ventricular ejection fraction. Atelectasis happened after AE and non invasive positive pressure ventilation attenuated the atelectasis of one patient. The atelectasis of the other patient was corrected 10 hours after weaning from ECMO. Both patients were discharged successfully. Awake VA ECMO for post-cardiac surgery patients should be performed with prudence and needs further research. PMID- 28820028 TI - Extracorporeal membrane oxygenation for acute respiratory distress syndrome in adults: an analysis of differences between survivors and non-survivors. AB - OBJECTIVES: Over the last decade, extracorporeal membrane oxygenation (ECMO) has become a promising option for patients with severe acute respiratory distress syndrome (ARDS). In this single-center observational cohort study, data from a patient group with severe ARDS treated with ECMO was analyzed. METHODS: Data from 46 patients [median age 54 years (18 to 72), male: 65.2%] were evaluated retrospectively between January 2009 and September 2015. RESULTS: Diagnosis leading to ARDS was pneumonia in 63.1% of the patients. The median SOFA Score was 13 (10 to 19) and the median LIS was 3.5 (2.67 to 4). The median duration of ECMO support was 12 days (1 to 86). Twenty-eight patients (60.9%) were successfully weaned from ECMO and 22 patients survived (47.8%). Non-survivors needed significantly more frequent renal replacement therapy (37.5% vs. 18.2%; p<0.01) and transfusion of red blood cell concentrates [0.4 units (0.3 to 1.2) vs. 0.9 units (0.5 to 1.6); p<0.01] during ECMO support compared to patients who survived. CONCLUSION: This report suggests that ECMO currently allows treatment of severe ARDS with presumed improved survival. The incidence rate of acute kidney injury and transfusion are associated with adverse outcomes. PMID- 28820029 TI - Ninety-two days of extracorporeal membrane oxygenation support following congenital heart surgery. AB - We report on a case involving a 10-month-old infant who received prolonged ECMO therapy following cardiac surgery for multiple ventricular septal defects (VSD). The patient was successfully weaned from 92 days of ECMO support without any long term deficits. PMID- 28820030 TI - Epidemiology of cardiovascular disease in the United States: implications for the perfusion profession. A 2017 update. AB - INTRODUCTION: By analyzing epidemiological trends in cardiovascular disease (CVD), key stakeholders can make informed decisions on the future of disease burden and treatment. Accordingly, the cardiovascular perfusion community would benefit from data that would help predict future professional resource utilization. METHODS: In 2003, the changes in the number of hospital discharges for CVD from 1990 to 2000 were published, based on data from the National Center for Health Statistics (NCHS). In this study, the NCHS database was reviewed, as well as other resources, to compile the procedure data. RESULTS: Deaths due to heart disease and the number of hospital admissions for CVD have decreased over the last decade in contrast to the previous decade. Acute myocardial infarction (AMI), cardiac catheterization and angioplasty rates have also decreased. However, the percentage of the population older than 65 years of age is increasing at a much faster rate than the population growth in general. As a result, there has been a consistent increase in cardiac services utilization, such as transcatheter aortic valve replacement (TAVR), ventricular assist devices and extracorporeal life support (ECLS). CONCLUSIONS: There are many different factors affecting the need for perfusionists in the future. An increasing and aging population with a higher prevalence of CVD, an increased number of hospitals offering cardiovascular services and increased access to care increases the need for perfusion services. It is important for the perfusion profession to follow these changing trends in CVD and treatment in order to plan for the future. PMID- 28820031 TI - Elimination of Mycobacterium chimaera in a heater cooler device used during on pump cardiothoracic surgery. AB - Since 2014, several infections with non-tuberculous mycobacteria (NTM) belonging to the species Mycobacterium ( M.) chimaera have been associated with the use of heater-cooler devices during on-pump cardiothoracic surgery both in European countries and the United States of America. Infections have been detected after surgery, with a delay of a few months and up to five years. Bacterial contamination of heater-cooler devices has also been described without any associated infections. In many centres, it has been a challenging task to eliminate NTM from the heater-cooler devices in order to reduce the risk to patients. In this case-report, we describe how we managed to achieve negative cultures for M. chimaera by changing the cleaning procedure of the Sorin Group Heater-Cooler System with three tanks. PMID- 28820032 TI - Science and the "fake news" conundrum. PMID- 28820033 TI - Unregulated saphenous vein graft distension decreases tissue viscoelasticity. AB - OBJECTIVES: Unregulated intraoperative distension of human saphenous vein (SV) graft leads to supraphysiologic luminal pressures and causes acute physiologic and cellular injury to the conduit. The effect of distension on tissue viscoelasticity, a biophysical property critical to a successful graft, is not well described. In this investigation, we quantify the loss of viscoelasticity in SV deformed by distension and compare the results to tissue distended in a pressure-controlled fashion. MATERIALS AND METHODS: Unmanipulated porcine SV was used as a control or distended without regulation and distended with an in-line pressure release valve (PRV). Rings were cut from these tissues and suspended on a muscle bath. Force versus time tracings of tissue constricted with KCl (110 mM) and relaxed with sodium nitroprusside (SNP) were fit to the Hill model of viscoelasticity, using mean absolute error (MAE) and r2-goodness of fit as measures of conformity. RESULTS: One-way ANOVA analysis demonstrated that, in tissue distended manually, the MAE was significantly greater and the r2-goodness of fit was significantly lower than both undistended tissues and tissues distended with a PRV (p<0.05) in KCl-induced vasoconstriction and SNP-induced vasodilation. CONCLUSIONS: Unregulated manual distension of SV graft causes loss of viscoelasticity and such loss may be mitigated with the use of an in-line PRV. PMID- 28820034 TI - The value of adding sub-valvular procedures for chronic ischemic mitral regurgitation surgery: a meta-analysis. AB - BACKGROUND: The most performed repair technique for the treatment of chronic ischemic mitral regurgitation in patients referred for bypass grafting remains restricted annuloplasty. However, it is associated with a high rate of failure, especially if severe tenting exists. OBJECTIVES: To understand if adjunctive sub valvular mitral procedures may provide better repair performance. METHODS: A systematic literature review identified six studies of which five fulfilled the criteria for meta-analysis. Outcomes for a total of 404 patients (214 had adjunctive sub-valvular procedures and 190 restricted annuloplasty) were meta analyzed using random effects modeling. Heterogeneity and subgroup sensitivity analysis were assessed. Primary endpoints were: late recurrence of moderate mitral regurgitation, left ventricle remodeling and coaptation depth at follow up. Secondary endpoints were: early mortality, mid-term survival and operative outcomes. RESULTS: Sub-valvular procedure technique was associated with a significantly lower late recurrence of mitral regurgitation (Odds ratio (OR) 0.34, 95% Confidence Interval (CI) [0.18, 0.65], p=0.0009), smaller left ventricle end-systolic diameter (Weighted Mean Difference (WMD) -4.06, 95% CI [ 6.10, -2.03], p=0.0001) and reduced coaptation depth (WMD -2.36, 95% CI [-5.01, 0.71], p=0.009). These findings were consistent, even in studies that included patients at high risk for repair failure (coaptation depth >10 mm and tenting area >2.5 cm2). A low degree of heterogeneity was observed. There was no difference in terms of early mortality and mid-term survival; sub-valvular technique was associated with prolonged cardiopulmonary and cross-clamp time. CONCLUSIONS: Adding sub-valvular procedures when repairing ischemic chronic mitral valve regurgitation may be associated with better durability, even in the case of the presence of predictors for late failure. PERSPECTIVE: Surgical sub valvular adjunctive procedures have to be considered in the case of the presence of echocardiographic predictors for late failure. PMID- 28820035 TI - Changes in heparin dose response slope during cardiac surgery: possible result in inaccuracy in predicting heparin bolus dose requirement to achieve target ACT. AB - INTRODUCTION: The substantial interpatient variability in heparin requirement has led to the use of a heparin dose response (HDR) technique. The accuracy of Hepcon based heparin administration in achieving a target activated clotting time (ACT) using an HDR slope remains controversial. METHODS: We prospectively studied 86 adult patients scheduled for cardiac surgery requiring cardiopulmonary bypass. The total dose of calculated heparin required for patient and pump priming was administered simultaneously to achieve a target ACT of 450 s for HDR on the Hepcon HMS system. Blood samples were obtained after the induction of anesthesia, at 3 min after heparin administration and after the initiation of CPB to measure kaolin ACT, HDR slope, whole-blood heparin concentration based on the HDR slope and anti-Xa heparin concentration, antithrombin and complete blood count. RESULTS: The target ACT of 450 s was not achieved in 68.6% of patients. Compared with patients who achieved the target ACT, those who failed to achieve their target ACT had a significantly higher platelet count at baseline. Correlation between the HDR slope and heparin sensitivity was poor. Projected heparin concentration and anti-Xa heparin concentration are not interchangeable based on the Bland-Altman analysis. CONCLUSION: It can be hypothesized that the wide discrepancy in HDR slope versus heparin sensitivity may be explained by an inaccurate prediction of the plasma heparin level and/or the change in HDR of individual patients, depending on in vivo factors such as extravascular sequestration of heparin, decreased intrinsic antithrombin activity level and platelet count and/or activity. PMID- 28820036 TI - Efficacy and Safety of the Early Addition of Vasopressin to Norepinephrine in Septic Shock. AB - BACKGROUND: Delays in achievement of target mean arterial pressure (MAP) have been associated with increased mortality in patients with septic shock. Vasopressin may be added to norepinephrine to raise MAP or decrease norepinephrine dosage. The purpose of this study was to determine whether early initiation of vasopressin to norepinephrine resulted in a reduced time to target MAP compared to norepinephrine monotherapy. METHODS: This retrospective cohort study compared early addition of vasopressin within 4 hours of septic shock onset to norepinephrine versus initial norepinephrine monotherapy in medically, critically ill patients with septic shock admitted from May 2014 to October 2015. Time to goal MAP was compared using Student t test and examined with Kaplan-Meier curves. Changes in Sequential Organ Failure Assessment (SOFA) scores were evaluated with Wilcoxon rank sum test. RESULTS: Each group contained 48 patients. Mean arterial pressure (61.5 vs 58.6 mm Hg) and intravenous fluid volume received at vasopressor initiation (14.3 vs 25.2 hours, P = .014) were similar. Patients started on early vasopressin achieved and maintained goal MAP sooner (6.2 vs 9.9 hours, P = .023), experienced greater reductions in SOFA scores at 72 hours (-4 vs -1, P = .012), and had shorter hospital durations (343 vs 604 hours, P = .014). Not initiating early vasopressin trended toward an association with increased time to goal MAP ( P = .067). CONCLUSION: Early initiation of vasopressin in patients with septic shock may achieve and maintain goal MAP sooner and resolve organ dysfunction at 72 hours more effectively than later or no initiation. PMID- 28820037 TI - Efficacy and Safety of High Loading Dose of Colistin in Multidrug-Resistant Acinetobacter baumannii: A Prospective Cohort Study. AB - OBJECTIVES: We aimed to assess the efficacy and safety of a high loading dose of colistin and no loading dose of colistin to treat multidrug-resistant (MDR) Acinetobacter baumannii infections. METHODS: We conducted a prospective cohort study of patients with MDR A baumannii infections at a university-affiliated hospital from December 2014 to January 2016. In the high loading dose group, the patients received a high loading dose of 300 mg colistin base activity (CBA) followed by a maintenance dose of 150 mg CBA twice daily, and patients in the no loading dose group received only the maintenance dose. The primary outcome was clinical response. The secondary outcomes were 28-day mortality and microbiological response. RESULTS: A total of 255 cases were identified. The high loading dose of colistin strategy provided no significant difference in good clinical response when compared to the no loading dose group (65.5% vs 70.4%; P = .442), without a significant difference in the development of renal dysfunction (52.3% vs 49.4%; P = .664). However, microbiological eradication was significantly higher among patients who received the high loading dose of colistin when compared to those who received the no loading dose (87.9% vs 70.4%; P = .0006). CONCLUSIONS: The high loading dose of colistin strategy was effective and safe for treating patients with MDR A baumannii. PMID- 28820038 TI - Comparison of Clevidipine and Nicardipine for Acute Blood Pressure Reduction in Patients With Stroke. AB - OBJECTIVE: The aim of this study was to determine whether clevidipine (CLEV) achieved faster blood pressure control compared to nicardipine (NIC) in patients presenting with either an acute ischemic stroke (AIS) or a spontaneous intracerebral hemorrhage (ICH). METHODS: This was a retrospective, observational, cohort study conducted in patients with AIS or ICH admitted to the emergency department of a Comprehensive Stroke Center from November 2011 to June 2013 who received CLEV or NIC continuous infusion for acute blood pressure management. RESULTS: The study included 210 patients: 70 in the CLEV group and 140 in the NIC group. There was no difference in mean time (standard deviation [SD]) from initiation of the infusion to goal systolic blood pressure (SBP), CLEV: 50 (83) minutes versus NIC: 74 (103) minutes, P = .101. Comparison of the 2 agents within diagnosis showed no difference. Hypotension developed in 5 (7.1%) CLEV patients versus 14 (10%) NIC patients ( P = .003). There was no difference in the percentage change at 2 hours; CLEV: -20% (16%) versus NIC: -16% (16%), P = .058. Mean (SD) time to alteplase administration from admission was 56 (22) minutes in the CLEV group versus 59 (25) minutes in the NIC group ( P = .684). CONCLUSIONS: There was no difference in the mean time from initiation of the infusion to the SBP goal between agents or in the secondary outcomes. Due to the lack of differences observed, each agent should be considered based on the patient care needs of the institution. PMID- 28820039 TI - Sepsis at a Safety Net Hospital: Risk Factors Associated With 30-Day Readmission. AB - BACKGROUND: Sepsis is a leading cause of hospitalization, and subsequent readmissions are frequent and costly. There is an expanding body of literature describing risk factors for readmissions in patients with sepsis. However, there are little data studying medically underserved patients who typically receive their care at a safety net hospital. METHODS: In a retrospective cohort study, we evaluated 1355 sepsis survivors at risk of hospital readmission in fiscal year 2013 at a safety net hospital. We described patient characteristics during their initial and readmission hospitalizations and analyzed risk factors associated with 30-day readmission. RESULTS: The 30-day readmission rate among sepsis survivors was 22.6%. Comorbid conditions associated with readmissions included end-stage renal disease (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.17-1.36), malignancy (OR, 1.14; 95% CI, 1.08-1.21), and cirrhosis (OR, 1.11; 95% CI, 1.02-1.20). Bacteremia during the initial hospitalization (OR, 1.07; 95% CI, 1.01-1.15) and being discharged with a vascular catheter (OR, 1.10; 95% CI, 1.01-1.20) were associated with readmission. Less severe sepsis during the initial hospitalization was associated with a reduced risk of 30-day readmission (OR, 0.91; 95% CI, 0.87-0.94). CONCLUSIONS: At a safety net hospital, patients who survived their initial sepsis hospitalization had a 30-day readmission rate to our institution of 22.6% that is comparable to rates described in prior studies. Readmission was commonly due to infection. Factors associated with readmission included multiple comorbid medical conditions, bacteremia, and being discharged with a vascular catheter. Further studies in this population are needed to determine potential modifiability of these risk factors in an attempt to reduce sepsis readmissions. PMID- 28820040 TI - Effect of Interhospital ICU Relocation on Patient Physiology and Clinical Outcomes. AB - Relocation of large numbers of critically ill patients between hospitals is sometimes necessary and the risks associated with relocation may be high. In the setting of adherence to an interhospital intensive care unit (ICU) relocation protocol, we aimed to determine whether the interhospital relocation of all ICU patients in a single day is associated with changes in vital signs, device removal, and worse clinical outcomes. We conducted a prospective, observational, cohort study of all critically ill adults admitted to a tertiary medical center's ICUs on the day of a planned hospital relocation and exposed to interhospital ICU relocation compared with unexposed critically ill adults. Changes in vital signs were evaluated by the before-and-after interhospital relocation measurement of vital signs, and clinical outcomes were collected for all patients. A total of 699 patients were admitted to the ICU during the observation period, 24 of whom were exposed to interhospital ICU relocation on a single day. The median interhospital transport duration was 28 minutes (interquartile range: 24-35) and 29% of patients were receiving invasive mechanical ventilation. Patients exposed to interhospital ICU relocation had no significant change in any vital sign measurement and no devices were unintentionally removed. Inhospital mortality was similar (8.3%) to patients not exposed to interhospital ICU relocation (9.2%, P > .99). In the setting of adherence to an ICU relocation protocol, the interhospital ICU relocation of all critically ill adults during a single day is not associated with changes in vital signs, device removal, or worse clinical outcomes. PMID- 28820041 TI - A Report of 7-Year Experience on Pediatric Continuous Renal Replacement Therapy. AB - BACKGROUND: Continuous renal replacement therapies (CRRTs) either as continuous venovenous hemofiltration (CVVH) or hemodiafiltration (CVVHD) are used frequently in critically ill children. Many clinical variables and technical issues are known to affect the result. The factors that could be modified to increase the survival of renal replacement are sought. As a contribution, we present the data on 104 patients who underwent CRRT within a 7-year period. MATERIALS AND METHOD: A total of 104 patients admitted between 2009 and 2016 were included in the study. The demographic information, admittance pediatric risk of mortality (PRISM) scores, indication for CRRT, presence of fluid overload, CRRT modality, durations of CRRT, and pediatric intensive care unit (PICU) stay were compared between survivors and nonsurvivors. RESULTS: The overall rate of survival was 51%. Patients with fluid overload had significantly increased rate of death, CRRT duration, and PICU stay. Multiorgan dysfunction syndrome as the indication for CRRT was significantly related to decreased survival when compared to acute renal failure and acute attacks of metabolic diseases. The CRRT modality was not different between survivors and nonsurvivors. Standardized mortality ratio of the group was calculated to be 0.8. CONCLUSION: The CRRT in critically ill patients is successful in achieving fluid removal and correction of metabolic imbalances caused by organ failures or attacks of inborn errors of metabolism. It has a positive effect on expected mortality in high-risk PICU patients. To affect the outcome, follow-up should be focused on starting therapy in early stages of fluid overload. Prospective studies defining relative importance of risk factors causing mortality can assist in building up guidelines to affect the outcome. PMID- 28820042 TI - Biodegradation of Remazol Brilliant Blue R using isolated bacterial culture (Staphylococcus sp. K2204). AB - Staphylococcus sp. K2204, a bacterial isolate, was employed in this work to decolorize Remazol Brilliant Blue R (RBBR), which belongs to the anthraquinone class of textile dye. Staphylococcus sp. K2204 biodegraded 100 mg/L RBBR at 37 degrees C under static condition with the help of extracellular laccase and peroxidases. The products of RBBR degradation were characterized using analytical tools including mass spectral technique. The phytotoxicity tests evaluated the toxicity of RBBR and the products of biodegradation. The research outlined here is the first attempt to utilize Staphylococcus sp. K2204 for remediating the wastewater containing anthraquinone textile dye. PMID- 28820043 TI - Rapid removal of chloroform, carbon tetrachloride and trichloroethylene in water by aluminum-iron alloy particles. AB - Water contamination with chlorinated hydrocarbons such as chloroform (CHCl3), carbon tetrachloride (CCl4) and trichloroethylene (TCE) is one of the major public health concerns. In this study, we explored the use of aluminum-iron alloys particles in millimeter scale for rapid removal of CHCl3, CCl4 and TCE from water. Three types of Al-Fe alloy particles containing 10, 20 and 58 wt% of Fe (termed as Al-Fe10, Al-Fe20 and Al-Fe58) were prepared and characterized by electrochemical polarization, X-ray diffraction and energy dispersive spectrometer. For concentrations of 30-180 MUg/L CHCl3, CCl4 and TCE, a removal efficiency of 45-64% was achieved in a hydraulic contact time of less than 3 min through a column packed with 0.8-2 mm diameter of Al-Fe alloy particles. The concentration of Al and Fe ions released into water was less than 0.15 and 0.05 mg/L, respectively. Alloying Al with Fe enhances reactivity towards chlorinated hydrocarbons' degradation and the enhancement is likely the consequence of galvanic effects between different phases (Al, Fe and intermetallic Al-Fe compounds such as Al13Fe4, Fe3Al and FeAl2) and catalytic role of these intermetallic Al-Fe compounds. The results demonstrate that the use of Al-Fe alloy particles offers a viable and green option for chlorinated hydrocarbons' removal in water treatment. PMID- 28820044 TI - Determination of Fusarium toxins in functional vegetable milks applying salting out-assisted liquid-liquid extraction combined with ultra-high-performance liquid chromatography tandem mass spectrometry. AB - Vegetable milks are considered as functional foods due to their physiological benefits. Although the consumption of these products has significantly increased, they have received little attention in legislation with regard to contaminants. However, they may contain mycotoxins resulting from the use of contaminated raw materials. In this work, ultra-high-performance liquid chromatography tandem mass spectrometry has been proposed for the determination of the most relevant Fusarium toxins (fumonisin B1 and B2, HT-2 and T-2 toxins, zearalenone, deoxynivalenol and fusarenon-X) in different functional beverages based on cereals, legumes and seeds. Sample treatment consisted of a simple salting-out assisted liquid-liquid extraction with no further clean-up. The method provided limits of quantification between 3.2 and 57.7 ug L-1, recoveries above 80% and precision with RSD lower than 12%. The method was also applied for studying the occurrence of these mycotoxins in market samples of vegetable functional beverages and deoxynivalenol was found in three oat-based commercial drinks. PMID- 28820045 TI - Effect of air flow rate and C/N ratio on biological nitrogen removal through the CANON process treating reject water. AB - The CANON process is a promising method for nitrogen removal in wastewaters with low organic carbon content like reject water. This study investigated the effect of important factors for optimization of the CANON process through inhibition of nitrite-oxidizing bacteria (NOB). In the acclimation period, complete ammonium removal and 43.3% total N removal were obtained at hydraulic retention time of 12 h, temperature of 30 degrees C +/- 0.5 degrees C and DO equal to 7-9 mg/L. The effects of air flow rate (AFR) (representative of DO), SRT and C/N were evaluated. Air flow rate was the most important factor for controlling the process, but the effect of SRT was negligible. When AFR was increased from 100 to 500 mL/min, both ammonium removal efficiency (33-43% to 81-83%) and nitrite accumulation (nitritation, 40 mgN/L to 100-120 mgN/L) were increased, but with increasing AFR to 1000 mL/min only ammonium removal efficiency was increased and because of better condition (high DO) for NOBs, nitritation was decreased. C/N had an effect like AFR of 1000 and only increased ammonium removal efficiency and total N removal. With increasing AFR and C/N, both OUR and AUR were increased, but SVI was decreased. PMID- 28820046 TI - 'Nurture the sprouting bud; do not uproot it'. Using saving groups to save for maternal and newborn health: lessons from rural Eastern Uganda. AB - BACKGROUND: Saving groups are increasingly being used to save in many developing countries. However, there is limited literature about how they can be exploited to improve maternal and newborn health. OBJECTIVES: This paper describes saving practices, factors that encourage and constrain saving with saving groups, and lessons learnt while supporting communities to save through saving groups. METHODS: This qualitative study was done in three districts in Eastern Uganda. Saving groups were identified and provided with support to enhance members' access to maternal and newborn health. Fifteen focus group discussions (FGDs) and 18 key informant interviews (KIIs) were conducted to elicit members' views about saving practices. Document review was undertaken to identify key lessons for supporting saving groups. Qualitative data are presented thematically. RESULTS: Awareness of the importance of saving, safe custody of money saved, flexible saving arrangements and easy access to loans for personal needs including transport during obstetric emergencies increased willingness to save with saving groups. Saving groups therefore provided a safety net for the poor during emergencies. Poor management of saving groups and detrimental economic practices like gambling constrained saving. Efficient running of saving groups requires that they have a clear management structure, which is legally registered with relevant authorities and that it is governed by a constitution. CONCLUSIONS: Saving groups were considered a useful form of saving that enabled easy acess to cash for birth preparedness and transportation during emergencies. They are like 'a sprouting bud that needs to be nurtured rather than uprooted', as they appear to have the potential to act as a safety net for poor communities that have no health insurance. Local governments should therefore strengthen the management capacity of saving groups so as to ensure their efficient running through partnerships with non-governmental organizations that can provide support to such groups. PMID- 28820047 TI - Reversal of Spinal Cord Ischemia Following Endovascular Thoracic Aortic Aneurysm Repair With Hyperbaric Oxygen and Therapeutic Hypothermia. AB - BACKGROUND: Neurological adverse events with spinal cord ischemia (SCI) remain one of the most feared complications in patients undergoing thoracic endovascular aortic repair (TEVAR). These patients can develop irreversible paraplegia with lifelong consequences with physical and psychological agony. CASE PRESENTATION: We herein present a patient who developed SCI with bilateral lower leg paraplegia on the third postoperative day following TEVAR. Spinal catheter was inserted for spinal fluid drainage. A hyperbaric oxygen therapy was initiated for 90 minutes for 2 days, which was followed by therapeutic hypothermia for 24 hours with a target temperature of 33 degrees C. The patient exhibited significant neurological recovery following these treatments, and he ultimately regained full neurological function without spinal deficit. DISCUSSION: This represents the first reported case of full neurological recovery of a patient who developed complete SCI following TEVAR procedure. The neurological recovery was due in part to immediate therapeutic hypothermia and hyperbaric oxygen therapy which reversed the spinal ischemia. PMID- 28820048 TI - Direct determination of 3-chloropropanol esters in edible vegetable oils using high resolution mass spectrometry (HRMS-Orbitrap). AB - A series of refined edible oils derived from mixed seeds, peanuts, corn, sunflower and palm obtained from the local supermarket were analyzed for their content of 3-MCPD esters. A direct analytical method for the determination of 3 monochloropropane-1,2-diol esters (3-MCPD esters) was applied to investigate the major MCPD esters found in common edible oils; in particular seven types of monoesters and eleven types of diesters were detected. The limits of detection (LODs) for monoesters and diesters of 3-MCPD were in the range of 0.079-12.678 ug kg-1 and 0.033-18.610 ug kg-1 in edible oils, and the ranges of limits of quantitation (LOQs) were 0.979-38.035 ug kg-1 and 0.100-55 ug kg-1, respectively. The recoveries of 3-MCPD esters from oil samples were in the range of 80-100%, with RSD ranging between 1.9 and 11.8%. The concentration levels of total 3-MCPD diesters in vegetable oil samples were in the range from 0.106 up to 3.444 MUg g 1 whereas total monoesters ranged from 0.005 up to 1.606 MUg g-1. PMID- 28820049 TI - Receptor binding assay for the detection of paralytic shellfish poisoning toxins: comparison to the mouse bioassay and applicability under regulatory use. AB - The receptor-binding assay (RBA) method for the detection of paralytic shellfish poisoning (PSP) toxins was evaluated for its overall performance in comparison with the mouse bioassay (MBA). An initial study to evaluate the effects of filtering shellfish extracts prior to running the RBA indicated no significant difference between filtered and unfiltered extracts on the determined saxitoxin (STX) concentrations. Next, we tested the RBA assay on 295 naturally contaminated mussel tissue samples, ranging in concentrations from 320 ug STX equiv. kg-1 to 13,000 ug STX equiv. kg-1 by MBA. An overall trend was observed with the RBA giving higher results (256 ug STX equiv. kg-1 on average) than the MBA; however, at low concentrations (< 500 ug STX equiv. kg-1) the RBA results were marginally lower. A third study was conducted using spiked mussel tissue analysed by three independent laboratories, two of which performed the RBA and one the MBA. This multi-laboratory study again showed the RBA to give higher results than the MBA; however, it also revealed that STX determination was accurate by the RBA, unlike the MBA. To optimise the assay for efficient usage under regulatory practice, three suggestions have been made: the use of an initial screening plate to separate those samples that exceed the alert level; use of rapid PSP test kits in the field and in the laboratory for screening negative samples and for early detection of toxicity; and use of an alternate commercially available porcine membrane in place of the laboratory-prepared rat membrane homogenate. The large number of samples analysed and the diversity of the tests conducted in this study further support the RBA as an affordable rapid method for STX detection that is also free of the routine sacrifice of live animals. PMID- 28820050 TI - In Defense of Parity, Females, and Pathology in Research. PMID- 28820051 TI - Bisthiourea Derivatives of Dipeptide Conjugated Benzo[d]isoxazole as a New Class of Therapeutics: Synthesis and Molecular Docking Studies. AB - BACKGROUND: Studies on anti-inflammatory and antimicrobial agents remains a challenging and important area in medicinal chemistry research due to more toxic and rapid development of resistance against first effective drugs. In search of novel anti-inflammatory and antimicrobials agents, bisthiourea derivatives of dipeptide conjugated to 6-fluoro-3- (piperidin-4-yl)benzo[d]isoxazole were synthesized. METHODS: The peptides were synthesized by solution phase method and conjugated to 6- fluoro-3-(piperidin-4-yl)benzo[d]isoxazole using 1-ethyl-3-(3 dimethyl aminopropyl)carbodiimide (EDCI)/hydroxybenzotriazole (HOBt) as a coupling agent and N-methylmorpholine (NMM) as a base. The protecting group, 2 chlorobenzyloxycarbonyl (2-ClZ) and tertbutyloxycarbonyl (Boc) were deblocked and further reacted with substituted phenyl isothiocyanates to obtain bisthiourea derivatives. RESULTS: The molecules 1-24 were examined for their in vitro anti inflammatory activity by employing human erythrocyte suspension test and it was found that the IC50 values of 9, 12, 21 and 24 were lower than the IC50 of standard references indomethacin and ibuprofen. Further, all the molecules were also evaluated for their in vitro antibacterial and antifungal activities against various pathogens of human origin by agar well diffusion method. In addition, binding interaction of active molecules (7-12 and 19-24) was performed on active site of cyclooxygenase-2 (COX-2) and Staphylococcus aureus (SA) TyrRS showing good binding profile. CONCLUSION: Molecular docking result, along with the biological assay data, revealed that the compounds containing electron withdrawing group (F) on phenyl ring of thiourea moiety were potential anti inflammatory and antimicrobial agents. PMID- 28820052 TI - New Insights on Neuronal Nicotinic Acetylcholine Receptors as Targets for Pain and Inflammation: A Focus on alpha7 nAChRs. AB - BACKGROUND: Nicotine and nicotinic acetylcholine receptors (nAChRs) have been explored for the past three decades as targets for pain control. The aim of this review is to introduce readers particularly to alpha7 nAChRs in a perspective of pain and its modulation. METHODS: Developments for alpha7 nAChR modulators and recent animal studies related to pain are reviewed. RESULTS: Accumulating evidences suggest that selective ligands for alpha7 nAChRs hold promise in the treatment of chronic pain conditions as they lack many of side effects associated with other nicotinic receptor types. CONCLUSION: This review provides the reader recent insights on alpha7 nAChRs from structure and function to the latest findings on the pharmacology and therapeutic targeting of these receptors for the treatment of pain and inflammation. PMID- 28820054 TI - QSAR Modeling of Histamine H3R Antagonists/inverse Agonists as Future Drugs for Neurodegenerative Diseases. AB - BACKGROUND: Histamine H3 receptor (H3R) is associated with several neuropsychological diseases, and thus it is an important target involved in several CNS disorders, such as narcolepsy, attention deficit hyperactivity disorder and schizophrenia. Since QSAR modeling is a feasible approach to explain the role of the molecular substituents in the biological activity, it can help in improving the design of better H3R ligands for these conditions. METHODS: This article reviews papers previously published in literature to show the current status of the contribution from QSAR modeling to reach H3R antagonists/inverse agonists. RESULTS: Classical and 3D-QSAR models were retrieved, showing that the steric and hydrophobic properties of the H3R ligands are most important to reach good affinity. CONCLUSION: Although QSAR methods are valuable to design better H3R antagonists/inverse agonists, pharmacokinetics should also be considered in future models to ensure good CNS penetration. PMID- 28820055 TI - An Update on Circumventing Multidrug Resistance in Cancer by Targeting P Glycoprotein. AB - BACKGROUND: The ultimate emergence of multidrug resistance remains a severe limitation of chemotherapy treatment for patients with cancer. The best characterized cause of drug resistance involves the overexpression of P glycoprotein (Pgp), which decreases the intracellular accumulation of chemotherapeutic agents in drug-resistant cancer cells. Thus, Pgp has become an attractive potential target for treating chemotherapy-resistant cancer, but the outcomes of using chemotherapy in combination with Pgp inhibitors in clinical trials to date have been disappointing. OBJECTIVE: We herein examine the relationship between Pgp and drug resistance and update the strategies for overcoming drug resistance by targeting Pgp, with a special focus on the recent progress in the area of preventing the development of drug resistance by targeting Pgp both in vitro and in vivo. Given the essential roles of drug resistant cancer models in these investigations, commonly used approaches for establishing drug-resistant models in the laboratory are also addressed. CONCLUSION: Considering the roles of Pgp in normal physiological conditions and its appreciated roles in detoxification, the currently available Pgp inhibitors undoubtedly cannot be used to reverse drug resistance in the clinic. Although agents that target Pgp to prevent and/or reverse drug resistance are not beneficial at the doses used in the laboratory when administered to patients with cancer who are enrolled in clinical trials, compounds targeting Pgp are widely acknowledged to be promising for circumventing drug resistance. PMID- 28820056 TI - Involvement of CD24 in Multiple Cancer Related Pathways Makes It an Interesting New Target for Cancer Therapy. AB - CD24 (cluster of differentiation 24) is a small heavy glycosylated protein, which is overexpressed in many cancer and some cancer stem cells and is associated with the development, invasion, and metastasis of cancer cells. The exact role of CD24 in these processes is not fully understood, however, in this article, it has been tried to present a collection of cancer-related mechanisms attributed to CD24. Based on the literature, CD24 dis-regulates different signaling pathways in various cancer cells, including; Src kinases, STAT3, EGFR, Wnt/beta-catenin and MAPK. Src kinases play an important role in the signaling pathways which activate p38 MAPK and STAT3 pathways. Akt and ERK are downstream effectors of CD24 activated EGFR, which promote cell proliferation, invasion and metastasis. CD24 increases the expression of HER2 by the activation of NF-kappaB transcription factor. Moreover, CD24 up-regulates the expression of miR-21 oncomir through the activation of Src kinases. Identification of the details of these pathways and also new pathways will help researchers to explore new CD24 targeted therapies. PMID- 28820057 TI - Impact of Angiotensin Converting Enzyme Inhibitors/Angiotensin Receptors Blockers on Mortality in Acute Heart Failure Patients with Left Ventricular Systolic Dysfunction in the Middle East: Observations from the Gulf Acute Heart Failure Registry (Gulf CARE). AB - AIMS: To evaluate the impact of Angiotensin-Converting Enzyme Inhibitors (ACEIs)/ Angiotensin Receptors Blockers (ARBs) on in-hospital, 3- and 12-month all-cause mortality in Acute Heart Failure (AHF) patients with left ventricular systolic dysfunction in 7 countries of the Middle East. METHODS AND RESULTS: Data was analysed from 2,683 consecutive patients admitted with AHF and Left Ventricular Ejection Fraction (LVEF) (<40%) from 47 hospitals from February to November 2012. Analyses were evaluated using univariate and multivariate statistics. The overall mean age of the cohort was 58+/-15, 72% (n=1,937) were males, 62% (n=1,651) had coronary artery disease, 57% (n=1,539) were hypertensives and 47% (n=1,268) had diabetes. Overall cumulative mortality at inhospital, 3- and 12-month follow-up was 5.8% (n=155), 12.6% (n=338) and 20.4% (n=548), respectively. Adjusting for demographic and clinical characteristics as well as medication in a multivariate logistic regression model, ACEIs were associated with lower risk of in-hospital mortality (adjusted odds ratio (aOR), 0.48; 95% Confidence Interval (CI): 0.25 to 0.94; p=0.031). At 3-month follow-up, both ACEIs (aOR, 0.64; 95% CI: 0.43 to 0.95; p=0.025) and ARBs (aOR, 0.34; 95% CI: 0.18 to 0.62; p<0.001) were associated with lower risk of mortality. Additionally, at 12-month follow-up, those prescribed ACEIs (aOR, 0.71; 95% CI: 0.53 to 0.96; p=0.027) and ARBs (aOR, 0.47; 95% CI: 0.31 to 0.71; p<0.001) were still associated with lower risk of mortality. CONCLUSION: ACEIs and ARBs treatments were associated with lower mortality risk during admission and up to 12-month of follow-up in Middle East AHF patients with left ventricular systolic dysfunction. PMID- 28820058 TI - Editorial: Neurodegenerative Disorders: Synthesis, Drug Delivery Strategies and Biological Evaluation of New Therapeutic Agents. PMID- 28820059 TI - Histone Modifications in Aging: The Underlying Mechanisms and Implications. AB - BACKGROUND: Aging is characterized by time-dependent functional decline, which results in the reduced ability to cope with physiological challenges. The aging process can be affected by genetic factors, environment factors, epigenetic factors, and several stochastic factors. Epigenetic marker alteration during aging has been widely monitored and studied recently, since these epigenetic alterations are theoretically reversible. OBJECTIVES: In this review, we will elaborate on the connection between aging and histone modifications, mainly focusing on the major modification participated in aging and its underlying mechanism. We will also summarize the latest research progress of the potential and promising treatments or strategies that aim to reverse aging through the intervention of histone modifications. CONCLUSION: Histone post-translational modifications play a crucial role in epigenetic alteration during aging, among which histone methylation and histone acetylation are emerging as two prominent modification methods. These modifications can serve as the therapeutic targets in the pursuit of rejuvenation. PMID- 28820060 TI - Peptide Specificity Analysis of Peptide: N-glycanases Using Synthetic Chitobiose pentapeptides. AB - BACKGROUND: Peptide: N-glycanase is a deglycosylation enzyme releasing N-glycan from glycoproteins. Although glycan specificity analysis of this enzyme has been reported, recognition requirements for the peptide sequence have not been precisely elucidated. OBJECTIVE: In this study, we carried out peptide specificity analysis of several peptide:N-glycanases. METHODS: Using synthetic chitobiose-pentapeptide substrates having a systematic series of amino acid sequences composed of hydrophobic leucine and hydrophilic serine, we examined the peptide specificities of peptide: N-glycanases comprising yeast cytoplasmic PNGase, bacterial PNGase F, and plant PNGase A by ultra-performance liquid chromatography combined with electrospray ionization mass spectrometry. RESULTS: We found that each of the PNGases had higher activity for the more hydrophobic (leucinerich) chitobiose-pentapeptides, although the sensitivities of the PNGases for hydrophobicity varied. Cytoplasmic PNGase showed broad specificity. In contrast, PNGase A showed moderate specificity. PNGase F showed the highest specificity. CONCLUSION: PNGases from different origins had similar but significantly independent peptide specificities. PMID- 28820061 TI - Renin Angiotensin System and Cytokines in Chronic Kidney Disease: Clinical and Experimental Evidence. AB - INTRODUCTION: Chronic kidney disease (CKD) has been considered an important public health issue in all countries. Experimental and clinical studies support the general idea that the pathophysiology of CKD is associated with the interaction of several endogenous mediators, including components of the renin angiotensin system (RAS) and cytokines. OBJECTIVE: This review aims to report available evidence on the interaction of RAS molecules and cytokines in CKD. RESULTS: Therapeutic administration of angiotensin converting enzyme (ACE) inhibitors and/or angiotensin type 1 (AT1) receptor antagonists can slow down the deterioration of renal function. These medications reduce the formation (ACE inhibitor) or the receptor-mediated effects of Angiotensin II (AT1 antagonist) and by so doing inhibit cytokine-mediated kidney tissue inflammation. In sharp contrast, the activation of ACE2, the stimulation of Angiotensin-(1-7) synthesis and/or the effects mediated by its G-protein coupled receptor, named Mas receptor, ameliorates experimental renal injury by reducing renal tissue inflammation and fibrosis in many experimental models of renal diseases. CONCLUSION: Novel compounds that activate and/or stimulate ACE2-Angiontensin-(1 7)-Mas receptor axis may also play a role in the treatment of CKD, mainly by controlling inflammatory response and pathways of fibrosis at kidney tissue. Clinical trials with these new pharmacological compounds will, in due course, determine whether this promise will become a helpful treatment. PMID- 28820062 TI - Urokinase Type Plasminogen Activator and the Molecular Mechanisms of its Regulation in Cancer. AB - BACKGROUND: Urokinase type plasminogen activator (uPA) is a 53-kDa serine protease initially synthesized as a catalytically inactive single chain polypeptide. Inactive-uPA is subject to proteolytic cleavage, which results in the two-chain active protein. uPA plays key roles in the enhancement of cell malignancy during tumor progression. OBJECTIVES: The main objective of this review was to analyze and describe the main molecular mechanisms involved in the regulation of uPA expression in cancer Methods: Searching literature to evaluate and define the relevant information regarding to the state of the arts on uPA functionality and regulation in cancer, including intracellular signaling regulation, tumor progression, invasion, epigenetic mechanism, and finally uPA as therapeutic target in cancer. RESULTS: uPA expression is dysregulated in tumor cells, which results in increased cellular invasion capacities reflecting changes in uPA activity and expression during tumor progression. In this review we discuss the main aspects of uPA, from its capacity to activate plasminogen to plasmin, to the main intracellular signal transduction mechanisms as well as the epigenetic mechanisms involved in the regulation of uPA expression, including regulation by microRNAs. As well as, the current therapeutic methodologies targeting uPA for cancer treatment are described. CONCLUSION: Although, uPA is dysregulate in tumor progression, its expression is finely regulated at both enzymatic activity and at protein expression as well, which allow cancer cells efficiently survive, proliferate, and spread into neighbouring tissues and distant organs. Moreover, since uPA implications in tumor development and cancer cell invasion and metastasis, it is an attractive target for cancer chemotherapies. PMID- 28820053 TI - Neurobiological Mechanisms of Stress Resilience and Implications for the Aged Population. AB - BACKGROUND: Stress is a common reaction to an environmental adversity, but a dysregulation of the stress response can lead to psychiatric illnesses such as major depressive disorder (MDD), post-traumatic stress disorder (PTSD), and anxiety disorders. Yet, not all individuals exposed to stress will develop psychiatric disorders; those with enhanced stress resilience mechanisms have the ability to adapt successfully to stress without developing persistent psychopathology. Notably, the potential to enhance stress resilience in at-risk populations may prevent the onset of stress-induced psychiatric disorders. This novel idea has prompted a number of studies probing the mechanisms of stress resilience and how it can be manipulated. METHODS: Here, we review the neurobiological factors underlying stress resilience, with particular focus on the serotoninergic (5-HT), glutamatergic, and gamma-Aminobutyric acid (GABA) systems, as well as the hypothalamic-pituitary axis (HPA) in rodents and in humans. Finally, we discuss stress resiliency in the context of aging, as the likelihood of mood disorders increases in older adults. RESULTS: Interestingly, increased resiliency has been shown to slow aging and improved overall health and quality of life. Research in the neurobiology of stress resilience, particularly throughout the aging process, is a nascent, yet, burgeoning field. CONCLUSION: Overall, we consider the possible methods that may be used to induce resilient phenotypes, prophylactically in at-risk populations, such as in military personnel or in older MDD patients. Research in the mechanisms of stress resilience may not only elucidate novel targets for antidepressant treatments, but also provide novel insight about how to prevent these debilitating disorders from developing. PMID- 28820063 TI - Loss in Toxic Function of Aggregates of α -Synuclein Mutants by a β Synuclein Derived Peptide. AB - BACKGROUND: Parkinson's disease (PD) primarily results from a severe and selective damage of dopaminergic neurons. The neuropathological hallmark of the disease is the presence of protein inclusions of alpha-Synuclein (alphaS) within the surviving neurons. To date, several researchers have been focused on screening for the inhibitors that are able to block, slow down, or reverse alphaS aggregation, particularly at its early stages. OBJECTIVES: In this work, we aimed to investigate the effects of a beta-Synuclein derived peptide on oligomerization of pathological mutants of alphaS (A53T, A30P, E46K). METHOD: The effects of the peptide on aggregation of native and mutant of alphaS were examined by fluorescence spectroscopy and electron microscopy. The influence of the peptide inhibitor on cell toxicity of aggregation products of alphaS and its mutants were investigated by MTT assay and flow cytometry. RESULTS: It was shown that the peptide inhibitor effectively blocks the fibrillation of not only the native alphaS but also the PD related alphaS mutants in vitro, suggesting a similar mechanism of oligomerization for native and mutants of alphaS. The peptide inhibitor greatly diminished the cell toxicity of the aggregation products of native and mutants of alphaS. CONCLUSION: Our findings suggest the therapeutic potential of this peptide for treatment of the rare inherited forms of PD. PMID- 28820064 TI - Flow Cytometric Analysis of Protein Aggregates. AB - BACKGROUND: Misfolding of proteins often leads to aggregation. Accumulation of diverse protein aggregates in various cells, tissue and organs is the hallmark of many diseases, such as Alzheimer's disease and Parkinson's disease. OBJECTIVES: The main objective of this study was to present a novel method of characterization of protein aggregates, associated with differential toxicity with different size and composition in vitro using flow cytometry. METHODS: A Beckman Coulter Epics XL flow cytometer with argon ion laser operating at 488 nm was used for flow cytometry analysis. The voltage and the gain settings for individual channels were set at high voltage and gain for the detections of autofluorescence, fluorescence of adsorbed Congo red, forward scattering (FSC) and side scattering (SSC) intensities from the aggregates of proteins and nanoparticles. Each sample was analyzed to characterize and quantify the number of aggregates with a limit of maximum 20,000 events. The flow cytometry data were analyzed using Flowing software version 2.5.1 and Origin 8.0. RESULTS: Autofluorescence and scattering intensities could distinguish between amyloid and nonamyloid aggregates. Dot plots of both side scattering (SSC) and forward scattering (FSC) intensities also showed characteristic fingerprint of both the types of aggregates when compared with those of well known nanoparticles of oxides of Fe and Cu. CONCLUSION: This work reports a novel, simple and robust flow cytometric method of characterization of protein aggregates of different size and composition which would find wider application in characterization of biomolecular aggregates, in general. PMID- 28820065 TI - BCG Increased Membrane Expression of TRIM59 Through the TLR2/ TLR4/IRF5 Pathway in RAW264.7 Macrophages. AB - OBJECTIVE: In our previous study, we showed that Bacillus Calmette-Guerin (BCG)- activated macrophages have the ability to directly kill tumor cells. One of the main properties of these macrophages is the high expression of tripartite motif family protein 59 (TRIM59). This study was conducted to investigate the mechanism of BCG-induced TRIM59 expression on macrophages and to identify the subcellular localization of TRIM59. METHODS: TRIM59 expression and TNF-alpha secretion were compared in RAW264.7 macrophage cells that were stimulated using BCG with or without Toll-like receptor 2/4 (TLR2/4)-neutralizing antibodies. Next, small interfering RNA (siRNA) was used to down-regulated interferon regulatory factor 5 (IRF5) gene expression in RAW264.7 cells. Transfected cells were stimulated with BCG, after which TRIM59 expression and TNF-alpha secretion were evaluated in cells pre-treated with siRNA or scramble control. After treatments, supernatants were co-cultured with MCA207, and cell viabilities were determined. Moreover, BCG stimulated RAW264.7 cells were stained for TRIM59 and F4/80 expression. RESULTS: In this study, we showed that TRIM59 was expressed on the membrane of RAW264.7 cells. After blocking TLR2/4, treatment with BCG failed to induce the expression of TRIM59, IRF5, and TNF-alpha on RAW264.7 cells. In addition, down-regulation of IRF5 inhibited TRIM59 and TNF-alpha expression. CONCLUSION: Our study showed that TRIM59 is a membrane protein, and that BCG treatment upregulated TRIM59 expression on macrophages via TLR2/4 and IRF5 pathways. PMID- 28820066 TI - Mutational Impact on the Interaction Between Human IL27 and gp130: In silico Approach for Defending HIV Infection. AB - INTRODUCTION: With advances in proteomics, it is essential to investigate the molecularlevel participation of IL27 and gp130 to hinder HIV infection. Their interaction causes cell-cycle arrest in HIV+ cells by activating the receptor associated JAK signaling and causing apoptosis of cancerous cells. METHODOLOGY: The best human wild-type WT_IL27 model was prepared after varied molecular modeling techniques. The vital tyrosine residues in WT_IL27 were identified, mutated and IL27 was re-modeled. Both wild-type and mutant IL27 were docked individually with human gp130 ectodomain complex. Best cluster sized complex was opted and the complexes (WT and MT) were MD (molecular dynamics) simulated. Protein-protein interacting residues, binding patterns, thermodynamic stability, solvent accessibility and many such parameters were evaluated to affirm the stability in the mutant complex. Statistical significances were drawn too. RESULT AND DISCUSSION: With statistical significances also, the mutant type (MT) IL27 was comprehended as the most stable one. Their functionality remained the same. Ionic interactions were the most dominating ones. Exceptionally several Arg residues from MT_IL27 appeared to play a major role, thereby stabilizing the simulated MT_IL27-gp130 complexes. Manifold energy estimations for the complexes, electrostatic potential and increment in %helices and %beta-sheets revealed the simulated MT_IL27-gp130 complex to be more stable. In the MT_complex, residues forming 3-ten helices remained constant with major increase in alpha-helices. This thereby infers the complex as the steadiest and most interactive one. CONCLUSION: The residual exploration with the detailed structural analysis would aid in the effective drug discovery by targeting the drugs at the interacting sites with the specific binding patterns as analyzed from the study. Conformational stability and other several parameters for thermodynamic stability and accomplishment of strong interaction were also explored. Altogether, this probe provides a limelight towards the mutational alterations in WT IL27, which might allow it to act as a strong peptide inhibitor by shielding HIV entry, more potently. PMID- 28820067 TI - Comprehensive Review on Ebola (EBOV) Virus: Future Prospects. AB - Ebola virus (EBOV) was discovered for the first time in 1976. It belongs to the family Filoviridae, which causes hemorrhagic fever that could lead to death in a few days. West Africa faced a major outbreak where symptoms appeared in the form of chills, myalgia, fever, diarrhea, and vomiting, and the disease finally reached a severe state as a result of hemorrhagic complications and failure of multiple organs. EBOV spreads by contact with body fluids of an infected person such as blood, saliva, urine, and seminal fluid, and also spreads by a contact with contaminated surfaces. Viral infection depends on the virus and host defenses. When the virus invades the body, the immune system becomes activated in an attempt to neutralize it. However, if this fails, EBOV viral infection spreads and leads to impaired innate and adaptive immune responses and uncontrollable viral replication. Consequently, the symptomatic patient is isolated and various medicinal regimens such as BCX-4430n TKM- EBOV are used, to cure EBOV, though, a specific treatment is not available. Accordingly, the aim of the present review is to survey and summarize the recent literature pertaining to the outbreak of EBOV, systematic infection of the human body, along with transmission and treatment. In addition, the review also aims to identify areas that need more research and development in combatting this dangerous virus. In the meantime, it should be noted that there is no fully FDA approved drug to treat infections by this virus. Therefore, there is a pressing need to focus on drug discovery along with public awareness to effectively manage any outbreaks in the future. PMID- 28820068 TI - Known Triterpenes and their Derivatives as Scaffolds for the Development of New Therapeutic Agents for Cancer. AB - BACKGROUND: Plants produce several bioactive secondary metabolites whose are used as therapeutic agents to treat several diseases, among whom cancer. Triterpenes are secondary metabolites that exert inhibitory activity against multiple intracellular and extracellular targets in euchariotic cells. These targets are proteins involved in apoptosis, cell development and differentiation, angiogenesis, metastasis and inflammatory processes. The inhibition of their functions leads to decreased cellular growth, differentiation and migration, resulting in antitumor activity, as shown by several authors. Furthermore, during recent years synthetic triterpenoid derivatives have also been developed to implement potency and efficacy of starting compounds, allowing the obtainment of new agents having promising anticancer activity. OBJECTIVE: In this review we report the latest results regarding anticancer activity of some of the most studied triterpenes in the field, as well as of their semi-synthetic derivatives, with the aim to summarize the role of triterpenes as molecular leads for the development of new classes of antitumor agents. METHODS: We focused on the most recent literature regarding triterpenes in cancer treatment, highlighting the potential of developing new drugs starting from these natural compounds. CONCLUSION: Several "old" triterpenes as ursolic, betulinic and oleanolic acids were recently reconsidered as model compounds for the development of innovative anticancer agents. Their activity against proteins involved in tumor development enhances the opportunity to exploit these compounds as new multi-target therapeutic agents. Furthermore, the possibility to synthetize new compounds from their natural-occurring structures could be an alternative to overcome cellular resistance to drugs and could improve their therapeutic efficacy. PMID- 28820070 TI - MUC1 Story: Great Expectations, Disappointments and the Renaissance. AB - In the course of studying human mucin MUC1, an attitude towards this molecule has been changing time and again. Initially, the list of presumable functions of MUC1 was restricted to protecting and lubricating epithelium. To date, it is assumed to play an important role in cell signaling as well as in all stages of oncogenesis, from malignant cell transformation to tumor dissemination. The story of MUC1 is full of hopes and disappointments. However, the scientific interest to MUC1 has never waned, and the more profoundly it has been investigated, the clearer its hidden potential turned to be disclosed. The therapeutic potential of mucin MUC1 has already been noted by various scientific groups at the early stages of research. Over forty years ago the first insights into MUC1 functions became a strong grounds for considering this molecule as potential target for anticancer therapy. Therefore, this direction of research has always been of particular interest and practical importance. More than 200 papers on MUC1 were published in 2016; the majority of them are dedicated to MUC1-related anticancer diagnostics and therapeutics. Here we review the history of MUC1 studies from the very first attempts to reveal its functions to the ongoing renaissance. PMID- 28820069 TI - Apixaban: Effective and Safe in Preventing Thromboembolic Events in Patients with Atrial Fibrillation and Renal Failure. AB - BACKGROUND: Thromboembolic events, principally stroke, represent one of the leading causes of morbidity and mortality among subjects with atrial fibrillation. Chronic kidney disease determines a further increase of thromboembolic events, bleeding and mortality and complicates the pharmacological management of patients with atrial fibrillation, mainly due to the side effects of antiarrhythmic and anticoagulant drugs with renal excretion. Apixaban is a new oral anticoagulant characterized by good bioavailability and renal elimination accounting for only 25%, showing a safety profile and effectiveness in patients with renal impairment. OBJECTIVE: In this manuscript, we reviewed literature data on the use of apixaban in the management of non-valvular atrial fibrillation in patients with renal failure, in order to clarify an often-debated topic in clinical practice. METHOD: A PubMed search was performed on the terms atrial fibrillation, apixaban and renal failure with the aim of identifying relevant manuscripts, large randomized clinical trials, meta-analyses, and current guidelines. RESULTS: Literature data show that apixaban could represent an interesting alternative to warfarin and other selective antagonists of coagulation factors in patients with impaired renal function. About the risk of major bleeding, apixaban appears to be safer than warfarin in the presence of any degree of renal failure. CONCLUSION: Apixaban show to be an effective anticoagulant in patients with atrial fibrillation, even superior to warfarin in reducing the risk of stroke and systemic embolism regardless of the presence of renal insufficiency. Moreover, Food and Drug Administration allows the use of apixaban in patients with end stage renal disease on hemodialysis. PMID- 28820071 TI - Antibody Fragments as Potential Biopharmaceuticals for Cancer Therapy: Success and Limitations. AB - Monoclonal antibodies (mAbs) are an important class of therapeutic agents approved for the therapy of many types of malignancies. However, in certain cases applications of conventional mAbs have several limitations in anticancer immunotherapy. These limitations include insufficient efficacy and adverse effects. The antigen-binding fragments of antibodies have a considerable potential to overcome the disadvantages of conventional mAbs, such as poor penetration into solid tumors and Fc-mediated bystander activation of the immune system. Fragments of antibodies retain antigen specificity and part of functional properties of conventional mAbs and at the same time have much better penetration into the tumors and a greatly reduced level of adverse effects. Recent advantages in antibody engineering allowed to produce different types of antibody fragments with improved structure and properties for efficient elimination of tumor cells. These molecules opened up new perspectives for anticancer therapy. Here we will overview the structural features of the various types of antibody fragments and their applications for anticancer therapy as separate molecules and as part of complex conjugates or structures. Mechanisms of antitumor action of antibody fragments as well as their advantages and disadvantages for clinical application will be discussed in this review. PMID- 28820072 TI - Structural Design and Physicochemical Foundations of Hydrogels for Biomedical Applications. AB - Biomedical research, known as medical research, is conducive to support and promote the development of knowledge in the field of medicine. Hydrogels have been extensively used in many biomedical fields due to their highly absorbent and flexible properties. The smart hydrogels, especially, can respond to a broad range of external stimuli such as temperature, pH value, light, electric and magnetic fields. With excellent biocompatibility, tunable rheology, mechanical properties, porosity, and hydrated molecular structure, hydrogels are considered as promising candidate for simulating local tissue microenvironment. In this review article, we mainly focused on the most recent development of engineering synthetic hydrogels; moreover, the classification, properties, especially the biomedical applications including tissue engineering and cell scaffolding, drug and gene delivery, immunotherapies and vaccines, are summarized and discussed. PMID- 28820073 TI - Immunomodulatory Role of Arsenic in Regulatory T Cells. AB - BACKGROUND AND OBJECTIVE: Chronic Arsenic (As) exposure continued to be a cause of major problem associated with different kind of diseases including skin problem and different types of cancer. As exposure leads to numerous other pathological conditions that affect millions of people worldwide on a regular basis. It was recently established that As toxicity affects immune system and modulates the function and survival of cells involved in immune regulation. Arsenic trioxide (As2O3) was reported to be an effective apoptosis inducer in a variety of cell types. Despite intensive research, the exact immune-modulatory role of As is poorly understood till now. METHODS: We reviewed the immunological imbalance caused due to As exposure and focused on regulatory T cells (Tregs cells). In this review, we mainly focused on role of As and its potential mechanisms in the induction and modulation of Tregs cells. CONCLUSION: The multiple effects of As on immune system tend to decrease the immune surveillance system and increase the rate of infection, autoimmune disease, cancer and other immune mediated problems. As exposed individuals showed induction of oxidative stress, inflammation and impaired lymphocytes activation. The effect of As on T cell population is mainly attributed to altered expression of key immune regulator molecules impaired T cell functions, cytokines production, induction of apoptosis, and oxidative stress induction in T cells. PMID- 28820074 TI - Exploring the Cardio-metabolic Relevance of T-cadherin: A Pleiotropic Adiponectin Receptor. AB - BACKGROUND AND OBJECTIVE: T-cadherin is a unique member of the cadherin family and is primarily expressed in the cardiovascular system. T-cadherin has not been abundantly studied, but the studies conducted to date have explored the impact of this protein on health and the function of organs involved in metabolic regulation. METHODS: This article examines the recent knowledge of the ligand partners for T-cadherin and the potential contribution(s) of T-cadherin to cardio metabolic function. RESULT AND DISCUSSION: One significant role for T-cadherin is its ability to bind high molecular weight adiponectin in cardiovascular tissue, thereby mediating the cardio-protective benefits of adiponectin. It also has the ability to bind low-density lipoprotein via its glycosylphosphatidylinositol anchor; however, the exact physiological consequence of this ligand-receptor relationship is not known. T-cadherin appears to affect multiple conditions of cardio-metabolic disease, including atherosclerosis and insulin resistance. Research into T-cadherin has suggested that it may be useful as a diagnostic marker for the early stages of cardiovascular disease. However, with regard to insulin, T-cadherin is necessary for pancreatic insulin secretion, but overexpression of T-cadherin on vascular cells may promote endothelial insulin resistance. CONCLUSION: This review provides evidence that T-cadherin has an influential role on key cardiometabolic molecules and warrants further investigation. PMID- 28820075 TI - T-Regulatory Cell Subsets in Children with Type 1 Diabetes Mellitus: Relation to Control of the Disease. AB - BACKGROUND: Type 1 diabetes mellitus is described as a chronic metabolic disorder characterized by aggressive immune β-cell destruction. There are a number of varied immune mechanisms for sustaining self-tolerance in opposition to the autoimmune disorders. A recessive tolerance is accomplished by thymic gland via a negative assortment of different clones, while a dominant tolerance is accomplished by the regulatory T cells (Treg) in the periphery. Treg (CD4+ CD25+FOXP3+) are subsets of T cells which have an essential role in maintaining tolerance. OBJECTIVE: To evaluate peripheral Treg (CD4+; CD25+; FOXP3+) in children cohort with T1DM. METHODS: This study included 64 children diagnosed with T1DM and 35 age- and sex-matched healthy children as controls. All children were clinically evaluated and subjected to assessment of complete blood count (CBC), glycated hemoglobin, surface and cytoplasmic detection of Treg by flow cytometry. RESULTS: This study showed that the frequency of Treg (CD4+; CD25+; FOXP3+) was significantly lower in diabetic children than with normal controls (P<0.001). There was a significant (P <0.001) reduction in the Treg (CD4+; CD25+; FOXP3+) in T1DM children with uncontrolled (Hemoglobin A1c>7%) as compared to those with controlled (Hemoglobin A1c<7%) disease. CONCLUSION: Diminished Treg in T1DM proved that auto-reactivation of T-cell as a result of the breakdown of immune tolerance takes part in the elaboration of autoimmune disorders as T1DM. Treg may be used in immunotherapy, thus preventing T1DM development due to its pivotal role in immune tolerance. PMID- 28820076 TI - A Novel Danshensu-Tetramethylpyrazine Conjugate DT-018 Provides Cardioprotection by Preserving Mitochondrial Function Through the MEF2D/PGC-1alpha Pathway. AB - In this work, we explored the protective effect of DT-018, a danshensu and tetramethylpyrazine conjugate, on mitochondrial injury induced by tert butylhydroperoxide (t-BHP) and its possible mechanisms of action. DT-018 effectively quenched intracellular and mitochondrial reactive oxygen species (ROS), preserved the mitochondrial function, restored the intracellular level of ATP and augmented mitochondrial membrane potential (Deltapsim) while suppressed mitochondrial swelling in isolated myocardial mitochondria. DT-018 increased the expression of MEF2D and PGC-1alpha as well as Nrf2 and Tfam in H9c2 cells. Transfection of MEF2D-siRNA and PGC-1alpha-siRNA down-regulated the protein expression of PGC-1alpha and partially abolished the cardioprotection of DT-018 in t-BHP injured cells. For the in vivo studies, administration of DT-018 significantly alleviated infarct area induced by ischemia and reperfusion injury. These observations demonstrated that the cardioprotective effect of DT-018 is mediated, at least in part, by preservation of mitochondrial integrity through up regulation of MEF2D/PGC-1alpha pathway. PMID- 28820077 TI - Genetic Variants of PEAR1 are Associated with Platelet Function and Antiplatelet Drug Efficacy: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Platelet endothelial aggregation receptor 1 (PEAR1) may affect platelet-platelet contact and aggregation. The aim of this study was to assess the association between PEAR1 polymorphisms and risks of platelet aggregation. METHODS: We searched the PubMed, EmBase, and Cochrane Library electronic databases for articles published through November 30th. 2016. Meta-analysis was performed to examine the relationship between PEAR1 and platelet aggregation and sensitivity analysis by removing individual study from meta-analysis. We collected and analyzed the results of 5 trials involving 5466 patients. RESULTS: Our results demonstrated that the G allele of rs12041331 was associated with a greater platelet aggregation by multiple agonists, both in the presence and absence of antiplatelet drugs, in several separate cohorts of different ethnicities along with an apparent allelic dose-response effect. However, the results of studies on rs2768759 locus were inconsistent and further studies are required. In the presence or absence of antiplatelet drugs treatment, the lowest platelet aggregation was observed in rs2768759 wild-type (AA) patients, followed by heterozygous (AC) and homozygous mutant (CC). CONCLUSION: PEAR1 rs12041331 is associated with platelet function and antiplatelet drug pharmacodynamics. Future studies on relationship between single nucleotide polymorphisms of PEAR1 and incidence of cardiovascular diseases are required. PMID- 28820078 TI - Effects of Excitotoxic Lesion with Inhaled Anesthetics on Nervous System Cells of Rodents. AB - Different anesthesia methods can variably influence excitotoxic lesion effects on the brain. The main purpose of this review is to identify potential differences in the toxicity to nervous system cells of two common inhalation anesthesia methods, isoflurane and sevoflurane, used in combination with an excitotoxic lesion procedure in rodents. The use of bioassays in animal models has provided the opportunity to examine the role of specific molecules and cellular interactions that underlie important aspects of neurotoxic effects relating to calcium homeostasis and apoptosis activation. Processes induced by NMDA antagonist drugs involve translocation of Bax protein to mitochondrial membranes, allowing extra-mitochondrial leakage of cytochrome C, followed by sequence of changes that ending in activation of CASP-3. The literature demonstrates that the use of these anesthetics in excitotoxic surgery increases neuroinflammation activity facilitating the effects of apoptosis and necrosis on nervous system cells, depending on the concentration and exposure duration of the anesthetic. High numbers of microglia and astrocytes and high levels of proinflammatory cytokines and caspase activation possibly mediate these inflammatory responses. However, it is necessary to continue studies in rodents to understand the effect of the use of inhaled anesthetics with excitotoxic lesions in different developmental stages, including newborns, juveniles and adults. Understanding the mechanisms of regulation of cell death during development can potentially provide tools to promote neuroprotection and eventually achieve the repair of the nervous system in pathological conditions. PMID- 28820079 TI - Validation of a system for monitoring individual feeding and drinking behaviour and intake in young cattle. AB - The objective of this study was to validate an electronic system for monitoring individual feeding and drinking behaviour and intake developed for young cattle housed in group. A total of 35 Holstein-Gyr crossbred heifers (BW: 180+/-52 kg; age: 121.5+/-32.5 days), fitted with an ear tag containing a unique passive transponder, were distributed in three groups of 12, 12 and 11 animals per period and had free access to 12 electronic feed bins and two electronic water bins (Intergado(r) Ltd). The dimensions of feed and water bins, as well as the sensors position were appropriate for young cattle. The system documented the visit frequency and duration, as well as the feed and water intakes, by recording the animal's identification tag, bin number, initial and final times of visits and the difference of feed/water weight at the start and end of each bin visit. Feed bins were monitored using time-lapse video recording over 4 days and the water bins were monitored over 6 days. For each feed bin, two feeding events were monitored using manual weighings with an external scale immediately before and after the animal's visit and the difference between them was assumed as feed intake (n=24 observations). For the water bins, 60 manual weighings were made. Video and manual weighing data were regressed on the electronic feeding and drinking behaviour and intake data to evaluate the system's precision and accuracy. The system showed high specificity (98.98% and 98.56% for the feed and water bins, respectively) and sensitivity (99.25% and 98.74%, respectively) for identifying an animal's presence or absence. Duration of feed and water bin visits as well as feed and water consumption per visit estimated by the system were highly correlated and precise compared with the observed video and manual weighing data (r 2=0.917, 0.963, 0.973 and 0.986, respectively). It was concluded that Intergado(r) system is a useful tool for monitoring feeding and drinking behaviour as well as water and feed intakes in young cattle housed in groups. PMID- 28820080 TI - Diet quality and its implications on the cardio-metabolic, physical and general health of older men: the Concord Health and Ageing in Men Project (CHAMP). AB - The revised Dietary Guideline Index (DGI-2013) scores individuals' diets according to their compliance with the Australian Dietary Guideline (ADG). This cross-sectional study assesses the diet quality of 794 community-dwelling men aged 74 years and older, living in Sydney, Australia participating in the Concord Health and Ageing in Men Project; it also examines sociodemographic and lifestyle factors associated with DGI-2013 scores; it studies associations between DGI-2103 scores and the following measures: homoeostasis model assessment - insulin resistance, LDL-cholesterol, HDL-cholesterol, TAG, blood pressure, waist:hip ratio, BMI, number of co-morbidities and medications and frailty status while also accounting for the effect of ethnicity in these relationships. Median DGI 2013 score was 93.7 (54.4, 121.2); most individuals failed to meet recommendations for vegetables, dairy products and alternatives, added sugar, unsaturated fat and SFA, fluid and discretionary foods. Lower education, income, physical activity levels and smoking were associated with low scores. After adjustments for confounders, high DGI-2013 scores were associated with lower HDL cholesterol, lower waist:hip ratios and lower probability of being frail. Proxies of good health (fewer co-morbidities and medications) were not associated with better compliance to the ADG. However, in participants with a Mediterranean background, low DGI-2013 scores were not generally associated with poorer health. Older men demonstrated poor diet quality as assessed by the DGI-2013, and the association between dietary guidelines and health measures and indices may be influenced by ethnic background. PMID- 28820081 TI - Effects of 1,5-anhydroglucitol on postprandial blood glucose and insulin levels and hydrogen excretion in rats and healthy humans. AB - The inhibition by 1,5-anhydro-d-glucitol (1,5-AG) was determined on disaccharidases of rats and humans. Then, the metabolism and fate of 1,5-AG was investigated in rats and humans. Although 1,5-AG inhibited about 50 % of sucrase activity in rat small intestine, the inhibition was less than half of d-sorbose. 1,5-AG strongly inhibited trehalase and lactase, whereas d-sorbose inhibited them very weakly. 1,5-AG noncompetitively inhibited sucrase. The inhibition of 1,5-AG on sucrase and maltase was similar between humans and rats. 1,5-AG in serum increased 30 min after oral administration of 1,5-AG (600 mg) in rats, and mostly 100 % of 1,5-AG was excreted into the urine 24 h after administration. 1,5-AG in serum showed a peak 30 min after ingestion of 1,5-AG (20 g) by healthy subjects, and decreased gradually over 180 min. About 60 % of 1,5-AG was excreted into the urine for 9 h following ingestion. Hydrogen was scarcely excreted in both rats and humans 24 h after administration of 1,5-AG. Furthermore, 1,5-AG significantly suppressed the blood glucose elevation, and hydrogen excretion was increased following the simultaneous ingestion of sucrose and 1,5-AG in healthy subjects. 1,5-AG also significantly suppressed the blood glucose elevation following the simultaneous ingestion of glucose and 1,5-AG; however, hydrogen excretion was negligible. The available energy of 1,5-AG, which is absorbed readily from the small intestine and excreted quickly into the urine, is 0 kJ/g (0 kcal/g). Furthermore, 1,5-AG might suppress the blood glucose elevation through the inhibition of sucrase, as well as intestinal glucose absorption. PMID- 28820082 TI - High-dose B-vitamin supplements and risk for age-related cataract: a population based prospective study of men and women. AB - Previous studies that have investigated the association between B-vitamin supplement use and risk for cataract yield conflicting results. The aim of this study was to examine the association between use of high-dose B-vitamin supplements (approximately 10 times recommended daily intake) and risk for age related cataract in a population-based prospective study of 13 757 women from the Swedish Mammography Cohort and 22 823 men from the Cohort of Swedish Men. Dietary supplement use and potential confounders were assessed using a questionnaire at baseline. Information on cataract diagnosis and extraction was obtained through linkage to registers. During the follow-up period between January 1998 and December 2011, we identified 8395 cataract cases (3851 for women and 4544 for men). The use of B vitamins plus other supplements and B vitamins only was associated with 9 % (95 % CI 2, 17) and 27 % (95 % CI 12, 43) increased risk for cataract, respectively. The hazard ratios for use of B vitamins only and risk for cataract stratified by different age groups were as follows: <60 years: 1.88 (95 % CI 1.47, 2.39); 60-69 years: 1.21 (95 % CI 0.96, 1.53); and >=70 years: 1.09 (95 % CI 0.91, 1.31) (P interaction=0.002). Our results suggest that the use of high-dose B-vitamin supplements was associated with an increased risk for cataract. This association might be confined to younger participants. PMID- 28820084 TI - The effectiveness of healthy meals at work on reaction time, mood and dietary intake: a randomised cross-over study in daytime and shift workers at an university hospital. AB - Our dietary habits affect both cognitive performance and mood. The aim of the study was to examine the effect of increased availability of healthy meals and water at work on healthcare staff. The study used an 8-week randomised cross-over design. A total of sixty physicians, nurses and nursing assistants, including sixteen working on shifts, were recruited. The participants received a self selected keyhole-labelled (Nordic nutrition label) lunch, snack and bottled water during each shift throughout the intervention period. Reaction time (Go/No-Go test), mood-related scores (POMS) and dietary intake were assessed at run-in, and at the end of the intervention and the control periods. The intake of fat (P=0.030) and PUFA (P=0.003) was lower, and the intake of carbohydrate (P=0.008), dietary fibre (P=0.031) and water (P<0.001) was greater in the intervention period than in the control period. The intervention had no effect on reaction time or any of the mood-related scores in the group as a whole. In shift-working participants, the intervention period resulted in a 31.1 % lower Fatigue-Inertia Score (P=0.003), a 15.3 % higher Vigour-Activity Score (P=0.041) and a 42.7 % lower Total Mood Disturbance Score (P=0.017), whereas the only dietary component that significantly improved was water intake (P=0.034), when compared with the control period. Providing healthy meals, snacks and water during working hours seems to be an effective way of improving employees' dietary intake. Moreover, increased intake of water may be associated with beneficial effects on fatigue, vigour and total mood in shift-working healthcare staff. PMID- 28820083 TI - Threonine deficiency decreased intestinal immunity and aggravated inflammation associated with NF-kappaB and target of rapamycin signalling pathways in juvenile grass carp (Ctenopharyngodon idella) after infection with Aeromonas hydrophila. AB - This study aimed to investigate the impacts of dietary threonine on intestinal immunity and inflammation in juvenile grass carp. Six iso-nitrogenous semi purified diets containing graded levels of threonine (3.99-21.66 g threonine/kg) were formulated and fed to fishes for 8 weeks, and then challenged with Aeromonas hydrophila for 14 d. Results showed that, compared with optimum threonine supplementation, threonine deficiency (1) decreased the ability of fish against enteritis, intestinal lysozyme activities (except in the distal intestine), acid phosphatase activities, complement 3 (C3) and C4 contents and IgM contents (except in the proximal intestine (PI)), and it down-regulated the transcript abundances of liver-expressed antimicrobial peptide (LEAP)-2A, LEAP-2B, hepcidin, IgZ, IgM and beta-defensin1 (except in the PI) (P<0.05); (2) could up-regulate intestinal pro-inflammatory cytokines TNF-alpha, IL-1beta, IL-6, IL-8 and IL-17D mRNA levels partly related to NF-kappaB signalling; (3) could down-regulate intestinal anti-inflammatory cytokine transforming growth factor (TGF)-beta1, TGF beta2, IL-4/13A (not IL-4/13B) and IL-10 mRNA levels partly by target of rapamycin signalling. Finally, on the basis of the specific growth rate, against the enteritis morbidity and IgM contents, the optimum threonine requirements were estimated to be 14.53 g threonine/kg diet (4.48 g threonine/100 g protein), 15.05 g threonine/kg diet (4.64 g threonine/100 g protein) and 15.17 g threonine/kg diet (4.68 g threonine/100 g protein), respectively. PMID- 28820085 TI - Reclassification of Mzabimyces algeriensis Saker et al. 2015 as Halopolyspora algeriensis comb. nov. AB - Halopolyspora alba AFM10251T was proposed to represent a novel species of a new genus belonging to the family Actinopolysporaceae in a previous study. The family Mzabimycetaceae , containing one genus, Mzabimyces, was proposed subsequently and Mzabimyces algeriensis H195T was the type strain. However, analysis of 16S rRNA gene sequence similarity showed that the two strains were highly similar (99.2 %). Phenotypic and chemotaxonomic data, as well as DNA-DNA hybridization confirmed that the two strains are different genomic species of the same genus, Halopolyspora. Mzabimyces algeriensis should be classified in the genus Halopolyspora as Halopolysporaalgeriensis comb. nov. The type strain of Halopolysporaalgeriensis is H195T (=DSM 46680T=CECT 8575T). PMID- 28820087 TI - Reinstating Mycobacterium massiliense and Mycobacterium bolletii as species of the Mycobacterium abscessus complex. AB - TheMycobacterium abscessus complex is a group of rapidly growing, multiresistant mycobacteria previously divided into three species. Proposal for the union of Mycobacterium bolletii and Mycobacterium massiliense into one subspecies, so called M. abscessus subsp. massiliense, created much confusion about the routine identification and reporting of M. abscessus clinical isolates for clinicians. Results derived from multigene sequencing unambiguously supported the reinstatement of M. massiliense and M. bolletii as species, culminating in the presence of erm(41)-encoded macrolide resistance in M. bolletii. Present genome based analysis unambiguously supports the reinstatement of M. massiliense and M. bolletii as species after the average nucleotide identity values of 96.7 % for M. abscessus versus M. bolletii, and 96.4 % for M. abscessus versus M. massiliense, and the 96.6 % identity between M. bolletii and M. massiliense was put into the perspective of a larger, 28-species analysis. Accordingly, DNA-DNA hybridization values predicted by the complete rpoB gene sequencing analysis were between 68.7 and 72.3 % in this complex. These genomic data as well as the phenotypic characteristics prompted us to propose to reinstate the previously known M. massiliense and M. bolletii into two distinct species among the M. abscessus complex. PMID- 28820086 TI - Stenotrophomonas bentonitica sp. nov., isolated from bentonite formations. AB - A Gram-stain negative, rod-shaped, aerobic bacterial strain, BII-R7T, was isolated during a study targeting the culture-dependent microbial diversity occurring in bentonite formations from southern Spain. Comparative 16S rRNA gene sequence analysis showed that BII-R7T represented a member of the genus Stenotrophomonas (class Gammaproteobacteria), and was related most closely to Stenotrophomonas rhizophila e-p10T (99.2 % sequence similarity), followed by Stenotrophomonas pavanii ICB 89T (98.5 %), Stenotrophomonas maltophilia IAM 12423T, Stenotrophomonas chelatiphaga LPM-5T and Stenotrophomonas tumulicola T5916-2-1bT (all 98.3 %). Pairwise sequence similarities to all other type strains of species of the genus Stenotrophomonas were below 98 %. Genome-based calculations (orthologous average nucleotide identity, original average nucleotide identity, genome-to-genome distance and DNA G+C percentage) indicated clearly that the isolate represents a novel species within this genus. Different phenotypic analyses, such as the detection of a quinone system composed of the major compound ubiquinone Q-8 and a fatty acid profile with iso-C15 : 0 and anteiso-C15 : 0 as major components, supported this finding at the same time as contributing to a comprehensive characterization of BII-R7T. Based on this polyphasic approach comprising phenotypic and genotypic/molecular characterization, BII-R7T can be differentiated clearly from its phylogenetic neighbours, establishing a novel species for which the name Stenotrophomonas bentonitica sp. nov. is proposed with BII-R7T as the type strain (=LMG 29893T=CECT 9180T=DSM 103927T). PMID- 28820088 TI - Bacillus praedii sp. nov., isolated from purplish paddy soil. AB - A Gram-stain-positive, rod-shaped, endospore-forming, aerobic bacterium, designated strain FJAT-25547T, was isolated from the purplish paddy soil collected from Linshan Township, Yanting Prefecture of Sichuan Province in PR China (31 degrees 16' N 105 degrees 27' E). Growth was achieved aerobically at temperatures between 15 and 40 degrees C (optimum 30 degrees C), with between 0 and 10.0 % NaCl (w/v) (optimum 4 %) and in the range of pH 5.0-12.0 (optimum pH 9.0). The cell-wall peptidoglycan contained meso-diaminopimelic acid, and the main isoprenoid quinone was MK-7. The major fatty acids were iso-C15 : 0 (55.4 %), anteiso-C15 : 0 (22.2 %), iso-C16 : 0 (5.1 %) and iso-C14 : 0 (6.5 %). The main polar lipids were diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain FJAT-25547T was a member of the genus Bacillus and was most closely related to Bacillus horneckiae DSM 23495T (97.7 % similarity), Bacillus eiseniae A1-2T (97.5 %), Bacillus mesophilum IITR-54T (97.2 %) and Bacillus kochii WCC 4582T (97.0 %). The average nucleotide identity value between strain FJAT-25547T and the type strain of the most closely related species, B. horneckiae DSM 23495T, was 77.7 %, less than the proposed cut-off value of 96.0 % for differentiating species within the genus. The in silico DNA-DNA hybridization value of strain FJAT-25547T with the most closely related species was 22.7 %, <70 %, again indicating they belong to different taxa. The DNA G+C content of strain FJAT-25547T was 39.1 mol%. This taxono-genomics study revealed that strain FJAT 25547T represents a novel species of the genus Bacillus for which the name Bacillus praedii sp. nov. (type strain FJAT-25547T=CCTCC AB 2015208T=DSM 101002T) is proposed. PMID- 28820089 TI - Alteromonas aestuariivivens sp. nov., isolated from a tidal flat. AB - A Gram-stain-negative, aerobic, non-spore-forming, motile and ovoid or rod-shaped bacterial strain, JDTF-113T, was isolated from a tidal flat in Jindo, an island of South Korea. Strain JDTF-113T grew optimally at 30 degrees C, at pH 7.0-8.0 and in the presence of 2.0 % (w/v) NaCl. A neighbour-joining phylogenetic tree, based on 16S rRNA gene sequences, revealed that strain JDTF-113T fell within the clade enclosing the type strains of species of the genus Alteromonas. Strain JDTF 113T exhibited 16S rRNA gene sequence similarity values of 97.1-98.1 % to the type strains of Alteromonaslipolytica, Alteromonaslitorea, Alteromonasmediterranea, Alteromonasconfluentis, Alteromonas hispanica, Alteromonasgenovensis and Alteromonasmarina, and of 94.8-96.9 % to those of the other species of the genus Alteromonas. Strain JDTF-113T contained Q-8 as the predominant ubiquinone and C16 : 0, summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and C18 : 1omega7c as the major fatty acids. The major polar lipids of strain JDTF-113T were phosphatidylethanolamine, phosphatidylglycerol and one unidentified glycolipid. The DNA G+C content of strain JDTF-113T was 51.1 mol% and its mean DNA-DNA relatedness values with the type strains of seven closely phylogenetically related species of the genus Alteromonaswere was 10-23 %. The differential phenotypic properties and phylogenetic and genetic distinctiveness support strain JDTF-113T being separated from species of the genus Alteromonaswith validly publishednames. On the basis of the data presented, strain JDTF-113T is considered to represent a novel species of the genus Alteromonas, for which the name Alteromonas aestuariivivens sp. nov. is proposed. The type strain is JDTF-113T (=KCTC 52655T=NBRC 112708T). PMID- 28820091 TI - Alloscardovia venturai sp. nov., a fructose 6-phosphate phosphoketolase-positive species isolated from the oral cavity of a guinea-pig (Cavia aperea f. porcellus). AB - A slightly irregular, short rod-shaped bacterial strain, MOZIV/2T, showing activity of fructose 6-phosphate phosphoketolase was isolated from the oral cavity of a home-bred guinea-pig. Based on comparative 16S rRNA gene sequence analyses, its closest relatives were Alloscardovia omnicolens DSM 21503T and Alloscardovia criceti DSM 17774T with 96.0 and 95.6 % pairwise similarities, respectively. Completeness of the compared sequences was 97.3 and 96.9 %, respectively. Growth was found only under anaerobic conditions. Activities of alpha- and beta-gluco(galacto)sidases were detected in strain MOZIV/2T, which is characteristic for almost all members of the family Bifidobacteriaceae. Sequencing of other molecular markers (fusA, gyrB and xfp) revealed low gene sequence similarities to A. omnicolens DSM 21503T ranging from 72.7 to 87.5 %. Strain MOZIV/2T differed from other species within the genus Alloscardovia by the presence of C18 : 1omega9t. In addition, much higher proportions of C8 : 0, C11 : 0, C12 : 0, C14 : 1, C16 : 1 and C17 : 0 fatty acids were found in cells of strain MOZIV/2T. The peptidoglycan structure was of type A4alpha [l-Lys(l-Orn)-d Asp], which is consistent with its classification within the genus Alloscardovia. The DNA G+C content (45.8 mol%) was lower than those found in other alloscardovia. Phylogenetic studies and evaluation of phenotypic characteristics including the results of biochemical, physiological and chemotaxonomic analyses confirmed the novel species status for strain MOZIV/2T, for which the name Alloscardovia venturai sp. nov. is proposed. The type strain is MOZIV/2T (=DSM 100237T=CCM 8604T=LMG 28781T). PMID- 28820090 TI - Description of Conyzicola nivalis sp. nov., isolated from glacial snow, and emended description of the genus Conyzicola and Conyzicola lurida. AB - A cold-tolerant, translucent, yellow-pigmented, Gram-stain-positive, non-motile, rod-shaped bacteria was isolated from snow of the Zadang Glacier on the Tibetan Plateau, PR China. 16S rRNA gene sequence similarity analysis indicated that the isolate was closely related to Conyzicola lurida KCTC 29231T and Leifsonia psychrotolerans DSM 22824T at a level of 97.72 and 97.49 %, respectively. Other close relatives had a 16S rRNA gene sequence similarity of less than 97 %. The major cell-wall amino acid was 2,4-diaminobutyric acid. The cell-wall sugars were rhamnose, ribose, glucose, galactose and mannose. The major menaquinones were MK 9, MK-10 and MK-11. The major polar lipids were diphosphatidylglycerol and phosphatidylglycerol. The predominant fatty acids were anteiso-C15 : 0 and iso C16 : 0. In DNA-DNA hybridization tests, strain ZD5-4T shared 43.6 and 34.2 % relatedness with C. lurida KCTC 29231T and L. psychrotolerans DSM 22824T, respectively. Based on phenotypic and chemotaxonomic characteristics, strain ZD5 4T was considered to represent a novel species of the genus Conyzicola, for which the name Conyzicola nivalis sp. nov. is proposed. The type strain is ZD5-4T (=JCM 30076T=CGMCC 1.12813T). Emended descriptions of the genus Conyzicola and Conyzicola lurida are also provided. PMID- 28820092 TI - Rhizobium wenxiniae sp. nov., an endophytic bacterium isolated from maize root. AB - A novel Gram-stain-negative, aerobic, rod-shaped strain designated 166T was isolated from surface-sterilized root tissue of maize planted in the Fangshan District of Beijing, PR China. The 16S rRNA gene sequence analysis indicated that strain 166T belongs to the genus Rhizobium and is closely related to Rhizobium cellulosilyticum ALA10B2T and Rhizobium yantingense H66T with sequence similarities of 98.8 and 98.3 %, respectively. According to atpD and recA sequence analysis, the highest sequence similarity between strain 166T and R. cellulosilyticum ALA10B2T is 93.8 and 84.7 %, respectively. However, the new isolate exhibited relatively low levels of DNA-DNA relatedness with respect to R. cellulosilyticum DSM 18291T (20.8+/-2.3 %) and Rhizobium yantingense CCTCC AB 2014007T (47.2+/-1.4 %). The DNA G+C content of strain 166T was 59.8 mol%. The main polar lipids consisted of phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, diphosphatidylglycerol, an unidentified aminophospholipid and an unidentified aminolipid. The major fatty acids of strain 166T were summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c). The results of the physiological and biochemical tests and minor differences in the fatty acid profiles allowed a clear phenotypic differentiation of strain 166T from the type strains of closely related species, R. cellulosilyticum DSM 18291T and R. yantingense CCTCC AB 2014007T. Strain 166T represents a novel species within the genus Rhizobium, for which the name Rhizobium wenxiniae sp. nov. is proposed, with the type strain 166T (=CGMCC 1.15279T=DSM 100734T). PMID- 28820094 TI - Massilia solisilvae sp. nov., Massilia terrae sp. nov. and Massilia agilis sp. nov., isolated from forest soil in South Korea by using a newly developed culture method. AB - Using a newly developed culture method for not yet cultured soil bacteria, three Gram-stain-negative, aerobic, non-spore-forming, motile, and rod-shaped bacteria (strain designated J18T, J11T and J9T) were isolated from forest soil at Kyonggi University, South Korea. Isolates were subjected to a taxonomic study by using a polyphasic approach. According to a phylogenetic tree based on 16S rRNA gene sequences, strains J18T, J11T and J9T belonged to the genus Massilia and clustered with Massilia haematophila CCUG 38318T (similarity range: 97.6~98.0 %). The major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol, and the genomic DNA G+C contents of strains J18T, J11T and J9T were 63.4, 68.7 and 64.5 mol%, respectively. The major polyamines were putrescine and 2-hydroxyputescine, which were detected in all three strains. DNA DNA between the three tested strains and the reference strains much lower than 70 %, the recommended threshold value for the delineation of genomic species. The predominant respiratory quinine was ubiquinone-8 (Q-8) and the major cellular fatty acids were Summed feature 3 (C16 : 1omega6c/C16 : 1omega7c) and C16 : 0. On the basis of phenotypic and genotypic data and DNA-DNA hybridization results, the three isolates are considered to represent three novel species of the genus Massilia, for which the names Massilia solisilvae sp. nov. for type strain J18T (=KEMB 9005-366T=JCM 31607T), Massilia terrae sp. nov. for type strain J11T (=KEMB 9005-360T=JCM 31606T) and Massilia agilis sp. nov. for type strain J9T (=KEMB 9005-359T=JCM 31605T) are proposed. PMID- 28820093 TI - Sphingomonas limnosediminicola sp. nov. and Sphingomonas palustris sp. nov., isolated from freshwater environments. AB - Two aerobic, Gram-stain-negative, gliding and yellow-pigmented bacteria, designated strains 03SUJ6T and WM95T were isolated from freshwater sediment of Juam reservoir and freshwater of Woopo wetland, Republic of Korea, respectively. Cells of the two strains are motile by gliding and catalase- and oxidase positive. The 16S rRNA gene sequence similarity between 03SUJ6T and WM95T was 97.7 %, but their DNA-DNA relatedness was 55.1 %. A maximum-likelihood phylogenetic tree based on 16S rRNA gene sequences showed that 03SUJ6T and WM95T each form independent lineages within the genus Sphingomonas. 03SUJ6T was related distantly to Sphingomonas daechungensis CH15-11T (97.4 % 16S rRNA gene sequence similarity), Sphingomonas ginsengisoliGsoil 634T (97.3 %) and Sphingomonas astaxanthinifaciens DMS 22298T (97.1 %). Closest relatives of strain WM95T were S. daechungensis CH15-11T (98.2 %), Sphingomonasjaspsi DSM 18422T (97.6 %), Sphingomonas sediminicolaDae 20T (97.5 %), Sphingomonaslutea JS5T (97.4 %) and S. ginsengisoliGsoil 634T (97.2 %). The major fatty acids of the two isolates were summed feature 8 and C16 : 0. The predominant isoprenoid quinone was ubiquinone 10. The major polar lipids were diphosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol and sphingoglycolipid. sym Homospermidine was the major polyamine of the isolates. Phenotypic characteristics distinguished 03SUJ6T and WM95T from the related species of the genus Sphingomonas. On the basis of the evidence presented in this study, the novel species, Sphingomonas limnosediminicola sp. nov. and Sphingomonas palustris sp. nov. are proposed for strain 03SUJ6T (=KCTC 23331T=JCM 17543T) and strain WM95T (=KACC 18738T=JCM 31399T), respectively. PMID- 28820095 TI - Proposal of Henriciella barbarensis sp. nov. and Henriciella algicola sp. nov., stalked species of the genus and emendation of the genus Henriciella. AB - Two Gram-negative, heterotrophic, aerobic, prosthecated, marine bacteria, designated strains MCS23T and MCS27T, were isolated from seawater samples. NaCl was required for growth. The major polar lipid detected in strain MCS27T was phosphatidylglycerol, whereas those detected in MCS23T were phosphatidylglycerol, sulfoquinovosyl diacylglycerol and 1,2-diacyl-3-alpha-d-glucuronopyranosyl-sn glycerol taurineamide. The most abundant cellular fatty acids were C18 : 1omega7 and C16 : 0, hydroxyl-fatty acids were 3-OH C12 : 0 in both strains and 3-OH C11 : 0 in MCS23T. Strains MCS23T and MCS27T had DNA G+C contents of 57.0 and 55.0 mol%, respectively. The two strains shared 99.3 % 16S rRNA gene sequence similarity; levels of similarity with the type strains of species of the genus Henriciella were 99.4-97.8 % but DNA-DNA hybridizations were 53 % or lower. Besides their 16S rRNA gene sequences, the novel strains can be differentiated from other species of the genus Henriciella by cell morphology, lipid and fatty acid patterns and enzyme activities. The data obtained led to the identification of two novel species, for which the names Henriciella barbarensis sp. nov. (type strain MCS23T=LMG 28705T=CCUG 66934T) and Henriciella algicola sp. nov. (type strain MCS27T=LMG 29152T=CCUG 67844T) are proposed. As these two novel species are the first prosthecate species in the genus Henriciella, an emended genus description is also provided. PMID- 28820096 TI - Lactobacillus caviae sp. nov., an obligately heterofermentative bacterium isolated from the oral cavity of a guinea pig (Cavia aperea f. porcellus). AB - A Gram-stain-positive, facultatively anaerobic, and catalase- and oxidase negative bacterial strain designated MOZM2T, having 98.4 % 16S rRNA gene sequence identity with Lactobacillus reuteri DSM 20016T, was isolated from a swab of the oral cavity of a home-bred guinea pig. Comparative analyses based on the hsp60, pheS and tuf genes confirmed L. reuteri as its closest relative species, with calculated sequence similarities of 92.8, 88.8 and 96.9 %, respectively. DNA-DNA hybridisation revealed a 42 % degree of genetic similarity between the novel strain and L. reuteri DSM 20016T. Strain MOZM2T degrades carbohydrates via the 6 phosphogluconate/phosphoketolase pathway, evidenced by its production of gas from glucose and the end products of hexose catabolism. Comparative analysis of the cellular fatty acid profiles determined significant differences between MOZM2T and L. reuteri DSM 20016T in their proportions of C8 : 0, C14 : 1, C17 : 0, C18 : 2omega6t and C20 : 0 fatty acids. Results of genotypic analyses also demonstrated differences between these two strains. They also differed in DNA G+C content, and some biochemical and physiological characteristics. We therefore believe that the examined bacterial isolate should be considered as a new taxon within the group of obligately heterofermentative lactobacilli. The species name Lactobacillus caviae sp. nov. is proposed, of which the type strain is MOZM2T (=CCM 8609T=DSM 100239T=LMG 28780T). PMID- 28820097 TI - Emticicia soli sp. nov., a novel member of the family 'Flexibacteraceae', isolated from tetrabromobisphenol A-contaminated soil. AB - Bacterial strain ZZ-4T, a Gram-stain-negative, aerobic, non-spore-forming, non motile, non-flagellated, rod-shaped bacterium, was isolated from tetrabromobisphenol A-contaminated soil in PR China. The taxonomic position of this strain was investigated using a polyphasic approach. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain ZZ-4T was a member of the genus Emticicia and showed the highest sequence similarity to Emticicia fontis IMCC1731T (98.0 %) and Emticicia ginsengisoli Gsoil 085T (97.2 %), and lower (<97 %) sequence similarity to other known Emticicia species. Chemotaxonomic analysis revealed that strain ZZ-4T possessed menaquinone MK-7 as the major isoprenoid quinone; and iso-C15 : 0, summed feature 3 (C16 : 1omega6c and/or C16 : 1omega7), iso-C17 : 0 3-OH and C16 : 1omega5c were the predominant fatty acids. Strain ZZ 4T showed low DNA-DNA relatedness with E. fontis IMCC1731T (39.8+/-3.1 %) and E. ginsengisoli Gsoil 085T (44.51+/-1.5 %). The DNA G+C content was 38.3 mol%. Based on the phylogenetic and phenotypic characteristics, chemotaxonomic data and DNA DNA hybridization results, strain ZZ-4T is considered to represent a novel species of the genus Emticicia, for which the name Emticicia soli sp. nov. is proposed. The type strain is ZZ-4T (=KCTC 52344T=CCTCC AB 2016137T). PMID- 28820098 TI - Mucilaginibacter craterilacus sp. nov., isolated from sediment soil of a crater lake. AB - A novel bacterial strain, designated N60AT, was isolated from sediment soil of crater lake, Baekrokdam, Hallasan, Jeju, Republic of Korea. Cells of N60AT were Gram-reaction-negative, oxidase- and catalase-positive, non-motile rods and formed transparent white colonies on ten-fold diluted R2A agar. N60AT contained summed feature 3 (C16 : 1omega7c/C16 : 1omega6c), iso-C15 : 0 and iso-C17 : 0 3 OH as the major fatty acids and MK-7 as the predominant isoprenoid quinone. It contained phosphatidylethanolamine as the predominant polar lipid. The DNA G+C content was 44.4 mol%. Phylogenetic analysis based on 16S rRNA gene sequencing revealed that N60AT formed a separate lineage in the genus Mucilaginibacter and that it was most closely related to Mucilaginibacter frigoritolerans FT22T (96.5 % sequence similarity). Phenotypic, chemotaxonomic and phylogenetic characteristics supported the conclusion that N60AT represents a novel species of the genus Mucilaginibacter, for which the name Mucilaginibacter craterilacus sp. nov. is proposed. The type strain is N60AT (=KCTC 52404T=NRRL B-65396T). PMID- 28820099 TI - Hymenobacter pallidus sp. nov., isolated from a freshwater fish culture pond. AB - A bacterial strain designated LYH-12T was isolated from a freshwater fish culture pond in Taiwan, ROC and characterized by taking a polyphasic taxonomy approach. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain LYH-12T belonged to the genus Hymenobacter and was most closely related to Hymenobacter xinjiangensis X2-1gT and Hymenobacter rigui WPCB131T with a sequence similarity of 96.6 % and less than 96.5 % with other members of the genus. Cells of strain LYH-12T were Gram-stain-negative, aerobic, non-motile rods that were covered by large capsules and formed light pink-coloured colonies. Growth occurred at 10-37 degrees C (optimum, 20-30 degrees C), at pH 6.5-7.5 (optimum, pH 7) and with 0-1 % NaCl (optimum, 0.5 %). Strain LYH-12T contained iso-C15 : 0, C16 : 1omega5c, C16 : 0, iso-C17 : 0 3-OH, summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and anteiso-C17 : 1omega9c as the predominant fatty acids. The only isoprenoid quinone detected was MK-7. The polar lipid profile consisted of phosphatidylethanolamine, one uncharacterized aminophospholipid, four uncharacterized aminolipids, two uncharacterized phospholipids and three uncharacterized lipids. The major polyamine was homospermidine. The DNA G+C content of the genomic DNA was 64.3 mol%. On the basis of the phylogenetic inference and phenotypic data, strain LYH-12T should be classified as a novel species, for which the name Hymenobacter pallidus sp. nov. is proposed. The type strain is LYH-12T (=BCRC 80919T=LMG 29171T=KCTC 42898T). PMID- 28820100 TI - Erythrobacter aquimixticola sp. nov., isolated from the junction between the ocean and a freshwater spring. AB - A Gram-stain-negative, aerobic, non-motile and coccoid, ovoid or rod-shaped bacterial strain, designated JSSK-14T, was isolated from the place where the ocean and a freshwater spring meet at Jeju island, South Korea. Strain JSSK-14T grew optimally at pH 7.0-8.0, at 30 degrees C and in the presence of 1.0-2.0 % (w/v) NaCl. A neighbour-joining phylogenetic tree based on 16S rRNA gene sequences showed that strain JSSK-14T fell within the clade comprising the type strains of species of the genus Erythrobacter. Strain JSSK-14T exhibited 16S rRNA gene sequence similarity values of 97.09-98.42 % to the type strains of Erythrobactergangjinensis, Erythrobacteratlanticus and Erythrobacterluteus and of 94.31-96.97 % to the type strains of the other species of the genus Erythrobacter. Strain JSSK-14T contained Q-10 as the predominant ubiquinone and C18 : 1omega7c as the major fatty acid. The major polar lipids of strain JSSK-14T were phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol and sphingoglycolipid. The DNA G+C content of strain JSSK-14T was 63.5 mol%, and its mean DNA-DNA relatedness values with the type strains of Erythrobactergangjinensis, Erythrobacteratlanticus and Erythrobacterluteus were 13-25 %. Differential phenotypic properties, together with the phylogenetic and genetic distinctiveness, revealed that strain JSSK-14T is separated from recognized species of the genus Erythrobacter. On the basis of the data presented, strain JSSK-14T is considered to represent a novel species of the genus Erythrobacter, for which the name Erythrobacter aquimixticola sp. nov. is proposed. The type strain is JSSK-14T (=KCTC 52764T=NBRC 112765T). PMID- 28820101 TI - Henriciella pelagia sp. nov., isolated from seawater. AB - Strain LA220T, isolated from seawater of the Eastern Pacific Ocean, was subjected to a polyphasic taxonomic study. Cells of the strain were Gram-stain-negative, aerobic, motile and short rod-shaped. On the basis of 16S rRNA gene sequence analysis, strain LA220T showed high similarity to Henriciella litoralis SD10T (98.5 %), Henriciella marina DSM 19595T (98.3 %) and Henriciellaaquimarina P38T (97.5 %), and exhibited less than 97.0 % 16S rRNA gene sequence similarity with respect to the type strains of other Hyphomonadaceae species. Phylogenetic analyses revealed that strain LA220T fell within the cluster of the genus Henriciella. The average nucleotide identity and in silico DNA-DNA hybridization values between strain LA220T and the type strains of Henriciella species were 74.8-76.8 and 18.4-20.8 %, respectively. The sole respiratory quinone was ubiquinone-10 (Q-10). The principal fatty acids were summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c) and C16 : 0. The major polar lipids were three unidentified glycolipids. The DNA G+C content was 59.9 mol%. Phylogenetic distinctiveness, chemotaxonomic differences and phenotypic properties revealed that strain LA220T could be differentiated from recognized Henriciella species. Therefore, strain LA220T is considered to represent a novel species of the genus Henriciella, for which the name Henriciella pelagia sp. nov. (type strain LA220T=CGMCC 1.15928T=KCTC 52577T) is proposed. PMID- 28820102 TI - Umboniibacter caenipelagi sp. nov., isolated from a tidal flat. AB - A Gram-stain-negative, non-motile, aerobic and ovoid or rod-shaped bacterium, designated SCTF-16T, was isolated from a tidal flat on the Yellow Sea, South Korea. Strain SCTF-16T grew optimally at 30 degrees C, at pH 7.0-7.5 and in the presence of 2.0 % (w/v) NaCl. In the neighbour-joining, maximum-likelihood and maximum-parsimony phylogenetic trees based on 16S rRNA gene sequences, strain SCTF-16T clustered with the type strains of two species of the genus Umboniibacter. Strain SCTF-16T exhibited 16S rRNA gene sequence similarities of 99.6 and 97.1 % to the type strains of Umboniibacterroseus and Umboniibactermarinipuniceus, respectively, and of less than 93.4 % to the type strains of the other recognized species. Strain SCTF-16T contained Q-7 as the predominant ubiquinone and summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and C13 : 0 as the major fatty acids. The major polar lipids detected in strain SCTF-16T were phosphatidylethanolamine and phosphatidylglycerol. The DNA G+C content of strain SCTF-16T was 50.0 mol%, and its mean DNA-DNA relatedness values with the type strains of U. roseus and U. marinipuniceus were 31 and 9 %, respectively. The differential phenotypic properties, together with the phylogenetic and genetic distinctiveness, revealed that strain SCTF-16T is separated from the two recognized species of the genus Umboniibacter. On the basis of the data presented, strain SCTF-16T is considered to represent a novel species of the genus Umboniibacter, for which the name Umboniibacter caenipelagi sp. nov. is proposed. The type strain is SCTF-16T (=KCTC 52628T=NBRC 112760T). PMID- 28820103 TI - Two novel Lipomycetaceous yeast species, Lipomyces okinawensis sp. nov. and Lipomyces yamanashiensis f.a., sp. nov., isolated from soil in the Okinawa and Yamanashi prefectures, Japan. AB - Four novel Lipomyces strains were isolated from soil collected in the Okinawa and Yamanashi prefectures, Japan. Based on their morphological and biochemical characteristics, along with sequence typing using the D1/D2 domain of the LSU rRNA, internal transcribed spacer (ITS) region including 5.8S rRNA, and translation elongation factor 1 alpha gene (EF-1alpha), the four strains were shown to represent two novel species of the genus Lipomyces, described as Lipomyces okinawensis sp. nov. (type strain No.3-a(35)T=NBRC 110620T=CBS 14747T) and Lipomyces yamanashiensis f.a., sp. nov. (type strain No.313T=NBRC 110621T=CBS 14748T). PMID- 28820104 TI - Nocardia cavernae sp. nov., a novel actinobacterium isolated from a karst cave sample. AB - A novel actinobacterial strain, designated YIM A1135T, was isolated from a soil sample collected from a karst cave in Xingyi county, Guizhou province, south western China. The taxonomic position of the strain was investigated using a polyphasic approach. Cells of the strain were aerobic, Gram-stain-positive and partially acid-alcohol-fast. Strain YIM A1135T shared 98.3 % 16S rRNA gene sequence similarity with Nocardia jejuensis NBRC 103114T and 97.6 % with Nocardia alba YIM 30243T. DNA-DNA hybridization values between strain YIM A1135T and related type strains of the genus Nocardia were less than 70 %. In addition, meso diaminopimelic acid was the diagnostic diamino acid in cell-wall peptidoglycan. The whole-cell sugars were fructose, mannose, galactose and glucose. The major isoprenoid quinone was MK-8(H4,omega-cycl), while the major fatty acids (>10 %) were C16 : 0, C18 : 1omega9c, C18 : 0 10-methyl and summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c). The polar lipids contained diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol and phosphatidylinositol mannoside. Mycolic acids were present. The genomic DNA G+C content of strain YIM A1135T was 66.7 mol%. Based on the results of the molecular studies supported by its morphological, physiological, chemotaxnomic and other differential phenotypic characteristics, strain YIM A1135T is considered to represent a novel species within the genus Nocardia, for which the name Nocardia cavernae sp. nov. is proposed. The type strain is YIM A1135T (=KCTC 39595T=CCTCC AA 2017030T). PMID- 28820105 TI - Roseomonas hibiscisoli sp. nov., isolated from the rhizosphere of Mugunghwa (Hibiscus syriacus). AB - A Gram-stain-negative, aerobic, non-motile and coccoid to short-rod-shaped bacterial strain (THG-N2.22T) was isolated from the rhizosphere of Mugunghwa (Hibiscus syriacus). Growth occurred at 20-40 degrees C (optimum 28 degrees C), at pH 5-9 (optimum 7) and with 0-4 % (w/v) NaCl (optimum 1 %). Based on 16S rRNA gene sequence analysis, the nearest phylogenetic neighbours of strain THG-N2.22T were identified as Roseomonas rhizosphaerae YW11T (98.5 % similarity), Roseomonas rubra S5T (98.5 %), Roseomonas cervicalis ATCC 49957T (98.2 %), Roseomonas aestuarii JC17T (97.8 %), Roseomonas oryzae JC288T (97.3 %) and Roseomonas ludipueritiae 170/96T (97.3 %); levels of similarity with the type strains of other Roseomonas species were lower than 97.0 %. The polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, two unidentified aminolipids, three unidentified phospholipids and three unidentified lipids. The major quinone was ubiquinone-10. The major fatty acids were C16 : 0, C18 : 1 2-OH, C18 : 1omega7c and summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c). The DNA G+C content of strain THG-N2.22T was 64.1 mol%. DNA-DNA hybridization values between strain THG-N2.22T and R. rhizosphaerae YW11T, R. rubra S5T, R. cervicalis ATCC 49957T, R. aestuarii JC17T, R. oryzae JC288T and R. ludipueritiae 170/96T were 43.1 % (30.2 %, reciprocal analysis), 39.0 % (24.7 %), 34.4 % (15.2 %), 18.0 % (14.5 %), 14.7 % (9.7 %) and 11.0 % (5.6 %), respectively. On the basis of the phylogenetic analysis, chemotaxonomic data, physiological characteristics and DNA-DNA hybridization data, strain THG-N2.22T represents a novel species of the genus Roseomonas, for which the name Roseomonas hibiscisoli sp. nov. is proposed. The type strain is THG-N2.22T (=KACC 18935T=CCTCC AB 2016176T). PMID- 28820106 TI - Sphingomonas gotjawalisoli sp. nov., isolated from soil of a lava forest. AB - A bacterial strain, designated SN6-9T, was isolated from soil of the Gotjawal, lava forest, located in Jeju, Republic of Korea. Strain SN6-9T was Gram-stain negative, motile, oxidase- and catalase-negative, yellow-pigmented and rod shaped. It contained summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c) as the major fatty acids, Q-10 as the predominant isoprenoid quinone, sym-homospermidine as the major polyamine and diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, sphingoglycolipid and two unidentified phospholipids as the polar lipids. The DNA G+C content was 64.1 mol%. Phylogenetic analysis based on 16S rRNA gene sequences revealed that the strain formed a separate lineage in the genus Sphingomonas. Based on the results from this polyphasic taxonomic study, it is concluded that strain SN6-9T represents a novel species in the genus Sphingomonas. The name Sphingomonas gotjawalisoli sp. nov. is proposed; the type strain is SN6-9T (=KCTC 52405T=NRRL B-65395T). PMID- 28820107 TI - Ogataea neixiangensis sp. nov. and Ogataea paraovalis f.a., sp. nov., two methanol-assimilating yeast species isolated from rotting wood. AB - Four yeast strains were isolated from rotting wood samples collected in the Baotianman Nature Reserve in Henan Province, central China. The sequences of the D1/D2 domains of the large subunit rRNA gene and the internal transcribed spacer regions showed that these four strains represent two different undescribed yeast species belonging to the Ogataea clade. Ogataea neixiangensis sp. nov. produces two to four hat-shaped ascospores per ascus, and its closest relative among recognized species is Candida nitratophila. Ogataea paraovalis f.a., sp. nov. is closely related to Candida ovalis but the formation of ascospores was not observed on various sporulation media. The type strain of O. neixiangensis sp. nov. (MycoBank number MB 820697) is NYNU 16951T (=CICC 33166T=CBS 14695T), and the type strain of O. paraovalis f.a., sp. nov. (MycoBank number MB 820698) is NYNU 167106T (=CICC 33168T=CBS 14697T). PMID- 28820108 TI - Nakamurella intestinalis sp. nov., isolated from the faeces of Pseudorhynchus japonicus. AB - One strain, designated 63MJ-1T, was isolated from fresh faeces of broad-winged katydids collected in Jinan-gun, Jeollabuk-do, the Republic of Korea. The organism stained Gram-positive and was an aerobic, non-flagellated and short-rod shaped bacterium. The organism grew in the range of 4-35 degrees C (optimum, 28 30 degrees C) and pH 6.0-9.0 (optimum, pH 7.0), and in the presence of 5 % NaCl (w/v), but not in media containing 7 % NaCl. According to the 16S rRNA gene sequence analysis, strain 63MJ-1T showed the highest sequence similarities with Nakamurella panacisegetis P4-7T (95.9 %), Nakamurella endophytica 2Q3S-4-2T (95.8 %) and Nakamurella multipartita DSM 44233T (95.7 %). Phylogenetic trees also indicated that strain 63MJ-1T formed one robust cluster with members of the genusNakamurella. The predominant quinone of strain 63MJ-1T was MK-8(H4). Polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, an unidentified aminophospholipid and two unidentified lipids. The major fatty acids were C16 : 0, anteiso-C15 : 0 and iso-C15 : 0. The peptidoglycan type was A1gamma with meso-diaminopimelic acid as the diagnostic amino acid. The DNA G+C content was 64.6 mol%. Based on the phylogenetic, physiological and chemotaxonomic data, it was demonstrated that strain 63MJ-1T represents a novel species of the genus Nakamurella, for which the name Nakamurella intestinalis sp. nov. is proposed. The type strain is 63MJ-1T (=KACC 18662T=NBRC 111844T). PMID- 28820109 TI - Pseudomonas wadenswilerensis sp. nov. and Pseudomonas reidholzensis sp. nov., two novel species within the Pseudomonas putida group isolated from forest soil. AB - Within the frame of a biotechnological screening, we isolated two Pseudomonas strains from forest soil. 16S rRNA gene sequence analysis indicated that strain CCOS 864T shared 99.8 % similarity with Pseudomonas donghuensis HYST, while strain CCOS 865T shared 99.0 % similarity with Pseudomonas putida DSM 291T and lower similarity with other P. putida group type strains. Based on multilocus sequence analysis, the two strains were genotypically distinct from each other, each forming a separate clade. Strains CCOS 864T and CCOS 865T were Gram-stain negative, motile and rod-shaped, growing at a temperature range of 4-37 degrees C. Strain CCOS 864T could be phenotypically distinguished from P. putida group species by the combination of gelatinase-positive reaction and positive growth on N-acetyl-d-glucosamine, p-hydroxyphenylacetic acid and inosine but lack of fluorescein production on King's B medium, while strain CCOS 865T could be distinguished from P. putida group species by the combination of positive growth with saccharic acid and negative growth with p-hydroxyphenylacetic acid and l pyroglutamic acid. The major polar lipid for both strains was phosphatidylethanolamine; the major quinone was ubiquinone Q-9. DNA-DNA hybridization and average nucleotide identities confirmed the novel species status for the two strains. The DNA G+C contents of CCOS 864T and CCOS 865T were 62.1 and 63.8 mol%, respectively. The phenotypic, phylogenetic and DNA-DNA relatedness data support the suggestion that CCOS 864T and CCOS 865T represent two novel Pseudomonas species. The names Pseudomonas wadenswilerensis sp. nov. (type strain CCOS 864T=LMG 29327T) and Pseudomonas reidholzensis sp. nov. (type strain CCOS 865T=LMG 29328T) are proposed. PMID- 28820110 TI - Flavivirga eckloniae sp. nov. and Flavivirga aquimarina sp. nov., isolated from seaweed Ecklonia cava. AB - Two Gram-stain-negative, non-spore-forming, rod-shaped, aerobic and yellow coloured bacterial strains, designated strains ECD14T and EC2D5T, were isolated from a seaweed Eckloniacava. The isolates required sea salts for growth. Flexirubin-type and carotenoid pigment was produced. The 16S rRNA gene sequence similarity between the two new strains was 95.5 %. Flavivirga amylovorans JC2681T was the nearest neighbour of strains ECD14T and EC2D5T with 96.5 and 96.8 % 16S rRNA gene sequence similarity, respectively. The common major fatty acids and respiratory quinones were iso-C15 : 0, iso-C15 : 1 G and unknown 13.565 and menaquinone 6 (MK-6), respectively. The common major polar lipids were phosphatidylethanolamine, an unknown amino lipid and an unknown lipid. The DNA G+C contents of strains ECD14T and EC2D5T were 33 and 31 mol%, respectively. On the basis of the polyphasic characterization of the two strains, it is suggested that the two isolates represent novel species of the genus Flavivirga, for which the names Flavivirga eckloniae sp. nov. (type strain, ECD14T=KCTC 52352T=JCM 31797T) and Flavivirga aquimarina sp. nov. (type strain, EC2D5T=KCTC 52353T=JCM 31796T) are proposed. PMID- 28820111 TI - Description of Actinokineospora acnipugnans sp. nov., an actinomycete isolated from soil, showing potential uses in cosmetics. AB - During isolation of soil bacteria having antibacterial functions, an aerobic, Gram-stain-positive, oxidase-negative, catalase-positive bacterium, designated strain R434T, was isolated. Strain R434T showed antimicrobial activity against Propionibacterium acnes and Staphylococcus epidermidis and significant enzyme inhibitory capability. The diagnostic diamino acid of the cell-wall peptidoglycan was meso-diaminopimelic acid, and the whole-cell sugars were galactose, arabinose and glucose. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that strain R434T formed a lineage within the family Pseudonocardiaceae. Strain R434T showed highest sequence similarity with type strains of the genus Actinokineospora, including Actinokineospora guangxiensis Gk-6T (99.4 % sequence similarity), Actinokineospora soli YIM 75948T (98.5 %), Actinokineospora fastidiosa IMSNU 20054T (98.0 %), Actinokineospora cibodasensis ID03-0784T (97.9 %), Actinokineospora terrae IFO 15668T (97.6 %) and Actinokineospora auranticolor IFO 16518T (97.4 %). The predominant respiratory quinone of strain R434T was MK 9(H4). The major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, hydroxyphosphatidylethanolamine and unidentified glycolipid. The major cellular fatty acids were iso-C16 : 0, iso-C16 : 1 H and C17 : 1omega6c. The DNA G+C content of strain R434T was 71.6 mol%. On the basis of phenotypic, genotypic, chemotaxonomic and phylogenetic analysis, strain R434T represents a novel species of the genus Actinokineospora, for which the name Actinokineospora acnipugnans sp. nov. is proposed. The type strain of 'Actinokineospora acnipugnans' is R434T (=KEMB 9005-403T=KACC 18904T=JCM 31557T). PMID- 28820112 TI - Prevalence study of plasmid-mediated AmpC beta-lactamases in Enterobacteriaceae lacking inducible ampC from Saudi hospitals. AB - PURPOSE: Enterobacteriaceae encoding plasmid-mediated AmpC (pAmpC) beta lactamases confer resistance to the third generation cephalosporins. pAmpC association with extended spectrum beta-lactamases (ESBLs), plasmid-mediated quinolone resistance (PMQR) and aminoglycoside modifying enzymes (AMEs) is well documented. There are limited data regarding the epidemiology and clinical significance of pAmpC in Saudi Arabia. This study aimed to determine the prevalence of pAmpC and its coexistence with ESBLs, PMQR and AMEs in Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis isolates in Saudi hospitals from January to December 2015. METHODOLOGY: The VITEK 2 system was used for organism identification and susceptibility testing. PCR and sequencing were used to detect pAmpC, ESBL, AME and PMQR genes. RESULTS: Out of 3625 isolates of E. coli, K. pneumoniae and P. mirabilis, 200 cefoxitin-resistant isolates were identified, making the prevalence of cefoxitin resistance 5.5 % (200/3625). CMY-2 and DHA were detected in 24 and 12 isolates, respectively. The prevalence of pAmpC was 1 % (36/3625). In several isolates, pAmpC beta-lactamases were associated with PMQR genes including aac(6')-Ib-cr and qnrB and/or with AMEs including aacA4, aacC2, aadA1, aphA6, armA and rmtB genes. No ESBLs were detected in pAmpC beta-lactamase-harbouring isolates. CONCLUSIONS: To our knowledge, this is the first study determining the prevalence of pAmpC beta-lactamases and their association with PMQR and/or AME genes in Saudi Arabia and the Gulf States. CMY-2 is the most prevalent pAmpC beta-lactamase in this study. These data emphasize the importance of surveillance studies and implementation of antimicrobial stewardship programmes to reduce infections caused by such resistant organisms. PMID- 28820113 TI - Blastomonas marina sp. nov., a bacteriochlorophyll-containing bacterium isolated from seawater. AB - A Gram-stain-negative, facultatively anaerobic, dark-yellow-pigmented bacterium, named SSR2A-4-2T, was isolated from coastal water in the East China Sea. Cells were ovoid or short rods with peritrichous flagella and contained carotenoid in addition to bacteriochlorophyll a pigment. A phylogenetic dendrogram based on 16S rRNA gene sequences showed that strain SSR2A-4-2T formed a distinct clade with members of the genus Blastomonas, with Blastomonasnatatoria EY 4220T (=DSM 3183T) (similarity 95.6 %), Blastomonasursincola KR-99T (=DSM 9006T) (95.5 %) and Blastomonasaquatica PE4-5T (=JCM 30179T) (94.8 %) as its closest phylogenetic relatives. Q-10 was the predominant respiratory quinone. The major fatty acids were summed feature 8 (C18 : 1omega6c and/or C18 : 1omega7c), summed feature 3 (C16 : 1omega6c and/or C16 : 1omega7c), C17 : 1omega6c and C18 : 1omega7c 11 methyl. The polar lipids contained diphosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, sphingoglycolipid, four unknown glycolipids and one unknown lipid. The DNA G+C content was 65.1 mol%. On the basis of the evidence presented in this study, strain SSR2A-4-2T represents a novel species of the genus Blastomonas, for which the name Blastomonas marina sp. nov. is proposed, with strain SSR2A-4-2T (=CGMCC 1.15297T=DSM 103453T) as the type strain. PMID- 28820114 TI - Pseudonocardia nigra sp. nov., isolated from Atacama Desert rock. AB - Eleven actinobacterial strains were isolated from a rock sample collected in the Atacama Desert. Molecular typing by BOX-PCR divided the strains into three clusters and showed that, although very similar, they were not clones. Three strains, ATK01, ATK03T and ATK17, each representing one of the defined BOX clusters, were chosen for further characterization. Phylogenetic analysis indicated that the strains were related to the genus Pseudonocardia and were recovered in a cluster together with Pseudonocardia bannensis YIM 63101T and Pseudonocardia xinjiangensis AS 4.1538T. Chemotaxonomic analyses confirmed their affiliation to the genus Pseudonocardia but differences were found between the new strains and their closest phylogenetic relatives. Physiological and fatty acid analyses also revealed differences between these strains and their phylogenetic neighbours supporting their status as a distinct species. Based on the overall data, it is proposed that strains ATK01, ATK03T and ATK17 represent a novel species of the genus Pseudonocardia for which the name Pseudonocardia nigra sp. nov. is proposed (type strain ATK03T=DSM 104088T=CECT 9183T). PMID- 28820115 TI - Six Key Traits of Fungi: Their Evolutionary Origins and Genetic Bases. AB - The fungal lineage is one of the three large eukaryotic lineages that dominate terrestrial ecosystems. They share a common ancestor with animals in the eukaryotic supergroup Opisthokonta and have a deeper common ancestry with plants, yet several phenotypes, such as morphological, physiological, or nutritional traits, make them unique among all living organisms. This article provides an overview of some of the most important fungal traits, how they evolve, and what major genes and gene families contribute to their development. The traits highlighted here represent just a sample of the characteristics that have evolved in fungi, including polarized multicellular growth, fruiting body development, dimorphism, secondary metabolism, wood decay, and mycorrhizae. However, a great number of other important traits also underlie the evolution of the taxonomically and phenotypically hyperdiverse fungal kingdom, which could fill up a volume on its own. After reviewing the evolution of these six well-studied traits in fungi, we discuss how the recurrent evolution of phenotypic similarity, that is, convergent evolution in the broad sense, has shaped their phylogenetic distribution in extant species. PMID- 28820116 TI - Sphingobium naphthae sp. nov., with the ability to degrade aliphatic hydrocarbons, isolated from oil-contaminated soil. AB - A light yellow-coloured, Gram-stain-negative, non-motile and rod-shaped bacterium, designated strain K-3-6T, capable of degrading aliphatic hydrocarbons was isolated from oil-contaminated soil of Biratnagar, Morang, Nepal. It was able to grow at 15-45 degrees C, at pH 5.0-9.5 and with 0-6 % (w/v) NaCl. Based on 16S rRNA gene sequence analysis, strain K-3-6T belongs to the genus Sphingobium and is closely related to Sphingobium olei IMMIB HF-1T (98.4 % similarity), Sphingobium abikonense NBRC 16140T (98.3 %), Sphingobium rhizovicinum CC-FH12-1T (97.9 %), Sphingobium lactosutens DS20T (97.9 %), Sphingobium amiense NBRC 102518T (97.2 %), Sphingobium phenoxybenzoativorans SC_3T (97.2 %) and Sphingobium fontiphilum Chen16-4T (97.0 %). The predominant respiratory quinone was ubiquinone-10 and the major polyamine was spermidine. The polar lipid profile revealed the presence of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylcholine, phosphatidyldimethylethanolamine, sphingoglycolipid and phosphatidylmonomethylethanolamine. The predominant fatty acids of strain K-3-6T were summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c), summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), C14 : 0, C16 : 0 and C14 : 0 2-OH. The genomic DNA G+C content was 65.6 mol%. Levels of DNA DNA relatedness between strain K-3-6T and S. olei IMMIB HF-1T, S. abikonense NBRC 16140T, S. lactosutens DS20T, S. rhizovicinum CC-FH12-1T, S. amiense NBRC 102518T and S. fontiphilum Chen16-4T were 34.0, 33.3, 28.7, 26.3, 29.0 and 22.3 %, respectively. The morphological, physiological, chemotaxonomic and phylogenetic analyses clearly distinguished this strain from its closest phylogenetic neighbours. Thus, strain K-3-6T represents a novel species of the genus Sphingobium, for which the name Sphingobium naphthae sp. nov. is proposed. The type strain is K-3-6T (=KEMB 9005-449T=KACC 19001T=JCM 31713T). PMID- 28820117 TI - Mucilaginibacter rubeus sp. nov., isolated from rhizosphere soil. AB - A Gram-stain-negative, aerobic, non-motile, rod-shaped and non-spore-forming bacterium, designated EF23T, was isolated from rhizosphere soil of watermelon. Growth of strain EF23T was observed at 10-37 degrees C, at pH 5.0-9.0 and in the presence of 0-0.5 % (w/v) NaCl. Strain EF23T contained menaquinone 7 (MK-7) as the major isoprenoid quinone, and summed feature 3 (C16:1omega7c and/or iso-C15 : 0 2-OH), iso-C15 : 0, C16 : 0 and iso-C17 : 0 3-OH as the major fatty acids. Phosphatidylethanolamine was identified as the major polar lipid. The genomic DNA G+C content of strain EF23T was 43.7 mol%. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain EF23T was most closely related to Mucilaginibacter gossypii Gh-67T (98.9 % similarity) and Mucilaginibacter gossypiicola Gh-48T (97.6 %). DNA-DNA relatedness values between strain EF23T and M. gossypii KCTC 22380T and M. gossypiicola KCTC 22379T were 31.6 and 53.7 %. On the basis of the evidence presented in this polyphasic taxonomic study, strain EF23T is considered to represent a novel species of the genus Mucilaginibacter, for which the name Mucilaginibacter rubeus sp. nov. is proposed. The type strain is EF23T (=CGMCC 1.15913T=KCTC 52516T). PMID- 28820118 TI - Arcobacter haliotis sp. nov., isolated from abalone species Haliotis gigantea. AB - A Gram-negative, aerobic, polar-flagellated and rod-shaped, sometimes slightly curved bacterium, designated MA5T, was isolated from the gut of an abalone of the species Haliotis gigantea collected in Japan. Phylogenetic analyses based on 16S rRNA, gyrB, hsp60 and rpoB gene sequences placed strain MA5T in the genus Arcobacter in an independent phylogenetic line. Comparison of the 16S rRNA gene sequence of this strain with those of the type strains of the established Arcobacter species revealed A. nitrofigilis (95.1 %) as nearest neighbour. Strain MA5T grew optimally at 25 degrees C, pH 6.0 to 9.0 and in the presence of 2 to 5 % (w/v) NaCl under both aerobic and microaerobic conditions. The predominant fatty acids found were summed feature 3 (iso-C15 : 0 2-OH and/or C16 : 1 omega7c), C12 : 0 3-OH and C18 : 1 omega7c. Menaquinone-6 (MK-6) and menaquinone 7 (MK-7) were found as the major respiratory quinones. The major polar lipids detected were phosphatidylethanolamine and phosphatidylglycerol. Strain MA5T could be differentiated phenotypically from the phylogenetic closest Arcobacter species by its ability to grow on 0.05 % safranin and 0.01 % 2,3,5-triphenyl tetrazolium chloride (TTC), but not on 0.5 % NaCl. The obtained DNA G+C content of strain MA5T was 27.9 mol%. Based on the phylogenetic, chemotaxonomic and phenotypic distinctiveness of MA5T, this strain is considered to represent a novel species of the genus Arcobacter, for which the name Arcobacter haliotis sp. nov. is proposed. The type strain is MA5T (=LMG 28652T=JCM 31147T). PMID- 28820119 TI - Blastomonas fulva sp. nov., aerobic photosynthetic bacteria isolated from a Microcystis culture. AB - Two Gram-stain-negative, aerobic, non-motile, non-spore-forming and rod-shaped bacteria, designated strains T2T and T5, were isolated from a culture of Microcystis from Daejeon, Republic of Korea. Comparative 16S rRNA gene sequence studies placed the new isolates in the class Alphaproteobacteria and, notably, most closely related to Blastomonasaquatica PE 4-5T, Blastomonas natatoria DSM 3183T and Blastomonas ursincola KR-99T showing 99.4 %, 98.2 % and 97.9 % 16S rRNA gene sequence similarities, respectively. The two novel strains shared 100 % similarity with each other. The cells of strains T2T and T5 formed yellow colonies on R2A agar and contained Q-10 as the only ubiquinone, sphingoglycolipid, phosphatidylethanolamine, phosphatidylcholine, and phosphatidylglycerol as major polar lipids, and C17 : 1omega6c, summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c), C17 : 1omega8c and C17 : 0 as the major fatty acids (>5 %). The DNA G+C content of the genomes was determined to be 64.2 mol% for strain T2T and 64.4 mol% for strain T5. The DNA-DNA hybridization values of strains T2T and T5 with B.aquatica PE 4-5T, B. natatoria DSM 3183T, and B. ursincola KR-99T were 19.7-42.4 %. Based on the combined genotypic and phenotypic data, we propose that strains T2T and T5 represent a novel species of the genus Blastomonas, for which the name Blastomonas fulvasp. nov. is proposed. The type strain is T2T (=KCTC 42354T=JCM 30467T). PMID- 28820120 TI - Spiribacter aquaticus sp. nov., a novel member of the genus Spiribacter isolated from a saltern. AB - A moderately halophilic bacterium, designated strain SP30T, was isolated from a solar saltern located in Santa Pola, Alicante, on the East coast of Spain. It was a Gram-stain-negative, strictly aerobic bacterium, able to grow in 7.5-25 % (w/v) NaCl and optimally in 12.5 % (w/v) NaCl. Phylogenetic analyses, based on 16S rRNA gene sequences, showed that the novel isolate is a member of the genus Spiribacter, with the most closely related species being Spiribacter roseus SSL50T (99.9 % sequence similarity) and Spiribacter curvatus UAH-SP71T (99.4 % sequence similarity). The 16S rRNA gene sequence similarity with the type species Spiribacter salinus M19-40T was 96.6 %. The DNA-DNA relatedness value between strain SP30T and S. roseus SSL50T and S. curvatus UAH-SP71T was 40 and 55 %, respectively; these values are lower than the 70 % threshold accepted for species delineation. The major fatty acids were C16:0, C18 : 1omega7c, C19 : 0 cyclo omega8c and C12 : 0. Similarly to other species of the genus Spiribacter, strain SP30Twas observed as curved rods and spiral cells. Metabolic versatility was reduced to the utilization of a few organic compounds as the sole carbon and energy sources, as with other members of Spiribacter. However, it differed in terms of colony pigmentation (brownish-yellow instead of pink) and in having a higher growth rate. Based on these data and on the phenotypic, genotypic and chemotaxonomic characterization, we propose the classification of strain SP30T as a novel species within the genus Spiribacter, with the name Spiribacter aquaticus sp. nov. The type strain is SP30T (=CECT 9238T=LMG 30005T). PMID- 28820121 TI - Aureimonas endophytica sp. nov., a novel endophytic bacterium isolated from Aegiceras corniculatum. AB - A Gram-negative, motile, aerobic and coccoid rod-shaped bacterium, designated strain 2T4P-2-4T, was isolated from a piece of surface-sterilized bark of Aegiceras corniculatum collected from Cotai Ecological Zones in Macao, China, and tested by a polyphasic approach to clarify its taxonomic position. Strain 2T4P-2 4T grew optimally without NaCl at 28-30 degrees C, pH 7.0-8.0. The 16S rRNA gene sequence of strain 2T4P-2-4T had the highest similarity (96.2 %) to Aureimonas rubiginis CC-CFT034T. Phylogenetic analysis showed that the strain grouped with species of the genus Aureimonas. The predominant quinone system of strain 2T4P-2 4T was ubiquinone 10 (Q-10). The polar lipid profile contained diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, sulfoquinovosyldiacylglycerol, phosphatidylmethylethanolamine, two unidentified amino lipids, an unidentified aminophospholipid and five unidentified lipids. The predominant cellular fatty acid was C18 : 1omega7c (61.2 %). The DNA G+C content of strain 2T4P-2-4T was 69.8 mol%. Based on the phylogenetic, phenotypic and chemotaxonomic features, strain 2T4P-2-4T is a representative of a novel species of the genus Aureimonas, for which the name Aureimonas endophytica sp. nov. is proposed. The type strain of Aureimonas endophytica sp. nov. is 2T4P-2-4T (=KCTC 52217T=CGMCC 1.15367T). PMID- 28820122 TI - Desulfosarcina widdelii sp. nov. and Desulfosarcina alkanivorans sp. nov., hydrocarbon-degrading sulfate-reducing bacteria isolated from marine sediment and emended description of the genus Desulfosarcina. AB - In previous studies, two hydrocarbon-degrading sulfate-reducing bacteria, strains PP31T and PL12T, were obtained from oil-polluted marine sediments of Shuaiba, Kuwait. They had been reported as organisms capable of anaerobic degradation of p xylene and n-alkanes, respectively. The 16S rRNA gene sequence of strain PP31T showed 98.8 % sequence similarities to that of Desulfosarcina variabilis'Montpellier'T. Strains PL12T had 97.8 % of sequence similarity to Desulfosarcina ovata oXys1T. They both have been partially characterized, but not been validly published as new species of the genus Desulfosarcina. In this study, additional characterizations of these strains were made to describe them as two new species of the genus Desulfosarcina. Major cellular fatty acids of strain PP31T were C15 : 0 (25.9 %) and anteiso-C15 : 0 (22.3 %), whereas those of strain PL12T were C15 : 0 (21.3 %), C16 : 0 (17.8 %) and anteiso-15 : 0 (11.6 %). The phylogenetic tree based on 16S rRNA gene revealed that these isolates should not be classified as any of the known species in the genus Desulfosarcina. On the basis of phenotypic and phylogenetic analyses, these two sulfate reducers are proposed to form two novel species of the genus Desulfosarcina : Desulfosarcina widdelii sp. nov. (PP31T=JCM 31729T=DSM 103921T) and Desulfosarcina alkanivorans sp. nov. (PL12T=JCM 31728T=DSM 103901T). In addition, emended description of the genus Desulfosarcina is presented in this study. PMID- 28820123 TI - Laceyella thermophila sp. nov., a thermophilic bacterium isolated from a hot spring. AB - A novel themophilic bacterium, designated YIM 79486T, was isolated from a sediment sample collected from Jinze hot spring in Tengchong county, Yunnan province, south-west China. Phylogenetic analysis based on 16S rRNA gene sequence analysis revealed that strain YIM 79486T should be assigned to the genus Laceyella and formed a monophyletic clade with the type strain Laceyella putida KCTC 3666T (98.7 % similarity). Strain YIM 79486T formed white aerial mycelium and brown substrate mycelium. Abundant endospores were produced on short sporophores. Cell-wall peptidoglycan contained meso-diaminopimelic acid. The predominant menaquinones were MK-9 and MK-8. The genomic DNA G+C content observed for strain YIM 79486T was 47.8 mol%. Based on low DNA-DNA hybridization data, chemotaxonomic characteristics and differential physiological properties, strain YIM 79486T is considered to represent a novel species within the genus Laceyella, for which the name Laceyella thermophila sp. nov. is proposed. The type strain is YIM 79486T (=CCTC AB 2015040T=NBRC 110772T). PMID- 28820124 TI - Bacillus wudalianchiensis sp. nov., isolated from grass soils of the Wudalianchi scenic area. AB - A Gram-stain-positive, rod-shaped, endospore-forming, aerobic bacterium, designated FJAT-27215T, was isolated from grass soil collected from Wudalianchi in the Heilongjiang Province of China. Growth was observed at 10-60 degrees C (optimum 30 degrees C), in 0 and 3.0 % NaCl (optimum 0 %) and at pH 5.0-10.0 (optimum 7.0), respectively. The cell-wall peptidoglycan contained meso diaminopimelic acid and the isoprenoid quinone was MK7. The main fatty acids were iso-C15 : 0, anteiso-C15 : 0, anteiso-C17 : 0, and iso-C16 : 0. The main polar lipids were diphosphatidylglycerol, phosphatidylglycerol and phosphatidyl ethanolamine. Phylogenetic analysis based on 16S rRNA gene sequences affiliated strain FJAT-27215T to the genus Bacillus. Strain FJAT-27215T showed high sequence similarities to Bacillus encimensis SGD-V-25T (98.6 %), Bacillus badius NBRC 15713T (98.6 %), Domibacillus indicus SD111T (96.9 %) and Bacillus thermotolerans SgZ-8T (96.5 %). The average nucleotide identity values between strain FJAT 27215T and the type strains of closely related species were much lower than the 96 % threshold value for delineation of genomic prokaryotic species. The in silico DNA-DNA hybridization values between strain FJAT-27215T and the most closely related strain B. encimensis SGD-V-25T showed a similarity of 22.4 % and lower than 70 %, indicating that they belong to different taxa. The phenotypic characters and taxono-genomics study revealed that strain FJAT-27215T represents a novel Bacillus species, for which the name Bacillus wudalianchiensis sp. nov. is proposed. The type strain is FJAT-27215T (=CCTCC AB 2015266T=DSM 100757T). PMID- 28820127 TI - Mongoliimonas terrestris gen. nov., sp. nov., isolated from desert soil. AB - A Gram-stain-negative, non-motile, aerobic, non-spore-forming, spherical bacterium (strain MIMtkB18T) was isolated from desert soil collected from part of a Mongolian Plateau, territory of Inner Mongolia, PR China. Cell growth could be observed at 20-45 degrees C (optimum at 40 degrees C), at a pH of 6-9 (optimum at pH 8.6) and in the presence of 0-1 % (w/v) NaCl (optimum 0 %). The genomic DNA G+C content was 69.6 mol%. 16S rRNA gene sequence analysis showed that strain MIMtkB18T was most closely related to Methylobrevis pamukkalensis PK2T (94.1 %), species of the genus Pleomorphomonas(93.4-94.0 %), and Hartmannibacter diazotrophicus E19T (93.9 %). The sole respiratory quinone was Q-10. The major fatty acids (>5 %) were C18 : 0 (5.7 %) and summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c) (81.6 %). Polar lipids were mainly composed of phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, phosphatidylmonomethylethanolamine and unidentified phospholipids. Based on phenotypic, chemotaxonomic and phylogenetic characteristics, it is concluded that strain MIMtkB18T represents a novel genus and species, for which the name Mongoliimonas terrestris sp. nov. is proposed. The type strain is MIMtkB18T (=KCTC 42635T=MCCC 1K00571T). PMID- 28820126 TI - Adhaeribacter terrae sp. nov., a novel bacterium isolated from soil. AB - Strain HY02T was isolated from a soil sample collected at Namyangju-si, Gyeonggi do, Republic of Korea. Cells of this strain were observed to be Gram-stain negative, short and rod-shaped. Colonies were red in colour. A 16S rRNA gene sequence analysis identified this strain as a member of the genus Adhaeribacter in the family Cytophagaceae, with the highest level of 16S rRNA gene sequence similarity to Adhaeribacter terreus DNG6T (98.08 %). This strain was positive for oxidase but negative for catalase activity and acid production from glucose. Growth of strain HY02T was observed at 15-30 degrees C, pH 7-8 and in the presence of 0-1 % NaCl. The isolate contained MK-7 as the predominant respiratory quinone, and C18 : 0, iso-C15 : 0, summed feature 4 (anteiso-C17 : 1 B/iso-C17 : 1 I) and C16 : 0 were the major fatty acids. The major polar lipid was phosphatidylethanolamine. The genomic DNA G+C content of strain HY02T was 44.0 mol%. Phenotypic and chemotaxonomic data supported the affiliation of strain HY02T with the genus Adhaeribacter. However, strain HY02T exhibited a relatively low level of DNA-DNA relatedness with A. terreus(16.3+/-3.5 %). Based on its phenotypic and genotypic properties, together with its phylogenetic distinctiveness, strain HY02T should be considered a representative of a novel species in the genus Adhaeribacter, for which the name Adhaeribacter terrae sp. nov. is proposed. The type strain is HY02T (=KCTC 52512T=JCM 31652T). PMID- 28820125 TI - Fungal Genomes and Insights into the Evolution of the Kingdom. AB - The kingdom Fungi comprises species that inhabit nearly all ecosystems. Fungi exist as both free-living and symbiotic unicellular and multicellular organisms with diverse morphologies. The genomes of fungi encode genes that enable them to thrive in diverse environments, invade plant and animal cells, and participate in nutrient cycling in terrestrial and aquatic ecosystems. The continuously expanding databases of fungal genome sequences have been generated by individual and large-scale efforts such as Genolevures, Broad Institute's Fungal Genome Initiative, and the 1000 Fungal Genomes Project (http://1000.fungalgenomes.org). These efforts have produced a catalog of fungal genes and genomic organization. The genomic datasets can be utilized to better understand how fungi have adapted to their lifestyles and ecological niches. Large datasets of fungal genomic and transcriptomic data have enabled the use of novel methodologies and improved the study of fungal evolution from a molecular sequence perspective. Combined with microscopes, petri dishes, and woodland forays, genome sequencing supports bioinformatics and comparative genomics approaches as important tools in the study of the biology and evolution of fungi. PMID- 28820128 TI - Molecular Antimicrobial Resistance Surveillance for Neisseria gonorrhoeae, Northern Territory, Australia. AB - Neisseria gonorrhoeae antimicrobial resistance (AMR) is a globally recognized health threat; new strategies are needed to enhance AMR surveillance. The Northern Territory of Australia is unique in that 2 different first-line therapies, based primarily on geographic location, are used for gonorrhea treatment. We tested 1,629 N. gonorrhoeae nucleic acid amplification test positive clinical samples, collected from regions where ceftriaxone plus azithromycin or amoxicillin plus azithromycin are recommended first-line treatments, by using 8 N. gonorrhoeae AMR PCR assays. We compared results with those from routine culture-based surveillance data. PCR data confirmed an absence of ceftriaxone resistance and a low level of azithromycin resistance (0.2%), and that penicillin resistance was <5% in amoxicillin plus azithromycin regions. Rates of ciprofloxacin resistance and penicillinase-producing N. gonorrhoeae were lower when molecular methods were used. Molecular methods to detect N. gonorrhoeae AMR can increase the evidence base for treatment guidelines, particularly in settings where culture-based surveillance is limited. PMID- 28820129 TI - Role of Food Insecurity in Outbreak of Anthrax Infections among Humans and Hippopotamuses Living in a Game Reserve Area, Rural Zambia. AB - In September 2011, a total of 511 human cases of anthrax (Bacillus anthracis) infection and 5 deaths were reported in a game management area in the district of Chama, Zambia, near where 85 hippopotamuses (Hippopotamus amphibious) had recently died of suspected anthrax. The human infections generally responded to antibiotics. To clarify transmission, we conducted a cross-sectional, interviewer administered household survey in villages where human anthrax cases and hippopotamuses deaths were reported. Among 284 respondents, 84% ate hippopotamus meat before the outbreak. Eating, carrying, and preparing meat were associated with anthrax infection. Despite the risk, 23% of respondents reported they would eat meat from hippopotamuses found dead again because of food shortage (73%), lack of meat (12%), hunger (7%), and protein shortage (5%). Chronic food insecurity can lead to consumption of unsafe foods, leaving communities susceptible to zoonotic infection. Interagency cooperation is necessary to prevent outbreaks by addressing the root cause of exposure, such as food insecurity. PMID- 28820130 TI - Convergence of Humans, Bats, Trees, and Culture in Nipah Virus Transmission, Bangladesh. AB - Preventing emergence of new zoonotic viruses depends on understanding determinants for human risk. Nipah virus (NiV) is a lethal zoonotic pathogen that has spilled over from bats into human populations, with limited person-to-person transmission. We examined ecologic and human behavioral drivers of geographic variation for risk of NiV infection in Bangladesh. We visited 60 villages during 2011-2013 where cases of infection with NiV were identified and 147 control villages. We compared case villages with control villages for most likely drivers for risk of infection, including number of bats, persons, and date palm sap trees, and human date palm sap consumption behavior. Case villages were similar to control villages in many ways, including number of bats, persons, and date palm sap trees, but had a higher proportion of households in which someone drank sap. Reducing human consumption of sap could reduce virus transmission and risk for emergence of a more highly transmissible NiV strain. PMID- 28820131 TI - Norovirus in Bottled Water Associated with Gastroenteritis Outbreak, Spain, 2016. AB - In April 2016, an outbreak of gastrointestinal illness (4,136 cases) occurred in Catalonia, Spain. We detected high levels of norovirus genotypes I and II in office water coolers associated with the outbreak. Infectious viral titer estimates were 33-49 genome copies/L for genotype I and 327-660 genome copies/L for genotype II. PMID- 28820132 TI - Prevalence of Yersinia enterocolitica Bioserotype 3/O:3 among Children with Diarrhea, China, 2010-2015. AB - Yersinia enterocolitica is thought to not significantly contribute to diarrheal disease in China, but evidence substantiating this claim is limited. We determined the prevalence of Y. enterocolitica infection and strain types present among children <5 years of age with diarrhea in China. The overall prevalence of pathogenic isolates was 0.59%. Prevalence of pathogenic bioserotype 3/O:3 varied geographically. In this population, the presence of fecal leukocytes was a characteristic of Y. enterocolitica infection and should be used as an indication for microbiological diagnostic testing, rather than for the diagnosis of bacillary dysentery. In contrast with Y. enterocolitica isolates from adults, which were primarily biotype 1A, isolates from children were primarily bioserotype 3/O:3. Most pathogenic isolates from children shared pulsed-field gel electrophoresis patterns with isolates from pigs and dogs, suggesting a possible link between isolates from animals and infections in children. Our findings underscore the need for improved diagnostics for this underestimated pathogen. PMID- 28820133 TI - Epidemiology of Salmonella enterica Serotype Dublin Infections among Humans, United States, 1968-2013. AB - Salmonella enterica serotype Dublin is a cattle-adapted bacterium that typically causes bloodstream infections in humans. To summarize demographic, clinical, and antimicrobial drug resistance characteristics of human infections with this organism in the United States, we analyzed data for 1968-2013 from 5 US surveillance systems. During this period, the incidence rate for infection with Salmonella Dublin increased more than that for infection with other Salmonella. Data from 1 system (FoodNet) showed that a higher percentage of persons with Salmonella Dublin infection were hospitalized and died during 2005-2013 (78% hospitalized, 4.2% died) than during 1996-2004 (68% hospitalized, 2.7% died). Susceptibility data showed that a higher percentage of isolates were resistant to >7 classes of antimicrobial drugs during 2005-2013 (50.8%) than during 1996-2004 (2.4%). PMID- 28820134 TI - Patterns of Human Plague in Uganda, 2008-2016. AB - Plague is a highly virulent fleaborne zoonosis that occurs throughout many parts of the world; most suspected human cases are reported from resource-poor settings in sub-Saharan Africa. During 2008-2016, a combination of active surveillance and laboratory testing in the plague-endemic West Nile region of Uganda yielded 255 suspected human plague cases; approximately one third were laboratory confirmed by bacterial culture or serology. Although the mortality rate was 7% among suspected cases, it was 26% among persons with laboratory-confirmed plague. Reports of an unusual number of dead rats in a patient's village around the time of illness onset was significantly associated with laboratory confirmation of plague. This descriptive summary of human plague in Uganda highlights the episodic nature of the disease, as well as the potential that, even in endemic areas, illnesses of other etiologies might be being mistaken for plague. PMID- 28820135 TI - Bioinformatic Analyses of Whole-Genome Sequence Data in a Public Health Laboratory. AB - The ability to generate high-quality sequence data in a public health laboratory enables the identification of pathogenic strains, the determination of relatedness among outbreak strains, and the analysis of genetic information regarding virulence and antimicrobial-resistance genes. However, the analysis of whole-genome sequence data depends on bioinformatic analysis tools and processes. Many public health laboratories do not have the bioinformatic capabilities to analyze the data generated from sequencing and therefore are unable to take full advantage of the power of whole-genome sequencing. The goal of this perspective is to provide a guide for laboratories to understand the bioinformatic analyses that are needed to interpret whole-genome sequence data and how these in silico analyses can be implemented in a public health laboratory setting easily, affordably, and, in some cases, without the need for intensive computing resources and infrastructure. PMID- 28820136 TI - Protective Effect of Val129-PrP against Bovine Spongiform Encephalopathy but not Variant Creutzfeldt-Jakob Disease. AB - Bovine spongiform encephalopathy (BSE) is the only known zoonotic prion that causes variant Creutzfeldt-Jakob disease (vCJD) in humans. The major risk determinant for this disease is the polymorphic codon 129 of the human prion protein (Hu-PrP), where either methionine (Met129) or valine (Val129) can be encoded. To date, all clinical and neuropathologically confirmed vCJD cases have been Met129 homozygous, with the exception of 1 recently reported Met/Val heterozygous case. Here, we found that transgenic mice homozygous for Val129 Hu PrP show severely restricted propagation of the BSE prion strain, but this constraint can be partially overcome by adaptation of the BSE agent to the Met129 Hu-PrP. In addition, the transmission of vCJD to transgenic mice homozygous for Val129 Hu-PrP resulted in a prion with distinct strain features. These observations may indicate increased risk for vCJD secondary transmission in Val129 Hu-PrP-positive humans with the emergence of new strain features. PMID- 28820137 TI - Estimated Annual Numbers of Foodborne Pathogen-Associated Illnesses, Hospitalizations, and Deaths, France, 2008-2013. AB - Estimates of the annual numbers of foodborne illnesses and associated hospitalizations and deaths are needed to set priorities for surveillance, prevention, and control strategies. The objective of this study was to determine such estimates for 2008-2013 in France. We considered 15 major foodborne pathogens (10 bacteria, 3 viruses, and 2 parasites) and estimated that each year, the pathogens accounted for 1.28-2.23 million illnesses, 16,500-20,800 hospitalizations, and 250 deaths. Campylobacter spp., nontyphoidal Salmonella spp., and norovirus accounted for >70% of all foodborne pathogen-associated illnesses and hospitalizations; nontyphoidal Salmonella spp. and Listeria monocytogenes were the main causes of foodborne pathogen-associated deaths; and hepatitis E virus appeared to be a previously unrecognized foodborne pathogen causing ~68,000 illnesses in France every year. The substantial annual numbers of foodborne illnesses and associated hospitalizations and deaths in France highlight the need for food-safety policymakers to prioritize foodborne disease prevention and control strategies. PMID- 28820138 TI - Processes Underlying Rabies Virus Incursions across US-Canada Border as Revealed by Whole-Genome Phylogeography. AB - Disease control programs aim to constrain and reduce the spread of infection. Human disease interventions such as wildlife vaccination play a major role in determining the limits of a pathogen's spatial distribution. Over the past few decades, a raccoon-specific variant of rabies virus (RRV) has invaded large areas of eastern North America. Although expansion into Canada has been largely prevented through vaccination along the US border, several outbreaks have occurred in Canada. Applying phylogeographic approaches to 289 RRV whole-genome sequences derived from isolates collected in Canada and adjacent US states, we examined the processes underlying these outbreaks. RRV incursions were attributable predominantly to systematic virus leakage of local strains across areas along the border where vaccination has been conducted but also to single stochastic events such as long-distance translocations. These results demonstrate the utility of phylogeographic analysis of pathogen genomes for understanding transboundary outbreaks. PMID- 28820139 TI - Risk for Low Pathogenicity Avian Influenza Virus on Poultry Farms, the Netherlands, 2007-2013. AB - Using annual serologic surveillance data from all poultry farms in the Netherlands during 2007-2013, we quantified the risk for the introduction of low pathogenicity avian influenza virus (LPAIV) in different types of poultry production farms and putative spatial-environmental risk factors: distance from poultry farms to clay soil, waterways, and wild waterfowl areas. Outdoor-layer, turkey (meat and breeder), and duck (meat and breeder) farms had a significantly higher risk for LPAIV introduction than did indoor-layer farms. Except for outdoor-layer, all poultry types (i.e., broilers, chicken breeders, ducks, and turkeys) are kept indoors. For all production types, LPAIV risk decreased significantly with increasing distance to medium-sized waterways and with increasing distance to areas with defined wild waterfowl, but only for outdoor layer and turkey farms. Future research should focus not only on production types but also on distance to waterways and wild bird areas. In addition, settlement of new poultry farms in high-risk areas should be discouraged. PMID- 28820140 TI - Clarity of objectives and working principles enhances the success of biomimetic programs. AB - Biomimetics, the transfer of functional principles from living systems into product designs, is increasingly being utilized by engineers. Nevertheless, recurring problems must be overcome if it is to avoid becoming a short-lived fad. Here we assess the efficiency and suitability of methods typically employed by examining three flagship examples of biomimetic design approaches from different disciplines: (1) the creation of gecko-inspired adhesives; (2) the synthesis of spider silk, and (3) the derivation of computer algorithms from natural self organizing systems. We find that identification of the elemental working principles is the most crucial step in the biomimetic design process. It bears the highest risk of failure (e.g. losing the target function) due to false assumptions about the working principle. Common problems that hamper successful implementation are: (i) a discrepancy between biological functions and the desired properties of the product, (ii) uncertainty about objectives and applications, (iii) inherent limits in methodologies, and (iv) false assumptions about the biology of the models. Projects that aim for multi-functional products are particularly challenging to accomplish. We suggest a simplification, modularisation and specification of objectives, and a critical assessment of the suitability of the model. Comparative analyses, experimental manipulation, and numerical simulations followed by tests of artificial models have led to the successful extraction of working principles. A searchable database of biological systems would optimize the choice of a model system in top-down approaches that start at an engineering problem. Only when biomimetic projects become more predictable will there be wider acceptance of biomimetics as an innovative problem-solving tool among engineers and industry. PMID- 28820141 TI - Silicon synaptic transistor for hardware-based spiking neural network and neuromorphic system. AB - Brain-inspired neuromorphic systems have attracted much attention as new computing paradigms for power-efficient computation. Here, we report a silicon synaptic transistor with two electrically independent gates to realize a hardware based neural network system without any switching components. The spike-timing dependent plasticity characteristics of the synaptic devices are measured and analyzed. With the help of the device model based on the measured data, the pattern recognition capability of the hardware-based spiking neural network systems is demonstrated using the modified national institute of standards and technology handwritten dataset. By comparing systems with and without inhibitory synapse part, it is confirmed that the inhibitory synapse part is an essential element in obtaining effective and high pattern classification capability. PMID- 28820142 TI - Nanomelatonin triggers superior anticancer functionality in a human malignant glioblastoma cell line. AB - Melatonin (MEL) has promising medicinal value as an anticancer agent in a variety of malignancies, but there are difficulties in achieving a therapeutic dose due to its short half-life, low bioavailability, poor solubility and extensive first pass metabolism. In this study chitosan/tripolyphosphate (TPP) nanoparticles were prepared by an ionic gelation method to overcome the therapeutic challenges of melatonin and to improve its anticancer efficacy. Characterization of the melatonin-loaded chitosan (MEL-CS) nanoformulation was performed using transmission and scanning electron microscopies, dynamic light scattering, Fourier transform infrared spectroscopy, Raman spectroscopy and x-ray diffraction. In vitro release, cellular uptake and efficacy studies were tested for their enhanced anticancer potential in human U87MG glioblastoma cells. Confocal studies revealed higher cellular uptake of MEL-CS nanoparticles and enhanced anticancer efficacy in human malignant glioblastoma cancer cells than in healthy non-malignant human HEK293T cells in mono- and co-culture models. Our study has shown for the first time that MEL-CS nanocomposites are therapeutically more effective as compared to free MEL at inducing functional anticancer efficacy in the human brain tumour U87MG cell line. PMID- 28820143 TI - Endoscopic ultrasound-guided drainage of pelvic abscesses with lumen-apposing metal stents. PMID- 28820144 TI - Chinese expert consensus statement on issues related to small specimen sampling of lung cancer. PMID- 28820145 TI - Endoscopic ultrasound-guided gastroenterostomy: Are we ready for prime time? AB - Interventional endoscopic ultrasonography (EUS) is currently becoming the less invasive therapeutic approach for the drainage of pancreatic fluid collections, of acute cholecystitis in patients unfit for surgery and for biliary drainage after failed endoscopic retrograde cholangiopancreatography. In addition, EUS guided gastroenterostomy (EUS-GE) has recently emerged as a feasible procedure to treat patients with gastric outlet obstruction, as an alternative to surgery or to standard endoscopy when endoscopic stent placement is not possible. Prior animal studies have shown that the procedure is safe and can create a stable anastomosis. However, the major challenge in translating the results of the animal studies into clinical practice is represented by the proper identification of the distal duodenal or proximal jejunal loop to be accessed in order to create the anastomosis. Currently, there are three EUS-GE techniques available: the direct EUS-GE technique, assisted EUS-GE technique, and its variant called the EUS-guided double-balloon-occluded gastrojejunostomy bypass. The present review describes the current EUS-GE techniques, depicts the different procedural aspects of the procedure, and presents the clinical evidences available so far, with a focus on the future perspectives of this EUS-guided technique. PMID- 28820146 TI - Head up, heels down, posture perfect: Ergonomics for an ophthalmologist. PMID- 28820147 TI - Learning curve in femtosecond laser-assisted cataract surgery. PMID- 28820148 TI - Optical models for intraocular lens planning in keratoconus: A step in the right direction and more to do. PMID- 28820149 TI - What a reviewer wants? PMID- 28820150 TI - Component corneal surgery: An update. AB - Several decades ago, penetrating keratoplasty was a challenge to corneal surgeons. Constant effort by the corneal surgeon to improve the outcomes as well as utilization of the available resources has led to a revolutionary change in the field of keratoplasty. All these efforts have led to the evolution of techniques that allow a corneal surgeon to disease-specific transplant of individual layers of corneal "so-called component corneal surgery" depending on the layer of cornea affected. This has led to an improvement in corneal graft survival as well as a better utilization of corneal tissues. This article reviews the currently available literature on component corneal surgeries and provides an update on the available techniques. PMID- 28820151 TI - A literature review and update on the incidence and microbiology spectrum of postcataract surgery endophthalmitis over past two decades in India. AB - PURPOSE: The purpose of this study was to review the incidence and microbiology of acute postcataract surgery endophthalmitis in India. METHODS: Systematic review of English-language PubMed referenced articles on endophthalmitis in India published in the past 21 years (January 1992-December 2012), and retrospective chart review of 2 major eye care facilities in India in the past 5 years (January 2010-December 2014) were done. The incidence data were collected from articles that described "in-house" endophthalmitis and the microbiology data were collected from all articles. Both incidence and microbiological data of endophthalmitis were collected from two large eye care facilities. Case reports were excluded, except for the articles on cluster infection. RESULTS: Six of 99 published articles reported the incidence of "in-house" acute postcataract surgery endophthalmitis, 8 articles reported the microbiology spectrum, and 11 articles described cluster infection. The clinical endophthalmitis incidence was between 0.04% and 0.15%. In two large eye care facilities, the clinical endophthalmitis incidence was 0.08% and 0.16%; the culture proven endophthalmitis was 0.02% and 0.08%. Gram-positive cocci (44%-64.8%; commonly, Staphylococcus species), and Gram-negative bacilli (26.2%-43%; commonly Pseudomonas species) were common bacteria in south India. Fungi (16.7%-70%; commonly Aspergillus flavus) were the common organisms in north India. Pseudomonas aeruginosa (73.3%) was the major organism in cluster infections. CONCLUSIONS: The incidence of postcataract surgery clinical endophthalmitis in India is nearly similar to the world literature. There is a regional difference in microbiological spectrum. A registry with regular and uniform national reporting will help formulate region specific management guidelines. PMID- 28820152 TI - Back pain in ophthalmology: National survey of Indian ophthalmologists. AB - PURPOSE: The aim is to assess the prevalence, severity, and associations of back pain among Indian ophthalmologists. METHODS: A self-reporting questionnaire was sent to ophthalmologists with valid e-mail addresses registered with the All India Ophthalmological Society. The survey was open for responses for 2 months. RESULTS: A total of 651 (5.96%) responses were obtained; 394 (61%) males and 257 (39%) females. Half (50%) of responses were obtained from doctors belonging to 31 40 years' age group. Two hundred and thirty (35%) of the ophthalmologists had height ranging from 161 to 170 cm and 443 (68%) had weight ranging from 51 to 75 kg. Four hundred and eighty-one (73.8%) of the respondents had <15 years of ophthalmic experience. Cataract (346; 53.1%) and general ophthalmology (342; 52.5%) were commonly practised by the ophthalmologists. Time spent in the outpatient department (OPD) was 39.37 +/- 16.32 h/week and in the operating theater 13.64 +/- 9.89 h/week, respectively. Self-reported prevalence of back pain was 70.5%. Fully 49% of respondents had low back pain, followed by neck pain (33%) and upper extremity symptoms (16%). Age <50 years (odds ratio [OR] = 2.4485), female gender (OR = 2.0265), long working hours in OPD (OR = 1.6524), and performing retinal lasers and indirect ophthalmoscopy (OR = 3.3251) showed positive association with back pain. The intolerable back pain was noted in <7% of the respondents. Around 398 (61%) respondents felt that their back pain was exacerbated while doing work and 86.6% felt that up to 5 h/week was lost due to persistent backache. Yoga and some form of exercise (74.3%) was practised to alleviate back pain. CONCLUSION: Back pain symptoms appear to be common among ophthalmologists. Awkward posture and prolonged working hours are responsible for developing back pain among ophthalmologists. Performing yoga and regular exercises, modifications in instrumentation and creating a larger workforce of eye care practitioners are needed to prevent ophthalmologists from developing back pain. PMID- 28820153 TI - Learning curve of femtosecond laser-assisted cataract surgery: Experience of surgeons new to femtosecond laser platform. AB - PURPOSE: The purpose of this study is to assess the learning curve in the initial 100 cases of cataract surgery performed using femtosecond laser-assisted cataract surgery (FLACS) by experienced cataract surgeons without prior experience in femtosecond laser platform. METHODS: This study was conducted at tertiary care eye hospital, South India. This was a prospective interventional study. The first 100 consecutive eyes undergoing FLACS were studied to understand docking time, number of docking attempts, problems encountered during docking, and complications attributable to docking. Phacoemulsification performed after femtosecond laser was also studied for complications, need for additional instrumentation, and total time required for surgery. Comparison was also made between two operating surgeons. RESULTS: Successful docking was recorded in 70% eyes at the first attempt. Mean time taken for successful docking was 9.3 +/- 6.4 min (median = 6 min, interquartile range (IQR) = 5-10 min, range = 4-35 min). When surgeries were divided into quartiles, docking time reduced significantly from 16.2 +/- 7.9 min in the first quartile to 6.2 +/- 2.7 min in the fourth quartile (P < 0.001). Phacoemulsification postdocking required 12.9 +/- 6.2 min (median = 10 min, IQR = 9-17.5 min). Six eyes showed anterior capsular tags, one had radial extension of capsulorhexis, and two eyes showed pupillary miosis after femtosecond laser application. At 6 weeks, 79% eyes attained uncorrected vision of 20/20, and all eyes had best-corrected vision of 20/20. CONCLUSION: Approximately 25-30 cases were required before obtaining reproducible results with FLACS, irrespective of cataract surgical experience, suggesting that training programs must offer a minimum 25 surgeries. Very few complications occurred during the learning curve, making it patient friendly. PMID- 28820154 TI - Preliminary validation of an optimized algorithm for intraocular lens power calculation in keratoconus. AB - PURPOSE: This study aimed to evaluate the theoretical influence on intraocular lens power (PIOL) calculation of the use of keratometric approach for corneal power (Pc) calculation in keratoconus and to develop and validate an algorithm preliminarily to minimize this influence. METHODS: Pcwas calculated theoretically with the classical keratometric approach, the Gaussian equation, and the keratometric approach using a variable keratometric index (nkadj) dependent on r1c(Pkadj). Differences in PIOLcalculations (DeltaPIOL) using keratometric and Gaussian Pcvalues were evaluated. Preliminary clinical validation of a PIOLalgorithm using Pkadjwas performed in 13 keratoconus eyes. RESULTS: PIOLunderestimation was present if Pcwas overestimated, and vice versa. Theoretical PIOLoverestimation up to -5.6 D and -6.2 D using Le Grand and Gullstrand eye models was found for a keratometric index of 1.3375. If nkadjwas used, maximal Delta PIOLwas +/-1.1 D, with most of the values <=+/-0.6 D. Clinically, PIOLunder- and over-estimations ranged from -1.1 to - 0.4 D. No statistically significant differences were found between PIOLobtained with Pkadjand Gaussian equation (P > 0.05). CONCLUSION: The use of the keratometric Pcfor PIOLcalculations in keratoconus can lead to significant errors that may be minimized using a Pkadjapproach. PMID- 28820155 TI - Double-head pterygium excision with modified vertically split-conjunctival autograft: Six-year long-term retrospective analysis. AB - PURPOSE: The aim of this study is to describe a modified technique of vertically split-conjunctival autograft (CAG) for primary double-head pterygium and evaluate its postoperative outcome. METHODS: In this retrospective, noncomparative, interventional case series, 87 eyes of 87 patients of double-head pterygium from June 2009 to June 2015 were included. They underwent vertical split CAG. A limbus limbus orientation was not strictly maintained. Primary outcome measure was recurrence rate. Other outcome measures studied were graft retraction, Tenon's granuloma, dellen, and so on. RESULTS: Mean age was 54.54 +/- 11.51 years; M:F was 41:46. Mean follow-up was 17.28 +/- 10.28 months. The only significant complication was recurrence rate of 3.45% (3 eyes out of 87). Other most common secondary outcome was graft edema, 42.52% (37 eyes out of 87) which resolved without any intervention. Other outcomes such as graft retraction (31.03%), dellen (1.15%), Tenon's granuloma (3.45%), and subconjunctival hemorrhage (36.78%) were recorded. CONCLUSION: Modified vertical split CAG without maintaining limbus-limbus orientation, just large enough to cover the bare scleral defect, appears to be a successful technique with lower recurrence rate in treating double-head pterygium. PMID- 28820156 TI - Viscoelastic-augmented trabeculectomy: A newer concept. AB - PURPOSE: Comparison of conventional trabeculectomy (CT) and viscoelastic augmented trabeculectomy (VAT) in primary open-angle glaucoma. METHODS: A total of 65 primary open-angle glaucoma cases were taken for each of the two groups, i.e., CT and VAT. Viscoelastic-augmented trabeculectomy constituted lamellar scleral flap, deep scleral flap, penetrating trabeculectomy, peripheral iridectomy, filling of the anterior chamber with viscoelastic (sodium hyaluronate) and balanced salt solution, movement of visco in bleb, and tight flap closure. Success criteria included intraocular pressure (IOP) <14 mmHg with no devastating complications. P < 0.05 was considered statistically significant. RESULTS: Mean IOP was significantly lower after VAT compared to CT at 6 weeks, 12 weeks, and 6 months postoperatively. Target IOP was achieved in 60% cases in VAT group compared to 36.92% in CT group. CONCLUSION: VAT is effective in reducing IOP to the target level for advanced glaucoma with lower postoperative complications. PMID- 28820157 TI - Incidence, outcomes, and risk factors for hemorrhagic complications in eyes with polypoidal choroidal vasculopathy following photodynamic therapy in Indian subjects. AB - PURPOSE: To evaluate the incidence, outcomes, and risk factors for hemorrhagic complications in eyes with polypoidal choroidal vasculopathy (PCV) following photodynamic therapy (PDT). METHODS: Medical records of 94 eyes of 86 consecutive patients with PCV who underwent PDT between January 2007 and December 2014 were retrospectively reviewed. The diagnosis of PCV was based on clinical features and indocyanine green angiography. Eyes were treated with PDT monotherapy or a combination of PDT plus anti-vascular endothelial growth factor. PDT was performed at (standard [SFPDT] or reduced fluence RFPDT). RESULTS: Ninety-four eyes had 119 PDT treatment sessions (mean: 1.3 sessions). Mean presenting vision was 0.46 +/- 0.44 logarithm of the minimum angle of resolution (logMAR). Following PDT, ten eyes (11%) of nine patients had hemorrhagic complications such as subretinal hemorrhage (SRH; n = 5), subretinal pigment epithelium (RPE) hemorrhage (n = 1), breakthrough vitreous hemorrhage (BVH; n = 3), and SRH with sub-RPE hemorrhage and BVH (n = 1). Median interval to hemorrhage following PDT was 2 months. Age (P = 0.842), duration of symptoms (P = 0.352), number of laser spots (P = 0.219), and laser spot size (LSS) (P = 0.096) were not significantly associated with increased risk of hemorrhagic complications. Female gender was associated with reduced risk of hemorrhage (P = 0.045). SFPDT was significantly associated with increased risk of hemorrhage (P = 0.026). The probability of developing hemorrhagic complications in SFPDT group was 0.24 compared to 0.07 in RFPDT group (P = 0.039). Multivariate logistic regression analysis showed SFPDT as the only significant risk factor for hemorrhage following PDT (odds ratio 5.3, 95% confidence interval 1.1-24.8, P = 0.03). Mean final vision was 0.61 +/- 0.53 logMAR at mean follow-up of 33 months (median = 22 months; range = 2-157 months). CONCLUSION: Age, LSS, number of laser spots, preexisting hemorrhages, or use of anticoagulants were not associated with increased risk of hemorrhagic complications. SFPDT was significantly associated with increased risk of hemorrhagic complications in such eyes. PMID- 28820158 TI - Systematic analysis of ocular trauma by a new proposed ocular trauma classification. AB - PURPOSE: The current classification of ocular trauma does not incorporate adnexal trauma, injuries that are attributable to a nonmechanical cause and destructive globe injuries. This study proposes a new classification system of ocular trauma which is broader-based to allow for the classification of a wider range of ocular injuries not covered by the current classification. METHODS: A clinic-based cross sectional study to validate the proposed classification. We analyzed 535 cases of ocular injury from January 1, 2012 to February 28, 2012 over a 4-year period in an eye hospital in central India using our proposed classification system and compared it with conventional classification. RESULTS: The new classification system allowed for classification of all 535 cases of ocular injury. The conventional classification was only able to classify 364 of the 535 trauma cases. Injuries involving the adnexa, nonmechanical injuries and destructive globe injuries could not be classified by the conventional classification, thus missing about 33% of cases. CONCLUSIONS: Our classification system shows an improvement over existing ocular trauma classification as it allows for the classification of all type of ocular injuries and will allow for better and specific prognostication. This system has the potential to aid communication between physicians and result in better patient care. It can also provide a more authentic, wide spectrum of ocular injuries in correlation with etiology. By including adnexal injuries and nonmechanical injuries, we have been able to classify all 535 cases of trauma. Otherwise, about 30% of cases would have been excluded from the study. PMID- 28820159 TI - Surgical treatment of superior oblique palsy: Predictors of outcome. AB - PURPOSE: The purpose of this study was to evaluate the incidence and outcome of surgically treated superior oblique palsy (SOP) and the factors involved in its resolution. METHODS: We performed a retrospective study of 76 patients who underwent surgery for SOP. We recorded data from the physical examination and the number and type of procedures performed. Favorable outcome was defined as resolution of or improvement in torticollis (<=5 degrees ) and diplopia in primary position (PP) and downgaze or as vertical deviation (VD) <5 prism diopters (pd) in PP and 10 pd in the oblique diagnostic position. RESULTS: Mean age was 33.12 years. Congenital SOP was the most frequent type (65.8%). Mean preoperative VD was 15.89 +/- 9.94 pd, decreasing to 3.07 +/- 4.36 pd after surgery. Associated horizontal deviation was recorded in 51.32% of cases. The mean number of procedures was 1.37 +/- 0.62 (range 1-4), with 69.7% of patients requiring only one procedure. The mean number of muscles operated on was 1.96 +/- 1.01 (inferior oblique being the most frequent). A greater reduction in VD after surgery was observed in patients with congenital SOP (P = 0.04). Although none of the factors evaluated influenced surgical outcome, amblyopic patients had a greater risk of reoperation (P = 0.04). A favorable outcome was achieved in 75% of cases. Mean follow-up was 37.08 months. CONCLUSION: Congenital SOP was twice as frequent as acquired SOP and although surgery was successful in most cases, a greater reduction in VD was obtained in congenital cases. Amblyopia was identified as a risk factor for reoperation. PMID- 28820160 TI - Patient satisfaction and acceptance of spherical equivalent spectacles correction wear in rural India. AB - PURPOSE: The aim of this study was to explore the possibilities of acceptance of a ready-to-dispense spherical equivalent (SE) of spherocylindrical (SC) correction spectacles in rural India. METHODS: Snellen visual acuity with SE power of refracted SC lenses was prospectively collected from all individuals visiting vision centers in Phase 1 (vision correction accuracy) of the study conducted in two South Indian districts. The satisfaction level was recorded by asking one standard question. The SE spectacles were dispensed in vision centers of one district in Phase 2 (SE acceptance) with a suggestion to return, if unsatisfied, for free exchange of spectacles within a month of dispensing. RESULTS: In Phase 1, 929 of 3529 patients were refracted and it was found that 320 patients and one eye of one patient (641 eyes) had astigmatism. The average age was 41 (+/-16; range: 7-84) years. There was no reduction of visual acuity in SE of 0.25 Dcyl (100% satisfaction) and progressive decrease in satisfaction to 43%, 26%, and 19% with SE correction of 0.50, 0.75, and 1.00 Dcyl, respectively. In Phase 2, 988 of 6168 patients needed refraction and 240 had astigmatism. A total of 103 patients (206 eyes) accepted SE equivalent spectacles. No client returned for the free exchange of spectacles. CONCLUSION: Dispensing SE power up to 1 Dcyl in ready - made spectacles could be considered in remote rural populations in resource-poor economic conditions. PMID- 28820161 TI - Ocular morbidity patterns among children in schools for the blind in Chennai. AB - PURPOSE: To identify the morbidity patterns causing blindness in children attending schools for the blind in Chennai and comparing our data with similar studies done previously. METHODS: A cross-sectional prevalence study was carried out in two schools for the blind in Chennai. Blind schools were visited by a team of ophthalmologists and optometrists. Students with best-corrected visual acuity (BCVA) worse than 3/60 in the better eye were included and relevant history was noted. Every student underwent anterior segment evaluation and detailed fundus examination. Morbidity of the better eye was taken as cause of blindness. Health records maintained by the school were referred to wherever available. RESULTS: The anatomical causes of blindness include optic nerve disorders in 75 (24.8%) cases, retinal disorders in 55 (18.2%), corneal disorders in 47 (15.6%), lens related disorders in 39 (12.9%), congenital anomalies in 11 (3.6%), and congenital glaucoma in 20 (6.6%) cases. The whole globe was involved in six cases (1.99%). Among conditions causing blindness, optic atrophy seen in 73 (24.17%) cases was the most common, followed by retinal dystrophy in 44 (14.56%), corneal scarring in 35 (11.59%), cataract in 22 (7.28%), and congenital glaucoma in 20 (6.6%) cases. CONCLUSION: It was found that avoidable causes of blindness were seen in 31% of cases and incurable causes in 45%. Optic nerve atrophy and retinal dystrophy are the emerging causes of blindness, underlining the need for genetic counseling and low vision rehabilitation centers, along with a targeted approach for avoidable causes of blindness. PMID- 28820162 TI - Nasal involvement in X-linked retinoschisis. PMID- 28820163 TI - Sympathetic ophthalmia related to conjunctival invasive squamous-cell carcinoma. AB - Sympathetic ophthalmia (SO) is a rare, diffuse, bilateral, and granulomatous nonnecrotizing panuveitis that may follow intraocular penetrating trauma. Our aim is to report a rare case of SO following orbital exenteration. Orbital exenteration was performed on a 48-year-old african female due to conjunctival keratinizing squamous cell carcinoma with intraocular involvement of the left eye. Five days after the uneventful procedure, the patient presented signs and symptoms compatible with SO. Key differential diagnoses were excluded, and prompt and aggressive immunosuppression was started with a favourable but slow clinical response. This case highlights the fact that SO can also be induced by a neoplasm with intraocular invasion or by aggressive nonpenetrating surgery. While the underlying pathogenesis of SO is still not fully elucidated, we hereby contribute with a novel potential mechanism leading to its development. PMID- 28820164 TI - Cyclophotocoagulation-induced sympathetic ophthalmia in a Coats' disease patient supported by histopathology and immunohistochemistry. AB - We describe a case of a 13-year-old male patient of Coats' disease who developed sympathetic ophthalmia (SO) following contact diode laser cyclophotocoagulation. There was no history of invasive surgery or any perforating injuries preceding cyclodestructive therapy. The eye had neovascular glaucoma secondary to Coats' disease, which was treated once with contact cyclophotocoagulation. Subsequently, the intraocular pressure slowly decreased, and the eye became phthisical. Intraocular inflammation developed in the fellow eye and SO was suspected, which was confirmed by characteristic findings seen on fluorescein angiography. The case was successfully managed with the help of topical and systemic immunosuppression. Enucleation with silicone ball implantation was performed in the right phthisical eye and specimen was sent for histopathological examination. Histopathology and immunostaining supported the diagnosis of SO. PMID- 28820165 TI - Extraocular needle- guided haptic insertion technique of scleral fixation intraocular lens surgeries (X-NIT). AB - The most challenging step in sutureless scleral fixation of intraocular lens (SFIOL) is exteriorization of haptics. The conventional handshake technique has a learning curve since it involves intraocular handing over of haptics from one forceps to another. Here, we describe "extraocular needle-guided haptic insertion technique" (X-NIT), a novel technique of exteriorizing haptics that totally eliminates intraocular manipulations. This method involves sequential introduction of two bent 26-gauge needles through the sclera (pars plicata zone) into the eye which are brought out through a sclerocorneal wound. The intraocular lens haptics are threaded through these needles and exteriorized. Nineteen consecutive patients underwent surgery by this technique. There were no intraoperative complications. The mean best-corrected visual acuity (BCVA) of these patients at 1-month follow-up was 0.5 +/- 0.3 (logarithm of the minimum angle of resolution) with 18 of 19 eyes showing one or more lines of improvement in BCVA. X-NIT is a safe, easy, cost-effective, and highly reproducible technique, especially for beginners. PMID- 28820166 TI - Commentary: Comprehending haptic exteriorization in intrascleral haptic fixation of an intraocular lens. PMID- 28820167 TI - Swept source optical coherence tomography-angiography of choroid in choroidal hemangioma before and after laser photocoagulation. AB - Swept source optical coherence tomography-angiography (OCT-angiography) gives us a unique opportunity to study the vasculature of choroidal lesions in vivo. We describe the OCT angiographic characteristics of circumscribed choroidal hemangioma before and after laser photocoagulation. Medium-sized choroidal vessels/vessels on the tumor surface become predominantly visible after laser photocoagulation due to laser-induced damage to the overlying choriocapillaris. OCT-angiography adds a new dimension to in vivo analysis of vascular changes in choroid due to choroidal tumors and their response to therapy. PMID- 28820168 TI - Therapeutic surprise! Photodynamic therapy for cavernous haemangioma of the disc. AB - PURPOSE: To report the response of cavernous haemangioma of the disc to PDT. METHODS AND PATIENTS: A 32 years old lady presented to us with complaints of sudden onset of blurry vision in her right eye. What seemed initially as polypoidal choroidal vasculopathy turned out as cavernous haemangioma of the disc after pneumatic displacement of the sub-retinal haeme. She was treated with PDT as she was prone to recurrent haemorrhage from the lesion due to her low platelet count. RESULTS: Complete regression of the cavernous haemangioma was noted as early as the second week itself and remained regressed for 4 months. CONCLUSION: PDT can be safe option for patients presenting with symptomatic cavernous haemangioma of the disc or retina. PMID- 28820169 TI - Aflibercept for recurrent or recalcitrant polypoidal choroidal vasculopathy in Indian eyes: Early experience. AB - Treatment guidelines for symptomatic polypoidal choroidal vasculopathy (PCV) have been described, but the management of recurrent or recalcitrant PCV is a challenge. The newer anti-vascular endothelial growth factor: aflibercept has shown promise in the treatment of both treatment naive and recalcitrant PCV in studies outside India. We present the minimum 6 months results of intravitreal aflibercept in recurrent and recalcitrant PCV in Indian eyes after multiple injections of bevacizumab/ranibizumab with or without photodynamic therapy. Of 10 eyes, 7 resolved of which 4 recurred needing continued aflibercept. Three of the ten eyes did not show a response. To the best of our knowledge, this is the first report from India in this challenging situation. PMID- 28820170 TI - Paradoxical worsening of a case of TB subretinal abscess with serpiginous-like choroiditis following the initiation of antitubercular therapy. AB - A 37-year-old immunocompetent male patient presented with the blurring of vision, both eyes for the past1 year. Fundus examination revealed bilateral multiple subretinal abscesses with areas of healed serpiginous-like choroiditis. Laboratory investigations showed positive tuberculin skin test, positive QuantiFERON TB-Gold Test, and high resolution computed tomography chest showed enlarged mediastinal lymph nodes. The aqueous sample revealed polymerase chain reaction (PCR) positive for Mycobacterium tuberculosis (MTB) (MPB64 genome). He was treated antitubercular therapy (ATT) along with oral steroids. Although he responded well initially, he had recurrent inflammation and paradoxical worsening. This was managed with a high dose of intravenous corticosteroids, immune suppressive and ATT. He also had a diagnostic vitreous biopsy which was also PCR positive for MTB (IS6110 gene). He subsequently continued ATT along with corticosteroids and immune suppressive and responded well. We present this case report for its unusual presentation. PMID- 28820171 TI - Molecular pathologic interpretation of new retinoblastoma rosettes. AB - Newly described retinoblastoma (RB) rosettes have various kinds of pathological significance. Some of their characteristics have been revealed in this immunohistochemistry study. Five paraffin-embedded eyeballs with RB and new rosettes were studied for neuron-specific enolase (NSE), p53, p16, BAX, c-Myc, glial fibrillary acidic protein, synaptophysin, and chromogranin. They were compared and interpreted using control specimens. NSE, P53, and P16 were significantly expressed in the cells of the new rosettes. The presence of new RB rosettes that mostly have histopathological high-risk factors and p53 positivity may be a strong marker of poor prognosis of RB. PMID- 28820172 TI - Timing of surgery in traumatic globe dislocation. AB - Traumatic globe dislocation into the maxillary sinus is a rare event and usually associated with a poor visual outcome if not managed appropriately. We report a 45-year-old female patient who presented to the emergency after blunt injury to her face with a door. Initial evaluation revealed nil perception of light and an apparently anophthalmic socket. Neuroimaging revealed large floor and medial wall fracture with dislocation of the globe into the maxillary sinus. The patient underwent exploration with repositioning of the globe and fracture repair. She was also administered 1 g intravenous methylprednisolone along with tapering course of oral steroids for 3 days. Patient's final visual acuity at 18 months of follow-up improved to counting fingers at 1 m. A thorough review of the literature suggests immediate surgery might improve the final visual outcome in such cases. PMID- 28820173 TI - Devastating complication of cosmetic iris implants. PMID- 28820174 TI - The effect of color overlays on the reading ability of dyslexic children. PMID- 28820175 TI - Noninvasive mechanical ventilation in early acute respiratory distress syndrome. AB - Noninvasive ventilation (NIV) has a well--established role in the treatment of acute--on--chronic respiratory failure and cardiogenic pulmonary edema. Its role in acute hypoxemic respiratory failure has been increasingly investigated, but its impact on the management and outcome of the subset of patients with acute respiratory distress syndrome (ARDS) is still to be determined. ARDS could be a risk factor for NIV failure, and in these patients, delayed endotracheal intubation can lead to an increased mortality. On the other hand, in a subset of patients with ARDS, endotracheal intubation can be avoided when NIV is applied. This review summarizes the current practice of NIV use in patients with ARDS and underlines the importance of proper patient selection before an NIV trial as well as criteria that should be used to predict failure early enough. A brief overview of high--flow nasal cannula is also provided. The use of NIV in ARDS is still debated, and it is important to be aware of the potential limitations and pitfalls of this treatment, which, when properly applied, could reduce the incidence of endotracheal intubation. PMID- 28820177 TI - Simple beta-lactones are potent irreversible antagonists for strigolactone receptors. PMID- 28820176 TI - 5-Hydroxymethylcytosine signatures in cell-free DNA provide information about tumor types and stages. AB - 5-Hydroxymethylcytosine (5hmC) is an important mammalian DNA epigenetic modification that has been linked to gene regulation and cancer pathogenesis. Here we explored the diagnostic potential of 5hmC in circulating cell-free DNA (cfDNA) using a sensitive chemical labeling-based low-input shotgun sequencing approach. We sequenced cell-free 5hmC from 49 patients of seven different cancer types and found distinct features that could be used to predict cancer types and stages with high accuracy. Specifically, we discovered that lung cancer leads to a progressive global loss of 5hmC in cfDNA, whereas hepatocellular carcinoma and pancreatic cancer lead to disease-specific changes in the cell-free hydroxymethylome. Our proof-of-principle results suggest that cell-free 5hmC signatures may potentially be used not only to identify cancer types but also to track tumor stage in some cancers. PMID- 28820178 TI - Erratum: E3 Ubiquitin ligase ZNRF4 negatively regulates NOD2 signalling and induces tolerance to MDP. AB - This corrects the article DOI: 10.1038/ncomms15865. PMID- 28820179 TI - Effects of DCK knockdown on proliferation, apoptosis and tumorigenicity in vivo of cervical cancer HeLa cells. AB - The present study explored the effect that deoxycytidine kinase (DCK) knockdown had on proliferation, apoptosis and tumorigenicity in vivo of cervical cancer HeLa cells. Human cervical cancer HeLa cells that had received no prior treatment were selected from the HeLa group. The HeLa-negative control (NC) group consisted of cells that had undergone an empty vector treatment, and finally the HeLa-short hairpin RNA (shRNA) group included cells that were treated by means of shRNA-DCK expression. DCK expressions were evaluated by quantitative real-time polymerase chain reaction in addition to western blotting assays. Cell proliferation was estimated using the Cell Counting Kit-8 (CCK-8) assay and cell cycle progression. Cell apoptosis was determined by flow cytometry. BALB/c nude mice (n=24) were selected to establish transplanted tumor models, with gross tumor volume measured every 3 days. The results in vitro were as follows: compared with the HeLa group, the HeLa-shRNA group exhibited downregulation of DCK expression and inhibition of cell proliferation at 48, 72 and 96 h. Additionally, more cells in the HeLa-shRNA group were arrested in G0/G1 stage and less in S and G2/M stages, as well as in promotion of cell apoptosis. In vivo results are as follows: when comparing the HeLa and HeLa-NC groups, the gross tumor volume of the transplanted tumor in nude mice in the HeLa-shRNA group was found to have decreased in 13, 16, 19 and 22 days. Based on these findings, our study suggests that DCK knockdown facilitates apoptosis while inhibiting proliferation and tumorigenicity in vivo of cervical cancer HeLa cells. PMID- 28820180 TI - Osteogenesis imperfecta. AB - Skeletal deformity and bone fragility are the hallmarks of the brittle bone dysplasia osteogenesis imperfecta. The diagnosis of osteogenesis imperfecta usually depends on family history and clinical presentation characterized by a fracture (or fractures) during the prenatal period, at birth or in early childhood; genetic tests can confirm diagnosis. Osteogenesis imperfecta is caused by dominant autosomal mutations in the type I collagen coding genes (COL1A1 and COL1A2) in about 85% of individuals, affecting collagen quantity or structure. In the past decade, (mostly) recessive, dominant and X-linked defects in a wide variety of genes encoding proteins involved in type I collagen synthesis, processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells have been shown to cause osteogenesis imperfecta. The large number of causative genes has complicated the classic classification of the disease, and although a new genetic classification system is widely used, it is still debated. Phenotypic manifestations in many organs, in addition to bone, are reported, such as abnormalities in the cardiovascular and pulmonary systems, skin fragility, muscle weakness, hearing loss and dentinogenesis imperfecta. Management involves surgical and medical treatment of skeletal abnormalities, and treatment of other complications. More innovative approaches based on gene and cell therapy, and signalling pathway alterations, are under investigation. PMID- 28820181 TI - Microglia Activation in Subjects at Risk for Psychosis: Fact or Fiction? PMID- 28820182 TI - Corrigendum: Adrenergic-mediated loss of splenic marginal zone B cells contributes to infection susceptibility after stroke. AB - This corrects the article DOI: 10.1038/ncomms15051. PMID- 28820183 TI - Technique of retinal gene therapy: delivery of viral vector into the subretinal space. AB - PurposeSafe and reproducible delivery of gene therapy vector into the subretinal space is essential for successful targeting of the retinal pigment epithelium (RPE) and photoreceptors. The success of surgery is critical for the clinical efficacy of retinal gene therapy. Iatrogenic detachment of the degenerate (often adherent) retina in patients with hereditary retinal degenerations and small volume (eg, 0.1 ml) subretinal injections pose new surgical challenges.MethodsOur subretinal gene therapy technique involved pre-operative planning with optical coherence tomography (OCT) and autofluorescence (AF) imaging, 23 G pars plana vitrectomy, internal limiting membrane staining with Membrane Blue Dual (DORC BV, Zuidland, Netherlands), a two-step subretinal injection using a 41 G Teflon tipped cannula (DORC) first with normal saline to create a parafoveal bleb followed by slow infusion of viral vector via the same self-sealing retinotomy. Surgical precision was further enhanced by intraoperative OCT (Zeiss Rescan 7000, Carl Zeiss Meditec AG, Jena, Germany). Foveal functional and structural recovery was evaluated using best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity, microperimetry and OCT.ResultsTwo patients with choroideremia aged 29 (P1) and 27 (P2) years, who had normal and symmetrical levels of best-corrected visual acuity (BCVA) in both eyes, underwent unilateral gene therapy with the fellow eye acting as internal control. The surgeries were uncomplicated in both cases with successful detachment of the macula by subretinal vector injection. Both treated eyes showed recovery of BCVA (P1: 76-77 letters; P2: 84-88 letters) and mean threshold sensitivity of the central macula (P1: 10.7-10.7 dB; P2: 14.2-14.1 dB) to baseline within a month. This was accompanied by normalisation of central retinal thickness on OCT.ConclusionsHerein we describe a reliable technique for subretinal gene therapy, which is currently used in clinical trials to treat choroideremia using an adeno-associated viral (AAV) vector encoding the CHM gene. Strategies to minimise potential complications, such as avoidance of excessive retinal stretch, air bubbles within the injection system, reflux of viral vector and post operative vitritis are discussed. PMID- 28820185 TI - Can Lester Jones tubes be tolerated for decades? AB - PurposeLester Jones described canalicular bypass tubes 50 years ago. We present a cohort of patients with Jones' tubes first placed between 1969 and 1989, and who were reviewed within the last 15 years.Patients and methodsRetrospective case note review for living patients identified as having had Jones' tube placement prior to 1990. The duration of Jones' tube usage was noted and the number of replacements recorded.ResultsTwenty-nine patients (33 eyes) had maintenance of their Jones' tube(s) within the last 15 years, and had first tube placement before 1990. The average follow-up was 29.5 years (median 28.8 years, range 17 45.7 years). The original tube was present in 8/33 (24%) of eyes, at a mean survival of 34 years (33.3 years; range 29.4-44.4 years). The number of tube replacements during follow-up ranged from 0 to 9 (mean 1.7; median 1). When considering the initially placed tube in all 33 eyes, however, the survival ranged between 18 days and 44.4 years (mean 13.6 years; median 6.9 years). At last follow-up, 11/33 (33%) of eyes had lost their tubes, with 9 having minimal or no symptoms.ConclusionsThese patients with Jones' tube placement before 1990 provides the first recorded evidence that the device can be tolerated for at least four decades, and that some patients will-with appropriate outpatient maintenance-retain their originally placed tube. This information may be useful in counselling patients about the lifetime expectation for bypass tubes. PMID- 28820184 TI - Age-related macular degeneration and mortality: the Melbourne Collaborative Cohort Study. AB - AimsTo assess associations between features of age-related macular degeneration (AMD) and mortality.MethodsA total of 21 129 participants from the Melbourne Collaborative Cohort Study aged 47-85 years (60% female) were assessed for AMD (2003-2007). Mortality data to December 31, 2012 were obtained through linkage with the National Death Index. Associations were assessed using Cox regression, adjusting for age, sex, smoking, region of birth, education, physical activity, diet and alcohol.ResultsLate AMD was identified in 122 (0.6%) participants, including those with choroidal neovascularisation (n=55, 0.3%), geographic atrophy (n=87, 0.4%) and reticular pseudodrusen (n=87, 0.4%). After a median follow-up period of 8.1 years, 1669 (8%) participants had died, including those from cardiovascular diseases (386), tobacco-related cancers (179), and neurodegenerative disease (157). There was evidence of an increased rate of all cause mortality for those with choroidal neovascularisation (Hazard Ratio (HR) 1.71 95% CI 1.06-2.76) and geographic atrophy (HR 1.46 95% CI 0.99-2.16). Choroidal neovascularisation was also associated with an increased rate of cardiovascular mortality (HR 3.16 95% CI 1.62-6.15) and geographic atrophy was associated with an increased rate of death from tobacco-related cancer (HR 2.86 95% CI 1.15-7.09). Weak evidence was also present for an association between choroidal neovascularisation and death from neurodegenerative disease (HR 2.49 95% CI 0.79-7.85). Neither reticular pseudodrusen nor the earlier stages of AMD were associated with mortality.ConclusionsLate AMD is associated with an increased rate of all-cause mortality. Choroidal neovascularisation and geographic atrophy were associated with death from cardiovascular disease and tobacco-related cancer, respectively. PMID- 28820186 TI - Parental inability to detect eye diseases in children: barriers to access of childhood eye-care services in south India. PMID- 28820188 TI - Stroke: Twist in artery linked to stroke in young adults. PMID- 28820190 TI - Mechano-, thermo-, solvato-, and vapochromism in bis(acetato-kappa1O)[4'-(4 (diphenylamino)phenyl)](2,2':6',2''-terpyridine-kappa3N,N',N'')zinc(ii) and its polymer. AB - The titled complex exhibits multi-functional luminochromism in the solid state, despite its simple chemical structure. The complex shows solid-state vapochromism and mechanochromism. The polymer analogue of the complex undergoes solvatochromism and thermochromism. PMID- 28820191 TI - Comparative photophysics and ultrafast dynamics of dimethylaminochalcone and a structurally rigid derivative: experimental identification of TICT coordinate. AB - Photophysical parameters and ultrafast dynamics of dimethylaminochalone (DMAC-A) have been compared with a structurally bridged analogue (namely, c-DMAC) in solvents of varying polarities. Conformational locking of the single bond connecting the donor and acceptor groups in c-DMAC arrests the twisted intramolecular charge transfer (TICT) relaxation and consequently the photophysical parameters such as fluorescence yield, fluorescence lifetime and triplet yield change significantly. The intramolecular charge transfer character of the LE state is found to be unaffected by conformational restriction. Femtosecond transient absorption spectroscopic studies confirmed that in polar solvents, solvation is the only relaxation process in c-DMAC as opposed to the ultrafast TICT of DMAC-A. The solvent polarity effect on the relaxation dynamics has also been discussed. PMID- 28820187 TI - Cerebral venous thrombosis. AB - Cerebral venous thrombosis (CVT) is an important cause of stroke in young adults. Data from large international registries published in the past two decades have greatly improved our knowledge about the epidemiology, clinical manifestations and prognosis of CVT. The presentation of symptoms is highly variable in this disease, and can range from a patient seen at the clinic with a 1-month history of headache, to a comatose patient admitted to the emergency room. Consequently, the diagnosis of CVT is often delayed or overlooked. A variety of therapies for CVT are available, and each should be used in the appropriate setting, preferably guided by data from randomized trials and well-designed cohort studies. Although deaths from CVT have decreased in the past few decades, mortality remains ~5-10%. In this Review, we provide a comprehensive and contemporary overview of CVT in adults, with emphasis on advancements made in the past decade on the epidemiology and treatment of this multifaceted condition. PMID- 28820192 TI - Comparison of classical reaction paths and tunneling paths studied with the semiclassical instanton theory. AB - Atom tunneling in the hydrogen atom transfer reaction of the 2,4,6-tri-tert butylphenyl radical to 3,5-di-tert-butylneophyl, which has a short but strongly curved reaction path, was investigated using instanton theory. We found the tunneling path to deviate qualitatively from the classical intrinsic reaction coordinate, the steepest-descent path in mass-weighted Cartesian coordinates. To perform that comparison, we implemented a new variant of the predictor-corrector algorithm for the calculation of the intrinsic reaction coordinate. We used the reaction force analysis method as a means to decompose the reaction barrier into structural and electronic components. Due to the narrow energy barrier, atom tunneling is important in the abovementioned reaction, even above room temperature. Our calculated rate constants between 350 K and 100 K agree well with experimental values. We found a H/D kinetic isotope effect of almost 106 at 100 K. Tunneling dominates the protium transfer below 400 K and the deuterium transfer below 300 K. We compared the lengths of the tunneling path and the classical path for the hydrogen atom transfer in the reaction HCl + Cl and quantified the corner cutting in this reaction. At low temperature, the tunneling path is about 40% shorter than the classical path. PMID- 28820193 TI - A modeling study of methane hydrate decomposition in contact with the external surface of zeolites. AB - The behavior of methane hydrate (MH) enclosed between the (010) surfaces of the silicalite-1 zeolite was studied by means of molecular dynamics simulations at temperatures of 150 and 250 K. Calculations reveal that the interaction with the hydrophilic surface OH groups destabilizes the clathrate structure of hydrate. While MH mostly conserves the structure in the simulation at the low temperature, thermal motion at the high temperature breaks the fragilized cages of H-bonded water molecules, thus leading to the release of methane. The dissociation proceeds in a layer-by-layer manner starting from the outer parts of the MH slab until complete hydrate decomposition. The released CH4 molecules are absorbed by the microporous solid, whereas water is retained at the surfaces of hydrophobic silicalite and forms a meniscus in the interlayer space. Methane uptake reaches 70% of the silicalite sorption capacity. The energy necessary for the endothermic MH dissociation is supplied by the exothermic methane absorption by the zeolite. PMID- 28820194 TI - Exceptional high selectivity of hydrogen/methane separation on a phosphonate based MOF membrane with exclusion of methane molecules. AB - A phosphonate-based metal-organic framework membrane was constructed on a porous anodic alumina membrane (PAAM) substrate for H2/CH4 separation for the first time. Owing to the ultra-micro pore windows, this membrane exhibited effective size exclusion for CH4 molecules but suitable permeance for H2 molecules, giving rise to an exceptional high H2/CH4 separation selectivity. PMID- 28820195 TI - Photoelectron spectroscopy of isolated luciferin and infraluciferin anions in vacuo: competing photodetachment, photofragmentation and internal conversion. AB - The electronic structure and excited-state dynamics of the ubiquitous bioluminescent probe luciferin and its furthest red-shifted analogue infraluciferin have been investigated using photoelectron spectroscopy and quantum chemistry calculations. In our electrospray ionization source, the deprotonated anions are formed predominantly in their phenolate forms and are directly relevant to studies of luciferin and infraluciferin as models for their unstable oxyluciferin and oxyinfraluciferin emitters. Following photoexcitation in the range 357-230 nm, we find that internal conversion from high-lying excited states to the S1(1pipi*) state competes efficiently with electron detachment. In infraluciferin, we find that decarboxylation also competes with direct electron detachment and internal conversion. This detailed spectroscopic and computational study defines the electronic structure and electronic relaxation processes of luciferin and infraluciferin and will inform the design of new bioluminescent systems and applications. PMID- 28820196 TI - On the mobility of carriers at semi-coherent oxide heterointerfaces. AB - In the quest to develop new materials with enhanced ionic conductivity for battery and fuel cell applications, nano-structured oxides have attracted attention. Experimental reports indicate that oxide heterointerfaces can lead to enhanced ionic conductivity, but these same reports cannot elucidate the origin of this enhancement, often vaguely referring to pipe diffusion at misfit dislocations as a potential explanation. However, this highlights the need to understand the role of misfit dislocation structure at semi-coherent oxide heterointerfaces in modifying carrier mobilities. Here, we use atomistic and kinetic Monte Carlo (KMC) simulations to develop a model of oxygen vacancy migration at SrTiO3/MgO interfaces, chosen because the misfit dislocation structure can be modified by changing the termination chemistry. We use atomistic simulations to determine the energetics of oxygen vacancies at both SrO and TiO2 terminated interfaces, which are then used as the basis of the KMC simulations. While this model is approximate (as revealed by select nudged elastic band calculations), it highlights the role of the misfit dislocation structure in modifying the oxygen vacancy dynamics. We find that oxygen vacancy mobility is significantly reduced at either interface, with slight differences at each interface due to the differing misfit dislocation structure. We conclude that if such semi-coherent oxide heterointerfaces induce enhanced ionic conductivity, it is not a consequence of higher carrier mobility. PMID- 28820197 TI - Helium-3 gas self-diffusion in a nematically ordered aerogel at low temperatures: enhanced role of adsorption. AB - We performed 3He gas diffusion measurements for the first time in a highly porous ordered Al2O3 aerogel sample at a temperature of 4.2 K using a nuclear magnetic resonance field gradient technique. A strong influence of 3He adsorption in the aerogel on self-diffusion is observed. The classical consideration of adsorptive gas diffusion in mesopores leads to anomalously high tortuosity factors. The application of a more sophisticated model than the simple combination of empirical two-phase diffusion and the Knudsen gas diffusion models is required to explain our results. Anisotropic properties of the aerogel are not reflected in the observed gas diffusion even at low gas densities where the anisotropic Knudsen regime of diffusion is expected. The observed gas densification indicates the influence of the aerogel attractive potential on the molecular dynamics, which probably explains the reduced diffusion process. Perhaps this behavior is common for any adsorptive gases in nanopores. PMID- 28820198 TI - Dark excitons and tunable optical gap in graphene nanodots. AB - By using a configuration interaction approach with up to the fifth excitations taken into account, we study the excitonic effect in the optical absorption in graphene nanodots. While the many-electron states are either singlet or doublet in a triangular nanodot system, all the excited singlet states are found to be optically dark in the absorption. These dark excitons are shown to originate mainly from the geometric symmetry of the system and would remain inactive even when the electron-hole or sublattice symmetry is broken. The first excited state in most of the cases is found to be a dark singlet; however, the order of dark and bright excitonic states is shown to be quite sensitive to the strength of electron-electron interactions such as the dielectric screening from the substrate. All the double degeneracies in the excitonic spectrum are found to be lifted when the rotational symmetry is absent such as in the case of a trapezoidal nanodot; however, the first excited state is shown to still remain a dark exciton when there is a strong screening effect. In order that the optical gap of a graphene nanodot can be efficiently tuned by its dielectric environment, the geometric symmetry is revealed to be a crucial factor. PMID- 28820199 TI - Tuning the copper(ii) coordination properties of cyclam by subtle chemical modifications. AB - The acid-base and copper(ii) coordination properties of three previously described cyclam derivatives are reported. Potentiometry, mass spectrometry, UV vis absorption spectroscopy, electrochemistry and theoretical calculations were combined to investigate the protonation and binding properties of Bn-cyclam-EtOH (L1), oxo-cyclam-EtOH (L2) and oxo-Bn-cyclam-EtOH (L3). These three cyclams are C functionalized by a hydroxyethyl pendant arm and display either one N-benzyl group and/or an amide replacing one macrocyclic secondary amine. The N-benzylic substitution has a significant effect of lowering the basicity of the corresponding protonation sites, while the presence of the amide function lowers the first protonation constants of the ligands. Regardless of the system considered, ESI mass spectrometry showed that only monocupric chelates are formed. Compared to the literature data, the stability constants measured by potentiometry (pCu L1 = 14.67; pCu L2 = 16.95; pCu L3 = 15.28) showed that: (i) the C-appended group has a negligible influence on Cu2+ complexation, (ii) N benzylation decreases the cupric complex stability, and (iii) the "oxo" function significantly increases the stability of the Cu2+ complex. Furthermore, UV-vis absorption versus pH measurements are in excellent agreement with the potentiometric titrations and show an equal involvement of the four nitrogen atoms in L1 and the strong binding properties of L2 and L3 related to the deprotonation of the carboxamide. The electrochemistry parameters determined by cyclic voltammetry showed the predominance of the [CuL1]2+, [CuL2-H]+ and [CuL3 H]+ species but also the irreversibility of the three Cu2+/Cu+ systems. Finally, density functional theory (DFT) and multiconfigurational CASSCF/NEVPT2 calculations confirmed that the protonation of the cupric complexes occurs at the oxygen atom of the amide group of the "oxo" ligands, which is in agreement with the experimental data. PMID- 28820200 TI - Statistical thermodynamics unveils the dissolution mechanism of cellobiose. AB - In the study of the cellulose dissolution mechanism opinion is still divided. Here, the solution interaction components of the most prominent hypotheses for the driving force of cellulose dissolution were evaluated quantitatively. Combining a rigorous statistical thermodynamic theory and cellobiose solubility data in the presence of chloride salts, whose cations progress in the Hofmeister series (KCl, NaCl, LiCl and ZnCl2), we have shown that cellobiose solubilization is driven by the preferential accumulation of salts around the solutes which is stronger than cellobiose hydration. Yet contrary to the classical chaotropy hypothesis, increasing salt concentration leads to cellobiose dehydration in the presence of the strongest solubilizer ZnCl2. However, thanks to cellobiose dehydration, cellobiose-salt interaction still remains preferential despite weakening salt accumulation. Based on such insights, the previous hypotheses based on hydrophobicity and polymer charging have also been evaluated quantitatively. Thus, our present study successfully paved a way towards identifying the basic driving forces for cellulose solubilization in a quantitative manner for the first time. When combined with unit additivity methods this quantitative information could lead to a full understanding of cellulose solubility. PMID- 28820201 TI - CO2 electroreduction performance of a single transition metal atom supported on porphyrin-like graphene: a computational study. AB - Searching for low-cost, efficient, and stable electrocatalysts for CO2 electroreduction (CO2ER) reactions is highly desirable for the reduction of CO2 emission and its conversion into useful products, but remains a great challenge. In this work, single transition metal atoms supported on porphyrin-like graphene catalysts, i.e., TMN4/graphene, acting as electrocatalysts for CO2 reduction were explored by means of comprehensive density functional theory (DFT) computations. Our results revealed that these anchored TM atoms possess high stability due to their strong hybridization with the unsaturated N atoms of the substrate and function as the active sites. On the basis of the calculated adsorption strength of CO2ER intermediates, we have identified that single Co, Rh, and Ir atoms exhibit superior catalytic activity towards CO2 reduction. In particular, CH3OH is the preferred product of CO2ER on the CoN4/graphene catalyst with an overpotential of 0.59 V, while the RhN4/graphene and IrN4/graphene catalysts prefer to reduce CO2 to CH2O with an overpotential of 0.35 and 0.29 V, respectively. Our work may open a new avenue for the development of catalytic materials with high efficiency for CO2 electroreduction. PMID- 28820202 TI - Electroluminescence of [Ru(bpy)3]2+ at gold and silver screen-printed electrodes followed by real-time spectroelectrochemistry. AB - Real-time spectroelectrochemistry of [Ru(bpy)3]2+ electroluminescence showed a strong correlation with electrochemical processes occurring at metal screen printed electrodes. Luminescence was quenched when the metal oxidation takes place, but it behaved differently when gold or silver were reduced, which suggests that changes in the structural characteristics of metallic electrodes play a decisive role in luminescence spectroelectrochemistry. PMID- 28820203 TI - Excess charge driven dissociative hydrogen adsorption on Ti2O4. AB - The mechanism of dissociative D2 adsorption on Ti2O4-, which serves as a model for an oxygen vacancy on a titania surface, is studied using infrared photodissociation spectroscopy in combination with density functional theory calculations and a recently developed single-component artificial force induced reaction method. Ti2O4- readily reacts with D2 under multiple collision conditions in a gas-filled ion trap held at 16 K forming a global minimum-energy structure (DO-Ti-(O)2-Ti(D)-O)-. The highly exergonic reaction proceeds quasi barrier-free via several intermediate species, involving heterolytic D2-bond cleavage followed by D-atom migration. We show that, compared to neutral Ti2O4, the excess negative charge in Ti2O4- is responsible for the substantial lowering of the D2 dissociation barrier, but does not affect the molecular D2 adsorption energy in the initial physisorption step. PMID- 28820204 TI - Droplet microfluidics for synthetic biology. AB - Synthetic biology is an interdisciplinary field that aims to engineer biological systems for useful purposes. Organism engineering often requires the optimization of individual genes and/or entire biological pathways (consisting of multiple genes). Advances in DNA sequencing and synthesis have recently begun to enable the possibility of evaluating thousands of gene variants and hundreds of thousands of gene combinations. However, such large-scale optimization experiments remain cost-prohibitive to researchers following traditional molecular biology practices, which are frequently labor-intensive and suffer from poor reproducibility. Liquid handling robotics may reduce labor and improve reproducibility, but are themselves expensive and thus inaccessible to most researchers. Microfluidic platforms offer a lower entry price point alternative to robotics, and maintain high throughput and reproducibility while further reducing operating costs through diminished reagent volume requirements. Droplet microfluidics have shown exceptional promise for synthetic biology experiments, including DNA assembly, transformation/transfection, culturing, cell sorting, phenotypic assays, artificial cells and genetic circuits. PMID- 28820205 TI - A comparative study of C2H2 adsorption properties in five isomeric copper-based MOFs based on naphthalene-derived diisophthalates. AB - In this work, five positional isomeric ligands consisting of two peripheral isophthalate moieties attached to the central naphthyl core in different ways, namely, 5,5'-(naphthyl-1,3-diyl) diisophthalate (H4L1), 5,5'-(naphthyl-1,4-diyl) diisophthalate (H4L2), 5,5'-(naphthyl-1,5-diyl) diisophthalate (H4L3), 5,5' (naphthyl-1,6-diyl) diisophthalate (H4L4) and 5,5'-(naphthyl-2,6-diyl) diisophthalate (H4L5), have been used to generate five copper-based MOF isomers. As revealed by single-crystal X-ray diffraction studies, they adopted two different types of topologies depending on the organic ligands: ssa topology for the MOFs ZJNU-71 and ZJNU-74 based on the ligands H4L1 and H4L4, respectively, and nbo topology for the MOFs ZJNU-72, ZJNU-73 and NOTT-103 derived from the ligands H4L2, H4L3 and H4L5, respectively. Furthermore, their C2H2 adsorption properties were systematically investigated, revealing that their different C2H2 uptake capacities can be mainly related to their different pore sizes since they possess the same chemical compositions and gravimetric densities of open metal sites. In particular, among these five MOF compounds investigated, ZJNU-71 exhibits the highest gravimetric C2H2 uptake of 208.1 cm3 (STP) g-1 at 295 K and 1 atm. The value is also among the highest reported for MOF compounds under the same conditions. This work provides a fundamental understanding of the impact of the positional isomerism of the organic ligands on the structures as well as gas adsorption properties of the resulting MOFs. PMID- 28820206 TI - A cross-platform metabolomics workflow for volume-restricted tissue samples: application to an animal model for polycystic kidney disease. AB - Metabolic profiling provides an unbiased view of the physiological status of an organism as a "function" of the metabolic composition of a measured sample. Here, we propose a simple LC-MS based workflow for metabolic profiling of volume restricted samples, namely individual 20 MUm-thick histological sections of a mouse kidney. The main idea of this workflow is to re-use the material after an RPLC-MS run, namely using the volume remaining in the vial after injection, and then introducing a phase changing step to enable HILIC-MS analysis. To test the applicability of the workflow and its ability to extract valuable biological information, we applied it to an animal model of polycystic kidney disease (PKD). PMID- 28820207 TI - Condensing the information in DNA with double-headed nucleotides. AB - A normal duplex holds as many Watson-Crick base pairs as the number of nucleotides in its constituent strands. Here we establish that single nucleotides can be designed to functionally imitate dinucleotides without compromising binding affinity. This effectively allows sequence information to be more compact and concentrated to fewer phosphates. PMID- 28820208 TI - Positive zeta potential of nanodiamonds. AB - In this paper, the origin of positive zeta potential exhibited by nanodiamond particles is explained. Positive zeta potentials in nano-structured carbons can be explained by the presence of graphitic planes at the surface, which leave oxygen-free Lewis sites and so promotes the suppression of acidic functional groups. Electron Microscopy and Raman Spectroscopy have been used to show that positive zeta potential of nanodiamond is only exhibited in the presence of sp2 carbon at the surface. PMID- 28820209 TI - NiZn double hydroxide nanosheet-anchored nitrogen-doped graphene enriched with the gamma-NiOOH phase as an activity modulated water oxidation electrocatalyst. AB - Herein, we report a facile solvothermal process to synthesize an active electrocatalyst for the oxygen evolution reaction (OER) in an alkaline medium by anchoring nanosheets of a NiZn double hydroxide over nitrogen doped reduced graphene oxide after enriching the system with the gamma-NiOOH phase. This catalyst possesses a thin, porous and open layered structure, which makes the system more efficient and accessible for a better electrochemical water oxidation reaction. Moreover, we experimentally demonstrated that incorporation of Zn via a single-step solvothermal method provides an easy approach to obtain plenty of exposed gamma-NiOOH phases to make the system more viable for OER with a small overpotential of 290 mV at 10 mA cm-2 and a Tafel slope of 44 mV per decade. In addition to this, the oxophilic nature of Zn in the (Zn)Ni-LDH/N-rGO catalyst helps to improve the long-term stability of the whole system. The obtained results open up possibilities for the design of future robust OER electrocatalysts by the use of very cheap and abundant materials like Ni and Zn in place of expensive Ir and Ru in the present commercial electrocatalysts. PMID- 28820210 TI - Spiers Memorial Lecture:. Progress and prospects of reticular chemistry. AB - Reticular chemistry, the linking of molecular building units by strong bonds to make crystalline, extended structures such as metal-organic frameworks (MOFs), zeolitic imidazolate frameworks (ZIFs), and covalent organic frameworks (COFs), is currently one of the most rapidly expanding fields of science. In this contribution, we outline the origins of the field; the key intellectual and practical contributions, which have led to this expansion; and the new directions reticular chemistry is taking that are changing the way we think about making new materials and the manner with which we incorporate chemical information within structures to reach additional levels of functionality. This progress is described in the larger context of chemistry and unexplored, yet important, aspects of this field are presented. PMID- 28820211 TI - Reactivity of the parent amido complexes of iridium with olefins: C-NH2 bond formation versus C-H activation. AB - Herein we report on the different chemical reactivity displayed by two mononuclear terminal amido compounds depending on the nature of the coordinated diene. Hence, treatment of amido-bridged iridium complexes [{Ir(MU-NH2)(tfbb)}3] (1; tfbb = tetrafluorobenzobarrelene) with dppp (dppp = bis(diphenylphosphane)propane) leads to the rupture of the amido bridges forming the mononuclear terminal amido compound [Ir(NH2)(dppp)(tfbb)] (3) in the first stage. On changing the reaction conditions, the formation of a C-NH2 bond between the amido moiety and the coordinated diene is observed and a new dinuclear complex [{Ir(1,2-eta2-4-kappa-C12H8F4N)(dppp)}2(MU-dppp)] (4) has been isolated. On the contrary, the diiridium amido-bridged complex [{Ir(MU-NH2)(cod)}2] (2; cod = 1,5-cyclooctadiene) in the presence of dppb (dppb = bis(diphenylphosphane)butane) allows the isolation of a mononuclear complex [Ir(1,2,3-eta3-6-kappa-C8H10)H(dppb)] (5), as a consequence of the extrusion of ammonia. The monitoring of the reaction of 2 with dppb (and dppp) allowed us to detect terminal amido complexes [Ir(NH2)(P-P)(cod)] (P-P = dppb (6), dppp (7)) in solution, as confirmed by an X-ray analysis of 7. Complex 7 was observed to evolve into hydrido species 5 at room temperature. DFT studies showed that C-H bond activation occurs through the deprotonation of one methylene fragment of the cod ligand by the highly basic terminal amido moiety instead of C-H oxidative addition to the Ir(i) center. PMID- 28820212 TI - Self-rectifying bipolar resistive switching memory based on an iron oxide and graphene oxide hybrid. AB - A resistive random access memory (RRAM) device with self-rectifying I-V characteristics was fabricated by inserting a silicon nitride (Si3N4) layer between the bottom electrode and solution-processed active material of an iron oxide-graphene oxide (FeOx-GO) hybrid. The fabricated Au/Ni/FeOx-GO/Si3N4/n+-Si memory device exhibited an excellent resistive switching ratio and a rectification ratio higher than 104. In the Au/Ni/FeOx-GO/Si3N4/n+-Si device, resistive switching occurs in both the FeOx-GO and Si3N4 layers separately, resulting in a highly uniform and stable switching performance. The resistive switching from a high resistance state to a low resistance state in the Au/Ni/FeOx-GO/Si3N4/n+-Si device occurs through a trap-assisted tunneling process in the Si3N4 layer, enabled by the FeOx-GO layer which prevents diffusion of the migrating Ni metal into the switching nitride layer. The intrinsic self rectifying characteristics of our memory devices arise from the asymmetric barriers for electrons tunneling into the traps of the Si3N4 layer which is sandwiched between the top and bottom electrodes having dissimilar work functions. Our study confirmed that integrating a suitable dielectric layer into the conventional RRAM cell is an innovative strategy to simplify the architecture and fabrication process to realize self-rectifying crossbar arrays. PMID- 28820213 TI - Chip-scale alignment of long DNA nanofibers on a patterned self-assembled monolayer. AB - Controlled alignment of long DNA nanofibers is challenging. This communication reports a method to align human genomic DNA with nearly unlimited length using lithographically produced micro-patterns of self-assembled monolayers (SAMs) with positively charged terminal groups. The micro-patterns act as local DNA reservoirs to supply DNAs for nanofiber formation, and can also stretch and align DNA nanofibers to form an ordered array by controlling the dewetting profile. By reducing the size and inter-patch distance of a micro-patch, a nearly uniform array of long DNA nanofibers can be patterned over a large area. A controlled motion of a DNA containing droplet allows for free patterning of DNA nanofibers and production of complex structures without a transfer process. Bending of DNA nanofibers due to local distortion of the contact line bridges more adjacent micro-patches and increases the chance of producing continuous nanofibers. The interplay between surface tension and electrostatic attraction of positively charged micro-patterns allows the production of long DNA nanofibers in a simple yet powerful way. PMID- 28820214 TI - Mediated water electrolysis in biphasic systems. AB - The concept of efficient electrolysis by linking photoelectrochemical biphasic H2 evolution and water oxidation processes in the cathodic and anodic compartments of an H-cell, respectively, is introduced. Overpotentials at the cathode and anode are minimised by incorporating light-driven elements into both biphasic reactions. The concepts viability is demonstrated by electrochemical H2 production from water splitting utilising a polarised water-organic interface in the cathodic compartment of a prototype H-cell. At the cathode the reduction of decamethylferrocenium cations ([Cp2*Fe(III)]+) to neutral decamethylferrocene (Cp2*Fe(II)) in 1,2-dichloroethane (DCE) solvent takes place at the solid electrode/oil interface. This electron transfer process induces the ion transfer of a proton across the immiscible water/oil interface to maintain electroneutrality in the oil phase. The oil-solubilised proton immediately reacts with Cp2*Fe(II) to form the corresponding hydride species, [Cp2*Fe(IV)(H)]+. Subsequently, [Cp2*Fe(IV)(H)]+ spontaneously undergoes a chemical reaction in the oil phase to evolve hydrogen gas (H2) and regenerate [Cp2*Fe(III)]+, whereupon this catalytic Electrochemical, Chemical, Chemical (ECC') cycle is repeated. During biphasic electrolysis, the stability and recyclability of the [Cp2*Fe(III)]+/Cp2*Fe(II) redox couple were confirmed by chronoamperometric measurements and, furthermore, the steady-state concentration of [Cp2*Fe(III)]+ monitored in situ by UV/vis spectroscopy. Post-biphasic electrolysis, the presence of H2 in the headspace of the cathodic compartment was established by sampling with gas chromatography. The rate of the biphasic hydrogen evolution reaction (HER) was enhanced by redox electrocatalysis in the presence of floating catalytic molybdenum carbide (Mo2C) microparticles at the immiscible water/oil interface. The use of a superhydrophobic organic electrolyte salt was critical to ensure proton transfer from water to oil, and not anion transfer from oil to water, in order to maintain electroneutrality after electron transfer. The design, testing and successful optimisation of the operation of the biphasic electrolysis cell under dark conditions with Cp2*Fe(II) lays the foundation for the achievement of photo-induced biphasic water electrolysis at low overpotentials using another metallocene, decamethylrutheneocene (Cp2*Ru(II)). Critically, Cp2*Ru(II) may be recycled at a potential more positive than that of proton reduction in DCE. PMID- 28820215 TI - How exfoliated graphene oxide nanosheets organize at the water interface: evidence for a spontaneous bilayer self-assembly. AB - In this study, we have characterized graphene oxide films formed at the air-water interface by X-ray reflectivity and grazing incidence X-ray diffraction using synchrotron sources. Surprisingly, the results of both measurements show that at non zero surface pressures, the film is organized as a bilayer of sheets interfaced between air and water with water molecule bridges. Such a spontaneous bilayer structure and its evolution with respect to the surface pressure has been observed for the first time. These results should allow precise control of the density of sheets deposited on the substrate when these films are transferred through the Langmuir Blodgett or Schaefer procedures. Indeed, graphene oxide keeps on attracting more and more attention, increasing the need for the production of well-controlled graphene oxide thin films due to its application in energy devices or in sensor domains. PMID- 28820216 TI - Criticality of the phase transition on stage two in a lattice-gas model of a graphite anode in a lithium-ion battery. AB - Herein, a Monte Carlo study within the canonical assembly has been applied to elucidate the lithium-ion phase transition order of a stage II lithium-graphite intercalation compound (LiC12) around the critical point. The results reveal a weakly first-order phase transition at 354.6 +/- 0.5 K via measurements that follows the power laws with effective exponents. The graphite-lithium system was emulated within a lattice-gas model, comprising specific insertion sites arranged in four parallel planes with a triangular geometry. Moreover, two different types of energetic interactions were used: a Lennard-Jones potential, for particle interactions in the same plane, and a power law potential that decreased with distance, for particles in different planes. The energy per site and order parameter distribution were used to classify the order of the transition. Furthermore, the order parameters, susceptibility, and heat capacity were computed and analyzed. PMID- 28820217 TI - Hysteretic spin crossover driven by anion conformational change. AB - A new air stable FeIII spin crossover (SCO) complex has been synthesized. The compound undergoes abrupt SCO near room temperature with T1/2 (?) = 244 K and T1/2 (?) = 278 K. Structural studies of the complex in the high spin and low spin state show that the strong cooperativity and thus the wide hysteresis is driven by an unprecedented anionic conformational change. PMID- 28820218 TI - Photophysical characterization and time-resolved spectroscopy of a anthradithiophene dimer: exploring the role of conformation in singlet fission. AB - Quantitative singlet fission has been observed for a variety of acene derivatives such as tetracene and pentacene, and efforts to extend the library of singlet fission compounds is of current interest. Preliminary calculations suggest anthradithiophenes exhibit significant exothermicity between the first optically allowed singlet state, S1, and 2 * T1 with an energy difference of >5000 cm-1. Given the fulfillment of this ingredient for singlet fission, here we investigate the singlet fission capability of a difluorinated anthradithiophene dimer (2ADT) covalently linked by a (dimethylsilyl)ethane bridge and derivatized by triisobutylsilylethynyl (TIBS) groups. Photophysical characterization of 2ADT and the single functionalized ADT monomer were carried out in toluene and acetone solution via absorption and fluorescence spectroscopy, and their photo-initiated dynamics were investigated with time-resolved fluorescence (TRF) and transient absorption (TA) spectroscopy. In accordance with computational predictions, two conformers of 2ADT were observed via fluorescence spectroscopy and were assigned to structures with the ADT cores trans or cis to one another about the covalent bridge. The two conformers exhibited markedly different excited state deactivation mechanisms, with the minor trans population being representative of the ADT monomer showing primarily radiative decay, while the dominant cis population underwent relaxation into an excimer geometry before internally converting to the ground state. The excimer formation kinetics were found to be solvent dependent, yielding time constants of ~1.75 ns in toluene, and ~600 ps in acetone. While the difference in rates elicits a role for the solvent in stabilizing the excimer structure, the rate is still decidedly long compared to most singlet fission rates of analogous dimers, suggesting that the excimer is neither a kinetic nor a thermodynamic trap, yet singlet fission was still not observed. The result highlights the sensitivity of the electronic coupling element between the singlet and correlated triplet pair states, to the dimer conformation in dictating singlet fission efficiency even when the energetic requirements are met. PMID- 28820219 TI - Mo doped Ni2P nanowire arrays: an efficient electrocatalyst for the hydrogen evolution reaction with enhanced activity at all pH values. AB - We report the successful synthesis of Mo doped Ni2P nanowires (NWs) on a Ni foam (NF) substrate by a two-step strategy, which could be used as an efficient and stable hydrogen evolution reaction (HER) electrocatalyst over the whole pH range (0-14). Electrochemical investigations demonstrated that Mo doping made the catalytic activity of Ni2P significantly enhanced. To achieve a current density of 10 mA cm-2, Mo-Ni2P NWs/NF required an overpotential of 67 mV in acidic solution, 78 mV in alkaline solution and 84 mV in neutral solution. It also showed superior stability with negligible activity decay after its use in the HER under different pH conditions for 24 h. Such excellent HER activity might originate from the synergistic effect between molybdenum (Mo) and nickel (Ni) atoms. The present work provides a valuable route for the design and synthesis of inexpensive and efficient all-pH HER electrocatalysts. PMID- 28820220 TI - Real-time plasmon spectroscopy study of the solid-state oxidation and Kirkendall void formation in copper nanoparticles. AB - Oxidation and corrosion reactions have a major effect on the application of non noble metals. Kinetic information and simple theoretical models are often insufficient for describing such processes in metals at the nanoscale, particularly in cases involving formation of internal voids (nano Kirkendall effect, NKE) during oxidation. Here we study the kinetics of solid-state oxidation of chemically-grown copper nanoparticles (NPs) by in situ localized surface plasmon resonance (LSPR) spectroscopy during isothermal annealing in the range 110-170 degrees C. We show that LSPR spectroscopy is highly effective in kinetic studies of such systems, enabling convenient in situ real-time measurements during oxidation. Change of the LSPR spectra throughout the oxidation follows a common pattern, observed for different temperatures, NP sizes and substrates. The well-defined initial Cu NP surface plasmon (SP) band red shifts continuously with oxidation, while the extinction intensity initially increases to reach a maximum value at a characteristic oxidation time tau, after which the SP intensity continuously drops. The characteristic time tau is used as a scaling parameter for the kinetic analysis. Evolution of the SP wavelength and extinction intensity during oxidation at different temperatures follows the same kinetics when the oxidation time is normalized to tau, thus pointing to a general oxidation mechanism. The characteristic time tau is used to estimate the activation energy of the process, determined to be 144 +/- 6 kJ mol-1, similar to previously reported values for high-temperature Cu thermal oxidation. The central role of the NKE in the solid-state oxidation process is revealed by electron microscopy, while formation of Cu2O as the major oxidation product is established by X-ray diffraction, XPS, and electrochemical measurements. The results indicate a transition of the oxidation mechanism from a Valensi-Carter (VC) to NKE mechanism with the degree of oxidation. To interpret the optical evolution during oxidation, Mie scattering solutions for metal core-oxide shell spherical particles are computed, considering formation of Kirkendall voids. The model calculations are in agreement with the experimental results, showing that the large red-shift of the LSPR band during oxidation is the result of Kirkendall voiding, thus establishing the major role of the NKE in determining the optical behavior of such systems. PMID- 28820221 TI - Real-time monitoring of plasmon-induced proton transfer of hypoxanthine in serum. AB - Intramolecular proton transfer of hypoxanthine, induced by application of a laser on the surface of a bare noble nanomaterial, was monitored in real time using surface-enhanced Raman spectroscopy (SERS). This monitoring demonstrated the dependence of the reaction on the identity of the nanomaterial and on the laser power density. The results pave the way for monitoring the proton transfer reaction in various relevant fields. In addition, we observed the presence of the proton transfer phenomenon of hypoxanthine in serum, providing a way to avoid the effect of proton transfer and hence achieve more reliable spectra of sera for clinical diagnosis. PMID- 28820222 TI - Quasi-zero-dimensional cobalt-doped CeO2 dots on Pd catalysts for alcohol electro oxidation with enhanced poisoning-tolerance. AB - Deactivation of an anode catalyst resulting from the poisoning of COad-like intermediates is one of the major problems for methanol and ethanol electro oxidation reactions (MOR & EOR), and remains a grand challenge towards achieving high performance for direct alcohol fuel cells (DAFCs). Herein, we report a new approach for the preparation of ultrafine cobalt-doped CeO2 dots (Co-CeO2, d = 3.6 nm), which can be an effective anti-poisoning promoter for Pd catalysts towards MOR and EOR in alkaline media. Compared to Pd/CeO2 and pure Pd, the hybrid Pd/Co-CeO2 nanocomposite catalyst exhibited a much enhanced activity and remarkable anti-poisoning ability for both MOR and EOR. The nanocomposite catalyst showed much higher mass activity (4*) than a state-of-the-art PtRu catalyst. The promotional mechanism was elucidated using extensive characterization and density-functional theory (DFT). A bifunctional effect of the Co-CeO2 dots was discovered to be due to (i) an enhanced electronic interaction between Co-CeO2 and Pd dots and (ii) the increased oxygen storage capacity of Co-CeO2 dots to facilitate the oxidation of COad. Therefore, the Pd/Co-CeO2 nanocomposite appears to be a promising catalyst for advanced DAFCs with low cost and high performance. PMID- 28820223 TI - A dual modal silver bumpy nanoprobe for photoacoustic imaging and SERS multiplexed identification of in vivo lymph nodes. AB - Multimodal imaging can provide complementary biomedical information which has huge potential in pre-clinical and clinical imaging and sensing. In this study, we introduce dual modal NIR silver bumpy nanoprobes for in vivo imaging and multiplexed detection of biomolecules by both photoacoustic imaging (PAI) and surface-enhanced Raman scattering (SERS) techniques. For this study, we used silica-coated silver bumpy nanoshell probes (AgNS@SiO2). AgNS@SiO2 have strong NIR-absorption and scattering properties compared with other nanostructures, and therefore, can be a good candidate for photoacoustic (PA) and SERS multimodal imaging. We obtained PA images of the skin and SLNs of rats by injecting various kinds of Raman-labeled AgNS@SiO2. Multiplexed identification of the injected AgNS@SiO2 was achieved by measuring SERS signals. AgNS@SiO2 have the potential to be applied in detecting cancer biomarkers by locating biomarkers quickly using PA imaging, and identification by multiplexed target measurement using SERS signals in vivo. PMID- 28820224 TI - Label-free fluorescent immunoassay for Cu2+ ion detection based on UV degradation of immunocomplex and metal ion chelates. AB - A mouse anti Cu2+-EDTA monoclonal antibody was used to capture EDTA chelated Cu2+ ions. Then UV radiation was utilized to degrade immunocomplex and Cu2+-EDTA chelates to release free Cu2+ ions. Based on their quenching effect to the fluorescent emission of CdSe/ZnS quantum dots, the released Cu2+ ions could be detected with ideal specificity and high sensitivity. PMID- 28820225 TI - Bilateral Thalamic Edema from Coexisting Choroid Plexus Arteriovenous Malformation and Sinus Thrombosis: Case Report. AB - Bilateral thalamic dysfunction secondary to venous congestion may result from either venous sinus thrombosis or high flow arteriovenous malformations or a combination of both. We present a case of bilateral thalamic edema resulting from concomitant choroid plexus arteriovenous malformation (AVM) and straight sinus thrombosis and describe our treatment approach. The patient presented with several weeks of progressive confusion and memory deficits. Magnetic resonance imaging and venography (MRI/ MRV) showed bilateral thalamic T2 hyperintensities and straight sinus thrombosis. Subsequent cerebral angiography revealed a choroid plexus AVM within the right lateral ventricle. The patient underwent surgical resection of the AVM resulting in postoperative resolution of bilateral thalamic edema on MRI and improvement of his confusion and memory deficits. This case demonstrates a rare example of reversible bilateral thalamic edema secondary to venous hypertension from both an AVM and sinus occlusion after appropriate treatment of the AVM. PMID- 28820226 TI - Women's status in disasters: A gap between experts' desk and affected fields of Iran. AB - Although international agreements have achieved significant milestones in the improvement of women's status, experiences from the fields show a discrepancy between words and actions. The aim of this brief communication was to identify the gap between experts' perceptions and the findings of a large qualitative field survey on women's status in the recent natural disasters of Iran. A total of 10 experts were asked to fill a checklist, which consisted of the concepts extracted from field data. The range of agreement between experts' perceptions and field data was between 40 and 100 percent. In conclusion, although literature review and international research papers can provide appropriate information for both experts and managers, meeting the various needs of women living in the affected regions requires field-based surveys. PMID- 28820228 TI - Use of geographical information system data for emergency management points of distribution analysis with POD Locator 2.0. AB - In 2010, the article Location and Analysis of Emergency Management Point of Distributions (PODs) for Hurricane Ike was published in the Journal of Emergency Management. Using a program titled point of distribution locator (POD Locator 1.0), the article reported a 46 percent improvement in positioning PODs over the locations selected by emergency managers during Hurricane Ike in 2008. While the program could produce more effective POD locations for a given situation, a major weakness of the program was the difficulty with which population and location data were manually entered into the program for subsequent analysis. This prevented organizations that could have otherwise benefited from the program from successfully utilizing it without additional training. This research effort focuses on the leveraging of readily available geographic information system (GIS) electronic data to address this problem. Analysis of the difference between the previous manual data entry method and the GIS assisted method was statistically significant. PMID- 28820227 TI - Emergency management leadership in 2030: Shaping the next generation meta-leader. AB - The complexities, interdependencies, and ambiguity that face next generation emergency management meta-leaders in an ever-evolving global community heighten the expectation and need for competencies that far exceed those common in practice today and necessitate the ability to move seamlessly through the dimensions of meta-leadership (ie, the person, the situation, and connectivity) while utilizing scientific-based evidence, information, resources, processes, and tools. The objective of this effort was to examine the recently developed next generation emergency management competencies through a meta-leadership lens by juxtaposing the competencies and the meta-leadership model. This resulted in a new framing of the skills and attributes within the meta-leadership model as they are relevant to each competency. Selected trends, drivers, and challenges were used to provide examples within each competency area of the utility of meta leadership to next generation emergency management practice. This effort also offers training and education implications for next generation emergency management meta-leaders. The examination of the new framing created in this effort is intended to prompt dialog and research within the emergency management practice and academic communities that furthers the practice and study of emergency management. PMID- 28820229 TI - Resilience mediates the relationship between social support and post-traumatic stress symptoms in police officers. AB - OBJECTIVE: Police officers in the New Orleans geographic area faced a number of challenges following Hurricane Katrina in 2005. DESIGN: This cross-sectional study examined gratitude, resilience, and satisfaction with life as mediators in the association between social support and post-traumatic stress disorder (PTSD) symptoms in 82 male and 31 female police officers. The Gratitude Questionnaire, Connor-Davidson Resilience Scale, Satisfaction with Life Scale, and the Interpersonal Support Evaluation List were used to measure gratitude, resilience, satisfaction with life, and social support, respectively. PTSD symptoms were measured using the PTSD Checklist-Civilian (PCL-C). Ordinary least square regression mediation analysis was used to estimate direct and indirect effects among gratitude, resilience, satisfaction with life, social support, and PTSD symptoms. All models were adjusted for age, alcohol, race, and previous military experience. RESULTS: Mean PCL-C symptoms were 29.1 (standard deviation [SD] = 14.4) for females and 27.9 (SD = 12.1) for males. There was no direct relationship between social support and PTSD symptoms (c9 = -0.041; 95% confidence interval [CI] = -0.199, 0.117) independent of the indirect effect through resilience (effect = -0.038; 95%CI = -0.099, -0.002). Neither gratitude (effect = -0.066; 95% CI = -0.203, 0.090) nor satisfaction with life (effect = 0.036, 95% CI = -0.131, 0.046) contribute to the indirect effect. CONCLUSIONS: These results indicate that resilience mediates the relationship between social support and symp-toms of PTSD. Targeting social support and resilience in officers may facilitate reduction of PTSD symptoms. PMID- 28820230 TI - Are you ready? Crisis leadership in a hyper-VUCA environment. AB - The current hyper-volatile, -uncertain, -complex, and -ambiguous (VUCA) threat environment demands a more cohesive support structure for crisis leaders who may be faced with crises of increasing magnitude and frequency and, in some instances, multiple crisis events simultaneously. The project team investigates the perceptions of crisis leaders regarding establishing a crisis leader advisor position for crisis leaders to benefit from their experience while prosecuting crisis response activities. The team linked hyper-VUCA crises, crisis response frameworks, meta-leadership, crisis leader attributes, and advisor attributes. The overall goal of the project is to increase the ability of the crisis leaders to more effectively and efficiently navigate crisis events resulting in more efficient and effective response and recovery. Three research questions were developed to assess the following: thoughts of integrating a crisis leader advisor position; development of a crisis leader advisor certification program; and attributes of crisis leader advisors. A qualitative research methodology using a phenomenological approach was employed. Forty-one participants were purposefully selected and administered a short, on-line survey consisting of 11 questions. Data were analyzed using percentage analysis, weighted sums, and inductive thematic analysis. The project team found an overwhelming support for the crisis leader advisor position and the crisis leader advisor certification program. Additionally, experience and trustworthiness ranked among the top sought after attributes of a crisis leader advisor. The team recommendations included (1) implement a crisis leaders advisor guide/framework; (2) create a formal crisis leader advisor position in national incident management system; (3) implement a crisis leader advisor certification framework; (4) benchmark established advisor programs; and (5) implement a framework to match leaders and advisors. PMID- 28820231 TI - Interventions for treating persistent pain in survivors of torture. AB - BACKGROUND: Persistent (chronic) pain is a frequent complaint in survivors of torture, particularly but not exclusively pain in the musculoskeletal system. Torture survivors may have no access to health care; where they do, they may not be recognised when they present, and the care available often falls short of their needs. There is a tendency in state and non-governmental organisations' services to focus on mental health, with poor understanding of persistent pain, while survivors may have many other legal, welfare, and social problems that take precedence over health care. OBJECTIVES: To assess the efficacy of interventions for treating persistent pain and associated problems in survivors of torture. SEARCH METHODS: We searched for randomised controlled trials (RCTs) published in any language in CENTRAL, MEDLINE, Embase, Web of Science, CINAHL, LILACS, and PsycINFO, from database inception to 1 February 2017. We also searched trials registers and grey literature databases. SELECTION CRITERIA: RCTs of interventions of any type (medical, physical, psychological) compared with any alternative intervention or no intervention, and with a pain outcome. Studies needed to have at least 10 participants in each arm for inclusion. DATA COLLECTION AND ANALYSIS: We identified 3578 titles in total after deduplication; we selected 24 full papers to assess for eligibility. We requested data from two completed trials without published results.We used standard methodological procedures expected by Cochrane. We assessed risk of bias and extracted data. We calculated standardised mean difference (SMD) and effect sizes with 95% confidence intervals (CI). We assessed the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: Three small published studies (88 participants) met the inclusion criteria, but one had been retracted from publication because of ethical problems concerned with confidentiality and financial irregularities. Since these did not affect the data, the study was retained in this review. Despite the search including any intervention, only two types were represented in the eligible studies: two trials used cognitive behavioural therapy (CBT) with biofeedback versus waiting list on unspecified persistent pain (58 participants completed treatment), and one examined the effect of complex manual therapy versus self-treatment on low back pain (30 participants completed treatment). Excluded studies were largely either not RCTs or did not report pain as an outcome.There was no difference for the outcome of pain relief at the end of treatment between CBT and waiting list (two trials, 58 participants; SMD -0.05, 95% CI -1.23 to 1.12) (very low quality evidence); one of these reported a three-month follow-up with no difference between intervention and comparison (28 participants; SMD -0.03, 95% CI -0.28 to 0.23) (very low quality evidence). The manual therapy trial also reported no difference between complex manual therapy and self-treatment (30 participants; SMD -0.48, 95% CI 9.95 to 0.35) (very low quality evidence). Two studies reported dropouts, one with partial information on reasons; none of the studies reported adverse effects.There was no information from any study on the outcomes of use of analgesics or quality of life.Reduction in disability showed no difference at the end of treatment between CBT and waiting list (two trials, 57 participants; SMD 0.39, 95% CI -1.17 to 0.39) (very low quality evidence); one of these reported a three-month follow-up with no difference between intervention and comparison (28 participants; SMD 0, 95% CI -0.74 to 0.74) (very low quality evidence). The manual therapy trial reported superiority of complex manual therapy over self treatment for reducing disability (30 participants; SMD -1.10, 95% CI - 1.88 to 0.33) (very low quality evidence).Reduction in distress showed no difference at the end of treatment between CBT and waiting list (two trials, 58 participants; SMD 0.07, 95% CI -0.46 to 0.60) (very low quality evidence); one of these reported a three-month follow-up with no difference between intervention and comparison (28 participants; SMD -0.24, 95% CI -0.50 to 0.99) (very low quality evidence). The manual therapy trial reported superiority of complex manual therapy over self-treatment for reducing distress (30 participants; SMD -1.26, 95% CI - 2.06 to -0.47) (very low quality evidence).The risk of bias was considered high given the small number of trials, small size of trials, and the likelihood that each was underpowered for the comparisons it reported. We primarily downgraded the quality of the evidence due to small numbers in trials, lack of intention-to-treat analyses, high unaccounted dropout, lack of detail on study methods, and CIs around effect sizes that included no effect, benefit, and harm. AUTHORS' CONCLUSIONS: There is insufficient evidence to support or refute the use of any intervention for persistent pain in survivors of torture. PMID- 28820232 TI - Recognizing and managing adrenal disorders in the emergency department AB - Primary and secondary adrenal insufficiency are underrecognized conditions among emergency department patients, affecting an estimated 10% to 20% of critically ill patients. The signs and symptoms of cortisol deficit can be nonspecific and wide-ranging, and identification and swift treatment with stress-dosing of hydrocortisone is vital to avoid life-threatening adrenal crisis. Laboratory evaluation focuses on identification of electrolyte abnormalities typical of adrenal insufficiency, and while additional testing may depend on the type and severity of symptoms, it should not delay corticosteroid replacement. This issue provides recommendations on effective management of patients presenting with adrenal insufficiency, with particular attention to the management of critically ill and septic patients, pregnant patients, and children. PMID- 28820233 TI - Regioselective Synthesis of Eight-Armed Cyclosiloxane Amphiphile for Functional 2D and 3D Assembly Motifs. AB - A crystalline tetramethylcyclotetrasiloxane (TMCS)-derived amphiphile was regioselectively synthesized with eight peripheral hydrophilic amide groups and hydrophobic dodecyl chains by Pt(0)-catalyzed hydrosilylation and amidation reactions. The as-synthesized materials showed ordered lamellar structure formation in the powder form. It also exhibits superior two-dimensional (2D) monolayer formation properties at the air-water interface with unexpectedly high collapse surface pressure and elastic modulus. The monolayers act as two dimensional building blocks with finely controllable thickness on a several nanometer scale irrespective of the substrate type and properties. The amphiphile forms nanofibers spontaneously by good-poor solvent strategies, which contributes to porous three-dimensional (3D) structures possessing superhydrophobic surface wettability. PMID- 28820234 TI - Halide Welding for Silver Nanowire Network Electrode. AB - We developed a method of chemically welding silver nanowires (AgNWs) using an aqueous solution containing sodium halide salts (NaF, NaCl, NaBr, or NaI). The halide welding was performed simply by immersing the as-coated AgNW film into the sodium halide solution, and the resulting material was compared with those obtained using two typical thermal and plasmonic welding techniques. The halide welding dramatically reduced the sheet resistance of the AgNW electrode because of the strong fusion among nanowires at each junction while preserving the optical transmittance. The dramatic decrease in the sheet resistance was attributed to the autocatalytic addition of dissolved silver ions to the nanowire junction. Unlike thermal and plasmonic welding methods, the halide welding could be applied to AgNW films with a variety of deposition densities because the halide ions uniformly contacted the surface or junction regions. The optimized AgNW electrodes exhibited a sheet resistance of 9.3 Omega/sq at an optical transmittance of 92%. The halide welding significantly enhanced the mechanical flexibility of the electrode compared with the as-coated AgNWs. The halide-welded AgNWs were successfully used as source-drain electrodes in a transparent and flexible organic field-effect transistor (OFET). This simple, low-cost, and low power consumption halide welding technique provides an innovative approach to preparing transparent electrodes for use in next-generation flexible optoelectronic devices. PMID- 28820235 TI - TiO2-Containing Carbon Derived from a Metal-Organic Framework Composite: A Highly Active Catalyst for Oxidative Desulfurization. AB - A new metal-organic framework (MOF) composite consisting of Ti- and Zn-based MOFs (ZIF-8(x)@H2N-MIL-125; in brief, ZIF(x)@MOF) was designed and synthesized. The pristine MOF [H2N-MIL-125 (MOF)]- and an MOF-composite [ZIF(30)@MOF]-derived mesoporous carbons consisting of TiO2 nanoparticles were prepared by pyrolysis (named MDC-P and MDC-C, respectively). MDC-C showed a higher surface area, larger pore sizes, and larger mesopore volumes than MDC-P. In addition, the TiO2 nanoparticles on MDC-C have more uniform shapes and sizes and are smaller than those of MDC-P. The obtained MDC-C and MDC-P [together with MOF, ZIF(30)@MOF, pure/nanocrystalline TiO2, and activated carbon] were applied in the oxidative desulfurization reaction of dibenzothiophene in a model fuel. The MDC-C, even with a lower TiO2 content than that of MDC-P, showed an outstanding catalytic performance, especially with a very low catalyst dose (i.e., a very high quantity of dibenzothiophene was converted per unit weight of the catalyst), fast kinetics (~3 times faster than that for MDC-P), and a low activation energy (lower than that for any reported catalyst) for the oxidation of dibenzothiophene. The large mesopores of MDC-C and the well-dispersed/small TiO2 might be the dominant factors for the superior catalytic conversions. The oxidative desulfurization of other sulfur-containing organic compounds with various electron densities was also studied with MDC-C to understand the mechanism of catalysis. Moreover, the MDC-C catalyst can be reused many times in the oxidative desulfurization reaction after a simple washing with acetone. Finally, composing MOFs and subsequent pyrolysis is suggested as an effective way to prepare a catalyst with well dispersed active sites, large pores, and high mesoporosity. PMID- 28820236 TI - Regulatory Mechanism of Mycotoxin Tenuazonic Acid Production in Pyricularia oryzae. AB - Tenuazonic acid (TeA) is a mycotoxin produced by the rice blast fungus Pyricularia oryzae and some plant pathogenic fungi. We previously demonstrated that TeA is biosynthesized in P. oryzae by TeA synthetase 1 (TAS1) and that its production is induced by osmo-sensory MAPK-encoding gene (OSM1) deletion or the addition of 1% DMSO to cultures; however, the regulatory mechanisms of TeA production were unknown. Here, we identify a Zn(II)2-Cys6-type transcription factor in the upstream region of TAS1, which is encoded by TAS2 and regulates TeA production. We also find PoLAE1, which is a homologue of LaeA, a regulator of fungal secondary metabolism. Analysis of PoLAE1 deletion and overexpression strains indicate that PoLAE1 drives TeA production. We also demonstrate that two TeA-inducing signals, 1% DMSO addition and OSM1 deletion, were transmitted through PoLAE1. Our results indicate that TeA production is regulated by two specific regulators, TAS2 and PoLAE1, in P. oryzae. PMID- 28820237 TI - Conformal Silk-Azobenzene Composite for Optically Switchable Diffractive Structures. AB - The use of biomaterials as optical components has recently attracted attention because of their ease of functionalization and fabrication, along with their potential use when integrated with biological materials. We present here an observation of the optical properties of a silk-azobenzene material (Azosilk) and demonstrate the operation of an Azosilk/PDMS composite structure that serves as a conformable and switchable optical diffractive structure. Characterization of thermal and isomeric properties of the device, along with its overall performance, is presented in terms of diffractive characteristics and response times. The ease of manufacturing and functionalization opens a promising avenue for rapid device prototyping and interfaces of expanded utility. PMID- 28820238 TI - Combustion-Assisted Photonic Annealing of Printable Graphene Inks via Exothermic Binders. AB - High-throughput and low-temperature processing of high-performance nanomaterial inks is an important technical challenge for large-area, flexible printed electronics. In this report, we demonstrate nitrocellulose as an exothermic binder for photonic annealing of conductive graphene inks, leveraging the rapid decomposition kinetics and built-in energy of nitrocellulose to enable versatile process integration. This strategy results in superlative electrical properties that are comparable to extended thermal annealing at 350 degrees C, using a pulsed light process that is compatible with thermally sensitive substrates. The resulting porous microstructure and broad liquid-phase patterning compatibility are exploited for printed graphene microsupercapacitors on paper-based substrates. PMID- 28820239 TI - Capping Layer (CL) Induced Antidamping in CL/Py/beta-W System (CL: Al, beta-Ta, Cu, beta-W). AB - For achieving ultrafast switching speed and minimizing dissipation losses, the spin-based data storage device requires a control on effective damping (alphaeff) of nanomagnetic bits. Incorporation of interfacial antidamping spin orbit torque (SOT) in spintronic devices therefore has high prospects for enhancing their performance efficiency. Clear evidence of such an interfacial antidamping is found in Al capped Py(15 nm)/beta-W(tW)/Si (Py = Ni81Fe19 and tW = thickness of beta-W), which is in contrast to the increase of alphaeff (i.e., damping) usually associated with spin pumping as seen in Py(15 nm)/beta-W(tW)/Si system. Because of spin pumping, the interfacial spin mixing conductance (g??) at Py/beta-W interface and spin diffusion length (lambdaSD) of beta-W are found to be 1.63(+/ 0.02) * 1018 m-2 (1.44(+/-0.02) * 1018 m-2) and 1.42(+/-0.19) nm (1.00(+/-0.10) nm) for Py(15 nm)/beta-W(tW)/Si (beta-W(tW)/Py(15 nm)/Si) bilayer systems. Other different nonmagnetic capping layers (CL), namely, beta-W(2 nm), Cu(2 nm), and beta-Ta(2,3,4 nm) were also grown over the same Py(15 nm)/beta-W(tW). However, antidamping is seen only in beta-Ta(2,3 nm)/Py(15 nm)/beta-W(tW)/Si. This decrease in alphaeff is attributed to the interfacial Rashba like SOT generated by nonequilibrium spin accumulation subsequent to the spin pumping. Contrary to this, when interlayer positions of Py(15 nm) and beta-W(tW) is interchanged irrespective of the fixed top nonmagnetic layer, an increase of alphaeff is observed, which is ascribed to spin pumping from Py to beta-W layer. PMID- 28820241 TI - Interactions of Verkade's Superbase with Strong Lewis Acids: From Labile Mono- and Binuclear Lewis Acid-Base Complexes to Phosphenium Cations. AB - A series of mono- and binuclear Lewis acid-base complexes of the formulas N[CH2CH2N(Pri)]3P->LA [LA = BH3 (8), Ga(C6F5)3 (10), GaCl3 (11)], LA< N[CH2CH2N(Pri)]3P [LA = Al(C6F5)3 (6a), AlMe3 (6b), AlEt3 (6c), AlBui3 (6d), BF3 (13)], and LA<-N[CH2CH2N(Pri)]3P->LA [Lewis acid (LA) = Al(C6F5)3 (7a), AlMe3 (7b), AlEt3 (7c), AlBui3 (7d), AlCl3 (7e), BH3 (9)] were generated from reactions of Verkade's base, N[CH2CH2N(Pri)]3P (1), with various boron-, aluminum-, and gallium-containing Lewis acids, and characterized by multinuclear NMR spectroscopy. {N[CH2CH2N(Pri)]3P->C7H7}[BF4] (5) was synthesized via the treatment of 1 with [C7H7][BF4]. The reaction of 1 with B(C6F5)3, followed by the addition of [Ph3C]2[B12Cl12], gave rise to the rearranged borate salt [PN4C9H17(Pri)2][B12Cl12] (3), while treating 1 with [Ph3C]2[B12Cl12] exclusively afforded {N[CH2CH2N(Pri)]3PH}2[B12Cl12] (4). Reactions of 1 with 2 equiv of GaCl3 and BF3, respectively, afforded the novel phosphenium gallate and borate salts 12a, 12b, and 15. The solid-state structures of 1, 3-5, 6b, 7a, 7b, 7e, 8, 10, 11, 12b, 13, and 15 were determined by X-ray crystallography. PMID- 28820240 TI - The Interaction between the Third Type III Domain from Fibronectin and Anastellin Involves beta-Strand Exchange. AB - Anastellin is a small recombinant fragment derived from the extracellular matrix protein fibronectin; it comprises the first type III (FN3) domain without the two N-terminal beta-strands. It inhibits angiogenesis, tumor growth, and metastasis in mouse models and requires endogenous fibronectin for its in vivo anti angiogenic activity. It binds to fibronectin in vitro and converts the soluble protein to insoluble fibrils that structurally and functionally resemble fibronectin fibrils deposited in the extracellular matrix by cells. Anastellin binds to several FN3 domains in fibronectin, but how it interacts with these domains and why the interactions lead to aggregation of fibronectin are not well understood. In this work, we investigated the interaction between anastellin and the third FN3 domain (3FN3) from fibronectin. We show that anastellin binds with high affinity to a peptide comprising the two N-terminal beta-strands from 3FN3, and we present here the structure of the resulting complex. The peptide and anastellin form a composite FN3 domain, with the two N-terminal beta-strands from 3FN3 bound in place of the two beta-strands that are missing in anastellin. We also demonstrate using disulfide cross-linking that a similar interaction involving the two N-terminal beta-strands of 3FN3 occurs when intact 3FN3 binds to anastellin. 3FN3 adopts a compact globular fold in solution, and to interact with anastellin in a manner consistent with our data, it has to open up and expose a beta-strand edge that is not accessible in the context of the folded domain. PMID- 28820242 TI - Expanding the Scope of Ligand Substitution from [M(S2C2Ph2] (M = Ni2+, Pd2+, Pt2+) To Afford New Heteroleptic Dithiolene Complexes. AB - The scope of direct substitution of the dithiolene ligand from [M(S2C2Ph2)2] [M = Ni2+ (1), Pd2+ (2), Pt2+ (3)] to produce heteroleptic species [M(S2C2Ph2)2Ln] (n = 1, 2) has been broadened to include isonitriles and dithiooxamides in addition to phosphines and diimines. Collective observations regarding ligands that cleanly produce [M(S2C2Ph2)Ln], do not react at all, or lead to ill-defined decomposition identify soft sigma donors as the ligand type capable of dithiolene substitution. Substitution of MeNC from [Ni(S2C2Ph2)(CNMe)2] by L provides access to a variety of heteroleptic dithiolene complexes not accessible from 1. Substitution of a dithiolene ligand from 1 involves net redox disproportionation of the ligands from radical monoanions, -S*SC2Ph2, to enedithiolate and dithione, the latter of which is an enhanced leaving group that is subject to further irreversible reactions. PMID- 28820244 TI - Rapid and Quantitative Measurement of Single Quantum Dots in a Sheath Flow Cuvette. AB - Semiconducting quantum dots (QDs) are finding a wide range of biomedical applications due to their intense fluorescence brightness and long-term photostability. Here, we report precise quantification of the fluorescence intensity of single QDs on a laboratory-built high-sensitivity flow cytometer (HSFCM). The nearly uniform illumination of the particles at the intense portions of the radiation field resulted in narrowly distributed signals with high signal to-noise ratios. By analysis of thousands of QDs individually in as little time as 1 min, intrinsic polydispersity was quickly revealed in a statistically robust manner. Applications of this technique in QD quality assessment, study of metal ion influence, and evaluation of aggregation upon biomolecule coupling are presented. Moreover, an accurate measurement of the QD particle concentration was achieved via single-particle enumeration. HSFCM is believed to provide a powerful characterization tool for QD synthesis and application development. PMID- 28820243 TI - Interpreting Reverse Transcriptase Termination and Mutation Events for Greater Insight into the Chemical Probing of RNA. AB - Chemical probing has the power to provide insight into RNA conformation in vivo and in vitro, but interpreting the results depends on methods to detect the chemically modified nucleotides. Traditionally, the presence of modified bases was inferred from their ability to halt reverse transcriptase during primer extension and the locations of termination sites observed by electrophoresis or sequencing. More recently, modification-induced mutations have been used as a readout for chemical probing data. Given the variable propensity for mismatch incorporation and read-through with different reverse transcriptases, we examined how termination and mutation events compare to each other in the same chemical probing experiments. We found that mutations and terminations induced by dimethyl sulfate probing are both specific for methylated bases, but these two measures have surprisingly little correlation and represent largely nonoverlapping indicators of chemical modification data. We also show that specific biases for modified bases depend partly on local sequence context and that different reverse transcriptases show different biases toward reading a modification as a stop or a mutation. These results support approaches that incorporate analysis of both termination and mutation events into RNA probing experiments. PMID- 28820245 TI - 1,2-Migration of N-Diarylboryl Imidazol-2-ylidene through Intermolecular Radical Process. AB - 1,2-Boryl migration of N-boryl N-heterocyclic carbene to 2-boryl imidazole is proposed to proceed through generation and recombination of two radical intermediates, namely, a neutral diarylboron radical and a N-heterocyclic carbene radical. Crossover experiments suggest that these two radical species are stable enough to escape solvent cages and recombine intermolecularly. The presence of radical intermediates is further supported by spin trapping experiments. Besides, the coordination of Li+ cation is found to be critical for the stability of the NHC radical. PMID- 28820246 TI - Manganese-Catalyzed Upgrading of Ethanol into 1-Butanol. AB - Biomass-derived ethanol is an important renewable feedstock. Its conversion into high-quality biofuels is a promising route to replace fossil resources. Herein, an efficient manganese-catalyzed Guerbet-type condensation reaction of ethanol to form 1-butanol was explored. This is the first example of upgrading ethanol into higher alcohols using a homogeneous non-noble-metal catalyst. This process proceeded selectively in the presence of a well-defined manganese pincer complex at the parts per million (ppm) level. The developed reaction represents a sustainable synthesis of 1-butanol with excellent turnover number (>110 000) and turnover frequency (>3000 h-1). Moreover, mechanistic studies including control experiments, NMR spectroscopy, and X-ray crystallography identified the essential role of the "N-H moiety" of the manganese catalysts and the major reaction intermediates related to the catalytic cycle. PMID- 28820247 TI - DFT Study on C-F Bond Activation by Group 14 Dialkylamino Metalylenes: A Competition between Oxidative Additions versus Substitution Reactions. AB - The C-F bond activation of pentafluoropyridine (PFP) by group 14 dialkylamino metalylenes has been studied employing DFT calculations. Emphasis is placed on the group 14 central atom (M = SiII, GeII, and SnII) and substituents (-NMe2, NiPr2, -Cl, -NH2, and -PH2) dependent switching of oxidative addition to the metathesis/substitution reaction route, using state-of-the-art theoretical methods (M062X/def2-QZVP(SMD)//M062X/def2-TZVP) to provide a systematic classification of the individual mode of reactions. Moreover, an energy decomposition analysis (EDA) is implemented to get a brief insight into the physical factors that control the activation barriers originating via the different mode of reactions, viz., oxidative addition and metathesis routes. The key finding is that the distortion of PFP is the principal guiding factor in the oxidative addition reaction, while distortions imposed on both the PFP and metalylenes are inevitable toward the origin of the metathesis reaction barrier. The preferable oxidative addition reaction over metathesis of substituted silylenes can be explained on the basis of electron concentration and the HOMO LUMO gap between the reacting substrates. However, the dramatic switch between oxidative addition and metathesis reaction in substituted germylenes depends on both the electronic and steric nature of the substituents. Similar observations are also noted for the reactivity of substituted stannylenes. PMID- 28820248 TI - Modulating Wettability of Layered Materials by Controlling Ligand Polar Headgroup Dynamics. AB - Integrating functionalized 2D materials into multilayer device architectures increasingly requires understanding the behavior of noncovalently adsorbed ligands during solution processing. Here, we demonstrate that the headgroup dynamics of polymerized monolayers of functional alkanes can be controlled to modify surface wetting and environmental interactions. We find that headgroup dynamics are sensitive to the position of the polymerizable diyne group; thus, the polymerization process, typically used to stabilize the noncovalent monolayer, can also be used to selectively destabilize chain-chain interactions near the headgroups, making the headgroups more solvent-accessible and increasing surface hydrophilicity. Conversely, interactions with divalent ions can be used to tether headgroups in-plane, decreasing surface hydrophilicity. Together, these results suggest a strategy for the rational design of 2D chemical interfaces in which the polymerization step reconfigures the monolayer to promote the desired environmental interactions. PMID- 28820249 TI - Correction to "A Microporous Aluminosilicate with 12-, 12-, and 8-Ring Pores and Isolated 8-Ring Channels". PMID- 28820250 TI - Coordination and Thermodynamics of Trivalent Curium with Malonate at Increased Temperatures: A Spectroscopic and Quantum Chemical Study. AB - The complexation of Cm(III) with malonate is studied by time-resolved laser fluorescence spectroscopy (TRLFS) in the temperature range from 25 to 90 degrees C. Three complexes ([Cm(Mal)n]3-2n, n = 1, 2, 3) are identified and their molar fractions are determined as a function of the ligand concentration, the ionic strength, and the temperature. A general shift of the chemical equilibrium toward higher complexes with increasing temperature is observed, with the [CmMal3]3- complex forming only at T > 40 degrees C. The conditional stability constants (log K'n(T)) are calculated and extrapolated to Im = 0 with the specific ion interaction theory (SIT). The log Kn0(T) values increase by 0.25 to 0.5 logarithmic unit in the studied temperature range. The temperature dependency of the log K degrees n(T) is fitted by the integrated Van't Hoff equation, yielding the thermodynamic functions DeltarH degrees m and DeltarS degrees m. The results show positive reaction enthalpies and entropies for each complexation step. While the DeltarH degrees n values are constant within their error range, the DeltarS degrees n values decrease successively with each ligand added. To explain this effect, quantum chemical calculations of binding energies and bond lengths of the different Cm(III) malonate species are performed. The results show that malonate is capable of stabilizing its end-on coordination mode to some extent by forming hydrogen bonds to first-shell water molecules. As a result, an equilibrium between side-on and end-on coordinated malonate ligands is present, with the latter becoming more pronounced for the higher complexes due to steric reasons. PMID- 28820251 TI - Aluminum Doped MCM-41 Nanoparticles as Platforms for the Dual Encapsulation of a CO-Releasing Molecule and Cisplatin. AB - Mesoporous silica Al-MCM-41 nanoparticles have been used, for the first time, as vehicles for the single and dual encapsulation of the cationic CO-releasing molecule (CORM) [Mn(1,4,7-triazacyclononane)(CO)3]+ (ALF472+) and the well-known antineoplastic drug, cis-[PtCl2(NH3)2] (cisplatin). Thus, two new hybrid materials, namely, ALF472@Al-MCM-41 and ALF472-cisplatin@Al-MCM-41, have been isolated and fully characterized. The results reveal that the presence of CORM molecules enhances cisplatin loading 3-fold, yielding a cargo of 0.45 mmol g-1 of ALF472+ and 0.12 mmol g-1 of the platinum complex for ALF472-cisplatin@Al-MCM-41. It is worth noting that ALF472@Al-MCM-41 shows a good dispersion in phosphate buffered saline solution, while the dual hybrid material slightly aggregates in this simulated physiological medium (hydrodynamic size: 112 +/- 23 and 336 +/- 50 nm, respectively). In addition, both hybrid materials (ALF472@Al-MCM-41 and ALF472-cisplatin@Al-MCM-41) behave as photoactive CO-releasing materials, delivering 0.25 and 0.11 equiv of CO, respectively, after 24 h and exhibiting a more controlled CO delivery than that of the free CORM. Finally, metal leaching studies have confirmed the good retention capacity of Al-MCM-41 toward the potentially toxic manganese fragments (86% of retention after 72 h) as well as the low release of cisplatin (ca. 7% after 72 h). PMID- 28820252 TI - Computational Study on M1/POM Single-Atom Catalysts (M = Cu, Zn, Ag, and Au; POM = [PW12O40]3-): Metal-Support Interactions and Catalytic Cycle for Alkene Epoxidation. AB - Geometrical structures, metal-support interactions, and infrared (IR) spectroscopy of a series of M1/POM (M = Cu, Zn, Ag, and Au; POM = [PW12O40]3-) single-atom catalysts (SACs), and catalytic cycle for alkene epoxidation catalyzed by M1/POM SACs were studied using density functional theory (DFT) calculations. The calculations demonstrate that the most probable anchoring sties for the isolated single atoms studied here in the M1/POM SACs are the fourfold hollow sites on the surface of POM support. The bonding interaction between single metal atom and surface of POM support comes from the molecular orbitals with a mixture of d atomic orbital of metal and 2p group orbital of surface oxygen atoms of POM cage. The calculated adsorption energy of isolated metal atoms in these M1/POM SACs indicates that the early transition metals (Cu and Zn) have high thermal stability. The DFT-derived IR spectra show that the four characteristic peaks of free Keggin-type POM structure split into six because of introduction of isolated metal atom. Compared with other metal atoms, the Zn1/POM SAC has the high reactivity for activity of dioxygen molecule, because the dioxygen moiety in Zn1/POM SAC displays O2-. radical feature with [POM4-.Zn2+O2 .]3- configuration. Finally, a catalytic cycle for ethylene epoxidation by O2 catalyzed by Zn1/POM SAC was proposed based on our DFT calculations. Supported noble-metal SACs are among the most important catalysts currently. However, noble metals are expensive and of limited supply. Development of non-noble-metal SACs is of essential importance. Therefore, the reported Zn1/POM SAC would be very useful to guide the search for SACs into non-noble metals. PMID- 28820253 TI - Bioinorganic Chemistry of Parkinson's Disease: Affinity and Structural Features of Cu(I) Binding to the Full-Length beta-Synuclein Protein. AB - Alterations in the levels of copper in brain tissue and formation of alpha synuclein (alphaS)-copper complexes might play a key role in the amyloid aggregation of alphaS and the onset of Parkinson's disease (PD). Recently, we demonstrated that formation of the high-affinity Cu(I) complex with the N terminally acetylated form of the protein alphaS substantially increases and stabilizes local conformations with alpha-helical secondary structure and restricted motility. In this work, we performed a detailed NMR-based structural characterization of the Cu(I) complexes with the full-length acetylated form of its homologue beta-synuclein (betaS), which is colocalized with alphaS in vivo and can bind copper ions. Our results show that, similarly to alphaS, the N terminal region of betaS constitutes the preferential binding interface for Cu(I) ions, encompassing two independent and noninteractive Cu(I) binding sites. According to these results, betaS binds the metal ion with higher affinity than alphaS, in a coordination environment that involves the participation of Met-1, Met-5, and Met-10 residues (site 1). Compared to alphaS, the shift of His from position 50 to 65 in the N-terminal region of betaS does not change the Cu(I) affinity features at that site (site 2). Interestingly, the formation of the high affinity betaS-Cu(I) complex at site 1 in the N-terminus promotes a short alpha helix conformation that is restricted to the 1-5 segment of the AcbetaS sequence, which differs with the substantial increase in alpha-helix conformations seen for N-terminally acetylated alphaS upon Cu(I) complexation. Our NMR data demonstrate conclusively that the differences observed in the conformational transitions triggered by Cu(I) binding to AcalphaS and AcbetaS find a correlation at the level of their backbone dynamic properties; added to the potential biological implications of these findings, this fact opens new avenues of investigations into the bioinorganic chemistry of PD. PMID- 28820254 TI - Blockade of Asparagine Endopeptidase Inhibits Cancer Metastasis. AB - Asparagine endopeptidase (AEP), also called legumain, is highly expressed in various solid tumors, promoting cancer cell invasion, migration, and metastasis. It has been proposed to be a prognostic marker and therapeutic target for cancer treatment. However, an effective nonpeptide, small-molecule inhibitor against this protease has not yet been identified. Here we show that a family of xanthine derivatives selectively inhibit AEP and suppress matrix metalloproteinase (MMP) cleavage, leading to the inhibition of cancer metastasis. Through structure activity relationship (SAR) analysis, we obtained an optimized lead compound (38u) that represses breast cancer invasion and migration. Chronic treatment of nude mice, which had been inoculated with MDA-MB-231 cells, with inhibitor 38u via oral administration robustly inhibits breast cancer lung metastasis in a dose dependent manner, associated with blockade of MMP-2 by AEP. Therefore, our study supports that 38u might act as a potent and specific AEP inhibitor useful for cancer treatment. PMID- 28820256 TI - Comparison of Physicochemical Membrane Properties of Vesicles Modified with Guanidinium Derivatives. AB - Bilayer vesicles have garnered considerable research attention as molecular vehicles capable of noncovalent interaction with biomolecules via electrostatic and hydrophobic bonds and van der Waals interactions. Guanidinium strongly interacts with phosphate groups. Thus, guanidinium modification of vesicles helps intensify the interaction between lipid membranes and nucleic acids. Here, two kinds of guanidinium derivatives, stearylguanidinium (SG) and myristoylarginine (MA), were synthesized and incorporated into 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphatidylcholine (POPC) vesicles. Differences in their membrane properties were evaluated using Fourier transform infrared spectroscopy, Raman spectroscopy, and the fluorescent probes 1,6-diphenyl-1,3,5-hexatriene (DPH), 6-lauroyl-2 dimethylaminonaphthalene (Laurdan), and 2-p-toluidinylnaphthalene-6-sulfonate (TNS). The increased SG ratio increased overall hydrophobicity and lipid packing density compared to POPC vesicles, and SG-modified vesicles successfully attracted and then denatured negatively charged tRNAs (tRNAs). In contrast, MA modified vesicles did not affect the stiffness of POPC membranes, wherein no conformational change in tRNAs was observed in the presence of POPC/MA vesicles. Analyses of the pH-dependent fluorescence emission of TNS suggested that SG and MA molecules render the membrane surfaces cationic and anionic, respectively, which was also revealed by zeta potential measurements. Our results enabled the construction of a model of the headgroup orientation of zwitterionic POPC molecules controlled by modification with guanidinium derivatives. The results also indicate the possibility to regulate the interaction and conformation of biological molecules, such as nucleic acid. PMID- 28820255 TI - Discovery of a Potent Inhibitor Class with High Selectivity toward Clostridial Collagenases. AB - Secreted virulence factors like bacterial collagenases are conceptually attractive targets for fighting microbial infections. However, previous attempts to develop potent compounds against these metalloproteases failed to achieve selectivity against human matrix metalloproteinases (MMPs). Using a surface plasmon resonance-based screening complemented with enzyme inhibition assays, we discovered an N-aryl mercaptoacetamide-based inhibitor scaffold that showed sub micromolar affinities toward collagenase H (ColH) from the human pathogen Clostridium histolyticum. Moreover, these inhibitors also efficiently blocked the homologous bacterial collagenases, ColG from C. histolyticum, ColT from C. tetani, and ColQ1 from the Bacillus cereus strain Q1, while showing negligible activity toward human MMPs-1, -2, -3, -7, -8, and -14. The most active compound displayed a more than 1000-fold selectivity over human MMPs. This selectivity can be rationalized by the crystal structure of ColH with this compound, revealing a distinct non-primed binding mode to the active site. The non-primed binding mode presented here paves the way for the development of selective broad-spectrum bacterial collagenase inhibitors with potential therapeutic application in humans. PMID- 28820257 TI - Residues Comprising the Enhanced Aromatic Sequon Influence Protein N Glycosylation Efficiency. AB - N-Glycosylation is an important co- and/or post-translational modification that occurs on the vast majority of the one-third of the mammalian proteome that traverses the cellular secretory pathway, regulating glycoprotein folding and functions. Previous studies on the sequence requirements for N-glycosylation have yielded the Asn-X-Ser/Thr (NXS/T) sequon and the enhanced aromatic sequons (Phe-X Asn-X-Thr and Phe-X-X-Asn-X-Thr), which can be efficiently N-glycosylated. To further investigate the influence of sequence variation on N-glycosylation efficiency in the context of a five-residue enhanced aromatic sequon, we used the human CD2 adhesion domain (hCD2ad) to screen the i-2, i-1, i+1, and i+2 residues flanking Asn at the i position. We found that aromatic residues, especially Trp, and sulfur-containing residues at the i-2 position improved N-glycosylation efficiency, while positively charged residues such as Arg suppressed N glycosylation. Thiol, hydroxyl, and aliphatic-based side chains at the i-1 position had higher N-glycosylation efficiency, and Cys, in particular, compensated for the negative effect of Arg at the i-2 position. Small residues and Ser at the i+1 position increased the likelihood of N-glycosylation, and Thr is better than Ser at the i+2 position. We devised an algorithm for prediction of N-glycosylation efficiency using the SAS software, employing the 120 sequences studied as a training set. We then introduced the optimized-enhanced aromatic sequons into other glycoproteins and observed an enhancement in N-glycan occupancy that was further supported by modeling the high-affinity interaction between the optimized sequence on hCD2ad and a human oligosaccharyltransferase (OST) subunit. The findings in this study provide useful information for enhancing or suppressing N-glycosylation at a site of interest and valuable data for a better understanding of OST-catalyzed N-glycosylation. PMID- 28820258 TI - Transition-Metal-Free Trifluoromethylation of Aldehyde Derivatives with Sodium Trifluoromethanesulfinate. AB - A metal-free and cost-effective synthetic protocol for the trifluoromethylation of N,N-disubstituted hydrazones with Langlois's reagent (CF3SO2Na) to afford the corresponding functionalized trifluoromethyl ketone hydrazones has been established. It is proposed that a radical/SET mechanism proceeding via a trifluoroalkyl radical may be involved in the reaction. Applications of the methodology in industry will be found and the development of new methods for trifluoromethylation with Langlois's reagent will be continued in our laboratory. PMID- 28820259 TI - Oxidant-Controlled C-sp2/sp3-H Cross-Dehydrogenative Coupling of N-Heterocycles with Benzylamines. AB - Oxidant controlled ionic liquid mediated cross-dehydrogenative coupling (CDC) of benzylamines with N-heterocycles having sp2 or sp3 carbon resulted in the formation of C-benzoylated or alkenylated products. Benzoylation of N heterocycles occurs via (NH4)2S2O8 catalyzed benzoyl radical formation. An oxidative alkenylation of N-heterocycles having C-sp3 carbon (2-methylaza-arenes) occurs via deamination of benzylamine followed by C-sp3-H bond activation in high stereoselectivity. Both benzoylation and alkenylation protocols are metal-free, green, simple, efficient, and tolerate a wide variety of functional groups. PMID- 28820260 TI - Thermally Induced Self-Assembly and Cyclization of l-Leucyl-l-Leucine in Solid State. AB - Thermal treatment of oligopeptides is one of the methods for synthesis of organic nanostructures. However, heating may lead not only to self-assembly of the initial molecules, but also to chemical reactions resulting in the formation of new unexpected nanostructures or change in the properties of the existing ones. In the present work, the reaction of cyclization of dipeptide l-leucyl-l-leucine in solid state under heating was studied. The change in morphology of dipeptide thin film and formation of nanostructures after heating was visualized using atomic force microscopy. This method also was used for demonstration of differences in self-assembly of linear and cyclic dipeptides. The chemical structure of reaction product was characterized by NMR spectrometry, FTIR spectroscopy and GC-MS analysis. Kinetic parameters of cyclization were estimated within the approaches of the nonisothermal kinetics ("model-free" kinetics and linear regression methods for detection of topochemical equation). The results of present work are useful for explanation the changes in the properties of nanostructures based on short-chain oligopeptides, notably leucyl-leucine, after thermal treatment, as well as for the synthesis of cyclic oligopeptides. PMID- 28820261 TI - Correction for Discovery of a Human Neuromedin U Receptor 1-Selective Hexapeptide Agonist with Enhanced Serum Stability. PMID- 28820262 TI - Single-Layer Tl2O: A Metal-Shrouded 2D Semiconductor with High Electronic Mobility. AB - The first metal-shrouded two-dimensional semiconductor, single-layer Tl2O, is discussed from first principles. It is thermally and dynamically stable, has a low cleavage energy calling for exfoliation from layered Tl2O bulk, and has a very small interface mismatch compared to (001) Tl metal. Single-layer Tl2O exhibits a direct bandgap of 1.56 eV and a very high charge carrier mobility of 4.3 * 103 cm2 V-1 s-1. The metal-shrouded 2D semiconductor promises interesting applications in 2D electronics. An intriguing layer-thickness-dependent direct-to indirect bandgap transition is observed, and contrary to early literature, the bulk is also a semiconductor. PMID- 28820263 TI - Hydrodynamic Steering in Protein Association Revisited: Surprisingly Minuscule Effects of Considerable Torques. AB - We investigate the previously postulated hydrodynamic steering phenomenon, resulting from complication of molecular shapes, its magnitude and possible relevance for protein-ligand and protein-protein diffusional encounters, and the kinetics of diffusion-controlled association. We consider effects of hydrodynamic interactions in a prototypical model system consisting of a cleft enzyme and an elongated substrate, and real protein-protein complexes, that of barnase and barstar, and human growth hormone and its binding protein. The kinetics of diffusional encounters is evaluated on the basis of rigid-body Brownian dynamics simulations in which hydrodynamic interactions between molecules are modeled using the bead-shell method for detailed description of molecular surfaces, and the first-passage-time approach. We show that magnitudes of steering torques resulting from the hydrodynamic coupling of associating molecules, evaluated for the studied systems on the basis of the Stokes-Einstein type relations for arbitrarily shaped rigid bodies, are comparable with magnitudes of torques resulting from electrostatic interactions of binding partners. Surprisingly, however, unlike in the case of electrostatic torques that strongly affect the diffusional encounter, overall effects of hydrodynamic steering torques on the association kinetics, while clearly discernible in Brownian dynamics simulations, are rather minute. We explain this result as a consequence of the thermal agitation of the binding partners. Our finding is relevant for the general understanding of a wide spectrum of molecular processes in solution but there is also a more practical aspect to it if one considers the low level of shape detail of models that are usually employed to evaluate hydrodynamic interactions in particle-based Stokesian and Brownian dynamics simulations of multicomponent biomolecular systems. Results described in the current work justify, in part at least, such a low-resolution description. PMID- 28820264 TI - Ir-Catalyzed Enantioselective, Intramolecular Silylation of Methyl C-H Bonds. AB - We report highly enantioselective intramolecular, silylations of unactivated, primary C(sp3)-H bonds. The reactions form dihydrobenzosiloles in high yields with excellent enantioselectivities by functionalization of enantiotopic methyl groups under mild conditions. The reaction is catalyzed by an iridium complex generated from [Ir(COD)OMe]2 and chiral dinitrogen ligands that we recently disclosed. The C-Si bonds in the enantioenriched dihydrobenzosiloles were further transformed to C-Cl, C-Br, C-I, and C-O bonds in final products. The potential of this reaction was illustrated by sequential C(sp3)-H and C(sp2)-H silylations and functionalizations, as well as diastereoselective C-H silylations of a chiral, natural-product derivative containing multiple types of C-H bonds. Preliminary mechanistic studies suggest that C-H cleavage is the rate-determining step. PMID- 28820265 TI - Pressure-Induced Polymerization and Disproportionation of Li2C2 Accompanied with Irreversible Conductivity Enhancement. AB - Li2C2 has the highest theoretical capacity (1400 mA.h.g-1) as the electrode material for Li-ion battery, but suffers from low conductivity. Here we found that under external pressure its conductivity was irreversibly enhanced by 109 fold. To explain that, we performed X-ray diffraction, Raman, IR, gas chromatography-mass spectrometry, and theoretical investigations under external pressure. We found that the C22- anions approached to each other and polymerized upon compression, which is responsible for the irreversible enhancement of conductivity. The polymer has a ribbon structure and disproportionates into Li3C4 (Li2-0.5C2) ribbon structure, Li6C3 (Li propenide) and Li4C3 (Li allenide) upon decompression, implying that the carbon skeletal is highly electrochemically active. Our work reported polymerized Li2C2 for the first time, demonstrated that applying pressure is an effective method to prepare novel Li-C frameworks, and hence shed light on the search for novel carbon-based electrode materials. PMID- 28820266 TI - On-Surface Synthesis of Porous Carbon Nanoribbons from Polymer Chains. AB - We demonstrate the on-surface synthesis of porous carbon nanoribbons on Ag(111) via a preprogrammed isomerization of conformationally flexible polymer chains followed by dehydrogenation reactions using thermal annealing. The carbon chains are fabricated by polymerization of prochiral 1,3,5-tris(3-bromophenyl)benzene (mTBPB) directly on the surface using an Ullmann-type reaction. At room temperature, mTBPB partially self-assembles in halogen-bonded 2D networks, which transform into organometallic chains and rings after debromination. The chain and ring formation is facilitated by conformational switching from a C3h to Cs symmetry of mTBPB via rotation of m-phenylene units. The high conformational selectivity toward Cs-conformers is templated by the twofold coordination to Ag adatoms. After thermally induced covalent-linking through aryl-aryl coupling, well-ordered nanoporous chains are created. Finally, the rotation of single phenylene units in combination with dehydrogenation cross-linking reactions within the polymer chains leads to the unexpected formation of porous carbon nanoribbons. We unveil the reaction mechanism in a low-temperature scanning tunneling microscopy study and demonstrate that the rotation of m-phenylene units is a powerful design tool to promote structural control in the synthesis of cyclic covalent organic nanostructures on metal surfaces. PMID- 28820267 TI - Causes and Significance of Increased Compound Potency in Cellular or Physiological Contexts. AB - Compound potency is a key metric that is often used to drive medicinal chemistry programs. Compound potency is also taken into account when identifying the mechanism of action of compounds whose pharmacological target is unknown, particularly when these compounds are identified in phenotypic screens. Often compound potency is determined from assays using recombinantly generated, purified protein. It is well understood in the medicinal chemistry community that potency measured with recombinant enzyme and potency measured in cell may not entirely coincide. Decreases in cellular vs recombinant potency are often anticipated or explainable. What is less often realized is that compound potency can increase in a cellular environment due to several factors including cellular metabolism of compounds, protein-protein interactions, post-translational modifications, and asymmetric intracellular localization of compound. Here we discuss these factors and highlight examples where increases in cellular compound potency were critical to the development of probes or drugs. PMID- 28820268 TI - Automated Transition State Theory Calculations for High-Throughput Kinetics. AB - A scarcity of known chemical kinetic parameters leads to the use of many reaction rate estimates, which are not always sufficiently accurate, in the construction of detailed kinetic models. To reduce the reliance on these estimates and improve the accuracy of predictive kinetic models, we have developed a high-throughput, fully automated, reaction rate calculation method, AutoTST. The algorithm integrates automated saddle-point geometry search methods and a canonical transition state theory kinetics calculator. The automatically calculated reaction rates compare favorably to existing estimated rates. Comparison against high level theoretical calculations show the new automated method performs better than rate estimates when the estimate is made by a poor analogy. The method will improve by accounting for internal rotor contributions and by improving methods to determine molecular symmetry. PMID- 28820269 TI - Reaction phenotyping to assess victim drug-drug interaction risks. AB - INTRODUCTION: Reaction phenotyping provides critical information regarding the fraction metabolized (fm) of drug candidates. It has become increasingly important in drug discovery and development as it can be used to assess victim drug-drug interaction potential, guide structural modification to reduce fm, inform clinical study design, predict individual variability in pharmacokinetics, and evaluate the impact of genetic polymorphisms. Areas covered: The currently available in vitro and in vivo methods for reaction phenotyping are summarized along with their advantages, limitations and timings for application during the different stages of drug discovery and development. Challenges of reaction phenotyping for low clearance compounds, non-Cytochrome P450 (CYP) enzymes, extrahepatic contribution and atypical kinetics are highlighted and various approaches are discussed. Expert opinion: Certain areas of reaction phenotyping remain challenging with the current state of the science. In order to better define fm in this challenging space, there needs to be future advances in selective inhibitors and specific substrate reactions for non-CYP enzymes, availability of high quality and low cost recombinant enzymes, tissue distribution and in vitro-in vivo correlation, scaling factors for extrahepatic enzymes and the next generation of low clearance tools. PMID- 28820270 TI - Second line treatment options for pancreatic cancer. AB - INTRODUCTION: Patients with advanced pancreatic cancer (APC) refractory to first line therapy have a dismal prognosis and limited therapeutic options, with only one option consisting of nanoliposomal irinotecan in combination with fluorouracil and folinic acid which was approved by FDA based upon results of the phase III NAPOLI-1 study. Areas covered: We performed a literature search for relevant published clinical trials, abstracts of trials in progress and ongoing or planned trials for the second line treatment of APC using Pubmed.com, ClinicalTrials.gov and American Society of Clinical Oncology (ASCO) abstract search as sources. We present an in-depth analysis of the phase I-III clinical trials determining the role and efficacy of second-line treatment in patients with APC. We also describe ongoing studies and rationale for future investigation. Expert opinion: Despite advances in first-line therapy such as gemcitabine/nab-paclitaxel and FOLFIRINOX in APC, median overall survival remains less than 12 months, highlighting the need to develop second-line therapies. In order to establish much needed effective second-line treatment options, we need cooperative efforts among institutions and community practices in enrolling these refractory patients in clinical trials. It should be emphasized that in addition to chemotherapy options, all patients should have the opportunity to consult with nutritionist, social worker and palliative care health providers to assist with goals of care, symptom management and end of life discussions. PMID- 28820271 TI - Cam Deformities and Limited Hip Range of Motion Are Associated With Early Osteoarthritic Changes in Adolescent Athletes: A Prospective Matched Cohort Study. AB - BACKGROUND: The natural history of femoroacetabular impingement (FAI) remains incompletely understood. In particular, there is limited documentation of joint damage in adolescent patients with limited range of motion (LROM) of the hip, which is commonly associated with FAI. PURPOSE: To evaluate changes in magnetic resonance imaging (MRI), radiographs, and clinical examinations over 5 years in a group of athletes from a wide variety of sports with asymptomatic LROM of the hip compared with matched controls. STUDY DESIGN: Cohort study (prognosis); Level of evidence, 2. METHODS: The authors screened 226 male and female athletes aged 12 to 18 years presenting for preparticipation sports physical examinations. Using a goniometer, we identified 13 participants with at least one hip having internal rotation <10 degrees with the hip flexed to 90 degrees . Overall, 21 of 26 hips (81%) had internal rotation <10 degrees . These participants were age- and sex matched to 13 controls with internal rotation >10 degrees . At the time of enrollment, all participants were asymptomatic and underwent a complete hip examination and radiographic imaging with radiographs (anteroposterior [AP] and von Rosen views) and non-arthrogram MRI. Participants returned at 5-year follow up and underwent repeat hip examinations, imaging (AP and lateral radiographs and non-arthrogram MRI), and hip function questionnaires. MRI scans were classified as "normal" versus "abnormal" based on the presence of any of 13 scored chondral, labral, or osseous abnormalities. Comparisons between the LROM group and control group were performed using generalized linear models (either linear, logistic, or log-binomial regression as appropriate for the outcome) with generalized estimating equations to account for the within-participant correlation due to patients having both hips included. Relative risk (RR) estimates are reported with 95% CIs. RESULTS: At the time of study enrollment, 16 of 26 hips (62%) in the LROM group had abnormal MRI findings within the acetabular labrum or cartilage compared with 8 of 26 hips (31%) in the control group (RR, 2.0; 95% CI, 0.95-4.2; P = .067). The mean alpha angle measured from radial MRI sequences was 58 degrees in the LROM group versus 44 degrees in the control group ( P < .0001). In the LROM group, 13 of 26 hips (50%) had a positive anterior impingement sign, whereas 0 of 26 hips (0%) had a positive anterior impingement sign in the control group. At 5-year follow-up, 18 of 19 hips (95%) in the LROM group had abnormal MRI findings compared with 14 of 26 hips (54%) in the control group (RR, 1.7; 95% CI, 1.1-2.7; P = .014). New or progressive findings were documented on MRI in 15 of 20 hips in the LROM group compared with 8 of 26 hips in the control group (RR, 2.4; 95% CI, 1.2-4.8; P = .011). Six of 22 hips (27%) in the LROM group progressed from Tonnis grade 0 to Tonnis grade 1 in degenerative changes, whereas all 26 hips in the control group remained at Tonnis grade 0 on hip radiographs. In the LROM group, 11 of 22 hips (50%) had a positive anterior impingement sign, whereas 1 of 26 hips (4%) had a positive anterior impingement sign in the control group. A cam deformity (alpha angle >55 degrees on lateral radiographs) was present in 20 of 22 hips (91%) in the LROM group and 12 of 26 hips (46%) in the control group ( P = .0165). The following variables at baseline were associated with an increased risk of degenerative changes at 5-year follow-up for the entire cohort: decreased hip internal rotation, positive anterior impingement sign, decreased hip flexion, increased alpha angle, and presence of a cam lesion. CONCLUSION: At 5 years, young athletes with LROM of the hip showed increased progressive degenerative changes on MRI and radiographs compared with matched controls. Although the majority of these participants remained asymptomatic, those with features of FAI had radiographic findings consistent with early osteoarthritis. These outcomes suggest that more aggressive screening and counseling of young active patients may be helpful to prevent hip osteoarthritis in those with FAI. PMID- 28820272 TI - A Comparison of Clinical Outcomes After Unilateral or Bilateral Hip Arthroscopic Surgery: Age- and Sex-Matched Cohort Study. AB - BACKGROUND: A significant number of patients undergoing hip arthroscopic surgery for femoroacetabular impingement (FAI) have bilateral deformities and may require surgery for both hips. PURPOSE: To compare outcomes between patients who underwent bilateral hip arthroscopic surgery to a matched cohort of patients who underwent unilateral hip arthroscopic surgery. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A consecutive series of patients who underwent primary hip arthroscopic surgery for FAI by a single fellowship-trained surgeon from January 2012 to January 2014 and had a minimum follow-up of 2 years were evaluated. Patients who underwent staged bilateral hip arthroscopic surgery were identified and matched 1:2 to patients who underwent unilateral hip arthroscopic surgery based on age, sex, and body mass index (BMI). Demographic, preoperative, and postoperative variables were compared between the groups. RESULTS: Forty three patients in the bilateral group were matched with 86 patients in the unilateral group based on sex (24 female [56%] vs 48 female [56%], respectively; P > .99), age (28.6 +/- 10.8 years vs 28.9 +/- 10.8 years, respectively; P = .88), and BMI (24.8 +/- 5.8 kg/m2 vs 24.8 +/- 4.0 kg/m2, respectively; P = .98). There were no significant preoperative demographic or radiographic differences between the groups. Both groups demonstrated significant preoperative to postoperative improvements in the Hip Outcome Score-Activities of Daily Living (HOS-ADL), Hip Outcome Score-Sports Subscale (HOS-SS), and modified Harris Hip Score (mHHS) ( P < .0001 for all). When compared with patients in the unilateral group, patients who underwent bilateral hip arthroscopic surgery had less improvement in mHHS and pain scores. Sixty-five (76%) patients in the unilateral group achieved the minimum clinically important difference (MCID) for the mHHS compared with 21 (49%) in the bilateral group ( P = .03), while 64 (74%) patients achieved the patient acceptable symptomatic state (PASS) for the mHHS compared with 22 (51%) in the bilateral group ( P = .02). Patients in the bilateral group with greater than 10 months between surgical procedures had lower postoperative HOS-ADL scores ( P = .04) and lower improvement in pain and HOS-SS scores ( P < .0001 and P = .05, respectively). CONCLUSION: Patients who underwent unilateral and bilateral hip arthroscopic surgery for FAI had improved functional outcomes after 2 years. However, patients who underwent bilateral hip arthroscopic surgery had less improvement in their mHHS and pain scores compared with those who underwent unilateral hip arthroscopic surgery but no differences in HOS-ADL, HOS SS, or satisfaction scores. Patients in the bilateral group with longer than 10 months between surgical procedures had lower outcome scores than patients who underwent their second surgical procedure within 10 months of their primary surgery. PMID- 28820273 TI - Psychological distress, health and treatment-related factors among individuals initiating ART in Oromia, Ethiopia. AB - HIV diagnosis may be a source of psychological distress. Late initiation of antiretroviral therapy (ART) and treatment-related beliefs may intensify psychological distress among those recently diagnosed. This analysis describes the prevalence of psychological distress among people living with HIV (PLWH) and examines the association of recent HIV diagnosis, late ART initiation and treatment-related beliefs with psychological distress. The sample includes 1175 PLWH aged 18 or older initiating ART at six HIV clinics in Ethiopia. Psychological distress was assessed with Kessler Psychological Distress Scale. Scores >= 29 were categorized as severe psychological distress. Individuals who received their first HIV diagnosis in the past 90 days were categorized as recently diagnosed. Multivariable logistic regression modeled the association of recent diagnosis, late ART initiation and treatment-related beliefs on severe psychological distress, controlling for age, sex, education, area of residence, relationship status, and health facility. Among respondents, 29.5% reported severe psychological distress, 46.6% were recently diagnosed and 31.0% initiated ART late. In multivariable models, relative to those who did not initiate ART late and had longer time since diagnosis, odds of severe psychological distress was significantly greater among those with recent diagnosis and late ART initiation (adjusted OR [aOR]: 1.9 [95% CI 1.4, 2.8]). Treatment-related beliefs were not associated with severe psychological distress in multivariable models. Severe psychological distress was highly prevalent, particularly among those who were recently diagnosed and initiated ART late. Greater understanding of the relationship between psychological distress, recent diagnosis, and late ART initiation can inform interventions to reduce psychological distress among this population. Mental health screening and interventions should be incorporated into routine HIV clinical care from diagnosis through treatment. PMID- 28820274 TI - Arterial stiffness in preschool children. PMID- 28820275 TI - In vitro anti-acne activity of phytoactives from the stem bark of Artocarpus hirsutus Lam. and characterisation of pyranocycloartobiloxanthone A as a mixture of two anomers. AB - This study is aimed to isolate the phytoactives from the stem bark of Artocarpus hirsutus and evaluate their in vitro anti-acne activity. The ethanolic stem bark extract of A. hirsutus provided two major phytoactive constituents: (i) pyranocycloartobiloxanthone A, (1) and (ii) Artonine E, (2) whose structures were determined by NMR and MS spectroscopic analysis. The present study is the first to report compound 1 as a mixture of two anomers (alpha and beta), approximately 70:30 ratio. Both compounds 1 and 2 were isolated for the first time from this plant. In vitro anti-acne activity of compounds 1 and 2 were evaluated by agar well diffusion method and the minimum inhibition was determined by broth micro dilution method. The result of anti-microbial activity (MIC = 2.0 MUg/mL each) is comparable to antibiotic, Clindamycin (MIC = 0.03 MUg/mL) and clearly demonstrate their potential as anti-acne agents. PMID- 28820276 TI - Attenuation of Sulfite-Induced Testicular Injury in Rats by Zingiber officinale Roscoe. AB - Sulfite salts, including sodium metabisulfte, are widely used as preservatives in foods and pharmaceutical agents. Previous studies suggest that oxidative stress may be an important mediator of testicular injury. The present study was designed to elucidate the effect of exposure to sodium metabisulfite by gavage without or with Zingiber officinale (ginger) extract on the rat testes. Thirty-two male Wistar rats were randomly divided into control, ginger-treated (500 mg/kg/day), sodium metabisulfite- (SMB-) treated (260 mg/kg/day), and SMB + ginger- (SZ-) treated groups. After 28 days, the rats were anesthetized by ether and, after laparotomy, blood was collected from the heart to determine testosterone level by the enzyme-linked immunosorbent assay (ELISA) kit. Then left testes and cauda epididymis of all animals were removed for histological examination and sperm analysis, and right testes were removed for assessing lipid peroxidation (indexed by malondialdehyde [MDA]) and antioxidant enzymes. The results showed that spermatogenesis, epididymal morphometry, and sperm parameters were affected by SMB. There was a significant increase in MDA level and a significant reduction in the activities of glutathione peroxidase (GPx), glutathione reductase (GR), and catalase (CAT) in the SMB-treated rats compared to the control. Ginger treatment of SMB-exposed rats significantly increased testosterone level and the number of different spermatogenic cells. The level of MDA reversed to the control levels and the activities of GPx and GR were significantly increased when SMB was coadministered with ginger extract. It is concluded that coadministration of ginger, through its antioxidant and androgenic properties, exerts a protective effect against SMB-induced testicular oxidative stress. PMID- 28820277 TI - Natural phospholipids: Occurrence, biosynthesis, separation, identification, and beneficial health aspects. AB - During the last years, phospholipids (PLs) have attracted great attention because of their crucial roles in providing nutritional values, technological and medical applications. There are considerable proofs that PLs have unique nutritional benefits on human health, such as reducing cholesterol absorption, improving liver functions, and decreasing the risk of cardiovascular diseases. PLs are the main structural lipid components of cell and organelle membranes in all living organisms, and therefore, they occur in all organisms and the derived food products. PLs are distinguished by the presence of a hydrophilic head and a hydrophobic tail, consequently they possess amphiphilic features. Due to their unique characteristics, the extraction, separation, and identification of PLs are critical issues to be concerned. This review is focused on the content of PLs classes in several sources (including milk, vegetable oils, egg yolk, and mitochondria). As well, it highlights PLs biosynthesis, and the methodologies applied for PLs extraction and separation, such as solvent extraction and solid phase extraction. In addition, the determination and quantification of PLs classes by using thin layer chromatography, high-performance liquid chromatography coupled with different detectors, and nuclear magnetic resonance spectroscopy techniques. PMID- 28820278 TI - Does Additional Biceps Augmentation Improve Rotator Cuff Healing and Clinical Outcomes in Anterior L-Shaped Rotator Cuff Tears? Clinical Comparisons With Arthroscopic Partial Repair. AB - BACKGROUND: The repair of anterior L-shaped tears is usually difficult because of the lack of anterior rotator cuff tendon to cover the footprint. The biceps tendon is usually exposed from the retracted anterolateral corner of the torn tendon and can be easily used to augment rotator cuff repair. Hypothesis/Purpose: This study compared the clinical outcomes of the biceps augmentation technique with those of partial tendon repair for the arthroscopic treatment of large anterior L-shaped rotator cuff tears to evaluate the role of additional biceps augmentation in tendon healing. We hypothesized that the biceps augmentation technique would lead to a lower rotator cuff tendon retear rate and provide satisfactory functional outcomes. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: This study included 64 patients with anterior L-shaped rotator cuff tears who underwent arthroscopic repair. Patients were divided into 2 groups: group A (31 patients) underwent repair of an anterior L-shaped tear combined with biceps augmentation, and group B (33 patients) had a partially repaired tendon whose footprint was exposed after repair without undue tension on the retracted tendon. Clinical evaluations were performed using the American Shoulder and Elbow Surgeons (ASES) score, Constant score, muscle strength, visual analog scale for pain, and patient satisfaction. Magnetic resonance imaging (MRI) was performed for tendon integrity at 6 months postoperatively. RESULTS: The mean period of follow-up was 29.1 +/- 3.5 months (range, 24-40 months). The mean ASES and Constant scores significantly improved from 52.8 +/- 10.6 and 43.2 +/- 9.9 preoperatively to 88.2 +/- 6.9 and 86.8 +/- 6.2 at final follow-up in group A ( P < .001) and from 53.0 +/- 11.8 and 44.3 +/- 11.3 preoperatively to 87.4 +/- 7.2 and 87.9 +/- 7.3 at final follow-up in group B ( P < .001). Overall muscle strength (given as % of the other side's strength) significantly increased from preoperatively to final follow-up in group A (forward flexion [FF]: 62.0 +/- 8.2 to 89.0 +/- 8.6; external rotation [ER]: 57.5 +/- 9.9 to 86.8 +/- 9.3; internal rotation [IR]: 68.1 +/- 10.8 to 88.1 +/- 8.4; P < .001) and group B (FF: 59.9 +/- 9.6 to 87.7 +/- 9.0; ER: 58.6 +/- 9.3 to 86.2 +/- 7.5; IR: 70.0 +/- 9.3 to 87.0 +/- 8.4; P < .001). Twenty-one patients (67.7%) in group A and 20 patients (60.6%) in group B showed a healed rotator cuff tendon on postoperative MRI. The retear rate between the 2 groups showed no significant difference ( P = .552). Regarding clinical outcomes, both groups had no significant difference in the ASES score ( P = .901), Constant score ( P = .742), and muscle strength. CONCLUSION: There was no significant difference in the clinical outcomes and retear rate of anterior L-shaped tears between biceps augmentation and partial tendon repair. Additional biceps augmentation proved to have no enhancement in tendon healing. A precise method such as only partial tendon repair for reducing the footprint exposure without undue tension may be considered as one of the treatment options for large anterior L-shaped rotator cuff tears. PMID- 28820279 TI - MRI and clinical characteristics of suspected cerebrovascular accident in nine cats. AB - Objectives Cerebrovascular accidents (CVAs) are infrequently reported in cats. To date, clinical characteristics, including lesion localisation and MRI findings, have only been reported in two cats. The aim of the current study is to document MRI findings in cats presenting with CVAs over an 11 year period. Cases were reviewed according to initial clinical presentation, subsequent physical and neurological findings, predisposing systemic disease and short- and long-term (when available) outcome with a view to identifying any typical pattern in disease occurrence. Methods Patient records of cats presenting to a single referral centre from January 2005 to September 2016 with acute onset, non progressive (after 24 h) intracranial signs compatible with a CVA and where an MRI was performed within 72 h were retrospectively reviewed. Results Nine cats met the inclusion criteria. All cats had ischaemic CVAs (presumptively diagnosed in eight cats and confirmed in one cat following post-mortem examination). No cases of haemorrhagic CVAs were identified. Four cats presented with territorial infarcts that were confined to the territory of the rostral or caudal cerebellar arteries (n = 4). Lacunar infarcts were identified in five cats in the location of the cerebrum (n = 1), the thalamus/midbrain (n = 2) and the medulla oblongata (n = 2). Concurrent systemic disease was identified in most (n = 8/9). In the present study short-term prognosis was favourable and 8/9 cats survived to 48 h following admission. Conclusions and relevance CVAs in cats occur in the same vascular territories as in dogs and have similar MRI features. This study notes that the presenting cats had a high likelihood of concurrent disease (8/9 cases) but had a favourable short-term prognosis, if neither the clinical presentation nor concurrent disease were severe. PMID- 28820280 TI - Review of periorbital nerve enlargement and biopsy techniques. AB - Periorbital nerve enlargement commonly indicates perineural invasion of malignancy or inflammatory conditions. This study reviews the role of supraorbital and infraorbital nerve biopsies in patients presenting with radiographic enlargement and to elucidate the surgical technique involved. A retrospective chart review (1997-2014) was performed at a single tertiary center. Patients with radiographic confirmation of enlarged supraorbital/infraorbital nerves that underwent biopsy were included. Charts were reviewed for: patient demographics and history, clinical symptoms and findings, radiographic findings, surgical method, and treatment. Five patients (4 female, 1 male) met inclusion criteria. Average age was 72.4 years (range 36-90). Four patients had history of cutaneous malignancy. All presented with diplopia and/or dysesthesias. Clinical examination confirmed decreased V1 and/or V2 sensation for 4 patients. Imaging revealed enlargement of V1, V2, and/or V3 in all patients. Infraorbital nerve biopsies were performed in 3 patients via transconjunctival fornix-based orbitotomy with subperiosteal dissection along orbital floor followed by unroofing of infraorbital canal. The remaining 2 underwent supraorbital nerve biopsy via sub-brow incision onto superior orbital rim with reflection of periosteum. Biopsies confirmed squamous cell carcinoma(3), mucoepidermoid carcinoma(1), and idiopathic orbital inflammation(1). Three patients initiated treatment in <1 month. One decided to follow-up closer to home, one was lost to follow-up. For patients presenting with enlarged supraorbital/infraorbital nerves, biopsy can rapidly confirm the underlying condition and facilitate early treatment. A sub-brow approach offers direct access to supraorbital nerve while transconjunctival fornix-based anterior orbitotomy with canal unroofing allows access to infraorbital nerve. PMID- 28820281 TI - Isolated cranio-orbitofacial neurofibroma mimicking vascular malformation. AB - Isolated neurofibromas in the absence of systemic neurofibromatosis are known as solitary or localized neurofibromas. When present in the orbit, these lesions may appear clinically and radiographically similar to other tumors, complicating diagnosis and management. Key radiographic signs may guide clinicians to the correct diagnosis when the presentation and patient demographic data obfuscate the disease entity. We present a case of a large multi-lobulated neurofibroma misdiagnosed as a lymphangioma. A brief review of these tumors emphasizing key radiographic features is also included. PMID- 28820282 TI - Mir505-3p regulates axonal development via inhibiting the autophagy pathway by targeting Atg12. AB - In addition to the canonical role in protein homeostasis, autophagy has recently been found to be involved in axonal dystrophy and neurodegeneration. Whether autophagy may also be involved in neural development remains largely unclear. Here we report that Mir505-3p is a crucial regulator for axonal elongation and branching in vitro and in vivo, through modulating autophagy in neurons. We identify that the key target gene of Mir505-3p in neurons is Atg12, encoding ATG12 (autophagy-related 12) which is an essential component of the autophagy machinery during the initiation and expansion steps of autophagosome formation. Importantly, axonal development is compromised in brains of mir505 knockout mice, in which autophagy signaling and formation of autophagosomes are consistently enhanced. These results define Mir505-3p-ATG12 as a vital signaling cascade for axonal development via the autophagy pathway, further suggesting the critical role of autophagy in neural development. PMID- 28820283 TI - N-3 PUFAs induce inflammatory tolerance by formation of KEAP1-containing SQSTM1/p62-bodies and activation of NFE2L2. AB - Inflammation is crucial in the defense against infections but must be tightly controlled to limit detrimental hyperactivation. Our diet influences inflammatory processes and omega-3 polyunsaturated fatty acids (n-3 PUFAs) have known anti inflammatory effects. The balance of pro- and anti-inflammatory processes is coordinated by macrophages and macroautophagy/autophagy has recently emerged as a cellular process that dampens inflammation. Here we report that the n-3 PUFA docosahexaenoic acid (DHA) transiently induces cytosolic speckles of the autophagic receptor SQSTM1/p62 (sequestosome 1) (described as SQSTM1/p62-bodies) in macrophages. We suggest that the formation of SQSTM1/p62-bodies represents a fast mechanism of NFE2L2/Nrf2 (nuclear factor, erythroid 2 like 2) activation by recruitment of KEAP1 (kelch like ECH associated protein 1). Further, the autophagy receptor TAX1BP1 (Tax1 binding protein 1) and ubiquitin-editing enzyme TNFAIP3/A20 (TNF alpha induced protein 3) could be identified in DHA-induced SQSTM1/p62-bodies. Simultaneously, DHA strongly dampened the induction of pro inflammatory genes including CXCL10 (C-X-C motif chemokine ligand 10) and we suggest that formation of SQSTM1/p62-bodies and activation of NFE2L2 leads to tolerance towards selective inflammatory stimuli. Finally, reduced CXCL10 levels were related to the improved clinical outcome in n-3 PUFA-supplemented heart transplant patients and we propose CXCL10 as a robust marker for the clinical benefits mobilized by n-3 PUFA supplementation. PMID- 28820284 TI - BNIP3L/NIX-mediated mitophagy protects against ischemic brain injury independent of PARK2. AB - Cerebral ischemia induces massive mitochondrial damage. These damaged mitochondria are cleared, thus attenuating brain injury, by mitophagy. Here, we identified the involvement of BNIP3L/NIX in cerebral ischemia-reperfusion (I-R) induced mitophagy. Bnip3l knockout (bnip3l-/-) impaired mitophagy and aggravated cerebral I-R injury in mice, which can be rescued by BNIP3L overexpression. The rescuing effects of BNIP3L overexpression can be observed in park2-/- mice, which showed mitophagy deficiency after I-R. Interestingly, bnip3l and park2 double knockout mice showed a synergistic mitophagy deficiency with I-R treatment, which further highlighted the roles of BNIP3L-mediated mitophagy as being independent from PARK2. Further experiments indicated that phosphorylation of BNIP3L serine 81 is critical for BNIP3L-mediated mitophagy. Nonphosphorylatable mutant BNIP3LS81A failed to counteract both mitophagy impairment and neuroprotective effects in bnip3l-/- mice. Our findings offer insights into mitochondrial quality control in ischemic stroke and bring forth the concept that BNIP3L could be a potential therapeutic target for ischemic stroke, beyond its accepted role in reticulocyte maturation. PMID- 28820285 TI - Oligometastatic cancer: stereotactic ablative radiotherapy for patients affected by isolated body metastasis. AB - BACKGROUND: To evaluate the outcome of patients affected by a single isolated body metastasis treated with stereotactic body radiotherapy (SBRT). MATERIAL AND METHODS: Seven-eight patients were treated with SBRT for isolated body metastasis. The most frequent primary tumor was prostate cancer (28.2%), followed by colorectal cancer (23.1%) and lung cancer (20.5%). Median age at diagnosis of oligometastatic disease was 70 years (range 47-88). Median Karnofsky Performance Status (KPS) was 90 (range 70-100). The most common SBRT fractionation scheme was 5 * 7 Gy (total dose 35 Gy). Response to radiotherapy was determined according to RECIST criteria v1.1. Toxicity was registered according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0. The survival analysis was performed with the Kaplan-Meier method. The correlation between time actuarial incidence and clinical parameters was studied, and the Kaplan-Meier method of log-rank test was applied. RESULTS: With a median follow-up of 22.68 months, local control was achieved in 89.7% of the cases. The two-year overall survival (OS) and progression-free survival (PFS) were 68% and 42%, respectively. On univariate analysis, KPS >=80 is predictive for improved OS (p = .001) and PFS (p = .001). Acute toxicity of grade >=2 occurred in eight (10.2%) patients and late grade >=2 toxicity in five (6.4%) patients. CONCLUSIONS: Ablative radiotherapy in 'early oligometastatic state' is a safe, effective and minimally invasive treatment modality. A good performance status (KPS >=80) seems to influence the clinical outcome. PMID- 28820287 TI - Comparison of PET and CT radiomics for prediction of local tumor control in head and neck squamous cell carcinoma. AB - PURPOSE: An association between radiomic features extracted from CT and local tumor control in the head and neck squamous cell carcinoma (HNSCC) has been shown. This study investigated the value of pretreatment functional imaging (18F FDG PET) radiomics for modeling of local tumor control. MATERIAL AND METHODS: Data from HNSCC patients (n = 121) treated with definitive radiochemotherapy were used for model training. In total, 569 radiomic features were extracted from both contrast-enhanced CT and 18F-FDG PET images in the primary tumor region. CT, PET and combined PET/CT radiomic models to assess local tumor control were trained separately. Five feature selection and three classification methods were implemented. The performance of the models was quantified using concordance index (CI) in 5-fold cross validation in the training cohort. The best models, per image modality, were compared and verified in the independent validation cohort (n = 51). The difference in CI was investigated using bootstrapping. Additionally, the observed and radiomics-based estimated probabilities of local tumor control were compared between two risk groups. RESULTS: The feature selection using principal component analysis and the classification based on the multivariabale Cox regression with backward selection of the variables resulted in the best models for all image modalities (CICT = 0.72, CIPET = 0.74, CIPET/CT = 0.77). Tumors more homogenous in CT density (decreased GLSZMsize_zone_entropy) and with a focused region of high FDG uptake (higher GLSZMSZLGE) indicated better prognosis. No significant difference in the performance of the models in the validation cohort was observed (CICT = 0.73, CIPET = 0.71, CIPET/CT = 0.73). However, the CT radiomics-based model overestimated the probability of tumor control in the poor prognostic group (predicted = 68%, observed = 56%). CONCLUSIONS: Both CT and PET radiomics showed equally good discriminative power for local tumor control modeling in HNSCC. However, CT-based predictions overestimated the local control rate in the poor prognostic validation cohort, and thus, we recommend to base the local control modeling on the 18F-FDG PET. PMID- 28820288 TI - Cohesive silicone gel implants with smooth, textured or polyurethane-coated surface to restore volume in eviscerated sockets. AB - The purpose of this article is to evaluate the three different surface coating on cohesive silicone gel implants in eviscerated rabbit eye sockets. Forty-five albino rabbits underwent right eye evisceration and received hemisphere-shaped cohesive silicone gel implants with smooth (Group 1), textured (Group 2), or polyurethane-coated surface (Group 3) in the socket. The animals were euthanized at 7, 30, and 90 days postoperatively. Computed tomography of the orbits was performed prior to euthanasia. Subsequently, the orbital contents were removed and underwent histologic and morphometric examination. Data were statistically analyzed. There were no adverse effects throughout the study. The majority of implants in the Group 1 exhibited 180 degrees rotation. The Group 3 experienced an intense inflammatory reaction around the implant and implant deformation probably due to pseudocapsule contraction. Cohesive silicone gel implants had good integration into the scleral socket. Optimal results were obtained with cohesive silicone gel textured implants (Group 2). Smooth implants (Group 1) rotated significantly, whereas polyurethane (Group 3) coated implants precipitated an intense inflammatory reaction and were deformed postoperatively. PMID- 28820286 TI - Autophagy-monitoring and autophagy-deficient mice. AB - Discovery of yeast autophagy-related (ATG) genes and subsequent identification of their homologs in other organisms have enabled researchers to investigate physiological functions of macroautophagy/autophagy using genetic techniques. Specific identification of autophagy-related structures is important to evaluate autophagic activity, and specific ablation of autophagy-related genes is a critical means to determine the requirements of autophagy. Here, we review currently available mouse models, particularly focusing on autophagy (and mitophagy) indicator models and systemic autophagy-related gene-knockout mouse models. PMID- 28820290 TI - Local histone acetylation by ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy. AB - Overcoming metabolic stress is a critical step in tumorigenesis. Acetyl coenzyme A (acetyl-CoA) converted from glucose or acetate is a substrate used for histone acetylation to regulate gene expression. However, how acetyl-CoA is produced under nutritional stress conditions is unclear. Herein we report that nutritional stress induces nuclear translocation of ACSS2 (acyl-CoA synthetase short-chain family member 2). This translocation is mediated by AMP-activated protein kinase (AMPK)-dependent ACSS2 Ser659 phosphorylation and subsequent exposure of the nuclear localization signal of ACSS2 to KPNA1/importin alpha5 for binding. In the nucleus, ACSS2 forms a complex with TFEB (transcription factor EB) and utilizes the acetate generated from histone deacetylation to locally produce acetyl-CoA for histone acetylation in the promoter regions of TFEB target genes. Knock-in of nuclear translocation-deficient or inactive ACSS2 mutants in glioblastoma cells abrogates glucose deprivation-induced lysosomal biogenesis and autophagy, reduces cell survival, inhibits brain tumorigenesis, and enhances the inhibitory effect of the glucose metabolism inhibitor 2-deoxy-d-glucose on tumor growth. These results reveal a novel biologic role for ACSS2 in recycling of nuclear acetate for histone acetylation to promote lysosomal and autophagy-related gene expression and counteract nutritional stress, highlighting the importance of ACSS2 in maintaining autophagy and lysosome-mediated cellular energy homeostasis during tumor development. PMID- 28820291 TI - Rationale for bipolar androgen therapy (BAT) for metastatic prostate cancer. PMID- 28820289 TI - Recent advances in quantitative and chemical proteomics for autophagy studies. AB - Macroautophagy/autophagy is an evolutionarily well-conserved cellular degradative process with important biological functions that is closely implicated in health and disease. In recent years, quantitative mass spectrometry-based proteomics and chemical proteomics have emerged as important tools for the study of autophagy, through large-scale unbiased analysis of the proteome or through highly specific and accurate analysis of individual proteins of interest. At present, a variety of approaches have been successfully applied, including (i) expression and interaction proteomics for the study of protein post-translational modifications, (ii) investigating spatio-temporal dynamics of protein synthesis and degradation, and (iii) direct determination of protein activity and profiling molecular targets in the autophagic process. In this review, we attempted to provide an overview of principles and techniques relevant to the application of quantitative and chemical proteomics methods to autophagy, and outline the current landscape as well as future outlook of these methods in autophagy research. PMID- 28820293 TI - Lacrimal gland abscess in children: Two case reports and literature review. AB - Acute suppurative bacterial dacryoadenitis (ASBD) with abscess formation is rarely seen in clinical practice. A retrospective review of medical records in the past 8 years identified two unilateral cases in children, one developed presumably after methicillin-sensitive Staphylococcus aureus (MSSA) conjunctivitis and the other due to community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infection. Computerized tomography scans showed globe indentation by the enlarged lacrimal glands with rim-enhancing lesions. After failing to respond to intravenous antibiotics, both abscesses resolved promptly with surgical drainage without any long-term sequelae. PMID- 28820292 TI - p53 binding sites in normal and cancer cells are characterized by distinct chromatin context. AB - The tumor suppressor protein p53 interacts with DNA in a sequence-dependent manner. Thousands of p53 binding sites have been mapped genome-wide in normal and cancer cells. However, the way p53 selectively binds its cognate sites in different types of cells is not fully understood. Here, we performed a comprehensive analysis of 25 published p53 cistromes and identified 3,551 and 6,039 'high-confidence' binding sites in normal and cancer cells, respectively. Our analysis revealed 2 distinct epigenetic features underlying p53-DNA interactions in vivo. First, p53 binding sites are associated with transcriptionally active histone marks (H3K4me3 and H3K36me3) in normal-cell chromatin, but with repressive histone marks (H3K27me3) in cancer-cell chromatin. Second, p53 binding sites in cancer cells are characterized by a lower level of DNA methylation than their counterparts in normal cells, probably related to global hypomethylation in cancers. Intriguingly, regardless of the cell type, p53 sites are highly enriched in the endogenous retroviral elements of the ERV1 family, highlighting the importance of this repeat family in shaping the transcriptional network of p53. Moreover, the p53 sites exhibit an unusual combination of chromatin patterns: high nucleosome occupancy and, at the same time, high sensitivity to DNase I. Our results suggest that p53 can access its target sites in a chromatin environment that is non-permissive to most DNA binding transcription factors, which may allow p53 to act as a pioneer transcription factor in the context of chromatin. PMID- 28820295 TI - Corrigendum. PMID- 28820294 TI - K+ deficiency caused defects in renal tubular cell proliferation, oxidative stress response, tissue repair and tight junction integrity, but enhanced energy production, proteasome function and cellular K+ uptake. AB - Hypokalemia is a common electrolyte disorder in hospitalized patients and those with chronic diseases and is associated with renal tubular injury. Our recent expression proteomics study revealed changes in levels of several proteins in renal tubular cells during K+ deficiency. However, functional significance and mechanisms underlying such changes remained unclear. The present study, thus, aimed to investigate functional changes of renal tubular cells induced by K+ deficiency. MDCK cells were maintained in normal-K+ (ANK; [K+] = 5.0 mM), Low-K+ (ALK; [K+] = 2.5 mM), or K+-depleted (AKD; [K+] = 0 mM) medium. Cell count and cell death assay showed that ALK and AKD groups had marked decrease in cell proliferation without significant change in cell death. Other functional investigations revealed that AKD cells had significantly increased levels of carbonylated proteins (by OxyBlot assay), impaired tissue repair (by scratch assay), defective tight junction (by Western blotting, immunofluorescence staining and measuring transepithelial electrical resistance), increased intracellular ATP level (by ATP measurement), decreased levels of ubiquitinated proteins (by Western blotting), and increased level of Na+/K+-ATPase (by Western blotting), which was consistent with the increased cellular K+ uptake after K+ repletion. Our findings have shown that AKD caused defects in cell proliferation, oxidative stress response, tissue repair and tight junction integrity, but on the other hand, enhanced energy production, proteasome function and cellular K+ uptake. These findings may shed light onto cellular response to K+ deficiency and better understanding of both pathogenic and compensatory mechanisms in hypokalemic nephropathy. PMID- 28820296 TI - Long-term hemodynamic changes and blood pressure in atherosclerotic major cerebral artery disease. AB - In patients with major cerebral artery disease, lower blood pressure might reduce blood flow in the collateral pathways, thereby impairing the growth of cerebral collaterals, inhibiting hemodynamic improvement. We evaluated the hemodynamic status twice using positron emission tomography and 15O-gas, over time, in 89 medically treated patients with atherosclerotic internal carotid artery or middle cerebral artery disease that had no ischemic episodes during follow-up (mean, 28 +/- 23 months). Changes in the mean hemispheric values of hemodynamic parameters in the territory of the diseased artery at follow-up were correlated with the mean blood pressure values at the baseline and follow-up examinations. There was a positive linear relationship between the degree of hemodynamic improvement and systolic blood pressure. Patients with low systolic blood pressure (<130 mmHg) ( n = 18) showed hemodynamic deterioration as indicated by significant decreases in cerebral blood flow, cerebral blood flow/cerebral blood volume ratio, and increases in oxygen extraction fraction during follow-up. In contrast, there were no significant changes in patients without low systolic blood pressure. In patients with atherosclerotic internal carotid artery or middle cerebral artery disease and no ischemic episodes of stroke during follow-up, lower systolic blood pressure was associated with lesser hemodynamic improvement. PMID- 28820297 TI - The formation of autophagosomes during lysosomal defect: A new source of cytotoxicity. AB - Macroautophagy/autophagy comprises autophagosome synthesis and lysosomal degradation. It is well known that lysosomal defects cause toxicity to cells. However, it has not been investigated previously if cytotoxicity is conferred by autophagosome formation during lysosomal defect. Recently, we found that the formation of autophagosomes in such conditions also causes cytotoxicity, in addition to lysosomal defect insults. We revealed that a partial reduction in autophagosome synthesis was beneficial for cell survival in cells bearing the autophagosome formation-based toxicity. Our study suggests that production/accumulation of autophagosomes during lysosomal defect directly induces cellular toxicity, and this process may be implicated in the pathological conditions where lysosomes are defective. PMID- 28820298 TI - SURVEILLANCE FOR HEMORRHAGIC SEPTICEMIA IN BUFFALO ( BUBALUS BUBALIS) AS AN AID TO RANGE EXPANSION OF THE JAVAN RHINOCEROS ( RHINOCEROS SONDAICUS) IN UJUNG KULON NATIONAL PARK, INDONESIA. AB - The Javan rhinoceros ( Rhinoceros sondaicus) of Ujung Kulon National Park (UKNP) is the crown jewel of Indonesia's rich natural history. The park lies on a peninsula surrounded by coastline and agriculture-dominated landscapes. The invasion of water buffalo ( Bubalus bubalis) into the park carries a substantial health risk to the Javan rhinoceros and threatens plans to establish a new population outside of its only current range in UKNP. Hemorrhagic septicemia (HS), known locally as septicemia epizootica and caused by Pasteurella multocida B:2, could thwart Indonesia's efforts to expand the range of the Javan rhinoceros. Because HS was considered eradicated from Banten Province, few preventative programs have been available to farmers. During June 2012-July 2013, biologic samples were collected from 770 water buffalo in 19 villages. Deep nasal swabs ( n=85) were taken for bacterial culture and blood samples ( n=770) were collected for serologic testing. No animals were positive on culture. The prevalence of antibody to P. multocida in this population was 1.8% (14 of 770 animals). A structured questionnaire was used to gather information about possible risk factors. Husbandry practices associated with presence of antibody in water buffalo included lack of a permanent area to house buffalo at night, low body condition score (=2), high body temperature (>=40 C), a history of clinical signs or sudden death in the previous year, and a grazing system that utilized significant forage inside the park. Antibody was not associated with sex, age, vaccination status, or season. Understanding HS disease dynamics in the buffalo adjacent to UKNP may improve the livelihoods of people and health of endangered rhinoceroses in this ecosystem. PMID- 28820299 TI - ALEUTIAN DISEASE VIRUS-LIKE VIRUS ( AMDOPARVOVIRUS SP.) INFECTING FREE-RANGING STRIPED SKUNKS ( MEPHITIS MEPHITIS) IN THE MIDWESTERN USA. AB - : Aleutian disease virus (ADV) and closely related (ADV-like) viruses are Parvoviridae members (genus Amdoparvovirus) that primarily infect farmed mustelids and have been detected in humans and free-ranging Carnivora from North America. We describe ADV-like/ Amdoparvovirus sp. infection in four free-ranging striped skunks ( Mephitis mephitis) from the Midwestern US. PMID- 28820300 TI - MENINGEAL WORM ( PARELAPHOSTRONGYLUS TENUIS) AS A CAUSE OF MORTALITY IN THE RESTORED ELK ( CERVUS CANADENSIS) POPULATION IN MISSOURI, USA. AB - : Meningeal worm ( Parelaphostrongylus tenuis) is an important cause of mortality of elk ( Cervus canadensis) in populations in the eastern US and has been implicated in the failure of several restoration attempts. From 2011 to 2013, the Missouri Department of Conservation translocated 108 adult and yearling elk from Kentucky (US) to southern Missouri (US) to establish a free-ranging population. From release in spring 2011 through August 2015, we monitored 167 elk (adult, yearling, and calf) to determine causes of mortality. Of 78 mortalities, 26 (33%) were linked to meningeal worm based on necropsy results and/or observed behavior; this group included 19 elk with confirmed or suspected cases of meningeal worm infection that died of other proximate causes. Other important mortality sources included euthanasia ( n=11, 14%), emaciation ( n=7, 9%), and predation ( n=5, 6%). Eleven of the 26 (42%) meningeal worm-related mortalities were adults, and 22 (85%) were female. Meningeal worm was an important cause of mortality during the restoration of Missouri elk, potentially contributing to the loss of 16% of the monitored individuals. Greater mortality in adult female elk could reduce initial population growth by limiting reproductive output in the restored herd, especially given that females were disproportionately affected in Missouri. Because translocated Missouri elk undoubtedly were exposed to meningeal worm in Kentucky, our results could be explained by exposure to a different genetic strain of meningeal worm once in Missouri, loss of immune response due to translocation, increased dose of larval worms, or some unquantified factor. PMID- 28820301 TI - Translabyrinthine microsurgical resection of small vestibular schwannomas. AB - OBJECTIVE Translabyrinthine resection is one of a number of treatment options available to patients with vestibular schwannomas. Though this procedure is hearing destructive, the authors have noted excellent clinical outcomes for patients with small tumors. The authors review their experience at a tertiary acoustic neuroma referral center in using the translabyrinthine approach to resect small vestibular schwannomas. All operations were performed by a surgical team consisting of a single neurosurgeon and 1 of 7 neurotologists. METHODS Data from a prospectively maintained clinical database were extracted and reviewed. Consecutive patients with a preoperative diagnosis of vestibular schwannoma that had less than 1 cm of extension into the cerebellopontine angle, operated on between 2008 and 2013, were included. Patents with neurofibromatosis Type 2, previous treatment, or preexisting facial weakness were excluded. In total, 107 patients were identified, 74.7% of whom had poor hearing preoperatively. RESULTS Pathologically, 6.5% of patients were found to have a tumor other than vestibular schwannoma. Excluding two malignancies, the tumor control rates were 98.7%, as defined by absence of radiographic disease, and 99.0%, as defined by no need for additional treatment. Facial nerve outcome was normal (House-Brackmann Grade I) in 97.2% of patients and good (House-Brackmann Grade I-II) in 99.1%. Complications were cerebrospinal fluid leak (4.7%) and sigmoid sinus thrombosis (0.9%), none of which led to long-term sequelae. CONCLUSIONS Translabyrinthine resection of small vestibular schwannomas provides excellent results in terms of complication avoidance, tumor control, and facial nerve outcomes. This is a hearing-destructive operation that is advocated for selected patients. PMID- 28820302 TI - Letter to the Editor. An extent of resection threshold for recurrent glioblastoma: why wait until recurrence? PMID- 28820303 TI - Rapid ventricular pacing for clip reconstruction of complex unruptured intracranial aneurysms: results of an interdisciplinary prospective trial. AB - OBJECTIVE To date, treatment of complex unruptured intracranial aneurysms (UIAs) remains challenging. Therefore, advanced techniques are required to achieve an optimal result in treating these patients safely. In this study, the safety and efficacy of rapid ventricular pacing (RVP) to facilitate microsurgical clip reconstruction was investigated prospectively in a joined neurosurgery, anesthesiology, and cardiology study. METHODS Patients with complex UIAs were prospectively enrolled. Both the safety and efficacy of RVP were evaluated by recording cardiovascular events and outcomes of patients as well as the amount of aneurysm occlusion after the surgical clip reconstruction procedure. A questionnaire was used to evaluate aneurysm preparation and clip application under RVP. RESULTS Twenty patients (mean age 51.6 years, range 28-66 years) were included in this study. Electrode positioning was easy in 19 (95%) of 20 patients, and removal of electrodes was easily accomplished in all patients (100%). No complications associated with the placement of the pacing electrodes occurred, such as cardiac perforation or cardiac tamponade. RVP was applied in 16 patients. The mean aneurysm size was 11.1 +/- 5.5 mm (range 6-30 mm). RVP proved to be a very helpful tool in aneurysm preparation and clip application in 15 (94%) of 16 patients. RVP was used for a mean duration of 60 +/- 25 seconds, a mean heart rate of 173 +/- 23 bpm (range 150-210 bpm), and a reduction of mean arterial pressure to 35-55 mm Hg. RVP leads to softening of the aneurysm sac facilitating its mobilization, clip application, and closure of the clip blades. In 2 patients, cardiac events were documented that resolved without permanent sequelae in both. In every patient with successful RVP (n = 14) a total or near total aneurysm occlusion was documented. In the 1 patient in whom the second RVP failed due to pacemaker electrode dislocation, additional temporary clipping was required to secure the aneurysm, but was not as sufficient as RVP. This led to an incomplete clipping of the aneurysm and finally a remnant on postoperative digital subtraction angiography. A pacemaker lead dislocation occurred in 3 (19%) of 16 patients, but intraoperative repositioning requires less than 20 seconds. Outcome was favorable in all patients according to the modified Rankin Scale. CONCLUSIONS To the best of the authors' knowledge this is the first prospective interdisciplinary study of RVP use in patients with UIAs. RVP is an elegant technique that facilitates clip reconstruction in complex UIAs. The safety of the procedure is good. However, because this procedure requires extensive preoperative cardiological workup of the patient and an experienced neurosurgery and neuroanesthesiology team with much cerebrovascular expertise, actually it remains reserved for selected elective cases and highly specialized centers. Clinical trial registration no.: NCT02766972 (clinicaltrials.gov). PMID- 28820305 TI - Erratum. Thirty-day postoperative morbidity and mortality after temporal lobectomy for medically refractory epilepsy. PMID- 28820304 TI - Predictors of quality of life and survival following Gamma Knife surgery for lung cancer brain metastases: a prospective study. AB - OBJECTIVE Lung cancer (LC) patients who develop brain metastases (BMs) have a poor prognosis. Estimations of survival and risk of treatment-related deterioration in quality of life (QOL) are important when deciding on treatment. Although we know of several prognostic factors for LC patients with BMs, the role of QOL has not been established. Authors of this study set out to evaluate changes in QOL following Gamma Knife surgery (GKS) for BMs in LC patients and QOL as a prognostic factor for survival. METHODS Forty-four of 48 consecutive LC patients with BMs underwent GKS in the period from May 2010 to September 2011, and their QOL was prospectively assessed before and 1, 3, 6, 9, and 12 months after GKS by using the Functional Assessment of Cancer Therapy-Brain (FACT-BR) questionnaire. A mixed linear regression model was used to identify potential predictive factors for QOL and to assess the effect of GKS and the disease course on QOL at follow-up. RESULTS Mean QOL as measured by the brain cancer subscale (BRCS) of the FACT-BR remained stable from baseline (score 53.0) up to 12 months post-GKS (57.1; p = 0.624). The BRCS score improved for 32 patients (72.3%) with a total BM volume <= 5 cm3. Mean improvement in these patients was 0.45 points each month of follow-up, compared to a decline of 0.50 points each month despite GKS treatment in patients with BM volumes > 5 cm3 (p = 0.04). Asymptomatic BMs (p = 0.01), a lower recursive partitioning analysis (RPA) classification (p = 0.04), and a higher Karnofsky Performance Scale (KPS) score (p < 0.01) at baseline were predictors for a high, stable QOL after GKS. After multivariate analysis, a high KPS score (p < 0.01) remained the only positive predictor of a high, stable QOL post-GKS. Median survival post-GKS was 5.6 months (95% CI 1.0-10.3). A higher BRCS score (p = 0.01), higher KPS score (p = 0.01), female sex (p = 0.01), and the absence of liver (p = 0.02), adrenal (p = 0.02), and bone metastases (p = 0.03) predicted longer survival in unadjusted models. However, in multivariate analyses, a higher BRCS score (p < 0.01), female sex (p = 0.01), and the absence of bone metastases (p = 0.02) at GKS remained significant predictors. Finally, the BRCS score's predictive value for survival was compared with the values for the variables behind well-known prognostic indices: age, KPS score, extracranial disease status, and number and volume of BMs. Both BRCS score (p = 0.01) and BM volume (p = 0.05) remained significant predictors for survival in the final model. CONCLUSIONS Patient-reported QOL according to the BRCS is a predictor of survival in patients with BMs and may be helpful in deciding on the optimal treatment. Gamma Knife surgery is a safe and effective therapeutic modality that improves QOL for LC patients with a BM volume <= 5 cm3 at treatment. Careful follow-up and salvage therapy on demand seem to prevent worsening of QOL due to relapse of BMs. PMID- 28820306 TI - Prognostic value of estrogen receptor in WHO Grade III meningioma: a long-term follow-up study from a single institution. AB - OBJECTIVE Malignant meningioma is rare and classified as Grade III in the WHO classification of CNS tumors. However, the presence of estrogen receptor (ER) in WHO Grade III meningiomas and its correlation with patients' outcomes are still unclear. In this single-center cohort study, the authors analyzed clinical features, treatment, and prognosis of these malignant tumors in patients with long-term follow-up. METHODS A total of 87 patients who were pathologically diagnosed with WHO Grade III meningiomas between 2003 and 2008 were enrolled in this study and followed for at least 7 years. Clinical information was collected to analyze the factors determining the prognosis. RESULTS Twelve patients with rhabdoid, 12 with papillary, and 63 with anaplastic meningioma were included. The mean progression-free survival (PFS) and overall survival (OS) were 56.2 +/- 49.8 months and 68.7 +/- 47.4 months, respectively. No significant differences were observed among the 3 histological subtypes in either PFS (p = 0.929) or OS (p = 0.688). Patients who received gross-total resection had a longer PFS (p = 0.001) and OS (p = 0.027) than those who received subtotal resection. Adjuvant radiotherapy was associated with OS (p = 0.034) but not PFS (p = 0.433). Compared with primary meningiomas, patients with recurrent disease had worse PFS (p < 0.001). For patients who had malignant transformations, the prognosis was poorer than for patients without malignant transformations for both PFS (p = 0.002) and OS (p = 0.019). ER-positive patients had a significantly worse prognosis than ER negative patients regarding both PFS (p = 0.003) and OS (p < 0.001), whereas no association between progesterone receptor and patients' outcomes was observed. Multivariate analysis demonstrated that ER expression was an independent prognostic factor for both PFS (p = 0.008) and OS (p < 0.001). CONCLUSIONS This retrospective study showed that patients with meningioma with ER-positive expression had a much worse prognosis than those with ER weak-positive or ER negative status. The results demonstrated that ER is an independent prognostic factor for both PFS and OS of patients with WHO Grade III meningioma. The authors also found that more radical resection of the tumor, as well as postoperative radiotherapy, may prolong patients' survival time. PMID- 28820307 TI - Editorial. To pace or not to pace: that is the question. PMID- 28820308 TI - Resection of pituitary macroadenomas via the pseudocapsule along the posterior tumor margin: a cohort study and technical note. AB - OBJECTIVE Extracapsular resection of pituitary microadenomas improves remission rates, but the application of pseudocapsular techniques for macroadenomas has not been well described. In larger tumors, the extremely thin, compressed normal gland or its complete absence along the tumor's anterior surface limits the application of the traditional pseudocapsular technique that can be used for microadenomas. However, in the authors' experience, the interface between the pseudocapsule at the posterior margin of the adenoma and the compressed normal gland behind it is universally present, providing a surgical dissection plane. In mid-2010, the authors began using a new surgical technique to identify and use this interface for the resection of larger macroadenomas, a technique that can be used with the microscope or the endoscope. METHODS The authors performed a cohort study using prospectively collected preoperative imaging reports and operative details and retrospectively reviewed postoperative images and clinical follow-up of patients with a pituitary macroadenoma 20-40 mm in maximum diameter undergoing microscopic transsphenoidal resection. Since dissection of the tumor capsule only pertains to encapsulated tumor within the sella and not to tumor invading the cavernous sinus, assessment of tumor removal of noninvasive tumors emphasized the entire tumor, while that of invasive tumors emphasized the intrasellar component only. The incidence of residual tumor on postoperative imaging, new-onset endocrinopathy, and recovery of preoperative pituitary deficits was compared between patients who underwent surgery before (Group A) and after (Group B) implementation of the new technique. RESULTS There were 34 consecutive patients in Group A and 74 consecutive patients in Group B. Tumors in 18 (53%) Group A and 40 (54%) Group B patients had no evidence of cavernous sinus invasion on MRI. Use of the posterior pseudocapsule technique reduced the incidence of intrasellar residual tumor on postoperative MRI for tumors without cavernous sinus invasion (39% [Group A] vs 10%, p < 0.05) and in all tumors regardless of invasion (50% vs 18%, p < 0.005). The incidence of new endocrinopathy was less likely (25% vs 12%, p = 0.098) and the recovery of prior deficits more likely (13% vs 27%, p = 0.199) among patients treated using the pseudocapsule approach, although the differences are not statistically significant. CONCLUSIONS Use of the posterior pseudocapsule dissection plane can enhance the resection of pituitary macroadenomas. PMID- 28820309 TI - Advanced cone-beam CT venous angiographic imaging. AB - OBJECTIVE The evaluation of the venous neurovasculature, especially the dural venous sinuses, is most often performed using MR or CT venography. For further assessment, diagnostic cerebral angiography may be performed. Three-dimensional rotational angiography (3D-RA) can be applied to the venous system, producing 3D rotational venography (3D-RV) and cross-sectional reconstructions, which function as an adjunct to traditional 2D digital subtraction angiography. METHODS After querying the database of Baylor St. Luke's Medical Center in Houston, Texas, the authors reviewed the radiological and clinical data of patients who underwent 3D RV. This modality was performed based on standard techniques for 3D-RA, with the catheter placed in the internal carotid artery and a longer x-ray delay calculated based on time difference between the early arterial phase and the venous phase. RESULTS Of the 12 cases reviewed, 5 patients had neoplasms invading a venous sinus, 4 patients with idiopathic intracranial hypertension required evaluation of venous sinus stenosis, 2 patients had venous diverticula, and 1 patient had a posterior fossa arachnoid cyst. The x-ray delay ranged from 7 to 10 seconds. The 3D-RV was used both for diagnosis and in treatment planning. CONCLUSIONS Three-dimensional RV and associated cross-sectional reconstructions can be used to assess the cerebral venous vasculature in a manner distinct from established modalities. Three-dimensional RV can be performed with relative ease on widely available biplane equipment, and data can be processed using standard software packages. The authors present the protocol and technique used along with potential applications to venous sinus stenosis, venous diverticula, and tumors invading the venous sinuses. PMID- 28820310 TI - Orbital mantle cell lymphoma presenting as myasthenia gravis. AB - A 69-year-old man, previously treated with pyridostigmine for myasthenia gravis (manifesting as ptosis and diplopia) was evaluated for several concomitant bilateral anterior orbital masses. Imaging revealed 3 discrete, solid masses within and around the orbits. An incisional biopsy demonstrated atypical lymphocytes positive for CD20 and Cyclin-D1, consistent with mantle cell lymphoma. The patient received induction chemotherapy with a rituximab-based regimen. He experienced resolution of his diplopia and ptosis after one cycle of chemotherapy and achieved complete remission of the orbital masses and myasthenia symptoms after 6 cycles. Myasthenia gravis is most commonly associated with thymoma, but may also be observed with other malignancies. Recognition that orbital lymphoma may coexist with myasthenia gravis will help in expediting the diagnosis of future cases and in guiding treatment decisions. PMID- 28820311 TI - Clinical radiobiology of proton therapy: modeling of RBE. AB - PURPOSE: To better estimate relative biological effectiveness (RBE) in therapeutic proton beams by using a modeled approach, in order to improve their clinical safety and effectiveness. INTRODUCTION: Concerns exist about the 1.1 RBE used in proton therapy, since it may lead to unintentional over- and under-dosage in patients and so lead to unexpected clinical outcomes. Late reacting normal tissues (with low alpha/beta values), might be overdosed if RBE >1.1; very radiosensitive tumors (with high alpha/beta), might be under-dosed if RBE <1.1. Some physicists recommend ignoring RBE in favor of a LET * dose product to predict effects. MATERIAL AND METHODS: Extensive linear-quadratic based modeling is scaled between a standard hospital megavoltage photon reference radiation (low LET of 0.22 keV MUm-1) alpha and beta values and their values at higher LETs, representative of the middle and end of the SOBPs. A previously published energy efficiency model provide RBE estimates for different alpha/beta (2-27 Gy). The concept of using a LET * dose product is assessed by comparing it with surviving fraction and the equivalent dose in 2 Gy fractions (EQD-2). RESULTS: Low alpha/beta value biosystems have the widest RBE ranges with dose per fraction changes and increasing LET, often above 1.1 even within the SOBP LET range, with lower values at higher dose per fraction. Highly radiosensitive tumors (alpha/beta 10-27 Gy) have the lowest RBEs, often below 1.1, and are not fraction sensitive. RBE's generally increase with LET, so curtailment of LET in normal tissues is important. The LET * dose product is insufficiently discriminating when compared with surviving fraction and biological effective dose (BED) or EQD 2. CONCLUSIONS: An overall research framework is suggested. Proton therapy advantages will only be fully realized if reasonably correct RBE values are used. PMID- 28820313 TI - RIP off STAT3 to counteract tumor progression. PMID- 28820312 TI - Architecture of the ATG2B-WDR45 complex and an aromatic Y/HF motif crucial for complex formation. AB - PtdIns3P signaling is critical for dynamic membrane remodeling during autophagosome formation. Proteins in the Atg18/WIPI family are PtdIns3P-binding effectors which can form complexes with proteins in the Atg2 family, and both families are essential for macroautophagy/autophagy. However, little is known about the biophysical properties and biological functions of the Atg2-Atg18/WIPI complex as a whole. Here, we demonstrate that an ortholog of yeast Atg18, mammalian WDR45/WIPI4 has a stronger binding capacity for mammalian ATG2A or ATG2B than the other 3 WIPIs. We purified the full-length Rattus norvegicus ATG2B and found that it could bind to liposomes independently of PtdIns3P or WDR45. We also purified the ATG2B-WDR45 complex and then performed 3-dimensional reconstruction of the complex by single-particle electron microscopy, which revealed a club-shaped heterodimer with an approximate length of 22 nm. Furthermore, we performed cross-linking mass spectrometry and identified a set of highly cross-linked intermolecular and intramolecular lysine pairs. Finally, based on the cross-linking data followed by bioinformatics and mutagenesis analysis, we determined the conserved aromatic H/YF motif in the C terminus of ATG2A and ATG2B that is crucial for complex formation. PMID- 28820315 TI - Immune responses to Mucorales growth forms: Do we know everything? PMID- 28820314 TI - Flow pattern-dependent endothelial cell responses through transcriptional regulation. AB - Blood flow provides endothelial cells (ECs) lining the inside of blood vessels with mechanical stimuli as well as humoral stimuli. Fluid shear stress, the frictional force between flowing blood and ECs, is recognized as an essential mechanical cue for vascular growth, remodeling, and homeostasis. ECs differentially respond to distinct flow patterns. High laminar shear flow leads to inhibition of cell cycle progression and stabilizes vessels, whereas low shear flow or disturbed flow leads to increased turnover of ECs and inflammatory responses of ECs prone to atherogenic. These differences of EC responses dependent on flow pattern are mainly ascribed to distinct patterns of gene expression. In this review, we highlight flow pattern-dependent transcriptional regulation in ECs by focusing on KLF2 and NFkappaB, major transcription factors responding to laminar flow and disturbed flow, respectively. Moreover, we introduce roles of a new flow-responsive transcriptional co-regulator, YAP, in blood vessel maintenance and discuss how these transcriptional regulators are spatiotemporally regulated by flow and then regulate EC functions in normal and pathological conditions. PMID- 28820316 TI - Cell cycle-related metabolism and mitochondrial dynamics in a replication competent pancreatic beta-cell line. AB - Cell replication is a fundamental attribute of growth and repair in multicellular organisms. Pancreatic beta-cells in adults rarely enter cell cycle, hindering the capacity for regeneration in diabetes. Efforts to drive beta-cells into cell cycle have so far largely focused on regulatory molecules such as cyclins and cyclin-dependent kinases (CDKs). Investigations in cancer biology have uncovered that adaptive changes in metabolism, the mitochondrial network, and cellular Ca2+ are critical for permitting cells to progress through the cell cycle. Here, we investigated these parameters in the replication-competent beta-cell line INS 832/13. Cell cycle synchronization of this line permitted evaluation of cell metabolism, mitochondrial network, and cellular Ca2+ compartmentalization at key cell cycle stages. The mitochondrial network is interconnected and filamentous at G1/S but fragments during the S and G2/M phases, presumably to permit sorting to daughter cells. Pyruvate anaplerosis peaks at G1/S, consistent with generation of biomass for daughter cells, whereas mitochondrial Ca2+ and respiration increase during S and G2/M, consistent with increased energy requirements for DNA and lipid synthesis. This synchronization approach may be of value to investigators performing live cell imaging of Ca2+ or mitochondrial dynamics commonly undertaken in INS cell lines because without synchrony widely disparate data from cell to cell would be expected depending on position within cell cycle. Our findings also offer insight into why replicating beta-cells are relatively nonfunctional secreting insulin in response to glucose. They also provide guidance on metabolic requirements of beta-cells for the transition through the cell cycle that may complement the efforts currently restricted to manipulating cell cycle to drive beta-cells through cell cycle. PMID- 28820317 TI - ULK1 ubiquitylation is regulated by phosphorylation on its carboxy terminus. AB - Autophagy is a highly conserved process that acts sequestering cytoplasmic components for their degradation by the lysosomes. It consists of several sequential steps that have to be finely regulated to ensure both its progression and termination. Post-translational modifications (PTMs) play an important role in regulating ATG proteins function in different stages of autophagy. Recently, we demonstrated that, during prolonged starvation, ULK1 protein is specifically ubiquitylated by NEDD4L, and that this regulation is important to protect cells against excessive autophagy. In this Extra view, we show that ULK1 phosphorylation at 3 different sites on the same ULK1 target region for NEDD4L is preparatory for its ubiquitylation and subsequent degradation. This adds to the complexity of ULK1 multi-level regulation by several factors, including kinases, phosphatases and acetylases, with each contributing to autophagy homeostasis. PMID- 28820318 TI - 7SK small nuclear RNA, a multifunctional transcriptional regulatory RNA with gene specific features. AB - The 7SK small nuclear RNA is a multifunctional transcriptional regulatory RNA that controls the nuclear activity of the positive transcription elongation factor b (P-TEFb), specifically targets P-TEFb to the promoter regions of selected protein-coding genes and promotes transcription of RNA polymerase II specific spliceosomal small nuclear RNA genes. PMID- 28820319 TI - A-to-I RNA editing - thinking beyond the single nucleotide. AB - Adenosine-to-inosine RNA editing is a conserved process, which is performed by ADAR enzymes. By changing nucleotides in coding regions of genes and altering codons, ADARs expand the cell's protein repertoire. This function of the ADAR enzymes is essential for human brain development. However, most of the known editing sites are in non-coding repetitive regions in the transcriptome and the purpose of editing in these regions is unclear. Recent studies, which have shown that editing levels of transcripts vary between tissues and developmental stages in many organisms, suggest that the targeted RNA and ADAR editing are both regulated. We discuss the implications of these findings, and the possible role of RNA editing in innate immunity. PMID- 28820320 TI - Autologous Platelet-Rich Fibrin in the Treatment of 3-Wall Intrabony Defects in Aggressive Periodontitis: A Randomized Controlled Clinical Trial. AB - BACKGROUND: Platelet-rich fibrin (PRF) has recently been applied in osseous regeneration. The aim of the present study is to explore the efficacy of PRF in treatment of intrabony defects (IBDs) in aggressive periodontitis. METHODS: Fifty four IBDs in 17 patients were treated either with autologous PRF with open flap debridement (OFD) or OFD alone. Clinical and radiologic parameters such as probing depth (PD), clinical attachment level (CAL), IBD depth, and percentage defect change were recorded at baseline and 9 months postoperatively. RESULTS: Mean PD reduction and mean CAL gain were significantly greater in PRF compared with the control group. Furthermore, a significantly greater percentage of mean bone defect change was found in the PRF group. CONCLUSION: Within the limits of the present study, there is greater bone fill at sites treated with PRF with conventional OFD than conventional OFD alone. PMID- 28820321 TI - Non-Surgical Therapy Reduces Presence of JP2 Clone in Localized Aggressive Periodontitis. AB - BACKGROUND: Previous studies have provided substantial evidence of the association of Aggregatibacter actinomycetemcomitans, and its highly leukotoxic JP2 genotype, with localized aggressive periodontitis (LAgP). The present study aims to evaluate presence of JP2 in individuals with LAgP after periodontal treatment. METHODS: Sixty African-American patients with LAgP, aged 5 to 25 years, were examined. At baseline, probing depth (PD), clinical attachment level (CAL), bleeding on probing, and plaque index were measured, and subgingival plaque was collected from LAgP diseased and healthy sites for each participant. Patients received whole-mouth ultrasonic debridement, scaling and root planing, and a 7-day prescription of amoxicillin and metronidazole. Participants were reevaluated and resampled and received regular maintenance therapy at 3, 6, and 12 months after treatment. Polymerase chain reaction was used to detect presence of the JP2 genotype before and after treatment. RESULTS: At baseline, the JP2 sequence was identified in 75% of LAgP diseased sites and in 56.67% of healthy sites. At 3, 6, and 12 months after treatment, the number of patients was 40, 31, and 31, respectively, and JP2 detection decreased to 17.5%, 6.45%, and 3.23%, respectively, in diseased sites (P <0.001) and to 2.5%, 3.23%, and 0%, respectively, in healthy sites (P <0.001). Clinical parameters of disease were also significantly reduced after therapy (P <0.001). Additionally, significant correlations were observed between JP2 presence and mean PD (P <0.002) and CAL (P <0.001), after therapy. CONCLUSION: Periodontal therapy was successful in reducing clinical parameters of LAgP and subgingival presence of JP2 in diseased and healthy sites. PMID- 28820322 TI - Platelet-Rich Fibrin in Regeneration of Intrabony Defects: A Randomized Controlled Trial. AB - BACKGROUND: Platelet-rich fibrin (PRF) is an autologous non-transfusional hemo component with a high concentration of platelets. It incorporates leukocytes, platelets, and growth factors within the dense fibrin matrix and can be used as healing biomaterial. This study assesses the adjunctive use of PRF in regenerative management of intrabony defects in comparison with open flap debridement (OFD). METHODS: Twenty-six bilateral defects (13 per group) in 13 patients were randomized as either PRF (test group) or OFD alone (control group) sites. Probing depth (PD), clinical attachment level (CAL), and bone PD were recorded. Reduction in defect depth and percentage of bone fill was assessed radiographically. Primary outcomes assessed were changes in PD, CAL, and percentage of bone fill, and they were assessed at 6, 9, and 12 months. Secondary outcome was assessment of wound healing using a wound healing index (WHI). RESULTS: The PRF group showed significant improvement in clinical parameters compared with the control group at 6, 9, and 12 months. The PRF group showed a bone fill of 45.18% +/- 7.57%, which was statistically significant compared with 21.6% +/- 9.3% seen in the control group at the end of the study period. The PRF group also showed significant soft tissue healing and reduction in PD. WHI also showed significant advantages for the PRF group. CONCLUSION: The adjunctive use of PRF to conventional OFD may be potentially used in the treatment of intrabony defects. PMID- 28820323 TI - Non-Surgical Model for Alveolar Bone Regeneration by Bone Morphogenetic Protein 2/7 Gene Therapy. AB - BACKGROUND: Alveolar bone is a critical tissue for tooth retention; however, once alveolar bone is lost, it may not spontaneously regenerate. Currently, bone grafts or artificial bone are commonly used for alveolar bone regeneration therapy. However, these therapies require surgical procedures, which present risks, particularly in aged patients. Therefore, the development of alveolar bone regeneration techniques that do not require surgical procedures is critical. It is well known that stem cells present in the periosteal and periodontal ligament may be induced to differentiate into osteogenic cells. In this study, we hypothesize that transfer of the Bone Morphogenetic Protein (BMP) -2/7 gene into periodontal tissues via in vivo electroporation induces exogenous BMP production and induces stem cells in the periodontal tissues to differentiate to osteogenic cells, enabling the generation of new alveolar bone. METHODS: The BMP-2/7 gene expression vector was introduced via electroporation into the target site in the periodontal tissues of the first molar of the rat maxilla. RESULTS: Exogenous BMP 2 and -7 were detected in the target areas, and the growth of new alveolar bone tissue was observed five days after gene transfer. On day seven, the new alveolar bone tissues were found to connect to the original bone tissues. Moreover, the mineral apposition rates of the alveolar bone following BMP-2/7 gene transfer were significantly higher than those in the control group following lacZ gene transfer. CONCLUSIONS: The present findings indicate that a combination of the BMP-2/7 non-viral vector and in vivo electroporation represents a promising non surgical option for alveolar bone regeneration therapy. PMID- 28820324 TI - Road to perdition: Zeb1-dependent and -independent ways to metastasis. PMID- 28820326 TI - Heavy metal in cancer: The cell cycle jams with arsenic. PMID- 28820325 TI - Small Alarmone Synthetases as novel bacterial RNA-binding proteins. AB - The alarmone nucleotides guanosine pentaphosphate (pppGpp) and tetraphosphate (ppGpp), collectively referred to as (p)ppGpp, are key regulators of bacterial growth, stress adaptation, antibiotic tolerance and pathogenicity. We have recently shown that the Small Alarmone Synthetase (SAS) RelQ from the Gram positive pathogen Enterococcus faecalis has an RNA-binding activity (Beljantseva et al. 2017). RelQ's activities as an enzyme and as an RNA-binding protein are mutually incompatible: binding of single-stranded RNA potently inhibits (p)ppGpp synthesis in a sequence-specific manner, and RelQ's enzymatic activity destabilizes the RNA:RelQ complex. RelQ's allosteric regulator, pppGpp, destabilizes RNA binding and activates RelQ's enzymatic activity. Since SAS enzymes are widely distributed in bacteria, and, as has been discovered recently, are also mobilized by phages (Dedrick et al. 2017), RNA binding to SASs could be a widespread mechanism. The initial discovery raises numerous questions regarding RNA-binding function of the SAS enzymes: What is the molecular mechanism underlying the incompatibility of RNA:SAS complex formation with pppGpp binding and (p)ppGpp synthesis? What are the RNA targets in living cells? What is the regulatory output of the system - (p)ppGpp synthesis, modulation of RNA structure and function, or both? PMID- 28820327 TI - mTORC1 promotes Schwann cell cycling and myelinogenesis. PMID- 28820328 TI - LPS-induced inflammatory response triggers cell cycle reactivation in murine neuronal cells through retinoblastoma proteins induction. AB - Cell cycle reactivation in adult neurons is an early hallmark of neurodegeneration. The lipopolysaccharide (LPS) is a well-known pro-inflammatory factor that provokes neuronal cell death via glial cells activation. The retinoblastoma (RB) family includes RB1/p105, retinoblastoma-like 1 (RBL1/p107), and retinoblastoma-like 2 (Rb2/p130). Several studies have indicated that RB proteins exhibit tumor suppressor activities, and play a central role in cell cycle regulation. In this study, we assessed LPS-mediated inflammatory effect on cell cycle reactivation and apoptosis of neuronally differentiated cells. Also, we investigated whether the LPS-mediated inflammatory response can influence the function and expression of RB proteins. Our results showed that LPS challenges triggered cell cycle reactivation of differentiated neuronal cells, indicated by an accumulation of cells in S and G2/M phase. Furthermore, we found that LPS treatment also induced apoptotic death of neurons. Interestingly, we observed that LPS-mediated inflammatory effect on cell cycle re-entry and apoptosis was concomitant with the aberrant expression of RBL1/p107 and RB1/p105. To the best of our knowledge, our study is the first to indicate a role of LPS in inducing cell cycle re-entry and/or apoptosis of differentiated neuronal cells, perhaps through mechanisms altering the expression of specific members of RB family proteins. This study provides novel information on the biology of post-mitotic neurons and could help in identifying novel therapeutic targets to prevent de novo cell cycle reactivation and/or apoptosis of neurons undergoing neurodegenerative processes. PMID- 28820329 TI - Sources to variability in circulating human miRNA signatures. AB - An increasing number of studies propose circulating microRNAs (miRNAs) as biomarkers for a large number of human diseases including cancer, cardiovascular diseases, neurologic pathologies and others. To further validate miRNA as biomarkers it is indispensable to understand the variability of circulating miRNAs in healthy individuals. We determined the longitudinal miRNomes of 90 serum samples from the Janus Serum Bank in Norway, which have been stored between 23 and 40 y at -25 degrees Celsius. We profiled 3 serum samples with microarrays for 30 individuals, each. For each individual the samples were collected with a time interval of approximately 5 y. This design allowed insights into inter individual variability, age dependent miRNA variability and the impact of storage length and pre-processing. A significant proportion of the miRNome was affected by the age of the blood donor and a not negligible, albeit small, part of the miRNome by the storage time. A substantial part of miRNAs was differentially abundant between individuals, independent of the time when samples were collected. Stepwise filtering of the 529 miRNAs that were detected in the serum samples showed 168 miRNAs with differential abundance depending on the time point analyzed, 56 miRNAs differentially abundant between individuals, and 169 miRNAs with an abundance depending on the sampling procedure. While these groups of miRNAs contain generally interesting and biologically important miRNAs, the remaining 135 miRNAs constitute very promising biomarker candidates as they show an overall low variability between healthy individuals, a likewise overall low variability across a longer life span, and a high independence of the sampling process and the storage length. PMID- 28820330 TI - Our evolving view of cell motility. PMID- 28820331 TI - Polo-like kinase 1 (PLK1)-dependent phosphorylation of methylenetetrahydrofolate reductase (MTHFR) regulates replication via histone methylation. AB - Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating the folate cycle and its genetic variations have been associated with various human diseases. Previously we identified that MTHFR is phosphorylated by cyclin dependent kinase 1 (CDK1) at T34 and MTHFR underlies heterochromatin maintenance marked by H3K9me3 levels. Herein we demonstrate that pT34 creates a binding motif that docks MTHFR to the polo-binding domain (PBD) of polo-like kinase 1 (PLK1), a fundamental kinase that orchestrates many cell cycle events. We show that PLK1 phosphorylates MTHFR at T549 in vitro and in vivo. Further, we uncovered a role of MTHFR in replication. First, MTHFR depletion increased the fraction of cells in S phase. This defect could not be rescued by siRNA resistant plasmids harboring T549A, but could be restored by overproduction of Suv4-20H2, the H4K20 methyltransferase. Moreover, siMTHFR attenuated H4K20me3 levels, which could be rescued by Suv4-20H2 overproduction. More importantly, we also investigated MTHFR E429A, the protein product of an MTHFR single nucleotide variant. MTHFR-E429A overexpression also increased S phase cells and decreased H4K20me3 levels, and it is linked to a poor glioma prognosis in the Chinese population. Collectively, we have unveiled a vital role of PLK1-dependent phosphorylation of MTHFR in replication via histone methylation, and implicate folate metabolism with glioma. PMID- 28820332 TI - Using rating of perceived exertion in assessing cardiorespiratory fitness in endometrial cancer survivors. AB - For cancer survivors, who also often present with co-existing health conditions, exercise testing is often performed using submaximal protocols incorporating linear heart rate response for estimating the cardiorespiratory capacity and assessing exercise tolerance. However, use of beta-blocker medications, during sub-maximal protocols based on linear HR response can be problematic. Rating of perceived exertion (RPE), which takes into account an individual's overall perception of effort, can be used as a complementary tool that does not rely solely on the heart rate response to increased workload. We compared heart rate response (VO2HR) and self-rating of perceived exertion (VO2RPE) in a graded submaximal exercise test (GXT) in 93 endometrial cancer survivors. The results of the GXT were stratified according to whether participants were taking beta blocker (BB) medications or not (non-BB). Among non-BB participants, there was no difference between the mean VO2HR and the mean VO2RPE estimates of cardiorespiratory capacity (mlO2//kg/min) (20.4 and 19.3, respectively; p = 0.166). Among BB participants, the mean VO2HR approached significant difference than the mean VO2RPE (21.7 mlO2//kg/min and 17.6 mlO2//kg/min, respectively; p = 0.087). Bland-Altman plots for both methods showed a proportional bias for the non-BB group; but not the BB group. Our results suggest that sub-maximal protocols based on Borg's Rating of Perceived exertion (RPE) produce differing results from sub-maximal protocols based on HR response when applied to clinical population taking BB medications. Using RPE instead of HR for participants on BB medications may be a better method for assessing the exercise tolerance for estimating the cardiorespiratory capacity in sub-maximal exercise testing. PMID- 28820334 TI - Evolutionary analysis of a novel zinc ribbon in the N-terminal region of threonine synthase. AB - Threonine synthase (TS) catalyzes the terminal reaction in the biosynthetic pathway of threonine and requires pyridoxal phosphate as a cofactor. TSs share a common catalytic domain with other fold type II PALP dependent enzymes. TSs are broadly grouped into two classes based on their sequence, quaternary structure, and enzyme regulation. We report the presence of a novel zinc ribbon domain in the N-terminal region preceding the catalytic core in TS. The zinc ribbon domain is present in TSs belonging to both classes. Our sequence analysis reveals that archaeal TSs possess all zinc chelating residues to bind a metal ion that are lacking in the structurally characterized homologs. Phylogenetic analysis suggests that TSs with an N-terminal zinc ribbon likely represents the ancestral state of the enzyme while TSs without a zinc ribbon must have diverged later in specific lineages. The zinc ribbon and its N- and C-terminal extensions are important for enzyme stability, activity and regulation. It is likely that the zinc ribbon domain is involved in higher order oligomerization or mediating interactions with other biomolecules leading to formation of larger metabolic complexes. PMID- 28820335 TI - New insights into the pRB/ Condensin II interaction. PMID- 28820333 TI - Protease dead separase inhibits chromosome segregation and RAB-11 vesicle trafficking. AB - Separase cleaves cohesin to allow chromosome segregation. Separase also regulates cortical granule exocytosis and vesicle trafficking during cytokinesis, both of which involve RAB-11. We investigated whether separase regulates exocytosis through a proteolytic or non-proteolytic mechanism. In C. elegans, protease-dead separase (SEP-1PD::GFP) is dominant negative. Consistent with its role in cohesin cleavage, SEP-1PD::GFP causes chromosome segregation defects. As expected, partial depletion of cohesin rescues this defect, confirming that SEP-1PD::GFP acts through a substrate trapping mechanism. SEP-1PD::GFP causes cytokinetic defects that are synergistically exacerbated by depletion of the t-SNARE SYX-4. Furthermore, SEP-1PD::GFP delays furrow ingression, causes an accumulation of RAB 11 vesicles at the cleavage furrow site and delays the exocytosis of cortical granules during anaphase I. Depletion of syx-4 further enhanced RAB-11::mCherry and SEP-1PD::GFP plasma membrane accumulation during cytokinesis, while depletion of cohesin had no effect. In contrast, centriole disengagement appears normal in SEP-1PD::GFP embryos, indicating that chromosome segregation and vesicle trafficking are more sensitive to inhibition by the inactive protease. These findings suggest that separase cleaves an unknown substrate to promote the exocytosis of RAB-11 vesicles and paves the way for biochemical identification of substrates. PMID- 28820336 TI - It takes energy to resist force. PMID- 28820338 TI - Letter to the Editor. Raised intracranial pressure and cognitive delay in craniosynostosis. PMID- 28820337 TI - Circular RNAs: Isolation, characterization and their potential role in diseases. AB - Circular RNA (circRNA) generated by alternative splicing represents a special class of non-coding RNA molecule. CircRNAs are abundant in the eukaryotic cell cytoplasm and have a characteristic organization, timing of action and disease specificity. In contrast to linear RNA, circRNAs are resistant to RNA exonuclease. Consequently, circRNA escapes normal RNA turnover and this improves circRNA stability. CircRNAs can be degraded by microRNA (miRNA) and this results in linearization of the circRNA, which can then act as competitor to endogenous RNA. Through interactions with disease-related miRNA, circRNA can play an important regulatory role in specific diseases. Furthermore, circRNAs have significant potential to become new clinical diagnostic markers. PMID- 28820339 TI - Emergence of visceral leishmaniasis in Sri Lanka: a newly established health threat. AB - BACKGROUND: Sri Lanka is a new focus of human cutaneous leishmaniasis caused by a genetic variant of usually visceralizing parasite Leishmania donovani. Over 3000 cases have been reported to our institution alone, during the past two decades. Recent emergence of visceral leishmaniasis is of concern. METHODS: Patients suspected of having visceral leishmaniasis (n = 120) fulfilling at least two of six criteria (fever > 2 weeks, weight loss, tiredness affecting daily functions, splenomegaly, hepatomegaly and anemia) were studied using clinic-epidemiological, immunological and haematological parameters. Seven cases (four progressive, treated (group A) and 3 non- progressive, potentially asymptomatic and observed (group B) were identified. Clinical cases were treated with systemic sodium stibogluconate or amphotericin B and all were followed up at the leishmaniasis clinic of University of Colombo for 3 years with one case followed up for 9 years. RESULTS: All treated cases responded well to anti leishmanial treatment. Relapses were not noticed. Clinical features subsided in all non-progressive cases and did not develop suggestive clinical features or change of laboratory parameters. Visceral leishmaniasis cases have been originated from different districts within the country. Majority had a travel history to identified local foci of cutaneous leishmaniasis. CONCLUSION: Visceral leishmaniasis is recognized as an emerging health threat in Sri Lanka. At least a proportion of locally identified strains of L. donovani possess the ability to visceralize. Apparent anti leishmanial sensitivity is encouraging. Timely efforts in disease containment will be important in which accurate understanding of transmission characteristics, increased professional and community awareness, improved diagnostics and availability of appropriate treatment regimens. PMID- 28820340 TI - Effect of support supervision on maternal and newborn health services and practices in Rural Eastern Uganda. AB - BACKGROUND: Support supervision is one of the strategies used to check the quality of services provided at health facilities. From 2013 to 2015, Makerere University School of Public Health strengthened support supervision in the district of Kibuku, Kamuli and Pallisa in Eastern Uganda to improve the quality of maternal and newborn services. OBJECTIVE: This article assesses quality improvements in maternal and newborn care services and practices during this period. METHODS: District management teams were trained for two days on how to conduct the supportive supervision. Teams were then allocated particular facilities, which they consistently visited every quarter. During each visit, teams scored the performance of each facility based on checklists; feedback and corrective actions were implemented. Support supervision focused on maternal health services, newborn care services, human resources, laboratory services, availability of Information, education and communication materials and infrastructure. Support supervision reports and checklists from a total of 28 health facilities, each with at least three support supervision visits, were analyzed for this study and 20 key-informant interviews conducted. RESULTS: There was noticeable improvement in maternal and newborn services. For instance, across the first, second and third quarters, availability of parenteral oxytocin increased from 57% to 75% and then to 82%. Removal of retained products increased from 14% to 50% to 54%, respectively. There was perceived improvement in the use of standards and guidelines for emergency obstetric care and quality of care provided. Qualitatively, three themes were identified that promote the success of supportive supervision: changes in the support supervision style, changes in the adherence to clinical standards and guidelines, and multi-stakeholder engagement. CONCLUSION: Support supervision helped district health managers to identify and address maternal and newborn service-delivery gaps. However, issues beyond the jurisdiction of district health managers and facility managers may require additional interventions beyond supportive supervision. PMID- 28820342 TI - Expected years of life lost through road traffic injuries in Mexico. AB - BACKGROUND: Road traffic injuries (RTIs) are a leading cause of premature mortality, mainly in low- and middle-income countries Objective: To estimate the 2014 burden of RTIs in Mexico calculating years of life lost (YLL) and age standardized YLL rates (ASYLL), and to evaluate sex, age, and region-related differences in premature mortality. METHODS: Mortality data were obtained from the National Institute of Statistics and Geography and 14,637 deaths of individuals 15 years of age and older were analyzed. The YLL and ASYLL were computed. RESULTS: The overall burden of RTIs was 332,922 YLL and 82.4% of the deaths occurred in males. Males from 25 to 34 years of age and females from 15 to 24 years of age showed the highest age-adjusted YLL rates (933 and 158 YLL per 100,000 inhabitants, respectively). The national ASYLL rate was 416 per 100,000 inhabitants and the highest state-stratified mortality rates were observed in Tabasco (851), Sinaloa (709), Durango (656), Zacatecas (642), and Baja California Sur (570). CONCLUSIONS: RTIs contributed to the premature mortality rate in the study population. Our findings may be useful from a health policy perspective for designing and prioritizing interventions focused on the prevention of premature loss of life. PMID- 28820341 TI - Cell cycle dynamics and complement expression distinguishes mature haematopoietic subsets arising from hemogenic endothelium. AB - The emergence of haematopoietic stem and progenitor cells (HSPCs) from hemogenic endothelium results in the formation of sizeable HSPC clusters attached to the vascular wall. We evaluate the cell cycle and proliferation of HSPCs involved in cluster formation, as well as the molecular signatures from their initial appearance to the point when cluster cells are capable of adult engraftment (definitive HSCs). We uncover a non-clonal origin of HSPC clusters with differing cell cycle, migration, and cell signaling attributes. In addition, we find that the complement cascade is highly enriched in mature HSPC clusters, possibly delineating a new role for this pathway in engraftment. PMID- 28820343 TI - Population Structure of Pseudocercospora fijiensis in Costa Rica Reveals Shared Haplotype Diversity with Southeast Asian Populations. AB - Pseudocercospora fijiensis is the causal pathogen of black Sigatoka, a devastating disease of banana that can cause 20 to 80% yield loss in the absence of fungicides in banana crops. The genetic structure of populations of P. fijiensis in Costa Rica was examined and compared with Honduran and global populations to better understand migration patterns and inform management strategies. In total, 118 isolates of P. fijiensis collected from Costa Rica and Honduras from 2010 to 2014 were analyzed using multilocus genotyping of six loci and compared with a previously published global dataset of populations of P. fijiensis. The Costa Rican and Honduran populations shared haplotype diversity with haplotypes from Southeast Asia, Oceania, and the Americas but not Africa for all but one of the six loci studied. Gene flow and shared haplotype diversity was found in Honduran and Costa Rican populations of the pathogen. The data indicate that the haplotypic diversity observed in Costa Rican populations of P. fijiensis is derived from dispersal from initial outbreak sources in Honduras and admixtures between genetically differentiated sources from Southeast Asia, Oceania, and the Americas. PMID- 28820344 TI - Are health and demographic surveillance system estimates sufficiently generalisable? AB - Sampling rules do not apply in a Health and Demographic Surveillance System (HDSS) that covers exhaustively a district-level population and is not meant to be representative of a national population. We highlight the advantages of HDSS data for causal analysis and identify in the literature the principles of conditional generalisation that best apply to HDSS. A probabilistic view on HDSS data is still justified by the need to model complex causal inference. Accounting for contextual knowledge, reducing omitted-variable bias, detailing order of events, and high statistical power brings credence to HDSS data. Generalisation of causal mechanisms identified in HDSS data is consolidated through systematic comparison and triangulation with national or international data. PMID- 28820345 TI - Erythema multiforme triggered by Treponema pallidum infection in an HIV-infected patient. AB - We are currently facing a worldwide epidemic of syphilis. Clinical manifestations that are rarely seen have been encountered, leading the dermatologist to confront unusual clinical conditions in daily practice. Erythema multiforme triggered by syphilis is very rare and is also seldom reported in the literature. We report a case of secondary syphilis in an HIV-positive patient, whose clinical, pathologic and serologic features were consistent with the diagnosis of erythema multiforme triggered by syphilis. PMID- 28820346 TI - Attitudes and potential barriers towards hepatitis C treatment in patients with and without HIV coinfection. AB - This study aimed to assess attitudes and potential barriers towards treatment in patients with hepatitis C virus (HCV) infection, comparing those with and without HIV coinfection. A cross-sectional survey of 82 HCV-infected adults with and without HIV was conducted in greater Los Angeles between November 2013 and July 2015. Overall, there were 53 (64.6%) with HIV coinfection, 20 (25.0%) with self reported cirrhosis, and 22 (26.8%) with a history of prior HCV treatment. Of all, 93.2% wanted HCV treatment, but 45.9% were unwilling/unable to spend anything out of pocket, 29.4% were waiting for new therapies, and 23.5% were recommended to defer HCV treatment. HIV/HCV-coinfected patients were more likely to want treatment within one year (90.2% versus 68.2%, p = 0.02), more willing to join a clinical trial (74.5% versus 8.0%, p < 0.01), more willing to take medications twice daily (86.3% versus 61.5%, p = 0.01), and more likely to prefer hepatitis C treatment by an infectious diseases/HIV physician (36.7% versus 4.0%, p < 0.01). Of all, 77.1% of coinfected patients were willing to change antiretroviral therapy if necessary to treat HCV, but only 48.0% of patients were willing to take a medication if it had not been studied in HIV-positive patients. Treatment preferences differ between HIV/HCV-coinfected and HCV-monoinfected patients. Despite a strong willingness among the study cohort to start HCV treatment, other factors such as cost, access to medications, and provider reluctance may be delaying treatment initiation. PMID- 28820347 TI - Association between eye diagnosis and positive syphilis test results in a large, urban sexually transmitted infection/primary care clinic population. AB - In 2015, the Centers for Disease Control and Prevention (CDC) and the American Academy of Ophthalmology (AAO) released clinical advisories on rising cases of ocular syphilis. We examined the association between eye disease and syphilis infection among primary care and sexually transmitted infection (STI) clinic patients attending an urban lesbian, gay, bisexual, transgender (LGBT) health center. We conducted a retrospective medical record review of all patients who underwent syphilis testing at Howard Brown Health between 1 January 2010 and 31 December 2015. Confirmed eye diagnosis was based on International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes for conjunctivitis, uveitis, keratitis, retinitis, and red eye. Demographic information, syphilis treatment, HIV status, and high-risk behaviors were abstracted. Syphilis diagnosis was defined by available laboratory data (enzyme immunoassay [EIA], rapid plasma reagin [RPR] titer, fluorescent treponemal antibody absorption [FTA-Abs], Treponema pallidum Ab). Multivariable logistic regression with robust variance was used to identify independent associations. During the study period, 71,299 syphilis tests were performed on 30,422 patients. There were 2288 (3.2%) positive syphilis tests. Seventy-seven patients had a confirmed eye diagnosis (0.25%). Patients with eye disease had higher probability of at least one positive syphilis test (33%) compared to those without eye disease (8%) ( p < 0.01). Of patients with eye disease, 77% were men who had sex with men (MSM) and 65% were HIV-positive. Patients with eye disease had 5.97 (95% CI: 3.70, 9.63) higher odds of having syphilis compared to patients without eye disease. When adjusted for age, race, gender/sexual orientation, insurance status, and HIV status, this association between positive syphilis test and eye disease decreased but was still significant (OR 2.00, 95% CI 1.17, 3.41). Patients who present with an eye diagnosis to STI/primary care clinic have a higher probability of positive syphilis tests even after adjusting for other risk factors for syphilis. High risk patients with eye symptoms should have routine STI testing and in keeping with CDC and AAO recommendations, full ophthalmologic examination. PMID- 28820348 TI - Where to now? AVERT answered an important question, but raised many more. AB - A Very Early Rehabilitation Trial (AVERT) was a Phase 3 randomized trial with over 2100 subjects post stroke that had unexpected results with better outcomes for usual care than those receiving very early mobilization. This review of published stroke clinical practice guidelines highlights that recommendations for mobilization have changed after publication of AVERT but also that developers have struggled to provide recommendations for appropriate dose, duration and intensity of mobilization in the acute post stroke period with available analyses from AVERT and other literature. This review highlights the priority research questions about early rehabilitation post stroke that need to be addressed through future large scale randomized controlled trials. PMID- 28820349 TI - Evaluation of different methods for DNA extraction from human burnt bones and the generation of genetic profiles for identification. AB - Bone exposure to heat in the presence of moisture breaks the phosphodiester bonds of the backbone, leaving sheared DNA in bone cells. This also limits the possibility of generating a complete profile of the victim. With the increasing incidence of fire outbreaks over the past few years, a paradigm shift to establish identity has been observed, from morphological identification of victims to STR profiling. For this study, 10 bone samples were taken from burnt human bodies that were recovered from different fire outbreak scenes. The DNA from these burnt human tissues was isolated using four different extraction methods: the organic extraction method, the total demineralisation method, the Qiagen kit method, and the Chelex extraction method. STR profiles of victims were generated on a genetic analyser using an AmpFlSTR Identifiler(r) Plus Kit and analysed on Gene Mapper ID-X. DNA isolated from bones using the total demineralisation extraction method and organic extraction method was of the highest quality due to the efficient removal of inhibitors. DNA obtained using these two methods successfully generated the STR profiles of the victims. The quality of isolated DNA obtained through the Qiagen kit was comparatively low, but STR profiles of the victims were successfully generated. The Chelex kit failed to extract good quality DNA of high quantity from the burnt bones, encountering inhibition in all samples at varying degrees. This study concludes that total demineralisation and the Qiagen kit are sophisticated and reliable methods to obtain a good yield of DNA from burnt human bones, which can be used for the identification of victims. PMID- 28820350 TI - Key factors influencing management decisions concerning safety equipment selection. AB - The construction industry involves many hazardous activities that may expose workers to a wide variety of health hazards. Selection of construction safety equipment is crucial in ensuring workers' safety. This article aims to examine key factors influencing management decisions concerning safety equipment selection, utilizing exploratory factor analysis (EFA) and the analytic hierarchy process (AHP). A questionnaire survey is conducted in the construction companies in Bangkok, Thailand. The factor analysis extracts 103 sets of data into six key factors - namely supplier agreements, supplier support, personal, equipment design, safety-related policies and cost value factors - with a total of 20 associated items. The AHP results conclude that the safety-related policies, equipment design and personal factors are the most important factors when selecting construction safety equipment. A construction company can use the study results as a checklist to help assess different safety equipment, and to select the best equipment. PMID- 28820353 TI - A novel determination of energy expenditure efficiency during a balance task using accelerometers. A pilot study. AB - The objectives of this study are to determine the displacement of the center of pressure (CoP) and its association with the spectral energy density of the acceleration required for the maintenance of postural balance in different standing positions in healthy participants using design observational and setting laboratorial studies. Participants were 30 healthy university students aged between 18 and 32 years old (mean [M] +/- standard deviation [SD] = 21,57 +/- 3,31 years). Triaxial accelerometer and a pressure platform were used in order to obtain energy spectral density and CoP sway measurements during four balance tasks. Statistically significant differences were found for anteroposterior (p = 0.002) and mediolateral (p = 0.009) CoP displacement between the conditions eyes closed and stable surface and the conditions eyes closed and unstable surface. A statistically significant correlation was also observed between Z-axis (anterior posterior) of the accelerometer and mediolateral axis of the CoP (r = 0.465; p = 0.01) and between Y-axis accelerometer (mediolateral) and displacement of the CoP in the anteroposterior axis (r = 0.413; p = 0.023). Spectral energy density appears to be associated with the displacement of CoP in healthy participants. PMID- 28820352 TI - Challenging questions regarding the international standards. AB - Objective/Context To highlight questions with regards to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) and provide historical perspectives to help SCI professionals gain fuller insights into the classification system. Methods Frequently asked questions to the ISNCSCI were collected and a review of literature and personal communications with International Standards committee members and Chairs were undertaken. Results Background and explanations for nine questions, detailing decision processes and challenging classification rules are presented. Conclusion While the ISNCSCI can be challenging, this background and historical explanation may provide a greater understanding and the ability to critically analyze this classification system. PMID- 28820351 TI - Genomic and chromatin features shaping meiotic double-strand break formation and repair in mice. AB - The SPO11-generated DNA double-strand breaks (DSBs) that initiate meiotic recombination occur non-randomly across genomes, but mechanisms shaping their distribution and repair remain incompletely understood. Here, we expand on recent studies of nucleotide-resolution DSB maps in mouse spermatocytes. We find that trimethylation of histone H3 lysine 36 around DSB hotspots is highly correlated, both spatially and quantitatively, with trimethylation of H3 lysine 4, consistent with coordinated formation and action of both PRDM9-dependent histone modifications. In contrast, the DSB-responsive kinase ATM contributes independently of PRDM9 to controlling hotspot activity, and combined action of ATM and PRDM9 can explain nearly two-thirds of the variation in DSB frequency between hotspots. DSBs were modestly underrepresented in most repetitive sequences such as segmental duplications and transposons. Nonetheless, numerous DSBs form within repetitive sequences in each meiosis and some classes of repeats are preferentially targeted. Implications of these findings are discussed for evolution of PRDM9 and its role in hybrid strain sterility in mice. Finally, we document the relationship between mouse strain-specific DNA sequence variants within PRDM9 recognition motifs and attendant differences in recombination outcomes. Our results provide further insights into the complex web of factors that influence meiotic recombination patterns. PMID- 28820354 TI - Validity of screening for psychiatric disorders in unaccompanied minor asylum seekers: Use of computer-based assessment. AB - Self-report screening is an important element of transcultural research. Problems concerning illiteracy, cultural sensitivity, and possible misunderstandings have been handled differently in different settings. The aim of this study was to evaluate the validity of two well-known instruments: the Hopkins Symptoms Check List (HSCL-25), and the Harvard Trauma Questionnaire (HTQ, Part IV), with a sample of 160 unaccompanied asylum-seeking adolescents from Afghanistan and Somalia. Assessments were performed 4 months after arrival in Norway, and the screening instruments were presented to the informants on computers with touch screen function, using the program MultiCASI. Sound-files in the native languages of the informants appeared simultaneously with the written items and could be repeated by touch. We found that the screening procedures were well received and understood by the informants regardless of reading and writing abilities. Agreement between diagnoses (CIDI) and screening results were similar to other studies. Computer-based assessment in this setting was practical, cost effective, and can be recommended. PMID- 28820355 TI - Alpha Particles and X Rays Interact in Inducing DNA Damage in U2OS Cells. AB - Survivors of the atomic bombings of Hiroshima and Nagasaki are monitored for health effects within the Life Span Study (LSS). The LSS results represent the most important source of data about cancer effects from ionizing radiation exposure, which forms the foundation for the radiation protection system. One uncertainty connected to deriving universal risk factors from these results is related to the problem of mixed radiation qualities. The A-bomb explosions generated a mixed beam of the sparsely ionizing gamma radiation and densely ionizing neutrons. However, until now the possible interaction of the two radiation types of inducing biological effects has not been taken into consideration. The existence of such interaction would suggest that the application of risk factors derived from the LSS to predict cancer effects after pure gamma-ray irradiation (such as in the Fukushima prefecture) leads to an overestimation of risk. To analyze the possible interaction of radiation types, a mixed-beam exposure facility was constructed where cells can be exposed to sparsely ionizing X rays and densely ionizing alpha particles. U2OS cells were used, which are stably transfected with a plasmid coding for the DNA repair gene 53BP1 coupled to a gene coding for the green fluorescent protein (GFP). The induction and repair of DNA damage, which are known to be related to cancer induction, were analyzed. The results suggest that alpha particles and X rays interact, leading to cellular and possibly cancer effects, which cannot be accurately predicted based on assuming simple additivity of the individual mixed beam components. PMID- 28820356 TI - A phantom study for the comparison of different brands of computed tomography scanners and software packages for endovascular aneurysm repair sizing and planning. AB - Objectives Correct sizing of endoprostheses used for the treatment of abdominal aortic aneurysms is important to prevent endoleaks and migration. Sizing requires several steps and each step introduces a possible sizing error. The goal of this study was to investigate the magnitude of these errors compared to the golden standard: a vessel phantom. This study focuses on the errors in sizing with three different brands of computed tomography angiography scanners in combination with three reconstruction software packages. Methods Three phantoms with a different diameter, altitude and azimuth were scanned with three computed tomography scanners: Toshiba Aquilion 64-slice, Philips Brilliance iCT 256-slice and Siemens Somatom Sensation 64-slice. The phantom diameters were determined in the stretched view after central lumen line reconstruction by three observers using Simbionix PROcedure Rehearsal Studio, 3mensio and TeraRecon planning software. The observers, all novices in sizing endoprostheses using planning software, measured 108 slices each. Two senior vascular surgeons set the tolerated error margin of sizing on +/-1.0 mm. Results In total, 11.3% of the measurements (73/648) were outside the set margins of +/-1.0 mm from the phantom diameter, with significant differences between the scanner types (14.8%, 12.1%, 6.9% for the Siemens scanner, Philips scanner and Toshiba scanner, respectively, p-value = 0.032), but not between the software packages (8.3%, 11.1%, 14.4%, p-value = 0.141) or the observers (10.6%, 9.7%, 13.4%, p-value = 0.448). Conclusions It can be concluded that the errors in sizing were independent of the used software packages, but the phantoms scanned with Siemens scanner were significantly more measured incorrectly than the phantoms scanned with the Toshiba scanner. Consequently, awareness on the type of computed tomography scanner and computed tomography scanner setting is necessary, especially in complex abdominal aortic aneurysms sizing for fenestrated or branched endovascular aneurysm repair if appropriate the sizing is of upmost importance. PMID- 28820357 TI - Screening of extravascular findings in pulmonary embolism computer tomography: 397 patients with 1950 non-pulmonary artery findings. AB - Objectives The aim of this study was to investigate the possible benefits from computed tomography scans of patients with a suspected pulmonary artery embolism with a focus on relevant extravascular findings. Methods A total of 400 consecutive computed tomography pulmonary angiographies were evaluated. Computed tomography scans were analyzed in detail for the presence of pulmonary artery embolisms, as well as any other findings. Extra-artery discoveries were classified into none-relevant (Group A), intermediate (Group B), or relevant (Group C) findings. Results Aggregated computed tomography pulmonary angiographies detected other diagnosis than pulmonary artery embolism in 236 patients (59%). There were 1950 non-pulmonary artery embolism findings (4.9 per patient; n = 397). In the pulmonary artery embolism group, there were 447 extra pulmonary artery embolism findings (5.2 per patient; n = 86) and in the non pulmonary artery embolism group, 1503 findings (4.8 per patient; n = 311). Patients with pulmonary artery embolism had a significantly higher rate of pro coagulate risk factors ( p < 0.001). Conclusions Computed tomography pulmonary angiographies may help to identify further diagnoses. This study represents a retrospective review of a single center experience for incidental computed tomography findings during pulmonary artery embolism work-up and emphasizes the importance of analyzing the whole field-of-view. PMID- 28820358 TI - Response: Toe brachial index measured by automated device compared to duplex ultrasonography for detecting peripheral arterial disease in older people. PMID- 28820359 TI - Clinical outcomes of direct oral anticoagulants after lower extremity arterial procedures. AB - Objectives The use of postoperative anticoagulation is not uncommon for patients undergoing lower extremity arterial procedures as adjunctive therapy. Longer postoperative length of stay is necessary to achieve adequate therapeutic international normalized ratio with traditional protocols that call for the use of unfractionated heparin and warfarin therapy. We hypothesized the direct oral anticoagulants are an attractive alternative to provide adequate anticoagulation in patients who undergo lower extremity arterial procedures. Methods We retrospectively studied patients who had lower extremity arterial procedures between 2012 and 2015 to examine the safety and efficacy of the direct oral anticoagulants in a single institution. Patency, freedom from re-intervention, and major adverse limb event were evaluated. The direct oral anticoagulant agents used included dabigatran, rivaroxaban, and apixaban. The primary patency, adverse effects and freedom from re-intervention were then compared to a control group of patients who were treated with traditional heparin-warfarin therapy after lower extremity bypass procedures. Results Direct oral anticoagulants were utilized in a total of 23 patients (48% men; mean age 69 +/- 11 years) during the study period. Indication for use of direct oral anticoagulant after procedure included use of polytetrafluoroethylene (PTFE) bypass graft below the knee joint or after lower extremity angioplasty with disadvantaged runoff. Mean follow-up of the drugs was 23 months (SD +/- 16 months). At the end of follow-up, the direct oral anticoagulants have been discontinued in four patients, who are currently only on plavix. Among 82.6% of patients who were given direct oral anticoagulants for PTFE bypasses, graft patency, freedom from re-intervention, and major adverse limb event were 100%, 100%, and 0%, respectively. Patients (17.4%) treated with direct oral anticoagulants for disadvantaged runoff after balloon angioplasty of the lower extremity, patency, freedom from re-intervention, and major adverse limb event were 100%, 100%, and 0%, respectively. For the patients who underwent direct oral anticoagulant administration for disadvantaged runoff primary patency was 100%. One patient developed wound dehiscence which was unrelated to direct oral anticoagulant administration. Our control group consisted of 100 patients who were treated with heparin-warfarin therapy for 30 days after lower extremity bypass procedures. The graft patency, freedom from intervention, and major adverse limb event were 93%, 12%, and 0%, respectively. There was however no statistically significant difference in graft patency rate ( P = .34) or freedom from intervention ( P = .07) between the two groups. Conclusions The preliminary data suggest that there may be a role for using the direct oral anticoagulants with patients who undergo lower extremity arterial procedures for prevention of thrombosis and warrants further investigation. PMID- 28820360 TI - Preliminary study on the changes of ovarian reserve, menstruation, and lymphocyte subpopulation in systemic lupus erythematosus (SLE) patients of childbearing age. AB - Objective The main aim of this study was to investigate the ovarian reserve, menstruation, and lymphocyte subpopulation in systemic lupus erythematosus (SLE) patients of childbearing age. Methods We enrolled 40 SLE patients of childbearing age and 40 age-matched healthy controls. Anti-Mullerian hormone (AMH) was tested by electrochemiluminescence, and lymphocyte subsets were tested by flow cytometry. Menstruation situation was obtained by interview. Results The AMH level of the SLE group was significantly lower than that of the control group ( p < 0.001), which was negatively correlated with erythrocyte sedimentation rate (ESR ( r = -0.316, p = 0.047)) and disease activity (SLEDAI ( r = -0.338, p = 0.033)). The AMH concentration of SLE patients with normal menstruation was higher than those with abnormal menstruation ( p < 0.001). The percentages of CD4+ T lymphocytes and NK (natural killer) cells in the SLE group were significantly lower than those in the control group ( p < 0.001). However, the percentages of B cells and CD8+ T lymphocytes in the SLE group were higher than those in the control group ( p < 0.05). Conclusion Decreased AMH and high incidence of abnormal menstruation indicated that autoimmunity activities of SLE can impair the ovarian reserve of female patients. Lymphocytes in SLE patients were in a state of disorder. PMID- 28820361 TI - The clinical relevance of repeat renal biopsies in the management of lupus nephritis: a South African experience. AB - Purpose Clinically, repeat renal biopsies (RRBs) have been performed in lupus nephritis to identify changes in class, plan treatment and assist in prognostication. We set out to compare the histopathological features and outcomes of disease flare and protocol biopsy patients. Methods A retrospective descriptive study was conducted on repeat biopsies performed between January 1984 and December 2015 in lupus nephritis patients. Disease flares and protocol biopsies were compared. Results Of 614 systemic lupus erythematosus (SLE) renal biopsies, 127 (20.7%) RRBs were identified. Disease flare patients accounted for 96 (75.6%) and protocol biopsies for 31 (24.4%) of RRBs. Seventy (72.9%) disease flare patients retained their original class on repeat biopsy. When categorised as proliferative and non-proliferative histology, 83 (87.4%) of the disease flare biopsy patients remained histologically unchanged. Treatment remained unchanged in 57 (60.0%) patients following RRBs for disease flares. Response to immunosuppression in disease flare patients was poorer. Non-response was associated with increased chronicity index (OR = 1.33; 95% CI 1.01-1.76; p = 0.045). Thirty-three (36.3%) disease flare patients developed end-stage kidney disease (ESKD) in one year as compared to one (3.6%) protocol biopsy patient ( p = 0.003). ESKD in disease flare patients was associated with non-response to treatment (OR = 24.6; 95% CI 2.7-219.3; p = 0.004) on multivariate analysis. One year mortality was 30.0% in the disease flare patients and 3.5% in protocol biopsy patients ( p = 0.018). Conclusion Repeat biopsies in disease flare patients infrequently led to histological class changes, failed to lead to change of treatment in the majority of patients, and were associated with poorer outcomes. PMID- 28820362 TI - Characterization of patients with systemic lupus erythematosus who meet the diagnostic criteria for TAFRO syndrome. AB - Purpose TAFRO syndrome is a novel disorder manifesting as fever, anasarca, thrombocytopenia, renal insufficiency and organomegaly, and its etiology has not been clarified. The aim of this study was to elucidate similarities and differences between systemic lupus erythematosus (SLE) and TAFRO syndrome. Methods We examined 46 consecutive patients diagnosed with SLE and determined whether they meet the proposed diagnostic criteria for TAFRO syndrome (2015 version). Results Of the 46 patients with SLE, four (8.7%) also met the TAFRO syndrome criteria (TAFRO-like group). All patients in the TAFRO-like group were males, and their mean age was significantly higher than that of the non-TAFRO group (67.5 +/- 8.7 vs. 39.3 +/- 18.1 years, p = 0.004). C-reactive protein and gamma-glutamyl transpeptidase levels were significantly higher, and frequencies of anti-dsDNA and anti-Sm antibodies were significantly lower in the TAFRO-like than non-TAFRO group. Elder cases (onset age >= 50 years) met significantly more categories of the diagnostic criteria for TAFRO syndrome than did those with younger cases. Conclusions Several patients with SLE, especially elder cases, showed features similar to those of TAFRO syndrome. Although exclusion of SLE is needed in the diagnostic criteria for TAFRO syndrome, TAFRO syndrome-like SLE should be considered. PMID- 28820363 TI - Incidence of perioperative medical complications and mortality among elderly patients undergoing surgery for spinal deformity: analysis of 3519 patients. AB - OBJECTIVE Using 2 complication-reporting methods, the authors investigated the incidence of major medical complications and mortality in elderly patients after surgery for adult spinal deformity (ASD) during a 2-year follow-up period. METHODS The authors queried a multicenter, prospective, surgeon-maintained database (SMD) to identify patients 65 years or older who underwent surgical correction of ASD from 2008 through 2014 and had a minimum 2 years of follow-up (n = 153). They also queried a Centers for Medicare & Medicaid Services claims database (MCD) for patients 65 years or older who underwent fusion of 8 or more vertebral levels from 2005 through 2012 (n = 3366). They calculated cumulative rates of the following complications during the first 6 weeks after surgery: cerebrovascular accident, congestive heart failure, deep venous thrombosis, myocardial infarction, pneumonia, and pulmonary embolism. Significance was set at p < 0.05. RESULTS During the perioperative period, rates of major medical complications were 5.9% for pneumonia, 4.1% for deep venous thrombosis, 3.2% for pulmonary embolism, 2.1% for cerebrovascular accident, 1.8% for myocardial infarction, and 1.0% for congestive heart failure. Mortality rates were 0.9% at 6 weeks and 1.8% at 2 years. When comparing the SMD with the MCD, there were no significant differences in the perioperative rates of major medical complications except pneumonia. Furthermore, there were no significant intergroup differences in the mortality rates at 6 weeks or 2 years. The SMD provided greater detail with respect to deformity characteristics and surgical variables than the MCD. CONCLUSIONS The incidence of most major medical complications in the elderly after surgery for ASD was similar between the SMD and the MCD and ranged from 1% for congestive heart failure to 5.9% for pneumonia. These complications data can be valuable for preoperative patient counseling and informed consent. PMID- 28820364 TI - Patterns of C-2 fracture in the elderly: comparison of etiology, treatment, and mortality among specific fracture types. AB - OBJECTIVE Previous studies have focused on Type II odontoid fractures and have failed to report on the effect of other C-2 fracture types on treatment and outcome. The purpose of this study was to compare patient characteristics, cause of injury, predisposing factors to fracture, treatments, and mortality rates among C-2 fracture types in a cohort of elderly patients 70 years of age and older. METHODS A retrospective cohort study design was used. Patients who sustained a C-2 fracture between 2002 and 2011 and who were admitted to the authors' Level 1 trauma center were identified using the Discharge Abstract Database and the International Statistical Classification of Diseases and Related Health Problems (ICD-10) code S12.1. Fractures were classified as odontoid Type I, II, or III; hangman's; C-2 complex (hangman's appearance on sagittal images, Type III odontoid on coronal cuts); and other (miscellaneous). Age, sex, predisposing factors to falls, cause of injury, treatment, presence of autofusion in the subaxial cervical spine, and mortality rates were compared between fracture patterns. RESULTS One hundred forty-one patients were included; their mean age was 82 years. Fractures included Type II odontoid (57%), complex (19%), Type III odontoid (11%), hangman's (8%), and other (5%). Falls from a standing height accounted for 47% of injuries, and 65% of patients had >= 3 risk factors for falls. Subaxial autofusion was more common in odontoid fractures (p = 0.002). Treatment was mainly nonoperative (p < 0.0001). The 1-year mortality rate was 27%. Four patients died of spinal cord injury. CONCLUSIONS Although not as common as Type II odontoid fractures, other C-2 fractures including hangman's, complex, and Type III odontoid fractures accounted for close to half of the injuries in the study cohort. There were few differences between the fracture types with respect to cause of injury, predisposing factors, or mortality rate. However, surgical treatment was more common for Type II odontoid fractures. PMID- 28820365 TI - Erratum: Diversity of the auxotrophic requirements in natural isolates of Escherichia coli. PMID- 28820366 TI - Determination of Ferret Enteric Coronavirus Genome in Laboratory Ferrets. AB - Ferret enteric coronavirus (FRECV) RNA was detected in laboratory ferrets. Analysis of the complete genome sequence of 2 strains, FRCoV4370 and FRCoV063, revealed that FRECV shared 49.9%-68.9% nucleotide sequence identity with known coronaviruses. These results suggest that FRECV might be classified as a new species in the genus Alphacoronavirus. PMID- 28820367 TI - White-Nose Syndrome Fungus in a 1918 Bat Specimen from France. AB - White-nose syndrome, first diagnosed in North America in 2006, causes mass deaths among bats in North America. We found the causative fungus, Pseudogymnoascus destructans, in a 1918 sample collected in Europe, where bats have now adapted to the fungus. These results are consistent with a Eurasian origin of the pathogen. PMID- 28820368 TI - Emergence of Plasmid-Mediated Fosfomycin-Resistance Genes among Escherichia coli Isolates, France. AB - FosA, a glutathione S-transferase that inactivates fosfomycin, has been reported as the cause of enzymatic resistance to fosfomycin. We show that multiple lineages of FosA-producing extended spectrum beta-lactamase Escherichia coli have circulated in France since 2012, potentially reducing the efficacy of fosfomycin in treating infections with antimicrobial drug-resistant gram-negative bacilli. PMID- 28820369 TI - Imported Infections with Mansonella perstans Nematodes, Italy. AB - We report 74 patients in Italy infected with Mansonella perstans nematodes, a poorly described filarial parasite. M. perstans nematodes should be included in the differential diagnosis for patients with eosinophilia from disease-endemic countries. Serologic analysis is useful for screening, and testing for microfilaremia in peripheral blood should be performed for parasite-positive patients. PMID- 28820370 TI - Antimicrobial Drug-Resistant Shiga Toxin-Producing Escherichia coli Infections, Michigan, USA. AB - High frequencies of antimicrobial drug resistance were observed in O157 and non O157 Shiga toxin-producing E. coli strains recovered from patients in Michigan during 2010-2014. Resistance was more common in non-O157 strains and independently associated with hospitalization, indicating that resistance could contribute to more severe disease outcomes. PMID- 28820371 TI - Serologic Evidence for Influenza C and D Virus among Ruminants and Camelids, Africa, 1991-2015. AB - Influenza D virus has been identified in America, Europe, and Asia. We detected influenza D virus antibodies in cattle and small ruminants from North (Morocco) and West (Togo and Benin) Africa. Dromedary camels in Kenya harbored influenza C or D virus antibodies, indicating a potential new host for these viruses. PMID- 28820372 TI - Microcephaly Caused by Lymphocytic Choriomeningitis Virus. AB - We report congenital microencephaly caused by infection with lymphocytic choriomeningitis virus in the fetus of a 29-year-old pregnant women at 23 weeks' gestation. The diagnosis was made by ultrasonography and negative results for other agents and confirmed by a positive PCR result for lymphocytic choriomeningitis virus in an amniotic fluid sample. PMID- 28820373 TI - Identification of Clade E Avipoxvirus, Mozambique, 2016. AB - Analysis of scab samples collected from poultry during outbreaks of fowlpox in Mozambique in 2016 revealed the presence of clade E avipoxviruses. Infected poultry were from flocks that had been vaccinated against fowlpox virus. These findings require urgent reevaluation of the vaccine formula and control strategies in this country. PMID- 28820374 TI - Use of Blood Donor Screening to Monitor Prevalence of HIV and Hepatitis B and C Viruses, South Africa. AB - Among 397,640 first-time blood donors screened in South Africa during 2012-2015, HIV prevalence was 1.13%, hepatitis B virus prevalence 0.66%, and hepatitis C virus prevalence 0.03%. Findings of note were a high HIV prevalence in Mpumalanga Province and the near absence of hepatitis C virus nationwide. PMID- 28820375 TI - Epidemiology of Neisseria gonorrhoeae Gyrase A Genotype, Los Angeles, California, USA. AB - We investigated the epidemiology of the mutant gyrase A gene, a reliable predictor of ciprofloxacin resistance, in Neisseria gonorrhoeae infections at UCLA Health in Los Angeles, California, USA, during November 1, 2015-August 31, 2016. Among 110 patients with N. gonorrhoeae infections, 48 (44%) had the mutant gyrase A gene. PMID- 28820376 TI - Influenza A(H3N2) Virus in Swine at Agricultural Fairs and Transmission to Humans, Michigan and Ohio, USA, 2016. AB - In 2016, a total of 18 human infections with influenza A(H3N2) virus occurred after exposure to influenza-infected swine at 7 agricultural fairs. Sixteen of these cases were the result of infection by a reassorted virus with increasing prevalence among US swine containing a hemagglutinin gene from 2010-11 human seasonal H3N2 strains. PMID- 28820377 TI - Rabies Virus Transmission in Solid Organ Transplantation, China, 2015-2016. AB - We report rabies virus transmission among solid organ transplantation recipients in Changsha, China, in 2016. Two recipients were confirmed to have rabies and died. Our findings suggest that more attention should be paid to the possibility of rabies virus transmission through organ transplantation for clinical and public health reasons. PMID- 28820378 TI - Indication of Cross-Species Transmission of Astrovirus Associated with Encephalitis in Sheep and Cattle. AB - We report the identification of a neurotropic astrovirus associated with encephalitis in a sheep. This virus is genetically almost identical to an astrovirus recently described in neurologically diseased cattle. The similarity indicates that astroviruses of the same genotype may cause encephalitis in different species. PMID- 28820379 TI - Conveyance Contact Investigation for Imported Middle East Respiratory Syndrome Cases, United States, May 2014. AB - In 2014, the Centers for Disease Control and Prevention conducted conveyance contact investigations for 2 Middle East respiratory syndrome cases imported into the United States, comprising all passengers and crew on 4 international and domestic flights and 1 bus. Of 655 contacts, 78% were interviewed; 33% had serologic testing. No secondary cases were identified. PMID- 28820380 TI - Similarities of Variant Creutzfeldt-Jakob Disease Strain in Mother and Son in Spain to UK Reference Case. AB - We investigated transmission characteristics of variant Creutzfeldt-Jakob disease in a mother and son from Spain. Despite differences in patient age and disease manifestations, we found the same strain properties in these patients as in UK vCJD cases. A single strain of agent appears to be responsible for all vCJD cases to date. PMID- 28820381 TI - Possible Role of Fish as Transport Hosts for Dracunculus spp. Larvae. AB - To inform Dracunculus medinensis (Guinea worm) eradication efforts, we evaluated the role of fish as transport hosts for Dracunculus worms. Ferrets fed fish that had ingested infected copepods became infected, highlighting the importance of recommendations to cook fish, bury entrails, and prevent dogs from consuming raw fish and entrails. PMID- 28820382 TI - Myocarditis Caused by Human Parechovirus in Adult. AB - The infectious etiology of myocarditis often remains unidentified. We report a case of myocarditis associated with human parechovirus (HPeV) infection in an adult. HPeV is an emerging pathogen that can cause serious illness, including myocarditis, in adults. Testing for HPeV should be considered in differential diagnosis of myocarditis. PMID- 28820383 TI - Carbapenemase-Producing Enterobacteriaceae and Nonfermentative Bacteria, the Philippines, 2013-2016. AB - During 2013-2016, we isolated blaNDM- and blaVIM-harboring Enterobacteriaceae and nonfermentative bacteria from patients in the Philippines. Of 130 carbapenem resistant isolates tested, 45 were Carba NP-positive; 43 harbored blaNDM, and 2 harbored blaVIM. Multidrug-resistant microbial pathogen surveillance and antimicrobial drug stewardship are needed to prevent further spread of New Delhi metallo-beta-lactamase variants. PMID- 28820384 TI - Chronic Wasting Disease Prion Strain Emergence and Host Range Expansion. AB - Human and mouse prion proteins share a structural motif that regulates resistance to common chronic wasting disease (CWD) prion strains. Successful transmission of an emergent strain of CWD prion, H95+, into mice resulted in infection. Thus, emergent CWD prion strains may have higher zoonotic potential than common strains. PMID- 28820385 TI - Group A Rotavirus Associated with Encephalitis in Red Fox. AB - In 2011, a group A rotavirus was isolated from the brain of a fox with encephalitis and neurologic signs, detected by rabies surveillance in Italy. Intracerebral inoculation of fox brain homogenates into mice was fatal. Genome sequencing revealed a heterologous rotavirus of avian origin, which could provide a model for investigating rotavirus neurovirulence. PMID- 28820386 TI - Cost of Nosocomial Outbreak Caused by NDM-1-Containing Klebsiella pneumoniae in the Netherlands, October 2015-January 2016. AB - During October-December 2015, 29 patients in a hospital in the Netherlands acquired nosocomial infection with a multidrug-resistant, New Delhi-metallo-beta lactamase-positive Klebsiella pneumoniae strain. Extensive infection control measures were needed to stop this outbreak. The estimated economic impact of the outbreak was $804,263; highest costs were associated with hospital bed closures. PMID- 28820387 TI - Infectious polymorphic toxins delivered by outer membrane exchange discriminate kin in myxobacteria. AB - Myxobacteria are known for complex social behaviors including outer membrane exchange (OME), in which cells exchange large amounts of outer membrane lipids and proteins upon contact. The TraA cell surface receptor selects OME partners based on a variable domain. However, traA polymorphism alone is not sufficient to precisely discriminate kin. Here, we report a novel family of OME-delivered toxins that promote kin discrimination of OME partners. These SitA lipoprotein toxins are polymorphic and widespread in myxobacteria. Each sitA is associated with a cognate sitI immunity gene, and in some cases a sitB accessory gene. Remarkably, we show that SitA is transferred serially between target cells, allowing the toxins to move cell-to-cell like an infectious agent. Consequently, SitA toxins define strong identity barriers between strains and likely contribute to population structure, maintenance of cooperation, and strain diversification. Moreover, these results highlight the diversity of systems evolved to deliver toxins between bacteria. PMID- 28820389 TI - Hippo pathway - brief overview of its relevance in cancer. AB - The Hippo pathway is the major regulator of organ growth and proliferation. Described initially in Drosophila, it is now recognized as one of the most conserved molecular pathways in all metazoan. Recent studies have revealed the Hippo signalling pathway might contribute to tumorigenesis and cancer development. The core components of the Hippo pathway include the mammalian sterile 20-like kinases (MSTs), large tumour suppressor kinases (LATSs), the adaptor proteins Salvador homologue 1 (SAV1, also called WW45) and Mps One Binder kinase activator proteins. The major target of the Hippo core kinases is the mammalian transcriptional activator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). In cancer, the Hippo signalling is inactivated and YAP and TAZ are activated and free to translocate into the nucleus to promote cell proliferation. Nuclear YAP/TAZ activate or suppress transcription factors that regulate target genes involved in cell proliferation, tissue growth, control of organ size and shape or metastasis. The Hippo signalling pathway that controls the most important cellular processes like growth and division appears to be a very promising research subject in the field of cell biology and tissue engineering. It consists of elements that in the cell play the roles of tumour suppressors as well as oncogenes. This 'Janus like' - an opposite activity hidden within one and the same signalling pathway represents a significant obstacle for studying it. This property of the Hippo pathway is worth remembering, as it will appear several times during the discussion of its properties. Here, we will review certain data regarding biology of the Hippo signalling and its interplay with other prominent signalling pathways in the cell, its relevance in cancer development and therapies that might target elements of the Hippo pathway in most human cancers. PMID- 28820390 TI - Small molecule inhibitors of DNA-PK for tumor sensitization to anticancer therapy. AB - The most sensitive cell structure - a DNA molecule, is the common target of cancer therapy. DNA damage response (controlled by enzymes from the phosphatidylinositol 3-kinase-related kinases family - PIKK) presents many encouraging targets for improving both conventional cytotoxic anticancer therapy and individualized monotherapy. DNA-dependent protein kinase (DNA-PK) is a member of the PIKK superfamily and plays an important role in the detection and repair of DNA double-strand breaks via the non-homologous end-joining pathway. The ability of cancer cells to repair DNA damage is an important element determining their sensitivity to radio- or chemo-therapy. The overactivation of DNA-PK in cancers can result in resistance to anticancer therapy. The inhibition of DNA-PK is a very promising target in anticancer research. However, the specific DNA-PK inhibitors currently known are limited by poor solubility and high metabolic lability in vivo, leading to a short serum half-life. Construction of new compounds based on existing drugs is the most important strategy to improve drug efficacy, pharmacokinetic parameters and to reduce toxicity. This review will describe small molecule inhibitors and summarize their efficacy in synergizing radio- and chemotherapy in vitro. PMID- 28820388 TI - Blockade of the LRP16-PKR-NF-kappaB signaling axis sensitizes colorectal carcinoma cells to DNA-damaging cytotoxic therapy. AB - Acquired therapeutic resistance by tumors is a substantial impediment to reducing the morbidity and mortality that are attributable to human malignancies. The mechanisms responsible for the dramatic shift between chemosensitivity and chemoresistance in colorectal carcinoma have not been defined. Here, we report that LRP16 selectively interacts and activates double-stranded RNA-dependent kinase (PKR), and also acts as scaffolds to assist the formation of a ternary complex of PKR and IKKbeta, prolonging the polymers of ADP-ribose (PAR)-dependent nuclear factor kappa B (NF-kappaB) transactivation caused by DNA-damaging agents and confers acquired chemoresistance. We also identified a small molecule, MRS2578, which strikingly abrogated the binding of LRP16 to PKR and IKKbeta, converting LRP16 into a death molecule and forestalling colon tumorigenesis. Inclusion of MRS2578 with etoposide, versus each drug alone, exhibited synergistic antitumor cytotoxicity in xenografts. Our combinatorial approach introduces a strategy to enhance the efficacy of genotoxicity therapies for the treatment of tumors. PMID- 28820391 TI - Deep brain stimulation alters light phase food intake microstructure in rats. AB - Treatment of eating disorders like obesity or anorexia is challenging. Options are limited and new approaches desired. An interesting approach is the application of deep brain stimulation (DBS). The nucleus accumbens (NAcc) is part of the food reward system. A pilot study reported that DBS of the NAcc shell modulates food intake and body weight in rats. Underlying mechanisms such as the food intake microstructure are unknown so far. Normal weight female Sprague Dawley rats were equipped with a custom-made DBS electrode placed unilaterally in the NAcc shell. Biphasic stimulation was performed for seven days. Body weight and food intake including the microstructure were assessed over the experimental period. Behavior was monitored manually. DBS tended to increase body weight gain (28.1 +/- 5.4 g) compared to sham-stimulated controls (16.7 +/- 3.4, P = 0.05) without affecting daily food intake (P > 0.05). Further analyses showed that light phase food intake was stimulated, whereas dark phase food intake was decreased in the DBS group (P < 0.05). During the light phase bout frequency (+50%), bout duration (+64%), meal duration (+71%) and overall time spent in meals (+92%) were increased in DBS rats (P < 0.05), while during the dark phase no alterations were observed (P > 0.05). Behavior did not show differences regarding overall eating and drinking behavior (including food/water approach), grooming or locomotion (P > 0.05). Summarized, although overall food intake was not changed by DBS, light phase food intake was stimulated likely via a reduction of satiation. PMID- 28820392 TI - Orally administered angiotensin-converting enzyme-inhibitors captopril and isoleucine-proline-proline have distinct effects on local renin-angiotensin system and corticosterone synthesis in dextran sulfate sodium-induced colitis in mice. AB - The effects of angiotensin-converting enzyme (ACE) inhibition by an antihypertensive drug, captopril, and milk casein-derived ACE-inhibiting bioactive tripeptide isoleucine-proline-proline (Ile-Pro-Pro), on local renin angiotensin system (RAS) and glucocorticoid production in the intestine were studied in the dextran sodium sulfate induced colitis in mice. Mice received water or 3% dextran sodium sulfate with or without either 15.7 mg/l captopril or 833 mg/l Ile-Pro-Pro for 7 days. Captopril and Ile-Pro-Pro were found to have distinct effects on local renin-angiotensin system and mRNA expression of glucocorticoid synthesis components in colon in vitro. Captopril reduced intestinal mRNA expression of angiotensin-converting enzyme, angiotensinogen and Cyp11b1, whereas Ile-Pro-Pro reduced angiotensin-converting enzyme protein shedding from colon. Neither captopril nor Ile-Pro-Pro changed the expression of glucocorticoid-synthesis driving transcription factor Lrh-1 expression or intestinal glucocorticoid production. Contrary to previous studies, captopril did not alleviate DSS-induced colitis. Furthermore, Ile-Pro-Pro was mildly pro inflammatory as exhibited by increased pro-inflammatory cytokine interleukin 1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) levels in colon. The nutritional component Ile-Pro-Pro had different effect on intestinal RAS and glucocorticoid (GC) synthesis pathway than ACE inhibitor captopril, which suggests that the bioactivity of Ile-Pro-Pro is not limited to inhibition of ACE. PMID- 28820393 TI - Fibroblast growth factor-21 and omentin-1 hepatic mRNA expression and serum levels in morbidly obese women with non-alcoholic fatty liver disease. AB - Fibroblast growth factor-21 (FGF21) and omentin-1 have been recognized as potent antidiabetic agents with potential hepatoprotective activity. The aim of this study was to evaluate hepatic FGF21 and omentin-1 mRNA expression as well as their serum levels as predictive markers of liver injury and insulin resistance in morbidly obese women with non-alcoholic fatty liver disease (NAFLD). This study included 56 severely obese women who underwent intraoperative wedge liver biopsy during the bariatric surgery. Hepatic FGF21 and omentin-1 mRNA were assessed by quantitative real-time PCR, while their serum concentrations were measured with commercially available enzyme-linked immunosorbent assays. The FGF21 serum level was significantly higher in patients with a greater extent of steatosis (grade 2 and 3) compared to those without or with mild steatosis (grade 0 and 1) (P = 0.049). Receiver Operating Characteristic analysis, however, showed poor discriminant power for the FGF21 serum levels in differentiating between more and less extensive steatosis with an AUC = 0.666. There was a tendency towards higher levels of hepatic FGF21 mRNA in patients with lobular inflammation and fibrosis and towards lower levels in the case of hepatocyte ballooning and steatosis. There was a positive mutual correlation between hepatic FGF21 and omentin-1 mRNA levels (r = 0.78; P < 0.001). Fibrosis stage was associated with serum glucose and homeostatic model assessment for insulin resistance (HOMA-IR) (P = 0.03 and P = 0.02, respectively). Serum omentin-1 was not associated with histopathological features. The hepatic omentin-1 mRNA levels showed a tendency to be lower in patients with advanced steatosis and hepatocyte ballooning. In conclusion, our study, which focused on hepatic FGF21 and omentin-1 mRNA expression, confirmed marked expression of both molecules in the liver of morbidly obese patients with NAFLD. More extensive steatosis was associated with evident changes in the serum FGF21 concentration in morbidly obese women with NAFLD, but the difference did not reach statistical significance. The vast amount of fat, both visceral and subcutaneous, in severely obese patients may be the additional source and influence the FGF21 and omentin-1 serum levels. PMID- 28820394 TI - The C-terminal region of the focal adhesion kinase F1 domain binds Akt1 and inhibits pressure-induced cell adhesion. AB - Increased extracellular pressure or shear stress activate a complex signal pathway that stimulates integrin binding affinity and potentiates metastatic cell adhesion. Inhibiting either focal adhesion kinase (FAK) and Akt1 can block this pathway, but risks interfering with the diverse other functions of each kinase. However, the mechanotransduced signal pathway involves a novel Akt1-FAK interaction not required for most FAK or Akt1 function, so modeling and blocking this interaction seems a desirable target. Building upon previous work suggesting that FAK-Akt1 binding is mediated by the FAK F1 lobe, we demonstrated that independently expressing the F1 domain in human Caco-2 or murine CT-26 colon cancer cells by transient or stable inducible plasmid expression respectively prevents the stimulation of cancer cell adhesion by increased extracellular pressure. Serial further truncation of the FAK F1 lobe identified shorter regions capable of pulling down Akt1 on a glutathione S-transferase (GST) - conjugated column. Ultimately, we identified a 33 residue segment (residues 94-126) at the C terminal of the F1 lobe as sufficient to pull down Akt1. These findings raise the possibility of developing a treatment modality around the disruption of the FAK Akt1 interaction using peptides modeled from FAK. PMID- 28820395 TI - Chemokine (C-X-C motif) ligand 1 (CXCL1) and chemokine (C-X-C motif) ligand 2 (CXCL2) modulate the activity of TRPV1+/IB4+ cultured rat dorsal root ganglia neurons upon short-term and acute application. AB - CXCL1 and CXCL2 are two chemokines with 78% homology of their sequence. CXCL1 was associated with atopic dermatitis, a highly pruritic skin disease, but it is not clear what is its mechanism of action, while for CXCL2 there are no data about an association with itch sensitivity. CXCL1 and CXCL2 can modulate TRPV1 receptors, which are one of the most important downstream effectors for itch sensitivity, upon short-term (4 h) or long-term (24 h) incubation, but the data are incomplete. Therefore, the aims of this study were to better characterize the short-term effects of CXCL1 and CXCL2 on TRPV1+/IB4+ dorsal root ganglia neurons known to include nociceptor and itch-sensitive neurons, and to obtain new data about the acute application (12 min) of the two chemokines on the same population of neurons. The results showed that 4 nM CXCL1 and 3.6 nM CXCL2 significantly reduce TRPV1 desensitization in TRPV1+/IB4+ DRG +neurons after short-term incubation, but when acutely applied CXCL1 activated a sub-population of itch sensitive TRPV1+/IB4+ cells in a slow, low amplitude manner, while CXCL2 had a similar effect but on non-itch TRPV1+/IB4+ DRG neurons. These data contribute to a better understanding of CXCL1 and CXCL2 mechanism of action for both pain and itch inducing effects. PMID- 28820396 TI - The role of mTOR inhibitors and HMG-CoA reductase inhibitors on young and old endothelial cell functions, critical for re-endothelialisation after percutaneous coronary intervention: an in vitro study. AB - Percutaneous coronary intervention (PCI) has become a standard treatment in patients with acute coronary syndrome. However, it is associated with endothelial cell denudation, which may predispose to in-stent thrombosis and restenosis. Pharmacological methods which prevent restenosis can delay post-PCI re endothelialisation. We have therefore examined how atorvastatin (HMG-CoA reductase inhibitor), sirolimus and everolimus (mTOR inhibitors) affect young and old endothelial cell functions which are responsible for wound healing after PCI. Replicative senescence was induced by serial passages of human umbilical vein endothelial cells (HUVECs). The cells which were examined at their first passages and last passages were designated as 'young' and 'old' respectively. Young and old endothelium were grown to confluence and were wounded by scraping. Scratch healing in the presence or absence of atorvastatin (AT), rapamycin (SR) and everolimus (EV) was monitored by time-lapse microscopy. In addition cells were assessed for viability (MTT assay), migration (chemotaxis chamber), proliferation (3H-thymidine), and cytokine production (immunoassays). Senescent endothelial cells produce more proinflammatory cytokines, angiogenic VEGF and extracellular matrix proteins. They stop proliferating and have diminished migration. When compared to young endothelium, they have similar viability and can regenerate wounds in comparable time. The drugs that have been tested have anti-inflammatory properties but even after pretreatment old cells still produced significantly higher concentration of tested mediators in comparison with young ones. In the concentration obtained in serum after stent implantation, mTOR inhibitors in dose dependent manner reduced cell proliferation, migration and wound healing. Reduced healing is more pronounced in young endothelium. Atorvastatin, at clinically relevant concentration, is safe for young and old cells. Atorvastatin, sirolimus and everolimus inhibited the secretion of pro-inflammatory mediators in young and old endothelium. In concentrations seen in serum during standard therapy, rapalogs impair endothelial cell regeneration after injuries mimicking those occurring during PCI, while atorvastatin does not affect the healing. PMID- 28820397 TI - Long-term feeding with bioactive tripeptides in aged hypertensive and normotensive rats: special focus on blood pressure and bradykinin-induced vascular reactivity. AB - Bradykinin is the main player of the kallikrein-kinin system. Bradykinin-induced vasodilatation is age-dependent; this is believed to be associated with the level of expression of the two bradykinin receptors (BR1 and BR2) in the vasculature. The aim of this study was to clarify bradykinin-induced vascular reactivity of spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto rats (WKY) after 6 weeks' consumption of a drink containing bioactive tripeptides (Ile-Pro Pro, Val-Pro-Pro and Leu-Pro-Pro). Two age groups were used: young (10 weeks at the end of experiment) and old (24 weeks). Blood pressure was monitored weekly by the tail-cuff method. After six weeks, vascular reactivity was assessed in vitro in mesenteric artery rings focusing on bradykinin induced activity. Blood pressure was lowered in old SHR after 6 weeks' tripeptide consumption compared to water drinking controls (P < 0.05). Blood pressure was lowered by peptide consumption also in old WKY (P < 0.05) but tripeptide consumption exerted no effect on the blood pressure of young animals. Old SHR suffered from endothelial and smooth muscle dysfunction which was not improved by these tripeptides. Interestingly, bradykinin caused vasoconstriction even in young SHR; this was blocked by a non-selective cyclooxygenase (COX) inhibitor but not by a B1 and B2 receptor antagonist. The expressions of mRNA of COX-1 and COX-2 in aorta were slightly upregulated in old SHR. ACE-1 activity in aorta and protein level in kidney, but not ACE-1 mRNA expression was upregulated in old animals (P < 0.05). To conclude, long-term feeding with a drink containing tripeptides lowers or prevents the age-associated increase in blood pressure in hypertensive and normotensive animals. ACE-1 activity, protein level but not mRNA expression are elevated in old animals. We also demonstrated that the vascular inflammation and dysfunction present in aged hypertensive animals cause bradykinin to induce vasoconstriction; this is not prevented by tripeptide feeding but involves the prostaglandin pathway. PMID- 28820398 TI - Chronic kidney disease leads to hypoxia inducible factor-1alpha to hypoxia inducible factor-2alpha switch in the gastrocnemius muscle. AB - Hipoxia inducible factor-1 and HIF-2 are responsible for the adaptation of cell metabolism to hypoxia. Previously, a more severe capillary rarefaction was found in locomotor than in postural muscles of uremic animals. The aim of this study was to analyze the expression patterns of HIF and prolyl hydroxylases (PHDs) in functionally different skeletal muscles in uremic rats, an experimental model of chronic kidney disease (CKD). Rats were randomized to sham operation - CON, uninephrectomy - CKD1/2 or subtotal nephrectomy - CKD5/6. After 4 weeks, expression of HIF-1alpha and -2alpha and PHD proteins was measured using WB in locomotor, gastrocnemius muscle (MG) and postural, longissimus thoracis muscle (ML). Serum concentrations of creatinine (Cr), hemoglobin (Hb), haptoglobin (Hp), MCP-1, AGEs, homocysteine (Hcy) were measured. HIF-1alpha increased in MG and ML for CKD1/2 versus CON. HIF-1alpha decreased in MG and increased in ML for CKD5/6 versus CON and CKD1/2. HIF-2alpha increased in MG for CKD5/6 and CKD1/2 versus CON. HIF-2alpha was not detected in ML in any group. PHD1 was not detected in MG in any group. PHD1 in ML was not detected in CON, but increased in CKD5/6 and CKD1/2. PHD2 decreased in MG but increased in ML for CKD5/6 versus CKD1/2 and CON. PHD3 did not differ between groups in MG, but in ML decreased in CKD5/6 versus CON and CKD1/2. There were significant differences for CKD5/6 and CKD1/2 versus CON in: Cr (1.2 +/- 0.2; 0.7 +/- 0.1 versus 0.8 +/- 0.3 mg/dl), Hb (11.4 +/- 3.1; 13.7 +/- 0.7 versus 14.1 +/- 1 g/dl), Hp (1.6 +/- 0.6; 1.6 +/- 0.6 versus 0.7 +/- 0.4 mg/ml), AGEs (5.1 +/- 0.6; 4.3 +/- 1.2 versus 4.6 +/- 0.9 AU), Hcy (7.2 +/- 1.2; 5.1 +/- 0.5 versus 4.9 +/- 0.5 MUM), MCP-1 (609 +/- 255; 489 +/ 265 versus 292 +/- 113 pg/ml), respectively. CKD had a different effect on protein expression patterns of HIF-1alpha, -2alpha and PHDs depending on muscle type. A HIF-1alpha to HIF-2alpha switch in glycolytic MG in CKD5/6 might be a protective mechanism against tissue hypoxia and oxidative stress. PMID- 28820399 TI - Repetitive muscle compression reduces vascular mechano-sensitivity and the hyperemic response to muscle contraction. AB - Animal studies have shown that the rapid hyperemic response to external muscle compression undergoes inactivation upon repetitive stimulation, but this phenomenon has never been observed in humans. The aim of the present study was to determine whether 1) the vascular mechano-sensitivity underlying muscle compression-induced hyperemia is inactivated in an inter-stimulus interval (ISI) dependent fashion upon repetitive stimulation, as suggested by animal studies, and 2) whether such inactivation also attenuates contraction-induced hyperemia. Brachial artery blood flow was measured by echo Doppler sonography in 13 healthy adults in response to 1) single and repetitive cuff muscle compression (CMC) of the forearm (20 CMCs, 1 s ISI); 2) a sequence of CMC delivered at decreasing ISI from 120 to 2 s; and 3) electrically-stimulated contraction of the forearm muscles before and after repetitive CMC. The peak amplitude of hyperemia in response to CMC normalized to baseline decreased from 2.2 +/- 0.6 to 1.4 +/- 0.4 after repetitive CMC and, in general, was decreased at ISI < 240 s. The peak amplitude of contraction-induced hyperemia was attenuated after as compared to before repeated CMC (1.7 +/- 0.4 and 2.6 +/- 0.6, respectively). Mechano sensitivity of the vascular network can be conditioned by previous mechanical stimulation, and such preconditioning may substantially decrease contraction induced hyperemia. PMID- 28820400 TI - Alteration in expressions of RhoA and Rho-kinases during pregnancy in rats: their roles in uterine contractions and onset of labour. AB - Activation of RhoA and Rho-associated kinases (ROCKs) is known to play a pivotal role in the regulation of smooth muscle contraction via phosphorylation of myosin light chain and myosin phosphatase. There are few data on the RhoA and ROCKs expression levels in rat uteri. Therefore, our aim was to investigate the mRNA and protein concentration of RhoA and ROCKs in rat uterus during pregnancy, during parturition and post-partum using real time PCR and Western blot analysis. The other purpose was to evaluate the effects of the ROCK (Y-27632, fasudil and RKI 1441) and RhoA inhibitors (simvastatin) on uterine contractility in isolated organ bath experiments. The mRNA and protein levels of RhoA decreased on the 5th day of pregnancy to day 22, then a sharp increase was detected at term. The mRNA and protein concentration of ROCKs was down-regulated in the early stage of pregnancy, while it sharply increased during parturition. The RhoA-inhibitor simvastatin relaxed the uterus contractions, although its inhibitory effects were not followed by the alteration of RhoA. The strongest inhibitory effect of non selective ROCK inhibitor fasudil was found on non-pregnant uterus, while it elicited milder relaxation on day 22, during parturition and postpartum day 1. The maximum relaxing effects of Y-27632 and RKI 1441 were altered in a proportional way with the target protein expressions. The RhoA/ROCK signalling pathway might be a potential target for the development of new tocolytic agents; however, high specificity to RhoA, ROCK I or ROCK II seems to be fundamental to the high efficacy of uterine relaxation. PMID- 28820401 TI - Intraepidermal nerve fiber density in vulvar lichen sclerosus and normal vulvar tissues. AB - Lichen sclerosus (LS) is a chronic and inflammatory disease causing sensory symptoms such as itch and pain and affecting most frequently genital skin of women. Intraepidermal nerve fiber density (IENFD) was examined immunohistologically in 20 vulvar skin biopsies of patients affected by LS and in 20 control vulvar skin biopsies, in order to determine if these sensory sensations originate in changes in the epidermal innervation. Obtained results show fewer protein gene product 9.5 (PGP 9.5) positive intraepidermal nerve fibers (IENF) in LS tissues compared to controls (P = 0.004), while the number of calcitonin gene-related peptide (CGRP) positive IENF in LS was increased compared to normal vulvar tissue (P = 0.03). No differences in the number of vasoactive intestinal peptide (VIP) expressing IENF could be observed. To our best knowledge, this is the first study to describe intraepidermal nerve fiber density in vulvar LS. Significant differences in IENFD between LS and control skin samples, which have been found, point to the damage to the small nerve fibers in the disease process of LS, which may contribute to pathogenesis of LS sensory symptoms. PMID- 28820402 TI - Does signaling of estrogen-related receptors affect structure and function of bank vole Leydig cells? AB - To get a deeper insight into the function of estrogen-related receptors (ERRs) and dissect underlying mechanism in Leydig cells, ERRs (type alpha, beta and gamma) were blocked or activated in testes of adult bank voles (Myodes glareolus) which show seasonal changes in the intratesticular sex hormones level. Both actively reproducing animals (long day conditions; LD) and those with regression of the reproductive system (short day conditions; SD) received intraperitoneal injections of selective ERRalpha antagonist 3-[4-(2,4-Bis trifluoromethylbenzyloxy)-3-methoxyphenyl]-2-cyano-N-(5-trifluoromethyl-1,3,4 thiadiazol-2-yl)acrylamide (XCT 790) or selective ERRbeta/ERRgamma agonist N-(4 (Diethylaminobenzylidenyl)-N'-(4-hydroxybenzoyl)-hydrazine (DY131) (50 MU/kg bw; six doses every other day). Markedly more, XCT 790 (P < 0.05) but also DY131 affected interstitial tissue histology whose volume increased in both LD and SD males while seminiferous epithelium structure was untouched. Ultrastructure analysis revealed alterations in mitochondria number as well as endoplasmic reticulum and Golgi complexes volume and structure especially after ERRalpha blockage. Diverse and complex ERRs regulation at mRNA level and protein expression (P < 0.05; P < 0.01 and P < 0.001) of steroidogenic (lutropin receptor (LHR), translocator protein (TSPO), steroidogenic acute regulatory protein (StAR)) and secretory (insulin-like protein 3 (INSL3) and relaxin (RLN)) molecules were revealed in relations to endogenous estrogen level in treated males. Notably, immunolocalization of ERRs and above proteins, exclusively in Leydig cells, indicated their involvement in Leydig cell function control based on interactions with endogenous estrogen level and/or estrogen signaling via ERRs. Treatment with XCT 790 or DY131 significantly decreased (P < 0.05; P < 0.01 and P < 0.001) intratesticular estrogens concentration, with exception in SD DY131 males. In addition, androgens level was decreased, but not in LD DY131 voles. Similarly, ERRbetagamma activation significantly reduced (P < 0.05; P < 0.01 and P < 0.001) cAMP and calcium ions (Ca2+) concentrations particularly in DY131 voles. Overall, for the first time, we have shown that ERRs are involved in maintenance of Leydig cell architecture and supervision of its steroidogenic and secretory activity that is closely related to endogenous estrogen status in the testis. Further understanding of mechanism(s) by which individual types of ERRs can control Leydig cell function is relevant for predicting and preventing steroidogenic and spermatogenic disorders. PMID- 28820403 TI - High levels of soluble vascular endothelial growth factor receptor 1/sFlt1 and low levels of vascular endothelial growth factor in follicular fluid on the day of oocyte retrieval correlate with ovarian hyperstimulation syndrom regardless of the stimulation protocol. AB - The aim of the study was to assess the predictive value of vascular endothelial growth factor (VEGF), its soluble receptor - sVEGF-R1/sFlt1 and endocrine gland derived vascular endothelial growth factor (EG-VEGF) concentrations in serum and follicular fluid (FF) for ovarian hyperstimulation syndrome (OHSS) in women undergoing controlled ovarian hyperstimulation (COH) protocols. Patients have been divided into 3 groups: control group on natural cycle, patients stimulated with GnRH agonist and patients stimulated with GnRH antagonist. The FF and serum concentrations of VEGF, EG-VEGF, sVEGF R1 and the expression of VEGF and EG-VEGF mRNA in GC in small and large follicles collected from patients were investigated. When we compared all patients in a trial, OHSS occurrence was correlated with higher level of sVEGF R1 and a lower level of VEGF in a follicular fluid from large follicles in a day of oocyte retrieval. The VEGF/sVEGF-R1 ratio for patients in COH groups, above which the risk of developing OHSS is very low (OR 0.1 (95% CI 0.01 - 0.29, P = 0.0006) was found to be 0.281 pg/ml, with AUC - 0.738, P = 0.042, (95% CI 0.656 - 0.82). High levels of sVEGF-R1 and low level of VEGF in FF on the day of oocyte retrieval correlate with OHSS regardless of the stimulation protocol. PMID- 28820404 TI - RESPONDING PROFESSIONALLY TO REQUESTS FOR CESAREAN DELIVERY. AB - Patients' requests for non-indicated cesarean delivery challenge the professionalism of obstetricians. This is because physicians should not provide clinical management in the absence of an evidence-based indication for it. The ethics of responding professionally to requests for non-indicated cesarean delivery would appear to be simple: just say "No." This paper presents an ethically and clinically more nuanced approach, on the basis of the professional responsibility model of obstetric ethics, emphasizinga preventive ethics approach. Preventive ethics deploys the informed consent process to minimize ethical conflict in clinical practice. This process should focus on when to recommend against cesarean delivery - rather than simply saying no. There is no evidence of net clinical benefit for pregnant, fetal, and neonatal patients from non-indicated cesarean delivery. Obstetricians should therefore respond to such requests by recommending against cesarean delivery, recommending vaginal delivery, and explaining the evidence base for these recommendations. PMID- 28820405 TI - ANTIPHOSPHOLIPID SYNDROME AND MONOCYTES: NEW ASPECTS. AB - After discovery of antiphospholipid syndrome (APS) our understanding of molecular mechanisms of living matter has become more sophisticated and on this way monocytes has become crucial player, particularly in pathogenesis of APS. Thrombotic and non-thrombotic complications of APS could be explained by monocytes' activation too. But mechanisms underlying their activation are poorly investigated. So we aimed to determine transcriptional activity of monocytes after exposing them to low concentrations of lipopolysaccharide (LPS) and LPS+ATP using comparative of RT-PCR. Our study included eleven women suffering from recurrent miscarriages and APS (mean age 30+/-5,6 years). Nine healthy women (mean age of 29+/-8,5 years) without a positive family history of APS, autoimmune diseases and thrombosis were chosen as a control group. The results showed increasing levels of TLR2, IL-23, CCL2, CXCL10, IL-1beta and IL-6 in APS cells, while in healthy cells LPS resulted in IL-6 and STAT3 elevated mRNAs. Double stimulation of APS cells resulted in decreased mRNA levels of CCL-2, IL-1beta, and mRNA NLRP3 in healthy cells. At the same time TLR2 mRNAs were elevated in both groups after double stimulation. Thus increased sensitivity of APS cells to LPS may contribute to thrombus formation. Low concentration of ATP diminishes LPS induced inflammatory state of APS monocytes, which might be one of potential regulatory mechanisms. PMID- 28820406 TI - [RESULTS OF PREPARATION AND IMPLEMENTATION OF IVF PROGRAM IN PATIENTS WITH THROMBOPHILIA AND HISTORY OF FAILED IVF]. AB - The problem of infertility and reproductive losses maintains its urgency, as well as medical and social significance. Frequency of infertility in overall population, according to the data from different authors, varies from 9 to 18 per cent. Methods of aided reproductive technologies (ART) opened a new era in the field of correction of infertile marriage. As a result, more and more couples choose to solve this problem by means of aided reproductive technologies (ART): in-vitro fertilization (IVF) and embryo transfer (ET). However, despite of all achievements, the frequency of pregnancy development remains relatively low and makes 25-30% per treatment cycle, furthermore, during the last decade this value did not change to any significant extent. Analysis of literature sources revealed that genetic, acquired and combined forms of thrombophilia, which often cause severe complications at ART, are among main causes of IVF failures. The aim of the research was to develop and to introduce main principles of prophylaxis of repeated IVF failures in women with thrombophilia and history of failed IVF. In order to achieve the goal we have examined 80 patients (main group) with genetic, acquired or combined thrombophilia, identified on the first stage of standard examination. One of the main reasons of IVF failure is genetic, acquired or combined thrombophilia. Delivery of pathogenetically justified antithrombotic prophylaxis (75 mg. of aspirin and low molecular heparin - enoxaparinum) in patients with thrombophilia and history of failed IVFs allowed improvement of hemostasiogram profile and efficiency of IVF. Frequency of pregnancy in patients with history of failed IVF after the therapy made 31,3% in the first cycle of simulation (in 25 women), 20,0% in the second cycle of simulation (in 16 women) and 11,3% (9 women) in the third cycle. Due to justified antithrombotic prophylaxis 50 cases of pregnancy was registered (62,5%). Introduction of long term therapy with application of antithrombotic preparations and vitamins in continuous mode promoted successful course of pregnancy, occurred as a result of IVF in patients with history of failed IVF. PMID- 28820407 TI - [EVALUATION OF PARAMETERS OF HEMOSTASIS IN THE THIRD TRIMESTER IN PREGNANT WOMEN WITH CONGENITAL HEMORRHAGIC DIATHESIS]. AB - The aim is to study the coagulogram indices in the III trimester of pregnancy in women with hemophilia and von Willebrand disease. Twenty-seven pregnant women with hereditary coagulopathies of mild and moderate form (mean age 27.9+/-3.3 years) in the third trimester of pregnancy were examined. Of the examined 12 women - carriers of hemophilia A and B, 15 - with Willebrand disease (BV). Clinico-laboratory examination, clinical and biochemical blood tests were carried out. Coagulologic examination was performed on 17 parameters. The mean gestation period was 38.5+/-1.04 weeks. In 81.5% of cases, the headache was determined, in 18.5% - the pelvic presentation. Pregnancy was complicated by placental insufficiency in 51.8% of cases, in 14.8% of cases there was a lag in the development of the fetus. In pregnant women with hemophilia prothrombin time was increased: by 18.9% and by 8.8% - in women with BV. In the third trimester of pregnancy, a significant increase in APTT, the duration of bleeding (according to Dike), and the prolongation of Lee White's coagulation time in pregnant women with hemophilia are noted in both groups of women under analysis. In pregnant women with congenital hemorrhagic diathesis, coagulogram parameters should be determined in each trimester. PMID- 28820408 TI - [THROMBOPHILIC GENETIC MUTATIONS AND POLYMORPHISMS IN WOMEN WITH INFERTILITY AND FAILED IN VITRO FERTILIZATION]. AB - : Occurrence of pregnancy after in vitro fertilization depends of two components: functional adequacy of the embryo at the blastocyst stage and receptivity of endometrium, which, according to modern perception, are determinate in achieving optimal conditions of implantation. From the pregnancy occurrence point of view, as well as in regard to its further development , implantation is the most crucial phase of IVF/ICSI and ET. As the same time, this phase is also the most vulnerable. Multiple researches have proven the role of mother thrombophilia for genesis of gestation complications and early embryo losses, but in relation to this problem i the context of IVF there is still a lot to be detailed. The objective of this work was to increase the efficiency of IVF and to research the causes of IVF failures, related to thrombophilic genetic mutations and polymorphisms. In order to achieve the set goal 354 women with infertility, who turned to the department of aided reproductive technologies (ART) for infertility treatment by means of IVF, were examined. 237 (66,9%) of women had primary infertility, 117 (33,1%) - secondary infertility. To 228 of these women the IVF (in vitro fertilization) program was introduced for the first time (study group 1), 126 patients had failed IVF history (1 to 9 failed attempts). Patients were 23 to 43 years of age. Obtained results confirm the relation between hemostasis defects, change of hemostasis system activity and efficiency of IVF. CONCLUSIONS: One of the main reason of IVF failure and, probably, of infertility is the hemostasis system disturbance of thrombophilic nature. High correlation is established between the hemostasis system disturbance of thrombophilic nature, preconditioned by genetic mutations and polymorphisms, as well as failed IVFs. Failure of IVF is the indication for expanded examination of genetically determined factors of hemostasis system. In case of presence of genetic defects of thrombophilic nature in hemostasis system the risk of failure in IVF program is 2 and more times higher. PMID- 28820409 TI - [THE ROLE OF ANGIOGENIC FACTORS IN THE DIAGNOSTICS OF PREGNANCY COMPLICATED WITH PREECLAMPSIA]. AB - The pathophysiology of preeclampsia remains largely unknown. It has been hypothesized that placental ischemia is an early event, leading to placental production of a soluble factor or factors that cause maternal endothelial dysfunction, resulting in the clinical findings of hypertension, proteinuria, and edema. Here, we confirm that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of vascular growth factor (VEGF) and placental growth factor (PIGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt1. Our research demonstrate that increased circulating sFlt1 in III trimester in patients with preeclampsia is associated with decreased circulating levels of free VEGF and PIGF, resulting in endothelial dysfunction, comparing with control group. These observations suggest that excess circulating sFlt1 contributes to the pathogenesis of preeclampsia. 45 pregnant women with preeclampsia of different severity degrees were under observation. Control group included 20 healthy pregnant. Pregnant women with preeclampsia were subdivided into 2 groups. There were 11 (24,4%) pregnant with severe degree of preeclamsia (I group), the II group included 34 pregnant with mild degree of preeclampsia. Increased expression of soluble tyrosine kinase-1 (sFlt-1), together with decreased PIGF and VEGF signaling, were first abnormalities described. Thus, determination of levels angiogenic factors: PIGF, VEGF and sFlt-1 is very important for prediction severity of preeclampsia. PMID- 28820410 TI - [CHANGING OF STILLBIRTH RISKS IN DIFFERENT OPTIONS OF ITS REGISTRATION]. AB - Purpose of the study - comparing of stillbirth rates and some of its risk factors in different options (after 22 and 28 completed weeks of gestation) of its registration. This study was conducted on the basis of a regional prenatal centre. Monitoring was conducted retrospectively with continuous coverage of all cases of completed pregnancy after 22 completed weeks of gestation. Stillbirth coefficient was calculated based on body weight (500 grams or more - I option, and a 1000 grams - II option) based on 100 of all birth cases (corresponding to 500 grams body weight or more, and 1,000 grams or more). According to data of Lenkoran Prenatal Centre 5,420/00 (95% confidence interval: 5,02-5,82) of born with body mass 500 grams and more (22 and more completed gestation weeks) are stillborns. Stillbirth factors are mother's age (25 years and more), the first, third and more birth, excess body weight of the mother, maternal hypertension and diabetes. Planned transfer to registration of alive birth cases after 22 completed weeks of gestation (weight 500 grams or more) will be associated with multiple growth of officially registered cases of stillbirth. Preventing the risk of growth of stillbirth may be gained by prenatal obstetric care. PMID- 28820411 TI - [IMPORTANCE OF SHEAR WAVE ELASTOGRAPHY OF LIVERS IN PRACTICALLY HEALTHY PREGNANT WOMEN]. AB - Pulse-wave elastography (SWE) that is one of the mostly used methods in the recent years holds important place in assessment of liver fibrosis. However there is no exact information on the results of liver elastography in healthy pregnant women in the world literature. The aim of the study was to investigate theSWE parameters of liver elastography in practically healthy pregnant women. The subject of the research was 50 practically healthy pregnant women within 18-45 years old (mean age 27.7+/-0.7). The pregnant women with genital and extragenital diseases were not included to the research. The research work was executed in the II Department of Obstetrics and Gynecology of Azerbaijan Medical University. SWE of liver in pregnant women was conducted in the I Department of Surgical Diseases of Azerbaijan Medical University through Supersonic Aixplorer Multi Wave device presented by the Scientific Development Foundation under the President of the Azerbaijan Republic. The obtained tissue hardness indicators are assessed under METAVIR scale. The results of the research showed that the measures of liver in practically healthy pregnant women are normal, edges flat, its echogenicity mainly normal, echostructure of its parenchyma homogenous, hardness was F0-F1 (normal) under METAVIR scale, fibrosis not observed. The obtained results were processed by variational (power average, percentile distribution) and correlation (rho-Spearman) analyzes using the statistical package SPSS-20. A statistical study of the distribution of liver density in healthy women showed that the average density was 4,43+/-0,01 with 95% confidence interval (4,23 - 4,63). The histogram of distribution of liver density in practically healthy women belongs to the family of normal distributions with coefficients of variation coefficient (16.3%), asymmetry (-0.861+/-0.337) and excess (-0.068+/-0.662). Correlation analysis in healthy women did not reveal a reliable relationship between age and liver density (rho=0.082, p=0.571), but a significant inverse correlation was found between the body mass index (BMI) and liver density (rho=-0.317; p=0.025). Easy application, non-invasiveness, maximum exactness within the real time, repeatedly application of procedure and no risk to fetus by Shear Wave elastography of liver allow applying this method in pregnant women. Study of liver elasticity in pregnant women allows assessing the grades of hepatic fibrosis and differentiating liver disease. PMID- 28820412 TI - [TO THE STATE OF THE FETOPLACENTAL COMPLEX IN WOMEN WITH THE THREAT OF ABORTION]. AB - : The goal is a comprehensive study of the morphofunctional state of the mother placenta-fetus system in placental insufficiency and infection. 250 pregnant and puerperas for the period 2008-2014 were examined. Detection of bacterial flora was carried out in 35 pregnant women aged 20.4+/-0.8 years with the threat of abortion from an early gestation period and a prolonged persistent infection of the genitals, bacterial vaginosis. Methods are applied: culture, ion chromatography, gas-liquid chromatography with mass spectrometry. The presence of placental insufficiency was found in 32.0% of patients. In the vagina, Staphylococcus epidermidis, Escherichia coli (culture method), in the vagina and placenta of the bacteria of the genus Staphylococcus aureus, Proteus mirabilis, Klebsiella pneumoniae (IC method) were detected; Proponibacterium, Bacteroides Afipia, Helocobacter musteloe, Actinomyces, Candida albicans. In the placental suspension, Pentadiecanoic acid, 14-methyl, methyl ester, Octadecanoic acid, methyl ester, 9-Octadecanoic acid, methyl ester (E), 9-Octadecanoic acid, methyl ester (Z), 9-12 Octadecanoic acid, methyl Ester (EE), Eicosanoic acid, methyl ester, 12,15 Octadecanoic acid, methyl ester (ZZZ). CONCLUSIONS: 1. The spectrum of detected microorganisms indicates the possibility of detecting not only aerosols, but also facultative anaerobes, capsular bacteria, facultative intracellular parasites using chromatomass spectrometry. 2. The detected infectious factor, which causes placental insufficiency, is confirmed by morphotopographic diagnosis. PMID- 28820413 TI - [INFECTIOUS CAUSES OF MISCARRIAGE]. AB - The aim of thiswork was to find out the infection causes and to assess the species composition of microflora of the vagina and cervix in women with miscarriage and chronic endometritis. The investigation of66 womenwith miscarriage (MC) with histological criteria of chronic endometritis (CE) has been done (main group). The control group consistsof 20 healthywomen of reproductiveage. The marked changes in the vagina and cervical canal mikroflora in women with MC and CE are registered. The latter is expressed is quantitative reduction of lactobacilli (20% and 75% in vagina, 7,5% and 60% in cervical canal in main and control groups correspondingly)andincrease in the number of opportunistic pathogens. Allthe aboveleads to imbalance of microflora of the vaginaand cervical canalthus contributing to theascentof infection from thelower part to the upper part of reproductive tract. These data regarding the disorders of vaginal and cervical microflora in women of the group indicates its pathogenic role in the development of miscarriage on the bases of chronic endometritis. The data obtainedallow to recommend theassessment of themicroflora of the vaginaandcervixin women withMC and CE forthe development of adequatepregravidar therapy. PMID- 28820414 TI - [IDENTIFICATION OF CAUSES OF EARLY PREGNANCY LOSSES ACCORDING TO HYSTOMORPHOLOGIC FEATURES]. AB - Retrospective analysis of the early spontaneous abortions has been conducted (486 cases). Histomorphologic analysis of the curettage material contents erveledinvolutive-regressive developmental chsnges in 108 (22,28%) cases, in 370 cases (77.78%) pathologic changes, like inflammatory changes of deciduas and chorionic villis in 302 cases (80.2%), pathologic prematurity of chorionic vili in 48 cases (12.6%), hydatidiform mole in 28 cases (7.4%). As most cases of pregnancy loss has been reported at 7-9 weeks /172 cases/, we compared histomorphologic data revealed at 7-8 (71 cases) weeks to 5-6 (135 cases) and 10 12 weeks of gestation. Morphologic research data confimed, that at 7-8 weeks compared to 5-6 weeks leading reason ofpregnancy loss was inflammatory changes (OR-1,584), what can be cause of 110 pregnancy losses at 1000 pregnant women (AR 0.11). Data comparing7-9 weeks to 10-12 weeks pregnancy losses, confirm the priority of pathologic immaturity (OR-1,279) and hydatidiform mole (OR-1,557) and could be the risk of 100 cases of pregnancy termination at 1000 pregnant women (AR-0.10).Existing results are of great importance for the preconceptional preparation of women. PMID- 28820415 TI - [COMPLICATIONS OF PREGNANCY, RESULTING FROM ASSISTED REPRODUCTIVE TECHNOLOGY]. AB - When pregnancy occurs as a result of assisted reproductive technologies (ART), there are more chances of developing complications and adverse outcomes for the mother and fetus compared to spontaneous pregnancies. Taking into account the noted features, the purpose of our study was to determine the nature of the complications of induced pregnancy and their frequency, depending on the causes of infertility. Under our supervision were 86 women with induced single pregnancy. Two clinical groups were formed depending on the causes of infertility: group I was represented by 53 observations, in which infertility of endocrine genesis took place; Group II included 33 women with tubal peritoneal infertility. Pregnancy, resulting from ART, should be attributed to the group at high risk of complications of pregnancy. Among the causes of female infertility, the tubal peritoneal factor is the least dangerous in terms of the complicated course of the gestational process, and the endocrine factors that can cause a two fold increase in the frequency of the threat of abortion and pre-eclampsia are more dangerous. In turn, the cause of endocrine infertility are various factors that need to be determined when predicting the course of induced pregnancy. A special feature of maintaining this category of pregnant women is the constant observation and correction of dyshormonal disorders, which not only cause anovulation, but can also negatively affect the course of pregnancy. PMID- 28820416 TI - [OVARIAN RESERVE AND EFFECTIVENESS OF IVF IN WOMEN OF VARIOUS AGE GROUPS]. AB - The purpose of this study is a comparative assessment of ovarian reserve parameters and the effect of these indices on the features of follicle and oogenesis in women of different age groups. A retrospective analysis of IVF results was conducted in 101 patients aged 21 to 49 years. All patients were divided into 4 groups according to age: I group up to 30 y.o. - 45 women, II group - 31-35 y.o - 14 women, III group - 36-40 y.o. - 26 women, IV Group - 41 or more - 16 women. A low ovarian reserve was found in the majority (84,6%) of women in group III and in all women in group IV. It was found that the lowest total dose of rFSH / hMG was used in women aged 21-30 years and 31-35 years, and in women in the age range of 36-40 years, the consumption of drugs was significantly higher and tended to further increase in the age group 41 and more years. A large consumption of rFSH/hMG is necessary to overcome the growing FSH level in the process of aging of the reproductive system and the reduced AMH level. However, at the same time, compared age groups had significant differences in the number of oocytes and embryos obtained. With age, a significant reduction in the number of mature oocytes and embryos obtained after follicle puncture and fertilization has been identified. The most promising in terms of pregnancy were the I and II groups. With age, the frequency of pregnancy decreased. The number of pregnancies was statistically lower in the III age group compared to groups I and II. In the IV group, no cases of pregnancy were recorded. Thus, it can be concluded that age is a statistically significant factor affecting the success of infertility treatment by IVF. PMID- 28820417 TI - [NEUROSONOGRAPHICAL CHARACTERISTICS OF DYSMATURE INFANTS DEPENDING ON CONDUCTED NEUROPROTECTION]. AB - The actual problem of modern obstetrics is a preterm delivery (PD), its tactics as the matter of specialists' discussions. One of the main components of "preterm delivery considerate management" is the conduction of fetus neuroprotection. Currently, the only wide spread preparation for fetus neuroprotection is magnesium sulphate, the advisability of that is criticized by several authors. The 62 neonatals of recurrent delivering women with monocarpous pregnancy, who delivered with 27-28- week gestation, were examined. Two groups were formed: the first included 37 women with conduction of neuroprotection, the second group - 25 cases without it. The neonatals of both groups had neurosonography to determine the quantity and severity of intraventricular hemorrhage (IVH). It has been determined that the conduction of neuroprotection does not significantly reduce IVH frequency at neonatals with gestation period of 27 - 28 weeks. It has a pronounced influence on IVH severity structure reducing its the degree by 3 or 4 from 69,2% to 27,7% (2,5 ties). PMID- 28820418 TI - PATHOLOGICAL ADHERENCE OF PLACENTA - CASE REPORTS. AB - Major obstetric hemorrhage is the leading cause of maternal morbidity and mortality. In rare cases, life-threatening hemorrhage in pregnant women may result from abnormal adherence of placenta. Three grades of abnormal placental attachment are defined according to the depth of invasion: placenta accreta, placenta increta, and placenta percreta. An important risk factor for placenta abnormal adherence of placenta is placenta previa in the presence of a uterine scar. The increased prevalence of cesarean section, uterine surgery, and increasing parturient age and parity have led to an increased incidence of abnormal placentation, from one in 2,500 a quarter century ago, to one in 533 deliveries currently. Placenta percreta significantly increases risk for both maternal and fetal morbidity and mortality. Placental invasion of the bladder carries a maternal morbidity of 9.5% and perinatal mortality of 24%. Prevention of the maternal death in the condition when the patients have uterine scarring or a history of other invasive procedures may be improved by the adequate preoperative diagnostics of these conditions. When it involves the urinary bladder, a multidisciplinary approach utilizing a team of physicians and surgeons representing urology, radiology, and obstetrics-gynecology is the key to successful management. PMID- 28820419 TI - [THE STATE OF FALLOPIAN TUBES IN WOMEN WITH UROGENITAL CHLAMYDIA AND INFERTILITY]. AB - The aim of this work was to assess the state of the fallopian tubes in women with urogenital chlamydia (UC) and infertility. 344 women 18-49 y.o with infertility have been investigated. UC was detected in 133 of them -38.7%, (main group), UC was absent in 211 (61.3%) patients (comparision group). In the main group prevailed the tubal or tubal peritoneal factor of infertility (51.9% versus 19.4% in the comparison group, p<0.001). UC in women in the main (62.4%) was in the form of mixed infection. Obstruction of the fallopian tubes and adhesions in the pelvic region were more often detected in patients of the main group (p<0.05). The most pronounced lesions of the fallopian tubes were observed in women with chlamydial mixed infection. Adhesive process in the small pelvis was established by laparascopy in 72.2% of women in the main group and in 27.8% in the comparison group (p<0.001). There was a correlation between the extent of the adhesion process in the small pelvis and the presence of chlamydial mixed infection. A histological study was carried out of the tissues of the fallopian tubes in 12 women diagnosed with an ectopic pregnancy, 5 of whom had UC. Women with UC have alternating areas with signs of acute inflammation and various stages of the reparative processand in 4 women with UC the above mentioned signs and sclerosis were detected also in the the submucosa, which can cause destruction of the functional activities of the fallopian tubes and obstruction as well. All this causes a violation of the transport of spermatozoa, the embryo and leads to a ectopic pregnancy and infertility. Obtained results explain the inefficiency of restoring reproductive function in women after elimination of UC with preserved patency of the fallopian tubes. PMID- 28820420 TI - ALTERATIONS IN PLACENTA REDOX-STATUS DURING EXPERIMENTAL MODEL OF HYPOXIA-INDUCED PREECLAMPSIA. AB - An important pathogenetic link of preeclampsia (PE) is hypoxia of uterine placental tissues, accompanied by damage of the vascular endothelium and the release of vasoactive mediators, violate vascular tone and microcirculation in the maternal organism and placenta and development of a number of pathological processes in the mother's and fetus body. The aim of the study was to establish metabolic abnormalities of oxidative metabolism of the placenta during experimental model of PE (uterine/placental hypoxia). Studies were performed in pregnant Wistar rats. Chronic reductions in uterus placental perfusion in rats, reduced uterine perfusion pressure by 35% to 45% during first trimester (10-th day) gestation was reached by placing a silk ligature around the abdominal aorta below the renal arteries and narrowed aortic lumen, in the third of its diameter (0.2 mm). All rats undergoing surgical procedures were anesthetized with 2% ether. The animals were sacrificed under ether anesthesia on 25th day of pregnancy under the Ether anesthesia and extirpation of genital system with a fetus was made. The histopathological study of placenta tissue, investigation of free NO, it's metabolites (HbNO and FeSNO) and lipoperoxides content and blood antioxidant enzymes (catalase and superoxide dismutase) activity was performed. The study's results indicate that during experimental model of PE oxidative stress conditions in rats developed, free nitric oxide content significant decreased and increased content of nitric oxide complexes with hemic and non hemic iron (FeSNO, HbNO). These data indicate that nitrosilation is crucial mechanism by which NO regulates placental metabolic pathways. By histopathological studies revealed an infringement of the process placentation, involution, destructive changes in varying degrees in the placenta of rats of hypoxia group in the end of the third trimester. These data indicate, that disorders of the placental blood supply are responsible for the alteration of its oxidative metabolism, development of the placenta's hypoxia, intensification of oxidative stress and disturbance of placenta's blood vessels proliferation and blood circulation, that brings the father dangerous complications of fetus. PMID- 28820421 TI - [THE ROLE OF PAPILLOMAVIRUS INFECTION IN THE DEVELOPMENT OF BACKGROUND DISEASE OF THE CERVIX]. AB - Papillomavirus infection is one of the most common sexually transmitted infections. The aim of the study was to study the etiologic significance of the papillomavirus infection in the development of background diseases of the cervix and neoplasia. Under observation were 62 patients aged 18 to 55 years infected with human papillomavirus. All patients underwent complex clinical and anamnestic, laboratory and instrumental examination. Also, a review and advanced colposcopy was performed. As a result of the study, 53 (85.4%) women under observation were found to have various pathologies of the cervix. Dysplasia of mild degree (CIN 1 degree) was found in 12 (57.1%), moderate dysplasia (CIN 2 degree) - in 9 (42.9%) women. With further examination, it was found that patients along with dysplasia of varying severity had concomitant pathology of the cervix uteri. Cervical dysplasia was most often diagnosed in combination with another pathology of the cervix, which accounted for 85.7% of cases. It has been established that squamous epithelial lesion of the cervix is most often a consequence of late diagnosis and an untreated background process. At the same time, modern diagnostics requires a whole range of diagnostic measures to establish a diagnosis in the early stages of development and conduct differential diagnosis of a benign or malignant process. PMID- 28820422 TI - [THE FREQUENCY OF FACTORS CONTRIBUTING TO THE FORMATION OF ADHESIONS IN THE ABDOMINAL CAVITY IN WOMEN]. AB - To determine the major factor that contributed to the formation of adhesions in the abdominal cavity in women with a history of surgical interventions, examined 86 women with adhesive disease (main group) in the past have suffered various surgeries. The average age of patients was 35,7+/-5,6 years. Clinical examination of patients included a collection of complaints, anamnesis of disease and life, physical examination. The degree of adhesion process in the abdominal cavity was evaluated according to the classification of the American Fertility Society (R AFS, 1985) and the macroscopic scale proposed by N.I. Ayushinova and co-authors. I severity of adhesions was detected in 32 (37.2%) II stage - in 13 (15.1%), grade III - 14 (16.3%) and IV degree in 27 (31.4%) patients. The duration of the adhesive process averaged 6.3+/-0.6 years. Adhesions lasting 1-3 years met in 43.0% of cases, 4-5 years - in 31.4% of cases and more than 5 years - in 25.6% of cases. The reason for the formation of adhesions served as inflammatory diseases at 39.5%, gynecological surgeries - in 32.7% of patients, appendectomy - 20.9%, surgery for acute intestinal obstruction - in 5.8% of patients. After laparotomy adhesions of grade III-IV were formed in 62.5% after laparoscopy - in 33.0% of cases, ie, in 1,9 times less (p <0,05). Adhesions in the abdominal cavity occurs in 39.5% of patients after salpingoophoritis and sexually transmitted infections, as well as in 32.7% women undergoing gynecological surgery. In 32.0% of patients with salpingoophoritis and 44.4% of STIs, there is a III-IV degree of adhesion. The frequency of high adhesion after laparotomy is 62.5%, after laparoscopy - 33.3%. PMID- 28820423 TI - [RISK FACTORS AND SPECIAL ASPECTS FORGENITAL TUBERCULOSIS DIAGNOSTICS]. AB - Was examined 453 women, who applied to National Center for Tuberculosis and Lung Diseases for genital tuberculosis diagnostics. GTB was detected in 289 cases, in 164 cases GTB results was negative (control group). In 10 cases GTB was combined with pulmonary tuberculosis (OR-1,13). Risk factors are previous diseases of female reproductive organs- intracellular infection (OR-1,08), sexually transmitted diseases (OR-1,25), nonspecific inflammatory diseases (OR-1,009), interruption of pregnancy (OR-1,26), artificial abortions (OR-1,11), the most specific signs of Genital Tuberculosis is a pain in the stomach area (P-0,023), dysmenorrhoea (P-0,00001), intestinal obstruction (P-0,0006), heat (P-0,00001), liquid presence in posterior vault (P-0,007), hydrosalpinx (P-0,00001), Fallopian tubes deformation (P-0,000003), oophoritic cyst (P-0,067), adhesive process in small pelvis (P-0,0006). Lab tests used to study material showed high specificity of cytological (Sp - 78,05%), bacteriological (Sp - 96.4%) and morphological (Sp 98.78%) methods, as a result of their low sensitivity (Se - 28.03%, 96.4%, 98.78%, respectively). As for PCR diagnostics, in this case both the sensitivity and specificity is of high level (Se - 77.98%, Sp - 82.11%). PMID- 28820424 TI - Observation of self-polarization in BSA protected Au20 clusters. AB - Bovine serum albumin (BSA)-protected gold clusters (atomicity ~ 20), prepared using a wet chemical route, show strong dipolar radiative transition with a gap energy of 1.93 eV due to the high oscillator strength, as confirmed by the emission studies. Self-arrangement of the clusters with fixed atomicity yields a low dispersive dielectric and electric self-polarization nature. The electrical hysteresis loop measurements returned a remanent polarization of 0.05 MUC cm-2, which can be correlated with the dipolar orientation (activation energy ~ 45.32 meV), originating from the structure-dependent deformation of the charge density. PMID- 28820425 TI - Bioinformatics Analysis of Phylogeny and Transcription of TAA/YUC Auxin Biosynthetic Genes. AB - Auxin is a main plant growth hormone crucial in a multitude of developmental processes in plants. Auxin biosynthesis via the tryptophan aminotransferase of arabidopsis (TAA)/YUCCA (YUC) route involving tryptophan aminotransferases and YUC flavin-dependent monooxygenases that produce the auxin indole-3-acetic acid (IAA) from tryptophan is currently the most researched auxin biosynthetic pathway. Previous data showed that, in maize and arabidopsis, TAA/YUC-dependent auxin biosynthesis can be detected in endoplasmic reticulum (ER) microsomal fractions, and a subset of auxin biosynthetic proteins are localized to the ER, mainly due to transmembrane domains (TMD). The phylogeny presented here for TAA/TAR (tryptophan aminotransferase related) and YUC proteins analyses phylogenetic groups as well as transmembrane domains for ER-membrane localisation. In addition, RNAseq datasets are analysed for transcript abundance of YUC and TAA/TAR proteins in Arabidopsis thaliana. We show that ER membrane localisation for TAA/YUC proteins involved in auxin biosynthesis is already present early on in the evolution of mosses and club mosses. ER membrane anchored YUC proteins can mainly be found in roots, while cytosolic proteins are more abundant in the shoot. The distribution between the different phylogenetic classes in root and shoot may well originate from gene duplications, and the phylogenetic groups detected also overlap with the biological function. PMID- 28820426 TI - Burn Eschar Stimulates Fibroblast and Adipose Mesenchymal Stromal Cell Proliferation and Migration but Inhibits Endothelial Cell Sprouting. AB - The majority of full-thickness burn wounds heal with hypertrophic scar formation. Burn eschar most probably influences early burn wound healing, since granulation tissue only forms after escharotomy. In order to investigate the effect of burn eschar on delayed granulation tissue formation, burn wound extract (BWE) was isolated from the interface between non-viable eschar and viable tissue. The influence of BWE on the activity of endothelial cells derived from dermis and adipose tissue, dermal fibroblasts and adipose tissue-derived mesenchymal stromal cells (ASC) was determined. It was found that BWE stimulated endothelial cell inflammatory cytokine (CXCL8, IL-6 and CCL2) secretion and migration. However, BWE had no effect on endothelial cell proliferation or angiogenic sprouting. Indeed, BWE inhibited basic Fibroblast Growth Factor (bFGF) induced endothelial cell proliferation and sprouting. In contrast, BWE stimulated fibroblast and ASC proliferation and migration. No difference was observed between cells isolated from dermis or adipose tissue. The inhibitory effect of BWE on bFGF-induced endothelial proliferation and sprouting would explain why excessive granulation tissue formation is prevented in full-thickness burn wounds as long as the eschar is still present. Identifying the eschar factors responsible for this might give indications for therapeutic targets aimed at reducing hypertrophic scar formation which is initiated by excessive granulation tissue formation once eschar is removed. PMID- 28820428 TI - Pharmacokinetic Analysis of an Oral Multicomponent Joint Dietary Supplement (Phycox(r)) in Dogs. AB - Despite the lack of safety, efficacy and pharmacokinetic (PK) studies, multicomponent dietary supplements (nutraceuticals) have become increasingly popular as primary or adjunct therapies for clinical osteoarthritis in veterinary medicine. Phycox(r) is a line of multicomponent joint support supplements marketed for joint health in dogs and horses. Many of the active constituents are recognized anti-inflammatory and antioxidant agents. Due to a lack of PK studies in the literature for the product, a pilot PK study of select constituents in Phycox(r) was performed in healthy dogs. Two novel methods of analysis were developed and validated for quantification of glucosamine and select polyphenols using liquid chromatography-tandem mass spectrometry. After a single oral (PO) administrated dose of Phycox(r), a series of blood samples from dogs were collected for 24 h post-dose and analyzed for concentrations of glucosamine HCl, hesperetin, resveratrol and naringenin. Non-compartmental PK analyses were carried out. Glucosamine was detected up to 8 h post-dose with a Tmax of 2 h and Cmax of 9.69 MUg/mL. The polyphenols were not found at detectable concentrations in serum samples. Co-administration of glucosamine in the Phycox(r) formulation may enhance the absorption of glucosamine as determined by comparison of glucosamine PK data in the literature. PMID- 28820429 TI - Propofol's Effects on the Fetal Brain for Non-Obstetric Surgery. AB - While the use of Propofol has been increasing in usage for general surgical procedures since its release to market, there has been little work done on its potential link to neurotoxicity in humans. Only recently, following the release of a warning label from the United States Food and Drug Administration (USFDA) regarding a potential link to "neurotoxicity" in the neonate, did the surgical and anesthesiology communities become more aware of its potential for harm. Given the widespread use of this drug in clinical practice, the warning label naturally raised controversy regarding intrapartum Propofol usage. While intended to generate further studies, the lack of a viable anesthetic alternative raises issues regarding its current usage for surgical procedures in pregnant women. To answer the question whether current evidence is supportive of Propofol usage at its current levels in pregnant women, this review summarizes available evidence of fetal Propofol exposure in animal studies. PMID- 28820427 TI - A Review of the Neuropsychological Dimensions of Tourette Syndrome. AB - Neurocognitive functioning in Tourette syndrome (TS) has been the subject of intensive research in the past 30 years. A variety of impairments, presumably related to frontal and frontostriatal dysfunctions, have been observed. These impairments were found in various domains, such as attention, memory, executive functions, language, motor and visuomotor functions, among others. In line with contemporary research, other neurocognitive domains have recently been explored in TS, bringing evidence of altered social reasoning, for instance. Therefore, the aims of this review are to give an overview of the neuropsychological dimensions of TS, to report how neuropsychological functions evolve from childhood to adulthood, and to explain how various confounding factors can affect TS patients' performance in neuropsychological tasks. Finally, an important contribution of this review is to show how recent research has confirmed or changed our beliefs about neuropsychological functioning in TS. PMID- 28820430 TI - Surface-Enhanced Raman Scattering in Molecular Junctions. AB - Surface-enhanced Raman scattering (SERS) is a surface-sensitive vibrational spectroscopy that allows Raman spectroscopy on a single molecular scale. Here, we present a review of SERS from molecular junctions, in which a single molecule or molecules are made to have contact from the top to the bottom of metal surfaces. The molecular junctions are nice platforms for SERS as well as transport measurement. Electronic characterization based on the transport measurements of molecular junctions has been extensively studied for the development of miniaturized electronic devices. Simultaneous SERS and transport measurement of the molecular junctions allow both structural (geometrical) and electronic information on the single molecule scale. The improvement of SERS measurement on molecular junctions open the door toward new nanoscience and nanotechnology in molecular electronics. PMID- 28820431 TI - High-Throughput Screening Assay for Laccase Engineering toward Lignosulfonate Valorization. AB - Lignin valorization is a pending issue for the integrated conversion of lignocellulose in consumer goods. Lignosulfonates (LS) are the main technical lignins commercialized today. However, their molecular weight should be enlarged to meet application requirements as additives or dispersing agents. Oxidation of lignosulfonates with fungal oxidoreductases, such as laccases, can increase the molecular weight of lignosulfonates by the cross-linking of lignin phenols. To advance in this direction, we describe here the development of a high-throughput screening (HTS) assay for the directed evolution of laccases, with lignosulfonate as substrate and the Folin-Ciocalteau reagent (FCR), to detect the decrease in phenolic content produced upon polymerization of lignosulfonate by the enzyme. Once the reaction conditions were adjusted to the 96-well-plate format, the enzyme for validating the assay was selected from a battery of high-redox potential laccase variants functionally expressed in S. cerevisiae (the preferred host for the directed evolution of fungal oxidoreductases). The colorimetric response (absorbance at 760 nm) correlated with laccase activity secreted by the yeast. The HTS assay was reproducible (coefficient of variation (CV) = 15%) and sensitive enough to detect subtle differences in activity among yeast clones expressing a laccase mutant library obtained by error-prone PCR (epPCR). The method is therefore feasible for screening thousands of clones during the precise engineering of laccases toward valorization of lignosulfonates. PMID- 28820432 TI - Rho-Kinase Blockade Attenuates Podocyte Apoptosis by Inhibiting the Notch Signaling Pathway in Diabetic Nephropathy. AB - Podocyte apoptosis is a key process in the onset of diabetic nephropathy. A significant body of evidence shows that the Notch signaling pathway plays a central role in this process. We found that Rho-kinase mediates transforming growth factor beta (TGF-beta)-induced Notch ligand Jag1 expression. Importantly, TGF-beta-mediated podocyte apoptosis was attenuated by Rho-kinase inhibition. Mechanistically, Rho-kinase regulated Jag1 induction via the extracellular signal regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) but not Smad pathways. Consistently, the Rho-kinase inhibitor fasudil prevented albuminuria and the urinary excretion of nephrin in db/db mice and reduced the prevalence of podocyte apoptosis and Jag1 expression. Finally, the expression of Jag1 and apoptosis markers such as Bax and cyclin-dependent kinase inhibitor 1A (CDKN1A) was decreased in podocytes derived from db/db mice treated with fasudil. The present study provides evidence that Rho-kinase plays a key role in podocyte apoptosis. Rho-kinase is an attractive therapeutic target for diabetic nephropathy. PMID- 28820433 TI - Targeting Persistent Human Papillomavirus Infection. AB - While the majority of Human papillomavirus (HPV) infections are transient and cleared within a couple of years following exposure, 10-20% of infections persist latently, leading to disease progression and, ultimately, various forms of invasive cancer. Despite the clinical efficiency of recently developed multivalent prophylactic HPV vaccines, these preventive measures are not effective against pre-existing infection. Additionally, considering that the burden associated with HPV is greatest in regions with limited access to preventative vaccination, the development of effective therapies targeting persistent infection remains imperative. This review discusses not only the mechanisms underlying persistent HPV infection, but also the promise of immunomodulatory therapeutic vaccines and small-molecular inhibitors, which aim to augment the host immune response against the viral infection as well as obstruct critical viral-host interactions. PMID- 28820435 TI - Healthy Ageing in People with Intellectual Disabilities from Managers' Perspective: A Qualitative Study. AB - An increasing number of people with intellectual disability (ID) are reaching older ages today although they experience more health problems than the older population without ID. Leaders in intellectual disability services can greatly influence the conditions for a healthy ageing, and the aim of the present study was to explore healthy ageing in this group from the perspective of the leaders. Interviews with 20 leaders were subjected to qualitative content analysis. The findings gave rise to the overall theme ageing in dependence, which emerged from the following six categories: Supporting self-determination; Inaccessible activities after retirement; Signs of decline; Increased and specific needs for support and care; A non-question of gender; Aspects concerning the end of life and death. A prerequisite for healthy ageing in the case of people with ID is, according to the leaders, that they can live the life according to their preferences and make independent choices whilst at the same time receiving adequate support. With the shrinking of their social network after retirement, they become increasingly dependent on staff and leaders in the group home, who need to know what healthy ageing implies. PMID- 28820434 TI - Neuroprotective and Nerve Regenerative Approaches for Treatment of Erectile Dysfunction after Cavernous Nerve Injury. AB - Erectile dysfunction (ED) is a significant cause of reduced quality of life in men and their partners. Cavernous nerve injury (CNI) during pelvic surgery results in ED in greater than 50% of patients, regardless of additional patient factors. ED related to CNI is difficult to treat and typically poorly responsive to first- and second-line therapeutic options. Recently, a significant amount of research has been devoted to exploring neuroprotective and neuroregenerative approaches to salvage erectile function in patients with CNI. In addition, therapeutic options such as neuregulins, immunophilin ligands, gene therapy, stem cell therapy and novel surgical strategies, have shown benefit in pre-clinical, and limited clinical studies. In the era of personalized medicine, these new therapeutic technologies will be the future of ED treatment and are described in this review. PMID- 28820436 TI - Minimal Pruning and Reduced Plant Protection Promote Predatory Mites in Grapevine. AB - Improving natural pest control by promoting high densities of predatory mites (Acari: Phytoseiidae) is an effective way to prevent damage by pest mites (e.g., Eriophyidae, Tetranychidae) and other arthropod taxa that can cause serious damage to vineyards. Here, we investigate the influence of innovative management on predatory mite densities. We compare (i) full versus reduced fungicide applications and (ii) minimal pruning versus a traditional trellis pruning system in four fungus-resistant grapevine varieties. As predatory mites also feed on fungus mycelium, we assessed fungal infection of grapevine leaves in the experimental vineyard. Predatory mites were significantly more abundant in both minimal pruning and under reduced plant protection. Increases in predatory mites appeared to be independent of fungal infection, suggesting mostly direct effects of reduced fungicides and minimal pruning. In contrast to predatory mites, pest mites did not increase under innovative management. Thus, conditions for natural pest control are improved in fungus-resistant grapevines and under minimal pruning, which adds to other advantages such as environmental safety and reduced production cost. PMID- 28820438 TI - Tree Alignment Based on Needleman-Wunsch Algorithm for Sensor Selection in Smart Homes. AB - Activity recognition in smart homes aims to infer the particular activities of the inhabitant, the aim being to monitor their activities and identify any abnormalities, especially for those living alone. In order for a smart home to support its inhabitant, the recognition system needs to learn from observations acquired through sensors. One question that often arises is which sensors are useful and how many sensors are required to accurately recognise the inhabitant's activities? Many wrapper methods have been proposed and remain one of the popular evaluators for sensor selection due to its superior accuracy performance. However, they are prohibitively slow during the evaluation process and may run into the risk of overfitting due to the extent of the search. Motivated by this characteristic, this paper attempts to reduce the cost of the evaluation process and overfitting through tree alignment. The performance of our method is evaluated on two public datasets obtained in two distinct smart home environments. PMID- 28820439 TI - Efficacy and Safety of Letibotulinum Toxin A for the Treatment of Dynamic Equinus Foot Deformity in Children with Cerebral Palsy: A Randomized Controlled Trial. AB - The objective of this clinical trial was to compare the efficacy and safety of letibotulinum toxin A and onabotulinum toxin A for improving dynamic equinus foot deformity in children with cerebral palsy (CP). In total, 144 children with spastic CP who had dynamic equinus foot deformity were assigned randomly to the Botulax group (injection of letibotulinum toxin A) or the Botox group (injection of onabotulinum toxin A). The Physician's Rating Scale (PRS), ankle plantar flexor spasticity using the Modified Tardieu Scale, the Gross Motor Function Measure (GMFM)-88, and the GMFM-66 were completed before injection and at 6, 12, and 24 weeks after injection. The PRS responder rate was 60.27% in the Botulax group and 61.43% in the Botox group at 12 weeks after treatment, and the lower limit of the 95% confidence interval for the between-group difference in responder rates was -17.16%, higher than the non-inferiority margin of -24.00%. The clinical efficacy and the safety profiles of the groups did not significantly differ. The results suggest that injection of letibotulinum toxin A is as effective and safe as that of onabotulinum toxin A for the treatment of dynamic equinus foot deformity in children with spastic CP. PMID- 28820440 TI - Medical Students' Attitudes and Beliefs towards Psychotherapy: A Mixed Research Methods Study. AB - Background: Research findings suggest that attitudes towards psychotherapy predict willingness to seek therapy. However, understanding how medical students think about using and referring their patients for psychotherapy is limited. Aims: The aims of this study are to measure medical students' attitudes towards professional help seeking, and to investigate the reasons for whether or not they would refer their patients to psychotherapy in their future role as doctors. Method: The participants were 127 medical students in their first and second year of the MBBS4 programme at the Cyprus campus of St George's University of London, who completed a self-report measure of attitudes towards psychotherapy and a semi structured interview. Findings: Participants showed general positive attitudes towards psychotherapy, but were reluctant to use or refer their patients, largely due to perceived stigma and accessibility. Conclusions: Medical students should be further trained in order to become more confident in using psychotherapy and referring their patients. PMID- 28820437 TI - Are Astrocytes the Predominant Cell Type for Activation of Nrf2 in Aging and Neurodegeneration? AB - Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates hundreds of antioxidant genes, and is activated in response to oxidative stress. Given that many neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and multiple sclerosis are characterised by oxidative stress, Nrf2 is commonly activated in these diseases. Evidence demonstrates that Nrf2 activity is repressed in neurons in vitro, and only cultured astrocytes respond strongly to Nrf2 inducers, leading to the interpretation that Nrf2 signalling is largely restricted to astrocytes. However, Nrf2 activity can be observed in neurons in post-mortem brain tissue and animal models of disease. Thus this interpretation may be false, and a detailed analysis of the cell type expression of Nrf2 in neurodegenerative diseases is required. This review describes the evidence for Nrf2 activation in each cell type in prominent neurodegenerative diseases and normal aging in human brain and animal models of neurodegeneration, the response to pharmacological and genetic modulation of Nrf2, and clinical trials involving Nrf2-modifying drugs. PMID- 28820441 TI - Genome-Wide Interaction Study of Omega-3 PUFAs and Other Fatty Acids on Inflammatory Biomarkers of Cardiovascular Health in the Framingham Heart Study. AB - Numerous genetic loci have been identified as being associated with circulating fatty acid (FA) levels and/or inflammatory biomarkers of cardiovascular health (e.g., C-reactive protein). Recently, using red blood cell (RBC) FA data from the Framingham Offspring Study, we conducted a genome-wide association study of over 2.5 million single nucleotide polymorphisms (SNPs) and 22 RBC FAs (and associated ratios), including the four Omega-3 FAs (ALA, DHA, DPA, and EPA). Our analyses identified numerous causal loci. In this manuscript, we investigate the extent to which polyunsaturated fatty acid (PUFA) levels moderate the relationship of genetics to cardiovascular health biomarkers using a genome-wide interaction study approach. In particular, we test for possible gene-FA interactions on 9 inflammatory biomarkers, with 2.5 million SNPs and 12 FAs, including all Omega-3 PUFAs. We identified eighteen novel loci, including loci which demonstrate strong evidence of modifying the impact of heritable genetics on biomarker levels, and subsequently cardiovascular health. The identified genes provide increased clarity on the biological functioning and role of Omega-3 PUFAs, as well as other common fatty acids, in cardiovascular health, and suggest numerous candidate loci for future replication and biological characterization. PMID- 28820442 TI - Tuning Properties of Iron Oxide Nanoparticles in Aqueous Synthesis without Ligands to Improve MRI Relaxivity and SAR. AB - Aqueous synthesis without ligands of iron oxide nanoparticles (IONPs) with exceptional properties still remains an open issue, because of the challenge to control simultaneously numerous properties of the IONPs in these rigorous settings. To solve this, it is necessary to correlate the synthesis process with their properties, but this correlation is until now not well understood. Here, we study and correlate the structure, crystallinity, morphology, as well as magnetic, relaxometric and heating properties of IONPs obtained for different durations of the hydrothermal treatment that correspond to the different growth stages of IONPs upon initial co-precipitation in aqueous environment without ligands. We find that their properties were different for IONPs with comparable diameters. Specifically, by controlling the growth of IONPs from primary to secondary particles firstly by colloidal and then also by magnetic interactions, we control their crystallinity from monocrystalline to polycrystalline IONPs, respectively. Surface energy minimization in the aqueous environment along with low temperature treatment is used to favor nearly defect-free IONPs featuring superior properties, such as high saturation magnetization, magnetic volume, surface crystallinity, the transversal magnetic resonance imaging (MRI) relaxivity (up to r2 = 1189 mM-1.s-1 and r2/r1 = 195) and specific absorption rate, SAR (up to 1225.1 W.gFe-1). PMID- 28820444 TI - A Novel Partial Discharge Localization Method in Substation Based on a Wireless UHF Sensor Array. AB - Effective Partial Discharge (PD) localization can detect the insulation problems of the power equipment in a substation and improve the reliability of power systems. Typical Ultra-High Frequency (UHF) PD localization methods are mainly based on time difference information, which need a high sampling rate system. This paper proposes a novel PD localization method based on a received signal strength indicator (RSSI) fingerprint to quickly locate the power equipment with potential insulation defects. The proposed method consists of two stages. In the offline stage, the RSSI fingerprint data of the detection area is measured by a wireless UHF sensor array and processed by a clustering algorithm to reduce the PD interference and abnormal RSSI values. In the online stage, when PD happens, the RSSI fingerprint of PD is measured via the input of pattern recognition for PD localization. To achieve an accurate localization, the pattern recognition process is divided into two steps: a preliminary localization is implemented by cluster recognition to reduce the localization region, and the compressed sensing algorithm is used for accurate PD localization. A field test in a substation indicates that the mean localization error of the proposed method is 1.25 m, and 89.6% localization errors are less than 3 m. PMID- 28820443 TI - Omega 3 Polyunsaturated Fatty Acids Improve Endothelial Dysfunction in Chronic Renal Failure: Role of eNOS Activation and of Oxidative Stress. AB - BACKGROUND: Endothelial dysfunction is a key vascular alteration in chronic kidney disease (CKD). Omega 3 (n-3) polyunsaturated fatty acids (PUFA) reduce vascular oxidative stress and inflammation. We investigated whether n-3 PUFA could reverse endothelial dysfunction in CKD by improving endothelial nitric oxide synthase (eNOS) function and oxidative stress. METHODS: 5/6 nephrectomized male Wistar rats (CKD; n = 10) and sham operated animals (SHAM; n = 10) were treated for 6 weeks with standard diet. An additional group of CKD rats were fed an n-3 PUFA enriched diet (CKD + PUFA; n = 10). We then measured endothelium dependent (EDD) and -independent vasodilation, markers of endothelial function and of oxidative stress in thoracic aortas. RESULTS: Compared to SHAM, in CKD aortas EDD and eNOS expression were reduced (p < 0.05) and 3-nitrotyrosine levels were increased, while expression of NADPH oxidase subunits NOX4 and p22phox was similar. In-vitro incubation with Tiron failed to reverse endothelial dysfunction in CKD. In CKD + PUFA, EDD improved (p < 0.05) compared with CKD rats, while blockade of eNOS by L-NAME worsened EDD. These effects were accompanied by increased (p < 0.05) eNOS and reduced (p < 0.05) expression of NOX4 and 3 nitrotyrosine levels. CONCLUSION: Collectively, these findings indicate that n-3 PUFA improve endothelial dysfunction by restoring NO bioavailability in CKD. PMID- 28820445 TI - Choline Intake and Its Food Sources in the Diet of Romanian Kindergarten Children. AB - The objective of this study is to assess the usual intake and food sources of choline in a group of Romanian kindergarten children. A cross-sectional study was performed among 71 children aged 4-6 years from four kindergartens from Cluj Napoca, Romania. Dietary intake data were collected by means of three-day food records. The mean (SD) daily intake of choline was 215 (32) mg/day, 22.5% of the participants fulfilling the adequate intake (AI) for children 4-6 years of age of 250 mg of choline per day. The main food sources were meat (mainly poultry), eggs, grains, cereals, and baked products (mainly bread), and dairy products (mainly milk). The results of the logistic regression analyses show that an appropriate consumption of choline/day was statistically significantly associated with the consumption of at least one egg per three days (OR = 7.5, p < 0.05), a minimum of two portions of milk or dairy products per day (500 mL milk or yoghurt, or 60 g of cheese/day) (OR = 4.4, p < 0.05), and at least one portion of meat/day (90 g/day) (OR = 14.4, p < 0.05). The results underline the need for future surveys in this field, as well as actions to encourage an appropriate diet for children, including an appropriate content of choline. PMID- 28820446 TI - Towards Scalable Strain Gauge-Based Joint Torque Sensors. AB - During recent decades, strain gauge-based joint torque sensors have been commonly used to provide high-fidelity torque measurements in robotics. Although measurement of joint torque/force is often required in engineering research and development, the gluing and wiring of strain gauges used as torque sensors pose difficulties during integration within the restricted space available in small joints. The problem is compounded by the need for a scalable geometric design to measure joint torque. In this communication, we describe a novel design of a strain gauge-based mono-axial torque sensor referred to as square-cut torque sensor (SCTS), the significant features of which are high degree of linearity, symmetry, and high scalability in terms of both size and measuring range. Most importantly, SCTS provides easy access for gluing and wiring of the strain gauges on sensor surface despite the limited available space. We demonstrated that the SCTS was better in terms of symmetry (clockwise and counterclockwise rotation) and more linear. These capabilities have been shown through finite element modeling (ANSYS) confirmed by observed data obtained by load testing experiments. The high performance of SCTS was confirmed by studies involving changes in size, material and/or wings width and thickness. Finally, we demonstrated that the SCTS can be successfully implementation inside the hip joints of miniaturized hydraulically actuated quadruped robot-MiniHyQ. This communication is based on work presented at the 18th International Conference on Climbing and Walking Robots (CLAWAR). PMID- 28820447 TI - Comprehensive Study of Multiple Stages Progressing to Nonalcoholic Steatohepatitis with Subsequent Fibrosis in SD Rats. AB - Because of the absence of the time course of histological nonalcoholic fatty hepatitis with subsequent fibrotic progression, the effective approaches available for controlling the onset and progression of non-alcoholic steatohepatitis (NASH) remain limited. Therefore, we detected the serum and liver tissue related lipid metabolism disorder, liver pathology and relative molecular makers alteration dynamically in a high fat-sucrose diet during different time points. High fat-sucrose diet significantly increased the serum lipid level on day 10. The excess lipid accumulation in liver was referred to as simple steatosis after the feeding of a high fat-sucrose diet for 20 days. The high fat sucrose diet induced a hepatic inflammation response on day 30. Similarly, hepatic fibrosis was also initiated on day 30 and gradually formed from the 30th to the 50th day. Oxidative stress may be related with the process from NASH to liver fibrosis. Insulin resistance was involved in the progression from hepatic steatosis to NASH with hepatic fibrosis from the 20th to the 50th day. In conclusion, we established a high fat-sucrose diet induced nonalcoholic fatty hepatitis with liver fibrosis rat model, which presented the time course of histological nonalcoholic steatohepatitis and the initiation and progression change of characteristic molecular makers in the process from steatosis to hepatic fibrosis. PMID- 28820449 TI - Applying a Consumer Behavior Lens to Salt Reduction Initiatives. AB - Reformulation of food products to reduce salt content has been a central strategy for achieving population level salt reduction. In this paper, we reflect on current reformulation strategies and consider how consumer behavior determines the ultimate success of these strategies. We consider the merits of adopting a 'health by stealth', silent approach to reformulation compared to implementing a communications strategy which draws on labeling initiatives in tandem with reformulation efforts. We end this paper by calling for a multi-actor approach which utilizes co-design, participatory tools to facilitate the involvement of all stakeholders, including, and especially, consumers, in making decisions around how best to achieve population-level salt reduction. PMID- 28820448 TI - Vitamin D Status of Residents in Taiyuan, China and Influencing Factors. AB - High prevalence of vitamin D deficiency has been reported worldwide. Residents of Taiyuan, China, were predicted to be at high risk of vitamin D deficiency due to its high latitude, heavy air pollution, and cultural sun avoidance. This study investigated the vitamin D status of office workers, and explored the potential determinants of capillary 25-hydroxyvitamin D (25(OH)D) concentration as well as the relationship between 25(OH)D and metabolic syndrome. Two hundred participants, aged 20 to 80 years, were recruited. Capillary dried blood spot (DBS) 25(OH)D was measured; together with anthropometric (height, weight, and waist circumference), biochemical (serum lipid profile and fasting glucose) measures and a lifestyle questionnaire. Thirty-four percent of participants had 25(OH)D concentrations below 30 nmol/L, indicating deficient vitamin D status. Women's 25(OH)D (median; 32.7 nmol/L (upper and lower quartile; 25.8, 43.8)) was significantly lower than men (44.0 nmol/L (32.3, 55.4)) (p < 0.01). Female gender, higher fasting glucose, and increased smoking (p < 0.05) were negatively associated with 25(OH)D concentration. However, there was no association found between metabolic syndrome (MetS) and 25(OH)D concentration and no significant difference in vitamin D status between men or women with MetS compared to healthy individuals. Vitamin D deficiency was common in urban residents of Taiyuan in winter and more so in women than men. PMID- 28820451 TI - Dynamic Fuzzy-Logic Based Path Planning for Mobility-Assisted Localization in Wireless Sensor Networks. AB - Mobile anchor path planning techniques have provided as an alternative option for node localization in wireless sensor networks (WSNs). In such context, path planning is a movement pattern where a mobile anchor node's movement is designed in order to achieve a maximum localization ratio possible with a minimum error rate. Typically, the mobility path planning is designed in advance, which is applicable when the mobile anchor has sufficient sources of energy and time. However, when the mobility movement is restricted or limited, a dynamic path planning design is needed. This paper proposes a novel distributed range-free movement mechanism for mobility-assisted localization in WSNs when the mobile anchor's movement is limited. The designed movement is formed in real-time pattern using a fuzzy-logic approach based on the information received from the network and the nodes' deployment. Our proposed model, Fuzzy-Logic based Path Planning for mobile anchor-assisted Localization in WSNs (FLPPL), offers superior results in several metrics including both localization accuracy and localization ratio in comparison to other similar works. PMID- 28820450 TI - Transcriptome Analysis Reveals Long Intergenic Noncoding RNAs Contributed to Growth and Meat Quality Differences between Yorkshire and Wannanhua Pig. AB - There are major differences between Yorkshire (lean-type) and Wannanhua pig (fat type) in terms of growth performance and meat quality. Long intergenic noncoding RNAs (lincRNAs) are a class of regulators that are involved in numerous biological processes and widely identified in many species. However, the role of lincRNAs in pig is largely unknown, and the mechanisms by which they affect growth and meat quality are elusive. In this study, we used published data to identify 759 lincRNAs in porcine longissimus dorsi muscle. These putative lincRNAs shared many features with mammalian lincRNAs, such as shorter length and fewer exons. Gene ontology and pathway analysis indicated that many potential target genes (PTGs) of lincRNAs were involved in muscle growth-related and meat quality-related biological processes. Moreover, we constructed a co-expression network between differentially expressed lincRNAs (DELs) and their PTGs, and found a potential mechanism that most DELs can use to upregulate their PTGs, which may finally contribute to the growth and meat quality differences between the two breeds through an unknown manner. This work details some lincRNAs and their PTGs related to muscle growth or meat quality, and facilitates future research on the roles of lincRNAs in these two types of pig, as well as molecular assisted breeding for pig. PMID- 28820452 TI - Population-Based Study on the Effect of a Forest Environment on Salivary Cortisol Concentration. AB - The purpose of this study was to evaluate the effect of a forest environment on salivary cortisol concentration, particularly on the characteristics of its distribution. The participants were 348 young male subjects. The experimental sites were 34 forests and 34 urban areas across Japan. The subjects viewed the landscape (forest or urban environment) for a period of 15 min while sitting in a chair. Saliva was sampled from the participants at the end of this 15-min period and then analyzed for cortisol concentration. Differences in the skewness and kurtosis of the distributions between the two environments were tested by performing a permutation test. The cortisol concentrations exhibited larger skewness (0.76) and kurtosis (3.23) in a forest environment than in an urban environment (skewness = 0.49; kurtosis = 2.47), and these differences were statistically significant. The cortisol distribution exhibited a more peaked and longer right-tailed curve in a forest environment than in an urban environment. PMID- 28820453 TI - Drinking Water Uranium and Potential Health Effects in the German Federal State of Bavaria. AB - Mainly due to its nephrotoxic and osteotoxic potential, uranium (U) increasingly finds itself in the spotlight of environmental and health-related research. Germany decided on a binding U guideline value in drinking water of 10 ug/L, valid since 2011. It is yet widely unknown if and how public health was affected by elevated U concentrations before that. In this ecological study we summarized available drinking water U data for the German federal state of Bavaria (703 analyses in total for 553 different municipalities) at county level (for 76 out of 96 Bavarian counties, representing about 83% of Bavaria's and about 13% of Germany's total population) in terms of mean and maximum U concentration. Bavaria is known to regionally exhibit mainly geogenically elevated groundwater U with a maximum value of 40 ug/L in the database used here. Public health data were obtained from federal statistical authorities at county resolution. These included incidence rates of diagnosed diseases suspected to be potentially associated with chronic U uptake, e.g., diseases of the skeleton, the liver or the thyroid as well as tumor and genito-urinary diseases. The datasets were analyzed for interrelations and mutual spatial occurrence using statistical approaches and GIS as well as odds ratios and relative risks calculations. Weak but significant positive associations between maximum U concentrations and aggregated ICD-10 diagnose groups for growths/tumors as well as liver diseases were observed, elevated incidence rates of thyroid diseases seem to occur where mean drinking water U concentrations exceed 2 ug/L. Here, we discuss obtained results and their implications for potential impacts of hydrochemistry on public health in southeast Germany. PMID- 28820454 TI - Personal Hygiene Practices among Urban Homeless Persons in Boston, MA. AB - Persons experiencing homelessness in the United States experience significant barriers to self-care and personal hygiene, including limited access to clean showers, laundry and hand washing facilities. While the obstacles to personal hygiene associated with homelessness may increase risk of infectious disease, hygiene-related behaviors among people experiencing homelessness has received limited attention. We conducted a cross-sectional study of individuals experiencing homelessness in Boston, MA (n = 194) to identify hygiene-related self-care practices and risk factors for reduced hygiene in this population. Most participants (72%) reported taking a daily shower. More than 60% reported hand washing with soap five or more times each day, and use of hand sanitizer was widespread (89% reported using sanitizer in the last week). A majority (86%) used a laundromat or laundry machine to wash clothing, while 14% reported washing clothing in the sink. Heavy drinking, injection drug use, and sleeping outdoors were identified as significant risk factors for reduced hygiene practices. People experiencing homelessness who also engage in these activities may be among the most difficult to reach for intervention, yet targeted efforts may decrease illness risk associated with reduced hygiene. Housed friends and family play a critical role in assisting homeless individuals maintain hygiene by providing showers and laundry facilities. PMID- 28820455 TI - Beverage Intake among Children: Associations with Parent and Home-Related Factors. AB - Beverage intake can influence child diet quality in a positive or negative manner depending on the beverage type and amounts consumed. Parenting practices such as role modeling and control of home beverage availability have been associated with child beverage intake, whereas examination of the influence of parental beverage nutrition knowledge has been more limited. The purpose of this study was to examine the relationships between sugar-sweetened and dairy beverage intake among children (9-12 years) and home and parental factors. A questionnaire was administered among a convenience sample of parents (n = 194) to assess beverage nutrition knowledge, beverage intake and home availability of beverages. Children completed a questionnaire to estimate usual beverage intake. Daily sugar sweetened beverage intake by children ranged from 0.4 to 48 oz. Logistic regression analysis was used to examine relationships. Parents were mostly female, white, well educated, and employed. Home availability of sugar-sweetened and dairy beverages was positively associated with child sugar-sweetened (OR = 1.48, p = 0.03) and dairy beverage intake (OR = 1.34, p = 0.03), respectively. Parent dairy beverage intake was associated with child dairy beverage intake (OR = 1.06, p = 0.01). Parent knowledge about sugar in beverages was related to child dairy beverage intake (OR = 1.46, p = 0.02), whereas calcium/dairy knowledge and general beverage nutrition knowledge were not related to child beverage intake. Parenting practices and knowledge may play a role in determining child beverage intake. PMID- 28820456 TI - Deciphering Single Nucleotide Polymorphisms and Evolutionary Trends in Isolates of the Cydia pomonella granulovirus. AB - Six complete genome sequences of Cydia pomonella granulovirus (CpGV) isolates from Mexico (CpGV-M and CpGV-M1), England (CpGV-E2), Iran (CpGV-I07 and CpGV I12), and Canada (CpGV-S) were aligned and analyzed for genetic diversity and evolutionary processes. The selected CpGV isolates represented recently identified phylogenetic lineages of CpGV, namely, the genome groups A to E. The genomes ranged from 120,816 bp to 124,269 bp. Several common differences between CpGV-M, -E2, -I07, -I12 and -S to CpGV-M1, the first sequenced and published CpGV isolate, were highlighted. Phylogenetic analysis based on the aligned genome sequences grouped CpGV-M and CpGV-I12 as the most derived lineages, followed by CpGV-E2, CpGV-S and CpGV-I07, which represent the most basal lineages. All of the genomes shared a high degree of co-linearity, with a common setup of 137 (CpGV I07) to 142 (CpGV-M and -I12) open reading frames with no translocations. An overall trend of increasing genome size and a decrease in GC content was observed, from the most basal lineage (CpGV-I07) to the most derived (CpGV-I12). A total number of 788 positions of single nucleotide polymorphisms (SNPs) were determined and used to create a genome-wide SNP map of CpGV. Of the total amount of SNPs, 534 positions were specific for exactly one of either isolate CpGV-M, E2, -I07, -I12 or -S, which allowed the SNP-based detection and identification of all known CpGV isolates. PMID- 28820457 TI - Role of CYP2C9, CYP2C19 and EPHX Polymorphism in the Pharmacokinetic of Phenytoin: A Study on Uruguayan Caucasian Subjects. AB - Phenytoin (PHT) oxidative route leads to its main metabolite p-hydroxyphenytoin (p-HPPH), by means of CYP2C9 and CYP2C19. Formation of p-HPPH proceeds via a reactive arene-oxide intermediate. This intermediate can also be converted into PHT dihydrodiol by microsomal epoxide hydrolase (EPHX). The three enzymes are polymorphically expressed and the genetic variants are responsible for changes in the enzyme activity. In order to evaluate the effect that these polymorphisms have on PHT metabolism, PHT and p-HPPH plasma concentrations were measured and the genotype for the three enzymes was assessed in 50 Uruguayan epileptic patients. 30% of the patients were intermediate and 2% were poor metabolizers for CYP2C9, while 20% were intermediate metabolizers for CYP2C19. 44%, 10%, and 46% of subjects had intermediate, increased and decreased activities of EPHX respectively. CYP2C9 was confirmed to be the main responsible enzyme for PHT biotransformation. CYP2C19 seemed to be preponderant in p-HPPH oxidative metabolism. Apart from being responsible for the production of the dihydrodiol metabolite, EPHX also seemed to contribute to pHPPH formation when its activity is low. PHT might be recovered with a decreased activity of EPHX regardless the activity of CYP2C9. PMID- 28820458 TI - Electrochemical Biosensors for Rapid Detection of Foodborne Salmonella: A Critical Overview. AB - Abstract:Salmonella has represented the most common and primary cause of food poisoning in many countries for at least over 100 years. Its detection is still primarily based on traditional microbiological culture methods which are labor intensive, extremely time consuming, and not suitable for testing a large number of samples. Accordingly, great efforts to develop rapid, sensitive and specific methods, easy to use, and suitable for multi-sample analysis, have been made and continue. Biosensor-based technology has all the potentialities to meet these requirements. In this paper, we review the features of the electrochemical immunosensors, genosensors, aptasensors and phagosensors developed in the last five years for Salmonella detection, focusing on the critical aspects of their application in food analysis. PMID- 28820459 TI - Spices in a Product Affect Emotions: A Study with an Extruded Snack Product ?. AB - Food commonly is associated with emotion. The study was designed to determine if a spice blend (cinnamon, ginger, nutmeg, and cloves) high in antioxidants can evoke changes in consumer emotions. This was an exploratory study to determine the effects of these four spices on emotions. Three extruded, dry snack products containing 0, 4, or a 5% spice blend were tested. One day of hedonic and just about-right evaluations (n = 100), followed by three days of emotion testing were conducted. A human clinical trial (n = 10), using the control and the 4% samples, measured total antioxidant capacity and blood glucose levels. The emotion "Satisfied" increased significantly in the 5% blend, showing an effect of a higher spice content. The 4% blend was significantly higher in total antioxidant capacity than the baseline, but blood glucose levels were not significantly different. PMID- 28820460 TI - Determination of Sphingosine-1-Phosphate in Human Plasma Using Liquid Chromatography Coupled with Q-Tof Mass Spectrometry. AB - Evidence suggests that high-density lipoprotein (HDL) components distinct from cholesterol, such as sphingosine-1-phosphate (S1P), may account for the anti atherothrombotic effects attributed to this lipoprotein. The current method for the determination of plasma levels of S1P as well as levels associated with HDL particles is still cumbersome an assay method to be worldwide practical. Recently, a simplified protocol based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the sensitive and specific quantification of plasma levels of S1P with good accuracy has been reported. This work utilized a triple quadrupole (QqQ)-based LC-MS/MS system. Here we adapt that method for the determination of plasma levels of S1P using a quadrupole time of flight (Q-Tof) based LC-MS system. Calibration curves were linear in the range of 0.05 to 2 uM. The lower limit of quantification (LOQ) was 0.05 uM. The concentration of S1P in human plasma was determined to be 1 +/- 0.09 uM (n = 6). The average accuracy over the stated range of the method was found to be 100 +/- 5.9% with precision at the LOQ better than 10% when predicting the calibration standards. The concentration of plasma S1P in the prepared samples was stable for 24 h at room temperature. We have demonstrated the quantification of plasma S1P using Q-Tof based LC-MS with very good sensitivity, accuracy, and precision that can used for future studies in this field. PMID- 28820461 TI - Thermal Response Analysis of Phospholipid Bilayers Using Ellipsometric Techniques. AB - Biomimetic planar artificial membranes have been widely studied due to their multiple applications in several research fields. Their humectation and thermal response are crucial for reaching stability; these characteristics are related to the molecular organization inside the bilayer, which is affected by the aliphatic chain length, saturations, and molecule polarity, among others. Bilayer stability becomes a fundamental factor when technological devices are developed-like biosensors-based on those systems. Thermal studies were performed for different types of phosphatidylcholine (PC) molecules: two pure PC bilayers and four binary PC mixtures. These analyses were carried out through the detection of slight changes in their optical and structural parameters via Ellipsometry and Surface Plasmon Resonance (SPR) techniques. Phospholipid bilayers were prepared by Langmuir-Blodgett technique and deposited over a hydrophilic silicon wafer. Their molecular inclination degree, mobility, and stability of the different phases were detected and analyzed through bilayer thickness changes and their optical phase-amplitude response. Results show that certain binary lipid mixtures-with differences in its aliphatic chain length-present a co-existence of two thermal responses due to non-ideal mixing. PMID- 28820462 TI - Wettability Investigations and Wet Transfer Enhancement of Large-Area CVD Graphene on Aluminum Nitride. AB - The two-dimensional and virtually massless character of graphene attracts great interest for radio frequency devices, such as surface and bulk acoustic wave resonators. Due to its good electric conductivity, graphene might be an alternative as a virtually massless electrode by improving resonator performance regarding mass-loading effects. We report on an optimization of the commonly used wet transfer technique for large-area graphene, grown via chemical vapor deposition, onto aluminum nitride (AlN), which is mainly used as an active, piezoelectric material for acoustic devices. Today, graphene wet transfer is well engineered for silicon dioxide (SiO2). Investigations on AlN substrates reveal highly different surface properties compared to SiO2 regarding wettability, which strongly influences the quality of transferred graphene monolayers. Both physical and chemical effects of a plasma treatment of AlN surfaces change wettability and avoid large-scale cracks in the transferred graphene sheet during desiccation. Spatially-resolved Raman spectroscopy reveals a strong strain and doping dependence on AlN plasma pretreatments correlating with the electrical conductivity of graphene. In our work, we achieved transferred crack-free large area (40 * 40 mm2) graphene monolayers with sheet resistances down to 350 Omega/sq. These achievements make graphene more powerful as an eco-friendly and cheaper replacement for conventional electrode materials used in radio frequency resonator devices. PMID- 28820463 TI - Cycle Tracks and Parking Environments in China: Learning from College Students at Peking University. AB - China has a historic system of wide cycle tracks, many of which are now encroached by cars, buses and bus stops. Even with these conditions, college students still bicycle. On campuses, students park their bikes on facilities ranging from kick-stand-plazas to caged sheds with racks, pumps and an attendant. In other countries, including Canada, some of the newer cycle tracks need to be wider to accommodate an increasing number of bicyclists. Other countries will also need to improve their bike parking, which includes garage-basement cages and two-tiered racks. China could provide lessons about cycle tracks and bike parking. This study applied the Maslow Transportation Level of Service (LOS) theory, i.e., for cycle tracks and bike parking, only after the basic needs of safety and security are met for both vehicle occupants and bicyclists can the higher needs of convenience and comfort be met. With random clustering, a self administered questionnaire was collected from 410 students in six dormitory buildings at Peking University in Beijing and an environmental scan of bicycle parking conducted in school/office and living areas. Cycle tracks (1 = very safe/5 = very unsafe) shared with moving cars were most unsafe (mean = 4.6), followed by sharing with parked cars (4.1) or bus stop users (4.1) (p < 0.001). Close to half thought campus bike parking lacked order. The most suggested parking facilities were sheds, security (guard or camera), bicycle racks and bicycle parking services (pumps, etc.). If parking were improved, three quarters indicated they would bicycle more. While caged sheds were preferred, in living areas with 1597 parked bikes, caged sheds were only 74.4% occupied. For the future of China's wide cycle tracks, perhaps a fence-separated bus lane beside a cycle track might be considered or, with China's recent increase in bike riding, shared bikes and E-bikes, perhaps cars/buses could be banned from the wide cycle tracks. In other countries, a widened cycle track entrance should deter cars. Everywhere, bike parking sheds could be built and redesigned with painted lines to offer more space and order, similar to car parking. PMID- 28820465 TI - Vertical-Strip-Fed Broadband Circularly Polarized Dielectric Resonator Antenna. AB - A vertical-strip-fed dielectric resonator antenna exhibiting broadband circular polarization characteristics is presented. A broad 3 dB axial ratio bandwidth (ARBW) is achieved by combining multiple orthogonal modes due to the use of a special-shaped dielectric resonator. The proposed antenna is fabricated to evaluate its actual performance capabilities. The antenna exhibits a measured 3 dB ARBW of 44.2% (3.35-5.25 GHz), lying within a -10 dB reflection bandwidth of 82.7% (2.44-5.88 GHz). The measured peak gain within 3 dB ARBW is found to be 5.66 dBic at 4.8 GHz. The measured results are in good agreement with the simulated results. PMID- 28820464 TI - Enhanced Susceptibility of Ogg1 Mutant Mice to Multiorgan Carcinogenesis. AB - The role of deficiency of oxoguanine glycosylase 1 (Ogg1) Mmh homolog, a repair enzyme of the 8-hydroxy-2'-deoxyguanosine (8-OHdG) residue in DNA, was investigated using the multiorgan carcinogenesis bioassay in mice. A total of 80 male and female six-week-old mice of C57BL/6J background carrying a mutant Mmh allele of the Mmh/Ogg1 gene (Ogg1-/-) and wild type (Ogg1+/+) mice were administered N-diethylnitrosamine (DEN), N-methyl-N-nitrosourea (MNU), N-butyl-N (4-hydroxybutyl) nitrosamine (BBN), N-bis (2-hydroxypropyl) nitrosamine (DHPN) and 1,2-dimethylhydrazine dihydrochloride (DMH) (DMBDD) to induce carcinogenesis in multiple organs, and observed up to 34 weeks. Significant increase of lung adenocarcinomas incidence was observed in DMBDD-treated Ogg1-/- male mice, but not in DMBDD-administered Ogg1+/+ animals. Furthermore, incidences of lung adenomas were significantly elevated in both Ogg1-/- males and females as compared with respective Ogg1-/- control and DMBDD-treated Ogg1+/+ groups. Incidence of total liver tumors (hepatocellular adenomas, hemangiomas and hemangiosarcomas) was significantly higher in the DMBDD-administered Ogg1-/- males and females. In addition, in DMBDD-treated male Ogg1-/- mice, incidences of colon adenomas and total colon tumors showed a trend and a significant increase, respectively, along with significant rise in incidence of simple hyperplasia of the urinary bladder, and a trend to increase for renal tubules hyperplasia in the kidney. Furthermore, incidence of squamous cell hyperplasia in the forestomach of DMBDD-treated Ogg1-/- male mice was significantly higher than that of Ogg1+/+ males. Incidence of small intestine adenomas in DMBDD Ogg1-/- groups showed a trend for increase, as compared to the wild type mice. The current results demonstrated increased susceptibility of Ogg1 mutant mice to the multiorgan carcinogenesis induced by DMBDD. The present bioassay could become a useful tool to examine the influence of various targets on mouse carcinogenesis. PMID- 28820466 TI - A DFT Calculation of Fluoride-Doped TiO2 Nanotubes for Detecting SF6 Decomposition Components. AB - Gas insulated switchgear (GIS) plays an important role in the transmission and distribution of electric energy. Detecting and analyzing the decomposed components of SF6 is one of the important methods to realize the on-line monitoring of GIS equipment. In this paper, considering the performance limits of intrinsic TiO2 nanotube gas sensor, the adsorption process of H2S, SO2, SOF2 and SO2F2 on fluoride-doped TiO2 crystal plane was simulated by the first-principle method. The adsorption mechanism of these SF6 decomposition components on fluorine-doped TiO2 crystal plane was analyzed from a micro perspective. Calculation results indicate that the order of adsorption effect of four SF6 decomposition components on fluoride-doped TiO2 crystal plane is H2S > SO2 > SOF2 > SO2F2. Compared with the adsorption results of intrinsic anatase TiO2 (101) perfect crystal plane, fluorine doping can obviously enhance the adsorption ability of TiO2 (101) crystal plane. Fluorine-doped TiO2 can effectively distinguish and detect the SF6 decomposition components based on theoretical analysis. PMID- 28820467 TI - Aquaporin-4 Functionality and Virchow-Robin Space Water Dynamics: Physiological Model for Neurovascular Coupling and Glymphatic Flow. AB - The unique properties of brain capillary endothelium, critical in maintaining the blood-brain barrier (BBB) and restricting water permeability across the BBB, have important consequences on fluid hydrodynamics inside the BBB hereto inadequately recognized. Recent studies indicate that the mechanisms underlying brain water dynamics are distinct from systemic tissue water dynamics. Hydrostatic pressure created by the systolic force of the heart, essential for interstitial circulation and lymphatic flow in systemic circulation, is effectively impeded from propagating into the interstitial fluid inside the BBB by the tightly sealed endothelium of brain capillaries. Instead, fluid dynamics inside the BBB is realized by aquaporin-4 (AQP-4), the water channel that connects astrocyte cytoplasm and extracellular (interstitial) fluid. Brain interstitial fluid dynamics, and therefore AQP-4, are now recognized as essential for two unique functions, namely, neurovascular coupling and glymphatic flow, the brain equivalent of systemic lymphatics. PMID- 28820469 TI - A Third Generation Glucose Biosensor Based on Cellobiose Dehydrogenase Immobilized on a Glassy Carbon Electrode Decorated with Electrodeposited Gold Nanoparticles: Characterization and Application in Human Saliva. AB - Efficient direct electron transfer (DET) between a cellobiose dehydrogenase mutant from Corynascus thermophilus (CtCDH C291Y) and a novel glassy carbon (GC) modified electrode, obtained by direct electrodeposition of gold nanoparticles (AuNPs) was realized. The electrode was further modified with a mixed self assembled monolayer of 4-aminothiophenol (4-APh) and 4-mercaptobenzoic acid (4 MBA), by using glutaraldehyde (GA) as cross-linking agent. The CtCDH C291Y/GA/4 APh,4-MBA/AuNPs/GC platform showed an apparent heterogeneous electron transfer rate constant (ks) of 19.4 +/- 0.6 s-1, with an enhanced theoretical and real enzyme surface coverage (Gammatheor and Gammareal) of 5287 +/- 152 pmol cm-2 and 27 +/- 2 pmol cm-2, respectively. The modified electrode was successively used as glucose biosensor exhibiting a detection limit of 6.2 MUM, an extended linear range from 0.02 to 30 mM, a sensitivity of 3.1 +/- 0.1 MUA mM-1 cm-2 (R2 = 0.995), excellent stability and good selectivity. These performances compared favourably with other glucose biosensors reported in the literature. Finally, the biosensor was tested to quantify the glucose content in human saliva samples with successful results in terms of both recovery and correlation with glucose blood levels, allowing further considerations on the development of non-invasive glucose monitoring devices. PMID- 28820468 TI - Resveratrol in Hepatitis C Patients Treated with Pegylated-Interferon-alpha-2b and Ribavirin Reduces Sleep Disturbance. AB - BACKGROUND: Hepatitis C virus infection and interferon treatment have shown to be risk factors for sleep disorder health-related quality of life. AIM: To determine whether the effects of resveratrol on sleep disorders were associated with different tests in subjects with chronic hepatitis C treated with Peg-IFN-alpha and RBV. PATIENTS AND METHODS: In this prospective, randomized, placebo controlled, double blind clinical trial, 30 subjects (Group A) with chronic hepatitis received Pegylated-Interferon-alpha2b (1.5 mg/kg per week), Ribavirin and placebo (N-acetylcysteine 600 mg and lactoferrin 23.6 g), while 30 subjects (Group B) received the same dosage of Pegylated-Interferon-alpha2b, Ribavirin and association of N-acetylcysteine 600 mg, lactoferrin 23.6 g and Resveratrol 19.8 mg for 12 months. All subjects underwent laboratory exams and questionnaires to evaluate mood and sleep disorders (General Health Questionnaire (GHQ), Profile of Mood States (POMS), Pittsburgh Sleep Quality Inventory (PSQI), Epworth Sleepiness Scale (ESS)). RESULTS: The comparison between Group A and Group B showed significant differences after six months in C-reactive protein (p < 0.0001); after 12 months in aspartate aminotransferase (AST) (p < 0.0001) Viremia (p < 0.0001), HAI (p < 0.0012) and C-reactive protein (p < 0.0001); and at follow up in AST (p < 0.0001), Viremia (p < 0.0026) and C-reactive protein (p < 0.0001). Significant differences were observed after 12 month and follow-up in General Health Questionnaire, after 1, 6, 12 and follow-up in Profile of Mood States, after 6, 12, follow-up in Pittsburgh Sleep Quality Inventory and Epworth Sleepiness Scale. CONCLUSIONS: Supplementation with Resveratrol decreased General Health Questionnaire score and reduced sleep disorders in patients treated with Peg-IFN-alpha and RBV. PMID- 28820470 TI - Adaption of FMDV Asia-1 to Suspension Culture: Cell Resistance Is Overcome by Virus Capsid Alterations. AB - Foot-and-mouth disease virus (FMDV) causes a highly contagious disease with catastrophic economic impact for affected countries. BHK21 suspension cells are preferred for the industrial production of FMDV vaccine antigen, but not all virus strains can be successfully propagated in these cells. Serotype Asia-1 is often affected by this phenomenon. In this study, the Asia-1 strain Shamir was used to examine viral, cellular and environmental factors that contribute to resistance to cell culture infection. Cell media composition, pH and ammonium chloride concentration did not affect Asia-1 differently than other serotypes. Virus replication after transfection of viral genome was not impaired, but the adhesion to the cells was markedly reduced for Asia-1 in comparison to serotype A. The Asia-1 Shamir virus was successfully adapted to grow in the resistant cells by using a closely related but susceptible cell line. Sequence analysis of the adapted virus revealed two distinct mutations in the capsid protein VP1 that might mediate cell attachment and entry. PMID- 28820472 TI - Mussel-Inspired Dopamine and Carbon Nanotube Leading to a Biocompatible Self Rolling Conductive Hydrogel Film. AB - We report a novel self-rolling, conductive, and biocompatible multiwall carbon nanotube (MWCNT)-dopamine-polyethylene glycol (PEG) hydrogel film. The gel can self-fold into a thin tube when it is transferred from a glass slide to an aqueous environment, regardless of the concentrations of the MWCNT. The film presents a highly organized pattern, which results from the self-assembly of hydrophilic dopamine and hydrophobic carbon nanotubes. By exploring the biomedical potential, we found that MWCNT-included rolled film is nontoxic and can promote cell growth. For further functional verification by qPCR (quantitative polymerase chain reaction), bone marrow derived mesenchymal cells present higher levels of osteogenic differentiations in response to a higher concentration of CNTs. The results suggest that the self-rolling, conductive CNT dopamine-PEG hydrogel could have multiple potentials, including biomedical usage and as a conductive biosensor. PMID- 28820473 TI - Effect of Pullulan Coating on Postharvest Quality and Shelf-Life of Highbush Blueberry (Vaccinium corymbosum L.). AB - Fruits form an important part of a healthy human diet as they contain many ingredients with proven pro-health effects such as vitamins, phenolic compounds, organic acids, fiber, and minerals. The purpose of this work was to evaluate the effect of pullulan coating on the quality and shelf life of highbush blueberry during storage. General appearance, weight loss, dry matter, soluble solid content, reducing sugars, content of L-ascorbic acid, phenolic compounds (total phenolics, phenolics acids and anthocyanins) were determined in uncoated and coated blueberries fruits. The microbiological efficiency of pullulan coating was also evaluated. All parameters were monitored during storage at 4 degrees C and 16 degrees C by 28 and 14 days, respectively. The study showed that pullulan coating protects perishable food products especially susceptible to mechanical injury including fruits such as blueberries. Pullulan acts as a barrier that minimizes respiration rate, delaying deterioration and controlling microbial growth. PMID- 28820471 TI - Metal-Based Nanoparticles for the Treatment of Infectious Diseases. AB - Infectious diseases can be transmitted and they cause a significant burden on public health globally. They are the greatest world killers and it is estimated that they are responsible for the demise of over 17 million people annually. The impact of these diseases is greater in the developing countries. People with compromised immune systems and children are the most affected. Infectious diseases may be caused by bacteria, viruses, and protozoa. The treatment of infectious diseases is hampered by simultaneous resistance to multiple drugs, indicating that there is a serious and pressing need to develop new therapeutics that can overcome drug resistance. This review will focus on the recent reports of metal-based nanoparticles that are potential therapeutics for the treatment of infectious diseases and their biological efficacy (in vitro and in vivo). PMID- 28820475 TI - EpCAM Expression in Lymph Node Metastases of Urothelial Cell Carcinoma of the Bladder: A Pilot Study. AB - In this retrospective pilot study, the feasibility of the epithelial cell adhesion molecule (EpCAM) as an imaging target for lymph node (LN) metastatic disease of urothelial cell carcinoma (UCC) of the bladder was investigated. LN metastases and LNs without metastases of patients who underwent pelvic lymph node dissection because of muscle invasive bladder cancer (MIBC) were used. Primary tumors of the same patients were used from cystectomy specimen, transurethral resections, and biopsies. A pathologist, blinded to clinical data, scored EpCAM immunoreactivity. This method determines a total immunostaining score, which is the product of a proportion score and an intensity score. EpCAM expression was observed in 19/20 (95%) LNs with UCC metastases and in 11/12 (92%) of the primary tumors. EpCAM expression was absent in 14/14 (100%) LNs without metastases. Median EpCAM expression (TIS) in LN metastases was 5 (IQR 2.0-8.0) and in the primary tumors 6 (IQR 2.3-11.0). Based on the absence of staining in LNs without metastases, EpCAM show high tumor distinctiveness. EpCAM seems to be a feasible imaging target in LN metastases of UCC of the bladder. Pre- and perioperative visualization of these metastases will improve disease staging and improve the complete resection of LN metastases in MIBC. PMID- 28820474 TI - Significance of Resveratrol in Clinical Management of Chronic Diseases. AB - Resveratrol could be beneficial to health and provides protection against a wide array of pathologies and age-associated problems, as evident from preclinical studies. However, a comparison of animal and human studies reveals that this dietary polyphenol cannot protect against metabolic diseases and their associated complications. The clinical outcomes are affected by many factors such as sample size. This article not only presents a comprehensive review of the current advances concerning the dose, the extent of absorption, interaction and toxicity of resveratrol in human studies, but also describes its therapeutic effects against several chronic diseases such as diabetes mellitus, obesity, cardiovascular diseases, cancer and aging and the related diseases. PMID- 28820477 TI - LoRa Mobile-To-Base-Station Channel Characterization in the Antarctic. AB - Antarctic conditions demand that wireless sensor nodes are operational all year round and that they provide a large communication range of several tens of kilometers. LoRa technology operating in sub-GHz frequency bands implements these wireless links with minimal power consumption. The employed chirp spread spectrum modulation provides a large link budget, combined with the excellent radio-wave propagation characteristics in these bands. In this paper, an experimental wireless link from a mobile vehicle which transmits sensor data to a base station is measured and analyzed in terms of signal-to-noise ratio and packet loss. These measurements confirm the usefulness of LoRa technology for wireless sensor systems in polar regions. By deploying directional antennas at the base station, a range of up to 30 km is covered in case of Line-of-Sight radio propagation in both the 434 and 868 MHz bands. Varying terrain elevation is shown to be the dominating factor influencing the propagation, sometimes causing the Line-of Sight path to be obstructed. Tropospheric radio propagation effects were not apparent in the measurements. PMID- 28820476 TI - Biosynthesis of S-Adenosylmethionine by Magnetically Immobilized Escherichia coli Cells Highly Expressing a Methionine Adenosyltransferase Variant. AB - S-Adenosylmethionine (SAM) is a natural metabolite having important uses in the treatment of various diseases. To develop a simple and effective way to produce SAM, immobilized Escherichia coli cells highly expressing an engineered variant of methionine adenosyltransferase (MAT) were employed to synthesize SAM. The recombinant I303V MAT variant was successfully produced at approximately 900 mg/L in a 10-L bioreactor and exhibited significantly less product inhibition and had a four-fold higher specific activity (14.2 U/mg) than the wild-type MAT (3.6 U/mg). To reduce the mass transfer resistance, the free whole-cells were permeabilized and immobilized using gellan gum gel as support in the presence of 100 mg/L Fe3O4 nanoparticles, and the highest activity (4152.4 U/L support) was obtained, with 78.2% of the activity recovery. The immobilized cells were more stable than the free cells under non-reactive conditions, with a half-life of 9.1 h at 50 degrees C. Furthermore, the magnetically immobilized cells were employed to produce SAM at a 40-mM scale. The residual activity of the immobilized cells was 67% of its initial activity after 10 reuses, and the conversion rate of ATP was >=95% in all 10 batches. These results indicated that magnetically immobilized cells should be a promising biocatalyst for the biosynthesis of SAM. PMID- 28820478 TI - Detection of Interactions between Proteins by Using Legendre Moments Descriptor to Extract Discriminatory Information Embedded in PSSM. AB - Protein-protein interactions (PPIs) play a very large part in most cellular processes. Although a great deal of research has been devoted to detecting PPIs through high-throughput technologies, these methods are clearly expensive and cumbersome. Compared with the traditional experimental methods, computational methods have attracted much attention because of their good performance in detecting PPIs. In our work, a novel computational method named as PCVM-LM is proposed which combines the probabilistic classification vector machine (PCVM) model and Legendre moments (LMs) to predict PPIs from amino acid sequences. The improvement mainly comes from using the LMs to extract discriminatory information embedded in the position-specific scoring matrix (PSSM) combined with the PCVM classifier to implement prediction. The proposed method was evaluated on Yeast and Helicobacter pylori datasets with five-fold cross-validation experiments. The experimental results show that the proposed method achieves high average accuracies of 96.37% and 93.48%, respectively, which are much better than other well-known methods. To further evaluate the proposed method, we also compared the proposed method with the state-of-the-art support vector machine (SVM) classifier and other existing methods on the same datasets. The comparison results clearly show that our method is better than the SVM-based method and other existing methods. The promising experimental results show the reliability and effectiveness of the proposed method, which can be a useful decision support tool for protein research. PMID- 28820479 TI - Esterification Mechanism of Bagasse Modified with Glutaric Anhydride in 1-Allyl-3 methylimidazolium Chloride. AB - The esterification of bagasse with glutaric anhydride could increase surface adhesion compatibility and the surface of derived polymers has the potential of immobilizing peptides or proteins for biomedical application. Due to its complicated components, the esterification mechanism of bagasse esterified with glutaric anhydride in ionic liquids has not been studied. In this paper, the homogenous esterification of bagasse with glutaric anhydride was comparatively investigated with the isolated cellulose, hemicelluloses, and lignin in 1-allyl-3 methylimidazolium chloride (AmimCl) to reveal the reaction mechanism. Fourier transform infrared (FT-IR) indicated that the three components (cellulose, hemicelluloses, and lignin) were all involved in the esterification. The percentage of substitution (PS) of bagasse was gradually improved with the increased dosage of glutaric anhydride (10-40 mmol/g), which was primarily attributed to the increased esterification of cellulose and hemicelluloses. However, the PS fluctuation of lignin led to a decrease in the PS of bagasse at high glutaric anhydride dosage (50 mmol/g). The esterification reactivity of bagasse components followed the order of lignin > hemicelluloses > cellulose. The esterification mechanism was proposed as a nucleophilic substitution reaction. Nuclear magnetic resonance (NMR) analysis indicated that lignin aliphatic hydroxyls were prior to be esterified, and primary hydroxyls were more reactive than secondary hydroxyls in cellulose and hemicelluloses. PMID- 28820480 TI - Phytochemicals of Euphorbia lathyris L. and Their Antioxidant Activities. AB - The objectives of this study were to characterize the antioxidant capacities and phytochemicals such as phenolics and flavonoids in four parts of Euphorbia lathyris L. HPLC was employed to detect the type and content of phenolic acids and flavonoids in the root, stem, seed, and testa of the plant. The total phenolic content (TPC) and total flavonoid content (TFC) were different among various parts of E. lathyris. The highest TPC were found in the testa (290.46 +/- 15.09 mg of gallic acid equiv/100 g dry weight (DW)). However, the root contained the highest TFC (215.68 +/- 3.10 mg of rutin equiv/g DW). Of the different antioxidant activities detected, DPPH free radical scavenging activity was highest in the testa (61.29 +/- 0.29 mmol Trolox/100 g DW), but the highest FRAP antioxidant activity was found in the seed (1131.25 +/- 58.68 mg FeSO4/100 g DW of free compounds and 1927.43 +/- 52.13 mg FeSO4/100 g DW of bound compounds). There was a positive correlation between the total phenolic contents and DPPH free radical scavenging activity in different parts of E. lathyris. PMID- 28820482 TI - In Situ Synthesis of Silver Nanoparticles on the Polyelectrolyte-Coated Sericin/PVA Film for Enhanced Antibacterial Application. AB - To develop silk sericin (SS) as a potential antibacterial biomaterial, a novel composite of polyelectrolyte multilayers (PEMs) coated sericin/poly(vinyl alcohol) (SS/PVA) film modified with silver nanoparticles (AgNPs) has been developed using a layer-by-layer assembly technique and ultraviolet-assisted AgNPs synthesis method. Ag ions were enriched by PEMs via the electrostatic attraction between Ag ions and PEMs, and then reduced to AgNPs in situ with the assistance of ultraviolet irradiation. PEMs facilitated the high-density growth of AgNPs and protected the synthesized AgNPs due to the formation of a 3D matrix, and thus endowed SS/PVA film with highly effective and durable antibacterial activity. Scanning electron microscopy, energy dispersive spectroscopy, X-ray diffractometry, Fourier transfer infrared spectroscopy, water contact angle, mechanical property and thermogravimetric analysis were applied to characterize SS/PVA, PEMs-SS/PVA and AgNPs-PEMs-SS/PVA films, respectively. AgNPs-PEMs-SS/PVA film has exhibited good mechanical performance, hydrophilicity, water absorption capability as well as excellent and durable antibacterial activity against Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa and good stability and degradability. This study has developed a simple method to design and prepare AgNPs-PEMs-SS/PVA film for potential antibacterial application. PMID- 28820481 TI - Studies on the Presence of Mycotoxins in Biological Samples: An Overview. AB - Mycotoxins are fungal secondary metabolites with bioaccumulation levels leading to their carry-over into animal fluids, organs, and tissues. As a consequence, mycotoxin determination in biological samples from humans and animals has been reported worldwide. Since most mycotoxins show toxic effects at low concentrations and considering the extremely low levels present in biological samples, the application of reliable detection methods is required. This review summarizes the information regarding the studies involving mycotoxin determination in biological samples over the last 10 years. Relevant data on extraction methodology, detection techniques, sample size, limits of detection, and quantitation are presented herein. Briefly, liquid-liquid extraction followed by LC-MS/MS determination was the most common technique. The most analyzed mycotoxin was ochratoxin A, followed by zearalenone and deoxynivalenol-including their metabolites, enniatins, fumonisins, aflatoxins, T-2 and HT-2 toxins. Moreover, the studies were classified by their purpose, mainly focused on the development of analytical methodologies, mycotoxin biomonitoring, and exposure assessment. The study of tissue distribution, bioaccumulation, carry-over, persistence and transference of mycotoxins, as well as, toxicokinetics and ADME (absorption, distribution, metabolism and excretion) were other proposed goals for biological sample analysis. Finally, an overview of risk assessment was discussed. PMID- 28820483 TI - A Microsomal Proteomics View of H2O2- and ABA-Dependent Responses. AB - The plant hormone abscisic acid (ABA) modulates a number of plant developmental processes and responses to stress. In planta, ABA has been shown to induce reactive oxygen species (ROS) production through the action of plasma membrane associated nicotinamide adenine dinucleotide phosphate (NADPH)-oxidases. Although quantitative proteomics studies have been performed to identify ABA- or hydrogen peroxide (H2O2)-dependent proteins, little is known about the ABA- and H2O2 dependent microsomal proteome changes. Here, we examined the effect of 50 uM of either H2O2 or ABA on the Arabidopsis microsomal proteome using tandem mass spectrometry and identified 86 specifically H2O2-dependent, and 52 specifically ABA-dependent proteins that are differentially expressed. We observed differential accumulation of proteins involved in the tricarboxylic acid (TCA) cycle notably in response to H2O2. Of these, aconitase 3 responded to both H2O2 and ABA. Additionally, over 30 proteins linked to RNA biology responded significantly to both treatments. Gene ontology categories such as 'response to stress' and 'transport' were enriched, suggesting that H2O2 or ABA directly and/or indirectly cause complex and partly overlapping cellular responses. Data are available via ProteomeXchange with identifier PXD006513. PMID- 28820484 TI - Platelet Aggregometry Testing: Molecular Mechanisms, Techniques and Clinical Implications. AB - Platelets play a fundamental role in normal hemostasis, while their inherited or acquired dysfunctions are involved in a variety of bleeding disorders or thrombotic events. Several laboratory methodologies or point-of-care testing methods are currently available for clinical and experimental settings. These methods describe different aspects of platelet function based on platelet aggregation, platelet adhesion, the viscoelastic properties during clot formation, the evaluation of thromboxane metabolism or certain flow cytometry techniques. Platelet aggregometry is applied in different clinical settings as monitoring response to antiplatelet therapies, the assessment of perioperative bleeding risk, the diagnosis of inherited bleeding disorders or in transfusion medicine. The rationale for platelet function-driven antiplatelet therapy was based on the result of several studies on patients undergoing percutaneous coronary intervention (PCI), where an association between high platelet reactivity despite P2Y12 inhibition and ischemic events as stent thrombosis or cardiovascular death was found. However, recent large scale randomized, controlled trials have consistently failed to demonstrate a benefit of personalised antiplatelet therapy based on platelet function testing. PMID- 28820486 TI - Urinary Levels of 4-Nonylphenol and 4-t-Octylphenol in a Representative Sample of the Korean Adult Population. AB - 4-Nonylphenol (4-NP) and 4-t-octylphenol (4-t-OP) are xenoestrogen compounds to which humans are exposed via contaminated food, water, and air. This study assessed the body burden of 4-NP and 4-t-OP in Koreans aged 18-69 years using data from the Korean National Human Biomonitoring Survey conducted in 2009. Based on data from 1865 representative Koreans, 83.2% and 91.8% had urinary 4-NP and 4 t-OP concentrations >0.05 ng/mL (limit of detection). Of the Korean adult population, the geometric mean urinary concentrations of 4-NP and 4-t-OP were 3.70 ng/mL (95% confidence interval (CI) = 3.20-4.27) and 0.60 ng/mL (95% CI = 0.55-0.66), respectively. Urine 4-NP concentrations were significantly associated with place of residence and smoking status, whereas urine 4-t-OP concentrations were not correlated with any of the demographic factors. These findings suggest that most Koreans have detectable levels of 4-NP and 4-t-OP in their urine and that the body burden of 4-NP, but not 4-t-OP, varies according to some demographic factors. PMID- 28820488 TI - Phase Behaviour and Miscibility Studies of Collagen/Silk Fibroin Macromolecular System in Dilute Solutions and Solid State. AB - Miscibility is an important issue in biopolymer blends for analysis of the behavior of polymer pairs through the detection of phase separation and improvement of the mechanical and physical properties of the blend. This study presents the formulation of a stable and one-phase mixture of collagen and regenerated silk fibroin (RSF), with the highest miscibility ratio between these two macromolecules, through inducing electrostatic interactions, using salt ions. For this aim, a ternary phase diagram was experimentally built for the mixtures, based on observations of phase behavior of blend solutions with various ratios. The miscibility behavior of the blend solutions in the miscible zones of the phase diagram was confirmed quantitatively by viscosimetric measurements. Assessing the effects of biopolymer mixing ratio and salt ions, before and after dialysis of blend solutions, revealed the importance of ion-specific interactions in the formation of coacervate-based materials containing collagen and RSF blends that can be used in pharmaceutical, drug delivery, and biomedical applications. Moreover, the conformational change of silk fibroin from random coil to beta sheet, in solution and in the final solid films, was detected by circular dichroism (CD) and Fourier transform infrared spectroscopy (FTIR), respectively. Scanning electron microscopy (SEM) exhibited alterations of surface morphology for the biocomposite films with different ratios. Surface contact angle measurement illustrated different hydrophobic properties for the blended film surfaces. Differential scanning calorimetry (DSC) showed that the formation of the beta sheet structure of silk fibroin enhances the thermal stability of the final blend films. Therefore, the novel method presented in this study resulted in the formation of biocomposite films whose physico-chemical properties can be tuned by silk fibroin conformational changes by applying different component mixing ratios. PMID- 28820487 TI - Copper-Catalyzed Synthesis of Unsymmetrical Diorganyl Chalcogenides (Te/Se/S) from Boronic Acids under Solvent-Free Conditions. AB - The efficient and mild copper-catalyzed synthesis of unsymmetrical diorganyl chalcogenides under ligand- and solvent-free conditions is described. The cross coupling reaction was performed using aryl boric acids and 0.5 equiv. of diorganyl dichalcogenides (Te/Se/S) in the presence of 3 mol % of CuI and 3 equiv. of DMSO, under microwave irradiation. This new protocol allowed the preparation of several unsymmetrical diorganyl chalcogenides in good to excellent yields. PMID- 28820485 TI - Disentangling the Frames, the State of Research on the Alphavirus 6K and TF Proteins. AB - For 30 years it was thought the alphavirus 6K gene encoded a single 6 kDa protein. However, through a bioinformatics search 10 years ago, it was discovered that there is a frameshifting event and two proteins, 6K and transframe (TF), are translated from the 6K gene. Thus, many functions attributed to the 6K protein needed reevaluation to determine if they properly belong to 6K, TF, or both proteins. In this mini-review, we reevaluate the past research on 6K and put those results in context where there are two proteins, 6K and TF, instead of one. Additionally, we discuss the most cogent outstanding questions for 6K and TF research, including their collective importance in alphavirus budding and their potential importance in disease based on the latest virulence data. PMID- 28820489 TI - The Effect of Hydrogen Bonding in Enhancing the Ionic Affinities of Immobilized Monoprotic Phosphate Ligands. AB - Environmental remediation requires ion-selective polymers that operate under a wide range of solution conditions. In one example, removal of trivalent and divalent metal ions from waste streams resulting from mining operations before they enter the environment requires treatment at acidic pH. The monoethyl ester phosphate ligands developed in this report operate from acidic solutions. They have been prepared on polystyrene-bound ethylene glycol, glycerol, and pentaerythritol, and it is found that intra-ligand hydrogen bonding affects their metal ion affinities. The affinity for a set of trivalent (Fe(III), Al(III), La(III), and Lu(III)) and divalent (Pb(II), Cd(II), Cu(II), and Zn(II)) ions is greater than that of corresponding neutral diethyl esters and phosphonic acid. In an earlier study, hydrogen bonding was found important in determining the metal ion affinities of immobilized phosphorylated polyol diethyl ester coordinating ligands; their Fourier transform infrared (FTIR) band shifts indicated that the basicity of the phosphoryl oxygen increased by hydrogen bonding to auxiliary -OH groups on the neighboring polyol. The same mechanism is operative with the monoprotic resins along with hydrogen bonding to the P-OH acid site. This is reflected in the FTIR spectra: the neutral phosphate diethyl ester resins have the P=O band at 1265 cm-1 while the monoethyl ester resins have the band shifted to 1230 cm-1; hydrogen bonding is further indicated by the broadness of this region down to 900 cm-1. The monoprotic pentaerythritol has the highest metal ion affinities of the polymers studied. PMID- 28820490 TI - The Potentiodynamic Bottom-up Growth of the Tin Oxide Nanostructured Layer for Gas-Analytical Multisensor Array Chips. AB - We report a deposition of the tin oxide/hydroxide nanostructured layer by the potentiodynamic method from acidic nitrate solutions directly over the substrate, equipped with multiple strip electrodes which is employed as a gas-analytical multisensor array chip. The electrochemical synthesis is set to favor the growth of the tin oxide/hydroxide phase, while the appearance of metallic Sn is suppressed by cycling. The as-synthesized tin oxide/hydroxide layer is characterized by mesoporous morphology with grains, 250-300 nm diameter, which are further crystallized into fine SnO2 poly-nanocrystals following heating to 300 degrees C for 24 h just on the chip. The fabricated layer exhibits chemiresistive properties under exposure to organic vapors, which allows the generation of a multisensor vector signal capable of selectively distinguishing various vapors. PMID- 28820491 TI - Mapping of QTLs for Seed Phorbol Esters, a Toxic Chemical in Jatropha curcas (L.). AB - Jatropha (Jatropha curcas L.) is an oil-bearing plant that has potential to be cultivated as a biodiesel crop. The seed cake after oil extraction has 40-50% protein that can be used in animal feeds. A major limitation in utilizing the cake is the presence of phorbol esters (PE), a heat-tolerant toxic chemical. To identify the quantitative trait loci (QTLs) for PE, we constructed a genetic linkage map from an F2 population of 95 individuals from a cross "Chai Nat" * "M10" using 143 simple sequence repeat (SSR) markers. M10 is low in seed PE while Chai Nat is high. Seeds from each F2 individual were quantified for PE content by high performance liquid chromatography. A single marker analysis revealed five markers from linkage group 3 (LG3) and nine markers from LG8 associated with seed PE. Inclusive composite interval mapping identified two QTLs, each on LG3 (qPE3.1) and LG8 (qPE8.1) responsible for the PE. qPE3.1 and qPE8.1 accounted for 14.10%, and 15.49% of total variation in seed PE, respectively. Alelle(s) from M10 at qPE3.1 increased seed PE, while at qPE8.1 decreased seed PE. qPE3.1 is a new loci for PE, while qPE8.1 is the same locus with that reported recently for PE. PMID- 28820492 TI - Variation in the Ovine KAP6-3 Gene (KRTAP6-3) Is Associated with Variation in Mean Fibre Diameter-Associated Wool Traits. AB - Polymerase chain reaction-single stranded conformational polymorphism (PCR-SSCP) analysis was used to investigate variation in the ovine KAP6-3 gene (KRTAP6-3) in 383 Merino * Southdown-cross lambs from four sire-lines, and to determine whether this variation affects wool traits. Five PCR-SSCP banding patterns, representing five different nucleotide sequences, were detected, including four previously identified (named A, B, C, and F) variants and one newly identified (named G) variant. A new non-synonymous single nucleotide polymorphism (SNP) and a 45-bp deletion were detected in variant G. Of the three common genotypes (AA, AB, and AG) identified in these sheep, wool from sheep that were AG, on average, had a lower mean fibre diameter (MFD), fibre diameter standard deviation (FDSD), and prickle factor (PF) than wool from AA sheep, whereas wool from AB sheep, on average, had a higher MFD, FDSD, and PF than wool from AA sheep. This suggests that variation in ovine KRTAP6-3 affect MFD, FDSD, and PF, and that this gene may have potential for use as a gene-maker for improving fibre diameter-associated wool traits. PMID- 28820493 TI - Marine Lipids on Cardiovascular Diseases and Other Chronic Diseases Induced by Diet: An Insight Provided by Proteomics and Lipidomics. AB - Marine lipids, especially omega-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have largely been linked to prevention of diet-induced diseases. The anti-inflammatory and hypolipidemic properties of EPA and DHA supplementation have been well-described. However, there is still a significant lack of information about their particular mechanism of action. Furthermore, repeated meta-analyses have not shown conclusive results in support of their beneficial health effects. Modern "omics" approaches, namely proteomics and lipidomics, have made it possible to identify some of the mechanisms behind the benefits of marine lipids in the metabolic syndrome and related diseases, i.e., cardiovascular diseases and type 2 diabetes. Although until now their use has been scarce, these "omics" have brought new insights in this area of nutrition research. The purpose of the present review is to comprehensively show the research articles currently available in the literature which have specifically applied proteomics, lipidomics or both approaches to investigate the role of marine lipids intake in the prevention or palliation of these chronic pathologies related to diet. The methodology adopted, the class of marine lipids examined, the diet-related disease studied, and the main findings obtained in each investigation will be reviewed. PMID- 28820496 TI - Energy Efficiency Maximization for WSNs with Simultaneous Wireless Information and Power Transfer. AB - Recently, the simultaneous wireless information and power transfer (SWIPT) technique has been regarded as a promising approach to enhance performance of wireless sensor networks with limited energy supply. However, from a green communication perspective, energy efficiency optimization for SWIPT system design has not been investigated in Wireless Rechargeable Sensor Networks (WRSNs). In this paper, we consider the tradeoffs between energy efficiency and three factors including spectral efficiency, the transmit power and outage target rate for two different modes, i.e., power splitting (PS) and time switching modes (TS), at the receiver. Moreover, we formulate the energy efficiency maximization problem subject to the constraints of minimum Quality of Service (QoS), minimum harvested energy and maximum transmission power as non-convex optimization problem. In particular, we focus on optimizing power control and power allocation policy in PS and TS modes to maximize energy efficiency of data transmission. For PS and TS modes, we propose the corresponding algorithm to characterize a non-convex optimization problem that takes into account the circuit power consumption and the harvested energy. By exploiting nonlinear fractional programming and Lagrangian dual decomposition, we propose suboptimal iterative algorithms to obtain the solutions of non-convex optimization problems. Furthermore, we derive the outage probability and effective throughput from the scenarios that the transmitter does not or partially know the channel state information (CSI) of the receiver. Simulation results illustrate that the proposed optimal iterative algorithm can achieve optimal solutions within a small number of iterations and various tradeoffs between energy efficiency and spectral efficiency, transmit power and outage target rate, respectively. PMID- 28820494 TI - Immune-Response Patterns and Next Generation Sequencing Diagnostics for the Detection of Mycoses in Patients with Septic Shock-Results of a Combined Clinical and Experimental Investigation. AB - Fungi are of increasing importance in sepsis. However, culture-based diagnostic procedures are associated with relevant weaknesses. Therefore, culture- and next generation sequencing (NGS)-based fungal findings as well as corresponding plasma levels of beta-d-glucan, interferon gamma (INF-gamma), tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-2, -4, -6, -10, -17A, and mid-regional proadrenomedullin (MR-proADM) were evaluated in 50 septic patients at six consecutive time points within 28 days after sepsis onset. Furthermore, immune response patterns during infections with Candida spp. were studied in a reconstituted human epithelium model. In total, 22% (n = 11) of patients suffered from a fungal infection. An NGS-based diagnostic approach appeared to be suitable for the identification of fungal pathogens in patients suffering from fungemia as well as in patients with negative blood cultures. Moreover, MR-proADM and IL-17A in plasma proved suitable for the identification of patients with a fungal infection. Using RNA-seq., adrenomedullin (ADM) was shown to be a target gene which is upregulated early after an epithelial infection with Candida spp. In summary, an NGS-based diagnostic approach was able to close the diagnostic gap of routinely used culture-based diagnostic procedures, which can be further facilitated by plasmatic measurements of MR-proADM and IL-17A. In addition, ADM was identified as an early target gene in response to epithelial infections with Candida spp. PMID- 28820495 TI - Human Papillomavirus and the DNA Damage Response: Exploiting Host Repair Pathways for Viral Replication. AB - High-risk human papillomaviruses (HPVs) are the causative agents of cervical and other genital cancers. In addition, HPV infections are associated with the development of many oropharyngeal cancers. HPVs activate and repress a number of host cellular pathways to promote their viral life cycles, including those of the DNA damage response. High-risk HPVs activate the ataxia telangiectasia-mutated (ATM) and ATM and Rad3-related (ATR) DNA damage repair pathways, which are essential for viral replication (particularly differentiation-dependent genome amplification). These DNA repair pathways are critical in maintaining host genomic integrity and stability and are often dysregulated or mutated in human cancers. Understanding how these pathways contribute to HPV replication and transformation may lead to the identification of new therapeutic targets for the treatment of existing HPV infections. PMID- 28820497 TI - Anesthetic Agents of Plant Origin: A Review of Phytochemicals with Anesthetic Activity. AB - The majority of currently used anesthetic agents are derived from or associated with natural products, especially plants, as evidenced by cocaine that was isolated from coca (Erythroxylum coca, Erythroxylaceae) and became a prototype of modern local anesthetics and by thymol and eugenol contained in thyme (Thymus vulgaris, Lamiaceae) and clove (Syzygium aromaticum, Myrtaceae), respectively, both of which are structurally and mechanistically similar to intravenous phenolic anesthetics. This paper reviews different classes of phytochemicals with the anesthetic activity and their characteristic molecular structures that could be lead compounds for anesthetics and anesthesia-related drugs. Phytochemicals in research papers published between 1996 and 2016 were retrieved from the point of view of well-known modes of anesthetic action, that is, the mechanistic interactions with Na+ channels, gamma-aminobutyric acid type A receptors, N methyl-d-aspartate receptors and lipid membranes. The searched phytochemicals include terpenoids, alkaloids and flavonoids because they have been frequently reported to possess local anesthetic, general anesthetic, antinociceptive, analgesic or sedative property. Clinical applicability of phytochemicals to local and general anesthesia is discussed by referring to animal in vivo experiments and human pre-clinical trials. This review will give structural suggestions for novel anesthetic agents of plant origin. PMID- 28820499 TI - Choline Supplementation Normalizes Fetal Adiposity and Reduces Lipogenic Gene Expression in a Mouse Model of Maternal Obesity. AB - Maternal obesity increases fetal adiposity which may adversely affect metabolic health of the offspring. Choline regulates lipid metabolism and thus may influence adiposity. This study investigates the effect of maternal choline supplementation on fetal adiposity in a mouse model of maternal obesity. C57BL/6J mice were fed either a high-fat (HF) diet or a control (NF) diet and received either 25 mM choline supplemented (CS) or control untreated (CO) drinking water for 6 weeks before timed-mating and throughout gestation. At embryonic day 17.5, HF feeding led to higher (p < 0.05) percent total body fat in fetuses from the HFCO group, while the choline supplemented HFCS group did not show significant difference versus the NFCO group. Similarly, HF feeding led to higher (p < 0.05) hepatic triglyceride accumulation in the HFCO but not the HFCS fetuses. mRNA levels of lipogenic genes such as Acc1, Fads1, and Elovl5, as well as the transcription factor Srebp1c that favors lipogenesis were downregulated (p < 0.05) by maternal choline supplementation in the HFCS group, which may serve as a mechanism to reduce fat accumulation in the fetal liver during maternal HF feeding. In summary, maternal choline supplementation improves indices of fetal adiposity in obese dams at late gestation. PMID- 28820498 TI - Interference of Apoptosis by Hepatitis B Virus. AB - Hepatitis B virus (HBV) causes liver diseases that have been a consistent problem for human health, leading to more than one million deaths every year worldwide. A large proportion of hepatocellular carcinoma (HCC) cases across the world are closely associated with chronic HBV infection. Apoptosis is a programmed cell death and is frequently altered in cancer development. HBV infection interferes with the apoptosis signaling to promote HCC progression and viral proliferation. The HBV-mediated alteration of apoptosis is achieved via interference with cellular signaling pathways and regulation of epigenetics. HBV X protein (HBX) plays a major role in the interference of apoptosis. There are conflicting reports on the HBV interference of apoptosis with the majority showing inhibition of and the rest reporting induction of apoptosis. In this review, we described recent studies on the mechanisms of the HBV interference with the apoptosis signaling during the virus infection and provided perspective. PMID- 28820501 TI - Interleukin-armed chimeric antigen receptor-modified T cells for cancer immunotherapy. AB - Chimeric antigen receptor-modified T cells (CAR-T) are endowed with cytotoxic specificity to tumor cells. Although CAR-T-based cancer immunotherapy presents curable therapeutic potential for hematological malignancies, achieving substantial efficacy for solid tumors remain challenging. Researchers have exploited many strategies to enhance the anti-tumor efficacy of CAR-T cells for solid tumors, among which cytokine-armed CAR-T cells improve the proliferation, survival, homing and other properties of CAR-T cells. Interleukins (ILs), pivotal cytokines that affect the function of immune cells, were co-expressed in CAR-T cells or combinatorially administered to enhance the therapeutic potential in clinical trials. In this review, we summarize the strategies exploited by ILs to improve the anti-cancer ability of CAR-T cells and the different impacts of different ILs on CAR-T cells. PMID- 28820500 TI - Odorous Compounds from Poultry Manure Induce DNA Damage, Nuclear Changes, and Decrease Cell Membrane Integrity in Chicken Liver Hepatocellular Carcinoma Cells. AB - Animal breeding and management of organic wastes pose a serious problem to the health of livestock and workers, as well as the nearby residents. The aim of the present study was to determine the mechanisms of toxicity of selected common odorous compounds from poultry manure, including ammonia, dimethylamine (DMA), trimethylamine (TMA), butyric acid, phenol, and indole. We measured their genotoxic and cytotoxic activity in the model chicken cell line (LMH), in vitro, by comet assay and lactate dehydrogenase assay, respectively. We also made microscopic observations of any morphological changes in these cells by DAPI staining. Four compounds, namely ammonia, DMA, TMA, and butyric acid increased DNA damage in a dose-dependent manner (p < 0.05), reaching genotoxicity as high as 73.2 +/- 1.9%. Phenol and indole induced extensive DNA damage independent of the concentration used. Ammonia, DMA, and TMA caused a dose-dependent release of lactate dehydrogenase (p < 0.05). The IC50 values were 0.02%, 0.05%, and 0.1% for DMA, ammonia and TMA, respectively. These compounds also induced nuclear morphological changes, such as chromatin condensation, shrinkage, nuclear fragmentation (apoptotic bodies), and chromatin lysis. Our study exhibited the damaging effects of odorous compounds in chick LMH cell line. PMID- 28820503 TI - Diabetes: Systemic effects of metformin revealed. PMID- 28820504 TI - Diabetes: Insulin pumps after injections and CGM in T1DM. PMID- 28820502 TI - Oligonucleotide-targeting periostin ameliorates pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a fatal disease with a median survival of 3-4 years after diagnosis. It is the most frequent form of a group of interstitial pneumonias of unknown etiology. Current available therapies prevent deterioration of lung function but no therapy has shown to improve survival. Periostin is a matricellular protein of the fasciclin 1 family. There is increased deposition of periostin in lung fibrotic tissues. Here we evaluated whether small interfering RNA or antisense oligonucleotide against periostin inhibits lung fibrosis by direct administration into the lung by intranasal route. Pulmonary fibrosis was induced with bleomycin and RNA therapeutics was administered during both acute and chronic phases of the disease. The levels of periostin and transforming growth factor-beta1 in airway fluid and lung tissue, the deposition of collagen in lung tissue and the lung fibrosis score were significantly reduced in mice treated with siRNA and antisense against periostin compared to control mice. These findings suggest that direct administration of siRNA or antisense oligonucleotides against periostin into the lungs is a promising alternative therapeutic approach for the management of pulmonary fibrosis. PMID- 28820505 TI - Gut microbiota: Gas-induced GLP1 release. PMID- 28820506 TI - Physiological and ecological implications of an iron- or hydrogen-oxidizing member of the Zetaproteobacteria, Ghiorsea bivora, gen. nov., sp. nov. AB - Chemosynthetic Fe-oxidizing communities are common at diffuse-flow hydrothermal vents throughout the world's oceans. The foundational members of these communities are the Zetaproteobacteria, a class of Proteobacteria that is primarily associated with ecosystems fueled by ferrous iron, Fe(II). We report here the discovery of two new isolates of Zetaproteobacteria isolated from the Mid-Atlantic Ridge (TAG-1), and the Mariana back-arc (SV-108), that are unique in that they can utilize either Fe(II) or molecular hydrogen (H2) as sole electron donor and oxygen as terminal electron acceptor for growth. Both strains precipitated Fe-oxyhydroxides as amorphous particulates. The cell doubling time on H2 vs Fe(II) for TAG-1 was 14.1 vs 21.8 h, and for SV-108 it was 16.3 vs 20 h, and it appeared both strains could use either H2 or Fe(II) simultaneously. The strains were close relatives, based on genomic analysis, and both possessed genes for the uptake NiFe-hydrogenase required for growth on H2. These two strains belong to Zetaproteobacteria operational taxonomic unit 9 (ZetaOTU9). A meta analysis of public databases found ZetaOTU9 was only associated with Fe(II)-rich habitats, and not in other environments where known H2-oxidizers exist. These results expand the metabolic repertoire of the Zetaproteobacteria, yet confirm that Fe(II) metabolism is the primary driver of their physiology and ecology. PMID- 28820507 TI - Hematopoietic Stem Cell Transplantation Recipient and Caregiver Factors Affecting Length of Stay and Readmission. AB - PURPOSE/OBJECTIVES: To evaluate the contributions of patient and caregiver factors to length of stay (LOS) and 30-day readmission status for recipients of allogeneic hematopoietic stem cell transplantation (HSCT).?. DESIGN: Secondary data analysis from a phase 2 clinical trial.?. SETTING: National Institutes of Health Clinical Center in Bethesda, Maryland.?. SAMPLE: 68 dyads (N = 136) comprised of patients receiving HSCT and their caregivers. ?. METHODS: Multiple linear regression and logistic regression analyses were used to investigate associations between caregiver and patient factors and outcomes.?. MAIN RESEARCH VARIABLES: Patients' initial LOS, 30-day readmission, and demographic and disease characteristics; caregiver demographic factors, health problems, psychological distress, burden, and self-efficacy. ?. FINDINGS: Twenty-five patients were readmitted within 30 days after hospital discharge following their initial hospitalization for HSCT. LOS was 34% longer for patients with infection than patients without infection. Patients with grade 2 or greater acute graft-versus host disease (GVHD) stayed longer compared to patients with no or mild acute GVHD. Patients who had nonspousal caregivers stayed longer than patients with spousal caregivers. Infection was significantly related to readmission.?. CONCLUSIONS: Knowledge regarding factors associated with increased LOS and 30-day readmission can help nurses and transplantation team members anticipate the healthcare needs of patients receiving HSCT, improve outcomes, and decrease the use of expensive health services. ?. IMPLICATIONS FOR NURSING: Educating patients and caregivers on infection prevention is critically important to reduce LOS and 30-day readmission after HSCT. PMID- 28820508 TI - Complementary Medicine and the Role of Oncology Nurses in an Acute Care Hospital: The Gap Between Attitudes and Practice. AB - PURPOSE/OBJECTIVES: To describe hospital nurses' knowledge, attitudes, and practices regarding complementary medicine (CM); to compare the knowledge and attitudes of nurse managers to staff nurses with diverse oncology experience; and to assess attitudes toward integrating CM into the role of the hospital oncology nurse. ?. DESIGN: Descriptive, cross-sectional study.?. SETTING: Rambam Health Care Campus in northern Israel.?. SAMPLE: A convenience sample of 434 hospital nurses with varied oncology experience.?. METHODS: Nurses completed a knowledge and attitude questionnaire developed for the current study. Data were analyzed using parametric and nonparametric statistical tests. ?. MAIN RESEARCH VARIABLES: Hospital nurses' knowledge of and attitudes toward CM, and attitudes toward integrating CM into the role of the hospital oncology nurse.?. FINDINGS: Nurses lack knowledge and are unaware of the risks associated with CM. However, they believe this approach can improve the quality of life of patients with cancer; 51% expressed an interest in receiving training. Oncology nurses were ambivalent about the feasibility of applying an integrative approach, whereas nurse managers expressed significantly more positive attitudes toward integrating CM within the scope of nursing practices.?. CONCLUSIONS: A large discrepancy remains between nurses' strong interest in CM and awareness of associated benefits, and their ambivalence toward its integration in their nursing practice. ?. IMPLICATIONS FOR NURSING: Although improving nurses' knowledge should be mandatory, it remains insufficient; a shift in the approach to integrating CM into conventional health care is needed, from practitioners' responsibility to healthcare policymakers' responsibility. Legislations and policies are necessary, along with providing respectable infrastructures. PMID- 28820509 TI - Conceptual Issues Surrounding Body Image for Oncology Nurses. AB - Cancer and its treatment can uniquely influence survivors' body image. Oncology nurses should understand how this quality-of-life issue can affect patients. To better understand the body image experiences of patients with cancer, this article will present a historic overview of body image conceptualization, as well as a more contemporary, cancer-specific approach to understanding how this population of patients may be particularly affected. PMID- 28820510 TI - Implementation and Use of a Patient Symptom Diary During Chemotherapy: A Mixed Methods Evaluation of the Nurse Perspective. AB - PURPOSE/OBJECTIVES: To gain a deeper understanding of nurses' experience working with a patient diary for tracking and treating side effects during chemotherapy.?. DESIGN: A mixed-methods design was used to learn about oncology nurses' use and perceptions of a symptom diary. ?. SETTING: Six oncology wards and two outpatient clinics at the University Hospitals Leuven, Belgium.?. SAMPLE: 79 nurses completed a survey, and 14 nurses participated in focus group discussions.?. METHODS: First, a survey sampled nurses' use and perceptions of the diary. Next, focus group discussions were held with the aim of arriving at a deeper understanding of the survey results.?. MAIN RESEARCH VARIABLES: Use and perceptions of a symptom diary.?. FINDINGS: Most nurses reported performing diary related behavior to some extent. The survey and focus groups indicated that many nurses strongly believed in the value of the diary, but some were still hesitant or had concerns about patients' perceptions of the diary. The focus group results showed that nurses' use of the diary in daily practice was influenced by their personal beliefs about the value of the diary, the team's, and those of their patients.?. CONCLUSIONS: Although a positive trend was noted, nurses' use of the symptom diary was suboptimal six months after its implementation.?. IMPLICATIONS FOR NURSING: This study highlights important issues that need to be addressed to advance the successful implementation of the symptom diary. PMID- 28820511 TI - Feasibility and Acceptability of a Dignity Therapy/Life Plan Intervention for Patients With Advanced Cancer. AB - PURPOSE/OBJECTIVES: To determine the feasibility and acceptability of a dignity therapy/life plan intervention in the outpatient oncology setting.?. RESEARCH APPROACH: Pilot descriptive study.?. SETTING: Outpatient clinic in a tertiary oncology center. ?. PARTICIPANTS: 18 patients within 12 months after diagnosis undergoing treatment for advanced pancreatic cancer or non-small cell lung cancer.?. METHODOLOGIC APPROACH: Patients received dignity therapy, consisting of a focused life review/values clarification interview session and two subsequent sessions to produce a generativity document, which they can use later as they wish. Participants also wrote a life plan, in which they listed future hopes and dreams. Intervention feasibility and acceptability for patients and oncology clinician satisfaction were assessed.?. FINDINGS: Among the 18 patients completing the intervention, almost all felt it was worthwhile, would do it again, had their expectations met or exceeded, would recommend it to others, and said the timing was just right.?. INTERPRETATION: This psychosocial intervention was found to be feasible and acceptable to patients with cancer undergoing active treatment.?. IMPLICATIONS FOR NURSING: Nurses may be in an ideal position to offer a dignity therapy/life plan intervention to patients with advanced cancer during treatment. PMID- 28820512 TI - Health Literacy: What Do You Know??. AB - Part of my clinical role involves educating and informing patients about the risks and benefits of the various treatment options related to prostate cancer. Like many bed- or chairside nurses, I spend a lot of time talking and listening to my patients. I am sometimes surprised when I get a call from a patient who seemingly did not hear or understand something that I told him or her. I know I told the patient, and I think I am a good educator, so why the confusion? The answer is, in part, simple-health literacy (or the lack thereof).?. PMID- 28820513 TI - Predictors of Unplanned Hospitalizations in Patients With Nonmetastatic Lung Cancer During Chemotherapy. AB - PURPOSE/OBJECTIVES: To determine predictors of unplanned hospitalizations in patients with lung cancer to receive chemotherapy in the outpatient setting and examine the potential financial burden of these events.?. DESIGN: Retrospective, longitudinal cohort study.?. SETTING: The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database.?. SAMPLE: Of 104,388 incident cases of lung cancer diagnosed from 2005-2009, 2,457 cases of patients with lung cancer who received outpatient chemotherapy were identified. Patients were aged 66 years or older at diagnosis, had uninterrupted Medicare Part A and B coverage with no health maintenance organization enrollment, and received IV chemotherapy at least once.?. METHODS: Generalized estimating equations was used.?. MAIN RESEARCH VARIABLES: Patient age, sex, race, marital status, degree of residential urbanization, median income, education level, stage, receipt of radiation therapy, and comorbidities.?. FINDINGS: Younger age, non-White race, lower education, higher income, receipt of radiation therapy, and lack of preexisting comorbidity were significant predictors of the likelihood of an initial unplanned hospitalization for lung cancer. Non-White race, receipt of radiation therapy, and comorbidity were factors associated with an increased number of hospitalizations. ?. CONCLUSIONS: Unplanned hospitalizations are frequent, disruptive, and costly. This article defines areas for further exploration to identify patients at high risk for unexpected complications. ?. IMPLICATIONS FOR NURSING: This article represents a foundation for development of risk models to enable nursing evaluation of patient risk for chemotherapy treatment interruption and unplanned hospitalization. PMID- 28820514 TI - Topical Opioids and Antimicrobials for the Management of Pain, Infection, and Infection-Related Odors in Malignant Wounds: A Systematic Review. AB - PROBLEM IDENTIFICATION: Patients with malignant wounds report pain, distress from odor and exudate, decreased self-esteem, and poor quality of life. This systematic review explores topical opioids, antimicrobials, and odor-reducing agents for preventing or managing malignant wound pain, infection, and odor.?. LITERATURE SEARCH: MEDLINE(r), EMBASE, the Cochrane Library, CINAHL(r), and reference lists were searched to identify relevant studies.?. DATA EVALUATION: Eligible study designs included interventions with pre- and postintervention data. Data extraction and risk-of-bias assessments were conducted using the Cochrane approach.?. SYNTHESIS: No studies evaluated opioid use. Five studies (four randomized, controlled trials) evaluated topical antimicrobials for infection and odor. All studies reported clinically (but generally not statistically) significant improvements in outcomes.?. CONCLUSIONS: Although not as prevalent as before, 5%-10% of tumors, particularly in breast cancer, sarcoma, and melanoma, are expected to fungate. Gaps in the literature exist for use of topical opioids and antimicrobials for managing pain, odor, and infection control in malignant wounds.?. IMPLICATIONS FOR RESEARCH: Current recommendations for topical control of malignant wounds are based on case reports and observational studies in patients with breast cancer. Robust, controlled trials of topical opioid and antimicrobial use are warranted in patients with melanoma, breast, or head and neck cancer. PMID- 28820515 TI - The Role of Oncology Nurses in Discussing Clinical Trials. AB - PURPOSE/OBJECTIVES: To describe oncology nurses' experiences discussing clinical trials with their patients, and to assess barriers to these discussions.?. RESEARCH APPROACH: A qualitative study designed to elicit narratives from oncology nurses. ?. SETTING: Community- and academic-based oncology clinics throughout the United States.?. PARTICIPANTS: 33 oncology nurses involved in direct patient care in community-based and large hospital-based settings. The sample was drawn from members of the Oncology Nursing Society. ?. METHODOLOGIC APPROACH: In-depth interviews were conducted and analyzed using a ?immersion/crystallization approach to identify themes and patterns. The analyses highlight specific issues, examples, and contexts that present challenges to clinical trial discussions with patients.?. FINDINGS: Oncology nurses view their roles as patient educators and advocates to be inclusive of discussion of clinical trials. Barriers to such discussions include lack of knowledge and strategies for addressing patients' common misconceptions and uncertainty about the timing of discussions.?. INTERPRETATION: These data indicate that enabling nurses to actively engage patients in discussions of clinical trials requires educational interventions to build self-efficacy and close knowledge gaps. ?. IMPLICATIONS FOR NURSING: Oncology nurses can play a critical role in advancing cancer care by supporting patients in decision making about clinical trial participation. This will require training and education to build their knowledge, reduce barriers, and increase their self-efficacy to fulfill this responsibility in various clinical settings. PMID- 28820516 TI - Caregiver-Reported Health Outcomes: Effects of Providing Reflexology for Symptom Management to Women With Advanced Breast Cancer. AB - PURPOSE/OBJECTIVES: To determine the effects of delivering a reflexology intervention on health outcomes of informal caregivers, and to explore whether intervention effects are moderated by caregiver characteristics. ?. DESIGN: Two group, randomized clinical trial.?. SETTING: Eight oncology clinics in urban and rural regions of Michigan and Illinois.?. SAMPLE: 180 informal caregivers of patients with advanced breast cancer.?. METHODS: Caregivers were randomized to provide reflexology to individuals with cancer during a four-week period or to attention control. Data collection occurred at baseline and at weeks 5 and 11. Linear mixed-effects modeling was used to test intervention effects among all participants and the effects of the number of sessions delivered in the reflexology group.?. MAIN RESEARCH VARIABLES: Caregiver characteristics; psychological, physical, and social outcomes.?. FINDINGS: Caregiver fatigue in the reflexology group was reduced compared to controls at weeks 5 (p = 0.02) and 11 (p = 0.05). No differences were found for anxiety, depression, pain, physical function, sleep disturbance, satisfaction with participation in social roles, and pain interference between caregivers who delivered reflexology and those who did not.?. CONCLUSIONS: Informal caregivers who provided reflexology to individuals with cancer did not have negative psychological, physical, or social outcomes. Fatigue levels were lower among caregivers who provided reflexology. ?. IMPLICATIONS FOR NURSING: Clinicians need to be aware that providing supportive care interventions, such as reflexology, to reduce symptom burden does not increase negative outcomes on informal caregivers who provide this care, and it may even lead to reduced fatigue. PMID- 28820517 TI - Global Oncology Volunteering: Making an Effective Contribution. AB - Elements of a good health system are lacking in most low- and middle-income countries (LMICs) and in many high-income countries, including the United States. ?A major problem is financing health care. On average, about 50% of healthcare financing in low-income countries comes from out-of-pocket payments, compared to 30% in middle-income countries and 14% in high-income countries. PMID- 28820518 TI - Living With Hepatocellular Carcinoma Near the End of Life: Family Caregivers' Perspectives. AB - PURPOSE/OBJECTIVES: To explore family caregivers' perspectives of caring for patients with terminal hepatocellular carcinoma (HCC) as patients approached the end of life.?. RESEARCH APPROACH: Longitudinal, qualitative descriptive design.?. SETTING: Oregon Health and Science University in Portland and Veterans Affairs Portland Health Care System in Oregon.?. PARTICIPANTS: 13 family caregivers with a mean age of 56 years (range = 22-68 years). The majority of family caregivers were female (n = 10) and identified as White (n = 11).?. METHODOLOGIC APPROACH: Interview data were collected from family caregivers once a month for as many as six months, for a total of 39 interviews. Data were analyzed using conventional content analysis.?. FINDINGS: Five core categories and nine subcategories were identified. From the time of the terminal diagnosis to the end of life, family caregivers felt unprepared, uncertain, and in need of information. They struggled with whether symptoms were HCC- or cirrhosis-related.?. INTERPRETATION: Nurses can support family caregivers by eliciting their knowledge and concerns, and attending to symptom presentation and interpretation and to treatment challenges. Understanding challenges caregivers experience is crucial for developing interventions that address their desire for information, support, and help along the HCC disease trajectory.?. IMPLICATIONS FOR NURSING: Nurses play a critical role in preparing caregivers to understand the importance of pain assessment and management and early referral to palliative care. PMID- 28820519 TI - How the Consolidated Framework for Implementation Research Can Strengthen Findings and Improve Translation of Research Into Practice: A Case Study. AB - PURPOSE/OBJECTIVES: To answer how the planned intervention was performed in routine care, which factors supported or distracted from its implementation, and how key organizational structures have been built and sustained.?. RESEARCH APPROACH: Mixed-methods process evaluation.?. SETTING: Two German outpatient cancer clinics.?. PARTICIPANTS: Purposive sampling of 297 recruited patients with gynecologic cancer, their treating oncology nurses, and their interprofessional healthcare team, and the clinical stakeholders of two different outpatient cancer clinics.?. METHODOLOGIC APPROACH: Guided by the Consolidated Framework for Implementation Research (CFIR), five distinct interrelated substudies were designed to evaluate intervention characteristics, inner and outer settings, characteristics of the individuals involved, and the process of implementation. Quantitative and qualitative data will be analyzed separately and then integrated into a framework analysis.?. FINDINGS: Oncology nurses found the regular process analytic sessions to be beneficial, not only for sharing their experience, but also for experiencing social support and social connectedness.?. INTERPRETATION: Key implementation facets of the nurse-led intervention will be examined systematically. The results can guide future implementation processes, which need to be tailored to interested facilities.?. IMPLICATIONS FOR NURSING: The CFIR framework is well established but not yet widely applied in supportive treatment research. The current study aims to apply and combine this framework with the concept of intervention fidelity. PMID- 28820520 TI - Response to "Assessing the Impact of Acupuncture on Pain, Nausea, Anxiety, and Coping in Women Undergoing a Mastectomy". AB - We read with interest the pilot randomized, controlled trial by Quinlan-Woodward et al. (2016) published in Oncology Nursing Forum about the impact of acupuncture on pain, nausea, anxiety, and coping in women undergoing a mastectomy. We think that there are both theoretical and methodologic issues that do not allow the authors to conclude that their study demonstrated that acupuncture delivered postoperatively in the hospital after mastectomy can reduce the severity of symptoms experienced and increase the patient's ability to cope with her symptoms.?. PMID- 28820521 TI - Feasibility of a Multicomponent Breast Health Education Intervention for Vietnamese American Immigrant Women. AB - PURPOSE/OBJECTIVES: To determine the feasibility and acceptability of an intervention with targeted cultural and health belief messages to increase rates of mammography among Vietnamese American (VA) immigrant women. ?. DESIGN: One group, pre-/post-test, pilot, quasiexperimental design.?. SETTING: Portland, Oregon, metropolitan area. ?. SAMPLE: 40 VA immigrant women aged 50 years or older.?. METHODS: Participants who had not had a mammogram within the past 12 months were recruited. The intervention consisted of one interactive group teaching session, followed by individual counseling delivered about 10 days later to overcome barriers to screening. Participants completed a baseline survey prior to the group teaching and again at 12 weeks after the session.?. MAIN RESEARCH VARIABLES: The intervention, guided by the Transtheoretical Model of Change and the Health Belief Model, involved movement in stage of change based on women's readiness, as well as perceived susceptibility, perceived benefits, perceived common barriers, and perceived cultural barriers. Mammogram completion and knowledge of breast cancer and mammography were examined.?. FINDINGS: The recruitment response rate was 58%. Knowledge about breast cancer, breast cancer susceptibility, and the benefits of mammography as related to breast cancer significantly increased following the intervention.?. CONCLUSIONS: Acceptability of the targeted program, good feasibility, and very low attrition was achieved. ?. IMPLICATIONS FOR NURSING: This intervention can be adapted for other populations, including other Asian groups, and other cancer screenings. PMID- 28820522 TI - Results of an Oncology Clinical Trial Nurse Role Delineation Study. AB - PURPOSE/OBJECTIVES: To evaluate the relevance of a five-dimensional model of clinical trial nursing practice in an oncology clinical trial nurse population. ?. DESIGN: Web-based cross-sectional survey.?. SETTING: Online via Qualtrics.?. SAMPLE: 167 oncology nurses throughout the United States, including 41 study coordinators, 35 direct care providers, and 91 dual-role nurses who provide direct patient care and trial coordination.?. METHODS: Principal components analysis was used to determine the dimensions of oncology clinical trial nursing practice.?. MAIN RESEARCH VARIABLES: Self-reported frequency of 59 activities.?. FINDINGS: The results did not support the original five-dimensional model of nursing care but revealed a more multidimensional model.?. CONCLUSIONS: An analysis of frequency data revealed an eight-dimensional model of oncology research nursing, including care, manage study, expert, lead, prepare, data, advance science, and ethics.?. IMPLICATIONS FOR NURSING: This evidence-based model expands understanding of the multidimensional roles of oncology nurses caring for patients with cancer enrolled in clinical trials. PMID- 28820523 TI - Ethical Considerations in Conducting Pragmatic Trials in Oncology. AB - Pragmatic trials evaluate interventions in real-life scenarios, which differ from explanatory trials that control for numerous factors and variables to best determine causal associations. Each approach has advantages and disadvantages. Conducting pragmatic research trials while maintaining the tenets of the ethical conduct of research can sometimes be challenging, particularly regarding informed consent. In this column, distinctions between pragmatic and explanatory trials are discussed from an ethical view. PMID- 28820524 TI - Patterns of Hand Grip Strength and Detection of Strength Loss in Patients Undergoing Bone Marrow Transplantation: A Feasibility Study. AB - PURPOSE/OBJECTIVES: To determine the feasibility of measuring hand grip strength (HGS) daily in a population of recipients of bone marrow transplantation (BMT), to describe changes in strength measured by HGS, and to describe relationships between laboratory values (hematocrit, hemoglobin, and absolute neutrophil count) and HGS.?. DESIGN: Prospective, longitudinal, repeated measures, within subject.?. SETTING: Inpatient units at the University of Washington Medical Center in Seattle.?. SAMPLE: 33 patients admitted in preparation for BMT or for complications from BMT.?. METHODS: HGS measured on admission and daily.?. MAIN RESEARCH VARIABLES: HGS, absolute neutrophil count, hemoglobin, and hematocrit.?. FINDINGS: Participants found HGS testing to be relatively easy. Average time to complete testing was 7.2 minutes (SD = 1.95). Nineteen experienced 20% or greater decline in HGS during hospitalization, with nine experiencing decline during the conditioning phase. Age, gender, and hemoglobin correlated with HGS. Strength loss was more likely in those undergoing allogeneic compared to autologous BMT.?. CONCLUSIONS: A majority of patients experienced strength decline during BMT, with a subgroup declining during conditioning. A positive relationship existed between HGS and hemoglobin and hematocrit in participants admitted for conditioning for BMT.?. IMPLICATIONS FOR NURSING: Weakness increases risk for falls. Patients may experience as much as 50% strength loss during the course of hospitalization for BMT. Strength loss occurs in the conditioning phase for some patients. PMID- 28820525 TI - The Content Validity of a Chemotherapy-Induced Peripheral Neuropathy Patient Reported Outcome Measure. AB - PURPOSE/OBJECTIVES: To test the content validity of a 16-item version of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy (QLQ-CIPN20). ?. RESEARCH APPROACH: Cross-sectional, prospective, qualitative design. ?. SETTING: Six outpatient oncology clinics within the University of Michigan Health System's comprehensive cancer center in Ann Arbor. ?. PARTICIPANTS: 25 adults with multiple myeloma or breast, gynecologic, gastrointestinal, or head and neck malignancies experiencing peripheral neuropathy caused by neurotoxic chemotherapy. ?. METHODOLOGIC APPROACH: Cognitive interviewing methodology was used to evaluate the content validity of a 16-item version of the QLQ-CIPN20 instrument.?. FINDINGS: Minor changes were made to three questions to enhance readability. Twelve questions were revised to define unfamiliar terminology, clarify the location of neuropathy, and emphasize important aspects. One question was deleted because of clinical and conceptual redundancy with other items, as well as concerns regarding generalizability and social desirability. ?. INTERPRETATION: Cognitive interviewing methodology revealed inconsistencies between patients' understanding and researchers' intent, along with points that required clarification to avoid misunderstanding. ?. IMPLICATIONS FOR NURSING: Patients' interpretations of the instrument's items were inconsistent with the intended meanings of the questions. One item was dropped and others were revised, resulting in greater consistency in how patients, clinicians, and researchers interpreted the items' meanings and improving the instrument's content validity. Following additional revision and psychometric testing, the QLQ-CIPN20 could evolve into a gold-standard CIPN patient-reported outcome measure. PMID- 28820526 TI - Silica nanoparticle monolayers on a macroion modified surface: formation mechanism and stability. AB - Even though silica nanoparticles and their monolayers find a broad field of applications, only a few studies providing a quantitative description of silica nanoparticle deposition at solid/liquid interfaces have been reported in the literature. Given the deficit of reliable experimental data, the goal of this work is to acquire thorough physicochemical characteristics of amorphous silica nanoparticle deposition. Silica nanoparticle monolayers of controlled coverage were formed on macroion (PAH)-modified mica. The size of the particles determined by dynamic light scattering (DLS), atomic force microscopy (AFM) and scanning electron microscopy (SEM) was equal to 28 nm. The electrophoretic mobility and the zeta potential of the particles were also determined as a function of ionic strength and pH. Using a well-defined suspension, systematic studies of particle deposition kinetics were carried out. The coverage of the self-assembled particle monolayers was determined by AFM and SEM imaging. Particle deposition was carried out under diffusion controlled transport conditions. For long deposition times, the saturation coverage was attained, systematically increasing with ionic strength up to 0.48 for I = 0.15 M NaCl. The deposition kinetic runs were adequately interpreted using the random sequential adsorption (RSA) model. This model was also used to determine the specific density of silica particles that confirmed their porous structure. In addition, the particle desorption kinetics was studied using AFM and SEM methods. It was confirmed that silica nanoparticle desorption was negligible within the time period of 60 hours. Our experimental data proved, therefore, that it is feasible to produce uniform and stable silica particle monolayers of desired coverage in the self-assembly processes, controlled by the bulk suspension concentration and the ionic strength. Such monolayers may find practical applications as substrates for selective protein and nanoparticle deposition, or various catalytic applications. PMID- 28820528 TI - Deciphering the photosensitization mechanisms of hypericin towards biological membranes. AB - Resorting to state-of-the art molecular modeling and simulation techniques we provide full characterization of the photophysical properties of the naturally occurring hypericin chromophore, currently used in photodynamic therapy. In particular, we reveal the different photophysical pathways leading to intersystem crossing and hence, triplet manifold population that is necessary for the subsequent production of singlet oxygen. In particular we identify an extended region of quasi-degeneracy between the first singlet excited state and three triplet state surfaces. This energetic factor allows the occurrence of intersystem-crossing even in the presence of a relatively small spin-orbit coupling. Furthermore, thanks to extended all-atom molecular dynamics simulations we provide insight into the interaction of hypericin with lipid bilayers. We demonstrate the formation of stable interactions with the membrane and, in particular, the penetration of hypericin into its hydrophobic core. This organization allows a spatial overlap between hypericin and the lipid oxidizable double bond pointing towards the production of singlet oxygen in close spatial proximity to its reactant, hence favoring photosensitization. PMID- 28820529 TI - Reactions between microhydrated superoxide anions and formic acid. AB - Reactions between water clusters containing the superoxide anion, O2-(H2O)n (n = 0-4), and formic acid, HCO2H, were studied experimentally in vacuo and modelled using quantum chemical methods. Encounters between microhydrated superoxide and formic acid were found to result in a number of different reactions, including (a) proton transfer, (b) ligand exchange, (c) H2-elimination (affording microhydrated CO4-), and (d) dihydrogen transfer (affording H2O2 and microhydrated CO2-). The effect of reactant-ion hydration on reaction rates was investigated and the involved reaction mechanisms were elucidated. PMID- 28820530 TI - CXCR7 attenuates the TGF-beta-induced endothelial-to-mesenchymal transition and pulmonary fibrosis. AB - Lung fibrosis is a progressive and often fatal lung disease characterized by fibroblast proliferation and excessive deposition of extracellular matrix in the lungs. The chemokine receptor CXCR7 has been shown to control cell adhesion, migration and proliferation by regulating the epithelial-to-mesenchymal transition (EMT), but the role of CXCR7 in regulating the endothelial-to mesenchymal transition (EndMT) and lung fibrosis remains largely unclear. In this study, we investigated the interrelation of CXCR7 and TGF-beta, a crucial player in lung fibrogenesis. We report herein that CXCR7 expression is significantly increased in animal models of TGF-beta1-induced pulmonary fibrosis and in TGF beta1-treated endothelial cells. TGF-beta1 up-regulates CXCR7 expression in a Smad2/3-dependent manner in endothelial cells. The overexpression of CXCR7 effectively attenuates TGF-beta1-induced EndMT in lung endothelial cells, whereas CXCR7 knockdown in endothelial cells further promotes TGF-beta1-induced EndMT. Mechanically, CXCR7 attenuates EndMT by inhibiting the Jag1-Notch pathway. CXCR7 overexpression in mice also results in a significant enhancement in endothelial markers and a decrease in mesenchymal markers, indicating a decreased susceptibility to TGF-beta1-induced lung fibrosis and deposition of extracellular matrix and collagen. These data suggest that CXCR7 upregulation induced by TGF beta is a feedback mechanism to regulate TGF-beta-induced EndMT and pulmonary fibrosis. PMID- 28820531 TI - Phytic acid-assisted electrochemically synthesized three-dimensional O, P functionalized graphene monoliths with high capacitive performance. AB - Three-dimensional functionalized graphene monoliths (3DFGMs) have attracted intensive attention as energy storage materials due to their unique interconnected porous structure, good electrical conductivity, excellent mechanical strength, and pseudocapacitive characteristic. Herein, we report a facile, green and low-cost strategy through a simple, one-step electrochemical process in a phytic acid solution to fabricate a 3DFGM. The 3D porous structure and functionalization of graphene can be obtained simultaneously. The as-obtained 3DFGM that consists of 3D porous O, P-functionalized few-layer graphene shows high specific surface area and good electrical conductivity. The 3DFGM with these characteristics exhibits excellent electrochemical performance, including an ultrahigh specific areal capacitance of 485 mF cm-2, superior rate performance, and outstanding cycling stability. Most importantly, the assembled 3DFGM//3DFGM symmetric supercapacitor exhibits a high specific areal capacitance of 225 mF cm 2 and delivers a maximum energy density of 1.2 W h L-1 and a power density of 560 W L-1 in aqueous electrolyte. Therefore, this work provides a promising method for the future design and fabrication of high performance 3D functionalized graphene-based electrodes for energy storage devices. PMID- 28820532 TI - Topotactic transition of alpha-Co(OH)2 to beta-Co(OH)2 anchored on CoO nanoparticles during electrochemical water oxidation: synergistic electrocatalytic effects. AB - Herein, we report a single step, anionic surfactant-assisted, low temperature hydrothermal synthetic strategy of CoO nanoparticles anchored on beta-Co(OH)2 nanosheets which show a low overpotential (295 mV @ 10 mA cm-2) for the oxygen evolution reaction (OER). They also demonstrate much better kinetic parameters compared to the state-of-the-art RuO2. Interestingly, under the OER operational conditions (in alkaline medium), the topotactic transformation of alpha-Co(OH)2 to a stable Brucite-like beta-Co(OH)2 phase leads to a synergistic interaction between the beta-Co(OH)2 sheets on the CoO nanoparticles for enhancing the OER electrocatalytic activity. PMID- 28820527 TI - Spatiotemporal hydrogel biomaterials for regenerative medicine. AB - Hydrogels mimic many of the physical properties of soft tissue and are widely used biomaterials for tissue engineering and regenerative medicine. Synthetic hydrogels have been developed to recapitulate many of the healthy and diseased states of native tissues and can be used as a cell scaffold to study the effect of matricellular interactions in vitro. However, these matrices often fail to capture the dynamic and heterogenous nature of the in vivo environment, which varies spatially and during events such as development and disease. To address this deficiency, a variety of manufacturing and processing techniques are being adapted to the biomaterials setting. Among these, photochemistry is particularly well suited because these reactions can be performed in precise three-dimensional space and at specific moments in time. This spatiotemporal control over chemical reactions can also be performed over a range of cell- and tissue-relevant length scales with reactions that proceed efficiently and harmlessly at ambient conditions. This review will focus on the use of photochemical reactions to create dynamic hydrogel environments, and how these dynamic environments are being used to investigate and direct cell behavior. PMID- 28820533 TI - Actinomycetes: still a source of novel antibiotics. AB - Covering: 2006 to 2017Actinomycetes have been, for decades, one of the most important sources for the discovery of new antibiotics with an important number of drugs and analogs successfully introduced in the market and still used today in clinical practice. The intensive antibacterial discovery effort that generated the large number of highly potent broad-spectrum antibiotics, has seen a dramatic decline in the large pharma industry in the last two decades resulting in a lack of new classes of antibiotics with novel mechanisms of action reaching the clinic. Whereas the decline in the number of new chemical scaffolds and the rediscovery problem of old known molecules has become a hurdle for industrial natural products discovery programs, new actinomycetes compounds and leads have continued to be discovered and developed to the preclinical stages. Actinomycetes are still one of the most important sources of chemical diversity and a reservoir to mine for novel structures that is requiring the integration of diverse disciplines. These can range from novel strategies to isolate species previously not cultivated, innovative whole cell screening approaches and on-site analytical detection and dereplication tools for novel compounds, to in silico biosynthetic predictions from whole gene sequences and novel engineered heterologous expression, that have inspired the isolation of new NPs and shown their potential application in the discovery of novel antibiotics. This review will address the discovery of antibiotics from actinomycetes from two different perspectives including: (1) an update of the most important antibiotics that have only reached the clinical development in the recent years despite their early discovery, and (2) an overview of the most recent classes of antibiotics described from 2006 to 2017 in the framework of the different strategies employed to untap novel compounds previously overlooked with traditional approaches. PMID- 28820534 TI - The ligand effect on the oxidative addition of dioxygen to gold(i)-hydride complexes. AB - The ligand effect on the recently uncovered feasible oxidative addition reaction of O2 on [LAuH] complexes has been investigated for a series of fifteen ligands. The activation barriers of this spin-forbidden reaction have been estimated at the minimum energy crossing points (MECP, relativistic scalar level) between the adiabatic triplet (reactants spin state) and singlet (product spin state) potential energy surfaces (PES) and calculated at the transition states by including Spin-Orbit Coupling (SOC) effects, as applied for the mechanistic study of this reaction in a previous study by us [Chem. Sci., 2016, 7, 7034-7039]. We find a sizeable effect of the ligand on the activation barriers, and some of the stronger electron donating phosphines are predicted to induce the highest catalyst efficiency. The inclusion of SOC effects lowers the activation barriers by about 3 kcal mol-1 systematically with respect to the MECP values independently of the ligand type. We used the Charge-Displacement (CD) analysis to quantify the net electron charge donation from the ligand L towards the metallic fragment AuH in the [LAuH] series, and surprisingly only a poor correlation was found between the net electron donor character of L and the activation barriers. Application of the CD-NOCV (Natural Orbitals for Chemical Valence) approach, which allows the quantification of the Dewar-Chatt-Duncanson (DCD) L-AuH bond components, suggests that the ligand effect on the activation barriers is not easily predictable on the basis of solely the electronic properties of the ligand and depends significantly on the ligand nature or carbene or phosphine type. We show that for both phosphine and carbene ligand subsets, however, the sigma donation component of the L-AuH bond quantitatively accounts for the ligand effect on the activation energy barriers (a larger sigma donor capability of L correlates with a smaller activation barrier), whereas the pi back-donation, strongly affected by geometrical rearrangement, is a poor reactivity descriptor (pi acceptor properties of the ligand L in the linear [LAuH] complexes are not transferable to the trigonal [LAuH(O2)] transition state structures). PMID- 28820535 TI - 7-Step total synthesis of (+)-EBC-329: Photoisomerisation reveals new seco casbane family member. AB - The first seco-casbane, EBC-329, isolated from the Australian rainforest, was synthesised from (+)-2-carene in seven steps. This endeavour not only established the absolute stereochemical assignment as (8R,9S)-EBC-329, but also identified, via photoisomerisation, a new seco-casbane family member. PMID- 28820536 TI - Atp7a and Atp7b regulate copper homeostasis in developing male germ cells in mice. AB - The maintenance of copper homeostasis is critical for all cells. As learned from mice with disturbed copper metabolism, this trace element is also important for spermatogenesis. The experiments conducted in yeasts have demonstrated that appropriate copper level must be preserved to enable meiosis progression; however, increased copper level is toxic for cells. This study aims to analyze the expression profile of Atp7a and Atp7b and other genes encoding copper-related proteins during spermatogenesis in mice. Using the transcripts and protein detection techniques, we demonstrate that within seminiferous tubuli, ATP7A is mainly present in early meiotic germ cells (leptotene to pachytene spermatocytes) and in Sertoli cells (SCs). During spermatogenesis, the progression Atp7a expression profile corresponds to Slc31a1 (encoding copper importer CTR1) and Atox1 (encoding chaperon protein, which delivers copper from CTR1 to ATP7A and ATP7B) expression, suggesting that male germ cells retrieve copper and ATP7A protects them from copper overdose. In contrast, ATP7B protein is observed in SCs and near elongated spermatids; thus, its function seems to be related to copper extraction during spermiogenesis. This is the first study to give a comprehensive view on the activity of copper-related genes during spermatogenesis in mice. PMID- 28820537 TI - syn-BN-heteroacene cored conjugated oligomers with finely tuned blue-violet luminescent properties. AB - Initiated by the effective dibromination of syn-BN-heteroacenes, a series of BN containing conjugated oligomers was successfully synthesized upon transition metal-catalyzed cross coupling. Their electronic structures can be finely tailored through varying the fused backbone or terminal substituents, endowing them with tunable luminescent properties within blue-violet regions. PMID- 28820538 TI - From blue to full color - theoretical design and characterization of a series of Ir(iii) complexes containing azoline ligand with potential application in OLEDs. AB - Two reported Ir(iii) complexes 1a and 1b containing oxazoline and imidazoline in ancillary ligand, respectively, were investigated by DFT/TD-DFT method. In order to obtain full-color display materials, we designed a group of Ir(iii) complexes 2a-3d based on 1a, which exhibits higher quantum efficiency in phosphorescence, by introducing electron-donating/electron-withdrawing moieties to different positions of the ancillary ligand to adjust emission color. In addition to calculating the radiation rate and analyzing its determining factors, we also estimated nonradiative ability by evaluating the spin-orbit coupling matrix element between the ground state (S0) and the lowest triplet state (T1) as well as the reorganization energy from T1 to S0 to estimate quantum efficiency more accurately. In particular, an in-depth analysis on the contribution of each vibration mode to reorganization energy helped us to identify the effect of substituents on the nonradiative process. Besides, charge injection/transfer properties and energy relation of the states related to exciton quenching via the triplet metal-centered state were also examined, which provide an estimation on the OLED performance of our designed complexes. Overall, we expect 2b and 3c to be more efficient blue-emitting emitters than 1a and 3a and 3b to be efficient green and red emitters, respectively. PMID- 28820539 TI - A survey of non-communicable diseases and their risk factors among university employees: a single institutional study. AB - BACKGROUND: The incidence of non-communicable diseases (NCDs) is rising globally, with its attendant morbidity and mortality, especially in developing countries. This study evaluated the prevalence of NCDs and their risk factors among members of a university community. METHODS: All employees of the university were invited to the University health clinic for screening, using the World Health Organisation's STEPwise approach to NCDs. RESULTS: A total of 883 (521; 59.0% males) employees with a mean age of 44 +/- 10 years were studied. The median (IQR) number of NCD risk factors was three (two to three) per participant. The most common NCD risk factors were inadequate intake of fruit and vegetables (94.6%; 95% CI: 92.8-95.9), physical inactivity (77.8%; 95% CI: 74.9-80.5%) and dyslipidaemia (51.8%; 95% CI: 48.4-51.6%). Others included obesity (26.7%; 95% CI: 23.9-29.8%), alcohol use (24.0%; 95% CI: 21.3-27.0%) and cigarette smoking (2.9%; 95% CI: 2.0-4.3). Hypertension was the most common NCD (48.5%; 95% CI: 45.1-51.8%), followed by chronic kidney disease (13.6%; 95% CI: 11.4-16.1) and diabetes mellitus (8.0%; 95% CI: 6.4-10.1). There was no gender-specific difference in the prevalence of NCDs. CONCLUSION: This study identified that NCDs and their modifiable risk factors are highly prevalent in this community. Workplace policy to support the adoption of healthy living is needed. PMID- 28820540 TI - Endoscopic Port Access Surgery for Late Orthotopic Cardiac Transplantation Atrioventricular Valve Disease. AB - BACKGROUND: The study aim was to present details of the perioperative and long term outcomes of redo-endoscopic port access surgery (REPAS) for late atrioventricular valve disease (AVVD) in orthotopic cardiac transplant (OCT) patients. METHODS: Between February 2004 and October 2015, REPAS was performed for late AVVD in seven consecutive OCT patients (mean age 57.9 +/- 17.2 years; EuroSCORE II 21.2 +/- 14.7%) at the authors' institution. The mean OCT-REPAS time interval was 7.8 +/- 4.6 years (range: 1.3-13.8 years). NYHA class III or IV symptoms were present in four patients (57%). The mean left ventricular ejection fraction was 52.9 +/- 3.9%, and surgical indications included severe mitral valve (MV) and tricuspid valve (TV) regurgitation in three patients (44%) and six patients (86%), respectively. Etiological factors included endomyocardial biopsy trauma (n = 6; 86%), degenerative disease (n = 2; 29%), and fungal endocarditis (n = 1; 14%). RESULTS: Procedures performed included MV repair (n = 3; 43%) and TV replacement (n = 3; 43%). There were no sternotomy conversions or revisions for any cause. The mean cardiopulmonary bypass and ischemic times were 178.4 +/- 48.6 min and 118.3 +/- 39.5 min, respectively. In-hospital morbidities included hospital-acquired pneumonia (n = 2; 29%). There were no wound infections or 30 day mortalities. The mean duration of hospitalization was 18.3 +/- 11.0 days. A mean of 29.2 +/- 45.6 patient-months (total 204.3 patient-months) was available for long-term clinical and echocardiographic analysis (n = 7; 100% complete). No MV or TV reinterventions were required. NYHA class <=II was achieved in five patients (71%). No patient presented with residual MV regurgitation greater than grade I. CONCLUSIONS: REPAS for late AVVD in OCT patients is a safe and durable procedure with favorable technique-related mortality, in-hospital morbidity, and long-term cardiac-specific outcomes at experienced centers. The present technique provided an attractive benchmark against which emerging percutaneous interventions may be measured, and earlier referral of patients should be considered. PMID- 28820541 TI - Automatic Estimation of Optimal Deployment of Transcatheter Aortic Valve Implantation Using Computed Tomography. AB - BACKGROUND: A comparison was made between the accuracy of and time saved by using novel automated software for pre-procedural computed tomography (CT) planning before transcatheter aortic valve implantation (TAVI) and manual methods. Preprocedural CT to assess aortic annulus dimensions and predict the optimal C arm implant angle before TAVI can reduce complications related to incorrect prosthesis sizing and positioning. METHODS: A total of 61 consecutive patients underwent TAVI using either the SAPIEN XT or CoreValve prosthesis. Pre-procedural CT scans were analysed using three methods: automatic; semi-automatic; and manual. For each method, annular dimensions were measured and the optimal implantation angle was predicted. After TAVI the actual post-deployment angle orthogonal to the prosthesis was determined using aortic fluoroscopy. The difference between the predicted angle by CT and the measured post-deployment angle was calculated for each method. RESULTS: For all methods the mean angular difference with the actual post-deployment angle was similar at ~9 +/- 7 degrees . There was a significant difference between the SAPIEN XT (6.6 +/- 5.8 degrees ) and CoreValve (11.5 +/- 6.9 degrees , p <0.001) prostheses due to a consistently greater left anterior oblique and caudal angulation for the CoreValve. Although the annular area correlated well among all methods, 'automatic' results were consistently larger than 'manual' results. Interobserver variability was low for all measures. The fully automatic method saved 98 s, and the semiautomatic method 40 s per case. CONCLUSIONS: The use of automatic software enabled a rapid and accurate prediction of implantation angles, though results differed for specific manufacturers. Annular areas were overestimated by the automatic method, and thus required manual adjustments. PMID- 28820542 TI - Efficacy and Complications of Transcatheter Aortic Valve Implantation With and Without Balloon Aortic Valvuloplasty. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) is an effective treatment for severe aortic stenosis in high-risk patients. Several complications related to the TAVI procedure, including aortic regurgitation (AR), cerebrovascular accident (CVA) and the requirement for permanent pacemaker (PPM), are thought to be secondary to balloon aortic valvuloplasty (BAV) before TAVI. The aim of the present review was to evaluate any beneficial role of the direct TAVI approach over BAVTAVI. METHODS: A comprehensive search of major databases was performed. Only studies comparing TAVI with and without BAV were included. A total of nine full length articles was included in the analysis. RESULTS: Among 2,650 patients, 1,043 underwent 'direct TAVI' without pre-BAV, while 1,607 underwent TAVI following BAV. Overall, there was no difference between the 30-day all-cause mortality (OR 0.96, 95% CI 0.63-1.47, p = 0.86), CVA (OR 0.81, 95% CI 0.34-1.92, p = 0.63) and PPM implantation (OR 0.84, 95% CI 0.66- 1.05, p = 0.12) between the two approaches. The rate of moderate to severe AR was significantly lower with direct TAVI implantation (OR 0.44, 95% CI 0.20-0.96, p = 0.04). In the case of self-expandable valves, direct TAVI was associated with a lower device success (OR 5.15, 95% CI 1.33-19.9, p = 0.02). CONCLUSIONS: No difference was identified in mortality between direct TAVI and BAV-TAVI. However, direct TAVI is associated with a lower incidence of AR, a finding that would only be confirmed by conducting further randomized studies. PMID- 28820543 TI - Minimally Invasive Versus Transcatheter and Surgical Aortic Valve Replacement: A Propensity Matched Study. AB - BACKGROUND: An increasing number of options exist for the treatment of severe symptomatic aortic stenosis. The study aim was to compare short-term outcomes in patients undergoing surgical aortic valve replacement (SAVR), minimally invasive aortic valve replacement (MIAVR), and transcatheter aortic valve replacement (TAVR). METHODS: A multi-institutional retrospective review of 2,571 patients undergoing SAVR (n = 842), MIAVR via right anterior thoracotomy (n = 699) and TAVR (n = 1,030) between 2011 and 2014 was conducted. TAVR patients were further stratified as either transfemoral (TF) or transapical (TA). Propensity matching was performed between MIAVR and SAVR (384 pairs), MIAVR and TA-TAVR (115 pairs), and MIAVR and TF-TAVR (247 pairs). RESULTS: Total numbers of AVR increased between 2011 and 2014. When stratified by procedure type, MIAVR and TF-TAVR accounted for most of the growth, while TA-TAVR and SAVR each experienced a decreased volume. Propensity matched comparisons of SAVR, TF-TAVR, and TA-TAVR versus MIAVR revealed no difference in 30-day mortality. TF-TAVR versus MIAVR revealed that MIAVR had a decreased rate of stroke (0.4% versus 3.6%, p = 0.02) and increased atrial fibrillation (AF; 19.4% versus 4%, p <0.01). When compared to SAVR, MIAVR had a lower incidence of AF (19% versus 32.6%, p <0.01). MIAVR exhibited decreased ventilation time (27.2 versus 134 h, p = 0.03) and intensive care unit time (63.7 versus 92.7 h, p = 0.02) compared to TA-TAVR. CONCLUSIONS: During recent years, MIAVR and TFTAVR have experienced significant growth in volume with near-comparable short-term outcomes, while SAVR and TA-TAVR volumes have declined. These results underscore the importance of surgeons adopting MIAVR and TF-TAVR techniques in order to offer patients optimal outcomes. PMID- 28820544 TI - Use of Adjuncts Reduces Cardiopulmonary Bypass Time During Minimally Invasive Aortic Valve Replacement. AB - BACKGROUND: Minimally invasive aortic valve replacement (MIAVR) through a mini thoracotomy is comparable to AVR through a sternotomy, but may have increased surgical times. The development of adjuncts such as the automatic knot fastener and percutaneous coronary sinus (CS) catheter may reduce this disadvantage. METHODS: A retrospective review conducted between 2002 and 2015 at a single institution revealed 78 patients who underwent MIAVR with adjuncts. The automatic knot fastener was used on all patients, and a successful CS catheter was placed and confirmed by echocardiography in 67 patients (86%). Patients were propensity matched against those who had MIAVR without adjuncts (n = 78) and through a median sternotomy (n = 78) for assessment of major morbidity. Variables were compared using an unpaired t-test, Wilcoxon rank sum test, chi-squared and Fisher's exact test where appropriate. RESULTS: Patients who underwent MIAVR with adjuncts had shorter cross-clamp times (70.5 versus 108.1 and 84.4 min; p <0.0001) and cardiopulmonary bypass (CPB) times (101.1 versus 166.12 and 127.7 min; p <0.0001) than those who underwent MIAVR without adjuncts or through a median sternotomy. Patients who underwent MIAVR received fewer blood transfusions compared to those undergoing AVR via a median sternotomy (0.6 and 1.2 versus 2.5; p <0.012). Patients who underwent MIAVR with adjuncts had similar rates of new onset atrial fibrillation (AF) than those undergoing MIAVR without adjuncts (33% versus 22%; p = 0.11), but had higher rates of AF compared to the sternotomy group (33% versus 17%; p = 0.02). Rates of in-hospital morbidity and mortality were similar between all groups. CONCLUSIONS: The use of adjuncts during MIAVR led to a significant shortening of cross-clamp and CPB times, and to a requirement for fewer blood transfusions. Morbidity and mortality rates after MIAVR were similar to those in patients undergoing a median sternotomy. PMID- 28820545 TI - Assessment and Management of Acute Severe Mitral Regurgitation in the Intensive Care Unit. AB - BACKGROUND AND AIM OF THE STUDY: Acute severe mitral regurgitation (MR) is a serious medical condition. Whilst clear guidelines exist regarding the management of chronic MR, acute severe MR is usually treated on an individual basis. Currently, few data exist regarding acute MR in the era of primary coronary interventions (PCI). The present study included patients admitted to the Department of Cardiology during recent years with acute severe MR of different etiologies, and an analysis of these data in the light of previous investigations. METHODS: The digital database of the present authors' hospital was searched for patients diagnosed with severe MR between 2008 and 2015. From a total of 228 patients identified, 19 with primary MR and 17 with secondary (functional) MR were admitted to the Department of Cardiology. The clinical data and outcome of these patients were analyzed. RESULTS: Among patients with MR due to acute myocardial infarction (MI), 13 had functional MR and six had MR due to mechanical complications, namely rupture of the papillary muscle or chordae tendineae. Among patients with MR not in the setting of MI, 13 had primary MR and four had functional MR. Patients with MR due to acute MI were more often in cardiogenic shock or had pulmonary edema and had a higher mortality. The strongest predictor of mortality was the presence of shock, followed by female gender, hypertension, age >=68 years; previous MI and pulmonary edema were also predictors of mortality. In patients with acute MI and secondary MR, PCI to the culprit coronary artery was associated with a lesser degree of MR on follow up. CONCLUSIONS: Patients with severe MR are at high risk of in-hospital death. Patients with functional MR are likely to benefit from prompt PCI to the culprit artery, and for those with primary MR urgent surgery is life-saving. PMID- 28820547 TI - Incidence and Clinical Impact of Cerebral Lesions after the MitraClipA(r) Procedure. AB - BACKGROUND: Clinically silent brain injury detected with cerebral magnetic resonance imaging (MRI) is well known after various cardiovascular interventions. Thus far, only one study has examined the periprocedural risk of cerebral ischemic events in patients undergoing percutaneous mitral valve reconstruction. The study aim was to examine the incidence and clinical impact of cerebral embolic events in patients undergoing percutaneous mitral valve reconstruction using the MitraClip(r) system. METHODS: Thirteen eligible high-risk patients without contraindications for MRI underwent MitraClip treatment at the authors' institution. Neurological testing with the assessment of global cognitive function was performed three days before and two days after the procedure. All patients underwent cerebral diffusion-weighted MRI (DWI) two days after the procedure. RESULTS: In nine patients, post-interventional MRI revealed newly acquired microembolic cerebral lesions. At follow up MRI scans recorded at 307 +/ 270 days after the procedure, ischemic scars were not detectable in any patient. Two patients with five or more new cerebral lesions in DW-MRI showed a significant decline in their test scores. CONCLUSIONS: The MitraClip procedure results in acute cerebral lesions in the vast majority of patients. All lesions seen on DWI post-procedure resolved completely, but the number of lesions may have had an impact on cognitive function. PMID- 28820548 TI - Extraction of Total RNA from Calcified Human Heart Valves for Gene Expression Analysis. AB - BACKGROUND: The isolation of high-quality RNA is an important first step in gene expression studies. However, difficult tissue disruption, low cell content and low RNA content makes consistent RNA extraction from human aortic valve tissue a challenging task. METHODS: A protocol has been developed for the successful isolation of high-quality RNA from human aortic valve samples by optimizing RNA extraction protocols based on a comparison of commercial kits. RESULTS: Guanidinium thiocyanate-phenolchloroform extraction was found to be a prerequisite for successful purification. Two protocols based on this extraction were further optimized. RNA quality and quantity were assessed spectrophotometrically, using a Bioanalyzer and by PCR analysis of several housekeeping genes. Optimized parameters included storage in RNAlaterTM, DNase digestion, the amount of tissue, homogenization time, and freezing of tissue after homogenization. CONCLUSIONS: The modified protocol for fatty and fibrous tissue achieved satisfactory results for gene expression analysis of human aortic valve samples. PMID- 28820546 TI - Initial Results of Combined MitraClipA(r) Implantation and Left Atrial Appendage Occlusion. AB - BACKGROUND: Atrial fibrillation is present in 30-50% of patients undergoing percutaneous mitral valve repair. The presence of a formal contraindication to oral anticoagulation is also very common in these patients. In this context, percutaneous left atrial appendage occlusion (LAAO) may be a valid alternative for these patients. The study aim was to assess the feasibility, safety, and technical considerations of the combination of percutaneous mitral valve repair using the MitraClip system and LAAO. The present study describes the multicenter experience of combined MitraClip and LAAO procedures. METHODS: Between April 2012 and April 2016, six patients were successfully treated with the combined procedure. RESULTS: In all patients, mitral valve repair was performed before LAAO. Both procedures were successfully performed in all cases without any relevant procedural complication or mortality. CONCLUSIONS: According to the results of the present study, a combination of both techniques appears to be feasible and safe, with favorable in-hospital outcomes. PMID- 28820550 TI - Is Fasting for Ramadan Safe in Patients with Mechanical Cardiac Valves? AB - BACKGROUND AND AIM OF THE STUDY: The study aim was to investigate the safety and effects of fasting during Ramadan on the International Normalized Ratio (INR) in patients with mechanical cardiac valves. METHODS: A total of 105 patients admitted to the authors' hospital between June and October 2015, who had history of prosthetic valve replacement, was investigated. The patients were allocated to two groups: those fasting during Ramadan (n = 42) and those not fasting (n = 63). All patients were examined by a cardiologist, and the clinical findings and complaints for the past three months were evaluated. The INR, complete blood count (CBC) and a basic biochemical panel were monitored for all patients. RESULTS: The mean corpuscular volume (MCV) of the fasting group was significantly higher than that of the non- fasting group (87.59 +/- 6.39 (MUm3) versus 84.28 +/ 6.387 (MUm3); p = 0.011). Other CBC parameters and basic biochemical values did not differ significantly different between groups. Neither were significant differences noted in INR values during Ramadan (fasting group 2.87 +/- 0.97; non fasting group 2.73 +/- 0.78; p = 0.50) and at routine control one month later (fasting group 3.07 +/- 1.55; non-fasting group 2.94 +/- 1.03; p = 0.601). No significant differences related to increased rates of hospitalization, valvular dysfunction on echocardiography, thrombus, embolism, bleeding and clinical complaints were identified between the groups. CONCLUSIONS: Fasting during Ramadan had no adverse effects on the INR of patients, and appears to be safe for patients with mechanical prosthetic cardiac valves. PMID- 28820549 TI - QishenYiqi Dripping Pill Improves Heart Failure by Up-Regulation of beta2 Adrenergic Receptor Expression. AB - BACKGROUND: QishenYiqi Dripping Pill (QYDP) is a Chinese herbal medicine that originally was used for the treatment of coronary artery disease. Recently, QYDP was used as a complementary treatment for heart failure (HF) in China. METHODS: An HF rat model was used to clarify the possible therapeutic effects of QYDP on HF. The HF rats were allocated to two groups, HF and HF+QYDP, while normal rats served as a negative control. Cardiac functions were evaluated echocardiographically and hemodynamically. Cardiac apoptosis and the expression of beta-adrenergic receptors were also investigated. RESULTS: Compared to the HF group, rats in the HF+QYDP group had a significantly higher fraction shortening (p<0.05), ejection fraction (p<0.05), left ventricular systolic pressure (p<0.05), maximum positive derivatives of left ventricular pressure (p<0.05), maximum negative derivatives of left ventricular pressure (p<0.05), and beta2 adrenergic receptor expression (p<0.05), and lower left ventricular end-diastolic pressure (p<0.05) and apoptotic index (p<0.05). CONCLUSIONS: The study results indicated that QYDP could efficiently improve HF, possibly by an inhibition of cardiac apoptosis via the beta2-adrenergic receptor signaling pathway. Hence, QYDP might be a promising candidate drug for HF therapy. PMID- 28820551 TI - Fungal Endocarditis Due to Aspergillus oryzae: The First Case Reported in the Literature. AB - Infective endocarditis (IE) is a severe disease with high mortality and morbidity. Prosthetic valve endocarditis is a life-threatening complication which can occur in less than 10% of patients with valve prosthesis. A fungal etiology of IE is rare and accounts for only 2-4% of all case of endocarditis, but is associated with a higher mortality and morbidity. Herein is reported the first case of fungal endocarditis of aortic valve prosthesis due to Aspergillus oryzae in a 67-year-old caucasian man who nine years previously underwent mitral and aortic valve replacement with mechanical prostheses, and tricuspid annuloplasty for acute IE due to Enterococcus spp. Seven months previously, the patient also underwent a redo cardiac procedure to replace a mitral valve prosthesis with a new mechanical device due to a leakage. Aspergillus oryzae showed impressive growth with strong and unexpected virulence in both local and systemic settings. PMID- 28820552 TI - (1->3)-beta-D-Glucan Assay in Monitoring Response to Anti-Fungal Therapy in Fungal Endocarditis. AB - BACKGROUND AND AIM OF THE STUDY: A case is reported of Candida glabrata infective endocarditis (IE) treated without surgical intervention. The study aim was to: (i) briefly discuss the outcomes of other documented cases of fungal IE managed medically with fluconazole; (ii) discuss the (1->3)-beta-D-glucan assay and its previously studied role in the diagnosis of invasive fungal infections; and (iii) examine a possible application of the (1->3)-beta-D-glucan assay to monitor response to antifungal treatment in patients with Candida endocarditis. METHODS: The serum Fungitell assay was used to trend (1->3)-beta-D-glucan in a patient with Candida endocarditis to determine treatment effectiveness with fluconazole, to provide an appropriate end date for antifungal therapy, and to survey infection suppression while off treatment. RESULTS: The (1->03)-beta-D-glucan assay began trending downwards at 197 days into treatment with oral fluconazole. After 16 months of therapy, fluconazole was stopped due to transaminitis. (1->3) beta-Dglucan levels were checked six weeks after the discontinuation of treatment and were negative. The patient has now been off therapy for 21 weeks with no signs of clinical disease, and values remain negative. CONCLUSIONS: The present case indicates that a trending (1->3)-beta-D-glucan assay may have valuable application in monitoring treatment response and infection suppression for Candida endocarditis. PMID- 28820553 TI - Is Transcatheter Tricuspid Valve-In-Valve Implantation Feasible in the Presence of Right Atrial Thrombus? AB - The case is reported of a successful transcatheter implantation of an Edwards SAPIEN 3 valve (29 mm) into a failing tricuspid bioprosthesis (Sorin Pericarbon, 31 mm). The procedure was performed in a 69-year-old woman with post-rheumatic mitral and tricuspid valve disease. Multiple previous cardiac surgeries precluded the use of another surgical approach. A large, organized, two-piece thrombus in the enlarged right atrium was not considered an absolute contraindication to the procedure. The SAPIEN 3 valve was implanted under general anesthesia, via a femoral venous access, under three-dimensional transesophageal echocardiography guidance. Postoperatively, the systolic right ventricular pressure was increased from 35 to 52 mmHg, but good function of the implanted valve was confirmed with transthoracic echocardiography. The clinical outcome was favorable and the patient was discharged home 72 h after the intervention. Video 1: Transthoracic echocardiography. Tricuspid color Doppler flow after the procedure. Video 2: Fluoroscopy. Fully expanded Edwards SAPIEN 3 valve in the tricuspid position. Video 3: Fluoroscopy. Expansion of the Edwards SAPIEN 3 valve on the balloon. Video 4: Fluoroscopy. Introduction of the Edwards SAPIEN 3 valve into the right atrium. Video 5: Transthoracic echocardiography. Tricuspid color Doppler flow before the procedure. PMID- 28820554 TI - Warfarin Therapy After Mechanical Valve Replacement: A Tool for Predicting Bleeding Events. AB - BACKGROUND AND AIM OF THE STUDY: Mechanical valve replacement is associated with positive outcomes, but patients must undergo life-long anticoagulation therapy with warfarin, which carries a significant risk of bleeding complications. Therefore, a systematic and continuous assessment and supervision of warfarin treatment is essential in such patients, and approaches that can predict the risk of bleeding in advance are required. The study aim was to develop a classification tool to predict bleeding events in South Korean patients with mechanical valve replacement undergoing oral warfarin therapy. METHODS: The retrospective cohort study included 2,453 patients followed up for at least one year after valve replacement surgery, between January 2003 and December 2012. Discriminant analysis was used to assess potential bleeding risk factors out of 31 patient- related and disease-related descriptors. The prediction capability of the descriptors was evaluated based on accuracy, sensitivity,specificity, positive predictive value, and negative predictive value. RESULTS: A total of 13 descriptors including general, clinical-related and medication-related risk factors was selected as suitable predictors for bleeding risk. A novel classification tool was developed using these risk factors, and evaluated for accuracy (91.5%), sensitivity (80.2%), and specificity (95.2%). CONCLUSIONS: The classification tool developed in the present study can be reliably used in a clinical context to predict bleeding events in patients with mechanical valve replacement undergoing oral warfarin therapy. PMID- 28820555 TI - Satellite Atrial Septal Vegetations Secondary to Mitral Valve Endocarditis. AB - Infective endocarditis is a challenging clinical problem with a high rate of mortality. Early recognition of this disease, and especially its complications, remain a critical task for the cardiologist. In this scenario, atrial endocarditis is a rare and sometimes unrecognized complication of mitral valve endocarditis. Herein is reported a clinical case that shows how a satellite vegetation in the atrial septum can be produced in a patient with mitral regurgitation secondary to mitral valve endocarditis. Video 1: Transthoracic echocardiography showing the presence of vegetation in the posterior mitral leaflet, severe secondary mitral regurgitation, and satellite vegetation in the atrial septum. PMID- 28820556 TI - Unusual Locations for Cardiac Papillary Fibroelastomas. AB - Papillary fibroelastomas (PFEs) are rare and benign cardiac tumors which usually are localized on the valves (mostly on the aortic valve), though they may originate also from the ventricles or atrial walls. Whilst, in the large majority of cases, these lesions are asymptomatic they may cause serious complications such as thromboembolic events, or more rarely valvular dysfunctions. Surgical excision is necessary for a symptomatic lesion. The management of asymptomatic lesions is not defined. Herein are reported the details of a miniseries of six cases operated on at the authors' institution between 2005 and 2015. A review of the current literature suggests that PFE is a rare but potentially treatable cause of thromboembolic events, and must be borne in mind during the differential diagnosis of cardioembolic stroke. The surgical excision of PFEs is safe and definitive. PMID- 28820557 TI - Papillary Muscle Rupture in an Adolescent with No Coronary Lesions. AB - A 21-year-old man with Wolff-Parkinson-White syndrome presented to the authors' hospital with ventricular fibrillation. Coronary angiography failed to demonstrate coronary stenosis, but temporary mechanical circulatory support resolved the ventricular fibrillation and the patient was extubated eight days later. On the next day, however, he had to be re-intubated with symptoms of congestive heart failure. Echocardiography revealed new severe mitral regurgitation and a mobile mass, while emergency surgery revealed a posteromedial papillary muscle rupture (PMR). The mitral regurgitation was repaired with ruptured papillary muscle relocation, artificial chordae implantation, and ring annuloplasty. Postoperative examinations suggested that an arrhythmia-induced coronary circulation hypoperfusion and septic embolization had caused the PMR. PMID- 28820558 TI - Young Patient with Advanced Heart Failure No Longer a Candidate for Heart Transplantation after MitraClipA(r) Procedure. AB - In Europe, mitral regurgitation (MR) is the second most common form of valvular heart disease requiring surgical treatment. The case is presented of a 36-year old woman with end-stage heart failure secondary to chemotherapy-induced cardiotoxicity, complicated by severe MR. She was listed for heart transplantation and underwent percutaneous MitraClip(r) implantation in order to preclude further clinical deterioration while awaiting a suitable donor. The one year follow-up showed a strong improvement of symptoms and mostly reverse left ventricular remodelling, with consequent removal from the heart transplantation list. Video 1: Four-chamber view at baseline. Video 2: Four-chamber view at one year follow up. Video 3: Tricuspid regurgitation and right ventricle at baseline. Video 4: Tricuspid regurgitation and right ventricle at one-year follow up. PMID- 28820559 TI - Percutaneous Mitral Balloon Valvuloplasty in a Pregnant Patient Under Guidance of Three-Dimensional Transesophageal Echocardiography and Right Atrial Mapping, without Using Fluoroscopy. AB - Mitral stenosis is the most common valvular pathology complicating pregnancy. Herein are reported the details of a 26-week pregnant patient with severe mitral stenosis and NYHA class 3-4 symptoms. Percutaneous mitral balloon valvuloplasty was performed under guidance of three-dimensional transesophageal echocardiography and right atrial mapping, without using fluoroscopy. Video 1: Two-dimensional transesophageal echocardiography. The four-chamber view shows limited opening of the rheumatic mitral valve. Video 2: Two-dimensional transesophageal echocardiography while the balloon is inflated. Video 3: Live/real time three-dimensional transesophageal echocardiography showing the uninflated balloon passing through the mitral valve. Video 4: Live/real time three-dimensional transesophageal echocardiography showing the inflated balloon passing through the mitral valve. PMID- 28820560 TI - Severe Valvular Aortic Stenosis and Fixed Subvalvular Aortic Stenosis: A Rare and Challenging Combination. AB - A 58-year-old man with a history of hypertension presented with accelerating angina. Transthoracic echocardiography revealed a thickened aortic valve with pressure gradients and an estimated aortic valve area suggestive of mild aortic stenosis. Left heart catheterization demonstrated non-significant coronary artery disease. Pressure tracings showed a high left ventricular pressure and a mean gradient across the aortic valve of 69 mmHg. Subsequent transesophageal echocardiography revealed a subvalvular aortic stenosis that was secondary to the subaortic membrane, with severe valvular aortic stenosis. The patient underwent surgical resection of the subaortic membrane followed by bioprosthetic aortic valve replacement, with resolution of his symptoms. Video 1: Transesophageal echocardiography, five-chamber view, showing the calcified aortic valve and subaortic membrane. Video 2: Transesophageal echocardiography, long-axis view, showing aliasing of the aortic flow at valvular and subvalvular levels. PMID- 28820561 TI - Quadricuspid Aortic Valve Associated with Aortic Regurgitation, Mitral Regurgitation, and Aortic Dilatation. AB - The quadricuspid aortic valve (QAV) is a very uncommon congenital malformation with an estimated incidence of 0.003% to 0.043% of all congenital heart diseases. Combinations of QAV with several different congenital malformations have been described. The case is reported of a type A QAV associated with moderate aortic regurgitation, mild mitral regurgitation, and ascending aorta dilatation. This interesting case was referred for close follow up. PMID- 28820562 TI - The HIPAA Privacy Rule and the EU GDPR: Illustrative Comparisons. PMID- 28820563 TI - The Extrapolation Conundrum: Finding a Unified Theory for the Use of Statistical Sampling in Medicare Fraud Cases Brought Under the False Claims Act. PMID- 28820564 TI - Telepharmacy Rules and Statutes: A 50-State Survey. AB - Purpose and Introduction. The purpose of this policy brief is to identify rules and laws enacted by states authorizing the use of community telepharmacy initiatives within their respective jurisdictions. Though telepharmacy exists in several forms, telepharmacy in this brief is defined as the delivery of pharmaceutical care to outpatients at a distance through the use of telecommunication and other advanced technologies. Pharmaceutical care includes, but is not limited to, drug review and monitoring, dispensing of medications, medication therapy management, and patient counseling. A significant advantage of telepharmacy is the ability to provide pharmacist access to patients in remote areas where a pharmacist is not physically available. Therefore, the implications of telepharmacy on increasing access to care are significant, particularly to patients in underserved rural communities, though it is important to note that underserved populations do not exist exclusively in rural settings. Key Findings. (1) The use of telepharmacy is authorized, in varying capacities, in 23 states (46 percent). (2) Pilot program development that could apply to telepharmacy initiatives is authorized by six states (12 percent). (3) Waivers to administrative or legislative pharmacy practice requirements that could allow for telepharmacy initiatives are permitted in five states (10 percent). (4) Nearly one-third of the states (16, or 32 percent) do not authorize the use of telepharmacy, nor do they currently have the ability to pursue telepharmacy initiatives via pilot programs or waivers. PMID- 28820565 TI - Are Opioid Deaths Affected by Macroeconomic Conditions? PMID- 28820566 TI - The Long-Run Effects of Pollution Exposure on Mortality. PMID- 28820567 TI - Does Early Preventive Care for Diabetes Improve Outcomes? PMID- 28820568 TI - Enhanced Drug Delivery into Cell Cytosol via Glycoprotein H-Derived Peptide Conjugated Nanoemulsions. AB - The key role of nanocarriers in improving the pharmacological properties of commonly used drugs is recognized worldwide. It is also known that in the development of new effective nanocarriers the use of targeting moieties integrated on their surface is essential. Herein, we propose a nanocarrier based on an oil in water nanoemulsion coated with a membranotropic peptide derived from the glycoprotein H of Herpes simplex virus 1, known as gH625, in order to reduce endolysosomal accumulation and to enhance cytosolic localization. In addition, we show an enhanced anti-inflammatory activity of curcumin, a bioactive compound isolated from the Curcuma longa plant, when loaded into our engineered nanocarriers. This effect is a consequence of a higher uptake combined with a high curcumin preservation exerted by the active nanocapsules compared to control ones. When loaded into our nanocapsules, indeed, curcumin molecules are directly internalized into the cytosol rather than into lysosomes. Further, in order to extend the in vitro experimental setting with a more complex model and to explore the possibility to use our nanocarriers for further biological applications, we tested their performance in a 3D sprouting angiogenesis model. Finally, we show promising preliminary in vivo results by assessing the anti-inflammatory properties of the proposed nanocarrier. PMID- 28820569 TI - Selective Ru ALD as a Catalyst for Sub-Seven-Nanometer Bottom-Up Metal Interconnects. AB - Integrating bottom-up area-selective building-blocks in microelectronics has a disruptive potential because of the unique capability of engineering new structures and architectures. Atomic layer deposition (ALD) is an enabling technology, yet understanding the surfaces and their modification is crucial to leverage area-selective ALD (AS-ALD) in this field. The understanding of general selectivity mechanisms and the compatibility of plasma surface modifications with existing materials and processes, both at research and production scale, will greatly facilitate AS-ALD integration in microelectronics. The use of self assembled monolayers to inhibit the nucleation and growth of ALD films is still scarcely compatible with nanofabrication because of defectivity and downscaling limitations. Alternatively, in this Research Article, we demonstrate a straightforward H2 plasma surface modification process capable of inhibiting Ru ALD nucleation on an amorphous carbon surface while still allowing instantaneous nucleation and linear growth on Si-containing materials. Furthermore, we demonstrate how AS-ALD enables previously inaccessible routes, such as bottom-up electroless metal deposition in a dual damascene etch-damage free low-k replacement scheme. Specifically, our approach offers a general strategy for scalable ultrafine 3D nanostructures without the burden of subtractive metal patterning and high cost chemical mechanical planarization processes. PMID- 28820570 TI - Engineering of Micro- to Nanostructured 3D-Printed Drug-Releasing Titanium Implants for Enhanced Osseointegration and Localized Delivery of Anticancer Drugs. AB - Primary and secondary bone cancers are major causes of pathological bone fractures which are usually treated through implant fixation and chemotherapy. However, both approaches face many limitations. On one hand, implants may suffer from poor osseointegration, and their rejection results in repeated surgery, patient's suffering, and extensive expenses. On the other hand, there are severe systemic adverse effects of toxic chemotherapeutics which are administrated systemically. In this paper, in order to address these two problems, we present a new type of localized drug-releasing titanium implants with enhanced implants' biointegration and drug release capabilities that could provide a high concentration of anticancer drugs locally to treat bone cancers. The implants are fabricated by 3D printing of Ti alloy followed by an anodization process featuring unique micro- (particles) and nanosurface (tubular arrays) topography. We successfully demonstrate their enhanced bone osseointegration and drug loading capabilities using two types of anticancer drugs, doxorubicin (DOX) and apoptosis inducing ligand (Apo2L/TRAIL). In vitro study showed strong anticancer efficacy against cancer cells (MDA-MB-231-TXSA), confirming that these drug-releasing implants can be used for localized chemotherapy for treatment of primary and secondary bone cancers together with fracture support. PMID- 28820572 TI - Functionality Selection Principle for High Voltage Lithium-ion Battery Electrolyte Additives. AB - A new class of electrolyte additives based on cyclic fluorinated phosphate esters was rationally designed and identified as being able to stabilize the surface of a LiNi0.5Mn0.3Co0.2O2 (NMC532) cathode when cycled at potentials higher than 4.6 V vs Li+/Li. Cyclic fluorinated phosphates were designed to incorporate functionalities of various existing additives to maximize their utilization. The synthesis and characterization of these new additives are described and their electrochemical performance in a NMC532/graphite cell cycled between 4.6 and 3.0 V are investigated. With 1.0 wt % 2-(2,2,2-trifluoroethoxy)-1,3,2 dioxaphospholane 2-oxide (TFEOP) in the conventional electrolyte the NMC532/graphite cell exhibited much improved capacity retention compared to that without any additive. The additive is believed to form a passivation layer on the surface of the cathode via a sacrificial polymerization reaction as evidenced by X-ray photoelectron spectroscopy (XPS) and nuclear magnetic resonsance (NMR) analysis results. The rational pathway of a cathode-electrolyte-interface formation was proposed for this type of additive. Both experimental results and the mechanism hypothesis suggest the effectiveness of the additive stems from both the polymerizable cyclic ring and the electron-withdrawing fluorinated alkyl group in the phosphate molecular structure. The successful development of cyclic fluorinated phosphate additives demonstrated that this new functionality selection principle, by incorporating useful functionalities of various additives into one molecule, is an effective approach for the development of new additives. PMID- 28820571 TI - Comparison of Spreading Depolarizations in the Motor Cortex and Nucleus Accumbens: Similar Patterns of Oxygen Responses and the Role of Dopamine. AB - Spreading depolarizations (SD) are pathophysiological phenomena that spontaneously arise in traumatized neural tissue and can promote cellular death. Most investigations of SD are performed in the cortex, a brain region that is susceptible to these depolarizing waves and accessible via a variety of monitoring techniques. Here, we describe SD responses in the cortex and the deep brain region of the nucleus accumbens (NAc) of the anesthetized rat with a minimally invasive, implantable sensor. With high temporal resolution, we characterize the time course of oxygen responses to SD in relation to the electrophysiological depolarization signal. The predominant oxygen pattern consists of four phases: (1) a small initial decrease, (2) a large increase during the SD, (3) a delayed increase, and (4) a persistent decrease from baseline after the SD. Oxygen decreases during SD were also recorded. The latter response occurred more often in the NAc than the cortex (56% vs 20% of locations, respectively), which correlates to denser cortical vascularization. We also find that SDs travel more quickly in the cortex than NAc, likely affected by regional differences in cell type populations. Finally, we investigate the previously uncharacterized effects of dopamine release during SD in the NAc with dopamine receptor blockade. Our results support an inhibitory role of the D2 receptor on SD. As such, the data presented here expands the current understanding of within- and between-region variance in responses to SD. PMID- 28820573 TI - Magnetically Aligned Co-C/MWCNTs Composite Derived from MWCNT-Interconnected Zeolitic Imidazolate Frameworks for a Lightweight and Highly Efficient Electromagnetic Wave Absorber. AB - Developing lightweight and highly efficient electromagnetic wave (EMW) absorbing materials is crucial but challenging for anti-electromagnetic irradiation and interference. Herein, we used multiwalled carbon nanotubes (MWCNTs) as templates for growth of Co-based zeolitic imidazolate frameworks (ZIFs) and obtained a Co C/MWCNTs composite by postpyrolysis. The MWCNTs interconnected the ZIF-derived Co C porous particles, constructing a conductive network for electron hopping and migration. Moreover, the Co-C/MWCNTs composite was aligned in paraffin matrix under an external magnetic field, which led to a stretch of the MWCNTs along the magnetic field direction. Due to the anisotropic permittivity of MWCNTs, the magnetic alignment considerably increased the dielectric loss of the Co-C/MWCNTs composite. Benefiting from the conductive network, the orientation-enhanced dielectric loss, and the synergistic effect between magnetic and dielectric components, the magnetically aligned Co-C/MWCNTs composite exhibited extremely strong EMW absorption, with a minimum reflection loss (RL) of -48.9 dB at a filler loading as low as 15 wt %. The specific RL value (RL/filler loading) of the composite was superior to that of the previous MOF-derived composite absorbers. It is expected that the proposed strategy can be extended to the fabrication of other lightweight and high-performance EMW-absorbing materials. PMID- 28820574 TI - Thiol-Containing Metallo-beta-Lactamase Inhibitors Resensitize Resistant Gram Negative Bacteria to Meropenem. AB - The prevalence of infections caused by metallo-beta-lactamase (MBL) expressing Gram-negative bacteria has grown at an alarming rate in recent years. Despite the fact that MBLs can deactivate virtually all beta-lactam antibiotics, there are as of yet no approved drugs available that inhibit their activity. We here examine the ability of previously reported thiol-based MBL inhibitors to synergize with meropenem and cefoperazone against a panel of Gram-negative carbapenem-resistant isolates expressing different beta-lactamases. Among the compounds tested, thiomandelic acid 3 and 2-mercapto-3-phenylpropionic acid 4 were found to efficiently potentiate the activity of meropenem, especially against an imipenemase (IMP) producing strain of K. pneumoniae. In light of the zinc dependent hydrolytic mechanism employed by MBLs, biophysical studies using isothermal titration calorimetry were also performed, revealing a correlation between the synergistic activity of thiols 3 and 4 and their zinc-binding ability with measured Kd values of 9.8 and 20.0 MUM, respectively. PMID- 28820575 TI - MBG-Modified beta-TCP Scaffold Promotes Mesenchymal Stem Cells Adhesion and Osteogenic Differentiation via a FAK/MAPK Signaling Pathway. AB - The beta-TCP scaffold has been widely used as a bone graft substitute, but the traditional PMMA molding method-induced undesirable mechanical strength and poor interconnectivity still have not been addressed until now. In this study, a MBG based PU foam templating method was developed to fabricate beta-TCP scaffolds with desirable microtopography. The MBG gel, as both binder and modifier, prepared by a modified sol-gel method with controlled viscosity is incorporated with beta-TCP powder and thereafter is impregnated into PU foam. The resultant hybrid scaffolds exhibited interconnected macropores (200-500 MUm) and distinctive micropores (0.2-1.5 MUm), especially for the TCP/25MBG (with 25 wt % content MBG). As expected, the compression strength of beta-TCP/MBG composite scaffolds was enhanced with increasing MBG content, and TCP/50MBG (with 50 wt % content MBG) exhibited almost 100-fold enhancement compared to the pure beta-TCP. Intriguingly, the cell affinity and osteogenic capacity of rBMSCs were also dramatically improved the best on TCP/25MBG. Further investigation found that the subtle, grainy-like microtopography, not the chemical composition, of the TCP/25MBG favored the adsorption of Fn and expression of integrin alpha5beta1 and further facilitated FA formation and the expression of p-FAK, following activation of the MAPK/ERK signaling pathway and ultimately upregulated expression of osteogenic genes. Further in vivo experiments confirmed the promoted osteogenesis of TCP/25MBG in vivo. The results suggest that such a novel MBG-based PU foam templating method offers new guidance to construct hierarchically porous scaffolds, and the prepared MBG-modified beta-TCP scaffold will have great potential for future use in bone tissue regeneration. PMID- 28820576 TI - Angiostrongyliasis (Rat Lungworm Disease): Viewpoints from Hawai'i Island. AB - Hawai'i, particularly east Hawai'i Island, is the epicenter for angiostrongyliasis in the United States. Case numbers have been increasing and appear to parallel the introduction and spread of the semislug (Parmarion martensi) to east Hawai'i. The infective larvae in rainwater catchment as a source for household and agricultural water may also play a role. The spread of Angiostrongylus cantonensis as well as the potential introduction of the semislug P. martensi should be a concern to the mainland United States. The State of Hawai'i should recognize the seriousness of this growing problem and thus collaborate to fund studies to address the growing challenges surrounding angiostrongyliasis. PMID- 28820577 TI - Universal Nature-Inspired Coatings for Preparing Noncharging Surfaces. AB - Static charge generated by contact electrification on surfaces can lead to many undesirable consequences such as a reduction in the efficiency of manufacturing processes, damage to equipment, and explosions. However, it is extremely challenging to avoid contact electrification because it is ubiquitous: almost all types of materials charge on contact. Here, we coated materials with naturally occurring polydopamine (PDA) and tannic acid (TA) for preparing noncharging surfaces. Importantly, these coatings are very versatile and can be coated on a wide range of materials, including metals, inorganic materials, semiconductors, and polymers. Once coated, the amount of charge generated was found to reduce dramatically at different humidities. The reduction in charge may be due to the radical-scavenging property of PDA and TA. This simple general approach is ideal for coating the vast variety of materials that need to resist charging by contact electrification. PMID- 28820578 TI - Integrated Microfluidic Platform with Multiple Functions To Probe Tumor Endothelial Cell Interaction. AB - Interaction between tumor and endothelial cells could affect tumor growth and progression and induce drug resistance during cancer therapy. Investigation of tumor-endothelial cell interaction involves cell coculture, protein detection, and analysis of drug metabolites, which are complicated and time-consuming. In this work, we present an integrated microfluidic device with three individual components (cell coculture component, protein detection component, and pretreatment component for drug metabolites) to probe the interaction between tumor and endothelial cells. Cocultured cervical carcinoma cells (CaSki cells) and human umbilical vein endothelial cells (HUVECs) show higher resistance to chemotherapeutic agents than single-cultured cells, indicated by higher cell viability, increased expression of angiogenic proteins, and elevated level of paclitaxel metabolites under coculture conditions. This integrated microfluidic platform with multiple functions facilitates understanding of the interaction between tumor and endothelial cells, and it may become a promising tool for drug screening within an engineered tumor microenvironment. PMID- 28820579 TI - Site-Specific Conjugation to Native and Engineered Lysines in Human Immunoglobulins by Microbial Transglutaminase. AB - The use of microbial transglutaminase (MTG) to produce site-specific antibody drug conjugates (ADCs) has thus far focused on the transamidation of engineered acyl donor glutamine residues in an antibody based on the hypothesis that the lower specificity of MTG for acyl acceptor lysines may result in the transamidation of multiple native lysine residues, thereby yielding heterogeneous products. We investigated the utilization of native IgG lysines as acyl acceptor sites for glutamine-based acyl donor substrates. Of the approximately 80 lysines in multiple recombinant IgG monoclonal antibodies (mAbs), none were transamidated. Because recombinant mAbs lack the C-terminal Lys447 due to cleavage by carboxypeptidase B in the production cell host, we explored whether blocking the cleavage of Lys447 by the addition of a C-terminal amino acid could result in transamidation of Lys447 by a variety of acyl donor substrates. MTG efficiently transamidated Lys447 in the presence of any nonacidic, nonproline amino acid residue at position 448. Lysine scanning mutagenesis throughout the antibody further revealed several transamidation sites in both the heavy- and light-chain constant regions. Additionally, scanning mutagenesis of the hinge region in a Fab' fragment revealed sites of transamidation that were not reactive in the context of the full-length mAb. Here, we demonstrate the utility of single lysine substitutions and the C-terminal Lys447 for engineering efficient acyl acceptor sites suitable for site-specific conjugation to a range of glutamine based acyl donor substrates. PMID- 28820580 TI - Enhanced Fluorescence Emission and Singlet Oxygen Generation of Photosensitizers Embedded in Injectable Hydrogels for Imaging-Guided Photodynamic Cancer Therapy. AB - Benefiting from their inherent localized and controlled release properties, hydrogels are ideal delivery systems for therapeutic drugs or nanoparticles. In particular, applications of hydrogels for the delivery and release of photoresponsive drugs or nanoparticles are receiving increasing attention. However, the effect of the hydrogel matrix on the fluorescence emission and singlet oxygen generation efficiency of the embedded photosensitizers (PSs) has not been clarified. Herein, meso-tetrakis(1-methylpyridinium-4-yl)porphyrin (TMPyP) as a water-soluble PS was encapsulated into an injectable hydrogel formed by glycol chitosan and dibenzaldehyde-terminated telechelic poly(ethylene glycol). Compared to free TMPyP solution, the TMPyP encapsulated in the hydrogel exhibits three distinct advantages: (1) more singlet oxygen was generated under the same laser irradiation condition; (2) much longer tumor retention was observed due to the low fluidity of the hydrogel; and (3) the fluorescence intensity of TMPyP was significantly enhanced in the hydrogel due to its decreased self-quenching effect. These excellent characteristics lead to remarkable anticancer efficacy and superior fluorescence emission property of the TMPyP-hydrogel system, promoting the development of imaging-guided photodynamic therapy. PMID- 28820581 TI - A Simple Approach to the Visible-Light Photoactivation of Molecular Metal Oxides. AB - This study explores a new method to maximize the visible-light-driven photocatalytic performance of organic-inorganic hybrid polyoxometalates (POMs). Experimental and theoretical investigations of a family of phosphonate substituted POMs show that modification of grafted organic moieties can be used to tune the electronic structure and photoactivity of the metal oxide component. Unlike fully inorganic polyoxotungstates, these organic-inorganic hybrid species are responsive to visible light and function as photocatalysts (lambda > 420 nm) in the decomposition of a model environmental pollutant. The degree of photoactivation is shown to be dependent on the nature of the inductive effect exerted by the covalently grafted substituent groups. This study emphasizes the untapped potential that lies in an orbital engineering approach to hybrid-POM design and helps to underpin the next generation of bespoke, robust, and cost effective molecular metal oxide photoactive materials and catalysts. PMID- 28820582 TI - Pathogenic Mutations Induce Partial Structural Changes in the Native beta-Sheet Structure of Transthyretin and Accelerate Aggregation. AB - Amyloid formation of natively folded proteins involves global and/or local unfolding of the native state to form aggregation-prone intermediates. Here we report solid-state nuclear magnetic resonance (NMR) structural studies of amyloid derived from wild-type (WT) and more aggressive mutant forms of transthyretin (TTR) to investigate the structural changes associated with effective TTR aggregation. We employed selective 13C labeling schemes to investigate structural features of beta-structured core regions in amyloid states of WT and two mutant forms (V30M and L55P) of TTR. Analyses of the 13C-13C correlation solid-state NMR spectra revealed that WT TTR aggregates contain an amyloid core consisting of nativelike CBEF and DAGH beta-sheet structures, and the mutant TTR amyloids adopt a similar amyloid core structure with nativelike CBEF and AGH beta-structures. However, the V30M mutant amyloid was shown to have a different DA beta-structure. In addition, strand D is more disordered even in the native state of L55P TTR, indicating that the pathogenic mutations affect the DA beta-structure, leading to more effective amyloid formation. The NMR results are consistent with our mass spectrometry-based thermodynamic analyses that showed the amyloidogenic precursor states of WT and mutant TTRs adopt folded structures but the mutant precursor states are less stable than that of WT TTR. Analyses of the oxidation rate of the methionine side chain also revealed that the side chain of residue Met-30 pointing between strands D and A is not protected from oxidation in the V30M mutant, while protected in the native state, supporting the possibility that the DA beta-structure might be disrupted in the V30M mutant amyloid. PMID- 28820583 TI - Processing 2-Methyl-l-Tryptophan through Tandem Transamination and Selective Oxygenation Initiates Indole Ring Expansion in the Biosynthesis of Thiostrepton. AB - Thiostrepton (TSR), an archetypal member of the family of ribosomally synthesized and post-translationally modified thiopeptide antibiotics, possesses a biologically important quinaldic acid (QA) moiety within the side-ring system of its characteristic thiopeptide framework. QA is derived from an independent l-Trp residue; however, its associated transformation process remains poorly understood. We here report that during the formation of QA, the key expansion of an indole to a quinoline relies on the activities of the pyridoxal-5'-phosphate dependent protein TsrA and the flavoprotein TsrE. These proteins act in tandem to process the precursor 2-methyl- l-Trp through reversible transamination and selective oxygenation, thereby initiating a highly reactive rearrangement in which selective C2-N1 bond cleavage via hydrolysis for indole ring-opening is closely coupled with C2'-N1 bond formation via condensation for recyclization and ring expansion in the production of a quinoline ketone intermediate. This indole ring-expansion mechanism is unusual, and represents a new strategy found in nature for l-Trp-based functionalization. PMID- 28820584 TI - Conjugated-Backbone Effect of Organic Small Molecules for n-Type Thermoelectric Materials with ZT over 0.2. AB - Conjugated backbones play a fundamental role in determining the electronic properties of organic semiconductors. On the basis of two solution-processable dihydropyrrolo[3,4-c]pyrrole-1,4-diylidenebis(thieno[3,2-b]thiophene) derivatives with aromatic and quinoid structures, we have carried out a systematic study of the relationship between the conjugated-backbone structure and the thermoelectric properties. In particular, a combination of UV-vis-NIR spectra, photoemission spectroscopy, and doping optimization are utilized to probe the interplay between energy levels, chemical doping, and thermoelectric performance. We found that a moderate change in the conjugated backbone leads to varied doping mechanisms and contributes to dramatic changes in the thermoelectric performance. Notably, the chemically doped A-DCV-DPPTT, a small molecule with aromatic structure, exhibits an electrical conductivity of 5.3 S cm-1 and a high power factor (PF373 K) up to 236 MUW m-1 K-2, which is 50 times higher than that of Q-DCM-DPPTT with a quinoid structure. More importantly, the low thermal conductivity enables A-DCV-DPPTT to possess a figure of merit (ZT) of 0.23 +/- 0.03, which is the highest value reported to date for thermoelectric materials based on organic small molecules. These results demonstrate that the modulation of the conjugated backbone represents a powerful strategy for tuning the electronic structure and mobility of organic semiconductors toward a maximum thermoelectric performance. PMID- 28820585 TI - Chemoenzymatic Assembly of Isotopically Labeled Folates. AB - Pterin-containing natural products have diverse functions in life, but an efficient and easy scheme for their in vitro synthesis is not available. Here we report a chemoenzymatic 14-step, one-pot synthesis that can be used to generate 13C- and 15N-labeled dihydrofolates (H2F) from glucose, guanine, and p aminobenzoyl-l-glutamic acid. This synthesis stands out from previous approaches to produce H2F in that the average yield of each step is >91% and it requires only a single purification step. The use of a one-pot reaction allowed us to overcome potential problems with individual steps during the synthesis. The availability of labeled dihydrofolates allowed the measurement of heavy-atom isotope effects for the reaction catalyzed by the drug target dihydrofolate reductase and established that protonation at N5 of H2F and hydride transfer to C6 occur in a stepwise mechanism. This chemoenzymatic pterin synthesis can be applied to the efficient production of other folates and a range of other natural compounds with applications in nutritional, medical, and cell-biological research. PMID- 28820586 TI - Dissociation Chemistry of 3-Oxetanone in the Gas Phase. AB - 3-Oxetanone is a strained cyclic molecule which plays an important role in synthetic chemistry. A few studies exist in the literature about the equilibrium properties of this molecule and the dissociation patterns of substituted 3 oxetanones. For the unsubstituted 3-oxetanone, formation of ketene (CH2CO) and formaldehyde (HCHO) was considered to be the major dissociation pathway. In a recent work, pyrolysis products of 3-oxetanone molecule in the gas phase were investigated by Fourier transform infrared spectroscopy and photoionization mass spectrometry. In this study, an additional dissociation channel forming ethylene oxide (c-C2H4O) and carbon monoxide CO was reported. In the present work, gas phase dissociation chemistry of 3-oxetanone was investigated by electronic structure theory, ab initio classical chemical dynamics simulations, and Rice Ramsperger-Kassel-Marcus (RRKM) rate constant calculations. The barrier height for the ethylene oxide channel was found to be much higher than the ketene pathway. The dynamics simulations were performed at three different total energies, viz., 150, 200, and 300 kcal/mol, and multiple reaction pathways and varying branching ratios observed. A new dissociation channel involving a ring opened isomer of ethylene oxide was identified in the simulations. This pathway has a lower energy barrier and was dominant in our dynamics simulations. PMID- 28820587 TI - Flupyrimin: A Novel Insecticide Acting at the Nicotinic Acetylcholine Receptors. AB - A novel chemotype insecticide flupyrimin (FLP) [N-[(E)-1-(6-chloro-3 pyridinylmethyl)pyridin-2(1H)-ylidene]-2,2,2-trifluoroacetamide], discovered by Meiji Seika Pharma, has unique biological properties, including outstanding potency to imidacloprid (IMI)-resistant rice pests together with superior safety toward pollinators. Intriguingly, FLP acts as a nicotinic antagonist in American cockroach neurons, and [3H]FLP binds to the multiple high-affinity binding components in house fly nicotinic acetylcholine (ACh) receptor (nAChR) preparation. One of the [3H]FLP receptors is identical to the IMI receptor, and the alternative is IMI-insensitive subtype. Furthermore, FLP is favorably safe to rats as predicted by the very low affinity to the rat alpha4beta2 nAChR. Structure-activity relationships of FLP analogues in terms of receptor potency, featuring the pyridinylidene and trifluoroacetyl pharmacophores, were examined, thereby establishing the FLP molecular recognition at the Aplysia californica ACh binding protein, a suitable structural surrogate of the insect nAChR. These FLP pharmacophores account for the excellent receptor affinity, accordingly revealing differences in its binding mechanism from IMI. PMID- 28820588 TI - Exploiting and Understanding the Selectivity of Ru-N-Heterocyclic Carbene Metathesis Catalysts for the Ethenolysis of Cyclic Olefins to alpha,omega-Dienes. AB - A library of 29 homologous Ru-based olefin metathesis catalysts has been tested for ethenolysis of cyclic olefins toward the goal of selectively forming alpha,omega-diene using cis-cyclooctene as a prototypical substrate. Dissymmetry at the N-heterocyclic carbene (NHC) ligand was identified as a key parameter for controlling the selectivity. The best-performing catalyst bearing an N-CF3 group significantly outperformed the benchmark second-generation Grubbs catalyst in the ethenolysis of cis-cyclooctene. Application of this optimal catalyst to the ethenolysis of various norbornenes allows the efficient synthesis of valuable diene intermediates in good yields. The observed ligand effect trends could be rationalized through univariate and multivariate parameter analysis involving steric and electronic descriptors of the NHC ligand in the form of the buried volume and the 77Se NMR chemical shift, in particular the sigmayy component of the shielding tensor of [Se(NHC)] model compounds, respectively. Natural chemical shift analysis of this chemical shielding tensor shows that sigmayy probes the pi acceptor property of the NHC ligand, the essential electronic parameter that drives the relative rate of degenerate metathesis and selectivity in ethenolysis with catalysts bearing dissymmetric NHC ligands. PMID- 28820589 TI - Investigation of Nonadiabatic Effects for the Vibrational Spectrum of a Triatomic Molecule: The Use of a Single Potential Energy Surface with Distance-Dependent Masses for H3. AB - On the basis of first-principles, the influence of nonadiabatic effects on the vibrational bound states of H3+ has been investigated using distance-dependent reduced masses and only one single potential energy surface. For these new vibrational calculations, potentials based on explicitly correlated wave functions are used where, in addition, adiabatic corrections and relativistic contributions are taken into account. For the first time, several different fully distance-dependent reduced mass surfaces in three dimensions have been incorporated in the vibrational calculations. PMID- 28820590 TI - Conformational Heterogeneity in a Fully Complementary DNA Three-Way Junction with a GC-Rich Branchpoint. AB - DNA three-way junctions (3WJs) are branched structures that serve as important biological intermediates and as components in DNA nanostructures. We recently derived the global structure of a fully complementary 3WJ and found that it contained unpaired bases at the branchpoint, which is consistent with previous observations of branch flexibility and branchpoint reactivity. By combining high resolution single-molecule Forster resonance energy transfer, molecular modeling, time-resolved ensemble fluorescence spectroscopy, and the first 19F nuclear magnetic resonance observations of fully complementary 3WJs, we now show that the 3WJ structure can adopt multiple distinct conformations depending upon the sequence at the branchpoint. A 3WJ with a GC-rich branchpoint adopts an open conformation with unpaired bases at the branch and at least one additional conformation with an increased number of base interactions at the branchpoint. This structural diversity has implications for branch interactions and processing in vivo and for technological applications. PMID- 28820591 TI - Predicting Relative Stability of Conformers in Solution with COSMO-RS. AB - The ability of the COSMO-RS method to predict the relative stability of different conformers of the same species in solution was evaluated by comparing computational results with experimental conformer data for 105 molecules from 20 literature sources. The solvents CDCl3, CD2Cl2, benzene, toluene, ethyl ether, tetrahydrofuran, acetone, dimethylformamide, DMSO (and DMSO-d6), water, and ethanol were used (dictated by the solvents used in the literature). In the case of 16 molecules the quantitative conformer abundances were also available and were compared with the data from computations. The results show that although COSMO-RS reproduces the conformer abundances only very approximately, the most stable conformer is determined correctly in 103 cases out of 105. This result validates the use of COSMO-RS in a number of applications (distribution coefficients, vapor pressures, solubilities, etc.) where the most stable conformer of a molecule can be different in different phases and accounting for this difference is important for obtaining meaningful results. PMID- 28820593 TI - Structure of Dynamic, Taxol-Stabilized, and GMPPCP-Stabilized Microtubule. AB - Microtubule (MT) is made of alphabeta-tubulin heterodimers that dynamically assemble into a hollow nanotube composed of straight protofilaments. MT dynamics is facilitated by hydrolysis of guanosine-5'-triphosphate (GTP) and can be inhibited by either anticancer agents like taxol or the nonhydrolyzable GTP analogues like GMPPCP. Using high-resolution synchrotron X-ray scattering, we have measured and analyzed the scattering curves from solutions of dynamic MT (in other words, in the presence of excess GTP and free of dynamic-inhibiting agents) and examined the effect of two MT stabilizers: taxol and GMPPCP. Previously, we have analyzed the structure of dynamic MT by docking the atomic model of tubulin dimer onto a 3-start left handed helical lattice, derived from the PDB ID 3J6F . 3J6F corresponds to a MT with 14 protofilaments. In this paper, we took into account the possibility of having MT structures containing between 12 and 15 protofilaments. MTs with 12 protofilaments were never observed. We determined the radii, the pitch, and the distribution of protofilament number that best fit the scattering data from dynamic MT or stabilized MT by taxol or GMPPCP. We found that the protofilament number distribution shifted when the MT was stabilized. Taxol increased the mass fraction of MT with 13 protofilaments and decreased the mass fraction of MT with 14 protofilaments. GMPPCP reduced the mass fraction of MT with 15 protofilaments and increased the mass fraction of MT with 14 protofilaments. The pitch, however, remained unchanged regardless of whether the MT was dynamic or stabilized. Higher tubulin concentrations increased the fraction of dynamic MT with 14 protofilaments. PMID- 28820592 TI - Copper(I)/NO(g) Reductive Coupling Producing a trans-Hyponitrite Bridged Dicopper(II) Complex: Redox Reversal Giving Copper(I)/NO(g) Disproportionation. AB - A copper complex, [CuI(tmpa)(MeCN)]+, effectively reductively couples NO(g) at RT in methanol (MeOH), giving a structurally characterized hyponitrito-dicopper(II) adduct. Hydrogen-bonding from MeOH is critical for the hyponitrite complex formation and stabilization. This complex exhibits the reverse redox process in aprotic solvents, giving CuI + NO(g), leading to CuI-mediated NO(g) disproportionation. The relationship of this chemistry to biological iron and/or copper mediated NO(g) reductive coupling to give N2O(g) is discussed. PMID- 28820594 TI - Restrained Proton Indicator in Combined Quantum-Mechanics/Molecular-Mechanics Dynamics Simulations of Proton Transfer through a Carbon Nanotube. AB - Recently, a collective variable "proton indicator" was purposed for tracking an excess proton solvated in bulk water in molecular dynamics simulations. In this work, we demonstrate the feasibility of utilizing the position of this proton indicator as a reaction coordinate to model an excess proton migrating through a hydrophobic carbon nanotube in combined quantum-mechanics/molecular-mechanics simulations. Our results indicate that applying a harmonic restraint to the proton indicator in the bulk solvent near the nanotube pore entrance leads to the recruitment of water molecules into the pore. This is consistent with an earlier study that employed a multistate empirical valence bond potential and a different representation (center of excess charge) of the proton. We attribute this water recruitment to the delocalized nature of the solvated proton, which prefers to be in high-dielectric bulk solvent. While water recruitment into the pore is considered an artifact in the present simulations (because of the artificially imposed restraint on the proton), if the proton were naturally restrained, it could assist in building water wires prior to proton transfer through the pore. The potential of mean force for a proton translocation through the water-filled pore was computed by umbrella sampling, where the bias potentials were applied to the proton indicator. The free energy curve and barrier heights agree reasonably with those in the literature. The results suggest that the proton indicator can be used as a reaction coordinate in simulations of proton transport in confined environments. PMID- 28820595 TI - Vibronic Origin of the Qy Absorption Tail of Bacteriochlorophyll a Verified by Fluorescence Excitation Spectroscopy and Quantum Chemical Simulations. AB - The long-wavelength tail of the lowest-energy Qy singlet absorption band of bacteriochlorophyll a in triethylamine peaking at 768.6 nm was examined by means of fluorescence excitation spectroscopy at ambient temperature of 22 +/- 1 degrees C. The tail, usually considered a Gaussian, does in fact weaken quasi exponentially, being clearly evident as far as 940 nm, nearly 2400 cm-1 (~12 kBT) away from the absorption peak. Quantum chemical simulations identified vibronic transitions from the thermally populated normal modes and their overtones in the ground electronic state as the origin of this tail. Because energy transfer and relaxation processes generally depend on vibronic overlap integrals, these findings may have important implications on the interpretation of numerous photoinduced phenomena that involve bacteriochlorophyll and similar molecules, including photosynthesis. PMID- 28820596 TI - Processing Solvent-Dependent Electronic and Structural Properties of Cesium Lead Triiodide Thin Films. AB - Cesium lead triiodide (CsPbI3) is an attractive material for photovoltaic applications due to its appropriate band gap, strong optical absorption, and high thermal stability. However, the perovskite phase suffers from moisture induced structural instability. Previous studies have utilized a range of solvent systems to establish the role of solvent choice in structural instabilities. Despite this, effects of different solvents on the electronic structure of this material have not been compared. We report substantial chemical and compositional differences in thin films of CsPbI3 prepared from a range of solvent systems. We confirm via X-ray diffraction thin films formed from DMF, DMSO, and a mixture of these solvent systems share the same crystal structure. However, secondary ion mass spectrometry, X-ray photoelectron spectroscopy, and low energy ion scattering measurements reveal significant differences between films processed via different solvent systems. Our findings reveal the critical impact solvents have upon compositional stoichiometry and thin-film morphology. PMID- 28820597 TI - Deterministic Symmetry Breaking of Plasmonic Nanostructures Enabled by DNA Programmable Assembly. AB - The physical properties of matter rely fundamentally on the symmetry of constituent building blocks. This is particularly true for structures that interact with light via the collective motion of their conduction electrons (i.e., plasmonic materials), where the observation of exotic optical effects, such as negative refraction and electromagnetically induced transparency, require the coupling of modes that are only present in systems with nontrivial broken symmetries. Lithography has been the predominant fabrication technique for constructing plasmonic metamaterials, as it can be used to form patterns of arbitrary complexity, including those with broken symmetry. Here, we show that low-symmetry, one-dimensional plasmonic structures that would be challenging to make using traditional lithographic techniques can be assembled using DNA as a programmable surface ligand. We investigate the optical properties that arise as a result of systematic symmetry breaking and demonstrate the appearance of pi type coupled modes formed from both dipole and quadrupole nanoparticle sources. These results demonstrate the power of DNA assembly for generating unusual structures that exhibit both fundamentally insightful and technologically important optical properties. PMID- 28820598 TI - Methylene Blue Location in (Hydroperoxized) Cardiolipin Monolayer: Implication in Membrane Photodegradation. AB - We present molecular dynamics simulations of cardiolipin (CL) and CL monohydroperoxized derivative (CLOOH) monolayers to investigate the initial steps of phospholipid oxidation induced by methylene blue (MB) photoexcitation under continuous illumination. We considered different MB atomic charge distributions to simulate the MB electronic distribution in the singlet ground and triplet excited states. Simulation results allied to experimental data revealed that initial CL photooxidation probably occurs via a type II mechanism, to produce lipid hydroperoxide by singlet oxygen attack to the alkyl chain unsaturations. The resulting hydroperoxide group prefers to reside near the aqueous interface, to increase the membrane surface area and to decrease lipid packing. Interestingly, MB orientation changes from nearly parallel to the water-monolayer interface in the ground state to normal to the interface in its triplet excited state. The latter orientation favors oxidative chain reaction continuity via a type I mechanism, during which the hydrogen atom must be transferred from the hydroperoxide group to triplet MB. Taken together, the present results can be extrapolated to improve our understanding of how oxidation progresses in lipidic biomembrane, which will lead to the formation of oxidized species with shortened chains and will cause severe photodamage to self-organized systems. PMID- 28820599 TI - Optical Gating of Black Phosphorus for Terahertz Detection. AB - Photoconductive antennas are widely used for time-resolved detection of terahertz (THz) pulses. In contrast to photothermoelectric or bolometric THz detection, the coherent detection allows direct measurement of the electric field transient of a THz pulse, which contains both spectral and phase information. In this Letter, we demonstrate for the first time photoconductive detection of free-space propagating THz radiation with thin flakes of a van der Waals material. Mechanically exfoliated flakes of black phosphorus are combined with an antenna that concentrates the THz fields to the small flake (~10 MUm). Similar performance is reached at gating wavelengths of 800 and 1550 nm, which suggests that the narrow bandgap of black phosphorus could allow operation at wavelengths as long as 4 MUm. The detected spectrum peaks at 60 GHz, where the signal-to noise ratio is of the order of 40 dB, and the detectable signal extends to 0.2 THz. The measured signal strongly depends on the polarization of the THz field and the gating pulse, which is explained by the role of the antenna and the anisotropy of the black phosphorus flake, respectively. We analyze the limitations of the device and show potential improvements that could significantly increase the efficiency and bandwidth. PMID- 28820600 TI - Magnesiate Addition/Ring-Expansion Strategy To Access the 6-7-6 Tricyclic Core of Hetisine-Type C20-Diterpenoid Alkaloids. AB - A synthetic strategy to access the fused 6-7-6 tricyclic core of hetisine-type C20-diterpenoid alkaloids is reported. This strategy employs a Diels-Alder cycloaddition to assemble a fused bicyclic anhydride intermediate, which is elaborated to a vinyl lactone-acetal bearing an aromatic ring in five steps. Aromatic iodination is followed by magnesium-halogen exchange with a trialkyl magnesiate species, which undergoes intramolecular cyclization. Subsequent oxidation provides the desired 6-7-6 tricyclic diketoaldehyde, with carbonyl groups at all three positions for eventual C-N bond formation and subsequent elaboration. PMID- 28820601 TI - Negatively Charged and Dark Excitons in CsPbBr3 Perovskite Nanocrystals Revealed by High Magnetic Fields. AB - The optical properties of colloidal cesium lead halide perovskite (CsPbBr3) nanocrystals are examined by time-resolved and polarization-resolved spectroscopy in high magnetic fields up to 30 T. We unambiguously show that at cryogenic temperatures the emission is dominated by recombination of negatively charged excitons with radiative decay time of 300 ps. The additional long-lived emission, which decay time shortens from 40 down to 8 ns and in which the decay time shortens and relative amplitude increases in high magnetic fields, evidences the presence of a dark exciton. We evaluate g-factors of the bright exciton gX = +2.4, the electron ge = +2.18, and the hole gh = -0.22. PMID- 28820602 TI - Intricate Resonant Raman Response in Anisotropic ReS2. AB - The strong in-plane anisotropy of rhenium disulfide (ReS2) offers an additional physical parameter that can be tuned for advanced applications such as logic circuits, thin-film polarizers, and polarization-sensitive photodetectors. ReS2 also presents advantages for optoelectronics, as it is both a direct-gap semiconductor for few-layer thicknesses (unlike MoS2 or WS2) and stable in air (unlike black phosphorus). Raman spectroscopy is one of the most powerful characterization techniques to nondestructively and sensitively probe the fundamental photophysics of a 2D material. Here, we perform a thorough study of the resonant Raman response of the 18 first-order phonons in ReS2 at various layer thicknesses and crystal orientations. Remarkably, we discover that, as opposed to a general increase in intensity of all of the Raman modes at excitonic transitions, each of the 18 modes behave differently relative to each other as a function of laser excitation, layer thickness, and orientation in a manner that highlights the importance of electron-phonon coupling in ReS2. In addition, we correct an unrecognized error in the calculation of the optical interference enhancement of the Raman signal of transition metal dichalcogenides on SiO2/Si substrates that has propagated through various reports. For ReS2, this correction is critical to properly assessing the resonant Raman behavior. We also implemented a perturbation approach to calculate frequency-dependent Raman intensities based on first-principles and demonstrate that, despite the neglect of excitonic effects, useful trends in the Raman intensities of monolayer and bulk ReS2 at different laser energies can be accurately captured. Finally, the phonon dispersion calculated from first-principles is used to address the possible origins of unexplained peaks observed in the Raman spectra, such as infrared-active modes, defects, and second-order processes. PMID- 28820603 TI - Walrobsins A and B, Two Anti-inflammatory Limonoids from Root Barks of Walsura robusta. AB - Walrobsins A (1) and B (2), two limonoids featuring an unprecedented 5 oxatricyclo[5.4.11,4]hendecane ring system, were isolated from the root barks of Walsura robusta. Their structures, including their absolute configurations, were determined by analyses of HR-ESIMS, 1D/2D NMR, and X-ray crystallography. Compounds 1 and 2 possessed a stable hemiketal structure formed between the OH-11 and 3-carbonyl group in the hexatomic oxoheterocyclic ring. Compound 1 showed significant anti-inflammatory activity with an IC50 value of 7.8 MUM and inhibited the expression of iNOS and IL-1beta in a dose-dependent manner. PMID- 28820604 TI - Correction to "Dynamics of Capillary-Driven Flow in 3D Printed Open Microchannels". PMID- 28820605 TI - Body Sovereignty and Body Liability in the Wake of an "Obesity Epidemic": A Poststructural Analysis of the Soda Ban. AB - Public discourse about the 2012 soda ban proposal and its eventual dissolution offers a useful context for interrogating how discursive processes constitute and regulate normality, risk, and obesity. Using poststructural sensibilities, I critique the soda ban and public discourse about it. Although architects of the soda ban and its proponents challenged the neoliberal narrative of free choice by self-governing citizens, their efforts were stymied by (1) arguments that offered a minimalist role for the state in regulating health, and (2) contemporary anxieties about losing the ability to self-determine what to let into the body. This analysis renders visible power struggles that inform cultural understandings of what produces good health and who is responsible for its maintenance. Ultimately, I argue that soda ban discourse constructs the body as a liability and is situated in a current cultural fixation on body sovereignty. My analysis of these two axes has implications regarding the limits of biopower and the ways the body is configured in the current political economy and the conventional neoliberal imaginary. PMID- 28820606 TI - The Analysis of Constitutions of Traditional Chinese Medicine in Relation to Cerebral Infarction in a Chinese Sample. AB - OBJECTIVE: To investigate the relationships between the constitutions of Traditional Chinese Medicine (TCM) and patients with cerebral infarction (CI) in a Chinese sample. METHODS: A total of 3748 participants with complete data were available for data analysis. All study subjects underwent complete clinical baseline characteristics' evaluation, including a physical examination and response to a structured, nurse-assisted, self-administrated questionnaire. A population of 2010 neutral participants were used as the control group. Multiple variable regression (MLR) were employed to estimate the relationship between constitutions of TCM and the outcome. DESIGN: A cross-sectional study was conducted to evaluate the association of body constitution of TCM and CI. SETTINGS/LOCATION: Communications and healthcare centers in Shanghai. SUBJECTS: A total of 3748 participants with complete data were available for data analysis. OUTCOME MEASURES: All study subjects underwent complete clinical baseline characteristics' evaluation, including a physical examination and response to a structured, nurse-assisted, self-administrated questionnaire. A population of 2010 neutral participants were used as the control group. MLR were employed to estimate the relationship between constitutions of TCM and the outcome. RESULT: The prevalence of CI was 2.84% and 4.66% in neutral participants and yang deficient participants (p = 0.012), respectively. Univariate analysis demonstrated a positive correlation between yang deficiency and CI. After adjustment for relevant potential confounding factors, the MLR detected significant associations between yang deficiency and CI (odds ratio = 1.44, p = 0.093). CONCLUSION: A yang-deficient constitution was significantly and independently associated with CI. A higher prevalence of CI was found in yang deficient participants as compared with neutral participants. PMID- 28820607 TI - Individual Differences in Optimum Sleep for Daily Mood During Adolescence. AB - Efforts to establish an empirical basis for recommended sleep durations during adolescence need to take into account individual differences in optimum sleep, defined as the amount of sleep at which peak functioning is observed. A total of 419 adolescents (Mage = 15.03 years) with Mexican American backgrounds reported their nightly sleep duration and daily mood for a 2-week period at 1 or 2 waves of data collection, 1 year apart. Adolescents also completed an established measure of symptomatology. Multilevel modeling revealed a nonlinear association between sleep duration and next-day mood, whereby both too little and too much sleep were associated with elevated levels of daily distress. Significant individual differences in optimum sleep were observed such that younger adolescents and those with elevated levels of internalizing and total symptomatology evidenced greater sleep durations on nights before they reported their lowest levels of daily distress. Younger adolescents and those with higher internalizing and total symptomatology may need more sleep to reach their peak functioning the next day, at least in terms of daily mood. PMID- 28820610 TI - Asthma treatment and outcomes for children in the emergency department and hospital. AB - OBJECTIVE: To describe and compare the treatment of acute asthma exacerbations in children given in the emergency department (ED) and admitted to acute care floor in the hospital or intensive care unit (ICU). METHODS: A retrospective chart review of visits for acute exacerbation of asthma treated at Phoenix Children's Hospital between January 1, 2014 and December 31, 2016. RESULTS: A total of 287 asthma exacerbation cases were identified including 106 (37%) ED visits, 134 (47%) hospital floor and 47 (16%) ICU admissions. A history of a previous ED visit (ED 88%, Floor 60% and ICU 68%; p < 0.0001) and prior pulmonology inpatient consultation (ED 30%, Floor 19% and ICU 15%; p = 0.05) varied significantly. Pulmonology inpatient consultations were performed more frequently in the ICU than on the hospital floor (54% versus 8%; p < 0.0001). Although overall 145 (51%) of the cases were already on inhaled corticosteroids (ICS) at the time of visit with no differences across locations, ICS initiation/step-up was greater in the ICU (72%) than on the hospital floor (54%) and ED (2%) (p < 0.0001). A recommendation given to the family for follow-up with pulmonology was more frequent for patients who had been admitted to the ICU (68%) as compared to those only admitted to the floor (31%) or ED (4%) (p < 0.0001). Readmission rates were similar for patients previously admitted to the hospital (Floor 42%; ICU 40%), but significantly higher for previous ED visits (77%) (p < 0.0001). CONCLUSIONS: Physicians in the ED have an opportunity to provide preventative care in the acute care setting and should be encouraged to initiate treatment with ICS. Consideration should be given to develop a program or clinical pathway focused on long-term asthma management and maintenance to reduce readmissions and long hospital stays. PMID- 28820611 TI - Nutrient Content Claims: How They Impact Perceived Healthfulness of Fortified Snack Foods and the Moderating Effects of Nutrition Facts Labels. AB - Nutrient content claims (NCCs) may inflate perceived healthfulness of nutritionally poor foods. The aim of this study is to experimentally test the effects of NCCs on consumers' perceptions of fortified snack foods in terms of the presence of both healthful and less healthful nutrients, as well as their intentions to consume such products. It also explores the potential moderating effects of reading Nutrition Facts Labels (NFL) on the influence of NCCs. Data for this study were collected through a web-based experiment (N = 5,076). Results indicated that the presence of an NCC on a fortified snack food product increased perceived healthfulness of that product, perceptions of the presence of healthful nutrients, and intentions to consume the product. The presence of NCCs also decreased perceptions of the presence of certain less healthful nutrients. Reading the NFL had mixed effects on the impact of NCCs. PMID- 28820609 TI - Cardiopulmonary Interactions: Physiologic Basis and Clinical Applications. AB - The hemodynamic effects of ventilation can be grouped into three concepts: 1) Spontaneous ventilation is exercise; 2) changes in lung volume alter autonomic tone and pulmonary vascular resistance and can compress the heart in the cardiac fossa; and 3) spontaneous inspiratory efforts decrease intrathoracic pressure, increasing venous return and impeding left ventricular ejection, whereas positive pressure ventilation decreases venous return and unloads left ventricular ejection. Spontaneous inspiratory efforts may induce acute left ventricular failure and cardiogenic pulmonary edema. Reversing the associated negative intrathoracic pressure swings by using noninvasive continuous positive airway pressure rapidly reverses acute cardiogenic pulmonary edema and improves survival. Additionally, in congestive heart failure, states increasing intrathoracic pressure may augment left ventricular ejection and improve cardiac output. Using the obligatory changes in venous return induced by positive pressure breathing, one can quantify the magnitude of associated decreases in venous flow and left ventricular ejection using various parameters, including vena caval diameter changes, left ventricular stroke volume variation, and arterial pulse pressure variation. These parameters vary in proportion to the level of cardiac preload reserve present, thus accurately predicting which critically ill patients will increase their cardiac output in response to fluid infusions and which will not. Common parameters include arterial pulse pressure variation and left ventricular stroke volume variation. This functional hemodynamic monitoring approach reflects a practical clinical application of heart-lung interactions. PMID- 28820608 TI - Skeletal Muscle Ultrasound in Critical Care: A Tool in Need of Translation. AB - With the emerging interest in documenting and understanding muscle atrophy and function in critically ill patients and survivors, ultrasonography has transformational potential for measurement of muscle quantity and quality. We discuss the importance of quantifying skeletal muscle in the intensive care unit setting. We also identify the merits and limitations of various modalities that are capable of accurately and precisely measuring muscularity. Ultrasound is emerging as a potentially powerful tool for skeletal muscle quantification; however, there are key challenges that need to be addressed in future work to ensure useful interpretation and comparability of results across diverse observational and interventional studies. Ultrasound presents several methodological challenges, and ultimately muscle quantification combined with metabolic, nutritional, and functional markers will allow optimal patient assessment and prognosis. Moving forward, we recommend that publications include greater detail on landmarking, repeated measures, identification of muscle that was not assessable, and reproducible protocols to more effectively compare results across different studies. PMID- 28820612 TI - The potential of signal peptide peptidase as a therapeutic target for hepatitis C. AB - INTRODUCTION: Chronic infection with hepatitis C virus (HCV) causes liver steatosis, cirrhosis, metabolic syndrome with inflammation, and eventually leads to hepatocellular carcinoma. HCV core protein is a well-known capsid protein and pathogenic factor related to lipid accumulation, type 2 diabetes mellitus, and carcinogenesis. Cleavage of the C-terminal transmembrane region by signal peptide peptidase (SPP) is required for maturation of the core protein. Areas covered: Herein, this review details the general aspects of the structure, lifecycle, pathogenesis, and maturation of the HCV core protein, the function of SPP, and clinically available direct-acting antivirals (DAAs). SPP is classified into a group of GXGD-type intramembrane proteases including presenilin-1, which is a component of gamma-secretase complex. Several SPP inhibitors were previously identified from gamma-secretase inhibitors, but have not yet been improved based on specificity to SPP. Finally, the author discusses the potential of SPP inhibitors for hepatitis C therapy. Expert opinion: Currently available DAAs therapies are limited because of different viral genotypes and underlying conditions in each patient. DAA-resistant viruses have also been reported. Development of SPP-selective inhibitors may improve current HCV therapies by decreasing in the emergence of DAA-resistant viruses irrespective of viral genotype. PMID- 28820613 TI - Influence of Paddock Size on Social Relationships in Domestic Horses. AB - The aim of this study was to explore whether the size of paddocks affected social interactions within a group of horses. Furthermore, the effects of the gender composition in groups on social behavior were investigated. The research was done in a horse-riding center. A total of 78 horses and ponies, forming 3 groups, were included in the study. The time of the observation was divided into 2 periods. The data obtained from the 1st period (the horses were on relatively small paddocks) and the 2nd period (the paddocks were significantly bigger) were compared. The findings uniformly indicated that an enlargement of grass paddocks resulted in a significant decline in the number of social interactions, both agonistic and play types, in all studied herds. A likely principal reason for a change in the number of social interactions seems to be feeding management and how it changed between seasons, rather than paddock size. No effect of group composition on social interaction was found in terms of aggressive interaction, and only 1 group differed regarding friendly interaction. PMID- 28820614 TI - Protective Effects of Cryoprotectants and Lyoprotectants on the Survival of Persipeptide Producing Streptomyces zagrosensis UTMC 1154. AB - Streptomyces sp. are bacteria recognized as the producers of more than half of the known bioactive compounds. Developing appropriate preservation methods for industrial strains of Streptomyces is necessary, as continuous subculture could have significant negative effects on their characteristics, including their potential to produce secondary metabolites. The effects of two common preservation methods on a bioactive metabolite producer, Streptomyces zagrosensis UTMC 1154, were studied. In the cryopreservation method, glycerol and dimethyl sulfoxide (DMSO) were evaluated as cryoprotectants. Three different suspending fluids including skimmed milk, sucrose+gelatin and Mist. dessicans were compared as the freeze-drying methods. Freeze-dried samples were stored at 4 degrees C for 6 months and at 37 degrees C for 1 and 2 weeks in an accelerated storage stability study, which approximately correspond to storage at 4 degrees C for 10 and 20 years, respectively. Frozen samples were stored at -20 degrees C, -70 degrees C and in the vapor phase of liquid nitrogen for 6 months. Skimmed milk and DMSO were the most efficient protectants for survival and functional maintenance of the strain during the lyophilization and cryopreservation processes (p < 0.05), respectively. The survival rate of S. zagrosensis was 95.0% and 99.3% after 6 months of preservation by using skimmed milk as lyoprotectant and DMSO as the cryoprotectant, respectively. The obtained results showed that cryopreservation is the method of choice for long-term preservation of S. zagrosensis. Cryopreservation also led to only 1%-3% reduction in the biological activity of the strain after 6 months preservation in vapor phase of the liquid nitrogen. PMID- 28820615 TI - Environmental Health: Lessons from the Past and Looking to the Future. PMID- 28820616 TI - Psychometrics of the Child PTSD Symptom Scale for DSM-5 for Trauma-Exposed Children and Adolescents. AB - This study evaluated psychometric properties of interview, self-report, and screening versions of the Child PTSD Symptom Scale for DSM-5 (CPSS-5), a measure of posttraumatic stress disorder (PTSD) for traumatized youth based on DSM-5 criteria. Participants were 64 children and adolescents (51.6% female, 45.3% African American/Black) between 8 and 18 years of age (M = 14.1, SD = 2.5) who had experienced a DSM-5 Criterion A trauma. Participants completed test-retest procedures for the self-report and interviewer versions of the CPSS-5 in 2 visits that were up to 2 weeks apart. Analyses revealed excellent internal consistencies, good to excellent test-retest reliability, and good convergent validity and discriminant validity for interview and self-report versions of the scale. Receiver operating characteristic analysis yielded a cutoff score of 31 on the CPSS-5 self-report version for identifying probable PTSD diagnosis. Six most frequently endorsed items by those with a possible PTSD diagnosis on the CPSS-5 were identified to constitute a screen version of the CPSS-5, showing good internal consistency and test-retest reliability. The three versions of the CPSS 5 scales are valid and reliable measures of DSM-5 PTSD symptomatology in traumatized youth. PMID- 28820618 TI - College Women's Responses to a Celebrity Health Disclosure. AB - Celebrities can have a powerful influence on people's health-related attitudes and behaviors, often by publicly disclosing their own personal health decisions. In May 2013, Angelina Jolie, an internationally recognized actress, director, and author, wrote an op-ed for the New York Times disclosing her decision to undergo a prophylactic double mastectomy to reduce her risk of breast cancer after learning that she carried the BRCA1 gene mutation. This cross-sectional study examined whether exposure to Angelina Jolie and her mastectomy disclosure and parasocial involvement (PSI) with Angelina Jolie were related to female college students' perceived risk of breast cancer and breast cancer screening intentions. Participants were 198 female undergraduate college students. Data were collected anonymously via an online questionnaire and analyzed using bivariate correlations and hierarchical linear regression analyses. Neither exposure to Angelina and her disclosure nor PSI with Angelina Jolie was related to participants' attitudes or behaviors related to breast cancer. However, having a family history of cancer was associated with more exposure to Angelina Jolie and her disclosure. Findings suggest that exposure to and PSI with a celebrity who has disclosed a health related message may not be sufficient to motivate young women to change their health-related attitudes and behaviors. Future studies should explore how celebrities disclosing different types of health issues might influence the attitudes and behaviors of young women. PMID- 28820619 TI - Associations Between Anxious and Depressive Symptoms and the Recognition of Vocal Socioemotional Expressions in Youth. AB - The current study examined the associations between internalizing symptoms and adolescents' recognition of vocal socioemotional expressions produced by youth. Fifty-seven youth (8-17 years old, M = 12.62, SD = 2.66; 29 anxious, 28 nonanxious; 32 female, 25 male) were asked to identify the intended expression in auditory recordings of youth's portrayals of basic emotions and social attitudes. Recognition accuracy increased with age, suggesting that the ability to recognize vocal affect continues to develop into adolescence. Anxiety symptoms were not associated with recognition ability, but youth's depressive symptoms were related to poorer identification of anger and happiness. Youth experiencing symptoms of depression may be likely to misinterpret vocal expressions of happiness and anger. PMID- 28820617 TI - Patient-centeredness in physiotherapy: What does it entail? A systematic review of qualitative studies. AB - PURPOSE: The literature review is aimed at examining and summarizing themes related to patient-centeredness identified in qualitative research from the perspectives of patients and physiotherapists. Following the review, a secondary aim was to synthesize the themes to construct a proposed conceptual framework for utilization within physiotherapy. METHODS: A systematic search of qualitative studies was conducted including all articles up to 2015 September. Methodological quality was examined with a checklist. The studies were examined for themes suggestive of the practice of patient centeredness from perspective of the therapists and/or the patients. Data were extracted using a data extraction form and analyzed following "thematic synthesis." RESULTS: Fourteen articles were included. Methodological quality was high in five studies. Eight major descriptive themes and four subthemes (ST) were identified. The descriptive themes were: individuality (ST "Getting to know the patient" and ST "Individualized treatment"), education, communication (ST "Non-verbal communication"), goal setting, support (ST "Empowerment"), social characteristics of a patient-centered physiotherapist, a confident physiotherapist, and knowledge and skills of a patient-centered physiotherapist. CONCLUSIONS: Patient centeredness in physiotherapy entails the characteristics of offering an individualized treatment, continuous communication (verbal and non-verbal), education during all aspects of treatment, working with patient-defined goals in a treatment in which the patient is supported and empowered with a physiotherapist having social skills, being confident and showing specific knowledge. PMID- 28820620 TI - Care Providers' Integration of Family Requests in End-of-life Communication: Understanding What to Do and Why to Do It. AB - End-of-life situations are fraught with challenges for patients, family members, and individuals working at the patient's bedside. Care workers must address needs of the patient, as well as his or her distressed family members. This article is an inductive investigation of care workers' (nurses, patient advocates, and clergy) experiences with end-of-life discussions when the family asks to "do everything." Participants also noted resistance to hospice in some of these encounters based on pre-existing connotations of hospice held by the family members. The article concludes with a discussion about how identifying end-of life terms may be transformed to be more accessible for family members. PMID- 28820621 TI - "Doctors Killed My Baby": Argumentative Patterns in Medical Disputes in China. AB - The recent surge in medical disputes requires that more attention be paid to the voices of laypeople. This article explores the argumentative nature of the public discourse of the reported "malpractice mobs" that strive to convince members of the public (in the place of health or legal experts) that they have been victims of medical errors and injustice. This case-based qualitative empirical study uses a pragma-dialectical approach to suggest a prototypical pattern of such public appeals that contains a basic argumentative pattern and various types of extensions. The presence and influence of cultural factors are identified and discussed. The results of the analysis indicate that "malpractice mobs" largely display a tendency to target certain drugs, treatments or therapeutic methods based on folk interpretations of medical phenomena among individual ethnic groups, which may be regarded as cultural preferences in the medical domain. Although these preferences have little coercive power, in the absence of institutional restraints, they may have a powerful impact. The introduction of cultural preferences into pragmatic argumentation explains not only why some critical questions are emphasized (whereas others are invariably ignored) but also why certain types of support are repeatedly demanded in public appeals. The findings suggest the importance of paying greater attention to the argumentation of laypeople in medical disputes in China and the essential role of a culturally sensitive model of argumentation theory in improving health communication. PMID- 28820623 TI - Anticipating Loss: Learning to Live with My Father's Cancer. AB - In this article, I explore my experience living with my father's cancer diagnosis and treatment, as well as how it has affected our family. I discuss how this 12 year journey of living with cancer as a chronic illness has impacted my experience and how living with the anticipation of loss has shaped me. I reflect on the dialectical tension faced by families dealing with chronic cancer and the implications for how health communication scholars explore the impact of cancer on family members. PMID- 28820622 TI - Latent Growth Curve Modeling of Non-Injection Drug Use and Condomless Sexual Behavior from Ages 18 to 21 in Gay, Bisexual, and Other YMSM: The P18 Cohort Study. AB - BACKGROUND: HIV/AIDS continues to be a health disparity faced by sexual minority men, and is exacerbated by non-injection drug use. OBJECTIVES: We sought to delineate growth in non-injection drug use and condomless sex in a sample of racially and economically diverse of gay, bisexual, and other young men who have sex with men (YMSM) as they emerged into adulthood between the ages of 18 and 21 and who came of age in the post-HAART era. METHODS: Behavioral data on drug use and condomless sex, collected via a calendar based technique over 7 waves of a cohort study of 600 YMSM, were analyzed using latent growth curve modeling to document patterns of growth in these behaviors, their associations, and the extent to which patterns and associations are moderated by race/ethnicity and socioeconomic status. RESULTS: Significant growth was noted in the frequencies of condomless oral and anal intercourse, alcohol to intoxication, marijuana use, and inhalant nitrate use. High levels of association were noted between all behaviors across time but associations did not differ by either race/ethnicity or socioeconomic status. The link between drug use and risky sexual behavior continue to be evident in YMSM with significant increases in these behaviors demonstrated as YMSM transition between adolescence and young adulthood. Conclusions/Importance: Healthcare for a new generation of sexual minority males must address the synergy of these behaviors and also nest HIV prevention and care within a larger context of sexual minority health that acknowledges the advances made in the last three decades. PMID- 28820624 TI - Retinopathy and optic atrophy: Expanding the phenotypic spectrum of pathogenic variants in the AARS2 gene. AB - BACKGROUND: Optic atrophy may be the sequela of optic nerve injury due to any insult, including isolated and syndromic genetic diseases. Alanyl-tRNA synthetase 2 (AARS2) pathogenic variants have been reported to cause leukodystrophy with ovarian failure, and cardiomyopathy (#615889) as well as combined oxidative phosphorylation deficiency-8 (#614096). We report a young child who presented with decreased vision due to optic atrophy and was found to harbor missense variants in the AARS2 gene expanding the phenotypic expression of the AARS2 gene. MATERIALS AND METHODS: Single observational case report with genetic testing, laboratory testing, neurologic and ophthalmic clinical examinations, and neuroimaging performed at a tertiary academic medical center. RESULTS: An 18 month old Korean boy was noted to have a progressive decline in visual function. The physical exam revealed bilateral optic atrophy, peripheral retinal bone spicule pigmentation, and absent patellar reflexes. Electromyography was consistent with demyelinating polyneuropathy. Magnetic resonance imaging (MRI) of the brain and spine showed cerebellar and supratentorial white matter multifocal changes with areas of restricted diffusion, and dorsal column signal abnormalities. Whole exome sequencing revealed two missense variants in the AARS2 gene [c.1519G>C (p.V507L) and c.2165G>A (p.R722Q)], found to be in trans on parental testing. CONCLUSIONS: Missense variants in the AARS2 gene are the likely cause of the retinopathy and optic atrophy in this patient. This finding expands the phenotypic spectrum of the AARS2 gene. PMID- 28820625 TI - Multimodal image analysis of the retina in Hunter syndrome (mucopolysaccharidosis type II): Case report. AB - INTRODUCTION: We report a case of retinal and posterior ocular findings in a 33 year-old man diagnosed with Hunter syndrome (Mucopolysaccharidosis type II) in a multimodal imaging way. CASE PRESENTATION: Our patient was complaining of blurred night vision for the past 3 years. He had not received any systemic treatment for Hunter syndrome. Vision acuity was 20/20 in both eyes and corneas were clear. Fundus examination revealed bilateral crowded and hyperemic optic nerve heads (elevated in the ocular ultrasound) and areas of subretinal hypopigmentation. There was hyperautofluorescence at the central fovea and perifovea, and a diffuse bilateral choroidal fluorescence in angiography. Macular SD-OCT showed a thinning of the external retina at the perifovea in both eyes. Visual field testing showed a bilateral ring scotoma. The full field ERG was subnormal, with a negative response in the scotopic phase. Visual Evoked Potencial test and cranial MRI were normal. CONCLUSION: Our multimodal analysis reported here attempted to contribute to the knowledge of the natural history of GAG deposition in the eye, focusing on the retina and retinal pigment epithelium. Defining this natural history is essential for a proper comparison with Hunter patients receiving systemic treatment, thus determining if it can or cannot improve retinal function in humans with this disorder. PMID- 28820626 TI - The clinical implementation of pain neuroscience education: A survey study. AB - Pain neuroscience education (PNE) has gained considerable attention in research. Three systematic reviews have shown increasing efficacy of PNE decreasing pain, disability, pain catastrophization, movement restrictions, and healthcare utilization. In the development of any new therapeutic approach, it is proposed that there are three stages: development, validation, and implementation. To date, the development and validation of PNE have been well-established. The third stage, implementation, however, lacks when it comes to PNE. The purpose of this study was to survey physical therapists (PT) on their experience and implementation of PNE, following a 15-hour PNE class. Upon development and validation of a PT-PNE survey, a random sample of PTs was invited to take the online survey. Two hundred and eighty-six PTs (female 56%) completed the PNE questionnaire. Ninety-one percent of PTs reported not being taught PNE in PT school. PT's are applying PNE into clinical practice to a variety of patients, experience outcomes in line with the current best-evidence, but struggle establishing which patients are ideal for PNE. The same five patient characteristics associated with success were also associated with failure, albeit in a different ranking order. This finding highlight the need to further investigate the factors associated with success and failure of PNE. PMID- 28820627 TI - Excellent customer service in the age of compromise. PMID- 28820628 TI - Errata. PMID- 28820629 TI - Errata. PMID- 28820631 TI - Links Between the Mother-Adolescent and Father-Adolescent Relationships and Adolescent Depression: A Genetically Informed Study. AB - This study examined the unique roles of support and conflict in the relationship with the mother and the father in predicting changes in adolescents' depressive symptoms over a 1-year period. Potential moderating effects of genetic factors (Gene * Environment interaction) and sex were also investigated. This study utilized a design of twins raised in the same family, based on a sample of 121 monozygotic and 88 dizygotic same-sex twin pairs (418 individuals; 52.2% girls) assessed in Grade 8 (M = 14.09, SD = .29) and in Grade 9 (M = 15.07, SD = .26). Depressive symptoms and the parent-adolescent relationship quality were measured with self-report questionnaires. Multilevel regressions revealed that a lack of support in the father-adolescent relationship predicted increased depressive symptoms among all adolescents, whereas conflict in the father-adolescent relationship predicted increased depressive symptoms more strongly as adolescents' genetic vulnerability for depressive symptoms increased. Moreover, a high level of support in the relationship with the mother predicted increased depressive symptoms in boys-but not girls-with a high genetic risk for such problems. In line with a diathesis-stress model of psychopathology, these findings suggest that relationship quality with both parents might impact girls' and boys' depressive symptoms but that these associations depend to some extent on adolescents' genetic vulnerabilities. PMID- 28820632 TI - Media Presentation of Breastfeeding Beliefs in Newspapers. AB - Despite numerous health benefits for babies and mothers, many women do not either initiate or continue breastfeeding for the recommended duration, and increasing breastfeeding is a national priority. It is important to understand media messages on the topic, given that breastfeeding is influenced by many environmental factors and that perceived norms, social support, and perceptions of difficulties predict breastfeeding. The current study analyzes how media covers (1) breastfeeding in general, (2) public breastfeeding, and (3) extended breastfeeding (past 1 year). Guided by the theory of planned behavior, this study analyzes 318 news articles sampled from 10 of the most commonly read mainstream newspapers from 2008-2013. This sample covers a wide range of topics related to breastfeeding, including health benefits, societal reform efforts, social/human interest stories, parenting choices, and stories about pumped breast milk and formula. The results indicate approving social norms by public health officials and medical professionals about breastfeeding in general. A significantly larger number of articles discussed positive behavioral beliefs associated with breastfeeding rather than negative behavioral beliefs. However, articles more often presented barriers, rather than factors that facilitate breastfeeding. Theoretical and practical implications are discussed. PMID- 28820634 TI - In Vivo and In Vitro Effects of ATM/ATR Signaling Pathway on Proliferation, Apoptosis, and Radiosensitivity of Nasopharyngeal Carcinoma Cells. AB - AIM: The study investigated the ability of ataxia-telangiectasia mutated (ATM)/Rad3-related (ATR) signaling pathway to influence the proliferation, apoptosis, and radiosensitivity of nasopharyngeal carcinoma (NPC) cells. MATERIALS AND METHODS: NPC tissues and corresponding adjacent normal tissues were collected from 143 NPC patients. The NPC CNE2 cells were assigned into a control group, X-ray group, CGK-733 group, and X-ray+CGK-733 group. The mRNA levels of ATM and ATR were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR) and the protein levels of ATM and ATR using western blotting. The positive expression of ATM and ATR in tissues and nude mouse tumor tissues was determined by immunohistochemistry. Cell proliferation, migration, invasion, and apoptosis rates were analyzed by the 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide (MTT) assay, scratch test, transwell assay, and flow cytometry, respectively. A nude mouse model of NPC was established to observe tumor volume and growth. RESULTS: The mRNA levels of ATR and ATM and the expression of ATR and ATM protein in NPC tissues were significantly higher than those in adjacent normal tissues. The colony formation assay showed that the colony-forming rate decreased, showing radiation dose-dependent and CGK-733 concentration-dependent manners. Expression of ATM, ATR, Chk1, and Chk2 was evidently increased in the X-ray, CGK-733, and X-ray+CGK-733groups compared with the control group, and the aforementioned expression was highest in the X-ray+CGK 733 group among the four groups. The cell proliferation, invasion, and migration were decreased, tumor volume decreased and cell apoptosis increased in the X-ray, CGK-733, and X-ray+CGK-733 groups compared with the control group; the X-ray+CGK 733 group exhibited lowest cell proliferation, invasion and migration, smallest tumor volume, and highest cell apoptosis among the four groups. CONCLUSIONS: Inhibition of ATM/ATR signaling pathway reduces proliferation and enhances apoptosis and radiosensitivity of NPC cells. PMID- 28820635 TI - Effects of Autologous Cytokine-Induced Killer Cells Infusion in Colorectal Cancer Patients: A Prospective Study. AB - AIM: To evaluate the efficacy and safety of postoperative adjuvant immunotherapy with cytokine-induced killer (CIK) cells in combination with chemotherapy (CT) in colorectal cancer (CRC) patients. MATERIALS AND METHODS: A total of 46 patients were randomly assigned to either group 1 (control group) or group 2 (CIK group) using blocked randomization. Both groups received the FOLFOX4 (5-fluorouridine, leucovorin, and oxaliplatin) CT. In the CIK group, patients were given CIK cell infusion after FOLFOX4 CT. Treatment efficacy, adverse effects, and quality of life (QOL) were assessed. RESULTS: During the first 2 years of follow-up, the recurrence rate in the CIK group (26.1%, 6 in 23 cases) was significantly lower than the control group (43.5%, 10 in 23). The survival time was significantly longer in the CIK group (41.9 months, 95% confidence interval [CI]: 38.2-45.7) than in the control group (33.8 months, 95% CI: 28.4-39.2). Although QOL was reduced in both treatment groups, adjuvant CIK cell transfusion significantly improved the QOL in patients with CRC. Toxicity was mild in patients with CIK treatment. CONCLUSIONS: Immunotherapy with CIK cells may serve as an adjuvant treatment in patients with CRC after CT with prolonged survival of patients, limited side-effects, and improved QOL. PMID- 28820637 TI - Re: "Stimulants and Pediatric Cardiovascular Risk" by Zito and Burcu (J Child Psychopharmacol 27: 538-545, 2017). PMID- 28820636 TI - Clinical Effects of CpG-Based Treatment on the Efficacy of Hepatocellular Carcinoma by Skewing Polarization Toward M1 Macrophage from M2. AB - OBJECTIVE: This study aims to explore the clinical efficacy of CpG-based therapy for treating hepatocellular carcinoma (HCC) by skewing polarization toward M1 macrophage from M2. METHODS: Pulmonary metastasis rate, overall survival time, and remission rate of 10 patients with HCC treated with transcatheter arterial chemoembolization (TACE) combined with CpG therapy and 10 age-, gender-, and TNM0 matched patients treated with TACE (control group) were compared. RESULTS: No pulmonary metastasis rate was 70% in the combined treatment group and 40% in the control group, respectively; and the differences between the two groups were statistically significant (p < 0.05). Median overall survival time was 22 months in the combined treatment group, compared with 6.65 months in the control group (p < 0.05). Remission rate in the combined treatment group (70%) was higher than in the control group (30%), but the differences between these two groups were not statistically significant (p > 0.05). CONCLUSION: Compared with TACE, CpG combined with TACE can decrease the pulmonary metastasis rate. This combined therapy can also improve the overall survival time of patients. PMID- 28820638 TI - Response to Adesman and Blaufox re: "Stimulants and Pediatric Cardiovascular Risk". PMID- 28820640 TI - From the Editor-in-Chief's Desk. PMID- 28820639 TI - Impulsive Aggressive Behavior Triggered by Headaches in a Child with Severe Attention-Deficit/Hyperactivity Disorder. PMID- 28820642 TI - Correction to: Astrobiology 2017;17(2):126-135. PMID- 28820641 TI - Identifying Communication Barriers to Colorectal Cancer Screening Adherence among Appalachian Kentuckians. AB - Utilizing data from 40 in-depth interviews, this article identifies both barriers and facilitators to colorectal screening guideline adherence among Appalachian Kentucky adults recruited through a community-based research network. Key findings identify (a) varying levels of knowledge about screening guidelines, (b) reticence to engage in screening processes, and (c) nuanced communication with healthcare providers and family members regarding screening adherence. What participants knew about the screening process was often derived from personal stories or recalled stories from family members about their screening experiences. Reticence to engage in screening processes reflected reports of cumbersome preparation, privacy issues, embarrassment, medical mistrust, fear of receiving a cancer diagnosis, and lack of symptoms. Participants cited many ways to enhance patient-centered communication, and the findings from this study have implications for health communication message design and communication strategies for healthcare practices in Appalachian Kentucky clinics. PMID- 28820643 TI - A Prototype Ice-Melting Probe for Collecting Biological Samples from Cryogenic Ice at Low Pressure. AB - In the Solar System, the surface of an icy moon is composed of irregular ice formations at cryogenic temperatures (<200 K), with an oxidized surface layer and a tenuous atmosphere at very low pressure (<10-6 atm). A lander mission, whose aim is to collect and analyze biological samples from the surface ice, must contain a device that collects samples without refreezing liquid and without sublimation of ice. In addition, if the samples are biological in nature, then precautions must be taken to ensure the samples do not overheat or mix with the oxidized layer. To achieve these conditions, the collector must maintain temperatures close to maintenance or growth conditions of the organism (<293 K), and it must separate or neutralize the oxidized layer and be physically gentle. Here, we describe a device that addresses these requirements and is compatible with low atmospheric pressure while using no pumps. The device contains a heated conical probe with a central orifice, which is forced into surface ice and directs the meltwater upward into a reservoir. The force on the probe is proportional to the height of meltwater (pressure) obtained in the system and allows regulation of the melt rate and temperature of the sample. The device can collect 5-50 mL of meltwater from the surface of an ice block at 233-208 K with an environmental pressure of less than 10-2 atm while maintaining a sample temperature between 273 and 293 K. These conditions maintain most biological samples in a pristine state and maintain the integrity of most organisms' structure and function. Key Words: Europa-Icy moon-Microbe-Eukaryote-Spacecraft. Astrobiology 17, 709-720. PMID- 28820644 TI - National Estimates of Genetic Testing in Women With a History of Breast or Ovarian Cancer. AB - Purpose In the United States, 3.8 million women have a history of breast (BC) or ovarian cancer (OC). Up to 15% of cases are attributable to heritable mutations, which, if identified, provide critical knowledge for treatment and preventive care. It is unknown how many patients who are at high risk for these mutations have not been tested and how rates vary by risk criteria. Methods We used pooled cross-sectional data from three Cancer Control Modules (2005, 2010, 2015) of the National Health Interview Survey, a national in-person household interview survey. Eligible patients were adult females with a history of BC and/or OC meeting select 2017 National Comprehensive Cancer Network eligibility criteria on the basis of age of diagnosis and family history. Outcomes included the proportion of individuals reporting a history of discussing genetic testing with a health professional, being advised to undergo genetic testing, or undergoing genetic testing for BC or OC. Results Of 47,218 women, 2.7% had a BC history and 0.4% had an OC history. For BC, 35.6% met one or more select eligibility criteria; of those, 29.0% discussed, 20.2% were advised to undergo, and 15.3% underwent genetic testing. Testing rates for individual eligibility criteria ranged from 6.2% (relative with OC) to 18.2% (diagnosis <= 45 years of age). For OC, 15.1% discussed, 13.1% were advised to undergo, and 10.5% underwent testing. Using only four BC eligibility criteria and all patients with OC, an estimated 1.2 to 1.3 million individuals failed to receive testing. Conclusion Fewer than one in five individuals with a history of BC or OC meeting select National Cancer Comprehensive Network criteria have undergone genetic testing. Most have never discussed testing with a health care provider. Large national efforts are warranted to address this unmet need. PMID- 28820645 TI - Genetic Testing: What Problem Are We Trying to Solve? PMID- 28820647 TI - Acute fatigue negatively affects risk factors for injury in trained but not well trained habitually shod runners when running barefoot. AB - INTRODUCTION: Many factors may contribute to running-related injury. These include fatigue and footwear, the combination of which has rarely been studied, in particular with reference to barefoot running, recently advocated as a method to reduce injury risk. METHODS: Twenty-two runners (12 well-trained and 10 trained) participated in a 10 km fatiguing trial. Knee and ankle joint kinematics and kinetics and electromyography were assessed during overground running in the barefoot and shod condition. This was performed pre- and post-fatigue using a motion capture system and force platforms. RESULTS: Initial loading rate increased in the trained runners when barefoot but not shod. Shod knee stiffness increased in both groups after fatigue, whereas barefoot knee stiffness decreased only in the trained group. A reduction in barefoot bicep femoris pre-activation was found in both groups. During stance, a reduction in vastus lateralis and biceps femoris and an increase in tibialis anterior activity were found over time in both groups and conditions. Trained runners decreased gluteus medius and increased lateral gastrocnemius median frequency for both conditions after fatigue. CONCLUSION: When fatigued, gait adjustments in habitually shod runners may increase injury risk when running barefoot. Training status may be a risk factor for injury, as less-trained runners experience muscular fatigue changes that may compromise ground reaction force attenuation. Caution is recommended when transitioning to pure barefoot running. PMID- 28820646 TI - Consequences of Puberty on Efficacy of Intraocular Pressure-Lowering Drugs in Male Dutch-Belted Rabbits. AB - PURPOSE: To investigate the changes in intraocular pressure (IOP), aqueous flow, and outflow facility, as well as efficacy of IOP-lowering drugs before and after sexual development in rabbits. METHODS: Male Dutch-belted rabbits were studied at night between the ages of 8 and 44 weeks. During these times, body weight, testicular volume, and serum testosterone were measured to monitor sexual maturity. Ocular measurements included anterior chamber depth, central corneal thickness, IOP, aqueous flow, and outflow facility. Systemic acetazolamide or topical timolol, latanoprost, or saline were administered pre- and postpuberty to assess drug effects on these parameters. RESULTS: Body weight, testicular volume, and serum testosterone increased until 28 weeks of age. IOP increased during prepuberty (R2 = 0.49, P = 0.003), dropped significantly during puberty, rising again immediate postpuberty, and changing little thereafter. Postpuberty compared with prepuberty found higher IOP (P < 0.0001), slower aqueous flow (P = 0.008), lower outflow facility (not statistically significant, P = 0.07), increased central cornea thickness, and increased anterior chamber volume. Timolol lowered IOP both pre- and postpuberty, whereas, latanoprost and acetazolamide decreased IOP postpuberty only. CONCLUSIONS: As male rabbits mature, the cornea thickens and the anterior chamber volume increases. At the same time, aqueous flow slows, yet, IOP increases. This suggests that decreased outflow facility and/or increased episcleral venous pressure might contribute to the puberty-related changes in IOP. Underdevelopment of tissues of the outflow pathways may contribute to the differences in drug efficacy in rabbits when young compared with after sexual maturity. PMID- 28820648 TI - Natural Bioactive Food Components for Improving Enteral Tube Feeding Tolerance in Adult Patient Populations. AB - Tube feeding (TF) is the most common form of nutrition support. In recent years, TF administration has increased among patient populations within and outside hospital settings, in part due to greater insurance coverage, reduced use of parenteral nutrition, and improved formularies suitable for sole source nutrition. With increasing life expectancy and improved access to TFs, the number of adults dependent on enteral nutrition is expected to grow. However, enteral TF intolerance (ETFI) is the most common complication of TFs, typically presenting with at least 1 adverse gastrointestinal event, including nausea, diarrhea, and constipation. ETFI often leads to reductions in TF volume with associated energy and protein deficits. Potentially ensuing malnutrition is a major public health concern due its effects on increased risk of morbidity and mortality, infections, prolonged hospital length of stay, and higher healthcare costs. As such, there is a need for intervention strategies to prevent and reduce ETFI. Incorporating whole foods with bioactive properties is a promising strategy. Emerging research has elucidated bioactive properties of whole foods with specific benefits for the prevention and management of adverse gastrointestinal events commonly associated with TFs. However, lack of evidence-based recommendations and technological challenges have limited the use of such foods in commercial TF formulas. This review addresses research gaps by discussing 5 whole foods (rhubarb, banana, curcumin, peppermint oil, and ginger) with bioactive attributes identified through literature searches and clinical experience as having substantial scientific rationale to consider their application for ETFI in adult populations. PMID- 28820651 TI - Starting and stopping kinetics of a rear mounted power assist for manual wheelchairs. AB - A rear mounted, powered, drive wheel has been developed to assist with mobility for manual wheelchairs. The version tested operates in two modes (indoor and outdoor). To start in the indoor mode users must initiate propulsion with sufficient force to trigger the motor. To stop users must apply a braking force through the handrims. . The objectives of this study were to compare (1) the minimum force required to start a wheelchair with and without the drive, and (2) the distances and forces needed to stop a wheelchair at different treadmill speeds with and without the device. We used a crossover study design with 24 able bodied persons. The main outcome measures were starting force single push speed, stopping distance, and stopping force. Participants did not have significantly increased starting force or single push speed using the drive. Participants had significantly shorter absolute stopping distance (p = 0.045 and reduced stopping force (p = 0.02) using the add-on at both treadmill speeds. Given the decreased stopping distances, the add-on may be a viable option for wheelchair users with limited upper limb strength. PMID- 28820650 TI - Critical Care Nutrition Support Best Practices: Key Differences Between Canadian and American Guidelines. AB - Since 2015, Society of Critical Care Medicine/American Society for Parenteral and Enteral Nutrition and Canadian critical care nutrition support guidelines have both been updated. Despite a similar evidentiary basis, there remain key differences between guideline recommendations. These differences in recommendations may pose confusion for the clinician and may encumber widespread applicability. The aim of this review was to enhance practitioner confidence in applying critical care nutrition support guidelines to patient care in their settings by outlining the similarities and differences between the American and Canadian methods for guideline development and describing the key differences and reasons behind the differences. PMID- 28820652 TI - Decreasing Stroke Code to CT Time in Patients Presenting with Stroke Symptoms. AB - Guided quality improvement (QI) programs present an effective means to streamline stroke code to computed tomography (CT) times in a comprehensive stroke center. Applying QI methods and a multidisciplinary team approach may decrease the stroke code to CT time in non-prenotified emergency department (ED) patients presenting with symptoms of stroke. The aim of this project was to decrease this time for non-prenotified stroke code patients from a baseline mean of 20 minutes to one less than 15 minutes during an 18-week period by applying QI methods in the context of a structured QI program. By reducing this time, it was expected that the door-to-CT time guideline of 25 minutes could be met more consistently. Through the structured QI program, we gained an understanding of the process that enabled us to effectively identify key drivers of performance to guide project interventions. As a result of these interventions, the stroke code to CT time for non-prenotified stroke code patients decreased to a mean of less than 14 minutes. This article reports these methods and results so that others can similarly improve the time it takes to perform nonenhanced CT studies in non-prenotified stroke code patients in the ED. (c)RSNA, 2017. PMID- 28820653 TI - Fibrous Skeleton of the Heart: Anatomic Overview and Evaluation of Pathologic Conditions with CT and MR Imaging. AB - The fibrous skeleton is concentrated at the base of the ventricular mass. It provides electrical insulation at the atrioventricular level and fibrous continuity for the leaflets of the mitral, aortic, and tricuspid valves. Its components include the fibrous trigones, the fibrous area of aortic-mitral continuity, the subvalvar collar of the mitral valve, the membranous septum, the interleaflet triangles, the tendon of Todaro, and likely the conus ligament. The majority of the mitral annulus is fibrous, but the only true fibrous part of the tricuspid annulus is where the valvar leaflets are attached to the central fibrous body. At the aortic annulus, the fibrous elements support only the noncoronary aortic sinus and parts of the right and left coronary sinuses. The ring-shaped annulus of the arterioventricular valves as localized with imaging techniques (imaging annulus) differs from the crown-shaped hemodynamic annulus of the arterial valves. The imaging annulus corresponds to the plane passing through the nadirs of the hinge-lines of the leaflets. The hinges of the pulmonary valve are not part of the fibrous skeleton. Computed tomography (CT) and magnetic resonance (MR) imaging are excellent modalities for evaluation of the anatomy, physiologic variations, and pathologic conditions of the fibrous skeleton. The submillimeter isotropic three-dimensional datasets obtained with CT and the high contrast resolution of MR imaging are the main advantages of these modalities in assessing anatomy. The function of the valves and associated annuli can best be studied with MR imaging. Pathologic conditions involving the area, including paravalvar leaks, abscesses, perforation, and pseudoaneurysms, usually occur as a complication of infective endocarditis or extensive calcifications after valvar surgery. MR imaging and CT can demonstrate these lesions equally well. CT is the preferred technique for showing the extent of calcifications in the fibrous skeleton. Large calcifications involving the central fibrous body can cause heart block by interfering with the normal function of the His bundle and its branches. (c)RSNA, 2017. PMID- 28820656 TI - Corrigendum: Prestimulus Inhibition of Saccades in Adults With and Without Attention-Deficit/Hyperactivity Disorder as an Index of Temporal Expectations. AB - Original article: Dankner, Y., Shalev, L., Carrasco, J., & Yuval-Greenberg, S. (2017). Prestimulus inhibition of saccades in adults with and without attention deficit/hyperactivity disorder as an index of temporal expectations. Psychological Science, 28, 835-850. doi:10.1177/0956797617694863. PMID- 28820655 TI - Art and the Brain-Plasticity, Embodiment, and the Unclosed Circle, by Amy Ione. PMID- 28820657 TI - Implications of no recent sexual activity, casual sex, or exclusive sex for college women's sexual well-being depend on sexual attitudes. AB - OBJECTIVE: We examine how sexual activity relates to sexual well-being within the context of sexual attitudes, sexual agency, and sexual desire. PARTICIPANTS/METHODS: We surveyed 471 college women in 2012-2014 who had ever had sex. RESULTS: Sexual agency and sexual desire consistently predicted well-being, regardless of recent sexual activity. There was a significant interaction between recent sexual activity (none, casual, or exclusive relationship) and sexual attitudes. Exclusive sex was associated with higher than average sexual well being, especially for women with permissive attitudes. Women who had casual sex and held permissive to average attitudes had the next highest levels of well being, but those with non-permissive attitudes fell substantially below the overall mean. Women who had no recent sex were consistently below the mean, especially for women with more permissive attitudes. CONCLUSIONS: A disconnect between sexual attitudes and recent sexual activity may lower women's sexual well being. PMID- 28820649 TI - Targets of Neuroprotection in Glaucoma. AB - Progressive neurodegeneration of the optic nerve and the loss of retinal ganglion cells is a hallmark of glaucoma, the leading cause of irreversible blindness worldwide, with primary open-angle glaucoma (POAG) being the most frequent form of glaucoma in the Western world. While some genetic mutations have been identified for some glaucomas, those associated with POAG are limited and for most POAG patients, the etiology is still unclear. Unfortunately, treatment of this neurodegenerative disease and other retinal degenerative diseases is lacking. For POAG, most of the treatments focus on reducing aqueous humor formation, enhancing uveoscleral or conventional outflow, or lowering intraocular pressure through surgical means. These efforts, in some cases, do not always lead to a prevention of vision loss and therefore other strategies are needed to reduce or reverse the progressive neurodegeneration. In this review, we will highlight some of the ocular pharmacological approaches that are being tested to reduce neurodegeneration and provide some form of neuroprotection. PMID- 28820658 TI - Snowy Campbell: Australian Pioneer Investigator of the Brain, by Malcom MacMillan. PMID- 28820659 TI - Politics, doctors, assisted reproductive technologies & religion: Transgenerational understandings and experiences of single motherhood in Spain. AB - The aim is to achieve a transgenerational view of single motherhood in Spain, to look at which contexts it arises in, how it changes with the introduction of assisted reproduction, and how the role of religion in Spanish society permeates medical practice and affects the lives of women patients. I examine single motherhood and investigate two interconnected themes: (a) being a mother and being mothered are both permeated with sociocultural, political, religious, economic and psychological significance; (b) Spain led Europe in multiple births due to assisted reproduction, thus ethical conflicts and patient rights are analyzed. PMID- 28820654 TI - Locus-specific DNA methylation in the placenta is associated with levels of pro inflammatory proteins in cord blood and they are both independently affected by maternal smoking during pregnancy. AB - We investigated the impact of maternal smoking during pregnancy on placental DNA methylation and how this may mediate the association between maternal smoking and pro-inflammatory proteins in cord blood. The study population consisted of 27 individuals exposed to maternal smoking throughout pregnancy, 32 individuals exposed during a proportion of the pregnancy, and 61 unexposed individuals. Methylation of 11 regions within 6 genes in placenta tissue was assessed by pyrosequencing. Levels of 7 pro-inflammatory proteins in cord blood were assessed by electrochemiluminescence. Differential methylation was observed in the CYP1A1 promoter and AHRR gene body regions between women who smoked throughout pregnancy and non-smokers on the fetal-side of the placenta and in the GFI1 promoter between women who quit smoking while pregnant and non-smokers on the maternal side of the placenta. Maternal smoking resulted in elevated levels of IL-8 protein in cord blood, which was not mediated by DNA methylation of our candidate regions at either the maternal or the fetal side of the placenta. Placental DNA methylation was associated with levels of inflammatory proteins in cord blood. Our observations suggest that maternal smoking during pregnancy affects both placental DNA methylation and the neonate's immune response. PMID- 28820660 TI - Driver's mental workload prediction model based on physiological indices. AB - Developing an early warning model to predict the driver's mental workload (MWL) is critical and helpful, especially for new or less experienced drivers. The present study aims to investigate the correlation between new drivers' MWL and their work performance, regarding the number of errors. Additionally, the group method of data handling is used to establish the driver's MWL predictive model based on subjective rating (NASA task load index [NASA-TLX]) and six physiological indices. The results indicate that the NASA-TLX and the number of errors are positively correlated, and the predictive model shows the validity of the proposed model with an R2 value of 0.745. The proposed model is expected to provide a reference value for the new drivers of their MWL by providing the physiological indices, and the driving lesson plans can be proposed to sustain an appropriate MWL as well as improve the driver's work performance. PMID- 28820662 TI - The Impact of Deep Muscle Training on the Quality of Posture and Breathing. AB - Postural control and breathing are mechanically and neuromuscularly interdependent. Both systems- of spinal stability and respiration- involve the diaphragm, transversus abdominis, intercostal muscles, internal oblique muscles and pelvic floor muscles. The aim of the study was to evaluate the effect of exercises activating deep stabilizer muscles on postural control and quality of breathing movements. Eighteen volunteers (25,7 +/- 3,5) were recruited from the general population. All the subjects implemented an exercise program activating deep muscles. Head, pelvic and trunk positions in the sagittal and frontal planes were assessed with the photogrammetric method. Breathing movements were estimated with the respiratory inductive plethysmography. The results indicate that the use of deep muscle training contributed to a significant change in the position of the body in the sagittal plane (p = 0.008) and the increase in the amplitude of breathing (p = 0.001). PMID- 28820661 TI - Impact of a sleep course on sleep, mood and anxiety symptoms in college students: A pilot study. AB - OBJECTIVE: To examine the impact of a sleep course on sleep-related behaviors, mood, and anxiety in college students. PARTICIPANTS: Participants were 145 students enrolled in either the sleep course (n = 70) or a psychology course (n = 75); data were collected in September 2014, November 2014, and February 2015. METHODS: Sleep characteristics and symptoms of depression and anxiety were assessed using validated questionnaires and sleep logs. Linear, logistic and proportional odds regression models were used to test course effects. RESULTS: In November, sleep course students reported significant differences in sleep hygiene (SHI; p < .001), perceived sleep latency (PSQI; p < .05), and circadian sleep phase (MEQ; p < .05), compared to controls. In February, the sleep course students maintained most of the aforementioned gains and reported fewer symptoms of depression (CES-D; p = .05) and anxiety (BAI; p < .05). CONCLUSIONS: These positive preliminary results indicate that focused education has the potential to improve sleep among college students. PMID- 28820663 TI - What Men Who Have Sex With Men in Peru Want in Internet-Based Sexual Health Information. AB - We aimed to gather information among gay men regarding their preferences for online sexual health information; 1,160 Peruvian MSM, 18 years or older, completed an online survey hosted on www.tunexo.org . The mean age was 26.8 years. Around 90% had post-high school education. The self-reported HIV prevalence was 12.3%. The acceptability of sexual health content was greater in the most highly educated group. The highest rated topics and services of interest were those related to improving sexual and mental health. The least educated group was significantly more interested in "getting prevention messages on mobiles" compared to men with the highest level of education (71% vs. 52%; p < 0.001). Men's sexual health was of more interest to the 30-39-year-old group compared to the 18-24-year-old one (97% vs. 87%; p = 0.005). Future Web-based interventions related to sexual health among targeted groups of MSM in Peru can be tailored to meet their preferences. PMID- 28820664 TI - Association of socioeconomic status with consumption of cigarettes, illicit drugs, and alcohol. AB - INTRODUCTION AND AIMS: Socioeconomic Status (SES) is considered as one of the important factors associated with use of various drugs. The present study aimed to investigate the effect of SES on cigarette smoking, alcohol use, drug use, and passive exposure to opium and cigarette smoke. DESIGN AND METHODS: In this study, which is part of a multicenter case-control study, the research hypothesis was checked among controls who had referred to hospitals. Data were collected through a questionnaire and laboratory tests to determine the actual consumers of opium and other illicit drugs. Then, the data were analyzed using STATA 13. RESULT: This study was performed on 364 individuals within the age range of 30 to 75 years. More than 55% of the participants had a history of life-time consumption of cigarettes and hookah as well as alcohol and drugs. The results revealed an inverse relationship between SES and life-time consumption of hookah and alcohol. Furthermore, individuals with higher SES were more likely to deny their drug use. DISCUSSION AND CONCLUSIONS: The results revealed little robust evidence supporting the assumption that SES level can have an important effect on illicit drug use. On the other hand, the participants' characteristics could have a prominent effect on precise evaluation of the relationship between SES and drug use. Further multicenter studies are needed with samples diversified in terms of age and ethnicity to identify these confounding relationships. PMID- 28820665 TI - Size Matters: Penis Size and Sexual Position in Gay Porn Profiles. AB - This article combines qualitative and quantitative textual approaches to the representation of penis size and sexual position of performers in 10 of the most visited gay pornography Web sites currently in operation. Specifically, in excess of 6,900 performer profiles sourced from 10 commercial Web sites are analyzed. Textual analysis of the profile descriptions is combined with a quantitative representation of disclosed penis size and sexual position, which is presented visually by two figures. The figures confirm that these sites generally market themselves as featuring penises that are extraordinarily large and find a sample wide correlation between smaller penis sizes (5-6.5 inches) and receptive sexual acts (bottoming), and larger (8.5-13 inches) with penetrative acts (topping). These observations are supported through the qualitative textual readings of how the performers are described on these popular sites, revealing the narratives and marketing strategies that shape the construction of popular porn brands, performers, and profitable fantasies. PMID- 28820667 TI - Helping Young People Stay Afloat: A Qualitative Study of Community Resources and Supports for LGBTQ Adolescents in the United States and Canada. AB - LGBTQ youth are at increased risk of poor health outcomes. This qualitative study gathered data from LGBTQ adolescents regarding their communities and describes the resources they draw on for support. We conducted 66 go-along interviews with diverse LGBTQ adolescents (mean age = 16.6) in Minnesota, Massachusetts, and British Columbia in 2014-2015, in which interviewers accompanied participants in their communities to better understand those contexts. Their responses were systematically organized and coded for common themes, reflecting levels of the social ecological model. Participants described resources at each level, emphasizing organizational, community, and social factors such as LGBTQ youth organizations and events, media presence, and visibility of LGBTQ adults. Numerous resources were identified, and representative themes were highly consistent across locations, genders, orientations, racial/ethnic groups, and city size. Findings suggest new avenues for research with LGBTQ youth and many opportunities for communities to create and expand resources and supports for this population. PMID- 28820668 TI - Mental Health and Coping Patterns in Jewish Gay Men in Israel: The Role of Dual Identity Conflict, Religious Identity, and Partnership Status. AB - This study examined the effects of dual-identity conflict, religious identity (religious/spiritual vs. sexual), and partnership status on the coping strategies and mental health of gay Jewish men in modern Israeli society. Participants were 73 religious and 71 secular gay men recruited via e-mail, social networking sites, and online resources targeting sexual minority men. Participants were assessed via measures of identity conflict, mental health, and coping strategies. Jewish gay men who reported more severe identity conflict also reported using less problem-focused and avoidance coping and more emotion-focused coping strategies and reported poorer mental health than their less identity-conflicted counterparts. Furthermore, gay men who self-identified as religious reported poorer mental health as well as less problem-focused coping and more emotion focused coping compared to secular men. Religious gay men in romantic relationships reported lower intensities of dual-identity conflict and better mental health compared to their nonpartnered counterparts. PMID- 28820669 TI - Preliminary Psychometric Evaluation of the Hamilton Depression Rating Scale in Methamphetamine Dependence. AB - OBJECTIVE: The purpose of this study was to test the initial psychometric properties of the 17-item Hamilton Depression Rating Scale (HAM-D) in individuals with and without major depressive disorder who use methamphetamine. We used data from two completed studies and two ongoing clinical trials. The HAM-D has well established reliability and validity in a variety of populations. However, there are no published reports of reliability and validity of the HAM-D in a methamphetamine-using population. METHODS: HAM-D and depression status data were extracted from four separate studies for this psychometric assessment. Using these data, we evaluated three measures of construct validity: internal consistency, contrasted group validity, and factorial validity. RESULTS: We found potential concerns with the construct validity of the HAM-D in users of methamphetamine. Intercorrelations between items were primarily less than 0.20 and the Cronbach's alpha value in this sample was 0.58, indicating potential issues with internal consistency. The results of two-sample t-tests suggest concerns with contrasted group validity, as no significant difference in average scores were found for nine items. Consistent with previous studies, a principal component analysis indicates that the HAM-D is multidimensional. CONCLUSIONS: The 17-item HAM-D might not reliably and validly measure depression severity in a methamphetamine-using population. Given our small sample, additional research is needed, though, to further test the psychometric properties of the HAM-D in individuals who use methamphetamine. PMID- 28820670 TI - A Retrospective Look at the Experience of Parental Incarceration and Family Reentry During Adolescence. AB - Few studies provide firsthand experiences of parental incarceration in adolescents' own voices. Fourteen young men and women retrospectively shared their experiences of parental incarceration and family reentry during adolescence. Individual interviews focused on the following qualitative research questions: (1) What is the experience of parental incarceration and reentry for adolescents? (2) How does the child-parent relationship change from pre- to postincarceration? Relationships with incarcerated parents tended toward estrangement. Negative emotions and need for emotional support were predominant in the sample. Findings have implications for improving mental health services for children and families, trauma work, and policy interventions across services. PMID- 28820672 TI - Association of religion and cultural tradition with alcohol use among some tribal communities of Arunachal Pradesh, India. AB - Arunachal Pradesh, a land of high mountains and dense forest, is home to many tribal communities, which comprise two thirds of the state's population. Alcohol is one of the common addictive substances used traditionally among them despite much awareness about its harmful effect on health. The present study is focused on finding the association of religion, ethnicity, and demographic characteristics with alcohol use among some tribal communities in Changlang district of Arunachal Pradesh. A cross-sectional household survey was conducted on substance use in Changlang district of Arunachal Pradesh, India. A sample of 3,421 tribal respondents (1,795 males and 1,626 females) aged 15 years and older was extracted and analyzed. Sociodemographic differences in the prevalence of alcohol use among the tribes were analyzed and compared using the chi-square and t test. Multivariate logistic regression analysis was applied to identify the predictor variables of alcohol use. Data analysis indicates high prevalence of alcohol use (39.1%) among the tribes; and it was higher among males (49.3%) than among females (27.9%). Alcohol use was higher among Indigenous (65%) and Hindu (55.1%) religions compared with Buddhist (24.7%) and Christian (10%). It was also recorded high among Tangsa (42.0%) and Tutsa (76%) tribes compared with Singpho (13.6%) and Khamti (11.4%). High association of alcohol use among the tribal community with age, occupation, ethnicity, and religion was also recorded. Association of alcohol use with demographic characteristics, religion, and ethnic group shows the traditional and cultural belief in alcohol use persists among the tribes. PMID- 28820673 TI - Asymmetric Compression of Representational Space for Object Animacy Categorization under Degraded Viewing Conditions. AB - Animacy is a robust organizing principle among object category representations in the human brain. Using multivariate pattern analysis methods, it has been shown that distance to the decision boundary of a classifier trained to discriminate neural activation patterns for animate and inanimate objects correlates with observer RTs for the same animacy categorization task [Ritchie, J. B., Tovar, D. A., & Carlson, T. A. Emerging object representations in the visual system predict reaction times for categorization. PLoS Computational Biology, 11, e1004316, 2015; Carlson, T. A., Ritchie, J. B., Kriegeskorte, N., Durvasula, S., & Ma, J. Reaction time for object categorization is predicted by representational distance. Journal of Cognitive Neuroscience, 26, 132-142, 2014]. Using MEG decoding, we tested if the same relationship holds when a stimulus manipulation (degradation) increases task difficulty, which we predicted would systematically decrease the distance of activation patterns from the decision boundary and increase RTs. In addition, we tested whether distance to the classifier boundary correlates with drift rates in the linear ballistic accumulator [Brown, S. D., & Heathcote, A. The simplest complete model of choice response time: Linear ballistic accumulation. Cognitive Psychology, 57, 153-178, 2008]. We found that distance to the classifier boundary correlated with RT, accuracy, and drift rates in an animacy categorization task. Split by animacy, the correlations between brain and behavior were sustained longer over the time course for animate than for inanimate stimuli. Interestingly, when examining the distance to the classifier boundary during the peak correlation between brain and behavior, we found that only degraded versions of animate, but not inanimate, objects had systematically shifted toward the classifier decision boundary as predicted. Our results support an asymmetry in the representation of animate and inanimate object categories in the human brain. PMID- 28820675 TI - On the Role of Situational Stressors in the Disruption of Global Neural Network Stability during Problem Solving. AB - When individuals are placed in stressful situations, they are likely to exhibit deficits in cognitive capacity over and above situational demands. Despite this, individuals may still persevere and ultimately succeed in these situations. Little is known, however, about neural network properties that instantiate success or failure in both neutral and stressful situations, particularly with respect to regions integral for problem-solving processes that are necessary for optimal performance on more complex tasks. In this study, we outline how hidden Markov modeling based on multivoxel pattern analysis can be used to quantify unique brain states underlying complex network interactions that yield either successful or unsuccessful problem solving in more neutral or stressful situations. We provide evidence that brain network stability and states underlying synchronous interactions in regions integral for problem-solving processes are key predictors of whether individuals succeed or fail in stressful situations. Findings also suggested that individuals utilize discriminate neural patterns in successfully solving problems in stressful or neutral situations. Findings overall highlight how hidden Markov modeling can provide myriad possibilities for quantifying and better understanding the role of global network interactions in the problem-solving process and how the said interactions predict success or failure in different contexts. PMID- 28820674 TI - Restoration of fMRI Decodability Does Not Imply Latent Working Memory States. AB - Recent imaging studies have challenged the prevailing view that working memory is mediated by sustained neural activity. Using machine learning methods to reconstruct memory content, these studies found that previously diminished representations can be restored by retrospective cueing or other forms of stimulation. These findings have been interpreted as evidence for an activity silent working memory state that can be reactivated dependent on task demands. Here, we test the validity of this conclusion by formulating a neural process model of working memory based on sustained activity and using this model to emulate a spatial recall task with retro-cueing. The simulation reproduces both behavioral and fMRI results previously taken as evidence for latent states, in particular the restoration of spatial reconstruction quality following an informative cue. Our results demonstrate that recovery of the decodability of an imaging signal does not provide compelling evidence for an activity-silent working memory state. PMID- 28820676 TI - Saccade Reorienting Is Facilitated by Pausing the Oculomotor Program. AB - As we look around the world, selecting our targets, competing events may occur at other locations. Depending on current goals, the viewer must decide whether to look at new events or to ignore them. Two experimental paradigms formalize these response options: double-step saccades and saccadic inhibition. In the first, the viewer must reorient to a newly appearing target; in the second, they must ignore it. Until now, the relationship between reorienting and inhibition has been unexplored. In three experiments, we found saccadic inhibition ~100 msec after a new target onset, regardless of the task instruction. Moreover, if this automatic inhibition is boosted by an irrelevant flash, reorienting is facilitated, suggesting that saccadic inhibition plays a crucial role in visual behavior, as a bottom-up brake that buys the time needed for decisional processes to act. Saccadic inhibition may be a ubiquitous pause signal that provides the flexibility for voluntary behavior to emerge. PMID- 28820677 TI - Comparing measures of general and abdominal adiposity as predictors of blood pressure in college students. AB - OBJECTIVE: To compare anthropometric measures of body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), and sagittal abdominal diameter (SAD) as predictors of blood pressure in college students. PARTICIPANTS: Students (N = 116) were recruited from November 2012 to May 2014 at an urban university and rural community colleges. METHODS: Students underwent a brief physical examination during which anthropometric measures were obtained and blood pressure was measured. Covariates were measured using self-reported questionnaires. Hierarchical multiple linear regressions were used for the data analysis. RESULTS: All anthropometric measures were predictive of systolic (SBP) and diastolic blood pressure (DBP). WC was the strongest predictor of SBP (beta = .582, p < .01) explaining an additional 3-4% of the variance than BMI, WHtR, or SAD. The measures were similar in predicting DBP. WC predicted SBP independent of BMI. CONCLUSIONS: Clinicians should consider using WC to assess the risk for hypertension in college students. PMID- 28820678 TI - A New Hybrid Model Using an Autoregressive Integrated Moving Average and a Generalized Regression Neural Network for the Incidence of Tuberculosis in Heng County, China. AB - It is a daunting task to eradicate tuberculosis completely in Heng County due to a large transient population, human immunodeficiency virus/tuberculosis coinfection, and latent infection. Thus, a high-precision forecasting model can be used for the prevention and control of tuberculosis. In this study, four models including a basic autoregressive integrated moving average (ARIMA) model, a traditional ARIMA-generalized regression neural network (GRNN) model, a basic GRNN model, and a new ARIMA-GRNN hybrid model were used to fit and predict the incidence of tuberculosis. Parameters including mean absolute error (MAE), mean absolute percentage error (MAPE), and mean square error (MSE) were used to evaluate and compare the performance of these models for fitting historical and prospective data. The new ARIMA-GRNN model had superior fit relative to both the traditional ARIMA-GRNN model and basic ARIMA model when applied to historical data and when used as a predictive model for forecasting incidence during the subsequent 6 months. Our results suggest that the new ARIMA-GRNN model may be more suitable for forecasting the tuberculosis incidence in Heng County than traditional models. PMID- 28820679 TI - Tuberculosis-Related Diabetes: Is It Reversible after Complete Treatment? AB - Individuals with newly diagnosed tuberculosis (TB) were screened for diabetes (DM) with fasting plasma glucose (FPG) in Pakistan. A significant decrease in FPG was observed when TB was treated. Of those with newly diagnosed DM, 46% and 62% no longer had hyperglycemia after 3 and 6 months, respectively. Individuals with known DM also showed a significant decrease in fasting plasma levels when treated for TB, but after 3 months none had normoglycemia, and after 6 months 9.2% were normoglycemic. Thus, TB-related DM may abate when the stress terminates, as is the case in gestational DM. However, because stress hyperglycemia may be associated with subsequent risk of developing DM, follow-up is recommended. PMID- 28820680 TI - Creating Online Training for Procedures in Global Health with PEARLS (Procedural Education for Adaptation to Resource-Limited Settings). AB - The authors describe a multiinstitutional collaborative project to address a gap in global health training by creating a free online platform to share a curriculum for performing procedures in resource-limited settings. This curriculum called PEARLS (Procedural Education for Adaptation to Resource-Limited Settings) consists of peer-reviewed instructional and demonstration videos describing modifications for performing common pediatric procedures in resource limited settings. Adaptations range from the creation of a low-cost spacer for inhaled medications to a suction chamber for continued evacuation of a chest tube. By describing the collaborative process, we provide a model for educators in other fields to collate and disseminate procedural modifications adapted for their own specialty and location, ideally expanding this crowd-sourced curriculum to reach a wide audience of trainees and providers in global health. PMID- 28820681 TI - Efficacy, Safety and Cost-Effectiveness of Thermotherapy in the Treatment of Leishmania donovani-Induced Cutaneous Leishmaniasis: A Randomized Controlled Clinical Trial. AB - Leishmania donovani causes cutaneous leishmaniasis (CL) in Sri Lanka. Standard treatment is multiple, painful doses of intralesional sodium stibogluconate (IL SSG). Treatment failures are increasingly reported, hence the need to investigate alternatives. Efficacy, safety, and cost-effectiveness of thermotherapy were assessed for the first time for L. donovani CL. A single blinded noninferiority randomized controlled trial was conducted on new laboratory-confirmed CL patients with single lesions (N = 213). Selected patients were randomly assigned to 1) test group (N = 98; single session of radiofrequency-induced heat therapy (RFHT) given at 50 degrees C for 30 seconds) and 2) control group (N = 115; 1-3 mL IL SSG given weekly, until cure/10 doses). Patients were followed-up fortnightly for 12 weeks to assess clinical cure. Cost of treatment was assessed using scenario building technique. Cure rates by 8, 10, and 12 weeks in RFHT group were 46.5%, 56.5%, and 65.9% as opposed to 28%, 40.8%, and 59.4% in IL-SSG group, with no major adverse events. Cure rate by RFHT was significantly higher at 8 weeks (P = 0.009, odds ratio [OR]: 2.236, confidence interval [CI]: 1.217-4.108) and 10 weeks (P = 0.035, OR: 1.881, CI: 1.044-3.388), but comparable thereafter. Cost of RFHT was 7 times less (USD = 1.54/patient) than IL-SSG (USD = 11.09/patient). A single application of RFHT is safe, cost-effective, and convenient, compared with multiple doses of IL-SSG in the treatment of L. donovani CL. Therefore, RFHT would be considered noninferior as per trial outcome when compared with standard IL-SSG therapy with multiple benefits for the patient and the national health care system. PMID- 28820682 TI - Case Report: A Case of Plasmodium falciparum hrp2 and hrp3 Gene Mutation in Bangladesh. AB - Several species of Plasmodium are responsible for causing malaria in humans. Proper diagnoses are crucial to case management, because severity and treatment varies between species. Diagnoses can be made using rapid diagnostic tests (RDTs), which detect Plasmodium proteins. Plasmodium falciparum causes the most virulent cases of malaria, and P. falciparum histidine-rich protein 2 (PfHRP2) is a common target of falciparum malaria RDTs. Here we report a case in which a falciparum malaria patient in Bangladesh tested negative on PfHRP2-based RDTs. The negative results can be attributed to a deletion of part of the pfhrp2 gene and frameshift mutations in both pfhrp2 and pfhrp3 gene. This finding may have implications for malaria diagnostics and case management in Bangladesh and other regions of South Asia. PMID- 28820683 TI - Malaria in the Guangxi Zhuang Autonomous Region in China: A Twelve-Year Surveillance Data Study. AB - The incidence of an indigenous malaria, defined as malaria acquired by a local mosquito transmission, declined from 2004 to 2015 in the Guangxi Zhuang Autonomous Region. However, imported malaria, defined as malaria acquired from other endemic regions outside of China, has been increasing in the region, as in the rest of the country, particularly the disease caused by Plasmodium falciparum. A retrospective study was conducted to explore malaria-endemic characteristics in Guangxi during the 2004-2015 timeframe; a total of 2,726 confirmed malaria cases were reported, and the majority (90.3%) were due to P. falciparum (N = 1,697 [62.2%]) and Plasmodium vivax (N = 765 [28.1%]). Thirty four indigenous cases (1.2%) were observed, with no cases of transmission recorded since 2012. Imported P. vivax and Plasmodium ovale infections increased since 2013. The interval between returning to China and the onset of illness was longer for P. vivax and P. ovale infections than for P. falciparum and Plasmodium malariae infections. The difference interval among the species is likely because of the relapse of P. vivax and P. ovale caused by the activation of the latent hypnozoites. Therefore, health clinics should raise awareness and carry out epidemiological studies and follow-up surveys on migrant workers to avoid misdiagnosis and mistreatment. The evaluation of radical treatment should be carried out using a genotyping technology based on glucose-6-phosphate dehydrogenase deficiency levels, and some new drugs active against the hypnozoites should be developed to mitigate malaria in the region. PMID- 28820684 TI - Lack of Efficacy of Liposomal Amphotericin B Against Acute and Chronic Trypanosoma cruzi Infection in Mice. AB - Acute and chronic infection with Trypanosoma cruzi affects millions of people. The current therapeutic options are highly toxic and often not effective. Liposomal amphotericin B (LAMB) has been demonstrated previously to have some activity in murine models. In our studies, higher dosages given multiple times were tested for activity against acute or chronic disease, exploring whether intermittent and brief regimens could be effective, as might then prove useful in human, particularly outpatient, therapy. For acute infection, LAMB 25 mg/kg intravenously (i.v.) given one to three times prolonged survival and caused a rapid disappearance of Y strain trypomastigotes from the blood. However, even four or six doses of LAMB 30 mg/kg i.v., did not result in the cure of Y strain infection, with all mice relapsing after being immunosuppressed with cyclophosphamide. Similarly, chronic infection due to the CL strain was found to be unaltered by 1-3 treatments with LAMB 25 mg/kg. All surviving mice had histopathological evidence of infection in one or more tissues and equivalent antibody titers regardless of treatment regimen. Overall, LAMB at doses up to 30 mg/kg i.v. prolonged survival, but these doses were not curative in the regimens studied. PMID- 28820685 TI - Immune Reconstitution Inflammatory Syndrome in HIV-Infected Immigrants. AB - Immune reconstitution inflammatory syndrome (IRIS) includes a group of potentially serious inflammatory processes that may be present in HIV-infected patients after initiating highly active antiretroviral therapy (HAART). Paradoxical IRIS is a worsening of symptoms, after an overwhelming response to a previously diagnosed opportunistic infection (OI); unmasking IRIS reveals a previously occult OI. The main objective of the study was to describe the epidemiological, clinical, and outcome data of HIV-infected immigrants, stratified according to high- or low-income countries of origin, who developed IRIS and to compare them with native-born Spanish patients. This retrospective study reviewed all patients with HIV infection admitted to the Unit of Infectious Diseases and Tropical Medicine between 1998 and 2014. IRIS was identified in 25/138 (18%) immigrant patients and 24/473 (5%) native-born Spanish patients infected with HIV. Most cases, 19/25 (76%), were of unmasking IRIS. The time elapsed between initiation of HAART and development of IRIS was significantly longer in patients with unmasking versus paradoxical IRIS. OIs, in particular due to mycobacteria, were the most frequently involved processes. Twenty percent of patients died. The comparison of immigrant and native-born patients found significant differences for both IRIS type (higher incidence of paradoxical forms among immigrants) and for the absence of malignancies in native-born patients. No significant differences were found when the data of immigrants from low- and high income countries were compared. PMID- 28820686 TI - The Emergence of Severe Fever with Thrombocytopenia Syndrome Virus. AB - Severe fever with thrombocytopenia syndrome (SFTS) is a newly recognized hemorrhagic fever disease found throughout Asia with a case fatality rate between 12% and 30%. Since 2009, SFTS has been reported in China throughout 14 Chinese Provinces. In addition, SFTS has been recognized in South Korea and Japan with the first confirmed cases reported in 2012. A similar disease, caused by the closely related Heartland virus, was also reported in the United States in 2009. SFTS is caused by SFTS virus, a novel tick-borne virus in the family Bunyaviridae, genus Phlebovirus. Unlike other mosquito- and sandfly-borne bunyaviruses, SFTS virus has not been extensively studied due to its recent emergence and many unknowns regarding its pathogenesis, life cycle, transmission, and options for therapeutics remains. In this review, we report the most current findings in SFTS virus research. PMID- 28820688 TI - The Phenotype of Circulating Neutrophils during Visceral Leishmaniasis. AB - Visceral leishmaniasis (VL) is a chronic parasitic disease associated with suppressed T cell responses. Although parasites reside intracellularly in macrophages during chronic VL, neutrophils are the first host cell to infiltrate the infection site and phagocytose the parasite. Subsets of neutrophils with unusual characteristics have been documented in human VL, but whether the total neutrophil population is aberrant during disease is not known. Therefore, we examined phenotypic characteristics of unfractionated polymorphonuclear leukocyte (neutrophils) from subjects with active VL, and compared these with neutrophils from healthy controls or subjects who have been treated for VL. The data showed decreased mRNA and diminished amounts of the neutrophil chemoattractant CXCL8 (interleukin [IL]-8), increased IL-10 mRNA and protein, and elevated transcripts encoding arginase-1, which is involved in suppressing T cell responses. Neutrophils from VL subjects showed enhanced capacity to phagocytose Leishmania spp. promastigotes. The results suggest that neutrophils may contribute to immunosuppression in subjects with active VL. PMID- 28820687 TI - Identification of Subsets of Enteroaggregative Escherichia coli Associated with Diarrheal Disease among Under 5 Years of Age Children from Rural Gambia. AB - Enteroaggregative Escherichia coli (EAEC) cause acute and persistent diarrhea, mostly in children worldwide. Outbreaks of diarrhea caused by EAEC have been described, including a large outbreak caused by a Shiga toxin expressing strain. This study investigated the association of EAEC virulence factors with diarrhea in children less than 5 years. We characterized 428 EAEC strains isolated from stool samples obtained from moderate-to-severe diarrhea cases (157) and healthy controls (217) children aged 0-59 months recruited over 3 years as part of the Global Enteric Multicenter Study (GEMS) in The Gambia. Four sets of multiplex polymerase chain reaction were applied to detect 21 EAEC-virulence genes from confirmed EAEC strains that target pCVD432 (aatA) and AAIC (aaiC). In addition, Kirby-Bauer disc diffusion antimicrobial susceptibility testing was performed on 88 EAEC strains following Clinical Laboratory Standard Institute guidelines. We observed that the plasmid-encoded enterotoxin [odds ratio (OR): 6.9, 95% confidence interval (CI): 2.06-29.20, P < 0.001], aggregative adherence fimbriae/I fimbriae (aggA) [OR: 2.2, 95% CI: 1.16-4.29, P = 0.008], and hexosyltransferase (capU) [OR: 1.9, 95% CI 1.02-3.51, P = 0.028] were associated with moderate-to-severe diarrhea among children < 12 months old but not in the older age strata (> 12 months). Our data suggest that some EAEC-virulent factors have age-specific associations with moderate-to-severe diarrhea in infants. Furthermore, our study showed that 85% and 72% of EAEC strains tested were resistant to sulphamethoxazole-trimethoprim and ampicillin, respectively. Sulphamethoxazole-trimethoprim and ampicillin are among the first-line antibiotics used for the treatment of diarrhea in The Gambia. PMID- 28820689 TI - Reliability of Diagnostic Criteria for Neurocysticercosis for Patients with Ventricular Cystic Lesions or Granulomas: A systematic review. AB - Intraventricular neurocysticercosis (NCC) is a severe form of NCC requiring prompt diagnosis and treatment. We aimed to assess the reliability of the most recent version of diagnostic criteria for this form of NCC. Two systematic literature reviews were performed; one included case reports of patients with intraventricular cysticercosis and the other included case reports of patients with intraventricular cystic lesions or granulomas caused by infections other than NCC. All assessed cases were categorized according to the last revision of the long-standing Del Brutto's set of diagnostic criteria to determine its sensitivity, specificity, and predictive value for this form of NCC. The search disclosed 128 patients with intraventricular NCC and 41 with other infections. The set of diagnostic criteria classified as definitive NCC 93 cases with intraventricular NCC (sensitivity 72.7%, 95% CI, 63.9-79.9%), as well as four cases with other infections (specificity 90.2%, 95% CI, 75.9-96.8%). The positive and negative predictive values of the criteria were 0.96 (95% CI, 0.89-0.99) and 0.51 (95% CI, 0.39-0.63), respectively. The revised Del Brutto's set of diagnostic criteria for NCC is acceptably sensitive and highly specific for diagnosing patients with the ventricular form of the disease. PMID- 28820690 TI - Scaling Up of an Innovative Intervention to Reduce Risk of Dengue, Chikungunya, and Zika Transmission in Uruguay in the Framework of an Intersectoral Approach with and without Community Participation. AB - To contribute to the prevention of dengue, chikungunya, and Zika, a process of scaling up an innovative intervention to reduce Aedes aegypti habitats, was carried out in the city of Salto (Uruguay) based on a transdisciplinary analysis of the eco-bio-social determinants. The intervention in one-third of the city included the distributions of plastic bags for all households to collect all discarded water containers that were recollected by the Ministry of Health and the Municipality vector control services. The results were evaluated in 20 randomly assigned clusters of 100 households each, in the intervention and control arm. The intervention resulted in a significantly larger decrease in the number of pupae per person index (as a proxy for adult vector abundance) than the corresponding decrease in the control areas (both areas decreased by winter effects). The reduction of intervention costs ("incremental costs") in relation to routine vector control activities was 46%. Community participation increased the collaboration with the intervention program considerably (from 48% of bags handed back out of the total of bags delivered to 59% of bags handed back). Although the costs increased by 26% compared with intervention without community participation, the acceptability of actions by residents increased from 66% to 78%. PMID- 28820691 TI - Field Trial of the CareStart Biosensor Analyzer for the Determination of Glucose 6-Phosphate Dehydrogenase Activity in Haiti. AB - Throughout many developing and tropical countries around the world, malaria remains a significant threat to human health. One barrier to malaria elimination is the ability to safely administer primaquine chemotherapy for the radical cure of malaria infections in populations with a high prevalence of glucose-6 phosphate dehydrogenase (G6PD) deficiency. In the current study, a field trial of the world's first quantitative, point-of-care assay for measuring G6PD activity was conducted in Haiti. The performance of the CareStart Biosensor Analyzer was compared with the gold standard spectrophotometric assay and genotyping of the G6PD allele in schoolchildren (N = 343) from the Ouest Department of Haiti. In this population, 19.5% of participants (67/343) had some form of G6PD deficiency (< 60% residual activity) and 9.9% (34/343) had moderate-to-severe G6PD deficiency (< 30% residual activity). Overall, 18.95% of participants had the presence of the A-allele (65/343) with 7.87% (27/343) considered at high risk for drug-induced hemolysis (hemizygous males and homozygous females). Compared with the spectrophotometric assay, the sensitivity and specificity to determine participants with < 60% residual activity were 53.7% and 94.6%, respectively; for participants with 30% residual activity, the sensitivity and specificity were 5.9% and 99.7%, respectively. The biosensor overestimated the activity in deficient individuals and underestimated it in participants with normal G6PD activity, indicating the potential for a systematic measurement error. Thus, we suggest that the current version of the biosensor lacks adequate sensitivity and should be improved prior to its use as a point-of-care diagnostic for G6PD deficiency. PMID- 28820692 TI - Following the Worms: Detection of Soil-Transmitted Helminth Eggs on Mothers' Hands and Household Produce in Rural Kenya. AB - Approximately one-quarter of the world's population is infected with at least one species of soil-transmitted helminth (STH). The role of produce and hands in STH transmission is not well understood. We collected and processed mother hand rinse and garden-grown produce rinse samples from 116 rural households in Kakamega, Kenya, in an area previously identified to have high STH egg contamination in household soil. Ascaris was the only STH species detected; 0.9% of hand rinse, 3.5% of leafy produce, and 1.8% of root produce samples had Ascaris eggs. Our results indicate produce and hands can carry Ascaris eggs. However, due to the low detected prevalence of eggs on hands and produce, and a high prevalence of cooking the produce items tested, these pathways might have a minor contribution to STH exposure in this setting. PMID- 28820693 TI - Case Report: Clinical Features of Intermittent Migratory Swelling Caused by Gnathostomiasis with Complete Follow-up. AB - A 15-year-old Thai girl was referred to the Hospital for Tropical Diseases of Mahidol University with a 3-week history of an intermittent migratory mass on the forehead. She was diagnosed with cutaneous gnathostomiasis. The patient was treated with albendazoleat 400 mg orally twice a day for 3 weeks, with good compliance. She revisited the hospital after 3 months and was seen to have been unresponsive to the initial treatment. There was intermittent swelling in her right upper eyelid along with mild redness around her right upper and lower eyelids. Another attempt of treatment was made with ivermectin 0.2 mg/kg/day for two consecutive days. This is a case of gnathostomiasis in full sequence, with complete follow-up. The case report starts from the beginning of the symptoms until the antibodies against Gnathostoma spinigerum decline to negative, confirmed by the western blot test. It took around 18 months to see the western blot test change to a negative result. The resolved clinical symptoms were possibly due to the responsiveness of the patient to ivermectin or the albendazole and ivermectin combination or even the coadministration of antibiotics afterward. PMID- 28820694 TI - Differential Neurovirulence of African and Asian Genotype Zika Virus Isolates in Outbred Immunocompetent Mice. AB - Although first isolated almost 70 years ago, Zika virus (ZIKV; Flavivirus, Flaviviridae) has only recently been associated with significant outbreaks of disease in humans. Several severe ZIKV disease manifestations have also been recently documented, including fetal malformations, such as microcephaly, and Guillain-Barre syndrome in adults. Although principally transmitted by mosquitoes, sexual transmission of ZIKV has been documented. Recent publications of several interferon receptor knockout mouse models have demonstrated ZIKV induced disease. Herein, outbred immunocompetent CD-1/ICR adult mice were assessed for susceptibility to disease by intracranial (i.c.) and intraperitoneal (i.p.) inoculation with the Ugandan prototype strain (MR766; African genotype), a low-passage Senegalese strain (DakAr41524; African genotype) and a recent ZIKV strain isolated from a traveler infected in Puerto Rico (PRVABC59; Asian genotype). Morbidity was not observed in mice inoculated by the i.p. route with either MR766 or PRVABC59 for doses up to 6 log10 PFU. In contrast, CD-1/ICR mice inoculated i.c. with the MR766 ZIKV strain exhibited an 80-100% mortality rate that was age independent. The DakAr41524 strain delivered by the i.c route caused 30% mortality, and the Puerto Rican ZIKV strain failed to elicit mortality but did induce a serum neutralizing immune response in 60% of mice. These data provide a potential animal model for assessing neurovirulence determinants of different ZIKV strains as well as a potential immunocompetent challenge model for assessing protective efficacy of vaccine candidates. PMID- 28820695 TI - Prevalence and Seroprevalence of Trypanosoma cruzi Infection in a Military Population in Texas. AB - Recent biosurveillance findings at Joint Base San Antonio (JBSA), a large military installation located in south-central Texas, indicate the potential for vector-borne human Chagas disease. A cross-sectional study was conducted to determine the prevalence and seroprevalence of Trypanosoma cruzi infection in highest risk subpopulations on the installation, including students and instructors who work and sleep in triatomine-endemic field settings. Real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and indirect immunofluorescent antibody assay were performed on enrolled subjects (N = 1,033), none of whom tested positive for T. cruzi or anti-T. cruzi antibodies. Current countermeasures used during field training on JBSA appear to be sufficient for preventing autochthonous human Chagas disease. PMID- 28820697 TI - Case Report: Treatment of Widespread Nodular Post kala-Azar Dermal Leishmaniasis with Extended-Dose Liposomal Amphotericin B in Bangladesh: A Series of Four Cases. AB - Post kala-azar dermal leishmaniasis (PKDL) is a skin manifestation which usually appears after visceral leishmaniasis. It is now proved that PKDL patients serve as a reservoir for anthropometric leishmanial transmission. Hence, to achieve the kala-azar elimination target set by the World Health Organization in the Indian Subcontinent, PKDL cases should be given priority. The goal of treatment for PKDL should be early reepithelizlization and rapid cure, but unfortunately this has been difficult to achieve, especially for patients with severe lesions. Therefore, we describe here four cases of PKDL who had widespread nodular and macular lesions and were treated with two cycles of LAmB doses with 20 mg/kg body weight divided into four equal doses (each dose contains 5 mg/kg) administered every alternate day. This treatment schedule achieved 100% treatment success with the minimal safety concern. PMID- 28820696 TI - New Surge of Syphilis among Patients Living with Human Immunodeficiency Virus in Martinique in 2015. AB - A syphilis outbreak began in Martinique, French Antilles, in 2004, initially among men who had sex with men (MSM) and who were living with human immunodeficiency virus (HIV). The outbreak subsequently affected all groups at risk, leading to a first epidemic peak in 2008. After an initial decrease, the outbreak started growing again in 2014 among patients living with HIV with unprecedented incidence among MSM. Herein, we describe the change in medical and social parameters of the outbreak since 2005. PMID- 28820698 TI - Case Report: Scalp Eschar and Neck Lymphadenopathy Associated with Bacteremia due to Coxiella-Like Bacteria. AB - Coxiella-like bacteria have been recently proposed as human pathogens. Using molecular techniques, we detected Coxiella-like bacteria in the blood and serum samples of a patient with a scalp eschar, neck lymphadenopathy, severe urticaria, edema, fever, and arthralgia indicating that this organism can provide systemic complications. PMID- 28820699 TI - In Vitro Testing of Potential Entamoeba histolytica Pyruvate Phosphate Dikinase Inhibitors. AB - Adverse effects and resistance to metronidazole have motivated the search for new antiamoebic agents against Entamoeba histolytica. Control of amoeba growth may be achieved by inhibiting the function of the glycolytic enzyme and pyruvate phosphate dikinase (PPDK). In this study, we screened 10 compounds using an in vitro PPDK enzyme assay. These compounds were selected from a virtual screening of compounds in the National Cancer Institute database. The antiamoebic activity of the selected compounds was also evaluated by determining minimal inhibitory concentrations (MICs) and IC50 values using the nitro-blue tetrazolium reduction assay. Seven of the 10 compounds showed inhibitory activities against the adenosine triphosphate (ATP)/inorganic phosphate binding site of the ATP-grasp domain. Two compounds, NSC349156 (pancratistatin) and NSC228137 (7-ethoxy-4-[4 methylphenyl] sulfonyl-3-oxido-2, 1, 3-benzoxadiazol-3-ium), exhibited inhibitory effects on the growth of E. histolytica trophozoites with MIC values of 25 and 50 MUM, and IC50 values of 14 and 20.7 MUM, respectively. PMID- 28820700 TI - Rapid Detection of Plasmodium knowlesi by Isothermal Recombinase Polymerase Amplification Assay. AB - In this study, we developed a recombinase polymerase amplification (RPA) assay for specific diagnosis of Plasmodium knowlesi. Genomic DNA was extracted from whole blood samples using a commercial kit. With incubation at 37 degrees C, the samples were successfully amplified within 20 minutes. The end product of RPA was further examined by loading onto agarose gel and a specific band was observed with a size of 128 bp. The RPA assay exhibited high sensitivity with limits of detection down to one copy of the plasmid. From the specificity experiments, it was demonstrated that all P. knowlesi samples (N = 45) were positive while other Plasmodium spp. (N = 42) and negative samples (N = 6) were negative. Therefore, the RPA assay is a highly promising approach with the potential to be used in resource-limited settings. This assay can be further optimized for bedside and on field application. PMID- 28820701 TI - The Sustainable Development Goals for Water: The Need to Consider Perception, Preference, and Safety. PMID- 28820702 TI - Predictive Model for Permanent Shunting in Cryptococcal meningitis. AB - Cryptococcal meningitis may have long-term morbidity and requires a permanent cerebrospinal fluid shunt. This study aimed to evaluate the risk factors and create a predictive model for permanent shunt treatment in cryptococcal meningitis patients. This was a retrospective analytical study conducted at Khon Kaen University. The study period was from January 2005 to December 2015. We enrolled all adult patients diagnosed with cryptococcal meningitis. Risk factors predictive for permanent shunting treatment were analyzed by multivariate logistic regression analysis. There were 341 patients diagnosed with cryptococcal meningitis. Of those, 64 patients (18.7%) were treated with permanent shunts. There were three independent factors associated with permanent shunt treatment. The presence of hydrocephalus had the highest adjusted odds ratio at 56.77. The resulting predictive model for permanent shunt treatment (y) is (-3.85) + (4.04 * hydrocephalus) + (2.13 * initial cerebrospinal fluid (CSF) opening pressure (OP) > 25 cm H2O) + (1.87 * non-human immune deficiency vrus (HIV)). In conclusion, non-HIV status, initial CSF OP greater than or equal to 25 cm H2O, and the presence of hydrocephalus are indicators of the future necessity for permanent shunt therapy. PMID- 28820703 TI - Assessment of U.S. Pediatrician Knowledge of Toxocariasis. AB - Toxocariasis, one of a group of parasitic diseases known as neglected parasitic infections, is a disease caused by the larvae of two species of Toxocara roundworms, Toxocara canis, from dogs, and less commonly Toxocara cati, from cats. Although most infected individuals are asymptomatic, clinical manifestations may include fever, fatigue, coughing, wheezing, or abdominal pain (visceral toxocariasis) or vision loss, retina damage, or eye inflammation (ocular toxocariasis). To assess U.S. pediatrician knowledge of toxocariasis, we conducted an electronic survey of American Academy of Pediatrics members. Of the 2,684 respondents, 1,120 (47%) pediatricians correctly selected toxocariasis as the diagnosis in an unknown case presentation with findings typical for toxocariasis; overall 1,695 (85%) stated they were not confident that their knowledge of toxocariasis was current. This knowledge gap suggests a need for improved toxocariasis awareness and education for U.S. pediatricians, especially those caring for children at risk for infection. PMID- 28820704 TI - The Price of Peace? Peacekeeping with Impunity Harms Public Health in Haiti. PMID- 28820706 TI - High Prevalence of Treponema pallidum Infection in Brazilian Prisoners. AB - The number of new syphilis cases in Brazil has risen alarmingly in recent years. However, there is limited data regarding syphilis prevalence in the Brazilian prison population. To facilitate the development of effective interventions, a cross-sectional study was undertaken to determine the prevalence of Treponema pallidum infection, active syphilis, and associated risk factors among Brazilian prisoners. We administered a questionnaire to a population-based sample of prisoners from 12 prisons in Central-West Brazil and collected sera for syphilis testing, from January to December 2013. Univariable and multivariable regression analyses were performed to assess associations with active syphilis. We recruited 3,363 prisoners (men: 84.6%; women: 15.4%). The overall lifetime and active syphilis prevalences were 10.5% (9.4% among men; 17% among women, P < 0.001) and 3.8% (2% among men; 9% among women, P < 0.001), respectively. The variables associated with active syphilis in men prisoners were homosexual preference, history of sexually transmitted infections, and human immunodeficiency virus status. Among women, the factors were sex with intravenous drug users, genital ulcer disease, and previous incarceration. Despite the high prevalence of active syphilis, 88.5% reported unawareness of their serological status and 67% reported unprotected sexual practices. Women had the highest rates of infection, including them in a high-risk group for the development of syphilis during pregnancy. Thus, implementing screening programs to enable continuous measures of control and prevention of T. pallidum infection in the prison environment, mainly in women institutions, is important to prevent severe forms of this disease and congenital infections. PMID- 28820705 TI - The Impact of Introducing Malaria Rapid Diagnostic Tests on Fever Case Management: A Synthesis of Ten Studies from the ACT Consortium. AB - Since 2010, the World Health Organization has been recommending that all suspected cases of malaria be confirmed with parasite-based diagnosis before treatment. These guidelines represent a paradigm shift away from presumptive antimalarial treatment of fever. Malaria rapid diagnostic tests (mRDTs) are central to implementing this policy, intended to target artemisinin-based combination therapies (ACT) to patients with confirmed malaria and to improve management of patients with nonmalarial fevers. The ACT Consortium conducted ten linked studies, eight in sub-Saharan Africa and two in Afghanistan, to evaluate the impact of mRDT introduction on case management across settings that vary in malaria endemicity and healthcare provider type. This synthesis includes 562,368 outpatient encounters (study size range 2,400-432,513). mRDTs were associated with significantly lower ACT prescription (range 8-69% versus 20-100%). Prescribing did not always adhere to malaria test results; in several settings, ACTs were prescribed to more than 30% of test-negative patients or to fewer than 80% of test-positive patients. Either an antimalarial or an antibiotic was prescribed for more than 75% of patients across most settings; lower antimalarial prescription for malaria test-negative patients was partly offset by higher antibiotic prescription. Symptomatic management with antipyretics alone was prescribed for fewer than 25% of patients across all scenarios. In community health worker and private retailer settings, mRDTs increased referral of patients to other providers. This synthesis provides an overview of shifts in case management that may be expected with mRDT introduction and highlights areas of focus to improve design and implementation of future case management programs. PMID- 28820707 TI - Prevalence of Strongyloides stercoralis and Other Intestinal Parasite Infections in School Children in a Rural Area of Angola: A Cross-Sectional Study. AB - Strongyloides stercoralis is widely distributed in the tropics and subtropics. The aim of this study was to determine the prevalence of S. stercoralis and other intestinal parasites and identify the risk factors for infection with S. stercoralis in a rural area of Angola. A cross-sectional study was conducted in school-age children (SAC) in Cubal, Angola. A questionnaire collecting clinical and epidemiological variables was used, and two stool samples were collected. A concentration technique (Ritchie) and a technique for detection of larvae migration (Baermann) were performed. Of 230 SAC, 56.1% were female and the mean age was 9.3 years (SD 2.45). Severe malnutrition, according to body mass index (BMI)-for-age, was observed in 20.4% of the SAC, and anemia was found in 59.6%. Strongyloides stercoralis was observed in 28 of the 230 (12.8%) SAC. Eggs of other helminths were observed in 51 (22.2%) students: Hymenolepis spp. in 27 students (11.7%), hookworm in 14 (6.1%), Schistosoma haematobium in four (1.7%), Enterobius vermicularis in four (1.7%), Ascaris lumbricoides in three (1.3%), Taenia spp. in two (0.9%), and Fasciola hepatica in one (0.4%). Protozoa were observed in 17 (7.4%) students. Detection of S. stercoralis was higher using the Baermann technique versus using formol-ether (11.3 vs. 3%). Overall prevalence of S. stercoralis in the school population of 16 studied schools in the municipal area of Cubal was greater than 10%. This fact must be considered when designing deworming mass campaigns. The use of specific tests in larvae detection is needed to avoid overlooking this parasite. PMID- 28820708 TI - Clinical Spectrum, Etiology, and Outcome of Neurological Disorders in the Rural Hospital of Mosango, the Democratic Republic of Congo. AB - There is little published information on the epidemiology of neurological disorders in rural Central Africa, although the burden is considered to be substantial. This study aimed to investigate the pattern, etiology, and outcome of neurological disorders in children > 5 years and adults admitted to the rural hospital of Mosango, province of Kwilu, Democratic Republic of Congo, with a focus on severe and treatable infections of the central nervous system (CNS). From September 2012 to January 2015, 351 consecutive patients hospitalized for recent and/or ongoing neurological disorder were prospectively evaluated by a neurologist, subjected to a set of reference diagnostic tests in blood or cerebrospinal fluid, and followed-up for 3-6 months after discharge. No neuroimaging was available. Severe headache (199, 56.7%), gait/walking disorders (97, 27.6%), epileptic seizure (87, 24.8%), and focal neurological deficit (86, 24.5%) were the predominant presentations, often in combination. Infections of the CNS were documented in 63 (17.9%) patients and mainly included bacterial meningitis and unspecified meningoencephalitis (33, 9.4%), second-stage human African trypanosomiasis (10, 2.8%), and human immunodeficiency virus (HIV) related neurological disorders (10, 2.8%). Other focal/systemic infections with neurological manifestations were diagnosed in an additional 60 (17.1%) cases. The leading noncommunicable conditions were epilepsy (61, 17.3%), psychiatric disorders (56, 16.0%), and cerebrovascular accident (23, 6.6%). Overall fatality rate was 8.2% (29/351), but up to 23.8% for CNS infections. Sequelae were observed in 76 (21.6%) patients. Clinical presentations and etiologies of neurological disorders were very diverse in this rural Central African setting and caused considerable mortality and morbidity. PMID- 28820710 TI - Accuracy of a Rapid Diagnostic Test (Cypress Chagas Quick Test(r)) for the Diagnosis of Chronic Chagas Disease in a Nonendemic Area: A Retrospective Longitudinal Study. AB - We analyzed the accuracy of Chagas Quick Test(r), a rapid diagnostic test, for the diagnosis of chronic Chagas disease through a retrospective study on a cohort of 669 patients consecutively examined at a single reference center in Italy, during a 7-year period. We observed high concordance with serological reference standard but low accuracy for screening purposes (sensitivity/specificity: 82.8%/98.7%) at least in our nonendemic context. PMID- 28820709 TI - Performance of a High-Sensitivity Rapid Diagnostic Test for Plasmodium falciparum Malaria in Asymptomatic Individuals from Uganda and Myanmar and Naive Human Challenge Infections. AB - Sensitive field-deployable diagnostic tests can assist malaria programs in achieving elimination. The performance of a new AlereTM Malaria Ag P.f Ultra Sensitive rapid diagnostic test (uRDT) was compared with the currently available SD Bioline Malaria Ag P.f RDT in blood specimens from asymptomatic individuals in Nagongera, Uganda, and in a Karen Village, Myanmar, representative of high- and low-transmission areas, respectively, as well as in pretreatment specimens from study participants from four Plasmodium falciparum-induced blood-stage malaria (IBSM) studies. A quantitative reverse transcription PCR (qRT-PCR) and a highly sensitive enzyme-linked immunosorbent assay (ELISA) test for histidine-rich protein II (HRP2) were used as reference assays. The uRDT showed a greater than 10-fold lower limit of detection for HRP2 compared with the RDT. The sensitivity of the uRDT was 84% and 44% against qRT-PCR in Uganda and Myanmar, respectively, and that of the RDT was 62% and 0% for the same two sites. The specificities of the uRDT were 92% and 99.8% against qRT-PCR for Uganda and Myanmar, respectively, and 99% and 99.8% against the HRP2 reference ELISA. The RDT had specificities of 95% and 100% against qRT-PCR for Uganda and Myanmar, respectively, and 96% and 100% against the HRP2 reference ELISA. The uRDT detected new infections in IBSM study participants 1.5 days sooner than the RDT. The uRDT has the same workflow as currently available RDTs, but improved performance characteristics to identify asymptomatic malaria infections. The uRDT may be a useful tool for malaria elimination strategies. PMID- 28820711 TI - Molecular Epidemiology of Cholera Outbreaks during the Rainy Season in Mandalay, Myanmar. AB - Cholera, caused by Vibrio cholerae, remains a global threat to public health. In Myanmar, the availability of published information on the occurrence of the disease is scarce. We report here that cholera incidence in Mandalay generally exhibited a single annual peak, with an annual average of 312 patients with severe dehydration over the past 5 years (since 2011) and was closely associated with the rainy season. We analyzed cholera outbreaks, characterized 67 isolates of V. cholerae serogroup O1 in 2015 from patients from Mandalay, and compared them with 22 V. cholerae O1 isolates (12 from Mandalay and 10 from Yangon) in 2014. The isolates carried the classical cholera toxin B subunit (ctxB), the toxin-coregulated pilus A (tcpA) of Haitian type, and repeat sequence transcriptional regulator (rstR) of El Tor type. Two molecular typing methods, pulsed-field gel electrophoresis and multiple-locus variable-number tandem repeat analysis (MLVA), differentiated the 89 isolates into seven pulsotypes and 15 MLVA profiles. Pulsotype Y15 and one MLVA profile (11, 7, 7, 16, 7) were predominantly found in the isolates from cholera outbreaks in Mandalay, 2015. Pulsotypes Y11, Y12, and Y15 with some MLVA profiles were detected in the isolates from two remote areas, Mandalay and Yangon, with temporal changes. These data suggested that cholera spread from the seaside to the inland area in Myanmar. PMID- 28820712 TI - Scrub Typhus as an Etiology of Acute Febrile Illness in Gorakhpur, Uttar Pradesh, India, 2016. AB - Seasonal outbreaks of acute encephalitis syndrome (AES) with high mortality occur every year in Gorakhpur region of Uttar Pradesh, India. Earlier studies indicated the role of scrub typhus as the important etiology of AES in the region. AES cases were hospitalized late in the course of their illness. We established surveillance for acute febrile illness (AFI) (fever >= 4 days duration) in peripheral health facilities in Gorakhpur district to understand the relative contribution of scrub typhus. Of the 224 patients enrolled during the 3-month period corresponding to the peak of AES cases in the region, about one-fifth had immunoglobulin M (IgM) antibodies against Orientia tsutsugamushi. Dengue and leptospira accounted for 8% and 3% of febrile illness cases. Treating patients with AFI attending the peripheral health facilities with doxycycline could prevent development of AES and thereby reduce deaths due to AES in Gorakhpur region. PMID- 28820713 TI - Quality Testing of Artemisinin-Based Antimalarial Drugs in Myanmar. AB - Artemisinin-based combination therapies are the frontline treatment of Plasmodium falciparum malaria. The circulation of falsified and substandard artemisinin based antimalarials in Southeast Asia has been a major predicament for the malaria elimination campaign. To provide an update of this situation, we purchased 153 artemisinin-containing antimalarials, as convenience samples, in private drug stores from different regions of Myanmar. The quality of these drugs in terms of their artemisinin derivative content was tested using specific dipsticks for these artemisinin derivatives, as point-of-care devices. A subset of these samples was further tested by high-performance liquid chromatography (HPLC). This survey identified that > 35% of the collected drugs were oral artesunate and artemether monotherapies. When tested with the dipsticks, all but one sample passed the assays, indicating that the detected artemisinin derivative content corresponded approximately to the labeled contents. However, one artesunate injection sample was found to contain no active ingredient at all by the dipstick assay and subsequent HPLC analysis. The continued circulation of oral monotherapies and the description, for the first time, of falsified parenteral artesunate provides a worrisome picture of the antimalarial drug quality in Myanmar during the malaria elimination phase, a situation that deserves more oversight from regulatory authorities. PMID- 28820714 TI - Epidemiology of Cutaneous Leishmaniasis in a Colombian Municipality. AB - This study describes the epidemiological and clinical characteristics of leishmaniasis and the pharmacological treatment of this disease in the municipality of Pueblo Rico, Risaralda, between January 2010 and December 2014. An observational study was conducted using information from the clinical records and epidemiological reports of patients diagnosed and confirmed with leishmaniasis of any age and sex, including sociodemographic, clinical, and pharmacological variables of the therapy received. Univariate and bivariate analyses were performed. A total of 539 cases of leishmaniasis were confirmed, with 29.5% occurring in children under 5 years of age. The median age was 10 years, with predominance in males (55.5%). The indigenous Embera (aboriginal Americans) were the most affected (50.8%), and 93.3% of cases occurred in people living in scattered rural areas. All lesions corresponded to cutaneous leishmaniasis, of which 251 patients had compromise of the upper limbs (46.6%), 221 of the face (41.0%), and 139 of the lower limbs (25.8%). Pentavalent antimony salts (n-methyl glucamine and sodium stibogluconate) were prescribed in 77.6% (N = 418) of the cases; miltefosine was the second most frequently prescribed medication (21.5%, N = 116). The inhabitants of rural areas and the indigenous communities are at a higher risk of acquiring the infection, particularly among infants, which highlights the importance of the biological, social, and demographic factors involved in the disease. There is a need to seek effective public health actions and further research this disease. PMID- 28820716 TI - Evaluation of Community-Directed Operation of Black Fly Traps for Entomological Surveillance of Onchocerca volvulus Transmission in the Madi-Mid North Focus of Onchocerciasis in Northern Uganda. AB - Entomological measures of transmission are important metrics specified by the World Health Organization to document the suppression and interruption of transmission of Onchocerca volvulus, the causative agent of onchocerciasis. These metrics require testing of large numbers of vector black flies. Black fly collection has relied on human landing collections, which are inefficient and potentially hazardous. As the focus of the international community has shifted from onchocerciasis control to elimination, replacement of human landing collections has become a priority. The Esperanza window trap (EWT) has shown promise as an alternative method for collection of Simulium damnosum s.l., the primary vector of O. volvulus in Africa. Here, we report the results of a community-based trial of the EWT in northern Uganda. Traps operated by residents were compared with human landing collections in two communities over 5 months. Three traps, when operated by a single village resident, collected over four times as many S. damnosum as did the two-men collection team. No significant differences were noted among the bait formulations. The results suggest that EWTs may be effectively operated by community residents and that the trap represents a viable alternative to human landing collections for entomological surveillance of O. volvulus transmission. PMID- 28820715 TI - Limited Transmission Potential of Takeda's Tetravalent Dengue Vaccine Candidate by Aedes albopictus. AB - Recombinant live-attenuated chimeric tetravalent dengue vaccine viruses, TDV-1, 2, -3, and -4, contain the premembrane and envelope genes of dengue virus serotypes 1-4 in the replicative background of the attenuated dengue virus type-2 (DENV-2) PDK-53 vaccine strain. Previous results have shown that these recombinant vaccine viruses demonstrate limited infection and dissemination in Aedes aegypti and are unlikely to be transmitted by the primary mosquito vector of DENVs. In this report, we expand this analysis by assessing vector competence of all four serotypes of the TDV virus in Aedes albopictus, the secondary mosquito vector of DENVs. Our results indicate that these vaccine viruses demonstrate incompetence or defective infection and dissemination in these mosquitoes and will likely not be transmissible. PMID- 28820717 TI - Short-Term Changes in Anemia and Malaria Parasite Prevalence in Children under 5 Years during One Year of Repeated Cross-Sectional Surveys in Rural Malawi. AB - In stable transmission areas, malaria is the leading cause of anemia in children. Anemia in children is proposed as an added sensitive indicator for community changes in malaria prevalence. We report short-term temporal variations of malaria and anemia prevalence in rural Malawian children. Data from five repeated cross-sectional surveys conducted over 1 year in rural communities in Chikwawa District, Malawi, were analyzed. Different households were sampled per survey; all children, 6-59 months, in sampled household were tested for malaria parasitemia and hemoglobin levels using malaria rapid diagnostic tests (mRDT) and Hemocue 301, respectively. Malaria symptoms, recent treatment (2 weeks) for malaria, anthropometric measurements, and sociodemographic details were recorded. In total, 894 children were included from 1,377 households. The prevalences of mRDT positive and anemia (Hb < 11 g/dL) were 33.8% and 58.7%, respectively. Temporal trends in anemia and parasite prevalence varied differently. Overall, unadjusted and adjusted relative risks of anemia in mRDT-positive children were 1.31 (95% CI: 1.09-1.57) and 1.36 (1.13-1.63), respectively. Changes in anemia prevalence differed with short-term changes in malaria prevalence, although malaria is an important factor in anemia. PMID- 28820718 TI - Water, Sanitation, and Hygiene in Rural Health-Care Facilities: A Cross-Sectional Study in Ethiopia, Kenya, Mozambique, Rwanda, Uganda, and Zambia. AB - Safe and sufficient water, sanitation, and hygiene (WaSH) prevent the spread of disease in health-care facilities (HCFs). Little research has been conducted on WaSH in HCF in sub-Saharan Africa. We carried out a cross-sectional study of WaSH in 1,318 randomly selected rural HCF (hospitals, health centers, health posts, and clinics) in regions throughout Ethiopia, Kenya, Mozambique, Rwanda, Uganda, and Zambia. Methods included questionnaires with head doctors and nurses to document WaSH access, continuity, quality, quantity and reliability, and analysis of drinking water samples for Escherichia coli. We found that fewer than 50% of rural HCFs had access to improved water sources on premises, improved sanitation, and consistent access to water and soap for handwashing (Ethiopia [7%), Kenya [30%], Mozambique [29%], Rwanda [50%], Uganda [30%], and Zambia [21%]). Adequate hand hygiene reduces disease transmission and health-care-acquired infections, but fewer than 25% of HCF in each country reported that a combination of water, soap, and hand-drying materials were always available. Our research points to a lack of basic WaSH services in rural HCFs in regions of sub-Saharan Africa, which poses a threat to the health of patients and health-care workers in these settings. PMID- 28820720 TI - Dengue Virus Serotypes 1 and 2 Responsible for Major Dengue Outbreaks in Nepal: Clinical, Laboratory, and Epidemiological Features. AB - Dengue virus (DENV) is expanding toward previously nonendemic areas. DENV has recently been introduced in Nepal with limited information. We report the clinical features and serotype distribution of DENV in Nepal during the major outbreaks. A total of 1,215 clinical dengue cases at two major hospitals of central and western Nepal were investigated. Demographic, clinical, and laboratory parameters were recorded. Serum specimens were tested for DENV by IgM/IgG enzyme-linked immunosorbent assays (ELISAs) and reverse transcription polymerase chain reaction (RT-PCR). We confirmed DENV infection in 403 (33%) patients from 12 districts with an estimated case fatality rate of 1.5%. DENV infection was more common in adults (87%) and urban settings (74%). We detected all four serotypes but DENV-1 and -2 were mainly responsible for major outbreaks (92%). Overall, 60% of all DENV infections were secondary and 17% were severe dengue; both being more frequent among the DENV-2 infections. Rash, bleeding, abdominal pain, hepatomegaly, elevated liver enzymes, and thrombocytopenia were significantly more common in severe dengue compared with nonsevere infections. We also confirmed the expansion of dengue to hill urban areas (DENV-1 and -2), including the capital Kathmandu (altitude, 1,300 m) though > 90% cases were from southern plains. Differential clinical and laboratory features probably helps in clinical decisions. Multiple serotypes circulation and elevated secondary infections pose potential risk of severe outbreaks and deaths in the future. Therefore, a country with recent dengue introduction, like Nepal, urgently requires a systematic surveillance and appropriate control measures in place to respond any disastrous outbreaks. PMID- 28820719 TI - Central Nervous System Infection Associated with Orientia tsutsugamushi in South Korea. AB - Orientia tsutsugamushi is a major cause of vector-borne infection in Asia. Prompt recognition and appropriate treatment are crucial because of its potentially fatal complications and lack of response to beta-lactam antibiotics. The present study retrospectively evaluated the clinical characteristics and laboratory findings of 16 patients with scrub typhus-related central nervous system (CNS) infections. Single titers >= 1:40 of total serum antibodies against O. tsutsugamushi detected by an indirect immunofluorescent assay were considered as positive results. The median age was 35.5 (range, 14-72) years, and 10 (62.5%) patients were female. The most common symptoms were headache (81.3%) and fever (81.3%). Eschar formation was found in three (18.8%) patients. Among patients with encephalitis, seizures and altered consciousness occurred in five (83.3%) and four (66.7%) patients, respectively. An abnormal liver function was noted in seven (43.8%) patients. The median antibody titer was 1:120 (range, 1:40 1:2,560). Typical cerebrospinal fluid profiles were lymphocytic pleocytosis, mild protein elevations, and normal glucose levels. All patients received an empirical treatment with doxycycline and most (93.8%) of them recovered without neurological sequelae. None of the patients reported side effects of the doxycycline treatment. An empirical treatment with doxycycline is needed in patients with CNS infections in scrub typhus endemic areas. PMID- 28820721 TI - Risk Factors Associated with Blood Exposure for Sporadic Hepatitis E in Dhaka, Bangladesh. AB - Fecal contamination of drinking water is associated with large hepatitis E virus (HEV) outbreaks of genotypes 1 and 2 in endemic areas. Sporadic transmission of HEV genotypes 3 and 4 in high-income countries has been associated with exposure to blood and animal contact. The objective of the study was to identify the risk factors for hepatitis E and the genotype(s) causing sporadic hepatitis E in Dhaka, Bangladesh. We selected, from a diagnostic center in Dhaka between November 2008 and November 2009, cases presenting with jaundice and anti-HEV IgM antibodies and age-matched controls were defined as those with no history of jaundice and normal blood test results. Serum samples were tested for HEV RNA using real-time reverse transcriptase polymerase chain reaction followed by a sequencing and phylogenetic analysis. A total of 109 cases and 109 controls were enrolled. The cases were more likely to be male (adjusted matched odds ratios [mOR] 2.2, 95% CI: 1.2-3.9; P = 0.01), or have reported contact with another person's blood or blood product, or contact with blood-contaminated sharp instruments (adjusted mOR 2.1, 95% CI: 1.1-4.1; P = 0.03) than controls. There were no significant differences between the cases and the controls in terms of reported high-risk sexual intercourse, consumption of undercooked meat, or contact or drinking fecally-contaminated water. The sera from three cases carried HEV RNA, all belonging to genotype 1. Findings from this study suggest that contact with human blood and sharing sharp instruments may transmit sporadic hepatitis E in Dhaka, Bangladesh. Efforts to prevent the transmission of blood borne pathogens may also prevent sporadic HEV transmission in this endemic setting. PMID- 28820722 TI - House Structure Is Associated with Plasmodium falciparum Infection in a Low Transmission Setting in Southern Zambia. AB - House structure may influence the risk of malaria by affecting mosquito entry and indoor resting. Identification of construction features associated with protective benefits could inform vector control approaches, even in low transmission settings. We examined the association between house structure and malaria prevalence in a cross-sectional analysis of 2,788 children and adults residing in 866 houses in a low-transmission area of Southern Province, Zambia, over the period 2008-2012. Houses were categorized according to wall (brick/cement block or mud/grass) and roof (metal or grass) material. Malaria was assessed by point-of-care rapid diagnostic test (RDT) for Plasmodium falciparum. We identified 52 RDT-positive individuals residing in 41 houses, indicating an overall prevalence in the sample of 1.9%, ranging from 1.4% to 8.8% among the different house types. Occupants of higher quality houses had reduced odds of P. falciparum malaria compared with those in the lowest quality houses after controlling for bed net use, indoor insecticide spraying, clustering by house, cohabitation with another RDT-positive individual, transmission season, ecologic risk defined as nearest distance to a Strahler-classified third-order stream, education, age, and gender (adjusted odds ratio [OR]: 0.26, 95% confidence interval [CI]: 0.09-0.73, P = 0.01 for houses with brick/cement block walls and metal roof; OR: 0.22, 95% CI: 0.09-0.52, P < 0.01 for houses with brick/cement block walls and grass roof). Housing improvements offer a promising approach to vector control in low-transmission settings that circumvents the threat posed by insecticide resistance, and may confer a protective benefit of similar magnitude to current vector control strategies. PMID- 28820724 TI - Neurologic Complications in Persons With HIV Infection in the Era of Antiretroviral Therapy. AB - Neurologic complications in persons with HIV infection are less severe in the era of potent antiretroviral therapy but remain highly prevalent. Prior to the use of antiretroviral therapy, opportunistic infections of the central nervous system (CNS) and CNS malignancy were common. Progressive multifocal leukoencephalopathy (PML), however, remains a diagnostic challenge in HIV-infected individuals, and no effective antiviral treatment for PML is currently available. Primary neurologic complications of acute HIV infection include aseptic meningitis and acute inflammatory demyelinating polyneuropathy. Among the neurologic complications of chronic HIV infection, HIV-associated neurocognitive disorders (HAND) remain most prevalent. The use of antiretroviral therapy has greatly reduced the severity of HAND, under which progressive HIV-associated dementia once predominated, to a milder chronic form of potentially disabling neurocognitive impairment. The persistence of HAND in individuals with virologic suppression suggests a need for adjunctive therapies for limiting its morbidity. This article summarizes a presentation by Dennis Kolson, MD, PhD, at the IAS-USA continuing education program, Improving the Management of HIV Disease, held in Chicago, Illinois, in May 2017. PMID- 28820725 TI - Understanding Hepatitis C Virus Drug Resistance: Clinical Implications for Current and Future Regimens. AB - Viral resistance to direct-acting antiviral drugs may impact their effectiveness during treatment of hepatitis C virus (HCV) infection. Most data on HCV drug resistance concern genotypes 1 and 3. The clinical impact of resistance to HCV nonstructural protein 5A (NS5A) inhibitors and a practical approach to indications and methods for resistance testing are discussed. PMID- 28820723 TI - A lncRNA fine tunes the dynamics of a cell state transition involving Lin28, let 7 and de novo DNA methylation. AB - Execution of pluripotency requires progression from the naive status represented by mouse embryonic stem cells (ESCs) to a state capacitated for lineage specification. This transition is coordinated at multiple levels. Non-coding RNAs may contribute to this regulatory orchestra. We identified a rodent-specific long non-coding RNA (lncRNA) linc1281, hereafter Ephemeron (Eprn), that modulates the dynamics of exit from naive pluripotency. Eprn deletion delays the extinction of ESC identity, an effect associated with perduring Nanog expression. In the absence of Eprn, Lin28a expression is reduced which results in persistence of let 7 microRNAs, and the up-regulation of de novo methyltransferases Dnmt3a/b is delayed. Dnmt3a/b deletion retards ES cell transition, correlating with delayed Nanog promoter methylation and phenocopying loss of Eprn or Lin28a. The connection from lncRNA to miRNA and DNA methylation facilitates the acute extinction of naive pluripotency, a pre-requisite for rapid progression from preimplantation epiblast to gastrulation in rodents. Eprn illustrates how lncRNAs may introduce species-specific network modulations. PMID- 28820726 TI - Barriers to Treatment Access for Chronic Hepatitis C Virus Infection: A Case Series. AB - Restrictive policies on access to new, curative hepatitis C treatments represent a substantial barrier to treating patients infected with hepatitis C. This case series demonstrates challenges experienced by patients and practitioners in accessing these treatments and highlights several strategies for navigating the treatment preauthorization process. PMID- 28820727 TI - Sustained Off-Treatment Response After Discontinuation of Long-Term Nucleos(t)ide Analogue Treatment in HBeAg-Seronegative Hepatitis B: A Case Series. AB - International guidelines recommend lifelong nucleos(t)ide analogue (NA) treatment in individuals with chronic hepatitis B (CHB) infection who are hepatitis B e antigen (HBeAg) seronegative, because hepatitis B surface antigen (HBsAg) seroconversion is rarely achieved. However, after terminating therapy, sustained responses and HBsAg loss have been observed. Clinical characteristics identifying persons with favorable outcomes after discontinuing NA therapy have not yet been defined. This case series describes outcomes of 6 individuals with HBeAg seronegative CHB infection without cirrhosis and low plasma levels of HBsAg who discontinued long-term NA treatment. All individuals had a virologic relapse and 4 of 6 had a biochemical relapse; but 5 of 6 later developed a sustained virologic and biochemical response and a marked reduction of quantitative HBsAg (qHBsAg). Two of the 6 individuals experienced HBsAg loss. Only 1 patient was retreated, and none showed signs of hepatic decompensation. NA treatment can be safely stopped in selected HBeAg-seronegative patients. Sustained offtreatment responses seem to be frequently preceded by a virologic and biochemical flare. Loss of HBsAg possibly reflects restoration of antiviral immunity during prolonged NA treatment. Predictive factors, such as qHBsAg, may be valuable in selecting patients who could benefit from NA discontinuation. PMID- 28820728 TI - Radiostereometric migration measurement of an uncemented Cerafit(r) femoral stem: 26 patients followed for 10 years. AB - Radiostereometric analysis (RSA) is the gold standard for evaluating micromotions of orthopaedic implants. The method is applied for identifying novel design weaknesses in endoprostheses. Current research frequently assesses relatively short time periods. Short-term RSA studies have been widely used for predicting the long-term stability of many hip prosthetic designs, but only a few studies have focused on uncemented hip implants, especially for extended periods. The purpose of this study was to analyse the migration pattern of the Cerafit(r) femoral stem within 10 years and to verify the predictive value of short-term RSA after 2 years for this uncemented femoral hip stem. Twenty-six patients were followed for 10 years. Ten years after implantation, a mean subsidence of 0.22 mm+/-0.56 mm, a mean internal rotation of 0.59 degrees +/-1.67 degrees and a mean maximum total point motion (MTPM) of 1.28 mm+/-0.54 mm were detected. The main migration took place in the first 6 weeks after surgery (subsidence of 0.36 mm+/-0.73 mm; internal rotation of 0.62 degrees +/-1.49 degrees , MTPM of 1.05 mm+/-0.68 mm). All the migration values measured were small. No late-onset migration was observed. This study suggests that the Cerafit(r) implants are stable after 10 years. Thus, RSA could be the best tool to assess long-term implant behaviour. PMID- 28820729 TI - Head phantoms for electroencephalography and transcranial electric stimulation: a skull material study. AB - Physical head phantoms allow the assessment of source reconstruction procedures in electroencephalography and electrical stimulation profiles during transcranial electric stimulation. Volume conduction in the head is strongly influenced by the skull, which represents the main conductivity barrier. Realistic modeling of its characteristics is thus important for phantom development. In the present study, we proposed plastic clay as a material for modeling the skull in phantoms. We analyzed five clay types varying in granularity and fractions of fire clay, each with firing temperatures from 550 degrees C to 950 degrees C. We investigated the conductivity of standardized clay samples when immersed in a 0.9% sodium chloride solution with time-resolved four-point impedance measurements. To test the reusability of the clay model, these measurements were repeated after cleaning the samples by rinsing in deionized water for 5 h. We found time-dependent impedance changes for approximately 5 min after immersion in the solution. Thereafter, the conductivities stabilized between 0.0716 S/m and 0.0224 S/m depending on clay type and firing temperatures. The reproducibility of the measurement results proved the effectiveness of the rinsing procedure. Clay provides formability, is permeable to ions, can be adjusted in conductivity value and is thus suitable for the skull modeling in phantoms. PMID- 28820730 TI - Knowledge of hepatitis B virus infection and its control practices among dental students in an Indian city. AB - Background Hepatitis B virus infection is a general cause of chronic hepatitis, liver cirrhosis and hepato-cellular carcinoma worldwide. It is highly contagious. It is an important reason for morbidity and mortality in the Indian population. Oral health professionals are at the highest risk. Vaccination for hepatitis B can prevent this deadly disease. Methods The present study was designed to evaluate the degree of awareness, knowledge of hepatitis B infection and status of hepatitis B vaccination among dental students. A cross-sectional study was conducted among 240 students of 3rd year, 4th year and interns of a professional dental course. A pre-tested questionnaire was given to the students of each year. All the data management and analysis were carried out using SPSS software version 16. Results Eighty-six percent of the students had knowledge about hepatitis B infection. The majority of the students had correct knowledge regarding mode of transmission, however, 21% failed to recognize saliva as the mode of hepatitis B transmission. Forty-five percent of the students were vaccinated for hepatitis B. Conclusion The present study concludes that there is reasonable awareness of hepatitis B infection hazards, its transmission and vaccination, among the dental students who will be entering into the profession. However, half of the students were not vaccinated for hepatitis B in our study group, which keeps them at risk to the disease. The Indian Health Ministry should make hepatitis B vaccination mandatory for all health care professionals. A strategy should be executed for health education and compulsory vaccination of all students joining the health care professional colleges. Antibody titers should be routinely checked among those who are vaccinated. PMID- 28820731 TI - Emphysematous infections of the urinary tract - an audit of 20 patients with review of literature. AB - Emphysematous infection of the urinary tract is a rapidly progressive, necrotizing infection which results into collection of gas and subsequent destruction of the tissues. Although very rare among general population, such necrotizing infection is common, particularly among those with compromised immune status. With the rising trend of people afflicted with diabetes mellitus globally, this fulminating infection may pose a serious threat to the medical fraternity. A high index of suspicion and abdominal CT scan usually helps to establish the diagnosis at an early stage and thereby facilitating aggressive antimicrobial therapy and percutaneous drainage where indicated. Although, extirpation of infected renal unit was the treatment of choice earlier, with the advent of modern imaging, endourological procedures and broad spectrum antibiotics, majority of such patients can be treated with minimal morbidity and mortality even with salvaging of the renal units. We present here the outcome of management of 20 cases with varied spectrum of emphysematous infection. PMID- 28820732 TI - Ecological perspectives on youth alcohol consumption in the Kuala Lumpur conurbation: a place-based study in Malaysia. AB - Objective The objectives of this study were to investigate the patterns of alcohol consumption and ecological factors influencing those patterns in the Klang Valley. The study focuses on youth from the Chinese, Indian and Malay ethnic groups in Malaysia, resident in urban and semi-urban areas of the Klang Valley. Methods Data were collected with a combination of interviews and self administered questionnaires available in Bahasa Malaysia and English were adapted from the Centers for Disease Control (CDC) Youth Risk Behavior Survey. The study sample consisted of 326 respondents: 103 Malays, 111 Chinese and 112 Indians. There were 171 males and 155 females, with mean age of 20.56 and 20.59 years, respectively, were identified by convenience sampling in six sites. Results A combination of at least one family member and one friend who consumed alcohol was a significant driver of alcohol use: 80% in this category had tried alcohol; 55% were current drinkers; and 35% were binge drinkers. With at least one family member, the respective figures were 72%, 48%, and 30%; and with at least one friend, but no family pattern of consumption, the figures dropped to 64%, 42% and 26%, respectively. With respect to ethnicity, 72% of Chinese youth had tried alcohol or were current drinkers (49%). The figure was lower for Indian youth (47% and 37%, respectively) and Malay youth (15% and 9%, respectively). In the binge drinking category, however, the highest figures were from the Indian youth (31%) followed by Chinese youth (23%) and significantly less in Malay youth (5%). Alcohol consumption was consistently higher among males: 54% had tried alcohol, 44% were current drinkers, and 30% were binge drinkers, compared to 36%, 18% and 9% of female youth, respectively. Conclusion Family alcohol consumption patterns were most strongly associated with consumption patterns which varied across the three ethnic groups. Family education regarding family influence on youth's alcohol consumption patterns is warranted. PMID- 28820733 TI - Pubertal assessment: targeted educational intervention for pediatric trainees. AB - Background Timely and periodic pubertal assessment in children is vital to identify puberty related disorders. Pediatricians need to have working knowledge of puberty time and tempo. Pediatric residency is an important platform to acquire physical examination skills including pubertal assessment. Objective An educational intervention for teaching pubertal assessment was piloted on pediatric residents at our institution. Methods The intervention comprised of interactive lecture series, ID badge size Tanner stage cards and Tanner posters placed in residents' continuity clinics. Pre-intervention, post-intervention and 3 months post-intervention surveys for participating trainees were administered to determine the effectiveness of the intervention. Attitudes, practices, knowledge scores, and barriers to Tanner staging conduct were analyzed. Results Forty-three residents participated in the intervention. Knowledge scores of PGY1 (5.95 +/- 1.6 vs. 7.47 +/- 1.4, p < 0.01) improved right after the intervention, as did self-reported clinical practices of all trainees 3 months post- intervention with regards to conducting external genital examination and performing pubertal assessment. Confidence levels of pediatric trainees in conducting pubertal assessment and comfort levels in assessing the need for endocrine referral based on abnormal Tanner staging improved after the intervention, although the effect was not statistically significant. Conclusion Our intervention is a worthwhile technique for teaching pubertal assessment to residents as it is simple to conduct, easily reproducible, provides baseline knowledge needed for recognition of normal pubertal development and puberty related conditions, and instills confidence in residents. PMID- 28820734 TI - Characteristics, reasons, behavior and knowledge towards waterpipe smoking in Saudi Arabia. AB - Background The present scenario shows that waterpipe smoking, one of tobacco smoking methods, the practice off which dates back at least 400 year is appealing to the youth. Waterpipe tobacco smoking is frequently linked with nations of the Eastern Mediterranean Region (EMR) comprising Egypt, Kuwait, Lebanon and Syria. The present study shows the socio-demographic characteristics, behavior and knowledge of youth towards waterpipe smoking. Recognizing these features may help emphasize intervention methods. Methods A self-administered questionnaire was used to collect the data about waterpipe smoking comprising sociodemographic, behavior, reasons and knowledge from 230 university students. Results 230 questionnaires were distributed from which only 199 were included in the study as 31 were excluded because of incompleteness of the survey. The mean age for starting smoking was 19.49 +/- 3.75 years with 32.5% of family members and the majority of their friends engaged with waterpipe smoking. Pleasure and happiness (76%), helps me to deal with pressure (78%) and acceptance by society (91%), were the major reasons cited for waterpipe smoking. It being less harmful and less addictive (55%) compared to cigarettes and no objection from the parents (58%) were the other cited reasons. Furthermore, less than 50% of the participants had correct knowledge of its harmful effects. Conclusion It is clearly evident from our findings that there is a meagre amount of knowledge regarding the harmful effects of waterpipe smoking. It is essential that programs to impart knowledge regarding the harmful effects of waterpipe smoking and dependence should be of the utmost importance. PMID- 28820735 TI - The use of siRNA as a pharmacological tool to assess a role for the transcription factor NF-IL6 in the brain under in vitro and in vivo conditions during LPS induced inflammatory stimulation. AB - BACKGROUND: Studies with NF-IL6-deficient mice indicate that this transcription factor plays a dual role during systemic inflammation with pro- and anti inflammatory capacities. Here, we aimed to characterize the role of NF-IL6 specifically within the brain. METHODS: In this study, we tested the capacity of short interfering (si) RNA to silence the inflammatory transcription factor nuclear factor-interleukin 6 (NF-IL6) in brain cells under in vitro and in vivo conditions. RESULTS: In cells of a mixed neuronal and glial primary culture from the rat area postrema (AP), short interfering RNA (siRNA) directed against NF-IL6 strongly reduced basal and lipopolysaccharide (LPS)-induced nuclear immunoreactivity of this transcription factor, with the strongest effect on astrocytes. The siRNA did not exert inflammatory effects in the primary culture as confirmed by unaltered levels of IL-6 in supernatants. In vivo, intracerebroventricular (i.c.v.) injections of fluorochrome labelled siRNA caused its appearance in relevant brain structures for fever induction pathways such as the vascular organ of lamina terminalis, the subfornical organ, the median preoptic nucleus (MnPO) and the AP in several cell types, including microglial cells. However, i.c.v. injections of siRNA per se caused signs of fever, anorexia and reduced locomotor activity, i.e. sickness behavior. CONCLUSIONS: This approach was, thus, not suitable to characterize the role NF-IL6 in the brain in vivo, namely during experimentally induced systemic inflammation. PMID- 28820736 TI - Long QT syndrome diagnosed in two sisters with propionic acidemia: a case report. AB - Propionic acidemia (PA) is a rare autosomal recessive metabolic disorder caused by deficiency of the mitochondrial enzyme propionyl-CoA carboxylase (PCC). This disorder mostly progresses with episodes of metabolic acidosis. Cardiomyopathy is among the cardiac complications known to occur during metabolic decompensation episodes. However, several recent papers emphasized the association of PA and long QT syndrome (LQTS) which may lead to extremely serious and fatal consequences. In this report, we describe two sisters with PA who have prolonged QT duration that were incidentally detected in an outpatient setting. LQTS was verified by electrocardiogram, stress test and 24 h rhythm holter monitoring. By this report, we want to emphasize the importance of early diagnosis of LQTS in asymptomatic patients with PA to prevent fatal complications. PMID- 28820737 TI - When one disease is not enough: succinyl-CoA: 3-oxoacid coenzyme A transferase (SCOT) deficiency due to a novel mutation in OXCT1 in an infant with known phenylketonuria. AB - A 9-month-old Turkish girl was admitted several times within 3 months to the hospital in reduced general condition and with extreme tachypnea. The patient had been diagnosed with phenylketonuria (PKU) in newborn screening and has been treated with a low phenylalanine diet and amino acid supplements. Each time an unexplained pronounced metabolic acidosis was noted, and the child was treated with sodium-bicarbonate and glucose-electrolyte infusions. The acidosis with only slightly abnormal glucose, normal lactate levels and pronounced ketonuria suggested a defect in ketone body utilization. Succinyl-CoA: 3-oxoacid CoA transferase (SCOT) enzyme activity was low in patient's fibroblasts. Mutation analysis of the corresponding OXCT1 gene revealed that the patient was a homozygous carrier of the mutation c.1523T>C (p.V508A). We conclude that SCOT deficiency should be considered in the differential diagnosis in patients with recurrent metabolic acidotic episodes, even if they are already known to have a metabolic disease unrelated to this. PMID- 28820738 TI - The effects of transcranial direct current stimulation on short-interval intracortical inhibition and intracortical facilitation: a systematic review and meta-analysis. AB - Transcranial direct current stimulation (tDCS) is increasingly being used to affect the neurological conditions with deficient intracortical synaptic activities (i.e. Parkinson's disease and epilepsy). In addition, it is suggested that the lasting effects of tDCS on corticospinal excitability (CSE) have intracortical origin. This systematic review and meta-analysis aimed to examine whether tDCS has any effect on intracortical circuits. Eleven electronic databases were searched for the studies investigating intracortical changes induced by anodal (a) and cathodal (c) tDCS, in healthy individuals, using two paired-pulse transcranial magnetic stimulation (TMS) paradigms: short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). Additionally, motor-evoked potential (MEP) size alterations, assessed by single pulse TMS, were extracted from these studies to investigate the probable intracortical origin of tDCS effects on CSE. The methodological quality of included studies was examined using Physiotherapy Evidence Database (PEDro) and Downs and Black's (D&B) assessment tools. Thirteen research papers, including 24 experiments, were included in this study scoring good and medium quality in PEDro and D&B scales, respectively. Immediately following anodal tDCS (a-tDCS) applications, we found significant decreases in SICI, but increases in ICF and MEP size. However, ICF and MEP size significantly decreased, and SICI increased immediately following cathodal tDCS (c-tDCS). The results of this systematic review and meta-analysis reveal that a-tDCS changes intracortical activities (SICI and ICF) toward facilitation, whereas c-tDCS alters them toward inhibition. It can also be concluded that increases and decreases in CSE after tDCS application are associated with corresponding changes in intracortical activities. The results suggest that tDCS can be clinically useful to modulate intracortical circuits. PMID- 28820739 TI - Metal-to-insulator transition induced by UV illumination in a single SnO2 nanobelt. AB - An individual tin oxide (SnO2) nanobelt was connected in a back-gate field-effect transistor configuration and the conductivity of the nanobelt was measured at different temperatures from 400 K to 4 K, in darkness and under UV illumination. In darkness, the SnO2 nanobelts showed semiconductor behavior for the whole temperature range measured. However, when subjected to UV illumination the photoinduced carriers were high enough to lead to a metal-to-insulator transition (MIT), near room temperature, at T MIT = 240 K. By measuring the current versus gate voltage curves, and considering the electrostatic properties of a non-ideal conductor, for the SnO2 nanobelt on top of a gate-oxide substrate, we estimated the capacitance per unit length, the mobility and the density of carriers. In darkness, the density was estimated to be 5-10 * 1018 cm-3, in agreement with our previously reported result (Phys. Status Solid. RRL 6, 262-4 (2012)). However, under UV illumination the density of carriers was estimated to be 0.2-3.8 * 1019 cm-3 near T MIT, which exceeded the critical Mott density estimated to be 2.8 * 1019 cm-3 above 240 K. These results showed that the electrical properties of the SnO2 nanobelts can be drastically modified and easily tuned from semiconducting to metallic states as a function of temperature and light. PMID- 28820740 TI - Subspace-based interference removal methods for a multichannel biomagnetic sensor array. AB - OBJECTIVE: In biomagnetic signal processing, the theory of the signal subspace has been applied to removing interfering magnetic fields, and a representative algorithm is the signal space projection algorithm, in which the signal/interference subspace is defined in the spatial domain as the span of signal/interference-source lead field vectors. This paper extends the notion of this conventional (spatial domain) signal subspace by introducing a new definition of signal subspace in the time domain. APPROACH: It defines the time domain signal subspace as the span of row vectors that contain the source time course values. This definition leads to symmetric relationships between the time domain and the conventional (spatial-domain) signal subspaces. As a review, this article shows that the notion of the time-domain signal subspace provides useful insights over existing interference removal methods from a unified perspective. Main results and significance. Using the time-domain signal subspace, it is possible to interpret a number of interference removal methods as the time domain signal space projection. Such methods include adaptive noise canceling, sensor noise suppression, the common temporal subspace projection, the spatio-temporal signal space separation, and the recently-proposed dual signal subspace projection. Our analysis using the notion of the time domain signal space projection reveals implicit assumptions these methods rely on, and shows that the difference between these methods results only from the manner of deriving the interference subspace. Numerical examples that illustrate the results of our arguments are provided. PMID- 28820742 TI - Spatial valley separation in strained graphene pn junction. AB - Valleytronics in analogy to spintronics aims to use the electron valley degree of freedom to carry and manipulate information, and one of urgent tasks in this field is to generate valley-polarized electrons. In this work, we propose using the electron focusing effect in a strained graphene pn junction to separate valleys spatially through a beam of valley-unpolarized electrons, since the strain-induced pseudo-gauge potentials are opposite for K and [Formula: see text] valleys and severely affect the trajectories of K and [Formula: see text] electron propagation. We numerically simulate this valley-separated Veselago lens effect in a lattice model and demonstrate that pseudo-gauge potentials can efficiently control valley separation patterns. PMID- 28820741 TI - Electromagnetic and optical characteristics of Nb5+-doped double-crossover and salmon DNA thin films. AB - We report the fabrication and physical characteristics of niobium ion (Nb5+) doped double-crossover DNA (DX-DNA) and salmon DNA (SDNA) thin films. Different concentrations of Nb5+ ([Nb5+]) are coordinated into the DNA molecules, and the thin films are fabricated via substrate-assisted growth (DX-DNA) and drop-casting (SDNA) on oxygen plasma treated substrates. We conducted atomic force microscopy to estimate the optimum concentration of Nb5+ ([Nb5+]O = 0.08 mM) in Nb5+-doped DX-DNA thin films, up to which the DX-DNA lattices maintain their structures without deformation. X-ray photoelectron spectroscopy (XPS) was performed to probe the chemical nature of the intercalated Nb5+ in the SDNA thin films. The change in peak intensities and the shift in binding energy were witnessed in XPS spectra to explicate the binding and charge transfer mechanisms between Nb5+ and SDNA molecules. UV-visible, Raman, and photoluminescence (PL) spectra were measured to determine the optical properties and thus investigate the binding modes, Nb5+ coordination sites in Nb5+-doped SDNA thin films, and energy transfer mechanisms, respectively. As [Nb5+] increases, the absorbance peak intensities monotonically increase until ~[Nb5+]O and then decrease. However, from the Raman measurements, the peak intensities gradually decrease with an increase in [Nb5+] to reveal the binding mechanism and binding sites of metal ions in the SDNA molecules. From the PL, we observe the emission intensities to reduce them at up to ~[Nb5+]O and then increase after that, expecting the energy transfer between the Nb5+ and SDNA molecules. The current-voltage measurement shows a significant increase in the current observed as [Nb5+] increases in the SDNA thin films when compared to that of pristine SDNA thin films. Finally, we investigate the temperature dependent magnetization in which the Nb5+-doped SDNA thin films reveal weak ferromagnetism due to the existence of tiny magnetic dipoles in the Nb5+-doped SDNA complex. PMID- 28820743 TI - Sleep apnea: a review of diagnostic sensors, algorithms, and therapies. AB - : While public awareness of sleep related disorders is growing, sleep apnea syndrome (SAS) remains a public health and economic challenge. Over the last two decades, extensive controlled epidemiologic research has clarified the incidence, risk factors including the obesity epidemic, and global prevalence of obstructive sleep apnea (OSA), as well as establishing a growing body of literature linking OSA with cardiovascular morbidity, mortality, metabolic dysregulation, and neurocognitive impairment. The US Institute of Medicine Committee on Sleep Medicine estimates that 50-70 million US adults have sleep or wakefulness disorders. Furthermore, the American Academy of Sleep Medicine (AASM) estimates that more than 29 million US adults suffer from moderate to severe OSA, with an estimated 80% of those individuals living unaware and undiagnosed, contributing to more than $149.6 billion in healthcare and other costs in 2015. Although various devices have been used to measure physiological signals, detect apneic events, and help treat sleep apnea, significant opportunities remain to improve the quality, efficiency, and affordability of sleep apnea care. As our understanding of respiratory and neurophysiological signals and sleep apnea physiological mechanisms continues to grow, and our ability to detect and process biomedical signals improves, novel diagnostic and treatment modalities emerge. OBJECTIVE: This article reviews the current engineering approaches for the detection and treatment of sleep apnea. APPROACH: It discusses signal acquisition and processing, highlights the current nonsurgical and nonpharmacological treatments, and discusses potential new therapeutic approaches. MAIN RESULTS: This work has led to an array of validated signal and sensor modalities for acquiring, storing and viewing sleep data; a broad class of computational and signal processing approaches to detect and classify SAS disease patterns; and a set of distinctive therapeutic technologies whose use cases span the continuum of disease severity. SIGNIFICANCE: This review provides a current perspective of the classes of tools at hand, along with a sense of their relative strengths and areas for further improvement. PMID- 28820744 TI - Simulation of morphologically structured photo-thermal neural stimulation. AB - OBJECTIVE: Rational design of next-generation techniques for photo-thermal excitation requires the development of tools capable of modeling the effects of spatially- and temporally-dependent temperature distribution on cellular neuronal structures. APPROACH: We present a new computer simulation tool for predicting the effects of arbitrary spatiotemporally-structured photo-thermal stimulation on 3D, morphologically realistic neurons. The new simulation tool is based on interfacing two generic platforms, NEURON and MATLAB and is therefore suited for capturing different kinds of stimuli and neural models. MAIN RESULTS: Simulation results are validated using photo-absorber induced neuro-thermal stimulation (PAINTS) empirical results, and advanced features are explored. SIGNIFICANCE: The new simulation tool could have an important role in understanding and investigating complex optical stimulation at the single-cell and network levels. PMID- 28820745 TI - Impact of Surgical Treatment for Recurrence After 2-Stage Hepatectomy for Colorectal Liver Metastases, on Patient Outcome. AB - OBJECTIVE: To evaluate the impact of repeat surgery for recurrence on the long term survival after 2-stage hepatectomy (TSH) for extensive colorectal liver metastases (CRLM). BACKGROUND: Although TSH is now deemed effective for selected patients with extensive bilobar CRLM, disease recurrence after TSH is very frequent because of the extensive tumor load. METHODS: Among a total cohort of 1235 patients who underwent hepatectomy for CRLM between 1992 and 2012, 139 with extensive bilobar CRLM were scheduled for TSH. Of these, 93 patients had completion of TSH and were enrolled in this study. RESULTS: The 5-year overall survival (OS) rate after TSH was 41.3%. Twenty-two patients (23.7%) had a concomitant extrahepatic disease (EHD), and curative resection of concomitant EHD was achieved in 13 patients. Among the 81 patients who achieved complete tumor removal for primary, CRLM, and concomitant EHD, 62 (76.5%) had recurrence. Repeat surgery was performed in 38 patients; 35 for recurrence after curative surgery and 3 for liver recurrence with unresected concomitant EHD or primary tumor. Of these 38 patients, 31 were salvaged. The patients who underwent repeat surgery had a significantly longer OS than those who did not (45.8% vs 26.3%; P = 0.0041). A multivariate analysis revealed that repeat surgery was an independent prognostic factor of the OS after TSH (hazard ratio 0.31, P = 0.0012). CONCLUSIONS: Repeat surgery for recurrence after TSH may be crucial for the long term survival in patients with extensive bilobar CRLM. Intensive oncosurgical surveillance is essential to avoid missing the chance for repeat surgery after TSH. PMID- 28820746 TI - No Effects of D-Cycloserine Enhancement in Exposure With Response Prevention Therapy in Panic Disorder With Agoraphobia: A Double-Blind, Randomized Controlled Trial. AB - PURPOSE/BACKGROUND: D-cycloserine (DCS) is a partial N-methyl-D-aspartate receptor agonist that potentially augments response to exposure therapy in anxiety disorders by enhancing extinction learning. This randomized, double blinded, placebo-controlled augmentation trial examined (1) the effectiveness of adding 125 mg of DCS to exposure therapy (before or directly after the first 6 treatment sessions) in patients with panic disorder with agoraphobia and (2) the effectiveness of DCS augmentation preceding exposure relative to DCS augmentation directly postexposure. METHODS/PROCEDURES: Fifty-seven patients were allocated to 1 of 3 medication conditions (placebo and pre-exposure and postexposure DCS) as an addition to 6 exposure sessions within a 12-session exposure and response prevention protocol. The primary outcome measure was the mean score on the "alone" subscale of the Mobility Inventory (MI). FINDINGS/RESULTS: No differences were found in treatment outcome between DCS and placebo, administered either pre exposure or postexposure therapy, although at 3-month follow-up, the DCS postexposure group compared with DCS pre-exposure, exhibited greater symptom reduction on the MI-alone subscale. Ancillary analyses in specific subgroups (responders vs nonresponders, early vs late responders, severely vs mildly affected patients) did not reveal any between-group DCS versus placebo differences. Finally, the study did not find an effect of DCS relative to placebo to be specific for successful exposure sessions. IMPLICATIONS/CONCLUSIONS: This study does not find an effect of augmentation with DCS in patients with severe panic disorder and agoraphobia administered either pretreatment or directly posttreatment sessions. Moreover, no preferential effects are revealed in specific subgroups nor in successful exposure sessions. Yet, a small effect of DCS administration postexposure therapy cannot be ruled out, given the relatively small sample size of this study. PMID- 28820747 TI - Involvement of hyperglycemia in the development of platelet procoagulant response: the role of aldose reductase and platelet swelling. AB - : Rise in mean platelet volume (MPV) has been demonstrated to be associated with increased platelet reactivity. In diabetes patients, augmented MPV was proposed to contribute to increased risk of thrombotic complications. Therefore, the aim of this study was to investigate whether under hyperglycemic conditions, aldose reductase (AR)-mediated sorbitol formation and associated rise in cell volume, which subsequently results in platelet hyperactivation. Platelets were obtained from 30 healthy volunteers and 13 patients with diabetes. We evaluated changes in platelet size, their reactivity (measured as aggregation and secretion), and sorbitol content evoked by glucose. Measurement of procoagulant activity and thromboelastography were performed to assess how hyperglycemia affects coagulation. We have found that incubation of platelets with glucose (>10 mmol/l) leads to increased MPV, potentiation of collagen-evoked platelet aggregation, secretion, and procoagulant response (measured as platelet-dependent thrombin generation and phosphatidylserine expression). Glucose-treated platelets had higher sorbitol content and demonstrated enhanced tubulin polymerization. All the above-mentioned phenomena were reduced following the blocking of AR or by vincristine (microtubule destabilizing agent). Thromboelastography measurements demonstrated that hyperglycemia is associated with reduction of clotting time (R) and increase in the alpha angle (reflects platelet activation). Addition of sorbinil (AR inhibitor) or vincristine normalized R variable and alpha angle. The hyperglycemic conditions may accelerate platelet-related thrombin generation through the activation of polyol pathway, enhanced tubulin polymerization and associated with it rise in platelet volume. PMID- 28820748 TI - Disclosure of Diagnosis in Early Recognition of Psychosis. AB - There is a debate concerning risks and benefits of early intervention in psychosis, especially concerning diagnosis disclosure. The present study reports preliminary findings on self-reported locus of control and psychological distress after the disclosure of diagnosis in an early recognition center. We compared the ratings of the locus of control and psychological distress before and after communication of diagnosis. The study included individuals with an at-risk mental state (ARMS) (n = 10), schizophrenia (n = 9), and other psychiatric disorders (n = 11). Results indicate greater endorsement of the internal locus of control in individuals with ARMS after communication of diagnosis in contrast to the other groups. Our results suggest that disclosure of diagnosis in an early recognition center leads to a reduction of psychological distress and increased feelings of control over one's health. Persons with ARMS seem to particularly benefit from disclosure of diagnosis as part of early intervention. PMID- 28820749 TI - Surgical Pathology of Gastrointestinal Stromal Tumors: Practical Implications of Morphologic and Molecular Heterogeneity for Precision Medicine. AB - Gastrointestinal stromal tumor (GIST), the most common mesenchymal neoplasm of the gastrointestinal tract, exhibits diverse histologic and clinical manifestations. With its putative origin in the gastrointestinal pacemaker cell of Cajal, GIST can arise in association with any portion of the tubular gastrointestinal tract. Morphologically, GISTs are classified as spindled or epithelioid, though each of these subtypes encompasses a broad spectrum of microscopic appearances, many of which mimic other histologic entities. Despite this morphologic ambiguity, the diagnosis of GIST is aided in many cases by immunohistochemical detection of KIT (CD117) or DOG1 expression. The natural history of GIST ranges from that of a tumor cured by surgical resection to that of a locally advanced or even widely metastatic, and ultimately fatal, disease. This clinicopathologic heterogeneity is paralleled by an underlying molecular diversity: the majority of GISTs are associated with spontaneous activating mutations in KIT, PDGFRA, or BRAF, while additional subsets are driven by genetic lesions-often inherited-of NF1 or components of the succinate dehydrogenase enzymatic complex. Specific gene mutations correlate with particular anatomic or morphologic characteristics and, in turn, with distinct clinical behaviors. Therefore, prognostication and treatment are increasingly dictated not only by morphologic clues, but also by accompanying molecular genetic features. In this review, we provide a comprehensive description of the heterogenous molecular underpinnings of GIST, including implications for the practicing pathologist with regard to morphologic identification, immunohistochemical diagnosis, and clinical management. PMID- 28820750 TI - The New Realization About Cribriform Prostate Cancer. AB - Data from the past 6 years have shown that the presence of any amount of cribriform (or more comprehensively, large acinar cribriform to papillary) pattern of invasive prostate cancer is associated with adverse pathologic features and leads to uniquely adverse outcomes. Sixteen papers and numerous abstracts have reached these conclusions concordantly. Not only does this justify removal of all cribriform cancer from Gleason grade 3, it shows that cribriform cancer has pathologic, outcome, and molecular features distinct from noncribriform Gleason grade 4. Suggestions for accommodating the presence of cribriform cancer into the 2014 Grade Group scheme are proposed. PMID- 28820752 TI - Antibiotic Combination Therapy for Patients With Gram-Negative Septic Shock. PMID- 28820753 TI - Prevention of Exposure Keratopathy in Critically Ill Patients: A Single-Center, Randomized, Pilot Trial Comparing Ocular Lubrication With Bandage Contact Lenses and Punctal Plugs. AB - OBJECTIVES: To compare the effectiveness of bandage contact lenses and punctal plugs with ocular lubricants in preventing corneal damage in mechanically ventilated and sedated critically ill patients. DESIGN: Single-center, prospective, randomized, pilot study. SETTING: Sixteen-bed, general ICU at a tertiary academic medical center. PATIENTS: Adults admitted to the ICU and anticipated to require mechanical ventilation and continuous sedation for greater than or equal to 4 days. INTERVENTIONS: Patients were randomized to receive eye care with ocular lubricants (n = 38), bandage contact lenses (n = 33), or punctal plugs (n = 33). The bandage contact lenses were changed every 4 days, whereas the punctal plugs remained in situ for the entire study. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the presence or absence of corneal damage as assessed by the grade of keratopathy. Patients were examined by an ophthalmologist blinded to the study group every 4 days and at the time of withdrawal from the study, due to cessation of sedation, discharge from the ICU, or death. The mean duration of the study was 8.6 +/- 6.2 days. The grade of keratopathy in the ocular lubricant group increased significantly in both eyes (p = 0.01 for both eyes) while no worsening was noted in either the lens or punctal plugs groups. In a post hoc analysis of patients with an initially abnormal ophthalmic examination, significant healing of keratopathy was noted in the lens group (p = 0.02 and 0.018 for left and right eyes, respectively) and in the right eye of the plugs group (p = 0.005); no improvement was noted in the ocular lubricant group. CONCLUSIONS: Compared with ocular lubrication, bandage contact lenses and punctal plugs were more effective in limiting keratopathy, and their use, particularly of bandage contact lenses, was associated with significant healing of existing lesions. PMID- 28820751 TI - Importance of PCR-based Tumor Testing in the Evaluation of Lynch Syndrome associated Endometrial Cancer. AB - Lynch syndrome (LS) is a hereditary cancer syndrome caused by a germline mutation in a DNA mismatch repair gene, usually MLH1, MSH2, MSH6, or PMS2. The most common cancers associated with LS are colorectal adenocarcinoma and endometrial carcinoma. Identification of women with LS-associated endometrial cancer is important, as these women and their affected siblings and children are at-risk of developing these same cancers. Germline testing of all endometrial cancer patients is not cost effective, and screening using young age of cancer diagnosis and/or presence of family history of syndrome-associated is underutilized and ineffective. Therefore, most groups now advocate for tumor tissue testing to screen for LS, with germline testing targeted to women with abnormal tissue testing results. Immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 is used in many clinical laboratories for this tumor screening step, as immunohistochemistry is relatively inexpensive and is technically more accessible for smaller clinical labs. PCR-based tissue testing, whereas technically more challenging, does play an important role in the identification of these patients. MLH1 methylation analysis identifies women with tumor MLH1 loss who likely have sporadic endometrial cancer and do not need heightened cancer prevention surveillance. High levels of microsatellite instability have been identified in tumors with retained positive expression of mismatch repair proteins. Somatic sequencing of mismatch repair genes from tumor DNA, whereas not currently available in most clinical laboratories, is helpful in resolution of cases in which germline sequencing fails to identify a mutation in a mismatch repair gene. The tumor tissue testing approach can help to identify most women at-risk for germline mutations in a LS gene, but not all patients will be captured using this approach. Clinical suspicion can still play a pivotal role in accurately identifying a subset of these patients. PMID- 28820754 TI - Sleep apps: what role do they play in clinical medicine? AB - PURPOSE OF REVIEW: Today's smartphones boast more computing power than the Apollo Guidance Computer. Given the ubiquity and popularity of smartphones, are we already carrying around miniaturized sleep labs in our pockets? RECENT FINDINGS: There is still a lack of validation studies for consumer sleep technologies in general and apps for monitoring sleep in particular. To overcome this gap, multidisciplinary teams are needed that focus on feasibility work at the intersection of software engineering, data science and clinical sleep medicine. SUMMARY: To date, no smartphone app for monitoring sleep through movement sensors has been successfully validated against polysomnography, despite the role and validity of actigraphy in sleep medicine having been well established. Missing separation of concerns, not methodology, poses the key limiting factor: The two essential steps in the monitoring process, data collection and scoring, are chained together inside a black box due to the closed nature of consumer devices. This leaves researchers with little room for influence nor can they access raw data. Multidisciplinary teams that wield complete power over the sleep monitoring process are sorely needed. PMID- 28820755 TI - Sleep complications following traumatic brain injury. AB - PURPOSE OF REVIEW: Recent research has provided extensive characterization as to the frequency and nature of sleep disturbances following traumatic brain injury (TBI). This review summarizes the current state of knowledge and proposes future directions for research. RECENT FINDINGS: Complaints of sleep disturbance are common following TBI, and objective assessments of sleep largely corroborate these complaints. Sleep is often disturbed in the acute phase postinjury and can persist for decades, with the prevalence of sleep disorders higher in patients with TBI as compared with the general population. The factors causing sleep disturbance appear to involve numerous interrelated primary and secondary factors, including direct damage to vital sleep-regulating regions of the brain, alterations in the circadian system, lowered mood as well as increased anxiety and pain. The complex web of contributing factors implies that combination therapies targeting a number of putative causal mechanisms may yield the greatest success in terms of improving sleep postinjury. SUMMARY: Sleep disturbance is a common consequence of TBI. Research is needed to ascertain the primary drivers of sleep disturbance postinjury to guide the development of targeted interventions. In the absence of a single mechanism, combination therapies may prove most fruitful. PMID- 28820756 TI - Telmesani Radiological Classification of the Location of the Vertical Segment of the Facial Nerve: Impact on Surgical Approach in Cochlear Implant Surgery. AB - OBJECTIVE: This study was conducted to establish a radiological classification of the location of the vertical segment of the facial nerve (VSFN) and to see if this has implications on the surgical technique needed to access the round window niche (RWN) in cochlear implant (CI) surgery. STUDY DESIGN: Observational case series study. SETTING: Tertiary referral center. PATIENTS: One hundred twenty seven patients underwent CI surgery, and high resolution computed tomography (HRCT) of 140 temporal bones was studied. The data that were collected consisted of the patient's age, sex, radiological inner ear malformations (IEM), and the surgical technique used to access the RWN. MAIN OUTCOME MEASURES: The radiologic location of the VSFN in relation to the lateral semicircular canal in the coronal plane of HRCT and its implication on the surgical approach used to access the RWN in CI surgery. RESULTS: A statistically significant association is present between the radiological location of the VSFN and the surgical approach used (p < 0.001).There was insignificant correlation between the locations of the VSFN and the patient's age, sex, and IEM as the p > 0.05. CONCLUSIONS: On HRCT (0.6 mm) in the coronal plane, the position of the VSFN in relation to the lateral semicircular canal is correlated with the alternative approaches that must be taken during CI surgery. PMID- 28820757 TI - Flipping the Nursing Classroom Without Flipping Out the Students. AB - Flipping the class has been touted as a method of increasing student participation and improving learning outcomes. In this study, nursing students were introduced to the flipped classroom. They were instructed to listen to narrated PowerPoint presentations before class and be ready to participate in case studies that would enhance their understanding of important concepts. When comparing student test scores before and after flipping the classroom, we found a statistically significant increase of 8.04 points after the change in instruction. Results support the hypothesis that a flipped classroom may improve learning outcomes. PMID- 28820758 TI - Lack of Association Between Interleukin 28B Polymorphism and Vertical Transmission of Hepatitis C. AB - OBJECTIVES: Single genetic nucleotide polymorphism (rs12979860) near the gene for interleukin 28B (IL28B) is known to be of importance for frequency of spontaneous clearance and treatment outcome in interferon-based therapies in patients with hepatitis C virus (HCV) infection. The aim of the present study was to investigate whether IL28B polymorphism in children and/or their mothers plays a role in vertical transmission of HCV (HCV-VT). METHODS: Plasma samples from 59 infected women, 76 uninfected children born to infected mothers, and 47 children with known vertically transmitted HCV infection, were analysed for IL28B polymorphism and classified by the IL28B genotype (C/C, C/T, and T/T) and by viral genotype. RESULTS: The proportion of children with genotype C/C was the same in the vertically infected (36%, 17/47) and the exposed uninfected children (38%, 29/76). No difference was seen when stratifying for viral genotype. There was no association between mothers' IL28B genotype and the risk of vertical transmission. CONCLUSIONS: Regardless of viral genotype we found no association between IL28B genotype and the risk of HCV-VT. The IL28B genotype CC, which has been shown to be favourable in other settings, was not protective of HCV-VT. Thus, other factors possibly associated with the risk of HCV-VT need to be explored. PMID- 28820759 TI - Thromboprophylaxis in Spinal Surgery. AB - STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: Determine the incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) in spinal surgery patients receiving no thromboprophylaxis, mechanoprophylaxis, and chemoprophylaxis. SUMMARY OF BACKGROUND DATA: The incidence of thromboembolic complications after spinal surgery is not well established. Although a variety of effective mechanical and chemical thromboprophylaxis interventions exist, their role in spinal surgery remains unclear. Spine surgeons are faced with the difficult decision of balancing the risk of death from a thromboembolic complication against the risk of permanent neurological damage from an epidural hematoma (EDH). METHODS: The Medline database was queried using combinations of the terms related to the aforementioned subject matter. Articles meeting our predetermined inclusion criteria were reviewed and relevant data extracted. Meta analyses were created using a random-effects model for incidence of DVT and PE by type of thromboprophylaxis, method of screening, and study type. RESULTS: Twenty eight articles were included in the final analyses. The higher mean incidence of DVT and PE in the mechanoprophylaxis group (DVT: 1%, PE: 0.81%) compared to the chemoprophylaxis group (DVT: 0.85%, PE: 0.58%) was not observed to be statistically significant. Six percent of PEs was fatal; the rate of EDHs was 0.3%. The incidence of DVT was higher in prospective studies (1.4%) compared to retrospective studies (0.61%); the incidence of DVT was not affected by whether the study screened only symptomatic patients. CONCLUSION: Although the incidence of DVT and PE was relatively low regardless of prophylaxis type, the true incidence is difficult to determine given the heterogeneous nature of the small number of studies available in the literature. Our findings suggest there may be a role for chemoprophylaxis given the relatively high rate of fatal PE. Future studies are needed to determine which patient population would benefit most from chemoprophylaxis. LEVEL OF EVIDENCE: 2. PMID- 28820760 TI - Theory-Driven Integrative Process/Outcome Evaluation of a Concept-Based Nursing Curriculum. AB - The study aim was to evaluate the effects of concept-based learning by comparing ATI Nursing Education test scores for a traditional curriculum and a concept based curriculum. The study also examined effects of the concept-based curriculum on critical thinking and motivation. No statistically significant differences were noted in ATI scores for the two groups; students neither agreed nor disagreed that they were engaged in critical thinking but did agree with motivation statements. Faculty were surveyed about their approach to teaching. PMID- 28820761 TI - Development and Evaluation of a Systems Thinking Education Strategy for Baccalaureate Nursing Curriculum: A Pilot Study. AB - Nurse educators are charged to develop and evaluate curricula on systems thinking to prepare future nurses to provide safe nursing care. The goal of this pilot study was to design and evaluate a four-hour educational strategy that prepares future professional nurses to use systems thinking approaches in the delivery of safe patient care. This study exposed prelicensure baccalaureate nursing students to systems thinking principles, which included didactic and experiential activities. A descriptive design was used to determine the effect of an on-campus educational strategy. A paired samples t-test revealed statistical significance from pretest to posttest. PMID- 28820762 TI - Collaborative Simulation: Enhancing the Transition to Clinical Practice. AB - Beginning nursing students typically report anxiety, low self-confidence, and difficulty transferring theoretical knowledge to the clinical setting prior to their first clinical experience. To address these issues, first-semester faculty in a prelicensure, undergraduate nursing program created a collaborative simulation experience (CSE). Implementation prior to the first clinical day provided real-life exposure to patient care, enhanced the transfer of knowledge, decreased anxiety, promoted self-confidence, and allowed faculty to identify students' strengths and weaknesses. Clinical faculty reported enhanced student performance following participation. PMID- 28820764 TI - SEVERE CASE OF RENAL COLOBOMA SYNDROME IN LONG-TERM FOLLOW-UP. AB - PURPOSE: To characterize the ocular features of a severe case of renal coloboma syndrome in a long-term follow-up. METHODS: Observational case report over a period of 45 years. Examination under anesthesia at the age of 3 months, repeated ophthalmologic examination (age 7, 14, 25, 45 years), fluorescein and indocyanine green angiography, electroretinography, ocular ultrasound, optical coherence tomography, computed tomography scan orbits, and magnetic resonance imaging of the brain. RESULTS: Presentation with severe bilateral posterior eye defects, optic nerve aplasia and a retrobulbar cyst in the left eye, renal abnormalities, and mental retardation. Over time, a progressive axial myopia in the right eye, band keratopathy in the left eye, and progressive bilateral posterior lens opacities were noted. There was only a minor decrease in visual acuity and visual field of the only functional right eye. The mother of this patient had a mild optic disk hypoplasia, progressive lens opacities, and late-onset renal disease. Both had a confirmed mutation in exon 2 of the PAX2 gene. CONCLUSION: This first published long-term follow-up of renal coloboma syndrome shows progressive posterior lens opacities, axial myopia, and band keratopathy with only a small decline in visual function over time. PMID- 28820763 TI - Concept Evaluation Using the PDSA Cycle for Continuous Quality Improvement. AB - As concept-based nursing education gains popularity, there is little literature on how to sustain quality after initiation of the curriculum. Critical appraisal of concepts in a university program revealed varying definitions, attributes, and exemplars resulting in student confusion. The Plan, Do, Study, Act (PDSA) cycle for continuous quality improvement was used for concept evaluation. The goals of the evaluation project were: 1) to develop common definition and attributes for concepts and 2) to develop horizontal and vertical leveling of exemplars to build on prior student learning. The continuous quality improvement process can be used to prevent "concept creep" and ensure internal consistency of concept definitions, attributes, and exemplars. PMID- 28820765 TI - Inespecific Macules in Legs: Challenge. PMID- 28820767 TI - Extensive Hyperkeratotic, Scaly Papules and Plaques in a 56-Year-Old Female: Answer. PMID- 28820766 TI - Subungual Pigmented Tumor With Onychodystrophy: Challenge. PMID- 28820768 TI - Inespecific Macules in Legs: Answer. PMID- 28820769 TI - A Subungual Pigmented Tumor With Onychodystrophy: Answer. PMID- 28820770 TI - Celebrating the 25th Anniversary of the International Association of Forensic Nurses. PMID- 28820771 TI - Sexual Violence Among College Students: An Examination of Individual and Institutional Level Factors Associated With Perpetration. AB - BACKGROUND: Sexual violence incidents involving college students have received media attention and increased awareness of this public health problem in the United States; prevention efforts are needed that target potential perpetrators. We examined characteristics of self-reported perpetrators of sexual violence on campuses. METHODS: This study used a secondary data analysis of the 2015 College Student Health Survey, an annual survey, which was completed by students attending 17 colleges/universities in Minnesota. The analytic sample included 6,548 18-to 24-year-old college students who answered at least one of two questions assessing perpetration in the past 12 months (i.e., sex/sexual touch without consent). Chi-square tests were used to detect associations between perpetration and individual (e.g., age, race, substance use, victimization) and institutional (e.g., school type, location) level characteristics. Multiple logistic regression analyses identified predictive models for being a perpetrator of sexual violence. RESULTS: Fifty-two students reported perpetration of sexual violence in the past year, including 29 rapes. Overall, self-reported perpetrators of sexual violence are more likely to be men, to have been a victim in his or her lifetime, to have smoked marijuana in the past 12 months (but not the past month), and to be younger (18 or 19 years old). Institutional level characteristics, including school type and location, did not yield significant associations with perpetration. DISCUSSION: Sexual violence prevention and response efforts toward college students need to be inclusive, especially targeting individual level factors, and considerate of the victimization perpetration comorbidity experienced by many students. PMID- 28820773 TI - Self-Care Management in Corrections: Perspectives From Persons With an Incarceration Experience. AB - The purpose of this study was to explore the perceptions and beliefs of what self care management looks like for a person with an incarceration experience. This is the first phase of a two-phase study. This qualitative study, held in three county jails in Massachusetts, utilized a focus group methodology. The Rediscovery of Self-Care: A Care Intervention for Persons with Incarceration Experience (RSC) model served as the framework for this study. On the basis of a priori constructs from the RSC model, a protocol was established and targeted questions outlined. The results from these focus groups support the constructs of the RSC model. Participants in all focus group interviews reported that self-care was very important and defined self-care, most of the time, in terms of meeting physical needs such as exercising and eating healthy and, more importantly, self identified mental health and substance use needs such as individual or group counseling. In conclusion, open-ended questions used to identify all instances of potential categories of self-care management supported the central concepts of the RSC model and will inform treatment interventions and modification of an existing self-care management instrument or provide the foundation for the development of a new instrument. PMID- 28820772 TI - The Individual Experience of Aging Patients and the Current Service Provision in the Context of Italian Forensic Psychiatry: A Case Study. AB - INTRODUCTION: After the recent development of residential units for the execution of security measures managed by the National Health Service and the closing down of forensic psychiatric hospitals, no study has been conducted to investigate the individual experience of aging patients and to assess whether the new service is adequately meeting their needs. We aimed to explore the experience of the service of a sample of patients aged 50 years and above living in one of the Italian residential units for the execution of security measures. METHODS: We adopted a case study design and included a sample of five patients. We collected their basic demographic data, administered the Camberwell Assessment Needs Forensic Short Version and carried out in-depth qualitative semi-structured interviews. RESULTS: Results from the Camberwell Assessment Needs Forensic Short Version evidenced that met needs were more prevalent than unmet needs. The qualitative interviews demonstrated high levels of satisfaction around accommodation, healthcare provision, activities, availability of benefits and company, and lower levels of satisfaction around psychological and practical support. DISCUSSION: This study gave voice to aging forensic psychiatric patients and provided through personal accounts, based on their lived experience, preliminary evidence around the benefits and limitations of the Italian residential forensic psychiatric system for this age group. Implications for clinical nursing forensic practitioners operating within different service frameworks are discussed. PMID- 28820774 TI - The Experience of Litigation From the Perspective of Midwives in Iran. AB - INTRODUCTION: Errors and notices to appear in court are a reality of life for many midwives and exert significant effects on both their professional and personal lives. Given the increasing population policies in place, this study was conducted to examine midwives' experiences of litigation in Iran. METHODS: A qualitative study was conducted in 2014 using an interpretive phenomenological approach. The interviews were recorded and transcribed and were then analyzed using the Diekelmann method. FINDINGS: Midwives who participated had professional experience ranging from 3 to 22 years at the time of the complaints. Five participants had received more than one complaint, and 10 participants were judged as guilty creating/leaving significant effects on various dimensions of their lives. CONCLUSION: The present research disclosed four main themes from the interviews including feeling ruined by the complaints, being conflicted between denial and belief, having shattered hopes of release, and experiencing the slowed down rhythm of midwifery. From these, a basic pattern of "living in despair" was extracted. Litigation is a painful experience for midwives. Anxiety regarding compensation for the patients' losses, public judgment, prolonged litigations, and undermined professional dignity create physical and psychological ramifications for these midwives. Negative feelings about litigation, compounded by the lack of legal support from the authorities, cause a sense of hopelessness regarding the future of the midwifery profession. PMID- 28820776 TI - Joint Position Statement: Care of Prepubescent Pediatric Sexual Abuse Patients in the Emergency Care Setting. PMID- 28820775 TI - The Doctrine of Deliberate Indifference: Reed vs. Krajca. AB - Facts of the Reed v. Krajca case are presented in which plaintiffs filed a lawsuit for civil damages under the doctrine of deliberate indifference and defendant, Nurse Krajca, invoked qualified immunity in a motion for summary judgment. The Court of Appeal's decision and the dissenting opinion on the issue of deliberate indifference are discussed. This case report provides a concrete example of how the doctrine of deliberate indifference was interpreted by the Court of Appeal and becomes a springboard for analysis and discussion for nurses to guide their practice. PMID- 28820777 TI - Sexual Violence among College Students: An Examination of Individual- and Institutional-Level Factors Associated with Perpetration. PMID- 28820778 TI - Src Kinase Inhibition Attenuates Morphine Tolerance without Affecting Reinforcement or Psychomotor Stimulation. AB - BACKGROUND: Prolonged opioid administration leads to tolerance characterized by reduced analgesic potency. Pain management is additionally compromised by the hedonic effects of opioids, the cause of their misuse. The multifunctional protein beta-arrestin2 regulates the hedonic effects of morphine and participates in tolerance. These actions might reflect u opioid receptor up-regulation through reduced endocytosis. beta-Arrestin2 also recruits kinases to u receptors. We explored the role of Src kinase in morphine analgesic tolerance, locomotor stimulation, and reinforcement in C57BL/6 mice. METHODS: Analgesic (tail withdrawal latency; percentage of maximum possible effect, n = 8 to 16), locomotor (distance traveled, n = 7 to 8), and reinforcing (conditioned place preference, n = 7 to 8) effects of morphine were compared in wild-type, u, u, and beta-arrestin2 mice. The influence of c-Src inhibitors dasatinib (n = 8) and PP2 (n = 12) was examined. RESULTS: Analgesia in morphine-treated wild-type mice exhibited tolerance, declining by day 10 to a median of 62% maximum possible effect (interquartile range, 29 to 92%). Tolerance was absent from mice receiving dasatinib. Tolerance was enhanced in u mice (34% maximum possible effect; interquartile range, 5 to 52% on day 5); dasatinib attenuated tolerance (100% maximum possible effect; interquartile range, 68 to 100%), as did PP2 (91% maximum possible effect; interquartile range, 78 to 100%). By contrast, c-Src inhibition affected neither morphine-evoked locomotor stimulation nor reinforcement. Remarkably, dasatinib not only attenuated tolerance but also reversed established tolerance in u mice. CONCLUSIONS: The ability of c-Src inhibitors to inhibit tolerance, thereby restoring analgesia, without altering the hedonic effect of morphine, makes c-Src inhibitors promising candidates as adjuncts to opioid analgesics. PMID- 28820780 TI - Clinical Effectiveness of Intravenous Exenatide Infusion in Perioperative Glycemic Control after Coronary Artery Bypass Graft Surgery: A Phase II/III Randomized Trial. AB - BACKGROUND: We aimed to assess the clinical effectiveness of intravenous exenatide compared to insulin in perioperative blood glucose control in coronary artery bypass grafting surgery patients. METHODS: Patients more than 18 yr old admitted for elective coronary artery bypass grafting were included in a phase II/III nonblinded randomized superiority trial. Current insulin use and creatinine clearance of less than 60 ml/min were exclusion criteria. Two groups were compared: the exenatide group, receiving exenatide (1-h bolus of 0.05 ug/min followed by a constant infusion of 0.025 ug/min), and the control group, receiving insulin therapy. The blood glucose target range was 100 to 139 mg/dl. The primary outcome was the proportion of patients who spent at least 50% of the study period within the target range. The consumption of insulin (Cinsulin) and the time to start insulin (Tinsulin) were compared between the two groups. RESULTS: In total, 53 and 51 patients were included and analyzed in the exenatide and control groups, respectively (age: 70 +/- 9 vs. 68 +/- 11 yr; diabetes mellitus: 12 [23%] vs. 10 [20%]). The primary outcome was observed in 38 (72%) patients in the exenatide group and in 41 (80%) patients in the control group (odds ratio [95% CI] = 0.85 [0.34 to 2.11]; P = 0.30). Cinsulin was significantly lower (60 [40 to 80] vs. 92 [63 to 121] U, P < 0.001), and Tinsulin was significantly longer (12 [7 to 16] vs. 7 [5 to 10] h, P = 0.02) in the exenatide group. CONCLUSIONS: Exenatide alone at the dose used was not enough to achieve adequate blood glucose control in coronary artery bypass grafting patients, but it reduces overall consumption of insulin and increases the time to initiation of insulin. PMID- 28820782 TI - Foreword. PMID- 28820781 TI - Inadvertent Endotracheal Cuff Hyperinflation Diagnosed by Magnetic Resonance Imaging. PMID- 28820783 TI - Epidemiology of Obesity in the Hispanic Adult Population in the United States. AB - Obesity is a major health concern in Hispanic populations. This study evaluated the epidemiology of obesity and associated factors among Hispanics using the data from the 2013-2014 National Health and Nutrition Examination Survey. Among the 1241 participants (20 years of age or older), the prevalence rates were as follows: overweight, 77.1%; obesity, 42.4%; and central obesity, 57.0%. These rates were consistent throughout most age groups. Significantly, more females than males were obese. Higher obesity rates were seen among those with diabetes, high cholesterol, hypertension, heart disease, and arthritis. Those born in the United States were more likely to be obese. Effective obesity prevention programs are vital for this population. PMID- 28820784 TI - Impact of Targeted Education on Colorectal Cancer Screening Knowledge and Psychosocial Attitudes in a Predominantly Hispanic Population. AB - Colorectal cancer remains a leading cause of cancer-related morbidity and mortality, with screening behavior found to be influenced by knowledge and other psychosocial attitudes. We recruited 784 participants 50 to 70 years of age. The intervention arm received a culturally sensitive, literacy-appropriate educational intervention by a promotora. Surveys were completed at baseline and 6 months post. Our intervention significantly increased knowledge at 6 months when compared with control (0.74 vs 0.18, P < .0001). We also report increase in perceived susceptibility to colorectal cancer and perceived benefits of colorectal cancer screening while decreasing sense of fatalism. Perceived barriers to screening did significantly increase. PMID- 28820785 TI - Collective Efficacy, Physical Activity, and Health Outcomes Among Mothers. AB - Motherhood is associated with low rates of physical activity that increase disease risk. Most theory-based approaches to increasing physical activity focus on personal rather than social factors. The purpose of this study was to examine the associations among perceptions of community collective efficacy and objectively measured physical activity, self-efficacy, social support, and health. Mothers completed questionnaires and wore a pedometer for 7 days. There was a significant, positive association between physical activity and collective efficacy-social cohesion subscale. In the regression analysis, only age and social support were independent predictors of physical activity. Future studies should examine relationships among collective efficacy and social support and physical activity. PMID- 28820786 TI - Models of Care Delivery for Patients With Parkinson Disease Living in Rural Areas. AB - The elderly who suffer from chronic conditions have an increasingly difficult time accessing health care in rural areas compared with their healthy counterparts who seek and utilize less specialty care. Parkinson disease affects approximately 0.3% to 5% of the elderly population. However, a large portion of that population has difficulty accessing health care. The purpose of this study was to obtain an understanding of the access to care issues for patients with Parkinson disease and review solutions to aid their provision of care. A review of the literature found several models of care available to improve access to care issues for patients with Parkinson disease. PMID- 28820787 TI - The Relationship Between Parental and Child Physical Activity in a Rural Community. AB - This study examined the relationship between parental and child physical activity (PA) in a rural community. Forty-one children and at least 1 parent wore pedometers to measure step count over the course of 4 days. Parents also completed a PA survey assessing parental support for PA, parental enjoyment for PA, perceived importance of PA, and their own PA levels. Parental PA level and mothers' support for PA were moderately associated with their child's PA levels. Thus, future PA promotion efforts could focus on encouraging parents, primarily mothers, to be more active to help improve their child's PA levels. PMID- 28820788 TI - Community Health Workers and the Management of Noncommunicable Diseases Among Rural Health Clinics in Limpopo Province, South Africa: A Pilot Study. AB - South Africa's rise in noncommunicable diseases (NCDs) and health care provider shortages has generated the need for community health workers (CHWs) in rural areas. However, roles and interactions with clinic staff are not well understood. Interviews with health care workers at community clinics in Limpopo Province revealed common themes, including resource scarcity, clinic-patient partnerships, management of NCDs, and collaboration between professionals. The data did not support CHW-physician interactions, necessitating further research to describe these practices and to evaluate CHWs' impact on patient outcomes. The CHW involvement in rural clinics is essential to patient-clinic partnerships and may help close treatment gaps in resource-poor areas. PMID- 28820789 TI - Suicide, Resilience, and Connectedness Across the Lifespan: Lessons From American Indian and Alaska Native Elders. AB - Rates of suicide and associated costs are high and increasing in the United States. From 1999 through 2014, the age-adjusted suicide rate increased 24%, with the pace of increase being greater since 2006. American Indian and Alaska Native persons have significantly lower rates of suicides than other ethnic groups as elders despite experiencing some of the highest rates during adolescence. This article examines literature pertaining to suicide rates in American Indian and Alaska Native communities and proposes a framework for understanding their lower rates of suicide as elders. Such understanding offers opportunities for developing strategies for suicide prevention across lifespan. PMID- 28820790 TI - Associations of Immigration Transition to Cardiovascular Symptoms Experienced in Menopausal Transition. AB - The purpose of this study was to explore the associations of immigration transition to cardiovascular symptoms among 4 major racial/ethnic groups of 1054 midlife women in the United States. This was a secondary analysis of the data from 2 large national survey studies. The instruments included questions on background characteristics and immigration transition and the Cardiovascular Symptom Index for Midlife Women. The data were analyzed using inferential statistics including hierarchical multiple regressions. Immigrants reported fewer numbers (t = 5.268, P < .01) and lower severity scores (t = 5.493, P < .01) of cardiovascular symptoms compared with nonimmigrants. Self-reported racial/ethnic identify was a significant factor influencing cardiovascular symptoms (P < .01). PMID- 28820792 TI - Corneal Endothelial Dystrophy Associated With Myotonic Dystrophy: A Report of 2 Cases. PMID- 28820791 TI - Teleophthalmic Approach for Detection of Corneal Diseases: Accuracy and Reliability. AB - PURPOSE: Corneal and anterior segment diseases cause most of the urgent visits to eye care professionals. We evaluated the diagnostic accuracy of detecting corneal diseases using external photographs from 2 portable cameras for telemedicine purposes. METHODS: This is a prospective study of adults with a clinical diagnosis of corneal pathology including corneal abrasions, ulcers, scars, and pterygia. A cornea specialist provided the gold standard diagnosis by slit-lamp examination. Images of both eyes were obtained using iTouch 5S and Nidek VersaCam cameras in multiple gazes and interpreted by 3 cornea specialists for the presence of pathology. Accuracy to detect disease was compared with gold standard diagnosis, stratified by the camera and grader. Reliability was evaluated with weighted kappa statistics. Graders assessed image quality on a Likert scale from 1 (poor) to 9 (optimal). RESULTS: A total of 198 eyes (110 subjects) were photographed. By gold standard diagnosis, 59 eyes (30%) had corneal scars, 34 (17%) had ulcers, 13 (7%) had abrasions, 10 (5%) had pterygia, and 82 (41%) were normal. Sensitivity to detect AS pathology ranged from 54% to 71% for the iTouch and 66% to 75% for the Nidek, across graders; specificity ranged from 82% to 96% for the iTouch and 91% to 98% for the Nidek. The intergrader reliability was moderate to strong (kappa ranges: 0.54-0.71 for the iTouch; 0.75-0.76 for the Nidek). Quality ratings were variable between graders. CONCLUSIONS: External photographs taken by standard, nonenhanced portable cameras and interpreted remotely by ophthalmologist graders yielded sensitivity values that are not yet suitable for telemedicine applications. Additional work is needed to improve the ability to detect AS pathology remotely. PMID- 28820793 TI - Codeine Plus Acetaminophen for Pain After Photorefractive Keratectomy: A Randomized, Double-Blind, Placebo-Controlled Add-On Trial. AB - BACKGROUND: Pain after photorefractive keratectomy (PRK) is significant, and the analgesic efficacy and safety of oral opioids in combination with acetaminophen has not been fully investigated in PRK trials. PURPOSE: To assess the efficacy and safety of the combination of codeine plus acetaminophen (paracetamol) versus placebo as an add-on therapy for pain control after PRK. STUDY DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Single tertiary center. METHODS: One eye was randomly allocated to the intervention, whereas the fellow eye was treated with a placebo. Eyes were operated 2 weeks apart. The participants were adults older than 20 years with refractive stability for >=1 year, who underwent PRK for correction of myopia or myopic astigmatism. Codeine (30 mg) plus acetaminophen (500 mg) was given orally 4 times per day for 4 days after PRK. The follow-up duration was 4 months. The study outcomes included pain scores at 1 to 72 hours, as measured by the visual analog scale, McGill Pain Questionnaire, and Brief Pain Inventory, as well as adverse events and corneal wound healing. RESULTS: Of the initial 82 eyes, 80 completed the trial (40 intervention, 40 placebo). Median (interquartile range) pain scores as measured by the visual analog scale were statistically and clinically lower during treatment with codeine/acetaminophen compared with the placebo: 1 hour: 4 (2-4) versus 6 (3-6), P < 0.001; 24 hours: 4 (3-6) versus 7 (6-9), P < 0.001; 48 hours: 1 (0-2) versus 3 (2-5), P < 0.001; and 72 hours: 0 (0-0) versus 0 (0-2), P = 0.001. Virtually identical results were obtained by the McGill Pain Questionnaire and Brief Pain Inventory scales. The most common adverse events with codeine/acetaminophen were drowsiness (42%), nausea (18%), and constipation (5%). No case of delayed epithelial healing was observed in both treatment arms. CONCLUSIONS: When added to the usual care therapy, the oral combination of codeine/acetaminophen was safe and significantly superior to the placebo for pain control after PRK. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02625753. PMID- 28820794 TI - Anterior Chamber Gas Fill After DMEK. PMID- 28820795 TI - Reply. PMID- 28820796 TI - Provider Approachability: An All-staff Survey Approach to Creating a Culture of Safety. AB - OBJECTIVES: A culture-of-safety survey of our hospital staff revealed fear-based reluctance to question those in authority. We aimed to examine provider approachability (words and actions that promote trust and reduce or eliminate fear of interaction). METHODS: Providers and staff completed an anonymous facility-wide survey (survey 1) regarding perceptions of provider approachability. Results were safely communicated to providers, and improvement resources were offered. A follow-up survey (survey 2 [S2]) was performed. RESULTS: The survey participation rate was 59% (389/658). Eighty-four percent of providers had improved scores in S2. Mean top-box scores improved from 0.63 to 0.76 (P < .001). Providers deemed less approachable by nonprovider staff were also deemed less approachable by their peers (r = 0.82; survey 1). Forty-four percent reported improvement in the safety culture in S2. Twenty-eight percent of providers reported making efforts to improve how they were perceived by others. CONCLUSIONS: Provider approachability surveys are a safe, effective method of assessing and encouraging positive interactions that promote trust and influence positive communication. The process created an opportunity to identify and assist providers who were less approachable. PMID- 28820797 TI - Postoperative renal dysfunction after noncardiac surgery. AB - PURPOSE OF REVIEW: The narrative review aims to discuss recent results and important knowledge gaps regarding acute kidney injury (AKI) in postoperative patients undergone major noncardiac surgery. RECENT FINDINGS: Postoperative AKI affects approximately one-fifth of patients after major surgery, but the incidence varies according to the type of surgery. Preexisting chronic kidney disease is a major risk factor for postoperative AKI. It carries a substantial risk for postoperative adverse outcomes, as well as long-term mortality and morbidity. To prevent postoperative AKI, avoiding intraoperative hypotension and hypoperfusion as well as nephrotoxic substances are important. Currently, no efficient pharmacotherapy for prevention or treatment of AKI is available. In general, goal-directed management protocols have reduced the incidence of postoperative AKI. Additionally, a restrictive fluid management regimen might reduce organ edema and be beneficial also for the kidney function. SUMMARY: AKI is a frequent postoperative complication with a substantial risk for both short and long-term adverse events, and its incidence is likely to rise because of increasing major surgical procedures. Studies investigating better strategies to prevent and treat AKI in this population are urgently needed. PMID- 28820798 TI - How to better identify patients at high risk of postoperative complications? AB - PURPOSE OF REVIEW: Preoperative risk assessment and perioperative factors may help identify patients at increased risk of postoperative complications and allow postoperative management strategies that improve patient outcomes. This review summarizes historical and more recent scoring systems for predicting patients with increased morbidity and mortality in the postoperative period. RECENT FINDINGS: Most prediction scores predict postoperative mortality with, at best, moderate accuracy. Scores that incorporate surgery-specific and intraoperative covariates may improve the accuracy of traditional scores. Traditional risk factors including increased ASA physical status score, emergent surgery, intraoperative blood loss and hemodynamic instability are consistently associated with increased mortality using most scoring systems. SUMMARY: Preoperative clinical risk indices and risk calculators estimate surgical risk with moderate accuracy. Surgery-specific risk calculators are helpful in identifying patients at increased risk of 30-day mortality. Particular attention should be paid to intraoperative hemodynamic instability, blood loss, extent of surgical excision and volume of resection. PMID- 28820799 TI - Regional anesthesia and analgesia after surgery in ICU. AB - PURPOSE OF REVIEW: The aim is to demonstrate that ICU physicians should play a pivotal role in developing regional anesthesia techniques that are underused in critically ill patients despite the proven facts in perioperative and long-term pain, organ dysfunction, and postsurgery patient health-related quality of life improvement. RECENT FINDINGS: Regional anesthesia and/or analgesia strategies in ICU reduce the surgical and trauma-stress response in surgical patients as well as complications incidence. Recent studies suggested that surgical/trauma ICU patients receive opioid-hypnotics continuous infusions to prevent pain and agitation that could increase the risk of posttraumatic stress disorder and chronic neuropathic pain symptoms, and chronic opioid use. Regional anesthesia use decrease the use of intravenous opioids and the ectopic activity of injured small fibers limiting those phenomena. In Cochrane reviews and prospective randomized trials in major surgery patients, regional anesthesia accelerates the return of the gastrointestinal transit and rehabilitation, decreases postoperative pain and opioids use, reduces ICU/hospital stay, improves pulmonary outcomes, including long period of mechanical ventilation and early extubation, reduces overall adverse cardiac events, and reduces ICU admissions when compared with general anesthesia and intravenous opiates alone. The reduction of long-term mortality has been reported in major vascular or orthopedic surgeries. SUMMARY: Promoting regional anesthesia/analgesia in ICU surgical/trauma patients could undoubtedly limit the risk of complications, ICU/hospital stay, and improve patient's outcome. The use of regional anesthesia permits a high doses opioid use limitation which is mandatory and should be considered as feasible and well tolerated in ICU. PMID- 28820800 TI - Regional Anesthesia "Block Rooms": Should They Be Universal? Look to Goldilocks (and Her 3 Bears) for the Answer. PMID- 28820801 TI - Precise Anatomical Targeting: Location, Location, Location! PMID- 28820802 TI - Antioxidation Role of Different Lateral Stellate Ganglion Block in Isoproterenol Induced Acute Myocardial Ischemia in Rats. AB - BACKGROUND AND OBJECTIVES: To determine whether stellate ganglion block (SGB) treatment exerts protective effects against isoproterenol (ISO)-induced acute myocardial ischemia (AMI) due to its antioxidant effects, we aimed to evaluate the protective effects of different lateral SGB agents on the tissue antioxidant status in ISO-induced AMI in male Sprague-Dawley rats. METHODS: The AMI model received an acute ISO overdose to make cardiac ischemia damage at a single dose of 110 mg/kg injected subcutaneously into the rats. The rats in the SGB groups received SGB 15 minutes after ISO treatment. The data were recorded at the following time points: 0 minutes (T0) and 15 minutes after SGB (T1). The levels of cardiac troponin T and cardiac troponin I and the ST-segment depression in lead III were measured at T0 and T1. The values of oxidative production and antioxidative enzymes in the SG and heart were tested. RESULTS: Stellate ganglion block significantly reduced serum cardiac troponin I and cardiac troponin T levels and mitigated the ST-segment depression and oxidative production levels, but it increased the antioxidative enzymes levels. Right SGB effect was more effective than that of left SGB, in the reduced nitric oxide and malonaldehyde levels, and in the increased superoxide dismutase, glutathione peroxidase, catalase, neuronal nitric oxide synthase, and endothelial nitric oxide synthase levels. CONCLUSIONS: These findings suggest that SGB could have antioxidative effects against AMI, and the protective effect of right SGB was more effective than that of left SGB. Thus, the right SGB could be an effective and safe method of local anesthesia to protect against cardiac damage due to oxidative stress. PMID- 28820803 TI - Perioperative Breast Analgesia: A Qualitative Review of Anatomy and Regional Techniques. AB - Breast surgery is exceedingly common and may result in significant acute as well as chronic pain. Numerous options exist for the control of perioperative breast pain, including several newly described regional anesthesia techniques, but anesthesiologists have an insufficient understanding of the anatomy of the breast, the anatomic structures disrupted by the various breast surgeries, and the theoretical and experimental evidence supporting the use of the various analgesic options. In this article, we review the anatomy of the breast, common breast surgeries and their potential anatomic sources of pain, and analgesic techniques for managing perioperative pain. We performed a systematic review of the evidence for these analgesic techniques, including intercostal block, epidural administration, paravertebral block, brachial plexus block, and novel peripheral nerve blocks. PMID- 28820804 TI - Anterior Approach to the Suprascapular Nerve. PMID- 28820805 TI - The Case for Thinking Beyond Classic Randomized Controlled Trial Design: A Response to "Distinguishing Between Efficacy and Real-World Effectiveness". PMID- 28820806 TI - Asleep Versus Awake and Standard of Care. PMID- 28820807 TI - Reply to Dr Neal et al. PMID- 28820808 TI - Reply: Why Women Request Labiaplasty. PMID- 28820809 TI - Reply: Intraoperative Comparison of Anatomical versus Round Implants in Breast Augmentation: A Randomized Controlled Trial. PMID- 28820811 TI - Blood Congestion Can Be Rescued by Hemodilution in a Random-Pattern Skin Flap. PMID- 28820810 TI - Role of Mitomycin C in Preventing Capsular Contracture in Implant-Based Reconstructive Breast Surgery: A Randomized Controlled Trial. PMID- 28820812 TI - High-Resolution Magnetic Resonance Imaging of Aging Upper Face Fat Compartments. PMID- 28820813 TI - Reply: Role of Mitomycin C in Preventing Capsular Contracture in Implant-Based Reconstructive Breast Surgery: A Randomized Controlled Trial. PMID- 28820814 TI - Reply: Medial Row Perforators Are Associated with Higher Rates of Fat Necrosis in Bilateral DIEP Flap Breast Reconstruction#8232. PMID- 28820815 TI - Direct-to-Implant Breast Reconstruction without the Use of an Acellular Dermal Matrix Is Cost Effective and Oncologically Safe. PMID- 28820816 TI - Should Immediate Autologous Breast Reconstruction Be Considered in Women Who Require Postmastectomy Radiation Therapy? A Prospective Analysis of Outcomes. PMID- 28820817 TI - Why Women Request Labiaplasty. PMID- 28820818 TI - Reply: Blood Congestion Can Be Rescued by Hemodilution in a Random-Pattern Skin Flap. PMID- 28820819 TI - Response of letter to the Editor on: High-Resolution Magnetic Resonance Imaging of Aging Upper Face Fat Compartments. PMID- 28820820 TI - Reply: The Impact of Two Operating Surgeons on Microsurgical Breast Reconstruction. PMID- 28820821 TI - Application of Posterior Thigh Three-Dimensional Profunda Artery Perforator Perforasomes in Refining Next-Generation Flap Designs: Transverse, Vertical, and S-Shaped Profunda Artery Perforator Flaps. PMID- 28820822 TI - The Impact of Two Operating Surgeons on Microsurgical Breast Reconstruction. PMID- 28820823 TI - Response to Letter by Dr. Ciancio to PRS manuscript 170529. PMID- 28820824 TI - Medial Row Perforators Are Associated with Higher Rates of Fat Necrosis in Bilateral DIEP Flap Breast Reconstruction. PMID- 28820826 TI - Reply: Simplifying the Forehead Flap for Nasal Reconstruction: A Review of 420 Consecutive Cases. PMID- 28820827 TI - Enoxaparin Dosing and the Prevention of Venous Thromboembolism in Plastic Surgery Patients. PMID- 28820828 TI - Reply: Primary Septal Cartilage Graft for the Unilateral Cleft Rhinoplasty. PMID- 28820829 TI - Primary Septal Cartilage Graft for the Unilateral Cleft Rhinoplasty. PMID- 28820830 TI - Intraoperative Comparison of Anatomical versus Round Implants in Breast Augmentation: A Randomized Controlled Trial. PMID- 28820831 TI - Incorporation of Perfluorocarbons into Fat Graft May Improve Oxygenation. PMID- 28820832 TI - Simplifying the Forehead Flap for Nasal Reconstruction: A Review of 420 Consecutive Cases. PMID- 28820833 TI - The Social Media Scrub-In. PMID- 28820834 TI - Superthin SCIP Flap for Reconstruction of Subungual Melanoma: Aesthetic Functional Surgery. AB - BACKGROUND: This study aimed to use a superthin, free superficial circumflex iliac artery perforator (SCIP) flap in functional surgery for treating subungual melanoma and to evaluate its outcomes. METHODS: Forty-one patients with primary subungual melanoma of less than or equal to 2-mm thickness who were treated with functional surgery were prospectively enrolled. After oncologic resection, a thin SCIP flap was harvested along the trans-superficial fat layer and transferred to the defect with further thinning by primary defatting. Complications and oncologic outcomes were investigated. Postoperative functional status was assessed, using the Quick Disabilities of the Arm, Shoulder and Hand questionnaire for finger cases and the Foot Function Index for toe cases, and was compared with that of patients treated with amputation. RESULTS: The SCIP flap was inset with a final thickness ranging from 1.5 to 4 mm after defatting. Total flap failure occurred in one patient. Complete wound healing was achieved within 3 weeks postoperatively in most cases (90.2 percent). The majority of patients achieved satisfactory contour without needing secondary debulking. Two recurrences developed during a mean follow-up period of 31 months: one local recurrence and one in-transit recurrence. The 3-year disease-free survival was 97.1 percent. Mean scores for the Quick Disabilities of the Arm, Shoulder and Hand questionnaire and the Foot Function Index following functional surgery were significantly lower than those following amputation. CONCLUSION: The superthin SCIP flap might serve as a valuable reconstruction option, providing aesthetically thin coverage and reliable outcomes, in functional surgery for treating early-stage subungual melanoma. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28820835 TI - Simultaneous Stiles-Bunnell Tendon Transfer Enhances Intrinsic Function of Second Toe Transplantations. AB - : Claw finger is a sequela of fingers without intrinsic function. Claw toe deformity is common after toe transfer, as simultaneous intrinsic reconstruction has yet to be reported in the literature. The authors present their experience of simultaneous tendon transfer during second-toe transplantation. Seven second-toe transfers were performed in five metacarpal-like and metacarpal hands. The Stiles Bunnell tendon transfer was incorporated into toe transfers. Toe lumbrical tendons were repaired to the flexor digitorum sublimis of the same recipient digit. The active motion values of the proximal interphalangeal joint were 61 +/- 9.5 degrees and 36 +/- 6.4 degrees in the middle and ring fingers, respectively. The extension lag overall was 19.9 +/- 9.9 degrees. The transferred toe proximal interphalangeal joints had minimal extensor lag with the metacarpophalangeal joint in flexion position. The flexion sweep of the toe was improved by the intrinsic reconstruction. The patients were able to use the transferred toes for sophisticated daily activities. From the results seen, simultaneous intrinsic reconstruction appears to enhance the dexterity and thus function of transferred toes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28820836 TI - The Surgeon's Fist with the Thumb Up to Guide the Design and Inset of the Osteoseptocutaneous Fibula Flap in Mandibular Reconstruction. AB - Successful reconstruction of an oromandibular defect with the osteoseptocutaneous fibula flap necessitates flawless design and inset, which is an experience demanding endeavor. Laterality of the fibula flap has been thought to pose a certain challenge to reconstruction. To address this concern and guide flap design and inset, the authors proposed using the surgeon's fist with the thumb up to replicate key anatomical landmarks of the fibula flap: the peroneal vessels and proximal bone end, and the posterior crural septum including the septal vessels, the skin, and the lateral surface of the fibula bone. This method facilities recipient vessels selection and skin paddle design, orientation, and inset to avoid complications regardless of laterality. PMID- 28820837 TI - Noncontrast Magnetic Resonance Lymphography for Evaluation of Lymph Node Transfer for Secondary Upper Limb Lymphedema. AB - BACKGROUND: The authors' purpose was to evaluate the results of axillary lymph node transplantation with noncontrast magnetic resonance lymphography in 15 patients with secondary upper limb lymphedema. METHODS: Fifteen female patients with lymphedema following breast cancer treatment underwent lymph node transplantation. Noncontrast magnetic resonance lymphography was obtained with a free-breathing three-dimensional fast spin-echo sequence. Image analysis included criteria both before surgery (i.e., severity of lymphedema graded as absent, mild, moderate, or severe; involvement of the muscular compartment; and distal dilated lymphatic vessels) and after surgery (i.e., visualization of the site of transplantation; visualization of transplanted lymph nodes; and severity of lymphedema with regard to pretransplantation severity, namely, improvement, stability, or aggravation). Clinically, circumferential measures were performed at four different levels. RESULTS: Follow-up magnetic resonance examinations were performed at least 6 months after lymph node transplantation, with a longest follow-up time of 42 months. In two patients, no lymphedema was visualized before lymph node transplantation with magnetic resonance lymphography. In the other 13 patients, lymphedema was mild in four patients, moderate in five patients, and severe in the other four patients. After lymph node transplantation, an improvement of upper limb lymphedema was observed in seven of nine patients with moderate or severe upper limb lymphedema. In the 11 patients in whom comparison of magnetic resonance lymphography with circumferential measurement was available, evaluations were concordant in 10 cases. CONCLUSION: Noncontrast magnetic resonance lymphography may be used as an objective technique to analyze the results of lymph node transplantation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28820838 TI - Five-Year Follow-Up of Midface Distraction in Growing Children with Syndromic Craniosynostosis. AB - BACKGROUND: Maxillary position in patients with syndromic craniosynostosis after midface distraction has been shown to be stable 1 year postoperatively. The purpose of this study is to assess midfacial position in the growing child with craniosynostosis 5 years after Le Fort III advancement with a rigid external device. METHODS: Seventeen consecutive patients were identified to have the diagnosis of syndromic craniosynostosis and had undergone midface advancement [corrected]. There were 10 boys and seven girls, seven patients had Crouzon syndrome, five had Apert syndrome, and five had Pfeiffer syndrome. A standard subcranial Le Fort III osteotomy was performed. Cephalometric analysis was performed to assess the position of the maxilla. RESULTS: After device removal, orbitale advanced 13.67 mm along the x axis and downward 1.70 mm along the y axis. The A point advanced 15.97 mm along the x axis and downward 1.14 mm along the y axis. At 1 year after distraction, both orbitale and A point had advanced an additional 0.47 mm and 0.24 mm along the x axis and downward 0.58 mm and 1.78 mm along the y axis, respectively. At 5 years after distraction, the orbitale moved posterior 0.58 mm and the A point advanced an additional 2.08 mm along the x axis. Orbitale and A point descended 3.23 mm and 5.2 mm along the y axis, respectively. CONCLUSION: After Le Fort III advancement with distraction, the maxillary position remains stable and continues to advance minimally along the x axis and demonstrates more growth along the y axis over the long term. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 28820840 TI - Discussion: Five-Year Follow-Up of Midface Distraction in Growing Children with Syndromic Craniosynostosis. PMID- 28820839 TI - Smaller Diameter Anastomotic Coupling Devices Have Higher Rates of Venous Thrombosis in Microvascular Free Tissue Transfer. AB - BACKGROUND: Smaller anastomotic coupling devices may increase the risk of complications in free flap reconstructions; however, the relationship between coupler size and venous thrombosis rates has not been adequately evaluated. The authors hypothesized that smaller diameter coupling devices are associated with higher rates of venous thrombosis than larger diameter devices in free tissue transfer. METHODS: The authors reviewed a prospectively maintained database for all patients who underwent microsurgical free tissue transfer at their institution from 2001 to 2013. The primary outcome measured was venous thrombosis, and the primary objective was to assess the relationship between venous coupler diameter and the rate of venous thrombosis. The secondary objective was to compare venous thrombosis rates between coupled and hand-sewn venous anastomoses. RESULTS: A total of 5643 consecutive free flap reconstructions were evaluated; 3257 (57.7 percent) had coupled venous anastomoses. The 1.5-mm-diameter coupler had an overall thrombosis rate of 6.9 percent, significantly higher than that of all other coupler sizes (p = 0.04). In multivariable regression with generalized estimating equations analysis, both use of a 1.5-mm coupler (OR, 7.75; 95 percent CI, 3.20 to 18.76; p < 0.0001) and preoperative radiation therapy (OR, 1.62; 95 percent CI, 1.04 to 2.52; p = 0.03) were significant independent predictors of venous thrombosis. CONCLUSIONS: The authors found a significantly higher rate of venous thrombosis with the 1.5-mm diameter coupler than with larger diameter devices or hand-sewn venous anastomoses. This evidence suggests that surgeons should choose an outflow vessel that does not require a coupler diameter smaller than 2.0 mm or perform a hand sewn anastomosis in situations where this is not possible. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28820841 TI - Oblique Osteotomy for the Correction of the Zigzag Deformity of Wassel Type IV Polydactyly. AB - BACKGROUND: Surgical treatment of Wassel type IV thumb polydactyly is technically challenging, especially when it has a zigzag deformity. However, the authors obtained good operative results by performing oblique osteotomy with autologous fat graft in 30 patients. METHODS: After removal of the extra digit, the radially deviated distal phalanx was corrected by performing oblique osteotomy at the proximal phalanx. Free fat tissue was grafted to the areas with soft-tissue deficiency. Surgical outcomes were evaluated in terms of the thumb length ratio compared to the normal counterpart, the angulation between the proximal phalanx and the distal phalanx, and the Tada score. As a negative control, the data of 46 type IV polydactyly patients without a significant axis deviation were evaluated. RESULTS: The thumb length ratio was maintained from 0.96 +/- 0.06 preoperatively to 1.01 +/- 0.07 4-year postoperatively. The angulation improved from 30.84 +/- 14.78 degrees to 11.03 +/- 7.67 degrees. In comparison, the length ratio and angulation of the control group changed from 0.97 +/- 0.04 to 0.98 +/- 0.02, and from 19.46 +/- 8.27 degrees to 14.10 +/- 6.61 degrees, respectively. The Tada scores were 5.3 +/- 0.88 in the oblique osteotomy group and 6.59 +/- 0.62 in the control group, both of which were graded as good. CONCLUSIONS: Oblique osteotomy with autologous fat graft is a good surgical option for treating the Wassel type IV polydactyly with zigzag deformity. This technique allows sufficient axis correction without bone shortening, and it provides adequate soft-tissue contouring. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 28820842 TI - Upper Extremity Innervation Patterns and Clinical Implications for Nerve and Tendon Transfer. AB - BACKGROUND: The authors previously studied the intramuscular innervation of 150 upper limb muscles and demonstrated that certain patterns of intramuscular innervation allowed muscles to be split into compartments with independent function. This study aims to determine the location, extramuscular course, and number of motor nerve branches of upper limb peripheral nerves. The authors want to combine this information with their previous work to create a blueprint of upper limb neuromuscular anatomy that would be useful in reconstructive surgery. METHODS: Ten fresh frozen cadaveric upper limbs were dissected. The origin of branches from the peripheral nerve trunk, their course, and the number of motor nerves per muscle were determined. The authors reviewed all the images of the Sihler-stained muscles from their earlier study. RESULTS: Motor nerve branches arise at the intersection of nerve trunk and muscle belly and are clustered near the origin of muscle groups. Two patterns of extramuscular innervation were noted, with one group having a single motor nerve and another group with consistently more than one motor nerve. A modified classification of muscles was proposed based on the orientation of muscle fibers to the long axis of the limb, the number of muscle compartments, and the number of heads of origin or the tendons of insertion. CONCLUSIONS: Motor nerve clusters can be located based on fixed anatomical landmarks. Muscles with multiple motor nerves have morphology that allows them to be split into individual compartments. The authors created a muscle and nerve blueprint that helps in planning nerve and split muscle transfers. PMID- 28820843 TI - Cephalometric Predictors of Clinical Severity in Treacher Collins Syndrome. AB - BACKGROUND: The aim of this study was to identify cephalometric measurements associated with clinical severity in patients with Treacher Collins syndrome. METHODS: A retrospective single-institution review of patients with Treacher Collins syndrome was conducted. Preoperative cephalograms and computed tomographic scans (n = 30) were evaluated. Fifty cephalometric measurements were compared to age-specific normative data using analysis of variance. These cephalometric measurements and the patient's Pruzansky classification were correlated to clinical severity using Spearman analysis. Clinical severity was defined as severe (required tracheostomy), moderate (obstructive sleep apnea, oral cleft, or gastrostomy-tube), or mild (absence of listed comorbidities). Cephalometric measurements with a strong correlation (r > 0.60) were identified as predictors of clinical severity. RESULTS: Cephalograms of the study population contained 30 measurements that were found to be significantly different from normative data (p < 0.01). These measurements were related largely to maxillary/mandibular projection, maxillary/mandibular plane angle, mandibular morphology, facial height, facial convexity, and mandible/throat position. Ten of these 30 statistically significant measurements in addition to Pruzansky classification were found to be strongly correlated (r > 0.60) to clinical severity. These measurements include the following: mandibular projection/position (sella-nasion-pogonion, r = -0.64; hyoid-menton, r = -0.62); posterior facial height (posterior facial height/anterior facial height, r = 0.60; condyle-gonion, r = -0.66); maxillary/mandibular plane angle (sella-nasion mandibular plane, r = 0.62; Frankfort horizontal-mandibular plane, r = 0.61; sella-nasion-palatal plane, r = 0.69; sella-nasion-symphysis, r = -0.69); and Pruzansky classification (r = 0.82). CONCLUSION: Specific cephalometric measurements of increased mandibular retrognathia, decreased posterior facial height, more obtuse maxillary/mandibular plane angle and more obtuse symphysis notch angle are strongly correlated to increased clinical severity in patients with Treacher Collins syndrome. PMID- 28820844 TI - A New Method for Reconstruction of Vermilion Deficiency in Cleft Lip Deformity: The Bi-Winged Myomucosa Switch Flap. AB - BACKGROUND: This study reviewed the method of using the bi-winged myomucosa switch flap for correction of secondary cleft lip deformity in patients with vermilion mucosa deficiency, lack of the central tubercle, and disproportionate lip projection, obviating the conventional Abbe flap when the prolabium has acceptable philtrum and Cupid's bow definition. METHODS: The technique was applied to adult patients with secondary vermilion deficiency after primary bilateral cleft lip repair. The flap consisted of the transverse vermilion mucosa and the superior part of the orbicularis oris muscle from the lower lip. It was elevated, leaving a central cuff of muscle and mucosa tissue for blood supply, and tapered down bilaterally. The flap was transposed cephalically and inset to the deficient upper vermilion. Division of the pedicle was performed 2 weeks later. The preoperative and postoperative vermilion heights were measured, and the upper-to-lower vermilion ratios were calculated. RESULTS: All consecutive patients tolerated the operations without perioperative or flap complications. The vermilion discrepancy was corrected in all cases. The vermilion height and projection were improved in the upper lip and the prominent lower lip was reduced. The average vermilion ratio was 0.38 before and improved to 1.00 after surgery, as compared with the norm of 0.96. Adequate lip function and mobility were maintained. All patients expressed satisfaction after surgery. CONCLUSION: The described technique of bi-winged myomucosa switch flap is an effective method for reconstruction of upper lip vermilion deficiency with excellent aesthetic outcome. PMID- 28820845 TI - Concomitant Panniculectomy Affects Wound Morbidity but Not Hernia Recurrence Rates in Abdominal Wall Reconstruction: A Propensity Score Analysis. AB - BACKGROUND: Studies of abdominal wall reconstruction with concurrent panniculectomy have reported contradictory results. The authors hypothesized that patients undergoing abdominal wall reconstruction with concurrent panniculectomy experience more wound healing complications but similar rates of hernia recurrence compared with abdominal wall reconstruction alone. METHODS: Of 548 consecutive patients, 305 patients (55.7 percent) underwent abdominal wall reconstruction alone and 243 (44.3 percent) underwent abdominal wall reconstruction with concurrent panniculectomy. Mean follow-up was 30 months. The authors compared these two groups' postoperative complications and outcomes before and after propensity score analysis. RESULTS: Abdominal wall reconstruction with concurrent panniculectomy patients had a significantly higher overall complication rate (38.3 percent versus 29.2 percent; p = 0.025) and a trend toward a higher surgical-site occurrence rate (27.6 percent versus 20.7 percent; p = 0.06) compared with abdominal wall reconstruction alone. There were significantly higher incidences of skin dehiscence (19.3 percent versus 12.5 percent; p = 0.032), fat necrosis (10.7 percent versus 3.6 percent; p = 0.002), and infection abscess (9.5 percent versus 4.3 percent; p = 0.023) but no significant difference in hernia recurrence (6.9 percent versus 11.5 percent; p = 0.27) at long-term follow-up. Propensity score analysis yielded 188 pairs of matched patients with no significant differences in overall complication and hernia recurrence rates. Significantly higher rates of fat necrosis (9.6 percent versus 4.3 percent; p = 0.041) and abscess (10.1 percent versus 3.2 percent; p = 0.007) were observed in the abdominal wall reconstruction with concurrent panniculectomy group. CONCLUSIONS: Abdominal wall reconstruction with concurrent panniculectomy is associated with higher wound morbidity but similar surgical site occurrence and hernia recurrence rates at long-term follow-up. The authors believe that panniculectomy can be safely performed when indicated. PMID- 28820846 TI - Noninvasive Assessment of Skeletal Muscle Myosin Heavy Chain Expression in Trained and Untrained Men. AB - Fry, AC, Housh, TJ, Cramer, JB, Weir, JP, Beck, TW, Schilling, BK, Miller, JD, and Nicoll, JX. Noninvasive assessment of skeletal muscle myosin heavy chain expression in trained and untrained men. J Strength Cond Res 31(9): 2355-2362, 2017-Numerous conditions and types of physical activity (e.g., exercise, aging, and muscle-related diseases) can influence muscle fiber types and the proteins expressed. To date, muscle fibers can only be characterized by actually obtaining a tissue sample using the invasive muscle biopsy procedure. Mechanomyography (MMG) is the assessment of the vibration properties of contracting skeletal muscle and has been proposed as a possible noninvasive method for muscle fiber analysis. Therefore, the purpose of this project was to examine the feasibility of using MMG and muscle performance measures to noninvasively assess muscle fiber characteristics. Fifteen men (5 endurance-trained, 5 weight-trained, and 5 sedentary) provided muscle samples from their vastus lateralis muscle. These samples were analyzed for relative myosin heavy chain (MHC) protein expression, which is highly correlated with % muscle fiber type areas. Additionally, each subject performed several muscle performance tests, and MMG of the quadriceps was assessed during a knee extension exercise. Multiple regression was used to develop prediction equations for determining relative muscle content of MHC types I, IIa, and IIx. A combination of MMG and knee extension performance variables estimated types I, IIa, and IIx MHCs with approximately 80% accuracy. Although preliminary, these data suggest that muscle performance tests in addition to MMG assessments during a simple muscle performance task (knee extension) can be used to estimate muscle fiber type composition in a healthy male population. Such methods could ultimately be used to noninvasively monitor muscle health and fitness. PMID- 28820848 TI - RANIBIZUMAB AND AFLIBERCEPT FOR THE TREATMENT OF PIGMENT EPITHELIAL DETACHMENT IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: Data from an Observational Study. AB - PURPOSE: To assess the effect of intravitreal ranibizumab and aflibercept on retinal pigment epithelial detachment (RPED) in patients with neovascular age related macular degeneration. METHODS: This was a retrospective analysis of data from a prospectively designed and implemented clinical audit. Analysis included change in RPED dimensions and visual acuity in 92/233 treatment-naive eyes with neovascular age-related macular degeneration and RPED 6 months after treatment with either aflibercept or ranibizumab. RESULTS: There was no significant between group difference in the adjusted mean change for maximum RPED height (P = 0.195), diameter (P = 0.522) or visual acuity (P = 0.836) at 6 months. Injection frequency was the only clinical variable that affected RPED height (P = 0.050) and visual acuity change for both treatment groups (P = 0.004). Around 30% of eyes in each group had complete resolution of RPED at 6 months. CONCLUSION: Eyes with neovascular age-related macular degeneration and RPED showed significant functional and anatomical responses after 6 months of intravitreal anti-vascular endothelial growth factor injections. However, we found no significant difference in anatomical response or change in visual acuity between eyes treated with ranibizumab compared with aflibercept. Larger, prospectively designed, randomized studies with longer term follow-up may identify a difference between the two drugs that we did not detect. PMID- 28820847 TI - Effectiveness of a 16-Week High-Intensity Cardioresistance Training Program in Adults. AB - Greenlee, TA, Greene, DR, Ward, NJ, Reeser, GE, Allen, CM, Baumgartner, NW, Cohen, NJ, Kramer, AF, Hillman, CH, and Barbey, AK. Effectiveness of a 16-week high-intensity cardioresistance training program in adults. J Strength Cond Res 31(9): 2528-2541, 2017-The purpose of this study was to determine the efficacy of a novel, 16-week high-intensity cardioresistance training (HICRT) program on measures of aerobic fitness, agility, aerobic power, muscular endurance, lower body explosive power, and self-reported activity level. The intervention group (N = 129; 63 f, 24.65 +/- 5.55 years) had a baseline V[Combining Dot Above]O2max of 39.83 +/- 9.13. These individuals participated in 26, 70-minute exercise sessions, and 4 fitness testing sessions. Participants were matched with a nonexercise control group, paired by sex, age, and baseline V[Combining Dot Above]O2max. Matched controls (N = 129, 63 f, 24.26 +/- 5.59 years) had a baseline V[Combining Dot Above]O2max of 39.86 +/- 8.59 and completed preintervention and postintervention V[Combining Dot Above]O2max testing only. The results demonstrate that participants in the fitness intervention group significantly increased their V[Combining Dot Above]O2max (2.72 +/- 0.31, Mdiff +/- SE; p < 0.001) and reported being more physically active (0.42 +/- 0.11, Mdiff +/- SE; p < 0.001) after the intervention. The matched control group showed no significant pre-post intervention changes. Participants in the fitness intervention showed a significant improvement in 3 of 5 components of the fitness field tests. Specifically, significant improvements were observed for the 1 minute rower (5.32 +/- 0.505, Mdiff +/- SE; p < 0.001), 1-minute push-up (8.168 +/- 0.709, Mdiff +/- SE; p < 0.001), and 1.5-mile run tests (1.79 +/- 0.169, Mdiff +/- SE; p < 0.001). No significant improvements were observed for the shuttle run (p = 0.173) or standing long jump (p = 0.137). These findings demonstrate the efficacy of a novel, HICRT intervention across multiple dimensions of fitness for young- and middle-aged adults. High-intensity cardioresistance training affords flexibility for tailoring to meet desired health and fitness outcomes and makes perceivably daunting high-intensity functional training and multimodal sports training more accessible to general, traditionally nonathletic, populations. PMID- 28820849 TI - Correspondence. PMID- 28820850 TI - ULTRASONOGRAPHIC FINDINGS IN THE VITREOUS OF PATIENTS WITH AGE-RELATED MACULAR DEGENERATION TREATED WITH INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR INJECTIONS. AB - PURPOSE: We aimed to assess the relationship of repeated intravitreal injection of anti-vascular endothelial growth factor, the main treatment for exudative age related macular degeneration, with changes in vitreous ultrasonographic findings in patients with age-related macular degeneration. METHODS: We retrospectively collected data from 41 patients (41 age-related macular degeneration eyes, 41 control eyes) on age, sex, number of injections, and type of anti-vascular endothelial growth factor (ranibizumab, aflibercept). Ocular ultrasonography was performed with open eyelids, under topical anesthesia, and using carbomers as ultrasonographic gel. Topographic, quantitative, and kinetic ultrasonography was performed in all eye quadrants using a 10-MHz posterior pole probe, and vitreous reflectivity was assessed. RESULTS: The mean age of patients was 79 (range: 59 94) years, with a mean of five intravitreal anti-vascular endothelial growth factor injections (range: 1-13). No significant ultrasonographic differences were found relative to the incidence of partial or complete posterior vitreous detachment. Vitreous hyperechogenicity increased in the treated eye (P < 0.001), and the vitreous reflectivity range increased with the number of injections (P = 0.041, R = 0.214). However, the type of anti-vascular endothelial growth factor used and the time elapsed since the last intravitreal injection was not significant (P > 0.05). CONCLUSION: These preliminary results indicate a proportional increase in ultrasonographic reflectivity of vitreous gel with the number of injections. PMID- 28820851 TI - Correspondence. PMID- 28820852 TI - Reply. PMID- 28820853 TI - Reply. PMID- 28820854 TI - A Brief Review of Handgrip Strength and Sport Performance. AB - Cronin, J, Lawton, T, Harris, N, Kilding, A, and McMaster, DT. A brief review of handgrip strength and sport performance. J Strength Cond Res 31(11): 3187-3217, 2017-Tests of handgrip strength (HGS) and handgrip force (HGF) are commonly used across a number of sporting populations. Measures of HGS and HGF have also been used by practitioners and researchers to evaluate links with sports performance. This article first evaluates the validity and reliability of various handgrip dynamometers (HGD) and HGF sensors, providing recommendations for procedures to ensure that precise and reliable data are collected as part of an athlete's testing battery. Second, the differences in HGS between elite and subelite athletes and the relationships between HGS, HGF, and sports performance are discussed. PMID- 28820855 TI - Resistance exercise order does not affect the magnitude and duration of post exercise blood pressure in older women. AB - The aim of this study was to compare the effects of two resistance exercise order on post-exercise blood pressure (BP) in trained, non-hypertensive older women. Sixteen women (68.3 +/- 3.3 years, 63.5 +/- 11.6 kg, 157.5 +/- 5.1 cm) performed two sessions witheight exercises (3 sets of 8-12 repetitions) in distinct orders (from multi- to single-joint exercises [MS] or from single- to multi-joint exercises [SM]) and a control session, without exercise. Blood pressure and heart rate were obtained pre and post-sessions (60 min). Post-exercise hypotension was observed for systolic and mean BP in both the MS session (systolic BP: -6.9 mmHg, mean BP: -3.3 mmHg, P< 0.05) and SM session (systolic BP: -4.6 mmHg; mean BP: 1.1 mmHg). Post-exercise heart rate was higher than pre-session values until 30 min of recovery in both training sessions. Furthermore, systolic and mean blood pressure, and heart rate were lower than the values obtained in the control session (30 to 60 min and 0 min, respectively; P<0.05). There were no differences between the SM and MS sessions in any variable or at any moment. In conclusion, resistance exercise order does not interfere in the magnitude and duration of post-exercise hypotension in trained, non-hypertensive older women. PMID- 28820856 TI - Perceived Wellness Associated With Practice And Competition In Ncaa Division I Football Players. AB - The present study assessed the influence of movement demands resulting from weekly practice sessions and games, on perceived wellness measurements taken post game (Sunday) and 48 hours pre-game (Thursday) throughout the in-season period in National Collegiate Athletic Association (NCAA) division I football players. Thirty players were monitored using GPS receivers (Catapult Innovations OptimEye S5, Melbourne, Australia) during 12 games and 24 in-season practices. Movement variables included low-intensity distance, medium-intensity distance, high intensity distance, sprint distance, total distance, player load, and acceleration and deceleration distance. Perceived wellness, including fatigue, soreness, sleep quality and quantity, stress, and mood, was examined using a questionnaire on a 1-5 Likert scale. Multi-level mixed linear regressions determined the differential effects of movement metrics on perceived wellness. Post-hoc tests were conducted to evaluate the pair-wise differentials of movement and significance for wellness ratings. Notable findings included significantly (p<0.05) less player load, low-intensity distance, medium-intensity distance, high-intensity distance, total distance, and acceleration and deceleration distance at all intensities, in those reporting more favorable (4-5) ratings of perceived fatigue and soreness on Sunday. Conversely, individuals reporting more favorable Sunday perceived stress ratings demonstrated significantly (p<0.05) higher player load, low-intensity and medium-intensity distance, total distance, low-intensity and medium-intensity deceleration distance, and acceleration distance at all intensities than individuals reporting less favorable (1-2) perceived stress ratings. Data from the present study provide a novel investigation of perceived wellness associated with college football practice and competition. Results support the use of wellness questionnaires for monitoring perceived wellness in NCAA division I college football players. PMID- 28820857 TI - Kinematic And Neuromuscular Measures Of Intensity During Plyometric Jumps. AB - The aim of this study was to assess jumping performance and neuromuscular activity in lower limb muscles after drop jumps (DJ) from different drop heights (intensity) and during continuous jumping (fatigue), using markers such as reactive strength, jump height, mechanical power and surface electromyography (sEMG). The eccentric (EC) and concentric (CON) sEMG from the medial gastrocnemius (MG), biceps femoris (BF) and rectus (R) muscles were assessed during all tests. In a cross-sectional, randomized study, eleven volleyball players (age 24.4+/-3.2 years) completed 20 to 90-cm (DJ20 to DJ90) drop jumps and a 60-s continuous jump test. A one-way ANOVA test was used for comparisons, with Sidak post-hoc. The alpha level was <0.05. Reactive strength was greater for DJ40 compared to DJ90 (p<0.05; ES: 1.27). Additionally jump height was greater for DJ40 and DJ60 compared to DJ20 (p<0.05; ES: 1.26 and 1.27, respectively). No clear pattern of neuromuscular activity appeared during DJ20 to DJ90: some muscles showed greater, lower, or no change with increasing heights for both agonist and antagonist muscles, as well as for eccentric and concentric activity. Mechanical power, but not reactive strength, was reduced in the 60-s jump test (p<0.05; ES: 3.46). No changes were observed in sEMG for any muscle during the eccentric phase nor for the R muscle during the concentric phase of the 60-s jump test. However, for both MG and BF, concentric sEMG was reduced during the 60-s jump test (p<0.05; ES: 5.10 and 4.61, respectively). In conclusion, jumping performance and neuromuscular markers are sensitive to DJ height (intensity), although not in a clear dose-response fashion. In addition, markers such as mechanical power and sEMG are especially sensitive to the effects of continuous jumping (fatigue). Therefore, increasing the drop height during DJ does not ensure a greater training intensity and a combination of different drop heights may be required to elicit adaptations. PMID- 28820858 TI - Technical and tactical aspects in Italian youth rugby union in relation to different academies, regional tournaments, and outcomes. AB - This study aimed to analyze the technical and tactical aspects of the Italian under-18 Academy Rugby Union in relation to different academies, regional tournaments, and game outcomes. A notational analysis (forty-four indicators) was performed on 16 games (2014-15 season) to evaluate strong differences (P <= 0.05; moderate-large effect sizes) according to variables. Among academies, strong differences were showed for defensive breakdown where the defending support is much (range=77-87%), equal (range=11-32%), and less (range=2-12%) numerous than the attacking support, total tackles (range=64-122) and passes (range=72-151), pass to possession ratio (range=6-10), possession lost due to an error (range=28 59%), and ball in play in own (range=8-25%) and opponent (range=7-31%) 22m area indicators. For tournaments, effects emerged for offensive breakdown when the ball is used quickly employing maximum 2 attacking supports (range=20-30%) and is not used quickly (range=28-41%), total penalty kicks (range=11-16), and sequences period 0-10 (range=26-35%) and 10-40 s (range=47-55%). Conversely, winning and losing academies reported differences with small effect sizes. These results highlight that the technical and tactical aspects of the Italian under-18 Academy Rugby Union are quite homogeneous, suggesting that FIR coaching staffs are more oriented to players' skills than successful games. However, tactical, and strength and conditioning coaches can benefit from the findings of this study, focusing training on cognitive, strength, and repeated sprint abilities with and without change of direction for improving the occurrence of "set pieces won/regained" and "ball in play in opponent 22m area", which appear as the key of the game in this rugby competition level. PMID- 28820859 TI - "It's not an Obvious Issue, Is It?" Office-Based Employees' Perceptions of Prolonged Sitting at Work: A Qualitative Study. AB - OBJECTIVE: Current UK workplace health promotion guidance recommends that employers minimize sedentary behaviors, but understanding the issues relating to prolonged workplace sitting has received little empirical attention. This study aimed to explore employees' perceptions of sitting time. METHODS: Participants at a small to medium-sized UK company were invited to join one of five focus groups. A framework analysis approach was used. RESULTS: Self-reported mean estimate of occupational sitting time was 6.4 hours/day with a mean estimate of leisure time sitting 6.5 hours/nonwork days. The study highlighted employees' lack of appreciation of the health risks associated with sedentary behavior. CONCLUSION: This study has highlighted that in addition to personal determinants, the workplace environment and organizational culture have a key role in supporting employees' potential adoption of healthier sitting behavior in the workplace. PMID- 28820860 TI - Not Extent of Telecommuting, But Job Characteristics as Proximal Predictors of Work-Related Well-Being. AB - OBJECTIVES: This study aimed to investigate the curvilinear relationship between extent of telecommuting and work-related well-being (ie, burnout, work engagement, and cognitive stress complaints), as well as to test whether job characteristics act as explanatory mechanisms underlying this relationship. METHODS: A sample of 878 employees from an international telecommunication company with a long history of telecommuting participated in a survey on psychosocial risk factors and well-being at work. Mediation path analyses were conducted to test the hypotheses. RESULTS: Social support from colleagues, participation in decision-making, task autonomy, and work-to-family conflict, but not extent of telecommuting, were directly related to work-related well-being. Extent of telecommuting was indirectly related to well-being via social support. CONCLUSION: Employers should invest in creating good work environments in general, among both telecommuters and nontelecommuters. PMID- 28820861 TI - Association of Poultry Processing Industry Exposures With Reports of Occupational Finger Amputations: Results of an Analysis of OSHA Severe Injury Report (SIR) Data. AB - OBJECTIVE: This analysis was conducted to identify industry exposures strongly associated with reports of finger amputation. METHODS: Reports of severe occupational injuries in the Occupational Safety and Health Administration (OSHA) Severe Injury Report (SIR) database were analyzed in relation to U.S. Census Bureau industry employment data. Industries with significantly elevated reporting odds ratios (RORs) and relative reporting risks (RRRs) were identified. Multiple population association measures including population attributable fraction (PAF) were calculated by industry. RESULTS: Among industries with statistically significant RRR and ROR, the poultry processing industry (RRR = 12.60, ROR = 3.37) accounted for the highest PAF by RRR (2.34%) and ROR (1.65%) CONCLUSION:: The results of this analysis identify the poultry processing industry as a leading source of reports of occupational finger amputations and substantiate the need for further collaboration with this industry. PMID- 28820863 TI - Improvements in Resilience, Stress, and Somatic Symptoms Following Online Resilience Training: A Dose-Response Effect. AB - OBJECTIVE: To determine if participation in an online resilience program impacts resilience, stress, and somatic symptoms. METHODS: Approximately 600 enrollees in the meQuilibrium resilience program received a series of brief, individually prescribed video, and text training modules in a user-friendly format. Regression models tested how time in the program affected change in resilience from baseline and how changes in resilience affected change in stress and reported symptoms. RESULTS: A significant dose-response was detected, where increases in the time spent in training corresponded to greater improvements in resilience. Degree of change in resilience predicted the magnitude of reduction in stress and symptoms. Participants with the lowest resilience level at baseline experienced greater improvements. CONCLUSION: Interaction with the online resilience training program had a positive effect on resilience, stress, and symptoms in proportion to the time of use. PMID- 28820862 TI - Shiftwork and the Retinal Vasculature Diameters Among Police Officers. AB - OBJECTIVE: To investigate associations of central retinal arteriolar equivalent (CRAE), a measure of retinal arteriolar width, and central retinal venular equivalents (CRVE), a measure of retinal venular width, with shiftwork in 199 police officers (72.9% men). METHODS: Shiftwork (day, afternoon, night) was assessed using electronic payroll records. Four digital retinal images per officer were taken. Mean diameters of the retinal vasculature were compared across shifts using analysis of variance (ANOVA)/analysis of covariance (ANCOVA). RESULTS: Among all officers (mean age = 46.6 +/- 6.8 years), shiftwork was not significantly associated with CRAE or CRVE. However, among current and former smokers, night-shift officers had a wider mean (+/-standard error [SE]) CRVE (230.0 +/- 4.5 MUm) compared with day shift officers (215.1 +/- 3.5 MUm); adjusted P = 0.014. CONCLUSIONS: Night shift schedule in current and former smokers is associated with wider retinal venules. Reasons for this association are not known. Longitudinal studies are warranted. PMID- 28820864 TI - Diffusion Kurtosis Imaging and Pathology in Spinal Cord Ischemia/Reperfusion Injury in Rabbits: A Case-Control Study. AB - BACKGROUND The aim of this study was to evaluate the application of diffusion kurtosis imaging (DKI) in spinal cord ischemia/reperfusion (SCI/R) injury and to explore its association with pathology. MATERIAL AND METHODS Japanese male long eared rabbits were chosen and divided into 7 groups (8 rabbits in each group): control group (C group), sham-operation control group (S group), and 5 experimental groups (E-2 h group, E-24 h group, E-48 h group, E-7 d group, and E 14 d group). Tarlov scoring and immunohistochemical staining were used to assess hindlimb motor function and observe the expression of glial fiber acidic protein (GFAP), respectively. The correlation between DKI and pathology after SCI/R injury was compared by 3.0TMR scanning DKI. RESULTS Neuroethology in each time point of E groups was significantly different from that in C and S groups (P<0.05). The E-24 h group had the lowest value (P<0.05), and the hindlimb motor function began to recover after 24 h. The expression of GFAP was gradually increased after SCI/R injury, and the maximum value was in the E-7 d group (P<0.05). MK (mean kurtosis) had a linear negative correlation with average optical density (OD) (r=-0.115, P<0.05) and was positively correlated with integral OD (IOD) (r=0.204, P<0.05), in which MD (mean dispersion) was positively correlated with OD and IOD, but without a significant difference (r=0.618, r=251, P>0.05). CONCLUSIONS DKI can be used to monitor the changes in SCI/R injury, and fractional anisotropy (FA) can reflect change in white matter structure. The changes in expression of MK and GFAP were related to the myelin sheath injury repair process. PMID- 28820865 TI - [Report of clinical cases in medical school]. PMID- 28820866 TI - [Surgical treatment of choledocholithiasis in a patient with situs inversus totalis: a case report and literature review]. AB - Situs inversus totalis (SIT) is a rare condition, in which there is transposition of the thoraco-abdominal organs. This situation leads to diagnostic and therapeutic difficulties in patients with acute surgical abdomen. The objective of this report is to present the case of a patient who presented with colonic pain in the epigastrium and left hypochondrium, in which the diagnosis of SIT, cholelithiasis and choledocholithiasis was reached after the respective imaging studies. Once the diagnosis was made, treatment was performed through retrograde endoscopic cholangiopancreatography (ERCP) and subsequent surgical exploration of bile ducts. Both procedures were failed due to technical difficulties generated by the patient's condition. In conclusion, in spite of the report of successful cases in the literature of ERCP and surgical treatment of the biliary tract in SIT, there may be situations that do not allow a successful approach, so meticulous surgical planning and the use of support methods are necessary In the management of these patients. PMID- 28820867 TI - Cyberbullying in Peruvian schoolchildren and associated factors: analysis of a national survey. PMID- 28820868 TI - Is cannabidiol an effective treatment for schizophrenia? AB - Cannabidiol has recently been proposed as an antipsychotic for schizophrenia. However, its clinical use and safety is controversial. To answer this question, we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We identified six systematic reviews incorporating four primary studies overall, including two randomized trials. We extracted data from the systematic reviews, reanalyzed data from primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. We concluded cannabidiol probably does not improve symptoms in schizophrenia and leads to frequent side effects. PMID- 28820869 TI - Necrotizing enterocolitis and high intestinal iron uptake due to genetic variants. AB - BackgroundIntestinal iron is a nutritional compound, which is essential for enteric microbiota. We evaluated the hypothesis that polymorphisms, which are known modifiers of intestinal iron uptake in adults, are associated with necrotizing enterocolitis (NEC) in preterm infants.MethodsPreterm infants (birth weight below 1,500 g) were studied. Single-nucleotide polymorphisms with known effects on serum iron levels (rs1800562, rs1799945, and rs855791) were determined using PCR. The effects of polymorphisms on NEC surgery were tested by Mendelian randomization. Outcome data were compared with chi2-test, Fisher's exact test, t test, and Cochran-Armitage test for trend and multiple logistic regression analysis.ResultsComplete genotyping data were available for 11,166 infants. High serum iron levels due to rs855791 genotype were associated with a significantly reduced risk of NEC surgery (odds ratio (OR) 0.265; 95% confidence interval (CI) 0.11-0.65; adjusted P=0.011). Carriers of the rs855791 A-allele not receiving prophylactic probiotics had a higher risk of NEC surgery (OR 1.12, 95% CI 1.08 1.70, nominal P=0.002). Prophylactic treatment with probiotics was associated with a reduced risk of NEC surgery in carriers of the rs855791 A-Allele. No differences were found with regard to other short- or long-term outcome data.ConclusionPolymorphisms inducing lower intestinal iron uptake like the rs855791 A-allele might be an underestimated risk factor for NEC. PMID- 28820872 TI - Bacterial immunity: A virtuous CRISPR cycle. PMID- 28820873 TI - Ubiquitin-proteasome system: Rescuing EBV latency. PMID- 28820871 TI - Genetic predisposition to fetal alcohol syndrome: association with congenital disorders of N-glycosylation. AB - BackgroundFetal alcohol syndrome (FAS) is caused by maternal alcohol consumption during pregnancy; although additional factors might be involved, as development and severity are not directly related to alcohol intake. The abnormal glycosylation caused by alcohol might play a role in FAS according to the clinical similarities shared with congenital disorders of glycosylation (CDG). Thus, mutations underlying CDG, affecting genes involved in glycosylation, could also be involved in FAS.MethodsA panel of 74 genes involved in N-glycosylation was sequenced in 25 FAS patients and 20 controls with prenatal alcohol exposure. Transferrin glycoforms were evaluated by HPLC.ResultsRare (minor allele frequency<0.009) missense/splice site variants were more frequent in FAS than controls (84% vs. 50%; P=0.034, odds ratio: 5.25, 95% confidence interval: 1.3 20.9). Remarkably, three patients, but no controls, carried variants with functional effects identified in CDG patients. Moreover, the patient with the most severe clinical phenotype was the only one carrying two variants with functional effects. Family studies support that the combination of a genetic defect and alcohol consumption during pregnancy might have a role in FAS development.ConclusionsOur study supports that the rare variants of genes involved in N-glycosylation could play a role in the development and severity of FAS under prenatal alcohol exposure. PMID- 28820874 TI - Protein design: I like to fold it, fold it. PMID- 28820875 TI - Extracellular vesicles: Taking metabolism on the road. PMID- 28820870 TI - Controversies in the identification and management of acute pulmonary hypertension in preterm neonates. AB - It is increasingly recognized that the abnormal physiologic consequences of pulmonary hypertension (PH) may contribute to poor cardiopulmonary health in premature babies. Conflicting literature has led to clinical uncertainty, pathological misinterpretation, and variability in treatment approaches among practitioners. There are several disorders with overlapping and interrelated presentations, and other disorders with a similar clinical phenotype but diverse pathophysiological contributors. In this review, we provide a diagnostic approach for acute hypoxemic respiratory failure in the preterm neonate, outline the pathophysiological conditions that may present as acute PH, and discuss the implications of high pulmonary vascular resistance (PVR) on the cardiovascular system. Although PVR and respiratory management are highly interrelated, there may be a population of preterm neonates in whom inhaled nitric oxide may improve illness severity and may relate to outcomes. A management approach based on physiology that considers common clinical conundrums is provided. A more comprehensive understanding of the physiology may help in informed decision making in clinical situations where conclusive scientific evidence is lacking. Regardless, high-quality research is required, and appropriate definition of the target population is paramount. A thoughtful approach to cardiovascular therapy may also provide an avenue to improve neurodevelopmental outcomes while awaiting more clear answers. PMID- 28820876 TI - Protein engineering: Redirecting membrane machinery. PMID- 28820877 TI - Drug development: Locking down metabolism. PMID- 28820878 TI - Neurobiology: Lighting up neurons. PMID- 28820879 TI - A kinetic view of GPCR allostery and biased agonism. AB - G-protein-coupled receptors (GPCRs) are one of the most tractable classes of drug targets. These dynamic proteins can adopt multiple active states that are linked to distinct functional outcomes. Such states can be differentially stabilized by ligands interacting with the endogenous agonist-binding orthosteric site and/or by ligands acting via spatially distinct allosteric sites, leading to the phenomena of 'biased agonism' or 'biased modulation'. These paradigms are having a major impact on modern drug discovery, but it is becoming increasingly apparent that 'kinetic context', at the level of both ligand-receptor and receptor-signal pathway kinetics, can have a profound impact on the observation and quantification of these phenomena. The concept of kinetic context thus represents an important new consideration that should be routinely incorporated into contemporary chemical biology and drug discovery studies of GPCR bias and allostery. PMID- 28820881 TI - Vector competence of populations of Aedes aegypti from three distinct cities in Kenya for chikungunya virus. AB - BACKGROUND: In April, 2004, chikungunya virus (CHIKV) re-emerged in Kenya and eventually spread to the islands in the Indian Ocean basin, South-East Asia, and the Americas. The virus, which is often associated with high levels of viremia in humans, is mostly transmitted by the urban vector, Aedes aegypti. The expansion of CHIKV presents a public health challenge both locally and internationally. In this study, we investigated the ability of Ae. aegypti mosquitoes from three distinct cities in Kenya; Mombasa (outbreak prone), Kisumu, and Nairobi (no documented outbreak) to transmit CHIKV. METHODOLOGY/PRINCIPAL FINDINGS: Aedes aegypti mosquito populations were exposed to different doses of CHIKV (105.6-7.5 plaque-forming units[PFU]/ml) in an infectious blood meal. Transmission was ascertained by collecting and testing saliva samples from individual mosquitoes at 5, 7, 9, and 14 days post exposure. Infection and dissemination were estimated by testing body and legs, respectively, for individual mosquitoes at selected days post exposure. Tissue culture assays were used to determine the presence of infectious viral particles in the body, leg, and saliva samples. The number of days post exposure had no effect on infection, dissemination, or transmission rates, but these rates increased with an increase in exposure dose in all three populations. Although the rates were highest in Ae. aegypti from Mombasa at titers >=106.9 PFU/ml, the differences observed were not statistically significant (chi2 <= 1.04, DF = 1, P >= 0.31). Overall, about 71% of the infected mosquitoes developed a disseminated infection, of which 21% successfully transmitted the virus into a capillary tube, giving an estimated transmission rate of about 10% for mosquitoes that ingested >=106.9 PFU/ml of CHIKV. All three populations of Ae. aegypti were infectious as early as 5-7 days post exposure. On average, viral dissemination only occurred when body titers were >=104 PFU/ml in all populations. CONCLUSIONS/SIGNIFICANCE: Populations of Ae. aegypti from Mombasa, Nairobi, and Kisumu were all competent laboratory vectors of CHIKV. Viremia of the infectious blood meal was an important factor in Ae. aegypti susceptibility and transmission of CHIKV. In addition to viremia levels, temperature and feeding behavior of Ae. aegypti may also contribute to the observed disease patterns. PMID- 28820880 TI - Knock-out of a mitochondrial sirtuin protects neurons from degeneration in Caenorhabditis elegans. AB - Sirtuins are NAD+-dependent deacetylases, lipoamidases, and ADP ribosyltransferases that link cellular metabolism to multiple intracellular pathways that influence processes as diverse as cell survival, longevity, and cancer growth. Sirtuins influence the extent of neuronal death in stroke. However, different sirtuins appear to have opposite roles in neuronal protection. In Caenorhabditis elegans, we found that knock-out of mitochondrial sirtuin sir 2.3, homologous to mammalian SIRT4, is protective in both chemical ischemia and hyperactive channel induced necrosis. Furthermore, the protective effect of sir 2.3 knock-out is enhanced by block of glycolysis and eliminated by a null mutation in daf-16/FOXO transcription factor, supporting the involvement of the insulin/IGF pathway. However, data in Caenorhabditis elegans cell culture suggest that the effects of sir-2.3 knock-out act downstream of the DAF-2/IGF-1 receptor. Analysis of ROS in sir-2.3 knock-out reveals that ROS become elevated in this mutant under ischemic conditions in dietary deprivation (DD), but to a lesser extent than in wild type, suggesting more robust activation of a ROS scavenging system in this mutant in the absence of food. This work suggests a deleterious role of SIRT4 during ischemic processes in mammals that must be further investigated and reveals a novel pathway that can be targeted for the design of therapies aimed at protecting neurons from death in ischemic conditions. PMID- 28820882 TI - Correlation between mosquito larval density and their habitat physicochemical characteristics in Mazandaran Province, northern Iran. AB - Characteristics of mosquito larval habitats are important in determining whether they can survive and successfully complete their developmental stages. Therefore, data on the ecological factors affecting mosquito density and abundance especially the physicochemical properties of water of their breeding sites, can possibly be helpful in implementing larval management programs. Mosquito larvae were collected using a standard 350 ml dipper from fixed habitats including: artificial pool, river edge, creek and etc, in 30 villages of 16 counties from May-December 2014. Water samples were collected during larval collection and temperature ( degrees C), acidity (pH), turbidity (NTU), electrical conductivity (MUS/cm), alkalinity (mg/l CaCO3), total hardness (mg/l), nitrate (mg/l), chloride (mg/l), phosphate (mg/l) and sulphate (mg/l) were measured using standard methods. Spearman correlation coefficient, Kruskal-Wallis test of nonparametric analysis, Chi-square (chi2) analysis, regression analysis and C8 interspecific correlation coefficient were used for data analysis. A total of 7,566 mosquito larvae belonging to 15 species representing three genera were collected from fixed larval breeding places. Culex pipiens was the dominant species except in four villages where An. maculipennis s.l. and Cx. torrentium were predominant. There was a significant positive correlation between the density of Cx. pipiens and electrical conductivity, alkalinity, total hardness and chloride, whereas no significant negative correlation was observed between physicochemical factors and larval density. The highest interspecific association of up to 0.596 was observed between An. maculipennis s.l/An. pseudopictus followed by up to 0.435 between An. maculipennis s.l/An. hyrcanus and An. hyrcanus/An. pseudopictus. The correlations observed between physicochemical factors and larval density, can possibly confirm the effect of these parameters on the breeding activities of mosquitoes, and may be indicative of the presence of certain mosquito fauna in a given region. PMID- 28820883 TI - Spatial clustering of patent and sub-patent malaria infections in northern Namibia: Implications for surveillance and response strategies for elimination. AB - BACKGROUND: Reactive case detection (RACD) around passively detected malaria cases is a strategy to identify and treat hotspots of malaria transmission. This study investigated the unproven assumption on which this approach is based, that in low transmission settings, infections cluster over small scales. METHODS: A prospective case-control study was conducted between January 2013 and August 2014 in Ohangwena and Omusati regions in north central Namibia. Patients attending health facilities who tested positive by malaria rapid diagnostic test (RDT) (index cases) were traced back to their home. All occupants of index case households (n = 116 households) and surrounding households (n = 225) were screened for Plasmodium infection with a rapid diagnostic test (RDT) and loop mediated isothermal amplification (LAMP) and interviewed to identify risk factors. A comparison group of 286 randomly-selected control households was also screened, to compare infection levels of RACD and non-RACD households and their neighbours. Logistic regression was used to investigate spatial clustering of patent and sub-patent infections around index cases and to identify potential risk factors that would inform screening approaches and identify risk groups. Estimates of the impact of RACD on onward transmission to mosquitoes was made using previously published figures of infection rates. RESULTS: Prevalence of Plasmodium falciparum infection by LAMP was 3.4%, 1.4% and 0.4% in index-case households, neighbors of index case households and control households respectively; adjusted odds ratio 6.1 [95%CI 1.9-19.5] comparing case households versus control households. Using data from Engela, neighbors of cases had higher odds of infection [adjusted OR 5.0 95%CI 1.3-18.9] compared to control households. All infections identified by RDTs were afebrile and RDTs identified only a small proportion of infections in case (n = 7; 17%) and control (0%) neighborhoods. Based on published estimates of patent and sub-patent infectiousness, these results suggest that infections missed by RDTs during RACD would allow 50-71% of infections to mosquitoes to occur in this setting. CONCLUSION: Malaria infections cluster around passively detected cases. The majority of infections are asymptomatic and of densities below the limit of detection of current RDTs. RACD using standard RDTs are unlikely to detect enough malaria infections to dramatically reduce transmission. In low transmission settings such as Namibia more sensitive field diagnostics or forms of focal presumptive treatment should be tested as strategies to reduce malaria transmission. PMID- 28820884 TI - Let's rise up to unite taxonomy and technology. AB - What do you think of when you think of taxonomy? An 18th century gentlemen in breeches? Or perhaps botany drawings hung on the walls of a boutique hotel? Such old-fashioned conceptions to the contrary, taxonomy is alive today although constantly struggling for survival and recognition. The scientific community is losing valuable resources as taxonomy experts age and retire, and funding for morphological studies and species descriptions remains stagnant. At the same time, organismal knowledge (morphology, ecology, physiology) has never been more important: genomic studies are becoming more taxon focused, the scientific community is recognizing the limitations of traditional "model" organisms, and taxonomic expertise is desperately needed to fight against global biodiversity declines resulting from human impacts. There has never been a better time for a taxonomic renaissance. PMID- 28820885 TI - Diagnostic efficacy of noninvasive liver fibrosis indexes in predicting portal hypertension in patients with cirrhosis. AB - BACKGROUND: Recent data suggest that noninvasive liver fibrosis indexes could be useful for predicting esophageal varices (EV) in cirrhotic patients. However, thus far, the diagnostic efficacy of these indexes in predicting portal hypertension (PH) in cirrhotic patients has been poorly evaluated. AIMS: To evaluate the diagnostic efficacy of noninvasive liver fibrosis indexes in the diagnosis of PH. METHODS: A total of 238 cirrhotic patients underwent hepatic venous pressure gradient (HVPG) evaluation and relevant serum tests to analyze the variables associated with PH grade. Then, the diagnostic performances of seven fibrosis indexes, the aspartate aminotransferase (AST)-to-alanine aminotransferase (ALT) ratio (AAR), AST-to-platelet (PLT) ratio index (APRI), fibrosis index (FI), FIB-4, Forns index, King's score and the Lok index, were evaluated to determine their efficacy in predicting clinically significant PH (CSPH) and severe PH (SPH). In addition, the performances of these fibrosis indexes in different subgroups were investigated. RESULTS: The results of a multivariate analysis of serum markers showed that AST values, platelet (PLT) count and albumin (ALB) were associated with PH grade. Among the seven-fibrosis indexes, King's score, APRI and the Lok index showed modest diagnostic accuracy in predicting CSPH and SPH, as indicated by AUC of 0.755 and 0.742, 0.740 and 0.742, and 0.722 and 0.717, respectively. In addition, combination of King's score (cutoff 23.47) and Lok index (cutoff 1.30) predicted presence of CSPH, with the highest PPV (95.38%) and +LR (5.49). A subgroup analysis indicated that the noninvasive screening model may be more applicable to patients with cirrhosis of viral etiology. CONCLUSIONS: Serum liver fibrosis indexes exhibited modest diagnostic accuracy for PH in cirrhotic patients. These indexes may not be able to replace HVPG measurements for the diagnosis of PH but may be used as a first line screening method for CSPH in liver cirrhosis patients. PMID- 28820886 TI - Circulating miRNAs in sepsis-A network under attack: An in-silico prediction of the potential existence of miRNA sponges in sepsis. AB - Biomarkers based on the molecular mechanism of sepsis are important for timely diagnosis and treatment. A large panel of small non-coding microRNAs was reported to modulate the immune response in sepsis but have not been tested in clinical practice. Large-scale identification of microRNA networks in sepsis might reveal a new biological mechanism that can be also targeted by gene therapy. Therefore, the main objective of this study is to perform a comparison of the miRNA network between septic patients and healthy controls. We used the previously measured levels of expression of 16 different circulating human and viral microRNAs in plasma from 99 septic patients and 53 healthy controls. We used three different computational methods to find correlations between the expressions of microRNAs and to build microRNA networks for the two categories, septic patients and healthy controls. We found that the microRNA network of the septic patients is significantly less connected when compared to miRNA network of the healthy controls (21 edges vs 52 edges, P < 0.0001). We hypothesize that several microRNAs (miR-16, miR-29a, miR-146, miR-155, and miR-182) are being sponged in sepsis explaining the loss of connection in the septic patient miRNA network. This was specific for sepsis, as it did not occur in other conditions characterized by an increased inflammatory response such as in post-surgery patients. Using several target prediction instruments, we predicted potential common sponges for the miRNA network in sepsis from several signaling pathways. Understanding the dynamics of miRNA network in sepsis is useful to explain the molecular pathophysiology of sepsis and for designing therapeutic strategies that target essential components of the immune response pathways. PMID- 28820888 TI - A new model integrating short- and long-term aging of copper added to soils. AB - Aging refers to the processes by which the bioavailability/toxicity, isotopic exchangeability, and extractability of metals added to soils decline overtime. We studied the characteristics of the aging process in copper (Cu) added to soils and the factors that affect this process. Then we developed a semi-mechanistic model to predict the lability of Cu during the aging process with descriptions of the diffusion process using complementary error function. In the previous studies, two semi-mechanistic models to separately predict short-term and long term aging of Cu added to soils were developed with individual descriptions of the diffusion process. In the short-term model, the diffusion process was linearly related to the square root of incubation time (t1/2), and in the long term model, the diffusion process was linearly related to the natural logarithm of incubation time (lnt). Both models could predict short-term or long-term aging processes separately, but could not predict the short- and long-term aging processes by one model. By analyzing and combining the two models, we found that the short- and long-term behaviors of the diffusion process could be described adequately using the complementary error function. The effect of temperature on the diffusion process was obtained in this model as well. The model can predict the aging process continuously based on four factors-soil pH, incubation time, soil organic matter content and temperature. PMID- 28820887 TI - Identification of putative QTLs for seedling stage phosphorus starvation response in finger millet (Eleusine coracana L. Gaertn.) by association mapping and cross species synteny analysis. AB - A germplasm assembly of 128 finger millet genotypes from 18 countries was evaluated for seedling-stage phosphorus (P) responses by growing them in P sufficient (Psuf) and P deficient (Pdef) treatments. Majority of the genotypes showed adaptive responses to low P condition. Based on phenotype behaviour using the best linear unbiased predictors for each trait, genotypes were classified into, P responsive, low P tolerant and P non-responsive types. Based on the overall phenotype performance under Pdef, 10 genotypes were identified as low P tolerants. The low P tolerant genotypes were characterised by increased shoot and root length and increased root hair induction with longer root hairs under Pdef, than under Psuf. Association mapping of P response traits using mixed linear models revealed four quantitative trait loci (QTLs). Two QTLs (qLRDW.1 and qLRDW.2) for low P response affecting root dry weight explained over 10% phenotypic variation. In silico synteny analysis across grass genomes for these QTLs identified putative candidate genes such as Ser-Thr kinase and transcription factors such as WRKY and basic helix-loop-helix (bHLH). The QTLs for response under Psuf were mapped for traits such as shoot dry weight (qHSDW.1) and root length (qHRL.1). Putative associations of these QTLs over the syntenous regions on the grass genomes revealed proximity to cytochrome P450, phosphate transporter and pectin methylesterase inhibitor (PMEI) genes. This is the first report of the extent of phenotypic variability for P response in finger millet genotypes during seedling-stage, along with the QTLs and putative candidate genes associated with P starvation tolerance. PMID- 28820890 TI - History based forward and feedback mechanism in cooperative spectrum sensing including malicious users in cognitive radio network. AB - In cognitive radio communication, spectrum sensing plays a vital role in sensing the existence of the primary user (PU). The sensing performance is badly affected by fading and shadowing in case of single secondary user(SU). To overcome this issue, cooperative spectrum sensing (CSS) is proposed. Although the reliability of the system is improved with cooperation but existence of malicious user (MU) in the CSS deteriorates the performance. In this work, we consider the Kullback Leibler (KL) divergence method for minimizing spectrum sensing data falsification (SSDF) attack. In the proposed CSS scheme, each SU reports the fusion center(FC) about the availability of PU and also keeps the same evidence in its local database. Based on the KL divergence value, if the FC acknowledges the user as normal, then the user will send unified energy information to the FC based on its current and previous sensed results. This method keeps the probability of detection high and energy optimum, thus providing an improvement in performance of the system. Simulation results show that the proposed KL divergence method has performed better than the existing equal gain combination (EGC), maximum gain combination (MGC) and simple KL divergence schemes in the presence of MUs. PMID- 28820889 TI - Altered fetal growth, placental abnormalities, and stillbirth. AB - BACKGROUND: Worldwide, stillbirth is one of the leading causes of death. Altered fetal growth and placental abnormalities are the strongest and most prevalent known risk factors for stillbirth. The aim of this study was to identify patterns of association between placental abnormalities, fetal growth, and stillbirth. METHODS AND FINDINGS: Population-based case-control study of all stillbirths and a representative sample of live births in 59 hospitals in 5 geographic areas in the U.S. Fetal growth abnormalities were categorized as small (<10th percentile) and large (>90th percentile) for gestational age at death (stillbirth) or delivery (live birth) using a published algorithm. Placental examination by perinatal pathologists was performed using a standardized protocol. Data were weighted to account for the sampling design. Among 319 singleton stillbirths and 1119 singleton live births at >=24 weeks at death or delivery respectively, 25 placental findings were investigated. Fifteen findings were significantly associated with stillbirth. Ten of the 15 were also associated with fetal growth abnormalities (single umbilical artery; velamentous insertion; terminal villous immaturity; retroplacental hematoma; parenchymal infarction; intraparenchymal thrombus; avascular villi; placental edema; placental weight; ratio birth weight/placental weight) while 5 of the 15 associated with stillbirth were not associated with fetal growth abnormalities (acute chorioamnionitis of placental membranes; acute chorioamionitis of chorionic plate; chorionic plate vascular degenerative changes; perivillous, intervillous fibrin, fibrinoid deposition; fetal vascular thrombi in the chorionic plate). Five patterns were observed: placental findings associated with (1) stillbirth but not fetal growth abnormalities; (2) fetal growth abnormalities in stillbirths only; (3) fetal growth abnormalities in live births only; (4) fetal growth abnormalities in stillbirths and live births in a similar manner; (5) a different pattern of fetal growth abnormalities in stillbirths and live births. CONCLUSIONS: The patterns of association between placental abnormalities, fetal growth, and stillbirth provide insights into the mechanism of impaired placental function and stillbirth. They also suggest implications for clinical care, especially for placental findings amenable to prenatal diagnosis using ultrasound that may be associated with term stillbirths. PMID- 28820891 TI - Scene text detection via extremal region based double threshold convolutional network classification. AB - In this paper, we present a robust text detection approach in natural images which is based on region proposal mechanism. A powerful low-level detector named saliency enhanced-MSER extended from the widely-used MSER is proposed by incorporating saliency detection methods, which ensures a high recall rate. Given a natural image, character candidates are extracted from three channels in a perception-based illumination invariant color space by saliency-enhanced MSER algorithm. A discriminative convolutional neural network (CNN) is jointly trained with multi-level information including pixel-level and character-level information as character candidate classifier. Each image patch is classified as strong text, weak text and non-text by double threshold filtering instead of conventional one-step classification, leveraging confident scores obtained via CNN. To further prune non-text regions, we develop a recursive neighborhood search algorithm to track credible texts from weak text set. Finally, characters are grouped into text lines using heuristic features such as spatial location, size, color, and stroke width. We compare our approach with several state-of-the art methods, and experiments show that our method achieves competitive performance on public datasets ICDAR 2011 and ICDAR 2013. PMID- 28820892 TI - Maternal autoimmune antibodies alter the dendritic arbor and spine numbers in the infragranular layers of the cortex. AB - An association between maternal IgG antibodies reactive against proteins in fetal brain and an outcome of autism in the child has been identified. Using a mouse model of prenatal intraventricular administration of autism-specific maternal IgG, we demonstrated that these antibodies produce behavioral alterations similar to those in children with ASD. We previously demonstrated that these antibodies bind to radial glial stem cells (RG) and observed an increase in the number of divisions of translocating RG in the developing cortex. We also showed an alteration in brain size and as well as a generalized increased of neuronal volume in adult mice. Here, we used our intraventricular mouse model of antibody administration, followed by Golgi and Neurolucida analysis to demonstrate that during midstages of neurogenesis these maternal autism-specific antibodies produced a consistent decrease in the number of spines in the infragranular layers in the adult cortical areas analyzed. Specifically, in the frontal cortex basal dendrites of layer V neurons were decreased in length and volume, and both the total number of spines-mature and immature-and the spine density were lower than in the control neurons from the same region. Further, in the occipital cortex layer VI neurons presented with a decrease in the total number of spines and in the spine density in the apical dendrite, as well as decrease in the number of mature spines in the apical and basal dendrites. Interestingly, the time of exposure to these antibodies (E14.5) coincides with the generation of pyramidal neurons in layer V in the frontal cortex and in layer VI in the occipital cortex, following the normal rostro-caudal pattern of cortical cell generation. We recently demonstrated that one of the primary antigens recognized by these antibodies corresponds to stress-induced phosphoprotein 1 (STIP1). Here we hypothesize that the reduction in the access of newborn cells to STIP1 in the developing cortex may be responsible for the reduced dendritic arborization and number of spines we noted in the adult cortex. PMID- 28820893 TI - A computational method for the identification of candidate drugs for non-small cell lung cancer. AB - Lung cancer causes a large number of deaths per year. Until now, a cure for this disease has not been found or developed. Finding an effective drug through traditional experimental methods invariably costs millions of dollars and takes several years. It is imperative that computational methods be developed to integrate several types of existing information to identify candidate drugs for further study, which could reduce the cost and time of development. In this study, we tried to advance this effort by proposing a computational method to identify candidate drugs for non-small cell lung cancer (NSCLC), a major type of lung cancer. The method used three steps: (1) preliminary screening, (2) screening compounds by an association test and a permutation test, (3) screening compounds using an EM clustering algorithm. In the first step, based on the chemical-chemical interaction information reported in STITCH, a well-known database that reports interactions between chemicals and proteins, and approved NSCLC drugs, compounds that can interact with at least one approved NSCLC drug were picked. In the second step, the association test selected compounds that can interact with at least one NSCLC-related chemical and at least one NSCLC-related gene, and subsequently, the permutation test was used to discard nonspecific compounds from the remaining compounds. In the final step, core compounds were selected using a powerful clustering algorithm, the EM algorithm. Six putative compounds, protoporphyrin IX, hematoporphyrin, canertinib, lapatinib, pelitinib, and dacomitinib, were identified by this method. Previously published data show that all of the selected compounds have been reported to possess anti-NSCLC activity, indicating high probabilities of these compounds being novel candidate drugs for NSCLC. PMID- 28820894 TI - Short-term apparent brain tissue changes are contributed by cerebral blood flow alterations. AB - Structural MRI (sMRI)-identified tissue "growth" after neuropsychological training has been reported in many studies but the origins of those apparent tissue changes (ATC) still remain elusive. One possible contributor to ATC is brain perfusion since T1-weighted MRI, the tool used to identify ATC, is sensitive to perfusion-change induced tissue T1 alterations. To test the hypothetical perfusion contribution to ATC, sMRI data were acquired before and after short-term global and regional perfusion manipulations via intaking a 200 mg caffeine pill and performing a sensorimotor task. Caffeine intake caused a global CBF reduction and apparent tissue density reduction in temporal cortex, anterior cingulate cortex, and the limbic area; sensorimotor task induced CBF increase and apparent tissue increase in spatially overlapped brain regions. After compensating CBF alterations through a voxel-wise regression, the ATC patterns demonstrated in both experiments were substantially suppressed. These data clearly proved existence of the perfusion contribution to short-term ATC, and suggested a need for correcting perfusion changes in longitudinal T1-weighted structural MRI analysis if a short-term design is used. PMID- 28820895 TI - Identification of Leishmania donovani antigen in circulating immune complexes of visceral leishmaniasis subjects for diagnosis. AB - The unreliability of most of the existing antibody-based diagnostic kits to discriminate between active and treated VL cases, relapse situation and reinfection are a major hurdle in controlling the cases of Kala-azar in an endemic area. An antigen targeted diagnostic approaches can be an attractive strategy to overcome these problems. Hence, this study was focused on identifying the Leishmania antigens, lies in circulating immune complex (CICs), can be used for diagnostic as well as prognostic purposes. The present study was conducted on peripheral blood samples of 115 human subjects, based on isolation of CICs. The SDS-PAGE patterns showed an up-regulated expression of 55 kDa and 23 kDa fractions in an antigens obtained from CICs of all clinical and parasitologically proven untreated visceral leishmaniasis patients before treatment (VL-BT), which ensured absolute sensitivity. However, light expressions of these bands were observed in some VL treated cases. To ascertain the prognostic value, 2D expression profiles of circulating antigens were carried out, which revealed 3 upregulated and 12 induced immunoreactive spots. Out of these, ten prominent spots were excised and subjected for enzymatic digestion to generate peptides. Mass spectrometry (MS) analysis successfully explored 20 peptides derived from kinase, kinesin, acetyl Co-A carboxylase, dynein heavy chains (cytoplasmic and axonemal/flagellar), 60S ribosomal protein, nucleoporin protein, RNA polymeraseII, protease gp63, tubulin, DNA polymerase epsilon subunit, GTP-binding protein and tyrosyl-methionyl t-RNA synthetase-like protein and 19 hypothetical protein of unknown function. Presence of L. donovani proteins in circulating antigens were further validated using anti-Ld actin and anti-alpha tubulin antibody. Besides, MS derived peptides confirmed its reactivity with patients' sera. Therefore, these shortlisted potential antigens can be explored as antigen based diagnostic as well as prognostic kit. PMID- 28820896 TI - A strategy for scaling up access to comprehensive care in adults with Chagas disease in endemic countries: The Bolivian Chagas Platform. AB - BACKGROUND: Bolivia has the highest prevalence of Chagas disease (CD) in the world (6.1%), with more than 607,186 people with Trypanosoma cruzi infection, most of them adults. In Bolivia CD has been declared a national priority. In 2009, the Chagas National Program (ChNP) had neither a protocol nor a clear directive for diagnosis and treatment of adults. Although programs had been implemented for congenital transmission and for acute cases, adults remained uncovered. Moreover, health professionals were not aware of treatment recommendations aimed at this population, and research on CD was limited; it was difficult to increase awareness of the disease, understand the challenges it presented, and adapt strategies to cope with it. Simultaneously, migratory flows that led Bolivian patients with CD to Spain and other European countries forced medical staff to look for solutions to an emerging problem. INTERVENTION: In this context, thanks to a Spanish international cooperation collaboration, the Bolivian platform for the comprehensive care of adults with CD was created in 2009. Based on the establishment of a vertical care system under the umbrella of ChNP general guidelines, six centres specialized in CD management were established in different epidemiological contexts. A common database, standardized clinical forms, a and a protocolized attention to adults patients, together with training activities for health professionals were essential for the model success. With the collaboration and knowledge transfer activities between endemic and non-endemic countries, the platform aims to provide care, train health professionals, and create the basis for a future expansion to the National Health System of a proven model of care for adults with CD. RESULTS: From 2010 to 2015, a total of 26,227 patients were attended by the Platform, 69% (18,316) were diagnosed with T. cruzi, 8,567 initiated anti-parasitic treatment, more than 1,616 health professionals were trained, and more than ten research projects developed. The project helped to increase the number of adults with CD diagnosed and treated, produce evidence-based clinical practice guidelines, and bring about changes in policy that will increase access to comprehensive care among adults with CD. The ChNP is now studying the Platform's health care model to adapt and implement it nationwide. CONCLUSIONS: This strategy provides a solution to unmet demands in the care of patients with CD, improving access to diagnosis and treatment. Further scaling up of diagnosis and treatment will be based on the expansion of the model of care to the NHS structures. Its sustainability will be ensured as it will build on existing local resources in Bolivia. Still human trained resources are scarce and the high staff turnover in Bolivia is a limitation of the model. Nevertheless, in a preliminary two-years-experience of scaling up this model, this limitations have been locally solved together with the health local authorities. PMID- 28820897 TI - Persistent infection due to a small-colony variant of Burkholderia pseudomallei leads to PD-1 upregulation on circulating immune cells and mononuclear infiltration in viscera of experimental BALB/c mice. AB - BACKGROUND: Melioidosis is a neglected tropical disease endemic across South East Asia and Northern Australia. The etiological agent, Burkholderia pseudomallei (B.pseudomallei), is a Gram-negative, rod-shaped, motile bacterium residing in the soil and muddy water across endemic regions of the tropical world. The bacterium is known to cause persistent infections by remaining latent within host cells for prolonged duration. Reactivation of the recrudescent disease often occurs in elders whose immunity wanes. Moreover, recurrence rates in melioidosis patients can be up to ~13% despite appropriate antibiotic therapy, suggestive of bacterial persistence and inefficacy of antibiotic regimens. The mechanisms behind bacterial persistence in the host remain unclear, and hence understanding host immunity during persistent B. pseudomallei infections may help designing potential immunotherapy. METHODOLOGY/PRINCIPAL FINDINGS: A persistent infection was generated using a small-colony variant (SCV) and a wild-type (WT) B. pseudomallei in BALB/c mice via intranasal administration. Infected mice that survived for >60 days were sacrificed. Lungs, livers, spleens, and peripheral blood mononuclear cells were harvested for experimental investigations. Histopathological changes of organs were observed in the infected mice, suggestive of successful establishment of persistent infections. Moreover, natural killer (NK) cell frequency was increased in SCV- and WT-infected mice. We observed programmed death-1 (PD-1) upregulation on B cells of SCV- and WT infected mice. Interestingly, PD-1 upregulation was only observed on NK cells and monocytes of SCV-infected mice. In contrast, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) downregulation was seen on NK cells of WT-infected mice, and on monocytes of SCV- and WT-infected mice. CONCLUSIONS/SIGNIFICANCE: The SCV and the WT of B. pseudomallei distinctly upregulated PD-1 expression on B cells, NK cells, and monocytes to dampen host immunity, which likely facilitates bacterial persistence. PD-1/PD-L1 pathway appears to play an important role in the persistence of B. pseudomallei in the host. PMID- 28820898 TI - Perceived effort for motor control and decision-making. AB - How effort is internally quantified and how it influences both movement generation and decisions between potential movements are 2 difficult questions to answer. Physical costs are known to influence motor control and decision-making, yet we lack a general, principled characterization of how the perception of effort operates across tasks and conditions. Morel and colleagues introduce an insightful approach to that end, assessing effort indifference points and presenting a quadratic law between perceived effort and force production. PMID- 28820899 TI - Two disjunct Pleistocene populations and anisotropic postglacial expansion shaped the current genetic structure of the relict plant Amborella trichopoda. AB - Past climate fluctuations shaped the population dynamics of organisms in space and time, and have impacted their present intra-specific genetic structure. Demo genetic modelling allows inferring the way past demographic and migration dynamics have determined this structure. Amborella trichopoda is an emblematic relict plant endemic to New Caledonia, widely distributed in the understory of non-ultramafic rainforests. We assessed the influence of the last glacial climates on the demographic history and the paleo-distribution of 12 Amborella populations covering the whole current distribution. We performed coalescent genetic modelling of these dynamics, based on both whole-genome resequencing and microsatellite genotyping data. We found that the two main genetic groups of Amborella were shaped by the divergence of two ancestral populations during the last glacial maximum. From 12,800 years BP, the South ancestral population has expanded 6.3-fold while the size of the North population has remained stable. Recent asymmetric gene flow between the groups further contributed to the phylogeographical pattern. Spatially explicit coalescent modelling allowed us to estimate the location of ancestral populations with good accuracy (< 22 km) and provided indications regarding the mid-elevation pathways that facilitated post glacial expansion. PMID- 28820900 TI - SecY-SecA fusion protein retains the ability to mediate protein transport. AB - In bacteria, the membrane protein complex SecY/E/G and SecA ATPase are essential for protein translocation. About 30% of newly synthesized proteins in the cytosol are targeted to and translocated across the cytoplasmic membrane by the Sec factors. Although a number of single-molecule analyses and structural studies, including the crystal structure of SecYEG complexed with SecA, have been published, the underlying molecular mechanisms and the functional oligomer states remain elusive. In this study, we constructed a fusion protein SecY-SecA, which induces the formation of the SecY-A/SecE/SecG complex (SecYAEG), to enable investigation of the molecular mechanisms by advanced single-molecule analyses. SecYAEG-reconstituted liposomes were found to possess protein translocation activity in vitro and form stable intermediates capable of the translocation using a mutant substrate protein. We additionally found that one unit of SecYAEG complex embedded into a nanodisc, using membrane scaffold proteins, interacts strongly with the substrate. The isolated SecYAEG-reconstituted nanodisc is a promising tool for investigation of the molecular mechanisms by which a single unit of Sec machinery mediates protein translocation. PMID- 28820901 TI - Using local ecological knowledge to monitor threatened Mekong megafauna in Lao PDR. AB - Pressures on freshwater biodiversity in Southeast Asia are accelerating yet the status and conservation needs of many of the region's threatened fish species are unclear. This impacts the ability to implement conservation activities and to understand the effects of infrastructure developments and other hydrological changes. We used Local Ecological Knowledge from fishing communities on the Mekong River in the Siphandone waterscape, Lao PDR to estimate mean and mode last capture dates of eight rare or culturally significant fish species in order to provide conservation monitoring baselines. One hundred and twenty fishermen, from six villages, were interviewed. All eight species had been captured, by at least one of the interviewees, within the waterscape within the past year. However the mean and mode last capture dates varied between the species. Larger species, and those with higher Red List threat status, were caught less recently than smaller species of less conservation concern. The status of the Critically Endangered Pangasius sanitwongsei (mean last capture date 116.4 months) is particularly worrying suggesting severe population decline although cultural issues may have caused this species to have been under-reported. This highlights that studies making use of Local Ecological Knowledge need to understand the cultural background and context from which data is collected. Nevertheless we recommend our approach, of stratified random interviews to establish mean last capture dates, may be an effective methodology for monitoring freshwater fish species of conservation concern within artisanal fisheries. If fishing effort remains relatively constant, or if changes in fishing effort are accounted for, differences over time in mean last capture dates are likely to represent changes in the status of species. We plan to repeat our interview surveys within the waterscape as part of a long-term fish-monitoring program. PMID- 28820902 TI - From hospitalization records to surveillance: The use of local patient profiles to characterize cholera in Vellore, India. AB - Despite availability of high quality medical records, health care systems often do not have the resources or tools to utilize these data efficiently. Yet, hospital-based, laboratory-confirmed records may pave the way for building reliable surveillance systems capable of monitoring temporal trends of emerging infections. In this communication, we present a new tool to compress and visualize medical records with a local population profile (LPP) approach, which transforms information into statistically comparable patterns. We provide a step by-step tutorial on how to build, interpret, and expand the use of LPP using hospitalization records of laboratory-confirmed cholera. We abstracted case information from the databases maintained by the Department of Clinical Microbiology at Christian Medical College in Vellore, India. We used a single year age distribution to construct LPPs for O1, O139, and non O1/O139 serotypes of Vibrio cholerae. Disease counts and hospitalization rates were converted into fitted kernel-based probability densities. We formally compared LPPs with the Kolmogorov-Smirnov test, and created multi-panel visuals to depict temporal trend, age distribution, and hospitalization rates simultaneously. Our first implementation of LPPs revealed information that is typically gathered from surveillance systems such as: i) estimates of the demographic distribution of diseases and identification of a population at risk, ii) changes in the dominant pathogen presence; and iii) trends in disease occurrence. The LPP demonstrated the benefit of increased resolution in pattern detection of disease for different Vibrio cholerae serotypes and two demographic categories by showing patterns and anomalies that would be obscured by traditional methods of analysis and visualization. LPP can be used effectively to compile basic patient information such as age, sex, diagnosis, location, and time into compact visuals. Future development of the proposed approach will allow public health researchers and practitioners to broadly utilize and efficiently compress large volumes of medical records without loss of information. PMID- 28820903 TI - Prominent facilitation at beta and gamma frequency range revealed with physiological calcium concentration in adult mouse piriform cortex in vitro. AB - Neuronal activity is characterized by a diversity of oscillatory phenomena that are associated with multiple behavioral and cognitive processes, yet the functional consequences of these oscillations are not fully understood. Our aim was to determine whether and how these different oscillatory activities affect short-term synaptic plasticity (STP), using the olfactory system as a model. In response to odorant stimuli, the olfactory bulb displays a slow breathing rhythm as well as beta and gamma oscillations. Since the firing of olfactory bulb projecting neurons is phase-locked with beta and gamma oscillations, structures downstream from the olfactory bulb should be driven preferentially at these frequencies. We examined STP exhibited by olfactory bulb inputs in slices of adult mouse piriform cortex maintained in vitro in an in vivo-like ACSF (calcium concentration: 1.1 mM). We replaced the presynaptic neuronal firing rate by repeated electrical stimulation (frequency between 3.125 and 100 Hz) applied to the lateral olfactory tract. Our results revealed a considerable enhancement of postsynaptic response amplitude for stimulation frequencies in the beta and gamma range. A phenomenological model of STP fitted to the data suggests that the experimental results can be explained by the interplay between three mechanisms: a short-term facilitation mechanism (time constant ~160 msec), and two short-term depression mechanisms (recovery time constants <20 msec and ~140 msec). Increasing calcium concentration (2.2 mM) resulted in an increase in the time constant of facilitation and in a strengthening of the slowest depression mechanism. As a result, response enhancement was reduced and its peak shifted toward the low beta and alpha ranges while depression became predominant in the gamma band. Using environmental conditions corresponding to those that prevail in vivo, our study shows that STP in the lateral olfactory tract to layer Ia synapse allows amplification of olfactory bulb inputs at beta and gamma frequencies. PMID- 28820904 TI - Parametric studies of metabolic cooperativity in Escherichia coli colonies: Strain and geometric confinement effects. AB - Characterizing the complex spatial and temporal interactions among cells in a biological system (i.e. bacterial colony, microbiome, tissue, etc.) remains a challenge. Metabolic cooperativity in these systems can arise due to the subtle interplay between microenvironmental conditions and the cells' regulatory machinery, often involving cascades of intra- and extracellular signalling molecules. In the simplest of cases, as demonstrated in a recent study of the model organism Escherichia coli, metabolic cross-feeding can arise in monoclonal colonies of bacteria driven merely by spatial heterogeneity in the availability of growth substrates; namely, acetate, glucose and oxygen. Another recent study demonstrated that even closely related E. coli strains evolved different glucose utilization and acetate production capabilities, hinting at the possibility of subtle differences in metabolic cooperativity and the resulting growth behavior of these organisms. Taking a first step towards understanding the complex spatio temporal interactions within microbial populations, we performed a parametric study of E. coli growth on an agar substrate and probed the dependence of colony behavior on: 1) strain-specific metabolic characteristics, and 2) the geometry of the underlying substrate. To do so, we employed a recently developed multiscale technique named 3D dynamic flux balance analysis which couples reaction-diffusion simulations with iterative steady-state metabolic modeling. Key measures examined include colony growth rate and shape (height vs. width), metabolite production/consumption and concentration profiles, and the emergence of metabolic cooperativity and the fractions of cell phenotypes. Five closely related strains of E. coli, which exhibit large variation in glucose consumption and organic acid production potential, were studied. The onset of metabolic cooperativity was found to vary substantially between these five strains by up to 10 hours and the relative fraction of acetate utilizing cells within the colonies varied by a factor of two. Additionally, growth with six different geometries designed to mimic those that might be found in a laboratory, a microfluidic device, and inside a living organism were considered. Geometries were found to have complex, often nonlinear effects on colony growth and cross-feeding with "hard" features resulting in larger effect than "soft" features. These results demonstrate that strain-specific features and spatial constraints imposed by the growth substrate can have significant effects even for microbial populations as simple as isogenic E. coli colonies. PMID- 28820905 TI - Estimating the evidential value of significant results in psychological science. AB - Quantifying evidence is an inherent aim of empirical science, yet the customary statistical methods in psychology do not communicate the degree to which the collected data serve as evidence for the tested hypothesis. In order to estimate the distribution of the strength of evidence that individual significant results offer in psychology, we calculated Bayes factors (BF) for 287,424 findings of 35,515 articles published in 293 psychological journals between 1985 and 2016. Overall, 55% of all analyzed results were found to provide BF > 10 (often labeled as strong evidence) for the alternative hypothesis, while more than half of the remaining results do not pass the level of BF = 3 (labeled as anecdotal evidence). The results estimate that at least 82% of all published psychological articles contain one or more significant results that do not provide BF > 10 for the hypothesis. We conclude that due to the threshold of acceptance having been set too low for psychological findings, a substantial proportion of the published results have weak evidential support. PMID- 28820906 TI - Exposure to fine particulate matter in the air alters placental structure and the renin-angiotensin system. AB - METHODS: Female Wistar rats were exposed to filtered air (F) or to concentrated fine particulate matter (P) for 15 days. After mating, the rats were divided into four groups and again exposed to F or P (FF, FP, PF, PP) beginning on day 6 of pregnancy. At embryonic day 19, the placenta was collected. The placental structure, the protein and gene expression of TGFbeta1, VEGF-A, and its receptor Flk-1 and RAS were evaluated by indirect ELISA and quantitative real-time PCR. RESULTS: Exposure to P decreased the placental mass, size, and surface area as well as the TGFbeta1, VEGF-A and Flk-1 content. In the maternal portion of the placenta, angiotensin II (AngII) and its receptors AT1 (AT1R) and AT2 (AT2R) were decreased in the PF and PP groups. In the fetal portion of the placenta, AngII in the FP, PF and PP groups and AT2R in the PF and PP groups were decreased, but AT1R was increased in the FP group. VEGF-A gene expression was lower in the PP group than in the FF group. CONCLUSIONS: Exposure to pollutants before and/or during pregnancy alters some characteristics of the placenta, indicating a possible impairment of trophoblast invasion and placental angiogenesis with possible consequences for the maternal-fetal interaction, such as a limitation of fetal nutrition and growth. PMID- 28820907 TI - Positive regulatory interactions between YAP and Hedgehog signalling in skin homeostasis and BCC development in mouse skin in vivo. AB - Skin is a highly plastic tissue that undergoes tissue turnover throughout life, but also in response to injury. YAP and Hedgehog signalling play a central role in the control of epidermal stem/progenitor cells in the skin during embryonic development, in postnatal tissue homeostasis and in skin carcinogenesis. However, the genetic contexts in which they act to control tissue homeostasis remain mostly unresolved. We provide compelling evidence that epidermal YAP and Hedgehog/GLI2 signalling undergo positive regulatory interactions in the control of normal epidermal homeostasis and in basal cell carcinoma (BCC) development, which in the large majority of cases is caused by aberrant Hedgehog signalling activity. We report increased nuclear YAP and GLI2 activity in the epidermis and BCCs of K14-CreER/Rosa-SmoM2 transgenic mouse skin, accompanied with increased ROCK signalling and ECM remodelling. Furthermore, we found that epidermal YAP activity drives GLI2 nuclear accumulation in the skin of YAP2-5SA-DeltaC mice, which depends on epidermal beta-catenin activation. Lastly, we found prominent nuclear activity of GLI2, YAP and beta-catenin, concomitant with increased ROCK signalling and stromal fibrosis in human BCC. Our work provides novel insights into the molecular mechanisms underlying the interplay between cell signalling events and mechanical force in normal tissue homeostasis in vivo, that could potentially be perturbed in BCC development. PMID- 28820908 TI - Ribosomopathy-like properties of murine and human cancers. AB - Ribosomopathies comprise a heterogeneous group of hematologic and developmental disorders, often characterized by bone marrow failure, skeletal and other developmental abnormalities and cancer predisposition. They are associated with mutations and/or haplo-insufficiencies of ribosomal proteins (RPs) and inefficient ribosomal RNA (rRNA) processing. The resulting ribosomal stress induces the canonical p19ARF/Mdm2/p53 tumor suppressor pathway leading to proliferative arrest and/or apoptosis. It has been proposed that this pathway is then inactivated during subsequent neoplastic evolution. We show here that two murine models of hepatoblastoma (HB) and hepatocellular carcinoma (HCC) unexpectedly possess features that mimic the ribosomopathies. These include loss of the normal stoichiometry of RP transcripts and proteins and the accumulation of unprocessed rRNA precursors. Silencing of p19ARF, cytoplasmic sequestration of p53, binding to and inactivation of Mdm2 by free RPs, and up-regulation of the pro-survival protein Bcl-2 may further cooperate to drive tumor growth and survival. Consistent with this notion, re-instatement of constitutive p19ARF expression in the HB model completely suppressed tumorigenesis. In >2000 cases of human HCC, colorectal, breast, and prostate cancer, RP transcript deregulation was a frequent finding. In HCC and breast cancer, the severity of this dysregulation was associated with inferior survival. In HCC, the presence of RP gene mutations, some of which were identical to those previously reported in ribosomopathies, were similarly negatively correlated with long-term survival. Taken together, our results indicate that many if not all cancers possess ribosomopathy-like features that may affect their biological behaviors. PMID- 28820909 TI - Dose of physical activity, physical functioning and disability risk in mobility limited older adults: Results from the LIFE study randomized trial. AB - : Understanding the minimal dose of physical activity required to achieve improvement in physical functioning and reductions in disability risk is necessary to inform public health recommendations. To examine the effect of physical activity dose on changes in physical functioning and the onset of major mobility disability in The Lifestyle Interventions and Independence for Elders (LIFE) Study. We conducted a multicenter single masked randomized controlled trial that enrolled participants in 2010 and 2011 and followed them for an average of 2.6 years. 1,635 sedentary men and women aged 70-89 years who had functional limitations were randomized to a structured moderate intensity walking, resistance, and flexibility physical activity program or a health education program. Physical activity dose was assessed by 7-day accelerometry and self-report at baseline and 24 months. Outcomes included the 400 m walk gait speed, the Short Physical Performance Battery (SPPB), assessed at baseline, 6, 12, and 24 months, and onset of major mobility disability (objectively defined by loss of ability to walk 400 m in 15 min). When the physical activity arm or the entire sample were stratified by change in physical activity from baseline to 24 months, there was a dose-dependent increase in the change in gait speed and SPPB from baseline at 6, 12, and 24 months. In addition, the magnitude of change in physical activity over 24 months was related to the reduction in the onset of major mobility disability (overall P < 0.001) (highest versus the lowest quartile of physical activity change HR 0.23 ((95% CI:0.10-0.52) P = 0.001) in the physical activity arm. We observed a dose-dependent effect of objectively monitored physical activity on physical functioning and onset of major mobility disability. Relatively small increases (> 48 minutes per week) in regular physical activity participation had significant and clinically meaningful effects on these outcomes. TRIAL REGISTRATION: ClinicalsTrials.gov NCT00116194. PMID- 28820910 TI - Impaired dendritic growth and positioning of cortical pyramidal neurons by activation of aryl hydrocarbon receptor signaling in the developing mouse. AB - The basic helix-loop-helix (bHLH) transcription factors exert multiple functions in mammalian cerebral cortex development. The aryl hydrocarbon receptor (AhR), a member of the bHLH-Per-Arnt-Sim subfamily, is a ligand-activated transcription factor reported to regulate nervous system development in both invertebrates and vertebrates, but the functions that AhR signaling pathway may have for mammalian cerebral cortex development remains elusive. Although the endogenous ligand involved in brain developmental process has not been identified, the environmental pollutant dioxin potently binds AhR and induces abnormalities in higher brain function of laboratory animals. Thus, we studied how activation of AhR signaling influences cortical development in mice. To this end, we produced mice expressing either constitutively active-AhR (CA-AhR), which has the capacity for ligand-independent activation of downstream genes, or AhR, which requires its ligands for activation. In brief, CA-AhR-expressing plasmid and AhR-expressing plasmid were each transfected into neural stems cells in the developing cerebrum by in utero electroporation on embryonic day 14.5. On postnatal day 14, mice transfected in utero with CA-AhR, but not those transfected with AhR, exhibited drastically reduced dendritic arborization of layer II/III pyramidal neurons and impaired neuronal positioning in the developing somatosensory cortex. The effects of CA-AhR were observed for dendrite development but not for the commissural fiber projection, suggesting a preferential influence on dendrites. The present results indicate that over-activation of AhR perturbs neuronal migration and morphological development in mammalian cortex, supporting previous observations of impaired dendritic structure, cortical dysgenesis, and behavioral abnormalities following perinatal dioxin exposure. PMID- 28820911 TI - Phosphatidlyinositol-3-kinase C2 beta (PI3KC2beta) is a potential new target to treat IgE mediated disease. AB - Cross linking of the IgE receptor (FcepsilonRI) on mast cells plays a critical role in IgE-dependent allergy including allergic rhinitis, asthma, anaphylaxis, and delayed type hypersensitivity reactions. The Ca2+ activated K+ channel, KCa3.1, plays a critical role in IgE-stimulated Ca2+ entry and degranulation in mast cells by helping to maintain a negative membrane potential, which provides an electrochemical gradient to drive Ca2+ influx. Of the 3 classes of PI3K, the class II PI3Ks are the least studied and little is known about the roles for class II PI3Ks in vivo in the context of the whole organism under normal and pathological conditions. Studying bone marrow derived mast cells (BMMC) isolated from PI3KC2beta-/- mice, we now show that the class II PI3KC2beta is critical for FcepsilonRI stimulated KCa3.1 channel activation and the subsequent activation of mast cells. We found FcepsilonRI-stimulated Ca2+ entry, cytokine production, and degranulation are decreased in BMMC isolated from PI3KC2beta-/- mice. In addition, PI3KC2beta-/- mice are markedly resistant to both passive cutaneous and passive systemic anaphylaxis. These findings identify PI3KC2beta as a new pharmacologic target to treat IgE-mediated disease. PMID- 28820913 TI - Erratum to: Numerical method to compute acoustic scattering effect of a moving source. AB - [This corrects the article DOI: 10.1186/s40064-016-3080-x.]. PMID- 28820912 TI - Impact of novel palmitoylated prolactin-releasing peptide analogs on metabolic changes in mice with diet-induced obesity. AB - Analogs of anorexigenic neuropeptides, such as prolactin-releasing peptide (PrRP), have a potential as new anti-obesity drugs. In our previous study, palmitic acid attached to the N-terminus of PrRP enabled its central anorexigenic effects after peripheral administration. In this study, two linkers, gamma glutamic acid at Lys11 and a short, modified polyethylene glycol at the N terminal Ser and/or Lys11, were applied for the palmitoylation of PrRP31 to improve its bioavailability. These analogs had a high affinity and activation ability to the PrRP receptor GPR10 and the neuropeptide FF2 receptor, as well as short-term anorexigenic effect similar to PrRP palmitoylated at the N-terminus. Two-week treatment with analogs that were palmitoylated through linkers to Lys11 (analogs 1 and 2), but not with analog modified both at the N-terminus and Lys11 (analog 3) decreased body and liver weights, insulin, leptin, triglyceride, cholesterol and free fatty acid plasma levels in a mouse model of diet-induced obesity. Moreover, the expression of uncoupling protein-1 was increased in brown fat suggesting an increase in energy expenditure. In addition, treatment with analogs 1 and 2 but not analog 3 significantly decreased urinary concentrations of 1-methylnicotinamide and its oxidation products N-methyl-2-pyridone-5 carboxamide and N-methyl-4-pyridone-3-carboxamide, as shown by NMR-based metabolomics. This observation confirmed the previously reported increase in nicotinamide derivatives in obesity and type 2 diabetes mellitus and the effectiveness of analogs 1 and 2 in the treatment of these disorders. PMID- 28820914 TI - Erratum to: Associations between adherence, depressive symptoms and health related quality of life in young adults with cystic fibrosis. AB - [This corrects the article DOI: 10.1186/s40064-016-2862-5.]. PMID- 28820916 TI - The Solar Eclipse of 2017-A (Protected) View From the Path of Totality. PMID- 28820915 TI - Erratum to: Implication of Paris Agreement in the context of long-term climate mitigation goals. AB - [This corrects the article DOI: 10.1186/s40064-016-3235-9.]. PMID- 28820918 TI - Safely Viewing Solar Eclipses. PMID- 28820917 TI - Whole Exome Sequencing of Lacrimal Gland Adenoid Cystic Carcinoma. AB - Purpose: To identify genomic mutations in lacrimal gland adenoid cystic carcinoma (LGACC) samples from patients. Methods: Genomic DNA was extracted from LGACC specimens. Whole exome sequencing (exome-seq) was conducted to screen for mutations. Capillary sequencing was performed to verify mutations in genes shared by multiple samples. Luciferase assays were used to evaluate functional consequences of NOTCH1 mutations. Results: The mutation profile of LGACC was complicated. The most frequently mutated gene observed (28.6%) was bromodomain PHD finger transcription factor (BPTF). No mutation was identified in common cancer genes such as TP53, KRAS, and BRAF. However, mutations predicted to be functionally severe were accumulated in the Notch signaling pathway including NOTCH1 and NOTCH2, of which mutations have been reported in head/neck adenoid cystic carcinoma (ACC). Of 14 LGACC samples, five samples carry mutations in Notch pathway genes. Capillary sequencing verified all the mutations in the two NOTCH genes identified by exome-seq. Compared to the wild-type NOTCH1, three frame shifting mutations and two missense mutations (C387W and L1600Q) increased luciferase activity approximately 10- to 25-fold. Conclusions: Major genomic mutation profiles in LGACC were uncovered by exome-seq. Although preliminary in nature, the Notch pathway could be a potential therapeutic target for LGACC. PMID- 28820920 TI - Presumed Solar Retinopathy in Child With Juvenile Open-Angle Glaucoma. PMID- 28820919 TI - A Preliminary Comparison of Reading Subtypes in a Clinical Sample of Children With Specific Language Impairment. AB - Purpose: The purpose of this preliminary study was to (a) compare the pattern of reading subtypes among a clinical sample of children with specific language impairment (SLI) and children with typical language and (b) evaluate phonological and nonphonological language deficits within each reading impairment subtype. Method: Participants were 32 children with SLI and 39 children with typical language in Grades 2 through 4. Each child was classified as demonstrating 1 of 4 reading subtypes on the basis of word-level and text-level skills: typical reading, dyslexia, specific reading comprehension impairment, or garden variety reading impairment. In addition, phonological and nonphonological language skills were evaluated. Results: Children with SLI were more likely to exhibit reading impairments than children with typical language. Children with SLI were more likely to exhibit text-level deficits than children with typical language. Phonological language deficits were observed in children with word-level deficits, and nonphonological language deficits were observed in children with text-level deficits. Conclusions: The results indicate that the patterns of reading subtypes differ among children with SLI and children with typical language. The findings highlight the importance of simultaneously but separately considering word-level and text-level skills in studies of reading impairment. PMID- 28820921 TI - Analysis of Cone Mosaic Reflectance Properties in Healthy Eyes and in Eyes With Nonproliferative Diabetic Retinopathy Over Time. AB - Purpose: We investigate the reflectance properties of the cone mosaic in adaptive optics (AO) images of healthy subjects and subjects with nonproliferative diabetic retinopathy (NPDR) over time. Methods: We acquired images of the parafoveal cone mosaic over 5 years in 12 healthy subjects and in six patients with mild NPDR. We analyzed the parameters of the cone intensity histogram distribution (mean, SD, and skewness), two metrics of the cone mosaic texture (sharpness and entropy), and two novel metrics (cone/intercone intensity and slope of the variogram). Each metric was calculated on the same four retinal locations (200 * 200 MUm areas, 2 degrees from the fovea along the four meridians) over time for each subject. Results: The histogram distributions of cone intensities were similar between the two study groups. However, the cone/intercone intensity, slope of the variograms and entropy showed a significant difference between healthy and NPDR subjects (P = 0.036, P = 0.002, P = 0.014, respectively). All parameters, except for mean cone intensity, did not change with time in this study. Conclusions: We observed significant differences in cone mosaic reflectance properties between healthy eyes and eyes with NPDR, in its spatial organization and in its intensity, especially between directional and nondirectional backscattering. We introduced a novel method for the study of the spatial distribution of cone reflectance, the variogram, which was able to quantify differences of the spatial dependence of cone intensities over a short range between NPDR and healthy eyes. PMID- 28820924 TI - Author Response: Do High mtDNA Copy Numbers Truly Prevent LHON Manifestations? PMID- 28820922 TI - A Self-Assembling Peptide Gel as a Vitreous Substitute: A Rabbit Study. AB - Purpose: To evaluate a self-assembling peptide gel as a potential vitreous substitute. Methods: PanaceaGel SPG-178, a self-assembling peptide gel, was diluted with distilled water and a balanced salt solution to achieve a final peptide concentration of 0.1%. The gel's refractive index, visible light transmission rate, and rheologic properties were investigated. The gel's biocompatibility was evaluated by examining the cellular viability (live and dead staining) and proliferation rate (alamarBlue assay). A 25-G pars plana vitrectomy was performed on the right eye of 21 New Zealand white rabbits. The gel was then injected into the vitreous cavity of 15 eyes. Six eyes were injected with a balanced salt solution (BSS) and served as controls. Toxicity was examined using electroretinography and histologic analysis after the injection of the gel. Results: The gel's physical properties closely resembled those of human vitreous. The gel showed no apparent toxicity. When the gel was injected into the vitreous cavity, fragmentation was not observed. Additionally, the gel remained transparent in the vitreous cavity and no complications were observed for 3 months after the injection. Electroretinography and histology confirmed the gel's biocompatibility. Conclusions: This diluted self-assembling peptide gel could be provide a promising vitreous substitute. PMID- 28820923 TI - Do High mtDNA Copy Numbers Truly Prevent LHON Manifestations? PMID- 28820926 TI - Treatment of Convergence Insufficiency. PMID- 28820925 TI - Oxidative Stress-Related Molecular Biomarker Candidates for Glaucoma. AB - Purpose: Glaucoma-related molecular biomarkers can improve clinical testing to diagnose the disease early, predict its prognosis, and monitor treatment responses. Based on the evidence of increased oxidative stress in glaucomatous tissues, this study analyzed oxidative stress-related biomarker candidates in blood and aqueous humor samples with or without glaucoma. Methods: The blood and aqueous humor samples collected from carefully selected groups of 96 patients with glaucoma and 64 healthy subjects without glaucoma were included in the study. The samples were analyzed for protein carbonyls and advanced glycation end products (AGEs) through ELISA-based quantification assays. To allow proper comparisons, the Goldmann-Witmer coefficient that reflects the ratio of aqueous humor to blood values corrected to total protein concentration in individual samples was calculated. Results: Blood and aqueous humor levels of protein carbonyls and AGEs were found significantly higher in glaucomatous samples compared with age-matched nonglaucomatous controls (P < 0.001). The glaucoma related increase in protein carbonyls and AGEs was more prominent in aqueous humor samples than blood samples (2.6-fold versus 1.9-fold for protein carbonyls, and 3.1-fold versus 1.9-fold for AGEs; P < 0.001). Comparison of the Goldmann Witmer coefficients indicated greater values for protein carbonyls (1.37 +/- 0.3 vs. 3.07 +/- 0.8) and AGEs (1.2 +/- 0.3 vs. 3.2 +/- 1.1) in the glaucoma group (P < 0.001). Conclusions: Findings of this study encourage further validation studies of oxidative stress-related biomarkers in glaucoma. Analysis of protein carbonyls and AGEs in longitudinal studies of larger and heterogeneous patient cohorts should better assess the value of these promising candidates as molecular biomarkers of glaucoma for clinical predictions. PMID- 28820927 TI - "My Son's Darker Eye Also Has Increased Pressure". PMID- 28820928 TI - The Wild-Type NF1 Gene: It's a Real Turnoff. PMID- 28820929 TI - The Use of Electronic Devices for the Treatment of Amblyopia. PMID- 28820930 TI - Comparison of Minimally Invasive Strabismus Surgery (MISS) and Conventional Strabismus Surgery Using the Limbal Approach. AB - PURPOSE: To compare minimally invasive strabismus surgery (MISS) with conventional strabismus surgery for horizontal recti in terms of functional outcome and complications. METHODS: A total of 40 patients requiring surgery for horizontal recti were divided into two groups: those undergoing MISS and those operated on using the conventional limbal technique. In the MISS group, two small keyhole radial cuts were made superior and inferior to the insertion of the muscle margin. Keyhole cut size was almost 1 mm less than the amount of muscle recessed or resected. RESULTS: There were significant differences in conjunctival redness and swelling in both groups on postoperative days 1 and 7 and week 3. However, after the third week, both groups had a similar appearance. Visual acuity was decreased at postoperative day 1 in both groups, but the difference was not significant. No significant differences were found for final alignment, binocular single vision, other visual acuities, refractive changes, or complications. CONCLUSIONS: This study shows that this new, small incision, minimal dissection technique is feasible. The MISS technique seems to be superior in the immediate postoperative period because there were fewer conjunctival and eyelid swelling complications. Long-term results did not differ between the two groups. [J Pediatr Ophthalmol Strabismus. 2017;54(4):208-215.]. PMID- 28820931 TI - String of Pearls: Macroaneurysms in Coats Disease. PMID- 28820932 TI - Titanium Oxynitride Thin Films with Tunable Double Epsilon-Near-Zero Behavior for Nanophotonic Applications. AB - Titanium oxynitride (TiOxNy) thin films are fabricated using reactive magnetron sputtering. The mechanism of their growth formation is explained, and their optical properties are presented. The films grown when the level of residual oxygen in the background vacuum was between 5 nTorr to 20 nTorr exhibit double epsilon-near-Zero (2-ENZ) behavior with ENZ1 and ENZ2 wavelengths tunable in the 700-850 and 1100-1350 nm spectral ranges, respectively. Samples fabricated when the level of residual oxygen in the background vacuum was above 2 * 10-8 Torr exhibit nonmetallic behavior, while the layers deposited when the level of residual oxygen in the background vacuum was below 5 * 10-9 Torr show metallic behavior with a single ENZ value. The double ENZ phenomenon is related to the level of residual oxygen in the background vacuum and is attributed to the mixture of TiN and TiOxNy and TiOx phases in the films. Varying the partial pressure of nitrogen during the deposition can further control the amount of TiN, TiOx, and TiOxNy compounds in the films and, therefore, tune the screened plasma wavelengths. A good approximation of the ellipsometric behavior is achieved with Maxwell-Garnett theory for a composite film formed by a mixture of TiO2 and TiN phases suggesting that double ENZ TiOxNy films are formed by inclusions of TiN within a TiO2 matrix. These oxynitride compounds could be considered as new materials exhibiting double ENZ in the visible and near-IR spectral ranges. Materials with ENZ properties are advantageous for designing the enhanced nonlinear optical response, metasurfaces, and nonreciprocal behavior. PMID- 28820933 TI - Surface Chemistry of La0.99Sr0.01NbO4-d and Its Implication for Proton Conduction. AB - Acceptor-doped LaNbO4 is a promising electrolyte material for proton-conducting fuel cell (PCFC) applications. As charge transfer processes govern device performance, the outermost surface of acceptor-doped LaNbO4 will play an important role in determining the overall cell performance. However, the surface composition is poorly characterized, and the understanding of its impact on the proton exchange process is rudimentary. In this work, the surface chemistry of 1 atom % Sr-doped LaNbO4 (La0.99Sr0.01NbO4-d, denoted as LSNO) proton conductor is characterized using LEIS and SIMS. The implication of a surface layer on proton transport is studied using the isotopic exchange technique. It has shown that a Sr-enriched but La-deficient surface layer of about 6-7 nm thick forms after annealing the sample under static air at 1000 degrees C for 10 h. The onset of segregation is found to be between 600 and 800 degrees C, and an equilibrium surface layer forms after 10 h annealing. A phase separation mechanism, due to the low solubility of Sr in LaNbO4, has been proposed to explain the observed segregation behavior. The surface layer was concluded to impede the water incorporation process, leading to a reduced isotopic fraction after the D216O wet exchange process, highlighting the impact of surface chemistry on the proton exchange process. PMID- 28820935 TI - Accelerating Palladium Nanowire H2 Sensors Using Engineered Nanofiltration. AB - The oxygen, O2, in air interferes with the detection of H2 by palladium (Pd) based H2 sensors, including Pd nanowires (NWs), depressing the sensitivity and retarding the response/recovery speed in air-relative to N2 or Ar. Here, we describe the preparation of H2 sensors in which a nanofiltration layer consisting of a Zn metal-organic framework (MOF) is assembled onto Pd NWs. Polyhedron particles of Zn-based zeolite imidazole framework (ZIF-8) were synthesized on lithographically patterned Pd NWs, leading to the creation of ZIF-8/Pd NW bilayered H2 sensors. The ZIF-8 filter has many micropores (0.34 nm for gas diffusion) which allows for the predominant penetration of hydrogen molecules with a kinetic diameter of 0.289 nm, whereas relatively larger gas molecules including oxygen (0.345 nm) and nitrogen (0.364 nm) in air are effectively screened, resulting in superior hydrogen sensing properties. Very importantly, the Pd NWs filtered by ZIF-8 membrane (Pd NWs@ZIF-8) reduced the H2 response amplitude slightly (DeltaR/R0 = 3.5% to 1% of H2 versus 5.9% for Pd NWs) and showed 20-fold faster recovery (7 s to 1% of H2) and response (10 s to 1% of H2) speed compared to that of pristine Pd NWs (164 s for response and 229 s for recovery to 1% of H2). These outstanding results, which are mainly attributed to the molecular sieving and acceleration effect of ZIF-8 covered on Pd NWs, rank highest in H2 sensing speed among room-temperature Pd-based H2 sensors. PMID- 28820934 TI - Supramolecular Sensors for Opiates and Their Metabolites. AB - The present study highlights a sensing approach for opiates using acyclic cucurbituril (aCBs) sensors comprising four glycouril units terminated on both ends with naphthalene fluorophore walls. The connectivity between the glycourils and naphthalene rings largely defines the opening size of the cucurbituril cavity and its diameter. The large hydrophobic binding cavity is flexible and is able to adapt to guests of various size and topology. The recognition event between the aCBs and guests results in modification of the fluorescence of the terminal walls, a fluorescence response that can be used to sense the drugs of abuse morphine, heroin, and oxycodone as well as their metabolites. Molecular dynamics is employed to understand the nature of the binding interactions. A simple three sensor cross-reactive array enables the determination of drugs and their metabolites in water with high fidelity and low error. Quantitative experiments performed in urine using a new three-way calibration model allows for determination of drugs and their metabolites using one sensor from a single fluorescence reading. PMID- 28820936 TI - Elucidating Substrate Promiscuity within the FabI Enzyme Family. AB - The rapidly growing appreciation of enzymes' catalytic and substrate promiscuity may lead to their expanded use in the fields of chemical synthesis and industrial biotechnology. Here, we explore the substrate promiscuity of enoyl-acyl carrier protein reductases (commonly known as FabI) and how that promiscuity is a function of inherent reactivity and the geometric demands of the enzyme's active site. We demonstrate that these enzymes catalyze the reduction of a wide range of substrates, particularly alpha,beta-unsaturated aldehydes. In addition, we demonstrate that a combination of quantum mechanical hydride affinity calculations and molecular docking can be used to rapidly categorize compounds that FabI can use as substrates. The results here provide new insight into the determinants of catalysis for FabI and set the stage for the development of a new assay for drug discovery, organic synthesis, and novel biocatalysts. PMID- 28820937 TI - Impact of Shell Thickness on Photoluminescence and Optical Activity in Chiral CdSe/CdS Core/Shell Quantum Dots. AB - Core/shell quantum dots (QDs) are of high scientific and technological importance as these nanomaterials have found a number of valuable applications. In this paper, we have investigated the dependence of optical activity and photoluminescence upon CdS shell thickness in a range of core-shell structured CdSe/CdS QDs capped with chiral ligands. For our study, five samples of CdSe/CdS were synthesized utilizing successive ion layer adsorption and reaction to vary the thickness of the CdS shell from 0.5 to 2 nm, upon a 2.8 nm diameter CdSe core. Following this, a ligand exchange of the original aliphatic ligands with l- and d-cysteine was carried out, inducing a chiroptical response in these nanostructures. The samples were then characterized using circular dichroism, photoluminescent spectroscopy, and fluorescence lifetime spectroscopy. It has been found that the induced chiroptical response was inversely proportional to the CdS shell thickness and showed a distinct evolution in signal, whereas the photoluminescence of our samples showed a direct relationship to shell thickness. In addition, a detailed study of the influence of annealing time on the optical activity and photoluminescence quantum yield was performed. From our work, we have been able to clearly illustrate the approach and strategies that must be used when designing optimal photoluminescent optically active CdSe/CdS core-shell QDs. PMID- 28820938 TI - Multiscale Simulation of Receptor-Drug Association Kinetics: Application to Neuraminidase Inhibitors. AB - A detailed understanding of the drug-receptor association process is of fundamental importance for drug design. Due to the long time scales of typical binding kinetics, the atomistic simulation of the ligand traveling from bulk solution into the binding site is still computationally challenging. In this work, we apply a multiscale approach of combined Molecular Dynamics (MD) and Brownian Dynamics (BD) simulations to investigate association pathway ensembles for the two prominent H1N1 neuraminidase inhibitors oseltamivir and zanamivir. Including knowledge of the approximate binding site location allows for the selective confinement of detailed but expensive MD simulations and application of less demanding BD simulations for the diffusion controlled part of the association pathway. We evaluate a binding criterion based on the residence time of the inhibitor in the binding pocket and compare it to geometric criteria that require prior knowledge about the binding mechanism. The method ranks the association rates of both inhibitors in qualitative agreement with experiment and yields reasonable absolute values depending, however, on the reaction criteria. The simulated association pathway ensembles reveal that, first, ligands are oriented in the electrostatic field of the receptor. Subsequently, a salt bridge is formed between the inhibitor's carboxyl group and neuraminidase residue Arg368, followed by adopting the native binding mode. Unexpectedly, despite oseltamivir's higher overall association rate, the rate into the intermediate salt-bridge state was found to be higher for zanamivir. The present methodology is intrinsically parallelizable and, although computationally demanding, allows systematic binding rate calculation on selected sets of potential drug molecules. PMID- 28820939 TI - Attachment of a RuII Complex to a Self-Folding Hexaamide Deep Cavitand. AB - We report the design, synthesis and characterization of a new RuII metallocavitand that is catalytically active in alkene epoxidation reactions. The elaboration of the resorcin[4]arene's aromatic cavity produced a self-folding, deep hexaamide cavitand featuring a single diverging terpyridine (tpy) group installed at its upper rim. The construction of the metallocavitand involved the initial chelation of a RuIII chloride complex by the tpy ligand followed by the incorporation of 2-(phenylazo)pyridine (azpy) as an ancillary ligand. The resulting RuII chloro complex was converted into the catalytically active aqua counterpart by a ligand exchange process. PMID- 28820940 TI - Polyoxometalate, Cationic Cluster, and gamma-Cyclodextrin: From Primary Interactions to Supramolecular Hybrid Materials. AB - Herein, we report on a three-component supramolecular hybrid system built from specific recognition processes involving a Dawson-type polyoxometalate (POM), [P2W18O62]6-, a cationic electron-rich cluster [Ta6Br12(H2O)6]2+, and gamma cyclodextrin (gamma-CD). Such materials have been investigated using a bottom-up approach by studying the specific interactions between gamma-CD and both types of inorganic units. Their ability to interact has been investigated in the solid state by single-crystal X-ray diffraction (XRD) and in solution using multinuclear NMR methods (including DOSY, EXSY, and COSY), electrospray ionization mass and UV-vis spectroscopies, electrochemistry, and isothermal titration calorimetry experiments. Single-crystal XRD analysis reveals that POM:gamma-CD constitutes a highly versatile system which gives aggregates with 1:1, 1:2, and 1:3 stoichiometry. Surprisingly, these arrangements exhibit a common feature wherein the gamma-CD moiety interacts with the Dawson-type POMs through its primary face. We present also the first structural model involving an octahedral-type metallic cluster with gamma-CD. XRD study reveals that the cationic [Ta6Br12(H2O)6]2+ ion is closely embedded within two gamma-CD units to give a supramolecular ditopic cation, suitable to be used as a linker within extended structure. Solution study demonstrates clearly that pre-associations exist in solution, for which binding constants and thermodynamic parameters have been determined, giving preliminary arguments about the chaotropic nature of the inorganic ions. Finally, both building blocks, i.e., the ditopic supramolecular cation {[Ta6Br12(H2O)6]@2CD}2+ and the Dawson-type anion, react together to give a three-component, well-ordered hybrid material derived either as a supramolecular hydrogel or single crystals. The solid-state structure shows an unprecedented helicoidal tubular chain resulting from the periodic alternation of POM and supramolecular cation, featuring short hydrogen-bonding contacts between the electron-poor POM and electron-rich cluster. The 1D tubular ionic polymer observed in the single crystals should make it possible to understand the long range ordering observed within the hydrogel hybrid material. The supramolecular chemical complementarities between the gamma-CD-based ditopic cation and POM open a wide scope for the design of hybrid materials that accumulate synergistic functionalities. PMID- 28820941 TI - A Photoactivatable Probe for Super-Resolution Imaging of Enzymatic Activity in Live Cells. AB - A dual-activatable, fluorogenic probe was developed to sense esterase activity with single-molecule resolution. Without enzymatic pre-activation, the diazoindanone-based probe has an electron-poor core and, upon irradiation, undergoes Wolff rearrangement to give a ring-expanded xanthene core that is nonemissive. If the probe is pre-activated by carboxylesterases, the tricyclic core becomes electron-rich, and the photoinduced Wolff rearrangement produces a highly emissive rhodol dye. Live-cell and solution studies confirmed the selectivity of the probe and revealed that the photoactivated dye does not diffuse away from the original location of activation because the intermediate ketene forms a covalent bond with surrounding macromolecules. Single-molecule localization microscopy was used to reconstruct a super-resolved image of esterase activity. These single-molecule images of enzymatic activity changed significantly upon treatment of the cells with inhibitors of human carboxylesterase I and II, both in terms of total number of signals and intracellular distribution. This proof-of-principle study introduces a sensing mechanism for single-molecule detection of enzymatic activity that could be applied to many other biologically relevant targets. PMID- 28820942 TI - Effects of Preheating and Storage Temperatures on Aroma Profile and Physical Properties of Citrus-Oil Emulsions. AB - Citrus oils are used as good carrier oil for emulsion fabrication due to their special flavor and various health-promoting functions. In this study, the effects of preheating temperature (30, 40, 50, 60, and 70 degrees C) and storage temperature (4, 25, and 37 degrees C) on aroma profiles and physical properties of three citrus-oil (i.e., mandarin, sweet orange, and bergamot oils) emulsions were systematically investigated for the first time. The results demonstrated the significant impact of temperature on aroma profile and physical properties. The abundance of d-limonene was found to be the main factor determining the aroma of the three citrus-oil emulsions at different preheating and storage temperatures, while beta-linalool and linalyl acetate were important for the aroma of bergamot oil emulsion. Preheating temperature showed a profound impact on the aroma of citrus-oil emulsions, and the aroma of different citrus oil emulsions showed different sensitivity to preheating temperature. Storage temperature was also able to alter the properties of citrus oil emulsions. The higher was the storage temperature, the more alteration of aroma and more instability of the emulsions there was, which could be attributed to the alteration of the oil components and the properties of emulsions. Among all three emulsions, bergamot-oil emulsion was the most stable and exhibited the most potent ability to preserve the aroma against high temperature. Our results would facilitate the application of citrus oil emulsions in functional foods and beverages. PMID- 28820943 TI - Active Site Flexibility of Mycobacterium tuberculosis Isocitrate Lyase in Dimer Form. AB - Tuberculosis (TB) still remains a global threat due to the emergence of a drug resistant strain. Instead of focusing on the drug target of active stage TB, we are highlighting the isocitrate lyase (ICL) at the dormant stage TB. ICL is one of the persistent factors for Mycobacterium tuberculosis (MTB) to survive during the dormant phase. In addition, the absence of ICL in human has made ICL a potential drug target for TB therapy. However, the dynamic details of ICL which could give insights to the ICL-ligand interaction have yet to be solved. Therefore, a series of ICL dimer dynamics studies through molecular dynamics simulation were performed in this work. The ICL active site entrance gate closure is contributed to by hydrogen bonding and electrostatic interactions with the C terminal. Analysis suggested that the open-closed behavior of the ICL active site entrance depends on the type of ligand present in the active site. We also observed four residues (Ser91, Asp108, Asp153, and Cys191) which could possibly be the nucleophiles for nucleophilic attack on the cleavage of isocitrate at the C2-C3 bond. We hope that the elucidation of ICL dynamics can benefit future works such as lead identification or antibody design against ICL for TB therapeutics. PMID- 28820944 TI - Exploration of Macroporous Polymeric Sponges As Drug Carriers. AB - Achieving high drug loading capacity and controlling drug delivery are two main challenges related to drug carriers. In this study, polymeric macroporous sponges with very high pore volume and large porosity are introduced as a new-type of drug carrier. Due to the high pore volume (285 and 166 cm3/g for the sponges with densities of 3.5 and 6.0 mg/cm3, respectively), the sponges exhibit very high drug loading capacities with average values of 1870 +/- 114 and 2697 +/- 73 mg/g in the present study, which is much higher than the meso and microporous drug carriers (<1500 mg/g). In order to control the release profiles, an additional poly(p-xylylene) (PPX) coating was deposited by chemical vapor deposition on the drug loaded sponge. Consequently, Artemisone (ART) release in the aqueous medium could be retarded, depending on the density of the sponge and the thickness of the coating. In future, the new 3D polymeric sponges would be highly beneficial as drug carriers for the programmed release of drugs for treatment of chronic diseases. PMID- 28820945 TI - A Chiral Gas-Hydrate Structure Common to the Carbon Dioxide-Water and Hydrogen Water Systems. AB - We present full in situ structural solutions of carbon dioxide hydrate-II and hydrogen hydrate C0 at elevated pressures using neutron and X-ray diffraction. We find both hydrates adopt a common water network structure. The structure exhibits several features not previously found in hydrates; most notably it is chiral and has large open spiral channels along which the guest molecules are free to move. It has a network that is unrelated to any experimentally known ice, silica, or zeolite network but is instead related to two Zintl compounds. Both hydrates are found to be stable in electronic structure calculations, with hydration ratios in very good agreement with experiment. PMID- 28820946 TI - Proteogenomic Investigation of Strain Variation in Clinical Mycobacterium tuberculosis Isolates. AB - Mycobacterium tuberculosis consists of a large number of different strains that display unique virulence characteristics. Whole-genome sequencing has revealed substantial genetic diversity among clinical M. tuberculosis isolates, and elucidating the phenotypic variation encoded by this genetic diversity will be of the utmost importance to fully understand M. tuberculosis biology and pathogenicity. In this study, we integrated whole-genome sequencing and mass spectrometry (GeLC-MS/MS) to reveal strain-specific characteristics in the proteomes of two clinical M. tuberculosis Latin American-Mediterranean isolates. Using this approach, we identified 59 peptides containing single amino acid variants, which covered ~9% of all coding nonsynonymous single nucleotide variants detected by whole-genome sequencing. Furthermore, we identified 29 distinct peptides that mapped to a hypothetical protein not present in the M. tuberculosis H37Rv reference proteome. Here, we provide evidence for the expression of this protein in the clinical M. tuberculosis SAWC3651 isolate. The strain-specific databases enabled confirmation of genomic differences (i.e., large genomic regions of difference and nonsynonymous single nucleotide variants) in these two clinical M. tuberculosis isolates and allowed strain differentiation at the proteome level. Our results contribute to the growing field of clinical microbial proteogenomics and can improve our understanding of phenotypic variation in clinical M. tuberculosis isolates. PMID- 28820947 TI - Dysregulated mitogen-activated protein kinase and matrix metalloproteinase in ethanol-induced cavernosal dysfunction. AB - We evaluated the effects of ethanol consumption on the mitogen-activated protein kinases (MAPK) and metalloproteinases (MMP) pathways in the rat cavernosal smooth muscle (CSM). Male Wistar rats were treated with ethanol (20% v/v) for 6 weeks. Quantitative real-time polymerase chain reaction experiments showed that ethanol consumption did not alter mRNA levels of p38MAPK, SAPK/JNK, ERK1/2, MMP-2, or MMP 9 in the rat CSM. Western immunoblotting experiments revealed decreased protein expression of p38MAPK and phosphorylation of SAPK/JNK in the CSM from ethanol treated rats. Additionally, ethanol consumption decreased the expression of MMP 2. Functional assays showed that SP600125, an inhibitor of SAPK/JNK, prevented the increase in endothelin (ET)-1-induced contraction in the CSM from ethanol treated rats. Treatment with ethanol decreased MMP-2 activity, but did not change net MMP activity in the rat CSM. Ethanol consumption increased the circulating levels of MMP-2, MMP-9, and TIMP-2 as well as the MMP-9/TIMP-1 ratio. The major finding of our study is that ethanol consumption down-regulates both MAPK and MMP pathways in the rat CSM, whereas it increases the circulating levels of MMP-9. Additionally, we found that SAPK/JNK plays a role in ethanol-induced increase on ET-1 contraction in the isolated rat CSM. PMID- 28820948 TI - Prevalence and expression of staphylococcal enterotoxin genes in Staphylococcus aureus isolated from food poisoning outbreaks. AB - Staphylococcus aureus is an important pathogen of foodborne origin. The pathogen produces a variety of toxins that include the staphylococcal enterotoxins (SE). The present study aimed to evaluate the prevalence and expression of 5 SE genes (sea, seb, sec, sed, and see) in S. aureus isolated from outbreaks occurred in the state of Rio Grande do Sul, Brazil. All isolates, with the exception of 2, presented the same or higher transcriptional expression than the reference strains for at least 1 of these genes. The presence of SE genes combined with high levels of transcriptional expression suggests that 1 or more SEs were involved with the staphylococcal food poisoning outbreak analyzed in the present study. PMID- 28820949 TI - Association Between Patient Factors and Outcome of Synthetic Cartilage Implant Hemiarthroplasty vs First Metatarsophalangeal Joint Arthrodesis in Advanced Hallux Rigidus. AB - BACKGROUND: We evaluated data from a clinical trial of first metatarsophalangeal joint (MTPJ1) implant hemiarthroplasty and arthrodesis to determine the association between patient factors and clinical outcomes. METHODS: Patients >=18 years with hallux rigidus grade 2, 3, or 4 were treated with synthetic cartilage implant MTPJ1 hemiarthroplasty or arthrodesis. Pain visual analog scale (VAS), Foot and Ankle Ability Measure (FAAM) sports and activities of daily living (ADL) scores, and Short Form-36 Physical Function (SF-36 PF) subscore were obtained preoperatively, and at 2, 6, 12, 24, 52, and 104 weeks postoperatively. Final outcome data, great toe active dorsiflexion motion, secondary procedures, radiographs, and safety parameters were evaluated for 129 implant hemiarthroplasties and 47 arthrodeses. The composite primary endpoint criteria for clinical success included VAS pain reduction >=30%, maintenance/improvement in function, no radiographic complications, and no secondary surgical intervention at 24 months. Predictor variables included hallux rigidus grade; gender; age; body mass index (BMI); symptom duration; prior MTPJ1 surgery; preoperative hallux valgus angle, range of motion (ROM), and pain. Two-sided Fisher exact test was used ( P < .05). RESULTS: Patient demographics and baseline outcome measures were similar. Success rates between implant MTPJ1 hemiarthroplasty and arthrodesis were similar ( P > .05) when stratified by hallux rigidus grade, gender, age, BMI, symptom duration, prior MTPJ1 surgery status, and preoperative VAS pain, hallux valgus, and ROM. CONCLUSION: Synthetic cartilage implant hemiarthroplasty was appropriate for patients with grade 2, 3, or 4 hallux rigidus. Its results in those with associated mild hallux valgus (<=20 degrees) or substantial preoperative stiffness were equivalent to MTPJ1 fusion, irrespective of gender, age, BMI, hallux rigidus grade, preoperative pain or symptom duration. LEVEL OF EVIDENCE: Level II, randomized clinical trial. PMID- 28820950 TI - Combined aerobic and resistance exercise training for improving reproductive function in infertile men: a randomized controlled trial. AB - This randomized controlled trial was conducted to examine the effects of 24 weeks of combined aerobic and resistance exercise training on seminal markers of inflammation and oxidative stress as well as markers of male reproductive function and reproductive performance in infertile patients. Of a total of 1296 infertile patients (aged 25-40 years) who were screened, 556 were randomly assigned to exercise (n = 278) and nonexercise (n = 278) groups. Semen samples were taken before and at 12 and 24 weeks as well as 7 and 30 days post intervention. The training program reduced seminal proinflammatory cytokines (interleukin (IL)-1beta, IL-6, IL-8, and tumor necrosis factor alpha) and markers of oxidative stress (reactive oxygen species, malondialdehyde, and 8-isoprostane) (P < 0.05). Additional improvements were also achieved in seminal antioxidant defense system (superoxide dismutase, catalase, and total antioxidant capacity) (P < 0.05). Training-induced changes in inflammation and oxidative stress status correlated with favorable improvements in semen parameters, sperm DNA integrity, and pregnancy rate (P < 0.05). In conclusion, these results support the evidence for the favorable effects of combined aerobic and resistance exercise training in male factor infertility. PMID- 28820951 TI - Lactation Consultants' Perceived Barriers to Providing Professional Breastfeeding Support. AB - BACKGROUND: Addressing suboptimal breastfeeding initiation and duration rates is a priority in the United States. To address challenges to improving these rates, the voices of the providers who work with breastfeeding mothers should be heard. Research aim: The purpose of this study was to explore lactation consultants' perceived barriers to managing early breastfeeding problems. METHODS: This qualitative study was conducted with a grounded theory methodological approach. In-depth interviews were conducted with 30 International Board Certified Lactation Consultants across Florida. Lactation consultants were from a range of practice settings, including hospitals, Special Supplemental Nutrition Program for Women, Infants, and Children clinics, private practice, and pediatric offices. Data were digitally recorded, transcribed, and analyzed in Atlas.ti. RESULTS: A range of barriers was identified and grouped into the following categories/themes: indirect barriers (social norms, knowledge, attitudes); direct occupational barriers (institutional constraints, lack of coordination, poor service delivery); and direct individual barriers (social support, mother's self efficacy). A model was developed illustrating the factors that influence the role enactment of lactation consultants in managing breastfeeding problems. CONCLUSION: Inadequate support for addressing early breastfeeding challenges is compounded by a lack of collaboration among various healthcare providers and the family. Findings provide insight into the professional management issues of early breastfeeding problems faced by lactation consultants. Team-based, interprofessional approaches to breastfeeding support for mothers and their families are needed; improving interdisciplinary collaboration could lead to better integration of lactation consultants who are educated and experienced in providing lactation support and management of breastfeeding problems. PMID- 28820952 TI - Adult Intelligence: The Construct and the Criterion Problem. AB - Over 100 years have passed since Binet and Simon proposed scales for assessment of intelligence of children to predict academic success and failure. The extension of these assessments to adults largely resulted from efforts of psychologists to provide insights for military selection in World War I. At the time, relatively little thought was given to how adult intelligence might differ from child and adolescent intelligence. Traditional approaches for assessing adult intelligence have largely survived. However, there is little reference to adult intellectual functioning outside of laboratory-based tasks and clinical assessments of pathology. The result is that there are insufficient criterion measures for adult intelligence. Moreover, researchers have shifted from treating intelligence tests as predictors to treating them as criterion measures. The result is a disconnection between basic research on one hand and understanding adult intelligence on the other hand. This lack of connection is a serious impediment for predicting individual differences in performance on tasks which adults perform in their day-to-day work and nonwork lives. This article explores how the field has come to the current situation, and what remedies might be explored. Ultimately, a fundamental reexamination of how adult intelligence is studied and applied is suggested. PMID- 28820953 TI - A Fluorescence-Based High-Throughput Assay for the Identification of Anticancer Reagents Targeting Fructose-1,6-Bisphosphate Aldolase. AB - A high rate of glycolysis, which supplies energy and materials for anabolism, is observed in a wide range of tumor cells, making it a potential pathway to control cancer growth. ALDOA is a multifunctional enzyme in the glycolytic pathway and also promotes HIF-1alpha, which is of importance in hypoxic solid tumors. The current method for assaying ALDOA activity involves monitoring the consumption of NADH in vitro using absorbance or intrinsic fluorescence via a coupled enzymatic reaction. Here, we report the development of a homogeneous biochemical assay that can overcome limitations of current methods, in particular for the application of high-throughput drug screening. The assay utilizes the commercially available Elite NADH Assay Kit, which incorporates an enzymatic reaction to measure the level of NADH using a fluorescent probe. Assay optimization and validation are discussed. Its feasibility for high-throughput screening (HTS) was demonstrated by screening 65,000 compounds for the identification of small molecules that inhibit ALDOA. Through a validation screen and dose-response evaluation, four inhibitors with IC50 below 10 uM were identified. In conclusion, we demonstrate that a traditional ALDOA assay can be transformed readily into a fluorescence based assay utilizing a commercial NADH detection kit that is rapid, sensitive, inexpensive, and HTS friendly. PMID- 28820954 TI - An Interview With Felicity M. A. Savage, MA, BM, BCh, FRCP, FRCPCH, FFPH, FIAP, FABM. PMID- 28820955 TI - Integration of an In Situ MALDI-Based High-Throughput Screening Process: A Case Study with Receptor Tyrosine Kinase c-MET. AB - Mass spectrometry (MS) is known for its label-free detection of substrates and products from a variety of enzyme reactions. Recent hardware improvements have increased interest in the use of matrix-assisted laser desorption/ionization time of-flight (MALDI-TOF) MS for high-throughput drug discovery. Despite interest in this technology, several challenges remain and must be overcome before MALDI-MS can be integrated as an automated "in-line reader" for high-throughput drug discovery. Two such hurdles include in situ sample processing and deposition, as well as integration of MALDI-MS for enzymatic screening assays that usually contain high levels of MS-incompatible components. Here we adapt our c-MET kinase assay to optimize for MALDI-MS compatibility and test its feasibility for compound screening. The pros and cons of the Echo (Labcyte) as a transfer system for in situ MALDI-MS sample preparation are discussed. We demonstrate that this method generates robust data in a 1536-grid format. We use the MALDI-MS to directly measure the ratio of c-MET substrate and phosphorylated product to acquire IC50 curves and demonstrate that the pharmacology is unaffected. The resulting IC50 values correlate well between the common label-based capillary electrophoresis and the label-free MALDI-MS detection method. We predict that label-free MALDI-MS-based high-throughput screening will become increasingly important and more widely used for drug discovery. PMID- 28820956 TI - Breastfeeding Support for Criminalized Women in Canada. PMID- 28820957 TI - The Association Between Pregnancy Intention and Breastfeeding. AB - BACKGROUND: Although breastfeeding is associated with proven benefits to both mother and child, there are many factors that influence a mother's decision to breastfeed. Pregnancy intentionality at the time of conception is associated with postpartum maternal behavior including breastfeeding. Research aim: We sought to understand how maternal and paternal pregnancy intentions were associated with breastfeeding initiation and duration in a nationally representative sample. METHODS: We used a cross-sectional, retrospective study of the CDC National Survey of Family Growth data to examine the link between pregnancy intentionality and breastfeeding initiation and duration among women ages 15 to 44 years. RESULTS: We found that whereas the mother's intention to have a child was a factor in how long she breastfed, the paternal intention to have a child predicted whether the mother breastfed at all. Additionally, Hispanic mothers were most likely to breastfeed and breastfed the longest of any other group. Age and education were also positive predictors of ever breastfeeding. CONCLUSION: Understanding the father's and mother's attitudes toward the pregnancy and influence on breastfeeding intention is important for intervention planning. PMID- 28820958 TI - Erratum to "Mass spectrometric detection combined with bioinformatic analysis identified possible protein markers and key pathways associated with bladder cancer" [Gene 626C (2017) 407-413]. PMID- 28820960 TI - Principles of Chemical Biology: Iron and CSCs, Histone Acylation sans Enzymes, Eliciting Silent Gene Clusters, and 2'-deoxy-ADPR as a Second Messenger. AB - This month: Lysosomal iron linked to cell death in cancer stem cells, non enzymatic catalyst SynCAc for histone acylation, cytotoxins ivermectin and etoposide bring new anti-fungals out of the crypt, and 2'-deoxy-ADPR as second messenger activating TRPM2. PMID- 28820959 TI - Takinib, a Selective TAK1 Inhibitor, Broadens the Therapeutic Efficacy of TNF alpha Inhibition for Cancer and Autoimmune Disease. AB - Tumor necrosis factor alpha (TNF-alpha) has both positive and negative roles in human disease. In certain cancers, TNF-alpha is infused locally to promote tumor regression, but dose-limiting inflammatory effects limit broader utility. In autoimmune disease, anti-TNF-alpha antibodies control inflammation in most patients, but these benefits are offset during chronic treatment. TAK1 acts as a key mediator between survival and cell death in TNF-alpha-mediated signaling. Here, we describe Takinib, a potent and selective TAK1 inhibitor that induces apoptosis following TNF-alpha stimulation in cell models of rheumatoid arthritis and metastatic breast cancer. We demonstrate that Takinib is an inhibitor of autophosphorylated and non-phosphorylated TAK1 that binds within the ATP-binding pocket and inhibits by slowing down the rate-limiting step of TAK1 activation. Overall, Takinib is an attractive starting point for the development of inhibitors that sensitize cells to TNF-alpha-induced cell death, with general implications for cancer and autoimmune disease treatment. PMID- 28820961 TI - Optimized Streptavidin for Fluorescent Labeling of Biotinylated Targets. AB - In order to develop a streptavidin-biotin system with optimal performance in fluorescent labeling, in this issue of Cell Chemical Biology, Jacobsen et al. (2017) focused on changing the surface density of amino groups present on streptavidin via lysine mutagenesis. The streptavidin mutant containing only one free amino group was found superior to other streptavidin variants and was named Flavidin for fluorophore-friendly streptavidin. PMID- 28820962 TI - Wanted Alive: Finding Bacteria in Your Food. AB - In this issue of Cell Chemical Biology, Pezacki and co-workers (Sherratt et al., 2017) report a simple method to metabolically label viable bacteria, which can be used to detect and capture foodborne pathogens. The method may also find many other applications because it can be used to recover live cells, pathogens and non-pathogens, from various biomedical and environmental samples. PMID- 28820963 TI - Ketone Body Acetoacetate Buffers Methylglyoxal via a Non-enzymatic Conversion during Diabetic and Dietary Ketosis. AB - The alpha-oxoaldehyde methylglyoxal is a ubiquitous and highly reactive metabolite known to be involved in aging- and diabetes-related diseases. If not detoxified by the endogenous glyoxalase system, it exerts its detrimental effects primarily by reacting with biopolymers such as DNA and proteins. We now demonstrate that during ketosis, another metabolic route is operative via direct non-enzymatic aldol reaction between methylglyoxal and the ketone body acetoacetate, leading to 3-hydroxyhexane-2,5-dione. This novel metabolite is present at a concentration of 10%-20% of the methylglyoxal level in the blood of insulin-starved patients. By employing a metabolite-alkyne-tagging strategy it is clarified that 3-hydroxyhexane-2,5-dione is further metabolized to non-glycating species in human blood. The discovery represents a new direction within non enzymatic metabolism and within the use of alkyne-tagging for metabolism studies and it revitalizes acetoacetate as a competent endogenous carbon nucleophile. PMID- 28820964 TI - Modulating the Modulator: Regulation of Protein Methylation by Nitric Oxide. AB - Protein methylation is an important modulator of signal transduction pathways, but methyltransferases themselves may also be modulated. Hu et al. (2017) demonstrate in this issue of Molecular Cell that S-nitrosylation selectively modulates enzymatic activity of a protein arginine methyltransferase vital to abiotic stress tolerance. PMID- 28820966 TI - Reactive oxygen species-responsive polymeric nanoparticles for alleviating sepsis induced acute liver injury in mice. AB - Sepsis-associated acute liver injury contributes to the pathogenesis of multiple organ dysfunction syndrome and is associated with increased mortality. Currently, no specific therapeutics for sepsis-associated liver injury are available. With excess levels of reactive oxygen species (ROS) being implicated as key players in sepsis-induced liver injury, we hypothesize that ROS-responsive nanoparticles (NPs) formed via the self-assembly of diblock copolymers of poly(ethylene glycol) (PEG) and poly(propylene sulfide) (PPS) may function as an effective drug delivery system for alleviating sepsis-induced liver injury by preferentially releasing drug molecules at the disease site. However, there are no reports available on the biocompatibility and effect of PEG-b-PPS-NPs in vivo. Herein, this platform was tested for delivering the promising antioxidant therapeutic molecule melatonin (Mel), which currently has limited therapeutic efficacy because of its poor pharmacokinetic properties. The mPEG-b-PPS-NPs efficiently encapsulated Mel using the oil-in-water emulsion technique and provided sustained, on-demand release that was modulated in vitro by the hydrogen peroxide concentration. Animal studies using a mouse model of sepsis-induced acute liver injury revealed that Mel-loaded mPEG-b-PPS-NPs are biocompatible and much more efficacious than an equivalent amount of free drug in attenuating oxidative stress, the inflammatory response, and subsequent liver injury. Accordingly, this work indicates that mPEG-b-PPS-NPs show potential as an ROS-mediated on-demand drug delivery system for improving Mel bioavailability and treating oxidative stress-associated diseases such as sepsis-induced acute liver injury. PMID- 28820967 TI - Identifying predictors for bleeding in hospitalized cancer patients: A cohort study. AB - BACKGROUND: Bleeding and thrombosis are both major complications of hospitalization in cancer patients. Concern regarding bleeding risk may reduce compliance with thromboprophylaxis. We assessed incidence of major and clinically relevant non-major bleeding (MCRNMB) and identified risk factors associated with in-hospital bleeding risk in hospitalized cancer patients. METHODS: We conducted a retrospective cohort study of consecutive adults admitted to general oncology floor at Cleveland Clinic from 11/2012-12/2014 (n=3525). Patients were excluded for bleeding on admission (n=108), age<18 (n=1), non-malignant disease (n=2) and incomplete data (n=56). Data collected included demographics, body mass index (BMI), cancer type, length of stay (LOS), use of anticoagulants and baseline laboratory values (+48h). Univariate risk factors were identified with logistic regression analysis. Multivariable risk factors were identified with stepwise logistic regression and confirmed with bootstrap analysis. RESULTS: The study population comprised 3358 patients of whom 69 (2.1%) developed MCRNMB. Median age was 62 (range, 19-98) years and 56% male. Median length of stay was 5 (range, 0 152) days. The majority of bleeding events were either gastrointestinal (GI) (N=23, 33%) or retroperitoneal (N=10, 14%). In multivariable analysis, anemia as the reason for admission (7.78, 95% CI 4.0-15.1, P<0.001), GI cancer site (2.96, 95% CI 1.7-5.2 P<0.001), BMI>=40 (3.08, 95% CI 1.3-2.9, P=0.008) and thrombocytopenia (1.7, 95% CI 1.0-2.9, P=0.05) were predictive. CONCLUSION: The incidence of MCRNMB in a population of hospitalized cancer patients was 2.1%. Risk factors at admission included type of cancer and morbid obesity. Improved prediction of bleeding risk can assist physicians in optimizing selection of thromboprophylaxis in this population that is also at increased risk of VTE. PMID- 28820965 TI - Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical Screening. AB - The mitochondrial calcium uniporter complex is essential for calcium (Ca2+) uptake into mitochondria of all mammalian tissues, where it regulates bioenergetics, cell death, and Ca2+ signal transduction. Despite its involvement in several human diseases, we currently lack pharmacological agents for targeting uniporter activity. Here we introduce a high-throughput assay that selects for human MCU-specific small-molecule modulators in primary drug screens. Using isolated yeast mitochondria, reconstituted with human MCU, its essential regulator EMRE, and aequorin, and exploiting a D-lactate- and mannitol/sucrose based bioenergetic shunt that greatly minimizes false-positive hits, we identify mitoxantrone out of more than 600 clinically approved drugs as a direct selective inhibitor of human MCU. We validate mitoxantrone in orthogonal mammalian cell based assays, demonstrating that our screening approach is an effective and robust tool for MCU-specific drug discovery and, more generally, for the identification of compounds that target mitochondrial functions. PMID- 28820968 TI - Reduced activin receptor-like kinase 1 activity promotes cardiac fibrosis in heart failure. AB - INTRODUCTION: Activin receptor-like kinase 1 (ALK1) mediates signaling via the transforming growth factor beta-1 (TGFbeta1), a pro-fibrogenic cytokine. No studies have defined a role for ALK1 in heart failure. HYPOTHESIS: We tested the hypothesis that reduced ALK1 expression promotes maladaptive cardiac remodeling in heart failure. METHODS AND RESULTS: In patients with advanced heart failure referred for left ventricular (LV) assist device implantation, LV Alk1 mRNA and protein levels were lower than control LV obtained from patients without heart failure. To investigate the role of ALK1 in heart failure, Alk1 haploinsufficient (Alk1+/-) and wild-type (WT) mice were studied 2 weeks after severe transverse aortic constriction (TAC). LV and lung weights were higher in Alk1+/- mice after TAC. Cardiomyocyte area and LV mRNA levels of brain natriuretic peptide and beta myosin heavy chain were increased similarly in Alk1+/- and WT mice after TAC. Alk 1 mice exhibited reduced Smad 1 phosphorylation and signaling compared to WT mice after TAC. Compared to WT, LV fibrosis and Type 1 collagen mRNA and protein levels were higher in Alk1+/- mice. LV fractional shortening was lower in Alk1+/- mice after TAC. CONCLUSIONS: Reduced expression of ALK1 promotes cardiac fibrosis and impaired LV function in a murine model of heart failure. Further studies examining the role of ALK1 and ALK1 inhibitors on cardiac remodeling are required. PMID- 28820969 TI - A disulfide-stabilized human VL single-domain antibody library is a source of soluble and highly thermostable binders. AB - We have previously shown that incorporation of a second intradomain disulfide linkage into camelid VHH and human VH/VL single-domain antibodies confers increased thermostability. Here, we explored the effects of introducing an additional disulfide linkage, formed between Cys48 and Cys64 (Kabat numbering), into a phage-displayed synthetic human VL library. In comparison to an identical library bearing only the highly conserved Cys23-Cys88 disulfide linkage, the disulfide-stabilized VL library tolerated a similar degree of randomization but retained a higher level of functional diversity after selection with protein L. Both libraries yielded soluble, antigen-specific VLs that recognized a model antigen (maltose-binding protein) with similar affinities, in the micromolar range; however, the disulfide-stabilized antigen-specific VLs were much more thermostable (average DeltaTm ~10 degrees C) than non-disulfide-stabilized VLs. This work provides proof-of-concept for building synthetic antibody libraries using disulfide-constrained immunoglobulin domains, thus avoiding pitfalls of post-hoc disulfide linkage engineering such as impaired antigen binding and reduced expression yield. PMID- 28820971 TI - Ultrasensitive detection of Ag(I) based on the conformational switching of a multifunctional aptamer probe induced by silver(I). AB - We for the first time confirmed that the low concentrations of Ag(I) could induce a silver specific aptamer probe (SAP) from a random coil sequence form to G quadruplex structure. Thereby, a novel highly sensitive fluorescence strategy for silver(I) assay was established. The designed multifunctional SAP could act as a recognition element for Ag(I) and a signal reporter. The use of such a SAP can ultrasensitively and selectively detect Ag(I), giving a detection limit down to 0.64nM. This is much lower than those reported by related literatures. This strategy has been applied successfully for the detection of Ag(I) in real samples, further proving its reliability. Taken together, the designed SAP is not only a useful recognition and signal probe for silver, but also gives a platform to study the interaction of monovalent cations with DNA. PMID- 28820970 TI - Utility of the comprehensive marijuana motives questionnaire among medical cannabis patients. AB - BACKGROUND: Little is known about motives for cannabis use among the population of adults using cannabis medically. Therefore, we evaluated the performance of the 12 factor, 36-item Comprehensive Marijuana Motives Questionnaire (CMMQ) among a sample of medical cannabis patients. METHODS: Study participants were adults ages 21years or older with scheduled appointments to obtain new or renewed medical cannabis certification from clinics in one Midwestern state (n=1116). Confirmatory factor analysis was used to evaluate properties of the CMMQ. Multiple regressions were used to estimate associations between motives and cannabis use, physical health functioning, and mental health functioning. RESULTS: Fit indices were acceptable, and factor loadings ranged from 0.57 to 0.94. Based on regression analyses, motives accounted for 7% of the variance in recent cannabis use, and independent of cannabis use, accounted for 5% and 19% of physical and mental health functioning, respectively. Regression analyses also revealed that distinct motives were associated with cannabis use and physical and mental health functioning. CONCLUSIONS: Among adults seeking medical cannabis certification, the factor structure of the CMMQ was supported, and consistent with prior studies of adolescents and young adults using cannabis recreationally. Thus, individuals who use cannabis medically may have diverse reasons for use that extend beyond the management of medical symptoms. In addition, coping and sleep-related motives may be particularly salient for this population. Findings support the utility of the CMMQ in future research on medical cannabis use; however, expansion of the scale may be needed to address medical motives for use. PMID- 28820972 TI - Fluorescent pseudorotaxanes of a quinodicarbocyanine dye with gamma cyclodextrin. AB - Spectrophotometric titration of buffered solutions of gamma cyclodextrin (gammaCD) and 1,1'-diethyl,2,2'-dicarbocyanine (DDI) demonstrates extension of the known 1:2 host:guest complex to form a previously unreported 2:2 complex near the gammaCD solubility limit. Though DDI is predominantly hosted as a non fluorescent H-aggregate, both complexes exist in respective equilibria with two secondary complexes hosting unaggregated DDI as 1:1 and 2:1 complexes. The 2:1 complex exhibits significant fluorescence emission, with a quantum yield six times that of DDI in organic solvents, but ten times lower than that of an analogous indodicarbocyanine. Fragment Molecular Orbital calculations suggest that the 2:1 complex has the tail-to-tail conformation, and that solvent access to the dye strongly favors photoisomerization. In the host-guest complex, gammaCD limits solvent access to the dye and hinders rotation of the quinolyl terminal groups, but nevertheless pairwise rotation of methine carbons within the gammaCD cavity likely remains as a significant nonradiative relaxation pathway for the excited state. PMID- 28820973 TI - An in-situ Raman study on pristane at high pressure and ambient temperature. AB - The CH Raman spectroscopic band (2800-3000cm-1) of pristane was measured in a diamond anvil cell at 1.1-1532MPa and ambient temperature. Three models are used for the peak-fitting of this CH Raman band, and the linear correlations between pressure and corresponding peak positions are calculated as well. The results demonstrate that 1) the number of peaks that one chooses to fit the spectrum affects the results, which indicates that the application of the spectroscopic barometry with a function group of organic matters suffers significant limitations; and 2) the linear correlation between pressure and fitted peak positions from one-peak model is more superior than that from multiple-peak model, meanwhile the standard error of the latter is much higher than that of the former. It indicates that the Raman shift of CH band fitted with one-peak model, which could be treated as a spectroscopic barometry, is more realistic in mixture systems than the traditional strategy which uses the Raman characteristic shift of one function group. PMID- 28820974 TI - A fast method for the determination of lead in honey samples using stabilizer free silver nanoparticles. AB - A sensitive, rapid and robust method based on the use of stabilizer-free silver nanoparticles was developed for lead detection in honey. Silver nanoparticles were synthesized without the presence of any stabilizers using silver nitrate and sodium borohydride as precursors where the latter was applied as reducing agent. The optimization of the experimental variables (AgNO3 and NaBH4) for the formation of the nanoparticles was carried out using varying volumes of these solutions. Spectrophotometric measurements at 393nm showed a linear working range between 0.0500 and 0.167mgL-1 lead (R=0.994), with limits of detection (LOD) and quantification (LOQ) of 0.0135 and 0.0451mgL-1, respectively. The proposed method proved to be a significantly sensitive mechanism for lead detection in honey samples. PMID- 28820975 TI - Features of proteolytic properties of tetraphenylporphyrin complex with lanthanide group metals. AB - : Demetallation of metalloporphyrin molecules is one of the essential degradation reactions in photosynthesis. The effect of metalloporphyrin nature on removal of central metals from tetraphenylporphyrin complexes based on lanthanide group metals (Dy, Er, Lu, Ho) has been studied. pH values, at which the metal ions leave the metalloporphyrin complex were established using two-phase spectrophotometric titration with potentiometric pH-control. The pH values decrease with the increase of atomic numbers of lanthanide groups, as well as with increase of 4f-electrons. The reaction of an extra ligand exchange for the hydroxide ion was studied. For Dy-, Er- and Ho-tetraphenylporphyrin complexes one particle of extra ligand coordinates with one porphyrin complex. A complex with dimeric particles can be formed for the system of Lu-tetraphenylporphyrin. Constants of the ion exchange reactions were calculated. SYNOPSIS: The effect of metalloporphyrin nature on removal of central metals from tetraphenylporphyrin complexes based on lanthanide group metals (Dy, Er, Lu, Ho) has been studied. The heterophase reaction of ion-selective electrodes were calculated, as well as the reaction of an extra ligand exchange for the hydroxide ion. PMID- 28820976 TI - A hydrophobic organelle probe based on aggregation-induced emission: Nanosuspension preparation and direct use for endoplasmic reticulum imaging in living cells. AB - Organic fluorophores have a wide range of biological uses and are usually needed to be prepared as water-soluble compounds or nanoparticles for applications in aqueous biosystems owing to their hydrophobic properties, which often is a complex, time-consuming and high-cost process. Here, the nanoparticle preparation of hydrophobic fluorophores and their application in cell imaging have been investigated. It was found: a) fetal bovine serum (FBS) shows an excellent dispersion effect on hydrophobic small-molecule organic compounds; b) a hydrophobic C6-unsubstituted tetrahydropyrimidine (Me-THP-Naph) can be prepared as nanosuspensions utilizing cell culture medium with 10% FBS and directly be used as a specific real-time imaging probe for the endoplasmic reticulum (ER), a dynamic organelle playing a crucial role in many cellular processes. Compared with existing ER-targeted organic fluorescent probes, Me-THP-Naph, a product of an efficient five-component reaction that we developed, has unconventional aggregation-induced emission characteristics and shows advantages of low cost, long-term staining, good photostability, high signal-to-noise ratio and excellent biocompatibility, which make it a potential specific probe for real-time ER imaging. More importantly, this work affords a simple strategy for direct application of hydrophobic organic compounds in aqueous biological systems. PMID- 28820977 TI - A newly validated and characterized spectrophotometric method for determination of a three water pollutants metal ions. AB - A simple, fast and accurate spectrophotometric method had been developed to determine lead (II), chromium (III) and barium (II) ions in pure forms and in spiked water samples using thoron (THO) as a reagent forming colored complexes. It was found that the formed complexes absorbed maximally at 539, 540 and 538nm for Pb(II)-THO, Cr(III)-THO and Ba(II)-THO complexes, respectively. The optimum experimental conditions for these complexes had been studied carefully. Beer's law was obeyed in the range 1-35, 1-70, and 1-45MUgmL-1 for Pb (II), Cr(III) and Ba(II) ions with THO reagent, respectively. Different parameters such as linearity, selectivity, recovery, limits of quantification and detection, precision and accuracy were also evaluated in order to validate the proposed method. The results showed that, THO was effective in simultaneous determination of Pb(II), Cr(III) and Ba(III) ions in pure forms and in spiked water samples. Also, the results of the proposed method were compared with that obtained from atomic absorption spectrometry. The isolated solid complexes had been characterized using elemental analysis, X-ray powder diffraction (XRD), IR, mass spectrometry and TD-DFT calculations. Their biological activities were investigated against different types of bacteria and fungi organisms. PMID- 28820978 TI - Concentration addition and independent action model: Which is better in predicting the toxicity for metal mixtures on zebrafish larvae. AB - The joint toxicity of chemical mixtures has emerged as a popular topic, particularly on the additive and potential synergistic actions of environmental mixtures. We investigated the 24h toxicity of Cu-Zn, Cu-Cd, and Cu-Pb and 96h toxicity of Cd-Pb binary mixtures on the survival of zebrafish larvae. Joint toxicity was predicted and compared using the concentration addition (CA) and independent action (IA) models with different assumptions in the toxic action mode in toxicodynamic processes through single and binary metal mixture tests. Results showed that the CA and IA models presented varying predictive abilities for different metal combinations. For the Cu-Cd and Cd-Pb mixtures, the CA model simulated the observed survival rates better than the IA model. By contrast, the IA model simulated the observed survival rates better than the CA model for the Cu-Zn and Cu-Pb mixtures. These findings revealed that the toxic action mode may depend on the combinations and concentrations of tested metal mixtures. Statistical analysis of the antagonistic or synergistic interactions indicated that synergistic interactions were observed for the Cu-Cd and Cu-Pb mixtures, non interactions were observed for the Cd-Pb mixtures, and slight antagonistic interactions for the Cu-Zn mixtures. These results illustrated that the CA and IA models are consistent in specifying the interaction patterns of binary metal mixtures. PMID- 28820979 TI - Data-driven analysis of nutrient inputs and transfers through nested catchments. AB - A data-driven screening methodology is developed for estimating nutrient input and retention-delivery in catchments with measured water discharges and nutrient concentrations along the river network. The methodology is applied to the Sava River Catchment (SRC), a major transboundary catchment in southeast Europe, with seven monitoring stations along the main river, defining seven nested catchments and seven incremental subcatchments that are analysed and compared in this study. For the relatively large nested catchments (>40,000km2), characteristic regional values emerge for nutrient input per unit area of around 30T/yr/km2 for dissolved inorganic nitrogen (DIN) and 2T/yr/km2 for total phosphorus (TP). For the smaller nested catchments and incremental subcatchments, corresponding values fluctuate and indicate hotspot areas with total nutrient inputs of 158T/yr/km2 for DIN and 13T/yr/km2 for TP. The delivered fraction of total nutrient input mass (termed delivery factor) and associated nutrient loads per area are scale-dependent, exhibiting power-law decay with increasing catchment area, with exponents of around 0.2-0.3 for DIN and 0.3-0.5 for TP. For the largest of the nested catchments in the SRC, the delivery factor is around 0.08 for DIN and 0.03 for TP. Overall, the nutrient data for nested catchments within the SRC show consistency with previously reported data for multiple nested catchments within the Baltic Sea Drainage Basin, identifying close nutrient relationships to driving hydro-climatic conditions (runoff for nutrient loads) and socio-economic conditions (population density and farmland share for nutrient concentrations). PMID- 28820980 TI - Isotope fractionation in phase-transfer processes under thermodynamic and kinetic control - Implications for diffusive fractionation in aqueous solution. AB - Diffusive isotope fractionation of organic compounds in aqueous solution was investigated by means of liquid-liquid and liquid-gas partitioning experiments under kinetic control. The two-film model was used to describe phase-transfer kinetics. It assumes the diffusion of solutes across a stagnant water boundary layer as the rate-controlling step. For all investigated solutes (benzene-D0 and D6, toluene-D0, -D5, and -D8, cyclohexane-D0 and -D12), there was no significant observable fractionation effect between nondeuterated and perdeuterated isotopologues, resulting in a ratio of diffusion coefficients Dlight: Dheavy=1.00+/-0.01. In addition, isotope fractionation due to equilibrium partitioning of solutes between water and n-octane or gas phase was measured. The deuterated compounds are more hydrophilic than their light isotopologues in all cases, giving rise to fractionation coefficients alphaHpart=Koctane/water,H: Koctane/water,D=1.085 to 1.15. Thus, thermodynamic fractionation effects are much larger than diffusion fractionation effects. Methodical and environmental implications of these findings are discussed. PMID- 28820981 TI - Risk factors for postoperative acute mesenteric ischemia among adult patients undergoing cardiac surgery: A systematic review and meta-analysis. AB - PURPOSE: We aimed to seek risk factors for AMI among adult patients undergoing cardiac surgery. MATERIALS AND METHODS: We searched electronic bibliographic databases for studies reporting risk factors for AMI among adult patients undergoing cardiac surgery. Pooled odds ratios (OR) and standard mean differences (SMD or MD) for risk factors between AMI and control group were estimated. RESULTS: 11 studies with 67,195 patients met the inclusion criteria. 14 risk factors were found to be statistically significant: preoperative factors including age (MD 4.62years, 95% CI (1.97,7.27)), cardiac shock (OR 5.17, (1.17,22.81)), peripheral vascular disease (OR 3.53, (2.05,6.09)), need for intra aortic balloon pump (IABP) (OR 5.89, (3.26,10.65)), emergency surgery (OR 3.75, (1.69,8.33)), and postoperative factors including atrial fibrillation (OR 2.41, (1.79,3.24)), CK-MB level (SMD 1.06, (0.62 to 1.50)), serum creatinine >200MUmol/L (OR 23.39, (11.61,47.12)), blood loss (MD 358.32mL, (53.56,663.07)), prolonged ventilation (OR 9.04, (5.24,15.62)), need for IABP (OR 6.32, (3.19,12.54)), inotropic treatment (OR 8.40, (3.19,22.14)), blood transfusion (OR 9.15, (4.79,17.48)), reoperation (OR 3.30, (1.55,7.04)). CONCLUSIONS: 14 risk factors were associated with an increased risk of AMI, which indicated that AMI might occur via stenosis or occlusion of mesenteric vessels, reduced blood volume or maldistribution of blood flow. PMID- 28820982 TI - Direct analysis - no sample preparation - of bioavailable cortisol in human plasma by weak affinity chromatography (WAC). AB - Pre-analytical treatment of blood plasma is a time consuming and often rate limiting step in the workflow of LC/MS analysis. We present in this pilot study a new approach for quantitative LC/MS based on weak affinity chromatography (WAC) of crude plasma. The steroid hormone cortisol was selected as a clinically relevant biomarker, as it currently requires extensive pre-analytical preparation. A WAC unit with saturating, immobilized albumin as a prototypic weak binder was used in combination with an ion-funnel MS/MS detector to perform zonal affinity chromatography of cortisol directly from a plasma sample, followed by quantitative multiple reaction monitoring (MRM). This procedure also allowed us to determine the amount of bioavailable cortisol in the clinical plasma sample which is of significant therapeutic interest. This WAC-MS approach showed an excellent correlation (R2=0.86 (P<0.0001 (highly significant); n=60) with a state of-the-art, clinical competitive immunoassay procedure for plasma cortisol analysis. With integration of WAC into LC/MS workflow, it may be possible to both accelerate and improve assay performance by eliminating the sample extraction step. Preliminary data with other steroid hormones indicate that WAC-MS can be applied to various biomolecules using a plasma transport protein such as albumin. PMID- 28820983 TI - A sensitive method for the separation and quantification of low-level adenine nucleotides using porous graphitic carbon-based liquid chromatography and tandem mass spectrometry. AB - A liquid chromatography coupled to heated electrospray ionization/tandem mass spectrometry (LC-HESI-MS/MS) method was developed for the simultaneous quantitative analysis of low nanomolar level adenine nucleotides AMP, ADP, ATP, cyclic AMP (cAMP), and the nucleoside adenosine. For analyte retention and separation, reverse phase chromatography using porous graphitic carbon (PGC) was employed as it provided full resolution. The erratic chromatographic behaviour characteristic of PGC, including deterioration of analyte resolution and increased peak tailing (leading to decreased sensitivity), was mitigated by incorporating acidic equilibration within runs using a quaternary gradient. Analyte resolution and chromatographic sensitivity were still lost after a period of column inactivity; hence a pre-conditioning protocol was implemented between batches to regenerate the column. These column regeneration measures also allowed elution of AMP, ADP and ATP in the sequence of mono- to tri- nucleotides, differing from conventional reverse phase elution where analytes elute with decreasing polarity. This nucleotide elution sequence has the advantage of overcoming potential mis-annotation and inaccurate quantification of smaller nucleotides caused by in-source fragmentation of ATP. The method was validated in granulosa cell conditioned media, with the LLOQs ranging between 10-50nM for most analytes. To verify the method using biological samples, nucleotide secretion was measured in granulosa cell conditioned media under various treatments known to alter their levels. Moreover, the method was applied to cumulus-oocyte complex cell lysates to examine its linearity in a complex matrix. PMID- 28820984 TI - Identification of M. tuberculosis antigens in the sera of tuberculosis patients using biomimetic affinity chromatography in conjunction with ESI-CID-MS/MS. AB - The profiling of abnormally-expressed proteins in host cells using mass spectrometry (MS) analysis is a classical approach for screening disease associated biomarkers in clinical diagnosis. However, few pathogen-specific antigens can currently be detected in serum using this proteomic approach, since these are very low-abundant proteins that are easily masked by host high-abundant proteins. Identification of pathogen-specific antigens in the sera of tuberculosis patients is crucial for the clinical diagnosis of this infectious disease, especially in immune-compromised patients. In the present study, two biomimetic affinity chromatography (BiAC) media, At-23 and A115-94, were selected from a library of BiAC media and used to selectively fractionate Albumin and Immunoglobulin from sera, respectively, prior to MS analyses. Each fraction was collected and screened against the proteomic database of M. tuberculosis complex. Three antigens, FbpA, FbpB and BfrB, were identified with two distinct peptides in BiAC-fractionated sera from tuberculosis patients, which were confirmed by Western blotting. Moreover, the identification of pathogen-specific antigens in sera by BiAC in conjunction with ESI-CID-MS/MS represents a promising strategy for the discovery of disease-associated biomarkers in other diseases. PMID- 28820985 TI - Human bone marrow as a tissue in post-mortem identification and determination of psychoactive Substances-Screening methodology. AB - The aim of this study was to apply a new instrumental approach to the analysis of human bone marrow for forensic purposes. A new screening method for the detection of more than 30 psychoactive drugs in bone marrow was developed and applied to case samples. The drugs used in this study belonged to the following groups: benzodiazepines (BZDs, n=16), tricyclic antidepressants (TCAs, n=5), selective serotonin reuptake inhibitors (SSRI, n=4), serotonin-norepinephrine reuptake inhibitors (n=1), anticonvulsants (n=1), imidazopyridines (n=1) and piperazines (n=3). The sample preparation procedure involved microwave-assisted extraction (MAE) and the experimental settings were optimized using the simplex method. Separation and detection was carried out using a UHPLC-TOF system. The method were validated using marrow samples, and further applied in the analysis of three case samples, in which diazepam, nordiazepam, citalopram, doxepin and paroxetine were successfully detected. Finally the presented method is a good example of an assay that could potentially find an application in forensic analysis. PMID- 28820986 TI - An ultrasensitive sandwich-type electrochemical immunosensor based on the signal amplification strategy of echinoidea-shaped Au@Ag-Cu2O nanoparticles for prostate specific antigen detection. AB - Highly sensitive determination of tumor markers plays an important role in early diagnosis of cancer. Herein, a novel and ultrasensitive sandwich-type electrochemical immunosensor was fabricated for quantitative detection of prostate specific antigen (PSA). In this process, gold nanoparticles functionalized nitrogen-doped graphene quantum dots (Au@N-GQDs) was synthesized through a simple and green hydrothermal procedure to enhance conductivity, specific electrode surface area and quantity of immobilized primary antibodies (Ab1). Subsequently, the prepared echinoidea-shaped nanocomposites (Au@Ag-Cu2O) composed of Au@Ag core-shell nanoparticles and disordered cuprous oxide were prepared successfully to label the secondary antibodies (Ab2), which convened the advantages of good biocompatibility and high specific surface area. Because of the synergetic effect present in Au, Ag and Cu2O, the novel nanocomposites exhibited excellent electrocatalytic activity towards the reduction of hydrogen peroxide (H2O2) for the amplified detection of PSA. Therefore, the as-proposed immunosensor for the detection of PSA possessed wide dynamic range from 0.01pg/mL to 100ng/mL with a low detection limit of 0.003pg/mL (S/N = 3). Furthermore, this sandwich-type immunosensor revealed high sensitivity, high selectivity and long term stability, which had promising application in bioassay analysis. PMID- 28820987 TI - A new label-free electrochemical immunosensor based on dendritic core-shell AuPd@Au nanocrystals for highly sensitive detection of prostate specific antigen. AB - Herein, bimetallic dendritic core-shell AuPd@Au nanocrystals (AuPd@Au NCs) were prepared by a simple one-pot aqueous method using xanthine as a green growth directing agent. By virtue of the enhanced peak currents in the H2O2 reduction catalyzed by AuPd@Au NCs, a label-free immunosensor was constructed for the detection of prostate specific antigen (PSA). The immunosensor exhibited significantly improved analytical performance for the assay of PSA with wide linear range of 0.1-50ngmL-1 and low detection limit of 0.078ngmL-1 (S/N = 3), coupled with the improved stability, reproducibility and selectivity. It provides a promising platform for clinical research and diagnosis. PMID- 28820988 TI - Integrating printed microfluidics with silicon photomultipliers for miniaturised and highly sensitive ATP bioluminescence detection. AB - Bioluminescence has been widely used for important biosensing applications such as the measurement of adenosine triphosphate (ATP), the energy unit in biological systems and an indicator of vital processes. The current technology for detection is mainly based on large equipment such as readers and imaging systems, which require intensive and time-consuming procedures. A miniaturised bioluminescence sensing system, which would allow sensitive and continuous monitoring of ATP, with an integrated and low-cost disposable microfluidic chamber for handling of biological samples, is highly desirable. Here, we report the design, fabrication and testing of 3D printed microfluidics chips coupled with silicon photomultipliers (SiPMs) for high sensitive real-time ATP detection. The 3D microfluidic chip reduces reactant consumption and facilitates solution delivery close to the SiPM to increase the detection efficiency. Our system detects ATP with a limit of detection (LoD) of 8nM and an analytical dynamic range between 15nM and 1uM, showing a stability error of 3%, and a reproducibility error below of 20%. We demonstrate the dynamic monitoring of ATP in a continuous-flow system exhibiting a fast response time, ~4s, and a full recovery to the baseline level within 17s. Moreover, the SiPM-based bioluminescence sensing system shows a similar analytical dynamic range for ATP detection to that of a full-size PerkinElmer laboratory luminescence reader. PMID- 28820989 TI - Permanganate/bisulfite (PM/BS) conditioning-horizontal electro-dewatering (HED) of activated sludge: Effect of reactive Mn(III) species. AB - A novel activated sludge (AS) conditioning method through permanganate/bisulfate (PM/BS) process was proposed. The method involved a new conditioner of reactive Mn(III) intermediate. Moreover, a Mn(III) conditioning-horizontal electro dewatering (Mn(III) C-HED) process was established to improve AS dewatering performance. Underlying mechanisms were unraveled by investigating changes in physicochemical characteristics, scanning electron microscope (SEM) morphology, and transformation of water and organic matters. The optimum dewatering conditions for Mn(III) C-HED process with the final water content of 86.94% were determined as the combination of KMnO4 0.01 mol/L AS and NaHSO3 0.05 mol/L AS at 20 V for 120 min. Results showed that Mn(III) C-HED process effectively reduced free water and bound water with the corresponding removal ratios of 51.68% and 87.62% at the anode-side as well as 36.55% and 85.08% at the cathode-side, respectively. During the PM/BS process, the produced Mn(III), Mn2+, and MnO2 exerted chemical and physical effects on AS conditioning and dewatering. Mn(III) disintegrated extracellular polymeric substances (EPS) fractions and cells in AS, as well as induced partial bound water release. Additionally, flocculation effect induced by Mn2+ and MnO2 skeleton building also benefited AS dewatering. AS cells were further disrupted under the effect of a horizontal electric field. Accordingly, EPS within the AS matrix was solubilized, tightly bound (TB)-EPS or loosely bound (LB)-EPS was converted to their corresponding outer EPS fractions, and AS dewaterability improved. Additionally, changes in pH and temperature at HED stage damaged the AS cells and changed the floc properties, thereby leading to easy separation of liquid and AS particles. PMID- 28820990 TI - Relative importance of humic and fulvic acid on ROS generation, dissolution, and toxicity of sulfide nanoparticles. AB - In this study, the effect of natural organic matter (NOM) composition (humic acid (HA) or fulvic acid (FA)) on dissolution, reactive oxygen species (ROS) generation, and toxicity of sulfide nanoparticles (NPs) was investigated under UV irradiation. NOM acted as a UV filter or antioxidant, decreasing ROS (O2-, OH, and 1O2) generation by WS2 and MoS2 NPs. The higher light-absorbing fractions of HA in NP/HA mixtures and the faster reaction rate of HA with ROS resulted in higher inhibition effect of HA than FA on O2- and OH generation by WS2 and MoS2 NPs. Both HA and FA completely inhibited 1O2 generation by WS2 and MoS2 NPs. NOM could transfer electrons to CdS and promote its O2- generation. No measurable amount of OH was generated by CdS with or without NOM. FA decreased 1O2 generation by CdS more significantly than HA due to the higher reaction rate between FA and 1O2. HA showed a higher inhibition effect on the dissolution rate of CdS and WS2 NPs than FA. Both HA and FA played minor roles in the toxicity of CdS toward Escherichia coli but decreased the toxicity of MoS2 and WS2 due to the reduced ROS generation and/or dissolution concentrations. PMID- 28820991 TI - Robust evaluation of performance monitoring options for ozone disinfection in water recycling using Bayesian analysis. AB - Ozonation of wastewater has gained popularity because of its effectiveness in removing colour, UV absorbance, trace organic chemicals, and pathogens. Due to the rapid reaction of ozone with organic compounds, dissolved ozone is often not measurable and therefore, the common disinfection controlling parameter, concentration integrated over contact time (CT) cannot be obtained. In such cases, alternative parameters have been shown to be useful as surrogate measures for microbial removal including change in UV254 absorbance (DeltaUVA), change in total fluorescence (DeltaTF), or O3:TOC (or O3:DOC). Although these measures have shown promise, a number of caveats remain. These include uncertainties in the associations between these measurements and microbial inactivation. Furthermore, previous use of seeded microorganisms with higher disinfection sensitivity compared to autochthonous microorganisms could lead to overestimation of appropriate log credits. In our study, secondary treated wastewater from a full scale plant was ozonated in a bench-scale reactor using five increasing ozone doses. During the experiments, removal of four indigenous microbial indicators representing viruses, bacteria and protozoa were monitored concurrent with DeltaUVA, DeltaTF, O3:DOC and PARAFAC derived components. Bayesian methods were used to fit linear regression models, and the uncertainty in the posterior predictive distributions and slopes provided a comparison between previously reported results and those reported here. Combined results indicated that all surrogate parameters were useful in predicting the removal of microorganisms, with a better fit to the models using DeltaUVA, DeltaTF in most cases. Average adjusted determination coefficients for fitted models were high (R2adjusted>0.47). With DeltaUVA, one unit decrease in LRV corresponded with a UVA mean reduction of 15-20% for coliforms, 59% for C. perfringens spores, and 11% for somatic coliphages. With DeltaTF, a one unit decrease in LRV corresponded with a TF mean reduction of 18-23% for coliforms, 71% for C. perfringens spores, and 14% for somatic coliphages. Compared to previous studies also analysed, our results suggest that microbial reductions were more conservative for autochthonous than for seeded microorganisms. The findings of our study suggested that site-specific analyses should be conducted to generate models with lower uncertainty and that indigenous microorganisms are useful for the measurement of system performance even when censored observations are obtained. PMID- 28820992 TI - Bioavailability of dissolved organic nitrogen (DON) in wastewaters from animal feedlots and storage lagoons. AB - Dissolved organic nitrogen (DON) from animal wastes can contribute to pollution of surface waters. Bioavailable DON (ABDON) is a portion of DON utilized by algae with or without bacteria. This study determined DON and ABDON levels in animal wastewater collected from two different sources: an animal feedlot wastewater storage tank and a sheep wastewater storage lagoon. Inocula for the ABDON bioassays were comprised of individual species and several combinations involving two algae (Chlamydomonas reinhardtii and Chlorella vulgaris) and a mixed liquor suspended solids (MLSS) bacterial culture. The ratio of initial DON to initial total dissolved nitrogen was 18% in the feedlot wastewater samples and 70% in the lagoon wastewater samples. The results showed that between 1.6 and 4.5 mg-NL-1 DON (45-79% of initial DON) in the feedlot samples and between 3.4 and 7.5 mg-NL 1 DON (36%-79% of initial DON) in the lagoon samples were bioavailable with the inocula tested. These results suggest that when considering eutrophication potential of livestock wastewater, organic nitrogen should be included in addition to the obvious culprits, ammonia and nitrate. PMID- 28820993 TI - Changing profiles of bound water content and distribution in the activated sludge treatment by NaCl addition and pH modification. AB - Currently the dewatering of activated sludge from wastewater treatment plants is a problem not well solved. Extracellular polymeric substances (EPS), including loosely bound EPS (LB-EPS) and tightly bound EPS (TB-EPS), are highly hydrated biopolymers and play important roles in sludge dewatering. In the present work, two types of treatments, i.e., salt addition and pH modification, were proposed to evaluate the effects of bound water content and its distribution on the dewatering performance of activated sludge. Results show that the bound water content in activated sludge was deeply related to the floc structures and EPS compositions. Both salt addition and acid treatment altered the flocculated matrix and increased the contents of LB-EPS, resulting in the release of trapped water and reduction in sludge volume. In addition, the chemical treatments also affected the distribution of bound water. The internal water content increased upon the dose of NaCl, leading to a decreased water content trapped in EPS. Hence, salt addition caused a slower filtration rate, but did not effectively decrease the total water content, although the EPS were decomposed. Under acidic conditions, cell lysis helped to release the intracellular water and further enhance the sludge dewatering performance. In contrast, conditioning with low dosage alkali increased the bound water content and deteriorated the sludge dewaterability. Therefore, an in-depth investigation into the mechanisms is useful to optimize the activated sludge dewatering process. PMID- 28820994 TI - Relative bioavailability and bioaccessibility of PCBs in soils based on a mouse model and Tenax-improved physiologically-based extraction test. AB - In this study, bioavailability of polychlorinated biphenyls (PCBs) in soil samples aged for various time intervals (7 days, 1 and 5 months) was assessed by in vivo tests using mice. The in vivo bioavailability of PCBs in soil ranged from 45% (PCB180 in soil aging for 5 month) to 119% (PCB52 in soil aging for 1 month), indicating that not all PCBs was available for absorption after ingestion of soil samples. The bioaccessibility was assessed using both physiologically-based extraction test (PBET) and Tenax improved PBET (TI-PBET). Acceptable in vivo-in vitro correlation (r2 = 0.70 and slope = 1.30 +/- 0.20) was observed for TI-PBET, not for PBET. Due to dominant role played by Tenax and bile, the TI-PBET was further simplified to Tenax and Tenax-bile extraction methods. However, poor in vivo-in vitro correlation (r2 = 0.14 and 0.05) was observed for the two simplified methods, which may be attributed to the combined effect between sorption sink and components in PBET. Therefore, in order to simply TI-PBET or standardize in vitro methods, it is highly necessary to explore the mechanism about the interaction between in vitro method components and sorption sink, or to screen key factors for bioaccessibility results in the future studies. PMID- 28820995 TI - Influence of monitoring data selection for optimization of a steady state multimedia model on the magnitude and nature of the model prediction bias. AB - SimpleBox is an important multimedia model used to estimate the predicted environmental concentration for screening-level exposure assessment. The main objectives were (i) to quantitatively assess how the magnitude and nature of prediction bias of SimpleBox vary with the selection of observed concentration data set for optimization and (ii) to present the prediction performance of the optimized SimpleBox. The optimization was conducted using a total of 9604 observed multimedia data for 42 chemicals of four groups (i.e., polychlorinated dibenzo-p-dioxins/furans (PCDDs/Fs), polybrominated diphenyl ethers (PBDEs), phthalates, and polycyclic aromatic hydrocarbons (PAHs)). The model performance was assessed based on the magnitude and skewness of prediction bias. Monitoring data selection in terms of number of data and kind of chemicals plays a significant role in optimization of the model. The coverage of the physicochemical properties was found to be very important to reduce the prediction bias. This suggests that selection of observed data should be made such that the physicochemical property (such as vapor pressure, octanol-water partition coefficient, octanol-air partition coefficient, and Henry's law constant) range of the selected chemical groups be as wide as possible. With optimization, about 55%, 90%, and 98% of the total number of the observed concentration ratios were predicted within factors of three, 10, and 30, respectively, with negligible skewness. PMID- 28820996 TI - Exploring ozonation as treatment alternative for methiocarb and formed transformation products abatement. AB - Despite the high toxicity and resistance to conventional water treatments exhibited by methiocarb (MC), there are no reports regarding the degradation of this priority pesticide by means of alternative purification technologies. In this work, the removal of MC by means of ozonation was studied for the first time, employing a multi-reactor methodology and neutral pH conditions. The second order rate constants of MC reaction with molecular ozone (O3) and formed hydroxyl radicals (OH.) were determined to be 1.7.106 and 8.2.109 M-1 s-1, respectively. During degradation experiments, direct ozone reaction was observed to effectively remove MC, but not its formed intermediates, whereas OH. could oxidize all species. The major identified TPs were methiocarb sulfoxide (MCX), methiocarb sulfoxide phenol (MCXP) and methiocarb sulfone phenol (MCNP), all of them formed through MC oxidation by O3 or OH. in combination with hydrolysis. A toxicity assessment evidenced a strong dependence on MCX concentration, even at very low values. Despite the OH. capability to degrade MC and its main metabolites, the relative resistance of TPs towards ozone attack enlarged the oxidant dosage (2.5 mg O3/mg DOC) necessary to achieve a relatively low toxicity of the medium. Even though ozonation could be a suitable technique for MC removal from water compartments, strategies aimed to further promote the indirect contribution of hydroxyl radicals during this process should be explored. PMID- 28820997 TI - NH2Fe3O4@SiO2 supported peroxidase catalyzed H2O2 for degradation of endocrine disrupter from aqueous solution: Roles of active radicals and NOMs. AB - In this work, magnetic Fe3O4 was utilized to immobilize horseradish peroxidase (IM-HRP) in order to improve its stability and reusability by crosslinking method process with glutaraldehyde. The physicochemical properties of NH2Fe3O4@SiO2 and IM-HRP were characterized by powder X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), Thermo-gravimetric Analysis (TGA) and Transmission electron microscopy (TEM). The thermal stability of immobilized-HRP was considerably improved in comparison with free counterpart. The catalytic performance of IM-HRP for estrogens removal from aqueous solution was evaluated, it was found that the presence of natural organic matters (NOM) have no significant effects on E2 removal and the E2 enzyme-degradation reached around 80% when pH = 7.0 with 0.552 * 10-3 ratio of IM-HRP/H2O2. In addition, the active radicals responsible for estrogens degradation were identified with electro-spin resonance spectra (ESR). It was found that immobilization process on Fe3O4 showed no adverse effects on catalytic performance on HRP, estrogens degradation could be fitted well with pseudo-second kinetic equation. Estrogens degradation efficiency was reduced in the presence of humic substances. Both O2- and OH were detected in IM-HRP catalyzed H2O2 system and radicals quenching test indicated O2 played a more important role in estrogens removal. IM-HRP exhibited excellent stability and E2 removal efficiency could reach 45.41% after use seven times. Therefore, HRP enzymes immobilized on NH2Fe3O4@SiO2 by cross-linking method in glutaraldehyde solutions was an effective way to improve stability and reusability of HRP, and which could avoid potential secondary pollution in water environment caused by free HRP after treatment. PMID- 28820998 TI - Photosynthesis of alfalfa (Medicago sativa) in response to landfill leachate contamination. AB - Thousands of unlined landfills and open dumpsites have put great threat on the security of soil and ground water due to leachate leakage. Alfalfa is believed potential as a phytoremediation plant for leachate contamination based on strong root system and the excellent capacity of removing various kinds of pollutants. A lab-scale investigation was conducted to figure out the sensitiveness of alfalfa photosynthesis in response to leachate contamination. The results demonstrated that both of the maximum photosynthetic efficiency (Fv/Fm) and net photosynthetic rate (Pn) were slightly inhibited in the high-dosage group. Based on statistical analysis, higher sensitivity of Pn to leaching parameters than Fv/Fm was observed. There were significant correlations between most of leaching parameters (pH, ammonium and COD) and Pn with correlation coefficients of 0.530, -0.580 and 0.578 (p < 0.01), respectively. Therefore, Pn is potential for acting as an effective indicator for staple leaching characteristics of leachate contaminated soils. PMID- 28820999 TI - Absorption, tissue distribution, metabolism, and elimination of decabrominated diphenyl ether (BDE-209) in rats after multi-dose oral exposure. AB - Human and ecological risks of BDE-209 have drawn much attention, particularly with growing e-waste recycling activities in developing countries. To further address the issue of BDE-209 biotransformation, a laboratory-controlled study was conducted. Female Sprague-Dawley rats were dosed orally by gavage at a daily dose of 1 mg kg-1 body weight for 7 d and a depuration period of 22 d, to characterize absorption, distribution, metabolism, and elimination dynamics of BDE-209 during multi-dose exposures simulating short-term oral exposure of e-waste workers. The concentrations of BDE-209 in all tissues increased exponentially during the 7-d exposure period, indicating that multi-dose exposure could lead to increased accumulation of BDE-209 in rats. The liver accumulated the greatest amount of BDE 209 on a wet-weight basis, while adipose tissue had the highest concentration by the end of the 22-d depuration period. Half-lives of BDE-209, 207, and 197 during depuration were 1.1 +/- 0.1, 2.7 +/- 0.3, and 10.5 +/- 3.1 d in serum and 0.9 +/- 0.1, 2.2 +/- 0.2, and 11.8 +/- 2.3 d in liver, i.e., the half-life increased with decreasing level of bromination from deca- to octa-BDEs and was similar in both serum and liver. By contrast, the half-life of the debromination metabolite BDE 207 (21.7 +/- 7.7 d) was longer in small intestine than in serum and liver, suggesting slower depletion of BDE-209 metabolites in small intestine. The metabolism of BDE-209 was not responsible for the occurrence of low brominated BDE congeners and OH and MeO-PBDEs in human tissues. PMID- 28821000 TI - Simultaneous liquid chromatography-tandem mass spectrometry analysis of brominated flame retardants (tetrabromobisphenol A and hexabromocyclododecane diastereoisomers) in French breast milk. AB - TBBPA and HBCDs are the two classes of flame retardants that are still allowed for use by the European Commission. In May 2013, HBCDs were listed as Persistent Organic Pollutants under the Stockholm Convention, and they were banned with an exemption on EPS/XPS for cavity wall insulation. This study describes the development and optimisation of a rapid LC-ESI-MS/MS method using isotopic dilution quantification including a simplified extraction step using a mixture of solvents and sulphuric acid hydrolysis followed by the one-shot analysis of TBBPA and each of the alpha-, beta- and gamma-HBCD diastereoisomers. The limits of detection and quantification (LOD and LOQ) were 0.5 and 2.5 ng g-1 (lipid weight, lw) for TBBPA and HBCD diastereoisomers, respectively. The method was applied to analyse 106 samples of individual mature breast milk. TBBPA was quantified in 42% of these samples within a range of